1976 666Studies on Lactams. Part 1V.l Relation between Cotton Effect andConformation of a Seven-membered Lactam RingBy Haruo Ogura,' Hiroaki Takayanagi, and Kimio Furuhata, School of Pharmaceutical Sciences, KitasatoUniversity, Shirokane, Minato-ku, Tokyo 108, JapanThe n--;7 * Cotton effects of seven-membered lactams have been investigated ; from the results seven-memberedlactams have been classified into two types: A having a negative and B a positive Cotton effect. The derived' lactam rule ' has been applied to conformational studies on N-methyl-A-aza-A-homo-tetrahydro-a-santonins andcomparisons have been made with N-methyl- (-)-menthone lactam. The conformational equilibrium of a fusedseven-membered laciarn ring is discussed in the light of c.d. data.RECENTLY we enunciated a lactam rule, linking the signof the n+n* carbonyl Cotton effect with the con-formation of the lactam ring.We based the rule onevidence derived from 0.r.d. and c.d. data of four-membered,l five-membered,3 six-membered,3 and seven-membered lactam r i n g ~ , ~ j ~ including (-)-menthonelactam and N-methyl-( -)-menthone 1actam.l Forexample, in the latter cases, lactams of type A showednegative Cotton effects, whereas lactams of type Bshowed positive Cotton effects (Figure 1). A linkbetween the conformation of the lactam ring and thesign of the n- X* Cotton effect had already beenobserved 4-6 and in particular Beecham and Klynert aZ.8 had suggested that the sign of the TZ+ ;r*Cotton effect of bridged lactam and lactone chromo-phores depends solely on the enantiomeric nature of thelactam or lactone bridge and not at all on molecularasymmetry elsewhere in the molecule.In this paper, we report c.d.and 0.r.d. data of A-aza-A- homo- tet rahydro- a-sant on in^,^ their N-met h yl deriva-tives, and A-aza-A-homo-steroids,l0 The peaks studiedall showed bathochroniic shifts of about 6-15 nm in aless polar solvent, characteristic of an n -+ d: transi-tion.ll The data confirm the relationship between theconformation of the seven-membered lactam ring, asIA(6-1 B( S+lFIGURE 1shown in Figure 1, and the sign of the PZ si* Cottoneffect.The spectra of the santonin derivatives (1)--(6) arecomplicated, as the molecules possess two chromophores,the lactam and the lactone carbonyl systems.Thus thespectra consist of two overlapping bands. Klyne et aZ.12Part 111, H. Ogura, H. Takayanagi, K. Kubo, and K. Furu-Iiata, J . Amer. Chem. SOC., 1973, 95, 8056.H. Ogura, H. Takayanagi, and K. Furuhata, Chent. Letters,1973, 387.H. Ogura, H. Takayanagi, and K. Furuhata, Abstracts ofPapers, 17th Symposium on the Chemistry of Natural Products,1965, p. 183.H. Wolf, Tetrahedron Letters, 1965, 1075.A. I;. Beecham, Tetrahedron Letters, 1968, 2355, 3591.13 M. Legrand and R. Bucourt, Bull. SOC. chim. FTaizce, 1967,2241,have measured the 0.r.d. spectra of some a-santoninderivatives, and found that they show a positive Cottont 1 6 1200 220 240 260h / n mFIGURE 2effect due to the lactone ring with [+] about +2 500 at225-240 nm.Overberger and Kaye13 have notedsimilar spectra with substituted hexan-6-olides, withsimilar intensities. It is reasonable to assume thereforethat the contribution of the lactone cliromophore instructures (1)-(6) is positive with a [+] value similar tothose found earlier.12 trans-Fused 3-aza-~-homo-tetra-h ydro-a-sant onin (2), cis-f used 4-aza-~-homo-t et rahydro-cc-santonin (3) and their N-methyl derivatives all show anegative Cotton effect (Figures 2 and 3), and thereforethe contribution to the Cotton effect by the lactam ringmust be negative. On the other hand, transfused 4-aza-a-homo- t e t rahydro- a-sant onin derivatives (1) and(4) show a positive Cotton effect with [+] +5 200 at 230nm and [el 4-2 660 at 216 nm, respectively.Thesevalues are larger than those of related compounds con-taining only a lactone ring (e.g. + +1 200 to +3 500),12' A. F. Beecham, Tetrahedron Letters, 1969, 489i.J. P. Jennings, W. Klyne, and P. M. Scopes, J . Chew. SOC.,H. Ogura, H. Takayanagi, and C . Miyahara, J . Org. Chem.,lo K. Oka and S. Hara, Chem. and I n d . , 1969, 168.l1 B. J. Litman and J. A. Schellman, J . Phys. Cheln., 1966, 89,978.1965, 7229.1972, 37, 519.l2 J. P. Jennings, W. Klyne, and P. RI. Scopcs, J . Chem. SOC.,1965.7211.l3 'C. G. Overberger and H. Kaye, J . Amev. Chem. SOC., 1967,89, 5646, 5649666 J.C.S. Perkin Iand therefore the contribution of the lactam chromo- (Figure 4), and 17~-acetoxy-3-aza-~-homo-5~-androstan-phore to the Cotton effect is still positive. In all these 4-one (8) and 17~-acetoxy-4-aza-~-homo-5~-androstan-cases the contribution of the lactone chromophore 3-one (9) show positive Cotton effects.appears to be less than that of the lactam chromophore.It is well established 14-16 that the peptide linkageComparison of these spectra with those of the steroid CO*NH is nearly planar, because of the partial doublederivatives (7)-(12) shows that the 4a-methyl group in bond character of the carbon-nitrogen bond. A recent8t-2-6-8200 220 240-10- I 1 I I I I 1200 220 240h / n m h / n mFIGURE 3A / n mOAcIOAcO H\ 5z -9--1'5 -\ ,&. '\ ' -12 \ /-1 1 1 1 1 1 1200 220- 240A l n m8-6-4 -2 -0-1-2 --4-6 --8 --\ ,I-\\/ ced.200 220 240h I n mFIGURE 4L$0-A/nmthe former series has little influence on the shape or X-ray analysis has confirmed that the lactam group in aintensity of the spectrum. 17P-Acetoxy-4-aza-~-homo- seven-membered ring l7 is nearly planar and that the5a-androstan-3-one (7) and 17P-hydroxy-3-aza-~-homo- ring adopts a modified chair conformation.Relatedandrostan-4-one (10) show negative Cotton effects lactam systems also possess a nearly planar lactam group(X-ray analysis) .18J9 19F N.m.r. studies on 4,4difluoro-'* C . C . Costain and J. M. Doffling, J . Chem- PhYS., 1960, 32, hexane-6-lactm,20 and consistent force field calculations168.l5 A. E. Tonelli, J . Amer. Chem. SOC., 1971, 93, 7153.16 M. Tichy, E. Duskova, and K. Blaha, Tetrahedron Letters,17 I.Nitta. M. Haisa. N. Yasuoka. K. Kasami. Y . Tomiie. Co,mm.. 1973. 2. 223.F. K. Winkler and I. D. Dunitz, J . MoZ. Biol., 1971, 59, 169.l9 V. Pattabhi, K. Venkatesan, and S. R. Hall, Cryst. Struct. 1974, 237.and Y. Okaya. Ann. Reports Fiber Res: Inst. Osaka.Univ., 1966;17, 1. 93, 7261.2o E: A. Noe. and J. D. Roberts, J . Amer. Chem. SOC., 19711976on hexane-6-lactam 2 l also support the planar nature of (-)-menthone lactam and N-methyl-( -)-menthonethe CO*NH group in the seven-membered ring. 1actam.lOur n .m. r . studies on the A-aza- A-homo-tet rahydro- a- Preparatiout of Com?omds.-The A-aza-A-homo-com-santonins (1)-(3) suggested that ring A existed in a pounds (1)-(3) were prepared via Beckmann rearrange-chair conformation.The similarity of the n.m.r. spectra ment of the corresponding oximes, and the N-methylof the corresponding N-methyl derivatives (4)-(6) compounds (4)-(6) by methylation of (1)-(3) withsuggests that these also possess a chair ring A (Table 1). methyl iodide.TABLE 1N.m.r. data of s-aza-A-liomo-tetrahydro-a-santonins (100 MHz; CDCI,; 6 values; J in Hz)H- 52.18 (dd)J 4 e . 5 6.5Jj. 6 7.02.25 (dd)2.05 (dd)J ~ a . 6 8.0J 5 . 6 8'6J4a.5 9.0J s , ~ 4.32.352.0H-6 4a-CH3 1 O-CH,3.76 (dd) 1.35 (d) 1.09 (s)J5.6 7.0 J 6.9J6.7 11.03.86 (dd) 1.27 (d) 1.14 (s)Js, 7 11.04.36 (dd) 1.24 (d) 1.16 (s)J5,6 4.3 J 6.73.80 1.40 (d) 1.04 ( 5 )3.83 1.33 (d) 1.06 (s)4.37 (dd) 1.34 (d) 1.12 (s)JjS6 4.4 J 7.0J6.6 8.6 J 7.4J6.7 11.0J 7.1J 7.4J 6 .7 11.3a J Valuc nt -30 "C.1 1 -CH,1.20 (d)J 6.751.17 (a)J 7.01.23 (d)J 6.751.20 (a)J 6.91.18 (d)J 6.91.21 (d)J 6.6N-CH, KH5.97 (d)J 4.06.74 (t)J 5.35.99 (d)J 4.62.85 (s)2.96 (s)2.85 (s)111 the A-aza-steroids, ring A should also possess a chairconformation.Of the established relationships between the sign of theCotton effect and the configuration around a carbonylgroup, the well-known octant rule for ketones 22 does notexplain our results. This is not unexpected, but, moresurprisingly, neither Klyne's sector rule for l a ~ t o n e s , s * ~ ~ ~ ~ ~nor the quadrant rule for amides24-26 is satisfactory(Table 2). On the other hand, our lactam rule fits theexperimental facts, for both the santonin derivatives(Table 2; Figures 2 and 3) and the steroid derivatives(Figure 4).An unusual feature appears in the c.d.data of (4), which shows a negative Cotton effect at234 nm ([0lzo -720) in addition to the expected positiveeffect at 216 nm ([OlZ0 +2 700). This negative peakdoes not occur in the spectra of the other N-methylcompounds (5) and (6) nor in that of the parent com-pound (I). It does not appear at lower temperatures(-80 to -150 "C), and the positive peak increases inamplitude and suffers a red shift of about 2 nm. Thelactam rule predicts that the conformer A (Figure 5 )should have a negative Cotton effect whereas conformer€3 should have a positive Cotton effect. We suggest thata conformational equilibrium is set up between the two,and that conformer B is the stable one at lower tempera-tures.Similar results have been obtained in the case of21 0. Ermer and S. Lifson, J. Artzev. Chew. SOC., 1973, 95, 4121.22 W. Moffitt, R. B. Woodward, A. Moscowitz, W. Klyne, andO3 W. Klyne, P. M. Scopes and A. Williams, J. Chem. SOC.,'.j J . A . Schellman and P. Oriel, J . Chcm. Plzys., 1962, 37,C. Djerassi, J. Amer. Chem. SOC., 1961, 83, 4013.1965, 7237.2114.Shoppee et aL2' have reported that 5a-cholestan-3-oneoxime undergoes the Beckmann rearrangement to give3-aza-~-homo-5a-cholestan-Pone (12) and 4-aza-~-homo-5a-cholestan-3-one ( l l ) , both with m.p. 295". In anTABLE 2C.d. and 0.r.d. data of seven-membered lactams (inMeOH)Predicted signObserved of Cotton effect7 -------- [OJ x 10-3 [+I x lo-,- Octant Amide LactamCompd. nm nm rule rule rule ++(1) 4-11.8 211 +5.2 230 4- I (2) -114.8 210 -3.9 220 + -!--9.7 218 -4.2 230 - ++2.7 216' + -+ (6) -4.1 21lja + + (6) -5.8 218' -(7) -12.8 218 -6.0 230 + -(8) +16.7 205 +18.0 209 - -(9) +7.0 211 +7.7 226 - -(10) -7.5 211 -4.6 228 + + (11) +7.4 210 +4.7 223 - -(12) -0.6 211' + +------- + + -I 7- --10.2 214' -4.3 227"(1 In EtOH-MeOH ( 4 : 1).M.p. 268--271"; preparedby the method of Shoppee and Sly.28 M.p. 278-279';prepared by the method of Shoppee, Kriiger, and Mirrington.27earlier paper,= Shoppee and Sly described material, m.p.268-271", which they believed to be pure 4-ketone (12).B. J. Litman and J. A.Schellman, J. Phys. Chew., 1965,69, 978.26 J. A. Schellman, Accounts Chew. Res., 1968,1, 144.27 C. W. Shoppee, G. Kruger, and R. N. Mirrington, J. Chem.28 C . W. Shoppee and J. C. P. Sly, J. Chew. SOC., 1968, 3458.SOC., 1962, 1050668 J.C.S. Perkin IIn our hands, the oxime obtained by isomerisation of5u-cholest an-3-one oxime with hydrochloric acid re-arranged to give the 3-ketone (II), m.p. 300'. Theisomeric Pketone (12) was prepared by hydrogenation ofMeMeIo e e Me MeB 6 + )FIGURE 53-aza-~-homo-5a-cho~est-4a-en-3-one,~~ and had m.p.278-279'. Comparison of Cotton effects (see Table 2)shows that the mixture prepared by the method ofShoppee and Sly 28 was a ca. 1 : 1 mixture of (1 1) and (12).EXPERIMENTALN.m.r. spectra were measured for solutions in CDCI, a t100 MHz with a JMS-PS-100 spectrometer (tetramethyl-silane as internal standard).C.d. curves were measuredwith a Japan Spectroscopic model J-20 recording polari-meter.N-Methyl-4-aza-~-hmo-trans-tetrahydro-u-santonin (4) .-Sodium hydride (360 mg) was added to a stirred solution of4-aza-~-homo-trans-tetrahydro-ol-santonin (1) (1.3 g) in drybenzene (30 ml) under nitrogen. The mixture was heated toreflux, methyl iodide (1.07 g) in dry benzene (20 ml) wasadded dropwise, and the mixture was refluxed for a further7 h and set aside overnight. Ethanol was added to destroythe excess of hydride, followed by water. The benzene layerwas separated, dried (CaCl,), and evaporated, and the residuewas crystallised from methanol-ether to give the N-methyl-Zactam (4) as prisms (300 mg), m.p.223--224", [8]2,,20+2 660,+6 130 (EtOH-MeOH, 4 : l), v-(KBr) 1 774 (lactone) and1031 (lactam) cm-1 (Found: C,68.75; H, 9.05; N, 4.75%;M+, 279. C,6H25N0, requires C, 68.8; H, 9.0; N, 5.0%;M , 279).N-Methyl-3-aza-~-horno-trans-tetrahydro-a-santon~n (5) .-3-Aza-~-homo-trans-tetrahydro-a-santonin (2) (420 mg)[e-~,,~2* - 720, [e1,,;80 + 5 010, [e1,~~.~-110 + 5 520, [ e - ~ ~ ~ p ounder the same conditions afforded the corresponding N-methyl-lactam (5) which was purified by chromatographyover silica gel (elution with chloroform), Crystallisationfrom ether-methanol gave needles (100 mg), m.p. 207-209",-8 320 (EtOH-MeOH, 4 : l), vma (KBr) 1 758 (lactone) and1633 (lactam) cm-l (Found: C, 68.8; H, 8.9; N, 4.8%;M+, 279).N-Met~~yl-4-aza-~-homo-cis-tetra~~ydro-a-santon~n (6) .-4-Aza-A-homo-cis-tetrahydro-u-santonin (3) under the sameconditions afforded the corresponding N-methyl-lactam (6)as prisms (30%) (from ether), m.p.113-114", [0]21820-21 750 (EtOH-MeOH, 4 : l), v,,.(KBr) 1765 (lactone)and 1 640 (lactam) cm-l (Found: C, 68.85; H, 9.1 ; N, 5.1 %).Beckmann Rearrangemaent of 5a-Cholestan-3-one 0xime.-(a) Shoppee's method2' 5a-Cholestan-3-one oxime (2.4 g)[m.p. 196-197" (lit.,29 199"; lit.,30 197--201")J in drydioxan (70 ml) was warmed to 40 OC, and thionyl chloride(3.0 ml) was added with stirring over 5 min. The mixturewas kept at 40 "C for 10 min, and then neutralised withsodium hydrogen carbonate solution.Water was added,and the aqueous solution was extracted with a large volumeof ether. The ether layer afforded a solid (2.2 g) which waschromatographed on alumina (elution with benzene-ether) .The product (1.6 g) was a mixture of A-aza-compounds, m.p.268-271O (lit.,27 268-271"), v,,.(KBr) 3 200, 3 070 (NH),1675, 1667, and 1630 (CO) cm-l (Found: C, 80.65; H,11.9; N, 3.4%; M f , 401. Calc. for C,,H,,NO: C, 80.75;H, 11.8; N, 3.5%; M , 401).(b) Dry hydrogen chloride was bubbled through a solutionof 5u-cholestan-3-one oxime (4.8 g) (m.p. 196-197') in dryether (100 ml) . The oxime hydrochloride was precipitated.The precipitate was neutralised with sodium hydrogencarbonate solution to afford the isomerised oxime (4.5 g),m.p. 195-196". Beckmann rearrangement of this oximein the same manner as in (a) afforded 4-aza-~-horno-5~-choZesta?z-3-one (ll), m.p. 300°, v,,(KBr) 3 200, 3 075(NH), 1680, and 1630 (CO) cm-l (Found: C, 80.6; H,11.8; N, 3.55%; M+, 401. C,,H,,NO requires C, 80.75;H, 11.8; N, 3.5%; M , 401).3-Axa-~-honzo-5a-cho~estan-4-one ( 12b) .-3-Aza-~-homo-5cc-cholest-4a-en-4-one (400 mg) (prepared by a Schmidtreaction of cholest-4-en-3-one) was hydrogenated to give3-aza-~-homo-5a-cholestan-4-one (12) (250 mg), m.p. 278-279" (lit.,28 294--296"), v,,(CHC13) 3 420, 3 300, 3 220 (NH),and 1 652 cm-l (CO) (Found: C, 80.85; H, 11.85; N, 3.6%;Mf, 401).yejBl520 -4 110, [ e ~ ~ , ~ - s o -6 840, p1,,~-110 -7 300, [e],,;~~~-5 840, [e],,;so -15 660, [e1,~,-110 -18 570, [6]1215.5-150We thank Professor S. Hara and Dr. K. Oka, TokyoCollege of Pharmacy, for supplying compounds (7)-( lo),and Professor T. B. H. McMurry for help in drafting themanuscript.[6/460 Received, 10th March, 1976129 J. 0. Ralls, J. Amer. Chem. SOC., 1938, 60, 174.4.3O J. R. Bull, E. R. H. Jones, and G. D. Meakins, J. ChemSOC., 1962, 1060
展开▼
