Chemoenzymatic dynamic kinetic resolution of axially chiral alienes

Article abstract of DOI:10.1002/chem.201000301

(Chemical Equation Presented) At the palladium: Dimeric palladium bromide complexes bearing monodentate N-heterocyclic carbene ligands have been identified as efficient catalysts for the chemoselective racemization of axially chiral allenyl alcohols. In combination with porcine pancreatic lipase as biocatalyst, a dynamic kinetic resolution has been developed, giving access to optically active alienes in good yield and high enantiomeric purity (see scheme).

Full text of DOI:10.1002/chem.201000301

COMMUNICATION
DOI: 10.1002/chem.201000301
Chemoenzymatic Dynamic Kinetic Resolution of Axially Chiral Allenes
Jan Deska, Carolina del Pozo Ochoa, and Jan-E. Bꢀckvall*[a]
Dedicated to Professor Uli Kazmaier on the occasion of his 50th birthday
Although racemization is normally an undesired reaction
in asymmetric synthesis, its combination with a resolution
process is a powerful approach for obtaining enantiomeri-
cally pure compounds. Resolution of racemic mixtures[1] by
physical or chemical means, and particularly by enzyme cat-
alysis,[2] is still often the method of choice when it comes to
the production of optically pure material. However, kinetic
resolution of racemates suffers from the limitation of a max-
imum theoretical yield of 50% for one pure enantiomer.
The undesired enantiomer remains as waste and has to be
removed from the product in an additional purification step.
At this point, controllable and selective racemization proto-
cols come into play as they allow for in situ interconversion
of the slow reacting enantiomer into its mirror image (and
vice versa) leading to dynamic kinetic resolution (DKR),
where 100% yield together with high enantiomeric purity
becomes possible.
cellent enantioselectivities.[9] With this tool in hand, the
strategy was to develop a DKR by combining the enzymatic
transesterification[10] with a Pd-catalyzed allene racemization
previously developed in our laboratory (Scheme 1).[11] In
Based on this strategy, a plethora of novel approaches has
arisen over the past decade, combining various different
Scheme 1. Principle of a chemoenzymatic allene DKR.
raceACHTUNGTRENNUNG
mization processes with chemical[3] or enzymatic[4] reso-
lution making DKR a versatile and powerful tool in asym-
metric synthesis. Although DKR procedures are well known
for centrochiral compounds, dynamic kinetic approaches
dealing with axially, planar or helically chiral substrates are
extremely rare.[5,6] Allenes are an important class of axially
chiral compounds[7] and in the present study we report on a
novel chemoenzymatic DKR of allenes, in which an NHC–
palladium complex is employed as racemization catalyst.
In the field of dynamic kinetic resolution, our group is
particularly interested in the combination of transition
metal mediated racemization processes with enzymatic reso-
lution.[8] Recently, we reported the use of porcine pancreatic
lipase (PPL) as a highly efficient biocatalyst for the kinetic
resolution of axially chiral primary allenic alcohols with ex-
contrast to other DKR approaches, the chiral group that is
racemized in the starting material is also present in the
product. To avoid undesired product racemization, catalytic
systems with a substantial selectivity for the starting materi-
al are required, that is, a faster racemization of the chiral
allene moiety in the allenol compared to the allenyl ester.
Unfortunately, the reported[11] catalysts, [Pd
ACTHUNTRGNE(UGN OAc)2]/LiBr
and [(PhCN)2PdBr2]), racemized the allenol and the product
allenyl ester with about the same rate (vide infra). Further-
more, these catalysts were incompatible with the enzyme
PPL, leading to a dramatically reduced biocatalytic activity.
Nevertheless, by combining PPL-catalyzed kinetic resolution
of allenol 1a with the [PdACTHNUTRGNE(UGN OAc)2]/LiBr-catalyzed racemiza-
tion in a sequential fashion, optically active butyrate (R)-2a
was obtained in high enantiomeric excess and 71% isolated
yield after only one recycling (Scheme 2). Thus, after a first
kinetic resolution, the remaining enantioenriched alcohol
(S)-1a was isolated, racemized, and subjected to a second
enzymatic cycle.
[a] Dr. J. Deska, C. del Pozo Ochoa, Prof. J.-E. Bꢀckvall
Department of Organic Chemistry, Arrheniuslaboratoriet
Stockholm University, S-10691 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: jeb@organ.su.se
Chem. Eur. J. 2010, 16, 4447 – 4451
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4447

Scheme 2. Sequential kinetic resolution/racemization.
Scheme 3. NHC–palladium complexes used in allene racemization.
For a one-pot dynamic kinetic resolution, novel racemiza-
tion catalysts are required that are compatible with the bio-
catalyst and racemize the substrate faster than the product.
Therefore, a screening of potential catalysts for the allene
racemization was performed, studying the progressive loss
of enantiopurity over time of (S)-1a and (R)-2a. Both [Pd-
Further advantages of these complexes are tolerance to-
wards air and easy accessibility from the parent carbene and
an appropriate palladium source.[12c] To our delight racemi-
zation occurred smoothly at 508C with 1 mol% of
AHCTUNGRTENNG[UN {(IMes)PdBr2}2] or [{(IPr)PdBr2}2] and, importantly, with
about a fivefold preference for allenic alcohol 1a over buty-
rate 2a (Table 1, entries 6 and 7). Saturated NHC complex,
[{(SIPr)PdBr2}2] showed good selectivity and enzyme com-
patibility, but the catalyst suffered from lower activity as in-
dicated by extended half times of racemization (Table 1,
ACHTUNGTRENNUNG(OAc)2]/LiBr and [(MeCN)2PdBr2] (5 mol%) gave fast race-
mization of alcohol (S)-1a and butyrate (R)-2a at 508C with
only a marginally longer half time of the latter. As men-
tioned above these catalysts are not compatible with PPL
and were therefore not applicable in a DKR process
(Table 1, entries 1 and 2). With stronger binding ligands,
entry 8).
The
bioxazoline-derived
complex
[{(IBiox6)PdBr2}2], however, did not show any selectivity in
racemization of alcohol 1a versus butyrate 2a (Table 1,
entry 9).
Table 1. Palladium-catalyzed racemization of allenol (S)-1a and butyrate
(R)-2a.[a]
With these selective racemization catalysts in hand, the
question arose whether the bulky NHC ligands would also
be able to diminish the undesirable enzyme inhibition and
thereby facilitate an integrated chemoenzymatic DKR pro-
cess. Hence, we conducted PPL-catalyzed kinetic resolution
of 1a in the presence of different concentrations of palladi-
um bromide and studied the relative activities of the biocat-
alyst at 358C. Gratifyingly, none of the NHC–Pd dimers
caused the severe enzyme poisoning observed with other
palladium sources. As illustrated for [{(IPr)PdBr2}2]
(Figure 1) good activity of PPL was maintained even at high
Entry
Pd source
t1/2 (1a)
t1/2 (2a)
Selectivity[c]
[h][b]
[h][b]
1[d]
2
3
4
5
6
7
8
9
[Pd
[(MeCN)2PdBr2]
[(PPh3)2PdBr2]
[(Py)2PdBr2]
[(Bipy)PdBr2]
[{(IMes)PdBr2}2]
[{(IPr)PdBr2}2]
[{(SIPr)PdBr2}2]
[{(IBiox6)PdBr2}2]
(OAc)2]/LiBr
0.12
0.27
0.13
0.43
1.1
1.6
ACHTUNGTRENNUNG
A
no racemization
no racemization
no racemization
67
69
ACHTUNGTRENNUNG
N
12
13
31
70
5.4
R
5.3
4.5
1.1
T
141
74
ACHTUNGTRENNUNG
[a] Reactions performed at 508C with (S)-1a (50 mmol) or (R)-2a
(50 mmol) and Pd catalyst; entries 1–5: 2.5 mmol (5 mol%); entries 6–9:
0.5 mmol (1 mol%) in toluene (1 mL). [b] Determined by chiral HPLC.
[c] Selectivity=t1/2ACHTUNGTRENNUNG(2a):t1/2CAHTUNGTRENN(UGN 1a). [d] MeCN was used as solvent.
such as triphenylphosphine, pyridine, or 2,2’-bipyridine, vir-
tually no racemization was detected (Table 1, entries 3–5).
These observations suggest that efficient racemization re-
quires at least one labile ligand to open up a coordination
site for the allene. Furthermore, we argued that sterically
demanding ligands on Pd would minimize undesired metal–
protein interaction. Large ligands might also favor racemiza-
tion of the allenol over the allenyl butyrate. In search of
suitable catalysts complying with these demands, the class of
dimeric N-heterocyclic carbene palladium complexes at-
tracted our attention (Scheme 3).
Figure 1. Relative activity of PPL in the presence of [(MeCN)2PdBr2] and
[{(IPr)PdBr2}2]. Reaction conditions: rac-1a (50 mmol), vinyl butyrate
(250 mmol), PPL (20% on Celite 500, 7.5 mg) in toluene (1 mL) at 358C
for 8 h; conversion and ee determined by chiral HPLC.
The NHC–Pd complexes offer one bulky, strictly nondis-
sociating ligand along with a relatively labile bridging bro-
mide[12] that is readily displaced by the cumulated diene.
4448
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4447 – 4451

Chemoenzymatic DKR of Axially Chiral Allenes
COMMUNICATION
metal concentrations (up to 1 mm). In contrast, by using
[(MeCN)2PdBr2] a significant drop in activity of about 50%
was already observed at 10 mm and almost complete inhibi-
tion took place at 1 mm (Figure 1). In the same experiments,
the impact of the NHC–Pd species on the enzymeꢂs enantio-
selectivity was analyzed. Just as for the activity, also the se-
lectivity was only marginally affected by the presence of
[{(IPr)PdBr2}2]. The E value for the kinetic resolution of
rac-1a decreased from 270 under palladium-free conditions
to 200 in a 0.5 mm [{(IPr)PdBr2}2] solution.[13]
ieved combining good yield (81%) with high enantiomerical
purity (e.r.=93:7; Table 2, entry 6). These results reflect the
delicate balance between required catalyst activity and un-
desired product racemization, and reveal the necessity for
the further development of more selective racemization cat-
alysts. Nonetheless, regarding the important task of this
novel DKR approach, the results obtained with this relative-
ly simple and readily available catalytic system can be con-
sidered as more than satisfying.
Next, the transferability of this first chemoenzymatic dy-
namic kinetic resolution of axially chiral molecules to relat-
ed substrates was investigated. Thereby, different substituted
allenic alcohols were treated under optimized conditions.
All aryl substituted butyrates (2a–2d) could be isolated in
similarly high enantiomeric excess >85% and in good yield
(Table 3, entries 1–4). The lower conversion obtained for the
meta-tolyl derivative (R)-2b can be explained by the lower
reactivity of the parent alcohol, as already observed in the
ordinary kinetic resolution.[9]
Taking into account different properties, such as racemiza-
tion rates, substrate selectivity, protein tolerance and solubil-
ity, [{(IPr)PdBr2}2] was chosen as the racemization catalyst
for further studies of an integrated DKR process (Table 2).
Table 2. Dynamic kinetic resolution of rac-1a.[a]
Table 3. Influence of substituents in allene DKR.[a]
Entry
Enzyme[b]
Pd
catalyst
T
[8C]
Time
[h]
Yield
[%]
ee[c]
[%]
[mgmmolÀ1
]
AHCTUNGTRENGN[UN mol%]
1
2
3
15
15
15
15+15
30
1
1
1
1
1
2
40
50
60
50
50
50
32
30
24
30
30
23
47
72
69
76
77
81
96
89
83
84
78
86
Entry
Alcohol
R
Time
[h]
Yield
[%]
ee[b]
[%]
4[d]
5
6
30
1
2
3
4
5
1a
1b
1c
1d
1e
phenyl
3-tolyl
2-naphthyl
4-chlorophenyl
n-pentyl
23
27
24
21
20
2a: 81
2b: 70
2c: 83
2d: 80
2e: 87
86
89
89
87
66
[a] Reactions performed with rac-1 (100 mmol), vinyl butyrate
(500 mmol), [{(IPr)PdBr2}2] (1–2 mmol) and porcine pancreatic lipase
(20 wt% on Celite 500) in toluene (2 mL); [b] weight specification refers
to the amount of protein excluding solid support; [c] ee determined by
chiral HPLC; [d] PPL was added in two steps, 15 mgmmolÀ1 at the begin-
ning of the reaction and 15 mgmmolÀ1 after 10 h.
[a] Reactions performed at 508C with allenic alcohol (100 mmol), vinyl
butyrate (500 mmol), [{(IPr)PdBr2}2] (2 mmol) and PPL (20 wt% on Celite
500, 15 mg) in toluene (2 mL); [b] ee determined by chiral HPLC.
PPL shows its optimal performance below 508C. At an ele-
vated temperature, a decrease in selectivity and activity was
observed.[14] To reduce these effects, immobilized PPL was
used in the DKR studies, with Celite as solid support.[15] On
the other hand, the racemization catalyzed by
[{(IPr)PdBr2}2] could not reach sufficient rate below 508C
without prohibitive increase of catalyst loading. Therefore,
at 408C despite the presence of the dimeric Pd complex,
only ordinary kinetic resolution was obtained (Table 2,
entry 1). By increasing the reaction temperature, a dynamic
behavior was achieved and the best results were observed at
508C (Table 2, entry 2). At 608C, probably as a consequence
of thermal deactivation[16] of the enzyme in combination
with faster product racemization, yield and enantiopurity of
(R)-2a decreased (Table 2, entry 3). Attempts to counteract
thermal protein deactivation by increasing the enzyme load-
ing, both in a single addition (Table 2, entry 4) or in a step-
wise manner (Table 2, entry 5) led to a slight improvement
in yield, but at the expense of enantioselectivitiy due to
over-acylation. However, with double amounts of both
enzyme and palladium catalyst, a successful DKR was ach-
Only the aliphatic allenyl butyrate (R)-2e did not reach
the same degree in optical purity (Table 3, entry 5). A
reason for this is the significantly lower enantioselectivity of
the biocatalyst for this kind of substrate.[9]
An exceptional feature of lipases is their ability to cata-
lyze reactions in aqueous media as well as in highly unpolar
organic solvents. The same enzyme used to conduct a kinetic
resolution by means of stereoselective esterification of alco-
hols under nonaqueous conditions is also capable of media-
ting stereoselective ester hydrolysis when water is used as
solvent. In case of allene DKR, subsequent enzymatic hy-
drolysis of the enantioenriched esters was exploited as a
second stereoselection step, allowing for further enhance-
ment of optical purity. Thus, treatment of butyrate (R)-2a
(86% ee) with catalytic amounts of crude PPL in neutral
phosphate buffer and acetone as cosolvent led to fast hy-
drolysis and after 30 min enantiopure alcohol (R)-1a was
isolated in 91% yield (Scheme 4).[17]
In conclusion, we have developed a novel method in the
field of coupled bio- and transition metal catalysis, allowing
Chem. Eur. J. 2010, 16, 4447 – 4451
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4449

J.-E. Bꢀckvall et al.
[M+Na]+: 183.0785, found: 183.0780; HPLC (Chiralcel OB, isohexane/
iPrOH, 92:8, 0.5 mLminÀ1, 249 nm): tR(R)=14.2 min, tR(S)=15.7 min.
Acknowledgements
Scheme 4. Enantioenrichment by enzymatic deprotection.
Financial support from the German Academic Exchange Service
(DAAD), the Swedish Research Council, the Berzelii Center Exselent,
the European FP7 network INTENANT and the Knut & Alice Wallen-
berg foundation is gratefully acknowledged. Special thanks to Prof. M. G.
Organ for an encouraging and fruitful discussion.
for the first time the chemoenzymatic dynamic kinetic reso-
lution of axially chiral allenes. Thus, the combination of an
NHC–palladium catalyst together with porcine pancreatic
lipase provides allenyl butyrates in good to high yields and
in ee values up to 89%. Detailed studies regarding the race-
mization mechanism of these palladium catalysts are pres-
ently being investigated in our laboratories.
Keywords: allenes
·
biocatalysis
·
dynamic kinetic
resolution · palladium · racemization
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[5] In an early example Bringmann et al. exploited the configurational
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5839.
Experimental Section
Synthesis of [{(IPr)PdBr2}2]:[12c] A solution of 1,3-(2,6-diisopropylphen-
ACHTUNGTRENNUNGyl)imidazol-2-ylidene (198 mg, 0.51 mmol) in dry THF (3 mL) was added
dropwise to a suspension of [(MeCN)2PdBr2] (174 mg, 0.50 mmol) in dry
THF (2 mL) and dry toluene (3 mL) at room temperature under argon.
The reaction mixture was stirred at room temperature for 3 h resulting in
a deep red solution. After filtration through Celite and washing with
THF, the filtrate was concentrated and subjected to flash chromatogra-
phy (SiO2, pentane/Et2O/CH2Cl2, 10:1:1) yielding an orange powder
(224 mg, 0.171 mmol, 68% yield). Crystallization was performed by slow
evaporation from chloroform in an open flask; m.p. 264–2678C
(decomp.); 1H NMR (400 MHz, CDCl3): d [ppm]=0.92 (d, J=7.0 Hz,
12H), 1.03 (d, J=7.0 Hz, 12H), 1.21 (d, J=7.0 Hz, 12H), 1.39 (d, J=
7.0 Hz, 12H), 2.64 (hept, J=7.0 Hz, 4H), 3.03 (hept, J=7.0 Hz, 4H), 6.99
(s, 4H), 7.24 (d, J=8.0 Hz, 4H), 7.33 (d, J=8.0 Hz, 4H), 7.52 (t, J=
8.0 Hz, 4H); 13C NMR (100 MHz, CDCl3): d [ppm]=23.4, 26.4, 28.8,
124.2, 124.4, 125.5, 130.3, 134.6, 146.1, 146.6, 153.0; HRMS (ESI): calcd
for C54H72Br4N4NaPd2 [M+Na]+: 1333.0439, found 1333.0436.
Dynamic kinetic resolution: rac-1a (32.0 mg, 200 mmol) and
[{(IPr)PdBr2}2] (5.2 mg, 4 mmol) were dissolved in toluene (4 mL). Por-
cine pancreatic lipase (30 mg, 20 wt% on Celite 500) and vinyl butyrate
(126 mL, 1.0 mmol) were added and the mixture was stirred at 508C for
23 h. After filtration through silica and concentration of the filtrate in
vacuo, the residual oil was purified by column chromatography (SiO2,
pentane/Et2O, 93:7) yielding (R)-2a as a colorless oil (37.2 mg, 162 mmol,
1
81%, 86% ee). [a]2D0 =À8.68 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3):
d [ppm]=0.90 (t, J=7.4 Hz, 3H), 1.61 (tq, J=7.4 Hz, 2H), 1.83 (d, J=
2.8 Hz, 3H), 2.28 (t, J=7.3 Hz, 2H), 4.58–4.67 (m, 2H), 6.17 (tq, J=
2.8 Hz, 1H), 7.18–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): d [ppm]=
13.6, 15.9, 18.4, 36.1, 64.8, 95.7, 99.9, 126.9, 127.0, 128.5, 134.4, 173.3,
203.2; HRMS (ESI): calcd for C15H18NaO2 [M+Na]+: 253.1199, found:
253.1199; HPLC (Chiralcel OB, isohexane/iPrOH, 92:8, 0.5 mLminÀ1
249 nm): tR(R)=12.1 min, tR(S)=18.5 min.
,
Enzymatic hydrolysis: (R)-2a (34.5 mg, 150 mmol, 86% ee) was dissolved
in acetone (0.5 mL) and aqueous phosphate buffer (1 mL, pH 7.4). The
solution was warmed to 358C, crude PPL (3.5 mg) was added and the
mixture was stirred for 30 min at 358C. After filtration through a plug of
Celite, the filtrate was extracted three times with Et2O, the combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo. Column
chromatography (SiO2, pentane/Et2O, 7:3) yielded (R)-1a (21.8 mg,
136 mmol, 91%, >99% ee) as colorless needles; m.p. 898C; [a]2D0 =À10.98
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1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3): d [ppm]=1.69 (bs, 1H), 1.84
(d, J=2.9 Hz, 3H), 4.10–4.18 (m, 2H), 6.28 (tq, J=3.0 Hz, 1H), 7.17–7.32
(m, 5H); 13C NMR (100 MHz, CDCl3): d [ppm]=15.4, 63.8, 97.0, 106.7,
126.8, 127.0, 128.6, 134.7, 200.8; HRMS (ESI) calcd for C11H12NaO
4450
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4447 – 4451

Chemoenzymatic DKR of Axially Chiral Allenes
COMMUNICATION
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[13] Racemization catalyzed by [{(IPr)PdBr2}2] was negligible at 358C
and did not affect this calculations. E values were calculated accord-
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Received: February 3, 2010
Published online: March 22, 2010
Chem. Eur. J. 2010, 16, 4447 – 4451
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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