J. Org. Chem. 1980,45, 3846-3856
3846
56-9; 2,Z’-dithienyl ketone, 704-38-1; 3,3’-dinitrobenzophenone, 21222-05-9; trans-3,3-dimethyl-l-butenylmercuric chloride, 3652502-7; trans-1-hexenylmercuric chloride, 50874-36-7; trans-2-phenylethenylmercuric chloride, 36525-03-8; trans-1,3,3-trimethyl-l-butenylmercuric chloride, 38010-69-4; trans-2-(1-cyclohexeny1)ethenylmercuric chloride, 56453-89-5; trans-3-methyl-1,3-butadienyl73838-78-5; trans,trans-trideca-5,8-dien-7-one, 73838-79-6; trans,mercuric chloride, 56453-81-7; ethenylmercuric chloride, 762-55-0; trans-1,5-diphenylpenta-1,4-dien-3-one, 35225-79-7; trans,transtrans-2-chloroethenylmercuricchloride, 1190-78-9;phenylmercuric 2,2,4,6,8,8-hexamethylnona-3,6-dien-5-one, 73838-80-9; trans,transchloride, 100-56-1;2-naphthylmercuric chloride, 39966-41-1; 2-thie1,5-bis(l-cyclohexenyl)penta-1,4-dien-3-one, 73838-81-0; trans,nylmercuric chloride, 5857-39-6; 3-nitrophenylmercuric chloride, trans-2,&dimethylnona-1,3,6,8-tetraen-5-one, 73838-82-1; 1,4-pentadien-3-one, 1890-28-4;trans,trans-l,5-dichloropenta-l,4-dien-3-one, 2865-17-0; CO, 630-08-0; bis(3,3-dimethyl-l-butynyl)mercury, 73838-84-3; 2,2,7,7-tetramethyl-3,5-octadiyne, 6130-98-9. 73838-83-2; benzophenone, 119-61-9; 2,2’-dinaphthyl ketone, 613-
Department of Health, Education, and Welfare for a Graduate Professional Opportunities Program Fellowship (to S.S.H.) which helped make this work possible. Registry No.trans,trans-2,2,8,8-Ctramethylnona-3,6-dien-5-one,
Acyclic Stereoselection. 9. Stereochemistry of the Addition of Lithium Enolates to a-Alkoxy Aldehydes’ Clayton H. Heathcock,* Steven D. Young, James P. Hagen, Michael C. Pirrung, Charles T. White, and Don VanDerveer Departments of Chemistry, University of California, Berkeley, California 94720,and Georgia Institute of Technology, Atalnta, Georgia 30332 Received February 20, 1980 ‘The stereochemistry of addition of lithium enolates derived from esters and ketones to the a-alkoxy aldehydes 1-5 has been investigated. In all cases, the predominant product is that predicted by application of Felkin’s
model for asymmetric induction and by assuming the alkoxy group to be the “large” group. The Cram cyclic model for asymmetric induction is not followed. Stereostructures have been assigned by a combination of conversion to products of known stereostructure, 13C and ‘HNMR correlations, and single-crystal X-ray analysis.
Any program aimed at the total synthesis of macrolide antibiotics or polyether ionophores using stereoselective aldol condensations’ must confront the problem of diastereoface selectivity in additions to chiral a-alkoxy aldehydes (relative asymmetric induction).2 To examine this question, we have studied the additions of several lithium enolates to the a-alkoxy aldehydes 1-5. The carbonyl compounds which have been utilized are ketones 6-9 and esters 10-13 (Chart I). The preparation of a-alkoxy aldehydes was accomplished as follows. Aldehydes 1-3 were prepared in racemic form by ozonolysis of ethers 14-16. The R enan-
14,R = t-BuMe,Si 15; R = C,H,CH,16, R = C,H,CH,OCH,-
tiomer of 4 was prepared from D-mannitol by the method of Baer and Fischera3 Aldehyde 54 was prepared in racemic form by the route outlined in Scheme I. Condensation of the known5dioxolanone 17 with propionaldehyde affords adduct 18 as a 70:30 mixture of diastereomers. After hydrolytic removal of the isopropylidine group, the major erythro6 dihydroxy acid may be obtained by crys(1) For paper 8, see: C. H. Heathcock and M. C. Pirrung, J . Org. Chem., 45, 1727 (1980). (2) P. A. Bartlett, Tetrahedron, 36, 2 (1980). (3) (a) E. Baer and H. 0. L. Fischer, J. Bioi. Chem., 128,463 (1939); (b) E. Baer, J. Am. Chem. SOC.,67, 338 (1975); (c) D. Horton, J. B. Hughes, and J. K. Thomson, J. Org. Chem., 33, 728 (1968). (4) J. Inananga, A. Takeda, N. Okukado, and M. Yamaquchi, Mem. Fac. Sci., Kyushi Univ., Ser. C, 9(2),295 (1975). ( 5 ) M. Farines and J. Soulier, Bull. SOC. Chim. Fr., 332 (1970). (6) It has been convenient for us to have a stereostructural nomenclature which is invariant of the nature of R and R’ (eq 2). We prefer the prefixes erythro and threo and use them in the following sense: when the backbone of the aldol is written in an extended (zigzag) manner and the a-alkyl and 8-hydroxy substituents both extend toward the viewer or away from the viewer, this is the erythro diastereomer.
0022-3263/80/1945-3846$01.00/0
Chart I
1, R = t-BuMe,Si
%O
%O
O d C H F 0
OC *O:E t
2, R = C,H,CH, 3, R = C,H,CH,OCH,
6,R=H 7, R = CH,
R
J (
OMe
10,R = H 11, R = CH,
4 5
8,R=H 9, R = CH,
RJcq 12, R = H 13, R = CH, Chart IIU
21
22
23
24
(I a, R = t-BuMe,Si; b, R = C,H,CH,; c, R = C,H,CH,OCH,.
tallization. The overall yield of crystalline 19’ is 30% from dioxolanone 17. Although this synthesis of Bergel’son’s 0 1980 American Chemical Society
Acyclic Stereoselectiori
J. Org. Chem., Vol. 45, No. 19, 1980 3847 Scheme Ia
17
18
chart 111a
19
20 5 a a, LDA, CH,CH,CHO, -78 "C; b, 4 M KOH, MeOH; c, fractional crystallization; d, MeOH, ClCH,CH,CI, H,SO,, reflux 6 h ; e, acetone, H,SO,, 20 "C, 2 h ; f , LAH, Et,O, 0 "C; g, PCC, CH,CI,, 20 "C, 1 2 h. Table I. Reaction of Aldehydes 1-3 with Ketone 9 and Ester 10 product distribution, % enolate aldehyde precursor 21 22 23 24 1 9 66 34 2 9 66 34 3 9 78 22 1 10 50 50 2 10 50 50 3 10 50 50 Table 11. I3C NMR chemical Shifts (ppm) of y l a c t o n e s compd 25 26 43 44
C-2
43.8 43.3 43.2 39.1
c-3 80.1 75.1 73.1 70.1
C-4
80.3 78.3 84.6 86.9
C-5 17.9 13.7 60.0 60.9
c-2 methyl 12.4 12.9 12.5 8.3
acid is not stereospecific, it is a convenient method for preparing large amounts of this important intermediate and the derived dioxolane 20, which have now been used in three macrolide total syntheses.8 In fact, the overall yields (30% 19, 24% 20) are comparable to those obtainable by the other published procedure^.^*^^
Results Aldol condensations were carried out as previously des ~ r i b e dexcept ,~ that longer reaction times are required with certain combinations of reactants (see Experimental Section). Product mixtures were analyzed by 13C NMR spectra of the crude products and in some cases by analytical high-pressure LC. Lactaldehyde ethers 1-3 were studied with methyl acetate (10) and the a-trimethylsiloxy ketone 9.9 In each case a mixture of two diastereomeric products was obtained, 21 and 22 (Chart 11) from ester 10 and 23 and 24 from ketone 9. Results are summarized in Table I. All three aldehydes show no diastereoselection with methyl acetate, equimolar mixtures of 21 and 22 being obtained in each case. Some selectivity is observed with the more sterically demanding enolate derived from ketone (7) L. D. Bergel'son, E. V. Dyatlovitskaya, M. Tichy, and V. V. Voronkova, Zzv. Akad. Nauk SSSR, Ser. Khim., 9,1612 (1962). (8)(a) S. Masamune C. U. Kim, K. E. Wilson, G. 0. Spessard, P. E. Georghiou, and G. S. Bates, J.Am. Chem. Soc., 97,3512 (1975);(b) P. A. Grieco, Y. Ohfune, Y. Yokoyama, and W. Owens, ibid., 101, 4749 (1979);(c) J. Inanaga, T. Kabuki, S. Takimoto, S. Ouchida, A. Nakano, M. Aiga, N. Okukado, and M. Yamaguchi, Proceedings of the 21st Symposium on the Chemistry of Natural Products, Sapporo, Japan, 1978,324. (9)C. H.Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J. Lampe, J. Org. Chem., 45,1066 (1980).
28
29
30
31
32
33
\L a
a, R = MeO; b, R =
Me d
o
;
c, R = t-Bu; d , R =
k Me,C(OH); e, R = Me,C(OSiMe,). Table 111. Reaction of Aldehyde 4 with Ketones 6-9 and Esters 10-13 product distribution, %
enolate Drecursor 6
28
29
>95
