Synthesis of Enantioenriched 2-Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts

Article abstract of DOI:10.1021/acs.orglett.6b02401

An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.

Full text of DOI:10.1021/acs.orglett.6b02401

Letter
pubs.acs.org/OrgLett
Synthesis of Enantioenriched 2‑Alkyl Piperidine Derivatives through
Asymmetric Reduction of Pyridinium Salts
Bo Qu,* Hari P. R. Mangunuru, Xudong Wei, Keith R. Fandrick, Jean-Nicolas Desrosiers,
Joshua D. Sieber, Dmitry Kurouski, Nizar Haddad, Lalith P. Samankumara, Heewon Lee, Jolaine Savoie,
Shengli Ma, Nelu Grinberg, Max Sarvestani, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States
S
* Supporting Information
ABSTRACT: An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-
pyridines has been developed using ligand MeO-BoQPhos. High levels of
enantioselectivities up to 93:7 er were obtained. The resulting
enantioenriched piperidines can be readily converted into biologically
interesting molecules such as the fused tricyclic structures 5, 6, and 7 in
99:1 er, providing a novel, concise synthetic route to this family of chiral
piperidine-containing compounds.
hiral 2-alkyl piperidine is a ubiquitous motif found in a wide
range of medicinally important compounds including many
Zhou’s10 and Zhang’s11 groups then activated the pyridines by
forming N-benzylpyridinium salts. A number of 2-aryl derived
pyridines are reduced successfully with high enantioselectivities,
but with limited application to 2-alkylpyridines. Herein, we report
the development of an Ir-catalyzed enantioselective hydro-
genation of 2-alkyl N-benzylpyridinium salts using BI P,N ligand
MeO-BoQPhos, and its application toward the synthesis of the
fusedtricyclicpiperidine-containingpharmacophoreshexahydro-
pyridoindole (R)-5, hexahydrobenzopyridooxazepine (R)-6, and
benzoquinolizidine (R)-7 in enantiomerically pure form.
C
naturally occurring alkaloids (Figure 1).1,2 2-Alkyl piperidine-
Figure 1. 2-Alkyl piperidine-containing alkaloids.
Our investigation started with the readily accessible compound
2-benzyl-N-benzylpyridinium bromide salt 1a. Commercially
available chiral phosphine ligands were initially the focus under
the conditions of 1 mol % [Ir(COD)Cl]2, 30 °C, and 450 psi H2
pressure (Scheme 1). Disappointing enantioselectivities resulted
containing molecules have exhibited a broad spectrum of
interesting biological activities such as potential analgetics,3
antiamnestic agents,4 and for the treatment of neurological
diseases and psychiatric disorders.5
The reported synthetic strategies generally require long
synthetic sequences to obtain the target chiral piperidines,6
starting from the chiral pool, use of chiral auxiliaries, or through
resolutionofracemicmixtures. Weareinterestedinsynthesizinga
series of chiral 2-alkylpiperidine derivatives and sought to access
these molecules through an efficient and enantioselective
approach. To this end, we envisioned installing the chiral center
directly through asymmetric hydrogenation (AH) of 2-
alkylpyridine derivatives. Substituted pyridines are readily
available; the successful implementation of this protocol would
provide an efficient atom-economical fashion for the preparation
of enantiomerically enriched 2-alkyl piperidines.
Recent advances in asymmetric reduction of the heteroarenes
have enabled a straightforward synthesis for enantioenriched
heterocyclic compounds.7 To facilitate the asymmetric reduction
of pyridines, Charette and Legault first demonstrated an
activation process for pyridine derivatives by forming N-
acyliminopyridinium ylides; high enantioselectivity was provided
for2-alkylpyridines.8 Nevertheless, safety concerns9 related tothe
use of amination reagents for the preparation of the requisite
ylides prevent us from utilizing this elegant method on large scale.
a
Scheme 1. Selected Known Ligands for AH of 1a
a
THF/MeOH 9:1, 100% conv to product unless specified, determined
by HPLC area % at 220 nm. In the presence of 5 mol % I2, ratio of I2/
b
Ir = 2.5:1.
including Synphos10 and MP2-Segphos,11 which are highly
effective for 2-arylpyridinium salt reduction. Iodine is known to
activate the iridium catalyst for catalytic hydrogenation
reactions.8,12 However, it was found that, for the reduction of
1a with bisphosphine ligands, the presence of iodine was
detrimental to both reactivity and enantioselectivity.
Received: August 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. BoQPhos Ligands for AH of 1a
Table 1. Solvent Screening for AH of 1a Using Complex 3
b
entry
solvent
2a (%)
er
1
2
THF/MeOH (9:1)
THF/MeOH (3:1)
THF
100
100
100
93
86:14
82:18
90:10
75:24
67:33
80:20
82:18
74:26
82:18
52:48
c
3
4
DCM
5
DCE
79
6
1,4-dioxane
toluene
92
7
92
8
toluene/DCM (1:1)
THF/n-BuOH (3:1)
acetone
80
9
100
99
10
a
Reaction conditions: 30 mg of 1a, 2 mol % 3, 5 mol % I2, 30 °C, 450
b
c
psi H2 in 0.6 mL of solvent. HPLC area % at 220 nm. 20 °C.
a
Scheme 4. AH of 2-Alkyl-N-benzylpyridinium Salts
a
THF/MeOH 9:1, 20 h, 100% conv to 2a unless specified, determined
by HPLC area % at 220 nm.
We have recently introduced a family of new phosphorus
ligands derived from a modular dihydrobenzooxaphosphole core
and demonstrated their unique capability for a wide range of
catalytic transformations.13 In particular, the phosphorus-
pyridine BoQPhos ligands have shown to reduce unfunctional-
ized alkenes enantioselectively with an iridium catalyst.14 Since 2-
alkylpyridines contain largely uncoordinating functionalities, we
postulated these ligands could be also effective for the asymmetric
reduction of pyridinium salts (Scheme 2). We first tested the
unsubstituted ligand L1 for hydrogenation of 1a with [Ir(COD)-
Cl]2 at 30 °C and 450 psi H2 pressure; 25% conversion was
observed. To enhance the reactivity, electron-donating alkoxy
groups were incorporated into the ligand structure. Methoxy
substitution on the left-hand side of the phenyl ring improved the
conversion slightly to 40%, but again with no enantioselectivity
(L2). On the other hand, ligand L3 with a methoxy group on
pyridyl generated the desired product 2a in 97% conversion and
an 82:18 er. The best enantioselectivity (86:14 er)15 was achieved
when methoxy groups were installed on both the phenyl and
pyridylringsasin(S,S)-L4(MeO-BoQPhos). Furtherfine-tuning
of substitution on the pyridyl group did not significantly improve
the selectivity (L5 to L9). Aryl substitution on the phenyl group
or phosphorus atom (L10 to L12) decreased the reactivity.
We have previously observed that an iridacyclic complex is
formed through Ir insertion to the C−H bond of the neighboring
OMe group in the presence of a noncoordinating anion such as
BArF (Scheme 3).14 This complex is unreactive toward the
asymmetric reduction of alkenes. In the presence of a strongly
coordinating chloride, the anticipated neutral complex IrCl-
a
Reaction conditions: pyridinium salt (0.5 g), 20 mL of THF, 5−24 h,
b
c
isolation yield. 20 °C. [Ir(COD)Cl]2 2 mol %, ligand 6 mol %, I2 10
mol % at 10 °C and 600 psi H2 for 24 h.
(MeO-BoQPhos)(COD) 3 was successfully isolated. The single
crystal structure of 316 clearly indicated an intact MeO group on
pyridine in the molecule.
Complex 3 proved to be effective toward asymmetric
hydrogenation of the pyridinium salt 1a and was directly
employed for solvent screening to eliminate the uncertainty of
incomplete ligation in various solvents (Table 1). A variety of
solvents and solvent mixtures were examined, with THF
identified as optimal furnishing a 90:10 er (entry 3). This
represents the highest enantioselectivity reported for 2-benzyl-N-
benzylpyridinium salt 1a compared to those obtained with
bisphosphine ligands.10,11
With the optimized conditions in hand, the substrate scope was
then evaluated (Scheme 4). An enantiomeric ratio of 93:7 was
observed for the piperidine 2b with 2-bromo-4-cyano benzyl
substitution. Most importantly, the catalyst system proved to be
chemoselective at reducing the pyridine ring without affecting the
reduction sensitive bromo and cyano groups. Hindered substrate
2-diphenylmethylpyridinium salt 1c was reduced as well to
produce an 84:16 er. The TBS protected 2-methanol pyridinium
salt1dand1eareexpectedtobeunfavorablesubstratesintermsof
enantioselectivity; 82:18 er and 84:16 er were obtained,
respectively. The catalyst is also effective for 2-alkylpyridinium
salts containing long alkyl chains. N-Benzyl-2-phenethylpyridi-
nium 1f was reduced to the corresponding chiral piperidine 2f
Scheme 3. Structure of the Complex [IrCl(MeO-
BoQPhos)(COD)] (3)
B
DOI: 10.1021/acs.orglett.6b02401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with an 88:12 er. Pyridinium salts with acetal and ketal
functionality on the alkyl group were reduced successfully to
yield 89:11 er (2g) and 85:15 er (2h). 2-Methylpyridinium salt 1i
was reported to afford product 2i in a 67:33 er upon
hydrogenation using MP2-Segphos as a ligand.11 With Ir-MeO-
BoQPhos, 2-methylpiperidine 2i was obtained in a much
improved 82:18 er. Similarly, 2-propylpiperidine 2j and 2-
isopropylpiperidine 2k were obtained in 88:12 er and 91:9 er,
respectively. A cyclopropyl substituent is tolerated to generate
chiral piperidine 2l in a 92:8 er.
Enantioselective reduction of the more challenging 2,3-
disubstituted pyridinium salts including cyclic compound 1m
and acyclic compound 1n was also evaluated. Presumably,
complete hydrogenation proceeds through a tetrasubstituted
enamine intermediate, which has been shown to be the most
demanding substrate toward hydrogenation due to a high energy
barrierandchallengingfacialdifferentiation.17 Theresultingfused
bicyclic chiral piperidine would be an interesting structure that
contains two embedded contiguous stereogenic centers.18 To our
delight, the asymmetric reduction of 1m produced the
enantioenriched 2m in an exclusive cis-fashion with a 81:19 er
and 86% yield. The acyclic 2,3-dimethylpiperidine 2n was
obtained in >99.5:0.5 dr and 78:22 er in 82% isolation yield.
Computational studies were conducted on the key enamine
intermediate with (S,S)-L4 to understand the enantioinduction
process(Figure2). AllcalculationswereconductedwithGaussian
cally important molecules such as chiral Desoxylpipradrol25
(from2c). Furthermore, theyweredemonstratedinthesyntheses
of several enantiomerically pure fused tricyclic piperidine-
containing molecules.
The reaction mixture of 2b was subjected to debenzylation by
treatment with α-chloroethyl chloroformate26 in the presence of
0.2 equiv of iPr2NEt in refluxing MeOH (Scheme 5).
Recrystallization of the resulted HCl salt enriched the
enantiomeric purity of 4−HCl to 99:1 er. The deprotected chiral
piperidine was isolated in 76% yield. An intramolecular Hartwig−
Buchwald amination furnished (R)-5 in 78% yield upon isolation.
To our knowledge, this is the first enantioselective synthesis of
hexahydropyridoindole derivatives.27
Scheme 5. Synthesis of Hexahydropyridoindole (R)-5
Scheme 6. Synthesis of hexahydrobenzopyridooxazepine (R)-
6
The N-benzyl fragment canalso be utilized as an integral part of
the molecule for further transformation (Scheme 6). Chiral
enrichment on the corresponding alcohol from 2d increased the
enantiomeric purity to 96:4 er. Intramolecular ether formation
and recrystallization of the HCl salt afforded the enantiomerically
pure (R)-65,28 in 99:1 er.
Finally, a benzoquinolizidine derivative 712d,29 was conven-
iently prepared from 2f (Scheme 7). It was first subjected to chiral
enrichment and then converted into compound (R)-7 via
debenzylation and an intramolecular amination (Scheme 7).
Figure 2. Outer-sphere dissociative catalytic cycle of the Ir-catalyzed
reduction of enamine intermediate. DFT calculations: B3LYP/
LANL2DZ, CPCM solvation model with THF. Thermal corrections:
298.15 K at 1 atm. Plot: 3D-Model of TS-2.
Scheme 7. Synthesis of Tricyclic Benzoquinolizidine (R)-7
0919 at the DFT level of theory with the B3LYP20 and LANL2DZ
basis set with ECP for iridium21 and D95v for the remaining
atoms.22 A viable reaction pathway was found employing an
outer-sphere dissociated mechanism23 similar to the mechanism
of iridium catalyzed asymmetric reduction of imines24a and
quinolone derivatives.24b This pathway indicates that iodine
activatedtheIr(I)precatalyst;theresultingIr(III)iodocomplexis
maintained as a neutral or charge balanced state throughout the
two-step protonation and hydride delivery catalytic cycle.
Although the rate-limiting step is the protonation (TS-1), the
hydride delivery proceeds through a dissociative mechanism (TS-
2) and thus the second transition state would dictate the facial
selectivity of the process. Of the three potential hydrides on the
iridium(III) intermediate, the one adjacent to the methoxy-
pyridine residue of the ligand is sterically more accessible. The
methoxy appendage of the pyridine orients the iminium substrate
to expose the si-face for hydride delivery and generating the R-
enantiomer of 2a.
In summary, an Ir-catalyzed enantioselective hydrogenation of
2-alkyl-pyridinium salts has been developed using MeO-
BoQPhos as the ligand. High levels of enantioselectivity up to
93:7 er were obtained, which represents an efficient and practical
method for the preparation of enantioenriched piperidines. The
resulting piperidines can be readily transformed into biologically
interesting molecules such as fused tricyclic hexahydropyrido-
indole, benzoquinolizidine, and hexahydrobenzopyrido-
oxazepine derivatives in 99:1 er, providing a concise and novel
synthetic route to this family of chiral piperidine-containing
compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The resulting enantioenriched 2-alkyl piperidines can be
readily converted into naturally occurring alkaloids including
Coniine (from 2j) and Pelletierine (from 2h) and pharmaceuti-
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02401.
C
DOI: 10.1021/acs.orglett.6b02401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental details and characterization data (PDF)
Letter
H. Angew. Chem., Int. Ed. 2014, 53, 14428. (d) Du, K.; Guo, P.; Chen, Y.;
Cao, Z.;Wang, Z.;Tang, W. Angew. Chem., Int. Ed. 2015,54, 3033. (e)Fu,
W.; Nie, M.; Wang, A.; Cao, Z.; Tang, W. Angew. Chem., Int. Ed. 2015, 54,
2520. (f) Qu, B.; Haddad, N.; Rodriguez, S.; Sieber, J. D.; Desrosiers, J.-
N.; Patel, N. D.; Zhang, Y.; Grinberg, N.; Lee, H.; Ma, S.; Ries, U. J.; Yee,
N. Y.; Senanayake, C. H. J. Org. Chem. 2016, 81, 745.
(14) Qu, B.; Samankumara, L. P.; Savoie, J.; Fandrick, D. R.; Haddad,
N.; Wei, X.; Ma, S.; Lee, H.; Rodriguez, S.; Busacca, C. A.; Yee, N. K.;
Song, J. J.; Senanayake, C. H. J. Org. Chem. 2014, 79, 993.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bo.qu@boehringer-ingelheim.com.
Notes
The authors declare no competing financial interest.
(15) The major enantiomer is (R)-configuration, derived from DFT
calculation and the X-ray single crystal structure of (R)-7-HCl salt.
(16) CCDC-1477152 and CCDC-1478240 contain supplementary
crystallographic data for compounds 3 and 7, respectively. This material
is free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(17) (a) Wang, Q.; Huang, W.; Yuan, H.; Cai, Q.; Chen, L.; Lv, H.;
Zhang, X. J. Am. Chem. Soc. 2014, 136, 16120. (b) Molinaro, C.; Scott, J.
́
P.; Shevlin, M.; Wise, C.; Menard, A.; Gibb, A.; Junker, E. M.; Lieberman,
D. J. Am. Chem. Soc. 2015, 137, 999.
REFERENCES
■
(1) (a) Ripoche, I.; Gelas, J.; Gree, D.; Gree, R.; Troin, Y. Tetrahedron
Lett. 1995, 36, 6675. (b) Arend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. 1998, 37, 1044. (c) Mitchinson, A.; Nadin, A. J. J. Chem.
Soc., Perkin Trans. 1 1999, 1, 2553. (d) Takahashi, M.; Micalizio, G. C. J.
Am. Chem. Soc. 2007, 129, 7514.
(2) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(b) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40,
4169. (c)Lloyd, G. K.;Williams, M. J. J. Pharm. Exp. Ther. 2000, 292, 461.
(d) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003, 125,
(18) (a) Burns, N. Z.; Krylova, I. N.;Hannoush, R. N.;Baran, P. S. J. Am.
Chem. Soc. 2009, 131, 9172. (b) Ito, T.; Overman, L. E.; Wang, J. J. Am.
Chem. Soc. 2010, 132, 3272.
15878. (e)Par
M. J.; Caignard, D.-H.; Figader
Chem. 2014, 86, 700.
́
raga, J.;Moreno, L.;Diaz, A.;ElAouad, N.;Galan
́
, A.;Sanz,
e, B.; Cabedo, N.; Cortes, D. Eur. J. Med.
̀
(19) Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.;Montgomery, J. A., Jr.;Peralta, J. E.;Ogliaro, F.;Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
(3)Beckett, A. H.;Lingard, R. G.;Theobald, A. E. E. J. Med. Chem. 1969,
12, 563.
(4) Zhao, S.; Totleben, M. J.; Freeman, J. P.; Bacon, C. L.; Fox, G. B.;
O’Driscoll, E.; Foley, A. G.; Kelly, J.; Farrell, U.; Regan, C.; Mizsak, S. A.;
Szmuszkovicz, J. Bioorg. Med. Chem. 1999, 7, 1637.
(5) (a) Anthony, N. J.; Gomez, R. P.; Li, J.; Mercer, S. P.; Roecker, A. J.;
Stump, C. A.; Williams, T. M. PCT Int. Appl. 2012, WO 2012061019A2
20120510. (b) Grove, S. J. A.; Zhang, M.; Shahid, M. PCT Int. Appl.
2002, WO 2002100865A1 20021219.
(6) (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633 and references cited therein. (b) Leighty, M. W.; Georg, G. I.
ACSMed. Chem. Lett. 2011, 2, 313. (c)Reddy, B. V. S.;Ghanty, S.;Reddy,
N. S. S.; Reddy, Y. J.; Yadav, J. S. Synth. Commun. 2014, 44, 1658.
(7) (a) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang,
X. J. Am. Chem. Soc. 2010, 132, 8909. (b) Dobereiner, G. E.; Nova, A.;
Schley, N. D.; Hazari, N.; Miller, S. J.; Eisenstein, O.; Crabtree, R. H. J.
Am. Chem. Soc. 2011, 133, 7547. (c) Woodmansee, D. H.; Pfaltz, A. Top.
Organomet. Chem. 2011, 34, 31. (d) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.;
Zhou, Y.-G. Chem. Rev. 2012, 112, 2557. (e)Huang, W.-X.;Liu, L.-J.;Wu,
B.; Feng, G.-S.; Wang, B.; Zhou, Y.-G. Org. Lett. 2016, 18, 3082.
(f) Gualandi, A.; Savoia, D. RSC Adv. 2016, 6, 18419.
(8) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.
(9) Compounds o-(2,4-dinitrophenyl)hydroxylamine and N-Boc-
hydroxylamine show high energy decomposition at a relatively low
onset temperature. Handling, shipment, and storage of these materials
pose significant safety risks on large scales. See the Supporting
Information for the Differential Scanning Calorimetry (DSC) plots.
(10) Ye, Z.-S.; Chen, M.-W.; Chen, Q.-A.; Shi, L.; Duan, Y.; Zhou, Y.-G.
Angew. Chem., Int. Ed. 2012, 51, 10181.
̈
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc.,
Wallingford CT, 2010.
(20) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785.
(21) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (b) Wadt,
W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 299.
(22) Dunning, T. H., Jr.; Hay, P. J. In Modern Theoretical Chemistry, Vol.
3; Methods of Electronic Structure Theory; Schaefer, H. F., III, Ed.;
Plenum: New York, 1977; pp 1−28.
(23) (a) Martín, M.; Sola, E.; Tejero, S.; Andres
Eur. J. 2006, 12, 4043. (b) Martín, M.; Sola, E.; Tejero, S.; Andres
Oro, L. A. Chem. - Eur. J. 2006, 12, 4057.
́
, J. L.; Oro, L. A. Chem. -
́
, J. L.;
(24) (a) Hopmann, K. H.; Bayer, A. Organometallics 2011, 30, 2483.
(b) Dobereiner, G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller, S. J.;
Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2011, 133, 7547.
(25) Corkery, J. M.; Elliott, S.; Schifano, F.; Corazza, O.; Ghodse, A. H.
Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2012, 39, 253.
(26)(a)Olofson, R.A.;Martz, J. T.;Senet, J.-P.;Piteau, M.;Malfroot, T.
J. Org. Chem. 1984, 49, 2081. (b) Yang, B. V.; O’Rourke, D.; Li, J. Synlett
1993, 1993, 195.
(27) For nonenantioselective syntheses, see: (a) Ozaki, S.; Mitoh, S.;
Ohmori, H. Chem. Pharm. Bull. 1996, 44, 2020. (b) Krogsgaard-Larsen,
N.; Begtrup, M.; Herth, M. M.; Kehler, J. Synthesis 2010, 2010, 4287.
(c) Mahoney, S. J.; Fillion, E. Chem. - Eur. J. 2012, 18, 68. (d) Kaldas, S. J.;
Cannillo, A.; McCallum, T.; Barriault, L. Org. Lett. 2015, 17, 2864.
(28) For nonchiral analogues: Schultz, A. G.; Macielag, M.;
Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc. 1988,
110, 7828.
(11) Chang, M.; Huang, Y.; Liu, S.; Chen, Y.; Krska, S. W.; Davies, I. W.;
Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 12761.
(12) (a) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400.
(b) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (c) Blaser,
H.-U. Adv. Synth. Catal. 2002, 344, 17. (d) Wang, D.-W.; Wang, X.-B.;
Wang, D.-S.; Lu, S.-M.; Zhou, Y.-G.; Li, Y.-X. J. Org. Chem. 2009, 74,
2780. (e) Tang, W.-J.; Tan, J.; Xu, L.-J.; Lam, K. H.; Fan, Q.-H.; Chan, A.
S. C. Adv. Synth. Catal. 2010, 352, 1055.
(13) (a) Tang, W.; Qu, B.; Capacci, A. G.; Rodriguez, S.; Wei, X.;
Haddad, N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.;
Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2010, 12, 176.
(b) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. D.;
Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.;
Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed.
2010, 49, 5879. (c) Qu, B.; Samankumara, L. P.; Ma, S.; Fandrick, K. R.;
Desrosiers, J.-N.; Rodriguez, S.; Li, Z.; Haddad, N.; Han, Z. S.; McKellop,
K.; Pennino, S.; Grinberg, N.; Gonnella, N. C.; Song, J. J.; Senanayake, C.
(29) (a) Ito, Y.; Miyata, S.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc.
1981, 103, 5250. (b) Rueping, M.; Hubener, L. Synlett 2011, 2011, 1243.
D
DOI: 10.1021/acs.orglett.6b02401
Org. Lett. XXXX, XXX, XXX−XXX