Role of Regioisomeric Bicyclo[3.3.0]octa-2,5-diene Ligands in Rh Catalysis: Synthesis, Structural Analysis, Theoretical Study, and Application in Asymmetric 1,2- and 1,4-Additions

Article abstract of DOI:10.1021/acs.joc.7b02601

In order to study the impact of regioisomeric diene ligands on the formation and catalytic activity of Rh complexes, a series of C₂- and C_S-symmetric 2,5-disubstituted bicyclo[3.3.0]octa-2,5-dienes C₂-L and C_S-L, respectively, were synthesized from Weiss diketone by simultaneous deprotonation/electrophilic trapping of both oxo functions, and the catalytic behavior was studied in the presence of [RhCl(C₂H₄)₂]₂. Complexes [RhCl(C₂-L)]₂ bearing C₂-symmetric ligands catalyzed effectively the asymmetric arylation of N-tosylaldimines to (S)-diarylamines with yields and ee values up to 99%. In Hayashi-Miyaura reactions, however, the complexes showed poor catalytic activity. When complexes [RhCl(C_S-L)]₂ with C_S-symmetric ligand or mixtures of [RhCl(C₂-L)]₂ and [RhCl(C_S-L)]₂ were employed in 1,2-additions, racemic addition products were observed, suggesting a C=C isomerization of the diene ligands. X-ray crystal structure analysis of both Rh complexes formed from the [RhCl(C₂H₄)₂]₂ precursor and ligands C₂-L and C_S-L revealed that only the C₂-symmetric ligand C₂-L coordinated to the Rh, whereas C_S-L underwent a Rh-catalyzed C=C isomerization to rac-C₂-L, which then gave the racemic [RhCl(rac-C₂-L)]₂ complex. DFT calculations of the relative stabilities of the Rh complexes and the proposed intermediates provided a mechanistic rationale via Rh-mediated hydride transfer.

Full text of DOI:10.1021/acs.joc.7b02601

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Article
The Role of Regioisomeric Bicyclo[3.3.0]octa-2,5-diene Ligands
in Rh Catalysis: Synthesis, Structural Analysis, Theoretical
Study and Application in Asymmetric 1,2- and 1,4-Additions
Tina Mühlhäuser, Alex Savin, Wolfgang Frey, Angelika Baro, Andreas J. Schneider,
Heinz-Günter Döteberg, Florian Bauer, Andreas Köhn, and Sabine Laschat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02601 • Publication Date (Web): 13 Nov 2017
Downloaded from http://pubs.acs.org on November 15, 2017
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The Role of Regioisomeric Bicyclo[3.3.0]octaꢀ2,5ꢀ
diene Ligands in Rh Catalysis: Synthesis, Structural
Analysis, Theoretical Study and Application in
Asymmetric 1,2ꢀ and 1,4ꢀAdditions
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Tina Mühlhäuser,† Alex Savin,† Wolfgang Frey,† Angelika Baro,† Andreas J. Schneider,‡
Heinz-Günter Döteberg,§ Florian Bauer,|| Andreas Köhn,|| and Sabine Laschat*,†,iD
†Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart,
Germany
‡KekuléꢀInstitut für Organische Chemie und Biochemie, Rheinische FriedrichꢀWilhelmsꢀ
Universität Bonn, GerhardꢀDomagkꢀStr. 1, 53121 Bonn, Germany
§HD Separation GmbH, Industriepark Niederau, Kreuzauer Str. 46, 52355 Düren, Germany
||Institut für Theoretische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart,
Germany
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ABSTRACT: In order to study the impact of regioisomeric diene ligands on the formation and
catalytic activity of Rh complexes, a series of C2ꢀ and CSꢀsymmetric 2,5ꢀdisubstituted
bicyclo[3.3.0]octaꢀ2,5ꢀdienes C2ꢀL and CSꢀL, respectively, were synthesized from Weiss
diketone by simultaneous deprotonation/electrophilic trapping of both oxo functions and the
catalytic behavior was studied in the presence of [RhCl(C2H4)2]2. Complexes [RhCl(C2ꢀL)]2
bearing C2ꢀsymmetric ligands catalyzed effectively the asymmetric arylation of Nꢀtosylaldimines
to (S)ꢀdiarylamines with yields and eeꢀvalues up to 99%. In HayashiꢀMiyaura reactions,
however, the complexes showed poor catalytic activity. When complexes [RhCl(CSꢀL)]2 with
CSꢀsymmetric ligand or mixtures of [RhCl(C2ꢀL)]2 and [RhCl(CSꢀL)]2 were employed in 1,2ꢀ
additions, racemic addition products were observed, suggesting a C=C isomerization of the diene
ligands. Xꢀray crystal structure analysis of both Rh complexes formed from the [RhCl(C2H4)2]2
precursor and ligands C2ꢀL and CSꢀL, respectively, revealed that only the C2ꢀsymmetric ligand
C2ꢀL coordinated to the Rh, whereas CSꢀL underwent a Rhꢀcatalyzed C=C isomerization to racꢀ
C2ꢀL, which then gave the racemic [RhCl(racꢀC2ꢀL)]2 complex. DFT calculations of the relative
stabilities of the Rh complexes and the proposed intermediates provided a mechanistic rationale
via Rhꢀmediated hydride transfer.
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KEYWORDS: asymmetric catalysis, CꢀC coupling, density functional calculations, diene
ligands, rhodium, Xꢀray diffraction
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INTRODUCTION
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Chiral olefin ligands have received increased attention over the last decade particularly in Rhꢀ
and Irꢀcatalysis, and complement the well established set of Pꢀ, P,Nꢀ and Nꢀligands.1 Since the
early discoveries by Hayashi,2 Carreira3 and Grützmacher,4 most work has been devoted to
asymmetric 1,4ꢀ and 1,2ꢀadditions.5,6 Furthermore, the scope of diene ligands was expanded to
cross couplings,7 cyclopropanations,8 arylative cyclizations,9 intramolecular [4+2] cycloꢀ
additions,10 polymerizations,11 hydrogenations,12 [3+2] annulations of 1,3ꢀdienes,13 1,6ꢀaddiꢀ
tions,14 C–H alkylation of ferrocenes,15 threeꢀcomponent reactions,16 or carbeneꢀinsertions into
B–H17 and Si–H bonds.18 In addition, practical synthetic procedures to a variety of chiral diene
ligands have been developed.19 Quantitative structure–property relationships,20 nonlinear effects
(NLE)21 and density functional theory (DFT) calculations provided valuable mechanistic insight
on catalytic 1,4ꢀadditions22–24 and 1,2ꢀadditions.25 However, the impact of regioisomeric dienes
on the catalytic properties of the corresponding Rhꢀcomplexes has never been considered.
Previously, the groups of Laschat26 and Lin27 independently disclosed C2ꢀsymmetric chiral
dienes 1 with bicyclo[3.3.0]octane skeleton (Chart 1) and successfully implemented 1 in catalytic
HayashiꢀMiyaura reactions and nucleophilic additions to imines. The versatility of diene ligands
1 in various Rhꢀ, Irꢀ and Pdꢀcatalysis was subsequently demonstrated6b,27,28 and their catalytic
performance studied in detail. Waterꢀsoluble bicyclo[3.3.0]octaꢀ2,5ꢀdienes such as 2 were
reported by Lin.29 Surprisingly the corresponding regioisomeric dienes 4 (Chart 1) have not been
used in catalytic reactions so far. Only diene 4a was mentioned in a theoretical investigation by
Kantchev.22b,c Thus, we were interested whether the different topology of the double bonds in
chiral 2,5ꢀdisubstituted ligands 4 as compared to 3,6ꢀdisubstituted ligands 1 while keeping the
overall C2ꢀsymmetry would influence the catalytic behavior. In addition, a much shorter
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synthesis of diene ligands 4 from Weiss diketone30 was anticipated as compared to diene ligands
1, which are derived from the chiral C2ꢀsymmetrical diketone 3 requiring a considerable
synthetic effort, e.g. 7 steps for (R,R)ꢀdiphenylꢀdiene (R,R)ꢀ1a and 6 steps for (S,S)ꢀ1a
respectively from 1,5ꢀcyclooctadiene.26 In the current manuscript we not only present the
synthesis of a new member of the diene ligand family and its performance in catalytic 1,4ꢀ and
1,2ꢀadditions, but provide also experimental and theoretical insight for a Rhꢀcatalyzed C=C
isomerization. The results are reported below.
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Chart 1. Known 3,6ꢀDisubstituted Bicyclo[3.3.0]octadiene Ligands 1, 2 Derived from
Diketone 3 and the C2ꢀSymmetric 2,5ꢀDisubstituted Dienes 4 Derived from Weiss
Diketone 5
RESULTS AND DISCUSSION
Synthesis of Ligands. A double asymmetric deprotonation of Weiss diketone 530 utilizing chiral
base 6 was envisaged as initial reaction in the synthesis of diene ligands 4 (Scheme 1).
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Scheme 1. Synthesis of Bicyclo[3.3.0]octadiene Ligands 4 and 9
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While enantioselective desymmetrizations of mesoꢀketones with chiral bases are long known31
and sequential deprotonation/electrophilic trapping sequences for bicyclo[3.3.0]octane precurꢀ
sors of natural products have been reported,32,33 the simultaneous deprotonation/electrophilic
trapping of two oxo functions remained elusive.
In order to obtain racemic products as analytical reference samples, Weiss diketone 5 was deꢀ
protonated with 2.25 equiv. of KHMDS in THF at –78°C for 1 h, followed by quenching with 2ꢀ
pyridyltriflimide and warming the solution to 0°C over 4 h. After workup, a (33 : 67) mixture of
C2ꢀsymmetric (7) and CSꢀsymmetric bis(enoltriflate) 8 was isolated in 49% combined yield
(Table 1, entry 1). Replacing KHMDS with the chiral base (S,S)ꢀ6a · LiCl, which was generated
in situ from the (S)ꢀ1ꢀphenylethylamineꢀderived (S,S)ꢀbis(1ꢀphenylethyl)ammonium chloride and
BuLi,32b,33,34 inverted the ratio of regioisomers 7, 8 in favor of the desired C2ꢀsymmetric product
7 giving a (79 : 21) mixture in 74% (entry 2). The isomeric ratio was found to be influenced by
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the addition rate of 5, i.e. the slower its addition the higher the amount of 7, resulting in a
(89 : 11) mixture of 7 / 8 (entry 4). Neither the unsymmetric base (R)ꢀ6b · LiCl nor the sterically
more demanding naphthylethylamineꢀderived base (S,S)ꢀ6c was capable of further decreasing the
amount of the undesired regioisomer 8 (entries 5, 6).
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Table 1. Preparation of Regioisomeric Bis(enoltriflates) 7 and 8 Using Various Bases
entry base
ratio 7 : 8a
33 : 67
79 : 21
84 : 16
89 : 11
71 : 29
74 : 26
yield (%)
49
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KHMDS
(S,S)ꢀ6a·LiCl
(S,S)ꢀ6a·LiCl
(S,S)ꢀ6a·LiCl
(R)ꢀ6b·LiCl
(S,S)ꢀ6c
74
62
80
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n.d.
aDetermined from 1H NMR spectra.
Due to the sensitivity of the enoltriflates separation of the regioisomers 7, 8 was not considered
at this stage, but cross coupling was performed with the mixture (Scheme 1). Cross coupling of a
(84 : 16) mixture of enoltriflates 7 / 8 with 20 mol% of Fe(acac)3 and BnMgCl following our
previously described method26,28 gave regioisomeric dibenzylated dienes 4b and 9b in 61% yield
as a (84 : 16) mixture (method A). Suzuki cross coupling employing 10 mol% of PdCl2(PPh3)2
and PPh3 as a catalyst (method B)35 yielded 71% of a (84 : 16) mixture of the corresponding
phenylꢀsubstituted ligands 4a and 9a, whereas Kumada coupling in the presence of 2 mol% of
36
Pd(PPh3)4 provided anisylꢀsubstituted dienes 4c and 9c as a (84 : 16) mixture in 75% yield
(method C).
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All attempts to separate the regioisomeric dienes 4 and 9 by flash chromatography failed.
Therefore, we tested a method initially developed by Askani for the separation of isomeric
semibullvalene precursors via Pd complexes.37
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Scheme 2. Separation of Diene 4a from a Regioisomeric Mixture of 4a / 9a via Pd Complex
and Decomplexation with KCN36
eeꢀValues were determined by HPLC on chiral stationary phases
In a preliminary experiment a (78 : 22) mixture of 2,5ꢀdiphenylꢀsubstituted regioisomers 4a / 9a
was treated with PdCl2(PhCN)2 (1 equiv.) in benzene at room temperature (Scheme 2). After
18 h, Pdꢀdiene complex 10 precipitated as a red solid, which was isolated in 45% yield. As
observed for related Pd complexes,37 complex 10 was poorly soluble and thus characterized only
13
1
by 1H and C NMR. According to H NMR spectra the filtrate consisted of a (68 : 32) mixture
of 4a / 9a with regioisomer 4a as the major compound. Decomplexation of 10 with a saturated
KCN solution in the presence of K2CO3 in pentane at room temperature37 gave exclusively
regioisomer 4a with 92%ee as determined by analytical HPLC on a chiral Chiracel OJꢀH
column, however, only in meager 33% yield. Further attempts were therefore abandoned and we
focussed on the separation of regioisomers 4 / 9 by preparative HPLC using various chiral
stationary phases. With both Chiracel OJꢀH and DAICEL Chiralpak IA the separation of
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regioisomers 4a / 9a succeeded, and pure 4a was obtained in 46% yield with >99%ee and 9a in
13% yield. Regioisomeric mixture 4b / 9b was successfully separated on a Chiracel OJꢀH phase
yielding 4b in 24% (>99%ee) while 9b was not isolated. In contrast, the regioisomeric pair
4c / 9c could not be separated anymore.
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As discussed below, the absolute configuration of ligand 4a was assigned to be (R,R) by Xꢀray
crystal structure analysis of the corresponding diene 4a ligated Rh catalyst.38
Rhꢀcatalyzed Reactions with Dienes 4, 9 as Steering Ligands. In initial experiments the
application of dienes 4 and 9 as ligands in the HayashiꢀMiyaura reaction with phenylboronic acid
was studied in comparison with the known benchmark dienes 1a and 1b. As substrates cyclohexꢀ
2ꢀenꢀ1ꢀone (11a) and cyclopentꢀ2ꢀenꢀ1ꢀone (11b) were chosen.39 The results are summarized in
Table 2.
Table 2. RhodiumꢀCatalyzed 1,4ꢀAddition of Phenylboronic Acid to Cyclic Enones 11
entry enone ligand L*
t (h) prod. yielda (%)
ee (%)
29 (R)
0
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(R,R)ꢀ4a
9a
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10 (12)b
15
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11b
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12a
12a
12b
12b
4a/9a (78:22)
(R,R)ꢀ4b
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26 (R)
47 (R)
69 (R)
>99 (S)
68 (S)
12 (R)
0
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4b/9b (67:33) 2
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(R,R)ꢀ1a
(R,R)ꢀ1b
(R,R)ꢀ4a
9a
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20 (23)b
20 (19)b,c
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(R,R)ꢀ4b
4b/9b (83:17) 2
2
20 (25)b,c
22
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36 (R)
77 (S)
79 (S)
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11b
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11b
12b
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12b
12b
(R,R)ꢀ1a
2
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78
(R,R)ꢀ1b
99 (99)b
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b
aIsolated yield. NMR yield in parentheses. The crude product was
dissolved in a small volume of CHCl3 and 1,3,5ꢀtrimethylbenzene (1.0
equiv. related to starting enone) was added and the mixture stirred. In its
1H NMR spectrum the signal of the aromatic protons of trimethylꢀ
benzene at δ = 6.80 ppm was set to 3 as reference correlating with the
amount of starting enone. Integration of the 3ꢀH proton in the product at
c
δ = 3.00–3.50 ppm corresponds to the percentage yield. Starting 11b
was detected by 1H NMR in 29% (entry 9) and 40% (entry 10)
Treatment of cyclopentenone (11a) with phenylboronic acid in the presence of [RhCl(C2H4)2]2
and diphenyldiene 4a under common HayashiꢀMiyaura reaction conditions yielded 1,4ꢀaddition
product 3ꢀphenylcyclopentanone (12a) in only 10% with 29%ee in favor of the (R)ꢀproduct
(entry 1), while CSꢀsymmetric ligand 9a gave 12a in 15% yield, however, with 0% ee (entry 2).
When 1.5 mol% of Rh precursor and a (78 : 22) ligand mixture 4a / 9a (3.3 mol% related to 4a)
were employed, addition product 12a was isolated in 26% yield with 26%ee (entry 3).
Dibenzyldiene 4b gave comparable yield, but improved enantioselectivity (47%ee) of (R)ꢀ12a
(entry 4). However, both yield and enantiomeric excess were increased to 42% yield and 69%ee
(R) using diene mixture 4b / 9b (67 : 33) as ligand (entry 5). For comparison, under the used
conditions [RhCl(C2H4)2]2 ligated with the known diene 1a and 1b,26 respectively, provided
product 12a in yields up to 88% with >99%ee and 68%ee in favor of the (S)ꢀenantiomer
(entries 6, 7).
The Rhꢀcatalyzed 1,4ꢀaddition of phenylboronic acid to cyclohexenone (11b) in the presence
of diphenyldiene 4a again proceeded with low yield (20%) and poor enantioselectivity (12%ee)
(entry 8). The use of CSꢀsymmetric diphenyldiene 9a surprisingly resulted in 20% of 3ꢀpheꢀ
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nylcyclohexanone (12b) and 29% of starting material 11b according to NMR (entry 9).
Obviously catalysis is taking place either by the Rh complex generated from CSꢀsymmetric diene
9a or through rearrangement of 9a to C2ꢀsymmetric 4a and subsequent complexation. C2ꢀ
symmetric dibenzylated diene 4b reacted similarly to diphenyldiene 4a giving addition product
12b in 20% isolated yield with 41%ee together with 40% of enone 11b according to the NMR
(entry 10), while the mixture of benzyldienes 4b / 9b (83 : 17) provided 22% of 12b (36%ee)
(entry 11). Again, the known ligands (R,R)ꢀ1a and (R,R)ꢀ1b were superior providing (S)ꢀ12b in
78–99% yield with 77–79%ee (entries 12, 13).39 Surprisingly, acyclic nonꢀ3ꢀenꢀ2ꢀone gave
nearly racemic 1,4ꢀaddition product with ligand 4a (see Scheme S2, ESI), whereas Kantchev
calculated high enantioselectivities for this substrate / ligand combination.22
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Recently Sieffert reported a detailed mechanistic study of the arylation of Nꢀtosylimines by
boronic acids or boroxines catalyzed by a complex of Rh/diene 1a.25 By this type of reaction
chiral αꢀarylamines, prevalent building blocks for pharmaceutically relevant compounds, are
accessible.40 We therefore turned our attention to the catalytic 1,2ꢀaddition of phenylboroxine to
electron poor aldimines 13. NꢀTosylꢀ(4ꢀchloro)benzaldimine 13a was used as substrate for
reaction optimization (Table 3).
Table 3. RhodiumꢀCatalyzed 1,2ꢀAddition of Phenylboroxine to NꢀTosylimines 13 under
Various Reaction Conditions
entry
1
ligand L*
solvent conc. 13 (
M
)
yielda (%) ee (%)
25 (29) >99 (S)
13
14
(R,R)ꢀ4a
dioxane 0.125
13a
14a
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dioxane 0.125
4c/9c (79:21) dioxane 0.125
(R,R)ꢀ4b dioxane 0.125
– (8)
–
13a 9a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14b
14c
14d
14e
14a
14a
14a
3
34 (40)
40 (48)
40 (45)
60 (69)
80 (83)
– (16)
– (48)
– (68)
83 (97)
– (57)
– (71)
86 (96)
9 (12)
47 (48)
29 (34)
91 (95)
99 (99)
99 (99)
85
77 (S)
>99 (S)
81 (S)
75 (S)
84 (S)
–
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13a
13a
13a
13a
13a
13a
13a
13a
13a
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13b
13c
13d
13e
13a
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13a
4
5
4b/9b (67:33) dioxane 0.125
4b/9b (67:33) MeOH 0.125
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7
4b/9b (67:33) THF
4b/9b (67:33) THF
4b/9b (67:33) THF
4b/9b (67:33) THF
4b/9b (67:33) THF
4b/9b (67:33) THF
4b/9b (67:33) THF
0.125
0.125
0.125
0.074
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
8b
9c
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12d
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–
–
86 (S)
–
–
(R,R)ꢀ4b
(R,R)ꢀ4a
THF
THF
>99 (S)
40 (S)
76 (S)
97 (S)
99 (S)
98 (S)
97 (S)
99 (S)
97 (R)
89 (R)
4c/9c (79:21) THF
(R,R)ꢀ4b
(R,R)ꢀ4b
(R,R)ꢀ4b
(R,R)ꢀ4b
(S,S)ꢀ1a
(R,R)ꢀ1a
(R,R)ꢀ1b
THF
THF
THF
THF
dioxane 0.18
THF
0.18
90 (92)
THF
0.18
79 (93)
aIsolated yield; yield by NMR in parenthesis. At room temperature. At 40 °C.
d1 mol% of [Rh], 2 mol% of ligand. e3 mol% of [Rh], 7 mol% of ligand
b
c
In a first attempt, 13a was treated with 1.2 equiv. of phenylboroxine in the presence of 3.1 M
KOH, 2.5 mol% of [RhCl(C2H4)2]2 and 6 mol% of diphenyldiene 4a in dioxane at 60°C for 24 h
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to give 29% of the Nꢀtosylamine 14a according to reaction monitoring by NMR. After
chromatography, 14a was isolated in 25% yield albeit with exceptional enantioselectivity of
>99%ee (entry 1). Under identical conditions the CSꢀsymmetric diene 9a revealed 8% of the 1,2ꢀ
adduct 14a (entry 2), again supporting the “background catalysis” via Rhꢀcatalyzed C=C
isomerization and formation of racemic racꢀ4a. Conducting the reaction with dianisyldiene
mixture 4c / 9c (67 : 33) increased the yield of 14a to 34% with decreased eeꢀvalue of 77%
(entry 3). When dibenzyldiene 4b was employed the yield raised to 40% with outstanding
enantioselectivity of >99%ee (entry 4).
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In order to minimize synthetic efforts required for separation of the regioisomeric dienes 4b / 9b,
a (67 : 33) mixture was used for the subsequent optimization studies (entries 5–13). Thus, 14a
was isolated in 40% yield but somewhat decreased enantioselectivity of 81% by using the
(67 : 33) mixture of 4b / 9b (entry 5). Replacement of the solvent dioxane by MeOH or THF
improved the yields, while eeꢀvalues were only little affected (entries 6, 7). A temperature
reduction to 40°C or room temperature, a higher dilution (0.074 M) as well as a reduced catalyst
loading of 1 mol% or 3 mol% turned out to decrease reaction rates considerably (entries 8–10,
12, 13). Optimal reaction conditions were found with an aldimine concentration of 0.18 M, THF
as solvent and a catalyst loading of 5 mol% (entry 11) that were applied to pure dibenzylated
diene (R,R)ꢀ4b, resulting in a high yield and excellent enantioselectivity (86%, >99%ee) in favor
of (S)ꢀproduct 14a (entry 14). Under these conditions the arylation of 13a in the presence of
rhodium preꢀcatalyst with either diphenyldiene 4a or the dianisyldiene mixture 4c / 9c (79 : 21)
as ligand proceeded poorly with conversions below 47% and eeꢀvalues between 76%ee (entry
15) and 40%ee (entry 16). It should be noted that the known ligands 1a and 1b gave results
comparable to those of diene 4b, however, in favor of the (R)ꢀcongener 14a (entries 22, 23).
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Under optimized reaction conditions further aldimine substrates 13b–e with varying substitution
pattern were tested in the presence of dibenzyldiene (R,R)ꢀ4b. 4ꢀMethoxyphenylimine 13b
yielded the corresponding diarylamine 14b in only 29% (34% by NMR) but 97%ee (S) (entry
17). The arylation of 3ꢀfluorophenylimine 13c, 2ꢀmethylphenylimine 13d as well as 3ꢀmethoxyꢀ
phenylimine 13e with phenylboroxine gave the desired products 14c–e in excellent yields (91–
99%) and selectivities (97–99%ee) for the respective (S)ꢀenantiomers (entries 18–20).
These results reveal that the novel diene ligands 4 are poorly suited for catalytic 1,4ꢀadditions
to enones, but complement well the asymmetric Rhꢀcatalyzed arylation of aldimines. In
particular the dibenzylated diene (R,R)ꢀ4b exhibited excellent catalytic activity in nucleophilic
additions of phenylboroxine to Nꢀtosylimines.
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The rhodiumꢀcatalyzed reactions using pure CSꢀsymmetric ligands 9 resulted in racemic addiꢀ
tion products. Consequently, ligand mixture of 4 / 9 may give lower eeꢀvalues of the products as
compared to the pure C2ꢀsymmetric ligands 4. Such decrease of the enantioselectivity was indeed
experimentally observed (see for example Table 3, entry (4) vs. (5) and entry (11) vs. (14)). The
palladium complexation of tetrahydropentalene derivatives is known to proceed via isomerizaꢀ
tion of the double bond.37 Taking this finding into account an analogous Rhꢀcatalyzed isoꢀ
merization of ligand 9a may lead to partial racemization of regioisomer 4a and thus decreased
enantioselectivity.
The mechanistic considerations were further fueled by previous results from Nguyen,27d,41 who
successfully utilized the π−σ−π isomerization of πꢀallylrhodium intermediates for a catalytic
dynamic kinetic asymmetric amination of allylic trichloroacetimidates. From deuteration
experiments in Rhꢀcatalyzed nucleophilic allylations of cyclic imines Lam and coworkers
deduced rapid interconversion of σꢀallylrhodium(I) intermediates.6a Very recently the same
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group reported chain walking of allylrhodium species, when δꢀtrifluoroboryl β,γꢀunsaturated
esters were employed in nucleophilic allylation of cyclic imines.42 Based on DFT calculations
Hayashi proposed an 1,4ꢀrhodium shift upon conjugate addition of arylethenylboronic acids to
enones.43 However, in neither of the reported cases an isomerization via allylrhodium species
involving the diene ligand was observed. To further proof, whether CSꢀsymmetric dienes 9 are
able to form Rh complexes, both dienes 4a and 9a were submitted to complexation experiments
and subsequent crystallization.
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XꢀRay Crystal Structure Analyses of Ligands and their Rh Complexes. Fortunately, we
obtained suitable single crystals of both regioisomeric C2ꢀ and CSꢀsymmetric free diphenyldiene
ligands 4a and 9a as well as their corresponding Rh complexes (Figures 1 and 2).
C2ꢀsymmetric diene 4a crystallized as fragment in the asymmetric unit of the acentric space
group C2. The whole molecule is completed by a coupled symmetry operation of rotation and
translation (–x+1, y, –z) (Figure 1a). The C1=C2 (and C1A=C2A) double bond was unambiꢀ
guously identified by a distance of 1.3412(18) Å. The interplanar angle between the fiveꢀ
membered ring systems is 78.24(6)°, and the torsion angle between the double bonds C1–C2–
C2A–C1A is 153.7(2)°. A slight envelope conformation of the ring system is evident, where the
bridge atom C4 (C4A) is –0.331(2) Å out of plane.
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Figure 1. a) Structure of C2ꢀsymmetric 2,5ꢀdiphenylbicyclo[3.3.0]octadiene 4a in the solid state
and b) structure of the corresponding complex [RhCl(4a)]2 in the solid state. The complex
crystallized with two independent conformers A and B in the acentric space group P212121. The
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absolute configuration of C2ꢀsymmetric 4a could be clearly determined by anomalous dispersion,
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characterized by the Flack x parameter of –0.03(3).44
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The ꢀꢀchloroꢀbridged rhodium complex [RhCl(4a)]2 crystallized with two independent complex
conformers A and B in the acentric space group (Figure 1b). As all geometric aspects differ only
very slightly in conformer B, only conformer A is discussed in detail in the following. An
elongation of the double bonds with respect to the standꢀalone structure of 4a was observed.
Double bond distances of 1.400(8) Å (C4A=C5A), 1.376(8) Å (C1A=C8A), 1.374(8) Å
(C21A=C28A) and 1.405(9) Å (C24A=C25A) were determined.
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The torsion angles between the double bonds C1A–C8A–C4A–C5A and C21A–C28A–C24A–
C25A are 157.0(5)° and 156.7(5)°, respectively, which result in an equivalent orientation. The
bicyclic systems of both molecules 4a possess nearly the same interplanar angle of 77.1(3)° and
76.2(3)°. In the same way the four cyclopentyl subunits exhibit an envelope behavior with
similar magnitudes of 0.56(1) to 0.60(1) Å out of plane. The Rh–Rh distance of conformer A is
3.0975(6) Å. It must be noted that the Rh–Rh distance in conformer B clearly differs and is
significantly longer (3.2258(6) Å). The distance of the Rh atoms to the double bond centers of
the dienes in conformer A are nearly identical with 2.159(6) Å and 2.155(6) Å. The distances of
Rh to the phenyl atoms C9A, C15A and C29A, C35A attached to the bicycles ranged from
3.054(6) to 3.104(6) Å. The biteꢀangles C8A–Rh1A–C5A and C28A–Rh2–C25A are with
82.0(2)° and 83.4(2)° comparable. A similar trend was found for the angles values between Rh
and the double bond atoms: 104.3(2)° for C1A–Rh1A–C5A and 103.9(2)° for C21A–Rh2A–
C25A as well as 82.1(2)° for C8A–Rh1A–C4A and 81.4(2)° for C28A–Rh2A–C24A. Overall,
the experimentally observed Rh–Rh distances and biteꢀangles are in good agreement with those
reported for related Rh diene complexes.29,45
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The crystal structure of the CSꢀsymmetric diene 9a is depicted in Figure 2. Diene 9a crystallized
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7
as racemic specimen in the centrosymmetric space group R
3
(Figure 2a). Both bridged
8
9
cyclopentyl moieties show an ideal planar conformation. The interplanar angle of them is
60.17(7)°. The double bonds were identified by the distances of 1.365(2) Å (C2=C3) and
1.361(2) Å (C5C6). The torsion angle between the double bonds C2–C3–C5–C6 is 0.5(2)°.
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Figure 2. a) Structure of pure Csꢀsymmetric diene 9a in the solid state and b) structure of the Rh
complex [RhCl(racꢀ4a)]2 in the solid state obtained from complexation of 9a.
Complexation of pure diene 9a resulted in a Rh complex, which crystallized as half fragment in
the asymmetric unit of the centrosymmetric space group C2/c (Figure 2b). The complex will be
completed by the coupled symmetry operation (2.0–x, y, 1.5–z) of rotation and translation.
Surprisingly, starting CSꢀsymmetric diene 9a did not act as ligand but the C2ꢀsymmetric
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regioisomer 4a. Diphenyldiene 4a itself is not generated by a symmetry operation as in its Xꢀray
structure (Figure 1a). An elongation of the double bond C1=C8 by 0.038 Å as compared to
C21A=C28A in [RhCl(4a)]2 conformer A was observed, while the length of 1.408(3) Å for
C4=C5 is comparable to that of C24A=C25A (1.405(9) Å). Moreover, the envelope
conformation of the bicyclic system is pronounced, where C7 and C3 are 0.586(4) Å and
0.569(4) Å, respectively, out of plane. The interplanar angle between the bicycle is found to be
75.9(1)°, and the torsion angle between the double bonds C1–C8–C4–C5 is 156.8(2)°. The Rh–
Rh distance is 3.1107(4) Å. The Rh distances to the double bond centers of C1=C8 and C4=C5
resemble (2.146(2) Å and 2.152(2) Å). The Rh1 distances to C9 and C15 of the phenyl
substituent are 3.096(2) Å and 3.059(2) Å. The angles of C1–Rh1–C5 and C8–Rh1–C4 are
104.55(9)° and 82.02(9)°, respectively. The biteꢀangle C8–Rh1–C5 is 82.75(9)°.
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The outcome that the Rh complex derived from pure CSꢀsymmetric ligand 9a contained the C2ꢀ
symmetric ligand racꢀ4a instead of 9a further supported the Rhꢀcatalyzed isomerization with
concomitant racemization. Consequently, the CSꢀsymmetric dienes 9 do not form suitable, i.e.
catalytically active dimeric Rh precursor complexes.
DFT Calculations of Various Complexes of 4a and 9a. To further verify our assumption,
complex [RhCl(9a)]2 was investigated by density functional theory (DFT) using dispersion
corrected hybrid and double hybrid functionals and large basis sets as detailed in the
experimental part. We consider the relative stability of both [RhCl(4a)]2 and [RhCl(9a)]2 as well
as a possible reaction mechanism to complex [RhCl(racꢀ4a)]2. Computed complex [RhCl(4a)]2
and experimental Xꢀray structure A are very similar (Table S2 in the Supporting Information).
A number of relevant computed energy differences are summarized in Table 4. Both isolated
ligands 9a and 4a are very close in energy, compound 9a is slightly less stable by 5 kJ mol–1
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when calculated with DFT (entry 1). This difference in energy is much more pronounced in the
respective complexes, where [RhCl(9a)]2 is by 137 kJ mol–1 less stable than [RhCl(4a)]2. Hence
this difference must originate from either the steric situation or the bonding situation of the
complexes.
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Table 4. Calculated Best Estimates of Relative Energies and Formation Energies of 4a and
9a Complexes on a COSMO/B3LYPꢀD3/def2ꢀTZVP Level Corrected with B2PLYP
entry reaction
∆G (kJ mol–1)
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137
105
66
4a ꢀ 9a
[RhCl(4a)]2 ꢀ [RhCl(9a)]2
[RhCl(4H)]2 ꢀ [RhCl(9H)]2
[4a(RhCl(C2H4))2] ꢀ [9a(RhCl(C2H4))2]
2 4a + [RhCl(C2H4)2]2 ꢀ 4 C2H4 + [RhCl(4a)]2
2 9a + [RhCl(C2H4)2]2 ꢀ 4 C2H4 + [RhCl(9a)]2
–141
–13
4a + [RhCl(C2H4)2]2 ꢀ 2 C2H4 + [4a(RhCl(C2H4))2] –66
9a + [RhCl(C2H4)2]2 ꢀ 2 C2H4 + [9a(RhCl(C2H4))2] –5
To investigate the influence of the bulky phenyl groups [RhCl(4a)]2 and [RhCl(9a)]2 were
modified by replacing the phenyl groups with hydrogen atoms, as exemplarily shown for 9a
(Figure 3). Still [RhCl(9H)]2 is less stable than [RhCl(4H)]2 by 105 kJ mol–1 (entry 3). Therefore
it is not mainly the steric interaction of the phenyl groups that makes [RhCl(9a)]2 unfavorable.
Comparison of the mono complexes [4a(RhCl(C2H4))2] and [9a(RhCl(C2H4))2], which are
assumed to be formed in a first step during complexation, once again reveals that
[9a(RhCl(C2H4))2] is less stable than [4a(RhCl(C2H4))2] (Entry 4). Since this energy difference is
about half of the energy difference between the full complexes, it is clear that ligand 9a does not
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coordinate the Rh centers as well as 4a does. The close proximity of the two double bonds in 9a
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appears to lead to a nonꢀoptimal overlap of the orbitals of the ligands and the Rh dꢀorbitals.
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9
a)
b)
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Figure 3. a) Complex [RhCl(9a)]2 and b) truncated complex [RhCl(9H)]2 based on DFT
calculations (COSMO/B3LYPꢀD3/def2ꢀTZVP).
In the actual complexation reaction [RhCl(C2H4)2]2 reacted with 4a and 9a, respectively. Both
the reactions towards the mono complex as well as towards the full complex [RhCl(4a)]2 are
strongly exergonic (Table 4, entries 5, 7). In contrast, the formation of the analogous complexes
with 9a is slightly favored with an overall reaction energy of only –13 kJ mol–1 (entries 6, 8).
Nevertheless, a 9a/Rh complex can be formed under the experimental conditions. It should be
noted that rhodium complexes are known for their catalytic activity in hydride transfer
reactions,46 and thus an isomerization of 9a to racꢀ4a via hydride transfer seems to be
reasonable. The mono complex [9a(RhCl(C2H4))2] (Scheme 3) was considered as the starting
point for a hydride transfer reaction, because it is a necessary intermediate in the formation of
[RhCl(9a)]2 and hydride transfers are usually fast processes.
From CSꢀsymmetric compound [9a(RhCl(C2H4))2] two equivalent reaction paths may start,
leading to the two enantiomers of [4a(RhCl(C2H4))2]. A possible mechanism of this hydride
transfer was determined computationally for the pathway to enantiomer [(S,S)ꢀ4a(RhCl(C2H4))2]
and can be described as follows (Scheme 3, Figure 4).
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Scheme 3. Proposed Mechanism for the RhꢀCatalyzed Isomerization of Complexed
CSꢀSymmetric Ligand 9a Based on DFT Calculations
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H
H
H
H
H
H
H
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Ph
Ph
Ph
Ph
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Ph
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Ph
H
H
H
H
H
H
H
H
H
Rh
Rh
Rh
Rh
Rh
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Rh
Rh
Rh
Rh
Rh
9a
mono [ (RhCl(C2H4))2]
Int 1
Int 2
Int 3
4a
[(S,S)ꢀ (RhCl(C2H4))2]
As this reaction can also proceed at the opposite side in 9a giving enantiomeric
[(R,R)ꢀ4a(RhCl(C2H4))2], racemization was observed
Figure 4. Computed best estimate of the Gibbs free energy profile of the proposed hydride
transfer reaction on a COSMO/B3LYPꢀD3/def2ꢀTZVP level corrected with B2PLYP (see
computational details). An equivalent path may provide [(R,R)ꢀ4a(RhCl(C2H4))2].
In the first step, proceeding via transition state TS1, one of the η2 bonds is broken and
simultanously an agostic interaction between rhodium and one of the hydrogens from the
methylene bridges is formed, leading to a first intermediate (Int1). In the next transition state
(TS2) a true Rh–H bond is formed, while the remaining η2 bond is converted to an η3 bond
giving second intermediate Int2. Subsequently the hydride is shifted towards the η3 bound carbon
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on the far side of the molecule (TS3), resulting in an agostic interaction of rhodium and
hydrogen, while retrieving an η2 bond. This complex Int3 is very similar to Int1. Analogously to
TS1 in the last transition state (TS4) the agostic interaction is given up in favor of a restoration of
the second η2 bond to form the complex [(S,S)ꢀ4a(RhCl(C2H4))2].
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If TS1 is regarded as the rate determining step of the reaction of 9a to racꢀ4a at 50°C, this
reaction will have an effective barrier of only 83 kJ mol–1. Using transition state theory and
assuming a first order reaction this leads to a half life τ0.5 ≈ 3 s of [9a(RhCl(C2H4))2]. In contrast,
a possible back reaction with an effective barrier of 149 kJ mol–1 will be very slow with a half
life τ0.5 ≈ 4·103 years of [4a(RhCl(C2H4))2]. Therefore, in agreement with the experiment,
racemization of 4a is not expected during its complexation, while 9a will react to racꢀ4a.
CONCLUSION
We provided a synthetic access to chiral C2ꢀsymmetric bicyclo[3.3.0]octadienes 4 utilizing an
enantioselective deprotonation/electrophilic trapping of Weiss diketone 5 followed by cross
coupling as the key steps. When comparing the synthetic routes towards diene ligands 4 with the
preparation of known ligands 1, it should be noted that (R,R)ꢀdiphenylꢀdiene (R,R)ꢀ4a and (R,R)ꢀ
dibenzylꢀdiene (R,R)ꢀ4b, respectively, were obtained in 3 steps from dimethyl acetoneꢀ1,3ꢀdiꢀ
carboxylate (i.e. the starting material for Weiss diketone 5) in 28% and 31% overall yield (20%
and 10% after HPLC) respectively. In order to access the (S,S)ꢀligands 4 the enantiomeric chiral
●
base (R,R)ꢀ6a LiCl can be employed. In contrast, known (R,R)ꢀdiphenylꢀdiene (R,R)ꢀ1a and its
antipode (S,S)ꢀ1a, respectively, were prepared in 7 and 6 steps (5% and 11% overall)
respectively from 1,5ꢀcyclooctadiene and required large amounts of toxic lead(IV)acetate.26 Rhꢀ
catalyzed conjugate additions of phenylboronic acid to cyclic enones 11 did not meet the
expectations raised by a previous comparative DFT study,22 giving yields of 10–42% and
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enantioselectiveties up to 69%ee, regardless of the used diphenylꢀ (R,R)ꢀ4a or dibenzyldiene
(R,R)ꢀ4b.
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In contrast, the rhodium/dibenzyldiene 4b complex is capable of catalyzing the nucleophilic
addition of phenylboroxine to Nꢀtosylimines 13 to provide the corresponding diarylamines 14 in
yields of 86–99% with excellent enantioselectivities of 97–99%ee.
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Furthermore, when mixtures of chiral C2ꢀsymmetric diene (R,R)ꢀ4 and achiral CSꢀsymmetric
diene 9 were employed in the catalytic reactions, experimental evidence for a Rhꢀcatalyzed C=C
isomerization of diene 9 to racꢀ4 was found based on optical rotations, NMR studies and Xꢀray
crystal structure data of the Rh complexes. The finding could be supported by DFT calculation.
The calculated relative energies reveal that [RhCl(4a)]2 and even its truncated analogue
[RhCl(4H)]2 are more stable than the respective complexes with regioisomer 9a. Furthermore,
the energy difference between mono complexes [4a(RhCl(C2H4))2] and [9a(RhCl(C2H4))2],
assumed to be the first intermediate during complexation, is about half of the energy difference
between the full complexes. This indicates that ligand 9a does not coordinate the Rh centers as
4a does. Under contribution of Rh complexed 9a can undergo a hydride transfer reaction which
finally leads to the racꢀ4a ligated Rh catalyst.
Future work is necessary to figure out, which parameters govern such isomerizations also with
respect to other diene ligands in order to avoid deterioration of the enantioselectivity and to
obtain reliable catalysts for C–C bond formation.
EXPERIMENTAL SECTION
General. NMR spectra were recorded on a Bruker Avance 300, a Bruker Avance 400 or a
Bruker Avance 500 spectrometer in CDCl3 with TMS as an internal standard. Assignment of the
resonances was supported by 2D experiments (COSY). IR spectra were recorded on a Bruker
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FTꢀIRꢀspectrometer Vektor 22 with MKII golden gate single reflection Diamant ATRꢀsystem.
Mass spectra were recorded on a Varian MAT 711 (EI, 70 eV) and a Bruker Daltonics
micrOTOF_Q (ESI) with nitrogen as carrier gas. Optical rotations were measured with a Perkinꢀ
Elmer 241 polarimeter at 20 °C. Flash chromatography was performed on silica gel, grain size
40–63 µm (Fluka). Moistureꢀsensitive reactions were performed under nitrogen atmosphere in
ovenꢀdried glassware. All reagents were used as purchased unless otherwise noted. Solvents used
for chromatography were distilled. THF was distilled from potassium/ benzophenone, CH2Cl2
and toluene from CaH2. The reactions were monitored by TLC (Merck 60 F254 plates).
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Singleꢀcrystal Xꢀray Structure Analyses. Analyses were performed on a Bruker kappa
APEXII Duo diffractometer at 130 K. Data collection: APEX2 Software Suite; cell refinement:
SAINT (both Bruker 2008). The structures were solved by using the program SHELXS 97
(Sheldrick 2008). The structures were refined by using the program SHELXL 97 (Sheldrick
2008). Molecular graphics: XP in SHELXTLꢀPlus (Sheldrick 2008). For details see Table S1 in
the Supporting Information.
Computational Details. All calculations were carried out with the TURBOMOLE V6.6
program package.47 The resulting structures were visualized with TmoleX 4.0.48 Molecular
geometries were optimized using density functional theory (DFT) in conjunction with the
B3LYP functional49 including dispersion effects through Grimme's D3 correction50 with Beckeꢀ
Johnson damping.51a Numerical integration was carried out on a m3 grid and density fitting
(multipole accelerated resolution of the identity)51b–e was enabled to speed up the integral
evaluation. For all calculations the def2ꢀTZVP basis set52 was used. Solvent effects were
accounted for with the conductorꢀlike screening model (COSMO)53 using a relative dielectric
constant of
ε
= 2.2 to mimic the polarity of 1,4ꢀdioxane. Gibbs free energies G were calculated
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for a temperature of 50°C using partition functions obtained with the rigidꢀrotor harmonic
oscillator (RRHO) approximation. The temperature was chosen to match the experimental
conditions during the ligand exchange reaction.
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The Gibbs free energies computed at the B3LYPꢀD3/COSMO level were corrected by additional
single point calculations with the double hybrid functional B2PLYPꢀD3.54 The corrected
energies were obtained as G = G(B3LYPꢀD3/COSMO)−E(B3LYPꢀD3)+ E(B2PLYPꢀD3), where
E refers to purely electronic energies.
The following compounds were prepared according to literature procedures: 5,30 6a,32b,33,34 6b,55
6c,56 phenylboroxine,57 13a, 13b,58 13c,59 13d,60 13e.61
Synthesis of triflates racꢀ7 / 8. According to ref.,26 to a solution of 5 (100 mg, 0.72 mmol) and
2ꢀPyNTf2 (623 mg, 1.76 mmol) in THF (3 mL) at –78 °C was added dropwise a solution of
KHMDS (330 mg, 1.65 mmol) in THF, and the reaction mixture was warmed up to 0 °C over
4 h. The reaction was quenched by addition of a saturated solution of NaHCO3 (10 mL). THF
was removed under reduced pressure and the residue was extracted with Et2O (3 × 20 mL). The
combined organic layers were dried (MgSO4) and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography on SiO2 with
hexanes/EtOAc (25:1) (Rf = 0.21, hexanes/EtOAc 4:1) to give a mixture of racꢀ7 / 8 (141 mg,
0.35 mmol, 49%) as a colorless oil in an isomeric ratio racꢀ7 / 8 = 33 : 67, which was used in the
next step without further purification. The spectroscopic data of racꢀ7 / 8 are in agreement with
the (R,R)ꢀ7 / 8.
Synthesis of triflates (R,R)ꢀ7 / 8. To a solution of (S,S)ꢀ6a, generated from (S,S)ꢀbis(1ꢀpheꢀ
nylethyl)ammonium chloride (3.18 g, 12.1 mmol, 2.4 eq.) (or (R)ꢀNꢀ(1ꢀphenylethyl)propanꢀ2ꢀ
ammonium chloride) in THF (15 mL) at –80 °C by dropwise addition of nꢀBuLi (2.5 M in
hexane, 9.1 mL, 22.8 mmol, 4.5 eq.), warming the mixture to room temperature and recooling to
–78 °C,55 was added a solution of 5 (700 mg, 5.07 mmol, 1 eq.) in THF (8 mL). The reaction
mixture was stirred at –78 °C for 1 h and then warmed up to –40 °C over 4 h. The reaction was
quenched by addition of a saturated solution of NaHCO3 (20 mL). The water layer was extracted
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with Et2O (3 × 50 mL), and the combined organic layers were dried (MgSO4) and evaporated
under reduced pressure. The crude product was purified by column chromatography on SiO2
with hexanes/EtOAc (25:1) (Rf = 0.21, hexanes/EtOAc 4:1) to give (R,R)ꢀ7 / 8 (1.48 g,
3.70 mmol, 74%) as yellow oil in the respective isomeric ratio (R,R)ꢀ7 / 8. The mixture was used
in next steps without further purification. The NMR signals of (R,R)ꢀ7 and 8 are assigned by
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using 2DꢀNMR spectorscopy. (R,R)ꢀ7: H NMR (500 MHz, CDCl3): δ (ppm) = 2.38–2.45 (m,
2H, 3ꢀHb, 6ꢀHb), 2.87–2.96 (m, 2H, 3ꢀHa, 6ꢀHa), 3.50–3.59 (m, 2H, 3'ꢀH, 6'ꢀH), 5.55 (d,
13
J = 2.3 Hz, 2H, 1ꢀH, 4ꢀH); C NMR (126 MHz, CDCl3): δ (ppm) = 38.9 (Cꢀ3, Cꢀ6), 41.4 (Cꢀ3',
1
Cꢀ6'), 119.41 (q, J = 320 Hz, SO2CF3), 120.0 (Cꢀ1, Cꢀ4), 148.8 (Cꢀ2, Cꢀ5). 8: H NMR (500
MHz, CDCl3): δ (ppm) = 2.44–2.52 (m, 2H, 3ꢀHb, 4ꢀHb), 2.95–3.03 (m, 2H, 3ꢀHa, 4ꢀHa), 3.14–
13
3.24 (m, 1H, 3'ꢀH), 3.85 (d, J = 8.1 Hz, 1H, 6'ꢀH), 5.66 (q, J = 2.3 Hz, 2H, 1ꢀH, 6ꢀH), C NMR
(126 MHz, CDCl3): δ (ppm) = 34.6 (Cꢀ3'), 36.0 (Cꢀ3, Cꢀ4), 49.0 (Cꢀ6'), 119.41 (q, J = 320 Hz
SO2CF3), (Cꢀ1, Cꢀ6), 149.6 (Cꢀ2, Cꢀ5). Isomers (R,R)ꢀ7 / 8: IR (cm–1): ꢀȬ = 1420, 1248, 1202,
1136, 895, 608; GC/MS (EI, 70 eV): m/z (%) = 402 (35) [M+], 269 (67) [M+ – CF3], 227 (96), 69
(100) [CF3]; MS (EI, 70 eV): m/z (%) = 402 (25) [M+], 252 (11) [M+ – SO2CF3], 227 (24), 163
(20), 119 (100) [C8H8O], 91 (55), 77 (54), 69 (70) [CF3], 39 (16); HRMS (ESI): m/z calcd. for
C10H8F6O6S2Na+: 424.9559, found: 424.9558; HRMS (EI): m/z calcd. for C10H8F6O6S2 :
+
401.9666, found: 401.9666.
Suzuki cross coupling of (R,R)ꢀ7 / 8 to ligands (R,R)ꢀ4a / 9a. PdCl2(PPh3)2 (202 mg,
0.29 mmol, 0.1 eq.), PPh3 (152 mg, 0.58 mmol, 0.2eq.) and K2CO3 (1.98 g, 14.38 mmol) were
evacuated for 1 h. Then H2O (7 mL), a solution of (R,R)ꢀ7 / 8 (84 : 16) (1.16 g, 2.88 mmol, 1 eq.)
in degassed 1,2ꢀdimethoxyethane (12 mL) and a solution of PhB(OH)2 (1.74 g, 14.38 mmol,
5 eq.) in EtOH (5 mL) were added, and the reaction mixture was heated at 85 °C for 24 h. After
cooling to room temperature, the reaction was quenched by addition of H2O (20 mL). The
mixture was extracted with Et2O (3 × 50 mL), the combined extracts were dried (MgSO4) and
the solvent was removed under reduced pressure. The residue was purified by column
chromatography on SiO2 with hexanes/Et2O (500:1) to give (R,R)ꢀ4a / 9a (84 : 16) (526 mg,
2.04 mmol, 71%). The isomers were separated by chiral HPLC to give (R,R)ꢀ4a (243 mg,
0.94 mmol, 32%) and 9a (59 mg, 0.22 mmol, 8%) as colorless solids. (R,R)ꢀ4a: Rf = 0.43
(hexanes/Et2O 500:1), mp = 125−129 °C; [α]2D0 = –27.2 °(c = 1.0, CHCl3, >99%ee Rꢀenantioꢀ
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mer); H NMR (500 MHz, CDCl3): δ (ppm) = 2.70 (dq, J = 15.9 Hz, 2.1 Hz, 2H, 3ꢀHb, 6ꢀHb),
2.99–3.07 (m, 2H, 3ꢀHa, 6ꢀHa), 3.70–3.75 (m, 2H, 3'ꢀH, 6'ꢀH), 6.06 (s, 2H, 1ꢀH, 4ꢀH), 7.18–7.24
(m, 2H, pꢀAr), 7.28–7.33 (m, 4H, mꢀAr), 7.41–7.45 (m, 4H, oꢀAr); 13C NMR (126 MHz,
CDCl3): δ (ppm) = 38.8 (Cꢀ3, Cꢀ6), 48.6 (Cꢀ3', Cꢀ6'), 125.9 (oꢀAr), 127.2 (pꢀAr), 128.4 (mꢀAr),
130.3 (Cꢀ1, Cꢀ4), 136.7 (iꢀAr), 140.1 (Cꢀ2, Cꢀ5); IR (cm–1) 2897, 2838, 1493, 1446, 907, 748,
733, 689; MS (EI): m/z (%): 258 (100), 243 (21), 202 (5), 179 (5), 167 (14), 155 (33), 141 (12),
129 (7), 117 (21), 103 (6), 91 (9), 77 (8), 63 (2), 51 (3), 39 (1); HRMS (EI): m/z calcd. for
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+
C20H18 : 258.1409, found: 258.1407. 9a: Rf = 0.43 (hexanes/Et2O 500:1), mp = 104−106 °C;
1H NMR (400 MHz, CDCl3): δ (ppm) = 2.63 (ddt, J = 16.0 Hz, 4.3 Hz, 2.2 Hz, 2H, 3ꢀHb, 4ꢀHb),
3.13 (ddt, J = 16.0 Hz, 9.3 Hz, 1.7 Hz, 2H, 3ꢀHa, 4ꢀHa), 3.24–3.35 (m, 1H, 3'ꢀH), 4.06–4.12 (m,
1H, 6'ꢀH), 6.18 (q, J = 2.1 Hz, 2H, 1ꢀH, 6ꢀH), 7.22 (d, J = 7.3 Hz, 2H, pꢀAr), 7.27–7.34 (m, 4H,
13
mꢀAr), 7.40–7.46 (m, 4H, oꢀAr); C NMR (101 MHz, CDCl3): δ (ppm) = 39.2 (Cꢀ3, Cꢀ4), 41.7
(Cꢀ3'), 59.5 (Cꢀ6'), 125.9 (o-Ar), 127.0 (Cꢀ1, Cꢀ6), 127.2 (pꢀAr), 128.4 (mꢀAr), 136.8 (iꢀAr),
141.4 (Cꢀ2, Cꢀ5); IR (cm–1) 2914, 1492, 1445,750, 735, 689; MS (EI): m/z (%): 258 (100), 243
(16), 228 (5), 215 (5), 202 (2), 189 (1), 179 (7), 167 (17), 154 (18), 141 (16), 129 (6), 115 (16)),
+
103 (7), 91 (11), 77 (8), 63 (2), 51 (3), 39 (1); HRMS (EI): m/z calcd. for C20H18 : 258.1409,
found: 258.1409. Analytical HPLC of (R,R)ꢀ4a / 9a: DAICEL Chiracel OJꢀH (250 × 4.6 mm,
5 ꢀm), flow rate 0.7 mL min–1, hexane/isopropanol (20 : 80), tR1 = 12.630 min (major, (R,R)-4a),
tR2 = 17.930 min (minor, 9a), tR3 = 25.41 min (minor, (S,S)-4a); HDꢀSeparations: DAICEL
Chiracel OJꢀH (250 × 4.6 mm), flow rate 1 mL min–1, 100% MeOH, tR1 = 17.132 min (major,
(R,R)-4a), tR2 = 24.225 min (minor, 9a); University Bonn: DIACEL Chiralpak IA (5 ꢁm, 4,6 mm
× 250 mm), flow rate 1 mL min–1, MeCN/H2O (75:25), tR1 = 11.55 min (major, (R,R)-4a), tR2 =
15.52 min (minor, 9a).
Kumada coupling of (R,R)ꢀ7 / 8 with BnMgBr to ligands (R,R)ꢀ4b / 9b. According to ref.,26 to
a solution of (R,R)ꢀ7 / 8 (84 : 16) (1.16 g, 2.88 mmol, 1 eq.) and Fe(acac)3 (202 mg, 0.56 mmol,
0.2 eq.) in THF (27 mL) at 0 °C was added dropwise a solution of benzylmagnesiumchloride
(2 M in THF, 2.70 mL, 5.46 mmol, 1.8 eq.). After complete addition, the reaction mixture was
stirred for 15 min at 0 °C and the reaction quenched by addition of a solution of saturated NH4Cl
(20 mL). The reaction mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude
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product was purified by column chromatography on SiO2 with hexanes/Et2O (500:1) to give
(R,R)ꢀ4b / 9b (84 : 16) (500 mg, 1.75 mmol, 61%, Rf = 0.43 (hexanes/Et2O 500:1) as a yellowish
oil. The isomers were separated by chiral HPLC to give (R,R)ꢀ4b (210 mg, 0.69 mmol, 24%) as a
colorless solid. (R,R)ꢀ4b: Mp = 46−49 °C, [α]2D0 = + 58.4 (c = 1.0, CHCl3, >99%ee of Rꢀenantioꢀ
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mer); H NMR (500 MHz, CDCl3): δ (ppm) = 2.00 (d, J = 16.3 Hz, 2H, 3ꢀHb, 6ꢀHb), 2.37–2.44
(m, 2H, 3ꢀHa, 6ꢀHa), 3.30–3.41 (s, 6H, 3'ꢀH, 6'ꢀH, 7ꢀH), 5.14 (s, 2H, 1ꢀH, 4ꢀH), 7.13–7.21 (m,
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48.4 (Cꢀ3', Cꢀ6'), 126.0 (pꢀAr), 128.3 (oꢀAr), 128.9 (mꢀAr), 130.5 (Cꢀ1, Cꢀ4), 140.2 (iꢀAr), 141.2
(Cꢀ2, Cꢀ5). 9b: 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.91–1.97 (m, 2H, 3ꢀHb, 4ꢀHb), 2.49 (dd,
J = 16.5 Hz, 9.4 Hz, 2H, 3ꢀHa, 4ꢀHa), 2.92–3.03 (m, 1H, 3'ꢀH), 3.30–3.41 (m, 4H, 7ꢀH), 3.64–
13
3.72 (m, 1H, 6'ꢀH), 5.32 (s, 2H, 1ꢀH, 6ꢀH), 7.12–7.30 (m, 10H, ArꢀH); C NMR (126 MHz,
CDCl3): δ (ppm) = 38.0 (Cꢀ7), 40.0 (Cꢀ3'), 43.2 (Cꢀ3, Cꢀ4), 58.4 (Cꢀ6'), 126.0 (Ar, pꢀAr), 127.9
(Cꢀ1, Cꢀ6), 128.4 (o-Ar), 128.9 (mꢀAr), 140.2 (iꢀAr), 142.5 (Cꢀ2, Cꢀ5). Isomers 4b/9b: IR (cm–1)
2899, 2837, 1493, 696; MS (EI, 70 eV): m/z (%) = 286 (34) [M+], 195 (100) [M+– C7H7], 155
(10), 117 (10) [M+– C7H7C5H5], 91 (43) [C7H7]; HRMS (ESI): m/z calcd. for C22H22 : 286.1722,
+
found: 286.1714. Analytical HPLC: Chiracel OJꢀH (250 × 4.6 mm, 5 ꢀm), flow rate 0.5 mL
min–1, hexane/isopropanol (20 : 80), tR1 = 16.17 min (major, (R,R)-4b), tR2 = 18.187 min (minor,
9b). HDꢀSeparations: Chiracel OJꢀH (250 × 4.6 mm, 5 ꢀm), flow rate 1 mL min–1, 100% MeOH,
tR1 = 13.919 min (major, (R,R)-4b), tR2 = 16.239 min (minor, 9b).
Kumada coupling of (R,R)ꢀ7 / 8 to ligand (R,R)ꢀ4c / 9c. To a solution of Pd(PPh3)4 (15 mg,
0.01 mmol, 0.02 eq.) and (R,R)ꢀ7 / 8 (84 : 16) (225 mg, 0.56 mmol, 1 eq.) in THF(4 mL) at 50 °C
was added dropwise 4ꢀmethoxyphenylmagnesiumbromide (3.4 mL, 1.68 mmol, 3.0 eq., 0.5 M in
THF). After complete addition, the reaction mixture was stirred for 6 h at 50 °C. The reaction
was quenched by addition of a solution of saturated NaHCO3 (5 mL). The mixture was extracted
with Et2O (3 × 15 mL), the combined extracts were dried (MgSO4) and concentrated. The crude
product was purified by column chromatography on SiO2 with hexanes/ EtOAc (50:1) (Rf =
0.61, hexanes/EtOAc 9:1) to give (R,R)ꢀ4c / 9c (84 : 16) (134 mg, 0.42 mmol, 75%) as a colorꢀ
less solid. The NMR signals of (R,R)ꢀ4c and 9c are assigned by using 2DꢀNMR spectroscopy.
(R,R)ꢀ4c : 1H NMR (500 MHz, CDCl3): δ (ppm) = 2.61–2.68 (m, 2H, 3ꢀHa, 6ꢀHa), 2.93–3.02 (m,
2H, 3ꢀHb, 4ꢀHb), 3.66–3.73 (m, 2H, 3'ꢀH, 6'ꢀH), 3.80 (s, 6H, OCH3), 5.91 (d, J = 2.2 Hz, 2H, 1ꢀH,
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4ꢀH), 6.80–6.86 (m, 4H, mꢀAr), 7.32–7.39 (m, 4H, oꢀAr);13C NMR (126 MHz, CDCl3): δ (ppm)
= 39.0 (Cꢀ3, Cꢀ6), 48.6 (Cꢀ3', Cꢀ6'), 55.4 (OCH3), 113.8 (m-Ar), 127.1 (o-Ar), 128.3 (Cꢀ1, Cꢀ4),
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129.6 (Cꢀ2, Cꢀ5), 139.4 (i-Ar), 158.9 (p-Ar). 9c: H NMR (500 MHz, CDCl3): δ (ppm) = 2.55–
2.62 (m, 2H, 3ꢀHa, 4ꢀHa), 3.05–3.13 (m, 2H, 3ꢀHb, 4ꢀHb), 3.22–3.31 (m, 1H, 3'ꢀH), 3.80 (s, 6H,
OCH3), 4.06 (d, J = 7.7 Hz, 1H, 6'ꢀH), 6.04 (d, J = 2.5 Hz, 2H, 1ꢀH, 6ꢀH), 6.80–6.86 (m, 4H, mꢀ
Ar), 7.32–7.39 (m, 4H, oꢀAr);13C NMR (126 MHz, CDCl3): δ (ppm) = 39.3 (Cꢀ3'), 41.9 (Cꢀ3, Cꢀ
4), 55.4 (OCH3), 59.4 (Cꢀ6'), 113.8 (m-Ar), 125.2 (Cꢀ1, Cꢀ6), 127.1 (o-Ar), 129.6 (Cꢀ2, Cꢀ5),
139.4 (i-Ar), 158.9 (p-Ar). Isomers 4c / 9c: IR (cm–1) 2908, 2837, 1606, 1511, 1251, 1178, 1033,
824; MS (EI, 70 eV): m/z (%) = 318 (100), 303 (10), 185 (17), 171 (14), 147 (11), 121 (10);
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HRMS (ESI): m/z calcd. for C22H22O2 : 318.1620, found: 318.1612.
Synthesis of the ligand racꢀ4a. a) According to ref.,26 CeCl3 · 7 H2O (1.51 g, 4.05 mmol) was
heated for 1.5 h at 110 °C to remove H2O. Then dry THF (7 mL) was added and the suspension
was stirred for 1 h prior to be cooled to –78 °C. PhLi (2.40 mL, 4.05 mmol, 1.8 M in
dibutylether) was added and the suspension was stirred for a further 1 h at –78 °C. After
dropwise addition of a solution of 5 (200 mg, 1.45 mmol) in THF (2 mL), the reaction mixture
was warmed up to –40 °C over 6 h. The reaction was quenched by addition of H2O (10 mL). The
mixture was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried
(MgSO4). The solvent was removed under reduced pressure and the crude product was purified
by column chromatography on SiO2 with hexanes/EtOAc (4:1→1:1) (Rf = 0.26, hexanes/EtOAc
1:1) to give a 72 : 28 product mixture of (2RS,3aRS,5SR,6aSR)ꢀ2,5ꢀdiphenyloctahydropentaleneꢀ
2,5ꢀdiol : (3aSR,5SR,6aRS)ꢀ5ꢀhydroxyꢀ5ꢀphenylhexahydropentalenꢀ2ꢀone (383 mg, 1.02 mmol,
69%) as a colorless solid. The product was used in the next step without further purification. The
NMRꢀsignals are assigned by using 2DꢀNMR spectorscopy. (2RS,3aRS,5SR,6aSR)ꢀ2,5ꢀ
1
diphenyloctahydropentaleneꢀ2,5ꢀdiol: H NMR (500 MHz, CDCl3): δ (ppm) = 2.28 (dd, J =
14.2 Hz, 3.0 Hz, 4H, 1ꢀHa, 3ꢀHa, 4ꢀHa, 6ꢀHa), 2.46–2.55 (m, 4H, 1ꢀHb, 3ꢀHb, 4ꢀHb, 6ꢀHb), 2.87–
2.96 (m, 2H, 3′ꢀH, 6′ꢀH), 3.64 (s, 2H, OH), 7.21–7.27 (m, 1H, p-Ar), 7.29–7.35 (m, 2H, m-Ar),
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7.46–7.51 (m, 2H, o-Ar); C NMR (126 MHz, CDCl3): δ (ppm) = 43.1 (Cꢀ3′, Cꢀ6′), 49.1 (Cꢀ1,
Cꢀ3, Cꢀ4, Cꢀ6), 85.6 (Cꢀ2, Cꢀ5), 125.2 (o-Ar), 126.8 (p-Ar), 128.2 (m-Ar), 147.0, (i-Ar).
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(3aSR,5SR,6aRS)ꢀ5ꢀhydroxyꢀ5ꢀphenylhexahydropentalenꢀ2ꢀone: H NMR (500 MHz, CDCl3):
δ (ppm) = 1.94–2.01 (m, 2H, 4ꢀHa, 6ꢀHa), 2.38–2.45 (m, 4H, 3ꢀHb, 4ꢀHb, 1ꢀHb, 3ꢀHb), 2.58–2.66
(m, 2H, 1ꢀHa, 3ꢀHa), 3.06–3.14 (m, 2H, 3′ꢀH, 6′ꢀH), 3.64 (s, 1H, OH), 7.21–7.27 (m, 2H, p-Ar),
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