Catalytic asymmetric acylation of (silyloxy)nitrile anions

Article abstract of DOI:10.1002/anie.200353354

An enantiopure (salen)aluminum alkoxide complex catalyzes the asymmetric coupling of acylsilanes and cyanoformate esters [Eq. (1), R = Bn, Et]. The reactions afford unsymmetrical, fully protected malonic acid derivatives that may be elaborated to nonnatural β-amino acid derivatives, and represent the first asymmetric catalytic reactions involving protected cyanohydrin anions.

Full text of DOI:10.1002/anie.200353354

Communications
Cyanohydrin Anions
Catalytic Asymmetric Acylation of
(Silyloxy)nitrile Anions**
David A. Nicewicz, Christopher M. Yates, and
Jeffrey S. Johnson*
Anions of protected cyanohydrins are useful intermediates in
the formation of carbon–carbon bonds.[1–4] These stabilized
carbanions offer considerable potential for asymmetric syn-
thesis, but stereoselective transformations involving them are
surprisingly rare.[5–8] One barrier to enantioselective catalysis
is the apparent requirement of one equivalent of a strong base
to generate the key carbanionic species. As an alternative, we
considered the possibility that protected cyanohydrin anions
might be generated by the reaction of chiral metal cyanide
complexes with acylsilanes. This hypothesis was predicated on
the observation of the facile Brook rearrangement of
acylsilanes in the presence of alkali metal cyanides.[9–12]
Here we describe the successful development of asymmetric
cyanation/1,2-Brook rearrangement/C-acylation reactions of
acylsilanes mediated by (salen)aluminum alkoxides
(Scheme 1). These represent, to the best of our knowledge,
Scheme 1. Catalytic asymmetric acylation of (silyloxy)nitrile anions.
[*] D. A. Nicewicz, C. M. Yates, Prof. J. S. Johnson
Department of Chemistry
University of North Carolina, Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
Fax: (+1)919-962-2388
E-mail: jsj@unc.edu
[**] The authors acknowledge partial funding of this work by the Donors
of the Petroleum Research Fund, administered by the American
Chemical Society (PRF no. 37868-G1), by Research Corporation
(Research Innovation Award to J.S.J.), 3M (Nontenured Faculty
Award to J.S.J.), and UNC (W. R. Bost Fellowship to D.A.N.). We also
thank the research groups of Professors J. P. Morken and M. R.
GagnØ (both UNC) for their generous donation of some of the
ligands used in the catalyst screening.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353354
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Angewandte
Chemie
the first catalytic asymmetric reactions of protected cyanohy-
drin anions.
catalytically active (cyanido)aluminum complex (1-OR!
1-CN, Scheme 1). 2) The enantioselectivity is subject to
In an attempt to render the acylation of (silyloxy)nitrile
anions[13] enantioselective, we chose to investigate a variety of
chiral metal cyanide sources. We speculated that such
complexes might be conveniently prepared according to
Equation (1). Ligand exchange between a chiral diol and a
significant effects of remote substituents on the ligand, with
a
para-chlorine substituent delivering optimal results
(79% ee, entry 10). 3) The enantioselectivity is strongly
dependent on concentration: in dilute solutions, more highly
enantioenriched acylated products are formed.
With good levels of enantiocontrol achieved using com-
plex 7-Cl, we investigated the scope of the reaction. Acylsi-
lanes bearing a variety of aryl substituents (Ar) with either
triethylsilyl or tert-butyldimethylsilyl groups (SiR3) were
treated with either benzyl or ethyl (R’) cyanoformate in the
presence of catalytic amounts of 7-Cl to give the desired
enantioenriched cyano ester products 6 [Eq. (3)]. The results
metal alkoxide should result in loss of two equivalents of
alcohol and formation of a new, chiral metal alkoxide. Upon
treatment with the appropriate amount of Me3SiCN, chiral
metal cyanide complexes were expected.
Evaluation of 96 metal–ligand complexes prepared by the
described protocol revealed the Jacobsen (salen)aluminum
complexes[14] as promising candidates for effecting the
catalyzed acylation with good enantiocontrol [Eq. (2)].[15]
of these experiments are summarized in Table 2. Varying the
silyl group led to a significant reduction in selectivity
(entries 1 and 2). Conversely, variation of the cyanoformate
made little or no difference on either yield or enantioselec-
tivity (see entries 1 vs. 3 and 7 vs. 8). Electron-donating
substituents on the aryl ring of the acylsilane (entries 4 and 6)
provided good levels of enantioinduction (up to 82% ee,
entry 6), while the enantioenrichment with their electron-
withdrawing counterparts (entries 5, 7, 8, and 10) was only
moderate (61–64% ee). The only exception was 4-
FC6H4C(O)SiEt3 (78% ee, entry 9). Overall, the substrates
examined gave moderate to good enantioselectivities with
good to excellent yields. An air-stable aluminum oxo complex
derived from the p-Cl-salen ligand, [(Cl-salen)Al(O)Al(sa-
len-Cl)],[14c] effected the formation of 6a with identical
selectivity (80% ee) as complex 7-Cl (entry 1). Alkyl acylsi-
lanes (MeC(O)SiMe3, iPrC(O)SiEt3) were unreactive under
(salen)Al catalysis, in contrast to catalysis by KCN/[18]crown-
6.[13]
Optimization experiments, the results of which are summar-
ized in Table 1, demonstrated that: 1) The reaction may be
conducted with the metal alkoxide in the absence of Me3SiCN
as activator; the observation of the mixed carbonate iPrO-
1
C(O)OBn by H NMR spectroscopy suggests that the metal
The products of the asymmetric cyanation/Brook rear-
rangement/C-acylation sequence are fully substituted malonic
acid derivatives. Preliminary experiments suggest that the
dense functionality may be selectively manipulated: exposure
of adduct 6c to Raney Ni/H2 results in reduction of the nitrile
group to afford the protected b-amino-a-hydroxy-a-phenyl
acid derivative 8 in 74% yield [Eq. (4)].
alkoxide reacts with benzyl cyanoformate[16] to form a
Table 1: Optimization of catalyzed reactions of acylsilanes and cyano-
formate esters [Eq. (2)].[a]
Entry
X in 7-X
c0(PhC(O)SiEt3) [m]
ee[b] [%]
Conv. [%][c]
1
2
3
4
5
6
7
8
9
CMe3
CMe3
CMe3
NO2
NO2
NO2
Cl
Cl
Cl
Cl
OMe
NMe2
2.5
1.5
0.5
2.5
1.5
0.5
2.5
1.5
0.5
26
34
46
44
54
54
56
62
67
79
70
46
>95
>95
80
>95
90
30
>95
>95
>95
>95
>95
>95
In summary, a new catalytic asymmetric cyanation/1,2-
Brook rearrangement/C-acylation reaction of acylsilanes with
cyanoformates was developed. Access to chiral (silyloxy)ni-
trile anions is facilitated by metal cyanide-promoted Brook
rearrangement reactions of acylsilanes. The asymmetric
acylsilane/cyanoformate coupling provides compounds (6)
10
11
12
0.05
0.05
0.05
[a] PhC(O)SiEt3 (1.0 equiv), BnO2CCN (2.0 equiv). [b] Determined by
CSP-SFC. [c] Determined by H NMR spectroscopy.
1
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Communications
Table 2: Catalytic asymmetric cyanation/Brook rearrangement/C-acylation of acylsilanes [Eq. (3)].[a]
Entry
1
Ar
SiR3
R’
Product
Yield [%][b]
83
ee [%][c]
Ph
SiEt3
Bn
6a
6b
6c
6d
6e
6 f
79[d]
2
3
4
5
6
Ph
S tBuMe2
SiEt3
i
Bn
Et
82[e]
93[f]
79
64[d]
77[d,g]
80[h]
62[h]
82[h]
Ph
4-MeC6H4
2-naphthyl
4-MeOC6H4
SiEt3
Bn
Bn
Bn
SiEt3
90
SiEt3
84[i]
7
8
4-ClC6H4
4-ClC6H4
4-FC6H4
SiEt3
SiEt3
SiEt3
SiEt3
Bn
Et
6g
6h
6i
87
87
81
70
64[h,j]
61[d,g]
78[h,j]
64[h]
9
Bn
Bn
10
4-NCC6H4
6j
[a] ArC(O)SiR3 (1.0 equiv, 0.05m), NCCO2R’ (2.0 equiv) for 72 h unless otherwise noted. [b] Yield of analytically pure material; average of at least two
experiments. [c] Determined by CSP-SFC analysis of the adduct, unless otherwise noted. [d] Absolute configuration determined by correlation to a
compound of known configuration. See the Supporting Information for details. [e] 20 mol% catalyst used. [f] c0(2)=0.025m. [g] Determined by CSP-
SFC analysis after reduction of the nitrile and coupling to (S)-mandelic acid. See Supporting Information for details. [h] Absolute configuration
assigned by analogy. [i] c0(2)=0.1m. [j] Determined by CSP-SFC analysis after reduction of the nitrile and protection as the N-Boc carbamate. See the
Supporting Information for details.
data for 6a: [a]2D5 = + 4.2 (c = 1.97, CH2Cl2); IR (thin film): n˜ = 3067,
ꢀ
that may be considered formally as products of R3Si CN
3035, 2958, 2878, 2245, 1766, 1588, 1451, 1241, 1152, 1003, 835 cmꢀ1
;
addition to a-keto esters, a transformation that has yet to be
rendered asymmetric. The interception of intermediates like 4
(Scheme 1) in other stereoselective bond constructions will be
the focus of future work.
1H NMR (400 MHz, CDCl3): d = 7.63–7.61 (m, 2H), 7.38–7.35(m,
3H), 7.29–7.26 (m, 3H), 7.19–7.17 (m, 2H), 5.17 (s, 2H), 0.93 (t, J =
7.6 Hz, 9H), 0.70 ppm (q, J = 7.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d = 167.1, 134.5, 129.9, 128.9, 128.8, 128.7, 128.2, 125.7, 118.3,
75.1, 68.9, 6.8, 5.4 ppm; TLC (95:5 hexanes/EtOAc): Rf = 0.35;
elemental analysis calcd for C22H27NO3Si: C 69.25, H 7.13, N 3.67;
found: C 69.37, H 7.28, N 3.60.
Experimental Section
Received: November 18, 2003 [Z53354]
Synthesis of 6a (representative procedure): A flame-dried Schlenk
tube equipped with a magnetic stir bar was charged with the
aluminum complex 7-Cl (19.4 mg, 0.033 mmol, 0.15equiv) under
Ar. Acylsilane (60 mg, 0.27 mmol, 1.0 equiv), benzyl cyanoformate
(88 mg, 0.54 mmol, 2.0 equiv), and toluene (5.4 mL, 0.05m) were all
added to the Schlenk tube under Ar, and the tube was sealed and
heated to 458C. After 72 h the flask was cooled to 258C, the solvent
was removed under vacuum, and the crude product was purified by
flash chromatography with 95:5 petroleum ether/EtOAc to afford
85.3 mg (83%) of 6a as a colorless oil in 79% ee as determined by
CSP-SFC analysis (CSP = chiral stationary phase, SFC = supercritical
Keywords: acylation · aluminum · asymmetric catalysis ·
.
cyanides · rearrangement
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