Synthesis of leucascandrolide A via a spontaneous macrolactolization

Article abstract of DOI:10.1021/ja028428g

We have developed a concise, convergent, and stereocontrolled synthesis of (±)-leucascandrolide A (18 steps from commercially available precursors), featuring a complete relay of the initial stereochemical information via a series of diastereoselective transformations. Spontaneous macrolactolization discovered during this synthetic exercise has provided unprecedented access to this macrolide and demonstrated the possibility of accessing even large-ring systems in a highly controlled and efficient manner. Copyright

Full text of DOI:10.1021/ja028428g

Published on Web 10/24/2002
Synthesis of Leucascandrolide A via a Spontaneous Macrolactolization
Ying Wang, Jelena Janjic, and Sergey A. Kozmin*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received September 5, 2002
Scheme 1
In 1996, Pietra identified a new genus of calcareous sponges,
Leucascandra caVeolata, which resulted in the discovery of a
natural product designated as leucascandrolide A (1, Scheme 1).1
In preliminary studies, this metabolite displayed potent cytotoxicity
against KB and P388 tumor cell lines, and strong inhibition of the
animal-pathogenic yeast Candida albicans. Structurally, leucas-
candrolide A was shown to embody several unique features,
including a dioxotricyclic core, featuring a 14-membered lactone,
and a highly unsaturated, oxazole-containing side chain. Complex
molecular architecture of leucascandrolide A, highly unusual for
metabolites produced by calcareous sponges, led Pietra to hypothe-
size that this natural product originated from an unknown microbial
organism present in L. caVeolata.2 The structural complexity of
leucascandrolide A, potent cytotoxic and antifungal properties,
combined with the uncertainty of the biogenetic origin, stimulated
considerable synthetic interest in this target,3,4 with the first total
synthesis recently achieved by Leighton.3a
In this communication, we present a unique synthetic solution
of the leucascandrolide problem, featuring a concise, convergent,
and stereocontrolled approach to this complex natural product. Our
synthesis led to the discoVery of a spontaneous intramolecular
macroacetalization, proViding an unprecedented and efficient route
to this macrolide.5
Our strategy was designed to exploit the substrate-directed
diastereoselection in establishing all of the stereogenic elements
of leucascandrolide A (Scheme 1).4 Following the initial discon-
Scheme 2
nection at the C5 ester linkage, macrolide 2 would originate from
three simplified segments 4, 5, and 6. The chirality of macrolide 2
would solely derive from pyran 5 via a series of diastereoselective
transformations. Following this logic, one of us previously described
an efficient synthesis of the fully functionalized C1-C15 fragment
(12, Scheme 3) of leucascandrolide A, featuring Prins desymme-
trization, convergent 1,5-anti-selective aldol condensation, and
highly chemo- and diastereoselective Pt-catalyzed hydrosilylation.4
The remaining challenges entailed the efficient conversion of this
segment to the macrolide 2, assembly of the oxazole-bearing side
chain 3, and effective union of the two fragments en route to the
final target 1.
Construction of the side chain 3 commenced with the conversion
of alkyne 7 to nitrile 8 via a one-pot silylation-cyanation protocol
employing TsCN (Scheme 2).6 Assembly of the oxazole subunit
was designed to probe the participation of alkynyl nitriles in the
metal-catalyzed condensations with diazo carbonyl compounds.7
In the event, subjection of nitrile 8 to diazomalonate in the presence
of Rh2(OAc)4 (5 mol %) according to the Helquist protocol,7b
followed by protodesilylation, afforded oxazole 9. Hydrogenation,
Super-Hydride reduction, followed by bromination of the resulting
alcohol, furnished bromide 10. Alkylation of the lithium enolate
of imine 11 with bromide 10 efficiently afforded the two-carbon
extended aldehyde. Z-Selective olefination,8 followed by saponifica-
tion, completed the assembly of the side chain subunit 3 (eight
steps, Z:E ) 11:1).
Synthesis of the macrolide continued from the previously
described alcohol 124 (Scheme 3) efficiently assembled from
aldehyde 4 and ketone 5. Following the dioxolane removal, and
acetylation of the resulting lactol, C-glycosidation with enol silane
* To whom correspondence should be addressed. E-mail: skozmin@uchicago.edu.
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J. AM. CHEM. SOC. 2002, 124, 13670-13671
10.1021/ja028428g CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
139 furnished ynone 14 as a single diastereomer. L-Selectride
reduction,10 followed by chemoselective dihydroxylation of the
terminal alkene and Red-Al reduction of the alkyne, gave triol 15.
Unexpectedly, treatment of triol 15 with Pb(OAc)4 afforded lactol
17 in 92% yield as a single diastereomer,11 arising spontaneously
via intramolecular macroacetalization of the intermediate hydroxy
aldehyde 16.12 Subjection of lactol 17 to pyridinium chlorochromate
in CH2Cl2 gave lactone 18, providing further evidence of the
unusual thermodynamic stability of this 14-membered macrocycle.
Oxidative removal of the benzyl ether with DDQ13 completed the
construction of macrolide 2 (17 steps).
Acknowledgment. Financial support of this work was provided
by the National Institute of Health (National Cancer Institute, R01
CA93457). We thank Professor Leighton for a copy of the 500
1
MHz H NMR spectrum of leucascandrolide A.
Supporting Information Available: Full characterization of new
compounds and selected experimental procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim. Acta
1996, 79, 51.
Designed to invert the relative stereochemistry at the C5, the end
game entailed Mitsunobu esterification of alcohol 2 with carboxylic
acid 3 (Scheme 4). To our delight, despite the highly congested
steric environment, treatment of the two coupling fragments with
PPh3 and DIAD afforded the final target (()-1 directly in 78%
yield. 500 MHz 1H NMR and 125 MHz 13C NMR spectra of
synthetic leucascandrolide A were in excellent agreement with those
reported in the literature.1,3a
(2) Subsequent samples of the sponge did not contain leucascandrolide A,
strongly suggesting the microbial origin of this natural product.
(3) (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc.
2000, 122, 12894. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2001, 123, 8420. (c) Crimmins, M. T.; Carroll, C. A.; King, B. W.
Org. Lett. 2000, 2, 597. (d) Wipf, P.; Graham, T. H. J. Org. Chem. 2001,
66, 3242. (e) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066.
(4) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(5) For formation of 1,3-dioxanes via Lewis acid or Brønsted acid-catalyzed
macrotransacetalization, see: (a) Still, W. C.; Li, G. J. Am. Chem. Soc.
1993, 115, 3804. (b) Wender, P. A.; Brabander, J. D.; Harran, P. G.;
Jimenez, J. M.; Koehler, M. F. T.; Lippa, B.; Park, C. M.; Shiozaki, M.
J. Am. Chem. Soc. 1998, 120, 4534.
Scheme 4
(6) For cyanation of alkynyl zincs, see: Klement, I.; Lennick, K.; Tucker, C.
E.; Knochel, P. Tetrahedron Lett. 1993, 34, 4623. For cyanation of lithium
enolates, see: Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011.
(7) (a) Doyle, M. P. Chem. ReV. 1986, 86, 919 and reference cited therein.
(b) Connell, R. D.; Scavo, F.; Helquist, P.; Åkermark, B. Tetrahedron
Lett. 1986, 27, 5559.
(8) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(9) For details, see the Supporting Information.
(10) While moderate diastereoselection was observed (67:33), the desired
alcohol was obtained in 65% isolated yield after routine chromatographic
separation. In addition, the undesired epimer can be readily converted to
the requisite diastereomer via a one-pot Mitsunobu esterification-hydrolysis
protocol (p-NO2C6H4CO2H, DMAD, PPh3; K2CO3, 89% yield).8
(11) Relative stereochemistry at the C1 was assigned by a combination of DQF
COSY and NOESY, revealing an intramolecular hydrogen bonding motif
between C1-OH and C3-O-C7.
(12) In contrast, subjection of the C17 epimeric triol 19 to the oxidative cleavage
conditions resulted only in formation of the corresponding hydroxy
aldehyde 20.
In closing, we have developed an efficient synthesis of leucas-
candrolide A, which provided access to the natural product with
the longest linear sequence of 18 steps from commercially available
precursors. The spontaneous intramolecular acetalization demon-
strated the possibility of accessing large-ring systems in a highly
controlled and efficient manner.
(13) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885. (b) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114,
2524.
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