N-silyl oxyketene imines are underused yet highly versatile reagents for catalytic asymmetric synthesis

Article abstract of DOI:10.1038/nchem.857

The reactions of acyl anion equivalents (d1 synthons) with carbonyl electrophiles allow for the construction of a wide range of molecules useful for the synthesis of biologically active compounds, natural products and chiral ligands. Despite their utility, significant challenges still exist for developing catalytic, enantioselective variants of these reactions. For example, the asymmetric benzoin process, arguably the most characteristic reaction of d synthetic equivalents, finds no general solution for reactions involving aliphatic acyl anions. In this Article, we introduce a new class of stable, isolable silyl ketene imines derived from protected cyanohydrins. These nucleophiles serve as acyl anion equivalents in Lewis base catalysed aldol addition reactions and allow for the preparation of cross-benzoin and glycolate-aldol products in high yield and with exceptional diastereo- and enantioselectivities.

Full text of DOI:10.1038/nchem.857

ARTICLES
PUBLISHED ONLINE: 3 OCTOBER 2010 | DOI: 10.1038/NCHEM.857
N-silyl oxyketene imines are underused yet
highly versatile reagents for catalytic
asymmetric synthesis
Scott E. Denmark and Tyler W. Wilson
*
The reactions of acyl anion equivalents (d1 synthons) with carbonyl electrophiles allow for the construction of a wide range
of molecules useful for the synthesis of biologically active compounds, natural products and chiral ligands. Despite their
utility, significant challenges still exist for developing catalytic, enantioselective variants of these reactions. For example,
the asymmetric benzoin process, arguably the most characteristic reaction of d1 synthetic equivalents, finds no general
solution for reactions involving aliphatic acyl anions. In this Article, we introduce a new class of stable, isolable silyl
ketene imines derived from protected cyanohydrins. These nucleophiles serve as acyl anion equivalents in Lewis base
catalysed aldol addition reactions and allow for the preparation of cross-benzoin and glycolate-aldol products in high yield
and with exceptional diastereo- and enantioselectivities.
N
he deprotonation of protected cyanohydrins and the subsequent
reactions of the resulting metallo ketene imines with carbon-
based electrophiles is a well-established method for constructing
O
R3Si
C
OPg
+
H
R2
R1
T
carbon 2 carbon bonds1–5. When applied to carbonyl additions,
extremely versatile b-hydroxy cyanohydrins (2) are obtained
(Fig. 1). The usefulness of these products arises from the ability of
cyanide to act as either a leaving group through deprotection/retro-
cyanation (path a, Fig. 1), or to be revealed as a carbonyl compound
through hydrolysis, reduction or organometallic addition (path b,
Fig. 1). Unfortunately, the generation of metalated ketene imines
requires stoichiometric quantities of strong amide or alkyllithium
bases, which severely limits the extension of this process to a catalytic,
enantioselective variant. In this Article, a new class of stable, isolable
N-silyl oxyketene imines (1) derived from protected cyanohydrins is
introduced. These latent nucleophiles harness the reactivity of a
metallo ketene imine and allow for the catalytic, enantioselective syn-
thesis of b-hydroxy cyanohydrins and their subsequent application to
cross-benzoin and glycolate aldol reactions.
1
cat*
OH
N
C
R2
R1
PgO
2
Path a
Path b
R3(H)
OH
O
OH
R1
R2
R2
R1
PgO
O
Cross-benzoin
Glycolate-aldol
The potential benefits that nucleophilic cyanohydrins offer in asym-
metric addition reactions have been recognized in recent years. A
chiral-auxiliary-based method has been developed in which benzal-
dehyde cyanohydrin, modified with an ephedrine-derived O-phos-
phate, undergoes highly diastereoselective alkylations and Michael
reactions6. The obvious drawbacks to this process are the use of stoi-
chiometric amounts of alkyllithium bases and the additional steps
required for removal and recovery of the auxiliary. A novel strategy
for accessing the anions of protected cyanohydrins that circumvents
Figure 1 | Reaction pathways available to N-silyl oxyketene imines. Aldol
reactions of N-silyl oxyketene imines (1) with aldehydes to afford b-hydroxy
nitrile products (2) are presented. The ability of the N-silyl oxyketene imines
to serve as acyl anion equivalents is realized by deprotection and
retrocyanation of 2 (path a). Alternatively, glycolate-aldol products
containing a protected stereogenic tertiary alcohol are revealed by reduction
or organometallic addition to the nitrile (path b).
the need for strong bases is the cyanide-promoted 1,2-Brook rearrange- proceed through a nucleophile-promoted Brook rearrangement,
ment7,8 of acyl silanes9–13. Others have successfully applied this process but do not involve the intermediacy of a cyanohydrin anion.
to catalytic, enantioselective acylations of cyanohydrins by using a Cross-benzoin adducts comprising two different aromatic alde-
chiral (salen)aluminium alkoxide catalyst and benzyl cyanoformate hydes are obtained in good yield and enantioselectivity (91:9 to
as both the source of cyanide and the acylating reagent14,15
.
96.5:4.5 er), but the yields and selectivities are significantly
Although this reaction represents a benchmark for asymmetric reac- reduced with aliphatic aldehydes or acyl silanes. Although limit-
tions of metallated cyanohydrins, the observed enantioselectivities ations in substrate scope are observed, this method represents the
are highly substrate-dependent and reach a maximum at 91:9 er.
current state of the art for achieving non-enzymatic, catalytic, enan-
A related study reported the catalytic, enantioselective cross- tioselective cross-benzoin products17.
benzoin reaction of acyl silanes with aldehydes catalysed by
Among all the useful addition reactions of cyanohydrin-derived
TADDOL-derived metallophosphites16. These reactions also anions, curiously, the aldol process remains underdeveloped. The
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois, 61801, USA. e-mail: sdenmark@illinois.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
ARTICLES
products of these reactions are analogous to the aldol additions
of a-substituted glycolate enolates and have a fully substituted
a-stereogenic centre. Very few methods are capable of delivering
this structure in a stereocontrolled fashion. A chiral auxiliary
method has been reported in which a boron enolate is generated
by the 1,2-Wittig rearrangement of an O-benzylglycolate derived
from a chiral alcohol18. More recently, the catalytic, enantioselective
additions of 5H-oxazole-4-ones with aldehydes catalyzed by chiral
guanidines have been reported19. The oxazole-4-one products are
obtained in good yield and enantioselectivity, but the diastereo-
selectivity is highly dependent on the substrates. Additionally, the
reaction is limited to cyclic donors, which further emphasizes
the challenges inherent in controlling enolate geometry for acyclic
disubstituted substrates20,21. Although the preparation of secondary
alcohols by catalytic, enantioselective glycolate aldol additions is
known22–24, this last method is the first in which tetrasubstituted
stereogenic centres are obtained.
Table 1 | Preparation of N-silyl oxyketene imines from
tert-butyl protected cyanohydrins.
KHMDS (1.2 equiv.)
i-Pr3SiCl (1.1 equiv.)
N
N
C
R
i-Pr3Si
C
R
THF, –78°C, 2h
Ot-Bu
Ot-Bu
3b–f
4b–f
ymax (cm21 †
Entry
R
Product
Yield (%)*
)
1
Me
Et
4b
4c
4d
4e
4f
94
94
93
93
97
2,037
2,033
2,036
2,039
2,037
2
3
4
5
i-Bu
Bn
Allyl‡
General reaction conditions: 3 (3.6–5.9 mmol), KHMDS (1.2 equiv.), i-Pr3SiCl (1.1 equiv.), THF
(1.0 M), 278 8C, 2 h. *Yield of crude ketene imine obtained after filtration and removal of
volatiles by high vacuum. †FT-IR of neat liquids on NaCl plates. ‡Starting material prepared by
alkylation of tert-butyl protected formaldehyde cyanohydrin.
Previous studies from these laboratories25 and others26 have
documented the advantages that silyl ketene imines offer in the cat-
alytic, enantioselective synthesis of compounds containing quatern- protecting group must be stable to alkyl lithium and amide bases;
ary stereogenic centres. These nucleophiles are readily prepared in and (iv) the introduction and removal of the protecting group
high yield and purity by the deprotonation of disubstituted alkyl must be high yielding and scalable.
or aryl nitriles, followed by trapping of the resulting anion with
The tert-butyl group embodies all of these characteristics;
an appropriate trialkylsilyl chloride. Surprisingly, the analogous however, methods for installing this moiety on a cyanohydrin are
reactions of protected cyanohydrins are practically unknown. A very rare. A single example by Watt and colleagues describes a scal-
single account on the deprotonation of trimethylsilyl-protected cya- able process for the protection of formaldehyde cyanohydrin using
nohydrins by lithium diisopropylamide, and subsequent trapping isobutylene and a catalytic amount of sulfuric acid28. Following this
with trimethylsilyl chloride, appeared in 1992 (ref. 27). This study precedent, tert-butyl protected cyanohydrins derived from aliphatic
revealed that the site of silylation of the metallo ketene imine is aldehydes could be obtained reproducibly in 30240% yields and on
1
highly responsive to the size of the alkyl substituent of the cyanohy- a multigram scale. Careful inspection of the H nuclear magnetic
drin. For example, the cyanohydrins derived from acetaldehyde resonance (NMR) spectra of the crude reaction mixtures revealed
gave, exclusively, the C-silylated nitrile, whereas the cyanohydrin that the low yields were in part due to a competitive Ritter
derived from 2-methylpropanal gave primarily the N-silylated process29, which consumed one equivalent of the cyanohydrin
ketene imine (90:10 ratio, N- to C-silylation). Intermediate results and yielded the corresponding tert-butyl amide. In the mechanism
are observed with the cyanohydrin prepared from 1-hexanal (60:40, of the Ritter reaction, water is required to hydrolyse the tert-butyl
N- to C-silylation), but interestingly the ratio changes in favour of nitrilium ion intermediate. Thus, rigorous exclusion of moisture
C-silylation upon standing for 5 days at 25 8C (16:84, N- to C-silyla- from these reactions should prevent this side process from occur-
tion). These results suggest that the initial product distribution is, at ring. To this end, a new procedure was developed, in which the
least partially, under kinetic control and that the C-silylated isomer crude cyanohydrins were thoroughly dried with MgSO4 and then
is the thermodynamically more stable product. Despite these promis- distilled before use. Additionally, anhydrous methanesulfonic acid
ing findings, no subsequent reports on the preparation and/or use of was used as the acid catalyst and the loading was raised to increase
silyl ketene imines derived from protected cyanohydrins are the reaction rate. Under these optimized reaction conditions,
on record.
analytically pure tert-butyl protected cyanohydrins were obtained
in moderate to good yield and on a multigram scale after distillation
(Fig. 2). With a practical and scalable route for the preparation
Results
Synthesis of t-butyl protected cyanohydrins. The work of Cunico of various tert-butoxy nitriles, studies aimed at the synthesis of
and Kuan demonstrates the crucial role that steric effects play N-silyl oxyketene imines were undertaken.
in obtaining N-silyl oxyketene imines versus the more
thermodynamically favoured C-silylated isomers. Therefore, the Synthesis of N-silyl oxyketene imines from tert-butyl protected
first goal of the current study was to identify and synthesize a cyanohydrins. The capacity for metallated nitriles to undergo
suitably protected cyanohydrin that would allow for the selective competitive C-silylation is well documented, and previous studies
formation of the ketene imine. Specifically, an O-protecting group have shown that the size of the silylating agent influences the site
was sought that met the following criteria: (i) the protecting of silylation30–32. In the case of protected cyanohydrins, the
group must be sterically bulky so that silylation at the less smaller size of the intervening oxygen atom could attenuate the
encumbered N-terminus will be favoured; (ii) the protecting influence of the protecting group and result in a higher degree of
group must be able to be installed under acidic conditions C-silylation relative to disubstituted alkyl or aryl nitriles. In this
because of the sensitivity of cyanohydrins to basic media; (iii) the case, the steric bulk of the silyl group could play an important
role in the selective synthesis of N-silyl oxyketene imines.
Isobutylene (25 equiv.)
Accordingly, triisopropylsilyl chloride (TIPSCl) was selected as
the silylating agent and the deprotonation/silylation of tert-butyl
protected cyanohydrins was studied under various conditions.
Gratifyingly, it was found that N-silyl oxyketene imines could be
prepared in excellent yield and selectivity by the use of potassium
bis(trimethylsilyl)amide (KHMDS) as the base at 278 8C in tetra-
hydrofuran (THF) (Table 1)33. The products were obtained as
liquids in high purity by simple filtration through Celite and
N
N
MsOH (40 mol%)
C
R
C
R
CH2Cl2 (2M), 24°C, 60h
OH
Ot-Bu
'Multigram scale'
5 examples
(50–70% yield)
3a–e
R = H, Me, Et
i-Bu, Bn
Figure 2 | Synthesis of tert-butyl protected cyanohydrins.
938
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
ARTICLES
Table 2 | Survey of N-silyl oxyketene imines in the addition
to benzaldehyde catalysed by (R,R)-7.
Table 3 | Survey of aromatic aldehydes in the addition of
phenylacetaldehyde-derived ketene imine 4e.
SiCl4 (1.1 equiv.)
OH
SiCl (1.1 equiv.)
4
N
i-Pr2EtN (1.0 equiv.)
O
i-Pr2EtN (1.0 equiv.)
R
i-Pr3Si
C
R
OH
N
+
Ph
O
CH2Cl2 (0.2M), –78°C, 2h
(R,R)-7 (2.5 mol%)
i-Pr3Si
C
CN
H
Ph
t-BuO
+
Ph
Ot-Bu
Ph
t-BuO
Aryl
Me
CH2Cl2 (0.2M), –78°C, 2h
H
Aryl
5b–h
Ot-Bu
N
P
N
CN
O
6ba-6fa
CH2
4b-f
5a
N
4e
6eb–6eh
Me
Me
(R,R)-7 (2.5 mol%)
Entry
Aldehyde
Product
Yield
(%)*
dr†
er‡
2
Entry
Nucleophile
Product
Yield (%)* dr†
er‡
O
OH
CN
1
93
93
91
98:2 .99:1
99:1 .99:1
98:2 98.6:1.4
N
OH
H
Ph
t-BuO
1
3
84
92
92
96:4 .99:1§
98:2 .99:1
98:2 .99:1
i-Pr Si
C
Me
Me
OMe
OMe
Ot-Bu
CN
t-BuO
5b
6eb
4b
6ba
O
OH
CN
2
3
N
OH
H
Ph
t-BuO
C
Et
i-Pr Si
2
3
3
Et
CF
CF
3
3
Ot-Bu
CN
t-BuO
5c
6ec
4c
6ca
O
OH
N
OH
C
i-Bu
Ot-Bu
H
Ph
i-Pr Si
3
i-Bu
CN
t-BuO
CO Me
2
CO Me
2
CN
t-BuO
4d
5d
6ed
6da
O
OH
N
OH
4
5
6
95
93
89
98:2 .99:1
99:1 98.9:1.1
99:1 93.5:6.5
i-Pr Si
C
4
5
3
93
90
99:1 .99:1
99:1 .99:1
H
Ph
Ph
Ph
t-BuO
CN
t-BuO
Ot-Bu
CN
Br
Br
4e
6ee
5e
6ea
O
Me
OH
Me
N
OH
C
i-Pr Si
3
H
Ph
t-BuO
CN
6ef
Ot-Bu
CN
t-BuO
4f
5f
6fa
O
OH
General reaction conditions: 5 (1.0 mmol), 4 (1.2 equiv.), (R,R)-7 (2.5 mol%), SiCl4 (1.1 equiv.),
i-Pr2EtN (1.0 equiv.), CH2Cl2 (0.2 M), 278 8C, 2 h. *Yield of analytically pure material.
†Determined by 1H NMR analysis of the crude reaction mixture. ‡Determined by chiral stationary
phase supercritical fluid chromatography (CSP-SFC). §Determined by CSP-SFC analysis after
conversion to the 3,5-dinitrobenzoyl ester.
Ph
H
CN
t-BuO
5g
6eg
O
OH
7
91
99:1 .99:1
O
O
H
Ph
removal of volatile materials under vacuum. The N-silyl oxyketene
imines were stable for months when stored at 4 8C, although
partial isomerization to the C-silylated nitrile was observed upon
distillation. Additionally, the compounds were surprisingly resistant
to hydrolysis and could be filtered and handled in air without sig-
nificant decomposition. Analysis of the liquids by infrared spec-
troscopy revealed an intense band at 2,030 cm21, which is a
characteristic feature of the ketene imine functional group
CN
6eh
t-BuO
5h
General reaction conditions: 5 (1.0 mmol), 4 (1.2 equiv.), (R,R)-7 (2.5 mol%), SiCl4 (1.1 equiv.),
i-Pr2EtN (1.0 equiv.), CH2Cl2 (0.2 M), 278 8C, 2 h. *Yield of analytically pure material.
†Determined by 1H NMR analysis of the crude reaction mixture. ‡Determined by CSP-SFC analysis.
(Table 1). The exclusive formation of the N-silyl isomer highlights imine 4b was combined with benzaldehyde, 2.5 mol% of (R,R)-7
the importance of the O-tert-butyloxy and N-triisopropylsilyl and a stoichiometric quantity of SiCl4. Under these reaction con-
groups. This feature is especially relevant in the context of pre- ditions the aldol product 6ba was produced in good yield, high dia-
liminary studies performed with methyl, benzyl and trimethylsilyl stereoselectivity and excellent enantioselectivity (Table 2, entry 1).
protected cyanohydrins, all of which provided mixtures of N- and To establish the generality of this transformation, other N-silyl oxy-
C-silylated products.
ketene imines were evaluated in the addition to benzaldehyde. In all
cases, the resulting diol products were obtained in high yield and
with exceptional diastereo- and enantioselectivities for a number
Aldol reactions of N-silyl oxyketene imines
Although the selective synthesis of N-silyl oxyketene imines rep- of different N-silyl oxyketene imines (Table 2, entries 225). The
resents a significant advance in ketene imine chemistry, the ability diastereoselectivity for the addition was responsive to the size of
of these compounds to participate in catalytic, enantioselective car- the alkyl substituent of the ketene imine such that the dr increased
bonyl addition reactions was unknown. Previous studies showed with more sterically demanding groups. Importantly, a synthetically
that a broad range of silylated nucleophiles24,34–39, including silyl versatile allyl-substituted diol product 6fa was produced in excellent
ketene imines25, are susceptible to Lewis base catalysed40, SiCl4- yield and stereoselectivity (Table 2, entry 5).
mediated aldol additions. To determine if N-silyl oxyketene
To further explore the scope of this aldol process a number of
imines would be competent nucleophiles in this system, ketene different aromatic aldehydes were examined in the addition of
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
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Table 4 | Lewis base catalysed cross-benzoin reactions of N-silyl oxyketene imines with aromatic aldehydes.
SiCl4 (1.1 equiv.)
i-Pr2EtN (1.0 equiv.)
(R,R)-7 (2.5 mol%)
OH
OSiCl3
N
O
MeOH (3.3 equiv.)
KF/NaHCO3 (aq.)
C
R
i-Pr3Si
R
R
+
Aryl
Aryl
CH2Cl2 (0.2M), –78 °C, 2h
H
Aryl
5a–d
Ot-Bu
CN
t-BuO
O
4c–e
8
9ca–9ea
& 9ea–ed
Entry
Nucleophile
Aldehyde
Product
Yield (%)
er
N
O
OH
99.0:1.0‡
C
Et
i-Pr Si
1
79*
3
H
Me
Ot-Bu
O
4c
5a
9ca
N
O
H
OH
98.9:1.1‡
.99/1§
.99/1§
C
i-Bu
i-Pr Si
2
3
4
82*
84†
75†
3
Me
Ot-Bu
Me
O
4d
5a
9da
N
O
H
OH
i-Pr Si
C
3
Ph
Ph
Ot-Bu
O
4e
5a
9ea
N
O
OH
i-Pr Si
C
3
Ph
Ph
H
Ot-Bu
O
OMe
5b
OMe
4e
9eb
N
O
H
OH
i-Pr Si
C
5
6
3
77†
.99/1§,ꢀ
Ph
Ph
Ot-Bu
O
CF
3
CF
3
4e
5c
9ec
N
O
H
OH
78†
.99/1§,}
i-Pr Si
C
3
Ph
Ph
Ot-Bu
O
CO Me
2
CO Me
2
4e
5d
9ed
General reaction conditions: 5 (1.0 mmol), 4 (1.4 equiv.), (R,R)-7 (2.5 mol%), SiCl4 (1.1 equiv.), i-Pr2EtN (0.2 equiv.), MeOH (3.3 equiv.), CH2Cl2 (0.2 M), 278 8C, 2 h. *Yield of chromatographically
homogeneous material. †Yield of analytically pure material after single recrystallization from toluene. ‡Determined by CSP-SFC analysis on chromatographically homogeneous material. §Determined by CSP-
SFC analysis after single recrystallization from toluene. ꢀ96.1:3.9 er was obtained before recrystallization. }96.5:3.5 er was obtained before recrystallization.
phenylacetaldehyde-derived ketene imine 4e (Table 3). Reactions immediate product of the reaction, trichlorosilyl ether 8 (Table 4).
with electron-rich-, electron-poor-, sterically hindered- and hetero- The hydrolytically labile trichlorosilyl ether could be used for
aromatic aldehydes all afforded diol products in high yield and in situ deprotection (through the release of HCl) and then the
excellent diastereo- and enantioselectivities. Only in the addition cross-benzoin products could be obtained following a basic work-
to 1-naphthaldehyde was a moderate reduction in the enantioselec- up. To test this hypothesis, the aldol addition of propionaldehyde-
tivity observed (entry 6, 93.5:6.5 er); however, other hindered aro- derived N-silyl oxyketene imine 4c with benzaldehyde was
matic aldehydes such as 2-tolualdehyde participated with high performed and the reaction was quenched with 3.3 equiv. of
enantioselectivity (entry 5, 98.9:1.1 er). The reaction rates for the methanol. The corresponding cross-benzoin product 9ca was
addition of N-silyl oxyketene imines to aliphatic aldehydes were obtained in good yield and excellent enantioselectivity after the
very slow, and studies aimed at increasing this rate are ongoing37. standard basic work-up with aqueous KF/NaHCO3 (Table 4,
Interestingly, a,b-unsaturated aldehydes undergo highly site-selective entry 1). Following this encouraging result, other combinations of
1,4-additions; however, the current catalyst structure is not suitable for N-silyl oxyketene imines and aromatic aldehydes were examined
achieving even modest stereoselectivities at this remote position41.
to test the generality of this novel process (Table 4, entries 226).
The resulting a-hydroxy carbonyl compounds were isolated in
good yield and excellent enantioselectivity. Importantly, good
correlations were observed between the enantiomeric ratios of the
aldol products and the corresponding cross-benzoin adducts (for
example, entry 2, Table 2 versus entry 1, Table 4). This
correlation demonstrates that the stereogenic centre in the cross-
benzoin product does not undergo significant epimerization
during the basic work-up. Only in the cases of strongly
Cross-benzoin reactions of N-silyl oxyketene imines. On the basis
of the now classic studies by Stork1, it was initially imagined that
cross-benzoin products would be obtained by deprotection of the
isolated aldol products (6) under acidic conditions, followed by
basic work-up to trigger retrocyanation. Although this route
should be viable, it was envisioned that cross-benzoin adducts
could also be obtained more directly, by taking advantage of the
940
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
ARTICLES
easily be obtained by a single recrystallization from toluene. To
our knowledge, these are the first examples of a catalytic,
enantioselective cross-benzoin reaction that involve an aliphatic
aldehyde as one of the coupling partners.
a
Scale-up
PhCHO (5a)
SiCl4 (1.1 equiv.)
i-Pr2EtN (1.0 equiv.)
OH
N
N
TIPS
C
Me
C
Ph
Ot-Bu
CH2Cl2 (0.2M), –78°C, 2h
Ot-Bu
Me
Transformations of the aldol products. The ability to access cross-
benzoin products in high yield and enantioselectivity through
deprotection and retrocyanation of the b-hydroxy cyanohydrins
demonstrates the highly versatile nature of these products. Other
useful pathways available to these compounds are transformations
of the nitrile by reduction or organometallic addition. An
important advantage of these manipulations is that the
stereochemically defined tertiary alcohol, which was set in the
aldol addition, is preserved. The products would allow access to
stereochemically complex polyols and amino alcohols, which
could be relevant synthetic intermediates en route to biologically
active compounds. Although the functional group manipulations
of nitriles are well described42,43, the application to hindered
nitriles is not trivial. For this reason, a thorough examination of
these transformations was undertaken for the nitrile products
relevant to this work (Fig. 3).
b-Hydroxy nitrile 6ba was chosen for the current study, and was
prepared with high diastereoselectivity and on a gram scale by the
addition of N-silyl oxyketene imine 4b to benzaldehyde catalysed
by racemic biphenyl-derived bisphosphoramide 10 (Fig. 3a).
Because 6ba was obtained with high diastereoselectivity, any evi-
dence for epimerization in the subsequent transformations could
easily be secured by inspection of the 1H NMR spectra of the
crude reaction mixtures. To evaluate the nucleophilic transform-
ations, it was deemed prudent to first protect the secondary
alcohol of the aldol product as its 4-methoxybenzyl (PMB) ether.
Treatment of the sodium salt of 6ba with 4-methoxybenzyl
bromide afforded 11 in high yield and with no change in the diaster-
eomeric composition (Fig. 3b).
Me
4b
N
O
( )-6ba
1.65 g, 89%
95:5 dr
P
CH
2
N
N
Me
Me
2
10 (2.5 mol%)
b
PMB-protection
OH
OPMB
4-MeOC6H4CH2Br
NaH (1.1 equiv.)
N
C
N
C
Ph
Ot-Bu
Ph
DMF (0.2M), 0°C, 2h
Ot-Bu
Me
Me
( )-11
( )-6ba
95:5 dr
2.37 g, 95%
95:5 dr
c
Hydride reductions
OPMB
OPMB
N
LiAlH4
C
Ph
H2N
Ph
Ot-Bu
Et2O, 23°C
Ot-Bu
Me
Me
( )-11
95:5 dr
( )-12
343 mg, 96%
95:5 dr
OPMB
Ph
O
OPMB
N
DIBAL-H
C
H
Ph
Ot-Bu
THF, -78 °C
Ot-Bu
Me
Me
( )-11
95:5 dr
( )-13
344 mg, 84%
95:5 dr
Next, the reduction of 11 with two different metal hydride agents
was studied (Fig. 3c). Reduction of the nitrile to the corresponding
protected amino alcohol 12 was accomplished with LiAlH4. No epi-
merization was observed and analytically pure 12 was conveniently
obtained in excellent yield after distillation. Partial reduction of 11
with diisobutylaluminum hydride (DIBAL-H) and hydrolysis of
the resulting imine afforded aldehyde 13 in good yield and
high diastereoselectivity.
d
Carbon-carbon bond formation
OPMB
NH
OPMB
a. MeLi
b. NH4Cl (aq.)
N
C
Ph
Me
Ph
Ot-Bu
THF, 0 °C
Ot-Bu
Me
Me
( )-11
95:5 dr
( )-14
395 mg, 96%
95:5 dr
Finally, the addition of organometallic reagents to 11 was
studied. These reactions are highly valuable as they allow for the cre-
ation of new carbon 2 carbon bonds with a variety of nucleophilic
species. Preliminary investigations with methylmagnesium bromide
showed a slow rate of addition (.24 h); however, the analogous
reaction with methyllithium showed complete consumption of 11
in less than 2 h. Interestingly, quenching the reaction with
aqueous NH4Cl solution resulted in the isolation of analytically
pure imine 14 in high yield after distillation (Fig. 3d). Although
the isolation of imines is uncommon for nitrile addition reactions,
it is not unprecedented for cases where sterically hindered nitriles
are used44. The methyl ketone product 15 could also be obtained
in similar yield by simply changing the conditions of the hydrolysis
to the use of concentrated aqueous acetic acid. Importantly, both
imine 14 and ketone 15 were obtained without loss
in diastereoselectivity.
OPMB
O
OPMB
a. MeLi
b. AcOH (aq.)
N
C
Ph
Ot-Bu
Me
Ph
Ot-Bu
THF, 0 °C
Me
Me
( )-11
95:5 dr
( )-15
360 mg, 92%
95:5 dr
Figure 3 | Transformations of nitriles 6ba and 11. a, The scalability of the
Lewis base catalysed aldol addition of N-silyl oxyketene imine 4b with
benzaldehyde is demonstrated by increasing the scale to 8 mmol in aldehyde.
b, Complementary protection of the secondary alcohol of aldolate product
6ba as a p-methoxybenzyl ether sets the stage for manipulation of the nitrile
functionality. c, The transformations of product 11 by hydride reduction of the
nitrile is illustrated. In these reactions, either amine 12 or aldehyde 13 could
be obtained by judicious choice of the metal hydride reagent. d, The
versatility of product 11 is further demonstrated by methyl lithium addition to
the nitrile. In these reactions, both the direct product of addition (methyl
imine 14) or the product resulting from hydrolysis (methyl ketone 15) could
be obtained by simply varying the acidity of the reaction work-up.
Discussion
In situ kinetic analysis (infrared spectroscopy) for the addition of
N-silyl oxyketene imines to benzaldehyde in the presence of stoichio-
metric quantities of SiCl4 revealed that, in the absence of the Lewis
electronegative aryl substituents (Table 4, entries 5,6) were minor base, no appreciable background reaction occurred (t1/2 . 4 h, see
losses in the enantioselectivity of the cross-benzoin products Supplementary Information). Alternatively, executing the reaction
observed; nevertheless, enantiomerically pure compounds could with 2.5 mol% of
a
chiral bisphosphoramide catalyst and
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
941
© 2010 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
ARTICLES
OSiCl3
N
modification allowed for the preparation of cross-benzoin products
derived from aliphatic aldehydes in good yields and excellent enan-
tioselectivities. The versatility of the b-hydroxy cyanohydrins was
highlighted by three different transformations of the nitrile group.
These functional group manipulations allowed access to amino alco-
hols and a-hydroxy aldehydes or ketones containing a stereogenic
tertiary alcohol in good yields and high selectivities. Future work
will focus on the application of this novel class of nucleophiles to
other classes of umpolung reactions such as Stetter-type additions
and homoenolate chemistry.
LB:
C
SiCl4
LB:
1
R
Lewis base
Lewis acid
Ot-Bu
R2
IV
d
a
+
i-Pr3SiCl
+
i-Pr3Si
Cl–
Cl
Cl–
OSiCl (LB)
3
+
2
N
LB
LB
C
Si Cl
1
R
Ot-Bu
Cl
2
R
III
I
Methods
Full experimental details and characterization of compounds can be found in the
Supplementary Information. The crystallographic coordinates of 6da have been
deposited with the Cambridge Crystallographic Data Centre (CCDC; deposition no.
761034). These data can be obtained free of charge from the CCDC at www.ccdc.
cam.ac.uk/data_request/cif.
b
c
O
+
Cl–
Cl
LB
LB
Cl
O
R1
N
Si
Cl
H
i-Pr3Si
C
R2
General procedure for the preparation of N-silyl oxyketene imines. To a flame-dried,
50-ml Schlenk flask under an atmosphere of argon was added 0.96 g of KHMDS
(4.8 mmol, 1.2 equiv.) and 4.8 ml of anhydrous THF (1.0 M in KHMDS). The
solution was cooled to 278 8C (internal) and a mixture of 0.82 g tert-butoxy nitrile
3e (4.0 mmol) and 0.95 ml (4.4 mmol, 1.1 equiv.) TIPSCl in 6.3 ml of anhydrous
THF was added via cannula over 10 min while stirring. The resulting bright yellow
reaction mixture was stirred for 2 h at 278 8C and then allowed to warm to 0 8C.
The reaction mixture was concentrated under vacuum (1.0 mmHg) to give a thick,
orange gel (ꢁ3 ml). Anhydrous hexanes was added (20 ml) and the mixture was
stirred vigorously under argon. The heterogeneous solution was opened to air and
filtered through a pad of Celite into a flame-dried, tared flask. The resulting, clear
orange filtrate was concentrated under high vacuum (0.5 mmHg) to afford 1.33 g
(93%) of 4e as an orange liquid, which was used in subsequent reactions without
further purification.
R1
Ot-Bu
H
II
Figure 4 | Proposed catalytic cycle for N-silyl oxyketene imine additions to
aromatic aldehydes via Lewis base activation of Lewis acids. The proposed
catalytic cycle commences with the binding of the bisphosphoramide Lewis
base to the weak Lewis acid silicon tetrachloride. This complexation of the
Lewis base leads to polarization of the Lewis acid and eventually ionization
of a chloride ion to generate a chiral trichlorosilyl cation (I). Coordination of
the aldehyde to the activated Lewis acid and enantioselective addition of the
N-silyl oxyketene imine leads to the nitrilium ion intermediate III. Desilylation
of III by nucleophilic chloride and subsequent regeneration of the Lewis base
catalyst delivers aldol product IV as the trichlorosilyl ether.
General procedure for aldol reaction of N-silyl oxyketene imines with aromatic
aldehydes. To a flame-dried, 10-ml, Schlenk flask were added 21 mg of (R,R)-7
(0.025 mmol, 0.025 equiv.), 102 ml of benzaldehyde (1.00 mmol) and 5.0 ml of
anhydrous CH2Cl2 (0.2 M) under an atmosphere of argon. The solution was
stirred, cooled to 278 8C (internal) and 175 ml of N,N-diisopropylethylamine
(1.00 mmol, 1.0 equiv.) and 130 ml of SiCl4 (1.1 mmol, 1.1 equiv.) were added via
syringe. The resulting yellow solution was stirred for 5 min at 278 8C, then 0.9 ml of
a 1.33 M solution of silyl ketene imine 4e (1.2 mmol, 1.2 equiv.) in anhydrous
CH2Cl2 was added dropwise via syringe. The reaction was stirred for 2 h at 278 8C
before 0.65 ml of a 2:1:1 mixture of Et3N/CH2Cl2/MeOH was added via syringe.
1.1 equiv. of SiCl4, an extremely facile addition is observed as noted
by loss of the aldehyde absorbance at 1,702 cm21 (t1/2 , 2 min).
The rate data are striking when compared to previous studies on
Lewis base catalysed aldol additions of silyl ketene imines25. In
such cases, a significant background reaction is observed in the The quenched reaction mixture was stirred for 5 min at 278 8C and then
transferred to a stirred, sat. aq. solution of NaHCO3 (10 ml) and KF (10 ml).
The biphasic mixture was stirred vigorously for 1 h at room temperature and
then filtered through a pad of Celite and transferred to a separatory funnel
where the organic layer was removed. The aqueous layer was extracted with
addition to benzaldehyde, although the relative catalysed rates
were still competitive enough to achieve high enantioselectivities.
The extraordinary enantioselectivities observed in the current
study might be ascribed to the absence of an achiral background
reaction. This scenario is ideal for achieving high enantioselectiv-
ities, because reaction can only occur when the Lewis base is
bound to the weakly Lewis acidic SiCl4. This mode of catalysis
ensures that the chiral Lewis base is present during the stereo-
chemistry-determining step of the reaction, and showcases the
power of Lewis base catalysis (Fig. 4)45.
CH2Cl2 (2 × 20 ml) and the organic extracts were combined, washed with
brine (1 × 25 ml), and dried over MgSO4. The solution was filtered and
concentrated in vacuo and the resulting crude material was purified by column
chromatography (25 g silica gel, hexanes/EtOAc gradient; 9:1 to 8:1) to afford
286 mg of 6ea (93%) as viscous yellow oil. The diastereomeric ratio was determined
to be 99:1 by 1H NMR (500 MHz) analysis of the crude product. The enantiomeric
ratio was determined to be .99:1 by CSP-SFC analysis of the chromatographically
homogeneous material.
The absolute and relative configurations of the aldol products
were unambiguously assigned by single-crystal X-ray diffraction
analysis of 6da obtained by addition of ketene imine 4d to benzal-
dehyde. Independent assignment of the absolute configuration for
the cross-benzoin products was achieved by comparison of the
optical rotation of 9ca to a known compound46. Both methods con-
firmed an S-absolute configuration at the secondary alcohol centre
and verify that the aldehyde undergoes nucleophilic addition to
the Re face. This sense of asymmetric addition is in agreement
with all other addition reactions to aldehydes reported for this cat-
alyst system37.
In conclusion, a new class of silyl ketene imines derived from
tert-butyl protected cyanohydrins has been described. Use of
these nucleophiles in Lewis base catalysed aldol additions affords
b-hydroxy cyanohydrins in good yields, high diastereoselectivities
and exceptional enantioselectivities. The ability of N-silyl oxyketene
imines to act as acyl anion equivalents was also demonstrated by
General procedure for the cross-Benzoin reaction of N-silyl oxyketene imines
with aromatic aldehydes. To a flame-dried, 10-ml, single-necked Schlenk flask were
added 21 mg of (R,R)-7 (0.025 mmol, 0.025 equiv.), 102 ml of benzaldehyde
(1.00 mmol) and 5.0 ml of anhydrous CH2Cl2 (0.2 M in aldehyde) under an
atmosphere of argon. The solution was cooled to 278 8C (internal) and then 35 ml
of N,N-diisopropylethylamine (0.2 mmol, 0.2 equiv.) and 130 ml of SiCl4 (1.1 mmol,
1.1 equiv.) were added via syringe. The solution was stirred for 5 min at 278 8C and
then 0.84 ml of a 1.66 M solution of silyl ketene imine 4e (1.4 mmol, 1.4 equiv.) in
anhydrous CH2Cl2 was added dropwise via syringe. The reaction mixture was stirred
for 2 h at 278 8C and then 135 ml of CH3OH (3.3 mmol, 3.3 equiv.) was added. The
quenched reaction mixture was stirred for 30 min at 278 8C and then warmed to
0 8C and stirred for 1.5 h before being transferred to a stirred, sat. aq. solution of
NaHCO3 (10 ml) and KF (10 ml). The biphasic mixture was stirred vigorously for
2 h at room temperature and then filtered through a pad of Celite and transferred to
a separatory funnel where the organic layer was removed. The aqueous layer was
extracted with CH2Cl2 (2 × 20 ml) and the organic extracts were combined,
washed with brine (1 × 25 ml), and dried over Na2SO4. The solution was filtered
and concentrated in vacuo to produce a crude white solid that was purified by
column chromatography (25 g silica gel, CH2Cl2/Et2O, 40:1) to afford 200 mg of
9ea (88%) as a white solid. The solid was further purified by recrystallization from
merely altering the conditions of the reaction work-up. This hot toluene (ꢁ5 ml) to provide 190 mg (84%) of fine, white needles. The
942
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© 2010 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.857
ARTICLES
enantiomeric ratio was determined to be 99.4:0.6 by CSP-SFC analysis of the
chromatographically homogeneous material and .99:1 after recrystallization.
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Received 7 June 2010; accepted 19 August 2010;
published online 3 October 2010
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Acknowledgements
The authors are grateful to the National Science Foundation (NSF CHE-0414440 and
0717989) for financial support. T.W.W. thanks Abbott Laboratories for a Graduate
Fellowship in Synthetic Organic Chemistry.
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Author contributions
T.W.W. planned and carried out the experimental work. S.E.D. initiated and directed the
project. The manuscript was written jointly by the authors.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to S.E.D.
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