Chiral auxiliaries enamines

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Coordination of the aluminum atom of the reducing complex was proposed to take place both to the oxygen atom of the hydroxy group and to the nitrogen atom of the amino group. The asymmetric reduction of enamine perchlorates and ketimines with menthol and bomeol chiral auxiliary reagents (50,51) presumably involves coordination of aluminum to the nitrogen atom of the substrate. 

As mentioned, the present methodology affords an effective means for the synthesis of optically active aldols. A high level of asymmetric induction was observed with a wide range of ketones such as methyl, ethyl and O-methoxy. Furthermore, when (1S,2R)-norephedrine is employed as a chiral auxiliary, it is always the si-face of aldehydes that is attacked by the tin(II) enamine. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

While nonracemic trifluoroalanines can easily undergo racemization or dehydro-fluorination, many asymmetric syntheses oftrifluoroalanines have been proposed. These syntheses generally involve an asymmetric reduction step of an imine or an enamine. This step can be performed by utilizing either chiral catalysts or chiral auxiliaries. 

The scheme used to produce a somewhat more complex 5-a-reductase inhibitor relies on a chiral auxiliary to yield the final product as a single enantiomer. The first step in a sequence similar to that above starts with the reaction of bromotetralone (23-1) with R-a-phenethyl amine (23-2) to afford the enamine (23-3). Reaction with methyl iodide adds the methyl group at what will be a steroid-like AB ring junction... 

Second-Ceneration Chiral Auxiliary Route. The PGA Enamine-amide Route... 

Whatever the explanation for the stereocontrol, these processes are quite useful synthetically, enabling one to prepare nearly pure erythro or threo diastereomers in high yield. A number of groups have shown that by using a chiral auxiliary in the enamine, ester or amide unit, products of very high enantiomeric excess can be obtained.69... 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

In order to develop a removable analogue of 83, unsaturated compound 85 was devised as a new chiral auxiliary that can be displaced at the end of the synthesis via a retro Diels-Alder reaction and subsequent acid treatment of the resulting enamine (Scheme 1.28). 

Several efforts were also made by the same group to achieve chiral auxiliary control in 7V-acyl enamines 155, but only moderate diastereoselec-tivities for the 3-amido oxetanes 156 were reported (Sch. 54) [152]. The photocycloaddition of an axial chiral 7V-acyl enamine 157 with benzalde-hyde resulted in oxetane (158) formation with moderate diastereomeric excess [153],... 

Better yields, but lower enantiomeric excesses, were obtained by an alternative method, the cycloaddition of ethoxycarbonyl azide, followed by irradiation to give the aziridine64. Interestingly, the opposite configuration at the stereogenic center was formed by the two methods. The enantiomeric excess of the product was determined by ketalization with (2/, 3/ )-2,3-butanediol and GC or l3C-NMR analyses of the reaction mixture. The choice of the chiral auxiliary is crucial unfortunately, the enamine derived from //ww-2,5-dimethyl pyrrolidine does not react with either the nitrene or the azide. 

Asymmetric Alkylations. The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazo-lines) is often the most efficient procedure for achieving a-alkylations. Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-f-leucine f-butyl ester (eq 1). High enantiomeric excesses and predictability of absolute configuration make this method attractive. 

Chiral enamines may be prepared by condensation of ketones with enantioenriched 5ec-amines. The C2-symmetric rran5-2,5-dimethylpyrrolidine is a frequently used chiral auxiliary for the preparation of enantiomeric enamines. Alkylation of chiral enamines followed by hydrolysis is an effective method for the enantioselective alkylation of ketones. ... 

Control of absolute stereochemistry in ketone alkylation through the use of chirality in the amine component of an enamine represents a nearly ideal case for asymmetric induction where the chiral auxiliary is present in an equimolar amount. The formation of enamines is generally straightforward, cleavage of the product immonium ion is trivial in most cases, and the amine can be readily separated from the prouct for recovery and reuse. Indeed, the first example of such a process was reported by Yamada in 1969 using proline esters as the chiral amine (equation 28). " ... 

We (Novartis) reported ] an enantioselective synthesis of (2S,2 71)- zyf/iro-methylphenidate (3) utilizing Evans (S)-4-benzyl-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate (65 Scheme 16). Acylation of (S)-4-benzyl-V-phenylace-tyl-2-oxazolidinone (61) with the mixed anhydride 63, followed by deprotection of the V-Boc group with TFA, and neutralization of the reaction mixture with NaHCOs afforded the enamine intermediate 65. Hydrogenation of enamine 65 with 10% Pd-C in ethyl acetate furnished 66 in 95% yield with an excellent diastereoselectivity (97 5). Treatment of 66 with methanol in the presence of EnR afforded the desired... 

Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as an ester or an amide. There is no such obvious place to attach an auxiliary to a diene but the chiral analogue 161 of Danishefsky s diene has a C2 symmetric amine 164 attached as an enamine. Cycloaddition without a Lewis acid gives good selectivity in the formation of adduct21 162. Reduction and hydrolysis releases the enone 163 in reasonable ee. 

Azides into Amines 20,23,771,772 H2/Pd or H2/Pt 317,318,339,450,773 H2/Pd-(Boc)20 in N-acyloxazolidinoncs to prevent reaction of the amine with the chiral auxiliary 774 Raney nickel 444 SnCh 444,450,458,775,776 Zn 777 Al/Hg 777 sodium borohydride under phase-transfer conditions 778 lithium aluminum hydride 779 H2S 780 triphenylphosphine.325,781,782 Azides into Imines base.783 785 Azides into Enamines NaReC>4.331... 

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. 

---