Chiral building blocks asymmetric synthesis

The chemistry of aziridine-2-carboxylates and phosphonates has been discussed in part in several reviews covering the literature through 1999 [1-3], This chapter is intended to give an overview of asymmetric syntheses using chiral nonracemic aziridine-2-carboxylates and -phosphonates with particular emphasis on their applications as chiral building blocks in asymmetric synthesis since 2000. Some overlap with earlier reviews is necessary for the sake of continuity. 

The stereogenic centers of chiral dendrimers synthesized so far are either generated by asymmetric synthesis, or they are derived from molecules of the pool of chiral building blocks. The only investigation on chiral dendrimers, consisting of achiral building blocks exclusively, was published by Meijer et al., who synthesized dendrimers such as 31 [61] (Fig. 14). This compound ows its chiral-... 

Similarly, whole-cell Lactobacillus kefir DSM 20587, which possesses two alcohol dehydrogenases for both asymmetric reduction steps, was applied in the reduction of tert-butyl 6-chloro-3,5-dioxohexanoate for asymmetric synthesis of ft rf-butyl-(31 ,5S)-6-chloro-dihydroxyhexanoate (Figure 7.5), a chiral building block for the HMG-CoA reductase inhibitor [ 17]. A final product concentration of 120 him and a specific product capacity of 2.4 mmol per gram dry cell were achieved in an optimized fed-batch process. Ado 99% was obtained for (3R,5S)- and (3.S, 55)-te/ f-butyl-6-chloro-dihydroxyhexanoate with the space-time yield being 4.7 mmolL-1 h-1. 

Havel, J. and Weuster-Botz, D. (2006) Comparative study of cyanobacteria as biocatalysts for the asymmetric synthesis of chiral building blocks. Engineering in Life Sciences, 6, 175-179. 

Enantiomerically pure sulfoxides play an important role in asymmetric synthesis either as chiral building blocks or stereodirecting groups [156]. In the last years, metal- and enzyme-catalyzed asymmetric sulfoxidations have been developed for the preparation of optically active sulfoxides. Among the metal-catalyzed processes, the Kagan sulfoxidation [157] is the most efficient, in which the sulfide is enantioselectively oxidized by Ti(OzPr)4/tBuOOH in the presence of tartrate as chirality source. However, only alkyl aryl sulfides may be oxidized by this system in high enantiomeric excesses, and poor enantioselectivities were observed for dialkyl sulfides. 

The cyclopropane aldehyde 156 was identified as a versatile chiral building block for the enantioselective synthesis of 4,5 disubstituted y-butyrolactones of type 158 or 159. Both enantiomers of 156 can be easily obtained in a highly diastereo- and enantioselective manner from fixran-2-carboxylic ester 154 using an asymmetric copper-catalyzed cyclopropanation as the key step followed by an ozonolysis of the remaining double bond (Scheme 25) [63]. Addition of... 

In the asymmetric addition to alkenylphosphonate 33 (Eq. 2) [25], the yield is dependent on the amount of water present. The combination of boroxine and water (1 equiv. relative to boron) gave a high yield of the desired product 34, with 96% enantiomeric excess. The alkylphosphonate 34 can be used as a chiral building block for the synthesis of optically active alkenes, using a Horner-Emmons type of reaction. 

The vinylcyclopropane 10 is a useful chiral building block for organic synthesis, as the vinyl group can be oxidatively cleaved if desired and further functionahzed (Scheme 14.1). Either diastereomer 20 or 21 of the cyclopropane analog of phenylalanine can be readily prepared from 10 [40]. Corey has reported another elegant appHcation of the vinylcyclopropane 10 in the asymmetric synthesis of the antidepressant (-i-)-sertraline 22 [52]. 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

Optically pure l,l -binaphthol and its derivatives have been evaluated as versatile chiral auxiliaries and ligands in asymmetric transformations. Research in this area has provided many efficient and useful methods for the preparation of key chiral building blocks, some of which have been used for the construction of complex natural products. The wide ranging and important applications of such compounds in organic synthesis have stimulated great interest in developing efficient methods... 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

We describe herein our recent achievement of total syntheses of (-)-strychnine and fostriecin. The key stereocenters were constructed using catalytic asymmetric reactions developed in our group. Catalytic asymmetric reactions that can produce versatile chiral building blocks with high practicality should ensure further efficient total synthesis of complex molecules in future. 

The asymmetric catalytic nitroaldol reaction, also known as the asymmetric Henry reaction, is another example of an aldol-related synthesis of high general interest. In this reaction nitromethane (or a related nitroalkane) reacts in the presence of a chiral catalyst with an aldehyde, forming optically active / -nitro alcohols [122], The / -nitro alcohols are valuable intermediates in the synthesis of a broad variety of chiral building blocks, e.g. / -amino alcohols. A highly efficient asymmetric catalytic nitroaldol reaction has been developed by the Shibasaki group, who used multifunctional lanthanoid-based complexes as chiral catalysts [122-125],... 

Hydrolases are widely used enzymes in organic synthesis, with most applications concentrating on lipases and esterases. This chapter discloses the possibilities of asymmetric accesses to chiral building blocks for the synthesis of natural products... 

Levoglucosenone and its functionalized analogue have been synthesized from furan by employing either enzymatic resolution or asymmetric synthesis. The potential of the latter as a chiral building block has been demonstrated by synthesis of all eight hexose diastereomers and some other natural products. 

In principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

Davis and Andermichael recently described a new method for the asymmetric synthesis of 3-substituted-1 -(2//)-isoquinolones which are important chiral building blocks for alkaloid synthesis.83 This procedure involved the highly diastereose-... 

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