Diastereoselectivity allyl amine derivatives

While reaction of the acetate 40 as well as the acetyl- and phthalimide derivatives of chiral amine (41b and 41c) proceeded with erythro diastereoselectivity (in accordance with the classical cis effect, minimization of 1,3-allylic strain) (Table 6, entries 8, 10, 11), for the allylic alcohols 39, primary allylic amine 41a, silyl enol ethers 42 and enol ether 43 threo selectivity was observed (Table 6, entries 1-7, 9, 12-14) (see also Scheme 24). For allylic alcohols with an alkyl group R4 cis to the substituent carrying the hydroxyl group, diastereoselectivity was high (Table 6, entries 1-7) in contrast, stereoselection was low for allylic alcohols which lack such an R4 (cis) substituent (substrates 39h and 39i, see Figure 4). 

This alkylation strategy has been successfully implemented to the diastereoselective synthesis of a number of biologically active compounds,17 19 32 72 73 including the orally active HIV protease inhibitor Crixivan (>95% de)17-19 and nucleoside antibiotic (+)-sinefungin (51) (>99% de).72 The C-6 amine stereochemistry of (+)-sinefungin was set by a highly diastereoselective allylation of (lS,2/ )-l-amino-2-indanol-derived oxazolidinone 52 (Scheme 24.10). 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

The hydroboration of allylic amine or alcohol derivatives can be used for the preparation of alkylzinc reagents with excellent diastereoselectivity (Equation (34)). Rhodium-catalyzed hydroborations are also compatible... 

An asymmetric variant of this kind of allylic amination, based on their phenylcyclohexanol-derived chiral N-sulfinyl carbamates, was developed by Whitesell et al. (see also Sect. 3.2) (Scheme 34) [85]. After the asymmetric ene reaction with Z-configured olefins (not shown) had occurred, nearly di-astereomerically pure sulfinamides 127 were obtained which were found to be prone to epimerization. Their rapid conversion via O silylation and [2,3]-a rearrangement dehvered the carbamoylated allyhc amines 128 with around 7 1 diastereoselectivity as crystalline compounds that can be recrystallized to enhance their isomeric purity to 95 5. Obviously the imiform absolute configuration at Cl in the ene products 127 was difficult to transfer completely due to the already mentioned ease of epimerization. Unhke the sulfonamides of Delerit (Scheme 33) [84], the carbonyl moiety can easily be cleaved by base treatment. 

The Petasis reaction is a mild multicomponent reaction that allows the conden sation of a boronic acid, an amine, and a carbonyl derivative to generate an allylic amine. Although several diastereoselective Petasis reactions have been reported [106], the first catalytic asymmetric reaction was described in 2008 (Scheme 1.29) [107]. It was shown that the condensation proceeds in high yields and enantiomeric excesses, affording the corresponding protected a vinylglycine derivatives. 

Brilnker, H.-G. and Adam, W., Diastereoselective and regioselective singlet oxygen ene oxyfunc-tionalization (Schenck reaction) photooxygenation of allylic amines and their acyl derivatives,/. Am. Chem. Soc., 117, 3976,1995. 

In 2006, Jung et al. reported another synthesis of (—)-lentiginosine (209) starting from the D-xylose-derived olefin 211 [72]. Subjection to chlorosulfonyl isocyanate (CSI) provided the allylic amine 212 with a high diastereoselectivity (syn/anti =... 

Allylic acetoxy groups can be substituted by amines in the presence of Pd(0) catalysts. At substituted cyclohexene derivatives the diastereoselectivity depends largely on the structure of the palladium catalyst. Polymer-bound palladium often leads to amination at the same face as the aoetoxy leaving group with regioselective attack at the sterically less hindered site of the intermediate ri -allyl complex (B.M. Trost, 1978). 

Chiral oxime ethers 229 of R)- and (5 )-0-(l-phenylbutyl)-hydroxylamine (ROPHy/ SOPHy) react with Grignard reagents in the presence of BFs OEta in toluene at —78°C yielding addition products with high diastereoselectivities (equation 154) . The resulting chiral hydroxylamine derivatives have been converted enantioselectively to primary amines, or (when R = allyl) to / -amino acids. 

Although substrate-induced diastereoselection can be conveniently achieved when the alkenylmetal was coordinated by an oxygen atom, other heteroatoms such as sulfur and nitrogen resulted in high inductions as illustrated by the crotylzincation of the organolithium reagents derived from the allylic sulfide 238 or the tertiary amine 239 (equation 117)154. 

TABLE 6. Results of the regio- and diastereoselective ene reaction of singlet oxygen with chiral allylic alcohols, acetates, amines (and acyl derivatives), silyl ethers and ethers... 

In 1989 Oppolzer reported that the enolates of A-acyl sultams derived from camphor afford highly diastereoselective alkylation products with a variety of electrophiles including those which are not allylically activated [88]. The sultam is deprotonated using either butyllithium with a catalytic amount of cyclohexyl isopropyl amine, or butyllithium alone, or sodium hexamethyldisilyl amide.As illustrated in Scheme 3.18, alkylation occurs selectively from the Re face of the Z(( )-enolate to give monoalkylated sultams which can be cleaved by LAH reduction or lithium hydroperoxide catalyzed hydrolysis. Representative examples are listed in Table 3.7. 

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