Toward the synthesis of reidispongiolide a: stereocontrolled synthesis of the C17-C22 and C23-C35 degradation fragments.

Article abstract of DOI:10.1021/ol034558y

[structure: see text] By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C(17)-C(22) and C(23)-C(35) degradation fragments of reidispongiolide A has been achieved. This permits a configuratio

Full text of DOI:10.1021/ol034558y

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1963-1966
Toward the Synthesis of
Reidispongiolide A: Stereocontrolled
Synthesis of the C −C and C −C
17
22
23
35
Degradation Fragments
Ian Paterson,* Kate Ashton, Robert Britton, and Henner Knust
Department of Chemistry, UniVersity Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, United Kingdom
ip100@cam.ac.uk
Received March 31, 2003
ABSTRACT
By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C −C and C −C degradation
17
22
23
35
fragments of reidispongiolide A has been achieved. This permits a configurational assignment of the complete C −C region of this antimitotic
17
36
macrolide, along with providing advanced intermediates for a projected total synthesis.
The discovery of new cytotoxins that retain activity toward
multidrug resistant (MDR) cancer cell lines continues to fuel
the burgeoning field of cancer chemotherapy. Recently, a
number of actin-binding macrolides of marine origin have
attracted attention as novel antimitotic agents that cause rapid
loss of microfilaments in cells, without affecting microtubule
organization.1 In particular, the scytophycins,2 aplyronines,3
sphinxolides,4 and reidispongiolides5 demonstrate pronounced
antimicrofilament activity in vitro and potently inhibit the
growth of MDR cancer cells. While these preliminary
findings highlight their potential, both as candidates for new
anticancer drugs and versatile molecular probes of the
organization and function of the actin cytoskeleton, the
scarcity from the natural sources has generally hampered the
biological evaluation and preclinical development of these
stereochemically complex macrolides.
The sphinxolide/reidispongolide family of 26-membered
macrolactones are prominent members of this emerging class
of actin-binding cytotoxic macrolides (Scheme 1). Originally
isolated from an unidentified Pacific nudibranch,5a these
polyketide metabolites have more recently been obtained
from the marine sponges Neosiphonia superstes and Reidi-
spongia coerulea,5b-d collected off the coast of New Cale-
donia. Extensive analysis of sphinxolide A by NMR methods,
based largely on the interpretation of proton-carbon 2,3J
couplings, has recently enabled an assignment of the relatiVe
configurations in the five isolated stereoclusters, as indicated
in the boxed regions of structure 1.6 Additionally, controlled
ozonolysis of the closely related macrolide reidispongiolide
A (having the proposed stereostructure in 2), followed by
(1) Reviews: (a) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002,
41, 4632. (b) Spector, I.; Braet, F.; Shochet, N. R.; Bubb, M. Microsc. Res.
Technol. 1999, 47, 18.
(2) Smith, C. D.; Carmeli, S.; Moore, R. E.; Patterson, G. M. L. Cancer
Res. 1993, 53, 1343.
(3) Saito, S.; Watabe, S.; Ozaki, H.; Kigoshi, H.; Yamada, K.; Fusetani,
N.; Karaki, H. J. Biochem. 1996, 120, 552.
(4) Zhang, X.; Minale, L.; Zampella, A.; Smith, C. D. Cancer Res. 1997,
57, 3751.
(5) (a) Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. HelV. Chim. Acta
1989, 72, 237. (b) D’Auria, M. V.; Gomez-Paloma, L.; Minale, L.; Zampella,
A.; Verbist, J. F.; Roussakis, C.; Debitus, C. Tetrahedron 1993, 49, 8657.
(c) Carbonelli, S.; Zampella, A.; Randazzo, A.; Debitus, C.; Gomez-Paloma,
L. Tetrahedron 1999, 55, 14665. (d) D’Auria, M. V.; Gomez-Paloma, L.;
Minale, L.; Zampella, A.; Verbist, J. F.; Roussakis, C.; Debitus, C.; Patissou,
J. Tetrahedron 1994, 50, 4829.
10.1021/ol034558y CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003

Scheme 1
reductive workup with NaBH4, provided three distinct polyol
Scheme 2a
fragments, assigned as structures 3 (mixture of C5 epimers)
and 4 and 5 (mixture of C31 epimers), whose spectroscopic
data appeared consistent with that of the corresponding
segments in 1.7 While the full configuration of the sphinx-
olide/reidispongiolide macrolides could be determined by
completing a total synthesis, which remains our ultimate
objective, the preparation of these three degradation frag-
ments (or stereoisomers thereof) should simplify the stereo-
chemical quandary and establish the interconnections be-
tween the isolated stereoclusters.
We now report an expedient stereocontrolled synthesis of
the reidispongiolide fragments 4 and 5, as well as the
diastereomer 6 having the opposite configuration at C32 and
C33, following the retrosynthetic analysis outlined in Scheme
1. On the basis of our reservations regarding the relationship
between the isolated stereoclusters, we designed a flexible
and modular synthetic approach using appropriate aldol
reactions of the chiral ketones 7, 8, 9, and ent-9. The present
work leads to a configurational assignment for 10 out of the
15 stereocenters in reidispongiolide A, and also sets a solid
foundation for ongoing total synthesis efforts.
a Conditions: (a) (-)-Ipc2BCl, Et3N, Et2O, -78 °C; crotonal-
dehyde; LiBH4; (b) NaH, MeI, THF; (c) O3, CH2Cl2, -78 °C;
MeOH, NaBH4, -78 °C; (d) TBAF, THF; (e) p-nitrobenzoyl
chloride, Et3N, DMAP, CH2Cl2.
First, an asymmetric synthesis of the C17-C22 fragment 4
of reidispongiolide A using a convenient one-pot aldol/reduc-
tion sequence8 with methyl ketone 79 and crotonaldehyde
was developed (Scheme 2). In previous work with such ke-
tones,8-11 we had shown that high levels of diastereoselec-
tivity can be obtained for 1,4-syn adducts by appropriate
choice of Ipc ligand chirality in boron aldol reactions. By
using our standard conditions with (-)-Ipc2BCl/Et3N, the
resulting boron aldolate was reduced8b in situ with LiBH4 to
provide the 1,3-syn diol 10 with high diastereoselectivity
(91%, 91:9 dr). Conversion into the bis-methyl ether (NaH,
MeI) was then followed by ozonolysis and in situ reduc-
tion (NaBH4) of the ozonide to give the corresponding
alcohol. Finally, TBS ether removal (TBAF) afforded the
diol 4, obtained in four synthetic transformations and 27%
yield from 7.
(6) Bassarello, C.; Bifulco, G.; Zampella, A.; D’Auria, M. V.; Riccio,
R.; Gomez-Paloma, L. Eur. J. Org. Chem. 2001, 39.
(7) Zampella, A.; Bassarello, C.; Bifulco, G.; Gomez-Paloma, L.;
D’Auria, M. V. Eur. J. Org. Chem. 2002, 785.
(8) (a) Paterson, I.; Goodman, J. M; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801.
(9) Prepared in 3 steps (51%) from methyl (S)-2-methyl-3-hydroxypro-
pionate in an analogous manner to the corresponding TIPS ether, see:
Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241.
(10) For a review on asymmetric aldol reactions with boron enolates,
see: Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(11) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581.
1964
Org. Lett., Vol. 5, No. 11, 2003

1
The H and 13C NMR data exhibited by this diol 4 were
afford the anti-adduct 17 in 81% yield (95:5 dr, 95% ee).17
Following methyl ether formation (NaH, MeI), the terminal
alkene was oxidized to give 9 (71%)18 under modified19
Wacker conditions. By using (+)-Ipc2BOMe, the enantio-
meric methyl ketone ent-9 was prepared from 16 in an
analogous manner.
consistent with that reported by D’Auria and co-workers for
both the C17-C22 fragment obtained from the chemical
degradation of natural reidispongiolide A and that of a
synthetic sample of ent-4.7 The absolute configuration of the
degradation fragment was further confirmed as (18S,19S,-
21R) through comparison of the specific rotation values.12
Additionally, treatment of the diol 4 with p-nitrobenzoyl
chloride (Et3N, DMAP) gave the bis-ester 11, where single-
crystal X-ray analysis confirmed the all-syn stereochemistry.
The convergent assembly of the C23-C35 fragments
commenced with a substrate-controlled, boron-mediated aldol
reaction (c-Hex2BCl, Et3N)8a,10 between the ethyl ketone 813
and aldehyde 12 (Scheme 3). Upon standard oxidative
We next examined the coupling of the ketone 9 and the
aldehyde 18, obtained by Dess-Martin oxidation of 15
(99%). This pivotal aldol coupling step was best achieved
by generation of the lithium enolate of 9 (LDA, THF, -78
°C) and addition of a solution of 18 (0.5 equiv, 30 min) to
give the â-hydroxy ketone 19 in 85% yield, as an inconse-
quential 4:1 mixture of diastereomers. Subsequent elimina-
tion, through formation of the corresponding mesylate (MsCl,
Et3N) and in situ treatment with DBU, provided (E)-enone
20 (65%). Subjection of 20 to standard hydrogenation
conditions (H2, Pd/C) then effected both clean hydrogenolysis
of the PMP acetal and reduction of the alkene. Finally, ketone
reduction (NaBH4) and TBS ether removal (TBAF) provided
the alcohols 5, obtained as a 4:1 mixture of epimers at C31,
which were separated by flash chromatography.
Scheme 3a
1
Notably, the H NMR data (500 MHz, CD3OD) of the
alcohols 5 were in close agreement20 to that reported by
D’Auria and co-workers for the C23-C35 fragment obtained
in their degradation work,7 thus supporting this relation-
ship between the two remote stereoclusters at C24-C28 and
C31-C33 in reidispongiolide A. At the time, inconsistencies
between our 13C NMR data and that reported by the Naples
group led us to prepare 6 having the other anti stereorela-
tionship at C31-C32. This involved the analogous aldol
coupling between 18 and ent-9 to give 21 followed by
elaboration into 6, obtained as a 4:1 mixture of epimers at
C31. Spectroscopic analysis20 of the separated alcohols 6
revealed that these were clearly diastereomers of the
C23-C35 fragment obtained by ozonolysis of reidispongiolide
A. Subsequently, comparison of the 13C NMR data for
synthetic fragments 5 and 6 with the revised data provided21
for material obtained by chemical degradation allowed the
confident assignment of the relatiVe stereochemistry for the
C23-C35 sequence of reidispongiolide A.
a Conditions: (a)c-Hex2BCl,Et3N,Et2O,-78°C;(b)Me4NBH(OAc)3,
MeCN/AcOH; (c) DDQ, 4 Å MS, CH2Cl2; (d) NaH, MeI, THF;
(e) TBAF, THF.
workup, the expected anti-anti adduct 13, resulting from
the high level of π-face discrimination exercised by the
intermediate (E)-enolate,8 was obtained in 95% yield (95:5
dr). This adduct provided a suitable substrate for hydroxyl-
directed reduction to set up the C23-C29 stereopentad. By
employing Me4NBH(OAc)3,14 the desired 1,3-anti diol 14
was obtained cleanly (90%, >99:1 dr). With the five
contiguous stereocenters now secured in a concise manner,
the differentiation of the two hydroxyl groups was required.
Treatment of the diol 14 under DDQ-mediated oxidative
cyclization conditions15 resulted in the exclusive formation
of the corresponding six-membered PMP acetal, as a single
diastereomer. Finally, methylation of the free hydroxyl (NaH,
MeI) and removal of the TIPS ether (TBAF) afforded the
crystalline alcohol 15 in 80% overall yield from 14. At this
point, the relative stereochemistry of this C23-C29 subunit
was confirmed by X-ray crystallographic analysis of 15.
With the required stereopentad 15 in hand, we turned to
preparing the methyl ketones 9 and ent-9 to access both pos-
sible anti-relationships at C32 and C33 in the extended
C23-C35 fragment (Scheme 4). By using Brown’s methodol-
ogy,16 the aldehyde 16 was treated with the (E)-crotylborane
reagent derived from trans-butene and (-)-Ipc2BOMe to
(12) The low value of [R]20 recorded for synthetic 4 (+4.1, MeOH)
D
was in accord with that reported (ref 7) for the corresponding degradation
fragment. The bis-(S)-MTPA ester was also prepared for spectroscopic
comparison.
(13) (a) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287. (b) Paterson, I.; Florence, G.
J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123,
9535.
(14) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988.
(15) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
(16) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570.
(17) The [R]20D value recorded for 17 (-8.4, CHCl3) was in accord with
that previously reported. McRae, K. J.; Rizzacasa, M. A. J. Org. Chem.
1997, 62, 1196.
(18) Accompanied by small amounts of the corresponding aldehyde (8%).
(19) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998,
39, 8765.
(20) For tables of spectroscopic data (1H and 13C NMR) for 5 and 6, see
Supporting Information.
(21) Professor D’Auria has since provided us with revised 13C NMR
data for their C23-C35 degradation fragment which are in complete
agreement with the data we have acquired for the alcohols 5.
Org. Lett., Vol. 5, No. 11, 2003
1965

Scheme 4a
a Conditions: (a) trans-butene, t-BuOK, THF, n-BuLi; (-)-Ipc2BOMe; BF3‚OEt2; 16, -78 °C; (b) NaH, MeI, THF; (c) O2, Cu(OAc)2
(20 mol %), PdCl2 (10 mol %), AcNMe2/H2O (4:1); (d) Dess-Martin periodinane, NaHCO3, CH2Cl2; (e) LDA, THF, -78 °C; (f) MsCl,
NEt3, CH2Cl2; DBU; (g) H2, cat. Pd/C, EtOH; (h) NaBH4, MeOH; (i) TBAF, THF.
Acknowledgment. We thank the EPSRC (GR/S19929),
EC (HPRN-CT-2000-00018), NSERC (Fellowship to R.B.),
Ernst-Schering Research Foundation (Fellowship to H.K.)
and AstraZeneca for support and Dr. Ray Finlay (AstraZen-
eca) for helpful discussions. We thank Professor D’Auria
(University of Naples “Federico II”) for providing copies of
their NMR spectra for the natural degradation fragments and
illuminating correspondence.
In conclusion, on the basis of the established absolute con-
figuration in the C17-C22 sequence and the relative config-
uration at C23-C35, and relying on a common biogenesis for
the sphinxolide/reidispongioloide family and the structurally
related scytophycin and aplyronine macrolides,1a a full as-
signment of the complete C17-C36 region of reidispongiolide
A, as indicated in 22, is strongly suggested. Confirmation
of this proposal will rely on completing the total synthesis
of reidispongiolide A, work that is ongoing in our laboratory.
Supporting Information Available: Physical and spec-
troscopic data for new compounds and CIF files for 11 and
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL034558Y
1966
Org. Lett., Vol. 5, No. 11, 2003