Selective Excitation 1D-NMR Experiments for the Assignment of theAbsolute Configuration of Secondary AlcoholsIon Ghiviriga*
Chemistry Department, University of Florida, Gainesville, Florida 32611-7200, United States
*S Supporting Information
ABSTRACT: Routine selective excitation experiments, easy to set up onmodern NMR spectrometers, allow for the determination of the absoluteconfiguration of chiral secondary alcohols by double derivatization directly inthe NMR tube. As a general method, TOCSY1D with selective excitation ofthe α proton in the MPA esters and with a short mixing time reveals only thenearby protons in the coupling network. Typically, the analysis takes lessthan 30 min. A longer mixing time, selective excitation of other signals, orNOESY1D experiments can be used for measuring ΔδRS of other protons.
■ INTRODUCTIONThe assignment of the absolute configuration of secondaryalcohols is commonly done by the NMR-based method of Daleand Mosher.1 In its original form, the method implies theesterification of the secondary alcohol with the twoenantiomers of a chiral arylmethoxyacetic acid (AMAA), suchas methoxyphenylacetic acid (MPA) or methoxytrifluorome-thylphenylacetic acid (MTPA, Mosher’s reagent), and compar-ison of the chemical shifts of the resulting diastereomers. Thestereochemical assignment of the two moieties, L1 and L2,bound to the α carbon in the alcohol is based on a modelconformation having the α hydrogen in the alcohol, thecarbonyl oxygen, and the methoxy group in MPA syn-periplanar(Figure 1). In MTPA, the trifluoromethyl group is syn-
periplanar with the carbonyl oxygen and the α hydrogen.2
Calculations indicate that this “NMR-significant” conformationis only one of several populated conformations, and in the caseof MTPA, not even the most stable;3 however, this empiricalmethod is validated by a large number of alcohols of knownabsolute configuration.
Most of the assignments of the absolute configuration ofsecondary alcohols reported in the literature employed thederivatization with MTPA or MPA, as originally described byDale and Mosher1a and recently detailed in a protocol by Hoyeet al.4 The alcohol, the chiral arylmethoxyacetic acid, and N,N′-dicyclohexylcarbodiimide (DCC) react in methylene chlorideor chloroform in the presence of 4-N,N-dimethylaminopyridine(DMAP). Although the reaction itself takes less than 1 h, theanalysis requires 4−6 h of active effort over 1−2 days, because(i) the esters are prepared and analyzed serially rather than inparallel, to eliminate the risk that the esters are interchanged,and (ii) the esters have to be separated from the reactionmixture, which implies washing with water, extracting withdiethylether, drying the extract, and then evaporating thesolvent. Alternately, one can filter the N,N′-dicyclohexylurea(DCU) and isolate the esters through flash chromatography.5
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) can beused as a coupling reagent, instead of DCC.6
The assignment of the absolute configuration can be donewith only one AMAA ester, by recording the spectra at twosufficiently separated temperatures,7 or by comparing thechemical shifts in the alcohol and the 9-anthrylmethoxyaceticacid (AMA) ester, which induces larger anisotropic shifts.8
The work and the expenses with the materials associatedwith the separation of the esters can all be avoided if theidentification of the signals of the esters in the reaction mixtureis possible. When using the acyl chloride of MTPA, one can runthe reaction directly in an NMR tube, in a deuterated solvent;the signals of the ester in the aliphatic region, free from signalsfrom MTPA or pyridine, can be used for analysis. However, the
Received: February 17, 2012Published: April 4, 2012
Figure 1. “NMR significant” conformations of the R-MPA and S-MPAesters of L1L2CH−OH. In the R-MPA ester, the phenyl group shieldsthe protons in L2, whereas in the S-MPA ester, it shields the protonsin L1. The difference in chemical shifts for a particular proton in thetwo esters, ΔδRS = δR − δS, is positive for the protons in L1 andnegative for the protons in L2.
acyl chloride cannot be used for MPA esters, becauseracemization occurs under these reaction conditions. MPA isto be preferred over MTPA because it yields larger ΔδRS;9however, the use of DCC obscures the signals in the aliphaticregion as well. Careful weighing of the reagents in the reactionof MPA and decantation of the dicyclohexylurea (DCU) yieldan NMR sample in which some signals of the alcohol moiety inthe ester may be identified in the spectrum of the reactionmixture and used for analysis.10 A major development inpreparing clean samples of the MPA esters in the NMR tubewas the “mix-and-shake” method using resin-bound MPA.11
We introduce in this paper the application of selectiveexcitation 1D-NMR experiments as the next development inthe analysis, which follows the advances in NMR instrumenta-tion. The hardware required for these experiments, pulsed fieldgradients and waveform generator on the proton channel, arestandard on the spectrometers manufactured in the last 10years. The software on these spectrometers automaticallycalculates the shaped pulse for the selective excitation, leavingthe experimental setup as simple as selecting the experimenttype from a drop-down menu and defining the region forselective excitation with two cursors on the spectrum.Selecting the signal of the α proton in the MPA esters
prepared in the NMR tube, one can generate a spectrum thathas only the signals of the nearby protons in the same couplingnetwork, in TOCSY1D, or the signals of the protons nearby inspace, in NOESY1D or ROESY1D.12 This approach has twoobvious advantages: First, only the signals of the protonsrelevant for the assignment of the absolute configuration aredisplayed, free from the overlap with the signals of less relevantprotons in the same molecule, and second, the signals of theMPA moiety, DCC, DCU, and DMAP are removed from thespectrum.Since the resulting spectra have a small number of signals, the
selective excitation experiments allow for the simultaneouspreparation and analysis of the two diastereomeric esters in thesame NMR tube. The signals of the R-MPA and S-MPA estersare identified by their ratio.Practical details of the method, as well as its scope will be
discussed further on, on the examples of the alcohols in Figure2.
■ RESULTS AND DISCUSSIONA mixture of two parts R-MPA to one part S-MPA was alwaysused for derivatizationthe R-enantiomer is cheaper. Stocksolutions of 2R+1S-MPA with DMAP and of DCC wereprepared and added to the alcohol solution in volume ratioscalculated using the TMS signal of the solvent (see theExperimental Section ) to ensure an excess of 10−20%. Thesignal of the α proton in the ester was identified in thespectrum of the reaction mixture and used for selectiveexcitation in the TOCSY1D or NOESY1D experiment. Thefollowing abbreviations will be used in this discussion to explainthe multiplicities: s = singlet, d = doublet, t = triplet, q =quartet.(1R,2S,5R)-(−)-Menthol (1). Figure 3b displays the proton
spectrum of the reaction mixture of menthol with a slight excessof 2R+1S-MPA, DCC, and DMAP. Upon esterification, thesignal of H1 (td) moved from 3.41 ppm in the alcohol (Figure3a) to 4.65 ppm in the R-MPA ester and 4.74 ppm in the S-MPA ester. This is the only pair of signals that can be identifiedin this spectrum, although the excess of reagents is small andmany signals from the menthol esters can be recognized. The
TOCSY1D spectrum with selective excitation of the region of4.55−4.85 ppm and with a mixing time of 0.01 s (Figure 3c)displays three pairs of signals, corresponding to H2, H6eq, andH6ax. The signals of the methine protons in the MPA moietiesalso show up in the selective excitation region, but they do notgenerate any signals in the TOCSY1D spectrum since they donot couple with any other protons. These six signals can beassigned based on their multiplicity, since H6eq, H2, and H6axhave one, two, and three large coupling constants, correspond-ingly. Within a pair, the signals can be assigned to the R- or S-MPA esters based on their intensity. The TOCSY1Dexperiment does not preserve the intensity of the signalsfrom the proton spectrum,13 but the relative intensity of theprotons in the same position is expected to be the same as inthe proton spectrum, because of the similarity of the couplingconstants in the two diastereomers. In principle, one ΔδRSvalue is enough to assign the absolute stereochemistry of thealcohol; however, more ΔδRS values for the protons close tothe chiral center should be used for a reliable assignment.5 Thethree values measured directly on the spectrum in Figure 3c allindicate that the configuration at C1 is R.The more ΔδRS values, the better the confidence in the
assignment of the absolute configuration; therefore, weexplored next the utility of the TOCSY1D experiment inmeasuring ΔδRS for protons further down the couplingnetwork. The signals of these protons show up as a functionof the mixing time and of the values of the coupling constantson the coupling pathway. In principle, all of the protons in thementhol moiety can be revealed by increasing the mixing timein the TOCSY1D experiment in Figure 3c, but the resultingspectrum, although it would have fewer signals than thespectrum of the mixture obtained in the NMR tube by the“mix-and-shake” method,11a would be too complicated tointerpret. We took advantage of the fact that, in the case ofmenthol, the signals of H1 in the MPA esters can be irradiated
Figure 2. Secondary alcohols of diverse structural features, selected forthis study.
The Journal of Organic Chemistry Article
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853979
Figure 3. (a) 1H spectrum of menthol. (b) 1H spectrum of the reaction mixture with 2R+1S-MPA, DCC, DMAP. (c) TOCSY1D spectrum withselective excitation of H1 in the MPA esters (top).
Figure 4. (a−e) TOCSY1D spectra with selective excitation of H1 in the R-MPA ester of menthol and increased mixing time. (f) Selectivedecoupling in the TOCSY1D spectrum with mix = 0.16 s.
The Journal of Organic Chemistry Article
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853980
separately; the TOCSY1D spectra of the R-MPA ester with anarray of values for the mixing time (mix) is presented in Figure4.The spectrum with mix = 0.01 s displays the signals of H2,
H6ax, and H6eq; for mix = 0.02 s, the signals of H3ax, H3eq,H5, and H7 show up also. Additional signals for H4ax, H4eq,and H10 rise at mix = 0.04, and finally all of the signals in the R-MPA ester of menthol are visible at mix = 0.08 s. All of thesignals can be assigned on their unique multiplicity (H4eq andH6eq have a W-coupling), except for those of H3ax, H4ax, H8,and H9. Selective decoupling of the most shielded quartet ofdoublets in the TOCSY1D experiment (Figure 4f) removed thelarge coupling from H4eq and one of the small couplings fromH3eq, allowing for the assignment of this doublet of quartets toH4ax. The doublets at 0.43 and 0.64 ppm were assigned basedon their large chemical shift difference, the most shielded toH8, like in menthol. The stereochemical assignment of thesignal at 0.81 ppm to H8, pro-S, and of the signal at 0.91 ppm asH9, pro-R, in menthol was based on the calculated chemicalshifts for C8 and C9,14 and confirmed by a larger couplingconstant of H2 with C8 than with C9 in the gHMBC spectrum(Figure S3, Supporting Information).TOCSY1D spectra with selective excitation of H1 in the S-
MPA ester display more and more signals with increasing
mixing time (Figure S4, Supporting Information); however, thesignals of H7 and H9 failed to show up. They were revealed in aTOCSY1D experiment with selective excitation at H8 (FigureS5, Supporting Information). Selective decoupling of the mostdeshielded quartet of doublets (Figure S4f, SupportingInformation) removed one of the large couplings of H2,which, therefore, was assigned as H3ax. In this way, all of thesignals of the protons in the two MPA esters of menthol wereidentified; their chemical shifts and the calculated ΔδRS aregiven in Table 1. The ΔδRS values are practically identical tothose published by Hoye et al.9
(1S,2R,4S)-(−)-Borneol (2). The TOCSY1D spectrum of(−)-borneol with selective excitation of H1, recorded with amixing time of 0.01 s (Figure S6b, Supporting Information),displays only the signals of H6-exo and H6-endo, which can beidentified by their multiplicity. A positive ΔδRS of theseprotons confirms the R configuration of C1 in (−)-borneol.Increasing the mixing time to 0.08 s (Figure S6c, SupportingInformation) reveals the signals of H5 and of some otherprotons that were not identified.In a quest for ΔδRS values on the other side of C1, we ran a
NOESY1D experiment with selective excitation of H1. Thespectrum (Figure 5b) displayed the signals of four methylgroups that could eventually be assigned to H9 and H10 in the
Table 1. 1H Chemical Shifts in Menthol and Its MPA Esters, and ΔδRSposition
Figure 5. (a) 1H spectrum of the reaction mixture of borneol with 2R+1S-MPA, DCC, DMAP. (b) NOESY1D spectrum with selective excitation ofH1 in the MPA esters. (c) NOESY1D spectrum with selective excitation of H6exo in the MPA esters.
The Journal of Organic Chemistry Article
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853981
two esters by their nOes with H6exo (Figure 5c). The protonchemical shifts revealed by selective excitation experiments andthe calculated ΔδRS are given in Table 2.
Quinine, (8S,9R)-6′-Methoxycinchonan-9-ol (3). In thecase of quinine, the absolute stereochemistry at C9 can besolved without selective excitation experiments. In the protonspectrum of the reaction mixture, one can easily identify thesignals of H2′, H8′ (Figure S7, Supporting Information), H3,H10, and of the methoxy protons in position 6′ (Figure 6b).Positive ΔδRS values for the quinoline moiety and negativevalues for H3 and H10 confirm the R configuration at C9.Selective excitation experiments allowed for the measure-
ment of 14 of the remaining 16 protons. The results arepresented in Table 3. The TOCSY1D experiment with selectiveexcitation of the α proton, H9, and with a mixing time of 0.02 srevealed H8 in the two esters (Figure 6c), demonstrating thusthe generality of our approach. A longer mixing time revealedmore signals that could not be assigned (Figure 6d).Selective excitation of H10 in the TOCSY1D experiment
with a mixing time of 0.02 s reveals H3 (Figure 6e). Thespectrum with a mixing time of 0.16 s (Figure 6f) displays alsothe signals of H2-syn, H2-anti (relative to the vinyl group), andH4. The former was identified in the NOESY1D spectrum withselective excitation of H10 (Figure 6g). This spectrum alsodisplays the signals of H8 and H11-cis (to H10), and one moreset of signals, at 1.71 (S-MPA) and 1.49 (R-MPA) ppm, whichwas assigned to H7-exo. The NOESY1D spectrum withselective excitation of H9 (Figure 6h) displays three sets ofsignals, for H8, H7-endo, and H6-endo. The assignment of thelast two was based on their chemical shifts. Selective excitationof H3 produced a NOESY1D spectrum (Figure 6i) displayingthe signals of H10, H11-trans, H2-anti, and H4 and another setof signals that were assigned as H5-exo.Protons in position H3′ in the two esters have been identified
in TOCSY1D experiments with selective excitation of H2′(Figure S7c, Supporting Information), while selective excitationof H8′ revealed H5′ and H7′ (Figure S7d, SupportingInformation).Egg Sphingomyelin, (2S,3R,4E)-2-Acylaminooctadec-
4-ene-3-hydroxy-1-phosphocholine (4). The reactionmixture of egg sphingomyelin (Figure S8b, SupportingInformation) presents the challenge of α protons overlappingthe alkene ones. In this case, all of these protons were includedin the selective excitation of the TOCSY1D experiment. In theresulting spectra (Figure S8c, Supporting Information), one caneasily identify the signals of H2 (triplet of triplets at 4.30 and4.21), NH (doublet at 7.54 and 7.40), and H6 (quartet at 1.97and 1.82). The signals of H1a,b are also visible in the region of3.30−4.00 ppm, but their assignment is not straightforward.TOCSY1D experiments with separate selective excitation of thesignal of H2 in the R and S ester (Figure S9, SupportingInformation) revealed that the doublet at 3.97 belongs to the S-
MPA esterH1a and H1b have the same chemical shift andcouple only with H2. The doublet of doublets at 3.85 ppm andthe triplet of doublets at 3.45 ppm belong to the R-MPA ester,and the extra couplings are with 31P.The chemical shifts identified for the MPA esters of
sphingomyelin are presented in Table 4. Positive ΔδRS forH4−H6 and negative ΔδRS for H1a, H1b, and H2 indicate thatthe absolute configuration at C3 is R. The fact that NHpresents an unexpected ΔδRS value (which can be explained bythe preference for a conformation in which the alkyl chains areclose to each other, but this is beyond the scope of this paper)is one more argument for the necessity of obtaining as manyΔδRS values as possible.5
Pregnenolone, 3β,17-Dihydroxy-5-pregnen-20-one(5). The proton spectrum of the reaction mixture ofpregnenolone (Figure S10b, Supporting Information) displaysthe signals of H6 in the R- and S-MPA esters in a clean region,at 5.34 and 5.28 ppm, correspondingly (ΔδRS = 0.06), and theabsolute configuration of C3 can be assigned as S. AdditionalΔδRS values can be obtained from the TOCSY1D spectrumwith selective excitation of H3 in the esters (Figure S10c,Supporting Information). The quartets of doublets at 1.48 and1.60 ppm lose one large coupling upon selective decoupling ofH3 (Figure S10d, Supporting Information); therefore, they arethe signals of H2 axial in the R- and S-MPA esters,correspondingly (ΔδRS = −0.12).
(2S,3S)-Ethyl 2-Fluoro-3-hydroxybutanoate (6). Thespectrum of alcohol 6 is given in Figure S11a (SupportingInformation). The proton in position 2 shows up at 4.74 ppmas a doublet of doublets (dd), coupling with a constant of 48.4Hz with the geminal fluorine and with 3.3 Hz with H3. H3 is at4.20 ppm dqd J = 22.1 (F), 6.7 (H4), and 3.6 (H2) Hz. H4 is adoublet at 1.33 ppm, overlapping the triplet at 1.32 ppm (H2′).The protons in position 1′ overlap at 4.29 pm.Figure S11b (Supporting Information) displays the spectrum
of the reaction mixture with a small excess of the solutions of2R+1S-MPA and DCC. The dqd pattern of H3 in the twoesters is easy to recognize in the region of 5.2−5.5 ppm. Theonly signals in this spectrum that can be used for theassignment of the absolute configuration are the ones of H1′,identified by their doublet of quartets multiplicity and thatshow up in a clean region at 4.2−4.4 ppm in the R-MPA esterand at 3.79 and at 3.54 ppm in the S-MPA ester. However,ΔδRS cannot be measured for these protons because they lackthe stereochemical assignment.The TOCSY1D spectrum with selective excitation of the
region 5.2−5.5 ppm, Figure S11c (Supporting Information),displays just the signals of the protons in the same couplingnetwork with the α proton in the alcohol, namely, H2 at 4.83ppm in the R-MPA ester and at 4.75 ppm in the S-diastereomer, and H4, at 1.23 ppm in the R-MPA ester andat 1.43 ppm in the S one. Values of ΔδRS of −0.20 ppm for H4and 0.08 ppm for H2 allow the assignment of the configurationat C3 as S.
■ CONCLUSIONSelective excitation experiments allow for the determination ofthe absolute configuration of chiral secondary alcohols directlyin the NMR tube, reducing thus significantly the time andexpenses required to solve the problem. A set of alcohols withlarge structural diversity (1−6) demonstrate that theTOCSY1D experiment with selective excitation of the αproton and a short mixing time (0.01−0.02 s) is applicable to
Table 2. 1H Chemical Shifts in (−)-Borneol and Its MPAEsters, and ΔδRS
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853982
Figure 6. (a) 1H spectrum of quinine, expansion. (b) 1H spectrum of the reaction mixture of quinine with 2R+1S-MPA, DCC, DMAP. (c)TOCSY1D spectrum with selective excitation of H9 in the MPA esters, mix = 0.02 s. (d) Same as (c), mix = 0.16 s. (e) TOCSY1D spectrum withselective excitation of H10 in the MPA esters, mix = 0.02 s. (f) Same as (e), mix = 0.16 s. (g−i) NOESY1D spectra with selective excitation of H10(g), H9 (h), and H3 (i).
The Journal of Organic Chemistry Article
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853983
the vast majority of alcohols because (i) the α protons in thealcohol moiety of the esters show up in a region free of signalsthat would interfere with the analysis and (ii) at least one ΔδRScan be measured for the vicinal protons. Selective excitation ofthe α proton not only is possible but also makes sense, since itreveals the protons around the chiral derivatization agent,protons for which the largest ΔδRS values are expected. MoreΔδRS values can be measured for protons in the same couplingnetwork by lengthening the mixing time. Alternately, ΔδRSvalues for the protons that are not in the same couplingnetwork with the α proton can be measured in the NOESY1Dexperiment with selective excitation of the latter.The larger the number of ΔδRS values that are measured, the
higher the confidence in the assignment; additional values canbe obtained in experiments with selective excitation of othersignals that show up in a clear region. Selective decouplingduring acquisition may help with the assignment.Simplification of the spectra in selective excitation experi-
ments makes possible the double derivatization in the sameNMR tube, and the measurement of the ΔδRS directly on thespectrum. The requirements for the preparation of the esters inthe NMR tube are minimal: the reagents are the same as in theusual protocol, and the method is tolerant to an excess ofreagents or to smaller conversion in the reaction.The method has potential for application in the assignment
of the absolute configuration of β-chiral primary alcohols and α-chiral primary amines, which have been shown to follow similarlines of derivatization and analysis as Mosher’s method forsecondary alcohols.1b,5 It could also be used in methodsinvolving derivatization with only one enantiomer of AMAAs,such as those developed in Riguera’s group,7,8 or in Curran’sshortcut method for assigning configurations of stereocenters innearly symmetric environments.15
■ EXPERIMENTAL SECTION
NMR spectra were recorded on a three-channel spectrometer, withwaveform generators on all three, operating at 500 MHz for 1H, andequipped with a 5 mm indirect detection probe with z-axis gradients.The solvent was, in all cases, chloroform-d and the temperature 25 °C.1H chemical shifts were referenced to internal TMS. Compounds 1−5were purchased from commercial sources and used as received.Compound 6 is a known compound.16 The concentrations of thealcohol solutions used to prepare the MPA esters were in the range of0.1−1 mmol/L.
The concentration of all of the solutions was estimated based on theTMS signal of the commercially available chloroform-d with 0.05% v/vTMS, which corresponds to 0.3 mmol/L. All the solutions wereprepared with chloroform-d from the same bottle, and the intensity ofthe signal of one proton relative to the intensity of the TMS signalswas used all throughout to mix the solutions in equivalent amounts. A35 mmol/L stock solution of R-MPA and S-MPA in an approximate2:1 ratio was prepared from solutions of the individual enantiomers(Figure S1, Supporting Information). To this solution was addedDMAP in a 0.22:1 molar ratio. A second stock solution contained 20mmol/L DCC (Figure S2, Supporting Information).
The TOCSY1D and NOESY1D experiments were set with thestandard software on the spectrometer. The selective excitation pulsewas created by the software from the selective excitation region, whichwas defined with two cursors on the proton spectrum. Typically,spectra were acquired on a window from 14 to −2 ppm, with anacquisition time of 2 s and a relaxation delay of 1 s, in one or moreblocks of 32 transients. The mixing time in the TOCSY1D spectravaried from 0.01 to 0.16 s and is given in the captions of the figures.The mixing time in the NOESY1D spectra was 0.5 s. Most of theTOCSY spectra were run for 2−4 blocks (3−5 min). NOESY1Dspectra took typically half an hour.
Table 3. 1H Chemical Shifts in Quinine and Its MPA Esters, and ΔδRSposition
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853984
■ ASSOCIATED CONTENT*S Supporting InformationThe other spectra mentioned in the text are presented in theSupporting Information. This material is available free of chargevia the Internet at http://pubs.acs.org.
■ ACKNOWLEDGMENTSThe author thanks Prof. Alan R. Katritzky for a generous gift ofcompounds 1−3 and 5, and Prof. Jon Stewart for a sample ofcompound 6.
■ REFERENCES(1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95 (2), 512.(b) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104 (1), 17.(c) Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15 (3), 256.(2) (a) Oh, S. S. S.; Butler, W. M.; Koreeda, M. J. Org. Chem. 1989,54 (19), 4499. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.Am. Chem. Soc. 1991, 113 (11), 4092.(3) (a) Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org.Chem. 1995, 60 (3), 504. (b) Latypov, S. K.; Seco, J. M.; Quinoa, E.;Riguera, R. J. Org. Chem. 1996, 61 (24), 8569.(4) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2 (10),2451.(5) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001,12 (21), 2915.(6) (a) Moraga, J.; Pinedo, C.; Duran-Patron, R.; Collado, I. G.;Hernandez-Galan, R. Tetrahedron 2011, 67 (2), 417. (b) Freire, F.;Seco, J. M.; Quinoa, E.; Riguera, R. Org. Lett. 2010, 12 (2), 208.(7) Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Am. Chem.Soc. 1998, 120 (5), 877.(8) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron 1999, 55 (2),569.(9) Hoye, T. R.; Erickson, S. E.; Erickson-Birkedahl, S. L.; Hale, C. R.H.; Izgu, E. C.; Mayer, M. J.; Notz, P. K.; Renner, M. K. Org. Lett.2010, 12 (8), 1768.(10) Orlov, N. V.; Ananikov, V. P. Green Chem. 2011, 13 (7), 1735.(11) (a) Porto, S.; Duran, J.; Seco, J. M.; Quinoa, E.; Riguera, R. Org.Lett. 2003, 5 (17), 2979. (b) Porto, S.; Seco, J. M.; Espinosa, J. F.;Quinoa, E.; Riguera, R. J. Org. Chem. 2008, 73 (15), 5714.(12) Kessler, H.; Oschkinat, H.; Griesinger, C. J. Magn. Reson. 1986,70 (1), 106.(13) Braunschweiler, L.; Ernst, R. R. J. Magn. Reson. 1983, 53 (3),521.(14) Hartner, J.; Reinscheid, U. M. J. Mol. Struct. 2008, 872 (2−3),145.(15) Curran, D. P.; Sui, B. J. Am. Chem. Soc. 2009, 131 (15), 5411.(16) Szori, K.; Szollosi, G.; Bartok, M. Adv. Synth. Catal. 2006, 348(4−5), 515.
The Journal of Organic Chemistry Article
dx.doi.org/10.1021/jo3003375 | J. Org. Chem. 2012, 77, 3978−39853985
