Synthesis of an advanced intermediate enroute to (?)-clavosolide A

Article abstract of DOI:10.1016/j.tetlet.2017.05.033

A stereoselective route to an advanced intermediate toward the synthesis of clavosolide A is disclosed. The key steps include Wadsworth-Emmons cyclopropanation, utilization of a sulfinyl moiety as an internal nucleophile to open a cyclopropane ring activated by Hg(II)- to create the C3-C5 stereogenic centers, C–C bond formation employing an α-chloro sulfide, asymmetric transfer hydrogenation, regioselective hydrosilylation and Tamao-Fleming oxidation.

Full text of DOI:10.1016/j.tetlet.2017.05.033

Accepted Manuscript
Synthesis of an advanced intermediate enroute to (–)-Clavosolide A
Sadagopan Raghavan, Ravi Kumar Chiluveru
PII:
S0040-4039(17)30614-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.033
TETL 48926
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Tetrahedron Letters
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Revised Date:
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2 May 2017
11 May 2017
Please cite this article as: Raghavan, S., Chiluveru, R.K., Synthesis of an advanced intermediate enroute to (–)-
Clavosolide A, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.033
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Tetrahedron Letters
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Synthesis of an advanced intermediate enroute to (–)-Clavosolide A
Sadagopan Raghavan∗, Ravi Kumar Chiluveru
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Hyderabad-500007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A stereoselective route to an advanced intermediate toward the synthesis of clavosolide A is
disclosed. The key steps include Wadsworth-Emmons cyclopropanation, utilization of a sulfinyl
moiety as an internal nucleophile to open a cycloprpane ring activated by Hg(II)- to create the
C3-C5 stereogenic centers, C-C bond formation employing an α- chloro sulfide, asymmetric
transfer hydrogenation, regioselective hydrosilylation and Tamao-Fleming oxidation.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Wadswoth-Emmons cyclopropanation
α-Chloro sulfide
Sulfinyl group
Noyori transfer hydrogenation
Tamao-Fleming oxidation
Introduction
of ketone 3, an advanced intermediate in the synthesis toward
clavosolide A, by Hg(II)-promoted cyclopropane ring opening to
(–)-Clavosolide
A
1, Fig-1 is
a
dimeric glycosidic
create the stereogenic carbons of the tetrahydropyran ring,
hydroxy directed regioselective hydrosilylation of
macrolide isolated from the marine sponge Myriastra clavosa by
Faulkner and co-workers.1 The structure comprises of a C-2
symmetric 16-membered macrolide, two 2,3-trans-2,6-cis-
substituted tetrahydropyrans, two trans-cyclopropanes and two
permethylated xylose sugar units. Clavosolide A has attracted
significant interest from the synthetic community. The first
synthesis2 by Willis revealed a discrepancy in the structure
assignment of the cyclopropane ring resulting in its structural
revision. Lee and co-workers confirmed the revised structure by
synthesis.3,4
a
functionalized alkyne followed by Tamao-Fleming oxidation to
introduce a keto group at C-7 and the synthesis of the
cyclopropane ring from an epoxide using a phosphonate anion.
Results and Discussion
Hydrosilylation &
Tamao-Fleming oxidation
OP OP
OP
OP
OP
H
O
PO
O
OMe
MeO
O
OMe
PO
Ionic hydrogenation
2
Monomeric aglycon
H
3
O
Stereoselective
reduction
O
O
O
H
OH
O
O
H
OP OP
S
Tol
OBn
S
H
O
Tol
OP
5
H
O
Reaction with
α−chloro sulfide
O
O
O
1
PO
OMe
H
N
MeO
OMe
4
Noyori transfer
hydrogenation
H
Me
OMe
P = Protecting
group
6
Wadsworth-Emmons
cyclopropanation
Fig-1: Structure of (–)-Clavosolide A
In connection with our interest in employing the sulfinyl
moiety as an intramolecular nucleophile and an α-chloro sulfide
for carbon-carbon bond formation, we report herein the synthesis
———
Scheme-1: Retrosynthetic Analysis of Clavosolide A
∗ Corresponding author.
E-mail: sraghavan@iict.res.in (S Raghavan)

2
The retrosynthetic analysis is depicted in Scheme-1. The
monemeric aglycon 2 can be obtained from ketone 3 by ionic
hydrogenation of the hemiketal obtained by deprotection of the
diol protecting group. Ketone 3 in turn was envisioned to be
obtained by C-C bond formation by reaction of an α-chloro
sulfide with an alkynylzinc reagent. The sulfide and alkyne
reaction partners can be traced to sulfoxide 5 and amide 6
respectively.
O
n-BuLi
O
H
TMS
17
(EtO)2P(O)CH2COOEt
iPrMgCl
X
THF, 0 oC,
2 h, 70%
O
Toluene, reflux,
16 h, 75%
18
TMS
15
AlMe3
16, X= OEt
6,
NH(OMe)Me.HCl
Toluene, 0 oC,
6 h, 75%
X= NMe(OMe)
OH
OP
(R,R)-Noyori catalyst
HCOONa
The synthesis of sulfoxide 5 commenced with the epoxide
7,5 obtained by hydrolytic kinetic resolution,6 which on
Wadsworth-Emmons cyclopropanation7 furnished the trans-
cyclopropyl ester 8 (85% yield, er 99:1).8 Treatment of the lithio
anion of (R)-methyl p-tolyl sulfoxide 9 with ester 8 afforded the
β-keto sulfoxide 10.9 Diastereoselective reduction10 of the keto
group with DIBAL-H in the presence of ZnCl2 yielded alcohol 5
(82% yield, dr >95:<5). The reaction of cyclopropyl sulfoxide 5
with mercuric trifluoroacetate in the presence of mercuric oxide11
and water proceeded cleanly to furnish mercuric bromide 11 after
treatment with aq KBr solution. Demercuration of compound 11
using Bu3SnH and catalytic Et3B12 proceeded cleanly to furnish
diol 12. The diol was protected as the acetonide 13 under
standard condition.13 The sulfinyl moiety in compound 13 was
reduced cleanly to sulfide 14 by employing NaI and (CF3CO)2,14
Scheme-2.
K2CO3, MeOH
30 min, rt, 90%
Ionic lquid,
EtOAc/H2O (1:1),
rt, 6 h, 90%
TMS
19
TBS-Cl, Imidazole
DCM, 0 oC-rt,
1 h, 90%
20 P= H
21 P= OTBS
Ts
N Ru
Cl
NH2
Ph
Ph
(R,R)-No yori's catalyst
Scheme-3: Synthesis of Propargylic Ether 21
The synthesis of propargylic sulfide 4 was achieved by
reaction of the α-chloro sulfide 22, prepared by reaction of
sulfide 14 with N-chlorosuccinimide in benzene, with the alkynyl
zinc bromide 23, prepared from alkyne 21 by treatment with
iPrMgCl.LiCl and transmetalation with ZnBr2. The next step
called for a regioselective oxidation of the alkyne to a ketone.
Toward this end, the silyl ether in compound 4 was deprotected
and the resulting alcohol 24 was subjected to regioselective
hydrosilylation following Trost’s protocol19 to afford alkynyl
silane 25. Desulfurization of acetate 26, obtained from alcohol
25, using Ra-Ni afforded an alkenyl silane which was subjected
to Tamao-Fleming oxidation20 to yield ketone 3,21 Scheme 4.
Ketone 3, constitutes an advanced intermediate toward the
synthesis of clavosolide and further efforts are in progress to
convert ketone 3 into clavosolide A.
O
NaH,
O
S
O
Tol
Me
(EtO)2P(O)CH2COOEt
9
OBn
EtO
OBn
LDA, -78 oC,
Toluene, reflux,
16 h, 85%
7
8
1 h, 80%
O
S
O
O
S
OH
DIBAL, ZnCl2
Tol
OBn
Tol
OBn
THF, -78 oC,
1 h, 82%
5
10
Hg(OCOCF3)2,
HgO, H2O,
O
S
OH OH
Bu3SnH, Et3B, O2
Tol
OBn
THF, 0 oC, 1 h, 75%
DCM, KBr,
5 h, 80%
11
HgBr
O
O
O
O
NCS, PhH
rt, 30 min
O
S
OH OH
O
S
O
O
S
S
2,2 DMP, CSA
Tol
OBn
Tol
OBn
Tol
OBn
Tol
OBn
DCM, 4 h, 90%
Cl
12
13
22
14
OTBS
O
O
TFAA, NaI,
Acetone,
S
O
O
Tol
OBn
-40 oC, 30 min,
85%
CpRu(CH3CN)3PF6
BnMe2SiH, DCM
S
21
iPrMgCl,
ZnBr2, THF
Tol
OBn
14
30 min, 0 oC-rt,
80%
OTBS
Scheme-2: Synthesis of Sulfide 14
23
ZnBr
PO
4 h, 0 oC-rt, 80%
The synthesis of the alkyne partner 22 began with (S)-
propylene oxide,15 obtained by hydrolytic kinetic resolution.
Cyclopropyl ester 16 was prepared by reaction of epoxide 15
with the lithio anion of triethylphosphono acetate (75% yield, er
99:1).15 Ester 16 was readily converted16 to Weinreb amide 6,
that on reaction with alkynylmagnesium chloride, prepared from
TMS-acetylene 17 and iPrMgCl, resulted in propargylic ketone
18. Stereoselective transfer hydrogenation using (R,R)-Noyori
catalyst17 following Spur’s protocol18 yielded propargylic alcohol
19. Removal of the TMS group by treatment with K2CO3 in
methanol afforded the terminal alkyne 20. Protection of the
hydroxy group as its silyl ether furnished alkyne partner 21,
Scheme-3.
H
4, P = OTBS
24, P = H
TBAF, THF
3 h, 80%
O
O
O
O
1. Ra-Ni, EtOH
2 h, rt
S
Tol
OBn
OBn
2. TBAF, THF,
30 min, 0 o
Si
O
C
Ph
KHCO3, H2O2,
MeOH, 16 h, 70%
(Two steps)
PO
AcO
H
H
Ac2O, Et3N
DMAP
DCM, 0 oC-rt,
2 h, 90%
3
25, P = H
26,
P = Ac
Scheme-4: Synthesis of Ketone 3

Synthesis 1981, 141. (ii) Raghavan, S.; Chiluveru, R. K.;
Subramanian, S. G. J. Org. Chem. 2016, 81, 4252.
15. Delhaye, L.; Merschaert, A.; Delbeke, P.; Brione, W. Org.
Process Research & Development. 2007, 11, 689.
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Chem. Soc. 1997, 119, 8738.
Conclusion
In conclusion, we have disclosed a stereoselective route to a
key intermediate toward the synthesis of clavosolide A. The key
steps include the stereoselective synthesis of cyclopropyl esters
from the terminal epoxides employing the Wadsworth-Emmons
protocol, intramolecular nucleophilic opening of a cyclopropyl
moiety activated by Hg(II)- by a sulfinyl group, transfer
hydrogenation, C-C bond formation via an α-chloro sulfide and
regioselective hydrosilylation.
18. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 1912.
19. Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc.
2005, 127, 10028.
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Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett. 1988,
29, 6955.
21. Attempted oxidation of the alkenyl silane 25 led to competitive
oxidation of the sulfide to sulfoxide and further [2,3] sigmatropic
rearrangement.
Acknowledgments
Ravi Kumar Ch. is thankful to CSIR for SRF fellowship.
S.R. acknowledges funding from DST (SR/S1/OC-5/2011) and
CSIR, New Delhi as a part of the XII five-year plan programme
under the title ORIGIN (CSC-108).
Supplementary Material
Supplementary data (included are experimental procedures
and characterization data of all compounds) associated with this
article.
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OMe
Ph
COOH
O
EDC, DMAP
LAH, THF
MeO
8
HO
OBn
O
OBn
0o C-rt, 2 h,
90%
DCM, 0o C-rt,
4 h, 90%
Ph
(i)
(ii)
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Synthesis of an advanced intermediate
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Raghavan Sadagopan,* and Ravi Kumar Chiluveru
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Highlights
The synthesis of an intermediate to clavosolide A is
disclosed.
Wadsworth-Emmons cyclopropanation.
Sulfinyl moiety as a nucleophile to open a
cyclopropane activated by mercuric (II) salt.
Asymmetric transfer hydrogenation to create the
carbinol stereogenic center.
α-Chloro sulfide for C-C bond formation and
hydroxy directed hydrosilylation are key steps.