Total syntheses of the assigned structures of lituarines B and C

Article abstract of DOI:10.1021/ja078293k

The first syntheses of the structures assigned to the marine natural products lituarines B and C have been achieved via a highly convergent sequence. The structures comprise complex, highly oxygenated 25-membered macrolactones possessing a rare tricyclic

Full text of DOI:10.1021/ja078293k

Published on Web 12/21/2007
Total Syntheses of the Assigned Structures of Lituarines B and C
Amos B. Smith, III,* Matthew O. Duffey, Kallol Basu, Shawn P. Walsh, Hans W. Suennemann, and
Michael Frohn
Department of Chemistry, The Monell Chemical Senses Center, and the Laboratory for Research on the
Structure of Matter, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received October 30, 2007; E-mail: smithab@sas.upenn.edu
Scheme 2. Synthesis of C(20-26) Dithiane (-)-6
The lituarines A-C comprise an architecturally novel, biologi-
cally active family of marine natural products (1-3; Figure 1)
reported by Vidal and co-workers in 1992.1a Isolated from the sea
pen Lituaria australasaie, endemic to the western region of the
New Caledonian Lagoon near the Baie de St. Vincent, their
structures, including the connectivities and relative stereochemis-
tries, were assigned on the basis of multidimensional NMR
techniques;1b the absolute stereochemistry remains undefined. From
the biomedical perspective, the lituarines display significant cyto-
toxicities toward KB cells [(1): IC50 ) 5.5-7.5 nM; (2): IC50
)
1-3 nM; (3): IC50 ) 7-9 nM]. Intrigued both by the architecture
and the biological activities of the lituarines, we initiated a research
program directed toward the total synthesis of the lituarines.2,3 The
Robertson laboratory has also reported progress in this area.4
hydrogenation, delivered alcohol 9 as a mixture (1:1) of diastereo-
mers. A two-step sequence involving oxidation of the primary
alcohol and diastereoselective addition of vinyl zinc7 to the resulting
aldehyde provided allylic alcohol 10. Silyl protection followed by
hydroboration of the terminal olefin then yielded 11, which in turn
was subjected to TMSOTf-mediated dithiane formation to furnish
dithiane (-)-12 in moderate overall yield for the three steps (45%).
The structure of (-)-12 was confirmed via X-ray crystallography.5
Treatment of diol (-)-12 with p-methoxyphenyl dimethylacetal
resulted in a seven-membered PMP-acetal, which upon DIBALH
reduction led to (-)-13. Protection of the terminal hydroxyl as the
TBS ether completed construction of dithiane (-)-6. The overall
yield for this 10-step sequence was 23%.
Figure 1. Lituarines A-C.
To maximize convergency, we envisioned a synthesis exploiting
fragment union between dithiane 6 and advanced alkyl iodide
(+)-7,2,3 followed by macrolactonization and late stage introduction
of the C(26-33) (E,Z)-dienamide side chain employing cis-vinyl
stannane 5 (Scheme 1).
Fragment union was achieved by lithiation of (-)-6 in the
presence of HMPA (Scheme 3), followed by addition of alkyl iodide
(+)-7 to furnish (+)-14; the yield was 62%. With the core skeleton
of lituarines B and C in hand, we advanced to the macrocycle
without major difficulty. Removal of the terminal TBS group,
followed by an oxidation/Takai olefination8 sequence, furnished
vinyl iodide (+)-15. Release of the C(23) PMB group (DDQ) then
Scheme 1. Retrosynthetic Scheme
Scheme 3. Synthesis of C(1-24) Macrolactone (+)-17
After development of a viable route to iodide (+)-7,2,3 the
structure was confirmed by X-ray analysis.5 Our attention thus
turned toward the synthesis of dithiane 6 (Scheme 2). Reduction
of known lactone (-)-86 to the corresponding lactol, followed by
9
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paved the way for oxidation to the ketone. Subsequent treatment
with TMSOTf resulted both in hydrolysis of the tert-butyl ester
and protection of the C(4) hydroxyl as the TMS ether. A remarkably
selective removal of the TBDPS group (TBAF, 0 °C) in the presence
of the tertiary TMS and secondary TBS ethers was then achieved.
Macrolactonization employing the Yamaguchi conditions9 com-
pleted construction of the desired macrolactone (+)-17 in good yield
(ca. 77%).
Synthesis of the requisite vinyl stannane (5) for installation of
the C(26-33) (E,Z)-dienamide side chain began with known cis-
2-iodomethylacrylate (Scheme 4);10 a copper-mediated union11 with
butyramide led to the cis-enamide 18. Hydrolysis of the methyl
ester, followed by stereospecific iododecarboxylation,12 furnished
the desired cis-iodoenamide 20 as a single isomer. Surprisingly,
however, Pd-catalyzed stannylation of 20 resulted in isomerization
of the olefin to the trans isomer. As a result, we reversed the Stille
coupling partners for the side-chain attachment, making use of cis-
iodoenamide 20. This tactical revision required preparation of the
vinyl stannane from (+)-17.
extensive 2D NMR studies (COSY, TOCSY, NOESY, HMBC,
HSQC) of (+)-3 both confirmed the connectivities and permitted
unambiguous assignment of all carbon resonances in the 13C NMR.
Finally, no epimerization was observed in any of the transformations
after construction of (+)-14.
In addition to the synthesis of the proposed structure for lituarine
C [(+)-3], we also completed the synthesis of the proposed structure
of lituarine B (2) (Scheme 6). To this end, addition of acetic
anhydride to (+)-3 led chemoselectively to acetylation of the C5
hydroxyl to provide (+)-2. As with (+)-3 and lituarine C, the
spectral properties of synthetic (+)-2 did not match those reported
for lituarine B.
Scheme 6. Synthesis of the Proposed Structure of Lituarine B
Scheme 4. Synthesis of C(28-33) Enamide Coupling Partner
Taken together, the X-ray crystallographic data, in conjunction
with the 1D and 2D NMR studies, permit assignment of the
structures of synthetic (+)-2 and (+)-3. Current work is directed
toward the determination of the structures of the natural lituarines
by synthesis of related diastereomers.
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant CA-
19033 and Merck & Co., Inc. M.O.D. is grateful to the NIH (NCI)
for a postdoctoral fellowship. We also thank Drs. George W. Furst
and Sangrama Sahoo for NMR expertise, Dr. Patrick M. Carroll
for the X-ray analyses, and Professor Vidal for helpful discussions.
Toward this end, removal of the dithiane in (+)-17 employing
the Stork protocol13 was followed by stannylation of the C(27) vinyl
iodide moiety (Scheme 5). Stille union with cis-iodoenamide 20
resulted in installation of the requisite C(26-33) (E,Z)-dienamide.
Completion of the proposed structure of lituarine C [(+)-3] was
then achieved by removal of the silicon protecting groups (TASF).14
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 5. Completion of Synthesis
References
(1) (a) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-M.;
Aumelas, A. J. Org. Chem. 1992, 57, 5857. (b) Optical rotation data were
not obtained for the lituarines.
(2) Smith, A. B., III; Frohn, M. Org. Lett. 2001, 3, 3979.
(3) Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett. 2005,
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With (+)-3 in hand, we quickly recognized that the spectral
properties did not match those of the natural lituarine C.1,15 Although
to date we have been unable to obtain crystals of (+)-3 suitable
for X-ray crystallographic analysis, we do have convincing data to
support the structural assignment of (+)-3. First, X-ray crystal-
lography confirmed the stereochemical assignments of the
C(1-19) tricyclic iodide (+)-7,5 as well as the C(21) and C(24)
stereogenicity in (-)-12.5 The geometry of the (E,Z)-dienamide was
assigned by 1H NMR; specifically, the H28-H29 coupling constant
(J ) 10 Hz) is consistent with a Z olefin, while the H26-H27
coupling constant (J ) 15 Hz) verifies an E olefin.16 For com-
parison, the C(26-33) (E,E)-dienamide corresponding to (+)-3 was
also constructed.5 In the E,E congener, the H28-H29 coupling
constant (J ) 14 Hz) was significantly larger, thereby supporting
the Z character of the C(28-29) olefin in (+)-3. In addition,
(5) See Supporting Information.
(6) Myers, A. G.; McKinskey, L. J. Org. Chem. 1996, 61, 2428.
(7) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
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(14) TASF was selected due to the mild basicity to avoid the possibility of
Payne rearrangement; see: Scheidt, K. A.; Chen, H.; Follows, B. C.;
Chemler, S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63,
6436.
(15) For an excellent review on misassigned natural product structures and
the role of chemical synthesis, see: Nicolaou, K. C.; Snyder, S. A. Angew.
Chem., Int. Ed. 2005, 44, 1012.
(16) Bothner-By, A. A.; Naar-Colin, C. J. Am. Chem. Soc. 1961, 83, 236.
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