Palladium-catalysed Cyclisation and Cyclisation^ Carbonylation of Unsaturated C-Glycoside Derivatives. The Importance of Relative Stereochemistry CedricW. Holzapfel* and Lizel Marais Department of Chemistry and Biochemistry, Rand Afrikaans University, P.O. Box 524, Auckland Park, 2006, South Africa The Pd-catalysed `metallo-ene type' cyclisation and cyclisation^carbonylation of selected 2,3-unsaturated C-glycosides is described and attention is drawn to the importance of relative stereochemistry in the latter type of reactions.The palladium(0)-catalysed intramolecular carbocyclisation of allyl acetates with alkenes, a type of palladium-ene reaction,1 exempli¢çes an attractive methodology leading to usefully functionalised ¢çve- and six-membered carbo- and hetero-cyclic compounds. Not only are these reactions regio- and most often stereo-selective, but they are also entropically favoured. Palladium-catalysed cyclisation onto carbohydrate tem- plates2 o€ers a fast and e.cient route to chiral, highly func- tionalised polycyclic compounds that can be transformed into versatile synthetic intermediates.Recently, we described the Pd0-catalysed cyclisation of selected pseudoglycal 1,6- diene and 1,6-enyne derivatives for the synthesis of cis-annu- lated pyranoside products.3 We herein describe4 the for- mation of 5,6-bicyclic systems by palladium(0)-catalysed cyclisation of acetoxy-1,6-diene and 1,6-enyne C-glycoside derivatives.The catalysing properties of palladium were also exploited in the preparation of the starting material C-glyco- sides 3 and 7 (Scheme 2). `Metallo-ene type' cyclisation of 3 in acetic acid13 at 70 8C in the presence of a catalytic amount of Pd(PPh3)4 a€orded the cis-fused annulated C-glycoside derivative 4 as the sole product. The same product was obtained, in a somewhat reduced reaction time and in a slightly higher yield, when the isomeric C-glycoside 7 was subjected to similar reaction conditions. Although the precise mechanism for the cyclisation reac- tion is as yet unknown, it has been established that it pro- ceeds in a suprafacial manner, i.e. the alkene inserts predominantly into an intermediate p- (or s-)allylpalladium species, cis relative to the palladium atom.1 The observation that both the cis and trans substituted allyl acetate deriva- tives 3 and 7 gave the same cis annulated cyclisation pro- duct 4, analogous to observations made by Oppolzer,14 presumably implies a relatively slow trans¡¾cis isomerisation (Scheme 3) of the intermediate p-allylpalladium complex, allowing the palladium to be situated syn to the `enophile'.Additional useful functionality was incorporated into the molecule when the cyclised alkylpalladium intermediate was trapped1 with carbon monoxide instead of undergoing a b- elimination termination step. The trans disposed C-glycoside 7 was converted (Scheme 4) into the cyclised carboxylic acid product (isolated as the methyl carboxylate derivative 8) by Pd2(dba)3CHCl3/trio-o-tolylphosphine catalysis (dba= di- benzylideneacetone) in acetic acid at 46 8C in the presence of carbon monoxide (1 atm).Interestingly, similar treatment of 3 under prolonged reac- tion conditions produced only unreacted starting material (Scheme 4). This phenomenon can best be ascribed to a decrease in the electron density at the metal centre caused by the strong p-acceptor properties of the CO ligand, J.Chem. Research (S), 1998, 60¡¾61 J. Chem. Research (M), 1998, 0411¡¾0422 O OAc AcO AcO O OAc AcO OAc O OAc AcO CE2 i,ii iii E = CO2Et 1 2 3 O OAc O OAc AcO OAc O OAc AcO CE2 vi.viii iii 5 6 7 AcO OBut v O OAc H H E E 4 iv iv 1 2 3 4 5 6 7 8 9 Scheme 2 Reagents and conditions: i, water^1,4-dioxane, reflux; ii, Ac2O, py (1to 2; 93%); iii, diethyl allylmalonate, NaH, Pd(PPh3)4, THF (90%); iv, Pd(PPh3)4, HOAc,70 8C (83^89%); v,ButOH, BF3Et2O,THF (75%); vi, K2CO3,MeOH (99%); vii, PPh3, HOAc, DEAD,THF (93%); viii, Ac2O, ZnCl2, CH2Cl2Cl2, 0 8C (85%) O OAc CE2 Pd AcO L n O OAc CE2 Pd AcO L n Scheme 3 O OAc AcO CE2 E = CO2Et 3 O OAc AcO CE2 7 O OAc H H E E i i,ii H CO2Me 8 Scheme 4 Reagents and conditions: i, Pd2(dba)3CHCl3, tri-o-tolylphosphine, CO (1atm), HOAc, 46 8C; ii, CH2N2^diethyl ether, CH2Cl2, 0 8C (7 to 8; 80%) *To receive any correspondence. 60 J. CHEM. RESEARCH (S), 1998thereby suppressing p-allylpalladium complex formation.16 As a consequence, the rate of trans±cis isomerisation so dramatically decreased and only the trans substituted allyl acetate 7, which has favourable relative stereochemistry, undergoes cyclisation±carbonylation.Finally, cyclisation±carbonylation of the enyne 11 (Scheme 5) under the above reaction conditions proceeded faster17 with the alkyne `enophile', as compared to the alkene `enophile', to furnish 12, after diazomethane methyl- ation, in a high yield. In conclusion, we believe that this facile palladium cata- lysed preparation of chiral, functionalised 5,6-bicyclic sys- tems will be of value in the preparation of intermediates for the synthesis of polycyclic natural products.Furthermore, attention is drawn to the importance of paying due con- sideration to the relative stereochemistry of a precursor when planning and executing a palladium catalysed cyclisa- tion±carbonylation reaction. We are grateful to AECI (Ltd) and the Rand Afrikaans University for ®nancial support.Techniques used: NMR (1H, 13C and ROSY), ms, polarimetry Schemes: 5 References: 21 Received, 2nd September 1997; Accepted, 6th October 1997 Paper E/7/06399G References cited in this synopsis 1 Reviews: (a) W. Oppolzer, Pure Appl. Chem., 1990, 62, 1941; (b) W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1989, 28, 38; (c) W. Oppolzer, In Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 5, p. 29. 2 Further examples include: (a) J.-F. Nguefack, V. Bolitt and D. Sinou, J. Org. Chem., 1997, 62, 1341; (b) J.-F. Nguefack, V. Bolitt and D. Sinou, Tetrahedron Lett., 1996, 37, 59. 3 C. W. Holzapfel, G. J. Engelbrecht, L. Marais and F. Toerien, Tetrahedron, 1997, 53, 3957. 4 Preliminary results on a part of this work: G. J. Engelbrecht and C. W. Holzapfel, Tetrahedron Lett., 1991, 32, 2161. 13 The acetic acid is thought to promote the reaction by protonation of the acetate ligand, thereby facilitating the formation of a cationic ( 3-allyl)palladium complex, a key inter- mediate in these reactions: E. Go mez-Bengoa, J. M. Cuerva, A. M. Echavarren and G. Martorell, Angew. Chem., Int. Ed. Engl., 1997, 36, 767. 14 (a) W. Oppolzer and J.-M. Gaudin, Helv. Chim. Acta, 1987, 70, 1477; (b) W. Oppolzer, Pure Appl. Chem., 1988, 60, 39. 16 L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules, University Science Books, Mill Valley, USA, 1994, 23. 17 This observation has been previously made, see: W. Oppolzer and J. Ruiz-Montes, Helv. Chim. Acta, 1993, 76, 1266. O AcO AcO O AcO OAc O AcO CE2 i,ii iii E = CO2Et 9 10 11 O H H E E iv,v CO2Me 12 Scheme 5 Reagents and conditions: i, ButOH, I2,THF, reflux (70%); Ac2O, ZnCl2 (90%); iii, dimethyl prop-2-ymylmalonate, Pd(PPh3)4, NaH, THF (50%); iv, Pd2(dba)3CHCl3, tri-o-tolylphosphine, CO (1atm), HOAc, 46 8C; v, CH2N2-diethyl ether, CH2Cl2, 0 8C (11to 12, 65%) J. CHEM. RESEARCH (S), 1998 61