4,8-disubstituted bicyclo[3.3.1]nona-2,6-dienes as chiral ligands for rh-catalyzed asymmetric 1,4-addition reactions

Article abstract of DOI:10.1002/ejoc.201500202

C₂-symmetric chiral diene ligands based on 4,8-endo,endo-disubstituted bicyclo[3.3.1]nona-2,6-diene framework have been designed and synthesized. The rhodium complexes of the dienes, which were obtained in a few straightforward steps from enantiomerically pure bicyclo[3.3.1]nonane-2,6-dione, exhibited excellent catalytic activity and high enantioselectivity (up to 96% ee) in the conjugate addition reaction of arylboronic acids to cyclic enones under mild reaction conditions with high atom efficiency. Chiral C₂-symmetric 4,8-endo,endo-disubstituted bicyclo[3.3.1]nona-2,6-diene ligands were synthesized from easily available bicyclo[3.3.1]nonane-2,6-dione and utilized in the asymmetric 1,4-addition reaction of arylboronic acids to cyclic enones. The catalyst prepared in situ from ligand 4b and [RhCl(C₂H₄)₂]₂ exhibited excellent catalytic activity and high enantioselectivity (up to 96% ee) under mild reaction conditions with high atom efficiency.

Full text of DOI:10.1002/ejoc.201500202

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500202
4,8-Disubstituted Bicyclo[3.3.1]nona-2,6-dienes as Chiral Ligands for Rh-
Catalyzed Asymmetric 1,4-Addition Reactions
[a]
[a]
[a]
ˇ
Renaldas Rimkus, Marius Jurgele˙nas, and Sigitas Stoncius*
Keywords: Asymmetric catalysis / Diene ligands / Michael addition / Rhodium
C2-symmetric chiral diene ligands based on 4,8-endo,endo-
disubstituted bicyclo[3.3.1]nona-2,6-diene framework have
been designed and synthesized. The rhodium complexes of
the dienes, which were obtained in a few straightforward
steps from enantiomerically pure bicyclo[3.3.1]nonane-2,6-
dione, exhibited excellent catalytic activity and high enantio-
selectivity (up to 96% ee) in the conjugate addition reaction
of arylboronic acids to cyclic enones under mild reaction con-
ditions with high atom efficiency.
acid is generally required as a result of competing protode-
boronation[1b] and homocoupling[7g] side reactions. The
multistep synthesis and, most notably, the necessity to use
preparative chiral HPLC to access enantiomerically pure
dienes or their synthetic precursors[7c,9] also remains a con-
cern. Hence, the development of readily accessible chiral
diene ligands with increased selectivity and catalytic activity
is highly desirable. To this end, we have demonstrated the
utility of (+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione (1)
(Scheme 1), which can be easily obtained by kinetic resolu-
tion of the racemate with baker’s yeast,[13] for the synthesis
of related enantiomerically pure structures[14] and self-as-
sembling supramolecular tectons.[15] We anticipated that the
unsaturated diol 3 derived from diketone 1 would provide
a convenient intermediate to access 4,8-endo,endo-disubsti-
tuted dienes 4, where the steric bulk of the substituents and
consequently the chiral environment around the diene-coor-
dinated Rh atom could be tuned in a straightforward man-
ner.
Introduction
The rhodium-catalyzed asymmetric conjugate addition
of organoboron reagents to activated alkenes has emerged
as one of the most functional-group-tolerant and reliable
carbon–carbon bond-forming reactions.[1] The ability to im-
part high levels of enantioselectivity across a broad range
of alkene acceptors, combined with the high stability and
ready availability of many organoboron reagents, makes
this methodology particularly attractive for the assembly of
complex molecules and intermediates in drug discovery.[2]
Recent developments in this research area included the utili-
zation of bidentate diolefins as steering ligands for transi-
tion-metal-catalyzed asymmetric transformations. Since the
first application of chiral dienes in asymmetric rhodium[3]
and iridium[4] catalyzed reactions, the research efforts di-
rected towards design, synthesis and study of novel ligands
has burgeoned.[5] A variety of C2- and C1-symmetric chiral
dienes based on rigid bicyclic and polycyclic skeletons, such
as bicyclo[2.2.1]heptadienes,[3,6] bicyclo[2.2.2]octadienes,[7]
bicyclo[3.3.0]octadienes,[8] bicyclo[3.3.1]nonadienes[9] and
dicyclopentadienes,[10] as well as acyclic ligands,[11] have
been developed. In terms of both catalytic activity and
enantioselectivity chiral dienes often surpass other types of
ligands, such as chiral bisphosphines, especially in the con-
jugate addition of boronic acids to α,β-unsaturated carb-
onyl compounds and arylation of imines,[6–11] as well as
other synthetically useful asymmetric rhodium-catalyzed re-
actions.[12] Nevertheless, even though diene–Rh catalyzed
arylation reactions are conducted under milder conditions,
in order to achieve high yields an excess of aryl boronic
Scheme 1. Reagents and conditions: a) NaH, Ph(S=O)OMe, THF,
then Na2CO3, Ph-CH3, reflux (80–83%); b) NaBH4, CeCl3·7H2O,
MeOH (72–78%); c) MeI, NaH, DMF (82%); d) BnCl, NaH,
DMF (81–87%); e) tBuO(C=NH)CCl3, BF3·Et2O, CH2Cl2 (24%);
f) TBDMSCl or TBDPSCl, imidazole, DMF (99%); g) PhCOCl,
DMAP, Py (72%). Bn = benzyl; TBDMS = tert-butyldimethylsilyl;
TBDPS = tert-butyldiphenylsilyl; DMAP = 4-dimethylaminopyr-
idine.
[a] Department of Organic Chemistry
Vilnius University
Naugarduko 24, 03225 Vilnius, Lithuania
E-mail: sigitas.stoncius@chf.vu.lt
http://www.chf.vu.lt/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500202.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
R. Rimkus, M. Jurgelenas, S. Stoncˇius
˙
SHORT COMMUNICATION
Herein, we report the preparation of 4,8-disubstituted bi- Table 1. Ligand screening and optimization of reaction condi-
tions.[a]
cyclo[3.3.1]nona-2,6-diene ligands and their application in
the Rh-catalyzed asymmetric 1,4-addition reaction of
boronic acids to cyclic enones. Structural features of the
active catalyst obtained from an X-ray crystallographic
analysis are also presented.
Entry
Ligand
Solvent
Yield[b] [%] ee[c] [%]
Results and Discussion
1[d]
2[d]
3
4
5
3
Dioxane
Dioxane
Dioxane
MTBE[e]
THF
THF
Toluene
H2O
THF
THF
THF
THF
97
91
97
98
92
98
96
96
96
91
90
–
90
92
94
93
92
95
86
88
94
92
78
–
4a
4b
4b
3
Synthesis of chiral dienes commenced with the prepara-
tion of (+)-(1R,5R)-bicyclo[3.3.1]nona-3,7-diene-2,6-dione
(2)[16] by sulfinylation[17] of enantiomerically pure 2,6-dione
1 with methyl phenylsulfinate in the presence of sodium
hydride, followed by thermal elimination (Scheme 1). Luche
reduction[18] (NaBH4/CeCl3) of the obtained bis(enone) 2
in methanol afforded diol 3 as a mixture of endo,endo- and
endo,exo-diastereomers in ca. 88:12 ratio. Subsequent puri-
fication by column chromatography and fractional crystalli-
zation furnished diastereomerically pure endo,endo-diol 3[19]
in 72–78% yield.
6
4b
4b
3
4c
4d
4e
4f
7
8[f]
9
10
11[g]
12
[a] The reactions were carried out with enone 5a (0.3 mmol), 6a
(0.36 mmol, 1.2 equiv.), [Rh(C2H4)2Cl]2 (3 mol-% Rh), ligand
(3.3 mol-%) and 1.5 m aq. KOH (0.1 mL, 50 mol-%) in correspond-
ing solvent (1 mL) at room temperature for 30 min, unless stated
otherwise. [b] Isolated yield. [c] ee values determined by chiral
O-Alkyl derivatives 4a and 4b were prepared in good
yields by alkylation of 3 with the corresponding alkyl hal-
ides in DMF, by using sodium hydride as a base. However, HPLC; all products 7aa were of (R)-configuration, as revealed by
the comparison of their optical rotations with the literature data.
the methyl ether 4a was found to be rather unstable at room
temperature; the O-benzyl congener 4b also partially de-
[d] The reaction was carried out with 2 equiv. of 6a. [e] MTBE =
methyl tert-butyl ether. [f] The reaction was carried out for 1 h.
composes on storage at room temperature apparently
[g] The reaction was carried out at 50 °C.
through a retro-ene reaction releasing benzaldehyde, but
can be stored in the freezer for indefinite periods of time
without appreciable signs of decomposition. Reaction of demonstrated with O-methyl and O-benzyl congeners 4a
diol 3 with tert-butyl 2,2,2-trichloroacetimidate in the pres- and 4b, which exhibited enhanced levels of asymmetric in-
ence of a catalytic amount of boron trifluoride etherate[20] duction (92 and 94% ee, respectively; entries 2 and 3). No-
in dichloromethane afforded 4c in rather low yield (24%), tably, the reaction could be performed with only 1.2 equiv.
along with the monoprotected derivative 6-(tert-butoxy)- of phenylboronic acid (6a) without adverse effect on yield
bicyclo[3.3.1]nona-3,7-dien-2-ol (24%) and recovered start- and enantioselectivity (entry 3; reaction in the presence of
ing material. Imidazole-catalyzed silylation[21] of 3 with 2 equiv. of 6a yielded 7aa in 98% yield and 94% ee). Paral-
TBDMSCl or TBDPSCl in DMF proceeded uneventfully, lel screenings aimed at identifying an optimal combination
providing the corresponding silylethers 4d and 4e in quanti- of solvent and base by using ligand 4b revealed virtually no
tative yields. Bis(benzoate) 4f was obtained by standard effect on yield and enantioselectivity, when other bases,
benzoylation of diol 3 with benzoyl chloride in pyridine.
such as triethylamine, potassium carbonate or potassium
With bicyclic diene ligands 3 and 4a–4f in hand, their phosphate, were used in aqueous dioxane. Comparable re-
efficiency in the Rh-catalyzed Michael addition reaction of sults were obtained when dioxane was replaced with methyl
phenylboronic acid (6a) to 2-cyclohexenone (5a) was evalu- tert-butyl ether (93% ee, entry 4) and marginally improved
ated (Table 1).
enantioselectivities were attained in tetrahydrofuran with
We were pleased to find that the catalyst prepared in situ both 3 and 4b (entries 5 and 6, compare with entries 1 and
from diene 3 and [RhCl(C2H4)2]2 (3 mol-% Rh) exhibited 3). By contrast, the use of toluene as a solvent had a detri-
excellent activity under standard[3] conditions; complete mental effect on enantioselectivity (86% ee, entry 7). It is
conversions were attained in ca. 10–15 min at room tem- interesting to note that the high solubility of diol 3 in water
perature, by using 2 equiv. of phenylboronic acid (6a), aque- allowed us to perform the reaction without any organic co-
ous potassium hydroxide as a base and dioxane as a solvent. solvent, nevertheless, a decrease in enantioselectivity was
(1R,2R,5R,6R)-Configured diol 3 favoured the formation of observed (entry 8, compare with entries 1 and 5).
(R)-configured 3-phenylcyclohexanone (7aa) in 90% ee and
In light of the above observations, the efficiency of the
97% isolated yield (Table 1, entry 1). Ligand 3 exhibited the remaining ligands 4c–4f was evaluated in THF, by using
same sense of asymmetric induction, but notably outper- 1.2 equiv. of PhB(OH)2 (6a) and aqueous KOH as a base
formed the parent bicyclo[3.3.1]nona-2,6-diene (8)[22] (Fig- (Table 1, entries 9–12). Bis(tert-butyl) ether 4c exhibited
ure 2, vide infra) both in terms of activity and enantio- asymmetric induction comparable to that of 4b (entry 9),
selectivity [1.25 h, 83% yield of 7aa (86% ee)]. The benefi- whereas TBDMS-silylated ligand 4d was found to offer
cial effect of the endo-substituents on selectivity was further slightly lower selectivity (92% ee, entry 10). Further in-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
Chiral Ligands for Rh-Catalyzed 1,4-Addition Reactions
crease in the steric bulk of endo-substituents, as in tert-butyl ity significantly; high enantioselectivities (94–96% ee) were
diphenylsilyl congener 4e, had a detrimental effect on cata- maintained when sterically unhindered p- and m-substituted
lytic activity. The Rh/4e-catalyzed reaction at room tem- arylboronic acids 6a–6g were employed (entries 1–7). On
perature was extremely sluggish, providing only trace the other hand, a drop in asymmetric induction was ob-
amounts of 7aa; nevertheless, at elevated temperature served when sterically encumbered o-substituted aryl-
(50 °C) full conversion was achieved in 30 min at the sub- boronic acids 6h–6j (entries 8–10) or (E)-styreneboronic
stantial expense of enantioselectivity (78% ee, entry 11). In acid 6k were used (entry 11).
stark contrast to the behaviour of diol 3 and ethers 4a–
Conjugate addition reactions to 2-cyclopentenone (5b)
4d, bis(benzoate) 4f was found to be totally ineffective in also proceeded uneventfully, albeit with lower enantio-
promoting the reaction under standard conditions at room selectivity (entries 12–13). By contrast, 2-cycloheptenone
temperature (entry 12).[23]
(5c) exhibited lower reactivity under standard conditions
With the diene 4b as the ligand of choice, the substrate and 1.6 equiv. of the aryl boronic acids were required to
scope was investigated under the optimal reaction condi- achieve full conversions in 30 min. The stereochemistry fol-
tions, by using 3 mol-% of Rh catalyst (Table 2). In the case lowed the scenario observed for 5a, i.e. high enantio-
of 2-cyclohexenone (5a), the expected addition products selectivities (93–95% ee) were attained with a range of p-
were produced smoothly at room temperature in excellent and m-substituted arylboronic acids 6a–6g (entries 14–20).
yields.[24]
In diene-Rh catalyzed arylations excess of aryl boronic acid
The electron-donating or withdrawing groups on the (typically two equivalents) is necessary in order to achieve
phenyl ring of boronic acids did not seem to affect selectiv- high yields. This requirement for use of excess arylboronic
acid was attributed to the competing protodeboronation[1b]
and homocoupling[7g] side reactions. From this point of
view, the high catalytic activity of the Rh/4b complex is
Table 2. Rhodium/4b-catalyzed asymmetric 1,4-addition reac-
tions.[a]
noteworthy – in the presence of 0.5 mol-% of the catalyst, 3-
phenylcyclohexanone (7aa) was obtained in 93% yield and
95% ee (Table 2, entry 21, compare with entry 1) with only
1.2 equiv. of 6a.
Structural information on the active catalyst was ob-
tained from an X-ray crystallographic analysis of the com-
plex [RhCl(4b)]2.[25] Treatment of the diene (1R,2R,5R,6R)-
4b with [Rh(C2H4)2Cl]2 in benzene at 50 °C afforded corre-
sponding complex, which exhibited the same catalytic ac-
tivity and asymmetric induction (Table 2, entry 22) as the
catalyst formed in situ. The X-ray crystal structure of
[RhCl(4b)]2 is depicted in Figure 1.
Entry
5
Ar (6)
Product Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
5a C6H5 (6a)
7aa
7ab
7ac
7ad
7ae
7af
7ag
7ah
7ai
98
97
97
89
96
90
94
90
97
89
63
98
97
97
97
97
97
95
94
97
93
96
95
96
96
94
95
94
94
83
76
72
84
79
73
95
95
95
93
95
94
94
95
95
5a 4-FC6H4 (6b)
5a 4-BrC6H4 (6c)
5a 4-MeOC6H4 (6d)
5a 3-ClC6H4 (6e)
5a 3-MeOC6H4 (6f)
5a 2-naphthyl (6g)
5a 2-ClC6H4 (6h)
5a 2-MeOC6H4 (6i)
5a 1-naphthyl (6j)
7aj
5a (E)-C6H5CH=CH (6k) 7ak
5b 4-BrC6H4 (6c)
5b 4-MeOC6H4 (6d)
5c C6H5 (6a)
5c 4-FC6H4 (6b)
5c 4-BrC6H4 (6c)
5c 4-MeOC6H4 (6d)
5c 3-ClC6H4 (6e)
5c 3-MeOC6H4 (6f)
5c 2-naphthyl (6g)
5a C6H5 (6a)
7bc
7bd
7ca
7cb
7cc
7cd
7ce
7cf
13
14[d]
15[d]
16[d]
17[d]
18[d]
19[d]
20[d]
21[e]
22[f]
Figure 1. X-ray structure of [RhCl(4b)]2 with thermal elipsoids
drawn at the 50% probability (shown as a monomer; hydrogen
atoms are omitted for clarity). Selected bond lengths [Å] and angles
[°]: Rh–C2 2.12, Rh–C3 2.09, ЄC2–Rh–C6 85, ЄC3–Rh–C7
102, ЄC2–C3/C7–C6 21.
7cg
7aa
7aa
5a C6H5 (6a)
[a] The reactions were carried out with enone 5 (0.3 mmol), aryl-
boronic acid 6 (0.36 mmol, 1.2 equiv.), [Rh(C2H4)2Cl]2 (3 mol-%
Rh), ligand 4b (3.3 mol-%) and 1.5 m aq. KOH (0.1 mL, 50 mol-
%) in THF (1 mL) at room temperature for 30 min, unless stated
otherwise. [b] Isolated yield. [c] ee values determined by chiral
HPLC; all products 7 were of (R)-configuration, as revealed by the
comparison of their optical rotations with the literature data.
[d] The reaction was conducted with 1.6 equiv. of 6. [e] The reaction
was carried out for 1.5 h on a 1.8 mmol scale with 1.2 equiv. of 6a
and 0.5 mol-% catalyst loading. [f] Preformed [RhCl(4b)]2 complex
(3 mol-% Rh) used as a catalyst.
Analysis of the key structural parameters of [RhCl(4b)]2
reveals a very close resemblance to the Rh complexes of
2,6- and 3,7-disubstituted bicyclo[3.3.1]nona-2,6-diene li-
gands 9[9b] and 10a,[9c] reported by Hayashi (Figure 2).
Thus, the core bicyclo[3.3.1]nona-2,6-diene scaffold in
[RhCl(4b)]2 complex shows similar structural data, i.e. the
two double bonds (C2=C3 and C6=C7) coordinated to the
rhodium centre are not parallel to each other but twisted
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
R. Rimkus, M. Jurgelenas, S. Stoncˇius
˙
SHORT COMMUNICATION
by 21°, resulting in very different C2–Rh–C6 and C3–Rh– 1,4-addition of arylboronic acids to α,β-unsaturated
C7 angles (85° and 102°, respectively). The bite angle of the ketones. Chiral dienes 4a–4f were obtained in three straight-
diene coordination in [RhCl(4b)]2 (87°) is almost identical forward synthetic steps from bicyclo[3.3.1]nonane-2,6-dione
to those reported for aryl-substituted bicyclo[3.3.1]nona- (1), easily available in an enantiomerically pure form by ki-
2,6-diene congeners 9 (89°) and 10a (88°).
netic resolution of racemic 1 with baker’s yeast. In compari-
son with the parent bicyclo[3.3.1]nona-2,6-diene (8),
compounds 3 and 4a–4d displayed enhanced levels of
enantioselectivity, demonstrating the beneficial effect of 4,8-
endo,endo-substitution on asymmetric induction. Rhodium
catalyst with 4,8-bis(benzyloxy) diene 4b, which emerged as
a champion ligand, exhibited excellent activity under mild
reaction conditions (30 min at room temperature) and high
enantioselectivity (up to 96% ee) for cyclic enones with high
atom efficiency (1.2–1.6 equiv. arylboronic acid). Further
structural modification of chiral diene ligands based on 4,8-
disubstituted bicyclo[3.3.1]nona-2,6-diene framework is
currently under investigation.
Figure 2. Other chiral bicyclo[3.3.1]nona-2,6-diene ligands.
Diene ligands 3–4 (Scheme 1) and 8–10 (Figure 2) belong
to the same chiral series regardless of the actual chirality
descriptors and all, with the exception of 9, favour the for-
mation of (R)-3-phenylcyclohexanone (7aa). Comparison
of the results for bicyclo[3.3.1]nona-2,6-diene (8) (86 and
90% ee in dioxane and THF, respectively),[22] and ligands
Experimental Section
3
(Table 1, entries 1 and 5), 4b (Table 1, entries 3
Typical Procedure for the 1,4-Addition of Boronic Acids to Cyclic
Enones: [Rh(C2H4)2Cl]2 (1.75 mg, 9.0 μmol Rh), ligand 4b (3.3 mg,
9.9 μmol) and corresponding aryl boronic acid 6 (0.36 mmol,
1.2 equiv.) were combined in a flask equipped with a magnetic stir
bar. The flask was flushed with argon, charged with deoxygenated
THF (1 mL) and the resulting solution was stirred at 50 °C for
15 min to allow for ethylene–ligand exchange. The solution was
and 6) clearly demonstrates the beneficial effect of the
4,8-endo,endo-substitution on asymmetric induction. In the
[RhCl(4b)]2 complex, the Rh–O distance was found to be
3.3 Å, whereas the distance between Rh and the methylene
carbons of the benzyl groups ranged from 4.2 to 4.6 Å, de-
pending on the conformation of the O-benzyl side chains.
Inspection of the X-ray structure of [RhCl(4b)]2, however,
revealed no apparent steric distinction between the two dia-
stereomeric reaction pathways that could rationalize the
formation of (R)-configured 3-arylcycloalkanones 7 or di-
minished selectivity in the case of 2-cyclopentenone (5b)
(Table 2, entries 12–13).[26,27] Similarly, in the case of the
parent ligand 8, which lacks bulky substituents but exhibits
rather remarkable selectivity, no direct evidence of un-
favourable steric hindrance to either diastereomeric transi-
tion state was found by theoretical calculations.[22] Appar-
ently the stereochemical course of the reaction is deter-
mined by the cooperative effect of “crossed diene coordina-
tion” (expressed as the angle between the two Rh-coordi-
nated C=C bonds) and by multiple, weak interactions be-
tween the spectator diene ligand and two substrate-derived,
actor ligands arranged around the central Rh atom.[28] The
enantioselectivity attained with 4b in the reaction of cyclic
enones with arylboronic acids matches the level reported
for the most enantioselective ligand of bicyclo[3.3.1]nona-
2,6-diene series, 3,7-bis(4-methoxybenzyl)bicyclo[3.3.1]-
nona-2,6-diene (10b). The latter, however, is obtained from
achiral bicyclo[3.3.1]nonan-3,7-dione, thus necessitating the
preparative enantiomer resolution of diene 10b by chiral
HPLC.[9c]
cooled to room temperature and neat enone
5 (0.3 mmol,
1.0 equiv.) was added, followed by aqueous potassium hydroxide
(100 μL, 1.5 m solution, 50 mol-%). The reaction mixture was al-
lowed to stir for 30 min at room temperature, then diluted with
ethyl acetate (10 mL), washed with a 10% aqueous solution of
NaOH (2ϫ 5 mL) and brine (2ϫ 5 mL). The organic phase was
dried (Na2SO4), evaporated and the obtained residue was purified
by column chromatography on silica gel to afford corresponding 3-
arylcycloalkanones 7 (for further details see the Supporting Infor-
mation).
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of the ligands, characterization
1
of asymmetric 1,4-addition products, copies of H and 13C NMR
spectra of new compounds, chiral HPLC traces and X-ray diffrac-
tion data.
Acknowledgments
This research was funded by the European Social Fund under the
ˇ
Global Grant measure (VP1-3.1-SMM-07-K-01-030). We are grate-
ful to Dr. G. Bagdziunas, Department of Polymer Chemistry and
ˇ
¯
Technology, Kaunas University of Technology, for the X-ray analy-
sis. Mr. L. Taujenis is acknowledged for the HRMS analysis.
[1] For reviews, see: a) T. Hayashi, Synlett 2001, 879–887; b) T.
Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829–2844; c)
K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169–196.
[2] H. J. Edwards, J. D. Hargrave, S. D. Penrose, C. G. Frost,
Chem. Soc. Rev. 2010, 39, 2093–2105.
[3] T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am.
Chem. Soc. 2003, 125, 11508–11509.
Conclusions
In conclusion, we have designed and synthesized 4,8-
endo,endo-disubstituted bicyclo[3.3.1]nona-2,6-dienes as
new C2-symmetric chiral diene ligands for the Rh-catalyzed
[4] C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am.
Chem. Soc. 2004, 126, 1628–1629.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
Chiral Ligands for Rh-Catalyzed 1,4-Addition Reactions
[5] For reviews, see: a) C. Defieber, H. Grutzmacher, E. M. Car-
reira, Angew. Chem. Int. Ed. 2008, 47, 4482–4502; Angew.
Chem. 2008, 120, 4558; b) J. B. Johnson, T. Rovis, Angew.
Chem. Int. Ed. 2008, 47, 840–871; Angew. Chem. 2008, 120,
852; c) R. Shintani, T. Hayashi, Aldrichim. Acta 2009, 42, 31–
38; d) C.-G. Feng, M. H. Xu, G.-Q. Lin, Synlett 2011, 10,
1345–1356.
[6] a) G. Berthon-Gelloz, T. Hayashi, J. Org. Chem. 2006, 71,
8957–8960; b) M. K. Brown, E. J. Corey, Org. Lett. 2010, 12,
172–175; c) W.-T. Wei, J.-Y. Yeh, T.-S. Kuo, H.-L. Wu, Chem.
Eur. J. 2011, 17, 11405–11409; d) C.-C. Liu, D. Janmanchi, C.-
C. Chen, H.-L. Wu, Eur. J. Org. Chem. 2012, 2503–2507; e) C.-
C. Chen, B. Gopula, J.-F. Syu, J.-H. Pan, T.-S. Kuo, P.-Y. Wu,
J. P. Henschke, H.-L. Wu, J. Org. Chem. 2014, 79, 8077–8085;
f) T. Noël, K. Vandyck, J. Van der Eycken, Tetrahedron 2007,
63, 12961–12967; g) Y.-C. Chung, D. Janmanchi, H.-L. Wu,
Org. Lett. 2012, 14, 2766–2769.
[7] a) N. Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R.
Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126, 13584–
13585; b) C. Defieber, J.-F. Paquin, S. Serna, E. M. Carreira,
Org. Lett. 2004, 6, 3873–3876; c) Y. Otomaru, K. Okamoto, R.
Shintani, T. Hayashi, J. Org. Chem. 2005, 70, 2503–2508; d) T.
Gendrineau, O. Chuzel, H. Eijsberg, J.-P. Genet, S. Darses, An-
gew. Chem. Int. Ed. 2008, 47, 7669–7672; Angew. Chem. 2008,
120, 7783; e) K. Okamoto, T. Hayashi, V. H. Rawal, Org. Lett.
2008, 10, 4387–4389; f) Y. Luo, A. J. Carnell, Angew. Chem.
Int. Ed. 2010, 49, 2750–2754; Angew. Chem. 2010, 122, 2810;
g) R. Brönnimann, S. Chun, R. Marti, S. Abele, Helv. Chim.
Acta 2012, 95, 1809–1817.
8434; g) Y. Luo, A. J. Carnell, H. W. Lam, Angew. Chem. Int.
Ed. 2012, 51, 6762–6766; Angew. Chem. 2012, 124, 6866; h) K.-
C. Huang, B. Gopula, T.-S. Kuo, C.-W. Chiang, P.-Y. Wu, J. P.
Henschke, H.-L. Wu, Org. Lett. 2013, 15, 5730–5733; i) B. Go-
pula, C.-W. Chiang, W.-Z. Lee, T.-S. Kuo, P.-Y. Wu, J. P.
Henschke, H.-L. Wu, Org. Lett. 2014, 16, 632–635.
C. J. Wallentin, E. Orentas, E. Butkus, K. Wärnmark, Synthesis
2009, 864–867.
[13]
[14]
ˇ
a) E. Butkus, S. Stoncˇius, A. Zilinskas, Chirality 2001, 13, 694–
ˇ
698; b) E. Butkus, A. Zilinskas, S. Stoncˇius, R. Rozenbergas,
M. Urbanová, V. Setnicˇka, P. Bourˇ, K. Volka, Tetrahedron:
Asymmetry 2002, 13, 633–638.
ˇ
[15]
a) S. Stoncˇius, E. Butkus, A. Zilinskas, K. Larsson, L.
Öhrström, U. Berg, K. Wärnmark, J. Org. Chem. 2004, 69,
5196–5203; b) S. Stoncˇius, E. Orentas, E. Butkus, L. Öhrström,
O. F. Wendt, K. Wärnmark, J. Am. Chem. Soc. 2006, 128,
8272–8285.
ˇ
[16]
[17]
[18]
[19]
E. Orentas, G. Bagdziunas, U. Berg, A. Zilinskas, E. Butkus,
Eur. J. Org. Chem. 2007, 4251–4256.
ˇ
¯
J. E. Resek, A. I. Meyers, Tetrahedron Lett. 1995, 36, 7051–
7054.
A. L. Gemal, J.-L. Luche, J. Am. Chem. Soc. 1981, 103, 5454–
5459.
C.-J. Wallentin, E. Orentas, M. T. Johnson, N. B. Bathori, E.
Butkus, O. F. Wendt, K. Wärnmark, L. Öhrström, Crys-
tEngComm 2012, 1, 178–187.
A. Armstrong, I. Brackenridge, R. F. W. Jackson, J. M. Kirk,
Tetrahedron Lett. 1988, 29, 2483–2486.
[20]
[8] a) S. Helbig, S. Sauer, N. Cramer, S. Laschat, A. Baro, W. Frey, [21] E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,
Adv. Synth. Catal. 2007, 349, 2331–2337; b) Z.-Q. Wang, C.-G. 6190–6191.
Feng, M.-H. Xu, G.-Q. Lin, J. Am. Chem. Soc. 2007, 129, [22] S. Gosiewska, J. A. Raskatov, R. Shintani, T. Hayashi, J. M.
5336–5337; c) C.-G. Feng, Z.-Q. Wang, P. Tian, M.-H. Xu, G.-
Q. Lin, Chem. Asian J. 2008, 3, 1511–1516; d) C.-G. Feng, Z.-
Q. Wang, C. Shao, M.-H. Xu, G.-Q. Lin, Org. Lett. 2008, 10,
4101–4104; e) Z. Cui, H.-J. Yu, R.-F. Yang, W.-Y. Gao, C.-G.
Feng, G.-Q. Lin, J. Am. Chem. Soc. 2011, 133, 12394–12397.
[9] a) Y. Otomaru, N. Tokunaga, R. Shintani, T. Hayashi, Org.
Lett. 2005, 7, 307–310; b) Y. Otomaru, A. Kina, R. Shintani,
T. Hayashi, Tetrahedron: Asymmetry 2005, 16, 1673–1679; c)
R. Shintani, Y. Ichikawa, K. Takatsu, F.-X. Chen, T. Hayashi,
J. Org. Chem. 2009, 74, 869–873.
Brown, Chem. Eur. J. 2012, 18, 80–84.
[23] It is unlikely that inactivity of bis(benzoate) 4f is due to saponi-
fication under the reaction conditions. Control experiments re-
vealed no signs of hydrolysis when 4f (9.9 μmol) was stirred for
2 h at room temp. in a mixture of THF and 1.5 m aqueous
KOH (10:1, 1.1 mL), whereas only partial hydrolysis occurred
after 24 h at 50 °C.
[24] Typically, no starting enone in the reaction mixture could be
detected by TLC after 10–15 min, but the reaction was carried
out for 30 min to ensure full conversion.
[10] a) C. Shao, H.-J. Yu, N.-Y. Wu, C.-G. Feng, G.-Q. Lin, Org. [25] CCDC-1047973 contains the supplementary crystallographic
Lett. 2010, 12, 3820–3823; b) C. Shao, H.-J. Yu, C.-G. Feng,
R. Wang, G.-Q. Lin, Tetrahedron Lett. 2012, 53, 2733–2735.
[11] a) Y. Wang, X. Hu, H. Du, Org. Lett. 2010, 12, 5482–5485; b)
Q. Li, Z. Dong, Z.-X. Yu, Org. Lett. 2011, 13, 1122–1125; c)
B. M. Trost, A. C. Burns, T. Tautz, Org. Lett. 2011, 13, 4566–
4569.
[12] For selected examples, see: a) R. Shintani, Y. Sannohe, T. Tsuji,
T. Hayashi, Angew. Chem. Int. Ed. 2007, 46, 7277–7280; Angew.
Chem. 2007, 119, 7415; b) R. Shintani, S. Isobe, M. Takeda, T.
Hayashi, Angew. Chem. Int. Ed. 2010, 49, 3795–3798; Angew.
Chem. 2010, 122, 3883; c) T. Nishimura, Y. Maeda, T. Hayashi,
Angew. Chem. Int. Ed. 2010, 49, 7324–7327; Angew. Chem.
2010, 122, 7482; d) T. Nishimura, Y. Yasuhara, T. Sawano, T.
Hayashi, J. Am. Chem. Soc. 2010, 132, 7872–7873; e) J. S. Ar-
nold, H. M. Nguyen, J. Am. Chem. Soc. 2012, 134, 8380–8383;
f) Y. Luo, H. B. Hepburn, N. Chotsaeng, H. W. Lam, Angew.
Chem. Int. Ed. 2012, 51, 8309–8313; Angew. Chem. 2012, 124,
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[26] Acyclic enones, such as 4-phenylbut-3-en-2-one (5d) and 1,3-
diphenyl-2-propen-1-one (5e), exhibited diminished reactivity
and rather modest enantioselectivity in Rh/4b catalyzed reac-
tion with 6c (40 and 17% ee, respectively) under standard con-
ditions. In this case, the use of sterically encumbered boronic
acids, such as 6j, has beneficial effect on selectivity (89 and
81% ee with 5d and 5e, respectively).
[27] Rh/4b catalyzed arylation of unsaturated lactone furan-2(5H)-
one with 6a (1.2 equiv.) under standard conditions (30 min at
room temp.) provided corresponding adduct in good yield
(82%), but unsatisfactory enantioselectivity (30% ee).
[28] E. A. B. Kantchev, Chem. Sci. 2013, 4, 1864–1875.
Received: February 10, 2015
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O50202
/KAP1
Date: 07-04-15 11:46:56
Pages: 6
R. Rimkus, M. Jurgelenas, S. Stoncˇius
˙
SHORT COMMUNICATION
Asymmetric Catalysis
R. Rimkus, M. Jurgele˙nas,
ˇ
S. Stoncius* ...................................... 1–6
4,8-Disubstituted Bicyclo[3.3.1]nona-2,6-
dienes as Chiral Ligands for Rh-Catalyzed
Asymmetric 1,4-Addition Reactions
Chiral C2-symmetric 4,8-endo,endo-disub-
stituted bicyclo[3.3.1]nona-2,6-diene li-
gands were synthesized from easily avail-
able bicyclo[3.3.1]nonane-2,6-dione and
utilized in the asymmetric 1,4-addition reac-
tion of arylboronic acids to cyclic enones.
The catalyst prepared in situ from ligand
4b and [RhCl(C2H4)2]2 exhibited excellent
catalytic activity and high enantioselectiv-
ity (up to 96% ee) under mild reaction con-
ditions with high atom efficiency.
Keywords: Asymmetric catalysis / Diene
ligands / Michael addition / Rhodium
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0