Auxiliaries, chiral phenethylamine

The origin of the observed 1,4-asymmetric induction in Michael reactions of chiral imines (Scheme 28) has been rationalized by conformational transmission of chirality. Thus, the phenethylamine auxiliary forces the cyclohexene part of the intermediate enamine into a half-chair conformation (140) that is 0.8 kcal mol-1 lower in energy than (141). Axial attack as shown then leads to the major product the energy difference between (140) and (141) roughly correlates with the observed diastereoselectivity ( 9 l).105... 

S)-l-Alkyl-l,2, 4-tetrahydroisoquinolines. The bis(trimethylsilyl) ether (2) of 1 has been used as a chiral auxiliary to effect alkylation of tetrahydroisoquinoline (equation 1) with high enantioselectivity. The chiral propanediol is much more effective than (R)-(— )-a-phenethylamine, and moreover leads consistently to (S)-l-alkyl derivatives. 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

An achiral ketone (S OS) was used to prepare protected alcohol 5.206 via condensation with S-phenethylamine, and that protecting group was also an auxiliary Removal of the benzylic group and re-protection with Boc allowed Birch reduction s of the aromatic ring to give 5.207. Ozonolysis in methanol led to methyl 4-(N-Boc amino)-6-methyl-3-oxoheptanoate, 5208. In this synthesis, the phenyl ring functioned as the carboxyl surrogate and asymmetric induction in 5.208 arose from the chiral auxiliary introduced earlier in the sequence. 

The reaction of S-phenethylamine and ethyl acetoacetate led to 5.209 (ethyl 3-(N-phenethyl)but-2-enoate)S9.90 as seen in chapter one, section l.l.C.ii. Reduction of the double bond would give the ethyl 3-aminobutanoate derivative, and the presence of the chiral auxiliary would lead to asymmetric induction during that reduction. 

There are several reaction sequences that use a chiral auxiliary to produce chiral, nonracemic GABOB, but are rather di arate in their approaches. In one, cyclobuta-none 6.5553 reacted with R-phenethylamine to give an imine, and this was oxidized with m-chloroperoxybenzoic acid to give spiro-oxaziridine derivative 6.59.54 Photolysis of 6.59 led to a mixture of lactams 6.60 and 6.61. Separation of these... 

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