Enantioselective route to -silyl - Keto esters by organocatalyzed regioselective Michael addition of methyl ketones to a (silylmethylene)malonate and their use in natural product synthesis

Article abstract of DOI:10.1055/s-0030-1260036

The direct Michael addition of alkyl methyl ketones through the acetyl methyl terminal to diethyl {[dimethyl(phenyl)silyl]methylene}malonate was catalyzed by the (S)-N-(pyrrolidin-2-ylmethyl)pyrrolidine/trifluoroacetic acid combination with high yield and excellent regio- and enantioselectivity. The ketone adducts can easily undergo de-ethoxycarbonylation to give β-silyl-δ keto esters with excellent synthetic potential. This has been demonstrated by the synthesis of a suitably substituted β-silyl-δ ester as an advanced intermediate for a chiral hydroxylated pyrrolidine natural product, (+)-preussin. Silicon-controlled diastereoselective reduction of the ketone functionality of β-silyl- δesters followed by lactonization of the resulting hydroxy esters gave disubstituted -valerolactones. Advanced intermediates for the antipodes of natural products, namely (+)-massoialactone and (+)-mevinolin analogue, and natural products, namely (-)-tetrahydrolipstatin and (+)-5-hexadecanolide, have been achieved. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260036

1936
PAPER
Enantioselective Route to b-Silyl-d-keto Esters by Organocatalyzed
Regioselective Michael Addition of Methyl Ketones to a
(Silylmethylene)malonate and Their Use in Natural Product Synthesis
Raghunath Chowdhury, Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre Trombay, Mumbai 400085, India
Fax +91(22)25505151; E-mail: ghsunil@barc.gov.in
Received 28 February 2011
desymmetrization of anhydrides with a limited type of
carbon nucleophiles13,14 has been reported recently to pro-
duce keto esters. Enantio/diastereoselective conjugative
silylation of simple unsaturated carbonyl compounds are
Abstract: The direct Michael addition of alkyl methyl ketones
through the acetyl methyl terminal to diethyl {[dimethyl(phenyl)si-
lyl]methylene}malonate was catalyzed by the (S)-N-(pyrrolidin-2-
ylmethyl)pyrrolidine/trifluoroacetic acid combination with high
yield and excellent regio- and enantioselectivity. The ketone ad- also well known.15 However, such types of reactions have
ducts can easily undergo de-ethoxycarbonylation to give b-silyl-d-
keto esters with excellent synthetic potential. This has been demon-
strated by the synthesis of a suitably substituted b-silyl-d-keto ester
as an advanced intermediate for a chiral hydroxylated pyrrolidine
natural product, (+)-preussin. Silicon-controlled diastereoselective
reduction of the ketone functionality of b-silyl-d-keto esters fol-
lowed by lactonization of the resulting hydroxy esters gave disub-
stituted d-valerolactones. Advanced intermediates for the antipodes
of natural products, namely (+)-massoialactone and (+)-mevinolin
analogue, and natural products, namely (–)-tetrahydrolipstatin and
(+)-5-hexadecanolide, have been achieved.
not been applied to the synthesis of b-silyl-d-keto esters.
We envisage an alternate and straightforward method that
involves an atom-economic,16 regio- and enantioselective,
direct Michael addition of an alkyl methyl ketone to the b-
silylacrylate 4 or (silylmethylene)malonate 517 (Figure 1).
SiMe2Ph
O
SiMe2Ph
CO2Et
SiMe2Ph
CO2Et
R
E
O
O
O
E
1 E = H
2 E = CO2Et
3
4 E = H
5 E = CO2Et
Key words: Michael addition, organosilicon compounds, methyl
ketone, organocatalysis, regioselective, natural product
N
The unique properties of silicon1 have led to its wide uti-
lization in organic chemistry these range in general from
protecting functional groups2 to a temporary tether,3 and
specifically from masking the hydroxy group,4 to highly
controlled and selective organic reactions.1,5 Carbonyl
compounds having a silyl group at the b-position are pop-
ular targets because of their versatile nature6 and they are
also an excellent surrogate for the acetate aldol7 reaction.
We are interested in the asymmetric synthesis of interme-
diates of type 1 or 2 (Figure 1) containing a silicon group
positioned at b to both a ketone and an ester functional-
ities because they are potential synthons8 for privileged
structures containing chiral N- and O-heterocycles. The
synthesis of b-silyl-d-keto esters 1 has been reported9,10 by
asymmetric desymmetrization of 3-[dimethyl(phenyl)si-
lyl]glutaric anhydride 3 followed by selective alkylation
of one of the carboxy functionalities. Although high
selectivity10 was achieved in the desymmetrization pro-
cess, it required specially designed SuperQuat11 oxazoli-
din-2-ones. The choice of the dimethyl(phenyl)silyl group
was made due to its easy incorporation into the carbon
framework and also it can be easily converted into the cor-
responding alcohol under oxidative conditions (Fleming–
Tamao)12 with complete retention of stereochemistry. The
N
Ph
Ph
N
N
H
H
N
RO
H
6a R = H
6b R = OSiMe3
6c
6d
Figure 1 Structures of substrates and catalysts
OH
H11C5
O
O
H23C11
O
O
H23C11
O
O
(+)-massoialactone (7)
8
(+)-5-hexadecanolide (9)
NHCHO
OH
O
O
O
O
O
O
H23C11
C6H11
(–)-tetrahydrolipstatin (10)
OH
(+)-mevinolin analogue (11)
Ph
H19C9
N
Me
(+)-preussin (12)
Figure 2 Structures of N- and O-heterocycles
SYNTHESIS 2011, No. 12, pp 1936–1945
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x.
x
x
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2
0
1
1
Advanced online publication: 11.05.2011
DOI: 10.1055/s-0030-1260036; Art ID: C23311SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Route to b-Silyl-d-keto Esters
1937
The Michael addition18 is one of the most frequently used acetone to (silylmethylene)malonate 5 using a catalytic
reactions because of its efficiency and effectiveness. Sig- amount of racemic amino acids for the synthesis of sily-
nificant development has been made in the asymmetric lated keto diester rac-2a has already been demonstrated,30
version of this reaction, providing adducts with high enan- as a part of a goal to develop silicon-based linkers for
tiomeric purity.19 Aldehydes and ketones have generally solid-phase organic synthesis.31 We, therefore, began our
been used as donors after their modification to more acti- studies for the asymmetric version of this reaction using a
vated species such as enolates or enamines.20,21 The major few natural amino acid catalysts with N-methylpyrrolidin-
drawbacks for the use of enolates/enamines are the addi- 2-one as the solvent at room temperature. The result with
tion of extra synthetic step(s) and stoichiometric use of a (S)-proline as the catalyst resulted in the formation of 2a
chiral induction reagent. In recent times, an in good yield but very poor enantioselectivity (Table 1,
organocatalysis22 route has been developed for the direct entry 1). With (S)-arginine and (S)-tryptophan, the reac-
addition of ketones or aldehydes to activated alkenes, tion was slow and also the enantioselectivity was very
especially to nitroalkenes with satisfactory results. How- poor (entries 2 and 3). Simple pyrrolidines derived from
ever, the addition of the same donors23 to alkylidenema- proline, viz. diphenylprolinol 6a32 and its silyl ether 6b,33
lonates is less successful. Barbas and co-workers24 for the are well-known catalysts for the addition of aldehydes and
first time demonstrated that acetone can add to various ketones to nitroalkenes. The silyl ether 6b has recently
(arylmethylene)- and alkylidenemalonates under organo- been found to be an efficient catalyst for direct addition of
catalysis with moderate yields and enantioselectivities. unmodified aldehydes to (silylmethylene)malonate 534a
Natural proline-catalyzed25 direct addition of acetone to and (trifluoroethylidene)malonates34b with adducts
an (arylmethylene)malonate took place with good yield, formed in good yields and diastereo- and enantioselectiv-
but poor enantioselectivity. Recent reports showed that ities. Unfortunately, both 6a and 6b were not effective for
N-(pyrrolidin-2-ylmethyl)trifluoromethanesulfonamide26
this addition (entries 4 and 5). Pyrrolidine-based diamines
and pyrrolidinyl-camphor27 derivatives can catalyze the derived from natural proline such as N-(pyrrolidin-2-ylm-
Michael addition between ketones and (arylmethyl- ethyl)pyrrolidine 6c and N-(pyrrolidin-2-ylmethyl)piperi-
ene)malonates; the adducts were formed in moderate to dine 6d (Figure 1) are popular organocatalysts for aldol,35
good yields and good to high enantioselectivities, depend- Michael,24,36 and Mannich reactions.37 They can be easily
ing upon the substituents present on the ketones and the made from proline38 and also, Barbas has used such cata-
(arylmethylene)malonates. Alkylidenemalonates were lysts for the asymmetric addition of ketones to alkyliden-
not good acceptors for this reaction. Although cyclic ke- emalonates.24 When pyrrolidine 6c was used under the
tones reacted with good diastereo- and enantioselectivi- reported conditions,24 the addition of acetone to (silyl-
ties, acyclic ketones gave poor results.24,26 Despite some methylene)malonate 5 was very slow and the desired keto
success with these methodologies, reaction with acyclic diester adduct 2a was formed in poor yield, but with mod-
unsymmetrical ketones, especially methyl ketones, re-
mains very challenging. Besides yield and enantioselec-
tivity, the regioselectivity of the addition is also an
important issue.28 Herein, we report a full account29 of our
efforts for the development of an efficient, highly regio-
and enantioselective organocatalytic conjugate addition
of acyclic methyl ketones to (silylmethylene)malonate 5
(Figure 1) providing b-silyl-d-keto diesters 2, and their
application in the synthesis of intermediates for O-and N-
heterocyclic natural products or their counterparts, viz.
(+)-massoialactone (7), (+)-5-hexadecanolide (9), (–)-tet-
rahydrolipstatin (10), and (+)-mevinolin analogue (11)
(Figure 2).
Table 1 Catalyst Screening for Direct Acetone Addition on (Silyl-
methylene)malonate 5
organocatalyst
(30 mol%)
28 °C, NMP
SiMe2Ph
CO2Et
O
SiMe2Ph
CO2Et
O
+
CO2Et
5
CO2Et
12 equiv
2a
Entry
Catalyst
(S)-Pro
(S)-Trp
(S)-Arg
6a
Temp, time
28 °C, 1 d
28 °C, 1 d
28 °C, 5 d
28 °C, 7 d
28 °C, 7 d
28 °C, 6 d
28 °C, 3.5 d
28 °C, 3.5 d
Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
75
<5
<5
12
56
42c
trace
trace
10e
61
As discussed above, direct addition of cyclic and acyclic
ketones to nitroalkenes and few more activated alkenes
has been well studied. Although alkylidenemalonates are
well known for their Michael acceptor properties and use-
ful functionalities for further elaboration, direct addition
of various ketones to them have not been studied in detail.
Especially, the reactivity and regioselectivity issues were
not addressed in case of unsymmetrical ketones. We re-
solved these issues one-by-one using (silylmethylene)ma-
lonate 5 as the acceptor. We first chose acetone as the
model ketone to obviate the regioselectivity issue and
d
–
d
6b
–
6c
66
55
55
6c
6d
40c
a Yield of chromatographically homogeneous product.
b Determined by HPLC.
concentrated our effort on optimization of the yield and c Incomplete reaction.
enantioselectivity of the adduct. The direct addition of
d Not determined.
e Reaction was performed in THF as reported in ref. 24b.
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

1938
R. Chowdhury, S. K. Ghosh
PAPER
erate enantioselectivity (entry 6). The catalytic ability of the carbonyl donors. It is well established36 that in the
pyrrolidine 6c was increased substantially with slight ero- presence of acid, the prototropy of the reactive enamine is
sion of enantioselectivity by changing the solvent to N- more favorable and the equilibration between the more
methylpyrrolidin-2-one (entry 7). Similarly, pyrrolidine and the less-substituted enamines I and II (Scheme 1)
6d also showed moderate yield and selectivity in N-meth- could occur. This leads to the formation of the more stable
ylpyrrol idin-2-one (entry 8).
substituted enamine I on thermodynamic grounds. How-
ever, the regiocontrol of the reaction is often governed by
Curtin–Hammett kinetics. Therefore, the balance between
Curtin–Hammett kinetics and acidity decides the regiose-
lectivity. Many research groups have addressed the issue
of regioselectivity during aldol41 and Michael42 additions
involving unsymmetrical ketone donors, by tuning the
acidity of the a and a¢ protons with suitable functional
groups. When methyl isopropyl ketone was reacted with
(silylmethylene)malonate 5 under the optimized condi-
tions as described in Table 2, we obtained only one regio-
isomeric product 2b, as revealed by the 1H NMR spectrum
of the crude reaction product, in very high yield and with
excellent enantioselectivity (Table 3, entry 2). Initially it
was envisaged that the high regioselectivity might be an
outcome of the steric crowding by the isopropyl group.
However, this was discounted from the results with sever-
al other ketones lacking any such steric congestion. In all
the cases (Table 3) the adducts 2c–k were formed only by
reaction at the methyl terminal of the acetyl group of the
ketones. Also, the adducts were obtained in very good
yields and enantioselectivities. The reactions required ex-
cess amount of the ketone (2–12 equiv) to get an apprecia-
ble rate of reaction and completion within the time period
We next planned to introduce different additives in asso-
ciation with catalysts 6c and 6d to improve the yield and
the enantioselectivity of adduct 2a. Many research groups
have used varying amounts of Bronsted acids as additives
to accelerate the amine-catalyzed Michael addition of al-
dehydes and ketones to nitroalkenes36,39 resulting in good
yields and stereoselectivities. Barbas24 has suggested that
these
reactions
proceed
through
enamine
intermediates20a,b of the carbonyl donors. It is well known
that enamine formation between an amine and a carbonyl
compound is facilitated by acids. Hine40 in his seminal
work has shown that the process was 15 times faster with
protonated primary amines than the free base. Therefore,
the Michael addition of acetone with (silylmethylene)ma-
lonate 5 was next examined with the pyrrolidine catalysts
6c and 6d in the presence of organic acids such as acetic
acid and 4-nitrobenzoic acid (PNBA) in N-methylpyrroli-
din-2-one.
The addition of 10 mol% of acetic acid or 4-nitrobenzoic
acid and 30 mol% of catalyst 6c at 4 °C provided the de-
sired product 2a in good yield (Table 2, entries 1 and 2)
with a significant improvement of enantioselectivity.
Next, the temperature of the reaction was lowered for fur-
ther enhancement of selectivity. Therefore, the reactions
using catalyst 6c and with or without 10 mol% acetic acid
were carried out at –10 °C for seven days. Although this
improved the enantioselectivity, the conversion was abys-
mally poor (entries 3 and 4). Interestingly, trifluoroacetic
acid appeared to be a better additive and using 10 mol%
of it with 30 mol% of catalyst 6c at –10 °C for seven days
gave a decent yield of the product 2a with excellent enan-
tioselectivity (entry 5). Additional experiments with vary-
ing amounts of trifluoroacetic acid (5–30%) (entries 5–8)
established 10 mol% of trifluoroacetic acid to be optimum
for the reaction. We also wanted to see the effect of sol-
vents on the enantioselectivity and examined the reaction
in N,N-dimethylformamide and toluene. Although the
yield was comparable in these solvents, the enantioselec-
tivity was lower (entries 9 and 10). The other catalyst 6d
turned out to be poor (entry 11). Therefore, the optimized
conditions are to use 12 equivalents of acetone with re-
spect to (silylmethylene)malonate 5 and 30 mol% of cata-
lyst 6c in combination with 10 mol% of trifluoroacetic
acid in N-methylpyrrolidin-2-one (0.25 M) at –10 °C for
seven days providing the adduct 2a in 76% yield and with
90% ee (Table 2, entry 5).
Table 2 Optimization of Direct Acetone Addition on (Silylmethyl-
ene)malonate 5 Using Additives
SiMe2Ph
CO2Et
O
SiMe2Ph
CO2Et
6c/6d (30 mol%)
O
conditions
+
CO2Et
5
CO2Et
12 equiv
2a
Entry Catalyst/additive Solvent, temp, time
(mol%)
Yielda eeb
(%)
(%)
84
80
80
88
90
88
88
90
84
82
84
1
2
6c/AcOH (10)
6c/PNBA (10)
6c/nil
NMP, 4 °C, 5 d
72
NMP, 4 °C, 5 d
79
3
NMP, –10 °C, 7 d
NMP, –10 °C, 7 d
NMP, –10 °C, 7 d
NMP, –10 °C, 7 d
NMP, –10 °C, 7 d
NMP, –10 °C, 7 d
DMF, –10 °C, 7 d
toluene, –10 °C, 7 d
NMP, –10 °C, 10 d
<5c
<5c
76
4
6c/AcOH (10)
6c/TFA (10)
6c/TFA (5)
6c/TFA (15)
6c/TFA (30)
6c/TFA (10)
6c/TFA (10)
6d/TFA (10)
5
6
56
7
57
8
44c
78
9
With optimal catalyst, additive, and reaction conditions
established with acetone, we went one step further by in-
troducing unsymmetrical alkyl methyl ketones as donors.
Unlike acetone, alkyl methyl ketones introduce the prob-
lem of regioselectivity. Barbas24 has suggested that these
reactions proceed through enamine intermediates20a,b of
10
11
88
44c
a Yield of chromatographically homogeneous product.
b Determined by HPLC.
c Incomplete reaction.
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

PAPER
Enantioselective Route to b-Silyl-d-keto Esters
1939
R1
R2
Table 3 Regioselective Addition of Alkyl Methyl Ketone to (Silyl-
methylene)malonate 5
R1
R2
O
H+
N+
+
R3
NH
R3
6c (30 mol%)
TFA (10 mol%)
NMP, –10 °C
3–7 days
SiMe2Ph
CO2Et
O
SiMe2Ph
CO2Et
H+
R2
O
+
R
R1
R1
R2
R
H+
N
CO2Et
CO2Et
2a–k
N
R3
R3
5
II
Equiv of Time Product Yielda eeb (%)
I
Entry
R
ketone
(d)
(%)
76
82
82
81
85
88
94
80
76
92
78
Scheme 1 Enamines of alkyl methyl ketones
1
2
Me
i-Pr
i-Bu
Et
12
12
5
7
2a
2b
2c
2d
2e
2f
90.0
99.5
96.7
92.8
91.2
91.1
99.6
87c
mentioned. Valuable ketones can be recovered as other
byproduct formations were not observed.
7
3
6
We next attempted to generalize this regio- and enantiose-
lective methyl ketone addition to (arylmethylene)- and
alkylidenemalonates. Therefore, diethyl benzylidene-, 4-
fluorobenzylidene-, and (3-phenylpropylidene)malonates
13a–c were reacted with methyl ethyl ketone in the pres-
ence of catalyst 6c under the optimized conditions de-
scribed for (silylmethylene)malonate 5; no reaction took
place with any of these methylenemalonates. Even at
higher temperature (28 °C), the reaction between diethyl
4-fluorobenzylidenemalonate (13b) and methyl ethyl ke-
tone catalyzed by 6c and trifluoroacetic acid in N-meth-
ylpyrrolidin-2-one was very sluggish. The reaction was
incomplete even after five days. Moreover, it produced a
3:2 regioisomeric mixture of adducts 14 and 15 in 18%
yield and with the acetyl terminal adduct as the major
product43 (Scheme 2). The internal adduct 15 also ap-
4
12
12
5
7
5
Pr
7
6
(CH2)8Me
3
7
(CH2)4Me
5
3
2g
2h
2i
8
(CH2)10Me
(CH2)2-c-C6H11
(CH2)6OBn
CH(OMe)2
6
6
9
5
5
90.5
91.3
85.4
10
11
2
6
2j
6
7
2k
a Yield of chromatographically homogeneous product.
b Determined by HPLC.
c Reaction performed at 4 °C.
peared to be the syn-diasteroisomer24b as judged by H
1
NMR spectroscopy (JHaHb = 7 Hz). In addition, a substan-
tial amount (32%) of an unsaturated ketone 16 was also
produced. The source of this ketone 16 could be the retro-
Knoevenagel of 4-fluorobenzylidenemalonate (13b) pro-
ducing 4-fluorobenzaldehyde followed by its organocata-
lyzed aldol dehydration24,44 with methyl ethyl ketone.
This study clearly indicated that silyl substitution is cru-
cial for the reactivity of the (silylmethylene)malonate 5 as
well as for the regioselectivity of the addition.
very good yields. The keto esters can further be trans-
formed into natural products with well-known biological
activity. For example, keto ester 1f (Scheme 4) was hy-
drolyzed with lithium hydroxide followed by esterifica-
tion with diazomethane to give the keto methyl ester 17.
By comparing the sign and magnitude of the optical rota-
24
tion value of 17 {[a]D –0.8 (c 0.8, CHCl3)} with the
21
reported8a value {[a]D –0.8 (c 0.79, CHCl3)}, the silyl-
bearing chiral center was concluded to be of S-configura-
tion. This also confirmed the absolute stereochemistry of
the adduct 2f. This keto ester 17 can be converted into a
pyrrolidine skeleton easily and has already been trans-
To show the utility of these adducts, a few keto diesters
2f–i were subjected to Krapcho de-ethoxycarbonylation45
leading to keto esters 1f–i, respectively (Scheme 3) in
6c (30 mol%)
TFA (10 mol%)
NMP, –10 °C
7 d
R
CO2Et
CO2Et
O
+
no reaction
Et
13
13a R = Ph
13b R = 4-FC6H4
13c R = PhCH2CH2
6c (30 mol%)
TFA (10 mol%)
NMP, 28 °C, 5 d
C6H4-F-4
CO2Et
O
C6H4-F-4
CO2Et
O
C6H4-F-4
Ha
C6H4-F-4
O
CO2Et
+
+
+
Hb
O
CO2Et
13b
CO2Et
CO2Et
12 equiv
14
15
16
Scheme 2 Addition of methyl ethyl ketone to (arylmethylene)- and alkylidenemalonates
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

1940
R. Chowdhury, S. K. Ghosh
PAPER
25
formed into (+)-preussin (12), a hydroxylated pyrrolidine [Lit.49 [a]D +78.7 (c 1, THF)}. (–)-Tetrahydrolipstatin
natural product in a few steps.8a,b The absolute configura- (10) has also been prepared from the lactone 850
tion of other products 2a–e and 2j,k were tentatively as- (Scheme 6). Lactone 11 is the antipode of a reported
signed in analogy with 2f.
mevinolin analogue. The relative and absolute stere-
ochemistry of 11 was further confirmed from the physical
and spectral data {mp 74–75 °C, Lit. 51 72–74 °C for the
NaCl
DMSO–H2O
165–180 °C
O
SiMe2Ph
CO2Et
25
antipode of 11; [a]D27 –32.9 (c 0.94, CHCl3) [Lit.51 [a]D
O
SiMe2Ph
+29 (c 0.28, CHCl3) for the antipode of 11}.
R
CO2Et
R
CO2Et
SiMe2Ph
2f R = (CH2)8Me
2g R = (CH2)4Me
2h R = (CH2)10Me
2i R = (CH2)2-c-C6H11
1f R = (CH2)8Me
1g R = (CH2)4Me
1h R = (CH2)10Me
85%
90%
80%
1. LiOH, MeOH–H2O
O
SiMe2Ph
CO2Et
NaBH4, EtOH
2. dil. HCl
1i R = (CH2)2-c-C6H11 80%
58–66%
18/19 ~ 8/2
R
CO2Et
1g R = (CH2)4Me
R
OH
Scheme 3 Synthesis of d-keto-b-silyl esters
1h R = (CH2)10Me
18 α-OH
1i R = (CH2)2-c-C6H11
19 β-OH
1. LiOH, MeOH–H2O
2. dil. HCl
SiMe2Ph
OH
O
O
SiMe2Ph
CO2Et
O
SiMe2Ph
CO2Me
3. CH2N2
KBr, AcOOH
AcOH, r.t.
90%
H19C9
H19C9
53–58%
1f
17
R
O
O
R
O
20a R = (CH2)4Me
21 R = (CH2)4Me
OH
20b R = (CH2)10Me
20c R = (CH2)2-c-C6H11
8 R = (CH2)10Me
11 R = (CH2)2-c-C6H11
steps
ref. 8a
Ph
Scheme 5 Synthesis of hydroxy lactones
H19C9
N
Me
12
OH
Scheme 4 Synthesis of (+)-preusssin
ref. 48
H11C5
O
7
O
H11C5
O
21
O
The absolute configurations of other products 2g–i were
assigned by converting them into keto esters 1g–i and then
into known chiral valerolactone intermediates
(Scheme 5). These valerolactones are known to be used
for the synthesis of natural products having a large spec-
trum of biological properties including important pharma-
ref. 49b
1. MsCl, Et3N
2. DBU
OH
O
R
O
O
R
O
O
22 R = n-C11H23
9 R = n-C11H23
65%
cological activity. For this,
a
silicon-directed
NHCHO
R
O
ref. 50
stereoselective reduction46 of the ketones 1g–i with sodi-
um borohydride gave an inseparable mixture of diastereo-
meric alcohols 18a–c and 19a–c (18/19 ~ 80:20) in very
good yield (Scheme 5). The diastereomeric hydroxy ester
mixture in each case was then hydrolyzed and the inter-
mediate hydroxy acids underwent smooth cyclization to
give the major lactones 20a–c.47 The dimethyl(phenyl)si-
lyl group in 20a–c was then converted into the hydroxy
group following Fleming oxidation12c using potassium
bromide and peracetic acid with retention of configuration
leading to hydroxy lactones 21, 8, and 11, respectively.
Lactone (–)-21 is the antipode of the hydroxy lactone that
has already been converted into the natural product (+)-
massoialactone (7) (Figure 2, Scheme 6). The relative and
absolute stereochemistry of the hydroxy and the alkyl
groups in 21 were assigned from the 1H and 13C chemical
shift values, and comparing the specific rotation value
8 R = n-C11H23
O
O
O
O
H23C11
C6H11
10
Scheme 6 Synthesis of valerolactone based natural products
Considering the enamine mechanism proposed by
Barbas,24b the stereochemical outcome for the formation
of 2g–i can be explained by the transition-state assembly26
depicted in Figure 3. The (silylmethylene)malonate 5 ap-
proaches the enamine from the less hindered Si face. The
hydrogen bonding interaction of tertiary nitrogen, one of
the carbonyl group of (silylmethylene)malonate and tri-
fluoroacetic acid activated the substrates by bringing them
28
{[a]D –34.7 (c 1.5, CHCl3) [Lit.48 [a]D +29.4 (c 1.4,
N
CHCl3) for the antipode of 21}. The hydroxy valerolac-
tone 8 was converted into the intermediate unsaturated
lactone 22 which has already been converted49 into (S)-
hexadecanolide. The absolute stereochemistry of alkyl
bearing stereocenter of 8 was assigned to be S by compar-
O
N
H
O
O
R
O
CF3
EtO
PhMe2Si
OEt
29
ing the specific rotation value {[a]D +57 (c 1, THF)
Figure 3 Potential transition state
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

PAPER
Enantioselective Route to b-Silyl-d-keto Esters
1941
H, 2 CO2CH2CH3, CH3(CH2)8CH2CH2CO], 1.34–1.51 [m, 2 H,
CH3(CH2)8CH2CH2CO], 2.04–2.44 [m, 3 H, CH3(CH2)9CH2CO,
SiCH], 2.57 [dd, J = 6.0, 18.6 Hz, 1 H, CH3(CH2)9CH2COCHAHB],
2.71 [dd, J = 6.2, 18.6 Hz, 1 H, CH3(CH2)9CH2COCHAHB], 3.48 (d,
J = 5.8 Hz, 1 H, CH(CO2CH2CH3)2], 4.06 (q, J = 7 Hz, 4 H, 2
CH3CH2OCO), 7.28–7.33 (m, 3 H, Ph), 7.47–7.52 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –3.4, –3.2, 13.8 (2 C), 13.9, 20.3,
22.6, 23.8, 29.1, 29.2, 29.3, 29.4, 29.5 (2 C), 31.8, 40.9, 42.5, 51.9,
61.0, 61.1, 127.6 (2 C), 129.0, 134.2 (2 C), 137.4, 169.4, 169.8,
209.6.
to proximity, explaining well that a catalytic amount of
trifluoroacetic acid can speed up the reaction.
In conclusion, we have developed a directly organocata-
lytic asymmetric Michael addition of alkyl methyl ke-
tones to a (silylmethylene)malonate with high regio- and
enantioselectivity. This is the first successful attempt to
engage unsymmetrical methyl ketones to add via methyl
terminal of acetyl group in such reactions. The ketone ad-
ducts thus obtained can easily undergo de-ethoxycarbon-
ylation to give variety of b-silylated keto esters which can
be further transformed to O- and N-heterocyclic natural
products.
Anal. Calcd for C29H48O5Si: C, 69.00; H, 9.58. Found: C, 69.21; H,
9.61.
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-2-(ethoxycarbonyl)-7-cy-
clohexyl-5-oxoheptanoate (2i)
Following general procedure 1 using 4-cyclohexylbutan-2-one (386
mg, 2.5 mmol), malonate 5 (153 mg, 0.5 mmol), pyrrolidine 6c (23
mg, 0.15 mmol, 0.3 equiv), and TFA (4 mL, 0.05 mmol, 0.1 equiv)
in NMP (2 mL) at –10 °C for 5 d gave 2i (175 mg, 76%); HPLC:
(Daicel Chiralpak AD-H, i-PrOH–hexane, 0.7:99.3), flow rate = 1.0
mL/min): tR = 14.0 (95.27%) [(3S)-2i], 23.7 min (4.73%) [(3R)-2i].
HPLC-grade acetone, NMP, DMF, toluene, THF, MeOH were used
as received. Isopropyl methyl ketone, MEK, methyl propyl ketone,
isobutyl methyl ketone, heptan-2-one, tridecan-2-one, and pyruval-
dehyde dimethyl acetal were distilled prior to use. Characterization
data for the products 2a–g,j,k are available in the Supporting Infor-
mation of a previous publication29 hence they are not included here.
Silylmethylene malonate 5 was prepared following a procedure re-
ported by us.17 Diphenylprolinol 6a was commercially available
and its TMS ether 6b was prepared according to the literature37 pro-
cedure. All the amino acids were purchased from commercial
sources. The catalysts 6c and 6d were prepared following literature
procedures.38
[a]D23 +3.62 (c 2.76, CHCl3).
IR (neat): 2980, 1745, 1729, 1448, 1369, 1249, 1151, 1111, 1034,
818 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.30 (s, 3 H, SiCH3), 0.32 (s, 3 H,
SiCH3), 0.69–0.86 (m, 2 H, c-C6H11), 0.96–1.35 (m, 12 H, 2
CO2CH2CH3, c-C6H11CH2CH2CO, c-C6H11), 1.50–1.61 (m, 5 H, c-
C6H11), 2.04–2.33 (m, 3 H, c-C6H11CH2CH2CO, SiCH), 2.57 (dd,
J = 6.0, 18.6 Hz, 1 H, c-C6H11CH2CH2COCHAHB), 2.71 (dd,
J = 6.4, 18.6 Hz, 1 H, c-C6H11CH2CH2COCHAHB), 3.48 [d, J = 5.6
Hz, 1 H, CH(CO2CH2CH3)2], 4.04 (q, J = 7.2 Hz, 4 H, 2
CH3CH2OCO), 7.27–7.32 (m, 3 H, Ph), 7.46–7.50 (m, 2 H, Ph).
Solvent removal was carried out using a rotary evaporator connect-
ed to a dry ice condenser. TLC (0.5 mm) was carried out using
home-made silica plates with fluorescence indicator. Column chro-
matography was performed on silica gel (230–400 mesh).
1H and 13C NMR spectra were recorded on 200 MHz (1H: 200 MHz,
13C: 50 MHz), 500 MHz (1H: 500 MHz, 13C: 125 MHz) or 700 MHz
(1H: 700 MHz, 13C: 175 MHz) spectrometers relative to internal
CHCl3 and CDCl3 as standards, respectively. HRMS were recorded
at 60–70 eV on a Q-TOF spectrometer (ESI, Ar). Enantiomeric ex-
cess (ee) determinations were carried out by HPLC with a Chiralpak
AD-H/OD-H column and UV detector at l = 254 nm. Optical rota-
tions were measured in a polarimeter.
13C NMR (50 MHz, CDCl3): d = –3.5, –3.1, 13.8 (2 C), 20.3, 26.2
(2 C), 26.5, 31.0, 33.0 (3 C), 40.0, 40.9, 51.9, 61.0, 61.1, 127.6 (2
C), 129.0, 134.2 (2 C), 137.4, 169.4, 169.8, 210.0.
Anal. Calcd for C26H40O5Si: C, 67.79; H, 8.75. Found: C, 67.75; H,
8.72.
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-5-oxoalkanoates 1f–i;
General Procedure 2
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-2-(ethoxycarbonyl)-5-
oxoalkanoates 2a–k; General Procedure 1
A stirring soln of 2f–i (0.8 mmol), NaCl (58 mg, 1.0 mmol), and
H2O (1.5 mL) in DMSO (40 mL) was heated at 165–180 °C under
N2 for 6 h. The mixture was diluted with H2O (200 mL) and extract-
ed with Et2O. The organic extract was washed with H2O and brine,
dried (Na2SO4), and evaporated under reduced pressure. The resi-
due was chromatographed (silica gel, hexane–EtOAc, 95:5) to give
1f–i (80–90%).
Respective alkyl methyl ketone (1–6 mmol, 2–12 equiv) was added
to a stirring mixture of (silylmethylene)malonate 5 (153 mg, 0.5
mmol, 1 equiv), pyrrolidine 6c (23 mg, 0.15 mmol, 0.3 equiv) and
TFA (4 mL, 0.05 mmol, 0.1 equiv) in NMP (2 mL) at –10 °C. After
3–7 d at –10 °C, the mixture was diluted with H2O and extracted
with EtOAc–hexane (1:1). The organic extract was washed with
brine, dried (MgSO4), and evaporated. The residue was purified by
column chromatography (silica gel, hexane–EtOAc, 95:5) to give
2a–k (76–94%).
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-5-oxotetradecanoate (1f)
Following general procedure 2 using 2f (170 mg, 0.357 mmol),
NaCl (40 mg, 0.68 mmol), H2O (1 mL), and DMSO (28 mL) gave
1f (123 mg, 85%); HPLC (Daicel Chiralpak AD-H, i-PrOH–hex-
ane, 1:99, flow rate = 1.0 mL/min): tR = 9.9 (94.87%) [(3S)-1f], 15.3
min (5.13%) [(3R)-1f].
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-2-(ethoxycarbonyl)-5-oxo-
hexadecanoate (2h)
Following general procedure 1 using tridecan-2-one (595 mg, 3
mmol), malonate 5 (153 mg, 0.5 mmol), pyrrolidine 6c (23 mg, 0.15
mmol, 0.3 equiv), and TFA (4 mL, 0.05 mmol, 0.1 equiv) in NMP
(2 mL) at 4 °C for 6 d gave 2h (201 mg, 80%); HPLC (Daicel
Chiralpak AD-H, i-PrOH–hexane, 0.7:99.3, flow rate = 0.6 mL/
min): tR = 17.2 (93.55%) [(3S)-2h], 27.4 min (6.45%) [(3R)-2h].
[a]D25 –6.93 (c 2.31, CHCl3).
IR (neat): 2956, 2927, 2855, 1724, 1718, 1216, 1112, 1036, 816,
754 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.29 (s, 3 H, SiCH3), 0.30 (s, 3 H,
SiCH3), 0.87 [t, J = 6.5 Hz, 3 H, (CH2)8CH3], 1.10–1.33 [m, 15 H,
(CH2)7CH3, CH3CH2OCO], 1.40–1.52 (m, 2 H, CH2), 1.87–2.01 (m,
1 H, SiCH), 2.12–2.44 (m, 6 H, CH2COCH2, CH2CO2Et), 4.00 (q,
J = 7.2 Hz, 2 H, CH3CH2OCO), 7.32–7.37 (m, 3 H, Ph), 7.46–7.51
(m, 2 H, Ph).
[a]D23 +4.67 (c 1.07, CHCl3).
IR (neat): 2981, 1748, 1730, 1465, 1367, 1249, 1151, 1111, 1034,
819 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.32 (s, 3 H, SiCH3), 0.33 (s, 3 H,
SiCH3), 0.87 [t, J = 6.3 Hz, 3 H, CH3(CH2)10CO), 1.16–1.30 [m, 22
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

1942
R. Chowdhury, S. K. Ghosh
PAPER
13C NMR (50 MHz, CDCl3): d = –4.5, –4.3, 14.1, 17.2, 22.7, 23.8,
29.2 (2 C), 29.3 (2 C), 29.4 (2 C), 31.9, 34.7, 42.7, 60.3, 127.8 (2
C), 129.2, 133.9 (2 C), 136.9, 173.6, 210.5.
HRMS (ESI): m/z [M + Na]+ calcd for C23H36O3NaSi: 411.2331;
found: 411.2329.
Methyl (3S)-3-[Dimethyl(phenyl)silyl]-5-oxotetradecanoate
(17)
MS (EI, 70eV): m/z (%) = 389 (13), 371 (13), 327 (20), 135 (100),
78 (43).
LiOH·H2O (20 mg, 0.43 mmol) was added to a stirring soln of 1f (92
mg, 0.228 mmol) in 5% aq MeOH (2 mL) at r.t. After 6 h, the sol-
vent was evaporated under reduced pressure and the residue was di-
luted with H2O (1 mL), acidified with dil. HCl and extracted with
EtOAc. The extract was dried (Na2SO4) and evaporated under re-
duced pressure. The residue was esterified with ethereal diazo-
methane, the solvent was evaporated, and the residue was
chromatographed to give the methyl ester 17 (80 mg, 90%).
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-5-oxodecanoate (1g)
Following general procedure 2 using 2g (360 mg, 0.857 mmol),
NaCl (60 mg, 1 mmol), H2O (1.5 mL), and DMSO (40 mL) gave 1g
(268 mg, 90%).
[a]D27 –7.62 (c 0.63, CHCl3).
IR (film): 3070, 3019, 2957, 2931, 2872, 1730, 1715, 1216, 1112,
1041, 836, 817, 758 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.29 (s, 3 H, SiCH3), 0.32 (s, 3 H,
SiCH3), 0.85 [t, J = 7.3 Hz, 3 H, (CH2)4CH3], 1.28–1.59 [m, 7 H,
[a]D24 –0.8 (c 0.8, CHCl3) [Lit.8a [a]D21 –0.8 (c 0.79, CHCl3)].
IR (neat): 2952, 2925, 2854, 1736, 1715, 1250, 1112, 816, 774, 701
cm–1
CH3(CH2)2CH2CH2CO, CH3CH2OCO], 1.38–1.53 [m,
2 H,
1H NMR (200 MHz, CDCl3): d = 0.29 [s, 6 H, Si(CH3)2], 0.86 (t,
CO(CH2)3CH2CH3], 1.90–2.00 (m, 1 H, SiCH), 2.11–2.43 [m, 6 H,
CH2COCH2(CH2)3CH3, CH2CO2CH2CH3], 4.00 (q, J = 7 Hz, 2 H,
CH3CH2OCO), 7.32–7.35 (m, 3 H, Ph), 7.45–7.50 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –4.6, –4.3, 13.8, 14.0, 17.2, 22.3,
23.4, 31.2, 34.6, 42.5, 42.6, 60.2, 127.7 (2 C), 129.1, 133.9 (2 C),
136.9, 173.5, 210.0.
J = 6.4 Hz,
3 H, CH3CH2CH2), 1.12–1.38 [br s, 12 H,
CH2(CH2)6CH3], 1.41–1.50 (m, 2 H, COCH2CH2), 1.87–2.00 (m, 1
H, SiCH), 2.12–2.43 (m, 6 H, CH2COCH2, CH2CO2CH3), 3.55 (s, 3
H, OCH3), 7.33–7.36 (m, 3 H, Ph), 7.45–7.5 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –4.6, –4.4, 14.0, 17.2, 22.6, 23.7,
29.1, 29.2, 29.3 (2 C), 31.8, 34.5, 42.6 (2 C), 51.4, 127.8 (2 C),
129.2, 133.9 (2 C), 136.8, 173.9, 210.4.
MS (EI, 70eV): m/z (%) = 333 (15), 271 (25), 249 (15), 135 (100).
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-5-oxohexadecanoate (1h)
Following general procedure 2 using 2h (600 mg, 1.19 mmol), NaCl
(100 mg, 1.7 mmol), H2O (2 mL), and DMSO (60 mL) gave 1h (412
mg, 80%).
(4S,6S)-4-[Dimethyl(phenyl)silyl]-6-pentyl-tetrahydro-2H-pyr-
an-2-one (20a)
NaBH4 (30 mg, 0.78 mmol) was added portionwise to a stirring soln
of 1g (109 mg, 0.31 mmol) in EtOH (1.5 mL) at 0 °C. After 5 h, the
mixture was quenched with sat. NH4Cl soln and extracted with
CH2Cl2. The organic extract was washed with brine, dried
(Na2SO4), and evaporated under reduced pressure to give an insep-
arable diastereomeric mixture of alcohols 18a and 19a (18a/19a
80:20) (86 mg). The alcohol mixture was dissolved in 10% aq
MeOH (1 mL) and LiOH (42 mg 1.0 mmol, 4 equiv) was added por-
tionwise at r.t. The mixture was stirred overnight and the solvent
was evaporated under reduced pressure. The residue was diluted
with H2O (1 mL), acidified with dil. HCl and extracted with EtOAc.
The organic extract was dried (Na2SO4) and evaporated under re-
duced pressure. The residue was purified by column chromatogra-
phy to give 20a (55 mg, 58%).
[a]D26 –6.0 (c 2.97, CHCl3).
IR (film): 2957, 2932, 2871, 1730, 1715, 1212, 1112, 1041, 836,
817, 758 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.29 [s, 6 H, Si(CH3)2], 0.86 (t,
J = 6.4 Hz, 3 H, [CH2]10CH3), 1.16–1.23 [m, 19 H, CH3CH2OCO,
COCH2CH2(CH2)8CH3],
COCH2CH2(CH2)8CH3], 1.87–2.00 (m, 1 H, SiCH), 2.11–2.35
[m, H, CH2COCH2(CH2)9CH3], 2.40–2.44 (m, H,
1.38–1.53
[m,
2
H,
4
2
CH2CO2CH2CH3), 4.00 (q, J = 7 Hz, 2 H, CH3CH2OCO), 7.27–7.35
(m, 3 H, Ph), 7.46–7.50 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –4.7, –4.4, 13.8, 13.9, 17.2, 22.5,
23.6, 29.0, 29.1, 29.2, 29.3, 29.4 (2 C), 31.7, 34.5, 42.4, 42.6, 60.0,
127.6 (2 C), 128.9, 133.7 (2 C), 136.9, 173.1, 209.8.
[a]D28 –52.0 (c 1.75, CHCl3).
IR (film): 3010, 2960, 2931, 2859, 1740, 1427, 1256, 1113, 1064,
834, 812, 701 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C26H45O3Si: 433.3138; found:
433.3141.
1H NMR (200 MHz, CDCl3): d = 0.32 [s, 6 H, Si(CH3)2], 0.86 [t,
J = 6.5 Hz, 3 H, (CH2)4CH3], 1.25–1.51 [m, 7 H, SiCH,
CH2(CH2)3CH3], 1.59–1.83 [m, 4 H, COCH2, CH3(CH2)3CH2], 2.22
(dd, J = 11.2, 16.0 Hz, 1 H, SiCHCHAHBCHOCO), 2.42 (dd,
J = 5.6, 16.0 Hz, 1 H, SiCHCHAHBCHOCO), 3.97–4.09 (m, 1 H,
CHOCO), 7.35–7.38 (m, 3 H, Ph), 7.44–7.49 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –5.6, –5.5, 13.9, 14.9, 22.4, 24.8,
28.0, 29.9, 31.4, 34.9, 78.2, 128.0 (2 C), 129.5, 133.7 (2 C), 135.6,
173.6.
Ethyl (3S)-3-[Dimethyl(phenyl)silyl]-7-cyclohexyl-5-oxohep-
tanoate (1i)
Following general procedure 2 using 2i (827 mg, 1.79 mmol), NaCl
(130 mg, 2.24 mmol), H2O (2 mL), and DMSO (60 mL) gave 1i
(555 mg, 80%).
[a]D25 –6.4 (c 2.64, CHCl3).
IR (film): 2958, 2931, 2871, 1731, 1715, 1216, 1112, 1041, 836,
817, 759 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.29 [s, 6 H, Si(CH3)2], 0.72–0.89
(m, 3 H, c-C6H11), 1.01–1.23 (m, 6 H, c-C6H11, CO2CH2CH3), 1.29–
1.40 (m, 2 H, COCH2CH2C6H11), 1.50–1.67 (m, 5 H, c-C6H11),
HRMS (ESI): m/z [M + H]+ calcd for C18H29O2Si: 305.1934; found:
305.1931.
(4S,6S)-4-Hydroxy-6-pentyl-tetrahydro-2H-pyran-2-one (21)
To a stirring soln of 20a (150 mg, 0.49 mmol) and AcOOH (35%
soln in AcOH, 3 mL) at 0 °C was added KBr (72 mg, 0.6 mmol),
then H2O2 (30%, 0.1 mL). The mixture was allowed to attain r.t. and
stirred for 24 h. The solvent was removed under reduced pressure
and the residue was dissolved in CH2Cl2. The organic phase was
dried (Na2SO4) and evaporated under reduced pressure. The residue
1.87–2.00 (m,
1
H, SiCH), 2.11–2.35 (m,
4
H,
CH2COCH2CH2C6H11), 2.41–2.50 (m, 2 H, CH2CO2CH2CH3), 4.00
(q, J = 7 Hz, 2 H, CH3CH2OCO), 7.30–7.36 (m, 3 H, Ph), 7.45–7.50
(m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –4.6, –4.3, 14.0, 17.3, 26.1 (2 C),
26.5, 31.0, 33.0 (2 C), 34.6, 37.2, 40.1, 42.7, 60.1, 127.7 (2 C),
129.1, 133.9 (2 C), 137.0, 173.3, 210.4.
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

PAPER
Enantioselective Route to b-Silyl-d-keto Esters
1943
was purified by column chromatography to give 21 (53 mg, 58%)
as an oil.
[a]D28 –34.7 (c 1.5, CHCl3) [Lit.48 value for the antipode of 21 [a]D
+29.4 (c 1.4, CHCl3)].
CH2(CH2)9CH3, CHOHCH2CHOCO], 2.61 (dd, J = 3.8, 17.6 Hz, 1
H, CHAHBCOO), 2.72 (dd, J = 5.0, 17.6 Hz, 1 H, CHAHBCOO),
4.32–4.39 (m, 1 H, CHOH), 4.60–4.74 (m, 1 H, CHOCO).
13C NMR (50 MHz, CDCl3): d = 13.9, 22.6, 24.8, 29.3, 29.4, 29.5,
(2 C), 29.6 (2 C), 31.8, 35.5, 35.8, 38.5, 62.2, 76.2, 171.3.
IR (film): 3419, 3015, 2956, 2930, 2860, 1715, 1376, 1256, 1035
758 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C16H31O3: 271.2273; found:
271.2282.
1H NMR (700 MHz, CDCl3): d = 0.90 [t, J = 7 Hz, 3 H, (CH2)4CH3],
1.28–1.34 [m, 4 H, CH2CH2(CH2)2CH3], 1.36–1.43 [m, 1 H,
(S)-6-Undecyl-5,6-dihydro-2H-pyran-2-one (22)
CH2CHAHB(CH2)2CH3],
CH2CHAHB(CH2)2CH3],
CHAHBCH2(CH2)2CH3],
1.48–1.55
1.57–1.62
1.69–1.77
[m,
[m,
[m,
1
1
2
H,
H,
H,
MsCl (23 mL, 0.32 mmol) was added to a stirring soln of 8 (80 mg,
0.29 mmol) and Et3N (40 mL, 0.64 mmol) in CH2Cl2 (2.5 mL) at 0
°C. After 1 h, the mixture was quenched with sat. NH4Cl soln. The
mixture was extracted with CH2Cl2 and the extract was evaporated
to give the crude mesylate. The mesylate and DBU (185 mL, 1.24
mmol) were dissolved in anhyd CH2Cl2 (1 mL) and the mixture was
stirred overnight. The mixture was diluted with CH2Cl2 and washed
with sat. NH4Cl soln. The organic layer was separated, dried
(Na2SO4), and evaporated under reduced pressure. The residue was
purified by column chromatography (silica gel) to give 22 (47 mg,
65%); mp 48–51 °C [Lit.49a 45–47 °C].
CHAHBCH2(CH2)2CH3, OCHCHAHBCHOH], 1.96 (m, 1 H, OCH-
CHAHBCHOH), 2.13 (br s, 1 H, OH), 2.62 (dd, J = 4, 18 Hz, 1 H,
CHAHBCOO), 2.73 (dd, J = 5, 18 Hz, 1 H, CHAHBCOO), 4.36–4.40
(m, 1 H, CHOH), 4.65–4.72 (m, 1 H, CHOCO).
13C NMR (175 MHz, CDCl3): d = 13.9, 22.5, 24.5, 31.5, 35.4, 35.8,
38.6, 62.6, 76.0, 170.9.
MS (EI, 70 eV): m/z (%) = 187 (3) [M + H]+, 169 (2), 140 (7), 115
(79), 97 (100), 73 (42).
[a]D29 +57.0 (c 1.0, THF) [Lit.49b [a]D25 +78.7 (c 1.0, THF)].
(4S,6S)-4-[Dimethyl(phenyl)silyl]-6-undecyl-tetrahydro-2H-
pyran-2-one (20b)
1H NMR (200 MHz, CDCl3): d = 0.86 [t, 3 H, (CH2)10CH3], 1.24
[br s, 20 H, (CH2)10CH3], 2.26–2.34 (m, 2 H, CH2CHOCO), 4.33–
4.46 (m, 1 H, CHOCO), 6.00 (dt, J = 1.6, 9.8 Hz, 1 H,
CH2CH=CHCO), 6.86 (dt, J = 4.4, 9.6 Hz, 1 H, CH2CH=CHCO).
13C NMR (50 MHz, CDCl3): d = 14.0, 22.6, 24.8, 29.2, 29.3, 29.4
(2 C), 29.5, 29.6 (2 C), 31.9, 34.9, 78.0, 121.5, 144.8, 164.5.
NaBH4 (88 mg, 2.3 mmol) was added portionwise to a stirring soln
of 1h (400 mg, 0.92 mmol) in EtOH (4.5 mL) at 0 °C. After 5 h, the
mixture was quenched with sat. NH4Cl soln and extracted with
CH2Cl2. The organic extract was washed with brine, dried
(Na2SO4), and evaporated under reduced pressure to give an insep-
arable diastereomeric mixture of alcohols 18b and 19b (18b/19b
80:20) (370 mg). The alcohol mixture was dissolved in 10% aq
MeOH (4 mL) and LiOH (144 mg 3.4 mmol, 4 equiv) was added
portionwise at r.t. The mixture was stirred overnight and the solvent
was evaporated under reduced pressure. The residue was diluted
with H2O (4 mL), acidified with dil. HCl, and extracted with
EtOAc. The organic extract was dried (Na2SO4) and evaporated un-
der reduced pressure. The residue was purified by column chroma-
tography to give 20b (235 mg, 66%).
(4S,6S)-6-(2-Cyclohexylethyl)-4-[dimethyl(phenyl)silyl]-tetra-
hydro-2H-pyran-2-one (20c)
NaBH4 (115 mg, 3 mmol) was added portionwise to a stirring soln
of 1i (455 mg, 1.17 mmol) in EtOH (5 mL) at 0 °C. After 5 h, the
mixture was quenched with sat. NH4Cl soln and extracted with
CH2Cl2. The organic extract was washed with brine, dried
(Na2SO4), and evaporated under reduced pressure to give an insep-
arable diastereomeric mixture of alcohols 18c and 19c (18c/19c
80:20) (394 mg). The alcohol mixture was dissolved in 10% aq
MeOH (4 mL) and LiOH (170 mg 4 mmol) was added portionwise
it at r.t. The mixture was stirred overnight and the solvent was evap-
orated under reduced pressure. The residue was diluted with H2O (4
mL), acidified with dil. HCl and extracted with EtOAc. The organic
extract was dried (Na2SO4)and evaporated under reduced pressure.
The residue was purified by column chromatography to give 20c
(250 mg, 62%).
[a]D25 –39.9 (c 1.93, CHCl3).
IR (film): 3010, 2960, 2930, 2860, 1741, 1425, 1256, 1113, 1064,
834, 812, 701 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.30 [s, 6 H, Si(CH3)2], 0.87 [t,
J = 6.2 Hz, 3 H, (CH2)10CH3], 1.24 [br s, 18 H, (CH2)9CH3], 1.33–
1.51 [m, 3 H, SiCH, CH2(CH2)9CH3], 1.66–1.81 (m, 2 H,
CHOCH2CHSi), 2.21 (dd, J = 13, 16 Hz, 1 H, CHAHBCOO), 2.42
(dd, J = 7.6, 16 Hz, 1 H, CHAHBCOO), 3.97–4.09 (m, 1 H,
CHOCO), 7.33–7.39 (m, 3 H, Ph), 7.44–7.49 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –5.7, –5.6, 13.8, 14.9, 22.5, 24.9,
27.9, 29.1 (2 C), 29.2, 29.3, 29.4 (2 C), 29.9, 31.7, 34.9, 77.9, 127.8
(2 C), 129.4, 133.6 (2 C), 135.6, 173.0.
[a]D23 –49.5 (c 2.0, CHCl3).
IR (film): 3011, 2922, 2850, 1743, 1448, 1256, 1113, 1066, 834,
815, 736 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.32 [s, 6 H, Si(CH3)2], 0.76–0.95
(m, 2 H, c-C6H11), 1.01–1.54 (m, 7 H, SiCH, CH2CH2-c-C6H11,
c-C6H11), 1.62–1.83 (m, 9 H, SiCHCH2CHOCO, CH2CH2-c-C6H11,
c-C6H11), 2.21 (dd, J = 13, 15.8 Hz, 1 H, CHAHBCOO), 2.42 (dd,
J = 5.6, 15.8 Hz, 1 H, CHAHBCOO), 3.94–4.06 (m, 1 H, CHOCO),
7.33–7.39 (m, 3 H, Ph), 7.39–7.49 (m, 2 H, Ph).
13C NMR (50 MHz, CDCl3): d = –5.7, –5.6, 14.9, 26.0 (2 C), 26.4,
27.9, 29.9, 32.2, 32.5, 32.9, 33.0, 37.3, 78.4, 127.9 (2 C), 129.4,
133.6 (2 C), 135.6, 173.2.
(4S,6S)-4-Hydroxy-6-undecyl-tetrahydro-2H-pyran-2-one (8)
To a stirring soln of 20b (235 mg, 0.6 mmol) and AcOOH (35%
soln in AcOH, 4 mL) at 0 °C was added KBr (88 mg, 0.74 mmol),
then H2O2 (30%, 0.1 mL). The mixture was allowed to attain r.t. and
stirred for 24 h. The solvent was removed under reduced pressure
and the residue was dissolved in CH2Cl2. The organic phase was
dried (Na2SO4) and evaporated under reduced pressure. The residue
was purified by column chromatography to give 8 (87 mg, 53%) as
an oil.
HRMS (ESI): m/z [M + H]+ calcd for C21H33O2Si: 345.2250; found:
345.2236.
[a]D25 –22.9 (c 2.1, CHCl3).
(4S,6S)-6-(2-Cyclohexylethyl)-4-hydroxy-tetrahydro-2H-pyr-
an-2-one (11)
To a stirring soln of 20c (232 mg, 0.67 mmol) and AcOOH (35%
soln in AcOH, 4 mL) at 0 °C was added KBr (102 mg, 0.86 mmol),
IR (film): 3420, 3017, 2956, 2930, 2853, 1715, 1376, 1256, 1035,
758 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 [t, J = 6.0 Hz, 3 H,
(CH2)10CH3], 1.47 [br s, 18 H, (CH2)9CH3], 1.45–2.06 [m, 4 H,
Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York

1944
R. Chowdhury, S. K. Ghosh
PAPER
(15) For recent methodologies, see: Walter, C.; Oestreich, M.
Angew. Chem. Int. Ed. 2008, 47, 3818; and references cited
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(16) Trost, B. M. Science 1991, 254, 1471.
then H2O2 (30%, 0.1 mL). The mixture was allowed to attain r.t. and
stirred for 24 h. The solvent was removed under reduced pressure
and the residue was dissolved in CH2Cl2. The organic phase was
dried (Na2SO4) and evaporated under reduced pressure. The residue
was purified by column chromatography to give 11 (84 mg, 56%);
mp 74–75 °C [Lit.50 72–74 °C].
(17) Date, S. M.; Singh, R.; Ghosh, S. K. Org. Biomol. Chem.
2005, 3, 3369.
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[a]D –32.9 (c 0.94, CHCl3) [Lit.50 value for the antipode of 11
27
[a]D25 +29 (c 0.28, CHCl3)].
IR (film): 3419, 3019, 2955, 2930, 2853, 1717, 1066, 758 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.78–0.94 (m, 2 H, c-C6H11),
1.00–1.52 (m, 6 H, CH2CH2-c-C6H11, c-C6H11), 1.57–1.78 (m, 7 H,
CHOHCH2CHOCO, CH2CH2-c-C6H11, c-C6H11), 1.91–2.03 (m, 3
H, c-C6H11, OH), 2.59 (dd, J = 2.8, 17.8 Hz, 1 H, CHAHBCOO),
2.71 (dd, J = 4.8, 17.8 Hz, 1 H, CHAHBCOO), 4.32–4.40 (m, 1 H,
CHOH), 4.57–4.71 (m, 1 H, CHOCO).
13C NMR (50 MHz, CDCl3): d = 26.2 (2 C), 26.6, 32.3, 32.9, 33.2,
33.3, 35.9, 37.5, 38.6, 62.6, 76.4, 170.9.
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Enantioselective Route to b-Silyl-d-keto Esters
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Synthesis 2011, No. 12, 1936–1945 © Thieme Stuttgart · New York