Synthesis of bis-macrocyclic HCV protease inhibitor mk-6325 via intramolecular sp 2- sp 3 Suzuki-Miyaura coupling and ring closing metathesis

Article abstract of DOI:10.1021/acs.orglett.5b00418

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp²-sp³ Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.

Full text of DOI:10.1021/acs.orglett.5b00418

Letter
pubs.acs.org/OrgLett
Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via
Intramolecular sp2−sp3 Suzuki−Miyaura Coupling and Ring Closing
Metathesis
Hongmei Li,*,† Jeremy P. Scott,*,‡ Cheng-yi Chen,† Michel Journet,† Kevin Belyk,† Jaume Balsells,†
Birgit Kosjek,† Carl A. Baxter,‡ Gavin W. Stewart,‡ Christopher Wise,‡ Mahbub Alam,‡ Zhiguo Jake Song,†
and Lushi Tan†
†Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
‡Department of Process Chemistry, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11
9BU, U.K.
S
* Supporting Information
ABSTRACT: A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is
described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-
membered macrocycle with an intramolecular sp2−sp3 Suzuki−Miyaura cross-coupling to append the 18-membered macrocycle,
multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.
Scheme 1. Discovery Chemistry Approach to Key
Bis(Macrocyclic) Intermediate 10
nfection with the Hepatitis C virus (HCV) is a worldwide
a
1,2
Iepidemic, affecting approximately 170 million individuals.
The chymotrypsin-like NS3/4A serine protease plays an
essential role in the HCV viral replication process and has
proven a viable target for intervention. In 2011, the first-
generation direct acting NS3/4A antivirals boceprevir3 and
telaprevir4 were approved by the FDA. Vaniprevir (MK-7009)5
has subsequently been approved in Japan, and grazoprevir (MK-
5172)6 is currently in phase III clinical trials. As part of efforts to
discover an enhanced therapeutic profile, MK-6325 (1) was
recently identified as a potent HCV NS3/4A protease inhibitor
with improved genotype and mutant coverage.7 To support
clinical evaluation, a practical and efficient synthesis of this
unique bis-macrocyclic compound was needed. The synthesis of
MK-6325 (1) represents a substantial development challenge
due to the high complexity of the molecule which contains not
one but two fused macrocyclic rings. In this letter, we describe
the development of a practical asymmetric synthesis of MK-6325
(1).
a
Conditions: (a) VinylSnBu3, (tBu3P)2Pd, BHT, CsF, dioxane, 90%
yield. (b) RCM, 6 mol % Zhan-1B (see Scheme 3 for structure), 180
mL/g CH2Cl2, 40 °C, 67% yield. (c) BiCl3, KBH4, 68% yield.
quickly recognized that the vinylation, RCM, and reduction
sequence to the key intermediate 10 had a number of liabilities
for large-scale production. Specifically, (1) vinylation via Stille
coupling was undesirable due to the generation of toxic Sn
residues whereas the alternative vinylation via Suzuki−Miyaura
coupling with vinyl boronic acid gave very low yields; (2) the
Our efforts began by evaluating the approach used to discover
MK-6325 (1) which employed a ring-closing metathesis (RCM)
strategy to construct the 18-membered ring (Scheme 1).7,8 We
Received: February 9, 2015
Published: March 10, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00418
Org. Lett. 2015, 17, 1533−1536

Organic Letters
Letter
vinyl quinoxaline RCM precursor 9 is unstable; (3) the RCM
reaction required a high catalyst loading and high dilution
conditions and only proceeded in moderate yields; and (4)
selective reduction of the alkene isomers with BiCl3/KBH4 was
unscalable with lower yields of the desired product 10 at
increasing scale. Macrocyclization through intramolecular Heck
coupling of an analogue of 8 to form the 18-membered ring was
also investigated;5b,9 however, extensive screening of a variety of
Pd sources and phosphine ligands only provided <20%
conversion to a mixture of 18- and 17-membered macrocycles.
We envisaged an alternative approach to construct the 18-
membered ring macrocyclization of 1 through Pd-catalyzed
intramolecular sp2−sp3 Suzuki−Miyaura coupling.10 The use of
such an sp2−sp3 coupling would directly set the required
oxidation state without need for a subsequent selective alkene
reduction step. Retrosynthetically, MK-6325 (1) could be
assembled from cyclopropane sulfonamide side chain 4, 15-
membered macrocycle 2, and the cyclopentyl building block 11
(Scheme 2). The 15-membered macrocycle 2 could in turn be
constructed from commercially available amino ester 6, amino
acid 7, and quinoxaline derivative 5 via an RCM approach.
Scheme 3. Preparation of 15-Membered Macrocycle 2
Scheme 2. Retrosynthesis Analysis of MK-6325 (1)
heptane to afford RCM precursor 16 in 87% isolated yield over
the two steps.
The RCM of 16 to form 15-membered macrocycle 2 proved
robust and scalable and could be performed at low catalyst
loadings. For example, metathesis of diene 16 proceeded
efficiently with 0.75 mol % Zhan-1B catalyst11 and 1.5 mol %
p-benzoquinone in ClCH2CH2Cl (50 mL/g) at 60 °C. When
toluene was used as solvent, the RCM reaction could be carried
out with as low as just 0.45 mol % of Zhan-1B catalyst at a
concentration of 20 mL/g with full conversion within 1 h at 80
°C. The macrocycle 2 was isolated in 91% yield as a crystalline
solid.
For the preparation of the cyclopentanol 3 we envisioned an
enzymatic resolution of the corresponding racemic alcohol
(Scheme 4).12 Racemic cyclopentanol 3 was prepared in 67%
Scheme 4. Preparation of (1R,2S)-Cyclopentanol 3 via
Enzymatic Resolution
Our synthesis of the 15-membered macrocycle 2 started with
quinoxaline derivative 5 (Scheme 3), a known intermediate in
the synthesis of grazoprevir (MK-5172).6b Treatment of 5 with
lithium hydroxide in THF and water afforded acid 12 in 98%
yield. Acid 12 and amino ester 6 were then coupled using 1.25
equiv of EDC in the presence of 0.1 equiv of HOBt, and the
product 13 was isolated in 90% yield after crystallization.
Deprotection of 13 with HCl followed by neutralization with a
base afforded crude 14, which was subsequently coupled with
amino acid 7 followed by Boc protection and crystallization in
yield through copper-catalyzed epoxide opening of 1,2-epoxy-
cyclopentane 17 with a Grignard reagent freshly prepared from
magnesium turnings and 5-bromopent-1-ene 18. The crude
racemic cyclopentanol was then enzymatically resolved using
Novozymes 435 and succinic anhydride in t-BuOMe to give the
undesired ent-3 and succinic acid derivative 20, both with >98%
ee. Upon basification with aqueous Na2CO3, the undesired
alcohol ent-3 and other neutral organic impurities were readily
removed with a tBuOMe wash. The aqueous layer containing 20
was then hydrolyzed with NaOH, and the product was extracted
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DOI: 10.1021/acs.orglett.5b00418
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Organic Letters
Letter
Table 1. Optimization of sp2−sp3 Intramolecular Suzuki−
Miyaura Coupling of BPin Substrate 25
with tBuOMe to afford the desired chiral alcohol 3 in 48% yield
and 99% ee.
Activation of cyclopentanol 3 with N,N-disuccinimidyl
carbonate and pyridine as a base at 40 °C afforded intermediate
22 in 98% yield (Scheme 5).13 Intermediate 22 is stable in weakly
Scheme 5. Preparation of Suzuki−Miyaura Substrate 25
a
entry
ligand
X-Phos
solvent
efficiency
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMAc
CPME
0
2
JohnPhos
RuPhos
0
3
0
4
BrettPhos
dtbpf
0
5
0
6
Q-Phos
0.08
0.13
0.15
0.19
1.37
3.18
0.73
3.47
7
S-Phos
8
DavePhos
(tBu)3P·HBF4
AmPhos
9
10
11
12
13
cataCXium A
cataCXium A
cataCXium A
a
Conditions: 25, 8 mol % Pd(OAc)2, 16 mol % ligand, 2.0 equiv of aq
K3PO4, 100 °C. Ligand to Pd = 2:1. Efficiency reflects the A% ratio by
HPLC at 254 nm of the product 10 vs biphenyl internal standard.
dtbpf = 1,1′-Bis(di-tert-butylphosphino)ferrocene.
acidic and neutral conditions, and the succinimidyl group in 22
functioned as both an activating and protecting group for the
subsequent two transformations. Hydroboration of crude
intermediate 22 with 1.5 mol % [Ir(COD)Cl]2 and 3 mol %
1,1-bis(diphenylphosphino)methane (DPPM) in a mixture of
CPME and CH2Cl2 at 40 °C gave a 91% yield of desired product
11.14 The reaction was quenched with water, and the crude
product solution was used directly in the formation of carbamate
25. Deprotection of macrocycle 2 in neat TFA afforded amine 24
in 97% yield which was then combined with 11 in a basic biphasic
system to afford BPin Suzuki−Miyaura substrate 25 in 77% yield.
With the BPin compound 25 in hand, we next evaluated the
18-membered macrocyclization through Pd catalyzed intra-
molecular sp2−sp3 Suzuki−Miyaura coupling. Extensive phos-
phine ligand screening clearly showed that cataCXium A
(Ad2PBu)15 was superior to all other ligands evaluated (Table
1). After careful evaluation of the reaction parameters including
Pd salt, inorganic bases, solvents, temperature, and concen-
tration, the optimized cyclization conditions for 25 were
identified as 4 mol % Pd2dba3, 16 mol % cataCXium A, and 2.5
equiv of Na2CO3 in 30 vol of a 5:1 ratio of CPME/water (0.04
M) at 110 °C. Temperature was found to be crucial to the success
of this cyclization, as at a lower temperature of 85−90 °C the
reaction produced a large amount of proto-deborylated side
product (∼50% A%). Practically, the Suzuki−Miyaura coupling
was carried out under pressure to enable a reaction temperature
of 110 °C to be achieved. Under these conditions, the coupling
reaction gave >98% conversion with only 5% proto-deborylation.
The macrocyclized product 10 was crystallized and isolated as
the p-TSA salt from CPME in 70% yield. The use of the
potassium trifluoroborate salt 26 for this Suzuki−Miyaura
macrocyclization was also investigated.16 The BF3K salt 26 was
formed when BPin-compound 25 was washed with aqueous
KHF2. While the ligands S-Phos, X-Phos, and RuPhos only
produced ∼20% of the desired product 10, cataCXium A with
Pd(OAc)2 could efficiently promote the RBF3K intramolecular
Suzuki−Miyaura coupling with high conversion at 90 °C,
obviating the need to operate under pressure. Optimization led
to the use of 4 mol % Pd(OAc)2 and 8 mol % cataCXium A with 3
equiv of K2CO3 in a 30 vol solvent mix containing a toluene/
DMAc/water ratio of 20:7:3 (0.04 M). Interesting, the presence
of DMAc was observed to suppress dimer formation and the
desired product 10 could be obtained in 77% yield. The
intramolecular sp2−sp3 Suzuki−Miyaura 18-membered macro-
cyclizations of RBPin 25 and RBF3K 26 have both been
successfully demonstrated on multikilogram scale and, to the
best of our knowledge, represent the largest ring size to date
forged in this way.
Completion of the synthesis of MK-6325 (1) required the
installation of the cyclopropylsulfonamide side chain (Scheme
6). Saponification of the p-TSA salt of 10 with NaOH in DMAc
Scheme 6. Final Amidation To Form MK-6325 (1)
at 50 °C for 2 h produced acid 27 quantitatively, which was
isolated in 92% yield through direct crystallization from the
reaction mixture by addition of aqueous HCl. Activation of acid
27 with EDC or PivCl gave exclusively intermediate 28, whereas
activation with CDI gave a mixture of the CDI adduct and
intermediate 28. The subsequent ring opening of azlactone 28
with sulfonamide 4 proved to be challenging, as the reaction was
plagued by the formation of acid 27 as well as the desired product
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DOI: 10.1021/acs.orglett.5b00418
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Organic Letters
Letter
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27. Compound 1 was then crystallized from iPrOH/water as a
white solid in 90% yield and >99% purity.
In summary, we have developed a practical asymmetric
synthesis of the bis-macrocyclic HCV protease inhibitor
candidate MK-6325 (1) which has been used to produce
multikilogram quantities. A high yielding 15-membered RCM
macrocyclization of 16 together with an intramolecular sp2−sp3
Suzuki−Miyaura cross-coupling of 25 or 26 to form the 18-
membered macrocycle are the key carbon−carbon bond-forming
steps. The latter transformation showcases the power of this
bond formation for large ring formation in the context of
complex molecule total synthesis and represents the largest sp2−
sp3 Suzuki−Miyaura macrocyclization disclosed to date.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization, and
1
copies of H and 13C NMR spectra. This material is available
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hongmei06@gmail.com.
*E-mail: jeremy_scott@merck.com.
Notes
The authors declare no competing financial interest.
(9) Song, Z. J.; Tellers, D. M.; Dormer, P. G.; Zewge, D.; Janey, J. M.;
Nolting, A.; Steinhuebel, D.; Oliver, S.; Devine, P. N.; Tschaen, D. M.
Org. Process Res. Dev. 2014, 18, 423.
ACKNOWLEDGMENTS
■
We thank Rong-Sheng Yang (Merck) for analytical support and
David M. Tschaen, Michael Rudd, and John McCauley (Merck)
for technical input.
(10) Representative examples of macrocyclization via intramolecular
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