Chiral acetals asymmetric synthesis from

An asymmetric synthesis of ethyl 2,3-dideoxy-4-C-methyl-3-C-methylene-D-g/ycero-pentofuranosides has been described. Thus, regioselective cyclization of the chiral acetal 62 (derived from 2,3-dimethyl-2-butenal) under acidic conditions. 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

A concise and efficient asymmetric synthesis of L-( + )-carbafuranomycin 452, a novel analog of L-( + )-furanomycin, which is an unusual antibiotic amino acid of great interest, due to its activity as an isoleucine antagonist, has been reported (496). The synthesis starts with the 1,3-dipolar cycloaddition of a chiral nitrile oxide (obtained in situ from hydroximinoyl chloride 453 via slow addition of NEt3) with cyclopentadiene. Then methylation of cyclopentenyl acetate 454,... 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6-oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu-taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 2 mixture of C-6 epimeric oxazolidine (387) having the (2S) configuration. Reaction of 387 with... 

Mannosides of phosphatidylinositol are important serologically active components of Mycobacterium tuberculosis. For the synthesis of the 2-O-mannosyl derivative (421), Stepanov et al. [291] treated the chiral prop-l-enyl ether (414) [and the corresponding racemic prop-l-enyl ether and racemic benzoate (415)] with the orthoesters (416) or (417) to give the disaccharide (418) [from chiral (414) and acetate (416)] in moderate yield. The disaccharide obtained from racemic (414) contained a high proportion of (418) as a result of asymmetric synthesis. Acidic hydrolysis of (418) gave in low yield (30%) the alcohol (419). 

Diols such as the optically active 1,1 -binaphthyl-2-2 -diol (BINOL) have been used as versatile templates and chiral auxiliaries in catalysts employed successfully in asymmetric synthesis. The application of enzymes in the enantioselective access to axially dissymmetric compounds was first reported by Fujimoto and coworkers.83 In aqueous media, the asymmetric hydrolysis of the racemic binaphthyl dibutyrate (the ester) using whole cells from bacteria species afforded the (A)-diol with 96%ee and the unreacted substrate (A)-ester with 94% ee at 50 % conversion. Recently, in non-aqueous media, lipases from Pseudomonas cepacia and Ps. fluorescens have been employed in the enantioselective resolution and desymmetrization of racemic 6,6 -disubstituted BINOL derivatives using vinyl acetate.84 The monoacetate (K)-73 (product) was obtained in 32-44 % chemical yields and 78-96% ee depending on the derivatives used. The unreacted BINOL (S)-72 was obtained in 30-52 % chemical yield and 55-80% ee. 

Chiral aryl acetic acids constitute a privileged class of target structures due to their prevalence in bioactive natural products and pharmaceuticals and so, unsurprisingly, they constitute attractive targets for asymmetric synthesis [198]. The face-selective addition of a nucleophile to an aryl alkyl ketene provides a very direct entry for the preparation of such compounds. Although this can be achieved by the use of a chiral nucleophile or acid (cf. Scheme 8.1) [199], catalysis of the addition of an achiral nucleophile is clearly attractive from the standpoint of efficiency. 

Scheme 30 Tandem action of chiral Pd(II) and Co/C catalyst for the asymmetric synthesis of cydopentenones from propargyl malonate and allylic acetates...

A wide variety of substituted y-butyrolactones can be prepared directly from olefins and aliphatic carboxylic acids by treatment with manganic acetate. This procedure is illustrated in the preparation of 7-( -OCTYL)-y-BUTYROLACTONE. Methods for the synthesis of chiral molecules are presently the target of intensive investigation. One such general method developed recently is the employment of certain chiral solvents as auxiliary agents in asymmetric synthesis. The preparation of (S.SM+H, 4-BIS(DIMETHYLAMINO)-2,3-DIMETHOXY-BUTANE FROM TARTARIC ACID DIETHYL ESTER provides a detailed procedure for the production of this useful chiral media an example of its utility in the synthesis of (+)-(/ )-l-PHENYL-l-PEN-TANOL from benzaldehyde and butyllithium is provided. 

The first use of crystals to achieve asymmetric induction in a chemical reaction was reported by Penzien and Schmidt in 1969 [3]. In what the authors termed an absolute asymmetric synthesis because it occurs in the absence of any external source of optical activity, Penzien and Schmidt showed that the achiral compound 4,4 -dimethylchalcone 1 crystallizes spontaneously from ethyl acetate in the chiral space group P2i2121, and when enantiomorphously pure... 

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. 

In Kiyooka s approach to acetate aldols by use of a stoichiometric amount of 3f, the enantiomeric excess obtained in the reaction with silyl ketene acetals derived from a-unsubstituted acetates was much lower (ca 10-20 %) than that obtained in the reaction with l-ethoxy-2-methyl-l-(trimethylsiloxy)-l-propene (> 98 % ee). Introduction of an removable substituent, e.g., a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters, resolved this problem [43e], Asymmetric synthesis of dithiolane aldols was achieved in good yield by using the silyl ketene acetal derived from l,3-dithiolane-2-carboxylate in the 3f-promoted aldol reaction, and desulfurization of the dithiolane aldols resulted in production of the acetate aldols in high enantiomeric purity (Eq. 56). 

A chiral carbon present in the alcohol portion of acetals might control the stereochemistry of the allylation. A few examples conducted in the presence of a titanium Lewis acid are shown in Eqs (82) [225], (83) [226], and (84) [227]. In contrast, an allylsilane with a chiral auxiliary derived from arabinose on the silicon atom has been used for asymmetric synthesis, although diastereoselectivity was low [228],... 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

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