Vitamin asymmetric synthesis

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Takaya and co-workers46 found that BINAP-based Ru(II) dicarboxylate complexes 31 can serve as efficient catalyst precursors for enantioselective hydrogenation of geraniol (2E)-32 and nerol (2Z)-32. (R)- or (iS )-citroncllal 33 is obtained in nearly quantitative yield with 96-99% ee. The nonallylic double bonds in geraniol and nerol were intact. Neither double bond migration nor (fi)-/(Z)-isomerization occurred during the catalytic process. Furthermore, the S/C ratio was extremely high, and the catalyst could easily be recovered (Scheme 6-18). This process can be applied to the asymmetric synthesis of a key intermediate for vitamin E. 

However, the effects of chelation allow the formation of one geometric isomer. One example, where the exclusive formation of the lithiated Z-isomer is due to chelation of lithium with an acetal oxygen is described in the asymmetric synthesis of vitamin E62. 

An asymmetric synthesis of the vitamin (+)-biotin has been reported 241 a> using thiazoline (241) as substrate. 

D-(-)-Pantoyl lactone 1s a key intermediate for the synthesis of pantothenic acid which is a member of the vitamin B-complex and is an important constituent of Coenzyme A. Although D-(-)-pantoyl lactone has been obtained by classical optical resolution using quinine, ephedrine, and other chiral amines, catalytic asymmetric synthesis appears to be more effective... 

Yamamoto reported an efficient asymmetric synthesis of the Vitamin E side chain 44.6 in which the key step was an Sn2 reaction of the C2-symmetric dioxolane 44 3 with trimethylaluminium [Scheme 2.44].1<>0 The reaction was slow at -15 °C but delivery of the methyl group was highly diastereoselective (dr -98 2) giving the dioxolane 44 5. 

They can also be used as vinylic carbanion species as shown by the asymmetric synthesis of the chro-man ring of vitamin The (E)/(Z) mixture of chiral sulfoxide (9) was readily isomerized into the ( )-isomer with LDA in THF (the exclusive formation of the ( )-isomer was due to the chelation of lithium with an oxygen of the acetal). Condensation to trimethylhydroquinonecarbaldehyde gave only one diastereoisomer and then the cyclization in presence of sodium methoxide was also fully stereoselective (the stereochemistry of the cyclization being controlled by that of the allylic hydroxy group which is eliminated during the cyclization Scheme 48). 

The growing interest manifested by synthetic chemists towards the use of the asymmetric dihydroxylation of olefins has resulted in so many varied apphca-tions that it is beyond the scope of this limited review to enumerate them all. Throughout this concise review, the specificities of the catalytic AD of alkenes have been discussed and the salient features of the almost limitless transformations of the resulting chiral diols have been illustrated through the use of selected examples. Whilst the AD of olefins is now considered as one of the most important tools in asymmetric synthesis, let us not forget that the enantioselectiv-ity displayed by the asymmetric dihydroxylation process can depend upon subtle steric, electronic or conformational effects that are far less pronounced in other asymmetric catalytic reactions. Such is the case in our last example [141], featuring an elegant approach towards vitamin E by Tietze and coworkers... 

This transamination reaction mimicks vitamin B6 enzymes. Other pyridoxamine analogs and their successful use in the asymmetric synthesis of natural amino acids by a transamination reaction have also been described18, l9. 

Asymmetric synthesis, the selective generation of new chirality elements (as one definition goes), has developed from a specialty pursued by outsiders to an art cultured by some learned ones, and now may be considered a standard laboratory methodology for everybody s use. This development has taken place exponentially (explosively ) in the last two decades, triggered by a number of circumstances. Also the practitioners of pharmaceutical, vitamin, and agro synthesis need to produce enantiopure, rather than racemic active compounds (for registration ). 

An asymmetric synthesis of a vitamin D ring a synthon employed this intramolecular cyclopropanation reaction (eq 23). ... 

Contents B. FRASER-REID and R. C. ANDERSON, Carbohydrate Derivatives in the Asymmetric Synthesis of Natural Products — H. JONES and G. H. RASMUSSON, Recent Advances in the Biology and Chemistry of Vitamin D — S. LIAAEN-JENSEN, Stereochemistry of Naturally Occurring Carotenoids — T. KASAI and P. O. LARSEN, Chemistry and Biochemistry of y -Glutamyl Derivatives from Plants Including Mushrooms (Basidiomycetes) - Author Index - Subject Index. 

The total synthesis of enantiopure natural products has been one of the key developments of the modem era of asymmetric synthesis. Since the Hajos-Wiechert reaction allows ready access to useful chiral bicyclic building blocks, the reaction has been widely employed to constmct a variety of precursors for the synthesis of steroids, vitamin D derivatives, and other natural products. The remainder of the review will look at select examples from the total synthesis literature to illustrate this point. 

Trost and Asakawa have evolved an efficient asymmetric synthesis of the vinylchroman 293, an important building block for the synthesis of vitamin E. The requisite substrate 292 was prepared as previously described from hydroquinone in a 45% overall yield. Using the ligand RJt)-44, the reaction proceeded satisfactorily with either Tj -aUylpaUadium chloride dimer or (dba)3Pd2-CHCl3 as palladium source. The yields were generally nearly quantitative but the enantiomeric excess was modest. A variety of... 

Vitamin E (a) L. F. Tietze, J. Gorlitzer, A. Schuffenhauer, M. HUbner, Eur. J. Org. Chem. 1999, 1075-1084. Enantioselective synthesis of the chromane moiety of vitamin E. (b) L. F. Tietze, J. Gorlitzer, Synlett 1997, 1049-1050. Preparation of enantiopure precursors for the vitamin E synthesis. A comparison of the asymmetric allylation of ketones and the sharpless bishydroxylation. (+)-Hydroxymyoporone (c) L. F. Tietze, C. Wegner, C. Wulff, Chem.-Eur. J. 1999, 5, 2885-2889. First total synthesis and determination of the absolute configuration of the stress factor (+)-hydroxymyoporone. 5,6-Dihydrocineromycin B (d) L. F. Tietze, L. Vblkel, Angew. Chem. Int. Ed. 2001, 40, 901-902. Total synthesis of the macrolide antibiotic 5,6-dihydrocineromycin B. 

Asymmetric synthesis can also sometimes be done by biocatalysis. This has been used in large-scale syntheses for years. For example, the Reich-stein process for the synthesis of vitamin C, established in 1933 and still in use, involves the biotransformation of sorbitol to L-sorbose [41]. L-camitine is used as a thyroid inhibitor. It is prepared by enzymatic hydroxylation of 4-butyrobetaine [42]. 

Roche ester, (R)-3-hydroxy-2-methylpropionic acid methyl ester (16b), is a chiral building block for the synthesis of vitamins (a-tocopherol), natural products (spiculoic acid A), antibiotics (calcimycin), and fragrance components (muscone) and therefore of high interest for industry. Faber and coworkers employed ERs for the asymmetric synthesis of methyl 2-hydroxymethylacrylate derivatives... 

Recent studies revealed that (2S)-tocopherols have no antioxidant effect in biological systems because they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. As a result, the enantioselective synthesis of the a-tocopherol became attractive, and several groups have reported on its asymmetric synthesis. In addition, Tietze and co-workers reported on an enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction (Scheme 21.15). ° In their study, reaction of 64 with methyl acrylate in CH2CI2 with catalytic amounts of Pd(TFA)2 (TEA = trifluoroacetate), the chiral ligand (5,5)-Bn-BOXAX 65, and p-benzoquinone afforded the desired chroman 66 with 96% ee in 84% yield. The enantioselective cascade reaction described therein provided the efficient construction of the chroman firamework of vitamin E 67 with concomitant introduction of part of the side chain in high yields and high enantioselectivities. 

This first chemoenzymatic synthesis [48] is not included m Fig. 1 but can be considered as a preparation of A-ring synthons in general in the steroid field, and particularly in area of vitamin D (Scheme 9). The stereo control of the quaternary chiral carbon center is one of the important subjects in asymmetrical synthesis. This issue prompted research on the use of chiral monoester 197, which can be obtained in multihundred gram scale by the pig liver esterase (PLE)-mediated hydrolysis of the corresponding symmetrical diester 196 [49]. Thus, an efficient methodology was developed for the preparation of chiral cyclohexene derivatives from cw-diester 196, using PLE in a biphasic system using phosphate buffer and acetone, to afford the chiral half-ester 197. Scheme 9 shows the efficient... 

The compatibility with different functional groups, the remarkable regio-and stereoselectivity, and the development of asymmetric procedures have made benzannulation an attractive methodology for the synthesis of natural products with densely functionalized quinoid or fused phenolic substructures [13-20], Some pertinent examples are the syntheses of vitamins K and E [17], and the production of anthracyclinones or naphtoquinone antibiotics [13, 14a, 15, 21]. 

---