Total synthesis of aspinolide B: a ring-closing metathesis approach

Article abstract of DOI:10.1016/j.tetlet.2007.07.176

A highly convergent stereoselective total synthesis of aspinolide B, a 10-membered lactone is described. The key step includes a ring-closing metathesis reaction to construct the 10-membered ring and the E-olefinic moiety. d-Mannitol was used as a chiral

Full text of DOI:10.1016/j.tetlet.2007.07.176

Tetrahedron Letters 48 (2007) 6937–6940
Total synthesis of aspinolide B: a ring-closing
metathesis approachI
Subhash Ghosh* and R. Vengal Rao
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 14 June 2007; revised 16 July 2007; accepted 25 July 2007
Available online 31 July 2007
Abstract—A highly convergent stereoselective total synthesis of aspinolide B, a 10-membered lactone is described. The key step
includes a ring-closing metathesis reaction to construct the 10-membered ring and the E—olefinic moiety. D-Mannitol was used
as a chiral pool material for the construction of the key fragments—the olefinic acid and the olefinic alcohol moieties.
Ó 2007 Elsevier Ltd. All rights reserved.
In recent years naturally occurring 10-membered lac-
tones, commonly known as decanolides have attracted
considerable attention from synthetic, as well as bioor-
ganic chemists, because of their interesting structures
and important biological activities.1 Representative
examples of this class of molecules are (Fig. 1) aspino-
lide B (1),2 microcarpalide (2),3 lethaloxin (3)4 and
decarestrictine D (4).5 Aspinolide B was isolated from
cultures of Aspergillus ochraceus, whose relative stereo-
chemistry was established by X-ray analysis. The abso-
lute stereochemistry was established on the basis of
Helmchen’s method,6 followed by total synthesis.7 As
part of our continuing interest on stereoselective synthe-
ses of natural products from the chiral pool,8 herein we
report a convergent approach for the total synthesis of
aspinolide B (1) starting from the cheap and easily avail-
able starting material, D-mannitol.
Retrosynthetically (Scheme 1), aspinolide B could be
obtained via esterification of crotonic acid with alcohol
5, which in turn could be obtained from bis-alkene 6
via ring closing metathesis,9 an important reaction,
which has been widely used for the synthesis of natu-
ral products having similar decanolide frameworks.10
OH
OH
OH
O
OH
O
O
O
O
OH
O
Microcarpalide (2)
Aspinolide B (1)
O
O
HO
HO
O
O
HO
OH
O
O
OH
Decarestrictine D (4)
(+)-Lethaloxin (3)
Figure 1.
Keywords: Aspinolide B; Ring-closing metathesis; D-Mannitol.
q IICT Communication No. 070605.
*
Corresponding author. Tel.: +91 40 2719 3154; fax: +91 40 27193108; e-mail: subhashbolorg3@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.176

6938
S. Ghosh, R. V. Rao / Tetrahedron Letters 48 (2007) 6937–6940
OH OBn
OBn
O
OH
HO
OBn PMBO
OBn
O
O
O
O
O
O
O
6
Aspinolide B (1)
5
OBn
PMBO
OBn
D-Mannitol
HOOC
OH
9
7
8
Scheme 1. Retrosynthetic analysis of 1.
Bis-alkene 6 could be obtained via the esterification of
7 and 8, which in turn could both be synthesized from
D-mannitol.
deprotection with AcOH–THF–H2O (2:1:1) afforded
diol 15. Selective tosylation of the primary hydroxyl
group gave the corresponding tosylate, which on treat-
ment with K2CO3 in anhydrous methanol gave epoxide
16. Finally, epoxide opening with DIBAL–H in CH2Cl2
afforded alcohol fragment 7 in 88% yield.
The synthesis of olefinic alcohol 7 (Scheme 2) com-
menced from 10, which was prepared from D-mannitol
according to the reported procedure.11 Oxidative cleav-
age of the diol in 10 with NaIO4, followed by in situ
reduction of the resulting aldehyde with NaBH4 gave
primary alcohol 11. Compound 11 was converted to
allylic alcohol 1312 in two steps, involving formation
of iodide 12 with TPP, I2 and imidazole in THF fol-
lowed by activated Zn dust-mediated elimination to fur-
nish allylic alcohol 13. PMB protection of the resulting
secondary alcohol afforded 14, which on acetonide
The synthesis of fragment 8 (Scheme 3) commenced
from compound 13. Acetonide deprotection followed
by selective protection of the primary hydroxyl group
as the TBDPS ether gave 17. Benzylation of 17 with
BnBr, NaH and TBAI (cat) in THF gave 18. Dihydr-
oxylation of 18 with OsO4 gave a diol, which on oxida-
tive cleavage with NaIO4, followed by Wittig olefination
with Ph3P@CHCOOEt in dichloromethane gave 19
O
O
O
O
ref 11
i
D-mannitol
O
I
O
OH
OH
O
9
O
OH
O
11
O
10
O
O
O
O
iv
ii
iii
O
O
14
12
13 OH
OPMB
OH
OH
O
v
vi
vii
HO
OPMB
16
OPMB
7
OPMB
15
Scheme 2. Reagents and conditions: (i) NaIO4, THF–H2O (2:1), 0 °C, 1 h, then NaBH4, 70%; (ii) TPP, I2, imidazole, THF, 90 °C, 1 h; (iii) activated
Zn dust, EtOH, reflux, 1 h, 75% over two steps; (iv) NaH, PMBBr, TBAI (cat), THF, 0 °C, 2 h, 90%; (v) AcOH–THF–H2O (2:1:1), rt, 18 h, 90%; (vi)
(a) TsCl, Et3N, DMAP (cat), CH2Cl2, 0 °C, 2 h; (b) K2CO3, MeOH, 0 °C, 6 h, 75% over two steps; (vii) DIBAL–H, CH2Cl2, 0 °C, 2 h, 88%.
OBn
OH
O
i
ii
TBDPSO
OBn
TBDPSO
O
18
OBn
17 OH
13 OH
OBn
iii
iv
TBDPSO
OBn
COOEt
TBDPSO
COOEt
19
OBn
20
OBn
OBn
COOEt
COOEt
HO
v
vi
vii
8
22
OBn
OBn
21
Scheme 3. Reagents and conditions: (i) (a) PTSA, MeOH, 0 °C, 6 h; (b) TBDPSCl, imidazole, DMF, rt, 12 h, 90% over two steps; (ii) NaH, BnBr,
TBAI (cat), THF, 0 °C, 12 h, 80%; (iii) (a) NMO, OsO4, acetone–water (2:1), rt, 24 h; (b) NaIO4, THF–water (2:1), 0 °C , 1 h; (c) Ph3P@CHCOOEt,
CH2Cl2, rt, 6 h, 70% over three steps; (iv) H2, Pd/C, n-BuNH2, MeOH, rt, 2 h, 90%; (v) TBAF, THF, rt, 6 h, 90%; (vi) (a) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 °C, 0.5 h; (b) Ph3P@CH2, ether, 0 °C, 75% over two steps; (vii) LiOH, THF–H2O–MeOH (3:1:1), 0 °C, 2 h, 95%.

S. Ghosh, R. V. Rao / Tetrahedron Letters 48 (2007) 6937–6940
OBn OBn
6939
PMBO
OBn
PMBO
OBn
i
ii
7 + 8
O
O
O
6
O
23
MesN
NMes
G 2
Ph
Cl
Ru
Cl
PCy3
OBn
OBn
O
OBn
HO
OBn
v
iii
1
iv
O
O
O
O
O
24
5
Scheme 4. Reagents and conditions: (i) 2,4,6-trichlorobenzoyl chloride, Et3N, THF 0 °C, 3 h, then 8, DMAP, toluene, rt, 1 h 90%; (ii) 20 mol % of
Grubbs’ second generation catalyst G2, toluene, 90 °C, 20 h, 35%; (iii) TFA, CH2Cl2, rt, 1 h, 95%; (iv) crotonic acid, DIC, DMAP (cat), 0 °C, 12 h,
80%; (v) TiCl4, CH2Cl2, 0 °C, 0.5 h, 90%.
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THF afforded primary alcohol 21. Compound 21 was
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with Ph3P@CH2 in ether gave alkene ester 22. Finally,
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´
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Condensation of fragments 7 and 8 was achieved under
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(Scheme 4). The crucial ring closing metathesis of 6 using
Grubbs’ 1st generation catalyst failed under various
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14
deprotection of the PMB group with TFA in CH2Cl2
furnished alcohol 5. Finally, acylation of 5 with crotonic
acid gave ester 24, which on debenzylation with TiCl4
afforded aspinolide B (1).15,16 The spectroscopic and
analytical data of compound 5 and other compounds
were in good agreement with the literature data.2,7
´
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In conclusion, we have achieved the highly convergent
stereoselective total synthesis of aspinolide B from the
commercially available, cheap starting material D-man-
nitol, using ring-closing metathesis as a key step. The
synthesis of other natural products of this family and
their analogues are underway and will be reported in
due course.
Acc. Chem. Res. 2001, 34, 18–19; (f) Furstner, A. Angew.
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´
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Acknowledgements
R.V.R. is thankful to CSIR, New Delhi, for a research
fellowship. We are also thankful to Dr. T. K. Chakr-
aborty, Dr. A. C. Kunwar and the Director, IICT for
their support and encouragement.
´
2005, 61, 4427–4436;; (g) Garcıa-Fortanet, J.; Murga, J.;
Falomir, E.; Carda, M.; Marco, J. A. J. Org. Chem. 2005,
70, 9822–9827; (h) Sharma, G. V. M.; Cherukupalli, G. R.
Tetrahedron: Asymmetry 2006, 17, 1081–1088; (i) Prasad,
K. R.; Penchalaiah, K.; Choudhary, A.; Anbarasan, P.
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¨
1. For a review on synthetic, biosynthetic, and pharmaco-
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6940
S. Ghosh, R. V. Rao / Tetrahedron Letters 48 (2007) 6937–6940
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127.1, 122.3, 83.8, 78.9, 76.2, 72.1, 70.8, 70.6, 33.8, 25.2,
17.9, 16.9; MS (LCMS): m/z: 487.2 [M+Na]+; HRMS
(ESI) calcd for C28H32O6Na[M + Na]+ 487.2096. Found:
487.2082.
11. Wiggins, L. J. Chem. Soc. 1946, 13–14.
12. Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737–738.
13. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
14. Yan, L.; Kahne, D. Synlett 1995, 523–524.
16. Analytical and spectral data of aspinolide B (1): mp: 98–
27
99 °C (reported 102–103)7 ½aꢁD ꢀ43.1 (c 0.5, MeOH),
reported ꢀ43.1 (c 1, MeOH);7 1H NMR (300 MHz,
CDCl3): d 7.01 (dq, 1H, J = 15.8, 6.8 Hz), 5.85 (dq, 1H,
J = 15.1, 1.5 Hz), 5.68 (dd, 1H, J = 15.8, 2.2 Hz), 5.57
(ddd, 1H, J = 15.8, 8.3, 2.2 Hz), 5.09 (dq, 1H, J = 9.1,
6.0 Hz), 4.95 (dd, 1H, J = 9.1, 7.6 Hz), 4.52 (br m, 1H),
3.64 (td, 1H, J = 10.6, 2.2 Hz), 2.51–2.46 (m, 1H), 2.36–
2.22 (m, 2H), 1.89 (dd, 3H, J = 6.8, 2.2 Hz), 1.81–1.71 (m,
1H), 1.32 (d, 3H, J = 6.8 Hz); 13C NMR (CDCl3,
150 MHz) d 175.6, 165.6, 146.2, 131.3, 127.5, 121.9, 78.6,
75.1, 72.7, 71.8, 32.5, 27.1, 18.2, 16.7; MS (LCMS): m/z:
307.1 [M+Na]+; HRMS (ESI) calcd for C14H20O6Na-
[M+Na]+ 307.1157. Found: 307.1147.
27
15. Analytical and spectral data of 24: mp: 95–96 °C; ½aꢁD
ꢀ60.5 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.34–
7.14 (m, 10H, Ar–H), 6.93 (dq, 1H, J = 15.5, 6.8 Hz), 5.78
(dq, 1H, J = 15.5, 1.7 Hz), 5.59 (ddd, 1H, J = 15.6, 8.5,
2.1 Hz), 5.39 (dd, 1H, J = 15.6, 2.1 Hz), 5.05–4.87 (m,
2H), 4.64 (q, 2H, J = 12.6), 4.39 (q, 2H, J = 12.4 Hz), 4.33
(m, 1H), 3.25 (td, 1H, J = 10.4, 1.5 Hz), 2.64–2.41 (m,
2H), 2.1–1.88 (m, 2H), 1.81 (dd, 3H, J = 6.8, 1.7 Hz), 1.22
(d, 3H, J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz) d 175.1,
165.5, 146.5, 138.9, 138.2, 131.2, 128.3, 128.1, 127.5, 127.3,