Stereoselective synthesis of an advanced seco ester intermediate as a precursor toward the synthesis of amphidinolides T1, T3, and T4

Article abstract of DOI:10.1016/j.tet.2010.05.012

An efficient, convergent, and stereoselective synthesis of a very advanced intermediate toward the total synthesis of amphidinolides T1, T3, and T4 utilising Evan's aldol and alkylation reactions, oxy-Michael, cross metathesis, stereoselective Grignard ad

Full text of DOI:10.1016/j.tet.2010.05.012

Tetrahedron 66 (2010) 5000e5007
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Stereoselective synthesis of an advanced seco ester intermediate as a precursor
toward the synthesis of amphidinolides T1, T3, and T4q
,
a
,
,
Pradip K. Sasmal a , Chandrasekhar Abbineni b, Javed Iqbal a c, K. Mukkanti b
*
a Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India
c Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, convergent, and stereoselective synthesis of a very advanced intermediate toward the total
synthesis of amphidinolides T1, T3, and T4 utilising Evan’s aldol and alkylation reactions, oxy-Michael,
cross metathesis, stereoselective Grignard addition, and Yamaguchi esterification reactions as key steps is
described.
Received 20 March 2010
Received in revised form 3 May 2010
Accepted 5 May 2010
Available online 8 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amphidinolide T family
Evan’s aldol
Evan’s alkylation
Oxy-Michael
Cross metathesis
CBS reduction
1. Introduction
OH
O
13
O
O
HO
O
12
The amphidinolides are a rapidly growing family of macrolides
produced by marine dinoflagellates of the genus Amphidinium.1
Though structurally quite diverse all members are distinguished
by a pronounced cytotoxicity against various cancer cell lines.
In contrast to macrolide antibiotics derived from terrestrial
microorganisms, however, the majority of amphidinolides features
an odd-numbered macrolactone ring, which is biosynthesized by
a complex, nonsuccessive mixed polyketide pathway.2 In particular,
the amphidinolide T class (Fig. 1) has garnered significant attention
since its discovery in 2000.3
10
OH
18
7
O
O
O1
O
Amphidinolide T2 (2)
Amphidinolide T1 (1)
O
O
13
HO
HO
12
Members of this subclass, amphidinolides T1e5 (1e5), contain
a 19-membered macrocycle, a trisubstituted tetrahydrofuran moi-
ety, a-hydroxy ketone, an exocyclic methylene group, and a homo-
allylic ester linkage. Amphidinolides T3eT5 (3e5) are the most
closely related molecules, all containing a ketone at C13, hydroxyl
group at C12, and methyl group at C14, and they differ only in their
configuration at C12 and C14. AmphidinolideT2 (2) displays the
O
O
O
O
O
O
12R: Amphidinolide T3 (3)
Amphidinolide T5 (5)
12S: Amphidinolide T4 (4)
Figure 1. Amphidinolide T family of natural products.
same functionality at C12eC14 as 3e5, but contains 3-hydroxybutyl
substituent at C18 where the other four members have an n-propyl
group. Amphidinolide T1 (1) differs from amphidinolides T3e5
(3e5) in the oxidation states at C12 and C13, possessing the re-
versed hydroxy ketone moiety.
q
This paper is dedicated to Dr. J. S. Yadav on the occasion of his 60th birthday.
DRL Publication No. 718
* Corresponding author. Present address: Dr. Reddy’s Laboratories Ltd.,
Innovation Plaza, Bachupally, Hyderabad 500072, India. Tel.: þ91 40 4434 6865;
fax: þ91 40 4434 6125; e-mail address: sasmalpk@yahoo.co.in (P.K. Sasmal).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.012

P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
5001
Because of the significant cytotoxicity against human epider-
O
O
O
O
OH
O
moid carcinoma KB and murine lymphoma L1210 cell lines3 and
unusual structural characteristics, these marine natural products
constitute highly relevant target structures for total synthesis4e6 as
well as to understand the SAR of this class of molecules.
a
O
O
N
N
O
N
11
b
Bn
Bn
10
For the total synthesis of amphidinolides T1, T3, and T4, we
envisioned that all these targets might be realized from an in-
termediate like 6 by suitable protection/deprotection, oxidation
and stereochemical adjustments. Retrosynthetically intermediate 6
will be obtained via an intramolecular McMurry coupling on in-
termediate dialdehyde 7 (Scheme 1) to construct the C12eC13
bond. Compound 7, in turn, could be obtained by coupling two
fragments 8 and 9. Herein, we describe an efficient and stereo-
selective synthesis of dialdehyde 7.
OTBS
O
OTBS
c
HO
13
12
Bn
d
OTBS
OTBS
e
NC
TsO
McMurry Coupling
OR2
13
15
Evan's
R1O
12
14
alkylation
f
OTBS
1, 3, 4
O
g
O
O
16
Evan's aldol
6
O
Scheme 2. Reagents and conditions: (a) TiCl4, (ꢀ)-sparteine, 3-butenal, dry CH2Cl2,
Cross metathesis
0
0
ꢁC, 30 min, 92%; (b) TBSOTf, DIPEA, dry CH2Cl2, 0 ꢁC, 2 h, 90%; (c) NaBH4, THF/H2O,
Yamaguchi
ꢁCdrt, 40 h, 80%; (d) TsCl, Et3N, DMAP, CH2Cl2, 0 ꢁCdrt, 16 h, 92%; (e) NaCN, dry
esterification
DMF, rt, 4 days, 88%; (f) DIBAL-H, dry CH2Cl2, ꢀ78 ꢁC, 5 h, 90%; (g) (i) DMP, DCM, 0 ꢁC,
2 h; (ii) CH3OCH2PPhþ3 Clꢀ, NaHMDS, THF, ꢀ20 ꢁC, 2 h; (iii) PPTS, dioxane/H2O, 50 ꢁC,
4 h, 65% in three steps.
O
13
TBSO
O
O
OTBS
OH
12
OTBS
O
a
16
O
EtO2C
OH
9
17
8
7
O
O
b
Scheme 1. Retrosynthetic analysis.
CO2Me
OH
2
O
2. Results and discussion
c
H3C
EtO2C
4
Synthesis of compound 8 commenced with the Crimmins
modified Evans’ strategy7 involving condensation of 3-butenal8
with (R)-4-benzyl-N-propionyloxazolidinone (10), to give the syn
aldol adduct 11 in 92% yield as a single diastereomer, as confirmed
by NMR spectroscopy (Scheme 2). The hydroxyl group was pro-
tected as its TBS ether 12. The chiral auxiliary within 12 was
reductively removed9 with NaBH4 to give the corresponding alco-
hol 13 in 80% yield. The hydroxyl functionality was converted to its
tosyl derivative 14, which on treatment with NaCN in DMF at room
temperature afforded the corresponding cyanide 15. Reduction of
cyanide was achieved by the treatment with DIBAL-H at ꢀ78 ꢁC to
furnish the aldehyde 16. Alternatively aldehyde 16 was produced
from alcohol 13 utilising Dess/Martin periodinane oxidation of the
alcohol followed by Wittig homologation and hydrolysis of the
intermediate enol ether in overall 65% yields.
18
6
2R: 19a
2S: 19b
Scheme 3. Reagents and conditions: (a) Ph3P]CHCO2Et, C6H6, reflux, 16 h, 90%;
(b) 3 N HCl, THF, rt, 16 h, 94%; (c) NaOMe, MeOH, ꢀ15 ꢁC, 24 h, 95%.
studies. Upon irradiation of the C2 hydrogen at
NOE was observed for C4 methyl protons in case of 19a whereas
such effect was absent in case of 19b. Similarly, when the C4 methyl
d 0.95 within 19a was irradiated, significant NOE was observed
for C2 hydrogen along with C6 methylene protons.
d 4.48 significant
at
The ester group within 19a was reduced with LiAlH4 in THF at
room temperature to give alcohol 20 in 70% yield (Scheme 4). The
hydroxyl group was protected as its TBS ether 21. The olefinic
moiety within 21 was subjected to a cross metathesis13 reaction
with (S)-2-methylpent-4-enoic acid (22)14 in dichloromethane
under refluxing conditions in the presence of the ‘second genera-
tion’ ruthenium carbene complex 23 as the precatalyst bearing an
imidazol-2-ylidene ligand.15 The crude material of this metathesis
reaction was subjected to hydrogenation using 10% Pd/C in ethyl
acetate to afford the desired compound 8 as the first fragment in
61% yield over two steps.16
Synthesis of compound 9 commenced with the alkylation of (S)-4-
benzyl-N-propionyloxazolidinone (24) with tert-butyl(3-(iodomethyl)
but-3-enyloxy)dimethylsilane (25)17 under Evans conditions18 to
afford compound 26 (Scheme 5). Desilylation of TBS ether within 26
using 3 N HCl in THF furnished the corresponding alcohol 27 in 87%
The aldehyde 16 was homologated with carbethoxy-
methylenetriphenylphosphorane to afford the corresponding a,b-
unsaturated ester 17 (E/Z 19:1) in 90% yield (Scheme 3). Compound
17 was desilylated with 3 N HCl in THF at room temperature to
furnish alcohol 18 in 94% yield. At this juncture we explored an
intramolecular oxy-Michael reaction10 to construct the crucial
tetrahydrofuran ring with desired 2,5-trans selectivity. After de-
tailed investigation6a we found that treatment of 18 with NaOMe in
MeOH at ꢀ15 ꢁC afforded the cyclized product with concomitant
transesterification to produce an 82:18 mixture of compounds 19a
and 19b in 95% yield.11
Compound 19a and 19b were separated under preparative HPLC
conditions12 and their stereochemistry was confirmed by NOE

5002
P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
a
OH
OTBS
30
9
Ph
a
b
H
N
O
O
Ph
31
H3C
H3C
19a
O
34
d
B
20
21
b
OH
c
c
N
N
Mes
23
TBSO
TBSO
Mes
22
O
OH
O
Cl
Ru
Cl
32
33
Ph
PCy3
8
Scheme 6. Reagents and conditions: (a) TBDMS-Cl, imidazole, DCM, 0 ꢁC, 80%;
(b) TBDMS-Cl, imidazole, DCM, 0 ꢁC, 84%; (c) DMP, DCM, 0 ꢁC, 2 h, 89%; (d) 34, BH3/
DMS, THF, ꢀ78 ꢁC, 1 h, 80%.
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, 0 ꢁCdrt, 20 min, 70%; (b) TBDMS-Cl,
imidazole, DMF, rt,1 h,90%;(c)(i)Grubb’ssecondgenerationcatalyst(23),DCM,reflux, 5 h;
(ii) 10% Pd/C, EtOAc, H2, rt, 1 h, 61% in two steps.
smoothly by employing Yamaguchi conditions24 to afford com-
pound 35 (Scheme 7). Global deprotection of TBS groups within 35
using TBAF afforded the corresponding diol 36 in 77% yield. Dess/
Martin oxidation of diol 36 produced our desired dialdehyde 7 in
88% yield. Few selected reaction conditions were investigated to
construct the crucial C12eC13 bond within compound 7. When
Swindell’s reaction conditions25 (TiCl4/Zn/pyridine in THF) were
examined, the formation of cyclized product was realized.26 Addi-
tional screening of reagents and optimization of reaction protocols
are required for further progress toward our target structures.
yield. The hydroxyl group within 27 was oxidized to aldehyde 28 using
Dess/Martin periodinane.19 The aldehyde 28 was then reacted with
n-propylmagnesium chloride in diethyl ether at ꢀ78 ꢁC to afford
compound 29 as a mixture of two diastereomeric alcohols.20 Reductive
removal of the chiral auxiliary within 29 by LiBH421 resulted alcohols
30 and 31 in 55% and 27% yields, respectively after their separation by
flash chromatography.
OTBS
I
O
O
O
O
25
OTBS
a
O
N
O
N
OTBS
TBSO
Bn
Bn
26
24
a
b
8
9
O
O
O
O
O
O
OH
O
c
O
N
O
N
35
O
b
OH
Bn
Bn
HO
O
28
27
c
d
7
HO
HO
O
O
OH
OH
O
e
30
O
N
+
36
O
OH
Scheme 7. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP,
toluene, rtd70 ꢁC, 24 h, 44%; (b) TBAF, THF, rt, 3 h, 77%; (c) DMP, DCM, 0 ꢁC, 4 h, 88%.
Bn
29
31
Scheme 5. Reagents and conditions: (a) NaHMDS, 25, THF, ꢀ78 ꢁC, 5 h, 62%; (b) 3 N
n
HCl, THF, 3 h, 87%; (c) DMP, DCM, 0 ꢁC, 4 h, 84%; (d) PrMgCl, Et2O, ꢀ78 ꢁC, 5 h, 44%;
3. Conclusion
(e) LiBH4, THF, 0 ꢁC, 1 h, 55% (30) and 27% (31).
In conclusion, we have achieved an efficient and stereoselective
synthesis of a very advanced intermediate toward the total syn-
thesis of amphidinolides T1, T3, and T4 utilising Evan’s aldol and
alkylation reactions, oxy-Michael, cross metathesis, stereoselective
Grignard addition, and Yamaguchi esterification reactions as key
steps. The overall assembly is flexible enough to address structure/
activity relationship (SAR) around this class of molecules. Further
work is ongoing for the total synthesis and SAR studies of these
targets results of which will be published in due course.
The primary hydroxyl group within 30 was selectively protected
as its TBS ether to furnish our desired compound 9 in 80% yield
(Scheme 6). The stereochemistry of the chiral center bearing sec-
ondary hydroxyl group was confirmed to be in R-configuration
following the protocol of Riguera.22
The minor diastereomer 31 was also converted to our desired
compound 9 (Scheme 6). For this purpose, the primary hydroxyl
group within 31 was selectively protected as its TBS ether 32 in 84%
yield. Dess/Martin oxidation of the secondary hydroxyl group
afforded the corresponding ketone 33 in 89% yield. Selective re-
duction of the carbonyl group within 33 employing Corey/Bakshi/
Shibata (CBS) conditions23 using chiral oxazaborolidine (34) as li-
gand also furnished compound 9 in 80% yield with 84% de as
measured by 1H NMR. These three steps protocol was really at-
tractive as it not only allowed the recycling of 31 to 9 but also in-
dependently proved the stereochemistry in 9.
4. Experimental
4.1. General
All reactions were carried out under inert atmosphere. All sol-
vents were distilled prior to use. Anhydrous solvents were distilled
following standard protocols. Low temperature baths were ice/
water (0 ꢁC) and CO2(s)/acetone (ꢀ78 ꢁC). Reaction temperatures
Once both the coupling partners 8 and 9 in hand, the stage was
set for the crucial esterification reaction. This was carried out

P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
5003
refer to that of the bath. IR spectra were recorded either neat or as
KBr pallet with a Shimadzu IR-Prestige-21 instrument and only
diagnostic and/or intense peaks are reported. Mass spectra were
recorded with PE Sciex model API 3000 instrument. HRMS spectra
were with Waters LCT Premier XE (Micromass Oa-TOF) instrument.
HPLC separation was done using Alliance 2695 HPLC system. Op-
tical rotations were measured by using JASCO DIP-370 polarimeter
at 25 ꢁC. 1H NMR spectra were recorded in CDCl3 and DMSO-d6 with
either Varian Gemini 200 MHz or Varian Mercury Plus 400 MHz
instruments. 13C NMR spectra were recorded in CDCl3 at 50 MHz
with Varian Gemini 200 MHz instrument. Signals due to the solvent
2H), 2.32 (dt, J¼6.0, 1.6 Hz, 2H), 1.22 (d, J¼10.4 Hz, 3H), 0.89 (s, 9H),
0.06 (s,3H), 0.02 (s, 3H); 13C NMR (50 MHz, CDCl3):
175.3, 152.9,
135.3, 134.7, 129.4, 128.9, 127.3, 116.9, 72.3, 65.9, 55.6, 42.9, 40.6,
37.7, 25.8, 17.9, 12.4, ꢀ4.2, ꢀ4.9; IR (KBr): 2960, 2929, 2858, 1765,
1702,1391,1209 cmꢀ1; MS (ES): m/z 418.2 (Mþ1); HRMS: m/z found
418.2419, calcd for C23H36NO4Si 418.2414.
d
4.1.3. (2S,3S)-3-(tert-Butyldimethylsilyloxy)-2-methylhex-5-en-1-ol
(13). To an ice cooled solution of compound 12 (9.1 g, 21.82 mmol)
in THF (910 mL) was added a solution of sodium borohydride
(16.5 g, 436.45 mmol) dissolved in cold water (182 mL) drop wise
and stirred at room temperature for 90 h. The reaction was
quenched by the addition of saturated ammonium chloride solu-
tion. The organic volatiles were removed in vacuo. The residue was
diluted with ethyl acetate, washed successively with water and
brine. The organic layer was dried over anhydrous Na2SO4 and ro-
tary evaporated. The residue was purified over silica gel
(100e200 mesh) using 10% ethyl acetate in petroleum ether as el-
uent to afford compound 13 as colorless oil (4.26 g, 80%). Rf¼0.55
(
13C NMR) or residual protonated solvent (1H NMR) served as the
internal standard. The 1H NMR chemical shifts and coupling con-
stants were determined assuming first-order behavior. Multiplicity
is indicated by one or more of the following: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), br (broad); the list of couplings
constants (J) corresponds to the order of the multiplicity assign-
ment. Unless otherwise noted, all ‘J’ refers to 3JHH coupling constant.
All reported compounds were homogeneous by thin layer chro-
matography (TLC) and by NMR.
(10% ethyl acetate in petroleum ether); [
NMR (400 MHz, CDCl3):
a
]
D þ5.5 (c 1.0, CHCl3); 1H
d
5.83e5.73 (m, 1H), 5.10e5.02 (m, 2H),
4.1.1. (R)-4-Benzyl-3-((2R,3S)-3-hydroxy-2-methylhex-5-enoyl)oxazolidin-
2-one (11). A solution of (R)-4-benzyl-N-propionyloxazolidinone
(10) (2.66 g, 11.42 mmol) in dichloromethane (6 mL) was cooled to
0 ꢁC. Titanium tetrachloride (1.3 mL, 11.99 mmol) was added drop
wise and the solution was allowed to stir for 5 min. To the yellow
slurry was added (ꢀ)-sparteine (6.6 mL, 28.54 mmol) drop wise.
The dark red enolate was stirred for 20 min at 0 ꢁC. To this was
added a solution of 3-butenal (0.88 g, 12.56 mmol) in dichloro-
methane (5 mL) drop wise and the reaction mixture was stirred at
0 ꢁC for 30 min. The reaction was quenched by the addition of
saturated aqueous ammonium chloride solution and stirred at
room temperature for 10 min. Reaction mixture was diluted with
dichloromethane, washed successively with water and brine. The
organic layer was dried over anhydrous Na2SO4 and rotary evapo-
rated. The residue was purified on silica gel (100e200 mesh) using
20% ethyl acetate in petroleum ether as eluent to afford compound
11 as colorless oil (3.18 g, 92%). Rf¼0.30 (20% ethyl acetate in
3.87e3.83 (m, 1H), 3.67 (t, J¼9.0 Hz, 1H), 3.55e3.50 (m, 1H),
2.38e2.34 (br s, 1H), 2.26 (t, J¼1.1 Hz, 2H), 1.97e1.91 (m, 1H), 0.89
(s, 9H), 0.85 (d, J¼7.0 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 135.4, 116.9, 74.6, 65.8, 39.5, 38.0, 25.8, 17.9, 11.4,
ꢀ4.3, ꢀ4.7; IR (Neat): 3382, 3078, 2968, 2930, 2858, 1472, 1255,
1046 cmꢀ1; MS (ES): m/z 245.2 (Mþ1); HRMS: m/z found 245.1940,
calcd for C13H29O2Si 245.1937.
4.1.4. (2S,3S)-3-(tert-Butyldimethylsilyloxy)-2-methylhex-5-enyl 4-
methylbenzenesulfonate (14). To an ice cooled solution of com-
pound 13 (9.89 g, 40.53 mmol) in dichloromethane (100 mL) was
added triethyl amine (16.9 mL,121.60 mmol) drop wise followed by
p-toluenesulfonyl chloride (15.5 g, 81.06 mmol) and DMAP (0.99 g,
8.10 mmol). After stirring for 16 h at room temperature, the re-
action mixture was diluted with dichloromethane, washed suc-
cessively with water and brine. The organic layer was dried over
anhydrous Na2SO4 and rotary evaporated. The residue was purified
over silica gel (100e200 mesh) using 5% ethyl acetate in petroleum
ether as eluent to afford compound 14 as colorless oil (14.8 g, 92%).
petroleum ether); [
CDCl3):
a
]
D
ꢀ62.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
d
7.36e7.30 (m, 2H), 7.29e7.26 (m, 1H), 7.22e7.19 (m, 2H),
5.89e5.78 (m, 1H), 5.18e5.10 (m, 2H), 4.73e4.67 (m, 1H), 4.25e4.17
(m, 2H), 4.03e4.01 (m, 1H), 3.85e3.79 (m, 1H), 3.26 (dd, J¼13.3,
3.4 Hz, 1H), 2.79 (dd, J¼13.2,9.7 Hz, 2H), 2.38e2.22 (m, 2H),1.28
Rf¼0.52 (5% ethyl acetate in petroleum ether); [
a
]
þ1.4 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
7.78 (d, J¼8.3 Hz, 2H), 7.33 (d,
J¼7.8 Hz, 2H), 5.71e5.60 (m, 1H), 5.30e5.01 (m,1H), 4.99e4.98 (m,
1H), 3.98 (dd, J¼9.4, 6.6 Hz, 1H), 3.85 (dd, J¼9.6, 6.8 Hz, 1H),
3.76e3.72 (m, 1H), 2.45 (s, 3H), 2.21e2.12 (m, 2H), 1.95e1.89 (m,
1H), 0.83 (d, J¼6.7 Hz, 3H), 0.81 (s, 9H), 0.02 (s, 3H), ꢀ0.04 (s, 3H);
(d, J¼7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 177.0, 152.9, 135.0,
134.5, 129.3, 128.9, 127.4, 117.7, 70.8, 66.1, 55.0, 41.6, 38.4, 37.7, 10.7;
IR (Neat): 3509, 2925, 1779, 1694, 1386, 1210 cmꢀ1; MS (ES): m/z
304.0 (Mþ1); HRMS: m/z found 304.1543, calcd for C17H22NO4
304.1549.
13C NMR (50 MHz, CDCl3):
d 144.5, 134.5, 133.0, 129.7, 127.8, 117.1,
72.7, 71.0, 38.9, 37.0, 25.7, 21.5, 17.9, 10.0, ꢀ4.17, ꢀ4.98; IR (Neat):
2956, 2929, 2857, 1366, 1189, 1178 cmꢀ1; MS (ES): m/z 399.1 (Mþ1);
HRMS: m/z found 399.2032, calcd for C20H35O4SSi 399.2025.
4.1.2. (R)-4-Benzyl-3-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-
methylhex-5-enoyl) oxazolidin-2-one (12). To an ice cooled solution
of compound 11 (1.08 g, 3.56 mmol) in dichloromethane (10 mL)
was added N-ethyldiisopropylamine (1.5 mL, 8.91 mmol) drop wise
followed by tert-butyldimethylsilyl trifluoromethanesulfonate
(1.2 mL, 5.35 mmol) and stirred at room temperature for 2 h. Re-
action mixture was diluted with dichloromethane, washed suc-
cessively with aqueous NaHCO3 solution, water, and brine. The
organic layer was dried over anhydrous Na2SO4 and rotary evapo-
rated. The residue was purified over silica gel (100e200 mesh)
using 5% ethyl acetate in petroleum ether as eluent to afford
compound 12 as a gummy material (1.34 g, 90%). Rf¼0.58 (10% ethyl
4.1.5. (3S,4S)-4-(tert-Butyldimethylsilyloxy)-3-methylhept-6-eneni-
trile (15). To a solution of compound 14 (4.54 g, 11.40 mmol) in
DMF (45 mL) was added sodium cyanide (1.12 g, 22.80 mmol) and
stirred at room temperature for 96 h. The reaction mixture was
diluted with ethyl acetate, washed successively with water and
brine. The organic layer was dried over anhydrous Na2SO4 and ro-
tary evaporated. The residue was purified over silica gel
(100e200 mesh) using 5% ethyl acetate in petroleum ether as an
eluent to afford compound 15 as a viscous oil (2.53 g, 88%). Rf¼0.60
(2% ethyl acetate in petroleum ether); [
NMR (400 MHz, CDCl3): d 5.78e5.68 (m, 1H), 5.11e5.06 (m,
a
]
þ3.5 (c 1.0, CHCl3); 1H
D
acetate in petroleum ether); [
(400 MHz, CDCl3):
a
]
ꢀ49.0 (c 1.0, CHCl3); 1H NMR
D
d
7.35e7.31 (m, 2H), 7.29e7.27 (m, 1H),
2H),3.75 (dt, J¼6.4, 3.2 Hz, 1H), 2.41 (dd, J¼16.4, 6.8 Hz, 1H),
2.26e2.17 (m,3H), 2.04e1.97 (m, 1H), 1.02 (d, J¼6.8 Hz, 3H), 0.89 (s,
7.25e7.20 (m, 2H), 5.90e5.79 (m, 1H), 5.04e4.99 (m, 2H),4.62e4.57
(m, 1H), 4.18e4.13 (m, 2H), 4.12e4.07 (m, 1H), 3.83 (dt, J¼12.8,
6.8 Hz, 1H), 3.27 (dd, J¼13.6, 3.2 Hz, 1H), 2.77 (dd, J¼13.4,9.8 Hz,
9H), 0.08 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 134.1, 119.4, 117.5,
73.2, 38.7, 35.1, 25.8, 25.1,18.0,13.3, ꢀ4.1, ꢀ4.7; IR (KBr): 2930, 2858,

5004
P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
2247, 1465, 1032 cmꢀ1; MS (ES): m/z 254.3 (Mþ1); HRMS: m/z
5.09e5.01 (m, 2H),4.18 (q, J¼6.3 Hz, 2H), 3.65e3.60 (m, 1H),
2.40e2.33 (m, 1H), 2.28e2.18 (m, 2H), 2.04e1.95 (m, 1H), 1.78e1.70
(m, 1H), 1.29 (t, J¼6.3 Hz, 3H), 0.89 (s, 9H), 0.86 (d, J¼7.0 Hz, 3H),
found 254.1941, calcd for C14H28NOSi 254.1940.
4.1.6. (3S,4S)-4-(tert-Butyldimethylsilyloxy)-3-methylhept-6-enal
(16). Method A: To a solution of compound 15 (2.45 g, 9.68 mmol)
in dichloromethane (25 mL) at ꢀ78 ꢁC was added DIBAL-H (20%
solution in toluene) (34.4 mL, 48.41 mmol) drop wise and stirred at
the same temperature for 5 h. The reaction mixture was quenched
by the addition of saturated aqueous sodium potassium tartrate
solution, stirred at room temperature for 1 h and then diluted with
dichloromethane. The organic layer was separated and washed
successively with water and brine, and dried over anhydrous
Na2SO4. Concentration and chromatographic purification over silica
gel (100e200 mesh) using 1% diethyl ether in petroleum ether as
eluent afforded compound 16 as a colorless liquid (2.22 g, 90%).
Method B: To an ice cooled solution of compound 13 (0.35 g,
1.43 mmol) in DCM (10 mL) and H2O (0.1 mL) was added Dess/
Martin periodinane (0.73 g, 1.72 mmol) and stirred at the same
temperature for 2 h. Reaction mixture was diluted with additional
DCM and quenched with saturated sodium thiosulphate solution.
To this was added saturated sodium bicarbonate solution and
stirred at room temperature for 30 min. The organic layer was
separated and was washed successively with water and brine, and
dried over anhydrous Na2SO4, and rotary evaporated to afford the
corresponding crude aldehyde. A separate round bottomed flask
was charged with MeOCH2PPhþ3 Clꢀ (0.91 g, 2.65 mmol) and dry
THF. The solution was cooled to ꢀ20 ꢁC and to it was added drop
wise NaHMDS (2.4 mL, 1.0 M in THF, 2.40 mmol) and stirred for
30 min. The resulting orange red suspension was cooled to ꢀ40 ꢁC
and to it was added a solution of above aldehyde in THF (3 mL) drop
wise. The reaction mixture was warmed ꢀ20 ꢁC over a period of 3 h
and then quenched with aqueous saturated NH4Cl solution (10 mL).
The aqueous layer was extracted with ether thrice and the com-
bined organic layers were washed with brine, and dried over
Na2SO4 and, concentrated in vacuo. The resulting residue (crude
enol ether) was dissolved in dioxane/H2O (10 mL, 9:1) and treated
with pyridinium p-toluenesulphonate (0.61 g, 2.44 mmol). The re-
action mixture was stirred at 50 ꢁC for 16 h, then cooled to room
temperature, and quenched with saturated aqueous NaHCO3 so-
lution. The aqueous layer was extracted with ether thrice and the
combined organic layers were dried over anhydrous Na2SO4, and
rotary evaporated. The residue was purified over silica gel
(100e200 mesh) using 1% diethyl ether in petroleum ether as an
eluent to afford compound 16 as a colorless liquid (0.24 g, 65% over
0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 166.5, 148.4,
135.3, 122.3, 116.7, 75.0, 60.1, 38.6, 37.3, 35.7, 25.9, 18.1, 14.3, 13.9,
ꢀ4.5, ꢀ4.1; IR (Neat): 2932, 2858, 1724, 1256, 1046 cmꢀ1; MS (ES):
m/z 327.1 (Mþ1); HRMS: m/z found 327.2351, calcd for C18H35O3Si
327.2355.
4.1.8. (5S,6S,E)-Ethyl 6-hydroxy-5-methylnona-2,8-dienoate (18). To
a solution of compound 17 (2.26 g, 6.93 mmol) in THF (40 mL) was
added 3 N HCl (10 mL) and stirred at room temperature for 16 h.
Reaction mixture was diluted with ethyl acetate, washed succes-
sively with water and brine. The organic layer was dried over an-
hydrous Na2SO4 and rotary evaporated. The residue was purified
over silica gel (100e200 mesh) using 10% ethyl acetate in petro-
leum ether as eluent to afford compound 18 as colorless oil (1.38 g,
94%). Rf¼0.47 (20% ethyl acetate in petroleum ether); [
a
]
þ6.0 (c
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
6.95 (dt, J¼15.6, 7.3 Hz,
1H), 5.85 (d, J¼15.6 Hz, 1H), 5.87e5.76 (m, 1H), 5.18e5.16 (m, 1H),
5.16e5.13 (m, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.60e3.56 (m, 1H),
2.44e2.37 (m, 1H), 2.30e2.23 (m, 1H), 2.21e2.07 (m, 2H), 1.78e1.72
(m, 1H), 1.49 (d, J¼3.8 Hz, 1H), 1.29 (t, J¼7.1 Hz, 3H), 0.94 (d,
J¼7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 166.5, 147.9, 135.0, 122.5,
118.1, 72.9, 60.1, 38.9, 37.2, 36.1, 14.1, 13.4; IR (Neat): 3485, 2978,
2938, 2905, 1720, 1703, 1651, 1177 cmꢀ1; MS (ES): m/z 213.2 (Mþ1);
HRMS: m/z found 235.1319, calcd for C12H20O3Na 235.1310.
4.1.9. Methyl 2-((2R,4S,5S)-5-allyl-4-methyltetrahydrofuran-2-yl) ace-
tate (19a). A solution of compound 18 (200 mg, 0.94 mmol) in
methanol was cooled to ꢀ15 ꢁC and NaOMe (51 mg, 0.94 mmol)
was added portion wise and stirred at the same temperature for
16 h. Reaction mixture was diluted with ethyl acetate, washed
successively with water and brine. The organic layer was dried over
anhydrous Na2SO4 and rotary evaporated. The residue was purified
over silica gel (100e200 mesh) using 10% ethyl acetate in petro-
leum ether as eluent to afford the cyclized product as di-
astereomeric mixture (177 mg, 95%). Separation of diastereomers
using HPLC12 afforded compound 19a as a colorless liquid (136 mg,
73% yield, 94% recovery in HPLC). Rf¼0.62 (20% ethyl acetate in
petroleum ether); 1H NMR (400 MHz, CDCl3):
d 5.86e5.76 (m, 1H),
5.13e5.03 (m, 2H), 4.52e4.45 (m, 1H), 3.98e3.94 (m, 1H), 3.68 (s,
3H), 2.63 (dd, J¼15.2, 6.8 Hz, 1H), 2.43 (dd, J¼15.2, 6.2 Hz, 1H),
2.34e2.26 (m, 2H), 2.20e2.13 (m, 1H), 1.90e1.78 (m, 2H), 0.95 (d,
three steps). Rf¼0.55 (1% diethyl ether in petroleum ether); [
a
]
J¼7.4 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 171.6, 135.2, 116.5, 80.8,
D
þ6.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
9.73 (t, J¼2.0 Hz,
73.2, 51.6, 41.3, 39.7, 35.7, 34.9, 13.9; IR (Neat): 2963, 2876, 1740,
1437, 1171 cmꢀ1; MS (ES): m/z 199.2 (Mþ1); HRMS: m/z found
221.1161, calcd for C11H18O3Na 221.1154.
1H), 5.83e5.73 (m, 1H), 5.09e5.02 (m, 2H),3.65 (dt, J¼6.4, 3.2 Hz,
1H), 2.61e2.54 (m, 1H), 2.29e2.11 (m, 4H), 0.90 (d, J¼6.8 Hz, 3H),
0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (50 MHz, CDCl3):
d
202.4, 135.2, 116.9, 74.8, 47.2, 38.2, 32.9, 25.8, 18.0, 14.5, ꢀ4.3,
4.1.10. 2-((2R,4S,5S)-5-Allyl-4-methytetrahydrofuran-2-yl)ethanol
(20). To an ice cooled solution of compound 19a (50 mg,
0.25 mmol) in THF (10 mL) was added lithium aluminum hydride
(14 mg, 0.38 mmol) portion wise and stirred at room temperature
for 20 min. The reaction mixture was quenched by careful addition
of aqueous saturated sodium sulfate solution at 0 ꢁC and stirred at
room temperature for 30 min. The separated solid was filtered and
washed with excess ethyl acetate. The filtrate was diluted with
ethyl acetate, washed successively with water and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified over silica gel (100e200 mesh) using 30% ethyl acetate in
petroleum ether as eluent to afford compound 20 as a colorless
liquid (30 mg, 70%). Rf¼0.28 (30% ethyl acetate in petroleum ether);
ꢀ4.6; IR (Neat): 3078, 2957, 2930, 2857, 1728, 1254 cmꢀ1; MS (ES):
m/z 257.5 (Mþ1); HRMS: m/z found 257.1933, calcd for C14H29O2Si
257.1937.
4.1.7. (5S,6S,E)-Ethyl 6-(tert-butyldimethylsilyloxy)-5-methylnona-
2,8-dienoate (17). To a solution of compound 16 (8.0 g, 31.25 mmol)
in benzene (80 mL) was added carbethoxymethylene-
triphenylphosphorane (21.8 g, 62.5 mmol) and stirred at room
temperature for 16 h. The reaction mixture was diluted with ethyl
acetate, washed successively with water and brine. The organic
layer was dried over anhydrous Na2SO4 and rotary evaporated. The
residue was purified over silica gel (100e200 mesh) using 1% ethyl
acetate in petroleum ether as eluent to afford compound 17 as
colorless oil (8.8 g, 90%). Rf¼0.67 (1% ethyl acetate in petroleum
[a
]
ꢀ22.6 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d 5.86e5.76
D
(m, 1H), 5.13e5.03 (m, 2H), 4.29 (ddt, J¼11.2, 7.2, 3.2 Hz, 1H),
3.99e3.95 (m, 1H), 3.84e3.78 (m, 2H), 3.04e2.96 (br s, 1H),
2.31e2.23 (m, 2H), 2.21e2.14 (m, 1H), 1.82e1.79 (m, 2H), 1.77e1.66
ether); [
d
a
]
D
ꢀ2.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
6.96e6.89 (m, 1H), 5.84e5.73 (m, 1H), 5.81 (d, J¼15.6 Hz, 1H),

P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
5005
(m, 2H), 0.94 (d, J¼6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d
135.2,
colorless oil (5.7 g, 62%). Rf¼0.42 (20% ethyl acetate in petroleum
116.5, 80.6, 77.2, 61.9, 40.3, 38.1, 35.5, 34.9, 14.0; IR (Neat): 3435,
2961, 2934, 2876, 1088, 1055 cmꢀ1; MS (ES): m/z 171.5 (Mþ1);
HRMS: m/z found 171.1377, calcd for C10H19O2 171.1385.
ether); [
a]
þ20.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
D
d
7.34e7.31 (m, 2H), 7.28e7.25 (m, 1H), 7.22e7.20 (m, 2H), 4.85 (s,
2H), 4.71e4.65 (m, 1H), 4.21e4.13 (m, 2H), 4.02 (q, J¼7.1 Hz, 1H),
3.73 (t, J¼6.8 Hz, 2H), 3.29 (dd, J¼13.2, 2.8 Hz, 1H), 2.69 (dd, J¼13.4,
9.8 Hz, 1H), 2.58 (dd, J¼14.4, 7.2 Hz, 1H), 2.29 (t, J¼7.0 Hz, 2H), 2.12
(dd, J¼14.0, 7.6 Hz, 1H), 1.17 (d, J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
4.1.11. (2-((2R,4S,5S)-5-Allyl-4-methyltetrahydrofuran-2-yl)ethoxy)
(tert-butyl)dimethylsilane (21). To a solution of compound 20
(1.38 g, 8.11 mmol) in DMF (14 mL) was added TBDMS chloride
(1.35 g, 8.93 mmol) followed by imidazole (0.829 g,12.17 mmol) and
stirred at room temperature for 1 h. The reaction mixture was di-
luted with water and extracted with ethyl acetate thrice. The com-
bined organic layers were washed successively with water and
brine. The organic layer was dried overanhydrous Na2SO4 and rotary
evaporated. The residue was purified on silica gel (100e200 mesh)
using 5% ethyl acetate in petroleum ether as eluent to afford com-
pound 21 as colorless oil (2.07 g, 90%). Rf¼0.65 (10% ethyl acetate in
6H); 13C NMR (50 MHz, CDCl3):
d 176.9, 153.0, 144.0, 135.3, 129.4,
128.9, 127.3, 112.9, 65.9, 62.1, 55.3, 40.4, 39.0, 37.9, 35.7, 25.9, 18.2,
16.9, ꢀ5.3; IR (Neat): 2928, 2856, 1782, 1699, 1385, 1099 cmꢀ1; MS
(ES): m/z 432.1 (Mþ1); HRMS: m/z found 432.2578, calcd for
C24H38NO4Si 432.2570.
4.1.14. (S)-4-Benzyl-3-((S)-6-hydroxy-2-methyl-4-methylenehex-
anoyl)oxazolidin-2-one (27). A solution of compound 26 (1.3 g,
3.02 mmol) in THF (13 mL) was added 3 N HCl (6.5 mL) and stirred
at room temperature for 3 h. The reaction mixture was diluted with
ethyl acetate, washed successively with water and brine, and dried
over anhydrous Na2SO4. Concentration and purification over silica
gel (100e200 mesh) afforded compound 27 as colorless oil (0.83 g,
petroleum ether); [
CDCl3):
a
]
ꢀ27.0 (c 0.5, CHCl3); 1H NMR (400 MHz,
D
d
5.83e5.73 (m, 1H), 5.08e4.97 (m, 2H), 4.17e4.09 (m, 1H),
3.89e3.84 (m, 1H), 3.68e3.61 (m, 2H), 2.27e2.18 (m, 2H), 2.14e2.11
(m, 1H), 1.79e1.62 (m, 3H), 1.61e1.54 (m, 1H), 0.88 (d, J¼7.3 Hz, 3H),
0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (50 MHz, CDCl3):
d
135.6, 116.2,
87%). Rf¼0.25 (30% ethyl acetate in petroleum ether); [
a
]
D þ39.7 (c
80.3, 74.0, 60.3, 40.1, 39.8, 35.8, 35.1, 25.9, 18.3, 14.1, -5.3; IR (Neat):
2957, 2930, 2857, 1256, 1092 cmꢀ1; MS (ES): m/z 285.0 (Mþ1);
HRMS: m/z found 285.2249, calcd for C16H33O2Si 285.2250.
1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
7.35e7.32 (m, 2H),
7.29e7.27 (m, 1H), 7.22e7.20 (m, 2H), 4.93 (s, 2H), 4.71e4.66 (m,
1H), 4.22e4.15 (m, 2H), 4.06 (q, J¼7.1 Hz, 1H), 3.76 (t, J¼5.1 Hz, 2H),
3.26 (dd, J¼13.2, 3.4 Hz, 1H), 2.71 (dd, J¼13.2, 9.8 Hz, 1H), 2.62 (dd,
J¼14.5, 3.8 Hz, 1H), 2.40e2.31 (m, 2H), 2.11 (dd, J¼14.5, 6.8 Hz, 1H),
1.69e1.64 (br s, 1H) 1.19 (d, J¼6.8 Hz, 3H); 13C NMR (50 MHz,
4.1.12. (S)-6-((2S,3S,5R)-5-(2-(tert-Butyldimethylsilyloxy)ethyl)-3-
methyltetrahydrofuran-2-yl)-2-methylhexanoic acid (8). A mixture
of compound 21 (0.2 g, 0.70 mmol) and (S)-2-methylpent-4-enoic
acid (22) (0.32 g, 2.82 mmol), and catalyst (23) (60 mg, 0.07 mmol)
in dry DCM (5 mL) was refluxed for 5 h. After cooling to room
temperature, the reaction mixture was diluted with additional
DCM (5 mL). The organic layer was washed successively with water
and brine, and dried over anhydrous Na2SO4, and passed through
a short pad of silica gel. The silica pad was further washed with 2%
acetone in DCM. The solvents were evaporated to give the crude
metathesis product, which was then dissolved in EtOAc (5 mL). To
this solution was added 10% Pd/C (0. 4 g) and the reaction mixture
was stirred under hydrogen atmosphere using a hydrogen balloon
at room temperature for 1 h. The reaction mixture was filtered
through Celite, washed the bed with EtOAc. The filtrate and the
washings were concentrated in vacuo and the residue was purified
over silica gel (100e200 mesh) using 2% acetone in dichloro-
methane as eluent to afford compound 8 as an oil (0.16 g, 61% yield
CDCl3):
d 176.7, 153.0, 143.5, 135.0, 129.2, 128.7, 127.1, 113.5, 65.9,
60.4, 55.2, 39.4, 38.7, 37.7, 35.5, 16.6; IR (Neat): 3491, 2976, 2933,
2878, 1778, 1697, 1389, 1211 cmꢀ1; MS (ES): m/z 318.1 (Mþ1);
HRMS: m/z found 340.1537, calcd for C18H23NO4 Na 340.1525.
4.1.15. (S)-6-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-5-methyl-3-meth-
ylene-6-oxohexanal (28). To an ice cooled solution of compound 27
(1.77 g, 5.56 mmol) in DCM (20 mL) and H2O (0.1 mL) was added
Dess/Martin periodinane (2.8 g, 6.68 mmol) and stirred at the same
temperature for 4 h. The reaction mixture was quenched with
saturated sodium thiosulphate solution (5 mL) and saturated so-
dium bicarbonate solution (5 mL) and stirred at room temperature
for 30 min. The DCM layer was separated and the aqueous layer was
extracted with additional DCM. The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4 and,
rotary evaporated. The residue was purified over silica gel
(100e200 mesh) to afford compound 28 as colorless oil (1.48 g,
84%). Rf¼0.65 (40% ethyl acetate in petroleum ether); 1H NMR
over two steps). Rf¼0.28 (5% methanol in chloroform); [
a
]
D ꢀ3.4 (c
0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d
4.17e4.09 (m, 1H),
3.85e3.78 (m, 1H), 3.74e3.66 (m, 2H), 2.51e2.41 (m, 1H), 2.26e2.14
(m, 1H), 1.87e1.58 (m, 4H), 1.50e1.27 (m, 8H), 1.18 (d, J¼7.0 Hz, 3H),
0.89 (s, 9H), 0.89 (d, J¼7.0 Hz, 3H), 0.05 (s, 6H); 13C NMR (50 MHz,
(400 MHz, CDCl3):
d
9.69 (t, J¼2.1 Hz, 1H), 7.35e7.31 (m, 2H),
7.29e7.27 (m, 1H), 7.25e7.20 (m, 2H), 5.11 (s, 1H), 4.99 (s, 1H),
4.71e4.65 (m, 1H), 4.22e4.15 (m, 2H), 3.30e3.14 (m, 3H), 2.71 (dd,
J¼13.2, 9.6 Hz, 1H), 2.62 (dd, J¼14.2, 7.0 Hz, 1H), 2.16 (dd, J¼14.0,
CDCl3):
d 182.2, 80.8, 73.8, 60.7, 40.2, 39.9, 39.3, 35.9, 33.5, 30.3,
27.4, 26.6, 26.0, 18.3, 16.9, 14.1, ꢀ5.3; IR (Neat): 2955, 2930, 1738,
1707, 1090 cmꢀ1; MS (ES): m/z 395.0 (MþNa); HRMS: m/z found
395.2594, calcd for C20H40O4SiNa 395.2589.
7.6 Hz, 1H), 1.18 (t, J¼6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 199.5,
176.3, 153.2, 138.2, 135.2, 129.4, 128.9, 127.4, 117.2, 66.1, 55.4, 50.2,
40.8, 38.0, 35.6, 16.6; IR (Neat): 2976, 2934, 1778, 1699, 1387 cmꢀ1
;
MS (ES): m/z 316.0 (Mþ1); HRMS: m/z found 316.1551, calcd for
4.1.13. (S)-4-Benzyl-3-((S)-6-(tert-butyldimethylsilyloxy)-2-methyl-
4-methylenehexanoyl)oxazolidin-2-one (26). A solution of (S)-4-
benzyl-N-propionyloxazolidinone 24 (5 g, 21.45 mmol) in THF
(20 mL) was cooled to ꢀ78 ꢁC. To this solution was added NaHMDS
(1 M solution in THF) (25.6 mL, 25.6 mmol) drop wise. After stirring
for 30 min at the same temperature, a solution of compound 25
(7.7 g, 23.60 mmol) in THF (30 mL) was added drop wise and stirred
for 5 h. The reaction mixture was quenched by the addition of
saturated ammonium chloride solution and brought it to room
temperature while stirring. The reaction mixture was diluted with
ethyl acetate, washed successively with water and brine, and dried
over anhydrous Na2SO4. Concentration and chromatographic pu-
rification over silica gel (100e200 mesh) afforded compound 26 as
C18H22NO4 316.1549.
4.1.16. (S)-4-Benzyl-3-((2S,6RS)-6-hydroxy-2-methyl-4-methyl-
enenonanoyl)oxazolidin-2-one (29). To a solution of compound 28
(1.66 g, 5.27 mmol) in diethyl ether (17 mL) at ꢀ78 ꢁC was added n-
propylmagnesium chloride (7.9 mL, 2 M solution in diethyl ether,
15.8 mmol) drop wise. After stirring for 5 h at the same tempera-
ture, the reaction mixture was quenched by the addition of satu-
rated ammonium chloride solution and stirred at room
temperature for 30 min. The aqueous part was extracted with ethyl
acetate thrice. The organic layer was washed successively with
water and brine, dried over anhydrous Na2SO4, and rotary evapo-
rated. The residue was purified over silica gel (100e200 mesh) to

5006
P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
afford 2:1 diastereomeric mixture of compound 29 as colorless oil
(0.83 g, 44%; recovered 28, 21%). Data for the mixture: Rf¼0.72 (5%
acetone in dichloromethane); 1H NMR (400 MHz, CDCl3):
saturated sodium thiosulphate solution followed by saturated so-
dium bicarbonate solution and stirred at room temperature for
30 min. The aqueous layer was extracted with DCM thrice and the
organic layer was washed with water and brine, and dried over
anhydrous Na2SO4. Concentration and purification over silica gel
(100e200 mesh) afforded compound 33 as colorless oil (0.15 g,
89%). Rf¼0.85 (10% ethyl acetate in petroleum ether); 1H NMR
d
7.38e7.26 (m, 3H), 7.22e7.19 (m, 2H), 4.95e4.93 (m, 2H),
4.71e4.65 (m,1H), 4.22e4.07 (m, 2H), 4.07e3.97 (m,1H), 3.86e3.76
(br s, 1H), 3.29e3.24 (m, 1H), 3.29e3.24 (m, 2H), 2.74e2.60 (m, 2H),
2.36e2.26 (m, 1H), 2.15e2.04 (m, 1H), 1.95e1.87 (m, 1H), 1.54e1.38
(m, 4H), 1.21e1.16 (m, 3H), 0.94 (t, J¼7.0 Hz, 3H); IR (Neat): 3514,
2957, 2931, 2872, 1778, 1699, 1387, 1209 cmꢀ1; MS (ES): m/z 360.3
(Mþ1).
(400 MHz, CDCl3):
d
4.94 (d, J¼1.2 Hz, 1H), 4.88 (d, J¼1.2 Hz, 1H),
3.44e3.36 (m, 2H), 3.08 (s, 2H), 2.43 (t, J¼7.2 Hz, 2H), 2.24e2.17 (m,
1H), 1.77e1.74 (m, 2H), 1.59 (dd, J¼14.8, 7.6 Hz, 2H), 0.91 (t,
J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.85(d, J¼6.4 Hz, 3H), 0.03 (s, 6H); 13C
4.1.17. (2S,6R)-2-Methyl-4-methylenenonane-1,6-diol (30) and (2S,6S)-
2-methyl-4-methylenenonane-1,6-diol (31). To a solution of com-
pound 29 (0.71 g, 1.97 mmol) in THF (7 mL) was added at 0 ꢁC
methanol (0.16 mL, 3.95 mmol) followed by lithium borohydride
(86 mg, 3.95 mmol). The reaction mixture was stirred at the same
temperature for 1 h and then quenched by the addition of saturated
ammonium chloride solution. The aqueous layer was extracted with
ethyl acetate thrice. The combined extracts were washed successively
with water and brine, dried over anhydrous Na2SO4, and rotary
evaporated. Purificationoftheresidueoversilicagel(230e400 mesh)
using a mixture of ethyl acetate/DCM/petroleum ether (1:1:8) as el-
uent resulted in the separation of two diastereomers affording com-
pound 30 (0.203 g, 55%) and 31 (0.101 g, 27%) as oils. Compound 30:
NMR (50 MHz, CDCl3): d 208.9, 141.6, 115.2, 67.8, 50.3, 43.9, 40.1,
33.6, 25.9, 18.3, 17.2, 16.4, 13.6, ꢀ5.4; IR (Neat): 2957, 2930, 1715,
1462, 1092 cmꢀ1; MS (ES): m/z 299.3 (Mþ1); HRMS: m/z found
299.2408, calcd for C17H35O2Si 299.2406.
4.1.20. (4R,8S)-9-(tert-Butyldimethylsilyloxy)-8-methyl-6-methyl-
enenonan-4-ol (9). Method A: Toan ice cooledsolution of compound
30 (0.066 g, 0.35 mmol) in DCM (1 mL) was added TBDMS chloride
(0.064 mg, 0.43 mmol), imidazole (0.036 g, 0.53 mmol) and stirred
at the same temperature for 16 h. The reaction mixture was diluted
with DCM, washed successively with water and brine. The organic
layer was dried over anhydrous Na2SO4 and rotary evaporated and
the residue was purified over silica gel (100e200 mesh) to afford
compound 9 as colorless oil (0.085 g, 80%).
Rf¼0.35 (35% ethyl acetate in petroleum ether); [
a
]
ꢀ1.0 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
4.91 (s, 2H), 3.76e3.70 (m, 1H),
Method B: To a solution of compound 33 (0.05 g, 0.168 mmol) in
3.52 (d, J¼5.6 Hz, 2H), 2.27e2.20 (m, 2H), 2.05 (dd, J¼14.0,
9.6 Hz, 1H), 1.86e1.80 (m, 2H), 1.50e1.37 (m, 4H), 0.94 (t,
J¼7.2 Hz, 3H), 0.90 (d, J¼6.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
THF (2 mL) at ꢀ78 ꢁC was added drop wise chiral oxazaborolidine
34 (0.34 mL, 0.033 mmol) followed by BH3/DMS (18 mL,
0.252 mmol). The reaction mixture was stirred at the same tem-
perature for 1 h and quenched with methanol (0.5 mL). The re-
action was warmed to room temperature, concentrated in vacuo,
and the residue was purified over silica gel (100e200 mesh) to
afford compound 9 as colorless oil (0.04 g, 80%). Rf¼0.52 (10% ethyl
d
145.2, 114.0, 68.8, 68.0, 44.1, 40.0, 39.3, 33.8, 18.9, 16.4, 14.0; IR
(Neat): 3350, 2957, 2928, 2872, 1643, 1454, 1036 cmꢀ1; MS (ES):
m/z 187.2 (Mþ1); HRMS: m/z found 185.1542, calcd for C11H21O2
185.1542. Compound 31: Rf¼0.34 (35% ethyl acetate in petroleum
ether); 1H NMR (400 MHz, CDCl3):
d
4.91 (d, J¼4.4 Hz, 2H),
acetate in petroleum ether); [
(400 MHz, CDCl3): d 4.89 (s, 2H), 3.74e3.66 (m, 1H), 3.46e3.37 (m,
a
]
ꢀ3.7 (c 1.0, CHCl3); 1H NMR
D
3.77e3.72 (m, 1H), 3.54e3.46 (m, 2H), 2.26 (dd, J¼13.2, 9.6 Hz,
1H) 2.20e2.10 (m, 1H), 2.10e2.06 (m, 1H), 1.95e1.88 (m, 2H),
1.50e1.38 (m, 4H), 0.94 (t, J¼7.2 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H);
2H), 2.30 (dd, J¼13.4, 4.2 Hz, 1H) 2.24 (dd, J¼13.8, 3.0 Hz, 1H), 2.01
(dd, J¼13.6, 9.6 Hz,1H),1.80e1.71(m, 2H),1.52e1.33 (m, 4H), 0.94 (t,
J¼7.0 Hz, 3H), 0.90 (s, 9H), 0.83 (d, J¼6.6 Hz, 3H), 0.04 (s, 6H); 13C
13C NMR (50 MHz, CDCl3):
d 145.4, 113.5, 69.0, 67.7, 44.1, 40.3,
39.3, 33.6, 18.8, 16.6, 14.0; IR (Neat): 3352, 2957, 2926, 2872,
1643, 1452, 1379 cmꢀ1; MS (ES): m/z 187.3 (Mþ1); HRMS: m/z
found 185.1544, calcd for C11H21O2 185.1542.
NMR (50 MHz, CDCl3): d 145.3, 114.1, 68.3, 68.1, 44.0, 39.5, 39.3,
33.9, 25.9, 18.9, 18.3, 16.2, 14.1, ꢀ5.4; IR (Neat): 3393, 2957, 2930,
2857, 1464, 1252, 1092 cmꢀ1; MS (ES): m/z 301.3 (Mþ1); HRMS: m/z
found 301.2558, calcd for C17H37O2Si 301.2563.
4.1.18. (4S,8S)-9-(tert-Butyldimethylsilyloxy)-8-methyl-6-methyl-
enenonan-4-ol (32). To anice cooled solutionofcompound 31 (0.2 g,
1.07 mmol) in DCM (1 mL) were added TBDMS chloride (0.194 mg,
1.29 mmol) and imidazole (0.110 g, 1.61 mmol). After stirring at the
same temperature for 2 h, the reaction mixture was diluted with
DCM and the organic layer was washed successively with water and
brine, and dried over anhydrous Na2SO4. Concentration and puri-
fication over silica gel (100e200 mesh) afforded compound 15 as
colorless oil (0.27 g, 84%). Rf¼0.52 (10% ethyl acetate in petro-
4.1.21. (R)-((4R,8R)-9-(tert-Butyldimethylsilyloxy)-8-methyl-6-methyl-
enenonan-4-yl) 6-((2S,3S,5R)-5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-
methyltetrahydrofuran-2-yl)-2-methylhexanoate (35). To a solution of
8 (114 mg, 0.306 mmol) in toluene (4 mL) was added triethyl amine
(0.13 mL, 0.92 mmol) followed by 2,4,6-trichlorobenzoyl chloride
(0.14 mL, 0.924 mmol). The reaction mixture was stirred at room
temperature for 1 h and to this solution was added a solution of 9
(84 mg, 0.28 mmol) and DMAP (34 mg, 0.28 mmol) in toluene
(4 mL) drop wise. The mixture was stirred for 16 h at room tem-
perature followed by heating at 70 ꢁC for 24 h. After cooling to
room temperature, the reaction mixture was diluted with ethyl
acetate and was washed successively with water and brine. The
organic layer was dried over anhydrous Na2SO4 and rotary evapo-
rated. The residue was purified over silica gel (100e200 mesh) to
afford compound 35 as colorless oil (80 mg, 44%). Rf¼0.65 (10%
leum ether); 1H NMR (400 MHz, CDCl3):
d 4.88 (s, 2H), 3.73e3.66
(m, 1H), 3.45e3.36 (m, 2H), 2.26e2.17 (m, 2H), 2.06 (dd, J¼13.9,
9.6 Hz, 1H), 1.84e1.76 (m, 3H), 1.56e1.33 (m, 4H), 0.94 (t,
J¼7.1 Hz, 3H), 0.89 (s, 9H), 0.89 (d, J¼7.3 Hz, 3H), 0.04 (s, 6H); 13C
NMR (50 MHz, CDCl3):
d 145.2, 113.5, 68.7, 67.6, 44.5, 40.0, 39.2,
33.8, 25.9, 18.9, 18.3, 16.9, 14.1, ꢀ5.4; IR (Neat): 3393, 2957, 2930,
2857, 1470, 1252, 1092 cmꢀ1; MS (ES): m/z 301.3 (Mþ1); HRMS:
m/z found 301.2558, calcd for C17H37O2Si 301.2563.
ethyl acetate in petroleum ether); [
(400 MHz, CDCl3):
a
]
D ꢀ8.54 (c 0.8, CHCl3); 1H NMR
d
5.07e5.00 (m, 1H), 4.79 (s, 1H), 4.76 (s, 1H),
4.1.19. (S)-9-(tert-Butyldimethylsilyloxy)-8-methyl-6-methyl-
enenonan-4-one (33). To a solution of compound 32 (0.17 g,
0.58 mmol) in DCM (10 mL) at 0 ꢁC was added successively water
(0.1 mL), solid NaHCO3 (0.099 g, 1.16 mmol) followed by Dess/
Martin periodinane (0.49 g, 1.16 mmol). The reaction mixture was
stirred at the same temperature for 2 h and quenched with
4.16e4.09 (m, 1H), 3.82e3.77 (m, 1H), 3.74e3.65 (m, 2H), 3.44 (dd,
J¼9.8, 5.4 Hz, 1H), 3.37 (dd, J¼9.8, 6.2 Hz, 1H), 2.40e2.34 (m, 1H),
2.28e2.14 (m, 4H), 2.40e2.34 (m, 1H), 2.28e2.14 (m, 4H), 1.80e1.61
(m, 6H), 1.54e1.46 (m, 2H), 1.46e1.25 (m, 1H), 1.11 (d, J¼6.4 Hz, 3H),
0.94e0.88 (m, 24H), 0.84 (d, J¼6.8 Hz, 3H), 0.05 (s, 6H), 0.03(s, 6H);
13C NMR (50 MHz, CDCl3):
d 176.3, 144.0, 113.5, 80.8, 73.8, 71.4, 68.1,

P.K. Sasmal et al. / Tetrahedron 66 (2010) 5000e5007
5007
2. (a) Review: Rein, K. S.; Borrone, J. Comp. Biochem. Physiol., B 1999, 124, 117; (b)
For representative studies, see: Kobayashi, J.; Takahashi, M.; Ishibashi, M. J.
Chem. Soc., Chem. Commun. 1995, 1639; (c) Ishibashi, M.; Takahashi, M.; Ko-
bayashi, J. Tetrahedron 1997, 53, 7827; (d) Sato, M.; Shimbo, K.; Tsuda, M.;
Kobayashi, J. Tetrahedron Lett. 2000, 41, 503.
3. For the isolation, structure determination, and biological studies of Amphidi-
nolides T1e5, see: (a) Kobayashi, J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem.
2001, 66, 134; (b) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2000, 65, 1349;
(c) Kubota, T.; Endo, T.; Tsuda, M.; Shiro, M.; Kobayashi, J. Tetrahedron 2001, 57,
6175.
4. For total synthesis of amphidinolides T family, see: (a) Fürstner, A.; Aissa, C.;
Riveiros, R.; Ragot, J. Angew. Chem., Int. Ed. 2002, 41, 4763; (b) Aissa, C.; Riveiros,
R.; Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512; (c) Ghosh, A. K.; Liu,
C. J. Am. Chem. Soc. 2003, 125, 2374; (d) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J.
Am. Chem. Soc. 2005, 127, 4297; (e) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org.
Chem. 2006, 71, 4625; (f) Yadav, J. S.; Reddy, C. S. Org. Lett. 2009, 11, 1705.
5. For synthesis of C13eC22 fragment of amphidinolide T2, see: O’Brien, K. C.;
Colby, E. A.; Jamison, T. F. Tetrahedron 2005, 61, 6243.
60.7, 40.9, 40.3, 40.0, 39.8, 36.5, 35.9, 33.9, 33.8, 30.4, 29.7, 27.5,
26.6, 26.0, 18.6, 18.4, 17.3, 16.6, 14.1, ꢀ5.3; IR (Neat): 2957, 2930,
1732, 1462, 1092 cmꢀ1; MS (ES): m/z 655.6 (Mþ1); HRMS: m/z
found 655.5184, calcd for C37H75O5Si2 655.5153.
4.1.22. (R)-((4R,8R)-9-Hydroxy-8-methyl-6-methylenenonan-4-yl)
6-((2S,3S,5R)-5-(2-hydroxyethyl)-3-methyltetrahydrofuran-2-yl)-2-
methylhexanoate (36). To an ice cooled solution of compound 35
(80 mg, 0.12 mmol) in THF (1 mL) was added TBAF (0.6 mL, 1.0 M
solution in THF) and stirred at room temperature for 5 h. The re-
action mixture was diluted with ethyl acetate and washed with
water and brine. The organic layer was dried over anhydrous
Na2SO4 and rotary evaporated. The residue was purified over silica
gel (100e200 mesh) to afford compound 36 as colorless oil (40 mg,
6. For synthesis of C1eC12 fragment of amphidinolide T1, see: (a) Abbineni, C.;
Sasmal, P. K.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2007, 48, 4259; (b) Luo, J.;
Li, H.; Wu, J.; Xing, X.; Dai, W.-M. Tetrahedron 2009, 65, 6828.
77%). Rf¼0.25 (40% ethyl acetate in petroleum ether); [
a
]
D ꢀ8.54 (c
0.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d
5.08e5.02 (m, 1H), 4.82 (s,
7. (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113,
1047; (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894 and references cited therein.
8. Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth. Commun. 1998, 28,
3675.
1H), 4.81 (s, 1H), 4.30e4.23 (m, 1H), 3.89e3.85 (m, 1H), 3.83e3.75
(m, 2H), 3.50 (dd, J¼10.6, 5.4 Hz, 1H), 3.42 (dd, J¼10.8, 6.0 Hz, 1H),
2.42e2.17 (m, 6H), 1.86e1.77 (m, 4H), 1.74e1.62 (m, 3H), 1.55e1.51
(m, 2H), 1.47e1.26 (m, 8H), 1.12 (d, J¼7.2 Hz, 3H), 0.92e0.89 (m,
9H); 13C NMR (100 MHz, CDCl3):
d 176.5,143.8, 113.8, 81.3, 77.1, 71.5,
9. Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har, D.; Repic, O.; Blacklock, T. J.; Gian-
nousis, P. J. Org. Chem. 1999, 64, 1750.
68.1, 62.0, 40.8, 40.4, 40.0, 39.7, 38.0, 36.4, 35.6, 33.7, 33.6, 30.2, 27.3,
26.6, 18.6, 17.2, 16.5, 14.0, 13.9; IR (Neat): 3431, 2959, 2934, 2872,
1728, 1192 cmꢀ1; MS (ES): m/z 427.4 (Mþ1); HRMS: m/z found
427.3409, calcd for C25H47O5 427.3424.
10. For recent examples of the oxy-Michael reaction, see: (a) Honda, T.; Ishikawa, F. J.
Org. Chem.1999, 64, 5542; (b) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3,
1363; (c)Kigoshi,H.;Kita,M.;Ogawa, S.;Itoh, M.;Uemura, D. Org. Lett. 2003, 5, 957.
11. Under this condition, the Z-isomer of 18 showed the similar 2,5-trans selectivity
in oxy-Michael process.
12. HPLC conditiondcolumn: inertsil ODS 3V(250ꢂ4.6 mm), 5
mm; eluent: 30%
MeCN in water; flow: 1.5 mL/min; UV: 210 nm; rt for 19a, 31.888 min and rt for
19b, 36.180 min.
4.1.23. (R)-((4R,8R)-8-Methyl-6-methylene-9-oxononan-4-yl)
2-
methyl-6-((2S,3S,5R)-3-methyl-5-(2-oxoethyl)tetrahydrofuran-2-yl)
hexanoate (7). To an ice cooled solution of diol 36 (35 mg,
0.082 mmol) in DCM (4 mL) was added solid NaHCO3 (21 mg,
0.25 mmol) followed by Dess/Martin periodinane (104 mg,
0.25 mmol) and stirred at the same temperature for 2 h. The reaction
mixture was diluted with additional DCM, quenched with saturated
sodium thiosulphate solution and stirred for 30 min. The DCM layer
was separated and washed with water and brine, and dried over
anhydrous Na2SO4. Concentration and chromatographic purifica-
tion over silica gel (100e200 mesh) furnished compound 7 as col-
orless oil (30 mg, 88%). Rf¼0.35 (30% ethyl acetate in petroleum
13. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
14. Riley, R. G.; Silverstein, R. M. Tetrahedron 1974, 30, 1171.
15. (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121,
2674; (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett.
1999, 40, 2247; (c) Ackermann, L.; Fürstner, A.; Weskamp, T.; Kohl, F. J.; Herr-
mann, W. A. Tetrahedron Lett. 1999, 40, 4787; (d) Fuerstner, A.; Thiel, O. R.;
Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204.
16. Based on the ES MS analysis, two primary byproducts were found to be gen-
erated from homodimerization of compounds 21 and 22. Homodimerization of
21 was significantly reduced using 4 equiv of 22 instead of 1 equiv. Trace
amount of the O-desilylated product of compound 8 was also observed based
on the ES MS analysis.
17. Hughes, R. C.; Dvorak, C. A.; Meyers, A. I. J. Org. Chem. 2001, 66, 5545.
18. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737.
19. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277.
20. The ratio of two diastereomers in compound 29 was calculated to be 2:1 based
on the 1H NMR analysis of their corresponding acetate derivatives.
21. Wu, Y.; Shen, X.; Tang, C. J.; Chen, Z. L.; Hu, Q.; Shi, W. J. Org. Chem. 2002, 11,
3809.
ether); [
a]
D ꢀ14.5 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3):
d 9.80
(t, J¼2.1 Hz, 1H), 9.63 (d, J¼1.8 Hz, 1H), 5.07e5.01 (m, 1H), 4.87 (s,
1H), 4.81 (s, 1H), 4.56e4.50 (m, 1H), 3.88e3.84 (m, 1H), 2.70e2.63
(m, 1H), 2.56e2.47 (m, 3H), 2.40e2.35 (m, 1H), 2.31e2.16 (m, 3H),
2.11e2.03(m,1H),1.91e1.84 (m,1H),1.81e1.76 (m,1H),1.69e1.61 (m,
3H),1.56e1.50 (m, 3H),1.48e1.27 (m, 6H),1.12 (d, J¼7.0 Hz, 3H),1.08
(d, J¼6.7 Hz, 3H), 0.93e0.89 (m, 6H); 13C NMR (100 MHz, CDCl3):
22. Seco, J. M.; Quinoá, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915.
23. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551; (b)
Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587.
24. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989; (b) Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc.
2004, 126, 15970.
d
204.5, 201.6,176.4,142.1,114.7, 81.5, 71.6, 71.2, 50.5, 44.2, 41.2, 40.0,
39.8, 36.7, 36.4, 35.8, 33.6, 30.2, 27.4, 26.5,18.6,17.2,13.9,13.8,13.4; IR
(Neat): 2961, 2934, 2874, 1728, 1462, 1167 cmꢀ1; MS (ES): m/z 423.3
(Mþ1); HRMS: m/z found 423.3107, calcd for C25H43O5 423.3110.
25. Swindell, C. S.; Chander, M. C.; Heerding, J. M.; Klimko, P. G.; Rahman, L. T.;
Raman, J. V.; Venkataraman, H. J. Org. Chem. 1996, 61, 1101.
26. The ES MS analysis of the crude reaction mass showed two strong mass peaks
at m/z 447.3 (Mþ23) and m/z 425 (Mþ1), which supports the formation of
cyclized product(s) 70. Due to limited availability of 70 detailed stereochemical
analysis could not be done.
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd. for the support and
encouragement. Help from the analytical department in the form
of spectral data is also appreciated.
O
OH
13
13
HO
O
O
O
12
12
TiCl4, Zn,
pyridine, THF
References and notes
1. Reviews: (a) Kobayashi, J. J. Antibiot. 2008, 61, 271; (b) Kobayashi, J.; Tsuda, M.
Nat. Prod. Rep. 2007, 21, 77; (c) Chakraborty, T. K.; Das, S. Curr. Med. Chem: Anti-
Cancer Agents 2001, 1, 131; (d) Kobayashi, J. In Comprehensive Natural Products
Chemistry; Mori, K., Ed.; Elsevier: New York, NY, 1999; Vol. 8, p 619.
O
O
7
7'
O
O