Enantioselective [4 + 2]-Annulation of Chiral Crotylsilanes: Application to the Synthesis of a C1-C22 Fragment of Leucascandrolide A

Article abstract of DOI:10.1021/ol035581m

(Formula presented). The asymmetric synthesis of a C1-C22 fragment (2) of leucascandrolide A is described. Synthetic highlights include the construction of the C9-C22 pyran fragment using a formal [4 + 2]-annulation of a chiral organosilane. A diastereose

Full text of DOI:10.1021/ol035581m

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3995-3998
Enantioselective [4 + 2]-Annulation of
Chiral Crotylsilanes: Application to the
Synthesis of a C1−C22 Fragment of
Leucascandrolide A
Les A. Dakin and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received August 21, 2003
ABSTRACT
The asymmetric synthesis of a C1−C22 fragment (2) of leucascandrolide A is described. Synthetic highlights include the construction of the
C9−C22 pyran fragment using a formal [4 + 2]-annulation of a chiral organosilane. A diastereoselctive Mukaiyama aldol was used to introduce
the C9 stereocenter and complete the assembly of the macrocycle’s carbon skeleton.
Leucascandrolide A 1 is a doubly O-bridged 18-memebered
macrolide isolated from the calcareous sponge Leucascandra
caVeolata, obtained from the northeastern coast of New
Calendonia, Coral Sea.1 This macrolide exhibits high in vitro
cytotoxicity against human KB and P388 tumor cell lines
displaying low IC50 values of 0.05 and 0.26 µg/mL,
respectively. The natural product also possesses potent
antifungal ability against Candida albicans, a pathogenic
yeast that attacks AIDS patients and other immunocompro-
mised individuals. A subsequent report indicates that leu-
cascandrolide A is no longer available from its initial natural
source.2 It has been postulated that 1 is not a metabolite of
Leucascandra caVeolata but rather an opportunistic bacteria
as evidenced by the large amounts of dead tissue in the initial
harvest of Leucascandra caVeolata. Currently there is no
natural source of leucascandrolide A.
The lack of a natural source of 1, together with its unique
doubly oxygenated 18-membered macrolide, has made
leucascandrolide A, a target of interest for the synthetic
community. Following the first total synthesis by Leighton,3
there have been additional reports detailing total,4 formal,5
and fragment syntheses of 1.6 Herein we discuss our approach
(3) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894-12895.
(4) (a) Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098-
4101. (b) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343-
347. (c) Wang, Y.; Janic, J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124,
13670-13671.
(5) (a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420-8421. (b) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066-
2067.
(6) (a) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
597-599. (b) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242-
3245. (c) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002,
67, 6812-6815.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta. 1996, 79, 51-60.
(2) (a) D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F.
HelV. Chim. Acta 1999, 82, 347-353. (b) D’Ambrosio, M.; Tato, M.;
Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV. Chim. Acta 1999, 82, 1135.
10.1021/ol035581m CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/19/2003

to macrolide and describe the synthesis of the C1-C22
advanced intermediate. Concerning the retrosynthesis of 1,
disconnection of the C5 ester gives the macrocyclic lactone,
which could be derived from the C1-C22 fragment 2
(Scheme 1). Further analysis of 2 suggests that it could be
The utility of the annulation is illustrated in the efficient
manner in which it installs the C11, C12, and C15 stereo-
centers of the target molecule (Scheme 2).
Scheme 2. Construction of the Left-Hand Pyran Subunit
Scheme 1. Retrosynthetic Analysis of Leucascandrolide A
With efficient access to dihydropyran 8, construction of
the aldehyde 3 was initiated (Scheme 3). Elaboration of 8
Scheme 3. Synthesis of Pyran 3a
divided at the C8-C9 bond to give the Mukaiyama aldol-
coupling partners: pyran 3 and silyl enol ether 4.7 The C9-
C22 pyran 3 could be synthesized using the [4 + 2]
annulation of chiral crotylsilanes developed in our labora-
tories between chiral silane (S,S)-5 and an appropriate
aldehyde.8
a Key: (a) (i) H2, Pd/C, EtOAc, rt, 99%; (ii) Hg(OAc)2,
CH3CO3H, rt, 76%. (b) (i) TBDPSCl, imidazole, DMF, rt; (ii) Dibal-
H, CH2Cl2, 0 °C; (iii) (PhO)3P+CH3I-, DMF, 0 °C, 77% for three
Silyl enol ether 4, could be synthesized in a straightforward
manner starting with enantioenriched epoxide (S)-6 as an
initial building block, readily available via Jacobsen’s
hydrolytic kinetic resolution (HKR).9
t
steps. (c) 11, BuLi, THF/HMPA (10:1), 78 f 0 °C, 97%. (d)
Dess-Martin periodinane, MeOH/H2O/THF (8:1:1), rt, 91%. (e)
(i) (S)-CBS (14), BH3‚THF, THF, -20 °C, 80%, (dr > 15:1); (ii)
NaH, BnBr, n-Bu4NI, DMF, rt, 90%. (f) (i) TBAF, THF, rt, 99%;
(ii) Dess-Martin periodinane, pyridine, CH2Cl2, rt, 80%.
To begin the synthesis of fragment 3, a [4 + 2] annulation
of (S,S)-5 with selected aldehydes capable of serving as a
precursor to the C9 aldehyde was evaluated. After a brief
examination of the reaction, it was determined that reaction
of (S,S)-5 with aldehyde 7 catalyzed by TMSOTf at -50
°C gave the requisite dihydropyran 8 in excellent yield (95%)
and diastereoselctivity (dr > 20:1).10
began with the hydrogenation of the olefins under the
standard conditions (H2, Pd/C) followed by a Fleming-
Tamao oxidation11 of the dimethylphenylsilyl substituent.
This was best performed by treatment with Hg(OAc)2 in
(7) Mukaiyama, T.; Banno, K.; Naraska, N. J. Am. Chem. Soc. 1974,
96, 7503-7509.
(8) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836-9837.
(9) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E. Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1316.
(10) Several other protected 3-hydroxy-propionaldehyde derivates were
surveryed in the annulation with (S,S)-5 all giving inferior yields and
diastereoselectivities.
(11) (a) Fleming, I.; Henning, R.; Parker, D. C. Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin. Trans. 1 1995, 317-337. (b) Tamao, K.;
Ishida, N. J. Organomet. Chem. 1984, C37-C39.
3996
Org. Lett., Vol. 5, No. 21, 2003

peracetic acid giving alcohol 9 in 74% yield for two steps.
Protection of the primary alcohol as the tert-butyldiphenyl-
silyether, Dibal-H reduction of the methyl ester to the primary
alcohol, and subsequent treatment with (PhO)3P+CH3I- in
DMF gave alkyl iodide 10 (77% yield over three steps).
Iodide 10 was then alkylated (97%) by treatment with the
lithium anion of dithiane 11 in a THF/HMPA (10:1) solvent
system.12 At this stage it was necessary to unveil the R,â-
unsaturated ketone 13. This proved to be challenging, and
after an extensive review of conditions that promote the
removal of dithiane protecting groups, it was discovered that
treamtent of 12 with Dess-Martin periodinane in wet
methanol for 12 h afforded R,â-unsaturated ketone 13 in
good yield.13 Subsequent reduction of ketone 13 with a
catalytic amount of Corey’s chiral borane, (S)-CBS (14), in
the presence of BH3‚SMe2, cleanly installed the C17 stereo-
center (80%, dr ≈ 15:1).14 Protection of the emerged allylic
alcohol as the benzyl ether (BnBr, n-Bu4NI, DMF, 90%) and
deprotection of the primary silyl ether (TBAF, 99%),
followed by Dess-Martin oxidation15 of the resulting
primary alcohol (80%), afforded the aldehyde, completing
the synthesis of intermediate 3.
sium bromide in the presence of 20 mol % CuI provided
â-hydroxy ketone 17 (75%). Subsequent treatment of 17 with
Zn(BH4)216 in CH2Cl2 at -78 °C afforded a 1,3-syn reduction
to the 1,3-diol (80%, dr > 15:1). This material was then
treated with 2,2-dimethoxypropane in the presence of a
catalytic amount of p-TsOH, which provided acetonide 18.
Completion of 4 was accomplished by cleavage of the
terminal olefin by ozonolysis giving ketone 19, which, when
treated the bulky lithium anion of 2,2,6,6-tetramethylpiperi-
dine, gave the desired regiochemical enolate, which was then
trapped with TMS-Cl, completing the C1-C8 silyl enol
ether coupling partner 4.
To undertake the assembly of the C1-C22 fragment 2, a
Mukaiyama aldol between aldehyde 3 and silyl enol ether 4
was investigated. After a brief survey of the reaction, it was
determined that the coupling was best effected by treatment
of a mixture of 3 and 4 in CH2Cl2 with BF3‚OEt2 at -78 °C
for 4 h (Scheme 5). Gratifyingly, the coupling proceeded in
Scheme 5. Synthesis of the C1-C22 Fragment 2a
Synthesis of the C1-C8 silyl enol ether 4 began with
enantiomerically pure epoxide (S)-6 readily available in
multigram quantities from HKR of (() 6 (Scheme 4).
Scheme 4. Synthesis of Silyl Enol Ether 4a
a Key: (a) (ii) BF3‚OEt2, CH2Cl2, -78 °C, 81% dr > 15:1; (ii)
Me3OBF4, Proton Sponge, 4 Å molecular sieves, CH2Cl2, rt, 99%.
good yield (81%) and diastereoselectivity (dr > 15:1).
Despite the monodentate nature of BF3‚OEt2, there is ample
precedent for 1,3-anti induction in similar systems.17 The
absolute stereochemistry at C9 was unambiguously assigned
using the method of Mosher.18 The methylation of the C9
hydroxyl was then accomplished by treatment with Meer-
wein’s reagent and Proton sponge (99%) giving the C1-
C22 fragment 2.19
a Key: (a) tert-butyl acetate, LDA, THF, -50 °C, 70%. (b)
Isopropenylmagnesium bromide, 20 mol % CuI, THF, -50 °C,
75%. (c) (i) Zn(BH4)2, CH2Cl2, -78 °C, 80%, dr > 15:1; (ii) 2,2-
dimethoxypropane, cat. p-TsOH, rt, 99%. (d) O3, MeOH, Me2S,
-78 °C, 95%. (e) Lithium tetramethylpiperidine, TMSCl, -78 °C,
77%.
Treatment of (S)-6 with the lithium anion of tert-butyl acetate
in THF at -50 °C gave the unstable â-ketoester 16 in 70%
yield. Subsequent treatment of 16 with isopropenylmagne-
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(16) For reviews on the synthetic applications of zinc borohydride, see:
(a) Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31, 19-27.
(b) Hoyveda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 1307-
1370. (c) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am.
Chem. Soc. 1998, 120, 5921-5942.
(12) For leading references on dithiane alkylation, see: Smith, A. B.;
Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925-6926. and references
therein.
(13) For an initial communication and discussion of this reaction, see:
Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 4, 575-578.
(14) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990,
31, 611-614. (c) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 1986-2012.
(17) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994,
35, 8537-8540. (b) Paterson, I.; Smith, J. D. J. Org. Chem. 1992, 57, 3261-
3264.
(18) (a) Dale, J. A.; Mosher, H. S. L. J. Am. Chem. Soc. 1973, 96, 512-
519. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, D. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370-2374.
Org. Lett., Vol. 5, No. 21, 2003
3997

In conclusion, we have described a convergent synthesis
to an advanced intermediate of leucascandrolide A. The
approach features an enantioselective synthesis of the C9-
C22 fragment 3 through the use of a formal [4 + 2]
annulation between chiral crotylsilane (S,S)-5 and aldehyde
6 and a 1,3-anti diastereoselective Mukaiyama aldol coupling
between fragments 3 and 4, which completed the carbon
framework of the macrocycle of leucascandrolide A. Studies
toward the completion of leucascandrolide A are underway
and will be reported at a later time.
Acknowledgment. The authors are grateful to Mr.
Hongbing Huang for helpful discussions. Financial support
was obtained the NIH-NCI (CA56404) and NIH (P50
GM067041).
Supporting Information Available: General experimen-
tal procedures, including spectroscopic characterization of
novel compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(19) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt.
Chem. 1937, 147, 257.
OL035581M
3998
Org. Lett., Vol. 5, No. 21, 2003