Tetrahedron Letters 54 (2013) 5562–5566

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Tetrahedron Letters

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A highly stereocontrolled asymmetric total synthesis of epimerof (+)-7-deoxypancratistatin

O

O

HOOH

NH

OH

OH

OX

1 X = OH, Pancratistatin2 X = H, 7-Deoxypancratistatin

1 23

44a10b O

O

OH

NH

OX

3 X = OH, Narcicla4 X = H, Lycoricid

Figure 1. Structures of pancratistatin (1), 7-deoxypancratistatin (2), nar(3) and lycoricidine (4).

0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.07.125

⇑ Corresponding author. Fax: +91 20 5892629.E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).

Subhash P. Chavan a,⇑, Sumanta Garai a, Chandan Dey b, Rajesh G. Gonnade b

a Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, Indiab Physical/Materials Chemistry Division, CSIR-NCL (National Chemical Laboratory), Pune 411008, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 22 May 2013Revised 22 July 2013Accepted 24 July 2013Available online 31 July 2013

Keywords:Amaryllidaceous alkaloids7-DeoxypancratistatinEpimerSharpless asymmetric dihydroxylationDeoxygenation

A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin has beenachieved from readily available starting materials via unified strategy employing Sharpless asymmetricdihydroxylation, ring closing metathesis, Overman rearrangement, hydrogenolysis and Bischler–Napieralskireaction in 15 purification steps with 15% overall yield.

� 2013 Elsevier Ltd. All rights reserved.

OH

OH

sine

The amaryllidaceous alkaloids are a diverse group of structur-ally complex natural products which are used for medicinal pur-poses dating back to at least the fourth century1 and thesealkaloids possess a wide spectrum of biological activities. In1984, Pettit et al.,2 reported isolation of pancratistatin (1), whichwas shown to display promising antineoplastic and antiviral activ-ity. In 1989, Ghosal et al.,3 isolated the 7-deoxy compound 2,in vitro antiviral assays of which have been shown to exhibit a bet-ter therapeutic index than 1.

The potent biological activity and unique yet challenging struc-tural features of these molecules possessing phenanthridone skel-eton with four or six contiguous stereogenic centres in the C ringand trans-fused BC-ring (C10b–C4a) have rendered them attractivesynthetic targets for organic chemists Fig. 1.

The potent biological activity of these compounds with novelframework coupled with their low natural abundance/availabilityprompted us to undertake practical synthesis of this class of com-pounds. Several total syntheses of 7-deoxypancratistatin (2) havebeen reported till date in the literature.4 The first total synthesisof epimer of 7-deoxypancratistatin (2) has been reported by Hud-licky and co-workers.4h,5 In this Letter we wish to describe a newhighly stereo-controlled asymmetric total synthesis of epimer of(+)-7-deoxypancratistatin.

Scheme 1 highlights the overall retrosynthetic strategy towards(+)-7-deoxypancratistatin (2). The B ring of 7-deoxypancratistatin

could be constructed by Bischler–Napieralski reaction and the ste-reochemistry of 10b centre could be fixed via deoxygenation of ter-tiary benzylic alcohol of intermediate 5. Allylic nitrogenfunctionality could be installed via Overman rearrangement ofallylic alcohol 6. We envisioned that the requisite precursor 6,which contains four stereocentres in the C ring, could be stereose-lectively synthesized from diene 7 via ring closing metathesis. Thediene 7 in turn could be obtained from keto compound 8 takingadvantage of existing chiral centres to direct the other two chiralcentres to be installed. Further retrosynthetic analysis indicatedthat the keto compound 8 could be synthesized from commerciallyavailable, cheap starting material 9 via Grignard reaction followedby Sharpless asymmetric dihydroxylation.

Accordingly, the synthesis began with the Grignard reaction of4-bromo-1,2-(methylenedioxy)benzene 9 with succinic anhydride.

ine

ciclasine

O

O

O

O

O

O

O

OO

O

O

O

OO

OBr

O

O

Br

9 10

1112

a b

c

Scheme 2. Reagents and conditions: (a) (i) Mg, succinic anhydride, THF, 3 h, 0 �C-rt;(ii) Me2SO4, K2CO3, acetone, 3 h, 85% (over two steps); (b) NBS, NH4OAc, CCl4, reflux,98%; (c) Et3N, DCM, 10 min, quant.

O

O

OH

OHNH

OHHO

O

O

O

OPPO

NHO

O

O

O

OHOP

POHO

O

O

O

O

O

OP

PO

O

O

OvermannRearrangement

Ring-ClosingMetathesis

Grignardreaction

Bischler-Napieralskireaction

A B

C

Asymmetricdihydroxylation

Deoxygenationreaction2 5

6

7

8 9

Br

O

O

HOPO

OPOH

10b 10b

Scheme 1. Retrosynthetic analysis of 7-deoxypancratistatin.

S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566 5563

Aryl Grignard reagent was prepared from 9 and it was quenchedwith succinic anhydride to give acid and the crude acid thus ob-tained was directly treated with Me2SO4 to give corresponding es-ter 10 in 85% yield over two steps. Attempts to install the doublebond in one pot under IBX/DMSO6 reaction condition was unsuc-cessful leading to recovery of starting materials. Then we decidedto introduce the olefin by stepwise addition and elimination oper-ation. Accordingly, a-bromination7 of ketone 10 was carried outwith NBS to give selectively mono a-bromoketone 11 in 98% yield.Treatment of compound 11 with Et3N gave olefin 12 in quantita-tive yield (Scheme 2).

This prochiral enone 12 was deemed to be a suitable substratefor the installation of the chiral centres. Compound 12 was sub-jected to Sharpless asymmetric dihydroxylation (SAD)8 to yieldchiral diol 13 in 85% yield with P98% ee.9 After screening variousliterature reports on SAD we have observed that surprisingly SADon such type of double bond is not reported in the literature.MOM protection of diol was smoothly performed with MOMCl toafford di-MOM protected diol 14 in 92% yield without epimeriza-tion.10 Ketone 14 was subjected to treatment with vinylmagne-sium bromide to give lactol 15 in 60% yield which was found tobe unstable at room temperature (under controlled experiment

we were able to isolate lactone intermediate 19). The diastereose-lectivity observed during the Grignard reaction of 14 can be ex-plained by Cram’s chelation model11 (a, Fig. 2). After purification,it was immediately treated under Luche reduction12 with CeCl3-

�7H2O and NaBH4 to yield diene 16 in 95% yield as a sole observablediastereomer (determined by 1H and 13C NMR). The stereochemis-try at the C3 centre was surprisingly controlled by the Felkin-Anhmodel (b, Fig. 2).13

It is well known in the literature that Ce+3 has good affinity to-wards chelation and hence it was assumed that the Luche reduc-tion should furnish the product as predicted by Cram’s chelationmodel. Although the exact reason for the observation remains un-clear, it can be surmised that due to the bulky size of both Ce+3 ionand MOM group, chelation is not favourable. Cram’s chelation tran-sition state (B) was more sterically congested as compared to Fel-kin-Ahn transition state (C), which resulted in the hydride attackon the less hindered face of the non-chelated transition state (C)(Fig. 2).

Having accomplished the assembly of requisite carbon atomsand appropriately placed functionalities, the stage was set for theconstruction of the cyclohexene ring. Accordingly, the resultantdiene 16 was subjected to ring closing metathesis using Grubbs’1st generation catalyst to gratifyingly afford substituted cyclohex-ene advanced intermediate 17 in 96% yield. It should be empha-sized that the synthesis of arylcyclohexene 17 is operationallysimple and it can be readily synthesized on gram scale. The sec-ondary alcohol in arylcyclohexene 17 was selectively convertedto corresponding imidate with Cl3CCN for the ensuing Overmanrearrangement.14 Unfortunately, imidate did not undergo theanticipated rearrangement to give the desired product 18, insteadthe reaction led to the recovery of the starting imidate (Scheme 3).

The failure of the rearrangement might be attributed to theinfluence of the bulky MOM group for which the b-face of doublebond was sterically congested which prevented the migration ofthe imidate group (E). At this stage, we decided to invert the C3stereo-centre where a-face was sterically less congested (F)(Scheme 3, Fig. 3).

In view of the unfavorable steric effect of the MOM group onthe rearrangement of allylic alcohol 17, it was subjected to Mits-unobu reaction15 with p-nitrobenzoic acid to afford crude nitro-benzoate ester which was hydrolysed with NaOMe to afford theadvanced intermediate 20 in 65% yield. It should be noted that1-arylconduritols B and F16 have very close structural resemblancewith compounds 17 and 20, respectively, and can be potentiallyreadily synthesized in multi-gram scale from these compounds17 and 20.

The secondary hydroxyl group of alcohol 20 was selectivelyconverted to corresponding imidate by treating with Cl3CCN. Withthis imidate in hand, we then tried the Overman rearrangement14

with K2CO3 in xylene under the reflux conditions and were grati-fied to find that it worked very well as per our hypothesis. After3 h, we obtained our desired rearranged product 21 as a single iso-mer in 98% yield giving credence to our hypothesis. Treatment ofthis bicyclic compound 21 with OsO4 afforded diol 22 as a sole iso-lable diastereomer in 99% yield. The relative stereochemistry ofalcohol 22 was confirmed by 2D NMR study and finally by singlecrystal XRD analysis.17 This stereochemical outcome can be attrib-uted to the approach of the reagent from the b-face of the doublebond because the nearby carbamate ring and the bulky MOMgroup at C2 position provided steric bias for a-face of the doublebond. After successful installation of all the requisite functionalgroups around the cyclohexane ring with the desired stereochem-istry, next task was deoxygenation of the tertiary hydroxyl groupat C10b. Towards this end, despite significant efforts, we were un-able to get desired deoxygenated product18 under different reac-tion conditions like hydrogenolysis (Pd/C,19 Pd(OH)2/C20 and

R1

H

OMOM

O

Ar

Ar

O

R1

OMOM OMOM

R1H

Ar

OMg+2

BrMg

R1

HMOMOAr

OH

R2

OMOM

O

R2

H

MOMO

O

O

R2H

O

Ce+3

H R2H

MOMOHO

H

R2

HMOMO

O

H

R2

HMOMOOH

H

-

A

B

C

Cram's chelation model

Cram's chelation model

Felkin-Anh model

-

OCH3

Ce+3

(a)

(b)

Figure 2. Felkin-Anh and Cram’s chelation model transition state.

O

O

O

O

O

OH

OMOMMOMO

O

O

HOMOMO

OMOMOH

O

O

HOMOMO

OMOMOH

O

O

HOMOMO

OMOM

O

MOMOOMOM

O

OO

O

O

HOOH

O

O12

13 14

1516

17 18

1 2

10b

O

O

O

OMOMMOMO

O

19

10b

31

HN

O

CCl3

3

a b

c d

e f

Scheme 3. Reagents and conditions: (a) (i) (DHQD)2PHAL, OSO4, K3[Fe(CN)6],K2CO3, tBuOH:H2O (1:1), 4 days, 85%, P98% ee; (b) MOM-Cl, DIPEA, DCM, reflux,92%; (c) vinylmagnesium bromide (2 equiv), THF, 0 �C, 60%; (d) CeCl3�7H2O, NaBH4,MeOH, 0 �C, 15 min, 95%; (e) Grubbs’ 1st generation catalyst, DCM, reflux, 4 h, 96%;(f) (i) CCl3CN, DBU, DCM, 0 �C, 30 min; (ii) K2CO3, xylene, reflux.

O

OH OMOM

O

OO

NH

CCl3

More steric crowding

E

3 H

OH

Less steric crowding

OMOM

OHOMOMO

OO

CCl3

NHH

F

3

Figure 3. Effect of the MOM group on Overman rearrangement.

O

O

MOMOOMOM

NHO

O

O

O

MOMOOMOM

NHO

O

OH

OH O

O

MOMOOMOM

NH2

OH

OH

O

O

HOMOMO

OMOMOH

1720

21

22 23

10b

22

a b

c

Scheme 4. Reagents and conditions: (a) (i) Bu3P, DEAD, p-NO2C6H4CO2H, toluene,0 �C, 5 h; (ii) NaOMe, MeOH, 0 �C, 2 h, 65% (over two steps); (b) (i) CCl3CN, DBU,DCM, 0 �C, 30 min; (ii) K2CO3, xylene, reflux, 3 h, 98%; (c) OsO4, NMO, CH3CN–H2O(9:1), rt, 3 days, 99%.

5564 S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566

Raney Ni21) ionic hydrogenation22 (Et3SiH/BF3�OEt2 and Et3SiH/TFA) and Birch reduction23 (Scheme 4).

The above results indicated that the carbamate ring is very sta-ble and is highly resistant under the above reaction conditions.This finding prompted us to activate the carbamate ring. Accord-ingly, the diol of compound 22 was protected as its acetonide fol-

lowed the treatment with dimethyldicarbonate to furnishcompound 24 where the carbamate ring was activated. With the

Table 1Deoxygenation of activated carbamate

Entry Reaction conditions Producta

1 Pd(OH)2, CH3COOH, H2, EtOH cis Stereochemistry2 Pd(OH)2, H2, EtOH cis Stereochemistry3 Pd/C, CH3COOH, H2, EtOH cis Stereochemistry4 Pd/C, H2, EtOH cis Stereochemistry5 Li, liq. NH3, THF Complex reaction mixture6 BF3�OEt2/TFA, Et3SiH, DCM Complex reaction mixture7 Raney Ni, H2, EtOH, reflux SMb was recovered

a Relative stereochemistry at C4a–C10b centres.b Starting material.

O

O

AcOOAc

NH

OAc

OAc

O

O

O

HOOH

NH

OH

OH

OEpimer of (+)-7-deoxypancratistatin

28

26

27

a b

Scheme 6. Reagents and conditions: (a) Tf2O, DMAP, DCM, �5 �C, 16 h, 70%; (b)K2CO3, MeOH, rt, overnight, 85%.

S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566 5565

activated compound 24 in hand, our next aim was to carry out thedeoxygenation reaction in order to fix the desired stereochemistryat C10b centre (Table 1). Hydrogenolysis of compound 24 gratify-ing furnished the deoxygenated compound as a single diastereo-mer, however, with cis stereochemistry leading to the formationof product 25 (entries 1–4). Under ionic hydrogenation and Birchreduction conditions, it resulted in a complex reaction mixture (en-tries 5 and 6). Under Raney nickel reduction conditions, we failedto get deoxygenated product (entry 7). Although the desired transstereochemistry at C4a–C10b centre as required to obtain (+)-7-deoxypancratistatin (2) could not be achieved under these reactionconditions, an advanced intermediate 22, bearing the exact re-quired stereochemistry at C4a–C10b for the synthesis of (+)-7-deoxypancratistatin (2) was obtained in good yields. We believethat by proper choice of reagents and reaction conditions, interme-diate 22 can be converted to (+)-7-deoxypancratistatin (2).

With cis deoxygenated product 25 in hand, it was carried for-ward to accomplish the total synthesis of epimer of 7-deoxypanc-ratistatin. Accordingly, acetonide and MOM groups were globallydeprotected in one-pot by addition of 2–3 drops of concd HCl inMeOH. Then the free hydroxyl groups were protected with aceticanhydride to yield tetraacetate 26 in 97% yield. The relative stereo-chemistry and structure were confirmed by XRD analysis24

(Scheme 5).The carbamate 26 was treated with Tf2O and DMAP under mod-

ified the Bischler–Napieralski protocol25 for the construction of theB ring to afford compound 27. Finally, global removal of all fouracetate groups was achieved by treatment with K2CO3 in MeOHto furnish epimer of (+)-7-deoxypancratistatin (28) (Scheme 6).The absolute stereochemistry of 28 was assigned by comparisonof the reported optical rotations.5,4h

In summary, we have completed a new and potentially practicalsynthetic route to the epimer of (+)-7-doxypancratistatin starting

O

O

MOMOOMOM

ON

O

O

O

O

O

O

O

MOMOOMOM

HN

O

O

O

O

22

24 25

O

O

AcOOAc

HN

OAc

OAc

O

O26

10b 4a

10b 4a

10b 4aa b

Table 1

26

Scheme 5. Reagents and conditions: (a) (i) Me2C(OMe)2, cat. PTSA, DCM, 0 �C, 1 h;(ii) dimethyldicarbonate, Et3N, DMAP, DCM, 1 h, rt, 97%; (b) (i) concd HCl (2–3drops), MeOH, rt, 4 h; (ii) Ac2O, pyridine, rt, overnight, 97%.

from inexpensive, commercially and easily available starting mate-rials in 15% overall yield after 15 purification steps which is thehighest overall yield reported so far. We have synthesized an ad-vanced intermediate 20 on multi-gram scale which can be elabo-rated for the efficient synthesis of different 1-arylconduritols andLycrocidine (4). Synthesis of other related natural products andthe evaluation of biological activity of 1-arylconduritols and epi-mer of (+)-7-deoxypancratistatin (28) are under progress and willbe reported in due course.

Acknowledgments

S.G. thanks CSIR, New Delhi, India, for a fellowship and S.P.C.acknowledges funding from NCL in-house projects [MLP 017226and MLP012726]. We thank Dr. Rahul Banerjee, CSIR-NCL forX-ray analysis and we also thank the Director, CSIR-NCL for thisfacility.

References and notes

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Am. Chem. Soc. 1988, 110, 1968; (b) Kolb, H. C.; VanNieuwenhze, M. S.;Sharpless, K. B. Chem. Rev. 1994, 94, 2483. and references therein.

9. Enantiomeric excess (% ee) was determined by Chiral HPLC analysis (ChiralcelOJ-H (250 � 4.6 mm), mobile phase:isopropanol:pet ether = 40:60, wavelength = 254 nm, flow rate = 0.5 ml/min).

10. Enantiomeric excess (% ee) was determined by Chiral HPLC analysis (Kromasil5-Amy Coat (250 � 4.6 mm), mobile phase:isopropanol:n-hexane = 5:95, wavelength = 254 nm, flow rate = 1 ml/min).

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5566 S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566

15. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; (b)Mitsunobu, O. Synthesis 1981, 1.

16. For ‘1-aryl-1-deoxyconduritols F’ see (a) Nadein, O. N.; Kornienko, A. Org. Lett.2004, 6, 831; For review on conduritols see (b) Balci, M.; Sütbeyaz, Y.; Secen, H.Tetrahedron 1990, 46, 3715.

17. Crystallographic data (excluding structure factors) for the structures have beendeposited with the Cambridge Crystallographic Data Centre as supplementarypublication no. CCDC 918587. Copies of the data can be obtained, free ofcharge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (Fax:+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).

18. Previously Pettit and co-workers (Pettit, G.R. Melody, N. Herald, D.L. Knight, J.C.Chapuis, J.-C. J. Nat. Prod. 2007, 70, 417) were also unable to get the correctstereochemistry at C10b centre by a radical deoxygenation reaction for thesynthesis of pancratistatin.

19. Webster, R.; Boyer, A.; Fleming, M. J.; Lautens, M. Org. Lett. 2010, 12, 5418.20. Yoshida, M.; Watanabe, T.; Ishikawa, T. Tetrahedron Lett. 2002, 43, 6751.21. Krafft, M. E.; Crooks, W. J. J. Org. Chem. 1988, 53, 432.22. Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J. Am. Chem. Soc. 1991, 113,

5402.23. Small, G. H.; Minnella, A. E.; Hall, S. S. J. Org. Chem. 1975, 40, 3151.24. Crystallographic data (excluding structure factors) for the structures have been

deposited with the Cambridge Crystallographic Data Centre as supplementarypublication no. CCDC 918586. Copies of the data can be obtained, free ofcharge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (Fax:+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).

25. (a) Tian, X.; Hudlicky, T.; Konigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643; (b)Banwell, M. G.; Bisset, B. D.; Busato, S.; Cowden, C. J.; Hockless, D. C. R.;Holman, J. W.; Read, R. W.; Wu, A. W. J. Chem. Soc., Chem. Commun. 1995, 2551.