Asymmetric Conjugate Addition of Grignard Reagents to 3-Silyl Unsaturated Esters for the Facile Preparation of Enantioenriched β-Silylcarbonyl Compounds and Allylic Silanes

Article abstract of DOI:10.1002/chem.201403849

A highly enantioselective conjugate addition of Grignard reagents to 3-silyl unsaturated esters to deliver synthetically useful chiral β-silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched β-hydroxyl esters and the facile access granted to various α-chiral allylic silanes. A plethora of diastereoselective transformations of β-silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity.

Full text of DOI:10.1002/chem.201403849

DOI: 10.1002/chem.201403849
Full Paper
&
Enantioselective Synthesis
Asymmetric Conjugate Addition of Grignard Reagents to 3-Silyl
Unsaturated Esters for the Facile Preparation of Enantioenriched
b-Silylcarbonyl Compounds and Allylic Silanes
Kai Zhao[b] and Teck-Peng Loh*[a, b]
Abstract: A highly enantioselective conjugate addition of
Grignard reagents to 3-silyl unsaturated esters to deliver syn-
thetically useful chiral b-silylcarbonyl compounds was devel-
oped. The synthetic value of this methodology was further
illustrated by the synthesis of enantioenriched b-hydroxyl
esters and the facile access granted to various a-chiral allylic
silanes. A plethora of diastereoselective transformations of
b-silylenolates were also investigated and afforded manifold
organosilanes that contained contiguous stereogenic centers
with excellent enantioselectivity.
Introduction
Enantioenriched organosilanes have received tremendous
attention as versatile building blocks due to their substantial
utility in the construction of an enormous number of natural
products and pharmaceutical agents.[1] In particular, chiral b-si-
lylcarbonyl compounds[2] have been considered one of the
most fascinating synthetic targets due to the potential role of
the CÀSi bond as a hydroxyl precursor (accessed by stereospe-
cific Fleming–Tamao[3,4]oxidation) and its unique ability to
induce a great number of stereoselective organic transforma-
tions at neighboring prostereogenic sites.[5] Over the past few
decades, several pioneering breakthroughs in the synthesis of
enantioenriched b-silylcarbonyl compounds were established
by the groups of Hayashi,[6b,c,7b] Hoveyda,[6g,h,7c] Oestreich,[6d–f]
Riant,[6i] Cꢀrdova,[6j] Jacobsen,[7a] and Lipshutz,[8] which could be
classified as follows:
1) Enantioselective CÀSi bond formation by transition-metal-
catalyzed silyl conjugate addition to a,b-unsaturated
carbonyl compounds (Scheme 1a).[6]
2) Asymmetric CÀC bond formation by 1,4-addition of organo-
zinc reagents, organoboronic acids, or stabilized carbanions
to b-silylsubstituted Michael acceptors (Scheme 1b).[7]
3) Asymmetric hydrosilylation of trisubstituted olefins with
[a] Prof. Dr. T.-P. Loh
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P. R. China)
[b] K. Zhao, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax: (+65)67911961
E-mail: teckpeng@ntu.edu.sg
Scheme 1. Selected examples for the synthesis of chiral b-silylcarbonyl com-
pounds. COD=1,5-cyclooctadiene, BINAP=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl, Salen= 6,6’-((1E,1’E)-((1S,2S)-cyclohexane-1,2-diylbis(azanyl-
ylidene))bis(methanylylidene))bis(2,4-di-tert-butylphenol), PMB=4-methoxy-
benzyl.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403849.
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b-silylesters.[8]
Table 1. Optimization of the reaction conditions.[a]
Despite these remarkable achievements, efforts to explore
novel, efficient, and practical catalytic systems to deliver
enantioenriched b-silylcarbonyl compounds in excellent
enantioselectivity with wider substrate scope still attract
increasing attention among synthetic chemists.
Solvent
T
[oC]
X/Y
n
t
Yield ee
[h] [%][b] [%][c]
In this article, we describe a highly efficient strategy that
uses catalytic CuI and commercially available (R)-(+)-2,2’-bis(di-
p-tolylphosphino)-1,1’-binaphthyl [(R)-Tol-BINAP] to promote
the enantioselective Michael addition of Grignard reagents to
3-silyl unsaturated esters to afford enantioenriched b-silylcar-
bonyl compounds in considerable yields (65–96%) and excel-
lent enantioselectivity [92–99% enantiomeric excess (ee)]. No-
tably, this methodology is compatible with a variety of easily
accessible alkylmagnesium reagents, which renders this proto-
col an attractive and robust option for the preparation of syn-
thetically important enantioenriched b-silylesters with various
aliphatic functional moieties, which are versatile building
blocks for a plethora of organic transformations (Scheme 2).
1
2
3
4
5
6
7
8
9
tBuOMe
tBuOMe
tBuOMe
tBuOMe
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
À40 1:1
5.0 20
51
73
61
75
67
96
91
88
80
81
83
87
89
97
89
93
97
95
À40 1:1.5 5.0 16
À40 1:1.5 2.5 16
À60 1:1.5 2.5 20
À60 1:1.5 2.5 16
À60 1:1.5 2.5 24
À70 1:1.5 2.5 30
À78 1:1.5 2.5 30
tBuOMe/CH2Cl2 (2:1 v/v) À40 1:1.5 2.5 16
[a] Reaction conditions: 1 (0.4 mmol), RMgBr (2.5 equiv), CuI (5 mol%),
(R)-Tol-BINAP (7.5 mol%) in solution under argon, unless otherwise de-
scribed. [b] Isolated yield. [c] Determined by chiral HPLC analysis with
a Daicel Chiralcel OD-H column. The absolute configuration was deter-
mined by comparison of the optical rotation of the products with those
reported in the literature (see ref. [6g]).
when 2:1 tBuOMe/CH2Cl2 was employed as the solvent, the re-
action proceeded efficiently at À408C, with a shortened reac-
tion time, to give the desired product in considerable yield
and enantioselectivity, which made this method more appeal-
ing for practical application (Table 1, entry 9).
With the optimized conditions in hand, a variety of alkyl
Grignard reagents were employed for the conjugate addition
to 1 to investigate the scope of this methodology; the results
are summarized in Table 2.
Scheme 2. Asymmetric conjugate addition of Grignard reagents to 3-silyl
unsaturated esters.
Gratifyingly, for the unbranched alkyl Grignard reagents ex-
amined, the reaction proceeded smoothly to give the desired
products with excellent yields and enantioselectivities (Table 2,
entries 1–6). Relatively bulkier Grignard reagents were also well
tolerated and afforded the corresponding products with excel-
lent yields and enantioselectivities (Table 2, entries 7 and 8).
Notably, Grignard reagents with alkenyl moieties could also
participate in the ACA reaction successfully without any loss of
enantioselectivity (Table 2, entries 9 and 10). For the notorious-
ly less-reactive reagent MeMgBr, the target product could also
be isolated in moderate yield and high enantioselectivity by
employing tBuOMe as the solvent and switching the addition
sequence of the Grignard reagent and substrate (Table 2,
entry 11). To our delight, the catalyst loading could be further
decreased to as low as 2 mol% of CuI and 3 mol% of
(R)-Tol-BINAP without compromising the reactivity or enantio-
selectivity (Table 2, entry 2).
Results and Discussion
Asymmetric conjugate addition of Grignard reagents to
3-silyl unsaturated esters
Interestingly, although Grignard reagents are one of the most
commonly used organometallic reagents, their role as nucleo-
philes in copper-catalyzed asymmetric conjugate addition
(ACA) reactions has only received considerable attention in the
past decade,[9] with several significant contributions
established by the groups of Feringa,[10] Alexakis,[11] Hall,[12]
Tomioka,[13] Schmalz,[14] and our group.[15]
Guided by our previous success when the CuI/Tol-BINAP
system was used to promote ACA of Grignard reagents to a,b-
unsaturated esters, the reaction of EtMgBr with 3-silyl unsatu-
rated methyl ester 1a catalyzed by this system was investigat-
ed to ascertain the optimal reaction conditions (Table 1). The
optimal ratio of CuI/Tol-BINAP was found to be 1:1.5, in
agreement with our previous reports.[15a]
It is also notable that when Z enoate 1b was employed, the
absolute stereochemistry of the product was totally reversed
to afford the enantiomer of 2a in considerable yield and excel-
lent enantioselectivity (Table 2, entry 12). The plausible de-
crease of the enantioselectivity ascribed to Z–E isomerization
was not observed in this case.
After scrutiny of the effects of solvents, temperature, and
amount of Grignard reagent, we determined that the reaction
performed in CH2Cl2 at À788C gave the optimal combination
of yield and enantioselectivity (Table 1, entry 8). Moreover,
One of the most important uses of enantioenriched b-silyles-
ters 2 is the synthesis enantiopure secondary b-hydroxyl esters
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for example, oxidation of chiral
boronate derivatives[12] or enan-
tioselective acetate aldol and Re-
formatsky reactions (which are
less compatible with aliphatic
substrates).[16]
Table 2. Substrate scope for the asymmetric conjugate addition of Grignard reagents to 3-silyl unsaturated
esters.[a]
Substrate
RMgBr
Product
Yield
of 5 [%][b]
ee
[%][c]
Enantioselective synthesis of
allylic silanes
1
EtMgBr
88
75
86
97
95
97
Enantiomerically enriched allylic
silanes are increasingly attractive
compounds in modern synthetic
chemistry as ubiquitous building
blocks for the construction of
various complex molecules.[17]
Recently, a large number of
synthetic methodologies for the
preparation of chiral allylic si-
lanes have been successfully em-
ployed.[18] Nevertheless, efforts
to develop new strategies to de-
liver structurally versatile allylic
silanes with excellent site- and
2[d]
3
1a
1a
EtMgBr
2a
CH3(CH2)3MgBr
4
5
1a
1a
CH3(CH2)4MgBr
CH3(CH2)5MgBr
84
93
97
96
6
7
8
9
1a
1a
1a
1a
CH3(CH2)6MgBr
Ph(CH2)3MgBr
85
73
89
90
96
99
98
93
enantio-selectivities
highly sought after.
remains
To further illustrate the poten-
tial utility of the enantioenriched
b-silylester
2
generated by
ACA of
copper-catalyzed
Grignard reagents to 3-silyl unsa-
turated esters, we demonstrate
a facile synthetic route towards
a variety of chiral allylic silanes.
In this protocol, the chiral b-sily-
lester 2 was converted to the
corresponding alcohol 5, which
10
1a
1a
96
65
78
91
97
93
94
92
11[e]
12
MeMgBr
EtMgBr
EtMgBr
could
successfully
undergo
Grieco dehydration[19] to give the
desired allylic silanes 6 in moder-
ate yield and excellent enantio-
selectivity (Table 3).
13
[a] Reaction conditions: 1 (0.4 mmol), RMgBr (2.5 equiv), CuI (5 mol%), (R)-Tol-BINAP (7.5 mol%) in CH2Cl2 under
argon, unless otherwise described. [b] Isolated yield. [c] Determined by chiral HPLC analysis with a Daicel Chir-
alcel OD-H column. [d] Catalyst loading: CuI (2 mol%)/(R)-Tol-BINAP (3 mol%). [e] Reaction conditions: MeMgBr
was added dropwise to a solution of CuI/(R)-Tol-BINAP complex in tBuOMe, then substrate 1a was added drop-
wise over 1 h at À408C.
A plethora of enantioenriched
tertiary allylic silanes with vari-
ous aliphatic substituents were
obtained with excellent enantio-
selectivities and moderate yields
(Table 3, entries 1–6). In addition,
substrates with alkenyl moieties
by stereospecific transformation of the silyl group into a hy-
droxyl group by Fleming–Tamao oxidation. The oxidation of
enantiopure 2g could be smoothly executed at gram scale
under very mild conditions to give the enantioenriched b-hy-
droxyl ester 4 in excellent yield with retention of the absolute
configuration (Scheme 3). This methodology manifests an alter-
native approach for the preparation of alkyl-substituted b-hy-
Scheme 3. Stereospecific oxidation of the CÀSi bond for the systhesis of
b-hydroxyl ester. m-CPBA=meta-chloroperbenzoic acid.
droxyl esters, which complements existing synthetic methods,
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Table 3. The facile synthesis of enantioenriched allylic silanes.[a]
Substrate
Product
Yield [%][b]
56
ee [%][c]
1
2
3
2a
97
2b
2c
60
71
97
96
Scheme 5. Gram-scale preparation of cyclic allylic silane 7i.
cient and robust tools to access chiral cyclic allylic silanes be-
cause of the considerable yield and excellent enantioselectivity
of the reaction.
4
5
2d
2 f
57
63
96
99
Diastereoselective transformations of enantioenriched
b-silylcarbonyls
6
7
8
2g
2h
2i
68
62
64
98
Aside from its potential capability as a masked hydroxyl surro-
gate, the phenyldimethylsilyl group in b-silylenolates could
also act as a robust tool to induce extraordinary diastereoselec-
tive control during electrophilic attack on neighboring proster-
eogenic carbon centers. Guided by this principle, we proceed-
ed to investigate the utility of enantioenriched b-silylester 2 in
a series of diastereoselective transformations, which included
diastereoselective alkylation with MeI,[21] aldol reaction with al-
dehydes,[22] and condensation with imines.[23] Manifold
enantioenriched chiral silanes with up to three stereogenic
centers were obtained with excellent diastereo- and enantio-
selectivities (Scheme 6).[24]
93[d]
97[d]
[a] Reaction conditions: 2 (0.3 mmol), LiAiH4 (0.36 mmol), 2-nitrophenyl-se-
lenocyanate (0.36 mmol), P(n-Bu)3 (0.36 mmol), pyridine (0.6 mmol), H2O2
(3.0 mmol), unless otherwise described. [b] Isolated yield. [c] Determined
by chiral HPLC analysis of the corresponding alcohol 5 generated by the
hydroboration–oxidation reaction of 6. [d] Enantioselectivity was
determined from the ee of the corresponding precursors 2 and 5.
In these reactions, the excellent diastereoselectivity between
the chiral center that carries the b-silyl group and its neighbor-
Scheme 4. The synthesis of cyclic allylic silanes 7h and 7i by ring-closing
metathesis. Mes=mesityl.
tolerated the oxidative conditions of the Grieco dehydration
and gave the target allylic silanes 6 with excellent enantiose-
lectivity (Table 3, entries 7 and 8), which could be readily sub-
jected to ring-closing metathesis[20] to deliver enantiomerically
pure cyclic allylic silanes 7h and 7i in excellent yield
(Scheme 4).
Intriguingly, this approach is suitable for gram-scale synthe-
sis without deterioration of the yield or enantioselectivity
(Scheme 5), which allows it to serve as one of the most effi-
Scheme 6. Diastereoselective transformations of enantioenriched b-silylcar-
bonyl compounds. LDA=lithium diisopropylamide.
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construct enantioenriched b-si-
lylcarbonyls 9 with three contig-
uous stereocenters. The steric
hindrance posed by the phenyl-
dimethylsilyl group effectively di-
rected the electrophilic attack of
the aldehyde from its anti posi-
Scheme 7. Transition-state model for the diastereoselective transformation.
tion, which led to good stereo-
control between C2 and C3. On
ing prostereogenic site could be rationalized by the transition
state of the b-silylenolates (Scheme 7).[21] The transition state
TS1 is more favorable than TS2 because of the minimized A1,3-
allylic strain. Electrophilic attack would then occur anti to the
bulky phenyldimethylsilyl group and lead to formation of the
desired products in a highly diastereoselective manner.
the other hand, the Z-configured magnesium enolate, formed
preferentially at low temperatures, contributed to the excellent
diastereoselectivity between C2 and C3’.[30] To our delight, the
tandem 1,4-addition/aldol reaction proceeded smoothly and
gave the desired product with three contiguous stereocenters
in good yield and excellent enantioselectivity in one pot,
rather than by the two-step protocol depicted in Scheme 6b.
In addition, eight stereoisomers could be generated in this
process but only two were predominantly observed and, in
most cases, product 9 was isolated as the major product with
moderate-to-good diastereoselectivity (Table 4).
One-pot catalytic asymmetric 1,4-addition/aldol reactions
Catalytic enantioselective one-pot tandem reactions have at-
tracted increasing attention because of their unique abilities to
construct polyfunctionalized molecules with multiple stereo-
genic centers from simple pro-
chiral building blocks.[25] Among
Table 4. The trapping of the magnesium enolate formed in situ by tandem 1,4-addition/aldol reaction.[a]
these reactions, the cascade 1,4-
addition/aldol reaction repre-
sents a particularly attractive cat-
egory because of its wide-spread
application in the synthesis of
a number of biologically impor-
tant natural products.[26] Never-
theless, the construction of mul-
tiple stereogenic centers in acy-
clic systems has proven to be
a challenging task due to the
difficulty of controlling the ge-
ometry of the acyclic enolate in-
termediates.[26a] Recently, several
stunning examples of copper-
catalyzed asymmetric domino
conjugate-addition/electrophilic-
trapping reactions applied to
acyclic substrate were disclosed,
which afforded a variety of mul-
tifunctional compounds that
contained contiguous stereocen-
ters with excellent diastereo-
and enantio-control.[27–29] Encour-
aged by these exciting break-
throughs, we proceeded to in-
vestigate the one-pot tandem
1,4-addition/aldol reaction by
employing b-silylated enoate 1a
as the substrate. We envisioned
that the magnesium enolate
generated in situ from the Mi-
chael addition could be success-
fully trapped by the aldehyde to
RMgBr
Yield
[%][b]
Products[c]
d.r.[d]
(9/9’)
ee [%][e]
9 (9’)
1
2
3
4
5
EtMgBr
65
68
66
58
70
81:19
83:17
78:22
72:28
67:33
99 (99)
94 (94)
98 (98)
99 (99)
98 (98)
[a] Reaction conditions: 1a (0.4 mmol), RMgBr (2.5 equiv), CuI (5 mol%), (R)-Tol-BINAP (7.5 mol%), and 4-bromo-
benzaldehyde (1.6 mmol) in solution under argon, unless otherwise described. [b] Isolated yield. [c] The relative
1
and absolute configurations were assigned by H NMR analysis of the acetonide derivatives (see the Supporting
Information for details). [d] Diastereomeric ratio determined from the 1H NMR spectrum of the crude product.
[e] Determined by chiral HPLC analysis.
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Compound 2a: Colorless oil; 88%; 97% ee determined by HPLC:
Daicel Chiralcel OD-H column, hexane/isopropanol=99.8:0.2, flow
rate 1.0 mLminÀ1, l=220 nm, retention time (tR)=7.887 (minor),
13.868 min (major); [a]2D0 =+10.1 (c=1.25 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.51–7.49 (m, 2H; ArH), 7.35–7.34 (m, 3H;
ArH), 3.58 (s, 3H; OCH3), 2.34 (dd, J=15.5, 5.3 Hz, 1H), 2.25 (dd, J=
15.6, 8.3 Hz, 1H), 1.56–1.50 (m, 1H), 1.42–1.26 (m, 1H), 0.87 (t, J=
7.2 Hz, 3H), 0.29 ppm (s, 6H; 2ꢂSiCH3); 13C NMR (100 MHz, CDCl3):
d=174.90, 138.13, 134.05, 129.13, 127.88, 51.55, 34.51, 23.98,
23.23, 13.62, À3.94, À4.18 ppm; IR (KBr): n˜ =2960, 2937, 1734,
1459, 1436, 1428, 1354, 1259, 1250, 1198, 1152, 1112, 1016, 812,
701 cmÀ1; HRMS (ESI): m/z calcd for C14H23O2Si: 251.1467 [M+H+];
found: 251.1461.
Conclusion
We have outlined a highly efficient enantioselective conjugate
addition of Grignard reagents to silylated enoates catalyzed by
CuI/(R)-Tol-BINAP, which provides an attractive, efficient, and
concise route to alkyl-substituted enantioenriched b-silylesters.
The potential synthetic value of this methodology was exem-
plified by a mild CÀSi bond oxidation to delivered enantioen-
riched b-hydroxyl esters and by the facile entry to various syn-
thetically valuable acyclic and cyclic allylic silanes. A plethora
of diastereoselective transformations of b-silylcarbonyl com-
pounds, which included alkylation, one-pot tandem 1,4-addi-
tion/aldol reaction, and ester–imine condensation were investi-
gated to further highlight the application of this methodology
to construct various synthetically important enantiopure
organosilanes that contain multiple stereogenic centers.
Experimental procedure for the stereospecific Fleming–
Tamao oxidation (4)
A solution of 2g (1.02 g, 3.5 mmol) in Et2O (6.0 mL) was added to
an oven-dried Schlenk tube equipped with a stirrer bar. BF4·Et2O
(580 mL) was added at 08C. The mixture was warmed to RT over
10 min. After stirring for 2 h at RT, the reaction was quenched with
cold water (10 mL). The mixture was extracted with Et2O (3ꢂ
20 mL), the combined organic phases were washed with brine
(30 mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure to give the corresponding fluorosilane 3, which
was directly subjected to the next step without further purification.
m-CPBA (1.5 g, 80% purity) and anhydrous potassium fluoride
(470 mg, 8.1 mmol) were added to a solution of crude fluorosilane
(766 mg, 3.3 mmol) in freshly distilled DMF (15.0 mL). The suspen-
sion was stirred for 3 h at RT and diluted with CH2Cl2 (200 mL). The
mixture was washed successively with a saturated aqueous solu-
tion of Na2S2O3 (20 mL), a saturated aqueous solution of NaHCO3
(20 mL), water (10 mL), and brine (10 mL). The combined organic
phases were dried over MgSO4, filtered, and concentrated under
reduced pressure to give the crude product as a viscous oil, which
was purified by column chromatography (1:5 Et2O/pentane) to
afford the desired b-hydroxyl ester 4 as colorless oil (81% overall
yield?, 98% ee); [a]D20> =+23.8 (c=1.21 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=4.01–3.94 (m, 1H), 3.72 (s, 3H), 2.86 (d, J=
4.0 Hz, 1H), 2.53 (dd, J=16.4, 3.1 Hz, 1H), 2.42 (dd, J=16.4, 9.0 Hz,
1H), 1.56–1.48 (m, 2H), 1.46–1.40 (m, 1H), 1.38–1.29 (m, 1H), 1.27–
1.14 (m, 1H), 0.90 (d, J=1.8 Hz, 3H), 0.88 ppm (d, J=1.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=173.63, 68.47, 51.84, 41.24, 34.71,
34.51, 28.10, 22.70, 22.61 ppm; IR (KBr): n˜ =3584, 3418, 2957, 2934,
2870, 1738, 1439, 1368, 1259, 1169, 1080, 799 cmÀ1; HRMS (ESI): m/
z calcd for C9H19O3: 175.1334 [M+H+]; found: 175.1327.
Experimental Section
General considerations
Unless otherwise stated, experiments that involve moisture and/or
air sensitive components were performed in oven-dried glassware
under a positive pressure of argon with freshly distilled solvents.
1H NMR spectra were recorded in CDCl3 on a Bruker AMX 400 spec-
trophotometer. Chemical shifts (d) are reported in parts per million
(ppm) downfield from SiMe4 (d=0.0). Coupling constants (J) are re-
ported in (Hz). 13C NMR are reported in ppm downfield from SiMe4
(d=0.0) and relative to the signal of CDCl3 (d=77.16, t). The pro-
portion of diastereomers and geometric isomers was determined
by integration of signals in the H and 13C NMR spectra. Analytical
1
TLC was performed with Merck 60 F254 precoated silica gel plates.
IR spectra were recorded on a Bio-Rad FTS 165 FTIR spectrometer.
HRMS was performed with a Finnigan MAT95XP GC/HRMS instru-
ment. Enantioselectivities were determined by HPLC analysis with
a Daicel Chiracel OD-H or Chiralpak AD-H column at 258C. Optical
rotations were measured in solution in CHCl3 (c=g/100 mL) on
a Schmidt+Haensch polarimeter (Polartronic MH8) with a 1 cm
cell. The absolute configuration of the products was determined
by comparison to previously published data.
General experimental procedure for asymmetric conjugate
addition
CuI (3.8 mg, 0.02 mmol, 5 mol%) and (R)-Tol-BINAP (20.4 mg,
0.03 mmol, 7.5 mol%) were added to an oven-dried Schlenk tube
under a positive pressure of argon. Anhydrous CH2Cl2 (1.0 mL) was
added and the solution was left to stir at RT for 30 min. Subse-
General experimental procedure for the synthesis of allylic
silanes 6
A solution of b-silylester 2 (0.3 mmol) in anhydrous Et2O (1.0 mL)
was added to an oven-dried Schlenk tube equipped with a stirrer
bar. LiAlH4 (0.36 mL, 1.0m in Et2O, 1.2 equiv) was added dropwise
over 10 min at 08C. After stirring at 08C for 1 h, the reaction was
quenched with a saturated aqueous solution of NH4Cl (2.0 mL) and
the mixture was allowed to warm to RT. The crude mixture was ex-
tracted with Et2O (3ꢂ15 mL) and the combined organic phases
were dried over Na2SO4, filtered, and concentrated under vacuum
to give alcohol 5. Subsequently, 5 and 2-nitrophenylselenocyanate
(81.7 mg, 0.36 mmol, 1.2 equiv) were dissolved in anhydrous THF
(2.0 mL). Tri-n-butyl phosphine (90 mL, 0.36 mmol, 1.2 equiv) was
added dropwise and the mixture was stirred for 1 h at RT under
argon. The solvent was removed under reduced pressure and the
crude selenoxide was re-dissolved in CH2Cl2 (2.0 mL). Pyridine
quently,
a solution of 3-silyl unsaturated ester 1a (88.1 mg,
0.4 mmol) in anhydrous CH2Cl2 (5.5 mL) was added to the reaction
mixture, which was stirred for 10 min then cooled to À788C.
RMgBr (1.0 mmol, 2.5 equiv) was added to the reaction mixture
dropwise over 10 min. After complete consumption of 1a (moni-
tored by TLC), the reaction was quenched with MeOH (1.0 mL) and
NH4Cl (1.0m, 4.0 mL) and the mixture was warmed to RT. The
layers were separated and the aqueous layer was extracted with
Et2O (3ꢂ15 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated under reduced pressure to give
the crude product, which was purified by flash chromatography
(1:80 Et2O/petroleum ether) to afford the desired product 2 as
a colorless oil.
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(50 mL, 0.6 mmol, 2.0 equiv) was added. Hydrogen peroxide solu-
tion (30%w/w in H2O, 350 mL) was added dropwise over 10 min at
08C. The solution was allowed to warm to RT, then stirred for 16 h
at RT. The reaction mixture was diluted with water (5.0 mL) and ex-
tracted with Et2O (3ꢂ10 mL). The combined organic phases were
washed successively with a saturated aqueous solution of sodium
yield, 96% ee). HPLC: Daicel Chiralcel OD-H column, hexane/isopro-
panol=99.9:0.1, flow rate=1.0 mLminÀ1, l=220 nm, tR =19.603
(minor), 21.897 min (major); [a]2D0 =+38.3 (c=1.16 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.54–7.51 (m, 2H; ArH), 7.37–7.33 (m,
3H; ArH), 3.57 (s, 3H; OCH3), 2.61 (qd, J=7.1, 3.4 Hz, 1H), 2.25 (dd,
J=15.6, 8.3 Hz, 1H), 1.56–1.49 (m, 1H), 1.47–1.39 (m, 2H), 1.06 (d,
J=7.1 Hz, 3H), 0.83 (t, J=7.2 Hz, 3H), 0.33 ppm (s, 6H; 2ꢂSiCH3);
13C NMR (100 MHz, CDCl3): d=177.81, 138.96, 134.01, 129.03,
127.88, 51.56, 39.06, 30.82, 19.71, 14.66, 14.04, À2.78, À2.91 ppm;
IR (KBr): n˜ =2958, 2876, 1736, 1733, 1460, 1434, 1428, 1197, 1179,
1111, 811, 735, 703 cmÀ1; HRMS (ESI): m/z calcd for C15H25O2Si:
265.1624 [M+H+]; found: 265.1621.
hydrogencarbonate (10 mL),
a saturated aqueous solution of
copper sulfate (10 mL), and brine (10 mL), then dried over Na2SO4
and filtered. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (1:100 Et2O/pe-
troleum ether) to afford 6 as colorless oil.
Compound 6c: Colorless oil; 71% yield; [a]2D0 =+12.7 (c=1.42 in
CHCl3); 96% ee determined by chiral HPLC: Daicel Chiralpak AD-H
column, substrate=alcohol 5c generated by the hydroboration–
oxidation reaction of 6c, hexane/isopropanol=99:1, flow rate=
1.5 mLminÀ1, l=220 nm, tR =8.720 (major), 9.665 min (minor);
1H NMR (400 MHz, CDCl3): d=7.51–7.46 (m, 2H; ArH), 7.36–7.33 (m,
3H; ArH), 5.58 (ddd, J=17.1, 10.2, 9.6 Hz, 1H; CHCH=CH2), 4.88
(ddd, J=10.3, 2.0, 0.5 Hz, 1H; CH=CHH), 4.80 (ddd, J=17.1, 2.0,
1.0 Hz, 1H; CH=CHH), 1.75–1.69 (m, 2.9 Hz; 1H), 1.43–1.12 (m, 8H),
0.82 (t, J=7.1 Hz, 3H; CH3), 0.26 (s, 3H; SiCH3), 0.25 ppm (s, 3H;
SiCH3); 13C NMR (100 MHz, CDCl3): d=140.08, 138.13, 134.20,
129.01, 127.72, 112.51, 34.56, 31.78, 29.09, 28.54, 22.72, 14.25,
À4.30, À5.03 ppm; IR (KBr): n˜ =3397, 2956, 2924, 2854, 1624, 1466,
1427, 1248, 1113, 895, 835, 698 cmÀ1; HRMS (ESI): m/z calcd for
C16H27Si: 247.1882 [M+H+]; found: 247.1887.
General experimental procedure for the one-pot tandem
1,4-addition/aldol reaction
In an oven-dried Schlenk tube, CuI (3.8 mg, 0.02 mmol, 5 mol%)
and (R)-Tol-BINAP (20.4 mg, 0.03 mmol, 7.5 mol%) were dissolved
in anhydrous CH2Cl2 (1.6 mL) and the mixture was stirred for
30 min at RT. Subsequently, 3-silyl unsaturated ester 1a (88.1 mg,
0.4 mmol) dissolved in freshly distilled tBuOMe (3.2 mL) was added
to the mixture. The solution was cooled to À788C and RMgBr
(1.0 mmol, 2.5 equiv) was added dropwise over 10 min. Upon com-
plete consumption of 1a (monitored by TLC), a solution of 4-bro-
mobenzaldehyde (296 mg, 1.6 mmol) in CH2Cl2 (0.5 mL) was added
dropwise over 5 min at À788C. After stirring for an additional
5 min, the reaction was quenched with a saturated aqueous solu-
tion of NH4Cl (4.0 mL). The mixture was extracted with Et2O (3ꢂ
15 mL) and the combined organic phases were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography (1:60 ethyl acetate/hexane)
to afford 9 (the desired major diastereomer) together with 9’ (the
minor diastereomer).
General experimental procedure for the synthesis of allylic
silanes 7
A solution of 6 (0.2 mmol) in CH2Cl2 (4.0 mL) and Hoveyda–Grubbs
second generation catalyst (12.5 mg, 0.02 mmol) were added to an
oven-dried Schlenk tube under argon. The mixture was left to stir
for 1 h at RT, then the solvent was evaporated under reduced pres-
sure and the residue was purified by column chromatography to
give the cyclic allylic silane 7.
Compound 9a: Colorless oil; 65% yield; 99% ee determined by
HPLC: Daicel Chiralpak AD-H column, hexane/isopropanol=98:2,
flow rate=1.0 mLminÀ1
,
l=220 nm; tR =12.001 (minor),
16.909 min (major); [a]2D0 =+13.9 (c=2.03 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.64–7.62 (m, 2H; ArH), 7.39–7.36 (m, 5H;
ArH), 7.04–7.02 (m, 2H; ArH), 4.64 (dd, J=9.6, 3.4 Hz, 1H), 3.37 (s,
3H; OCH3), 2.95 (dd, J=9.6, 2.9 Hz, 1H), 1.87 (d, J=3.7 Hz, 1H),
1.70–1.60 (m, 1H), 1.54–1.50 (m, 1H), 1.48–1.40 (m, 1H), 0.93 (t, J=
7.2 Hz, 3H), 0.42 (s, 3H; SiCH3), 0.36 ppm (s, 3H; SiCH3); 13C NMR
(100 MHz, CDCl3): d=174.36, 142.22, 140.10, 134.30, 131.52, 129.02,
128.55, 127.83, 121.84, 72.48, 53.77, 51.35, 28.55, 21.57, 14.20,
À2.56, À2.59 ppm; IR (KBr): n˜ =3385, 2968, 2930, 1730, 1715, 1427,
1379, 1366, 1248, 1161, 1109, 1011, 951, 831, 818, 773, 735,
Compound 7h: Colorless oil; 95% yield; 93% ee; [a]2D0 =À107.6
1
(c=0.73 in CHCl3); H NMR (400 MHz, CDCl3): d=7.53–7.51 (m, 2H;
ArH), 7.36–7.34 (m, 3H; ArH), 5.70–5.68 (m, 1H; CH=CH), 5.64–5.62
(m, 1H; CH=CH), 2.37–2.28 (m, 1H), 2.21–2.11 (m, 2H), 2.08–1.98
(m, 1H), 1.88–1.80 (m, 1H), 0.25 (s, 3H; SiCH3), 0.24 ppm (s, 3H;
SiCH3); 13C NMR (100 MHz, CDCl3): d=138.82, 133.99, 132.14,
129.01, 128.55, 127.79, 34.15, 33.03, 25.30, À4.50, À4.54 ppm; IR
(KBr): n˜ =3051, 2957, 2928, 2835, 1639, 1427, 1247, 1113, 895, 835,
721, 698 cmÀ1
; HRMS (ESI): m/z calcd for C13H19Si: 203.1256
[M+H+]; found: 203.1255.
703 cmÀ1 HRMS (ESI): m/z calcd for C21H28O3Si79Br: 435.0991
;
[M+H+]; found: 435.0999.
Experimental procedure for the diastereoselective alkylation
(8)
Experimental procedure for the ester–imine condensation
(10)
A solution of b-silylester 2a (75.1 mg, 0.3 mmol) in anhydrous THF
(3.0 mL) was added to an oven-dried Schlenk tube equipped with
a stirrer bar. The solution was cooled to À788C and LDA (0.36 mL,
1.0m in THF/hexanes, 1.2 equiv) was added dropwise over 10 min.
After stirring at À788C for 30 min, a solution of MeI (75 mL,
1.2 mmol) in THF (1.0 mL) was added dropwise over 5 min, then
the mixture was slowly warmed to 08C over 3 h and left to stir for
an additional 5 h. The reaction was quenched with a saturated
aqueous solution of NH4Cl (2.0 mL). The crude mixture was extract-
ed with Et2O (3ꢂ15 mL), then the combined organic phases were
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash column chromatog-
raphy (1:100 Et2O/petroleum ether) to give 8 as colorless oil (78%
A solution of b-silylester 2a (75.1 mg, 0.3 mmol) in anhydrous THF
(3.0 mL) was added to an oven-dried Schlenk tube equipped with
a stirrer bar. The solution was cooled to À788C and LDA (0.36 mL,
1.0m in THF/hexanes, 1.2 equiv) was added dropwise over 10 min.
After stirring at À788C for 30 min, a solution of (E)-N-benzylidene-
1,1,1-trimethyl-silanamine (65 mg, 0.36 mmol) in anhydrous THF
(0.5 mL) was added dropwise over 5 min. The mixture was stirred
at À788C for 1 h, the cold bath was removed, and the mixture was
allowed to slowly warm to RT. The mixture was stirred for 2 h at RT,
then diluted with Et2O (20 mL) and washed with 1.0m HCl (3ꢂ
10 mL). The combined organic phases were dried over MgSO4, fil-
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asymmetric boron addition to deliver enantioenriched b-boryl carbonyl
compounds, which is similar to silyl conjugate addition, see: l) S. Ra-
domkit, A. H. Hoveyda, Angew. Chem. Int. Ed. 2014, 53, 3387–3391;
Angew. Chem. 2014, 126, 3455–3459; and references therein; m) J. C. H.
Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894–899; and referen-
ces therein.
tered, and concentrated under vacuum. The crude product was pu-
rified by flash column chromatography (1:10 ethyl acetate/hexane)
to give 10 as white solid (61% yield; 98% ee). HPLC: Daicel Chiral-
pak AD-H column, hexane/isopropanol=98:2, flow rate=
1.0 mLminÀ1, l=220 nm, tR =20.798 (major), 27.731 min (minor);
m.p.=122–1238C; [a]D20 =+51.3 (c=0.66 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.56–7.53 (m, 2H; ArH), 7.39–7.31 (m, 8H;
ArH), 5.90 (s, 1H), 4.78 (d, J=5.1 Hz, 1H), 3.31 (ddd, J=12.5, 5.1,
1.3 Hz, 1H), 0.98 (dq, J=12.5, 7.1 Hz, 1H), 0.45 (s, 3H; SiCH3), 0.39
(d, J=7.1 Hz, 3H; CH3), 0.36 ppm (s, 3H; SiCH3); 13C NMR (100 MHz,
CDCl3): d=170.58, 137.95, 137.93, 134.52, 128.94, 128.43, 128.33,
127.95, 127.65, 61.70, 55.83, 16.45, 13.71, À2.89, À3.86 ppm; IR
(KBr): n˜ =3406, 1715, 1255, 1018, 833, 739, 721 cmÀ1; HRMS (ESI):
m/z calcd for C26H30NO2Si: 416.2046 [M+H+]; found: 416.2047.
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Acknowledgements
We gratefully acknowledge the Nanyang Technological Univer-
sity, the Singapore Ministry of Education Academic Research
Fund Tier 2 (MOE2010-T2-2-067 and MOE2011-T2-1-013) and
the National Environment Agency (NEA-ETRP Project Ref. No.
1002 111) for financial support. We thank Dr. Yong-Xin Li for
X-ray analyses.
Keywords: asymmetric synthesis · domino reactions · Grignard
reagents · Michael addition · organosilanes
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absolute configuration of compound 10 was assigned by X-ray analysis.
CCDC-917484 contains the supplementary crystallographic data for
compound 10. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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Received: June 6, 2014
Published online on October 16, 2014
Chem. Eur. J. 2014, 20, 16764 – 16772
www.chemeurj.org
16772
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