General method for the synthesis of chiral 2,3-bisarylmethoxy-1,4- butanediols from L-(+)-tartrate

Article abstract of DOI:10.1055/s-2004-815997

Various (2S,3S)-23-bisarylmethoxy-1,4-butanediols 3a-h were synthesized from L-(+)-tartrate through bisallylether 12. Protection of the primary alcohol as an allyl ether was essential for selective deprotection in the presence of reactive arylmethyl ether

Full text of DOI:10.1055/s-2004-815997

960
FEATURE ARTICLE
General Method for the Synthesis of Chiral 2,3-Bisarylmethoxy-1,4-
Butanediols from L-(+)-Tartrate
S
ynthesis of Chir
i
al 2,3-B
i
isarylm
c
ethoxy-1,
h
4-Butanediol
i
s
f
rom
r
L
-(+)-T
a
o
rtarate Tsuji, Shigeru Arai, Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax +81(43)2902909; E-mail: nishida@p.chiba-u.ac.jp
Received 28 November 2004
HO
OH
Abstract: Various (2S,3S)-2,3-bisarylmethoxy-1,4-butanediols 3a–
h were synthesized from L-(+)-tartrate through bisallylether 12.
Protection of the primary alcohol as an allyl ether was essential for
selective deprotection in the presence of reactive arylmethyl ethers.
Ar
Ar
O
HO2C
CO2H
1
2
O
HO
OH
Key words: tartaric acid, allyl ether, catalyst, palladium, deprotec-
tion
HO
3a : Ar = Ph
OH
EtO2C
CO2Et
3b : Ar = 1-naphthyl
3c : Ar = 4-OMe-Ph
3d : Ar = 9-anthranyl
3e : Ar = 2,4,6-Me3-Ph
3f : Ar = 3,5-(CF3)2-Ph
3g : Ar = 2-CF3-Ph
Ar
Ar
O
Tartaric acid is one of the most useful and readily avail-
able chiral building blocks for asymmetric synthesis.1 In
fact, 3a derived from 1 has been used as an intermediate
in the synthesis of natural products,2 chiral ligands,3 and
catalysts.4 Recently, we developed a catalytic asymmetric
Michael reaction of glycine Schiff base 5 using novel
chiral quaternary salts 4 derived from 3a.4a In this reac-
tion, Michael adduct of glycine derivative 6 was isolated
O
N
3h : Ar = 2,3,4,5,6-F5-Ph
O
O
Br
Ar
Ar
4a : Ar = Ph
4b : Ar = 4-CF3-Ph
in up to 77% ee using 4b as a chiral catalyst (Scheme 1).4a Figure 1
We also found that 4b catalyzed enantioselective alkyla-
tion of 5 to give phenylalanine derivative 7 in up to 57%
were not shown to be applicable to other substrates. We
prepared 3a from 2 according to Yamamoto’s procedure
for the synthesis of novel PTCs.4a Although this method is
facile and efficient, the reaction is highly dependent on the
structure of the alkylating agents, and attempts to produce
3b and 3c were unsuccessful, and gave either a messy or
no reaction. Moreover, forced conditions would promote
undesired racemization or b-elimination. Therefore, a fac-
ile and general method for the preparation of 3 is required.
We report here a new method for the synthesis of chiral 3
from 2.
ee.4b The substituent on the aromatic rings of 4 dramati-
cally influenced the reaction time and ee in these reac-
tions.
However, despite its utility, only two methods have been
reported for the preparation of 3a. Seebach reported the
use of thallium alkoxide as a base for the O-alkylation of
2, though its high toxicity is problematic.5a Yamamoto de-
scribed the preparation of 3a using sodium hydroxide in
the presence of Bu4NI and 18-crown-6.5b Although, this
method seemed to be quite practical, these conditions
asymmetric Michael addition
Ph
CO2-t-Bu
CO2-t-Bu
4a or 4b (10 mol%)
H2C=CHCO2-t-Bu
Ph
N
6
CsOH•H2O
t-BuOMe, -60 °C
using 4a : 87%, 73% ee (70 h)
using 4b : 73%, 77% ee (26 h)
Ph
Ph
N
CO2-t-Bu
asymmetric alkylation
5
Ph
Ph
4b (5 mol%)
BnBr
Ph
N
CO2-t-Bu
CsOH•H2O
7
t-BuOMe, -60 °C
21%, 57% ee (45 h)
Scheme 1
SYNTHESIS 2004, No. 6, pp 0960–0966
x
x
.
x
x
.2
0
0
4
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-815997; Art ID: F11603SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Synthesis of Chiral 2,3-Bisarylmethoxy-1,4-Butanediols from L-(+)-Tartrate
961
HO
OH
O
O
O
O
1) Allyl-Br
NaH, DMF
rt, 13 h
known(7)
PX, base
OH
O
O
2
PO
OP
HO
11
80%
(2 steps)
11
8a : P = TBS (78%)
8b : P = Tr (74%)
8c : P = TBDPS (94%)
8d : P = MPM (82%)
2) 1N HCl
THF-H2O
reflux, 9 h
12
94%
(2 steps)
H+
Scheme 3
Ar
O
Ar
HO
OH
ArCH2X, NaH
Initially, we chose chiral bis O-protected ethers (8) as a
common intermediate, which we prepared from 2 in 3
steps (Scheme 2). Unfortunately, the selective removal of
acetonide in 8a and 8b was unsuccessful under all of the
conditions tested. In the case of bis-TBDPS ether 8c,
deprotected 9c was obtained in 32% yield, but was found
to be unstable under subsequent alkylation conditions, re-
sulting in decomposition. Moreover, bis-MPM ether 10d
was found to be problematic with regard to the removal of
MPM groups because of the high reactivity of anthranyl
O
PO
OP
9a : P = TBS (0%)
9b : P = Tr (0%)
9c : P = TBDPS (32%)
9d : P = MPM (76%)
RO
OR
10d : Ar = 9-anthranyl
R = MPM (51%)
3d : Ar = 9-anthranyl
R = H (0%)
DDQ or
Pd/C-H2
Scheme 2
Biographical Sketches
Riichiro Tsuji was born in Tokyo, Ja- University (2001), working with finish in March 2004. His scientific
pan, in 1975. He received his B.S. Prof. Masako Nakagawa. He is now a interests include synthetic organic
from the Science University of To- graduate student of Pharmaceutical chemistry using organocatalysts and
kyo (1999) and his M.S. from Chiba Sciences, Chiba University and will transition metal catalysts.
Shigeru Arai was born in Sapporo, then received his PhD degree in (Prof. G. C. Fu) as a postdoctral fel-
Japan, in 1968. He received his B.S. 1998. In 1996, he started his academ- low (JSPS) during 1999–2000. His
at Hokkaido University (1992), ic career with Prof. Takayuki Shioiri research interests are concentrated on
where he worked with Prof. Masakat- at Nagoya City University and be- design and synthesis of a new phase-
su Shibasaki. He moved to graduate came an associate professor at Chiba transfer catalysts and its application
school of the University of Tokyo to University (Prof. Atsushi Nishida) in to the synthesis of biologically active
start rare earth metal chemistry under December 2001. He also spent time compounds.
the direction of Prof. Shibasaki and in the chemistry department at MIT
Atsushi Nishida was born in Muro- 1985. After spending one year, he at the Graduate School of Pharma-
ran, Japan in 1954 and received B.S. moved back to Hokkaido University ceutical Sciences in 2001. His re-
in 1976 and M.S. in 1978 from Hok- as an Assistant Professor in the Fac- search interests concern the total
kaido University. He joined Prof. ulty of Pharmaceutical Sciences. He synthesis of biologically active natu-
Ikegami’s group at Teikyo Universi- moved to Hokkaido College of Phar- ral products, development of useful
ty and received his PhD in 1985 from macy in 1990 as an Associate Profes- radical reactions, and asymmetric re-
Hokkaido University. Then he sor. He joined Professor Nakagawa’s actions.
moved to MIT (Prof. Rick L. Dan- group in Chiba University in1996
heiser) as a postdoctoral fellow in and was promoted to Full Professor
Synthesis 2004, No. 6, 960–966 © Thieme Stuttgart · New York

962
R. Tsuji et al.
FEATURE ARTICLE
Table 1 Alkylation of Diol 12 with Various Alkyl Halides
substituents with DDQ or Pd/C under H2. Finally, we
found that bis-allylether was quite stable under acidic and
basic conditions, and 116 was successfully converted to 12
in 94% yield (2 steps), as shown in Scheme 3. Next, we
examined the synthesis of 14 from 12 with various alkyl-
ating agents 13. After testing different solvents and tem-
peratures, we found that the reaction proceeded well in
DMF at room temperature. Under these mild conditions,
the alkylation reaction occurred to give 14 in excellent
yield without any side products. For example, benzylation
proceeded within 1.5 hours to give 14a in 95% yield (en-
try 1). Other arylmethyl halides such as 14b and 14c were
also converted into the corresponding bis-O-alkylated
products in yields of 94% and 92% respectively (entries 2
and 3). In particular, we were pleased to find that bulkier
reagents such as 13d and 13e, which were ineffective in
Yamamoto’s method, smoothly converted to give the de-
sired products 14d and 14e, at 50 °C. Electron-withdraw-
ing groups in the aromatic ring had no effect, and gave the
corresponding ethers in good to high yields (entries 6 and
7) except that pentafluorobenzylether (14h) was extreme-
ly unstable. These results are summarized in Table 1.
Entry Alkyl
Halide
Time
(h)
Temp
Product Yield
(%)a
BnBr
1
2
1.5
11
r.t.
r.t.
14a
14b
95
94
13a
Br
13b
Cl
3
5
r.t.
14c
92
OMe
13c
4
5
4
7
50 °C
50 °C
14d
14e
84
99
Cl
Cl
13d
Me
Me
Me
13e
6
11
r.t.
14f
75
Br
HO
OH
O
O
F3C
CF3
Ar
Ar
alkyl halide, NaH
DMF
13f
O
O
O
O
7b
8
1
50 °C
r.t.
14g
14h
70
27
F3C
12
Br
14
13g
Scheme 4
24
F
F
F
F
F
Finally, the deprotection of allyl groups was investigated.
To remove them clearly, it is essential to keep the reaction
media either neutral or basic because some arylmethyl
ethers are quite unstable under acidic conditions. An ini-
Br
13h
a Isolated yield.
b THF–DMF (2:1) was used as a solvent.
7
tial trial using NaBH4/I2 resulted in none of the desired
product.8 However, the deallylation 14a catalyzed by Pd
in the presence of K2CO3, as reported by Thayumanavan,9
proceeded to give exclusively 3a in 89% yield (entry 1).
No racemization was observed when the optical rotation
In conclusion, we have succeeded in establishing a gener-
al and efficient method for preparing various chiral diols
3a–h through bis-allylether 12 as a common intermediate.
The mildness and overall feasibility make this process
suitable for synthesizing a variety of 2,3-dialkoxy-1,4-bu-
tanediols. We have recently found that one of the novel
quaternary salts derived from 3g catalyzed enantioselec-
tive Michael reaction with more than 90% ee. The details
of these results will be reported in due course.
23
was compared to the previously reported value {[a]D
+13.1 (EtOH, c 1.30)}.5a Encouraged by these results, we
next studied the deallylation of other bisallylethers. As ex-
pected, allyl groups were smoothly removed to give the
corresponding 1,4-diols in excellent yields. Although
greater catalyst loading was required in the reaction of
14d, 14f, and 14g, two allylgroups were removed to give
3d, 3f, and 3g in yields of 96%, 76%, and 83%, respec-
tively. These results are summarized in Table 2.
(2S,3S)-1,4-Bis(tert-butyldimethylsiloxy)-2,3-O-isopropylidene-
dioxybutane (8a)
O
O
Ar
Ar
O
[a]D23 +0.84 (c 1.67, CHCl3).
Pd(PPh3)4
K2CO3
Ar
Ar
IR (neat): 2930, 1254, 1085, 837 cm–1.
O
O
O
1H NMR (400 MHz, CDCl3): d = 0.06 (12 H, s), 0.89 (18 H, s), 1.39
EtOH, reflux
HO
OH
(6 H, s), 3.74–3.78 (4 H, m), 3.91–3.97 (2 H, m).
14
3
13C NMR (100 MHz, CDCl3): d = 18.3, 25.9, 27.1, 63.8, 78.6, 109.0.
Scheme 5
Synthesis 2004, No. 6, 960–966 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Chiral 2,3-Bisarylmethoxy-1,4-Butanediols from L-(+)-Tartrate
963
1H NMR (400 MHz, CDCl3): d = 1.41 (6 H, s), 3.53–3.57 (4 H, m),
3.79 (6 H, s), 3.96–4.02 (2 H, m), 4.47 (2 H, d, J = 12.0 Hz), 4.51 (2
H, d, J = 11.6 Hz), 6.83–6.87 (4 H, m), 7.20–7.24 (4 H, m).
13C NMR (100 MHz, CDCl3): d = 26.2, 54.4, 69.5, 72.3, 76.7, 108.8,
112.9, 128.4, 129.2, 158.3.
MS (FAB): m/z = 401 (M+–H).
HRMS (FAB): m/z calcd for C23H29O6 (M+ – H), 401.1964; found,
Table 2 Deprotection of Allyl Function of 14
Entry Ar
Pd Cat.
(mol%)
Time
(h)
Product
Yield
(%)a
Ph
1
2
5
5
16
4
3a
3b
89
95
401.1930.
3
5
2.5
3c
99
(2S,3S)-1,4-Bis(tert-butyldiphenylsiloxy)butane-2,3-diol (9c)
[a]D23 +3.28 (c 0.85, CHCl3).
OMe
IR (neat): 3440, 2930, 1428, 1112 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.04 (18 H, s), 2.73 (2 H, d, J = 4.4
Hz), 3.70–3.85 (6 H, m), 7.34–7.44 (12 H, m), 7.62–7.66 (8 H, m).
13C NMR (100 MHz, CDCl3): d 19.1, 26.8, 65.4, 71.2, 127.7, 129.8,
132.9, 133.0, 135.4, 135.5.
4
5
20
5
8
5
3d
3e
96
76
Me
Me
Me
6
10
2
3f
96
MS (FAB): m/z = 637 (M+ + K).
HRMS (FAB): m/z calcd for C36H46O4Si2K (M+ + K), 637.2572;
found, 637.2537.
F3C
F3C
CF3
7
8
10
10
12
13
3g
3h
83
52
(2S,3S)-1,4-Bis(4-methoxyphenylmethoxy)butane-2,3-diol (9d)
Mp 59–60 °C; [a]D23 –8.10 (c 0.32, CHCl3).
IR (KBr) 3262, 2862, 1514, 1253, 817 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.03 (2 H, br s), 3.50 (2 H, dd,
J = 5.8, 9.8 Hz), 3.54 (2 H, dd, J = 4.4, 6.0 Hz), 3.73–3.81 (2 H, m),
3.77 (6 H, s), 4.43 (4 H, dd, J = 11.4, 16.4 Hz), 6.82–6.84 (4 H, m),
7.20–7.24 (4 H, m).
F
F
F
F
F
a Isolated yield.
13C NMR (100 MHz, CDCl3): d = 55.1, 70.4, 71.4, 73.0, 113.7,
129.3, 129.7, 159.1.
MS (FAB): m/z = 401 (M+ + K).
HRMS (FAB): m/z calcd for C20H26O6K (M+ + K), 401.1366; found,
(2S,3S)-1,4-Bis(triphenylmethoxy)-2,3-O-isopropylidenedioxy-
butane (8b)
Mp 126–129 °C; [a]D23 –17.2 (c 1.27, CHCl3).
401.1335.
IR (KBr) 1448, 1078, 700 cm–1.
(2S,3S)-2,3-Bis(anthracen-9-ylmethoxy)-1,4-bis(4-methoxyphen-
ylmethoxy)butane (10d)
1H NMR (400 MHz, CDCl3): d = 1.41 (6 H, s), 3.21 (4 H, dd,
J = 6.0, 10.4 Hz), 3.99–4.04 (2 H, m), 7.16–7.40 (30 H, m).
13C NMR (100 MHz, CDCl3): d = 27.2, 64.8, 77.6, 86.7, 109.3,
126.9, 127.7, 128.6, 143.8.
Mp 172–175 °C; [a]D23 +20.14 (c 0.57, CHCl3).
IR (KBr) 2903, 1512, 1240, 1092, 730 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.32 (2 H, dd, J = 3.4, 5.8 Hz),
3.54 (2 H, dd, J = 2.4, 10.0 Hz), 3.74–3.89 (8 H, m), 4.14 (4 H, dd,
J = 11.6, 15.6 Hz), 5.53 (2 H, d, J = 11.6 Hz), 5.60 (2 H, d, J = 12.0
Hz), 6.80–6.83 (4 H, m), 7.08–7.10 (4 H, m), 7.33–7.43 (8 H, m),
7.96 (4 H, d, J = 8.4 Hz), 8.34–8.40 (6 H, m).
13C NMR (100 MHz, CDCl3): d = 55.1, 64.6, 70.5, 72.7, 77.3, 113.5,
124.7, 125.8, 128.7, 129.0, 129.1, 130.2, 131.1, 131.2, 158.9.
MS (FAB): m/z = 403 (M+ – Tr).
HRMS (FAB): m/z calcd for C26H27O4 (M+– Tr), 403.1909; found,
403.1891.
(2S,3S)-1,4-Bis(tert-butyldiphenylsiloxy)-2,3-O-isopropylidene-
dioxybutane (8c)
[a]D23 –11.05 (c 1.72, CHCl3).
MS (FAB): m/z = 742 (M+).
HRMS (FAB): m/z calcd for C50H46O6 (M+), 742.3294; found,
IR (neat): 2930, 1428, 1112, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (18 H, s), 1.41 (6 H, s), 3.72–
3.83 (4 H, m), 4.12 (2 H, s), 7.24–7.70 (20 H, m).
742.3296.
13C NMR (100 MHz, CDCl3): d = 19.2, 26.8, 27.1, 64.2, 78.3, 109.1,
(2S,3S)-1,4-Bis(allyloxy)-2,3-dihydroxybutane (12)
127.6, 129.6, 133.2, 135.6.
To a solution of 11 (1.62 g, 10 mmol) in THF (30 mL) was added a
suspension of 60% NaH (1.20 g, 30 mmol) in oil at 0 °C. After vig-
orous stirring for 20 min at r.t., allyl bromide (2.5 mL, 30 mmol)
was added and the mixture was stirred vigorously for 13 h at r.t. The
reaction was quenched by addition of sat. NH4Cl aqueous solution
(20 mL) and extracted with EtOAc. Combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
MS: m/z = 637 (M+ – H).
HRMS (FAB): m/z calcd for C39H49O4Si2 (M+ – H), 637.3169;
found, 637.3182.
(2S,3S)-1,4-Bis(4-methoxyphenylmethoxy)-2,3-O-isopropyl-
idenedioxybutane (8d)
[a]D23 –7.09 (c 0.53, CHCl3).
The residue was dissolved in a mixture of THF (100 mL) and 1 N
aqueous solution HCl (1 mL), the mixture was heated under reflux
for 9 h. Then the resulting mixture was concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel,
hexane–EtOAc, 1:2) to furnish 12 [1.89 g, 94% yield (2 steps)].
IR (neat): 2934, 2862, 1513, 1247, 819 cm–1.
Synthesis 2004, No. 6, 960–966 © Thieme Stuttgart · New York

964
R. Tsuji et al.
FEATURE ARTICLE
(2S,3S)-1,4-Bis(allyloxy)-2,3-O-isopropylidenedioxybutane
[a]D23 –10.43 (c 1.80, CHCl3).
HRMS (FAB): m/z calcd for C32H35O4 (M+ + H), 483.2535; found,
483.2522.
IR (KBr): 2986, 1370, 1086 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 (6 H, s), 3.57–3.60 (4 H, m),
3.99–4.08 (6 H, m), 5.17–5.30 (4 H, m), 5.85–5.95 (2 H, m).
13C NMR (100 MHz, CDCl3) d 26.9, 70.7, 72.4, 77.4, 109.6, 117.1,
134.4.
MS (FAB): m/z = 243 (M+ + H).
HRMS (FAB): m/z calcd for C13H23O4 (M+ + H), 243.1596; found,
(2S,3S)-2,3-Bis(4-methoxyphenylmethoxy)-1,4-bis(allyloxy)bu-
tane (14c)
[a]D23 +21.41 (c 1.11, CHCl3).
IR (neat): 2909, 2864, 1513, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.51 (2 H, dd, J = 6.0, 10.0 Hz),
3.56 (2 H, dd, J = 4.0, 10.0 Hz), 3.68–3.72 (4 H, m), 3.79 (6 H, s),
3.91–3.93 (2 H, m), 4.53 (2 H, d, J = 12.0 Hz), 4.62 (2 H, d, J = 11.2
Hz), 5.13–5.27 (4 H, m), 5.82–5.91 (2 H, m), 6.82–6.88 (4 H, m),
7.23–7.27 (4 H, m).
243.1607.
13C NMR (100 MHz, CDCl3): d = 55.2, 69.9, 72.1, 72.6, 77.3, 113.6,
(2S,3S)-1,4-Bis(allyloxy)-2,3-dihydroxybutane (12)
[a]D23 –3.65 (c 1.05, CHCl3).
IR (KBr) 3194, 2866, 1429, 1103, 995 cm–1.
116.6, 129.6, 130.7, 134.8, 159.1.
MS (FAB): m/z = 481 (M+ + K).
1H NMR (400 MHz, CDCl3): d = 2.87 (2 H, br s), 3.55–3.62 (4 H,
m), 3.85 (2 H, br s), 3.99–4.07 (4 H, m), 5.18–5.30 (4 H, m), 5.85–
5.95 (2 H, m).
HRMS (FAB): m/z calcd for C26H34O6K (M+ + K), 481.1992; found,
481.2002.
13C NMR (100 MHz, CDCl3): d = 70.4, 71.9, 72.4, 117.4, 134.2.
MS (FAB): m/z = 203 (M+ + H).
HRMS (FAB): m/z calcd for C10H19O4 (M+ + H), 203.1283; found,
(2S,3S)-2,3-Bis(anthracen-9-ylmethoxy)-1,4-bis(allyloxy)bu-
tane (14d)
Mp 71–72 °C; [a]D23 +40.97 (c 0.62, CHCl3).
IR (KBr): 2853, 1062, 888, 730 cm–1.
203.1269.
1H NMR (400 MHz, CDCl3): d = 3.37 (2 H, dd, J = 3.6, 10.0 Hz),
3.54 (2 H, dd, J = 6.4, 10.0 Hz), 3.70–3.83 (6 H, m), 5.09–5.20 (4
H, m), 5.51 (2 H, d, J = 11.6 Hz), 5.61 (2 H, d, J = 11.6 Hz), 5.76–
5.85 (2 H, m), 7.39–7.44 (8 H, m), 7.92–7.97 (4 H, m), 8.36–8.39 (6
H, m).
13C NMR (100 MHz, CDCl3): d = 64.8, 70.6, 72.0, 77.4, 116.7,
124.7, 124.8, 125.9, 128.1, 128.7, 129.0, 131.1, 131.3, 134.6.
(2S,3S)-2,3-Bis(phenylmethoxy)-1,4-bis(allyloxy)butane
(14a);Typical Procedure
To a stirred suspension of 60% NaH (96 mg, 2.4 mmol) in DMF (2
mL) was added a solution of 12 (202 mg, 1.0 mmol), in DMF (3
mL), and the mixture was stirred at r.t. After 20 min, BnBr (0.28
mL, 2.4 mmol) was added slowly and the mixture was stirred at r.t.
for an additional 1.5 h. The mixture was cooled to 0 °C and sat.
NH4Cl aqueous solution (5 mL) was carefully added. The separated
aqueous layer was extracted with Et2O. The combined organic lay-
ers were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude residue was purified by flash column chromatog-
raphy (silica gel, hexane–EtOAc, 10:1) to furnish 14a (362 mg,
95% yield).
[a]D23 +18.40 (c 1.35, CHCl3).
IR (neat): 2864, 1454, 1097, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.53–3.63 (4 H, m), 3.73–3.77 (2
H, m), 3.93 (4 H, dd, J = 1.2, 5.6 Hz), 4.60 (2 H, d, J = 11.6 Hz),
4.70 (2 H, d, J = 11.6 Hz), 5.14–5.27 (4 H, m), 5.82–5.91 (2 H, m),
5.82–5.91 (2 H, m), 7.24–7.34 (10 H, m).
MS (FAB): m/z = 582 (M+).
HRMS (FAB): m/z calcd for C40H38O4 (M+), 582.2770; found,
582.2750.
(2S,3S)-2,3-Bis(2,4,6-trimethyl-phenylmethoxy)-1,4-bis(allyl-
oxy)butane (14e)
[a]D23 –7.36 (c 0.42, CHCl3).
IR (neat): 2915, 1614, 1087, 849 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.24 (6 H, s), 2.34 (12 H, s), 3.48
(2 H, dd, J = 6.4, 9.6 Hz), 3.63 (2 H, dd, J = 2.8, 9.6 Hz), 3.71–3.75
(2 H, m), 3.92 (4 H, d, J = 5.6 Hz), 4.57 (2 H, d, J = 10.0 Hz), 4.68
(2 H, d, J = 10.0 Hz), 5.12–5.26 (4 H, m), 5.82–5.92 (2 H, m), 6.81
(4 H, s).
13C NMR (100 MHz, CDCl3): d = 19.5, 20.9, 67.0, 70.0, 72.1, 77.7,
116.6, 128.7, 131.5, 134.8, 137.4, 137.9.
13C NMR (100 MHz, CDCl3): d = 69.8, 72.1, 73.1, 77.8, 116.7,
127.5, 128.0, 128.2, 134.7, 138.6
MS (FAB): m/z = 383 (M+ + H).
HRMS (FAB): m/z calcd for C24H31O4 (M+ + H), 383.2222; found,
MS (FAB): m/z = 466 (M+).
HRMS (FAB): m/z calcd for C30H42O4 (M+) 466.3083; found,
383.2200.
466.3074.
(2S,3S)-2,3-Bis(naphthalene-1-ylmethoxy)-1,4-bis(allyloxy)bu-
tane (14b)
(2S,3S)-2,3-Bis(3,5-bis-trifluoromethylphenylmethoxy)-1,4-
bis(allyloxy)butane (14f)
[a]D23 +44.54 (c 2.27, CHCl3).
Mp 56.5–57.5 °C; [a]D23 +5.69 (c 1.62, CHCl3).
IR (neat): 2863, 1509, 1094, 777 cm–1.
IR (KBr): 2904, 1376, 1283, 1129, 886 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.45 (2 H, dd, J = 4.0, 10.0 Hz),
3.50 (2 H, dd, J = 5.6, 10.0 Hz), 3.69–3.81 (6 H, m), 4.96 (2 H, d,
J = 12.0 Hz), 5.08–5.18 (4 H, m), 5.17 (2 H, d, J = 12.0 Hz), 5.72–
5.82 (2 H, m), 7.31–7.48 (8 H, m), 7.75–7.83 (4 H, m), 8.15–8.18 (2
H, m).
13C NMR (100 MHz, CDCl3): d = 69.9, 71.2, 71.9, 77.3, 116.5,
124.4, 125.0, 125.5, 125.9, 126.9, 128.2, 128.5, 131.9, 133.6, 133.8,
134.6.
1H NMR (400 MHz, CDCl3): d = 3.62 (2 H, dd, J = 5.6, 10.0 Hz),
3.67 (2 H, dd, J = 3.6, 10.4 Hz), 3.80–3.85 (2 H, m), 3.97–3.99 (4
H, m), 4.75 (2 H, d, J = 12.8 Hz), 4.87 (2 H, d, J = 12.8 Hz), 5.17–
5.28 (4 H, m), 5.82–5.92 (2 H, m), 7.78–7.82 (6 H, m).
13C NMR (100 MHz, CDCl3): d = 69.8, 71.8, 72.4, 79.4, 117.4,
121.4 (q, J = 4.1 Hz), 123.3 (q, J = 272 Hz), 127.3, 131.5 (q, J = 33
Hz), 134.2, 141.2.
MS (FAB): m/z = 655 (M+ + H).
MS (FAB): m/z = 483 (M+ + H).
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FEATURE ARTICLE
Synthesis of Chiral 2,3-Bisarylmethoxy-1,4-Butanediols from L-(+)-Tartrate
965
HRMS (FAB): m/z calcd for C28H27O4F12 (M+ + H), 655.1718;
found, 655.1691.
(2S,3S)-2,3-Bis(4-methoxyphenylmethoxy)-1,4-butanediol (3c)
[a]D23 +13.92 (c 1.60, CHCl3).
IR (neat): 3416, 2935, 1513, 1248 cm–1.
(2S,3S)-2,3-Bis(2-trifluoromethylphenylmethoxy)-1,4-bis(allyl-
oxy)butane (14g)
1H NMR (400 MHz, CDCl3): d = 2.53 (2 H, br s), 3.61–3.68 (4 H,
m), 3.75–3.79 (8 H, m), 4.55 (4 H, s), 6.85–6.88 (4 H, m), 7.22–7.25
(4 H, m).
13C NMR (100 MHz, CDCl3): d = 55.2, 60.7, 72.1, 78.4, 113.8,
129.5, 129.9, 159.3.
MS (FAB): m/z = 401 (M+ + K).
HRMS (FAB): m/z calcd for C20H26O6K (M+ + K), 401.1366; found,
[a]D23 +3.03 (c 1.35, CHCl3).
IR (neat): 2865, 1314, 1118, 769 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.64 (2 H, dd, J = 5.6, 10.4 Hz),
3.74 (2 H, dd, J = 3.6, 10.0 Hz), 3.86–3.90 (2 H, m), 3.97–3.99 (4
H, m), 4.82 (2 H, d, J = 13.2 Hz), 4.95 (2 H, d, J = 13.2 Hz), 5.14–
5.18 (2 H, m), 5.23–5.29 (2 H, m), 5.83–5.93 (2 H, m), 7.34 (2 H, t,
J = 7.6 Hz), 7.50 (2 H, t, J = 7.6 Hz), 7.60 (2 H, d, J = 7.6 Hz), 7.76
(2 H, d, J = 8.0 Hz).
401.1345.
13C NMR (100 MHz, CDCl3): d = 68.9 (dd, J = 2.5, 3.3 Hz), 69.6,
72.2, 79.0, 116.9, 124.3 (q, J = 272 Hz), 125.4 (q, J = 5.8 Hz),
127.1, 127.1 (q, J = 30.4 Hz), 129.1, 131.7, 134.5, 137.4.
(2S,3S)-2,3-Bis(anthracene-9-ylmethoxy)-1,4-butanediol (3d)
Mp 174–175 °C; [a]D24 +21.58 (c 1.00, CHCl3).
IR (KBr): 3371, 1286, 1118, 888 cm–1.
MS (FAB): m/z = 519 (M+ + H).
HRMS (FAB): m/z calcd for C26H29O4F6 (M+ + H), 519.1970;
1H NMR (400 MHz, CDCl3): d = 2.11 (2 H, br s), 3.65 (2 H, d,
J = 11.6 Hz), 3.76 (2 H, d, J = 12.0 Hz), 3.84–3.88 (2 H, m), 5.56 (2
H, d, J = 11.6 Hz), 5.61 (2 H, d, J = 11.6 Hz), 7.43–7.49 (8 H, m),
7.98–8.02 (4 H, m), 8.30–8.33 (4 H, m) 8.46 (2 H, s).
found, 519.1960.
13C NMR (100 MHz, CDCl3): d = 61.0, 64.4, 79.1, 123.9, 125.0,
(2S,3S)-2,3-Bis(2,3,4,5,6-pentafluorophenylmethoxy)- 1,4-
bis(allyloxy)butane (14h)
126.49, 128.3, 128.6, 129.1, 130.8, 131.3.
[a]D23 +9.79 (c 1.50, CHCl3).
MS (FAB): m/z = 502 (M+).
HRMS (FAB): m/z calcd for C34H30O4 (M+), 502.2144; found,
IR (neat): 2917, 1505, 1125 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.53–3.62 (4 H, m), 3.71–3.75 (2
H, m), 3.95–3.97 (4 H, m), 4.68 (2 H, d, J = 11.2 Hz), 4.80 (2 H, d,
J = 11.2 Hz), 5.16–5.27 (4 H, m), 5.82–5.91 (2 H, m).
13C NMR (100 MHz, CDCl3): d = 59.9, 69.0, 72.3, 78.4, 111.3 (m),
116.9, 134.3, 137.3 (br d, J = 250 Hz), 141.3 (br d, J = 205 Hz),
145.6 (br d, J = 251 Hz).
MS (FAB): m/z = 563 (M+ + H).
HRMS (FAB): m/z calcd for C24H21O4F10 (M+ + H), 563.1280;
502.2100.
(2S,3S)-2,3-Bis(2,4,6-trimethylbenzyloxy)-1,4-butanediol (3e)
Mp 154–155 °C; [a]D23 +1.67 (c 1.00, CHCl3).
IR (KBr): 3418, 2913, 1613, 1034, 849 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.26 (6 H, s), 2.35 (12 H, s), 3.70–
3.73 (4 H, m), 3.82 (2 H, dd, J = 4.8, 12.8 Hz), 4.63 (4 H, s), 6.85 (4
H, s).
13C NMR (100 MHz, CDCl3): d =19.5, 20.9, 60.6, 66.4, 78.7, 129.0,
130.9, 137.7, 138.0.
MS (FAB): m/z = 388 (M+ + H).
HRMS (FAB): m/z calcd for C24H35O4 (M+ + H), 387.2535; found
found: 563.1262.
(2S,3S)-2,3-Bis(phenylmethoxy)-1,4-butanediol (3a)5a; Typical
Procedure
To a stirred solution of allyl compound 14a (38.2 mg, 0.1 mmol) in
EtOH (1.0 mL) was added catalytic amounts of Pd(PPh3)4 (5.7 mg,
5 mmol, 5 mol%) under an argon atmosphere. The slightly yellow
solution was stirred for 5 min, K2CO3 (82.8 mg, 0.6 mmol, 6 equiv)
was added. After 16 h, the starting material and mono allyl com-
pound were completely consumed (monitoring by TLC. The reac-
tion mixture was cooled to 0 °C, and quenched by addition of 1 N
HCl and CH2Cl2. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The crude residue was purified by flash column chromatography
(silica gel, EtOAc) to furnish 3a (27 mg, 89% yield).
387.2517.
(2S,3S)-2,3-Bis(3,5-bistrifluoromethylphenylmethoxy)-1,4-bu-
tanediol (3h)
Mp 84–84.5 °C; [a]D24 +17.67 (c 1.00, CHCl3).
IR (KBr): 3468, 1076, 730 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.28 (2 H, br s), 3.79 (2 H, d,
J = 2.4 Hz), 3.83 (2 H, d, J = 13.6 Hz), 3.94 (2 H, d, J = 12.0 Hz),
4.76 (2 H, d, J = 12.4 Hz), 4.86 (2 H, d, J = 12.8 Hz), 7.77–7.82 (6
H, m).
13C NMR (100 MHz, CDCl3): d = 60.8, 71.2, 80.4, 121.5–121.7 (m),
123.1 (q, J = 271 Hz), 127.0 (d, J = 3.0 Hz), 131.7 (q, J = 33 Hz),
140.6.
(2S,3S)-2,3-Bis(naphthalene-1-ylmethoxy)-1,4-butanediol (3b)
[a]D23 +11.60 (c 1.82, CHCl3).
IR (neat): 3409, 2878, 1101, 793, 776 cm–1.
MS (FAB): m/z = 575 (M+ + H).
1H NMR (400 MHz, CDCl3): d = 2.33 (2 H, br s), 3.65–3.75 (6 H,
m), 5.03 (4 H, dd, J = 12.0, 16.4 Hz), 7.36–7.49 (8 H, m), 7.78–7.87
(4 H, m), 8.07–8.10 (2 H, m).
HRMS (FAB): m/z calcd for C22H19O4F12 (M+ + H), 575.1092;
found, 575.1108.
13C NMR (100 MHz, CDCl3): d = 60.6, 70.8, 78.6, 123.7, 125.1,
(2S,3S)-2,3-Bis(2-trifluoromethylphenylmethoxy)-1,4-butane-
diol (3g)
125.8, 126.4, 126.8, 128.6, 128.9, 131.6, 133.3, 133.7.
Mp 97–98 °C; [a]D23 +14.82 (c 1.00, CHCl3).
MS (FAB): m/z = 441 (M+ + K).
HRMS (FAB): m/z calcd for C26H26O4K (M+ + K), 441.1468; found,
IR (KBr): 3354, 1320, 1160, 1108, 768 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.34 (2 H, br s), 3.79–3.92 (6 H,
m), 4.82 (2 H, d, J = 12.8 Hz), 4.88 (2 H, d, J = 12.8 Hz), 7.37–7.41
(2 H, m), 7.51–7.54 (2 H, m), 7.63–7.67 (4 H, m).
441.1443.
Synthesis 2004, No. 6, 960–966 © Thieme Stuttgart · New York

966
R. Tsuji et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): d = 60.4, 68.5 (d, J = 2.4 Hz), 80.0,
124.2 (q, J = 272 Hz), 125.7 (q, J = 5.8 Hz), 127.4 (q, J = 30 Hz),
127.5, 129.3, 131.9, 136.6.
MS (FAB): m/z = 439 (M+ + H).
HRMS (FAB): m/z calcd for C20H21O4F6 (M+ + H), 439.1344;
References
(1) Morrison, J. D.; Scott, A. I. Asymmetric Synthesis, Vol. 4;
Academic Press Inc.: New York, 1984, 1.
(2) Liu, W.; Szewczyk, J. M.; Waykole, L.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2002, 43, 1373.
(3) (a) Flores-Santos, L.; Martin, E.; Diéguez, M.-B.; Claver, C.
Tetrahedron: Asymmetry 2001, 12, 3029. (b) Gonsalves, A.
M. d’A. R.; Bayon, J. C.; Pereira, M. M.; Serra, M. E. S.;
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Tetrahedron Lett. 2002, 43, 9539.
(5) (a) Kalinowski, H.; Crass, G.; Seebach, D. Chem. Ber. 1981,
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Org. Chem. 1991, 56, 1321.
(6) (a) Rubin, L. J.; Lardy, H. A.; Fischer, H. O. L. J. Am. Chem.
Soc. 1952, 74, 425. (b) Palomo, C.; Oiarbide, M.; Landa, A.;
Esnal, A.; Linden, A. J. Org. Chem. 2001, 66, 4180.
(c) Inoue, M.; Fujimoto, K.; Furusyo, M.; Nakazumi, H. J.
Am. Chem. Soc. 1999, 121, 1452.
found, 439.1359.
(2S,3S)-2,3-Bis(2,3,4,5,6-pentafluorophenylmethoxy)-1,4-bu-
tanediol (3f)
Mp 89–91 °C; [a]D23 +15.18 (c 1.50, CHCl3).
IR (KBr) 3306, 1500, 940 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.21 (2 H, br s), 3.67–3.70 (4 H,
m), 3.82 (2 H, d, J = 9.2 Hz), 4.76 (4 H, s).
13C NMR (100 MHz, CDCl3): d = 59.6, 60.8, 80.4, 111.0 (m) 137.4
(br d, J = 249 Hz), 141.4 (br d, J = 254 Hz), 145.5 (br d, J = 247
Hz).
MS (FAB): m/z = 483 (M+ + H).
HRMS (FAB): m/z calcd for C18H13O4F10 (M+ + H), 483.0654;
found, 483.0680.
Acknowledgment
(7) Thomas, R. M.; Mohan, G. H.; Iyenger, D. S. Tetrahedron
Lett. 1997, 38, 4721.
(8) We assume hydroboration would proceed exclusively
because no olefinic signals were observed in the 1H NMR
spectra of crude products.
This research was supported by a Grant-in-Aid from the Ministry of
Education, Culture, Sports, Sciences, and Technology. Financial
support from The Uehara Memorial Foundation and The Naito
Foundation is also gratefully acknowledged.
(9) Vutukuri, D. R.; Bharathi, P.; Yu, Z.; Rajasekaran, K.; Tran,
M.-H.; Thayumanavan, S. J. Org. Chem. 2003, 68, 1146.
Synthesis 2004, No. 6, 960–966 © Thieme Stuttgart · New York