Highly diastereoselective preparation of anti-1,2-diols by catalytic addition of alkynylsilanes to α-silyloxyaldehydes

Article abstract of DOI:10.1021/ol061579u

The catalytic, diastereoselective coupling of α-silyloxy aldehydes and alkynylsilanes catalyzed by a nickel(0) N-heterocyclic carbene complex provides an effective entry to anti-1,2-diols. The scope of couplings and extent of diastereoselection are excell

Full text of DOI:10.1021/ol061579u

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4441-4443
Highly Diastereoselective Preparation of
anti-1,2-Diols by Catalytic Addition of
Alkynylsilanes to
r-Silyloxyaldehydes
Kanicha Sa-ei and John Montgomery*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
jmontg@umich.edu
Received June 27, 2006
ABSTRACT
The catalytic, diastereoselective coupling of
r-silyloxy aldehydes and alkynylsilanes catalyzed by a nickel(0) N-heterocyclic carbene complex
provides an effective entry to anti-1,2-diols. The scope of couplings and extent of diastereoselection are excellent across a range of substrates.
Diastereoselective nucleophilic additions to R-alkoxy alde-
hydes provide an attractive method for the preparation of
1,2-diols. Synthesis of anti-1,2-diols can be achieved by
additions to chiral aldehydes following the Felkin model for
diastereoselection, although control of stereochemistry can
often be a challenge. A number of studies involving
alkenylation of R-alkoxy aldehydes illustrate that anti
selectivity can sometimes be achieved but that the results
are variable depending upon the precise structure of both
the chiral aldehyde and the vinyl organometallic.1,2 Several
attractive alternative strategies that rely upon aldol technol-
ogy have also been developed to avoid these limitations.3
The nickel-catalyzed addition of aldehydes and alkynes
has emerged as a useful way to prepare allylic alcohols in a
variety of contexts.4,5 Several reports of nickel-catalyzed
reductive couplings of this class involving highly stereose-
lective additions to chiral R-alkoxy aldehydes have ap-
peared.6,7 Absent among the reports involving nickel catalysis
is the intermolecular diastereoselective addition of nonaro-
matic alkynes, terminal alkynes, and silyl alkynes. Addition-
ally, intermolecular additions involving R-alkoxyaldehydes
bearing an unbranched substituent at the R-carbon proceeded
with modest diastereoselectivity.6c Given the utility of
catalytic couplings of aldehydes and alkynes involving
(1) For alkenylations of R-alkoxy aldehydes, see: (a) Spino, C.; Granger,
M.-C.; Boisvert, L.; Beaulieu, C. Tetrahedron Lett. 2002, 43, 4183. (b) Iio,
H.; Mizobuchi, T.; Tsukamoto, M.; Tokoroyama, T. Tetrahedron Lett. 1986,
27, 6373.
(2) For alkenylations of other classes of chiral aldehydes, see: (a) Wipf,
P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Garner, P.; Park, J. M.;
Malecki, E. J. Org. Chem. 1988, 53, 4395. (c) Coleman, R. S.; Carpenter,
A. J. Tetrahedron Lett. 1992, 33, 1697.
(3) (a) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752.
(b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (c) Evans, D.
A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem. 1992, 57, 1961.
(d) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591. (e)
Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc.
2002, 124, 3292. (f) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E.
L.; Dalley, N. K. Org, Lett. 2000, 2, 3035. (g) Dixon, D. J.; Ley, S. V.;
Polara, A.; Sheppard, T. Org. Lett. 2001, 3, 3749.
(4) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065.
(b) Lozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124, 2106. (c)
Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743.
(d) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (e)
Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342.
(5) For reviews, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004,
43, 3890. (b) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (c) Miller,
K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymmetry 2003, 14,
3619. (d) Ikeda, S.-i. Angew. Chem., Int. Ed. 2003, 42, 5120.
(6) (a) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098.
(b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950. (c)
Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett. 2005, 7,
2937.
(7) For an emerging body of work involving titanium promoters, see:
(a) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005,
127, 3694. (b) Bahadoor, A. B.; Micalizio, G. C. Org. Lett. 2006, 8, 1181.
10.1021/ol061579u CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

nickel(0)/N-heterocyclic carbene catalysts recently disclosed
from our group,8 we have examined this catalyst formulation
in diastereoselective additions of alkynes to R-silyloxyalde-
hydes. The reaction scope and extent of diastereoselection
are excellent for substrate combinations and substitution
patterns not previously reported, and an attractive entry to
anti-1,2-diols is thus provided.
Although our group previously demonstrated that the
structure of an N-heterocyclic carbene ligand can play an
important role in determining the yield and regioselectivity
in nickel-catalyzed aldehyde/alkyne reductive couplings, the
current study focused exclusively on reactions involving Ni-
(COD)2 and the N-heterocyclic carbene (IMes) derived from
imidazolium 1 in THF. From our prior studies, we recognized
that silane structure was important to select for the desired
three-component coupling over undesired hydrosilylation of
the aldehyde or alkyne moieties. We thus compared the
catalytic addition of a TBS-protected silyloxy aldehyde with
trimethylsilyl(phenyl)acetylene using various silanes. Be-
cause of competing hydrosilylation processes with unhin-
dered silanes, chemical yields with (i-pr)3SiH were superior
to (t-Bu)Me2SiH and Et3SiH (Table 1, entries 1-3). We next
of alkynyl silanes vs terminal alkynes, phenyl acetylene was
examined as a reaction partner. This terminal alkyne
underwent addition in low yield (Table 1, entry 8), clearly
illustrating that alkynylsilanes were a preferred synthetic
equivalent of terminal alkynes. Interestingly, the syn dias-
tereomer was slightly favored starting from this terminal
alkyne.9 1-Phenylpropyne underwent efficient coupling with
an aliphatic aldehyde, although diastereoselectivities were
modest in comparison to couplings with alkynylsilanes (Table
1, entry 9). Analysis of the above examples suggested that
(i-pr)3SiH as the reducing agent, (t-Bu)Me2Si as the R-hy-
droxy protecting group on the aldehyde, and trimethylsilyl
alkynes would be a good combination for further study
(Table 1, entries 3 and 6). Notably, exhaustive deprotection
of the tris-silylated products is straightforward, or chemose-
lective deprotections are also possible if partially deprotected
structures are desired.
Using this optimized set of reaction parameters, several
combinations of R-silyloxyaldehydes and alkynes were
examined. Both aliphatic and aromatic alkynyl silanes
underwent couplings in high yield and good diastereoselec-
tivity (Table 2, entries 1-3).10 Next, a series of siloxyl
Table 2. Examination of Reaction Scope
Table 1. Optimization of Diastereoselectivitya
entry
R1
CH3
CH3
CH3
n-pentyl
(CH2)2Ph
n-pentyl
(CH2)2Ph
n-pentyl
n-pentyl
R2
% yield
anti/syn
1
2
3
4
5
6
7
8
9
CH3
Ph
81
75
85
80
85
85
85
78
80
88:12
89:11
89:11
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
entry
R1
R2
R3
R4 R53Si % yield anti/ syn
p-(CH3O)C6H4
p-(CH3O)C6H4
CH3
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
TBS
TBS
TBS
TMS Ph TES
TMS Ph TBS
TMS Ph TIPS
36
48
75
81
75
81
73
20
82
89:11
88:12
89:11
78:22
81:19
88:12
88:12
41:59
73:27
CH3
CH2Ph TMS Ph TIPS
n-butyl
n-butyl
Ph
TES
TBS
TIPS
TMS Me TIPS
TMS Me TIPS
TMS Me TIPS
n-pent TBS
n-pent TBS
H
Me
Ph TIPS
Ph TIPS
aldehydes that possess unbranched substituents at the R-posi-
tion were examined. This structural modification of extending
the length of the R-alkyl substituent (R1) in the aldehyde
resulted in a marked improvement in diastereoselectivity. As
illustrated by the examples provided (Table 2, entries 4-9),
diastereoselectivities and yields were uniformly outstanding
for this class of aldehydes with both aliphatic and aromatic
alkynyl silanes. The combination of silyloxy aldehydes and
silyl alkynes was most effective with unbranched R1 groups.
The participation of more hindered aldehydes requires
modifications of the protecting group and alkyne structure,
thus making the procedure reported herein complementary
to previously reported variants.6
a Abbreviations: TMS ) Me3Si; TES ) Et3Si; TBS ) (t-Bu)Me2Si;
TIPS ) (i-pr)3Si.
compared (i-pr)3SiH-mediated couplings of TMS-propyne
with various R-oxyaldehydes (Table 1, entries 4-7). Both
diastereoselectivities and yields were only modestly impacted
in comparing R-benzyloxy to various R-silyloxy groups, and
the t-butyldimethylsilyloxy group was selected for further
study given the ease of installation and removal and the
slightly superior yield and diastereoselectivity compared with
other options examined. To compare the addition reaction
(8) (a) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc.
2004, 126, 3698. (b) Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J.
J. Am. Chem. Soc. 2005, 127, 13156. (c) For an earlier example of the
unique role of N-heterocyclic carbene ligands in nickel-catalyzed reductive
couplings, see: Sato, Y.; Sawaki, R.; Mori, M. Organometallics 2001, 20,
5510.
(9) The minor isomer from tetrabutylammonium fluoride-mediated
exhaustive desilylation of the product from Table 1, entry 8, was identical
to that derived from desilylation of the major product from Table 2, entry
9.
(10) Entries 1 and 2 in Table 2 are duplicated from the optimization
studies described in Table 1.
4442
Org. Lett., Vol. 8, No. 20, 2006

The anti stereochemical assignment of the products was
made by exhaustive silyl deprotection followed by acetonide
protection of products 2a and 2b (from Table 2, entries 2
and 8). NOE analysis of products 3a and 3b thus provided
unambiguous assignment of stereochemistry (eq 1). The
stereochemistry of other products was assigned by analogy.11
(Table 2) is unclear. One can simply argue that the Felkin
model for diastereoselectivity is operative.13 However, we
are reluctant to draw close analogies between aldehyde
addition reactions of classical metalated nucleophiles in
comparison to nickel couplings, which we have proposed to
proceed via the formation of a nickel metallacycle derived
from a carbonyl π-complex. The requisite orbital interactions,
steric considerations, and trajectories of approach for a
classical nucleophile adding to a carbonyl are clearly different
from the requirements for formation and oxidative cyclization
of a late metal-aldehyde π-complex. Additionally, we have
illustrated that the mechanism of nickel-catalyzed aldehyde-
alkyne reductive couplings is ligand dependent,8a thus adding
further ambiguity to any mechanistic model. Nonetheless,
the classic Felkin model serves as a useful predictor of
stereochemistry in this reaction even though the underlying
basis for the effect will require further study.
Additionally, conservation of enantiopurity in a coupling
was illustrated by the conversion of the aldehyde 4 (>98%
ee), derived from (S)-ethyl lactate,12 into product 5 (>98%
ee) (Scheme 1).
In summary, the nickel-catalyzed three-component cou-
pling of R-silyloxy aldehydes, alkynyl silanes, and (i-pr)3SiH
provides protected allylic alcohol products in excellent yield
and diastereoselectivity. This particular combination of
substrates, reagents, and catalyst significantly expands the
scope of anti-1,2-diols that are available by alternate
procedures. Application of the process in complex synthetic
problems is in progress.
Scheme 1. Conservation of Enantioselectivity
Acknowledgment. Support for this work was provided
by the National Institutes of Health (GM 57014).
Supporting Information Available: Experimental pro-
cedures and a copy of spectral data for all new compounds
is provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
The mechanistic basis for the outstanding diastereoselec-
tivities in the specific substrate combinations described
OL061579U
(11) Additionally, the stereochemistry of the example from Table 1, entry
4, was confirmed by conversion of that product into the dibenzylated
material, which was identical to the dibenzylated compound derived from
the Table 1, entry 3, product. See Supporting Information for details.
(12) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.;
Chobanian, H. R. Org. Synth. 2004, 81, 157.
(13) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199. (b) For a discussion of silyloxy-based effects, see: Chen, X.;
Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114,
1778.
Org. Lett., Vol. 8, No. 20, 2006
4443