5- -2,2-dimethyl stereoselective reactions

The enantioselective hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates with enol ethers catalyzed by Cu(II)bzT(oxazoline) complexes have been investigated in depth. It was found that Cu(II)bA(oxazoline) complexes activate a,p-unsaturated acylphosphonates to the extent that they undergo facile cycloaddition reactions at low temperature with electron-rich alkenes. For example, dimethyl ( )-l-oxo-2-butenylphosphonate reacts with ethyl vinyl ether in the presence of Cu[(S,5)-t-Bu-box] (OTf)2 complex (10 mol% catalyst) to generate the cycloadduct in 89% yield (Scheme 7.86) with exceptional stereoselectivity (endo/exo = 99/1, 99% ee). Cyclic enol ethers also undergo stereoselective reactions with dimethyl ( )-l-oxo-2-butenylphosphonate. It specifically reacts with 2,3-dihydrofuran in the presence of Cu[(5,5)-t-Bu-box] (OTf)2 to deliver the bicyclic enolphosphonate. Of particular merit is the fact that a large variety of p.y-unsaturated acylphosphonates may be tolerated with no loss in selectivity for the derived cycloadducts. ... 

Added lithium salts, especially lithium chloride, can affect stereoselective reactions dramatically162. In the case of the lithium enolate of 2,2-dimethyl-4-phenyl-l,3-oxathiolan-5-one the enantiomeric enrichment from protonation with diisopropyl tartrate increases from 39 to 66% ee when one equivalent of lithium chloride and to 70-78% ee when five equivalents of lithium chloride are added to a solution of the enolate in tetrahydrofuran159b. 

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

It is well known that aziridination with allylic ylides is difficult, due to the low reactivity of imines - relative to carbonyl compounds - towards ylide attack, although imines do react with highly reactive sulfur ylides such as Me2S+-CH2-. Dai and coworkers found aziridination with allylic ylides to be possible when the activated imines 22 were treated with allylic sulfonium salts 23 under phase-transfer conditions (Scheme 2.8) [15]. Although the stereoselectivities of the reaction were low, this was the first example of efficient preparation of vinylaziridines by an ylide route. Similar results were obtained with use of arsonium or telluronium salts [16]. The stereoselectivity of aziridination was improved by use of imines activated by a phosphinoyl group [17]. The same group also reported a catalytic sulfonium ylide-mediated aziridination to produce (2-phenylvinyl)aziridines, by treatment of arylsulfonylimines with cinnamyl bromide in the presence of solid K2C03 and catalytic dimethyl sulfide in MeCN [18]. Recently, the synthesis of 3-alkyl-2-vinyl-aziridines by extension of Dai s work was reported [19]. 

Preliminary experiments prove that the substitution pattern of the /V-aryl moiety of imine 1 is crucial for the stereoselectivity of this reaction. The 2-substituent on the aryl group is of special importance. Namely, introduction of a methoxy group leads to a considerable decrease of enantioselectivity compared to the corresponding 2-H derivative, probably due to disfavor-able coordination with the organolithium complex. In contrast, alkyl groups show the reverse effect along with increased bulkiness (e.g., Tabic 1, entries l-3a) but 2,6-dimethyl substitution provides lower ee values. Furthermore, the 4-substituent of the TV-aryl moiety is of minor importance for the stereoselectivity of the reaction [the Ar-phcnyl and the /V-(4-methoxyphenyl) derivatives give similar results], whereas a substituent in the 3-position results in lower stereoselectivities (e.g., Et, Cl, OCHj)41. 

The inherent plane of chirality in the metal carbene-modified cyclophane 45 was also tested in the benzannulation reaction as a source for stereoselectivity [48]. The racemic pentacarbonyl(4-[2.2]metacyclophanyl(methoxy)carbene)-chromium 45 reacts with 3,3-dimethyl-1-butyne to give a single diastereomer of naphthalenophane complex 46 in 50% yield the sterically less demanding 3-hexyne affords a 2 1 mixture of two diastereomers (Scheme 30). These moderate diastereomeric ratios indicate that [2.2]metacyclophanes do not serve as efficient chiral tools in the benzannulation reaction. 

The discovery that Lewis acids can promote Diels-Alder reactions has become a powerful tool in synthetic organic chemistry. Yates and Eaton [4] first reported the remarkable acceleration of the reactions of anthracene with maleic anhydride, 1,4-benzoquinone and dimethyl fumarate catalyzed by aluminum chloride. The presence of the Lewis-acid catalyst allows the cycloadditions to be carried out under mild conditions, reactions with low reactive dienes and dienophiles are made possible, and the stereoselectivity, regioselectivity and site selectivity of the cycloaddition reaction can be modified [5]. Consequently, increasing attention has been given to these catalysts in order to develop new regio- and stereoselective synthetic routes based on the Diels-Alder reaction. 

Soluble organic solvents have often been used as cosolvents to solubilize miscible organic substrates. Since organic compounds including solvents are possibly incorporated inside of the enzyme, they may affect the stereoselectivity of enzymatic reactions. For example, dimethyl sulfoxide (DMSO) (10%) enhance not only chemical yield but also enantioselectivity of yeast reduction. Thus, the poor yield of 23% with 80% ee was increased to 65% yield with >99% ee (Figure 8.20) [17]. 

Nitroalkenes with Chiral Auxiliaries The use of carbohydrates as chiral auxiliary in Diels-Alder reactions for the stereoselective preparation of carbocyclic and heterocyclic chiral rings is well documented.48 For example, D-manno-nitroalkene reacts with 2,3-dimethyl-1,3-butadiene to give a 65 35 mixture of adducts, as shown in Eq. 8.29. The configurations at C-4 and C-5 have been determined to be (4R,5R) and (45,55), respectively. Hydrolysis of the product followed by degradative oxidation of the sugar side chains leads to enantiomerically... 

C—H bond 174-280,28i por comparison, only trace amounts of cyclopentane resulted from the CuS04-catalyzed decomposition of 1 -diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone 277). It is obvious that the use of Rh2(OAc)4 considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyelization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyelization reaction can also be highly diastereo-selective, as the exclusive formation of a m is-2,3-disubstituted cyclopentane carboxylate from 307 shows281 a). The stereoselection has been rationalized by... 

It is supposed that the nickel enolate intermediate 157 reacts with electrophiles rather than with protons. The successful use of trimethylsilyl-sub-stituted amines (Scheme 57) permits a new carbon-carbon bond to be formed between 157 and electrophiles such as benzaldehyde and ethyl acrylate. The adduct 158 is obtained stereoselectively only by mixing nickel tetracarbonyl, the gem-dibromocyclopropane 150, dimethyl (trimethylsilyl) amine, and an electrophile [82]. gem-Functionalization on a cyclopropane ring carbon atom is attained in this four-component coupling reaction. Phenyl trimethyl silylsulfide serves as an excellent nucleophile to yield the thiol ester, which is in sharp contrast to the formation of a complicated product mixture starting from thiols instead of the silylsulfide [81]. (Scheme 58)... 

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