Natural product synthesis desymmetrization

In contrast, tautens and coworkers recently focused on asymmetric hydroalumination using Ni-BINAP as catalyst [177]. The reaction involves ring-opening desymmetrization of several 1,4-dihydrofuran derivatives that produce important chiral building blocks for natural product synthesis high ee is usually obtained (Scheme 6.138) [178]. 

Cyclohexadieones. Since cyclohexadienones are highly useful synthetic intermediates for natural product synthesis and drug discovery efforts, the catalytic asymmetric desymmetrization of cyclohexadienones has received much attention and several success have been made in recent years. Hayashi et al. [109] developed the first oragnocatalytic asymmetric desymmetrization of cyclohexadieones. Screening different secondary amines revealed that cysteine-derived amine is the most effective organocatalyst, affording the bicyclo[4,3,0]nonene skeleton in... 

Stereoselective carbon-carbon bond formations with hypervalent iodine reagents are also prominently described in the literature. Direct asynunetric a-arylation reactions are not easy to perform. Ochiai et al. synthesized chiral diaryliodonium salts such as [l,l -binaphthalen]-2-yl(phenyl)iodonium tetrafluoroborate derivatives 21 via a BFs-catalyzed tin-X -iodane exchange reaction and developed the direct asymmetric a-phenylation of enolate anions derived from cyclic p-ketoesters (Scheme 7) [37]. A beautiful example of direct asymmetric a-arylation of cyclohexanones in the course of a natural product synthesis was presented through the desymmetrization of 4-substituted cyclohexanones using Simpkin s base, followed by coupling with diaryliodonium salts [38]. Other binaphthyl iodonium salts related to 21 have also been reported [39]. 

This chapter illustrates the application of lipases and esterases as user-friendly biocatalysts in (i) desymmetrization of prochiral or meso-diols and diacetates, (ii) kinetic resolution of racemic alcohols, and (iii) preparation of enantiopure intermediate(s) from a mixture of stereoisomers by enzymatic differentiation. All the examples were taken from our own works in natural products synthesis. 

Holland, J.M., Lewis, M and Nelson, A. (2001) First desymmetrization of a centrosymmetric molecule in natural product synthesis Preparation of a key fragment in ffie synffiesis of hemibrevetoxin B. Angew. Chem. Lnt. Ed., 40,4082—4084. 

A [2 + 2] photoaddition-cycloreversion was applied to the enantioselective synthesis of the natural product byssocMamic add (Figure 6.11). Desymmetrization of a meso-cyclopentene dimethyl ester with PLE in pH 7 buffer-acetone (5 1) provided a monoacid, one of the photopartners. It is noteworthy that both enantiomers of this natural product were synthesized from the same monoacid [58]. 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Enantiomerically pure cyclopropanes are a frequent motif in the structure of natural products. Their synthesis is often demanding and many approaches have been made [50, 51]. Porcine pancreatic lipase (PPL) was used for the stereoselective desymmetrization of a cyclopropane dibutanoate (Fig. 2). The asymmetric hydrolysis of the meso compound yielded the corresponding enantiopure alcohol almost quantitatively. The intermediate obtained was successfully applied in the total synthesis of dictyopterenes A and C, sexual pheromones of brown algae [52], and constanolactones (see below) [53]. 

Allyl amines can also be formed by desymmetrization of allyl diols with tosyl isocyanate in the presence of chiral palladium complexes [19d,27]. Trost et al., as well as others, have recently used this approach for the synthesis of natural products [28]. 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

The hydroacylation of alkynals was also reported by Tanaka and Fu, who found that the Rh(I)-Tol-BlNAP system was the catalyst of choice for the hydroacylation-desymmetrization of 3-6is-alkynals 194 to give 4,4-disubstituted cyclopentenones 195 in excellent yields and high enantioselectivities. Cyclopentenones are important intermediates in the synthesis of natural products such as prostaglandins. This catalyst system was also found to be extremely effective in the kinetic resolution of racemic 3-disubstituted alkynals 196 giving the unreacted aldehyde 197a with near perfect enantioselection. 

An elegant approach, somewhat related to the strategies described earlier, was recently applied to the total synthesis of Cavicularin, a natural product. A sulfinyl group was first introduced in a nonasymmetric way to facilitate a subsequent Sj Ar it was then replaced by sulfoxide/lithium interchange, by the same sulfinyl group but, enantioselectively, for the desymmetrization of an advanced intermediate (Scheme 28.16) [88]. 

Synthesis of polypropionate marine natural product (+)-membrenone C and its 7-epi-isomer has been reported using a key desymmetrization technique to create five contiguous chiral centers frombicyclic precursor 36. The diol was protected using di-f-butylsilyl bis(trifluoromethanesulfonate) and further elaborated into the natural product and its epimer (eq 14). In a separate communication, Perkins et al. utilized di-f-butylsilyl bis(trifluoromethanesulfonate) for synthesis of a model system en route to the pol)q)ropionate natural products auripyrones A and... 

You and coworkers developed a desymmetrization protocol based on an intramolecular oxo-Micliael reaction, using as catalyst the phosphoric acid derivative 121 [110]. Cyclohexadienones 120 were transformed into the corresponding bicyclic systems 122 with high yields and enantioselectivities. Remarkably, the 4-substituent in the cyclohexadienone has a great influence on the enantioselective outcome of the reaction. Bulkier substituents at the 4-position lead to lower reaction rates and enantioselectivities (Scheme 33.35). This desymmetrization reaction was used as a key reaction for the efficient synthesis of the natural products cleroindicins C,... 

This next procedure is another hydrolysis, but differs in several ways from the first example. First, this is an enantioselective hydrolysis of a secondary alcohol ester, one of the most common and useful applications of hydrolases (Figure 5.8). Second, the reaction is not a kinetic resolution, but an asymmetric synthesis or desymmetrization, which yields up to 100% of the desired enantiomer (96% isolated yield in this example). The product (lk,4S)-(+)-4-hydroxy-2-cyclopentenylacetateisaprecursorforenantiopure4-hydroxy-2-cyclopentenones. This compound was historically a key intermediate for synthesis of prostaglandins, but its application has been extended to a wide range of complex natural products [28]. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

This methodology was later applied to the desymmetrization of the pendant dione moiety 235 to give products 236 embodying four contiguous stereocenters with complete stereochemical control resulting in high enantiomeric excesses (Scheme 106) (186). The resulting products can be used as synthons to set chiral centers in the total synthesis of both natural and unnatural products. 

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