Diastereoselective alkylations of oxazolidinone glycolates: A useful extension of the Evans asymmetric alkylation

Article abstract of DOI:10.1021/ol006091m

matrix presented The diastereoselective alkylation of glycolate oxazolidinones has been demonstrated as a method for the enantioselective preparation of α-alkoxy carboxylic acid derivatives and selectively protected 1,2-diols. Various protecting groups on

Full text of DOI:10.1021/ol006091m

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2165-2167
Diastereoselective Alkylations of
Oxazolidinone Glycolates: A Useful
Extension of the Evans Asymmetric
Alkylation
Michael T. Crimmins,* Kyle A. Emmitte, and Jason D. Katz
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received May 22, 2000
ABSTRACT
The diastereoselective alkylation of glycolate oxazolidinones has been demonstrated as a method for the enantioselective preparation of
r-alkoxy carboxylic acid derivatives and selectively protected 1,2-diols. Various protecting groups on the glycolate hydroxyl and multiple
substitution patterns on allylic iodides are tolerated in the alkylation. Yields for the alkylations are typically 70−85% with diastereoselectivities
of >98:2.
The enantioselective construction of chiral R-hydroxy acids
and chiral 1,2-diols has been extensively studied because of
their importance in asymmetric synthesis.1,2 The manipulation
of tartaric acid, malic acid, and glycidol for complex
synthesis supports the utility of these chiral building blocks.3
Various methods including asymmetric dihydroxylations,4
asymmetric enolate hydroxylations,5 and asymmetric glyco-
late alkylations6-14 have been employed for the preparation
of R-hydroxy acids and their derivatives. The asymmetric
glycolate alkylation is an attractive approach because of the
relative ease of interchanging the alkyl group as well as the
protecting group on the glycolate hydroxyl. Chiral auxiliaries
attached to the carbonyl, the hydroxyl group, and to both
have been employed in diastereoselective alkylations of chiral
glycolates.6-14
For ongoing studies, we required access to both simple
R-alkoxy carboxylic acid derivatives and more complex R,R′-
disubstituted ether derivatives.15,16 The asymmetric glycolate
alkylation offered an attractive solution to both these needs.
As such, we required a highly diastereoselective asymmetric
glycolate enolate which allowed for easy interchange of the
hydroxyl protecting group (P, Scheme 1). The well-
(1) Coppola, G. M.; Schuster, H. F. Hydroxy Acids in EnantioselectiVe
Synthesis; VCH: Weinheim, 1997.
(2) Hannession, S. Total Synthesis of Natural Products. The Chiron
Approach; Pergamon Press: New York, 1983; Chapter 2.
(3) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Soo, Y. K.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. Hanson, R. M.
Chem. ReV. 1991, 91, 437-475.
(4) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
Scheme 1
(5) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc.
1985, 107, 4346-4348.
(6) Frater, G. Y.; Muller, U.; Gunther, W. Tetrahedron Lett. 1981, 22,
4221-4224.
(7) d’Angelo, J.; Pages, O.; Maddaluno, J.; Dumas, F. Revial, G.
Tetrahedron Lett. 1983, 24, 5869-5872.
(8) Helmchen, G.; Wierzchowski, R. Angew. Chem., Int. Ed. Engl. 1984,
23, 60-61.
(9) Kelly, T. R.; Arvanitis, A. Tetrahedron Lett. 1984, 25, 39-42.
10.1021/ol006091m CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/16/2000

documented Evans alkylation17 of N-acyl 4-substituted ox-
azolidinones (R ) Bn, CHMe2, Scheme 1) seemed a logical
choice. A survey of the literature uncovered only a single,
fairly complex example18 of a glycolate oxazolidinone
alkylation with methallyl bromide.19 This was surprising
given the extensive application of 4-substituted oxazolidinone
auxiliaries in asymmetric synthesis.20 They are readily
available (both commercially and synthetically), easily
removed, and can be recovered and recycled. We have
previously reported the use of asymmetric glycolate alkyl-
ations for some specific applications.15,16 Here, we report on
the utility and generality of asymmetric alkylations of sodium
enolates of numerous glycolate oxazolidinones with a variety
of allylic iodides for the preparation of R-hydroxy carboxylic
acids and 1,2-diols with selective protection of the secondary
alcohol.
tion of the products by flash chromatography provided the
alkylated product in 70-85% yield essentially diastereo-
merically pure (>99:1).24
As illustrated in Table 1, a wide range of protecting groups
(or ethers) is tolerated on the glycolate hydroxyl. Benzyl,
p-methoxybenzyl, MOM, allyl, trialkylsilyl, and complex
Table 1. Asymmetric Glycolate Alkylations28
A variety of oxazolidinone glycolates can be prepared by
one of three methods: (1) acylation of the auxiliary with
the appropriate alkoxyacetyl chloride (P ) Me, Bn),17,21 (2)
one-pot preparation from the alkoxycarboxylic acid through
the in situ formation of the mixed pivalic anhydride (P )
PMB, allyl, complex alkyl),22,23 or (3) protection of the parent
glycolate oxazolidinone (P ) Et3Si, MOM, t-BuMe2Si,
t-BuPh2Si). The latter method functions well for the prepara-
tion of less hindered silyl ethers and other acid sensitive
protecting groups. The parent glycolate 4 was prepared in
99% yield by exposure of benzyl ether 320 to hydrogen and
Pd(OH)2 in ethyl acetate. Treatment of oxazolidinone gly-
colate 4 with triethylsilyl chloride and imidazole produced
silyl ether 5 in 96% yield. The methoxymethyl ether, the
tert-butyldimethylsilyl ether, and the tert-butyldiphenylsilyl
ether were prepared in a similar manner (Scheme 2).
Scheme 2
Generation of the sodium enolate of the acyl oxazolidinone
[1.5 equiv of NaN(SiMe3)2, -78 °C, 30 min] followed by
addition of 3-5 equiv of the required alkylating agent, and
warming the reaction mixture to - 40 to - 45 °C, results in
relatively rapid (1-3 h) alkylation of the enolate with
excellent diastereoselectivity (generally >96% de). Purifica-
(10) Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett.
1985, 25, 1343-1344.
(11) Ludwig, J. W.; Newcomb, M.; Bergbreiter, D. E. Tetrahedron Lett.
1986, 26, 2731-2734.
(12) Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1986, 51, 3746-3748.
(13) Cardillo, G.; Orena, M.; Romero, M.; Sandri, S. Tetrahedron 1989,
45, 1501-1508.
(14) Jung, J. E.; Ho, H.; Kim, H.-D. Tetrahedron Lett. 2000, 41, 1793-
1796.
(15) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 899-903.
(16) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-2032.
2166
Org. Lett., Vol. 2, No. 14, 2000

alkyl ethers all function well in this regard. Both relatively
simple (entries 1-14) and highly complex examples proceed
with similar yields and levels of diastereoselection. One of
the more attractive aspects of this procedure is the ability to
selectively prepare R,R′- disubstituted ethers with high levels
of diastereocontrol (entries 17-19).
the standard Evans hydrolysis procedure with lithium
hydroxide and hydrogen peroxide (Scheme 4).30
Scheme 4
Several points regarding the procedure are worthy of note.
In our experience,25 the use of the allylic iodides is essential
since rates of alkylation with allylic bromides are slow and
yields drop substantially due to competitive deacylation of
the enolates. Excess iodide (3-5 equiv) is also preferred to
achieve acceptable rates. For most cases, rates are sluggish
at -78 °C and warming the reaction to -40 to -45 °C
appears to be optimal for most examples. The methyl ether
is relatively unstable at -45 °C, and the alkylation is better
accomplished at -78 °C. The methyl ether resulted in
substantial deacylation of the auxiliary even at -78 °C and
produced a somewhat impure product in modest yields
(entries 4 and 10).26 The MOM ether (entry 11) and allyl
ether (entry 6) showed similar trends, but to a lesser extent.
It is also of particular interest that the valine-derived enolates
(R ) CHMe2) are slightly more reactive and tend to give
somewhat improved yields when compared to the phenyl-
alanine-derived (R ) CH2Ph) auxiliaries (compare, for
example, entries 1 vs 7 and 2 vs 8). Alkylation with
iodomethylbenzyl27 ether as the electrophile proceeded
rapidly at - 78 °C (entry 15).
In summary, the asymmetric glycolate alkylation of
4-substituted oxazolidinones can be used for the enantio-
selective preparation of highly useful R-alkoxy acids and 1,2-
diols with the secondary hydroxyl selectively protected after
removal of the auxiliary. Since the asymmetric glycolate
alkylation with allyl iodides results in the production of
protected homoallylic alcohols, this procedure also compli-
ments existing methods for the enantioselective preparation
of homoallylic alcohols.31
Acknowledgment. This work was supported by grants
from the National Institutes of Health (GM38904, CA63572
and GM60567).
The auxiliary can be reductively removed by simple
exposure to sodium borohydride in THF-H2O to provide
primary alcohol 7 in high yield (Scheme 3).29 Lithium
OL006091M
(22) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031. Crimmins, M. T.; Choy, A. L. J.
Am. Chem. Soc. 1999, 121, 5663-5660.
(23) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39, 7775-
7778.
Scheme 3
(24) Typical procedure for the alkylaiton of oxazolidinone glycolates:
A solution of 5.0 mL (3 mmol) of sodium bistrimethylsilylamide (0.6 M in
toluene) in 10 mL of THF was cooled to -78 °C. A solution of
oxazolidinone glycolate (2 mmol) in 5 mL of THF was added dropwise
over 5 min. The solution was stirred at -78 °C for 30 min. A solution of
allyl iodide (10 mmol) in 5 mL of THF was added dropwise. The solution
was stirred at -78 °C for 5 min and allowed to warm to -40 to -45 °C
at which temperature it was stirred for 1-3 h. The reaction was monitored
by TLC. After the reaction was deemed to be complete, saturated aqueous
ammonium chloride was added and the mixture was warmed to room
temperature. The mixture was partitioned between 1:1 ethyl acetate/hexanes
and water. The organic layer was washed with saturated sodium chloride
solution, dried, and concentrated. The residue was purified by flash
chromatography to provide the pure alkylation product. Yields are for
isolated, chromatographically purified products which were homogeneous
by TLC and NMR.
(25) One example of an alkylation with methallyl bromide has appeared,
see ref 18.
(26) The chlorotitanium enolate of the methyl glycolate oxazolidinone
has been alkylated with BOMCl. Paterson, I.; Bower, S.; McLeod, M. D.
Tetrahedron Lett. 1995, 36, 175-178.
borohydride was used to reductively remove the auxiliary
in the triethysilyl glycolate alkylation products to avoid silyl
ether migration. Carboxylic acids 10 are available through
(27) Ditrich, K.; Hoffmann, R. W. Liebigs Ann. Chem. 1990, 15-21.
(28) Yields are for isolated, chromatographically purified material,
homogeneous by TLC and NMR. Diastereomeric ratios were determined
either by HPLC or by NMR (>98:2 indicates that the minor isomer could
not be detected by NMR).
(17) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(18) Burke, S. D.; Quinn, K. J.; Chen, V. J. Org. Chem. 1998, 63, 8626-
8627.
(19) During the preparation of this manuscript an additional example
appeared. Chappell, M. D.; Stachel, S. J.; Lee, C. B.; Danishefsky, S. J.
Org. Lett. 2000, 2, 1633-1636.
(20) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875.
(21) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506-2526.
(29) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067-7070.
(30) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141-6144.
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U. S. J. Am. Chem. Soc. 1990, 112, 2389-2392. Roush W. R.; Walts A.
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