Catalytic nucleophilic glyoxylation of aldehydes

Article abstract of DOI:10.1021/ol100996w

(Figure presented) β-Silyloxy-α-keto esters are prepared through a cyanide-catalyzed benzoin-type reaction with silyl glyoxylates and aldehydes. The products undergo a dynamic kinetic resolution to provide enantioenriched orthogonally protected alcohols and can be converted to the corresponding β-silyloxy-α-amino esters.

Full text of DOI:10.1021/ol100996w

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2864-2867
Catalytic Nucleophilic Glyoxylation of
Aldehydes
Kimberly M. Steward and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received April 30, 2010
ABSTRACT
ꢀ-Silyloxy-r-keto esters are prepared through a cyanide-catalyzed benzoin-type reaction with silyl glyoxylates and aldehydes. The products
undergo a dynamic kinetic resolution to provide enantioenriched orthogonally protected alcohols and can be converted to the corresponding
ꢀ-silyloxy-r-amino esters.
R-Keto esters play an important role in organic synthesis1
and are prevalent substructures of many biologically active
natural products such as 3-deoxy-D-manno-2-octulosonic acid
(KDO), 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid
(KDN), and N-acetylneuraminic acid.2 Due to inductive
effects of the attached ester and opportunities for chelation,
R-keto esters exhibit dramatically enhanced electrophilicity
relative to normal ketones.3 They react readily with nucleo-
philes to give tertiary R-hydroxy esters and undergo reduc-
tion4 and reductive amination5 to provide access to stere-
ochemically defined R-hydroxy esters and R-amino esters,
respectively.
Although the R-keto ester is a highly versatile building
block, its de novo introduction has not been generalized,
particularly those R-keto esters bearing a ꢀ-stereogenic
center.6 Germane to the present work are several methodolo-
gies that have been developed to construct the R-keto acid
derivative via electrophilic trapping of glyoxylate anion
equivalents. Eliel demonstrated that 1,3-dithiane-2-lithio-2-
carboxylates (I) undergo alkylation to provide 1,2-dicarbonyl
compounds after deprotection,7 and Takahashi has utilized
2-metallo-2-alkoxy-2-cyanoacetates (II) in a related manner
(Figure 1).8 Chiral glyoxylate anion equivalents have been
reported by Enders, who used a chiral R-amino cyanoacetate
(6) For a recent example see Nakamura, A.; Lectard, S.; Hashizume,
D.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036.
(7) Eliel, E.; Hartmann, A. J. Org. Chem. 1972, 37, 505.
(8) (a) Takahashi, T.; Okano, T.; Harada, T.; Imamura, K.; Yamada, H.
Synlett 1994, 38, 121. (b) Takahashi, T.; Tsukamoto, H.; Kurosaki, M.;
Yamada, H. Synlett 1997, 41, 1065.
(1) (a) Cooper, A.; Meister, G. A. Chem. ReV. 1983, 83, 321. (b) Kovacs,
L. Rec. TraV. Chim. PaysBas 1993, 112, 471.
(2) Kiefel, M. J.; von Itzstein, M. Chem. ReV. 2002, 102, 471.
(3) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am.
Chem. Soc. 1999, 121, 686.
(4) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527.
(5) Kang, Q.; Zhao, Z. A.; You, S. L. AdV. Synth. Catal. 2007, 349,
1657.
(9) (a) Enders, D.; Bonten, M. H.; Raabe, G. Synlett 2007, 51, 885. (b)
Enders, D.; Bonten, M. H.; Raabe, G. Angew. Chem., Int. Ed. 2007, 46,
2314.
10.1021/ol100996w  2010 American Chemical Society
Published on Web 05/19/2010

A common reactivity pathway explored in our laboratory
with silyl glyoxylates involves nucleophilic addition, 1,2-
Brook rearrangement,15 and electrophilic trapping (Figure
2b).16 These multicomponent reactions are believed to
proceed through glycolate enolate intermediates. Various
examples incorporate the nucleophile as a stoichiometric
component; however, we postulated that in the presence of
a nucleophilic catalyst and aldehyde we could arrive at
ꢀ-silyloxy-R-keto esters via a silyl benzoin mechanism.12c,d
Alternative methods for the preparation of the proposed
product ꢀ-hydroxy-R-keto acid derivatives include the ad-
dition of diazoacetates to aldehydes followed by oxidation17
and Baylis-Hilman reaction followed by alkene ozonoly-
sis.18
Figure 1. Glyxoylate anion synthetic equivalents.
(III),9 and Rovis, who employed glyoxyamides as the
glyoxylate donor in a catalytic enantioselective Stetter
reaction proceeding via the chiral acyl-Breslow intermediate
IV.10 The purpose of this communication is to introduce silyl
glyoxylates (1) as synthetic equivalents to the glyoxylate
anion synthon in the context of carbonyl addition reactions.
Acyl silanes11 have been developed as acyl anion equiva-
lents for use in the racemic12 and enantioselective13 cross
silyl benzoin reaction (Figure 2a). While broad in scope, it
Preliminary studies focused on identifying a viable nu-
cleophilic catalyst. We evaluated various metal cyanides with
benzaldehyde as the test substrate (Scheme 1). Sodium
Scheme 1
.
Optimization of Reaction Conditions with Metal
Cyanides
cyanide, potassium cyanide, and potassium cyanide/18-
crown-6 complex were the initial metal cyanides screened.
In each case, the desired ketone product was not obtained;
instead, the reaction yielded the R-silyoxy-ꢀ-keto ester 2.
This product is likely derived from isomerization of the
initially formed R-keto ester under the basic reaction
conditions (Scheme 2).
Figure 2. Comparison of acylsilane and silyl glyoxylate reactivity.
We sought to identify a less basic source of cyanide that
could potentially stop at the desired ketone product. Lan-
thanide isopropoxides have been reported as efficient cata-
lysts in the transhydrocyanation from acetone cyanohydrin
to aldehydes and ketones.19 We were pleased to find that
the combination of Yb(OiPr)3 (10 mol %) and acetone
cyanohydrin (Me2C(OH)Ct N, 1 equiv) yielded the desired
occurred to us that in certain instances carboxyl functionality
adjacent to the ketone might be desirable and could
significantly expand the product types delivered by this
reaction class (Figure 2c). Silyl glyoxylates14 are related
reagents that have proven useful for the geminal linking of
nucleophile and electrophile pairs at a glycolic acid junction.
(10) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066.
(11) (a) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta,
V. Gazz. Chim. Ital. 1987, 117, 645. (b) Reich, H. J.; Holtan, R. C.; Bolm,
C. J. Am. Chem. Soc. 1990, 112, 5609. (c) Takeda, K.; Ohnishi, Y.
Tetrahedron Lett. 2000, 41, 4169.
(15) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(16) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 6170.
(b) Linghu, X.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006,
128, 9302. (c) Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson,
J. S. J. Am. Chem. Soc. 2008, 130, 17281. (d) Greszler, S. N.; Johnson,
J. S. Org. Lett. 2009, 11, 827. (e) Greszler, S. N.; Johnson, J. S. Angew.
Chem., Int. Ed. 2009, 3689. (f) Schmitt, D. C.; Johnson, J. S. Org. Lett.
2010, 12, 944.
(12) (a) Degl’Innocenti, A.; Pike, S.; Walton, D. R. M. J. Chem. Soc.
Chem. Commun. 1980, 1201. (b) Schinzer, D.; Heathcock, C. H. Tetrahedron
Lett. 1981, 22, 1881. (c) Linghu, X.; Johnson, J. S. Angew. Chem., Int. Ed.
2003, 42, 2534. (d) Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem.
Soc. 2005, 127, 1833.
(17) (a) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527. (b) Hasegawa, K.;
Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390. (c) Trost, B. M.; Malhotra,
S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674.
(13) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 3070.
(18) Frezza, M.; Soule`re, L.; Queneau, Y.; Doutheau, A. Tetrahedron
Lett. 2005, 46, 6495.
(14) Nicewicz, D. A.; Bre´te´che´, G.; Johnson, J. S. Org. Synth. 2008,
85, 278.
(19) Ohno, H.; Mori, A.; Inoue, S. Chem. Lett. 1993, 375.
Org. Lett., Vol. 12, No. 12, 2010
2865

Scheme 2
.
Isomerization Pathway
Table 1. Scope of Aldehyde Glyoxylation
ketone product, albeit as the cyanohydrin adduct 3 (dr: 1.2:
1). A catalytic amount of acetone cyanohydrin afforded the
desired ꢀ-silyloxy-R-keto ester in 64% yield. Optimization
of the reaction conditions revealed that the R-keto ester 4a
could be obtained in up to 90% yield using 5 mol %
Yb(OiPr)3, 20 mol % acetone cyanohydrin, and 2 equiv of
aldehyde.
With optimized conditions in hand, we wished to examine
the scope of the reaction (Table 1). Electron-rich, electron-
poor, heteroaromatic, and aliphatic aldehydes all performed
well in the reaction with yields ranging from 75 to 96%.
The reaction has steric limitations as pivalaldehyde failed
to provide any desired product. It is notable that all reactions
were complete within twenty minutes, and in most cases the
silyl glyoxylate was completely consumed immediately upon
addition of all reagents (see the Supporting Information). An
attractive feature of this reaction is that the products can be
obtained in analytically pure form after passing the crude
reaction mixture through a short silica plug and removing
the excess aldehyde under reduced pressure.
The title reaction appears amenable to enantioselective
catalysis. When deuterated benzaldehyde (PhCDO) was used
as the electrophile, full deuterium incorporation at the
methine was observed in 4a-d1, suggesting that the product
is stable toward enolization under the silyl benzoin condi-
tions. The ideal chiral catalyst would need to both facilitate
the transhydrocyanation and direct the facial selectivity in
the subsequent aldehyde addition. Preliminary studies em-
ploying chiral metallocyanides20 yielded racemic material,
and reactions with chiral metallophosphites13,21 provided no
desired product; however, due to the acidity of the R-keto
ester, we thought our substrates would be good candidates
to undergo a dynamic kinetic resolution delivering enan-
tioenriched orthogonal diols (6, Table 2).
There are a number of examples of dynamic asymmetric
(transfer) hydrogenations of benzoin-type substrates employ-
ing chiral ruthenium(II) complexes.22 We initially examined
the use of Noyori-type conditions23 with BINAP-derived
catalysts and 4a, but no reaction was observed. We attributed
this lack of reactivity to the steric bulk of the TBS protected
a Yields of analytically pure material after workup. b Sm(OiPr)3 (10 mol
%) was employed.
alcohol. Unfortunately, initial attempts to remove the silyl
group led to decomposition, perhaps through retro-aldol
reaction. We then turned our attention to using catalysts of
the type 5 in an asymmetric transfer hydrogenation with
triethylamine as the base and formic acid as the hydride
source.24 The ketone was reduced under these conditions,
albeit with low enantioselectivity and moderate anti-dias-
teroselectivity (Table 2, entry 1).
(20) (a) Nicewicz, D. A.; Yates, C. M.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2004, 43, 2652. (b) Nicewicz, D. A.; Yates, C. M.; Johnson, J. S.
J. Org. Chem. 2004, 64, 6548.
(21) (a) Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am.
Chem. Soc. 2006, 128, 2751. (b) Garrett, M. R.; Tarr, J. C.; Johnson, J. S.
J. Am. Chem. Soc. 2007, 129, 12944
.
(22) (a) Ikariya, T.; Hashiguchi, S.; Murata, K.; Noyori, R. Org. Syn.
2005, 82, 10. (b) Arai, N.; Ooka, H.; Azuma, K.; Yabuuchi, T.; Kurono,
N.; Inoue, T.; Ohkuma, T. Org. Lett. 2007, 9, 939. (c) Ooka, H.; Arai, H.;
Azuma, K.; Kurono, N.; Ohkuma, T. J. Org. Chem. 2008, 73, 9084.
(23) Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am. Chem.
Soc. 2003, 125, 13490.
Increasing the equivalents of base led to higher enanti-
oselectivities (entry 3), and this result can possibly be
(24) Ikariya, T.; Blacker, J. Acc. Chem. Res. 2007, 40, 1300.
Org. Lett., Vol. 12, No. 12, 2010
2866

catalyst structure to achieve optimal enantio- and diaster-
oselectivity.
The R-keto ester products may also be converted to their
derived ꢀ-silyloxy-R-amino esters (i.e., 7, Scheme 3). Under
Table 2. Dynamic Kinetic Resolution of 4a
Scheme 3. Synthesis of ꢀ-Silyoxy-R-amino Esters
conva
erb
entry
[H-]/base (equiv)
(%) (6:2) (anti) drcanti/syn
1
HCOOH/NEt3 (3.2/4.4)
HCOOH/NEt3 (12.5/5.0)
HCOOH/NEt3 (3.2/10.0)
HCOONa (5.0)
88:12
79:21
35:65
97:0
67:33
67:33
78:22
67:33
71:29
72:28
75:25
70:30
70:30
70:30
76:24
70:30
5:1
4:1
4:1
3:1
3:1
3:1
2:1
3:1
3:1
3:1
3:1
3:1
2
3
standard reductive amination conditions, competitive ketone
reduction was observed.25 The desired product was obtained
from a three-step sequence (72% overall yield) consisting
of conversion to the oxime, reduction, and Boc protection.26
Preference for the syn-diastereomer in a 3:1 ratio was
observed.
4d
5e
6
HCOONa (5.0)
93:7
HCOONa (5.0)
92:8
67:33
91:9
73:27
46:2
51:5
89:6
7
HCOOH/DIEA (3.2/10.0)
HCOOH/Cs2CO3 (3.2/10.0)
HCOOH/Li2CO3 (3.2/10.0)
HCOOH/BaCO3 (3.2/10.0)
HCOOH/CdCO3 (3.2/10.0)
HCOOCs (5.0)
8
9
10
11
12
In summary, we have developed a nucleophilic glyoxy-
lation of aldehydes with silyl glyoxylates. The products are
able to undergo a subsequent dynamic kinetic resolution,
providing enantioenriched monoprotected diols with enan-
tioselectivity up to 76:24 and diastereoselection up to 5:1.
The glyoxylation products can be further elaborated to
ꢀ-silyloxy-R-amino esters, highlighting their potential as
small-molecule building blocks. Future studies will focus on
developing catalytic asymmetric glyoxylation and optimizing
dynamic kinetic resolutions of racemic glyoxylation adducts.
a Conversion determined by 1HNMR spectroscopy. b Enantiomeric
excess determined by SFC. c Diastereomeric excess determined by 1H NMR
spectroscopy. d Reaction run at 0 °C. e Reaction run at 40 °C.
attributed to more rapid racemization of the starting material;
however, these basic conditions also facilitated formation
of the isomerized product 2. Interestingly, this ketone is not
reduced under these reaction conditions. We then explored
the use of sodium formate as the hydride source (entries 4-6)
with the expectation that its decreased basicity would still
be sufficient for racemization but would not facilitate silyl
transfer. We were pleased to find that these conditions
reduced 4a with only trace amounts of the isomerized product
2 at room temperature (entry 6), and at 0 °C silyl transfer is
completely suppressed (entry 4). Unfortunately, under these
conditions the er is diminished.
An assessment of other bases in combination with formic
acid revealed that the degree of isomerization could be
lowered (entries 7-11). However, the highest er observed
was 76:24, with a dr of 3:1 (entry 11). Future work will
focus on: (1) increasing the rate of starting material racem-
ization; (2) minimizing silyl transfer; and (3) fine-tuning the
Acknowledgment. The project described was supported
by Award Number R01 GM084927 from the National
Institute of General Medical Sciences, Novartis, and Amgen.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100996W
(25) Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. DeV. 2006,
10, 971.
(26) (a) Abiraj, K.; Gowda, D. C. J. Chem. Res. 2003, 332. (b)
Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390.
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2867