2.3.4- Trisubstituted pyrrolidines

By analogy with the synthesis of oxygen heterocycles, the zinc-ene-allene cychzation was applied to the synthesis of 2,3,5-trisubstituted pyrrolidines with moderate diastereo-selectivity (equation 170)199,200. 

The BF3-catalyzed reaction of a-aminoaldehydes with 10 is valuable for highly stereoselective synthesis of 2,3,5-trisubstituted pyrrolidines with all -cis configurations (Equation (50)).197 The stereochemical outcome like chelation-controlled stereochemistry might result from the inherent conformational arrangement of the aldehyde-BF3 complex. />-Quinoneimines, o-quinones, and a-alkoxyhydroperoxides undergo similar types of [3 + 2]-cycloadditions with allylsilanes to afford dihydro indoles, dihydrobenzofurans, and 1,2-dioxolanes, respectively.164,175,198... 

Hydrogen-bonding between the 3-oxo group of 1,4,4-trisubstituted pyrrolidine-2,3,5-triones and catalytic amounts of cinchonidine controls the stereospecific hydrogenation of the system over Pt/Al203 to yield chiral 3-hydroxy compounds (-100% yield with ee >60) [21] the nature of the (V-substituent appears to be the controlling factor for the stereoselectivity with PhCH2> Et > n-Bu > cyclo-C6H . 

A stereocontrolled route to the trisubstituted pyrrolidine 146 is achieved using either a concurrent Chugaev-ene reaction or a retro-Diels-Alder-ene reaction <20000L3181, 2001TL4523>, both approaches giving the pyrrolidine in good yields and with complete stereoselectivity. Thus, the thermolysis of either 147 or 148 produces a common intermediate which subsequently undergoes intramolecular ene reaction under the reaction conditions (Scheme 10). 

The regiospecific nucleophilic displacement of 1,2-cyclic sulfamidates 130 with methyl thioglycolate or a-amino esters 130 can be accompanied by lactamization (thermal, base mediated, or cyanide catalyzed) to give thiomorpho-lin-3-ones and piperazin-2-ones 131 (Scheme 19) <20030L811>. If malonate esters, phosphonate-stabilized esters, or aryl-substituted enolates were used as nucleophiles in this reaction, trisubstituted pyrrolidines were obtained in high yield <2004OL4727>. 

Disubstituted pyrrolidines 2 were similarly prepared, but the degree of stereocontrol was dependent on the steric bulk of the substituents25. The configuration of the single or the prevalent diastereomer obtained was not determined, but is most probably cis by analogy with 1. Furthermore, the method has been exploited in the stereoselective synthesis of ( + )-iV-methylanisomycin via the 2,3,4-trisubstituted pyrrolidine 4, obtained by the cyclization of the 4-alkenylamine 365. Notably, the cyclization of 3 did not occur in the presence of butyllithium alone. 

Homochiral 4,5-dihydroimidazolium ylides 595 derived from chiral l-benzyl-4-phenyl-2-imidazoline 594, undergo diastereoselective endo 1,3-dipolar cycloaddition with a range of alkene dipolarophiles to form hexahydropyrrolo[l,2- t]-imidazoles 596. These reactions are best carried out in one pot by refluxing a mixture of 594, bromoacetate, and a dipolarophile in the presence of DBU (Scheme 142) <1996TL1707, 1998J(P1)2061>. Bicyclic adducts 596 are readily converted into enantiopure pyrrolidines in a two-step procedure <1996TL1711>. An intramolecular system (597 to 598) provided a rapid assembly of 2,3,4-trisubstituted pyrrolidines <1997TL1647>. 

A concise route to (-)-kainic acid was developed by K. Ogasawara and co-workers by employing sequentially a Chugaev syn-elimination and an intramolecular ene reaction as the key steps.After preparing the xanthate under standard conditions, the compound was heated to reflux in diphenyl ether in the presence of sodium bicarbonate. The desired tricyclic product bearing the trisubstituted pyrrolidine framework was formed as a single diastereomer in 72% yield. 

The deprotonation of a stereogenic carbon in chiral non-racemic substrates with KHMDS has been used as a first step of sequences relying on the memory of chirality for asymmetric synthesis of organic products. The treatment of Al-Boc-protected amino esters featuring a Michael acceptor group with KHMDS in DMF-THF (1 1) at —78°C for 30 min provided trisubstituted pyrrolidines, piperidines and tetrahydroisoquinolines, and in good yields (65-74%) and diastereoselectivities (4 1 for pyrrolidine, and 1 0 for piperidines and tetrahydroisoquinoline) and excellent enantiomeric excesses (91-98% ee) (eqs 66 and 67). ... 

Hale, J.J. et al. (2001) 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2 lead optimization affording selective, orally bioavailable compounds with potent Anti-HIV activity. Bioorgank S, Medkirud Chemistry Letters, 11 (20), 2741-2745. 

Kim, D. et al. (2005) Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists effects of fused heterocydes on antiviral activity and pharmacokinetic properties. Bioorgank Medkirud Chemistry Letters, 15 (8), 2129-2134. 

Radical cyclization of 482, prepared from the alkylation of MBH adducts 481 with 1,4-dibromo-2-butene in the presence of K2CO3, has been utilized to synthesize 3,3,4-trisubstituted pyrrolidines 483 (Scheme 4.145). As shown in... 

Finally, the aza-Michael reaction may also be combined with Michael addition for the development of enantioselective cascades as efficient tools in heterocyclic chemistry. The highly diastereo- and enantioselective synthesis of trisubstituted pyrrolidines involving amino ester substrates and promoted by chiral secondary... 

This heterocycle can easily be ring opened to aminodiol 117, which, without any protection steps, can be cydized to one single trisubstituted pyrrolidine (see 119) by means of the Appel reaction. 

A number of routes can be envisioned for the preparation of polysubstituted pyrrolidines, and the intramolecular addition of a silyl ketene acetal to an oxime ether has been employed in the synthesis of ABT-627 (4). However, the reductive cyclization of a nitroketone, which could be obtained via the conjugate addition of a ketoester to a nitrostyrene, was viewed as being the most direct, convergent approach to ABT-546. In this approach, the nitro functionality is reduced to generate the cyclic imine, which is then further reduced to the trisubstituted pyrrolidine (Figure 2). As the trans-trans isomer is thermodynamically favored, both it and the cis-cis isomer are usable intermediates. 

The pyrrolidine enamine of 2-methylcyclohexanone (7) was in fact found to be quite inert toward further alkylation and was shown to consist only of the trisubstituted isomer (4) on the basis of the NMR spectral data. The... 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

The magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

In practice, the [2 + 2] cycloadduct of 3-(pyrrolidin-l-yl)-l-benzothiophene (3) and dimethyl acetylenedicarboxylate isomerizes at 40°C to give the 3,4,5-trisubstituted 1-benzothiepin 5.12 In this synthesis cycloadduct 4 is not isolated. 

The reactions of 16 with pyrrolidine and diethylamine were studied at 0.60 GPa in a similar way described above, with or without triethylamine, as shown in Table 17. It can be observed that even with 10.0 molar equivalent of diethylamine only mono-substitution products 18c, 19c and 20c were obtained, whereas pyrrolidine yielded the trisubstitution product 23b in higher yield than did morpholine. The authors explained these results on the basis of the bulkiness of the amines135. 

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