Model studies for the synthesis of galbonolide B

Article abstract of DOI:10.1039/b505378a

The construction of the fourteen membered ring present in galbonolide B 1 is reported. The 10,11-diene system present in the southern portion of 1 has been constructed using an ester enolate rearrangement/silicon mediated fragmentation cascade, whilst the macrocycle has been synthesised following a Johnson rearrangement/mercury assisted ring closure protocol. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505378a

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A R T I C L E
Model studies for the synthesis of galbonolide B†‡
James Eshelby,b Matthias Goessman,a Philip J. Parsons,*a Lewis Pennicotta and
Adrian Hightonc
a Department of Chemistry, The University of Sussex, Falmer, Brighton, UK BN1 9QJ.
E-mail: P.J.Parsons@sussex.ac.uk; Fax: 01273 677196; Tel: 01273 678861
b Pfizer Pharmaceuticals Limited, Sandwich, Kent, UK CT13 9NJ
c AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
Received 18th April 2005, Accepted 9th June 2005
First published as an Advance Article on the web 4th July 2005
The construction of the fourteen membered ring present in galbonolide B 1 is reported. The 10,11-diene system
present in the southern portion of 1 has been constructed using an ester enolate rearrangement/silicon mediated
fragmentation cascade, whilst the macrocycle has been synthesised following a Johnson rearrangement/mercury
assisted ring closure protocol.
Introduction
The isolation and structural elucidation of members of the
galbonolide family of macrocycles was reported in 1985 by
1
2
˜
two independent groups led by Achenbach and Otake. The
structure of galbonolide B was initially incorrectly assigned as
23 but a total synthesis of galbonolide B by Tse4 proved the
structure to be epimeric at C4 and C13 and hence structure 1 was
assigned to galbonolide B.
Our synthetic approach to galbonolide B, outlined in
Scheme 1, was designed to offer a route which could be tailored
to analogue preparation. Although the structure of galbonolide
B 1 has been revised, we have synthesised a parallel series of
compounds that are epimeric at C13 in order to establish absolute
proof of structure in the family of galbonolides.
Results and discussion
The galbonolide family of macrocycles has an interesting array
of biological properties. Galbonolides A and B (3 and 1
respectively) showed good activity against a significant pro-
portion of Deuteromycota organisms.5 Among these are fungi
that are pathogenic towards man, such as Candida albicans
and Rhodotorula rubra, as well as fungi which are harmful in
agriculture, such as Botrytis cinerea and Rhizoctonia solani.5
Although galbonolide A 3 was found to be significantly more
active than galbonolide B 1 against every organism tested,5
its instability over galbonolide B 1 could enhance the profile
of galbonolide B 1 as a potent antifungal agent. Galbonolide
C 4 was found to be almost as active as galbonolide B 1
and galbonolide D 5 was inactive; recently novel galbonolide
derivatives have been prepared as IPC synthase inhibitors.6
We wished to develop a novel and flexible route to galbono-
lides A, B, C and D, which would also allow the construction of
more stable analogues with the biological profile of galbonolides
A, B and C remaining intact. Smith and Thomas7 have reported
an elegant approach to galbonolide B, which features a Wittig
reaction to furnish the southern half of the molecule in question.
† This paper is dedicated to the memory of Dr Robert Giles of
GlaxoSmithKline (Tonbridge) who was tireless in his support of UK
chemistry.
Scheme 1
We envisaged that the thioester 7 could be either ring closed
at an early stage, or initially converted into the ketal 6, followed
‡ Electronic supplementary information (ESI) available: experimental
details. See http://dx.doi.org/10.1039/b505378a
2 9 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 4 – 2 9 9 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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by macrocyclisation according to the procedure of Masamune
et al.8
In order to construct the thioester 7 we required an efficient
synthesis of the carboxylic acid 8, which could in turn be
prepared from the carboxylic acid 10 as shown in Scheme 2.
Treatment of the propionate esters 14a and 14b with LDA
and LDA–DMPU, respectively, gave the desired allylic silanes
for fragmentation to furnish the C7 to C13 portion of galbonolide
B epimeric at C13 (Scheme 4).
Deprotonation of 14a with LDA followed by the addition
of TBSCl gave the E-silylketene acetal 16, which rearranged to
give the allylsilane 15.12 Deprotonation of 14b with LDA in the
presence of DMPU, followed by addition of TBSCl gave the
Z-ketene acetal 17, which also rearranged to give the allylsilane
15 (Scheme 5).
Scheme 2
The carboxylic acid 10 was made using a method that we have
previously reported (Scheme 3 and Scheme 4).9
Epoxidation of the allylic alcohol 11 using a Sharpless
oxidation,10 followed by treatment of the resulting epoxyalcohol
11a with the sulfur trioxide–pyridine complex in dimethyl
sulfoxide11 gave the aldehyde 12. Reaction of 12 with 1-
trimethylsilylprop-2-enylmagnesium bromide gave the allylic
alcohols 13a and 13b as a 1.0 to 1.5 ratio of diastereoiso-
mers, which were easily separated by column chromatography.
Conversion of each of the allylic alcohols into their respective
propionate esters proceeded in high yield.
Scheme 5 Reagents and conditions: (a) LDA, THF, −78 ◦C, then
TBSCl, DMPU; (b) LDA, THF, DMPU, −78 ◦C, then TBSCl.
As shown in Scheme 4, we found that treatment of the
allylsilane 15 with ammonium chloride, followed by the addition
of 2 M hydrochloric acid gave the desired diene 10. It is inter-
esting to note that reaction of the allylsilane 15 with aqueous
ammonium chloride gave the lactone 18, which underwent ring
opening in the presence of mineral acid to give 10 (Scheme 6).
◦
i
t
˚
Scheme 3 Reagents and conditions: (a) Ti(OPr )4, L-(−)-DET, Bu OOH, DCM, −25 C, 4 A molecular sieves, 74%; (b) SO3–pyridine, Et3N, DMSO,
DCM, 0 ◦C, 70%; (c)
; (d) (CH3CH2CO)2O, DMAP, Et3N, DCM, 0 ◦C, 96%.
Scheme 4 Reagents and conditions: (a) LDA, THF, −78 ◦C, then TBSCl, DMPU; (b) LDA, THF, DMPU, −78 ◦C, then TBSCl; (c) NH4Cl, H2O,
then HCl (2 M), 90%.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 4 – 2 9 9 7
2 9 9 5

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Scheme 8 Reagents and conditions: (a) MeC(OEt)3, C5H11CO2H, ;
(b) KOH–EtOH–H2O, then HCl (0.1 M) 88%.
Scheme 6 Reagents and conditions: (a) NH4Cl, H2O; (b) HCl (2 M).
Although the lactone 18 was not isolated due to its instability,
its formation proved to be crucial for the generation of the E-
double bond in 10. With the carboxylic acid 10 in hand, the
allylic alcohol 9 was synthesised as shown in Scheme 7.
The allylic alcohol 9 proved to be a very versatile intermediate
in our synthesis. Reaction of 9 with triethyl orthoacetate in the
presence of hexanoic acid followed by solvolysis of the ester gave
the acid 23b in high yield (Scheme 8).
Scheme 9 Reagents and conditions: (a) CDI; (b) (ButSCOCH(CH3)-
CO2)2Mg, THF, 97%.
In view of the successful preparation of the carboxylic acid
23b, which contains a range of relatively labile functionalities,
we decided to elaborate the acid 23b into the thioester 7 using
a method described by Masamune et al.8 and designed for the
acylation of carboxylic acids under almost neutral conditions.
To our delight, the desired coupling occurred in quantitative
yield (Scheme 9).
After extensive research, it was found that aqueous acetic acid
in tetrahydrofuran removed the triethylsilyl group in moderate
to good yield. Treatment of 7 with aqueous acetic acid gave
the alcohol 24 in 70% yield and, after further experiments, the
alcohol 24 was converted into the desired macrocyclic lactone 25
in quantitative yield, using mercuric acetate in tetrahydrofuran
(Scheme 10).
Scheme 10 Reagents and conditions: (a) HOAc–H2O–THF, 2 : 2 : 1,
70%; (b) Hg(OAc)2, PriNEt2, THF, 99%.
When the lactones 25 were exposed to DBU in
dichloromethane, gradual epimerisation at C2 occurred giving
a 2 : 1 mixture in favour of the correct diastereoisomer
(Scheme 11).
Scheme 11 Reagents and conditions: (a) DBU, DCM.
Experimentation was continued on the series epimeric at C13
in order to introduce the desired diol present in galbonolide
B. Attempted formation of the dianion derived from 25 resulted
in an interesting ring contraction reaction. Treatment of 25
with an excess of LDA in THF, followed by the addition of
formaldehyde gave the ring contracted lactone 28 as the sole
reaction product (Scheme 12).
A possible explanation for the formation of the lactone 28
arises from an intermolecular aldol reaction, followed by an
intramolecular acylative ring contraction and then dehydration
(Scheme 13).
Scheme 12 Reagents and conditions: (a) LDA (10 eq.), THF, DMPU;
=
(b) H2C O, THF, 39%.
Scheme 7 Reagents and conditions: (a) MeI, DBU, DCM, 0 ◦C, 75%; (b) TESCl, DMAP, Et3N, DCM, 0 ◦C, 99%; (c) DIBAL-H, DCM, 0 ◦C, 100%;
(d) SO3–pyridine, Et3N, DMSO, DCM, 0 ◦C, 76%; (e)
, THF, 0 ◦C, 76%.
2 9 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 4 – 2 9 9 7

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Scheme 13 Reagents and conditions: (a) LDA (10 eq.), THF, DMPU;
=
(b) H2C O, THF, 39%.
Conclusions
We have developed an efficient route to the macrocyclic skeleton
present in the galbonolides. We are currently making a series
of compounds with the S-configuration of C13. The ring
contraction step showninScheme12 has now beencircumvented
by the use of an ester enolate rearrangement in order to furnish
the requisite diol functionality at C4 in galbonolide B. The total
synthesis of galbonolide B and its analogues will be the subject
of a further publication. Experimental details can be found in
the electronic supplementary information.‡13–16
Acknowledgements
We wish to thank Drs Clive Penkett, Adrian Murray, Mike
Urquhart and Eddy Viseux for their interest in this work and the
EPSRC, AstraZeneca and Tocris Cookson for research funding.
Technical assistance from Drs Avent, Hitchcock and Abdul-
Sada is gratefully acknowledged.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 9 9 4 – 2 9 9 7
2 9 9 7