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LETTER
Synthesis of Acetylene 10 (Scheme 2) and Bromide 7.
The synthesis of acetylene 10 commenced with the alkyl-
ation of propanoyloxazolidinone 11 with allyl iodide 1216
to form alkene 13. Based on the Sharpless mnemonic,
asymmetric dihydroxylation17 of the terminal olefin using
potassium osmate and (DHQ)2PHAL, was expected to af-
ford diol 15, however, in the final stages of this work, X-
ray diffraction studies subsequently revealed that lactone
16, produced by cyclisation of the unexpected diol 14,
was in fact the major product. Lactone 16 contains the in-
correct stereochemistry at C-4 to that required for the for-
mation of acetylene 10. It is unclear why the facial
selectivity of dihydroquinine ligands did not follow the
Sharpless mnemonic, however, the presence of the chiral
oxazolidinone moiety may have been a contributing fac-
tor. The development of methodology to reverse this
stereochemical outcome in order to obtain the correct diol
15 is currently being investigated. Work reported herein
provides methodology to produce a fragment resembling
the B,C,D and E rings of antibiotic CP44,161 using acet-
ylene 19.
The synthesis of acetylene 19 was completed by reduction
of lactone 16 with lithium borohydride to afford triol 17
which, after protection of the 1,2-diol as an acetonide, was
oxidised at the remaining primary alcohol to afford alde-
hyde 18. Grignard reaction of aldehyde 18 with propar-
gylmagnesium bromide resulted in the formation of an
alcohol which, after protection as a silyl ether afforded
acetylene 19 as a 1:1 mixture of diastereomers.
Scheme 2
The major aldehyde 27 prepared in Scheme 3 is epimeric
at C-2, C-5 and C-7 to that required for the bis-spiroacetal
portion of the right hand fragment 5 of antibiotic
CP44,161 1 while acetate 25 has the correct stereochem-
istry for the bis-spiroacetal moiety but is epimeric at C-2.
Conversion of the epimeric bis-spiroacetal centres (C-5,
C-7) in aldehyde 27 to the naturally occurring cis bis-
spiroacetal conformation present in acetate 25 (which is
also found in salinomycin 2) may be achieved by acid ca-
talysed equilibration at a later stage in the synthesis as
demonstrated by Kocienski et al.10 in the synthesis of sali-
nomycin 2. In order to obtain the correct stereochemistry
at C-2 however, a synthesis of acetylene 10 is required.
Synthesis of Aldehyde 27 (Scheme 3). With acetylene 19
and lactone 9 in hand, assembly of the bis-spiroacetal core
was effected based on related work.15 Addition of the lith-
ium acetylide derived from acetylene 19 to lactone 9 fol-
lowed by treatment with acidic methanol afforded acetal
20. After protection of the primary hydroxyl group as an
acetate 21, partial hydrogenation to a cis olefin followed
by acid catalysed cyclisation resulted in a 1:1 mixture of
spiroacetals 22a and 22b.
Spiroacetals 22a and 22b were treated with iodobenzene
diacetate and iodine18 to afford a 1:3.3 mixture of tricyclic
bis-spiroacetals 23 and 24. The preference for cis bis-
spiroacetal 24 in this cyclisation reaction can be attributed
to the presence of the C-4 methyl group, which causes un-
favourable steric interactions upon formation of the minor
trans bis-spiroacetal 23. trans Bis-spiroacetal 23 therefore
undergoes rapid epimerisation at the allylic spirocentre to
cis bis-spiroacetal 25. The presence of the C-4 methyl
group exhibited a marked effect on the stereochemical
outcome of the oxidative cyclisation in that earlier studies
on the oxidative cyclisation of spiroacetals which lack this
methyl group provided the trans isomer as the major prod-
uct.
Synthesis of Bromide 7. Bromide 7 was prepared in six
steps from 2-acetyl-g-butyrolactone following Julia olefi-
nation methodology previously used in the synthesis of a
related bromide.19
Synthesis of Polyether 32 - a Fragment Resembling
the B,C,D and E rings of Antibiotic CP44,161 1
(Scheme 4).
Applying methodology established in synthetic approach-
es to the D and E rings of salinomycin 2,19 the union of
bromide 7 and aldehyde 27 using a Barbier reaction re-
sulted in the successful synthesis of alcohols 28 and 29 as
a 4.7:1 mixture of erythro and threo isomers in 85% yield.
After separation of erythro alcohol 28, treatment with
dimethyl dioxirane resulted in a 1:1 mixture of epoxides
30 and 31 which, after treatment with a catalytic quantity
of PPTS cyclised in 60% overall yield to afford polyethers
32 and 33 which were separated by HPLC.
Hydrolysis of the bis-spiroacetal acetate 24 afforded alco-
hol 26 which upon oxidation using tetrapropylammonium
perruthenate afforded aldehyde 27.
Synlett 1999, No. 3, 295–298 ISSN 0936-5214 © Thieme Stuttgart · New York