Formaldehyde asymmetric reaction

Osinovskii A.G. and Erofeev B.V. (1986) Asymmetric synthesis of carbohydrates based on formaldehyde on catalysts modified with L-amino acid esters in " First Republic Meeting on Asymmetric Reactions , Batumi, Gruz. SSR (Georgia), Abstracts, p.41. 

QM/MM calculations and experimental kinetic study have explored the effects of solvation on the transition states for reaction between nitromethane and formaldehyde and between nitropropane and benzaldehyde. Asymmetric reactions of nitromethane with various aldehydes have been promoted by Cu(II) coordinated with amino alcohols, 0 imidazolium/pyrrolidinium-tagged Indabox, and imidazolium-taggedbis(oxazoline)-based chiral ligands. The Henry reaction has also been promoted by Mn(OAc)2/Schiff bases bearing a triazole structure, with up to 99% yield, and by phosphonium ionic ligands MeP+(octyl)3 R0C02 without solvent. ... 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

BINOL-Ti catalysis is also applicable to carbonyl-ene reaction with formaldehyde or vinylogous and alkynylogous analogs of glyoxylates in the catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Scheme 8C.7) [24],... 

Scheme 8C.7. Asymmetric carbonyl-ene reaction of formaldehyde or vinyl and alkynyl analogues of glyoxylale.

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

Most reports in this category deal with asymmetric processes. For example, classic Mannich reaction of unmodified ketones, aqueous formaldehyde, and aromatic amines produces a-aminomethylation of the ketones in >99% ee, using L-proline as catalyst. 24 Methyl ketones regioselectively reacted on the methylene carbon. The method is simple, using wet solvents in the presence of air. 

Aldehydes, symmetric and asymmetric ketones, such as formaldehyde, acetaldehyde, substituted benzaldehydes and cyclic ketones, were introduced into the reaction along with acetone. The reaction is reversible azirenoimidazoles undergo reverse transformation forming tnms-aziridinyl ketones in acetic acid. 

It should, however, be pointed out that - where applicable - product composition can be significantly different. For example, whereas thiazolium catalysts afford exclusively dihydroxyacetone with formaldehyde as substrate, the triazolium systems afford glycolic aldehyde (plus glyceraldehyde and C4 and C5 sugars as secondary products) [246], Catalyst-dependent differences in the relative rates of the partial reactions within the catalytic cycle (Scheme 6.105) most probably account for this phenomenon. A subsequent study by Enders et al. on chiral triazolium salts identified the derivative 233 as a first catalyst for the asymmetric benzoin condensation that affords substantial enantiomeric excesses (up to 86%) with satisfactory chemical yields (Table 6.3) [247]. 

The mechanism of the cycloaddition of singlet dibromocarbene to formaldehyde was studied using DFT at the B3LYP/6-31G level of theory 47 The energy barrier is estimated as 13.7 kJ mol-1. Reaction paths for the addition of dichlorocarbene to 1,2-disubstituted cyclopropenes were studied using the same level of theory as above.48 The addition gives 1,3-dienes or bicyclobutanes and was predicted to be concerted following an asymmetric approach. 

Proline and its derivatives also catalyze the classical asymmetric Mannich reaction between aqueous formaldehyde, anilines, and ketones. This was the first successful direct catalytic a-hydroxymethylation of ketones, and the corresponding a-aminomethyl ketones were isolated in excellent yields with up to >99 % ee (Scheme 4) [34]. 

The triazol-5-ylidene 12 was found to be a powerful catalyst for the conversion of formaldehyde to glycolaldehyde in a formoin reaction [25.] The concept of triazolium salt catalysis appeared to show promise, and consequently our research group undertook the synthesis of a variety of chiral triazolium salts for the asymmetric benzoin reaction [26]. However, the ce-values and catalytic activities shifted widely with slight structural changes in the substitution pattern of the triazolium system. The most active catalyst 15 (Fig. 9.4) afforded benzoin (6, Ar = Ph) in its (R -configuration with 75% ee and a satisfactory yield of 66%. 

Treatment of the A-substituted piperidinones 317 with primary amines and formaldehyde gave bispidinones 198. This double Mannich reaction provided a valuable and versatile approach to a large number of bispidinone derivatives. The reaction took place with a wide variety of primary amines and provided both symmetric and asymmetric bispidinones depending on whether the primary amine and the piperidinone nitrogen bore the same or different substituents. 

The prochirality of aldehydes other than formaldehyde is frequently exploited in order to obtain asymmetric Mannich bases 99A and B, as the reaction with substrate may occur from either side of the double bond plane of the aminomethylating agent (Fig. 38). 

The proline-catalyzed asymmetric Mannich reaction between cyclohexanone, formaldehyde and an aniline has been described by Bolm and co-workers [182]. With only 0.5 mol% of homochiral catalyst, the Mannich products have been obtained with excellent ee s up to 98% after a short irradiation time using a constant low power of 10-15 W in conjunction with simultaneous cooling with compressed air. These reaction conditions allow achieving a high reaction rate and an excellent enantioselectivity. In situ reduction of the resulting ketones 129 afford the V-aryl amino alcohols 130 in high yield (syn/anti in ratio 1 5) (Scheme 101). 

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

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