Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides

Article abstract of DOI:10.1021/jacs.5b05934

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

Full text of DOI:10.1021/jacs.5b05934

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Communication
Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed
C-N Coupling with Chiral Bisphosphine Mono-Oxides
Hongming Li, Kevin M. Belyk, Jingjun Yin, Qinghao Chen, Alan Hyde, Yining JI,
Steven Oliver, Matthew T. Tudge, Louis-Charles Campeau, and Kevin R Campos
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b05934 • Publication Date (Web): 28 Sep 2015
Downloaded from http://pubs.acs.org on September 28, 2015
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Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N
Coupling with Chiral Bisphosphine Mono-Oxides
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Hongming Li*, Kevin M. Belyk*, Jingjun Yin, Qinghao Chen, Alan Hyde, Yining Ji, Steven Oliver,
Matthew Tudge, LouisꢀCharles Campeau, and Kevin R. Campos
Department of Process Chemistry, Merck & Co. Inc., Rahway, New Jersey 07065, United States
Supporting Information Placeholder
Figure 2. Design Plan
ABSTRACT: A novel approach to hemiaminal synthesis via
palladiumꢀcatalyzed CꢀN coupling with chiral bisphosphine
monoꢀoxides is described. This efficient new method exhibits
broad scope, provides a highly efficient synthesis of HCV drug
candidate elbasvir, and has been applied to the synthesis of chiral
N,Nꢀacetals.
Recently, the World Health Organization reported that 150 milꢀ
lion people are infected with the hepatitis C virus (HCV). It is
estimated that as many as 5 million of these people are coꢀinfected
with the human immunodeficiency virus (HIV), which typically
leads to higher viral loads and results in accelerated disease proꢀ
gression in these patients.1 With limited treatment options for coꢀ
infected patients, HCV has become a leading cause of death for
HIV patients. Elbasvir, an inhibitor of the HCV NS5A protein,
administered in combination with grazoprevir, an HCV protease
inhibitor, has been clinically studied as an oral, highly efficacious,
and well tolerated regimen for the treatment of HCV infection,
including patients with HIV coꢀinfection (Figure 1).2
palladium/chiral phosphine complex capable of catalyzing the
BuchwaldꢀHartwig CꢀN coupling would also control the forꢀ
mation of the stereogenic center at the hemiaminal (Figure 2).7
This would allow us to leverage highꢀthroughput experimentation8
to rapidly evaluate the vast collection of existing chiral phosphine
ligands available for asymmetric transition metalꢀcatalysis. We set
out to test this hypothesis by preparing eneꢀimine B but discovꢀ
ered that it readily cyclized to the benzoxazine A. We then estabꢀ
lished that the stereogenic center in the hemiaminal A was stereoꢀ
chemically labile under basic conditions, presumably through the
intermediacy of B.9 This rapid equilibration of enantiomers proꢀ
vided the experimental foundation to test our desired reaction.
Figure 1. Elbasvir Structure
We began our investigation using racemic 1a. A variety of
commercially available chiral phosphines (L1ꢀL10) were surꢀ
veyed utilizing highꢀthroughput experimentation tools and techꢀ
niques.10 These ligands, in combination with either 10 mol%
Pd(OAc)2 or 5 mol% Pd2(dba)3, were found to cleanly catalyze
formation of indole 2a under mild conditions utilizing toluene as
solvent and K3PO4 as base at 55 °C (see Figure 3). Several of
these ligands provided 2a with good to excellent enantioselectiviꢀ
ty; however, the Pdꢀsource was found to have a very profound
effect on the overall performance of each class of ligands investiꢀ
gated. This difference was readily identified by comparing the
graphs in Figure 3 which show enantiomeric excess (%) vs. %
conversion of 1a to 2a under the standard conditions for both Pdꢀ
precursors.11 Overall, a significant decrease in indole formation
was observed with all nonꢀbisꢀphosphine monoꢀoxide (BPMO)
ligands when switching from Pd(OAc)2 to Pd2(dba)3. Josiphos12
ligands L1ꢀL3 in combination with Pd(OAc)2 provided some of
A defining structural feature of elbasvir is the benzoxazinoꢀ
indole core containing a chiral hemiaminal juncture. Many other
biologically active molecules contain the synthetically challengꢀ
ing chiral hemiaminal functionality, which is often critical to the
biological activity.3 Previous reports of catalytic asymmetric
syntheses are rare and mostly rely on the chiral Brønsted acidꢀ
catalyzed asymmetric addition of an oxygen nucleophile to an
imine.4,5 These methods require specific activating groups on
nitrogen to effect reactivity, which limits their general application.
Inspired by the synthetic challenge of assembling the benzoxaꢀ
zinoꢀindole core of elbasvir to enable the manufacture of this
important HCV therapy for patients, we developed a conceptually
novel approach to this new class of important hemiaminals.6
We envisioned an enantioselective formation of the chiral hemiꢀ
aminal with concomitant arylation of the nitrogen, directly yieldꢀ
ing the benzoazino indole present in elbasvir. In our design, a
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Figure 3. Ligand Screening of Model Substrate with Pd(OAc)2 and Pd2(dba)3
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the highest selectivities with (S)ꢀ2a being formed in up to 95% ee
with SLꢀ304ꢀ1 (L3). In contrast, these same phosphines were
found to be nearly inactive with Pd2(dba)3, resulting in the forꢀ
mation of only small amounts of 2a. Duphos13 ligands L4 and L5,
along with their respective BPMO derivatives14 L6 and L7, gave
poor to modest reactivities and selectivities with Pd(OAc)2. In the
presence of Pd2(dba)3 the BPMO ligands L6 and L7 showed exꢀ
cellent reactivity while L4 and L5 gave almost no conversion to
2a. Indole formation was also significantly depressed when (R,R)ꢀ
QuinoxP* (L10)15 was used with Pd2(dba)3; however, the same
ligand produced the best performing catalyst with Pd(OAc)2. The
(S)ꢀ2a indole was cleanly obtained in 96% ee with L10 under the
standard conditions. The substantial reactivity difference between
the BPMOs and parent bisꢀphosphines shown in Figure 3 suggestꢀ
ed that the bisꢀphosphines surveyed may undergo in-situ oxidation
to the corresponding BPMO.
Based on the experimental results and literature precedent,16 we
hypothesized that BPMO L11 was formed from L10 under the
standard conditions with Pd(OAc)2. We separately prepared
BPMO L11 to test this hypothesis.17 In contrast to L10, L11 proꢀ
vided a very active catalyst with Pd2(dba)3 cleanly giving (S)ꢀ2a
in 89% ee and almost complete conversion of 1a as shown in
Figure 3. Conversely, bisꢀphospine oxide L12 results in an inacꢀ
tive catalyst for the cyclization with either Pd(OAc)2 or Pd2(dba)3.
To further support our hypothesis, a series of 31P NMR spectrosꢀ
copy experiments18 following the catalyst formation and reaction
with either iodobenzene or model substrate 1a provides evidence
supporting in-situ formation of a BPMOꢀPd complex. A mixture
of L10 and Pd(OAc)2 in the presence of base, water, and dba in
tolueneꢀd8 produces 31P NMR signals at ~20 and ~60 ppm. These
signals compare favorably to those observed when L11 is mixed
with Pd2(dba)3. Alternatively, substitution of dba with iodobenꢀ
zene in simlar experiments produces 31P NMR signals matching
those formed starting from either L10/Pd(OAc)2 or L11/Pd(0).
Finally, 31P NMR monitoring of the standard reaction conditions
with Pd(OAc)2 using 1a shows the formation of a signals that also
match those observed when starting with L11/Pd(0). Based on
these experimental results, we believe that many of the bisꢀ
phosphines surveyed may undergo in-situ oxidation to the correꢀ
sponding BPMO by Pd(OAc)2 to generate active and selective
catalysts.
A plausible catalytic cycle for this transformation is shown in
Figure 4. In the presence of K3PO4 and water, L10/Pd(OAc)2 unꢀ
dergoes intramolecular redox reaction to generate the active
BPMOꢀPd(0) catalyst. Starting material 1a can isomerize via its
open form 1a’, and oxidative addition gives Pd(II) complex E
which may also isomerize via its open form E’. Deprotonation
leads to the stereodefined imidoꢀPd complex C’ and then reducꢀ
tive elimination affords the benzoxazinoꢀindole product and reꢀ
generates the Pd(0) catalyst. The exact nature of the enantiodeꢀ
termining step in this process is currently under investigation.
Figure 4. Plausible Catalytic Cycle
Additional reaction parameter screening to reduce catalyst loadꢀ
ing established that ligand L10 and Pd(OAc)2 provided the most
robust catalyst system. There was almost no detectable backꢀ
ground reaction observed with Pd(OAc)2 or Pd2(dba)3 in absence
of ligand (Table 1, entries 1ꢀ2). Other bases were also found to
cleanly facilitate indole formation (entries 3ꢀ5). However, optimiꢀ
zation of the reaction with L10 using K3PO4 was found to cleanly
provide (S)ꢀ2a in 96% isolated yield (94% ee) at 1.0 mol%
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Pd(OAc)2 (entry 6). Ligands L1ꢀL3 proved inferior at this lower
Pd loading (entries 7ꢀ8).19
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Table 1. Effect of Reaction Parameters
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Using these optimized reaction conditions, we explored the
substrate scope, which proved to be quite general (Table 2). Exꢀ
cellent yields and enantioselectivities (up to 96% ee) were obꢀ
tained with substrates containing various aryl and heteroaryl subꢀ
stituents (2a-2i). Alkyl substituted hemiaminals (1jꢀl) gave lower
product ee (~70%) with L10; however, ligand L320 afforded better
enantioselectivities particularly with αꢀbranched hemiaminals (2j,
2l). Modification of the dichlorobenzoxazine backbone demonꢀ
strated that high levels of stereoinduction were still attainable.
Table 2. Substrate Scope
Benzoxazines 1mꢀ1q provided 2mꢀ2q in excellent enantioselecꢀ
tivities (90ꢀ93% ee). Varying the aryl halide coupling partner was
also possible with aryliodide 1rꢀI cleanly giving product 2r in
93% ee. Arylchloride 1rꢀCl only gave trace amounts of product
with L10 as ligand; however, the more electronꢀrich ligand L3,
provided a suitable catalyst giving 2r in 92% ee.
Encouraged by these results, we envisioned that this approach
might be applicable to the synthesis of chiral N,Nꢀacetals which
are also very valuable pharmacophores, with few reported catalytꢀ
ic asymmetric syntheses.21 We found that substrate 3a and 3b
underwent the Pdꢀcatalyzed asymmetric CꢀN coupling using L2
as ligand, to provide 4a and 4b in 94% ee and 90% ee respectiveꢀ
ly (Scheme 1).
Scheme 1. Chiral N,N-acetal Synthesis
Based on this novel reaction methodology, we developed a new
6ꢀstep synthesis of elbasvir (Scheme 2).6 Racemic hemiaminal 1a
was assembled via Fries rearrangement, imine formation, and
condensation with benzaldehyde. After establishing the key hemiꢀ
aminal center in 96% yield (94% ee), elbasvir could be accessed
via Pdꢀcatalyzed borylation and then Suzuki coupling with
sidechain 8 in 42% overall yield.
Scheme 2. New Approach towards Synthesis of Elbasvir
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Chem., Int. Ed. 2012, 51, 9684.
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(6) For a chiral relay strategy to elbasvir, see: (a) Mangion, I.; Chen, Cꢀ
y; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon, I.;
Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zaꢀ
vialov, I. Org. Lett. 2014, 16, 2310. (b) Li, H.; Chen, Cꢀy; Nguyen, H.;
Cohen, R.; Maligres, P.; Yasuda, N.; Mangion, I.; Zavialov, I.;
Reibarkh, M.; Chung, J. J. Org. Chem. 2014, 79, 8533.
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Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (b) Surry, D. S.; Buchꢀ
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Chem. Soc. Rev. 2013, 42, 9283. For kinetic resolution by enantioselecꢀ
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dron Lett. 2009, 50, 4170. For desymmetrization via copperꢀcatalyzed
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In conclusion, we have developed an unprecedented approach to
the enantioselective synthesis of hemiaminals via a Pdꢀcatalyzed
CꢀN coupling using chiral bisphosphine monoꢀoxides. Essential to
this discovery was the observation that benzoxazine derivatives
such as 1a readily undergo racemization via the open form 1a’,
and this equilibration process could be terminated via entioselecꢀ
tive Pdꢀcatalyzed CꢀN coupling. Furthermore, we discovered that
an unexpected in-situ formation of a bisphosphine monoꢀoxide
from the bisphosphine by Pd(OAc)2 was a key step in the forꢀ
mation of the active catalyst necessary for CꢀN coupling. This
new approach was successfully applied to the highly efficient
synthesis of the HCV drug candidate, elbasvir, and the methodolꢀ
ogy has been successfully applied to the enantioselective syntheꢀ
sis of N,Nꢀacetals. Further applications of this methodology are
being investigated as well as mechanistic studies to identify the
enantioꢀ and rateꢀdetermining steps of this novel reaction.
ASSOCIATED CONTENT
Supporting Information
Full characterization, analysis of enantioselectivities, copies of all
spectral data, experimental procedures, and Xꢀray crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
hongming.li@merck.com
kevin_belyk@merck.com
(8) For recent reviews highlighting the utility of highꢀthroughput exꢀ
perimentation in academia and industry, see: (a) Schmink, J. R.; Belꢀ
lomo, A; Berritt, S. Aldrichim. Acta 2013, 46, 71ꢀ80. (b) Collins, K. D.;
Gensch, T.; Glorius, F. Nat. Chem. 2014, 6, 859.
Notes
The authors declare no competing financial interests.
(9) Treatment of 1a with KOBut afforded the corresponding Kꢀsalt of
open form 1a’. The ee of optically enriched 1a decreased from 96% to
2% within 30 mins in THF with K3PO4 at 50 ˚C. Alternatively, the ee
of optically enriched 1a decreased from 96% to 0% within 5 h in toluꢀ
ene with K3PO4 at 50 ˚C. In the absence of added base, the ee of optiꢀ
cally enriched 1a (96% ee) decreased to 11% and 0% ee respectively in
THF and toluene within 23 h at 50 ˚C.
ACKNOWLEDGMENT
We thank Ji Qi and Jing Li for the development of a general
method for the formation of diverse hemiaminal substrates 1,22 as
well as Wensong Xiao (Pharmaron Inc), Aaron Dumas and Edꢀ
ward Cleator for supporting starting material preparation. We
thank Andrew Brunskill, Alexei Buevich, Peter G. Dormer, Jinꢀ
chu Liu, Lisa Frey, RongꢀSheng Yang, Leonard Hargiss, and
Wilfredo Pinto for analytical and separations support. We also
thank Tetsuji Itoh, Kallol Basu, Yonggang Chen, Ian Davies,
Artis Klapars, Mark McLaughlin, Rebecca Ruck, and Professor
Stephen Buchwald (MIT) for additional experimental support and
very useful discussions. We thank Michele Mccolgan for graphic
design.
(10) For recent applications of highꢀthroughput experimentation see:
(a) Belyk, K. M.; Xiang, B.; Bulger, P. G.; Leonard, W. R., Jr.;
Balsells, J.; Yin, J.; Chen, C. Org. Process Res. Dev. 2010, 14, 692.
(b) Robbins, D. W.; Hartwig, J. F. Science 2011, 333, 1423.
(c) Friedfeld, M. R.; Shevlin, M.; Hoyt, J. M.; Krska, S. W.; Tudge, M.
T.; Chirik, P. J. Science 2013, 342, 1076. (d) Chung, C. K.; Bulger, P.
G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G.;
Limanto, J.; Bachert, D. C.; Emerson, K. M. Org. Process Res.
Dev. 2014, 18, 215. (e) DiRocco, D. A.; Dykstra, K.; Krska, S.;
Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem. Int. Ed. 2014, 53,
4802.
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analysis at a wavelength of 210 nm.
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(18) See supporting information for experimental details and results.
(19) The poor reactivity and diminished selectivity observed for L1ꢀ
L3 could be the result of nonꢀselective monoꢀoxidation.
(20) Josiphos ligand SLꢀJ304ꢀ1 (L3) is commercially available from
Solvias and has not received absolute stereochemical assignment.
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6366 and references cited therein.
(22) This work will be the subject of a future publication.
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