Fine-Tuning the Bicyclo[3.3.1]nona-2,6-diene Ligands: Second Generation 4,8-Substituted Dienes for Rh-Catalyzed Asymmetric 1,4-Addition Reactions

Article abstract of DOI:10.1002/cctc.202100638

Design and synthesis of the second generation C₂-symmetric 4,8-endo,endo-bis(alkoxy) bicyclo[3.3.1]nona-2,6-diene ligands possessing additional 4,8-exo,exo substituents is reported. The 4,8-exo,exo groups provide a further element for fine-tuning of the ligand structure by enforcing conformational rigidity of the 4,8-endo,endo side chains. Such tetrasubstituted bicyclo[3.3.1]nona-2,6-dienes were employed as steering ligands in the rhodium-catalyzed arylation of cyclic enones with arylboronic acids, providing the corresponding 1,4-addition products in good to excellent yields (69–99 %) and enantioselectivities up to 99 % ee.

Full text of DOI:10.1002/cctc.202100638

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Fine-Tuning the Bicyclo[3.3.1]nona-2,6-diene Ligands:
Second Generation 4,8-Substituted Dienes for Rh-Catalyzed
Asymmetric 1,4-Addition Reactions
Vidmantas Bieliūnas[b, c] and Sigitas Stončius*[a]
Design and synthesis of the second generation C2-symmetric
4,8-endo,endo-bis(alkoxy) bicyclo[3.3.1]nona-2,6-diene ligands
possessing additional 4,8-exo,exo substituents is reported. The
4,8-exo,exo groups provide a further element for fine-tuning of
the ligand structure by enforcing conformational rigidity of the
4,8-endo,endo side chains. Such tetrasubstituted bicyclo[3.3.1]
nona-2,6-dienes were employed as steering ligands in the
rhodium-catalyzed arylation of cyclic enones with arylboronic
acids, providing the corresponding 1,4-addition products in
good to excellent yields (69–99%) and enantioselectivities up
to 99% ee.
Introduction
complex chiral molecules, intermediates and building blocks in
drug discovery.[13]
Over the past two decades chiral dienes have emerged as a
new type of bidentate steering ligands for transition metal-
catalyzed asymmetric transformations.[1] The pioneering reports
on the application of bicyclic dienes in the asymmetric rhodium
and iridium-catalyzed reactions by Hayashi[2] and Carreira[3]
spurred intense research effort directed towards the synthesis
and study of novel steering ligands. A variety of structurally
diverse dienes based on bicyclo[2.2.1]heptadiene,[2,4] bicyclo
Chiral dienes often surpass conventional phosphine ligands
in terms of both catalytic activity and enantioselectivity, there-
fore it is not surprising that their synthesis, structural studies
and application in the Rh-catalyzed asymmetric transformations
remains active research endeavor. Plentiful examples include
1,2-,[14] 1,4-[15] and 1,6-additions[16] to
a wide variety of
substrates, intramolecular [4+2] cycloadditions[17] and arylative
(carbo)cyclizations,[18] benzannulations,[19] cyclopropanations,[20]
dynamic kinetic asymmetric transformations of allylic
trichloroacetimidates,[21] carbene insertions into BÀ H[22] and
SiÀ H[23] bonds and other synthetically useful procedures.[24]
While the utility of privileged bicyclo[2.2.1]heptadiene, bicyclo
[2.2.2]octadiene and bicyclo[3.3.0]octadiene skeletons is partic-
ularly amply demonstrated, the potential of the bicyclo[3.3.1]
nonadiene framework for construction of steering ligands
remains underexplored. To this end, we have reported synthesis
of C2-symmetric 4,8-endo,endo-disubstituted bicyclo[3.3.1]nona-
2,6-diene chelating ligands and demonstrated their utility in the
asymmetric rhodium-catalyzed 1,4-addition of boronic acids to
cyclic enones.[9] In contrast to the common tactics, which
involves manipulation of steering substituents at the vinylic
positions, our approach to tuning the chiral environment
around the diene-coordinated Rh atom relied on the function-
alization of the ligand skeleton at the allylic positions. In
comparison with the parent bicyclo[3.3.1]nona-2,6-diene,[25] the
4,8-bis(alkoxy) congeners displayed enhanced levels of enantio-
selectivity, thus demonstrating the beneficial effect of 4,8-
endo,endo-substitution on asymmetric induction. Herein, we
report the design and synthesis of the second generation C2-
symmetric 4,8-endo,endo-bis(alkoxy) bicyclo[3.3.1]nona-2,6-di-
enes, decorated with additional bulky 4,8-exo,exo substituents
for fine-tuning of the ligand structure. The scope of benchmark
Rh-catalyzed arylation of cyclic enones using the novel bicyclo
[3.3.1]nona-2,6-diene steering ligands is also presented.
[2.2.2]octadiene,[3,4c,5]
bicyclo[3.3.0]octadiene[6]
bicyclo[3.3.1]nonadiene,[8,9]
dicyclopenta-
and
propelladiene,[7]
diene,[10] cyclooctadiene,[11] as well as acyclic[12] frameworks have
been developed. Ligands of this type have been found to be
particularly effective in the asymmetric rhodium-catalyzed
conjugate addition of boronic acids to α,β-unsaturated carbonyl
compounds and arylation of imines. Due to exceptional levels
of stereoselectivity, functional group tolerance, and ready
availability and stability of many organoboron reagents this
methodology became a practical tool for the assembly of
[a] Dr. S. Stončius
Department of Organic Chemistry
Center for Physical Sciences and Technology
Akademijos 7
LT-08412 Vilnius (Lithuania)
E-mail: sigitas.stoncius@ftmc.lt
[b] V. Bieliūnas
Department of Organic Chemistry
Vilnius University
Naugarduko 24
LT-03225 Vilnius (Lithuania)
[c] V. Bieliūnas
Present Address: Molecular Design and Synthesis
Department of Chemistry
KU Leuven
Celestijnenlaan 200F
Box 2404
3001 Leuven (Belgium)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.202100638
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Results and Discussion
former of 3aa, the 4,8-exo,exo substitution enforces a spatial
arrangement of methyl groups proximal to double bonds, i.e.,
synclinal and antiperiplanar conformation of the methoxy
groups with respect to C4(8)À C3(7) and C4(8)À C5(1) bonds, respec-
tively (Figure S4). This effect is even more pronounced in the
case of 3ba, 3fa and 3ha with bulky exo-aryl substituents –
virtually single stable C2-symmetric (-sc, -sc)-conformation with
two methoxy groups synclinal to C4(8)À C3(7) bonds was found
(Figures S5–S6), whereas other conformers were found to be
insignificantly populated. Coordination of the chiral dienes with
Rh(I) obviously induces conformational changes of both bicyclic
framework and side chains. Nevertheless, calculations suggest
that the second generation ligands 3 should provide a more
effective chiral environment in their transition metal complexes
due to the steric restrictions imposed by the 4,8-exo,exo
substituents.
The design of the first generation diene ligands 2 (Scheme 1)
derived from endo,endo-diol 1 was based on the assumption
that the chiral environment around the diene-coordinated
rhodium atom could be tuned in a straightforward manner by
changing the steric bulk of the 4,8-endo,endo substituents.
Indeed, rhodium complex with 4,8-bis(benzyloxy) diene 2b,
which emerged as a champion ligand, exhibited excellent
catalytic activity and high enantioselectivity (up to 96% ee) in
the asymmetric arylation of cyclic enones 4 with arylboronic
acids 5.[9] Nevertheless, conformational analysis of 2b (vide infra)
and inspection of the X-ray structure of [RhCl(2b)]2 revealed
that 4,8-benzyloxy side chains are rather conformationally
flexible and distant from the catalytically active center (for
details, see Supporting Information, Figure S1).
We reasoned that introduction of 4,8-exo,exo substituents
could enforce conformational rigidity of the 4,8-endo,endo side
chains and provide another element for fine-tuning of the
ligand structure. To test this hypothesis, conformational analysis
of the selected ligands 2a–b, 3aa–ba, 3fa and 3ha was
performed using MMFF94 force field, followed by further
geometry optimization at the B3LYP/6-31G(d) level.[26] Analysis
of 2a–b revealed that (ap, ap)-, (-sc, ap)- and (-sc, -sc)-
conformers with alkoxy groups synclinal (sc) and antiperiplanar
(ap) to C4(8)À C3(7) bonds are close in energy and thus comparably
populated (Figures S2–S3). Steric hindrance imposed even by
the smallest exo-substituents, such as methyl groups in 3aa, is
sufficient to significantly affect conformational mobility of the
4,8-endo,endo side chains. Moreover, in the most stable con-
It was envisioned that a library of bicyclo[3.3.1]nonadiene
ligands 3 could be prepared from a single starting compound
(+)-(1R,5R)-bicyclo[3.3.1]nona-3,7-diene-2,6-dione
(7,
Scheme 2)[9,27] via reaction with corresponding organometallic
reagents, followed by O-alkylation. The 1,2-addition of meth-
ylmagnesium bromide and phenyllithium to dienone 7 in THF
proceeded uneventfully to give the respective diols 8a–b in
72–77% yields (Scheme 2). Subsequent alkylation of 8a–b in
DMF using methyl iodide and benzyl bromide as alkylating
agents and NaH as a base afforded the corresponding C2-
symmetric second generation ligands 3aa–ab and 3ba–bb in
moderate to good yields (43–84%).
With new dienes 8a–b, 3aa–ab and 3ba–bb in hand, we
tested their performance as chiral ligands in the rhodium-
catalyzed asymmetric 1,4-addition reaction (Table 1). In order to
obtain an early insight about the properties of second
generation ligands, arylation of 2-cyclohexenone (4a) with
phenylboronic acid (5a) and 2-cyclopentenone (4b) with 4-
bromophenylboronic acid (5b)[28] were tested with in situ
formed diene-Rh catalysts (3 mol% Rh) under optimal condi-
tions, previously established for ligand 2b.[9]
In the arylation of 2-cyclohexenone (4a) with 5a, rhodium
complexes of diols 8a–b (entries 2 and 3) and corresponding O-
methyl derivatives 3aa–ba (entries 6 and 7) exhibited catalytic
activity similar to that observed with the first generation
Scheme 1. Asymmetric Rh-catalyzed 1,4-addition of arylboronic acids to
cyclic enones and 4,8-substituted bicyclo[3.3.1]nona-2,6-diene ligands.
Scheme 2. Synthesis of 2nd generation 4,8-substituted bicyclo[3.3.1]nona-2,6-
diene ligands. For R and R1, see Scheme 1.
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Table 1. Rhodium-catalyzed asymmetric arylation of cyclic enones with arylboronic acids: ligand screening.
Entry[a]
Ligand
R
R1
4
Ar (5)
t [h]
Product
Yield [%][b]
ee [%][c]
1[d]
2
1
8a
8b
2a
H
Me
Ph
H
H
Me
Ph
Me
H
H
H
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
4-BrC6H4 (5b)
0.5
0.75
0.5
0.5
0.5
0.5
1
0.5
1.25
1
1
1
1
1
3
1
0.5
1.5
1
2
2
1
1
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6bb
6bb
6bb
6bb
6bb
6bb
6bb
92
90
92
91
98
88
90
86
85
86
94
90
88
57
59
57
98
63
70
28
14
47
39
92
92
94
92
95
96
96
89
94
97
96
97
98
97
85
96
79
87
87
54
63
88
84
3
4[d,e]
5[d]
6
Me
Bn
Me
Me
Bn
Bn
Me
Me
Me
Me
Me
Me
Et
Bn
Me
Me
Bn
Bn
Me
Et
2b
3aa
3ba
3ab
3bb
3ca
3da
3ea
3fa
3ga
3ha
3fc
2b
3aa
3ba
3ab
3bb
3fa
3fc
7
8
9
Ph
10
11
12
13
14
15
16
17[d]
18
19
20
21
22
23
4-FC6H4
4-MeC6H4
4-MeOC6H4
3,5-Me2C6H3
3,5-(MeO)2C6H3
2,4,6-(MeO)3C6H2
3,5-Me2C6H3
H
Me
Ph
Me
Ph
3,5-Me2C6H3
3,5-Me2C6H3
[a] The reactions were carried out with enone 4 (0.3 mmol), 5 (0.36 mmol, 1.2 equiv.), [RhCl(C2H4)2]2 (3 mol% Rh), ligand (3.3 mol%) and 1.5 M aq. KOH
(100 μL, 50 mol%) in THF (1 mL) at room temperature. [b] Isolated yield. [c] ee values determined by chiral HPLC; products 6aa and 6bb were of (R)-
configuration, as revealed by the comparison of their HPLC behavior with the data reported earlier.[9] [d] Ref. [9]. [e] The reaction was carried out in 1,4-
dioxane.
congeners 1 (entry 1) and 2a–b (entries 4 and 5), respectively.
In terms of enantioselectivity, marginally improved asymmetric
induction was attained with both 3aa and 3ba (entries 6 and
7 vs entry 5), whereas 1,4-addition of 5b to 2-cyclopentenone
(4b) revealed clear superiority of second generation ligands
3aa–ba (entries 18 and 19 vs entry 17). 4,8-Bis(benzyloxy)
dienes 3ab (entries 8 and 20) and 3bb (entries 9 and 21), on
the other hand, displayed notably lower activity and selectivity
than their O-methyl counterparts 3aa–ba and parent diols 8a–
b. This stands in stark contrast to the behavior of the first
generation ligands, where O-benzyl derivative 2b offered the
best performance. An overall decrease of reaction rate with the
second generation ligands, especially in the case of cyclo-
pentenone 4b, resulting from increased steric crowding at the
catalytic site is also noteworthy.
yields by 1,2-addition of corresponding aryllithium reagents to
dienone (Scheme 2). Aryllithium reagents were freshly
prepared from the appropriate aryl bromides or iodides and n-
7
butyllithium by lithium-halogen exchange in diethyl ether at
°
0 C. Exceptions include 2,4,6-trimethoxyphenyllithium, which
was prepared from 1,3,5-trimethoxybenzene by direct ortho-
lithiation
with
n-butyllithium,[30]
and
2,4,6-trimeth-
ylphenyllithium, which had to be prepared by lithiation of 1-
bromo-2,4,6-trimethylbenzene with metallic lithium.[31] The
latter, however, failed to produce corresponding diol from
dienone 7 (Scheme 2) under a number of different conditions
tested. Alkylation of the diols 8c–h with methyl iodide and
diethyl sulphate under standard conditions (NaH, DMF) pro-
ceeded uneventfully to yield corresponding O-alkyl derivatives
3ca–ha and 3fc in moderate to excellent yields (51–93%,
Scheme 2).
Efficiency of the obtained diene ligands 3ca–ha and 3fc in
the Rh-catalyzed asymmetric 1,4-addition reaction was then
examined (Table 1), terminating the reactions after 60 minutes
to get better insight into the catalytic activity. Apart from 3ha
(entry 15), dienes 3ca–ga provided similar levels of enantiose-
lectivity (entries 10–14) in the 1,4-addition of phenylboronic
acid (5a) to 2-cyclohexenone (4a). The 4,8-exo,exo-bis(3,5-
dimethylphenyl) congener 3fa exhibited marginally enhanced
levels of asymmetric induction in arylation of both 2-cyclo-
Numerous attempts to introduce bulkier exo-isopropyl
substituents by a reaction of dienone 7 (Scheme 2) with
isopropyl magnesium bromide or the corresponding organo-
[29]
°
cerium reagent (anh. CeCl3, i-PrMgBr, THF, À 78 C to r.t.)
produced only traces of the desired diol. Thus, despite the good
performance of ligand 3aa, 4,8-exo,exo-dialkyl substituted series
offered little room for further modifications. Properties of ligand
3ba, however, could be further fine-tuned by changing the
substitution pattern of the 4,8-exo,exo-aryl substituents. There-
fore, a small library of diols 8c–h was prepared in 27–90%
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hexenone (4a) (entry 13 vs entries 7, 10–12 and 14) and 2-
cyclopentenone (4b) (entry 22 vs entry 19), and was selected as
a ligand of choice for further studies. A ligand exchange
reaction of [RhCl(C2H4)2]2 with dienes 3ba and 3fa cleanly
produced corresponding [RhCl(3ba)]2 and [RhCl(3fa)]2 com-
plexes, which were characterized by NMR spectroscopy; never-
theless, numerous attempts to obtain single crystals suitable for
X-ray analysis were unsuccessful.
Table 2. Rhodium/3fa-catalyzed asymmetric arylation of cyclic enones
with arylboronic acids: substrate scope.
Homologation of the O-alkyl chains, as exemplified by 3fc,
proved to be detrimental to both catalytic activity and
selectivity (entries 16 and 23), likely due to increased steric
congestion at the catalytic site. This assumption is further
supported by the inferior performance of extremely sterically
hindered 4,8-exo,exo-bis(2,4,6-trimethoxyphenyl) congener 3ha
(entry 15), which, in sharp contrast to every other member of
the series, exhibited virtually the same selectivity as the parent
diol 8h (86% ee) and the lowest selectivity out of the
investigated dienes overall. In addition, Rh/3ha complex was
much less catalytically active and required 3 hours to achieve
appreciable level of conversion. In comparison with 3ba, 3fa
and the first generation ligands 2a–b, DFT calculations suggest
different geometry of the cyclooctadiene core in 3ha and the
parent diol 8h (for details, see Supporting Information). The
difference in “crossed diene coordination”,[32] expressed by a
notably smaller dihedral angle between the two double bonds,
likely accounts for the moderate enantioselectivity attained
Entry[a]
4
Ar (5)
Product
Yield[b] [%]
ee[c] [%]
1[d]
2[d]
3[d]
4[d]
5[d]
6[d]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13
14
15
16
17
18
19
20
21
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
C6H5 (5a)
4-BrC6H4 (5b)
4-FC6H4 (5c)
4-MeOC6H4 (5d)
3-BrC6H4 (5e)
3-ClC6H4 (5f)
3-MeOC6H4 (5g)
2-naphthyl (5h)
2-ClC6H4 (5i)
2-MeOC6H4 (5j)
1-naphthyl (5k)
2-MeC6H4 (5l)
4-BrC6H4 (5b)
4-FC6H4 (5c)
4-MeOC6H4 (5d)
3-BrC6H4 (5e)
3-MeOC6H4 (5g)
2-naphthyl (5h)
2-ClC6H4 (5i)
2-MeOC6H4 (5j)
1-naphthyl (5k)
2-MeC6H4 (5l)
C6H5 (5a)
4-BrC6H4 (5b)
4-FC6H4 (5c)
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
99
96
97
97
99
97
98
99
97
99
77
96
96
97
99
96
98
97
70
98
79
69
94
89
95
96
91
86
92
96
82
98
99
99
94
99
99
99
98
99
97
97
94
88
86
82
92
91
80
86
72
68
55
97
98
97
95
98
97
97
95
99
6aj
6ak
6al
6bb
6bc
6bd
6be
6bg
6bh
6bi
6bj
6bk
6bl
6ca
6cb
6cc
6cd
6ce
6cg
6ch
6cj
22
23
24
25
1
with both 8h[33] and 3ha. As evidenced by the H and 13C NMR
data, rotation about C4(8)-aryl bonds in 3ha is also severely
restricted. Thus, poor catalytic activity of Rh/3ha complex
probably is a result of both the unfavorable geometry of
cyclooctadiene core and difficulty to undergo conformational
changes needed to accommodate two substrate-derived actor
ligands around the Rh atom.
26
4-MeOC6H4 (5d)
3-BrC6H4 (5e)
3-MeOC6H4 (5g)
2-naphthyl (5h)
2-MeOC6H4 (5j)
2-MeC6H4 (5l)
27[e]
28
29[e]
30
31
6cl
Finally, with the diene 3fa as the ligand of choice, the scope
of asymmetric 1,4-addition of different arylboronic acids 5 to 5-,
6- and 7-membered cyclic enones was investigated (Table 2). To
ensure full conversion, loading of 5 was increased to 1.4–1.8
equivalents and reaction time was increased to 3 h for 2-
cyclohexenone (4a), and to 5 h for both 2-cyclopentenone (4b)
and 2-cycloheptenone (4c). Arylation of 2-cyclohexenone (4a)
afforded the desired products 6aa–al in good to excellent
yields (entries 1–12, Table 2). Excellent enantioselectivities were
maintained with a number of p- and m-substituted boronic
acids 5a–c (entries 1–3) and 5e–h (entries 5–8), with the
exception of electron-rich 4-methoxyphenylboronic acid (5d),
which led to product 6ad in a slightly lower selectivity (94% ee,
entry 4). Ortho-substituents on the boronic acids were also well
tolerated and the adducts were isolated in high enantioselectiv-
ities (94–99% ee, entries 9–12). The superiority of ligand 3fa in
arylation of enone 4a with sterically encumbered boronic acids
is particularly noteworthy, as the first generation diene 2b
exhibited notably decreased levels of enantioselection with 5i–
k (83, 76 and 72% ee, respectively).[9]
[a] The reactions were carried out with enone 4 (0.3 mmol), 5 (1.4 equiv.
for 4a–b, 1.8 equiv. for 4c), [RhCl(C2H4)2]2 (3 mol% Rh), 3fa (3.3 mol%) and
1.5 M aq. KOH (100 μL, 50 mol%) in THF (1 mL) at room temperature for
5 h, unless stated otherwise. [b] Isolated yield. [c] ee values determined by
chiral HPLC; products 6aa–ad, 6af–ak, 6bb, 6bd, 6ca, 6cc–cd and 6cg–
ch were of (R)- configuration, as revealed by the comparison of their HPLC
behavior with the data reported earlier;[9] the configuration of the
remaining 3-arylcycloalkanones 6 is assumed to be (R) in analogy with the
rest of the series. [d] The reaction was carried out for 3 h. [e] The reaction
was carried out in 1,4-dioxane for 2 h.
sterically hindered o-substituted donors 5j–l provided notably
decreased stereoselectivities (55–72% ee, entries 20–22). Such
erosion of asymmetric induction with smaller ring enone 4b is
in accord with the behavior of ligand 2b,[9] as well as
unsubstituted bicyclo[3.3.0]octadiene and propelladiene steer-
ing ligands reported by Lin[6d] and Christmann.[7] 2-cyclohepte-
none (4c) exhibited lowest reactivity under standard conditions
and 1.8 equivalents of the arylboronic acids 5 were required to
achieve full conversions. Surprisingly, reaction of 4c with some
boronic acids, such as 5e and 5h (entries 27 and 29), was
extremely sluggish in tetrahydrofuran and produced only traces
of the desired addition products. Poor reactivity could be
remedied by performing the reaction in 1,4-dioxane, in which
Similar trends were also observed with 5- and 7-membered
enones 4b and 4c. 1,4-adition reactions to 2-cyclopentenone
(4b) proceeded in high yields, but with a generally lower
enantioselectivity (Table 2, entries 13–22). In particular, the
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arylation occurs much faster at the expense of Conclusion
enantioselectivity.[34] The stereochemistry followed the scenario
observed for 4a, i.e., high enantioselectivities (95–99% ee) were
attained with a range of p-, m- and o-substituted boronic acids
(entries 23–31). Once again, electron-rich boronic acid (5d)
furnished addition product 6cd in a marginally lower selectivity
(95% ee, entry 26) than that attained with the other p- and m-
substituted boronic acids (97–98% ee, entries 23–25, 27–29).
A plausible asymmetric induction model based on DFT
calculations at the PBE0/DGDZVP level of theory (for details, see
Supporting Information), which features binding of 2-cyclo-
hexenone (4a) to [Rh]À Ph species coordinated to 3fa diene
ligand in (-sc, -sc)-conformation, is depicted in Figure 1.
According to this model, the acceptor preferentially binds
into the [(diene)Rh]-aryl complex from one of the two prochiral
faces of the double bond. The minimization of steric repulsion
between the enone and 4,8-endo,endo methoxy substituents of
the ligand accounts for the favorable coordination of the metal
center to 2re,3re prochiral face and leads to the formation of
(R)-configured product. DFT molecular modelling of analogous
complexes of PhÀ [Rh(3fa)] and 4a suggests that structures
involving diene ligand in (-sc, ap)- or (ap, ap)- conformations are
unfavored by 2.9–6.5 kcal/mol (Figure S7) and thus are unlikely
to be involved in the catalytic cycle. In comparison with the
best first generation ligand 2b, diene 3fa exhibited enhanced
enantioselectivity throughout the whole substrate range and, as
far as 6- and 7-membered cyclic enones are concerned, rivals
the best steering ligands reported in the literature.[35] Further
In conclusion, synthesis of novel C2-symmetric 4,8-endo,endo-
substituted bicyclo[3.3.1]nona-2,6-dienes endowed with addi-
tional 4,8-exo,exo substituents was accomplished and their
performance as steering ligands in the rhodium-catalyzed
asymmetric 1,4-addition reaction was explored. Bulky 4,8-
exo,exo substituents provide an element for fine-tuning of the
chiral environment around the diene-coordinated Rh atom by
enforcing conformational rigidity of the 4,8-endo,endo side
chains. Rhodium complexes of the second generation ligands
were found superior to the previously reported first generation
Rh/2b catalyst in terms of stereoselectivity at the expense of
catalytic activity as a result of increased steric hindrance at the
catalytically active site. Diene 3fa bearing exo-3,5-dimeth-
ylphenyl and endo-methoxy substituents exhibited highest
stereoselectivity (up to 99% ee) in the asymmetric 1,4-addition
of arylboronic acids to cyclic enones, whereas further increase
of steric bulk of endo-substituents had a detrimental effect on
catalytic activity and selectivity. As far as 6- and 7-membered
cyclic enones are concerned, in terms of enantioselectivity
diene 3fa rivals the best steering ligands reported in the
literature. The somewhat lower level of asymmetric induction in
the arylation of smaller ring cyclopentenone appears to be a
feature common to both first and second generation 4,8-
substituted bicyclo[3.3.1]nona-2,6-diene ligands.
application of the second generation steering ligands in other Experimental Section
rhodium-catalyzed asymmetric transformations is currently
under investigation.
1
General Methods. H and 13C NMR spectra were recorded in CDCl3
on a Bruker AvanceTM HD III (400 MHz) spectrometer equipped with
a 5 mm PABBO probe. Chemical shifts are reported in ppm relative
to solvent resonance signal (1H NMR δ=7.26 ppm, 13C NMR δ=
77.0 ppm). FTIR spectra were recorded on a PerkinElmer Spectrum
BX in KBr pellets, unless stated otherwise. Optical rotations were
20
measured at 589 nm on a KRUSS P3001RS polarimeter; ½a�D values
are given in 10À 1 degcm2 gÀ 1, and concentrations are given in units
of g/100 cm3. Melting points were recorded in open capillaries with
a Gallenkamp melting apparatus. High-resolution mass spectra
(HRMS) were recorded on an Agilent 6203 LC/TOF spectrometer
with electrospray ionization (ESI) in direct injection mode. The
enantiomeric excess values were determined using an Agilent 1260
Infinity HPLC system, equipped with a diode array detector and
CHIRALPAK IA-3, IB-3 and IC-3 analytical (250×4.6 mm) columns.
The chiral HPLC methods were calibrated with the corresponding
racemic mixtures.
All reactions involving air and/or moisture sensitive materials were
conducted under an argon atmosphere. All reagents for the
reactions were of reagent grade and were used as received.
Solvents were dried and distilled under argon before use as follows:
diethyl ether and tetrahydrofuran were distilled from sodium/
benzophenone and kept over 4 Å molecular sieves before use.
Thin-layer chromatography was carried out on Kieselgel 60 F254
(Merck) silica gel coated aluminum sheets and Kieselgel 60 silica gel
(0.040–0.063 mm, Merck) was used for column chromatography.
°
Petroleum ether refers to the fraction boiling in the range 40–60 C.
(+)-(1R,5R)-bicyclo[3.3.1]nona-3,7-diene-2,6-dione (7) was prepared
following the procedure reported earlier.[9]
(+)-(1R,2R,5R,6R)-2,6-dimethylbicyclo[3.3.1]nona-3,7-diene-2,6-
diol (8a). Methylmagnesium bromide (270 μL, 0.8 mmol, 3.0 M
Figure 1. Plausible asymmetric induction model for the rhodium-catalyzed
asymmetric 1,4-addition to 2-cyclohexenone.
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solution in diethyl ether) was added dropwise to a vigorously
stirred solution of dienone 7 (29.6 mg, 0.2 mmol) in THF (1 mL) at
ether – ethyl acetate mixture (7:3) and subsequent recrystallization
from ethyl acetate – hexane mixture afforded diol 8d (100 mg,
0 C. The reaction mixture was stirred for 5 min., quenched with
60%) as colorless needles, mp 182–183 C. ½a�2D0 = +212 (c=1.00,
°
°
aqueous 2 M NH4Cl (8 mL) and extracted with MTBE (3×10 mL).
Pooled organic extracts were washed with brine (2×5 mL), dried
with Na2SO4 and evaporated under reduced pressure. Residue was
purified by flash chromatography on silica gel with petroleum ether
– ethyl acetate mixture (6:4) to afford diol 8a (26 mg, 72%; dr
(diendo:endo,exo) 95:5) as a colorless crystalline mass, mp 183–
CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.46 (d, J=8.1 Hz, 4H), 7.16 (d,
J=8.0 Hz, 4H), 6.37 (dd, J=10.0, 5.4 Hz, 2H), 5.83 (d, J=10.0 Hz,
2H), 2.66–2.59 (m, 2H), 2.34 (s, 6H), 1.97 (s, 2H), 1.56 (t, J=2.8 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3): δ=142.7 (C), 137.2 (C), 133.0
(CH), 130.6 (CH), 128.8 (CH), 126.5 (CH), 78.1 (C), 41.2 (CH), 25.6
~
(CH2), 21.0 (CH3) ppm; IR: v=3456, 3427, 1601, 1449, 1156,
184 C (EtOAc:Hexane). ½a�2D0 = +245 (c=1.00, CHCl3); 1H NMR
1064 cmÀ 1
;
HRMS (ESI-TOF): m/z calcd for C23H23O [MÀ OH]+:
°
(400 MHz, CDCl3): δ=5.84 (ddt, J=10.1, 5.8, 0.7 Hz, 2H), 5.61 (dq,
J=10.1, 0.8 Hz, 2H), 2.36–2.29 (m, 2H), 1.93 (tt, J=3.2, 0.7 Hz, 2H),
1.64 (s, 2H), 1.38 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ=135.7
(CH), 128.2 (CH), 74.2 (C), 40.3 (CH), 29.4 (CH2), 27.6 (CH3) ppm; IR:
315.1743; found 315.1743.
(+)-(1R,2R,5R,6R)-2,6-bis(4-methoxyphenyl)bicyclo[3.3.1]nona-
3,7-diene-2,6-diol (8e). Organolithium reagent was prepared from
1-iodo-4-methoxybenzene. Filtration through a short pad of silica
gel with ethyl acetate and subsequent recrystallization from ethyl
v=3357, 3318, 1365, 1137, 1115, 1099 cmÀ 1; HRMS (ESI-TOF): m/z
~
calcd for C11H16O2Na [M+Na]+: 203.1043; found 203.1036.
acetate – hexane mixture afforded diol 8e (49 mg, 27%) as
1
colorless needles, mp 192–193 C. ½a�2D0 = +225 (c=1.00, CHCl3); H
°
(+)-(1R,2R,5R,6R)-2,6-diphenylbicyclo[3.3.1]nona-3,7-diene-2,6-
diol (8b). Phenyllithium solution (1.5 mL, 3.0 mmol, 2.0 M in dibutyl
ether) in THF (5 mL) was added dropwise to a vigorously stirred
NMR (400 MHz, CDCl3 +CD3OD): δ=7.47 (d, J=8.6 Hz, 4H), 6.84 (d,
J=8.5 Hz, 4H), 6.32 (dd, J=10.0, 5.4 Hz, 2H), 5.79 (d, J=10.1 Hz,
2H), 3.77 (s, 6H), 2.60–2.53 (m, 2H), 1.85 (s, 2H), 1.51 (t, J=2.7 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3 +CD3OD): δ=158.8 (C), 137.9
(C), 132.8 (CH), 130.5 (CH), 127.7 (CH), 113.3 (CH), 77.7 (C), 55.2
°
solution of dienone 7 (148.2 mg, 1.0 mmol) in THF (5 mL) at 0 C.
The reaction mixture was stirred for 5 min., quenched with aqueous
2 M NH4Cl (10 mL) and extracted with MTBE (3×10 mL). Pooled
organic extracts were washed with brine (2×5 mL), dried with
Na2SO4 and evaporated under reduced pressure. Residue was
purified by flash chromatography on silica gel with petroleum ether
– ethyl acetate mixture (7:3) and subsequently recrystallized from
cyclohexane to afford diol 8b (234 mg, 77%) as fine colorless
~
(CH3), 41.3 (CH), 25.5 (CH2) ppm; IR: v=3034, 1602, 1501, 1174,
1060, 1025 cmÀ 1; HRMS (ESI-TOF): m/z calcd for C23H23O3 [MÀ OH]+
347.1642; found 347.1640.
(+)-(1R,2R,5R,6R)-2,6-bis(3,5-dimethylphenyl)bicyclo[3.3.1]nona-
3,7-diene-2,6-diol (8f). Organolithium reagent was prepared from
1-bromo-3,5-dimethylbenzene. Purification by flash chromatogra-
phy on silica gel with petroleum ether – ethyl acetate mixture (7:3)
and subsequent recrystallization from ethyl acetate – hexane
mixture afforded diol 8f (121 mg, 67%) as colorless needles, mp
needles, mp 141–143 C. ½a�2D0 = +200 (c=2.00, CHCl3); 1H NMR
°
(400 MHz, CDCl3): δ=7.62–7.51 (m, 4H), 7.39–7.30 (m, 4H), 7.30–
7.22 (m, 2H), 6.38 (dd, J=10.1, 5.4 Hz, 2H), 5.83 (dq, J=10.0, 0.9 Hz,
2H), 2.66–2.60 (m, 2H), 2.05 (s, 2H), 1.54 (t, J=3.1 Hz, 2H) ppm; 13C
NMR (100 MHz, CDCl3): δ=145.5 (C), 132.9 (CH), 130.7 (CH), 128.0
(CH), 127.5 (CH), 126.5 (CH), 78.2 (C), 41.2 (CH), 25.4 (CH2) ppm; IR:
212–214 C. ½a�2D0 = +200 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
°
δ=7.19 (s, 4H), 6.92 (s, 2H), 6.38 (dd, J=10.0, 5.4 Hz, 2H), 5.84 (d,
J=10.0 Hz, 2H), 2.70–2.65 (m, 2H), 2.32 (s, 12H), 1.98 (s, 2H), 1.58 (t,
J=3.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=145.6 (C), 137.6
(C), 133.1 (CH), 130.6 (CH), 129.2 (CH), 124.3 (CH), 78.2 (C), 41.1 (CH),
v=3461, 3421, 1489, 1446, 759, 702 cmÀ 1; HRMS (ESI-TOF): m/z
~
calcd for C21H19O [MÀ OH]+: 287.1430; found 287.1425.
General procedure for the synthesis of 2,6-exo,exo-diaryl diols
8c-g. n-butyllithium (625 μL, 1.5 mmol, 2.4 M solution in hexanes)
~
25.6 (CH2), 21.4 (CH3) ppm; IR: v=3456, 3427, 1601, 1449, 1156,
was added dropwise to
a
vigorously stirred solution of
a
1064 cmÀ 1; HRMS (ESI-TOF): m/z calcd for C25H28O2Na [M+Na]+:
°
corresponding haloarene (2.00 mmol) in Et2O (1 mL) at 0 C, and the
reaction mixture was stirred for 15 min. The formed organolithium
reagent was then added dropwise to a stirred solution of dienone 7
383.1984; found 383.1981.
(+)-(1R,2R,5R,6R)-2,6-bis(3,5-dimethoxyphenyl)bicyclo[3.3.1]
nona-3,7-diene-2,6-diol (8g). Organolithium reagent was prepared
from 1-iodo-3,5-dimethoxybenzene. Purification by flash chroma-
tography on silica gel with petroleum ether – ethyl acetate mixture
°
(74.1 mg, 0.50 mmol) in Et2O (5 mL) at 0 C. The resulting mixture
was stirred for 15 min., quenched with aqueous 2 M NH4Cl (5 mL)
and extracted with MTBE (3×10 mL). Pooled organic extracts were
washed with brine (2×5 mL), dried with Na2SO4 and evaporated
under reduced pressure. Residue was purified by flash chromatog-
raphy on silica gel to afford the corresponding diols.
°
(7:3) afforded diol 8g (83 mg, 39%) as colorless foam, mp 56–59 C.
½a�2D0 = +112 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=6.73 (d,
J=2.3 Hz, 4H), 6.38 (t, J=2.3 Hz, 2H), 6.35 (dd, J=10.0, 5.4 Hz, 2H),
5.81 (d, J=10.0 Hz, 2H), 3.79 (s, 12H), 2.66–2.60 (m, 2H), 2.04 (br. s,
2H), 1.62 (t, J=3.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=
160.5 (C), 148.1 (C), 132.8 (CH), 130.8 (CH), 105.0 (CH), 99.4 (CH),
(+)-(1R,2R,5R,6R)-2,6-bis(4-fluorophenyl)bicyclo[3.3.1]nona-3,7-
diene-2,6-diol (8c). Organolithium reagent was prepared from 1-
fluoro-4-iodobenzene. Purification by flash chromatography on
silica gel with petroleum ether – ethyl acetate mixture (6:4)
afforded diol 8c (153 mg, 90%) as colorless oil that solidified on
~
78.3 (C), 55.4 (CH3), 40.9 (CH), 25.6 (CH2) ppm; IR: v=3424, 1596,
1458, 1426, 1205, 1155 cmÀ 1; HRMS (ESI-TOF): m/z calcd for C25H27O5
[MÀ OH]+: 407.1853; found 407.1860.
standing, mp 68–71 C. ½a�2D0 = +146 (c=1.00, CHCl3); 1H NMR
°
(+)-(1R,2R,5R,6R)-2,6-bis(2,4,6-trimethoxyphenyl)bicyclo[3.3.1]
nona-3,7-diene-2,6-diol (8h). n-butyllithium (0.83 mL, 2.0 mmol,
2.4 M solution in hexanes) was added dropwise to a vigorously
stirred solution of 1,3,5-trimethoxybenzene (505 mg, 3 mmol) in
(400 MHz, CDCl3): δ=7.59–7.51 (m, 4H), 7.06–6.99 (m, 4H), 6.39 (dd,
J=10.1, 5.4 Hz, 2H), 5.85 (d, J=10.0 Hz, 2H), 2.62–2.57 (m, 2H), 1.97
(s, 2H), 1.53 (t, J=3.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=
162.2 (d, J=246.3 Hz, C), 141.2 (d, J=3.2 Hz, C), 132.9 (CH), 130.8
°
THF (2 mL) at 0 C and the reaction mixture was stirred for 1 h. The
(CH), 128.4 (d, J=8.1 Hz, CH), 114.8 (d, J=21.3 Hz, CH), 77.9 (C),
resulting suspension was added dropwise to a stirred solution of
À 1
~
41.3 (CH), 25.3 (CH2) ppm; IR: v=3031, 1507, 1199, 1064, 820 cm
;
°
dienone 7 (74.1 mg, 0.50 mmol) in Et2O (5 mL) at 0 C. The resulting
HRMS (ESI-TOF): m/z calcd for C21H17OF2 [MÀ OH]+: 323.1242; found
mixture was stirred for 3 h, quenched with aqueous 2 M NH4Cl
(5 mL) and extracted with MTBE (3×10 mL). Pooled organic extracts
were washed with brine (2×5 mL), dried with Na2SO4 and
evaporated under reduced pressure. Residue was purified by flash
chromatography on silica gel with petroleum ether – ethyl acetate
323.1235.
(+)-(1R,2R,5R,6R)-2,6-di-p-tolylbicyclo[3.3.1]nona-3,7-diene-2,6-
diol (8d). Organolithium reagent was prepared from 4-iodotoluene.
Purification by flash chromatography on silica gel with petroleum
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°
mixture (1:1) and subsequent recrystallization from ethyl acetate –
142–143 C. ½a�2D0 = +145 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
δ=7.62–7.55 (m, 4H), 7.40–7.21 (m, 16H), 6.54 (dd, J=10.4, 5.3 Hz,
2H), 6.13 (dq, J=10.4, 0.9 Hz, 2H), 4.45 (d, J=12.0 Hz, 2H), 4.20 (d,
J=12.0 Hz, 2H), 2.71 (dt, J=4.0, 3.3 Hz, 2H), 1.45 (br. t, J=3.1 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3): δ=143.8 (C), 139.8 (C), 133.2
(CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.5 (CH), 126.93 (CH),
126.91 (CH), 125.8 (CH), 83.7 (C), 64.7 (CH2), 41.9 (CH), 25.0 (CH2)
hexane mixture to afford diol 8h (120 mg, 49%) as a colorless
crystalline solid, mp 168–170 C. ½a�2D0 = +200 (c=1.00, CHCl3); 1H
°
NMR (400 MHz, CDCl3): δ=6.14 (s, 4H), 5.97–5.88 (m, 4H), 4.64 (s,
2H), 3.79 (s, 12H), 3.78 (s, 6H), 2.90 (s, 2H), 1.56 (t, J=2.9 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3): δ=159.8 (C), 159.2 (C), 133.1 (CH),
124.6 (CH), 116.1 (C), 92.7 (CH), 77.1 (C), 56.1 (CH3), 55.2 (CH3), 39.5
ppm; IR: v=3031, 2911, 1191, 1084, 1055, 702 cmÀ 1; HRMS (ESI-
À 1
~
~
(CH), 26.3 (CH2) ppm; IR: v=1607, 1583, 1147, 1122, 1109, 814 cm
;
HRMS (ESI-TOF): m/z calcd for C27H31O7 [MÀ OH]+: 467.2064; found
TOF): m/z calcd for C35H32O2K [M+K]+: 523.2034; found 523.2032.
467.2064.
(+)-(1R,4R,5R,8R)-4,8-bis(4-fluorophenyl)-4,8-dimethoxybicyclo
[3.3.1]nona-2,6-diene (3ca). Prepared from 8c and methyl iodide.
Purification by flash chromatography on silica gel with petroleum
ether – ethyl acetate mixture (95:5) afforded diene 3ca (50 mg,
General procedure for the synthesis of O-alkylated derivatives 3.
Alkylating agent (0.8 mmol) and sodium hydride (32 mg, 0.8 mmol,
60% suspension in mineral oil) were sequentially added to a stirred
solution of a corresponding diol 8 (0.2 mmol) in DMF (0.8 mL) at
68%) as a colorless foam, mp 49–51 C. ½a�2D0 = +183 (c=1.00,
°
1
°
0 C. The resulting mixture was allowed to warm up to room
CHCl3); H NMR (400 MHz, CDCl3): δ=7.49–7.40 (m, 4H), 7.08–6.95
temperature and stirred overnight, then poured into aqueous 0.1 M
HCl solution (20 mL) and extracted with MTBE (3×10 mL). Pooled
organic extracts were washed with brine (2×5 mL), dried with
Na2SO4 and evaporated under reduced pressure. The obtained
residue was purified by flash chromatography on silica gel to afford
the corresponding O-alkyl derivatives.
(m, 4H), 6.40 (dd, J=10.4, 5.3 Hz, 2H), 6.06 (ddd, J=10.4, 1.7, 0.9 Hz,
2H), 3.03 (s, 6H), 2.59–2.50 (m, 2H), 1.33 (br. t, J=3.0 Hz, 2H) ppm;
13C NMR (100 MHz, CDCl3): δ=162.1 (d, J=246.1 Hz, C), 138.9 (d, J=
3.1 Hz, C), 132.9 (CH), 129.5 (d, J=8.0 Hz, CH), 125.2 (CH), 114.8 (d,
J=21.2 Hz, CH), 82.9 (C), 50.5 (CH3), 41.8 (CH), 24.9 (CH2) ppm; IR:
v=2938, 1600, 1505, 1074, 832 cmÀ 1; HRMS (ESI-TOF): m/z calcd for
~
C22H19OF2 [MÀ CH3O]+: 337.1398; found 337.1398.
(+)-(1R,4R,5R,8R)-4,8-dimethoxy-4,8-dimethylbicyclo[3.3.1]nona-
2,6-diene (3aa). Prepared from 8a and methyl iodide. Purification
by flash chromatography on silica gel with petroleum ether – ethyl
acetate mixture (9:1) afforded diene 3aa (18 mg, 43%) as a
colorless oil. ½a�2D0 = +237 (c=1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): δ=5.81 (ddt, J=10.4, 5.6, 0.7 Hz, 2H), 5.65 (dq, J=10.3,
0.8 Hz, 2H), 3.28 (s, 6H), 2.49–2.30 (m, 2H), 1.90 (t, J=3.2 Hz, 2H),
1.36 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ=130.9 (CH), 129.1
(CH), 78.1 (C), 49.7 (CH3), 38.5 (CH), 28.4 (CH2), 23.6 (CH3) ppm; IR
(+)-(1R,4R,5R,8R)-4,8-dimethoxy-4,8-di-p-tolylbicyclo[3.3.1]nona-
2,6-diene (3da). Prepared from 8d and methyl iodide. Purification
by flash chromatography on silica gel with petroleum ether – ethyl
acetate mixture (95:5) afforded diene 3da (48 mg, 67%) as a
1
colorless foam, mp 52–53 C. ½a�2D0 = +237 (c=1.00, CHCl3); H NMR
°
(400 MHz, CDCl3): δ=7.36 (d, J=8.1 Hz, 4H), 7.14 (d, J=8.0 Hz, 4H),
6.39 (dd, J=10.3, 5.2 Hz, 2H), 6.07 (d, J=10.3 Hz, 2H), 3.04 (s, 6H),
2.72–2.50 (m, 2H), 2.34 (s, 6H), 1.38 (t, J=2.7 Hz, 2H) ppm; 13C NMR
(100 MHz, CDCl3): δ=140.2 (C), 137.0 (C), 132.6 (CH), 128.7 (CH),
127.8 (CH), 125.6 (CH), 83.2 (C), 50.5 (CH3), 41.5 (CH), 25.2 (CH2), 21.0
(neat): v=2943, 1119, 1096, 1074, 759 cmÀ 1; HRMS (ESI-TOF): m/z
~
calcd for C13H20O2Na [M+Na]+: 231.1356; found 231.1353.
(CH3) ppm; IR: v=2934, 1508, 1176, 1079, 814 cmÀ 1; HRMS (ESI-
~
(+)-(1R,4R,5R,8R)-4,8-bis(benzyloxy)-4,8-dimethylbicyclo[3.3.1]
nona-2,6-diene (3ab). Prepared from 8a and benzyl bromide.
Purification by flash chromatography on silica gel with toluene
afforded diene 3ab (50 mg, 69%) as a colorless oil. ½a�2D0 = +158
(c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.37–7.28 (m, 8H),
7.27–7.20 (m, 2H), 5.93 (dd, J=10.3, 5.6 Hz, 2H), 5.74 (ddd, J=10.2,
1.4, 0.7 Hz, 2H), 4.60 (ABq, JAB =12.4 Hz, ΔδAB =3.3 Hz, 4H), 2.55–
2.49 (m, 2H), 1.98 (t, J=3.2 Hz, 2H), 1.49 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3): δ=139.9 (C), 131.1 (CH), 129.7 (CH), 128.2 (CH),
127.00 (CH), 126.98 (CH), 79.0 (C), 64.4 (CH2), 39.3 (CH), 28.9 (CH2),
TOF): m/z calcd for C24H25O [MÀ CH3O]+: 329.1900; found 329.1897.
(+)-(1R,4R,5R,8R)-4,8-dimethoxy-4,8-bis(4-methoxyphenyl)bicyclo
[3.3.1]nona-2,6-diene (3ea). Prepared from 8e and methyl iodide.
Purification by flash chromatography on silica gel with petroleum
ether – ethyl acetate mixture (9:1) afforded diene 3ea (73 mg,
93%) as a colorless foam, mp 121–123 C. ½a�2D0 = +236 (c=1.00,
°
1
CHCl3); H NMR (400 MHz, CDCl3): δ=7.39 (AA’XX’, JAX+AX’ =8.8 Hz,
4H), 6.86 (AA’XX’, JAX+A’X =8.8 Hz, 4H), 6.38 (dd, J=10.3, 5.2 Hz, 2H),
6.07 (ddd, J=10.3, 1.7, 0.9 Hz, 2H), 3.80 (s, 6H), 3.03 (s, 6H), 2.61–
2.53 (m, 2H), 1.37 (t, J=2.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3):
δ=158.8 (C), 135.2 (C), 132.5 (CH), 129.0 (CH), 125.6 (CH), 113.3
(CH), 83.0 (C), 55.2 (CH3), 50.4 (CH3), 41.7 (CH), 25.2 (CH2) ppm; IR:
À 1
~
25.1 (CH3) ppm; IR (neat): v=3029, 1453, 1118, 1101, 696 cm
;
HRMS (ESI-TOF): m/z calcd for C25H28O2K [M+K]+: 399.1721; found
399.1728.
v=2942, 1607, 1508, 1079, 1071, 753 cmÀ 1; HRMS (ESI-TOF): m/z
~
(+)-(1R,4R,5R,8R)-4,8-dimethoxy-4,8-diphenylbicyclo[3.3.1]nona-
2,6-diene (3ba). Prepared from 8b and methyl iodide. Purification
by flash chromatography on silica gel with petroleum ether – ethyl
acetate mixture (95:5) afforded diene 3ba (56 mg, 84%) as an
calcd for C24H25O3 [MÀ CH3O]+: 361.1798; found 361.1796.
(+)-(1R,4R,5R,8R)-4,8-bis(3,5-dimethylphenyl)-4,8-dimeth-
oxybicyclo[3.3.1]nona-2,6-diene (3fa). Prepared from 8f and meth-
yl iodide. Purification by flash chromatography on silica gel with
toluene and subsequent recrystallization from hexane afforded
amorphous colorless solid, mp 118–119 C (Hexane). ½a�2D0 = +228
°
(c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.52–7.45 (m, 4H),
7.38–7.30 (m, 4H), 7.29–7.23 (m, 2H), 6.43 (dd, J=10.4, 5.3 Hz, 2H),
6.10 (ddd, J=10.4, 1.6, 0.9 Hz, 2H), 3.05 (s, 6H), 2.64–2.58 (m, 2H),
1.38 (br. t, J=3.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=143.2
(C), 132.8 (CH), 127.93 (CH), 127.88 (CH), 127.4 (CH), 125.4 (CH), 83.4
20
°
diene 3fa (63 mg, 81%) as colorless crystals, mp 180–182 C. ½a�D
=
1
+186 (c=1.00, CHCl3); H NMR (400 MHz, CDCl3): δ=7.08 (s, 4H),
6.89 (s, 2H), 6.39 (dd, J=10.3, 5.2 Hz, 2H), 6.07 (d, J=10.3 Hz, 2H),
3.04 (s, 6H), 2.71–2.55 (m, 2H), 2.31 (s, 12H), 1.40 (br. t, J=3.0 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3): δ=143.1 (C), 137.3 (C), 132.5
(CH), 129.0 (CH), 125.74 (CH), 125.71 (CH), 83.3 (C), 50.6 (CH3), 41.4
~
(C), 50.6 (CH3), 41.6 (CH), 25.1 (CH2) ppm; IR: v=2897, 1445, 1086,
1069, 753, 701 cmÀ 1
;
HRMS (ESI-TOF): m/z calcd for C22H21O
[MÀ CH3O]+: 301.1587; found 301.1581.
(CH), 25.3 (CH2), 21.4 (CH3) ppm; IR: v=2935, 1606, 1598, 1084,
~
854 cmÀ 1; HRMS (ESI-TOF): m/z calcd for C26H29O [MÀ CH3O]+:
(+)-(1R,4R,5R,8R)-4,8-bis(benzyloxy)-4,8-diphenylbicyclo[3.3.1]
nona-2,6-diene (3bb). Prepared from 8b and benzyl bromide.
Purification by flash chromatography on silica gel with hexane –
toluene mixture (7:3) and subsequent recrystallization from hexane
afforded diene 3bb (60 mg, 62%) as fine colorless needles, mp
357.2213; found 357.2209.
(+)-(1R,4R,5R,8R)-4,8-bis(3,5-dimethylphenyl)-4,8-diethoxybicyclo
[3.3.1]nona-2,6-diene (3fc). Prepared from 8f and diethyl sulfate.
Purification by flash chromatography on silica gel with petroleum
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ether – ethyl acetate mixture (97:3) afforded diene 3fc (70 mg,
Typical procedure for the 1,4-addition of boronic acids to cyclic
enones. [RhCl(C2H4)2]2 (1.75 mg, 9.0 μmol Rh), ligand 3fa (3.9 mg,
9.9 μmol) and corresponding arylboronic acid 5 (1.4–1.8 equiv.; for
details, see Table 2) 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
°
84%) as a colorless oil that solidified on standing, mp 152–154 C.
1
½a�2D0 = +230 (c=1.00, CHCl3); H NMR (400 MHz, CDCl3): δ=7.10 (s,
4H), 6.88 (s, 2H), 6.35 (dd, J=10.3, 5.2 Hz, 2H), 6.01 (br. d, J=
10.3 Hz, 2H), 3.36 (dq, J=8.7, 6.9 Hz, 2H), 3.08 (dq, J=8.7, 6.9 Hz,
2H), 2.66–2.58 (m, 2H), 2.31 (s, 12H), 1.41 (t, J=3.4 Hz, 2H), 1.10 (t,
J=6.9 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ=144.2 (C), 137.1
(C), 132.3 (CH), 128.8 (CH), 126.7 (CH), 125.5 (CH), 82.9 (C), 57.8
°
50 C for 15 min to allow for ethylene-ligand exchange. The solution
was cooled to room temperature and neat enone 4 (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 allowed
to stir for 3–5 hours at room temperature, then diluted with ethyl
acetate (10 mL), washed with 10% aqueous solution of NaOH (2×
5 mL) and brine (2×5 mL). The organic phase was dried (Na2SO4),
evaporated and the obtained residue was purified by column
chromatography on silica gel to afford corresponding 3-arylcycloal-
kanones 6.
~
(CH2), 41.0 (CH), 25.1 (CH2), 21.4 (CH3), 15.8 (CH3) ppm; IR: v=3034,
1606, 1598, 1156, 1072, 703 cmÀ 1; HRMS (ESI-TOF): m/z calcd for
C27H31O [MÀ C2H5O]+: 371.2369; found 371.2365.
(+)-(1R,4R,5R,8R)-4,8-bis(3,5-dimethoxyphenyl)-4,8-dimeth-
oxybicyclo[3.3.1]nona-2,6-diene (3ga). Prepared from 8g and
methyl iodide. Purification by flash chromatography on silica gel
with petroleum ether – ethyl acetate mixture (9:1) and subsequent
recrystallization from cyclohexane afforded diene 3ga (70 mg,
77%) as colorless crystals, mp 186–187 C. ½a�2D0 = +112 (c=1.00,
°
1
CHCl3); H NMR (400 MHz, CDCl3): δ=6.64 (d, J=2.1 Hz, 4H), 6.37
(dd, J=10.3, 5.6 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H), 6.04 (br. d, J=
10.3 Hz, 2H), 3.79 (s, 12H), 3.07 (s, 6H), 2.64–2.53 (m, 2H), 1.43 (br. t,
J=3.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=160.5 (C), 145.9
(C), 132.8 (CH), 125.3 (CH), 106.3 (CH), 99.2 (CH), 83.4 (C), 55.4 (CH3),
Conflict of Interest
The authors declare no conflict of interest.
~
50.7 (CH3), 41.4 (CH), 25.2 (CH2) ppm; IR: v=1598, 1454, 1426, 1202,
1155, 738 cmÀ 1; HRMS (ESI-TOF): m/z calcd for C26H29O5 [MÀ CH3O]+:
Keywords: Asymmetric catalysis · Rhodium · Diene ligands ·
Michael addition · Enones
421.2010; found 421.2010.
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δ=7.41 (app. d, J=7.0 Hz, 4H), 7.28 (app. t, J=7.3 Hz, 4H), 7.22
(app. t, J=7.2 Hz, 2H), 4.73 (ddd, J=7.4, 5.1, 2.1 Hz, 2H), 4.66 (br. d,
J=7.4 Hz, 2H), 3.68 (s, 6H), 1.99–1.95 (m, 2H), 0.64 (br. t, J=3.6 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3): δ=141.3 (C), 127.8 (CH), 127.7
(CH), 127.4 (CH), 88.6 (C), 77.6 (d, 1JC-Rh =13.3 Hz, CH), 71.6 (d, 1JC-Rh
=
~
13.6 Hz, CH), 51.2 (CH3), 40.5 (CH), 25.2 (CH2) ppm; IR: v=2919,
1445, 1084, 1066, 756, 697 cmÀ 1
.
1
[RhCl(3fa)]2. Orange glass (38 mg, 96%); H NMR (400 MHz, CDCl3):
δ=7.0 (br. s, 4H), 6.84 (br. s, 2H), 4.71 (ddd, J=7.4, 5.1, 1.9 Hz, 2H),
4.65 (br. d, J=7.4 Hz, 2H), 3.67 (s, 6H), 2.27 (s, 12H), 1.98–1.95 (m,
2H), 0.66 (br. t, J=3.6 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ=
141.4 (C), 137.1 (C), 128.9 (CH), 125.6 (br. CH), 88.5 (C), 77.6
1
1
(d, JC-Rh =13.0 Hz, CH), 71.6 (d, JC-Rh =13.6 Hz, CH), 51.2 (CH3), 40.5
~
(CH), 25.3 (CH2), 21.4 (CH3) ppm; IR: v=2920, 1600, 1439, 1080,
1071, 848, 706 cmÀ 1
.
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ChemCatChem
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[33] Rh complexes of diols 8b (Table 1, entry 3) and 8c–g consistently
produced 6aa in 65–96% yields and 94–95% ee.
[34] Rh/3fa-catalyzed arylation of 4a with 5a (1.4 equiv.) in 1,4-dioxane
(3 mol% Rh, 50 mol% KOH, 1 h) afforded 6aa in 96% yield and 96% ee.
[35] Rh/3fa-catalyzed arylation of acyclic 4-phenylbut-3-en-2-one and un-
saturated lactone furan-2(5H)-one with 5k and 5a, respectively, was
also tested and afforded corresponding addition products in high
yields, but unsatisfactory enantioselectivity (22 and 16% ee, respec-
tively).
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Manuscript received: May 3, 2021
Revised manuscript received: June 29, 2021
Accepted manuscript online: June 29, 2021
Version of record online: ■■■, ■■■■
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FULL PAPERS
V. Bieliūnas, Dr. S. Stončius*
1 – 10
Fine-Tuning the Bicyclo[3.3.1]
nona-2,6-diene Ligands: Second
Generation 4,8-Substituted Dienes
for Rh-Catalyzed Asymmetric 1,4-
Addition Reactions
Asymmetric catalysis: Room tempera-
ture asymmetric Rh-catalyzed
arylation of cyclic enones with
boronic acids in the presence of the
second generation C2-symmetric 4,8-
endo,endo-bis(alkoxy) bicyclo[3.3.1]
nona-2,6-diene ligands affords corre-
sponding 1,4-addition products in 69–
99% yields and enantioselectivities up
to 99% ee. Bulky 4,8-exo,exo groups in
such tetrasubstituted bicyclo[3.3.1]
nona-2,6-dienes provide a further
element for fine-tuning of the ligand
structure.