Enantioselective approach to polyhydroxylated compounds using chiral sulfoxides: Synthesis of enantiomerically pure myo-inositol and pyrrolidine derivatives

Article abstract of DOI:10.1021/jo9811569

A short enantioselective Synthesis of the biologically important myo- inositol derivative I and the pyrrolidine derivative II is described. The molecule 3, a diketo disulfoxide readily made from tartaric acid, is the key intermediate. The sulfinyl group controlled completely the very high stereoselection observed.

Full text of DOI:10.1021/jo9811569

8918
J . Org. Chem. 1998, 63, 8918-8921
En a n tioselective Ap p r oa ch to P olyh yd r oxyla ted Com p ou n d s Usin g
Ch ir a l Su lfoxid es: Syn th esis of En a n tiom er ica lly P u r e
m yo-In ositol a n d P yr r olid in e Der iva tives
Franc¸oise Colobert,*,† Ame´lia Tito,*,‡ Noureddine Khiar,*,§ Donatienne Denni,†
Maria Angeles Medina,‡ Manuel Martin-Lomas,§ J ose´-Luis Garcia Ruano,‡ and
Guy Solladie´*,†
Ecole Europe´enne de Chimie, Polyme`res et Mate´riaux, Universite´ Louis Pasteur, Laboratoire de
Ste´re´ochimie associe´ au CNRS, 1 rue Blaise Pascal, 67008-Strasbourg, France, Departamento de Qu´ımica
Orga´nica, Universidad Autonoma de Madrid, Cantoblanco, 28049-Madrid, Spain, and Instituto de
Investigaciones Quimicas, CSIC c/ . Ame´rico Vespucio, s/ n Isla de la Cartuja, 41092-Sevilla, Spain
Received J une 16, 1998
A short enantioselective synthesis of the biologically important myo-inositol derivative I and the
pyrrolidine derivative II is described. The molecule 3, a diketo disulfoxide readily made from tartaric
acid, is the key intermediate. The sulfinyl group controlled completely the very high stereoselection
observed.
The increasing evidence indicating that oligosaccha-
rides play a pivotal role in important biological events
such as cell-cell communication and cell-mediated pro-
cesses has led to considerable interest in carbohydrates
and their analogues.1
The necessity for new preparations of enantiomerically
pure myo inositol derivatives such as I2a (Figure 1) arose
from the discovery of the phophoinositide pathway,3 a
new signal transduction system. Moreover, it has re-
cently been postulated that a family of uncharacterized
inositol phosphoglycans (IPG) bears the partial structure
of putative modulators involved in the cellular response
to insulin4,5 as the second messenger.
Compound II2b (Figure 1) belongs to the family of the
so-called azasugars, which are among the most powerful
glycosidase inhibitors and are potential chemotherapeutic
agents for the treatment of diabetes, cancer, or viral
replication, including the human immunodeficiency virus
(HIV).6
F igu r e 1.
and used a Sharpless epoxidation to create the two last
chiral hydroxylic centers.7d The aza-sugar II was also
synthesized from L-sorbose,8a D-glucose,8b and D-mannitol.8c
There is no report of a total synthesis for this compound.
We report in this paper a short enantioselective
synthesis of the two carbohydrate mimics I and II.
Our approach to cyclitols and azasugars is based on
the use of chiral sulfoxides in an efficient enantioselective
synthesis of the intermediate alditols 6 and 6′9 from D-
(-)- and L-(+)-dimethyl 2,3-O-isopropylidenetartrate.
Condensation of the anion of (-)-(S)-methyl p-tolyl sul-
foxide 2 with the readily available D-(-)-tartrate 1 led
to the â-diketo sulfoxide 3 in 76% yield (Scheme 1).
DIBAL reduction of 3 yielded the C2-symmetric dihydroxy
sulfoxide 4 as a single isomer, as shown by 1H NMR and
13C NMR of the crude product. The absolute configura-
tion of the newly created carbinols has been deduced from
our previous results with related systems.10 The large
nonequivalence (∆ν ) 64 Hz) of the two methylenic
protons R to the sulfinyl group was always observed for
myo-Inositol derivatives have already been prepared
by multistep syntheses from different carbohydrates:
D-glucurono-6,3-lactone,7a D-mannitol,7b and L-iditol.7c
Only one synthesis started from a tartaric acid derivative
† Universite´ Louis Pasteur.
‡ Universidad Autonoma de Madrid.
§ Instituto de Investigaciones Quimicas.
(1) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Furukawa, K.;
Kobata, A. In Carbohydrates: Synthetic Methods and Applications to
Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami, T., Eds.; VCH
Publishers: New York, 1992; pp 369-384. (c) Witczak, Z. J . In
Carbohydrates in Drug Designs; Witczak, Z. J ., Nieforth, K. A., Eds.;
Marcel Dekker: New York 1997; pp 1-37.
(2) Ogawa, S. In Carbohydrate mimics: Concepts and Methods;
Chapleur, Y., Ed.; wiley-VCH Publishers: Weinheim, 1998; pp 87-
106. (b) Depezay, J . C. Ibid. pp 307-326.
(3) Berridge, M. J . Nature 1993, 361, 315 and references therein.
(4) (a) Saltiel, A.; Cautrecasas, P. Proc. Natl. Acad. Sci. U.S.A. 1986,
83, 5793. (b) Mato, J . M.; Kelly, K. L.; Alber, A.; J anett, L. J . Biol.
Chem. 1987, 233, 2131. (c) Larner, J .; Huang, L. C.; Schwartz, C. F.
W.; Oswald, A. S.; Shen, T. Y.; Kinter, M.; Tang, G.; Zeller, K. Biochem.
Biophys. Res. Commun. 1988, 155, 1416.
(5) Khiar, N.; Martin-Lomas, M. In Carbohydrate mimics: Concepts
and Methods; Chapleur, Y., Ed.; Wiley-VCH Publishers: Weinheim,
1998; pp 443-462 and references therein.
(6) (a) Asano, N.; Oseki, K.; Kizu H.; Matsui, K. J . Med. Chem. 1994,
37, 3701. (b) Elbein, A. D. Semin. Cell Biol. 1991, 2, 309. Elbein, A. D.
Annu. Rev. Biochem. 1987, 56, 497.
(7) (a) Watanabe, Y.; Mitani, M.; Ozaki, S. Chem. Lett. 1987, 123.
(b) Chiara, J . L.; M. Martin-Lomas, M. Tetrahedron Lett. 1994, 35,
2969. (c) Guidot, J . P.; Le Gall, T.; Mioskowski, C. Tetrahedron Lett.
1994, 34, 6671. (d) Sawada, T.; Shirai, R.; Iwasaki, S. Tetrahedron
Lett. 1996, 37, 885.
(8) (a) Card, P. J .; Hitz, W. D. J . Org. Chem. 1985, 50, 891. (b) Fleet,
G. W. J .; Smith, P. W. Tetrahedron 1987, 43, 971. (c) Dureault, A.;
Portal, M.; Depezay, J . C. Synlett 1991, 225.
(9) Schreiber, S. L. Chem. Scr. 1987, 27, 563.
(10) (a) Solladie´, G. Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435. (b) Carren˜o, M. C.; Garcia Ruano, J . L.; Martin, A.; Pedregal,
C.; Rodriguez, J . H.; Rubio, A.; Sanchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120. (c) Solladie´-Cavallo, A.; Suffert, J .; Adib, A.; Solladie´,
G. Tetrahedron Lett. 1990, 31, 6649. (d) Solladie´, G.; Huser, N.; Garcia
Ruano, J . Adrio, J . L.; Carren˜o, M. C.; Tito, A. Tetrahedron Lett. 1994,
35, 5297.
10.1021/jo9811569 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/05/1998

Synthesis of Pure myo-Inositol and Pyrrolidine
J . Org. Chem., Vol. 63, No. 24, 1998 8919
Sch em e 1
Sch em e 2
prepared from 6′ in four steps (Scheme 2): acetonide
hydrolysis with acidic resin, followed by complete protec-
tion of the resulting tetrol with methoxymethyl chloride
affording the 2,5-di-O-benzyl-D-iditol derivative 7 in 65%
overall yield. Debenzylation of 7 with Pearlman catalyst
in methanol followed by dimesylation of the resulting diol
gave 8 in 80% overall yield. Stereoselective cyclization
to the azasugar 9 was carried out by heating the
dimesylate 8 in benzylamine at 120 °C for 18 h. The
displacement reaction occurred with complete inversion
of configuration8c at C-2 and C-5 leading to 2,5-dideoxy-
2,5-(N-benzylimino)-1,3,4,6-tetrakis-O-(methoxymethyl)-
D-iditol 9 in 70% yield. Removal of MOM groups followed
by debenzylation using Pearlman catalyst in acetic acid
gave, after neutralization and purification by ion-
exchange chromatography, 2(S),5(S)-bis(hydroxymethyl)-
3(S),4(S)-dihydroxypyrrolidine II (63% yield), showing all
the described characteristics8a,b of the known enantiomer
a (SS,2R) relative configuration. Bisprotection of the diol
4 was achieved with sodium hydride and benzyl bromide
in DMF to give the compound 5 in 80% yield. One-pot
Pummerer rearrangement11 using trifluoroacetic anhy-
dride at 0 °C and sodium borohydride reduction led to
the optically pure L-iditol derivative 6 in 80% yield.
The same reaction sequence (Scheme 2) from L-(+)-
diethyl 2,3-O-isopropylidenetartrate and (R)-(+)-methyl
p-tolyl sulfoxide afforded the optically pure D-iditol
derivative 6′. Thus, both L and D isomers of iditol
derivatives 6 and 6′ are obtained in 38% overall yield, in
only three steps from a dimethyl tartrate derivative.
Finally, a one-pot reaction including Swern oxidation
of the diol 6 to the dialdehyde followed by SmI2-promoted
pinacol coupling12 led to the cis-diol I13 in 60% yield
(Scheme 1, 22% overall yield in five steps).
of II and an opposite optical rotation [R]22 -54 (c 0.3,
D
H2O) [lit.8a,b [R]22 +53.8 (c 0.3, H2O)].
D
In conclusion, these results provide an efficient and
short enantioselective synthesis of L- and D-iditol deriva-
tives 6 and 6′. The same procedure can be easily applied
to the preparation of all the stereoisomers of the alditols
intermediates just by changing the absolute configuration
of the starting sulfoxide and tartrate.
The pyrrolidinic compound II was obtained by cycliza-
tion with benzylamine of the mesylate 8, which was
Exp er im en ta l Section
(11) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, M.; Zanda,
S. V.; Gavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61, 3375.
(12) For the use of SmI2 pinacol coupling in the synthesis of cyclitols
see ref 7b and: Kornienko, A.; D’Alarcao, M. Tetrahedron Lett. 1997,
35, 6497, and references therein.
(-)-[3(S),3′(S),S(S)]-1,1′-Di-p-tolylsu lfin yl-3,3′-isop r op y-
lid en ed ioxy-2,2′-h exa n ed ion e (3). To a solution of 1.14 mL
(4 equiv, 8.12 mmol) of diisopropylamine in 10 mL of THF was
added 5.24 mL of BuLi, 1.55 M in hexane (8.12 mmol, 4 equiv)
at -78 °C under argon. The solution was stirred for 30 min,
1.25 g (4 equiv, 8.12 mmol) of (-)-(S)-methyl p-tolyl sulfoxide
2 in 10 mL of THF was dropwise added, and immediately after
the addition the temperature was raised to -40 °C. Stirring
was continued for 30 min, and then the reaction mixture was
cooled again to -78 °C and 500 mg (2.03 mmol, 1 equiv) of
D-(-)-isopropylidenedimethyl tartrate 1 in 10 mL of THF was
added. After 2 h at -78 °C, the reaction was quenched with
saturated NH4Cl and extracted several times with AcOEt. The
(13) D-myo-Inositol derivative I: 1H NMR (200 MHz, CDCl3) δ 7.3
(m, 10H, arom), 4.83 (AB system, 2H, J AB ) 23.8 Hz, ∆ν ) 47.8 Hz,
CH2Ph), 4.79 (AB system, 2H, J AB ) 11.9 Hz, ∆ν ) 32.5 Hz, CH2Ph),
4.24 (br td, 1H, J ) 3.5, 1.5 Hz, H-2), 4.06 (t, 1H, J ) 10 Hz, H-4),
3.82 (dd, 1H, J ) 8.5, 10 Hz, H-6), 3.61 (dd, 1H, J ) 10 Hz, H-3), 3.58
(td, 1H, 8.5 Hz, J ) 3.5 Hz, H-1), 3.39 (t, 1H, J ) 10 Hz), 2.65 (d, 1H,
J ) 8.5 Hz, OH), 2.62 (d, 1H, J ) 1.5 Hz, OH), 1.49 (s, 3H, CH3), 1.47
(s, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ 138.44, 137.97, 128.61,
128.51, 128.05, 127.83, 127.09 (arom), 112.02, 79.4, 78.25, 77.67, 76.52,
73.6, 73.06, 71.83, 27.15, 27.10. The coupling constants of the cyclic
protons are identical to those of the known D-myo-inositol derivative7b
in which the benzyl protecting group was replaced by a TBDPS group.

8920 J . Org. Chem., Vol. 63, No. 24, 1998
Colobert et al.
organic layer was washed with HCl 10% and brine and dried
over MgSO4. Filtration and evaporation gave a white solid,
which was washed with Et2O to give the desired product 3 in
70% yield: mp 126 °C; [R]D ) -303 (c ) 2.0, CHCl3); 1H NMR
(200 MHz, CDCl3) δ 7.32-7.59 (AB system, 8H, J AB ) 8.2 Hz,
∆ν ) 29 Hz), 3.48 (X part of an ABX system, m, 2H), 2.38 (m,
2H), 1.43 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 138.07, 128.55,
128.10, 127.96, 109.54, 77.65, 77.16, 72.61, 61.93, 27.04. Anal.
Calcd for C27H30O6: C, 68;00. H, 7.50. Found: C, 67.56; H,
7.38.
∆ν ) 41 Hz), 4.61 (s, 2H, H-3), 4.08 (AB system, 4H, J AB
)
3,6-Di-O-ben zyl-4,5-O-isop r op ylid en e-m yo-in ositol (I).
To a solution of oxalyl chloride (50 mL, 0.57 mmol, 2.3 equiv)
in dry THF (1.5 mL) was added dimethyl sulfoxide (84 mL,
1.19 mmol, 4.8 equiv) at -60 °C under argon. After 15 min,
a solution of diol 6 (100 mg, 0.25 mmol, 1 equiv) in THF (2
mL) was added dropwise. After an additional 30 min, diiso-
propylamine (0.435 mL, 2.5 mmol, 10 equiv) was added and
the reaction warmed to 0 °C during 2 h. The solution was
diluted with THF (6.5 mL), cooled to -25 °C, and treated with
a freshly prepared 0.1 M solution of SmI2 (7.5 mL, 0.75 mmol)
and tert-butyl alcohol (70 mL, 0.75 mmol). The reaction
mixture was allowed to warm to room temperature during 3
h, stirred for another 12 h, and then hydrolyzed with saturated
NaHCO3. AcOEt (10 mL) was added, the reaction mixture was
stirred vigorously for 30 min, the aqueous layer was extracted
several times with AcOEt, and the combined organic layers
were washed with brine, dried over MgSO4, and concentrated
under vaccuum. The crude product was purified by flash
chromatography (silica gel, EtOAc/hexane 1:1) to give a 60%
yield of the compound I as a white solid: mp 104-106 °C; [R]D
) -55 (c ) 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.3 (m,
10H), 4.83 (AB system, 2H, J AB ) 23.8 Hz, ∆ν ) 47.8 Hz), 4.79
(AB system, 2H, J AB ) 11.9 Hz, ∆ν ) 32.5 Hz), 4.24 (br td,
1H, J ) 3.5, 1.5 Hz), 4.06 (t, 1H, J ) 10 Hz), 3.82 (dd, 1H, J
) 8.5, 10 Hz), 3.61 (dd, 1H, J ) 3, 10 Hz), 3.58 (td, 1H, 8.5
Hz, J ) 3.5 Hz), 3.39 (t, 1H, J ) 10 Hz), 2.65 (d, 1H, J ) 8.5
Hz), 2.62 (d, 1H, J ) 1.5 Hz), 1.49 (s, 3H), 1.47 (s, 3H); 13C
NMR (50 MHz, CDCl3), δ 138.44, 137.97, 128.61 128.51,
128.05, 127.83, 127.09, 112.02, 79.4, 78.25, 77.67, 76.52, 73.6,
73.06, 71.83, 27.15, 27.10. Anal. Calcd for C23H28O6: C, 68.90;
H, 7.0.04. Found: C, 68.43; H, 6.95.
13.75 Hz, ∆ν ) 48 Hz), 2.42 (s, 6H), 1.33 (s, 6H); 13C NMR (50
MHz, CDCl3) δ 199.52, 142.59, 139.69, 130.29, 124.25, 113.39,
81.52, 64.88, 26.07, 21.58. Anal. Calcd for C23H26O6S2: C,
59.70; H, 5.60. Found: C, 59.72; H, 5.5.
(-)-[2(S),2′(S),3(R),3′(R),S(S)]-1,1′-Di-p -t olylsu lfin yl-
3,3′-isop r op ylid en ed ioxy-2,2′-h exa n ed iol (4). To a solution
of 0.25 g (0.54 mmol, 1 equiv) of the bisketo sulfoxide 3 in 9.5
mL of THF was dropwise added 1.62 mL (1.62 mmol, 3 equiv)
of a 1 M solution of DIBAH at -78 °C. When all the starting
material had disappeared according to TLC (hexane/EtOAc
2:8), the reaction mixture was quenched by addition of 0.85
mL of MeOH. After evaporation of the solvents, 13 mL of
EtOAc and 13 mL of sodium tartrate were added. The mixture
was stirred at room temperature for 30 min. The organic layer
was washed with brine, dried over MgSO4, filtrated, and
concentrated. The resulting solid was washed with acetone
to give 4 in 85% yield: mp 186 °C; [R]D ) -196 (c ) 2.0,
1
CHCl3); H NMR (200 MHz, CDCl3) δ 7.28-7.53 (AB system,
8H, J AB ) 9 Hz), 5.12 (d, 2H, J ) 6 Hz), 4.22-4.3 (X part of
an ABX system, m, 2H), 4.15 (s, 2H), 2.89-3.23 (AB part of
an ABX system, 4H, J AB ) 12.5 Hz, J AX ) 10 Hz, J BX ) 2.5
Hz, ∆ν ) 64 Hz), 2.4 (s, 6H), 1.4 (s, 6H); 13C NMR (50 MHZ,
CDCl3) δ 141.6, 140.00, 130.00, 124.00, 110.00, 63.46, 62.50,
63.46, 26.90, 21.50. Anal. Calcd for C23H30O6S2: C, 59.20; H,
6.48. Found: C, 58.91; H, 6.43.
(-)-[2(S),2′(S),3(R),3′(R),S(S)]-1,1′-Di-p -t olylsu lfin yl-
2,2′-d iben zyloxy-3,3′-isop r op ylid en ed ioxyh exa n e (5). To
a solution of 50 mg of the di-â-hydroxy sulfoxide 4 (0.107 mmol,
1 equiv) in 5 mL of dry THF were slowly added under argon
NaH (60 mg, 0.235 mmol, 2.2 equiv), tetrabutylammonium
iodide (7.9 mg, 0.0214 mmol), and benzyl bromide (0.1 mL,
0.235 mmol) at 0 °C. The reaction mixture was stirred at room
temperature until all the starting material had disappeared
(TLC, hexane/EtOAc 2/8) and hydrolyzed at 0 °C with satu-
rated NH4Cl. After extraction with AcOEt (3 × 5 mL), the
organic layer was washed with brine, dried over MgSO4, and
concentrated under vacuum. Flash column chromatography
(hexane/EtOAc 4:6) of the crude product gave 80% yield of the
product 5 as a yellow solid: mp 37-38 °C; [R]D ) -131 (c )
0.8, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.39 (m, 18H), 4.74
(AB system, 4H, J AB ) 11 Hz, ∆ν ) 33.8 Hz), 4.02-3.95 (m,
4H), 2.90 (d, 4H, J ) 6 Hz), 2.4 (s, 6H), 1.34 (s, 6H); 13C NMR
(50 MHz, CDCl3), δ 141.58, 141.05, 137.55, 130.14, 128.58,
128.30, 128.10, 123.96, 109.33, 74.31, 78.62, 72.53, 61.14,
27.08, 21.48. Anal. Calcd for C37H42O6S2: C, 68.69; H, 6.54.
Found: C, 68.88; H, 6.51.
(-)-(2R,5R)-Diben zyloxy-(3S,4S)-1,3,4,6-tetr a (m eth oxy-
m et h yl) h exa n e (7). (a) (-)-[2(R),2′(R),3(S),3′(S)]-2,2′-Di-
benzyloxy-3,3′-isopropylidenedioxy-1,1′-hexanediol (6′), enan-
tiomer of 6, was prepared by the same route from (+)-(R)-
methyl p-tolyl sulfoxide and l-(+)-Isopropylidenedimethyl
tartrate.
(b) To a solution of the acetonide 6′ (823 mg, 2.04 mmol) in
43 mL of methanol was added 930 mg of acidic resin (Dowex
50W-X8). The reaction mixture was stirred for 16 h under
reflux, filtered, and concentrated under reduced pressure. The
crude residue was purified either by crystallization from
AcOEt-hexane or by flash chromatography (silica gel, AcOEt/
hexane 5:1) to give (-)-2(R),5(R)-dibenzyloxy-3(S),4(S)-dihy-
droxy-1,6-hexanediol in 88% yield as a white solid: mp 83 °C;
[R]D ) -18 (c ) 1, acetone); 1H NMR (200 MHz, CDCl3) δ 7,3
(s, 10 H), 4.59 (AB system, J ) 11.6 Hz, 4 H), 3.97 (d, J ) 3.6
Hz, 2 H), 3.78 (AB part of an ABX system, J ) 12.3 Hz (AB),
J AX )3.6, J BX ) 3.7 Hz, 4 H), 3.53 (X part of an of ABX system,
J ) 3.6, 3.7 Hz, 2 H), 3.15 (br s, 4 H); 13C NMR (75 MHz,
CDCl3), δ 137.7, 128.6, 128.02, 128.01, 79.2, 71.9, 70.2, 60.5;
IR (CHCl3) ν 3400, 1450 cm-1. Anal. Calcd for C20H26O6: C,
66.28; H, 7.23. Found: C, 65.98; H, 7.53.
(+)-[2(S ),2′(S ),3(R ),3′(R )]-2,2′-Dib e n zyloxy-3,3′-iso-
p r op ylid en ed ioxy-1,1′-h exa n ed iol (6). To a solution of the
bis-sulfoxide 5 (200 mg, 0.31 mmol, 1 equiv) in 3 mL of
acetonitrile at 0 °C were added successively sym-collidine
(0.239 mL, 1.81 mmol, 5.85 equiv) and trifluoroacetic anhy-
dride (0.423 mL, 3.01 mmol, 9.71 equiv). The reaction was
stirred for 30 min and then hydrolyzed by addition of 1 mL of
water; the pH was then adjusted to 7 by addition of K2CO3,
and the temperature was raised to room temperature. After
30 min, the thioacetal intermediate was reduced by addition
of 71.65 mg (1.86 mmol, 6 equiv) of NaBH4, and stirring was
continued for 40 min. The reaction was quenched with
saturated NH4Cl. The aqueous layer was extracted with
AcOEt, and the combined organic layers were washed succes-
sively with 10 mL of 1 N HCl, 10 mL of saturated NaHCO3,
and finally with 20 mL of brine. After being dried over MgSO4,
the solution was concentrated under vacuum, and the crude
product was purified by flash chromatography (silica gel,
EtOAc/hexane 1:1) to give 80% of compound 6 as a white
(b) To a solution of the preceding diol (415 mg, 1.14 mmol)
in 10 mL of anhydrous CH2Cl2 were added N,N-diisopropyl-
ethylamine (1.6 mL, 9.20 mmol) and chloromethyl methyl
ether (1.7 mL, 22.92 mmol). After being stirred for 3 h at rt
under argon, the reaction mixture was diluted with CH2Cl2,
and saturated aqueous NaHCO3 (250 mL) at 0 °C was added.
After extraction with CH2Cl2, the combined organics were
dried over MgSO4, filtered and, concentrated in vacuo. The
residue was purified by silica gel column chromatography
(AcOEt/hexane 4:5) to afford a 92% yield of compound 7 as a
colorless oil: [R]D ) -27.5 (c ) 2, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 7.30 (s, 10 H), 4.78 (AB, J ) 7 Hz, 4 H), 4.62 (s, 4 H),
4.63 (AB, J ) 11.7 Hz, 4 H), 3.94 (d, J ) 1.6 Hz, 2 H), 3.75 (s,
6 H), 3.37 (s, 6 H), 3.35 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ
137.6, 127.6, 127.3, 126.9, 97.98, 96.02, 77.7, 75.7, 72.2, 66.9,
1
solid: mp 52 °C; [R]D ) +21 (c ) 2.0, CHCl3); H NMR (200
MHz, CDCl3) δ 7.3 (m, 10H), 4.64 (AB system, 4H, J AB ) 12
Hz, ∆ν ) 24 Hz), 4.27 (dd, 2H, J ) 2, 1 Hz), 3.76 (AB part of
an ABX system, 4H, J AB ) 13 Hz, J AX ) 4.3 Hz, J BX ) 4.8 Hz,
55.6, 54.5; IR (CHCl3) ν 2890, 1595, 1450, 1115, 1035 cm-1
(+)-(3S,4S)-1,3,4,6-Tet r a (m et h oxym et h yl)-2(R),5(R)-
.

Synthesis of Pure myo-Inositol and Pyrrolidine
J . Org. Chem., Vol. 63, No. 24, 1998 8921
d im eth a n esu lfon ylh exa n e (8). (a) A solution of compound
7 (550 mg, 1 mmol) in methanol (180 mL) was debenzylated
with H2 over 20% Pd(OH)2 (0.39 mmol) at atmospheric
pressure for 3 h. The mixture was filtered through Celite, and
the solvent was evaporated in vacuo. The remaining residue
was purified by silica gel chromatography with AcOEt as
eluent, affording 85% of (-)-(3S,4S)-1,3,4,6-tetra(methoxy-
methyl)-2(R),5(R)-hexanediol as a colorless oil: [R]D ) -9.7 (c
MHz,CDCl3) δ 7.29 (m, 5 H), 4.7 (AB, J ) 6.5 Hz, 4 H), 4.58
(s, 4 H), 4.1 (d, J ) 4.3 Hz, 2 H), 3.97 (AB, J ) 14.5 Hz, 2 H),
3.65 (AB, J ) 11 Hz, 4 H), 3.36 (s, 6 H), 3.32 (s, 6 H), 3.20 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 139.5, 128.2, 128.1, 126.7,
96.6, 95.7, 83.3, 66.4, 65.4, 55.4, 55.2, 51.6; HRMS calcd for
C
21H35NO8H+ [M + H+] 430.2441, found 430.2433.
(-)-2(S),5(S)-Bis(h yd r oxym eth yl)-3(S),4(S)-d ih yd r oxy-
p yr r olid in e (II). (a) To remove the MOM protecting groups,
the pyrrolidine 9 (119 mg, 0.27 mmol) was dissolved in
trifluoroacetic acid (4 mL) and 0.1 mL of water was added.
The reaction mixture was stirred for 7 h at rt, and then
solvents were evaporated at reduced presure. The remaining
residue was chromatographed (Dowex 1 × 8-200 ion-exchange
resin and eluted with water); after evaporation of solvent in
vacuo, the product was purified by flash chromatography (silica
gel, AcOEt/methanol 12:1) to afford 70% of (+)-N-benzyl-2(S),5-
(S)-bis(hydroxymethyl)-3(S),4(S)-dihydroxypyrrolidine as a col-
orless oil: [R]D ) +20 (c ) 0.35, CH3OH); 1H NMR (200
MHz,CD3OD) δ 7.34 (m, 5 H), 4.02 (AB, J ) 4.5 Hz, 2 H), 4.01
(dd, J ) 8.6, 2.7 Hz, 2H), 3.69 (AB of ABX, J ) 11.3, 3.2, 4.8
Hz, 4 H), 3.07 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 141.3,
129.3, 127.8, 80.6, 71.1, 61.6, 52.6; HRMS for C13H19NO4H+
[M + H+] calcd 254.1392, found 254.1387.
1
) 0.65, CHCl3); H NMR (200 MHz, CDCl3) δ 4.72 (AB, J )
7.1 Hz, 4 H), 4.64 (s, 4 H), 4.14 (t, J ) 6.3 Hz, 2 H), 3.84 (s, 2),
3.52 (d, J ) 6.3 Hz, 4 H), 3.63 (s, 6H), 3.39 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 97.7, 96.4, 76.9, 68.8, 67.5, 55.84, 55.0; IR
(CHCl3), ν 3380 cm-1; HRMS for C14H30O10H+ [M + H+] calcd
359.1917, found 359.1930
(b) To a solution of the preceding diol (226 mg, 0.63 mmol)
in 8 mL of anhydrous CH2Cl2 was added triethylamine (229
mL, 1.64 mmol). The solution was cooled to 0 °C, and
methanesulfonyl chloride (107 mL, 1.39 mmol) was added
dropwise. The mixture was allowed to stir at 0 °C for 30 min
and then poured into 1 N HCl at 0 °C. The layers were
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with saturated
NaHCO3 and brine. After drying (MgSO4), the solution was
concentrated in vacuo. The crude residue was purified by silica
gel chromatography (AcOEt/hexane 2:1) to give the bis-
mesylate 8 in 94% yield as a colorless oil: [R]D ) +5 (c ) 1.5,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 5.08 (m, 2 H), 4.75 (AB
system, J ) 6.45 Hz, 4 H), 4.64 (AB, J ) 7 Hz, 4 H), 3.91 (AB
system, J ) 2.7 Hz, 4 H), 3.89 (s, 2 H), 3.42 (s, 6 H), 3.36 (s,
6 H), 3.10 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 98.8, 96.4,
80.8, 75.8, 66.6, 56.6, 55.5, 38.5; IR (CHCl3) ν 2900, 1200, 980,
770 cm-1; HRMS for C16H34O14S2Na+ [M + Na+] calcd 537.1288,
found 537.1286.
(b) A solution of the preceding N-benzylpyrrolidine (26 mg,
0.15 mmol) in acetic acid (15 mL) was debenzylated with H2
over 20% Pd(OH)2 (20 mg) at atmospheric pressure for 3 h.
The mixture was filtered through Celite, and the solvent was
evaporated in vacuo. The crude residue was purified by ion-
exchange chromatography Dowex 1 × 8-200 and then eluted
with methanol to give II in 90% yield as a colorless solid: [R]D
) -54.3 (c ) 0.3, H2O) [lit.8a,b ent-II [R]D ) +53.8 (c ) 0.3,
H2O)]; 1H NMR (200 MHz, D2O) δ 3.78 (dt, 2 H), 3.6, 3.5 (2dd,
4 H), 3.08 (m, 2 H); 13C NMR (75 MHz, D2O) δ 79.5, 65.4, 63.4.
(+)-N-Ben zyl-3(S),4(S)-d i(m et h oxym et h yl)-2(S),5(S)-
bis[(m eth oxym eth yl)m eth yl]p yr r olid in e (9). The dimes-
ylated compound 8 (290 mg, 0.56 mmol) and benzylamine (12
mL, 110 mmol) were heated to 120 °C for 18 h. The excess of
benzylamine was removed by distillation (bp 73 °C, 18 mmHg).
The remaining residue was purified by silica gel chromatog-
raphy (AcOEt/hexane 3:5) to afford 56% of the pyrrolidine 9
Ack n ow led gm en t. This research was supported by
CNRS as a part of an international program (PICS 537)
and the Direccio´n General de Investigacio´ Cientifica y
Te´cnica (grant no. PB 96-0820 and PB 95-0210).
1
as a colorless oil: [R]D ) +33 (c ) 0.5, CHCl3); H NMR (200
J O9811569