Short Access to (+)-Lupinine and (+)-Epiquinamide via Double Hydroformylation

Transcription

1 Short Access to (+)-Lupinine and (+)-Epiquinamide via Double Hydroformylation Kai Gao Checker: Changbin Yu Mann, A.* et al rg. Lett. 2009, ASAP

2 Strategy for the formation of quinolizidine alkaloids R H 2 [Pd] R H 2 /C [Rh] R HC 3 CH 3 R = CH 2 H, (+)-lupinine, 1a R = HAc, (+)-epiquinamide, 1b R = H, quinolizidine, 1c

3 Model Reaction H 2 /C (1:1) 5 bar Rh(C) 2 (acac) (1 mol%) biphephos (3 mol%) Me Me 3 3 THF, h, 65 o C 8% 2 3 t-bu P P t-bu 1c 5 bar H 2 Pd(H) 2 /C 20% THF or MeH, rt quant. biphephos

4 Sythesis of (+)-Lupinine, 1a Ph 3-Butenal 5 TiCl DIPEA Ph LiBH DCM, -78 o C to rt 77% H 80% 6 TBS TBS H 1) MsCl, Et 3 DMAP TBSCl Et 3, DMAP ) a 3, DMF 57% (2 steps) R 8, R = H 9, R = Ms 79% 7 H

5 TBS H 2 /C (1:1) 5 bar Rh(C) 2 (acac) (2 mol%) biphephos ( mol%) TBS 10 3 THF, 65 o C, 12 h 76% HC 3 11 CH H TBS TBAF H 2 (5 bar) Pd(H) 2 /C 20% (+)-lupinine, 1a THF, 5 o C 8% 12 87%

6 Retrosynthetic Analysis for (+)-Epiquinamide HAc AcCbz HCbz HC 3 CH reductive bis-amination double hydroformylation (+)-epiquinamide, 1b 20 3 syn-elimilation 18 S 2 HCbz HCbz HCbz C 2 H S Me Z-L-menthionine S Me H S allylation Me anti-selective reduction 1 16

7 Synthesis of (+)-Epiquinamide, 1b HCbz Me S C2 H Z-L-mehtionine 1) H(Me)Me-HCl HBTU, DIEA DMF, 0 o C 2) allylmgbr, THF, -10 o C 97% (2 steps) Me S HCbzR 13, R = (Me)Me 1, R = allyl HCbz HCbz H 17 1) ai, MeH R 2) CaC 3 o-dichlorobenzene 180 o C 8% (2 steps) H 15, R = SMe 16, R = S()Me LiAlH(t-Bu) 3 EtH, -78 o C 9% ee, 98% de

8 HCbz HCbz Me DIAD, PPh 3 Ac H 17 DPPA, THF 0 o C to rt 8% 3 18 ptsa 80% HAc (+)-epiquinamide, 1b 1) H 2 /C (1:1) 5 bar Rh(C) 2 (acac) (2 mol%) biphephos ( mol%) THF, 65 o C, 8 h, 67% 2) Pd(H) 2 /C 20%, H 2 5 bar MeH, rt 83% AcCbz 3 19

9 Huang s Work Retrosynthetic Analysis Bn HAc H 20 (-)-epiquinamide 29 TBS 21 MgX Huang, P.-Q. et al rg. Lett. 2006, 8,

10 Synthesis of 2-Piperidinone Alcohol 25 Bn 20 Bn TBS MgX 21 CH 2 Cl 2, -78 o C 93% H + 23 H TBS 22 Bn Et 3 SiH, BF 3 Et 2 CH 2 Cl 2, -78 o C to rt TBS Bn Bn H 60% BF 3 H TBS 25 2

11 Synthesis of the Common Intermediate 29 Bn TsCl, Py H CH 2 Cl 2 92% Bn Ts CA MeC-H 2 60%-70% H Bn ah, THF Ts 100 % Bn 10% Pd/C, H 2 MeH 98% H

12 Synthesis of (-)-Epiquinamide 3 H MsCl, Et 3 100% Ms a 3, DMF 65 o C to 70 o C 31 (53%) + HAc 1) LiAlH, THF 2) Ac 2 78% 32 (30%) (-)-epiquinamide

13 Summary This Work: Ph H 8 steps overall yield 15% (+)-lupinine, 1a HAc Me S HCbz C 2 H 9 steps overall yield 29% bidirectional regioselective hydroformylation (+)-epiquinamide, 1b tandem azide reduction/ reductive bis-amination

14 Huang s Work Bn HAc 10 steps total yield 1.6% (S)-3-benzyloxyglutarimide (-)-epiquinamide, 1c TBS MgX Bn H flexible introduction of a functionalized C side chain to (S)-3-benzyloxyglutarimide

15 In recent years, synthetic strategies toward piperidine- and pyrolidinecontaining alkaloids have often implemented transition-metal-catalyzed transformations. In this regard, the ring closing metathesis (RCM) has found its way for the construction of many alkaloids, but a prerequisite for performing a RCM is the presence of two olefinic partners in the substrate to be heterocyclized, one of them being generally a homoallylamine. As an alternative, a homoallylamine could also be identified as an ideal substrate for performing a hydroformylation. This atom-economic proprocess consists of a formal addition of H 2 /C across an olefin catalyzed by Rh(I) and has recently emerged as a powerful method in the synthesis of alkaloids. Thus, if the introduction of the aldehyde function occurs regioselectively at the terminal carbon atom of the alkene function, the presence of the nucleophilic nitrogen atom in the allylamine will allow us to form an internal imine directly amenable to a six-membered -heterocycle...

16 In conclusion, we successfully realized the total syntheses of two quinolizidine alkaloids, (+)-lupinine 1a (8 steps, overall yield 15% from ) and (+)-epiquinamide 1b (9 steps, overall yield 29% from Cbz-L-methionine), using a bidirectional regioselective hydroformylation of chiral bis-homoallylic azides as a key step followed by a highly efficient tandem catalytic azide reduction/reductive bis-amination process. Taking advantage of the exceptional stability of azides during the hydroformylation process, the proposed methodology is well suited for the preparation of quinolizidine alkaloids. Moreover, the use of methylsulfide compounds as a hidden terminal alkene function may be an attractive strategy for subsequent hydroformylation. Applying the hydroformylation reaction in the synthesis of other alkaloids is currently underway in our laboratories...