Scheme 1
generation from oxindoles,4 few 2-siloxyindoles are docu-
mented in the literature, and to the best of our knowledge
only two reactions of these species have been described.5
Moreover, Mukaiyama aldol reactions of prochiral enoxysi-
lanes or silyl ketene acetals have been employed rarely for
stereoselective construction of quaternary carbon stereo-
centers,6 perhaps a result of the low selectivities described
in the inaugural disclosure of this chemistry.7 In this
communication, we report that a variety of enantiopure 3,3-
disubstituted oxindoles can be prepared in high yield and
high diastereoselectivity by Mukaiyama aldol reactions of
2-siloxyindoles and chiral, enantiopure aldehydes having
nitrogen or oxygen substituents at the R carbon.8
Our investigations began by examining the reaction of
siloxyindole 7 and tert-butyl (R)-4-formyl-2,2-dimethyl-3-
oxazolinecarboxylate (8, Garner’s aldehyde),9 with the R
enantiomer being chosen on the expectation that Felkin
stereoselection would predominate and lead to the secondary
alcohol configuration found in leptosin D (Scheme 1).
Oxindole 6, which is available in high yield in three steps
from isatin,10 was converted to siloxyindole 7 by reaction at
room temperature with tert-butyldimethylsilyl triflate (TB-
DMS-OTf) and Et3N. Several Lewis acids commonly used
in Mukaiyama aldol reactions [LiClO4, Sc(OTf)3, and ZnI2]6
did not promote the reaction of 7 and aldehyde 8.11 However,
aldol condensation did take place in CH2Cl2 in the presence
of BF3‚Et2O at temperatures between -78 and -50 °C. This
reaction was slow in the presence of 1 equiv of this Lewis
acid; however, it proceeded in high yield at a useful rate in
the presence of excess BF3‚Et2O as long as 2,6-di-tert-butyl-
4-methylpyridine (DTBMP) was added to prevent desilyla-
tion of the siloxy nucleophile. Under optimum conditions
(3.5 equiv of BF3‚Et2O, 1.5 equiv DTBMP, -78 °C),
crystalline aldol adduct 9 was formed in 89% yield.12,13
HPLC-MS analysis of the crude reaction product showed
that diastereoselectivity was at least 80:1.14 Acidic cleavage
of the Boc and oxazolidine units of adduct 9 gave amino
diol 10, which after conversion to 1,3-dioxane derivative 11
and Fmoc protection provided crystalline 12 suitable for
X-ray analysis.15
The scope of the Mukaiyama aldol reaction of Garner’s
aldehyde with siloxyindoles having various carbon substit-
uents at C3 is illustrated by the data summarized in Table 1.
The relative and absolute configuration of ent-915 and 14e
was secured by single-crystal X-ray analysis, whereas the
absolute configuration of 14b-d at C3 was determined by
CD analysis. As expected, the major products have the anti
relationship of the hydroxy and N-acyloxyamino substituents.
(3) Takahashi, C.; Minoura, K.; Yamada, T.; Numata, A.; Kushida, K.;
Shingu, T.; Hagishita, S.; Nakai, H.; Sato, T.; Harada, H. Tetrahedron 1995,
51, 3483-3498.
(4) Klebe, J. F.; Finkbeiner, H.; White, D. M. J. Am. Chem. Soc. 1966,
88, 3390-3395.
(5) Rh(II)-catalyzed reaction with a diazoketone: (a) Sawada, T.; Fuerst,
D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44, 4919-4921. Mukaiyama
aldol reaction with formaldehyde: (b) Nicolaou, K. C.; Hao, J.; Reddy, M.
V.; Rao, P. B.; Rassias, G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.;
Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.; O’Brate, A. J. Am.
Chem. Soc. 2004, 126, 12897-12906.
(6) For a recent authoritative review, see: Carreira, E. Mukaiyama Aldol
Reaction. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E., Pfaltz,
E., Yamamoto, Y., Eds.; Springer: Berlin, 1999; Vol. 3, pp 997-1065.
(7) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503-7509.
(8) The closest analogy, of which we are aware, to the chemistry reported
herein is the high selectivity reported for the reaction of silylketene acetals
derived from methyl 2-methoxypropionate and (S)-2-(phenylmethoxy)-
propanal in the Heathcock group’s asymmetric synthesis of L-cladinose:
Montgomery, S. H.; Pirrung, M. C.; Heathcock, C. H. Carbohydr. Res.
1990, 202, 13-32.
(9) Garner, P.; Park, J. M. Organic Syntheses; Wiley: New York, 1998;
Collect. Vol. IX, pp 300-305.
(10) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh, E.; Dastidar,
P. J. Chem. Soc., Chem. Commun. 2002, 824-825.
(11) Attempted aldol reaction of the lithium enolate of 6 (LDA, THF,
-78 °C, 1 h) and 8 (in the presence or absence of HMPA or DMPU) at
temperatures from -78 °C to room temperature resulted only in the recovery
of starting materials.
(12) (a) The alcohol, not the silyl ether, is produced directly, as the
TBDMS derivative of 9 was stable to the reaction and workup conditions.13
(b) A similar reaction was seen with congeners of 7 in which the siloxyindole
nitrogen was protected with a p-methoxybenzyl or SEM group; however,
the reaction failed if this substituent was Boc or TBDMS.
(13) Carriera, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323-
4326.
(14) (a) Adduct 9 and related Mukaiyama aldol products having aryl
substituents at C3 undergo rapid retro-aldolization in the presence of base
and fragment slowly even under neutral conditions. This lability complicates
purification of these products. (b) No isomers were seen by HPLC analysis.
Stereoselectivity is estimated to be at least 80:1 as isomer ratios of 90:1
could be measured in this way. (c) Oxindole 9 and other similar products
derived from Garner’s aldehyde exhibit broad signals in their 1H NMR
spectra and multiple signals in their 13C NMR spectra because of carbamate
rotamers. Confirmation by NMR of high isomeric purity of 9 (at least >15:
1) is possible at the stage of 11, a derivative showing sharp NMR signals.
(15) X-ray analysis carried out with ent-12 prepared from the reaction
of 7 and ent-8.
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Org. Lett., Vol. 7, No. 13, 2005
Adhikari, Susanta
