Asymmetric tandem Wittig rearrangement/aldol reactions

Article abstract of DOI:10.1021/ja905930s

(Chemical Equation Presented) A new method for the asymmetric synthesis of α-alkyl-α,β-dihydroxy esters that involves tandem Wittig rearrangement/aldol reactions of O-benzyl- or O-allylglycolate esters derived from 2-phenylcyclohexanol is described. This sequence constructs two C-C bonds and two stereocenters, one of which is quaternary, to afford syn diol products with excellent stereocontrol. Cleavage of the chiral auxiliary affords enantiomerically enriched products with up to 95% ee. The application of this method to the preparation of a key intermediate in the synthesis of the antifungal agent alternaric acid is also described.

Full text of DOI:10.1021/ja905930s

Published on Web 08/14/2009
Asymmetric Tandem Wittig Rearrangement/Aldol Reactions
Natalie C. Giampietro, Jeff W. Kampf, and John P. Wolfe*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received July 16, 2009; E-mail: jpwolfe@umich.edu
Substituted R-alkyl-R,ꢀ-dihydroxy carboxylic acids and esters are
important building blocks for organic synthesis and are displayed in
many biologically active molecules, such as the antifungal agent
alternaric acid (1).1,2 The enantioselective construction of these groups
is often achieved through asymmetric dihydroxylation of R-alkyl-R,ꢀ-
unsaturated esters. However, this approach requires a multistep
stereoselective synthesis of the trisubstituted enoate starting material,
and the presence of other alkenes appended to the substrate is usually
not tolerated by the highly electrophilic oxidant.2b,3 Asymmetric aldol
reactions have been used to prepare derivatives bearing protected
hydroxyl groups that can be deprotected in subsequent steps.4 However,
only a single study of asymmetric aldol reactions that directly afford
R-alkyl-R,ꢀ-dihydroxy esters has appeared in the literature. The
selectivity for formation of syn as opposed to anti diols varied widely
from substrate to substrate, and syn diol products were obtained with
little or no enantioselectivity.5,6
provides a significantly improved route to a key intermediate in the
synthesis of alternaric acid.2b
Table 1. Chiral Auxiliary Screena
a Conditions: 1.0 equiv of 6, 1.5 equiv of PhCHO, 3.2 equiv of
Bu2BOTf, 4 equiv of Et3N, CH2Cl2, 0 °C f rt f 0 °C. b Isolated yield
(average of two or more experiments). c Diastereomeric ratios were
1
determined by H NMR analysis.
In our preliminary studies, we sought to achieve asymmetric induction
through the use of esters derived from chiral alcohols (Table 1). Although
the Masamune auxiliary has been shown to provide excellent results in
aldol reactions of trisubstituted ester enolates,11 an O-benzylglycolate ester
bearing this group (6a) failed to undergo [1,2]-Wittig rearrangement. In
contrast, promising results were obtained with menthyl ester 6b, and further
experiments indicated that the O-benzylglycolate ester prepared from
commercially available 2-phenylcyclohexanol12,13 (6f) was transformed
to 7f with excellent stereoselectivity.14
Removal of the chiral auxiliary from 7f was accomplished using
one of two methods (Scheme 2). A two-step sequence involving
conversion of 7f to an acetonide followed by hydrolysis of the ester
afforded carboxylic acid 8a in good yield. Alternatively, treatment of
7f with LiAlH4 afforded enantiomerically enriched triol 9a.
We recently reported a new method for the conversion of methyl
O-allylglycolate (2a) or methyl O-benzylglycolate (2b) into R-alkyl-R,ꢀ-
dihydroxy esters via a tandem 1,2-Wittig rearrangement/aldol reaction
sequence (Scheme 1).7 For example, treatment of 2 with excess Bu2BOTf
and Et3N at 0 °C followed by warming to room temperature (rt) effects
ester enolate 1,2-Wittig rearrangement to provide 3.8,9 Chelation between
the ester carbonyl and the boron alkoxide in intermediate 3 facilitates the
highly stereoselective formation of doubly borylated E enolate 4, which
undergoes aldol reaction upon addition of an aldehyde electrophile. This
tandem reaction sequence constructs two C-C bonds and two stereo-
centers, one of which is quaternary, to afford syn diol products 5 with
excellent stereocontrol. Moreover, the generation of 4 by way of 3 provides
a means for controlling the enolate geometry that is difficult to achieve
through direct deprotonation of R-alkyl-R-hydroxy esters.5,10
Scheme 2. Cleavage of Auxiliary
Scheme 1. Tandem Wittig Rearrangement/Aldol Reaction
As shown in Table 2, the asymmetric Wittig rearrangement/aldol
reactions were effective for the conversion of O-benzyl- and O-
allylglycolate esters 6f and 10, respectively, to a number of different
diol products. A wide range of aldehydes were transformed in good
yield, and all of the reactions proceeded with at least 20:1 syn/anti
selectivity of the diol. In seven of eight cases examined, the ratio of
(2′R,3′S)/(2′S,3′R) diol stereoisomers was g20:1,15 and cleavage of
the auxiliary from these products with LiAlH4 afforded enantiomeri-
cally enriched triols with 89-95% ee.
In this communication, we describe the development of asymmetric
tandem Wittig rearrangement/aldol reactions that provide enantiomerically
enriched R-alkyl-R,ꢀ-dihydroxy esters. These are the first examples of
tandem reactions involving enolate [1,2]-Wittig rearrangements that afford
nonracemic products and are also the first asymmetric aldol reactions of
R-alkyl-R-hydroxy ester enolates that generate unprotected diol products
with both high syn/anti selectivity and high ee. In addition, this new method
9
12556 J. AM. CHEM. SOC. 2009, 131, 12556–12557
10.1021/ja905930s CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Wittig Rearrangement/Aldol Reactionsa
enriched R-alkyl-R,ꢀ-dihydroxy esters in good yield with excellent
stereoselectivity. These transformations provide a new means for the
enantioselective construction of quaternary carbon stereocenters and
allow for straightforward preparation of compounds that are cumber-
some to access via existing methods. Further studies involving
extensions and applications of this chemistry are currently underway.
a Conditions: 1.0 equiv of 6f or 10, 1.5-2 equiv of R1CHO, 3.2
equiv of Bu2BOTf, 4 equiv of Et3N (R ) Bn) or iPrNEt2 (R ) allyl),
CH2Cl2, 0 °C f rt f 0 °C. b Isolated yield (average of two or more
experiments). c Ratios were determined by 1H NMR analysis. All
products were obtained with >20:1 syn/anti selectivity. d Enantiomeric
excess was determined by chiral HPLC or Mosher ester analysis after
reduction to the corresponding triol with LiAlH4.
Acknowledgment. The authors acknowledge the donors of the
ACS Petroleum Research Fund for financial support of this work.
Additional funding was provided by GlaxoSmithKline, 3M, Amgen,
and Eli Lilly. The authors thank Ms. Nicolette Guthrie and Dr. Myra
Beaudoin Bertrand for performing initial experiments in this area.
In order to illustrate the synthetic utility of this transformation, we
sought to prepare 19b, which is closely related to a key intermediate
(19a) in Trost’s synthesis of alternaric acid (Scheme 3).2b Ester 19a
was previously generated from commercially available (S)-2-methyl-
1-butanol (18) in seven steps (longest linear sequence).2b The C10,C11
diol functionality was introduced via Sharpless asymmetric dihydroxy-
lation (AD) of a trisubstituted enoate, and the pendant terminal alkene
was installed in subsequent steps.
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, and descriptions of
stereochemical assignments with supporting crystallographic structural
data for 7f (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
References
Scheme 3. Key Intermediate in Alternaric Acid Synthesis2b
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A. J. Org. Chem. 1994, 59, 4749. (b) Trost, B. M.; Probst, G. D.; Schoop,
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(6) For asymmetric aldol reactions that afford R-alkyl-R,ꢀ-dihydroxy ketones, see:
Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto,
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(8) For reviews of the 1,2-Wittig rearrangement, see: (a) Wolfe, J. P.; Guthrie,
N. J. In Name Reactions for Homologations, Part II; Li, J. J., Ed.; Wiley:
Hoboken, NJ, 2009; p 226. (b) Tomooka, K. In The Chemistry of
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2004; Vol 2, p 749. (c) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs
Ann./Recl. 1997, 1275.
(9) For other examples of enolate 1,2-Wittig rearrangements, see: (a) Curtin,
D. Y.; Proops, W. R. J. Am. Chem. Soc. 1954, 76, 494. (b) Paquette, L. A.;
Zeng, Q. Tetrahedron Lett. 1999, 40, 3823. (c) Vilotijevic, I.; Yang, J.;
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Tetrahedron Lett. 2001, 42, 7197. (b) Abiko, A.; Liu, J.-F.; Masamune, S.
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In principle, 19a could be generated through a Wittig rearrangement/
aldol reaction sequence between methyl ester 2b and enantiopure aldehyde
20 (prepared in one step from 18).16 However, addition reactions of
nucleophiles to 20 are known to occur with poor diastereoselectivity
because of the similar steric properties of the aldehyde C2 substituents
(Me vs Et). As anticipated, the coupling of 2b with 20 proceeded with
modest Felkin selectivity to afford 19a with only 2:1 dr (eq 1). In contrast,
the (1S,2R)-2-phenylcyclohexyl ester 21 was transformed to 19b in 80%
yield as a single stereoisomer (eq 2). Overall, our synthesis of 19b required
only three steps in the longest linear sequence, as ester 21 was prepared
in two steps from commercially available materials. Importantly, our
strategy complements Sharpless AD chemistry, as the Wittig rearrange-
ment/aldol reaction allows for preparation of R,ꢀ-dihydroxy esters bearing
relatively nucleophilic alkenes that would not tolerate typical dihydroxy-
lation conditions.2b,3
In view of the high selectivity observed in reactions of achiral
aldehydes with glycolate esters derived from 2-phenylcyclohexanol,
it seemed likely that the chiral auxiliary could override the slight
preference for Felkin selectivity typically observed with chiral aldehyde
20. This hypothesis proved to be correct, as the tandem Wittig
rearrangement/aldol reaction of (1R,2S)-10 with 20 provided 22 in 81%
yield with >20:1 dr (eq 3).
(12) Gonzalez, J.; Aurigemma, C.; Truesdale, L. Org. Synth. 2002, 79, 93.
(13) A single example of an asymmetric glycolate aldol reaction of a 2-phe-
nylcyclohexyl ester enolate has been described. See: Hattori, K.; Yamamoto,
H. J. Org. Chem. 1993, 58, 5301.
(14) The absolute stereochemistry of 7f was determined by X-ray analysis. See
the Supporting Information for full experimental details.
(15) Diastereomeric ratios were determined by 1H NMR analysis. Ratios listed
as >20:1 are conservative estimates and indicate that the other stereoisomer
could not be detected in the 1H NMR spectrum.
(16) Anelli, P. L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69, 212.
In conclusion, we have developed an asymmetric tandem Wittig
rearrangement/aldol reaction sequence that affords enantiomerically
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