Roche Group

Indofine Chemical La Roche Group (Switzerland) Matheson Tri-Gas Montedison (Italy)... 

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. 

During a synthesis of the antibiotic 1233A, a Hofmann-La Roche group investigated the isopropylidenation of the triol 35 1 under both kinetic and thermodynamic conditions [Scheme 335].18 All three possible 1,3-dioxane derivatives... 

The Hoffmann-La Roche group later followed up on their original synthesis of optically active LTA4 (Scheme 3.31, Ref. 59), using it in a total synthesis of LTC4, LTD4, and LTE4, as outlined in Scheme 3.41. 

Equally, derivatives of this compound, notably an a-methylenic ketone (ref.138) have led to simplifications by the Hoffmann-La Roche group in the synthesis of (+)-estrone methyl ether (ref. 139). For example 3-methoxybenzyl chloride (ref. 140) was reacted with this a-methylenic compound, readily available from A, and afforded in the presence of Cu(l) a 1,4-addition product in 88% yield with little accompanying 1,2-addition. Electrophilic cyclisation with methanolic HCI afforded the tetracyclic product by way of the protonated ketone in 77% yield. Hydrogenation, in which some 9p epimer also resulted, followed by treatment of the crude product with trifluoroacetic acid and Jones oxidation gave estrone methyl ether in 63% yield. 

In a previous discussion of the genus Melodinus (Volume XI, p. 242), the isolation and structure elucidation of meloscine (238) and 16-epimeloscine (239) were discussed. The Hoffmann-La Roche group has subsequently published a full presentation of the structure elucidation of these novel alkaloids (110). 

The Roche group (265) has also been interested in the synthesis of ellipticine derivatives. In particular, 8,9-dimethoxy- and 8,9-methyl-enedioxyellipticines (659) and 660 were their synthetic targets. 

An auxiliary-directed asymmetric Simmons-Smith reaction was used by a Hoff-mann-La Roche group for the synthesis of an ethynyl cyclopropane that served as the A-ring precursor to Vitamin D derivatives [Scheme 2.41]. High diastereoselectivity was achieved with the aid of the dioxolane ring prepared from (/ ,/ )-(-)-butane-23-diol. The acid conditions for hydrolysis of the dioxolane ring were mild enough to leave the cyclopropane ring unperturbed. Dia-stereoselective cyclopropanation of acetals derived from 1,2-di-G-benzyl-L-threi-tol have also been reported. - ... 

At the 4th International Symposium on Carotenoids in Berne in 1975, the total synthesis of (3/, 3 / )-zeaxanthin (119) was reported by the Roche group. The 3-hydroxy-p end group is the most abundant chiral end group of the naturally occurring carotenoids almost 100... 

The Roche group extended this work and in 1981, at the 6th International Symposium on Carotenoids in Liverpool, reported the total synthesis of several of the ten optical isomers of e,8-carotene-3,3 -diol (tunaxanthin, 149) and of four diastereoisomers of p,e-carotene-3,3-diol, including the most common (3R,3 / ,6 / )-isomer, lutein (133). The starting material for these syntheses was 6-oxoisophorone, which the Roche scientists went on to use to synthesize a large number of dicyclic carotenoids in optically inactive and active form, as reported at the 7th International Symposium on Carotenoids in Munich in 1984. 

Assuming that this initial disassembly could handle the selective formation of the C-9 stereocenter, the Hoffmann-La Roche group then anticipated that they could install the C-8 stereocenter in 29 in a controlled manner upon application of a cyclization reaction between the nitrogen atom in 30 and a neighboring group that could be suitably displaced. Although this disconnection involved... 

In a related piece of work, imidazolines have been prepared from A -chloro-N-phenyl amidines and enamines. (Scheme 79). Pyrazomycins have been synthesized by the Roche group, the key step being the preparation of the pyrazolone ring by the addition of toluene- -sulphonyl azide to the anion from diethyl acetone dicarboxylate (Scheme 80). Imidazolidines (201) have been prepared by the action of isocyanates and isothiocyanates with an aziridine ester a dipolar intermediate is implicated. Imidazolidine-4,5-diones have been prepared by the... 

Recently, the Hoffman-La Roche group reported an efficient convergent synthesis of ajmalicine, in which the D/E-rings of the molecule have been constructed from ffons-3-vinyl-4-piperidine acetic acid. ... 

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