Auxiliaries, chiral, synthesis

Disubstituted 2-oxazolidines as chiral auxiliaries synthesis from 2-oxazolones 97YZ339. 

Use as a Chiral Auxiliary Synthesis of Cyclopropylboronic Acids. The chiral dioxaborolane unit can also be used as an effective chiral auxiliary in the synthesis of enantiomerically enriched cyclopropylboronic acids. For example, 1-alkenylboronic esters bearing the tetramethyltartramide group undergo diastereoselec-tive cyclopropanations to afford the cyclopropylboronic acid (eq 11). These products can be used for in situ Suzuki coupling reactions or can be oxidized to produce 2-substituted cyclopropanols. 

S.G. Davies, A.C. Gamer, P.M. Roberts, A.D. Smith, M.J. Sweet, J.E. Thomson, Oxazinanones as chiral auxiliaries synthesis and evaluation in enolate alkylations and aldol reactions, Org. Biomol. Chem. 4 (2006) 2753-2768. 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Novel chiral auxiliary, 2 -isopropyl-5 -methylbenzoxazine-spiro-[2.1 ]cyclo-hexan-4-one, and its application to the synthesis of carbapenem antibiotics 97YGK858. 

Dithiane 1-oxide derivatives as chiral auxiliaries and asymmetric building blocks for organic synthesis 980PP145. 

The powerful influence of an oxygen substituent on the rate and stereoselectivity of cyclopropanation augured well for the development of a chiral auxiliary based approach to asymmetric synthesis [54]. The design of the chiral auxiliary would take into account ... 

An alternative approach to asymmetric synthesis that avoids covalent modification of the substrate is chiral modification of the active reagent. This not only streamlines the number of synthetic manipulations, but it simplifies the isolation of the desired product. In the case of zinc carbenoids, such modifications are feasible alternatives to the use of a standard chiral auxiliary. Two important factors combine... 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Solladie-Cavallo has recently reported a two-step asymmetric synthesis of dis-ubstituted N-tosylaziridines from (R,R,R,Ss)-(-)-sulfonium salt 2 (derived from Eliel s oxathiane see Section 1.2.1.1) and N-tosyl imines with use of phosphazine base (EtP2) to generate the ylide (Scheme 1.42) [67], Although the diastereoselectiv-ity was highly substrate-dependent, the enantioselectivities obtained were very high (98.7-99.9%). The chiral auxiliary, although used in stoichiometric quantities, could be isolated and reused, but the practicality and scope of this procedure is limited by the use of the strong - as well as expensive and sensitive - phospha-zene base. 

Scheme 211 Asymmetric synthesis of vinylaziridines by use of a chiral auxiliary.

In most of these examples, the chiral auxiliary is introduced to the allylic reagent at a very late stage in the synthesis of the precursor, thus providing a facile access. It is obvious that in most examples, the central metal atom is kept from becoming stereogenic, and in addition, a C2-symmet-ric cation is desirable, in order to minimize the possible number of competing transition states. 

An efficient stereoselective Strecker synthesis of phenylglycine has been achieved using the tert-butyl ester tm-leucine as the chiral auxiliary. Its benzaldimine reacts with hydrogen cyanide in hexane at — 23 °C to furnish the ( )-diastereomer with the excellent diastereoselectivity of >98 254. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

The latter work is a rare example in which a high stereoselectivity was reported for a substrate-controlled Ugi synthesis. In asymmetric Ugi reactions carried out with removable chiral auxiliaries, however, high diastei eoselections were achieved (see Section 1.4.4.3.1.). 

The principle discussed in the previous section can be used in asymmetric synthesis, utilizing a chiral auxiliary in the 2-position of the cyclopentenone in order to achieve diastereofacial selectivity. Three types of chiral auxiliaries, the 4-methylphenylsulfinyl (E), menthyloxycar-bonyl (C), and 8-phenylmenthyloxycarbonyl groups (D), have been studied32. 

Waldmann H. Amino Add Esters Versatile Chiral Auxiliary Groups for the Asymmetric Synthesis of Nitrogen Heterocycles Synlett 1995 133-141... 

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone (50). In this case, >99% of the product was the (5) enantiomer. Compound 49 is called a chiral auxiliary because it is used to induce asymmetry and then is removed. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

The 4-thiazolidinyl phosphonates 143 (Scheme 44) are known for their therapeutical properties, in particular as anti-inflammatory agents [5,89]. Their asymmetric synthesis by hydrophosphonylation of 3-thiazolines has been described using various chiral auxiliaries chiral phosphites such as (2S,4i )-2H-2-oxo-5,5-dimethyl-4-phenyl-l,3,2-dioxaphosphorinane (de = 2-8%) [90] or BINOL-phos-phite (de = 65-90%) [91] and also chiral catalyst such as titanium or lanthanide chiral complexes (ee = 29-98%) [92]. Hydrophosphonylation of C2-chiral3-thi-azolines has also been performed (de = 32-38%) [93]. 

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