Tris(trimethylsilyl)silyl-governed aldehyde cross-aldol cascade reaction

Article abstract of DOI:10.1021/ja054725k

The use of the tris(trimethylsilyl)silyl (TTMSS) group in aldehyde-derived silyl enol ethers affords aldehyde cross-aldol products with high yields and allows for unprecedented reactivity. The reaction is catalyzed by 0.05 mol % of HNTf₂, and c

Full text of DOI:10.1021/ja054725k

Published on Web 12/13/2005
Tris(trimethylsilyl)silyl-Governed Aldehyde Cross-Aldol Cascade Reaction
Matthew B. Boxer and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received July 14, 2005; E-mail: yamamoto@uchicago.edu
Table 1. Mukaiyama Aldol Reactiona
Polyketides constitute a large class of natural products, and
approximately 1% exhibit biological activity, which is 5 times
higher than the average in natural products.1 â-Hydroxy carbonyls
and/or 1,3-diols are a common motif in this class of biologically
important compounds, and the aldol reaction has emerged as a
recurrent method for formation of these substructures.2 Numerous
aldol methods utilize ester-, thioester-, or ketone-enolates as the
nucleophile to circumvent problems associated with the aldehyde
cross-aldol products.3 Frequently, these products are converted to
hydroxy-protected aldehydes for further transformations.1,4 Although
the Mukaiyama aldol synthesis is one of the most powerful
approaches for cross-aldol reactions, the most basic aldehyde cross-
aldol reaction has never been effectively achieved.3,4c Herein we
report the first highly diastereoselective Mukaiyama aldehyde cross-
aldol reaction of acetaldehyde silyl enol ethers as well as the first
cascade Mukaiyama aldol synthesis.
Due to our recent success with the bulky tris(trimethylsilyl)silyl
(TTMSS) group for [2 + 2] cyclizations,5 and its superb reactivity
in the presence of acid catalysis, we decided to try the silyl enol
ether (SEE) derived from acetaldehyde (1a) for the Mukaiyama
aldol reaction. Gratifyingly, the 1:1 adduct (2a) was obtained as
the only isolable product in 87% yield using octanal as the
electrophile and triflimide (0.05 mol %) as the catalyst. When the
TBS enol ether 1b was used, the 1:1 adduct (2b) was obtained in
<10% yield (Scheme 1).
Scheme 1. Mukaiyama Aldol Reaction
a Reactions run by adding acid to 1 equiv SEE (0.1 M) and 1 equiv
aldehyde. b Entries 1-5 run at room temperature, entries 6-11 were cooled
to -78 °C, the catalyst added and the solution removed from cold bath and
allowed to warm to room temperature. c 95/5 Z/E. d Isolated yield. e Dr
1
based on H NMR of crude material.
Scheme 2. Formation of Silyltriflimide and Its “Self-Repair” Ability
Acid screening (various Ti, Al, Sn, and Brønsted acids) led to
the finding that triflimide was superior, and catalyzed the reaction
with a loading of 0.05 mol %, giving the 1:1 adducts in high yield.
The use of TTMSSNTf2 (0.05 mol %) as the catalyst led to results
identical to those obtained by using triflimide, implicating the silyl
triflimide as likely the true catalyst (Table 1).6 Due to these
observations as well as the extrememly low catalyst loading (S/C,
2000/1), we propose that the silyltriflimide is a self-repairing
catalyst, which can be regenerated even in the presence of water
or other protic Lewis bases (Scheme 2). Significantly, triflic acid
and TTMSSOTf as catalysts gave a mixture of complex products
with only trace amounts of the desired 1:1 adduct, further
distinguishing the triflimide anion from the triflate anion.6c,7b
The scope of aldehydes for this reaction was tested and showed
consistently high yields of 1:1 adducts with primary, secondary,
tertiary, benzyl, and even R,â-γ,δ-unsaturated aldehydes (Table
1, entries 1-5). The use of (S)-2-phenylpropanal for diastereose-
lective aldol additions was tested and showed extrememly high
Felkin selectivity (Table 1, entry 6) and syn selectivity for
â-substituted aldehydes (Table 1, entry 7).8 While a previous study
showed anti selectivity for open transition state Mukaiyama aldol
additions to â-alkoxy aldehydes,9 we believe our selectivity resides
in the extreme size in the TTMSS group (vide infra). The use of
propionaldehyde-derived SEE gave comparably high yields with
good syn/anti ratios (Table 1, entries 8-11). Importantly, this
provides a complementary method to the anti selectivity obtained
by MacMillan.4b The use of (S)-2-phenylpropanal exhibited high
Felkin control in conjunction with syn selectivity providing three
adjacent stereocenters (Table 1, entry 11).8
We became curious as to why the reaction was stopping at the
1:1 adduct in such high yield. The use of anywhere from 2 to 5
equivalents of the SEE all led to a 2:1 adduct isolated in high yield
as a single diastereomer when pivalaldehyde was used. The use of
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10.1021/ja054725k CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cascade Mukaiyama Aldol Reaction Catalyzed
by HNTf2
of TTMSSNTf2 was shifted significantly downfield (>6 ppm)
compared to TMS and TBSNTf2, and only slightly downfield from
pentamethyldisilane-NTf2 (62.2, 55.9, 55.5, and 60.8 ppm respec-
tively).7 This trend shows a considerable difference in the cationic
nature of silyl groups with only silicon-carbon bonds versus those
with silicon-silicon bonds.
a
In conclusion, we have shown that the tris(trimethylsilyl)silyl
group is unique and allows for high-yielding construction of
â-hydroxy aldehydes for a very broad range of aldehydes (primary,
secondary, tertiary, aromatic, R,â-γ,δ-unsaturated). Chirality in
the aldehyde substrate affords Felkin products when there are
nonchelating substituents, chelation products when there is a
chelating sbustituent, and syn products when there is â-substitution.
The TTMSS group is distinctiVe in that it combines the highest Lewis
acidity as a silicon catalyst, high nucleophilic reactiVity as a SEE,
and large steric bulk for superior diastereoselection. Satisfaction
of these conflicting requirements allows for unprecedented one-
pot cascade reactions that can create synthetically useful â,δ-bis-,
â,δ,γ-tris-, and â,δ,ú-tris-hydroxy-aldehydes with extremely high
selectivity.
a Reactions run by premixing 2.2 equiv SEE (0.1 M) and 1 equiv
aldehyde and then adding acid. b Isolated yield. c Dr based on crude 1H
NMR. d Dr could not be determined through 1H NMR; yield given is isolated
yield of pure diastereomer shown.
Acknowledgment. This work was supported by the SORST
project of Japan Science and Technology Agency (JST) and The
University of Chicago. Special thanks to Ian Steele for X-ray
analysis and Antoni Jurkiewicz for NMR expertise.
Supporting Information Available: Experimental procedures,
compound characterization, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 1. Syn selectivity for â-chiral aldehydes. Conformation A leads to
syn products, while B leads to anti, but contains unfavorable steric
interactions including R-carbonyl and R-silyltriflimide.
References
(1) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677.
(2) For reviews of aldol reaction, see: (a) Nielsen, A. T.; Houlihan, W. J. In
Organic Reactions; Adams, R., Blatt, A. H., Boekelheide, V., Cairns, T.
L., Cram, D. J., House H. O., Eds.; John Wiley & Sons: New York,
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(c) Heathcock, C. H. In ComprehensiVe Organic Synthesis, Trost, B. M.,
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B. A. B. Synth Comm. 1985, 15, 39.
(4) Recent examples of the enantioselective aldehyde cross-aldol reaction
producing unprotected hydroxy aldehydes: (a) Denmark, S. E.; Ghosh,
S. K. Angew. Chem., Int. Ed. 2001, 40, 4759 (b) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (c) During the
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2.2 equiv of SEE was found to be optimal for the highest yields of
2:1 adduct, and the relative stereochemistry was determined to be
syn through single-crystal X-ray analysis (Table 2, entry 1).8
Cyclohexyl and octyl aldehydes gave similar results with the former
giving 95/5 syn selectivity and the latter 90/10 selectivity (Table
2, entries 2 and 3).8 The cascade reaction using (S)-2-phenylpropanal
gave high selectivity with all syn stereochemistry as the major
product (Table 2, entry 4).8 The â-TIPSoxy aldehyde afforded the
all syn protected â,δ,ú-tris-siloxyaldehyde in 64% yield (Table 2,
entry 5).8,10 R-Benzyloxy propanal gave the adduct that is consistent
with a chelation-controlled first addition followed by a syn-selective
second addition furnishing the â,δ,γ-tris-siloxyaldehyde in 61%
yield (Table 2, entry 6).8,10,11
The exceptional diastereoselectivity and control associated with
the TTMSS group can likely be attributed to its steric size. The
TTMSS group is extraordinarily bulky7a,12 and has been determined
to shield molecular skeletons with a “H3C-skin.”12b After the first
addition and silyl transfer, the steric encumberment of this group
is likely to kinetically slow the rate of the addition of a second
equivalent of SEE to a rate that does not compete with the rate of
the first addition. When all of the aldehyde starting material has
been consumed, a second addition occurs giving the products in
Table 2 with high diastereoselectivity. The reasoning for the syn
selectivity is shown in Figure 1 where conformation A does not
suffer the unfavorable steric interaction between the Lewis acid-
coordinated oxygen and the R group that is present in conformation
B. This explains the higher selectivity obtained with the bulkier R
groups (i.e., pivalaldehyde) due to the increased steric interactions
in conformation B. After this second addition occurs, the aldehyde
has â- and δ-TTMSSoxy groups, and if catalyst coordination occurs,
the complex is likely too bulky for further additions.
(5) Boxer, M. B.; Yamamoto, H. Org. Lett. 2005, 7, 3127.
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Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 12, 1851. (c)
Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005, 127, 3668.
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(b) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219 and references
therein.
(8) For derivatization and single-crystal X-ray analysis or comparison to
known compounds see Supporting Information.
(9) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc.
1996, 118, 4322.
(10) Dr could not be determined by crude 1H NMR. The major product was
isolated in the yield given in Table 2. The minor diastereomers were
formed in small amounts and were not isolable in quantitities needed for
structure elucidation.
(11) The chelation control results of this system will be studied and reported
in due course.
(12) (a) Elsner, F. H.; Woo. H-G. Tilley, T. D. J. Am. Chem. Soc. 1988, 110,
313. (b) Bock, H.; Meuret, J.; Ruppert, K. Angew. Chem., Int. Ed. Engl.
1993, 32, 414. (c) Bock, H.; Meuret, J.; Baur, R.; Ruppert, K. J.
Organomet. Chem. 1993, 446, 113. (d) Frey J.; Schottland, E.; Rappoport,
Z.; Bravo-Zhivotovskii D.; Nakash, M.; Botoshansky, M.; Kaftory, M.;
Apeloig, Y. J. Chem. Soc., Perkin Trans. 2 1994, 2555.
Intrigued by TTMSSNTf2 catalysis, we used 29Si NMR as an
indicator of silicon Lewis acidity and found that the central silicon
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