Construction of quaternary stereogenic carbon centers by the Lewis base catalyzed conjugate addition of silyl ketene imines to α,β- unsaturated aldehydes and ketones

Article abstract of DOI:10.1055/s-0029-1219963

Highly site-selective Mukaiyama-Michael additions of silyl ketene imines to α,β-unsaturated aldehydes and ketones are described. The combination of silicon tetrachloride and a chiral bisphosphoramide provides an effective catalyst system for promoting the addition of silyl ketene imines to a variety of aromatic enals with high site selectivity and moderate to good diastereo- and enantioselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219963

CLUSTER
1723
Construction of Quaternary Stereogenic Carbon Centers by the Lewis Base
Catalyzed Conjugate Addition of Silyl Ketene Imines to a,b-Unsaturated
Aldehydes and Ketones
C
onstruction o
c
f
Quaternar
o
y Stereogen
t
ic Carb
t
on Centers E. Denmark,* Tyler W. Wilson
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Fax +1(217)3333984; E-mail: sdenmark@illinois.edu
Received 11 May 2010
Lewis basic oxygen (anti vs. syn, Scheme 1) and also con-
Abstract: Highly site-selective Mukaiyama–Michael additions of
silyl ketene imines to a,b-unsaturated aldehydes and ketones are de-
scribed. The combination of silicon tetrachloride and a chiral bis-
phosphoramide provides an effective catalyst system for promoting
trol the conformation of the conjugated double bonds in
the acceptor (s-cis vs. s-trans, Scheme 1).4 In recent years,
creative solutions to these challenges have appeared that
the addition of silyl ketene imines to a variety of aromatic enals with provide Michael addition products containing quaternary
stereogenic carbons in good yield and high selectivity.1,2
high site selectivity and moderate to good diastereo- and enantiose-
lectivity.
Key words: Lewis base, asymmetric catalysis, Michael addition,
aldehydes, quaternary carbon
MLn
MLn
O
O
MLn
MLn
O
O
R1
R1
R1
R2
R1
R2
R2
R2
s-trans, syn
The catalytic, enantioselective synthesis of compounds
containing quaternary stereogenic carbon centers contin-
ues to provide organic chemists with challenges for cata-
lyst design and reaction development.1 The key issue in
the construction of these centers is to identify catalyst sys-
s-trans, anti
s-cis, syn
s-cis, anti
Scheme 1
tems that can overcome the substantial steric encum- Despite these achievements some limitations still exist for
brance encountered in the carbon–carbon bond-forming certain combinations of donors and acceptors. For exam-
event, while still providing an effective environment for ple, existing methods are limited to readily enolizable car-
obtaining high asymmetric induction. Although a number bonyl compounds, such as b-keto esters, a-cyano ketones,
of elegant solutions have recently been devised for and b-diketones in combination with acyclic and cyclic
achieving this goal, certain types of reaction frameworks ketones. The addition of simple ketones, esters or nitriles
still present significant obstacles and provide platforms to a,b-unsaturated aldehydes or ketones finds no general
for novel catalyst design and innovation in synthetic solution for the synthesis of quaternary stereogenic car-
methods.
bon centers because of the problem of controlling enolate
geometry.5 One notable exception is the work of Yama-
moto et al. on the Mukaiyama variant of the Michael
addition6 of silyl enol ethers to a,b-unsaturated acyl phos-
phonates catalyzed by tethered bis(8-quinolato)aluminum
complexes.7 In this report, the authors obtained 1,4-addi-
tion products in moderate to good yield and with high
enantioselectivity; however, the reaction scope was limit-
ed to cyclic enol ethers and acyl phosphonate electro-
philes. This single accomplishment notwithstanding, no
methods for the catalytic, enantioselective Mukaiyama–
Michael (MM) addition of simple unsaturated aldehydes
or ketones with acyclic, disubstituted nucleophiles are on
record.8,9
An important transformation that presents promising op-
portunities for setting quaternary stereogenic centers is
the Michael reaction.2 This venerable process has long
been recognized as one the most reliable methods for car-
bon–carbon bond formation as it allows for the prepara-
tion of the synthetically useful class of 1,5-dicarbonyl
compounds. Moreover, the high exothermicity of the cat-
alytic Michael reaction provides the energy needed to
overcome the steric strain of setting a quaternary center.
The successful implementation of a catalytic, enantiose-
lective variant of this reaction3 requires a catalyst that can
control the relative and absolute topicity for the combina-
tion of two fully substituted sp2 centers. For activation of
the nucleophile, the catalyst has to control the configura- Recent studies from these laboratories10 and others11 have
tion of a disubstituted enolate. On the other hand, activa- documented the use of silyl ketene imines (SKIs) for the
tion of the electrophile requires the catalyst to be catalytic, enantioselective construction of quaternary ste-
coordinated selectively at one of the binding sites of the reogenic carbon centers. These nucleophiles possess a
pair of orthogonal substituent planes that place the bulky
silyl group in a region perpendicular and distal to the re-
active carbon. Because of this unique geometry, SKIs are
less hindered than carbonyl derived enolates and are thus
SYNLETT 2010, No. 11, pp 1723–1728
Advanced online publication: 10.06.2010
DOI: 10.1055/s-0029-1219963; Art ID: Y00710ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1724
S. E. Denmark, T. W. Wilson
CLUSTER
R3
O
R2
NC
OH
R2
R1
R3
N
TBS
C
R1
H
O
NC
R1
and/or
R3
catalyst
R2
H
1,4-adduct
1,2-adduct
Scheme 2
very reactive nucleophiles. In addition, the orthogonal greatly influence the site of addition in this reaction
planes obviate the problems of producing geometrically (Table 1, entry 3). The aromatic enone (E)-4-phenyl-3-
defined, disubstituted enoxysilane nucleophiles.5 The buten-2-one reacted exclusively via 1,4-addition, and the
Mukaiyama–Michael reaction of SKIs with unsaturated resulting ketone product 10 was isolated in good yield, but
aldehydes would produce g-cyano aldehydes containing a poor diastereoselectivity (Table 1, entry 4). Interestingly,
quaternary stereogenic carbon center (Scheme 2). These the enantioselectivity differed greatly within each diaste-
compounds can be versatile synthetic intermediates, as reomer; moderate er was obtained for the favored syn-di-
manipulation of the aldehyde and nitrile functional groups astereomer, whereas the minor anti-diastereomer was
could provide access to lactones, lactams, and pipe- racemic. This observation is consistent with a stereochem-
ridines.12
ical model in which each diastereomer is formed from dif-
ferent enone–catalyst bound complexes (Scheme 1);
however, other scenarios that account for the selectivity
cannot be ruled out at this time.18 Additional classes of
Early studies by Frainnet and co-workers on the uncata-
lyzed reactions of diphenyl silyl ketene imines with vari-
ous carbonyl acceptors show the tendency of this
nucleophile to undergo selective 1,4-additions with a,b-
unsaturated aldehydes such as crotonaldehyde and cinna-
maldehyde.13 Despite this promising result, no subsequent
reports have appeared on the enantioselective 1,4-addi-
tions of SKIs to conjugated carbonyl compounds. Herein
we report our initial studies on the Lewis base catalyzed,
SiCl4-mediated additions of disubstituted silyl ketene imi-
nes to a,b-unsaturated aldehydes and ketones for the cat-
Table 1 Survey of a,b-Unsaturated Electrophiles in the 1,4-Addi-
tion of SKI-1 Catalyzed by 5 mol% (R,R)-2
Me
SiCl4 (1.1 equiv)
(R,R)-2 (5 mol%)
Ph
NC
N
TBS
C
Ph
E
+
E
R
CH2Cl2, –78 °C, 2 h
E = CHO, COMe
Me
R
7–10
1
3–6
Me
alytic,
diastereoselective,
and
enantioselective
O
N
construction of quaternary stereogenic centers.
P
CH2
N
N
The combination of SiCl4 and a chiral, nonracemic bis-
phosphoramide is a highly effective catalyst system for
the enantioselective 1,2-addition of a number of different
silylated nucleophiles with aldehydes.14,15 Although a,b-
unsaturated aldehydes are known to be effective electro-
philes under these reaction conditions, selective 1,4-addi-
tion has rarely been observed with this catalyst system.16
To test the ability of SKIs to participate in a MM-type ad-
dition, 2-phenylpropanenitrile derived SKI 1 was pre-
pared by lithiation of the nitrile followed by trapping with
TBSCl and its reactivity was assayed in the addition to
cinnamaldehyde under the catalytic action of SiCl4 and
bisphosphoramide (R,R)-2 (Table 1, entry 1).17 Gratify-
ingly, the major product obtained after hydrolysis of the in
situ formed trichlorosilyl enol ether, resulted from selec-
tive 1,4-addition (92:8) and was produced in good yield
and with moderate diastereo- and enantioselectivity. On
the basis of this encouraging result, a broader survey of
a,b-unsaturated electrophiles was carried out (Table 1).
Me
Me
(R,R)-2
2
Entry Product
Yield (%)a 1,4/1,2b drb
erc
Me
Ph
NC
O
1
2
3
4
84
74
78
80
92:8
92:8
48:52
99:1
82:18 72:28
84:16 51:49
Ph
H
7
Me
Ph
O
O
O
NC
Me
Me
H
8
Ph
n.a.
55:45
NC
Me
Me
H
9
Me
Ph
Ph
54:46 80:20d
NC
a,b-Unsaturated aldehydes and ketones bearing both ali-
phatic and aromatic substituents underwent highly site-se-
lective 1,4-additions in good yield (Table 1, entries 1–4).
However, the stereoselectivity of the reactions were poor
for the cases of aliphatic enals such as crotonaldehyde
(Table 1, entry 2). Moreover, when the b-disubstituted
electrophile 3-methyl-2-butenal was tested, competitive
1,2-addition was observed, suggesting that steric effects
Me
10
a Overall yield of chromatographically homogeneous material.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Determined by CSP-SFC analysis on the major diastereomer after
NaBH4 reduction to the corresponding alcohol.
d CSP-SFC analysis performed on the cyano ketone. Minor diastereo-
mer er was determined to be 54:46 by CSP-SFC.
Synlett 2010, No. 11, 1723–1728 © Thieme Stuttgart · New York

CLUSTER
Construction of Quaternary Stereogenic Carbon Centers
1725
conjugated electrophiles, including a,b-unsaturated es- lectivities, but with increased diastereoselectivities. To
ters, nitriles, and nitroalkenes were also tested, but proved rule out whether the modest enantioselectivity was arising
unreactive under these reaction conditions.
from a competitive achiral background reaction, the addi-
tion was carried out at higher catalyst loading (Table 2,
entry 9). Performing the reaction with 15 mol% (R,R)-2
produced the 1,4-product in similar yield and selectivities
as compared to previous runs with 5 mol% catalyst.19 The
result demonstrates that even at 3× the loading of (R,R)-2,
no significant change in the enantioselectivity of the reac-
tion is observed, suggesting that the low selectivity is not
solely resulting from an uncatalyzed pathway. Alternative
explanations that could account for the moderate enanti-
oselectivity are that the catalyst modifications are not far
reaching enough to influence addition at the b-carbon of
the enal, and/or the reaction is proceeding through multi-
ple catalyst–acceptor complexes (Scheme 1).
To optimize the selectivity of the reaction, a survey of
Lewis base catalysts was performed (Table 2). The series
of catalysts tested in the 1,4-addition examined the sensi-
tivity of the reaction to a number of different structural
features of the parent phosphoramide catalyst (R,R)-2, in-
cluding: (1) the alkyl group on the nitrogens of both the bi-
naphthyldiamine and the diamine tether (Table 2, entries
2–4), (2) the tether length (Table 2, entry 1), (3) mono-
meric catalyst (Table 2, entry 6), and (4) the dihedral an-
gle of the biaryl unit (Table 2, entry 5 and entries 7 and 8).
Unfortunately, none of the structural modifications result-
ed in a significant increase in the enantioselectivity of the
addition. Surprisingly though, both the reduced dimeric
catalyst (Table 2, entry 5) and the biphenyl-derived cata-
lysts (Table 2, entries 7 and 8) afforded the 1,4-addition
products in similar yields, site selectivities, and enantiose-
The final study examined the scope of the reaction with
respect to the aryl substituent of the a,b-unsaturated alde-
hyde. In view of the beneficial effect of the biphenyl-
based catalyst on the diastereoselectivity, reactions were
carried out with 5 mol% of bisphosphoramide (R,R)-17.
Additionally, N,N-diisopropylethylamine was employed
in these reactions to scavenge any adventitious HCl
(formed by hydrolysis of SiCl4), which could be acting as
a promoter for an achiral background reaction. Under this
new set of reaction conditions the addition of SKI 1 to a
variety of commercially available b-aryl enals was con-
ducted (Table 3). The results of this study show that both
electron-rich and heteroaromatic enals undergo selective
1,4-addition in good yield and with moderate to good
diastereo- and enantioselectivity.
Table 2 Phosphoramide Catalyst Survey in the 1,4-Addition of SKI
1 with Cinnamaldehyde
SKI 1 (1.2 equiv)
SiCl4 (1.1 equiv)
11–18 (5 mol%)
Me
Ph
NC
Ph
O
O
CH2Cl2, –78 °C, 2 h
H
Ph
H
R1
R1
O
N
O
N
N
P
N
P
N
n
N
R2
CH2
R1
R1
One intriguing result that the survey revealed is that sub-
stitution on the aryl ring does affect the enantioselectivity
of the reaction. This influence was clearly exemplified by
the difference in enantiomeric ratio observed for the addi-
tion to (E)-3-(2-methoxyphenyl)propenal (Table 3, entry
4, 86:14 er) vs. (E)-3-(4-methoxyphenyl)propenal
(Table 3, entry 2, 72:28 er). The addition to a-methylcin-
namaldehyde illustrates the ability of this reaction to set
multiple stereogenic centers in a single reaction (Table 3,
entry 6). Furthermore, this example demonstrates that
protonation of the in situ formed trichlorosilyl enol ether
occurs with fairly high diastereoselectivity and suggests
that tandem processes could be developed that harness the
reactivity of the direct product formed under the reaction
conditions.20
(R,R)-16
2
(R,R)-2 R1,R2 = Me, n = 2
(R,R)-11 R1,R2 = Me, n = 1
R
Me
(R,R)-12 R1 = Et, R2 = Me, n = 2
(R,R)-13 R1 = i-Pr, R2 = Me, n = 2
(R,R)-14 R1 = Me, R2 = Et, n = 2
(S,S)-15 R1,R2 = Me n = 2, H8-BINAM
O
N
Me
Me
P
CH2
N
N
Me
Me
2
R
(S,S)-17 R = H
(R,R)-18 R = 3,5-(CH3)2C6H3
Entry
Catalyst
(R,R)-11
(R,R)-12
(R,R)-13
(R,R)-14
(S,S)-15
(R,R)-16
(S,S)-17
(R,R)-18
(R,R)-2
1,4/1,2a
94:6
dra
erb
1
2
3
4
5
6
7
8
9
82:18
80:20
78:22
82:18
90:10
85:15
91:9
64:36
65:35
52:48
69:31
65:35
60:40
68:32
70:30
74:26c
80:20
75:25
91:9
The syn relative configuration of the major diastereomer
resulting from 1,4-addition of SKI 1 to cinnamaldehyde
was unambiguously established by single crystal X-ray
analysis of the product.21 However, the depicted absolute
configuration is assumed from a Re-face addition of the
SKI to the enal bound in an s-cis conformation to the
Lewis base–catalyst complex. Although this assignment
employs the stereochemical model developed from previ-
ous mechanistic and computational studies on 1,2-addi-
tions to aldehydes catalyzed by (R,R)-2/SiCl4, it has not
been unequivocally confirmed for this reaction.22
92:8
92:8
94:6
92:8
90:10
90:10
92:8
a Determined by 1H NMR analysis of the crude mixture.
b Determined by CSP-SFC analysis on the major diastereomer result-
ing after NaBH4 reduction to the corresponding alcohol.
c Reaction ran with 15 mol% catalyst.
Synlett 2010, No. 11, 1723–1728 © Thieme Stuttgart · New York

1726
S. E. Denmark, T. W. Wilson
CLUSTER
Table 3 Survey of Aryl Enals in the Addition of SKI 1 Catalyzed by (R,R)-17
SiCl4 (1.0 equiv)
i-Pr2EtN (1.1 equiv)
(R,R)-17 (5 mol%)
R
Me
R
Ph
NC
N
TBS
C
Ph
O
Aryl
O
+
CH2Cl2, –78 °C, 2 h
Me
Aryl
7, 24–28
H
H
1
3, 19–23
Entry
Aryl
Ph
R
Product
7
Yield (%)a
1,4/1,2b
92:8
drb
erc
1
2
3
4
5
6
H
84
79
94
83
78
86
90:10
91:9
70:30
72:28
59:41
86:14d
79:21
69:31f
4-MeOC6H4
4-Me2NC6H4
2-MeOC6H4
2-furyl
H
24
95:5
H
25
95:5
68:32
68:32
81:19
84:10:4:2e
H
26
95:5
H
27
92:8
Ph
Me
28
93:7
a Overall yield of chromatograpically homogeneous material.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Determined by CSP-SFC analysis on the major diastereomer after NaBH4 reduction to the corresponding alcohol.
d Minor diastereomer er was determined to be 73:27 by CSP-SFC.
e The relative configuration at the a-stereogenic center could not be assigned.
f The er of 82:18 was obtained with 5 mol% (R,R)-2.
H), 3.63 (dd, J = 10.8, 3.5 Hz, 1 H), 3.17 (dd, J = 17.7, 10.8 Hz, 1
H), 2.58 (dd, J = 17.6, 3.5 Hz, 1 H), 1.48 (s, 3 H). 13C NMR (126
MHz, CDCl3): d = 199.0, 139.2, 137.8, 129.1, 129.0, 128.7, 128.3,
128.1, 125.8, 121.7, 49.0, 47.2, 45.7, 26.4. ESI-HRMS: m/z calcd
for C18H17NONa+: 286.1208; found: 286.1198.
In conclusion, a novel Lewis base catalyzed Mukaiyama–
Michael reaction has been described for the generation of
quaternary stereogenic carbon centers via the 1,4-addition
of silyl ketene imines to a,b-unsaturated aldehydes and
ketones. The reactions are selective for 1,4-addition and
yield aldehyde or ketone products in moderate to good
yield and diastereoselectivity and with moderate enan-
tioselectivity. Future work will focus on mechanistic stud-
ies to elucidate the conformation of the bound
electrophile–catalyst complex as well as new Lewis base
catalyst architectures that can engender higher stereose-
lectivities.
General Procedure for NaBH4 Reduction of Aldehydes
Preparationof 5-Hydroxy-2-methyl-2,3-diphenylpentanenitrile
(alc-7)
Aldehyde 7 (98 mg, 0.37 mmol) was dissolved in THF–EtOH (1:1,
3.7 mL, 0.1 M) and then NaBH4 (15 mg, 0.4 mmol, 1.1 equiv) was
added. The heterogeneous mixture was stirred for 15 min and then
was acidified with a few drops of 1 M HCl (pH 3). H2O (10 mL) was
added, the phases were separated, and the aqueous layer was ex-
tracted with EtOAc (2 × 20 mL). The combined organic extracts
were washed successively with NaHCO3 (1 × 20 mL) and brine
(1 × 20 mL), dried over Na2SO4, and then filtered and concentrated
in vacuo. The residue was purified by column chromatography (sil-
ica gel, hexanes–EtOAc, 2:1) to give 98 mg (98%) of alc-7 as a
clear, colorless oil.
General Procedure for the MM Reaction of 1 with Aryl Enals
Preparation of 2-Methyl-5-oxo-2,3-diphenylpentanenitrile (7)
To a flame-dried 10 mL Schlenk flask under Ar were added (R,R)-
2 (42 mg, 0.05 mmol, 0.05 equiv), cinnamaldehyde (126 mL, 1.00
mmol), and anhyd CH2Cl2 (5.0 mL, 0.2 M in enal). The solution was
stirred, cooled to –78 °C, and SiCl4 (130 mL, 1.1 mmol, 1.1 equiv)
and DIPEA (175 mL, 1.0 mmol, 1.0 equiv) were added via syringe.
The resulting solution was stirred for 5 min at –78 °C, and then a
1.38 M solution of SKI 1 (0.87 mL, 1.2 mmol, 1.2 equiv) in CH2Cl2
was added dropwise over 3 min. The reaction mixture was allowed
to stir for 2 h at –78 °C and was then quenched by pouring the cold
solution into a rapidly stirring solution of sat. aq NaHCO3 and KF
(1:1, 20 mL). This biphasic mixture was stirred for 1 h at ambient
temperature before being filtered through Celite. The phases were
separated and the aqueous layer was extracted with CH2Cl2 (3 × 25
mL). The combined organic extracts were dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, hexanes–EtOAc, 8:1) to give 183
mg (70%) of 7 as clear, colorless needles.
Data for Compound alc-7
1H NMR (400 MHz, CDCl3): d = 7.59–7.53 (m, 2 H), 7.46–7.30 (m,
8 H), 3.51–3.31 (m, 1 H), 3.18 (dd, J = 12.1, 3.1 Hz, 2 H), 3.22–3.11
(m, 2 H), 2.18–2.00 (m, 1 H), 1.83–1.66 (m, 1 H), 1.44 (s, 3 H), 1.01
(s, 1 H). 13C NMR (126 MHz, CDCl3): d = 140.2, 138.2, 129.1,
128.9, 128.6, 127.8, 127.8, 125.8, 122.3, 60.1, 51.5, 47.5, 33.8,
26.9. ESI-HRMS: m/z calcd for C18H20NO+: 266.1545; found:
266.1538. SFC: tR = 3.83 min (72.6%); tR = 4.42 min (27.4%) (AD,
125 bar, 8% MeOH in CO2, 3.0 mL/min, 220 nm, 40 °C).
2-Methyl-5-oxo-2,3-diphenylhexanenitrile (10)
1H NMR (500 MHz, CDCl3): d = 7.25–7.21 (m, 1 H), 7.19–7.15 (m,
1 H), 7.13–7.08 (m, 1 H), 6.93 (dd, J = 7.3, 2.0 Hz, 1 H), 3.67 (dd,
J = 9.4, 4.5 Hz, 1 H), 3.18 (dd, J = 17.1, 9.4 Hz, 1 H), 3.09 (dd,
J = 17.1, 4.5 Hz, 1 H), 2.05 (s, 1 H), 1.80 (s, 1 H). 13C NMR (126
MHz, CDCl3): d = 205.7, 138.3, 138.1, 128.9, 128.3, 127.9, 127.8,
127.4, 126.4, 122.7, 50.0, 46.9, 45.5, 30.8, 25.4. ESI-HRMS: m/z
calcd for C19H20NO+: 278.1545; found: 278.1543. SFC: tR = 5.8 min
Data for Compound 7
1H NMR (500 MHz, CDCl3): d = 9.35 (s, 1 H), 7.57 (d, J = 7.9 Hz,
2 H), 7.45 (dd, J = 15.1, 7.7 Hz, 4 H), 7.35 (dt, J = 24.9, 7.2 Hz, 4
Synlett 2010, No. 11, 1723–1728 © Thieme Stuttgart · New York

CLUSTER
Construction of Quaternary Stereogenic Carbon Centers
1727
(79.3%); tR = 6.3 min (20.7%) (Chiralpak AD, 125 bar, 2.5% MeOH
in CO2, 2.25 mL/min, 220 nm, 40 °C).
(t, J = 7.5 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 4.02 (dd, J = 12.4, 3.1
Hz, 1 H), 3.86 (s, 3 H), 3.33 (ddd, J = 10.6, 6.7, 4.0 Hz, 1 H), 3.21–
3.10 (m, 1 H), 2.03 (ddd, J = 13.1, 9.8, 4.8 Hz, 1 H), 1.83–1.64 (m,
1 H), 1.43 (s, 3 H), 1.27 (s, 1 H). 13C NMR (126 MHz, CDCl3):
d = 158.1, 140.8, 128.8, 128.4, 127.7, 127.6, 126.8, 125.9, 122.4,
121.2, 110.5, 60.4, 55.7, 48.1, 40.3, 33.8, 25.9. ESI-HRMS: m/z cal-
cd for C19H22NO2 : 296.1651; found: 296.1644. SFC: tR = 9.1 min
(14.3%); tR = 11.6 min (85.7%) (Chiralpak OD, 125 bar, 5.0%
MeOH in CO2, 2.5 mL/min, 220 nm, 40 °C).
3-(4-Methoxyphenyl)-2-methyl-5-oxo-2-phenylpentanenitrile
(24)
1H NMR (500 MHz, CDCl3): d = 9.34 (d, J = 1.1 Hz, 1 H), 7.56–
7.53 (m, 2 H), 7.43 (dd, J = 10.4, 4.9 Hz, 2 H), 7.36 (d, J = 8.8 Hz,
3 H), 6.90 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.57 (dd, J = 11.0, 3.7
Hz, 1 H), 3.10 (ddd, J = 17.4, 11.0, 2.0 Hz, 1 H), 2.53 (ddd,
J = 17.4, 3.6, 0.6 Hz, 1 H), 1.48 (s, 3 H). 13C NMR (126 MHz,
CDCl3): d = 199.2, 159.3, 139.3, 130.0, 129.6, 129.1, 128.2, 125.7,
121.8, 114.0, 55.2, 48.4, 47.5, 45.7, 26.3. ESI-HRMS: m/z calcd for
C19H19NO2Na+: 316.1313; found: 316.1312.
+
3-(Furan-2-yl)-2-methyl-5-oxo-2-phenylpentanenitrile (27)
1H NMR (500 MHz, CDCl3): d = 9.46 (s, 1 H), 7.51 (d, J = 8.5 Hz,
2 H), 7.47–7.39 (m, 3 H), 7.39–7.32 (m, 1 H), 6.37 (dd, J = 3.1, 1.8
Hz, 1 H), 6.33 (d, J = 3.2 Hz, 1 H), 3.81 (dd, J = 11.2, 3.2 Hz, 1 H),
3.14 (ddd, J = 17.7, 11.2, 1.4 Hz, 1 H), 2.50 (dd, J = 17.8, 3.3 Hz, 1
H), 1.58 (s, 3 H). 13C NMR (126 MHz, CDCl3): d = 198.5, 151.7,
142.3, 138.7, 129.2, 128.4, 125.7, 121.3, 110.6, 108.6, 47.2, 44.3,
5-Hydroxy-3-(4-methoxyphenyl)-2-methyl-2-phenylpentane-
nitrile (alc-24)
1H NMR (500 MHz, CDCl3): d = 7.52 (d, J = 7.4 Hz, 2 H), 7.41 (t,
J = 7.7 Hz, 2 H), 7.35–7.29 (m, 3 H), 6.90 (d, J = 8.8 Hz, 2 H), 3.82
(s, 3 H), 3.43–3.36 (m, 1 H), 3.20–3.15 (m, 1 H), 3.13 (dd, J = 12.2,
3.0 Hz, 1 H), 2.11–1.97 (m, 1 H), 1.76–1.63 (m, 1 H), 1.43 (s, 3 H),
1.16 (s, 1 H). 13C NMR (126 MHz, CDCl3): d = 159.01 140.3,
130.1, 128.9, 127.8, 125.9, 122.4, 113.9, 60.2, 55.2, 50.8, 47.8,
+
42.6, 26.0. ESI-HRMS: m/z calcd for C16H16NO2 : 254.1181;
found: 254.1171.
3-(Furan-2-yl)-5-hydroxy-2-methyl-2-phenylpentanenitrile
(alc-27)
33.8, 26.9. ESI-HRMS: m/z calcd for C19H22NO2 : 296.1651;
1H NMR (500 MHz, CDCl3): d = 7.49 (d, J = 7.4 Hz, 2 H), 7.44–
7.37 (m, 3 H), 7.33 (t, J = 7.3 Hz, 1 H), 6.37 (dd, J = 3.1, 1.9 Hz, 1
H), 6.32 (d, J = 3.2 Hz, 1 H), 3.55–3.45 (m, 1 H), 3.40 (dd, J = 12.2,
3.0 Hz, 1 H), 3.26 (dq, J = 15.2, 5.1 Hz, 1 H), 2.05 (tt, J = 13.4, 4.3
Hz, 1 H), 1.76–1.61 (m, 1 H), 1.54 (s, 3 H), 1.24 (s, 1 H). 13C NMR
(126 MHz, CDCl3): d = 152.6, 142.1, 139.6, 128.9, 128.0, 125.7,
122.0, 110.4, 108.5, 60.0, 47.5, 45.2, 33.1, 26.3. ESI-HRMS: m/z
+
found: 296.1657. SFC: tR = 2.89 min (72.5%); tR = 3.84 min
(27.5%) (AD, 125 bar, 12.5% MeOH in CO2, 3.0 mL/min, 220 nm,
40 °C).
3-[4-(Dimethylamino)phenyl]-2-methyl-5-oxo-2-phenylpen-
tanenitrile (25)
1H NMR (500 MHz, CDCl3): d = 9.34 (dd, J = 1.9, 0.9 Hz, 1 H),
7.55 (d, J = 7.3 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.35 (t, J = 6.8
Hz, 1 H), 7.29 (d, J = 8.7 Hz, 2 H), 6.71 (d, J = 8.8 Hz, 2 H), 3.51
(dd, J = 11.1, 3.8 Hz, 1 H), 3.09 (ddd, J = 17.2, 11.1, 2.2 Hz, 1 H),
2.96 (s, 6 H), 2.49 (ddd, J = 17.2, 3.7, 0.9 Hz, 1 H), 1.49 (s, 3 H).
13C NMR (126 MHz, CDCl3): d = 199.8, 150.2, 139.6, 129.7, 129.1,
128.11, 125.8, 124.8, 122.0, 112.3, 48.6, 47.7, 45.7, 40.4, 26.4. ESI-
HRMS: m/z calcd for C20H23N2O+: 307.1810; found: 307.1801.
calcd for C16H18NO2 : 256.1338; found: 256.1326. SFC: tR = 8.7
+
min (79.0%); tR = 9.4 min (21.0%) (Chiralpak AD, 125 bar, 4.0%
MeOH in CO2, 2.25 mL/min, 220 nm, 40 °C).
2,4-Dimethyl-5-oxo-2,3-diphenylpentanenitrile (28)
1H NMR (500 MHz, CDCl3): d = 9.57 (d, J = 2.5 Hz, 1 H), 7.62 (d,
J = 7.4 Hz, 2 H), 7.45 (t, J = 7.8 Hz, 4 H), 7.40–7.32 (m 4 H), 3.35
(d, J = 7.7 Hz, 1 H), 3.02 (ddq, J = 7.2, 2.4 Hz, 1 H), 1.41 (s, 3 H),
0.76 (d, J = 7.0 Hz, 3 H). 13C NMR (126 MHz, CDCl3): d = 201.9,
140.5, 137.6, 129.4, 129.2, 129.0, 128.2, 125.7, 122.4, 56.8, 49.5,
46.0, 29.2, 14.2. ESI-HRMS: m/z calcd for C19H19NONa+:
300.1364; found: 300.1354.
3-[4-(Dimethylamino)phenyl]-5-hydroxy-2-methyl-2-phenyl-
pentanenitrile (alc-25)
1H NMR (500 MHz, CDCl3): d = 7.53 (d, J = 7.5 Hz, 2 H), 7.40 (t,
J = 7.7 Hz, 2 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2 H),
6.72 (d, J = 8.8 Hz, 2 H), 3.43–3.31 (m, 1 H), 3.18 (dd, J = 14.0, 8.8
Hz, 1 H), 3.05 (dd, J = 12.2, 2.9 Hz, 1 H), 2.96 (s, 6 H), 2.03 (tt,
J = 13.4, 4.8 Hz, 1 H), 1.74–1.61 (m, 1 H), 1.44 (s, 3 H), 1.27 (s, 1
H). 13C NMR (126 MHz, CDCl3): d = 150.0, 140.5, 129.7, 128.8,
127.6, 125.8, 125.5, 122.6, 112.4, 60.4, 50.8, 47.9, 40.4, 33.7, 26.9.
ESI-HRMS: m/z calcd for C20H25N2O+: 309.1967; found: 309.1974.
SFC: tR = 3.5 min (59.4%); tR = 5.70 min (40.6%) (AD, 125 bar,
12.5% MeOH in CO2, 3.0 mL/min, 220 nm, 40 °C).
2,4-Dimethyl-5-hydoxy-2,3-diphenylpentanenitrile (alc-28)
1H NMR (500 MHz, CDCl3): d = 7.60 (d, J = 7.8 Hz, 2 H), 7.45–
7.36 (m, 5 H), 7.32 (t, J = 7.4 Hz, 3 H), 3.55 (dd, J = 10.7, 3.1 Hz,
1 H), 3.25–3.16 (m, 2 H), 2.32–2.22 (m, 1 H), 1.29 (s, 3 H), 0.71 (d,
J = 6.9 Hz, 3 H). 13C NMR (126 MHz, CDCl3): d = 142.0, 139.6,
128.9, 128.7, 127.5, 127.5, 125.5, 123.0, 66.0, 56.3, 45.8, 39.2,
30.4, 17.3. ESI-HRMS: m/z calcd for C19H22NO+: 280.1701; found:
280.1693. SFC: tR = 10.1 min (30.6%); tR = 11.7 min (69.4%)
(Chiralpak AD, 125 bar, 2.5% MeOH in CO2, 2.5 mL/min, 220 nm,
40 °C).
3-(2-Methoxyphenyl)-2-methyl-5-oxo-2-phenylpentanenitrile
(26)
1H NMR (500 MHz, CDCl3): d = 9.27 (s, 1 H), 7.61 (d, J = 7.8 Hz,
2 H), 7.56 (d, J = 7.3 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 2 H), 7.39–7.33
(m, 1 H), 7.33–7.28 (m, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 6.94 (d,
J = 8.3 Hz, 1 H), 4.45 (s, 1 H), 3.91 (s, 3 H), 3.17–2.97 (m, 1 H),
2.50 (dd, J = 17.2, 4.1 Hz, 1 H), 1.49 (s, 3 H). 13C NMR (126 MHz,
CDCl3): d = 199.6, 157.7, 139.8, 129.1, 128.9, 128.1, 127.7, 126.3,
125.8, 121.7, 121.1, 110.7, 55.6, 48.0, 45.5, 38.9, 25.3. ESI-HRMS:
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the National Science Foundation (NSF CHE-
0414440 and 0717989) for generous finical support. T.W.W. thanks
Abbott Laboratories for a Graduate Fellowship in Synthetic Orga-
nic Chemistry.
+
m/z calcd for C19H20NO2 : 294.1494; found: 294.1492.
5-Hydroxy-3-(2-methoxyphenyl)-2-methyl-2-phenylpentane-
nitrile (alc-26)
1H NMR (500 MHz, CDCl3): d = 7.65 (d, J = 7.6 Hz, 1 H), 7.59 (d,
J = 7.5 Hz, 2 H), 7.42 (t, J = 7.7 Hz, 2 H), 7.36–7.22 (m, 2 H), 7.06
Synlett 2010, No. 11, 1723–1728 © Thieme Stuttgart · New York

1728
S. E. Denmark, T. W. Wilson
CLUSTER
(9) For leading references on catalytic, asymmetric synthesis
of secondary and tertiary stereogenic centers using
organocatalyzed MM reactions, see: (a) Brown, S. P.;
Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 1192. (b) Wang, W.; Li, H.; Wang, J. Org. Lett.
2005, 7, 1637. (c) Robichaud, J.; Tremblay, F. Org. Lett.
2006, 8, 597. (d) Borths, C. J.; Carrera, D. E.; MacMillan,
D. W. C. Tetrahedron 2009, 65, 6746.
(10) For additions to aldehydes, see: Denmark, S. E.; Wilson, T.
W.; Burk, M. T.; Heemstra, J. R. Jr. J. Am. Chem. Soc. 2007,
129, 14864.
(11) For additions to acid chlorides and anhydrides, see:
Mermerian, A. H.; Fu, G. C. Angew. Chem. Int. Ed. 2005, 44,
949.
(12) (a) Tennant, G. In Comprehensive Organic Chemistry, Vol.
2; Barton, D. H. R.; Olis, W. D.; Sutherland, I. O., Eds.;
Pergamon: New York, 1979, 539–550. (b) Allen, F. H.;
Garner, S. E. In The Chemistry of Triple Bonded Functional
Groups, Vol. 2; Patai, S., Ed.; Wiley: New York, 1994.
(13) Cazeau, P.; Llonch, J.-P.; Simonin-Dabescat, F.; Frainnet, E.
J. Organomet. Chem. 1976, 105, 145.
(14) For review of Lewis base catalysis, see: Denmark, S. E.;
Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.
(15) (a) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199. (b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am.
Chem. Soc. 2002, 124, 13405. (c) Denmark, S. E.; Fan, Y.
J. Am. Chem. Soc. 2003, 125, 7825. (d) Denmark, S. E.;
Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800.
(e) Denmark, S. E.; Heemstra, J. R. Jr. Org. Lett. 2003, 5,
2303. (f) Denmark, S. E.; Heemstra, J. R. Jr. Synlett 2004,
13, 2411. (g) Denmark, S. E.; Beutner, G. L.; Wynn, T.;
Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774.
(h) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.
(i) Denmark, S. E.; Bui, T. J. Org. Chem. 2005, 70, 10190.
(j) Denmark, S. E.; Heemstra, J. R. Jr. J. Org. Chem. 2007,
72, 5668. (k) Denmark, S. E.; Chung, W.-J. J. Org. Chem.
2008, 73, 4582. (l) Denmark, S. E.; Fujimori, S. In Modern
Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004, Chap. 7.
References and Notes
(1) For recent reviews, see: (a) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105. (b) Douglas, C. J.; Overman,
L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
(c) Trost, B. M.; Chunhui, J. Synthesis 2006, 369. (d) For a
recent monograph, see: Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis;
Christoffers, J.; Baro, A., Eds.; Wiley-VCH: Weinheim,
2005.
(2) For a recent example of a Michael addition reaction to set
quaternary stereogenic centers, see: (a) Kawato, Y.;
Takahashi, N.; Kumagai, N.; Shibasaki, M. Org. Lett. 2010,
12, 1484. For reviews, see: (b) Jautze, S.; Peters, R.
Synthesis 2010, 365. (c) Ref 1d, Chap. 4.
(3) For reviews on catalytic, asymmetric Michael reactions,
see: (a) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, Chap. 31.1.
(b) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000,
569. (c) Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033.
(d) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(e) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M.
Synthesis 2007, 1279.
(4) Bernardi, A.; Karamfilova, K.; Sanguinetti, S.; Scolastico,
C. Tetrahedron 1997, 53, 13009.
(5) For a discussion of these problems and potential solutions,
see: (a) Das, J. P.; Chechik, H.; Marek, I. Nature Chem.
2009, 1, 128. (b) Manthorpe, J. M.; Gleason, J. L. J. Am.
Chem. Soc. 2001, 123, 2091.
(6) (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974,
1223. (b) Oare, D. A.; Heathcock, C. A. In Topics in
Stereochemistry, Vol. 20; Eliel, E. L.; Wilen, S. H., Eds.;
Wiley: New York, 1991, 125–170.
(7) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc.
2007, 129, 742.
(8) For leading references on catalytic, asymmetric synthesis of
secondary and tertiary stereogenic centers using Lewis acid
catalyzed MM reaction, see: (a) Bernardi, A.; Colombo, G.;
Scolastico, C. Tetrahedron Lett. 1996, 37, 8921.
(b) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53,
17015. (c) Kitajima, H.; Katsuki, T. Synlett 1997, 568.
(d) Nishikori, H.; Ito, K.; Katsuki, T. Tetrahedron:
Asymmetry 1998, 9, 1165. (e) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999,
121, 1994. (f) Evans, D. A.; Willis, M. C.; Johnston, J. N.
Org. Lett. 1999, 1, 865. (g) Evans, D. A.; Scheidt, K. A.;
Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123,
4480. (h) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.;
Kubo, M.; Oku, A. Org. Lett. 2001, 3, 2101. (i) Desimoni,
G.; Faita, G.; Filippone, S.; Mella, M.; Zampori, M. G.;
Zema, M. Tetrahedron 2001, 57, 10203. (j) Wang, X.;
Harada, T.; Iwai, H.; Oku, A. Chirality 2003, 15, 28.
(k) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.;
Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68,
10046. (l) Suga, H.; Kitamura, T.; Kakehi, A.; Baba, T.
Chem. Commun. 2004, 1414. (m) Ishihara, K.; Fushimi, M.
Org. Lett. 2006, 8, 1921. (n) Yang, H.; Kim, S. Synlett 2008,
555.
(16) See ref. 15j.
(17) For recent preparation of SKIs, see ref .10.
(18) For example, the observed selectivity could result from a
single catalyst–enone complex if reaction through an achiral
pathway was competitive with the catalyzed addition to form
only one of the diastereomers.
(19) The amount of 15 mol% should equate to 1.73× the rate at 5
mol%, based on kinetic studies of the SiCl4/(R,R)-2 catalyst
system, see: Denmark, S. E.; Eklov, B. M.; Yao, P. J.;
Eastgate, M. D. J. Am. Chem. Soc. 2009, 131, 11770.
(20) Previous studies have shown that trichlorosilyl enolates are
competent nucleophiles for Lewis base catalyzed aldol
additions, see: Denmark, S. E.; Stavenger, R. A. J. Am.
Chem. Soc. 2000, 122, 8837.
(21) The crystallographic coordinates of 7 have been deposited
with the Cambridge Crystallographic Data Centre (CCDC);
deposition no. 776146. These data can be obtained free of
charge from the CCDC via www.ccdc.cam.ac.uk/
data_request/cif.
(22) For computational and mechanistic studies, see ref. 15g. For
a full kinetic analysis, see ref. 19.
Synlett 2010, No. 11, 1723–1728 © Thieme Stuttgart · New York