Total synthesis of achaetolide from D-mannitol

Article abstract of DOI:10.1055/s-0030-1259056

A highly convergent stereoselective total synthesis of achaetolide, a ten-membered lactone is described. The ring-closing metathesis reaction was used to construct the macrocycle and E-olefinic moiety in the molecule. The key acid and alcohol fragments we

Full text of DOI:10.1055/s-0030-1259056

3078
LETTER
Total Synthesis of Achaetolide from D-Mannitol
Total
S
ynthesis of
.
A
chaetolide
S
from
D
-Manni
r
tol ipad Rao, Amit Kumar Chattapadhyay, Subhash Ghosh*
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27193108; E-mail: subhash@iict.res.in
Received 4 October 2010
As part of our continuing interest in stereoselective syn-
thesis of naturally occurring ten-membered lactones from
the chiral pool D-mannitol;8 herein, we wish to report a
convergent approach for the total synthesis of achaetolide.
Abstract: A highly convergent stereoselective total synthesis of
achaetolide, a ten-membered lactone is described. The ring-closing
metathesis reaction was used to construct the macrocycle and E-ole-
finic moiety in the molecule. The key acid and alcohol fragments
were synthesized from a single chiral pool material D-mannitol.
Inspection of the structure of achaetolide revealed that the
ten-membered lactone with E-olefinic moiety of the mol-
ecule could be constructed via ring-closing metathesis
reaction of the bisolefinic compound 5, which would be
obtained either through esterification reaction between
the olefinic acid 6 and olefinic alcohol 7 or via Mitsunobu
inversion of the alcohol 8 with the acid 6. Finally, the ole-
finic alcohol fragments 7 and 8 as well as acid fragment 6,
in turn could be obtained from D-mannitol (Scheme 1).
Key words: Achaetominum cristalliferum, Ophiobolus sp., achae-
tolide, D-mannitol, ring-closing metathesis
Due to their important biological activities and interesting
structure, naturally occurring ten-membered lactones
have attracted considerable attention of the synthetic or-
ganic chemists as well biologists.1 Representative exam-
ples of this class of molecules are achaetolide,2 aspinolide
B,3 microcarpalide,4 and lethaloxin5 (Figure 1). Achae-
tolide was initially isolated by Bodo et al. in 19832a from
the cultures of Achaetominum cristalliferum. In 2009, the
same compound was isolated by Tanaka and co-workers
from a fermentation broth of Ophiobolus sp.2b The abso-
lute stereochemistry of the molecule was established by
O
O
O
O
R1O
OR1
HO
OH
R1O
OH
5
achaetolide (1)
R1 = PMB
I
detailed H NMR studies as well as by Mosher method.6
The unknown biological activity along with interesting
structural features, have attracted considerable attention
from synthetic organic chemists, and as a result three syn-
theses have appeared in the literature.7
OR1
OH
1
6
4
+
OR1
O
2
OR1 R2
R
R
1 = PMB
1 = PMB
OH
6
7 R2 = C6OH(β)
O
O
OH
8 R2 = C6OH(α)
O
D-mannitol
O
O
O
Scheme 1 Retrosynthetic analysis
HO
OH
OH
achaetolide (1)
aspinolide B (2)
Thus our synthesis started from the known compound 9
(Scheme 2), which was prepared from D-mannitol accord-
ing to the reported procedure.9 PMB protection of the sec-
ondary alcohol and separation of the minor isomer via
standard silica gel column chromatography gave the pure
stereoisomer 10, in good yield. Dihydroxylation of the
olefinic compound 10 gave a diol compound, which on
oxidative cleavage with NaIO4 followed by NaBH4 reduc-
tion of the resultant aldehyde afforded the primary alcohol
11 in 55% yield over three steps. TBDPS protection of the
primary alcohol followed by acetonide deprotection fur-
nished diol compound 13 in 72% yield over two steps.
The diol compound 13 was converted to the epoxide 14 in
two steps in good yield. The epoxide was then opened
with Me3SI–n-BuLi10 to give a secondary allylic alcohol,
which was protected as its PMB ether to give the fully pro-
tected olefinic compound 15. TBDPS deprotection of 15
OH
HO
HO
OH
O
O
O
O
O
O
OH
microcarpalide (3)
(+)-lethaloxin (4)
Figure 1
SYNLETT 2010, No. 20, pp 3078–3080
Advanced online publication: 19.11.2010
DOI: 10.1055/s-0030-1259056; Art ID: G30310ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Achaetolide from D-Mannitol
3079
gave primary alcohol, which on oxidation followed by were analyzed and the DSR = (dS – dR) value was calculated
Grignard (heptyl magnesium bromide) addition afforded for all possible detectable protons and arranged in accor-
an inseparable mixture of compounds 7 and 8 (1.5:1). dance with the rule.11 The protons on the left side of the
However diastereomerically pure alcohols 7 and 8 were C6 stereocenter showed negative Dd values, and hence
obtained via their acetate protection, chromatographic were assigned as 6R, as per the proposed rule (Figure 2).
separation through silica gel and acetate deprotection.
OMe
O
–0.01
O
ref. 9
–0.02
i
D-mannitol
O
O
OH
–0.02
–0.11
0
0
0
–0.06
O
+0.01
9 (9:1)
0
0
0
O
O
ii
O
MTPA
iii
O
OH
–0.03
OPMB
11
OPMB
10
–0.01
MeO
O
OH
7a: (R)-MTPA
7b: (S)-MTPA
O
OTBDPS
iv
HO
OTBDPS
Figure 2
OPMB
OPMB
13
12
For the synthesis of acid fragment, we started with the diol
compound 13 (Scheme 3), which on treatment with TPP,
iodine and imidazole gave the olefinic compound 19 in
72% yield.12 TBDPS deprotection of 19 gave primary al-
cohol 20, which on two-step oxidation13 provided the ole-
finic acid fragment 6.
v
OPMB
O
vi
OTBDPS
OTBDPS
OPMB
OPMB
14
15
vii
OH
OPMB
OTBDPS
OPMB
O
HO
OTBDPS
viii
OH
i
OPMB
OPMB
OPMB
19
R
13
16
PMB
7: R = OH(β)
8: R = OH(α)
ii
OH
iii
6
OPMB
OPMB
20
ix
O
R
Scheme 3 Reagents and conditions: (i) I2, TPP, imidazole, toluene,
60 °C, 15 min, 80%; (ii) TBAF, THF, 0 °C to r.t., 3 h, 90%; (iii) (a)
DMP, NaHCO3, CH2Cl2, 0 °C to r.t., 1 h; (b) NaClO2, NaH2PO4, t-
BuOH, H2O, 2-methyl-2-butene, 0 °C to r.t., 1 h, 85% (over 2 steps).
PMB
17: R = OAc(β)
18: R = OAc(α)
x
x
7: R = OH(β)
8: R = OH(α)
Now esterification reaction between 6 and 7 using DCC
and DMAP (cat.) in CH2Cl2 gave the bisolefinic com-
pound 5,14a which was also obtained via Mitsunobu
inversion15 of the alcohol 8 with the acid 6 (Scheme 4).
The stage was set for the crucial ring-closing metathesis.
Accordingly compound 5 was subjected to the ring-
closing metathesis reaction16 with Grubbs 2nd generation
catalyst in refluxing toluene affording compound 21 as a
mixture of conformers (1:1) with exclusive E geometry.17
Finally global deprotection of PMB groups with TFA in
CH2Cl2 afforded achaetolide as a white solid [(mixture of
conformers (9:1)] in 80% yield, whose analytical data (1H
NMR and 13CNMR)14b and specific rotation {synthetic
[a]D25 –22 (c = 0.1, MeOH), reported [a]D25 –27 (c = 0.52,
Scheme 2 Reagents and conditions: (i) PMBCl, NaH, TBAI, THF,
0 °C to r.t., 2 h, 85%; (ii) (a) OsO4, NMO, THF–H2O, 0 °C to r.t.,
overnight, 80%; (b) NaIO4, NaBH4, MeOH–H2O, 1 h, 80%; (iii)
TBDPSCl, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 4 h, 90%; (iv) PTSA,
MeOH, 15 min, r.t., 80%; (v) (a) TsCl, Et3N, DMAP, CH2Cl2, 0 °C to
r.t., 1 h; (b) K2CO3, MeOH, r.t., 5 h, 70% (over 2 steps); (vi) (a)
Me3SI, n-BuLi, THF, –20 °C to r.t., 2 h; (b) PMBCl, NaH, TBAI,
THF, 0 °C to r.t., 2 h, 80% (over 2 steps); (vii) TBAF, THF, 0 °C to
r.t., 3 h, 87%; (viii) (a) DMP, NaHCO3, CH2Cl2, 0 °C to r.t.; (b) heptyl
magnesium bromide, Et2O, 0 °C to r.t., 30 min, 78%(over 2 steps);
(ix) Ac2O, Et3N, CH2Cl2, DMAP, 0 °C to r.t., 2 h; (x) K2CO3, MeOH,
0 °C to r.t., 5 h, 54%; (7), 36% (8) over two steps.
To establish the absolute stereochemistry of C6-OH, both
(R)- and (S)-MTPA esters (7a, 7b) of the major isomer 7
1
were synthesized. The H NMR data of both the esters
Synlett 2010, No. 20, 3078–3080 © Thieme Stuttgart · New York

3080
K. S. Rao et al.
LETTER
(7) (a) Chandrasekhar, S.; Balaji, S. V.; Rajesh, G. Tetrahedron
Lett. 2010, 51, 5164. (b) Das, T.; Rajib, B.; Samik, N.
Tetrahedron: Asymmetry 2010, 21, 2206. (c) Srihari, P.;
Kumaraswamy, B.; Sankar, P.; Ravishashidhar, V.; Yadav,
J. S. Tetrahedron Lett. 2010, 51, 6174.
(8) (a) Ghosh, S.; Rao, R. V.; Shashidhar, J. Tetrahedron Lett.
2005, 46, 5479. (b) Ghosh, S.; Rao, R. V. Tetrahedron Lett.
2007, 48, 6937.
MeOH)} were in good agreement with the literature val-
ues.2a
O
7, i
6
iii
OPMB
O
PMBO
PMBO
6
(9) (a) Mulzer, J.; Angermann, A.; Münch, W. Liebigs Ann.
Chem. 1986, 825. (b) Chattopadhyay, A. J. Org. Chem.
1996, 61, 6104.
8, ii
5
(10) Alcarez, L.; Hamett, J. J.; Mioskowski, C.; Martel, J. P.;
Le Gall, T.; Shin, D.-S.; Falck, R. J. Tetrahedron Lett. 1994,
35, 5449.
(11) Dale, J. A.; Mosher, S. H. J. Am. Chem. Soc. 1973, 95, 512.
(12) Garegg, P. G.; Samuelson, B. Synthesis 1979, 813.
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Balkrishna, S. B.; Childers, W. B.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091.
O
O
iv
O
O
HO
OH
PMBO
OPMB
OH
OPMB
(14) (a) Analytical data for 5: [a]25D –30.3 (c = 0.82, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.24–7.30 (m, 4 H), 7.19
(d, J = 8.4 Hz, 2 H), 6.84–6.90 (m, 4 H), 6.78 (d, J = 8.4 Hz,
2 H), 5.73–5.86 (m, 2 H), 5.23–5.36 (m, 5 H), 4.59 (d, J =
11.7 Hz, 1 H), 4.49 (d, J = 10.95 Hz, 1 H), 4.47 (d, J = 10.0
Hz, 1 H), 4.25–4.37 (m, 4 H), 3.82 (m, 1 H), 3.81 (s, 3 H),
3.80 (s, 3 H), 3.75 (s, 3 H), 3.48 (m, 1 H), 2.67 (dd, J = 15.3,
8.1 Hz, 1 H), 2.48 (dd, J = 15.3, 5.3 Hz, 1 H), 1.65–1.74 (m,
3 H), 1.45–1.56 (m, 2 H), 1.21–1.30 (br s, 9 H), 0.88 (t, J =
6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 170.6, 159.2,
159.1, 137.5, 135.8, 130.9, 130.7, 130.4, 130.0, 129.3,
118.9, 118.1, 113.7, 81.1, 78.0, 77.5, 76.9, 72.9, 71.6, 70.2,
70.1, 55.3, 41.3, 35.9, 35.2, 31.8, 29.6, 29.2, 25.2, 22.7, 14.1.
IR: 2926, 2858, 1730, 1512, 1246, 1034 cm–1. MS (ESI): m/
z = 711 [M + Na]+. HRMS (ESI): m/z [M + Na]+ calcd for
C42H56O8Na: 711.3872; found: 711.3884. (b) Analytical
data of achaetolide (1): mp 122–124 °C; [a]25D –22 (c = 0.1,
MeOH); {lit.2a [a]25D –27 (c = 0.52, MeOH)}. 1H NMR (300
MHz, CDCl3): d = 6.02 (ddd, J = 15.8, 3.02, 2.26 Hz, 1 H),
5.68 (dd, J = 15.8, 2.3 Hz, 1 H), 4.82 (q, J = 6.8 Hz, 1 H),
4.75 (m, 1 H), 4.57 (m, 1 H), 3.77 (d, J = 9.8 Hz, 1 H), 2.62
(dd, J = 12.1, 3.0 Hz, 1 H), 2.57 (dd, J = 12.1, 3.7 Hz, 1 H),
2.34 (ddd, J = 15.1, 10.5, 8.3 Hz, 1 H), 2.17 (br s, 2 H, OH),
2.03 (br s, 1 H, OH), 1.53–1.68 (m, 2 H), 1.48 (d, J = 15.8
Hz, 1 H), 1.21–1.31 (m, 10 H), 0.87 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.0, 130.8, 125.1, 75.3,
73.2, 67.1, 43.8, 36.9, 36.8, 31.7, 29.6, 29.3, 29.1, 24.9, 22.6,
14.0. IR: 2923, 2854, 1739, 1709, 1647, 1513, 1372, 1171
cm–1. MS (ESI): m/z = 323 [M + Na]+.
1
21
Scheme 4 Reagents and conditions: (i) DCC, DMAP, CH2Cl2, 0 °C
to r.t., overnight, 70%; (ii) TPP, DEAD, benzene, 0 °C to r.t., 1 h,
75%; (iii) Grubbs 2nd generation catalyst (10 mol%), toluene, 110 °C,
24 h, 45% (80% based on recovered starting material); (iv) TFA,
CH2Cl2, 0 °C to r.t., 0.5 h, 80%.
In conclusion we have achieved the total synthesis of
achaetolide starting from a single chiral pool material D-
mannitol using ring-closing metathesis as a key step. The
synthesis of its analogues and their biological screening is
under progress, which will be reported in due course.
Acknowledgment
We are thankful to DST, New Delhi, India for financial support
(S.G.) and CSIR, New Delhi, India, (K.S.R. and A.K.C.) for re-
search fellowships.
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(15) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.;
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