Catalytic Enantioselective Addition

Catalytic enantioselective addition to imines, in particular, aza-Diels-Alder reaction 99CRV1069. 

The catalytic enantioselective addition of vinylmetals to activated alkenes is a potentially versatile but undeveloped class of transformations. Compared to processes with arylmetals and, particularly alkylmetals, processes with the corresponding vinylic reagents are of higher synthetic utility but remain scarce, and the relatively few reported examples are Rh-catalysed conjugate additions. In this context, Hoveyda et al. reported very recently an efficient method for catalytic asymmetric allylic alkylations with vinylaluminum reagents that were prepared and used in Thus, stereoselective reactions... 

Reactions of organometallic derivatives with ketones, which are less electrophilic than aldehydes, usually require an equimolar amount of a chiral ligand. The first catalytic enantioselective addition of an organometallic reagent, namely ZnPh2, to dialkyl and aryl alkyl ketones was reported in 1998 by Dosa and Fu (Scheme 110).288 The procedure... 

CATALYTIC ENANTIOSELECTIVE ADDITION OF DIALKYLZINCS TO ALDEHYDES USING (2S)-(-)-3-exo-(DIMETHYLAMINO)ISOBORNEOL [(2S)-DAIB] (S)-I-PHENYL-I-PROPANOL (Benzenemethanol, a-ethyl-, (S)-)... 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

Enantioselective addition of alkynyl groups to aldehydes and ketones afford enantioen-riched alkynyl alcohols62. Early approaches to the catalytic enantioselective addition of dialkynylzincs and alkynylalkylzincs to aldehydes employed catalytic amounts of chiral amino alcohol63 and amino pyridine64. Stoichiometric enantioselective addition of alkynylzinc halide is reported using the lithium alkoxide of IV-methylephedrine65. 

In 2000, a catalytic enantioselective addition was reported using a chiral Lewis acid-ligand system. Tomioka and coworkers reported the enantioselective addition of... 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

As the follow up to our studies in connection to the development of Ti-cat-alyzed cyanide additions to meso epoxides [4], we developed the corresponding catalytic enantioselective additions to imines [5]. A representative example is shown in Scheme 1 chiral non-racemic products maybe readily converted to the derived cx-amino acids (not available through catalytic asymmetric hydrogenation methods). In these studies, we further developed and utilized the positional optimization approach effected by examination of parallel libraries of amino acid-based chiral ligands (e.g., 1 and 2). Thus, the facile modularity of these ligands and their ease of synthesis were further exploited towards the development of a new catalytic enantioselective method that delivers various ar-... 

Unsaturated aldehydes undergo catalytic enantioselective addition to give secondary allylic alcohols in good to excellent yields and up to 98% ee. (equation 113)450-456. 

A copper-free catalytic enantioselective addition to p-ch 1 oro-cr,/3-unsaturated esters has been developed in the presence of A-heterocyclic carbenes.92 The activation of Grignard reagents has been achieved using a Lewis base. ... 

A series of chiral (3i ,5 RHlihvdroxypiperidine derivatives have been conveniently prepared from trans -4-hvdrox v- r.-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. 

Catalytic enantioselective addition reactions of alkyllithium or -zinc reagents to preformed imines have been described [34, 35]. Hoveyda, Snapper, and co-workers have described a direct three-component variant of this reaction [36]. Accordingly, several chiral, non-racemic aromatic as well as aliphatic amines were synthesized by the reaction of the corresponding aldehydes, o-anisidine 132, and alkylzincs using a Zr catalyst with a chiral peptide ligand 133 (Scheme 9.24). 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

Scheme 15. Catalytic enantioselective addition of diethylzinc to N-diphenylphosphinoylimines [44b].

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

Kleinmann EF (1991) In Trost BM, Fleming I (eds) Comprehensive organic synthesis, vol 2. Pergamon, Oxford, p 893 Knowles WS (2002) Angew Chem Int Ed Engl 41 1998 Kobayashi S, Ishitani H (1999) Catalytic enantioselective addition to imines. Chem Rev 99 1069-1094... 

Kobayashi S, Ishitani H (2000) Novel binuclear chiral zirconium catalysts used in enantioselective strecker reactions. Chirality 12 540-543 Kobayashi S, Ishitani H, Nagayama S (1995) Synthesis 1995 1195 Kobayashi S, Ishitani H, Ueno M (1998) J Am Chem Soc 120 431 Kobayashi S, Kobayashi J, Ishitani H, Ueno M (2002) Catalytic enantioselective addition of propionate units to imines an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives. Chem Eur J 8 4185 1190 Krohn K, Kirst HA, Maag H (eds) (1993) Antibiotics and antiviral compounds. VCH, Weinheim... 

Kobayashi, S. Ishitani, H. Catalytic Enantioselective Addition to Imines, Chem. Rev 1999, 99, 1069-1094. 

Catalytic, Enantioselective Addition of Arylboronic Acids to Cycloalkenones. A complex between ligand 1 and a rhodium(I) salt was found to catalyze the asymmetric 1,4-addition reaction of arylboronic acids to cyclohexenone and cyclohep-tenone. The reaction proceeds with high enantiocontrol and excellent yields (eq 4). Lower enantiomeric excesses were observed with cyclopentenone (83% ee), but a variety of substituted phenyl-boronic acids could be used. 

Catalytic Enantioselective Addition of Dialkylzincs to Aldehydes. DPMPM (1) is a chiral amino alcohol which is a precursor to a chiral catalyst for the enantioselective addition of dialkylzincs to aldehydes. In the presence of 2 mol % of (.S)-(l), optically active alcohols of up to 100% ee are obtained from the enantioselective addition of dialkylzincs to aldehydes (eq 1, Table 1). When benzaldehyde is allowed to react with Diethylzinc using (5)-(l) (2 mol %), (5)-l-phenylpropan-l-ol with 97% ee is obtained in quantitative yield (entry 1). When the lithium alkoxide of (5)-(l) (5 mol %) is employed as a chiral ligand in the addition to aromatic aldehydes, ee s of the alcohols obtained increase... 

Enantioselective Addition of Various Organozinc Reagents to Aldehydes. Catalytic enantioselective addition of dialkynylz-inc reagents to aldehydes using (1 S,2R)-DBNE (20 mol %) affords optically active (R)-alkynyl alcohols with 43% ee in 99% yield. When an alkylalkynylzinc is used with (lS,2/ )-DBNE (5 mol %), an alkynyl alcohol with 40% ee is obtained. When 2-phenylzinc bromide is reacted with an aldehyde in the presence of 1 equiv of the lithium salt of (li ,25)-(l), the corresponding alkynyl alcohol is obtained in 88% ee (eq 8). ... 

Other organometallic compounds, including aUylic stannanes, allylic samarium, allylic germanium, and allylic indium compounds add to aldi-mines in the same manner. Aryltrialkylstannanes also add the aryl group to Al-tosyl imines using a rhodium catalyst and sonication. Catalytic enantioselective addition reactions are well known, including reactions in an ionic liquid.Allylic... 

Denmark, S. E., Fu, J. Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones. Chem. Rev. 2003, 103, 2763-2793. 

The catalytic, enantioselective additions of thioacetate-derived enol silanes has also been studied by Keck (Eq. (8.15)) [29]. In these studies, the active catalyst (62) is readily generated upon mixing binol, TiCl2(0/Pr)2, and 4 A molecular sieves in Et20 at -20 °C followed by an aging period. The addition reactions are best conducted with 10 mol% catalyst in ether at -20 °C the f rt-butyl thioacetate adducts are isolated in up to 98% ee and 90% yield. 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or-... 

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