Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

Article abstract of DOI:10.1021/jacs.6b09764

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]₂.

Full text of DOI:10.1021/jacs.6b09764

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Article
Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal
Asymmetric Entry to the Indenopiperidine Core of an 11#-HSD-1 Inhibitor
Xudong Wei, Bo Qu, Xingzhong Zeng, Jolaine Savoie, Keith R. Fandrick, Jean-Nicolas Desrosiers,
Sergei Tcyrulnikov, Maurice A. Marsini, Frederic G. Buono, Zhibin Li, Bing-Shiou Yang, Wenjun Tang,
Nizar Haddad, Osvaldo Gutierrez, Jun Wang, Heewon Lee, Shengli Ma, Scot Campbell, Jon C Lorenz,
Matthias Eckhardt, Frank Himmelsbach, Stefan Peters, Nitinchandra Dahyabhai Patel, Zhulin Tan,
Nathan K. Yee, Jinhua J. Song, Frank Roschangar, Marisa C Kozlowski, and Chris H. Senanayake
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09764 • Publication Date (Web): 30 Oct 2016
Downloaded from http://pubs.acs.org on October 31, 2016
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Development
Roschangar, Frank; Boehringer Ingelheim Pharmaceuticals, Inc., Chemical
Development
Kozlowski, Marisa; University of Pennsylvania, Department of Chemistry;
University of Pennsylvania, Department of Chemistry
Senanayake, Chris; Boehringer Ingelheim Pharmaceuticals, Inc., Process
Research Department
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Sequential C-H Arylation and Enantioselective Hydrogenation Ena-
bles Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-
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HSD-1 Inhibitor
Xudong Wei,*,† Bo Qu,*,† Xingzhong Zeng,† Jolaine Savoie,† Keith R. Fandrick,† Jean-Nicolas
Desrosiers,† Sergei Tcyrulnikov,§ Maurice A. Marsini,† Frederic G. Buono,† Zhibin Li,† Bing-Shiou
Yang,† Wenjun Tang,†,# Nizar Haddad,† Osvaldo Gutierrez,§ Jun Wang,† Heewon Lee,† Shengli Ma,†
Scot Campbell,† Jon C. Lorenz,† Matthias Eckhardt,‡ Frank Himmelsbach,‡ Stefan Peters,‡ Nitinchandra
D. Patel,† Zhulin Tan,† Nathan K. Yee,† Jinhua J. Song,† Frank Roschangar,† Marisa C. Kozlowski§ and
Chris H. Senanayake†
† Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
‡ Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach/Riss, Germa-
ny
§ Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
KEYWORDS (11β-HSD-1 Inhibitor, Piperidine, Pyridinium Salt, Asymmetric Hydrogenation, Pd-Catalyzed C-H Arylation)
ABSTRACT: A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials
with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps
and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H aryla-
tion and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a
unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.
INTRODUCTION
from 2,3-dichloropyridine.3 The lengthy, racemic synthesis
relies on a Pd-catalyzed cyanation with Zn(CN)2 and a late-
stage resolution to supply drug candidate for early toxicologi-
cal studies. The overall yield for the synthesis of 1 was less
than 3% over a total of 15 steps with poor atom efficiency. In
order to provide large quantities of compound for accelerated
clinical studies (>3 tons for Phase III), a more efficient and
economical synthesis was urgently required.
Herein, we describe our design and development of a con-
cise asymmetric route to 11β-HSD-1 inhibitor 1 based on the
successful, sequential implementation of an intramolecular C-
H pyridinium arylation and enantioselective hydrogenation of
the resulting fused indenopyridinium salt enabled by
Boehringer Ingelheim’s P,N-ligand BoQPhos.5,6
Type 2 diabetes is a metabolic disorder characterized by hy-
perglycemia, insulin resistance, and relative insulin deficien-
cy.1 The global prevalence of diabetes was estimated to be 9%
in 2014 among adults and is projected to increase annually.2
In the search for an effective therapeutic agent to curb this
global epidemic, inhibition of the sodium-dependent glucose
co-transporter enzyme, 11β-hydroxysteroid dehydrogenase
type 1 (11β-HSD-1), has been investigated as a clinically rele-
vant tactic for reduction of cortisol production in various tis-
sues believed to be responsible for obesity and insulin re-
sistance in children and adults. To this end, compound 1
emerged from our discovery program as a potent, metabolical-
ly stable 11β-HSD-1 inhibitor3 and has quickly advanced in
clinical trials.
Compound 1 contains an intriguing tricyclic chiral in-
denopiperidine core that has also been observed in several
other biologically active molecules and alkaloid natural prod-
ucts.4 Despite its relatively small molecular size and the de-
ceptively simple structure, the architecturally unusual tricyclic
indenopiperidine nucleus containing two embedded contigu-
ous stereogenic centers presented a formidable synthetic chal-
lenge. Indeed, the first generation route towards 1 required
twelve linear steps to construct the tricyclic core 2 starting
RESULTS AND DISCUSSION
Retrosynthetic Analysis Chiral piperidines are common
structural motifs exhibited in natural products and highly pur-
sued in drug discovery; in this vein, numerous synthetic meth-
odologies have been reported.7 In designing an ideal synthesis8
for compound 1, a synthetic strategy was crafted in order to
provide the shortest possible synthetic route to the target mol-
ecule by taking full advantage of catalytic technologies to
drive down cost and effectively increase throughput of the
synthesis.
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Scheme 1. Fifteen-Step Discovery Approach and New Streamlined Retrosynthesis towards 1
2
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Tactically, synthetic approaches to piperidines utilizing pyr-
idines as starting materials became attractive due to their high
abundance and low cost. We envisioned that the two stereo-
genic centers at the piperidine ring juncture could be intro-
duced via a catalytic asymmetric hydrogenation of a tetra-
substituted double bond as part of a piperidine or pyridine ring
(Scheme 1, Synthon A). Fully aware of the challenges associ-
ated with the asymmetric hydrogenation of tetra-substituted
olefins,9 we aspired to engineer a new catalytic system for this
important transformation by leveraging our recently developed
dihydrobenzooxaphosphole (BOP)-based ligand series (vide
infra).10.11 To access the requisite hydrogenation precursor A,
a conceptually concise sequence was devised involving an
SNAr coupling of fragments 4 and 5 followed by an intramo-
lecular C-H arylation. At the outset, the proposed cyclization
to the C-3 position of pyridine was expected to be challenging,
with few related examples found in the literature.12,13 Howev-
er, if successful, an expedient route to the key intermediate 2
could be developed from the simple and inexpensive starting
materials.
guided our investigations towards the coupling of 4a with 5c.
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To our delight, the reaction occurred smoothly in the presence
of NaHMDS at room temperature in high yield after 2 h, al-
lowing facile access to the key intermediates 3a-b in a
straightforward and economical fashion.
Pd-Catalyzed C-H Arylative Cyclization With compound
3 in hand, the key intramolecular cyclization was investigated
next. Direct intramolecular C-H arylation of heteroarenes has
become an increasingly popular approach for the construction
of fused aromatic structures due to the inherent cost ad-
vantages.12,13 However, C-H arylation of pyridines has re-
mained an outstanding challenge, especially in an intramolecu-
lar fashion. To the best of our knowledge, literature precedent
for this type of cyclization to forge the indenopyridine scaffold
is non-existent. Indeed, initial attempts to achieve this cycliza-
tion employing 3a as substrate using Pd or Cu catalysts failed
to deliver the desired indenopyridine product; undesired C-N
bond formation generated 6 as the sole product (Scheme 3).
Scheme 3. Pd-Catalyzed C-H Arylative Cyclization
Synthesis of Pyridine Precursors for Cyclization 2-
Benzyl-substituted pyridines are highly valuable compounds
in organic synthesis. Existing synthetic approaches employ
elaborate starting materials and require either high reaction
temperatures or the use of Pd catalysts at high loadings,14 both
of which negatively impact development of a cost-effective
process. The SNAr coupling reaction between 3-iodo-4-
methylbenzonitrile 4a and 2-fluoropyridine 5a was first exam-
ined in order to prepare the requisite benzyl pyridine precursor
3 for cyclization; however, 30% yield was observed with sig-
nificant amount of self-condensation side products. Switching
to 2-chloropyridine 5b provided again trace product formation
(Scheme 2).
To circumvent this undesired pathway, pyridine N-
alkylation and acylation were pursued as a means to block C-
N bond formation and potentially facilitate formation of ben-
zylpyridinylidene benzonitrile 8 via deprotonation, which, in
turn, allows access to a cyclization via a Heck type manifold.
N-Acylation of pyridine 3 with phenyl chloroformate, howev-
er, was unsuccessful due to non-regioselective C-acylation at
the benzylic position. Fortunately, crystalline pyridinium salts
7a and 7b could be directly isolated after benzylation with
BnBr at 75 °C in high yields, providing a convenient means
for purification following the SNAr coupling. An overall yield
of >80% was readily achieved on metric ton scale by perform-
ing the SNAr coupling and benzylation in a single batch to
obtain pyridinium salts 7a and 7b as white crystalline solids
with >99% purity.
Scheme 2. SNAr Reaction of Nitrile 4 with 2-Substituted
Pyridine Electrophiles
Prior experience from our laboratories15 has shown that the
reaction between a carbanion and a sulfonyl pyridine is an
efficient method for construction of pyridine derivatives; this
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The pyridinium salts 7a-b were then subjected to cyclization based on the computed equilibrium for the acid-base inter-
1
2
3
4
5
6
7
8
with Pd catalysts. In the presence of Pd(OAc)2, weaker organic
bases (Et3N or i-Pr2NEt) afforded low conversion even under
forcing conditions. On the other hand, stronger base DBU
provided the desired tricyclic structure 9 with complete con-
sumption of 7a-b. The highly conjugated neutral species 816
was observed as an intensely red-colored compound upon
treatment of 7a-b with DBU. A detailed screening of Pd cata-
lysts and reaction conditions for the economically preferred
aryl bromide 7b identified Pd(dppf)Cl2 as the best catalyst
system. With 1.25 mol% of Pd(dppf)Cl2 and 3 equiv of DBU
in DMF at 110 °C for 2-5 h, the highly conjugated indeno-
pyridine 9 was obtained as a deep-red crystalline solid in 93%
yield and >99% purity after direct crystallization from the
crude reaction mixture. This novel and direct C-H arylation
enabled the construction of the requisite tricyclic indeno-
pyridine structure in a concise and highly efficient manner,
and was successfully implemented for production of com-
pound 9 in >1 metric ton quantities. Moreover, this work fur-
ther serves as the basis for development of a nickel catalyzed
intramolecular arylation as a general method for the synthesis
of 1-azafluorenes.17,18
change, the subsequent migratory insertion onto a double bond
of the charged species is untenable (48.1 kcal/mol) due to the
aromatic stabilization of the pyridinium. On the other hand,
the energetic barrier (29.6 kcal/mol) for migratory insertion of
the neutral species is readily accessible under the reaction
conditions of this process.
The set of equilibria prior to migratory insertion is con-
sistent with the reaction kinetics, and the reaction is expected
to be first order in Pd catalyst and zeroth order in substrate
(see the Supporting Information). Moreover, since the depro-
tonation equilibria control the concentration of the pre-
insertion intermediates, a fractional order in base is expected.
The catalytic cycle proposed based on the reaction kinetics
and computational results is shown in Scheme 5. Base-
mediated deprotonation sets up an equilibrium favoring the
neutral species 7’, which undergoes oxidative addition of the
catalyst. Alternately, oxidative addition to the pyridinium form
8’ followed by base mediated-deprotonation generates the
same neutral precursor required for the migratory insertion to
occur. Isomerization to a syn configuration then facilitates β-
hydride elimination to yield the cyclization product and gener-
ate a PdII species that reforms the Pd0 catalyst closing the cata-
lytic cycle. Although a lower energy pathway is calculated for
the free base 8, we speculate that the higher yields obtained
from pyridinium salt 7b are due to its greater stability, mitigat-
ing byproduct formation.16
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Mechanistically, the intramolecular cyclization can occur
through either the neutral intermediate 8 or the cationic pyri-
dinium salt 7b (Scheme 4). To fully understand the mecha-
nism while optimizing for process robustness, DFT calcula-
tions were performed with Gaussian 0919 at the B3LYP/6-
31G(d)-LANL2DZ(for Pd) level in the gas phase.20 With
DBU, the free base form 8/DBU•H+ was computed to be 4.8
kcal/mol lower in energy than 7b/DBU, consistent with 8 be-
ing the major species in solution (see below, benzyl replaced
with methyl for all intermediates). Notably, computations (see
the Supporting Information) revealed that this situation is de-
pendent on both the nitrile substitution acidifying the pyridini-
um and the use of a stronger amine base DBU in accord with
experimental findings.
Scheme 5. Proposed Catalytic Cycle for Pd-Catalyzed Cy-
clization
Scheme 4. Equilibria and Key Reaction Barriers for Pd-
catalyzed Cyclization (computed using the basis set M06/6-
311+G(d,p)-LANL2DZ(Pd)-SMD-nitromethane//B3LYP/6-
31G(d)/LANL2DZ(Pd)-gas, values in kcal/mol)
Non-enantioselective Hydrogenation and Chiral Resolu-
tion With a concise approach to the highly conjugated tricy-
clic indenopyridine 9 in hand, we next focused our attention
on the desired ring reduction (Scheme 6). Unfortunately, ex-
tensive evaluation of the reduction of 9 in the presence of a
range of heterogeneous catalysts (Pd/C, Pt/C, Raney Ni, Rh/C
and Ru/C) clearly indicated that the cyano moiety is incompat-
ible under these conditions. A complex reaction mixture was
always obtained as a combination of partial ring reduction, de-
benzylation, and nitrile reduction.
Both 7b and 8 were found to undergo facile oxidative addi-
tion to the corresponding aryl palladium species, in contrast to
the related nickel system where oxidative addition to the pyri-
dinium species is markedly lower in energy.17 Although signif-
icant amounts of both aryl palladium species are expected
Scheme 6. Challenging Hydrogenation of Indenopyridine 9
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asymmetric hydrogenation; reactivit
NC
NC
1
+
partial aromaticity of the dihydropyridine fragment. Yet it was
quickly recognized that compound 9 is not a suitable substrate
due to the low reactivity of the highly conjugated system and
formation of the dimeric impurities derived from the non-
chemoselective reduction of the nitrile moiety.
NBn
NBn
Heterogeneous
Hydrogenation
2
3
NC
NC
NBn
H2N
+
NBn
N
4
5
6
7
8
9
9
N
BnN
NBn
H
N-Benzylation of pyridines has recently been shown to acti-
vate the substrates for heterocycle reduction and suppress cata-
lyst deactivation via coordination of the nitrogen atom.23c,23d In
addition, the activated pyridinium salts should, in principle,
undergo chemoselective ring reduction even in the presence of
a nitrile group. Therefore, we investigated the reduction of
pyridinium salt 13. Different transition metals have been ap-
plied in asymmetric reduction of heteroarenes including ruthe-
nium, rhodium and iridium catalysts. We first tested the cati-
onic ruthenium diamine catalysts, which have been reported to
reduce substituted quinolines with high enantioselectivity.24
Even though highly reactive, large amounts of nitrile reduction
were observed and the highest enantioselectivity was at 27%
ee (Figure 1).
In view of these significant challenges and urgent material
requirements during early stages of development, we pursued
a temporary solution in which the nitrile group was selectively
hydrolyzed to the corresponding amide as a protection step,
followed by ring reduction/debenzylation and subsequent res-
toration of the nitrile group by amide dehydration (Scheme 7).
Even though no nitrile hydrolysis occurs under forcing basic
conditions (NaOH or KOH), strongly acidic conditions were
found to facilitate the desired hydration. The corresponding
amide was cleanly generated in 24 h by using of HCl in diox-
ane. Highly conjugated amide 11 was isolated as a deep red
crystalline solid in 94% yield.
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Scheme 7. Resolution Route via Nitrile “Protection”
0.25 equiv
NC
NC
NC
D-DBTA
NH
NBn
NH
100%
ee
yield of product
46%
0.5 D-DBTA
0.5 -DBTA
D
10
9
.
80%
60%
40%
20%
0%
2
HCl
POCl3
80 oC
94%
80%
>99.5 % de
40 oC
O
O
1) Pd/C, H2
Na2CO3
NBn
H2N
H2N
HCl
NH
2) HCl
85%
12
11
Ru1
Ru2
Ru3
Ru4
Ru5
Ru6
Ru7
Ru8
Amide 11 was then subjected to hydrogenation conditions
for a concomitant pyridine ring reduction and debenzylation.
Screening of different types of heterogeneous catalysts identi-
fied the optimal conditions with 3 mol% Pd/C in methanol at
CH3
CH3
CH3
CH3
O
O
S
N
O
S
N
O
o
O
O
S
N
O
80 C and 200 psi H2. It was found that addition of Na2CO3
O
S
N
Ph
Ph
Ph
Ph
Ph
Ph
Ru
Ru
induced a mildly basic reaction medium that favored first re-
duction of the ring and then hydrogenolysis. In this manner,
piperidine 1221 was obtained as its hydrochloride salt in ~85%
isolated yield. Dehydration with POCl3 subsequently afforded
the racemic nitrile 10 as a white crystalline solid in 80% yield.
Resolution of piperidine 10 was successfully achieved using
0.25 equiv of D-dibenzoyl-tartaric acid (D-DBTA). Enantio-
merically pure amine salt 2∙ 0.5 D-DBTA (>99.5% de) was
obtained in an excellent isolated yield of 45% (theoretical
yield 50%).
Ru
Ru
Cl
N
N
H
Cl
Cl
N
H
OTf
N
H
Ru2
Ru3
Ru4
Ru1
RuCl-cymene-TsDACH
CH3
Ru(OTf)-cymene-TsDpen RuCl-cymene-MsDpen
F
RuCl-C3-teth-MsDpen
F
F
O
O
F
S
N
F
Ph
Ph
O
Ph
Ph
O
O
S
N
O
S
N
O
O
S
N
O
Ru
Ph
Ph
Ph
N
H
OTf
Ru
Ru
Ru
Cl
N
H
N
H
N
H
Ph
OTf
Cl
Ru5
Ru6
RuCl-cymene-C6F6-Dpen
Ru8
Ru(OTf)-iBu-SO2Dpen
Ru7
Ru(OTf)-cymene-Cs-Dpen
RuCl-mesitylene-TsDpen
Figure 1. Ruthenium Catalysts Examined for Asymmetric Hy-
drogenation of 13
Enantioselective Reduction via Known Ligands In search-
ing for a direct method to convert compound 9 to the reduced
product, we postulated that homogeneous hydrogenation could
potentially provide better control over chemoselectivity and
lead to an enantioselective reduction if the proper chiral ligand
was employed. Pioneering work over the last few years on
enantioselective reduction of substituted pyridines and het-
eroarenes was highly encouraging.22,23 Nevertheless, most of
the strategies are not applicable to the enantioselective hydro-
genation of this indenopyridine system, highlighting the chal-
lenges associated with 2,3-disubtituted and fused pyridines.
Additionally, industrial applications have not been reported.
The indenopyridine 9 was initially tested in iridium catalyzed
Rhodium bisphoshine catalysts are highly effective for
tetrasubstituted alkene reduction,25 and have been applied to
the reduction of tetrahydropyridine enamine derivative to pro-
duce chiral piperidines.26 We thus pursued the asymmetric
reduction of pyridinium salt 13 with rhodium catalysts in the
presence of different families of chiral phosphine ligands in-
cluding bisphosphines with axial chirality, Solvias’ ferrocene-
based ligands, Ferringa’s monophosphoramidite ligands and
other reported chiral ligands. Disappointingly, both low con-
version and low enantioselectivities were observed for all the
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ligands evaluated (Figure 2). Reactions stalled at different screening of related ligands did not further improve the enan-
tioselectivity (Figure 3). The best ligand MP2-Segphos report-
ed for 2-arylpyridine reduction23d provided only 20% ee. The
Solvias’ ligands are equally ineffective. In addition to the low
enantioselectivity, a major issue was the inability of the cata-
lyst system to fully reduce the substrate 13. When the catalyst
loading was decreased to an economically feasible level of 0.1
mol% [Ir(COD)Cl]2, less than 15% product formation was
observed (last four ligands in bracket). Existing P,N ligands
including PHOX ligands,23b Ph-LalithPhos28 and BIPI 21029
produced unsatisfactory reactivity and enantioselectivity even
with 1 mol% of [Ir(COD)Cl]2.
1
2
3
4
5
6
7
8
stages of reduction (dihydropiperidine, tetrahydropiperidine,
etc.).
100%
ee
yield of product
80%
60%
40%
20%
0%
9
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Enantioselective Hydrogenation with BoQPhos Ligands
To overcome the tremendous challenges associated with the
desired pyridinium hydrogenation, our efforts shifted toward
the development of a new chiral ligand system. Recently, our
group has reported a highly modular dihydrobenzooxaphos-
phole (BOP) core for ligand design.10 Many effective ligands
have been derived from this motif and have been found to
mediate a variety of different catalytic transformations.11 In
particular, the rigid bidentate BoQPhos P,N-ligands, which
were constructed from the BOP core by anchoring a less basic
nitrogen containing pyridine fragment onto the carbon atom of
the O,P ring system (see Figure 4), have been successfully
demonstrated for asymmetric hydrogenation of non-
functionalized tri- and tetrasubstituted olefins.6 Since the pre-
sumed final intermediate in the reduction of tricyclic substrate
13 contains a tetrasubstituted double bond (see compound 15
in Figure 3), we anticipated that the BoQPhos series would be
applicable to the asymmetric reduction of 2,3-disubstituted
pyridinium salts (Figure 4).
O
O
O
O
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
MeO
MeO
PPh2
PPh2
O
O
SegPhos
Synphos
BINAP
MeO-BIPHEP
MeO
Ph
H
P(c-Hex)2
P(tBu)2
P
P
PPh2
(c-hex)2P
CH3
Ph2P
CH3
Fe
Fe
H
H
Ph
PPh2
Norphos
(c-hex)2P
H
OMe
Josiphos-009
Josiphos-001
PPh2
DIPAMP
NMe2
P(c-hex)2
H
Ph
(c-hex)2P
Fe
CH3
CH3
O
Fe
Ph
H
H
(c-hex)2P
P N
H
Fe
NMe2
H
O
P(c-hex)2
NMe2
Taniaphos-002
Mandyphos-002
Walphos-003
H3C
Monophos
(c-Hex)2P
P
P
In our first approach, pyridinium salt 13 was subjected to
hydrogenation conditions in the presence of [Ir(COD)Cl]2 and
L1, which was the best ligand previously found for olefin hy-
drogenation.6 However, limited product formation (10%) and
low enantioselectivity (57:43 er) were observed. We postulat-
ed that the low reactivity was caused by the steric hindrance
from the dimethoxyphenyl moiety on the western hemisphere
of the ligand. Indeed, removal of this group (L2) increased the
desired product to 40% with the same enantioselectivity. To
identify the key interactions of the ligand, structural modifica-
tions were pursued on both the western aryl and eastern pyri-
dine rings. The substitution on the pyridine ring affects the
enantioselectivity significantly. An ortho-MeO substitution on
pyridine (L3) increased the er to 84:16 with 90% yield. The
highest enantiomeric ratio of 85:15 was obtained with MeO-
BoQPhos (L5) containing methoxy substituents on both the
aryl and pyridine rings, and producing 97% yield of the re-
duced product. Changing one of the methoxy groups to iso-
proxy (L6, L7) or adding an additional methoxy group on the
pyridine ring (L10) resulted in slight decrease in enantioselec-
tivity. As expected, use of the non-rigid open-chain ligand
L12 also decreased the enantioselectivity. Gratifyingly, the
P,N ligand is completely chemoselective; the dimeric impurity
derived from nitrile reduction was not observed. Furthermore,
the MeO-BoQPhos is highly reactive in this challenging cata-
lytic asymmetric hydrogenation process, allowing catalyst
load to be decreased as low as 0.1 mol% [Ir(COD)Cl]2 while
still providing 93% isolated yield and 85:15 er, clearly demon-
strating the superb activity and robustness of the BOP-pyridine
P,N-ligands for the effective asymmetric pyridine reduction.
PPh2
PPh2 PPh2
O
CH3
CH3
P
N
N
O
Ph2P
Me
N
O
H
H3C
Me-Duphos
Skewphos
H
MCCPM
(1-NPh)-Quinaphos
P
H
H
P
H
tBu
tBu
P
H
P
H
P
P
P
P
tBu
tBu
Chiraphos
Tangphos
Binaphine
Duanphos
Figure 2. Rhodium Catalysts Investigated for Asymmetric Hy-
drogenation of 13
Iridium catalysts are known to reduce alkenes without the
assistance of any coordinating group on the substrate.27 To
facilitate the asymmetric reduction of pyridines, Charette and
Legault first demonstrated an activation process for pyridine
derivatives by formation of N-acyliminopyridinium ylides;
effective reduction was achieved applying Pfaltz’s PHOX type
P,N ligands.23b Recently Zhou’s23c and Zhang’s23d groups
demonstrated efficient asymmetric pyridine reduction by
forming activated N-benzylpyridinium salts. A number of
mono-substituted 2-aryl derived pyridines were reduced suc-
cessfully using biaryl ligands with axial chirality including
Synphos and MP2-Segphos. With the N-benzylpyridinium salt
13 in hand, we first tested the biaryl ligands. Indeed, promis-
ing results were obtained compared to the Ru and Rh catalysts.
About 40% ee was observed with Segphos, C3-Tunephos,
MeO-biphep and Synphos ligands. However, comprehensive
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1 mol% [Ir(COD)Cl]2
NC
1
2
3
NC
NC
3 mol% L
NHBn
Br
NBn
Br
NBn
450 psi H2, 50 o
THF/MeOH 3:1, 24 h
C
13
14. HBr
15
4
5
ee
yield of product
6
7
8
9
100%
80%
60%
40%
20%
0%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
Reaction conditions: 30 mg 13, 1.0 mol% [Ir(COD)Cl]2 and 3 mol% ligand, at 450 psi H2 and 50 °C in 0.9 mL THF/MeOH (3:1) for 24 h;
I2 (5 mol%) was added to the mixture of the four P,N ligands listed in parenthesis. The last four ligands in bracket were run at low catalyst
load: 0.3 g 13, 0.1 mol% [Ir(COD)Cl]2 and 0.3 mol% ligand in 5 mL solvent under the same conditions. Product yield was calculated from
quantitative HPLC solution assay of the product 14 upon Et2NH treatment; ee was obtained on HPLC with a chiral stationary phase.
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Evaluation of Iridium Catalysts with Known Ligands in the Asymmetric Hydrogenation of 13
In contrast to the bisphosphine ligands,23c,23d the use of iodine
as an additive improves both the enantioselectivity and the
reactivity of the hydrogenation reaction using the P,N-ligands.
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ee
yield of product
Journal of the American Chemical Society
Page 8 of 11
100%
80%
85:15 er (7h)
58:42 er
(30 h)
1
2
3
4
5
6
7
8
100%
80%
60%
40%
20%
0%
60%
40%
20%
0%
75:25 er (0.5 h)
85:15 er (0.5 h)
0
5
10
15
20
25
30
Time (h)
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
Figure 5. Comparison of asymmetric hydrogenation reaction
profiles with low catalyst load. Red: Br- salt with 0.2 mol%
Ir(COD)Cl]2/0.5 mol% L5/1 mol% I2 at 50 °C and 450 psi H2;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
blue: PF6 salt with 0.5 mol% Ir(COD)Cl]2/1.2 mol% L5/2.5
mol% I2 at 50 °C and 450 psi H2
The catalytic cycle of this asymmetric hydrogenation pro-
cess was proposed as an outer-sphere reaction pathway (Figure
6) based on the previously described mechanism of quinoline
reduction,31 and the computational studies on the enantio-
determining step of the key enamine intermediate 15 (Figure
7). The anionic iodo-Ir(III) hydride complex C first delivers
one hydride to the cationic pyridinium salt 13 to afford the
1,4-hydride addition product 16, and a catalytic neutral species
D which then coordinates one hydrogen molecule to generate
B. Continuous proton transfer from B to 16, and hydride trans-
fer from C to 17 produces the key enamine intermediate 15,
which undergoes enantio-determining proton transfer and syn
hydride delivery to produce cis-14. The catalyst is regenerated
by coordinating hydrogen and proton transfer to yield the pro-
tonated amine salt 14·HBr.
I
P
N
H
IrIII
H
H
H
B
Reaction conditions: 300 mg 13, 0.1 mol% [Ir(COD)Cl]2 and 0.3
mol% ligand, 0.5 mol% I2, at 450 psi H2 and 50 C in 5 mL
THF/MeOH (3:1) for 24 h. Product yield was calculated from
quantitative HPLC solution assay of the product 14 upon Et2NH
treatment; ee is measured on HPLC with a chiral stationary phase.
o
X
HX
N
I
13
HBn
14 .
H
Br
1
NBn
P
N
H
H
IrIII
16
4
I
I
H
Hydride
transfer
Proton
C
P
N
H
P
N
H
transfer
IrIII
IrIII
H2
I
H
Figure 4. Evaluation of BI’s Pyridine Containing P,N Ligands for
Asymmetric Hydrogenation of 13
H
H
H
H2
D
B
P
N
H
I
IrIII
P
N
H
IrIII
H
We have also evaluated the pyridinium salts with different
H
H
H
B
counter ions including Cl-, I-, HSO4 , BF4 , and PF6 . All these
salts demonstrated similar enantioselectivity of 85:15 er at
high catalyst load of more than 3 mol% iridium.30 For a cost
effective process, low catalyst load at ≤ 1 mol% iridium was
further investigated. The chloride salt is highly hydroscopic,
and was isolated exists as a monohydrate (containing about
5% water); the unproductive pathways of enamine hydrolysis
and condensation become more competitive at low catalyst
-
-
-
D
H
16
Proton
transfer
Hydride
transfer
N
cis-14
H Bn
18
I
I
P
H
P
H
H
IrIII
H
H
IrIII
NBn
17
N
C
N
Hydride
transfer
Proton
transfer
H
C
I
H
I
17
P
N
H
P
N
H
IrIII
15
NBn
IrIII
H
load. BF4- and PF6 salts were found to be much more soluble;
-
H
18
H
H
D
N
B
H2
Bn
but reaction monitoring revealed that lower enantioselectivity
was obtained at low catalyst loads and the enantioselectivity
continued to decrease over the course of the reaction (Figure
5). The bromide salt of 13 was eventually selected for the pro-
cess. The optimized conditions with 0.1 mol% Ir(COD)Cl]2
and 0.3 mol% of L5 were successfully applied to deliver the
desired product 14·HBr on multi-kilogram scale.
15
Figure 6. Proposed Catalytic Cycle of Outer-Sphere Dissociative
Pathway for Asymmetric Hydrogenation of 13 (CN group omit-
ted)
Calculations were conducted with the Gaussian 0919 pro-
gram at the DFT level of theory employing B3LYP32 and the
LANL2DZ basis set with ECP for Ir20 and D95v for the re-
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maining atoms.33 An outer-sphere dissociated mechanism34
benzimidazole acid followed by the subsequent hydrochloride
salt formation yielded the target compound 1 in 76% yield
over two steps.
1
2
3
4
5
6
7
8
similar to the DFT-computed Ir-catalyzed hydrogenation
mechanism of imines35 and quinolines31 was used as the basis
for the computational studies of the asymmetric Ir-(S,S-L5)-
catalyzed hydrogenation of the enamine intermediate 15. An
iodo-Ir(III) complex B was found to be a viable catalyst for
the sequential protonation and hydride delivery pathway for
enamine reduction. Although the rate limiting step is hydride
delivery (TS-2), the initial hydrogen transfer (protonation)
dictates the stereochemical outcome of the transformation
(TS-1) as the diastereoselective iridium-hydride delivery
would preferentially occur from the less sterically demanding
convex face (syn) directed by the stereocenter of the iminium
intermediate 18. This result is consistent with the experimental
observation that the addition of the two hydrogens across the
double bond in enamine 15 occurs in an exclusively cis-
fashion, with no trans-isomer detected in the reaction mix-
ture.21
Scheme 8. Completion of the Synthesis
i) aq NaOH
0.1 mol% [Ir(COD)Cl]2
ii) 0.2 equiv i-PrNEt2
0.3 mol% (S,S)-L5
O
Cl
NC
0.5 mol% I2
NC
NBn
Br
450 psi H2, 24 h
NHBn
Br
O
Cl
60 °C, 1h
THF/MeOH 3:1
9
13
14 • HBr
50 o
C
iii) MeOH, 50 °C, 2 h
>99.9:0.1 dr
85:15 er
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
i) T3P, Et3N
HO2C
N
(R)
i) aq NaOH
ii) 0.4 equiv
D-DBTA
NC
NC
NH
N
H
NH
(S)
80%
•HCl
1
•0.5 D-DBTA
2•0.5 D-DBTA
>99.75: 0.25 er
>99.95: 0.05 er
ii) aq HCl, EtOH
95%
19
85:15 er
67% yield
from 13
CONCLUSION
a)
I
In summary, an efficient enantioselective synthesis of 11ß-
HSD1 inhibitor 1 was developed starting from inexpensive
starting materials utilizing low catalyst loadings and excellent
step-economy. The total synthesis of the target molecule was
achieved in 7 steps with 38% overall yield starting from 3-
bromo-4-methylbenzonitrile (4b). The key feature of the syn-
thesis is a sequential intramolecular direct C-H arylation to
construct the tricyclic indenopyridine and subsequent asym-
metric hydrogenation of the resulting fused indenopyridinium
salt. The key asymmetric hydrogenation process was achieved
by designing a unique, rigid P,N-ligand MeO-BoQPhos. With
a low catalyst loading of 1000 ppm [Ir(COD)Cl]2, the enantio-,
diastero-, and chemoselective reduction of three contiguous
double bonds of compound 13, including a most challenging
tetra-substituted alkene intermediate, was accomplished. This
concise and innovative synthetic approach avoided functional
group manipulation of the labile nitrile moiety and accelerated
the production of 1 on multi-kilogram scale for clinical studies
of this diabetes drug candidate.
P
N
H
NC
IrIII
NBn
I
H
H
H
15
N
-
Bn
I
H
TS-1
H
H
P
N
P
N
H
IrIII
H +12.3 kcal/mol
G +23.5 kcal/mol
IrIII
H
N
H
H
H
Bn
B
H 0 kcal/mol
G 0 kcal/mol
H +1.6 kcal/mol
G +18.3 kcal/mol
I
P
N
H
H
IrIII
H
NC
NBn
H
H2
14
N
Bn
TS-2
H +8.3 kcal/mol
G +26.0 kcal/mol
O
b)
N
P
H
MeO
OMe
H
Me
Me
NBn
Me
H
NC
NC
NBn
18
ASSOCIATED CONTENT
NC
Supporting Information
NBn
14
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, NMR spectra, chromatograms, calcula-
tion data, kinetics data (PDF)
Figure 7. a) Proposed asymmetric outer-sphere dissociative cata-
lytic cycle of the Ir-Hydrogenation enamine intermediate 15. DFT
calculations: B3LYP/LANL2DZ, CPCM solvation model with
THF. Thermal corrections at: 323.15 K at 1 atm. b) 3D-Model of
TS-1 and stereochemical model via syn-Ir-hydride reduction of
iminium intermediate 18.
AUTHOR INFORMATION
Corresponding Authors
* Xudong Wei: xudongwei@yahoo.com
* Bo Qu: bo.qu@boehringer-ingelheim.com
Completion of the Synthesis With enantioenriched in-
.
denopiperidine 14 HBr in hand, selective debenzylation was
pursued en route to the final API (Scheme 8). As previously
described, incompatibility of the nitrile to hydrogenolysis con-
ditions thwarted our initial efforts. Fortunately, α-chloroethyl
chloroformate has been shown to cleave N-alkyl bonds under
mild conditions while tolerating a variety of sensitive func-
tionalities.36 Following in situ salt break and extraction, appli-
cation of this method effects debenzylation to afford the amine
19 as its hydrochloride salt. Without isolation, chirality up-
grade of the amine with D-DBTA furnished salt 2 in
>99.75:0.25 er and 67% overall isolated yield for the telescop-
ic process starting from pyridinium salt 13. Propane phos-
phonic acid anhydride (T3P)-mediated amide coupling with
Present Address
# Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
ACKNOWLEDGMENT
We thank the National Institutes of Health (GM087605 to
M.C.K.) for financial support. Computational support for the in-
tramolecular cyclization was provided by XSEDE on SDSC Gor-
don (TG-CHE120052).
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15) a) Busacca, C. A.; Wei, X.; Haddad, N.; Kapadia, S.; Lorenz, J.
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