Amino groups SAMP

Having the electrophile 95 to hand, the synthesis proceeded by metallation of the SAMP hydrazone 96 followed by alkylation with the iodide affording the a-alkylated hydrazone 97 with diastereomeric excess de = 9S% (Scheme 1.2.21). The removal of the auxiliary proceeded smoothly with oxalic acid, leading to 98 in good yield (80%, two steps) and no epimerization without deprotection of the amino group. 

A very useful modification of the prolinol system is the introduction of an A -amino group. The products are (7 )-l-amino-2-methoxymethylpyrrolidine [RAMP, (7 )-19] and (5)-l-amino-2-methoxymethylpyrrolidine [SAMP, (S)-19], respectively (for reviews on their chemistry, see ref 12). Their preparation from proline is straightforward and extensively described9- 3, but the high price of synthetic D-proline has made the pathway for RAMP less attractive. A less expensive procedure starts with (7 )-pyroglutamic acid10-12. 

The asymmetric synthesis described in scheme 7 provides an efficient and stereochemically flexible entry to C2-synunetric HIV-1 protease inhibitors. The inhibiting effect and the pharmacological properties of these new agents may possibly be improved further for the treatment of AIDS, as certain properties can be varied almost at will the stereogenic centers, which can be selected by the choice of the auxiliary (SAMP/ RAMP) the side chain (here PhCH2), by the choice of electrophile and the substituents on the amino group. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

For the asymmetric alkylation of ketones and aldehydes, a highly practical method was developed by the Enders group, and uses SAMP-RAMP hydrazones (reviews [104-107]). SAMP and RAMP are acronyms for orR-l-amino-2-methoxymethylpyrrolidine. This chiral hydrazine is used in an asymmetric version of the dimethylhydrazone methodology originally developed by Corey and Enders... 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

Ort/io-substituted benzaldehyde complexes have been prepared in high enantiomeric purity (97% ee), and in a one-pot sequence, from an optically pure hydrazone derivative, readily available from -q -benzaldehyde chromium tricarbonyl and SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolidine]. The novelty derives from the combined use of a diastereoselective orthoaddition reaction of an organolithium nucleophile and a hydride abstraction with a triphenylmethyl cation. The subsequent acid hydrolysis serves to remove the hydrazone group, thus liberating the aldehyde functionality (Scheme 6.13). 

Ketones can present a problem in specificity. Under basic conditions, they may react with two or more molecules of the electrophile to give a mixture of products. Furthermore, unsymmetric ketones may present a choice of two enolate sites so that control is necessary to direct to the desired one. Many alternatives have been developed for this problem. One solution is to incorporate a temporary group on one enolate site to render that site more acidic so that the electrophile will react there. The familiar p-ketoester reactions (acetoacetic ester synthesis) are widely used. For another alternative, the ketone is first converted to an imine (Section 6.2.3) or a dimethyl hydrazone, and the enolate of that derivative is used with electrophiles [28]. Stereospecificity of the addition is obtained by forming a derivative with (5)-l-amino-2-methoxymethyl-pyrrolidine (SAMP) as shown in Equation 7.15 [29]. Without derivati-zation, alkylation of unsymmetric ketones will occur mostly at the more substituted enolate site under reversible deprotonating conditions. Using a base such as EDA will give alkylation primarily at the least substituted enolate. 

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