Tetrahedron report number 1079 Advances in dearomatization strategies of indoles St ephane P. Roche * , Jean-Jacques Youte Tendoung, Bret Tr eguier Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431, USA article info Article history: Received 14 February 2014 Available online 5 July 2014 Dedicated to Professor Phillip D. Magnus for his overall career accomplishments and his innovative contributions in developing in- dole dearomatization strategies for the synthesis of complex natural products Contents 1. Introduction ..................................................................................................................... 3550 2. Dearomatization via cycloadditions .................................................... ............................................. 3551 2.1. Cyclopropanations .......................................................................................................... 3551 2.2. [2þ2] Cycloaddition followed by a retro-Mannich fragmentation .................................. .............................. 3552 2.3. 1,3-Dipolar cycloadditions ................................................................................................... 3553 2.4. DielseAlder cycloadditions .................................................... ............................................. 3555 2.4.1. Indole acting as dienophile in DielseAlder cycloadditions ................................................................ 3555 2.4.2. Hetero-DielseAlder cycloadditions .................................................................................... 3555 2.4.3. Indole acting as diene in DielseAlder cycloadditions .................................................................... 3557 3. Arylative dearomatization ......................................................................................................... 3559 3.1. Palladium-catalyzed dearomatization of indoles ................................................................................ 3560 3.2. Transition metal and Brønsted acid mediated dearomatization of indoles ......................................................... 3560 3.3. Iodane-mediated dearomatization of indoles .................................................................................. 3560 4. Protonative dearomatization ...................................................................................................... 3563 5. Alkylative dearomatization ........................................................................................................ 3565 5.1. Reaction of indole with oxo- and thiocarbeniums .......................................... .................................... 3565 5.2. Interrupted PicteteSpengler and related aza-FriedelCrafts reactions ............................................................... 3566 5.3. Interrupted BischlereNapieralski reaction ............................................. ....................................... 3568 5.4. Oxidative cross-coupling ..................................................... .............................................. 3568 5.5. Radical cyclization ......................................................................................................... 3570 5.6. Carbon-centered electrophiles for dearomatization .............................................................................. 3571 5.6.1. sp 3 Hybridized carbon-centered electrophiles ........................................ .................................. 3571 5.6.2. sp 2 Hybridized carbon-centered electrophiles ....................................... .................................. 3574 5.6.3. sp Hybridized carbon-centered electrophiles ........................................................................... 3575 6. Heteroatomic oxidative dearomatization ............................................................................................. 3576 6.1. Electrophilic heteroatoms .................................................................................................... 3576 6.1.1. Selenium electrophile ................................................................................................ 3576 6.1.2. Sulfur electrophile .................................................... ............................................. 3577 6.1.3. Nitrogen electrophile ................................................................................................ 3578 6.1.4. Oxygen electrophile ................................................................................................. 3578 6.1.4.1. Dearomatization of achiral indolic substrates ................................... .............................. 3578 * Corresponding author. E-mail address: [email protected](S.P. Roche). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.06.054 0040-4020/Published by Elsevier Ltd. Tetrahedron 71 (2015) 3549e3591
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Tetrahedron 71 (2015) 3549e3591
Contents lists avai
Tetrahedron
journal homepage: www.elsevier .com/locate/ tet
Tetrahedron report number 1079
Advances in dearomatization strategies of indoles
St�ephane P. Roche *, Jean-Jacques Youte Tendoung, Bret Tr�eguierDepartment of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431, USA
a r t i c l e i n f o
Article history:Received 14 February 2014Available online 5 July 2014
Dedicated to Professor Phillip D. Magnus forhis overall career accomplishments and hisinnovative contributions in developing in-dole dearomatization strategies for thesynthesis of complex natural products
* Corresponding author. E-mail address: sroche2@f
http://dx.doi.org/10.1016/j.tet.2014.06.0540040-4020/Published by Elsevier Ltd.
Over the years, alkaloids derived from indole dearomatization,such as indolenine and indolines have been evolved as promisingtherapeutic agents due to their important biological activity againstcancer, inflammation and hypertension.1 Since the middle of the20th century, tremendous efforts and creativity have been devotedtoward the functionalization of indoles, tryptamines, tryptophans,and other b-carboline building blocks. Many transformations havebeen developed for the functionalization at the C3 position (e.g.,indole 1) or at C2 when the aforementioned position is alreadysubstituted (e.g., indole 2). In fact, the indole nucleus owes to itsstructural features both selective nucleophilic reactivities on thenitrogen and at C3 due to the enaminemoiety (depending on soft orhard electrophiles). Only if the C3 position is blocked, the indolenucleus may then react towards electrophiles at the C2 position(likely via delocalization from the inside of the benzene ring) beforeundergoing rearomatization to deliver 2,3-disubstituted indoles.On the other hand, when dearomatization occurs at the C3 position,the resulting indolenium 3 can further endure either a direct nu-cleophilic attack at C2 (path a) leading to indolenine 6, or anintramolecular rearrangement typically generated by a [1,2]-shiftfrom a substituent at C3 to C2 (path b) followed by the nucleo-phile addition at C3 trapping the benzylic carbocation 4. This im-portant array of reactivity from the indole nucleus upon activationby different electrophiles became an exciting field of study forsynthetic chemists as it enables facile ring formations, regiose-lective reactivity, and fascinating skeleton rearrangements(Scheme 1).
Scheme 1.
There is perhaps no better illustration of the history and powerof indole dearomatization than the rich history of efforts toward theindole alkaloid strychnine (7). As appropriately asked by Overman,“Is There No End to the Total Syntheses of Strychnine?”,2 there are noless than 17 reported total and formal syntheses strychnine (7) with5 relying on indole dearomatization at some stage. Efforts towardstrychnine began more than 70 years ago. After the epic endeavorsregarding the synthesis quinine during the final years of WWII, and
in constant competition with Sir D. Robinson, Woodward un-dertook the daunting synthesis of strychnine (7) in the late 1940s.In 1954, Woodward utilized a dearomative strategy to construct theC ring of strychnine (7) via a PicteteSpengler type reaction of anactivated tryptamine-derived iminium 9 affording indolenine 10 in64% yield (Scheme 2, Eq. 1).3 Thirty years later, both syntheses byMagnus and Kuehne also demonstrated the efficacy of dearomativestrategies highlighted by a transannular Mannich reaction ora Lewis acid-catalyzed cascade reaction, respectively (Scheme 2,Eqs. 2 and 3). Magnus reported the dehydrogenation of the tetra-cyclic indole 11 using mercury acetate producing regioselectivelyiminium 12, which spontaneously endured the intramolecularindolic attack from the C3 position to generate pentacyclic indoline13 in 65% yield, after a final iminiumeenamine tautomerizationmechanism (Scheme 2, Eq. 2).4 Kuehne reported the year aftera cascade reaction also involving a Mannich reaction in the firststep to enable the dearomatization of tryptamine 14 (Scheme 2, Eq.3). The boron trifluoride catalysis promoted a proposed [3,3]-sigmatropic rearrangement of indoline 15 to indole 16, which af-ter several enamineeiminium tautomerization interplays securedthe access to the four A, B, C, and E rings of strychnine in a singlestep (over 51% yield).5
These classical examples of indole dearomatization (selectedfrom Ref. 2) clearly highlight that achiral racemic syntheses ofpolycyclic indoline alkaloids were paramount until most recently.In the past 10 years, the efforts of several groups re-explored thechemistry of indole and tryptamines under asymmetric catalysishas blossomed and offered new possibilities for asymmetric con-struction of complex alkaloids. MacMillan, who is a recognized as
one of the pioneers in the arena of organocatalysis, reported thebrilliant use of imidazolidinone as chiral catalyst to synthesize inhigh enantiopurity the common tetracyclic alkaloidic scaffold 23 ofseveral Strychnos, Aspidosperma, and Kopsia alkaloids througha cascade reaction (Scheme 2, Eq. 4).6 MacMillan used an enan-tiodiscriminating activation of propargyl aldehyde to trigger thecomplex cascade reaction and the dearomatization of the relativelysimple selenyl-derived tryptamine 19 starting via a DielseAlder
Scheme 2.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3551
cycloaddition. The resulting enamine 21 may then undergo b-elimination to expulse the selenyl leaving group generatingtherefore a novel reactive iminium specie, which presumablycyclized in a 1,4-addition producing the desired tetracyclic core 22,which after enamineeiminium tautomerization and hydrolysis toregenerate the catalyst delivered compound 23 in 82% yield and97% enantiomeric excess (ee).
While the dearomatization of miscellaneous arenes7 and func-tionalization of indoles8 have been extensively covered elsewhere,only a few recent reviews covered specific indolic dearomatizationstrategies9 and recent advances in asymmetric dearomatization.10
Many syntheses of complex target molecules incorporatingindolic fragments have set the stage for new chemistry to be ex-plored and for novel applications of dearomatization to be de-veloped. In this review, we will have a broader overview of indolesdearomatization through cycloaddition (Section 2), arylation (Sec-tion 3), protonation (Section 4), alkylation (Section 5), and oxida-tion with several heteroatoms (Section 6), with a special emphasisand comparison in each section on unprotected versus protectedindole nitrogens and asymmetric and/or catalytic dearomativemethods and cascade reactions for the synthesis of complex alka-loids. In addition, to outline several selected dearomatizationstrategies in the context of complex natural product synthesis, wewill also describe future perspectives in the field including pros-pects for development of enantioselective dearomatization pro-cesses (Section 7). The authors apologize for any published workthat would not have been selected and shown in the present reviewdue to the large amount of literature covering the topic of indoledearomatization and the personal selection. Where relevant, wehave includedmechanistic details and have emphasized differencesbetween unprotected and N-protected indole reactivities with theaim that this report will stimulate the development of novelasymmetric and catalytic enantioselective methods for the dear-omatization of indoles.
2. Dearomatization via cycloadditions
Cycloadditions are powerful maneuvers for the formation ofcomplex polycyclic structures while controlling the simultaneousemergence of several stereocenters. This section will outline ex-amples of cyclopropanation strategies, [2þ2] photocycloadditions,1,3-dipolar cycloadditions, and many variants of the well-established DielseAlder reaction in the process of indoledearomatization.
2.1. Cyclopropanations
Numerous examples of indole cyclopropanations have beenreported mostly in an achiral fashion11 and it is only recently thatdiastereoselective cyclopropanations12 and enantioselective dear-omative cyclopropanations13 have been utilized in the context ofcomplex alkaloid synthesis. Based on the chemical ability of indolesto endure cyclopropanation and the fact that cyclopropane frag-mentation is a well-established transformation, tactics taking ad-vantages of both reactivities have emerged to synthesize complexpolycyclic indoline scaffolds (Scheme 3). Copper and rhodium car-benoid species have been reported to catalyze these types ofcyclopropanationerearrangement sequences. Jung reported that 3-substituted indole b-diazo-a-keto esters 24 endured the formationof a rhodium(II) carbenoid followed by cyclopropanation to com-pound 25, subsequent cyclopropane ring opening affording theiminium intermediate 26, which underwent cyclization via theester enolate attack to deliver, after hydrolysis, the final tetracycliccompound 28 as minor product of the reaction in 18% yield(Scheme 3, Eq. 1).14
A similar strategy was exploited to its full potential by Qin inseveral total syntheses endeavors as exemplified by the concisesyntheses of (�)-minfiensine (33) and (�)-ardeemins (38) (Scheme3, Eqs. 2 and 3). At first, Qin reported the achiral copper-catalyzed
Scheme 3.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913552
dearomatization/rearrangement sequence of tryptamine de-rivatives, as exemplified by cyclopropanationering opening of thetryptamine derivative 29, leading to the interception of indoleni-nium 31 by the pendant amine to form tetracyclic indoline 32 in62% yield (Scheme 3, Eq. 2).12a,b,15 Soon after, Qin also reported anintermolecular modification of the reaction, which was conductedon tryptophan 34 to achieve a diastereoselective dearomatizationleading to the tetracyclic hexahydropyrroloindoline 37 in 73% yield(w2:1 dr) on a 50 g scale (Scheme 3, Eq. 3).16 In 2013, Davies re-ported for the first time an enantioselective rhodium-catalyzedannulation of 3-alkylindoles 40 (Scheme 3, Eq. 4).17 In this re-action, 4-aryl-1-sulfonyl-1,2,3-triazoles 39 were used as diazoprecursors, which upon activation with a chiral rhodium(II)adamantanyl-tetracarboxylate catalyst 41 enabled the dearomati-zation and further rearrangement sequence of N-protected indoles40 to afford tricyclic pyrroloindolines 44 in excellent yields and
Scheme
high enantioselectivity (up to 95% ee). This extremely versatilereaction was also achieved on unprotected indoles resulting inlower enantiodiscrimination.
2.2. [2D2] Cycloaddition followed by a retro-Mannichfragmentation
Photocycloaddition involving the C2eC3 p-bond of indoles18
has been elegantly utilized by Winkler during his investigationstoward the formal synthesis of vindorosine (50) (Scheme 4).19 Thebulky orthoester moiety installed on the tryptophan derivative 45was found crucial to improve facial diastereoselectivity during thekey [2þ2] photocycloaddition. Photocycloaddition using Pyrex fil-ter through the favored transition state 460 was achieved simulta-neously with a retro-Mannich reaction leading to the cyclobutanering opening to synthesize the rearranged photoadduct 48 in 91%
4.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3553
yield as a single diastereomer. Treatment of cycloadduct 48 withLDA and a silyl triflate enables the ring closure to furnish the re-quired tetracyclic carbon skeleton and achieve a formal synthesis ofthe vindorosine natural product 50.
Several years later, White reported a similar strategy usinga [2þ2] photocycloaddition and retro-Mannich fragmentation se-quence, to access several b-carbolines and oxindole natural prod-ucts (Scheme 5).20 This useful sequence of [2þ2]photocycloaddition followed by a retro-Mannich fragmentationenabled the formation of a pyrrolidine fragment while functional-izing simultaneously the C2 position of the indole precursor 49 toafford indoline 51 in 62% yield. Using this tactic, White reported thetotal synthesis of oxindole elacomine (52) in eight steps.
Scheme 5.
2.3. 1,3-Dipolar cycloadditions
Twomain strategies to construct complex heterocyclic indolineshave taken advantages of 1,3-dipolar cycloaddition reactions. Thefirst approach mediated by Lewis acids enables three-memberedring cycles to be opened (e.g., cyclopropanes, epoxides), thus gen-erating 1,3-dipoles that further trigger the desired dipolar cyclo-additions (Scheme 6), while the second approach is usuallycatalyzed by rhodium complexes to promote metal insertion into1,n-diazocarbonyls moieties to further generate carbonyl ylides asdipolarophile for cycloadditions with the indolic C2eC3 doublebond (Scheme 7).
Scheme 6.
In the first approach to dipolar cycloadditions, several researchgroups have studied the regio and stereoselectivity of the 1,3-dipoleadditions to indole dipolarophiles. For instance, 1,1-cyclopropanediesters have been first reported by Kerr to enable efficient dear-omatizations of 3-alkylated indoles through activation with ytter-bium triflate, which overall promoted cyclopentannulationreactions.21 Recently, a similar transformation was reported ina catalytic and highly enantioselective manner by Xie and Tang by
activation of 1,1-cyclopropane diesters with BOX/Cu(II) catalysts.22
Venkatesh reported a similar and very convenient [3þ2] cyclopenta[b]annulation with a broader scope of indole substrates 53 throughthe activation of cyclopropanes 54 catalyzed by boron trifluoride(Scheme 6, Eq. 1).23 Interestingly this annulative reaction is takingadvantages of electron rich arylated cyclopropanes to favor carbo-cation formation, which further triggered the unprotected indoledipolarophile to react. In some cases, titanium tetrachloride wasfound to be a better catalyst to perform the annulation and obtainthe desired tricyclic indolines 56. A similar transformation wasaccomplished byWu and Zhang on epoxide substrates 58 leading tothe synthesis of oxygenated indoline derivatives 59 (Scheme 6, Eq.2).24 In this case nickel perchlorate was used as catalyst to enable
the [3þ2]-cycloaddition to take place. Wu also described a catalyticenantioselective version of the transformation, using a BOX-60/Ni(II) catalysts, which enable the synthesis of indoline 59 in 72%yield with high diastereoselectivity while low enantiomeric excesswere observed (>20:1 dr, 19% ee). Finally, an original oxyaminationreaction of N-acylindoles 61 was recently reported by Yoon, on theground of oxido-reductive possibilities of copper, which enable theregiospecific reactivity of oxaziridines 62 through a plausible rad-ical mechanism (Scheme 6, Eq. 3). In fact, upon radical initiation onthe oxaziridine 62, N-acetylated indole proved to react at C2 posi-tion before enduring the C3 ring closure to afford the heterocyclicindolenine 63 in good yields. When N-Boc-proline was utilized as
chiral auxiliary attached to the indolic nitrogen of compound 61,the two-step sequence oxyamination followed by ring opening andclosure delivers the pyrroloindoline core 64 in 78% yield and 91% ee(note: the chiral auxiliary was simultaneously extruded). Recentlytwo other examples of enantioselective oxyamination of indoleshave been reported by Feng and Ooi separately. While Feng and Liureported the use of a chiral oxaziridine to induce a highly enan-tioselective dearomatization,25 Ooi developed a very powerful
Scheme 7.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913554
catalytic enantioselective reaction highlighted by the situ forma-tion of a chiral oxaziridine based on the catalytic action of a chiraltriaminoiminophosphorane base.26
As mentioned above, rhodium(II)-catalyzed cyclization and 1,3-dipolar cycloaddition cascade also represents a powerful maneuveramenable to indole dearomatization as well as assembling complexheterocyclic ring systems in a single operation. Pioneering work byPadwa described such elegant cyclizationecycloaddition cascade in1995 to access the desacetoxy-4-oxo-6,7-dihydrovindorosine enroute to Aspidosperma alkaloids (Scheme 7, Eq. 1).27 In this ap-proach, the 1,4-diazo imide 65 endures a Rh(II)-catalyzed cycliza-tion, which generates 1,3-carbonyl ylide dipole 66, which furtherenable the C2eC3 indole double to react as a 2p component in thedesired 1,3-dipolar cycloaddition (Scheme 7, Eq. 1). In this case, thehexacyclic indoline 67 was formed in 95% yield as a single di-astereomer revealing the perfect stereochemical outcome (at C2,
Scheme 8.
C3, C5, and C12) required to achieve the total synthesis of vindor-osine (68). Since this early work, the carbonyl ylides reactivity in[3þ2]-cycloadditions with indole has been blossoming28 as high-lighted by the selected modification in Scheme 7 (Eq. 2).28c Oguriexpanded the rhodium-catalyzed cyclizationecycloaddition cas-cade, by the development of a divergent synthetic pathway, whichenables access to both polycyclic skeleton 71 and 72 selectively.Depending on the length of the pendant alkenyl side chain of thetertiary amide in the diazo ketoester 69 (n¼1 or 2), either theindolic C2eC3 double bond or the terminal alkene moieties par-ticipated in the cycloaddition reactions. After formation of
a common carbonyl ylide intermediate 70, if the pendant alkenecomprises two carbons (n¼1) both alkene and indole reacted un-selectively to afford a mixture of both hexacyclic products 71 and72 in 22% and 65% yields, respectively, but a divergent and selectiveprocess occurred when the pendant alkene contained three car-bons (n¼2), then only the indoline skeleton 71 was obtained in anexquisite 94% yield. Such design is very interesting in view of de-veloping library of biologically active small-molecules via a di-versity oriented synthesis (DOS).
Adding complexity to the original reports from Padwa, Bogerreported the brilliant tandem multi-step process with an initialintramolecular DielseAlder of 1,3,4-oxadiazole with an internalalkene, which after extrusion of nitrogen delivered the requiredcarbonyl ylide 75, ready to undergo the desired 1,3-dipolar cyclo-addition to afford hexacyclic indoline 76 as a single diastereomer in71% yield (Scheme 8).29
This elegant maneuver by which the nitrogen extrusion un-veils the highly reactive carbonyl ylide fragment (1,3-dipole) re-quired for 1,3-dipolar cycloadditions represents an extremelyuseful and powerful strategy that Boger exploited numeroustimes to construct polycyclic alkaloids with important biologicalactivity.30
On the other hand, efforts have also been reported for the de-velopment of catalytic enantioselective 1,3-dipolar cycloadditionwith indoles (Scheme 9, Eq. 1). For example, 1,4- and 1,5-diazoketone 79 have been reported by Hashimoto to participateefficiently in intermolecular Rh(II)-catalyzed 1,3-dipolar
Scheme 9.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3555
cycloadditions to afford tetracyclic indoline 80 with high enantio-selectivity and high exo/endo diastereoselectivity.31 Also fusedindolines 82 can be synthesized by a rhodium-catalyzed [3þ2]annulation of indoles 81 (Scheme 9, Eq. 2). In this particular re-action, the authors reported that tricyclic indolines 82 were ob-tained in excellent yields and with high enantioselectivity and thatsubstitution pattern at either C2 or C3 of the indole 81 was ex-tremely influential for the diastereoselectivity outcome of thereaction.32
2.4. DielseAlder cycloadditions
Indolic substrates have been extensively studied in DielseAlderreactions, either as dienophiles (C2eC3 double bond) (Sections2.4.1 and 2.4.2), or as dienes when substituted with vinylic pendantside-chains at either the C2 or the C3 position (Section 2.4.3).
2.4.1. Indole acting as dienophile in DielseAlder cyclo-additions. Normal electron demand DielseAlder cycloadditions ofindoles are challenging reactions, usually requiring specific sub-stitution patterns of the indolic ring (electronic factors) as well ashigh temperature or pressure for the reaction to occur. Because ofits low tendency to act as a dienophile, only indole substituted atthe N-1 and C3 positions with electron-withdrawing groups isamenable to normal electron demand DielseAlder cycloaddi-tions.33 Work by Piettre and Wenkert showed that high pressureaccelerates the normal demand DielseAlder to achieve the irre-versible dearomatization of the indole nucleus (Scheme 10).34 Forexample, dearomatization of indole 83 through a DielseAlder cy-cloaddition with the Danishefsky’ diene 84 was achieved at 45 �Cunder a 12 kbar pressure! to deliver tricyclic indoline 86 in 60%yield and 3:1 endo/exo ratio. Also, normal demand DielseAlder
Scheme
with 1,3-butadienes can be performed under high-energy photo-chemical irradiations.35
The intramolecular variant of a normal electron demand Diel-seAlder cycloaddition of indoles was reported by Padwa with thereaction of indole 87 C2eC3 double bond and a tethered furylamidemoiety to generate in a single step tetracyclic indolines 90 (50e91%yield) en route to several Strychnos alkaloids (Scheme 11).27a,36 Inthis reaction,36c a tertiary amide is necessary (R2¼alkyl or alkylenyl)to promote the equilibration between s-cis and s-trans conformerstherefore placing the furanyl moiety in close proximity of theindolic ring. One can observe that even though this strategy is ex-tremely efficient, high temperature and pressure are againrequired.
Some other examples supporting that indole C2eC3 doublebond acts as dienophile were reported from inverse demand Diel-seAlder cycloadditions with electron poor dienes partners. Seminalwork from Snyder demonstrated that indoles may react in formal[4þ2]-cycloadditions with 1,2,4,5-tetrazines, 1,2,4-triazine, andpyridazines at afford polycyclic indolines in a unique manner.37 Asshown in Scheme 12 (Eq. 1), the triazinotryptophan derivative 91undergoes an intramolecular an inverse demand cycloadditionfollowed by nitrogen extrusion to deliver the aza-analog 93 ofAspidosperma alkaloids. Related to the same concept, Bodwell re-ported soon after an extremely concise racemic synthesis ofstrychnine highlighted by a transannular inverse electron demandcycloaddition of compound 94, which after nitrogen extrusiondelivered the natural product pentacyclic core 96 in a quantitativemanner.38 Finally, another example of inverse electron demandcycloaddition was reported by Liao with the reaction of variousindoles 97 and some highly reactive masked ortho-benzoquinones98 leading to densely functionalized tetracyclic indolines 99 ingood yields (23e71%) (Scheme 12).39
Another approach to circumvent the harsh conditions requiredfor DielseAlder cycloadditions using the C2eC3 indolic doublebond as dienophile is to take advantage of the enhanced reactivityof deprotonated indoles.40 As reported in an early work by Mark�ofor a synthetic approach to manzamine alkaloids,41 the bis-cyclization of indole anion onto an electron poor diene can be ac-complished. Using this strategy, Vanderwal reported an extremelyexpedient synthesis of (�)-norfluorocurarine (106) in 16% overallyield and 9 steps (Scheme 13).42
Treatment of indole derivative 102 with t-BuOK in THF at 80 �Cin a sealed tube afforded the tetracyclic indoline structure 105(single diastereomer) in 84% yield, presumably via a formalDielseAlder cycloaddition (or double anionic addition) sponta-neously followed by the olefin isomerization of aldehyde 104.Even though a stepwise or concerted mechanism for this dear-omative cascade has not yet been elucidated, this spectaculartransformation via anionic bis-cyclization of 103 established, ina single dearomatization step, the tetracyclic core of the Strych-nos-type alkaloids.
2.4.2. Hetero-DielseAlder cycloadditions. Most of the hetero-Diel-seAlder reactions are inverse electron demand type cycloadditions
10.
Scheme 11.
Scheme 12.
Scheme 13.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913556
involving quinone methide-like dipolarophiles to react with theC2eC3 2p electrons of the indole nucleus. Early work by Funkdemonstrated that such synthetic strategy was very efficient toassemble complex alkaloids as exemplified by the communesin B0
skeleton 109 synthesis (Scheme 14, Eq.1) as well as a total synthesisof (�)-perophoramidine (115).43
Effectively, Funk described a highly stereoselective intra-molecular cycloaddition of an indole moiety tethered to an anilinebearing a leaving group at the nitrogen b-position. Upon heating oracidic treatment, a plausible aza-quinone methide intermediate108 could be formed, thereof triggering the intramolecular aza-DielseAlder reaction to occur and deliver the endo-cycloadduct 109
in high yield. A diastereoselective and intermolecular variation ofthis transformation was also developed by Qin for the total syn-thesis of (þ)-perophoramidine (115) (Scheme 14, Eq. 2).12a,b,44 Inthis event, the reaction between indole 111 and a putative aza-quinone methide generated from aniline 112 delivered the hex-acyclic indoline 114 in a single step, 88% yield and with high ster-eoselectivity (exo-selectivity). A silver(I) Lewis acid facilitated theformation of a reactive aza-quinonemethide intermediate from theN-protected aniline 112 via extrusion of the chloride leaving group(double s-trans conformation as shown in the exo-transition stateTS-113), which underwent an inverse electron demand DielseAldercycloaddition with indole 111 yielding the particularly complex
Scheme 14.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3557
spirocyclic indoline 114 in 88% yield with a high diastereocontrol(11:1 dr).
Inspired from the reports from Funk, the groups of Stoltz45 andCossy46 have both reported the utilization base-mediated aza-quinone methide formation to initiate inverse electron demandDielseAlder cycloadditions with indoles (Scheme 15).
Scheme 15.
Upon exposure to cesium carbonate, the chloromethyl-aniline 117 smoothly formed the required aza-quinonemethide 118, which reacted with a (�)-aurantioclavine (116)derivative to form cycloadduct 119 in 89% yield and a moderatediastereomeric ratio (2:1 dr) demonstrating a poor stereo-induction from the remote stereocenter at C11 (Scheme 15, Eq.1). Cossy reported that under similar basic conditions, a proba-ble indol-2-one derivative 122 reacted with the tryptaminederivative 120 to deliver cycloadduct 123, which spontaneouslyrearranged to afford the bis-alkylated oxindole 124 in 75% yieldand high diastereoselectivity. Upon the treatment of oxindole124 with Red-Al, all stereochemical information was lost and thedesmethyl-chimonanthine (125) was synthesized as a meso-product.
Recently, Porco reported the use of another o-quinone methide-like reagent 128 to trigger indole dearomatization (Scheme 16).47
During this hemi-synthesis endeavor towards pleiomaltinine(129) from the complex pleiocarpamine alkaloid 126, the authorsexamined a possible biomimetic approach for the introduction ofa pyrone unit in the pleiomaltinine’ skeleton. Under acidic condi-
tions, silyloxypyrone 127 likely generated a dearomatized form ofpyrones as presented by the ortho-quinone methide 128, whichlikely triggered an inverse electron demand DielseAlder cycload-dition with the indolic moiety of the natural product pleiocarp-amine (126). The plausible cycloaddition resulted in the obtentionof the highly functionalized alkaloid natural product 129 in a singlestep and 51% yield as a single diastereomer.
2.4.3. Indole acting as diene in DielseAlder cycloadditions. The twostructural isomers of vinylic indoles (substituted at C3 130 or at C2132) have been documented to react as electron rich dienes innormal demand DielseAlder cycloadditions (Scheme 17).
Pioneering work by Magnus reported in 1993 described a strat-egy for C2-vinlylic indole dearomatization via a DielseAlder
Scheme 16.
Scheme 17.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913558
cycloaddition, which through an intramolecular cycloadditiongenerates, in a single step, three rings (CeE rings) present in nu-merous Strychnos alkaloids.48 Soon after, Kuehne described a simi-lar intramolecular DielseAlder cycloaddition strategy, withasymmetric control, using a chiral ferrocenyl-auxiliary amenable tohigh facial-diastereodifferentiation during the reaction to accessthe tetracyclic indoline core 136 (Scheme 18, Eq. 1).49 Fukuyamaalso utilized the DielseAlder cycloaddition strategy to assemble ina single step the AeE rings of vindoline, a powerful tool that theauthor also employed for the biomimetic construction of vinblas-tine and several other complex alkaloids.50,51 Basic conditions usingpyrrolidine on indole 137 promoted a succession of several stepswith a deprotection, followed by the aminolactol moiety rear-rangement to the cyclic enamine 138, which upon heating un-derwent the desired inverse electron demand DielseAlder to affordcompound 139 in 73% overall yield.
Scheme 18.
More recently, MacMillan reported a remarkable total synthesisof (þ)-minfiensine (33) with the following key features: (i) orga-nocatalytic [4þ2]-cycloaddition coupled with hemi-aminal isom-erization/cyclization to allow rapid access to a complex tetracyclicframework and (ii) a second radical cyclization to install the lastring of the alkaloid (Scheme 19, Eq. 1).52
In the first event, protected tryptamine 140 participated ina dearomatizing cascade via a catalyzed DielseAlder reaction (fromimidazolidinone catalyst 142) with the propyne 4-imidazolidonium141 to generate enamine intermediate 143, which underwentspontaneous isomerization to indolinium 145. Further cyclizationof the pendant protected amine in a 5-exo-trig manner furnished
pyrroloindoline 146. The authors proposed a specific arrangementfor the DielseAlder cycloaddition wherein the acetylenic group ofthe iminium intermediate 143 may be positioned away from thetert-butyl substituent of catalyst 141, thereby facilitating endo se-lectivity during the cycloaddition (cf. 143) and establishing the C3stereocenter of indoline intermediate 144. Reductive workup in thesame pot delivered product 147 in 87% yield and 96% ee. This im-pressive organocatalytic cascade sequence allowed MacMillan andco-workers to produce the tetracyclic core of minfiensine (147) ina single step with high enantioselectivity and diastereocontrol.Since this seminal work, several other complex alkaloidic naturalproducts have been synthesized by the MacMillan group, whichclearly demonstrates that organocatalysis is amenable to novel,rapid, and most importantly highly enantioselective ways of con-structing complex indolic alkaloids.6,53 A related strategy of bis-annulation was reported by Zhao for an expedient assembly of
highly functionalized tetrahydrocarbazoles (Scheme 19, Eq. 2).54 Inthis event, a prolinol-derived catalysts dictated the enantiose-lectivity outcome of the DielseAlder cycloaddition between theindole derivative 148 and an a,b-unsaturated aldehyde via a possi-ble assembly 149. The DielseAlder cycloadduct 150, obtained ina 16:1 endo/exo diastereomeric ratio and 95% ee, spontaneouslyisomerized to endure the second annulation leading to isolation ofthe tetracyclic indolenine 151 in 67% yield.
Armstrong and Pindur demonstrated independently that C3-vinylic indoles are also potential substrates for DielseAlder re-actions.55 In 2008, Bernardi and Ricci reported a first example ofcatalytic enantioselective dearomatization of 3-vinylindoles with
Scheme 19.
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several maleimide and quinones as dipolarophiles andbifunctional-thioureaquinuclidines organocatalysts.56 Followingthis work, thiourea catalysts were also attractively exploit by Bar-bas III for the DielseAlder cycloaddition between 3-vinylindoles152 and a,b-unsaturated oxindoles 153 to assemble hexacyclicspiro-oxindoles 155 in a single step and with high enantiose-lectivity (Scheme 20, Eq. 1).57
Scheme 20.
Finally, the indolic heterodiene 156was described by Piettre andChataigner to undergo inverse demand cycloaddition under highpressure with ethyl vinyl ether (Scheme 20, Eq. 2) leading to a highendo/exo diastereocontrol during the cycloaddition.58 Upon cycli-zation a novel 1,3-dipole was generated, which reacted spontane-ously with the other acrylate partner already present in thereaction media to deliver in a single operation the tetracyclicindolines 158 in high yields. This well-designed sequence of [4þ2]-
and [3þ2]-cycloadditions was achieved with high chemo- andregioselectivity.
To conclude this section on dearomative cycloaddition, weshould not forget about the seminal work from Vollhardt, whoclearly demonstrated the viability of a [2þ2þ2]-cycloadditionstrategy during his epic synthesis of strychnine.59 While thismethod has been rarely employed, cobalt-mediated [2þ2þ2]-cy-
cloadditions between two alkynes and the indolic C2eC3 doublebond allowed for the rapid assembly of complex alkaloids skeleton.
3. Arylative dearomatization
Dearomatization of indole at the C3 position by any electrophilicarene surrogates is proposed to be involved in many naturalproduct biosyntheses. Synthetic methods have thereof been
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913560
developed, notably for indole dimerization with the C2 or C3 ary-lations to generate various types of indoline and indolenine prod-ucts. Palladium and other transition metals as well as Brønstedacids and iodane reagents have been largely utilized to promotesuch controlled arylative dearomatizations, whichwill be discussedin this section.
3.1. Palladium-catalyzed dearomatization of indoles
Palladium-catalyzed cross-coupling reactions and arylationsmethods have been widely developed in synthesis. In contrast,utilization of palladium to dearomatize arenes and heteroarenessuch as indoles is still very limited.
Three recent examples are paving the way for novel strategies tobe developed with palladium(0) or palladium(II) to create usefuland complex indolic polycyclic ring systems. As describe in Scheme21 (Eq. 1), Pd(II) under oxidative conditions in the presence of silveracetate enabled the oxidative Heck reaction (C2 intramoleculararylation) of substrate such as 159 leading after b-hydride elimi-nation to the tetracyclic styrenylindoline 160 in good yields.60
Other substitution patterns on the starting indole as shown instructure 161 are also amenable to react through oxidative Heckreactions thus generating a pyrroloindolenine type skeleton 162(Scheme 21, Eq. 2).61 Compounds 162 can be diversely modifiedeither to oxindole such as 163 or reduced to tetracyclic indolines164 in useful yields. Finally, a third substitution pattern at C362 wasstudied by You showing that substrates like 165 can easily undergospirocyclization again via an oxidative Heck type reaction (Scheme21, Eq. 3).63 The authors demonstrated a large scope of reactivity aswell further reduction of the indolenine scaffold using sodiumborohydride to deliver indoline 167. In the same study, You re-ported the catalytic enantioselective variation of the reaction thusemploying the chiral ligand 168 to access the desired compound166 in 71% yield and 61% ee. This example stands today as the onlyreport of a dearomative and enantioselective oxidative Heckreaction.
Scheme
3.2. Transition metal and Brønsted acid mediated dearoma-tization of indoles
Several other methods have also been reported for the arylativedearomatization at both C2 and C3 positions of indoles (Scheme22). Liu reported an innovative approach for the dearomatizationof keto-indole derivative like 168 (Scheme 22, Eq. 1) via a highlyregioselective addition of a Grignard reagent at the C2 carbon-center of the indole.64 Product 169 was obtained after a diaster-eoselective reprotonation under kinetic control as the cis-indolinestereoisomer 169. Treatment of the cis-derivative 169 with base athigher temperature allows for the C3 epimerization and full in-version to deliver the trans-indoline 169 in 82% yield as the soleproduct of the reaction. In a second campaign towards the naturalproduct haplophytine, Chen reported the arylative dearomatizationof b-carboline substrates such as 170 at the C3 position by means ofa para-quinone electrophile 171 (Scheme 22, Eq. 2).65 Triflic acidwas found to be the best promoter for this transformationwhile thesubstitution pattern of the quinone appears capricious in dictatingthe regioselectivity during the ring closure event. Similar productsfrom the fusion between indoles and quinones were also synthe-sized by Vincent using a FriedeleCrafts hydroarylation methodmediated by FeCl3 (Scheme 22, Eq. 3).66 In the present three-stepprocess, iron(III) facilitated the highly regioselective arylation ofacylindoles 173with phenols 174. Further removal of the protectinggroup by an acidic treatment followed by an oxidative cyclizationafforded the polycyclic indoline 176 in good overall yield.
3.3. Iodane-mediated dearomatization of indoles
Dearomative dimerization of indoles, tryptamine, and trypto-phans building blocks has been a long-standing problem for syn-thetic chemists in term of reactivity, but also scalability andstereocontrol. Barton first reported that organobismuth (bis-muth(V)) reagents were amenable to oxidative arylation at the C3position of indoles.67 A later work from Takayama, demonstrated
21.
Scheme 22.
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that hypervalent iodine(III) reagents enable the desired arylativedearomatization of tryptamine substrates with a concomitant an-nulation to furnish the pyrroloindoline dimeric products of theoxidative cascade.68 Until to date, several mechanism have beenproposed for the formation of such arylative indole dearomatiza-tion, either via single electron transfer (SET), or nitrene aziridina-tion or most presumably through the in situ formation of l3-iodaneat the indole C3 position as proposed in a seminal work byMoriarty.In Takayama’ report, the authors isolated after reduction threemainproducts having the meso and the racemic mixture of the naturalproduct chimonanthine (meso/racemic, 2.5:1.0 dr) in 43% overallyield. These results were later advantageously utilized by Willisthrough an ingeniousmeso-desymmetrization of the dearomatizeddimer 178 (Scheme 23, Eq. 1).69 Taking advantages of the well-established Trost asymmetric allylic alkylation strategy (AAA),
Scheme
Willis was able to desymmetrize diamine 178 in 76% yield and 99%enantiomeric excess on gram scale quantities. These efforts cul-minated with the total synthesis of hodgkinsine B (180) in 11 steps.More recently, Liang reported the dimerization of N-tosyl trypt-amine 181 unexpectedly mediated by iodine in presence of oxygen(Scheme 23, Eq. 2).70 The overall yield in dimer 182was reported as90% while the isomeric ratio was not commented by the authors.The crystallographic structure reported in the study presents bothconcave pyrroloindoline moieties dimerized as a C2-racemicproduct 182 different from the previously reported meso-products.This efficient dimerization strategy may pave the way to manyasymmetric variations of arylative dimerization annulation cas-cades to be discovered.
Since the seminal work from Haran during the total synthesiscampaign of diazonamide A, and the formal [3þ2]-cycloaddition,
23.
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revealing a C3 arylation strategy coupled with a C2 aminal cycli-zation, hypervalent iodine chemistry has been recognized as anextremely productive and somehow controllable tool for indoledearomatization.71
Haran demonstrated of the indole dearomatization through theimpressive oxidative macrocyclization strategy designed for thesynthesis ofdiazonamideA (Scheme24). Thekey stepof the synthesisthe hypervalent iodine reagent PIDA promoting the activation of thephenol moiety in substrate 183 for which the presence of lithiumacetate salt facilitates the electrophilic activation and the indole at-tack and further ring closure to the furanoindoline185 in reproduciblerange of 30% yield with useful diastereoselection (3:1 dr).
Scheme 24.
Later on, similar annulated products, from formal [3þ2]-cycloadditions were obtained by Danishefsky in a model studytoward the natural product phalarine.72 Soon after, Nicolaou andChen also reported an arylative dearomatization of new substratessuch as b-carboline 186 using the trifluoroacetate variant of PIDA(PIFA) to hindered CeC bond link of a quaternary carbon and arylsp2 carbon centers for the junction of the heterodimer hap-lophytine (189) (Scheme 25).73 Study for the diastereocontrolduring the key dearomatizing step concluded that the acetateprotecting group on the b-carboline 186was crucial to achieve highdiastereodiscrimination (10:1 dr) during the formation of thehexacyclic intermediate 188, which was obtained in 23% yield.
Scheme 25.
Taken together, the studies of Haran and Nicolaou (Schemes 24and 25, respectively) demonstrate how remote stereoelectronicfactors and innate structural conformation can affect the course ofthe oxidative arylations in terms of facial diastereo-induction. In-spired from Haran’ seminal work, Yao reported in 2013 the totalsynthesis of ent-(�)-azonazine via a biomimetic oxidative annula-tion, which enabled a concise synthesis and the natural productstructural’ reassignment to a cis-benzofuranoindoline ringjunction.74
Recently, several groups have been involved in optimizing ary-lative transformations and reported elegant synthetic methods forthe dearomatization of simpler substrates than the aforementionedto showcase aryl transfer reactions from hypervalent arylated-iodines (Scheme 26). First in this series of reports, Baran studiedthe dearomatization of tryptamine, tryptophan, and b-carbolinederivatives such as 190 applying oxidative reaction conditions us-ing a bisaryl l3-iodane reagent (Scheme 26, Eq. 1).75 The use ofa strong hindered organic base was presented as crucial by theauthors to achieve the dearomative step as shown below for thedearomatization of b-carbolines 190 with a bisaryl tetra-fluoroborate hypervalent iodine reagent, leading after reduction to
isolate indolines 192 in excellent overall yields. You reported anelegant and efficient dearomatization of tryptophols such as com-pound 193, tolerating electronwithdrawing or donating (R1) on theindole ring, but also alkyl groups at the C2 position (R2). Arylationwas shown to be catalyzed by copper(I) and (II) and optimized forcopper(I) triflate with some bisaryl iodonium reagent affording thedesired aryl group for transmetalation (Scheme 26, Eq. 2).76
Even though no discussion was offered in this paper, the use ofmesytil residue (R3) as a dummy ligand on the l3-iodane reagentprovided a very efficient and more economically viable method forarylation and vinylation (for the prospect of complex substrates).Extremely similar chemistry was described by Reisman for the
dearomatization study of N-tosyl-tryptamines 195 to access ina single step the C3 arylated pyrroloindoline building blocks 196 inhigh yields (Scheme 26, Eq. 3).77 First attempts of a catalyticenantioselective variation of this reaction have failed and representcertainly a desirable goal for new developments of this chemistry.In the same time, MacMillan reported an impressive step forwardin the same direction of asymmetric catalysis with the dearoma-tization tryptamides 197 to afford pyrroloamidoindoline 199 inhigh enantiopurity (Scheme 26, Eq. 4).78 Once again, the copper(I)
Scheme 26.
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strategy to achieve oxidative insertion of a mesytil-aryl l3-iodanereagent proved to be an efficient maneuver for transmetalationwhile several Box ligands were screened to achieve the bestenantiodiscrimination possible (see the proposed transition state198). In 2013, Reisman offered a novel diastereoselective arylativedearomatization of tryptophan derivatives 200 combined witha substrate annulation (Scheme 27).79 As shown in the postulatedcopper(III) assembly 201, using the appropriate copper catalystenables a decisive intramolecular chelation with the pendantdiketopiperazine moiety, which forces the arylation to occur at theC3 position from the bottom face of the substrate leading to thepentacyclic hexahydro-[2,3-b]pyrroloindole 202 in a single stepwith a high level of diastereocontrol. For this particular substrate200, the ligand used and the catalyst loading were optimized inorder to achieve this successful transformation in 62% yield. Fol-lowing two more steps with aniline deprotection and a modifiedLarock indolization delivered the natural product naseseazine B(203) in a very concise manner (only five linear steps fromtryptophan).
Scheme
As a conclusion of these related studies, it appears thatcopper(I)-catalyzed transmetalation of l3-iodane reagentsemerged as a powerful strategy for the simultaneous C3 arylationand C2 functionalization of indolic substrates.While subtlety on theiodonium reagents is noticeable (counter anion, and dummy ligandeffects), the ligand influence on the steric course of the copper-catalyzed transformation is presumably governed by the position-ing of the aryl group as shown in the proposed transition state TS-198 (Scheme 26). These recent results reveal that opportunitiesexist for the development of some more general asymmetricmethods for the catalytic arylative dearomatization of indoles.
4. Protonative dearomatization
Protonation of free indole preferentially occurs at the C3 posi-tion leading to the corresponding indoleninium, which can spon-taneously be trapped by the formation of a new bond at C2. In thisrespect, cyclic tautomers of tryptophan and tryptamine derivativeshave been prepared in various acids such as phosphoric acid or
27.
Scheme 30.
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trifluoroacetic acid at room temperature.80 Thus, tryptophan de-rivative 204 can be cyclized to afford a mixture of hexahy-dropyrroloindole (HPI) tautomers endo-205 and exo-205 (9:1 drrespectively) in 85% yield (Scheme 28). N-Sulfonylation of the lattermixture provided the more stable HPI 206 as a single di-astereoisomer, which presumably involves a dynamic kinetic res-olution.81 Movassaghi and Schmidt utilized this method anddisclosed an elegant enantioselective total synthesis of (þ)-chi-monanthine (178), (þ)-folicanthine (208), and (�)-calycanthine(209). Radical benzylic bromination of 206 afforded the key in-termediate 207 (Scheme 28).82 Intermediate 207was subsequentlytransformed in a very concise manner (five or six steps) to theaforementioned natural products.
Scheme 28.
Another application of dearomatization driven by tautomericprotonation was described by Loh during the chemical synthesis ofsome HPI-derived organocatalysts.83 This sequence involved a cy-clization strategy of tryptophan derivatives in TFA giving a mixtureof cyclic tautomers. Subsequent amine protection and hydro-genolysis efficiently furnished the desired HPI-derivedorganocatalysts.
In 2010, Chen reported an unexpected indole dearomatization inthe presence of a stoichiometric amount of Lewis acid (Scheme29).84 In this reaction, the indolic substrate 210 was transformedinto the substituted cyclopentyl[b]indoline 212 through a Lewisacid mediated tautomeric dearomatization. The authors believedthat AlCl3 enhances an enamineeimine isomerization throughproton transfer followed by intramolecular imino-ene reaction viathe formal assembly 211 to form the cyclic indoline tautomer 212 inhigh yield and excellent stereocontrol.
Scheme 29.
Scheme 31.
In this section of protonative dearomatization, we will also
present several examples of asymmetric hydrogenation of indoles.For instance, Kuwano was first to report a catalytic asymmetrichydrogenation of indole derivatives 213 and 214 (Scheme 30).85 N-Protected indoles substrates have been efficiently reduced, in goodto excellent yield and ee, by rhodium and ruthenium complexeswith a trans-chelate chiral bisphosphine PhTRAP ligand 217. Thechiral induction and the catalytic activity are significantly affectedby the N-protecting group nature on the indole nucleus.
Rhodium catalysts with monodentate phosphoramidite ligandPipPhos have also been used for the asymmetric hydrogenation ofmethyl N-acetyl-indole-2-carboxylate to yield the corresponding
indoline in quantitative yield with 74% ee.86 Pfaltz and Baeza dis-closed an efficient base free, hydrogenation of N-protected indoles,which are substituted at C2 or C3 positions, using air and moisturestable cationic iridium catalysts and some chiral N,P-ligands. Again,the chiral induction and the catalytic activity in this report can besignificantly affected by the N-protecting group appended on thestarting indoles.87
A related and interesting approach is the asymmetric reductionof highly stable and complexation free 2-substituted and 2,3-disubstituted indoles. The direct asymmetric reduction providesan atom-economic variant, avoiding the use of chelating groups (forthe transition metal used as catalyst) and the production of waste.Accordingly, Zhou reported the first highly enantioselective re-duction of N-unprotected indoles by using a palladium catalyst inthe presence of Brønsted acid (Scheme 31).88
It is likely that protonation of 2-substituted indoles 218 by L-camphorsulfonic acid (L-CSA) led to the corresponding highlyelectrophilic iminium salt 219, which is then reduced in situ byPd(OCOCF3)2/(R)-H8-BINAP catalysts to provide the correspondingindolines 220 (Scheme 31). This methodology has been successfullyextended to other 2,3-disubstituted indoles, leading to cis-
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indolines in good yields and with high ee. Mechanistic studiessuggested that the protonation and hydrogenation sequence in-volve a dynamic kinetic resolution (k1[k2), which favored therearomatization of indolenium ent-219 leading to a highly dia-stereoselective reduction of 219 to indoline 220.
Soon after, Zhou disclosed a simple, efficient, and rapid access to2,3-disubstituted indolines 226, in a sequential manner, from eitherthe 3-(a-hydroxyalkyl)indole 223a or the 3-(toluenesulfon-ami-doalkyl)-indoles 223b intermediates, or a one-pot manner, fromreactions between 2-substituted indoles and aldehydes or N-tosylimine (Scheme 32).89 The first step in this process is a Friedele-Crafts reaction between a 2-substituted indole 222 and an aldehyde(or N-tosyl imine) catalyzed by para-toluenesulfonic acid mono-hydrate (TsOH$H2O), giving the corresponding 3-substituted in-doles 223a,b. Water (or tosylamine) is then eliminated to give thecorresponding vinylogous iminium 224. Finally, a double in situasymmetric reduction of this iminium 224 gives rise to the 2,3-disubstituted indolines 226 with excellent yields and highenantioselectivity.
Scheme 32.
5. Alkylative dearomatization
5.1. Reaction of indole with oxo- and thiocarbeniums
Reactions involving dearomative and nucleophilic attacks ofindoles to carbenium-like electrophiles are described in the fol-lowing section. Interestingly, the literature involving dearomati-zation of indole through FriedeleCrafts-like reaction between theC3 position of the indole and aldehydes is quite limited presumablybecause of the high instability of the resulting 3-(a-hydroxyalkyl)indole products (hydroxyl leaving group abilities to facilitateelimination reactions).90
Cook reported an effective biomimetic strategy toward complexvincamajine-related indole alkaloids 230e231 as shown in Scheme33.91 The complex indole derivatives 227 were prepared in severalsteps starting from D-tryptophan methyl ester or Na-methyl-6-methoxy-D-tryptophan ethyl ester. When aldehyde 227 was
Scheme
treated in a mixture of Ac2O/TFA, a stereospecific intramolecularFriedeleCrafts reaction, followed by an acetylation resulted in theaminocarbinol 229 in 84% yield. It is interesting to note that TFAenhanced the exclusive formation of the kinetic product 229whereas in a mixture of Ac2O/HCl(gas), the other thermodynamicdiastereoisomer was obtained as the major product. The centralaminocarbinol 229 was subsequently transformed in several stepsto (�)-vincamajinine (230), (�)-vincamajine, (þ)-quebrachidine,(�)-11-methoxy-17-epi-vincamajine (231), and (þ)-vincarine.
Cyclopropanes are interesting reagents in organic chemistry,particularly 2-alkoxycyclopropanoate esters (donoreacceptor), asthey readily fragment through a retro-Aldol reaction to producezwitterionic intermediates, thus allowing possible annulationstrategies with appropriate dipolarophile substrates (e.g., indole).In this regards, Pagenkopf developed a useful synthetic method-ology for the synthesis of polycyclic compounds, based on the an-nulation of free indole and cyclopropane 2-alkoxycyclopropanoateesters in the presence of a Lewis acid (Scheme 34).92 2-Alkox-ycyclopropanoate ester 232 undergoes annulation with free indole
233 in the presence of Me3SiOTf, to afford the indoline carbinol-derivative 236 as sole diastereomer in 78% yield. It is noteworthythat this reaction has been extended to a number of indole de-rivatives and other cyclopropanes. However, it should be noticedthat reactions of 3-substituted indoles do not provide similar C2/C3annulated products.
In 1990, Bosch described an approach for the construction pyr-rolidine of Strychnos alkaloids (Scheme 35). In this reaction theindole bearing a dithioacetal unit was activated by dimethyl(me-thylthio)sulfonium tetrafluoroborate (DMTSF) to afford a thioniumion, which undergoes an FriedeleCrafts-type reaction.93 Thismethodology has culminated in the total synthesis of (�)-tubifo-lidine, (�)-tubifoline, and (�)-19,20-dihydroakuammicine.
More recently, this synthetic method has been readily appliedby Overman for the synthesis of Strychnos alkaloids (þ)-con-dylocarpine (239), (þ)-isocondylocarpine (240), and (þ)-tubotai-wine (241) from the dithioacetal 237 (Scheme 35).94
33.
Scheme 34.
Scheme 35.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913566
Finally, an example of FriedeleCrafts-like reactivity was alsoreported by Seidel with a one-step total synthesis of the naturalproduct neocryptolepine (245) (Scheme 36).95 The FriedeleCraftsbetween the aminobenzaldehyde 242 and indole 233was followedby the iminium 243 intramolecular capture and a final aerobicoxidation to conclude an efficient cascade.
Scheme 36.
5.2. Interrupted PicteteSpengler and related aza-Friedel-Crafts reactions
The PicteteSpengler reaction is originally a condensation of b-phenylethylamine and formaldehyde dimethylacetal in the pres-ence of acid, followed by a cyclization that produces some 1,2,3,4-tetrahydroisoquinoline (THIQ) molecules.96 In 1928, Tatsui ex-tended this reaction to tryptamine, which affords 1,2,3,4-tetrahydro-b-carboline (THBC) derivatives.97 Since then, the Pic-teteSpengler has become an efficient widely used ‘tool’ (e.g., withtryptamine or tryptophan derivatives) for the total synthesis ofcomplex natural products. While the original PicteteSpengler re-action ends through a rearomatization process, several type ofpolycyclic structures can be obtained through the interruption ofthe reaction, depending on the events occurring after the spi-rocyclization at the C3 position (migration or internal/externaltrapping of the imine), whichmainly depend on the structure of thestarting aldehyde involved in the reaction.
For example, modified tryptamines such as, Nb-hydroxytrypta-mines,98 Nb-alkoxytryptamine,99 have been successfully used ininterrupted PicteteSpengler reactions. The first total synthesis ofstrychnine reported by Woodward in 1954 also utilized a modifiedPicteteSpengler reaction to access a spiroindolenine scaffold in-termediate (see Scheme 2).3,100 The interrupted PicteteSpengler
reaction with a-amino aldehydes and L-tryptophan methyl ester isalso well known to afford dearomatized afford Nb-hydroxyoctahy-dro-bipyrroloindoles derivatives.101 Following this synthetic ap-proach, D-(þ)-Nb-benzyltryptophan methyl ester and methyl (E)-5-methoxy-3-oxopent-4-enoate, a synthetic equivalent of the corre-sponding unstable aldehyde in presence of methanesulfonic acid,was used by Cook to synthesize the tetracyclic core structure of
several Strychnos alkaloids with high diastereocontrol and yields.102
Similarly, an example of interrupted PicteteSpengler via iminiumion trapping by an alcohol was reported by T€oke.103 Delgado andBlakey developed a methodology to generate b,g-unsaturatediminium ion (from sensitive b,g-unsaturated aldehyde) in situ,which underwent polycyclization to deliver some tetracyclic alka-loidic skeleton and the structural core of the malagashaninealkaloids.104
One of the most impressive example of interrupted Pictete-Spengler was reported by Corey for the total synthesis of aspido-phytine, a natural product isolated from Haplophyton cimicidum(Scheme 37). To synthesize this structurally daunting molecule, thestrategy from Corey entailed a double condensation/PicteteSpen-gler/allylation/isomerization/reduction sequence of tryptaminederivative 246 and chiral di-aldehyde 247, which provided thecomplex core 251 in 66% overall yield (Scheme 37).105 It is note-worthy that, the stereochemistry outcome of the 251 is controlledat the PicteteSpengler reaction stage from the remote quaternarycenter stereo-information.
Pandey and Kumara also disclosed a related and very impressivedomino reaction for the synthesis of pentacyclic Aspidosperma al-kaloid (þ)-vincadifformine in which the resulting iminium speciefrom the interrupted PicteteSpengler was tautomerized to an en-amine to enable the final nucleophilic ring formation.106
Scheme 37.
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A recent example of interrupted and diastereoselective Pic-teteSpengler is presented in the impressive enantioselective totalsynthesis of (�)-phalarine (257) designed and executed by Dani-shefsky and co-workers (Scheme 38).107 In the key cyclization, the2-substituted-L-tryptophan derivative 252 reacts smoothly withformaldehyde in the presence of camphorsulfonic acid (CSA) givingrise to the core structure 256 in 91% yield. Danishefsky conducteda diastereoselective PicteteSpengler reaction using the enantio-pure tryptophan derivative 252 and a dearomatization of thecommon iminium 253 either at C2 or C3 (via intermediates 254 or255, respectively) to afford pentacycle 256 as a single diastereomerin 91% yield. Both pathways via the iminium 254 or stabilizedcarbocation 255 are plausible and provide a good handle for chi-rality transfer at both the C2 and C3 positions during the dear-omatization step. The total synthesis of (�)-phalarine (257) wasfurther completed with reductive decarboxylation and installationof the tryptamine portion via the Gassman oxindole synthesis.
Scheme 38.
Related to the interrupted PicteteSpengler tactics, multicom-ponent aza-FriedeleCrafts like reactions have been reported. Forexample, a sequence of condensation/aza-FriedeleCrafts/aza-DielseAlder between unprotected indoles, ethyl glyoxylate, andanilines in the presence of scandium triflate was reported to ef-ficiently synthesize tetrahydro-5H-indolo[3,2-c]quinolones in onestep.108 As shown in Scheme 39, the indole dearomatization of
Scheme
the hapalindole isothiocyanate D natural product (258) was alsoproposed to proceed through an aza-FriedeleCrafts like re-action.109 When treated with ethanolic hydrochloric acid, iso-thiocyanate D (258) provided a mixture of tetracyclic indoline g-thiolactams 260e262 in reasonable yields. The authors believethat in this case, the reaction is initiated by the isopropenyl groupaddition to the C2 position of the indole, followed by the trans-addition of the isothiocyanate electrophilic fragment. Finally, ei-ther elimination occurred or water added to the tertiary-carbocation intermediate 259 yielding a mixture of products260e262.
Recently, Matsuo developed a new strategy for the preparationof hydrocarbazoles 265 (Scheme 40).110 Conceptually, cyclo-butanones in the presence of a Lewis acid led to the correspondingzwitterionic dipole intermediates, which could subsequently reactwith indoles to provide the hydrocarbazoles through a formal[4þ2]-cycloaddition.
The authors applied this new method to the total synthesis of(�)-aspidospermidine (266). In the key intramolecular step,Me3SiOTf triggered first the cyclobutane ring opening in a retro-Mannich like fashion, thus creating the reactive acyl-iminium in-termediate 264, which endured the attack of the indole througha aza-FriedeleCrafts reaction and the final silylenolether cycliza-tion to give rise to the pentacyclic compound 265 in 46% yield.
39.
Scheme 40.
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In 2010, Floreancig devised a strategy for the construction ofquaternary carbon center of spirooxindole amides 269 (Scheme41).111 Indolyl cyanohydrin ether substrate 267 was first synthe-sized from readily accessible indoles by chlorination with NCS.Treatment of 267 with the Schwartz’s reagent [Cp2Zr(H)Cl] fol-lowed by addition of acid chlorides provided the acylimine 268 insitu, which after addition at the C3 position of the indole and hy-drolysis of the fragile chloroiminium ion intermediate provideda mixture of spiro-oxindoles stereoisomers 269a and 269b in 73%and 10% yields, respectively.
Scheme 41.
Another efficient and elegant access to tetrahydro-5H-indolo[3,2-c]quinoline heterocycles from benzyl azides and protectedindoles in the presence of triflic acid was reported in 2011 (Scheme42).112 It is noteworthy that theN-tosyl group is optimal to facilitatethe formal [4þ2]-cycloaddition. The mechanism proposed by theauthors started with the decomposition of the benzyl azide 272through a protonation and a rearrangement delivering the iminiumion 273 and releasing molecular nitrogen. The first aza-Friedel-Crafts reaction (intermolecular) occurred between the indole andthe iminium 273 followed by a second aza-FriedeleCrafts reaction(intramolecular) to generate the corresponding annulated tetra-hydro-5H-indolo[3,2-c]quinoline scaffold 274 and 275. It isnoteworthy that depending on the substitution pattern from thestarting indole, different skeletal isomers can be obtained.
Scheme 42.
5.3. Interrupted BischlereNapieralski reaction
In 1893, Bischler and Napieralski reported a newmethod for thesynthesis of isoquinolines.113 This type of FriedeleCrafts acylationreaction on electrophilic reactive imidates has been exploit onmany indolic substrates and is amenable to indole dearomatization
and cascade reactions due to the higher oxidation state of the re-active intermediate involved.
During the racemic synthesis by Magnus of the pentacyclicskeleton of Kopsia alkaloids, a cascade reaction involving a Bis-chlereNapieralski-like transformation was developed (Scheme43). Treatment of the elaborated carbamate 276 with triflicanhydride enabled a BischlereNapieralski to be achieved leadingto the final iminium 282 providing after quenching(with aqueous NaHCO3 or trimethylsilyl cyanide), the tetracyclicindoline dienes 283.114 Further transformations of the
common core structure 283 led to the synthesis of numerousalkaloids: (�)-pauciflorine B, (�)-lahadinine B, (�)-kopsidasine,(�)-kopsidasine-N-oxide, (�)-kopsijasminilam, (�)-11-methoxykopsilongine, and (�)-11,12-demethoxylahadinine B.
In 2012, Movassaghi and Medley designed and executed a bio-mimetic inspired synthesis of the monomeric alkaloid (�)-N-methylaspidospermidine (289) and its dimeric form as (þ)-didee-poxytabernaebovine (290) from the common precursor 286, ob-tained through an interrupted BischlereNapieralski reaction(Scheme 44).115 In this cascade of events, iminium 285 was pre-sumably trapped by an ene-type addition of the pendant alkene,which after elimination of the chloroaminal intermediate releasedthe common and presumably highly reactive di-iminiumspecie 286.
5.4. Oxidative cross-coupling
Within a few decades, dearomatizing oxidative coupling of in-doles has emerged as a powerful methodology for the synthesis ofpolycyclic skeletons and complex natural products.68,116 Generally,the C3 position of an indole anion and a tethered enolate reacts in
Scheme 43.
Scheme 44.
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the presence of an oxidant leading to radical cyclization to affordand indolenine intermediate, which can endure a second cycliza-tion in the presence of an internal nucleophile.
In 2010, Ma reported an asymmetric total synthesis of(�)-communesin F (295) (Scheme 45).117 The indole precursor 291(prepared in three steps in 63% yield) was first deprotonated withlithium hexamethyldisilazide (LiHMDS) at low temperature togenerate the required dianion 292. Upon addition of iodine, the keyoxidative cross-coupling reaction was achieved and spi-roindolenine 294 was delivered. The nitro group was subsequentlyreduced and selectively methylated leading to the correct di-astereomer, which was further transformed to (�)-communesin F(295) in a total of 13 steps.
Scheme 45.
A year later, the same group published enantioselective totalsyntheses of communesin A (296) and B (110) using the same strat-egy (Scheme 46).118 In this case the chirality from the azepine pre-cursor induced a higher stereoselectivity (due to steric hindrance)
during the oxidative coupling of the diradical intermediate 297, thusproviding the annulated product as a single diastereomer.
In 2012, Ma and Xie developed a general procedure usingLiHMDS and iodine as oxidizing agents to prepare polycyclic spi-roindolines 299 and polycyclic pyrroloindolines 301 (Scheme47).119 These polycyclic skeletons were, respectively, synthesizedfrom the corresponding b-ketoamides 298 and malonic diamides300 via a domino intramolecular oxidative coupling/condensationwith yields ranging from 20 to 87%. In both cases, the substitutionpattern on the indole ring (R1 group) did not affect the reactivityduring the polycyclization.
During the enantioselective total synthesis endeavor towards(�)-vincorine (305), the indole derivative 302 was cyclized by
employing intramolecular oxidative coupling conditions (Scheme48).120 Following the deprotonation step with LiHMDS, oxidativeenvironment afforded the annulated product 304 as a singleisomer with 67% yield. The later intermediate 304 led to an
Scheme 46.
Scheme 47.
Scheme 48.
Scheme 49.
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efficient synthesis of the (�)-vincorine (305) with an overall 5%yield.
5.5. Radical cyclization
At the beginning of the 19th century, Gomberg generated andcharacterized the first example of free radical. Since then, carbon-centered radicals have been used in many reactions and specifi-cally for indole dearomatizations. In 2007, Stevens and co-workersreported a straightforward synthesis of racemic benzospiro-indo-lizidinepyrrolidinones.121 The key reaction sequence of this workwas accomplished by a copper(I) chloride/tetramethyl ethylenediamine catalyzed atom transfer radical cyclization (ATRC) viaa domino reaction involving a 5-exo-trig, followed by a 6-endo-trigcyclization and represents a clear example of radical-mediatedcascade reaction.
Another radical-mediated transformation was achieved byReissig though an extremely efficient and highly diastereoselectiveintramolecular indole dearomatization by addition of a ketyl radicalspecie to the indole nucleus (Scheme 49).122 Under the action ofsamarium diiodide, indole substrates such as 306 (N-alkylated orN-acylated indoles) generate a samarium ketyl intermediate 307,which adds to the activated aromatic system through a six-mem-bered ring chair-like transition state. It is noteworthy that conver-sions of 3-methoxycarbonyl-substituted indole derivatives to thecorresponding polycyclic products can also be accomplishedwithout use of hexamethylphosphoramide (HMPA). The authorsalso demonstrated that the samarium enolates intermediate can betrapped with alkyl halides in an inter- or intra-molecular fashion.The Reissig group showcased their methodology in a racemic for-mal total synthesis of strychnine (Scheme 47).123
The synthesis begins with N-acylation of 3-indolylacetonitrilewith 4-oxopimelic acid monoester to yield the indole unit 306 in64% yield. A subsequent domino cyclization of 306 in the presenceof samarium diiodide and HMPA yields the tetracyclic core 309 in70e75% yield as the major product and as a single diastereomer.The tetracyclic acylated-indoline intermediate 306 was then fur-ther transformed to the known Rawal intermediate 309 to com-plete the formal total synthesis.
In 2001, Jones reported a route to Aspidosperma and Strychnosalkaloids core based on translocation-cyclizationecyclization ofaryl radical.124 In this case, an aryl radical undergoes a 1,5-hydrogenatom transfer to generate a nucleophilic amido radical triggeringtwo successive radical cyclizations leading to complex tetracyclicindoline structures.125
In 2004, Baldwin also reported the preparation of spiroindolinesby an intramolecular radical ipso-type cyclization.126 The
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dearomatizing spirocyclizations with aryl radicals (high energy)afford the corresponding spirocycles in good yield.
Nicolaou’s total synthesis of aspidophytine also illustrated theefficacy of radical to dearomatize the indole nucleus (Scheme50).127 In this reaction, the xanthate substrate 310 was heated inbenzene in the presence of n-Bu3SnH and AIBN to generate thereactive primary radical 311, which enderwent spirocyclization toafford the pentacyclic indoline 312 as a single diastereomer in 58%yield (allyl regioisomers in 16% yield). The pivotal intermediate 312was subsequently transformed in a single pot to the aspidophytine(313) natural product in 63% yield.
Scheme 50.
Takayama and co-workers reported a chemoselective synthesisof a pentacyclic skeleton containing a 1-aza-tricyclo[5.3.0.0]decanecore wherein they utilized a domino radical cyclization (Scheme51).128 Treatment of the b-carboline derivative 314 in the presenceof Et3B and n-Bu3SnH generated the vinylic carbon-centered radical315, which attacked the indole via a 5-exo-trig cyclization (onto C2position), before collapsing onto the Michael acceptor pendant ina second 5-exo-trig manner to obtain the complex indoline archi-tecture 316 in 72% yield (cis and trans mixture). Interestingly, whenother b-carboline derivatives (without ester moiety) were used asstarting material,129 a mixture of products were isolated (the octa-hydroquinolizine derivatives and the pentacyclic-bridged com-pounds), depending on the generation radicals method used. Theauthors believe that in the case of the b-carboline derivatives 314,a strong steric repulsion in the transition state between the tert-butoxycarbonyl and theNb-allyl groups is unfavorable thus avoidingthe formation of the octahydroquinolizine by-product.
Scheme 51.
Lastly, El Kaim, Grimaud, and Miranda reported a spectacularone pot synthesis of spiroindolines combining a multicomponentUgi reaction followed by an in situ copper(II) triggered oxidativecoupling as depicted in Scheme 52.130 The authors described thatthe key indole dearomatization of the Ugi adduct 317 undergoes anoxidation initiated by copper, leading to the corresponding peptidylradical 319, which cyclized at the C3 position of the indole. Thegenerated a-amido radical 320 oxidized spontaneously to the cor-responding iminium 321, which subsequently suffered cyclizationto the spiroindoline 322 in 43e78% yield (one pot process).
5.6. Carbon-centered electrophiles for dearomatization
hybridized carbons as electrophile are related to synthetic studiesor total synthesis of natural products and are found in studies ofStrychnos and Aspidosperma alkaloids. Thus we chose the naturalproduct aspidospermidine (266) as a case study to simplify thepresentation of this rich literature. The four main alkyative dear-omatizing strategies are described in this section: Harley-Masson/Kaplan, Heathcock/Toczko, Magnus/Gallagher, and Rubiralta(Scheme 53). However there are a number of strategies in addition,which we will also consider.
In the Harley-Masson and Kaplan strategy, the cyclization of theadvanced alcohol precursor was accomplished in acidic conditions,
probably through a carbocation, followed by a ring rearrangement,and subsequent reduction of the amide afforded aspidospermidine(266).131
Magnus and Gallagher’s strategy is based on the constructionof the pyrrolidine ring by an intramolecular alkylation at the C3position of the indole via a thionium ion (Pummerer reaction)followed by heating. Subsequent reduction of the thioether andthe amide completed the synthesis of aspidospermidine.132
Langlois also successfully applied this alkylation, and rear-rangement induced by the Pummerer reaction for the totalsynthesis of other Aspidosperma alkaloids vindorosine andvindoline.133
Heathcock and Toczko constructed the pyrrolidine ring froma chloroacetate through a Finkelstein reaction, in the presence ofsodium iodide, followed by a silver triflate assisted dearomatizationand final reduction of the amide to afford the aspidospermidine(266).134
Finally, Rubiralta and co-workers reported the construction ofthe pyrrolidine by an alkylative annulation.135 In this single stepprocedure, the primary alcohol was converted in situ by generatinga tosylate leaving group triggering the concomitant alkylativedearomatization of the indole moiety.
Recently, Fukuyama reported a stereoselective synthetic routeto the core skeleton of chartelline C (321) following the Heathcockand Toczko’ strategy described above (Scheme 54).136 In this syn-thesis, an intramolecular alkylative dearomatization of indole 323was used for the construction of the b-lactam fragment leading tothe isolation of indolenine 324 in good yield.
Activation of the primary allylic alcohol 326 (related to theRubiralta’ strategy) to trigger indolic dearomatization under actionof base was first reported by Magnus under well-established Mit-sunobu conditions en route to (þ)-koumine (328) (Scheme 55).137
Scheme 52.
Scheme 53.
Scheme 54.
Scheme 55.
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In 2002, the Rawal disclosed the synthesis of (þ)-aspido-spermidine (266) through an intramolecular two-step procedureinvolving the activation of the primary alcohol with meth-anesulfonyl chloride following by the alkylative dearomatization inthe presence of potassium tert-butoxide (related to the Rubiralta’strategy, Scheme 53).138 This alkylative strategy was reutilizedseveral years later by Bach for a synthesis of
(�)-aspidospermidine.139 In 2012, Smith applied the same exactprocess to the synthesis of (þ)-scholarisine A (332) (Scheme 56).140
In this synthesis, the pendant alcohol from indole 329 was acti-vated as a mesylate leaving group to trigger cyclization upon actionof BTPP leading to the cage product 331.
In 2010, Andrade executed a sequential, one-pot, alkylation/intramolecular aza-BayliseHillman (or an alternate intramolecularvinylogous Mannich/olefin isomerization cascade).141 Soon after,the same authors published the asymmetric total syntheses ofStrychnos alkaloids (�)-leuconicines A and B, highlighted by thesame strategy to build the tetracyclic indolenine framework 335(Scheme 57).142
The key precursor 333 (prepared in six steps) was treated withAgOTf and a hindered base 2,6-di-tert-butyl-4-methylpyridine(DTBMP) followed by another base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the double annulated compound 335 asa single stereoisomer in 60% yield. Further synthetic steps wereaccomplished to access both (�)-leuconicines A and B in 9 and 10%
overall yields, respectively. Recently, this methodology was alsoapplied to the total synthesis of (�)-melotenine A, which showedpotent cytotoxic activity against several cancer cell lines.143
The exceptional nucleophilicity of 2-thioindole was exploitedduring the total synthesis of (�)-dehaloperophoramidine (339)designed by Rainier (Scheme 58).144 Once again, an advanced al-cohol precursor 336 was reacted through a sequential one-potprocess involving first the activation of the secondary alcohol asa mesylate, followed by an in situ intramolecular alkylation andcyclization in the presence of DBU to afford the polycyclic indole-nine 338 in 79% yield.
Finally, Sakai described the semi-synthesis of Gelsemium-typealkaloids (342) through a transannular SN20 cyclization betweenthe C3 position of the indole moiety and allylic acetate from pre-cursor 340 (Scheme 59).145 In the presence of palladium(0) andsodium hydride the deprotonated indole as shown in the proposedassembly 341 may intramolecularly attack the palladated p-allyl
Scheme 56.
Scheme 57.
Scheme 58.
Scheme 59.
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moiety to give indolenine 342 in 54% yield. The later was thenconverted in two steps to provide 11-methoxykoumine.
The Kobayashi group reported a completely different activationof sp3-hybridized carbon electrophiles, which is an efficient andhighly diastereoselective method for the synthesis of 3-spiro-2-oxindole compounds such as 345 from 2-substituted haloindoles343 (Scheme 60).146 This domino reaction proceeds through anintramolecular copper-mediated Ullmann coupling, followed bya Claisen rearrangement of the cyclic intermediate 344.
Scheme 60.
Historically, strong and nucleophilic bases such as Grignard re-agents or sodium amide (NaNH2) were used to generate theambident indoyl anion before the addition of the alkylating re-agent.147 Nevertheless, this synthetic process is limited in terms of
functionality, tolerance, and regioselectivity, thus decreasing thesynthetic utility of this transformation.148 A number of other elec-trophiles such as 1,2-dibromoethane,149 1,1-cyclopropane die-sters,21a ethyl 2-nitrosoacrylate,150 CoreyeKim reagent151 oractivated aziridine152 have been successfully used for this bio-mimetic dearomatization of 3-substituted and 2,3-substituted in-doles. Furthermore, magnesium nitrate hexahydrate153 and zinctriflate154 have also demonstrated their potency to promote thisalkylative dearomatizing process.
More recently, different metal-catalyzed indole dearomatiza-tions tactics have emerged. Work by Tamaru has shown the feasi-bility of C3 selective palladium-catalyzed allylation of unprotected3-substituted indoles with allylic alcohols in the presence of
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913574
triethylborane.155 Rawal also developed two general methods forracemic allylation and benzylation of 3-substituted and 2,3-disubstituted indoles.156,157 This palladium-catalyzed reaction al-lows the transformation of such substrates (3-substituted and 2,3-disubstituted indoles) using allyl or benzyl carbonates into thecorresponding 3-alkylindolenine in good to high yields. While tri-furylphosphine is the best ligand for the allylation, benzylationreaction proceeds more efficiently in the presence of DPEphos li-gand. The Rawal allylation methodology has recently been appliedin the total synthesis of (�)-minfiensine.158 Recently, the samegroup demonstrated that N-alloc and N-Cbz 3-substituted indolesare excellent substrates for palladium-catalyzed decarboxylativeallylation to produce corresponding C3-allyl and C3-benzylindolenines.159
In 2006, Trost and Quancard were the first to apply an in-termolecular enantioselective allylic alkylation using various allylalcohols 347 as the electrophile with unprotected 3-substitutedindoles 346 in the presence of 9-BBN-C6H13, as the promoter anda chiral ligand 349 (Scheme 61).160 In the cases of 3-substitutedindole bearing a pendant nucleophile such as alcohol, phenol,carbamate, and malonate, indoline with cis-5,5- or 5,6-fused ringswere obtained, nicely underscoring the high level of chemo-selectivity of this reaction.
Scheme 61.
Similarly, You accomplished an iridium-catalyzed asymmetricintramolecular allylic alkylation reaction of unprotected 3-substituted indoles 350 (derived from tryptamine), in presence ofligand 353 to provide spiroindolenines 352 in good yields with highdiastereo- and enantioselectivity (Scheme 62).161 The same authorsfurther extended this reaction to carbon-tethered substrate, whichled to spiro cyclopentane-1,30-indoles after the reduction withNaBH3CN.162 Recently, the You group also reported palladium163
and ruthenium164 mediated enantioselective intramolecular syn-theses of fused spiroindolenines from substituted-indolyl allyliccarbonates.
Scheme 62.
5.6.2. sp2 Hybridized carbon-centered electrophiles. The innate re-activity of indoles allows them to undergo addition to activated p-systems, in both inter- and intramolecular fashions. In this context3-substituted indoles are substrates of choice to react with Michaelacceptors due to the stability of the resulting imino-spiroindoles,furthermore, this functionality can be trapped in the presence ofinternal or external nucleophiles.
In 1971, B€uchi reported the total synthesis of racemic vindor-osine (68), a pentacyclic Aspidosperma alkaloid (Scheme 63).165 Asmentioned above, the pivotal step of this synthesis is an intra-molecular domino MichaeleMannich mediated by the action of
boron trifluoride, which delivers the desired indoline 356 in a sin-gle step and 38% yield.
Since this B€uchi group’s disclosure of the tandem dearomatizingdomino MichaeleMannich transformation, this strategy has beenmodified for the total of many other Aspidosperma and Strychnosalkaloids. The most recent modifications in this strategy involvedthe replacement of boron trifluoride etherate with titanium tetra-chloride.166 Others main modifications are anionic poly-cyclization41b,48 and sequential Michael additions assisted by silicagel followed by the potassium tert-butoxide mediated Mannichcyclization.41c,167 An intermolecular cascade dearomatization be-tween N-substituted tryptophols and 3-acryloyloxazolidin-2-one,in the presence of Lewis acid, has also been recently reported byYou.168 Among the Lewis acid tested in this particular case, scan-dium triflate (Sc(OTf)3) proved to be best suited for the cascadereaction.
Similar cascades can be achieved using dehydro-a-amino estersas Michael acceptors. In 2010, Piersanti described a simple syn-thetic method to access hexahydropyrrolo[2,3-b]indole structures(HPI). This domino MichaeleMannich transformation involves 3-substituted indoles and N-acetamidoacrylate (dehydro-a-aminoesters derivative) in the presence of stoichiometric amount of zir-conium chloride.169 It should be noted that NeH and N-alkylindoles
are fine substrates for this reaction and that the authors were ableto achieve the racemic total synthesis of the esermethole naturalproduct using this methodology. Later, the Reisman group reportedthe first enantioselective variant of this reaction with the synthesisof chiral HPI molecules 361 from 1,3-disubstituted indoles 357 andbenzyl 2-trifluoroacetamidoacrylate 358 in the presence of tinLewis acid catalyst with (R)-BINOL$ligands (Scheme 64).170 Thisstepwise formal [3þ2]-cycloaddition process started by a Michaelconjugate addition between the indole derivative 357 and theLewis acid activated 2-amidoacrylate 358 leading to the electro-philic iminium salt 359. Subsequent asymmetric protonation under
catalyst-control delivered iminium 360, which was trapped by theproximate amide moiety to provide HPIs 361 in good yields withmoderate exo/endo diastereoselectivities and highenantioselectivity.
Another approach to domino processes was disclosed by Mac-Millan in 2004, highlighting an efficient enantioselective organo-catalytic methodology toward pyrroloindoline and furanoindolinederivatives (Scheme 65).171 The reversible condensation of theorganocatalyst with and a,b-unsaturated aldehyde 362 providedthe required iminium ion 363 (energy lowering effect of LUMO p*),enabling the addition of tryptamines or tryptols derivatives to
Scheme 63.
Scheme 64.
Scheme 65.
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furnish the indolenium 364 in an enantioselective fashion. A 5-exo-heterocyclization of the latter ion 364 and subsequent hydrolysisprovide pyrroloindoline and furanoindoline derivatives with ex-cellent yield, enantio- and diastereoselectivity (in the case of b-substituents). This elegant organocatalytic cascade addition/cycli-zation cascade was successfully applied to the synthesis of(�)-flustramine B (366) and debromoflustramine B.
5.6.3. sp Hybridized carbon-centered electrophiles. Alkynes andisonitriles have been successfully used in indole dearomatizationprocesses, but some of the postulated mechanisms still remainambiguous and could be depicted in the following section asstepwise or concerted.
For example, Barluenga reported a proposed stepwise annula-tion of polysubstituted indole 367with the alkynyl Fischer carbeneof tungsten 368 (Scheme 66, Eq. 1).172 Upon indole attack to the
Scheme
alkynyl fragment and further cyclization of the allenyl-tugnstenderivative 369, the menthol-derived chiral auxiliary was simulta-neously extruded to deliver the tricyclic indolinone 371 in goodyields and high enantioselectivity (up to 99% ee). Another in-teresting reaction for which the mechanism remains unclear ispresented in Scheme 66 (Eq. 2). Wang and Ji reported an efficientconstruction of polycyclic indolines 376 based on an isocyanidemulticomponent type reaction.173 Mixing the three componentsisonitrile 372, malonodinitrile 373 and aldehyde 374 may result ina Knoevenagel condensation forming alkylidenemalonodinitrile,which upon addition of the isonitrile 372 should produce the 1,3-dipole intermediate 375. Through either a stepwise or concertedmechanism, the indolic moiety will attack the nitrilium electro-phile, therefore triggering the final annulation step via the malo-nodinitrile anion collapse to form the polycyclic indoline 376 inhigh yields.
66.
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Mainly electrophilic transition-metal complexes with the abilityto behave as soft Lewis acid may activate unsaturated functional-ities such as alkynes and others, thus enabling the creation of newcarbonecarbon and carboneheteroatom bonds under mild condi-tions. Zhang disclosed a divergent indole dearomatization cata-lyzed by different metals.174 The reaction of the substrate 377 in thepresence of cationic Au(I) or PtCl2 provides, respectively, 2,3-indoline-fused cyclobutanes 382 or 2,3-indoline-fused cyclo-pentenes 383 in good yields depending on themetal engaged in thereaction. A plausible and divergent reaction pathway is outlined inScheme 67.
Scheme 67.
Initial complexation of the metal (Au(I) or PtCl2) to alkyne 378leads to a 3,3-rearrangement into the allene intermediate 379.Subsequent activation of the allene functionality with the samemetal generates to oxocarbenium specie 380, which upon nucleo-philic addition of the indole (at the C3 position) affords the reactivespiro-intermediate 381. At this stage, the alkenylgold(I) traps theiminium to deliver 382, whereas the alkenylplatinum(II) derivativecyclizes in a vinylogous manner to the cyclopentene 383 after b-hydride elimination of the platinum catalyst. The authors proposedthat the divergent regioselectivities of the two catalysts in-trinsically originates from their different metaleligand in-teractions. In PtCl2, the strong p-electron-donating chlorine ligandsinduce the intramolecular nucleophilic addition to give the [3þ2]cycloisomerization products. While in AuCl(PPh3)/AgSbF6, thestrong s-electron-donating phosphine ligand results in an intra-molecular nucleophilic addition reaction to form the [2þ2] cyclo-isomerization products. Another example of indoledearomatization via alkyne electrophilic activation (sp hybridiza-tion)175 really demonstrates that enantioselective transformationscan be implemented on indolic substrates (Scheme 68). Specifically,the alkenylation was followed by an intramolecular cyclizationleading to tetracyclic indolines 385 or 386 in a cascade of eventsfrom a variety of NeH protected or unprotected alkynylindoles 384.This transformations are mediated by gold(I) in a chiral manner.176
In this double annulative process reported by Bandini, the activa-tion of the alkyne moiety by Au(I) facilitated a FriedeleCraftsalkenylation (endo or exo) followed by the iminium trapping by thependant alcohol nucleophile, providing tetracyclic indolines 385 or386, in good yields and up to 87% ee.
Scheme
Finally, an approach to enantioselective dearomatizationthrough alkyne activation was reported by MacMillan during thetotal synthesis campaign towards diazonamideA (185) (Scheme69).
In this endeavor, the C-10 quaternary center of the central fur-anoindoline core was formed by employing an iminium-catalyzedalkylationecyclization cascade of the highly elaborated and func-tionalized compound 387 with propynal.177 This astonishing re-action was performed with a small organic molecule as catalystaffording the desired tetracyclic indoline 388 in 86% yield with anextremely high diastereocontrol (20:1 dr). After several steps, in-termediate 388 was transformed into the diazonamide A (185) to
conclude the most efficient synthesis of this natural product re-ported to date.
6. Heteroatomic oxidative dearomatization
6.1. Electrophilic heteroatoms
6.1.1. Selenium electrophile. As an element, selenium is rarelypresent in any natural product (except for selenoproteins), but asa reagent, N-phenylselenophthalimide (N-PSP)178 proved to be anextremely useful source of electrophilic selenium for indole dear-omatizations.81b,179 The early developments of N-PSP in indoledearomatization are attributed to Danishefsky, who intenselystudied the facial selectivity occurring during the dearomatizationof tryptophan derivatives 389 (Scheme 70).180 From these studies,Danishefsky was pleased to observe that the formation of onemajor stereoisomer was favored; which was attributed to a prefer-ential pre-endo-394a versus pre-exo-394b ensemble (the exo no-tation refers to syn-relationship between the methyl ester andphenylseleno moiety). In the endo pre-transition state assembly394a, the authors proposed that a steric clash between the methylester and the indole core may occur (see also Section 2.2), thereforeexplaining the more favorable attack of the nitrogen from thebackside of the exo-isomer leading to the HPI 390 as the majordiastereomer. Noteworthy, the indole requires being N-protected toperform the dearomatization, since it was proved that a free indolewould not react with the N-PSP reagent.179a
Danishefsky also developed the prenylation reaction of seleno-HPI 390 to access the C3-prenylated product 391 and achieve the
68.
Scheme 69.
Scheme 70.
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synthesis of the natural products 5-N-acetylardeemin and amaur-omine. In a separate report, Ley substituted the phenylselenomoiety of HPI 390 by an oxygen atom by usingm-CPBA181 to obtain392 while De Lera performed a photochemical dimerization of HPI390 to obtain the core of the chimonanthine natural product pre-cursor 393 as a single diastereomer.182
6.1.2. Sulfur electrophile. Dearomatization examples involvinga sulfur atom as an electrophile remain scarce in the current
Scheme
dearomatization literature and only a few sources of electrophilicsulfur reagents have been studied.183 A trifluoromethanesulfomylation of tryptamines has been developed by Qing (Scheme71, Eq. 1),184 to synthesize the corresponding tri-fluoromethanesulfomylated HPI building block 396 in 96% yield.Interestingly, (þ)-CSA was successfully used as additive in the re-action, but did not induce any noticeable stereoselectivity (dr<5%).Also, the intramolecular sulfur promoted dearomatization exem-plifies a second pathway for inserting a sulfur atom at the indolic C3
71.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913578
position (Scheme 71, Eq. 2). This can be achieved by means ofa methyl carbamodithioate, as Kutschy proposed during the prep-aration of spirobrassinin analogs.185 The methyl carbamodithioatesubstrate 398 is therefore activated by elementary bromine,forming the reactive intermediate 399, which triggers the ensuingdearomatization to form indolenium 400, which is finallyquenched by water to afford the 4,5-dihydrothiazole skeleton 401,characteristic of the spirobrassinin core, in 63% yield and an 82:18diastereomeric ratio. A similar transformationwas also proposed byPedras, for the synthesis of the natural product erucalexin.186
6.1.3. Nitrogen electrophile. In the field of indole dearomatizationsnitrogen atoms often react as nucleophiles, mostly to trap indole-nium reaction intermediates on the indolic C2 position after thedearomatization step. On the other end, the challenging insertionof a nitrogen atom on the indolic C3 position requires an electro-philic nitrogen atom. To achieve this nitrogen insertion, Padwarecently reported the use of some hypervalent iodine reagents(Scheme 72, Eq. 1).187 The first step is the formation of an imi-noiodinane intermediate 403 (nitrene) followed by a loss of iodo-benzene, catalyzed by the Rh(II) metal insertion, to give themetallonitrene 404.
Scheme 72.
The intramolecular dearomatization occurs onto the electro-philic nitrogen to form intermediate 405, followed by the attack ofan acetate nucleophile at the C2 position. This attack is only takingplace from the same face of the amide anion, due to the internaldeprotonation of the nucleophile, affording the syn-disubstitutedindoline 407 as a single diastereomer in 85% yield. Recently,a similar enabling method using rhodiumwas described by Xu.188 Asimilar method has been successfully used by Iwabuchi (Scheme72, Eq. 2).189 Iwabuchi described the dearomatization of anindolic carbamate 408 in which the presence of deuterium sub-stituents is crucial to confer robustness onto the methylene posi-tion that supports the acyl nitrenoidmoiety complexed to rhodium.Since the deprotonation and nucleophilic attack are oriented by thecarbenoid intermediate, chiral ligands on the rhodium are requiredto obtain enantiodiscrimination in the first step of the process.
Overall, the resulting indolenine 409was obtained in 70% yield and96% ee. A diastereoselective example of this reaction with hyper-valent iodine was reported by Ciufolini (Scheme 72, Eq. 3).190 Theauthors performed a dearomative double annulation of the tryp-tophane derivative 410 leading to two diastereomers (1:1 di-astereomeric ratio) of the morpholinoindoline 412 in 42% yield.
An alternative to hypervalent iodine and rhodium was de-veloped by Baran for the synthesis of the kapakahine F naturalproduct (417) (Scheme 73).205 Facing the difficulty of forming the a-carbolinone moiety required in the kapakahine core structure,Baran reported a novel type of nitrogen electrophiles generatedfrom anilines. For that purpose, o-iodoaniline and N-iodosuccini-mide were mixed to generate the electrophilic nitrogen specie. Themechanistic considerations stemming from the authors’ and theextensive studies suggest that two intermediates 414a and 414bmay reasonably be involved for the dearomatization to occur. In-deed, 414a and 414b arising from either C3-activation of the indoleor aziridinium formation, respectively, afford plausible explana-tions for the observed dearomatization. After ring closure of theindolenium 415, the C3-aniline-derived HPI 416 was obtained in78% yield as a single diastereomer. This innovative method allowsfor the nitrogen electrophilic fragment to be inserted in one single
operation and offers new opportunities for complex indole alka-loids syntheses.
6.1.4. Oxygen electrophile. Due to a substantial amount of naturalproducts bearing an oxygen atom at the C3 position of indolenineor indoline substructures, numerousmethods have been developedto achieve the oxygen promoted dearomatization of indoles. Whenan enantiopure dearomatized compound is desired, either a chiralsource of oxygen can be engaged onto an achiral indolic substrateor a diastereoselective dearomatization of tryptophan derivativescan be easily accomplished. Examples of both synthetic tactics willbe presented in the next two sections.
6.1.4.1. Dearomatization of achiral indolic substrates. For thesynthesis of the (�)-trigonoliimines AeC, Movassaghi
Scheme 73.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3579
accomplished the dearomatization of bistryptamine 418, by meansof 2 equiv of a camphor-derived Davis’ oxaziridine (Scheme 74, Eq.1).191 As a result, the two hydroxyindolenines regioisomers 419aand 419b were obtained in excellent yields and with high enan-tioselectivity (96% ee). Preparing the pair of hydroxyindoleninesregioisomers 419a and 419b, was part of Movassaghi’ strategy,which implied to carry the two isomers abreast to the penultimatestep to achieve in parallel both syntheses of the trigonoliimines Aand B. Later on, Movassaghi and Miller developed together a pow-erful catalytic enantioselective oxidation of tryptamines as shownfrom compound 420 (Scheme 74, Eq. 2).192 Pentapeptide 421bearing an aspartic acid residue was utilized as chiral catalyst inconjunction with hydrogen peroxide to catalytically form an
Scheme
aspartic peracid residue in situ (chiral alternative to m-CPBA),which will operate the required asymmetric oxidation and deliverthe C3-hydroxyindolenine 422 in 57% yield and 88% ee. Numerousexamples were reported for the scope of this method in which theenantiodiscrimination reached up to 90% ee.
In 2007, Martin has developed a concise approach to the spi-rocyclic ring system of citrinadin A, by an enantioselective oxidativerearrangement of the tetrahydrocarbazole 423, employing the Shiasymmetric epoxidation (Scheme 74, Eq. 3).193 While none of theoxaziridines tested were able to promote the epoxidation, the Shi’catalysts proved to be efficient on this particular substrate. Thus thechiral dioxirane generated from ketone 424 enabled the desiredoxidative dearomatization followed by the scaffold rearrangement
74.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913580
of intermediate 425 to access to the spirocyclic oxindole 426 in 77%yield and 74% ee.194
6.1.4.2. Dearomatization of chiral indolic substrates. During hisstudies on the formation of hydroxyl-HPI,195 Perrin planned todearomatize some tryptophan-alanine dipeptides using dime-thyldioxirane (DMDO), expecting that the chirality of the substratewould induce a facial selectivity (Scheme 75, Eq. 1). Moreover,a bulky trityl group was attached at the dipeptide N-terminus toinduce better diastereocontrol (Danishefsky also exploited succes-sively this strategy for the synthesis of the himastatin).196 Un-fortunately, these two features did not induce the desired selectivityduring the dearomatization, leading to an equimolar mixture of thetwo endo and exo diastereomers isolated in 53% yield.
Scheme 75.
Very interestingly, when the N-methylated tryptophan-alaninedipeptide 427 was engaged in the same reaction conditions, thedesired HPI product 428 was obtained with in good yield and withan outstanding 99:1 diastereomeric ratio (exo/diastereomer beingthe major product). DMDO has also been employed by Martin toperform the dearomatization of the chiral indole derivative 429bearing the (�)-8-phenylmenthol auxiliary (Scheme 75, Eq. 2).193
This substrate was part of a larger study related to the synthesisof citrinadin A (see Scheme 74, Eq. 3) in which Martin evaluatedboth chiral and achiral oxidation strategies. The spirocyclic oxin-dole 431 was obtained in 78% yield and 94:6 diastereomeric ratio(improved stereoselectivity compared to the original
enantioselective reaction with the Shi’ catalyst providing 74% ee,see Scheme 74, Eq. 3). During the total synthesis of isatisine A, thepreparation of the oxindole tetracyclic core 433 (2:1 diastereomericmixture) was achieved by Kerr usingm-CPBA (Scheme 75, Eq. 3).197
The configuration of 433 could not be unambiguously determined,leading the authors to further perform a cascade reaction on thediastereomeric mixture of 433 via indole addition and spontaneouslactamization. Interestingly, product 434 was obtained with anexcellent diastereoselectivity. This result is likely due to the equi-librium at the hemi-aminal center and even at the aminal centerafter the insertion of indole, which under thermodynamic controlfavors the formation of a single tetracyclic diastereomer 434 afterthe final lactamization (99:1 diastereomeric ratio). During his firstsynthesis of the (�)-chaetominine (437), Evano performed the
dearomatization of the a-carbolinone 435 using DMDO (Scheme75, Eq. 4).208b At low temperature, the stereoselectivity duringthe epoxidation was likely dictated by the approach of the dioxir-ane on the opposite face away from the bulkyN-phthalimide group.The epoxide was readily open to form the a-carbolinone 436 withboth excellent yield and diastereomeric excess (94% and 95%, re-spectively). This oxidative strategy inspired Evano to developa second generation synthesis of (�)-chaetominine (437),employing a combination of chlorine and singlet oxygen for thedearomatization to diastereoselectively form the desired corestructure from a tryptophan containing dipeptide in a single op-eration (see Scheme 80).207
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3581
The synthesis of the Okaramine N (440) was achieved throughthe photooxidation of the diindole 438, mediated by the N-meth-yltriazolinedione (Scheme 76).198 In this example, the authors tookadvantage of the N-methyltriazolinedione (MTAD) as a protectinggroup of the free indole, in order to selectively perform the pho-tooxidation on the targeted N-prenylated indole subunit. Thus, thedearomatization of the N-unsubstituted indole by MTAD occursmost rapidly and the ene product on the C3 position is exclusivelyformed. The subsequent photooxidation on the N-tert-prenylatedindole subunit catalyzed by methylene blue was followed by a re-duction with Me2S to afford the hydroxylated HPI 439, with a 1:5diastereomeric ratio. The synthesis of the Okaramine N (440) wasthen completed by the thermolysis of 439 through a retro-ene re-action in 70% yield (brsm).
Scheme 76.
6.1.4.3. Oxygen mediated indole opening. If the precedent ex-amples were dedicated to the development of polycyclic structures,several examples of stronger oxidative conditions are reported todeconstruct indoles by means of the C2eC3 bond breakage leadingto interesting macrocycles. Different sources of oxygen can be usedto achieve this efficient ring opening. For the synthesis of thedaptomycin, Li prepared one of the required building blocks for thetotal synthesis, by opening the N-Fmoc-tryptophan substrate 441via ozonolysis (Scheme 77, Eq. 1).199 While the acid moiety does notneed to be protected for this transformation, better results wereobtained when the indolic nitrogen was protected by a carbamategroup, leading to a quantitative yield of the dicarbonyl compound442. Using m-CPBA, Kozman performed the dearomative openingof the b-carboline 443 through C2eC3 bond full oxidation
Scheme
producing the nine-membered ring macrocycle 444 in 71% yield(Scheme 77, Eq. 2).200 During his attempts to insert an oxygen atomin the C3 position of the indole, Evano also observed the formationof the dicarbonyl by-product using m-CPBA at low temperature inmethylene chloride.207 This efficient reaction also occurred duringthe synthesis of the (�)-21-isopentenylpaxilline reported bySmith,201 in which a dicarbonyl adduct (undesired by-product) wasobtained quantitatively.
Finally, to synthesize the natural product melohenine B (447),Westwood planned to open the pentacyclic b-carboline 445 ina proposed biomimetic fashion to form the targeted nine-memberedring macrocycle 447 in a single step (Eq. 3).202 In fact, melohenine B(447) was obtained in a quantitative manner via a photochemicalreaction induced by singlet oxygen with was produced by visible
light irradiation of methylene blue in presence of oxygen. It is note-worthy, that other oxidations with m-CPBA or by ruthenium-mediated cleavage proved to be unsuccessful in this reaction.
6.2. Halogenation and halocyclization
6.2.1. Iodine electrophile. A unique example of a 3-iodoindoleninewas reported by Fukuyama and Tokuyama, for the synthesis ofthe (þ)-haplophytine (189) (Scheme 78),203 in which the enantio-pure tetrahydro-b-carboline 448 was converted into the C3-iodoindolenine product 449 by treatment with NIS. Further acti-vation of the iodoindolenine 449 by silver triflate in the presence of2,3-dimethoxy-N,N-diallylaniline led smoothly to the formation ofthe desired carbonecarbon bond affording arylated-indolenine 450
77.
Scheme 78.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913582
through a FriedeleCrafts reaction in 61% yield and a 71:29 di-astereomeric ratio.
6.2.2. Chlorine electrophile. Sources of electrophilic halogens aremost widely represented by chlorine in the field of halogen-trig-gered dearomatizations.
As a first example of halocyclization triggered dearomatizationof indoles, we will examine the total synthesis of the naturalproduct flustramine C (454), which is characterized by an indole-nine core substituted by a reversed prenyl group at the C3 position.Bohrer took advantage of a dearomatization process to proposea biomimetic synthesis of flustramine C (454) from the deformyl-flustrabromine (451) (Scheme 79, Eq. 1).204 tert-Butyl hypochlorite
Scheme
under basic conditions was used to form the desired indolenine 452leading to a collapse of the secondary amine to generate the aza-quinone methide 453, which further initiated a 1,2-shift of theprenylated side chain onto the C3 position to access directlyflustramine C (454) in 60% yield. An improved procedure using N-bromosuccinimide was also evaluated by the same authors, leadingto synthesize flustramine C (454) in 90% yield. A similar reaction,which was interrupted at the indolenine stage, likely due to theprotecting group present on the tryptamine a-nitrogen was re-ported by Baran. To insert a chlorine atom on the C3 position, Baranemployed the common reagent N-chlorosuccinimide under neutralconditions and obtained the corresponding chlorinated product456 in 94% yield (Scheme 79, Eq. 2).205 In another example, You
79.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3583
performed an enantioselective chlorination of 2-arylated indolederivative 457 using 1,3-dichloro-5,5-diphenylhydantoin (DCDPH)and the Cinchona alkaloid dimer (DHQD)2PHAL 460 as a chiralphase transfer reagent to achieve the desired enantioselectivehalocyclization (Scheme 79, Eq. 3).206 N-Protected indoles 457 areideal substrates in this transformation as the increased electro-philicity of the acyl-indolenium 458 intermediate, therefore facili-tating the spirocyclization step from the amide side chain.
Another use of chlorine in dearomative strategies was exploredby Evano for the synthesis of the (�)-chaetominine (437) (Scheme80).207 Facing the challenge of forming a a-carbolinone fragmentfrom a tryptophan containing dipeptide 461, Evano reported a dou-ble dearomative process to access stereoselectively to the core of the(�)-chaetominine (437). Using similar conditions to Bohrer,204 in-dole 461was first dearomatized byN-chlorosuccinimide, leading tothe chloroindoline 462, which after elimination delivered the rear-omatized indole product 463. The resulting indole then underwenta second dearomatization under a photochemical irradiation inpresence of oxygen to afford thea-carbolinone464 in 64% yieldwithexcellent diastereocontrol (98:2 dr).
Scheme 80.
This brilliant strategy allowed Evano to form the natural producta-carbolinone ring structure and insert an oxygen atom at the C3position during the same operation, which remains a remarkableperformance among the few reported syntheses of the
Scheme
(�)-chaetominine (437), all sharing similar indole dearomatizationstrategies.208
6.2.3. Bromine electrophile. N-Bromosuccinimide (NBS) has beenalso widely used to introduce a bromine atom on indoles whileinitiating dearomatization processes. Among the different brominepromoted dearomatization reported,209 the study of De Lera onelectrophilic activation of tryptophan derivatives is remarkable.210
During the course of this work, De Lera developed an efficientmethod to form a bromo-HPI unit, which was also employed byRainer later on for the synthesis of the kapakahines B and F(Scheme 81, Eq. 1).211 Upon exposure to NBS, tryptophan 465 wasreadily converted to the corresponding bromo-HPI 466 in goodyield and with an excellent exo-selectivity. The facial selectivityobserved in this reaction is likely due to the configuration and thesubstitution (protecting groups) of the starting tryptophan, whichfavors the formation of the pre-exo assembly (see Scheme 70). Thissubstrate 466was further functionalized by Rainier to form indolo-HPI 469 (key intermediate of the total synthesis) with a completeretention of configuration at the C3 position. Mechanistically,
a double SN2 is likely occurring, through the formation of a tran-sient cyclopropane 468 under basic condition from the back face ofthe HPI-467, followed by the nucleophilic attack of the indole andopening of the cyclopropane from the opposite face. This reaction
81.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913584
led to the formation of product 469 in 82% yield and an exo/endoratio of 1:5. This important discovery from the Rainer group led toan elegant synthesis of the kapakahine F (417) natural product.
It is only recently that the first catalytic and enantioselectivebromocyclization of tryptamine substrates was reported by Ma,using a DABCO-derived bromonium reagent as the electrophilicbromine source and a chiral phosphoric acid catalyst (Scheme 81,Eq. 2).212 From this successful method, numerous bromo-HPI 471were synthesized in moderate to excellent yields (37e100%) alongwith excellent diastereoselectivities (up to 98:2 dr) and even moreimportantly high enantioselectivity (79e99% ee). Some of thesynthesized bromo-HPI were then further transformed (arylation,alkylation, azide or dimerization) without any important erosion ofthe enantiomeric excess as highlighted by the total synthesis of(�)-chimonanthine.
Avery impressive example of dearomative strategy promoted byNBSwas also reported by Baran for the total synthesis of the naturalproduct chartelline C (321) (Scheme 82).213 After removal of thecarbamate under thermal conditions, the indole moiety was dear-omatized by NBS to form the plausible bromoindolenine in-termediate 475, which was subsequently trapped by the nearbynitrogen in a spectacular transannular fashion, causing the extru-sion of the bromine atom from the C3 position. The proposedresulting intermediate 476 finally underwent a [1,2]-shift to formthe required and unique spiro b-lactam ring structure of the char-telline core (477) in 88% yield.
Scheme 82.
6.2.4. Fluorine electrophile. The field of dearomatization involvingelectrophilic fluorine has been less extensively studied among allhalogens. Pioneering work from Barton on N-acylindoles in 1977214
described the first utilization of trifluoromethyl hypofluorite tosynthesize several 3-fluorooxindoles, 2,2-difluoroindolines or 2,3-difluorodihydroindoles.215 The first example of fluorocyclizationwas reported by Shibata in 2001 (Scheme 83, Eq. 1),216 in the courseof developing fluorinated analogs of the natural products brevia-namides E and gypsetin. To achieve the desired dearomatization,the fluoropyridinium FP-T300 was employed. The diketopiperazineamide moiety being a poor nucleophile, the reaction on 478
Scheme
occurred at 65 �C to enable the cyclization, leading to a 1:1 ratio ofthe exo and endo diastereomers of the tetracyclic indoline 479 ingood yields (67e88%).
A similar fluorocyclization was later reported by Gouverneurwhile studying several sources of fluorine electrophile such asselectfluor or the N-fluorosulfonimide (NFSI) to perform enantio-selective fluorocyclizations of tryptophols and tryptamines 480catalyzed by the Cinchona alkaloid (DHQ)2PHAL (Scheme 83, Eq.2).217 Similarly to the work of You (Scheme 79, Eq. 3), the role of theCinchona alkaloid in this reaction is to carry the electrophilic fluo-rine in a chiral environment to approach the indole derivatives 480,allowing for high enantiodiscrimination to occur during dearoma-tization andmultiples hexahydropyrro[2,3-b]indoles or tetrahydro-2H-furo-[2,3-b]indoles 481 to be formed in relatively good yields.Interestingly, the (DHQ)2PHAL was introduced as a catalyst withNFSI while selectfluor required a stoichiometric amount of thesame alkaloid to perform the required dearomatization and inducesimilar stereoselectivity.
Remarkably, Baran employed another source of fluorine elec-trophile in place of xenon difluoride during the key enabling step tothe synthesis of (þ)-welwitindolinone A (486) (Scheme 84).218 Inthis impressive cascade of events, the fluorine atom is first dear-omatizing indole 482, the resulting indolenium 483 was thenintercepted by water to access indoline 484, which prompted theelimination of fluorine prior to the final rearrangement through toa [1,2]-shift creating simultaneously both oxindole and cyclobutane
moieties of (þ)-welwitindolinone A (486) in an astonishing 44%overall yield.
6.3. Dearomative cascade reactions
Oxidative dearomatizations of unprotected indoles, regardlessthe oxidant employed, can be part of a strategy to access complexpolycyclic structures, by forming three carboneheteroatom bondsin a single process. In this event, the dearomatizationwould triggerthe cascade by forming the first indoleninium intermediate 487,which will be later trapped by a nucleophile to form a tricyclic
83.
Scheme 84.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3585
indolenine core 488 (n¼0 HPI or n¼1 a-carboline). The cascadecould be further concluded by the formation of the last cycle ifa proper C-terminus (Y group) enables the final cyclization to occurfrom the proximate indoline nitrogen to deliver a complex tetra-cyclic structure as highlighted in compound 489 (Scheme 85).
Scheme 85.
A first approach to such double annulative cascade was reportedby Herranz on the nitrile-functionalized tryptophan 490 via a pro-tonative tautomerization as dearomative strategy using TFA (seeSection 4) leading to the synthesis of tetracyclic amidine 491 asa single exo-diastereomer in a quantitative manner.219a Since then,Herranz reported a complete study of this elegant cascade reactionwith many different electrophiles for the C3-functionalization ofthe nitrile-functionalized tryptophan 490 (Scheme 86).219 In thisstudy, the authors noticed the steric effect of the cyclohexyl moietyon the stereoselectivity outcome of the reaction. By obtaining theexo and/or the endo tetracyclic compounds depending on reactionconditions, the authors concluded that unhindered nitriles exclu-sively provide tetracyclic exo-products 491 while more hinderednitrile derivatives provide predominantly exo-products under ki-netic control while endo-products can be obtained under thermo-dynamic control.
Scheme 86.
Later on, the nature of the dearomatizing agent was evaluatedand Herranz identified that N-PSP was not amenable for the dear-omatization of compound 490.219d On the other hand, NBS pro-moted dearomatization in acidic media successfully yielded the
corresponding brominated tetracyclic compound 492 in a 91% yieldas a single exo-diastereomer. Also the Corey-Kim reagent220 wasemployed and promoted the formation of the interrupted cascadeproduct alkylated-HPI 493 in 52% yield as a single exo-di-astereomer. In this case, the cascade of events does not proceed to
form the last ring, requiring an extra step (TFA/CH2Cl2) to access thecorresponding tetracyclic amidine product. Finally, under acidicconditions, DMDO also proved to be effective in promoting thedesired cascade.219c In this particular situation, the presence ofa 10% TFA/CH2Cl2 mixture is again essential to perform the fullcascade (the hydroxyl-HPI intermediate is obtained otherwise) andobtained the tetracyclic amidine 494 in 85% yield (1:7 ratio of endo/exo-diastereomers). In conclusion, Herranz reported the first cas-cade forming three carbon-heteroatom bonds in a single step in-volving an unprotected indole as substrate, which affordsnumerous complex tetracyclic indoline-derived structures withhigh diastereoselectivity.
A similar approachwas studied by Roche to accomplish a unifiedbiomimetic approach to both families of natural products kapaka-hine F (417) and (�)-chaetominine (437). Dearomatization of sev-eral tryptophan containing dipeptides was performed in presence
of selectfluor,216,217 under basic conditions and was utilized tosuccessfully trigger a dearomative cascade to synthesize the com-plex tetracyclic compound 497 (Scheme 87).221 Activated dipeptideNPhth-Trp-Phe-OPFP 495 suffering from an epimerization on the
Scheme 87.
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e35913586
aH of the phenylalanine residue (1:1 epimeric mixture) was en-gaged in the dearomatization promoted by selectfluor� in acetoneleading to the formation of the fluoroindolenine 496 intermediate,which endured a double annulation cascade via the first amidecyclization followed by indolenine lactamization through ejectionof the pentafluorophenol activating group. The tetracyclic fluori-nated analogue 497 of the kapakahine core was obtained in a rea-sonable 42% yield with modest diastereocontrol (3:5 overall anti/syn-ratio).
In this study, the authors also explored the effect of additionalchiral promoters, such as (DHQ)2PHAL, on the reaction diaster-eocontrol and were able on a model dipeptide NPhth-Trp-Gly-OPFPto achieve a cascade with higher diastereocontrol (4.1:1 anti/syn-ratio).
A similar strategy was reported earlier by Huang for a proposedbiomimetic synthesis of (�)-chaetominine (437) providing theshortest synthesis of this natural product reported to date (Scheme88).222 The key reaction features a DMDO-promoted dearomatiza-tion of the tryptophan containing dipeptide 498 (prepared in threesteps from L-Trp), followed by the intramolecular trapping of theindolenium intermediate 499 by the proximate amide moiety toform, after final lactamization in DMSO and extrusion of methoxideas leaving group, (�)-chaetominine (437) in a single step and 42%yield. This impressive cascade enabled Huang to assemble thecomplex ring structure of the natural product in a single step andremarkably as the last step of the total synthesis.
Scheme 88.
The DMDO dearomatization was very efficient as shown by theisolated syn-a-carbolinone by-product 500 in 51% yield, resultingby the fact that the syn-diastereomer 500 did not endure the fullcascade under the reaction conditions and stopped at the a-car-bolinone stage. The authors suggested that the syn-relationshipbetween the hydroxyl and the quinazolinone in 500 prevented thelactamization to happen. Through this cascade strategy, Huang wasable to achieve an impressive four-step synthesis of (�)-chaeto-minine (437).
7. Conclusion and outlook
The challenges associated with the synthesis of complex indo-lenine and indoline-based alkaloids, in conjunction with their in-teresting biological activity, have prompted chemists to developnumerous elegant methods for their preparation that are ever moreefficient. In this report, we wished to summarize seminal work onindole dearomatization as well as the most recent advances inasymmetric syntheses of complex polycyclic indoline-containingalkaloids, while also attempting to discuss the various reactivitiesof indoles induced by their C2eC3 substitution patterns and by thepresence or absence of indolic nitrogen protecting groups.
It should appear from this report that whilst a number of in-novative synthetic methods exist, there is a relative rareness ofcatalytic enantioselective means in total synthesis of complex al-kaloids. In Section 2, while DielseAlder and 1,3-dipolar cycloaddi-tions proved to be extremely powerful tactics to embed highcomplexity during the dearomatization step, only a few reactionson N-protected indoles are really amenable to enantioselectivecatalysis. Arylative dearomatization of indoles (section 3) also fol-lows the same trend, with only rare examples of enantioselectiveand catalyst-controlled diastereoselective arylation methods me-diated by copper with aryliodonium reagents. Alkylative dear-omatizations of indole (Section 5) provide enabling methods forcarbonecarbon and carboneheteroatom bonds formation in or-ganic synthesis. The use of indolic substrates in this context has
inspired many research groups, allowing for the development ofpowerful methods for the synthesis of extremely complex struc-tures. Finally, Heteroatomic oxidative dearomatization stands asa privileged tool to functionalize indoles at both C2 and C3 positions(Section 6). Depending on the nature of the oxidant, the indolemoiety may require protecting manipulations to avoid over-oxidation events. Most oxidative dearomatizations were reportedon tryptophan-derived scaffolds to exploit the chirality of the latterand innate facial stereocontrol during dearomatization. Recently,
S.P. Roche et al. / Tetrahedron 71 (2015) 3549e3591 3587
several efficient and catalytic enantioselective advances for oxida-tion and halocyclization have been reported, paving the way tochiral dearomatization of indoles to be utilized in alkaloid syn-thesis. Furthermore, heteroatoms installed at the C3 position en-able late stage functionalization to be easily accomplished(alkylation, arylation, and dimerization), which provides valuableroutes to complex alkaloidic natural products.
While the lessons of the past clearly present methods by whichto prepare nearly any indolic-based natural products and drug-likemolecules, the search for ever more selective and asymmetricmeans for their preparation remains an exciting area of research.
Acknowledgements
We thank Florida Atlantic University for financial support andour colleagues from the Chemistry and Biochemistry Departmentfor stimulating discussions during the preparation of this report.
References and notes
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St�ephane P. Roche was born in Thiers (France) in 1979. He received his Ph.D. degree(2006) in chemistry from the Blaise Pascal University under the supervision of Profes-sor D.J. Aitken. Afterward, he joined the Institute of Chemical and Engineering Sciences(ICES, @Star) in Singapore, as research fellow with Professor K.C. Nicolaou(2006e2008). As a second Post-doctoral position, St�ephane worked with ProfessorJohn Porco Jr. at Boston University (2008e2011). He started his independent careeras Assistant Professor at Florida Atlantic University and his research interests includethe development of novel ‘bio-inspired’ synthetic methodologies and dearomatizationstrategies to achieve concise total syntheses of biologically active small-molecules andnatural products.
Jean-Jacques Youte Tendoung earned his Ph.D. degree at Universit�e Ren�e Descartes,Paris in 2000, working under the direction of Dr. Francois Frappier and Dr. ChristianMarazano, working on the Zincke reaction at room temperature and applicationtoward herveline C. He carried out his post-doctoral studies with Professor Robert A.Holton at Florida State University, working on the synthesis of second and third gen-eration of taxol analogs and with Professor Roland Barret at Universit�e de Lyon I.Jean-Jacques then held several positions in medicinal organic chemistry groups, re-spectively, at the Institute of Chemical and Engineering Sciences in Singapore, theAuckland Cancer Research Center in New Zealand and The Walter and Eliza Hall Insti-tute of Medical Research in Australia. In 2011, he joined Schering-PlougheMerck inFrance as Team Leader. In 2012, Jean-Jacques became a Visiting Assistant Professorat Florida Atlantic University working on a new synthetic approach to peptides. Cur-rently, Jean-Jacques is starting a business focused in the areas of sustainable chemistry.
Bret Tr�eguier was born in 1982 in southern France (Tarbes) and studied fine chemistryat the University of Nantes, where he graduated. In 2011, he obtained his Ph.D. in me-dicinal chemistry, at the faculty of pharmacy of Chatenay-Malabry (France), under thesupervision of Professor M. Alami and Dr. A. Hamz�e. He next joined the Roche group atFlorida Atlantic University, as a post-doctoral associate to work on the synthesis ofcomplex natural products based on dearomatization of tryptophan containingpeptides.
