Processing of o -halobenzoates by toluene dioxygenase. the role of the alkoxy functionality in the regioselectivity of the enzymatic dihydroxylation reaction

Article abstract of DOI:10.1021/op400343c

In order to investigate the relationship between the size of a substituent on the aromatic substrate and its directing effect on the dihydroxylation, a series of 2-halobenzoates was synthesized and subjected to metabolism by toluene dioxygenase in preparative-scale fermentation cultures of Escherichia coli JM109 (pDTG601A). Larger ester substituents were shown to have a greater directing effect on the dihydroxylation reaction. Furthermore, significant increases in regioselectivity were observed using propargyl substituents, relative to the use of any other ester substituent. The selectivity and the product ratios are reported for o-fluoro-, o-chloro-, o-bromo-, and o-iodobenzoate esters (methyl, ethyl, n-propyl, allyl, and propargyl). Experimental and spectral data, as well as absolute stereochemistry, are provided for all new compounds.

Full text of DOI:10.1021/op400343c

Article
pubs.acs.org/OPRD
Processing of o‑Halobenzoates by Toluene Dioxygenase. The Role of
the Alkoxy Functionality in the Regioselectivity of the Enzymatic
Dihydroxylation Reaction
Jordan Froese, Mary Ann A. Endoma-Arias, and Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1,
Canada
S
* Supporting Information
ABSTRACT: In order to investigate the relationship between the size of a substituent on the aromatic substrate and its directing
effect on the dihydroxylation, a series of 2-halobenzoates was synthesized and subjected to metabolism by toluene dioxygenase in
preparative-scale fermentation cultures of Escherichia coli JM109 (pDTG601A). Larger ester substituents were shown to have a
greater directing effect on the dihydroxylation reaction. Furthermore, significant increases in regioselectivity were observed using
propargyl substituents, relative to the use of any other ester substituent. The selectivity and the product ratios are reported for o-
fluoro-, o-chloro-, o-bromo-, and o-iodobenzoate esters (methyl, ethyl, n-propyl, allyl, and propargyl). Experimental and spectral
data, as well as absolute stereochemistry, are provided for all new compounds.
for the separation of the diols originating from the aromatic
inducer.
INTRODUCTION
■
The cis-dihydroxylation of aromatic substrates by the enzyme
toluene dioxygenase (TDO) has been utilized to produce a
wide variety of chiral diols that have been used in the synthesis
of many natural products.1−6 In wild-type Pseudomonas putida
bacteria, aromatic dioxygenases and related enzymes are
involved in a cascade, which processes benzene, naphthalene,
biphenyl, and other aromatic compounds as carbon and energy
sources. In 1968, Gibson first reported the bio-oxidative
degradation of benzene and other simple derivatives, as well
as the isolation of the first stable cis-arene-dihydrodiol from a
fermentation of aromatics with Pseudomonas putida.7,8 In order
to allow for the build-up of diols of type 1 in the fermentation
culture, in 1970 Gibson developed a blocked mutant strain
(Pp39D) lacking the enzymes responsible for their further
degradation to catechol 2 and, eventually, to acetate.9 The gene
encoding toluene dioxygenase was later cloned into a
recombinant strain of Escherichia coli (JM109 pDTG601A),
which facilitates large-scale fermentation cultures and provides
a convenient method for the induction of enzyme transcription,
Figure 1. Unlike the blocked mutant, in which the protein
synthesis must be initiated by a known aromatic inducer, the
recombinant organism contains the inducer, isopropylthioga-
lactose (IPTG), on the plasmid.10 Thus, the use of the
recombinant strain leads only to the metabolite derived from
the substrate, and the isolation is not complicated by the need
There are more than 400 arene-dihydrodiols of type 1 known
to date, and the substrate scope was comprehensibly reviewed
up to 2004 by Johnson.11 New metabolites continue to be
isolated, and the diversity of the structures available from the
enzymatic dihydroxylation has led to a widespread use of cis-
dihydrodiols in organic synthesis.1−6,11−18 The first application
of the dihydrodiol metabolites in synthesis was reported by Ley
in 1987 who published the synthesis of racemic pinitol using
cis-1,2-dihydroxycyclohexa-3,5-diene derived from benzene.19
This event led us and many other groups to pursue applications
of these metabolites to the total synthesis of natural products.20
Figure 2. Examples of cis-dihydrodiols derived from benzoic acids,
benzoate esters, and para-substituted arenes.
Special Issue: Biocatalysis 14
Figure 1. Comparison of degradation pathways of aromatics by wild-
type organisms (P. putida), blocked mutants (Pp 39D), and
engineered strains (E. coli JM109 pDTG601A).
Received: December 2, 2013
Published: January 29, 2014
© 2014 American Chemical Society
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To date the metabolites derived from single-ring aromatics
comprise the largest group of compounds numbering into the
hundreds.11 Of the more than 400 compounds of this type only
about 12 have been used in total synthesis. On the basis of a
model proposed by Boyd13b it is possible to predict whether a
single-ring arene might be a good substrate for TDO.
Metabolites from fused aromatics and biphenyls are also
known but are less numerous.
A far smaller group of metabolites is composed of diols
derived from benzoic acids, benzoate esters, or p-disubstituted
arenes, as shown in Figure 2. The ipso-diol 3 was first identified
by Reiner and Hegeman as a metabolite of benzoic acid,
produced by a mutant strain of Alcaligenes eutrophus which was
blocked in benzoic acid catabolism.21 This compound is also
generated from benzoic acid by R. eutrophus B9 and has been
used in synthesis.22 There are limited reports on the use of
metabolites derived from benzoate esters.
RESULTS AND DISCUSSION
■
In order to examine the effect of steric bulk of the halogen
versus ester substituents on the dihydroxylation of 2-
halobenzoates, a series of five esters was prepared for each 2-
halobenzoate. The substrates were prepared from commercially
available 2-halobenzoic acids. Substrates were incubated in a
preparative-scale fermentation culture of E. coli JM109
(pDTG601A) in a 15-L Biostat C fermentor as has been
previously described.31 The crude fermentation extract was
1
immediately analyzed by H NMR spectroscopy in order to
determine the ratio of regioisomeric products. As shown in
Table 1, the enzymatic dihydroxylation of 2-iodobenzoates by
Table 1. Results of the enzymatic dihydroxylation of various
2-iodobenzoates by toluene dioxygenase
In 2009 we published a brief study on steric and functionality
limits of esters in the production of diols of type 4.23 At that
time, only the diol derived from methyl benzoate had been
described.24 Several new metabolites were identified and,
subsequently, we have used the diol produced from ethyl
benzoate in a short synthesis of oseltamivir (Tamiflu).25 For
metabolites of type 5 and 6 only the methyl o-halobenzoates
have been previously reported.26 Finally, a group of para-
substituted arenes was investigated recently and led to several
diol metabolites of type 7, Figure 2, that could potentially be
used in an approach to tetrodotoxin.27
In 2011 diol 9a, Figure 3, was identified as a minor product
*
Isomeric ratios obtained by 1H NMR spectroscopic analysis of crude
derived from dihydroxylation of methyl o-iodobenzoate26 and
fermentation extract.
toluene dioxygenase yielded a mixture of regioisomers (8 and 9,
Table 1) as was previously observed with methyl 2-
iodobenzoate.26 As might be predicted by the Boyd model,13b
increasing the size of the ester substituent resulted in a greater
directing effect on the dihydroxylation.
Figure 3. Chemoenzymatic preparation of the key fragment for the
synthesis of kibdelone C.
As shown in Table 2, 2-bromobenzoates displayed a similar
regioselectivity trend. Significantly increased yields were
obtained with ethyl and propargyl 2-bromobenzoates, relative
to the use of their iodo analogues.
used in a short synthesis of ester 1028 employed by Porco in the
total synthesis of kibdelone C.29 [In Porco’s original synthesis
of kibdelone C the key intermediate 10 was synthesized in 13
steps.29] Methyl o-iodobenzoate produced a 4:1 mixture of 8a
and 9a (as might be expected from the Boyd model13b), and
this observation led to a study of methyl o-halobenzoates where
such selectivity trend was reversed with methyl o-chloroben-
zoate.26
Table 2. Results of the enzymatic dihydroxylation of various
2-bromobenzoates by toluene dioxygenase
The short chemoenzymatic preparation of the key
intermediate 10 allowed for the more efficient synthesis of
kibdelone C and derivatives through a fruitful collaboration.30
However, the dihydroxylation of methyl o-iodobenzoate
produced a mixture of regioisomers in which the desired
metabolite 9a was only a minor product.26 The manipulation of
the ratio of dihydroxylation products through the use of
substituents of varying sizes should be possible, in line with the
results of the previous investigations. In this study, we report
the effect of altering both the halogen substituent and the
alkoxy functionality of the ester in 2-halobenzoates on the ratio
of regioisomeric products produced by the dihydroxylation of
such compounds by toluene dioxygenase.
*
Isomeric ratios obtained by 1H NMR spectroscopic analysis of crude
fermentation extract.
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With 2-chlorobenzoate substrates, increased regioselectivities
in favor of isomer 14 were observed with the yields comparable
to those of 2-bromobenzoates, as shown in Table 3.
substrate), an interesting trend emerged when examining the
isomeric ratios associated with the propargyl compounds. In the
case of iodo, bromo, and chloro compounds, the propargyl
ester substituent was shown to be a much stronger directing
group than any other. Attempts to quantify Boyd’s model by
only considering A-values of substituents leads to some
confusion: for example, the A-values of the halogens are
0.25−0.42, 0.53−0.64, 0.48−0.67, and 0.47−0.61 for fluorine,
chlorine, bromine, and iodine, respectively.32,33 Thus, other
factors need to be considered to justify any regioselectivity
trends associated with the steric bulk of the halogen atoms. For
esters, the A-values should roughly correspond to the A-values
of the alkyl group of the alkoxide as the carboxylates remain
constant. Thus, a comparison of methyl, ethyl, n-propyl, allyl,
and the propargyl group could, in principle, be made on the
basis of the difference between terminal substituents; i.e., H for
methyl ester, CH3 for ethyl ester, ethyl, vinyl, and acetylene for
n-propyl, allyl, and propargyl esters, respectively. These values
are: Me = 1.7, Et = 1.8, vinyl =1.5, and acetylene 0.4. Clearly
the A-values cannot be used to explain the directing effects.
Another metric to consider would be the Taft34 and Charton35
steric parameter values (Es and ν values, respectively) for both
halogens and ester alkyl groups. Unlike the A-values, these
follow a logical trend: F = 0.27; Cl = 0.55; Br = 0.65; I = 0.78.
For ester alkyl groups these are: H = 0; Me = 0.52; Et = 0.56;
nPr = 0.68, (C2H3 = 1.51).35 These values would correspond to
Me, Et, nPr, nBu, and allyl esters, respectively (the value for
alkynyl is not available). While there is no clear linear
relationship that would explain the reversal of directing trends
between the “apparent size” of the halogen versus that of the
ester, at least some of the trends may be rationalized by using
the internally consistent ν values for halogens and for the alkyl
groups. For the esters it is clear that propargyl groups,
regardless of apparent size with respect to that of other alkoxy
groups, override the directing effects of halogens, as evidenced
from the ratios of the two regioisomers obtained in all cases.
In the case of the iodo, bromo, and chloro substrates, the
regioisomeric mixtures of diols proved to be very difficult to
separate. This problem was exacerbated by the relative
instability of these compounds at room temperature,
particularly when being taken to dryness. In order to facilitate
isolation and characterization, a portion of the crude
regioisomeric mixture was subjected to partial reduction with
potassium azodicarboxylate (PAD) in the presence of acetic
acid (Scheme 1). Preparative high pressure liquid chromatog-
raphy (HPLC) was employed to separate the regioisomeric
mixtures, which facilitated partial characterization of the diene
diol compounds, and full characterization of their reduced
counterparts. This derivatization was not necessary in the case
of the fluoro compounds, as these were significantly more
stable.
Table 3. Results of the enzymatic dihydroxylation of various
2-chlorobenzoates by toluene dioxygenase
*
Isomeric ratios obtained by 1H NMR spectroscopic analysis of crude
fermentation extract.
Consistent with previous findings,26 2-fluorobenzoates
yielded only one regioisomer upon dihydroxylation by toluene
dioxygenase, irrespective of the size of the ester substituent,
Table 4. Furthermore, significantly higher yields were obtained
using 2-fluorobenzoates, relative to the use of the other
halogenated substrates.
Table 4. Results of the enzymatic dihydroxylation of various
2-fluorobenzoates by toluene dioxygenase
*
Isomeric ratios obtained by 1H NMR spectroscopic analysis of crude
fermentation extract.
In addition to the considerations of Boyd’s model13b for
directing effects in dihydroxylation (i.e., the relationship of
isomeric ratio to the size of the substituents on the aromatic
In order to facilitate the confirmation of absolute stereo-
chemistry in the new metabolites, all of the fluorinated
Scheme 1. Enzymatic dihydroxylation of 2-halobenzoates and subsequent derivation to facilitate isolation and characterization
[note that 17c, 19c, and 21c are not produced in sufficient quantities to allow full characterization]
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Scheme 2. Determination of absolute stereochemistry of the metabolites [note that 17c, 19c, and 21c are not produced in
sufficient quantities to allow full characterization]
derivatives were converted to the corresponding methyl ester
16a, (Scheme 2), the absolute stereochemistry of which has
been previously published.26 In the case of the iodo, bromo,
and chloro compounds, their reduced derivatives (17b, 18b−c,
19b, 20b−c, 21b, 22b−c) were converted to their correspond-
ing methyl esters (17a, 18a, 19a, 20a, 21a, 22a) in order to
confirm absolute stereochemistry (Scheme 2). The partially
reduced methyl ester metabolites (17a, 18a, 19a, 20a, 21a,
centrifugation and extraction with ethyl acetate. All diene diol
products were subjected to immediate reduction with
potassium azodicarboxylate, or stored at −78 °C. Where
possible, diene diol products were isolated by preparative
HPLC (60:40 v/v methanol/water) and recrystallized from
ethyl acetate and pentane. Reduced diol products were also
isolated by preparative HPLC (60:40 v/v methanol/water) and
recrystallized from ethyl acetate and pentane.
1
22a) were matched by H NMR, melting point, and [α]D to
General Procedure for Reduction with Potassium
Azodicarboxylate. To a stirred solution of diene diol (2.5
mmol) and potassium azodicarboxylate (PAD) (7.5−15.0
mmol) in MeOH (4 mL), glacial acetic acid was added
(17.5−37.5 equiv) dropwise at −15 °C. The reaction was
allowed to warm to room temperature over 14 h and then was
quenched by the addition of a saturated aqueous solution of
Na2CO3 (7−15 mL of a saturated aqueous solution),
concentrated under reduced pressure, and extracted with
ethyl acetate (5 × 5 mL). The combined organic layers were
washed with brine (1 × 7 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude material was
recrystallized from ethyl acetate/pentane.
General Procedure for the Transesterification of PAD-
Reduced Metabolites. To a stirred solution of an ester (0.5
mmol) in MeOH (5 mL) was added NaOMe until the solution
was observed to be just basic by pH paper. The reaction
mixture was allowed to stir at room temperature until the
starting material was consumed by TLC. The product was
purified by flash column chromatography (3:2 v/v ethyl
acetate/hexanes) and recrystallized from ethyl acetate/pentane.
Ethyl (3S,4S)-3,4-dihydroxy-2-iodocyclohex-1,5-dienecar-
boxylate (8b): off-white solid; mp 105−107 °C (pentane);
[α]D20 = −72.4 (c = 0.2, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.19 (d, J = 9.8 Hz, 1H), 6.13 (dd, J = 9.6, 3.7 Hz, 1H), 4.44
their corresponding compounds prepared from metabolites
(8a, 9a, 11a, 12a, 13a, 14a) previously published,26 Scheme 2.
CONCLUSION
■
The original hypothesis, that the directing effect of halogen and
ester substituents on the dihydroxylation of aromatic substrates
roughly follows the corresponding A-values of the functional
groups was not confirmed. The A-values alone cannot be used
to rationalize the ratios of the regioisomers produced. The
Charton ν values for halogens and for the alkyl groups of the
esters show a logical and linear trend with respect to the
“apparent size” of functionalities. They may certainly be used to
explain their relative directing effects but not necessarily their
mutual directing effects. We have shown that significantly greater
levels of regioselectivity, are obtained when propargylic ester
substituents are used for any of the halobenzoate substrates. At
this time, and without additional information, we cannot
explain the origin of the selectivity apparent for only
propargylic esters, nor can we explain the difference in
observed yields for some of the substrates.
EXPERIMENTAL SECTION
■
Viable cells were prepared in a 15-L Biostat C fermentor as
previously described.24 Substrates were fed in 1-g increments
over 3 h, with a total of 15 g being added into the media before
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20
(3:2 v/v ethyl acetate/hexanes); [α]D = −37.4 (c = 0.2,
CHCl3), [α]D20 = −38.0 (c = 0.2, CHCl3) [lit.36 [α]D20 = −39.5
(c = 1.1, CHCl3)]; IR (KBr, cm−1) 3268, 2950, 1727, 1634,
(br d, 1H), 4.39 (br d, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.37 (t, J
= 7.1 Hz, 3H).
1
1432, 1236, 1093; H NMR (300 MHz, CDCl3) δ 4.50 (br s,
1H), 3.94 (m, 1H), 3.86 (s, 3H), 3.00 (m, 2H), 2.77 (m, 2H),
1.97 (m, 1H), 1.74 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
168.2, 140.4, 103.2, 74.8, 68.2, 52.4, 27.2, 25.3; HRMS calcd for
+
C8H11IO4 297.9702, found 297.9707.
Ethyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1,3-dienecar-
boxylate (9b): off-white solid; mp 107−110 °C (pentane);
[α]D20 = 67.1 (c = 0.45, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.47 (d, J = 9.3 Hz, 1H), 5.86 (d, J = 9.4 Hz, 1H), 4.55 (m,
1H), 4.48 (m, 1H), 4.34 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).
Ethyl (3S,4S)-3,4-dihydroxy-2-iodocyclohex-1-enecarboxy-
late (17b): off-white solid; mp 108−109 °C (pentane); Rf =
0.46 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −32.6 (c = 0.75,
CHCl3); IR (KBr, cm−1) 3270, 2940, 1704, 1593, 1463, 1253;
1H NMR (300 MHz, CDCl3) δ 4.32 (br d, 1H), 4.30 (q, J = 7.1
Hz, 2H), 4.02 (m, 1H), 2.64 (dt, J = 18.1, 5.7 Hz, 1H), 2.39
(dt, J = 17.9, 6.7 Hz, 1H), 1.94 (m, 2H), 1.37 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 167.96,140.70, 102.69,
74.75, 68.19, 61.67, 27.21, 25.26, 14.06; HRMS calcd for
Allyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1,3-dienecar-
boxylate (9d): off-white solid; mp 63−66 °C (pentane);
[α]D20 = 68.0 (c = 0.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.50 (dd, J = 9.0, 2.3 Hz, 1H), 6.02 (m, 1H), 5.88 (ddd, J = 9.8,
1.9, 1.3 Hz, 1H), 5.43 (ddd, J = 17.2, 1.5, 1.4 Hz, 1H), 5.33 (dd,
J = 10.4, 1.2 Hz, 1H), 4.79 (m, 2H), 4.58 (d, J = 5.6 Hz, 1H),
4.51 (br d, 1H).
+
C9H13IO4 311.9859, found 311.9847.
Ethyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1-enecarboxy-
late (18b): off-white solid; mp 106−108 °C (pentane); Rf =
0.42 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −31.6 (c = 0.45,
CHCl3); IR (KBr, cm−1) 3282, 2950, 1714, 1642, 1461, 1241;
1H NMR (300 MHz, CDCl3) δ 4.52 (br d, 1H), 4.36 (q, J = 7.1
Hz, 2H), 3.95 (m, 1H), 3.00 (dt, J = 19.1, 5.4 Hz, 1H), 2.75
(dt, J = 18.6, 6.9 Hz, 1H), 1.98 (m, 1H), 1.77 (m, 1H), 1.37 (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.98, 136.67,
108.49, 68.38, 67.05, 61.73, 41.14, 28.37, 14.12; HRMS calcd
Propargyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1,3-dien-
ecarboxylate (9e): off-white solid; mp 70−72 °C (pentane);
[α]D20 = 77.1 (c = 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.51 (dd, J = 9.8, 2.4 Hz, 1H), 5.89 (ddd, J = 9.8, 1.8, 1.0 Hz,
1H), 4.87 (m, 1H), 4.59 (t, J = 5.9 Hz, 1H), 4.50 (m, 2H), 2.56
(t, J = 2.4 Hz, 1H).
+
for C9H13IO4 311.9859, found 311.9859.
Methyl (3S,4S)-3,4-dihydroxy-2-iodocyclohex-1-enecar-
boxylate (17a): white solid; mp 78−80 °C (pentane) [lit.36
mp 80−81 °C (hexanes)]; Rf = 0.23 (3:2 v/v ethyl acetate/
hexanes); [α]D = −32.5 (c = 0.1, CHCl3) [lit.36 [α]D
=
n-Propyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1-enecar-
boxylate (18c): off-white solid; mp 70−72 °C (pentane); Rf
= 0.43 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −42.6 (c = 0.5,
CHCl3); IR (KBr, cm−1) 3271, 2962, 2879, 1715, 1606, 1462,
1231; 1H NMR (300 MHz, CDCl3) δ 4.50 (br d, 1H), 4.23 (td,
J = 6.5, 1.9 Hz, 2H), 3.94 (m, 1H), 3.01 (dt, J = 19.1, 5.5 Hz,
1H), 2.77 (dt, J = 19.0, 7.1 Hz, 1H), 1.97 (m, 1H), 1.77 (m,
2H), 1.74 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.01, 136.73, 108.49, 68.43, 67.33, 67.07,
20
20
−34.5 (c = 1.1, CHCl3)]; IR (KBr, cm−1) 3259, 2949, 1722,
1
1635, 1433, 1347, 1094; H NMR (300 MHz, CDCl3) δ 4.33
(br s, 1H), 4.02 (m, 1H), 3.83 (s, 3H), 2.73 (s, 1H), 2.65 (dt, J
= 18.0, 5.7 Hz, 1H), 2.35 (dt, J = 18.0, 5.7 Hz, 1H), 1.97 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 167.5, 136.8, 108.5, 68.4,
+
67.1, 52.3, 41.0, 28.3; HRMS calcd for C8H11IO4 297.9702,
found 297.9713.
Methyl (5S,6R)-5,6-dihydroxy-2-iodocyclohex-1-enecar-
boxylate (18a): white solid; mp 83−85 °C (pentane), mp
84−86 °C (pentane) [lit.36 mp 85−86 °C (hexanes)]; Rf = 0.27
+
41.22, 28.37, 21.87, 10.63; HRMS calcd for C10H15IO4
326.0015, found 326.0015.
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(c = 0.7, CHCl3)]; IR (KBr, cm−1) 3237, 2953, 1731, 1430,
1217, 1099, 1037; 1H NMR (300 MHz, CDCl3) δ 4.53 (s, 1H),
3.90−3.93 (m, 1H), 3.86 (s, 3H), 2.87−2.90 (m, 1H), 2.60−
2.71 (m, 1H), 2.05−2.08 (m, 1H), 1.85−1.86 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 167.1, 132.5, 130.7, 68.5, 67.0, 52.3,
+
36.8, 27.1; HRMS calcd for C8H11BrO4 249.9841, found
Ethyl (5S,6R)-5,6-dihydroxy-2-bromocyclohex-1,3-diene-
carboxylate (12b): white solid; mp 78−80 °C (pentane);
[α]D20 = 46.1 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.19 (dd, J = 9.9, 2.3 Hz, 1H), 6.06 (ddd, J = 9.8, 1.9, 1.2 Hz,
1H), 4.59 (m, 1H), 4.51 (m, 1H), 4.35 (m, 2H), 1.38 (t, J = 7.1
Hz, 3H).
249.9832; Anal. Calcd for C8H11BrO4: C, 38.27; H, 4.42.
Found: C, 38.33; H, 4.34.
Ethyl (3S,4S)-3,4-dihydroxy-2-bromocyclohex-1-enecar-
boxylate (19b): white solid; mp 90−92 °C (pentane); Rf =
20
0.26 (3:2 v/v ethyl acetate/hexanes); [α]D = −52.9 (c = 1.0,
Allyl (5S,6R)-5,6-dihydroxy-2-bromocyclohex-1,3-diene-
carboxylate (12d): white solid; mp 59−61 °C (pentane);
[α]D20 = 52.3 (c = 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.20 (dd, J = 9.9, 2.4 Hz, 1H), 6.08 (ddd, J = 8.7, 1.9, 1.4 Hz,
CHCl3); IR (KBr, cm−1) 3255, 2950, 1708, 1461, 1252, 1094;
1H NMR (300 MHz, CDCl3) δ 4.31 (br d, 1H), 4.29 (q, J = 7.1
Hz, 2H), 4.01 (m, 1H), 2.61 (dt, J = 17.8, 6.0 Hz, 1H), 2.34
(dt, J = 17.9, 6.6 Hz, 1H), 1.95 (m, 1H), 1.86 (m, 2H), 1.35 (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.19, 134.72,
124.11, 72.22, 68.33, 61.55, 26.52, 25.15, 14.07; HRMS calcd
1H), 6.00 (m, 1H), 5.43 (ddd, J 17.3, 2.3, 1.5 Hz, 1H), 5.31
=
(dd, J = 10.4, 1.3 Hz, 1H), 4.78 (m, 2H), 4.63 (d, J = 5.9 Hz,
1H), 4.54 (br d, 1H).
+
for C9H12BrO4 (M − H species) 262.9919, found 262.9925;
Anal. Calcd for C9H13BrO4: C, 40.78; H, 4.94. Found: C, 40.57;
H, 4.87.
Propargyl (5S,6R)-5,6-dihydroxy-2-bromocyclohex-1,3-di-
enecarboxylate (12e): white solid; mp 83−85 °C (pentane);
[α]D20 = 65.6 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.22 (dd, J = 2.5, 9.8 Hz, 1H), 6.10 (ddd, J = 9.8, 1.9, 1.1 Hz,
1H), 4.88 (t, J = 2.6 Hz, 2H), 4.64 (dd, J = 6.0, 1.2 Hz, 1H),
4.54 (m, 1H), 2.55 (t, J = 2.4 Hz, 1H).
Ethyl (5S,6R)-5,6-dihydroxy-2-bromocyclohex-1-enecar-
boxylate (20b): white solid; mp 87−89 °C (pentane); Rf =
20
0.24 (3:2 v/v ethyl acetate/hexanes); [α]D = −59.8 (c = 1.0,
CHCl3); IR (KBr, cm−1) 3269, 2955, 1721, 1622, 1462, 1364,
1241, 1042; 1H NMR (300 MHz, CDCl3) δ 4.52 (t, J = 3.8 Hz,
1H), 4.32 (q, J = 7.2 Hz, 2H), 3.91 (m, 1H), 2.84 (dt, J = 19.0,
5.5 Hz, 1H), 2.63 (dt, J = 19.0, 7.3 Hz, 1H), 2.01 (m, 1H), 1.81
(m, 1H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 166.80, 131.69, 131.02, 68.51, 67.03, 61.67, 35.80, 27.06,
14.11; HRMS calcd for C9H13BrO4+ 263.9997, found 263.9996;
Anal. Calcd for C9H13BrO4: C, 40.78; H, 4.94. Found: C, 40.71;
H, 4.92.
Methyl (3S,4S)-3,4-dihydroxy-2-bromocyclohex-1-enecar-
boxylate (19a): white solid; mp 91−93 °C (pentane) [lit.36 mp
92−93 °C (pentane)]; Rf = 0.42 (2:1 v/v ethyl acetate/
hexanes); [α]D = −30.6 (c = 0.7, CHCl3), [lit.36 [α]D
=
20
20
−32.4 (c = 0.7, CHCl3)]; IR (KBr, cm−1) 3270, 2951, 1728,
1431, 1254, 1092, 756; 1H NMR (300 MHz, CDCl3) δ 4.29 (br
s, 1H), 4.01 (br s, 1H), 3.81 (s, 3H), 2.56−2.71 (m, 1H), 2.31−
2.37 (m, 1H), 1.85−1.96 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 134.4, 124.8, 72.2, 68.2, 52.3, 26.4, 25.2;
n-Propyl (5S,6R)- 5,6-dihydroxy-2-bromocyclohex-1-ene-
+
HRMS calcd for C8H11BrO4 249.9841, found 249.9852.
carboxylate (20c): white solid; mp 82−85 °C (pentane); Rf =
20
0.27 (3:2 v/v ethyl acetate/hexanes); [α]D = −49.8 (c = 0.6,
CHCl3); IR (KBr, cm−1) 3383, 2966, 1714, 1657, 1462, 1426,
1
1392, 1337, 1268, 1092, 1040, 913; H NMR (300 MHz,
CDCl3) δ 4.53 (t, J = 3.8 Hz, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.92
(m, 1H), 2.86 (dt, J = 19.0, 5.4 Hz, 1H), 2.65 (dt, J = 19.1, 7.2
Hz, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.77 (q, J = 7.2 Hz, 2H),
1.02 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.81,
132.27, 130.78, 68.59, 67.30, 67.04, 35.88, 27.08, 21.89, 10.60;
HRMS calcd for C10H15BrO4 278.0148, found 278.0169.
Ethyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1,3-diene-
carboxylate (14b): white solid; mp 78−80 °C (pentane);
Methyl (5S,6R)-5,6-dihydroxy-2-bromocyclohex-1-enecar-
boxylate (20a): white solid; mp 95−97 °C (pentane), mp 98−
100 °C (pentane) [lit.36 mp 98−100 °C (pentane)]; Rf = 0.36
+
20
(2:1 v/v ethyl acetate/hexanes); [α]D = −43.5 (c = 0.7,
CHCl3), [α]D20 = −52.8 (c = 0.7, CHCl3) [lit.36 [α]D20 = −44.9
806
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Article
(c = 1.0, CHCl3)]; IR (KBr, cm−1) 3228, 2956, 1731, 1430,
1336, 1245, 1101, 1040, 967, 931; 1H NMR (300 MHz,
CDCl3) δ 4.56 (br d, 1H), 3.87 (m, 4H), 2.69 (dt, J = 19.0, 5.3
Hz, 1H), 2.51 (dt, J = 19.0, 7.3 Hz, 1H), 2.02 (m, 1H), 1.82 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 166.69, 142.58, 127.30,
67.88, 67.22, 52.25, 33.39, 26.00; HRMS calcd for C9H13ClO4
206.0346, found 206.0352; Anal. Calcd for C9H13ClO4: C,
46.50; H, 5.37. Found: C, 46.63; H, 5.40.
+
[α]D20 = 46.1 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.18 (ddd, J = 9.8, 1.9, 1.0 Hz, 1H), 6.01 (dd, J = 9.8, 2.4 Hz,
1H), 4.64 (dd, J = 6.1, 1.4 Hz, 1H), 4.53 (m, 1H), 4.34 (m,
2H), 1.38 (t, J = 7.20 Hz, 3H).
Ethyl (3S,4S)-3,4-dihydroxy-2-chlorocyclohex-1-enecar-
Allyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1,3-dienecar-
boxylate (21b): white solid; mp 68−70 °C (pentane); Rf =
20
boxylate (14d): white solid; mp 61−63 °C (pentane); [α]D
=
20
0.30 (3:2 v/v ethyl acetate/hexanes); [α]D = −62.3 (c = 0.4,
33.8 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.16 (d,
J = 10.7 Hz, 1H), 5.99 (dd, J = 10.1, 2.6 Hz, 1H), 5.95 (m, 1H),
5.39 (dd, J = 17.2, 1.4 Hz, 1H), 5.27 (dd, J = 10.5, 1.5 Hz, 1H),
4.74 (m, 2H), 4.62 (br d, 1H), 4.50 (br d, 1H).
CHCl3); IR (KBr, cm−1) 3268, 2952, 1726, 1624, 1464, 1368,
1289, 1254, 1094, 940; 1H NMR (300 MHz, CDCl3) δ 4.29 (q,
J = 7.0 Hz, 1H), 4.25 (s, 2H), 4.02 (s, 1H), 2.65 (dt, J = 18.0,
5.9 Hz, 1H), 2.38 (dt, J = 18.0, 6.5 Hz, 1H), 1.95 (m, 1H), 1.83
(m, 1H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 166.46, 133.32, 131.05, 71.10, 68.09, 61.40, 25.41, 25.18,
14.10; HRMS calcd for C9H13ClO4+ 220.0402, found 220.0505.
Propargyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1,3-di-
enecarboxylate (14e): white solid; mp 66−69 °C (pentane);
[α]D20 = 29.5 (c = 0.65, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.22 (dt, J = 9.8, 1.8 Hz, 1H), 6.03 (dd, J = 2.5, 9.9 Hz, 1H),
4.87 (t, J = 2.0 Hz, 2H), 4.68 (d, J = 5.9 Hz, 1H), 4.55 (br d,
1H), 2.54 (t, J = 2.51 Hz, 1H).
Ethyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1-enecar-
boxylate (22b): white solid; mp 74−76 °C (pentane); Rf =
0.33 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −72.3 (c = 0.45,
CHCl3); IR (KBr, cm−1) 3271, 2958, 1717, 1624, 1461, 1424,
1
1365, 1241, 1097, 1043; H NMR (300 MHz, CDCl3) δ 4.54
(s, 1H), 4.36 (q, J = 7.11 Hz, 2H), 3.86 (s, 1H), 2.67 (dt, J =
19.0, 5.4 Hz, 1H), 2.49 (dt, J = 18.7, 7.3 Hz, 1H), 1.99 (m, 1H),
1.79 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.29, 142.24, 127.39, 67.89, 67.14, 61.50, 33.34,
26.03, 14.09; HRMS calcd for C9H13ClO4 220.0402, found
220.0405; Anal. Calcd for C9H13ClO4: C, 48.99; H, 5.94.
Found: C, 48.77; H, 5.91.
Methyl (3S,4S)-3,4-dihydroxy-2-chlorocyclohex-1-enecar-
boxylate (21a): white solid; mp 91−93 °C (pentane) [lit.36
mp 92−94 °C (pentane)]; Rf = 0.23 (3:2 v/v ethyl acetate/
+
hexanes); [α]D = −59.7 (c = 0.2, CHCl3) [lit.36 [α]D
=
20
20
−62.3 (c = 0.4, CHCl3)]; IR (KBr, cm−1) 3400, 2953, 1728,
1
1627, 1435, 1344, 1259, 1143, 1091, 985, 931; H NMR (300
MHz, CDCl3) δ 4.24 (br d, 1H), 4.00 (m, 1H), 3.82 (s, 3H),
2.64 (dt, J = 18.1, 5.7 Hz, 1H), 2.38 (dt, J = 18.0, 6.4 Hz, 1H),
1.94 (m, 1H), 1.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
166.86, 133.96, 130.65, 71.10, 68.07, 52.23, 25.42, 25.15;
HRMS calcd for C8H11ClO4 206.0346, found 206.0350; Anal.
Calcd for C8H11ClO4: C, 46.50; H, 5.37. Found: C, 46.69; H,
5.44.
n-Propyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1-ene-
carboxylate (22c): white solid; mp 60−63 °C (pentane); Rf
= 0.34 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −65.6 (c = 0.3,
CHCl3); IR (KBr, cm−1) 3420, 3304, 2964, 1714, 1661, 1552,
+
1
1521, 1392, 1344, 1271, 1094, 1056, 1009, 928, 795; H NMR
(300 MHz, CDCl3) δ 4.58 (m, 1H), 4.24 (t, J = 6.72 Hz, 2H),
3.90 (m, 1H), 2.73 (dt, J = 18.8, 5.7 Hz, 1H), 2.55 (dt, J = 18.4,
7.3 Hz, 1H), 2.03 (m, 1H), 1.85 (m, 1H), 1.77 (q, J = 7.05 Hz,
2H), 1.02 (t, J = 7.47 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.39, 142.99, 127.10, 68.01, 67.18, 67.12, 33.62, 26.13, 21.91,
10.58; HRMS calcd for C10H15ClO4 234.0659, found
234.06609.
Methyl (5S,6R)-5,6-dihydroxy-2-fluorocyclohexa-1,3-dien-
ecarboxylate (16a): white solid; mp 72−73 °C (pentane), mp
73−75 °C (pentane), mp 73−76 °C (pentane), mp 74−77 °C
+
Methyl (5S,6R)-5,6-dihydroxy-2-chlorocyclohex-1-enecar-
boxylate (22a): off-white solid; mp 74−75 °C (pentane), mp
74−76 °C (pentane) [lit.36 mp 75−77 °C (pentane)]; Rf = 0.18
20
(3:2 v/v ethyl acetate/hexanes); [α]D = −65.9 (c = 0.8,
CHCl3), [α]D20 = −66.5 (c = 1.0, CHCl3) [lit.36 [α]D20 = −68.5
807
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Allyl (5S,6R)-5,6-dihydroxy-2-fluorocyclohex-1,3-dienecar-
boxylate (16d): white solid; mp 56−58 °C (pentane); Rf = 0.32
20
(3:2 v/v ethyl acetate/hexanes); [α]D = −5.4 (c = 0.35,
CHCl3); IR (KBr, cm−1) 3418, 1694, 1651, 1600, 1404, 1259,
1138, 1095, 1044, 994, 930, 829; 1H NMR (300 MHz, CDCl3)
δ 6.35 (m, 1H), 5.95 (m, 2H), 5.40 (ddd, J = 17.2, 2.3, 1.4 Hz,
1H), 5.28 (dd, J = 10.5, 1.5 Hz, 1H), 4.75 (m, 3H), 4.57 (br d,
1H), 13C NMR (75 MHz, CDCl3) δ 165.28 (t, J = 2.9 Hz),
161.47 (s), 143.24 (d, J = 25.9 Hz), 131.71 (s), 119.67 (d, J =
35.8 Hz), 118.35 (s), 106.31 (d, J = 2.1 Hz), 69.07 (s), 67.04
(pentane) [lit.26 value: mp 74−76 °C (ethyl acetate)]; Rf =
20
0.15 (1:1 v/v ethyl acetate/hexanes); [α]D = +68.2 (c = 1.1,
MeOH), +69.4 (c = 1.0, MeOH), +70.2 (c = 0.9, MeOH),
+72.8 (c = 1.0, MeOH) [lit.26 value: [α]D = +73.2 (c = 1.05,
20
MeOH)]; IR (KBr, cm−1) 3558, 3025, 1694, 1439, 1401, 1040;
1H NMR (600 MHz, CDCl3) δ 6.33 (m, 1H), 5.94 (ddd, J =
10.2, 8.3, 2.6 Hz, 1H), 4.71 (t, J = 6.2 Hz, 1H), 4.55 (m, 1H),
3.83 (s, 3H), 3.17 (br s, 1H), 3.09 (br s, 1H) ppm; 13C NMR
(150 MHz, CDCl3) δ (ppm) 166.0 (d, J = 2.2 Hz), 163.2 (d, J
= 281.0 Hz), 143.1 (d, J = 12.1 Hz), 119.6 (d, J = 36.2 Hz),
106.2 (d, J = 2.2 Hz), 69.06 (s), 67.0 (d, J = 6.6 Hz), 52.2 (s);
+
(d, J = 6.2 Hz), 65.73 (s); HRMS calcd for C10H11FO4
214.0641, found 214.0642.
+
HRMS calcd for C8H9FO4 188.0485, found 188.0484; Anal.
Calcd for C8H9FO4: C, 51.07; H, 4.82; found: C, 51.18; H,
4.76.
Propargyl (5S,6R)-5,6-dihydroxy-2-fluorocyclohex-1,3-di-
enecarboxylate (16e): white solid; mp 82−84 °C (pentane);
20
Rf = 0.27 (3:2 v/v ethyl acetate/hexanes); [α]D = +13.4 (c =
1.7, CHCl3); IR (KBr, cm−1) 3296, 2949, 1703, 1654, 1599,
1
1405, 1256, 1135, 1095, 1045, 991, 828; H NMR (300 MHz,
CDCl3) δ 6.35 (m, 1H), 5.95 (ddd, J = 10.6, 8.3, 2.8 Hz, 1H),
4.82 (d, J = 2.5, 2H), 4.72 (t, J = 6.3 Hz, 1H), 4.56 (br d, 1H),
2.51 (t, J = 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.83
(s), 164.63 (d, J = 2.6 Hz), 162.08 (s), 143.85 (d, J = 12.7 Hz),
119.58 (d, J = 35.8 Hz), 105.83 (d, J = 2.1 Hz), 75.27 (s), 69.14
(s), 66.88 (d, J = 5.7 Hz), 52.52 (s); HRMS calcd for
Ethyl (5S,6R)-5,6-dihydroxy-2-fluorocyclohex-1,3-diene-
carboxylate (16b): white solid; mp 70−72 °C (pentane); Rf
20
= 0.24 (3:2 v/v ethyl acetate/hexanes); [α]D = −11.6 (c =
0.65, CHCl3); IR (KBr, cm−1) 3418, 2986, 1693, 1601, 1407,
1260, 1138, 1096, 1045, 992, 832; 1H NMR (300 MHz,
CDCl3) δ 6.34 (m, 1H), 5.96 (ddd, J = 10.6, 8.3, 2.7 Hz, 1H),
4.73 (t, J = 6.2 Hz, 1H), 4.56 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H),
1.35 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.60
(d, J = 2.4 Hz), 162.98 (d, J = 279.3 Hz), 142.90 (d, J = 12.1
Hz), 119.71 (d, J = 36.0 Hz), 106.54 (d, J = 3.2 Hz), 69.01 (s),
67.10 (d, J = 6.1 Hz), 61.28 (s), 14.22 (s); HRMS calcd for
+
C9H13ClO4 212.0485, found 212.0482. Anal. Calcd for
C9H13BrO4: C, 56.61; H, 4.28. Found: C, 56.87; H, 4.42.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR spectra for compounds (8b, 9b, 9d, 9e, 12b,
12d, 12e, 14b, 14d, 14e, 16a, 16b, 16c, 16d, 16e, 17a, 17b,
18a, 18b, 18c, 19a, 19b, 20a, 20b, 20c, 21a, 21b, 22a, 22b,
22c). This material is available free of charge via the Internet at
http://pubs.acs.org.
+
C9H11FO4 202.0641, found 202.0647; Anal. Calcd for
C9H11FO4: C, 53.47; H, 5.48. Found: C, 53.20; H, 5.51.
AUTHOR INFORMATION
Corresponding Author
*E-mail: thudlicky@brocku.ca. Tel: (905) 688-5550 x3406.
Fax: (905) 682-9020.
■
n-Propyl (5S,6R)-5,6-dihydroxy-2-fluorocyclohex-1,3-dien-
ecarboxylate (16c): white solid; mp 52−54 °C (pentane); Rf =
0.30 (3:2 v/v ethyl acetate/hexanes); [α]D20 = −11.3 (c = 0.55,
CHCl3); IR (KBr, cm−1) 3390, 2970, 1693, 1600, 1407, 1266,
1137, 1095, 1042, 993, 938, 829; 1H NMR (300 MHz, CDCl3)
δ 6.34 (m, 1H), 5.96 (ddd, J = 10.6, 8.2, 2.6 Hz, 1H), 4.73 (t, J
= 6.4, 1H), 4.57 (br d, 1H), 4.21 (m, 2H), 1.74 (m, 2H), 1.00
(t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.77 (d, J
= 3.3 Hz), 164.81 (s), 161.09 (s), 142.87 (d, J = 12.0 Hz),
119.74 (d, J = 36.0 Hz), 106.51 (d, J = 2.3 Hz), 68.95 (s), 67.12
(d, J = 11.4 Hz), 66.86 (s), 21.96 (s), 10.42 (s); HRMS calcd
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the following agencies for financial
support of this work: Natural Sciences and Engineering
Research Council of Canada (NSERC) (Idea to Innovation
and Discovery Grants), Canada Research Chair Program,
Canada Foundation for Innovation (CFI), TDC Research, Inc.,
TDC Research Foundation, the Ontario Partnership for
Innovation and Commercialization (OPIC), and The Advanced
Biomanufacturing Centre (Brock University).
+
for C10H13FO4 216.0798, found 216.0801.
REFERENCES
■
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