The First Catalytic, Asymmetric Α-Additions of Isocyanides. Lewis-Base-Catalyzed, Enantioselective Passerini-Type Reactions
The First Catalytic, Asymmetric a-Additions of Isocyanides. Lewis-Base-Catalyzed, Enantioselective Passerini-Type Reactions
Scott E. Denmark, and Yu Fan
Roger Adams Laboratory Department of Chemistry University of Illinois Isocyanides in Organic Chemistry
I + AgC N • Only functional moiety with a formally divalent carbon atom which provides a unique pattern of chemical reactivity. • Ally isocyanide, the first synthetic isocyanide, was generated in 1859 by Lieke from allyliodide and silver C N cyanide. R • Modern preparation of isocyanides usually entails the dehydration of phosgene, Et3N formamides with numerous reagents or POCl3, i-Pr2EtN H N H R O The Passerini Reaction
H O O O O a-addition + + 3 H 2 R N C R1 O R2 H R1 O R H
R1 O R2 3 O O H R Mumm Rearrangement H 1 N 3 N R O * R O H O R2
a-adduct a-acyloxycarboxamide The Ugi Reaction
R1 O R1 O H R1 + H2O N + O N NH H + 4 2 R2 H R3 O 2 R N C R2 H R3 O R H
R3 O R2 4 O O H a-addition R Mumm Rearrangement N N H R3 N * R4 N 1 H 1 R O R2 R a-acylaminocarboxamide a-adduct Synthesis of (+/-) hydrastine
O NC O O O O N + HN O Me O O O O O
O OH MeO OMe MeO MeO OMe O MeO Hydrastine
Falck, J. R.; Manna, S. Tetrahedron Lett. 1981, 22, 619-620. Synthesis of Azinomycin A, B
O
2 R O O R O R2 H H N O O H MeO O N 3 N 1 O + R O R O H + CN R1 O AcO R3 OH N Me HO azinomycin A R = H azinomycin B R = CHO
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131 Synthesis of Eurystatin A
NHCbz Me O O O H + O FmocHN FmocHN OH N R HN HN O BocHN H O Me O O O O NH O + BocHN O
O Eurystatin A: R = Me N C Eurystatin B: R = Et O CbzHN
Owens, T. D.; Araldi, G.-0L.; Nutt, R. F.; Semple, J. E. Tetrahedron Lett. 200142, 6271-6274. Some diastereoselective approaches to the a-addition of isocyanates in Passerini and Ugi chemistry
Camphor-2-cis-methilidene-isocyanide
NH Effective auxilliary for the Passerini reaction H 2 a-ferrocenylalkylamines R Reported reaction yields of 84-96% Early chiral auxilliaries used in the Ugi reaction Reported %de 92-93% Fe provided poor product yields N Auxilliary was not effective in the Ugi reaction. modest diastereoselectivities C
Demharter, A.; Ugi, I. J. Prakt. Chem. 1993, 335, 244. Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 385-9.
1-amino-5-deoxy-5-thio-2,3,4-O- isobutonyl- D-xylopyrannose . HCl O b- Recenly applied chiral aulilliary for the O Ugi reaction O O S . NH2 HCl Reported reaction yields and %de of up O to 92% O
Simple removal with TFA and Hg(OAc)2 in methanol Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127-6133. Why have asymmetric variants of these reactions failed to develop?
• Following Lewis acid activation of the MXn O aldehyde and a-addition of the first O R2 N C R1 equivalent of isonitrile, additional R1 H N MXn R2 equivalents can add to the zwitterionic intermediate i… What a mess! i • In order for catalyst turnover to occur, cleavage of the bond between MXn and MX O n the product must be facile. Often not the case in a-additions. N 2 R • Asymmetric modification of Lewis ... acids often leads to deactivation with N respect to their unmodified counterparts. R2 Potential Solution: Lewis base activation of the Lewis Acid
d+ d- L X X L X L L d- d+ LL X - D + A D A D A X X L X L X L X Lewis Base Lewis Acid increased increased negative positive charge charge
• Gutmann’s 4th rule: “….although a donor-acceptor interaction will result in a net transfer of electron density from a donor species to an acceptor species, it will, in the case of polyatomic species, actually lead to a net increase or “pileup” of electron density at the donor atom of the donor species and to a net decrease or “spillover” of electron density at the acceptor atom of the acceptor species…” Advantages of the Lewis base activation of Lewis acids in the Passerini and Ugi reactions
MX O n • Nitrilium ion can capture the now O R2 N C dissociated halide ion following R1 R1 H N carbonyl activation and isonitrile MXn R2 addition i • The attenuated activity of the Lewis acid-substrate complex MXn-1 O OH should promote dissociation of the H N N R1 R2 R1 R2 complex and activation of a new X O molecule of SiCl4. Addition of Isocyanides to Benzeldehyde
1a = N C
4a = HMPA
4b = pyridine-N-oxide Reaction Scope I (modified isonitriles)
1a = N C
1b = N C
O C 1c = N O
N C 1d = S O O
4a = HMPA
4b = pyridine-N-oxide Reaction Scope II (modified aldehydes) Facile Conversion of Imidoyl Chlorides to Methyl Esters Summary and Conclusions
• The first catalytic, enantioselective a-additions of isocyanides to aldehydes has been described
• Activation of a weak Lewis acid with a chiral Lewis base was demonstrated to catalyze asymmetric Passerini-type reactions