Synthesis of (R)-propane-1,2-diol from lactides by dynamic kinetic resolution

Article abstract of DOI:10.1016/j.tetlet.2014.04.097

The dynamic kinetic resolution (DKR) of rac-1-tert-butoxypropan-2-ol with isopropenyl acetate in the presence of Novozyme 435 and a ruthenium catalyst produces enantiomerically pure (R)-1-tert-butoxy-2-acetoxy-propane (>99.5 %ee) in a good yield. The product can be easily transformed into (R)-propane-1,2-diol without loss of stereoselectivity. Together with recently published procedures, the herein described DKR offers the possibility to use any lactide source as starting material for the production of (R)-propane-1,2-diol. The chiral diol may serve as the chiral building block for the synthesis of important enantiopure esters, like propylene carbonate, chiral polymers, etc.

Full text of DOI:10.1016/j.tetlet.2014.04.097

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (R)-propane-1,2-diol from lactides by dynamic kinetic
resolution
a
b
b
a,c,
Ivan A. Shuklov a, , Natalia V. Dubrovina , Joachim Schulze , Wolfgang Tietz , Armin Börner
⇑
⇑
a Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein Straße 29a, 18059 Rostock, Germany
b ThyssenKrupp Industrial Solutions GmbH, Am Haupttor, Bau 3668, 06237 Leuna, Germany
c Institut für Chemie der Universität Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The dynamic kinetic resolution (DKR) of rac-1-tert-butoxypropan-2-ol with isopropenyl acetate in the
presence of Novozyme 435 and a ruthenium catalyst produces enantiomerically pure (R)-1-tert-but-
oxy-2-acetoxy-propane (>99.5 %ee) in a good yield. The product can be easily transformed into (R)-pro-
pane-1,2-diol without loss of stereoselectivity. Together with recently published procedures, the herein
described DKR offers the possibility to use any lactide source as starting material for the production of
(R)-propane-1,2-diol. The chiral diol may serve as the chiral building block for the synthesis of important
enantiopure esters, like propylene carbonate, chiral polymers, etc.
Received 7 February 2014
Revised 23 April 2014
Accepted 25 April 2014
Available online xxxx
Keywords:
Propane-1,2-diol
Lactide
Ó 2014 Elsevier Ltd. All rights reserved.
Dynamic kinetic resolution
Ruthenium
PLLA
Lipase
Introduction
mely high prices of unnatural (R)-lactic acid and all its
derivatives such as (R,R)-dilactide or poly-D
-lactic acid (PDLA).6
Propane-1,2-diol (1,2-propylene glycol) is produced industrially
from propylene via propylene oxide (HPPO process).1 The annual
production is close to 1 Mio tons.2 The main part of this material
is employed for the manufacture of polyesters or polyurethanes.
Alternatively, it may serve for the production of propylene carbon-
ate (PC), which is a valuable and environmentally friendly solvent
for numerous applications.3 Usually the racemic diol is used how-
ever, an easy access to the enantiopure propane-1,2-diol would
offer new fields of application. Nonracemic 1,2-propandiol is
already frequently used as a chiral building block in the synthesis
of pharmaceuticals.4
Therefore we looked for an alternative procedure, which allows
to utilize rac-propane-1,2-diol and thus eventually any form of dil-
actide as the starting material, namely (S,S)-dilactide, rac-dilactide,
or even meso-dilactide. Our new approach to (R)-propane-1,2-diol
is based on the dynamic kinetic resolution (DKR)7 of the monopro-
tected diol proceeding via an Ru-catalyzed epimerization of the
alcohol combined with a highly stereodiscriminating enzymatic
acylation.
Results and discussion
Recently we discovered an ecologically benign access to pro-
pane-1,2-diol by a one pot alcoholysis-hydrogenation procedure
using di-, oligo-, and polylactides as feed (Scheme 1).5 At high tem-
peratures (150 °C) racemic propane-1,2-diol was formed. Interest-
ingly by use of enantiopure (S,S)-dilactide or poly-L-lactic acid
(PLLA) at lower temperatures (S)-propane-1,2-diol could be
obtained in the best case with 98 %ee.
For the DKR a properly 1-O-protected rac-propane-1,2-diol was
required (Scheme 1). The protective group should be inert towards
the conditions of the Ru-catalyzed DKR, cheap, and easily remov-
able after the transformation. As two promising candidates 1-ben-
zyloxypropane-2-ol (1a) and 1-tert-butoxypropan-2-ol (1b) were
selected. Both compounds could be synthesized by selective ether-
ification of propane-1,2-diol.8,9
Up to now, the kinetic resolution of rac-1-benzyloxypropan-2-
ol (1a) was unknown. Therefore the reaction has to be optimized
first. Two commercially available immobilized enzymes that are
stable also at high temperatures were chosen namely Candida ant-
arctica B (Novozyme 435) and Pseudomonas cepacia (Amano PS)
(Table 1).
Clearly, the same transformation with the opposite stereoiso-
mer is possible, but economically irrelevant because of the extre-
⇑
Corresponding authors.
E-mail addresses: ivan.shuklov@catalysis.de (I.A. Shuklov), armin.boerner@cata-
lysis.de (A. Börner).
http://dx.doi.org/10.1016/j.tetlet.2014.04.097
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shuklov, I. A.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.097

2
I. A. Shuklov et al. / Tetrahedron Letters xxx (2014) xxx–xxx
O
O
1. DKR
2. Deprotection
O
O
OH
OH
OH
Protection
Ref. 4
OH
OPg
OH
or
(R)
Pg = protective group
PLLA
Scheme 1. General approach to (R)-propan-1,2-diol by DKR.
The acylation with isopropenyl acetate proceeds very fast even
Ph5
Ru Cl
Bäckvall's catalyst
Novozyme 435
OH
OAc
at 40 °C with both enzymes. The reaction rate in toluene is slightly
slower than that in cyclohexane. The best stereoselectivity of
86 %ee in product 2a was induced in cyclohexane with Novozyme
435 (run 2).
OR
OR
Na2CO3, KOtBu
isopropenylacetate,
PhMe
OC
OC
1
a:
b:
2a
2b
R = Bn
R = t-Bu
up to 40 ee%
Bäckvall's
up to 99.5 ee% catalyst (4)
Subsequent trials to treat rac-1a under DKR-conditions in the
presence of Bäckvall’s Ru-catalyst 4 (Scheme 2) revealed that the
stereoselectivities are much lower than in the kinetic resolution.
Obviously, the elevated temperatures necessary for the epimeriza-
tion affect the enantioselectivity. In the best case 40 %ee were
noted with Novozyme 435 in toluene at 60 °C.
Scheme 2. DKR of 1-O-protected propane-1,2-diols (1a,b).
Table 2
Influence of the amount of enzyme on the rate of DKR of 1ba
These results prompted us to switch to 1-tert-butoxypropan-2-
ol (1b) as the substrate. The kinetic resolution of 1b has been
already described.10,11 We were pleased to see that in first trials
under DKR conditions (R)-1-tert-butoxypropan-2-ol was obtained
with 99 %ee. This result could be achieved even with 0.1 mol % of
catalyst. Noteworthy, this transformation is significantly slower
than the DKR of 1-phenoxypropan-2-ol that was taken as a refer-
ence however the synthesis of this O-arylated substrate is more
tedious and the deprotection protocol up to our knowledge is not
known.12
Run
t (h)
Novozyme 435 [mg (units)]
Conversion (%)
ee (%)
1
2
3
4
5
6
7
20
44
68
140
44
90
13 (55)
13 (55)
13 (55)
13 (55)
33 (165)
33 (165)
33(165)
40
53
60
77
66
80
85
99
99
99
99
99
99
99
190
a
Reaction conditions: 75 °C, 7.5 mL toluene, 20 mmol isopropenyl acetate,
19.8 mmol 1-tert-butoxypropan-2-ol, 0.02 mmol (Ph5Cp)Ru(CO)2Cl, 0.04 mmol tert-
BuOK, 50 mg Na2CO3.
The careful observation of the reaction process revealed that the
immobilized enzyme was slowly deactivated. Thus, after 140 h
reaction time a maximum yield of 77% was noted (Table 2, run
4). Nevertheless, the enantiomeric excess of product remained at
the extremely high level of 99% during the whole process (runs
1–4).
In order to improve the yield the amount of lipase was tripled.
Under these conditions the conversion raised from 53% to 66 %
within 44 h (Table 2, runs 2 and 5). Prolongation of the reaction
time to 90 h gave finally 80% of conversion (run 6).
Table 3
Influence of the amount of Na2CO3 on the rate of the DKR of 1ba
Run
Time (h)
Na2CO3 (mg)
Conversion (%)
ee (%)
1
2
3
4
48
120
48
50
50
150
150
65
85
85
92
99
99
99
99
120
a
Reaction conditions: 75 °C, 7.5 mL toluene, 20 mmol isopropenyl acetate,
19.8 mmol 1-tert-butoxypropan-2-ol, 0.02 mmol (Ph5Cp)Ru(CO)2Cl, 0.04 mmol tert-
The effect of sodium carbonate in the Ru-catalyzed DKR cannot
be clearly rationalized, but in general it has a positive effect on the
rate of the reaction.13 Therefore we investigated this aspect more
in detail. It was shown that the optimal amount of sodium carbon-
ate for a 20 mmol charge of the substrate is 150 mg (Table 3).
Within 48 h 85% conversion can be achieved (run 3). After reduc-
BuOK, Novozyme 435 33 mg (165 units), 0.1 mmol tert-BuOK.
tion of the amount of Na2CO3 the reaction proceeds significantly
slower (runs 1 and 2). Larger amounts do not improve the rate.
It is known from the literature that the enantiopure product 2b
of the DKR can be converted into (R)-propane-1,2-diol without loss
of enantioselectivity (Scheme 3).11
Alternatively we transformed it into (R)-2-acetoxy-1-bromo-
propane (6) by reaction with a solution of hydrogen bromide in
glacial acetic acid.14 The bromide was obtained in 99 %ee and
may serve for the synthesis of (R)-propylene oxide as shown by a
known protocol.15
Table 1
Kinetic resolution of rac-1-benzyloxypropan-2-ol (1a)a
OH
OAc
OH
Enzyme, 40 °C
OBn
OBn
+
OBn
isopropenyl acetate
1a
2a
3a
OH
Ref. 10
OH
Run Solvent
Enzyme
t (h) Conversion
ee of 2ac (%)
(%)
5
1
2
Toluene
Novozyme
435
3
1
62
47
58
86
OAc
Ot-Bu
Cyclohexaneb Novozyme
435
2b (99 %ee)
3
4
Toluene
Amano PS
3
1
40
62
70
64
Cyclohexaneb Amano PS
HBr/HOAc
2 h, r.t.
OAc
Ref. 14
Br
(99 %ee)
Scheme 3. Subsequent transformations of the DKR-product 2b.
a
O
Reaction conditions: 40 °C, 10 mL solvent, 200 units enzyme, 2.1 mmol iso-
propenylacetate, 1.8 mmol substrate.
7
6
b
1.2 mmol isopropenyl acetate.
Determined by GC on Lipodex E.
c
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I. A. Shuklov et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
7. (a) Persson, B. A.; Huerta, F. F.; Bäckvall, J.-E. J. Org. Chem. 1999, 64, 5237–5249;
(b) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park, J. Angew. Chem.,
Int. Ed. 2002, 41, 2373–2376; (c) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.;
Kim, E. J.; Kim, M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972–1977; (d) Larsson, A. L.
E.; Persson, B. A.; Bäckvall, J.-E. Angew. Chem., Int. Ed. 1997, 36, 1211–1212; (e)
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090–3100; (f) Xu, G.;
Wang, L.; Chen, Y.; Cheng, Y.; Wu, J.; Yang, L. Tetrahedron Lett. 2013, 54, 5026–
5030.
8. (a) Imaizumi, M.; Yasuda, M.; Souka, S. Ger. Patent DE 2,450,667, 1973; Chem.
Abstr. 1975, 83, 178305; (b) Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991,
39, 1972–1982.
9. Alternatively, rac-1-benzyloxypropan-2-ol is easily available by reaction of rac-
propylenoxide with benzylalcohol with 50% yield: Martin, J. C.; McGee, D. P. C.;
Jeffrey, G. A.; Hobbs, D. W.; Smee, D. F.; Matthews, T. R.; Verheyden, J. P. H. J.
Med. Chem. 1986, 29, 1384–1389.
Conclusion
The dynamic kinetic resolution (DKR) of rac-1-tert-butoxypro-
pan-2-ol with isopropenyl acetate in the presence of Novozyme
435 and ruthenium catalyst 4 gives under optimized conditions
enantiomerically pure (R)-1-tert-butoxy-2-acetoxy-propane in a
good yield propane in up to 26 g scale.16 The product can be easily
transformed into (R)-propane-1,2-diol. In combination with the
results reported earlier on the stereoselective alcoholysis-hydroge-
nation of enantiopure (S,S)-dilactide or PLLA,5 now any lactide
source can be used as starting material for the production of both
enantiomers of propylene glycol. Due to the broad availability of
the lactides and the simple and scalable processes for their stereo-
selective conversion, also enantiopure (R)-1,2-propylene glycol is
available now as building block for the production of other chiral
products like, esters, polymers, etc.
10. Goergens, U.; Scheider, M. P. J. Chem. Soc., Chem. Commun. 1991, 1064–1066.
11. Resnick, S. M.; Donate, F. A.; Frank, T. C.; Thyne, T. C.; Foley P. World Patent WO
03,083,126, 2003; Chem. Abstr. 2003, 139, 291194.
12. Bogar, K.; Martin-Matute, B.; Bäckvall, J.-E. Beilstein J. Org. Chem. 2007, 3, 3237–
3240.
13. Paetzold, J.; Bäckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620–17621.
14. (R)-2-Acetoxy-1-bromopropane 6: A two-necked, 50-mL, round-bottomed flask
fitted with a magnetic stirring bar, dropping funnel was charged with 1.00 g
(5.8 mmol) of (R)-2-O-acetyl-1-O-tert-butyl-propane-1,2-diol (2b). A solution
of 33% w/v hydrogen bromide–acetic acid (5.00 g, 20.0 mol) was added from
the dropping funnel with cooling over ca. 5 min. The homogeneous solution
was stirred at room temperature for 45 min. Then 30 mL of water was added
and the mixture was neutralized immediately with solid sodium carbonate.
The neutral solution was extracted three times with 40 mL of diethyl ether, the
organic phases were combined, dried over magnesium sulfate, and
concentrated at reduced pressure with a rotary evaporator. Distillation of the
crude product at reduced pressure afforded 0.7 g (70%) of (R)-2-acetoxy-1-
bromopropane, bp 55–57 °C (10 mbar), as a colorless liquid. Enantiomeric
purity was controlled with GC (Lipodex E).
Acknowledgements
We acknowledge financial support by ThyssenKrupp Industrial
Solutions GmbH Leuna. The authors thank Dr. C. Fischer,
S. Buchholz, and S. Schareina for excellent analytical support.
References and notes
1. See example: http://www.chemistryinnovation.co.uk/stroadmap/roadmap.
15. Ellis, M. K.; Golding, B. T. Org. Synth. 1985, 63, 140.
asp-id=445.htm;
150000046.
http://www.uhde-ftp.de/press/press_show.en.epl?stamp=
16. DKR of 1-tert-butoxypropane-2-ol on
a
multigram-scale: Chlorodicarbonyl
(400 mg, 0.6 mmol),
(1,2,3,4,5-pentaphenylcyclopentadienyl)ruthenium
4
2. Sullivan, C. J. Propanediols. In Ullmann’s Encyclopedia of Industrial Chemistry;
Wiley-VCH: Weinheim, 2005. doi: 10.1002/14356007.a22_163.
3. Schäffner, B.; Schäffner, F.; Verevkin, S.; Börner, A. Chem. Rev. 2010, 110, 4551–
4581.
4. Examples of application of nonracemic 1,2-propanediol or its derivatives in
pharmaceutical processes; (a) Levofloxacine: Fujiwara, T.; Ebata, T. US Patent
5,312,999, 1994; Tenofovir: (b) Ripin, D. H. B.; Teager, D. S.; Fortunak, J.; Basha,
S. M.; Bivins, N.; Boddy, C. N.; Byrn, S.; Catlin, K. K.; Houghton, S. R.; Jagadeesh,
S. T.; Kumar, K. A.; Melton, J.; Muneer, S.; Rao, L. N.; Rao, R. V.; Ray, P. C.; Reddy,
N. G.; Reddy, R. M.; Shekar, K. C.; Silverton, T.; Smith, D. T.; Stringham, R. W.;
Subbaraju, G. V.; Talley, F.; Williams, A. Org. Process Res. Dev. 2010, 14, 1194;
MK-0941: (c) Yoshikawa, N.; Xu, F.; Arredondo, J. D.; Itoh, T. Org. Process Res.
Dev. 2011, 15, 824–830.
immobilized CALB from Aldrich (330 mg), and Na2CO3 (1.5 g, 14 mmol) were
placed in a 500 mL three-necked flask equipped with a magnetic stirring bar
and thermometer. The flask was evacuated and filled with argon. Dry toluene
(200 mL) was added under an argon atmosphere. The reaction mixture was
stirred at room temperature until the ruthenium complex was dissolved, and
then a solution of tert-BuOK in THF (1 M) (1 mL, 1 mmol) was added. The
reaction mixture was stirred for 6 min. Then 1-tert-butoxypropan-2-ol (26.2 g,
198 mmol) was added via a syringe and the mixture was stirred for another
4 min. Finally, isopropenyl acetate (20.0 g, 200 mmol) was added via a syringe,
and the mixture was stirred under argon at 75 °C. After 120 h an aliquot
(50 lL) was taken and quenched with 1 M HCl. The sample was passed through
silica pad and analyzed by GLC (HP-5, 50 m). The analysis showed that almost
no starting material was left. The flask was cooled down to ambient
temperature, and the mixture was filtered and concentrated under reduced
pressure. The crude mixture was subjected to fractional distillation under
reduced pressure (65 °C, 15 mbar) yielding (R)-2-O-acetyl-1-O-tert-butyl-
propane-1,2-diol 23.5 g (68% yield, 99.5 %ee) as a colourless liquid.
5. Shuklov, I. A.; Dubrovina, N. V.; Schulze, J.; Tietz, W.; Kühlein, K.; Börner, A.
Chem. Eur. J. 2014, 20, 957–960.
6. (R)-Alkyl lactates are available by catalytic inversion of (S)-alkyl lactates:
Shuklov, I. A.; Dubrovina, N. V.; Schulze, J.; Tietz, W.; Kühlein, K.; Börner, A.
Tetrahedron Lett. 2012, 53, 6326–6328.
Please cite this article in press as: Shuklov, I. A.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.097