Highly enantioselective rhodium-catalyzed asymmetric 1,4-addition reactions of arylboronic acids to acyclic α,β-unsaturated compounds: The formal synthesis of (-)-indatraline

Article abstract of DOI:10.1002/chem.201102073

It's do or diene: Stable chiral bicyclo[2.2.1]diene ligands were synthesized from (-)-5-oxobornyl acetate and utilized in the asymmetric 1,4-addition reaction of arylboronic acids with acyclic α,β- unsaturated compounds. Low catalytic loading of the compl

Full text of DOI:10.1002/chem.201102073

COMMUNICATION
DOI: 10.1002/chem.201102073
Highly Enantioselective Rhodium-Catalyzed Asymmetric 1,4-Addition
Reactions of Arylboronic Acids to Acyclic a,b-Unsaturated Compounds: The
Formal Synthesis of (À)-Indatraline
Wei-Ting Wei,[a] Jiann-Yih Yeh,[a] Ting-Shen Kuo,[b] and Hsyueh-Liang Wu*[a]
In memory of Yung-Son Hon
(C2H4)],[1] also known as
Since the discovery of KACHTNUTRGENNUG[PtCl3ACHTUNGTRENNUGN
the Zeise salt, in 1827, considerable numbers of olefin-coor-
dinated transition-metal complexes have been synthesized
for extensive use in organometallic and organic chemistry.[2]
They also serve as useful precatalysts in the field of asym-
metric catalysis. The labile olefins are rapidly and quantita-
tively replaced by optically active ligands that bear heteroa-
toms, such as nitrogen and phosphorus, which exhibit a
stronger binding affinity towards metal atoms than the ole-
fins, efficiently enabling the in situ generation of chiral cata-
lysts.[3] However, the utilization of optically active olefin li-
gands as chiral modifiers had not received much attention
until the independent studies of Hayashi et al.[4] and Car-
reira et al.[5] Their discoveries have demonstrated that chiral
dienes with the appropriate geometry can form reasonably
stable metal complexes due to chelation effects. These chiral
diene–metal catalysts, particularly the rhodium complexes,
have since been tested in catalytic asymmetric carbon–
carbon bond-forming reactions and were found to exhibit
higher catalytic activities and enantioselectivities than phos-
phine ligands.[6] Since then, the design, synthesis, and investi-
gation of chiral dienes for a wide range of asymmetric trans-
formations has attracted much attention among synthetic or-
ganic chemists.[7,8]
Figure 1. The Hayashi (1) and Corey (2) bicycloACTHNUTRGNE[NUG 2.2.1]diene ligands
(BOM=benzyloxymethyl).
key step being the Pd–MOP-catalyzed (MOP=(R)-2-(di-
phenylphosphino)-2’-methoxy-1,1’-binaphthyl) asymmetric
hydrosilylation of norbornadiene.[9] Recently, Corey et al. re-
ported the synthesis of chiral norbornadiene 2 based on a
highly enantioselective Diels–Alder cycloaddition of b-chlor-
oacrylate and cyclopentadiene catalyzed by an N-protonated
oxazaborolidine complex.[8d,10] Due to their high catalytic ac-
tivity, the development of a straightforward synthesis of op-
tically active bicycloACTHNUTRGNE[NUG 2.2.1]heptadienes from a readily acces-
sible and inexpensive chiral pool is of great interest. Fur-
thermore, the bridged [2.2.1] bicyclic skeleton of camphor
has proven to be an effective stereocontrolling moiety.
Herein, we describe the preparation of chiral bicyclo-
AHCTUNGTREG[NNUN 2.2.1]diene ligands 3, and their application to the rhodium-
catalyzed asymmetric 1,4-addition reaction of boronic acids
to acyclic a,b-unsaturated compounds.
Ligands of bicyclic scaffolds have proven to be extremely
efficacious in this field. Among these, C2-symmetric bicyclo-
ACHTUNGTRENNUNG[2.2.1]heptadiene 1 (nbd*; Figure 1) was the first identified
chiral diene ligand that could be exploited in the highly
enantioselective rhodium-catalyzed asymmetric 1,4-addition
reaction[4a] and the asymmetric arylation of N-tosylarylimi-
nes.[4c] However, one drawback for the system is the require-
ment for several synthetic steps to form diene ligand 1, a
The synthesis of these chiral dienes began with enantio-
pure 5-ketobornyl acetate 4,[11] which underwent a four-step
reaction, as outlined in Scheme 1. Saponification of acetate
compound 4, followed by pyridinium chlorochromate (PCC)
oxidation gave desired diketone 5 in 83% yield over two
steps. Bistriflate 6 was then efficiently formed by using po-
[a] W.-T. Wei, Dr. J.-Y. Yeh, Prof. Dr. H.-L. Wu
Department of Chemistry, National Taiwan Normal University
No. 88, Section 4, Tingzhou Road, Taipei, 11677, ROC (Taiwan)
Fax : (+886)2-29324249
E-mail: hlw@ntnu.edu.tw
[b] T.-S. Kuo
Instrumentation Center, Department of Chemistry
National Taiwan Normal University
No. 88, Section 4, Tingzhou Road, Taipei, 11677, ROC (Taiwan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102073.
Scheme 1. The preparation of chiral dienes 3.
Chem. Eur. J. 2011, 17, 11405 – 11409
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11405

Table 2. Optimization of the reaction conditions.[a]
tassium bis(trimethylsilyl)amide (KHMDS; 2.5 equiv) and
the Comins triflating reagent.[12] Finally, a Suzuki cross-cou-
pling reaction of bistriflate 6 with a number of arylboronic
acids, in the presence of [Pd
ACHTUGNRTEN(NUGN PPh3)4], provided 2,5-disubsti-
tuted bicyclo[2.2.1]heptadienes 3 in moderate to high yields
(Scheme 1).
With bicyclic diene ligands 3a–h in hand, the Rh-cata-
lyzed enantioselective conjugate addition reaction was stud-
ied (Table 1). Initially, a model reaction of (E)-5-methylhex-
ACHTUNGTRENNUNG
Entry
x [mol%]
Solvent
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
0.5
0.1
0.05
dioxane
THF
diglyme
MeOH
EtOH
IPA
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Et3N
DIPA
DBACO
Et3N
Et3N
Et3N
87
72
67
63
98
93
91
94
90
8
94
94
96
96
95
96
96
96
95
65
96
96
96
96
Table 1. Ligand effects.[a]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d,e]
94
94
90
73[f]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
91
90
72
100
87
89
93
77
78
83
94
83
91
88
Et3N
[a] Reaction conditions: 7a (0.2 mmol), 8a (0.4 mmol), [{RhClACHTUNGTRENNUNG(C2H4)2}2]
(x mol% of Rh), ligand 3e (1.2x mol%), and aqueous KOH (50 mol%).
All reactions were conducted under an Argon atmosphere at room tem-
perature for 1 h. [b] Calibrated GC yield by using n-decane as the inter-
nal standard. [c] Determined by chiral HPLC. [d] 2.4 equivalents of base
was used. [e] The reaction was conducted for 22 h with 12 mmol of enone
7a. [f] Isolated yield.
85
74
[a] Reaction conditions: 7a (0.2 mmol), 8a (0.4 mmol), [{RhClACTHNUGTRNE(UNG C2H4)2}2]
(3 mol% of Rh), ligand (3.6 mol%), and aqueous KOH (50 mol%). All
reactions were conducted under an Argon atmosphere at room tempera-
ture for 1 h. [b] Calibrated GC yield by using n-decane as the internal
standard. [c] Determined by chiral HPLC.
We anticipated that high asymmetric induction could be
maintained as the loading of the catalytically active complex
was reduced under otherwise identical reaction conditions
to those in Table 2, entry 8.[4r,13] Therefore, further optimiza-
tion of the catalyst loading was studied. In the presence of
1 mol% of diene complex RhI–3e, the addition of 8a to
enone 7a in ethanol with Et3N as the base yielded 94% of
compound 9aa in 96% ee (Table 2, entry 11). In the pres-
ence of 0.5 or 0.1 mol% of the catalyst, the reaction gave
the desired adduct without losing the high catalytic activity
and enantioselectivity (Table 2, entries 12 and 13). Notably,
with merely 0.05 mol% of the catalyst, the asymmetric reac-
tion of nucleophile 8a with 7a smoothly yielded the desired
adduct in 73% isolated yield and 96% ee (Table 2,
entry 14).[14]
In light of the above observations, the addition of various
arylboronic acids to a range of acceptors was examined.[15]
As indicated in Table 3, the addition of arylboronic acids,
with either electron-donating or -withdrawing substituents,
to enone 7a gave the corresponding adducts 9aa–ag with
high enantioselectivities and yields (Table 3, entries 1–7).
Highly asymmetric induction and high yields were also ob-
served if the reactions were conducted by using a set of aryl-
boronic acids with receptor 7b, which contains a linear alkyl
group at the b position (Table 3, entries 8–13). Notably,
when 4-CF3- and 4-Me-substituted phenylboronic acids were
used, a >99.5% ee of adducts 9bf and 9bi (Table 3, en-
tries 10 and 12, respectively) was obtained. To further probe
the substrate scope of this catalytic system, the reactions of
b-aryl-a,b-unsaturated ketones and a,b-unsaturated esters
were studied. Excellent enantioselectivities (94–96% ee) and
yields were achieved in the catalytic addition of phenylbor-
3-en-2-one (7a) with phenylboronic acid (8a) in the pres-
ence of RhI–3a (3 mol%) in dioxane was conducted. Grati-
fyingly, the isolation of (R)-5-methyl-4-phenylhexan-2-one
ACHTUNGTRENNUNG(9aa) in 91% yield and 93% ee was observed (Table 1,
entry 1). When diene ligands containing alkyl or phenyl sub-
stituents at the 4-position of the benzene ring (3b–d) were
used, the enantioselectivities were significantly reduced (77–
83% ee; Table 1, entries 2–4); utilizing ligands with electron-
withdrawing aryl groups (3g and h) gave rise to asymmetric
induction (88–91% ee) to a slightly lower extent than that
obtained by using ligand 3a (Table 1, entries 7 and 8, respe-
cively). A slight improvement in enantioinduction (94% ee)
was observed by replacing both substituted phenyl groups
with the sterically bulky 1-naphthyl group (3e). Given this
encouraging result, the reaction conditions were optimized
by using ligand 3e.
Next, we investigated the effect of the solvent on the re-
action (Table 2). Reactions in ethereal solvents typically
provided adduct 9aa in moderate to high yields with enan-
tioselectivities up to 96% ee (Table 2, entries 1–4). The yield
of 9aa was improved to 98% without diminishing selectivity
if the reaction was carried out in alcohol solvents (Table 2,
entries 5–7). Substituting the aqueous KOH solution for trie-
thylamine (2.4 equiv) as the base afforded a comparable ee
value and higher yield (94%; Table 2, entry 8), whereas the
use of diisopropylamine (DIPA) or 1,4-diazabicyclo-
ACHTUNGTRENNUNG
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Chem. Eur. J. 2011, 17, 11405 – 11409

Asymmetric 1,4-Addition Reactions
COMMUNICATION
Table 3. The asymmetric 1,4-addition reaction of various acceptors.[a]
Entry
7
Ar
T [h]
Yield [%][b]
ee [%][c]
Scheme 2. The asymmetric 1,4-addition reaction to 2-cyclohexene-1-one.
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7c
7d
7e
7 f
7g
Ph (8a)
22
96
5.5
19
25
50
11
24
96
72
24
29
16
27
16
2
73 (9aa)
68 (9ab)
72 (9ac)
77 (9ad)
77 (9ae)
74 (9af)
86 (9ag)
94 (9ba)
80 (9bb)
99 (9bf)
98 (9bh)
98 (9bi)
99 (9bj)
98 (9ca)
95 (9da)
81 (9ea)
92 (9 fd)
88 (9ga)
96 (R)
98 (R)
97 (R)
93 (R)
95 (R)
96 (R)
94 (R)
90 (S)
95 (S)
>99.5 (S)
93 (S)
>99.5 (S)
96 (S)
96 (S)
2-MeC6H4 (8b)
4-PhC6H4 (8c)
4-MeOC6H4 (8d)
1-naphthyl (8e)
4-CF3C6H4 (8 f)
3-MeOC6H4 (8g)
Ph (8a)
2-MeC6H4 (8b)
4-CF3C6H4 (8 f)
4-ClC6H4 (8h)
4-MeC6H4 (8i)
3-ClC6H4 (8j)
Ph (8a)
10
11
12
13
14
15
16[d]
17[d]
18[d,e]
Ph (8a)
Ph (8a)
4-MeOC6H4 (8d)
Ph (8a)
94 (S)
98 (S)
99 (R)
96 (S)
Scheme 3. The formal total synthesis of (À)-indatraline.
14
23
[a] Reaction conditions: 7 (12.0 mmol), 8 (24.0 mmol), [{RhClACTHNUGTRNE(UNG C2H4)2}2]
(0.05 mol% of Rh), ligand 3e (0.06 mol%), and Et3N (2.4 equiv). All re-
actions were conducted under an Argon atmosphere at room tempera-
ture unless otherwise specified. [b] Isolated yield. [c] Determined by
chiral HPLC. [d] Conducted at 608C [e] 0.5 mol% of Rh was used.
Figure 2. Due to the presence of methyl group C13 in the
bridgehead position, the distance between Rh1 and C2 is
slightly longer than that between Rh1 and C21. The disub-
onic acids to (E)-4-(4-methoxyphenyl)but-3-en-2-one (7c)
and (E)-4-(4-fluorophenyl)but-3-en-2-one (7d, Table 3, en-
tries 14 and 15, respectively). Additionally, tert-butyl croto-
nate (7e) was found to be a good reaction partner, provid-
ing adduct 9ea in 90% yield and 98% ee at elevated tem-
perature (Table 3, entry 16). Both tert-butyl cinnamate (7 f,
Table 3, entry 17) and dichloro-substituted analogue 7g
(Table 3, entry 18) afforded the corresponding 1,4 adducts
with high enantioselectivities although in the latter case
0.5 mol% of the catalyst was required. For a cyclic a,b-unsa-
turated carbonyl compound, 2-cyclohexen-1-one (10), as the
substrate under the optimized reaction conditions an unsat-
isfactory result was observed; none of the desired product
was observed after 48 h. However, by using 3 mol% of RhI–
3a as the catalyst in dioxane the corresponding adduct 11
was formed in 94% yield and 91% ee (Scheme 2).
Figure 2. ORTEP illustration of [{RhCl
for clarity, with thermal ellipsoids drawn at the 30% probability level. Se-
lected bond lengths [ꢁ] and angles [8]: Rh1 C2 3.10, Rh1 C21 3.06;
aC1-Rh-C20 81.7, aC18-Rh1-C19 80.9, aC2-Rh1-C21 133.1.
ACHTUNGERTN(NUNG 3e)}2], shown in monomeric form
À
À
Adduct 9ga can be further functionalized for the formal
total synthesis of (À)-indatraline, as illustrated in Scheme 3.
Saponification of compound 9ga gave the corresponding
acid in 85% yield, which underwent a chlorosulfonic acid
mediated Friedel–Crafts cyclization reaction, providing the
known precursor 12 of (À)-indatraline in 74% yield without
racemization.[16]
stituted double bonds in the 2 and 5 positions of the bicyclo-
AHCTUNGTREG[NNUN 2.2.1] skeleton are almost parallel (18), a configuration that
is identical to the Rh–1 analogue,[4b] and bind to one rhodi-
um atom with a bite angle of 73.48. Based on the X-ray crys-
tal structure, our proposed rationale for the stereochemical
outcome of the 1,4 addition is illustrated in Figure 3.[4a] The
RhI–3e complex selectively reacts with one face of prochiral
enone 7a due to steric repulsion of the 2,5-disubstituted
naphthyl groups, which accounts for the favorable coordina-
tion of the metal center to the a-Si face of the enone, and
leads to formation of the (R) product.
Structural information on the active catalyst can be found
from an X-ray crystallographic analysis of the complex
[{RhCl
structure and selected bond lengths and angles are shown in
ACHTUNGTRENNUNG
(3e)}2].[17] For clarity, the monomeric form of the
Chem. Eur. J. 2011, 17, 11405 – 11409
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11407

H.-L. Wu et al.
Keywords: addition reactions
·
arylboronic acids
·
asymmetric catalysis · diene ligands · enantioselectivity ·
indatraline · rhodium
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Figure 3. The proposed rational for the stereochemical outcome of the
1,4-addition reactions.
In conclusion, we have synthesized a set of chiral 2,5-dis-
ubstituted bicycloACHTUNGTRENNUNG[2.2.1]heptadiene ligands 3a–h from keto-
bornyl acetate 4 in four steps with overall yields of 42–
60%.[18] These stable diene ligands are highly active
(0.05 mol%) in the asymmetric conjugate addition reaction
of arylboronic acids to acyclic a,b-unsaturated compounds.
The method presented herein provides an efficient synthetic
route to enantioenriched 1,4-addition products with 90 to
>99.5% ee and in 68 to 99% yield from readily available ar-
ylboronic acids. Moreover, this methodology could be fur-
ther extended to the highly enantioselective and concise
synthesis of 3-aryl-1-indanone compounds. A synthetic ap-
plication of this protocol was demonstrated by its utilization
in the enantioselective formal total syntheses of (À)-indatra-
line. Applications of the 2,5-disubstituted bicyclo-
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ACHTUNGTRENNUNG[2.2.1]heptadiene ligands 3 to the study of conjugate addi-
tion reactions to cyclic a,b-unsaturated carbonyl compounds
and other challenging asymmetric transformations are cur-
rently under investigation.
Experimental Section
General procedure for the rhodium(I)-catalyzed 1,4-addition reactions:
EtOH (42 mL) and Et3N (4.2 mL) were added to a mixture of [{RhCl-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3e; 2.8 mg, 0.0066 mmol, 0.00055 equiv), phenylboronic acid (8a, 2.93 g,
24 mmol, 2 equiv), and (E)-5-methylhex-3-en-2-one (7a, 1.35 g, 12 mmol,
1 equiv) at RT under an Argon atmosphere. After 22 h, the solvent was
removed under reduced pressure to give the crude product, which was
purified by flash column chromatography over silica gel (hexanes/ethyl
acetate, 40:1) to furnish 5-methyl-4-phenylhexan-2-one (9aa, 1.66 g,
8.8 mmol, 73%) as a colorless oil. The ee value was determined on a
Daicel Chiralcel OD-H column with hexanes/2-propanol: 99:1, flow:
0.5 mLminÀ1; retention times: 14.0 min [(R)-enantiomer], 15.9 min [(S)-
enantiomer]; 96% ee; [a]2D4 = +36.2 (c=0.92 in CHCl3).
Acknowledgements
Financial support provided by the National Science Council, Republic of
China (NSC 98-2113M-003-009-MY2) and the National Taiwan Normal
University (T9907000915) is gratefully acknowledged.
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11408
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Asymmetric 1,4-Addition Reactions
COMMUNICATION
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[14] No decomposition of ligand 3e in CDCl3 was observed in 1H NMR
experiments over several weeks.
[15] The configurations of the adducts were determined by comparing
the sign of the specific rotation with those of the reported samples
in the literature.
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[17] The crude complex, prepared from the reaction of 3e (1.0 equiv)
and [{RhClACHTNUGTRNEU(GN C2H4)2}2] (0.5 equiv) in CH2Cl2 at room temperature for
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[10] Both the instability of the phenyl analogue of ligand 1 and the facile
addition of nucleophiles to the unsubstituted double bond in ligand
2 have lead to the preparation and application of the chiral diene li-
14 h, was purified by flash column chromatography over silica gel
(ethyl acetate/hexanes, 1:10) to give the desire complex as a reddish-
brown solid (65%). Recrystallization of the solid from CH2Cl2/
hexane gave single crystals suitable for X-ray crystallographic analy-
sis.
[18] The overall yields of chiral dienes 3a–h are 17–25% from (À)-
bornyl acetate as a 40% yield of compound 4 was constantly ob-
served. Attempts to optimize the reaction conditions for the prepa-
ration of keto acetate 4 by using other oxidants and solvents result-
ed in no improvement. The fact that (À)-bornyl acetate is inexpen-
sive and the observed high yields and excellent enantioselectivities
in the Rh-catalyzed 1,4-addition reaction eliminate concerns over
the failure of attempts to improve the yield by optimizing the condi-
tions.
gands of the bicycloACTHNUTRGNEUGN[2.2.2] skeleton.
[11] Compound 4 can be prepared from chemical or microbiological
functionalization of (À)-bornyl acetate, which was received from
Received: July 6, 2011
Published online: August 31, 2011
Chem. Eur. J. 2011, 17, 11405 – 11409
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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