Metallophosphite-catalyzed asymmetric acylation of α,β- unsaturated amides

Article abstract of DOI:10.1021/ja056018x

The I-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate additions of acyl silanes to α,β- unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a variety of N,N-dimethyl acrylamide derivatives in the presence

Full text of DOI:10.1021/ja056018x

Published on Web 02/08/2006
Metallophosphite-Catalyzed Asymmetric Acylation of
r,â-Unsaturated Amides
Mary R. Nahm, Justin R. Potnick, Peter S. White, and Jeffrey S. Johnson*
Contribution from the Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received September 1, 2005; E-mail: jsj@unc.edu
Abstract: The l-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate
additions of acyl silanes to R,â-unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a
variety of N,N-dimethyl acrylamide derivatives in the presence of the lithium salt of 6b. In many instances
the R-silyl-γ-ketoamide product undergoes facile enantioenrichment (to 97-99% ee) upon recrystallization.
Desilylation with HF‚pyr affords the formal Stetter addition products. Baeyer-Villiger oxidation of the
desilylated γ-ketoamides affords useful ester products. An X-ray diffraction study of 6b reveals that the
isopropyl group of the menthone ketal influences the position of the syn-pseudoaxial phenyl group in the
TADDOL structure. Through a crossover experiment, the silicon migration step in the reaction mechanism
is shown to be strictly intramolecular.
Introduction
In parallel with the development of aldehydes as acyl donors
for conjugate additions, acyl silanes have shown promise as
suitable pronucleophiles in conjugate addition reactions. As in
the classic Stetter reaction, cyanide and heterazolium carbenes
can trigger the needed umpolung reactivity: -CN-catalyzed
addition of acyl silanes to cyclic enones and acyclic acrylates
was demonstrated by Degl’Innocenti,14 while carbene catalysis
was shown by Scheidt to be effective for the acylation of R,â-
unsaturated esters and ketones.15,16 Since the initiating steps in
these catalytic processes involving acyl silanes are presumed
The conjugate addition of acyl anion equivalents to R,â-
unsaturated carbonyls is a useful and direct approach to the
synthesis of 1,4-dicarbonyl compounds that can simultaneously
introduce two new stereocenters.1 The prototypical catalytic
reaction type involves the use of cyanide or heterazolium
carbenes as umpolung catalysts.2-4 Employing scalemic versions
of the latter, the asymmetric intramolecular Stetter reaction was
recently realized as a useful transformation by Enders and co-
workers.5,6 The transformation has undergone some significant
improvements in enantioselectivity and scope in a body of work
by Rovis and co-workers that now stands as the benchmark in
this family of reactions.7-12 Their optimized process lends itself
to a number of R,â-unsaturated ester and ketone acceptors
delivering the annulated products in high yield and enantiose-
lectivity; however, extension to asymmetric intermolecular
alkene acylation has generally proven challenging. Enders was
the first, to our knowledge, to successfully investigate this
variant, achieving the addition of butanal to chalcone in 4-29%
yield and 30-39% enantiomeric excess;13 these results represent
the current state-of-the-art.
to be carbonyl addition and [1,2]-Brook rearrangement,17,18
a
pressing question related to catalysis was whether other entities
might trigger these events. Indeed, Reich and Takeda had
already shown that lithium phosphites add to acyl silanes and
cause silicon migration.19,20 The latter study was particularly
relevant since a pendant R,â-unsaturated ester was employed
to trap the nascent (siloxy)phosphonate anion.21 The work of
Reich and Takeda was instrumental to our development of chiral
metallophosphites as nucleophilic catalysts for aldehyde and
alkene acylation.22,23 We recently demonstrated a preliminary
asymmetric variant of the alkene acylation reaction that
proceeded in 67% yield and 50% enantiomeric excess using
(1) Stetter, H.; Kuhlmann, H. Org. React. (N. Y.) 1991, 40, 407-496.
(2) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258.
(3) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328.
(4) For an exception using PBu3, see: Gong, J. H.; Im, Y. J.; Lee, K. Y.;
Kim, J. N. Tetrahedron Lett. 2002, 43, 1247-1251.
(13) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
(14) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta, V. Gazz.
Chim. Ital. 1987, 117, 645-648.
(15) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 2314-2315.
(16) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465-2468.
(17) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84.
(18) Moser, W. H. Tetrahedron 2001, 57, 2065-2084.
(19) Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609-
5617.
(20) Takeda, K.; Tanaka, T. Synlett 1999, 705-708.
(21) Koenigkramer, R. E.; Zimmer, H. J. Org. Chem. 1980, 45, 3994-3998.
(22) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
3070-3071.
(23) Nahm, M. R.; Linghu, X.; Potnick, J. R.; Yates, C. M.; White, P. S.;
Johnson, J. S. Angew. Chem., Int. Ed. 2005, 44, 2377-2379.
(5) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta 1996,
79, 1899-1902.
(6) Enders, D.; Breuer, K. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 3,
pp 1093-1102.
(7) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298-10299.
(8) Kerr, M. S.; Rovis, T. Synlett 2003, 1934-1936.
(9) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-8877.
(10) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284-6289.
(11) Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio, J. E.; Miller, S.
J. Chem. Commun. 2005, 195-197.
(12) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632-2634.
9
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J. AM. CHEM. SOC. 2006, 128, 2751-2756
2751

A R T I C L E S
Nahm et al.
Scheme 1. Alkene Acylation Catalyzed by Phosphites 1-Ar
the Enders (R,R)-TADDOL-phosphite 1-Ph.24,25 From that
platform we hypothesized that more highly enantioenriched 1,4-
dicarbonyl products could be obtained through tuning of the
phosphite catalyst and reagent functional groups. This article
details the development of an effective asymmetric metallo-
phosphite-catalyzed intermolecular addition of acyl silanes to
R,â-unsaturated amides that can be achieved under mild reaction
conditions in good yield and high enantioselectivity (eq 1).
Results and Discussion
Figure 1. TADDOL-phosphites containing the l-menthone ketal.
I. Optimization Studies. Phosphite Structure. The asym-
metric cross silyl benzoin reaction developed in our laboratory22
exhibited significant enantioselectivity enhancement through
varying the aromatic groups on the (R,R)-TADDOL-phosphite
(1-Ar). Due to this positive effect, our first instinct was to
examine those electronic modifications on the phosphite in the
1,4-addition of benzoyl dimethylphenylsilane 2 to morpholino-
cinnamide 3 (Scheme 1). Electron-withdrawing substituents on
1 gave very low conversion, but in all reactions, neither electron-
withdrawing nor electron-donating aromatic groups gave a
significant boost in enantioselectivity.
In fact, of the amides surveyed, only N,N-dimethylcinnamide
(7) exhibited significant improvement relative to the morpholi-
nocinnamide 3 in both conferred enantiocontrol (71% ee using
phosphite 6b) and diastereoselectivity for the derived R-silyl-
γ-ketoamide 9 (Scheme 2). The reaction proceeded at a
somewhat slower rate and product yield was lower (40%, Table
1, entry 3), but only a single diastereomer of the R-silyl-γ-
1
ketoamide 9 could be distinguished by H NMR spectroscopy
(anti/syn > 30:1).
Acyl Silane. Attention was then directed at improving the
enantiomeric excess and yield for the alkene acylation through
modification of the acyl donor. Our experiments in this vein
revealed that the identity of the silyl moiety was crucial for
maximizing enantiocontrol and that the aryl group of the acyl
silane was the key in modulating reactivity. The addition of
benzoyl triethylsilane to N,N-dimethylcinnamide (7) catalyzed
by 6b gave the product R-silyl-γ-ketoamide as one distinguish-
able diastereomer by 1H NMR spectroscopy and the desilylated
γ-ketoamide product 8 in 88% enantiomeric excess (Table 1,
entry 4). Further increases in the steric demand of the silyl group
(benzoyl triisopropylsilane, benzoyl trihexylsilane, benzoyl tert-
butyldimethylsilane) resulted in dramatic decreases in reactivity.
The use of benzoyl cyclohexyldimethylsilane27 furnished 8 in
comparable enantioselectivity to PhC(O)SiEt3 but conferred the
added bonus of crystallinity to the intermediate R-silyl-γ-
ketoamide. This characteristic was found to be relatively
common (vide infra) and was used advantageously in purifica-
tion and upgrades in product enantiomeric excess. Although the
boost in enantioselectivity using PhC(O)SiEt3 and PhC(O)-
SiCyMe2 was encouraging, product yields were still unaccept-
ably low. In probing this issue, we were fortunate to discover
that substitution of the phenyl group of the acyl silane with a
para-anisyl group reduced reaction times, provided the needed
increase in yield, and had little effect on the enantioselectivity.
Specifically, phosphite 6b catalyzed the efficient conjugate
addition of para-methoxybenzoyl cyclohexyldimethylsilane 10
to cinnamide 7; desilylation of an aliquot of R-silyl-γ-ketoamide
Another candidate for site modification in the catalyst
architecture was the ketal backbone. In previous studies, we
had observed minimal effect in changes at this site;22 however,
we were pleased to find that replacement of acetone with
l-menthone in the initial ketalization using either L- or D-diethyl
tartrate afforded, after Grignard addition and phosphinylation,
diastereomeric phosphite catalysts 6a and 6b (Figure 1) that
exhibited notably higher levels of enantiocontrol in the addition
of 2 to 3. Although the menthone tartrate has been reported by
Seebach,26 to the best of our knowledge, our preparation of 6a
and 6b constitutes the first synthesis of a menthone-based
TADDOL.25 The therapeutic effects of this modification were
noted in not only the enantiomeric excess of 5 (-60% ee using
6b, Table 1, entry 2) but also the improved anti/syn selectivity
for the intermediate R-silyl-γ-ketoamide 4 (6b: anti/syn ) 20:
1; 1-Ph: anti/syn ) 10:1). The latter point impacts the former
since we had previously demonstrated that anti and syn
diastereomers possess the opposite absolute configuration at the
phenyl-bearing stereocenter and that desilylation of the mixture
results in erosion in the enantiomeric excess of 5.23
Amide. The impact of the amide structure on enantioselec-
tivity and reactivity was probed through an examination of
eleven cinnamides; a complete summary of this study may be
found in the Supporting Information. Pyrrole, pyrazole, and
Weinreb cinnamides failed to provide any acylation product.
(24) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000, 39,
4605-4607.
(25) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40,
92-138.
(26) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A.
HelV. Chim. Acta 1987, 70, 954-974.
(27) Dimethylcyclohexylsilyl chloride is commerically available and is com-
parable in price to triethylsilyl chloride.
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Acylation of
R
,
â-Unsaturated Amides
A R T I C L E S
Table 1. Optimization Summary for Asymmetric Alkene Acylationa
a ArC(O)SiR3 (1.0 equiv), PhCHdCHC(O)NR′2 (1.5 equiv), phosphite (0.2 equiv.), and LiN(SiMe3)2 (0.2 equiv) in Et2O from -35 f 25 °C for 0.25-
2.0 h after slow addition of alkene and acyl silane.
Scheme 2. Enantioselective Acylation of N,N-Dimethylcinnamide
enantiomers can be obtained. A final operational modification
was made involving the deprotection step: the use of tetra-N-
butylammonium fluoride (TBAF) was occasionally found to
cause erosion in product enantioselectivity depending on contact
time with the substrate. Desilylation using HF‚pyridine in
acetonitrile gave comparable yields and consistent enantiose-
lectivities (entries 8,9).
After an optimized reaction protocol had been established
for the asymmetric conjugate addition of acylsilanes to R,â-
Scheme 3. Recrystallization and Enantiomeric Excess Upgrade of
unsaturated amides in the glovebox, it was necessary from a
R-Silyl-γ-ketoamide 11
practicality standpoint to achieve those yields and enantiose-
lectivities outside of the glovebox. Our initial efforts resulted
in inconsistent results with incomplete conversion arising as a
common problem even under nominally anhydrous and anerobic
conditions. Separation and isolation of materials from these
reactions and identification of them by 31P spectroscopy and
mass spectrometry revealed the presence of (1) the conjugate
addition product between the phosphite and unsaturated amide24
and (2) the (siloxy)phosphonate resulting from quenching of
the Brook rearrangement product. The precursors to these
byproducts are understandably sensitive to traces of proton
sources. The use of excess base was sufficient in our cross
benzoin studies to achieve a simple reaction protocol and avoid
this problem, but conditions employing excess base gave nearly
racemic product in the current study. To achieve full conversion
outside of the glovebox, we found it optimal to conduct reactions
on at least a 200 mg scale using 30 mol % of phosphite and 30
mol % of LiN(SiMe3)2 at room temperature. This gave a simple
and reproducible protocol and also simplified recrystallization
of the silylated product.
11 indicated that the kinetic enantioselectivity for the initial
addition was 95:5 (Scheme 3). The remainder of amide 11 was
recrystallized from hot hexanes and upon desilylation afforded
12a in 99% ee and 68% yield.
The key experiments in the reaction evolution are summarized
in Table 1, and a more extensive tabulation can be found in the
Supporting Information. All reactions were run on a 100 mg
scale in a glovebox using 20 mol % of the phosphite catalyst
and base, lithium hexamethyldisilazide. The optimized reagents
were also tested using catalyst 1-Ph (entry 7) for a direct
comparison to the menthone phosphite 6b, and phosphite 6a
(entry 9) was employed to demonstrate that both product
II. Substrate Scope and Limitations. The reaction scope
with respect to the Michael acceptor was then analyzed
employing the aforementioned reaction conditions. An aliquot
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J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2753

A R T I C L E S
Nahm et al.
Table 2. Substrate Scope of Asymmetric
the p-anisyl substitutent in 10 is needed for high yield and
enantioselectivity. We viewed this apparent limitation as an
opportunity to develop useful second-stage reactions involving
the acylation products. In particular, we considered that oxida-
tion of the Caryl-Ccarbonyl bond would provide a broader selection
of 1,4-dicarbonyl compounds with more flexibility for subse-
quent manipulation. Such Baeyer-Villiger reactions of (meth-
oxyphenyl)ketones in conjunction with asymmetric synthesis
are well-documented.28-32 Indeed, exposure of 12a and 12j to
m-chloroperbenzoic acid (m-CPBA) in chloroform resulted in
oxidation of the ketones to the derived p-methoxyphenyl (PMP)
esters 13a and 13j, respectively (eq 3). As expected, no loss in
optical purity was observed for the ester products. The difference
in the yield for 13a relative to 13j arises from a regioisomeric
Baeyer-Villiger product in the former case.
Metallophosphite-Catalyzed Alkene Acylationa
% ee
% ee
entry
R
% yield
(aliquot)
(12)
1
2
3
4
5
6
7
8
9
Ph (a)
68
63
78
67
15
66
60
80
66
56f
82
90
92
90
93
24
95
97
90
89
86f
71
99
b
b
99
c
p-MeOPh (b)
p-MePh (c)
m-MePh (d)
2-furyl (e)
p-ClPh (f)
98
97
b
N-tosylindol-3-yl (g)
p-CF3Ph (h)d
2-naphthyl (i)
Me (j)d
97e
g
10
11
Et (k)d
b
a Slow addition of p-MeOPhC(O)SiCyMe2 (1.0 equiv) and
RCHdCHC(O)NMe2 (1.5 equiv) to the phosphite (0.3 equiv) and LiN-
(SiMe3)2 (0.3 equiv) in Et2O at 25 °C; reaction times ) 0.25-3.0 h.
b Attempts at recrystallization of the R-silyl-γ-ketoamide or final product
(12) were unsuccessful. c Yield was too low to attempt recrystallization.
d 1.1 equiv of RCHdCHC(O)NMe2 was employed and was added with the
acyl silane to the metallophosphite mixture. e The major enantiomer was
found in the mother liquor after recrystallization of the final product. f Yield
and % ee after separation of the major diastereomer. g Recrystallization
yielded little improvement in enantioselectivity.
The PMP esters are useful compounds that permit differentia-
tion of the two carbonyl groups and provide access to other
useful building blocks (Scheme 4). Transesterification of 13a
with methanol occurs to afford the corresponding methyl ester
14 with little racemization. Ester 13a undergoes chemoselective
reduction with NaBH4 to give γ-hydroxyamide 15 in >95%
yield with negligible loss in enantiopurity.
The absolute configuration of 15 (and thence 13a and 12a)
was established through comparison of its optical rotation to
that reported in the literature for the 3(R) isomer.33 This
assignment was cross-verified through an X-ray diffraction study
of enantiomerically pure 12f; this amide also possessed the (R)
configuration.34 These stereochemical proofs are at odds with
the one provided in our original communication for compound
5. That analysis involved the conversion of γ-ketoamide 5 to
the γ-lactone 16, whose absolute stereostructure had been
previously proposed on the basis of CD studies on related
compounds (eq 4).35 The discrepancy between that assignment
from each reaction was removed and desilylated to determine
the kinetic enantioselectivity for the addition. When possible,
the remaining R-silyl-γ-ketoamide was recrystallized. Depro-
tection with HF‚pyridine in acetonitrile afforded γ-ketoamides
12a-k. Yields and enantioselectivities of the final products are
listed in Table 2.
The alkene acylation is applicable to R,â-unsaturated amides
containing both electron-donating (entries 2-4) groups and
electron-withdrawing groups (entries 6-8) in the â-position of
the Michael acceptor affording the product in reasonable yields
and high enantioselectivities except for the strongly electron-
donating furyl substituent (entry 5). â-Alkyl amides also undergo
productive coupling with somewhat lower product enantiose-
lectivities (entries 10-11). While the scope is good for the
Michael acceptor, a notable limitation of this acylation protocol
in its current form is its inability to successfully couple alkyl
acyl silanes (RC(O)SiR′3, R ) alkyl) with unsaturated amides
in yields > 10%. Since the metallophosphite addition and Brook
rearrangement steps have been demonstrated for alkyl acyl
silanes,22 this lack of reactivity is apparently due to the inability
of the (silyloxy)phosphonate anion to participate in conjugate
addition.
The optimized reaction conditions described above work well
on a reasonable laboratory scale. On a 5-g scale, the addition
of 10 to N,N-dimethylcinnamide catalyzed by 6b gives the
R-silyl-γ-ketoamide 11 in >99% enantiomeric excess after
crystallization. Deprotection with HF‚pyridine and recrystalli-
zation give the enantiopure γ-ketoamide 12a in 61% yield for
the two steps.
and the stereochemical assignments established in this article
through both chemical correlation and X-ray crystallography
suggests either (1) the stereochemical assignment made by
Chang et al. (and by corollary our assignment of 5) is incorrect
(28) Evans, P. A.; Lawler, M. J. J. Am. Chem. Soc. 2004, 126, 8642-8643.
(29) Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org. Chem. 2002, 67, 2556-
2565.
(30) Boyes, S. A.; Hewson, A. T. J. Chem. Soc., Perkin Trans. 1 2000, 2759-
2765.
(31) Reissig, H. U.; Schumacher, R.; Ferse, D. Liebigs Ann./Recl. 1997, 2119-
2124.
III. Product Manipulation and Stereochemistry. Table 1
suggests, and experiments with other acyl silanes confirm, that
(32) Baures, P. W.; Eggleston, D. S.; Flisak, J. R.; Gombatz, K.; Lantos, I.;
Mendelson, W.; Remich, J. J. Tetrahedron Lett. 1990, 31, 6501-6504.
9
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Acylation of
R
,
â-Unsaturated Amides
A R T I C L E S
Figure 2. X-ray structures of phosphites 1-Ph and 6b.
Scheme 4. Synthetic Operations Involving 13a
electrophiles, a fact that would seem to augur well for extension
to other electrophiles.
IV. Reaction Characteristics. Catalyst Structure. To better
understand the structural features of the l-menthone-modified
catalyst that result in enhanced enantiocontrol, we undertook
X-ray diffraction studies of phosphites 1-Ph and 6b (Figure 2).34
The structure of 6b reveals that the isopropyl group of the
menthone moiety is disposed approximately on the pseudo-C2
axis of the catalyst tartrate framework. Further inspection
indicates that the presence of the isopropyl group results in
nonbonded compression of the nearby pseudoaxial phenyl group
into the reaction site (i.e., toward the phosphorus atom). This
is most clearly manifested in the distance between the ketal
carbon and the para carbon of the pseudoaxial phenyl group
syn to the isopropyl group. For 6b this distance is 5.482 Å,
while the analogous measurement for 1-Ph gives a distance of
5.192 Å. For comparison, the distance from the ketal carbon to
the para carbon of the pseudoaxial phenyl group anti to the
isopropyl group in 6b is 5.110 Å. These observations may reveal
a structural basis for the enhanced enantioselectivity, since the
isopropyl group appears to force one of the phenyl groups in
closer proximity to the obligatory transition structure. Such
transmission effects have been observed crystallographically in
other nonacetonide TADDOL derivatives.25 The fact that 6a
and 6b provide opposite but equal enantioselectivity suggests
that the absolute configuration of the menthone is not important,
a supposition that is congruent with the position of the iso-
propyl group on the pseudo-C2 axis.
or (2) there is a turnover in absolute stereochemical preference
for acyl silane/amide combination 2/3 versus 7/10. Difficulty
in obtaining 5 in high enantiomeric excess has so far precluded
the use of derivatization and X-ray crystallography to resolve
this issue. The absolute configuration of 5 must therefore be
considered tentative. In practice, however, the most synthetically
useful and highly enantioenriched adducts described in this
article (i.e., 12) are those whose absolute stereostructures have
been unambiguously determined. It is noteworthy that the
topicity preference for the tartrate-based (silyloxy)phosphonate
anion intermediate is the same for both aldehyde and alkene
(33) Braun, M.; Unger, C.; Opdenbusch, K. Eur. J. Org. Chem. 1998, 2389,
9-2396.
Test for Silyl Group Transfer Pathway. A crossover
experiment was designed (Scheme 5) to distinguish whether the
silyl transfer in the title reaction was occurring via an intramo-
lecular or intermolecular pathway. Phosphite 6b was used to
catalyze the reaction of para-methoxybenzoyl cyclohexyldim-
(34) CCDC 282470 (1-Ph), CCDC 282471 (6b), and CCDC 293708 (12f)
contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(35) Chang, C. J.; Fang, J. M.; Liao, L. F. J. Org. Chem. 1993, 58, 1754-
1761.
9
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A R T I C L E S
Nahm et al.
Scheme 5. Crossover Experiment to Determine Silyl Group Transfer Pathway
Conclusion
ethylsilane (10) and benzoyl triethylsilane (17) with a single
R,â-unsaturated amide, N,N-dimethylcinnamide (7), under con-
ditions stated in the Supporting Information. By 1H NMR
spectroscopy, the R-silyl-γ-ketoamides 11 and 18 were each
obtained in >80% yield (versus internal standard) and to the
exclusion of any intermolecular Si-transfer products.
With the confirmation that the silicon migration is intramo-
lecular, we propose that the high anti diastereoselectivity10 can
be explained through consideration of some simple conforma-
tional issues. In the catalyzed alkene acylation, the reactive
conformer of the acceptor is presumed to be s-cis.36 Conjugate
addition of the (siloxy)phosphonate anion21 should provide the
nascent lithium enolate in the favored (Z)-geometry. In this
conformation, intramolecular retro-[1,4] Brook rearrangement37
is expected to be strongly favored from the rear face of the
enolate due to associated A1,3 constraints (as depicted in
Figure 3).
High enantioselectivities can now be achieved in the catalytic
intermolecular conjugate addition of acyl silanes to R,â-
unsaturated amides. The reactions take place at room temper-
ature in less than 2 h for a variety of aryl and alkyl substrates.
In many cases the R-silyl-γ-ketoamides formed after the
nucleophilic addition are stable, white solids that may be purified
by recrystallization. This simple purification leads to useful
enantioselectivity upgrades in several cases. While the catalyst
loading is not optimal in the current iteration, the phosphites
are trivial to prepare from cheap starting materials that are
available in either antipode. The levels of enantiocontrol realized
for the title reaction are the highest for any intermolecular
Stetter-type reaction to date, and the products may be trans-
formed to terminally differentiated chiral succinates.
Acknowledgment. Funding was provided by the National
Institutes of Health (National Institute of General Medical
Sciences, GM068443). Research support from Eli Lilly, 3M,
Amgen, and GSK is gratefully acknowledged.
Supporting Information Available: Experimental procedures,
compound characterization data, and crystallographic informa-
tion files. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA056018X
(36) Montaudo, G.; Librando, V.; Caccamese, S.; Maravigna, P. J. Am. Chem.
Soc. 1973, 95, 6365-6370.
(37) Gibson, C.; Buck, T.; Noltemeyer, M.; Bru¨ckner, R. Tetrahedron Lett. 1997,
38, 2933-2936.
Figure 3. Proposed model for anti diastereoselectivity.
9
2756 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006