Asymmetric total synthesis of callystatin A: Asymmetric aldol additions with titanium enolates of acyloxazolidinethiones [8]

Full text of DOI:10.1021/ja9817500

9084
J. Am. Chem. Soc. 1998, 120, 9084-9085
Scheme 1
Asymmetric Total Synthesis of Callystatin A:
Asymmetric Aldol Additions with Titanium Enolates
of Acyloxazolidinethiones
Michael T. Crimmins* and Bryan W. King
Venable and Kenan Laboratories of Chemistry
The UniVersity of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290
ReceiVed May 20, 1998
A number of highly cytotoxic polyketides, including the
anguinomycins,1 leptofuranins,2 leptomycin,3 and kazusamycin,4
having similar gross chemical structures have been isolated from
Streptomyces strains. Recently, a structurally related polyketide,
callystatin A 1, was isolated from the marine sponge, Callyspongia
truncata, in the Nagasaki Prefecture.5 Callystatin A shows
remarkable in vitro cytotoxicity (IC50 ) 0.01 ng/mL) against KB
cells. The relative and absolute stereostructure of callystatin A
was established by a combination of spectroscopic methods and
chemical synthesis.5-7 The limited quantities of callystatin A
available from natural sources, as well as the possibility for
carrying out syntheses and structure elucidation of the related
antitumor antibiotics, prompted us to pursue a total synthesis of
callystatin A.8 Here we disclose the asymmetric total synthesis
of (-)-callystatin A exploiting our recently developed asymmetric
aldol protocol with chlorotitanium enolates of acyl oxazolidi-
nethiones.9
Scheme 2
Strategically, E-selective olefination10 of aldehyde 2 (Scheme
1) with the phosphorane derived from tributylphosphonium salt
3 appeared to offer the most convergent assembly of callystatin
A. Aldehyde 2 representing C1 to C12 would be constructed
from a similar olefination between the masked pyranone aldehyde
4 (Scheme 2) and phosphonium salt 5 (Scheme 3). The C13 to
C22 propionate fragment 3 was to be constructed through
consecutive asymmetric aldol additions9 employing acyl oxazo-
lidinethione 6 (Scheme 4).
Scheme 3
The synthesis of aldehyde 4 began with S-glycidol 7 as
illustrated in Scheme 2. Protection of S-glycidol as its TBDPS
ether followed by copper-catalyzed epoxide opening with vinyl-
magnesium bromide provided the alcohol 8 in 85% overall yield.
Conversion of the secondary alcohol to the isopropoxy propenyl
ether provided a mixed acetal which was exposed to the Grubbs
catalyst11 to effect ring-closing metathesis to dihydropyran 9 (71%
overall). Removal of the TBPDS protecting group with n-Bu4-
* To whom correspondence may be addressed. E-mail: mtc@
net.chem.unc.edu.
(1) Hayakawa, Y.; Adachi, K.; Komeshima, N. J. Antibiot. 1987, 40, 1349-
1352. Hayakawa, Y.; Sohda, K.; Shin-ya, K.; Hidaka, T.; Seto, H. J. Antibiot.
1995, 48, 954-961.
(2) Hayakawa, Y.; Sohda, K.; Seto, H. J. Antibiot. 1996, 49, 980-984.
(3) Hammamoto, T.; Seto, H.; Beppu, T. J. Antibiot. 1983, 36, 646-650.
Hurley, T. R.; Bunge, R. H.; Willer, N. E.; Hokanson, G. C.; French, J. C. J.
Antibiot. 1986, 39, 1651-1656. Schaumberg, J. P.; Hokanson, G. C.; French,
J. C. J. Chem. Soc., Chem. Commun. 1984, 1450-1452.
(4) Komiyama, K.; Okada, K.; Oka, H.; Tomisaka, S.; Miyano, T.;
Funayama, S.; Umezawa, I. J. Antibiot. 1985, 38, 220-223.
(5) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S.
Tetrahedron Lett. 1997, 38, 2859-2862.
NF and Swern oxidation of the resultant alcohol provided a 90%
yield of the requisite aldehyde 4 (C1 to C6 fragment).
The C7 to C12 phosphonium salt 5, required for the olefination
reaction with aldehyde 4, was constructed as shown in Scheme
3. Oxidative cleavage of the known12 alkene 10 followed by in
situ reduction of the aldehyde and subsequent protection of the
primary alcohol provided 80% of the pivalate 11. Dibal-H
reduction of the pivalate ester followed by Swern oxidation of
the primary alcohol gave the aldehyde 12 in 88% overall yield.
The C8-C9 Z-olefin was installed by utilizing Still’s protocol
(6) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.;
Kobayashi, M. Tetrahedron Lett. 1997, 38, 5533-5536.
(7) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Higuchi, K.; Aoki,
S.; Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349-2352.
(8) During the preparation of this manuscript, the first total synthesis of
(-)-callystatin A was reported (see ref 7).
(9) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883-7884.
(10) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem. 1988,
53, 2723-2728.
(11) Grubbs, R. H.; Miller, S. J., Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452.
(12) Overman, L. E.; Robinson, L. A.; Zablocki, J. J. Am. Chem. Soc. 1992,
114, 368-369.
S0002-7863(98)01750-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/19/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 35, 1998 9085
Scheme 4
of the syn-aldol adduct 16 in 83% yield and greater than 98%
de. In preparation for the second asymmetric aldol to construct
the C16-C17 bond, the secondary alcohol was protected as its
TBS ether, the chiral auxiliary was reductively removed with
lithium borohydride, and the resultant alcohol was oxidized to
the aldehyde 17 in 83% overall yield. The facile reductive
removal of the oxazolidinethione auxiliary is noteworthy, given
the difficulty often encountered in the reductive cleavage of
oxazolidinone auxiliaries in hindered systems. Additionally,
recovery of the oxazolidinethione auxiliary (>90%) by simple
base extraction with aqueous NaOH further exemplifies the
practicality of oxazolidinethione-mediated asymmetric processes.
Execution of the second asymmetric aldol, under identical
conditions to the first, produced an 81% yield of the syn-aldol
adduct 18 (98:2 ds). At this point, orthogonal protection of the
C17 hydroxyl was required to allow its selective oxidation to a
carbonyl at a later stage. The TMS ether was obtained in 89%
yield by exposure of alcohol 18 to TMSOTf and 2,6-lutidine.
Reductive removal of the auxiliary again proceeded well, and
the resultant alcohol was oxidized under Swern conditions to
afford the aldehyde 19 in 71% yield for three steps. Installation
of the C14-C15 E-olefin to produce the ester 20 was ac-
complished in 93% yield with high selectivity (>97:3) by the
condensation of aldehyde 19 with carboethoxyethylidine-triph-
enylphosphorane. The ester 20 was then converted to the required
phosphonium salt 3 in three steps (82% overall) as described
above for the preparation of phosphonium salt 5.
The critical assembly of the two key subunits was completed
by the execution of a second E-selective olefination as for the
construction of the C6-C7 double bond. Addition of potassium
t-butoxide to a solution of aldehyde 2 and phosphonium salt 3 in
toluene at 0 °C resulted in the exclusive formation of the E-alkene
21 in 90% isolated yield. Completion of the synthesis of
callystatin A was accomplished by hydrolysis of the C1 acetal
and the C17 trimethylsilyl ether followed by TPAP15 oxidation
of the diol to the corresponding keto-lactone and finally hydrolysis
of the C19 TBS ether (43% overall for 3 steps). Synthetic
callystatin A was identical in all respects (1H, 13C NMR; CD;
IR; [R]D) to that reported for natural (-)-callystatin A.5-7
In summary, a highly efficient and selective total synthesis of
(-)-callystatin A has been accomplished. The synthesis hinges
on a ring-closing metathesis for the construction of the pyranone
fragment, two consecutive acyl oxazolidinethione asymmetric
aldol additions to prepare the propionate segment, and two
E-selective olefinations of tributylphosphonium ylides to ef-
ficiently assemble the three key subunits.
for construction of Z-unsaturated esters.13 Accordingly, treatment
of aldehyde 12 with the required phosphonate13 anion selectively
(8:1 E/Z) produced the Z-unsaturated ester which was immediately
reduced with Dibal-H to give 88% of the allylic alcohol 13. The
tributylphosphonium salt 5 was obtained from the alcohol 13 by
conversion of the allylic alcohol to the allylic bromide and the
subsequent displacement of the bromide with tributylphosphine
(92% from 13). The E-selective olefination of aldehyde 4 with
the phosphorane derived from salt 5 was attempted with several
bases in a variety of solvents. Yields were uniformly low (30%
or less) when the phosphonium salt was treated with base to form
the ylide followed by addition of the aldehyde.10 However, when
the base was added slowly to a mixture of the aldehyde and
phosphonium salt, yields were substantially improved. The best
conditions (t-BuOK, toluene, 0 °C) provided exclusively the
E-olefin 14 in 80% yield from the allylic bromide. The diene 14
was readily converted to the C1 to C12 aldehyde 2 by deprotection
of the C12 TBDPS ether followed by Swern oxidation (91% from
14).
Acknowledgment. Financial support of our programs by the NIH
and the NSF is acknowledged with thanks. Thanks are also due to Organic
Reactions for sponsoring a Division of Organic Chemistry Fellowship
for B.W.K. and Eastman Chemical Company for an Eastman Fellows
award to B.W.K. We thank Professor Motomasa Kobayashi for copies
of spectral data of natural (-)-callystatin A. We gratefully acknowledge
a generous donation of S-phenylalanine from NSC Technologies.
The synthesis of the C13 to C22 propionate fragment (Scheme
4) was predicated on the application of our recent success with
asymmetric aldol additions using chlorotitanium enolates of
acyloxazolidinethiones.9 Thus, treatment of propionyloxazolidi-
nethione 6 with titanium tetrachloride and (-)-sparteine followed
by addition of S-2-methylbutanal14 15 resulted in the formation
Supporting Information Available: Experimental procedures for
compounds 1-5, 8, 9, 11-14, 16-21 and spectral data (1H, 13C, IR) for
compounds 1, 2, 4, 8, 9, 11-14, 16-21 (22 pages, print/PDF). See any
current masthead page for ordering information and Web access
instructions.
(13) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(14) White, J. D.; Bolton, D. L.; Dantanarayana, A. P.; Fox, C. M. J.; Hiner,
R. N.; Jackson, R. W.; Sakuma, K.; Warrier, U. S. J. Am. Chem. Soc. 1995,
117, 1908-1939.
JA9817500
(15) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.