Total synthesis of (-)-clavosolide A

Article abstract of DOI:10.1016/j.tetlet.2006.08.055

The total synthesis of (-)-clavosolide A is achieved employing a radical-mediated route to build the substituted tetrahydropyran unit, a Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step.

Full text of DOI:10.1016/j.tetlet.2006.08.055

Tetrahedron Letters 47 (2006) 7435–7438
Total synthesis of (ꢀ)-clavosolide AI
Tushar Kanti Chakraborty,* Vakiti Ramkrishna Reddy and Amit Kumar Chattopadhyay
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 July 2006; revised 11 August 2006; accepted 17 August 2006
Abstract—The total synthesis of (ꢀ)-clavosolide A is achieved employing a radical-mediated route to build the substituted tetra-
hydropyran unit, a Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step.
Ó 2006 Elsevier Ltd. All rights reserved.
Clavosolides A–D were isolated from extracts of the
marine sponge Myriastra clavosa collected in the Philip-
pines.1 The symmetric structure of the 16-membered
core diolide ring in these molecules, with highly substi-
tuted tetrahydropyran units, disubstituted cyclopropyl
rings and permethylated xylose moieties, makes them
synthetically challenging targets.2–6 Syntheses of the
originally assigned structure of clavosolide A by us,2a
and earlier by Willis and co-workers,2b revealed that it
was actually an isomer of the natural product and Willis
and co-workers proposed a revised structure for clavo-
solide A based on NMR and molecular modelling.2b
Subsequently, a total synthesis of the revised structure
for clavosolide A was accomplished by Lee and
co-workers.3 Unfortunately, an error, which has been
corrected recently by Lee and co-workers,4 in the sign
of the optical rotation led them mistakenly to conclude
that the compound synthesized by them was the anti-
pode of the natural product. This error has been re-
vealed by Willis and co-workers,5 as well as by Smith
and Simov,6 who have synthesized the revised structure
and established that this is indeed the naturally occur-
ring (ꢀ)-clavosolide A. The clavosolides represent yet
another example of natural products whose structures
were first wrongly assigned, but corrected later by chem-
ical synthesis.7 In this communication, we describe our
synthesis of (ꢀ)-clavosolide A (1).
us2a applying a methodology developed for the synthesis
of highly substituted tetrahydropyrans by a Ti(III)-med-
iated opening of trisubstituted epoxy alcohols.8
OMe
20'
22'
MeO
OMe
15'
19'
O
O
14'
Me
O
4'
H
12'
Me
H
10'
7'
1'
O
13 H O
9'
9
1
O H 13'
O
7
10
Me
12
H
4
H
O
Me
14
O
O
15
19
MeO
OMe
22
20
OMe
1
Oxidation of 2 was followed by the nucleophilic addi-
tion of the lithium propynilide, generated from propyne
and LDA, to give propargylic alcohols 3 and 4 in an
85% overall yield with the former as the major product,
in a 2:1 ratio.2a The isomers could be separated easily by
standard silica gel column chromatography. Earlier we
carried out the reduction of 3 with Red-Al to provide
the corresponding E-allylic alcohol,2a which was sub-
jected to a modified Simmons–Smith cyclopropanation
reaction9 giving the syn product selectively. However,
the newly assigned structure of clavosolide A has an
anti-relationship between the C9–O and the cyclopro-
pane ring with (9S,10R,11R) and (90S,100R,110R) config-
urations. This necessitated the use of the 9R-
stereoisomer 4 to give the requisite (R,R)-cyclopropane
Our synthesis started with the tetrahydropyranyl chiral
alcohol 2 (Scheme 1), which was synthesized earlier by
Keywords: Clavosolides; Clavosolide A; Epoxide opening; 2-Methyl-
1,3-diol; Diolide.
q IICT Communication No. 060617.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275/
27193108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.055

7436
T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 7435–7438
OTBDPS
OTBDPS
ref. 2a
OTBDPS
OH
Me
Me
Me
BnO
OH
+
BnO
BnO
(2:1)
O
OH
O
O
2
3
4
1. p-nitrobenzoic acid, Ph3P, DEAD
THF, 0 oC to rt, 30 min
2. K2CO3, MeOH, rt, 30 min
92%
OTBDPS
OH
OTBDPS
Et2Zn. CH2I2, CH2Cl2,
Red-Al, Et2O,
0 oC to rt, 3 h
–20oC to 0 oC, 4 h
Me
Me
BnO
OH
4
BnO
96%
82%
O
O
5
6
OTBDPS
OTBDPS
OH
Zn(BH4)2, THF, 0 oC, 8 h
80% from 6
DMP, NaHCO3, CH2Cl2,
0 oC to rt, 20 min
Me
Me
BnO
O
BnO
O
O
7
8
Scheme 1.
ring, since the cyclopropanation reaction is predomi-
nantly syn-selective.10 It was envisaged that inversion
of the C9–OH would re-establish the S-configuration
in the product. In order to generate more of the requisite
propargylic alcohol 4, the major isomer 3 was subjected
to Mitsunobu inversion11 followed by benzoate depro-
tection under basic conditions to provide 4 in an 80%
overall yield from 2.
The final steps of the synthesis are shown in Scheme 2.
Silylation of the hydroxyl group of 8 furnished the
TES-protected intermediate, which was subjected to
benzyl ether deprotection to give the intermediate 9 in
81% yield. Next, a one-carbon extension by an oxida-
tion–olefination sequence furnished 10 in 75% yield.
Hydroboration of 10 gave, exclusively, a primary alco-
hol, which was oxidized to the corresponding acid 11
in two steps and 78% overall yield from 10. Esterifica-
tion of 11 with allyl bromide and K2CO3 followed by
acid-catalyzed desilylation furnished the hydroxy com-
ponent 12, ready to be coupled with acid 11, in 85%
yield. Following the Yamaguchi procedure,14 the mixed
anhydride obtained by reacting 11 with 2,4,6-trichloro-
benzoyl chloride was treated with alcohol 12 in the pres-
ence of DMAP to furnish the fully protected linear
dimer 13 in 85% yield. Acid-catalyzed desilylation of
13 was followed by Pd-catalyzed deallylation to give hy-
droxy acid 14 in 75% yield.
Red-Al reduction of 4 was followed by cyclopropana-
tion of the resulting E-allylic alcohol 5 to give the
expected syn-product 6 as the major isomer (de >96%)
in a 79% yield from 4. The stereochemistry of the major
product was assigned based on earlier reports.10 It now
remained to invert the C9-stereocentre; however,
Mitsunobu reaction failed to provide the inverted prod-
uct. Therefore, an oxidation–reduction sequence was
contemplated as there are many methods known for
diastereoselective hydride reduction of cyclopropyl
ketones.12
The stage was now set to carry out the crucial macro-
lactonization reaction. Following a reverse-addition
protocol, the mixed anhydride from 14 dissolved in tol-
uene, after evaporation of THF under reduced pressure,
was slowly added using a syringe pump over ca. 5 h to a
solution of DMAP in toluene (final concentration
10ꢀ3 M) at 80 °C to furnish the desired dilactone, which
on desilylation using TBAF and a catalytic amount of
acetic acid in THF gave the deprotected diolide aglycon
15 in 71% yield. A small amount of the cyclic tetramer
(in ca. 10:1 ratio) was also formed during the macrolact-
onization step, which could easily be separated by stan-
dard silica gel column chromatography.15 Schmidt
glycosidation16 of 15 with 2,3,4-tri-O-methyl-b-D-xylo-
pyranosyl trichloroacetimidate 1617 following the
Oxidation of 6 with Dess–Martin periodinane (DMP)13
provided the 9-keto intermediate 7, which was subjected
to hydride reduction using various reagents such as
Zn(BH4)2, LAH, LiBH4, NaBH4, DIBAL-H, NaBH4,
CeCl3Æ7H2O and K-Selectride. The highest anti-selectiv-
ity was achieved with Zn(BH4)2 in THF at 0 °C, which
gave the required 9S-isomer 8 as the major product in
a 5:1 ratio and in an 80% overall yield. Surprisingly,
K-Selectride, known to be an excellent anti-selective
reducing reagent for such cyclopropyl ketones,12 gave
exclusively the syn-isomer here, which had misled us ear-
lier to wrongly assign the structure of the resulting prod-
uct while trying to predict the probable stereochemistry
of the natural product.2a

T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 7435–7438
7437
OTBDPS
OTBDPS
OTES
1. DMP, NaHCO3, CH2Cl2,
0 oC to rt, 20 min
1. TESCl, Et3N, DMAP (cat.),
CH2Cl2, 0 oC to rt, 1 h
Me
HO
Me
OTES
8
O
2. Ph3P=CH2, Et2O,
0 oC to rt,1 h
75%
O
2. H2, Pd-C, hexane, rt, 1 h
81%
9
10
1. (cHex)2BH, THF, 0 oC,
1 h, then 30% H2O2, NaOH
2. same as in 6 to 7
OTBDPS
OTBDPS
OTES
1. allyl bromide, K2CO3,
Me
DMF, 0 oC to rt, 30 min
Me
HO2C
O
OH
O
O
3. NaClO2, NaH2PO4.2H2O,
2-methyl-2-butene, t-BuOH,
rt, 1 h
78%
2. CSA, CH2Cl2-MeOH
(4:1), 0 oC, 10 min
85%
O
12
11
OTBDPS
O
2,4,6-trichlorobenzoyl chloride, Et3N, THF,
rt, 3 h, then 12, DMAP, toluene, rt, 1 h
H
R1O
H
H
Me
O
11
85%
O H
O
Me
OR2
O
H
OTBDPS
13: R1 = allyl, R2 = TES
1. CSA, MeOH:CH2Cl2 (1:4), 0 °C, 10 min
2. Pd(PPh3)4, morpholine, THF, rt, 1 h
75%
14: R1 = H, R2 = H
OH
O
H
ref. 2a
H
Me
1
1. 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, 3 h,
the mixed anhydride then added to DMAP, toluene,
10-3 M, 80 oC, 5 h
O
H O
H
O H
O
O
O
CCl3
Me
H
O
NH
OMe
2. TBAF, AcOH (cat), THF, 0 °C to rt, 8 h
71%
MeO
OH
OMe
16
15
Scheme 2.
method reported earlier by us2a furnished the desired
2. For total syntheses of the first reported structure of
clavosolide A see: (a) Chakraborty, T. K.; Reddy, V. R.
Tetrahedron Lett. 2006, 47, 2099–2102; (b) Barry, C. S.;
Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding,
J. R.; Willis, C. L. Chem. Commun. 2005, 5097–5099; For
synthesis of the monomeric unit see: (c) Yakambram, P.;
Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
3781–3783.
b,b-product 1 in a 21% isolated yield along with the
1
unwanted a,a- (21%) and a,b- (43%) isomers. The H
and 13C NMR spectra and optical rotation, [a]D ꢀ42.4
(c 0.125, CHCl3), of our synthetic product 118 matched
with those reported for the natural clavosolide A (liter-
ature [a]D ꢀ48.5 (c 1, CHCl3)).1a
3. Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett.
2006, 8, 661–664.
4. Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett.
2006, 8, 3411.
Acknowledgement
5. Barry, C. S.; Elsworth, J. D.; Seden, P. T.; Bushby, N.;
Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett. 2006,
8, 3319–3322.
V.R.R. and A.K.C. wish to thank CSIR, New Delhi, for
research fellowships.
6. Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315–3318.
7. Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed.
2005, 44, 1012–1044.
References and notes
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7438
T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 7435–7438
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18. Selected physical data of 1: 1H NMR (CDCl3, 500 MHz) d
4.42 (2H, dt, J 9, 1, 9-H, 90-H), 4.26 (2H, d, J 7.5, 15-H
and 150-H), 3.95 (2H, dd, J 11.5, 5, 19-H and 190-H), 3.61
(6H, s, 21-H3 and 210-H3), 3.57 (6H, s, 20-H3 and 200-H3),
3.48–3.43 (4H, m, 3-H and 30-H, 7-H and 70-H), 3.46 (6H,
s, 22-H3 and 220-H3), 3.27–3.21 (4H, m, 18-H and 180-H,
5-H and 50-H), 3.09 (2H, t, J 8, 17-H and 170-H), 3.08 (2H,
dd, J 11.5, 8, 19-H0 and 190-H0), 2.95 (2H, t, J 8, 16-H
and 160-H), 2.54 (2H, dd, J 17, 3.5, 2-H and 20-H), 2.41
(2H, dd, J 17, 6.5, 2-H0 and 20-H0), 2.04 (2H, dd, J 11.5, 5,
6-H and 60-H), 1.88 (2H, dt, J 15.7, 9, 8-H and 80-H), 1.67
(2H, ddd, J 15.7, 2.4, 1, 8-H0 and 80-H0), 1.37 (2H, q,
J 11.5, 6-H0 and 60-H0), 1.37 (2H, m, 4-H and 40-H),
0.96 (12H, d, J 6.5, 12-H3 and 120-H3, 14-H3 and 140-H3),
0.83 (2H, m, 11-H and 110-H), 0.72 (2H, tt, J 9, 5, 10-H
and 100-H), 0.33 (2H, tt, J 8, 5, 13-H and 130-H), 0.22
(2H, tt, J 8, 5, 13-H0 and 130-H0); 13C NMR (CDCl3, 150
MHz) d 171.07, 105.52, 85.52, 83.79, 83.18, 79.33, 77.16,
77.00, 74.81, 63.21, 60.84 (2C), 58.81, 42.49, 41.24,
40.66, 39.17, 24.70, 18.50, 12.60, 11.95, 10.88; HRMS
(ESI) m/z 879.4687 [M+Na]+, C44H72O16Na requires
879.4718.
13. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
14. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
15. (a) Under standard Yamaguchi reaction conditions (Ref.
14), in which DMAP was added to a solution of 14 and
2,4,6-trichlorobenzoyl chloride in toluene, the cyclic
tetramer was formed as the major product; (b) The
hydroxy acid, obtained by selective deprotection of the
C9-OTES of 11, under normal Yamaguchi reaction
conditions gave a mixture of intramolecularly cyclized
monomer, the diolide dimer and also the triolide.