Hydroxymethyl compounds synthesis with addition

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120... 

Other chiral phosphine-phosphites with relevance to application in AHF are those derived from BIPHEN (Scheme 2.141), as claimed by ChiroTech Technology Ltd./Dr Reddy s Laboratories [35]. Their total synthesis starts with enantiopure l-hydroxy-2,5-diphenylphospholane 1-oxide, which is available via a multistep approach suggested by Fiaud et al. [36]. This material is converted via its borane adduct into the corresponding hydroxymethyl compound by addition to paraformaldehyde. Phosphorylation of the alcohol with enantiopure BIPHEN-X (X = C1, Br, or I) produces the phosphite. The use of phosphorbromidite or the relevant iodide sometimes avoids the need for higher temperatures, which... 

During formation of the addition compounds 12 and 16, no free formaldehyde accumulates. We assume that the liberated formaldehyde immediately reacts with tris-hydroxymethyl-phosphine, forming the quaternary tetrakis-hydroxymethyl-phosphonium salt 13. The addition compounds 12 and 16 are relatively unstable, but can be purified for analysis. Intermediates 12 and 16 can also be employed in the synthesis of symmetrical or unsymmetrical phosphamethin-cyanines. For example, Klapproth synthesized 18 in 60% yield by condensing 16 with 77. 

A variation of this route was applied to the preparation of a-methylenecyclo-pentane 179, an intermediate that was employed for the synthesis of prostaglandin PGF2o, (180) (Scheme 6.82). The acetonide-protected oxime-diol 175 [derived from propanal (174)] was treated with sodium hypochlorite without the addition of base. This led to the tricyclic adduct 176 with high stereoselectivity. One of the side chains was subsequently elaborated and the fully protected cyclopentano-isoxazo-line (177), when exposed to Raney Ni/boron trichloride, gave the 2-hydroxymethyl-cyclopentanone (178). This compound was dehydrated using mesyl chloride/ pyridine to furnish enone (179) (324). In another related synthesis of PGF2q, the p-side-chain (3-hydroxyoctenyl) was introduced prior to the cycloaddition (325). 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

Despite several synthetic approaches to the cyciopentane moiety of carbocyclic nucleosides, starting from noncarbohydrate synthons or readily available meso intermediates, no universally applicable methodology is yet available for the asymmetric synthesis of these compounds (28-31). An efficient access to chirality is via enantioselective resolution of a prochiral or a meso intermediate prior to the addition of the purine or pyrimidine base. For example, pig liver esterase (PLE) has been used in a chemoenzymatic approach to the synthesis of optically active (-l-aristeromycin and (-)-neplanocin (32), whereas cyclic y-acetamido esters were resolved to obtain (-)-4 d5-amino-2,3-trflTis-dihy-droxy hydroxymethyl cyciopentane as a key intermediate in the synthesis of carbocyclic nucleosides (33). Although hydrolytic enzymes often display a limited degree of enan-tiospecificity with such unnatural substrates, reaction conditions can in many cases be optimized to improve the enantioselectivity (34). 

Regioselective opening of 2 ,3 -/yxo-epoxides with a lithiated dithian gave rise to branched structures of type (63, B=U or T) which could be converted (Scheme 9) into 3 -C-difluoromethyl compounds (64) and thence into analogues (65) with an additional fluorine atom at C-2 . 22 Alternatively, intermediates (63) could be used as precursors for 3 -C-hydroxymethyl systems (66), 23 and, by successive fluorination, fluoromethyl analogues of types (67) and (68) were obtained. 22 jn a synthesis of 3 -deoxy-3 -hydroxymethyl adenosine (69), the branched-chain sugar derivative (70),... 

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