Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and homologues from carbohydrates

Article abstract of DOI:10.1016/S0957-4166(01)00053-2

Efficient routes to chiral 4-hydroxy-5-hexenoic acids and lactones from D-gluconic acid-δ-lactone and L-mannonic acid-γ-lactone are described. In this approach, the starting lactones are converted to 2,6-dibromo compounds that readily undergo zinc mediated elimination to generate the terminal alkene group in concert with 2-deoxygenation. The integrity of the remaining stereocenters is preserved during the reaction. The related important pharmaceutical intermediates (S)-3-hydroxy-4-pentenoic acid and (S)-1,3-dihydroxy-4-pentene were also prepared from 2-deoxyribose via the corresponding aldonolactone.

Full text of DOI:10.1016/S0957-4166(01)00053-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 387–391
Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and
homologues from carbohydrates
Jie Song and Rawle I. Hollingsworth*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 16 November 2000; accepted 17 January 2001
Abstract—Efficient routes to chiral 4-hydroxy-5-hexenoic acids and lactones from
D
-gluconic acid-d-lactone and
L-mannonic
acid-g-lactone are described. In this approach, the starting lactones are converted to 2,6-dibromo compounds that readily undergo
zinc mediated elimination to generate the terminal alkene group in concert with 2-deoxygenation. The integrity of the remaining
stereocenters is preserved during the reaction. The related important pharmaceutical intermediates (S)-3-hydroxy-4-pentenoic acid
and (S)-1,3-dihydroxy-4-pentene were also prepared from 2-deoxyribose via the corresponding aldonolactone. © 2001 Elsevier
Science Ltd. All rights reserved.
1
7–19
1
. Introduction
used.
Despite their utility, all of these methods have
drawbacks from a commercial standpoint. They may
involve the use of toxic metal catalysts,
materials or employ laborious synthetic schemes.
In the case of chiral allylic hydroxy acids, introduction
9–11
3
-Hydroxy-4-pentenoic and 4-hydroxy-5-hexenoic acids
are important synthetic building blocks in many natural
costly
13–16
7
,8
1
product syntheses. These include Mevinic acids, some
2
polyether antibiotics and a number of natural hor-
of the vinyl group is often effected by a Wittig reac-
3
–6
10,11,14,16
mones.
They are also intermediates of important
tion,
which is undesirable in industrial scale
metabolic processes such as the pentalene synthase
biosynthetic pathway, and are logical precursors for the
preparation of b- or g-amino acids and N-heterocycles,
which are key elements in the preparation of unnatural
amino acids, enzyme inhibitors and b-peptides. The
vinyl group in these molecules also affords a range of
possibilities for further transformation, including halo-
genation, epoxidation, reduction, ozonolysis and cyclo-
propanation, which can provide additional functional-
ity for integrating these chiral building blocks into
other molecular architectures.
processes. There is still, therefore, a need for more
direct, high yielding and cost efficient routes to these
compounds. In the approach we describe herein, we
take advantage of the low cost and structural richness
of carbohydrates to give an economic and environmen-
tally favorable entry to homochiral 3-hydroxy-4-pen-
tenoic and 4-hydroxy-5-hexenoic acids.
2
. Results and discussion
Because of their biological importance and synthetic
value, much effort has been expended on the synthesis
A simple three-step reaction sequence using mild condi-
tions to transform 2-deoxyribose 3 into (S)-3-hydroxy-
7
–19
of these compounds.
However, cost effective meth-
4
-pentenoic acid 1a and eventually to (S)-1,3-
ods for the preparation of homochiral 3-hydroxy-4-pen-
tenoic and 4-hydroxy-5-hexenoic acids are still lacking.
Current methods involve either asymmetric synthesis
dihydroxy-4-pentene 2 was first developed. The known
elimination of vicinal acyloxy halo compounds with
elemental zinc was utilized. The preparation of (S)-3-
hydroxy-4-pentenoic acid is summarized in Scheme
7,8
using chiral auxiliaries, chiral transition metal cata-
12–16
9
–11
lysts
or synthesis from natural a-amino acids;
1
. The key steps are conversion of the deoxypen-
traditional resolution procedures are also commonly
20
tose to the lactone 4, bromination of the 5-position
with simultaneous acetylation of the other two hy-
droxyl groups followed by zinc mediated elimina-
tion, which upon basic hydrolysis gave the 4,5-un-
saturated product 1a. Alcoholic acid work-up then
afforded ester 1b. Lithium aluminum hydride reduction
21
*
0
Corresponding author. Tel.: 517-353-0613; fax: 517-353-9334;
e-mail: rih@argus.cem.msu.edu
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00053-2

3
88
J. Song, R. I. Hollingsworth / Tetrahedron: Asymmetry 12 (2001) 387–391
Scheme 1. Synthesis of (S)-3-hydroxy-4-pentenoic acid and (S)-dihydroxy-4-pentene.
Scheme 2. Synthesis of (S)-4-hydroxy-5-hexenoic acid lactone and (S)-4-hydroxy-5-hexenoic acid methyl ester. Reagents,
conditions and yields: (a) 30% HBr in HOAc, 60°C for 1 h and rt overnight; (b) Zn dust, 50% HOAc in water, rt for 2 h, reflux
1
h, 58% (two steps); (c) 1.2 equiv. MsCl, 1.1 equiv. Et N, CH Cl , −40°C, 2 h; (d) 0.8 equiv. Et N, CH Cl , −78°C, 30 min, 70%
3 2 2 3 2 2
(
two steps, based on converted 3-mesylated intermediate); (e) 2 equiv. CuI, 5 equiv. LiCl, 4 equiv. TMSCl, 3.6 equiv. n-Bu SnH,
3
anhydrous THF, −70°C, 30–45 min, 80%; (f) 1.1 equiv. NaOMe, MeOH, 0°C, 3 h, quantitative. MsCl=methanesulfonyl chloride;
TMSCl=chlorotrimethylsilane.
of this ester at room temperature gave diol 2 quantita-
tively (66% overall yield). Chiral GC analysis of diol 2
indicated a >99% enantiomeric excess of the (S)-
enantiomer.
key intermediate (3R,4R)-3,4-dihydroxy-4-hexenoic
acid-g-lactone 5 in 58% yield. When -mannonic-g-lac-
tone was used instead of
L
D
-glucono-d-lactone, the
(3S,4S)-enantiomer 5% was obtained in comparable
1
yield (Scheme 3). H NMR spectroscopy indicated that
The method described above was used as a basis for the
transformations of hexonic acid lactones to the key
intermediates in the preparation of 4-hydroxy-5-
hexenoic acids. Unlike the homologous 4-pentenoic
acid compounds, 2-deoxygenation was effected from a
there was no scrambling of the stereocenters during this
process.
2
-bromo-2-deoxy function accompanying the elimina-
tion reaction. The relatively inexpensive
D
-glucono-d-
lactone was used as the starting material for the
synthesis of (S)-4-hydroxy-5-hexenoic acid and the cor-
responding lactone. The (R)-acid and its corresponding
lactone were obtained using
which has the opposite C-(4) stereochemistry to glu-
cose. The synthesis is summarized in Scheme 2. -Glu-
L
-mannonic-g-lactone,
D
cono-d-lactone was treated with 30% hydrogen bromide
in acetic acid (HBA) followed by zinc dust to open the
lactone ring and introduce the 5,6-vinyl function via
zinc facilitated elimination. During this process, an
effective simultaneous 2-debromination by zinc
occurred. This one-pot process quickly led to the first
Scheme 3. Synthesis of compound 5% from -mannonic-g-lac-
L
2
1
tone. Reagents, conditions and yields: (a) 30% HBr in HOAc,
60°C for 1 h and rt overnight; (b) Zn dust, 50% HOAc in
water, rt for 2 h and reflux for 1 h, 50% (two steps).

J. Song, R. I. Hollingsworth / Tetrahedron: Asymmetry 12 (2001) 387–391
389
Scheme 4. Proposed mechanism for dibromination of
L
-mannonic-g-lactone (A) and d-gluconolactone (B).
3. Conclusion
The formation of the 2-bromo-2-deoxy function
deserves some discussion. Despite the similar reaction
outcome, the dibromination of
and -mannonic-g-lactone may involve slightly different
D
-glucono-d-lactone
General and efficient routes to chiral unsaturated b-
hydroxy pentanoic acids and g-hydroxy hexanoic acids
from naturally occurring carbohydrates have been
L
26
reaction mechanisms. It is known that, in strongly
acidic medium, bromination of aldonolactones occurs
at either (or both) the 2- or primary positions. Lactones
having hydroxyl groups cis on the lactone ring tend to
form an acetoxonium ion, while trans-oriented hydroxy
developed in which aldonic acid lactones with the
D-
ribo, -gluco and -manno stereochemistries were uti-
D
L
lized and zinc mediated elimination and deoxygenation
were key processes. The products are important inter-
mediates in a wide spectrum of pharmacologically
important compounds.
2
6
groups do not. Opening of a 2,3-acetoxonium ion has
been found to take place exclusively at C-(2) with
inversion of the stereochemistry. This is probably the
case for the 2-bromination of
Scheme 4A). In the case of
L
-mannonic-g-lactone
This approach takes advantage of the variety of chiral
functionalities in carbohydrates in a way that does not
require the tedious protection and deprotection manip-
ulations commonly associated with the chemistry of
these substrates. It provides an efficient, economical
and environmentally benign alternative to existing
approaches to these important chiral intermediates.
(
D
-glucono-d-lactone,
despite the trans-relationship of the 2,3-hydroxy
groups, dibromination was still observed although pro-
2
1
longed reaction times were required. A possible ratio-
nalization of this, involving opening of the
six-membered lactone ring, is illustrated in Scheme 4B.
Deoxygenation at the 3-position was accomplished by
mesylation followed by elimination. A 1,4-reduction
27
4. Experimental
of the resulting a,b-unsaturated lactone 6 with LiCl/
CuI/iodotrimethylsilane/tributylzinc hydride reagent
followed by ring opening of saturated lactone 7 gave
4.1. 2-Deoxy-
D-ribonolactone 4
(
S)-4-hydroxy-5-hexenoic acid methyl ester 8 in a satis-
2-Deoxy- -ribose 1 (25 g) was stirred with bromine (29
D
factory yield. Because of the acidity of the doubly
allylic C-(4) proton of lactone 6, a rearrangement
tended to occur under basic conditions to give an
achiral conjugated side product (Scheme 5), and if the
amount of base used was not controlled carefully,
straightforward elimination of the 3-mesylate was not
observed.
mL) in water (1.5 L) at 0°C in the dark for 16 h. The
product was concentrated under vacuum with mild
heating to give a yellow syrup. NMR analysis indicated
1
clean conversion to 2-deoxyribonolactone. H NMR
(300 MHz, D O): l 4.34 (2H, m), 3.66 (1H, dd, J=
2
12.9, 3 Hz), 3.55 (1H, dd, J=12.9, 4.2 Hz), 2.84 (1H,
dd, J=18.6, 6.9 Hz), 2.36 (1H, dd, J=18.6, 3.0 Hz);
Scheme 5. Rearrangement and loss of chirality of compound 6 under basic conditions.

3
90
J. Song, R. I. Hollingsworth / Tetrahedron: Asymmetry 12 (2001) 387–391
1
3
C NMR (75 MHz, D O): l 174.72, 84.14, 63.49,
mL). Zinc dust (50 g) was added in portions and the
mixture stirred at room temperature for 2 h and then
refluxed for an additional 1 h. The mixture was filtered
and the filtrate concentrated under reduced pressure.
The resultant syrup was dissolved in water (100 mL)
and potassium hydroxide was added to precipitate the
remaining zinc as the insoluble hydroxide and effect
C-(3) deacetylation. After filtration, the basic filtrate
was acidified to pH 5 using concentrated hydrochloric
acid. Water was removed under reduced pressure and
the residue dissolved in cold ethanol. Precipitated
potassium chloride was removed by filtration, and the
filtrate evaporated. The evaporation residue was
purified by flash column chromatography using ethyl
2
5
6.19, + 32.94; FAB-HRMS (Gly): calcd C H O
5
9
4
[
M+H] : 133.0457; found: 133.0501.
4
.2. (S)-3-Hydroxy-4-pentenoic acid 1a and the ethyl
ester 1b
Lactone 3 (1 g) was stirred with 30% HBr in acetic acid
HBA, 5 mL) at room temperature overnight. Excess
(
HBA was evaporated and the resulting syrup was dis-
solved in 50% acetic acid in water (10 mL). Zinc dust (3
g) was added in portions and stirred at room tempera-
ture for 3 h. The mixture was filtered and the filtrate
concentrated. To remove zinc salt and deacetylate the
3
-OH position, the residue was dissolved in water and
acetate/hexanes (1:1 v:v) as eluent to yield pure 5 (10.5
1
the pH adjusted to 10 using KOH. A white precipitate
of zinc hydroxide formed and was removed by filtra-
tion. The filtrate was concentrated and the syrup was
dissolved in cold ethanol and acidified with concen-
trated HCl. The KCl salt formed was removed by
g, 58% overall yield for two steps). [h] +43 (c 1.15); H
D
NMR (300 MHz, CDCl ): l 5.93 (1H, m), 5.49 (2H,
3
m), 4.87 (1H, m), 4.51 (1H, m), 2.77 (1H, dd, J=17.7,
1
3
5.4 Hz), 2.58 (1H, dd, J=17.7, 1.5 Hz); C NMR (75
MHz, CDCl ): l 175.74, 130.12, 120.77, 84.65, 69.42,
3
+
filtration. Removal of ethanol gave crude compound 1a
38.60; FAB-HRMS (NBA): [M+H] C H O calcd:
129.0552; found: 129.0553.
6
9
3
1
(
(
0.7 g). H NMR (300 MHz, D O): l 5.72 (1H, m), 5.09
1H, m), 4.98 (1H, m), 4.31 (1H, m), 2.33 (2H, m);
2
13
C
NMR (75 MHz, D O): l 175.20, 134.16, 110.90, 65.05,
4.5. (3S,4S)-3,4-Dihydroxy-4-hexenoic acid-g-lactone 5%
2
+
3
1
8.51; FAB-HRMS (Gly): calcd C H O [M+H] :
5 9 3
17.0508; found: 117.0552. Ethyl ester 1b was prepared
L
-Mannonic-g-lactone (25 g) was subjected to the one-
by a similar method to lactone 3 (20 g) except that
warm acidic ethanol was used for extended time in the
final step. The product was isolated by flash chro-
matography (chloroform as eluent) with an overall
yield of 66% for three steps. [h] −5 (c 0.98, CHCl ); H
NMR (300 MHz, D O): l 5.85 (1H, m), 5.27 (1H, m),
pot reaction sequence described above for the -glu-
D
cono-d-lactone. After flash column chromatographic
purification, pure 5% was obtained (9.1 g, 50% overall
1
13
yield). [h] −44 (c 1.56, CHCl ); H and C NMR (300
D
3
1
MHz, CDCl ): identical with those of compound 5;
D
3
3
+
FAB-HRMS (NBA): [M+H] C H O calcd: 129.0552;
2
6
9
3
5
2
.11 (1H, m), 4.50 (1H, m), 4.14 (2H, q, J=7.2 Hz),
.52 (2H, m), 1.23 (3H, t, J=7.2 Hz); C NMR (75
found: 129.0551.
1
3
MHz, D O): l 172.22, 138.76, 115.33, 68.89, 60.74,
4.6. (R)-4-Hydroxyhexane-2,5-(Z)-dienoic acid lactone
2
1
13
4
1.11, 14.11 (both H and C NMR data agree with
6
2
2,23
literature data
C H O [M+H] : 145.0865; found: 145.0849.
); FAB-HRMS (NBA): calcd
+
Compound 5 (1.5 g) was dissolved in dichloromethane
7
13
3
(
25 mL) and the solution was cooled to −40°C.
4.3. (S)-1,3-Dihydroxy-4-pentene 2
Methanesulfonyl chloride (1.1 mL) was added followed
by addition of a solution of triethylamine (1.8 mL) in
dichloromethane (10 mL) over 30 min. After stirring
for 2 h at −40°C, TLC analysis indicated that com-
pound 5 was completely converted to the 3-mesylated
compound. The reaction temperature was then reduced
to −78°C and a solution of triethylamine (1.3 mL) in
dichloromethane (5 mL) was slowly introduced over 30
min. The reaction was monitored by TLC and stopped
when a less polar, UV-active product (from unwanted
rearrangement) started to form. N.B. At this point
some 3-mesylated compound was not completely con-
verted to the elimination product. The reaction mixture
was poured into ice cold dilute hydrochloric acid solu-
tion (40 mL) and extracted with dichloromethane. The
organic layer was dried over anhydrous sodium sulfate
and then concentrated and flash column chromatogra-
phy of the evaporation residue (chloroform as eluent)
afforded 6 (0.64 g, 50% yield) as a pale yellow liquid.
Unconverted 3-methylated product (0.7 g, 29%) was
Ester 1b (0.5 g) was dissolved in THF (15 mL) and
stirred with LAH (0.17 g) at room temperature for 3 h.
The reaction mixture was then quenched by slow addi-
tion of methanol and poured into cold acidified water
then extracted with ethyl acetate. Removal of solvent
yielded the 1,3-diol 2 quantitatively as a colorless liq-
2
4
uid. [h] +11 (c 1, MeOH) [lit. [h] +11 (c 1, MeOH)];
D
D
1
H NMR (300 MHz, CDCl ): l 5.87 (1H, m), 5.24 (1H,
3
m), 5.09 (1H, m), 4.34 (1H, m), 3.80 (2H, m), 3.04 (2H,
1
b), 1.74 (2H, m) ( H NMR data agree with literature
2
5
13
data ); C NMR (75 MHz, CDCl ): l 140.54, 114.60,
3
7
2.47, 60.84, 38.05; e.e. >99% by chiral GC; FAB-
+
HRMS (Gly): calcd C H O [M+H] : 103.0759; found:
5
11
2
103.0741.
4.4. (3R,4R)-3,4-Dihydroxy-4-hexenoic acid-g-lactone 5
D
-Glucono-d-lactone (25 g) was stirred at 60°C with
3
1
0% hydrogen bromide in acetic acid (HBA, 80 mL) for
h and then overnight at room temperature. Excess
also recovered. (3R,4R)-3-Mesyloxy-5-hexenoic acid
1
lactone: H NMR (300 MHz, CDCl ): l 5.88 (1H, m),
3
HBA was removed under reduced pressure. The resul-
tant oil was dissolved in 50% acetic acid in water (200
5.49 (2H, m), 5.36 (1H, m), 5.00 (1H, m), 3.01 (3H, s),
2.96 (1H, dd, J=18.3, 5.7 Hz), 2.82 (1H, dd, J=18.3,

J. Song, R. I. Hollingsworth / Tetrahedron: Asymmetry 12 (2001) 387–391
391
1
3
1
1
.5 Hz); C NMR (75 MHz, CDCl ): l 172.75, 129.01,
References
3
21.49, 82.49, 76.80, 38.52, 36.68. Rearrangement
1
product: H NMR (300 MHz, CDCl ): l 7.32 (1H, d,
1. Kumar, A.; Dittmer, D. C. J. Org. Chem. 1994, 59,
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2. Still, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108,
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3
J=5.1 Hz), 6.09 (1H, d, J=5.1 Hz), 5.32 (1H, q, J=7.5
Hz), 1.92 (3H, d, J=7.5 Hz); C NMR (75 MHz,
CDCl ): l 170.04, 150.30, 143.51, 118.70, 112.28, 11.88.
Compound 6: H NMR (300 MHz, CDCl ): l 7.39 (1H,
dd, J=5.7, 1.5 Hz), 6.12 (1H, dd, J=5.7, 2.1 Hz), 5.70
1H, m), 5.46 (1H, m), 5.41 (1H, m), 5.34 (1H, m);
NMR (75 MHz, CDCl ): l 172.67, 154.69, 131.62,
1
3
3
1
3
13
(
C
3
+
1
1
21.45, 119.82, 83.63; HRMS-EI(+): M C H O calcd:
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10.0368; found: 110.0352.
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4.7. (S)-4-Hydroxy-5-hexenoic acid lactone 7
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8
Lithium chloride (0.21 g) and copper(I) iodide (0.38 g)
were dissolved in anhydrous THF (10 mL) under nitro-
gen flow. After stirring for 20 min at room temperature,
the mixture was cooled to −70°C. Neat 6 (0.11 g) was
added followed by chlorotrimethylsilane (0.54 mL) and
the mixture stirred for 15 min. Tributyltin hydride (1
mL) was slowly added over 5 min. The reaction mixture
was then allowed to warm to 0°C over 1 h. The
reaction was quenched with 10% potassium fluoride
solution (5 mL) and stirred for 30 min. The mixture
was filtered through a Celite pad and the filtrate was
extracted with THF. The organic layer was concen-
trated and the residue was stirred with 10% potassium
fluoride solution (10 mL) for 15 min. Ether (10 mL)
was then added and the stirring was continued for
another 15 min. The mixture was passed through a
Celite pad and the filtrate was extracted with ether. The
ether solution was washed with brine, dried over anhy-
drous sodium sulfate and then concentrated. Flash
column chromatography afforded pure 7 as a colorless
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9196.
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1
liquid (90 mg, 80% yield). [h] +28 (c 1.48, CHCl ); H
D
3
NMR (300 MHz, CDCl ): l 5.85 (1H, m), 5.34 (1H,
3
m), 5.23 (1H, m), 4.92 (1H, m), 2.51 (1H, m), 2.39 (1H,
1
28
m), 1.98 (1H, m) [Lit. H NMR (60 MHz): l 4.78–
1
6
.20 (4H, m), 1.78–3.15 (4H, m); H NMR (60 MHz,
2
9–31
13
CD CN):
l 4.7–6.3 (4H, m), 1.6–2.7 (4H, m)];
C
3
NMR (75 MHz, CDCl ): l 176.94, 135.49, 117.44,
3
13
29–31
8
1
0.48, 31.54, 28.24 [Lit. C NMR (d -pyridine):
l
23. Smith III, A. B.; Levenberg, P. A. Synthesis 1981, 567–
570.
5
+
78.4, 137.8, 118.1, 81.9, 29.3 (2)]; HRMS-EI(+): M
C H O calcd: 112.0524; found: 112.0541.
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809.
6
8
2
4.8. (S)-4-Hydroxy-5-hexenoic acid methyl ester 8
Compound 5 (50 mg) was stirred with sodium methox-
ide (26 mg) in absolute methanol (5 mL) at 0°C for 3 h.
The solution was then neutralized with concentrated
hydrochloric acid. The reaction mixture was concen-
trated and the product was extracted with chloroform.
Compound 8 was obtained quantitatively. [h] +1.6 (c
D
1
1
.33, CHCl ); H NMR (300 MHz, CDCl ): l 5.84 (1H,
3
3
m), 5.24 (1H, m), 5.12 (1H, m), 4.16 (1H, m), 3.68 (3H,
s), 2.43 (2H, t, J=7.2 Hz), 1.85 (2H, m); C NMR (75
29. Wehrmeister, H. L. J. Org. Chem. 1961, 26, 3821.
30. Meyers, A. I.; Temple, D. L. J. Am. Chem. Soc. 1970, 92,
6644.
31. Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E.
D. J. Org. Chem. 1974, 39, 2778.
1
3
MHz, CDCl ): l 174.35, 140.33, 115.13, 72.13, 51.68,
3
+
3
1.58, 29.93; FAB-HRMS (NBA): [M+H]
calcd: 145.0865; found: 145.0866.
C
.
H O3
13
7