Synthesis of the spiroacetal-containing anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014

Article abstract of DOI:10.1039/b612757f

The first synthesis of the spiroacetal-containing anti-Helicobacter pylori agents ent-CJ-12,954 and ent-CJ-13,014 is reported based on the union of a heterocycle-activated spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragme

Full text of DOI:10.1039/b612757f

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Synthesis of the spiroacetal-containing anti-Helicobacter pylori agents
CJ-12,954 and CJ-13,014{
Margaret A. Brimble* and Christina J. Bryant
Received (in Cambridge, UK) 4th September 2006, Accepted 20th September 2006
First published as an Advance Article on the web 6th October 2006
DOI: 10.1039/b612757f
stereochemistry of the three stereogenic centres on the spiroacetal
ring. CJ-12,954 1 was assigned with 1,3-syn stereochemistry
between the C20-Me group and the C50–O60 bond with the
69-CH2 group 1,3-syn to C50–O10. In the case of CJ-13,014 2 the
C20-Me group was assigned as 1,3-anti to the C50–O60 bond with
the 69-CH2 group 1,3-anti to the C50–O10 bond. The structures of
CJ-12,954 1 and CJ-13,014 2 were initially arbitrarily depicted with
the (S)-configuration at both C20 and C70; however, the assign-
ment of absolute stereochemistry to these stereogenic centres and
C-3 on the phthalide unit requires the synthesis of these natural
products which has not been reported to date although several
simpler non spiroacetal-containing phthalides have been prepared
with lack of stereocontrol of the phthalide unit.7–9
The first synthesis of the spiroacetal-containing anti-
Helicobacter pylori agents ent-CJ-12,954 and ent-CJ-13,014
is reported based on the union of a heterocycle-activated
spiroacetal-containing sulfone fragment with a phthalide-
containing aldehyde fragment; comparison of the 1H and
13C NMR data, optical rotations and HPLC retention times
of the synthetic compounds (3S,20S,50S,70S)-(1a) and
(3S,20S,50R,70S)-(2a)
and
the
(3R)-diastereomers
(3R,20S,50S,70S)-(1b) and (3R,20S,50R,70S)-(2b) with the
naturally occurring compounds established that the syn-
thetic isomers (1a) and (2a) were in fact enantiomeric to the
natural products CJ-12,954 and CJ-13,014.
We have reported10 the synthesis of (+)-spirolaxine methyl ether
by coupling a 6,5-spiroacetal moiety of defined stereochemistry
with a stereochemically-defined phthalide moiety, thus establishing
the absolute stereochemistry of the natural product to be
(3R,20R,50R,70R). An alternative synthesis in which the stereo-
chemistry at C-3 in the phthalide unit was not controlled
necessitated separation of (+)-spirolaxine methyl ether from its
C-3 diastereomer by HPLC in the final step.11
Helicobacter pylori is a Gram-negative micro-aerophilic spiral
bacterium that resides in the mucus layer above the gastric
epithelium1 and can cause peptic ulcer disease and gastric cancer in
humans.2 The International Agency for Research on Cancer
classified H. pylori as a class I carcinogen in 1994.3 A variety of
effective drugs for the treatment and eradication of H. pylori
infection are clinically useful, including antibiotics (b-lactams,
macrolides and quinolones), bactericidal agents (bismuth salts),
and antiprotozoal agents (metronidazole); however, drug resis-
tance, side effects and non-compliance4 prompt development of
more effective and selective anti-H. pylori agents.
Dekker et al.5 isolated seven new 5,7-dimethoxyphthalide
antibiotics with specific anti-H. pylori activity from the basidio-
mycete Phanerochaete velutina CL6387. The two most potent
compounds, CJ-12,954 1 and its C-50 epimer CJ-13,014 2,
contained a 5,5-spiroacetal ring joined through a polymethylene
chain to the phthalide unit (Fig. 1). While changes in the
stereochemistry associated with the spiroacetal have little effect on
antibacterial activity, the diketone formed by ring opening exhibits
a decreased potency of approximately 100-fold. Two structurally
related helicobactericidal compounds, spirolaxine 3 and its methyl
We herein report a flexible convergent synthesis of CJ-12,954
and CJ-13,014 initially focusing on the synthesis of
(3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-(2a) arbitrarily chosen
with the (S)-configuration at C-3 on the phthalide unit and at C-20
and C-70 in the spiroacetal. The key step involves modified Julia
olefination of phthalide-aldehyde 5a (Scheme 1) with heterocycle-
activated sulfones 6 and 7 (Scheme 2).
The (S)-stereochemistry at C-3 in phthalide-aldehyde 5a
(Scheme 1) was established by asymmetric reduction of ketone
812 using (R)-2-Me-CBS-oxazaborolidine13 and borane–dimethyl
sulfide affording homoallylic alcohol 9 in 92% yield and 94% e.e.14
ether 4, contain
a 6,5-spiroacetal ring joined through a
polymethylene chain to a phthalide unit.6 Thus, phthalide-
containing spiroacetal compounds provide promising new leads
for the treatment of H. pylori-related diseases.
Whilst Dekker et al.5 were unable to assign the stereochemistry
of the stereogenic centre at C-3 on the phthalide unit in CJ-12,954
1 and CJ-13,014 2, they were able to assign the relative
Department of Chemistry, The University of Auckland, 23 Symonds St.,
Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz;
Fax: +64 9 3737599; Tel: +64 9 3737599 ext. 88259
{ Electronic supplementary information (ESI) available: Experimental
section and Fig. S2 depicting key NMR data for 1a/2a and 1b/2b. See
DOI: 10.1039/b612757f
Fig. 1
4506 | Chem. Commun., 2006, 4506–4508
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Attention next focused on the synthesis of sulfones 6 and 7
which are epimeric at the spirocentre (Scheme 2). 1-Phenyl-
1H-tetrazol-5-yl sulfones 6 and 7 were chosen in preference to the
use of benzothiazol-2-yl sulfones due to their increased stability in
heterocycle-modified Julia olefinations.15,16 Lithium (S)-acetylide
1717 provides access to the 5,5-spiroacetal ring system with (S)-
stereochemistry at C-20 and the (70S)-stereochemistry is derived
from homoallylic alcohol 14, available via asymmetric allylation of
aldehyde 13.18
Addition of allylmagnesium bromide to (+)-b-diisopinocam-
pheylmethoxyborane followed by addition of aldehyde 1318
afforded (S)-alcohol 1419 in 82% yield and 94% ee (determined
by chiral HPLC{). Silyl ether formation followed by hydrobora-
tion and oxidation of the resultant primary alcohol 15 afforded
aldehyde 16. Addition of aldehyde 16 to lithium acetylide 17 at
278 uC in the presence of lithium bromide20 provided alcohol 18
as a mixture of diastereomers that was oxidized to ketone 19 using
TPAP and NMO. Reduction of the acetylene over PtO2 followed
by spirocyclisation using camphorsulfonic acid in dichloromethane
afforded an inseparable 1 : 1 mixture of spiroacetals 21 and 22
after cleavage of the tert-butyldiphenylsilyl ether. Lack of
stereocontrol from the anomeric effect21 contributed to the
observed formation of equal quantities of 5,5-spiroacetals 21
and 22.
Scheme 1 Reagents and conditions: (i) (R)-MeCBS, BH3–SMe2, 15 min,
then THF, 8, 2 h, 92%, 94% ee; (ii) NBS, NH4OAc, Et2O, 24 h, 90%; (iii)
NaH, THF, 0 uC then N,N-diethylcarbamoyl chloride, 90%; (iv) t-BuLi,
THF, 278 uC, 2 h then camphorsulfonic acid, 20 uC, 12 h, 70%; (v)
2-methyl-2-butene, BH3–SMe2, THF, 0 uC then MeOH, NaOH, 30%
˚
H2O2, 71%; (vi) TPAP, NMO, CH2Cl2, 4A mol. sieves, 6 h, 20 uC, 72%
Regioselective bromination of the aromatic ring afforded bromide
10 and subsequent conversion to diethyl carbamate 11 facilitated
subsequent lithium–halogen exchange and intramolecular acyla-
tion to phthalide 12. Hydroboration of the allyl group followed by
oxidation then provided the desired phthalide-aldehyde 5a in
higher optical purity than its antipode which was prepared via an
asymmetric allylation strategy.10
Mitsunobu displacement of hydroxyspiroacetals 21 and 22 with
1-phenyl-1H-tetrazole-5-thiol, PPh3 and DEAD afforded sulfides
23 and 24 that underwent oxidation to an inseparable mixture of
sulfones 6 and 7. Finally the key heterocycle-activated15 modified
Scheme 2 Reagents and conditions: (i) allyl bromide, Mg, (+)-b-diisopinocampheylmethoxyborane, Et2O, 278 uC to 20 uC, 82%, 94% ee; (ii)
t-BuMe2SiCl, imidazole, DMAP, CH2Cl2, 20 uC, 12 h, 90%; (iii) 2-methyl-2-butene, BH3–SMe2, 0 uC, 76%; (iv) Dess-Martin periodinane, py, CH2Cl2,
˚
20 uC, 77%; (v) 17, n-BuLi, LiBr, THF, 278 uC, then 16, 84%; (vi) TPAP, NMO, 4A mol sieves, CH2Cl2, 20 uC, 94%; (vii) H2, PtO2, K2CO3, THF–MeOH
(1 : 1), 94%; (viii) CSA, CH2Cl2, 20 uC, 4 h, 93%; (ix) TBAF, CH2Cl2, 20 uC, 3 h, 77%; (x) 1-phenyl-1H-tetrazole-5-thiol, Ph3P, DEAD, 78%; (xi) m-CPBA,
NaHCO3, 71%; (xii) KHMDS, THF, 278 uC then 5a, 84%; (xiii) H2, PtO2, K2CO3, THF–MeOH (1 : 1), 85%.
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In summary, the first synthesis of the enantiomers of the
helicobactericidal agents CJ-12,954 and CJ-13,014, namely
(3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-(2a), has been achieved
via modified Julia olefination of (3S)-phthalide-aldehyde 5a with a
1 : 1 mixture of heterocyclic sulfones 6 and 7. Complementary
synthesis of the diastereomers (3R,20S,50S,70S)-(1b) and
(3R,20S,50R,70S)-(2b) facilitated confirmation of the relative
stereochemistry between C-3 on the phthalide unit and C50/C70
on the 5,5-spiroacetal moiety, establishing that the absolute
configuration of the natural product CJ-12,954 is
(3R,20R,50R,70R) and that of CJ-13,014 is (3R,20R,50S,70R).
We thank Dr Shinichi Sakemi (Pfizer R&D, Groton, USA) for
providing samples of natural CJ-12,954 and CJ-13,014.
Notes and references
Scheme 3 Reagents and conditions: (i) 6 and 7 (1 : 1), KHMDS, THF,
278 uC then 5b, 76%; (ii) H2, PtO2, K2CO3, THF–MeOH (1 : 1), 90%.
{ HPLC conditions: Chiracel1 OD-H column, i-propanol : hexane 5 : 95,
flow rate 0.5 mL min21, retention times: 7.5 min (minor, R-isomer) and
8.7 min (major, S-isomer).
Julia olefination using KHMDS proceeded in excellent yield (84%)
§ HPLC conditions: YMC-Pack ODS-AM column, methanol : water 3 : 1,
flow rate 0.5 mL min21
providing
a
1
:
1
mixture of phthalide-spiroacetals
.
(3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-(2a) after hydrogena-
tion over PtO2.
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12 Ketone 7 was prepared from 3,5-dimethoxybenzaldehyde and allylmag-
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The 1H and 13C NMR data recorded for phthalide-spiroacetals
1a and 2a were compared with the data reported for the natural
products.5 Notably the chemical shifts observed for the key
resonances at the stereogenic centres in the spiroacetal unit (C20,
C50, C70 and 20-Me) were in good agreement with the natural
products (Fig. S2{). However, the chemical shift reported for H3
(dH 5.29) in both 1a and 2a was at variance with the chemical shift
reported for the same resonance in natural CJ-12,954 and
CJ-13,014 (dH 5.27). Further clarification of the relative stereo-
chemistry between C3 on the phthalide with the stereogenic centres
in the 5,5-spiroacetal ring was clearly required.
Due to the ready availability of (3R)-phthalide-aldehyde 5b10 we
also prepared a 1 : 1 mixture of (3R,20S,50S,70S)-(1b) and
(3R,20S,50R,70S)-(2b) with (3R)-stereochemistry on the phthalide
(Scheme 3) via olefination of (3R)-phthalide-aldehyde 5b with a
1 : 1 mixture of sulfones 6 and 7 followed by hydrogenation.
Frustratingly, the 1H and 13C NMR data obtained for these latter
isomers were similar to those recorded for both synthetic isomers
(1a) and (2a) and the respective natural products (Fig. S2{).
Gratifyingly, procurement of samples of natural CJ-12,954 and
CJ-13,014 allowed direct comparison of the HPLC retention times
for the synthetic compounds with the natural products. Using the
reported HPLC conditions5§ the retention times for the 1 : 1
mixture of synthetic (3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-
(2a) were in agreement with those recorded for natural CJ-12,954
(1) and CJ-13,014 (2), and differed from the retention times
recorded for the 1 : 1 mixture of synthetic (3R,20S,50S,70S)-(1b)
and (3R,20S,50R,70S)-(2b). The [a]D 238.0 (c, 0.48, CHCl3) for the
1 : 1 mixture of (3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-(2a) was
of opposite sign and an average of the values reported5 for CJ-
12,954 (1), [a]D +6.0 (c, 0.07, CHCl3), and CJ-13,014 (2), [a]D +71.2
(c, 0.11, CHCl3), establishing that the synthetic isomers
(3S,20S,50S,70S)-(1a) and (3S,20S,50R,70S)-(2a) were in fact
enantiomeric to the natural products.
21 A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen, Springer-Verlag, New York, 1983.
4508 | Chem. Commun., 2006, 4506–4508
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