Recent Advances in the Chemistry of Alleneamides. Denmark Group Meeting Nate Duncan-Gould

Transcription

1 Recent Advances in the hemistry of Alleneamides Denmark Group eting ate Duncan-Gould

2 allene The Structure allenamine ummulenes!!! X X X!!! X X

3 ummulene omparison of M s FM at PM3 level M LUM alculated Energy level (ev) M LUM

4 Stability of the Parent Allenamine 2 flash thermolysis 700 o, 10-5 torr 2 MR and IR (-195 to -80 o ) isolable as l salt Molar to mmolar conc. -65 o t 1/2 minutes polymer Ripoll, et al.,tl 1984, 25, 3459.

5 Representative Known, Isolable allenamides A F 3 F 3 X Representative Reactions Et! <20% Broggini, et al., J. hem. Soc. Perking Trans , 533. R Ac, 2 rt R >80% raig and Ekwuribe, TL 1980, 21, 533.

6 Representative ycloaddition Et, reflux l 41 l l 7 l l l l l 10 l l 6 Broggini & Zecchi, J. hem. Soc. Perkin Trans , Broggini & Zecchi, J. hem. Soc. Perkin Trans , 533.

7 chanistic Rationale

8 Stability: Substitution and Thermal tautomerization ~ o ften undistillable oils tautomerization toluene, o 1 h 92% Mayer & Maas, Synlett, 1990, 339. Kurtz, J. 1966, 31, 2955 llix, hem. omm. 1972, 556. verman, JAS, 1976, 98, Mayer & Maas, TL, 1992, 33, 205.

9 Proposed chanism 1,4-proton shift 1,7-electrocyclization 1,5-hydride shift

10 utline Recent Advances in Preparation Lithiation and Subsequent 1,2-addition reactions Exploring their stability / reactivity etero [4+2] (Tamaru & sung) [2+1] and subsequent reactions (Seebach & sung) [2+2] and subsequent reactions (Tamaru & sung)

11 Seebach 1,2-Addition: a chiral homoenolate In this arrangement, the arger substituent R1 on the -atom adopts an equatorial position elv. him. Acta 2002, 85, 963.

12 1,2-Additions and Subsequent Rxns egedus ~80%, (>95:5) Aliphatic, aromatic Able to with Boronic acids

13 sung 1,2-Addition: a chiral homoenolate TBAF TMS TBAF, TF R PPTS, 2 l 2 R TMS 25-60% 1:1 dr 1:1 dr J. rg. hem. 2005, 70, 4038.

14 Probing Reactivity/Stability with etero Diels-Alder reaction sung, et al. TL, 1999, 40, 6903.

15 omparison of Allenamide reactivity (31%, 64 h) Performance in hetero-diels-alder unreactive sung, et al. TL, 1999, 40, o 60 o 3-5 h 60 o 7 h

16 R Diastereoselective etero-da 80 o R 1. a. 9-BB b PG (Si, piv, Ac) 3. B 3 / 2 2 A ~60% overall R Solvent Effect: 3 = 5 h l 2 2 l = 15h Implying stepwise mechanism Lower dr with oxazolidinones PG TMS SnBr 4, 2 l 2-78 to rt, 20 h R PG R yield d.r : : :5 1-nap 74 94:6 y 19 95:5 -hex 50 95:5 >60% >12:1 dr sung et al., L, 1999, 1, sung et al., Synlett, 2003, 1241.

17 etero Diels-Alder Stereochemical Model

18 A new class of allenamide (Tamaru) Representative Preparations See: Tamaru et al. AIE, 1999, 38, 121. Tamaru et al. JAS, 1997, 119, Tamaru et al. hem. Eur. J., 2003, 9, 2419.

19 Structural Analysis R R S a: b: o-ts n: Et q:

20 chanistic ontinuum observed with aldehydes and ketones enone (20 equiv) 80 º, neat Ts [4+2] and [2+2] pdts Pdt distribution rationalized qualitatively by donating ability of substituents

21 Tamaru s allenamide as 2π component Substrates T/t products oncerted??

22 Rationalizing concertedness M picture alculations (DFT) The unique reactivity associated with 2 might be primarily attributed to a strong σ*(-s 2 ) - π*( = beta ) interaction (or σ*(-)-π*( = beta ) interaction which causes 1) the lowering of the π*( = beta ) energy level (and hence, lowering of the activation energy for the [2+2] addition) and 2) the rehybridization of the π*( = beta ) orbitals (sp3-like, and hence, better overlap between the p orbitals of alkene 1 and allene in the opposite face to -Ts).

23 Allenamide as Latent allyl cation: entry into [4+3] [] Exothermic (~40 kcal/mol) Ea typical of rt reaction (~10-15 kcal/mol)

24 [4+3] Proof of Principle [] 60% nly endo observed TL 1980, 36, Tet 2002, 58, JAS 1982, 104, 1119.

25 ptimization of [4+3] Protocol Exploratory Studies additive Lil 4 MgB 42 Znl 2 Znl 2 T ( o ) facial selectivity (oxallyl cation) 75:25 not reported 94:6 >96:4 Scope: Substitution not Tollerated (slow) rotate counterclockwise Major pdt

26 [4+3] Stereochemical Rationale major Approach from bottom face of oxallyl cation Zn minor Approach from top face of oxallyl cation Zn rotate clockwise 90 o rotate horizontally 90 o

27 MR studies: epoxidaiton with m-pba

28 MR studies: epoxidaiton with DMD ot observed bserved

29 atalytic, Enantioselective via Lewis Acid 8-R yield ee R er S 54 : : : : : : : : : : 81 9 : 91 5 : : : 49

30 Scope of Diene

31 Enantioselective [4+3]: Stereochemical Model

32 Summary Synthesis of Allenamides ighly diasteriomerically enriched syntheses available an funcation as omoenolate (or Acyl anion) Reactivity Many interesting modes of reactivity available etero-diels-alder [4+3] of oxallyl cation (after [2+1]) [2+2] (all carbon) ot overed: Pauson-Khand Intramolecular Pd catalyzed cyclizations Radical cyclizations