J.Org. Chem., Vol. 41, No. 17,1976 2797
Synthesis and Absolute Configuration of Multistriatin zene-methanol (19:l) gave a partial separation in the form of an elongated band. Removal of the lower portion of this band followed by extraction with methanolxhloroform (1:l)and evaporation of the solvent gave pure @ isomer 11 as colorless microcrystals: 95 mg, mp 125-140 "C dec; 'H NMR (CDCl3) 6 1.31 and 1.55 (2 s, 6 H, isopropylidene CH3), 3.32 (m, 2 H, H-5',5"), 4.22 (m, 1H, H-4'), 4.67-4.93 (m, 2 H, H-2', H-3'),4.99 (d, 1H, H-1'). Anal. Calcd for C31H30N206: C, 70.71; H, 5.74; N, 5.32. Found: C, 70.58; H, 5.80; N, 5.15. From the upper layer portion of the elongated band in the thick layer chromatogram, only a mixture of the a and @ isomers (12 and 11) was obtained. 5-(j3-D-Ribofuranosyl)uracil (13, Pseudouridine).A mixture of 11 (105 mg, 0.2 mmol) and 10%methanolic HCl(2 ml) was stirred at room temperature for 15 min. During this time, a clear solution was obtained and then crystalline product 13 (20 mg) precipitated. The crystals were collected by filtration and washed with ether, mp 221-222 "C (lit.15 mp for pseudouridine 220-221 "C). 'H NMR spectrum (DzO) of this product was identical with that of pseudouridine.I2 From the filtrate a further quantity of 13 (26 mg) having the same melting point and lH NMR spectral characteristics was obtained upon dilution with 20 ml of ether. The combined yield was 92%.
Registry No.-1, 55726-19-7; 3, 57100-24-0; 4, 59464-13-0; 5, 59464-14-1; 6,57100-19-3; 7,57100-18-2; 7 HC1,59464-15-2; 8 HCl, 59464-16-3; 9, 59464-17-4; 10, 59464-18-5; 11, 59464-19-6; 12, 59464-20-9; 13, 1445-07-4; (ethoxycarbonylmethy1ene)triphenylphosphorane, 1099-45-2; guanidine HC1, 15827-40-4; thiourea, 6256-6.
References and Notes This investigation was supported in part by funds from the National Cancer institute, DHEW (Grants CA-08748, -18856, and -17805). (2) W. E. Cohen, Fed. Proc., Fed. Am. Soc, Exp. Biol., 16, 166 (1957); F. F. Davis and F. W. Ailen, J. Biol. Chem., 227, 907 (1957). (3) R. J. Suhadonik, "Nucleoside Antibiotics", Wiiey-lnterscience, New Yo&, N.Y., 1970. (4) K. A. Watanabe, D. H. Holienberg, and J. J. Fox, J. Carbohy&., Nucleos&s, Nucleotides, 1, i ( i 9 7 4 ) . (5) R. Shapiro and R . W. Chambers, J. Am. Chem. Soc., 83,3920 (1961); D. M Brown, M. G. Burdon, and R . P. Slatdrer. J. Chem. SOC., 1051 (1968); W. A. Asbun and S. B. Binkiey, J. Org. Chem., 31,2215 (1966); 33, 148 (1968); U. Lerch, M. G. Burdon, and J. G. Moffatt, ibid., 36, 1507 (1971). (6) S. David and A. Lubineau, Carbohydr. Res., 29, 15 (1973). (7) C. K. Chu, K. A. Watanabe. and J. J. Fox, J. Heterocycl. Chem., 12, 817 (1)
(1975). (8) J. H. Burchenai, K.
Ciovacco, K. Kalahar, T. O'Tooie, R. Kiefner, M. D. Dowling, C. K. Chu, K. A. Wa@nabe,I. Wempen, and J. J. Fox, Cancer Res.,
36, 1520 (1976). (9) H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T. Christensen, and S.K. Bryam, J. Am. Chem. SOC.,97,4602 (1975). (10) J. G. Buchanan, A. R. Edgar, M. J. Power, and?. D. Theaker, Carbohydr. Res., 38, C22 (1934). ( 1 1) J.-L. imbach and B. L. Kam, J. Carbohydr., Nucleosides, Nucleotides, I, 271 (1974). (12) R. Deslauriers and J. C. P. Smith, Can. J. Biochem., 50, 766 (1972). (13) F. E. Hruska, A. A. Gray, and J. C. P. Smith, J. Am. Chem. SOC.,92,4088 (1970). (14) R. W. Chambers, Prog. Nucleic AcidRes. Mol. Biol., 5, 349 (1966). (15) W. E. Cohen, J. Bid. Chem., 235, 1488 (1960); R. W. Chambers, V. Ktrkov, and R. Shapiro, Biochemistry, 2, 1192 (1963). (16) R. S. Klein, H. Dhrui, and J. J. Fox, J. W h y d r . . ,NucleosMSs,Nucleotides, 1, 265 (1974). (17) The previously reported extinction values for 7 and 8 are incorrect.
Synthesis and Absolute Configuration of Multistriatin Glenn T. Pearce, William E. Gore, and Robert M. Silverstein* State University of New York, College of Environmental Science and Forestry, Syracuse, New York 13210 Received January 20, 1976 Multistriatin, 2,4-dimethyl-5-ethyl-6,8-dioxabicyclo[3.2.l]octane ( l ) ,was synthesized as a mixture of the four diastereomers l a b . The key step was the formation of 4,6-dimethyl-7-octen-3-one (10) by the alkylation of 3-pentanone with the tosylate (7) of 2-methyl-3-buten-1-01 via the metalloenamine synthesis. Epoxidation of 10 with mchloroperoxybenzoic acid and intramolecular ketalization of the 4,6-dimethyl-7,8-epoxyocten-3-one (1 1) with SnC14 gave 1, whose l a content was maximized by equilibration of l y to l a with SnC14. Acid equilibration of 1 in the presence of excess peroxide leads to the formation of side products a t the expense of the multistriatin isomers. Synthesis of 1 from (S)-(+)-2-methyl-3-butenoic acid gave (2R)-(-)-la, which established the absolute configuration of natural (-)-la as lS:2R:44:5R. The enantiomeric compositisn of synthetic (-)- and ( + ) - l awas determined by I3C NMR with the chiral shift keagent, tris[3-(heptafluor~propylhydroxymethylene)-d-camphorato]europium(II1). Natural (-)-la consisted of a single enantiomer. a-Multistriatin, 2-endo,4-endo-dimethyl-5-ethyl-6,8- mediate (5) of known configuration into t h e synthetic dioxabicyclo[3.2.l]octane (la),is a novel component of t h e scheme. aggregation pheromone of t h e European elm bark beetle, Previous syntheses of the 6,8-dioxabicyclo[3.2.l]octanering Scolytus multistriatus. In a previous publication,2 we have system, including t h e synthesis of two other bark beetle determined t h e relative stereochemistry for each of t h e four pheromones, f r ~ n t a l i n ~(2) - ~and b r e v i ~ o m i n ~(3), - ~ have been possible pairs of multistriatin stereoisomers. W e report here a synthesis of racemic la-6 designed t o confirm the gross structure of multistriatin and provide quantities of 1 sufficient
4 2
R1
I
1
R
R c
.l.-a : 16 : ..Jr :
H
CH3
H
M3
M3
H
M3
H
H
M3
M,
H
:
M3
H
H
CH3
--16
(12)
txo : MZCHJ
endo :
1
for field tests. In addition, optically active (+)- a n d (-)multistriatin stereoisomers (la-6)of known absolute configurations were synthesized by inclusion of a chiral inter-
H
H M2M3
accomplished by two main routes, Schemes I a n d 11. Scheme I involves t h e Diels-Alder addition of a n a,@-unsaturated to~another ~~~ carbonyl either to an a,@-unsaturateda l c ~ h o lor, ~ a#-unsaturated carbonyl that acts as t h e d i e n ~ p h i l e . ~ JT~h Je ~ first variation of this route (Scheme la), is thought t o occur via a hydroxy dihydropyran intermediateg that cyclizes t o the desired product under t h e conditions of t h e initial addition.
Pearce, Gore, and Silverstein
2798 J.Org. Chem., Vol. 41, No. 17,1976 Scheme I r
w
R
Scheme I1
1
R2 endo
In the second variation (Scheme Ib), the initially formed keto dihydropyran is reduced to the corresponding alcohol, whereupon Lewis acid catalyzed ring closure yields the appropriately substituted 6,8-dioxabicyclo[3.2.l]octane ring. When applied to the synthesis of multistriatin ( l ) ,this route yielded only small amounts of 1 (5%)in a complex mixture of starting materials and reaction products.2 Although the stereospecificity of the Diels-Alder reaction was helpful in assigning the relative configurations of the C-1 and C-2 carbons of 1, this approach was not amenable to a large-scale synthesis. An alternative approach (Scheme 11),which was used in the present synthesis, involves the epoxidation of a 6-keto olefin, followed by thermal or acid-catalyzed cyclization of the keto epoxide.7J3J2J3 The keto epoxide rearrangement is stereospecific by both thermal and acidic catalysis as evidenced by the stereospecific syntheses of exo- and endo- brevicomin from the cis and trans epoxides, respectively. This reaction7J2J3 presumably involves attack of the carbonyl oxygen on the epoxide ring with inversion of the 6 carbon. Synthesis of Racemic Multistriatin. The key intermediate of our synthesis (Scheme 111) was the keto olefin, 4,6dimethyl-7-octen-3-one (10).The 2-methyl-3-butenyl moiety
of 10 was introduced as the tosylate (7) of 2-methyl-3-butenol (6), which was synthesized by the carbonation of butenylmagnesium bromide (4) followed by reduction of the resulting 2-methyl-3-butenoic acid ( 5 ) with lithium aluminum hydride. Alkylation of the magnesium bromide salt (9) of the ketimine (8) formed from 3-pentanone and cyclohexylamine with the tosylate (7) in THF gave, after acid hydrolysis, 10 in 70%yield (distilled) from 6.14 The spectra of each of the GLC-purified diastereomers of 10 were nearly identical with minor variations observed only in the ir and NMR spectra. The infrared spectra each exhibited a peak a t 1715 cm-l corresponding to the C=O stretching frequency; strong absorptions at 995 and 915 cm-l suggested the presence of a vinyl group, which was confirmed by a two-proton multiplet a t 4.85-5.1 ppm and a one-proton multiplet at 5.4-5.8 ppm. The mass spectrum showed a molecular ion (M+) a t mle 154, and an intense McLafferty rearrangement peak a t mle 86. Epoxidation of 10 was accomplished with m-chloroperoxybenzoic acid in benzene, but refluxing the reaction mixture15 gave only a 20-30% yield of cyclized product. Cyclization and equilibration2of the a l y and PI6 pairs were effected by removal of excess peracid and treatment of a benzene solution of crude 11 with SnC14 (stirring at room temperature for 20 h and refluxing for 1h). Under these conditions, cyclization occurred rapidly (
