Asymmetric total synthesis of spongistatins 1 and 2

Article abstract of DOI:10.1021/ja0262683

The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fra

Full text of DOI:10.1021/ja0262683

Published on Web 04/26/2002
Asymmetric Total Synthesis of Spongistatins 1 and 2
Michael T. Crimmins,* Jason D. Katz, David G. Washburn, Shawn P. Allwein, and Laura F. McAtee
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received March 21, 2002
In 1993 Pettit,1 Kitagawa,2 and Fusetani3 independently identified
members of a new class of potent antitumor agents that were named
the spongistatins, altohyrtins, and cinachyrolides. The spongistatins
(altohyrtins) elicit extraordinary (subnanomolar) growth inhibition
of a variety of chemoresistant tumor types included in the NCI
panel of 60 human cancer cell lines. Human melanoma and lung,
brain, and colon cancers were particularly susceptible to spongistatin
1, whose activity correlates well with the class of microtubule
interactive antimitotics.4 The remarkable biological profile and the
extremely limited supply of this class sparked intense synthetic
efforts toward their synthesis. The proposed structures of the three
subclasses featured six pyran rings: AB and CD spiroketal
fragments as well as an E ring hemiketal and a highly substituted
F ring tetrahydropyran, all embedded in a 42-membered macrolide.
The conflicting absolute configurations, which were based on
extensive spectroscopic analysis, remained unresolved until the
Kitigawa assignment2 was confirmed by the first synthesis of
spongistatin 2 (altohyrtin C) by Evans5 and spongistatin 1 (altohyrtin
A) by Kishi.6 Synthesis of spongistatin 2 by Smith7 and spongistatin
1 by Paterson8 followed these initial publications. Additional reports
of syntheses of various fragments have also been reported from
other laboratories9 (Figure 1).
We previously reported approaches to the AB10 and CD11
spiroketals as well as the fully elaborated EF segment.12 We disclose
here the elaboration of the AB spiroketal, a modification of the
approach to the EF segment, and the details of the efficient
confluence of the individual fragments. An important consideration
in our strategic plan was the ability to efficiently assemble four
major fragments (the C1-C15 AB fragment 2, the C16-C28 CD
fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side
chain 5) at a very advanced stage of the synthesis with minimal
functional group interconversion. Thus, we chose to incorporate
each individual fragment with its native functionality (or as nearly
as possible) and selected the fully elaborated CD fragment 3 as
the nexus about which to assemble the subunits.
An efficient synthesis of the C1-C13 portion 6 (Scheme 1) of
the AB fragment 2 through the aldol union of a metalated pyrone
with a â-alkoxyaldehyde followed by acid-catalyzed cyclization to
prepare the diaxial AB spiroketal core has been disclosed.10
Completion of the AB fragment 2 required the elaboration of the
C12-C15 side chain including introduction of the C14 stereogenic
center. The side chain at C11 was extended through the application
of our asymmetric aldol procedure that utilizes chlorotitanium
enolates of oxazolidinethiones.13 Thus, hydroboration of the alkene
6 with 9-BBN under ultrasonic irradiation,14 followed by Swern
oxidation of the resultant alcohol gave the aldehyde 7. Asymmetric
aldol addition of the chlorotitanium enolate of N-propionyl-(S)-4-
benzyloxazolidine-2-thione to aldehyde 7 provided the alcohol 8
(96:4 d.r.) after reductive removal of the auxiliary. Selective
Figure 1. Retrosynthesis for the spongistatins.
protection of the primary alcohol as its TES ether furnished the
secondary alcohol 9. Oxidation of the C13 hydroxyl was succeeded
by Wittig olefination of the resulting ketone to incorporate the C13
alkene in 86% yield. The C1 benzyl ether of alkene 10 was
reductively cleaved to deliver alcohol 11, which was subjected to
a two-stage oxidation to the carboxylic acid. The carboxylic acid
was esterified under standard Mitsunobu conditions15 to generate
the allyl ester 12. The allyl ester was chosen to allow hydrolysis
of the ester under very mild conditions immediately prior to the
macrolactonization. Any concern regarding the sensitivity of the
C50 vinyl chloride to the conditions required to remove the allyl
ester [Pd(0)] were alleviated during the construction of the C44-
C51 side chain.12 The C5 TES ether was transformed in three high-
yield steps to the C5 acetate 13. The AB spiroketal 2 was completed
by selective hydrolysis of the C15 silyl ether and careful oxidation
of the alcohol under Dess-Martin16 conditions immediately prior
to use in the ensuing aldol reaction.
The synthesis of the C29-C43 fragment 4 was completed as
shown in Scheme 2. Our previous approach to the EF fragment
was modified to accommodate protecting-group alterations for
successful implementation of the final assembly strategy. Methyl
ketone 14 was synthesized through an analogous sequence to our
previous route12 with the exception of the use of a triethylsilyl ether
rather than a TBS ether at C41. Enolization of the methyl ketone
* To whom correspondence should be addressed. E-mail: crimmins@
email.unc.edu.
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10.1021/ja0262683 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 5661-5663
5661

C O M M U N I C A T I O N S
Scheme 1: Synthesis of the C1-C15 AB Fragmenta
produced the ketal 17, which was then advanced to the silyl ether
18 by sequential protection of the C41 and C35 hydroxyls.9a The
C29 and C38 benzyl ethers were reductively cleaved by the action
of LDDB, the C29 alcohol was selectively tosylated, and the C38
hydroxyl was protected as its TES ether 19. Finally, the tosylate
was converted to the phosphonium salt 4 via the C29 iodide.
Having established viable approaches to the four key subunits
in sufficient quantities, the final assault on their assembly to the
spongipyrans was advanced as illustrated in Scheme 3. The critical
issue of minimal refunctionalization during the assembly was
addressed by using the CD fragment 3, as the aldehyde at C28 and
the ketone at C17, as the foundation of the assemblage. Thus, the
four fragments were connected in their required final oxidation
states in just four synthetic steps. The C28-C29 olefin was
constructed in a remarkably efficient manner through the 1:1
stoichiometric combination of the CD aldehyde 3 and the ylide
derived from EF phosphonium salt 4 by the metalation of the
phosphonium salt with MeLi-LiBr.17 The alkene 20 was obtained
as a single detectable diastereomer in 86% yield. The resultant ethyl
ketone was immediately treated with Cy2BCl and Et3N followed
by addition of the AB aldehyde 2 to furnish the anti aldol product
21 with good selectivity (65%, 6:1 d.r.) after acylation of the C15
hydroxyl.5,7,8
a a) 9-BBN, THF, ultrasound; then H2O2, NaOH, 92%; b) (COCl)2,
DMSO, Et3N, CH2Cl2, 88%; c) N-propionyl-(S)-4-benzyloxazolidine-2-
thione, TiCl4, (-)-sparteine, CH2Cl2; d) LiBH4, MeOH, 74%, 2 steps; 96:4
d.r.; e) TESCl, imidazole, CH2Cl2, 94%; f) n-Pr4NRuO4, NMO, CH2Cl2,
95%; g) Ph3PCH3Br, n-BuLi, 90%; h) LDBB, THF, 84%; i) Dess-Martin
periodinane, CH2Cl2; j) NaClO2, t-BuOH, 2-methyl-2-butene, pH 5 buffer;
k) CH2dCHCH2OH, DEAD, Ph3P, THF, 96% (3 steps); l) HF-pyr, pyridine,
CH3CN; m) TESCl, imidazole, CH2Cl2, 92% (2 steps); n) Ac2O, CH2Cl2,
96%; o) HF-pyr, pyridine, CH3CN; p) Dess-Martin periodinane, pyridine,
CH2Cl2, 84% (2 steps).
The C44-C51 side chains, X ) Cl and X ) H for spongistatins
1 and 2, respectively, were attached through the Evans protocol.5,18
Exposure of the enol ether 21 to excess dimethyldioxirane led to
exclusive epoxidation of the C42-C43 enol ether with no detectable
oxidation of any other alkenes. Direct exposure of the epoxide to
allyl stannanes 5a12 and 5b in the presence of Bu3SnOTf indepen-
dently led to the fully elaborated spongistatin 1 and 2 seco esters
22 and 23. It is noteworthy that the chlorodiene unit of spongistatin
1 can be introduced through this method.
Scheme 2: Synthesis of the C29-C43 EF Fragmenta
With the fully elaborated spongistatin framework in place, the
task of closing the macrolide and completing the synthesis was
addressed. The allyl ester was removed with (Ph3P)4Pd in the
presence of morpholine19 with no evidence of damage to the fragile
chlorodiene moiety. The C41 and C47 silyl ethers were selectively
removed with buffered HF-pyridine to access the seco acids 24
and 26. Attempted macrolactonization of the seco acids 24 and 26
under the Yamaguchi20 and Keck21 protocols led to complex
mixtures of products, which included acylation of the C47 hydroxyl
by 2,4,6-trichlorobenzoyl chloride. Exposure of seco acid 24 to
DCC, DMAP, and DMAP-HCl produced a 3:1 mixture of the C41
and C42 macrolides. It thus appeared that to improve the selectivity
of the macrolactonization, the C47 hydroxyl needed to be rendered
unreactive.5 To that end, when the spongistatin 2 precursor 26 was
treated with excess Et3SiCl and imidazole, the selective protection
of the C47 hydroxyl was achieved without event, as previously
reported in the Evans synthesis.5 However, attempts to execute the
same transformation on the spongistatin 1 precursor 24 led to partial
hydrolysis of the C37 methyl ketal, presumably due to the presence
of the mildly acidic imidazole hydrochloride. Fortunately, addition
of Et3N to the reaction mixture suppressed the ketal hydrolysis,
and the synthesis was advanced to the hydroxy acids 25 and 27.
The regioselective macrocyclic lactonization5-8 was subsequently
performed without difficulty through the Yamaguchi protocol,20 and
final removal of all the remaining protecting groups by treatment
with 5% HF in acetonitrile produced synthetic spongistatin 1 and
a a) Cy2BCl, Et3N, pentane; 93% (>98:2 d.r.); b) PPTS, 3:1 CH2Cl2:
MeOH, 72% c) TESCl, imidazole, CH2Cl2; d) TBSCl, KN(SiMe3)2, THF,
-78 °C, 93% (2 steps); e) LDBB, THF; f) TsCl, Et3N, DMAP; g) Et3SiCl,
imidazole, CH2Cl2, 76% (3 steps); h) NaI, acetone; i) Ph3P, CH3CN, C6H6,
Li2CO3, 85% (2 steps).
spongistatin 2, both identical in all respects {by 1H, 13C, IR, [R]D
14 with Cy2BCl and Et3N in pentane followed by addition of
aldehyde 1512 led to the isolation of a single diastereomeric aldol
adduct 16. The R and â oxygen substituents of the methyl ketone
apparently act in synergy to direct the highly selective aldol
process.12 Exposure of 16 to PPTS in 3:1 dichloromethane:methanol
25
and MS} to previously reported data.1,2,5,8
In summary, the synthesis of both spongistatin 1 and spongistatin
2 have been achieved from an advanced common intermediate. The
efficient assembly strategy, which centers on the CD fragment as
9
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C O M M U N I C A T I O N S
Scheme 3: Final Fragment Assemblya
a a) MeLi-LiBr, THF, -78 °C, then aldehyde 3, 86%; b) Cy2BCl, Et3N, pentane, -78 °C aldehyde 2; c) Ac2O, Et3N, DMAP, CH2Cl2, (6:1 d.r., 60%
isolated major diastereomer, 2 steps); d) dimethyldioxirane, acetone, 0 °C, then n-Bu3SnOTf, CH2Cl2, -78 °C, X ) Cl, 70% (X ) H, 74%); e) Pd(Ph3P)4,
morpholine, 85%(94%); f) HF-pyr, pyridine, 79%(78%); g) TESCl, imidazole, CH2Cl2, 94%(87%); h) 2,4,6-trichlorobenzoyl chloride, i-Pr2NEt, DMAP,
PhCH3, 55%(60%); i) 5% HF, CH3CN, H2O, 45%(50%).
M. Angew. Chem., Int. Ed. 2001, 40, 191. Smith, Amos B., III.; Lin, Q.;
the foundation for the final assembly, avoids the need for refunc-
tionalization of the late-stage, complex intermediates.
Acknowledgment. This work was supported by a research grant
(CA63572) and a postdoctoral fellowship (GM20817 for S.P.A.)
Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K. Brook, C. S.;
Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40, 196. Smith,
Amos B., III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.; Koyanagi,
J.; Takeuchi, M. Org. Lett. 2002, 4, 783.
(8) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acen˜a, J. L.; Bach, J.; Gibson,
K. R.; Keown, L. E.; Oballa. R. M.; Trieselmann, T.; Wallace, D. J.;
Hodgson, A. P.; Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055.
(9) For leading references to synthetic approaches from other laboratories
see: Wallace, G. A.; Scott, R. W.; Heathcock, C. H.; J. Org. Chem. 2000,
65, 4145. Zuev, D.; Paquette, L. A.; Org. Lett. 2000, 2, 679. Terauchi,
T.; Nakata, M. Tetrahedron Lett. 1998, 39, 3795. Lemaire-Audoire, S.;
Vogel, P. Tetrahedron Lett. 1998, 39, 1345. Lemaire-Audoire, S.; Vogel,
P. J. Org. Chem. 2000, 65, 3346. Zemribo, R.; Mead, K. T. Tetrahedron
Lett. 1998, 39, 3895. Fernandez-Megia, E.; Gourlaouen, N.; Ley, S. V.;
Rowlands, G. J. Synlett 1998, 991. Micalizio, G. C.; Pinchuk, A. N.;
Roush, W. R. J. Org. Chem. 2000, 65, 8730. Anderson, J. C.; McDermott,
B. P. Tetrahedron Lett. 1999, 40, 7135. Samadi, M.; Munoz-Letelier, C.;
Poigny, S.; Guyot, M. Tetrahedron Lett. 2000, 41, 3349. Terauchi, T.;
Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh, N.; Nakata, M. Tetrahedron
Lett. 2000, 41, 2649. Kary, P. D.; Roberts, S. M.; Tetrahedron Asymmetry
1999, 10, 217. Kim, H.; Hoffmann, M. R. Eur. J. Org. Chem. 2000, 2195.
Barrett, A. G. M.; Braddock, D. C.; de Koning, P. D.; White, A. J. P.;
Williams, D. J. J. Org. Chem. 2000, 65, 375
(10) Crimmins, M. T.; Washburn, D. G. Tetrahedron Lett. 1998, 39, 7487
(11) Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
(12) Crimmins, M. T.; Katz, J. D.; Captain, L. F.; Tabet, E. A.; Kirincich, S.
J. Org. Lett. 2001, 3, 949.
(13) Crimmins, M. T.; King, B. W.; Tabet, E. A., Chaudhary, K. J. Org. Chem.
2001, 65, 894. Crimmins, M. T. Chaudhary, K. Org. Lett. 2000, 2, 775.
Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883.
from the National Institutes of Health.
Supporting Information Available: 1H spectra of synthetic spongi-
statin 1 and spongistatin 2 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt,
J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302. Pettit, G. R.;
Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J. Chem. Soc., Chem.
Commun. 1993, 1166. Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.; Gao,
F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.; Boettner, F. E. J. Chem.
Soc., Chem. Commun. 1993, 1805. Pettit, G. R.; Herald, C. L.; Cichacz,
Z. A.; Gao, F.; Boyd, M. R.; Christie, N. D.; Schmidt, J. M. Nat. Prod.
Lett. 1993, 3, 239. Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.;
Boyd, M. R.; Hamel, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994,
1605. Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E.
Mol. Pharmacol. 1993, 44, 757. Pettit, R. K.; McAllister, S. C.; Pettit, G.
R.; Herald, C. L.; Johnson, J. M.; Cichacz, Z. A.; Hamel, E. Int. J.
Antimicrob. Agents 1998, 9, 147. Bai, R.; Taylor, G. F.; Cichacz, Z. A.;
Herald, C. L.; Pettit, G. R.; Hamel, E. Biochemistry 1995, 34, 9714.
(2) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.; Sasaki, T.;
Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. Kobayashi, M.; Aoki, S.;
Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243. Kobayashi, M.; Aoki, S.;
Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm. Bull. 1993,
41, 989. Kobayashi, M.; Aoki, S.; Gato, I.; Kitagawa, I. Chem. Pharm.
Bull. 1996, 44, 2412.
(14) Brown, H. C.; Racherla, U. S. Tetrahedron Lett. 1985, 26, 2187.
(15) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899. Dess, D. B.; Martin, J. C. J. Am.
Chem. Soc. 1991, 113, 7277.
(17) Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; O’Mahony, R.; Hollis,
W. G., Jr.; Bankaitis-Davis, D. M.; Lever, J. G. J. Am. Chem. Soc. 1996,
119, 7513.
(3) Fusetani, N.; Shinoda, K.; Matsunoga, S. J. Am. Chem. Soc. 1993, 115,
3977.
(4) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
(5) Evans, D. A.; Trotter, W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse,
H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671. Evans, D. A.; Coleman,
P. J.; Dias, L. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2738. Evans, D.
A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J. Angew. Chem., Int. Ed. Engl.
1997, 36, 2741. Evans, D. A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J.;
Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 2744.
(6) Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward,
M. M.; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 187. Hayward,
M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Stevens, K. L.; Guo, J.;
Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 192.
(18) Evans, D. A.; Trotter, B. W., Cote´, B. Tetrahedron Lett. 1998, 39, 1709.
(19) Friedrich-Bochnitshek, S.; Waldmann, H.; Kunz, H. J. Org. Chem. 1989,
54, 751.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu,
O. J. Org. Chem. 1990, 55, 7-9.
(21) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
(7) Smith, Amos B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar, M.
D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.; Sobukawa,
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