Biotin, total synthesis

Scheme 1. Model studies for the total synthesis of biotin (1).

The total synthesis of biotin (1) described in this chapter provides an impressive example of the intramolecular nitrone-olefin [3+2] cycloaddition reaction. Aiming for a practical process, the Hoff-mann-La Roche group utilized relatively simple and inexpensive starting materials, and ingeniously controlled the crucial [3+2] cycloaddition reaction to give only one stereoisomer by confining the cycloaddition precursor to a ten-membered ring. 

In a total synthesis of biotin from L-Cys, the thiophene derivative 24 is formed from A(-protected carbomethoxymethylcysteine ester with sodium methoxide (44JA1756). 

In a total synthesis of D-biotin, the first step involved a condensation of L-Cys with benzaldehyde (75JA5936 77JA7020). Consensation of Cys with glyoxylic acid gave thiazolidine-2,4-dicarboxylic acid as a mixture of two isomers, formed in an approximate ratio of 7 3, the major product having... 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

Y. Y. Chu, Y. Synthetic studies on d-biotin, part 6 an expeditious and enantiocontrolled approach to the total synthesis of d-biotin via a polymer-supported chiral oxazaborolidine-cata-lyzed reduction of meso-cyclic imide strategy. Synthesis 2003, 2155-2160. 

A noteworthy feature of the method is that turnover of the catalyst is achieved in the absence of a stoichiometric achiral base, despite the generation of an acidic product (cf. the use of pempidine in the Bolm catalytic protocol) [180-182]. The synthetic utility of this approach has been demonstrated in a formal total synthesis of (+)-biotin [183]. Recently a silica-supported heterogeneous analogue of (DHQD)2AQN has also been developed by Han [184, 185]. (For experimental details see Chapter 14.17.11). 

The last step in a stereospecific total synthesis of ( )-biotin consists of the facile reaction of the precursor diamine with phosgene (equation 5) (77JA6754). The reaction of a cyclic amidrazone precursor with phosgeniminium chloride gives thiazolo[3,2-6]-s-triazoles (equation 6) (73AG(E)405). Treatment of 4,5-diaminopyrazoles with thionyl chloride forms pyrazolo[3,4-c][l,2,5]thiadiazoles (equation 7) (68JMC1164). 

In the total synthesis of biotin, Marx and coworkers had to reduce a thiophene intermediate containing an endiamide function which was particularly refractory to hydrogenation. This was accomplished only by the use of 20% Pd(OH)2 on charcoal... 

The total synthesis of a novel hybrid lipid Pea-PIP2 (51), possessing a phosphatidyl ethanolamine (PE) headgroup at the 1-position and a phosphatidyl inositol 4,5-bisphosphate [PtdIns(4,5)P2] headgroup at the 4-position has been elaborated. Reporter groups (biotin, fluorophores, spin label) were... 

The first total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis, was completed by A. Marquet and co-workers. In order to prove its structure unambiguously, both the cis and trans isomers were prepared. The L-amino acid functionality was installed by a Strecker reaction using TMSCN in the presence of catalytic amounts of Znla. The resulting O-TMS protected cyanohydrin was exposed to saturated methanolic ammonia solution, which gave rise to the corresponding a-amino nitrile. Enzymatic hydrolysis with immobilized pronase afforded the desired L-amino acid. 

BIOTIN A CHALLENGE FOR INDUSTRIALLY VIABLE TOTAL SYNTHESIS OF NATURAL PRODUCTS... 

ABSTRACT The course of our investigation to develop an industrially viable total synthesis of (+)-biotin is described. Three synthetic approaches to (+)-biotin have been investigated to develop an efficient synthetic method asing L-cysteine and thiolactone as a starting material and a key intermediate, respectively. Short steps, high yield and ease of operation of the approach would permit the hitherto most efficient access to (+) biotin. 

Marx, M., Marti, F., Reisdorf, J., Sandtneier, R., and Clark, S. 1977. A stereospecific total synthesis of (+/—)-biotin. Journal of the American Chemical Society, 99 6754—6756. 

A rational total synthesis is used for some simple alkaloids (adrenaline, theophylline, papaverine), low molecnlar peptide hormones (oxytocin, vasopressin), vitamins (biotin, folk acid, thiamine, riboflavin), phenolic acids (sahcyhc acid). It should, however, be observed that the synthetic substances are all racemic forms, whereas many natural products occur in the 1-form. 

D-(+)-Biotin (1), a biocatalyst of reversible metabolic reactions of carbon dioxide transport in organisms, is one of the water-solnble B-complex gronp of vitamins and has immense commercial importance in ponltry feeds and animal nntrition. Componnd 1 was isolated from egg yolk, liver and milk concentrates. " It is an important vitamin for human nutrition and animal health. " Its structure was determined and confirmed by the first total synthesis. Its absolute configuration by X-ray crystallographic analysis was established. Syntheses of biotin from noncarbohydrate and its analogues from carbohydrate and noncarbohydrate have been reported. " Syntheses from carbohydrate precursors are discussed in this part. 

Synthesis from o-mannose A total synthesis of D-(- -)-biotin (1) from D-mannose has also been reported (Scheme Treatment of 2,3 5,6-di-0-isopropylidene-a-D-mannofuranose (17) with benzoyl chloride followed by selective hydrolysis of the terminal acetal group afforded 1-0-benzoyl-2,3-0-isopropylidene-a-D-mannofuranose (18). Subsequent periodate oxidation and chain extension with the proper phosphorane followed by hydrogenation gave the uronate derivative 19. Treatment of 19 with NaOCHs followed by reduction of the resulting aldehyde with sodium borohydride afforded compound 20. 

The first example, reported in 1975 by Marquet, concerns a novel total synthesis of biotin, based on stereoselective alkylation of a bicyclic, cw-fused, five-membered ring sulfoxide [126,127]. 

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