Facile synthesis of (2R,3S)-2-benzyloxy-3-hydroxybutyrolactone

Article abstract of DOI:10.1080/00397911.2012.714041

The heterocyclic diols derived from L-dimethyl tartrate are important chiral synthons in organic synthesis. In particular, L-threosolactone and L-threosolactam structures are versatile precursors for the synthesis of biologically active molecules. Structu

Full text of DOI:10.1080/00397911.2012.714041

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Facile Synthesis of (2R,3S)-2-
Benzyloxy-3-hydroxybutyrolactone
Amer El-Batta a
a Department of Chemistry , King Fahd University of Petroleum and
Minerals , Dhahran , Saudi Arabia
Accepted author version posted online: 30 Aug 2012.Published
online: 03 Jun 2013.
To cite this article: Amer El-Batta (2013): Facile Synthesis of (2R,3S)-2-Benzyloxy-3-
hydroxybutyrolactone, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 43:18, 2457-2463
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Synthetic Communications1, 43: 2457–2463, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.714041
FACILE SYNTHESIS OF (2R,3S)-2-BENZYLOXY-3-
HYDROXYBUTYROLACTONE
Amer El-Batta
Department of Chemistry, King Fahd University of Petroleum and Minerals,
Dhahran, Saudi Arabia
GRAPHICAL ABSTRACT
Abstract The heterocyclic diols derived from L-dimethyl tartrate are important chiral syn-
thons in organic synthesis. In particular, L-threosolactone and L-threosolactam structures
are versatile precursors for the synthesis of biologically active molecules. Structurally, these
functionalized five-membered rings contain two hydroxyl groups with R and S stereochem-
istry on C-2 and C-3 respectively. The preparation of (2R,3S)-2-benzyloxy-3-hydroxybu-
tyrolactone (3) and of its derivatives, drawing upon L-dimethyl tartrate as an inexpensive
chiral starting material, is described. The presented synthetic procedures are easy and effec-
tive for preparing L-threoso analogs. This protocol is also a better alternative in a large scale
setup. All structures 3–6 and 8 are characterized using 1H and 13C NMR spectroscopy.
Keywords Butyrolactone; chiral; L-threosolactone; organic; synthesis; tartrate
INTRODUCTION
Chiral synthons derived from L-ascorbic acid (vitamin C) have attracted great
attention because of their utility in total synthesis.[1] They assist in defining the
stereochemistry of biologically active products. This stereo- definition allows chemi-
cal structures to bind more efficient with the active sites in human body before they
can generate activity. Thus L-threosolactone (1), L-threosolactam 2 (Fig. 1), and
their derivatives have been utilized as precursors in the synthesis of antiviral drugs,[2]
b-lactam antibiotics,[3] platelet-activating factors,[4] and modified tartrate ligands
that are essential for catalysis.[5] Structurally, L-threoso analogs 1, 2, and 3 contain
two hydroxyl groups with R and S stereochemistry on C-2 and C-3 respectively.
As part of our research program targeting the synthesis of natural products,
we sought a simple method for the preparation of (2R,3S)-2-benzyloxy-3-
hydroxybutyrolactone (3) as well as other L-threoso analogs. Literature reported
Received May 28, 2012.
Address correspondence to Amer El-Batta, Department of Chemistry, King Fahd University of
Petroleum and Minerals, Dhahran 31261, Saudi Arabia. E-mail: aelbatta@kfupm.edu.sa
2457

2458
A. EL-BATTA
Figure 1. Structures of L-threosolactone (1), L-threosolactam (2), and benzyl ether of L-threosolactone (3).
the preparation of the 3,4-O-isopropylidene derivative of L-ascorbic acid
(Scheme 1).[3] Treatment of the acetonide with hydrogen peroxide in the presence
of calcium carbonate, followed by hydrogenation, afforded 3,4-O-isopropylidene-
L-threonic acid (4). Esterification of the acid then O-benzylation yielded methyl
(2R,3S)-2-benzyloxy-3,4-O-isopropylidene-3,4-dihydroxybutanoate (5).[6] The pre-
sented route is a better alternative to the current procedures in the aspects of easi-
ness, efficiency, and scale-up.
RESULTS AND DISCUSSION
The synthesis of 3 starts with the commercially available dimethyl L-tartrate
(Scheme 2). The diol is treated with benzaldehyde and a catalytic amount of p-tolue-
nesulfonic acid monohydrate in cyclohexane to give 67% (>99% ee) of the benzyli-
dene adduct 6.[4,7]
The benzylidene 6 is then reduced using lithium aluminum hydride and lithium
chloride to afford 2-O-benzyl-L-threitol (7) in 70% yield (>99% ee). Subsequently,
protection of the adjacent hydroxyl groups is accomplished with p-toluenesulfonic
acid monohydrate in acetone to give acetonide 8 in 97% (96% ee) (Scheme 3).[4]
Primary alcohol 8 is then oxidized under Swern conditions to yield aldehyde 9,
which readily is exposed to sodium bicarbonate and bromine in aqueous methanol to
Scheme 1. Literature route to prepare L-threoso analogs from L-ascorbic acid.
Scheme 2. Preparation of 2-O-benzyl-L-threitol (7).

SYNTHESIS OF L-THREOSO ANALOGS
2459
Scheme 3. Synthesis of (2R,3S)-2-benzyloxy-3-hydroxybutyrolactone (3).
give 80% (94% ee) of the methyl ester 5.[8] After treatment of 5 with 1.0 N
hydrochloric acid in tetrahydrofuran,[9] 87% yield (97% ee) of the benzyl ether of
L-threosolactone (3) is formed.
EXPERIMENTAL
CH2Cl2 was dried by distillation over CaH2 ꢀ Et2O was distilled from
sodium-benzophenone ketyl and was collected when the indicator became deep blue
or purple. All other reagents and solvents were purchased from Aldrich or Fisher
Scientific unless otherwise specified. All moisture-sensitive reactions were performed
under an argon atmosphere. The glassware was oven dried overnight prior use. Ana-
˚
lytical thin-layer chromatography (TLC) was performed on precoated silica gel 60 A
F-254 plates (particle size 0.040–0.055 mm, 230–400 mesh) and visualization was
accomplished with a 254-nm ultraviolet light. Flash chromatography was conducted
˚
using silica gel (Whatman, 60 A, 230–400 mesh). Chemical yields are based on
purified material (>98% by 1H NMR spectroscopy). All compounds were fully char-
1
1
acterized using H and 13C NMR. H (500 MHz) and 13C (125 MHz, standard:
13CDCl3, d ¼ 77.23 ppm) NMR spectra were recorded on a Varian 500-MHz spec-
trometer using tetramethylsilane (TMS) as internal standard (d ¼ 0 ppm) at ambient
temperature unless stated otherwise. Chemical shifts (d) are reported as follows:
chemical shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, b ¼ broad), J ¼ coupling constants (Hz), and integration. Optical
rotations were measured using a Rudolf Autopol III polarimeter.
Preparation of Dimethyl 2,3-O-Benzylidene-L-tartrate (6)[5]
An oven-dried, 500-mL, one-necked, round-bottomed flask equipped with a
stir bar and a Dean–Stark trap was charged with dimethyl L-tartrate (168.4 mmol,
30 g, 1.0 equiv), cyclohexane (200 mL), benzaldehyde (168.4 mmol, 17.2 mL, 1.0
equiv), and p-toluenesulfonic acid monohydrate (5 mmol, 95 mg, 0.03 equiv). The

2460
A. EL-BATTA
stirred mixture was heated with azeotropic removal of water for 12 h. The solution
was allowed to cool to ambient temperature and then concentrated. The residual
yellow oil was dissolved in Et2O (150 mL), transferred to a separatory funnel, and
washed with aqueous bisulfate solution (60 mL) and water (2 ꢁ 60 mL). The organics
were dried over anhydrous MgSO4, filtered, and concentrated. The crude product
was then collected via vacuum filtration and was triturated using 50 mL of hexanes
to give 67% (30 g) of 6 as a white solid. Mp 71–74 ꢂC (lit.[5] mp 73.2 ꢂC);
20
20
½aꢃD ¼ ꢄ46:4ꢂ (c 0.85, MeOH); lit.[4] ½aꢃD ¼ ꢄ47:2ꢂ (c 1.00 MeOH); 1H NMR
(CDCl3, 500 MHz) d 7.59–7.56 (m, ArH, 2H), 7.42–7.38 (m, ArH, 3H), 6.14 (s,
HCC6H5, 1H), 4.98 (d, CHO, J ¼ 4.2 Hz, 1H), 4.86 (d, CHO, J ¼ 4.0 Hz, 1H), 3.87
(s, OCH3, 3H), 3.82 (s, OCH3, 3H); 13C NMR (CDCl3, 125 MHz) d 170.1, 169.4,
135.3, 130.0, 128.4, 127.2, 106.8, 52.9.
Preparation of 2-O-Benzyl-L-threitol (7)[4]
An oven-dried, 1-L, three-necked, round-bottomed flask was flushed with
argon and equipped with a stir bar, an addition funnel, a condenser, and a bubbler.
The flask was charged with lithium aluminum hydride (225.6 mmol, 8.6 g, 2.02 equiv)
and cooled to ꢄ30 ꢂC. Then anhydrous Et2O (86 mL) was added with vigorous stir-
ring, and a solution of aluminum chloride (225.6 mmol, 30.1 g, 2.02 equiv) in anhy-
drous Et2O (69 mL) was added dropwise. Dry CH2Cl2 (69 mL) was placed in the
addition funnel and added rapidly while the temperature was allowed to rise to
0 ꢂC. A solution of 6 (111.7 mmol, 28.8 g, 1.0 equiv) in dry CH2Cl2 (69 mL) was
added dropwise. The mixture was stirred for 1 h at ambient temperature and heated
to reflux for an additional 2 h. The mixture was cooled to ꢄ20 ꢂC, and water (7.5 mL)
was added cautiously, followed by aqueous potassium hydroxide solution (16 g in
23.4 mL water) and tetrahydrofuran (THF) (100 mL). The reaction flask was heated
to reflux overnight while stirring efficiently. The mixture was then cooled, filtered
through a glass-fritted Buchner funnel containing a 2-cm layer of Celite, washed with
¨
EtOAc, and concentrated. The crude product was dissolved in CH2Cl2 (300 mL),
extracted via Soxhlet apparatus, and then recrystallized from CH2Cl2 to give 70%
20
(16.6 g) of 7 as a white solid, mp 76–80 ꢂC (lit.[10] mp 73–76 ꢂC); ½aꢃD ¼ þ16:8ꢂ (c
22
1
1.02, MeOH); lit.[4] ½aꢃD ¼ þ15:7ꢂ (c 1.00 MeOH); H NMR (CDCl3, 500 MHz) d
7.39–7.30 (m, ArH, 5H), 4.72 (d, HCHC6H5, J ¼ 11.6 Hz, 1H), 4.59 (d, HCHC6H5,
J ¼ 11.5 Hz, 1H), 3.91–3.82 (m, H2C-4, 2H), 3.80–3.72 (m, HC-3 and HCOBn, 2H),
3.71–3.55 (m, H2C-1, 2H), 2.86, 2.56, 1.67 (bs, 3 ꢁ OH, 3H); 13C NMR (CDCl3,
125 MHz) d 137.6, 128.7, 128.2, 128.0, 79.2, 72.5, 71.7, 63.0, 60.9.
Preparation of 3-O-Benzyl-1,2-O-isopropylidene-L-threitol (8)[11]
2-O-Benzyl-L-threitol (7) (2.44 mmol, 517 mg, 1.0 equiv) in dry acetone
(25 mL) was dissolved in a 100-mL, one-necked, round-bottom flask equipped with
a stir bar at ambient temperature. p-Toluenesulfonic acid monohydrate (0.244 mmol,
26 mg, 0.10 equiv) was then added, and the reaction flask was allowed to stir at ambi-
ent temperature for 12 h. Solid NaHCO3 (1 spatula) was added, and the mixture was
then allowed to stir for 10 min. The reaction mixture was filtered and concentrated,
and the residue was dissolved in EtOAc (100 mL). The organics were washed with

SYNTHESIS OF L-THREOSO ANALOGS
2461
saturated NaHCO3 (15 mL) and brine (15 mL), dried over anhydrous MgSO4, and
concentrated. The crude product was then used for the next step without further
purification. The yield obtained was 97% (600 mg) of 8 as a colorless oil,
20
22
½aꢃD ¼ ꢄ17:5ꢂ (c 1.08, CHCl3); lit.[4] ½aꢃD ¼ ꢄ16:8ꢂ (c 1.31 CHCl3); 1H NMR
(CDCl3, 500 MHz) d 7.37–7.28 (m, ArH, 5H), 4.79–4.68 (AB q, C6H5CH2O,
J ¼ 11.8 and 7.1 Hz, 2H), 4.33–4.29 (dd, BnOCH, J ¼ 12.8, 6.7 Hz, 1H), 4.03–3.99
(dd, H2C-1, J ¼ 8.4, 6.6 Hz, 1H), 3.84–3.79 (dd, J ¼ 8.4 and 7.0 Hz, H2C-1, 1H),
3.76–3.70 (m, HC-2, 1H), 3.63–3.56 (m, CH2OH, 2H), 2.12 (bt, OH, 1H), 1.45,
1.44 (2 ꢁ s, 2 ꢁ CH3, 6H); 13C NMR (CDCl3, 125 MHz) d 138.2, 128.5, 127.9,
127.8, 109.5, 79.2, 76.6, 72.8, 65.6, 61.8, 26.4, 25.3.
Preparation of (2R,3S)-2-Benzyloxy-3,4-O-isopropylidene-3,4-
dihydroxybutanal (9)[11]
Oxalyl chloride (3.24 mmol, 283 mL, 1.5 equiv) to dry CH2Cl2 (10 mL) was
added in an oven-dried, 50-mL, two-necked, round-bottomed flask equipped with
a stir bar under argon. At ꢄ60 ꢂC, dimethylsulfoxide (DMSO) (5.4 mmol, 383 mL,
2.5 equiv) was added slowly. The mixture was allowed to stir at ꢄ60 ꢂC for
45 min. Then, a solution of 8 (2.16 mmol, 544 mg, 1.0 equiv) in dry CH2Cl2 (2 mL)
was added dropwise. The reaction mixture was then stirred at ꢄ60 ꢂC for 1 h. Anhy-
drous triethylamine (10.8 mmol, 1.5 mL, 5.0 equiv) was added dropwise to the reac-
tion mixture, which then was allowed to warm to ꢄ20 ꢂC. Excess base was
neutralized by adding aqueous HCl (1 M, 60 mL). The mixture was transferred to
a separatory funnel and the layers were separated. The aqueous phase was extracted
with CH2Cl2 (3 ꢁ 30 mL). The combined organics were washed with saturated
NaHCO3 (20 mL) and water (20 mL), dried over anhydrous MgSO4, and concen-
trated. The crude product was then used in the next step without further purification.
The yield of 9 obtained was quantitative (541 mg).
Preparation of Methyl (2R,3S)-2-Benzyloxy-3,4-O-isopropylidene-3,4-
dihydroxybutanoate (5)[12]
Aldehyde 9 (1.92 mmol, 482 mg, 1.0 equiv) was dissolved in aqueous methanol
(2 mL water in 12 mL MeOH) in a one-necked, round-bottomed flask equipped with
a stir bar. Solid NaHCO3 (30.34 mmol, 2.6 g, 15.8 equiv) was added, followed by the
dropwise addition of bromine (6.24 mmol, 320 mL, 3.25 equiv). The reaction was
allowed to stir for 2 h at ambient temperature. The excess bromine was then
quenched by adding solid sodium thiosulfate, diluted with water (10 mL), and
extracted with CH2Cl2 (2 ꢁ 50 mL). The combined organics were dried over anhy-
drous MgSO4 and concentrated. The crude product was then purified by flash chro-
matography (10% EtOAc in hexanes; Rf 0.12) to give 80% (430 mg) of 5 as a colorless
20
1
oil, ½aꢃD ¼ þ53:8ꢂ (c 0.92, CH2Cl2); lit.[11] [a]D þ60.2 ꢂ (c 1.6 CH2Cl2); H NMR
(CDCl3, 500 MHz) d 7.37–7.26 (m, ArH, 5H), 4.77, 4.51 (2 ꢁ d, C6H5CH2O,
J ¼ 12.0 and 7.1 Hz, 2H), 4.41–4.37 (dd, HC-3, J ¼ 12.1, 6.1 Hz, 1H), 4.02–4.00
(dd, H2C-4, J ¼ 8.5, 6.8 Hz, 1H), 4.00–3.99 (d, BnOCH, J ¼ 12.6, 6.7 Hz, 1H),
3.98–3.94 (dd, H2C-4, J ¼ 8.7, 6.1 Hz, 1H), 3.75 (s, OCH3, 3H), 1.39, 1.34 (2 ꢁ s,

2462
A. EL-BATTA
2 ꢁ CH3, 6H); 13C NMR (CDCl3, 125 MHz) d 170.5, 137.0, 128.3, 128.1, 127.9,
109.8, 78.4, 75.8, 72.8, 65.4, 51.9, 26.2, 25.2.
Preparation of (2R,3S)-2-Benzyloxy-3-hydroxybutyrolactone (3)[13]
Compound 5 (1.53 mmol, 430 mg, 1.0 equiv) was dissolved in THF (15 mL) in a
100-mL, one-necked, round-bottomed flask equipped with a stir bar. Hydrochloric
acid (1.0 N, 15 mL) was then added dropwise at 0 ꢂC, and the reaction was allowed
to stir for 12 h. The mixture was diluted with EtOAc (100 mL), washed with satu-
rated NaHCO3 (2 ꢁ 25 mL) and brine (25 mL), dried over anhydrous MgSO4, and
concentrated. The crude product was then purified by flash chromatography (2:1
EtOAc in hexanes; Rf 0.53) to give 87% (277 mg) of 3 as a colorless oil,
20
25
½aꢃD ¼ þ10:3ꢂ (c 1.05, MeOH); lit.[13] ½aꢃD ꢄ 8:1ꢂ for the (2R,3R) diastereomer (c
0.58 EtOH); 1H NMR (CDCl3, 500 MHz) d 7.40–7.30 (m, ArH, 5H), 5.0, 4.72
(2 ꢁ d, C6H5CH2O, J ¼ 11.6 and 7.1 Hz, 2H), 4.50.4.45 (m, HCOH, 1H), 4.43–4.39
(dd, H2CO, J ¼ 9.3, 2.6 Hz, 1H), 4.07 (d, HCOBn, J ¼ 6.1 Hz, 1H), 3.98–3.94 (dd,
H2CO, J ¼ 9.3, 2.9 Hz, 1H), 2.71 (bd, OH, 1H); 13C NMR (CDCl3, 125 MHz) d
173.4, 136.7, 128.6, 128.3, 128.2, 79.1, 72.7, 72.1, 70.2.
CONCLUSION
Simple steps starting from inexpensive materials are utilized in the synthesis of
(2R,3S)-2-benzyloxy-3-hydroxybutyrolactone (3) and its derivatives, important syn-
thons with unlimited synthetic utility. The synthetic routes discussed are not only
easy and effective for achieving L-threoso analogs, but conducting these procedures
in large scale is also possible. Applications of these threitols will be described in
forthcoming publications.
ACKNOWLEDGMENTS
The author acknowledges the support provided by the Deanship of Scientific
Research (DSR) at King Fahd University of Petroleum and Minerals (KFUPM)
for funding this work through Project No. IN101005. The support of the
Department of Chemistry at KFUPM is also highly appreciated.
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