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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 -deficient nature of , direct nucleophilic addition is Postdoctoral Associate (A.I. Meyers), Colorado State University, 1977-1979 difficult without activating the in some fashion. This review will cover the use of acylating agents to activate the ring -- and the -- to nucleophilic addition. Reviews on Related Topics Other stratgies for activating the ring (which will not be covered in this review) include N-, N-fluorination, N-sulfonation, N-oxidation, and N-. 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-, subsequent nucleophilic addition, and further A review covering catalytic enantioselective methods of addition to : T. functionalization reactions can rapidly produce stereochemically and functionally Vilaivan, W. Banthumnavin, Y. Sritana-Anant. Curr. Org. Chem. 2005, 9, 1315. complex systems. This review will emphasize asymmetric methods for functionalizing pyridines.

Be sure to review the previous Baran Lab group seminar on a related topic, " and " (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 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 R or 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 2. PhOCOCl R2 R2 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 enolates yield somewhat lower regioselectivity (typically 70:30 mixtures of Cl CN 57% 1:2 at best) than the corresponding 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' 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 - 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 and 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. J. Am. Chem. Soc. 1993, 115, 8851.

Cl LDA, ZnCl2 92%, 96% de (+)-Cannabisativine N N Et2O/THF O o CO2R* -78 C CO2R* OMe OZnCl Me TIPS 89% TIPS MeONHMe-HCl R* = (-)-8- 92%de + O H phenylmenthyl 85% O AlMe3, CH2Cl2 Cl O Et N N Et >95% de H 97% O O Et Et CO2R* CO R* O TIPS 1,1'-carbonyl TIPS 2 O OH -diimidazole 30% HBr/AcOH R* = (+)-TCC O Et3N, THF CH2Cl2 O N Me N H ∆ rt, 24 h TIPS 91% TIPS O 92% O Li C3H7 Me O O Me 96% N N N H O O H OH CO2R* OMe OH CO2R* O O MgCl Me LDA, then O O Me N CuBr, BF -OEt Me N 3 2 Cl TIPS NaH TIPS 81%, 95% de NaBH4 O OH THF, rt OH H O O O O Me CeCl3 O N NTf2 96% N 88% N OTf >95% de H H O OH CO2R* O H2, Pd/C

Me N Li2CO3, EtOAc Me N Notice selectivity for The other possible 77% O O over enone in this system. is not observed. O O Me over 2 steps O O Me O O J.T. Kuethe and D.L. Comins. J. Org. Chem. 2004, 69, 5219.

6 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

(+)-Cannabisativine (cont'd) 1. KOH/MeOH O BnO H 2. BnO H H 1. benzyl trichloro- O H TIPS acetimidate, CO2Me COCl N 100% N OH H TfOH (cat.) C5H11 C5H11 86% BnO H H O H O N 2. H , Pt/C O O 2 N H O 97% C H 5 11 O O 3. 1:1 TFA/CHCl H 3 H O BnO H 1. 50% KOH 77% O BnHN N NBn MeOH, reflux OH C5H11 88% H O O O OTMS 10% NaOH/CH2Cl2 O 2. TsHN OTf 82% LiHMDS, PhSe PhSe Hunig's OMe then PhSeCl BnO H BnO H H CH2Cl2 OH CO2Me 84% 73%, N N C H BF3-OEt2 C H 3.5:1 mixture 5 11 100% 5 11 of diasteromers H O H O O O OBn O 1. MsCl OBn H H Et3N C5H11 N NBn 95% C5H11 N OH OH H H O OH 2. K2CO3 OH PhSe PhSe NBn NaBH4 MeCN H H CeCl3 BnO H BnO H reflux CO2Me + CO2Me NHTs 70% NTs N N C5H11 C5H11 OH H O H O O 65% O 20% In both diastereomers, addition occurs on the face opposite the bulky SePh group. For the next step, both diastereomers will be carried through separately. OH H

C5H11 N S S Na/NH3 H O OH 76% NH O N O N 1. S N N PhSe PhSe NH Im Im BnO H H BnO H H 2. Bu SnH CO2Me + CO2Me 3 (+)-cannabisativine AIBN N N C5H11 C5H11 85% H O H O O O J.T. Kuethe and D.L. Comins. J. Org. Chem. 2004, 69, 5219.

7 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

(+)-Luciduline OH O OMe O 1. Dess-Martin MgCl H H TIPS TIPS 1. NaOMe 99% Me MeOH 2. 5% Pd/C 80% 2. 10% HCl MeOH N Me N Me N Me N Cl other diastereomer 90%, two H Cbz H2, formalin H Me not observed steps CO2R* CO2R* 95% (+)-luciduline R* = (+)-TCC CO2Me D.L. Comins, C.A. Brooks, R.S. Al-awar, R.R. Goehring. Org. Lett. 1999, 1, 229. O O 1. cat. OsO4, O n-BuLi, then NaIO4 BnOCOCl 84% Comins' group has synthesized a number of other using his chiral acylpyridinium methodology, including: 2. CO2Me Me N Me N Me N O OH H Cbz Cbz Me P(O)(OMe)2 N Me OH KOtBu, THF OH Me Me 89% OH CO2Me Me N 1. NaBH4 Me H2 Me N CeCl3 xylenes Pd/C CO2Me CO2Me o 2. MsCl, 140 C 99% (+)-benzomorphan (+)-allopumiliotoxin 267A (+)-elaeokanine C DMAP 21 h CbzN HN Me N D.L. Comins, Y.-m. Zhang, S.P. D.L. Comins, S. Huang, C.L. McArdle, D.L. Comins, H. Hong. J. Am. 98% Cbz 86% Joseph. Org. Lett. 1999, 1, 657. C.L. Ingalls. Org. Lett. 2001, 3, 469. Chem. Soc. 1991, 113, 6672. O O 1. LDA, O Me iPr2NH OMe B OMe H H H -50 oC CO2Me H OH NMe B H N H 2. TMSCl H H H N H H H Me N Me N Me Me H H N Me N OTMS Me Me 1. BnOCOCl Me H Ac CH2Cl2 CO2Me 1. DIBAL OMe reflux 75% plumerinine spirolucidine H H H (incorrect structure) (model studies) + 2. H3O 2. SnCl4, Et3SiH o D.L. Comins, X. Zheng, R.R. Goehring. D.L. Comins, A.L. Williams. toluene, -20 C Org. Lett. 2002, 4, 1611. Org. Lett. 2001, 3, 3217. 51% over Me N Me N 61% H TMS 4 steps H Cbz

8 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

(±)-Cylindrospermopsin (Snider, 2000) OTBS TMS TBSO OMe Pd/C, H2, MeOH MeO TrocCl, -30 oC, then O MgBr NCbz N N N NTroc Me TMS MgBr CuBr-SMe2, TMSCl Me Me o then H O+ workup -78 C OMe 3 87% NHBn 92% OTBS Again allylic (1,3) strain favors axial attack 1. BrCN, OR and formation of the cis isomer. TBSO OMe 2. NaH, CbzCl, THF 1. L-Selectride 45%, 3 steps N O O Zn/AcOH -78 oC NH N N Me Me NH TMS O Me 2. NaOH/EtOH, OMe reflux NH2 Acidic deprotection conditions catalyze 90% OTBS TMS epimerization to the all-equatorial isomer. over 3 steps 1. TBAF (83%) TBSO OMe 2. MnO , CH Cl (87%) H H 2 2 2 OH 1. CbzCl, HO Na CO TBSO N N N 2 3 Me N ≡ 96% Cbz Me H NH NH NCbz NCbz OMe Me 2. TBSCl, Me O DMAP, HO OMe Ac O, pyridine 89% 2 1. EtMgBr, 0 oC, then N N N 87% OHC OMe Me N OTBS Cbz NCbz OMe OMe N N O TBSO 1. CuBr2, EtOAc, rt, 30 min N N O3, DMS AcO OMe OMe 83% 2. H2, Pd(OH)2/C, MeOH NCbz CH2Cl2 2. TBSCl, imidazole, Me OMe -78 oC N N N DMAP, CH Cl Me N 2 2 72% Cbz 88% NCbz OMe OTBS OH OH H H H H OMe 1. NH2Bn, AcOH AcO OMe AcO OMe 2. NaCNBH3 TBSO 68%, 2 steps + N N N NH N N N NH N N Me Me NCbz H H Me OMe NH 42% OMe NH OMe (desired) 28%

O C. Xie, M.T.C. Runnegar, B.B. Snider. J. Am. Chem. Soc. 2000, 122, 5017.

9 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

(±)-Cylindrospermopsin (Snider, 2000), cont'd. Charette's Chiral Auxiliary for 1,2-Addition OH OH Andre Charette and coworkers at the Universite de Montreal have developed a new H H H H AcO OMe conc. HO O chiral auxiliary which can direct enantioselective addition to unsubstituted HCl pyridinium rings. This relies on an E-imidate species where the directs the addition of organometallics to the C2 position with high regioselectivity: N NH N N 100 oC N NH N NH Me Me 6hr 1. Tf2O, H H O R NH OMe 95% NH OH

Ph NHMe R N + OH H H o R N N SO3-DMF N 2. RMgX, -78 C Mg pyridine O3SO O N Ph Me N Ph N Ph DMF N NH N NH rt, overnight Me the Z-imidate Me Me H 50-70% NH OH is NOT observed Major Treatment of the dihydropyridine with DDQ in THF at room temperature will (±)−cylindrospermopsin regenerate the aromatic pyridine, now with a C2 substituent.

C. Xie, M.T.C. Runnegar, B.B. Snider. J. Am. Chem. Soc. 2000, 122, 5017. Charette also developed a chiral version of the imidate, based on valinol, which exhibits robust regio- and diastereoselectivity.

blocked by R O iPr group Tf2O RM N + + Ph NH blocked by ONLY Ph group N R N N PERMITTED Ph N APPROACH

OMe Ph NR* Ph NR* 10 11 OMe

A.B. Charette, M. Grenon, A. Lemire, M. Pourashraf, J. Martel. J. Am. Chem. Soc. 2001, 123, 11829.

10 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

Wanner's Chiral Auxiliary for 1,2-Addition STRATEGIES FOR ASYMMETRIC 1,4-ADDITION

Klaus Wanner has developed an alternative chiral auxiliary for diastereoselective All strategies reported to date for asymmetric 1,4-addition also involve use of chiral additions to acylpyridiniums. He has found that using silyl triflate additives allow auxiliaries, with auxiliaries installed at C3 to direct diastereoselective addition to access to electron-deficient pyridines, although the diastereoselectivities and yields C4. are more modest in these cases than those explored by Comins and Charette. Meyers' Chiral Auxiliary Me Me O R Ph OMe OEt Me N R CN AcCl, EtOH R 8 HO NH2 NH2 Me Me O Et N O O 0 oC --> -15 oC 3 SiMe2Ph Cl 1,2-DCE Me RM N 92% N N CO2Me reflux, 24 h 79% Me Me O R O O SiMe2Ph Ph TfO Me CO2Me N 9 Ph Me O major O O O o R SiMe2Ph MeLi, -78 C, N OMe R then MeOCOCl CO2Me N OMe Ph N R = H, CO2Et, CO2Me N CONH2 Me O 65-80%, R 95:5 de N OMe

minor N CO2Me Intriguingly, Meyers elaborates this enantiopure dihydropyridine into a mimic of the biological reductant NADH that enantioselectively reduces methyl mandelate: C.E. Hoesl, M. Maurus, J. Pabel, K. Polborn, K. Th. Wanner. Tet. 2002, 58, 6757. Me R OH

O N OH Bn 30-60%, 88-95% ee Ph CO Me Ph CO Me 2 Mg(ClO4)2 2

A.I. Meyers, T. Oppenlaender. J. Am. Chem. Soc. 1986, 108, 1989.

Asymmetric reductions with chiral dihydropyridines are beyond the scope of this review. Interested readers should consult the following for an introduction to the field: V.A. Burgess, S.G. Davies, R.T. Skerlj. Tet. Asymm. 1991, 2, 299.

11 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

Mangeney and coworkers have constructed a similar auxiliary with the C3 : The geometry of the chiral auxiliary is such that one face of the pyridine ring interacts more strongly with with benzyl ring, resulting in a more stable π-stacking R1 intermediate which is then attacked by a nucleophile from the opposite face: Ph Ph R1M, then R COCl yields = 70-90% N 2 N Nu N N 1,4-addn:1,2-addn = 4:1 to 19:1 O Re MeO2C O Ph de = 32% to 95%, typically 90% N Si N Ph N N Si N Re N product MeO2C O O R2 O P. Mangeney, et al. J. Org. Chem. 1994, 59, 1877. Yamada's Chiral Auxiliaries 2.1 kcal/mol more stable Shinji Yamada has developed two different chiral auxiliaries which achieve high by ab initio calculations diastereoselectivity. One operates via an unusual π-cation interaction to shield one face of the pyridine from nucleophilic attack: S. Yamada, C. Morita. J. Am. Chem. Soc. 2002, 124, 8184. O Me Me Nu O Me Me Yamada has applied a similar chiral auxiliary to a formal synthesis of the serotonin 1. ClCO2Me reuptake inhibitors (-)-paroxetine and (+)-femoxetine. N O N O 2. nucleophile F N N Ph Ph O S CO Me 2 PhCOCl, then NaOMe yields = 56-90%, typically 70% N S O S (C6H4F)2CuLi2Br CH2Cl2 1,4-addn:1,2-addn = ~9:1 o rt, 3 h N -70 C N S de > 99% Ph 71% 78%, >95% de Acylation of the pyridine induces π-stacking, due to a π-cation interaction between N the benzyl ring and the pyridinium, as seen in X-ray crystal structures: COPh Ph

F F

O OMe

O O O O + OMe π-stacking N N N H H H (-)-paroxetine (+)-femoxetine pyridinium salt (N-methyl) unacylated pyridine S. Yamada, I. Jahan. Tet. Lett. 2005, 46, 8673.

12 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

Shibasaki's Chiral Catalyst Shibasaki has elaborated one of these substrates asymmetrically into CP-293,019:

Shibasaki and coworkers have developed an aluminum-based catalyst with BINOL- O like chiral for the enantioselective 1,2-addition of cyano groups to , O OH , and pyridines. NMe 2 N Z O Z O N TMSCN (2.0 eq), NC N N N R'OCOCl (1.4 eq) BocN R R O OMe N F Et2AlCl (5-10 mol%), intercepted F N catalyst (10 mol%), NC N intermediate CP-293,019 o CH2Cl2, -60 C Shibasaki's group has also applied this method to quinolines and isoquinolines, which are unfortunately beyond the scope of 5-36 hr O OR' this review. Interested readers may find a discussion of Shibasaki's work with these systems here: M. Takamura, et al, J. Am. Chem. Soc. 2000, 122, 6327; K. Funabashi, et al., J. Am. Chem. Soc. 2001, 123, 10784; M. Takamura, et al., J. Am. Chem. Soc. 2001, 123, 6801.

Interested readers may also find a recent report from Eric Jacobsen's laboratory describing another catalyst for enantioselective additions into isoquinolines: M.S. Taylor, N. Tokunaga, E.N. Jacobsen. Angew. Chem. Intl. Ed. Eng. 2005, 44, 6700.

E. Ichikawa, et al. J. Am. Chem. Soc. 2004, 126, 11808.

Et P S O S OH Et OH

OH Et OH S O P S Et

catalyst 3 catalyst 6

13 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

ACTIVATION OF ACYL GROUPS BY PYRIDINE SPECIES

Pyridines, of course, are excellent activating agents for nucleophilic addition into acyl groups, particularly the venerable catalysts 4-(dimethylamino)pyridine (DMAP) Me2N and 4-pyrrolidinopyridine (4-PPY). Their utility in organic synthesis has already been detailed in a number of comprehensive reviews and will not be discussed here. N Fe For representative reviews of DMAP and 4-PPY chemistry, see: Ph Ph R. Murugan, E.F.V. Scriven. Aldrichimica Acta 2003, 36 (1), 21. Ph Ph D.J. Berry, et al. ARKIVOC 2001 (i), 201, or at http://www.arkat-usa.org/ark/journal/ 2001/I01_General/401/review.pdf U. Ragnarsson, L. Grehn. Acc. Chem. Res. 1998, 31, 494. Ph In recent years there has been a growing interest in developing chiral pyridine analogs of DMAP and 4-PPY for enantioselective transformations. A few of these transformations are discussed below. N Nonenzymatic Kinetic Resolution of Racemic Secondary N Fe A number of groups have developed pyridine-based catalysts for the kinetic Ph Ph resolution of racemic secondary alcohols. Perhaps the first truly successful strategy, the first to match the enantioselectivities of the esterases, was a Ph Ph stoichiometric acylpyridinium species developed by Vedejs and Chen: Ph

NMe Fu's chiral planar 2 catalysts O Me Me Cl J.C. Ruble, H.A. Latham, G.C. Fu. J. Am. Chem. Soc. 1997, 119, 1492 (sec-alcohols); B. Tao, et al. J. Am. Chem. Soc. 1999, 121, 5091 (propargylic alcohols); S. Arai, S. Bellemin-Laponnaz, G.C. Fu. Angew. Chem. Intl. Ed. Eng. 2001, 40, 234 (). tBu O O CCl3 OH Me Me N Fu has demonstrated the enantioselective powers of these catalysts in a number of contexts. For reviews and other references, OMe consult his two recent accounts of his research: Acc. Chem. Res. 2000, 33, 412; Acc. Chem. Res. 2004, 37, 542. Me Me Cl3C O O 94% ee, Other catalysts have been developed in recent years, with variable results and 28% conversion enantioselectivities: Lewis acid, 2 eq (out of 50% base, 3 eq theoretical maximum) H Me E. Vedejs, X. Chen. J. Am. Chem. Soc. 1996, 118, 1809. N OH Me NEt Greg Fu and colleagues took this work a step further, deploying his planar chiral N 2 H pyridine catalysts in the kinetic resolution of alcohols and amines, to excellent effect: N Ph Co Ph

O Ph N Ph Ph Ac2O, N OH OH O catalyst (2 mol%) + 80-95% ee 30-85% ee 75% ee Ru Ra NEt3, Et2O, rt Ru Ra Ru Ra T. Kawabata, et al. J. Am. A.C. Spivey, et al. J. Chem. H.V. Nguyen, D.C.D. Butler, C.J. Chem. Soc. 1997, 119, 3169. Soc. Perkin Trans. 1 2001, 1785. Richards. Org. Lett. 2006, 8, 769.

14 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

C-Acylation and Asymmetric Synthesis of Quaternary Centers This also works on acyclic enol substrates:

Several groups have exploited activated acylpyridiniums for use in forming new OTMS Ac2O, catalyst (5 mol%) O O quaternary centers asymmetrically. Vedejs and coworkers have extended their Ph pyridine catalysts in such a way with oxindole substrates: OiPr toluene/CH2Cl2 Me OiPr 24 h, rt Et Ph NMe2 OAc Et 95%, 85%ee A.H. Mermerian, G.C. Fu. J. Am. Chem. Soc. 2005, 127, 5604. Me CPh3 O Me CO2Ph The mechanism proceeds through an N-acetylpyridinium intermediate which is then N 1 mol% attacked by the unmasked enolate to form the 1,3-dicarbonyl compound. O OPh O 92%, 92% ee O O N Et2O, rt N O O Me Me Me OiPr S.A. Shaw, P. Aleman, E. Vedejs. J. Am. Chem. Soc. 2003, 125, 13368. Me O Me Et Ph Fu's Asymmetric Method for 1,3-Dicarbonyl Compounds

Fu and coworkers have also applied his planar chiral pyridine catalysts to a OTMS bewildering array of reactions, based on addition of the pyridine catalyst into either a or an acyl ester or anhydride. O Ph O O OiPr Ph Et N Me N O Me N OiPr + + - TMSOAc Et O N Fe R O Me R Me Me A.H. Mermerian, G.C Fu. J. Am. Chem. Soc. 2003, 125, 4050. BnO O O Me Me Fu has demonstrated that silyl ketene imines are also are substrates of this reaction, m BnO2C 2 mol% Me as seen in a brief enantioselective total synthesis of the drug verapamil: O O o N 0 C N Ar 94%, 91% ee Ar 1. LDA, then O J.C. Ruble, G.C. Fu. J. Am. Chem. Soc. 1998, 120, 11532. O O NC Fu has also found this catalyst useful for intermolecular couplings of acyl groups TBS O Br and silyl enol to produce 1,3-dicarbonyl compounds. C N OMe 80% 2. LDA, TBSCl OSiR3 O O MeO Ac O, OMe 100% Ph 2 O catalyst (10 mol%) Me O MeO Ph Me 80%, 90% ee Me A.H. Mermerian, G.C. Fu. Angew. Chem. Intl. Ed. Eng. , 44, 949. Me Me 2005 A.H. Mermerian, G.C Fu. J. Am. Chem. Soc. 2003, 125, 4050.

15 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

O The mechanism apparently proceeds through an N-acylpyridinium zwitterion: O O O catalyst, 5 mol% O CN catalyst, 10 mol% NTf TBS Ac2O Me C C N Ph C6F6, rt CH2Cl2 or toluene Ph Me Ph Me O OMe MeO O OMe MeO 72%, 81%ee NTf O O NTf Me H Ph 1. MeMgBr Me 2. [Ph(CF ) CO]SPh CN N 3 2 2 Me N Ph 63%, 2 steps 1. oxalic acid Ph Ph Me 2. NaBH(OAc) , 3. H2, Pd/C O OMe 3 96% E.C. Lee, et al. J. Am. Chem. Soc. 2005, 127, 11586. NHMe This method has also been extended to : O OMe MeO O O 71%, O C O catalyst, 5 mol% MeO 2 steps Et Me THF, -78 oC Ph Et Et H Ph Et CN Me 91%, 92%ee OMe J.E. Wilson, G.C. Fu. Angew. Chem. Intl. Ed. 2004, 43, 6358. MeO OMe MeN

OMe (S)-verapamil

A.H. Mermerian, G.C. Fu. Angew. Chem. Intl. Ed. Eng. 2005, 44, 949.

Fu's pyridine catalyst will also induce the following transformation of :

O O O NTf NTf C NTf catalyst, 10 mol% + Ph Ph CH Cl or toluene Ph Ph Me Ph H Ph 2 2 Me Me 98 : 2 83%, 81%ee

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