Conversion of (-)-3-dehydroshikimic acid into derivatives of the (+)-enantiomer

Article abstract of DOI:10.1021/jo034689c

(-)-3-DHS (1), a compound available in large quantity through "engineering" of the shikimic acid pathway, has been converted over eight steps into the methyl ester, ent-2, of the (+)-enantiomer. Methyl (+)-shikimate (15) and its C-3 epimer (ent-5) have al

Full text of DOI:10.1021/jo034689c

SCHEME 1
Con ver sion of (-)-3-Deh yd r osh ik im ic Acid
in to Der iva tives of th e (+)-En a n tiom er
Martin G. Banwell,* Alison J . Edwards,†
Michael Essers, and Katrina A. J olliffe
Research School of Chemistry, Institute of Advanced
Studies, The Australian National University, Canberra,
ACT 0200, Australia
mgb@rsc.anu.edu.au
Received May 21, 2003
Our initial efforts were focused on direct means for
converting (-)-3-DHS into (+)-3-DHS. To these ends, the
former compound was subject to various Mitsunobu-type
reaction conditions with a variety of O-centered nucleo-
philes but only aromatic products resulting from elimina-
tion reactions were observed. These results led us to
conclude that achieving the desired “enantiomeric switch-
ing” would require we operate, as much as possible, at a
lower and, therefore, less sensitive oxidation level, viz.
with shikimates rather than dehydroshikimates. This
consideration became part of a strategy wherein the C-3
carbonyl within 1 would be reduced to the corresponding
â-alcohol, the C-5 hydroxyl oxidized to the corresponding
ketone, and the ∆1,2-double bond moved into conjugation
with the newly installed “C-5” carbonyl. The early stages
of the successful implementation of these ideas are shown
in Scheme 1 and involved initial conversion of (-)-3-DHS
(1) into the corresponding and previously reported4,5 ester
2 (80%) using diazomethane. The hydroxy groups within
the latter compound were then protected as TBS-ethers
so as to give compound 34,5 (81%). Stereoselective 1,2-
reduction of the enone moiety within product 3 proved
rather difficult to achieve and a variety of reagents was
investigated before we resorted to Falck’s conditions5
involving lithium tri-tert-butoxyaluminohydride and
thereby obtained the target allylic alcohol 45 in 82% yield.
Proof of the stereochemical outcome of this reduction
followed from single-crystal X-ray analysis of a derivative
(vide infra). Cleavage of the TBS-ethers within compound
4 was achieved using aqueous hydrochloric acid in
ethanol, and in this way, the pivotal methyl (-)-3-epi-
shikimate 58 was obtained in 84% yield.
Ab st r a ct : (-)-3-DHS (1), a compound available in large
quantity through “engineering” of the shikimic acid pathway,
has been converted over eight steps into the methyl ester,
ent-2, of the (+)-enantiomer. Methyl (+)-shikimate (15) and
its C-3 epimer (ent-5) have also been prepared by related
means.
Recent developments in “engineering” of the shikimic
acid pathway have enabled the high volume production
of (-)-3-dehydroshikimic acid [1, (-)-3-DHS] from glu-
cose.1 Indeed, such methodology has been finessed to the
extent that Frost and co-workers have identified recom-
binant strains of E. coli. and reaction conditions enabling
generation of this fascinating material at levels of 69 g/L
of fermentation broth.2 As such, (-)-3-DHS must now be
regarded as an important new chiron that should have
manifold uses as a starting material in the chemical
synthesis of a wide range of target molecules. The com-
pound has already been employed in the preparation of
protocatechuic acid, vanillin, catechol, adipic acid, gallic
acid, and pyrogallol.1,3 However, the chirality embodied
within (-)-3-DHS has only been exploited on three occa-
sions. Thus, Wood and Ganem4 employed this material
in the synthesis of (-)-3-homoshikimic acid and its 3-
phosphate derivative while Falck and co-workers5 used
enone 1 in the preparation of L-R-phosphatidyl-D-myo-
inositol 3,4,5-triphosphate, a compound which plays a
significant role in intracellular signal transduction. En-
twistle and Hudlicky6 have used the same starting
material for the preparation of certain pseudosugars. We
are also using compound 1 in the synthesis of novel carbo-
hydrate derivatives.7 In this and other contexts the utility
of (-)-3-DHS as a starting material for chemical synthe-
sis could be greatly enhanced if methods were available
for its conversion into the (+)-enantiomer, viz. ent-1, and/
or derivatives thereof. We now detail such methods.
An alternate and equally efficient route to compound
5 started from cheap and commercially available quinic
acid (6). It is based upon modifications of procedures
recently reported by Maycock and co-workers,8b as out-
lined in Scheme 2. Thus, reaction of acid 6 with a
methanolic solution of 2,2,3,3-tetramethoxybutane (2,2,3,3-
TMB) and trimethyl orthoformate in the presence of (+)-
camphorsulfonic acid monohydrate [(+)-CSA‚H2O] af-
forded the acetal ester 79 (82%). The 2°-alcohol moiety
associated with this product was oxidized, using the
(3) Chemicals and Materials from Renewable Resources; Draths, K.
M., Kambourakis, S., Li, K., Frost, J . W., Eds.; ACS Symposium Series
784; American Chemical Society: Washington, DC, 2001; p 133.
(4) Wood, H. B., J r.; Ganem, B. Tetrahedron Lett. 1993, 34, 1403.
(5) Reddy, K. K.; Saady, M.; Falck, J . R.; Whited, G. J . Org. Chem.
1995, 60, 3385.
(6) Entwistle, D. A.; Hudlicky, T. Tetrahedron Lett. 1995, 36, 2591.
(7) Banwell, M. G.; Hungerford, N.; J olliffe, K. A. To be submitted.
(8) (a) Brettle, R.; Cross, R.; Frederickson, M.; Haslam, E.; Mac-
Beath, F. S.; Davies, G. M. Tetrahedron 1996, 52, 10547. (b) Alves, C.;
Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron 1999, 55,
8443.
* Corresponding author.
† To whom correspondence should be addressed regarding X-ray
studies.
(1) Kambourakis, S.; Frost, J . W. J . Org. Chem. 2000, 65, 6904 and
references therein.
(2) Li, K.; Mikola, M. R.; Draths, K. M.; Worden, R. M.; Frost, J . W.
Biotechnol. Bioeng. 1999, 64, 61.
10.1021/jo034689c CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/30/2003
J . Org. Chem. 2003, 68, 6839-6841
6839

SCHEME 2
to selectively oxidize the allylic hydroxyl moiety within
the former product to the corresponding conjugated
ketone 12 (18% from 5).
Separation of this ketone (and the unidentified by
product) from the desired compound 11 (54% from 5) was
then easily effected by flash chromatography and the
structure of the latter confirmed by single-crystal X-ray
analysis (see the Supporting Information). The spectral
data derived from compound 12 proved identical with
those obtained from an authentic sample generated in
79% yield by reaction of compound 2 with bis-DHP under
the usual conditions. Oxidation of alcohol 11 to the
corresponding ketone 13 could be achieved with PCC,14
but use of PDC15 in the presence of 4 Å molecular sieves
proved more effective with the target compound thus
being obtained in 90% yield. NMR analysis of the
oxidation mixture obtained in this manner revealed that
it contained ca. 1% of the conjugated isomer ent-12. The
complete conversion of compound 13 into congener ent-
12 (95%) was best effected by treating the former with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform
at 0 °C. Alternately, successive treatment of compound
11 with oxalyl chloride/DMSO/Hu¨nig’s base then DBU
resulted in direct (one-pot) generation of the conjugated
enone ent-12 in 77% yield. Compound ent-12 obtained by
Swern reagent, to the corresponding ketone and the 3°-
hydroxyl group acetylated. The resulting â-acetoxy ke-
tone underwent spontaneous elimination of the elements
of acetic acid to give the protected 3-DHS derivative 88b
(72% from 6). Luche reduction10 of this enone then
afforded the 3-epi-shikimate derivative 98b (87%) together
with small quantities (7%) of a readily separable isomer
presumed to be the shikimate-configured epimer. Cleav-
age of the bis-acetal protecting group within compound
9 using 5:1 v/v TFA/water at 18 °C8b delivered the target
compound 5 (94%) which was identical, in all respects,
with material obtained by the first route (Scheme 1).
Treatment of the “all-trans” triol 5 with 6,6′-bi(3,4-
dihydro-2H-pyran)11 (bis-DHP) in the presence of (+)-
CSA‚H2O afforded, as shown in Scheme 3, a ca. 3:1
mixture of the expected regioisomeric dispiroketals 10
and 11 (ca. 80% combined yield)12 together with small
quantities (6%) of an as yet unidentified third isomer.
Since the components of this mixture could only be
separated from one another by tedious chromatographic
1
either means proved identical, as judged by H and 13C
NMR analyses, with enantiomer 12 while the specific
rotations for each were of essentially the same magnitude
but opposite sign (see the Supporting Information).
Furthermore, cleavage of bis-acetal ent-12 using aqueous
trifluoroacetic acid then gave methyl (+)-3-DHS (ent-2)
(60%) which proved identical with compound 2 save for
the sign of the specific rotation. In summary, then, the
conversion of (-)-3-DHS (1) or quinic acid (6) into ent-2
was achieved in eight steps, all involving operationally
simple procedures, and 13% overall yield. The pivotal
part of the sequence, viz. the converstion of compound 5
into enone ent-12, was achieved in three steps and 46%
overall yield.
Compound ent-12 has also proven to be a useful
precursor to non-natural shikimic acid derivatives (Scheme
4). Thus, Luche reduction10 of this enone produced an 84:
13
methods, it was treated with activated MnO2 in order
SCHEME 3
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SCHEME 4
16 mixture of ent-10 and its C3-epimer 14 (92% combined
yield) which could be separated from one another by flash
chromatography. Selective formation of compound 14
(79%, <3% of ent-10) could be achieved by reduction of
enone ent-12 with K-Selectride. Hydrolysis of each of bis-
acetals ent-10 and 14 using 10:1 v/v TFA/water at 18 °C
then afforded methyl (+)-3-epi-shikimate (ent-5) (100%)
and methyl (+)-shikimate (15)16 (94%), respectively.
The present work provides simple methods for the
conversion of abundant (-)-3-DHS (1) and (-)-quinic acid
(6) into derivatives of (+)-3-DHS, (+)-shikimic acid, and
(+)-3-epi-shikimic acid. As such the synthetic utility of
chirons 1 and 6 should be considerably enhanced.
(9) (a) Montchamp, J .-L.; Tian, F.; Hart, M. E.; Frost, J . W. J . Org.
Chem. 1996, 61, 3897. (b) Armesto, N.; Ferrero, M.; Ferna´ndez, S.;
Gotor, V. Tetrahedron Lett. 2000, 41, 8759.
(10) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.
(11) Ley, S. V.; Osbourne, H. M. I. Org. Synth. 1999, 77, 212.
Ack n ow led gm en t. We are grateful to the Institute
of Advanced Studies for provision of a Fellowship to
K.A.J . M.E. is the grateful recipient of a Deutscher
Akademischer Austausch Dienst (DAAD) postdoctoral
Fellowship. M.G.B. thanks the Australian Research
Council for financial support in the form of a Discovery
Grant, Dr. A. B. Hughes (La Trobe University) for
helpful discussions, and Dr. N. Hungerford for as-
sistance with various preliminary experiments.
(12) Reaction of compound
5 with 2,2,3,3-TMB and trimethyl
orthoformate in the presence of (+)-CSA‚H2O resulted in a ca. 2:1
mixture of bis-acetal 9 and its regioisomer (77% combined yield). The
use of chiral bis-DHP derivatives (see, for example: Boons, G.-J .;
Entwistle, D. A.; Ley, S. V.; Woods, M. Tetrahedron Lett. 1993, 34,
5649) to effect more selective conversion of compound 5 into target 11
was not considered because of the likely high cost of producing such
protecting agents and the multistep syntheses necessary for their
preparation.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 4, 5, ent-5, and 15; experimental
procedures and characterization for compounds ent-2, ent-10,
11, 12, ent-12, 13, and 14; crystallography for compound 11;
13C NMR spectra for compounds ent-2, ent-10, ent-12, 13, and
14. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) “Precipitated active” manganese dioxide as supplied by MERCK-
Schuchardt was used.
(14) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(15) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(16) (a) Dumortier, L.; Van der Eycken, J .; Vandewalle, M. Synlett
1992, 245. (b) J ohnson, C. R.; Adams, J . P.; Collins, M. A. J . Chem.
Soc., Perkin Trans. 1 1993, 1. (c) Evans, D. A.; Barnes, D. M.; J ohnson,
J . S.; Lectka, T.; von Matt, P.; Miller, S. J .; Murry, J . A.; Norcross, R.
D.; Shaughnessy, E. A.; Campos, K. R. J . Am. Chem. Soc. 1999, 121,
7582.
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