An organocatalytic route to the synthesis of (6S)-5,6-dihydro-6-[(2R)-2- hydroxy-6-phenylhexyl]-2H-pyran-2-one and ravensara lactones

Article abstract of DOI:10.1016/j.tetasy.2011.09.017

An organocatalytic enantioselective synthesis of the title compounds has been achieved. The stereogenic centers were generated by the iterative use of proline catalyzed α-aminoxylations and HWE olefination of aldehydes while the lactone ring was construct

Full text of DOI:10.1016/j.tetasy.2011.09.017

Tetrahedron: Asymmetry 22 (2011) 1749–1756
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Tetrahedron: Asymmetry
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An organocatalytic route to the synthesis of
(6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one
and ravensara lactones
⇑
Namrata Dwivedi, Divya Tripathi, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalytic enantioselective synthesis of the title compounds has been achieved. The stereogenic
Received 8 September 2011
Accepted 29 September 2011
Available online 1 November 2011
centers were generated by the iterative use of proline catalyzed
aldehydes while the lactone ring was constructed by ring closing metathesis.
Ó 2011 Elsevier Ltd. All rights reserved.
a-aminoxylations and HWE olefination of
1. Introduction
defined as a ‘universal catalyst’ because of its utility in different
reactions providing rapid, catalytic, atom-economical access to
enantiomerically pure products.14,15
The 5,6-dihydro-2H-pyran-2-one with an integrated 1,3-
skipped polyol1 system is a ubiquitous structural motif of several
biologically active compounds such as cryptocarya diacetate 1,2
passifloricin 2,3 strictifolione 3,4 ravensara lactones 4a and 4b,5
and (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyr-
an-2-one and its enantiomer 5a and 5b (Fig. 1).6 The broad range
of the biological activities associated with these natural products
are plant growth inhibition, antifeedant, antifungal activity,8 cyto-
toxicity against human tumor cells7 and inducing apoptosis.9
Therefore, this class of compounds is of marked interest not only
from a chemical, but also from a pharmacological perspective.
The 1,3,5-polyol/pyrones 4a and 4b5 have been isolated from Rav-
In a continuation of our interest in organocatalysis16 and the
asymmetric synthesis of biologically active compounds,17 we here-
in report a proline-catalyzed sequential a-aminoxylation, Horner–
Wadsworth–Emmons (HWE) olefination approach18 for the syn-
thesis of the (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-
2H-pyran-2-one and ravensara lactones. As shown in Scheme 1,
target molecules, 4a/4b and 5a could be obtained by the ring-clos-
ing metathesis (RCM) of the respective acryloyl esters I and IV. We
envisioned that acryloyl esters I and IV could be derived by pro-
line-catalyzed
lation of II, which in turn could be obtained from iterative
sequential -aminoxylation and Horner–Wadsworth–Emmons
a-aminoxylation and subsequent synthetic manipu-
ensara anisata and 5,6-dihydro-
a-pyrone derivatives with an alkyl
a
side chain at the C6 position viz 5a and 5b were isolated from Rav-
ensara crassifolia.6 Due to their strong and selective biological pro-
file, these molecules have attracted a great deal of interest from
synthetic organic chemists as an attractive synthetic target. The
main structural features of these compounds are a syn-1,3-diol
olefination of aldehyde 6, which is based on a method developed
to prepare both syn-and anti-1,3 polyols in a stereo- and enantiose-
lective manner.16a
2. Results and discussion
and a 6-substituted 5,6-dihydro-a-pyrone. Various methods are
available in the literature for the synthesis of these compounds.
Shibasaki et al.10 reported the enantioselective synthesis of these
pyrones, which relies upon catalytic asymmetric epoxidation of
As illustrated in Scheme 2, our synthesis commenced with phe-
nyl hexanal 6, which was subjected to sequential
a-aminoxylation
(L
-proline as a catalyst) followed by an HWE olefination reaction, to
a
,b-unsaturated imidazolides and amides, using lanthanide-BINOL
complexes, and the diastereoselective reduction of ketones. A car-
bohydrate based approach has also been reported starting from
-glucoheptonic-
-lactone for the synthesis of 4a and 4b.11 The
furnish the O-amino-substituted allylic alcohol. In an effort to min-
imize the handling of intermediates and time-consuming purifica-
tion, the crude product obtained after work-up was directly
subjected to hydrogenation conditions using a catalytic amount
a-
D
c
last decade has witnessed an upsurge of interest in using small or-
ganic molecules as highly selective and effective catalyst.12 As a re-
sult, this area of organocatalysis has emerged as powerful tool
available for asymmetric synthesis.13 Proline has recently been
of Pd/C to furnish
steps and one column purification,
in 65% yield and 98% ee. The TBS protection of the hydroxy group
furnished the TBS protected -hydroxy ester 8 in 92% yield. Ester 8
was reduced with DIBAL-H at ꢀ78 °C to furnish the aldehyde,
which was further subjected to -aminoxylation catalyzed by
c
-hydroxy ester 7 in good yield. Thus, in two
c
-hydroxy ester 7 was obtained
c
⇑
a
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.017

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N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
O
O
O
O
OAc OAc
O
OH
OH
O
O
OH OH
C14H29
Ph
Cryptocarya diacetate 1
Passifloricin 2
Strictifolione 3
OH
Ph
O
O
O
O
OR
OR'
O
OH
OH
Ph
4
Ph
5a
5b
R = H, R' = Ac 4a
R = Ac R' = H 4b
Figure 1. Representative skipped polyol natural product.
Organocatalytic aminoxylation
O
OH
*
Ph
*
*
OH
O
Ph
COOEt
OR
O
II
Ph
O
I
5a
O
Ph
6
OR
OR
*
OH
*
Ph
Ph
*
III
Organocatalytic methodology for the 1,3-syn diol
O
*
*
OR
OR
O
RCM
*
OR
OR
O
Ph
IV
O
4a /4b
Ravensara lactones
Scheme 1. Retrosynthetic route to 5a and ravensara lactones 4a/4b.
ONHPh
OH
H2/Pd-C, EtOAc, 8 h, 65%
nitrosobenzene, L-proline,DMSO;
(overall two steps)
O
trimethyl phosphonoacetate
Ph
COOCH3
Ph
COOCH3
Ph
7
6
DBU, LiCl, CH3CN
(i) DIBAL-H, DCM, -78 oC; (ii) L-proline, nitrosobenzene,
DMSO, 60 min then NaBH4, MeOH, 10 min
TBSO
OH
OTBS
TBSCl, imidazole, DCM,
overnight, 92%
OH
Ph
Ph
COOCH3
9
(iii) H2/Pd-C, EtOAc, 12 h, 78% (overall three steps)
8
TBSO
OH
OTBS
(i)TsCl, Bu2SnO, Et3N, DCM, 2 h
(ii) K2CO3, MeOH, rt, 1 h, 82% (overall two steps)
vinylmagnesium bromide
O
Ph
Ph
THF, CuI, -20 oC, 12 h, 85%
10
11
O
O
O
(PCy3)2Ru(Cl)2=CH-Ph
OH
O
TBSO
O
PTSA, methanol
20 min, 90%.
(20 mol%),CH2Cl2
TBSO
O
acryloyl chloride
i-Pr2NEt, DCM, -78 oC, 75%
Ph
reflux, 24 h, 92%
Ph
Ph
5a
12
13
Scheme 2. Synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one.
9 in 78% yield and >95% de (determined from the 1H and 13C
NMR spectral analysis of the crude reaction mixture). The crude
product, which was a mixture of the diastereoisomers, was purified
L
-proline followed by an in situ reduction using NaBH4 to furnish
the required -amino-substituted diol, which was subsequently
subjected to reductive hydrogenation to afford the required diol
a

N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
1751
by column chromatography to give a single diastereomer 9. The
diol 9 upon selective monotosylation and base treatment furnished
epoxide 10 in 82% yield. Ring opening of epoxide 10 with vinyl-
magnesium bromide in the presence of CuI gave the homoallylic
alcohol 11 in 85% yield. With the desired homoallylic alcohol 11
in hand, our next task was to construct the pyranone moiety via
ring-closing metathesis. Thus alcohol 11 was esterified with acry-
loyl chloride in the presence of iPr2NEt in DCM at ꢀ78 °C to afford
acryloyl ester 12. Subsequent ring-closing metathesis19 of ester 12
with commercially available Grubbs’ catalyst in refluxing CH2Cl2
was subjected directly to hydrogenation conditions using a cata-
lytic amount of Pd/C to furnish the -hydroxy ester 16 in 60% yield
and 95% ee. The free hydroxy group of -hydroxy ester 16 was pro-
tected as a TBS ether using TBSCl to furnish compound 17 in 90%
yield. With a substantial amount of TBS ether 17 in hand, we then
proceeded toward the first cycle of iteration. The DIBAL-H reduc-
tion of ester 17 furnished the corresponding aldehyde, which upon
c
c
a
-aminoxylation using
D
-proline as a catalyst followed by HWE
-hydroxy ester
olefination and subsequent Pd/C reduction gave
c
18. Further TBS protection of the free hydroxy group afforded
TBS ether 19 in 50% overall yield. The 1H and 13C NMR analysis
of the crude reaction mixture revealed the diastereomeric purity
to be >90%. The crude product, which was a mixture of diastereo-
isomers, was purified by column chromatography to give a single
diastereomer 19. The DIBAL-H reduction of compound 19 at
for 24 h afforded the a,b-unsaturated d-lactone 13 in 92% yield. Fi-
nally desilylation was achieved by treatment of 13 with PTSA in
methanol to give the target molecule 5a in 90% yield.
½
a 2D5
ꢁ
¼ ꢀ63:8 (c 0.5, CHCl3); lit.20
½
a 2D5
ꢁ
¼ ꢀ58:85 (c 0.65, CHCl3);
lit.21
½
a 2D5
ꢁ
¼ ꢀ53:1 (c 0.40, CHCl3). The physical and spectroscopic
data of 5a were in full agreement with the literature data.20,21
The relative stereochemistry of 1,3-diol 11 was determined via
Rychnovsky’s acetonide method22 (Scheme 3). The TBS deprotec-
tion of compound 11 furnished diol 14 in 92% yield. Diol 14 on
treatment with 2,2-DMP gave the syn acetonide 15 in 82% yield.
The appearance of the methyl resonance peaks at d 18.78 and
30.44 ppm and acetal carbon resonating at d 99.18 ppm confirmed
the presence of a syn-acetonide.
ꢀ78 °C furnished the aldehyde, which was again subjected to
aminoxylation catalyzed by -proline, followed by in situ reduction
using NaBH4 to furnish the required -amino-substituted diol,
a-
D
a
which upon reductive hydrogenation afforded diol 20 in 75% yield
and >85% de ratio. Again the diastereomeric ratio was calculated by
1H and 13C NMR analysis of the crude reaction mixture. The crude
product thus obtained was subjected to column chromatography
to give a single diastereomer 20. Diol 20 upon selective monotosy-
lation and base treatment afforded epoxide 21 in 80% yield, which
was opened with vinylmagnesium bromide to give the homoallylic
alcohol 22 in 80% yield. With the desired homoallylic alcohol 22 in
hand, our next task was to construct the pyranone moiety by ring-
closing metathesis. Thus, alcohol 22 was esterified with acryloyl
chloride in the presence of iPr2NEt in DCM at ꢀ78 °C to afford
We further extended this approach for the synthesis of a raven-
sara lactones 4a and 4b containing a syn/syn-1,3, 5-triol (Scheme 4).
The synthesis of the target compound commenced with commer-
cially available aldehyde 6, which was subjected to
tion using -proline as a catalyst followed by an HWE-olefination
reaction to furnish an O-amino-substituted allylic alcohol, which
a-aminoxyla-
D
TBSO
OH
OH OH
O
O
TFA, DCM,
2,2-DMP, p-TsOH
overnight, rt, 92%
DCM, 8 h, 82%
Ph
Ph
Ph
11
14
15
Scheme 3. Determination of the stereochemistry.
OH
OTBS
TBSCl, imidazole,
(i) nitrosobenzene, D-proline, DMSO;
HWE salt, DBU, LiCl, CH3CN
O
DCM, overnight, 90%
Ph
Ph
COOCH3
Ph
Ph
COOCH3
6
16
17
(ii) H2/Pd-C, EtOAc, 8 h, 60%
(overall two steps)
OR
OR
OR
OH
TBSCl, imidazole,
(i) DIBAL-H, DCM, -78 oC; (ii) nitrosobenzene,
D-proline, DMSO; HWE salt, DBU, LiCl, CH3CN
COOCH3
DCM, overnight, 50%
Ph
COOCH3
R = TBS
(overall four steps)
19
R = TBS
(iii) H2/Pd-C, EtOAc, 8 h
18
OR
OR
(i) DIBAL-H, DCM, -78 oC; (ii) D-proline,
(i) TsCl, Bu2SnO, Et3N,
OR
OR OH
O
2 h; (ii) K2CO3, MeOH, rt, 1 h
nitrosobenzene, DMSO, after 30 min NaBH4, MeOH, 0.5 h
OH
Ph
Ph
80% (overall two steps)
(ii) H2/Pd-C, EtOAc, 8 h, 75% (overall three steps)
R = TBS
21
R = TBS
20
O
O
OR OR
OR
OR OH
acryloyl chloride, i-Pr2NEt,
vinylmagnesium bromide, THF,
DCM, -78 oC, 4 h, 85%
CuI, -20 oC, 12 h, 80%
Ph
Ph
R = TBS
R = TBS
22
23
O
O
O
(PCy3)2Ru(Cl)2=CH-Ph
(20 mol%), CH2Cl2
TFA, DCM, 30 min,
rt, 90%
[11,23]
OR
OR'
O
OH
OH
O
OR OR
O
ref
Ph
Ph
reflux, 88%
Ph
4a R=Ac, R' = H
4b R=H, R' = Ac
R = TBS
24
25
Scheme 4. Synthesis of (6R)-6-[(2S,4S)-2,4-dihydroxy-8-phenyloctyl]-5,6-dihydro-2H-pyran-2-one.

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N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
the acryloyl ester 23 in 85% yield. Subsequent ring-closing metath-
esis19 of ester 23 with commercially available Grubbs’ catalyst
gave 24 in 88% yield. Finally global deprotection of the TBS group
was achieved by treatment of lactone 24 with TFA to give diol 25
was evaporated under vacuum. The reaction mixture was then
poured into water (100 mL) and extracted with Et2O
(5 ꢂ 100 mL). The combined organic layer was washed with water,
brine, dried (Na2SO4), and concentrated in vacuo to give the crude
product, which was directly subjected to the next step without
purification. To the crude allylic alcohol in ethyl acetate was added
Pd–C (10%) under hydrogenation conditions and the reaction mix-
ture was allowed to stir overnight. After completion of the reaction
(after 1H NMR analysis of the crude mixture indicated complete
conversion), the mixture was filtered through a pad of Celite and
in 90% yield. ½a 2D5
ꢁ
¼ þ62:1 (c 1, CHCl3); lit.11,23
½
a 2D5
ꢁ
¼ þ61:9 (c 1,
CHCl3) The physical and spectroscopic data of 25 were in full
agreement with the literature data.10,11 Since the monoacetylation
of lactone 25 to the target molecules has already been re-
ported,11,23 this constitutes a formal synthesis of 4a and 4b.
concentrated in vacuo to give the c-hydroxy ester. The crude prod-
uct was then purified by using flash column chromatography using
3. Conclusion
petroleum ether/EtOAc (85:15) as eluent to give 7 (1.95 g, 65%) as a
In conclusion, the stereoselective synthesis of 4a/4b and 5a has
been achieved by using a concise and efficient organocatalytic strat-
egy with a high degree of enantio- and diastereoselectivity. The de-
sired stereocenters can be simply achieved by changing the catalyst.
We believe that this approach would permit maximum variability in
the product structure with regards to stereochemical diversity
which is particularly important for the synthesis of various synthetic
analogues required for screening biological activity.
colorless liquid. ½a D25
ꢁ
¼ ꢀ12:4 (c 1, CHCl3). IR (neat cmꢀ1):
m max
3486, 1730, 1602, 1491, 1023, 931. 1H NMR (200 MHz, CDCl3): d
7.22–7.24 (m, 5H), 3.51–3.64 (m, 4H), 2.62 (t, J = 7.7 Hz, 2H), 2.30
(t, J = 7.3 Hz, 2H), 1.55–1.32 (m, 6H), 1.67–1.71 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 173.2, 141.3, 127.1, 124.3, 69.7, 35.6, 34.7,
30.4, 23.6, 28.5. LC–MS: m/z = 273 [M+Na]+.
4.1.2. Preparation of (R)-methyl 4-((tert-butyldimethylsilyloxy)-
8-phenyloctanoate 8
4. Experimental
To an ice-cold stirred solution of 7 (1.5 g, 5.99 mmol) in dichlo-
romethane (10 mL) were added imidazole (0.81 g, 11.91 mmol)
and TBSCl (1.358 g, 8.99 mmol) at 0 °C. The resulting mixture
was stirred overnight at room temperature before H2O (20 mL)
was added. The aqueous layer was extracted with CH2Cl2
(3 ꢂ 20 mL). The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. Silica
gel column chromatography of the crude product using petroleum
ether/ethyl acetate (99:1) gave TBS ether 8 (1.99 g, 92%) as a color-
4.1. General information
All reactions requiring anhydrous conditions were performed
under a positive pressure of argon using oven-dried glassware
(110 °C), which was cooled under argon. The solvents used for chro-
matography were distilled at respective boiling points using known
procedures. All commercial reagents were obtained from Sigma–Al-
drich Chemical Co. and Lancaster Chemical Co. (UK). The progress of
reactions was monitored by TLC using precoated aluminum plates
(Silica Gel 60 F254, Merck). Column chromatography was per-
formed on Silica Gel 60–120/100–200/230–400 mesh obtained
from S. D. Fine Chemical Co. India or Spectrochem India. Typical syr-
inge and cannula techniques were used to transfer air- and mois-
ture-sensitive reagents. IR spectra were recorded on a Perkin–
Elmer infrared spectrometer model 599-B and model 1620 FTIR.
1H NMR spectra were recorded on Bruker AC-200, Bruker AV-400,
and Bruker DRX-500 instruments using deuterated solvent. Chem-
ical shifts are reported in ppm. Proton coupling constants (J) are re-
ported as absolute values in Hertz and multiplicity (br broad, s
singlet, d doublet, t triplet, m multiplet). 13C NMR spectra were re-
corded on Bruker AC-200, Bruker AV-400, and Bruker DRX-500
instruments operating at 50 MHz, 100 MHz, and 125 MHz, respec-
tively. 13C NMR chemical shifts are reported in ppm relative to
the central line of CDCl3 (d = 77.0 ppm). Microanalytical data were
obtained using a Carlo–Erba CHNS-0 EA1108 elemental analyzer.
All melting points were recorded on a Büchi B-540 electrothermal
melting point apparatus. Yields refer to chromatographically and
spectroscopically pure compounds.
less liquid. ½a 2D5
ꢁ
¼ ꢀ17:0 (c 0.8, CHCl3). IR (neat cmꢀ1):
m max 2955,
1736, 1684, 1454. 1H NMR (200 MHz, CDCl3): d 7.16–7.24 (m, 5H),
3.60–3.72 (m, 4H), 2.58 (t, J = 8.0 Hz, 2H), 2.34 (t, J = 8.0 Hz, 2H),
1.69–1.78 (m, 2H) 1.22–1.45 (m, 6H), 0.85 (s, 9H), ꢀ0.02 (s, 6H),
13C NMR (50 MHz, CDCl3): d = 174.4, 142.6, 128.4, 125.6, 71.0,
51.5, 36.8, 35.9, 31.7, 29.7, 25.8, 24.9, 18.0, 4.4. Anal. Calcd for
C21H36O3Si (364.24): C, 69.18; H, 9.95. Found: C, 69.11; H, 9.91.
4.1.3. Preparation of (2R,4R)-4-((tert-butyldimethylsilyloxy)-8-
phenyloctane-1,2-diol 9
To a solution of ester 8 (1.0 g, 2.74 mmol) in dry dichlorometh-
ane (10 mL) at 0 °C was added dropwise DIBAL-H (5.49 mL,
5.49 mmol, 1 M in toluene) through a syringe. The reaction mixture
was warmed to room temperature over 1 h, then recooled to 0 °C
and treated with a saturated aqueous solution of sodium potas-
sium tartrate (50 mL). The organic phase was separated and the
aqueous layer was extracted with CH2Cl2 (3 ꢂ 50 mL). The com-
bined organic extracts were washed with water, brine, dried
(Na2SO4), filtered, and concentrated to give the crude aldehyde,
which was used for the next step without purification. To a stirred
solution of aldehyde (0.50 g, 1.49 mmol) and nitrosobenzene
(0.160 g, 1.49 mmol) in DMSO (9 mL) was added
L-proline
4.1.1. Preparation of (R)-methyl-4-hydroxy-6-phenyloctanoate
7
To a solution of phenyl hexanal 6 (2.0 g, 11.36 mmol) and nitro-
sobenzene (1.21 g, 11.36 mmol) in anhydrous DMSO (20 mL) was
(0.034 g, 0.29 mmol, 20 mol %) in one portion at 25 °C. After
60 min, the temperature was lowered to 0 °C, followed by dilution
with anhydrous MeOH (10 mL) and the careful addition of excess
NaBH4 (0.199 g, 5.2 mmol). The reaction was quenched after
10 min by pouring the reaction mixture into a vigorously stirred
biphasic solution of Et2O and aqueous HCl (1 M). The organic layer
was separated, and the aqueous phase was extracted with EtOAc
(3 ꢂ 20 mL). The combined organic phase was dried over anhy-
drous Na2SO4, concentrated, and purified by column chromatogra-
phy over silica gel using EtOAc/petroleum ether (40:60) as eluent
to give pure aminoxy alcohol as a pure diastereomer. The aminoxy
alcohol (0.30 g, 0.85 mmol) was dissolved in EtOAc (10 mL) and to
the solution was added 10% Pd/C (0.050 g). The reaction mixture
added -proline (0.52 g, 4.54 mmol) at 20 °C. The mixture was
L
stirred vigorously for 25 min under argon (the color of the reaction
changed from green to yellow during this time), then cooled to
0 °C. Next,
a pre-mixed and cooled (0 °C) solution of trim-
ethylphosphonoacetate (4.92 mL, 34.09 mmol), DBU (5.1 mL,
34.09 mmol), and LiCl (1.43 g, 34.09 mmol) in CH3CN (29 mL)
was added quickly (1–2 min) at 0 °C. The resulting mixture was
warmed to room temperature over 1 h, after which the reaction
was quenched by the addition of pieces of ice. The acetonitrile

N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
1753
was stirred in a hydrogen atmosphere (1 atm, balloon pressure) for
12 h. After completion of the reaction (monitored by TLC), the reac-
tion mixture was filtered through a Celite pad, concentrated, and
the crude product was then purified by silica gel chromatography
using petroleum ether/ethyl acetate (3:2) as eluent to give pure
4.1.6. Preparation of (4S,6R)-6-(tert-butyl dimethylsilyloxy)-10-
phenyldec-1-en-4-yl acrylate 12
To a stirred solution of compound 11 (130 mg, 0.358 mmol) in
dichloromethane (10 mL) were added acryloyl chloride
(0.067 mL, 0.716 mmol) and i-Pr2NEt (0.25 mL, 1.43 mmol) at
ꢀ78 °C. The mixture was allowed to warm to room temperature
and stirred for 4 h. The reaction mixture was diluted with water
(8 mL) and extracted with dichloromethane (2 ꢂ 10 mL). The com-
bined organic layer was dried over anhydrous Na2SO4 and the sol-
vent was removed under vacuum to give the crude residue, which
was purified by silica gel column chromatography (PE/EtOAc, 9:1)
to afford the pure product 12 (112 mg, 75%) as a colorless oil.
~
diol 9 (0.75 g, 78%) as a yellow liquid. ½a D25
¼ þ6:4 (c 0.5, CHCl3).
ꢁ
IR (neat cmꢀ1):
m max = 3412, 3018, 2938, 1612, 1513, 1248,
1215. 1H NMR (200 MHz, CDCl3): d 7.08–7.15 (m, 5H), 4.00–4.03
(m, 2H), 3.81 (dd, J = 4.0, 7.4 Hz, 1H), 3.48 (dd, J = 3.5, 7.25 Hz,
1H), 2.46–2.54 (m, 2H), 2.11 (br s, 2H), 1.15–1.53 (m, 8H), 0.79
(s, 9H), 0.01 (s, 6H). 13C NMR (50 MHz, CDCl3): d 142.4, 137.7,
128.2, 125.7, 72.7, 70.9, 66.6, 38.1, 35.8, 31.5, 25.8, 25.1, 24.4,
17.9, ꢀ4.0, ꢀ4.7. LC–MS: m/z = 375 [M+Na]+.
½
a 2D5
ꢁ
¼ þ4:7 (c 1, CHCl3). IR (neat cmꢀ1):
m max 3071, 2927, 2560,
1726, 1629, 1411, 1261, 1195, 1055. 1H NMR (200 MHz, CDCl3): d
7.25–7.17 (m, 5H), 6.41 (dd, J = 2.0 and 16.0 Hz, 1H), 6.09 (dd,
J = 10.0, 18.0 Hz 1H), 5.70–5.76 (m, 2H), 5.02–5.08 (m, 3H), 3.64–
3.75 (m, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.33–2.39 (m, 2H), 1.24–1.87
(m, 8H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (50 MHz,
CDCl3): d 165.6, 142.4, 133.2, 130.2, 128.5, 125.4, 117.7, 70.7,
68.0, 40.1, 38.8, 35.7, 31.3, 25.6, 24.6, 17.8, ꢀ4.6, ꢀ4.9. Anal. Calcd
for C25H40O3Si (416.27): C, 72.06; H, 9.68. Found: C, 72.01; H, 9.71.
4.1.4. Preparation of tert-butyldimethyl((R)-1-((R)-oxiran-2-yl)-
6-phenylhexan-2-yloxy)silane 10
To a mixture of diol 9 (0.2 g, 0.56 mmol), in dry dichloromethane
(5 mL) was added dibutyltin oxide (2.82 mg, 0.011 mol) followed by
the addition of p-toluenesulfonyl chloride (0.108 g, 0.56 mmol) and
triethylamine (0.07 mL, 0.56 mmol) and reaction was stirred at
room temperature under nitrogen. The reaction was monitored by
TLC; after completion of reaction the mixture was quenched by add-
ing water. The solution was extracted with DCM (3 ꢂ 10 mL) and
then the combined organic phase was washed with water, dried
(Na2SO4), and concentrated. To this crude mixture in MeOH at 0 °C
was added K2CO3 (117 mg, 0.85 mmol) and the resultant mixture
was allowed to stir for 1 h at same temperature. After completion
of reaction as indicated by TLC, the reaction was quenched by the
addition of pieces of ice and the methanol was evaporated. The con-
centrated reaction mixture was then extracted with ethyl acetate
(3 ꢂ 20 mL), the combined organic layer was washed with brine,
dried (Na2SO4), and concentrated. Column chromatography of the
crude product using petroleum ether/ethyl acetate (9:1) gave epox-
4.1.7. Preparation of (6S)-5,6-dihydro-6-[(2R)-2-(tert-butyl
dimethyl silanyloxy)-6-phenylhexyl]-2H-pyran-2-one 13
To a stirred solution of bis(tricyclohexyl phosphine)benzylidine
ruthenium(IV) dichloride (Grubbs catalyst, 10.4 mg, 5 mol %) in
dichloromethane (50 mL) at 55 °C was added compound 12
(100 mg, 0.24 mmol) dissolved in dichloromethane (25 mL). The
resulting mixture was heated for 24 h. After completion of the reac-
tion, the contents were cooled and the solvent was removed under re-
duced pressure to yield the crude product, which was purified on a
silica gel column eluting with petroleum ether/EtOAc (7:3) as eluent
to afford the pure compound 13 (81.6 mg, 92%). ½a D25
¼ þ10:4 (c 0.5
ꢁ
ide 10 (0.15 mg, 82%) as a colorless liquid. ½a D25
ꢁ
¼ þ4:8 (c 1.0, CHCl3).
CHCl3). IR (neat cmꢀ1): max 2938, 1719, 1638, 1399, 777. 1H NMR
m
IR(neatcmꢀ1):
m
max = 2934, 2858, 1612, 1586, 1513, 1463, 1248. 1H
(200 MHz, CDCl3): d 7.15–7.22 (m, 5H), 6.83–6.88 (m, 1H), 6.01 (d,
J = 10 Hz, 1H), 4.48–4.59 (m, 1H), 3.83–3.89 (m, 1H), 2.54 (t,
J = 8.0 Hz, 2H), 2.27–2.33 (m, 1H), 1.96–2.06 (m, 2H), 1.22–1.81 (m,
6H), 0.82 (s, 9H), 0.02 (s, 6H). 13C NMR (50 MHz, CDCl3): d 164.4,
145.0, 142.5, 128.4, 125.6, 121.5, 75.3, 67.4, 41.9, 36.4, 35.9, 31.5,
NMR (200 MHz, CDCl3): d 7.12–7.19 (m, 5H), 3.75–3.84 (m, 1H),
2.89–2.95 (m, 1H), 2.71 (t, J = 4.12 Hz, 1H), 2.58 (t, J = 7.9 Hz, 2H),
2.38–2.42 (m, 1H), 1.26–1.57 (m, 8H),) 0.82 (s, 9H), ꢀ0.01 (s, 6H).
13C NMR (50 MHz, CDCl3): d 142.5, 128.2, 125.6, 70.0, 49.9, 47.7,
40.2, 37.7, 35.9, 31.6, 25.8, 24.7, 18.0, ꢀ4.4. LC–MS: m/z = 357
[M+Na]+.
29.7, 25.8 24.8, 18.0, ꢀ4.2, ꢀ4.6 Anal. Calcd for
C23H36O3Si
(388.249): C, 71.08; H, 9.34. Found: C, 71.10; H, 9.39.
4.1.5. Preparation of (4S,6R)-6-(tert-Butyldimethylsilyloxy)-10-
phenyldec-1-en-4-ol 11
4.1.8. Preparation of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-
phenylhexyl]-2H-pyran-2-one 5a
A round bottom flask was charged with copper(I) iodide (8 mg,
0.044 mmol), gently heated under vacuum, and slowly cooled with
a flow of argon, and dry THF (2 mL) was added. This suspension
was cooled to ꢀ20 °C and vigorously stirred, after which vinylmag-
nesium bromide (1 M in THF, 0.898 mL, 0.898 mmol) was injected
into it. A solution of compound 10 (150 mg, 0.449 mmol) in THF
(1 mL) was added slowly to the above reagent, and the mixture
was stirred at ꢀ20 °C for 12 h. The reaction mixture was quenched
with a saturated aqueous solution of NH4Cl. The combined organic
layer was dried over anhydrous Na2SO4 and the solvent was re-
moved under vacuum to give the crude residue, which was purified
by silica gel column chromatography (PE/EtOAc, 4:1) to afford the
To a stirred solution of compound 13 (50 mg, 0.128 mmol) in
methanol, a catalytic amount of p-toluene sulfonic acid (5 mol %)
was added and stirred for 20 min. Then the reaction mixture was
treated with solid NaHCO3. The methanol was removed and ex-
tracted with ethyl acetate (3 ꢂ 10 mL). The combined organic layer
was dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure to yield the crude product, which was
purified on a silica gel column eluting with PE/EtOAc (6:4) to afford
the pure product 5a (62 mg, 90%) as a pale yellow solid. Mp 32–
35 °C; lit.20 34–36 °C.
½
a 2D5
ꢁ
¼ ꢀ63:8 (c 0.5, CHCl3); lit.20
½
a 2D5
ꢁ
¼ ꢀ58:85 (c 0.65, CHCl3); lit.21
½
a 2D5
ꢁ
¼ ꢀ53:1 (c 0.40, CHCl3).
IR (KBr cmꢀ1):
m max 3441, 2922, 2845, 1690, 1478, 1390, 1259.
pure product 11 (138 mg, 85%) as a colorless oil. ½a D25
ꢁ
¼ ꢀ7:1 (c
1H NMR (200 MHz, CDCl3) d 7.19–7.28 (m, 5H). 6.60–6.71 (m,
1H), 6.17 (dd, J = 1.7 and 9.72 Hz, 1H), 4.05–4.26 (m, 1H), 3.70–
3.75 (m, 1H), 3.30 (br s, 1H), 2.63 (t, J = 7.5 Hz, 2H), 2.39–2.45
(m, 2H), 1.99–2.06 (m, 2H), 1.37–1.68 (m, 6H) 13C NMR (75 MHz,
CDCl3): d 163.5, 146.6, 144.4, 128.3, 128.8, 129.4, 128.3, 122.3,
75.0, 68.5, 44.3, 37.1, 35.0, 31.9, 29.7, 24.1.
0.65, CHCl3). IR (neat cmꢀ1):
m max 3071, 2927, 2560, 1726,
1629, 1411, 1261, 1195, 1055. 1H NMR (200 MHz, CDCl3): d 7.07–
7.21 (m, 5H), 5.69–5.78 (m, 1H), 5.05–5.07 (m, 2H) 3.70–3.87 (m,
2H), 2.57 (t, J = 7.59 Hz, 2H), 2.14–2.17 (dd, J = 7.41, 12.72 Hz,
2H), 1.18–1.51 (m, 8H), 0.81 (s, 9H), 0.00 (s, 3H), ppm. 13C NMR
(50 MHz, CDCl3): d 142.5, 134.9, 128.3, 128.2, 125.6, 117.3, 71.1,
69.2, 67.8, 42.9, 40.1, 37.3, 36.0, 31.6, 25.8, 24.6, 17.9, ꢀ4.6, ꢀ4.7.
Anal. Calcd for C22H38O2Si (362.26): C, 72.87; H, 8.82. Found: C,
72.91; H, 8.86.
4.1.9. Preparation of (4S,6R)-10-phenyldec-1-ene-4,6-diol 14
A solution of compound 11 (100 mg, 0.2760 mmol) in dichloro-
methane (5 mL) at 0 °C, was treated with TFA (50 ll) and stirred for

1754
N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
30 min at 0 °C. The reaction was quenched by the addition of a sat-
urated bicarbonate solution and the aqueous layer was extracted
with DCM. The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure to yield a
crude product, which was purified with petroleum ether/EtOAc as
(1:1) as eluent to afford the pure compound 14 (0.062 g, 91%) as a
4.1.12. Preparation of (S)-methyl 4-(tert-Butyldimethylsilyloxy)
-8-phenyloctanoate 17
To an ice-cold stirred solution of 16 (3.0 g, 11.98 mmol) in
dichloromethane (10 mL) were added imidazole (1.63 g,
23.96 mmol) and TBSCl (2.70 g, 17.97 mmol) at 0 °C. The resulting
mixture was stirred overnight at room temperature before H2O
(20 mL) was added. The aqueous layer was extracted with CH2Cl2
(3 ꢂ 20 mL). The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. Silica
gel column chromatography of the crude product using petroleum
ether/ethyl acetate (99:1) gave TBS ether 17 (3.93 g, 90%) as a col-
foam. ½a 2D5
ꢁ
¼ ꢀ32:6 (c 1.0, CHCl3). IR (neat cmꢀ1):
m max 3675,
3121, 2934, 1522, 1476, 1215, 1055, 765, 650. 1H NMR
(200 MHz, CDCl3): d 7.11–7.30 (m, 5H), 6.89 (dt, J = 9.8, 3.8 Hz,
1H), 6.02 (d, J = 9.8, 1.8 Hz, 1H), 4.03–4.15 (m, 1H), 3.79–3.90 (m,
1H), 2.62 (t, J = 7.33 Hz, 2H), 2.39–2.45 (m, 2H), 1.32–1.81 (m,
8H), 13C NMR (50 MHz, CDCl3): d 142.4. 128.3, 128.2, 125.7,
114.2, 71.2, 69.5, 42.3, 38.1, 35.8, 31.4, 29.4, 24.9. C16H24O2
(248.17): Anal. Calcd for C16H24O2 (248.18): C, 77.38; H, 9.74.
Found: C, 77.33; H, 9.79.
orless liquid. ½a D25
ꢁ
¼ þ17:0 (c 1.5, CHCl3). IR (neat cmꢀ1):
m
max = 2955, 1736, 1684, 1454. 1H NMR (200 MHz, CDCl3): d
7.17–7.35 (m, 5H), 3.71–3.75 (m, 4H), 2.65 (t, J = 8.0 Hz, 2H), 2.40
(t, J = 8.0 Hz, 2H), 1.39–1.62 (m, 6H), 1.74–1.77 (m, 2H), 0.9 (s,
9H), 0.07 (s, 3H), 0.04 (s, 3H). 13C NMR (50 MHz, CDCl3): d 174.5,
142.5, 128.4, 128.2, 125.7, 70.9, 51.6, 36.8, 35.9, 31.6, 29.8, 25.8,
24.9, 18.0, ꢀ4.5. Anal. Calcd for C21H36O3Si (364.24): C, 69.18; H,
9.95. Found: C, 69.11; H, 9.91.
4.1.10. Preparation of (4S,6R)-4-allyl-2,2-dimethyl-6-(4-phenyl-
butyl)-1,3-dioxane 15
To a solution of diol 14 (0.30 g, 1.20 mmol), in dry dichloro-
methane (2 mL) was added 2,2-dimethoxypropane (1 mL), p-TsOH
(0.020 g) and stirred overnight. Solid NaHCO3 (0.05 g) was added
and stirred for 30 min. The reaction mixture was filtered through
a pad of neutral alumina and concentrated. Silica gel column chro-
matography using petroleum ether/ethyl acetate (24:1) gave 15 as
4.1.13. Preparation of (4S,6R)-ethyl 4,6-bis(tert-butyldimethyl-
silyloxy)-10-phenyldecanoate 19
To a solution of compound 17 (2.0 g, 5.49 mmol) and nitroso-
benzene (5.87 g, 5.49 mmol) in anhydrous DMSO (20 mL) was
added -proline (0.063 g, 0.590 mmol) at 20 °C. The mixture was
D
a colorless liquid (0.028 g, 82%). ½a D25
¼ ꢀ11:7 (c 0.6, CHCl3). IR
ꢁ
stirred vigorously for 25 min under argon (the color of the reaction
changed from green to yellow during this time), then cooled to
0 °C. Thereafter, a pre-mixed and cooled (0 °C) solution of trim-
ethylphosphonoacetate (1.55 mL, 16.47 mmol), DBU (2.50 mL,
16.47 mmol), and LiCl (0.698 g, 16.47 mmol) in CH3CN (40 mL)
was added quickly (1–2 min) at 0 °C. The resulting mixture was
warmed to room temperature over 1 h, the reaction was quenched
by the addition of pieces of ice. The acetonitrile was evaporated
under vacuum. The reaction mixture was then poured into water
(100 mL) and extracted with Et2O (5 ꢂ 100 mL). The combined or-
ganic layer was washed with water, brine, dried (Na2SO4), and con-
centrated in vacuo to give the crude product, which was directly
subjected to the next step without purification. To the crude allylic
alcohol in ethyl acetate was added Pd–C (10%) under hydrogena-
tion conditions and the reaction mixture was allowed to stir over-
night. After completion of the reaction (until 1H NMR analysis of
the crude mixture indicated complete conversion), the mixture
was filtered through a pad of Celite and concentrated in vacuo to
(neat cmꢀ1):
m
max 2926, 2856, 1604, 1454, 1262, 1118. 1H NMR
(200 MHz, CDCl3): d 7.08–7.35 (m, 5H), 5.80–5.87 (s, 1H), 4.96–
5.05 (m, 2H), 3.74–3.78 (m, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.00–2.20
(m, 2H), 1.30–1.55 (m, 8H), 1.27 (s, 6H). 13C NMR (75 MHz, CDCl3):
d 141.6, 133.4, 127.3, 127.2, 124.5, 115.5, 99.1, 67.6, 65.5, 39.1,
37.1, 34.8, 30.4, 24.0, 23.7, 18.7. LC–MS: m/z = 311 [M+Na]+.
4.1.11. Preparation of (S)-methyl 4-hydroxy-8-phenyloctanoate
16
To a solution of phenylhexanal 6 (6.0 g, 34.08 mmol) and nitro-
sobenzene (3.63 g, 34.08 mmol) in anhydrous DMSO (520 mL) was
added -proline (1.56 g, 13.62 mmol) at 20 °C. The mixture was
D
stirred vigorously for 25 min under argon (the color of the reaction
changed from green to yellow during this time), then cooled to
0 °C. Thereafter, a pre-mixed and cooled (0 °C) solution of trim-
ethylphosphonoacetate (14.78 mL, 102.27 mmol), DBU (15.3 mL,
102.27 mmol) and LiCl (4.293 g, 102.27 mmol) in CH3CN (80 mL)
was added quickly (1–2 min) at 0 °C. The resulting mixture was
warmed to room temperature over 1 h, and the reaction was
quenched by the addition of pieces of ice. The solvent acetonitrile
was evaporated under vacuum. The reaction mixture was then
poured into water (100 mL) and extracted with Et2O
(5 ꢂ 100 mL). The combined organic layer was washed with water,
brine, dried (Na2SO4), and concentrated in vacuo to give the crude
product, which was subjected directly to the next step without
purification. To the crude allylic alcohol in ethyl acetate was added
Pd–C (10%) under hydrogenation conditions and the reaction mix-
ture was allowed to stir for 8 h. After completion of the reaction
(until 1H NMR analysis of the crude mixture indicated complete
conversion), the mixture was filtered through a pad of Celite and
give the c-alcohol 18. The crude product was then used in the next
step without further purification. To an ice-cold stirred solution of
crude product CH2Cl2 (10 mL) were added imidazole (1.120 g,
16.47 mmol) and TBSCl (2.43 g, 16.47 mmol) at 0 °C. The resulting
mixture was stirred overnight at room temperature before H2O
(20 mL) was added. The aqueous layer was extracted with CH2Cl2
(3 ꢂ 20 mL). The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. Silica
gel column chromatography of the crude product using petroleum
ether/ethyl acetate (99:1) gave TBS ether 19 as a single diastereo-
mer (1.43 g, 50%) as a colorless liquid. ½a D25
¼ þ22:2 (c 1, CHCl3). IR
ꢁ
(neat cmꢀ1):
m
max = 2955, 1736, 1684, 1454. 1H NMR (200 MHz,
CDCl3): d 7.10–7.17 (m, 5H), 3.40–4.15 (m, 5H), 2.54 (t, J = 7.7 Hz,
2H), 2.24 (t, J = 7.3 Hz, 2H), 1.95–1.98 (m, 2H), 1.34–1.51 (m, 8H),
0.78 (s, 18H), 0.01 (s, 6H), ꢀ0.03 (s, 6H), 13C NMR (100 MHz,
CDCl3): d 174.4, 142.6, 128.4, 125.6, 75.5, 71.0, 51.5, 36.8, 35.9,
31.7, 29.7, 25.8, 24.9, 18.0, ꢀ4.4, ꢀ5.0. LC–MS: m/z = 545 [M+Na]+.
concentrated in vacuo to give the c-hydroxy ester. The crude prod-
uct was then purified by using flash column chromatography using
petroleum ether/EtOAc (85:15) as eluent to give 16 (5.11 g, 60%) as
a colorless liquid. ½a D25
ꢁ
¼ þ12:55 (c 0.8, CHCl3). IR (neat cmꢀ1):
m
max = 3368, 3022, 1728, 1602, 1496, 1454, 1217 1H NMR
(200 MHz, CDCl3): d 7.11–7.40 (m, 5H), 3.63–3.75 (m, 4H), 2.61
(t, J = 7.7 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 1.58–1.87(m, 2H), 1.20–
1.47 (m, 6H). 13C NMR (75 MHz, CDCl3): d 174.3 142.4, 128.2,
128.0, 125.5, 70.7, 36.6, 35.7, 31.4, 29.6, 24.7. LC–MS: m/z = 273
[M+Na]+.
4.1.14. Preparation of (2R,4S,6R)-4,6-bis(tert-butyldimethylsilyl-
oxy)-10-phenyldecane-1,2-diol 20
To a solution of ester 19 (2.0 g, 3.82 mmol) in dry dichlorometh-
ane (100 mL) at 0 °C was added dropwise DIBAL-H (7.65 mL,
7.65 mmol, 1 M in toluene) through a syringe. The reaction mixture

N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
1755
was warmed to room temperature over 1 h, then recooled to 0 °C
and treated with a saturated aqueous solution of sodium potas-
sium tartrate (50 mL). The organic phase was separated and the
aqueous layer was extracted with CH2Cl2 (3 ꢂ 50 mL). The com-
bined organic extracts were washed with water, brine, dried
(Na2SO4), filtered, and concentrated to give the crude aldehyde,
which was used for the next step without purification. To a stirred
solution of aldehyde (1.2 g, 2.43 mmol) and nitrosobenzene
127.2, 69.6, 68.3, 44.3, 51.1, 39.1, 36.8, 34.9, 28.6, 24.8, 23.3,
21.6, 16.8, ꢀ4.9, ꢀ5.5. LC–MS: m/z = 515 [M+Na]+.
4.1.16. Preparation of (4R,6R,8S)-6,8-bis(tert-butyldimethylsilyl-
oxy)-12-phenyldodec-1-en-4-ol 22
A round bottom flask was charged with copper(I) iodide
(5.78 mg, 0.030 mmol), gently heated under vacuum, and slowly
cooled with a flow of argon, and dry THF (20 mL) was added. This
suspension was cooled to ꢀ20 °C and vigorously stirred, after
which vinylmagnesium bromide (1 M in THF, 0.609 mL,
0609 mmol) was injected into it. A solution of compound 21
(150 mg, 0.3046 mmol) in THF (10 mL) was added slowly to the
above reagent, and the mixture was stirred at ꢀ20 °C for 12 h.
The reaction mixture was quenched with a saturated aqueous solu-
tion of NH4Cl. The combined organic layer was dried over anhy-
drous Na2SO4 and the solvent was removed under vacuum to
give the crude residue, which was purified by silica gel column
chromatography (PE/EtOAc, 4:1) to afford the pure product 22
(0.26 g, 2.43 mmol) in DMSO (9 mL) was added
D-proline
(0.056 g, 0.48 mmol, 20 mol %) in one portion at 25 °C. After 1 h,
the temperature was lowered to 0 °C, followed by dilution with
anhydrous MeOH (10 mL) and the careful addition of excess NaBH4
(0.185 g, 4.86 mmol). The reaction was quenched after 10 min by
pouring the reaction mixture into a vigorously stirred biphasic
solution of Et2O and aqueous HCl (1 M). The organic layer was sep-
arated, and the aqueous phase was extracted with EtOAc
(3 ꢂ 20 mL). The combined organic phase was dried over anhy-
drous Na2SO4, concentrated, and purified by column chromatogra-
phy over silica gel using EtOAc/petroleum ether (40:60) as eluent
to give pure aminoxy alcohol. The aminoxy alcohol (1.02 g,
1.69 mmol) was dissolved in EtOAc (10 mL) and to the solution
was added 10% Pd/C (0.1 g). The reaction mixture was stirred in a
hydrogen atmosphere (1 atm, balloon pressure) for 12 h. After
completion of the reaction (monitored by TLC), the reaction mix-
ture was filtered through a Celite pad, concentrated, and the crude
product was then purified by silica gel chromatography using
petroleum ether/ethyl acetate (3:2) as eluent to give pure diol 20
as a single diastereomer. (0.93 g, 75%) as a colorless liquid.
(129 mg, 80%) as a colorless oil. ½a D25
¼ þ8:7 (c 1, CHCl3). IR (neat
ꢁ
cmꢀ1):
m max = 3071, 2929, 2559, 1726, 1621, 1409, 1255, 1195,
1055. 1H NMR (200 MHz, CDCl3): d 7.05–7.22 (m, 5H), 5.61–5.82
(m, 1H), 4.96–5.04 (m, 2H), 3.47–4.13 (m, 3H), 2.55 (t,
J = 7.70 Hz, 2H), 2.02–2.25 (dd, J = 6.19, 11.88 Hz, 2H), 1.16–1.67
(m, 10H), 0.79 (s, 18H), 0.02 (s, 6H), ꢀ0.07 (s, 6H), 13C NMR
(50 MHz, CDCl3): d 142.5, 135.0, 128.4, 128.3, 125.6, 117.5, 71.1
69.9, 67.8, 46.4, 42.3, 40.1, 37.7, 36.0, 31.6, 25.8, 24.6, 17.9, 14.0,
ꢀ4.5, ꢀ4.0 Anal. Calcd for C30H56O3Si (520.37): C, 69.17; H,
10.84. Found: C, 69.11; H, 10.89.
½
a 2D5
ꢁ
¼ ꢀ7:8 (c 1.0, CHCl3). IR(neat cmꢀ1):
m max = 3411, 3012,
2923, 1634, 1523, 1249, 1211.1H NMR (200 MHz, CDCl3): d 7.12–
7.19 (m, 5H), 3.97–4.08 (m, 1H), 3.75–3.83 (m, 1H), 3.62–3,64
(m, 1H), 3.52–3.57 (m, 1H), 3.35–3.41 (m, 1H), 2.54 (t, J = 7.33,
2H) 1.18–1.69 (m, 10H), 0.80 (s, 18H), 0.05 (s, 6H), ꢀ0.06 (s, 6H).
13C NMR (50 MHz, CDCl3): d 142.4, 128.6, 128.2, 125.6, 73.1, 71.7,
69.2, 66.3, 46.6, 40.0, 35.8, 31.4, 25.8, 24.3, 17.9, ꢀ3.9, ꢀ4.6. Anal.
Calcd for C24H54O4Si2 (510.89): C, 65.83; H, 10.65. Found: C,
65.93; H, 10.61.
4.1.17. Preparation of (4R,6R,8S)-6,8-bis(tert-butyldimethylsilyl-
oxy)-12-phenyldodec-1-en-4-yl acrylate 23
To a stirred solution of compound 22 (110 mg, 0.211 mmol) in
dichloromethane (5 mL) were added acryloyl chloride (0.034 mL,
0.422 mmol) and i-Pr2NEt (0.146 mL, 0.841 mmol) at ꢀ78 °C. The
mixture was allowed to warm to room temperature and stirred
for 4 h. The reaction mixture was diluted with water (5 mL) and
extracted into dichloromethane (2 ꢂ 6 mL). The combined organic
layer was dried over anhydrous Na2SO4 and the solvent was re-
moved under vacuum to give the crude residue, which was purified
by silica gel column chromatography (PE/EtOAc, 9:1) to afford the
4.1.15. Preparation of ((5R,7S)-2,2,3,3,9,9,10,10-octamethyl-5-
((S)-oxiran-2-ylmethyl)-7-(4-phenylbutyl)-4,8-dioxa-3,9-disila-
undecane 21
pure product 23 (103 mg, 85%) as a colorless oil. [
a]
25 = +4.7 (c 1
D
To a mixture of diol 20 (0.75 g, 1.46 mmol), in dry dichloro-
methane (5 mL) was added dibutyltin oxide (3.65 mg, 0.014 mol)
followed by the addition of p-toluenesulfonyl chloride (0.28 g,
1.46 mmol) and triethylamine (0.1 mL, 1.46 mmol). The reaction
was stirred at room temperature for 2 h under nitrogen. The reac-
tion was monitored by TLC; after completion of reaction, the mix-
ture was quenched by adding water. The solution was extracted
with DCM (3 ꢂ 10 mL) and then the combined organic phase was
washed with water, dried (Na2SO4), and concentrated. To this
crude mixture in MeOH at 0 °C was added K2CO3 (303 mg,
2.20 mmol) and the resultant mixture was allowed to stir for 2 h
at same temperature. After completion of the reaction as indicated
by TLC, the reaction was quenched by the addition of pieces of ice
and the methanol was evaporated. The concentrated reaction mix-
ture was then extracted with ethyl acetate (3 ꢂ 20 mL), the com-
bined organic layer was washed with brine, dried (Na2SO4), and
concentrated. Column chromatography of crude product using
petroleum ether/ethyl acetate (9:1) gave epoxide 21 (yield
CHCl3). IR (KBr cmꢀ1
) m
max = 3045, 2921, 2556, 1716, 1622, 1415,
1267, 1199, 1051.1H NMR (200 MHz, CDCl3): d 7.17–7.29 (m, 5H),
6.41 (dd, J = 11.64, 15.54 Hz, 1H), 6.08 (dd, J = 11.75, 17.18 Hz, 1H),
5.63–5.84 (m, 2H), 5.01–5.09 (m, 2H), 3.59–4.21 (m, 3H), 2.63.
(t, J = 7.57 Hz, 2H), 2.33–2.39 (m, 2H), 1.27–1.80 (m, 10H), 0.85
(s, 18H), 0.04 (s, 6H), 0.03 (s, 6H). 13C NMR (50 MHz, CDCl3):
d = 162.9, 142.6, 133.4, 130.3, 128.8, 128.4, 128.2, 125.6, 117.9,
71.0, 69.2, 67.1, 41.0, 39.1, 36.0, 31.6, 29.7, 25.9, 24.6, 18.0, ꢀ4.1,
ꢀ4.3. Anal. Calcd for C33H58O4Si (574.39): C, 68.93; H, 10.17.
Found: C, 68.99; H, 10.19.
4.1.18. Preparation of (R)-6-((2R,4S)-2,4-bis(tert-butyldimethyl-
silyloxy)-8-phenyloctyl)-5,6-dihydro-2H-pyran-2-one 24
To a stirred solution of bis(tricyclohexyl phosphine)benzylidine
ruthenium(IV) dichloride (Grubbs catalyst, 14.3 mg, 10 mol %) in
dichloromethane (50 mL) at 55 °C was added compound 23
(100 mg, 0.17 mmol) dissolved in dichloromethane (25 mL). The
resulting mixture was heated for 12 h. After completion of the
reaction, the contents were cooled and the solvent was removed
under reduced pressure to yield the crude product, which was
purified on a silica gel column eluting with petroleum ether/EtOAc
as (7:3) as eluent to afford the pure compound 24 (83.7 mg, 88%).
0.57 mg, 80%) as a light yellow colored liquid. ½a D25
¼ ꢀ2:5 (c 1.5,
ꢁ
CHCl3). IR (neat cmꢀ1):
m max = 2929, 2858, 1608, 1578, 1523,
1476, 1254. 1H NMR (200 MHz, CDCl3): d 7.09–7.25 (m, 5H)
3.92–3.99 (m, 1H), 3.60–3.76 (m, 1H), 2.99–3.08 (m, 1H), 2.71–
2.78 (dd, J = 4.00, 4.80 Hz, 1H), 2.55 (t, J = 7.7 Hz, 2H), 2.40–2.46
(dd, J = 4.40, 4.80 Hz, 1H), 1.20–1.71 (m, 10H), 0.87 (s, 18H), 0.04
(s, 6H), ꢀ0.02 (s, 6H). 13C NMR (50 MHz, CDCl3): d 143.2, 127.3,
½
a 2D5
ꢁ
¼ ꢀ10:2 (c 0.45, CHCl3). IR (neat cmꢀ1):
m max = 2930, 1711,
1493, 1389, 1254, 1149, 1052, 746, 700. 1H NMR (200 MHz, CDCl3):
d 7.14–7.29 (m, 5H), 6.79–6.81 (m, 1H), 6.79–6.81 (m, 1H), 5.94–

1756
N. Dwivedi et al. / Tetrahedron: Asymmetry 22 (2011) 1749–1756
Gopal, P.; Yadav, J. S. Helv. Chim. Acta 2010, 93, 1432–1438; (e) Raoelison, G. E.;
Terreaux, C.; Queiroz, E. F.; Zsila, F.; Simonyi, M.; Antus, S.; Randriantsoa, A.;
Hostettmann, K. Helv. Chim. Acta 2001, 84, 3470–3476.
5.99 (d, J = 9.73 Hz, 1H), 4.51–4.55 (m, 1H), 4.08–4.18 (m, 1H),
3.61–3.70 (m, 1H), 2.56 (t, J = 7.33 Hz, 2H), 2.23–2.31 (m, 2H),
1.89–2.00 (m, 2H), 1.20–1.68 (m, 8H), 0.81 (s, 18H), 0.05 (s, 6H),
0.02 (s, 6H), 13C NMR (50 MHz, CDCl3): d 164.1, 146.97, 142.6,
128.4, 128.2, 125.6, 121.1, 117.6, 70.3, 69.1, 66.4, 36.9, 35.9, 31.6,
31.9, 29.3, 29.7, 25.9, 24.8, 18.0, ꢀ4.1, ꢀ4.8. Anal. Calcd for
7. (a) Jodynis-Liebert, J.; Murias, M.; Bloszyk, E. Planta Med. 2000, 66, 199–205; (b)
Drewes, S. E.; Schlapelo, B. M.; Horn, M. M.; Scott-Shaw, R.; Sandor, O.
Phytochemistry 1995, 38, 1427–1430.
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6563; (b) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garca-Rojas, C. M.
Tetrahedron 2001, 57, 47–53.
9. (a) Chan, K. M.; Rajab, N. F.; Ishak, M. H. A.; Ali, A. M.; Yusoff, K.; Din, L. B.;
Inayat-Hussain, S. H. Chem. Biol. Interact. 2006, 159, 129–140; (b) Newmeyer, D.
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C
31H54O4Si2 (546.35): C, 68.08; H, 9.95. Found: C, 68.10; H, 9.99.
4.1.19. Preparation of (R)-6-((2S,4S)-2,4-dihydroxy-8-phenyloc-
tyl)-5,6-dihydro-2H-pyran-2-one 25
A solution of compound 24 (80 mg, 0.146 mmol) in dichloro-
methane (5 mL) at 0 °C, was treated with TFA (40 ll) and stirred
for 30 min at 0 °C. The reaction was quenched by the addition of
a saturated bicarbonate solution and the aqueous layer was ex-
tracted with DCM. The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated to give a crude
product, which was purified on a silica gel column eluting with
petroleum ether/EtOAc as (1:1) as eluent to afford the pure com-
11. Ramana, C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K. J. Org. Chem. 2005, 70,
8216–8219.
12. (a) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175; (b)
Berkessel, A.; Groger, H. Asymmetric Organocatalysis: From Biomimetic Concepts
to Application in Asymmetric Synthesis; Wiley VCH: Weinheim, 2005; (c) Seayed,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724.
13. (a) Dalko, P. L. Enatioselective Organoctalysis: Reactions and Experimental
Procedures; Wiley VCH: Weinheim, 2007; (b) Macmillan, D. W. C. Nature
2008, 455, 304–308.
14. (a) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem., Int.
Ed. 2005, 44, 1343–1345; (b) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III
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pound 25 (41.1 mg, 90%). ½a D25
ꢁ
¼ þ62:1 (c 1, CHCl3); lit.11,23
½
a 2D5
ꢁ
¼ þ61:9 (c 0.55, CHCl3) IR (neat cmꢀ1):
m max = 3684, 3020,
2934, 1725, 1522, 1476, 1215, 1055, 759, 669. 1H NMR
(200 MHz, CDCl3): d 7.13–7.26 (m, 5H). 6.84 (dt, J = 9.95, 4.10,
3.98 Hz, 1H) 5.99 (dd, J = 9.50, 1.90 Hz, 1H), 5.01–5.03 (m, 1H)
4.88–4.93 (m, 1H), 4.42–4.47 (m, 1H), 2.57 (t, J = 7.33 Hz, 2H)
2.28–2.43 (m, 2H), 2.08–2.14 (m, 1H), 1.27–1.95 (m, 9H). 13C
NMR (50 MHz, CDCl3): d 163.4, 144.4, 142.0, 127.9, 125.4, 121.0,
74.6, 70.5, 67.5, 42.7, 42.1, 38.7, 35.3, 30.7, 28.8, 24.3.
Int. Ed. 2004, 43, 3958–3960; For a review on
Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304; For
comprehensive review on -aminoxylation, see: (e) Merino, P.; Tejero, T.
a-functionalization, see: (d)
a
a
Angew. Chem., Int. Ed. 2004, 43, 2995–2997. and references cited therein; (f)
List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657; (g) Zhong, G.; Yu, Y. Org. Lett.
2004, 6, 1637–1640; (h) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan, B.; Zhong, G.
Angew. Chem., Int. Ed. 2008, 47, 10187–10191; For a review of proline-catalyzed
asymmetric reactions, see: (i) List, B. Tetrahedron 2002, 58, 5573–5590.
15. (a) Cobb, J. A. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558–560; (b) Mitchell, C.
E. T.; Cobb, J. A. A.; Ley, S. V. Synlett 2005, 611–614; (c) Yamamoto, Y.;
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963; (d) Tori,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983–1986; (e) Cobb, J. A. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S.
V. Chem. Commun. 2004, 1808–1809; (f) Davies, S. G.; Sheppard, R. L.; Smith, A.
D.; Thomson, J. E. Chem. Commun. 2005, 3802–3804; (g) Davies, S. G.; Russell, A.
J.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3190–
3200; (h) Limbach, M. Tetrahedron Lett. 2006, 47, 3843–3847; (i) Cobb, J. A. A.;
Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84–86.
Acknowledgments
The authors thank the Council of Scientific and Industrial Re-
search (CSIR) and UGC New Delhi for the financial assistance.
Financial support from DST, New Delhi (Grant No. SR/OC-44/
2009) is gratefully acknowledged.
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