A practical and highly stereoselective umpolung alternative to the alkylation of chiral enolates [19]

Full text of DOI:10.1021/ja982525l

11832
J. Am. Chem. Soc. 1998, 120, 11832-11833
Scheme 1
A Practical and Highly Stereoselective Umpolung
Alternative to the Alkylation of Chiral Enolates
Claude Spino* and Christian Beaulieu
UniVersite´ de Sherbrooke
De´partement de Chimie
2500 Boul. UniVersite´
Sherbrooke, Quebec J1K 2R1, Canada
ReceiVed July 17, 1998
The synthetic organic chemist may nowadays select from an
impressive arsenal of chiral enolates, or equivalents, to construct
optically enriched carbonyls having an R-stereogenic center.1,2
These include enolates and equivalents derived from chiral amides,
esters, imines, enamines, and hydrazones and enolates possessing
chirality at the metal.1,3-6 However, reactivity imposes a serious
limitation to this strategy. Many chiral enolates will alkylate only
reactive electrophiles such as methyl, ethyl, and some primary
alkyl iodides and benzyl or allyl halides. s-Alkyl, t-alkyl or
phenyl halides are unreactive or lead to elimination products in
most cases. Also, the reaction sometimes leads to self-condensa-
tion byproducts. The Lewis acid induced alkylation of silyl enol
ethers allows reaction with SN1-prone electrophiles but is of
limited use with ester or amide derived O-silyl ketene acetals,
and s-alkyl electrophiles are poor electrophiles with this method.7,8
In this paper, we disclose our preliminary results on a
conceptually different approach to produce carbonyls with an
R-chiral center of high optical purity based on the SN2′ displace-
ment reaction of alkyl cuprates on chiral allyl carbonates.
Cuprates are known to add preferentially anti to allylic, propar-
gylic, and allenic halides, acetates, carbonates, and epoxides.9,10
Thus, in principle, the displacement reaction of a chiral allyl
carbonate 2 could lead to a carbonyl R to the newly created chiral
center after oxidative cleavage of the newly formed double bond
(cf. 4, Scheme 1).11 The success and practicality of such a strategy
rests on several issues, the stereoselective construction of the allyl
carbonate 2, restriction of the rotational freedom of the vinyl group
in 2 during the addition step, and the stereoselectivity of the
addition process itself. Ideally the chiral auxiliary 5 should be
inexpensive, readily available in either enantiomeric forms, and
recovered after the reaction sequence. For our purposes, men-
thone answered all of these requirements.
Scheme 2
Table 1. SN2′ Displacement Reactions of Cuprates on Chiral
Carbonates
R′2CuLi
R′CuCNLi
yieldsa
(%)
%
de
yieldsa
(%)
%
de
entry 10
R
R′
Et
n-Bu
t-Bu
Ph
11
1
2
3
4
5
6
7
8
9
10a Me
10a Me
10a Me
10a Me
10a Me
10b n-Bu Me
10c t-Bu Me
10c t-Bu Ph
11a
11b
11c
11d
75
70
>99
>99
67
55
78
40b
>99
>99
>99
>99
75
>99
>99
>99
>99
>99
>99
cyhex 11e
91c
70
The addition reaction of a series of alkynyl and alkenyl metals
11f
to (-)-menthone12 proceeded with complete stereoselectivity to
11 g
11h
11i
61
72d
61
0
* Correspondence author. Tel: (819)-821-7087. Fax: (819)-821-8017.
E-mail: cspino@courrier.usherb.ca.
10d Ph
Me
(1) Evans, D. A. In Asymmetric Synthesis. Stereodifferentiating Reactions,
Part B.; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, p 1.
(2) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 1.
a For two steps from corresponding alcohol 9. b Ph(thiophene)CuLi
was used. 80% based on recovered starting material. c From the
corresponding cyhexMgBr. d -30 to 25 °C for 6 h.
(3) Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(4) Bergbreiter, D. E.; Newcomb, M. In Asymmetric Synthesis. Stereodif-
ferentiating Reactions, Part A.; Morrison, J. D., Ed.; Academic Press: New
York, 1983; Vol. 2, p 243.
(5) Enders, D. In Asymmetric Synthesis. Stereodifferentiating Reactions,
Part B.; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, p
275.
(6) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(7) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1982, 21, 96.
(8) Examples of asymmetric alkylation with SN1 prone electrophiles, other
than s- or t-alkyl electrophiles, can be found in Evans, D. A.; Urpi, F.; Somers,
T. C.; Clark, S. J.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215.
(9) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186.
(10) For a leading reference, see: Corey, E. J.; Boaz, N. W. Tetrahedron
Lett. 1984, 25, 3063.
give the corresponding propargyl alcohols 8 or allylic alcohols 9
in yields of 70-99% (Scheme 2).13 The isopropyl group
effectively directed the incoming nucleophile to the opposite face
of the carbonyl. The alkynyl groups were then selectively reduced
in good yields (70-86%) to the (E)-allylic alcohols using Red-
Al. Each allylic alcohol 9 was converted to its corresponding
carbonate, and the crude mixture was treated with alkyl cuprates
of the type R2CuM or RCuCNLi, where M ) Li or Mg (Table
1). All addition reactions gave essentially only one detectable
diastereomer. The isopropyl may also assist in the anti selectivity
(11) (a) A D-glucose derived template has been used to make amino acids
from allylic alcohols by intramolecular rearrangement: Kakinuma, K.;
Koudate, T.; Li, H.-Y.; Eguchi, T. Tetrahedron Lett. 1991, 32, 5801. (b)
Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527.
(12) Eliel, E. L. In Asymmetric Synthesis. Stereodifferentiating Reactions,
Part A.; Morrison, J. D., Ed.; Academic Press: New York, 1983; Vol. 2, p
125.
(13) All new compounds gave satisfactory NMR and mass spectral data.
10.1021/ja982525l CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/30/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 45, 1998 11833
Scheme 3
Figure 1.
of the additions. In three cases we prepared separately the other
diastereomers by interchanging the substituent on the allyl moiety
and on the cuprate (entries 6, 7, and 9). The diastereomeric purity
of the individual adducts could then be cross-checked by injecting
an equimolar mixture of the pairs in a capillary GC. The other
adducts were judged to be also >99% pure from GCMS and 1H
and 13CNMR spectra. Tertiary, secondary, and primary alkyl as
well as aryl cuprates gave good yields and complete selectivities.
So far, we were unsuccessful in adding vinyl cuprates. We
explain this high level of selectivity from the large energy
difference between the two reactive rotamers A and B of the
alkenyl moiety in 10 (Figure 1).14 This energy difference must
remain at the transition state level during the anti-selective
addition of the cuprate reagent. Note that the Z-isomer of 10a
did not react under those conditions, presumably because the
required conformation A in unattainable due to steric repulsion.
The oxidative cleavage was accomplished by ozonolysis to
furnish either the acid, the aldehyde, or the alcohol directly. As
an example, compound 11d was cleaved by ozonolysis to give
40%, 90%, and 75% of the corresponding acid 12a, aldehyde
12b, and alcohol 14, respectively (Scheme 3). The construction
of the sterically congested tert-butylphenyl acetic acid 13 (61%)
and its alcohol 15 (70%) in >99% ee is noteworthy. Typically,
(-)-menthone (or menthol) could be recovered in unoptimized
yields of 60-65% after oxidative cleavage. The sense of
asymmetric induction in the cuprate addition was verified by
comparing the optical rotation of the alcohols with those in the
literature.15,16 It was consistent with an anti-selective addition
of the cuprates on rotamer A (Figure 1). The enantiomeric purity
of each isolated aldehyde or acid was established by first reducing
the carbonyl to the corresponding alcohol and then converting
the alcohol to its Mosher ester. Mosher esters from the racemic
acid were also prepared for comparison. 19F and 1H NMR
indicated no racemization in all cases so aldehydes and acids were
obtained in >99% ee.
Our method provides a useful and practical alternative to the
alkylation of chiral enolates. It is complementary since the
carbonyl product is obtained, starting from an alkene or an
alkyne.17 It is also ‘umpolung’ since the electrophile used in the
alkylation reaction becomes the nucleophile in our sequence and
the auxiliary bears an electrophilic rather than nucleophilic double
bond. Secondary and tertiary alkyl and aryl groups are reactive,
allowing access to hindered aldehydes and acids of high optical
purity. Further development and extension of this methodology
is currently underway.
Acknowledgment. We are grateful to the Natural Sciences and
Engineering Research Council of Canada and the Universite´ de Sher-
brooke for financial support.
Supporting Information Available: Experimental procedures, char-
1
acterization data and H NMR spectra for new compounds (41 pages,
print/PDF). See any current masthead page for ordering information and
Web access instructions.
(14) Conformer A (R ) Me, R′′ ) H) was found to be 4.1 kcal/mol lower
in energy than conformer B using CSChem3D Software.
(15) 14: [R]D ) +14.3° (CHCl3, c 1.65), lit. [R]D ) +15.75° (neat). Janssen,
A. J. M.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1991, 47, 7645.
(16) 15: [R]D ) +13.7° (EtOH, c 0.68), lit. [R]D ) +16.4° (EtOH, c 2.22).
Imajo, S.; Kuritani, H.; Shingu, K.; Nakagawa, M. J. Org. Chem. 1979, 44,
3587.
JA982525L
(17) For a different approach to chiral â-substituted alcohols from alkenes,
see: (a) Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 10771.
(b) Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem. Soc. 1996, 118, 1577.