Asymmetric glycolate aldol reactions using cinchonium phase-transfer catalysts

Article abstract of DOI:10.1021/ol051096a

(Chemical Equation Presented) Cinchona phase-transfer catalysts (PTC) were developed for glycolate aldol reactions to give differentially protected 1,2-diol products. Silyl enol ether 9 reacted to generate benzhydryl-protected products. O-Allyl trifluorob

Full text of DOI:10.1021/ol051096a

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3861-3864
Asymmetric Glycolate Aldol Reactions
Using Cinchonium Phase-Transfer
Catalysts
Merritt B. Andrus,* Jing Liu, Zhifeng Ye, and John F. Cannon
Department of Chemistry and Biochemistry, Brigham Young UniVersity, C100 BNSN,
ProVo, Utah 84602-5700
mbandrus@chem.byu.edu
Received May 11, 2005
ABSTRACT
Cinchona phase-transfer catalysts (PTC) were developed for glycolate aldol reactions to give differentially protected 1,2-diol products. Silyl
enol ether 9 reacted to generate benzhydryl-protected products. O-Allyl trifluorobenzyl cinchonium hydrofluoride CN-4 (20 mol %) catalyzed
the addition of 9 to benzaldehyde to give 8 as a single syn-product in 76% yield and 80% ee. Recrystallization enriched the product to 95%
ee, and a Baeyer−Villiger reaction transformed the product into useful ester intermediates.
Phase-transfer catalysis (PTC) is an attractive, general
approach to asymmetric synthesis where an enolate ion,
formed in situ, is paired with an enantiopure quaternary
ammonium cation. Partitioning to the organic phase is thus
facilitated, allowing the enolate to selectively react with an
organic soluble electrophile. Glycine alkylations, enone
epoxidation, conjugate additions, and other asymmetric
transformations have been successfully developed using this
strategy.1 We now report a new PTC asymmetric glycolate
aldol reaction, which employs a silyl enol ether derivative
of aryl ketone 1 to give differentially protected syn-products
2 that are readily converted to 1,2-diol esters 3 (Scheme 1).
PTC has numerous advantages including the use of inex-
pensive, cinchona alkaloid catalysts, which are readily
available in pseudo-enantiomeric antipodes, simple hydroxide
bases, and mild conditions performed in either liquid-liquid
or liquid-solid mode over an extended temperature range.
Systematic variation of cinchona-based and other nonnatural
catalysts (Scheme 2) have led to steady improvements for
Scheme 1. Glycolate Aldol
glycine alkylations with N-(diphenylmethylene)glycine tert-
butyl ester for the synthesis of amino acids.2
In contrast to glycine alkylation, PTC aldol reactions are
far less common. Protected glycine has been reacted with
aldehydes under various PTC conditions to give â-hydroxy-
R-amino acids.3,4 Although problems with syn/anti selectivity
(2) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353-2354. (b) O’Donnell, M. J.; Delgado, F.; Hostettler, C.;
Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775-8778. (c) Corey, E. J.;
Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-12415. (d) Lygo,
B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595-8598. (e) Corey,
E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000-
13001. (f) Ooi, T.; Kameda, K.; Maruoka, K. J. Am. Chem. Soc. 1999,
121, 6519-6520. (g) Jew, S.; Yoo, M.; Jeong, B.; Park, I. Y.; Park, H.
Org. Lett. 2002, 4, 4245-4248. (h) Park, H.; Jeong, B.; Yoo, M.; Lee, J.;
Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew. Chem., Int. Ed. 2002, 41, 3036-
3038.
(1) (a) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013-3028. (b)
Kacprzak, K.; Gawronski, J. Synthesis 2001, 961-998. (c) O’Donnell, M.
J. Aldrichimica Acta 2001, 3, 3-15.
10.1021/ol051096a CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/11/2005

method provides a convenient route to a variety of alkylated
hydroxy products with high selectivity. Previous to this work,
asymmetric glycolate alkylation was limited to chiral aux-
iliaries.7
Scheme 2. Phase Transfer Catalysts Investigated
Initially the direct aldol reaction of DPM (diphenylmethyl)-
protected 2,5-dimethoxyacetophenone 1 was explored using
the N-trifluorobenzyl cinchonidinium catalyst of Park and
Jew2g 4-CD+Br- (Table 1). Solid-liquid-phase conditions
Table 1. PTC Aldol with Ketone 1
base
solvent
yield (%)
syn/anti
ee (%, syn)
CsOH‚H2O
NaOMe
NaOH
THF
THF
toluene
toluene
45
83
53
45
3/1
2.5/1
4/1
0a
0a
7b
NaOH
4/1
22b,c
a The temperature was -40 °C. b The reaction was conducted at 0 °C
with 1% aqueous NaOH. c 4-CN+Br- was used as catalyst.
with either cesium hydroxide or sodium methoxide in THF
gave product 8 from dihydrocinnamaldehyde with poor
diastereoselectivity and no enantioselectivity. Liquid-liquid
conditions with 1% aqueous sodium hydroxide and toluene
showed only slight improvement in the syn/anti ratio. Use
of other bases (not shown) including sodium carbonate and
phosphazines (BTPP)2b failed to give product. The catalyst
was then changed to the pseudo-enantiomeric 4-CN+Br- with
only slight improvement in the enantioselectivity, 22% ee
for the syn-product. Surprisingly, this change to the cincho-
nium catalyst 4 resulted in production of the same enantio-
meric product. Use of ammonium chloride as an additive in
toluene, THF, or other solvents did not improve the yield or
selectivity. Use of Maruoka’s bis-binaphthyl catalyst 6 gave
only trace product with little selectivity (7%, 6% ee).2f Self-
condensation products were not observed under any condi-
tions with dihydrocinnamaldehyde used as the test substrate.
Benzaldehyde with 4-CD+Br- and NaOH gave a very low
yield (15%) under these conditions.
The silyl enol ether of 1 was then made and explored under
Corey’s cinchonium fluoride catalyst conditions.4 Compound
1 was treated with LDA and trapped with TMSCl to give 9
(Scheme 4) as a stable white solid, which is simply purified
by filtration and crystallization. Fortunately, as a silyl enol
ether, 9 is easily manipulated, unlike the corresponding silyl
ketene acetal of the protected glycine used in previous PTC
aldol studies, which is easily hydrolyzed.
and product isolation are typical. Maruoka and co-workers
have recently developed bis-binaphthyl catalysts that give
glycine aldol products with high selectivity.5 In an effort to
extend the PTC process to oxygenated glycolate products,
we previously reported asymmetric PTC-catalyzed alkyla-
tions with oxygenated substrates using the novel alkoxy-
acetophenone 1 (Scheme 3).6 The nature of the protecting
Scheme 3. PTC Alkylation
group and substitution pattern on the aryl ketone proved to
be critical for high selectivity and good reaction rates. This
(3) (a) Gasparski, C. M.; Miller, M. J. Tetrahedron 1991, 47, 5367-78.
(b) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58, 8289-96. (c)
Shimizu, S.; Shirakawa, S.; Suzuki, T.; Sasaki, Y. Tetrahedron 2001, 57,
6169. (d) Arai, S.; Hasegawa, K.; Nishida, A. Tetrahedron Lett. 2004, 45,
1023. (e) Mettath, S. Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L. J.
Org. Chem. 2004, 69, 6489-6492.
(4) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
1999, 40, 3843-3846.
(5) (a) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 4542-4522. (b) Ooi, T.; Kameda, M.; Taniguchi, M.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685-9694. For other recent
catalytic glycolate aldol reactios, see: Trost, B. M.; Ito, H.; Silcoff, E. R.
J. Am. Chem. Soc. 2001, 123, 3367-3368.
Reaction of 9 with benzaldehyde under PTC conditions
gave the differentially protected aldol product 8 following
(6) Andrus, M. B.; Hicken, E. J.; Stephens, J. S. Org. Lett. 2004, 6,
2289-2292.
(7) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165-2167.
3862
Org. Lett., Vol. 7, No. 18, 2005

Scheme 4. Silyl Enol Ether Synthesis
Table 3. PTC Aldol Addition with Various Aldehydes
treatment with cesium fluoride and water (Table 2). In dry
THF with the hydrogen difluoride catalyst 4-CN+HF2 at
-
-45 °C the yield of 8 was low (35%); however, the
selectivity was dramatically improved to 75% ee. In all cases
with this substrate, a single syn-diastereomer was obtained.
Protected glycine PTC aldol reactions typically give a
mixture of diastereomers. Use of DME and other solvents
explored did not improve the yield. Using the corresponding
-
cinchonidinium catalyst 4-CD+HF2 , the isolated yield
increased to 52%; however the selectivity dropped to 41%
-
ee. Surprisingly, use of reagent grade THF with 4-CN+HF2
improved the rate of the reaction, requiring 1.5 h for
completion, and the yield and selectivity also increased (78%,
75% ee). Trace water in this case appears to improve the
catalyst turnover and the selectivity. Use of the Corey-Lygo
-
catalyst4 5-CN+HF2 extended the reaction time and im-
proved the selectivity (78% ee) with a lower yield (52%).
-
Using the optimal catalyst 4-CN+HF2 , the temperature was
lowered to -55 °C, to give 8 in 76% yield and 80% ee. Use
-
of the novel difluoroanthracenyl catalyst 5-F2-CN+HF2 ,
recently found in the bromide form to give highly selective
glycine alkylations,8 improved the aldol reaction in 8 with
83% ee. Unfortunately, the isolated yield dropped to 40%
in this case. Variations of the aryl group of the silyl enol
ether 9 were also explored (not shown). With phenyl in place
of the 2,5-dimethoxyphenyl group, the aldol product with
benzaldehyde was obtained in 58% yield and greatly reduced
15% ee selectivity. With the 2-methoxyphenyl substrate
variation, 52% ee was obtained in 23% yield. 4-Methoxy
and 2,4-methoxy variants gave only trace aldol product.
Various solvents and combinations were also explored under
these aldol conditions. Finally, use of a 1/1 reagent THF/
DMF solvent mixture with 4-CN+HF2- proved superior, with
87% yield and 80% ee for the syn-product 8. Reagent grade
THF used alone proved to be the most practical and general
solvent for the other aldehyde substrates.
Table 2. PTC Aldol with Silyl Ether 9
-
Optimized conditions with 4-CN+HF2 in reagent grade
THF were used with a wide range of aldehydes (Table 3).
In most cases, a single syn-diastereomer 8 was again
produced. Aromatic aldehydes all reacted with good to
excellent results. 4-Biphenylcarboxaldehyde (Table 3, entry
5) and o-methoxybenzaldehyde (Table 3, entry 6) with yields
and selectivities from 70% to 80% were typical. Unfortu-
nately, alkyl and R,â-unsaturated aldehydes reacted with
lower yield and selectivity (Table 3, entries 9 and 10).
2-Naphthaldehyde (Table 3, entry 13) was also efficient again
with a single syn-diastereomer in 79% ee. Although conclu-
solvent
THF
catalyst
time (h)
yield (%)
ee (%)
-
4-CN+HF2
4-CN+HF2
24
24
24
1.5
11
24
24
19
35
19
52
78
52
76
40
87
75
37
41
75
78
80
83
80
-
DME
-
-
THF
4-CD+HF2
THFa
4-CN+HF2
5-CN+HF2
4-CN+HF2
-
-
THFa
THFa,b
THFb
5-F2-CN+HF2
4-CN+HF2
-
THF/DMFa,c
a Reagent grade solvent used. b Reaction conducted at -55 °C. c Reaction
conducted at -78 °C.
(8) Andrus, M. B.; Ye, Z.; Zhang, J. Tetrahedron Lett. 2005, 46, 3839-
3842.
Org. Lett., Vol. 7, No. 18, 2005
3863

analysis.9 This intermediate was then subjected to titanium
chloride at low temperature to effect removal of the diphen-
ylmethyl (DPM) group. The resultant hydroxy ketone 10 (Ar
) 2,5-dimethoxyphenyl) was subjected to Shibizaki modified
Baeyer-Villiger conditions,10 involving stiochiometric TMS-
peroxide, catalytic tin tetrachloride, and (()-cyclohexyl
bis-sulfonamide, to give aryl ester 11 in 79% isolated yield.
Transesterification, with concomitant acetate hydrolysis, gave
the known (S,R)-diol methyl ester 12.11
Scheme 5. Structure Proof and Elaboration
In summary, a new approach to asymmetric glycolate aldol
additions has been developed using readily available catalysts
under mild PTC conditions. Differentially protected syn-1,2-
diols are produced with very high diastereoselectivity and
good enantioselectivity. Simple recrystallization and Baeyer-
Villiger oxidation generate highly enantioenriched ester diol
products. Refinements to the substrate and catalyst are
anticipated to lead to further improvements and synthetic
applications.
sions concerning mechanistic details are premature at this
time, it can be pointed out that the C2 stereocenter in the
product 8 is S using either the cinchonine catalyst 4-CN or
cinchonidine 4-CD as demonstrated below. This is consistent
with the major S-isomer obtained previously for alkylation
of 1 using 4-CD.6
Acknowledgment. We are grateful to the American
Chemical Society Petroleum Research Fund (41552-AC1)
and the BYU Cancer Research Center for funding.
Supporting Information Available: Experimental pro-
cedures and characterization for selected compounds and
spectral, HPLC, and X-ray data in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
Fortunately, the enantioselectivity of the aldol product was
significantly raised on crystallization (Scheme 5). The major
(2S,3R) syn-diastereomer 8, obtained from addition to
benzaldehyde originally at 80% ee, was enriched to 95% ee
(65%) following crystallization and filtration of a racemic,
conglomerant solid. Elaboration to differentially protected
products and proof of the absolute stereochemistry were
carried out from this intermediate. Treatement with acetyl
chloride and pyridine gave an acetate intermediate, which
was unambiguously confirmed by single-crystal X-ray
OL051096A
(9) See Supporting Information for details.
(10) (a) Sawanda, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521-10532. (b) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki,
M. Synlett 1997, 971-974.
(11) Deng, J.; Hamada, Y.; Shiori, T. Synthesis 1998, 627-638.
3864
Org. Lett., Vol. 7, No. 18, 2005