Organometallic reagents, chiral

Table 8.2. Stereoselectivity in Addition of Organometallic Reagents to Some Chiral Aldelqrdes and Ketones"...

In his original paper,2 Cram disclosed an alternative model that rationalizes the preferred stereochemical course of nucleophilic additions to chiral carbonyl compounds containing an a heteroatom that is capable of forming a complex with the organometallic reagent. This model, known as the Cram cyclic or Cram chelate model, has been extensively studied by Cram9 and by others,410... 

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-... 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

In most cases of diastereoselective nucleophilic addition reactions where achiral organometallic reagents are added to chiral carbonyl compounds, the chirulity inducing asymmetric center is in close vicinity to the newly created center and cannot be removed without the loss of chirality of either the inducing center or the newly formed center. This type of reaction is very useful in propagating chirality in a molecule from one center to an adjacent one, or in immolative processes. 

A different approach to chiral oc-hydroxy acids 4 is the nucleophilic addition of organometallic reagents to chiral oc-oxo 4,5-dihydrooxazoles 2, which can be synthesized by oxidation of the corresponding 2-alkyl-4,5-dihydrooxazoles l17,19. 

As well as the addition of achiral organometallic reagents to chiral aldehydes (see also Sections 1.3.2. and 1.3.3.), the addition of chiral organometallic reagents to carbonyl compounds is a well-known and intensively studied process which may lead to enantiomerically and/or diastereomerically enriched products. Chiral organometallic reagents can be classified into three groups ... 

Among the a-hetero-substituted chiral organometallic reagents, a-lithio ethers 2 are an important class of compounds. A general route to these compounds is the reductive lithiation of a-(phcnylthio) ethers 1 with lithium (dimethylamino)naphthalenide (I.DMAN)4,5. The generality of this method lies in the ready availability of various types of a-(phenylthio) ethers. 

The a-lithiated sulfides 33 are another class of chiral organometallic reagent, readily available by deprotonation of the parent l-(phcnylthio)alkanes 32 with butyllithium in tetrahydrofuran at - 78 °C. 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

The highest ee s reported to date for the addition of achiral organometallic reagents in the presence of aprotic chiral additives were observed with the C2-symmetric diamines 10, 11 and 12 (Table 25)13 — 15. Enantioselectivities as high as 89% ee were observed with chiral auxiliary 1012. Addition of phenyllithium to pentanal proceeds with lower enantioselection that the analogous addition of butyllithium to benzaldehydeu. Generally, the enantioselcctivity in-... 

The organometallic reagent was prepared by adding the diorganomagnesium compound to the dilithium salt of (S)-l,1 -binaph-thalcnc-2.2 -diol, itself prepared by addition of 2 equivalents of BuLi to the chiral diol. b n.r. = not reported. 

Despite the undefined nature of the organometallic species, chirally modified organotita-nium reagents are useful tools in enantioselective synthesis. In particular, the binaphthol-mod-ified phenyltitanium reagent 41 shows excellent enantioselectivity in additions to aromatic aldehydes34-40,41. 

I.5.2.I.I.4. Conjugate Addition of Chiral Organometallic Reagents External Stoichiometric Chiral Ligands... 

G. H. Posner, Addition of Organometallic Reagents to Chiral Vinyl Sulfoxides in Asymmetric Synthesis. J. D. Morrison, Ed. Vol. 2, p. 225, Academic, New York 1983. 

Scheme 25 Diastereoselective addition of organometallic reagents to chiral a-amino hydrazones...

Scheme 38 Addition of organometallic reagents to a chiral glyoxal diimine...

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