Highly Diastereoselective Conjugate Addition of Lithiated γ-Crotonolactone (But-2-en-4-olide) to Cyclic Enones to Give Syn-Adducts: Application to a Brefeldin Synthesis

Full text of DOI:10.1021/jo970337s

4552
J . Org. Chem. 1997, 62, 4552-4553
reaction took place through C-4, the product was a
60:40 mixture of diastereomers of the (Z)-isomer 7 (cf. 5,
Scheme 1). The reaction is thus distinct to conjugate
High ly Dia ster eoselective Con ju ga te
Ad d ition of Lith ia ted γ-Cr oton ola cton e
(Bu t-2-en -4-olid e) to Cyclic En on es To Give
Syn -Ad d u cts: Ap p lica tion to a Br efeld in
Syn th esis†
Richard K. Haynes,*,‡ William W.-L. Lam,*,‡
Lam-Lung Yeung,‡ Ian D. Williams,‡
Andrew C. Ridley,§ Scott M. Starling,§
Simone C. Vonwiller,§ Trevor W. Hambley,§ and
Patrick Lelandais
Department of Chemistry, The Hong Kong University of
Science and Technology, Clear Water Bay Road,
Kowloon, Hong Kong, School of Chemistry, The University
of Sydney, New South Wales 2006, Australia, Universite´ de
Gene`ve, Faculte´ des Sciences, Section de Chimie, 30 Quai
Ernest-Ansermet, CH-1211 Gene`ve 4, Switzerland
Received February 24, 1997
addition of lithiated allylic esters, which react through
C-2.2,6 On the other hand, lithiated butenolide 2 added
cleanly to (()-4-tert-butoxycyclopent-2-enone (8) in THF
at -78 °C to give diastereomers 9-12 (60-65% overall),
in a ratio of 80:15:3:2, or at -90 °C to give 9 and 10 only
(92:8, 83%). The major product 9 corresponds to the syn-
isomer (cf. Scheme 1),1,7 and its formation is in accord
with the prediction of Scheme 1. THF was the best
among ether solvents, and HMPA or Lewis acids, such
as zinc chloride and magnesium tert-butoxide, depressed
yields of 9. The importance of lithium chelation is
underscored by the fact that the TMS ether 13 of
γ-crotonolactone with Lewis acids in dichloromethane or
MeCN at -78 °C with enone 8 gave as major products
the cis-disubstituted adducts 10 and 12. Thus, product
ratio of 9-12 with SnCl4 (0.1 equiv) in dichloromethane
was 5:44:3:48 (90%); with HgI2 in dichloromethane the
cis adducts 10 and 12 (50:50) only were formed, albeit in
low yield (30%).8
Lithiated allylic sulfoxides and phosphine oxides un-
dergo diastereoselective conjugate addition to cyclic
enones to provide vinylic products whose stereochemistry
concisely relates to the geometry of the double bond in
the starting allylic system.1 From (E)-allylic systems are
obtained syn-, and from (Z), the anti-, products.1 There
is substantial impetus for application of the process to
carbonyl-stabilized allylic systems,2 in particular those
bearing oxygen at C-4 (Scheme 1), as this would provide
synthetically useful, yet otherwise inaccessible, cyclic
enones bearing side chains with stereodefined R-hydroxyl
groups. Two systems were selected for examinations
lithiated (E)-4-alkoxy-3-butenoate esters 1 and lithiated
γ-crotonolactone 2. Should reactions of 1 proceed through
a 10-membered TS,1 or of 2 via a 9-membered “exo” TS3
with a cyclic enone, these will provide enolates 3 and 4
with equivalent stereochemistries (Scheme 1). The eno-
late 3 upon protonation would provide the syn-product
5. The enolate 4 upon protonation, ring opening, and
double-bond isomerization would also give 5. In both
cases, we are unaware of literature precedents.4
Addition of (4R)-enone 149 to 2-lithio-1,3-dithiane in
THF containing HMPA (2 equiv) at -78 °C gave adduct
15 (86%), treatment of which with TMSOTf (10 mol %)
in dichloromethane at room temperature furnished enone
16 (86%).10 Next, enone 16 at -90 °C was treated with
lithiated butenolide 2 in THF to give adducts 17 and 18
(95:5, 52% overall). The structure of the major isomer
from racemic enone as revealed by X-ray crystallographic
analysis again is in accord with the transition state model
of Scheme 1.22
Sch em e 1
Absolute configurations at C-1′ and C-3 in 17 cor-
respond to those at C-4 and C-5 in (+)-brefeldin A 23
(Scheme 2). While the butenolide ring in 17 was opened
by LiOH in aqueous MeOH to give the (E)-unsaturated
acid 19 and the (Z)-isomer, the use of LiSPh (1.1 equiv)
Ethyl (2E)-4-(benzyloxy)but-2-enoate (6)5 was treated
with LDA in THF at -60 °C, then with cyclopentenone,
and quenched at the same temperature. However, while
(5) Villieras, J .; Rambaud, M.; Graff, M. Tetrahedron Lett. 1985, 26,
53. Solladie´, G.; Hutt, J .; Fre´chou, C. Tetrahedron Lett. 1987, 28, 61.
(6) This result implies that the lithiated ester has the (Z)-configu-
ration, in accord with the structure of lithiated allyl ethers; see:
Yamamoto, Y.; Yatagi, H.; Maruyama, K. J . Org. Chem. 1980, 45, 195
and references therein.
(7) Structures of 9, 10, and 12 were established by X-ray crystal-
lography at the University of Sydney. Ratios of all isomers were
established by measurement of reaction mixtures at 600 MHz
(8) For a related case involving conjugate addition of silyl ketene
acetals, see: Danishefsky, S. J .; Cabal, M. P.; Chow, K. J . Am. Chem.
Soc. 1989, 111, 3456. Chow, K.; Danishefsky, S. J . J . Org. Chem. 1989,
54, 6016.
† Dedicated to Professor Dr. Dieter Seebach in honor of the occasion
of his 60th birthday.
‡ Hong Kong University of Science and Technology,
§ University of Sydney.
Universite´ de Gene`ve. Current address: Firmenich SA, Research
Laboratories, CH-1211 Geneva 8, Switzerland.
(1) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J . Am. Chem. Soc. 1988, 111, 5411. Oare, D. H.;
Heathcock, C. H. Top. Stereochem. 1992 19 338.
(2) Haynes, R. K.; Starling, S. M.; Vonwiller, S. C. J . Org. Chem.
1995, 60, 4690.
(3) However, the stereochemical outcome of the conjugate addition
of a five-membered zinc chelate to a cyclopentenone is rationalized in
terms of an endo-orientation of reactants: Takahashi, T.; Nakzawa,
M.; Kanoh, M.; Yamamoto, K. Tetrahedron Lett. 1990, 31, 7349.
(4) The proposals were set out in Honours proposal of A.C.R. at the
University of Sydney.
(9) Eschler, B. M.; Haynes, R. K.; Ironside, M. D.; Kremmydas, S.;
Ridley, D. D.; Hambley, T. W. J . Org. Chem. 1991, 56, 4760.
(10) The use of the catalytic reagent to cleave tert-butyl ethers has
been described recently: Franck, X.; Figade`re, B.; Cave´, A. Tetrahedron
Lett. 1995, 36, 711.
S0022-3263(97)00337-X CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 14, 1997 4553
selectivity in the reactions of the intensively examined
butenolide.17
The facile elimination of tert-butoxide from 15 to
produce the enantiomerically-equivalent enone 16 is also
significant; the enantiomer 14 serves as an operational
equivalent of “chiral” cyclopentadienone, which is ef-
fective under aprotic conditions. The use of racemic
4-acetoxycyclopentenone as an operational equivalent of
“racemic” cyclopentadienone was described some years
ago,18 but the enantiomers of the acetoxy enone cannot
be easily obtained,9 and cannot be used under aprotic
conditions.
While the current synthesis of brefeldin A is not as
convergent as originally planned,4,19,20 it has clear poten-
tial in preparation of analogues.21,22
and TiCl4 (1.5 equiv) in THF gave solely the (E)-acid (58%
overall). This method for opening of butenolides has not
been described previously.11 The acid 19 was esterified,
and the free hydroxy group was protected as the MEM
ether, a group that, as in a related case,12 controlled
stereoselectivity in the reduction of the cyclopentanone
carbonyl with L-Selectride. The resulting alcohol epimers
(75:25) were protected as MEM ethers, and the dithiane
in the major epimer was converted into the free aldehyde
20 (58%) with an excess of MeI and sodium bicarbonate
in aqueous MeCN.13 The aldehyde with the Wittig
reagent from phosphonium salt 2114 in THF containing
LiBr (1 equiv) gave the alkene (81%, E/Z 87:13), treat-
ment of which with aqueous HCl in THF and then with
LiOH in MeOH gave (E)-hydroxy acid 22 (86%).15 Lac-
tonization and deprotection gave (+)-brefeldin A, mp
Ack n ow led gm en t. We thank the Australian Re-
search Council and the School of Science, The Hong
Kong University of Science and Technology, for financial
support to R.K.H. (Direct Allocation Grant No. DAG 94/
95.SC07) for support of this work. The University of
Geneva and Professor Charles J efford are thanked for
financial support and use of facilities for work (by P.L.)
on enol ether 13.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for conjugate addition reactions of 2, lithiated 6, and
13 with enones, experimental procedures for synthesis of
brefeldin A, characterization data for all new compounds,
ORTEP plots, and X-ray data for compounds 9, 10, 12, and
(R,S)-17 (19 pages).
203-204 °C; [R]22 +83.0° (c 0.04, MeOH).16
D
Sch em e 2a
J O970337S
(14) The phosphonium salt 21 was prepared from the alkene i
obtained according to a literature sequence for
a closely related
compound; see: Boon, G. J .; Downham, R.; Kim, K. S.; Ley, S. V.;
Woods, M. Tetrahedron 1994, 50, 7157. (a) Pt/C, H2, EtOAc, rt (98%)
then 70% aqueous HOAc to give ii (83%); (b) NaBH4, MeOH at 0 °C
(94%) then CBr4, PPh3, DMF, 0 °C to give iii (95%); (c) PPh3, MeCN,
reflux to give 21 (77%).
Key: a(a) (i) CH2N2 then MEMCl, i-Pr2NEt , CH2Cl2, 12 h (86%);
(ii) K-Selectride, THF, -78 °C, 1 h (79%); (iii) MEMCl, i-Pr2NEt,
CH2Cl2, 10 h (85%); (iv) MeI, NaHCO3, MeCN, rt (58%); (b) (i)
n-BuLi, phosphonium bromide 21, LiBr (1 equiv), THF, -78 °C
then KOCMe3 (78%, E/Z 87:13); (ii) 1 mol L HCl, THF, 10 h, rt,
(15) Evidently, under these conditions, acid-catalyzed isomerisation
of the (Z)-alkene takes place.
(16) Corey, E. J .; Wollenberg, R. H. Tetrahedron Lett. 1976, 4705.
Corey, E. J .; Wollenberg, R. H.; Williams, D. R. Tetrahedron Lett 1977,
2243: mp 201-202 °C; [R]20 +90.0 (c 0.1, MeOH).
D
(17) For leading references, see: Boukouvalas, J . In Encyclopedia
of Reagents for Organic Synthesis; Wiley: Chichester, 1995; Vol. 2, pp
820-823; Vol. 7, pp 5297-5300.
workup then LiOH, MeOH, H2O, 10
h (86%); (c) (i) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, 6 h, DMAP, toluene, reflux,
14 h (78%); (ii) TiCl4, CH2Cl2, 0 °C, 2 h (96%).
(18) Koeksal, Y.; Raddatz, P.; Winterfeldt, E. Angew. Chem., Int.
Ed. Engl. 1980, 19, 472 and references cited therein.
(19) The original intention was to add the vinyl cuprate correspond-
ing to the protected (S)-heptenol side chain of brefeldin A to the enone
14 and then, after elimination of butoxide, treat the transposed enone
(cf. 16) with the lithiated butenolide 2. While syntheses of brefeldin A
employ conjugate additions of such organocuprates to cyclopentenones,
we could not obtain workable yields of adducts. For relevant examples,
see refs 4 and 12 and: Bernardes, V.; Kann, N.; Riera, A.; Moyano,
A.; Pericas, M. A.; Greene, A. E. J . Org. Chem. 1995, 60, 6670.
Kobayashi, Y.; Watatani, K.; Kikori, Y.; Mizojiri, R. Tetrahedron Lett.
1996, 37, 6125.
Clearly, the conjugate addition of lithiated butenolide
2 to (R)-enone 14 or the (S)-enantiomer9 and to other
cyclic enones such as 16 bearing a stereodirecting group
at C-4 presents a simple operational means of controlling
installation of absolute configuration at oxygen-bearing
functional groups exocyclic to the enone. The conjugate
addition reactions display a hitherto unrevealed stereo-
(20) For recent syntheses see refs 12 and 19 and: Miyaoka, H.;
Kajiwara, M. J . Chem. Soc., Chem. Commun. 1994, 483. Tomioka, K.;
Ishikawa, K.; Nakai, T. Synlett 1995, 901. Kim, D.; Lim, J . I.
Tetrahedron Lett. 1995, 36, 5035.
(21) For application of brefeldin A derivatives in induction of cell
differentiation and apoptosis in cancer cell lines, see: Zhu, J .-W.; Hori,
H.; Nojiri, H.; Tsukuda, T.; Taira, Z. Bioorganic Med. Chem. Lett. 1997,
7, 139.
(22) The authors have deposited atomic coordinates for 9, 10, 12,
and (R,S)-17 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(11) In the original strategy (ref 4), opening of the butenolide with
its (Z)-configured double bond by alkoxide nucleophiles would be
problematical. Conjugate addition of thiolate provides a saturated
butanolide whose thiophenoxide-mediated opening is now favorable.
Reversible elimination of thiolate provides the more stable (E)-
unsaturated thioester, which is hydrolyzed on quenching to the acid.
(12) Casy, G.; Gorins, G.; McCague, R.; Olivo, H. F.; Roberts, S. M.
J . Chem. Soc., Chem. Commun. 1994, 1085; Carnell, A. J .; Casy, G.;
Gorins, G.; Kompany-Saeid, A.; McCague, R.; Olivo, H. F.; Roberts, S.
M.; Willetts, A. J . J . Chem. Soc., Perkin Trans. 1 1994, 3431.
(13) Smith, A. B.; Rano, T. A.; Chida, N.; Sulikowski, G. A.; Wood,
J . L. J . Am. Chem. Soc. 1992, 114, 8008.