Enantioselective insertion of a carbenoid carbon into a C-C bond to expand cyclobutanols to cyclopentanols

Article abstract of DOI:10.1021/ja502229c

When a carbenoid species generated from a tosylhydrazone is reacted with a cyclobutanol in the presence of a chiral rhodium catalyst, a C-C single bond of the cyclobutanol is cleaved, and the carbenoid carbon is inserted therein to furnish a ring-expanded cyclopentanol in an enantioselective manner.

Full text of DOI:10.1021/ja502229c

Communication
pubs.acs.org/JACS
Enantioselective Insertion of a Carbenoid Carbon into a C−C Bond To
Expand Cyclobutanols to Cyclopentanols
Akira Yada, Shoichiro Fujita, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
Table 1. Rhodium-Catalyzed Reaction of Cyclobutanol 1a
with N-Tosylhydrazone 2a
a
ABSTRACT: When a carbenoid species generated from a
tosylhydrazone is reacted with a cyclobutanol in the
presence of a chiral rhodium catalyst, a C−C single bond
of the cyclobutanol is cleaved, and the carbenoid carbon is
inserted therein to furnish a ring-expanded cyclopentanol
in an enantioselective manner.
traightforward methods to construct carbon frameworks
Swith fewer steps are increasingly important. This goal has
largely driven the recent rise of new chemistry to activate
nonpolar C−H1 and C−C2 σ-bonds. It would significantly
streamline a synthetic pathway if a C−C single bond is cleaved
and an unsaturated organic compound is inserted therein to
directly extend the carbon skeleton with two C−C single bonds
newly formed. There have appeared in the past decade such
examples that incorporate alkenes,3 alkynes,4 and carbon
monoxide5,6 in inter- and intramolecular fashions. They may
be called as “cut-and-sew” protocols.2a We now report a new
reaction which expands cyclobutanols to cyclopentanols with
control of stereochemistry through insertion of a carbenoid
carbon7 into a C−C single bond8 of the four-membered
ring.9,10
b
b
yield, %
yield, %
c
entry
MOtBu
3a + 4a
3a:4a
5
1
2
3
LiOtBu
NaOtBu
KOtBu
59
82
31
81:19
86:14
85:15
32
9
56
a
1a (25 μmol), 2a (37.5 μmol), MOtBu (62.5 μmol), [RhOH(cod)]2
(5.0 mol %), rac-BINAP (11.0 mol %). NMR yield. Estimated by
b
c
GC.
Scheme 1. Possible Reaction Mechanism
We took the N-tosylhydrazone 2a as the carbenoid precursor
and reacted it with cyclobutanol 1a in the presence of an alkali
metal tertiary butoxide and catalytic amounts of [RhOH(cod)]2
and rac-BINAP. A diastereomeric mixture of cyclopentanols 3a
and 4a11 was obtained along with ring-opened product 5
(Table 1). When NaOtBu was used as the base to generate a
carbenoid species from 2a, the cyclopentanol 3a in which the
hydroxy and p-tolyl substituents were trans was produced in
preference to the other diastereomer 4a (86:14) in 82% yield
and 5 was formed only in 9% (entry 2).12
A possible reaction mechanism is illustrated in Scheme 1.
The substrate 1 is transferred onto rhodium(I) to generate
rhodium alkoxide A. The four-membered ring is opened by β-
carbon elimination, giving γ-keto alkylrhodium intermediate B
(Step 1). The diazo compound, generated from 2 and the base
NaOtBu, reacts with B to furnish (alkyl)(carbene)rhodium
complex C.13 The alkyl group migrates onto the carbenoid
carbon to form D (Step 2),7d,e which further undergoes
intramolecular addition to the carbonyl group in a five-exo
mode (Step 3). A diastereoselectivity arises during Step 3 upon
differentiation of the π-faces of the carbonyl group. The
resulting cyclopentoxyrhodium E is protonated with 1 to
furnish the products 3 and 4 with regeneration of A.
Induction of enantioselectivity in the ring-expanded products
by chiral ligands on rhodium was also investigated (Table 2).
(R)-BINAP favored the production of the diastereomer 3a over
4a and induced moderate enantioselectivities with the both
diastereomers (entry 1). Although biphenyl-type ligands, e.g.,
(R)-SEGPHOS (L1) and (R)-DIFLUORPHOS exhibited
Received: March 4, 2014
Published: April 25, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 2. Enantioselective Syntheses of Cyclopentanols via
Carbene Insertion
Table 3. Reaction of Various Cyclobutanols 1 with 2a
a
b
yield, %
% ee
c
entry
chiral ligand
(R)-BINAP
3a + 4a
3a:4a
3a/4a
1
2
3
4
76
86
84
89
86:14
84:16
84:16
12:88
80/65
95/93
96/90
96/99
(R)-SEGPHOS (L1)
(R)-DIFLUORPHOS
(R,S)-PPF-PtBu2 (L2)
a
1a (25 μmol), 2a (37.5 μmol), NaOtBu (62.5 μmol), [RhOH(cod)]2
b
(5.0 mol %), chiral ligand (11.0 mol %), toluene, 50 °C. NMR yield.
c
Estimated by GC.
similar diastereoselectivities favoring 3a, the enantioselectivities
observed for the both diastereomers were considerably higher
(entries 2 and 3). On the other hand, L2 having a ferrocene
backbone exhibited an opposite preference for 4a versus 3a
(3a:4a = 12:88), and in particular, 99% ee was attained with the
major diastereomer 4a (entry 4).
Various cyclobutanols 1 were subjected to the reaction with
2a under the two different conditions using L1 and L2 (Table
3). Those bearing 4-methoxyphenyl, 4-trifluoromethylphenyl,
thienyl, and styryl groups successfully participated in the ring-
expansion reaction (entries 3−10).14 When the ligand L1 was
used, the diastereomers 3 were preferentially produced with
good enantioselectivities over 94% ee. On the other hand, the
ligand L2 furnished the other diastereomers 4 in preference to
3 with excellent enantioselectivities ranging 95−99% ee.
However, cyclobutanols having a phenyl group at the 3-
position gave indanols rather than cyclopentanols as the major
product.10b,c The reactions of cyclobutanols having one or no
alkyl (or aryl) substituent at the 3-position also failed, probably
due to a competitive process of β-hydride elimination.15
The use of N-tosylhydrazones derived from various aryl
aldehydes was also examined in the reaction with 1a (Table 4).
Methoxy, fluoro, and chloro substituents were all tolerated at
the 4-position of the aryl group, giving the corresponding
products in good yields with high enantioselectivities (entries
3−8). The results of Table 4 show an analogous stereochemical
dichotomy depending on the employed ligand (L1 or L2) to
those of Table 3. On the other hand, N-tosylhydrazones
derived from aliphatic aldehydes failed to give the desired
cyclopentanols, presumably because of the instability of alkyl
substituted carbenoid intermediates. The reaction with N-
tosylhydrazones derived from ketones was also sluggish due to
the lower reactivity of sterically hindered carbenoid species and
formed 5 predominantly.
a
1 (0.2 mmol), 2a (0.3 mmol), NaOtBu (0.5 mmol), [RhOH(cod)]2
b
(5.0 mol %), L1 or L2 (11.0 mol %). Isolated yield.
a
Table 4. Reactions of Various Hydrazones 2 with 1a
b
b
entry
2
L
3
4
c
1
L1
L2
L1
L2
L1
L2
L1
L2
59%, 96% ee
12%, 97% ee
66%, 97% ee
9%, 96% ee
42%, 96% ee
15%, 97% ee
63%, 96% ee
9%, 97% ee
15%, 94% ee
68%, 99% ee
9%, 95% ee
65%, 99% ee
3%, 95% ee
79%, 99% ee
11%, 93% ee
70%, 99% ee
R = H (2b)
3f
4f
2
3
4
5
6
R = OMe (2c)
R = F (2d)
3g
3h
3i
4g
4h
4i
In the case of symmetrical cyclobutanol cis-1f having a
tertiary carbon with two different substituents at the 3-position,
the mechanistic pathway contains three steps, each of which
creates a new chiral center. The ring-opening step (Step 1 in
Scheme 1) makes the all-carbon tertiary center at the 3-
position chiral. The second chiral center is created upon
intramolecular migratory insertion of a ring-opened alkyl group
onto the neighboring prochiral carbenoid carbon (Step 2). The
third chiral center is created upon cyclization by intramolecular
d
7
R = Cl (2e)
8
a
1a (0.2 mmol), 2 (0.3 mmol), NaOtBu (0.5 mmol), [RhOH(cod)]2
b
c
(5.0 mol %), L1 or L2 (11.0 mol %). Isolated yield. NaOMe was
used. N-Benzenesulfonylhydrazone was used.
d
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Journal of the American Chemical Society
Communication
nucleophilic addition to the carbonyl group (Step 3). When L1
was used as the ligand, a mixture of all four possible
diastereomers 3j, 3k, 4j, and 4k (ca. 69:12:15:4) was formed.16
In contrast, the use of (R)-DTBM-SEGPHOS gave only 3j
(50%) and 4j (9%),17 although the starting cyclobutanol cis-1f
was not fully converted (Scheme 2a).18 Of particular note was
the reaction mixture, which was further stirred at 50 °C for 24
h. Chromatographic purification furnished the cyclopentanols
3a and 4a. Their yields and enantioselectivities were
comparable to those obtained with the isolated 2a.
In summary, cyclobutanols are expanded to cyclopentanols
by insertion of a carbenoid carbon with control of stereo-
chemistries. Up to three chiral centers can be created in a
stereoselective way by the single reaction involving C−C bond
cleavage.
Scheme 2. Reactions of cis- and trans-3-Butyl-3-ethyl-1-
phenylcyclobutanols 1f
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectra data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
murakami@sbchem.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This manuscript is dedicated to Professor Armin de Meijere in
celebration of his 75th birthday. This work was supported in
part by a Grant-in-Aid for Scientific Research on Innovative
Areas “Molecular Activation Directed toward Straightforward
Synthesis” and a Grant-in-Aid for Young Scientists (B) from
MEXT, and the ACT-C program of the JST.
that an excellent enantioselectivity of 99% ee was observed for
the both diastereomers. This stereochemical outcome is
explained by assuming the following scenario. In Step 1, the
chiral ligand (R)-DTBM-SEGPHOS directs exclusive cleavage
of one of the enantiotopic C−C bonds.10d In Step 2, the chiral
phosphine ligand and the existing tertiary chiral center induce a
moderate stereoselectivity (ca. 85:15) to bring about two
diastereomers.19 In Step 3, the chiral ligand rather than the
existing two chiral centers dominates differentiation of the two
faces of the carbonyl group with almost complete selectivity. As
a result, only the two diastereomers are formed both with 99%
ee.
The other diastereomer trans-1f was also subjected to the
reaction with 2a using (R)-DTBM-SEGPHOS as the chiral
ligand. Only the two diastereomers 3k and 4k were produced
again, and their enantioselectivities were both 99% ee (Scheme
2b).18 The same scenario with that assumed for cis-1f accounts
for this result as well, and thus only the two diastereomers 3k
and 4k are formed both with 99% ee from trans-1f.
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