Enantiopure 1,5-diols from dynamic kinetic asymmetric transformation. useful synthetic intermediates for the preparation of chiral heterocycles

Article abstract of DOI:10.1021/ol800468h

Dynamic kinetic asymmetric transformation (DYKAT) of a series of 1,5-diols has been performed in the presence of Candida antarctica lipase B (CALB), Pseudomonas cepacia lipase II (PS-C II), and ruthenium catalyst 4. The resulting optically pure 1,5-diacet

Full text of DOI:10.1021/ol800468h

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2027-2030
Enantiopure 1,5-Diols from Dynamic
Kinetic Asymmetric Transformation.
Useful Synthetic Intermediates for the
Preparation of Chiral Heterocycles
Karin Leijondahl, Linne´a Bore´n, Roland Braun, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received March 1, 2008
ABSTRACT
Dynamic kinetic asymmetric transformation (DYKAT) of a series of 1,5-diols has been performed in the presence of Candida antarctica lipase
B (CALB), Pseudomonas cepacia lipase II (PS-C II), and ruthenium catalyst 4. The resulting optically pure 1,5-diacetates are useful synthetic
intermediates, which was demonstrated by the syntheses of both an enantiopure 2,6-disubstituted piperidine and an enantiopure 3,5-disubstituted
morpholine.
The combined metal- and enzyme-catalyzed dynamic kinetic
resolution (DKR) has developed into a useful method for
the synthesis of enantiopure secondary alcohols.1–3 The
simplicity and scalability of the method has attracted
industrial interest,4 and we recently demonstrated a laboratory
procedure5 on a 1 mol scale using a low catalytic loading.
The DKR of secondary alcohols can be extended to the
simultaneous DKRs of two chiral sec-alcohol centers, which
leads to a dynamic kinetic asymmetric transformation
(DYKAT) of diols.6,7 Recently, efficient procedures for
DYKAT of symmetric 1,3- and 1,4-diols were reported,7
using the second-generation catalyst system.2a,8
Chiral 1,5-diols are important synthetic intermediates for
the preparation of enantiomerically pure 2,6-disubstituted and
3,5-disubstituted six-membered heterocycles.9,10 In this com-
munication, we report on a DYKAT of 1,5-diols, leading to
diol derivatives in high diastereo- and enantioselectivities.
The diols used in this study for the DYKAT are shown in
Figure 1 (1a-g). The symmetrical diols 1b, 1c, 1e, 1f, and
(1) (a) Pa`mies, O.; Ba¨ckvall, J. E. Chem. ReV. 2003, 103, 3247–3262.
(b) Kim, M. J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578–
587. (c) Pa`mies, O; Ba¨ckvall, J. E. Trends Biotechnol. 2004, 22, 130–135.
(d) Mart´ın-Matute, B.; Ba¨ckvall, J. E. Opin. Chem. Curr. Biol. 2007, 11,
226–232. (e) Pellissier, H. Tetrahedron 2003, 59, 8291–8327. (f) Pellissier,
(6) (a) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J. E. J. Org. Chem. 1999,
64, 5237–5240. (b) Edin, M.; Mart´ın-Matute, B.; Ba¨ckvall, J. E. Tetrahe-
dron: Asymmetry 2006, 17, 708–715
(7) Mart´ın-Matute, B.; Edin, M.; Ba¨ckvall, J. E. Chem. Eur. J. 2006,
12, 6053–6061
(8) For a mechanistic study of the second-generation ruthenium catalyst,
.
H. Tetrahedron 2008, 64, 1563–1601
.
.
(2) (a) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Kaynak, F. B.; Ba¨ckvall,
J. E. J. Am. Chem. Soc. 2005, 127, 8817–8825. (b) Mart´ın-Matute, B.;
see ref 2b
.
Åberg, J. B.; Edin, M.; Ba¨ckvall, J. E. Chem. Eur. J. 2007, 13, 6063–6072
.
(9) (a) Lieandro, E.; Maiorana, S.; Papagni, A.; Pryce, M.; Gerosa, A. Z.;
Riva, S. Tetrahedron: Asymmetry 1995, 6, 1891–1894. (b) Dave, R.; Sasaki,
A. Org. Lett. 2004, 6, 15–18
(3) (a) Kim, N.; Ko, S.-B.; Kwon, M. S.; Kim, M.-J.; Park, J. Org. Lett.
2005, 7, 4523–4526. (b) Norinder, J.; Boga´r, K.; Kanupp, L.; Ba¨ckvall,
.
J. E. Org. Lett. 2007, 9, 5095–5098
(4) Verzijl, G. K. M.; De Vries, J. G.; Broxterman, Q. B. WO 0190396
A1 20011129, CAN 136:4770.
.
(10) (a) Stereodefined 2,6-disubstituted piperidines occur as alkaloids
in nature: Strunzand, G. M.; Finlay, J. A. The alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1986; Vol. 26, p 89. (b) Jones, T. H.; Blum,
M. S.; Robertsson, H. G. J. Nat. Prod. 1990, 53, 429–435. (c) Escolano,
(5) Boga´r, K.; Mart´ın-Matute, B.; Ba¨ckvall, J. E. Beilstein J. Org. Chem.
2007, 3, 50.
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.
10.1021/ol800468h CCC: $40.75
Published on Web 04/11/2008
2008 American Chemical Society

therefore decided to use CALB for the first step and PS-C
II for the second step. The second acylation using PS-C II
was next investigated, and monoacetate (2RS,6R)-2a was
used as the substrate to determine the selectivity of that step.
Two different acyl donors, isopropenyl acetate (IPA) and
vinyl acetate (VA), were used, and in both cases, a pseudo
E value of 21 was obtained (Table 1, entry 1 vs 2). In the
case of IPA, the reaction was slightly slower.
Table 1. Kinetic Asymmetric Transformation of Monoacetate
(2RS, 6R)-2a Using Different Acyl Donorsa
Figure 1. Diols used in the DYKAT.
1g are dl/meso mixtures, and the unsymmetrical diols 1a and
1d are racemic diastereomeric mixtures. Diols 1b, 1e, and
1g were prepared according to literature procedures.11 The
other diols, 1a, 1c, 1d, and 1f, were synthesized from simple
starting materials, and their preparation is given in the
Supporting Information.
For the development of the enzyme and ruthenium-
catalyzed DYKAT process, we chose diol 1a as a model
substrate. Previous studies have shown that Candida ant-
arctica lipase B (CALB) is very selective in the acetylation
of secondary alcohols as well as diols when a methyl group
is the medium-sized group according to Kazlauskas’ rule.12
However, the presence of an ester as the medium-sized group
did not allow the acylation to occur,13 and this was confirmed
by the DYKAT of 1a with CALB that afforded monoacetate
(2RS,6R)-2a (Scheme 1). The resulting (2RS,6R)-monoac-
acyl time S,R:R,S
donor (h) diacetate diacetate
%
pseudo
E
entry
enzyme
1
2
0.5 mg of PS-C IPA
0.5 mg of PS-C VA
19
19
95:5
94:6
13
33
21
21
a The reactions were performed on a 0.1 mmol scale using 3 equiv of
acyl donor in 1 mL of toluene at 80 °C.
To achieve an efficient DYKAT, a fast epimerization
catalyst compatible with the enzyme is required. Our group
has used two different catalysts for racemization/epimeriza-
tion of secondary alcohols in different DKR/DYKAT
protocols (Figure 2).2a,14
Scheme 1. DYKAT of Diol 1a
Figure 2. Epimerization catalysts.
Shvo’s dimeric catalyst 3 is activated by heat, and both
monomers are active in the catalytic cycle. More recently,
catalyst 4 was developed in our laboratory.2a This catalyst
needs activation by base and is very efficient under mild
reaction conditions. In order to find out which catalyst would
give the most efficient epimerization of the alcohol closest
to the carbomethoxy group in diol 1a, enantiomerically pure
monoacetate 2a was required. The kinetic asymmetric
transformation (KAT) of monoacetate (2RS,6R)-2a when run
to higher conversion provided enantiopure (2R,6R)-2a, which
was further used for the epimerization studies.15 Both of the
catalysts were tested in the epimerization of (2R,6R)-2a, and
etate 2a was a diastereomeric mixture, in which the acetate
carbon (C-6) had the (R)-configuration ((6R)/(6S) ) 98:2).
Pseudomonas cepacia lipase, PS-C II, has been used in
similar reactions and can also tolerate larger groups, such
as esters as the medium-sized groups.13 However, attempts
to use PS-C II for both alcohol centers gave a moderate
selectivity at the alcohol next to the methyl group. We
(11) (a) 1b was synthesized by NaBH4 reduction of the 2,6-heptanedione
according to: Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.;
Portland, L. A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem.
1975, 40, 675–681. (b) For the synthesis of 1e, see: Dubois, L.; Fiaud,
J.-C.; Kagan, H. B. Tetrahedron 1995, 51, 3803–3812. (c) For the synthesis
of 1g, see: Sexton, A. R.; Britton, E. C. J. Am. Chem. Soc. 1953, 75, 4357–
4358. (d) Summerbell, R. K.; Jerina, D. M.; Grula, R. J. J. Org. Chem.
1962, 27, 4433–4436.
(14) Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall, J. E. J. Am.
(12) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656–2665.
Chem. Soc. 1999, 121, 1645–1650.
(15) The reaction was performed on a 1 mmol scale using 30 mg of
PS-C II, 3 equiv of p-ClPhOAc as acyl donor in 5 mL of toluene at 60 °C
for 48 h, yielding monoacetate (2R,6R)-2a in 41% yield and 96% de.
(13) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J. E. Org. Lett. 2000, 2,
1037–1040.
2028
Org. Lett., Vol. 10, No. 10, 2008

catalyst 4 proved to be the most efficient catalyst, decreasing
the de to 24% within 5 h (Scheme 2).
2.5 mol % of Ru-catalyst 4 in 1 mL of toluene gave a high
yield (93%), an excellent ee (99%), and an anti/syn ratio of
79:21 (entry 4).16
With the optimized results from Table 2 as a guideline, a
range of 1,5-diols were acylated, and the results are given
in Table 3. It was only for diol 1a that two different enzymes
Scheme 2. Epimerization of (2R,6R)-2a Using Catalysts 3 and 4
Table 3. DYKAT of 1,5-Diolsa
We next studied the DYKAT of 1a using ruthenium
catalyst 4 and a combination of the lipases CALB and PS-C
II. The DYKAT of diol 1a was performed as a one-pot, two-
step reaction using CALB and PS-C II as the acylation
catalysts for the first and the second step, respectively. The
results are given in Table 2.
entry
diol
time (h) temp(°C) % eeb anti/synb % yieldb,c
1ad e f
72
24
48
40
40
48
77
46
80
50
50
50
100
50
98
>99
>99
>99
>99
>99 >99:1
37
>99
80:20 91 (71)
,
,
1
2
3
4
5
6
7
8
1b
1cf
1c
96:4
94:6
96:4
94:6
96 (80)
96 (73)
89
83 (61)
99 (83)
Table 2. DYKAT of 1aa
e f g
,
,
1d
1e
1fe h
80
50
55:45 77
,
i
1g
95:5
98 (81)
a Unless otherwise stated, the reactions were performed on a 1 mmol
scale in 1 mL of toluene with 3 equiv of isopropenyl acetate, 2.5-5 mg of
CALB, 0.025 equiv of Ru-catalyst, 0.025 equiv of tBuOK, and 1 mmol of
Na2CO3 under argon. b Determined by chiral GC. c Isolated yield in
parenthesis. d The reaction was run on a 2 mmol scale using 60 mg of CALB,
and 20 mg of PS-C II was added after 5 h. e 6 equiv of isopropenyl acetate
acyl donor equiv of
(equiv)
%
%
f
t
entry
tBuOK time (h) eeb anti/sync diacetate
was used. 0.05 equiv of Ru-catalyst, 0.05 equiv of BuOK in 2.5 mL of
toluene. g The reaction was run at 100 °C using 100 mg of CALB. h 0.05
t
1d
2d
3e
equiv of Ru-catalyst, 10 mg of PS-C II, and 0.06 equiv of BuOK in 2.5
IPA (6)
VA (6)
IPA (6)
IPA (3)
0.05
0.05
0.05
0.025
77
77
77
72
99 53:47
80 61:39
95 70:30
99 79:21
21
75
96
93
mL of toluene was used. i The reaction was run on a 5 mmol scale.
4d f
,
a Unless otherwise noted, all reactions were performed on a 1 mmol
scale in 2.5 mL of toluene with 0.05 equiv of Ru-catalyst, 1 mmol of
Na2CO3, 30 mg of CALB, and 5 mg of PS-C II at 80 °C under argon.
b (S,R-R,S)/(S,R+R,S). c ((S,R+R,S)/(R,R+S,S+S,R+R,S)): ((R,R+S,S)/
(R,R+S,S+S,R+R,S)). d PS-C II was added after 5 h. e 10 mg of PS-C II
was added after 10 h. f The reaction was performed on a 1 mmol scale in
1 mL of toluene with 0.025 equiv of Ru-catalyst, 1 mmol of Na2CO3, 2.5
mg of CALB, and 2.5 mg of PS-C II at 80 °C under argon.
were employed for the two acylation steps. For all other diols,
the same single enzyme (CALB for 1b-1e, 1g; PS-C II for
1f) was used for both steps.
Using the optimized conditions from Table 2, 1a was
acylated into diacetate 5a in a good yield and high enantio-
selectivity (98% ee) within 72 h at 80 °C (Table 3, entry 1).
Diacetate 5a was formed in an anti/syn ratio of 80:20. Diol
1b, which is a symmetrical diol with methyl groups as
medium-sized groups at each stereogenic center, was trans-
formed into diacetate 5b in good yield using only CALB
and Ru-catalyst 4. Diacetate 5b was obtained in excellent
enantioselectivity (>99% ee) and high diastereoselectivity
(anti/syn ) 96:4) (entry 2). In a similar manner, diol 1c was
transformed into diacetate 5c in >99% ee (entries 3 and 4).
To enable a DYKAT of diol 1d, the temperature had to be
increased up to 100 °C for the epimerization to be efficient,
and due to the high temperature, a larger amount of enzyme
was required (entry 5). Under these conditions, diacetate 5d
was obtained in an excellent ee with a good diastereoselec-
tivity. DYKAT of 1e was highly efficient and afforded
The DYKAT conditions were optimized with respect to
two different acyl donors, IPA and VA (Table 2, entry 1 vs
2). When 5 mg of PS-C II was added after 5 h and no excess
of base was used, IPA gave a higher ee but a slightly lower
anti/syn ratio and a lower conversion than the reaction with
VA (entry 1 vs 2). We chose to continue our study using
IPA as the acyl donor since it gave a more selective reaction
in the CALB-catalyzed acylation, yielding the (6R)-monoac-
etate in 99% ee. Increasing the amount of PS-C II to 10 mg,
using IPA as an acyldonor, provided a higher yield and an
improved anti/syn ratio but a lower ee (95% ee) (entry 3).
Attempts to further increase the amount of PS-C II were
unsuccessful, causing a decrease in both the enantio- and
diastereoselectivities. A concentrated reaction, with 2.5 mg
of each enzyme (CALB and PS-C II), 3 equiv of IPA, and
(16) A control experiment was run without any enzyme present which
gave no detectable amount of diacetate ruling out the potential problem
with chemical acylation taking place in the reaction.
Org. Lett., Vol. 10, No. 10, 2008
2029

diacetate 5e in high yield and excellent diastereo- and
enantioselectivities (entry 6). Diol 1f, which is a symmetrical
diol with carbomethoxy groups as medium-sized groups on
each stereogenic center, can be transformed into diacetate
5f by using PS-C II instead of CALB. When 10 mg of PS-C
II was used together with a small excess of base, the diacetate
5f was formed in 77% yield but with only 37% ee and a
very low anti/syn ratio (55:45) (entry 7). The reason for this
low selectivity is most likely that the epimerization is very
slow for this substrate in the presence of the enzyme. Finally,
diacetate 5g was obtained from 1g in excellent enantio- and
diastereoselectivities (entry 8).
Scheme 4. Synthesis of Morpholine (S,S)-8
Scheme 3. Synthesis of Piperidine (S,S)-7
dimesylate (R,R)-6g via diol (R,R)-1g. Reaction of this
dimesylate with NaNHTs in DMF afforded N-tosyl-protected
morpholine (S,S)-8 in >99% ee (trans/cis ) 95:5) (Scheme
4).
In conclusion, an efficient enantio- and diastereoselective
synthesis of 1,5-diol diacetates via DYKAT has been
developed. The enantiopure diacetates are useful building
blocks for the enantioselective synthesis of important 2,6-
disubstituted and 3,5-disubstituted six-membered hetero-
cycles.
Acknowledgment. This work was financially supported
by the Swedish Foundation for Strategic Research, the
Swedish Research Council, and AstraZeneca. We thank Dr.
Jan-Erik Nystro¨m, AstraZeneca R&D, So¨derta¨lje, for fruitful
discussions.
To demonstrate the utility of the diacetates 5, the enan-
tiomerically pure diacetate (R,R)-5b (>99% ee) was hydro-
lyzed to the corresponding diol, which was subsequently
mesylated. Reaction of the thus-formed dimesylate (R,R)-
6b with sodium tosylamide (NaNHTs) in DMF at 50 °C
afforded the corresponding piperidine (S,S)-7 in >99% ee
(trans/cis ) 95:5) (Scheme 3).
Supporting Information Available: Synthesis and char-
acterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
In a similar manner, the enantiomerically pure diacetate
(R,R)-5g (>99% ee) was converted into the corresponding
OL800468H
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Org. Lett., Vol. 10, No. 10, 2008