Enantioselective synthesis of the elaiophylin aglycon

Full text of DOI:10.1021/jo9621884

454
J . Org. Chem. 1997, 62, 454-455
Sch em e 1a
En a n tioselective Syn th esis of th e
Ela iop h ylin Aglycon
David A. Evans* and Duke M. Fitch
Department of Chemistry & Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138
Received November 26, 1996
Elaiophylin (1) was isolated in 1959 by Arcamone and
co-workers from cultures of Streptomyces melanosporus.1
Subsequently, this natural product has also been ob-
tained from other strains of Streptomyces.2 Structure
elucidation of 1, including assignment of absolute ster-
eochemistry, was based on chemical degradation,3 NMR
studies,4 and ultimately X-ray crystallographic analysis.5
Isolation and characterization of the elaiophylin aglycon,
elaiolide (2), was accomplished by Zeeck and Bindseil in
1993 through deglycosylation of 1.6
a
Key: (a) LDA, THF; EtI, -78 °C; (b) 2,6-lutidine, TBSOTf,
CH2Cl2, 0 °C; (c) DIBAl-H, CH2Cl2, -78 to -40 °C; (d) oxalyl
chloride, DMSO, CH2Cl2; Et3N, -78 °C; (e) BF3‚OEt2, CH2Cl2, -78
°C; (f) TBAF, THF, 25 °C; (g) 2,6-lutidine, (t-Bu)2Si(OTf)2, CH2Cl2,
0 °C; (h) O3, 3:1 CH2Cl2/MeOH, -78 °C; Me2S.
Sch em e 2a
a
Key: (a) n-Bu2BOTf, Et3N, 0 °C; methacrolein, CH2Cl2, -78
°C; H2O2; (b) 2,6-lutidine, TESOTf, CH2Cl2, 0 °C; (c) LiBH4, Et2O,
H2O, 25 °C; (d) TrCl, Et3N, DMAP, CH2Cl2; (e) 9-BBN dimer, THF,
0 °C; H2O2; (f) oxalyl chloride, DMSO, CH2Cl2; Et3N, -78 °C; (g)
LiHMDS, triethyl 4-phosphonocrotonate, THF, -78 °C; 11; (h)
HF‚pyr., THF, 0 °C.
As a result of its structural complexity and potent
biological activity,7 elaiophylin has been a target of
considerable synthetic interest. The first synthesis of
elaiophylin was accomplished by Kinoshita and co-
workers in 1986.8 In the previous year, Seebach and co-
workers reported the synthesis of an aglycon derivative
originally obtained from the acidic methanolysis of elaio-
phylin,9 which was later identified as 11,13,11′,13′-tetra-
O-methylelaiolide (3).6 Several other studies directed
toward the synthesis of the elaiophylin framework have
also been published.10,11 The common fragment coupling
strategy in the majority of these syntheses has been the
double stereodifferentiating aldol bond construction of the
C9-C10 bond (eq 1).11 This aldol assemblage strategy
carries the inherent liability that any lack of selectivity
in the aldol process is magnified over two reaction sites,
producing a complex mixture of isomers. In both the
Kinoshita and Seebach syntheses, this problem resulted
in isolation of the desired aldol adduct as the minor
product diastereomer in low yield.
Recent studies from this laboratory concerned with the
synthesis of bafilomycin A1 have revealed a strategy for
rendering these types of aldol bond constructions highly
diastereoselective.12 In this investigation, it was found
that high aldol diastereoselectivity could be obtained by
restricting the conformational flexibility of the ketone
through the use of a linking cyclic protecting group for
the C13 and C15 hydroxyl groups in conjunction with the
use of an electronically altered phenylchloroboryl eno-
late.13 An application of this successful strategy to the
synthesis of elaiolide (2) is described below.
(1) Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T. G.
Microbiol. 1959, 7, 207.
(2) (a) Azalomycin B: Arai, M. J . Antibiot. Ser. A 1960, 13, 46, 51.
(b) Antibiotic 225 E: Khlebarova, E. I.; Georgieva-Borisova, I. K.;
Sheikova, G. N.; Blinov, N. O. Farmatsiya (Sofia) 1972, 22, 3. (c)
Salbomycin: Hoechst Patent DE 3248-280-A, 1972.
(3) (a) Takahashi, S.; Arai, M.; Ohki, E. Chem. Pharm. Bull. 1967,
15, 1651. (b) Takahashi, S.; Kurabayashi, M.; Ohki, E. Chem. Pharm.
Bull. 1967, 15, 1657. (c) Takahashi, S.; Ohki, E. Chem. Pharm. Bull.
1967, 15, 1726.
(4) Kaiser, H.; Keller-Scheirlein, W. Helv. Chim. Acta 1981, 64, 407.
(5) Neupert-Laves, K.; Dobler, M. Helv. Chim. Acta 1982, 65, 262.
(6) Bindseil, K. U.; Zeeck, A. J . Org. Chem. 1993, 58, 5487.
(7) (a) Omura, S. Macrolide Antibiotics: Chemistry, Biology, and
Practice; Academic Press: New York, 1984. (b) Liu, C.-M.; J ensen, L.;
Westley, J . W.; Siegel, D. J . Antibiot. 1993, 46, 350.
(8) (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett.
1986, 27, 4741. (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem.
Soc. J pn. 1988, 61, 2369.
(9) (a) Seebach, D.; Chow, H.-F.; J ackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmerman, J . Liebigs Ann. Chem. 1986, 1281. (b)
Seebach, D.; Chow, H.-F.; J ackson, R. F. W.; Lawson, K.; Sutter, M.
A.; Thaisrivongs, S.; Zimmerman, J . J . Am. Chem. Soc. 1985, 107, 5292.
(10) (a) Wakamatsu, T.; Nakamura, H.; Nara, E.; Ban, Y. Tetrahe-
dron Lett. 1986, 27, 3895. (b) Wakamatsu, T.; Yamada, S.; Nakamura,
H.; Ban, Y. Heterocycles 1987, 25, 43. (c) Formal total synthesis of
elaiophylin: Nakamura, H.; Arata, K., Wakamatsu, T.; Ban, Y.;
Shibasaki, M. Chem. Pharm. Bull. 1990, 38, 2435.
(11) A notable exception is the approach of Ziegler and co-workers,
which involves the design of a fully elaborated monomeric fragment
suitable for dimerization: Ziegler, F. E.; Tung, J . S. J . Org. Chem.
1991, 56, 6530.
Synthesis of ethyl ketone 8 began with the R-ethylation
of 4 according to the Seebach procedure9a to afford the
(12) (a) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(b) Calter, M. A. Ph.D. Dissertation, Harvard University, 1993. (c) This
same aldol reaction has been subsequently employed by Toshima and
co-workers in their synthesis of bafilomycin A1. Toshima, K.; Yamagu-
chi, H.; J yojima, T.; Noguchi, Y.; Nakata, M.; Matsumura, S. Tetra-
hedron Lett. 1996, 37, 1073.
S0022-3263(96)02188-3 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 3, 1997 455
Sch em e 3a
a
Key: (a) 1 N KOH, THF, MeOH, 25 °C; (b) 2,4,6-trichlorobenzoyl chloride, toluene, Et3N; DMAP, 25 °C; (c) CSA, MeOH, THF, 25 °C;
(d) oxalyl chloride, DMSO, CH2Cl2; Et3N, -78 °C; (e) PhBCl2, i-Pr2NEt, CH2Cl2, -78 °C; (f) HF‚pyr, pyridine, THF, H2O.
desired anti diastereomer in 82% yield (Scheme 1).
Silylation was followed by reduction with diisobutylalu-
minum hydride and Swern oxidation to produce aldehyde
5 in excellent overall yield. The requisite ketone was
constructed by successive Lewis acid-promoted addition
of allylstannane 614 to aldehyde 5, reconfiguration of
oxygen protecting groups, and subsequent ozonolysis of
the derived homoallylic alcohol 7 to afford ethyl ketone
8 in 74% overall yield for the four steps.
The diastereoselectivity of the preceding allylstannane
addition was found to be sensitive to the nature of the
protecting group on the â-oxygen in aldehyde 5 as the
data in eq 2 document.15 The correlation between Felkin
under Swern conditions. Horner-Wadsworth-Emmons
olefination following the Roush procedure18 provided the
requisite dienoate as a 92:8 mixture of E,E:Z,E isomers19
from which the major diastereomer was isolated in 85%
yield. Selective removal of the silyl protecting group was
accomplished with HF‚pyridine at 0 °C to reveal alcohol
12 in 93% yield.
At this point, the synthesis intersected with the
Seebach route to the dialdehyde fragment. Scheme 3
illustrates the four-step sequence, in which dienoate 12
was converted to dialdehyde 16 according to the pub-
lished procedure.9a,20 The cyclodimerization of hydroxy
acid 13 was operationally simplified through use of the
Yonemitsu modification21 to Yamaguchi’s macrocycliza-
tion methodology.
In the crucial aldol coupling, dialdehyde 16 was treated
with 3 equiv of the chlorophenylboryl enolate12,22 of 8 to
provide a 66% yield of bis-aldol adduct 17 as the only
detectable product isomer.19 We feel that the enhanced
rigidity of the enolate and the modified boron enolate
both contribute to the enhanced diastereoselectivity of
this reaction. Consecutive deprotection of the di-tert-
butylsilylene protecting groups and subsequent cycliza-
tion to the bis-lactol was accomplished with HF‚pyridine
containing 1 equiv of water, completing the synthesis of
elaiolide (2) in 91% yield as a white crystalline solid. All
spectral data obtained from the synthetic material was
in complete agreement with reported values (1H NMR,
13C NMR, IR, TLC, [R]D, HRMS).6
selectivity and the size of the protecting group can be
rationalized by the increase in steric discrimination
between the R-ethyl substituent and the R-alkoxyethyl
substituent. Use of the tert-butyldimethylsilyl protecting
group resulted in a 92:8 mixture of diastereomers from
which the desired Felkin isomer 7 was isolated in 89%
yield.
The synthesis of a monomeric subunit of dialdehyde
16 began with the addition of methacrolein to the boron
enolate of carboximide 9,16 establishing two of the three
requisite stereocenters in good yield (Scheme 2). Silyl
protection of the hydroxyl group was followed by consecu-
tive reductive cleavage of the auxiliary and trityl protec-
tion to afford the differentially protected diol 10. Dia-
stereoselective hydroboration17 of 10 with 9-BBN afforded
a single alcohol isomer was oxidized to the aldehyde
Ack n ow led gm en t. Support has been provided by
the NIH and NSF. D.M.F. gratefully acknowledges
support from the NIH through the Biochemistry and
Molecular Biology Training Grant.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds are provided (30
pages).
J O9621884
(18) Roush, W. R. J . Am. Chem. Soc. 1980, 102, 1390.
(19) Determined by 1H NMR analysis of the unpurified reaction
mixture.
(20) J ackson, R. F. W.; Sutter, M. A.; Seebach, D. Liebigs Ann. Chem.
1985, 2313.
(13) Toshima and co-workers later found that while using the di-
tert-butylsilylene, enolization with Bu2BOTf and i-Pr2NEt provided a
3:1 mixture of isomers, favoring the desired anti-Felkin, syn aldol
adduct (see ref 12c).
(14) Ueno, Y.; Sano, H.; Okawara, M. Tetrahedron Lett. 1980, 21,
1767.
(15) For a recent study on the effects of R and â aldehyde substit-
uents on the diastereoselectivity of allylstannane additions see: Evans,
D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem. Soc. 1996,
118, 4322.
(21) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetrahedron
1990, 46, 4613.
(22) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984,
1729. We have found that optimal enolization conditions involve the
addition of PhBCl2 (2.0 equiv) to the ketonic substrate (CH2Cl2)
followed by the addition of EtN(i-Pr)2 (2.8 equiv) and subsequent
enolization (30 min, -78 °C; 30 min, 0 °C). Subsequent aldol reactions
were performed at -78 °C.
(16) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77.
(17) Still, W. C.; Barrish, J . C. J . Am. Chem. Soc. 1983, 105, 2487.