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3526
of X provided the P-diketone ( X I I ):;: :A 5.66, 5.74 n.m.r. 3.22 6 (1 H, singlet), 1.26 6 (3 H, singlet), 1.03 6 ( 3 H, singlet) (the remaining protons appeared as a complicated series of multiple peaks from 2.1-3.0 6 indicating t h a t the equivalent bridge protons has moved downfield as expected). Mild base treatment of XI1 provided the keto acid X I I I: ;: :A 5 . i 4 and 5.86 p. The acid rearrangement of IV also gave small amounts of the isomeric ketone X I V :; : :A 3.27, 3.73 H~OH p ; xC max 305 mp ( e 282); n.m.r. 1.04 6 (3 H, singlet), 1.136 ( 3 H, singlet), 1.81 6 (3 H, doublet, J = 2.0 c.P.s.), 2.18 6 (2 H, narrow multiplet), 2.65 6 (1 H, triplet, J = 4.5 c.P.s.), 2.82 6 (1 H , doublet, J = 1.0 c.P.s.), and 6.15 6 (1 H, quartet, J = 2.0 c.P.s.). The structure of XIV was established by catalytic hydrogenation to XI. p;
X
XI11
XI1
columns, a technique which permits rapid comparison of the interaction under a variety of conditions. If it is assumed t h a t the binding of the amides is through peptide hydrogen bonds, then the association is a measure of hydrogen bond formation and strength. Several differing estimates of peptide hydrogen bond strength have been reported,"-" the most recent being that of Klotz and Franzen,2who found t h a t in water the bond is very weak. The data presented here confirm this conclusion. Polyglycine was prepared by polymerization of the N-carboxyanhydride in pyridine.j Thermostated columns (0.6 X 20 to 30 cm.) were operated under 5 Ib. pressure, with a flow rate of no more than 2 nil.,!'hr. Samples (0.1 ml.) were applied to the column, and the effluent fractions were analyzed for urea or acetamide by acid hydrolysis followed by ninhydrin determination of the ammonia liberated. The volume a t which unretarded material emerged was determined using solutes which would not interact with polyglycine ( z . e , , sodium chloride, acetic acid, or acetone, when water was the solvent, and azulene or acetic acid for dioxane). Simple chromatographic theory shows Rf = 1 ( 1 K d ) , where Rfis the mobility, and K d is the distribution coefficient of the solute between the liquid and solid phases.6 Table I presents values of k i d for chromatography of urea and acetamide on polyglycine, in water and dioxane, a t several temperatures. Neither
+
TABLE I THECHROMATOGRAPHY OF UREAA N D ACETAMIDE ON POLYGLYCINE
XIV
Pyrolysis of IV a t 340' provided isopiperitenone12 (XV) (2,4-dinitrophenylhydrazone, m .p. 155-156') and piperitenone (11) as the major products. A minor pyrolysis product was the aldehyde XVI 310 3.69, 5.95 p ; semicarbazone, m.p. mp ( 6 9800); 211-213'). The structure of XVI was established b y comparison with an authentic samplelY prepared from 3-methyl crotonaldehyde. Pyrolysis of IV a t higher temperatures led to piperitenone and m-xylene
Vol. 85
Solute
0 05
M
urea or acetamide 0 05 -21acetamide 0 05 df acetamide
Solvent
Temperature, OC.
Uistribu- Monomer Associaconcn., tion tion co.M constant efficient
0 or 40
owning, J. P h y s C ' h e m , 66, 14:32, ( 1 Q l i l ) ( 5 ) Y Go and H T a n i , Biril Chem. Soc J a p a n . 14, 510 ( 1 (6) J C Giddings and R,A . Keller, in "Chromatography," Ed , Reinhold Publishing Corp , S e w York, N Y . . 1961
Nov. 5 , 1963
COMMUNICATIONS TO
THE
EDITOR
3527
( - - ) - C a r v ~ m e n t h o n e(11, ~ ~ R1 = Rz = H ) was converted via the known a-hydroxymethylene derivatives to the diketo aldehyde I1 (R,= CHO, R?= CH2CHzCOCHs), using methyl vinyl ketone and triethylamine This suba t room temperature ( 3 days, i 1 % ) . 6 stance was deformylated by 2yc ethanolic potassium carbonate a t reflux (16 hr.) to give the diketone I1 (R1 = H , R2 = CH2CH?COCH3,570% yield, infrared max. 5.82 p, n.m.r. peaksR a t 0.Si-1.02 6 due to three methyl groups and a t 2.03 6 due to C-acetyl. Treatment of this diketone with boron trifluoride in methylene chloride solution a t 2.5' (16 hr.) afforded in 40y0 yield the bridged keto olefin 111 (X = 0) and its C-4 epimer in a ratio of 4 : 1. These liquid epimers were purified by v.p.c. or via the crystalline sernicarbazones. The major isomer has b.p. Ci6-6So (0.06 mm.), infrared absorption a t 5.83 p , n.m.r. peaks a t ().SO-1.01 6 due to three methyl groups attached to saturated carbon, a t 1.6 6 (doublet) due to one methyl attached to unsaturated carbon, and a t 5.60 6 due to one olefinic proton; both isomers lack ultraviolet absorption characteristic of a,p-unsaturated The assignment of configuration a t C-4 to 111 (X = 0) and its 4-epimer rests partly on the fact t h a t DEPARTMENT OF CHEMISTRY J . X . RUPLEY reduction with lithium aluminum hydride produces a UNIVERSITY O F ARIZOSA M . PRAISSMAN mixture of secondary alcohols from the former (ratio TUCSON, ARIZOSA 4: 1) b u t only a single alcohol from the latter. T h a t RECEIVEDSEPTEMBER 19, 1963 the predominating course of reduction of both I11 (X = 0) and its C-4 epimer is (as i t is expected to be) that which produces an hydroxyl with axial orientaTotal Synthesis of Helminthosporal tion of the cyclohexane ring (IV, R i = H, Rz = OH, Sir: and the C-4 epimer) is indicated by r1.m.r. data. The n.m.r. peak due to the -CH-0 proton is a t 3.54 6 Recently the constitution of helminthosporal, the important crop-destroying toxin of the fungus Helminfor I V (R1 = H , RZ= OH) and at 3.48 6 for the C-4 thosporizim sntioitm, has been demonstrated by an epimer; the corresponding prototi in the spectrum of incisive chemical investigation. Subsequent studies on the minor alcohol from I11 (X = 0) ( I V , R, = OH, this substance have also permitted the assignment of Rz= H ) shows a peak a t 3.10 6 . l " stereochemistry, exclusive of absolute configuration, Reaction of the unsaturated ketone 111 (X = 0) as in I.* We report here the total synthesis of helminwith methoxymethylene triphenylphosphorane in dithosporal by a method which confirms the previous methyl sulfoxide" a t 40' (12 hr.) gave a 90% yield of structural conclusions and which additionally allows the U-ittig product 111 (X = CHOCH3) which was furthe designation of absolute configuration. ther transformed into the ethylene acetal V (together with minor amounts of the C-2 epimer) with ethylene glycol--benzene-p-toluenesulfonic acid a t reflux (1 hr., S6Yc yield). Hydroxylation of V with osmium tetra-
experiments permit only comparison of the interaction under different conditions. However, this may be done simply and rapidly, and if independent data are available describing the interaction in one en\'iron' ment, then i t may be quantitatively evaluated for others. The enthalpy of the interaction between the amide and polyglycine can be calculated from the temperature dependence of K,,and will he independent of the concentration of available peptide bonds. For acetamide in dioxane the value obtained was -3600 cal./mole. Klotz and Franzen found an enthalpy of -800 cal./mole for the dinierization of E-niethylacetamide in dioxane. The more negative value obtained in the chromatographic experiments suggests that acetamide may bind to polyglycine with more than one peptide hydrogen bond. Since a maximum of three such bonds can be formed by each acetamide molecule, the value of the enthalpy niay be as low as - 1200 cal.,'niole of hydrogen bonds. An enthalpy could not be calculated for water, since binding waq not observed a t either 0 or 40' in this solvent , These experiments will be extended to evaluate the characteristics of the association in other solvents.
ho JJT I
II
X
m ( 1 ) P. d e h l a y o , E. Y Spencer,'and R . W . White, J A m . Chem SOC., 84, 191 ( l Q ( i 2 ) ; P. de Mayo, E. Y Spencer, and R W White, C a n . J . C h e m . , 39, 1008 (1961). 1 2 ) P d e hlayo, perso,ial communication
(3) Prepared b y hydrogenation of ! f ) - c a r v o n e ; see E. S. Rothman and A. R Day, J . A m . C h e m . S o c , 7 6 , 111 (19.54). (4) Formal total syntheses of both ( - 1 - and (+)-carvomenthone a r e provided by the terpene literature For example; a route for the ( - ) isomer appears in the series (a) W H Perkin, Jr.. J . Chein S O L . 8, 6 , 051 (19041, K. Alder and W. Vogt, A i i n . , 564, 109 (1949); ( b ) A . T Fuller a n d J. Kenyon, J . Chem Soc., 126, 2304 (1924), (c) K. Fujita and T M a t s u u r a , J . Sci H i i o ~ h i m aU n i v , M A , 1 5 3 (195.5) [ C h e m . Abstr , S O , 103i82 (1950)], (d) hf. G Vavon, C o m p l . u e n d . , 163,70 (1911) (5) V S kora, J. e e r n y , V. Herout. and F. Sorm, Collectron Cmech. Chem Commun , 19, S(,C, (1954). ( 6 ) K B . Turner, D. E Nettleton, Jr., and R. Ferebee, J A m Chem S O L . , 78, 3923 (1956). (7) Satisfactory analytical d a t a were obtained for this and the other major intermediates in this synthesis All the assigned structures are supported by spectral d a t a though these are not extensively reported here. (8) Expressed as parts per million shift (6) downfield f r o m tetramethylsilane. (9) T h e formation of bridged-ring products such as 111 (X = O ) , a s a side reaction in the Robinson annulation process, has been discussed recently by W. S Johnson, J. J. Korst, R. A Clement, and J . I l u t t a , J , A m , Cheni. S o c . , 8 2 , t i l 4 ( 1 9 G O ) ; S Julia, Bull. Soc. C h i m Fvanc-e, 21,780 (1954) I n the pre.ent instance the conditions are such as t o render the normal Robinson reactiim mode almost insignificant. Further, the ratio of C 4 epimers of I11 (X = 0 ) can also be altered markedly by vacying reaction conditions. (10) T h e c-rbinyl proton resonance in IV ( R I = O H , R z = H ) can be expected t o occur a t higher field t h a n t h a t in the epimeric IV (Kj = H, R 2 I OH) by ca. 0.5 p . p m. See, e e . , A H. Lewin and S Winstein. J A m [ h e m . Soc., 8 4 , 2104 ( I M Z ) , R . R. Fraser, C a n J Chem . 40, 7 8 (1962) (11) R . Greenwald, hl Chaykovsky, and E. J . Corey, J Ory Chem , 18. 1128 (1963)
