Metallophosphite-induced nucleophilic acylation of α,β- unsaturated amides: Facilitated catalysis by a diastereoselective retro [1,4] brook rearrangement

Article abstract of DOI:10.1002/anie.200462795

(Chemical Equation Presented) Intermolecular alkene acylation reactions between acyl silanes and α,β-unsaturated amides with metallophosphite catalysis afford α-silyl-γ-ketoamides with high diastereoselectivities (see scheme). These can be converted into

Full text of DOI:10.1002/anie.200462795

Angewandte
Chemie
Asymmetric Synthesis
Acyl silanes are effective aldehyde surrogates that confer
unique advantages in umpolung reactions. The acyl anion
equivalent formed on nucleophilic addition and subsequent
Metallophosphite-Induced Nucleophilic
[
5,6]
Acylation of a,b-Unsaturated Amides: Facilitated [1,2] Brook rearrangement
undergoes addition to a
Catalysis by a Diastereoselective Retro
number of electrophiles. DeglꢀInnocenti et al. found that the
1,4-addition of benzoyl trimethylsilane to cyclohexenone can
[
1,4] Brook Rearrangement**
[
7]
be catalyzed by cyanide ions, whereas Scheidt and co-
workers recently described the successful conjugate addition
of acyl silanes to unsaturated esters and ketones by using
Mary R. Nahm, Xin Linghu, Justin R. Potnick,
Christopher M. Yates, Peter S. White, and
Jeffrey S. Johnson*
[
8,9]
thiazolium carbene catalysis.
The substrate scope of the
latter process mirrors the classic Stetter reaction, and
conjugate acceptors bearing a b-alkyl substituent have not
[
10,11]
Nucleophilic acylation of enones and enoates catalyzed by
cyanide ions or heterazolium carbenes, commonly known as
the Stetter reaction, is a useful method for the synthesis of 1,4-
been reported. Metallophosphites
can be considered as
an alternative to cyanide ions and thiazolium carbenes, and
they have recently been described as carbonyl-umpolung
catalysts in the context of a new enantioselective cross-
benzoin reaction. We projected that this catalysis concept
might be applicable to alkene electrophiles as well.
The conjugate addition of acyl silanes (benzoyl trimethyl-
silane, benzoyl triethylsilane, and benzoyl dimethylphenylsi-
lane) to Michael acceptors (ethyl crotonate, methyl cinna-
mate, and cyclohexenone) catalyzed by the Enders phosphite
5 was initially examined. Potassium hydride gave the best
reactivity of the bases screened in these reactions; however,
few reactions provided appreciable quantities of the desired
[
1]
dicarbonyl compounds. The key feature of this reaction is
the carbonyl-polarity reversal initiated by the addition of a
cyanide ion or a heterazolium carbene to an aldehyde
facilitating subsequent 1,4-addition to an a,b-unsaturated
carbonyl compound. Although this reaction has proven
fruitful with a variety of acceptors, its success has been
[
12]
[
2]
largely limited to aryl or unsubstituted substrates. Acceptors
bearing a b-alkyl group normally give the 1,4-addition
[
3]
product in 30–40% yield, and achieving enantioselectivity
in the intermolecular Stetter reaction has also proven to be
[
4]
1
difficult. Herein, we provide a strategy to address both of
these issues through metallophosphite-catalyzed acylations of
a,b-unsaturated amides. These reactions are enabled by an
unusual [1,2] Brook rearrangement/conjugate addition/ret-
ro [1,4] Brook rearrangement sequence that proceeds with
good anti diastereoselectivity and allows access to a range of
stable a-silyl-g-ketoamides (Scheme 1).
acylation product. The H NMR spectra of the reactions
typically revealed incorporation of the phosphite in the acyl
silane/acceptor adduct, thus indicating that the proposed
cycle was initiated but not completed. Exposure of the
reaction mixture to tetrabutylammonium fluoride (TBAF)
afforded the desired g-ketoester. Ethyl crotonate provided
the best yields of the acceptors screened, but even under
optimized conditions these were unacceptably low [ ꢀ 37% of
6, Eq. (1)].
Scheme 1. Metallophosphite-catalyzed alkene acylation. X=OR, NR2.
The low turnover and aforementioned observations
[*] M. R. Nahm, X. Linghu, J. R. Potnick, C. M. Yates, P. S. White,
Prof. J. S. Johnson
suggested that enolate 3 did not undergo efficient silyl
Department of Chemistry
transfer. We hoped that replacement of the unsaturated
University of North Carolina, Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
Fax: (+1)919-962-2388
ester (X = OR) with an amide (X = NR ) would enhance the
2
nucleophilicity of the derived enolate, promote the desired
silyl transfer, and regenerate the metallophosphite catalyst.
Evaluation of this hypothesis revealed that amides did
indeed facilitate catalyst turnover (Table 1). We had expected
that O!O 1,6 transfer of the silyl group to form a silylketene
aminal might be energetically feasible but were surprised to
find that the O!C 1,4 silyl transfer was dominant to the
exclusion of the former. Furthermore, the derived a-silyl-
E-mail: jsj@unc.edu
[
**] We thank the National Institutes of Health (National Institute of
General Medical Sciences (GM068443)) for support of this
research. J.S.J. is an Eli Lilly Grantee and a 3 m Nontenured Faculty
Awardee.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 2377 –2379
DOI: 10.1002/anie.200462795
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2377

Communications
[
a]
[19]
Table 1: Catalytic conjugate addition of acyl silanes to unsaturated amides.
50% ee. Although the enantioselectivity
is moderate, it already eclipses the highest
enantioselectivity of which we are aware for
intermolecular Stetter-type reactions (4%
[
20]
yield, 39% ee). We further note that the
structure of 1,1,4,4-tetraphenyl-2,3-O-iso-
propylidene-l-threitol (TADDOL) phos-
phite is readily amenable to modifications
that we project will deliver more highly
enantioselective catalysts.
[
b]
[c]
Entry
Ar
SiR3
R’
Z
d.r. of 4
t [h]
Yield [%]
[
d]
1
2
3
4
5
6
7
8
9
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
SiMe Ph
SiMe Ph
SiMe Ph
SiMe Ph
SiMe Ph
SiMe Ph
SiMe3
SiEt3
SiEt3
SiEt3
Me
Me
Et
Ph
4-MeOPh
4-ClPh
Me
Me
Me
CH2
O
7:1 (4a)
4:1 (4b)
1.3:1 (4c)
10:1 (4d)
11:1 (4e)
8:1 (4 f)
10:1 (4g)
4:1 (4h)
3.5:1 (4i)
3:1 (4j)
2
73 (7a)
81 (7b)
74 (7c)
81 (7d)
57 (7e)
80 (7 f)
80 (7a)
91 (7a)
87 (7i)
62 (7j)
2
0.5
0.75
The proposed catalytic cycle is depicted
in Scheme 4 and is initiated by phosphite
addition and the [1,2] Brook rearrange-
2
2
CH2
[
[
[
e]
e]
e]
[f]
[g]
O
O
O
CH2
CH2
CH2
CH2
0.5
2
[g]
0.5
[21]
2
[g]
ment. Catalyst release is apparently trig-
0.5
2
gered after conjugate addition by an
3
2.5
1
unusual
diastereoselective
retro
[
22]
4-MeOPh
4-ClPh
[1,4] Brook rearrangement (3!10). The
0
Me
2
fact that the major enantiomer possesses the
a] ArC(O)SiR3 (1.0 equiv), R’CH CHC(O)NC H Z (1.1 equiv) unless otherwise stated. [b] anti/syn
=
1
same C3 configuration in both the syn and
anti diastereomers (Scheme 3) suggests that
[
4
8
isomers as determined by H NMR spectroscopic analysis unless otherwise stated. [c] Yield of the
isolated, analytically pure 7; average of at least two experiments. [d] Phosphite catalyst loading=
the chiral phosphite may be the dominant
diastereocontrol element rather than a
preferred transition-state topology.
1
0 mol%. [e] R’CH=CHC(O)NC H O (1.5 equiv). [f] As determined by yield of isolated product.
4 8
[
g] Including slow addition of acyl silane to other reagents.
A metallophosphite-catalyzed intermo-
lecular alkene acylation has been achieved
amide was unexpectedly delivered with good diastereoselec-
employing the Enders TADDOL phosphite, thus giving g-
ketoamides in generally good yields. These reactions allow
access to synthetically interesting a-silyl-g-ketoamides and
provide an attractive platform for enantioselective variants.
Ongoing work in our laboratory is directed toward the
tivity in a number of cases. Acceptors bearing a b-alkyl
[
13]
substituent for these metallophosphite-catalyzed reactions
are now synthetically useful substrates that generate alkene
acylation products in moderate to high yields (62–91%,
entries 1–3 and 7–10). A number of acyl silanes are competent
in the addition and show only subtle changes in reactivity
upon variation of the silyl group (entries 1, 7, and 8) but
exhibit more significant differences in reactivity between the
electron-rich and electron-poor acyl silanes (entries 9 and 10).
The a-silyl-g-ketoamides 4 were stable and could be easily
isolated by column chromatography. We were naturally
attracted to the stereospecific transformation of the function-
alized silane to its derived secondary alcohol through the
[
14,15]
Tamao–Fleming oxidation,
but were aware of only two
reported examples of such oxidations of a-silylcarbonyl
[
16,17]
2
compounds.
Attempts to activate the C(sp )ꢁSi bond by
a variety of protocols led to either desilylation, which yielded
7
, or bromination through cleavage of the C ꢁSi bond. The a-
a
bromo-g-ketoamides 8d and 8 f were obtained in 75 and 87%
yields, respectively, with a diastereomeric ratio of 3:1 in each
case (Scheme 2). An X-ray diffraction study of 8d revealed
Scheme 2. Functionalization of a-silyl-g-ketoamides.
[
18]
that the major diastereomer exhibits syn stereochemistry.
Interestingly, the addition of bromine to 4d in the absence of
AcOH/AcO H induces elimination to give the (Z)-a,b-
2
unsaturated ketoamide
Scheme 2). The olefin geometry was determined by
NOESY analysis.
9
exclusively in 96% yield
(
Finally, we found that this new catalyzed acylation
provides an attractive platform for enantioselective catalysis.
The enantiopure Enders phosphite (R,R)-5 was employed and
the major anti diastereomer was delivered in 60% ee, whereas
the minor syn isomer was obtained in 74% ee (Scheme 3).
Desilylation gave g-ketoamide (2R)-7d in 67% yield and
Scheme 3. Enantioselective metallophosphite-catalyzed alkene
acylation.
2
378
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Angew. Chem. Int. Ed. 2005, 44, 2377 –2379

Angewandte
Chemie
calcd for C H NO : C 74.10, H 8.16, N 5.40; found: C 74.21, H 8.27,
1
6
21
2
N 5.29.
Received: December 3, 2004
Published online: March 10, 2005
Keywords: acylation · asymmetric catalysis · rearrangement ·
.
umpolung
[
1] a) H. Stetter, M. Schreckenberg, Angew. Chem. 1973, 85, 89;
Angew. Chem. Int. Ed. 1973, 12, 81; b) H. Stetter, H. Kuhlmann,
Org. React. 1991, 40, 407 – 496.
[
2] J. H. Gong, Y. J. Im, K. Y. Lee, J. N. Kim, Tetrahedron Lett. 2002,
43, 1247 – 1251.
[
3] a) H. Stetter, Angew. Chem. 1976, 88, 695 – 736; Angew. Chem.
Int. Ed. 1976, 15, 639 – 647; b) H. Stetter, H. Kuhlmann, Chem.
Ber. 1976, 109, 2890 – 2896; c) H. Stetter, M. Schreckenberg, K.
Wiemann, Chem. Ber. 1976, 109, 541 – 545; d) H. Stetter, H. J.
Bender, Chem. Ber. 1981, 114, 1226 – 1233; e) H. Stetter, L.
Simons, Chem. Ber. 1985, 118, 3172 – 3187; f) H. Stetter, H.
Skobel, Chem. Ber. 1987, 120, 643 – 645.
Scheme 4. Proposed catalytic cycle.
[
4] a) D. Enders, K. Breuer in Comprehensive Asymmetric Catalysis,
Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
New York, 1999, pp. 1093 – 1102; for examples of enantioselec-
tive intramolecular Stetter reactions, see: b) D. Enders, K.
Breuer, J. Runsink, J. H. Teles, Helv. Chim. Acta 1996, 79, 1899 –
1902; c) M. S. Kerr, J. Read de Alaniz, T. Rovis, J. Am. Chem.
Soc. 2002, 124, 10298 – 10299; d) M. S. Kerr, T. Rovis, J. Am.
Chem. Soc. 2004, 126, 8876 – 8877; e) S. M. Mennen, J. T. Blank,
M. B. Tran-Dubꢂ, J. E. Imbriglio, S. J. Miller, Chem. Commun.
development of 1) those strategies that take advantage of the
high diastereoselectivity of the retro [1,4] Brook rearrange-
ment and 2) phosphite catalysts that deliver more highly
enantioenriched products.
2005, 195 – 197.
[5] A. G. Brook, Acc. Chem. Res. 1974, 7, 77 – 84.
[6] W. H. Moser, Tetrahedron 2001, 57, 2065 – 2084.
[7] A. DeglꢀInnocenti, A. Ricci, A. Mordini, G. Reginato, V.
Colotta, Gazz. Chim. Ital. 1987, 117, 645 – 648.
Experimental Section
7
a (entry 1, representative procedure): The acyl silane (0.42 mmol)
[8] A. E. Mattson, A. R. Bharadwaj, K. A. Scheidt, J. Am. Chem.
Soc. 2004, 126, 2314 – 2315.
[9] A. R. Bharadwaj, K. A. Scheidt, Org. Lett. 2004, 6, 2465 – 2468.
[10] K. Takeda, T. Tanaka, Synlett 1999, 705 – 708.
[11] D. Enders, L. Tedeschi, J. W. Bats, Angew. Chem. 2000, 112,
4774 – 4776; Angew. Chem. Int. Ed. 2000, 39, 4605 – 4607.
[12] X. Linghu, J. R. Potnick, J. S. Johnson, J. Am. Chem. Soc. 2004,
126, 3070 – 3071.
and amide (0.46 mmol, 1.1 equiv) were added to a dry pear-shaped
flask in the glovebox, while the TADDOL phosphite (0.084 mmol,
0
0
.2 equiv) and lithium hexamethyldisilazide (LHMDS; 0.29 mmol,
.7 equiv) were added to a dry round-bottom flask with a magnetic
stirring bar. The flasks were removed from the glovebox and Et O
2
(3.0 mL) was added to the metallophosphite and stirred in an N2
atmosphere. The acyl silane/amide mixture was added to the metal-
lophosphite by cannula and the delivery flask was rinsed with Et O
[13] The racemic TADDOL phosphite 5 regularly provided higher
yields than simpler phosphites, for example, diethyl phosphite.
[14] G. R. Jones, Y. Landais, Tetrahedron 1996, 52, 7599 – 7662.
[15] I. Fleming, Chemtracts: Org. Chem. 1996, 9, 1 – 64.
[16] M. M. Mader, J. C. Edel, J. Org. Chem. 1998, 63, 2761 – 2764.
[17] L. A. Dakin, S. E. Schaus, E. N. Jacobsen, J. S. Panek, Tetrahe-
dron Lett. 1998, 39, 8947 – 8950.
2
(7 mL). The resulting mixture was stirred in an N2 atmosphere at
room temperature until the starting material was consumed (TLC
analysis). The solvent was removed in vacuo and an aliquot was taken
1
to determine the diastereoselectivity by H NMR spectroscopic
analysis. The residue was redissolved in THF. The reaction mixture
was treated with a solution of tetrabutylammonium fluoride in THF
(
TBAF; 1m, 0.84 mmol, 2.0 equiv) and immediately quenched with
[18] CCDC-253985 (4d) and -253984 (8d) 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.
several milliliters of a saturated aqueous solution of NH Cl. The
product was then extracted with Et O, washed with water (2 ꢁ 10 mL),
and washed with a saturated aqueous solution of NaHCO3 (2 ꢁ
4
2
1
0 mL). The organic extracts were combined and dried over
[19] The 2R configuration of 7d was assigned through chemical
correlation (see the Supporting Information).
Na SO , filtered, and concentrated. The product then was purified
2
4
by flash chromatography with ethyl acetate/hexanes (30:70) as the
eluent to afford the pure 1,4-dicarbonyl compound in 76% yield.
Analytical data for 7a: IR (thin film): n˜ = 3061, 2933, 2856, 1684, 1639,
[20] D. Enders, T. Balensiefer, Acc. Chem. Res. 2004, 37, 534 – 541.
[21] (Silyloxy)phosphonate anion 2 has been previously prepared
stoichiometrically: R. E. Koenigkramer, H. Zimmer, Tetrahe-
dron Lett. 1980, 21, 1017 – 1020.
ꢁ1 1
1
444, 1369, 1223, 1196, 1122, 1016, 978, 706 cm ; H NMR (400 MHz,
CDCl ): d = 8.07–7.98 (m, 2H), 7.54–7.47 (m, 1H), 7.47–7.39 (m, 2H),
[22] C. Gibson, T. Buck, M. Noltemeyer, R. Brꢃckner, Tetrahedron
Lett. 1997, 38, 2933 – 2936, and references therein.
3
4
2
7
1
.10–4.00 (m, 1H), 3.53–3.36 (m, 4H), 3.02 (dd, J = 16.0, 8.8 Hz, 1H),
.40 (dd, J = 16.4, 4.8 Hz, 1H), 1.66–1.49 (m, 6H), 1.17 ppm (d, J =
1
3
.2 Hz, 3H); C NMR (100 MHz, CDCl ): d = 203.9, 169.3, 136.1,
3
32.6, 128.41, 128.40, 46.4, 42.6, 37.0, 36.9, 26.2, 25.4, 24.4, 17.8 ppm;
TLC (ethyl acetate/hexanes, 40:60) R = 0.32; elemental analysis (%)
f
Angew. Chem. Int. Ed. 2005, 44, 2377 –2379
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2379