A modular approach to marine macrolide construction. 3. Enantioselective synthesis of the C1-C28 sector of spongistatin 1 (altohyrtin A).

Article abstract of DOI:10.1021/ol0000049

[structure: see text] A completely stereocontrolled approach to assembly of the major C1-C28 subunit of spongistatin 1 (altohyrtin A) is described. Key steps included the control of two asymmetric aldols by means of Fujita-Nagao (chiral N-acyl-1,3-thiazol

Full text of DOI:10.1021/ol0000049

ORGANIC
LETTERS
2000
Vol. 2, No. 5
679-682
A Modular Approach to Marine
Macrolide Construction. 3.
Enantioselective Synthesis of the
C1−C28 Sector of Spongistatin 1
(Altohyrtin A)
Dmitry Zuev and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received January 5, 2000
ABSTRACT
A completely stereocontrolled approach to assembly of the major C1−C28 subunit of spongistatin 1 (altohyrtin A) is described. Key steps
included the control of two asymmetric aldols by means of Fujita−Nagao (chiral N-acyl-1,3-thiazolidine-2-thione auxiliary) and Mukaiyama
(BF3‚OEt2-promoted enolsilane coupling) protocols in complex settings.
The spongipyran marine macrolides, designated as the
spongistatins,1 altohyrtins,2 and cinachyrolides3 by their
independent discoverers, are currently the most potent
antineoplastic agents identified. The remarkable subnano-
molar cytotoxicity exhibited by these sponge metabolites
against several cancer cell lines,4 in combination with their
very limited supply, has prompted several groups to under-
take synthetic activity in this area.5-18 Our early efforts have
culminated in the concise stereocontrolled construction of
both the C1-C12 (AB)19 and C17-C28 (CD) spiroacetal
sectors.20 We now describe an efficient means for tethering
(4) (a) Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E.
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P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (c) 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. (d) Evans, D. A.; Trotter, B. W.; Coleman,
P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron
1999, 55, 8671.
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R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302. (b)
Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. J. Chem.
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Z. A.; Gao, F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.; Boettner, F.
E. J. Chem. Soc., Chem. Commun. 1993, 1805. (d) Pettit, G. R.; Cichacz,
Z. A.; Herald, C. L.; Gao, F.; Boyd, M. R.; Schmidt, J. M.; Hamel, E.; Bai,
R. J. Chem. Soc., Chem. Commun. 1994, 1605. (e) Pettit, G. R. Pure Appl.
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35, 1243. (b) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara,
N.; Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. (c) Kobayashi,
M.; Aoki, S.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm.
Bull. 1993, 41, 989. (d) Kobayashi, M.; Aoki, S.; Gato, K.; Kitagawa, I.
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Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187. (b)
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G. R.; Heathcock, C. H. Org. Lett. 1999, 1, 1475. (d) Claffey, M. M.; Hayes,
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115, 3977.
10.1021/ol0000049 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/03/2000

Scheme 1
a SEMCl, (i-Pr)2NEt, Bu4NI, THF, rt, 24 h (95%). b (i-Bu)2AlH, CH2Cl2, -78 °C, 45 min (98%). c TPAP, NMO, 4 Å MS, CH2Cl2, rt,
f
1 h (96%). d MeMgBr, THF, Et2O, -78 to 0 °C, 2.5 h (93%). e TBSOTf, (i-Pr)2NEt, CH2Cl2, -40 to 0 °C (93%). DDQ, CH2Cl2-H2O
i
(16:1), rt, 1 h (90%). g I2, PPh3, imidazole, benzene, rt, 1.5 h (82%). h KCN, DMF, 65 °C, 36 h (quant). (i-Pr)2AIH, CH2Cl2, -78 °C, 20
j
min. EtMgBr, Et2O, -78 to 0 °C, 3 h (74% for two steps). k TPAP, NMO, 4 Å MS, CH2Cl2, rt, 9 h (99%).
these structurally complex building blocks via an enantio-
selective scheme designed to ultimately access spongistatin
1 (1, corresponds to altohyrtin A).
sponded to the action of methylmagnesium bromide very
predominantly by way of equatorial attack to furnish 5a in
93% yield. The resulting axial disposition and tertiary nature
of the OH substituent in this intermediate required recourse
to tert-butyldimethylsilyl triflate23 for protection purposes.
With 5b in hand, the acquisition of alcohol 5c proceeded
without event. Homologation of the side chain in 5c began
with cyanide ion displacement on iodide 6a. To skirt potential
complications arising from â-elimination within 6b, this
nitrile was directly transformed into ethyl ketone 8 by
sequential low-temperature Dibal-H reduction, 1,2-addition
(10) (a) Hermitage, S. A.; Murphy, A.; Roberts, S. M. Bioorg. Med.
Chem. Lett. 1998, 8, 1635. (b) Hermitage, S. A.; Roberts, S. M.; Watson,
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Watson, D. J. Tetrahedron: Asymmetry 1999, 10, 213. (d) Kary, P. D.;
Roberts, S. M. Tetrahedron: Asymmetry 1999, 10, 217.
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Synlett 1998, 991.
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1999, 10, 1539.
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Chem. 1956, 21, 478.
One phase of the convergent assembly began with 2, an
alcohol readily obtained via the thermodynamically con-
trolled spirocyclization described previously19 (Scheme 1).
The remaining hydroxyl group was transformed into its SEM
ether21in advance of Dibal-H reduction to give 3b. Subse-
quent perruthenate oxidation22 gave ketone 4, which re-
(8) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett.
1996, 37, 8581. (b) Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38,
5727. (c) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585. (d) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241.
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39, 8545.
(9) (a) Smith, A. B., III.; Zhuang, L.; Brook, C. S.; Boldi, A. M.; McBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q.
Tetrahedron Lett. 1997, 38, 8667. (b) Smith, A. B., III.; Zhuang, L.; Brook,
C. S.; Lin, Q.; Moser, W. H.; Trout, R. E. L.; Boldi, A. M. Tetrahedron
Lett. 1997, 38, 8671. (c) Smith, A. B., III.; Lin, Q.; Nakayama, K.; Boldi,
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Soc. 1996, 118, 4322.
680
Org. Lett., Vol. 2, No. 5, 2000

of ethylmagnesium bromide to the resulting aldehyde, and
perruthenate oxidation.
Chiral N-acyl-1,3-thiazolidine-2-thiones have seen limited
use for controlling asymmetric induction in aldol condensa-
tions.24 When employed with tin(II) triflate and N-ethyl-
piperidine as promoters, Z-enolates are generated,25 chelated
transition states are kinetically favored,26 and syn products
appear to be formed with excellent diastereoselectivity.25 To
gauge the applicability of the Fujita-Nagao protocol in the
present context, (S)-9 was condensed with propionaldehyde
and afforded 10 in 95% yield (Scheme 2). The absolute
Scheme 2
a Sn(OTf)2, N-ethylpiperidine, CH2Cl2, -78 °C, 2 h; CH3CH2CHO,
-78 °C, 1 h (95%).
Figure 1. ORTEP diagram of 10.
to 15 under catalysis by boron trifluoride etherate at low
temperature would proceed in a syn-stereoselective manner
to set the substituents at C15 and C16 into an anti arrange-
ment. Related processes are recognized to exhibit a tendency
to afford anti-Felkin products predominantly via synclinal
transition states.30 In the present instance, the Mukaiyama
aldol reaction proceeded in a highly controlled manner to
deliver 16 as the only detectable product. The assignment
of stereochemistry was addressed by spectroscopic analysis
of 16 in C6D6 solution at 500 MHz. The syn relationship
between H14 (δ 2.88) and H15 (δ 4.22) was readily deduced
on the basis of the low magnitude (2.8 Hz) of the corre-
sponding coupling constant. Similarly, the significant spin-
spin interaction between H15 and H16 (9.2 Hz) unequivo-
cally defined their anti relationship. The ensuing olefination31
of ketone 17 with the Tebbe reagent32 conveniently provided
the targeted molecule 18.
configuration of 10 was ascertained by X-ray crystallographic
analysis (Figure 1).
Oxidative cleavage of the double bond in 11,20 best
accomplished under Lemieux-Johnson conditions,27 fur-
nished aldehyde 12 (Scheme 3). Union of 12 with (S)-9 led
to highly stereocontrolled introduction of two new stereo-
genic centers under the absolute control of the 1,3-thia-
zolidine-2-thione as previously demonstrated. The transfor-
mation of 13 into the Weinreb amide28 occurred in 97% yield
without any detectable epimerization. Following formation
of the TBS ether, reduction to give aldehyde 14 proceeded
quantitatively upon treatment with Dibal-H in THF at -78
°C. At this juncture, recourse was made to a second aldol
reaction, now involving 14, to establish absolute configu-
ration properly at C14 and C15. To this end, ketone 8 was
first converted to its Z-enolsilane according to the Masamune
protocol.29 This regio- and stereoselective transformation led
to 15 (Scheme 4). Our expectation was that coupling of 14
A convenient, highly enantioselective route to a major
portion of 1 has been brought to successful fruition. Our
Scheme 3
a OsO4, NMO, THF, H2O, rt, 50 min; NaIO4, rt, 1.5 h (87%). b (S)-9, Sn(OTf)2, N-ethylpiperidine, CH2Cl2, -78 °C, 2 h 15 min; 12, -78
°C, 1 h (96%). c Me3Al in hexanes, MeNH(OMe)‚HCl, CH2Cl2, THF, -5 °C, 1 h 50 min (95%). d TBSOTf, 2,6-lutidine, CH2Cl2, -20 °C,
1 h 15 min (88%). e (i-Bu)2AlH, THF, -78 °C, 15 min (quant).
Org. Lett., Vol. 2, No. 5, 2000
681

Scheme 4
a (PhMe2Si)2NLi, THF, -78 °C, 1 h; TMSCl, -78 °C to rt, 6 h (35%; 100% based on recovered 8). b BF3‚Et2O, toluene, -78 °C, 1.5
h (67%). c SEMCl, (i-Pr)2NEt, Bu4NI, THF, rt, 2 days (53%). d Cp2Ti(Cl)CH2AlMe2, THF, -78 °C to rt, 6 h (23%, 88% based on recovered
17).
synthetic pathway exploits the very utilitarian capability of
tin enolates derived from N-acyl-1,3-thiazolidine-2-thiones
to control aldol stereoselectivity with minimal regard for
matched/mismatched pairing, as well as the many advantages
associated with Lewis acid-promoted C-C bond formation
between aldehydes and stereodefined enolsilanes. Completion
of the synthesis of 1 is being actively pursued.33
Acknowledgment. We thank the Eli Lilly Company for
financial support.
Supporting Information Available: Tables of X-ray
crystal data, bond lengths and angles, and positional and
anisotropic displacement parameters for 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
This information can also be obtained on request from The
Director, Cambridge Crystallographic Data Centre, Univer-
sity Chemical Laboratory, Lensfield Road, Cambridge CB2
1EW, U.K.
(31) Pine, S. H. Org. React. (N.Y.) 1993, 43, 1.
(32) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(33) The structure assigned to each new compound is in full accord with
its IR, 300 MHz, 1H NMR, 75 MHz 13C NMR, and high-resolution MS
spectra.
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Org. Lett., Vol. 2, No. 5, 2000