Enantioselective Cleavage of Cyclobutanols Through Ir-Catalyzed C?C Bond Activation: Mechanistic and Synthetic Aspects

Article abstract of DOI:10.1002/chem.202004843

The Ir-catalyzed conversion of prochiral tert-cyclobutanols to β-methyl-substituted ketones proceeds under comparably mild conditions in toluene (45–110 °C) and is particularly suited for the enantioselective desymmetrization of β-oxy-substituted substrates to give products with a quaternary chirality center with up to 95 % ee using DTBM-SegPhos as a chiral ligand. Deuteration experiments and kinetic isotope effect measurements revealed major mechanistic differences to related Rh^I-catalyzed transformations. Supported by DFT calculations we propose the initial formation of an Ir^III hydride intermediate, which then undergoes a β-C elimination (C?C bond activation) prior to reductive C?H elimination. The computational model also allows the prediction of the stereochemical outcome. The Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for substrates bearing strongly coordinating groups. The method is of particular value for the stereo-controlled synthesis of substituted chromanes related to the tocopherols and other natural products.

Full text of DOI:10.1002/chem.202004843

Accepted Article
Accepted Article
Title: Enantioselective cleavage of cyclobutanols through Ir-
catalyzed C-C bond activation: Mechanistic and synthetic aspects
Authors: Friederike Ratsch, Joss Pepe Strache, Waldemar Schlundt,
Jörg-Martin Neudörfl, Andreas Adler, Sarwar Aziz, Bernd
Goldfuss, and Hans-Günther Schmalz
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202004843
Link to VoR: https://doi.org/10.1002/chem.202004843
01/2020

10.1002/chem.202004843
Chemistry - A European Journal
FULL PAPER
Enantioselective cleavage of cyclobutanols through Ir-catalyzed
C-C bond activation: Mechanistic and synthetic aspects
Friederike Ratsch, Joss Pepe Strache, Waldemar Schlundt, Jörg-Martin Neudörfl, Andreas Adler,
Sarwar Aziz, Bernd Goldfuss and Hans-Günther Schmalz*[a]
Dedication
[a]
Dr. F. Ratsch, J.-P. Strache, Dr. W. Schlundt, Dr. J.-M. Neudörfl, A. Adler, S. Aziz, Prof. Dr. B. Goldfuss and Prof. Dr. H.-G. Schmalz
Department of Chemistry
University of Cologne
Greinstraße 4, 50939 Köln
E-mail: schmalz@uni-koeln.de
Supporting information for this article is given via a link at the end of the document.
Abstract: The Ir-catalyzed conversion of prochiral tert-cyclobutanols
to b-methyl-substituted ketones proceeds under comparably mild
conditions in toluene (45–110°C) and is particularly suited for the
enantioselective desymmetrization of b-oxy-substituted substrates to
give products with a quaternary chirality center with up to 95% ee
using DTBM-SegPhos as a chiral ligand. Deuteration experiments
and kinetic isotope effect measurements revealed major mechanistic
differences to related Rh(I)-catalyzed transformations. Supported by
DFT calculations we propose the initial formation of an Ir(III) hydride
intermediate which then undergoes a b-C elimination (C-C bond
activation) prior to reductive C-H elimination. The computational
model also allows the prediction of the stereochemical outcome. The
Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for
substrates bearing strongly coordinating groups. The method is of
particular value for the stereo-controlled synthesis of substituted
chromanes related to the tocopherols and other natural products.
Uemura (2003)
Ar
R1
Pd(OAc)2 / L1
O
R1
OH
Cs2CO3
+ ArBr
*
R3
R2
R3
R2
toluene, 50 °C
1
2
up to 95% ee
Murakami (2007)
R2
R2
R2
Me
[Rh(OH)(COD)]2
O
*
L2
toluene, RT
OH
R1
O
O
O
O
R1
R1
up to 99% ee
Rh
3
4
Cramer (2008)
R1
R2
OH
R3
Me
*
O
[Rh(OH)(COD)]2 / L3
R1
R2
R3
toluene, 110 °C
1
5
up to 99% ee
H Me
O
Me
(S)-SegPhos
N
O
O
PAr2
PAr2
PPh2
Fe
Introduction
L2: Ar = Ph
L3: Ar = 3,5-But2-4-OMe-Ph
O
L1
The transition metal-catalyzed activation of C-C single bonds
has opened some unconventional strategies for the atom-
economic synthesis of complex molecules.[1,2] In many cases
cyclobutane derivatives have been employed as substrates
because the energy gain (22–26 kcal/mol) associated with the
opening of a strained four membered ring[3] represents a strong
driving force. Mechanistically, the cleavage of cyclobutanes
through metal-catalyzed C-C bond activation can follow different
pathways. For instance, cyclobutanones can undergo oxidative
addition to Rh(I)[4] or Pd(0)[5] to form reactive five-membered
metallacycles, which can then further react downstream in
different ways as reported by Murakami and coworkers.[6] Also
other cyclobutane derivatives, such as biphenylenes,[7] cyclo-
butenediones, or cyclobutenones can be activated by different
transition metals (e.g. Ni, Pt, Rh or Ru).[8] Furthermore, Ag[9] and
Mn[10] reagents are able to induce the ring-opening of cyclo-
butanols via radical processes (homolytic C-C bond cleavage).
From a synthetic point of view Pd-[11] and Rh-[12]-catalyzed
transformations of tert-cyclobutanols to ring-opened ketones are
of particular interest because such reactions can be exploited for
the enantioselective synthesis of b-substituted carbonyl
compounds if prochiral substrates are employed in the presence
of a chiral metal catalyst (Scheme 1).
Scheme 1. Selected metal-catalyzed cyclobutanol cleavage reactions
according to Uemura,[13] Murakami[14] and Cramer.[15]
As a first impressive example, Uemura reported the enantio-
selective Pd-catalyzed reaction of cyclobutanols of type 1 into g-
arylated products (2) in the presence of the chiral ferrocene-
derived ligand L1.[13] In contrast, the groups of Murakami[14,16]
and Cramer[15,17] used Rh catalysts to achieve the enantio-
selective conversion of prochiral cyclobutanols to b-methyl-
substituted carbonyl compounds (such as 4 or 5) in the
presence of SegPhos ligands L2 or L3, respectively. Extensive
mechanistic studies (including deuterium labeling experiments)
suggested these transformations to proceed according to the
general mechanism shown in Scheme 2. At first, the cyclo-
butanol substrate (6) is supposed to react with the catalyst to
form a Rh cylcobutanolate 8 which then undergoes a β-C
elimination as the key ring-opening step. In agreement to the
outcome of deuteration experiments, the resulting alkyl-Rh inter-
mediate 9 then isomerizes to a more stable Rh enolate 10 via
1,3-hydrogen shift. Final hydrolysis of 10 then closes the
catalytic cycle and affords the (a-deuterated) product 7.[14-15]
1
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10.1002/chem.202004843
Chemistry - A European Journal
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the metal-mediated ring-opening reaction to demonstrate the
pronounced reactivity differences between the Rh- and the Ir-
based catalysts (Table 1). In all cases, a solution of the
substrate and the catalyst precursors (metal salt and ligand) in
toluene was stirred under argon atmosphere for 30-60 min at
room temperature before the mixture was heated to the
specified temperature and the conversion was monitored by
means of TLC. While the catalyst generated in situ from
[Rh(COD)Cl]2 and rac-BINAP proved to be completely inactive,
the expected product (12a) was cleanly formed upon addition of
Cs2CO3 as a base (Table 1, entry 1-2). Remarkably, the use of
the hydroxy complex [Rh(COD)OH]2 as the rhodium source also
resulted in a smooth conversion without the necessity of a base
additive (entry 3). However, virtually no enantioselectivity was
observed under Rh catalysis when rac-BINAP was replaced by
either (R)-BINAP or (R)-DTBM-SegPhos (ent-L3), the latter
corresponding to the original conditions of Cramer (entry 4).[15] In
contrast, the iridium-based catalyst generated from the chloride
salt [Ir(COD)Cl]2 and rac-BINAP was found to be active even
without a base additive. Moreover, a dramatic ligand accelera-
tion was observed upon replacing BINAP by the (R)-DTBM-
SegPhos ligand in the Ir-catalyzed reaction. In this case, the
desired transformation proceeded smoothly already at 70°C to
give the product (R)-12a in 98% isolated yield and with an
enantiomeric excess of 93% ee (entry 6).[19]
Me
O
OD
R
O
R
D
6
7
L2RhOD
D2O
L2
Rh
H
O-RhL2
R
R
8
10
L2
Rh
1,3-H
shift
β-carbon
elimination
O
R
H
9
Scheme 2. General mechanism of the Rh-catalyzed cleavage of cyclobutanols
as suggested by Murakami[14] and Cramer[15] based on deuteration studies.
In the course of our research into the stereoselective synthesis
of a-tocopherol[18] we recently discovered and exploited an Ir-
catalyzed stereo-controlled ring-opening of spiro-cyclobutanols
of type 11 to establish the quaternary stereocenter with the
desired absolute configuration (Scheme 3).[19] Interestingly, no
stereo-induction could be achieved under Rh-catalysis in this
case. In contrast, the Ir-catalyzed reaction afforded the product
(12) with very high enantiomeric or diastereomeric excess (up to
99:1, depending on the nature of the group R) in the presence of
DTBM-SegPhos (L3) as a chiral ligand.
Table 1. Rh- versus Ir-catalyzed cleavage of cyclobutanol 11a.
Rh or Ir cat.
Ligand L*
MeO
MeO
MeO
MeO
O
OH
[Ir(COD)Cl]2
O
*
OH
R
L3
O
O
toluene, Δ
R
O
O
toluene, 80°C
11a
12a
11
12 (up to 94% ee)
(up to 99% de)
#
Catalyst
(mol%)
Ligand
(mol%)
T
[°C]
Base
Yield
ee[a]
(conf)
HO
1[b]
2[b]
3
[Rh(COD)Cl]2
(2.5)
rac-BINAP
(6.0)
110
110
110
110
100
70
-
-
-
2
O
13
[Rh(COD)Cl]2
(5.0)
rac-BINAP
(12.0)
Cs2CO3
93 %
92 %[c]
74 %[c]
32 %[c]
98 %
-
Scheme 3. Ir-catalyzed cleavage of spiro-cyclobutanols as a key step of our
total synthesis of (2R)-a-tocopherol.[19]
[Rh(COD)OH]2
(5.0)
(R)-BINAP
(10.0)
-
-
-
-
<2%
<2%
-
While the iridium-based methodology enabled us to complete
the total synthesis of (2R)-a-tocopherol (13), we were wondering
about the differences between the Rh- and the Ir-catalyzed
processes. As only very few examples for Ir-catalyzed C-C bond
activation have been reported in the literature[20] (without any
synthetic application[21] except our above-mentioned tocopherol
synthesis), we felt challenged to further explore the enantio-
selective Ir-catalyzed cyclobutanol cleavage both mechanis-
tically and with respect to its application scope. We here report
the results of our study which indeed revealed fundamental
mechanistic differences between the Ir- and the Rh-catalyzed
cyclobutanol fragmentation pathways and additionally pinpoints
the substrate scope and further synthetic applications of the Ir-
catalyzed methodology.
4
[Rh(COD)OH]2
(5.0)
ent-L3
(10.0)
5
[Ir(COD)Cl]2
(2.0)
rac-BINAP
(6.0)
6
[Ir(COD)Cl]2
(1.0)
ent-L3
(3.0)
93%
(R)
[a] Determined by GC (FID) on a chiral phase. [b] The cis diastereomer of the
alcohol was used. [c] Conversion as determined by GC-MS.
Mechanistic studies. The experiments summarized in Table 1
indicate the Ir- and the Rh-catalyzed reactions to follow different
mechanistic pathways. The fact that the Rh-catalyzed reaction
either essentially requires a base additive or the employment of
the hydroxy complex as catalyst precursor suggested the
formation of a rhodium cyclobutanolate intermediate of type 8
according to the established mechanism shown in Scheme 2.
However, we were puzzled by the question why the Ir-catalyzed
Results and Discussion
Initial experiments. Using the spiro-cyclobutanol 11a[19] as a
model substrate, we first re-investigated different conditions for
2
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10.1002/chem.202004843
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reaction proceeds smoothly in the absence of a base under
“acidic” conditions using the chloro complex for the in situ
generation of the active catalyst. We hypothesized that the
primary intermediate (14) formed by coordination of the
cyclobutanol substrate to the Ir(I)-catalyst does not lead to a
cyclobutanolate complex 13 (related to 8) in the absence of a
base (Scheme 4). Instead, it appeared feasible that the iridium
center in 14 might undergo oxidative addition (O-H bond
activation) to generate an Ir(III) hydride complex of type 15,[22]
which (as a 16 valence electron intermediate) could then be
involved in the subsequent C-C bond activation step.
MeO
MeO
O
OD
O
O
D
D-12a
D-11a
L2[Ir+]1Cl
oxidative
addition
reductive
elimination
Cl
+3
[Ir] L2
Cl
D
+3
D
[Ir] L2
MeO
MeO
O
O
O
O
H
O
H +3
Ir L2
Cl
+1
Ir L2
17
16
O
R
Ir L2
O
R
base
Cl
R
=
β-carbon
elimination
C-C bond
activation
13
14
15
Cl
D
[Ir] L2
Scheme 4. Possible reactions of the supposed primary Ir-intermediate 14.
Base-mediated generation of a cyclobutanolate 13 versus formation of an
Ir(III) hydride intermediate 15 by oxidative addition into the O-H bond.
MeO
O
O
TS(16-17)
We started our experimental investigation of the mechanism of
the Ir-catalyzed reaction with a deuteration experiment. For this
purpose, the substrate D-11a was prepared by O-deuteration of
11a either by partitioning between D2O/EtOAc (ca. 60% D) or by
treatment of an ethereal solution of 11a with 1.5 equivalents of
nBuLi followed by quenching the resulting lithium alkoxide with
D2O/DCl (ca. 70% D). The success of the O-deuteration was
confirmed by IR analysis (see the Supporting Information). The
reaction of D-11a under the proven conditions then proceeded
cleanly (Scheme 5) to afford the ring-opened ketone D-12a with
the deuterium label located at the newly formed (angular) methyl
group according to NMR analysis (see the Supporting Informa-
tion). Only a minor degree of deuteration (≤ 10%) was also
detected at the terminal α-carbonyl position.
Scheme 6. Proposed mechanism for the iridium-catalyzed cleavage of
cyclobutanol D-11a that takes into account the specific deuteration outcome.
When the Ir-catalyzed reaction of either 11a or D-11a was
performed in the presence of excess D2O (in toluene/D2O = 4:1),
the product D-12a again contained a (single) deuterium atom at
the angular methyl group – in agreement with the proposed
mechanism. In this case, however, the α-carbonyl methyl group
was completely deuterated as well, while still almost no
deuteration (<10% D) was observed at the methylene group.
This indicates the additional a-deuteration to occur at the stage
of the ketone product (D-12a) via kinetically controlled
enolization, preferentially to the terminal position.
To support the hypothesis that an iridium hydride species is
involved in the (rate determining) key step of the proposed
mechanism we decided to also investigate the kinetic isotope
effect (KIE) of the reaction. For this purpose, we performed four
parallel reactions (two with H-11a and two with D-11a) and
monitored the reaction rates by means of NMR. To minimize the
experimental error, these reactions were carried out very
carefully under absolute identical conditions as follows: A stock
solution containing [Ir(COD)Cl]2 and the chiral ligand L3 in dry
toluene was stirred for 60 min at room temperature before equal
amounts of this solution were transferred by syringe to the four
reaction vials containing the substrate (H/D-11a) to give a
0.12 M solution in toluene. After heating the stirred reaction
mixtures to 73 °C, small samples were taken after 30, 60, 90,
120, and 180 min. Two of the four reactions were stirred for
another 90 min to ensure full conversion. The taken samples
were immediately filtered through a tiny plug of silica and
[Ir(COD)Cl]2 (5 mol%)
MeO
MeO
O
L3 (15 mol%)
OD
toluene, 73-90 °C, 5 h
O
O
D
D-11a (≥70% D)
D-12a
Scheme 5. Selective deuteriation of the angular methyl group in the Ir-
catalyzed conversion of D-11a.
The outcome of this experiment (Scheme 5) unambiguously
proves the Ir-catalyzed process to mechanistically differ from the
Rh-catalyzed reaction as virtually no deuteration occurred under
Ir catalysis at the methylene position next to the keto function
(compare Scheme 2). Thus, an 1,3-hydrogen shift leading to a
metal enolate, as a characteristic feature of the Murakami/
Cramer mechanism, could be excluded. Also, these authors
never observed any deuteration of the newly formed methyl
group during their studies of the Rh-catalyzed cyclobutanol
cleavage.[14-15]
1
analyzed by H NMR. The degree of conversion was calculated
based on the integral changes of four selected signals: Product
signals at 2.79 ppm (d, 1H) and 1.86 ppm (m, 1H) and signals of
the starting material at 2.31 ppm (m, 2H) and 2.01 ppm (t, 2H).
The results of these measurements are depicted in Figure 1 and
clearly reveal that the deuterated cyclobutanol D-11a reacts
slower than the non-deuterated cyclobutanol 11a, which
indicates a significant kinetic isotope effect.
Based on our experimental results we devised the mech-
anism shown in Scheme 6 for the Ir-catalyzed transformation.
This mechanism starts with the oxidative addition of the Ir(I)-
complex into the O-D bond of D-11a leading to an Ir(III)-hydride
intermediate 16. Now, the iridium center is supposed to activate
the adjacent C-C bond to induce a β-carbon elimination via a
transition state of type TS(16-17). The resulting Ir(III)-alkyl-
intermediate 17 finally undergoes reductive elimination to
release the product D-12a under regeneration of the Ir(I)-catalyst.
3
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10.1002/chem.202004843
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D pseudo potential
ꢆbar, negꢀHarteeꢏs or kcalꢉmol
ꢂ
[Ir(COD)Cl]2 / L3
toluene, 73 °C
MeO
MeO
ꢆ
O
ꢇ2ꢀꢁ
ꢄꢅ
ꢆ
ꢆꢂ,ꢂ
OH/D
ꢉꢊ (ꢆꢋꢌꢍ)
1484.583201
-1177 ꢎꢏ-1
ꢈꢐ 26.8
ꢂ
O
ꢃꢂ3
O
ꢂ3ꢃ
kcalꢉmol
ꢀꢁ(ꢀ)
ꢉꢊ (ꢁ-ꢄ-ꢈꢅ)
ꢂꢆ
ꢇ2ꢀꢁ
ꢄꢅ
ꢍ
ꢆ
1484.590175
-310 ꢎꢏ-1
ꢈꢐ 16.2
ꢄ,ꢂ
232.692379
(ꢀ 1484.597001)
1251.904622
H/D
ꢄꢅ
11a
12a
ꢇ2ꢀꢁ
ꢄꢅ
ꢉꢊ (ꢑꢒꢍꢈꢅ.)
1484.602839
-526 ꢎꢏ-1
ꢈꢐ 23.5
ꢂ
ꢂ,ꢂ
ꢀꢄ,ꢂ
ꢆ
(ꢀ)
ꢇ2ꢀꢁ
ꢂ
ꢆ
ꢄꢅ
1484.612655
ꢈꢁ +17.3
ꢀꢆꢂ,ꢂ
ꢀꢆꢄ,ꢂ
ꢀꢅꢂ,ꢂ
ꢀꢅꢄ,ꢂ
ꢀꢃꢂ,ꢂ
ꢀꢃꢄ,ꢂ
ꢀꢁꢂ,ꢂ
ꢃꢂ3
ꢂ3
ꢃ
ꢂ
ꢀꢁ(ꢀ)
ꢄꢅ
1251.904622
ꢆ
ꢂ
ꢍ
(ꢀꢀꢀ)
ꢂ
ꢇ2ꢀꢁ
ꢂ
1484.616004
ꢈꢁ +6.2
232.719329
ꢄꢅ
(ꢀ 1484.623951)
ꢂ
(ꢀ)
ꢇ2ꢀꢁ
ꢈꢁ -7.1
ꢆ
ꢂ
1484.625856
ꢈꢁ -18.1
ꢆ
ꢂ
ꢄꢅ
(ꢀꢀꢀ)
ꢇ2ꢀꢁ
ꢄꢅ
1484.640240
ꢈꢁ -15.2
Figure 2. Results of a DFT computational study of the mechanism of the Ir(III)-
mediated cyclobutanol fragmentation using a simplified model system.
Understanding the enantioselectivity. While the absolute
(S)-configuration of the product 12a, prepared by Ir-catalyzed
fragmentation of 11a in the presence of (S)-DTBM-SegPhos
(L3) as a chiral ligand, had been unambiguously assigned by its
conversion into (2R)-a-tocopherol,[19] we felt challenged to
rationalize the stereochemical outcome. For this reason, we took
a closer look at the b-carbon elimination as the stereo-deter-
mining step of the catalytic cycle.[24] A first configurational
analysis (supported by DFT calculations) revealed that four
types of transition states (TS) can be distinguished, which are all
characterized by a pseudo-octahedral coordination geometry of
the iridium center with the bidentate P,P-ligand in maximum
distance to the activated C-C bond (Figure 3). Two of these
transition states lead to the (S)- and the other two to the (R)-
product, and in both series, the hydride and chloride ligands are
oriented either cis or trans to each other.
Figure 1. Determination of the H/D kinetic isotope effect (KIE) for the Ir-
catalyzed transformation of 11a to 12a by time-resolved monitoring of the
conversion of the deuterated and the non-deuterated substrate in four parallel
experiments. A KIE of 2.4 was calculated from the ratio of the initial reaction
rates (indicated by lines) and consideration of the deuteration degree (70%).
To quantify the kinetic isotope effect, the rate constants kH and
kD were calculated by determining the slope of the line for the
initial reaction rate (Figure 1). From the average value of kH
(0.872) and kD (0.520) a KIE of 1.68 was calculated for the Ir-
catalyzed cyclobutanol cleavage. Taking a deuteration degree of
70% for D-11a into account, the corrected KIE calculates to 2.4.
This corresponds to a primary kinetic isotope effect and supports
our mechanistic proposal (Scheme 6) that a O-H (or O-D) bond
activation is involved (even as a rate determining step) in the
catalytic cycle.
To probe the role of the chloride ligand and in particular
whether it possibly dissociates from the iridium during the
catalytic process, we added varying amounts of AgOTf to the
reaction mixture and monitored the conversion of 11a into 12a
under the standard conditions (4 mol % [Ir(COD)Cl]2, 12 mol%
L3, toluene, 73°C). While addition of 2 mol% of AgOTf had no
significant effect, the reaction was much slower upon addition of
8 mol% and totally inhibited in the presence of an excess of
AgOTf (40 mol%). This may be a hint that the chloride ligand
plays a certain role, however, oxidation of the Ir(I)-catalyst by
Ag(I) would also cause inhibition of the reaction. Therefore, a
cationic Ir-complex cannot be fully excluded.
broken in (S)-TS
MeO
O
[Ir]
O
broken in (R)-TS
=
=
=
P
Ir
H
Ir
MeO
MeO
H
P
P
Cl
Cl
P
O
O
O
O
Computational investigations. To shed additional light on
the proposed mechanism of the iridium-catalyzed cyclobutanol
cleavage we performed DFT (PW6B95D3) computations.[23]
Using a simplified test system (with L = PH3) the theoretic
analysis confirmed the feasibility of the proposed mechanism
(Figure 2). The calculations suggest the oxidative addition of the
iridium center to the O-H bond of the cyclobutanol (14 to 15) to
be the step with the highest activation energy (EA = 26.8
kcal/mol). This is in accordance with the experimentally found
KIE of = 2.4 as the activation energy of the b-C elimination step
(16.2 Kcal/mol) is significantly lower. The final reductive C-H
elimination (EA = 23.5 kcal/mol) leads to a complex which,
according to the calculations, dissociates without any barrier to
liberate the product and the catalyst.
(S)-TS with H-Cl trans (O-H cis)
(S)-TS with H-Cl cis (O-H trans)
=
P
H
MeO
MeO
P
H
P
P
Cl
Cl
Ir
Ir
O
O
O
O
(R)-TS with H-Cl trans (O-H cis)
(R)-TS with H-Cl cis (O-H trans)
Figure 3. Formal configurational analysis of possible transition states of the
Ir(III)-mediated C-C bond activation as the stereo-determining step.
Orienting DFT calculations on a small model system (see the
Supporting Information) suggested transition structures with
trans-oriented H and Cl ligands and the O-C-C-substrate atoms
4
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10.1002/chem.202004843
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aligned in-plane with the P2Ir ring being energetically most
favored for electronic reasons (Figure 4).
Figure 4. DFT computations (PW6B95D3/6-311G**(C,H,O,P,Cl)/SDD (+ECP,
Ir)-SCRF(toluene)//ONIOM(B97D3/SDD(+ECP,Ir), D95 (C,H,O,P,Cl):PM6) of a
simplified model system show the energetically most favourable transition
structures with a trans-orientation of H and Cl ligands and an in-plane align-
ment of the P-P-Ir(III) plane and the metal bound O-C-C unit of the substrate.
Figure 6. Most stable (S)-TS showing an H-Cl-trans orientation and a
favorable in-plane alignment of the C-C-O-Ir(III)P2 moiety, in harmony with a
co-planar orientation of the substrate's aryl unit and an equatorial P-aryl group.
To prepare for the computation of the competing transition
states (leading to the different enantiomers of 12a) at a higher
level of theory, the conformation of the axially chiral ligand (L3)
coordinated to the iridium metal center was analyzed. As shown
in Figure 5, two of the P-bound aryl groups adopt an axial and
the other two an equatorial position. The axial P-aryl groups are
fixed in coplanar orientation to the adjacent benzodioxol
moieties of the biaryl unit, whereas the equatorial P-aryl groups
were found to be conformationally more flexible and able to
intensely interact with the substrate. All in all, the (S)-DTBM-
SegPhos-iridium unit was found to adopt a right-turning C2-
symmetric propeller shape.
In contrast, in the lowest energy (R)-transition state (Figure 7)
such a co-planar alignment of an equatorial P-aryl group with the
substrate is only possible at the expense of an energetically
unfavorable out-of-plane orientation of the P2Ir and the C-C-O
units (H-Cl cis) (Figure 7).
OMe
But
But
But
OMe
But
O
O
ax
eq
P
P
Ir
But
O
O
eq
ax
MeO
But
But
But
OMe
Figure 5. Schematic view of the conformation of the C2-symmetric (S)-DTBM-
SegPhos ligand (L3) coordinated to the iridium center.
Figure 7. Most stable (R)-TS with a H-Cl cis orientation and an unfavorable
out-of-plane position of the P2Ir(III) and the C-C-O unit, enforced by a co-
planar arrangement of the substrate's aryl unit and an equatorial P-aryl group.
To limit the number of conformations, transition state opti-
mizations were performed initially only with an in-in-in-in orien-
tation of the methoxy groups, which can either point towards the
adjacent aryl unit (inwards) or away from it (outwards). Further
calculations to rationalize the origins of the enantioselectivity
were then performed on the complete system generated from
cyclobutanol 11a and (S)-DTBM-SegPhos-IrCl.[19] The quan-
titative energetic analysis then revealed a clear preference for
the (S)-enantiomeric transition structure with a calculated ee of
95% (for details see the Supporting Information).[24] This result,
which is in excellent agreement with the experimental facts, can
be “explained” as follows. In the most favorable (S) transition
state both the favorable anti H-Cl orientation and the favorable
alignment of the involved C-C-O unit with the P2Ir-plane are in
harmony with an optimal co-planar alignment of the equatorial P-
aryl groups with the substrate (Figure 6).
Substrate Scope. To explore the substrate scope of the
iridium-catalyzed cyclobutanol cleavage we initially used the
easily accessible spiro-cylobutanone 18 as a platform to prepare
a variety of potential substrates of type 11 through addition of
organometallic reagents. The results of the (mainly unoptimized)
reactions are summarized in Table 2. Interestingly, the dia-
stereoselectivity was found to depend on both the reagent and
the solvent used. For instance, the reaction of 18 with MeMgBr
in Et2O afforded selectively the trans product 11a while a mixture
of 11a and its cis diastereomer 11’a was formed either with the
same reagent in THF or with methyllithium in Et2O. As a general
trend, we found that Grignard reagents in THF (except iso-Pr-
MgCl and allyl-MgBr) react with 18 in a cis-selective fashion
while trans-products are favored in diethyl ether. This behavior
might result from a different aggregation of the reagents in the
5
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10.1002/chem.202004843
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different solvents.[25] Noteworthy, the branched Grignard reagent
iso-Pr-MgCl afforded the addition product only in low yield
because mainly reduction of the carbonyl group occurred in this
case to yield a 1:1 mixture of diastereomeric alcohols (11/11’
with R = H). Fortunately, the cis- and trans-diastereomers could
be separated by column chromatography in all cases (Table 2).
In a similar fashion the trans-isomer 19 (obtained from 11i) was
used to prepare the TBS-protected substrate 11e (structures
shown in Scheme 8). We also employed the vinyl-substituted
cyclobutanol 19’ to prepare the substrate 11’d with a phenylethyl
sidechain through Pd-catalyzed reductive Heck reaction.[27]
Remarkably, this transformation proceeded smoothly to afford
the product 11’d in high yield without any significant Pd-
mediated cyclobutanol cleavage (as described by Uemura,[13]
compare Scheme 1).
Table 2. Synthesis of cyclobutanols of type 11/11’.
With the various spiro-cylobutanol substrates in our hands,
the stage was set for the investigation of their performance in
the Ir-catalyzed ring-opening. As a first important result we found
that (using the same chiral ligand L3) the diastereomers 11a and
11’a afforded the products with opposite absolute configuration
(Scheme 8). However, in contrast to the trans-spiro-cyclobutanol
11a, which yields the methyl ketone 12a with high enantio-
selectivity, the corresponding cis-diastereomer 11’a gave the
product ent-12a with only 18% ee (non-optimized). Nevertheless,
other cis-configurated substrates, i.e. 11’b-d, gave rise to the
expected products (12b-d) with satisfying enantioselectivity.
MeO
MeO
MeO
R-[M]
+
OH
R
O
O
O
O
R
OH
18
11 (trans)
11’ (cis)
#
Reagent
Solvent
Yield (11)[a]
Yield (11’)[a]
trans
cis
1
MeLi
Et2O
Et2O
THF
THF
THF
THF
THF
Et2O
Et2O
THF
THF
THF
17%
93%
ca. 50%[b]
13%
-
53%
-
2
MeMgBr
3
MeMgBr
ca. 50%[b]
49%
13%[c]
85%
27%
24%
46%[f]
78%
-
4
PhMgCl
MeO
MeO
[Ir]L3
tol, Δ
O
5
BnMgBr
OH
Me
Me
O
O
98%
[a]
6
vinyl-MgBr[d]
2-butenyl-MgBr
propargyl-MgBr
9%
11a
12a (93% ee)
7
12%
71%
62%[f]
-
MeO
MeO
[Ir]L3
tol, Δ
O
Me
OH
8
Me
O
92%
O
9
TMS-propargyl-MgBr[e]
1-hexynyl-Li[g]
11’a
ent-12a (18% ee)
MeO
MeO
MeO
MeO
[Ir]L3
tol, Δ
10
11
12
O
O
O
44%
[b]
iso-propyl-MgCl
allyl-MgBr
17%
49%
OH
11’b
12b (92% ee)
41%
[Ir]L3
tol, Δ
O
The relative configuration of the products (cis/trans) was determined by means
of 1H NMR (NOE) or X-ray crystallography in the case of 11a (ref. 19), 11’I and
11’n (see the Supporting Information). Unless otherwise noted, the reactions
were performed at -78 °C [a] Isolated yield; [b] Ratio determined by 1H NMR of
the crude product mixture; [c] Low yield due to low quality of the Grignard
reagent used; [d] Addition at -100 °C; [e] Addition at -40 °C; [f] The product still
contained traces of solvent; [g] Prepared in situ from 1-hexyne and nBuLi.
O
O
91%
[c]
OH
11’c
12c (78% ee)
MeO
MeO
MeO
MeO
MeO
MeO
[Ir]L3
tol, Δ
O
O
O
91%
[d]
OH 2
OH
2
Additional substrates of type 11/11’ were prepared from the
readily accessible vinylated compound 11’I (Scheme 7). Hydro-
boration of 11’I with 9-BBN and subsequent oxidation with
H2O2[26] gave the diol 19’, which in turn could easily be protected
selectively at the primary OH group to give substrates 11’f (OAc),
11’g (OMOM), and 11’h (OBn).
11’d
12d (84% ee)
[Ir]L3
tol, Δ
O
OTBS
O
O
99%
[e]
OTBS
OR
11e
12e (92% ee)
[Ir]L3
tol, Δ
O
18
MeO
a
85%
OR
O
O
b
OH
OH
99%
O
R = Ac:
11’f
11’g
11’h
0%
47%
55%
12f (-)
12g (83% ee)
12h (93% ee)
MeO
OH
[f]
[g]
MOM:
benzyl:
19’
O
Scheme 8. Enantioselective conversion of various substrates of type 11 or 11’
in the Ir-catalyzed cyclobutanol cleavage. Standard conditions: mol%
OH
5
11’i
MeO
[Ir(COD)Cl]2, 15 mol% L3, 0.1 M solution of substrate in dry toluene,110 °C
(colour change).[a] 1 mol% cat., 3 mol% L3, 70 °C; [b] 9 mol% cat., 26 mol%
L3, toluene:H2O 4:1; [c] 10 mol% cat., 30 mol% L3; [d] 7 mol% cat., 19 mol%
L3; [e] 85 – 95 °C; [f] 7 mol% cat., 23 mol% L3; [g] 8 mol% cat., 24 mol% L3;
(for details see the Supporting Information).
c
77%
O
OH
11’d
Scheme 7. Synthesis of cyclobutanols 19’ and 11’d. Reagents and conditions:
a. see Table 2, entry 2; b. 9-BBN, THF, 0°C to r.t., 5 h, then NaOH, H2O2, r.t.,
24 h; c. Ph-I, Pd2(dba)3(5 mol%), PPh3, K3PO4, Me4NHCO2, DMF, 81°C, 20 h.
6
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Interestingly, the investigation of the three cis-cyclobutanols
11’b-d with different spacer lengths between the phenyl group
and the cyclobutanol unit showed that the reactivity drops with
an increasing bulk of the side chain. Actually, the phenyl-
substituted substrate 11’b proved to be rather unreactive and
the addition of water[15] was required to achieve at least a decent
yield (44%). In the case of 11’c, the catalyst load had to be
increased to ensure a high yield. The enantioselectivity of the
reaction of 11’c to 12c increased from 78% to 87% ee upon
lowering the temperature to 100°C, however, at the expense of
conversion (34% yield). The bulky iso-propyl-substituted
substrate (prepared according to Table 2, entry 11) did not react
at all under the standard conditions. In contrast, the 2-oxy-ethyl
substituted substrates, especially the TBS-protected (11e) and
the benzyl-protected (11’h) compounds, reacted smoothly to
give the products 12e and 12h, respectively, in high yield and
enantioselectivity (92-93% ee). The corresponding acetyl-
protected substrate 11’f, however, proved to be completely
unreactive and the MOM-derivative 11’g only reacted very
slowly and unreacted starting material could be partly reisolated.
Possibly, the catalysis is inhibited in the latter cases by
coordination of the Ir to the polar functional groups.
delivered a mixture of unreacted starting material and some
unidentified side products (even after 20 h), the corresponding
TMS-protected alkyne 11l quantitatively afforded 22 as the
product of an Ir-catalyzed 5-endo-dig cyclization. Noteworthy,
the TIPS-protected alkyne related to 11l (not shown), the alkyne
11’n, and also both diastereomers of the allyl-substituted
cyclobutanol 11o/11’o showed no conversion under the
standard conditions, possibly due to inactivation of the catalyst
through formation of a cyclic resting state formed by b-insertion
of the O-bound Ir-hydride to the unsaturated side chain.
To further probe the scope of the Ir-based methodology
employing more simple prochiral cyclobutanols lacking the spiro-
chromane moiety we converted the easily accessible cyclobu-
tanone 23[19] through addition of alkyl Grignard reagents and
functional group manipulation into the substituted tertiary cyclo–
butanols 26 and 28 (Scheme 10). Noteworthy, the addition of
MeMgBr in Et2O to the ketone 27 proceeds diastereoselectively
to afford the trans-product 28 in high yield as the only isolated
product.
TBSO
OH
13%
OH
26
PivO
PivO
While the examples given in Scheme 8 illustrate a fair scope
of the method, a number of substrates with unsaturated
sidechains failed to undergo the expected Ir-catalyzed
cyclobutanol cleavage (Scheme 9).
a
24’
24
c
49%
PivO
O
b
23
HO
54%
88%
OH
OH
25
MeO
MeO
MeO
83%
MeO
MeO
MeO
d,e
[Ir]L3
tol, Δ
HO
f
37%
O
O
O
O
OH
20 (rac)
21 (rac)
OTBS
OTBS
76%
11’i
28
27
[Ir]L3
tol, Δ
Scheme 10. Synthesis of cyclobutanols 26 and 28. Reagents and conditions:
a) n-BuMgCl, THF, -78 °C, 1 h; b) NaOH, EtOH, 30 °C, 24 h; c) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C to r.t., 2.5 h; d) DMP, CH2Cl2, 0 °C to r.t., 2 h; e) TBSOTf,
2,6-lutidine, CH2Cl2, 0 °C to r.t., 1.5 h; f) MeMgBr (3M in Et2O), Et2O, -78 °C,
1 h.
43%
O
OH
OH
11’k
[Ir]BINAP
tol, Δ
Under the proven conditions of the Ir-catalyzed cyclobutanol
cleavage both of these substrates (26 and 28) afforded the
corresponding chiral ketones (29 and 30, respectively) with high
yields and good enantioselectivity (Scheme 11). Noteworthy,
when 28 was treated with the corresponding Rh(OH)-catalyst
under the conditions of Cramer[15], a 2:1 mixture of the enone 31
and its non-conjugated isomer 32 was formed, probably through
elimination of TBS-OH from the primary product 30. This again
proves the advantage of our Ir-based protocol for the enantio-
selective cleavage of 3-oxy-substituted cyclobutanols.
O
99%
TMS
O
O
TMS
11l
22
MeO
MeO
MeO
[Ir]L3
tol, Δ
OH
O
11m
[Ir]L3
tol, Δ
O
OH
11’n
[IrCl]L3 (6 mol%)
TBSO
O
[Ir]L3
tol, Δ
toluene, 110°C
TBSO
HO
OH
80%
O
29 (70% ee)
26
28
OH
11o/11’o
[IrCl]L3 (4 mol%)
O
OTBS
toluene, 100°C
Scheme 9. Substrates of type 11/11’ which did not undergo Ir-catalyzed
cyclobutanol cleavage.
OTBS
98%
30 (85% ee)
[Rh(OH)]L3
(12 mol%)
toluene, 110°C
For instance, the vinyl-cyclobutanol 11’i and the related
higher substituted allylic alcohol 11’k mainly afforded the dienes
20 and 21, respectively, possibly via formation of a π-allyl-Ir
intermediate and subsequent b-H elimination. Chiral GC analysis
indicated that both of these compounds were formed as racemic
mixtures. While the unprotected terminal alkyne 11m only
O
O
+
75%
31
32
(2:1)
Scheme 11. Ir- and Rh-catalyzed cleavage of cyclobutanols 26 and 28.
7
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Enantioselective synthesis of chromanes related to
natural products. As already mentioned above, the starting
point of the present study was our synthesis of α-tocopherol (13)
(Scheme 3) and in particular the discovery that the enantio-
selective opening of the prochiral spiro-cyclobutanol 11a to the
methylketone 12a could be efficiently achieved using an Ir-
catalyst, while the related Rh-based protocol only afforded the
racemic product. In a similar fashion, the Ir-catalyzed reaction of
the more elaborated substrate 11q afforded the α-tocopherol
precursor 12q with virtually complete stereocontrol (Scheme
12).[19]
Treatment of the β,γ-enone 12r with trifluoromethane sulfonic
acid in dichloromethane resulted in the migration of the double
bond to give of the more stable conjugated enone 34 as a
separable mixture of E and Z-isomers (Scheme 13).
While E-34 already displays some characteristic structural
features of the natural product 33, we decided to also probe the
Ir-catalyzed cyclobutanol opening employing the spiro-chromane
38 with an aromatic substitution pattern related to 33 (Scheme
14). For this purpose, the literature-known building blocks 35[29]
and 36[19] were first fused to 37 in a Friedel-Cafts related
condensation. While the use of BF3•Et2O as a Lewis acid[19] was
not successful in this case, the desired reaction took place in the
presence of an excess (4 equiv.) of methane sulfonic acid in
dichloromethane to afford 37 in 38% yield as a mixture of cis
and trans isomers. Subsequent saponification of the ester
moiety, oxidation[30] and reaction of the resulting ketone with
MeMgBr in diethylether then cleanly afforded the trans-
cyclobutanol 38 as the desired desymmetrization precursor. And
much to our satisfaction, the Ir-catalyzed ring opening then
proceeded smoothly under the proven conditions to give the
ketone 39 in high yield and with excellent enantioselectivity
(95% ee).
MeO
[Ir]L3
tol, Δ
OH
O
3
96%
11q
MeO
O
α-tocopherol (13)
O
3
3
12q (d.r. > 99 : 1)
Scheme 12. Ir-catalyzed key step of our total synthesis of a-tocopherol.
Against this background, we asked ourselves whether the
methodology could be applied also to the synthesis of other
tocopherol-related compounds such as the antimalarial
chromane natural product 33 recently isolated from Koeberlinia
spinosa which displays an interesting activity against the malaria
parasite plasmodium falciparum (IC50=24 µM). (Figure 8).[28]
MeO
OH
MeO
MsOH, CH2Cl2
35
38%
O
OPiv
H
HO
OPiv
37
36
1. NaOH, EtOH
2. PIDA, TEMPO
3. MeMgBr, Et2O
MeO
O
75%
OH
O
[Ir(COD)Cl]2 (5 mol%)
33
L3 (15 mol%)
toluene, 45 °C, 19 h
MeO
MeO
O
OH
Figure 8. Structure of an antiplasmodial chromane 33 isolated from
Koeberlinia spinosa.
93%
O
O
39 (95% ee)
38
To probe the installation of an unsaturated (enone) sidechain,
we used the substrate 11r which was obtained by TBS
deprotection of an intermediate of our α-tocopherol synthesis.[19]
In this case (Scheme 13), the trisubstituted olefin in the side
chain was well tolerated and the desired desymmetrized ketone
12r was obtained in excellent yield (98%) and diastereoselec-
tivity (d.r. = 98.5 : 1.5; determined by HPLC after transformation
into α-tocopherol methyl ether, see the Supporting Information).
Scheme 14. Synthesis of the model chromane 39 (related to 33).
The expected absolute (S)-configuration of the chiral 2,2-
disubstitued chromane 39 was confirmed by X-ray
crystallography (Figure 9).[34]
[Ir]L3
toluene
85-95°C
MeO
OH
O
3
98%
11r
MeO
O
O
3
12r
(d.r. ≥ 98 : 2)
MeO
TfOH
CH2Cl2
Figure 9. Structure of 39 in the crystalline state.
O
O
3
34 (50%)
+ Z-isomer (37%)
Conclusion
Scheme 13. Synthesis of the enone 34 (as a model compound related to 33)
through cyclobutanol fragmentation and subsequent acid-mediated double
bond isomerization.
We have demonstrated that the Ir-catalyzed conversion of
prochiral tert-cyclobutanols proceeds under comparably mild
8
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2
3
conditions to afford b-methyl-substituted ketones in a variety of
cases. In the presence of DTBM-SegPhos as a chiral ligand the
products are formed with up to 95% ee. Our protocol appears to
be particularly suited for the enantioselective desymmetri-
zation[31] of prochiral b-oxy-substituted cyclobutanols which fail
to react in a similar fashion under Rh-catalysis. And indeed,
deuteration experiments and kinetic isotope effect measure-
ments revealed major mechanistic differences to related Rh(I)-
catalyzed transformations. Based on the experimental data, we
3H), 2.14 (s, 3H), 2.09 (s, 3H), 1.96 (dt, JH,H = 13.9 Hz, JH,H =
7.0 Hz, 1H), 1.86 (dt, 2JH,H = 13.6 Hz, 3JH,H = 6.7 Hz, 1H), 1.35 (s,
3H). 13C NMR (125 MHz, CDCl3): δ [ppm] = 208.0, 150.0, 147.1,
128.3, 126.2, 123.0, 117.4, 74.2, 60.6, 52.8, 32.4, 31.6, 24.4,
20.7, 12.7, 12.1, 11.8. FT-IR (ATR) ꢀ [cm ] = 1707 (m), 1457
(m), 1404 (m), 1253 (s), 1090 (s). GC-MS [tR] = 9.932 min, m/z
(%) = 276 ([M]+, 74), 243 (16), 219 (19), 203 (41), 179 (100),
135 (14), 91 (11), 43 (18). HRMS (ESI): Calc. 299.16177
[M + Na]+; Found 299.16167. [ꢂ]ꢃꢆꢄꢇꢅ= 1.04° (c = 0.58 in CHCl3).
-1
ꢁ
derived
a plausible mechanism which involves the initial
2-(6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)-1-phenyleth-
an-1-one (12b) According to the general procedure, a solution
of 12 mg (35.4 µmol) of cyclobutanol 11’b, 2.2 mg (3.27 µmol,
9 mol%) of [Ir(COD)Cl]2 and 10.9 mg (9.24 µmol, 26 mol%) of
(S)-DTBM-SegPhos in 0.4 ml of dry toluene and 0.1 ml of water
was heated for 20 h to 110 °C to give 5.3 mg (15.7 µmol, 44%)
of 12b (92% ee) after purification by preparative TLC (SiO2,
cHex/EtOAc 7:1). C22H26O3 (M = 338.45 g/mol). 1H NMR
(500 MHz, CDCl3): δ [ppm] = 7.94 – 7.92 (m, 2H), 7.55 – 7.52 (m,
formation of an Ir(III) hydride intermediate by oxidative addition
of Ir(I) into the O-H bond of the cyclobutanol substrate. In the
key C-C bond activating step, the four-membered ring is cleaved
by b-C elimination, and the catalytic cycle is closed by reductive
C-H elimination. This mechanism is supported by DFT
calculations, and the computational analysis of competing
transition states of the enantioselectivity-determining b-carbon
elimination step even allowed the prediction of the stereo-
chemical outcome. While simple tert-cyclobutanols such as 28
could be successfully employed as well, the developed protocol
is of particular value for the stereo-controlled synthesis of 2,2-
disubstituted chromanes related to natural products such as α-
tocopherol. Thus, we are optimistic that the Ir-catalyzed
cyclobutanol cleavage will find future application also in other
laboratories. At least, it opens a new chapter in the use of Ir-
catalyzed reactions in natural product synthesis[21] and also
compliments existing methods for the catalytic ring-opening of
cyclic alcohols to generate ketones with a (quaternary) chirality
center in ß-position.[1,12b,13b,17,32] Furthermore, the protocol may
find application in the preparation of selectively deuterated (or
even tritium-labeled) compounds.[33]
2
1H), 7.42 – 7.39 (m, 2H), 3.62 (s, 3H), 3.38 (d, JH,H = 14.5 Hz,
2
3
1H), 3.13 (d, JH,H = 14.5 Hz, 1H), 2.63 (t, JH,H = 6.9 Hz, 2H),
2.16 – 2.10 (m, 1H), 2.14 (s, 6H), 2.00 – 1.95 (m, 1H), 1.84 (s,
3H), 1.43 (s, 3H). 13C NMR (125 MHz, CDCl3): δ [ppm] = 199.0,
150.0, 147.2, 138.1, 133.1, 128.8, 128.5, 128.2, 126.1, 123.4,
117.5, 74.9, 60.6, 47.1, 31.6, 24.8, 20.8, 12.7, 11.9, 11.8. FT-IR
-1
ꢁ
(ATR) ꢀ [cm ] = 1676 (m), 1449 (m), 1254 (m), 1090 (s). GC-MS
[tR] = 11.668 min, m/z (%) = 338 ([M]+, 56), 305 (18), 218 (18),
203 (42), 179 (68), 135 (18), 105 (100), 91 (12), 77 (43), 44 (12).
HRMS (ESI): Calc. 339.19547 [M + H]+; Found 339.19585; Calc.
361.17742 [M + Na]+; Found 361.17750. [ꢂ]ꢃꢆꢄꢇꢅ= 8.30° (c = 0.27
in CHCl3).
1-(6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)-3-phenylpro-
pan-2-one (12c) According to the general procedure, a solution
of 11 mg (31.2 µmol) of cyclobutanol 11’c, 2.1 mg (3.12 µmol,
10 mol%) of [Ir(COD)Cl]2 and 11.1 mg (9.41 µmol, 30 mol%) of
(S)-DTBM-SegPhos in 0.4 ml of dry toluene was heated for 20 h
to 110 °C to give 10.0 mg (28.4 µmol, 91%) of 12c (78% ee)
after purification by preparative TLC (SiO2, cHex/EtOAc 5:1).
C23H28O3 (M = 352.47 g/mol). 1H NMR (500 MHz, CDCl3): δ
[ppm] = 7.31 – 7.28 (m, 2H), 7.25 – 7.23 (m, 1H), 7.13 – 7.12 (m,
Experimental Section
General procedure for the Ir-catalyzed cyclobutanol
cleavage.
A glass vial was charged under argon with
[Ir(COD)Cl]2 and (S)-DTBM-SegPhos and the vial was sealed
with a septum. After injection of a 0.1 M solution of the
respective cyclobutanol in dry toluene at r.t. the solution was first
stirred for 1.5 h and then heated to 85-110°C. The reaction
progress was monitored by TLC. Noteworthy, successful
reactions were always associated with a color change of the
solution from yellow-orange to dark red. Once the starting
material was fully consumed (or nor further conversion was
detected), the mixture was cooled to r.t. and a few milligrams of
QuadraSil AP® were added. After stirring for 30 min the mixture
was filtered over a short pad of silica and all volatiles were
removed under reduced pressure. The crude product was finally
subjected to column chromatography to yield the ketone
product (12) as a colorless oil.
2
2
2H), 3.82 (d, JH,H = 15.3 Hz, 1H), 3.75 (d, JH,H = 15.3 Hz, 1H),
2
2
3.64 (s, 3H), 2.83 (d, JH,H = 14.2 Hz, 1H), 2.65 (d, JH,H
=
14.2 Hz, 1H), 2.60 – 2.47 (m, 2H), 2.20 (s, 3H), 2.13 (s, 6H),
2.00 – 1.94 (m, 1H), 1.88 – 1.83 (m, 1H), 1.36 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ [ppm] = 206.8, 150.1, 147.1, 134.2, 129.7,
128.8, 128.3, 127.1, 126.2, 123.0, 117.5, 74.5, 60.6, 51.9, 50.6,
-1
ꢁ
31.6, 24.6, 20.7, 12.7, 12.2, 11.8. FT-IR (ATR) ꢀ [cm ] = 1714
(m), 1454 (m), 1403 (m), 1253 (s), 1088 (s). GC-MS [tR] =
11.828 min, m/z (%) = 352 ([M]+, 62), 219 (20), 203 (19), 179
(57), 135 (13), 91 (100), 65 (15). HRMS (ESI): Calc. 375.19307
[M + Na]+; Found 375.19326. [ꢂ]ꢃꢆꢄꢇꢅ = - 21.85° (c = 0.18 in
CHCl3).
(S)-1-(6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)propan-2-
one (12a). According to the general procedure, a solution of
150 mg (0.543 mmol) of cyclobutanol 11a, 3.7 mg (5.51 µmol,
1 mol%) of [Ir(COD)Cl]2 and 20.0 mg (16.96 µmol, 3 mol%) of
(S)-DTBM-SegPhos in 4.5 ml of dry toluene was heated for 18 h
to 70 °C to give 142 mg (0.514 mmol, 95%) of 12a (92% ee)
after purification by column chromatography (SiO2, cHex/EtOAc
12:1). C17H24O3 (M = 276.38 g/mol). 1H NMR (499 MHz, CDCl3):
1-(6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)-4-phenylbu-
tan-2-one (12d) According to the general procedure, a solution
of 11 mg (30.0 µmol) of cyclobutanol 11’d, 1.5 mg (2.23 µmol,
7 mol%) of [Ir(COD)Cl]2 and 6.7 mg (5.68 µmol, 19 mol%) of (S)-
DTBM-SegPhos in 0.5 ml of dry toluene was heated for 2 h to
100 °C and 2 h to 110 °C to give 10 mg (27.3 µmol, 91%) of 12d
(84% ee) after purification by column chromatography (SiO2,
cHex/EtOAc 35:1). C24H30O3 (M = 366.50 g/mol). 1H NMR
(500 MHz, CDCl3): δ [ppm] = 7.27 – 7.24 (m, 2H), 7.18 – 7.14 (m,
2
δ [ppm] = 3.63 (s, 3H), 2.79 (d, JH,H = 14.0 Hz, 1H), 2.64 (d,
2JH,H = 14.0 Hz, 1H), 2.61 – 2.53 (m, 2H), 2.22 (s, 3H), 2.19 (s,
9
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10.1002/chem.202004843
Chemistry - A European Journal
FULL PAPER
2
3H), 3.63 (s, 3H), 2.91 – 2.77 (m, 4H), 2.74 (d, JH,H = 14.0 Hz,
heated for 4 h to 110 °C to give 11 mg (27.7 µmol, 55%) of 12h
(93% ee) after purification by column chromatography (SiO2,
cHex/EtOAc 10:1). C25H32O4 (M = 396.53 g/mol). 1H NMR
(600 MHz, CDCl3): δ [ppm] = 7.34 – 7.27 (m, 5H), 4.49 (s, 2H),
2
1H), 2.61 (d, JH,H = 14.0 Hz, 1H), 2.60 – 2.50 (m, 2H), 2.17 (s,
3H), 2.13 (s, 3H), 2.05 (s, 3H), 1.97 – 1.92 (m, 1H), 1.87 – 1.82
(m, 1H), 1.33 (s, 3H). 13C NMR (125 MHz, CDCl3): δ [ppm] =
208.8, 150.0, 147.1, 141.2, 128.6, 128.5, 128.3, 126.2, 126.2,
123.0, 117.4, 74.4, 60.6, 51.9, 46.5, 31.6, 29.7, 24.6, 20.7, 12.7,
3
4
3.72 (td, JH,H = 6.3 Hz, JH,H = 4.1 Hz, 2H), 3.63 (s, 3H), 2.86 –
2
2.74 (m, 3H), 2.69 (d, JH,H = 14.4 Hz, 1H), 2.62 – 2.52 (m, 2H),
ꢁ
12.1, 11.8. FT-IR (ATR) ꢈ [cm-1] = 2927 (m), 1711 (m), 1454 (s),
2.18 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H), 2.00 – 1.96 (m, 1H), 1.88
– 1.84 (m, 1H), 1.35 (s, 3H). 13C NMR (150 MHz, CDCl3): δ
[ppm] = 208.0, 150.0, 147.1, 138.3, 128.5, 128.3, 127.8, 127.8,
1403 (m), 1252 (s), 1088 (s), 1062 (m), 1009 (m), 699 (m). GC-
MS [tR] = 12.293 min, m/z (%) = 366 ([M]+, 100), 257 (13), 234
(18), 219 (26), 203 (32), 179 (79), 105 (32), 91 (62). HRMS
(ESI): Calc. 389.20872 [M + Na]+; Found 389.20879. [ꢂ]ꢃꢆꢇꢄꢅ
126.2, 123.1, 117.5, 74.3, 73.3, 65.4, 60.5, 52.3, 44.9, 31.5, 24.6,
-1
ꢁ
=
20.7, 12.7, 12.1, 11.8. FT-IR (ATR) ꢈ [cm ] = 1711 (m),
- 27.58° (c = 0.33 in CHCl3).
1454 (m), 1403 (m), 1252 (m), 1088 (s), 1062 (m), 1007 (m),
736 (m), 698 (m). GC-MS [tR] = 12.929 min, m/z (%) = 396 ([M]+,
97), 281 (16), 255 (12), 217 (78), 203 (46), 179 (53), 135 (14),
105 (19), 91 (100), 77 (27). HRMS (ESI): Calc. 419.21928
[M + Na]+; Found 419.21948. [ꢂ]ꢃꢆꢄꢇꢅ = -3.64° (c = 0.17 in CHCl3).
4-((tert-Butyldimethylsilyl)oxy)-1-(6-methoxy-2,5,7,8-tetrame-
thyl-chroman-2-yl)butan-2-one (12e) According to the general
procedure, a solution of 15 mg (35.7 µmol) of cyclobutanol 11e,
1.3 mg (1.94 µmol, 5 mol%) of [Ir(COD)Cl]2 and 6.5 mg
(5.51 µmol, 15 mol%) of (S)-DTBM-SegPhos in 0.5 ml of dry
toluene was heated for 2 h to 85 °C, 1 h to 90 °C and 1 h to
95 °C to give 15 mg (35.7 µmol, 99%) of 12e (92% ee) after
purification by column chromatography (SiO2, cHex/EtOAc 50:1).
C24H40O4Si (M = 420.67 g/mol). 1H NMR (500 MHz, CDCl3): δ
2-((tert-Butyldimethylsilyl)oxy)octan-4-one (29) According to
the general procedure, a solution of 30 mg (0.116 mmol) of
cyclobutanol 26, 2.4 mg (3.57 µmol, 3 mol%) of [Ir(COD)Cl]2 and
12.5 mg (10.60 µmol, 9 mol%) of (S)-DTBM-SegPhos in 0.6 ml
of dry toluene was heated for 4 h to 100 °C to give 24 mg
(0.093 mmol, 80%) of 29 (70% ee, determined after deprotection
of the alcohol) after purification by column chromatography (SiO2,
cHex/EtOAc 100:1). C14H30O2Si (M = 258.48 g/mol). 1H NMR
(500 MHz, CDCl3): δ [ppm] = 4.32 – 4.26 (m, 1H), 2.63 (dd, 2JH,H
[ppm] = 3.86 (t, 3JH,H = 6.3 Hz, 2H), 3.63 (s, 3H), 2.80 (d, 2JH,H
=
14.5 Hz, 1H), 2.76 – 2.64 (m, 3H), 2.60 – 2.53 (m, 2H), 2.19 (s,
3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.02 – 1.96 (m, 1H), 1.90 – 1.84
(m, 1H), 1.35 (s, 3H), 0.85 (s, 9H), 0.02 (s, 3H), 0.02 (s, 3H).
13C NMR (125 MHz, CDCl3): δ [ppm] = 208.7, 150.0, 147.1,
128.3, 126.1, 123.1, 117.5, 74.3, 60.5, 58.8, 52.4, 47.6, 31.5,
3
= 15.0 Hz, JH,H = 7.3 Hz, 1H), 2.44 – 2.41 (m, 2H), 2.38 (dd,
3
2JH,H = 15.0 Hz, JH,H = 5.1 Hz, 1H), 1.57 – 1.50 (m, 2H), 1.34 –
3
3
ꢁ
26.0, 24.6, 20.7, 18.3, 12.7, 12.1, 11.8, -5.3. FT-IR (ATR) ꢈ
1.27 (m, 2H), 1.16 (d, JH,H= 6.1 Hz, 3H), 0.90 (t, JH,H = 7.4 Hz,
3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H). 13C NMR (125 MHz,
[cm-1] = 2953 (m), 2930 (m), 2887 (m), 2857 (m), 1713 (m), 1462
(m), 1404 (m), 1254 (s), 1090 (s), 836 (m), 777 (m). GC-MS
[tR] = 11.834 min, m/z (%) = 420 ([M]+, 13), 219 (100), 203 (13),
179 (18), 145 (6), 115 (5), 91 (6), 75 (10), 41 (6). HRMS (ESI):
Calc. 443.25881 [M + Na]+; Found 443.25887. [ꢂ]ꢆꢃꢄꢇꢅ = 9.74°
(c = 0.38 in CHCl3).
CDCl3): δ [ppm] = 210.3, 65.8, 52.4, 44.5, 25.9, 25.7, 24.2, 22.4,
-1
ꢁ
18.1, 14.0, -4.4, -4.8. FT-IR (ATR) ꢈ [cm ] = 1715 (m), 1254 (m),
1134 (m), 1060 (m), 1040 (m), 1005 (m), 993 (m), 835 (s), 809
(m), 776 (s). GC-MS [tR] = 7.009 min, m/z (%) = 243 (2), 201
(91), 157 (100), 115 (12), 101 (18), 75 (88), 57 (22), 41 (46).
HRMS (EI): Calc. 201.1311 [M-tBu]+; Found 201.14. [ꢂ]ꢃꢆꢇꢄꢅ
=
1-(6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)-4-(methoxy-
methoxy)butan-2-one (12g) According to the general
procedure, a solution of 15 mg (42.8 µmol) of cyclobutanol 11’g,
2.0 mg (2.98 µmol, 7 mol%) of [Ir(COD)Cl]2 and 12.0 mg
(10.2 µmol, 23 mol%) of (S)-DTBM-SegPhos in 0.6 ml of dry
toluene was heated for 4.5 h to 110 °C to give 7 mg (20.0 µmol,
47%) of 12g (83% ee) after purification by column chroma-
tography (SiO2, cHex/EtOAc 9:1). C20H30O5 (M = 350.46 g/mol).
1H NMR (500 MHz, CDCl3): δ [ppm] = 4.59 (s, 2H), 3.78 (t, 3JH,H
= 6.2 Hz, 2H), 3.63 (s, 3H), 3.34 (s, 3H), 2.87 – 2.73 (m, 3H),
23.79° (c = 0.33 in CHCl3).
4-((tert-Butyldimethylsilyl)oxy)-4-methyloctan-2-one
(30)
According to the general procedure, a solution of 45 mg
(0.165 mmol) of cyclobutanol 28, 2.2 mg (3.28 µmol, 2 mol%) of
[Ir(COD)Cl]2 and 11.7 mg (9.92 µmol, 6 mol%) of (S)-DTBM-
SegPhos in 0.8 ml of dry toluene was heated for 5.5 h to 100 °C
to give 44 mg (0.161 mmol, 98%) of 30 (85% ee) after
purification by column chromatography (SiO2, cHex/EtOAc 80:1).
C15H32O2Si (M = 272.50 g/mol). 1H NMR (500 MHz, CDCl3): δ
2
2
2
2.69 (d, JH,H = 14.3 Hz, 1H), 2.61 – 2.57 (m, 2H), 2.19 (s, 3H),
[ppm] = 2.61 (d, JH,H = 13.6 Hz, 1H), 2.48 (d, JH,H = 13.6 Hz,
2.14 (s, 3H), 2.09 (s, 3H), 2.01 – 1.96 (m, 1H), 1.90 – 1.85 (m,
1H), 1.36 (s, 3H). 13C NMR (125 MHz, CDCl3): δ [ppm] = 207.7,
150.0, 147.1, 128.3, 126.2, 123.0, 117.5, 96.7, 74.3, 62.7, 60.5,
1H), 2.19 (s, 3H), 1.57 – 1.53 (m, 2H), 1.39 – 1.20 (m, 4H), 1.31
(s, 3H), 0.90 (t, JH,H = 7.1 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H). 13C NMR (125 MHz, CDCl3): δ [ppm] = 208.7, 75.6,
3
55.4, 52.3, 44.8, 31.5, 24.5, 20.7, 12.7, 12.1, 11.8. FT-IR (ATR)
55.0, 43.0, 32.8, 28.1, 26.6, 26.1, 23.3, 18.4, 14.2, -1.7. FT-IR
-1
-1
ꢁ
ꢁ
ꢈ [cm ] = 1714 (m), 1457 (m), 1253 (s), 1151 (m), 1111 (s),
(ATR) ꢈ [cm ] = 2957 (m), 2930 (m), 1712 (m), 1253 (m), 1075
1089 (s), 1059 (s), 1041 (s), 1017 (m). GC-MS [tR] = 11.273 min,
m/z (%) = 350 ([M]+, 100), 288 (15), 255 (13), 219 (49), 203 (50),
179 (52), 135 (14), 91 (15), 45 (29). HRMS (ESI): Calc.
373.19855 [M + Na]+; Found 373.19859. [ꢂ]ꢃꢆꢄꢇꢅ = 3.87° (c = 0.16
in CHCl3).
(m), 1028 (m), 1005 (m), 834 (s), 772 (s). GC-MS [tR] =
6.757 min, m/z (%) = 239 (8), 215 (15), 157 (33), 132 (10), 115
(53), 75 (79), 57 (100). HRMS (EI): Calc. 215.1467 [M-tBu]+;
ꢆꢇ
Found 215.17. [ꢂ]
= 28.41° (c = 0.21 in CHCl3).
ꢃꢄꢅ
(R,E)-1-((S)-6-Methoxy-2,5,7,8-tetramethylchroman-2-yl)-4,8,
12-trimethyltridec-4-en-2-one (12r). According to the general
procedure, a solution of 54 mg (0.118 mmol) of cyclobutanol 11r,
4.0 mg (5.95 µmol, 5 mol%) of [Ir(COD)Cl]2 and 21.0 mg
(17.81 µmol, 15 mol%) of (S)-DTBM-SegPhos in 0.8 ml of dry
toluene was heated for 2 h to 85 °C, 1 h to 90 °C and 0.5 h to
4-(Benzyloxy)-1-(6-methoxy-2,5,7,8-tetramethylchroman-2-
yl)-butan-2-one (12h) According to the general procedure, a
solution of 20 mg (50.4 µmol) of cyclobutanol 11’h, 2.7 mg
(4.01 µmol, 8 mol%) of [Ir(COD)Cl]2 and 14.0 mg (11.87 µmol,
24 mol%) of (S)-DTBM-SegPhos in 0.6 ml of dry toluene was
10
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10.1002/chem.202004843
Chemistry - A European Journal
FULL PAPER
Cramer, Asymmetric Transformations via C–C Bond Cleavage,
published in: C-C Bond Activation, Vol. 346 (Ed.: G. Dong), Springer-
Verlag, 2014, 163 - 193; e) Cleavage of Carbon-Carbon Single Bonds
by Transition Metals (Eds.: M. Murakami, N. Chatani), Wiley-VCH, 2016.
T. Seiser, N. Cramer, Org. Biomol. Chem. 2009, 7, 2835 - 2840.
P. R. Khoury, J. D. Goddard, W. Tam, Tetrahedron 2004, 60, 8103 -
8112.
95 °C to give 53 mg (0.116 mmol, 98%) of 12q (97% de) after
purification by column chromatography (SiO2, cHex/EtOAc 80:1).
The diastereomeric purity was determined after conversion to α-
tocopherol methyl ether (see Supporting Information). C30H48O3
(M = 456.71 g/mol). 1H NMR (500 MHz, CDCl3): δ [ppm] = 5.18 –
5.15 (m, 1H), 3.63 (s, 3H), 3.14 (d, 2JH,H = 14.8 Hz, 1H), 3.10 (d,
[2]
[3]
2
2JH,H = 14.8 Hz, 1H), 2.81 (d, JH,H = 14.4 Hz, 1H), 2.62 – 2.53
[4]
[5]
M. Murakami, H. Amii, Y. Ito, Nature 1994, 370, 540 - 541.
a) N. Ishida, W. Ikemoto, M. Murakami, Org. Lett. 2012, 14, 3230 -
3232; b) N. Ishida, W. Ikemoto, M. Murakami, J. Am. Chem. Soc. 2014,
136, 5912 - 5915.
(m, 3H, H-1’b), 2.19 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 2.04 –
1.96 (m, 3H, H-3a), 1.89 – 1.84 (m, 1H), 1.60 (s, 3H), 1.52 (sept.,
3JH,H = 6.7 Hz, 1H), 1.35 (s, 3H), 1.40 – 1.19 (m, 5H), 1.15 –
1.05 (m, 4H), 0.87 – 0.85 (m, 9H, H-2’’). 13C NMR (125 MHz,
CDCl3): δ [ppm] = 208.3, 150.0, 147.2, 130.6, 128.5, 128.2,
126.1, 123.0, 117.5, 74.4, 60.5, 55.9, 50.1, 39.5, 37.3, 36.9, 32.6,
[6]
[7]
M. Murakami, K. Takahashi, H. Amii, Y. Ito, J. Am. Chem. Soc. 1997,
119, 9307 - 9308.
W. D. Jones, Mechanistic Studies of Transition Metal-Mediated C–C
Bond Activation, published in: C-C Bond Activation, Vol. 346 (Ed.: G.
Dong), Springer-Verlag, Berlin, Heidelberg 2014, 1 - 32.
T. Xu, A. Dermenci, G. Dong, Transition Metal-Catalyzed C–C Bond
Activation of Four-Membered Cyclic Ketones, published in: C-C Bond
Activation, Vol. 346 (Ed.: G. Dong), Springer-Verlag, Berlin, Heidelberg,
2014, 233 - 258.
31.5, 28.1, 25.8, 24.9, 24.6, 22.9, 22.8, 20.7, 19.7, 16.5, 12.7,
-1
ꢁ
12.1, 11.8. FT-IR (ATR) ꢈ [cm ] = 2951 (s), 2926 (s), 2869 (m),
[8]
1713 (m), 1458 (s), 1404 (m), 1253 (s), 1089 (s). GC-MS [tR] =
13.671 min, m/z (%) = 456 ([M]+, 40), 234 (23), 219 (100), 203
(90), 179 (92). HRMS (ESI): Calc. 479.34957 [M + Na]+; Found
ꢆꢇ
[9]
X H. Zhao, X. Fan, J. Yu, C. Zhu, J. Am. Chem. Soc. 2015, 137, 3490 -
3493.
479.34946. [ꢂ] = 29.4 ° (c = 0.36 in CHCl3).
ꢃꢄꢅ
[10] a) L. Huan, C. Zhu, Org. Chem. Front. 2016, 3, 1467 - 1471; b) R. Ren,
H. Zhao, L. Huan, C. Zhu, Angew. Chem. Int. Ed. 2015, 54, 12692 -
12696.
(S)-1-(6-Methoxy-2,8-dimethylchroman-2-yl)propan-2’-one
(39). According to the general procedure, a solution of 71 mg
(0.285 mmol) of cyclobutanol 38, 9.5 mg (14.3 µmol, 5 mol%) of
[Ir(COD)Cl]2 and 50.5 mg (42.8 µmol, 15 mol%) of (S)-DTBM-
SegPhos in 2.8 ml of dry toluene was heated for 21 h to 45 °C to
give 66 mg (0.266 mmol, 93%) of 39 (95% ee) after purification
by column chromatography (SiO2, cHex/EtOAc 15:1). C15H20O3
[11] a) A. Ziadi, A. Correa, R. Martin, Chem. Commun. 2013, 49, 4286 -
4288; b) L. Chen, F.-N. Sun, Y.-L. Sun, Z. Xu, Z.-J. Zheng, Y.-M. Cui, J.
Cao, L.-W. Xu, Adv. Synth. Catal. 2018, 360, 411 - 415; c) Q. Wang, R.
Chen, J. Lou, D. H. Zhang, Y.-G. Zhou, Z. Yu, ACS Catal. 2019, 9,
11669 - 11675.
[12] a) Y. Xia, Z. Liu, Z. Liu, R. Ge, F. Ye, M. Hossain, Y. Zhang, J. Wang, J.
Am. Chem. Soc. 2014, 136, 3013 - 3015; b) A. Masarwa, M. Weber, R.
Sarpong, J. Am. Chem. Soc. 2015, 137, 6327 - 6334.
1
(M = 248.32 g/mol). H NMR (600 MHz, CDCl3): δ [ppm] = 6.58
(d, 4JH,H = 2.6 Hz, 1H), 6.45 (d, 4JH,H = 2.6 Hz, 1H), 3.73 (s, 3H),
2.80 (d, 2JH,H = 14.0 Hz, 1H), 2.77 – 2.67 (m, 2H), 2.63 (d, 2JH,H
14.0 Hz, 1H), 2.23 (s, 3H), 2.16 (s, 3H), 1.94 (ddd, JH,H
=
=
=
[13] a) S. Matsumura, Y. Maeda, T. Nishimura, S. Uemura, J. Am. Chem.
Soc. 2003, 125, 8862 - 8869; for a recent application of the Pd-
catalyzed opening of cyclobutanols in total synthesis, see: b) I.
Kerschgens, A. R. Rovira, R. Sarpong, J. Am. Chem. Soc. 2018, 140,
9810 - 9813.
2
3
3
2
13.5 Hz, JH,H = 8.0 Hz, JH,H = 6.5 Hz, 1H), 1.84 (dt, JH,H’
3
13.5 Hz, JH,H = 6.5 Hz, 1H), 1.35 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ [ppm] = 207.9, 152.7, 145.4, 127.4, 120.8, 115.3,
[14] a) T. Matsuda, M. Shigeno, M. Murakami, J. Am. Chem. Soc. 2007,
129, 12086 - 12087; for a more recent mechanistic study on Rh-
catalyzed stereoselective C-C/C-H activation of tert-cyclobutanols, see
also: b) H. Yu, C. Wang, Y. Yang, Z.-M. Dang, Chem. Eur. J. 2014, 20,
3839 - 3848.
111.2, 74.9, 55.8, 53.0, 32.4, 31.7, 24.4, 22.7, 16.5. FT-IR (ATR)
-1
ꢁ
ꢀ [cm ] = 2971 (m), 2936 (m), 1705 (m), 1481 (s), 1453 (m),
1440 (m), 1358 (m), 1207 (s), 1175 (m), 1149 (s), 1098 (s), 1057
(s), 950 (m), 914 (m), 855 (m). GC-MS m/z (%) = 248 ([M]+,
100), 230 (20), 215 (25), 175 (45), 150 (70), 115 (21), 91 (77),
[15] T. Seiser, N. Cramer, J. Am. Chem. Soc. 2010, 132, 5340 - 5341.
[16] a) T. Matsuda, M. Shigeno, M. Makino, M. Murakami, Org. Lett. 2006, 8,
3379 - 3381.; b) N. Ishida, Y. Nakanishi, M. Murakami, Angew. Chem.
Int. Ed. 2013, 52, 11875 - 11878; c) A. Yada, S. Fujita, M. Murakami, J.
Am. Chem. Soc. 2014, 136, 7217 - 7220.
77 (50), 65 (21). HRMS (ESI): Calc. 271.1304657 [M + Na]+;
ꢆꢇ
Found 271.13080. [ꢂ] = - 6.9 ° (c = 0.42 in CHCl3).
ꢃꢄꢅ
[17] a) N. Cramer, T. Seiser, Synlett 2011, 4, 449 - 460; b) N. Cramer, T.
Seiser, Quaternary Stereogenic Centers by Enantioselective β-Carbon
Eliminations from tert-Cyclobutanols, published in Asymmetric
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Acknowledgements
Support of this work by the University of Cologne is gratefully
acknowledged. We sincerely thank Thomas Netscher from DSM
Nutritional Products for the determination of the enantiomeric
purity of samples of α-tocopherol methyl ether by means of
HPLC. We also thank Nils Schlörer and the local NMR facility for
the excellent service and help in context of NMR-based ee
measurements. Additionally, we thank the computing center of
the University of Cologne (RRZK) for providing CPU time on the
DFG-funded supercomputer CHEOPS.
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Keywords: Asymmetric catalysis • Iridium • C-C bond activation
• Cyclobutanols • Desymmetrization • Deuteration
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12
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Entry for the Table of Contents
MeO
MeO
cat. [Ir(COD)Cl]2/L*
O
OD
L* = (S)-DTBM-SegPhos
O
R
O
R
=
D
P
up to 95% ee
+III
MeO
KIE = 2.4
D
P
Ir
Cl
oxidative addition
C-C bond activation
β-elimination
reductive elimination
O
O
R
Iridium behaves differently! Unexpectedly, the Ir-catalyzed cleavage of cyclobutanols to give ß-chiral ketones proceeds through a
different mechanism as compared to related Rh-catalyzed reactions. This was shown by deuteration experiments, kinetic isotope
effect measurements and DFT calculations. The developed method for the catalytic-enantioselective desymmetrization is of particular
value in the synthesis of chromane natural products from readily accessible spiro-cyclobutanols.
13
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