Isopropylidene- -glyceraldehyde

The lower diastereoselectivity found with aldehyde 15 (R = CH3) can be explained by the steric influence of the two methyl substituents in close vicinity to the stereogenic center, which probably diminishes the ability of the ether oxygen to coordinate. In contrast, a significant difference in the diastereoselectivity was found in the additions of phenyllithium and phenylmagnesium bromide to isopropylidene glyceraldehyde (17)58 (see also Section 1.3.1.3.6.). Presumably the diastereo-sclcctivity of the phenyllithium addition is determined by the ratio of chelation-controlled to nonchelation-controlled attack of the nucleophile, whereas in the case of phenylmagnesium bromide additional chelation with the / -ether oxygen may occur. Formation of the -chelate 19 stabilizes the Felkin-Anh transition state and therefore increases the proportion of the anZz -diastereomeric addition product. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

With respect to the nucleophilic addition of organocopper reagents, a sharp contrast between the rigid isopropylidene glyceraldehyde and its open-chained analog, 2,3-bis(benzyloxy)propanal. was observed (compare Tables 15 and 16). With the isopropylidene-protected aldehyde a high syn diastereoselectivity could only be obtained when tetrahydrofuran was used as reaction solvent, and the diastereoselectivity dropped considerably in diethyl ether. In contrast, the latter solvent allows excellent syn selectivities in additions to the dibenzyl-protected glyceraldehyde81. On the other hand, tetrahydrofuran yields better results than diethyl ether in the... 

A different type of heterocyclic compound, 1,2-oxazines 201, are accessible from the addition of 1-lithio-l-methoxyallene 183 to isopropylidene glyceraldehyde-derived nitrone 200. The predominant formation of the yw-configurated product 201 (syn anti > 98 2) results. Nevertheless, the stereochemical outcome can be reversed by a precomplexation of the nitrone 200 with diethyl aluminum chloride (equation 79)"". ... 

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

Difluorocyclopentadiene was prepared via a pyrolysis reaction the difluoro-methylene centre was installed (Eq. 119) using a DAST fluorination [318]. A fluorobutenolide building block was prepared by a Wadsworth-Emmons reaction of isopropylidene glyceraldehyde removal of the ketal protecting group led to the formation (Eq. 120) of the unsaturated lactone in acceptable overall yield... 

The uses of chiral 3-carbon synthons are many and have been discussed in several reviews and other sources 18-23). Molecules that have been prepared from isopropylidene glyceraldehydes include various trialkoxynitrobutanes such as 35 and 36 24), Corey lactone variants 37 and 38 (25,26), nucleoside analogs 39-42 (27), verrucarinolactone isomers 43-46 (25), the enantiomers of roccellaric acid 47 (29), rubrenolide 48 30) and (+)-laurencin 49 (37). 

Optically active C3-building blocks of type 1 are key starting compounds in organic synthesis.6 The most important member of this class is 2,3-O-isopropylidene-glyceraldehyde 2.67... 

So we concentrated on the synthesis of fragment 129. The two stereogenic centers at C-7 and C-8 were established from (7 )-2,3-isopropylidene glyceraldehyde 132 as shown in Scheme 22 via a sequence already employed in the total synthesis of erythronolide B (18). Stereotriad 135 is available in multigram quantities on this route via 133 and 134 (Scheme 22). After protection of the secondary OH as a p-methoxybenzyl (PMB) ether the base induced 1,3-rearrangement was achieved under standard conditions to furnish the desired olefin 137 (Scheme 23). 

Reaction of isopropyliden-glyceraldehyd with the corresponding organometallic. 

The discovery that -imines obtained from a variety of isopropylidene protected sugar open-chain aldehydes and ketenes, or ketene equivalents afford cz5-substituted 8-lactam adducts usually with a high asymmetric induction and definite relative geometry depending on the absolute configuration of the stereogenic center next to the imine carbon atom (Scheme 1) [21-24], prompted many laboratories to exploit this reaction in a number of syntheses. Imines derived from both easily available enantiomeric forms of 2,3-0-isopropylidene-glyceraldehyde are particularly attractive. 

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