Aldehydes chiral amino alcohol catalyzed

Scheme 1 Chiral amino alcohol catalyzed asymmetric dialkylzinc addition to aldehydes...

The alcohol portion of ester 1 was derived from the aldehyde 4, prepared from D-ribose. The absolute configuration of the secondary aUylic alcohol was established by chiral amino alcohol catalyzed addition of diethyl zinc to the unsaturated aldehyde 5. 

Catalytic amounts of chiral amino alcohols both catalyze the reactions of alkylzinc reagents with aldehydes and induce a high degree of enantioselec-tivity. Two examples are given below. Formulate a mechanism for this catalysis. Suggest transition structures consistent with the observed enantioselectivity. 

Nucleophilic addition of metal alkyls to carbonyl compounds in the presence of a chiral catalyst has been one of the most extensively explored reactions in asymmetric synthesis. Various chiral amino alcohols as well as diamines with C2 symmetry have been developed as excellent chiral ligands in the enantiose-lective catalytic alkylation of aldehydes with organozincs. Although dialkylzinc compounds are inert to ordinary carbonyl substrates, certain additives can be used to enhance their reactivity. Particularly noteworthy is the finding by Oguni and Omi103 that a small amount of (S)-leucinol catalyzes the reaction of diethylzinc to form (R)-l-phenyl-1 -propanol in 49% ee. This is a case where the... 

Various catalytic or stoichiometric asymmetric syntheses and resolutions offer excellent approaches to the chiral co-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL-H reduction18 are all worth mentioning. 

Enantioselective addition of CjH zZn to aldehydes.1 Addition of diethylzinc to either aromatic or aliphatic aldehydes catalyzed by 1 (6 mole %) results in (S)-secondary alcohols in generally 90-95% ee. Although several chiral amino alcohols are known to effect enantioselective addition of R2Zn to aromatic aldehydes, this one is the first catalyst to be effective for aliphatic aldehydes. The dibutylamino group of 1 is essential for the high enantioselectivity the dimethylamino analog of 1, (lS,2R)-N-methylephedrine, effects this addition in only about 60% ee. 

Chiral to side-chain units can also be obtained by various catalytic and stoichiometric asymmetric synthesis as well as by resolution (30). Scheme 14 shows the preparation of these side-chain units using kinetic resolution by the Sharpless epoxidation (31), amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde (32), lithium acetylide ad-... 

The amino alcohol-catalyzed enantioselective addition of dialkylzincs to aldehydes, detailed in Chapter 5 (27), is accomplished with polymer catalysts containing DAIB, a camphor-derived auxiliary, and other chiral amino alcohols (28). Reactions that involve matrix isolation of the catalyst not only result in operational simplicity but also greatly facilitate understanding of the reaction mechanism. In solution, the catalytic chiral alkylzinc alkoxide derived from a dialkylzinc and DAIB exists primarily as dimer (27) however, when immobilized, its monomeric structure can be maintained. 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

Asymmetric addition of diorganozincs to aldehydes catalyzed by chiral -amino alcohols provides a general method for the preparation of chiral secondary alcohols. Oguni, Noyori, and co-workers found that the aminoalcohol, (2S)-3-exo-(dimethylamino)isobornenol ((2S)-DAIB), acts as a particularly efficient promoter for this asymmetric reaction [9, 10]. Reaction of benzalde-hyde with diethylzinc in the presence of 2 mol% of (2S)-DAIB gives, after aqueous workup, (S)-l-phenylpropanol in high yield with 99% ee as shown in Scheme 8. Detailed mechanistic and theoretical studies of the (2S)-DAIB-pro-moted asymmetric addition have been reported [11]. 

The addition of diethylzinc to aldehydes produces secondary alcohols. This process can be stereoselectively catalyzed by chiral amino alcohols that form Schiff-base zinc complexes with the aldehyde and the metal. With the aim of simplifying the work-up of these reactions and to use continuous-flow processes, the polymer-supported amino alcohols 115 and 116 were synthesized (Scheme 21) [91]. The polymers were obtained by co-polymerization of the chiral monomer 117 and styrene 58 in the presence of divinylbenzene (118) or cross-tinldng agent 119 containing a flexible oxyethylene chain. The latter was used to ensure sufficient flexibility within the cross-linked network of the polymer and to further activate the nucleophile by coordination of the oxyethylene chain to the metal. 

Oguni also reported that the titanium complex of a chiral amino alcohol whose amino group was modified with a salycylal-type Schiff base as shown in 11 (Fig. 1) catalyzed the cyanosilylation of aromatic and aliphatic aldehydes [44,45,... 

Chiral Amino Alcohol/Zn/Racemic Amino Alcohol-Catalyzed Asymmetric Diethylzinc Addition to Aldehydes... 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

To obtain information about the structural requirements of a ligand capable of catalyzing the addition of dialkylzincs to aldehydes, various simple amines, alcohols and amino acid derived amino alcohols were tested as chiral catalysts (Table 27). 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

Hayashi et al.147 reported another highly enantioselective cyanohydrination catalyzed by compound 138. In this reaction, a Schilf base derived from fl-amino alcohol and a substituted salicylic aldehyde were used as the chiral ligand, and the asymmetric addition of trimethylsilylcyanide to aldehyde gave the corresponding cyanohydrin with up to 91% ee (Scheme 2-56). 

Figure 5.3 Four alternative TS structures for catalyzed addition of diethylzinc to benzaldehyde. The descriptors refer to the side of the four-membered ring on which the aldehyde carbon is found relative to the alkoxide carbon - same (syn) or opposite (anti) - and the absolute configuration of the new stereogenic center formed following ethyl transfer, R or S. In the absence of chirality in the /3-amino alcohol ligand, indicated by the G group(s), the TS structures at opposite corners would be enantiomeric with one another, and no preference for R over 5 product would...

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