Dynamic kinetic resolution of primary alcohols with an unfunctionalized stereogenic center in the β-position

Article abstract of DOI:10.1002/adsc.200700222

Primary alcohols with an unfunctionalized stereogenic center in the β-position undergo an enzyme- and metal-catalyzed dynamic kinetic resolution (DKR). The in situ racemization of the primary alcohol, required for the DKR, takes place via: (i) ruthenium-c

Full text of DOI:10.1002/adsc.200700222

COMMUNICATIONS
DOI: 10.1002/adsc.200700222
Dynamic Kinetic Resolution of Primary Alcohols with an
Unfunctionalized Stereogenic Center in the b-Position†
Dirk Strübing,a Patrik Krumlinde,a Julio Piera,a and Jan-E. Bäckvalla,*
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 10691 Stockholm, Sweden
Fax : (+46)-8-154-908; e-mail: jeb@organ.su.se
Part of this work was reported in a lecture at the Third International Conference on Biocatalysis (Biocat 2006), Hamburg,
†
September 3–7, 2006.
Received: March 6, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Primary alcohols with an unfunctionalized
stereogenic center in the b-position undergo an
enzyme- and metal-catalyzed dynamic kinetic reso-
lution (DKR). The in situ racemization of the pri-
mary alcohol, required for the DKR, takes place
via: (i) ruthenium-catalyzed dehydrogenation of the
alcohol, (ii) enolization of the aldehyde formed, and
(iii) ruthenium-catalyzed readdition of hydrogen to
the aldehyde. The present method widens the scope
of metal- and enzyme-catalyzed DKR, which has so
far been limited to a-chiral alcohol and amine de-
rivatives.
Scheme 1. Principle of a dynamic kinetic resolution (DKR).
During the past decade, various DKR methods
based on the combination of an enzyme and an addi-
tional racemization catalyst have been developed.[5d,6]
In particular, the combination of an enzyme and a
transition metal catalyst has proven to be useful for
DKR of secondary alcohols.[5d] In the first efficient
system developed,[7] Shvoꢀs ruthenium catalyst 1
(Scheme 2) was employed, and this catalyst requires a
Keywords: dynamic kinetic resolution; enzyme cat-
alysis; metal catalysis; primary alcohols
The development of efficient protocols for the synthe- slightly elevated temperature. This procedure has
sis of optically active compounds has attracted major been successfully applied to the DKR of various sub-
attention in organic chemistry, because of the increas- stituted secondary alcohols including diols[8] and allyl-
ing demand for such compounds as building blocks in ic alcohols.[9] The method was recently extended to
the pharmaceutical or agrochemical industry.[1] The amines.[10]
most common way to prepare enantiomerically pure
Further developments have led to room tempera-
compounds in the chemical industry is still via resolu- ture procedures for DKR of secondary alcohols that
tion and separation of enantiomers from racemic mix- employ a new type of racemization catalyst together
tures.[2] In this respect, enzymatic resolution plays an with an enzyme.[11–13] In all these applications, the
important and dominant role[3] and a number of metal catalyst can be compared with the dehydrogen-
multi-ton industrial processes are based on enzymatic ase/hydrogenase activity by enzymes having NAD(P)/
resolution.[4] A drawback with these kinetic resolu- NAD(P)H as cofactor.
tions (KR) is the maximum theoretical yield of 50%
All of the protocols for chemoenzymatic DKR of
leading to waste of half of the material. A solution to alcohols and amines described to date have been lim-
this problem is dynamic kinetic resolution (DKR),[5] ited to substrates that are chiral at the a-carbon (A,
which takes advantage of an in situ racemization of Figure 1). An extension of chemoenzymatic DKR to
the remaining substrate enantiomer (Scheme 1). In alcohols and amines with a non-functionalized chiral
this way a yield of up to 100% of enantiopure materi- carbon, for example, B (Figure 1) would significantly
al can be achieved.
broaden the scope of the method.
Adv. Synth. Catal. 2007, 349, 1577 – 1581
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1577

Dirk Strübing et al.
COMMUNICATIONS
Scheme 2. Shvoꢀs catalyst 1 and its role in the racemization of secondary alcohols.
position, where the in situ racemization occurs via an
indirect pathway in the DKR process.
As outlined in Scheme 1, a DKR process relies on
an in situ racemization of the remaining substrate en-
antiomer by a chosen catalyst. In the case of catalyst
1 and secondary alcohols, this process takes place via
a reversible oxidation of the unreactive enantiomer of
the substrate to the corresponding ketone, which is re-
duced again by the generated ruthenium hydride 1a
Figure 1. Alcohols and amines for dynamic kinetic resolu-
tion.
Compound B has a chiral center in the b-position (Scheme 2). Since the hydrogenation of the prochiral
to the alcohol or amine and it is not straightforward ketone by 1a can occur from either face, this process
to racemize this center, which is a requirement for leads to racemization of the remaining starting mate-
DKR. A multitude of biologically active compounds rial.
are related to structure B and in particular b-aryl-sub-
In contrast to secondary alcohols, the racemization
À
stituted alcohols are, either by themselves or after ox- of b-branched primary alcohols by C H bond cleav-
idation to the corresponding acid, part of many im- age is not straightforward. However, an indirect
portant non-steroidal anti-inflammatory drugs like method for racemization of alcohol 2a would be to
Naproxol, Naproxen and Ibuprofen (Scheme 3).[14]
utilize the dehydrogenase/hydrogenase activity of
Herein, we report on a DKR of primary alcohols metal catalyst 1 to create an equilibrium between pri-
with an unfunctionalized stereogenic center in the b- mary alcohol and aldehyde, where the latter can un-
dergo enolization (Scheme 4). Enolization of the alde-
hyde, which can be facilitated by elevated tempera-
ture or acid/base catalysis, would lead to racemiza-
tion. In contrast to the racemization of secondary al-
cohols, it is important to note that catalyst 1 serves
only as an indirect racemization catalyst for the pri-
mary alcohols.
In addition to the choice of a suitable metal catalyst
1, a highly enantioselective enzyme is required for the
esterification of b-branched primary alcohols. Kawa-
saki et al. have reported a highly efficient kinetic res-
olution protocol for various primary alcohols.[15]
A
KR system incorporating a lipase from Burkholderia
cepacia in the presence of differently substituted vinyl
3-phenylpropanoates as acyl donors was found to be
the most selective. Encouraged by their findings, we
investigated the DKR of the chosen model substrate
Scheme 3. Some representative examples for b-aryl-substi-
tuted alcohols and derived carboxylic acids with anti-inflam-
matory activity.
1578
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 1577 – 1581

Dynamic Kinetic Resolution of Primary Alcohols
COMMUNICATIONS
Scheme 4. Proposed mechanism for the DKR of the primary alcohol 2a as model substrate.
2a in an initial screening. Hereby, the influence of var- high enantioselectivity (92% ee, 79% yield, entry 1,
ious solvents, reaction temperatures and reaction Table 1). However, as we have already reported in
times, vinyl 3-arylpropanoates and different prepara- our previous work on the DKR of secondary alco-
tions of immobilized Burkholderia cepacia lipases hols[7b], the nature of the acyl donor also plays an im-
were investigated (data not shown). As a result, a portant role in the selectivity of the reaction. There-
combination of Amano Lipase PS-D I and vinyl 3-[4- fore, we studied the influence of different acyl donors
(trifluoromethyl)phenyl]propanoate (3) as acyl more carefully. As depicted in Table 1, the use of iso-
donor[16] afforded the desired product in good yield in propenyl- (4) and 2,2,2-trifluoroethyl- (5) substituted
Table 1. Optimization of reaction conditions.[a]
Entry
Acyl donor
Time [h]
Conversion [%]
Yield [%][f]
ee [%]
1
2
3
4
3
4
5
6
7
3
6
6
6
6
24
24
24
24
24
24
24
36
24
36
>99
60
85
>99
>99
>99
83
87
>99
>99
79
39
83
92
89
80
78
80
79
93
92
91
66
84
81
74
93
92
93
93
5
6[b]
7[c]
8[c]
9[c,d]
10[c,e]
[a]
Reaction conditions: unless otherwise noted 0.1 mmol 2a, 0.15 mmol acyl donor, 5 mg PS-D I, 5 mol% 1, 808C, toluene.
Reaction was run under one atmosphere of hydrodrogen.
3 mg PS-D I.
10 mol%1.
1 mg PS-D I added after 24 h, reaction went to completion after additional 12 h.
Yield determined by HPLC.
[b]
[c]
[d]
[e]
[f]
Adv. Synth. Catal. 2007, 349, 1577 – 1581
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1579

Dirk Strübing et al.
COMMUNICATIONS
acyl donors resulted either in lower yield or decreased subjected various racemic primary alcohols with a chiral
enantiomeric excess (ee) of the desired product (en- center at the b-carbon to the reaction conditions devel-
tries 2 and 3, Table 1). However, the employment of oped. As shown in Table 2, the chosen catalytic system
4-nitrophenyl- (6) or 4-chlorophenyl 3-[4-(trifluoro- was suitable for a wide range of primary alcohols. For
methyl)phenyl]propanoates (7) as acyl donors furnish- instance, varying the alkyl part towards ethyl- and n-
ed the model product in very good yield but in slight- propyl-subtituents afforded the corresponding products
ly decreased enantioselectivities (entries 4 and 5, in good yields and enantiomeric excess (70–80% yield,
Table 1). Therefore, we decided to investigate the use 78–86% ee, entries 2 and 3, Table 2). Furthermore, dif-
of acyl donor 6 in detail. A significant improvement ferent aryl-substituted alcohols were tested as well. The
in enantioselectivity was achieved by lowering the desired products were generally isolated in good to high
amount of the enzyme, which was also accompanied yields (70–85%) with ees up to 99% (entries 4–8,
by a lower conversion (93% ee, 83% conversion, Table 2). Importantly, the method developed is not only
entry 7, Table 1). Most probably, the latter observa- limited to b-aryl-substituted primary alcohols, since also
tion can be rationalized by a deactivation of the the cyclohexyl-derived alcohol 2i was converted success-
enzyme, since prolonging the reaction time to 36 h fully to the enantiomerically enriched ester (84% ee,
did not lead to full conversion (entry 8, Table 1). To 84% yield, entry 9, Table 2).
increase the concentration of the intermediate alde-
In conclusion, we have shown that DKR of primary
hyde species, which would presumably increase the alcohols with an unfunctionalized stereogenic center
reaction rate, the amount of ruthenium catalyst 1 was at the b-carbon can be achieved via combined
raised to 10 mol%. Unfortunately, this resulted in a enzyme and metal catalysis. The in situ generation of
lower yield at full conversion, which made this ap- an a-branched aldehyde is of vital importance for the
proach unfeasible (entry 9, Table 1). However, the DKR process, since this intermediate can be race-
best results were achieved by simply adding fresh mized by means of a straightforward enolization reac-
enzyme to the reaction mixture after 24 h. Using this tion. Various b-racemic primary alcohols were con-
approach, the desired product was obtained in very verted to the enantiomerically enriched alcohol esters
good yield and enantioselectivity (93% ee, 93% yield, in good to high yields and with a good to high optical
entry 10, Table 1).
purity (up to 99% ee).
After determining the optimized DKR conditions,
the scope of the method was investigated. Hence, we
Experimental Section
Table 2. Scope of the method.[a]
Representative Procedure for the DKR of Primary
Alcohols 2a–i: DKR of 2a to 8a
A flame-dried Schlenk tube was charged under Ar with
0.5 mmol 2a, 0.6 mmol 4-nitrophenyl 3-[4-(trifluoromethyl)-
phenyl]propanoate (6), 5 mol% Shvo catalyst 1, 15 mg PS-
D “Amano” I and toluene (5 mL). The mixture was stirred
for 24 h at 808C. Afterwards 5 mg of fresh PS-D “Amano” I
were added and the reaction was allowed to continue for ad-
ditional 12 h at 808C. After cooling, all volatile compounds
were removed under reduced pressure. Silica gel flash chro-
matography (n-pentane/EtOAc) afforded 8a as a colorless
Entry Product R1/R2
Yield [%][b] ee [%]
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
8g
8h
8i
Ph/Me
Ph/Et
Ph/n-Pr
2-MeO-C6H4/Me 72
3-MeO-C6H4/Me 85
4-MeO-C6H4/Me 70
4-O2N-C6H4/Me
4-Br-C6H4/Me
cyclohexyl/Me
87
80
70
93
78[c]
86[c]
>99[c]
83[c]
71[c]
67[c]
70[c]
84[c]
1
oil; yield: 87%. H NMR (400 MHz, CDCl3): d=7.51 (d, J=
8.1 Hz, 2H), 7.33–7.17 (m, 7H), 4.20 (dd, J=10.8 Hz,
7.1 Hz, 1H), 4.13 (dd, J=10.8 Hz, 7.0 Hz, 1H), 3.06 (m,
1H), 2.94 (t, J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.26
(d, J=7.0 Hz); 13C{1H} NMR (100 MHz, CDCl3): d=172.3,
7[d]
8[d]
9[d]
85[e]
3
144.5, 143.0, 128.6, 128.5, 127.2, 126.7, 125.4 (q, JCF
=
81
84
3.7 Hz), 69.5, 38.9, 35.3, 30.6, 18.0; HR-MS (ESI): m/z=
359.1229, calcd. for C19H19F3O2Na [M+Na]+: 359.1234.
[a]
Reaction conditions: unless otherwise noted 0.5 mmol al-
cohol, 0.6 mmol 6, 15 mg PS-D I, 5 mol% 1, 808C, 5 mL
toluene for 24 h, then 5 mg PS-D I to complete reaction
after additional 12 h.
Isolated yield.
Acknowledgements
[b]
[c]
Determined after hydrolysis to the corresponding alco-
hol.
We are grateful for financial support from the Swedish Re-
search Council, the Swedish Foundation for Strategic Re-
search, the Wenner-Gren Foundation and the Ministerio de
Educación y Ciencia of Spain.
[d]
[e]
48 h.
Yield determined by 1H NMR.
1580
asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 1577 – 1581

Dynamic Kinetic Resolution of Primary Alcohols
COMMUNICATIONS
References
[8] a) M. Edin, J. Steinreiber, J.-E. Bäckvall, Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5761; b) B. Martín-Matute,
J.-E. Bäckvall, J. Org. Chem. 2004, 69, 9191.
[1] a) J. Halpern, B. M. Trost, Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5347; b) H. B. Kagan, Historical perspective,
in: Comprehensive Asymmetric Catalysis, (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin,
1999; c) A. M. Rouhi, Chem. Eng. News 2004, 82, 47;
d) Catalytic Asymmetric Synthesis, 2nd edn., (Ed.: I.
Ojima), Wiley-VCH, New York, 2000.
[2] M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keb
eler, R. Stürmer, T. Zelinski, Angew. Chem. Int. Ed.
2004, 43, 788.
[3] a) C.-H. Wong, Nature 2001, 409, 232; b) K. Faber, Bio-
transformations in Organic Chemistry, 5th edn., Spring-
er, Berlin, 2004; c) U. T. Bornscheuer; R. J. Kazlauskas.
Hydrolases in Organic Synthesis, 2nd edn., Wiley-VCH,
Weinheim, 2005.
[4] a) A. Liese, K. Seelbach, C. Wandrey, (Eds.), Industrial
Biotransformations, 2nd edn., Wiley-VCH, Weinheim,
2006; b) A. M. Thayer, Chem. Eng. News 2006, 84, 29.
[5] a) K. Faber, Chem. Eur. J. 2001, 7, 5005; b) R. Noyori,
M. Tokunaga, M. Kitamura, Bull. Chem. Soc. Jpn.
1995, 68, 36; c) R. S. Ward, Tetrahedron: Asymmetry
1995, 6, 1475; d) O. Pàmies, J.-E. Bäckvall, Chem. Rev.
2003, 103, 3247.
[9] D. Lee, E. A. Huh, M. J. Kim, H. M. Jung, J. H. Koh, J.
Park, Org. Lett. 2000, 2, 2377.
[10] J. Paetzold, J.-E. Bäckvall, J. Am. Chem. Soc. 2005,
127, 17620.
[11] a) J. H. Choi, Y. K. Choi, Y. H. Kim, E. S. Park, E. J.
Kim, M.-J. Kim, J. Park, J. Org. Chem. 2004, 69, 1972;
b) N. Kim, S.-B. Ko, M. S. Kwon, M.-J. Kim, J. Park,
Org.Lett. 2005, 7, 4523.
[12] a) B. Martín-Matute, M. Edin, K. Bogµr, F. B. Kaynak,
J.-E. Bäckvall, J. Am. Chem. Soc. 2005, 127, 8817; b) L.
BorØn, B. Martín-Matute, Y. Xu, A. Cꢂrdova, J.-E.
Bäckvall, Chem. Eur. J. 2006, 12, 225; c) B. Martín-
Matute, M. Edin, J.-E. Bäckvall, Chem. Eur. J. 2006, 12,
6053.
[13] For a recent lipase-based DKR at room temperature
using AlMe3 for the racemization see: A. Berkessel,
M. L. Sebastian-Ibarz, T. N. Müller, Angew. Chem. Int.
Ed. 2006, 45, 6567.
[14] a) T. Y. Shen, Angew. Chem. Int. Ed. Engl. 1972, 11,
460; b) A. J. Hutt, J. Caldwell, Clin. Pharmacokinet.
1984, 9, 371; c) J. H. Fried et al., J. Med. Chem. 1970,
13, 203; d) P. J. Hayball, Drugs 1996, 52, 47; e) M. F.
Landoni, A. Soraci, Curr. Drug. Metab. 2001, 2, 37.
[15] a) M. Kawasaki, M. Goto, S. Kawabata, T. Kodama, T.
Kometani, Tetrahedron Lett. 1999, 40, 5223; b) M. Ka-
wasaki, M. Goto, S. Kawabata, T. Kometani, Tetrahe-
dron: Asymmetry 2001, 12, 585.
[6] a) O. Pàmies, J.-E. Bäckvall, Trends Biotechnol. 2004,
22, 130; b) O. Pàmies, J.-E. Bäckvall, Curr. Opin. Bio-
technol. 2003, 14, 407; c) M.-J. Kim, Y. Anh, J. Park,
Curr. Opin. Biotechnol. 2002, 13, 578.
[7] a) A. L. E. Larsson, B. A. Persson, J.-E. Bäckvall,
Angew. Chem. Int. Ed. Engl. 1997, 36, 1211; b) B. A.
Persson, A. L. E. Larsson, M. Le Ray, J.-E. Bäckvall, J.
Am. Chem. Soc. 1999, 121, 1645.
[16] Vinyl esters as acyl donors in the transterification lead
to an irreversible reaction due to formation of acetal-
dehyde: Y. F. Wang, J. J. Lalonde, M. Momongam,
D. E. Bergbreiter, C.-H. Wong, J. Am. Chem. Soc.
1988, 110, 7200.
Adv. Synth. Catal. 2007, 349, 1577 – 1581
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1581