The first synthesis of a 12-membered macrolide natural product via a RCM protocol: determination of absolute stereochemistry

Article abstract of DOI:10.1016/j.tetasy.2008.04.016

The first synthesis of (10S,12R)-10-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione and its C12 epimer is reported, thereby assigning the absolute stereochemistry of the natural product. The strategy utilizes a syn selective reduction, Yamaguchi esterification, and ring-closing metathesis as the key steps.

Full text of DOI:10.1016/j.tetasy.2008.04.016

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Tetrahedron: Asymmetry 19 (2008) 1153–1160
The first synthesis of a 12-membered macrolide natural product
via a RCM protocol: determination of absolute stereochemistry
Palakodety Radha Krishna* and Ravula Srinivas
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Received 7 February 2008; accepted 16 April 2008
Abstract—The first synthesis of (10S,12R)-10-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione and its C12 epimer is reported, thereby
assigning the absolute stereochemistry of the natural product. The strategy utilizes a syn selective reduction, Yamaguchi esterification,
and ring-closing metathesis as the key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The (10S,12R)-10-hydroxy-12-methyl-1-oxacyclododecan-
2,5-dione 2, whose absolute stereochemistry of the two
hydroxyl functionalities at C10 and C12 was originally
assigned as depicted in structure 1, was isolated from the
endophytic fungal strain Cladosporium tenuissimum
LR463 of Maytenus hookeri,1 and is found to rapidly
induce the systematic defense responses in plants, that is,
the production of peroxidase, phenylalanine ammonia
lyase, ligin, and salicylic acid. As part of our interest in
the synthesis of bioactive natural products,2 herein, we
report the synthesis of macrolides 1 and 2 and revise the
absolute stereochemistry of the natural product as 2. Our
strategy involves the esterification of the two appropriately
functionalized components under Yamaguchi conditions,
followed by the Grubbs’ catalyst-mediated ring-closing
metathesis to afford the macrocycle first and its subsequent
elaboration to the target compound.
The synthesis of 1 (Scheme 1) began with the conversion of
commercially available 1,4-butane diol into 9. Thus, mono-
protection (DHP/PTSA/CH2Cl2/rt), Swern oxidation fol-
lowed by the Barbier reaction (Zn/allyl bromide/aq
NH4Cl/THF/rt), benzylation (NaH/BnBr/THF/rt) of the
ensuing alcohol 9a, and THP deprotection (PTSA/
MeOH/rt) furnished 9. The required acid 8 was obtained
in two consecutive steps. Alcohol 9 was first oxidized to
an aldehyde under Swern conditions; the crude aldehyde
thus obtained was then oxidized to acid 8 (80% over two
steps) under sodium chlorite oxidation (NaClO2–
NH2PO4/2H2O–t-BuOH–2-methyl-2-butene) conditions.
Simultaneously, another intermediate 3 was synthesized
from the known homoallylic alcohol2a,6 12 whose hydroxyl
functionality was protected as its TPS ether (TPSCl/imid-
azole/CH2Cl2) and then the benzyl ether was deprotected
(Li/liq. NH3/THF) to give alcohol 3 (68%). Later, the
esterification of 8 with 3 under Yamaguchi conditions3 fur-
nished bis-olefin 4 (67%). Subsequently, the Grubbs’ cata-
lyst-mediated ring-closing metathesis4 (Grubbs’ catalyst
II/CH2Cl2/reflux) of 4 afforded the cyclic ester 5 (72%),
which upon treatment with Pd/C in MeOH afforded 6
(82%), wherein two reactions of benzyl deblocking as well
as the reduction of the double bond were addressed in
one-pot. The ensuing secondary hydroxyl was oxidized
using Dess–Martin periodinane in CH2Cl2 to give ketone
7 (90%), and consequently deprotection of the TPS ether
O
O
O
O
1
12
OH
OH
10
5
O
O
2
1
Revised
Proposed
*
by HF–py in THF afforded compound 1 (85%) as a white
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
25
solid, mp: 70–72 °C; ½aꢀD ¼ þ68:1 (c 0.25, MeOH) {lit.1
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.016

1154
P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
O
a
d
b, c
THPO
1,4-butane diol
OH
OR1
OH
OBn
OR
9a R =H, R =THP
9b
10
8
R =Bn, R =THP
9 R = Bn, R =H
OBn OH
OBn OTPS
OH OTPS
e
f
12
11
3
O
O
O
O
O
O
OTPS
h
OTPS
g
i
OTPS
k
8
1
BnO
BnO
R
j
5
6. R = OH
7. R = =O
4
Scheme 1. Reagents and conditions: (a) DHP, PTSA, CH2Cl2, 2 h; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, 2 h, (ii) Zn, allyl bromide, aq NH4Cl, THF, 4 h,
90%, (c) (i) NaH, benzyl bromide, THF, 2 h, (ii) PTSA, MeOH, rt, 4 h; (d) (i) (COCl)2 DMSO, Et3N, CH2Cl2, 2 h, (ii) NaClO2, NaH2PO4, 2-methyl-2-
butene, t-BuOH, 6 h, (80% over two steps); (e) imidazole, CH2Cl2, 0 °C to rt, 98%; (f) Li, liq. NH3, ꢁ78 °C, 68%; (g) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF DMAP, toluene, 3, 67%; (h) Grubbs-II (10 mol %), CH2Cl2, reflux, 12 h, 72%; (i) Pd/C, MeOH, 6 h, 82%; (j) Dess–Martin periodinane, CH2Cl2, 2 h,
90%; (k) HFꢂpy, THF, 4 h, 85%.
25
½aꢀD ¼ ꢁ54:5 (c 0.91, MeOH)}. Moreover, the physical and
spectroscopic data of 1 were different to the reported values
of the natural product.1
prepared from commercially available L-malic acid. The
primary alcohol in 16 was oxidized under Swern conditions
to afford aldehyde 16a, which on Barbier reaction (Zn/allyl
bromide/aq NH4Cl/THF) afforded homoallyl alcohol 15a
(90%). This mixture of alcohols was converted to the
desired (10S)-diastereomer via an oxidation/selective
reduction sequence. Thus, alcohol 15a was oxidized using
IBX, DMSO in CH2Cl2 to afford the ketone, which upon
treatment with LiI, LAH at ꢁ40 to ꢁ78 °C gave the syn-
alcohol 15 (72%, 95% de).5 The ensuing hydroxyl was pro-
tected (TPSCl/imidazole/CH2Cl2) as a TPS ether, followed
by deprotection (PTSA/MeOH/rt) of the cyclohexylidene
This synthesis thus implies that the proposed structure for
macrolide 1 is incorrect. Hence, to arrive at the first synthe-
sis of the macrolide natural product and to determine the
absolute stereochemistry as well, another synthesis was
planned.
Accordingly, the synthesis of 2 (Scheme 2) was achieved by
adopting a related stratagem from the known2c alcohol 16
O
OH
O
OH
O
d
c
Ref. 2c
b
O
R
O
Malic acid
O
16 R=CH2OH
16a R=CHO
15a
a
15 R = H
14 R = TPS
OH OTPS
R
13 R=OH
13a R=OTs
3a R=H
O
O
O
O
O
O
g
e
i
f
OTPS
OTPS
OTPS
8
2
BnO
BnO
R
6a. R = OH
7a R = =O
5a
h
4a
Scheme 2. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, 2 h; (b) Zn, allyl bromide, aq NH4Cl, THF, 4 h, 90%; (c) (i) IBX, DMSO,
CH2Cl2, 2 h, 89%, (ii) LiI, LAH, diethyl ether, ꢁ40 to ꢁ78 °C, 72%; (d) (i) TPSCl, imidazole, CH2Cl2, 95%, (ii) PTSA, MeOH, 2H, 85%, (iii) TsCl,
CH2Cl2, 2 h, 95%, (iv) LAH, THF, 1 h, reflux, 73%; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene, 3a, 69%; (f) Grubbs’-II
(10 mol %), CH2Cl2, reflux, 12 h, 70%; (g) Pd/C, MeOH, 6 h, 85%; (h) Dess–Martin periodinane, CH2Cl2, 2 h, 92%; (i) HFꢂpy, THF, 4 h, 85%.

P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
1155
group to afford diol 13 (85%), mono tosylation (TsCl/
Et3N/CH2Cl2) of which gave tosylate 13a (75%), which
upon treatment with LAH in THF gave alcohol 3a
(73%). Further reactions such as esterification and RCM,
dried over anhydrous Na2SO4 and concentrated below
40 °C in vacuo. The software ACD/Name Version 1.0,
developed by M/s Advanced Chemistry Development
Inc., Toronto, Canada, assisted nomenclature used in the
experimental section.
adopted are similar to those described in Scheme 1 to
25
afford macrolide 2 as a colorless oil with ½aꢀD ¼ ꢁ52:2
25
(c 0.25, MeOH) {lit.1 ½aꢀD ¼ ꢁ54:5 (c 0.91, MeOH)}. The
physical and spectroscopic data of 2 were identical to the
reported values of the natural product.1 Thus, the absolute
stereochemistry assigned was (10S,12R) (Table 1).
4.1.1. 7-Tetrahydro-2H-2-pyranyloxy-1-hepten-4-ol 9a. To
a stirred solution of oxalyl chloride (2.73 mL, 31.2 mmol)
in CH2Cl2 (20 mL) at ꢁ78 °C, DMSO (4.4 mL, 61.4 mmol)
was added followed by the alcohol (4.6 g, 28.4 mmol) in
CH2Cl2 (30 mL) and the reaction mixture stirred for 1 h
at ꢁ78 °C, quenched with Et3N (23.9 mL, 170.3 mmol),
and extracted with CH2Cl2 (2 ꢃ 120 mL). The combined
organic layer was washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo to afford the alde-
hyde (4.2 g, 95%) as a colorless liquid, which was directly
used for further reaction.
3. Conclusions
Thus in summary, the stereoselective total synthesis of the
12-membered macrolide natural product 2 was accom-
plished by the strategy wherein a syn selective reduction,
Yamaguchi esterification, and ring-closing metathesis are
the key steps and its absolute stereochemistry was revised
as (10S,12R).
To a stirred solution of aldehyde (4.6 g, 28.7 mmol) in THF
(50 mL), Zn (3.7 g, 56.5 mmol), and allyl bromide (4.8 mL,
57.5 mmol) were added at 0 °C. Then satd aq NH4Cl
(15 mL) was added slowly and stirred for 4 h. Later,
quenched with satd aq NH4Cl (40 mL), extracted with
EtOAc (2 ꢃ 50 mL), and the organic layer was separated.
The combined organic layers were washed with brine
(50 mL), dried (Na2SO4), and concentrated in vacuo. The
crude residue was purified by column chromatography (sil-
ica gel, 60–120 mesh, EtOAc/hexane, 4:21) to afford 9a
4. Experimental
4.1. General methods
Varian Gemini 200 MHz, Bruker Avance-300 MHz spec-
trometers with 7–10 mM solutions in deuteriochloroform,
tetramethylsilane as internal standard. J values are given
in Hertz. Optical rotations were measured with a JASCO
P-1020 instrument and [a]D values are in units of
10ꢁ1 deg cm2 gꢁ1 at 25 °C. IR spectra were taken with a
Perkin–Elmer 1310 spectrometer. Mass spectra were
recorded on CEC-21-11013 or Finnigan Mat 1210 double
focusing mass spectrometers operating at a direct inlet
system and ESI-MS was measured using ion-trap mass
spectrometer. Elemental analysis was recorded on ELE-
MENTAR (Vario EL, Germany). Organic solutions were
1
(5.4 g, 90%) as a light yellow liquid. H NMR (200 MHz,
CDCl3): d 5.90–5.73 (m, 1H), 5.14–5.03 (m, 2H), 4.58
(t, J 3.7 Hz, 2H), 3.88–3.72 (m, 2H), 3.66 (sept, J 12.0,
8.3, 4.5 Hz, 1H), 3.52–3.33 (m, 2H), 2.30–2.12 (m, 2H),
1.88–1.41 (m, 10H); 13C NMR (75 MHz, CDCl3): d
132.2, 118.2, 98.6, 71.6, 67.2, 66.9, 38.5, 30.6, 25.5 and
25.3, 19.4; IR (neat) m: 3452, 2925, 2861, 1229, 950 cmꢁ1
;
ESI-MS; 223 [M+Na]+; Anal. Calcd for C11H20O3: C,
65.97; H, 10.07. Found: C, 65.93; H, 9.95.
Table 1. Comparative NMR values for natural product and synthetic compounds
Position
Natural product
Compound 1
Compound 2
H1
13C
H1
13C
H1
13C
1
2
3
—
—
—
171.4
30.5
—
—
—
172.0
29.8
—
—
—
171.1
30.1
2.57–2.55 (m)
2.61–2.58 (m)
2.58–2.55 (m)
2.93–2.91 (m)
—
2.60–2.53 (m)
2.60–2.15 (m)
4
38.2
2.94–2.63 (m)
38.8
3.00–2.66 (m)
37.7
5
6
210.2
41.8
—
209.9
44.0
—
210.1
41.3
2.04–2.02 (m)
2.61–2.58 (m)
1.19–1.17 (m)
1.38–1.33 (m)
1.19–1.17 (m)
1.38–1.33 (m)
1.38–1.33 (m)
1.67–1.66 (m)
3.82–3.78 (m)
1.67–1.66 (m)
1.67–1.66 (m)
5.04–4.98 (m)
1.19 (d, J 6.4)
2.42 (t, J 5.12)
2.60–2.15 (m)
7
8
9
23.5
35.3
23.2
1.89–1.36 (m)
1.89–1.36 (m)
1.89–1.36 (m)
23.2
36.1
21.8
1.89–1.35 (m)
1.89–1.35 (m)
1.89–1.35 (m)
23.4
34.3
23.2
10
11
67.0
41.4
3.75 (p, J 6.75)
1.89–1.36 (m)
68.6
41.5
3.79 (p, J 5.12)
1.89–1.35 (m)
, 67.5
40.4
12
12-Me
69.0
20.4
4.98–4.81 (m)
1.21 (d, J 6.58)
70.9
21.0
5.10 (sext, J 13.18, 5.85)
1.25 (d, J 6.42)
68.5
20.0

1156
P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
1
4.1.2.
2-{[4-(Benzyloxy)-6-heptenyl]oxy}tetrahydro-2H-
78%) as a colorless liquid. H NMR (200 MHz, CDCl3):
d 7.38–7.21 (s, 5H), 5.92–5.74 (m, 1H), 5.20–5.06 (m,
2H), 4.53 (dd, J 11.25 Hz, 2H), 3.49 (p, J 11.8, 8.2 Hz,
1H), 2.44–2.23 (m, 4H), 1.91–1.76 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 180.0, 134.1, 129.2, 128.4, 127.9,
127.9, 117.8, 77.9, 71.1, 38.1, 30.2 and 28.1; IR (neat) m:
3580, 2932, 2870, 1701, 1280, 689 cmꢁ1; ESI-MS; 234
[M+Na]+; Anal. Calcd for C14H18O3: C, 71.77; H, 7.74.
Found: C, 71.69; H, 7.71.
pyran 9b. To a stirred solution of alcohol 9a (1.0 g,
4.6 mmol) in THF (10 mL), NaH (0.3 g, 13.0 mmol) was
added at 0 °C and stirred for 30 min. Then, benzyl bromide
(0.7 mL, 5.6 mmol) was added and stirred for 2 h. Later,
the reaction was quenched with satd aq NH4Cl (10 mL)
and then extracted with EtOAc (2 ꢃ 20 mL), and the com-
bined organic layers were washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
was purified by column chromatography (silica gel, 60–
120 mesh, EtOAc/hexane, 1:9) to afford 9b (1.3 g, 95%)
4.1.5.
{(1S)-1-[(2S)-2-(Benzyloxy)propyl]-3-butenyloxy}-
1
as a light yellow syrup. H NMR (200 MHz, CDCl3): d
(tert-butyl)diphenylsilane 11. To a stirred solution of alco-
hol 12 (2.5 g, 11.3 mmol) in CH2Cl2 (25 mL), imidazole
(1.93 g, 28.3 mmol) was added at 0 °C and stirred for
30 min followed by TPSCl (3.56 mL, 15.0 mmol) and then
stirred for an additional 2 h at room temperature. After
completion of the reaction (TLC), the reaction mixture
was diluted with CH2Cl2 (20 mL), the organic layer was
washed with brine (25 mL), dried (Na2SO4), and concen-
trated in vacuo. The crude residue was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc/hexane,
7.69–7.25 (m, 5H), 5.90–5.75 (m, 1H), 5.16–5.05 (m, 2H),
4.58 (dd, J 10.98 Hz, 3H), 3.85–3.70 (m, 2H), 3.54–3.34
(m, 3H), 2.32–2.11 (m, 2H), 1.82–1.45 (m, 2H); 13C
NMR (75 MHz, CDCl3): d 133.4, 132.7, 130.0, 129.5,
128.2, 127.7, 98.8, 67.5, 67.1, 66.9, 62.3, 38.6, 30.6, 30.3,
25.5, 25.4 and 19.5; IR (neat) m: 2925, 2851, 1221,
939 cmꢁ1; ESI-MS; 304 [M+NH4]+; Anal. Calcd for
C19H28O3: C, 74.96; H, 9.27. Found: C, 74.93; H, 9.25.
4.1.3. 4-(Benzyloxy)-6-hepten-1-ol 9. To a stirred solution
of alcohol 9b (1.3 g, 4.2 mmol) in MeOH (10 mL), PTSA
(0.02 g) was added at 0 °C and stirred for 4 h at room tem-
perature. The reaction mixture was quenched with satd aq
NaHCO3 solution (2 mL), extracted with EtOAc
(2 ꢃ 15 mL) and the organic layer separated. The com-
bined organic layers were washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
was purified by column chromatography (silica gel, 60–
120 mesh, EtOAc/hexane, 1:9) to afford 8 (0.84 g, 90%)
as a colorless liquid. 1H NMR (200 MHz, CDCl3): d
7.39–7.24 (m, 5H), 5.90–5.75 (m, 1H), 5.16–5.05 (m, 2H),
4.52 (dd, J 11.33 Hz, 2H), 3.57 (t, J 6.04 Hz 2H), 3.54–
3.43 (m, 1H), 2.46–2.28 (m, 2H), 1.72–1.54 (m, 4H); 13C
NMR (75 MHz, CDCl3): d 135.1, 128.5, 128.0, 127.9,
117.0, 78.8, 70.8, 62.9, 38.0, 30.9 and 28.2; IR (neat)
m: 3480, 2930, 2860, 1215, 952 cmꢁ1. ESI-MS; 243
[M+Na]+; Anal. Calcd for C14H20O2: C, 76.33; H, 9.15.
Found: C, 76.29; H, 9.09.
1:49) to afford 11 (0.58 g, 78%) as a light yellow syrup.
25
½aꢀD ¼ þ11:2 (c 1.3, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.72–7.60 (m, 4H), 7.45–7.10 (m, 11H), 5.80–5.59 (m,
1H), 5.00–4.80 (m, 2H), 4.37 (d, J 9.75 Hz, 1H), 4.10–
4.00 (m, 2H), 3.68–3.50 (m, 1H), 2.21–2.10 (m, 2H),
1.80–1.48 (m, 2H), 1.07 (s, 9H), 1.05 (d, J 6.03 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 135.9, 134.6, 134.0, 132.7,
129.8, 129.7, 129.5, 128.2, 127.5, 117.4, 71.8, 70.3, 69.8,
43.2, 42.0, 41.3, 27.0, 23.5 and 19.5; IR (neat) m: 2915,
2851, 1221 cmꢁ1; ESI-MS; 481 [M+Na]+; Anal. Calcd for
C30H38O2Si: C, 78.55; H, 8.35; Si, 6.12. Found: C, 78.48;
H, 8.29; Si, 6.07.
4.1.6.
(2S,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-6-
hepten-2-ol 3. To a solution of THF (3 mL) and liq.
NH3 (10 mL), Li (0.16 g, 23.3 mmol) was added and the
reaction mixture was stirred for 30 min at ꢁ78 °C. Then,
compound 11 (2.5 g, 5.88 mmol) was added and further
stirred for 1 h at the same temperature. Later, the reaction
mixture was quenched with satd NH4Cl (50 mL), extracted
with EtOAc (2 ꢃ 30 mL), and the organic layer was washed
with brine (25 mL), dried (Na2SO4), and concentrated in
vacuo. The crude residue was purified by column chroma-
tography (silica gel, 60–120 mesh, EtOAc/hexane, 1:24) to
4.1.4. 4-(Benzyloxy)-6-heptenoic acid 8. To a stirred solu-
tion of oxalyl chloride (0.34 mL g, 3.9 mmol) in CH2Cl2
(120 mL) at ꢁ78 °C, DMSO (0.55 mL, 7.8 mmol) was
added followed by alcohol 9 (0.73 g, 3.5 mmol) in CH2Cl2
and the reaction mixture stirred for 1 h at ꢁ78 °C,
quenched with Et3N (3.0 mL, 21.4 mmol), and extracted
with CH2Cl2 (2 ꢃ 10 mL). The combined organic layer
was washed with brine, dried (Na2SO4), and concentrated
in vacuo to afford the aldehyde (0.7 g, 97.2%) as a colorless
liquid, which was directly used for further reaction.
afford alcohol 3 (1.3 g, 68%) as a light yellow liquid.
25
½aꢀD ¼ þ41:3 (c 0.9, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.75–7.61 (m, 4H), 7.42–7.30 (m, 6H), 5.60–5.38 (m, 1H),
4.94–4.75 (m, 2H), 4.13–3.90 (m, 2H), 2.42–2.09 (m, 2H),
1.63–1.42 (m, 2H), 1.08 (s, 9H), 1.07 (d, J 6.04 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 136.0, 134.2, 130.1, 127.9,
127.9, 117.5, 96.2, 72.1, 64.0, 43.4, 41.0, 27.2, 27.2 and
23.8; IR (neat) m: 3441, 3015, 2898, 1855, 1268, 1251,
To a stirred solution of aldehyde (0.7 g, 3.4 mmol) in
t-BuOH/2-methyl 2-butene (2:1, 6 mL), NaClO2 (0.62 g,
6.8 mmol), and NaH2PO4 (1.1 g, 6.8 mmol) [dissolved in
water (2 mL)] were added and stirred for 6 h at room
temperature. Solvent was removed under reduced pressure
and extracted with EtOAc (2 ꢃ 5 mL), the combined
organic layers were washed with brine (5 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
was purified by column chromatography (silica gel, 60–
120 mesh, EtOAc/hexane, 1:4) to afford acid 8 (0.58 g,
695 cmꢁ1
;
ESI-MS; 369 [M+1]+; Anal. Calcd for
C23H32O2Si: C, 74.95; H, 8.75; Si, 7.62. Found: C, 74.89;
H, 8.70; Si, 7.56.
4.1.7.
(1S,3S)-3-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-
methyl-5-hexenyl-4-(benzyloxy)-6-heptenoate 4. To a stir-
red solution of acid 8 (0.8 g, 3.6 mmol) in dry THF
(6 mL), Et3N (1.5 mL, 10.9 mmol) was added at room tem-
perature and stirred for 1 h. Then, 2,4,6-trichlorobenzoyl

P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
1157
chloride (1.14 mL, 7.3 mmol) was added and stirred for 2 h
at room temperature. The solvent was evaporated, the res-
idue diluted with toluene (6 mL), treated with DMAP
(1.12 g, 9.16 mmol) and alcohol 3 (1.2 g, 3.6 mmol). After
6 h, the toluene was evaporated in vacuo and the crude res-
idue purified by column chromatography (silica gel, 60–
4.1.10. (10S,12S)-10-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-
12-methyl-1-oxacyclododecane-2,5-dione 7. To a stirred
solution of alcohol 6 (0.06 g, 0.14 mmol) in CH2Cl2
(2 mL), DMP (0.08 g, 0.18 mmol) was added and stirred
for 2 h at room temperature. Then, the reaction was
quenched with aq solution of NaHCO3:hypo (1:1, 1 mL)
and concentrated in vacuo. The crude residue was purified
by column chromatography (silica gel, 60–120 mesh,
120 mesh, EtOAc/hexane, 1:24) to afford ester 4 (1.2 g,
25
67%) as a colorless syrup. ½aꢀD ¼ þ25:3 (c 0.3, CHCl3);
1H NMR (200 MHz, CDCl3): d 7.68–7.60 (m, 4H), 7.38–
7.20 (m, 11H), 5.86–5.54 (m, 2H), 5.11–4.82 (m, 5H),
4.58–4.37 (m, 2H), 3.78–3.68 (m, 1H), 3.45–3.34 (m, 1H),
2.40–2.09 (m, 6H), 1.82–1.50 (m, 4H), 1.07 (s, 9H), 1.06
(d, J 6.39 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 173.0,
143.1, 140.9, 135.8, 134.3, 134.2, 139.1, 38.5, 137.5, 137.4,
137.3, 117.8, 117.5, 71.0, 69.6, 68.0, 42.2, 40.9, 38.2, 30.0,
29.0, 27.1, 22.9, 22.5 and 20.8; IR (neat) m: 2928, 2890,
1718, 1085, 1060 cmꢁ1; ESI-MS; 585 [M+1]+; Anal. Calcd
for C37H48O4Si: C, 75.98; H, 8.27; Si, 4.80. Found: C,
75.88; H, 8.21; Si, 4.75.
EtOAc/hexane, 1:9) to afford ketone 7 (0.05 g, 90%) as a
25
light yellow syrup. ½aꢀD ¼ þ23:2 (c 0.3, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.70–7.59 (m, 4H), 7.43–7.30
(m, 6H), 4.48–4.31 (m, 1H), 3.61–3.50 (p, J 11.35,
6.81 Hz, 1H), 2.60–2.32 (m, 4H), 2.21 (t, J 5.0 Hz, 2H),
1.80–1.21 (m, 8H), 1.05 (s, 9H), 1.04 (d, J 6.49 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 209.9, 171.7, 135.8, 129.6,
127.5, 70.9, 70.7, 42.9, 41.3, 37.9, 35.5, 29.7, 26.9, 22.3,
21.9, 20.9 and 19.8; IR (neat) m: 2929, 1721, 1678,
1250 cmꢁ1; ESI-MS; 489 [M+Na]+; Anal. Calcd for
C28H38O4Si: C, 72.06; H, 8.21; Si, 6.02. Found: C, 71.92;
H, 8.09; Si, 5.91.
4.1.8.
(10S,12S)-5-[1-(Benzyloxy)]-10-[1-(tert-butyl)-1,1-
4.1.11. (10S,12S)-10-Hydroxy-12-methyl-1-oxacyclodode-
cane-2,5-dione 1. To a stirred solution of 7 (0.05 g,
0.11 mmol) in dry THF (2 mL), HFꢂpy (0.3 mL, 0.3 mmol)
was added and stirred for 4 h at room temperature. The
reaction mixture was quenched with CuSO4 solution and
extracted with EtOAc (2 ꢃ 2 mL), and the organic layer
was washed with brine (2 mL), dried (Na2SO4), and con-
centrated in vacuo. The crude residue was purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc/
diphenylsilyl]oxy-12-methyl-1-oxa-7-cyclododecen-2-one 5.
To a solution of bis-olefin 4 (0.2 g, 0.37 mmol) and Grub-
bs’ second generation catalyst (0.03 g, 10 mol %) in CH2Cl2
(20 mL) was stirred at reflux temperature for 12 h. Later,
the solvent was removed under reduced pressure and the
crude residue purified by column chromatography (silica
gel, 60–120 mesh, EtOAc/hexane, 1:49) to afford cyclized
product
5 (0.13 g, 72%) as a light yellow liquid.
25
1
½aꢀD ¼ þ9:5 (c 0.1, CHCl3); H NMR (300 MHz, CDCl3):
d 7.72–7.59 (m, 4H), 7.45–7.18 (m, 11H), 5.88–5.64 (m,
1H), 5.40–5.24 (m, 1H), 5.18–4.93 (m, 1H), 4.54–4.88 (m,
2H), 3.72–3.48 (m, 1H), 3.42–3.16 (m, 1H), 2.50–2.21 (m,
6H), 1.51–1.24 (m, 4H), 1.09 (s, 9H), 1.07 (d, 3H, J
6.4 Hz); 13C NMR (75 MHz, CDCl3): d 173.4, 143.5,
140.0, 135.8, 135.6, 134.3, 131.2, 127.8, 130.1, 127.4,
127.4, 70.5, 69.5, 68.2, 66.7, 42.2, 30.9, 30.7, 26.5, 26.3,
22.8 and 19.3; IR (neat) m: 2920, 2885, 1721, 1095,
1080 cmꢁ1; ESI-MS; 579 [M+Na]+; Anal. Calcd for
C35H44O4Si: C, 75.50; H, 7.96; Si, 5.04. Found: C, 75.45;
H, 7.91; Si, 4.98.
hexane, 3:7) to afford 1 (0.02 g, 85%) as a white solid.
25
Mp 70–72 °C; ½aꢀD ¼ þ68:1 (c 0.25, MeOH); 1H NMR
(200 MHz, CDCl3): d 4.98–4.81 (m, 1H), 3.75 (p, J
6.75 Hz, 1H), 2.94–2.63 (m, 2H), 2.60–2.53 (m, 3H), 2.42
(t, J 5.12 Hz, 2H), 1.89–1.36 (m, 7H), 1.21 (d, J 6.58 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 209.9, 172.0, 70.9,
68.6, 44.0, 41.5, 38.8, 36.1, 29.8, 23.2, 21.8 and 21.0; IR
(neat): 3444, 2920, 1710, 1662, 1251 cmꢁ1; ESI-MS; 251
[M+Na]+; Anal. Calcd for C12H20O4: C, 63.14; H, 8.83.
Found: C, 63.07; H, 8.73.
4.1.12.
1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-4-penten-2-ol
15a. To a stirred solution of oxalyl chloride (1.91 mL,
21.8 mmol) in CH2Cl2 (30 mL) at ꢁ78 °C, DMSO
(3.1 mL, 43.7 mmol) was added followed by compound
17 (3.7 g, 19.8 mmol) in CH2Cl2 and the reaction mixture
stirred for 1 h at ꢁ78 °C, then quenched with Et3N
(8.3 mL, 59.6 mmol), and extracted with CH2Cl2
(2 ꢃ 40 mL). The combined organic layer was washed with
brine (50 mL), dried (Na2SO4), and concentrated in vacuo
to afford the aldehyde (3.62 g, 99%) as a colorless liquid,
which was directly used for further reaction.
4.1.9. (10S,12S)-10-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-5-
hydroxy-12-methyl-1-oxacyclododecan-2-one 6. To a stir-
red solution of 5 (0.1 g, 0.19 mmol) in MeOH (1 mL),
10% Pd/C (catalytic) was added under hydrogen atmo-
sphere and stirred for 6 h. Later, the reaction mixture
was filtered through a pad of Celite and concentrated in va-
cuo. The crude residue so obtained was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc/hexane,
1:4) to afford cyclic alcohol 6 (0.06 g, 82%) as a colorless
25
1
liquid. ½aꢀD ¼ þ2:8 (c 0.13, CHCl3); H NMR (300 MHz,
CDCl3): d 7.61–7.48 (m, 4H), 7.40–7.22 (m, 6H), 5.14–
5.08 (m, 1H), 3.95–3.80 (m, 1H), 3.78–3.60 (m, 1H),
2.52–2.31 (m, 2H), 1.61–1.25 (m, 12H), 1.06 (s, 9H), 1.05
(d, J 6.46 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 173.0,
135.8, 130.0, 127.5, 127.4, 70.3, 70.2, 66.7, 42.0, 30.7,
28.7, 28.5, 27.9, 26.8, 26.5, 26.1, 22.9 and 19.1; IR (neat)
m: 3482, 2920, 1718, 1462, 1262 cmꢁ1; ESI-MS; 486
[M+NH4]+; Anal. Calcd for C28H40O4Si: C, 71.75; H,
8.60; Si, 5.99. Found: C, 71.66; H, 8.49; Si, 5.85.
To a stirred solution of the above aldehyde (3.62 g,
20.1 mmol) in THF (40 mL), Zn (2.6 g, 39.7 mmol), and
allyl bromide (3.3 mL, 40.0 mmol) were added at 0 °C
followed by the slow addition of satd NH4Cl (11 mL)
and stirred for 4 h. Later, the reaction mixture was
quenched with satd aq solution of NH4Cl (30 mL),
extracted with EtOAc (2 ꢃ 30 mL), and the organic layer
separated. The combined organic layers were washed with
brine (50 mL), dried (Na2SO4), and concentrated in vacuo.

1158
P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
The crude residue was purified by column chromatography
1H), 2.39–2.10 (m, 2H), 1.81–1.34 (m, 12H), 1.05 (s, 9H);
13C NMR (75 MHz, CDCl3): d 135.9, 134.4, 129.8, 129.8,
117.5, 72.1, 70.4, 69.2, 41.0, 39.5, 36.7, 35.2, 27.6, 25.2,
23.9 and 23.9; IR (neat) m: 3020, 2900, 1850, 1275, 1250,
(silica gel, 60–120 mesh, EtOAc/hexane, 1:4) to afford 15a
25
(4.1 g, 92%) as a colorless liquid. ½aꢀD ¼ þ2:8 (c 0.5,
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.90–5.73 (m,
1H), 5.13–5.04 (m, 1H), 4.29–4.18 (m, 1H), 4.15–3.98 (m,
1H), 3.96–3.80 (m, 1H), 3.50 (t, J 6.79 Hz, 1H), 3.10 (m,
1H), 2.32–2.14 (m, 2H), 1.74–1.51 (m, 12H); 13C NMR
(75 MHz, CDCl3): d 134.2, 118.1, 75.5, 70.4, 69.1, 42.0,
40.1, 36.5, 35.1, 25.4, and 23.9; IR (thin film): 3448, 3059,
2918, 1580, 1050 cmꢁ1; ESI-MS; 226 [M+H]+; Anal. Calcd
for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.95; H, 9.70.
751 cmꢁ1
;
ESI-MS; 465 [M+1]+; Anal. Calcd for
C29H40O3Si: C, 74.95; H, 8.68; Si, 6.04. Found: C, 74.88;
H, 8.61; Si, 5.95.
4.1.15. (2S,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-6-
hepten-1,2-ol 13. To a stirred solution of 14 (1.0 g,
2.1 mmol) in MeOH (10 mL), PTSA (0.02 g) was added
at 0 °C and stirred for 4 h at room temperature. The reac-
tion mixture was quenched with satd aq NaHCO3 solution
(2 mL), extracted with EtOAc (2 ꢃ 15 mL), the combined
organic layers were washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
was purified by column chromatography (silica gel, 60–
4.1.13. (2S)-1-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-4-penten-2-
ol 15. To a stirred solution of oxalyl chloride (0.42 mL g,
4.8 mmol) in CH2Cl2 (10 mL) at ꢁ78 °C, DMSO (0.69 mL,
9.6 mmol) was added followed by compound 15a (1 g,
4.4 mmol) in CH2Cl2 and the reaction mixture stirred for
1 h at ꢁ78 °C, then quenched with Et3N (1.86 mL,
12.8 mmol), and extracted with CH2Cl2 (2 ꢃ 15 mL). The
combined organic layer was washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo to afford the
ketone (0.94 g, 95%) as a colorless liquid, which was di-
rectly used for further reaction.
120 mesh, EtOAc/hexane, 2:3) to afford 13 (0.7 g, 85%)
25
as a colorless syrup. ½aꢀD ¼ þ94:8 (c 0.45, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.77–7.65 (m, 4H), 7.49–7.34
(m, 6H), 5.67–5.45 (m, 1H), 4.94–4.76 (m, 2H), 3.97 (q, J
12.75, 6.71 Hz, 1H), 3.87–3.73 (m, 1H), 3.44 (dd, J
3.35 Hz, 1H), 3.27 (dd, J 6.04 Hz, 1H), 2.18–2.10 (m, 2H)
1.63–1.56 (m, 2H), 1.06 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 135.8, 133.8, 129.9, 129.7, 127.7, 127.7, 127.6,
117.6, 72.6, 70.4, 66.8, 41.8, 38.9, 26.9 and 19.2; IR (neat)
m: 3450, 3020, 2895, 1850, 1275, 1250, 750 cmꢁ1; ESI-MS;
402 [M+NH4]+; Anal. Calcd for C23H32O3Si: C, 71.83;
H, 8.39; Si, 7.30. Found: C, 71.80; H, 8.34; Si, 7.22.
To a stirred solution of ketone (0.94 g, 4.1 mmol), in dry
ether (10 mL), lithium iodide (1.68 g, 12.5 mmol) was
added at 0 °C and stirred for 10 min. Then at ꢁ78 °C, lith-
ium aluminum hydride (0.48 g, 12.5 mmol) was added and
the mixture stirred for 10 min after which the temperature
was decreased to ꢁ100 °C and stirred for 30 min. Later, the
reaction was quenched with satd aq KOH (10 mL) solution
and extracted with ether (2 ꢃ 20 mL). The combined or-
ganic layer was washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
purified by column chromatography (silica gel, 60–
120 mesh, EtOAc/hexane, 1:9) to afford 15 (0.67 g, 72%)
4.1.16. (2S,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-2-
hydroxy-6-heptenyl-4-methyl-1-benzenesulfonate 13a. To
a stirred solution of diol 13 (0.2 g, 0.52 mmol) in CH2Cl2
(4 mL), Et3N (0.22 mL, 1.5 mmol) was added at 0 °C and
stirred for 1 h. Then, tosyl chloride (0.11 g, 0.57 mmol)
was added and stirred for further 5 h at room temperature.
Later, the reaction mixture was diluted with CH2Cl2
(5 mL), washed with water (5 mL), brine (5 mL), dried
(Na2SO4), and concentrated in vacuo. The crude residue
was purified by column chromatography (silica gel, 60–
120 mesh, EtOAc/hexane, 1:4) to afford 13a (0.24 g, 87%)
25
1
as a colorless syrup. ½aꢀD ¼ þ12:2 (c 1, CHCl3); H NMR
(300 MHz, CDCl3): d 5.90–5.73 (m, 1H), 5.13–5.04 (m,
1H), 4.29–4.18 (m, 1H), 4.05 (q, J 8.3, 6.0 Hz, 1H), 3.9–
3.8 (m, 1H), 3.52 (t, J 6.79 Hz, 1H), 3.10 (br s, 1H),
2.32–2.14 (m, 2H), 1.74–1.51 (m, 12H); 13C NMR
(75 MHz, CDCl3): d 134.2, 118.1, 75.5, 70.4, 69.1, 42.0,
40.1, 36.5, 35.1, 25.4, and 23.9; IR (thin film): 3440, 3050,
2920, 1590, 1054 cmꢁ1; ESI-MS; 226 [M+H]+; Anal. Calcd
for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.90; H, 9.78.
25
1
as a light yellow liquid. ½aꢀD ¼ þ56:5 (c 0.15, CHCl3); H
NMR (200 MHz, CDCl3): d 7.78 (d, J 8.3 Hz, 2H), 7.67–
7.65 (m, 4H), 7.47–7.32 (m, 8H), 5.66–5.51 (m, 1H),
4.99–4.81 (m, 2H), 4.01–3.86 (m, 3H), 3.74 (dd, J
6.04 Hz, 1H), 2.48 (s, 3H), 2.25–2.10 (m, 2H), 1.62–1.56
(m, 2H), 1.06 (s, 9H); IR (neat) m: 2941, 1709, 1661,
1241 cmꢁ1; ESI-MS; 561 [M+Na]+; Anal. Calcd for
C30H38O5SSi: C, 66.88; H, 7.11; S, 5.95; Si, 5.21. Found:
C, 66.81; H, 7.02; S, 5.90; Si, 5.10.
4.1.14. tert-Butyl (1S)-1-[(2S)-1,4-dioxaspiro[4.5]dec-2-
ylmethyl}-3-butenyloxy diphenylsilane 14. To a stirred
solution of alcohol 15 (1.9 g, 8.4 mmol) in CH2Cl2
(20 mL), imidazole (1.4 g, 20.5 mmol) was added at 0 °C
and stirred for 30 min, then TPSCl (2.6 mL, 10.0 mmol)
was added and the mixture stirred for 2 h at room temper-
ature. After the completion of the reaction (TLC), the reac-
tion mixture was diluted with CH2Cl2 (20 mL), the organic
layer was washed with brine (20 mL), dried (Na2SO4), and
concentrated in vacuo. The crude residue purified by
column chromatography (silica gel, 60–120 mesh, EtOAc/
4.1.17. (2R,4S)-4-{[1-(tert-Butyl)-1,1-diphenylsilyl]oxy}-6-
hepten-2-ol 3a. To a stirred solution of lithium aluminum
hydride (0.01 g, 0.26 mmol) in dry THF (1 mL), compound
14 dissolved in dry THF (1 mL) was added at 0 °C, the
reaction mixture brought to reflux temperature and stirred
for 1 h, quenched with satd aq Na2SO4 solution filtered
through a pad of Celite, dried (Na2SO4), and concentrated
in vacuo. The crude residue was purified by column chro-
matography (silica gel, 60–120 mesh, EtOAc/hexane, 1:9)
to afford 3a (0.09 g, 73%) as a light yellow syrup.
hexane, 1:9) to afford 14 (3.7 g, 95%) as a colorless liquid.
25
½aꢀD ¼ þ30:9 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): d
7.69–7.60 (m, 4H), 7.40–7.26 (m, 6H), 5.83–5.61 (m, 1H),
4.98–4.83 (m, 2H), 4.19–4.05 (m, 1H), 3.86 (p, J 10.93,
5.47 Hz, 1H), 3.74 (dd, J 6.25 Hz, 1H), 3.25 (t, J 7.03 Hz,
25
1
½aꢀD ¼ ꢁ3:3 (c 2.3, CHCl3); H NMR (200 MHz, CDCl3):

P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
1159
d 7.74–7.65 (m, 4H), 7.46–7.32 (m, 6H), 5.87–5.71 (m, 1H),
5.12–5.05 (m, 2H), 4.11 (q, J 6.04 Hz, 1H), 3.90–3.79 (m,
1H), 2.17 (t, J 6.04 Hz, 2H), 1.80–1.51 (m, 2H), 1.07 (s,
9H), 1.02 (d, J 6.04 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 135.8, 134.8, 129.7, 127.7, 127.4, 117.5, 70.0, 69.6, 45.5,
41.9, 26.9, 26.5 and 23.9; IR (neat) m: 3445, 3010, 2895,
1860, 1268, 1251, 695 cmꢁ1; ESI-MS; 391 [M+Na]+; Anal.
Calcd for C23H32O2Si: C, 74.95; H, 8.75; Si, 7.62. Found:
C, 74.90; H, 8.66; Si, 7.59.
was filtered through a pad of Celite and concentrated in
vacuo. The crude residue thus obtained was purified by
column chromatography (silica gel, 60–120 mesh, EtOAc/
hexane, 1:4) to afford cyclic alcohol 6a (0.1 g, 85%) as a col-
25
orless syrup. ½aꢀD ¼ þ37:2 (c 0.15, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.69–7.49 (m, 4H), 7.41–7.19 (m,
6H), 5.19–5.11 (m, 1H), 4.13–3.98 (m, 1H), 3.81–3.70 (m,
1H), 2.50–2.28 (m, 2H), 1.75–1.31 (m, 12H), 1.12–1.05
(m, 12H); IR (neat) m: 3480, 2925, 1720, 1475, 1250 cmꢁ1
;
ESI-MS; 469 [M+1]+; Anal. Calcd for C28H40O4Si:
C, 71.75; H, 8.60; Si, 5.99. Found: C, 71.71; H, 8.55;
Si, 5.91.
4.1.18. (1R,3S)-3-[1-(tert-Butyl)]-1,1-diphenylsilyl]oxy-1-
methyl-5-hexenyl-4-(benzyloxy)-6-heptenoate 4a. To a
stirred solution of acid 8 (0.6 g, 2.7 mmol) in dry THF
(6 mL), Et3N (1.14 mL, 8.2 mmol) was added at room tem-
perature and stirred for 1 h. Then, 2,4,6-trichlorobenzoyl
chloride (0.85 mL, 5.4 mmol) was added and the reaction
mixture was further stirred for 2 h at room temperature.
The solvent was evaporated, residue diluted with toluene
(6 mL), treated with DMAP (0.84 g, 6.8 mmol) and alcohol
3a (0.92 g, 2.7 mmol). After 6 h, the toluene was evapo-
rated in vacuo and the crude residue purified by column
chromatography (silica gel, 60–120 mesh, EtOAc/hexane,
4.1.21. (10S,12R)-10-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-
12-methyl-1-oxacyclododecane-2,5-dione 7a. To a stirred
solution of alcohol 6a (0.09 g, 0.18 mmol) in CH2Cl2
(2 mL), DMP (0.13 g, 0.31 mmol) was added and stirred
for 2 h at room temperature. Then, the reaction was
quenched with aq solution of NaHCO3:hypo (1:1,
1 mL), extracted with CH2Cl2 (2 mL), and the organic
layer was washed with brine (2 mL), dried (Na2SO4),
and concentrated in vacuo. The crude residue so obtained
was purified by column chromatography (silica gel, 60–
1:24) to afford bis-olefin 4a (0.96 g, 69%) as a colorless
25
liquid. ½aꢀD ¼ þ36:5 (c 0.35, CHCl3); 1H NMR (200
120 mesh, EtOAc/hexane, 1:9) to afford ketone 7a
25
MHz, CDCl3): d 7.69–7.57 (m, 4H), 7.35–7.21 (m, 11H),
5.88–5.50 (m, 2H), 5.09–4.89 (m, 5H), 4.46 (q, 2H, J
11.72 Hz), 3.88–3.70 (m, 1H), 3.51–3.33 (m, 1H), 2.32–
2.08 (m, 6H), 1.88–1.48 (m, 4H), 1.14–0.96 (m, 12H); 13C
NMR (75 MHz, CDCl3): d 173.1, 138.9, 136.0, 135.5,
134.3, 133.5, 129.4, 128.3, 127.6, 127.5, 118.0, 117.4, 77.5,
71.1, 70.3, 66.7, 43.1, 38.9, 38.1, 30.1, 28.9, 27.0, 23.0 and
19.0; IR (neat) m: 2927, 2896, 1720, 1095, 1060 cmꢁ1; ESI-
MS; 607 [M+Na]+; Anal. Calcd for C37H48O4Si: C,
75.98; H, 8.27; Si, 4.80. Found: C, 75.91; H, 8.19; Si, 4.71.
(0.08 g, 92%) as a colorless syrup. ½aꢀD ¼ ꢁ12:9 (c 0.36,
CHCl3); 1H NMR (200 MHz, CDCl3): d 7.62–7.45 (m,
4H), 7.40–7.22 (m, 6H), 5.28–5.11 (m, 1H), 3.95–3.81
(m, 1H), 2.80–2.42 (m, 4H), 2.32–2.05 (m, 2H), 1.92–
1.55 (m, 4H), 1.50–1.13 (m, 4H), 1.06–0.98 (m, 12H);
13C NMR (50 MHz, CDCl3): d 210.0, 171.1, 135.8,
129.6, 127.5, 70.7, 70.6, 42.8, 41.3, 37.7, 35.5, 29.6, 26.7,
22.1, 21.8, 20.9, 19.9; IR (neat) m: 2928, 1729, 1670,
1252 cmꢁ1; ESI-MS; 489 [M+Na]+; Anal. Calcd for
C28H38O4Si: C, 72.06; H, 8.21; Si, 6.02. Found: C,
72.01; H, 8.18; Si, 5.99.
4.1.19. (10S,12R)-5-[1-(Benzyloxy)]-10-[1-(tert-butyl)-1,1-
diphenylsilyl]oxy-12-methyl-1-oxa-7-cyclododecen-2-one 5a.
A solution of bis-olefin 4a (0.1 g, 0.18 mmol) and Grubbs’
second generation catalyst (0.02 g, 10 mol %) in CH2Cl2
(15 mL) was stirred at reflux temperature for 12 h. Later,
the solvent was removed under reduced pressure and the
crude residue purified by column chromatography (silica
gel, 60–120 mesh, EtOAc/hexane, 1:49) to afford cyclized
4.1.22. (10S,12R)-10-Hydroxy-12-methyl-1-oxacyclodode-
cane-2,5-dione 2. To a stirred solution of 7a (0.06 g,
0.14 mmol) in dry THF (2 mL), HFꢂpy (0.4 mL,
0.41 mmol) was added and stirred for 4 h at room temper-
ature. The reaction mixture was quenched with CuSO4
solution, extracted with EtOAc (2 mL), and the organic
layer was washed with brine (2 mL), dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by
column chromatography (silica gel, 60–120 mesh, EtOAc/
product 5a (0.06 g, 70%) as a light yellow liquid.
25
½aꢀD ¼ þ45:9 (c 0.25, CHCl3); 1H NMR (200 MHz,
CDCl3): d 7.66–7.60 (m, 4H), 7.42–7.21 (m, 11H), 5.56–
5.24 (m, 2H), 5.03–4.84 (m, 1H), 4.57–4.45 (m, 2H), 3.84
(q, 1H, J 6.25 Hz), 3.65–3.47 (m, 1H), 2.50–2.16 (m, 2H),
2.09–1.48 (m, 4H), 1.39–1.25 (m, 4H), 1,12 (d, 3, J
6.25H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3): d
171.4, 142.0, 140.5, 135.3, 135.6, 134.1, 131.5, 130.1,
127.6, 127.4, 70.6, 69.3, 68.2, 66.9, 42.2, 30.9, 30.5, 26.5,
26.3, 22.6 and 19.0; IR (neat) m: 2925, 2895, 1719, 1090,
1050 cmꢁ1; ESI-MS; 579 [M+Na]+; Anal. Calcd for
C35H44O4Si: C, 75.50; H, 7.96; Si, 5.04. Found: C, 75.39;
H, 7.89; Si, 4.90.
hexane, 3:7) to afford 2 (0.02 g, 85%) as a colorless oil.
25
½aꢀD ¼ ꢁ52:2 (c 0.25, MeOH); 1H NMR (300 MHz,
CDCl3): d 5.10 (sext, J 13.18, 5.86 Hz, 1H), 3.79 (p, J
10.25, 5.12 Hz, 1H), 3.00–2.66 (m, 3H), 2.60–2.15 (m,
5H), 1.89–1.35 (m, 6H), 1.25 (d, J 6.42 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 210.1, 171.1, 68.5, 67.5, 41.3,
40.4, 37.7, 34.3, 30.1, 23.4, 23.2, 20.0; IR (neat): 3431,
2931, 1716, 1665, 1460, 1255 cmꢁ1
;
ESI-MS; 251
[M+Na]+; Anal. Calcd for C12H20O4: C, 63.14; H, 8.83.
Found: C, 63.10; H, 8.79.
4.1.20. (10S,12R)-10-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-5-
hydroxy-12-methyl-1-oxacyclododecan-2-one 6a. To
a
Acknowledgment
stirred solution of 5a (0.15 g, 0.29 mmol) in MeOH
(2 mL), 10% Pd/C (catalytic) was added under hydrogen
atmosphere and stirred for 6 h. Later, the reaction mixture
One of the authors (R.S.) thanks the UGC, New Delhi, for
financial support in the form of a fellowship.

1160
P. R. Krishna, R. Srinivas / Tetrahedron: Asymmetry 19 (2008) 1153–1160
3. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
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