A formal total synthesis of leucascandrolide A

Article abstract of DOI:10.1039/b207383h

A convergent synthesis of the macrocyclic core of the marine macrolide leucascandrolide A has been accomplished.

Full text of DOI:10.1039/b207383h

A formal total synthesis of leucascandrolide A
Peter Wipf* and Jonathan T. Reeves
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. E-mail: pwipf@pitt.edu;
Fax: 412-624-0787; Tel: 412-624-8606
Received (in Cambridge, UK) 26th July 2002, Accepted 5th August 2002
First published as an Advance Article on the web 16th August 2002
A convergent synthesis of the macrocyclic core of the marine
macrolide leucascandrolide A has been accomplished.
The synthesis of the C10–C17 iodide began with the known
silyloxyacetaldehyde 811 (Scheme 2). Brown’s E-crotylbora-
tion12 provided the homoallylic alcohol in 55% yield as an 8+1
mixture of diastereomers. Attempted benzylation of this alcohol
under standard conditions (NaH, BnBr, DMF or THF) resulted
in significant ( ~ 40%) migration of the TBS group. Application
of the conditions developed by Marshall13 (t-BuLi, 278 °C;
BnBr/HMPA) completely suppressed silyl migration to provide
the desired benzyl ether in 86% yield. Ozonolysis of the olefin
furnished the aldehyde in 74% yield. Wittig reaction led to
benzyl ester 9, which upon exposure to catalytic hydrogenation
in EtOAc gave the lactone 10 in 87% yield. Partial reduction of
the lactone carbonyl functionality with DIBAL-H and acetyla-
tion of the resultant lactol furnished the anomeric acetate in 87%
yield as a 1.4+1 a+b mixture of anomers. Allylsilane addition14
to this mixture of lactol acetates provided the tetrahydropyran
11 in 80% yield with excellent diastereoselectivity (15.6+1)
favoring the desired axial isomer. Ozonolytic cleavage of the
olefin gave the corresponding aldehyde which was subjected to
a catalytic asymmetric vinylzinc addition reaction using
conditions developed in our laboratories.15 Thus, hydro-
zirconation of 4-methylpentyne, in situ transmetallation to the
more reactive vinylzinc species, and addition of the aldehyde in
the presence of 25 mol% of aminothiol ligand 12 provided the
Leucascandrolide A (Fig. 1) is a structurally unique macrolide
isolated in 1996 from the sponge Leucascandra caveolata.1 The
natural product has been shown to possess impressive antic-
ancer and antifungal activities. This synthetically appealing
structure, in combination with its remarkable biological activ-
ity, has solicited considerable interest in the synthetic commu-
nity. Leighton and coworkers2 published the first total synthesis
of leucascandrolide A in 2000, and one formal total synthesis3
and several fragment preparations4 have been reported. We now
report a synthesis of the macrocyclic core of leucascandrolide
A, which constitutes a second formal total synthesis of the
natural product.
Our retrosynthetic analysis of the macrocycle simplified the
structure into two major fragments, with the key disconnection
at the C9–C10 bond. We anticipated that a C9-dithiane/C10-
iodide coupling would effectively unite the two fragments. The
synthesis of the C1–C9 dithiane began with the known allyl
sulfide 15 (Scheme 1). Lithiation of 1 with n-BuLi followed by
addition of m-xylylene dibromide furnished the bis-sulfide 2 in
78% yield. A double Mislow-Evans rearrangement6 was
induced by oxidation to the bis-sulfoxide with m-chloroperox-
ybenzoic acid and subsequent reductive trapping of the
sulfenate ester with diethylamine to provide diol 3 in 81% yield
with complete trans-selectivity. Monoprotection7 with TBSCl,
Sharpless asymmetric epoxidation8 with (2)-diisopropyl tar-
trate (86%, 97% ee by Mosher’s ester analysis) and reductive
opening of the epoxide with Red–Al gave diol 4. The primary
alcohol was selectively protected with TIPSCl, the olefin was
cleaved by ozonolysis and the resultant aldehyde was protected
as a 1,3-dioxolane. The ‘masked’ 1,3-dicarbonyl of the m-
disubstituted arene was then ready to be revealed. As expected,9
Birch reduction provided 1,4-cyclohexadiene 5 as a single
regioisomer in 89% yield. Ozonolysis of the diene and reductive
workup provided the crude 5-hydroxy-1,3-diketone which was
directly dehydrated to give pyranone 6 in 43% yield over 2
steps.9 Hydrogenation of 6 proceeded with good facial selectiv-
ity (dr = ~ 11+1). L-Selectride reduction of the resulting ketone
provided the axial C5-alcohol in 79% yield with a 12+1
diastereoselectivity. Subsequent silylation with TBDPSCl and
transacetalization10 with propane-1,3-dithiol led to dithiane 7.
Scheme 1 Reagents and conditions: (a) n-BuLi, THF, 278 °C; m-
(CH2Br)2C6H4, 78%; (b) m-CPBA, MeOH; Et2NH, 81%; (c) NaH, THF;
TBSCl, 73% based on recovered 3; (d) (2)-DIPT, Ti(i-PrO)4, t-BuO2H,
86%; (e) Red-Al, THF, 215 °C, 96%; (f) TIPSCl, im, CH2Cl2, 91%; (g) O3,
CH2Cl2, 278 °C; PPh3; (h) (CH2OH)2, TsOH, PhH, reflux, 62% for two
steps; (i) Li, NH3, THF, 250 °C; EtC(Me)2OH, 89%; (j) O3, EtOAc, 278
°C; H2, Pd(OH)2; (k) TsOH, PhH, reflux, 43% for two steps; (l) H2, Pd/C,
EtOAc, 71%; (m) L-Selectride, THF, 278 °C, 79%; (n) TBDPSCl, im,
DMAP, DMF, 83%; (o) CH2(CH2SH)2, TiCl4, CH2Cl2, 64%.
Fig. 1 Structure of Leucascandrolide A.
2066
CHEM. COMMUN., 2002, 2066–2067
This journal is © The Royal Society of Chemistry 2002

Scheme 2 Reagents and conditions: (a) (2)-Ipc2B(E-crotyl), THF, Et2O,
278 °C; NaOH, H2O2, 55%; (b) t-BuLi, THF, 278 °C; BnBr, HMPA, 86%;
(c) O3, CH2Cl2, 278 °C; PPh3, 74%; (d) Ph3PCHCO2Bn, CH2Cl2, 63%; (e)
H2, Pd/C, EtOAc, 87%; (f) DIBAL-H, PhCH3, 278 °C; (g) Ac2O, pyr, 87%
for two steps; (h) Allyl-TMS, BF3OEt2, CH2Cl2, 278 °C, 80%; (i) O3,
CH2Cl2, 278 °C; PPh3, 86%; (j) 4-methylpentyne, Cp2Zr(H)Cl, CH2Cl2;
Me2Zn, PhCH3, 12 (25 mol%), 230 °C, 62%; (k) TIPSCl, im, DMAP,
DMF, 76%; (l) EtOH, PPTS, 82%; (m) PPh3, I2, im, 87%.
Scheme 3 Reagents and conditions: (a) t-BuLi, THF/HMPA; 14, 74%; (b)
PhI(O2CCF3)2, THF/MeOH/H2O, 61%; (c) L-Selectride, THF, 278 °C,
98%; (d) MeOTf, 2-Me-4,6-(t-Bu)2pyr., CH2Cl2, 93%; (e) EtOH, TsOH,
71%; (f) Dess-Martin periodinane, CH2Cl2; (g) NaClO2, 2-methyl-
2-butene, t-BuOH, THF, H2O, 94% for two steps; (h) 1 M HCl, THF, 78%;
(i) PPh3, DIAD, THF, 0 °C, 58%; (j) TBAF, THF, 78%.
allylic alcohol 13 in 62% yield with a 5.1+1 diastereoselectivity.
This ratio was initially assumed to be in favor of the desired C17
(R)-alcohol, i.e. the configuration which the chirality of the
ligand and 1,3-chelate control by the substrate should both
enforce. However, elaboration of the major diastereomer into an
epimeric macrocycle proved that the vinylzinc addition actually
favored the opposite C17 (S)-diastereomer. Accordingly, we
changed our strategy to using a Mitsunobu macrolactonization16
to rectify the C17 stereochemistry. Silylation of the secondary
alcohol of the major diastereomer with TIPSCl followed by
selective TBS deprotection under mildly acidic conditions and
finally iodide formation provided the C10–C17 fragment 14.
Lithiation of dithiane 7 using the conditions developed by
Williams17 and addition of iodide 14 gave the C1–C17
intermediate in 74% yield (Scheme 3). Dithiane deprotection18
provided ketone 15. Excellent diastereoselectivity was obtained
in the reduction of this ketone with L-Selectride (98% yield, dr
= 13.6+1). Methylation of the sterically hindered C9-alcohol
with methyl triflate and deprotection of the primary TIPS-ether
provided alcohol 16. Two step oxidation to the carboxylic acid
using Dess-Martin periodinane followed by NaClO2 proceeded
in 94%. Removal of the secondary TIPS-ether with aqueous
HCl in THF gave the C17-epi seco acid in 78% yield.
Gratifyingly, application of a slight modification of the
conditions developed by Simon and coworkers19 for Mitsunobu
macrolactonization [syringe pump addition of the hydroxy acid
to premixed PPh3 (25 eq.) and DIAD (20 eq.) in THF at 0 °C]
furnished the desired TBDPS-protected macrocycle in 58%
yield. No products of allylic inversion or retention of configura-
tion were detected in this reaction. Finally, desilylation with
TBAF in THF provided the leucascandrolide A macrocycle 17,
which was identical in all respects with spectral data and
specific rotations reported by Leighton,2 Rychnovsky,3 and
Pietra.1
The National Science Foundation (CHE-0078944) and
Merck Research Laboratories are gratefully acknowledged for
financial support.
Notes and references
1 M. D. D’Ambrosio, A. Guerriero, C. Debitus and F. Pietra, Helv. Chim.
Acta, 1996, 79, 51.
2 K. R. Hornberger, C. L. Hamblett and J. L. Leighton, J. Am. Chem. Soc.,
2000, 122, 12894.
3 D. J. Kopecky and S. D. Rychnovsky, J. Am. Chem. Soc., 2001, 123,
8420.
4 M. T. Crimmins, C. A. Carroll and B. W. King, Org. Lett., 2000, 2, 597;
P. Wipf and T. H. Graham, J. Org. Chem., 2001, 66, 3242; A.
Vakalopoulos and H. M. R. Hoffmann, Org. Lett., 2001, 3, 177; S. A.
Kozmin, Org. Lett., 2001, 3, 755; T. J. Hunter and G. A. O’ Doherty,
Org. Lett., 2001, 3, 1049.
5 J. B. Baudin, G. Hareau, S. A. Julia, R. Lorne and O. Ruel, Bull. Soc.
Chim. Fr., 1993, 130, 856.
6 D. A. Evans and G. C. Andrews, Acc. Chem. Res., 1974, 7, 147.
7 P. G. McDougal, J. G. Rico, Y.-I. Oh and B. D. Condon, J. Org. Chem.,
1986, 51, 3388.
8 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune and K.
B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
9 D. A. Evans, J. A. Gauchet-Prunet, E. M. Carreira and A. B. Charette,
J. Org. Chem., 1991, 56, 741; P. Wipf and S. Lim, J. Am. Chem. Soc.,
1995, 117, 558; P. Wipf and S. Lim, Chimia,, 1996, 50, 157.
10 N. Kanoh, J. Ishihara, Y. Yamamoto and A. Murai, Synthesis, 2000, 13,
1878.
11 P. J. Parsons, P. Lacrouts and A. D. Buss, J. Chem. Soc., Chem.
Commun., 1995, 4, 437.
12 H. C. Brown and K. S. Bhat, J. Am. Chem. Soc., 1986, 108, 5919.
13 J. A. Marshall and D. G. Cleary, J. Org. Chem., 1986, 51, 858.
14 J. A. C. Romero, S. A. Tabacco and K. A. Woerpel, J. Am. Chem. Soc.,
2000, 122, 168.
15 P. Wipf and S. Ribe, J. Org. Chem., 1998, 63, 6454; P. Wipf and C.
Kendall, Chem. Eur. J., 2002, 8, 1778.
16 O. Mitsunobu, Synthesis, 1981, 1, 1.
17 D. R. Williams and S.-Y. Sit, J. Am. Chem. Soc., 1984, 106, 2949.
18 G. Stork and K. Zhao, Tetrahedron Lett., 1989, 30, 287.
19 K. W. Li, J. Wu, W. Xing and J. A. Simon, J. Am. Chem. Soc., 1996,
118, 7237.
In conclusion, highlights of our formal total synthesis include
the bidirectional synthesis of segment 4 and its elaboration into
pyran 7 by arene reduction–diene ozonolysis. Furthermore,
efficient thioacetal alkylation and Mitsunobu macrocyclization
via inversion were used for segment coupling and lactonization.
Work is in progress to elucidate the fundamental mechanism
responsible for the unexpected doubly mismatched ster-
eochemical outcome in the formation of the secondary allylic
alcohol stereocenter at C17.
CHEM. COMMUN., 2002, 2066–2067
2067