Highly diastereocontrolled synthesis of the C1-C25 domain of sanglifehrin A

Article abstract of DOI:10.1016/S0040-4039(00)00504-9

We report a diastereoselective synthesis of 2 containing the core structure of the entire eastern sector of sanglifehrin A. The route proceeds by directed chain extension of appropriate building blocks, their timely convergent amalgamation, and ultimate c

Full text of DOI:10.1016/S0040-4039(00)00504-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3789–3792
Highly diastereocontrolled synthesis of the C1–C25 domain of
sanglifehrin A
Maosheng Duan and Leo A. Paquette ∗
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Received 26 January 2000; revised 17 March 2000; accepted 20 March 2000
Abstract
We report a diastereoselective synthesis of 2 containing the core structure of the entire eastern sector of
sanglifehrin A. The route proceeds by directed chain extension of appropriate building blocks, their timely
convergent amalgamation, and ultimate coupling to a preformed tripeptide subunit. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: immunosuppressive agents; aldol reaction; enol borinate; peptide coupling; vinyl iodide.
Scientists at Novartis Pharma reported in a 1997 patent application on the isolation of sanglifehrins
A–D from cultures of Streptomyces sp. A92–308110.1a In a later disclosure, the characterization of
additional members of this compound class was detailed.1b Although the absolute configurations at C17,
C38 and C40 were self-contradicted several times in these documents, this issue was ultimately rectified
by X-ray crystallography2 and more recently verified by partial3,4 and total synthesis.5 As reflected in
the structure of the A factor (1), the conformationally rigid 22-membered ring that is richly adorned with
functionality is linked via a dienyl tether to a spiro aminal subunit. This combination of structural features
causes 1 to exhibit a 20-fold higher binding affinity for cyclophilin A than cyclosporin, and otherwise
to differ from known immunosuppressant agents by displaying neither FK binding protein affinity nor
calcineurin inhibiting capability. These striking biological properties make 1 and analogs thereof very
attractive synthetic targets. Here we define a convenient means for constructing the entire eastern sector
that houses C1–C25 (see 2).
∗
Corresponding author. Fax: 1-614-292-1685; e-mail: paquette.1@osu.edu (L. A. Paquette)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00504-9
tetl 16783

3790
In a continuation of our synthetic plan,3 which is to involve Stille coupling of the major molecular
segments across C25 and C26 in the last step, the acetylenic diene acetal 10 was initially generated from
the enantiopure oxazolidinone 36 as summarized in Scheme 1. Thus, sequential Wacker oxidation and
thioketal formation furnished 5 efficiently, thereby allowing for highly diastereoselective conversion to 7
by acylation of the lithium enolate with propionyl chloride. As anticipated from the prior observations of
Evans,7 the stereogenecity of 7 at the newly formed chiral center was not eroded during chromatographic
purification due to the low kinetic acidity brought on by allylic strain effects.
Scheme 1.
The ensuing convergent step required the availability of aldehyde 15. To this end, easily accessible 118
was subjected to ozonolysis and Wittig–Horner reaction with methyl 4-(diethylphosphono)crotonate as
promoted by lithium hexamethyldisilazide (13, Scheme 2).9,10 Chromatographic removal of the minor
(2E,4Z) isomer gave rise to pure 14 (32%). Reduction of this ester with diisobutylaluminum hydride and
perruthenate oxidation made available the required intermediate 15 in very good yield.
Formation of the (E)-boron enolate from treatment of 7 with chlorodicyclohexylborane and
ethyldimethylamine11 followed by the addition of 15 afforded the anti aldol 8. Efficiency was
improved if the workup conditions defined by Paterson12 were implemented. Direct reduction of 8 with
tetramethylammonium triacetoxyborohydride13 served to complete elaboration of the four contiguous
stereogenic centers and delivered 9 in 48% overall yield as the major product. Dethioacetalization of

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Scheme 2.
Scheme 3.
9 with phenyliodine(III) bis(trifluoroacetate)14 skirted troublesome problems encountered with other
carbonyl unmasking protocols,15 and emerged as the preferred route to 10 (66%). Our inability to carry
10 onward to 2 now surfaced from two directions: (a) the lack of a means to functionalize the terminal
acetylenic functionality even under conditions where steric congestion was abated by removal of the
silyl protecting group;16 and (b) substantial reluctance on the part of the chiral auxiliary to undergo
oxidative cleavage.17 These complications caused us to install the vinyl iodide functionality from the
very outset (Scheme 3).

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The new approach began from the known aldehyde 16,18 which was homologated into 17 in the
predescribed manner. Two-step reduction of 17 delivered 18 whose coupling to the (E)-boron enolate
of 7 and stereocontrolled hydride reduction proceeded uneventfully as before. Once ketal 20 had been
obtained by dethioacetalization, we were pleased to recognize that reduction with sodium borohydride
in THF and water (3:1) as solvent19,20 did indeed proceed regioselectively to furnish 21 in 69% yield.
Two-step oxidation of this primary carbinol to carboxylic acid 22 was accomplished in notably efficient
fashion (97%). In preparation for peptidic coupling, the previously synthesized 233 was simultaneously
freed of its Boc protecting group by stirring with trifluoroacetic acid. The final conjoining of 22 with
unmasked 23, accomplished with HATU21 because of the hindered nature of the reacting components,
gave rise to 2 in 53% overall yield.
The described chemistry not only opens up a possibly efficient entry to sanglifehrin A, but is expected
to find useful application in analog synthesis.
Acknowledgements
This work was financially supported by Eli Lilly and Company.
References
1. (a) Fehr, T.; Oberer, L. Intern. Patent Appl. W097/02285, January 23, 1997. (b) Fehr, T.; Oberer, L.; Quesniaux, R. V.;
Sanglier, J.-J.; Schuler, W.; Sedrani, R. Intern. Patent Appl. W098/07743, March 3, 1998.
2. (a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnuke, M.; Memmert, K.; Schuler. W.; Zeknke, G.; Gschwind,
L.; Maurer, C.; Schilling, W. J. Antibiot. 1999, 52, 466. (b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W. J.
Antibiot. 1999, 52, 474.
3. Paquette, L. A.; Konetzki, I.; Duan, M. Tetrahedron Lett. 1999, 40, 7441.
4. (a) Bänteli, R.; Brun, I.; Hall, P.; Metteruich, R. Tetrahedron Lett. 1999, 40, 2109. (b) Metternich, R.; Denni, D.; Thai, B.;
Sedrani, R. J. Org. Chem. 1999, 64, 9632.
5. (a) Nicolaou, K. C.; Xu, J.; Murphy, F.; Barluenga, S.; Baudoin, O.; Wei, H.-x.; Gray, D. L. F.; Ohshima, T. Angew.
Chem., Int. Ed. 1999, 38, 2447. (b) Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. Chem.
Commun. 1999, 809.
6. Rivero, R. A.; Greenlee, W. J. Tetrahedron Lett. 1991, 32, 2453.
7. Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc. 1984, 106, 1154.
8. The TBS analog of 3 has been previously reported: Smith III, A. B.; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935.
9. Roush, W. R. J. Am. Chem. Soc. 1980, 102, 1390.
10. Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli, G. Tetrahedron Lett. 1988, 29, 5885.
11. Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127.
12. Paterson, I.; Yeung, K.-S.; Watson, C.; Ward, R. A.; Wallace, P. A. Tetrahedron 1998, 54, 11935. The specific experimental
details can be found on page 11 946.
13. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
14. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
15. Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112,
5583.
16. The Negishi conditions (Negishi, E.; Van Horn, D. E.; King, A. O.; Okukado, N. Synthesis 1979, 501) proved to be too
harsh for 10 and its derivatives.
17. Evans, D. A.; Britton, T. C.; Ellman, J. H. Tetrahedron Lett. 1987, 28, 6141.
18. Nicolaou, K. C.; King, N. P.; Finlay, M. V. R.; He, Y.; Roschangar, F.; Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic,
S.; Hepworth, D. Bioorg. Med. Chem. 1999, 7, 665.
19. In this instance, the customary use of LiBH4 in THF with methanol as a co-solvent resulted in reductive deiodination.
20. Prashad, M.; Har, P.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998, 39, 7067.
21. Albericio, F.; Kates, S. A.; Carpino, L. A. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Editor-in-
chief; John Wiley: Chichester, 1995; Vol. 3, pp. 2028–2031.