Enamide-aldehyde cyclization

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Treating the protected amine 141 in the presence of the Rh-BIPHEPHOS catalyst (see Figure 3) under hydroformylation conditions, leads to enamide 142. The consecutive reactions are hydroformylation to give the linear aldehyde, cyclization to give aminoacetal and the elimination of water. Compound 142 is a key intermediate in the synthesis o rosopinine 143 [86]. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Aldehyde 100 was cyclized to the tetracyclic enamide 101 in chloroform containing boron trifluoride at room temperature in 87% yield (75JA2503). A similar cyclization of aldehyde 102 was brought about with molecular sieves at room temperature to give 69% of the dibenzo-4-azaazulene 10 containing a fully conjugated 7i-system (82H75). 

Conventionally, this reaction is conducted in the presence of a Lewis acid. We had to check that the catalyst used in the hydroformylation was still active in the presence of such an acidic additive. To this point, only catalytic amounts of PPTS (pyridinium p-toluenesulfonate) had been used in CHC reactions. This study was conducted on substrate 21, which was designed to allow only the hydroformylation/cyclization sequence (Scheme 9). It was synthesized by peptide coupling between 0-Me-phenylglycinol and vinyl acetic acid in a yield of 84%. Without an acidic additive, the hydroformylation reaction of this substrate proceeded in 93% yield and produced the linear aldehyde/branched aldehyde in a ratio of 92 8. We obtained the enamide after the CHC reaction in very good yields both in the presence of pTSA and Lewis acids (e.g., BF3-Et20, Zn (OTf)2). In addition, it should be noted that the regioselectivity of the hydroformylation reaction dictated by chelation of the BiPhePhos ligand is not disturbed by the presence of the acidic additive. 

A similar approach was later taken to the alkaloids lupinine and epilupinine [90]. Ester (260) was obtained by sulfolene alkylation and easily converted to enamide (261). Thermolysis of this gave Diels-Alder cyclization product (262), from which aldehyde (263) was obtained. Hydrogenation produced a mixture of... 

Shortly later, within 2 months, a similar reaction, the enantioselective cascade aza-ene-type cyclization reactions of a,p-unsaturated aldehydes 28 and enamide 154, was also reported by Wang et al. In addition, the reaction product hemiaminal 157 was converted to ketoaldehyde 158, pyridine 159 and enamide 160, Scheme 3.51 [67]. Similarity, the reaction mechanism started from a nucleophilic attack of enamide (an aza-ene-type reaction), followed by reversible enamine-iminium transformation and hydrolysis to provide the hemiaminal. 

Because of the chelate control of the process, allylamides such as 129 react under hydroformylation conditions to give mainly the branched aldehyde 131, together with cyclic derivatives 132 and 133 (Table 5) [82, 83]. Products 132 and 133 are formed from the linear aldehyde through a sequence of reactions involving cyclization to give the enamide 134, followed by hydrogenation or hydroformylation, respectively [84]. 

The aldehyde could readily be converted to the desired y-amidoallylboronate 50 by the standard enamide formation method (Schiff-bavSe formation, followed by acetylation, followed by deprotonation of the acylirnmonium ion to the enamide). Treatment of 50 with either Yb(OTf>3or LiBp4 in moist dichloromethane or acetonitrile did liberate the desired aldehyde 47 which indeed cyclized as anticipated to the desired trans-2-vinyl-3-piperidinol 46. Yet the yields remained unsatisfactory (40 - 45%). The main reaction was the acid-catalyzed hydrolysis of the enamide function, which eventually gave rise to the formation of the undesired pyrrolidine derivative 51. (25)... 

Hayashi and co-workers reported on an ene reaction followed by alkylative cyclization of a, 3-unsaturated aldehyde 240 and enamide 241, using OTBS protected pyrrolidine derivative 243 as the organocatalyst to obtain... 

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