Rhodium-catalyzed C-C bond cleavage: Construction of acyclic methyl substituted quaternary stereogenic centers

Article abstract of DOI:10.1021/ja101469t

A rhodium-catalyzed enantioselective insertion into the C?C bond of tert-cyclobutanols and subsequent proto-demetalation provides access to methyl substituted quaternary stereogenic centers in excellent yields and enantioselectivities. The reaction was used for a synthesis of (S)-4-ethyl-4-methyl-octane, the simplest saturated hydrocarbon with a quaternary stereogenic center.

Full text of DOI:10.1021/ja101469t

Published on Web 03/26/2010
Rhodium-Catalyzed C-C Bond Cleavage: Construction of Acyclic Methyl
Substituted Quaternary Stereogenic Centers
Tobias Seiser and Nicolai Cramer*
Laboratory for Organic Chemistry, ETH Zurich, HCI H 304, CH-8093 Zurich, Switzerland
Received February 19, 2010; E-mail: nicolai.cramer@org.chem.ethz.ch
The catalytic and selective functionalization of carbon-hydrogen
and carbon-carbon bonds by transition-metal complexes is a
significant challenge for organometallic chemistry. The lack of
required prefunctionalizations renders such processes ecologi-
cally and economically attractive. C-H activations are a vibrant
and very active research area with impressive progress.1
Compared to C-H activations, the development of related C-C
activation reactions lags behind.2 Examples for efficient enan-
tioselective processes are scarce.3 Hartwig and co-workers
recently showed that triarylcarbinols and rhodium complexes
are in equilibrium with the corresponding diarylketones and aryl-
rhodium species.4 Substrates having a stronger bias toward this
ꢀ-carbon elimination pathway can provide an attractive entry
into highly reactive organometallic species. In this respect,
strained tertiary alcohols are performing substrates to generate
alkyl metals.5 Especially symmetrically substituted cyclobutane
derivatives are an attractive substrate class, as a selective
insertion into one of the two enantiotopic C-C bonds of the
cyclobutane ring opens opportunities for enantioselective activa-
tions. We6 and others7 investigated this reactivity to access
transient enantioenriched organometallic species and subse-
quently capitalized on their reactivity in downstream reactions.
The significance and vast occurrence of methyl substituted
quaternary stereogenic centers in natural products prompted us
to explore the applicability of rhodium-catalyzed ꢀ-carbon
cleavages for their selective construction.8 Murakami obtained
linear ketones with racemic tertiary methyl substituents by
rhodium(I)-catalyzed addition of arylboronic acids to cyclobu-
tanones.9 This process was extended toward an enantioselective
construction of benzocyclopentanones and dihydrocoumarines
with cyclic stereocenters using an intramolecular addition.7c,d
Herein we report the construction of acyclic quaternary stereo-
genic centers from cyclobutanol derivatives using a chiral
rhodium(I) catalyst. We anticipated accessing crucial rhodium
cyclobutanoxide 2 through ligand exchange of cyclobutanol 1
and a rhodium(I) hydroxy complex. Subsequent enantioselective
ꢀ-carbon cleavage of 2 would lead to alkyl rhodium(I) species
3, that might hydrolyze in the presence of a suitable proton
source or 1 itself (Scheme 1).
ligands led to the identification of DTBM-Segphos (L8) as the
most selective ligand, providing ketone 4a in 87% ee (Entry
8).10 Using dioxane as solvent and 15 equivalents of water further
improved the selectivity to 92% ee (entries 9-11).
Table 1. Optimization of the C-C Cleavage/Protonation Reactiona
entry
ligand L*
yield [%]b
ee [%]c
1
2
3
4
5
6
7
(R)-Binap (L1)
(R)-H8-Binap (L2)
(R)-MeOBiphep (L3)
(R)-Segphos (L4)
(R)-Difluorphos (L5)
(R)-DM-Segphos (L6)
(R)-DTBM-MeOBiphep (L7)
(R)-DTBM-Segphos (L8)
(R)-DTBM-Segphos (L8)
(R)-DTBM-Segphos (L8)
(R)-DTBM-Segphos (L8)
93
96
94
99
83
87
94
93
93
98
99
7
10
16
20
19
29
79
87
91
90
92
8
9d
10e
11d e
,
a Conditions: 0.1 mmol 1a, 2.5 mol % [Rh(OH)(cod)]2, 6.0 mol %
L*, toluene (0.25 M), 110 °C, 2 h. b Isolated product. c ee’s were
determined by HPLC with a chiral stationary phase. d 15 equiv of H2O.
e Dioxane.
With these optimized conditions, we then explored the scope
of the process (Table 2). The selectivity of the cleavage is largely
independent from the substitution pattern on the 1-position of
the cyclobutanol (Entries 1-5). Cyclobutanols bearing aromatic
substituents in the 3-position generally give rise to indanols
through a 1,4-rhodium shift/1,2-addition sequence.6b For ex-
ample, indanol 5 was obtained exclusively with Difluorphos (L5)
from 1g (entry 8). Notably, the bulky DTBM-MeOBiphep (L7)
mostly suppresses this pathway and instead provides 4g in good
yields (entry 9). A 2-pyridyl substituent as well blocks this 1,4-
Rh shift by forming a stable chelate with the nitrogen atom and
providing the ketones 4h and 4i (entries 10-12). Conforma-
tionally restricted spirocyclic substrates yield the linear ketone
4e and 4f (entries 6-7).
We subsequently applied this reaction for an enantioselective
synthesis of 4-ethyl-4-methyl-octane (7), the simplest unbranched
saturated hydrocarbon with a quaternary stereogenic center
(Scheme 2).11 1j provides under the aforementioned conditions
ketone 4j in 99% yield and an ee-value of 93% (entry 13).
Additionally, 1j can be directly converted Via a one pot reaction
into its dithiane derivative 6 in 86% yield over both steps.
Subsequent Raney-nickel promoted desulfurization gave (S)-4-
ethyl-4-methyl-octane (7) in 99% yield.
Scheme 1. Rh-Catalyzed Ring-Opening/Protonation Process
Heating trans-1a in the presence of catalytic amounts of [Rh(OH)-
(cod)]2 and (R)-Binap (L1) in toluene resulted in the anticipated
ring-opening and gave ketone 4a in excellent yield albeit very
poor enantioselectivity (Table 1, entry 1). A short survey of chiral
Deuterium-labeling experiments of trans-1a revealed that the
protonation does not occur as originally proposed at the alkyl-
9
5340 J. AM. CHEM. SOC. 2010, 132, 5340–5341
10.1021/ja101469t  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the C-C Cleavage/Protonation Processa
Scheme 3. A 1,3-Rh Shift Leads to Diastereoselective Deuteration
substituted quaternary stereogenic centers in excellent enantiose-
lectivities. Its utility was demonstrated by a synthesis of (S)-4-ethyl-
4-methyl-octane, the simplest hydrocarbon with a quaternary
stereogenic center. Further ongoing research in this direction is
directed to the development of methods for the activation of C-C
bonds enabling novel and useful transformations.
Acknowledgment. We thank the SNF (21-119750.01), Solvias
for MeOBiphep ligands, Takasago for Segphos ligands, and Prof.
E. M. Carreira for generous support. The Fonds der Chemischen
Industrie is acknowledged for a Liebig-Fellowship to N.C.
Supporting Information Available: Experimental procedures and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Scheme 2. Synthesis of (S)-4-Ethyl-4-methyl-octane (7)a
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a Conditions: (a) 2.5 mol % [Rh(OH)(cod)]2, 6 mol % L8, toluene, 110
°C, 4 h, then BF3 ·Et2O, propane-1,3-dithiol, 23 °C, 12 h; (b) Raney-nickel,
MeOH, 23 °C, 2 h.
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a more stable rhodium enolate is formed Via a 1,3-rhodium shift.7c,12
The subsequent deuteration quench proceeded with a diastereomeric
ratio of 86:14 in favor of the depicted (2S,3R) isomer d-4a. Subjecting
cis-1a to the identical reaction conditions using ent-L8 as ligand gave
diastereomer (2R,3R)-d-4a with a dr of 15:85, indicating a remarkably
selective catalyst controlled protonation.13
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In summary, we demonstrated a rhodium-catalyzed C-C bond
cleavage/protonation sequence providing an entry to acyclic methyl
JA101469T
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J. AM. CHEM. SOC. VOL. 132, NO. 15, 2010 5341