Synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol

Article abstract of DOI:10.1055/s-2008-1067174

(2R,3R)-1,4-Dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol proved to be an excellent auxiliary and stable protective group for boronic acids. Herein we report an improved practical procedure for its synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067174

2488
PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (2R,3R)-1,4-Dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol
(
2
R
,3
R
)-1, 4-Dimethox
a
y-1,1, 4,4-te
r
trapheny
t
lbutan
i
niol a Bischop, Vesna Cmrecki, Vera Ophoven, Jörg Pietruszka*
Institut für Bioorganische Chemie, Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich,
Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received 14 March 2008; revised 2 May 2008
PSP
No128
Abstract: (2R,3R)-1,4-Dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol proved to be an excellent auxiliary and stable protective group for
boronic acids. Herein we report an improved practical procedure for its synthesis.
Key words: tartrate-derived auxiliary, boron, protective group, asymmetric synthesis
Ph Ph
TsOH (1.1 equiv),
toluene, reflux, 2 h
PhMgBr (10.0 equiv), THF,
0 °C to r.t., overnight
CO2Me
CO2Me
CO2Me
CO2Me
HO
HO
O
O
O
OH
OH
PMP
PMP
OMe
OMe
PMP = p-methoxyphenyl
O
MeO
2
4 (98%)
Ph Ph
3
5
NaH (3.0 equiv),
MeI (3.0 equiv),
THF, r.t., 1–3 d
NaBrO3 (3.0 equiv),
Na2S2O4 (3.0 equiv),
H2O–EtOAc,
Ph Ph
Ph Ph
Ph Ph
LiAlH4 (3.0 equiv), Et2O,
r.t., overnight
HO
HO
O
O
O
OMe
OMe
r.t., 24 h
OMe
OMe
OMe
OMe
PMP
HO
O
PMP
Ph Ph
Ph Ph
Ph Ph
1
6
7
(62% over 4 steps)
Scheme 1 Synthesis of diol 1
Introduction
Synthetic Applications
The synthesis of C2-symmetric diols is of considerable in- A literature survey showed several applications of diol 1
terest due to their applications as chiral inducers.1,2 Tar- in asymmetric synthesis. It is interesting to note that
trate-based diols are especially popular. Contrary to the Nakayama and Rainier reported a preliminary result on a
well-documented TADDOLs,3 the corresponding 1,2-di- potential application in boron chemistry. An allyl addition
ols are less regularly applied. The first synthesis of diol 1 was achieved albeit in moderate selectivity.4 Despite the
was put forward by Nakayama and Rainier.4 In the present fact that later Zhang et al. successfully used the auxiliary
paper, we wish to report in detail an improved synthesis 1 as best chiral inducer for the titanium-mediated asym-
(Scheme 1) of the sterically hindered, conformationally metric synthesis of a,a-disubstituted amino acids,6 the fo-
rigid, chiral auxiliary and efficient protective group 1 for cus remained on utilizing boronic acids.
boronic acids (Scheme 2). In contrast to common boronic
esters, boronic acids are considerably stable after esterifi-
cation with auxiliary 1 allowing many functional group
transformations in the side-chain.5
Ph Ph
Ph Ph
HO
HO
O
O
OMe
OMe
OMe
OMe
R
B
Ph Ph
Ph Ph
1
auxiliary and
protecting group
transformations in R
transformations via B
SYNTHESIS 2008, No. 15, pp 2488–2490
Advanced online publication: 08.07.2008
x
x.
x
x
.
2
0
0
8
Scheme 2 Diol 1 as auxiliary and protecting group for boronic acids
DOI: 10.1055/s-2008-1067174; Art ID: T04008SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
(2R,3R)-1,4-Dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol
2489
dried at 120 °C overnight. Solvents were dried and purified by con-
ventional methods prior to use; THF was freshly distilled from so-
dium/benzophenone. Common solvents for chromatography (PE,
EtOAc) were distilled prior to use; PE refers to a fraction with a
boiling point between 40–60 °C. Flash column chromatography
was performed on silica gel 60, 0.040–0.063 mm (230–400 mesh).
TLC (monitoring the course of the reactions) was performed on pre-
coated plastic sheets (Polygram® SIL G/UV254, MachereyNagel)
with detection by UV (254 nm) or by coloration with cerium molyb-
denum solution [phosphomolybdic acid (25 g), Ce(SO4)2·H2O
The potential of 1 for cyclopropane chemistry was first
described in 1997.7 In the meantime the scope was dem-
onstrated: Not only cis-8 and trans-disubstituted5,9 cyclo-
propanes were synthesized, but also 1,2,3-tri-10 and
1,2,3,3-tetrasubstituted10b derivatives. Furthermore, nu-
merous transformations via boron, as well as via the side-
chain, were established.11
Boronic esters derived from diol 1 were also utilized as re-
mote activating group. While the level of 1,8-stereoinduc-
tion observed for Diels–Alder reactions was low,12
additions to furyl aldehyde bearing a chiral boronate in the
C-3 position were highly selective.13 The approach was
extended to the corresponding furyl sulfonylamides.14
1
(10 g), conc. H2SO4 (60 mL), H2O (940 mL)]. H and 13C NMR
spectra were recorded at 20 °C in CDCl3 on a Bruker ARX 300/500
spectrometer. Chemical shifts are given in ppm relative to TMS as
internal standard (1H) or relative to the resonance of the solvent
(13C: CDCl3 = 77.0 ppm); coupling constants J are given in Hz.
Higher order d and J values are not corrected. Microanalyses were
performed at the Institut für Organische Chemie, Stuttgart. Melting
points or softening ranges (Büchi 510) are not corrected. Specific
rotations were measured at 20 °C. IR spectra were obtained on a
Perkin-Elmer 283 spectrometer.
Auxiliary 1 also enabled [3,3]-sigmatropic rearrange-
ments of boron-containing allyl alcohols leading to enan-
tio- and diastereomerically pure allylboronic esters with a
stereogenic centre in the a-position to the boron moiety.15
Highly selective allyl additions led to homoallylic alco-
hols with a Z-double bond. The versatility was recently
demonstrated in a natural product synthesis.16
(4R,5R)-Dimethyl 2-(4-Methoxyphenyl)-1,3-dioxolane-4,5-di-
carboxylate (4)
A 250 mL round-bottomed flask fitted with a magnetic stir bar and
a Claisen condenser with a drying tube was charged with anisalde-
hyde dimethylacetal17 (3; 35.6 g, 195 mmol), L-(+)-dimethyl tar-
trate (2; 32.9 g, 185 mmol), p-toluenesulfonic acid (43 mg,
0.12 mol%), and toluene (165 mL). MeOH–toluene was continu-
ously removed from the stirred solution by distillation. The crude
product was dissolved in CH2Cl2 (150 mL) and neutralized with
K2CO3. The mixture was filtered through a pad of Celite and the re-
sulting solution concentrated under reduced pressure to furnish a
yellow oil, which was recrystallized from PE to yield 53.8 g (98%)
of 4 as a pale yellow solid; mp 71 °C; Rf = 0.07 (PE–EtOAc, 85:15);
[a]D20 –21 (c = 1.6, CHCl3).
Synthesis of Auxiliary 1
The first two steps were conventionally performed as pre-
viously reported (Scheme 1).3,9a L-(+)-Dimethyl tartrate
(2) was protected with anisaldehyde dimethylacetal (3)17
under acidic conditions furnishing diester 4 in 98% yield
after recrystallization. For the addition of phenylmagne-
sium bromide, minimum amounts of solvent were used,
yet the formation of biphenyl could not be prevented. The
side-product caused no problems in the following se-
quence, purification was not essential at this stage. How-
ever, complete conversion into diol 5 (omitting the
contamination of the product with the intermediate mo-
noester) was important to facilitate the ultimate workup
procedure, hence the use of excess of Grignard reagent.
The next step was previously the least reliable and most
cumbersome to work up. Sequential methylation with
dimsyl anion/MeI was replaced by directly using excess
NaH in THF (instead of DMSO) followed by MeI. The in-
termediate 6 was thus obtained in higher purity. The
cleavage of the PMP-group required two steps, an oxida-
tion leading to ester 7 and a final reduction to furnish the
desired diol 1. For the first transformation we replaced the
toxic and expensive 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) with commercially available cheap sodi-
um bromate and sodium dithionite.18,19 The final release
of auxiliary 1 was accomplished by reduction with
LiAlH4; purification was achieved by flash column chro-
matography (the packed column was reused several times
after flushing with EtOAc). The yield over 4 steps was
62%. A typical scale is 100 mmol, but regular scaling up
to 50 g of product was also successfully achieved without
loss of yield.
IR (KBr): 3080, 2950, 1650, 1494, 1446, 1422, 1370, 1304, 1264,
1193, 1147, 1076, 1033, 1015, 964, 760, 738, 703, 648, 637 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 3.86 (s, 3 H, ArOCH3), 4.84 (d, 3J = 4.1 Hz, 1 H, 4-H or 5-
H), 4.95 (d, 3J = 4.1 Hz, 1 H, 4-H or 5-H), 6.09 (s, 1 H, 2-H), 6.91
(mc, 2 Harom), 7.51 (mc, 2 Harom).
13C NMR (126 MHz, CDCl3): d = 52.79, 52.81 (CO2CH3), 55.3
(ArOCH3), 77.3 (C-4 and C-5), 106.7 (C-2), 113.8 (CHarom), 127.4
(Carom), 128.8 (CHarom), 161.0 (Carom), 169.5, 170.2 (CO2CH3).
Anal. Calcd for C14H16O7 (296.3): C, 56.76; H, 5.44. Found: C,
56.52; H, 5.44.
Bis(diphenylmethanol) 5
A flame dried 2 L three-necked, round-bottomed flask equipped
with a magnetic stir bar, 250 mL pressure-equalizing addition fun-
nel, reflux condenser and a N2 inlet was charged with Mg turnings
(24.3 g, 1 mol), a small crystal of I2, and THF (280 mL). Bromoben-
zene (105 mL, 157 g, 1 mol) was then added dropwise so that THF
was gently refluxing. The suspension was refluxed for an additional
1 h. The mixture was cooled to 0 °C and a solution of the acetal 4
(29.6 g, 100 mmol) in THF (180 mL) was slowly added. The stir-
ring was continued overnight at r.t. After dilution with Et2O
(500 mL), the reaction was quenched with aq NH4Cl (1 L, 50%) and
the ethereal layer was separated. The aqueous layer was extracted
with Et2O (3 × 200 mL); the combined organic layers were washed
with brine (300 mL), dried (MgSO4), and the solvents were re-
moved under reduced pressure to yield 60.0 g of the crude product
5 as a yellow foam, which was used in the next step without further
purification; Rf = 0.17 (PE–EtOAc, 85:15).
The reactions were carried out by using standard Schlenk tech-
niques under dry N2 with magnetic stirring. Glassware was oven-
Synthesis 2008, No. 15, 2488–2490 © Thieme Stuttgart · New York

2490
M. Bischop et al.
PRACTICAL SYNTHETIC PROCEDURES
Dimethyl Ether 6
13C NMR (CDCl3, 126 MHz): d = 53.4 (OCH3), 71.1 (C-2 and C-3),
85.1 (C-1 and C-4), 127.1, 127.2, 127.7, 127.8, 128.0, 128.7
(CHarom), 141.2, 142.5 (Carom).
A flame dried 1 L Schlenk flask equipped with a magnetic stir bar
and a silicone septum was charged with the crude bis(diphenyl-
methanol) 5 (60.0 g) from the previous step and THF (220 mL).
NaH (95%; 7.58 g, 300 mmol) was added at 0 °C. The solution was
stirred for 30 min at r.t. before MeI (18.7 mL, 300 mmol) was added
and then stirred overnight at r.t. The reaction was followed by TLC,
and if needed, one or two more portions of NaH and MeI were add-
ed. The mixture was diluted with Et2O (250 mL) and hydrolyzed
with H2O (250 mL). The aqueous layer was extracted with Et2O
(3 × 250 mL), and the combined organic layers were washed with
H2O (5 × 200 mL) and brine (200 mL), and dried (MgSO4). The
solvent was removed under reduced pressure to yield 58.9 g of
crude dimethyl ether 6 as a yellow foam, which was used in the next
step without further purification; Rf = 0.40 (PE–EtOAc, 85:15).
Anal. Calcd for C30H30O4 (454.6): C, 79.27; H, 6.65. Found: C,
79.16; H, 6.71.
Acknowledgment
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
and the Jürgen Manchot Stiftung for the generous support of our
projects. We also thank both past and present co-workers as well as
undergraduate students who helped us to optimize the procedure du-
ring the course of their work.
References
4-Methoxybenzoate 7
A 1 L two-necked, round-bottomed flask equipped with a magnetic
stir bar and a 250 mL pressure-equalizing addition funnel was
charged with crude dimethyl ether 6 (58.9 g) in EtOAc (200 mL). A
solution of NaBrO3 (45.3 g, 300 mmol in 150 mL H2O) was added
over a period of 15 min. To the vigorously stirred two-phase mix-
ture was added dropwise a solution of Na2S2O4 (52.2 g, 300 mmol
in 150 mL H2O) while cooling the reaction vessel with an ice-bath.
After stirring for 24 h at r.t., the mixture was diluted with EtOAc
(200 mL) and the aqueous layer was extracted with EtOAc (3 × 250
mL). The combined organic layers were washed with aq 2 M
Na2S2O3 solution (8 × 200 mL) and brine (200 mL), dried
(MgSO4), and concentrated under reduced pressure to yield the
crude product 7 as a yellow foam. The ester 7 was further purified
by dissolving and refluxing it in CH2Cl2 (400 mL) with charcoal
(4 g) for 1 h. The mixture was brought to r.t. and filtered through a
pad of Celite. The solvent was removed under reduced pressure to
yield 4-methoxybenzoate 7 as a yellow foam, which was used in the
next step without further purification; Rf = 0.24 (PE–EtOAc, 85:15).
(1) Bhowmick, K. C.; Joshi, N. N. Tetrahedron: Asymmetry
2006, 17, 1901.
(2) Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
(3) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem. Int. Ed.
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Eur. J. Org. Chem. 2003, 3219.
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(2R,3R)-1,4-Dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol (1)
A flame-dried 500 mL Schlenk flask equipped with a magnetic stir
bar and a silicone septum was charged with 4-methoxybenzoate 7
and Et2O (350 mL). LiAlH4 (11.4 g, 300 mmol) was added at 0 °C
and the mixture was stirred overnight at r. t. After dilution with Et2O
(100 mL) and hydrolysis by the addition of H2O (11 mL), aq 15%
NaOH (11 mL), and H2O (11 mL), a yellowish precipitate was
formed, which was filtered through a pad of Celite. The filter cake
was thoroughly washed with Et2O. The filtrate was dried (MgSO4)
and concentrated under reduced pressure to yield the crude title
compound 1 as a yellow foam. The product was purified by flash
column chromatography on silica gel with PE–EtOAc (93:7) as elu-
ent; yield: 28 g (62% over 4 steps); colorless solid; mp 76–79 °C;
Rf = 0.44 (PE–EtOAc, 85:15); [a]D20 +59.7 (c = 1.0, CHCl3).
(14) Yim, H.-K.; Wong, H. N. C. J. Org. Chem. 2004, 69, 2892.
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IR (film): 3422, 1493, 1445, 1175, 1069, 757, 695 cm–1.
1H NMR (CDCl3, 500 MHz): d = 2.66 (br, 2 H, OH), 3.08 (s, 6 H,
3
OCH3), 4.64 (d, J = 3.7 Hz, 2 H, 2-H and 3-H), 7.13–7.37 (m, 20
Harom).
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Synthesis 2008, No. 15, 2488–2490 © Thieme Stuttgart · New York