Asymmetric 1,6-addition

Variations and Improvements on Asymmetric Additions to Naphthyl Oxazolines... 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

The asymmetric addition of naphthyl Grignard reagents to l-methoxy-2-... 

The asymmetric addition of organolithium reagents to arylox azolines has been used to construct highly complex polycyclic terpene structures found in natural products. For example, the asymmetric addition of vinyllithium to chiral naphthyloxazoline 3 followed by treatment of the resulting anionic intermediate with iodoethyl dioxolane 61... 

Although furan is usually a poor diene in the Diels-Alder reaction, the chiral copper reagent 24b promotes its asymmetric addition to acryloyloxazolidinone to afford the 7-oxabicyclo[2.2.1]hept-2-ene derivative in high optical purity (Scheme 1.40). Because a retro-Diels-Alder reaction occurs above -20 °C, the reaction must be performed at low temperature (-78 °C) to obtain a high optical yield. The bicy-... 

Tanner et al. also used an aziridine carbinol (viz. 54) as chiral ligand in asymmetric addition of diethylzinc to hT-(diphenylphosphinoyl)imines (Scheme 41) [54]. 

A similar method was later used by the group of Tomioka [10] for the asymmetric addition of thiazolylhthium 44 to prochiral aldimines (Scheme 10) for the preparation of (S)-Boc-Doe 46, a component of antileukemic marine natural product dolastatin 10. In this case, sparteine 1 was... 

Chiral diamino carbene complexes of rhodium have been merely used in asymmetric hydrosilylations of prochiral ketones but also in asymmetric addition of aryl boron reagents to enones. 

Dai X, Nikkei T, Romero JAC, Fu GC (2007) Enantioselective synthesis of protected amines by the catalytic asymmetric addition of hydrologic acid to ketenes. Angew Chem Int Ed 46 4367 369... 

Metal-catalyzed asymmetric addition of dialkyl phosphites to aldehydes (Pudovik reaction) has been extensively developed since the initial reports in 1993 by Shibuya. Scheme 5-25 illustrates the use of TiCh to promote diastereoselective addition of diethyl phosphite to an a-amino aldehyde. 

Shibasaki showed that an aluminum-lithium-BINOL complex (ALB) also catalyzes the asymmetric addition of dialkyl phosphites to aldehydes, with ees ranging from 55 to 90% for aryl or unsaturated aldehydes (Scheme 5-37). 

Scheme 5-39 Asymmetric addition of methyl phosphinate to aldehydes using heterobimetallic BINOLcatalysts LLB = La/Li/BINOL, LPB = La/K/BINOL, ALB = AI/Li/BINOL...

Chiral aluminum SALEN complexes have been used by Kee for asymmetric addition of dimethyl phosphite to benzaldehyde derivatives (Scheme 5-43). 

L-valine. The application of these ligands to the asymmetric addition of ZnEt2 to aldehydes provided the corresponding products with excellent enan-tioselectivities as high as 99% ee in almost all cases and with a catalytic loading as little as 0.02 mol% of the ligand depicted in Scheme 3.9. 

In 1999, Shi el al. showed that a diphenylthiophosphoramide derived from (li ,2i )-l,2-diaminocyclohexane could be used as a ligand in the catalytic asymmetric addition of ZnEt2 to aldehydes in the presence of Ti(Oi-Pr)4, providing the corresponding alcohols in enantioselectivities of 40-50% ee (Scheme 3.20). Another class of new ligands such as the phenylthio-phosphoramide of (7 )-1,1 -binaphthyl-2,2 -diamine was developed by the same group, and further tested as a ligand in the same conditions (Scheme 3.20). ... 

In 2001, Braga et al. reported the synthesis of new chiral C2-symmetric oxazolidine disulfide ligands from (R)-cysteine and successfully applied them as catalysts in the asymmetric addition of ZnEt2 to various aldehydes (Scheme 3.23). In the presence of 2mol% of ligand, excellent enantioselectivities of up to >99% ee were obtained even with aliphatic aldehydes such as n-decanal or n-hexanal. These authors proposed that the active catalyst did not maintain its C2-symmetry during the reaction. The disulfide bond was probably cleaved in situ by ZnEt2. 

In 1998, two other examples of chiral ligands that enabled the asymmetric addition of organozinc reagents to ketones were reported by two groups independently. Thus, Dosa and Fu employed the nonsulfur-containing Noyori s DAIB " ligand in the asymmetric addition of ZnPh2 to ketones with... 

Similar reactions were undertaken by Choi et al. in the presence of a new family of A -sulfonylated p-amino alcohols possessing two stereocentres as the chiral ligands. In using the chiral sulfonylated p-amino alcohol ligand depicted in Scheme 10.41, the asymmetric addition of McsSiCN to a wide range of aldehydes afforded the corresponding cyanohydrins in both excellent yields and enantioselectivities of up to 96% ee. 

Mejorado investigated the asymmetric addition of various organometallic nucleophiles using method A, but the reaction could not be catalyzed. The intermediates proved to be far too reactive. However, he established that the addition of a stoichiometric amount of a preformed chiral complex [an admixture of Taddol (r/om-a, -(dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenyl methanol)) and EtMgBr] to 5 affords some enantiomeric excess in the resulting phenol product 6 (Fig. 4.12).13... 

Efavirenz (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon-nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz . Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz . 

Protection of the nitrogen in 4 faced the classical N- versus O-alkylation selectivity issue, which was solved by selection of the solvent system. The original protecting group, pMB, was replaced with 9-anthrylmethyl (ANM), which provided the best enantioselectivity with the newly discovered asymmetric addition to the ketimine. 

Deprotection of the pMB group from 20 proceeded smoothly in TFA to provide the drug candidate 2. The isolation conditions of a suitable crystal form of 2 for development were optimized later since we had to change the protective group of the nitrogen of 4 for the subsequent asymmetric addition reaction. 

Asymmetric addition of 2-pyridylacetylide to ketimines 5 and 17 Even though the... 

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