April 20, 1962
COMMUNICATIONS TO THE EDITOR
2,4-dimethylpentane-1,3,5-triol or the alternative 2,3-dirnethylpentane-l,4,54riol.The latter was eliminated because X did not take up any periodate. The infrared spectrum of X is identical with that of 2,4-dimethylpentane-1,3,5-triol[m.p. 54-56’, -14.0’ (c 2%, methanol)] isolated as a degradation product of e r y t h r ~ m y c i n . ~Hence, the triol X is the enantiomorph of the “act-triol” from erythromycin. The above data establish the structure of I as 2,4-dimethyl-3-chalcosyloxy-6-oxoheptanoic acid.
1513
TABLE I1 MOLECULAR ROTATIONS’OF SOME OPTICALLY ACTIVE aAMINO ACID ESTERSAXD OTHER OPEN CHAINPRIMARY Amms IN ETHANOL AND IN ACETONE Time to reach constant
[+]p21-2~ [ + ] D n i - n s
In
Code
Compound
ethanol,
+ +
in acetone
[+ID In
acetpne, min.
390 Ethyl L-alaninate 3 - 70‘ 350 Ethyl D-phenylglyunate -217 - 68 1330 IIC 36 + l l O (R)-( )-a-Phenylethylamine (7) K . Gerzon, E. H. Flynn, M. V. Sigal, Jr., P. F. Wiley, R. 1360 IId (S)-( )-a-p-Tolylethyl- - 33 -115 Monahan and U. C. Quarck, J . Am. Chem. SOC.,78, 6396 (1956). amine PETERW.K. 1Voo RESEARCH DIVISION HENRYW.DION PARKE,DAVIS& COMPANY 1210 IIIb (S)-( )-2-Aminobutane 2 $72 QUENTITR. BARTZ DETROIT 32, MICHIGAN 1170 IVa Ethyl L-phenylalaninate 43 -249 RECEIVED FEBRUARY 19, 1962 1000 54d -278 IVd Methyl L-tyrosinate IVe Ethyl L-leucinate 1890 34 -252 OPTICALLY ACTIVE AMINES. I. 540 IVf Ethyl L-methioninate 13 -224 N-ISOPROPYLIDENE DERIVATIVES OF OPTICALLY Ethyl (S)-( - )-&amino- - 13 -117 330 IVg ACTIVE OPEN CHAIN PRIMARY AMINES AND THEIR hydrocinnamatee ROTATORY POWERS’ Va Ethyl L-isoleucinate 1130 60 -249 Sir: Ethyl L-alloisoleucinate’ Vb 2630 54 -174 Recently Bergel and co-workers2 reported that Calculated as [CY]D X mol. wt. of free base/100. No optically active a-amino acid esters and amides change in [+ID with time. c 1 : 1 Ethanol-acetone as solcontaining a primary amino group, and other vent. d Methanol as solvent. e (R)-Isomer used. f Doptically active open chain primary amines ex- Isomer used. IIa IIb
+
-
+
+ + + + +
+ +
amined in ketonic solvents (Table I) exhibit rotatory powers which change greatly with time, eventually reaching a constant value, highly levorotatory for L-a-amino acid esters and amides. They concluded2b that the mutarotation is due to the formation in ketonic solvents of unstable Schiff bases, RzC=NCHR’R’/, (I), and suggested that the maximal rotation of an a-amino acid ester in a ketonic solvent may help to decide its absolute configuration.
The possible confirmation of Bergel’s simple method seems especially important because for many of these compounds the direction and magnitude of the optical rotation is not certainly predicted with rules, such as the Atomic and Conformational Asymmetry Rules of B r e w ~ t e r . ~ As seen by an inspection of Tables I and 11, our results where comparable are essentially the same as those reported by Bergel, except that the times required for the attainment of constant optical TABLEI rotations in acetone were somewhat longer, due MOLECULAR ROTATIONS~ OF SOME L-a-AMINOACIDDERIVA- perhaps to the prevailing humidity, traces of water TIVES AND (s)-( +)--4MPHETAMINEs I N ETHANOL AND I N in the acetone being known2 to diminish the rate AS REPORTED BY BERGEL% ACETONE of change of rotatory power. Evidently the cause Time to of these slower rates had no great effect on the magreach constant nitudes of the the rotatory powers finally observed In in acetone (cf. IVa in Tables I and 11). [ $ l * l ~ i n[ + ] ~ Z D in acetone, Code Compound ethanol acetone min From an inspection of Table I1 i t is clear that a t IIa Ethyl L-alaninate 4 -153 160 least one D-a-amino acid ester is highly levorotaIIIa (S)-( +)-Amphetamine 4-45 $114 240 tory in acetone. The rotatory power of ethyl DIVa Ethyl L-phenylalaninate +43 -242 60 phenylglycinate in acetone is, indeed, displaced IVb Ethyl L-tyrosinate +38 -259 60 in a positive direction but is still nevertheless IVc L-Tyrosinamide -41 -133* days levorotatory. The work of Berge12 and these data a Calculated as [CIJD x mol. w t . of free base/100 from [CY] indicate, however, that the absolute configurations D’S reported in Ref. 2. * 1: 1 methanol-acetone as solvent. of these Schiff bases formed in acetone can be In another connection we had prepared a con- related to their rotatory powers using Brewster’s siderable number of optically active a-amino acid Atomic and Conformational Asymmetry Rules4 esters and other open chain primary amines, all of and thus measurements of this kind will be useful known absolute configurations, and it was decided in the deduction of the absolute configurations of to compare their rotatory powers in ethanol and amines of this type. Thus, using Brewster’s rules in conjunction with in acetone (Table 11) in order to provide a somewhat broader base for testing the reliability of the rotational ranks tabulated by him4 and conBergel’s suggested method for assigning the abso- sidering the rotatory powers of the N-isopropylidene derivatives of code I1 (Tables I and 11), all exlute configurations of such open chain compounds. pected to show atomic asymmetry and the simplest (1) This work was supported by a grant (G14524) from the National Science Foundation. type of conformational asymmetry, one obtains (2) (a) F. Bergel and G. E. Lewis, Chem. and Ind., 774 (1955); the empirical polarizability sequence of the substit(b) F. Bergel, G. E. Lewis, S. F. D. Orr and J. Butler, J. Chem. Soc., uent attachment atoms as decreasing in the order 1431 (1959); (c) F. Bergd and J. Butler,ibid., 4047 (1961).
+
(3) Absolute configurational designations according to R. 8. Cnhn,
C.K. Ingold and V. Prclog, BrPericstth, 1&81 (1066).
(4)
J. g. Btewmtet, 1.A m . C k r t ~See., . El, 5475
19, 106 (1961).
(1969); Tclrohcdron
1514
CORIMUNICATIOIiS TO THE
EDITOR
VOl. 84
N=C(CH3)2 > C6HS>COzR> CH3> H.6 As shown in the projection of the N-isopropylidene derivative of ethyl L-alaninate (IIa), the contribution to the rotatory power due to atomic asymmetry is negative. An additional negative contribution results from the preferred orientation, also shown in projection IIa, of the isopropylideneamino moiety about its attachment bond. For the other derivatives of code I1 both of these contributions are not as reinforcing, and in IIb a t least, the contribution due to atomic asymmetry appears to be the more important. These derivatives all display substantially lower rotatory powers than that of ethyl L-alaninate ( c f . Table I).'
formula C14H24N20,. Hydrolysis of this antibiotic with boiling 6.0 N hydrochloric acid gives actinamine (I) isolated as its dihydrochloride which has the molecular formula C8HlsN204.2HC1, m.p. 315' dec., optically inactive. Anal. Calcd. for CsHisNzOc.2HCl: C, 34.41; H, 7.12; N, 10.05; C1, 25.45; 0, 22.93; mol. wt., 279.2. Found: C, 34.46, 34.39; H, 7.12, 7.07; N, 10.02, 9.83; C1, 25.31; 0, 21.23; mol. wt. (electr. titr.), 280. Treatment of the dihydrochloride with an anion exchange resin (Dowex 2 ) gave the free base, m.p. 129'. Anal. Calcd. for CsHI8N204: C, 46.60; H , 8.74; N, 13.59; 0, 31.07; mol. wt., 206.2. Found: C, 46.99; H, 8.99; N, 14.06; 0, 31.00; mol. wt. (electr. titr.), 204. The free base in water is optically inactive in the range 310 to 589 mp and shows only end absorption in the ultraviolet region. A strong band a t 3200 cm.-' in the infrared spectrum of actinamine is indicative of hydroxyl and/or CH3 CH2R amino groups, but there are no bands attributable to IIa I11 unsaturation of any type. Both nitrogen atoms For the derivatives of code 111, the pre- are present as methylamino groups as shown by ferred conformation of the isopropylideneamino pKa' values of 7.2 and 8.9 and isolation of two group is as shown in 111, and as a result of the moles of methylamine, identified as its p-hydroxyflexible chains (CHzR), additional conformational azobenzene-p'-sulfonic acid salt, from each mole asymmetry contributions come into play. With of actinamine dihydrochloride after periodate the above sequence of polarizabilities, these deriva- oxidation. Acetylation of actinamine dihydrotives are correctly predicted, using only the Con- chlorjde with acetic anhydride and sodium acetate formational Asymmetry Rule, to be dextrorota- gave a hexaacetyl derivative (11), m.p. 196-19S0, tory. Similarly for those of codes IV and V, the optically inactive. Anal. Calcd. for CaH30N2same atomic and conformational symmetries pres- Olo(GCH&): C, 52.40; H, 6.53; N, 6.11; 0, 34.93; ent in I I a make, except for IVg, reinforcing nega- CH3C, 19.6. Found: C, 52.34; H, 6.71; N, 6.20; tive contributions to the rotatory powers, and as in 0, 34.46; CH3C, 18.9. The infrared spectrum of those of code 111, the flexible chains give rise to this compound has bands indicative of ester caradditional conformational contributions. These bonyl (1750 cm.-l) and amide carbonyl (1650 contributions considered, the derivatives of code cm.-l) but no bands in the OH/" region. The IV and V are all correctly predicted to be highly formation of hexaacetylactinamine established levorotatory, the additional asymmetric centers in that all the oxygen atoms were present as hydroxyl those of code V making, as predicted, only small SOUPScontributions to the rotatory powers. Actinamine dihydrochloride consumed six moles These same considerations can also be extended of periodate per mole with no formation of formto the rotatory powers of similar Schiff bases aldehyde. The periodate consumption data coupled formed in other ketonic solvents,2 and we are cur- with analysis and functional group determination rently extending this work to include optically point unequivocally to a bis-(methylamino)-tetraactive cyclic amines. hydroxycyclohexane structure for actinamine. There are three possible positional isomers aside ( 5 ) This sequence cannot be deduced uniquely from the data in Tables I and 11. The priority of the isopropylideneamino group is from stereoisomers having such a structure. assigned, however, on the basis of the atomic refraction (polarizability) These are 1,2-bis-(methylamino) -, 1,3-bis-(methylof nitrogen in Schiff bases of this type.' amino)- and 1,4-bis-(methylamino)-tetrahydroxy(6) S. S. Batsanov, "Refractometry and Chemical Structure cyclohexane. That actinamine is the 1,3-isomer Consultants Bureau, New York, N. Y.,1961,p. 22. (7) Here and in what follows, the somewhat justifiable assumption was shown by a study of the periodate oxidation of is made that no significant contributions to the rotatory powers arise N,N'-diacetylactinamine (111, prepared by methfrom preferred orientations of the carbethoxy, carbomethoxy and anolysis of hexaacetylactinamine), m.p. 250-252' carbamoyl groups about their attachment bonds. dec., infrared absorption bands a t 3280 cm.-l and DEPARTMENT OF CHEMISTRY HOWARD E. SMITH VANDERBILT UNIVERSITY MITCHUM E. WARREN,JR. 3180 em.-' (hydroxyl) and a t 1635 cm.-l (amide carbonyl). Anal. Calcd. for C I Z H Z ~ N(2CH3CO) ~O~ : A'ASHVILLE5, TENNESSEE ARTHUR w. INGERSOLL C, 49.65; H, 7.58; N, 9.65; CHaCO, 29.6. Found RECEIVED FEBRUARY 17, 1962 C, 49.77; H, 7.65; N, 9.47; CHsCO, 23.3. This diacetyl compound consumed two moles of perioTHE CHEMISTRY OF ACTINOSPECTACIN. I. date per mole with formation of one mole of formic ACTINAMINE acid, conclusively establishing structure I for Sir : actinamine. Actinospectacin,1,2,aa new broad spectrum antiActinamine and all of its derivatives are optically biotic produced by an actinomycete, Streptomyces inactive, indicating a meso compound. There are spectabilis, is a basic compound with the molecular (2) D. J. Mason, A. Dietz and R. M. Smith, Antibiotics and Chemo"
(1) The trade name of The Upjohn Company for actinospectacin is Trobicin.
therapy, 11, 118 (1961). ( 3 ) M. E. Bergy, T.E. Eble, end R. R . Herr, ibid., 11,661 (1'261).
