|Abstract or Summary
- Several approaches to the synthesis of methymycin were
investigated. Segment A (39), containing functionality corresponding
to C-9, 10, and 11 of methynolide was made in
six steps from propionaldehyde in an overall yield of 37%.
Oxidation of 34 with silver nitrate gave 35 which, upon hydroxylation
with hydrogen peroxide, gave the erythro isomer
of dihydroxy acid 36. This acid was resolved with brucine
and its absolute configuration determined by Horeau's method.
The (+) acid was found to have R,R configuration. This
substance was converted to its acetonide (+)-37, which was
reduced with lithium aluminium hydride to give (+)-38. Oxidation
of (+)-38 with Collins' reagent gave (+)-39.
An approach to the B segment (31), corresponding to
C₁₋C₈ of methymycin, from dicyclopentadiene was investigated.
Dicyclopentadiene, on reaction with selenium dioxide
followed by oxidation by Jones' reagent, gave 53. Treatment
of 53 with methyl magnesium iodide in the presence of cuprous chloride gave 54. The latter was converted to ketal
55, which was subjected to Lemieux-von Rudloff oxidation to
give diacid 56. This diacid was converted to its diester 57
which, on reduction with lithium aluminium hydride, gave
diol 58. Efforts to reduce the two primary alcohol functions
to methyl groups were unsuccessful. The ketal 55 was
converted to the dialdehyde 63 with sodium metaperiodate
and osmium tetroxide. However, attempted tosylhydrazone
formation led to complex mixtures.
An alternative approach via cycloaddition of 2,4-dibromo-
3-pentanone (64) to furan, using zinc-copper couple,
gave a mixture of adducts 65, 66 and 67 in a 8:1:1 ratio.
Efforts at reducing the ketone in these cycloadducts to a
methylene group led to recovery of starting material. The
mixture of cycloadducts was reduced with sodium borohydride
to yield alcohols 76 and 77 in a 2:1 ratio. On treatment of
this mixture with methanesulfonyl chloride only the exo mesylate
78 was formed. Attempts to displace this mesylate
with various reducing agents were unsuccessful. Hydroboration
of 65, followed by oxidation, led to diketone 82.
However efforts directed towards a Baeyer-Villiger oxidation
of this substance led to decomposition.
A cycloaddition approach to methynolide, using 2-furfuryl
benzyl ether (84), was also investigated. The reaction
of 64 with 84 in the presence of zinc-copper couple
gave 85, reduction of which with sodium borohydride led to alcohol 86. Epoxidation of 86 with m-chloroperbenzoic acid
gave alcohols 87 and 88 in a 85:15 ratio. The major isomer
was converted to its mesylate 89, but attempts to displace
the mesylate reductively were unsuccessful. Alcohol 86 was
converted to its mesylate 97 which, on reaction with m-chloroperbenzoic
acid, gave epoxide 98. Reduction of 98
with lithium aluminium hydride afforded a mixture of olefinic
alcohols assigned as 99 which, upon hydroboration,
gave 100. Attempts at oxidizing alcohols 99 and 100 were
unsuccessful. Also, an attempt to transform the alcohol 86
to bromohydrin 106 led instead to the bridged bromoethers
109 and 110 in a 1:1 ratio. Treatment of the mixture of
109 and 110 with lithium dimethylcuprate regenerated 86.
Cycloaddition of 64 with 3-methylfuran was briefly investigated
and was found to yield 112. Hydroboration of
112, followed by oxidation with sodium dichromate, gave diketone
116 which, on treatment with sodium methoxide, gave
the epimeric diketone 117. An attempted Baeyer-Villiger
oxidation of 117 with trifluoroperacetic acid was unsuccessful