Total synthesis of the polyene macrolide roflamycoin

Full text of DOI:10.1021/ja963800b

2058
J. Am. Chem. Soc. 1997, 119, 2058-2059
Total Synthesis of the Polyene Macrolide
Roflamycoin
Scott D. Rychnovsky,* Uday R. Khire, and Guang Yang
Department of Chemistry, UniVersity of California
IrVine, California 92697-2025
ReceiVed NoVember 1, 1996
Figure 1. Roflamycoin spiroacetal formed irreversibly on treatment
of natural roflamycoin with mild acid.
Roflamycoin is an unusual member of the polyene macrolide
antibiotics as it is the only oxopolyene macrolide that has been
shown to form well-defined ion channels.1 Most oxopolyene
macrolides are simple membrane disrupters, and the other well-
characterized ion-channel forming polyenes belong to the
mycosamine-containing polyene macrolide antibiotics like nys-
tatin and amphotericin B.2 Roflamycoin was isolated from
Streptomyces roseoflaVus as an antifungal agent and initially
named flavomycoin.3 The flat structure was reported in 1981,4
and the absolute configuration was determined in 1994 using
the 13C acetonide method.5 Prior to the stereochemical elucida-
tion, both Lipshutz6 and Rychnovsky7 had developed partial
syntheses of roflamycoin stereoisomers, but no complete
synthesis of roflamycoin or any stereoisomer has been described.
Reported herein is the first total synthesis of natural roflamycoin.
Roflamycoin presents several challenges to synthetic chemists.
In common with other oxopolyene macrolides like mycoticin8
and roxaticin,9 roflamycoin contains a stereochemically complex
polyol chain and a polyene segment that is sensitive both to
light and to many chemical reagents. Unlike these simpler
oxopolyenes, roflamycoin contains a hemiacetal that is trans-
formed to a spiroacetal irreVersibly on treatment with mild acid
(Figure 1).5 All of the synthetic work in this area makes use
of acid labile protecting groups to block the many hydroxyl
groups in the target, so a late-stage acid-catalyzed deprotection
would appear to be unavoidable.10 A two-stage deprotection
strategy was developed for the synthesis of roflamycoin in which
the hydroxyl groups were to be deprotected in the penultimate
step and the ketone would be liberated in the final step by neutral
periodate cleavage of a 1,2-diol. Model studies were successful,
and this deprotection strategy was incorporated into the synthetic
plan for roflamycoin.
Scheme 1
Scheme 2
Convergent synthesis of the protected roflamycoin polyol 15
used cyanohydrin acetonide couplings11 and optically pure C2-
symmetric electrophiles12 previously developed in our group.
(1) (a) Schlegel, R.; Grigorjev, P. A.; Thrum, H. Stud. Biophys. 1982,
92, 135-40. (b) Grigorjev, P.; Schlegel, R.; Thrum, H.; Ermishkin, L.
Biochim. Biophys. Acta 1985, 821, 297-304.
(2) Bolard, J. Biochim. Biophys. Acta 1986, 864, 257-304.
(3) (a) Schlegel, R.; Thrum, H. Experientia 1968, 24, 11-12. (b)
Schlegel, R.; Thrum, H. J. Antibiot. 1971, 24, 368-74. (c) Schlegel, R.;
Thrum, H. J. Antibiot. 1971, 24, 360-7. (d) Afzal, M.; Nimer, N. D.; Nazar,
M. Z. Allg. Mikrobiol. 1983, 23, 411-8.
The major segments of roflamycoin, compounds 6 and 11, were
prepared as outlined in Schemes 1 and 2. The C11-C22
segment 6 was prepared by joining diepoxide 1 and dibromide
4 with a dithiane unit (Scheme 1). To diepoxide 1, prepared
by Noyori hydrogenation of 1,5-dichloro-2,4-pentandione,12 was
added (benzyloxy)methyllithium.13 Monoaddition predominates
when BF3‚OEt2 was used as a promoter.12,14 The 2,2-bis-
(tributyltin)dithiane (2)15 was transmetallated with BuLi and
added to the hydroxy oxirane to give 56% yield of the anti-
diol 3. Acetonide protection, transmetallation, and alkylation
with excess dibromide 4 gave dithiane 5 in 60% overall yield.
The stannylated dithiane was required to facilitate the second
metallation reaction.6b,15 Compound 5 has all of the carbons
(4) Schlegel, R.; Thrum, H.; Zielinski, J.; Borowski, E. J. Antibiot. 1981,
34, 122-3.
(5) (a) Rychnovsky, S. D.; Griesgraber, G.; Schlegel, R. J. Am. Chem.
Soc. 1995, 117, 197-210. (b) Rychnovsky, S. D.; Griesgraber, G.; Schlegel,
R. J. Am. Chem. Soc. 1994, 116, 2623-4.
(6) (a) Lipshutz, B. H.; Kotsuki, H.; Lew, W. Tetrahedron Lett. 1986,
27, 4825-8. (b) Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett.
1989, 30, 15-18.
(7) Rychnovsky, S. D.; Griesgraber, G.; Kim, J. J. Am. Chem. Soc. 1994,
116, 2621-2.
(8) Synthesis of mycoticin: Poss, C. S.; Rychnovsky, S. D.; Schreiber,
S. L. J. Am. Chem. Soc. 1993, 115, 3360-1.
(9) Syntheses of roxaticin: (a) Rychnovsky, S. D.; Hoye, R. C. J. Am.
Chem. Soc. 1994, 116, 1753-65. (b) Mori, Y.; Asai, M.; Kawade, J.-I.;
Okumura, A.; Furukawa, H. Tetrahedron Lett. 1994, 35, 6503-6. (c) Mori,
Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 5299-
314. (d) Mori, Y.; Asai, M.; Kawade, J.-i.; Furukawa, H. Tetrahedron 1995,
51, 5315-30.
(12) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J.
Org. Chem. 1991, 56, 5161-9.
(10) (a) Beau, J. M. In Recent Progress in the Chemical Synthesis of
Antibiotics; Lukacs, G., Ohno, M., Ed.; Springer: Berlin, 1990; pp 135-
182. (b) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021-40.
(11) Rychnovsky, S. D.; Zeller, S.; Skalitzky, D. J.; Griesgraber, G. J.
Org. Chem. 1990, 55, 5550-1.
(13) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1482-7.
(14) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106,
3693-4.
(15) Seebach, D.; Willert, I.; Beck, A. K.; Grobel, B.-T. HelV. Chim.
Acta 1978, 61, 2510-23.
S0002-7863(96)03800-0 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 8, 1997 2059
Scheme 3
of the C11-C22 fragment, but the dithiane was not an
appropriate protecting group for the C17 ketone. Dithiane 5
was converted to the protected 1,2-diol 6 by deprotection,
olefination,16 dihydroxylation, and protection. Segment 6 was
generated as a 2:1 mixture of stereoisomers, both of which
would be viable precursors to roflamycoin. To facilitate NMR
analysis, the mixture was separated and the major isomer was
used in subsequent steps.
yield. Both nitriles were replaced by axial hydrogen atoms,
and the benzyl groups were removed in this single step. Diol
15 was next converted into the macrocyclic pentaene 18.
Acylation of both alcohols with diethyl phosphonopropionic
acid, followed by selective hydrolysis of the primary ester and
Dess-Martin oxidation gave aldehyde 16. Aldehyde 16 was
converted to a tetraenal by addition of the Grignard reagent
derived from Wollenberg’s 1-(tributylstannyl)-4-ethoxybutadi-
ene,23 followed by mesylation and solvolysis of the resulting
secondary alcohol.24 Repeating the Wollenberg homologation
sequence23 gave tetraenal 17, and intramolecular phosphonate-
Wittig cyclization gave the pentaene 18 in 44-51% yield as a
single alkene isomer.25 The key deprotection steps proceeded
uneventfully. Acid-catalyzed deprotection gave the polyol 19,
and periodate cleavage of the 1,2-diol gave roflamycoin.
Synthetic and natural roflamycoin were found to be identical
by TLC mobility and by 1H NMR, FAB MS, UV, and reversed-
phase HPLC analysis.
The C27-C37 segment was prepared as outlined in Scheme
2. Benzyl ether 7 was prepared by enantioselective crotylborane
addition to isobutyraldehyde followed by benzylation.17
A
Suzuki homologation18 and oxidation gave aldehyde 8 that was
coupled with Brown’s Ipc2B-allyl reagent.19 Protection and
oxidation gave aldehyde 9. The final relevant stereogenic center
in 11 could be introduced by another allylborane addition, but
it was more efficient to use Carreira’s enantioselective aldol
reaction20 because it led directly to the â-silyloxy ester 10.
DIBAL-H reduction, cyanohydrin formation, and acetonide
protection gave the C27-C37 segment 11 as a mixture of
cyanohydrin stereoisomers that was used without separation.
Roflamycoin was assembled as illustrated in Scheme 3.
Alkylation of bromide 6 with 2.5 equiv of the anion of nitrile
12 gave the alkylated nitrile in 85% yield. Compound 1211 can
be used in the iterative construction of polyol chains by
alkylation followed by conversion of the TIPS-protected alcohol
to an alkyl iodide.21 Deprotection of the TIPS alcohol and alkyl
iodide formation22 gave 13 in excellent yield. Alkylation of
the anion of the C27-C35 segment 11 with iodide 13 gave 14
in 70% yield based on 13. Reductive decyanation gave the
protected roflamycoin polyol 15 as a single stereoisomer in 69%
The longest linear sequence in the synthesis of roflamycoin
is 24 steps starting from isobutyraldehyde. This highly con-
vergent route to natural roflamycoin is well-suited to the
preparation of stereoisomers and other analogues.21
Acknowledgment. Support has been provided by the National Insti-
tutes of Health and the University of California, Irvine. S.D.R. would
like to acknowledge Pfizer Inc. for support of his research program.
Supporting Information Available: Experimental details for the
preparation of 6 and 11, the combination of 6, 11, and 12 to make 15,
and the final conversion of 15 to roflamycoin (26 pages). See any
current masthead page for ordering and Internet access instructions.
JA963800B
(16) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-4.
(17) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-23.
(18) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321.
(21) Rychnovsky, S. D.; Yang, G.; Hu, Y.; Khire, U. R. Unpublished
results.
(22) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
978-980.
(19) (a) Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-9. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem.
Soc. 1983, 105, 2092-3.
(23) Wollenberg, R. H. Tetrahedron Lett. 1978, 717-720.
(24) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C. J.
Am. Chem. Soc. 1980, 102, 1436-9.
(20) Carreira, E. M.; Singer, R. A.; Lee, W. S. J. Am. Chem. Soc. 1994,
116, 8837-8.
(25) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-6.