C O M M U N I C A T I O N S
Table 2. Acylsilane Scopea
entry
acylsilane
R1
product
yield (%)
Figure 1. Model for diastereoselection.
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
6
14
15
16
17
18
19
86
73
73
69
75
67
0b
diastereoselection for the tertiary alcohol products. Investigations
of this Umpolung strategy integrating enolates and the unique
reactivity of acylsilanes are ongoing and will be reported in due
course.
4-MePh
4-ClPh
4-BrPh
4-OMePh
2-ClPh
CH3
5g
Acknowledgment. Support has been provided by the NSF, the
PRF, and the Elizabeth Tuckerman Foundation (C.V.G.). We thank
Abbott Laboratories, Amgen, 3M, and Boerhinger-Ingelheim for
generous unrestricted research support, Wacker Chemical Corp. and
FMCLithium for providing reagents, and Professor Regan Thomson
(NU) and Dr. Jeremy Starr for helpful discussions.
a See Table 1 for reaction details. b Complex mixture.
The success of dimethylacetamide provided the foundation to
develop a stereoselective version of this process. The addition of
the enantiopure lithium enolate of 2111 to 5a, followed by quenching
with benzyl bromide, affords the desired carbinol (22, after
desilylation) with moderate diastereoselectivity under the established
kinetically controlled reaction conditions (-78 °C, entry 1, Table
3). However, when this sequence is conducted completely at 0 °C
(entries 2, 4-5), the selectivities improve to g10:1. Interestingly,
higher levels of selectivity are only observed when the initial adduct
(IV) is subjected to 0 °C (see entry 3), indicating the need for an
equilibration process to generate the most stable carbanion inter-
mediates (entry 3).
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
References
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Table 3. Diastereoselective Enolate/Acylsilane Reactionsa
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West, M. C. HelV. Chim. Acta 2002, 85, 3349-3365.
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entry
R
−
X
T1
(
°
C)
T2
(
°
C)b
T3
(
°
C)
yield (%)
drc
product
1
2
3
4
5
BnBr
”
-78
0
-78
-78
-78
0
-78
80
79
79
76
78
3:1
10:1
10:1
10:1
15:1
22
”
”
23
24
0
0
0
0
”
AllylBr
MeI
0
0
0
0
a Acylsilane and electrophile sequentially added to a 0.2 M enolate
solution in THF. Silyl ether products treated with n-Bu4NF in THF prior to
purification. b Reaction temp after consumption of 5a and before the addition
of R-X.12 c Determined by H NMR spectroscopy.
1
The current model for diastereoselection involves enolate addition
to 5a and subsequent Brook rearrangement with stereochemical
retention4,13 to give internally coordinated diastereomeric IV-(S)
and IV-(R).14 Importantly, O-alkylation is not observed when the
reactions are conducted at -78 or 0 °C, suggesting that the Brook
rearrangement occurs rapidly to generate carbanions (IV). The
unusual inverse relationship of selectivity on temperature suggests
that performing the reaction under thermodynamically controlled
conditions (0 °C) facilitates interconversion of IV prior to alkylation.
Since carbanion IV-(R) is destabilized by nonbonded interactions
between the trimethylsilylether and benzyl groups of the auxiliary,
the reaction proceeds via intermediate IV-(S) (Figure 1.
(10) Enolates from esters and imides afford complex mixtures.
(11) (a) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8631-8644. (b)
Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8645-8658.
(12) See Supporting Information for details.
In summary, we have developed a strategy for the synthesis of
tertiary â-hydroxy amides using â-silyloxy homoenolates accessed
from amide enolates and acylsilanes. These unconventional nu-
cleophilic species undergo addition to alkyl halides, aldehydes and
ketones. Importantly, amide enolates strongly favor C-alkylation
of the homoenolate over O-alkylation or the formation of alkoxy
cyclopropanes. The use of chiral acetamides affords high levels of
(13) Absolute stereochemistry of 22 determined by X-ray crystallography with
23 and 24 assigned by analogy.
(14) Strongly coordinating additives (e.g., DMPU, HMPA) reduce the dias-
tereoselectivity and yield of the reactions.
JA065605V
9
J. AM. CHEM. SOC. VOL. 128, NO. 49, 2006 15567