Prolinol-derived catalysts addition

Recently, and co-workers [41] Zhang reported the first highly efficient protocol for the synthesis of a-amino esters with prolinol-derivated catalyst. The (9-pivaloyl 7ra 5-4-hydroxyproline derivative (Cat. 10) achieved best results. Crucial for efficiency was the addition of small quantities of pentanoic acid. Through this approach, a broad range of chiral a-amino esters were synthesized in good yields (up to 97%) and with high levels of enantioselectivity (up to 93%) (Scheme 15.14). 

In the pioneering studies of Melchiorre and Jorgensen and colleagues, a variety of pyrrolidine-derived catalysts was tested (Scheme 2.51) [40]. Whilst modest selectivity was obtained with proline, and unhindered prolinol derivatives, (S)-2-(bis(phenyl)methyl)pyrrolidine derivative, 45c, allowed good conversion and enantio selectivity in the addition of linear aldehydes to methyl-vinyl ketone (MVK) (revalues up to 85%). Cyclic enones as well as -substituted enones afforded no, or perhaps poor, results. 

Other nucleophiles that have been used in this context are acetylides (alkynes). The addition of those to iminium cations generated in situ from aldehydes and secondary amines accomplishes a gold(III)-catalyzed three-component coupling for the synthesis of propargylamines, as can be observed in equation (124). The reactions are performed in water or in tetrahydrofuran (THF) when supported catalysts are employed.Chiral prolinol derivatives as... 

Prolinol derivatives of boron tribromide 4 give excellent results in the [4 + 2] cycloaddition of methacrolein (8a) to cyclopentadiene (exojendo ratio 99 1, 97% ee)21. Several boron catalysts derived from /V-sulfonamides of a-amino acids 7a-d have been developed. In the cycloaddition of methacrolein (8a) or croton aldehyde (8b) to cyclopentadiene these catalysts produce enan-tioselectivities ranging from medium to good8-22 23. Chiral oxazaborolidinone 6 is an excellent catalyst for the addition of 2-bromoacrolein (8e) to various dienes24 (see table overleaf)-... 

This transformation proved to be rather general with respect to the enoliz-able aldehyde and the enal, with higher yields obtained when aliphatic a,p-unsaturated aldehydes were employed. On the other hand, all the nitroalkenes tested were nitrostyrene derivatives, with no data provided with regard to the use of the more problematic aliphatic nitroalkenes. In addition, several selective transformations were carried out on the compounds obtained by this methodology, therefore proving the possibility of chemical manipulation of the different functionalities present in their structure. A version involving the use of recyclable polystyrene-supported prolinol-based catalysts has also been reported furnishing similar yields to those obtained by Enders in solution for a comparative example. 

Some years later, further developments by Alexakis et al. have shown that prolinol derivative 22a (10 mol%) is a better catalysts for the reaction [89]. The results vary from good, for conjugate addition of linear aldehydes to l,l-bis(benzenesulfonyl) ethylene (77-90% yields 76-93% ee), to moderate (12-91% ee) when using a-branched aldehydes as nucleophiles. Catalyst 22a has been also used by Palomo et al. for the enantioselective conjugate addition of linear and 3-branched aldehydes to E-a-ethoxycarbonyl vinyl sulfones and -a-cyano vinyl sulfones [90], derivatives that after further transformations, which usually involve a reductive desulfonylation process [91], have made possible the synthesis of different interesting chiral building blocks. 

In 2008, Li et al. reported a copper-catalyzed amine-alkyne-alkyne addition reaction as an efficient method for the synthesis of Y,5-alkynyl-p-amino acid derivatives 102 (Scheme 3.52) [137]. In this case, the first step of the reaction is proposed to be the hydroamination of the electron-deficient alkyne 100, which plays the role of the aldehyde component. Subsequent reaction of the resultant intermediate XXX with alkyne 101 would afford intermediate XXXI, which would be then protonated to give an iminium intermediate XXXII. Finally, an intramolecular transfer of the alkyne moiety to the iminium ion would yield the 7,8-alkynyl-p-amino ester 102 and regenerate the catalyst. The reaction was later extended using chiral prolinol derivatives as the amine component, which afforded the corresponding Y,5-alkynyl-p-amino acid derivatives with excellent diaste-reoselectivities (up to >99 1) [138]. 

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

The modified prolinol derivative (324) has been developed as a readily recyclable catalyst for the Michael addition of malonates CH2E2 (E = C02RO to enals RCH=CHCH=0, which proceeds at 10mol% loading in the presence of PhC02H (40%) as the Brpnsted acid cocatalysts in a mixture of H2O and Pr OH (3 2). The Michael adducts RCH(CHE2)CHCH=0 were thus obtained in <97% ee ... 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

In 1981, Hirao and others reported that the chiral borane-amine complex 25a, derived from (S)-prolinol and 1 equivalent of BH3 THF, enantioselec-tively reduced propiophenone to afford (R )-l -phenyl-1 -propanol (26) in 44% ee9 (Scheme 4.3h). The chiral complex 25b was even better than 25a, affording the same secondary alcohol in 60% ee. Two years after the initial disclosure, Hirao et al. uncovered a new catalyst system that improved the previous experimental conditions dramatically10 (Scheme 4.3i). When the chiral aminoalcohol 27, prepared from (S)-valine methyl ester hydrochloride and phenylmagnesium bromide, was used along with 2 equivalents of BH3 THF, the enantioselectivity of the alcohol 26 jumped to 94% ee. In addition, the reaction time was shortened to 2 hours. 

The same method, using Co(acac)2 and the chiral diamines has also been applied to several other stabilized carbanions and enones with up to 100% yield, however, the asymmetric inductions did not exceed 40% ee59. Similarly, a catalyst derived from Ni(acac), and (+ )-(S)-2-(anili-nomethyl)pyrrolidine, (—)-(5)-prolinamide or (—)-(S)-prolinol catalyzes the conjugate addition of nitromethane to benzalacetone, chalcone and 2-cyclohexenone with up to 59% ee62,67. 

Bromomalonate, selected as the pronucleophile, is proposed to undergo deprotonation by the diaryl prolinol catalysts lej to give the corresponding reactive enolate involved in the conjugate addition with different electron-poor alkenes (Scheme 7.9). The intramolecular alleviation proceeds with more nucleophilic indandione-derived enolate, under one-pot conditions, in... 

S.2.3.2. 0L, -Unsaturatecl Aldehydes as Acceptors. As an alternative strategy for the synthesis of y-nitro aldehyde compounds, the asymmetric Michael addition of nitroalkanes to a,(3-unsaturated aldehydes was also investigated in recent years. Due to the high reactivity of aldehydes, the competitive 1,2-addition reaction is the major limitation for the development of such a reaction. Disubstituted prolinol silyl ether derivatives [72] proved to be effective catalysts to tackle this synthetic challenge, and excellent results were obtained with 7 in the presence of acid or base additive (Scheme 5.35). 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

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