Organocatalytic Michael addition of aldehydes to a β-silylmethylene malonate to form intermediates for the enantioselective synthesis of hydroxylated valerolactones and piperidines

Article abstract of DOI:10.1016/j.tetasy.2010.10.011

The direct Michael addition of enolizable aldehydes to dimethyl(phenyl) silylmethylene malonate was catalysed by an (S)-diphenylprolinol trimethylsilyl ether/acetic acid combination. The adducts were formed in good yield, high diastereoselectivity and excellent enantioselectivity. Chiral valerolactone and piperidine skeletons embedded with a silyl and other functionalities have been made out of the adducts. A total synthesis (+)-simplactone B has been achieved from one of the adducts.

Full text of DOI:10.1016/j.tetasy.2010.10.011

Tetrahedron: Asymmetry 21 (2010) 2696–2702
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic Michael addition of aldehydes to a b-silylmethylene
malonate to form intermediates for the enantioselective synthesis
of hydroxylated valerolactones and piperidines
⇑
Raghunath Chowdhury, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct Michael addition of enolizable aldehydes to dimethyl(phenyl)silylmethylene malonate was
catalysed by an (S)-diphenylprolinol trimethylsilyl ether/acetic acid combination. The adducts were
formed in good yield, high diastereoselectivity and excellent enantioselectivity. Chiral valerolactone
and piperidine skeletons embedded with a silyl and other functionalities have been made out of the
adducts. A total synthesis (+)-simplactone B has been achieved from one of the adducts.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 27 September 2010
Accepted 15 October 2010
Available online 9 November 2010
1. Introduction
SiMe2Ph
CO2R
CO2R
O
PhMe2Si
R1
E
Chiral heterocyclic compounds are widely found as natural
products1 and have a wide range of biological properties including
important pharmacological activities. Amongst them, chiral
hydroxylated d-lactones and pyrrolidines have ‘privileged’ struc-
tures.2,3 We have proposed a general strategy for the synthesis of
these two classes of skeletons from intermediates 1–3 (Fig. 1) con-
taining a silicon group at the b-position with respect to the two
carbonyl functionalities. The dimethyl(phenyl)silyl group was pur-
posely chosen to take advantage of its easy installation, manipula-
tions, unique reactivity, regio- and stereo-chemical control offered
by a silicon group in general,4 and as a masked hydroxyl group.5–9
In general, carbonyl compounds with a silyl group at the b-posi-
tion are popular targets because of their versatile nature10 and also
their synthetic equivalence with aldols.11,12 Enantio/diastereoselec-
tive conjugate silylation13 of an unsaturated carbonyl compound is
an important tool, and the reaction is usually achieved with the
use of silyl nucleophiles, such as silyl copper14–17 or silyl zinc18 re-
agents. Transition metal-catalysed reactions of disilanes19–24 and
R2
R3
1; R3 = H, R1 = alkyl
2; R3 = CO2R, R1 = H
3; R3 = CO2R, R1 = alkyl
4; E = H
5; E = CO2R
OH
Ph
Ph
OSiMe3
N
N
H
N
H
O
O
6
7a
7b
Figure 1. Structures of substrates, catalysts and target molecule.
carbonyl compound28,29 and a desymmetrization30,31 of 3-silyl
substituted glutaric anhydride followed by selective functional
group manipulations. However, an alternative and straightforward
synthesis could be based on the enantioselective Michael addition
of an alkyl methyl ketone or an enolizable aldehyde to the b-silyl
acrylate 4 or b-silylmethylene malonate 532,33 (Fig. 1).
Amongst the asymmetric Michael reactions developed in the
field of organocatalysis,34–39 the direct addition of ketones or alde-
hydes to activated olefins has been tested with satisfactory results.
However, the addition of the same donors40 to alkylidene malo-
nates has been less successful in terms of generality, efficacy and
selectivity. Very recently, a number of efforts have been made by
several groups41–48 including our own49 to address those issues
in ketone addition to alkylidene malonates. Similar to ketones,
the addition of aldehyde donors to alkylidene malonates is a useful
a
,b-unsaturated carbonyl compounds have resulted in silylated
products equivalent to 1,4-silicon addition. Recently, Cu salts25,26
have been reported to promote the conjugate addition of silyl re-
agents to
nates. Enantioselective conjugate silyl transfer to acyclic and cyclic
,b-unsaturated carbonyl acceptors has been reported under Rh(I)
a,b-unsaturated carbonyl compounds or arylidene malo-
a
catalysis using silicon reagents with a Si–B linkage leading to b-silyl
carbonyl compounds.27 Other approaches involve the metal cata-
lysed conjugative C–C bond formation onto a b-silyl a,b-unsaturated
⇑
Corresponding author. Tel.: +91 22 25595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.011

R. Chowdhury, S. K. Ghosh / Tetrahedron: Asymmetry 21 (2010) 2696–2702
2697
objective. Initial studies42 on the use of unmodified aldehydes
were unsuccessful with regards to this class of Michael acceptors.
Only one successful report has appeared40 very recently wherein
unmodified aldehydes were engaged to add onto alkylidene malo-
nates with very high diastereo and enantioselectivity.
Herein, we report an efficient, highly regio and enantioselective
organocatalytic Michael addition of enolizable aldehydes to the b-
silylmethylene malonate 5a (R = Et; Fig. 1) leading to b-silylaldehy-
des 2. These adducts can be easily transformed into medium-sized
rings leading to skeletal and stereochemical diversity of complex
structures, patterned after the hydroxylated pyrrolidine and val-
erolactones. The potential of this general approach has also been
applied for the total synthesis of (+)-simplactone B 6.50
reaction was incomplete even after increasing the reaction time as
well as fresh addition of butyraldehyde. A significant amount of the
homoaldol product54 of butyraldehyde was also formed, which can
be easily removed by chromatographic purification. We also tried
the reaction in brine55 (Table 1, entry 3) using 15 mol % of catalyst
7b and 30 mol % of acetic acid at room temperature for 5 days. In
this case also, the yield was moderate due to incomplete reaction.
The diastereoselectivity was high and enantioslectivity of the ma-
jor diasteromer was also very good. When NMP was used as the
solvent, (Table 1, entry 4) the diastereoselectivity was poor.
Although acetonitrile (Table 1, entry 5) appeared to be very good
as improved ee and de were observed, it required low temperature
and longer reaction time in order to achieve these results. Similar
results were observed with isopropanol (Table 1, entry 6) as sol-
vent, but the enantioselectivity was slightly inferior to acetonitrile.
No reaction took place when THF (Table 1, entry 7) was used as the
solvent. Halogenated solvents, such as chloroform and dichloro-
methane were found to be good for this reaction. The reaction in
chloroform at room temperature underwent completion in
3.5 days providing the product in 81% yield but the de and ee were
only moderate (Table 1, entry 8). Switching the solvent from chlo-
roform to dichloromethane, significantly improved the diastero-
and enantioselectivity but the yield dropped (Table 1, entry 9).
We then carried out the reaction using catalyst 7b (15 mol %)
and a catalytic amount of acetic acid as an additive (Table 1, entry
10). An improvement in yield and de was observed without much
affecting the enantioselectivity. Increasing the amount of acetic
acid or adding benzoic acid as additive did not improve the yield
and selectivities (Table 1, entries 11 and 12). Therefore, we formu-
lated the optimized conditions by using 1 equiv of silylmethylene
2. Results and discussion
Recently we have shown49 a highly regioselective Michael addi-
tion of alkyl methyl ketones to b-silylmethylene malonate 5a using
N-(2-pyrrolidinylmethyl)pyrrolidine 7a51 (Fig. 1) and TFA combi-
nation as the catalyst system of choice and NMP as the solvent. A
large number of alkyl methyl ketones with varying steric or elec-
tronic natures were reacted with silylmethylene malonate 5a to
give exclusively the adducts 3 with excellent yield and high enanti-
oselectivity (Scheme 1). Unlike ketones, the regioselectivity issue
does not arise for aldehydes but the stereoselectivity and enanti-
oselectivity issues are very important. We chose butyraldehyde
as the model aldehyde and concentrated our efforts on optimizing
the yield, and the diastereo- and enantioselectivity of adduct 2a (R,
R2 = Et, Fig. 1). We initially used (S)-proline as a catalyst (20 mol %)
using 10 equiv of butyraldehyde with respect to substrate 5a in
NMP at room temperature, which provided adduct 2a in moderate
yield (42%) and high diastereoselectivity (dr = 96/4) but with very
poor enantioselectivity (12.4% ee for the major diastereoisomer)
(Scheme 2). Since N-(2-pyrrolidinylmethyl)pyrrolidine 7a in com-
bination with TFA in NMP49 gave very good results in the direct
addition of alkyl methyl ketones to 5a, we used the same condi-
tions for the butyraldehyde addition. The reaction was very slow
with about 20% conversion after 10 days. The reaction remained
incomplete even when it was carried out at room temperature
for over one week. The yield (40%), diastereoselctivity (dr = 80/
20) and enantioselectivity (37% ee) for adduct 2a were also found
to be moderate.
Pyrrolidines derived from prolines, such as diphenylprolinol si-
lyl ether 7b52 (Fig. 1) have been shown to be effective catalysts for
aldehydes addition onto nitro olefins. We also found that this cat-
alyst was good for the addition of butyraldehyde to the silylmeth-
ylene malonate 5a. We chose 7b as the catalyst for the addition and
carried out a number of experiments in different solvents and
under different conditions to obtain the optimum yield, and diaste-
reo- and enantioselectivity. The results are summarized in Table 1.
The reaction was carried out in water53 with 15–20 mol % of 7b at
room temperature for 3 days leading to the formation of the prod-
uct as a mixture of diatereoisomers with moderate selectivity and
in 62–64% yield (Table 1, entries 1 and 2). The enantiomeric excess
of the major diastereoisomer in these reactions was very high. The
malonate 5a, 10 equiv of butyraldehyde,
a combination of
15 mol % each of 7b and acetic acid as the catalyst system and
dichloromethane as the solvent. The reaction mixture was left
standing at room temperature for 4 days and gave the adduct 2a
in 79% yield as a mixture of diasteroisomers in a ratio of 86:14.
The enantiomeric excess of the major diastereoisomer was also
found to be excellent (98%) as analysed by HPLC using a chiral sta-
tionary phase.
Withtheoptimalcatalyst, additiveandreactionconditionsestab-
lishedwith butyraldehyde, we turned our attentionto generalize the
addition with three more aldehydes. The results are summarized in
Table 2. n-Pentanal reacted smoothly with the silylalkylidene mal-
onate 5a under the optimized conditions to give the desired product
in good yield. The diastereoselectivity was also very high and the
enantioselectivity for the major diasteroisomer was excellent
(Table 2, entry 2). n-Hexanal and n-heptanal also reacted providing
the adduct in good yield, high diastereoselectivity and excellent
enantioselectivity (Table 2, entries 3 and 4).
Both, the relative and absolute configurations of the majordiaste-
reoisomer 2a were assigned by converting it to (+)-simplactone B 6,
the antipode of a known and natural valerolactone58 (Scheme 3). For
this, adduct 2a was subjected to sodium cyanoborohydride reduc-
tion conditions followed by hydrolysis with lithium hydroxide. The
substituted malonic acid intermediate produced was heated at
110 °C which caused decarboxylation and concomitant lactoniza-
tion leading directly to the desired lactone 8 in very good yield after
SiMe2Ph
O
7a
O
PhMe2Si
CO2Et
CO2Et
(30 mol%)
CO2Et
R
+
TFA
R
Me
CO2Et
(10 mol%)
NMP, -10 oC
3-7 days
3
R = alkyl
5a
yield up to 94%
ee up to 99.6%
Scheme 1. Conjugate addition of alkyl methyl ketones to silylmethylene malonate 5a.49

2698
R. Chowdhury, S. K. Ghosh / Tetrahedron: Asymmetry 21 (2010) 2696–2702
O
SiMe2Ph
CO2Et
PhMe2Si
CO2Et
CO2Et
O
catalyst
NMP
H
+
H
CO2Et
2a
28 o
C
5a
10 equiv.
Conditions
yield (%) dr % ee (syn)
1. (S)-proline (20 mol%)
4 days
42
40
79
96/4
80/20
86/14
12.4
2. 7a/TFA (30 mol%)
7 days
37
3. 7b/AcOH (15 mol%)
4 days
98
Scheme 2. Organocatalysed direct addition of butyraldehyde to silylmethylene malonate 5a.
Table 1
Optimization of butyraldehyde addition to silylmethylene malonate 5a
O
SiMe2Ph
CO2Et
PhMe2Si
O
CO2Et
CO2Et
7b (15-20 mol%)
+
H
conditions
H
CO2Et
2a
5a
10 equiv.
Entry
Additive (mol %)
Solvent/temp (°C)/time (d)
Yielda (%) of 2a
drb
eec (%) of syn-2a
d
1
2
3
4
5
6
7
8
9
—
—
H2O/28/3
H2O/28/4
62e
64e
51e
50e
84
70/30
75/25
77/23
60/40
83/17
80/20
—
79/21
84/16
86/14
83/17
85/15
92.3f
97.1
93.1
ndg
>99f
93.3f
—
91
>99
98
d
AcOH (30)
AcOH (15)
Brine/28/5
NMP/28/4
MeCN/4/7
i-PrOH/4/7
THF/28/7
CHCl3/28/3.5
CH2Cl2/28/5
CH2Cl2/28/4
CH2Cl2/28/4
CH2Cl2/28/6
d
—
—
—
—
d
86
d
nrh
81
d
d
—
67e
79
10
11
12
AcOH (15)
AcOH (30)
BzOH (15)
66e
67e
>99
97
a
b
c
Yield refers to the mixture of diastereoisomeric products.
Diastereoisomer ratio (dr) was determined from the 1H NMR of the crude product.
Enantiomeric excess (ee) of the major diastereoisomer (separated by column chromatography) was determined by HPLC using a chiral OD-H column with hexane–
isopropyl alcohol (99.6:0.4) as eluent.
d
No additive was used.
Incomplete reaction.
20 mol % catalyst was used.
nd = Not determined.
e
f
g
h
nr = No reaction.
Table 2
Addition of unmodified aldehydes to silylmethylene malonate 5a
O
SiMe2Ph
CO2Et
7b
O
PhMe2Si
CO2Et
CO2Et
(15 mol%)
H
+
R
AcOH
(15 mol%)
CH2Cl2, 28 o
4 days
R
CO2Et
H
10 equiv.
5a
2a; R = Et
C
2b; R = n-Pr
2c; R = n-Bu
2d; R = n-Pent
Entry
Aldehyde
Product
Yielda (%) conversionb (%)
drc (syn/anti)
eed (%) (syn)
1
2
3
4
n-Butanal
n-Pentanal
n-Hexanal
n-Heptanal
2a
2b
2c
2d
79 (98)
70 (95)
73 (96)
75 (93)
86/14
86/14
84/16
81/19
98
98.8
>99
97.8
a
b
c
Yield refers to the mixture of diastereoisomeric products.
The % conversion was based on the disappearance of 5a and determined by 1H NMR of the crude product.
Diastereoisomer ratio was determined from the 1H NMR of the crude product.
Enantiomeric excess (ee) of the major, that is, syn-diastereoisomer (separated by column chromatography) was determined by HPLC using a chiral column with hexane–
d
isopropyl alcohol as the eluent.

R. Chowdhury, S. K. Ghosh / Tetrahedron: Asymmetry 21 (2010) 2696–2702
2699
SiMe2Ph
CO2H
SiMe2Ph
CO2Et
OH
1. NaCNBH3, THF
O
Bn
BnNH2
SiMe2Ph
CO2Et
O
SiMe2Ph
CO2Et
NH
2. LiOH, MeOH·H2O
Na(OAc)3BH
H
H
CH2Cl2, AcOH
65%
CO2H
CO2Et
CO2Et
CO2Et
2a
2a
OH
O
SiMe2Ph
SiMe2Ph
SiMe2Ph
CO2Et
110 oC
71%
KBr, AcOOH
55%
LiAlH4, THF
70%
OH
O
O
O
6
N
8
N
O
Bn
Bn
Scheme 3. Synthesis of (+)-simplactone B 6.
11
10
chromatographic purification. The minor diastereoisomeric product
also was eliminated during this purification step. The dimethyl(phe-
nyl)silyl group in 8 was then converted to a hydroxy group following
the Tamao–Fleming oxidation7 using potassium bromide and
peracetic acid with retention of configuration leading to (+)-sim-
plactone B 6, the antipode of the known (ꢀ)-simplactone B as
adjudged from the 1H and 13C spectra and specific rotation value
Scheme 5. Synthesis of a trisubstituted piperidine.
H
Ph
Ph
H
Ph
Ph
N
N
R'O
R'O
{½a 2D5
ꢁ
¼ þ22:3 (c 0.94, CHCl3); lit.56
½
a 2D5
ꢁ
¼ ꢀ23:0 (c 0.45, CHCl3) for
the antipode of 6}. The relative and absolute configurations of the
other products 2b–d were tentatively assigned in analogy with 2a.
Additional stereochemical centre(s) can easily be introduced to
obtain more complex products. For example, the lactone interme-
diate 8 was methylated to give the lactone 9 where the stereo-
chemistry of the alkylation was controlled by the silicon group.
The trans relationship between the silyl and methyl groups in 9
was confirmed from the 1H–1H ROESY interaction of both Ha and
Hb (Scheme 4) with the Si–Me and Si–Ph groups.
R
R
13
12
H
SiMe2Ph
Ph
Ph
O
E
N
E
Si,Re'
favored
(R)
E
O
H
H
(R)
SiMe3
H
H
R
E
PhMe2Si
R
Syn
I
ROESY
SiMe2Ph
SiMe2Ph
H
1. LiN(i-Pr)2 / THF
Ha
SiMe2Ph
E
Hb
ROESY
Me
Ph
Ph
O
E
N
E
-78 oC
Si,Si'
O
H
H
H
2. MeI
87%
O
O
SiMe3
H
O
O
R
E
SiMe2Ph
8
9
R
Anti
II
Scheme 4. Methylation of lactone 8.
Figure 2. Plausible transition states.
Reductive amination57 of the aldehyde group of adduct 2a with
benzylamine and sodium triacetoxyborohydride directly provided
the cyclic amide 10 (Scheme 5). At this stage the minor diastereo-
isomeric amide(s), which had formed due to the minor diastereo-
isomer present in 2a, could be eliminated by chromatographic
purification. The cis-relative stereochemistry between the silyl
and the ethyl ester groups in 10 was confirmed57 from the coupling
constant value (J = 5.8 Hz) of the protons attached to these centres.
Lithium aluminium hydride reduction of pure 10 then provided the
1,3,4,5-substituted piperidine derivative 11. The amide precursor
10 can be manipulated to introduce different alkyl groups at the
2(5)-position of the piperidine skeleton.
lesser steric interaction leading to the syn-diastereoisomer with an
(R,R)-configuration. The latter transition state suffers from the
steric hindrance between the PhMe2Si and CHNR2 groups. The
observed coupling of the trigonal centres with relative toxicity
´
Si/Re also follows the general rule proposed by Golinski and
Seebach.63 The hydrogen bonding interaction of the malonate
carbonyl groups and AcOH can activate 5a as well as lock the con-
formation of the carbonyl groups, thus demonstrating that a cata-
lytic amount of AcOH can speed up the reaction as well as improve
the diastereoselectivity.
Considering that the Michael addition of aldehydes to 5a goes
via the enamine intermediate58,59 of the aldehyde and the chiral
pyrrolidine 7b, the stereochemical outcome for the formation of
2a can be explained by the transition state assembly depicted in
Figure 2. Between the two conformational isomeric enamines,60,61
S-trans 12 and S-cis 13, the former is thermodynamically more
favoured.39 As the Re-face of the enamine 12 is efficiently shielded
by the bulky trimethylsilyloxy substituent62 of 7b, the silylmethyl-
enemalonate 5a can approach the enamine from the less hindered
Si-face. Between the two faces of the silylmethylenemalonate 5a,
an Re0-face attack would lead to transition state I while an Si0-face
attack would lead to II. The former attack was favoured due to the
3. Conclusion
In conclusion, we have developed an organocatalytic asymmet-
ric Michael addition of enolizable aldehydes to a b-silylmethylene
malonate with very high stereo- and enantioselectivity. The total
synthesis (+)-simplactone B has been achieved from one of the
aldehyde adducts. Stereo- and regiochemically diverse heterocyclic
skeletons comprised of six-membered rings with embedded
functionalities have been made out of the adducts. Many complex
heterocyclic skeletons and diverse stereochemical substitutions
can be obtained from the aldehyde adducts.

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R. Chowdhury, S. K. Ghosh / Tetrahedron: Asymmetry 21 (2010) 2696–2702
excess of syn-2b was determined by HPLC using Daicel OD-H column
4. Experimental
(k = 254 nm, hexane/i-PrOH = 99.6:0.4, 0.4 mL/min), tR = 27.27 min
(major), tR = 57.39 min (minor). 1H NMR (200 MHz, CDCl3): d 0.35
(s, 3H), 0.42 (s, 3H), 0.76 (t, J = 7.1 Hz, 3H), 1.14–1.29 (m, 8H),
1.33–1.40 (m, 2H), 2.26 (t, J = 5.2 Hz, 1H), 2.52–2.43 (m, 1H), 3.53
(d, J = 5.2 Hz, 1H), 4.00–4.13 (m, 4H), 7.32–7.35 (m, 3H), 7.53–7.58
(m, 2H), 9.52 (d, J = 2.2 Hz, 1H). 13C NMR (50 MHz, CDCl3): d ꢀ2.3,
ꢀ1.4, 13.7, 13.8 (2C), 20.9, 26.9, 30.6, 51.3, 51.6, 61.4, 61.6, 127.7
(2C), 129.0, 134.0 (2C), 138.6, 169.6 (2C), 204.1. IR (film): 3070,
3048, 2957, 2933, 2872, 1748, 1730, 1730, 1464, 1427, 1249, 1153,
1110, 1030, 819 cmꢀ1. HRMS (ESI) calcd for C21H33O5Si [M+H]+:
393.2097; found: 393.2104.
HPLC grade acetone, NMP, DMF, toluene, THF, methanol were
used as received. Butanal, pentanal, hexanal and heptanal are com-
mercially available, and were distilled prior to use. Silylmethylene
malonate 5a was prepared following a previously reported proce-
dure.64 Diphenylprolinol was commercially available and its
TMS-ether 7b was prepared according to a literature65 procedure.
(S)-Proline was purchased from commercial sources. The catalyst
7a was prepared following literature procedures.51
Solvent removal was carried out using a rotary evaporator con-
nected 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 in a 200 MHz (1H:
200 MHz, 13C: 50 MHz) or 500 MHz (1H: 500 MHz, 13C: 125 MHz)
or 700 MHz (1H: 700 MHz, 13C: 175 MHz) spectrometers. 1H and
13C shifts are given in ppm, d scale and are measured relative to
internal CHCl3 and CDCl3 as standards, respectively. High resolu-
tion mass spectra were recorded at 60–70 eV on a Q-TOF spec-
trometer (ESI, Ar). Enantiomeric excess (ee) determinations were
carried out by HPLC instrument fitted with a chiralpak AD-H/OD-
H column and UV detector with k fixed at 254 nm. Optical rotations
were measured in a polarimeter.
4.4. Ethyl (3R,4S)-3-dimethylphenylsilyl-2-ethoxycarbonyl-4-
formyloctanoate 2c
Prepared from silylmethylene malonate 5a and n-hexanal
according to General procedure 1: Yield: 148 mg, 73%. Diastereoiso-
mer ratio (syn/anti = 84/16) was determined from the 1H NMR of
the crude product. Data for syn-2c: ee = 99%. The enantiomeric ex-
cess of syn-2c was determined by HPLC using Daicel AD-H column
(k = 254 nm, hexane/i-PrOH = 99.7:0.3, 0.5 mL/min), tR = 34.56 min
(major), tR = 37.36 min (minor). 1H NMR (200 MHz, CDCl3): d 0.35
(s, 3H), 0.42 (s, 3H), 0.78 (t, J = 6.2 Hz, 3H), 1.12–1.39 (m, 12H),
2.27 (t, J = 5.2 Hz, 1H), 2.37–2.51 (m, 1H), 3.53 (d, J = 5.0 Hz, 1H),
4.01–4.17 (m, 4H), 7.32–7.35 (m, 3H), 7.53–7.58 (m, 2H), 9.52
(d, J = 2.0 Hz, 1H). 13C NMR (50 MHz, CDCl3): d ꢀ2.5, ꢀ1.4, 13.8,
13.9 (2C), 22.4, 26.9, 28.2, 29.8, 51.3, 51.8, 61.4, 61.6, 127.7 (2C),
129.0, 134.0 (2C), 138.7, 169.6 (2C), 204.2. IR (film): 3070, 3048,
2958, 2872, 2721, 1745, 1726, 1465, 1427, 1251, 1110, 912,
820 cmꢀ1. HRMS (ESI) calcd for C22H35O5Si [M+H]+: 407.2254;
found: 407.2236.
4.1. Michael addition of aldehydes to 5a using organocatalyst 7b
and AcOH additive
General procedure 1: The respective aldehyde (5 mmol,
10 equiv) was added to a stirred mixture of silylmethylene malon-
ate 5a (153 mg, 0.5 mmol, 1 equiv), pyrrolidine 7b (25 mg,
0.075 mmol, 0.15 equiv) and acetic acid (4 ll, 0.075 mmol,
0.15 eqiuv) in dichloromethane (1 mL) at 0 °C. After 4 days at
28 °C, the reaction mixture was diluted with water 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 on silica using hexane/EtOAc (95:5) as
eluent to give 2a–2d (70–79%).
4.5. Ethyl (3R,4S)-3-dimethylphenylsilyl-2-ethoxycarbonyl-4-
formylnonanoate 2d
Prepared from silylmethylene malonate 5a and n-heptanal
according to General procedure 1: Yield: 157 mg, 75%. Diastereoiso-
mer ratio (syn/anti = 81/19) was determined from 1H NMR of the
crude product. Data for syn-2d: ee = 97.8%. The enantiomeric ex-
cess of syn-2d was determined by HPLC using Daicel AD-H column
(k = 254 nm, hexane/i-PrOH = 99.6:0.4, 0.6 mL/min), tR = 18.63 min
(major), tR = 24.48 min (minor). 1H NMR (200 MHz, CDCl3): d 0.34
(s, 3H), 0.42 (s, 3H), 0.80 (t, J = 6.2 Hz, 3H), 1.10–1.57 (m, 14H),
2.66 (t, J = 5.2 Hz, 1H), 2.42–2.47 (m, 1H), 3.53 (d, J = 5.2 Hz, 1H),
4.01–4.17 (m, 4H), 7.31–7.37 (m, 3H), 7.52–7.58 (m, 2H), 9.51
(d, J = 2.2 Hz, 1H). 13C NMR (50 MHz, CDCl3): d ꢀ2.4, ꢀ1.4, 13.9
(3C), 22.3, 26.9, 27.4, 28.5, 31.5, 51.3, 51.8, 61.4, 61.6, 127.8 (2C),
129.0, 134.0 (2C), 138.7, 169.7 (2C), 204.2. IR (film): 3070, 3048,
2957, 2930, 2858, 1745, 1727, 1465, 1427, 1250, 1152, 1110,
4.2. Ethyl (3R,4S)-3-dimethylphenylsilyl-2-ethoxycarbonyl-4-
formylhexanoate 2a
Prepared from silylmethylene malonate 5a and n-butanal accord-
ing to General procedure 1: Yield: 149 mg, 79%. Diastereoisomer ratio
(syn/anti = 86/14) was determined from the 1H NMR of the crude
product. Data for syn-2a: ee = 98%. The enantiomeric excess of syn-
2a was determined by HPLC using Daicel OD-H column (k = 254 nm,
hexane/i-PrOH = 99.7:0.3, 0.6 mL/min), tR = 23.58 min (major),
tR = 52.15 min (minor). 1H NMR (200 MHz, CDCl3): d 0.34 (s, 3H),
0.42 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H), 1.17–1.27 (m, 6H), 1.35–1.72 (m,
2H), 2.29 (t, J = 5.2 Hz, 1H), 2.33–2.43 (m, 1H), 3.52 (d, J = 5.0 Hz,
1H), 4.01–4.14 (m, 4H), 7.24–7.35 (m, 3H), 7.53–7.58 (m, 2H), 9.53
(d, J = 2.0 Hz, 1H). 13C NMR (50 MHz, CDCl3): d ꢀ2.4, ꢀ1.4, 12.4, 13.9
(2C), 21.6, 26.7, 51.4, 53.7, 61.5, 61.6, 127.7 (2C), 129.1, 134.0 (2C),
138.6, 169.6 (2C), 204.1. IR (film): 3071, 2981, 2937, 2877, 1745,
1725, 1462, 1427, 1252, 1110, 909, 820 cmꢀ1. HRMS (ESI) calcd for
1029, 819 cmꢀ1
.
HRMS (ESI) calcd for C23H37O5Si [M+H]+:
421.2410; found: 421.2415.
4.6. (4S,5S)-5-Ethyltetrahydro-4-dimethylphenylsilyl-2H-2-
pyranone 8
Acetic acid (0.26 mL) was added to a stirred solution of aldehyde
2a (94.5 mg, 0.25 mmol) in THF (1 mL) at 0 °C followed by the addi-
tion of sodium cyanoborohydride (22 mg, 0.35 mmol). The reaction
mixture was allowed to return to room temperature and stirred
overnight. Brine (1 mL) was added to the reaction mixture and the
pHwasadjustedto 7 byaddingsaturatedNaHCO3 solution. Thereac-
tion mixture was extracted with CH2Cl2 and the organic extract was
dried over Na2SO4. The solvent was evaporated under reduced pres-
sure and the residue was dissolved in 10% aqueous methanol
(3.5 mL) after which lithium hydroxide (42 mg, 1.0 mmol) was
C
20H31O5Si [M+H]+: 379.1941; found: 379.1935.
4.3. Ethyl (3R,4S)-3-dimethylphenylsilyl-2-ethoxycarbonyl-4-
formylheptanoate 2b
Prepared from silylmethylene malonate 5a and n-pentanal
according to General procedure 1: Yield: 137 mg, 70%. Diastereoiso-
mer ratio (syn/anti = 86/14) was determined from the 1H NMR of
the crude product. Data for syn-2b: ee = 98.8%. The enantiomeric

R. Chowdhury, S. K. Ghosh / Tetrahedron: Asymmetry 21 (2010) 2696–2702
2701
added to the solution at room temperature. After being left over-
4.9. (3R,4S,5S)-1-Benzyl-4-dimethylphenylsilyl-5-ethyl-2-oxo-
night, the solvent was evaporated under reduced pressure and the
residue was diluted with water (1 mL), acidified with dil HCl and ex-
tractedwithethylacetate.TheorganicextractwasdriedoverNa2SO4
and evaporated under reduced pressure. The residue was heated un-
der an argon atmosphere at 110 °C for 0.5 h cooled to room temper-
ature and purified by column chromatography to give lactone 8
(47.0 mg, 71%) as a single diastereoisomer. Ee = 97%. The enantio-
meric excess was determined by HPLC using Daicel AD-H column
(k = 254 nm, hexane/i-PrOH = 99.0:1, 1.0 mL/min), tR = 15.65 min
piperidine-3-carboxylic acid ethyl ester 10
Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added to
a stirred solution of the aldehyde 2a (94.5 mg 0.25 mmol) and ben-
zylamine (30
the addition of acetic acid (15
l
l, 0.25 mmol) in CH2Cl2 (2 mL) at 0 °C followed by
l, 0.25 mmol). The reaction mixture
l
was allowed to return to room temperature and stirred overnight.
The reaction mixture was diluted with saturated NaHCO3 solution
and extracted with ethyl acetate. The organic extract was dried
over Na2SO4 and the solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography fol-
lowed by crystallization to give lactam 10 (68 mg, 65%) as a
(major), tR = 19.17 min (minor). ½a D26
ꢁ
¼ þ46:0 (c 1.34, CHCl3). 1H
NMR (200 MHz, CDCl3): d 0.34 (s, 6H), 0.81 (t, J = 7.2 Hz, 3H) 0.97–
1.05 (m, 1H), 1.19–1.41 (m, 2H), 1.71–1.83 (m, 1H), 2.26 (dd,
J = 11.2, 15.6 Hz, 1H), 2.42 (dd, J = 7, 5.4 Hz, 1H), 3.95 (dd, J = 4,
11.6 Hz, 1H), 4.09 (dd, J = 3.8, 11.6 Hz, 1H), 7.35–7.40 (m, 3H),
7.46–7.50 (m, 2H). 13C NMR (50 MHz, CDCl3): d ꢀ5.4, ꢀ5.1, 11.4,
23.0, 27.1, 29.5, 35.5, 69.6, 128.0 (2C), 129.6, 133.7 (2C), 135.8,
174.2. IR (film): 3069, 2960, 2876, 1746, 1427, 1378, 1257, 1112,
1045, 832, 815, 774, 737 cmꢀ1. HRMS (ESI) calcd for C15H22NaO2Si
[M+Na]+: 285.1292; found: 285.1281.
white crystalline solid and as a single diastereoisomer. ½a D27
¼
ꢁ
ꢀ19:0 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): d 0.30 (s, 3H),
0.32 (s, 3H), 0.58 (t, J = 7.3 Hz, 3H), 1.02–1.16 (m, 2H), 1.24
(t, J = 7.1 Hz, 3H), 1.65 (d, J = 3.2 Hz, 2H), 2.83–3.04 (m, 2H), 3.35
(d, J = 6 Hz, 1H), 4.01–4.21 (m, 2H), 4.35 (d, J = 14.6 Hz, 1H), 4.66
(d, J = 14.6 Hz, 1H), 7.17–7.28 (m, 5H), 7.31–7.38 (m, 3H), 7.48–
7.52 (m, 2H). 13C NMR (50 MHz, CDCl3): d ꢀ4.7, ꢀ4.6, 11.4, 13.9,
27.1, 27.8, 36.2, 49.0, 49.5, 50.4, 61.4, 127.4, 127.8 (2C), 128.3
(2C), 128.5 (2C), 129.4, 134.0 (2C), 136.3, 136.8, 168.3, 171.3. IR:
3068, 3000, 2961, 2917, 2874, 1731, 1659, 1428, 1252, 1215,
1183, 1113, 755 cmꢀ1. Mp: 92–93 °C (hexane). Anal. Calcd for
4.7. (4S,5S)-5-Ethyltetrahydro-4-hydroxy-2H-2-pyranone 6
Potassium bromide (54 mg, 0.46 mmol) was added to a stirred
solution of lactone 8 (100 mg, 0.38 mmol) and peracetic acid (35%
solution in acetic acid, 3 mL) at 0 °C followed by H2O2 (30%,
0.1 mL). The reaction mixture was allowed to return to room tem-
perature and stirred for 24 h. The solvent was removed under re-
duced pressure and the residue was dissolved in dichloromethane.
The organic phase was dried over Na2SO4 and evaporated under re-
duced pressure. The residue was purified by column chromatogra-
C25H33NO3Si: C, 70.88; H, 7.85; N, 3.31. Found; C, 70.46; H, 8.11;
N, 3.46.
4.10. (3R,4S,5S)-(1-Benzyl-4-dimethylphenylsilyl-5-ethyl-
piperidine-3-yl)-methanol 11
A solution of lactam ester 10 (78 mg, 0.18 mmol) in THF (3 mL)
was added dropwise to a stirred suspension of LiAlH4 (35 mg,
0.9 mmol) in THF (3 mL) at 0 °C. The reaction mixture was heated
at reflux overnight. A solution of sodium hydroxide (2 M, 3 mL)
was added to the reaction mixture and stirred for 30 min. The reac-
tion mixture was diluted with Rochelle’s salt solution (20 mL) and
extracted with ethyl acetate. The organic extract was washed with
brine and dried over Na2SO4. The solvent was evaporated under re-
duced pressure and the residue was purified by column chroma-
tography to give piperidine alcohol 11 (46 mg, 70%) as an oil.
phy to give lactone 6 (32 mg, 55%) as an oil. ½a D25
¼ þ22:3 (c 0.94,
ꢁ
CHCl3) {lit.56
½
a 2D5
ꢁ
¼ ꢀ23:0 (c 0.45, CHCl3) for the antipode of 6}. 1H
NMR (200 MHz, CDCl3): d 0.98 (t, J = 7.6 Hz, 3H), 1.22–1.43 (m,
1H), 1.52–1.85 (m, 2H), 2.4 (br s, OH), 2.52 (dd, J = 5.8, 17.4 Hz,
1H), 2.89 (dd, J = 5.0, 17.6 Hz, 1H), 3.89–3.99 (m, 2H), 4.46 (dd,
J = 4.4, 11.4 Hz, 1H). 13C NMR (50 MHz, CDCl3): d 11.2, 21.6, 38.0,
42.3, 67.8, 69.2, 171.1; IR (film): 3437, 3019, 2967, 2933, 2881,
1731, 1241, 1054, 910, 760, 733 cmꢀ1
.
½
a 2D6
ꢁ
¼ þ5:0 (c 2.36, CHCl3). 1H NMR (200 MHz, CDCl3): d 0.34 (s,
4.8. (3R,4S,5S)-5-Ethyltetrahydro-4-dimethylphenylsilyl-3-
methyl-2H-2-pyranone 9
3H), 0.35 (s, 3H), 0.71 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 5 Hz, 1H),
1.31–1.52 (m, 2H), 1.55–1.70 (m, 1H), 1.84–1.96 (m, 1H), 2.12–
2.46 (m, 5H), 3.34–3.63 (m, 4H), 7.26–7.35 (m, 8H), 7.48–7.53
(m, 2H). 13C NMR (50 MHz, CDCl3): d ꢀ2.5, ꢀ1.9, 12.2, 27.0, 29.4,
36.3, 37.5, 55.7, 57.4, 63.2, 67.9, 127.2, 127.8 (2C), 128.2 (2C),
128.9, 129.0 (2C), 133.7 (2C), 137.5, 139.1. IR (film): 3377, 2957,
2929, 2898, 2873, 2803, 1454, 1427, 1249, 1110, 1028 816, 754,
699 cmꢀ1. HRMS (ESI): calcd for C23H34NOSi [M+H]+: 368.2404;
found: 368.2385.
n-Butyl lithium (0.21 mL, 1.6 M in hexane, 0.33 mmol) was
added to
a stirred solution of diisopropylamine (0.05 mL,
0.33 mmol) in THF (1 mL) at ꢀ78 °C and the solution was stirred
at 0 °C for 0.5 h. The reaction mixture was cooled to ꢀ78 °C and
a solution of the lactone 8 (88 mg, 0.33 mmol) in THF (0.5 mL)
was added to it. After 1.5 h stirring under these conditions, methyl
iodide (0.1 mL, 1.6 mmol) was added to the reaction mixture and
allowed to return to room temperature. After being left overnight,
the reaction mixture was diluted with water and extracted with
1:1 hexane–ethyl acetate. The organic extract was washed with
brine and dried over Na2SO4. The solvent was evaporated and the
residue was purified to give the methylated lactone 9 (79 mg,
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