Total Synthesis of the Oxopolyene Macrolide (-)-Marinisporolide C

Article abstract of DOI:10.1021/acs.orglett.5b03352

The first total synthesis of (-)-marinisporolide C was performed in 25 steps (longest linear sequence) and an overall yield of 1%. Due to the high degree of convergence and robustness, the C9-C35 fragment that corresponds to the polyol portion was obtaine

Full text of DOI:10.1021/acs.orglett.5b03352

Letter
pubs.acs.org/OrgLett
Total Synthesis of the Oxopolyene Macrolide (−)-Marinisporolide C
Luiz C. Dias* and Emílio C. de Lucca, Jr.
Institute of Chemistry, University of Campinas, 13083-970, C.P. 6154, Campinas, SP, Brasil
S
* Supporting Information
ABSTRACT: The first total synthesis of (−)-marinisporolide C was
performed in 25 steps (longest linear sequence) and an overall yield of
1%. Due to the high degree of convergence and robustness, the C9−
C35 fragment that corresponds to the polyol portion was obtained in
gram quantity. Highlights of this synthesis include five highly
stereoselective aldol reactions responsible for the construction of five
C−C bonds and six stereogenic centers. Additionally, a very efficient
Julia−Kocienski reaction was used to install a C22−C23 double bond,
́
and the macrocyclic ring was closed using an intramolecular Horner−
Wadsworth−Emmons olefination.
arinisporolides A and B (1 and 2) were isolated in 2009
from a saline culture of the marine actinomycete
Marinispora, strain CNQ-140 (Figure 1). The structure of
confirmation of the stereochemical assignment by Fenical and
co-workers.2,3
M
Our retrosynthetic analysis4 began with an intramolecular
Horner−Wadsworth−Emmons olefination involving phospho-
nate-aldehyde 6 (Scheme 1). Compound 6 could be
disconnected into stannane 7 (C3−C7 fragment), aldehyde 8
(C10−C22 fragment), and sulfone 9 (C23−C35 fragment).
We envisioned that compounds 8 and 9 could be prepared
using several aldol reactions as key steps.5
Synthesis of sulfone 9 commenced with the protection of
commercially available (R)-4-penten-2-ol (10) with para-
methoxybenzyl 2,2,2-trichloroacetimidate (PMBTCA), fol-
lowed by a Wacker oxidation that delivered methylketone 11
in 59% yield over two steps (Scheme 2).6 An aldol reaction
between methylketone 11 and aldehyde 12 afforded the desired
1,5-anti aldol adduct 13 as a 95:05 mixture of diaster-
eoisomers.7 This mixture was reduced with Et2BOMe and
LiBH4 (70% over two steps, dr > 95:05),8 followed by
protection with 2,2-DMP to furnish the acetonide 14 in 81%
yield. Removal of PMB ether of the compound 14 with DDQ
(91%) and a Swern oxidation provided methylketone 15 in
97% yield.9
An aldol reaction between 15 and the known aldehyde 16
(90%, dr > 95:05),7 followed by a reduction with Et2BOMe and
LiBH4 (99%, dr > 95:05),8 and a protection with 2,2-DMP gave
compound 17 in 87% yield (Scheme 3). Compound 17 was
next transformed into sulfone 9 by removal of the C23 TBS
group with TBAF (99%),10 Mitsunobu reaction of the resulting
primary alcohol with 1-phenyl-1H-tetrazole-5-thiol (PTSH),
and oxidation with (NH4)6Mo7O24·4H2O and H2O2 of the
resulting sulfide.11 Overall, the C23−C35 sulfone 9 (more than
Figure 1. Marinisporolides A−C.
marinisporolide A consists of 11 stereogenic centers within a
34-membered macrolide, containing an internal spiroketal with
one anomeric effect, and a conjugated pentaene system. The
marinisporolide B is the corresponding hemiketal of the
marinisporolide A. Due to readily photoisomerization, mar-
inisporolide C (3), which is an olefin geometric isomer of
marinisporolide A, was also isolated.1
Herein, we describe our synthetic efforts which culminated in
the total synthesis of marinisporolide C (3) and the
Received: November 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03352
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Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of C23−C30 Fragment 15
diol (99%, dr > 95:05),13 which was protected with TBSOTf to
furnish compound 20 in 91% yield.14 Removal of PMB ether
with DDQ (97%), followed by a Swern oxidation (95%), and
the treatment of corresponding methylketone with TMSOTf
and Et3N gave enolsilane 21 in 99% yield.15
The BF3·Et2O-catalyzed Mukaiyama aldol reaction between
enolsilane 21 and known aldehyde 22 (see Supporting
Information) yielded the desired 1,3-anti aldol adduct 23 in
86% yield with a good level of diastereoselectivity (dr = 79:21)
(Scheme 5).16 Protection of compound 23 with TBSOTf
Scheme 5. Synthesis of C10−C22 Fragment 8
Scheme 3. Synthesis of C23−C35 Fragment 9
1.5 g prepared) was obtained in 13 steps and 18% yield from
alcohol 10.12
Synthesis of C10−C22 aldehyde 8 began with the aldol
reaction between methylketone 11 (a common intermediate in
the synthesis of C23−C35 fragment 9) and known aldehyde 18
to deliver the 1,5-anti aldol adduct 19 in 88% yield with high
diastereoselectivity (dr = 92:08) (Scheme 4).7 This mixture was
reduced with Me4NBH(OAc)3 to afford the desired 1,3-anti
(91%),14 followed by the removal of a trityl group with DDQ,
gave the corresponding primary alcohol as only one
diastereoisomer in 52% yield after silica flash column
chromatography.17 Finally, a Swern oxidation provided
aldehyde 8 in 99% yield.9 Additionally, the C10−C22 aldehyde
8 (more than 1.5 g prepared) was obtained in 10 steps and 29%
yield from methylketone 11.12
Scheme 4. Synthesis of C10−C18 Fragment 21
Having assembled sulfone 9 and aldehyde 8, these fragments
were coupled by using the Julia−Kocienski olefination to
́
provide compound 24 in 74% yield with high diastereose-
lectivity (dr > 95:05) (Scheme 6).18 Removal of C33 PMB
ether with DDQ (91%), followed by an olefin cross-metathesis
using the second-generation Hoveyda−Grubbs catalyst, fur-
nished aldehyde 25 in excellent yield and diastereoselectivity
(89%, dr > 95:05).19 Compound 25 that corresponds to the
C9−C35 fragment of marinisporolides was prepared in more
than 1.5 g. Finally, Takai−Utimoto olefination of aldehyde 25
B
DOI: 10.1021/acs.orglett.5b03352
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Letter
Scheme 6. Synthesis of C8−C35 Fragment 26
Scheme 7. Completion of the Total Synthesis of
Marinisporolide C (3)
Synthetic and natural marinisporolide C were found to be
identical by a variety of analytical methods (1H and 13C NMR,
HRMS, UV/vis, and circular dichroism), and this total synthesis
confirms the relative and absolute stereochemical assignment
by Fenical and co-workers.1
In conclusion, the first total synthesis of oxopolyene
macrolide (−)-marinisporolide C (3) was accomplished in 25
steps (longest linear sequence) and 1% overall yield, which
corresponds to an average yield of 83% per step. The pivotal
five aldol reactions, responsible for the construction of five C−
C bonds and six stereogenic centers, provide a straightforward
approach to the convergent synthesis of the marinisporolide C
(82%, dr = 89:11),20 followed by a Yamaguchi esterification,
gave compound 26 in 92% yield and a 1:1 mixture of
stereoisomers.21
Our initial strategy involved performing macrocyclization
prior to spiroketalization. However, the compounds with the
C17 free ketone were quite unstable and did not provide
consistent data for the completion of the total synthesis. Thus,
we decided to carry out the spiroketalization prior to the
macrocyclization step. At this point, a series of C17 epimers
were obtained; however, as the last step of synthesis would
involve the removal of acetonides groups in an acidic medium,
the initial mixture of spiroketals could be reisomerized or
equilibrated in favor of the desired compound.
Therefore, the removal of the TBS ethers of compound 26
with HF·py formed a mixture of spiroketals,22 which was
protected with TBSOTf to provide compound 27 in 87% yield
over two steps (Scheme 7).14 The Stille cross-coupling between
vinyl iodide 27 and known stannane 7 (98%),23 followed by an
oxidation with TEMPO and BAIB, provided aldehyde 28.24
Compound 28 was submitted to a Horner−Wadsworth−
Emmons macrocyclization under Masamune−Roush condi-
tions to furnish the desired macrolactone.25 To our complete
surprise, after full deprotection, first with HF·py and then with
HCl, (−)-marinisporolide C (3) was obtained in 15% yield
(over four steps).
́
skeleton. Furthermore, a very efficient Julia−Kocienski reaction
was used to install the C22−C23 double bond and an
intramolecular Horner−Wadsworth−Emmons reaction was
used to build the very hindered macrolactone.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03352.
Experimental details and spectra data for all new
compounds (1H and 13C NMR, IR, and HRMS)
(PDF)
C
DOI: 10.1021/acs.orglett.5b03352
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Letter
(b) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
AUTHOR INFORMATION
Corresponding Author
■
37, 8585. (c) Evans, D. A.; Coleman, P. J.; Co
̂ ́
te, B. J. Org. Chem. 1997,
62, 788. (d) Evans, D. A.; Cote, B.; Coleman, P. J.; Connell, B. T. J.
̂
́
*E-mail: ldias@iqm.unicamp.br.
Notes
Am. Chem. Soc. 2003, 125, 10893. For our recent work in this area,
see: (e) Dias, L. C.; de Lucca, E. C., Jr.; Ferreira, M. A. B.; Garcia, D.
C.; Tormena, C. F. Org. Lett. 2010, 12, 5056. (f) Dias, L. C.; de Lucca,
E. C., Jr.; Ferreira, M. A. B.; Garcia, D. C.; Tormena, C. F. J. Org.
Chem. 2012, 77, 1765. (g) Dias, L. C.; Polo, E. C.; Ferreira, M. A. B.;
Tormena, C. F. J. Org. Chem. 2012, 77, 3766. (h) Dias, L. C.; Kuroishi,
P. K.; Polo, E. C.; de Lucca, E. C., Jr. Tetrahedron Lett. 2013, 54, 980.
(i) Dias, L. C.; Kuroishi, P. K.; de Lucca, E. C., Jr. Org. Biomol. Chem.
2015, 13, 3575. For reviews on 1,5-anti remote induction, see:
(j) Dias, L. C.; Aguilar, A. M. Quim. Nova 2007, 30, 2007. (k) Dias, L.
C.; Aguilar, A. M. Chem. Soc. Rev. 2008, 37, 451. For theoretical
studies, see: (l) Paton, R. S.; Goodman, J. M. Org. Lett. 2006, 8, 4299.
(m) Goodman, J. M.; Paton, R. S. Chem. Commun. 2007, 2124.
(n) Paton, R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253.
(8) (a) Narasaka, K.; Pai, H. C. Chem. Lett. 1980, 9, 1415.
(b) Narasaka, K.; Pai, F.-C Tetrahedron 1984, 40, 2233. (c) Paterson,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to FAPESP (2012/02230-0 and 2013/07600-3)
for financial support and a fellowship to E.C.L.Jr. (2011/06721-
6). We also thank CNPq (300810/2010-5 and INCT-INOFAR
CNPq−Proc. 573.564/2008-6), and FAEPEX-UNICAMP
(Conv. 519.292). The authors thank Prof. Marcos N. Eberlin
(Thomson Laboratory) for HRMS analyses.
DEDICATION
■
We dedicate this paper to Professor Mauricio Gomes
Constantino (FFCLRP/USP) for his contributions to the
field of organic synthesis in Brazil.
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