Synthesis and enzyme-catalysed reductions of 2-oxo acids with oxygen containing side-chains

Article abstract of DOI:10.1039/a909677i

A series of novel 2-oxo esters with protected alcohols at the 3-, 4-, 5-, 6- and 7-positions has been prepared either via coupling of an aldehyde with an organometallic reagent (Zn, In or Cr) or via a one-carbon homologation of the precursor acid. A one-pot dual enzyme system was used to convert the simpler 2-oxo acids (with a single MOM ether at either C-3 or C-4) into enantiopure protected 2,3- and 2,4-dihydroxy acids in good yields, but in the cases of the more complex trisubstituted substrates, significant decomposition occurred. Biotransformations have proved valuable for the enantioselective synthesis of protected 2,6,7-trihydroxyhept-3-enoic acids.

Full text of DOI:10.1039/a909677i

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Synthesis and enzyme-catalysed reductions of 2-oxo acids with
oxygen containing side-chains
Gurdip Bhalay,b Sarah Clough,a Lee McLaren,a Andrew Sutherlanda and Christine L. Willis*a
1
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS
b Novartis Horsham Research Centre, Wimblehurst Road, Horsham, W. Sussex, UK RH12 4AB
Received (in Cambridge, UK) 8th December 1999, Accepted 21st January 2000
A series of novel 2-oxo esters with protected alcohols at the 3-, 4-, 5-, 6- and 7-positions has been prepared either
via coupling of an aldehyde with an organometallic reagent (Zn, In or Cr) or via a one-carbon homologation of the
precursor acid. A one-pot dual enzyme system was used to convert the simpler 2-oxo acids (with a single MOM
ether at either C-3 or C-4) into enantiopure protected 2,3- and 2,4-dihydroxy acids in good yields, but in the cases
of the more complex trisubstituted substrates, significant decomposition occurred. Biotransformations have proved
valuable for the enantioselective synthesis of protected 2,6,7-trihydroxyhept-3-enoic acids.
chains containing protected alcohols at the C-3 to C-7
Introduction
positions. Studies on the reduction of each 2-oxo acid with
two oxidoreductases, BS-LDH and a -hydroxyisocaproate
dehydrogenase are also described.
2-Hydroxy acids are valuable building blocks for use in the
synthesis of complex molecules and may be prepared in good
yields and excellent enantioselectivities by the lactate dehydro-
genase (LDH) catalysed reduction of 2-oxo acids. These reac-
tions are simple to perform on a multigram scale.1 - and
-LDHs have been obtained from various mammalian and
bacterial sources and exhibit reasonably broad substrate spe-
cificities. For example, -LDH from Bacillus stearothermophilus
(BS-LDH) and -LDH from Staphylococcus epidermidis (SE-
LDH) have been used in the enantioselective synthesis of
a range of 2-hydroxy acids with saturated and unsaturated
hydrocarbon side-chains as well as those containing halides and
aromatic rings (Scheme 1).2
2-Hydroxy acids with further oxygen containing substitu-
ents in the side-chain would be useful building blocks for a
wide range of natural products and oxygen containing hetero-
cycles but interestingly there have been only two reports of
the LDH-catalysed reduction of such a 2-oxo acid.3 Casy3b
has shown that 2,4-dioxo acids, e.g. 1, may be reduced to the
corresponding (S)-2-hydroxy acids, e.g. 2, with BS-LDH
(Scheme 2). A further selective reduction of the 4-ketone
either with DIBAL-H or tetramethylammonium triacetoxy-
borohydride gave, after lactonisation, the (3S,5S)- and
Although we have found that good yields of (R)-2-hydroxy
acids may be obtained from 2-oxo acids using SE-LDH, the
reactions can be too slow to be of practical use in the synthesis
of multigram quantities of (R)-2-hydroxy acids.4 -2-Hydroxy-
4-methylvalerate dehydrogenase (also known as -hydroxy-
isocaproate dehydrogenase5) from Lactobacillus delbrueckii
subsp. bulgaricus (LB-hicDH) has more favourable kinetic
parameters than -LDHs for certain substrates.6 Holbrook and
co-workers have used genetic engineering to prepare a rational
series of mutants of this enzyme and so analysed the important
residues involved in its active site.7 We have shown that the
H205Q mutant (exchange of the His-205 for Gln) exhibits
broader substrate specificity than LDHs. For example,
-leucine, valine and phenylalanine derived 2-oxo acids 5, 6 and
7 are not reduced with either BS- or SE-LDH but give excellent
yields of the corresponding (R)-2-hydroxy acids with the
H205Q mutant of LB-hicDH (Scheme 3).8 This broader
substrate specificity combined with a significantly enhanced
rate of reduction with LB-hicDH compared with SE-LDH
(for example, reduction of 1 mmol of (S)-4-(Cbz-amino)-2-
oxopentanoic acid 8 took just 4 hours with the H205Q mutant
compared with 4 days with SE-LDH) has exciting potential
in organic synthesis. Thus the use of LB-hicDH as well as
BS-LDH was investigated in the studies reported herein.
(3S,5R)-3-hydroxy-5-substituted-γ-lactones (e.g.
respectively) in good yields. We now report our investigations
on the synthesis of a series of novel 2-oxo acids with side-
3 and 4,
Scheme 1 For example: R = Me, Et, Pr, cyclopropyl, benzyl, pNO2-PhCH2, ClCH2, H2C᎐CHCH2CH2, CH3CH᎐CH.
᎐
᎐
Scheme 2
DOI: 10.1039/a909677i
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This journal is © The Royal Society of Chemistry 2000
901

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It was then necessary to hydrolyse the 2-oxo esters (R)-17
Results and discussion
and (R)-18 to the corresponding 2-oxo acids prior to the key
oxidoreductase catalysed reaction. This may be achieved by
saponification with sodium hydroxide,14 but a much more
convenient method proved to be a dual enzyme procedure to
hydrolyse the ester and reduce the ketone in a one-pot process.
Both BS-LDH and LB-hicDH require the co-factor NADH
which may be recycled using a formate–formate dehydrogenase
(FDH) protocol developed by Shaked and Whitesides15 which
allows the reactions to be performed economically on a multi-
gram scale. In a typical procedure the 2-oxo ester was incubated
with a lipase from Candida rugosa prior to the addition of the
dehydrogenase (either BS-LDH or LB-hicDH), FDH and the
requisite co-factors (Scheme 5). After work-up the products
were methylated with diazomethane prior to purification by
flash chromatography.
Hydrolysis of (R)-17 followed by reduction of the resultant
2-oxo acid (R)-19 catalysed by either BS-LDH or LB-hicDH
gave, after methylation, the (2S,3R)- and (2R,3R)-hydroxy
esters 21 and 23 respectively in good yields over the 3 steps and
each as a single diastereomer (Scheme 5). No racemisation
was apparent at C-3. Similarly, hydrolysis of methyl (R)-4-
methoxymethoxy-2-oxopentanoate (R)-18 and reduction of
(R)-20 catalysed by either BS-LDH or LB-hicDH gave, after
methylation, good yields of (2S,4R)- and (2R,4R)-hydroxy
esters 22 and 24 respectively. Hence it is apparent that 2-oxo
acids with a single MOM substituent at either C-3 or C-4 are
efficiently reduced by the oxidoreductases to the corresponding
2-hydroxy acid with complete stereocontrol.
We have previously found that incubation of racemic 3-
methoxymethoxy-2-oxobutanoic acid with leucine dehydro-
genase led not only to reductive amination of the ketone but
also to a kinetic resolution.16 To investigate whether a similar
difference in reactivity of (R)- and (S)-19 with the oxidoreduct-
ases BS-LDH and LB-hicDH was apparent, methyl (S)-3-
methoxymethoxy-2-oxobutanoate (S)-17 was prepared using
the same approach as for the (R)-enantiomer. Lipase catalysed
hydrolysis of the ester and reduction of the resultant 2-oxo
acid catalysed by either BS-LDH or LB-hicDH gave, after
methylation, the (2S,3S)- and (2R,3S)-diastereomers 25 and 26
respectively in good yields (Scheme 6). Hence, unlike leucine
Our first target compounds were 2-oxo esters 17 and 18 with a
methoxymethyl ether at either C-3 or C-4 (Scheme 4). The
methoxymethyl protecting group for the alcohols was selected
as it is stable to a range of conditions, in particular to the basic
conditions for the hydrolysis of the 2-oxo ester to the corre-
sponding 2-oxo acid required as an enzyme substrate, but the
group may be removed under mild conditions.
There has been considerable interest in the synthesis of
4-hydroxy-2-keto acids which occur in a variety of import-
ant natural products including N-acetylneuramic acid9 and 3-
deoxy--manno-oct-2-ulosonic acid (KDO).10 Several methods
have been developed for the construction of 4-hydroxy-2-oxo
esters and derivatives thereof11 and we favoured a general
approach that could be used for the synthesis of both 3- and
4-hydroxy-2-oxo esters as shown in Scheme 4. Treatment of
methyl (R)-lactate 9 with chloromethyl methyl ether and diiso-
propylethylamine followed by hydrolysis of the ester 11 with
lithium hydroxide gave acid 13. Many methods are known for
the conversion of carboxylic acids to 2-oxo esters.12 However,
we required a strategy which would maintain the stereo-
chemical integrity of the molecule and we favoured a method
involving ozonolysis of β-ketocyanophosphoranes originally
described by Wasserman and Ho.13 Treatment of the carboxylic
acid 13 with (cyanomethylene)triphenylphosphorane in the
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDCI) and 4-dimethylaminopyridine (DMAP) followed by
ozonolysis of 15 in methanol and dichloromethane gave the
required 2-oxo ester (R)-17. Methyl (R)-4-methoxymethoxy-2-
oxopentanoate (R)-18 was prepared from ethyl (R)-3-hydroxy-
butanoate 10 using an analogous approach.
Scheme 3
Scheme 4 Reagents: i, CH3OCH2Cl, either iPr2EtN or NaH; ii, LiOH; iii, Ph3PCHCN, EDCI, DMAP; iv, O3, MeOH, CH2Cl2.
Scheme 5 Reagents: i, Candida rugosa lipase; ii, a) BS-LDH, NADH, FDH; b) CH2N2; iii, a) LB-hicDH, NADH, FDH; b) CH2N2.
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Scheme 6 Reagents: i, Candida rugosa lipase; ii, a) BS-LDH, NADH, FDH; b) CH2N2; iii, a) LB-hicDH, NADH, FDH; b) CH2N2.
Scheme 7 Reagents: i, PBr3, ether; ii, Zn, NH4Cl, THF, H2O; iii, MOMCl, EtNiPr2, CH2Cl2; iv, O3, CH2Cl2; v, aq. LiOH.
dehydrogenase, BS-LDH and LB-hicDH showed no obvious
difference in rate of reduction of the two enantiomers of 19.
Racemic methyl 4-methoxymethoxy-2-oxopentanoate (rac)-
18 was also prepared and subjected to the dual enzyme
catalysed hydrolysis and reduction procedure. The BS-LDH
and LB-hicDH catalysed reductions of (rac)-20 both gave a 1:1
mixture of the expected diastereomers as shown in Scheme 6
indicating that there was no significant difference in the rate
of reduction of the two enantiomers of 2-oxo acid 20. The
mixture of (2S,4R)- and (2S,4S)-hydroxy esters 22 and 27 was
treated with hydrochloric acid in THF giving the corresponding
2-hydroxy-4-methyl-γ-lactones 4 and 3, which were readily
separated by flash chromatography thus giving an alternative
approach to these enantiopure γ-lactones to that outlined in
Scheme 2.
2-hydroxy acids which would be valuable building blocks for
use in synthesis, for example, as a precursor to the marine
natural product leptosphaerin.17 The approach selected for the
preparation of the required 2-oxo esters involved a Reformat-
sky type coupling18 between (R)-2,3-O-isopropylideneglycer-
aldehyde 29 and the allylic bromide 31 (Scheme 7). Allylic alco-
hol 30 was simply prepared in 70% yield via the Baylis–Hillman
reaction of methyl acrylate with paraformaldehyde in the pres-
ence of DABCO following a literature procedure.19 Treatment
of alcohol 30 with phosphorus tribromide gave the required
bromide 31 in 84% yield. The zinc mediated coupling20 of
aldehyde 29 (prepared in two steps following a literature
procedure21) with allylic bromide 31 gave a 2.5:1 mixture of
alcohols 32 and 33 in 78% yield. Recently a similar mixture
of these alcohols has been obtained by reaction of an
allylboronate with aldehyde 29.22 The effects of other metals on
the outcome of the coupling of allylic bromide 31 and aldehyde
29 were examined. We found that chromium chloride in THF23
Our next goal was to prepare protected 4,5,6-trihydroxy-2-
oxohexanoic acids required not only to examine the substrate
specificities of the oxidoreductases but also to give access to
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Scheme 8 Reagents: i, TPAP; ii, Zn, NH4Cl, THF, H2O; iii, MOMCl, EtNiPr2, CH2Cl2; iv, O3, CH2Cl2; v, Candida rugosa lipase, LB-hicDH, FDH,
NADH then CH2N2.
gave a 51% yield of 32 and 33, whilst the use of indium in
water24 led to a 60% yield of the two alcohols. In each case a
similar mixture of diastereomers was obtained.
the vicinal diol with acetone under acidic conditions). Oxid-
ation of 40 under Swern conditions26 gave a 70% yield of the
known27 aldehyde 41 whereas a quantitative yield was obtained
with tetrapropylammonium perruthenate (TPAP)28 (Scheme 8).
Treatment of aldehyde 41 with allylic bromide 31 in the pres-
ence of zinc gave a 1:1 mixture of alcohols 42 and 43. These
were protected as their MOM ethers 44 and 45, and oxidative
cleavage of the double bond gave a mixture of the required 2-
oxo esters. The mixture of 46 and 47 was then subjected to the
one-pot dual enzyme catalysed hydrolysis–reduction procedure
using LB-hicDH giving, after methylation and purification
by column chromatography, a 1:1 mixture of the expected
hydroxy esters 48 and 49 in just 14% yield and 4% of the
β,γ-unsaturated-α-hydroxy ester 50. Therefore, in contrast to
the dual enzyme catalysed hydrolysis–reduction of the pro-
tected 4,5,6-trihydroxy-2-oxo esters 36 and 37, which gave no
isolable products, the protected 4,6,7-trihydroxy-2-oxo esters 46
and 47 gave some of the expected 2-hydroxy esters 48 and 49 as
well as the unsaturated alcohol 50, albeit in low yield.
Iodolactonisation of simple β,γ-unsaturated-α-hydroxy
esters such as methyl (2R,3E)-2-hydroxypent-3-enoate have
been shown to proceed with excellent stereocontrol,29 thus
unsaturated 2-hydroxy esters such as 50 have potential for the
enantioselective synthesis of polyhydroxylated compounds.
With this in mind the final target substrate for the biotransform-
ations was the unsaturated 2-oxo ester 55 which was prepared
from the mixture of alcohols 42 and 43 (Scheme 9). Acetylation
of the alcohols, followed by ozonolysis of the resultant acetates
51 and 52 and elimination gave 55 in 90% overall yield. The
one-pot lipase catalysed hydrolysis of the ester and reduction of
the ketone using BS-LDH gave, after methylation and purifi-
cation by flash chromatography, (2S)-hydroxy ester 56 in 45%
yield over the 3 steps. When the reduction was carried out with
LB-hicDH, (2R)-hydroxy ester 50 was isolated in 55% yield.
Although we found that 32 and 33 could be separated by
column chromatography, partial decomposition occurred on
the silica. Hence, since we have already shown that both enantio-
mers of the MOM protected 4-hydroxy-2-oxo acid 20 are good
substrates for both BS-LDH and LB-hicDH, it was decided at
this stage to complete the synthesis of the required 2-oxo esters
36 and 37 with the mixture of diastereomers and to test them
both as substrates for the oxidoreductases. The mixture of
alcohols 32 and 33 were readily protected as the MOM ethers
and then ozonolysis of 34 and 35 in dichloromethane gave a
mixture of required 2-oxo esters 36 and 37 which were insepar-
able by flash chromatography. The mixture of 2-oxo esters
was then subjected to the one-pot, dual enzyme-catalysed
hydrolysis–reduction procedure, but with both BS-LDH and
LB-hicDH no products were isolated from the reaction mixture
and it was apparent that decomposition had occurred. It was
not clear whether decomposition was occurring during the
hydrolysis and/or the reduction. Thus the mixture of 36 and 37
was hydrolysed with aqueous lithium hydroxide to the corre-
sponding 2-oxo acids 38 and 39 prior to incubation with the
oxidoreductases. However, decomposition occurred again with
both BS-LDH and LB-hicDH and no products were isolated
from the reaction mixture.
The next two targets were 2-oxo esters 46 and 47 which
contained 3-oxygenated substituents in the side-chain at the 4-,
6- and 7-positions, i.e. these compounds contain an extra
methylene between the MOM ether and the protected diol
compared with 36 and 37. These were also prepared via a
Reformatsky type coupling. Aldehyde 41 was prepared from
the known alcohol 4025 (synthesised in 82% overall yield by
diborane reduction of (S)-malic acid, followed by protection of
904
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separated and the aqueous layer was washed with dichloro-
methane (40 cm3). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Purification by flash
column chromatography, eluting with 15% ethyl acetate in
light petroleum gave ethyl (R)-3-methoxymethoxybutanoate 12
as a colourless oil (3.43 g, 86%). [α]D Ϫ11.7 (c 0.7, CHCl3);
νmax(film)/cmϪ1 2980, 2935 and 1736 (CO); δH(400 MHz) 1.25
(3H, d, J 6, 4-H3), 1.27 (3H, t, J 7, CO2CH2CH3), 2.41 (1H, dd,
J 15 and 5, 2-HH), 2.59 (1H, dd, J 15 and 8, 2-HH), 3.36 (3H, s,
OCH3), 4.14 (3H, m, 3-H and CO2CH2), 4.65 (1H, d, J 7,
OCHHO) and 4.68 (1H, d, J 7, OCHHO); m/z (CI) 145.0867
([MH]ϩ Ϫ MeOH, C8H16O4 requires 145.0865, 80%), 130 (10),
115 (49), 102 (14), 86 (61) and 84 (100).
Methyl (R)-2-methoxymethoxypropionate 11
Methyl (R)-lactate 9 (5.0 g, 48 mmol) was slowly added to a
solution of sodium hydride (46 mmol) in THF (70 cm3) at 0 ЊC
under a nitrogen atmosphere. Chloromethyl methyl ether (4.52
cm3, 60 mmol) was added dropwise and, after 0.75 h, the reac-
tion was warmed to room temperature. After 7 h, the reaction
mixture was concentrated, acidified using 2 M HCl (20 cm3)
and extracted with ethyl acetate. The organic layer was dried
(MgSO4) and concentrated in vacuo and then purified by col-
umn chromatography giving methyl (R)-2-methoxymethoxy-
propionate 11 as a colourless oil (6.76 g, 95%). [α]D24 ϩ85.5 (c 1.0,
CHCl3); νmax(film)/cmϪ1 1753 (CO); δH(270 MHz) 1.43 (3H, d,
J 7, 3-H3), 3.39 (3H, s, OCH3), 3.75 (3H, s, CO2CH3), 4.24 (1H,
q, J 7, 2-H), 4.68 (1H, d, J 7, OCHHO) and 4.71 (1H, d, J 7,
OCHHO); m/z (CI) 117.0549 ([MH]ϩ Ϫ MeOH, C6H12O4
requires 117.0551, 4%), 117 (100), 89 (39) and 84 (32).
The above reaction was repeated using ethyl (S)-lactate (5.0
g, 42 mmol), giving ethyl (S)-2-methoxymethoxypropionate
as a colourless oil (6.52 g, 95%). [α]D23 Ϫ92.3 (c 1.0, CHCl3) (lit.,27
[α]D22 Ϫ88.1 (c 2.9, CHCl3)); δH(400 MHz) 1.29 (3H, t, J 7,
OCH2CH3), 1.43 (3H, d, J 7, 3-H3), 3.39 (3H, s, OCH3), 4.21
(2H, q, J 7, CO2CH2), 4.24 (1H, q, J 7, 2-H), 4.69 (1H, d, J 7,
OCHHO) and 4.72 (1H, d, J 7, OCHHO); m/z (CI) 131
([MH]ϩ Ϫ MeOH, 86%), 117 (20), 103 (42), and 84 (100).
Scheme 9 Reagents: i, Ac2O, py; ii, O3, CH2Cl2; iii, SiO2; iv, Candida
rugosa lipase, BS-LDH, FDH, NADH then CH2N2; v, Candida rugosa
lipase, LB-hicDH, FDH, NADH then CH2N2.
In conclusion, a series of novel 2-oxo esters with protected
alcohols at the 3-, 4-, 5-, 6- and 7- positions have been prepared
either via a one-carbon homologation of the precursor acid
or via coupling of an aldehyde with an organometallic (Zn, In
or Cr) reagent. Although the simple keto acids with a single
substituent at C-3 and C-4 (e.g. 19 and 20) were good substrates
for the oxidoreductases, giving high yields of enantiopure
protected 2,3- and 2,4-dihydroxy acids, in the cases of the more
complex trisubstituted keto acids significant decomposition
occurred under the reaction conditions. The use of the
biotransformations has proved valuable for the enantioselective
synthesis of the protected 2,6,7-trihydroxyhept-3-enoates 50
and 56.
(R)-3-Methoxymethoxybutanoic acid 14
Ethyl (R)-3-methoxymethoxybutanoate 12 (3.43 g, 19 mmol)
was dissolved in methanol (20 cm3) and cooled to 0 ЊC. Lithium
hydroxide monohydrate (1.06 g, 24.7 mmol) in water (10 cm3)
was added and the reaction mixture warmed to room temper-
ature. After 7 h, the reaction mixture was concentrated, acid-
ified to pH 2 by the addition of 2 M hydrochloric acid (15 cm3)
and extracted with ethyl acetate (2 × 30 cm3). The organic layer
was dried (MgSO4) and concentrated in vacuo to give (R)-3-
methoxymethoxybutanoic acid 14 as a colourless oil (2.39 g,
83%). [α]D Ϫ18.9 (c 0.5, CHCl3); νmax(film)/cmϪ1 3451 (OH) and
1719 (CO); δH(270 MHz) 1.27 (3H, d, J 6, 4-H3), 2.48 (1H, dd,
J 15 and 5, 2-HH), 2.63 (1H, dd, J 15 and 8, 2-HH), 3.36 (3H, s,
OCH3), 4.16 (1H, m, 3-H), 4.68 (1H, d, J 7, OCHHO) and 4.70
(1H, d, J 7, OCHHO); m/z (CI) 117.0551 ([MH]ϩ Ϫ MeOH,
C6H12O4 requires 117.0552, 36%), 107 (21), 91 (9), 87 (59) and
83 (100).
Experimental
General details
General experimental details have been reported.30 All NMR
spectra were run in deuteriochloroform with tetramethylsilane
as the internal reference unless otherwise stated. Chemical
shifts are reported in ppm on the δ scale. Coupling constants
are quoted in Hz. Optical rotations were measured at 25 ЊC
except where indicated otherwise. The enzymes were purchased
and stored as follows. Lipase from Candida rugosa (CRL),
Sigma, stored at 4 ЊC as a 1000 eU mlϪ1 solution in Tris buffer
(5 mM); formate dehydrogenase (FDH) from Candida boidinii,
Boerhinger, stored at 4 ЊC; lactate dehydrogenase from Bacillus
stearothermophilis, Sigma, stored at Ϫ20 ЊC; β-nicotinamide
adenine dinucleotide hydride (NADH), Genzyme, stored at
Ϫ20 ЊC.
(R)-2-Methoxymethoxypropanoic acid 13
The above reaction was repeated using methyl (R)-2-methoxy-
methoxypropionate 11 (6.28 g, 42 mmol). Purification by flash
column chromatography, eluting with 49% ethyl acetate in light
petroleum gave (R)-2-methoxymethoxypropanoic acid 13 as a
colourless oil (3.69 g, 65%). [α]D25 ϩ81.5 (c 1.6, CHCl3); νmax(film)/
cmϪ1 3485 (OH) and 1736 (CO); δH(270 MHz) 1.49 (3H, d, J 7,
3-H3), 3.41 (3H, s, OCH3), 4.28 (1H, q, J 7, 2-H), 4.72 (1H, d,
J 7, OCHHO) and 4.75 (1H, d, J 7, OCHHO); m/z 135.0653
([MH]ϩ, C5H10O4 requires 135.0657, 12%), 117 (7), 103 (76), 89
(16), 84 (32) and 75 (100).
Ethyl (R)-3-methoxymethoxybutanoate 12
Ethyl (R)-3-hydroxybutanoate 10 (3.0 g, 23 mmol) was added to
a solution of N-ethyldiisopropylamine (5.2 cm3, 30 mmol) in
dichloromethane (100 cm3) at 0 ЊC under a nitrogen atmos-
phere. After 0.5 h, chloromethyl methyl ether (2.62 cm3, 34.5
mmol) was added. The reaction mixture was warmed to room
temperature and left stirring overnight. Water (80 cm3) was then
added and the reaction mixture acidified to pH 2 by the addi-
tion of 2 M hydrochloric acid (15 cm3). The two layers were
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The above reaction was repeated using ethyl (S)-2-methoxy-
methoxypropionate (6.8 g, 42 mmol) giving (S)-2-methoxy-
methoxypropanoic acid as a colourless oil (3.82 g, 68%). [α]D24
Ϫ83.0 (c 1.4, CHCl3); spectroscopic data as for the (R)-
enantiomer.
by the addition of 1.0 M hydrochloric acid. The pH was main-
tained at a value between 7.0 and 7.5 by the addition of 0.1 M
sodium hydroxide. The reaction was complete after 3 days. The
solution was deoxygenated by bubbling a stream of nitrogen
through for 1 h. Dithiotreitol (20 µl) was then added, followed
by BS-LDH (10 mg), formate dehydrogenase (10 mg), sodium
formate (1 g, 15 eq.) and NADH (10 mg). The reaction was left
stirring under a nitrogen atmosphere with the pH kept constant
at approximately 6.1 by the addition of 1.0 M hydrochloric
acid. The reaction was complete after 2 days. The reaction mix-
ture was acidified to pH 2 by the addition of 2 M hydrochloric
acid and extracted with ethyl acetate (3 × 40 cm3). The organic
layer was dried (MgSO4) and concentrated in vacuo. The result-
ing 2-hydroxy acid was dissolved in acetone (15 cm3) and 0.5–
0.6 M ethereal diazomethane (2.5 cm3) was slowly added turn-
ing the solution a bright yellow colour. The solution was then
concentrated in vacuo. Purification by flash column chromato-
graphy, eluting with 41% ethyl acetate in light petroleum gave
methyl (2S,4R)-2-hydroxy-4-methoxymethoxypentanoate 22 as
a viscous oil (0.15 g, 78%). [α]2D4 Ϫ20.6 (c 0.1, CHCl3); νmax(film)/
cmϪ1 3425 (OH) and 1732 (CO); δH(270 MHz) 1.23 (3H, d, J 6,
5-H3), 1.71 (1H, ddd, J 14, 10 and 3, 3-HH), 1.99 (1H, ddd,
J 14, 10 and 3, 3-HH), 3.40 (3H, s, OCH3), 3.79 (3H, s,
CO2CH3), 3.98 (1H, m, 4-H), 4.42 (1H, dd, J 10 and 3, 2-H),
4.66 (1H, d, J 7, OCHHO) and 4.73 (1H, d, J 7, OCHHO); m/z
(CI) 161.0820 ([MH]ϩ Ϫ MeOH, C8H16O5 requires 161.0814,
5%), 141 (4), 131 (100), 113 (29), 101 (28) and 84 (91).
Methyl (R)-4-methoxymethoxy-2-oxopentanoate (R)-18
(Cyanomethylene)triphenylphosphonium chloride (8.05 g, 24
mmol) was dissolved in water (50 cm3) and dichloromethane
(50 cm3). Sodium hydroxide (2.43 g, 61 mmol) in water (10 cm3)
was slowly added. After 0.3 h, the two layers were separated.
The dichloromethane layer was dried (MgSO4) and added
to a solution of (R)-3-methoxymethoxybutanoic acid 14 (2.0 g,
13.5 mmol), DMAP (0.2 g) and EDCI (4.12 g, 22 mmol) in
dichloromethane (100 cm3) at 0 ЊC under a nitrogen atmos-
phere. After 0.5 h, the reaction mixture was warmed to room
temperature and left stirring for 15 h. Water (100 cm3) was
added and the two layers separated. The organic layer was dried
(MgSO4) and concentrated in vacuo. Purification by flash
column chromatography, eluting with 61% ethyl acetate in light
petroleum gave a mixture of (R)-5-methoxymethoxy-3-oxo-2-
(triphenylphosphoranylidene)hexanenitrile 16 and triphenyl-
phosphine oxide.
The mixture of 16 and triphenylphosphine oxide from the
previous reaction was dissolved in dichloromethane (100 cm3)
and methanol (100 cm3) and cooled to Ϫ78 ЊC. Ozone was then
bubbled through the solution until the reaction mixture turned
blue. Nitrogen was then passed through the solution to remove
excess ozone. The reaction mixture was warmed to room
temperature and concentrated in vacuo. Purification by flash
column chromatography, eluting with 41% ethyl acetate in light
petroleum gave methyl (R)-4-methoxymethoxy-2-oxopentano-
ate (R)-18 as a colourless oil (1.20 g, 47% over two steps). [α]D
Ϫ17.3 (c 0.5, CHCl3); νmax(film)/cmϪ1 1736 (br, 2 × CO); δH(270
MHz) 1.27 (3H, d, J 6, 5-H3), 2.81 (1H, dd, J 17 and 5, 3-HH),
3.20 (1H, dd, J 17 and 8, 3-HH), 3.32 (3H, s, OCH3), 3.89 (3H,
s, CO2CH3), 4.26 (1H, dqd, J 8, 6 and 5, 4-H), 4.61 (1H, d, J 7,
OCHHO) and 4.65 (1H, d, J 7, OCHHO); δC(75 MHz) 20.8
(C-5), 46.6 (C-3), 52.9 and 55.5 (each OCH3), 69.6 (C-4), 95.5
(OCH2O), 161.4 (C-1) and 192.0 (C-2); m/z (CI) 159.0662
([MH]ϩ Ϫ MeOH, C8H14O5 requires 159.0657, 36%), 129 (100),
115 (21), 101 (14), 89 (11) and 84 (14).
Methyl (2R,4R)-2-hydroxy-4-methoxymethoxypentanoate 24
The above reaction was repeated using LB-hicDH (1 cm3) in
place of BS-LDH. The reaction was complete after 1 day, giv-
ing after purification by flash column chromatography, eluting
with 40% ethyl acetate in light petroleum, methyl (2R,4R)-2-
hydroxy-4-methoxymethoxypentanoate 24 as a viscous oil (0.16
g, 81%). [α]D Ϫ12.3 (c 0.1, CHCl3); νmax(film)/cmϪ1 3435 (OH)
and 1736 (CO); δH(270 MHz) 1.23 (3H, d, J 6, 5-H3), 1.89–2.06
(2H, m, 3-H2), 3.37 (3H, s, OCH3), 3.78 (3H, s, CO2CH3), 3.97
(1H, m, 4-H), 4.29 (1H, t, J 5, 2-H), 4.59 (1H, d, J 7, OCHHO)
and 4.62 (1H, d, J 7, OCHHO); m/z (CI) 161.0812 ([MH]ϩ Ϫ
MeOH, C8H16O5 requires 161.0814, 5%), 131 (81), 113 (27), 101
(24), 86 (63) and 84 (100).
Methyl (2S,3R)-2-hydroxy-3-methoxymethoxybutanoate 21
Methyl (R)-3-methoxymethoxy-2-oxobutanoate (R)-17
The above reaction was repeated using 2-oxo ester (R)-17
(95 mg, 0.54 mmol) and BS-LDH, giving, after purification by
flash chromatography, methyl (2S,3R)-2-hydroxy-3-methoxy-
methoxybutanoate 21 (50 mg, 52%) as a colourless oil. [α]D
Ϫ20.5 (c 1.9, CHCl3); νmax(film)/cmϪ1 3435 (br, OH), 2930 (CH)
and 1735 (CO); δH(300 MHz) 1.24 (3H, d, J 6.6, 4-H3), 3.07
(1H, br s, OH), 3.41 (3H, s, OMe), 3.81 (3H, s, CO2CH3), 4.00
(1H, qd, J 6.6 and 2.8, 3-H), 4.28 (1H, d, J 2.8, 2-H), 4.71 (2H,
s, OCH2O); δC(75 MHz) 15.8 (C-4), 52.4 and 55.8 (each OCH3),
73.9 and 76.3 (C-2 and C-3), 96.1 (OCH2O), 172.7 (C-1); m/z
(CI) 147.0649 ([MH]ϩ Ϫ MeOH. C6H11O4 requires 147.0657,
46%), 117 (61), 87 (98), 85 (66) and 57 (100).
The above reaction was repeated using the enantiomeric
2-oxo ester (S)-17 (105 mg, 0.60 mmol) and LB-hicDH, giving,
after purification by flash chromatography, methyl (2R,3S)-2-
hydroxy-3-methoxymethoxybutanoate 26 (60 mg, 57%) as a
colourless oil. [α]D ϩ22.8 (c 0.8, CHCl3); spectroscopic data as
above.
The above reaction was repeated using (R)-2-methoxymethoxy-
propanoic acid 13 (1.82 g, 14 mmol). Purification by flash
column chromatography, eluting with 40% ethyl acetate in light
petroleum gave methyl (R)-3-methoxymethoxy-2-oxobutanoate
(R)-17 as a colourless oil (0.83 g, 35% over two steps). [α]D24 ϩ9.8
(c 1.2, CHCl3); νmax(film)/cmϪ1 1746 (br, 2 × CO); δH(270 MHz)
1.44 (3H, d, J 7, 4-H3), 3.34 (3H, s, OCH3), 3.89 (3H, s,
CO2CH3), 4.66 (1H, d, J 7, OCHHO), 4.71 (1H, d, J 7,
OCHHO) and 4.73 (1H, q, J 7, 3-H); δC(100.5 MHz) 16.8 (C-4),
52.9 and 55.6 (each OCH3), 74.9 (C-3), 96.4 (OCH2O), 161.9
(C-1) and 193.7 (C-2); m/z (CI) 145.0504 ([MH]ϩ Ϫ MeOH,
C7H12O5 requires 145.0501, 100%), 129 (13), 117 (45) and 84
(96).
The above reaction was repeated using (S)-2-methoxy-
methoxypropanoic acid (3.8 g, 28 mmol). Purification by flash
chromatography, eluting with 40% ethyl acetate in light petrol-
eum gave methyl (S)-3-methoxymethoxy-2-oxobutanoate as a
colourless oil (1.80 g, 36% over two steps). [α]D24 Ϫ10.5 (c 0.5,
CHCl3); spectroscopic data as for the (R)-enantiomer.
Methyl (2R,3R)-2-hydroxy-3-methoxymethoxybutanoate 23
The above reaction was repeated with 2-oxo ester (R)-17
(95 mg, 0.54 mmol) and LB-hicDH giving, after purification
by column chromatography, methyl (2R,3R)-2-hydroxy-3-
methoxymethoxybutanoate 23 (55 mg, 57%) as a colourless oil.
[α]D Ϫ36.8 (c 2.4, CHCl3); νmax(film)/cmϪ1 3435 (br, OH), 2930
Methyl (2S,4R)-2-hydroxy-4-methoxymethoxypentanoate 22
Methyl (R)-4-methoxymethoxy-2-oxopentanoate (R)-18 (0.19
g, 1 mmol) was dissolved in 5 mM Tris buffer (40 cm3). Candida
rugosa lipase (10000 eU) was added and the pH adjusted to 7.5
906
J. Chem. Soc., Perkin Trans. 1, 2000, 901–910

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(CH), 1735 (CO); δH(300 MHz), 1.32 (3H, d, J 6.3, 4-H3), 2.75
(1H, br s, OH), 3.32 (3H, s, OCH3), 3.81 (3H, s, CO2CH3), 4.05–
4.17 (2H, m, 2-H and 3-H), 4.57 (1H, d, J 7, OCHHO), 4.67
(1H, d, J 7, OCHHO); δC(75 MHz), 16.3 (C-4), 52.4 and 55.6
(each OCH3), 73.8, 74.3 (C-2 and C-3), 94.9 (OCH2O) and 173.3
(C-1); m/z (CI) 147.0655 ([MH]ϩ Ϫ MeOH, C6H11O4 requires
147.0657, 47%), 117 (53), 87 (82), 85 (55) and 57 (100).
The above reaction was repeated using the enantiomeric 2-
oxo ester (S)-17 (105 mg, 0.60 mmol) and BS-LDH giving after
purification by flash chromatography methyl (2S,3S)-2-
hydroxy-3-methoxymethoxybutanoate 25 (55 mg, 52%) as a
colourless oil. [α]D ϩ35.0 (c 1.0, CHCl3); spectroscopic data as
for 23.
dichloromethane (4 cm3) at 0 ЊC under an atmosphere of nitro-
gen. The mixture was allowed to warm to room temperature,
then chloromethyl methyl ether (0.9 cm3, 11.6 mmol) was added
dropwise over 20 min and stirring continued for a further 8 h.
The resulting solution was diluted with dichloromethane (20
cm3), washed with 1 M hydrochloric acid (10 cm3) and the wash-
ings extracted with dichloromethane (2 × 20 cm3). The com-
bined organic phase was washed with brine (10 cm3), dried
(Na2SO4) and the solvent evaporated to leave a diastereomeric
mixture of the methoxymethyl ethers 34 and 35 (2.05 g, 86%) as
a yellow oil, which was used in the next reaction without further
purification. A small portion was purified by flash chroma-
tography for characterisation. Major, less polar product: [α]D25
16.0 (c 1.32 in CHCl3); νmax (neat)/cmϪ1 2947 (C-H), 1731
(C=O), 1646 (C᎐C), 1438 and 1380; δ (300 MHz) 1.36 and 1.43
᎐
Lactonisation of a 1:1 mixture of hydroxy esters 22 and 27
H
(each 3 H, each s, 2 × CH3), 2.42 (1 H, dd, J 14.0 and 8.5,
3-HH), 2.55 (1 H, ddd, J 14.0, 4.1 and 0.8, 3-HH), 3.33 (3 H, s,
OCH3), 3.79 (3 H, s, CO2CH3), 3.75–4.17 (4 H, m, 4-H, 5-H,
6-H2), 4.61 (1 H, d, J 6.9, OCHHO), 4.74 (1 H, d, J 6.9,
2 M Hydrochloric acid (2.5 cm3, 5.0 mmol) was added to a
solution of a 1:1 mixture of the diastereomeric alcohols 22 and
27 (0.10 g, 0.52 mmol) in tetrahydrofuran (5 cm3). The mixture
was stirred for 16 h. The reaction mixture was concentrated and
extracted with ethyl acetate (3 × 10 cm3). The organic extracts
were combined and evaporated. The crude reaction mixture
was purified by flash column chromatography eluting with 40%
ethyl acetate in light petroleum to give (3S,5S)-3-hydroxy-5-
methyl-1-oxacyclopentan-2-one 3 as a clear oil (22 mg, 36%).
[α]D Ϫ51.4 (c 0.1, MeOH) (lit.31 [α]D Ϫ59.8 (c 1.0, MeOH));
δH(300 MHz) 1.42 (3H, d, J 6.6, CH3), 1.89 (1H, br s, OH), 2.25
(1H, ddd, J 13.0, 8.0 and 4.0, 4-HH), 2.38 (1H, dt, J 13.0 and
8.0, 4-HH), 4.54 (1H, t, J 8.0, 3-H) and 4.81 (1H, dqd, J 8.0, 6.5
and 4.0, 5-H); m/z (CI) 117 ([MH]ϩ, 90%), 99 (100) and 71 (59).
Further elution afforded (3S,5R)-3-hydroxy-5-methyl-1-oxa-
cyclopentan-2-one 4 as a clear oil (22 mg, 36%). [α]D Ϫ2.7 (c 0.4,
MeOH) (lit.31 [α]D ϩ3.6 (c 1.0, methanol) opposite enantiomer);
δH(300 MHz) 1.48 (3H, d, J 6.1, CH3), 1.87 (1H, dt, J 12.6 and
11.0, 4-HH), 2.29 (1H, br s, OH), 2.73 (1H, ddd, J 12.6, 8.4 and
5.1, 4-HH), 4.46–4.60 (2H, m, 3-H and 5-H); m/z (CI) 117
([MH]ϩ, 94%), 99 (100) and 71 (61).
OCHHO), 5.72 (1 H, d, J 0.9, ᎐CHH) and 6.25 (1 H, d, J 0.9,
᎐
᎐CHH); δ (75 MHz) 25.13 and 26.28 (2 × CH ), 34.18 (C-3),
᎐
C
3
51.85 and 55.66 (2 × OCH3), 65.76 (C-6), 76.32, 77.78 (C-4 and
C-5), 96.63 (OCH O), 109.29 (acetonide-CMe ), 127.90 (᎐CH ),
᎐
2
2
2
136.47 (C-2) and 167.23 (C-1). Minor, more polar product: [α]D25
12.7 (c 0.97 in CHCl3); δH(300 MHz) 1.35 and 1.42 (each
3 H, each s, 2 × CH3), 2.41 (1 H, dd, J 14.2 and 7.9, 3-HH), 2.70
(1 H, ddd, J 14.2, 4.2 and 1.1 3-HH), 3.32 (3 H, s, OCH3), 3.76
(3 H, s, CO2CH3), 3.81–4.60 (4 H, m, 4-H, 5-H, 6-H2), 4.61
(1 H, d, J 6.9, OCHHO), 4.65 (1 H, d, J 6.9, OCHHO), 5.72
(1 H, d, J 0.9, ᎐CHH) and 6.24 (1 H, d, J 0.9, ᎐CHH); δ (75
᎐
᎐
C
MHz) 25.34, 26.49 (2 × CH3), 34.43 (C-3), 51.99, 55.88
(2 × OCH3), 65.94 (C-6), 76.36 and 77.53 (C-4 and C-5), 96.84
(OCH O), 109.47 (acetonide-CMe ), 128.13 (᎐CH ), 136.75
᎐
2
2
2
(C-2) and 167.47 (C-1); m/z of mixture (CI) 275 (MHϩ, 16%),
261 (22), 243 (Mϩ Ϫ OMe, 100), 217 (35), 185 (70) and 113 (78).
Ozone was bubbled through a solution of a mixture of 34
and 35 (5.32 g, 19.54 mmol) in dichloromethane (200 cm3) at
Ϫ78 ЊC for 1 h until the solution turned blue. Nitrogen was then
bubbled through to remove excess ozone, then dimethyl sulfide
(6 cm3) was added and stirring continued for 10 min at Ϫ78 ЊC
and 0.5 h at room temperature. The solvent was removed
in vacuo to leave a yellow oil which was purified by column
chromatography (light petroleum–ethyl acetate, 3:1) to give
a mixture of diastereomers 36 and 37 as a colourless oil
(3.36 g, 63%). Major product: δH(300 MHz) 1.32 and 1.38 (each
3H, each s, 2 × CH3), 3.13 (2H, d, J 5.6, 3-H2), 3.31 (3H, s,
OCH3), 3.87 (3H, s, CO2CH3), 3.85–4.15 (4H, m, 4-H, 5-H,
6-H2), 4.65 (1H, d, J 7, OCHHO) and 4.68 (1H, d, J 7,
OCHHO); δC(75 MHz) 25.34 and 26.51 (2 × CH3), 42.26 (C-3),
53.25 and 56.04 (each -OCH3), 67.21 (C-6), 76.44 and 77.42
(C-4 and C-5), 97.13 (OCH2O), 110.03 (OCMe2O), 161.35 (C-1)
and 191.32 (C-2). Minor diastereomer: δH(300 MHz) 1.34, 1.42
(each 3H, each s, 2 × CH3), 2.95 (1H, dd, J 17.0 and 3.4,
3-HH), 3.18 (1H, dd, J 17.0 and 7.7, 3-HH), 3.31 (3H, s,
OCH3), 3.88 (3H, s, CO2CH3), 3.86–4.33 (4H, m, 4-H, 5-H,
6-H2), 4.63 (1H, d, J 7, OCHHO) and 4.71 (1H, d, J 7,
OCHHO); δC(75 MHz) 25.45 and 26.71 (2 × CH3), 40.84 (C-3),
53.61 and 56.36 (each -OCH3), 65.76 (C-6), 74.79 and 76.77
(C-4 and C-5), 97.78 (OCH2O), 110.34 (OCMe2O), 161.64 (C-1)
and 191.86 (C-2). For the mixture, m/z (CI) 277.1298 (MHϩ,
C12H21O7 requires 277.1287, 5%), 245 (35), 215 (43) and 187
(100).
Methyl (5R)-4-hydroxy-5,6-(isopropylidenedioxy)-2-methylene-
hexanoates 32 and 33
Powdered zinc (0.92 g, 14.0 mmol) was added in one portion
to a stirred solution of (R)-O-isopropylideneglyceraldehyde 29
(1.87 g, 14.34 mmol), methyl 2-(bromomethyl)acrylate 31 (1.98
g, 11.07 mmol), saturated aqueous ammonium chloride (12
cm3) and THF (10 cm3) at room temperature. After stirring for
18 h the reaction mixture was diluted with brine (10 cm3),
extracted into dichloromethane (3 × 25 cm3), the combined
dichloromethane extracts were washed with brine (10 cm3),
dried (MgSO4) and the solvent evaporated to leave a yellow
oil. The crude product was dissolved in a small volume of
dichloromethane and passed through a plug of silica eluting
with ethyl acetate to give a 2.5:1 mixture of diastereomers 32
and 33 as a pale yellow oil (2.0 g, 78%). Major diastereomer:
δH (300 MHz; CDCl3) 1.35 (3 H, s, acetonide), 1.43 (3 H, s,
acetonide), 2.34 (1 H, ddd, J 14.3, 8.6 and 0.7, 3-HH), 2.71
(1 H, ddd, J 14.3, 3.3 and 1.1, 3-HH), 3.10 (1 H, br s, OH), 3.77
(3 H, s, CO2CH3), 3.80–4.20 (4 H, m, 4-H, 5-H, 6-H2), 5.75
(1 H, d, J 1.1, 2-CHH) and 6.28 (1 H, d, J 1.4, 2-CHH); δC(75
MHz) 25.06, 26.40 (each CH3), 35.94 (C-3), 51.95 (CO2CH3),
65.77 (C-6), 70.80, 78.05 (C-4 and C-5), 109.00 (acetonide
CMe2), 128.06 (2-CH2), 136.58 (C-2) and 168.12 (C-1); m/z (EI)
215.0921 (Mϩ Ϫ CH3, C10H15O5 requires 215.0919, 31%), 201
(5), 183 (4), 155 (10), 141 (31), 101 (100) and 59 (88).
Coupling aldehyde 41 and allylic bromide 31
Methyl (5R)-5,6-(isopropylidenedioxy)-4-(methoxymethoxy)-2-
oxohexanoates 36 and 37
Powdered zinc (0.85 g, 13 mmol) was added to a stirred solution
of aldehyde 41 (1.44 g, 10 mmol) and bromide 31 (2.31 g, 13
mmol) in saturated aqueous ammonium chloride (15 cm3) and
tetrahydrofuran (15 cm3). The solution was stirred at room
temperature for 8 h. The mixture was diluted with brine (30
A solution of a mixture of 32 and 33 (2.0 g, 8.71 mmol) in
dichloromethane (3 cm3) was added in one portion to a stirred
solution of diisopropylethylamine (2.0 cm3, 11.6 mmol) in
J. Chem. Soc., Perkin Trans. 1, 2000, 901–910
907

View Article Online
cm3), extracted with dichloromethane (3 × 50 cm3), and the
combined organic extracts were washed with brine (50 cm3),
dried over sodium sulfate, filtered and concentrated in vacuo to
give unsaturated alcohols 42 and 43 as a 1:1 diastereomeric
mixture by 1H NMR spectroscopy. Purification by column
chromatography eluting with a 30% solution of ethyl acetate in
light petroleum effected partial separation of the diastereomers
giving the less polar alcohol (0.33 g, 14%); a mixture of alcohols
42 and 43 (0.67 g, 28%) and the more polar product (0.31 g,
13%) were obtained all as pale yellow oils.
m, 6-H), 4.58 (1H, d, J 7.0, OCHHO), 4.63 (1H, d, J 7.0,
OCHHO), 5.67 (1H, dd, J 1.7 and 0.2, 2-CHH) and 6.24 (1H,
d, J 1.7, 2-CHH); δC(75.5 MHz) 25.80 (CH3), 26.97 (CH3),
37.62, 37.93 (C-3 and C-5), 51.96 and 55.74 (each OCH3), 69.64
(C-7), 72.91, 73.57 (C-4 and C-6), 95.56 (OCH2O), 108.63
(OCO), 128.02 (2-CH2), 136.87 (C-2) and 167.44 (C-1); m/z (EI)
273.1335 (Mϩ Ϫ CH3, C13H21O6 requires 273.1338, 9%), 243
(10), 207 (11), 197 (11), 189 (4), 167 (16), 149 (40), 137 (13), 113
(12), 101 (27), 91 (100), 84 (68), 69 (67) and 57 (45).
The above reaction was repeated on the more polar alcohol
from the previous experiment to give a colourless oil (0.25 g,
72%). [α]D25 Ϫ14.0 (c 3.0, CHCl3); νmax(film)/cmϪ1 2950 (CH),
Less polar product: [α]D25 ϩ8.8 (c 1.4, MeOH); νmax(film)/cmϪ1
3415 (br, OH), 2930 (CH), 1720 (CO) and 1630 (C᎐C); δ (270
᎐
H
MHz), 1.36 (3H, s, CH3), 1.42 (3H, s, CH3), 1.70 (2H, m, 5-H2),
2.51 (2H, m, 3-H2), 3.29 (1H, br s, OH), 3.57 (1H, dd, J 8.0 and
7.3, 7-HH), 3.77 (3H, s, CO2CH3), 3.98 (1H, m, 4-H), 4.09 (1H,
dd, J 8.0 and 5.9, 7-HH), 4.28 (1H, m, 6-H), 5.70 (1H, dd, J 2.6
and 1.1, 2-CHH) and 6.26 (1H, d, J 1.5, 2-CHH); δC(75 MHz)
25.61 (CH3), 26.89 (CH3), 39.98 and 40.20 (C-3 and C-5), 52.01
(CO2CH3), 69.35 (C-4 or C-6), 69.65 (C-7), 76.69 (C-4 or C-6),
109.31 (OCO), 127.94 (2-CH2), 136.99 (C-2) and 167.85 (C-1);
m/z (EI) 229.1080 (Mϩ Ϫ CH3, C11H17O5 requires 229.1076,
7%), 197 (100), 155 (12), 137 (58), 129 (12), 119 (11), 109 (12),
101 (24), 97 (72), 91 (21), 87 (22), 81 (26), 67 (52) and 69 (56).
More polar product: [α]D25 Ϫ15.0 (c 1.2, MeOH); νmax(film)/
1720 (CO) and 1630 (C᎐C); δ (270 MHz) 1.35 (3H, s, CH ),
᎐
H 3
1.40 (3H, s, CH3), 1.65 (1H, ddd, J 14.0, 9.0 and 5.0, 5-HH),
1.78 (1H, ddd, J 14.0, 7.9 and 3.7, 5-HH), 2.53 (1H, ddd, J 14.0,
6.5 and 1.0, 3-HH), 2.61 (1H, ddd, J 14.0, 6.0 and 1.0, 3-HH),
3.38 (3H, s, OCH3), 3.52 (1H, t, J 7.7, 7-HH), 3.76 (3H, s,
CO2CH3), 3.95 (1H, m, 4-H), 4.07 (1H, dd, J 7.7 and 5.9,
7-HH), 4.23 (1H, m, 6-H), 4.65 (1H, d, J 7.0, OCHHO), 4.69
(1H, d, J 7.0, OCHHO), 5.65 (1H, d, J 1.4, 2-CHH) and 6.24
(1H, d, J 1.4, 2-CHH); δC(75 MHz) 25.79 (CH3), 27.01 (CH3),
37.94, 38.86 (C-3 and C-5), 51.96 and 55.83 (each OCH3), 69.90
(C-7), 73.10, 73.70 (C-4 and C-6), 95.92 (OCH2O), 108.57
(OCO), 127.81 (2-CH2), 136.87 (C-2) and 167.43 (C-1); m/z (EI)
273.1339 (Mϩ Ϫ CH3, C13H21O6 requires 273.1338, 14%), 243
(15), 207 (14), 197 (15), 189 (18), 167 (17), 149 (58), 137 (16),
113 (19), 101 (35), 91 (42), 84 (100), 69 (89) and 57 (50).
The above reaction was repeated on the mixture of
diastereomers 42 and 43 giving a mixture of 44 and 45 in 85%
yield.
cmϪ1 3415 (br, OH), 2930 (CH), 1720 (CO) and 1630 (C᎐C);
᎐
δH(270 MHz), 1.36 (3H, s, CH3), 1.41 (3H, s, CH3), 1.65 (1H,
ddd, J 14.0, 9.0 and 5.0, 5-HH), 1.80 (1H, ddd, J 14.0, 7.2 and
3.1, 5-HH), 2.43 (1H, ddd, J 13.9, 8.0 and 0.9, 3-HH), 2.60 (1H,
ddd, J 13.9, 4.2 and 1.1 3-HH), 2.79 (1H, br s, OH), 3.57 (1H, t,
J 8.0, 7-HH), 3.77 (3H, s, CO2CH3), 3.98 (1H, m, 4-H), 4.09
(1H, dd, J 8.0 and 6.0, 7-HH), 4.33 (1H, m, 6-H), 5.69 (1H, d,
J 1.3, 2-CHH) and 6.26 (1H, d, J 1.3, 2-CHH); δC(75 MHz)
25.63 (CH3), 26.97 (CH3), 40.04, 40.50 (C-3 and C-5), 52.12
(CO2CH3), 67.77 (C-4 or C-6), 69.53 (C-7), 73.68 (C-4 or C-6),
108.69 (OCO), 128.11 (2-CH2), 137.05 (C-2) and 168.08 (C-1);
m/z (EI) 229.1071 (Mϩ Ϫ CH3, C11H17O5 requires 229.1076,
11%), 197 (100), 155 (16), 137 (61), 109 (22), 101 (28), 97 (73),
91 (32), 87 (34), 81 (26), 67 (54) and 69 (60).
Ozonolysis of a mixture of unsaturated esters 44 and 45
Ozone was bubbled through a stirred solution of 44 and 45
(0.58 g, 2 mmol) in dichloromethane (30 cm3) at Ϫ78 ЊC until
the solution turned blue. Oxygen was then bubbled through the
solution until the blue colouration disappeared. Dimethyl sul-
fide (3.5 cm3) was added to the solution which was then allowed
to warm to room temperature and stir for a further 5 min. The
solvent was evaporated and the crude product purified by col-
umn chromatography to afford a mixture of 2-oxo esters 46 and
47 as a colourless oil (0.48 g, 82%). νmax(film)/cmϪ1 3455 (OH),
2935 (CH) and 1735 (CO); δH(300 MHz) 1.32, 1.34, 1.38, 1.40
(each 3H, each s, 4 × CH3), 1.70–2.00 (4H, m, 2 × 5-H2), 3.00–
3.30 (4H, m, 2 × 3-H2), 3.31 (3H, s, OCH3), 3.33 (3H, s, OCH3),
3.48–3.57 (2H, m, 2 × 7-HH), 3.88 (6H, s, 2 × CO2CH3),
4.03–4.12 (2H, m, 2 × 7-HH), 4.14–4.36 (4H, m, 2 × 4-H and
2 × 6-H) and 4.58–4.66 (4H, m, 2 × OCH2O); δC(75 MHz) 25.7,
25.8, 26.9, 27.0 (each CH3), 38.0, 39.7 (2 × C-5), 44.1, 45.2
(2 × C-3), 52.9, 53.0 (2 × CO2CH3), 55.7, 55.7 (2 × OCH3),
69.5, 69.7 (2 × C-7), 71.4, 72.3, 72.3, 72.8 (2 × C-4 and 2 ×
C-6), 96.2, 96.6 (2 × OCH2O), 108.9, 109.1 (2 × OCO), 161.2,
161.3 (2 × C-1), 191.5 and 191.9 (2 × C-2); m/z (CI) 259.1180
([MH]ϩ Ϫ CH3OH, C12H19O6 requires 259.1182, 3%), 231 (5),
229 (4), 213 (16), 201 (6), 171 (30), 153 (26), 129 (22), 111 (28),
101 (76), 93 (27), 85 (25), 71 (22) and 59 (100).
When the above reaction was repeated with no attempt to
separate the diastereomers, 42 and 43 were obtained in 75%
yield.
Protection of alcohols 42 and 43 to give 44 and 45
The following reactions were carried out on the individual
diastereomers for characterisation purposes only, but because
of problems of separating 42 and 43, the majority of the
material was converted to the methoxymethyl ethers 44 and 45
as a mixture of diastereomers.
A solution of the less polar alcohol from the previous
experiment (0.32 g, 1.3 mmol) in dichloromethane (0.5 cm3) was
added to a stirred solution of diisopropylethylamine (0.34 cm3,
1.9 mmol) in dichloromethane (0.7 cm3) at 0 ЊC under nitrogen.
The solution was stirred for 5 min then allowed to reach room
temperature. Chloromethyl methyl ether (0.14 cm3, 1.9 mmol)
was added dropwise over 20 min and the solution was allowed
to stir at room temperature overnight. The mixture was diluted
with dichloromethane (10 cm3), washed with 1 M hydrochloric
acid (10 cm3) and the washings were extracted with dichloro-
methane (3 × 10 cm3). The combined organic phases were
washed with brine, dried over sodium sulfate and the solvent
was removed in vacuo. The crude reaction mixture was purified
by column chromatography to afford the methoxymethyl ether
as a colourless oil (0.267 g, 71%). [α]D25 ϩ25.0 (c 2.73, CHCl3);
νmax(film)/cmϪ1 2950 (CH), 1720 (CO) and 1630 (C᎐C); δ (270
Hydrolysis of a mixture of 46 and 47 with Candida rugosa lipase
followed by reduction catalysed by LB-hicDH
The biotransformations were carried out as described earlier
using LB-hicDH. The reduction was extremely slow but was
worked up after 2 days. The crude reaction product was methyl-
ated with ethereal diazomethane and purified by flash column
chromatography eluting with 20% ethyl acetate in petroleum
ether to give methyl (2R,3E,6S)-6,7-O-isopropylidene-2,6,7-
trihydroxyhept-3-enoate 50 as a pale yellow oil (10 mg, 4%). [α]D25
Ϫ27.8 (c 2.4, CHCl3); νmax(film)/cmϪ1 3450 (OH), 2985 (CH)
and 1745 (CO); δH(300 MHz) 1.35, 1.42 (each 3 H, each s,
2 × CH3), 2.33 (1H, dddt, J 14.2, 7.5, 6.8 and 1.2, 5-HH), 2.42
(1H, dddt, J 14.2, 6.8, 6.1 and 1.2, 5-HH), 3.57 (1H, dd, J 8.1
᎐
H
MHz; CDCl3), 1.35 (3H, d, J 0.6, CH3), 1.40 (3H, d, J 0.6,
CH3), 1.70 (1H, ddd, J 14.1, 6.6 and 5.1, 5-HH), 1.93 (1H,
dt, J 14.1 and 6.3, 5-HH), 2.58 (2H, m, 3-H2), 3.34 (3H, s,
CH2OCH3), 3.50 (1H, t, J 7.8, 7-HH), 3.76 (3H, s, CO2CH3),
3.83 (1H, m, 4-H), 4.08 (1H, dd, J 7.8 and 5.9, 7-HH), 4.27 (1H,
908
J. Chem. Soc., Perkin Trans. 1, 2000, 901–910

View Article Online
and 6.8, 7-HH), 3.81 (3H, s, CO2CH3), 4.02 (1H, dd, J 8.1 and
6.1, 7-HH), 4.16 (1H, tt, J 6.8 and 6.8, 6-H), 4.63 (1H, br dd,
J 5.4 and 1.4, 2-H), 5.64 (1H, ddt, J 15.4, 5.8 and 1.2, 3-H), 5.88
(1H, dddd, J 15.4, 7.5, 6.8 and 1.4, 4-H); δC(75 MHz) 25.6, 26.9
(each CH3), 36.4 (C-5), 52.9 (CO2CH3), 68.8 (C-7), 71.1 (C-2),
74.9 (C-6), 109.1 (OCO), 129.0, 129.1 (C-3 and C-4) and 172.0
(C-1); m/z (EI) 215.0917 (Mϩ Ϫ CH3, C10H15O5 requires
215.0919, 31%), 155 (11), 129 (12), 123 (8), 113 (11), 101
(100), 95 (30), 86 (34) and 84 (47). Further elution with 50%
ethyl acetate in light petroleum gave a mixture of hydroxy
esters 48 and 49 (30 mg, 14%). νmax(film)/cmϪ1 3460 (OH),
2955 (CH) and 1740 (CO); δH(300 MHz), 1.34, 1.35, 1.40, 1.41
(each 3H, each s, 4 × CH3), 1.74–1.88 (4H, m, 2 × 3-H2 or
2 × 5-H2), 1.92–2.16 (4H, m, 2 × 3-H2 or 2 × 5-H2), 3.37 (3H,
s, OCH3), 3.42 (3H, s, OCH3), 3.51 (1H, t, J 7.5, 7-HH), 3.53
(1H, t, J 7.5, 7-HH), 3.78 (3H, s, CO2CH3), 3.79 (3H, s,
CO2CH3), 3.98 (2H, m, 2 × 4-H or 2 × 6-H), 4.06 (1H, dd,
J 7.3 and 5.9, 7-HH), 4.07 (1H, dd, J 7.3 and 5.9, 7-HH), 4.20
(2H, m, 2 × 4-H or 2 × 6-H), 4.33 (1H, dd, J 6.6 and 4.6,
2-H), 4.42 (1H, dd, J 10.3 and 2.9, 2-H), 4.57 (1H, d, J 6.8,
OCHHO), 4.62 (1H, d, J 6.8, OCHHO), 4.71 (1H, d, J 6.8,
OCHHO) and 4.75 (1H, d, J 6.8, OCHHO); δC(75 MHz),
25.8, 25.8, 27.0, 27.0 (each CH3), 38.1, 38.3, 39.7, 40.2
(2 × C-3 and 2 × C-5), 52.5, 52.5 (2 × CO2CH3), 55.8, 56.0
(2 × OCH3), 67.7, 68.0 (2 × C-2), 69.7, 69.7 (2 × C-7), 72.6,
72.7, 72.8, 73.3 (2 × C-4 and 2 × C-6), 96.3, 97.0 (2 ×
OCH2O), 108.9, 108.9 (2 × OCO), 175.2 and 175.4 (2 × C-1);
m/z (CI) 261.1345 ([MH]ϩ Ϫ CH3OH, C12H21O6 requires
261.1338, 32%), 245 (50), 203 (100), 185 (30), 173 (82), 171
(48), 155 (70), 153 (64), 113 (72) and 101 (74).
53 and 54 as a colourless oil (0.95 g, 94%) which were used
immediately in the next step.
A solution of acetates 53 and 54 (0.95 g, 3.30 mmol) in
chloroform (20 cm3) was treated with silica (0.5 g). The reaction
was allowed to stir at room temperature for 5 h after which the
silica was removed by filtration and washed with copious
amounts of a 70% solution of ethyl acetate in light petroleum.
The filtrate was evaporated to give unsaturated 2-oxo ester 55
(0.72 g, 96%). [α]D25 Ϫ1.0 (c 3.7, MeOH); νmax(film)/cmϪ1 2985
(CH) and 1740 (br, CO); δH(270 MHz) 1.36 and 1.43 (each 3H,
each d, J 0.5, 2 × CH3), 2.58 (2H, m, 5-H2), 3.60 (1H, dd, J 8
and 6, 7-HH), 3.90 (3H, s, -CO2CH3), 4.08 (1H, dd, J 8 and 6,
7-HH), 4.27 (1H, quintet, J 6, 6-H), 6.76 (1H, dt, J 16 and 1,
3-H) and 7.18 (1H, dt, J 16 and 7, 4-H); δC(75 MHz) 25.27 and
26.58 (2 × CH3), 37.07 (C-5), 52.16 (OCH3), 68.70 (C-7), 73.95
(C-6), 109.44 (C(CH3)2), 127.58 (C-4), 148.41 (C-3), 162.60
(C-1) and 182.56 (C-2); m/z (EI) 213.0767 (Mϩ Ϫ CH3,
C10H13O5 requires 213.0763, 20%), 199 (63), 169 (10), 139 (30),
129 (20), 127 (16), 113 (18), 111 (18), 101 (100), 84 (60) and 59
(83).
Hydrolysis of 55 with Candida rugosa lipase followed by
reduction catalysed by BS-LDH
The biotransformations were carried out as described earlier
using BS-LDH. The crude reaction product was methylated
with ethereal diazomethane and purified by flash column chro-
matography eluting with 20% ethyl acetate in light petroleum to
give methyl (2S,3E,6S)-6,7-O-isopropylidene-2,6,7-trihydroxy-
hept-3-enoate 56 as a pale yellow oil (105 mg, 45%). [α]D25 ϩ51.5
(c 1.9, CHCl3); νmax(film)/cmϪ1 3460 (OH), 2990 (CH) and 1745
(CO); δH(300 MHz) 1.35 and 1.42 (each 3H, each s, CH3), 2.33
(1H, m, 5-HH), 2.42 (1H, m, 5-HH), 3.57 (1H, dd, J 8.0 and
7.0, 7-HH), 3.81 (3H, s, CO2CH3), 4.03 (1H, dd, J 8.0 and 6.0,
7-HH), 4.16 (1H, br quintet, J 6.5, 6-H), 4.65 (1H, br dd, J 5.5
and 1.5, 2-H), 5.64 (1H, ddt, J 15.5, 5.5 and 1.5, 3-H) and 5.90
(1H, dtd, J 15.5, 7.5 and 1.5, 4-H); δC(75 MHz) 25.6, 26.9 (each
CH3), 36.3 (C-5), 52.9 (CO2CH3), 68.8 (C-7), 71.1 (C-2), 75.0
(C-6), 109.1 (C(CH3)2), 129.0, 129.1 (C-3 and C-4) and 173.9
(C-1); m/z (EI) 215.0919 (Mϩ Ϫ CH3, C10H15O5 requires
215.0919, 30%), 155 (5), 123 (86), 101 (100), 95 (25), 86 (44) and
84 (65).
Acetylation of alcohols 42 and 43
Acetic anhydride (0.5 ml, 5 mmol) was added to a stirred solu-
tion of diastereomeric alcohols 42 and 43 (0.244 g, 1 mmol) in
anhydrous pyridine (0.9 ml, 11 mmol) at 0 ЊC. The solution was
allowed to warm to room temperature and was stirred for a
further 48 h. The solution was diluted with water (5 cm3) and
extracted with dichloromethane (3 × 10 cm3), the organic
extracts were dried over sodium sulfate and the solvent removed
in vacuo. The crude product was purified by column chromato-
graphy to yield a mixture of acetates 51 and 52 as a colourless
oil (0.180 g, 63%). νmax(film)/cmϪ1 2950 (CH), 1720 (CO) and
1630 (C᎐C); δ (300 MHz) 1.32, 1.35, 1.37 and 1.43 (each 3H,
᎐
H
Acknowledgements
We are grateful to Novartis and EPSRC (SC), BBSRC (LM)
and the University of Bristol (AS) for financial support.
each s, 4 × -CH3), 1.70–1.99 (4H, m, 2 × 5-H2), 2.01 (6H, s,
2 × OCOCH3), 2.38–2.80 (4H, m, 2 × 3-H2), 3.50–3.75 (2H,
m, 2 × 7-HH), 3.77 (6H, s, 2 × CO2CH3), 4.00–4.25 (4 H, m,
2 × 6-H and 2 × 7-HH), 5.12–5.22 (2 H, m, 2 × 4-H), 5.63 (2 H,
m, 2 × 2-CHH) and 6.22 (2 H, m, 2 × 2-CHH); δC(75 MHz)
21.0, 21.1, 25.6, 25.7, 26.8 and 26.9 (each CH3), 37.1, 37.3, 37.7
and 38.1 (2 × C-3 and 2 × C-5), 52.0 (2 × OCH3), 69.3. 69.5,
69.9 and 70.2 (2 × C-4 and 2 × C-6), 72.9 and 73.1 (2 × C-7),
108.6 and 108.8 (2 × C-2), 127.6 and 127.7 (2 × 2-CH2), 136.2
and 136.3 (2 × C-6Ј), 167.0, 167.1 (2 × C-1 or 2 × C-4), 170.3
and 170.4 (each CO); m/z (EI) 271.1177 (Mϩ Ϫ CH3, C13H19O6
requires 271.1182, 18%), 265 (12), 263 (20), 246 (24), 244 (22),
197 (25), 191 (32), 169 (26), 153 (30), 137 (41), 129 (60), 84 (50),
79 (43), 69 (41) and 59 (100).
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Paper a909677i
910
J. Chem. Soc., Perkin Trans. 1, 2000, 901–910