J. Org. Chem. 1992,57,5141-5157
6747
(540 mg), which was purified by SiOz column (5.4 g, AcOEt) to afford the pure NH compound 23 (140 mg,52%) as a white solid. rac-Methyl(2R*,3aS*,6aS*,lOaS*)-3-Methyl-5,lO-dioxo- 23: mp 196.5-197 "C (CH,Cl,-AcOEt); IR 3300,2950,1730,1650 9-(p -toluenesulfonyl)-1,2,3,3a,4,5,6,6a,7,8,9,1O-dodecahydrocm-'; 'H NMR (500 MHz) 6 1.58-1.97 (4 H, m, 1,6,6a-H), 2.03 (1 H, d, J = 12.0 Hz, 1-H), 2.15 (2 H, m, 4, 7-H), 2.29 (2 H, m, pyrrolo[2,3-i]isoquinoline-2-carbxylate 5-Ethylene Ketal 4,6-H), 2.45 (3 H, s, NMe), 3.28 (1 H, m, SH), 3.41 (1 H, m, SH), (22). A mixture of the ketone 21b (653 mg,1.5 mmol), ethylene 3.67 (3 H,s,OMe),3.72-4.00 (6 H,m,0CHzCH20,2,3a-H), 5.76 glycol (620 mg,10 mmol), and TsOH-H20(65 mg)in dry benzene (1 H, brs, NH); LREIMS m/z 324 (M+),265 (100). Anal. Calcd (25 mL) was heated under reflux for 13 h with continuous removal for ClsHz4NzOs:C, 59.24; H, 7.46; N, 8.64. Found: C, 59.49; H, of water. The mixture was quenched by the addition of saturated NaHC03(aq) (10 mL) and extracted with AcOEt. The organic 7.49; N, 8.56. layer was washed with brine and dried over NazS04,followed by Acknowledgment. Special thanks are due to H. Ohmevaporation of the solvent to give a crude residue (720 mg). ori and A. Matsumoto in the Instrumentation and CharCrystallization of this material from AcOEtln-hexane (1.5/1) acterization Center, RIKEN for their technical assistance afforded almost pure ketal 22 (418 mg). The mother liquor was with the high-pressure Diels-Alder reaction. Financial concentrated and purifies by SiOzcolumn (5.0 g, AcOEt/n-hexane support by a Grant-in-Aid for ScientificResearch from the = 1/5) to afford a further amount of the desired ketal 22 (150 Ministry of Education, Science and Culture and Uehara mg, total yield 568 mg, 79%). 22: mp 171.5-172.5 "C Memorial Foundation is gratefully acknowledged. We also (CHzC12-AcOEt); IR 2950,1730,1680,1600,1350,1160 cm-l; lH thank Mrs. H. Seki, Miss R. Hara, and Mr. T. Kuramochi NMR (600 MHz) 6 1.35 (1 H, t, J = 13.4 Hz, 6a-H), 1.42 (1 H, dd, J 15.4,4.6 Hz, 4-H), 1.61 (1 H, dt, J 13.4, 3.3 Hz, 6-H), in the Analytical Center of Chiba University for spectral 1.75 (1 H, m, 7-H), 1.85 (1 H, dt, J = 15.4,3.3 Hz, 4-H), 2.02 (1 data. H, dd, J = 13.4,4.3 Hz, 1-HI, 2.24-2.34 (3 H, m, 1,6, 7-H), 2.38 Registry No. 1, 104196-68-1; 4, 132143-27-2; 4 (R = H), (3 H, s, NMe), 2.44 (3 H, s, Me) ,3.64 (3 H, s, OMe), 3.75 (1 H, 6052-73-9; 5, 54125-02-9; (*)-6, 132143-30-7; 10, 130291-45-1; td,J = 12.2,5.1Hz,8H), 3.M-3.98 (6 H, m, OCHzCHzO,3 4 2H), ( i ) - l l 143076-11-3; , (f)-12a, 143076-12-4; (*)-12c, 143076-20-4; 4.12 (1 H, m, 8-H), 7.30 (2 H, d, J = (8.3 Hz, aromatic), 7.87 (2 13 (R = Me), 130291-56-4; 13 (R = Bu-t), 56776-34-2; ( i ) - 1 4 H, d, J = 8.3 Hz, aromatic); LRFABMS m/z 479 (MH+, 100); (isomer l),143076-13-5; (*)-14 (isomer 2), 143076-22-6; (f)-15 HRFABMS m/z calcd for CBH3107N8(MH+)479.1852, found (isomer l),143076-14-6; (f)-15 (isomer 2), 143076-24-8; (i)-16, 479.1857. Anal. Calcd for CaHmO7NZS: C, 57.53; H, 6.32; N, 143076-15-7;(A)-17,143076-16-8; (*)-l8 (isomer l),143104-23-8; 5.86; Found C, 57.62; H, 6.26; N, 5.69. (f)-18 (isomer 2), 143076-23-7; 19, 130291-53-1; (f)-20 (isomer rac -Methyl(2R *Pas*,6aS *, lOaS*)-3-Methyl-5,lO-dioxol), 143076-17-9; (f)-20 (isomer 2), 143076-25-9; (f)-21a, 1,2,3,3a,4,5,6,6a,7,8,9,lO-dodecahydropyrrolo[2,3-~Iiso143167-08-2; (*)-2lb, 143167-09-3; (*)-22,143076-18-0; (i)-23, quinoline-2-carboxylate 5-Ethylene Ketal (23). Sodium na143076-19-1; CH,=C(COOMe)NHCOOMe, 76637-56-4; CH2= phthalenide was prepared by stirring a mixture of sodium metal C(CO0Me)NHCOOBu-t,55477-80-0;PhzSz,882-33-7;N-(meth(209 mg,9 m o l ) and naphthalene (1.53 g, 12 mmol) in dry DME oxycarbony1)-DL-serine methyl ester, 143076-21-5; N-tosyl-2(20 mL) under Ar at rt for 2 h. To a cooled (-78 "C) and stirred piperidone, 23438-61-1. solution of the N-Ts ketal (22,400 mg, 0.83 mmol) in DME (20 mL) was added dropwise the above-prepared sodium naphthalSupplementary Material Available: High-resolution lH enide solution by cannula until a blue color persisted (6 mL). After NMR spectra of compounds 10, 11,13, and 16-21 and 13C NMR TLC analysis, the mixture was quenched by the addition of spectra of 11,13,19, and 21 (17 pages). This material is contained saturated NH4Cl(aq)to obtain a neutral aqueous layer, which was in many libraries on microfiche, immediately follows this article extracted with AcOEt. The organic layer was washed with brine in the microfilm version of the journal, and can be ordered from and dried over N@O,. Evaporation of the solventsgave a residue the ACS; see any current masthead page for ordering information.
found 434.1542. Anal. Calcd for CzlH2&Jz06SC, 58.04; H, 6.04; N, 6.45. Found C, 58.16; H, 6.00; N, 6.37.
Tandem Cyclization-Cycloaddition Reaction of Rhodium Carbenoids. Studies Dealing with Intramolecular Cycloadditions Albert Padwa,* Susan F. Hornbuckle, Glen E. Fryxell, and Zhijia J. Zhang Department of Chemistry, Emory University, Atlanta, Georgia 30322 Received May 15, 1992 A series of Balkenyl-l-diazo-2,5-pentanediones, when treated with a catalytic quantity of rhodium(I1) acetate, were found to give cycloadducta derived from the intramolecular trapping of a carbonyl ylide intermediate. Tethers of three or four methylenes readily enter into intramolecular cycloaddition, while longer and shorter tethers were reluctant to do so. Alkenes attached to the formally cationic terminus of the carbonyl ylide readily undergo internal cycloaddition if the tether allows for a relatively strain-free transition state. The intemal cycloaddition reaction does not occur when the olefinic side chain is attached by means of an ester functionality. Bimolecular trapping experiments established that carbonyl ylide formation occurred, but the dipole does not undergo intramolecular cycloaddition The inability of theae a-diezo keto esters to undergo intemal cycloaddition is related to conformational factors. The equilibrium between the two possible conformations of the dipole lies predominantly on the side of the 2-isomer. In this orientation, intramolecular dipolar cycloaddition cannot occur, and instead the dipole collapses by means of a proton transfer to give an enol ether.
A major challenge in organic synthesis today is to devise reactions that can form several carbon-carbon bonds in one operation leading to the construction of polycyclic structures with proper regio- and stereochemical control. The predictability and selectivity with which intramolec0022-3263/92/1957-5747$03.00/0
ular 4 + 2-cycloaddition reactions occur has led to their widespread use in organic synthesis. Intramolecular Diels-Alder cycloadditionshave been particularly useful in natural product synthesis since this reaction results in the formation of an extra ring and exhibits increased re@ 1992 American Chemical Society
8748
J. Org. Chem., Vol. 57, No. 21, 1992
activity due to entropic factor~.l-~ Additional regiochemical constrainta frequently result in a marked increase in diastereceelectivity. Much interest has also been focused on reactions that effect formation of 5-membered rings through intramolecular 3 + 2-cy~loadditions."'~ Among these, cycloaddition reactions of l,&dipoles occupy a uniquely important position due to their synthetic as well as theoretical signifi~ance."-~Carbonyl ylides represent a well-investigated and synthetically useful class of 1,3dipole^.^^-^^ Except for a few isolated examples,2g34 however, the intramolecular dipolar cycloaddition reaction of carbonyl ylides with alkenes has not yet attained a synthetically useful level of development. Several years ago, we developed a 3 + 2-annulation method for the synthesis of tetrahydrofurans based on the rhodium(I1)-catalyzed reaction of diazo dienes.% The reaction sequence involves formation of a cyclic carbonyl ylide, followed by a l,&dipolar cycloaddition with a suitable dipolarophile.36 These reactions are performed under
(1)Brieger, G.; Bennett, J. N. Chem. Rev. 1980,80,63. (2)Ciganek, E. Org. React. 1984,32, 1. (3)Fallis, A. G. Can. J. Chem. 1984,62,183. (4)Hudlicky, T. Chem. Rev. 1989,89,1467. (5)Kauffmann, T.Top. Curr. Chem. 1980,92,109. (6)Beak, P.; Burg, D. A. J. Org. Chem. 1989,54,1647. (7) Padwa, A.; Yeske, P. E. J.Am. Chem. SOC. 1988,110,1617. (8) Mann, J. Tetrahedron 1986,42,4611. (9)Remaiah, M. Synthesis 1984,529. (10)Noyori, R.;Hayakawa, Y. Org. React. 1983,29,163. (11)Noyori, R. Acc. Chem. Res. 1979,12, 61. (12)Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,23,1. (13)Molander, G. A.; Shubert, D. C. J. Am. Chem. SOC.1986,108, 4683. (14)Curran, D. P.; Chen, N. H.; Spletzer, E.; Seong, C. M.; Chang, C. T. J. Am. Chem. SOC.1989,111,8872. (15)Little, R. D. Chem. Rev. 1986,86,875. (16)Trost, B.M.;Grese, T. A.; Chan, D. M. T. J. Am. Chem. SOC. 1991,113,7350. (17)Padwa, A,, Ed. 1,3-DipolarCycloaddition Chemistry; Wiley-Interscience: New York, 19W, Vols. I and 11. (18)Padwa, A. Angew. Chem., Int. Ed. Engl. 1976,15,123. (19)Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977,16,10. (20)Confalone, P.N.; Huie, E. M. Org. React. 1988,36,1. (21)Terao, Y.; Aono, M.; Achiwa, K. Heterocycles 1988,27,981. (22)Padwa, A.; Schoffetall, A. M. Advances in Cycloaddition; JAI Press, Inc.: Greenwich, CT, 1990,Vol. 2, p 1. (23)Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980,45,3359. (24)Griffin, G. W.; Padwa, A. In Photochemistry of Heterocyclic Compounde; Buchardt, O., Ed.; Wiley: New York, 1976; Chapter 2. (25)Bekhazi, M.; Smith, P. J.; Warkentin, J. Can. J. Chem. 1984,62, 1646. Warkentin, J. J. Org. Chem. 1984,49,343. (26)Shimizu, N.; Bartlett, P. D. J. Am. Chem. SOC. 1978,100,4260. (27)Hoffman, R. W.; Luthardt, H. Chem. Ber. 1968,101,3861. (28)Sammes, P. G.;Street, L. J. J. Chem. SOC., Chem. Commun. 1983, 666. (29)Sammes, P. G.; Street, L. J.; Whitby, R. J. J. Chem. SOC.,Perkin Trans. 1 1986,281. (30)Wender, P. A.; McDonald, F. E. J. Am. Chem. SOC.1990,112, 4956. Wender, P. A.; Maacarenae, J. L. J. Org. Chem. 1991,56,6267. (31)Feldman, K. S.Tetrahedron Lett. 1983,5855. (32)Brokatzky-Geiger, J.; Eberbach, W. Chem. Ber. 1983,116,2383; 1984,117,2157; Tetrahedron Lett. 1984,1137;Heterocycles 1983,20, 1519. (33)Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988,1677. Maier, M. E.;Schoffing, B. Chem. Ber. 1989,122,1081. (34)Hertzog, D. L.; Austin, D. J.; Nadler, W. R.; Padwa, A. Tetrahedron Lett. 1992,4731. (35)Padwa, A.; Carter, S. P.; Nimmesgem, H. J. Org. Chem. 1986,51, 1157. Padwa, A.; Carter, S. P.; Nimmesgem, H.; Stull, P. D. J. Am. Chem. SOC.1988,110,2894.Padwa, A.; Fryxell, G. E.; Zhi, L. J. Org. Chem. 1988, 53,2875.
Padwa et al.
cji. t;
;
QN2
Er
O
k
extremely mild conditions, t y p i d y at room temperature in a neutral organic solvent. Since these cycloadditions involve cyclic carbonyl ylides, the resulting products are oxabicycles of varying ring size. If the dipohphile is also intramolecularly tethered to the dipole, the subsequent cycloaddition affords complex oxapolycyclic ring systems with three (or more) component rir1ge.3~Our preliminary results have shown this to be a highly efficient and stereospecific approach to these In light of our earlier succ88888 and the increasing application of thb type of strategy,39we felt that a more detailed study of this reaction was warranted. This paper summarizse the results of these studies.
Results and Discussion The systems that we initially studied were ultimately derived from phthalic anhydride, such that the tethered dipolarophile was attached to the benzene ring backbone via an ester or amide linkage.% Thie arrangement results in a cyclic carbonyl ylide, the u-system of which contributes to an aromatic ring.a The carbonyl ylide is ale0 stabilized by the adjacent heteroatom of the dipolarophile tether. q
o
H
N
z
Q 0 /o+
L
XCH&H&H=CH,
-9
XCH&H&H=CHz
2
1
3
Since we were interested in learning what role these two factors played in the overall reaction pathway, we chose to study the stripped down, bare methylene system (i.e., 4). Both our original phthalate-based dipole precursor 1 as well as a-diazo ketone 4 have the tethered olefii attached to the carbonyl group that cyclizes onto the rhodium carbenoid to form the carbonyl ylide. We refer to this method of connection as yw attachment", using the carbenoid carbon as the point of reference. Treatment of 4 with Rh20Acl proceeded quite smoothly, producing cycloadduct 5 in 75% yield. It is worth noting that this
4
5
process begins from an acyclic precursor with no stereocenters and in one step, under extremely mild conditions, assembles a tricyclic backbone containing three new stereocenters with complete stereospecificity and in high yield. No bimolecular trapping product was observed when the reaction of 4 was carried out with rhodium(I1) acetate in the presence of dimethyl acetylenedicarboxylate (36)Padwa, A. Acc. Chem. Res. 1991,24, 22. (37)For another example of the tandem dipole generation-intramolecular dipolar cycloaddition sequence, we: Denmark, S.E.; Schnute, M. E. J. Org. Chem. 1991,56,6738. Denmark, 5.E.;Senanayake, C. B. W.; Ho, G. D. Tetrahedron 1990,46, 4857. Denmark, S. E.;Moon, Y. C.; Cramer, C. J.; Dappen, M. S.; Senanayake, C. B. Tetrahedron 1990,46, 7373. Denmark, S.E.; Moon, Y. C.; Senanayake, C. B. J.Am. Chem. SOC. 1990,112,311. (38)Padwa, A.; Hombuckle, S. F.; Fryxell, G. E.; Stull, P. D. J. Org. Chem. 1989,54,817. (39)Padwa, A.; Hornbuckle, S. F. Chem. Reu. 1991,91, 263. (40)For a review of oxidopyrylium cycloadditions, see: Sammes, P. G. Gazz. Chim. Ital. 1986,119,109.Katritzky, A. R.;Dennis, N. Chem. Rev. 1989,89,827-861. See also footnote 12 in ref 3011.
Cyclization-Cycloaddition of Rhodium Carbenoids
(DMAD). With this system, intramolecular cycloaddition to the internal ?r-bond is too rapid to allow bimolecular trapping of the intermediate carbonyl ylide. Of the many unexplored questions concerning the factors that govern the outcome of intramolecular carbonyl ylide trapping reactions, one that is very easy to formulate focuses upon the course of the reaction as a function of the length of the tether connecting the reacting groups. Our earlier studies have shown that the ring size of the resulting dipole played a significant role in the efficiency of the tandem cyclization-cycloaddition process.41 The primary spatial requirement for intramolecular cycloaddition is that the distance between the dipole and alkene should be sufficiently close so that effective overlap of the ?r-orbitals can occur. In this paper the geometric requirements of the intramolecular cycloaddition reaction were evaluated by varying the chain length of the tether and determining what effect that had on the overall process. Treatment of a-diazo dione 6 with rhodium(I1) acetate in benzene resulted in the formation of tricyclic species ketone 8 in 60% isolated yield. In the presence of DMAD, the intramolecular process was completely shut down, and the only product isolated was the bimolecular cycloadduct 9 derived from the trapping of carbonyl ylide 7. This
V r
8
1
7
4
9
observation indicates that the intramolecular cycloaddition involving a four-carbon tether (to form a six-membered ring) is slower than both bimolecular cycloaddition with DMAD and intramolecular cycloaddition involving a three carbon tether (Le., 4 6). Expansion of the tether with a fifth methylene group was accomplished by synthesizing a-diazo ketone 10 (see the Experimental Section). However, treatment of 10 with the rhodium(I1) catalyst gave no detectable quantities of an intramolecular cycloadduct. In order to confirm that the dipole was indeed being formed from 10, the reaction was repeated in the presence of excess DMAD. This reaction afforded the bimolecular cycloadduct 11 in 67% yield. Thus, a five-carbon tether (leading conceptually to a seven-membered ring) is ineffective at directing intramolecular cycloaddition. Going in the opposite direction, we also reduced the tether length to two methylene units, as shown in structure 12. Not surprisingly, treatment of 12 with R&(OAC)~ afforded no intramolecular cycloadduct. Apparently, the ring strain of the resulting tricyclic cyclobutane is sufficiently reflected in the transition state of cycloaddition 80 that a substantial kinetic barrier to this process exists. However, the carbonyl ylide is indeed formed, as an identical reaction carried out in the presence of DMAD provided bicyclic ketone 13 in good yield. The rate of the intramolecular dipolar cycloaddition reaction of these systems is dependent on the energy level
-
(41) Padwa, A.;Chinn, R. L.; Hornbuckle, 5.F.; Zhang, 2. J. J. Org. Chem. 1991,56, 3271.
J. Org. Chem., Vol. 57, No. 21, 1992 5749 Rh**
10, n J 12, ns2
IRh'+
43
c~,o,c
CHz=CH(CHz).COCHzCHlCOCHN, DMAD
CHz=Cn(CHz).
11,nJ 13, n=!2
NO W c l d d u c l
of the open-chain initial state, compared to the transition state reaembling the cyclic product. The activation energy of the process also reflects the strain energy of the ring to be formed, which is markedly dependent on ring size, as shown by strain energy data for the cy~loalkanes.~~ The magnitude of such strain has been evaluated by Allinger on the basis of force-field calculations.43 The probability of the alkenyl group coming close enough to the dipole for the reaction to occur decreases as the chain gets longer. In terms of entropy, this implies negative ASscontributions owing to reduction of freedom of internal rotation about the single bonds of the molecular backbone when the disordered open-chain precursor is converted into the cycloadduct. The ease of internal cycloaddition as a function of ring size was found to significantly diminish on going from five- to seven-membered rings in the cycloadduct. The success of the internal cycloaddition reaction is critically dependent on the relative rates of cycloaddition as compared to unproductive decomposition pathways. In the case of the seven-membered ring, the entropy of activation is significantly more negative than with the systems bearing the shorter tethers, and this can account for why no internal cycloadduct is observed with a-diazo ketone 10. In recent years, molecular mechanic3 has developed into an important technique for the calculation of molecular properties.44 We have used the Still-Steliou Model 2.94 program to model energy differences in the transition s t a b for the intramolecular carbonyl ylide cycloaddition reaction. Global minima were found by making use of multiconformer generation in Model (TTY,Conf, Statistical, Coordinate) followed by Batch minimization using Bakmdl. The particular parameters used were those of the NOH (no hydrogen) field developed by Still and implemented by Steliou in the program Model. Structures within 3 kcal/mol of the lowest (global) energy conformer were retained for study. The transition-stategeometry was approximated by fixing the distance between the reacting centers of the carbonyl ylide and alkene to be 3.0f 1.0 A. A Boltzmann distribution of the various conformers of the carbonyl ylide was obtained from the Bakmdl output. We assume that the relative energy difference between the lowest energy conformation of the starting dipole and "approximated" cycloadduct will parallel the activation energy of the reaction. The calculations show an increase from 0.28 kcal/mol (ETs- Eos) for the dipole derived from a-diazo ketone 4 to 1.66 kcal/mol for 6 and 3.86 kcal/mol for 10 (see Table I). These values are in perfect accord with the experimental findings. We also note that the "conformerpopulation" of the starting carbonyl ylide in the correct orientation to produce cycloadduct (i.e., distance between reacting centers =3.0 f 1.0 A) corresponds to 2.34% with 4 and diminishes significantly with the dipoles derived from 6 (0.6%) and 10 (
