Total synthesis of leucascandrolide A [16]

Full text of DOI:10.1021/ja003593m

12894
J. Am. Chem. Soc. 2000, 122, 12894-12895
Scheme 1a
Total Synthesis of Leucascandrolide A
Keith R. Hornberger, Christopher L. Hamblett, and
James L. Leighton*
Department of Chemistry
Columbia UniVersity
New York, New York, 10027
ReceiVed October 5, 2000
Leucascandrolide A (1) was isolated from the sponge Leucas-
candra caVeolata by Pietra and co-workers in 1996.1 The natural
product displays strong in vitro cytotoxicity against KB and P388
cancer cell lines and is also a potent antifungal, inhibiting the
growth of Candida albicans. The unusual molecular achitecture
of 1, consisting of a doubly O-bridged 18-membered macrolide,
a (a) HgClOAc, acetone, 5 mol% Yb(OTf)3, 0 °C to rt. (b) 4 mol%
Rh(acac)(CO)2, 4 mol% P(O-o-t-BuPh)3, 0.50 equiv DABCO, 800 psi
1:1CO/H2, EtOAc, 50 °C. (c) (E)-crotyl-(-)-diisopinocampheylborane,
BF3‚OEt2, THF, -78 °C; NaOH, H2O2, (d) 2 mol% Rh(acac)(CO)2,
8 mol% PPh3, 400 psi 1:1 CO/H2, THF, 50 °C. (e) Ac2O, DMAP, pyridine,
CH2Cl2. (f) H2CdCHCH2SiMe3, Ti(O-i-Pr)2Cl2, CH2Cl2, -78 °C.
(g) n-Bu4NF, THF. (h) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C to
-40 °C. (i) allyl-(-)-diisopinocampheylborane, Et2O, -78 °C to rt;
NaOH, H2O2. (j) TBDPSCl, imidazole, DMF. (k) AcOH, H2O, 40 °C.
(l) 10 mol% PdCl2, 4 equiv CuCl2, 1 atm CO, MeOH:PhCN (1:1).
(m) Me3OBF4, Proton Sponge, 4 Å molecular seives, CH2Cl2.
coupled with its biological activity, makes it an attractive target
for total synthesis.2 In fact, the specific biological source of
leucascandrolide is currently unknown, and thus total synthesis
is currently the only potential source of this intriguing molecule.
Herein we report an enantioselective total synthesis of leucas-
candrolide A.
The synthesis of leucascandrolide A commenced from known
homoallylic alcohol 83 (Scheme 1). Yb(OTf)3-catalyzed oxymer-
curation with HgClOAc in acetone furnished organomercury
chloride 9 in 76% yield.4 Rh(I)-catalyzed formylation of 9 in the
presence of 0.50 equiv of1,4-diazabicyclo[2.2.2]octane (DABCO)
then afforded aldehyde 10 in 62% yield.5 Crotylation of 10
according to the protocol of Brown6 provided alkene 11 in 67%
yield and with >10:1 diastereoselectivity. Regioselective Rh(I)-
catalyzed hydroformylation of 11 gave a ∼1:1 mixture of
hemiacetals 12 in 89% yield. Treatment of 12 with Ac2O, pyridine,
and a catalytic amount of 4-(dimethylamino)pyridine (DMAP)
in CH2Cl2 gave unstable acetate 13 as a mixture of diastereomers.
Treatment of 13 with allyltrimethylsilane and Ti(O-i-Pr)2Cl2 in
CH2Cl2 at -78 °C afforded tetrahydropyran 14 (>10:1 ds).7 After
removal of the TBS group with tetra-n-butylammonium fluoride
(TBAF), alcohol 15 was isolated in 62% yield over three steps
from 12. Swern oxidation8 of 15 and Brown allylation9 (>10:1
diastereoselectivity) of the resultant aldehyde afforded homo-
allylic alcohol 16 in 75% yield (two steps) from alcohol 15.
Protection of alcohol 16 as the corresponding tert-butyldiphen-
ylsilyl (TBDPS) ether10 gave 17 in 99% yield, and hydrolysis
(AcOH, H2O, 40 °C) of the acetonide then afforded diol 18 in
98% yield and set the stage for the third carbonylation reaction
in the sequence. Intramolecular alkoxycarbonylation according
to the Semmelhack protocol (cat. PdCl2, CuCl2, 1 atm CO, 1:1
MeOH:PhCN) proceeded smoothly to provide the desired 2,6-
cis-tetrahydropyran 19 in 75% yield and >10:1 diastereoselec-
tivity.11 In the course of optimizing this reaction, we have found
that the use of benzonitrile as a cosolvent with methanol leads to
cleaner and more efficient reactions. Strategically, the reaction
is noteworthy in that the two alcohols and the two alkenes in 18
have been differentiated, significantly simplifying the protecting-
group strategy. Finally, methylation of alcohol 19 with Me3OBF4
in the presence of 4 Å molecular sieves furnished methyl ether
20 in 96% yield.12 The synthesis of 20 thus proceeds in 13 steps
and 10% overall yield from alcohol 8, employing three different
carbonylation reactions.
The completion of the synthesis of the macrolide necessitated
the diastereoselective addition of a vinylmetal fragment to a C(17)
aldehyde. Toward this end, alkene 20 was subjected to ozonolysis
to give aldehyde 21 in 93% yield (Scheme 2). Hydroboration of
4-methyl-1-pentyne with Cy2BH, followed by transmetalation with
Et2Zn and addition of N,N-dibutylaminoethanol and Ti(O-i-Pr)4,
and addition of the resultant organozinc reagent to aldehyde 21
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-60.
(2) For another approach to the synthesis of leucascandrolide A, see:
Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 597-599.
(3) Paterson, I.; Wallace, D. J.; Gibson, K. R. Tetrahedron Lett. 1997, 38,
8911-8914.
(4) (a) Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 403-405. (b) Dreher,
S. D.; Hornberger, K. R.; Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2,
3197-3199.
(8) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(9) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1986, 51, 432-439.
(10) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975-2977.
(11) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106,
1496-1498. (b) Semmelhack M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner,
M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035-2040. (c) White,
J. D.; Hong, J.; Robarge, L. A. Tetrahedron Lett. 1999, 40, 1463-1466.
(12) Ireland, R. E.; Liu, L.; Roper, T. D.; Gleason, J. L. Tetrahedron 1997,
53, 13257-13284 and references therein.
(5) Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 3205-3208.
(6) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570-1576.
(7) (a) Lewis M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978. (b) Danishefsky, S. J.; Kerwin, J. F. J. Org. Chem. 1982, 47,
3803-3805. (c) Kozikowski, A. P.; Sorgi, K. L. Tetrahedron Lett. 1983, 24,
1563-1566. (d) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984,
25, 2383-2386. (e) Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26,
1479-1482.
10.1021/ja003593m CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/27/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12895
Scheme 2a
Scheme 4a
a (a) (CF3CH2O)2P(O)CH2CO2H, EDCI‚HCl, HOBt‚H2O, CH2Cl2.
(b) KHMDS, 18-crown-6‚CH3CN, THF, -100 °C.
disclosed one-pot method of Wipf and Williams (diethylamino-
sulfurtrifluoride (DAST); DBU; BrCCl3).16 Reduction of the ester
with DIBAL-H produced alcohol 30 (86% yield), which was then
treated with CBr4 and PPh3 in CH3CN to give bromide 31 in 83%
yield. Stille coupling17 with vinyltributyltin, catalyzed by Pd2-
dba3 modified by tri(2-furyl)phosphine18 then produced allyl-
oxazole 32 in 82% yield. Hydroboration (9-BBN) of the mono-
substituted alkene and oxidation of the resultant alcohol under
the conditions of Swern8 gave aldehyde 33 in 71% yield over
two steps. The synthesis of aldehyde 33 proceeds in 10 steps and
14% overall yield from propargylamine.
a (a) O3, CH2Cl2, -78 °C; PPh3, rt. (b) 4-Methyl-1-pentyne, Cy2BH,
Et2Zn, N,N-dibutylaminoethanol, Ti(O-i-Pr)4, toluene, -40 to -20 °C.
(c) KOSiMe3, Et2O. (d) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP,
PhH. (e) TBAF, THF.
Scheme 3a
In anticipation of a Horner-Emmons reaction using Still’s
modification19 to establish the cis enoate of the side chain, alcohol
25 was acylated with bis(2,2,2-trifluoroethyl)phosphonoacetic
acid, employing 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDCI‚HCl) and 1-hydroxybenzotriazole hydrate
(HOBt‚H2O) to give phosphonoacetate 34,20 which was used
immediately (Scheme 4). Deprotonation of 34 with potassium bis-
(trimethylsilyl)amide (KHMDS) at -78 °C in THF in the presence
of 18-crown-6, and treatment of the resulting anion with aldehyde
33 at -100 °C gave a 7:1 mixture of fully synthetic leucascan-
drolide A 1 and the corresponding E-olefin isomer in 55% overall
yield (two steps from 25). The spectral properties (1H and 13C
NMR, IR, optical rotation, MS) of our fully synthetic material
matched the reported data for natural 1.21
a (a) n-BuLi, CO2, THF, -78 °C to 0 °C. (b) Lindlar’s catalyst,
quinoline, 1 atm H2, EtOAc. (c) i-BuOCOCl, N-Me-Morpholine,
Ser-OMe‚HCl, THF. (d) DAST, CH2Cl2, -20 °C; BrCCl3, DBU, 0 °C.
(e) DIBAl-H, THF, 0 °C. (f) CBr4, PPh3, 2,6-lutidine, CH3CN.
(g) n-Bu3SnCHdCH2, Pd2dba3, tri(2-furyl)phosphine, THF, reflux.
(h) 9-BBN, THF, H2O2. (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C to
0 °C.
This synthesis of leucascandrolide A proceeds in 20 steps
(longest linear sequence) from known alcohol 8 and provides a
direct confirmation of the assignment of the absolute configuration
of leucascandrolide A. It is amenable to the synthesis of structural
variants and highlights the utility of the carbonylation-based
approach to the synthesis of polyol and polyol-derived natural
products.
produced a 3:1 mixture of the desired allylic alcohol 22 and the
corresponding diastereomer in 60% yield.13 Demethylation of ester
22 with potassium trimethylsilanolate14 provided seco-acid 23,
which was immediately subjected to macrolactonization, according
to the Yonemitsu-modified Yamaguchi protocol15 to afford
macrolide 24 in 76% yield (two steps). Finally, 24 was subjected
to the action of TBAF to provide alcohol 25 in 77% yield, ready
for attachment of the acyl side chain. Macrolide 25 is a known
compound synthesized from leucascandrolide A by Pietra and
co-workers,1 and full spectral comparison at this stage confirmed
the structure of our synthetic material as well as the assignment
of absolute configuration.
The synthesis of the side chain began with carbamate 26,
readily prepared from propargylamine and methyl chloroformate
in 93% yield. Deprotonation with n-BuLi and quenching with
CO2 afforded the ynoic acid, which was immediately subjected
to Lindlar reduction to give Z-enoic acid 27 in 73% yield over
two steps (Scheme 3). Coupling of acid 27 to L-serine methyl
ester via the mixed anhydride formed with isobutyl chloroformate
produced amide 28 in 75% yield. This amide was readily
converted to oxazole 29 in 64% yield by employing the recently
Acknowledgment. The National Institutes of Health (National
Institute of General Medical Sciences, R01 GM58133) is acknowledged
for financial support of this work. We thank Pharmacia and Upjohn for
a Graduate Fellowship to K.R.H. and Merck Research Laboratories and
DuPont Pharmaceuticals for generous financial support. J.L.L. is a
recipient of a Sloan Research Fellowship, a Camille Dreyfus Teacher-
Scholar Award, a Bristol-Myers Squibb Unrestricted Grant in Synthetic
Organic Chemistry, a Cottrell Scholar Award from the Research Corpora-
tion, an Eli Lilly Grantee Award, an AstraZeneca Excellence in Chemistry
Award, and a GlaxoWellcome Chemistry Scholar Award.
Supporting Information Available: Experimental procedures and
spectral data for 9-11, 15-22, 24-33, and 1 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA003593M
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(21) We thank Professor F. Pietra and co-workers for providing copies of
1
their H and 13C NMR spectra of natural 1 and 25.