OPTICAL ACTIVITY
Oct. 20, 1959 TABLEXI MOLECULAR K O I‘A PIUNS
OF
A N D METHYL
HYDROXVTETRAHYDROPYRAXS GLYCOSIDES [&f]D O f
Hydroxytetrahydropyran
-[MID-Calcd.
Obsd.‘
6-n-Ribose a-D-XybSe @-D-Xylose a-D-.kabinose ,3-D-.%rabinose d-D-Lyxose l,j-Anh?.dro-D-arabitol L’-Deox?.-B-D-x?lose
- 45 - 35 +145 +141 - 45 -105 -116 -295 -286 -10b -109 - 150 - 132 - 45 - 34
a-D-Glucose p’-D-Glucose or-n-Mannose $-D-Mannose a-D-Galactose J-n-Galactose a-D-Gulose fi-D-Gulose d-D-XllOSe a-D-Talose d-D-Talose
+ 30 + 34
1,5-Anhydro-usorbitol galactitol mannitol talitol ’-Deoxya-D-glucose B-D-glucose a-D-galactose p-D-galactose
i 220
+202
+ 25
i 53 - 30 - 31 +270 +272 80 95 115 135 - 55 0 30 122 75 20 24
+
+
+ +
+
+
+
+
+
+ i5
4- 71)
4- 125
+12fi
- 75 - 25
- 19
-
methyl glycoside Calcd Obsd
3-250 -150 0 -400
+253 -108 - 28 -403
+325 +309 - 75 - 66 130 154 - 135 - 135 380 $375 - 25 0
+
+ +
- 160
- 16.2
83
+ 130 + 30 + 180
+ 80 + 6 i
[CONTRIBUTION FROM
+%3 X > CHa in polarizabilitya; should this e f fect be dominant, the rule would be in error. This gencralization ai>plies to the rotatory effect of the atfachment alom of the substituent. If the substituent itself is optically active (because t h e ring provides a sterically asymmetric environment or because the atom in question is part of a fused ring) then epimerization may produce additional rotatory shifts; i t will be seen below that an isopropyl substituent would suffer reversal of its rotatory contribution on such epimerization. Finally the cyclohexene ring itself, in the two semi-chair conformations I I I a and I I I b , is optically active (see below); if the epimerization produces inversion of the ring conformation, the rotational shift can be in the opposite direction. Care should be used, then, when the epimers being compared have carbonyl substituents, have substituents which may s h o w conformational asymmetry of their own, or have enantiomorphic ring conformations. (9) J. A. Mills, J . Chem. Soc., 4976 (1952). The AIills rules, strictly speaking, apply only t o cyclohexenes with alkyl, hydroxy or acyloxy substituents, these being the only classes of compound considered by Mills.
Oct. 20, 1959
OPTICALACTIVITY OF ENDOCYCLIC OLEFINS
basis the predicted rotation change for the formation of IV from cyclohexene becomes
where the necessary values can be obtained from Tables I and I1 of part I. The predicted values for A ( x - H) are shown in Table 11. On the whole, they give satisfactory predictions of rotation changes in allylic steroid derivatives.’O Major discrepancies are noted with the androst-4-ene-3,170-diols (VIII) (which might be due to a low [MID for androst-4-ene-17p-01, since the difference in rotation of the epimeric 3-01s is of the right order of magnitude) and the 7p-bromo- and 7aminocholesterols (X). It is clear, from the discussion of cyclopentenes with flexible chains (see V), that discrepancies are to be expected when the substituent is flexible and especially when it has a highly polarizable group. In general this additional conformational asymmetry will increase the magnitude of A ( x - H), particularly when the conformation corresponding to Vb is strained by the presence of a substituent on the ring (as in the 7-substituted cholesterols, X). These effects are strikingly evident throughout this series. Further tests of this point can be made by use of rotatory data for the olefinic terpenes. Assignments of absolute configuration to the monocyclic terpenes depend, first, on a demonstration that menthone has a trans configuration,‘l next, on a correlation of one of the asymmetric centers with glyceraldehyde12; qnd, finally, on a network of correlations within the terpene series it~e1f.I~We require first an estimate of the rotatory properties of the two semi-chair forms of cyclohexene (IIIa, IIIb).I4 The sign of the expected rotatory contri(10) T h e configurations of the alcohols appear to be rigorously established (see H. Schaltegger and F. X. MUllner, H e b . Chim. Acta. 34, 1096 (1951), H. Heymann and L. F. Fieser, ibid., 86, 631 (1952) and W. Klyne, ibid., 36, 1224 (1952) for references). It should be noted that the trivial indices applied to the 7-substituted cholesterols in earlier papers are to be reversed in accord with the findings of Heymanu and Fieser. Schaltegger and MTlllner showed t h a t the more levorotatory of the 7-bromocholesterols is the more stable and suggested on these grounds t h a t it has the 9, (equatorial) configuration. An inspection of models shows, however, that an equatorial bromine atom is badly crowded by CIS,this crowding being absent in the axial isomers. On these grounds, the assignments of configuration by Schaltegger and Miillner should be reversed, as shown in X. (11) This relationship was first deduced by use of the AuwersSkita rules and from data on the relative stability of the epimeric menthones and carvomenthones [for a review see N. L. McNiven and J. Read, J . Chem. Soc., 153, 159 (195211 and was placed on a firmer basis by studies of the quasi-racemates formed in the mono-alkyl succinic acid series [A. Fredga and J. K. Miettinen, Acta Chem. Scond., 1, 371 (1947); A. Fredga, ibid., 3, 208 (1949)l. The issue was settled by direct chemical correlation of the optically active @-alkyl adipic acids derived from pulegone and 1-mentbene [K. Freudenberg and W. Lwowski, Ann., 687, 213 (1954)l. (12) This relationship was deduced by J. F. Lane, Science. 111, 577 (19511, on mechanistic grounds and by Fredga‘l by studies of quasi-racemates. An unequivocal relationship bas been established via degradations of cis-3-hydroxycyclohexanecarboxylic acid [D. S . S o y c e and D. B. Denney, TEXIS JOURNAL, 74, 5912 (1952); 76, 768 (1954); D. S . Noyce and J. H. Canfield, ibid., 76, 3630 (1954); see also H. L. Goering and C. Serres, ibid., 74, 5908 (1952) j. (13) Cf.W Hiickel, J . prakt. Chcm., 167, 225 (1941) (the absolute configurations shown by HClckel must be reversed) and A. J. Birch, A n n . Reports (Chcm. Soc.), 47, 191 (1950); see also J. L. Simonsen, “The Terpenes.” Cambridge University Press, Cambridge, Vol. I, 1947; Vol. 11, 1949, for individual correlations within this series. (14) T h e dark circles represent axial and semi-axial hydrogen atoms above t h e plane of the ring. It is important to note t h a t ring atoms
5495
bution of each bond is shown in I I I a and IIIb.lb The principles presented in part I1 suggest that an empirical estimate of the magnitude of this ring asymmetry effect can be made. A 4-alkylcyclohexene in configuration XI1 will exist mainly with the substituent in the equatorial orientation14 and, therefore, with the ring in conformation IIIa. Since a n equatorial substituent will have virtually no other rotatory efect (see part 11)) the rotations of such
compounds should be equivalent simply to that of IIIa and should be essentially independent of the nature of the substituent. As seen in Table 11, a number of terpenes are strongly dextrorotatory in configuration XI1 and have very nearly the same rotation despite an appreciable variation in the nature of the substituent. The rounded average of these values, 160°, will therefore be taken as the empirical rotation of IIIa16; this value is reasonable in size.16
+
XI1
When the 4-substituent is axial in configuration XI1 i t forms a dextrorotatory conformation with the nearest unsaturated atom ([MID +140°) and a levorotatory conformation with a saturated atom on the other side ([MID -60’) (see Table I, part I). The net rotatory change resulting from the introduction of this substituent is thus A [ M ] D +SOo. It follows that a compound having a substituent in configuration XI1 will be more dextrorotatory than its epimer (when the ring conformation i s the same in both compounds (substituent effect) or when the substituent i s equatorial in both compounds) (see Fig. 1). This statement (without the parenthetical qualifications) is equivalent to the 4 and 6 have essentially the geometry of cyclohexane ring atoms, while atoms 3 and 6 more closely resemble the ring atoms of cyclopentenc and can at most be described as having semi-axial and semiequatorial substituents. It is assumed t h a t the rotatory effects of semi-axial and semi-equatorial substituents are identical but that a large iubstituent will show some preference for a semi-equatorial orientation. (16) A ring bond next to the double bond is only slightly skewed, but the double bond itself is part of the asymmetric conformation. T h e sign of rotation can be predicted. but not the magnitude, hence the parentheses. T h e next most distant bonds are strongly skewed and, assuming the equivalence of phenyl and vinyl carbon atoms,: should have rotatory powers of +140° in I I I a and - 140° in I I I b (see Table I , part I). Note the presence of two such bonds in each ring conformation. The remaining bond is equivalent to a ring bond of cyclohexane a n d should contribute -60° to the rotation of I I I a , +60° to t h a t of I I I L These three bonds contribute, then, +220° to the rotation of 111s and -220O to I I I b ; since i t is doubtful t h a t the other bonds will be strongly optically active it seems safe to predict t h a t I I I a will be dextrorotatory, possibly strongly so, and t h a t I I I b will be correspondingly levorotatory. (16) In the present picture a saturated substituent attached to one of the unsaturated atoms will have little effect on the rotatory properties of the ring itself. This point requires further study, however, since sylvesterpineol is reported to have a very low rotation even though
x
OH
[MID + 4 its optical purity is quite high IW.N. Haworth and J . Chem. Soc., 101,‘2226 (1913)).
W. H.Perkin
J a u ~ H. s BREWSTER
5490
PREDICTED
TABLE I1 ROTATORY EFFECT OF ALLYLIC SUBSTITUENTS I N THE CONFIGURATION
'?i
H x
4(X 250 (est.) 790 184 570 SH 146 530 c1 144 510 0 300 C==C C02H - 122 70 CH3 0 130 2" 49 170 OH 53 160 h Values for k ( X - H ) (C - H ) from Table I , part I . \.slues for appropriate a-phenethyl derivatives; from 'I'nble 11, part I . e Rounded to uearest 10.'
\.ol. SI
a Huang-hlinlon, THIS JOURSAL, 71, 3301 (1949). The present treatment suggests that this value is much too low and should be about 340. This product may contain some ( ? much) As-17P-ol: cf. G. Lardelli and 0. Jeger, Helv. Chim. Acte. 32, 1817 (1949). T h e value 129 is used in the calculations. * A . Butenandt and A. Heusner, Ber., 71, 198 (1938).
X
I Br
542 390 379 369 303 195 130 119 108
f-- l
x H; x
X
151' 308" 38" - 143' 270 320 294 320 Aa-p a A . Windaus and 0. Kaufmann, Ann., 542, 218 (1939). Windaus and K . Buchholz, Ber., 71, 576 (1938). Idem., ibid., 72, 597 (1939). 3a-OH 38-OH
'-LkAx H
VI
[MID (chf.)
Obs.
Calcd.'
Y
X
OH
H OH OCHj 0.2~ OCsH5 OBz NH?
H +44,'+48" 3P-OH +212 206 24gc -0Xc - OBZ +46SC 38-Cl +405' 556 a By addition of values from Table I1 to +46, the mean of the two values cited for cholest-1-ene. R . B. Turner, \I:. K . Meador and R . E . Winkler, THISJOURSAI, 79,4122 H. B. Henbest and R . h. L. Wilson, J . Chem. (1957). SOC.,3289 (1956).
+
+
+
3H.4~
0.k
x
VI1 [hf]D-
7
7 -
Obsd
X
H OH OAc OCH3
3LI-
Calcd
+244" +445' +760' (f280)'
-36e
+404
+414
2"
NHAc
c1
+400d
Obsd
+244" +17'ib 43b 164'
+ + + 26"
Calcd
+ 84
Br
I
+ 74
ORz
'
Br I
Br
X H 3a-OH 3P-OH Am-B
7
Obsd.
129" (alc.) 543* (pyr.) 141' (alc.) 402
[MID
Calcd.
289 -31 320
H OH OCH? 0.4~ OCsH5 OBz
c1
C1
X
SH SCN H OH OCH3 OAc 0CsHs OBz
c1
+754 -110' -266 See VIb. C. 1%'. Shoppee, B. D. Agashe and G. H. R . Summers, J . Chem. Soc., 3107(1957). ' R . A . B. Bannard C. and A . F. McKay, Can. J . Chem., 33, 1166 (1955). W.Shoppee, D. E. Evans, H . C. Richards and G. H. R. By addition of valSummers, J . Chem. Soc., 1649 (1956). ues from Table I1 to f244, the [MID of cholest-Pene. J Probably not pure ( b ) . a
rn
H c1 Br H Br
X
--Obsd.
- 154a - 351b - 530' - 860' - 1017' -1350" - 1395d - 860" - 797d - 763e -1330' - 188" - 392' - 569' - 857'
~
7a--Calcd
an
- 364
- 379
649' 625' - 983' - l050P -1670' - 107h - 725; -1080% - 103h -1050%
+ 2Sb + 96h +325' +532' + 563' +727" +822d
78-
----
Calcd."a
+ 56 -k 71
+377 f359"
- 859
-
398
$551
- 292' - 188" - 22'
+ 83'
+ 22
+253' +433' $450'
- 868 - 938 -1228
- 74"
- 384
+ 71'
+I36
+203' $417' +665' ,575' f320'
+e06
+114"
+676
+
-
Obsd
- 154"
-
968' - 765' -1245' -2015h - 74" - 258' - 17ib - 665'
--
[MID
- 754
-
824
-1114
-
787 - 857
- 853
Values for A x - H obtained by adding appropriate values from Table I, part I, to values in Table I1 to take into acD. H . K . count asymmetric conformations with C14. Barton and J, D. Cox, J . Chem. Soc., 783 (1948). H. B. Henbest and E. R. H. Jones, zbid., 1798 (1948). J. Barnett,B.E.RymanandF.Smith,ibid.,524(1946).d C . W . aa
'
OPTICALACTIVITY OF ENDOCYCLIC OLEFINS
Oct. 20, 19.X
Shoppee. K. J . \V. Cremlyn, D. E . Evans and G. H . K. Summers, ibid., 4364 (1957). E. Frederiksen and S. Liisberg, Chenz. Bel., 88, 684 (1956). f K. Abildgaard-Elling, British Patent i14,624 (1954) [ C.A ., 49, 14042 (1955)l. 0 H. Schaltegger and F. X. Miillner, Helv. Chim. Acta, 34, 1096 (1951). h A . F. Wagner, N. E. Wolff and E. S. Wallis, J . Org. Chem., 17, 529 (1952). S . Bernstein, K. J. Sax and Y.SubbaRow, ibid., 13,837 (1948). 6
X
XI
HO 7 7 -
X
3a-OHObsd.
--
[MID
Ca1cd.O
+
-
3a-OAcObsd. Calcd."
H +179 (MeOH) 240 a-OH +400 (MeOH) +389 f446 (MeOH) +450 a-C1 +640 +859 +717 920 a-Br f985 +929 ,%OH +125b (MeOH) 19 a A 12a-substituent is semi-axial and shows positive conformational asymmetry with C17; the calculated A(x -H) values are, then: OH $210, C1 4-680, Br +750. A 12Psubstituent should show only the effects given in Table 11. b V . R. Mattox, R. B. Turner, B. F. McKenzie, L. L. Engel and E . C. Kendall, J . Biol. Chem., 173, 283 (1948); all other data: V. R. Mattox, R. B. Turner, L. L. Engel, B. F. McKenzie, W. F. McGuckin and E. C. Rendall, ibid., 164, 569 (1946). See also, B. F. McKenzie, V. R. Mattox and E. C. Kendall, ibid., 175, 249 (1948).
+
+
TABLE I11 MOLECULAR ROTATIOXS O F 4-ALKYLCYCLOHEXENES
R
R'
-CH3 -CH(CH3)? -CH(CH3)2 -CH3 CHz
Limonene a-Terpineol Phellandrol Perillyl alcohol
-CH3 -CHB -CH20H -CH?OH
[MID
Ref.
+161° +153
'
-C-CHa $169 -C(OH)(CHP)Z+155 -CH(CH~)Z 167 -C-CHI +148
'
a
II
+
II
-
second of Mills' empirical rules,g but more general. The qualifications given suggest that some caution be used in applying this rule to enantiomorphs and even to epimers if i t is likely that the substituent is axial in both compounds.
+
R'
1-Menthene 3-Menthene
125, 2304 (1924)l. The following derivatives >ave bee11 prepared by these workers; formate, [MID +161 ; acetate, [MID + 1 5 7 O ; propionate, [MID 4-158'; butyrate, [MID +l5S0; valerate, [MID +l55" (all homogeneous); phewl; urethan, [MID +112"; hydrogen phthalate, [MID $110 (both in chloroform.) e The (-)-alcohol is formed by reduction of the ( - )-aldehyde; the ( - )-aldehyde has been oxidized to (-)+-isopropyladipic acid (see a ) [G. Burger and A. K. Macbeth, ibid., 145 (1946)l. The following derivatives have been prepazed from the ( - )-alcohol: p nitrobenzoate, [MID - 172 ; 3,5-dinitrobenzoate, [ M I D - 173'; hydrogea phthalate, [MID - 164'; phenylurethane, [MID- 164 ; a-naphthylurethan, [MID- 170" [J.p. E. Human, A. K . Macbeth and H . J. Rodda, ibid., 350 (1949)l. The ( +)-alcohol is formed by selenium dioxide oxidation of (+)-limonene [H. Schmidt, Chem. Ber., 83, 193 (1950)l. The (-)-alcohol is formed by Ponndorf reduction of (-)-perilla aldehyde and forms a ( -)-acetate ([MID - 146') (Schmidt). The (-)-chloride, from alcohol with [MID-103', hasareported [MID-101' [F.W.%mmler and B. Zaar, Ber., 44, 52 (1911)l; using Schmidt2 value for the alcohol, this corresponds to [ M I D -145 . The ( )-chloride has been reduced to ( - )-limonene, [MID -70"; this corresponds to a rotation of [MID -350' for the chloride, which seems high.
+
160" 80" - 80" - 160" Fig. 1,-Estimated molecular rotations of individual conformations of 4-alkylcyclohexenes.
6
H'
-74%
e
We are now in a position to attempt to calculate the sign and magnitude of rotation of the terpene olefins having two asymmetric centers. The 2menthenes (trans, XIV; cis, XV) are shown with their rings in conformation I I I b (-160') and the isopropyl groups in the semi-equatorial orientation.17 In the trans isomer shown, the two alkyl groups make similar dextrorotatory contributions (+130' each) while in the cis isomer these contributions are opposed and cancel. Models show clearly that the isopropyl group will be predominantly in the conformation shown in XI11 and so contribute +SOo in each case. Here, where configurations are reliably established, l7 there is excellent agreement of calculated and observed results. The cryptols (XVI, XVII)ls should be
CHz a Prepared by catalytic hydrogenation of (+)-limonene [G. Vavon, Bull. SOL. chim. France, [4] 15, 282 (1914); J. von Braun and G. Werner, Ber., 62, 1057 (1929)] and by sodium reduction of ( +)-a-phellandrene [F. h'. Semmler, (17) The (+) trans olefin has been obtained from ( - ) menthone ibid., 36, 1033, 1749 (1903)j; the (-)-isomer has been pre- uia ( - ) menthylamine, while the (-) trans olefin has been obtained pared from ( +)-carvone oia ( - )-carvomenthone and ( - )- from ( - ) carvomenthone. The ( f ) c i s olefin has been obtained from neocarvomenthylamine [W. Huckel and E. Wilip, J . ( - ) piperitone eia (+) isomenthone and (+) isomentbylamine [ ( f ) prakt. Chem., 158, 21 (1941)] Both (+)-1-menthene and isomenthone and ( - ) menthone are Cd epimers]. [N. L. McNiven ( +)-a-phellandrene have been degraded to ( +)-isopropyland J. Read, J . Chem. Soc., 153, 159 (1952).] The absolute configurasuccinic acid [cf. A. Fredga, ref. 11; T. A . Henry and H . tions of the menthones and carvomenthones have rigorously been estabPaget, J . Chem. Soc., 70 (1928)l; (+)-1-menthene has been lished (references 11, 12). degraded to (+)-@-isopropyladipic acid [ cf. J. von Braun (18) Ponndorf reduction of (-)-cryptone gives ( - ) - t r a n s - and (+)and G. Werner, above 1, the absolute configuration of which cis-cryptol (the enantiomorphs of XVI and X V I I , respectively). has been established by the work cited in ref. 11 and 12. Relative configurations were assigned by reduction of these alcohols Prepared from ( )-menthone [cf. N. L. McSiven and J. to the corresponding 4-isopropylcyclohexanols,configurations being Read, J . Chem. Soc., 153 (1952), for a review], in turn pre- assigned here on the basis of the Auwers-Skita rule, relative rates of pared from (+)-pulegone [E. Beckmann and M. Pleissner, saponification of esters (trans > cis) and the formation of the b a n s Ann., 262, 1 (l891)], from which (+)-3-methylcyclohexalcohol by sodium-alcohol reduction of the ketone [R. G . Cooke. anone and (+)-@-methyladipicacid [ O . Wallach, Ann., 289, D. T . C. Gillespie and A. K. Macbeth, ibid., 518 (1939); D. T. C. 337 (1896)] can be obtained. The absolute configuration of Gillespie, A. K. Macbeth and J. A. Mills, ibid., 996 (1948)l. ( - ) the last named substance is shown by the work cited in ref. Cryptone has been oxidized to (+)-a-isopropylglutaric acid [A. R. 12. The absolute configuration of this substance follows Penfold and J. L. Simonsen, i b i d . , 403 (1930)l which has been related Prepared by from its relation to (+)-1-menthene (see a ) . to ( - )-isopropylsuccinic acid [A. Fredga and J. K . Miettinen, Acta hydration of ($)-limonene; can be dehydrated to (+)Chcm. Scand., 1, 371 (1947)l whence, from the work cited in ref. 11 limonene [cf. A. T. Fuller and J. Kenyon, J . ChPm. S O ~ . , and 12, the absolute configuration at C4 is established.
'
-
5498
JAMES
Vol. 81
H. BREWSTER
H.V R +160 - 160 50 = $50' a, R = -CH(CH& (see text) CHn
+I60 160 - 50 = $270' a, R = -CH(CH& (see t e x t ) CHz
b. R = -C-CH,, [MID +35°1g OH
b, R = -C-CHa, [MID +324'19 OH
+
U
C
I!
A[M] = k(C - H)(C - H ) = 140 - 60 = +SO" XI11
- k(C - H)'
XVIII
+
+
-160 260 80 = $180' Obsd. [MID +185017 XIV
H,' H
+
*
C
-160 80 = -80" Obsd. [MID -64'" XV
altogether analogous. The agreement of calculated and observed values is reasonably close. The allylic alcohols which have a 1-menthene ring
H" -160
+ 130 + 160 +
80 = +210" Obsd. [MID +165"18 XVI
H H" -
-160
c
+ 130 - 160 + 80 = -110'
Obsd. [MID -104°'8 XVII
structure (XVIII-XXI) are all shown with the ring in conformation IIIa (+160') and the alkyl group in the equatorial orientation. The hydroxy group makes contributions of i160' depending on its orientation relative to the double bond and of *50° (see Table I, part I; part 11) depending on its orientation relative to the methyl group. These effects are opposed in the six alcohols shown in XVIII and XIX. On this basis, the three cis isomers XVIII should have [ M I D +50° and the three trans isomers XIX [MID +270°. Of these six compounds, four, the carveols (XVIIIb, XIXb) and the sobrerols (XVIIIc, XIXc), have been prepared in apparently pure state and have been assigned reliable configuration^^^; the calculated and observed rotations are in reasonable agreement. The reduction of (+)-carvotanacetone (from (+)carvone) gives a carvotanacetol (XVIIIa, XIXa)20 (19) Reduction of the (+)-hydrate of (+)-cawone by the Ponndorf method gives ( + ) - c i s - and (+)-franr-sobrerol (XVIIIc, XIXc); these products were reduced to, respectively. (+)-dihydrosobrerol and (-)-neodihydrosobrerol (2.8-lians-~-menthanediols)[H. Schmidt, Chem. Ber., 88. 453 (1955)l. These products have in turn been dehydrated to (+)-dihydrocarveol and (-)-neodihydrocarveol; (+)dihydrocarveol is formed by sodium-alcohol reduction of (+)-camone and so probably has the all-equatorial configuration [H. Schmidt, ibid., 83, 193 (1950)l. (+)-Dihydrocarveol has been reduced to ( + ) carvomenthol and (-)-neodihydrocarveol to (-)-neocarvomenthol (both related to (-)-carvomenthone17) [R. G. Johnston and J. Read, J . Chem. Soc., 233 (1934)l. ($)-trans-Sobrerol has been dehydrated to (+)-trans-carveol (XIXb) and (+)-cis-sobrerol to (+)-cis-carveol (XVIIIb) some racemization occurring in each case [H. Schmidt, C h e w . Bey., 86, 1437 (1953)l; these substances have been prepared by Ponndorf reduction of (+)-cawone (Johnston and Read, above). All of these assignments are in accord with the Auwers-Skita rules. (20) J. Read and G. Swann. J. Chcm. Soc., 239 (1937). The product was purified via the p-nitrobenzoate, the rotation of which ([MID +258') is near enough to the average of the rotations of the p-nitrobans, [MID +800) benzoates of the carveols ( c i s , [MID -173;
H
+
I1
XIX
whose rotation suggests that it may be a 1:l mixture of the cis and trans formg (calculated for such a mixture, [MID 160'; observed [MID +166O). The piperitols (XX, XXI)**show a much greater difference in rotation than do the foregoing alcohols, reflecting the fact that here the two conformational asymmetry contributions of the hydroxy group (=t16Oo, =kt5O0) have the same sign. The two 4-menthene-3-01s (XXII, XXIII)22should be analogous in rotation to the 1-rnenthenes XVIII and XIX, since models indicate that the isopropyl group will 'straddle the double bond and make little or no contribution to optical activity. The agreement of calculated and observed values is good enough that absolute or relative configurations could have been assigned on this basis.
+
+160 - 160 - 50 = -50' Obsd. [MID -43"' XX
CHJ
C
A
Y
H
+
+
+160 160 50 = $370' Obsd. [MID +379"'l XXI CH,
h
+
+
+I60 160 - 50 = $270' +I60 - 160 50 = $50' Obsd. [MID $11;" (impure)z2 Obsd. [ht]D +255°2n XXII XXIII
HO
H -160 Obsd.
p
CH,
+ 160
0' [MID +SOz3
XXIV
H:p
CHP -160 - 160 = -320" Obsd. [MID -185OZ3 XXV
It is important to note that calculations such as those described above can safely be used only with [Johnston and Read, ref. 191 to suggest that it may be a sharp melting 1 : 1 mixture. This point has been discussed in more detail by Mills.9 (21) The enantiomorphic forms of the alcohols shown above were prepared by lithium aluminun hydride reduction of ( - )-piperitone. T h e (-)-cis isomer was hydrogenated to (-)-neomenthol and the (+)-trans isomer to (+) isomenthol; A. K. Macbeth and J. S. Shannon, ibid., 2852 (1952). (22) Ponndorf reduction of (-)-4-menthene-3-one gave ( - ) trans- and ( - )-cis-4-menthene-3-01, the latter substance not being obtained pure. These products were reduced to (+)-isomentho1 and (-)-menthol and are, accordingly, enantiomorphs of the compounds shown in X X I I and X X I I I ; D. Malcolm and J. Read, J. Chcm. sot., 1037 (1939).
OPTICAL ACTIVITYOF
Oct. 20, 1959
compounds of large rotation or of known epimeric relationships to one another. Thus, one can clearly decide which of the epimeric 3-hydroxy-5methylcyclohexenes, XXIV and XXV, is cis and which trans from the observed magnitudes of rotationZ3and, equally clearly, assign the indicated absolute configuration to XXV. Note, however, that no assignment of configuration could be made on the basis of the sign of rotation of XXIV. A possible explanation for the discrepancies found here is that the methyl group may adopt an axial orientation to some extent. The diaxial form of XXIV would have a rotation of about +240°; the observed rotation would obtain if the sample contained about 3% of this form. I n the case of the trans isomer, the form in which the methyl group is axial would have a rotation of about -80'; it would require about 55y0 of this form to bring the rotation down to that observed. The rotatory properties of many compounds of the pinene seriesz4 are consistent with the treatment given here. It is assumed, so that calculations can be made a t all, that atoms 1-5 of (+)-apinene (XXVI) are coplanar; this plane includes the methyl group a t position 2. On this basis, the optical activity of XXVI derives wholly from conformational asymmetry about the four bonds of the cyclobutane ring, the net effect being (23) The two alcohols shown can be oxidized to the corresponding (-)-ketone which, in turn, can be reduced to (+)-3-methylcyclohexanone (which has been related to (+)-pulegone and (-)-menthane) : XXIV has been reduced to ( -)-cis-3-methylcyclohexanol; H. L. Goering and E. F. Silversmith, THIS JOURNAL, 77, 5172 (1955). (24) Three separate lines of evidence indicate t h a t (+)-a-pinene has the configuration shown in XXVI; the configurations of most of the other bicyclic terpenes follow from their relationship to a-pinene. Treatment of (+)-a-pinene with dilute sulfuric acid [F. Flavitzky, Ber., 12, 1022, 1406,2354(1879): 20, 1956 (1887))or benzoic acid IM. Delepine, Bull. SOC. chim. France, [4] 95, 1463 (192411 gives (+)limonene; this reaction presumably occurs by a carbonium ion mechanism I
I
Hre
I
H 7 =
Second, the epoxide of (+)-a-pinene gives (+)-trans-sobrerol1@ on treatment with acid [G.0. Schenck, H. Eggert and W. Denk, Ann.,
684, 177 (1953)l
ENDOCYCLIC OLEFINS
5499
C
D =
k(C
It - H ) ( S * - H) - k(C - H)*
- 60 = +80
%40
(as with an axial substituent p to the double bond in XII). This value is a reasonable approximation to that observed ([MID +69O; see Table IV); the rotations of the other compounds in Table I11 are also close to this value if they have short
chains ut position 2 . 2 5
I
s-l:
7
4
5
XXVI
The &pinenes (XXVII, XXVIII) 26 have ring configurations enantiomorphic to that of XXVI. H@cH3 trans
cH&Hcis
+ 130 = +50"
-80 Obsd.
-
-80 130 -210' Obsd. [MID -146's XXVIII
+8OozK XXVII
[MID
The methyl groups a t position 2 are in essentially the environment of 3-methylcyclohexene, with the TABLE IV MOLECULAR ROTATIONS O F a - P I N E N B DERIVATIVES
[MID
Ref.
43
R
R
-CHa -CHsCHs -CHzOH -CH*CI -CH2Br -CH~C~HI
+69" +51 f72.5 +41 +69.5 +62.5
-(CH2)2CH3
$36
' *
' '
[MID Ref.
-(CHz)4CHa $39" - ( C H ~ ) ~ C K H ~ $37 -(CH2)3CeHs -37 -(CHZ)~CKH~ +12.5 -CHZCH=CHCKH~ 1-31 -CH2CECC6Hs +44 0
/I
-(CH,)zCCHs 0
+51
I/
-(CHz)zOH +63 -CH +24 a F. H. Thurber and R. C . Thielcke, THISJOURNAL, 53, 1030 (1931). H. Rupe and A. Heritier, Ann., 459,171 (1927). CF.W. Semmler and K. Bartelt, Ber., 40, 1363 (1907). J. P. Bain, THISJOURNAL, 68, 638 (1946). Finally (+)-homoterpenyl methyl ketone is formed by oxidative degradation of (+)-a-pinene [E. Gildemeister and H. Kdhler, B n . , Schimmcl and Co., 125 (1909); Chem. Zcnfr., 80, IT, 2158 (1909)l and of (-)-limonene [T. A. Henry and H. Paget, J. Chem. SOC.,70
(1928)l
The configurations of the compounds in Table I11 follow from their preparation from (+)-myrtenyl chloride. which has been reduced to (+)-a-pinene [F. W.Semmler and K. Bartelt, Be?.,40 1363 (1907)l.
(25) A chain length greater than two permits steric interactions with the gem-dimethyl group: this will introduce an element of conformational asymmetry and produce deviations from the calculated value (see the second column of Table 111). (26) Absolute configurations can be assigned to the rings of the 8-pinenes on the grounds t h a t the pinocampheols from which they are obtained can also form (+)-a-pinene. Both &pinenes are reduced t o (+)-pinane as is (+)-u-pinene. I t is highly probable t h a t the levorotatory 8-pinene has the trans configuration since i t is formed by dehydration of (+)-pinocampheol. Pinocampheol is the most stable of the alcohols of this series and is related to pinocamphone, the most stable ketone: these facts suggest that the methyl group is trans to the gem-dimethyl group [H. Schmidt, Chem. Z e n f r . , 119, I, 2531 (1942); Be?., 7 7 , 544 (1944): Chcm. Ber., 80,520 (1947)l. These assignments are not controverted by the arguments of A. K. Bose, J . Org. Chcm.. 90, 1003 (19551, who disputes some of Schmidt's assignments of configuration.
cyclobutane ring having virtually ~ z oefect beyonti this, and so should make rotatory contributions of 130'. The calculated rotations are reasonably close to those observed considering the assumptions used in the calculations. The predicted difference in rotation of the epimers ( A [ M ] -260') should be compared with that observed (- 226'). Rotations can be calculated for the verbenols (XXIX, XXX)*' in a similar way. The value calculated for the trans isomer XXX is in good agreement with that found for the isomer to which a trans configuration has been assigned. The observed value for the presumed cis-verbenol is badly out of line with that calculated; it is, however, quite close to that expected for a 1:1 mixture of the two isomers (+80°, observed +loo"). This case is to be compared with that of the carvotanacetols (above).
*
&--
Position of
C=C -1i B trn72S
1:% 2:3 3:4
Ring
Rotatory contributions a-Sub- ,%Substituent stituent Eiido Eno
- 160
+ 160
0 0
-160 $160 0
$130 -260 +130
A
1(C=C)
(CH-CH) Calcd.
Ohsd
- 80 - 47" 0 f SO +16ic
0 -80
+x0
$80 -80
0 -80 0
+ 50
$124'
-402" 8:9 +SO +%lo f 96d A/B cis 1:2 160 0 0 +80 $240 0 +80 0 - 80 - 24'i 2:3 - 160 3:4 -80 0 - 50 - 44fi +I60 -130 0 160 0 -80 -80 6:7 0 +130 0 0 $130 8:9 Both series 4:s a +160 +130 0 +130 +153' b -160 +130 0 0 5:6 -160 -130 0 0 -290 -294" 11:12" -160 $130 0 +SO 50 t33d 15: 16" 0 0 0 0 0 16: 1? 0 0 0 0 0 31d a Substituent a t C,,. bNo substituent at C,,. Data for cholestenes; A-values calculated from [MIDfor cholestane. +?I; data of R. B. Turner, W. R . Meador and R. E. WinkIer, THIS JOURNAL, 79, 4122 (1957). Average A-values as tabulated by IT.'. Klyne in E. A. Braude and F. C. Nachod, "Determination of Organic Structures by Physlcal Methods," Academic Press, Inc., New York, K. Y., 1955, p. 111. 6:;
-260
+
+
'\
'3i-r
i
TABLE1CHANGES IN MOLECULAR ROTATIOX o s IXTROIILTTIOS OY DOUBLEROXDINTO THE STEROID SVCLEVS
cis trans $80 - 160 = -80" +80 160 = +240° "Obsd. [MID" +l0Ooz7 Obsd. [MID +2!j7°27 (see text) xxx XXXI
+
It might, a t first thought, be expected that one could calculate the rotatory effects resulting from the introduction of a double bond into the steroid nucleus. An inspection of models suggests, however, that a fused cyclohexene ring may prefer a conformation in which five of the ring atoms are planar and in which three atoms have true axial and equatorial bonds (XXXII). It is to be noted that this form is only slightly altered, relative to the semi-chair form; it would be expected to have the same sign of rotation as the corresponding semichair form, but a different magnitude of rotation. Conversely, if the cyclohexene ring has the semichair conformation it may distort the ring fused to it and produce an additional rotatory shift. Accordingly, predictions in this series can be expected to be only rough and approximate.?* As seen in (27) One isomer, having a high rotation, is obtained by autoxidation of (+)-n-pinene and isolated via the p-nitrobenzoste. Another material, presumed to be isomeric, was obtained in a n i m p u r e sfale from the p-nitrobenzoate of the product of Ponndorf reduction of verbenone. Both products could be oxidized to the same verbenone, but there is no evidence that the last named alcohol w a s not a mixture of e p i meys. Relative configurations were assigned b y use of the AuwersSkita rules and by a comparison of rates of esterification [H. Schmidt, L. Schulz and W. Doll, Chem.Z e n l r . , 111,II,3038 (1940); L. Schulz and W. Doll. ibid., 1 1 5 , 11, 76.5 (1944).] ( 2 8 ) T h e empirical constants used to this point do not allow predic-
[COSTRIBUTION FROM THE
+
+
Table V, the present simple treatment gives correct predictions of the sign of rotatory change in every case, but the predictions of magnitude are, more often than not, rather poor. I n the case of the A4-steroids, ring A can assume either of the two ring conformations I I I a or I I I b ; the observed value is close to that calculated on the assumption that the two forms are present in equal amounts. The results suggest that caution be used in this application of the present method to fused ring compounds.
XXXII tion of t h e rotation shift for introduction of a double bond a t 7 : 8 , 9: 11 ur 1 4 : 15. Uncertainty as to t h e conformation of ring D prevents a prediction for introduction of a double bond a t 8: 14.
LAFAYETTE, IND.
RESEARCH DIVISION, PARKE, DAVIS&
COMPANY]
Chemistry of Streptimidone, A New Antibiotic BY ROGERP. FROHARDT, HENRYW. DION,ZBIGNIEW L. JAKUBOWSKI, ALBERTRYDER, JAMES C. FRENCH AND QUENTIN R. BARTZ RECEIVED APRIL17, 1959 .A new antibiotic, streptimidone (C16H23N0,),has been obtained from the culture filtrates of a Streptomyces. The charac teristic physical properties of the antibiotic have been determined. Degradative studies have demonstrated that streptimiA novel cross-conjugated chromophore is prodone is 3-(2-hydroxy-7-methyl-5-methylene-4-oxo-6-nonenyl)-glutarimide, posed for the dienone.
