Total synthesis of (+)-aspicilin from D-mannitol

Article abstract of DOI:10.1055/s-0029-1217974

The total synthesis of the 18-membered lichen macrolide, (+)-aspicilin, has been accomplished utilizing the Swern oxidation, Masamune-Roush olefination, and ring-closing metathesis of a trienic ester as key steps. d-Mannitol has been utilized as the chiral pool material for the construction of the olefinic aldehyde and the Jacobsen hydrolytic kinetic resolution has been employed for the construction of the olefinic phosphonate ester.

Full text of DOI:10.1055/s-0029-1217974

2828
LETTER
Total Synthesis of (+)-Aspicilin from D-Mannitol
Synthesis
.of (+)-Aspic
S
ilin from
D
-Ma
.
nnitol Yadav,* T. Srinivasa Rao, K. Ravindar, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 16 June 2009
As part of our interest in the total synthesis of various
complex natural products, we herein report a convergent
approach for the total synthesis of (+)-aspicilin. D-Manni-
tol was used as the chiral pool material for the synthesis of
Abstract: The total synthesis of the 18-membered lichen mac-
rolide, (+)-aspicilin, has been accomplished utilizing the Swern ox-
idation, Masamune–Roush olefination, and ring-closing metathesis
of a trienic ester as key steps. D-Mannitol has been utilized as the
chiral pool material for the construction of the olefinic aldehyde and an olefinic aldehyde, and a Jacobsen hydrolytic kinetic
the Jacobsen hydrolytic kinetic resolution has been employed for
resolution was employed for the synthesis of an olefinic
the construction of the olefinic phosphonate ester.
phosphonate ester.
Key words: (+)-aspicilin, Swern, Masamune–Roush olefination,
According to our strategy, (+)-aspicilin (1) could be syn-
ring-closing metathesis, D-mannitol, kinetic resolution
thesized from the union of fragments 2 and 3 via the
Masamune–Roush olefination and a subsequent ring-clos-
ing metathesis (RCM) for the formation of macrocycle 18.
The 18-membered polyhydroxy macrolide (+)-aspicilin
(1, Figure 1) was isolated in 1900 from lichen of the
Fragment 2 could be prepared from D-mannitol (4) by a
sequence of reactions, and fragment 3 could be achieved
Lecanoraceae family.1 The structure of (+)-aspicilin was
from commercially available 1,12-dodecanediol (5,
deduced by Huneck and co-workers using various spec-
Scheme 1).
troscopic methods.2 In 1985, both the relative and abso-
lute stereochemistry of (+)-aspicilin (1) were established
The synthesis of olefinic aldehyde fragment 2 began from
D-mannitol (4). Protection of the four outer hydroxyl
by X-ray crystallography, degradation and synthetic stud-
groups of D-mannitol (4) as diacetonide followed by
dibenzylation of the remaining internal alcohols accord-
ing to the reported procedure gave compound 5.5 Selec-
tive hydrolysis of one of the acetonides in compound 5
afforded compound 6,5 which on treatment with triphe-
nylphosphine, imidazole, and iodine gave the olefin 7.6
Deprotection of acetonide 7 with 60% aqueous acetic acid
gave the diol 8, which was converted into di-TES ether 9
by treating with TESCl and imidazole in dichlo-
romethane. Selective oxidative deprotection of the prima-
ry TES ether 9 by Swern oxidation conditions afforded the
desired olefinic aldehyde 2 (Scheme 2).7,8
ies.3 Although its biological function has yet to be deter-
mined, its fascinating structural features, which include
four stereogenic centers within a 18-membered macrolide
ring system have prompted numerous efforts to develop
routes for its total synthesis.4
OH OH
O
OH
O
1
The synthesis of fragment 3 began from commercially
available 1,12-dodecanediol (5). Accordingly, diol 5 was
converted into iodo compound 10 by a two-step sequence,
namely selective monobenzylation using BnBr in the
Figure 1 (+)-Aspicilin
OBn OTES
OH OH
OH
D-mannitol
CHO
O
4
OBn
2
O
O
O
P
OEt
OEt
O
1
HO
OH
(+)-aspicilin
8
8
5
3
Scheme 1 Retrosynthetic analysis of (+)-aspicilin
SYNLETT 2009, No. 17, pp 2828–2830
x
x
.x
x
.2
0
0
9
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217974; Art ID: D16509ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (+)-Aspicilin from D-Mannitol
2829
OBn
O
OBn
O
OBn O
O
a, b
c
d
O
O
HO
O
D-mannitol
OH OBn
O
OBn
OBn
4
7
5
6
OBn OTES
OBn OH
OBn OTES
e
f
g
OH
OTES
CHO
OBn
OBn
OBn
8
9
2
Scheme 2 Reagents and conditions: (a) 2,2-dimethoxypropane, DMF, PTSA (cat.), 80%; (b) NaH, BnBr, TBAI, THF, 0 °C to r.t., 95%; (c)
MeOH, concd HCl, 0 °C to r.t., 60%; (d) Ph3P, imidazole, I2, toluene, 80 °C, 88%; (e) 60% aq AcOH, r.t., 12 h, 62%; (f) TESCl, imidazole,
CH2Cl2, 6 h, 0 °C to r.t., 85%; (g) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to –40 °C, 80%.
presence of NaH followed by iodination of the remaining was treated with phosphonate ester 3, lithium chloride,
alcohol with iodine, triphenylphosphine, and imidazole. and Hünig’s base at room temperature to give a 10:1 mix-
Then, iodo compound 10 was treated with KOt-Bu to give ture of E/Z isomers. These isomers could easily be sepa-
olefin which in turn reacted with MCPBA in CH2Cl2 to rated by column chromatography to afford pure a,b-
furnish racemic epoxide 11. Compound 11 was subjected unsaturated ester 17. Treatment of compound 17 with the
to a Jacobsen hydrolytic kinetic resolution with 0.55 Grubbs second-generation catalyst (20) under high dilu-
equivalents of water using (R,R)-Jacobsen catalyst to tion conditions gave macrocyclic diene 18 as 4:1 mixture
yield enantiomerically pure epoxide 12 (>98% ee by of E/Z isomers.12 In our approach, the macrocyclic diene
chiral HPLC) and diol 13 each in 45% yield.9
18 was formed exclusively in 78% yield by RCM reac-
tion. Unlike previous approaches,4a,c no byproduct was
observed in RCM reaction as a result of the participation
of double bond of the carboxylic acid moiety. Partial hy-
drogenation of the isomeric mixtures of alkene 18 using
palladium on barium sulfate in ethyl acetate gave fully
protected (+)-aspicilin (19).13 Global deprotection of 19
using TiCl4 afforded the target molecule (+)-aspicilin {1,
mp 151–153 °C, [a]D25 +36.7 (c 0.11, CHCl3)}. The spec-
tral and analytical data of compound 1 were in agreement
with the data reported in the literature (Scheme 4).4a–c,14
Regioselective ring opening of epoxide 12 with LiAlH4
gave the secondary alcohol 14. Subsequently, compound
14 was protected as its TBS ether using TBSCl in the pres-
ence of imidazole in CH2Cl2 and then subjected to deben-
zylation using Birch conditions to give the primary
alcohol 15 which was further converted into terminal ole-
fin 16 by using two sequential reactions, that is, iodination
of alcohol using iodine, triphenylphosphine, and imida-
zole and b-elimination of the resulting iodo compound
with KOt-Bu in THF. Deprotection of TBS ether with
TBAF followed by coupling of the resulting alcohol with In conclusion, we have demonstrated a convergent total
2-(diethoxyphosphoryl)acetic acid using DCC furnished synthesis of polyhydroxy macrolide (+)-aspicilin from
the olefinic phosphonate ester 3 (Scheme 3).10
commercially available and cost-effective starting materi-
als D-mannitol and 1,12-dodecanediol. The overall yield
in the synthesis of (+)-aspicilin was 8.6% in eleven steps
The union of fragments 2 and 3 was achieved by using
Masamune–Roush conditions.11 Accordingly, aldehyde 2
O
e
a, b
c, d
BnO
I
HO
OH
BnO
8
8
8
5
10
11
O
BnO
8
OTBS
OH
12
f
g, h
b, c
HO
BnO
O
+
OH
8
8
OH
BnO
15
14
8
13
O
P
OEt
OEt
O
OTBS
i, j
8
8
3
16
Scheme 3 Reagents and conditions: (a) NaH, BnBr, DMF, 3 h, 0 °C to r.t., 45%; (b) Ph3P, imidazole, I2, CH2Cl2, 1 h, 92%; (c) KOt-Bu, THF,
0 °C to r.t., 96%; (d) MCPBA, CH2Cl2, 3 h, 84%; (e) (R,R)-Jacobsen catalyst, 45%; (f) LiAlH4, THF, 30 min, 94%; (g) TBSCl, imidazole,
CH2Cl2, 0 °C to r.t., 92%; (h) Li/liq. NH3, 10 min, 94%; (i) TBAF, CH2Cl2, r.t., 3 h, 90%; (j) (Et2O)P(O)CH2CO2H, DCC, DMAP, 0 °C to r.t.,
88%.
Synlett 2009, No. 17, 2828–2830 © Thieme Stuttgart · New York

2830
J. A. Yadav et al.
LETTER
OBn OTES
OBn
OBn OTES
OBn
O
O
b
a
2
+
3
O
O
18
17
OBn OTES
OH OH
OH
O
O
O
c
d
OBn
O
19
1
MesN
Cl
NMes
Ph
20
Ru
Cl
PCy3
Scheme 4 Reagents and conditions: (a) DBU, LiCl, MeCN, r.t., 84%; (b) 20 (10 mol%), CH2Cl2, reflux, 36 h, 78%; (c) H2, Pd/BaSO4 (cat.),
EtOAc, 1 h, 95%; (d) TiCl4 (1 M solution in CH2Cl2), 0 °C to r.t. 86%.
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Sreekanth, T. Tetrahedron Lett. 2006, 47, 5595.
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previous reports in terms of number of steps.4a,c,e The syn-
thesis utilizes simple and straightforward reactions such
as Swern oxidation, Masamune–Roush olefination, ring-
closing metathesis and Jacobsen hydrolytic kinetic resolu-
tion as key steps.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
T.S.R. and K.R. thank the CSIR, New Delhi, for the award of fel-
lowships.
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