Asymmetric tandem wittig rearrangement/mannich reactions

Article abstract of DOI:10.1002/anie.201000609

Figure Presented The choice is yours: A highly stereoselective synthesis of α-alkyl-α-hydroxy-β-amino esters is accomplished through a tandem Wittig-rearrangement/Mannich reaction sequence. Transformations of N-benzyl or N-Boc imines proceed with high selectivity for formation of syn-amino alcohol derivatives, whereas N-Boc-2-(phenylsulfonyl)amines generate antiammo alcohol products. Auxiliary cleavage (transesterification or reduction) yields enantiomerically enriched products with up to 96% ee.

Full text of DOI:10.1002/anie.201000609

Communications
DOI: 10.1002/anie.201000609
Tandem Reactions
Asymmetric Tandem Wittig Rearrangement/Mannich Reactions**
Natalie C. Giampietro and John P. Wolfe*
Asymmetric Mannich reactions provide a highly convergent
and efficient method to access enantiomerically enriched
b-amino acid derivatives.[1,2] In some instances these reactions
have proven effective for the generation of biologically
significant and synthetically useful b-amino acids that contain
a quaternary stereocenter substituted with a nitrogen atom
adjacent to the carbonyl group.[3] In principle, related
asymmetric Mannich reactions of a-alkyl-a-hydroxy esters 1
could provide efficient access to a-alkyl-a-hydroxy-b-amino
acids 2 [Eq. (1)], which have been used as intermediates in the
synthesis of taxol analogues,[4] and are displayed in natural
products such as leuhistin (a potent aminopeptidase inhib-
itor).[5] However, in practice, the transformation illustrated in
Equation (1) is difficult to achieve, and the direct asymmetric
synthesis of 2 by ester enolate Mannich reactions has not been
described. This may be due to the fact that deprotonation of
a-alkyl-a-hydroxy esters typically leads to formation of E and
Z ester enolate mixtures,[6] which are transformed to stereo-
isomeric amino alcohol products in the Mannich reactions.
reaction could provide an efficient means of preparing
a-alkyl-a-hydroxy-b-amino esters with a high degree of
stereocontrol. Herein we describe our preliminary studies in
this area, which have led to the first asymmetric Mannich
reactions of ester enolates that afford both syn- and anti-a-
alkyl-a-hydroxy-b-amino esters with high d.r. and ee. These
are also the first examples of asymmetric Mannich reactions
that proceed through tetrasubstituted enolboronate inter-
mediates.
In our initial efforts to effect tandem asymmetric Wittig
rearrangement/Mannich reactions we examined the coupling
of (À)-3a with several imines derived from benzaldehyde. As
shown in Table 1, the nature of the N-substituents had a large
effect on reactivity and selectivity. Imines bearing strongly
electron-withdrawing N-substituents such as tosyl or phos-
phoryl failed to undergo the Mannich reaction with the boron
enolate generated after the Wittig rearrangement (Table 1,
entries 4 and 5). Improved reactivity was observed with N-
aryl imines, but diastereoselectivity was modest (entries 2 and
3). However, use of the N-benzylimine provided satisfactory
results (entry 1).[12]
As shown in Table 2, tandem asymmetric Wittig rear-
rangement/Mannich reactions between O-alkyl-2-phenycy-
clohexyl glyclolate esters (À)-3a,b and a range of N-
benzylimines derived from aromatic aldehydes proceed in
good yield and with excellent stereoselectivity. In all cases
products were formed with at least 20:1 d.r., and enantio-
merically enriched aminodiols were obtained in 90–96% ee
To avoid this problem, asymmetric Mannich reactions of
chiral lactone enolates derived from enantiopure 1,3-dioxo-
lan-4-ones have been developed.[7] Although these reactions
do provide access to compounds related to 2, formation of
mixtures of syn and anti amino alcohol stereoisomers remains
problematic. Several alternative approaches to the synthesis
of a-alkyl-a-hydroxy-b-amino esters have also been explored,
but they either lack the convergence of a Mannich-based
strategy,[8] or suffer from limited stereocontrol.[9,10]
Table 1: Imine substituent effects.[a]
We recently reported a tandem asymmetric Wittig rear-
rangement/Aldol reaction between aldehydes and O-allyl or
O-benzyl glycolate esters of trans-2-phenylcyclohexanol. The
transformations proceed through Z-boron ester enolates, and
afford syn-a-alkyl-a,b-dihydroxy esters with up to 95% ee
and > 20:1 syn:anti selectivity after cleavage of the 2-phenyl-
cyclohexanol chiral auxiliary.[11] Based on these results, it
seemed likely that a related Wittig rearrangement/Mannich
Entry
R[b]
Yield
[%][c]
d.r.[d]
ee after
auxiliary
cleavage[e]
1
2
3
4
5
Bn
PMP
Ph
Ts
P(O)Ph2
71
85
71
0[f]
0[f]
>20:1
4:1
11:1
–
96%
58%
83%
–
–
–
[a] Conditions: 1.0 equiv (À)-3a, 3.2 equiv Bu2BOTf, 4.0 equiv Et3N,
CH2Cl2 (0.1m), 08C, 5 min, warm to RT for 15 min, cool to 08C, add
imine. [b] Bn=benzyl, PMP=p-methoxyphenyl, Ts=p-toluenesulfonyl.
[c] Yield of isolated product (average of two or more runs). [d] Diaste-
reomeric ratio of isolated material (determined by 1H NMR analysis).
The d.r. value of the crude product could not be determined because of
signal overlap with boron-containing by-products. [e] The enantiomeric
excess was determined by HPLC or Mosher ester analysis after
transesterification to the methyl ester or reduction to the aminodiol.
[f] The imine failed to undergo Mannich reaction.
[*] N. C. Giampietro, Prof. J. P. Wolfe
Department of Chemistry, University of Michigan
930 N. University Ave, Ann Arbor, MI 48109-1055 (USA)
E-mail: jpwolfe@umich.edu
[**] We acknowledge the ACS Petroleum Research Fund for financial
support of this work. Additional funding was provided by Glax-
oSmithKline, Amgen, and Eli Lilly.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000609.
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Chemie
Table 2: Asymmetric Wittig-rearrangement/Mannich reactions with
N-benzylimines.[a]
Table 3: Asymmetric Wittig-rearrangement/Mannich reactions with
N-Boc-2-(phenylsulfonyl)amines.[a]
R1
Product
Yield
[%][b]
d.r.[c]
ee after
Entry
R
R1
Product
Yield
[%][b]
d.r.[c]
ee after
Entry
R
auxiliary
auxiliary
cleavage[d]
cleavage[d]
1
2
3
Bn
Bn
Allyl
Ph (15a)
iBu (15b)
Cy (15c)
16
17
18
58
75
60
>20:1
20:1
20:1
96%
91%
90%
1
2
3
4
5
6
Bn
Bn
Bn
Bn
Allyl
Allyl
Ph
4
7
8
9
10
11
71
85
70
54
63
69
>20:1
20:1
20:1
>20:1
>20:1
>20:1
96%
90%
90%
93%
94%
94%
PMP
2-furyl
Cy
Ph
p-F-C6H4
[a] Conditions: 1.0 equiv (À)-3a or (À)-3b, 3.2 equiv Bu2BOTf, 4.0 equiv
iPr2NEt, CH2Cl2 (0.1m), 08C, 5 min, warm to RT for 20 min, cool to 08C,
add 15. [b] Yield of isolated products (average of two or more runs).
[c] Diastereomeric ratio of isolated material (determined by 1H NMR
analysis). The d.r. value of the crude product could not be determined
because of signal overlap with boron-containing by-products. [d] The
enantiomeric excess was determined by HPLC or Mosher ester analysis
after reduction to the corresponding aminodiol.
[a] Conditions: 1.0 equiv (À)-3a or (À)-3b, 3.2 equiv Bu2BOTf, 4.0 equiv
Et3N (R=Bn) or 4.0 equiv iPr2NEt (R=allyl), CH2Cl2 (0.1m), 08C, 5 min,
warm to RT for 15–20 min, cool to 08C, add imine. [b] Yield of isolated
product (average of two or more runs). [c] Diastereomeric ratio of
isolated material (determined by 1H NMR analysis). The d.r. value of the
crude product could not be determined because of signal overlap with
boron-containing by-products. [d] The enantiomeric excess was deter-
mined by HPLC or Mosher ester analysis after transesterification to the
methyl ester or reduction to the aminodiol.
14 and Boc-protected amino alcohol 16 also proceeded
smoothly [Eqs. (5) and (6)].
after reduction with LiAlH4. The N-benzylimine prepared
from cyclohexane carboxaldehyde was also transformed with
high stereoselectivity, but in slightly lower yield (Table 2,
entry 4). However, N-benzylimines derived from unbranched
aliphatic aldehydes failed to undergo the Mannich reaction.
Although imines bearing strong electron-withdrawing
groups failed to undergo Mannich reaction (Table 1, entries 4
and 5), use of N-Boc imine 12 as an electrophile in the tandem
reaction with 3a generated isoxazolidin-2-one 13 (derived
from the corresponding syn-amino alcohol) in 74% yield and
> 20:1 d.r. (94% ee after reduction) [Eq. (2)]. A similar result
was obtained for the coupling of 12 with O-allyl glycolate
ester (À)-3b to give 14.
The mechanism of the tandem reactions likely occurs
through an initial ester enolate Wittig-rearrangement fol-
lowed by a second enolization to yield 23.[11,13,14] The relative
stereochemical configuration of the amino-alcohol product is
set during the subsequent Mannich reaction, and is dependent
on the nature of the electrophile. In reactions involving
N-benzyl- or N-Boc-imine electrophiles the Mannich reac-
tions occur through boat-like transition state 24 to afford the
syn-amino alcohol products 4–11 and oxazolidin-2-ones 13
and 14.[15] In contrast, reactions of N-Boc-2-(phenylsulfonyl)-
amines 15a–c likely involve intermediate N-Boc iminium
ions. The Mannich reactions between 23 and the electrophilic
iminium ions occur through open transition states 25 in which
R2 is positioned away from the two bulky boron groups. This
gives rise to the observed anti-amino alcohol products 16–18
(Scheme 1).
Reactions of N-Boc imines or enamides derived from
aliphatic aldehydes failed to afford the desired amino alcohol
products. However, we were pleased to discover that trans-
formations of N-Boc-2-(phenylsulfonyl)amines 15a–c bearing
either aliphatic or aromatic R1 groups proceeded in moderate
to good yields with excellent stereocontrol (Table 3). In
contrast to reactions of imine electrophiles, which afforded
syn-amino alcohols (or oxazolidinones), use of 15 led to the
formation of anti-amino alcohol products 16–18.
Cleavage of the chiral auxiliary from the amino alcohol
products was accomplished either through methanolysis or
reduction. For example, treatment of 4 with NaOMe/MeOH
provided methyl ester 19 in 62% yield [Eq. (3)]. Alterna-
tively, reduction of 11 with LiAlH4 generated amino-diol 20 in
97% yield [Eq. (4)]. Selective reduction of cyclic carbamate
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2923

Communications
Risch, Angew. Chem. 1998, 110, 1096; Angew. Chem. Int. Ed.
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[2] For reviews on the asymmetric synthesis of b-amino acids, see:
a) J. A. Ma, Angew. Chem. 2003, 115, 4426; Angew. Chem. Int.
Ed. 2003, 42, 4290; b) M. Liu, M. P. Sibi, Tetrahedron 2002, 58,
7991.
[3] For recent reviews on the asymmetric Mannich Reaction, see:
a) R. G. Arrayꢁs, J. C. Carretero, Chem. Soc. Rev. 2009, 38, 1940;
b) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
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[4] a) I. Ojima, S. Lin, T. Wang, Curr. Med. Chem. 1999, 6, 927; b) I.
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c) J. Kant, W. S. Schwartz, C. Fairchild, Q. Gao, S. Huang, B. H.
Long, J. F. Kadow, D. R. Langley, V. Farina, D. Vyas, Tetrahe-
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[5] a) S. J. Hecker, K. M. Werner, J. Org. Chem. 1993, 58, 1762; b) T.
Aoyoagi, S. Yoshida, N. Matsuda, T. Ikeda, M. Hamada, T.
Takeuchi, J. Antibiot. 1991, 44, 573; c) B. Bauvois, D. Dauzonne,
Med. Res. Rev. 2006, 26, 88.
Scheme 1. Stereochemical hypothesis.
In conclusion, we have developed a new, highly stereose-
lective synthesis of enantiomerically enriched a-alkyl-a-
hydroxy-b-amino esters through tandem asymmetric Wittig
rearrangement/Mannich reactions. This method provides
access to a range of syn- and anti-amino alcohol products
from simple starting materials, and further illustrates the
utility of Wittig rearrangements for stereoselective generation
of enolates derived from a-alkyl-a-hydroxy esters.
[6] A. Clerici, N. Pastori, O. Porta, J. Org. Chem. 2005, 70, 4174, and
references therein.
[7] a) A. Guerrini, G. Varchi, R. Daniele, C. Samori, A. Battaglia,
Tetrahedron 2007, 63, 7949; b) A. Guerrini, G. Varchi, A.
Battaglia, J. Org. Chem. 2006, 71, 6785; c) A. Battaglia, A.
Guerrini, C. Bertucci, J. Org. Chem. 2004, 69, 9055.
[8] For multistep approaches involving b-lactam, epoxide, or
aziridine ring-opening, see: a) J. L. Garcꢂa Ruano, C. G. Paredes,
Tetrahedron Lett. 2000, 41, 5357; b) C. Papa, C. Tomasini, Eur. J.
Org. Chem. 2000, 1569; c) F. Fringuelli, F. Pizzo, M. Rucci, L.
Vaccaro, J. Org. Chem. 2003, 68, 7041.
Experimental Section
Representative procedure for tandem Wittig rearrangement/Mannich
reactions: A flame-dried flask was cooled under a stream of nitrogen
and charged with a 1m solution of dibutylboron triflate in dichloro-
methane (0.56 mL, 0.56 mmol). The pale yellow solution was cooled
to 08C, and triethylamine (62 mL, 0.45 mmol) was added dropwise to
afford a colorless solution. A solution of ester 3a (47 mg, 0.14 mmol)
in CH2Cl2 (0.14 mL) was then added dropwise, and the reaction
mixture was warmed to room temperature, stirred for 15 min, and
then cooled to 08C. A solution of N-(benzylidene)benzylamine
(42 mg, 0.22 mmol) in CH2Cl2 (0.22 mL) was added dropwise, and the
reaction mixture was warmed to room temperature and stirred for
3 h. The reaction vessel was then opened to air, and pH 7 buffer
(1.4 mL), and methanol (2.8 mL) were added. The resulting mixture
was cooled to 08C, 30% aqueous H2O2 (2.8 mL) was added slowly,
and the reaction mixture was warmed to room temperature and
stirred for 1 h. The mixture was diluted with ether (14 mL) and water
(7 mL), then was transferred to a separatory funnel. The layers were
separated, and the organic layer was washed with a saturated aqueous
solution of FeSO4 (4 ꢀ 7 mL) until a red-orange aqueous phase no
longer persisted in order to quench any remaining peroxide. Caution!
This procedure is exothermic. The FeSO4 solution should be added
through a glass pipette SLOWLY DROPWISE. The organic layer was
then washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel to afford 54 mg (72%) of
(À)-(1R,2S,2’R,3’S)-2-phenylcyclohexyl-2’-benzyl-3’-benzylamino-2’-
hydroxy-3’-phenylpropanoate (4) as a white foam.
[9] A. M. Nocioni, C. Papa, C. Tomasini, Tetrahedron Lett. 1999, 40,
8453.
[10] For conjugate addition reactions between enantiopure chiral
amines and a,b-unsaturated esters bearing chiral auxiliaries, see:
a) M. E. Bunnage, A. N. Chernega, S. G. Davies, C. J. Goodwin,
J. Chem. Soc. Perkin Trans. 1 1994, 2373; b) S. G. Davies, S. W.
Epstein, A. C. Garner, O. Ichihara, A. D. Smith, Tetrahedron:
Asymmetry 2002, 13, 1555.
[11] a) N. C. Giampietro, J. W. Kampf, J. P. Wolfe, J. Am. Chem. Soc.
2009, 131, 12556; b) For a “racemic” variant of this trans-
formation, see: M. B. Bertrand, J. P. Wolfe, Org. Lett. 2006, 8,
4661.
[12] The configuration of 4 was determined by X-ray crystallographic
analysis. CCDC 763869 (4) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[13] For reviews on the 1,2-Wittig rearrangement, see: a) J. P. Wolfe,
N. J. Guthrie in Name Reactions for Homologations Part II (Ed.:
J. J. Li), Wiley, Hoboken, 2009, p. 226; b) K. Tomooka in The
Chemistry of Organolithium Compounds, Vol. 2 (Eds.: Z.
Rappoport, I. Marek), Wiley, London, 2004, p. 749; c) K.
Tomooka, H. Yamamoto, T. Nakai, Liebigs Ann. 1997, 1275.
[14] For other examples of enolate 1,2-Wittig rearrangements, see:
a) D. Y. Curtin, W. R. Proops, J. Am. Chem. Soc. 1954, 76, 494;
b) L. A. Paquette, Q. Zeng, Tetrahedron Lett. 1999, 40, 3823; c) I.
Vilotijevic, J. Yang, D. Hilmey, L. A. Paquette, Synthesis 2003,
1872; d) A. Garbi, L. Allain, F. Chorki, M. Ourevitch, B.
Crousse, D. Bonnet-Delpon, T. Nakai, J. P. Begue, Org. Lett.
2001, 3, 2529; e) T. Hameury, J. Guillemont, L. Van Hijfte, V.
Bellosta, J. Cossy, Synlett 2008, 2345.
Received: February 1, 2010
Published online: March 15, 2010
Keywords: asymmetric synthesis · imines · Mannich reaction ·
.
rearrangements · stereoselectivity
[15] The syn-amino alcohol products could also be formed by
reaction of the minor Z-imine stereoisomers through chair-like
transition states. For further discussion, see: C. Gennari, A.
Vulpetti, G. Pain, Tetrahedron 1997, 53, 5909, and references
therein.
[1] For general reviews on the Mannich reaction, see: a) P. Galatsis
in Name Reactions for Homologations Part II (Ed.: J. J. Li),
Wiley, Hoboken, 2009, p. 653; b) M. Arend, B. Westermann, N.
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