1,5-rhodium shift in rearrangement of N -arenesulfonylazetidin-3-ols into benzosultams

Article abstract of DOI:10.1021/ja410910s

Benzosultams are synthesized in an enantiopure form starting from α-amino acids through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols. Mechanistically, this reaction involves C-C bond cleavage by β-carbon elimination and C-H bond cleavage by a 1,5-rhodium shift.

Full text of DOI:10.1021/ja410910s

Communication
pubs.acs.org/JACS
1,5-Rhodium Shift in Rearrangement of N‑Arenesulfonylazetidin-3-
ols into Benzosultams
Naoki Ishida, Yasuhiro Shimamoto, Takaaki Yano, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
activity to promote quantitative transformation of 1a. Simple
elution of the reaction mixture through a pad of silica gel
afforded 2a in 96% isolated yield (Scheme 1).
ABSTRACT: Benzosultams are synthesized in an enan-
tiopure form starting from α-amino acids through a
rhodium-catalyzed rearrangement reaction of N-arenesul-
fonylazetidin-3-ols. Mechanistically, this reaction involves
C−C bond cleavage by β-carbon elimination and C−H
bond cleavage by a 1,5-rhodium shift.
Scheme 1. Rhodium-Catalyzed Rearrangement of 1a to 2a
arbon−carbon (C−C) and carbon−hydrogen (C−H)
Cbonds constitute the major frameworks of organic
molecules. Such nonpolar σ-bonds are kinetically inert and
thermodynamically stable in general and, therefore, remain
intact under most conventional reaction conditions. The past
few decades, however, have seen the rise of methods to
selectively transform such intrinsically unreactive bonds with
the use of transition-metal catalysts.1,2
A stepwise mechanism involving a 1,5-rhodium shift from
C(sp3) to C(sp2) is proposed to explain the formation of 2a
from 1a (Scheme 2). Initially, the hydroxy group of 1a is
A 1,4-metal shift is defined as an intramolecular metal−
hydrogen exchange process occurring between 1- and 4-
positions. This process provides a convenient way to activate a
specific C−H bond, and a number of unique reactions involving
a 1,4-metal shift have been reported.3−6 For example, Catellani
et al. have reported a palladium-catalyzed reaction of
bromobenzenes with norbornenes, in which multiple C−C
bonds are introduced on the benzene ring through a 1,4-
palladium shift. 4a A 1,4-rhodium shift has been also successfully
exploited.5 Phenylboronic acid is multiply alkylated with
Scheme 2. Proposed Mechanism for the Rearrangement of
1a to 2a
5a
norbornene through repetition of a 1,4-rhodium shift.
Indanones are synthesized through rearrangement of 1-
arylpropargyl alcohols.5c,d A rearrangement reaction of cyclo-
butanols affords indanols in an enantio- and diastereoselective
way.5h,i On the other hand, there are significantly less
precedents reported for a 1,5-metal shift.7 Herein, we report
a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 1,5-rhodium shift as the key
mechanistic element. It provides a stereoselective synthetic
pathway starting from natural α-amino acids leading to
enantiopure benzosultams, which are substructures of potent
pharmaceuticals like piroxicam and meloxicam.9
Initially, N-p-toluenesulfonylazetidinol 1a was prepared from
commercially available azetidin-3-ol in 3 steps.10 Then, the
reaction of 1a was examined in the presence of [Rh(OH)-
(cod)]2 (2 mol %) and various phosphine ligands (Rh:P =
1:2.5).10 Whereas almost no reaction occurred when ligands
like PPh3, DPPB, DPPF were employed, the use of rac-BINAP
prompted a rearrangement reaction to give 2a in 46% yield. rac-
DM-BINAP, which possessed 3,5-xylyl groups in place of
phenyl groups on phosphorus, exhibited considerably higher
exchanged onto the rhodium hydroxide to generate rhodium
alkoxide A. Subsequently, β-carbon elimination follows to
cleave the C−C bond of the symmetrical azetidine ring, thereby
relieving the ring strain.11 The generated alkylrhodium B then
undergoes a 1,5-rhodium shift to furnish arylrhodium species C.
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to construct the six-membered ring structure of a
benzosultam skeleton. Finally, the rhodium alkoxide D is
exchanged with the hydroxy group of another azetidinol 1a to
release the benzosultam 2a with regeneration of intermediate A.
Received: October 24, 2013
Published: December 11, 2013
© 2013 American Chemical Society
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We next carried out the reaction of 1a-d, whose p-tolyl group
Scheme 5. Synthesis of Enantiopure Azetidinol 1e
was fully deuterated (Scheme 3). One of the deuterium atoms
Scheme 3. Rhodium-Catalyzed Reaction of 1a-d to 2a-d
Scheme 6. Rearrangement of 1e to 2e
on the ortho positions of the p-tolyl moiety was transferred
onto the N-methyl group of 2a-d, being consistent with the
proposed mechanism. The H/D ratio of the N-methyl group
and the 8-position were 1.9/1.1 and 0.1/0.9, respectively. The
slightly lower than expected H/D ratios at the N-methyl and
the slightly higher than expected at the 8-positions may suggest
the microscopic reversibility between the intermediary
arylrhodium C and the alkylrhodium B.
Next, optically active diphosphine ligands were examined to
induce enantioselectivity at the step of intramolecular carbonyl
addition, i.e., from C leading to D.12 Although (R)-DM-BINAP
exhibited the best reactivity among the chiral ligands examined
to give 2a in 94% yield, the enantiomeric ratio (er) was low
(62:38).10 (R)-DIFLUORPHOS afforded the best selectivity of
92:8 er (91% yield) (Scheme 4). Application of this reaction
conditions to various azetidinols 1 furnished benzosultams 2 in
the range of 91:9 to 93:7 er.13
quantitative yield with the enantiopurity retained. The
stereochemistry was confirmed by X-ray crystallography.10
The exclusive formation of 2e demonstrates that β-carbon
elimination occurs site-selectively at the methylene side rather
than at the methyne side, probably due to steric reasons. In
addition, intramolecular carbonyl addition takes place in a
diastereoselective fashion. We assume that the six-membered
ring transition state adopts a boat-like conformation, in which
the C−Rh bond can align with the CO bond for the
maximum orbital interaction as shown in Scheme 7. With the
Scheme 4. Enantioselective Rearrangement of 1
Scheme 7. Models for Diastereoselective 6-exo-trig
Cyclization
Asymmetrical azetidinol 1e was prepared in an enantiopure
form from (L)-alanine according to a modified version of
Seebach’s method (Scheme 5).14 Initially, (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4.
Subsequent treatment with oxalyl chloride followed by coupling
with diazomethane gave diazo ketone 5. Copper-catalyzed
denitrogenative cyclization of 5 afforded azetidinone 6.
Addition of phenylmagnesium bromide to 6 occurred
selectively from the face opposite to the methyl group to
furnish azetidinol 1e in an enantiopure form.
The azetidinol 1e was heated at 60 °C in toluene for 8 h in
the presence of [Rh(OH)(cod)]2 (2 mol %) and rac-DM-
BINAP (5 mol %) (Scheme 6). The rearrangement reaction
proceeded diastereoselectively to furnish benzosultam 2e in
conformer E, the methyl group at the α-position adopts a
pseudoequatorial position, whereas the α-methyl group of the
conformer E′ takes a pseudoaxial position. Thus, the conformer
E is favored over the conformer E′ to produce the adduct F
diastereoselectively.
Various benzosultams were synthesized in an enantio- and
diastereopure form (Table 1). The reaction of N-p-
toluenesulfonylazetidinol 1f, the diastereomer of 1e, also
furnished the same stereoisomer 2e exclusively, being
consistent with the proposed mechanism; the stereochemistry
of the alcohol moiety once disappears upon β-carbon
elimination to produce the same intermediate C. Azetidinols
1g−j having various aryl groups on the sulfonyl moiety gave the
corresponding products 2g−j (entries 2−5). The reaction of N-
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Journal of the American Chemical Society
Communication
a
shift. Substituted aryl groups were allowed at the C3-position
(entries 6, 7).15 Benzosultam 2m was obtained from azetidinol
1m, which was prepared from valine (entry 8). The reaction of
methionine-derived 1n successfully furnished 2n, demonstrat-
ing the compatibility of a sulfide functionality (entry 9).
In summary, we have described the rhodium-catalyzed
rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams. The unique transformation mechanistically
involves reorganization of nonpolar σ-bonds via a 1,5-rhodium
shift and provides a method to synthesize enantio- and
diastereopure benzosultams starting from natural α-amino
acids.
Table 1. Rhodium-Catalyzed Rearrangement of 1 to 2
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
murakami@sbchem.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Y. Nagata (Kyoto Univ.) for his assistance in X-
ray crystallographic analysis. This work was supported in part
by a Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward Syn-
thesis” and Grant-in-Aid for Scientific Research (B) from
MEXT, ACT-C from JST, and The Asahi Glass Foundation.
Y.S. is grateful to the Japan Society for the Promotion of
Science (JSPS) for a Research Fellowship for Young Scientists.
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