Convenient enantiopure synthesis of (2S,3R)-2-O-benzyl-3,4-O- isopropylidene-D-erythritol from D-(+)-glucono-δ-lactone: A potential C4 chiral building block

Article abstract of DOI:10.1055/s-2005-869986

A new convenient synthesis of (2S,3R)-2-O-benzyl-3,4-O-isopropylidene-D- erythritol has been achieved starting from extremely cheap and commercially available D-(+)-glucono-δ-lactone. It involves two carbon excisions using ozonolysis. The inbuilt stereoch

Full text of DOI:10.1055/s-2005-869986

PRACTICAL SYNTHETIC PROCEDURES
2267
Convenient Enantiopure Synthesis of (2S,3R)-2-O-Benzyl-3,4-O-isopro-
pylidene-D-erythritol from D-(+)-Glucono-d-lactone: A Potential C4 Chiral
Building Block
Convenient
E
n
i
antiop
v
S
ynthesis
a
of (2
S
,3
R
)
l
O
-B
e
enzyl-3, 4-
O
n
-isopropylid
k
ene-
D
-Eryth
a
ritol Vijayasaradhi, Manjunath Narayana Beedimane, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
Fax +91(44)22578241; E-mail: isingh@iitm.ac.in
PSP
Received 24 November 2004; revised 28 February 2005
This paper is dedicated to Professor N. S. Narasimhan.
No53
Abstract: A new convenient synthesis of (2S,3R)-2-O-benzyl-3,4-O-isopropylidene-D-erythritol has been achieved starting from extremely
cheap and commercially available D-(+)-glucono-d-lactone. It involves two carbon excisions using ozonolysis. The inbuilt stereochemistry
ensures the enantiopurity of the target compound.
Key words: lactones, eliminations, ozonolysis, reduction
O
O
1) O3, CH2Cl2
–78 °C
O
O
O
O
O
OH
X
OCH3
OBn
2) NaBH4, CH3OH
–78 °C to 0 °C
OBn
1: X = Br
OBn
2
3
65% for two steps
Scheme 1
In connection with our ongoing synthetic efforts towards procedure on a pentose sugar derivative. The route is
2-deoxy-C-aryl ribofuranosides, we needed a convenient lengthy and a comparatively expensive sugar, D-(–)-arabi-
and straight forward route to enantiomerically pure eryth- nose, is required as the starting substrate for one carbon
ritol halo derivative 1. Logically it should be possible to excision. The two other routes7,8 use D-isoascorbic acid as
prepare 1 from the corresponding differentially protected the starting material in an oxidative carbon chain excision.
enantiopure erythritol derivative 2. A quick survey of the One proceeds through a four carbon a-hydroxy ester inter-
literature revealed a complete surprise. In sharp contrast mediate and the other through D-erythronolactone. The
to the abundantly available threo configured derivatives former seems to be the most promising route, whereas the
1
(obtained from tartaric acids), the availability of the latter8 demands a regioselective introduction of the benzyl
erythro configured analogue is extremely scarce.2 Even ether protecting group onto the a-hydroxy group in D-
from the corresponding appropriately protected enan- erythronolactone in order to arrive at the erythritol deriv-
tiopure aldehyde, D-erythrose which could be converted ative 2. The dibutylstannylation/benzylation sequence
to the erythritol derivative 2 there is little known. Two of has, however, only been carried out on a small scale and
the routes for the synthesis of this aldehyde rely on one in moderate yields. In the light of this, the results present-
carbon chain homologation of 2,3-O-isopropylidene- ed herein are a significant improvement in the preparation
glyceraldehyde. Dondoni uses 2-(trimethylsilylthiazole) of enantiopure erythritol derivative 2.
as the formyl anion equivalent,3 while Arroyo-Gomez em-
ploys (+)-(R)-methyl p-tolyl sulfoxide for the chain exten-
sion.4 The latter depends on an effective Pummerer
rearrangement5 of the b-hydroxy sulfoxide to arrive at D-
functionalities of D-(+)-glucono-d-lactone 4 were selec-
erythrose. Although both routes proceed with good to
high stereoselectivity, they also involve tedious chro-
matographic techniques to separate the desired major dia-
Ph3P/I2/imidazole was used for direct deoxygenation10 of
stereoisomer from the minor contaminant. The other
routes available in the literature for this aldehyde are
group, we preferred to use a two-step method9a to arrive at
based on the carbon chain excision concept. Wang’s
method6 involves a two-step, one carbon chain excision
The a,b-unsaturated ester 3 required as the starting mate-
rial is conveniently obtained as depicted in Scheme 2 by
the earlier approach of Chittenden.9a The 3,4 and 5,6-diol
tively protected producing the di-O-isopropylidene a-hy-
droxy ester 5 in high yields.9b Initially a combination of
the a-hydroxy group in 5 activated by a vicinal carbonyl
methyl 2-deoxy-3,4:5,6-di-O-isopropylidene-D-(+)-glu-
conoate (7) in 77% overall yield. The steps involved are
initial chlorination to provide the manno-configured chlo-
ro-derivative 6 as an intermediate and subsequent hydro-
genolysis of the same to afford 7. This was purely because
of convenience and scalability. Treatment of 7 with sodi-
SYNTHESIS 2005, No. 13, pp 2267–2269
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-869986; Art ID: T14204SS
© Georg Thieme Verlag Stuttgart · New York

2268
S. Vijayasaradhi et al.
PRACTICAL SYNTHETIC PROCEDURES
um tert-butoxide in anhydrous DMF at –40 °C results in a flexibility; incorporation of other protecting groups on the
facile b-elimination and concomitant ring-opening of the C2-OH could lead to a range of derivatives. Since multi-
internal isopropylidene ketal to furnish the sodium salt 8 gram quantities of 7 can be routinely obtained by a well-
in situ. Quenching the reaction with benzyl bromide af- established procedure from extremely cheap and commer-
forded the a,b-unsaturated ester 3 in 50% yield. The for- cially available D-(+)-gluconolactone (4), there seems to
mation of the O-benzyl derivative was evident from two be no difficulty in applying the strategy based on the chain
1
doublets in the H NMR spectrum of the product at 4.42 excision concept and described herein for the target mol-
ppm and 4.64 ppm with a coupling constant of 11.7 Hz ecule 2. The complete enantiopurity is safeguarded and
each. The ester functionality was confirmed from the IR ensured by the inbuilt stereochemistry at C4 and C5 in 7 or
(1724 cm–1) and 13C NMR (166.3 ppm) spectrum of the consequently in 3, which remains intact during the syn-
product. Unfortunately, the isolated yield of the product 3 thetic sequence. One-pot ozonolysis and subsequent sodi-
could not be increased beyond 50%, despite stirring the um borohydride reduction of the a,b-unsaturated ester 3
sodium salt 8 with benzyl bromide at room temperature has been carried out on a two millimole scale. Other pro-
for a long period of time. However, quenching of salt 8 cedures and protocols from the literature for C=C double
with acid resulted in excellent yields of the hydroxy deriv- bond cleavage would be worthy of further exploration and
ative 9 (85%). Derivative 9 can be conveniently benzylat- may result in the optimization of this route.
ed in good yield to furnish 3. Finally, ozonolysis of the
double bond in compound 3 at –78 °C followed by addi-
tion of sodium borohydride at the same temperature
points were determined in a capillary tube with a Toshniwal melting
All the solvents and reagents were distilled before use. Melting
afforded the desired (2S,3R)-2-O-benzyl-3,4-O-isopro-
pylidene-D-erythritol (2) in 65% isolated yield. The
stereochemical integrity of the compound was evident
from the specific rotation of the compound {[a]D27 +21.7
(c 1, CHCl3)], which was in conformity with the value re-
ported in the literature11 {[a]D26 –22 (c 1, CHCl3), enantio-
mer of 2}.
point apparatus and are uncorrected. NMR spectra were recorded on
Bruker [300 MHz or 400 MHz (1H NMR), 75 MHz or 100 MHz
(13C NMR)] NMR spectrometer or Jeol 400 MHz NMR spectrome-
ter using TMS as a reference. IR spectra were recorded on Shimad-
zu IR 470 spectrometer. EI mass spectra and HRMS were
accomplished at 70 eV using a Finnigan MAT 8230 spectrometer.
Chemical ionization mass spectra and HRMS were accomplished at
10eV using a Q TOF MICRO spectrometer. Microanalyses were
performed on a Perkin Elmer Instrument Series II, CHNS/O Ana-
lyzer 2400 analyzer or Heraeus analyzer. Optical rotations were
measured with a Jasco, DIP-370-Digital polarimeter at room tem-
perature. To monitor the formation of compounds 3, 5–7, and 9,
TLC were performed on pre-coated silica gel plates (Merck 5554),
which were visualized by dipping them into a solution of ceri-
um(IV) sulfate (1 g), ammonium molybdate (21 g), concd H2SO4
(31 mL), and H2O (made up to 500 mL); the TLC plates were later
heated to 100 °C. Silica-gel column chromatography was per-
formed using silica gel (100–200 mesh) purchased from Acme (In-
dia).
The procedure presented herein offers an inexpensive and
convenient method to obtain optically pure and differen-
tially protected erythritol derivative 2, a potential C4
chiral building block. The route also has considerable
OH
O
O
O
O
2,2-DMP, (CH3)2CO
HO
HO
O
CH3OH, p-TSOH⋅H2O
OCH3
OH
O
40 h
O
OH
5
4
Methyl 2-deoxy-3,4:5,6-di-O-isopropylidene-D-gluconoate (7)
To a solution of a-hydroxy ester 59b (10 g, 34.48 mmol) in CH2Cl2
(50 mL) at 0 °C, PPh3 (20.95 g, 79.96 mmol) was added portionwise
over 10 min. After the complete dissolution of PPh3, imidazole
(2.57 g, 37.79 mmol) followed by CCl4 (19.2 mL, 206.88 mmol)
were added. The temperature of the reaction mixture was gradually
raised to r.t. (27–30 °C) and stirring was continued for 5 h. The re-
action mixture was concentrated by removal of the solvent at re-
duced pressure and the residue was purified by silica-gel column
chromatography (EtOAc–hexane, 9.5:0.5) to afford a-chloro ester 6
as a colorless oil (9.0 g, 85%).
CCl4, Ph3P,
imidazole
CH2Cl2, 6 h
NaOAc, H2, 10% Pd/C
in CH3OH, 14 h
O
O
O
O
O
O
O
O
OCH3
OCH3
H
Cl
O
O
7
6
77% over 3 steps
cf Ref 9a
To a solution of the a-chloro ester 6 (5 g, 16.23 mmol) in MeOH (30
mL) at r.t. (ca 27–30 °C), was added NaOAc (4.92 gm, 60 mmol)
and Pd/C (10%, 0.400 g). The reaction mixture was subjected to hy-
drogenation at r.t. and a pressure of 50 psi. After 6 h MeOH was
evaporated and EtOAc (50 mL) was added to the residue and the Pd/
C removed by filtration. The EtOAc layer was washed with H2O
(2 × 15 mL) and dried over anhyd Na2SO4. The residue obtained af-
ter concentration was purified by a silica-gel column chromatogra-
phy (EtOAc–hexane, 9:1), to afford pure 2-deoxy ester 7 as a low
melting solid (3.62 g, 82%).
NaOtBu, anhyd DMF
–40 °C, 45 min
O
O
O
O
BnBr, –40 °C to r.t.
O
O
OCH3
OCH3
or
aq acid
O Na
OR
8
1H NMR (400 MHz, CDCl3): d = 1.33, 1.37, 1.38, 1.39 (12 H, 4 s,
4 × CH3), 2.58 (1 H, dd, J = 15.6, 8.8 Hz, O=CCHH), 2.84 (1 H, dd,
J = 15.9, 3.2 Hz, O=CCHH), 3.59 (1 H, dd, J = 7.8, 8.3 Hz, CO-
CHOCO], 3.72 (3 H, s, OCH3), 3.95 (1 H, dd, J = 8.8, 4.9 Hz, CHH-
3 (50%) R = Bn
9 (85%) R = H
Scheme 29a
Synthesis 2005, No. 13, 2267–2269 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (2S,3R)-2-O-Benzyl-3,4-O-isopropylidene-D-erythritol
2269
CHO), 4.04 (1 H, m, CH2CHO), 4.14 (1 H, dd, J = 8.5, 6.1 Hz,
CHHCHO), 4.34 (1 H, td, J = 8.3, 2.9 Hz, CHOCH2C=O).
Rf 0.6 (hexane–EtOAc, 1:1); [a]D27 +21.7 (c 1, CHCl3) [Lit.11 –22.0
(c 1, CHCl3), ent-2].
13C NMR (100 MHz, CDCl3): d = 25.1, 26.6, 26.9, 27.0 (4 × CH3),
38.3 (CH2C=O), 51.7 (OCH3), 67.7 (CH2), 76.64 (COCOCO), 76.6
(CH2CO), 80.3 (COCH2C=O), 109.5, 109.6 [C(CH3)2], 171.0
(C=O).
IR (neat): 2936, 3456 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35, 1.42 (6 H, 2 s, 2 × CH3), 2.13
(1 H, br s, OH), 3.50–3.54 (1 H, m, CHOBn), 3.69–3.71 (1 H, m,
CHHOH), 3.81–3.84 (1 H, m, CHHOH), 3.88 (1 H, dd, J = 8.3, 5.9
Hz, CHHCH), 4.08 (1 H, dd, J = 8.3, 6.8 Hz, CHHCH), 4.16–4.19
(1 H, m, CHO), 4.63 (1 H, d, J = 11.7 Hz, CHHC6H5), 4.67 (1 H, d,
J = 11.7 Hz, CHHC6H5), 7.31–7.37 (5 H, m, ArH).
Methyl 4-O-Benzyl-5,6-O-isopropylidene-D-erythro-(E)-2-hex-
enoate (3)
To a solution of 2-deoxy ester 79a (0.548 g, 2 mmol), in anhyd DMF
(3 mL) under a nitrogen atmosphere cooled to –78 °C, was added
dropwise a solution of t-BuONa (0.230 g, 2.4 mmol) in anhyd DMF
(3 mL). The mixture was stirred at the same temperature for 30 min,
and later quenched with BnBr (0.354 mL, 3 mmol). The tempera-
ture of the reaction mixture was gradually raised to r.t. (27–30 °C)
and allowed to stir at this temperature for 8 h. Then the reaction
13C NMR (100 MHz, CDCl3): d = 25.1, 26.5 (2 × CH3), 61.6
(CH2O), 66.8 (CH2OH), 72.6 (CH2C6H5), 75.5 (CHO), 79.6
(CHOBn), 109.2 [C(CH3)2], 127.8, 128.3, 128.5, 137.8 (ArC).
HRMS: m/z calcd for C14H20O4: 252.136159; found: 252.135781.
mixture was poured into a solution of sat. NH4Cl (15 mL). The aq Acknowledgment
solution was extracted with Et2O (4 × 10 mL), and the combined or-
We thank DST, New Delhi, for the funding towards the project [SP/
ganic layers were washed with H2O (10 mL), dried over anhyd
Na2SO4, and evaporated to obtain a residue, which was purified by
silica-gel column chromatography (EtOAc–hexane, 0.5:9.5) to af-
ford pure 3 as a colorless oil (0.310 g, 50%).
S1/G-06/2000]. We also thank DST, New Delhi for the funding to-
wards the 400 MHz NMR machine, for the Department of Chemi-
stry, IITMadras under the IRPHA scheme.
Rf 0.75 (hexane–EtOAc, 9:1); [a]D25 +18.6 (c 1, CHCl3).
References
IR (neat): 2976, 1724, 1657, 1449, 1372 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33, 1.41 (6 H, 2 s, 2 × CH3), 3.76
(3 H, s, OCH3), 3.87–3.90 (1 H, m, CHHCO), 3.91–3.95 (1 H, m,
CHOBn), 4.02–4.04 (1 H, m, CHHCO), 4.07– 4.11 (1 H, m,
CHOBnCHO), 4.42 (1 H, d, J = 11.7 Hz, CHHC6H5), 4.64 (1 H, d,
J = 11.7 Hz, CHHC6H5), 6.12 (1 H, d, J = 15.0 Hz, COCH=CH),
6.92 (1 H, dd, J = 15.0, 6.0 Hz, CH=CH), 7.26–7.35 (5 H, m, ArH)
(1) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in
Enantioselective Syntheses; VCH-Wiley: New York, 1997,
313.
(2) Williams, D. R.; Moore, J. L.; Yamada, M. J. Org. Chem.
1986, 51, 3916.
(3) Dondoni, A.; Orduna, J.; Merino, P. Synthesis 1992, 201.
(4) Arroyo-Gómez, Y.; Rodriguez-Amo, J. F.; Santos-Garcia,
M.; Sanz-Tajedor, M. A. Tetrahedron: Asymmetry 2000, 11,
789.
(5) (a) DeLuchi, O.; Miotti, U.; Modena, G. Org. React. (N.Y.)
1991, 40, 157. (b) Moiseenkov, A. M.; Dragan, V. A.;
Veselovskii, V. V. Russ. Chem. Rev. 1991, 60, 643.
(6) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57,
468.
(7) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.;
Mikkilineni, A. B.; Wu, D. C.-J.; Sai Baba, R.; Panzica, R.
P. J. Org. Chem. 1988, 53, 2598.
(8) Flasche, M.; Scharf, H.-D. Tetrahedron: Asymmetry 1995, 6,
1543.
(9) (a) Regeling, H.; Chittenden, G. J. F. Recl. Trav. Chim.
Pays-Bas 1989, 108, 330. (b) Regeling, H.; Rouville, E. D.;
Chittenden, G. J. F. Recl. Trav. Chim. Pays-Bas 1987, 106,
461.
(10) Rauter, A. P.; Fernandes, A. C.; Figueiredo, J. A. J.
Carbohydr. Chem. 1998, 17, 1037.
(11) Flasche, M. PhD Thesis; RWTH Aachen: Germany, 1995.
13C NMR (75 MHz, CDCl3): d = 25.1, 26.6 (2 × CH3), 51.7 (OCH3),
66.7 (CH2), 71.7 (CH2C6H5), 76.64 (COBn), 78.8 (COBnCO),
109.8 [C(CH3)2], 123.6 (C=OCH=CH), 127.9, 128.5 and 137.4
(ArC), 145.0 (CH=CH), 166.3 (C=O).
2-O-Benzyl-3,4-O-isopropylidene-D-erythritol (2)
A solution of the ester 3 (306 mg, 1 mmol) in anhyd CH2Cl2 (5 mL)
was cooled to –78 °C and flushed with N2. Ozone gas was bubbled
through the solution until a pale blue color remained. Stirring was
continued for 10 min; a solution of Ph3P (288 mg, 1.1 mmol) in
CH2Cl2 (5 mL) was added at the same temperature. After 15 min,
MeOH (2 mL), and NaBH4 (43.2 mg, 1.2 mmol) were added at
–78 °C. The temperature was raised to r.t. (27–30 °C) and stirring
was continued at this temperature for 1 h. The organic solvents were
evaporated, and H2O (15 mL) was added. The pH of the aqueous
layer was adjusted to pH 7 by dropwise addition of HOAc. The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the com-
bined organic layers were dried over anhyd Na2SO4 and evaporated
to obtain a residue, which was purified by silica-gel column chro-
matography (hexane–EtOAc, 8.5:1.5) to afford pure 2 as a colorless
oil (0.163 g, 65%).
Synthesis 2005, No. 13, 2267–2269 © Thieme Stuttgart · New York