Three-component coupling reactions of silylglyoxylates, alkynes, and aldehydes: A chemoselective one-step glycolate aldol construction

Article abstract of DOI:10.1021/ja043884l

A single-pot three-component coupling reaction of silylglyoxylates (1), terminal alkynes, and aldehydes in the presence of ZnI₂ and Et₃N is presented. The products of the reaction, densely functionalized silyl-protected glycolate aldols (2), can be converted to the corresponding acetonides (3) in a one-pot deprotection/ketalization sequence. A variety of terminal alkynes and aldehydes can be successfully employed to give a range of highly functionalized, fully protected 1,2-diols in good yields and moderate diastereoselectivities. Mechanistic experiments suggest that the zinc acetylide reacts with the silylgyloxylate (1) in a chemoselective manner. Using an unoptimized (+)-N-methylephedrine and Zn(OTf)₂ system, silyl-deprotected adduct 2 was formed in 64% ee and 89:11 dr. Copyright

Full text of DOI:10.1021/ja043884l

Published on Web 04/06/2005
Three-Component Coupling Reactions of Silylglyoxylates, Alkynes, and
Aldehydes: A Chemoselective One-Step Glycolate Aldol Construction
David A. Nicewicz and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received October 7, 2004; E-mail: jsj@unc.edu
Scheme 1
Multicomponent coupling reactions can effect sequential bond
constructions and rapidly increase molecular complexity in a single
synthetic operation. In this context, acylsilanes1 have found broad
utility as reagents that act as a center of reactivity for both nucleo-
philes and electrophiles by virtue of a [1,2]-Brook rearrangement.2
Metallocyanide3,4 and metallophosphite5,6 nucleophiles reveal latent
(silyloxy)carbanions of acylsilanes following a nucleophilic addi-
tion/[1,2]-Brook rearrangement sequence (Scheme 1). Because silyl
migration is facilitated by the stabilization of the nascent anion by
the nitrile or phosphonate groups, one might conjecture that extant
Table 1. Reaction Scope with 1aa
electron-withdrawing functionality in the acylsilane moiety may
also promote silyl migration. For this reason silylglyoxylates7 (1),
a class of acylsilanes that possess an embedded anion stabilizing
group, captured our attention. Herein we report three-component
coupling reactions of silylglyoxylates (1), terminal alkynes, and
aldehydes to furnish glycolate aldols that bear two contiguous
stereocenters (eq 1, Table 1).
Kuwajima8 and Reich9 have shown that alkynylation of aliphatic
or vinylic acylsilanes initiates [1,2]-Brook rearrangement to furnish
propargyl anions that can engage a variety of electrophiles (H+,
DMF, 1° iodides, and disulfides) to give substituted silyloxyallenes.
A constraint in this chemistry that is common to multicomponent
couplings is reagent incompatibility: the high reactivity of the alkali
and alkaline earth acetylides employed by Kuwajima and Reich
necessitate a stepwise introduction of the acylsilane and terminating
electrophiles. We were interested in testing the feasibility of a
single-pot process in which the metal acetylide was generated in
the presence of both electrophilic components. This would be viable
only if the metal acetylide was a highly discriminating nucleophile;
in situ metal acetylide formation with a Lewis acid and amine base
as described by Carreira and Yamaguchi was the projected method
of choice.10,11
entry
R
′
R
yield (%)b
2:3c
1
2
3
4
5
6
7
8
9
10
Ph
Ph
Ph
Ph
Ph
Ph
77
77
60
48
81
65
73
76
66
77
78:22
74:26
72:28
71:29
76:24
80:20
80:20
78:22
47:53
53:47
n-C6H13
BnOCH2
PhthNCH2
Me3Si
Me3Si
2-(Me)C6H4
4-(MeO)C6H4
4-(Cl)C6H4
2-furyl
Me3Si
Me3Si
Me3Si
Me3Si
(E)-PhCHdCH
a Reaction carried out using 1.0 equiv of 1a, 3.0 equiv of alkyne, 1.5
equiv of PhCHO, 3.0 equiv of ZnI2, and 3.3 equiv of Et3N for 24-48 h.
b Average of two isolated yields. All reported yields are for two steps.
c Determined by H NMR analysis of the crude reaction. See Supporting
1
Information for determination of relative stereochemistry.
An evaluation of zinc salts confirmed the underlying premise
and revealed ZnI2 as the optimal Lewis acid to promote the desired
three-component coupling.12 The silylglyoxylate structure was
initially optimized for conversion and diastereoselectivity by varia-
tion of the ester functionality.13 A screen of trimethylsilylglyoxylates
indicated that tert-butyl trimethylsilylglyoxylate (1a) furnished the
desired adducts in the highest levels of conversion and diastereo-
control.
Employing tert-butyl trimethylsilylglyoxylate (1a), we explored
the scope of the reaction. The initial silyl ether adducts were found
to be susceptible to O-O silyl migration during the course of the
reaction and therefore were isolated as their derived acetonides. A
variety of alkynes (alkyl, aryl, trimethylsilyl, and heteroatom-substi-
tuted) were tolerated, affording the intended adducts (2/3) in mod-
erate to good yield (48-81%) and approximately 75:25 diastereo-
selectivity when benzaldehyde was the coupling partner (entries
1-5, Table 1). Substituted aromatic aldehydes also exhibited good
reactivity and diastereoselectivity (75:25 to 80:20; entries 6-8,
Table 1); disappointingly, aliphatic aldehydes were not suitable
substrates. Cinnamaldehyde and 2-furaldehyde also provided the
desired adducts in good yield, albeit with no diastereoselectivity
(53:47; entries 9 and 10, Table 1).
A second round of modifications to the silylglyoxylate structure
was undertaken to further improve the diastereocontrol.13 Systematic
variation of the silyl group revealed that by using tert-butyl tert-
butyldimethylsilylglyoxylate (1b), a marked increase in diastereo-
selectivity could be achieved (cf. Table 2, entries 1-3 with Table
1, entries 1, 2, and 6). The use of 1b allows for the isolation of
silyl-protected adducts (4/5) as differentially protected glycols.
Furthermore, deprotection of (4/5) with TBAF (1.1 equiv) followed
by a single recrystallization from hexanes afforded the diol in
diastereomerically pure form (entry 2).
Although the zinc acetylide appears to react in a chemoselective
manner with the silylglyoxylate, we also considered the possibility
of initial reversible alkynylation of the aldehyde. To test this
hypothesis, a suspension of phenylacetylene, benzaldehyde, Et3N,
and ZnI2 in toluene was allowed to stir for 48 h at -30 °C, giving
rise to an undefined intermediate A (presumably a zinc alkoxide,
Scheme 2). Aqueous ammonium chloride was added, and propargyl
9
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J. AM. CHEM. SOC. 2005, 127, 6170-6171
10.1021/ja043884l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scope with 1ba
cyclohexanecarboxaldehyde and 1b in THF at -78 °C with vinyl
Grignard results in the formation of glycol 8 in 76% yield and
complete diastereoselectivity.
In summary, a tandem alkynylation/Brook rearrangement/aldol
reaction of silylglyoxylates has been reported. This mode of
reactivity is divergent from that of the Kuwajima and Reich systems,
affording glycolate aldols rather than silyloxyallene aldols. The
reaction exhibits exquisite chemoselectivity at every potential branch
point in the reaction sequence. The identity of the silylglyoxylate
(1) is crucial for diastereocontrol; however, diastereomerically pure
diols of 4 can be isolated following a single recrystallization.
Additionally, it has been shown that enantioselective variants are
possible using simple enantiopure amino alcohols to mediate
chirality transfer. It is noteworthy that the identical functional group
arrays present in 416 and 817 have been utilized in natural product
synthesis, illustrating the potential value of these processes.
entry
R
′
R
yield (%)
4:5b
1
2
3
4
5
Ph
Ph
Ph
73
83:17
90:10 (>99:1)
n-C6H13
Me3Si
n-C6H13
n-C6H13
73 (53)
2-(Me)C6H4
4-(MeO)C6H4
2-(Me)C6H4
70c
91:9
72c
90:10
68c
92:8
a 1.0 equiv of 1b, 4.0 equiv of alkyne, 1.5 equiv of PhCHO, 4.0 equiv
of ZnI2, and 4.4 equiv of Et3N for 48 h. b Determined by 1H NMR analysis
of the crude reaction. c 5.0 equiv of alkyne, 5.0 equiv of ZnI2, and 5.5 equiv
of NEt3 used. Parenthetical yield and dr refers to the diol, revealed after
TBAF deprotection and recrystallization (two-step yield).
Acknowledgment. We are grateful to the National Institutes
of Health (National Institute of General Medical Sciences,
GM068443) for support of this research. D.A.N. acknowledges a
fellowship from Eli Lilly and an ACS Division of Organic
Chemistry Fellowship sponsored by Novartis. J.S.J. is an Eli Lilly
Grantee and a 3M Nontenured Faculty Awardee. Xin Linghu is
thanked for experimental assistance.
Scheme 2. Mechanistic Study
Supporting Information Available: Experimental details and
analytical data for all new compounds, CSP-SFC traces of racemic 7
and enantioenriched 7, and all stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Moser, W. H. Tetrahedron 2001, 57, 2065.
alcohol 6 was isolated in 99% yield. If intermediate A was instead
treated with 1a, after 24 h propargyl alcohol 6 was obtained 77%
yield, whereas 2a and 3a were formed in e8% yield (employing
the aforementioned deprotection/ketalization protocol).14 Because
the propargyl alcohol is formed in high yield and only trace amounts
of 2a/3a were observed, we are inclined to believe that zinc
acetylide addition to the silylglyoxylate occurs as the result of a
kinetic preference.
Initial experiments suggest that asymmetric induction may be
realized in this tandem process. Using Carreira’s conditions (Zn-
(OTf)2/(+)-N-methylephedrine),11 diol 7 was isolated after HCl/
MeOH workup in 30% yield, 89:11 dr, and 64% ee (eq 3).
(2) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(3) (a) Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112,
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(12) ZnBr2 and ZnCl2 also effected the transformation; however, higher
temperatures and reaction times were required.
(13) See Supporting Information for details.
(14) The yield of propargyl alcohol 6 was diminished by small amounts (<10%)
of Meerwein-Ponndorf-Verley reduction of 1a, presumably by inter-
mediate A:
Not only was there a marked increase in diastereoselectivity
relative to the ZnI2 system (75:25 dr; cf. entry 1, Table 1), but it
has been demonstrated, using unoptimized conditions, that an
enantioselective version of the title reaction is possible.15
We have extended this three-component coupling concept to
include aliphatic aldehydes (eq 4). Treatment of a solution of
However, neither side product was observed when the title reaction
reaction was run using the conditions described in eq 1, further supporting
our mechanistic interpretations.
(15) Only two examples of enantioenriched glycolate aldolates of this type
have been prepared, to our knowledge. One was by a chiral auxiliary
method: Murata, Y.; Kamino, T.; Hosokawa, S.; Kobayashi, S. Tetra-
hedron Lett. 2002, 43, 8121. The other was prepared by a direct catalytic
method involving chiral zinc complexes: Kumagai, N.; Matsunaga, S.;
Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169.
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