Total synthesis of (-)-reveromycin A

Article abstract of DOI:10.1021/ol048811l

(Equation Presented) The asymmetric total synthesis of (-)-reveromycin A is described. The key steps involved a Lewis acid catalyzed inverse electron demand hetero-Diels-Alder reaction followed by hydroboration/oxidation to afford the spiroketal core 4 in

Full text of DOI:10.1021/ol048811l

ORGANIC
LETTERS
2004
Vol. 6, No. 17
3001-3004
Total Synthesis of (−)-Reveromycin A
Mariana El Sous, Danny Ganame, Peter A. Tregloan, and Mark A. Rizzacasa*
School of Chemistry, The UniVersity of Melbourne, Victoria 3010, Australia
masr@unimelb.edu.au
Received June 22, 2004
ABSTRACT
The asymmetric total synthesis of (−)-reveromycin A is described. The key steps involved a Lewis acid catalyzed inverse electron demand
hetero-Diels−Alder reaction followed by hydroboration/oxidation to afford the spiroketal core 4 in a highly stereoselective manner and introduction
of the C18 hemisuccinate by high-pressure acylation.
The reveromycins A (1) and B (2) are members of a family
of compounds isolated from the soil actinomycete Stepto-
myces sp.1 Reveromycin A (1) is a potent inhibitor (IC50 0.7
µg mL-1) of the mitogenic activity of epidermal growth
factor (EGF) in a mouse keratinocyte. In addition, compound
1 exhibits antiproliferative activity against human tumor cell
lines (IC50 ) 1.3-2.0 µg mL-1), as well as antifungal activity
(MIC ) 2.0 µg mL-1, pH 3).1b Recently, reveromycin A (1)
has been identified as a specific inhibitor of Saccharomyces
cereVisiae isoleucyl-tRNA synthetase (IleRS) using yeast
genetics and biochemical studies.2
We now report the total synthesis of (-)-reveromycin A
(1) using a hetero-Diels-Alder (HDA) strategy to construct
the challenging spiroketal moiety of this molecule.6
It is known that the reveromycin A (1)-type 6,6-spiroketal
core I can undergo acid-catalyzed isomerization to afford
the spiroisomer II as the result of an unfavorable steric
interaction involving the axial C19 side chain in I that is
alleviated in II, albeit at the cost of an anomeric effect
(Figure 1). Thus, the energy difference between the 6,6-
(1) (a) Osada, H.; Koshino, H.; Isono, K.; Takahashi, H.; Kawanishi, G.
J. Antibiot. 1991, 44, 259. (b) Takahashi, H.; Osada, H.; Koshino, H.; Kudo,
T.; Amano, S.; Shimizu, S.; Yoshihama, M.; Isono, K. J. Antibiot. 1992,
45, 1409. (c) Takahashi, T.; Osada, H.; Koshino, H.; Sasaki, M.; Onose,
R.; Nakakoshi, M.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414.
(d) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J. Antibiot. 1992, 45,
1420.
(2) Miyamoto, Y.; Machida, K.; Mizunuma, M.; Emoto, Y.; Sato, N.;
Miyahara, K.; Hirata, D.; Usui, T.; Takahashi, H.; Osada, H.; Miyakawa,
T. J. Biol. Chem. 2002, 277, 28810.
So far, only one total synthesis of 1 has been reported,3
and several approaches to the 6,6-spiroketal core have been
described,4-6 while three total syntheses of reveromycin B
(2) have been completed.7-9
(3) Shimizu, T.; Masuda, T.; Hiramoto, K.; Nakata, T. Org. Lett. 2000,
2, 2153.
(4) Shimizu, T.; Kobayashi, R.; Osako, K.; Osado, H.; Nakata, T.
Tetrahedron Lett. 1996, 37, 6755.
(5) Drouet, K. E.; Ling, T.; Tran. H. V.; Theodorakis, E. A. Org. Lett.
2000, 2, 207.
(6) El Sous, M.; Rizzacasa, M. A. Tetrahedron Lett. 2000, 41, 8591.
(7) (a) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121,
456. (b) Drouet, K. E.; Theodorakis, E. A. Eur. J. Chem. 2000, 6, 1987.
(8) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1,
941.
(9) (a) Cuzzupe, A. N.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.;
Rizzacasa, M. A.; Zammit, S. C. Org. Lett. 2000, 2, 191. (b) Cuzzupe, A.
N.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.; McRae, K. J.; Rizzacasa, M.
A.; Zammit, S. C. J. Org. Chem. 2001, 66, 2382.
10.1021/ol048811l CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/22/2004

reaction should set the stereochemistry at the spiro center
by an axial approach of the carbonyl oxygen in the HDA
transition state.9 The stereochemistry at C18 and C19 is then
set by the hydroboration/oxidation sequence, which circum-
vents the thermodynamic lability of the reveromycin A type
spiroketal I. In addition to being stereoselective and con-
vergent, this route would also avoid the need for a large
number of different protecting groups.
Earlier, we had found that the HDA reaction of isomer-
izable methylene pyrans with simple hetero dienes can be
achieved thermally in the presence of K2CO3, which ef-
fectively reduced the amount of the thermodynamically
driven exo to endo isomerization of the dienophile.9,11 In the
case of diene 5, using this additive gave low yields of
spiroketal because of the base lability of the diene.6
Therefore, Lewis acid promotion of the cycloaddition was
surveyed using the diene and model dienophile 79 (Scheme
2). After some experimentation, we found that the HDA
Figure 1.
spiroketals I and II is small. In addition, when the C18
alcohol is free, acid-induced isomerization provides the more
stable reveromycin B (2) 5,6-spiroketal core III exclusively.
This energy profile has been observed in the reported
thermodynamic approaches (i.e., cyclization of a “dihydroxy-
ketone” precursor) to the 6,6-spiroketal of 1, which provided
mixtures of spiroisomers,3-5 and degradative4,10 and synthetic
studies6,7,9b,11 have demonstrated the strong preference for
the reveromycin B-type 5,6-spiroketal III.
In light of the above results, we envisioned that a kinetic
approach to the reveromycin A spiroketal may circumvent
the thermodynamic dilemma cited above. As shown in
Scheme 1, the indicated retrosynthetic disconnections of 1
Scheme 2
Scheme 1
13
reaction between 7 and diene 5 was promoted by Eu(fod)3
in hexane solvent at 0 °C to give the spiroketal 8 in excellent
yield. Unfortunately, in the case of the substituted methylene
pyran 6 required for the synthesis of 1, no HDA reaction
was observed in hexane solvent and only slow isomerization
occurred to give the endo isomer of 6. Eventually, we found
that the cycloaddition proceeded smoothly when a neat
mixture14 of the diene 5 and dienophile 6 was treated with
15 mol % Eu(fod)3 at 0 °C. Although the reaction gave the
desired spiroketal 4 as one diastereoisomer in a higher yield
than that obtained using K2CO3,6 the byproduct 9, resulting
from an ene reaction, was also isolated as a mixture of
diastereoisomers. This was not observed during the studies
using the model pyran 7. The HDA reaction between 5 and
6 was also promoted by ZnCl2 in THF at 0 °C to provide
the adduct 4 in a comparable yield.
lead to the intermediate 6,6-spiroketal 3. This could be
obtained from unsaturated spiroketal 4 by regio- and ste-
reoselective hydroboration from the direction shown followed
by alkyne homologation. Key spiroketal 4 could be obtained
by an inverse electron demand HDA reaction12 between the
diene 56 and the chiral methylene pyran 6.9 This critical
(10) Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J. Chem. Soc.,
Chem. Commun. 1994, 1877.
(11) McRae, K. J.; Rizzacasa, M. A. J. Org. Chem. 1997, 62, 1196.
(12) For examples of the HDA synthesis of spiroketals, see: Mead, K.
T.; Brewer; B. N. Curr. Org. Chem. 2003, 7, 227.
(13) Bednarski, M.; Danishefsky, S. J. J. Am. Chem. Soc. 1983, 105,
3716.
(14) Pale, P.; Bouquant, J.; Chuche, J.; Carrupt, P. A.; Vogel, P.
Tetrahedron 1994, 50, 8035.
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Org. Lett., Vol. 6, No. 17, 2004

steps. Reduction of 12 and subsequent oxidation provided
the substrate 13 required for the reagent-controlled aldol
reaction (Scheme 4). Treatment of aldehyde 13 with the tin
enolate derived from oxazolidine-2-thione 149,17 afforded the
desired syn-propionate 15, which when exposed to NaBH4
gave the diol 16 as a result of reductive auxiliary cleavage.
Removal of the C18 TBS ether required warming to 50
°C to proceed at an appreciable rate, and selective primary/
secondary alcohol protection yielded bis-TBS ether 17
(Scheme 5). The stage was now set for the somewhat risky
Scheme 3
Scheme 5
With the desired spiroketal in hand, we next tackled the
introduction of the C18 and C19 stereocenters and C5-C10
chain extension as shown in Scheme 3. Hydroboration of
spiroketal 4 followed by oxidation proceeded in good yield
to afford the tertiary alcohol 10 as the only isomer. The
integrity of the 6,6-spiroketal 10 was evidenced by the
characteristic 13C NMR chemical shift observed for the spiro
carbon,9,11 and the stereochemistry was confirmed by its
conversion into a known reveromycin A degradation product4
as described previously.6 Protection of the tertiary alcohol
followed by debenzylation afforded alcohol 11 ready for
alkyne homologation. Oxidation15 of 11 and alkyne formation
following the Bestmann protocol16 then gave compound 3.
Selective desilylation of the primary TBS group (TBAF, rt)
followed by oxidation and two-stage Wittig extension
provided the diene 12 in excellent overall yield for the four
late-stage introduction of the C18 hemisuccinate. Several
methods for the acylation of hindered alcohols failed,18
affording mostly the isomerized 5,6-spiroketal as found in
2, so we turned to the application of high pressure according
to the procedure described by Shimizu and Nakata.3,19 Thus,
treatment of a mixture of alcohol 17 and monoprotected
succinic acid 189b with DCC and DMAP at 0.4 GPa in CH2-
Cl2 solvent gave the desired ester 19 in very high yield.
Interestingly, we found that the reaction proceeded efficiently
at much lower pressures than reported previously (1.5
GPa)3,19 and required the use of relatively simple high-
pressure equipment. Selective deprotection of the primary
alcohol in 19 proceeded well using HF‚pyridine complex
buffered with pyridine20 to afford the alcohol 20. Hydro-
stannylation of the alkyne in 20 proved somewhat difficult
under Pd-catalyzed conditions21 owing to the steric hindrance
Scheme 4
(15) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(16) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, J. Synlett 1996, 521.
(17) Nagao, Y.; Hagiwara, Y.; Kumagi, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(18) For example see: Zhao, H.; Pendri, A.; Greenwald, R. B. J. Org.
Chem. 1998, 63, 7559.
(19) Shimizu, T.; Hiramoto, K.; Nakata, T. Synthesis 2001, 1027.
(20) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434.
(21) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
Org. Lett., Vol. 6, No. 17, 2004
3003

at the axial alkyne functionality, and excessive amounts of
protodestannylation occurred during the reaction. We found
that slow addition of the catalyst (up to 30 mol % over 5 h)
was required to give the vinyl stannane 21 in acceptable
yields.
The final steps to the target 1 are outlined in Scheme 6.
Stille coupling between stannane 21 and vinyl iodide 229b
afforded the required tetraene 23 along with a small amount
of what was tentatively identified as the 22E-isomer. This
type of isomerization was observed by us during our studies
on the total synthesis of reveromycin B (2).9 Oxidation of
the free primary alcohol and Wittig extension22 afforded the
fully protected reveromycin A precursor 24, which upon
exposure to TBAF in DMF gave reveromycin A (1) in high
yield. The synthetic material was purified by reverse-phase
chromatography (C18 SPE cartridge, 900 mg, 40-60%
MeOH/H2O) and was identical (NMR, IR, UV, HRMS) to
the natural product in all respects {[R]22 -122.4 (c, 0.16,
D
MeOH); lit.1b [R]23 -115 (c, 0.1, MeOH)} including
D
retention time on RP-HPLC.
In conclusion, we have completed the total synthesis of
(-)-reveromycin A (1), which utilized a HDA reaction
hydroboration sequence to construct the spiroketal core in a
convergent and stereoselective manner. Application of this
methodology to related natural products is underway.23
Scheme 6
Acknowledgment. We are indebted to Dr. Hiroyuki
Osada (RIKEN Institute, Japan) for an authentic sample of
reveromycin A (1) as well as copies of the NMR spectra.
We also thank Professor Rob Capon (University of Queen-
sland) for the HPLC comparisons. This work was financially
supported by the Australian Research Council.
Supporting Information Available: Characterization
data for compounds 1, 3, 4, 9-12, 15-17, 19, 20, 23, and
24 and copies of the NMR spectra, as well as a comparison
of 13C NMR chemical shifts and HPLC traces for natural
and synthetic reveromycin A (1). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL048811L
(22) Hungerbu¨hler, E.; Seebach, D.; Wasmuth, D. HelV. Chim. Acta 1981,
64, 1467.
(23) Zanatta, S. D.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6,
1041.
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