Practical synthesis of chiral 9,9′-spirobixanthene-1,1′-diol

Article abstract of DOI:10.1039/b610879b

A concise four-step synthesis of 9,9′-spirobixanthene-1,1′-diol is reported, featuring a practical preparation at large scale without the use of column chromatography purification. Co-crystallization with N-benzylcinchonidinium chloride and N-benzylquinin

Full text of DOI:10.1039/b610879b

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ꢀ
ꢀ
Practical synthesis of chiral 9,9 -spirobixanthene-1,1 -diol
a
a
a
b
a
Weicheng Zhang, Shulin Wu, Zhaoguo Zhang, Hemant Yennawar and Xumu Zhang*
Received 31st July 2006, Accepted 25th October 2006
First published as an Advance Article on the web 9th November 2006
DOI: 10.1039/b610879b
ꢀ
ꢀ
A concise four-step synthesis of 9,9 -spirobixanthene-1,1 -diol is reported, featuring a practical
preparation at large scale without the use of column chromatography purification. Co-crystallization
with N-benzylcinchonidinium chloride and N-benzylquininium chloride rendered the optically pure
product in both enantiomers.
Introduction
alcohol intermediate was unsuccessful due to an uncontrollable
side reaction under bromination conditions. For our target
4
Connected with quaternary carbon, spiro aromatic compounds
are of more conformational rigidity than atropisomeric biaryl
analogues, constituting a desirable element in the design of
chiral ligands for transition metal catalyzed asymmetric reactions.
molecule 3, we envisaged that a straightforward route can be
accessed through the key intermediate 6, which will be subject
to cyclization and then demethylation to give the desired product
(
Scheme 1). A prerequisite for this approach is that the precursor 1-
1
Although first synthesized in the 1930s, the significance of spirans
methoxyxanthone 5 shall be assembled in an efficient way. Inspired
2
in asymmetric catalysis has not been well recognized until recently.
by recent advances in synthetic chemistry utilizing directed
2a
Soon after Chan’s work on spirophosphinite, Birman designed
5
metalation strategy, we found that 5 can be prepared directly
ꢀ
ꢀ
and synthesized a new C
2
-symmetric 1,1 -spirobiindane-7,7 -diol
Improved resolution of 1 via co-crystallization enabled
from 3-phenoxyanisole 4 via tandem directed ortho metalation
2b
3
1.
6
(
DoM) and directed remote metalation (DreM). Thus 2-methoxy-
Zhou et al. to prepare a series of spiro ligands for asymmetric
N,N-dimethyl-6-phenoxybenzamide was first generated via DoM
2
d,e,i
catalysis.
1
Following a strategy similar to the synthesis of
◦
by selective deprotonation of 4 with n-BuLi at −78 C and then
ꢀ
ꢀ
4
, Zhou et al. also prepared 9,9 -spirobifluorene-1,1 -diol 2.
Meanwhile, we have developed 9,9 -spirobixanthene-1,1 -diol 3
treatment with equivalent amount of dimethylcarbamyl chloride.
ꢀ
ꢀ
Without being isolated, this intermediate was in situ converted to
and its phosphoramidite derivatives for highly enantioselective
5
4
in the presence of LDA via DreM. Addition of another lithiated
to 5 produced the tertiary alcohol 6 as expected, which further
2f,g
hydrogenation and conjugate addition reactions. Although the
two step synthesis of 3 is highly convergent without the extra pro-
tection and deprotection steps that are required for the preparation
of 1 and 2, the Lewis-acid mediated simultaneous cyclization and
demethylation involve harsh work up with hydrochloric acid and
column chromatography separation. In searching for a practical
underwent ring closure in refluxing HCl and HOAc to form the
spirocyclic backbone. In the final step, BBr was initially tested as
3
demethylation reagent. To our surprise, side reaction occurred
without the formation of 3. After screening several available
reagents, we found that refluxing 7 in melt pyridine·HCl for less
than 30 minutes gave the desired product 3 in satisfactory yield.
ꢀ
ꢀ
synthesis of 9,9 -spirobixanthene-1,1 -diol, 3, on a large scale, we
report herein a convenient four step procedure without the use of
column chromatography purification.
Results and discussion
Acid-mediated cyclization of tertiary alcohols is a classic method
1
for the synthesis of spirans. Compared with double cyclization
of ketones, it remains rarely explored so far for the preparation
of spiro diols such as 1, 2, and 3. An attempt to prepare 2 via an
Scheme 1 Reagents and conditions: (a) (i) n-BuLi (1.2 equiv.), THF,
◦
◦
−
78 C, (ii) Me
2
NCOCl (1 equiv.), THF, −78 C, (iii) LDA (2.4 equiv.),
◦
◦
THF, 0 C; (b) lithiated 4 (1 equiv.), THF, −78 C; (c) HCl, HOAc, reflux;
(
d) pyridine·HCl, reflux.
a
1
04 Chemistry Research Building, Department of Chemistry, the Pennsyl-
vania State University, University Park, PA, 16802, USA. E-mail: xumu@
chem.psu.edu; Fax: (+1) 814-865-3932
The Department of Chemistry X-ray Crystallography Lab, the Pennsylvania
State University, University Park, PA, 16802, USA
2
f
b
Our recent studies showed that rac-3 can be resolved efficiently
via co-crystallization with some alkaloid-derived quaternary
4
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ammonium salts, i.e., N-benzylcinchoninium chloride 8 and
N-benzylquininium chloride 9. Differing only in a methoxy group,
Conclusions
ꢀ
In summary, we have established a concise synthesis of 9,9 -
spirobixanthene-1,1 -diol 3 in four steps. Because no column
8
3
preferentially forms co-crystals with (R)-3 whereas 9 with (S)-
. X-ray diffraction experiments further confirmed the absolute
ꢀ
chromatography is applied throughout the whole procedure, the
title compound can be prepared and resolved conveniently at large
scale. Application of chiral 3 and its derivatives for asymmetric
catalysis will be reported in due course.
configuration of the resolved enantiomers, revealing distinct
molecular packing modes of the co-crystals of (R)-3:8 and (S)-
3:9 developed from acetonitrile (Fig. 1 and 2).
Experimental
General
All reactions were carried out using standard Schlenk techniques
unless specified otherwise. The degassed dry solvents are used
throughout each experiment. 3-Phenoxyanisole was prepared
according to literature. The other chemicals used in this work
1
were purchased from either Aldrich or Acros Inc. H NMR
1
3
and C NMR data were recorded on Bruker DPX-300, CDPX-
00, and AMX-360 spectrometers. MS data were recorded on
3
KRATOS mass spectrometer for LR-APCI and HR-APCI. Chiral
HPLC anaylsis was carried out on a Waters 600 chromatography
equipped with an UV detector (254 nm) and a Chiralcel OD-
H column. X-ray single crystal diffraction intensity data were
measured on a Bruker SMART APEX CCD area detector system
equipped with a graphite monochromator and a MoKa fine-focus
˚
sealed tube (k = 0.71073 A) operated at 1600 watts power (50 kV,
3
2 mA).
Synthetic details
-Methoxyxanthone (5). To the solution of 4 (24.6 g,
1
0
0
.123 mol) in THF (100 mL) was added n-BuLi (2.5 M, 50.7 mL,
.142 mol) at −78 C in 1.5 h. After being stirred at this tempera-
◦
ture for 1 h, it was allowed to warm slowly to room temperature
Fig. 1 ORTEP representation of co-crystal of (R)-3 and N-benzyl-
cinchoninium chloride 8 (1 : 1) at 50% probability for the drawing of
thermal ellipsoids (hydrogen atoms and solvent molecules are omitted for
clarity).
◦
over 1 h. Then it was cooled to −78 C and added into the solution
of dimethylcarbamic chloride (11.3 mL, 0.123 mol) in THF
◦
(
50 mL) at −78 C in 30 min. After stirring at this temperature
for 1 h, the cooling bath was removed and it was warmed to room
temperature over 4 h. Then it was added dropwise into freshly pre-
◦
pared LDA solution (0.3 mol in 370 mL dry THF) at 0 C, which
was stirred overnight. Aqueous HCl (3 N, 100 mL) was introduced
◦
carefully to quench the reaction mixture at 0 C. The organic phase
was separated and washed with saturated NaHCO
brine. The water layer was extracted with EtOAc, washed with
saturated NaHCO solution, and brine. The combined organic
solution was dried with anhydrous Na SO and concentrated. The
crude product was triturated with EtOAc/hexane (1 : 9) to afford 5
3
solution and
3
2
4
1
as light yellow powder (24.8 g, 89%). H NMR (300 MHz, CD
d 3.98 (s, 3H, ArO–CH
), 6.83 (d, 1H, J = 8.3 Hz, Ar–H), 7.06
dd, 1H, J = 0.9 Hz, Ar–H), 7.34 (td, 1H, J
= 8.5 Hz, J
.9 Hz, J
= 1.0 Hz, Ar–H), 7.41–7.44 (m, 1H, Ar–H), 7.59–7.68
m, 2H, Ar–H), 8.22 (dd, 1H, J = 1.7 Hz, Ar–H); C
= 8.0 Hz, J
NMR (100 MHz, CDCl ) d 56.7, 105.6, 110.3, 112.8, 117.5, 123.3,
24.0, 127.1, 134.4, 135.0, 155.3, 158.4, 161.0, 176.8. HRMS m/z
found: 226.0636, calculated: 226.0630.
2
Cl
2
)
3
(
7
(
1
2
1
=
2
1
3
1
2
3
1
1
-Methoxy-9-(2-methoxy-6-phenoxyphenyl)xanthen-9-ol
(6).
Fig. 2 ORTEP representation of co-crystal of (S)-3 and N-benzyl-
quininium chloride 9 (1 : 1) at 50% probability for the drawing of thermal
ellipsoids (hydrogen atoms and solvent molecules are omitted for clarity).
Lithiation of 4 (20.6 g, 0.103 mol) was achieved as described in
the previous step (43.3 mL 2.5 M n-BuLi and 100 mL THF were
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2
D
0
used), and the solution was added into the solution of 5 (23.3 g,
[a] = +40.2 (c 1.0, CHCl ). To obtain the other enantiomer of
3
◦
0
.103 mol) in THF (400 mL) at −78 C within 1 h, then stirred
3, the mother solution was concentrated, and refluxed with N-
benzylquininium chloride 9 (1.97 g, 4.37 mmol) in CH CN (30 mL)
for 6 h. After being cooled to room temperature, the precipitate
overnight. The reaction mixture was quenched with saturated
3
◦
NH
4
Cl solution at 0 C, and then extracted with CH
2
Cl
2
. The
organic phase was washed with brine, dried with anhydrous
Na SO , and concentrated. The crude product was triturated
with acetone to afford 6 as white powder (34.7 g, 79%).
NMR (360 MHz, CDCl ) d 3.73 (s, 3H, ArO–CH ), 3.83 (s,
), 6.38 (d, 1H, J = 8.2 Hz, Ar–H), 6.49–6.56 (m,
H, Ar–H), 6.66–6.71 (m, 2H, Ar–H), 6.87 (d, 1H, J = 7.9 Hz,
(1 : 1 complex of (S)-3 and 9) was collected by filtration, washed
2
4
with small amount of CH CN. Treatment of the co-crystal with
3
1
H
EtOAc (30 mL) and 2 N HCl (20 mL) resulted in two layers.
3
3
The organic phase was separated, washed with 2 N HCl (20 mL)
and brine, and dried over Na SO . Evaporation of the solvent
3
3
H, ArO–CH
3
2
4
under reduced pressure produced enantiomerically pure (S)-3 as
white powder (1.22 g, 78% yield, 99.8% ee). The ee value of 3 was
Ar–H), 6.94–7.00 (m, 3H, Ar–H), 7.07–7.16 (m, 5H, Ar–H), 7.48
1
3
◦
(
d, 1H, J = 7.9 Hz, Ar–H); C NMR (75 MHz, CD
2
Cl
2
) d 56.1,
determined by HPLC at 25 C using isopropanol/hexane (4 : 96)
−
1
5
1
1
4
7.3, 70.8, 105.7, 108.8, 109.3, 114.1, 115.4, 116.8, 118.1, 122.6,
as eluent, 1 mL min , t = 31.6 min, t = 36.3 min.
R
S
23.0, 128.1, 128.2, 128.3, 128.6, 129.1, 129.5, 149.8, 150.6, 154.6,
57.4, 158.4, 158.5. HRMS m/z found: 426.1473, calculated:
26.1467.
Crystal structure determination of (R)-3:8. A clear flat-needle
shaped crystal of (R)-3:8 grown from CH CN was selected with
approximate dimensions 0.40 × 0.18 × 0.15 mm, and used for
the X-ray crystallographic analysis. Crystal data. C53
3
ꢀ
ꢀ
H
48ClN
3
O
5
1
,1 -Dimethoxy-9,9 -spirobixanthene (7). The tertiary alcohol
(
moiety formula C26
H
29
N
2
O·C25
H
16
O
4
·C
2
H
˚
3
N·Cl), M = 842.39,
6
(34.7 g, 0.081 mol), acetic acid (300 mL), and concentrated HCl
˚
˚
monoclinic, a = 14.322(4) A, b = 8.975(2) A, c = 17.157(4) A, U =
(
200 mL) were refluxed for 6 h. After acetic acid was removed under
reduced pressure, the residue was dissolved in CH Cl , washed
with saturated NaHCO solution, brine, and dried with anhydrous
Na SO , and then concentrated. The crude product was triturated
with acetone to afford 7 as white powder (27.5 g, 83%). H NMR
360 MHz, CDCl ) d 3.25 (s, 6H, ArO–CH ), 6.39 (dd, 2H, J
.2 Hz, J
= 1.0 Hz, Ar–H), 6.77–6.84 (m, 6H, Ar–H), 7.04–7.16
m, 6H, Ar–H); C NMR (90 MHz, CDCl ) d 42.1, 55.8, 100.6,
11.6, 116.5, 122.6, 124.1, 128.2, 130.4, 131.9, 132.6, 149.6, 150.5,
59.6. HRMS m/z found: 408.1347, calculated: 408.1362.
3
˚
2
0
185.2(10) A , T = 95(2) K, space group P2
1
, Z = 2, l(Mo Ka) =
2
2
−
1
.141 mm , the R value for the refinement with 6628 observed
value for refinement of all 9403 data is
3
data is 0.0571 and the wR
.1637.†
2
2
4
1
0
(
8
(
3
3
1
=
Crystal structure determination of (S)-3:9. A clear brick
shaped crystal of (S)-3:9 grown from CH CN was selected with
approximate dimensions 0.28 × 0.21 × 0.20 mm, and used for the
X-ray crystallographic analysis. Crystal data. C63.53
2
3
1
3
3
1
1
H
64.29Cl
1
N
7.76
O
6
(
moiety formula C27
H
31
N
2
O
2
·C25
H
16
O
4
·5.764(C
2
H
3
N)·Cl), M =
˚
˚
ꢀ
ꢀ
1068.00, orthorhombic, a = 9.2512(15) A, b = 19.807 (3) A, c =
9
,9 -Spirobixanthene-1,1 -diol (3). The mixture of 7 (4.9 g,
3
˚
˚
−
3
4.048(5) A, U = 6238.7(17) A , T = 98(2) K, space group P2
1
2
1
1
2 ,
0
.013 mol) and pyridine·HCl (30.4 g, 0.263 mol) were melted with
1
Z = 4, l(Mo Ka) = 0.120 mm , the R value for the refinement with
a heating mantle and reflux for 25 minutes. After cooled to room
temperature, the reaction mixture was diluted with HCl solution
1
2467 observed data is 0.0670 and the wR value for refinement of
2
all 14773 data is 0.1690.†
(
4 N, 90 mL) and extracted with EtOAc (100 mL). The organic
phase was washed with HCl (4 N, 10 mL) twice, water, saturated
NaHCO solution, brine, and dried with anhydrous Na SO , and
Acknowledgements
3
2
4
then concentrated. The crude product was triturated with acetone
1
Financial support from National Institutes of Health (GM58832)
and the NSF grant CHE-0131112 are appreciated.
to afford 3 as white powder (3.2 g, 70%). H NMR (300 MHz,
CD
.60 (dd, 2H, J
Ar–H), 6.96–7.10 (m, 6H, Ar–H), 8.15 (s, 2H, Ar–OH); C NMR
75 MHz, CD COCD ) d 38.3, 107.3, 110.8, 115.5, 116.4, 123.1,
27.6, 128.7, 131.5, 131.9, 150. 0, 151.7, 156.5. HRMS m/z found:
3
COCD
3
) d 6.30 (dd, 2H, J
1
= 8.0 Hz, J
2
= 1.2 Hz, Ar–H),
6
1
= 8.2 Hz, J = 1.2 Hz, Ar–H), 6.78–6.80 (m, 4H,
2
1
3
References
(
3
3
1
2
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3
80.1036, calculated: 380.1049.
Resolution of rac-(3). The mixture of rac-3 (3.14 g, 8.26 mmol)
and N-benzylcinchonidinium chloride 8 (1.84 g, 4.37 mmol) was
suspended in 30 mL of acetonitrile (CH CN) and refluxed for 6 h.
3
After cooled naturally to room temperature, the white precipitate
was collected by filtration, which was again suspended in 20 mL
(
g) W. Zhang, C.-J. Wang, W. Gao and X. Zhang, Tetrahedron Lett.,
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2
of CH CN and refluxed for another 6 h. When it was cooled to
3
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room temperature, the precipitate (1 : 1 complex of (R)-3 and 8)
was collected from the mother solution by filtration and washed
twice with small amount of CH CN. The solid was then stirred in
3
3
†
EtOAc (30 mL) and diluted HCl (2 N, 20 mL) until the entire solid
was dissolved. The organic phase was then separated and washed
with 2 N HCl (20 mL) and brine, dried over Na
2
SO . Evaporation
4
of the solvent under reduced pressure produced enantiomerically
CCDC reference numbers 616446–616447. For crystallographic data in
pure (R)-3 as a white powder (1.24 g, 79% yield, >99.9% ee).
CIF or other electronic format see DOI: 10.1039/b610879b
4
476 | Org. Biomol. Chem., 2006, 4, 4474–4477
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4
5
X. Cheng, G.-H. Hou, J.-H. Xie and Q.-L. Zhou, Org. Lett., 2004, 6,
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2
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4474–4477 | 4477