Chemoenzymatic synthesis of (+)-aspicilin from chlorobenzene

Article abstract of DOI:10.1021/ol006457v

(matrix presented) The enantiomerically pure cis-1,2-dihydrocatechol 2, which is obtained by microbial oxidation of chlorobenzene, has been converted, via intermediate 3, into the natural product (+)-aspicilin (1).

Full text of DOI:10.1021/ol006457v

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3583-3586
Chemoenzymatic Synthesis of
(+)-Aspicilin from Chlorobenzene
Martin G. Banwell* and Kenneth J. McRae
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received August 14, 2000
ABSTRACT
The enantiomerically pure cis-1,2-dihydrocatechol 2, which is obtained by microbial oxidation of chlorobenzene, has been converted, via
intermediate 3, into the natural product (+)-aspicilin (1).
The macrocyclic lactone (+)-aspicilin (1) is a crystalline solid
that was first isolated in 19001 by Hesse from a lichen of
the Lecanoraceae family, but it was not until 1973 that
Huneck and co-workers2 deduced, by application of various
spectroscopic methods, the basic structure of this material.
In 1985 both the relative and absolute stereochemistries
associated with (+)-aspicilin were finally established through
a combination of X-ray crystallographic, degradation, and
synthesis studies.3 No significant biological properties have
been attributed to (+)-aspicilin, but the synthetic challenges
presented by the presence of three contiguous stereogenic
centers within an 18-membered macrocyclic ring system have
prompted a significant number of efforts to develop total
syntheses of the compound.4 It is against this background
that we now report a chemoenzymatic synthesis of the title
compound wherein the pivotal stereochemical triad, as
embodied within intermediate 3, has been constructed from
the cis-1,2-dihydrocatechol 2. Starting material 2 is available
in enantiomerically pure form (>99.8% ee) and a large
quantity by whole-cell-mediated dihydroxylation of chlo-
robenzene using a genetically engineered strain of Echerichia
coli [JM109 (pDTG601)] which overexpresses the toluene
dioxygenase (TDO) enzyme system.5 The present work
serves to further highlight the considerable utility of such
microbial oxidation products for the synthesis of polyoxy-
genated secondary metabolites and their congeners.6
(1) Hesse, O. J. Prakt. Chem. 1900, 62, 430. (b) Hesse, O. J. Prakt.
Chem. 1904, 70, 449.
(2) Huneck, S.; Schreiber, K.; Steglich, W. Tetrahedron 1973, 29, 3687.
(3) Quinkert, G.; Heim, N.; Bats, J. W.; Oschkinat, H.; Kessler, H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 987.
(4) Waanders, P. P.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1987,
28, 2409. (b) Quinkert, G.; Heim, N.; Glenneberg, J.; Do¨ller, U.; Eichhorn,
M.; Billhardt, U.-M.; Schwarz, C.; Zimmermann, G.; Bats, J. W.; Du¨rner,
G. HelV. Chim. Acta 1988, 71, 1719. (c) Quinkert, G.; Fernholz, E.; Eckes,
P.; Neumann, D.; Du¨rner, G. HelV. Chim. Acta 1989, 72, 1753. (d) Quinkert,
G.; Becker, H.; Du¨rner, G. Tetrahedron Lett. 1991, 32, 7397. (e) Sollad´ıe,
G.; Fernandez, I.; Maestro, C. Tetrahedron: Asymmetry 1991, 2, 801. (f)
Oppolzer, W.; Radinov, R. N.; de Brabander, J. Tetrahedron Lett. 1995,
36, 2607. (g) Enders, D.; Prokopenko, O. F. Liebigs Ann. 1995, 1185. (h)
Sinha, S. C.; Keinan, E. J. Org. Chem. 1997, 62, 377. (i) Chenevert, R.;
Lavoie, M.; Dasser, M. Can. J. Chem. 1997, 75, 68. (j) Nishioka, T.;
Our initial attempts to prepare target 1 from compound 2
are shown in Scheme 1 and involved, as the first step,
Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Tetrahedron Lett. 1998, 39, 5597.
(k) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org. Chem.
1998, 63, 7505. (l) Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000,
2, 123. (m) Maezaki, N.; Li, Y-X.; Ohkubo, K.; Goda, S.; Iwata, C.;
Tanaka, T. Tetrahedron 2000, 56, 4405.
(5) Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264, 14940.
10.1021/ol006457v CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Scheme 1a
a Reagents and conditions: (i) Me2C(OMe)2 (excess), p-TsOH (catalyst), 18 °C, 1 h; (ii) m-CPBA (1.0 molar equiv), CH2Cl2, 0 to 18 °C,
15 h; (iii) DIBAL-H (2.0 molar equiv of a 1 M solution in hexane), Et2O, -40 to -20 °C, 1 h; (iv) TBDMS-Cl (2.0 molar equiv),
imidazole (2.5 molar equiv), DMF, 18 °C, 8 h; (v) ozone (excess), MeOH, -78 °C, 0.16 h then NaBH4 (2.0 molar equiv), 0 °C, 0.5 h; (vi)
Ph3PdCH2 (2.0 molar equiv), THF, 0 to 18 °C, 2 h; (vii) DIBAL-H (1.1 molar equiv of a 1 M solution in hexane), hexane, -78 °C, 0.75
h; (viii) compound 10 (1.5 molar equiv), NaH (1.5 molar equiv), THF, 0 °C, 0.5 h, then compound 3 (1.0 molar equiv), 0 °C, 1 h; (ix)
(PCy3)2Cl2RudCHPh (10 mol %), CH2Cl2, 18 °C, 4 h.
conversion of the latter compound into the well-known7
acetonide derivative 4 (97%). Regio- and diastereoselective
epoxidation of diene 4 was achieved with m-chloroperbenzoic
acid (m-CPBA), and oxide 57 (92%) thereby obtained was
subjected to reductive cleavage with diisobutylaluminum
hydride (DIBAL-H) in diethyl ether. The ensuing alcohol 6
{87%,8 [R]D -55 (c 1.5)9} was converted, by standard
methods, into the corresponding tert-butyldimethylsilyl (TB-
DMS) ether 7 {91%, mp 36-39 °C, [R]D -30 (c 1.4)} which
was subjected to cleavage with ozone in methanol followed
by in situ reduction of the intermediate peroxidic material
with sodium borohydride. The resulting ester-aldehyde 8
was somewhat unstable and, therefore, immediately submit-
ted to standard Wittig-methylenation conditions. Alkene 9
{71% from compound 7, [R]D +23 (c 1.7)} thus formed was
treated with DIBAL-H and thereby afforded the pivotal
aldehyde 310 {83%, [R]D -17 (c 2.8)}. In anticipation of
following the closing stages associated with Hatakeyama’s
recently reported4j,11 synthesis of (+)-aspicilin, compound
3 was treated with the phosophonoacetate 1012,13 and in this
(10) Selected spectral data for compound 3: 13C NMR (75 MHz, CDCl3)
δ 200.9 (CH), 133.9 (CH), 117.8 (CH2), 110.4 (C), 81.2 (CH), 80.6 (CH),
70.2 (CH), 38.0 (CH2), 27.0 (CH3), 25.9 (CH3), 25.1 (CH3), 18.2 (C), -4.1
(CH3) and -4.3 (CH3); 1H NMR (300 MHz, CDCl3) δ 9.70 (d, J ) 2.3
Hz, 1H), 5.81 (m, 1H), 5.15-5.02 (complex m, 2H), 4.30 (m, 2H), 3.82
(dd, J ) 5.9 and 11.3 Hz, 1H), 2.42 (m, 1H), 2.23 (m, 1H), 1.58 (s, 3H),
1.39 (s, 3H), 0.88 (s, 9H) and 0.06 (s, 6H).
(11) During the course of this work, Ley et al. reported4l a related
approach to (+)-aspicilin.
(12) The phosphonoacetate 10 was prepared from commercially available
alcohol a according to the sequence shown below. The key step involved
enantioselective nucleophilic methylation of aldehyde b using procedures
described by Knochel et al. (Tetrahedron Lett. 1994, 35, 4539).
(6) For an excellent and up-to-date review on the production and synthetic
utility of enzymatically derived cis-1,2-dihydrocatechols, see: Hudlicky,
T.; Gonzalez, D.; Gibson, D. T. Aldrichimica Acta 1999, 32, 35.
(7) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994,
116, 5099.
(8) All new compounds had spectroscopic data [IR, UV (where ap-
propriate), NMR, mass spectrum] consistent with those of the assigned
structure. Satisfactory combustion and/or high-resolution mass spectral
analytical data were obtained for new compounds and/or suitable derivatives.
(9) Unless stated otherwise, specific rotations were recorded in chloro-
form at 22 °C.
Reagents and conditions: (i) oxalyl chloride (1.2 molar equiv), DMSO (2.6
molar equiv), CH2Cl2, -78 °C, 4 h, then Et3N (2.6 molar equiv), -78 to
-10 °C, 0.66 h; (ii) Ti(OPri)4 (0.6 molar equiv), (1R-trans)-N,N-(cyclo-
3584
Org. Lett., Vol. 2, No. 23, 2000

Scheme 2a
a Reagents and conditions: (i) HCl (2 M solution in MeOH), 0 °C, 3 h; (ii) TBDMS-Cl (2.5 molar equiv), imidazole (3 molar equiv),
DMF, 18 °C, 12 h; (iii) DIBAL-H (1.5 molar equiv of a 1 M solution in hexane), hexane, -78 °C, 0.16 h; (iv) compound 10 (1.5 molar
equiv), NaH (1.5 molar equiv), THF, 0 °C, 0.5 h, then compound 16 (1.0 molar equiv), 0 °C, 0.5 h; (v) (PCy3)2Cl2RudCHPh (20 mol %),
CH2Cl2, 18 °C, 14 h; (vi) H2 (1 atm), 5% Pd on BaSO4 (catalyst), ethyl acetate, 18 °C, 0.4 h; (vii) HCl (2 M solution in MeOH), 0 °C, 3
h.
manner the desired ring-closing metathesis (RCM)14 sub-
strate, viz. R,â-unsaturated ester 1115 {91%, [R]D +34
(c 0.5)}, was obtained. However, reaction of a dilute solution
of compound 11 in dichloromethane with 10 mol % of
Grubbs’ catalyst16 failed to give the target compound 12.
Rather, the alternate, and undesired, RCM product cyclo-
hexene 13 {81%, [R]D -72 (c 1.3)} was observed.
We reasoned that selective formation of alkene 13 occurs
because the conformationally rigid acetonide protecting group
within compound 11 facilitates simultaneous interaction of
the double bonds of the carboxylic acid residue with Grubbs’
catalyst and, therefore, metathesis of these olefinic moieties.
On this basis we sought to replace the acetonide protecting
group within the metathesis substrate by two independent
hydroxy-protecting groups. However, all attempts to effect
acid-catalyzed hydrolysis of the offending acetonide unit
within compound 11 resulted in complex mixtures of
products, perhaps because of the presence of the rather acid-
sensitive acrylate moiety. To circumvent these problems,
appropriate protecting group manipulations were carried out
on a less-advanced intermediate (Scheme 2). Thus, treatment
of ester 9 with methanolic HCl effected global deprotection
and concomitant lactonization to give compound 14 {91%,
mp 111-113 °C, [R]D +42 (c 0.9, MeOH)} which was
reprotected as the corresponding bis-TBDMS ether 15 {95%,
mp 67-69 °C, [R]D +3 (c 1.3)}. Reduction of the last
compound with DIBAL-H then afforded the corresponding
lactol 16 (obtained as predominantly one anomer). Subjection
of the latter compound to a Wadsworth-Emmons reaction
with phosphonoacetate 10 then gave the RCM substrate 17
{[R]D +12 (c 1.1)} in 80% overall yield from lactone 15.
Gratifyingly, exposure of compound 17 to Grubbs’ catalyst
under high-dilution conditions afforded the desired product
18 (70%) as a ca. 3:1 mixture of E- and Z-isomers. This
material was immediately hydrogenated in the presence of
the Rosenmund catalyst and the bis-TBDMS ether of (+)-
aspicilin {mp 78-81 °C, [R]D +19 (c 0.8, MeOH)} was
thereby obtained in 92% yield.
hexane-1,2-diyl)bis(trifluoromethanesulfonamide) (0.04 molar equiv), tolu-
ene, 40 °C, 0.33 h, then Me2Zn (2.2 molar equiv of a 2 M solution in
toluene) and b, -78 °C, warm to -25 °C over 4 h; (iii) trimethyl
phosphonoacetate (3.0 molar equiv), DMAP (0.3 molar equiv), toluene,
111 °C, 14 h.
(13) A comparison of the optical rotations of our samples of compounds
c12 and 10 with those determined (S. Hatakeyama, personal communication
to M. G. Banwell) for their enantiomerically pure counterparts suggests
that the phosphonate ester obtained by the present route to be of ca. 88%
ee.
(14) For a useful point-of-entry to the current literature on RCM
processes, see: Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073.
(15) The reaction of the sodium salt of compound 10 with aldehyde 3
delivers only the illustrated diastereoisomeric form 11 of the coupling
product despite the fact that the former substrate is obtained in only 88%
ee.13 We attribute the selectivity associated with this Wadsworth-Emmons
reaction to the operation of Horeau’s amplification of chirality principle
(see Rautenstrauch, V. Bull. Soc. Chim. Fr. 1994, 131, 515). Thus, when a
stoichiometric excess of compound 10 is employed in this bimolecular
process, there is, throughout the course of the reaction, a kinetic selection
for condensation of the enantiomerically pure aldehyde 3 with the more
abundant enantiomeric form of the sodium salt of phosphonoacetate 10.
(16) Purchased from Strem Chemicals, Inc.
Smooth deprotection of this last compound was achieved
with methanolic HCl to provide the target natural product
(1) {76%, mp 152-154 °C, [R]D +39 (c 1.10)} which was
identical, in all respects, with an authentic sample.18
(17) The reaction of the sodium salt of compound 10 with lactol 16
delivers only the illustrated diastereoisomeric form 17 of the coupling
product despite the fact that the former substrate is obtained in 88% ee.13
Once again, this outcome is attributed to the operation of Horeau’s
amplification of chirality principle.15
Org. Lett., Vol. 2, No. 23, 2000
3585

Acknowledgment. We thank the Australian Research
Council for provision of an Australian Postgraduate Award
to K.J.M. and The Institute of Advanced Studies for generous
financial support. Professor J. Elix (The Australian National
University) is thanked for providing an authentic sample of
(+)-aspicilin. We gratefully acknowledge Professor S.
Hatakeyama (Nagasaki University) for providing us with
various experimental procedures and spectroscopic data.
Supporting Information Available: Experimental pro-
cedures and full characterization of compounds 1 (synthetic
material), 6-11, 13-15, 17, and (+)-aspicilin bis-TBDSM
1
ether; experimental procedures together with H and 13C
NMR spectral data for compound 3; experimental procedure
1
and H NMR spectral data for compound 16; experimental
1
procedure for compound 18; H and 13C NMR spectra for
1
synthetic (+)-aspicilin; H NMR spectrum for natural (+)-
aspicilin. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) For a comprehensive listing of the physical and spectroscopic
properties of (+)-aspicilin, see: Huneck, S.; Yoshimura, I. Identification
of Lichen Substances; Springer-Verlag: Berlin, 1996; p 137.
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