2744
J. Org. Chern., Vol. 37, No. 17, 1972
KRETCHMER
nmr, melting point, mixture melting point, and tlc mobility (Ri0.36, silica gel G,ether)] as the previously prepared sample. Isotulipinolide (24).-Tulipinolide (1, 175 mg) was suspended in 1N KOH and warmed for 2 hr on a steam bath. The solution was quickly evaporated, treated with 3 ml HOAc, and evaporated, and the process repeated again. The residue was dissolved in CHCh, extracted with 5% NaHC03 and HtO, dried (NaZSO,), and evaporated to leave a 50-mg residue. Chromatography of the residue over 4 g of silica gel G with CHClsEt20 (1: 1) as eluting solvent gave 27 mg of an oil that was one spot on tlc and was formulated as desacetylisotulipinolide (23): [CY]~?D +130’ (c 0.054, MeOH); ir 3610, 3460, 1760, and 1660 cm-l; mass spectrum m / e (re1 intensity) M+ 248.1417 (3.5) (CleHtoO3 calcd 248.1412), 230 (3), 108 (13), 84 (36), and 18 (100). Acetylation of desacetylisotulipinolide (23, 27 mg) with Acto-pyridine at room temperature for 20 hr gave a residue that after chromatography on silica gel G using CHCls-Et?O (20: 1) as eluting solvent gave 15 mg of an oil that was one spot on tlc and was formulated as isotulipinolide (24): [alZz~ f 3 6 (c 0,056, MeOH), ir 1760, 1735, 1660, and 1250 cm-l; mass spectrum m / e (re1 intensity) M+290.1507 (0.6) (C1,HtzO1 calcd 290.1538), 230 ( 5 ) , 107 (14), 84 (50), and 43 (100). A comparison (ir, nmr, and tlc) of this material with laurenobiolide13 showed them to be the same. Eupatolide Methanesulfonate (25).-A 500-mg sample of eupatolide (11) dissolved in 4 ml of pyridine and cooled in an ice bath was treated with 0.3 ml of CH8S02C1. After 17 hr the solution was diluted with HzO and extracted with CHC& and the CHC13 extract was washed with 1% HCl and HzO. The CHC13-soluble residue was crystallized from EtOH-isopropyl ether to give 412 mg of eupatolide methanesulfonate (25): mp 112-113’; ir 1770,1670,1350, and 1175 cm-1. Anal. Calcd for CleH2?OaS: C, 58.88 H , 6.80 S, 9.81. Found: C,58.57 H,6.93 S,9.68.
Treatment of Eupatolide Methanesulfonate (25) with K0H.A 400-mg sample of 25 was stirred with 8 ml of EtOH, and 72 ml of 0.4 N KOH was added. After 24 hr at room temperature, the reaction solution was acidified with dilute HOAc, saturated with NaC1, and extracted with ether. The ether extract was washed with water, dried (NazSOI), and evaporated t o leave 243 mg of an oily residue. Chromatography of the oil was on 15 g of silica gel G with CHCl3-Et20 (1: 1) as eluting agent. Early fractions gave 37 mg of deacetylisotulipinolide (23) identical (tlc, ir, and nmr) with the product of alkaline hydrolysis of tulipinolide (1). Later fractions contained eupatolide (11). Reduction of Dehydroeupatolide (27).-To a solution of dehydroeupatolide? (100 mg) in 7 ml of i-PrOH a t 40’ was added 6 mg of NaBH4. After 10 min the solution was acidified with dilute HOAc, diluted with HzO, and extracted with ether. The ether-soluble residue (95 mg) showed three spots on tlc. Separation of these substances was accomplished on 5 g of silica gel G using CHC13-Et?0 (1: I) as solvent system. Two products were identified as eupatolide (11) and dihydroeupatolide (12), while the third from spectral evidence appeared to be 11,13dihydrodehydroeupatolide, but deacetyltulipinolide (26) was not detected.
Registry No.-1, 24164-12-3; 2, 24164-13-4; 3, 35001-07-1; 4, 35001-08-2; 5, 35001-09-3; 6, 2416420-3; 7, 24165-31-9; 8, 35001-12-8; 9, 35001-13-9; 10, 35001-14-0; 12, 35001-16-2; 13, 35001-1.5-1 14, 35001-17-3; 15, 35001-18-4; 16, 35001-19-9 17, 35001-204; 18, 35001-21-9; 19, 35001-22-0 22, 35001-23-1; 23, 35001-24-2; 24, 35001-25-3 25,35001-26-4; 28,35001-27-5.
1,4 Addition of Organometallic Reagents to a,P-Unsaturated Ketones in the Presence of (-)-Sparteine RICHARD A. KRETCHMER Department of Chemistry, Illinois Institute of Technology, Chicago, Illinois
60616
Received February 28, 1972 The reaction of 2-cyclohexenone, 3-penten-2-one, and 1,3-diphenyl-2-propen-l-onewith a series of Grignard reagents has been studied in the presence of (-)-sparteine (4) and other additives. The resulting conjugate addition products possess an optical purity cf 3-6% and represent the first examples of asymmetric 1,4 addition of achiral organometallic reagents to prochiral a,@-unsaturatedketones. Subsequent reactions of enolate anions initially produced by conjugate addition of the organometallic reagents are discussed. (- )-Sparteine is shown to reduce the reactivity of met,hylmagnesiumiodide toward a,p-unsaturated ketones.
The ability of a,@-unsaturated ketones (1) to add Grignard reagents (2a) and organocopper(1) compounds (2b)2 in a 1,4 manner is well documented in RCH=CH 1
8
R f
R’M + 2a, M = MgX b, M = CU 0- M +
I
RCHCHzCR
I
ckY3 H
0
I/
+RCHCHzCR Hz0
1
R’
R’
reagent,zb,c In view of this, we have examined the reaction of some a,@-unsaturatedketones with Grignard reagents in the presence of (-)-sparteine (4). The
3
the literature. Recently, it has been shown that the course of this reaction can be influenced to some extent by solvent or the ligands attached to the organometallic (1) (a) M. S. Kharasch and 0. Reinmuth, “Grignard Reactions of Nonmetallic Substances.” Prentice-Hall, New York, N. Y., 1954, pp 196-234; (b) J. Munch-Petersen, Bull. SOC.Chzm. F r . , 471 (1966). (2) (a) H. Gilman, R. G. Jones, and L. A. Woods, 3 . Orp. Chem., 17, 1630 (1952); (b) H.0.House, W. L. Respess, and G. M. Whitesides, zbzd., 31, 3128 (1966); (c) H. 0. House and W. F‘. Fischer, ibid., 33, 949 (1968).
4
results, indicated in Tables I and 11, represent the first examples of asymmetric 1,4 addition of achiral organometallic reagents to prochiral a$-unsaturated ketones. The most apparent effect of an equimolar amount of (-)-sparteine (4) on an ether solution of methylmagnesium iodide is a drastic reduction of reactivity tox-ard the enone substrates (Table I). Both 2-cyclohexenone and 1,3-diphenyl-2-propen-l-onewere recovered unchanged after exposure to this reagent system for over 1 hr at room temperature. Enolization
1,4 ADDITION TO
J . Org. %hem.,Vol. 37, No. 17, 1972 2745
UNSATURATED KETONES TABLE I
1,4 ADDITION OF GRIGNARD REAGENTS TO ~,B-UNSATURATED KETONES IN Organometallic (mol %)"
THE
PRESENCE OF VARIOUS ADDITIVES Time, hrb
Yield,
Additive (mol %)
Substrate
Product
2-Cy clohexenone 2-Cyclohexenone 2-Cy clohexenone
3-Methylcyclohexanone 3-Methylcyclohexanone 3-Methylcyclohexanone
EtzO Benzene 0.50 Et20
2-Cyclohexenone
3-Phenylcyclohexanone
1
5 CHaMgI (156)
Sparteine (124) Sparteine (125) Sparteine (200) CuCl (99) Sparteine (221) CuCl (110) None
6 CHsMgI (155)
Sparteine (170)
7 CHaMgI (120)
Sparteine (120)
1,3-Diphenyl-2propen-1-one 1,3-Diphenyl-2propen-1-one 1,3-Diphenyl-2propen-1-one 1,3-Diphenyl-2propen-1-one 1,3-Diphenyl-2propen-1-one 1,3-D iph enyl-2propen-1-one 3-Penten-2-one
1,3-Dipheny1-3-methyl1-propanone 1,3-Diphenyl-3-methyl1-propanone 1,3-Diphenyl-3-methyl1-propanone I ,3-Diphenyl-3-methyl1-propanone 1,3-Diphenyl-3-methyl1-propanone 1,3-Diphenyl-3-methyl1-propanone 4-Methyl-2-hexanone
Run
1 CHaMgI (124) 2 CHsMgI (125) 3 CHaMgI (100) 4
CeHsMgBr (124)
+
+
Solvent
Substrate recovery,
%c
%O
I. S.Kharasch and D. C. Sayles, ibad., 64, 2972 (1942).
0 I/
C6H5
I C,HSCC=CCH=CHC,H, I
CH3
0
I II C,H,CHCH,CC,Hs
CHCBH5
c H, 2
3
We recently had occasion to examine the reaction between 1 and methylmagnesium iodide. A major product (200j0) of this reaction had properties consistent with those reported for 2, but the spectroscopic data
