Enantioselective cyanation/brook rearrangement/C-acylation reactions of acylsilanes catalyzed by chiral metal alkoxides

Article abstract of DOI:10.1021/jo049164e

New catalytic enantioselective cyanation/1,2-Brook rearrangement/C- acylation reactions of acylsilanes (4) with cyanoformate esters (7) are described. The products of the reaction are fully substituted malonic acid derivatives (8). Catalysts for this transformation were discovered via a directed candidate screen of 96 metal-ligand complexes. Optimization of a (salen)aluminum complex revealed significant remote electronic effects and concentration effects. The scope of the reaction was investigated by using a number of aryl acylsilanes and cyanoformate esters. Chemoselective reduction of the reaction products (8) afforded new enantioenriched α-hydroxy-α- aryl-β-amino acid derivatives (32-34) and β-lactams (35 and 36). This reaction provides a simple method for the construction of new nitrogen-containing enantioenriched chiral building blocks.

Full text of DOI:10.1021/jo049164e

En a n tioselective Cya n a tion /Br ook Rea r r a n gem en t/C-Acyla tion
Rea ction s of Acylsila n es Ca ta lyzed by Ch ir a l Meta l Alk oxid es
David A. Nicewicz, Christopher M. Yates, and J effrey S. J ohnson*
Department of Chemistry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received May 17, 2004
New catalytic enantioselective cyanation/1,2-Brook rearrangement/C-acylation reactions of acyl-
silanes (4) with cyanoformate esters (7) are described. The products of the reaction are fully
substituted malonic acid derivatives (8). Catalysts for this transformation were discovered via a
directed candidate screen of 96 metal-ligand complexes. Optimization of a (salen)aluminum complex
revealed significant remote electronic effects and concentration effects. The scope of the reaction
was investigated by using a number of aryl acylsilanes and cyanoformate esters. Chemoselective
reduction of the reaction products (8) afforded new enantioenriched R-hydroxy-R-aryl-â-amino acid
derivatives (32-34) and â-lactams (35 and 36). This reaction provides a simple method for the
construction of new nitrogen-containing enantioenriched chiral building blocks.
SCHEME 1. P r otected Cya n oh yd r in
In tr od u ction
F u n ction a liza tion a n d Hyd r olysis to Keton es
Protected cyanohydrins (1) may be converted to their
derived anions 2 through the action of strong base. The
utility of these nucleophilic species in the formation of
new carbon-carbon bonds is documented.1 Seminal work
from Stork and Maldonado established the feasibility of
accessing anion 2 through deprotonation of a suitably
protected cyanohydrin with stoichiometric quantities of
a strong base such as lithium diisopropylamide (Scheme
1).2 That work, and subsequent contributions from Hu¨nig
and co-workers, showed that intermediate 2 can be
intercepted by a variety of electrophiles to yield new
ketone products after deprotection and retrocyanation.3,4
Intermediate 2 serves as an acyl anion equivalent in this
context; however, preservation of the newly functional-
ized cyanocarbinol derivative (3) gives rise to chiral
compounds that may be regarded formally as products
of ketone cyanation.
access an analogous product.7 Catalytic asymmetric
reactions proceeding via intermediates resembling 2 are
rare.8
A significant challenge in the development of catalytic
reactions involving intermediate 2 is the low acidity of
1, which necessitates stoichiometric quantities of an
amide or alkyllithium base. An alternative method of
generating anions of protected cyanohydrins can be
realized through the use of acylsilanes (4).9 Nucleophilic
addition of a metal cyanide to an acylsilane can initiate
a carbon-to-oxygen silyl migration (Brook rearrange-
ment)10 that generates a carbanion analogous to 2.
Takeda, Reich, and Degl’Innocenti have effectively uti-
lized this in situ method to achieve alkylation, enone
acylation, and â-elimination reactions of the derived
(silyloxy)nitrile anions.11-14
Little is known about stereocontrolled versions of these
reactions (2 f 3).5 Schrader has shown that when 1 bears
a chiral ephedrine-based O-phosphate auxiliary, alkyla-
tion reactions may be achieved with high diastereoselec-
tivity.6 Cativiela and co-workers developed a diastereo-
selectivemethylation ofan R-acetoxycyanoacetatederivative
controlled by an isoborneol-derived chiral auxiliary to
(1) Albright, J . D. Tetrahedron 1983, 39, 3207-3233.
(2) Stork, G.; Maldonado, L. J . Am. Chem. Soc. 1971, 93, 5286-
5287.
(3) Stork, G.; Maldonado, L. J . Am. Chem. Soc. 1974, 96, 5272-
5274.
(4) (a) Deuchert, K.; Hertenstein, U.; Hu¨nig, S. Synthesis 1973, 777-
779. (b) Hu¨nig, S.; Wehner, G. Synthesis 1975, 1180-1182. (c) Hu¨nig,
S.; Wehner, G. Synthesis 1975, 1391-1972.
(5) Analogous reactions of lithiated (amino)nitriles have been
developed extensively by Enders. For an excellent review, see: Enders,
D.; Shilvock, J . P. Chem. Soc. Rev. 2000, 29, 359-373.
(6) Schrader, T. Chem. Eur. J . 1997, 3, 1273-1282.
(7) Cativiela, C.; Diaz-de-Villegas, M. D.; Ga´lvez, J . A. Tetrahedron
1996, 52, 687-694.
(8) Castells, J .; Dun˜ach, E. Chem. Lett. 1984, 1859-1860.
(9) Moser, W. H. Tetrahedron 2001, 57, 2065-2084.
(10) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84.
(11) Takeda, K.; Ohnishi, Y. Tetrahedron Lett. 2000, 41, 4169-4172.
10.1021/jo049164e CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/09/2004
6548
J . Org. Chem. 2004, 69, 6548-6555

Enantioselective Acylation of (Silyloxy)nitrile Anions
SCHEME 2. Ta n d em Cya n a tion /1,2-Br ook
Rea r r a n gem en t/C-Acyla tion Rea ction of
Acylsila n es (4)
SCHEME 3. Ca ta lytic En a n tioselective Cya n a tion /
1,2-Br ook Rea r r a n gem en t/Acyla tion Rea ction s
SCHEME 4. Gen er a tion of Ch ir a l Meta l Cya n id e
Com p lexes
mediated by (salen)aluminum alkoxides (Scheme 3).23
These represent, to the best of our knowledge, the first
catalytic asymmetric reactions of protected cyanohydrin
anions.
Resu lts
In a previous report we employed a Brook rearrange-
ment strategy in a tandem cyanation/C-acylation reaction
between acylsilanes and cyanoformate esters catalyzed
by KCN/18-crown-6.15 The reactions yielded a variety of
aryl and alkyl R-cyano-R-silyloxy esters (8). To account
for the observed products, a catalytic cycle involving
acylation of the (silyloxy)nitrile intermediate 6 by a
cyanoformate (7) was proposed (Scheme 2).16-19 The
reactions are rendered catalytic by virtue of -CN expul-
sion in the C-acylation event. Access to enantiomerically
enriched silylcarbinol 8 could provide expeditious syn-
theses for a number of new nonracemic 3,3-disubstituted
â-lactams and unnatural R-hydroxy-â-amino acids. Previ-
ously reported approaches to 8 typically involved the
Lewis acid- or Lewis base-promoted additions of silyl-
cyanide reagents to R-ketoesters (R′ ) alkyl).20,21 While
enantioselective additions of Me3SiCN to ketones are
common,22 to the best of our knowledge there are no
reported examples of enantioselective R-ketoester cya-
nation. Additionally, aromatic R-ketoester cyanosilylation
will be extremely challenging with sterically undemand-
ing silyl groups (e.g., Me3SiCN) due to retrocyanation
tendencies of the derived products.15
We expected that chiral (cyanide)metal complexes
might be conveniently prepared from the two-step se-
quence depicted in Scheme 4. Exchange between a chiral
diol and metal alkoxide should result in loss of 2 equiv
of alcohol and formation of a new alkoxide 10. Upon
treatment with the appropriate amount of Me3SiCN,
metal cyanide 11 is the expected product. Cyanation of
an acylsilane by complex 11 could, in principle, initiate
a 1,2-Brook rearrangement and thereby lead to the
desired chiral metal anion intermediate (6). Effective
chirality transfer from the ligand in the acylation step
is essential for high levels of stereoselectivity. Sali-
cylimine (salen) ligands were judged promising candi-
dates for two reasons: (1) ease of structural modification
of the diamine backbone and aryl substituents for evalu-
ation of steric and electronic factors; and (2) precedent
for the use of (salen)metal complexes as catalysts involv-
ing delivery of cyanide.24-28
Ca ta lyst Develop m en t. With many metal alkoxides
and salen ligands available, we presumed that a screen
of several different metals and ligands would be the most
efficient method for catalyst determination. Eight metal
alkoxides (Al(OiPr)3, Er(OiPr)3, Sm5O(OiPr)13, Ti(OMe)4,
Ti(OiPr)4, Y5O(OiPr)13, Yb(OiPr)3, Zr(OiPr)4) were em-
ployed in conjunction with twelve common chiral ligands
(12-23, Figure 1) to give 96 individual metal complexes
to be examined for reactivity and enantioselectivity in
the title reaction. Individual complexes were prepared
by mixing equimolar amounts of the ligand and metal
alkoxide in toluene for 30 min. The solvent along with
the alcohol generated was subsequently removed under
reduced pressure. A solution of benzoyl triethylsilane (1.0
equiv), benzyl cyanoformate (4.0 equiv), and Me3SiCN
As a mechanistic alternative to asymmetric R-ketoester
cyanation, we speculated that it might be possible to
control the absolute stereochemical course of the acyla-
tion reaction (6 f 8) through judicious selection of the
metal counterion. This report provides a full account of
the development of new enantioselective cyanation/1,2-
Brook rearrangement/C-acylation reactions of acylsilanes
(12) Reich, H. J .; Holtan, R. C.; Bolm, C. J . Am. Chem. Soc. 1990,
112, 5609-5617.
(13) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta,
V. Gazz. Chim. Ital. 1987, 117, 645-648.
(14) Linghu, X.; J ohnson, J . S. Angew. Chem., Int. Ed. 2003, 42,
2534-2536.
(23) A portion of this work has been previously communicated:
Nicewicz, D. A.; Yates, C. M.; J ohnson, J . S. Angew. Chem., Int. Ed.
2004, 43, 2652-2655.
(15) Linghu, X.; Nicewicz, D. A.; J ohnson, J . S. Org. Lett. 2002, 4,
2957-2960.
(16) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-
(24) Sigman, M. S.; J acobsen, E. N. J . Am. Chem. Soc. 1998, 120,
5315-5316.
5428.
(17) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991,
70, 256-264.
(18) Babler, J . H.; Marcuccilli, C. J .; Oblong, J . E. Synth. Commun.
1990, 20, 1831-1836.
(25) Sammis, G. M.; J acobsen, E. N. J . Am. Chem. Soc. 2003, 125,
4442-4443.
(26) Taylor, M. S.; J acobsen, E. N. J . Am. Chem. Soc 2003, 125,
11204-11205.
(19) Hu¨nig, S.; Wehner, G. Chem. Ber. 1980, 113, 302-323.
(20) Wilkinson, H. S.; Grover, P. T.; Vandenbossche, C. P.; Bakale,
R. P.; Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2001,
3, 553-556.
(21) Foley, L. H. Synth. Commun. 1984, 14, 1291-1297.
(22) North, M. Tetrahedron: Asymmetry 2003, 14, 147-176.
(27) Belokon, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.;
Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu,
C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J .
Am. Chem. Soc. 1999, 121, 3968-3973.
(28) J iang, Y.; Gong, L.; Feng, X.; Hu, W.; Pan, W.; Li, Z.; Mi, A.
Tetrahedron 1997, 53, 14327-14338.
J . Org. Chem, Vol. 69, No. 20, 2004 6549

Nicewicz et al.
F IGURE 1. Catalyst evaluation for enantioselective cyanation/Brook rearrangement/C-acylation of acylsilanes (reagents and
conditions: PhC(O)SiEt3 (1.0 equiv, 0.025 M), NCCO2Bn (4.0 equiv), PhMe for 72 h). Enantioselectivities were determined by
CSP-SFC analysis.
(0.8 equiv) in toluene was then added to the preformed
(salen)M(OR)n complex (0.4 equiv) and allowed to react
for 72 h.
displaying good to excellent selectivity (80% ee with 15,
20; 92% ee with 21), albeit with only small amounts of
product formation (<5%). J acobsen has recently reported
a highly enantioselective conjugate addition reaction of
Me3SiCN to R,â-unsaturated imides catalyzed by in situ
generated (salen)Al(CN) complexes.25 Additionally, it was
observed that Al(OiPr)3 alone does not facilitate catalysis,
whereas Y5O(OiPr)13, Sm5O(OiPr)13, and Er(OiPr)3 pro-
mote the title reaction in as little as 5 mol % without
the aid of a supporting ligand. When these points were
considered in the context of the catalyst screen, (salen)-
Al(OiPr) complexes were selected for further evaluation
and optimization.
The results from the catalyst screen are depicted in
Figure 1. Lanthanide alkoxide complexes (Er, Sm, Y, Yb)
were generally reactive; however, they gave only low
levels of enantioselectivity (0-26% ee). Zr(OiPr)4 cata-
lysts were not selective, with the exception of the complex
with 14, which otherwise rendered the Zr series ineffec-
tive. Catalysts derived from Ti(OiPr)4 and Ti(OMe)4 gave
good reactivity and moderate enantioselectivity with most
of the ligands tested (Ti(OiPr)4 and 20 gave 58% ee).
Aluminum alkoxides gave the most promising results,
6550 J . Org. Chem., Vol. 69, No. 20, 2004

Enantioselective Acylation of (Silyloxy)nitrile Anions
SCHEME 5. Isop r op oxid e Exch a n ge w ith Ben zyl Cya n ofor m a te
CHART 1. Liga n d a n d Con cen tr a tion Effects in En a n tioselective Cya n a tion /Br ook Rea r r a n gem en t/
C-Acyla tion Rea ction s (Eq 2)a -c
a
PhC(O)SiEt3 (1.0 equiv), NCCO2Bn (2.0 equiv), for 72 h. bEnantioselectivities determined by CSP-SFC analysis. cPercent conversions
shown in parentheses determined by 1H NMR spectroscopy.
Initial attempts to reproduce the results from the
catalyst screen proved problematic. Only trace product
formation (<10%) after several days could be attained
with use of any of the (salen)aluminum catalysts pre-
pared by the initial screening protocol. Variable amounts
of a cyanohydrin byproduct (1, R′ ) SiEt3) were also
obtained. Monitoring the complexation of Al(OiPr)3 with
15 by 1H NMR spectroscopy revealed that catalyst
formation was negligible at 25 °C. Complete complexation
between the corresponding salen ligand and Al(OiPr)3
required 3 days at 80 °C in toluene,29 in contrast with
the complexation conditions that were employed in the
catalyst screen (25 °C for 30 min). Cyanohydrin formation
was attributed to small quantities of adventitious water
leeching into the reaction over the long reaction times.
To circumvent this problem, the reactions were carried
out in sealed tubes. With this protocol, reactivity was
significantly enhanced: the complex derived from Al-
(OiPr)3 and 15 in conjunction with Me3SiCN (40 mol %)
gave 100% conversion and no cyanohydrin formation
when employed at 20 mol % of catalyst loading.
The role of and need for Me3SiCN as a catalyst
activator was next examined. We presume that the active
catalyst is a (salen)Al(CN) species (27), generated ini-
tially upon reaction with Me3SiCN. Gorsi and Mehrotra
had shown that titanium and zirconium alkoxides un-
dergo exchange reactions with cyanoacetates to afford
mixed (alkoxy)metal(cyanides): M(OiPr)4 + n NCCOMe
30
f n iPrOCOMe + (NC)nM(OiPr)4-n
.
If an analogous
reaction were possible between cyanoformates and alu-
(29) Zhong, Z.; Dijkstra, P. J .; Feijen, J . Angew. Chem., Int. Ed. 2002,
41, 4510-4513. In contrast, exchange reactions of diol ligands with
lanthanide alkoxides are known to proceed rapidly at ambient tem-
perature. See, for example: Yoshikawa, N.; Yamada, Y. M. A.; Das,
J .; Sasai, H.; Shibasaki, M. J . Am. Chem. Soc. 1999, 121, 4168-4178.
(30) Gorsi, B. L.; Mehrotra, R. C. J . Ind. Chem. Soc. 1978, 55, 321-
324.
J . Org. Chem, Vol. 69, No. 20, 2004 6551

Nicewicz et al.
minum alkoxides, the putative catalyst could be accessed
and the Me3SiCN would be superfluous. Indeed, the
reaction of benzoyl triethylsilane (24) with benzyl cyano-
formate (25) in the presence of (salen)Al(OiPr) (26-tBu ,
15 mol %) at 45 °C furnished the desired product 8a in
the absence of an additional cyanide source. Examination
lutidine35 or triphenylphosphine oxide36 were not suc-
cessful. It is also of note that reaction time has no effect
on enantioselectivity; employing 26-Cl, 8a was formed
in nearly identical levels of enantiomeric excess at 4 h
(e20% conversion; 79% ee) and at 72 h (100% conversion;
80% ee).
1
of the exchange reaction by H NMR spectroscopy sup-
Rea ction Scop e. The scope of the enantioselective
acylation reaction was investigated using 26-Cl. Several
different acylsilanes bearing a variety of aryl substituents
(R′) with either triethylsilyl or tert-butyldimethylsilyl
groups (SiR3) were treated with either benzyl or ethyl
cyanoformate (R′′) in the presence of catalytic amounts
of 26-Cl to give the desired enantioenriched cyano ester
product 8 (eq 3). The results of these experiments are
summarized in Table 1. Varying the silyl goup (entries
1 and 2) from triethylsilyl to tert-butyldimethylsilyl led
to a significant reduction in selectivity (79% to 64% ee,
respectively). In contrast, variation of the cyanoformate
from benzyl to ethyl affected neither yield nor enanti-
oselectivity (cf. entries 1 vs 3 and 7 vs 8). Electron-
releasing substituents on the aryl ring of the acylsilane
(entries 4 and 6) provided good levels of enantioselectivity
(up to 82% ee, entry 6), while electron-poor acylsilanes
(entries 5, 7, 8, and 10) underwent coupling with only
moderate enantioenrichment (61% to 64% ee). The only
exception was 4-FPhC(O)SiEt3 (78% ee, entry 9). Overall,
the substrates examined gave moderate to good enanti-
oselectivities with good to excellent yields. An air-stable
aluminum oxo complex derived from the p-Cl-salen
ligand, (Cl-salen)Al(O)Al(salen-Cl),26 also catalyzes the
coupling of acylsilane 24 with cyanoformate 25 to give
8a with identical selectivity (80% ee) as complex 26-Cl
(entry 1). Alkyl acylsilanes (MeCOSiMe3, iPrCOSiEt3)
were unreactive under (salen)Al catalysis, in contrast to
catalysis by KCN/18-crown-6.15
Der iva tiza tion a n d Absolu te Ster eoch em ica l As-
sign m en t. Since the products (8) derived from the title
reaction are susceptible to NCSiR3 loss to form R-keto-
esters, the nitrile functionality must be manipulated at
the outset. Reduction of the nitrile by H2/Raney nickel
to the free amine is best suited for ethyl ester products
(8c, eq 4).37 This reaction proceeds smoothly at 23 °C to
afford 32 in 74% yield. Nitrile reduction of compounds
bearing benzyl ester groups requires different conditions.
Tertiary nitrile 8a is reduced in the presence of NaBH4/
CoCl2‚6H2O in MeOH at 0 °C to give a 48% isolated yield
of the primary amine (33).38 Alternatively, nitrile 8g can
be reduced in the presence of (BOC)2O to give a tert-
butoxycarbonyl-protected amine (34), a fully protected
R-hydroxy-â-amino acid that bears a tertiary carbinol
center.
ported the proposed mode of activation. The reaction of
(salen)Al(OiPr) (26-tBu ) with an excess of benzyl cyano-
formate in CDCl3 at 23 °C for 120 min afforded a mixture
of the expected isopropyl benzyl carbonate (28; 47% vs
internal standard) as well as isopropylcyanoformate (29;
42% vs internal standard) and dibenzyl carbonate (30;
observed, unable to quantify, Scheme 5).31 It is interest-
ing to note that although isopropylcyanoformate is
observed, it does not participate in the acylation step.
Formation of 28 implicates a (salen)Al(CN) complex (27);
1
however, the H NMR resonances of the organometallic
product could not be conclusively assigned. Efforts to
crystallize complexes from this reaction have been unsuc-
cessful to date.
Although complete conversion with complex 26-tBu
was now possible in the absence of TMSCN, the level of
stereoselection was still not consistent with the results
from the initial screen.32 An enantiomeric excess of 80%
with trace product formation was observed in the catalyst
screen with 26-tBu ; however, when repeated with the
optimized conditions, the desired product 8a could only
be obtained in 36% ee, albeit with 100% conversion. Since
(salen)metal catalysts often exhibit second-order rate
dependence with respect to the catalyst,33 the impact of
catalyst concentration was evaluated. A closer examina-
tion of substituent effects on the salen ligand structure
was simultaneously undertaken since the electronic
properties of salen ligands are known to exert dramatic
effects in the epoxidation of simple olefins.34 Chart 1
depicts the coupled effect of [26-X]o and the para sub-
stituent on the ligand. Using the parent 26-tBu catalyst
at 45 °C in toluene ([26-tBu ]o ) 0.38 M) afforded 8a in
26% ee. However, diluting to 0.23 M gave an increase in
enantiomeric excess (34%). Switching to complex 26-Cl
significantly increased the selectivity (80% ee) and
complete conversion at high dilution was still possible
(7.5 × 10-3 M). Seeking to improve this selectivity, we
investigated the strongly electron-withdrawing 26-NO2
catalyst, but observed a sharp decrease in enantiomeric
ratio (54% ee at 0.075 M compared to 67% ee with 26-Cl
at 0.075 M). Electron-releasing substituents (26-OMe
and 26-NMe2) at high dilution (7.5 × 10-3 M) did not
improve on the selectivity achieved with 26-Cl. These
data consistently correlated lower reaction concentrations
with enhanced enantioselectivity; however, remote sub-
stituent effects unfortunately failed to reveal a general
trend. Attempts to further enhance the selectivity ob-
served with 26-Cl by employing additives such as 2,6-
Absolute stereochemical assignment of the products (8)
of eq 3 was achieved via transformation to a known
enantiopure â-lactam (36, Scheme 7).39 Lactamization of
amine 32 required 3.0 equiv of MeMgBr but cleanly
afforded the cyclized product 35 in 67% yield. N-Methy-
(31) Ferrocene was used as an internal standard
(32) Although ligand 21 provided the most promising levels of
enantioselectivity in the initial screen, attempts to optimize reaction
efficiency (i.e., conversion) with this ligand were uniformly unsuccess-
ful. This difference in reactivity and the large changes in enantiose-
lectivity within the (salen)Al series are subtleties that to date have
eluded explanation.
(33) J acobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.
(34) Palucki, M.; Finney, N. S.; Pospisil, P. J .; Gu¨ler, M. L.; Ishida,
T.; J acobsen, E. N. J . Am. Chem. Soc. 1998, 120, 948-954.
(35) Bandini, M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-
Ronchi, A. Tetrahedron Lett. 2003, 44, 5843-5846.
(36) Daikai, K.; Kamaura, M.; Inanaga, J . Tetrahedron Lett. 1998,
39, 7321-7322.
(37) Testa, E.; Fontanella, L.; Cristiani, G.; Mariani, L. J . Lieb. Ann.
Chem. 1961, 639, 166-180.
(38) Heinzman, S. W.; Ganem, B. J . Am. Chem. Soc. 1982, 104,
6801-6802.
(39) Kaftory, M. J . Org. Chem. 1988, 53, 4391-4393.
6552 J . Org. Chem., Vol. 69, No. 20, 2004

Enantioselective Acylation of (Silyloxy)nitrile Anions
TABLE 1. Ca ta lytic En a n tioselective Cya n a tion /Br ook
SCHEME 6. Der iva tiza tion of Title Rea ction
P r od u cts
Rea r r a n gem en t/C-Acyla tion of Acylsila n es (Eq 3)a
SCHEME 7. La cta m iza tion a n d Absolu te
Ster eoch em istr y of 36
SCHEME 8. P ossible (Silyloxy)n itr ile An ion
Str u ctu r es
same compound and found to have the same absolute
configuration.40
Discu ssion
The results from the catalyst screen revealed a wide
range of potentially useful (ligand)metal(CN) catalysts.
From the 1H NMR experiment in Scheme 5, the presence
of isopropyl benzyl carbonate 28 implies the existence of
a (salen)Al-CN (27) or (salen)Al-NC complex. Although
there is no direct spectroscopic evidence for 27, its
existence has also been proposed by J acobsen.25 Implicit
in the successful catalysis of the cyanation/Brook rear-
rangement/C-acylation sequence are metal complexes
that (1) are sufficiently nucleophilic to add to the acyl-
silane, (2) form M-O bonds that are weak enough to
allow the Brook rearrangement to occur, and (3) afford
(metallo)silyloxynitriles that are sufficiently reactive to
undergo acylation reactions. Circumstantial evidence
suggests that all of these criteria are met with (salen)-
Al-CN complexes. The formation of silylcyanohydrin 38
when water is present suggests the intermediacy of 6 or
37, perhaps as equilibrating species. Similar (lithio)-
a
R′C(O)SiR3 (1.0 equiv), NCCO2R′′ (2.0 equiv), C7H8 (0.05 M)
for 72 h unless otherwise noted. b Isolated yield of analytically pure
material; average of at least two experiments. c Determined by
d
CSP-SFC analysis of the adduct, unless otherwise noted. 20 mol
% of catalyst used. e [26-Cl]0 ) 3.75 × 10-3 M. f [26-Cl]0 ) 0.015
g
M. Determined by CSP-SFC analysis after reduction of the
nitrile and coupling to (S)-mandelic acid. See Supporting Informa-
h
tion. Determined by CSP-SFC analysis after reduction of the
nitrile and protection as the N-BOC carbamate. See Supporting
Information. i Absolute configuration determined by derivatization
j
to â-lactam 36. Absolute configuration assigned by analogy.
lation of 35 by a NaH/MeI protocol followed by silyl
deprotection furnished the known â-lactam 36 in 70%
yield (2 steps). Optical rotation measurements [R]25
D
-54.2 (c 0.18, CHCl3; 62% ee) indicated that the â-lactam
derived from 32 was the (S)-enantiomer after comparison
to the literature value [R]25 -99.7 (c 0.34, CHCl3; 99%
D
ee).39 Products 8a , 8b, and 8h were also correlated to the
(40) See the Supporting Information for details.
J . Org. Chem, Vol. 69, No. 20, 2004 6553

Nicewicz et al.
SCHEME 9. P ossible Mech a n ism s for Ch ir a lity Tr a n sfer
aminonitriles (39) have been isolated by Enders and their
existence in the solid state provides support for structure
6.41 The exact structure of the nucleophile undergoing
acylation is not known, however.
been noted.44 The broad resonances in the 1H NMR
spectrum for the putative (salen)Al-CN complex do not
allow confirmation of aggregation, but may be suggestive.
Lower bulk concentrations should increase the relative
quantity of the monomer; if it were the most selective
complex, the observed enantioselectivity would increase.
Several limiting mechanisms can be advanced for
chirality transfer to the nascent stereogenic center.
Enantioselective cyanation of acylsilane followed by
stereospecific 1,2-Brook rearrangement with retention42
or inversion43 could lead to a configurationally defined
organoaluminum that undergoes stereospecific acylation
with cyanoformate (Scheme 9, eq 7). Alternatively, acyl-
silanes may undergo nonselective cyanation and/or Brook
rearrangement to afford interconverting organoalumi-
num diastereomers that undergo acylation at different
rates (eq 8). The interconversion could take place via the
intermediacy of the 1-azaallene-type structure 6, also a
reasonable candidate for enantioselective acylation. We
have not been able to observe intermediates in these
reactions, but the homology between known, isolated
structure 39 and proposed structure 6 should be noted.
At this point it is not possible to assess the reversibility
of either the cyanation or the 1,2-Brook rearrangement
step.
The observed concentration/enantioselectivity effects
indicate that the overall mechanism is more complex
than Scheme 2 depicts. A possible explanation for the
inverse relationship between concentration and selectiv-
ity may be competing first- and second-order reaction
manifolds whose rates depend on [catalyst]1 and [cata-
lyst]2, respectively. At lower concentrations the first-order
pathway should become more dominant; however, this
would imply that the second-order cycle is less enantio-
selective. Such a condition would be unique in (salen)-
metal catalysis.33 Alternatively, the observations could
be explained by interconverting aggregates in solution
that are all catalytically active. The propensity of alu-
minum cyanide complexes to bridge in the solid state has
Con clu sion
A new catalytic enantioselective cyanation/1,2-Brook
rearrangement/C-acylation reaction of acylsilanes with
cyanoformates in the presence of a chiral aluminum
complex was developed. This represents the first reported
instance of a catalytic asymmetric reaction of a (silyloxy)-
nitrile anion. Screening a variety of chiral metal com-
plexes proved key in developing the enantioselective
variant of the title reaction. Substrate concentration and
remote ligand substituent effects play an important role
in both enantioselectivity and reactivity. The scope of the
reaction proved general for an array of aryl acylsilanes
and cyanoformates, affording moderate to good selectivi-
ties in all cases studied. Further manipulation of the
reaction products provided a simple means for preparing
enantioenriched, fully protected R-hydroxy-â-amino acids
as well enantioenriched â-lactams. This reaction provides
access to a new series of chiral building blocks.
Exp er im en ta l Section
(R,R)-26-Cl. To a flamed-dried Schlenk tube equipped with
a magnetic stir bar was added, in a drybox, 900 mg of (R,R)-
N,N′-bis(3-tert-butyl-5-chlorosalicylidene)-1,2-diaminocyclohex-
ane (1.79 mmol, 1.0 equiv), 365 mg of Al(OiPr)3 (1.79 mmol,
1.0 equiv), and 6 mL of C7H8. The tube was sealed and heated
to 80 °C and was maintained at that temperature with stirring
for 72 h. After 72 h, the yellow-green solution was transferred
back to a glovebox and the toluene was removed under reduced
pressure. The residual solid was washed with pentane three
times and the solid was again dried under reduced pressure
to give 910 mg (87%) of pure 26-Cl as a yellow powder.
Analytical data for title compound: 1H NMR (400 MHz, CDCl3)
δ 8.27 (s, 1H), 8.05 (s, 1H), 7.33 (d, J ) 2.8 Hz, 1H), 7.31 (d, J
(41) Enders, D.; Kirchhoff, J .; Gerdes, P.; Mannes, D.; Raabe, G.;
Runsink, J .; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur.
J . Org. Chem. 1998, 63, 3-72.
(42) Linderman, R. J .; Ghannam, A. J . Am. Chem. Soc. 1990, 112,
2392-2398.
(44) Ulh, W.; Schu¨tz, U.; Hiller, W.; Heckel, M. Z. Anorg. Allg. Chem.
1995, 621, 823-828. The authors thank Professor R. Hancock (UNC-
Wilmington) for alerting us to this reference.
(43) Brook, A. G.; Pascoe, J . D. J . Am. Chem. Soc. 1971, 93, 6224-
6227.
6554 J . Org. Chem., Vol. 69, No. 20, 2004

Enantioselective Acylation of (Silyloxy)nitrile Anions
) 2.8 Hz, 1H), 7.08 (d, J ) 2.8 Hz, 1H), 3.90-3.87 (m, 1H),
3.62 (sept, J ) 6.0 Hz, 1H), 3.12-3.11 (m, 1H), 2.56-2.52 (m,
1H), 2.37-2.34 (m, 1H), 2.08-2.05 (m, 2H), 1.50 (s, 18H), 1.47
(s, 18H), 1.45-1.40 (m, 4H), 0.83 (d, J ) 6.0 Hz), 0.79 (d, J )
6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 166.8, 164.8, 163.2,
161.4, 144.1, 143.9, 130.6, 130.5, 130.2, 130.1, 120.9, 120.5,
120.1, 119.9, 63.2, 62.9, 62.7, 35.9, 35.8, 29.9, 29.8, 29.7, 29.6,
27.6, 27.5, 27.4, 27.3. A 1H NMR spectrum of 26-Cl is attached
in Appendix B of the Supporting Information.
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 (q, J ) 7.6 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 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; TLC (95:5
hexanes/EtOAc) Rf 0.35. Anal. Calcd for C22H27NO3Si: C,
69.25; H, 7.13; N, 3.67. Found: C, 69.37; H, 7.28; N, 3.60.
Ack n ow led gm en t. D.A.N. acknowledges a W. R.
Bost fellowship (UNC). Acknowledgment is made to
Research Corporation, the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, and the National Institutes of Health
(National Institute of General Medical Sciences, R01
GM068443) for partial support of this research. We also
thank the research groups of Professors J . P. Morken
and M. R. Gagne´ for their generous donation of some of
the ligands used in the catalyst screen.
Rep r esen ta tive P r oced u r e for En a n tioselective Acy-
la tion Rea ction s. (S)-(+)-Ben zyl 2-Cya n o-2-p h en yl-2-
tr ieth ylsiloxya ceta te (8a ): A flame-dried Schlenk tube
equipped with a magnetic stir bar was charged with aluminum
complex 26-Cl (23.8 mg, 0.04 mmol, 0.15 equiv) under Ar.
Benzoyl triethylsilane (60 mg, 0.27 mmol, 1.0 equiv), benzyl
cyanoformate (87.8 mg, 0.54 mmol, 2.0 equiv), and C7H8 (5.4
mL, 0.05 M) were all added to the Schlenk tube under Ar and
the tube was sealed and heated to 45 °C. After 72 h at 45 °C,
the crude product was purified by flash chromatography with
95:5 petroleum ether-EtOAc to afford 85.3 mg (83%) of 8a as
a colorless oil in 79% ee as determined by chiral SFC analysis
(Chiralpak OD, 0.3% MeOH, 0.5 mL/min, 150 psi, 40 °C, 240
nm, tr-major 37.0 min, tr-minor 41.5 min). Analytical data for title
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data for all new compounds, CSP-SFC
traces of racemic and enantioenriched compounds, and details
of stereochemical proofs. This material is available free of
charge via the Internet at http://pubs.acs.org.
compound: [R]25 +4.2 (c 1.97, CH2Cl2); IR (thin film, cm-1
)
D
3067, 3035, 2958, 2878, 2245, 1766, 1588, 1451, 1241, 1152,
1
1003, 835; H NMR (400 MHz, CDCl3) δ 7.63-7.61 (m, 2H),
J O049164E
J . Org. Chem, Vol. 69, No. 20, 2004 6555