Chemoenzymatic synthesis of carbasugars (+)-pericosines A-C from diverse aromatic cis-dihydrodiol precursors

Article abstract of DOI:10.1021/ol100525r

cis-Dihydrocatechols, derived from biological cis-dihydroxylation of methyl benzoate, iodobenzene and benzonitrile, using the microorganism Pseudomonas putida UV4, were converted into pericosines A, C, and B, respectively. This approach constitutes the shortest syntheses, to date, of these important natural products with densely packed functionalities.

Full text of DOI:10.1021/ol100525r

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2206-2209
Chemoenzymatic Synthesis of
Carbasugars (+)-Pericosines A-C from
Diverse Aromatic cis-Dihydrodiol
Precursors
Derek R. Boyd,† Narain D. Sharma,† Carmen A. Acaru,† John F. Malone,† Colin
R. O’Dowd,† Christopher C. R. Allen,‡ and Paul J. Stevenson*,†
School of Chemistry and Chemical Engineering, and School of Biological Sciences,
Queen’s UniVersity of Belfast, Belfast BT9 5AG, United Kingdom
p.steVenson@qub.ac.uk
Received March 3, 2010
ABSTRACT
cis-Dihydrocatechols, derived from biological cis-dihydroxylation of methyl benzoate, iodobenzene and benzonitrile, using the microorganism
Pseudomonas putida UV4, were converted into pericosines A, C, and B, respectively. This approach constitutes the shortest syntheses, to
date, of these important natural products with densely packed functionalities.
The naturally occurring pericosines A, B, and C, Figure 1,
were originally isolated as metabolites from the fungus
Periconia byssoides found in the gastrointestinal tract of the
sea hare Aplysia kurodai.1 There has been considerable
interest in the synthesis of pericosines, due to their cytotox-
icity against P388 lymphocytic leukemia cells, antitumor
activity against murine P388 cells, and selective growth
inhibition against human cancer cell lines HBC-5 and SNB-
75.2a,b The first synthesis of pericosine B was accomplished
by Donohoe3 over ten years ago and recently there has been
an upsurge of interest in these molecules. This has culminated
in syntheses leading to a structural reassignment of pericosine
A,4 the synthesis of pericosine A plus a diastereoisomer,5
pericosine B,6 an epimer thereof,7 pericosine C,8 and
pericosine D.9 Unusually, for a natural product, pericosine
C was found to exist as a mixture of enantiomers with a
low preference for the (-)-isomer (14% ee).2 This observa-
tion may be linked to the pseudosymmetry present within
the pericosine structures, in which allylic rearrangement
provides a potential mechanism for partial racemization. The
structural similarities between pericosines (polyhydroxylated
cyclohexenes) and the pseudosugars (polyhydroxylated cy-
clohexanes) are obvious and both may be classified as
carbasugars.10
(4) (a) Usami, Y.; Takaoka, I.; Ichikawa, H.; Horibe, Y.; Tomiyama,
S.; Ohtsuka, M.; Imanishi, Y.; Arimoto, M. J. Org. Chem. 2007, 72, 6127–
6134. (b) Usami, Y.; Horibe, Y.; Takaoka, I.; Ichikawa, H.; Arimoto, M.
Synlett 2006, 1598–1600. (c) Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34,
1062–1063.
† School of Chemistry and Chemical Engineering.
‡ School of Biological Sciences.
(1) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.;
Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215–8218.
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Doi, M.; Numata, A. Org. Biomol. Chem. 2007, 5, 3979–3986. (b) Usami,
Y.; Ichikawa, H.; Arimoto, M. Int. J. Mol. Sci. 2008, 9, 401–421.
(3) Donohoe, T. J.; Blades, K.; Helliwell, M.; Waring, M. J.; Newcombe,
N. J. Tetrahedron Lett. 1998, 39, 8755–8758.
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10.1021/ol100525r  2010 American Chemical Society
Published on Web 04/22/2010

In contrast, cis-dihydrodiol metabolites derived from
cyanobenzene16a-d,17a,b and methyl benzoate12b,18 have, to
date, seen limited application in synthesis. Use of these cis-
dihydrodiols is growing in popularity and both have been
used as precursors to carbasugars.12b,16b,18 These metabolites
seemed ideal precursors for pericosine syntheses, as all the
carbon atoms were in place and only regio- and stereo-
selective functional group manipulations were required. We
now report that enantiopure cis-diol metabolites derived
from methyl benzoate,12d,16d,18 iodobenzene,13d and cyano-
benzene13d,16a,d,17 can be converted to the carbasugar peri-
cosines A, C, and B, respectively (Schemes 1-3).
Figure 1. Structures of pericosines A-C.
Dioxygenase-catalyzed oxidation of arene substrates
provides a direct route to a wide range of enantiopure
mono- and poly-hydroxylated bioproducts. Earlier studies
of aromatic substrates in these and other laboratories, using
mutant strains (e.g. UV4, 39D) of the soil bacterium
Pseudomonas putida and Escherichia coli recombinant
strains, each containing toluene dioxygenase, have pro-
vided access to an extensive range of over 400
metabolites.11a-i
Scheme 1. Synthesis of Pericosine A
To date, only a very small number of benzene cis-
dihydrodiols have been used as “chiral pool” intermediates
and these have recently resulted in a diverse range of
syntheses.12a-d The majority of synthetic studies using cis-
dihydrodiols as precursors have focused on those derived
from bromobenzene, chlorobenzene, and toluene. The re-
markable synthetic versatility of the cis-diol derived from
iodobenzene has been utilized extensively in our
laboratories,13a-i and others,14a,b and is a key precursor in
the synthesis of a range of carbasugars.14b,15
(8) Usami, Y.; Ohsugi, M.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Org.
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Dihydroxylation of cis-dihydrodiol 1, using the Donohoe
protocol,19 gave a 4:1 mixture of two cis,cis-tetraol diaste-
reoisomers, resulting from oxidative attack on the same face
at the 5,6 and 3,4 double bonds, respectively, from which
the desired regioisomer 2 could be isolated in 70% yield
after chromatography.18 As expected, and in line with other
dihydroxylations, the existing cis-hydroxyl groups dictated
the stereochemical outcome of this reaction;the new diol
being created on the same alkene face as the existing
hydroxyl groups. Since the hydroxyl group at the C-6
(11) (a) Resnick, S. M.; Lee, K.; Gibson, D. T. J. Ind. Microbiol. 1996,
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1999, 32, 35–62. (d) Gibson, D. T.; Parales, R. E. Curr. Opin. Biotechnol.
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Allen, C. C. R. Org. Biomol. Chem. 2007, 5, 2267–2273. (b) Boyd, D. R.;
Sharma, N. D.; Llamas, N. M.; Malone, J. F.; O’Dowd, C. R.; Allen, C. C. R.
Org. Biomol. Chem. 2005, 3, 1953–1963. (c) Boyd, D. R.; Sharma, N. D.;
O’Dowd, C. R.; Hempenstall, F. Chem. Commun. 2000, 2151–2152. (d)
Boyd, D. R.; Sharma, N. D.; Byrne, B.; Hand, M. V.; Malone, J. F.;
Sheldrake, G. N.; Blacker, J.; Dalton, H. J. Chem. Soc., Perkin Trans. 1
1998, 1935–1943. (e) Boyd, D. R.; Sheldrake, G. N. Nat. Prod. Rep. 1998,
15, 309–324. (f) Boyd, D. R.; Sharma, N. D.; Dalton, H.; Clarke, D. A.
Chem. Commun. 1996, 45–46. (g) Boyd, D. R.; Blacker, J.; Byrne, B.;
Dalton, H.; Hand, M. V.; Kelly, S. C.; O’Ferrall, R. A. M.; Rao, S. N.;
Sharma, N. D.; Sheldrake, G. N. J. Chem. Soc., Chem. Commun. 1994,
313–314. (h) Boyd, D. R.; Sharma, N. D.; Hand, M. V.; Groocock, M. R.;
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Org. Lett., Vol. 12, No. 10, 2010
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1
the H NMR spectrum of the crude product. No acetal
formation was observed between the hydroxyl groups at C-4
and C-5. It was previously reported that in cyclohex-1-ene-
cis-3,4,5-triols under thermodynamic control, acetal forma-
tion favored positions 3 and 4.20 Separation of the mono-
and bis-acetonides, followed by repeated recyling of the
unwanted acetals 4 and 5 by hydrolysis and reacetalization
of the recovered tetraol 2, gave the required acetonide 3 in
74% overall yield. Interestingly, on selective hydrolysis of
the bis-acetal 5, the monoacetal 4 formed first allowing ready
access to both monoacetonide-protected diols 3 and 4.
In previous syntheses of pericosine A, introduction of the
sensitive allylic chloride, from the allylic alcohol adjacent
to the electron deficient alkene, proved troublesome, as there
was a strong tendency for an allylic rearrangement coupled
with low yields.4a,b By using Mattocks’ procedure,21 diol 3
was regio- and stereo-selectively converted to the trans-
chloroacetate 6, by reaction with chlorocarbonyl-1-methyl-
ethyl acetate. This reaction proceeded cleanly, with inver-
sion at C-6, no allylic rearrangement side products were
observed, and it was not necessary to prior protect the hy-
droxyl group on C-5. Finally, a one-pot acid-catalyzed de-
protection of both acetate and acetonide protecting groups,
under mild acidic conditions,22 gave (+)-pericosine A
(Scheme 1). This four-step synthetic sequence, achieved in
an overall yield of 41% from diol 1, constitutes the shortest
efficient synthesis of (+)-pericosine A, the most biologically
active of the pericosines.2a
Scheme 2. Synthesis of Pericosine C
Scheme 3. Synthesis of Pericosine B
(+)-Pericosine C, in principle, should be available from
(+)-perocosine A, by conversion of the trans-chloroacetate
6 to the corresponding epoxide, followed by a regioselective
ring-opening reaction with sodium methoxide at the allylic
position. However, suitable reaction conditions could not be
found for epoxide formation; only intractable material was
recovered under basic reaction conditions. It was reasoned
that the carbomethoxy group, attached to the alkene, was
destabilizing the desired allylic epoxide by facilitating
nucleophilic addition reactions to the alkene with epoxide
ring-opening, under the basic conditions required for its
formation. To get around this difficulty, for the synthesis of
(+)-pericosine C, the carbomethoxy group was introduced
after epoxide formation.
The synthesis of (+)-pericosine C, outlined in Scheme 2,
was accomplished by using (1S,2S)-3-iodocyclohexa-3,5-
diene-1,2-ol (7) as the starting material. This alternative
approach to the base sensitivity problem highlights the
advantage of having a range of bioproducts available as chiral
pool precursors. Dihydroxylation of cis-dihydrodiol 7, em-
ploying the literature procedure (OsO4, TMNO, DCM),15
gave a 10:1 mixture of cis,cis- and cis,trans-tetraol diaste-
reoisomers from which the required major cis,cis isomer 8
could be isolated in 71% yield after column chromatography.
Again selective acetalization was accomplished under kinetic
control, and on repeated recycling of unwanted acetals 10
position of compound 2 was hydrogen bonded to the adjacent
carbomethoxy group, it was expected to be less reactive in
the subsequent acetal reaction. Treatment of tetraol 2, at room
temperature, with acetone under acidic conditions gave a
(7:4:9) mixture of acetonides 3, 4, and 5, as indicated by
(20) Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.; Chiaroni,
A.; Riche, C.; Grierson, D. S. J. Org. Chem. 1995, 60, 2753–2761.
(21) Mattocks, A. R. J. Chem. Soc. 1964, 1918–1930.
(22) Yeom, C.; Lee, S. Y.; Kim, Y. J.; Kim, B. M. Synlett 2005, 10,
1527–1530.
2208
Org. Lett., Vol. 12, No. 10, 2010

and 11, the required acetal 9 was obtained in 70% yield. On
partial hydrolysis of bis-acetonide 11 the monoacetonide 10
formed first giving access to both mono-protected forms of
the tetraol (9 and 10). Reaction of diol 9 with 1-chlorocar-
bonyl-1-methylethyl acetate gave chloroacetate 12, which on
treatment with sodium methoxide in diethyl ether furnished
the desired epoxide 13. Treatment of epoxide 13 with sodium
methoxide in a methanol solution resulted in regioselective
ring-opening to give the methyl ether 14. One of the
advantages of using vinyl iodides was the ease with which
the iodide group could be replaced. Thus, room temperature
palladium-catalyzed carbomethoxylation of the vinyl iodide
14 with carbon monoxide in methanol solution gave the
methyl ester 15. Finally, removal of the acetonide group from
ester 15, under acidic conditions in methanol,22 gave (+)-
pericosine C. This is, to date, the shortest synthesis of (+)-
pericosine C, six steps from (1S,2S)-3-iodocyclohexa-3,
5-diene-1,2-ol (7), in an overall yield of 17%.
It was envisaged that (+)-pericosine B could be easily
synthesized from tetraol 2, after selective protection of the
three hydroxyl groups on carbons C-3, C-4, and C-5. The
protection of these hydroxyl groups was readily achieved,
using the bulky TBS protecting group. However, the remain-
ing hydroxyl group at C-6 proved recalcitrant to methylation
under a wide range of conditions.
Our next choice to accomplish the synthesis was to utilize
(1S,2R)-3-cyano-cyclohex-3-ene-1,2-diol (16) bearing a CN
group, which is less bulky than a CO2Me group (Scheme
3). Dihydroxylation of diol 16 under conditions similar to
those used for cis-dihydrodiols 1 and 7 gave (4:1) a mixture
of cis,cis- and cis,trans-tetraols from which the major cis,cis
isomer 17 was isolated in 54% yield by column chromatog-
raphy. Reaction of tetraol 17 with 3 mol of tert-butyldim-
ethylsilyl triflate gave the tri-TBS derivative 18 as the major
product in 85% overall yield, together with small amounts
of other unidentified inseparable isomers. The free C-6
hydroxyl group of the crude sample of silyl derivative 18
was methylated, under mild conditions, and a purified sample
of methyl ether 19 was readily separated from the product
mixture. The nitrile group in compound 19 was converted
to the carboxylic acid 21 via partial reduction/hydrolysis to
the aldehyde 20 followed by oxidation. Carboxylic acid 21
was reacted with excess diazomethane in an attempt to form
the methyl ester 23. However, the product from this reaction
was the crystalline pyrazoline cycloadduct 22. It is well-
known that shikimic acid derivatives react with diazomethane
to give pyrazolines,23 but given the steric crowding around
the alkene in compound 21 it is remarkable that the
cycloaddition proceeds with such speed and ease. The methyl
ester was efficiently introduced by base-mediated methylation
of carboxylic acid 21 to give 23. Finally, acid-catalyzed
removal of the TBS protecting groups furnished (+)-
pericosine B in seven steps and an overall yield of 12%.
In conclusion, we have demonstrated that cis-dihydrodiols
derived from methyl benzoate, iodobenzene, and cyanoben-
zene are versatile complementary intermediates for the rapid
synthesis of pericosines A, C, and B, respectively.
Acknowledgment. We gratefully acknowledge financial
support from SFI (NDS Grant No 04/IN3/B581), Queen’s
University of Belfast (CRO’D) and the Department of
Education and Learning (CAA).
Supporting Information Available: Experimental pro-
1
cedures, product characterization, and copies of H NMR
and 13C NMR. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL100525R
(23) Barrero, A. F.; Manzaneda, E. A.; Manzaneda, R. A. Bull. Soc.
Chim. Fr. 1989, 859–863.
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