Chemoenzymatic synthesis and application of bicyclo [2.2.2] octadiene ligands: Increased efficiency in rhodium-catalyzed asymmetric conjugate additions by electronic tuning

Article abstract of DOI:10.1002/anie.200907033

(Figure Presented) On your bi(cycle)kel A series of 1,4dimethyl bicyclic [2.2.2] diene ligands with tunable substitution at the bridge positions was accessed using a lipase resolution and a high yielding six step sequence (see scheme). The bridgehead meth

Full text of DOI:10.1002/anie.200907033

Communications
DOI: 10.1002/anie.200907033
Asymmetric Catalysis
Chemoenzymatic Synthesis and Application of Bicyclo[2.2.2]octadiene
Ligands: Increased Efficiency in Rhodium-Catalyzed Asymmetric
Conjugate Additions by Electronic Tuning**
Yunfei Luo and Andrew J. Carnell*
Chiral dienes are a new class of highly effective ligands,
developed independently by Hayashi and Carriera et al., that
have shown great promise in the field of asymmetric catalysis
for reactions catalysed by rhodium and iridium.[1] A range of
synthetically useful transformations have been realized in
excellent yield and enantiomeric excess using C1-symmetric
and C2-symmetric dienes.[2–10]
Herein we report a chemoenzymatic approach giving
access to a new series of chiral 1,4-disubstituted C2-symmetric
[2.2.2] diene ligands (Scheme 1).
However, compared with phosphine ligands and C1-
symmetric dienes, the accessibility and structural variation
in the most widely employed C2-symmetric [2.2.2] diene
ligands has been limited by inflexible synthetic routes and,
most notably, the difficulty in resolution of the dienes or their
synthetic precursors, which is currently achieved using chiral
HPLC separation of the diene or a late-stage intermedia-
te.[1b,2,11–14] As a result, the electronic effects on activity and
enantioselectivity in these ligands have not been well studied.
Although structural modifications including both electronic
and steric changes have been made with the current bicyclic
frameworks,[2b,c,5,6d,7] the results have shown that steric factors
are dominant. Hayashi et al. have shown that C1-symmetric
[2.2.2] dienes in which one alkene was conjugated with an
ester group gave a remarkable rate increase in arylation of
imines.[6d] In this example it is believed that an electron
withdrawing naphthyl ester substituent on one of the alkenes
accelerates transmetallation to form a trans aryl–rhodium
bond.
Although the chiral diene–Rh catalyst allows reactions to
be conducted at lower temperatures compared with phos-
phine ligands, in diene–rhodium-catalyzed arylations with
aryl boronic acids generally more than two equivalents of the
arylboronic acid are necessary in order to achieve a high yield,
and for particularly inactive substrates as many as 5 equiv-
alents.[2h,15,16] This is attributed to the competing protode-
boronation side-reaction[17] and indicates that reaction tem-
perature is not the only factor responsible for the low atom
efficiency.
Scheme 1. Biotransformation of (ꢀ)-enol ester 1 with PPL and prepa-
ration of 1,4-disubstituted bicyclo[2.2.2] ligands from (S,S)-enol ester
1: a) Na2CO3, MeOH (99%); b) LHMDS, Tf2O, THF, ꢁ788C (70%);
c) ArB(OH)2, [Pd(PPh3)4], Tol/EtOH/aq, Na2CO3, RT (80–95%);
d) LiAlH4, THF, (99%); e) Tf2O, CH2Cl2/pyridine, ꢁ788C!RT (99%);
f) LiHBEt3, THF, 08C!RT (93–99%). LHMDS=lithium hexamethyldi-
silazide, Tf=trifluoromethanesulfonyl.
The scalability and ease of operation of the key enzyme
resolution step, in addition to high yielding chemical trans-
formations, provides a highly practical route that could
quickly satisfy demands for greater quantities. Moreover, a
significant electronic effect was observed in the diene ligands
for rhodium-catalyzed arylation reactions. Both catalytic
activity and, more interestingly from a mechanistic perspec-
tive, enantioselectivity depend on the electronic properties of
the ligands. In addition, atom efficiency for the aryl boronic
acids was correlated.
[*] Y. Luo, Dr. A. J. Carnell
Department of Chemistry, University of Liverpool
Crown Street, Liverpool, L69 7ZD (UK)
Fax: (+44)151-794-3587
E-mail: acarnell@liv.ac.uk
[**] We acknowledge Dr. John Whittall for initial inspiration, Dr. Neil
Berry for preliminary modeling and the EPSRC for a Dorothy
Hodgkin Postgraduate Award to Y.L.
The key step in the route is a reliable and scalable lipase-
catalysed chiral resolution of the (ꢀ )-enol ester 1, derived
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907033.
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Table 1: Ligand screen for the asymmetric conjugate addition to 6a.
from the (ꢀ )-diketone 2, which is made from commercially
available succinate dimer.[18] After substrate and enzyme
screening we found that porcine pancreatic lipase (PPL) in a
biphasic system comprising Et2O/citrate buffer (2:1; 100 mm,
pH 5.2) gave reasonable selectivity (E = 17). The reaction was
carried out on 40 g of substrate to afford 10 g of enantiopure
enol ester (S,S)-1,[19] after purification by crystallisation. The
crystals were found to be racemic enol ester, with enantiopure
(S,S)-enol ester 1 remaining in solution, greatly facilitating
isolation of the homochiral product. We found that enol ester
of lower ee can also be purified to homochirality in a single
crystallization.[20] Although the E value for this enzyme
reaction is modest, the scalability and ease of purification
make it an extremely attractive method to obtain quantities of
the chiral dione (S,S)-2 for our diene ligand synthesis. The
antipodal (R,R)-2 can be recovered and crystallized to optical
purity through the (R,R)-enol ester 1.[20]
Entry[a]
Ligand
2,5-Aryl
Yield[b]
ee 8a[c]
Ln
1
2
3
4
5
6
7
L3a
L3b
L3c
L3d
L3e
L3 f
L3g
Ph
95
93
98
95
99
43
96
75
83
73
82
74
89
70
3-CF3C6H4
3-CH3C6H4
4-CF3C6H4
4-MeOC6H4
3,5-(CF3)2C6H3
3,5-(CH3)2C6H3
than those with electron-donating groups, (e.g. comparing
entry 2 with 3, entry 4 with 5 and entry 6 with 7 in Table 1).
The methyl ester groups were converted into methyl
groups, and ligands L5a and L5 f were evaluated for a range
of acyclic and cyclic enones 6a–e (Scheme 2, Table 2). For
The enantiopure (S,S)-dione 2 was obtained in near
quantitative yield by methanolysis of the biotransformation
product (S,S)-enol ester 1. Formation of the bis-enol triflate
was followed by introduction of the aryl substituents by
palladium-catalysed cross-coupling to give ligands (S,S)-L3a–
g.[2c,7,21] Lithium aluminum hydride reduction, activation as
the ditriflate 4a,e,f and displacement by superhydride gave
(R,R)-ligands L5a,e,f.
The 1,4-diester ligands (S,S)-L3a–g (Scheme 1), were
evaluated for the asymmetric conjugate addition of phenyl-
boronic acid 7a to 3-nonen-2-one 6a using previously
reported conditions (Scheme 2, Table 1).[2a,5]
The results for enantioselectivity were not encouraging
compared to other [2.2.2] bicyclic ligands.[2j] From a purely
structural perspective, it was logical that the substituent ester
groups at the 1 and 4-positions may be giving a detrimental
effect on the enantioselectivity. However, we also noted an
interesting trend that for substrate 6a, ligands with electron-
withdrawing aryl substituents gave better enantioselectivities
Table 2: Comparison between L5a and L5b with various substrates.
Entry[a]
6
Prod. 8
Yield (%)[b] [ee (%)][c]
Config.
L5a
L5b
1
2
3
4
5
6a
6b
6c
6d
6e
8a
8b
8c
8d
8e
99 [52]
99 [97]
99 [95]
92 [98]
80 [96]
76 [92][d]
S
S
R
R
R
99 [67]
98 [99]
100 [99]
95 [98]
[a] Reaction conditions: 6a (0.5 mmol), 7a (0.6 mmol for L5a, 1.0 mmol
for L3a–g and L5 f), [{Rh(C2H4)2Cl}2] (1.8 mol% Rh), Ligand Ln
(2 mol%), MeOH/CH2Cl2; 10:1 (2.3 mL), KOH (2 mol%) (2.3 mL), RT,
1 h for L5a and 3 h at 308C for L5 f and L3a–g. [b] Yield of isolated
product. [c] Ee values were determined by chiral HPLC (see Supporting
Information). [d] 3.0 equiv of phenylboronic acid used.
substrate 6a, we were surprised to find a more pronounced
difference in enantioselectivity between ligands L5a
(52% ee) and L5 f (97% ee) than between L3a (75% ee)
and L3 f (89% ee) (Table 1). The enantioselectivity improve-
ment between L3 f (89% ee) and L5 f (97% ee) may result
from removing a detrimental effect of 1,4-ester groups whilst
maintaining the electron withdrawing aryl substituents. How-
ever, comparison of the results for L3a and L5a contradict
this, where the 1,4-diester ligand L5a out-performs the 1,4-
dimethyl ligand L3a. Similar results were obtained with
substrate 6b (Table 2, entry 2). Nevertheless, ligand L5a gave
excellent yields and selectivity for enones 6c–e affording (R)-
configured products 8c–e. Results for cyclohexanone 6c are
similar to those obtained by Hayashi with diene ligand L5g.[2c]
For the lactone 6e both yield and ee were improved (95%,
98% ee) compared with Carreiraꢀs carvone derived ligand
(80%, 90% ee)[3b] and Darsesꢀ ligand (56%, 90% ee).[5]
Unlike L5a, ligand L5 f gives excellent ee for both acyclic
and cyclic enones in the expected product configuration,
which is consistent with the space differentiation model for
chiral C2-symmetric diene ligands developed by Haya-
shi.[2a,c,j,6a,15]
Despite the discrepancy between acyclic and cyclic enones
for L5a in terms of enantioselectivity, we were pleased to find
that the reactions completed smoothly at room temperature
Scheme 2. Asymmetric conjugate addition to substrates 6a–e.
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in 1 h with only 1.2 equivalents of phenyl boronic acid,
temperature in 1 h (Scheme 4). This is the most efficient
ligand for this transformation to date.
compared with at least 2 equivalents for current diene ligands.
The requirement for use of excess arylboronic acid is thought
to arise as a result of the competing rhodium-catalysed
protodeboronation.[17] This significant and unexpected
advantage can reasonably be attributed to the 1,4-dimethyl
substitution in ligand L5a as compared to Hayashiꢀs ligand
L5g and other ligands. On the other hand, in order obtain a
high yield when using our ligand L5 f, more than 2 equivalents
of phenyl boronic acid was required. For example, the yield of
8e when using ligand L5 f was only 76% although 3 equiv-
alents phenyl boronic acid were used (Table 2, entry 5).
The only major difference between ligands L5a and L5 f is
that L5a is more electron rich. These results suggest that the
electronic properties of diene ligands are associated with
activity, enantioselectivty (for linear substrates) as well as the
productivity (ability to avoid the protodeboronation of aryl
boronic acid). Increasing the electron density of the ligand
benefits the reactivity and suppresses the protodeboronation
reaction, but can undermine the enantioselectivity for linear
substrates, as for L5a. To retain the high enantioselectivity for
the linear substrates requires the ligand not be too electron
rich. However, this can sacrifice some reactivity and allow the
side reaction, as for L5 f.
The product resulting from the conjugate addition of
phenyl boronic acid to 6-methylcoumarin (13) has been used
Scheme 4. Asymmetric conjugate addition to N-benzyl maleimide 11.
in a synthesis of the urological drug tolterodine.[24] Examples
reported by the Hayashi group show that phosphine ligands
can give excellent ee (> 99%), however 10 equivalents of
phenylboronic acid were necessary to achieve a high yield.[24]
Only one example using a chiral diene for this reaction has
been reported by Carreira et al., where 43% yield and
98% ee were obtained in the addition of phenylboronic acid
to the coumarin at 508C using his carvone derived ligand.[3b]
We tested our ligands L5a, L5e and L5 f and also ran
comparative reactions with Hayashiꢀs ligand L5g and Carrei-
raꢀs ligand L5h (Table 3).
In order to further test this electronic effect, ligands L5a
and L5 f were examined for the 1,2-addition to tosyl imine 9,
which can be categorized as a linear substrate (Scheme 3).
The enantioselectivity for all ligands was uniformly high
(98% ee). However, a remarkable difference in reaction rate
and yield was found between the ligands when comparing
conversion and isolated yield at 308C and 508C after 6 h. and
Table 3: Ligand screen for asymmetric conjugate addition to 13.
Scheme 3. Asymmetric arylation of N-tosyl benzylimine 9.
The results were as expected; as with the 1,4-addition to linear
enones, L5a gave much higher reactivity but lower ee with less
arylboronic acid, while L5 f gave excellent enantioselectivity
but lower reactivity and some protodeboronation side-
reaction. To the best of our knowledge, this is the first time
that such a unique electronic effect has been observed in
diene ligands closely linking reactivity, enantioselectivity and
productivity.
The asymmetric conjugate addition of aryl boronic acids
to N-benzyl maleimide (11) is known to be a challenging
reaction, and the products are synthetically useful.[22] The
chiral phosphine ligand, binap, gave only 70% yield and
58% ee, while a chiral norbornadiene diene ligand gave 88%
yield and 69% ee.[2b] The phosphine–alkene hybrid ligands
developed by Grꢁtzmacher and Hayashi et al. both gave the
desired product in high yield with Hayashiꢀs hybrid ligand
giving 89–95% ee.[15,23] However, multiple equivalents
(3 equiv) of arylboronic acid were required to ensure a high
yield. Again it was found that ligand L5a achieves both high
activity and enantioselectivity for the formation of (R)-12a–d
using only 1.1 equivalents of ArB(OH)2 (7a–d) at room
Entry[a]
Ligand
T
[8C]
t
[h]
Conv.
[%][b]
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
7
8
L5g
L5g
L5h
L5h
L5a
L5a
L5 f
30
50
30
50
30
50
50
30
24
6
24
6
24
6
24
3
<5
40
22
48
66
85
0
–
n.d.
98
98
98
98
98
–
32
20
39
63
72
0
L5e[e]
100
95
98
[a] Reaction conditions: Ref. [2c]. [b] Conversion determined by GC (EC-1
column; calibrated with standard 10 and 11). [c] Yield of isolated
product. [d] Ee values determined by chiral HPLC. [e] As footnote [a]
except 25 mol% KOH and 1.2 equiv PhB(OH)2 were used.
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2008, 120, 4558 – 4579; Angew. Chem. Int. Ed. 2008, 47, 4482 –
4502.
24 h. Hayashiꢀs ligand L5g gave the lowest rate of conversion,
Carreiraꢀs ligand L5h gave increased conversion, our L5a
gave a further increase but the most active ligand for this
reaction was ligand L5e, containing the 4-methoxyphenyl
groups. This gradual increase in reactivity may be attributed
to an increase in electron density in the ligand system;
Hayashiꢀs diene L5g contains no bridge substituents, Carrei-
raꢀs diene L5h contains one methyl substituent (but the 2,5-
positions are alkyl-substituted rather than aryl), ligand L5a
has two bridge methyl groups and L5e has two bridge methyl
groups and electron donating 4-methoxyphenyl substituents.
This is corroborated by the fact that our electron-deficient
ligand L5 f gave no reaction for this substrate.
In summary, we have developed an efficient synthesis of
the chiral C2-symmetric bicyclic [2.2.2] diene ligand system
that enables flexible substitution at the 1- and 4-positions. The
synthesis is short, high yielding and includes a practical lipase
resolution as a key step that can be done on scale and provides
an attractive alternative to resolution by chiral preparative
HPLC. We have assessed a new series of 1,4-dimethyl 2,5-
diaryl bicyclo [2.2.2] octadiene ligands for rhodium-catalysed
asymmetric conjugate addition to a range of cyclic and acyclic
enones. The addition of 1,4-methyl substituent groups in the
ligands enabled us for the first time to observe a significant
electronic effect which affects catalytic performance. The
catalysts with electron rich ligands gave excellent activity for
all substrates and excellent enantioselectivity for cyclic
enones with high atom efficiency (only 1.1–1.2 equiv arylbor-
onic acid), even for a challenging substrate such as 6-
methylcoumarin. However, this advantage was not shared
by linear enones as far as enantioselectivity is concerned. This
problem could be abrogated by introducing electron-with-
drawing groups on the ligand to achieve high ee for all type
substrates, although 2-3 equivalents of arylboronic acid are
required to compensate for protodeboronation and to achieve
high yield. Mechanistic studies to gain a deeper understanding
into this phenomenon are ongoing.
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5628 – 5629; i) N. Tokunaga, T. Hayashi, Adv. Synth. Catal. 2007,
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1628 – 1629.
[9] Arylative cyclisation of alkynals and alkyne enones: a) R.
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Experimental Section
General procedure for the Rh–diene-catalyzed asymmetric conjugate
addition: To a Schlenk reaction tube [{RhCl(C2H4)2}2] (1.8 mg, 9 mmol
of Rh) and diene ligand (10 mmol) in DCM (0.3 mL) were added
under a nitrogen atmosphere. The solution was stirred for 5 min
followed by addition of 0.2m KOH/methanol solution (50 mL,
10 mmol). The resultant mixture was stirred for 15 min before addition
of methanol (2 mL), arylboronic acid (0.6–1.5 mmol) and enone
(0.5 mmol). The reaction mixture was stirred at the required temper-
ature for 1–3 h, then filtered through a silica pad and purified with
preparative TLC to give pure product.
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Received: December 14, 2009
Published online: March 12, 2010
Keywords: asymmetric catalysis · chemoenzymatic synthesis ·
.
chiral dienes · conjugate addition · rhodium
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Communications
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99.9% ee (48% of theory)).
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[19] The absolute configuration of the (S,S)-enol ester
1 was
established by X-ray crystallographic analysis of a bis-ketal
bis-triflate derivative (see Supporting Information).
[20] In a non-optimised biotransformation, where the aim was to
isolate the unreacted enol ester in high ee, the (R,R)- dione
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Angew. Chem. Int. Ed. 2010, 49, 2750 –2754