First asymmetric total synthesis of aspinolide A

Article abstract of DOI:10.1016/j.tetlet.2009.09.151

The first total synthesis of aspinolide A has been achieved using ring-closing metathesis as a key step. The stereogenic centers were generated by means of hydrolytic kinetic resolution (HKR) of racemic epoxides.

Full text of DOI:10.1016/j.tetlet.2009.09.151

Tetrahedron Letters 50 (2009) 7018–7020
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First asymmetric total synthesis of aspinolide A
*
Partha Sarathi Chowdhury, Priti Gupta, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of aspinolide A has been achieved using ring-closing metathesis as a key step. The
stereogenic centers were generated by means of hydrolytic kinetic resolution (HKR) of racemic epoxides.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 September 2009
Revised 24 September 2009
Accepted 28 September 2009
Available online 1 October 2009
Keywords:
Decanolides
Hydrolytic kinetic resolution
Ring-closing metathesis
Epoxides
Medium-sized-ring systems, those containing 8–11 atoms in
the ring1,2 are a subject of continuous interest to organic chemists,
as they form the core of many bioactive natural products. Aspino-
lide A 1a, a decanolide, was isolated in 1997 from the cultures of
Aspergillus ochraceus3 along with aspinolide B 1b and aspinolide
C 1c (Fig. 1). The (R)-configuration of the secondary alcohol was as-
signed by applying the Helmchen method,4 while the (R)-configu-
ration of C-9 is assumed by analogy with aspinolide B.
using (R,R)-salen-Co-OAc catalyst to give (R)-propylene oxide (R)-
2 as a single isomer, which was easily isolated from the diol 3 by
O
O
O
HO
HO
HO
O
O
O
O
O
O
OH
As a part of our research program aimed at developing enantio-
selective synthesis of biologically active natural products based on
hydrolytic kinetic resolution (HKR),5 we became interested in
devising a simple and concise route to aspinolide A. Herein, we re-
port our successful endeavor toward the first total synthesis of 1a
employing HKR6 and ring-closing metathesis (RCM)7 as key steps.
The HKR method involves the readily accessible cobalt-based
chiral salen complex as a catalyst and water to resolve a racemic
epoxide into an enantiomerically enriched epoxide and diol, which
serve as a useful precursor in the synthesis of various compounds
of biological importance.8
Our retrosynthetic analysis for the synthesis of aspinolide A 1a
is based on the convergent approach as outlined in Scheme 1. We
envisioned that the ring-closing could be effected by ring-closing
metathesis of diene 14. Diene 14 could be prepared by EDCI cou-
pling of the alcohol 4 and acid 12. Alcohol 4 could be obtained from
rac-propylene oxide 2 via HKR, while acid fragment could be pre-
pared from 1,5-pentane diol 5.
O
O
Aspinolide C 1c
Aspinolide A 1a
Aspinolide B 1b
Figure 1. Aspinolides (A–C).
O
O
O
O
OH
OH
1a
14
OH
O
OTBS
+
HO
4
12
5
Thus, as shown in Scheme 2, commercially available propylene
oxide 2 was subjected to Jacobsen’s hydrolytic kinetic resolution
O
HO
OH
2
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
Scheme 1. Retrosynthetic analysis of aspinolide A.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.151

P. S. Chowdhury et al. / Tetrahedron Letters 50 (2009) 7018–7020
7019
OH
a
O
OTBS
3
O
OH
OTBS
O
a
+
OH
HOOC
+
O
(R)-2
2
3
3
4
12
OH
b
O
13
O
OH
3
O
(R)-2
4
O
c
b
O
Scheme 2. Reagents and conditions: (a) (R,R)-salen-Co-(OAc) (0.5 mol %), distd H2O
(0.55 equiv), 0 °C, 14 h, (45% for (R)-2, 43% for 3); and (b) vinylmagnesium bromide
THF, CuI, ꢁ20 °C, 88%, 12 h.
14
1a
OH
Scheme 4. Reagents and conditions: (a) EDClꢂHCl, DMAP, CH2Cl2, 0 °C, 5 h, 86%; (b)
distillation.6b (R)-Propylene oxide was treated with vinylmagne-
sium bromide in the presence of cuprous iodide to give the re-
quired homoallylic alcohol 4 in 88% yield.5e
TBAF, THF, 7 h, 80%; and (c) (PCy3)2 Ru(Cl)2@CH–Ph (20 mol %), CH2Cl2, reflux, 42 h,
60%.
The synthesis of acid fragment 12 started from commercially
available 1,5-pentanediol 5 as illustrated in Scheme 3. Thus selec-
tive monoprotection of 5 with p-methoxybenzyl bromide gave
PMB ether 6, which was subjected to Swern oxidation9 followed
by Corey–Chaykovsky reaction10 with dimethylsulfoxonium
methylide to afford the racemic epoxide 7 in 70% yield. Compound
7 was subjected to Jacobsen’s hydrolytic kinetic resolution using
(R,R)-salen-Co-OAc catalyst to give (R)-epoxide (R)-7 in >99%
ee,11 which was easily separated from the (S)-diol 8 by column
chromatography. Epoxide (R)-7 on reaction with dimethylsulfo-
nium methylide12 afforded the required allylic alcohol 9 in 72%
yield. Protection of hydroxy group of 9 as TBS ether followed by
deprotection of PMB group13 by DDQ gave the primary alcohol
11 in 92% yield. The alcohol 11 was oxidized to aldehyde using
IBX followed by subsequent oxidation using NaClO2 to give the re-
quired acid fragment 1214 in 76% yield.
nolide A is identical (IR, 1H NMR, 13C NMR) with the natural prod-
uct and also has an optical rotation (½a D25
ꢁ41.6 (c 0.25, MeOH))
ꢀ
which is in good agreement with the literature value [½a D23
ꢁ43.8
ꢀ
(c 0.3, MeOH)].3 Thus, the absolute stereochemistry of aspinolide
1a was established as 5R and 9R (Scheme 4).
In conclusion, a convergent and efficient first total synthesis of
aspinolide A, with high enantioselectivities has been accomplished
and its absolute stereochemistry has been fixed. The stereocenters
were generated by means of Jacobsen’s hydrolytic kinetic resolu-
tion and cyclization was achieved by ring-closing metathesis. This
approach could be used for the synthesis of other members of aspi-
nolide family for structure–activity relationship. Currently work is
in progress in this direction.
Acknowledgments
With substantial amount of both the fragments in hand the cou-
pling of alcohol 4 and acid 12 was achieved by using EDCI to afford
diene 1315 in 86% yield. Ring-closing metathesis of 13 under vari-
ous conditions using Grubbs’ 1st and 2nd generation catalyst failed
to provide the required 10-membered lactone. In order to circum-
vent the problem, we thought it appropriate to first deprotect the
TBS group and then use the ring-closing metathesis for macrocyc-
lization. Thus the TBS group of diene 13 was deprotected to get the
alcohol 1416 which on ring-closing metathesis by using Grubb’s
first generation catalyst under high dilution conditions furnished
a 10:1 (E/Z) mixture, which on chromatographic purification gave
the target molecule 1a17 in 60% yield. The prepared synthetic aspi-
P.S.C. and P.G. thank CSIR, New Delhi for the award of Senior Re-
search Fellowship and Research Associateship, respectively.
References and notes
1. Back, T. G. Tetrahedron 1977, 33, 3041–3059.
2. Roxburgh, C. J. Tetrahedron 1993, 49, 10749–10784.
3. Fuchser, J.; Zeeck, A. Liebigs Ann. Recl. 1997, 87–95.
4. Helmchen, G. Tetrahedron Lett. 1984, 16, 1527–1530.
5. (a) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 849–851; (b)
Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2005, 46, 6571–6573; (c)
Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2005, 46, 6625–6627; (d) Kumar, P.;
Naidu, S. V. J. Org. Chem. 2006, 71, 3935–3941; (e) Kumar, P.; Gupta, P.; Naidu,
S. V. Chem. Eur. J. 2006, 12, 1397–1402; (f) Pandey, S. K.; Kumar, P. Synlett 2007,
2894–2896; (g) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2007, 48, 3793–3796;
(h) Gupta, P.; Kumar, P. Eur. J. Org. Chem. 2008, 1195–1202; (i) Pandey, S. K.;
Pandey, M.; Kumar, P. Tetrahedron Lett. 2008, 49, 3297–3299.
6. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277,
936–938; (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K.
B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–
1315.
7. For reviews on ring-closing metathesis see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450; (b) Prunet, J. Angew. Chem., Int. Ed. 2003, 42,
2826–2830.
8. For various application of HKR in synthesis of bioactive compounds, see
review: (a) Kumar, P.; Naidu, S. V.; Gupta, P. Tetrahedron 2007, 63, 2745–2785.
account; (b) Kumar, P.; Gupta, P. Synlett 2009, 1367–1382.
O
a
b
HO
OH
PMBO
OH
PMBO
OH
3
3
3
6
5
7
O
3
c
OH
PMBO
PMBO
3
8
(R)-7
OH
OTBS
d
9. For reviews on the Swern oxidation, see: (a) Tidwell, T. T. Synthesis 1990, 857–
870; (b) Tidwell, T. T. Org. React. 1990, 39, 297–572.
10. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–1364.
11. The enantiomeric excess was determined by converting homoallylic alcohol 9
into its Mösher ester and analyzing the F19 spectrum.
e
O
PMBO
PMBO
f
PMBO
3
3
3
10
9
(R)-7
12. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Dong-Soo, S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452.
OTBS
g
OTBS
HOOC
13. Ulrike, K.; Schmidt, R. R. Synthesis 1985, 1060–1061.
HO
14. Spectral data of 12: ½a D25
ꢀ
ꢁ6.56 (c 1.15, CHCl3), IR (CHCl3):
m 3442, 2930, 2858,
3
3
11
12
1713, 1463, 1254, 1087, 923 cmꢁ1
;
1H NMR (CDCl3, 200 MHz): 5.86–5.72 (m,
1H), 5.18–5.00 (m, 2H), 4.15–4.06 (m, 1H), 2.36 (t, J = 7.5 Hz, 2H), 1.76–1.63 (m,
2H), 1.60–1.46 (m, 2H), 0.88 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3,
50 MHz): d 179.9, 141.3, 114.0, 73.4, 37.2, 34.0, 29.7, 25.8, 20.3, 18.2, ꢁ4.4,
ꢁ4.9; Anal. Calcd for C13H26O3Si (258.429): C, 60.42; H, 10.14. Found: C, 60.28;
H, 10.31.
Scheme 3. Reagents and conditions: (a) PMBBr, NaH, THF, 0 °C to rt, 6 h, 92%; (b) (i)
(COCl)2, DMSO, ꢁ78 °C to ꢁ60 °C, Et3N, CH2Cl2, (ii) (CH3)3S(O)I, NaH, DMSO, 60 °C,
1.5 h, 70%; (c) (R,R)-salen-Co-(OAc) (0.5 mol %), distd H2O (0.55 equiv), 0 °C, 22 h,
(44% for (R)-7, 45% for 8); (d) (CH3)3SI, 2 h, n-BuLi, THF, 72%; (e) TBDMSCl,
imidazole, CH2Cl2, 0 °C to rt, 93%; (f) DDQ, CH2Cl2/H2O (1:1), rt, 1 h, 92%; and (g) (i)
IBX, EtOAc, reflux, and (ii) NaClO2, NaH2PO4, DMSO, overnight, 76% from two steps.
15. Spectral data of 13: ½a D25
ꢀ
ꢁ14.9 (c 0.50, CHCl3), IR (CHCl3):
m 2931, 2864, 1732,
1655, 1466, 1425, 1218, 1170, 781 cmꢁ1
;
1H NMR (CDCl3, 200 MHz): 5.83–5.70

7020
P. S. Chowdhury et al. / Tetrahedron Letters 50 (2009) 7018–7020
(m, 2H), 5.17–5.02 (m, 4H), 5.0–4.93 (m, 1H), 4.12–4.08 (m, 1H), 2.28 (t,
J = 6.31, 3H); 13C NMR (CDCl3, 50 MHz): d 173.1, 140.9, 136.1, 117.7, 116.9, 72.7,
69.9, 40.3, 36.2, 34.2, 20.7, 19.5; Anal. Calcd for C12H20O3(212.285): C, 67.89; H,
9.5. Found: C, 67.77; H, 9.23.
J = 7.5 Hz, 2H), 1.72–1.47 (m, 6H), 1.21 (d, J = 6.53 Hz, 3H), 0.09 (s, 9H), 0.06 (s,
3H), 0.03 (s, 3H); 13C NMR (CDCl3, 50 MHz): d 173.1, 141.4, 133.7, 117.6, 113.8,
73.5, 69.7, 40.3, 37.3, 34.6, 25.9, 20.8, 19.5, 18.2, ꢁ4.4, ꢁ4.9; Anal. Calcd for
C18H34O3Si (326.546): C, 66.21; H, 10.49. Found: C, 66.45; H, 10.22.
17. Spectral data of 1a: ½a D25
ꢀ
ꢁ41.6 (c 0.25, MeOH), IR (CHCl3):
m 3435, 2925, 2854,
1729, 1462, 1275, 1073, 971 cmꢁ1
;
1H NMR (CDCl3, 200 MHz): d 5.5 (ddd,
16. Spectral data of 14 : ½a D25
ꢀ
ꢁ10.2 (c 0.3, CHCl3), IR (CHCl3):
m
3438, 2933, 1731,
J = 15.6, 10.3, 4.5, 1H), 5.30 (dd, J = 15.6, 9.5, 1H), 5.05–4.8 (m, 1H), 4.03–3.98
(m, 1H), 2.46–2.41 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.92–1.85 (m, 2H), 1.72–1.5
(m, 2H), 1.23 (d, J = 6.27, 3H); 13C NMR (CDCl3, 50 MHz): d 174.6, 137.23, 131.5,
74.4, 71.6, 42.0, 38.7, 35.5, 22.9, 19.1.
1645, 1424, 1380, 1245, 1061; 1H NMR (CDCl3, 200 MHz): d 5.95–5.65 (m, 2H),
5.27–5.04 (m, 4H), 5.02–4.93 (m, 1H), 4.16–4.07 (m, 1H), 2.64–2.45 (m, 1H), 2.32
(t, J = 7.3 Hz, 2H), 2.27–2.17 (m, 1H), 1.78–1.67 (m, 2H), 1.61–1.5 (m, 2H), 1.20 (d,