Synthesis and resolution of 2,2-dimethyl-1,3-diphenyl-1,3-propanediol, a new C2-symmetric and conformationally rigid acyclic diol

Article abstract of DOI:10.1016/S0957-4166(02)00185-4

Diastereomerically pure (+)- and (-)-2,2-dimethyl-1,3-diphenyl-1,3-propanediols were synthesized starting from diethyl malonate and resolved through diesters of (-)-camphanic acid and also N-carbethoxy-L-proline. The absolute configuration of the (-)-enantiomer was established by X-ray crystallography.

Full text of DOI:10.1016/S0957-4166(02)00185-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 851–855
Synthesis and resolution of
2,2-dimethyl-1,3-diphenyl-1,3-propanediol, a new C2-symmetric
and conformationally rigid acyclic diol†
K. C. Bhowmick, K. R. K. Prasad and N. N. Joshi*
Division of Organic Synthesis, National Chemical Laboratory, Pune 411008, India
Received 15 March 2002; accepted 17 April 2002
Abstract—Diastereomerically pure (+)- and (−)-2,2-dimethyl-1,3-diphenyl-1,3-propanediols were synthesized starting from diethyl
malonate and resolved through diesters of (−)-camphanic acid and also N-carbethoxy-L-proline. The absolute configuration of the
(−)-enantiomer was established by X-ray crystallography. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
hydroxy ketones; (b) enantioselective reduction of b-
diketones and (c) diastereoselective reduction of
b-diketones followed by resolution of the resulting diol.
For the synthesis of the title diol 1, the first two
methodologies failed: we were unable to bring about an
enantioselective Mukaiyama aldol condensation
between benzaldehyde and the silyl enol ether of isobu-
tyrophenone.6 Also, attempts at reduction using either
BH3 in the presence of an oxazaborolidine catalyst7 or
Ipc2BCl8 failed to reduce the starting dione, dimethyl
dibenzoyl methane 2. We therefore resorted to the third
option, reduction followed by resolution. The required
dione 2 could be easily obtained in four known steps as
shown in Scheme 1.9,10
C2-Symmetric chiral diols are known to be useful chiral
auxiliaries and ligands in asymmetric synthesis.1
Amongst these, hydrobenzoin (a 1,2-diol),2 BINOL (a
1,4-diol)3 and TADDOL (a 1,4-diol)4 have been applied
with particular success. Although a few C2-symmetric
chiral 1,3-diols are known in the literature,5 none have
proved to be very good sources of chirality. It is
important that the diol is conformationally rigid for it
to be an effective chiral auxiliary/ligand. The present
report describes our efforts to develop one such chiral
molecule, (+)-/(−)-2,2-dimethyl-1,3-diphenyl-1,3-prop-
anediol 1.
Prior to our work, Maier et al. had described the
reduction of the diketone 2 with LAH in moderate
diastereoselectivity.10 In order to enhance the selectiv-
ity, we examined various reducing agents including
LiBH4, Zn(BH4)2 and a few modified reagents derived
2. Results and discussion
Chiral 1,3-diols can be obtained via the following three
methods: (a) diastereoselective reduction of chiral b-
Scheme 1. Reagents and conditions: (a) Me2SO4, NaOEt; (b) KOH/MeOH, reflux; (c) SOCl2, reflux; (d) C6H6, AlCl3; (e)
LiAl(OtBu)2H2, THF, 0°C.
* Corresponding author. Fax: +91-20-5893153; e-mail: joshi@ems.ncl.res.in
† Dedicated to Professor H. C. Brown on his 90th birthday.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00185-4

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K. C. Bhowmick et al. / Tetrahedron: Asymmetry 13 (2002) 851–855
Since (−)-camphanic acid is an expensive resolving
reagent, we examined the possibility of using N-carb-
ethoxy-L-proline, a cheap alternative. To the best of
our knowledge, this acid has never been used as a
resolving agent for alcohols or amines. It was obtained
from LAH. It was found that lithium di-tert-butoxyalu-
minium hydride reduces 2 with very high diastereoselec-
tivity, providing ( )-1 in almost quantitative yield. No
1
meso-diol was detected by H NMR.
in almost quantitative yield by reacting sodium L-proli-
We then examined various procedures known for the
resolution of the diols. These included the separation of
diastereomeric ester derivatives of (−)-menthylacetic
acid,11 (+)-hydratropic acid,12 (−)-5-oxo-2-tetra-
hydrofurancarboxylic acid,13 ketals of (+)-camphor14
nate with ethyl chloroformate in aqueous THF. The
acid was converted to the corresponding acid chloride 6
by treatment with SOCl2 at room temperature for 12 h.
Esterification of ( )-1 with 2.5 equiv. of 6 gave the
diastereomeric diesters 7 and 8 which could not be
separated by crystallization, but were separable by flash
chromatography on silica gel. Subsequent saponifica-
tion of the diesters provided (−)-1 (40% yield, >99% ee)
from the less polar diester 7 and (+)-1 (33% yield, >99%
ee) from more polar diester 8 as depicted in Scheme 3.
and resolution with boric acid/L
-proline.15 However all
of these methods failed to resolve ( )-1. We were
eventually successful with the esters of (−)-camphanic
acid.16 It was found that the diesters 4 and 5 could be
easily separated by crystallization from toluene. The
diastereomeric purity could be monitored by TLC and
estimated by 1H NMR (benzylic protons). The solid
diester 4 was obtained in >99% de, whereas the diester
5 obtained from the mother liquor was of 66% de.
These were saponified with methanolic KOH to obtain
(+)-1 (>99% ee) and (−)-1 (66% ee), respectively
(Scheme 2). The enantiomeric purity was further con-
firmed by chiral HPLC analysis on a Chiralcel-OD®
column.
Both the resolution procedures described above were
optimized at 20 mmol of the diol. We recommend the
first method (crystallization) for procuring multigram
quantities of diastereomerically pure (+)-diol. On the
other hand, when both enantiomers are required in
relatively small amounts, the second procedure (separa-
tion by chromatography) can be adopted. Finally the
Scheme 2. Reagents and conditions: (a) PCl5; (b) 0.1N H2SO4, reflux; (c) SOCl2, reflux; (d) ( )-1, C5H5N, CH2Cl2, 0°C; (e)
crystallization; (f) KOH/MeOH, reflux.
Scheme 3. Reagents and conditions: (a) ClCOOEt, Na2CO3, H2O/THF; (b) SOCl2; (c) ( )-1, C5H5N, CH2Cl2, 0°C; (d)
chromatography; (e) KOH/MeOH, reflux.

K. C. Bhowmick et al. / Tetrahedron: Asymmetry 13 (2002) 851–855
853
absolute configuration of the diol was determined by
X-ray crystallography using the anomalous dispersion
method. It was found that (−)-1 has (R,R)-configura-
tion. The ORTEP diagram reveals that there are two
molecules in the asymmetric unit (Fig. 1).
cooled to 0°C and treated dropwise with a solution of
the diketone 2 (7.56 g, 30 mmol) dissolved in THF (30
mL). After the addition, stirring at 0°C was continued
for 2 h. The reaction was quenched by the addition of
MeOH (5 mL) followed by water (5 mL). The resulting
mixture was filtered and the solid was repeatedly
washed with EtOAc. Combined organic extract was
dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was crystallized from
aqueous MeOH to obtain pure ( )-1 (6.9 g, 90% yield);
3. Conclusion
We have thus established synthesis resolution and abso-
lute configuration of a new chiral C2-symmetric acyclic
1,3-diols. It is likely that the procedure can be extended
to several variations in the structure depending upon
the starting material. We are currently examining these
diols as chiral auxiliaries as well as ligands for certain
enantioselective reactions.
1
>99% de by H NMR; mp 110–112°C; IR (cm−1) 3288;
1H NMR l 0.81 (s, 6H), 1.85 (br. s, 2H), 4.62 (s, 2H),
7.25–7.35 (m, 10H); 13C NMR l 21.3, 41.1, 80.8, 127.2,
127.5, 127.8, 141.4. Anal. calcd for C17H20O2: C, 79.65;
H, 7.86; found: C, 79.75; H, 7.96%.
4.3. Preparation of (−)-camphanoyl chloride 3
4. Experimental
4.1. General
The literature procedure was slightly modified as fol-
lows. A mixture of (−)-camphanic acid (9.9 g, 50 mmol)
and thionyl chloride (30 mL) was heated under reflux
for 3 h. Excess thionyl chloride was distilled off and the
remaining traces were removed under vaccum to obtain
an almost quantitative yield of 3, mp 72–73°C (lit.17
69–71°C). It was dissolved in CH2Cl2 to obtain a 1 M
stock solution.
Tetrahydrofuran was freshly distilled from sodium ben-
zophenone ketyl. Dichloromethane was distilled from
calcium hydride and stored over molecular sieves. H
1
and 13C NMR spectra were recorded on Bruker 200.
Optical rotations were measured on Bellingham+Stan-
ley ADP220 digital polarimeter. HPLC analysis was
performed on DIACEL Chiralcel-OD® column. The
diketone 2 was synthesized starting from diethyl-
malonate as described in the literature.9,10 (−)-Cam-
phanic acid was prepared from (+)-camphoric acid
following the literature procedure.17
4.4. Preparation and resolution of diesters 4 and 5
To the above described solution of 3 (50 mL, 50 mmol),
a solution of ( )-1 (5.12 g, 20 mmol) in anhydrous
pyridine (12.9 mL, 160 mmol) was added dropwise at
0°C. The progress of the reaction was monitored by
TLC. After 2 h the reaction mixture was diluted with
CH2Cl2 and washed successively with 1N HCl, water
and saturated aqueous NaHCO3. The organic solution
was dried over anhydrous Na2SO4 and concentrated
under reduced pressure to obtain a mixture of the
diesters 4 and 5 (12 g, 98% crude yield). The above
4.2. Reduction of 2 to ( )-1
To a stirred suspension of LAH (3.42 g, 90 mmol) in
anhydrous THF (30 mL), t-butyl alcohol (17.2 mL, 180
mmol) was added dropwise. The resulting solution was
Figure 1. ORTEP diagram of (R,R)-(−)-1.

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K. C. Bhowmick et al. / Tetrahedron: Asymmetry 13 (2002) 851–855
crude mixture was dissolved in the minimum volume of
hot toluene and cooled gradually to 0°C over a period
of 24 h. The crystals were separated from the mother
liquor and recrystallized from toluene to obtain pure 4
Since the two diesters were easily separable on TLC,
they were purified by flash chromatography on silica gel
(300–400 mesh) using petroleum ether–ethyl acetate
(4:1) as the eluent. The diester 7 (Rf=0.37) eluted first;
4.78 g (42% overall yield); mp 62°C; [h]D −84.3 (c 1,
CHCl3); IR (cm−1): 1742, 1707, 1693; 1H NMR l
0.67–1.1 (m, 9H), 1.21–1.49 (m, 2H), 1.71–2.41 (m, 9H),
3.43–4.62 (m, 10H), 5.66–5.93 (m, 2H), 7.17–7.44 (m,
10H); 13C NMR l 14.2, 14.9, 18.4, 23.7, 24.2, 29.1,
29.3, 30.4, 41.9, 46.3, 46.8, 59.5, 61.4, 78.2, 127.8, 128.2,
137.0, 137.3, 154.7, 155.1, 171.4. Anal. calcd for
C33H42N2O8: C, 66.65; H, 7.12; N, 4.71; found: C,
66.56; H, 7.55; N, 4.56%.
1
(5.2 g, 43% overall yield); H NMR revealed >99% de
of the product: mp 234–235°C; [h]D +1.6 (c 1, CHCl3;
1
IR (cm−1) 1794, 1747; H NMR l 0.86 (s, 6H), 0.88 (s,
6H), 1.03 (s, 6H), 1.12 (s, 6H), 1.49–2.61 (m, 8H), 6.05
(s, 2H), 7.30–7.40 (m, 10H); 13C NMR l 9.5, 16.4, 18.1,
28.8, 30.9, 42.0, 54.2, 54.8, 78.6, 90.9, 127.6, 128.2,
136.5, 166.5, 178.3. Anal. calcd for C37H44O8: C, 72.06;
H, 7.19; found: C, 71.93; H, 7.54%.
4.5. Preparation of N-carbethoxy-
L-proline
The diester 8 (Rf=0.28) eluted next; 4.1 g (36% overall
yield); mp 68°C; [h]D +15.1 (c 1, CHCl3); IR (cm−1):
A solution of -proline (6.9 g, 60 mmol) in water (60
L
1
1749, 1715, 1699; H NMR l 0.73–0.99 (m, 9H), 1.18–
mL) at 0°C, was treated with sodium carbonate (7.63 g,
72 mmol) and the resulting solution was stirred for 30
min. To this mixture, a solution of ethyl chloroformate
(6.9 mL, 72 mmol) in THF (15 mL) was added drop-
wise at 0°C. After the addition, stirring was continued
for 2 h. The reaction mixture was brought to ambient
temperature and washed with CHCl3 (30 mL). The
aqueous portion was acidified to pH 3 and extracted
with CHCl3. The extract was dried over anhydrous
1.36 (m, 2H), 1.82–2.41 (m, 9H), 3.37–4.64 (m, 10H),
5.76–5.96 (m, 2H), 7.22–7.47 (m, 10H); 13C NMR l
14.3, 14.7, 18.3, 23.5, 24.3, 41.9, 46.3, 46.7, 59.0, 59.3,
61.2, 78.3, 127.7, 128.2, 137.4, 154.6, 155.0, 171.5. Anal.
calcd for C33H42N2O8: C, 66.65; H, 7.12; N, 4.71;
found: C, 66.21; H, 7.01; N, 4.68%.
4.8. Preparation of (+)-1
Na2SO4 and concentrated to obtain N-carbethoxy-L-
The diester 4 or 8 (4 g) was heated under reflux with 1N
KOH in methanol (20 mL) for 1 h. Excess solvent was
removed on a rotavapor, water (20 mL) was added and
the reaction mixture was extracted with ether. The
extract was washed with brine, dried over anhydrous
Na2SO4 and concentrated. The residue of the diol (+)-1
was crystallized from hexane–THF (10:1); mp 125–
126°C; [h]D +8.0 (c 1, CHCl3). The spectral data of the
product was identical to that of the racemate. The
enantiomeric excess was found to be >99% by HPLC
analysis on Chiralcel-OD® column using hexane–iso-
propyl alcohol as the solvent.
proline as a viscous liquid which solidifies upon tritura-
tion with cold petroleum ether; 11 g (quantitative
yield); mp 65°C; [h]D −98.2 (c 1, CHCl3); IR (cm−1):
1
1740, 1664, 1651; H NMR l 1.08–1.50 (m, 3H), 1.75–
2.44 (m, 4H), 3.29–3.83 (m, 2H), 3.96–4.58 (m, 3H),
10.53 (br. s, 1H); 13C NMR l 14.2, 23.1, 23.9, 29.4,
30.5, 46.2, 46.4, 58.4, 58.7, 61.3, 61.4, 154.7, 155.5,
176.0, 176.5. Anal. calcd for C8H13NO4: C, 51.33; H,
7.00; N, 7.48; found: C, 51.38; H, 7.17; N, 7.29%.
4.6. Preparation of the acid chloride 6
4.9. Preparation of (−)-1
N-Carbethoxy-L-proline (9.35 g, 50 mmol), thionyl
chloride (10 mL) and benzene (10 mL) were stirred at
room temperature for 12 h (reaction monitored by the
rate of HCl and SO2 evolution). Benzene and excess
thionyl chloride were removed under reduced pressure
using a rotavapor. The light yellow residue was almost
pure 6 in quantitative yield. It was dissolved in CH2Cl2
to obtain a 1 M solution, which can be kept for several
days with gradual decomposition.
Saponification of the diester 5 or 7 as described above
provided (−)-1 which was also crystallized from hex-
ane–THF (10:1) to obtain white needles; mp 125–
126°C; [h]D −8.0 (c 1, CHCl3). Absolute configuration
of the enantiomer was found to be (R,R) by X-ray
crystallography.
4.10. Crystallographic analysis of (−)-1
4.7. Preparation of the diesters 7 and 8
Colourless, needle-like crystals were grown from hex-
ane–THF (10:1), C17H20O2, M=256.35, a=11.8587 (6),
,
,
To the above described solution of 6 (50 mL, 50 mmol),
a solution of ( )-1 (5.12 g, 20 mmol) in anhydrous
pyridine (12.9 mL, 160 mmol) was added dropwise at
0°C. The progress of the reaction was monitored by
TLC. After 2 h the reaction mixture was diluted with
CH2Cl2 and washed successively with 1N HCl, water
and saturated aqueous NaHCO3. The organic solution
was dried over anhydrous Na2SO4 and concentrated
under reduced pressure to obtain a mixture of the
diesters 7 and 8 as a viscous liquid (11.4 g, 96% crude
yield).
b=10.0497 (3), c=12.3563 (11) A, v=1472.4 (3) A,
T=299 K, Z=4, Dcalcd=1.16 g/cm3. Final goodness of
fit=1.045, R=0.031, wR=0.088. Absolute structure
determination was completed using the Flack
parameter.18
Crystallographic data (excluding structure factors) for
(R,R)-(−)-1 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 179858. Copies of the data can
be obtained, free of charge, on application to CCDC,

K. C. Bhowmick et al. / Tetrahedron: Asymmetry 13 (2002) 851–855
855
12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.
uk].
7. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem.
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Acknowledgements
8. (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran,
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This work was supported by grants from Department
of Science and Technology. We are thankful to Dr. P.
E. Fanwick, Purdue University, Indiana, USA, for the
X-ray crystallographic analysis. We are also thankful to
CSIR for a Research Fellowship to K.C.B.
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11. Dietl, F.; Merz, A.; Tomahogh, R. Tetrahedron Lett.
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