The first enantioselective total synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether

Article abstract of DOI:10.1039/b418106a

The first enantioselective synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether has been carried out in a convergent fashion by heterocycle-activated Julia olefination of a spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragment. The total synthesis of (+)-spirolaxine methyl ether establishes the absolute stereochemistry of the natural product to be (3R,2″R,5″R,7″R). The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b418106a

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The first enantioselective total synthesis of the anti-Helicobacter pylori
agent (+)-spirolaxine methyl ether{
James E. Robinson and Margaret A. Brimble*
Received (in Cambridge, UK) 30th November 2004, Accepted 24th December 2004
First published as an Advance Article on the web 26th January 2005
DOI: 10.1039/b418106a
the large polymethylene side chain occupied the thermodynami-
cally preferred equatorial position. Having settled on the
(50R,70R)-stereochemistry we then decided to develop a flexible
approach wherein the stereochemistry at C-3 on the phthalide ring
and C-20 on the spiroacetal ring could be varied. The retrosynthesis
adopted (Scheme 1) thus hinged on the union of (3R)-phthalide-
The first enantioselective synthesis of the anti-Helicobacter
pylori agent (+)-spirolaxine methyl ether has been carried out in
a convergent fashion by heterocycle-activated Julia olefination
of a spiroacetal-containing sulfone fragment with a phthalide-
containing aldehyde fragment. The total synthesis of (+)-spir-
olaxine methyl ether establishes the absolute stereochemistry of
the natural product to be (3R,20R,50R,70R).
aldehyde
4
with (2R,5R,7S)-sulfone 3, wherein the
(2R)-stereochemistry of sulfone 3 was derived from commercially
available (R)-3-butyn-2-ol 5 and the use of a titanium-mediated
asymmetric allylation of aldehyde 6 using (+)-BINOL introduced
the (3R)-stereochemistry of phthalide-aldehyde 4 (Scheme 2). Use
of (S)-3-butyn-2-ol and/or (2)-BINOL allows access to the
alternative stereoisomers.
Gastric and duodenal ulcers affect a significant proportion of the
human population worldwide. Initially these ulcers were thought
to be caused by the action of digestive fluids (acid and pepsin) on
stomach and duodenal tissue and patients were usually treated
with H2 blockers. More recent studies have shown a strong
relationship between the presence of the micro-aerophilic Gram-
negative bacterium Helicobacter pylori, which appears to live
beneath the mucus layer of the stomach, and the development of
gastric and duodenal ulcers.1 Therapy to eliminate Helicobacter
pylori from the gastroduodenal tract removes the primary cause of
gastric and duodenal ulcers and eliminates the need for an ulcer
patient to continue long and costly treatment with H2 blockers.
Current treatment of Helicobacter pylori infection involves the
prescription of one or more antibiotics in combination with H2
blockers; however, none of the existing treatments are capable of
complete eradication of Helicobacter pylori.1
The (3R)-stereochemistry in phthalide-aldehyde 4 was set up via
titanium (+)-BINOL mediated asymmetric allylation4 of 3,5-
dimethoxybenzaldehyde 6 providing (R)-homoallylic alcohol 7 in
78% yield and 86% ee (determined by chiral HPLC).{
Regioselective bromination of the aromatic ring using NBS
afforded bromide 8 in preparation for subsequent installation of
the phthalide functionality at this position. Attempts to effect
direct carboxylation of bromide 8 proved fruitless hence the
alcohol was converted to diethylcarbamate 9 with subsequent
lithium-halogen exchange followed by intramolecular acylation
Spirolaxine 1 and spirolaxine methyl ether 2 are produced by
various strains of white rot fungi belonging to the genera
Sporotrichum and Phanerochaete.2 Spirolaxine 1 and spirolaxine
methyl ether 2 are potent helicobactericidal compounds and are
therefore useful compounds for the treatment of gastroduodenal
disorders and the prevention of gastric cancer. Spirolaxine methyl
ether 2 contains a 5,7-dimethoxyphthalide nucleus linked through
a polymethylene sidechain to a 6,5-spiroacetal group and belongs
to the class of endecaketide derivatives that includes phanerosporic
and corticiolic acids.3 The absolute and relative stereochemistry of
the four stereogenic centres present in spirolaxine 1 and spirolaxine
methyl ether 2 has not been established and a synthesis of these
unique helicobactericidal agents has not been reported to date. We
therefore herein report the first enantioselective total synthesis of
(+)-spirolaxine methyl ether 2 thus establishing unequivocally that
the absolute configuration of the natural product is
(3R,20R,50R,70R).
In planning our synthesis of spirolaxine methyl ether 2 we
decided to prepare the stereoisomer in which the 6,5-spiroacetal
ring adopted the anomerically stabilized bis-axial arrangement and
{ Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b4/b418106a/
*m.brimble@auckland.ac.nz
Scheme 1
1560 | Chem. Commun., 2005, 1560–1562
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For the synthesis of spiroacetal sulfone 3 with the (2R,7S)
configuration it was noted that (R)-epoxide 11 was a suitable
starting point for introduction of the (S)-stereochemistry at C-7.
Additionally, lithium (R)-acetylide 155 can be used to form C-2 of
the spiroacetal ring with the desired (R)-stereochemistry
(Scheme 3). In an adaptation of the method used by Frick et al.,6
(R)-epoxide 117 was prepared by a one-pot intramolecular
cyclization of bromo-diol 12 and protection of the primary alcohol
as a silyl ether. Bromo-diol 12 in turn was readily available via
brominative diazotisation of L-aspartic acid followed by reduction
of the carboxylic acid groups. Allyl cupration of (R)-epoxide
11 afforded a secondary alcohol that was protected as a
tert-butyldimethylsilyl ether 13. Subsequent hydroboration and
oxidation of the resultant primary alcohol using Dess–Martin
periodinane afforded aldehyde 14.
Addition of aldehyde 14 to lithium acetylide 15 at 278 uC in the
presence of lithium bromide8 provided alcohol 16 in 76% yield.
Oxidation of the alcohol to a ketone using tetrapropyl ammonium
perruthenate (TPAP) and NMO, followed by reduction of the
acetylene, afforded the protected dihydroxyketone 17.
Deprotection of the tert-butyldimethylsilyl ethers and facile
spirocyclisation was then readily effected using camphorsulfonic
acid in dichloromethane to give spiroacetal 18 after cleavage of the
tert-butyldiphenylsilyl ether with tetrabutylammonium fluoride.
The bis-axial stereochemical orientation of spiroacetal 18 is the
major thermodynamically-favoured isomer due to its stabilisation
by the anomeric affect.9
Scheme 2 Reagents and conditions: (i) TiF4, (+)-BINOL, allyltrimethyl-
silane, CH2Cl2–MeCN (97:3), 220 uC, 72 h then n-Bu4NF, 78%; (ii) NBS,
CHCl3, reflux, 88%; (iii) NaH, THF, 0 uC then N,N-diethylcarbamoyl
chloride, 82%; (iv) t-BuLi, THF, 278 uC, 45 min then p-toluenesulfonic
acid, 20 uC, 12 h, 76%; (v) BH3.SMe2, THF, 0 uC then NaOH, H2O2, 56%;
(vi) PCC, Celite, 0 uC, 72%.
and lactonisation providing phthalide 10. Elaboration of the allyl
group via hydroboration and oxidation then provided the desired
phthalide-aldehyde 4.
Conversion of the side chain alcohol group in spiroacetal 18 to
sulfone 3 proceeded readily in two steps by treatment with
Scheme 3 Reagents and conditions: (i) NaNO2, KBr, H2SO4, 0 uC, 2 h, 92%; (ii) BH3?SMe2, THF, 0 uC then MeOH, 97%; (iii) NaH (2 equiv.), THF, 0 uC
then TBDPSCl, 82%; (iv) cuprate, THF, 278 uC, 2 h, 90%; (v) TBDMSCl, imidazole, DMAP, CH2Cl2, 98%; (vi) BH3?SMe2, THF, 0 uC, NaOH, H2O2,
83%; (vii) Dess–Martin periodinane, pyridine, CH2Cl2, 86%; (viii) LiBr, THF, 278 uC, 76%; (ix) TPAP, NMO, CH2Cl2, 78%; (x) H2, PtO2, THF, 6 h, 95%;
(xi) CSA, CH2Cl2, 85%; (xii) TBAF, THF, 0 uC, 83%; (xiii) DEAD, PPh3, 2-mercaptobenzothiazole; (xiv) m-CPBA, CH2Cl2, 51% over two steps; (xv)
LDA, THF, 278 uC then aldehyde 4; (xvi) PtO2, H2, THF, 2 h, 40% over 2 steps.
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Chem. Commun., 2005, 1560–1562 | 1561

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2 A. Arnone, G. Assante, G. Nasini and O. Vajna de Pava,
Phytochemistry, 1990, 29, 613; M. A. Gaudliana, L. H. Huang,
T. Kaneko and P. C. Watts, PCT Int. Appl., 1996, W0 9605204; CAN
125:58200.
3 G. Deffieu, R. Baute, M.-A. Baute and A. Neven, C. R. Hebd. Seances
Acad. Sci., Ser. D, 1979, 288, 647.
4 D. R. Gauthier, Jr. and E. M. Carreira, Angew. Chem., Int. Ed. Engl.,
1996, 35, 2363.
5 Spectral data for the (S)-enantiomer has been reported see:
A. S. Cotterill, M. Gill, A. Gimenez and N. M. Milanovic, J. Chem.
Soc., Perkin Trans 1, 1994, 3269.
6 J. A. Frick, J. B. Klassen, A. Bathe, J. M. Abramson and H. Rapoport,
Synthesis, 1992, 7, 621.
7 The absolute stereochemistry of 11 was confirmed as (R) by comparison
of its optical rotation with that of the (S)-enantiomer as reported by
Y. Mori, A. Takeuchi, H. Kageyama and M. Suzuki, Tetrahedron Lett.,
1988, 29, 5423.
8 The effect of LiBr on acetylide addition reactions has been noted:
P. E. van Rijn, S. Mommers, R. G. Visser, H. D. Verkruijsse and
L. Brandsma, Synthesis, 1981, 451; E. M. Carreira and J. Du Bois,
J. Am. Chem. Soc., 1994, 116, 10825.
9 For reviews on the anomeric effect see: P. Deslongchamps,
Stereoelectronic Effects in Organic Chemistry, Pergamon Press,
New York, 1983; A. J. Kirby, The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen, Springer-Verlag, New York,
1983.
mercaptobenzothiazole, PPh3 and DEAD followed by oxidation
using m-CPBA. With phthalide-aldehyde 4 and sulfone 3 readily in
hand the key heterocycle-activated10 modified Julia olefination was
undertaken.11 Thus treatment of sulfone 3 with LDA at 278 uC
followed by the addition of phthalide-aldehyde 4 provided
spirolaxine methyl ether 2 in 40% yield{ after careful hydrogena-
tion of the initial olefin over PtO2. The 1H and 13C NMR data and
optical rotation of the synthetic spirolaxine methyl ether 2 were in
agreement with that reported in the literature.2,12 We also thank
Dr Takushi Kaneko (Pfizer R&D, Groton, USA) for an authentic
sample of spirolaxine 1 for comparative purposes.
In summary a convergent enantioselective synthesis of the
helicobactericidal agent spirolaxine methyl ether 2 has been
achieved. The cornerstone of the synthesis entailed a heterocycle-
activated modified Julia-Kocienski olefination to join sulfone 3
with phthalide-aldehyde 4. The successful execution of the
synthesis establishes the absolute configuration of the four
stereogenic centres in the natural product to be (3R,20R,50R,70R).
James E. Robinson and Margaret A. Brimble*
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
10 For
a review on the heterocycle-activated modified Julia
reaction see: P. R. Blakemore, J. Chem. Soc., Perkin Trans 1, 2002,
2563.
11 For examples of the use of the heterocycle-activated modified Julia
reaction using heterocyclic sulfones bearing a spiroacetal functionality
see: S. V. Ley, A. C. Humphries, H. Eick, R. Downham, A. R. Ross,
R. J. Boyce, J. B. J. Pavey and J. Pietruszka, J. Chem. Soc., Perkin Trans
1, 1998, 3907; T. Shimizu, T. Masuda, K. Hiramoto and T. Nakata,
Org. Lett., 2000, 2, 2153.
Notes and references
{ HPLC Conditions: Chiracel1 OD-H column, i-propanol:hexane 1:9,
flow rate 0.5 mL min21, retention times: 17.8 min (major, R-isomer) and
22.4 min (minor, S-isomer).
12 T. Adachi, I. Takagi, K. Kondo, A. Kawashima, A. Kobayashi,
I. Taneoka, S. Morimoto, B. M. Hi and Z. Chen, PCT Int. Appl., 1996,
W0 9610020; CAN 125:86482.
1 M. J. Blaser, Clin. Infect. Dis., 1992, 15, 386; J. H. Walsh and
W. L. Peterson, New England J. Med., 1995, 333, 984; B. Rathbone,
Scrip Magazine, 1993, 25.
1562 | Chem. Commun., 2005, 1560–1562
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