Enantioselective synthesis of the macrolide antibiotic oleandomycin aglycon

Full text of DOI:10.1021/ja963002l

J. Am. Chem. Soc. 1996, 118, 11323-11324
11323
Scheme 1
Enantioselective Synthesis of the Macrolide
Antibiotic Oleandomycin Aglycon
David A. Evans* and Annette S. Kim
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed August 26, 1996
The stereochemical and heterofunctional complexity of the
polypropionate-derived macrolide antibiotics poses a formidable
challenge for stereoselective synthesis, and these target structures
have provided the stimulus for the development of a host of
new enantio- and diastereoselective bond constructions.1 In this
paper we illustrate, in the context of an efficient synthesis of
oleandolide aglycon (1),2 how polypropionate chains may be
rapidly assembled using the chiral â-ketoimide building block
2 and its associated aldol reaction methodology recently
developed in these laboratories.3,4
As illustrated in Scheme 1, the synthesis plan relied upon
â-ketoimide 2 for the construction of both the C1-C8 and C9-
C14 oleandolide fragments. Concurrent application of a se-
quential aldol reduction strategy to both fragments established
8 of the 10 requisite stereocenters, while an imide enolate
alkylation reaction was employed to control the lone C6
stereocenter in the C5-C8 subunit. In the final stereoselective
transformation, the introduction of the C8-epoxide with the
desired stereochemistry was effected through the directed VO-
(acac)2/t-BuO2H epoxidation of the 9-(S)-allylic alcohol prior
to macrocyclization.5,6 This last step becomes much more
challenging to implement when it is postponed until after
macrocycle construction as the two previous syntheses of
oleandolide have revealed.2
Scheme 2
The synthesis of the C1-C8 fragment began with the titanium-
mediated syn aldol reaction between aldehyde 47 and â-ketoim-
ide 2 (Scheme 2).3a,8 This double stereodifferentiating reaction
(eq 1) proceeded in excellent yield with high anti Felkin
diastereoselection. Treatment of aldol adduct 5 with Zn(BH4)2
established the C5-hydroxyl stereocenter Via a chelate-controlled
a Reagents and conditions: (a) LDA, 2,3-dibromopropene, -78 to
-35 °C. (b) LiBH4, H2O, 25 °C. (c) (COCl)2, DMSO, Et3N, -78 to 0
°C. (d) Ti(O-i-Pr)Cl3, Et3N, 4, -78 °C. (e) Zn(BH4)2, -78 to -50 °C.
(f) (MeO)2CHPh, CSA, 10 Torr, 25 °C. (g) (Me3Sn)2, Pd(PPh3)4,
i-Pr2NEt, 80 °C.
(1) (a) Mulzer, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1452-1454.
(b) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569-3624. (c)
Recent Progress in the Chemical Synthesis of Antibiotics and Related
Microbial Products; Lukas, G., Ed.; Springer-Verlag: Berlin, 1993; Vol.
2.
Scheme 3
(2) (a) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M.
A. J. Am. Chem. Soc. 1994, 116, 11287-11314. (b) Paterson, I.; Lister, M.
A.; Norcross, R. D. Tetrahedron Lett. 1992, 33, 1767-1770. (c) Paterson,
I. Tetrahedron Lett. 1983, 24, 1311-1314. (d) Tatsuta, K.; Ishiyama, T.;
Tajima, S.; Koguchi, Y.; Gunji, H. Tetrahedron Lett. 1990, 31, 709-712.
(e) Tatsuta, K.; Kobayashi, Y.; Gunji, H. J. Antibiot. 1988, 41, 1520-
1523. (f) Tatsuta, K.; Kobayashi, Y.; Gunji, H.; Masuda, H. Tetrahedron
Lett. 1988, 29, 3975-3978.
(3) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866-868. (b) Evans, D. A.; Ng, H. P.;
Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127-2142.
(4) The sequence of â-ketoimide aldol coupling followed by reduction,
thereby establishing four stereocenters in two steps, has been applied to
the recent total syntheses of calyculin, rutamycin, and lonomycin: (a) Evans,
D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-
9453. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993,
115, 11446-11459. (c) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard,
G. S. J. Am. Chem. Soc. 1995, 117, 3448-3467.
(5) (a) The precedent for the stereochemical outcome of this reaction
has been established: Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta
1979, 12, 63-73. (b) For a general review of directed reactions, see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
(6) Initial attempts to directly form the C9 stereocenter from vinyl metal
addition to the aldehyde proved either unselective or resulted in decomposi-
tion.
(7) The known aldehyde 4 was prepared from N-propionyl-4-(R)-
(phenylmethyl)-oxazolidinone in direct analogy to the reported procedure:
Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-
2526.
a Reagents and conditions: (a) Sn(OTf)2, Et3N, acetaldehyde, -78
°C. (b) NaBH(OAc)3, HOAc, 25 °C. (c) TIPS-OTf, 2,6-lutidine, -5
°C. (d) TES-OTf, 2,6-lutidine, 25 °C. (e) LiOOH, 0 °C. (f) (COCl)2,
DMF, 25 °C.
syn reduction (diastereoselection >95:5)9 while subsequent diol
protection afforded vinyl bromide 6. Further elaboration of this
intermediate to the 1,1-disubstituted vinylstannane 7 completed
the synthesis of the C1-C8 oleandolide subunit.
The synthesis of the C9-C14 subunit was initiated from the
same â-ketoimide building block 2 Via a Sn(II)-mediated aldol
reaction with acetaldehyde to afford the complimentary syn aldol
adduct (Scheme 3, eq 2).3a It is noteworthy that both of the
requisite syn aldol bond constructions may be accessed from
(8) Use of Ti(O-i-Pr)Cl3 rather than the standard TiCl4 was found to
maximize conversion in the coupling of â-ketoimide 2 with aldehyde 4.
(9) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338-344.
S0002-7863(96)03002-8 CCC: $12.00 © 1996 American Chemical Society

11324 J. Am. Chem. Soc., Vol. 118, No. 45, 1996
Communications to the Editor
Scheme 4
a Reagents and conditions: (a) Pd2(dba)3, i-Pr2NEt, benzene, 25 °C. (b) HF‚pyr, 0 °C. (c) Zn(BH4)2, -45 °C. (d) VO(acac)2, t-BuOOH, 25 °C.
(e) TBS-OTf, 2,6-lutidine, -78 °C. (f) LiOOH, 0 °C. (g) Et3N‚HF, 25 °C. (h) 2,4,6-trichlorobenzoyl chloride, i-Pr2NEt, DMAP, 25 °C. (i) HF‚pyr,
25 °C. (j) SO3‚pyr, Et3N, 25 °C. (k) 20% Pd(OH)2/C, H2, dioxane 25 °C.
the (Z)-enolate of 2 by judicious choice of metal center (eq 1
that only the C9-position was silylated; all attempts to modify
the C11-alcohol failed. Nonetheless, this added protecting group
did attenuate the reactivity of the epoxide, possibly through
enforcing a conformation less prone to rearrangement by an
alteration of the hydrogen bonding network. Following imide
hydrolysis, the C13-OTIPS ether was selectively removed in the
presence of the C9-OTBS moiety through the use of triethyl-
ammonium fluoride to afford 15a.13 Gratifyingly, the macro-
cyclization of this substrate proceeded in quantitative yield with
2,4,6-trichlorobenzoyl chloride.14 Silyl deprotection, oxidation,
and acetal hydrogenolysis then afforded oleandolide (1) in 84%
overall yield. The spectral and chromatographic characteristics
of 1 proved identical to the published data.2a As further proof
of structure, the triacetate derivative of 1 was also prepared,
and its properties proved to be identical to published data as
well.2a
10
vs eq 2).3a Subsequent anti reduction of 8 with NaBH(OAc)3
and regioselective protection of the C13-alcohol yielded triiso-
propylsilyl (TIPS) ether 9 in good overall yield and selectivity.
At this stage, the C11-hydroxyl moiety was protected as its
derived triethylsilyl (TES) ether with the anticipation that it
might be selectively revealed after fragment coupling in the
presence of the C13-OTIPS protecting group (Vide infra). Imide
hydrolysis followed by treatment with oxalyl chloride provided
the C9-C14 acid chloride 11 suitably activated for fragment
coupling.
The palladium-catalyzed acylation11 of vinylstannane 7 (C1-
C8) with acid chloride 11 (C9-C14) proved to be an excellent
fragment coupling process (Pd2(dba)3, i-Pr2NEt, benzene, 25
°C, 88% yield) (Scheme 4). The use of the trimethylstannyl
derivative was found to be essential for a high-yielding
transformation, in accord with literature precedent indicating
reaction sensitivity to steric effects at the stannyl moiety.11
Treatment of enone 12a with HF‚pyridine effected selective
deprotection of the C11-OTES moiety in the presence of the
C13-OTIPS ether, and the subsequent Zn(BH4)2 reduction,
directed by the newly revealed C11-OH, afforded allylic alcohol
13 with the desired (S)-stereochemistry at C9 as a single isomer.
It is noteworthy that the analogous reduction of benzyl ether
12b, contrary to expectation, produced the undesired 9-(R)-
alcohol diastereomer as the major product, despite ample
precedent for the operation of chelate control on similar
substrates.12 With the 9-(S)-hydroxyl configuration established
as a controller for directed epoxidation, treatment of 13 with
VO(acac)2/tert-butylperoxide afforded the desired epoxy alcohol
14 as a single diastereomer,5 thereby establishing the 10 requisite
oleandolide stereocenters in 11 linear steps.
Synthesis of oleandolide was completed in 18 linear steps
with a 15% overall yield. Utilizing auxiliary-controlled aldol
reactions, directed reductions, and a directed epoxidation, the
10 stereocenters of oleandolide were established on the acyclic
carbon framework from the chiral â-ketoimide building block
2.
Acknowledgment. Support has been provided by the NIH and NSF.
We thank Dr. Andrew Tyler of the Harvard Mass Spectrometry Facility
for providing mass spectra, Professor Ian Paterson for NMR spectral
data of independently prepared sample of 1, and the NIH BRS Shared
Instrumentation Grant Program 1-S10-RR04870 and the NSF (CHE
88-14019) for providing NMR facilities. A.S.K. gratefully acknowl-
edges support from the NIH through the Medical Scientist Training
Program and from the DuPont Merck Pharmaceutical Company.
Unfortunately, attempts to move forward with the C9,C11-
diol 14 met with failure, since the diol epoxide moieties proved
too labile to survive subsequent steps. Although some of the
carboxylic acid triol 15b was obtained, all macrocyclization
attempts led only to substrate decomposition. Even under
buffered conditions, this series of epoxide-containing intermedi-
ates readily rearranged to the corresponding tetrahydrofurans,
as shown for the conversion of 14 to 17 (eq 3).
Supporting Information Available: Spectral data for all com-
pounds are provided (7 pages). See any current masthead page for
ordering and Internet access instructions.
JA963002L
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(11) (a) Labadie, J. L.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129-
6137 and references cited therein. (b) Scott, W. J.; Stille, J. K. J. Am. Chem.
Soc. 1986, 108, 3033-3040.
(12) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468 and references
cited therein.
(13) Et3N‚HF was prepared from the HF‚pyridine complex and Et3N.
The excess base was removed in Vacuo, and the resultant white crystalline
solid was stored under argon.
(14) (a) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1990, 31, 6367-6370. (b) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu,
O. J. Org. Chem. 1990, 55, 7-9. (c) Inanaga, J.; Hirata, K.; Saeki, H.;
Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.
In an attempt to inhibit this rearrangement, diol 14 was treated
with tert-butyldimethylsilyl triflate (TBS-OTf). It is of note