Regiodivergent Desymmetrization Reaction of meso-Azabicycloheptene Providing Two Enantioenriched Structural Isomers

Article abstract of DOI:10.1021/acs.orglett.1c00036

A novel catalytic asymmetric reaction is reported where the regiodivergent desymmetrisation of meso-azabicycloheptene via allylic oxidation using a single chiral copper catalyst produced two different, enantioenriched structural isomers in high optical pu

Full text of DOI:10.1021/acs.orglett.1c00036

pubs.acs.org/OrgLett
Letter
Regiodivergent Desymmetrization Reaction of meso-
Azabicycloheptene Providing Two Enantioenriched Structural
Isomers
Yuxin Zheng, Yanze Huang, Peng Gao, Hongyan Liu, Suguru Murakami, Ryosuke Matsubara,
and Masahiko Hayashi*
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ABSTRACT: A novel catalytic asymmetric reaction is reported
where the regiodivergent desymmetrisation of meso-azabicyclohep-
tene via allylic oxidation using a single chiral copper catalyst
produced two different, enantioenriched structural isomers in high
optical purity starting from a single compound. The enantiose-
lectivity of the two structurally isomeric compounds was enriched
to >99.5% ee after derivatization.
atalytic asymmetric reactions are widely applicable, easily
Creproducible, and economically feasible. Alongside the
development of chiral catalysts, discovering new phenomena
regarding these reactions is also desirable.1 Herein, we disclose
new phenomena relating to the asymmetric reaction, where
two structural isomers were obtained from a single starting
material using a single chiral catalyst with high enantiose-
lectivity. In asymmetric reactions the product is an enantiomer
of one compound, except for those obtained via parallel kinetic
resolution (PKR). Kinetic resolution can be classified into
three modes, one of which being PKR (Scheme 1).
kinetic resolution reactions use racemic compounds (i.e.,
enantiomeric mixtures) as the starting material, while the
present method employs a single meso compound (Scheme 2).
Scheme 2. Regiodivergent Desymmetrization
Scheme 1. Classification of Kinetic Resolution: (a) Normal
Kinetic Resolution (KR); (b) Dynamic Kinetic Resolution
(DKR); (c) Parallel Kinetic Resolution (PKR)
The oxidation of allylic alkenes by a peroxy ester and copper
catalyst is called Kharasch−Sosnovsky reaction.9 The enantio-
topic relationship between the allylic protons of cycloalkenes,
such as cycloheptene and cyclohexene, suggests that
enantioselective Kharasch−Sosnovsky reactions could be
possible,10−13 which we reported an example of such a
reaction.14 In addition, a single reaction using meso-4,5-
epoxyhex-1-ene as the substrate constructed three stereo-
centers.15 During the course of this study, we found that
reacting 7-tosyl-7-azabicyclo[4.1.0]hept-3-ene (1) with tert-
butyl-perbenzoate in the presence of 5 mol % Cu-
(CH3CN)4PF6 and 6 mol % (R,E)-N-(3,3-dimethylbutan-2-
In PKR,2 a single catalyst gives two products from a racemic
mixture. When the products are not isomers but compounds
with different structures, this reaction is called chemodivergent
PKR.3 Furthermore, regiodivergent PKR uses a single catalyst
to afford regioisomeric products from racemic compounds,4−7
and stereodivergent PKR reactions transform racemic com-
pounds into diastereomeric isomers.8 In this letter, we report
the first example of a novel asymmetric reaction in which a
single catalyst was employed to give two, enantioenriched,
structural isomers with high enantioselectivity from a single
substrate. This reaction appears to be similar to PKR; however,
Received: January 6, 2021
Published: March 22, 2021
https://doi.org/10.1021/acs.orglett.1c00036
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2411−2414
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yl)-1-(quinolin-2-yl)ethan-1-imine afforded a 1:1 mixture of
(1R,2R,6R)-7-tosyl-7-azabicyclo[4.1.0]hept-3-en-2-yl benzoate
(2) and (1R,3R,6S)-7-tosyl-7-azabicyclo[4.1.0]hept-4-en-3-yl
benzoate (3) in 80% ee and 90% ee, respectively, in an overall
yield of 62% (Scheme 3). The absolute configuration was
determined by X-ray crystal structure analysis.16
Scheme 5. An Alternative Proposed Reaction Mechanism
Scheme 3. Reacting meso-Aziridine 1 with tert-Butyl-
Perbenzoate in the Presence of a Chiral Cu Catalyst
Several species and reaction paths were proposed and have
been reported for copper-catalyzed Kharasch−Sosnovsky-type
allylic oxidations, including the Beckwith−Zavitsasa mecha-
nism,17 the Slough mechanism,18 and Salvatella’s theoretical
mechanism.19 For the present asymmetric reaction, we propose
two plausible pathways (Scheme 4 and Scheme 5). The first
tivity for the formation of compounds 2 and 3. The use of the
ligand having ethyl or phenyl instead of tert-butyl afforded a
lower chemical yield and enantioselectivity (ethyl: 46% yields,
36% ee of 2 and 54% ee of 3; phenyl: 54% yields, 66% ee of 2
and 44% ee of 3). This Cu(I)L* complex reacts with tert-butyl
perbenzoate to form peroxide complex Cu(I)XL*, which
subsequently reacts with 1 to afford diastereomeric Cu(III)-π-
allyl intermediates A and B in a 1:1 ratio. From diastereomeric
intermediate A, there are two regioselective routes that form σ-
allyl-Cu(III) complexes C and D, the formation of C being
preferred. Similarly, from intermediate B, two regioselective
routes will form σ-allyl-Cu(III) complexes E and F, in which E
formation is preferred. In both cases each set of complexes (C
and D; E and F) will be in equilibrium. The origin of the
preferences for C and E is complicated and is detailed in the
Supporting Information. Attack by the benzoate carbonyl
oxygen to the bottom face (opposite side to the aziridine
moiety) of C affords compound 2 in 45% yield. On the other
hand, in a less regioselective manner, similar carbonyl oxygen
attack of D afforded ent-3 in 2.5% yield. From intermediate B,
allyl σ-Cu(III) complex E was formed regioselectively to afford
3 in a 47.5% yield. The regiomer minor complex F gave ent-2
in 5% yield. As for the role of the chiral ligand on copper, the
bulky tert-butyl moiety in the N,N-bidentate ligand is essential
for the formation of compounds 2 (vs ent-3 from intermediate
A to C vs D) and 3 (vs ent-2 from intermediate B to E vs F)
predominantly in high enantioselectivity. The steric effect of
the tert-butyl group was depicted in Scheme S1 (Supporting
Information). Compounds 2 and 3 are structural isomers;
therefore, we named this phenomenon ‘regiodivergent
desymmetrization’. The unique feature of this reaction is that
two structural isomers were formed with high enantioselectiv-
ity from a single compound using a single catalyst.
Scheme 4. Proposed Reaction Pathway
An alternative reaction mechanism (Scheme 5) was
proposed in which the reaction of the Cu(I)XL* complex
with 1 regioselectively gives the σ-allyl-Cu(III) complexes C
and D via π-allyl radical G. Compound 2 was obtained in 45%
yield from C by a regio- and stereospecific oxygen attack, and
ent-3 was obtained in 2.5% yield from D through the same
process. σ-Allyl-Cu(III) complexes E and F could also be
formed via π-allyl radical H, where 3 (the structural isomer of
proposed pathway (Scheme 4) begins with the chiral catalyst
species Cu(I)L*,which is composed of a chiral N,N-bidentate
ligand and a Cu(I) precursor. As for the role of the used chiral
ligand on copper, after screening of a variety of similar N,N-
bidentate we developed,14 the used N,N-bidentate ligand
having the bulky tert-butyl afforded the highest enantioselec-
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2) was obtained in 47.5% yield from E, and ent-2 was obtained
in 2.5% yield from F.
Scheme 7. Ring Opening Reactions of Aziridines to Give
Chiral Building Blocks
We then carried out the separation of 2 and 3 and enriched
the optical purity as follows. The separation of 2 and its
structural isomer 3 was achieved by preparative high-
performance liquid chromatography (PHPLC). Compound 2
(80% ee) was recrystallized from the 1:4 mixture to afford 2
with an improved ee of 97%.
The ee of compound 3 (90% ee) was also increased to
>99.5% ee by recrystallization from toluene/hexane (1:2) or
from ethyl acetate/hexane (1:4). An alternative procedure
without the use of PHPLC is shown in Scheme 6. Two, direct
Scheme 6. Increasing Optical Purity of the Aziridines
noted that in the case of compound 3 ring opening of aziridine
occurred regioselectively next to the carbon of the double
bond. These chiral building blocks are useful intermediates for
synthesizing (−)-oseltamivir phosphate (Tamiflu)20 and its
derivatives. Furthermore, after ozonolysis, a variety of acyclic
natural21 and unnatural products can be synthesized using
these chiral building blocks.22
In conclusion, the first example is reported of an asymmetric
reaction in which two structural isomers with high
enantioselectivity from a single compound using a single chiral
catalyst was developed. Our findings demonstrate further
utility of meso compounds in catalytic asymmetric reactions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00036.
Classification of kinetic resolution; Additional consid-
eration of reaction mechanism; General Information
Procedure for synthesis of 7-tosyl-7-azabicyclo[4.1.0]-
hept-3-ene (1) and characterization of compound 1;
Typical procedure for asymmetric allylic oxidation of 7-
tosyl-7-azabicyclo[4.1.0]hept-3-ene (1) and character-
ization of compounds 2 and 3; Characterization of
compounds 4−8 and procedure and characterization of
1
compound 5−8; HPLC charts of compounds 2−4; H
and 13C{1H} spectra of compounds 1−8; Crystallo-
graphic details of compounds 3−8 (PDF)
recrystallizations of the 1:1 mixture of 2 and 3 gave >99.5% ee
of 3. The benzoyl group in the residual product mixture
(1:0.3) was deprotected and then protected as its 4-
nitrobenzoate, and two successive recrystallizations afforded
>99.5% ee of 4.
To obtain useful chiral building blocks, we carried out
aziridine ring opening of compounds 4 and 3 by H2O and
NaN3. The reaction took place in both a regio- and
stereoselective manner to afford optically pure chiral building
blocks 5, 6, 7, and 8 in >99.5% ee (Scheme 7). It should be
Accession Codes
CCDC 2032340−2032345 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Letter
(10) Andrus, M. B.; Lashley, J. C. Copper catalyzed allylic oxidation.
Tetrahedron 2002, 58, 845−866.
AUTHOR INFORMATION
■
Corresponding Author
(11) Beller, M.; Bolm, C., Eds. Transition metal for organic synthesis;
Wiley-VCH: Weinheim, 2004; Vol. 2, pp 256−266.
(12) Frison, J.-C.; Legros, J.; Bolm, C. Handbook of CH
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005; pp
445−454.
Masahiko Hayashi − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan;
orcid.org/0000-0002-1716-6686; Email: mhayashi@
kobe-u.ac.jp
(13) Punniyamurthy, T.; Rout, L. Recent advances in copper-
catalyzed oxidation of organic compounds. Coord. Chem. Rev. 2008,
252, 134−154.
Authors
Yuxin Zheng − Department of Chemistry, Graduate School of
Science, Kobe University, Kobe 657-8501, Japan
Yanze Huang − Department of Chemistry, Graduate School of
Science, Kobe University, Kobe 657-8501, Japan
Peng Gao − Department of Chemistry, Graduate School of
Science, Kobe University, Kobe 657-8501, Japan
Hongyan Liu − Department of Chemistry, Graduate School of
Science, Kobe University, Kobe 657-8501, Japan
Suguru Murakami − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan
Ryosuke Matsubara − Department of Chemistry, Graduate
School of Science, Kobe University, Kobe 657-8501, Japan;
orcid.org/0000-0001-8941-2391
(14) Tan, Q.; Hayashi, M. Novel N,N-bidentate ligands for
enantioselective Copper (I)-catalyzed allylic oxidation of cyclic
olefins. Adv. Synth. Catal. 2008, 350, 2639−2644.
(15) Tan, Q.; Hayashi, M. Asymmetric desymmetrization of 4,5-
epoxyhex-1-ene by enantioselective allylic oxidation. Org. Lett. 2009,
11, 3314−3317.
(16) The details for determination of the absolute configuration by
X-ray analysis, see Supporting Information.
(17) Beckwith, A. L. J.; Zavitsas, A. A. Allylic oxidations by peroxy
esters catalyzed by copper salts. The potential for stereoselective
syntheses. J. Am. Chem. Soc. 1986, 108, 8230−8234.
(18) Smith, K.; Hupp, C. D.; Allen, K. L.; Slough, G. A. Catalytic
allylic amination versus allylic oxidation: A mechanistic dichotomy.
Organometallics 2005, 24, 1747−1755.
(19) Mayoral, J. A.; Rodríguez-Rodríguez, S.; Salvatella, L.
Theoretical insights into enantioselective catalysis: the mechanism
of the Kharasch-Sosnovsky reaction. Chem. - Eur. J. 2008, 14, 9274−
9285.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00036
(20) For example, see: Tanaka, T.; Tan, Q.; Kawakubo, H.; Hayashi,
M. Formal total synthesis of (−)-oseltamivir phosphate. J. Org. Chem.
2011, 76, 5477−5479.
Notes
The authors declare no competing financial interest.
(21) For example, see: Srinivas, J.; Namito, Y.; Matsubara, R.;
Hayashi, M. Synthesis of enantiomerically pure (8S,9S,10R,6Z)-
trihydroxyctadec-6-enoic acid. J. Org. Chem. 2017, 82, 5146−5154.
(22) We are now synthesizing optically pure ceramides using the
present method.
ACKNOWLEDGMENTS
■
Financial support for this project was partially provided
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), Japan. We thank Prof. Makoto Tokunaga of
Kyushu University for his kind discussion.
REFERENCES
■
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John
Wiley & Sons, Inc.: New York, 1994. (b) Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds. Comprehensive Asymmetric Catalysis I, II, III;
Springer: 1999.
(2) Vedejs, E.; Chen, X. Parallel kinetic resolution. J. Am. Chem. Soc.
1997, 119, 2584−2585.
(3) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.;
Martin, S. F.; Spaller, M. R.; Liras, S. Highly selective enantiomer
differentiation in intramolecular cyclopropanation reaction of racemic
secondary allylic diazoacetate. J. Am. Chem. Soc. 1995, 117, 11021−
11022.
(4) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L.
Highly enantioselective regiodivergent and catalytic parallel kinetic
resolution. Angew. Chem., Int. Ed. 2001, 40, 930−932.
(5) Tanaka, K.; Fu, G. C. Parallel kinetic resolution of 4-alkynals
catalyzed by Rh(I)/Tol-BINAP: Synthesis of enantioenriched cyclo-
butanones and cyclopentanones. J. Am. Chem. Soc. 2003, 125, 8078−
8079.
(6) Wu, B.; Parquette, J. R.; RajanBabu, T. V. Regiodivergent ring
opening of chiral aziridines. Science 2009, 326, 1662.
(7) Webster, R.; Boing, C.; Lautens, M. Reagent-controlled
regiodivergent resolution of unsymmetrical oxabicyclic alkenes using
a cationic rhodium catalyst. J. Am. Chem. Soc. 2009, 131, 444−445.
(8) Dehli, J. R.; Gotor, V. Preparation of enantiopure ketones and
alcohols containing a quarternary stereocenter through parallel kinetic
resolution of β-keto nitriles. J. Org. Chem. 2002, 67, 1716−1718.
(9) Kharasch, M. S.; Sosnovsky, G. The reactions of t-butyl
perbenzoate and olefin__A stereospecific reaction. J. Am. Chem. Soc.
1958, 80, 756.
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