First stereoselective total synthesis of Phomolide G and H via RCM protocol

Article abstract of DOI:10.1016/j.tetlet.2012.04.118

A first total synthetic route has been reported for the synthesis of Phomolide G and H. The syntheses of fragments were initiated from commercially available and inexpensive starting material (R)-epichlorohydrin. The synthesis involves a key Sharpless epo

Full text of DOI:10.1016/j.tetlet.2012.04.118

Tetrahedron Letters 53 (2012) 3735–3738
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First stereoselective total synthesis of Phomolide G and H via RCM protocol
⇑
Palakuri Ramesh, B. Chennakesava Reddy, H.M. Meshram
Organic Chemistry Division – I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A first total synthetic route has been reported for the synthesis of Phomolide G and H. The syntheses of
fragments were initiated from commercially available and inexpensive starting material (R)-epichlorohy-
drin. The synthesis involves a key Sharpless epoxidation, stereoselective epoxide opening, lactonization
and ring closing metathesis (RCM).
Received 20 March 2012
Revised 23 April 2012
Accepted 26 April 2012
Available online 7 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(R)-Epichlorohydrin
Epoxidation
Lactonization
Ring closing metathesis (RCM)
Grubb’s catalyst
Many natural products pose considerable synthetic challenge
because of their stereochemical complexity. Therefore the develop-
ment of new and efficient methods for the regio and stereoselec-
tive synthesis of biologically active compounds is an active area
of research. Nature provides many biologically active metabolites.
The genus Cordyceps is an abundant source of biologically active
secondary metabolite, for example erythrostominones,1 cordypyri-
dones2 antimalarial and sterols as antitumor agents.3 In addition,
some metabolites are widely used as food and herbal medicine in
Asia. Among the metabolites Phomolide G (1) and Phomolide H
(2)4 (Fig. 1) have attracted attention because of the medicinal prop-
erties. The Phomolides were endophytic fungal stain Phomopsis sp.
A123, a isolated from leaves of the mangrove species, Kandelia can-
del, collected in the Fugong Mangrove Conservation Area, Fujian
(China).
Recently, we initiated a research programme for the total syn-
thesis of bioactive natural products from a chiral source.5 Our ap-
proach to the total synthesis of Phomolide G and H and its
diastereomer involves the use of commercially available (R)-epi-
chlorohydrin as a starting material. The retro synthetic analysis
of Phomolide G (1) is shown in Scheme 1. The crucial 10-mem-
bered lactones was to be prepared by ring closing metathesis
(RCM). The hydrolysis of the lactone gave the PMB protected ole-
finic acid 5 and the acetonide protected olefinic alcohol 4. Precur-
sors 4 and 5 would be constructed from commercially available
chiral (R)-epichlorohydrin.
epoxide 7 was regioselectively opened with (Me)3S+IÀ, n-BuLi in
THF at À10 °C to afford secondary allylic alcohol 11 in 76% yield.7
Protection of alcohol 11 with p-methoxybenzyl bromide (PMB-
Br) in the presence of NaH gave 6 in 82% yield. The dithane 6 on
hydrolysis provided aldehyde which was converted into olefinic
acid fragment 5 by using NaH2PO4, NaClO2, 2-methyl-2-butene in
CH3CN:H2O (1:1), rt, 74% (Scheme 2).8
OH
OH
OH
O
HO
HO
HO
HO
O
O
O
O
O
O
OH
Phomolide F
Phomolide E
Phomolide D
OH
OH
OH
OH
HO
O
O
O
Synthesis of fragment 5 started from the (R)-epichlorohydrin
O
O
and the anion derived from 1,3-dithane to give epoxide 7.6 The
Phomolide G (1)
Phomolide H (2)
⇑
Corresponding author.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Figure 1. Structure of Phomolide D–H.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.118

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P. Ramesh et al. / Tetrahedron Letters 53 (2012) 3735–3738
OH
OH
OH
O
OH
HO
or
O
O
O
O
Phomolide H (2)
Phomolide G (1)
O
O
PMBO
O
O
3
O
PMBO
S
OPMB
O
HO
OH
TBDPSO
OH
+
S
HO
6
O
5
8
4
TBDPSO
O
S
O
O
O
Cl
S
9
(R)-epichlorohydrin
10
7
Scheme 1. Retrosynthesis of Phomolide G and H
O
a
S
b
S
OH
O
Cl
S
(R)-epichlorohydrin
S
7
11
PMBO
c
d
S
OPMB
OH
S
O
6
5
Scheme 2. Reagents and conditions: (a) Ref.6; (b) (Me)3S+IÀ, n-BuLi, THF, À10 °C, 1 h, 76%; (c) NaH, PMB-Br, TBAI, THF, 0o to rt, 82%; (d) CaCO3, MeI, CH3CN:H2O (9:1), 45 °C,
3 h; (ii) NaH2PO4, NaClO2, MeCN, H2O, 2-methyl-2-butene, rt, 6 h, 74% (for two steps).
The synthesis of fragment 4 was initiated from the enantio-
meric pure (R)-2-propyloxirane 10 which was also prepared from
(R)-epichlorohydrin.9 The epoxide 10 was subjected to regioselec-
tive ring opening with THP protected propargyl alcohol in the pres-
ence of n-BuLi, BF3ÁOEt2 to furnish alcohol 12.10 The secondary
hydroxyl group in 12 was protected with tert-butyldiphenylsilyl
chloride (TBDPS-Cl) and imidazole to afford the silylether 13 in
86% yields. Depyranylation of compound 13 using PPTS (cat.) in
methanol afforded compound 14 in 84% yield. The cis-allyl alcohol
15 was obtained by the reduction of 14 by using Ni(OAc)2Á2H2O,
NaBH4, EtOH, ethylene glycol in 92% yield.11 The acetonide 4 was
conveniently obtained from the allylic alcohol 8 in three steps-
via allylic epoxide 9 through a sequence of reactions involving
the Sharpless asymmetric epoxidation,12 Swern oxidation13 and
one-carbon homologation with PPh3CH3+IÀ, (68% overall yield after
3 steps).14Treatment of olefinic epoxide 9 with Sc(OTf)3 in THF and
H2O (10:1, 0.25 molar) cleanly afforded diol 8 in 79% yield.15 Pro-
tection of diol 8 with 2,2-DMP, PPTS (cat.) in CH2Cl2 gave acetonide
17 in 86% yield and subsequent deprotection of TBDPS with TBAF
afforded alcohol 4 in 82% yield (Scheme 3).
With the two key intermediates acid 5 and alcohol 4 in hand,
the stage was set for their coupling to afford the macrolide

P. Ramesh et al. / Tetrahedron Letters 53 (2012) 3735–3738
3737
OH
O
a
OTHP
O
b
OTHP
+
Cl
10
12
(R)-epichlorohydrine
OR
g
OR
c
e
OTHP
OH
d
13
14
R = TBDPS
OR
OR
OR
O
O
f
OH
OH
9
15
16
O
O
O
HO
O
OR
OH
OR
i
h
j
HO
17
8
4
Scheme 3. Reagents and conditions: (a) Ref.9; (b)(i) n-BuLi, BF3ÁOEt2, THF, À78 °C, 2 h, 90%;(c) TBDPS-Cl, imidazole, CH2Cl2, 0 °C to rt, 86%; (d) p-TSA(cat.), MeOH, 0 °C to rt;
84%; (e) Ni(OAc)2.2H2O, NaBH4, EtOH, ethylene glycol, rt, 6 h, 92%; (f) (+)ÀDIPT, Ti(Oipr)4, 4A° MS, TBHP, CH2Cl2, À20 °C, 12 h, 82%; (g) (i) (COCl)2, DMSO, CH2Cl2, NEt3, À78 °C;
(ii) PPh3CH3+IÀ, NaHMDS, THF, 0 °C to rt, (72% overall yield after 2 steps); (h) Sc(OTf)3, THF:H2O (9:1), rt, 12 h, 79%; (i) 2,2-DMP, CSA (cat.), CH2Cl2, 0 °C to rt, 86%; (j) TBAF, THF,
0 °C to rt, 82%.
O
O
O
O
PMBO
O
PMBO
PMBO
O
Grubbs-I
a
+
O
OH
O
HO
O
O
5
4
O
3
18
b
O
O
O
O
O
PMBO
PMBO
O
HO
d
O
+
O
O
O
O
O
19
18
E:Z: 70 : 30
21
e
c
c
OH
OH
OH
OH
OH
OH
HO
O
HO
O
O
O
O
O
O
1
20
2
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C to rt, 4 h, then DMAP, toluene, 0 °C to rt, 12 h, 80%; (b) 10 mol % Grubb’s 2nd
generation catalyst, CH2Cl2 reflux, 70%; (c) TFA/ CH2Cl2, 0 °C to rt, 48 h, 70%; (d) DDQ, CH2Cl2:H2O(9:1), 0 °C to rt, 2 h, 90%; (e) (i) NaH, MeI, THF, 0 °C to rt, 6 h; (ii) TFA, CH2Cl2,
0 °C to rt, 4 h, 58% (for two steps).

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P. Ramesh et al. / Tetrahedron Letters 53 (2012) 3735–3738
skeleton. The coupling of acid 5 and alcohol 4 was achieved under
Yamaguchi conditions16 (2,4,6-trichlorobenzoyl chloride–Et3N–
THF then DMAP–toluene) to afford the dienoic ester 3 in 80% yield
References and notes
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(Scheme 4). The RCM of compound
3 was attempted with
(10 mol %) Grubbs first generation catalyst in dry CH2Cl2 under re-
flux conditions, but the reaction did not proceed. Reaction of 3 with
Grubb’s second-generation catalyst (10 mol %) in CH2Cl2 at reflux
afforded mixture of E:Z ratio 70:30 (18 and 19) as the sole product
in 70% yield.17,18 The E:Z isomers were separated by column chro-
matography. The geometry of the olefin in 18 was established as ‘E’
from its coupling constants.19 The removal of acetonide and PMB-
protect of groups using trifluoroacetic acid (TFA) in CH2Cl2 afforded
the target molecule Phomolide G (1) and its Z-isomer 20. Deprotec-
tion of the PMB group present in 18 with DDQ in CH2Cl2/water
(9:1) system furnished 21 in 90% yield. The methoxylation of alco-
hol 21 with methyl iodide (MeI) in the presence of NaH followed
by deprotection of acetonide by using TFA in CH2Cl2 afforded the
required Phomolide H (2) in 58% yield (for two steps) (Scheme 4).
Synthetic Phomolide G (1) and Phomolide H (2) exhibited identical
spectral data (IR, 1H NMR, 13C NMR and Mass) to that of the natural
product.4
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PCy3
MesN
Cl
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Ph
Cl
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PCy3
Ph
PCy3
Grubbs 1st generation
Grubbs 2nd generation
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19. While one of the olefinic proton signal appeared at d 5.40 ppm as a dd (J = 9.82,
15.86 Hz) and the signal due to other double proton appeared at d 5.82 ppm as
a dd (J = 9.82, 15.86 Hz). And the geometry of the olefin in 19 was established
as ‘Z’ from its coupling constants, while one of the olefinic proton signal
appeared at d 5.78 ppm as a dd (J = 2.26, 7.55 Hz) and the signal due to other
double proton appeared at d 5.82 ppm as a dd (J = 2.26, 7.55 Hz).
In conclusion, we described the stereoselective total synthesis
of Phomolide G, H and its Z-isomer (20) via an RCM of the respec-
tive dienoic esters. Phomolide G, H and its Z-isomer was achieved
using inexpensive and commercially available starting material
(R)- epichlorohydrin. The synthesis highlights Sharpless epoxida-
tion and ring closing metathesis (RCM) reactions as key steps.
Acknowledgments
P. R. and B. C. K. R. thank CSIR-UGC for the award of a fellowship
and to Dr. J. S. Yadav, Director IICT, for his support and
encouragement