The low value of the molar refraction for $tropine might be due to intratnolecular hydrogen bonding contributed by configuratioii I. The cvitlciice rel)ortetl licrc. thus coi~firinsthe
assignment of the cis-configuration for pseudotropine and the tmns configuration for tropine as proposed by Fodor and N ~ i d o r . ~ REYSSELAER, N.Y.
1
OF IIARVARD r \ I V E R S I T \
IC'ClVTRII17TIOU FROM r11T CIIEhfICAl. x , + B l ) K . A r O R \
Configuration of Tropine and Pseudotropine BY ;\LEX NICK ON^
AND
LOUISF. FIESER
RECEIVED JCVE 23, 1952 Attempts t o establish the orientation of the hydroxyl group in tropine and pseudotropine by forming a bridge between oxygen and nitrogen in one or the other epimer were unsuccessful. In confirmation of recent work of Fodor and NBdor, we found a ready solution of the problem in the method of ,icy1 nngrations, which established that pseudotropine ( X I I ) is cisoid a n d tropine transoid.
Willstatter2$3established that reduction of tropinone affords two isomeric alcohols, tropine (tropanol) and pseudotropine (pseudotropanol) ; both are readily oxidized to the original ketone".' and dehydrated to tropidine.5*6 The inference that the two alcohols are epimeric was examined critically and eventually Sirice tropine is isomerized by boiling sodium amylate to pseudotropine,2-8the latter is the thermodynamically more stable epimer. Both alcohols have been isolated from plant sources, but tropine is the more abundant of the two; it is obtained readily by hydrolysis of I-hyoscyamine." The present work was undertaken with the objective of establishing the configurations of the epimeric alcohols. After trying various approaches we found a solution of the problem in application of the method of acyl migrations. Our work, however, has been anticipated by Fodor arid Njdor, 10,lOa whose recent note reports application of the same method. We thus wish to present independent evidence confirming the conclusion of Fodor and NAdor that members of the pseudotropine series have the cisoid orientation of the hydroxyl group and nitrogen bridge (see Ivj and that the tropine epimers are transoid. Exploratory experiments to ascertain if hindrance of the hydroxyl group is markedly greater in one epimer than the other were carried out by ester interchange with ethyl acetoacetate.ll Under the ( 1 ) h'atiunal Institutes of Health Predoctoral Fellow, 19.50 .19.\2. ( 2 ) R. Willstiitter, Ber., 29, 936 (1890). ( 3 ) R. Willstiitter and F. Iglauer, ibid., 33, 1170 (1F001. (4) R . R'illstitter, i b i d . , 29, 393 (1890). ( 3 ) C . Liebermann and L . Iiinpach, ibid., 2 6 , 9'27 [1.?!12), (6) A. Ladenburg, A n n . , 217, 7-1 (1883). ( 7 ) J. Gadamer, Arch. Phrrrm., 239, 294 (1901). ( 8 ) M. Bairuwcliff a n d F. Tutin, J. Chem. S~x., 96, 1006 (1909). (9) For references, see R . H, F. Xfanske and 1%. L. Holmes. "The
conditions employed, however, both tropine and pseudotropine were converted in high yield (94%) into their corresponding acetoacetates, isolated as the picrates. The obvious method of effecting cyclization between oxygen and nitrogen in one or the other of the epimers has been considered by Schiipf and Arnold,12who state in a footnote to a paper on another subject that attempts to effect ring closure in nortropine or norpseudotropine had met with no success. We first explored an approach starting with N-cyanonortropinone ( I 9, prepared from tropinone by the von Braun cyanogen bromide method. Although the cyanamide group ordinarily is susceptible to ready reduction, the bridging group in I proved resistant to sodium borohydride, which merely reduced the carbonyl group and gave a mixture of the epimeric alcohols 11 and 111. The alcohols were separated by N/CN
/CN
r
h7 Na BH4
0
I
h , , = m n H
II
N/cN
L HO
I5 chroinatography and the higher melting epimer ( m p . tt3-113.5°) was shown to belong to the tropine series by acetylation to a product identical with a sample of N-cyanonortropine acetate prepared by a reported procedure." The lower melting alcohol (100-1 00.5') on acetylation yielded Ncyanonorpseudotropine acetate (VIII), prepared unambiguously from pseudotropine. Each alcohol, I1 and 111,was subjected to various
Alkaloids," Academic Press, New Pork, N . P,, 1S30. Chapter V I . ( 1 0 ) G. Fodor and IC. NBdur, .Vdfure, 169, 462 ( 1 0 5 2 ) . (10a) ADDEDI U Pnoua.--Frorn the relative riitrq oi hydrolysis of esters of tropine anrl pseudotropine and on the 1,aiis oi assigned hinixfni, C. X I . Siegmann and II. C. Reyermaii, . I , 64B, 4.52 (19,51) [Chem. Z e a l ? . , 36, 3742 ( l ! l 5 ? ) 1. :ittril)uted tu the epimeric alkaloids configurations just the (12) C Schopf and W Arnold, A n n , 668, 109 (1947) reverse of thuse estaldirhed b y Forlor and Widor anrl by us: evidently ( I ? ) T h e formulation of the piperidine ring in the chair conformation their estimate of the relxtive hindrance effects wns not valid. 15 purely arbitrary a s is the ~ ~ r o j e c t edirection d of the nitrogen w b . i I I) A . Ir
