Studies directed towards the total synthesis of clavosolides: Synthesis of an isomer of clavosolide A

Article abstract of DOI:10.1016/j.tetlet.2006.01.130

The total synthesis of clavosolide A, employing a radical-mediated route to build its substituted tetrahydropyran unit, a Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step, revealed that the report

Full text of DOI:10.1016/j.tetlet.2006.01.130

Tetrahedron Letters 47 (2006) 2099–2102
Studies directed towards the total synthesis
of clavosolides: synthesis of an isomer of clavosolide Aq
Tushar Kanti Chakraborty* and Vakiti Ramkrishna Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 14 December 2005; revised 17 January 2006; accepted 26 January 2006
Available online 13 February 2006
Abstract—The total synthesis of clavosolide A, employing a radical-mediated route to build its substituted tetrahydropyran unit, a
Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step, revealed that the
reported structure is an isomer of the natural product.
Ó 2006 Elsevier Ltd. All rights reserved.
The unusual, novel 16-membered diolides, clavosolides
A–D were isolated from extracts of the marine sponge
Myriastra clavosa collected in the Philippines.1 The sym-
metric structure of the 16-membered core diolide ring in
these molecules, with highly substituted tetrahydropy-
ran units, disubstituted cyclopropyl rings and permethyl-
ated D-xylose moieties, makes them synthetically
challenging targets. In this letter, we describe the total
synthesis of the reported structure of clavosolide A (1).
However, the spectral data of the synthetic product
did not match those reported for the natural product.
While we were attempting the synthesis of the correct
diastereomer, Willis and co-workers reported their syn-
thesis of the same isomer that we had prepared in our
first attempt.2 This prompted us to communicate our
preliminary results at this stage.
OMe
20'
MeO
22'
OMe
15'
19'
O
O
14'
Me
O
4'
H
12'
Me
H
10'
9'
O H 13'
1'
7'
O
13 H O
9
1
O
7
10
Me
12
H
4
H
O
Me
14
O
O
19
15
MeO
OMe
20
22
OMe
1
(an isomer of clavosolide A)
[the reported structure (ref. 1)]
The salient feature of our synthesis is the application of
a methodology that we developed recently for the syn-
thesis of highly substituted tetrahydropyrans from a
polyketide-based building block containing a 2-methyl-
1,3-diol moiety,3 which in turn was prepared by a
Ti(III)-mediated opening of a trisubstituted epoxy alco-
hol.4 The Yamaguchi method5 was utilized to cyclodi-
merize the intermediate hydroxyl acid unit in a
stepwise fashion to build the symmetric 16-membered
dilactone framework and, for attaching the sugar units
to the aglycon, the Schmidt glycosidation method6 was
employed.
Our synthesis started with the suitably protected inter-
mediate 2 (Scheme 1), which was synthesized earlier
by the Ti(III)-mediated opening of a trisubstituted
2,3-epoxy alcohol.7 A three-step process—oxidation,
olefination and reduction—transformed 2 into the allylic
alcohol 3 in 82% overall yield. Sharpless epoxidation8 of
3 with (ꢀ)-DIPT furnished an epoxy alcohol (de >96%)
which was opened selectively using, Red-Al, at the
2-position to give the 1,3-diol 4 in 92% yield. Following
the procedure reported by us earlier,3 compound 4 was
transformed into a tetrahydropyran in three steps—
selective silylation of the primary hydroxyl, mesylation
Keywords: Clavosolides; Clavosolide A; Epoxide opening; 2-Methyl-
1,3-diol; Diolide.
q IICT Communication No. 051018.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/
27160757; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.130

2100
T. K. Chakraborty, V. R. Reddy / Tetrahedron Letters 47 (2006) 2099–2102
reports.12 Deprotection of the benzyl ether of 8 was fol-
Me
Me
OH
lowed by a one-carbon extension by an oxidation–olefi-
nation sequence to furnish 9 in 62% yield. Hydro-
boration of 9 gave a primary alcohol which was oxidized
to the acid 10 in two steps and 67% overall yield from 9.
Esterification of 10 with diazomethane and desilylation
followed by conversion to an allyl ester furnished the
hydroxy component 11, to be coupled with the acid
10, in 70% yield.
OH
BnO
BnO
i
O
O
O
O
3
2
Me
OH
iii
OH
BnO
Me
ii
O
O
OH
BnO
4
O
OH
5
The final steps of the synthesis are shown in Scheme 2.
Following the Yamaguchi procedure,5 the mixed anhy-
dride obtained by reacting 10 with 2,4,6-trichloro-
benzoyl chloride was treated with the alcohol 11 in the
presence of DMAP to furnish the fully protected linear
dimer 12 in 80% yield. Acid-catalyzed desilylation of 12
was followed by Pd-catalyzed deallylation to give the
hydroxyl acid 13 in 72% yield. The stage was now set
to carry out the crucial macrolactonization reaction.
Following a reverse-addition protocol, the mixed anhy-
dride from 13 dissolved in toluene, after evaporation of
THF under reduced pressure, was slowly added using a
syringe pump over ca. 5 h to a solution of DMAP in tol-
uene (final concentration 10ꢀ3 M) at 80 °C to furnish the
desired dilactone 14 in 65% yield. A small amount of the
cyclic tetramer (in ca. 10:1 ratio) was also formed which
could easily be separated by standard silica gel column
chromatography.13 Desilylation of 14 using TBAF and
a catalytic amount of acetic acid in THF gave the depro-
tected diolide aglycon 15 in 85% yield. Glycosidation of
15 using 2,3,4-tri-O-methyl-b-D-xylopyranosyl trichlo-
roacetimidate 1614 furnished, as expected, a mixture of
three products, which could be separated easily to give
OTBDPS
OTBDPS
OH
Me
Me
iv
v
BnO
BnO
O
6
OH
O
7
OTBDPS
OTBDPS
Me
Me
vii
OTES
vi
BnO
OTES
O
O
8
9
OTBDPS
Me
OR2
viii
O
R1O
ix
O
10: R1 = H, R2 = TES
11: R1 = H2C=CH-CH2-, R2 = H
Scheme 1. Synthesis of the protected hydroxyl acids 10 and 11.
Reagents and conditions: (i) (a) (COCl)2, DMSO, Et3N, DCM, ꢀ78 to
0 °C, 1 h; (b) Ph3P@CH–CO2Et, DCM, rt, 4 h; (c) DIBAL-H, DCM,
ꢀ78 °C, 20 min (82% from 2); (ii) (a) D-(ꢀ)-DIPT, Ti(OiPr)4, TBHP,
˚
4 A MS, DCM, ꢀ20 °C, 3 h; (b) Red-Al, THF, ꢀ10 °C, 3 h (92% from
3); (iii) (a) TBDPSCl, Et3N, DMAP (cat), DMF, 0 °C to rt, 5 h; (b)
MsCl, Et3N, DMAP (cat), DCM, 0 °C to rt, 30 min; (c) CSA (cat),
MeOH, rt, 48 h (75% from 4); (iv) (a) TBDPSCl, imidazole, DMAP
(cat), DMF, 0 °C to rt, 24 h; (b) TBAF, THF, 0 °C, 3 h; (v) (a) step
(i)(a); (b) propyne, LDA, THF, ꢀ78 °C (44% from 5); (vi) (a) Red-Al,
Et2O, 0 °C to rt, 2 h; (b) Et2Zn, CH2I2, DCM, ꢀ20 to 0 °C, 4 h; (c)
TESCl, Et3N, DMAP, DCM, 0 °C to rt, 1 h (70% from 7); (vii) (a) H2,
Pd–C, hexane, rt, 1 h; (b) SO3–py, Et3N, DCM, 0 °C to rt, 1 h; (c)
Ph3P@CH2, Et2O, 0 °C to rt, 1 h (62% from 8); (viii) (a) BH3–Me2S,
THF, 0 °C, 30 min, then H2O2, NaOH; (b) step (vii)(b); (c) NaClO2,
NaH2PO4Æ2H2O, 2-methyl-2-butene, t-BuOH, rt, 1 h (67% from 9); (ix)
(a) CH2N2, Et2O, 0 °C, 10 min; (b) CSA, MeOH–DCM (1:4), 0 °C,
10 min; (c) allyl alcohol, K2CO3, rt, 1 h (70% from 10).
OTBDPS
i
O
H
10
11
+
H
R1O
O
O H
O
OR2
O
OTBDPS
12: R1 = allyl, R2 = TES
13: R1 = H, R2 = H
ii
OR
of the secondary hydroxyl and acid-catalyzed deprotec-
tion of the acetonide with concomitant cycloetherifica-
tion via a 6-exo SN2 type ring closure—to furnish 5 in
75% overall yield. Disilylation of 5 followed by selective
deprotection of the primary hydroxyl group furnished
the intermediate 6. Oxidation of 6 was followed by
nucleophilic addition of the lithium propynilide, gener-
ated from propyne and LDA, to give the desired prop-
argylic alcohol 7 with the 9S-stereochemistry as the
major product in 44% overall yield in four steps from
5.9,10 Reduction of 7 with Red-Al provided the E-allylic
alcohol which was subjected to a modified Simmons–
Smith cyclopropanation reaction11 to give, selectively,
the syn product (de >96%). Finally silylation of the hy-
droxyl group furnished the protected intermediate 8 in
70% overall yield for the three steps. The stereochemis-
try of the major product was assigned based on earlier
O
iii
H
H
O
H O
H
v
O H
O
1
H
O
O
O
CCl3
OR
NH
MeO
14: R = TBDPS
OMe
iv
OMe
16
15: R = H
Scheme 2. Synthesis of 1 (the reported structure of clavosolide A).
Reagents and conditions: (i) 10, 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, rt, 3 h, then 11, DMAP, toluene, rt, 1 h (80%); (ii) (a) CSA,
MeOH–DCM (1:4), 0 °C, 10 min; (b) Pd(PPh3)4, morpholine, THF, rt,
1 h (72% from 12); (iii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt,
3 h, the mixed anhydride then added to DMAP, toluene, 10ꢀ3 M,
80 °C, 5 h (65%); (iv) TBAF, AcOH (cat), THF, 0 °C to rt, 8 h (85%);
˚
(v) 16, TMSOTf, DCM, 4 A MS, 0 °C to rt, 2 h (21%).

T. K. Chakraborty, V. R. Reddy / Tetrahedron Letters 47 (2006) 2099–2102
2101
the desired b,b-product 1 in 21% isolated yield along
with the unwanted a,a (21%) and a,b (43%) isomers.
pane ring protons of 19 did not match with those of
either the natural product or 1. The chemical shifts of
the cyclopropane ring protons of 20 were similar to
those of 19. This tempts us to suggest that the natural
product may have an anti-relationship between the
C9–O and the cyclopropane ring, as shown in 18, with
1
13
The H and C NMR spectra of synthetic 115 did not
match those reported for natural clavosolide A,1 but
were found to be identical with those reported for the
recently synthesized diastereomer.2 We believe that
the stereochemistry of the C9 centre, or C10–C11 cyclo-
propyl segment, was probably wrongly assigned since
the discrepancies in the spectra were mainly noticeable
for the cyclopropyl ring protons. This assumption was
further strengthened by 1H NMR analysis of the
model compounds, 17–20.
(9R,10S,11S)-
and
(90R,100S,110S)-configurations.
Efforts are now in progress to synthesize the correct
isomer of the natural product to assign its absolute
stereochemistry unambiguously.
Acknowledgements
Compound 17 was prepared in the same manner as 8,
except that the C9–OH was protected as an acetate.
Swern oxidation of the intermediate with C9–OH was
followed by diastereoselective reduction (K-selectride,
THF, ꢀ78 °C)16 to give exclusively the 9R isomer that
on acylation furnished 18. The minor 9R stereoisomer
obtained during the synthesis of 7 was used to prepare
19 following the same procedure used for the synthesis
of 17 and, once again, the same oxidation–reduction se-
quence described above was used to invert the C9-centre
to furnish the anti product 20. While the patterns of the
chemical shifts of the cyclopropane ring protons of 17
were similar to those of the synthetic product 1
(Fig. 1), those of 18 were similar to those reported for
the natural product,1 albeit with different chemical
shifts. The pattern of the chemical shifts of the cyclopro-
The authors wish to thank CSIR, New Delhi, for a
research fellowship (V.R.R.).
References and notes
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109, 5765–5780.
9. The (9S)-stereochemistry of the major product 7 was
confirmed by preparing the same product in the following
manner.
1. Swern oxidation
2. Ph3P=CHCO2Et
LDA, MeI
(ref.10)
OTBDPS
Me
BnO
7
6
O
3. DIBAL-H
4. Sharpless
O
Cl
epoxidation with (+)-DIPT
5. CCl4, Ph3P, NaHCO3 (cat.)
10. Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M.
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11. (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958,
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mura, J. Tetrahedron 1968, 24, 53–58.
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13. (a) Under standard Yamaguchi reaction conditions (Ref.
5), in which DMAP was added to a solution of 13 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 10, under normal Yamaguchi reaction
Figure 1. Sections of the 1H NMR spectra in CDCl3 (0.85–0.08 ppm)
showing the cyclopropane ring proton signals of 1 (A), natural
clavosolide A (B, reprinted with permission from Ref. 1a, Copyright
2002, American Chemical Society), 17 (C), 18 (D) and 20 (E).

2102
T. K. Chakraborty, V. R. Reddy / Tetrahedron Letters 47 (2006) 2099–2102
conditions, gave a mixture of intramolecularly cyclized
monomer, the diolide dimer 14 and also the triolide.
14. (a) Phelps, F. P.; Purves, C. B. J. Chem. Soc. 1929, 51,
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2.41 (2H, dd, J 17, 6.1, 2-H0 and 20-H0), 2.05 (2H, dd, J
11.5, 5, 6-H and 60-H), 1.92 (2H, dt, J 15.7, 9, 8-H and
80-H), 1.69 (2H, ddd, J 15.7, 2.4, 1, 8-H0 and 80-H0), 1.38
(2H, q, J 11.5, 6-H0 and 60-H0), 1.37 (2H, m, 4-H and 40-H),
1.00 (6H, d, J 6.1, 12-H3 and 120-H3), 0.96 (6H, d, J 6.8,
14-H3 and 140-H3), 0.70 (2H, tt, J 9, 4, 10-H and 100-H),
0.63–0.53 (4H, m, 11-H and 110-H, 13-H and 130-H), 0.22
(2H, tt, J 8, 4, 13-H0 and 130-H0); 13C NMR (CDCl3,
75 MHz): d 171.03, 105.47, 85.65, 83.92, 83.15, 79.50,
77.20, 77.00, 74.78, 63.27, 60.71, 60.70, 58.72, 42.62, 41.79,
40.80, 39.32, 24.95, 18.33, 12.63, 12.34, 10.97; HRMS (ESI)
m/z 879.4761 [M+Na]+, C44H72O16Na requires 879.4718.
16. Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto,
S. J. Org. Chem. 2003, 68, 3511–3521.
15. Selected physical data of 1: 1H NMR (CDCl3, 500 MHz): d
4.42 (2H, dt, J 9, 1, 9-H, 90-H), 4.27 (2H, d, J 7.5, 15-H and
150-H), 3.95 (2H, dd, J 11.7, 5.4, 19-H and 190-H), 3.61
(6H, s, 21-H3 and 210-H3), 3.58 (6H, s, 20-H3 and 200-H3),
3.50–3.40 (4H, m, 3-H and 30-H, 7-H and 70-H), 3.46 (6H,
s, 22-H3 and 220-H3), 3.28–3.20 (4H, m, 18-H and 180-H,
5-H and 50-H), 3.10 (2H, t, J 8, 17-H and 170-H), 3.09
(2H, dd, J 11.7, 8, 19-H0 and 190-H0), 2.96 (2H, dd, J 9, 7.5,
16-H and 160-H), 2.55 (2H, dd, J 17, 3.5, 2-H and 20-H),