Synthetic studies towards the B,C,D,E fragment of antibiotic CP44, 161

Article abstract of DOI:10.1055/s-1999-2607

The synthesis of polyethers 32 and 33 from tricyclic bis-spiroacetal aldehyde 27 and E-bromide 7 are described. A key step in the synthetic strategy involved the oxidative cyclisation of a bicyclic hydroxyspiroacetal 22a,b to a cis bis-spiroacetal unit, which resulted in preferential formation of cis aldehyde 27. A Barbier reaction of bromide 7 and tricyclic aldehyde 27 then afforded erythro alcohol 28 which after epoxidation and acid catalysed cyclisation completed the synthesis of polyethers 32 and 33 providing an effective framework on which to synthesise the B,C,D and E rings of antibiotic CP44,161 1.

Full text of DOI:10.1055/s-1999-2607

LETTER
295
Synthetic Studies Towards the B,C,D,E Fragment of Antibiotic CP44, 161
Paul A. Allen,b Margaret A. Brimblea* and Hishani Prabaharanb
aDepartment of Chemistry, University of Auckland, Private Bag 90219, Auckland, New Zealand
bDepartment of Chemistry, University of Sydney, Camperdown, NSW 2006, Australia
Received 5 January 1999
With these thoughts in mind, a synthesis of antibiotic
CP44,161 1 was proposed making use of an initial aldol
disconnection to afford aldehyde 4 and ketone 5 followed
by a second disconnection of ketone 5 to aldehyde 6 and
Abstract: The synthesis of polyethers 32 and 33 from tricyclic bis-
spiroacetal aldehyde 27 and E-bromide 7 are described. A key step
in the synthetic strategy involved the oxidative cyclisation of a bi-
cyclic hydroxyspiroacetal 22a,b to a cis bis-spiroacetal unit, which
resulted in preferential formation of cis aldehyde 27. A Barbier re- bromide 7 (Scheme 1).
acton of bromide 7 and tricyclic aldehyde 27 then afforded erythro
alcohol 28 which after epoxidation and acid catalysed cyclisation
completed the synthesis of polyethers 32 and 33 providing an effec-
tive framework on which to synthesise the B,C,D and E rings of an-
tibiotic CP44,161 1.
Key words: bis-spiroacetal, polyether, oxidative cyclisation
Antibiotic CP44,161 11 is a polyether antibiotic extracted
from three strains of a Dactylsporangiumin species which
contains a complex 1,6,8-trioxadispiro[4.1.5.3]pentadec-
13-ene moiety (like salinomycin 22) and an A ring which
is similar to that found in lasalocid A.3 Whilst several syn-
thetic approaches to salinomycin 2 have been published,4-
10 no chemical synthesis of antibiotic CP44,161 1 has been
reported. Like salinomycin 2, antibiotic CP44,161 1 has
been reported to exhibit activity against coccidiosis in
poultry and enhance feed utilisation in ruminants.11
Scheme 1
The synthesis of aldehyde 4 has been previously reported
by Kishi and Ireland et al.12,13 whilst construction of tricy-
clic bis-spiroacetal aldehyde 6 was anticipated to occur by
oxidative cyclisation of bicyclic hydroxyspiroketal 8 fol-
lowing methodology established in synthetic approaches
to the bis-spiroacetal core in epi-17-deoxy-(O-8)-salino-
mycin 3.14,15 Further disconnection of bicyclic hydroxy-
spiroketal 8 required the synthesis of lactone 9 and acety-
lene 10.
Figure 1
Our synthetic approach to antibiotic CP44,161 1 focuses
on the addition of the A and E rings after construction of
the central bis-spiroacetal unit whilst related syntheses of
salinomycin 2 have involved late assembly of ring C after
appending the D,E rings to ring B.
The synthesis of lactone 9 has been previously
reported10,14 hence initial construction of acetylene 10 and
bromide 7 was required.
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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.
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Synthetic Studies Towards the B,C,D,E Fragment of Antibiotic CP44, 161
297
Scheme 4
Acknowledgement
This work was supported by an Australian Research Council Grant.
References and Notes
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Scheme 3
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In conclusion, polyethers 32 and 33 were synthesised
from aldehyde 27 and bromide 7 using the methodology
described above. Noteworthy features of this synthetic
strategy include the oxidative cyclisation of a bicyclic hy-
droxyspiroacetal 22a,b to a bis-spiroacetal unit which
provides cis aldehyde 27 preferentially; the addition of a
bis-homoallylic bromide 7 to a neopentylic like aldehyde
27; and acid catalysed cyclisation of a g-hydroxyepoxide
to a disubstituted tetrahydrofuran in the presence of a sen-
sitive bis-spiroacetal. The work reported herein provides
a framework on which to synthesise the B,C,D and E rings
of antibiotic CP44,161 1 after synthesising diol 15 which
provides access to aldehyde 6.
(11) US Patent 76-724869 760920.
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Synlett 1999, No. 3, 295–298 ISSN 0936-5214 © Thieme Stuttgart · New York