Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin 1,4-addition A Big Player in The Acylpyridinium Field 1,2-addition 1,2-addition N O R acyl transfer 1,4-addition 1,2-addition acyl transfer Nu* O * * * N Nu Prof. Daniel Comins N * R Nu* N North Carolina State University O R * * O R B.S., SUNY Potsdam, 1972 Ph.D. (Robert Lyle, advisor), University of New Hampshire, 1977 Despite the electron-deficient nature of pyridines, direct nucleophilic addition is Postdoctoral Associate (A.I. Meyers), Colorado State University, 1977-1979 difficult without activating the pyridine in some fashion. This review will cover the use of acylating agents to activate the ring -- and the acyl group -- to nucleophilic addition. Reviews on Related Topics Other stratgies for activating the ring (which will not be covered in this review) include N-alkylation, N-fluorination, N-sulfonation, N-oxidation, and N-amination. The chemistry of N-alkylpyridiniums is not covered in this seminar. For a For an overview of this chemistry, see Joule and Mills' Heterocyclic Chemistry, 4th representative review, see: J. Bosch, Bennasar, M.-L. Synlett 1995, 587, and Edition (2000), Chapters 4-5. references therein. Notice that N-acylation, subsequent nucleophilic addition, and further A review covering catalytic enantioselective methods of addition to imines: T. functionalization reactions can rapidly produce stereochemically and functionally Vilaivan, W. Banthumnavin, Y. Sritana-Anant. Curr. Org. Chem. 2005, 9, 1315. complex piperidine systems. This review will emphasize asymmetric methods for functionalizing pyridines. Be sure to review the previous Baran Lab group seminar on a related topic, "Iminium and Pyridinium Photochemistry" (J. Richter, 2005). 1 Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin ADDITION OF NUCLEOPHILES INTO 1-ACYLPYRIDINIUM SALTS A. Regioselectivity of Addition 800 g scale! Addition of Grignards into 1-acylpyridinium salts with unsubstituted C2 and C4 positions results in mixtures of C2- and C4-substituted dihydropyridines. 1,2- addition is typically favored, although selectivity is not large. 1,4-addition is favored if either the nucleophile R or acyl chloride R' is sterically demanding. Use of organocuprates, however, strongly favors 1,4-addition, as seen below: R 1. RMgX + N N R N 2. R'COCl O R' O R' O R' 3 4 No Copper Additive With 5% CuI G.N. Boice, et al. Tet. Lett. 2004, 60, 11367. Titanium enolates also strongly favor 1,4-addition: O R Me 1. R2 R1 H R OM N R + 1 R2 R2 2. PhOCOCl Me R1 N O N R H D.L. Comins, A.H. Abdullah. J. Org. Chem. 1982, 47, 4315. Me O OPh O OPh Process chemists at Merck have applied this method on a process scale: PhOCOCl 1 2 CuI, THF CO2Ph N N -10 oC, then M = Li --> 50:50 (1:2) M = Ti --> 70:30 to 98:2, typically 90:10 (1:2) MgCl Ester enolates yield somewhat lower regioselectivity (typically 70:30 mixtures of Cl CN 57% 1:2 at best) than the corresponding ketone enolates. Cl CN D.L. Comins, J.D. Brown. Tet. Lett. 1984, 25, 3297. 2 Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin Certain nucleophiles - allyltin, allylindium, and alkynyl Grignard reagents - will OZn undergo 1,2-addition regioselectively. For example: SnMe3 Cl OEt SnMe3 Cl Cl Me then methyl chloroformate oxalic acid BrMg O Me O N THF N THF-water N -78 oC MeO2C CO2Et MeO2C CO2Et Me N Cl THF Me N o CO Me D.L. Comins, J.D. Brown. Tet. Lett. 1986, 27, 2219. CO2Me 0 C, 1.5 h 2 O O 89%, no 1,4-adduct Comins has employed this blocking method in an elegant synthesis of lasubine II: OMe O 1. BnOCOCl MgBr H Cl Me N 2. OMe 4 steps, CuBr(SMe)2 N BrMg OMe N 32% overall yield BF3-OEt2 Bu Cbz o OMe THF, -78 C (±)-monomorine I 75% OMe R. Yamaguchi, E. Hata, T. Matsuki, M. Kawanisi. J. Org. Chem. 1987, 52, 2094. axial addition favored O for 1,2-addition of allylstannanes see: R. Yamaguchi, M. Moriyasu, M. Yoshioka, M. Kawanisi. J. Org. Chem. 1985, 50, 287; and T.G.M. Dhar, C. Gluchowski. Tet. Lett. 1994, 35, 989. to avoid 1,3-allylic strain for 1,2-addition of allylindium reagents see: T.-P. Loh, P.-L. Lye, R.-B. Wang, K.-Y. Sim. Tet. Lett. 2000, 41, 7779. O O Ar OMe Generally, however, forcing 1,2-addition requires use of blocking groups or BzO N N substituents at the C4 position. O N Ar H Cbz 1,3-allylic strain O OMe OBz H Cl MgCl Cl Cl Cl 56%, de > 96% o-chloranil O OH Cl N THF N N H2 LS- o Selectride -78 C Pd/C OMe OMe N O OPh O OPh o N 42% Li2CO3 -78 C over 2 steps 82% 81% OMe OMe D.L. Comins, N.B. Mantlo. J. Org. Chem. 1985, 50, 4410. (±)-lasubine II J.D. Brown, M.A. Foley, D.L. Comins. J. Am. Chem. Soc. 1988, 110, 7445. 3 Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin STRATEGIES FOR ASYMMETRIC 1,2-ADDITION Me Me Comins' Chiral Auxiliary for 1,2-Addition Me Me Comins has developed a chiral acylating group which directs the stereoselectivity of OH OH 1,2-additions into the pyridinium ring. This group, when employed on a 3-silyl-4- Me methoxypyridine, permits highly diastereoselective 1,2-additions. (-)-trans-2-(α-cumyl)cyclohexanol (TCC) (-)-8-phenylmenthol 1. R*OCOCl OMe O O see reference below for route commercially available 2. RMgX for preparing enantiopure auxiliary, see: D.L. Comins, Y.C. Myoung. J. Org. Chem. , 55, 292. TIPS + TIPS TIPS 1990 3. H3O + Deprotection of either the TIPS group or the auxiliary is straightforward: N R N R N CO R* CO2R* 2 O major diastereomer major diastereomer TIPS with (-)-auxiliary with (+)-auxiliary H2, Pd/C This substrate has been chosen carefully to maximize diastereoselectivity. The rt bulky TIPS group directs addition to C over C , and the C -methoxy group blocks 1 h R N 6 2 4 H C4 addition. The chiral auxiliary blocks access to one face of the pyridinium salt. Me O O blocked by TIPS TIPS Me TIPS NaOMe/MeOH O N O reflux R N OMe TIPS 8 h H permitted approach back face blocked by aryl group O R N CO2R* 30%HBr/AcOH 0 oC --> rt R N 2 hr CO2R* O NaOMe/MeOH, reflux, 8 h; then oxalic acid, rt, 2 h R N H D.L. Comins, S.P. Joseph, R.R. Goehring. J. Am. Chem. Soc. 1994, 116, 4719. D.L. Comins, S.P. Joseph, R.R. Goehring. J. Am. Chem. Soc. 1994, 116, 4719. 4 Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin This strategy can also be applied to the 1,2-addition of enolates to define two The postulated transition state for E-enolate addition, yielding anti-stereochemistry: asymmetric centers with anti-stereochemistry: ClZnO O Me OMe O TIPS TIPS Me TIPS Me Me O N H H Cl Me O N THF/toluene N ClZn o H OMe -78 C R CO R* CO2R* 2 O R Me 83% isolated D.L. Comins, J.T. Kuethe, H. Hong, F.J. Lakner. J. Am. Chem. Soc. 1999, 121, 2651. D.L. Comins, J.T. Kuethe, H. Hong, F.J. Lakner. J. Am. Chem. Soc. 1999, 121, 2651. Interestingly, the pyrrole and indole anions can be used as nucleophiles as well: Good enolate facial selectivity is observed: OZnCl O N TIPS MgBr O O O TIPS 74% N Me Me CO2Bn Me H OMe N O H E-enolate Me N H TIPS OMe O CO2R* O Cl TIPS N 9:1 anti O CO Bn Cl 2 TIPS N Zn O O N CO2R* MgBr OBn TIPS N H 72% NH CO2Bn OBn BnO N H Z-enolate BnO CO2R* (also 8% of the C3- O pyrrole adduct) 4:1 syn D.L. Comins, J.T. Kuethe, H. Hong, F.J. Lakner. J. Am. Chem. Soc. 1999, 121, 2651. J.T. Kuethe, D.L. Comins. J. Org. Chem. 2004, 69, 2863. 5 Baran Lab T h e C h e m i s t r y o f 1 - A c y l p y r i d i n i u m s D. W. Lin Applications to Total Synthesis 1. TsOH KOH 2. Na CO Comins and coworkers have applied this chiral auxiliary methodology in a number 2 3 EtOH Me N of elegant, imaginative total syntheses. H 66% Me N reflux O (-)-porantheridine 48 h OH Me 85% O O OMe O O (-)-porantheridine 1. K-Selectride TIPS TIPS O 2. Na2CO3/MeOH D.L. Comins, H. Hong.