Enantioselective approach

MejZn (400 mol%) Nia2(PPh3)2(8mol%) PhMe, 0 °C Yield 50-92% ee 68-87% 

General Procedure for the Synthesis of -Amino Alkyl Propanoates 14 [19] To a stirred solution of aldehyde (9, 0.2 mmol) in toluene (2 mL) at room temperature, 2-methoxyaniline (11b, 0.2 mmol) was added. After 30 min, a solution of dimethylz-inc (0.4 mL, 2 M, 0.8 mmol) in toluene was added all at once. After 10 min, (15, 2R)-(V-methylephedrine (0.060 g, 0.33 mmol) was added, and the resulting solution was stirred at room temperature. After 60 min, the reaction was cooled down to -30 °C, alkyl bromoacetate (13,0.24 mmol) was added, followed immediately by tra-triphenylphosphine nickel(II)dichloride (10 mg, 0.015 mmol), stirred at the same temperature for 23-48 h, and then quenched by the addition of HCl 1 M (3 mL). The reaction was stirred for 3-10 min, and then the organic phase was separated, washed with saturated NaHC03 and brine, dried with Na2S04, and concentrated in vacuo to afford a crude product 14, which was purified by chromatography (cyclohexane/Et20, 8 2-95 5). 

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Some other enantioselective approaches have been attempted, still with moderate enantioselectivities, by making use of in situ systems containing a chiral NHC precursor. Luo and co-workers reported on the use of the bidentate chiral imidazo-lium salt 16, derived from L-proUne, in combination with [RhCia-COCcod)], leading to an enantiometic excess of around 20% [30]. The use of chiral imidazolium salt 17 in combination with [RhCl(CH2=CHj)j]j by Aoyama afforded slightly better ee (Fig. 7.3) [31 ]. So far, Bohn and co-workers have obtained the best enantioselectivities (up to 38% ee) for the catalytic addition of phenylboronic acid to aromatic aldehydes by using planar chiral imidazolium salts 18, derived from paracyclophane, in combination with [Rh(OAc)2]2 [32]. 

MelUlo, D.G., Cvetovich, R.L, Ryan, K.M., Sletzinger, M. (1986) An Enantioselective Approach to (-F)-Thienamycin from Dimethyl 1,3-Acetondicarboxylate and (-F)-a-Methylbenzylamine. Journal of Organic Chemistry, 51, 1498-1504. 

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

Scheme 3.33. Lewis acid-promoted free radical domino cyclization reaction and enantioselective approach.

Groeger, H., Saida, Y., Arai, S., Martens, J., Sasai, H., and Shibasaki, M., First catalytic asymmetric hydrophosphonylation of cyclic imines highly efficient enantioselective approach to a 4-thiazolidinylphosphonate via chiral titanium and lanthanoid catalysts,Tetrahedron Lett., 37, 9291, 1996. 

This reaction is now well understood, including its stereochemical features.209 242 It should be noted that six-membered rings can be formed besides five-membered rings through this pathway, and their formation is facile with the catalytic system Pd(ll)-Pd(rv). All of these set the stage for numerous synthetic applications, such as cycloisomerization [4 + 2] tandem processes,243 and the enantioselective approach to the total synthesis of potent antiulcerogenic cassiol 247 (Scheme 62).244... 

An enantioselective approach to both enantiomers of a-alkyl-a-methoxyarylacetic acid derivatives has been described from L-(- -)-tartaric acid. Key steps include stereoselective addition of Grignard reagents to 1,4-diketones derived from tartaric acid. This methodology has been applied in synthesizing the pine beetle pheromone frontalin. 

Pll The asymmetric synthesis of a-amino acids and derivatives is an important topic as a result of their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. Many highly enantioselective approaches have been reported. Industrial production of a-amino acids via the Strecker reaction is historically one of the most versatile methods to obtain these compounds in a cost-effective manner, making use of inexpensive and easily accessible starting materials. (From Boesten et al., 2001)... 

Present perfect (active Many highly enantioselective approaches... 

Hoechst has reported an enantioselective approach toward the key azabicyclo[3.3.0] octane-3-carboxylic acid 46 that preserves the stereochemistry of the L-serine-derived starting material (Urbach and Henning, 1991). L-Serine methyl ester (48) was alkylated... 

Recently, Feng and co-workers reported an asymmetric sulfide oxidation" catalyzed by titanium complexes bearing HydrOx ligands, for example, 576 (Scheme 8.199). ° Enantioselectivities approached a level of synthetic utility for oxidation of aryl alkyl sulfides 632 although the yields of the sulfoxide 633 were poor due to overoxidation to the sulfone 634. The overoxidation is especially significant for reactions with high enantioselectivity. 

H. Audrain, J. Thorhauge, R. G. Hazell, and K. A. Jorgensen, A novel catalytic and highly enantioselective approach for the synthesis of optically active carbohydrate derivatives, J. Org. Chem., 65 (2000) 4487-4497. 

Acherar, S. Audran, G. Vanthuyne, N. Monti, H. Use of lipase-catalyzed kinetic resolution for the enantioselective approach toward sesquiterpenes containing quaternary centers the cuparane family. Tetrahedron Asymmetry 2003, 14,2413-2418. 

An enantioselective approach to cytotoxic nor-calamenenes via electron-transfer-driven benzylic umpolung of an arene tricarbonyl chromium complex. Synthesis 2003, 1851-1855. 

Driven by the rapidly growing demand for highly enantiomeric pure substances in the pharmaceutical industry in order to provide safer and cheaper drugs, the development of a process which can achieve enantioselectivities approaching 100% has become desirable and challenging. 

In a study dedicated to enantioselective approaches and their limitations, chiral dipolarophiles and chiral azomethine ylids precursors were used and it was established that the chirality of the adduct is largely controlled by the chirality of the dipolarophile while that of the azomethine ylid has a very weak influence.434 435... 

The asymmetric catalytic aldol reaction of silyl allenolates ICH=C=CR2OSiMe3 with aldehydes R CHO has been achieved by Li et al. by using N-C3F7CO oxazaborolidine as the catalyst [43], The fluoroacyl group of the catalyst was found to be crucial for control of enantioselectivity. The reaction provides the first enantioselective approach to / -halo Baylis-Hillman-type adducts. 

The importance of carbanions a-substituted by heteroatoms in organic synthesis explains the vast amount of literature concerning the use of a-heterosubstituted organotins in transmetallation reactions. As the tin-lithium exchange is assumed to occur with a complete retention of configuration at the carbanion centre639, the enantioselective approach of such stabilized carbanions for synthesis has been the subject of recent developments. 

Evans and co-workers described the first catalyzed enantioselective enolate-elec-trophile bond construction which could be extended to a general catalytic enantioselective approach to the synthesis of a-amino acids. 

Enantioselective synthesis ofa-hydroxy acid derivatives. Recently, Aggarwal has reported an enantioselective approach to the synthesis of a-hydroxy acid derivatives using trans- 1,3-dithiane- 1,3-dioxide. For example, reaction of trans-1,3-dithiane-1,3-dioxide with an aromatic aldehyde liberates the alcohol which is protected as the tetrahydropyranyl (THP) ether the resulting product may then be subjected to a Pummerer reaction, using trifluoroacetic anhydride, to give a thiolester. Transthiolesterification of this product using LiSEt gives the... 

M. Seepersaud and Y. Al-Abed, An enantioselective approach to trehazolin A concise and efficient synthesis of the aminocyclopentitol core, Tetrahedron Lett., 42 (2001) 1471-1473. 

A catalytic, enantioselective approach towards the synthesis of polyol chains has recently been reported by Carreira et al. and has been applied in a synthesis of the polyol subunit of amphotericin B (Scheme 5) [13]. Aldol addition of the silyl dienolate 26 to furfural (27) catalyzed by the Tol-BlNAP-CuF -complex (2 mol-%) gives rise to the addition product 28 in 95 % yield and >99 % ee after one recrystallization. Spectroscopic evidence indicates that a copper dienolate is formed in situ from the silyl dienolate 26 and is actually the active nucleophile [14], Standard transformations including a j-yw-selective reduction of the ft-hydroxy ketone by the method of Prasad and the oxidative conversion of the furan ring to the car-... 

I.4 Synthesis of (-)-Calanolide A and (—)-Calanolide B Using a Catalytic Enantioselective Approach... 

Paquette, L. A., Pissamitski, D, and Barriault, L., 1998 A Modular Enantioselective Approach to Constmction of the Macrolactone Core of Polycavemoside A. Journal of Organic Chemistry 63(21), 7389-7398. 

Zhang, H.L., Zhao, G., Ding, Y, and Wu, B. 2005. An efficient and enantioselective approach to the azaspirocyclic core of alkaloids formal synthesis of halichlorine and pinnaic acid. J Org Chem 70, 4954-4961. 

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