Synthetic studies on spongistatins: Synthesis of the C29-C44 fragment

Article abstract of DOI:10.1016/S0040-4039(00)00383-X

A convergent synthesis of the C29-C44 fragment, the common subunit of the spongipyran macrolides is described. The key step of the synthesis is the C-glycosidation reaction which is based on coupling of the lithiated F-ring sulfone with the E-ring aldehyde, and subsequent reductive desulfonylation to afford the E-F bis (pyran) with high stereoselectivity at the anomeric carbon. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00383-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3349–3353
Synthetic studies on spongistatins: synthesis of the
C29–C44 fragment†
Mohammad Samadi,∗ Christian Munoz-Letelier, Stéphane Poigny and Michèle Guyot
Laboratoire de Chimie des Substances Naturelles, associé au CNRS, Muséum National d’Histoire Naturelle, 63, rue Buffon,
F-75005 Paris, France
Received 3 January 2000; accepted 1 March 2000
Abstract
A convergent synthesis of the C29–C44 fragment, the common subunit of the spongipyran macrolides is
described. The key step of the synthesis is the C-glycosidation reaction which is based on coupling of the lithiated
F-ring sulfone with the E-ring aldehyde, and subsequent reductive desulfonylation to afford the E–F bis (pyran)
with high stereoselectivity at the anomeric carbon. © 2000 Elsevier Science Ltd. All rights reserved.
The spongipyran macrolides, a new family of marine natural products have been isolated from
marine sponges: spongistatins 1–9 by Pettit,1 altohyrtins A–C by Kitagawa,2 and cinachyrolide A by
Fusetani3 groups. They display in vitro antitumor activities against a number of human cancer cell lines.
Spongistatin 1 (1) (altohyrtin A) was found to be extremely potent (GI50’s typically 2.5–3.5×10−11 M)
against NCI panel of 60 highly chemoresistant tumor cell lines.1 Further investigations revealed that
spongistatins efficiently inhibit mitosis by binding to tubulin and blocking microtubule assembly.4 All of
them feature two spiroketals AB and CD and highly substituted E- and F-rings in a 42-membered lactone
with 24 stereocenters (Fig. 1). Due to their prominent biological activities and the paucity of available
material from natural sources, these macrolides have stimulated considerable synthetic interests,5 leading
to total synthesis of altohyrtin C and A by Evans6 and Kishi7 groups. Both confirmed the absolute
configuration of altohyrtins C and A originally proposed by the Kitagawa group,2 and proved through
spectroscopic analysis that altohyrtins C and A were identical to spongistatins 2 (2) and 1 (1).
In this paper we report our approach to the synthesis of the C29–C44 segment 3, the common subunit
of the spongipyran macrolides, as this fragment could be synthesized by coupling the E and F subunits
in either clockwise or counterclockwise fashion. Previously, the strategy6–9 used for the synthesis of this
segment was based on coupling a lithiated species at C-37 of E-ring with the C-38 of F-ring subunit
serving as electrophile. Our retrosynthetic plan for the synthesis of C29–C44 fragment 3 is shown in
∗
†
Corresponding author. Tel: 33-1-40793144; fax: 33-1-40793147; e-mail: samadi@mnhn.fr (M. Samadi)
Presented at the 2nd Euroconference on Marine Natural Products, Santiago de Compostela, Spain, 12–16 Sept, 1999, page
43.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00383-X
tetl 16663

3350
Fig. 1.
Fig. 1. We envisioned that the reverse coupling (counterclockwise) would be feasible, in that the lithium
anion generated at anomeric carbon-C-39 of the F-ring sulfone 5 could be coupled with the C-38 E-ring
aldehyde 4, providing the E–F bis (pyran) 3. As outlined below we describe first the synthesis of E and
F subunits10 and finally their coupling by exploiting the methodology previously developed11 to achieve
the C-glycosidation reaction.
The substituted E-ring aldehyde 4 was prepared through two aldol reactions. First stereoselective aldol
coupling of the Evans oxazolidinone 612 with the protected pentanal 713 gave the syn adduct 8 (78%),
followed by protection of the hydroxyl group (1.1 equiv. TBSOTf, 2.2 equiv. 2,6-lutidine, CH2Cl2) to
furnish compound 9 in 98% yield. Reduction of the oxazolidinone moiety14 (4 equiv. NaBH4, THF–H2O)
gave alcohol 10 (74%), and subsequent oxidation (3 equiv. SO3·Py, 7 equiv. Et3N, DMSO) provided
aldehyde 11 in 97% yield. Second aldol reaction of aldehyde 11 with the protected acetol 1215 mediated
by Bu2BOTf produced an inseparable mixture of the syn 14a and anti 14b adducts (3:1) in 78% yield
(entry 2). The diastereoselectivity was improved (5:1) using Mukaiyama aldol reaction of aldehyde 11
with the silyl enol ether 1316 promoted by BF3OEt2 as Lewis acid17 (entry 3). In contrast, no selectivity
(1:1) was observed for the aldol coupling mediated by the chiralborane (−)-DIP-Cl (entry 1) (Scheme 1).
Subsequent deprotection of 14a,b (TBAF, THF) and ketalization (cat. CSA, MeOH) gave the desired
cyclic compound 15a (58% over three steps from 11) which was readily separated over column
chromatography from its isomer 15b (12%). Protection of the hydroxyl group (1.1 equiv. TBSOTf, 2.2
equiv. 2,6-lutidine, CH2Cl2) gave 16, followed by deprotection of the benzoyl group (2 equiv. KOH,
MeOH), afforded the primary alcohol 17 in 92% yield (over two steps). Further oxidation of the resulting
alcohol (3 equiv. SO3·Py, 7 equiv. Et3N, DMSO) furnished the desired aldehyde 4 in 94% yield (Scheme
1).
The F-ring sulfone 5 was prepared starting from the readily available D-glucal 18 which was converted
in one step to the known iodo compound 19 according to the procedure described.18 Thus, selective
protection of the less hindered hydroxyl group (1.1 equiv. TBSCl, 2.2 equiv. imidazole, DMF), followed
by in situ treatment of the resulting protected iodo intermediate with NaH (3 equiv.) gave epoxide 20 in
86% yield. The methyl group was introduced through a trans diaxial addition of Me2CuLi to the epoxide
20 to produce product 21 in 79% yield. Treatment of 21 with thiophenol (3 equiv. PhSH, MeCN) and
PTSA (1 equiv.) which effects thioglycosylation and deprotection of the TBS ether, followed by in situ
addition of PhCH(OMe)2 (5 equiv.) furnished the protected thioglycoside 22 as a separable mixture of
α and β isomers (5:1) in 93% yield.19 The remaining hydroxyl group was protected as a TBS ether (1.1

3351
Scheme 1. (i) Bu2BOTf, Et3N, 7: BnO(CH2)4CHO, CH2Cl2, −78 to 0°C, 3 h (78%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, −78°C,
1 h (98%); (iii) NaBH4, THF–H2O, rt, 48 h, (74%); (iv) SO3·Py, Et3N, DMSO, rt, 1 h, (97%); (v) a. 2 equiv. of 12, 2 equiv. of
reagent, 2 equiv. of Et3N, CH2Cl2, −78 to 0°C, 3 h; or b. 2.5 equiv. 13, 2.5 equiv. BF3·OEt2, CH2Cl2, −78°C, 3 h; (vi) TBAF,
THF, rt, 3 h; (vii) cat CSA, MeOH, rt, 1 h (58% for 15a, and 12% for 15b); (viii) TBSOTf, 2,6-lutidine, CH2Cl2, −78°C, 1 h;
(ix) KOH, MeOH, rt, 1 h (92%); (x) SO3·py, Et3N, DMSO, rt, 1 h (94%)
equiv. TBSOTf, 2.2 equiv. 2,6-lutidine, CH2Cl2) to give 23 and oxidation of the thiophenyl moiety (2.2
equiv. mCPBA, CH2Cl2) provided the desired F-ring sulfone 5 in 92% over two steps (Scheme 2).
Scheme 2. (i) see Ref. 18; (ii) TBSCl, imidazole, rt, 5 h, then NaH, DMF, 0°C to rt, 1 h (86%); (iii) Me2CuLi, ether, 0°C to rt,
5 h (79%); (iv) PhSH, PTSA, 3 h, then MS 3 Å, PhCH(OMe)2, MeCN, rt, 1 h (93%); (v) TBSOTf, 2,6-lutidine, CH2Cl2, −78
to 0°C, 3 h; (vi) mCPBA, CH2Cl2, 0°C, 3 h (92%)
Finally, coupling of sulfone 5 through its lithium anion generated at anomeric carbon (LDA, THF,
−78°C) in the presence of aldehyde 4, followed by in situ reductive desulfonylation of the phenylsulfone
moiety with lithium naphthalenide afforded the addition products 24(R) and 3(S) as a mixture of
isomers (R:S, 4:1) in 52% yield. Both compounds 24 and 3 showed a coupling constant (J=10.8 Hz)
corresponding to the axial–axial coupling of H-39 and H-40, which confirmed that the coupling reaction
proceeds with high stereoselectivity at the anomeric carbon (C-39), leading to the equatorial C-β-

3352
glycoside. The R alcohol 24 was converted to the desired S configuration by Ley oxidation20 (TPAP,
NMO, CH2Cl2) followed by Luche reduction21 (NaBH4, CeCl3, MeOH) to give compound 3 as the sole
observed isomer22 in 88% yield. Further, the absolute configuration at C-38 was confirmed by Mosher
esters analysis23,24 (Scheme 3).
Scheme 3. (i) 1.2 equiv. LDA, 5 min, then 4, 15 min, THF, −78°C, then 2.5 equiv. of Li-naphthalenide, 15 min, 5 equiv. of
MeOH, 15 min, THF, −78°C (52%, 4:1); (ii) TPAP, NMO, MS 3 Å, CH2Cl2, rt, 2 h; (iii) NaBH4, CeCl3·7H2O, MeOH, 0°C, 1
h (88%, over two steps)
In summary we have described a convergent synthesis of the C29–C44 subunit of spongistatins,
starting from the readily available oxazolidinone 6 in 12 steps. Having this advanced intermediate in
hand, studies toward the introduction of the triene side chain are currently underway.
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