Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338

Article abstract of DOI:10.1021/acs.orglett.9b03481

We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.

Full text of DOI:10.1021/acs.orglett.9b03481

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative
Antibiotic GDC-5338
́
Nicholas Wong,* Filip Petronijevic,* Allen Y. Hong,* Xin Linghu, Sean M. Kelly, Haiyun Hou,
Theresa Cravillion, Ngiap-Kie Lim, Sarah J. Robinson, Chong Han, Carmela Molinaro,
C. Gregory Sowell, and Francis Gosselin
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
S
* Supporting Information
ABSTRACT: We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum
antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding
macrocyclization via a Pd-catalyzed Suzuki−Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal
stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed
the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.
he emerging resistance of bacteria to our existing
antibiotic arsenal looms as a serious threat to the global
development. Thus, there is a need to develop a reliable and
robust synthetic route to enable both SAR studies of novel
arylomycin analogues and their clinical evaluation. Our
laboratories have recently described potential drug candidates
based on the arylomycin core that exhibit broad spectrum
antibiotic activity.5 Further SAR studies led to the
identification of GDC-5338 (1) as one of the best candidates
in this series. Herein, we report our development of a
preparatively useful synthesis of GDC-5338 (1) featuring a
high-yielding and robust Suzuki−Miyaura coupling reaction to
construct the macrocyclic arylomycin core that is comple-
mentary to our previously disclosed macrolactamization
approach.6
Our retrosynthetic analysis of 1 is shown in Figure 1. We
envisioned the amidoacetonitrile warhead could be installed
last following the amide bond formation steps; coupling the
macrocycle 2 with diamino acid 3 and pyrimidine acid 4.
Macrocycle 2 could be obtained through a Suzuki−Miyaura
macrocyclization to forge the biaryl linkage from the
corresponding linear tripeptide 6 assembled from derivatized
amino acid building blocks. A judicious selection of orthogonal
protecting groups would allow the flexible functionalization of
T
human healthcare system. In spite of extensive research and
development efforts, no new classes of antibiotics have been
approved for the treatment of Gram-negative bacterial
infections in the last 50 years.1 Arylomycin analogues have
been shown to represent a promising new class of inhibitors of
bacterial type I signal peptidase (SPase), an enzyme essential
for bacterial viability and growth.2 The unique mechanism of
action has thus attracted a broad interest in developing new
antibiotics based on the arylomycin core, resulting in multiple
syntheses reported by both the academic community3 and the
pharmaceutical industry.4 These syntheses share a common
strategy for macrocyclization centered on the construction of
the biaryl bond via either a catalytic Suzuki−Miyaura
reaction3,4 or a stoichiometric Cu-mediated oxidative cou-
pling3e from the corresponding linear tripeptide precursors.
Despite recent advancements, the absence of preparatively
useful chemistry to access suitable amounts of the arylomycin
macrocyclic core has likely thwarted progress toward
advancing new antibiotics to clinical development. The
drawbacks of previously reported syntheses lie in poor to
moderate overall yields, a lack of analytical characterization and
understanding of stereochemical integrity and chemical purity,
or the use of stoichiometric amounts of transition metals,
which make them unsuitable for pharmaceutical research and
Received: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03481
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Letter
the SI for details).8 Subsequent Miyaura borylation9 followed
by Boc removal with HCl in EtOAc provided advanced
intermediate 8 as an HCl salt in 86% yield over two steps. It is
noteworthy that bis(neopentylglycolato)diboron
(B2(NPG)2)10 was found to be the optimal organoboron
species, requiring a lower catalyst loading compared to
bis(pinacolato)diboron (B2Pin2) (1 mol % vs 7.5 mol %)
and resulting in faster hydrolysis to the corresponding boronic
acid in the next step of the synthesis.11,12 Coupling dipeptide 8
with functionalized Hpg 9 followed by hydrolysis of the
boronate ester and crystallization from EtOH/n-heptane
provided 6 in 97% yield without detectable stereochemical
erosion (>99:1 dr).13
We next studied the key Suzuki−Miyaura macrocyclization
of the linear tripeptide 6. There were several challenges that
remain unaddressed by past approaches on related substrates:
(1) low to moderate yields (10−48%) for substrates with
unprotected phenol on the Hpg residue;3a,d (2) high Pd
catalyst loadings (5−20 mol %) requiring tedious purification
by silica gel column chromatography; (3) lack of demon-
stration on preparative scale as the sole example reported
above gram scale afforded less than 20% yield;4 and (4)
insufficient analytical evidence for chemical purity and
stereochemical integrity of the desired product for pharma-
ceutical development.
Cognizant of these challenges, we decided to leverage our
microscale high-throughput experimentation (HTE) platform
to quickly evaluate reaction parameters such as catalyst, base,
and solvent to identify leads. The combination of KHCO3 as
base and CH3CN/H2O (1:1) as solvent was found to be
superior to others. Under these conditions, the three best
performing catalysts (AmPhos Pd G3, cataCXium A Pd G3,
and [(t-Bu3P)Pd(crotyl)]Cl) were further validated at 20 mol
% catalyst loading on mmol scale and [(t-Bu3P)Pd(crotyl)]-
Cl14 and gave the cleanest reaction profile (Table 1, entries 1−
Figure 1. Retrosynthesis of GDC-5338 (1).
the aromatic rings, appending appropriate side chains for SAR
purposes and the elaboration of the delicate architecture found
in 1.
Our initial strategy to assemble the linear tripeptide 6
followed literature precedent3a,d employing an N- to C-
terminus peptide coupling sequence (Scheme 1). However,
Scheme 1. Synthesis of Suzuki Macrocyclization Precursor 6
a
Table 1. Catalysts for Macrocyclization of 6
entry
catalyst
loading (mol %)
10 (HPLC A %)
1
2
3
4
5
AmPhos Pd G3
20
20
20
2
83
71
89
88
68
cataCXium A Pd G3
[(t-Bu3P)Pd(crotyl)]Cl
[(t-Bu3P)Pd(crotyl)]Cl
(t-Bu3P)2Pd
2
a
All reactions were run by heating the mixture of tripeptide 6 (80.0
mg, 97.0 μmol) and KHCO3 (10.2 mg, 1.05 equiv) in CH3CN/H2O
(4 mL; 1:1, v/v) at 60 °C for 2 h.
we observed >20% epimerization at the alanine stereocenter in
the coupling of Hpg-Ala dipeptide acid with the functionalized
Tyr amine. We envisioned that the alternative C- to N-
terminus coupling approach could minimize undesired stereo-
chemical erosion.3c Thus, our synthetic route to tripeptide 6
commenced with functionalized dipeptide 7, obtained from L-
tyrosine over four steps in 45% yield and high stereochemical
purity (>99:1 dr)7 using a modified literature procedure (see
3). Gratifyingly, the reaction reached full conversion using 2
mol % catalyst loading (cf. entries 3 and 4). Comparison with a
previously disclosed catalyst for the Suzuki−Miyaura macro-
cyclization, (t-Bu3P)2Pd, confirmed the superiority of [(t-
Bu3P)Pd(crotyl)]Cl presumably due to its improved oxygen
and moisture tolerance (entry 5).
B
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Table 2. Optimization of the Suzuki−Miyaura Macrocyclization
b
c
d
dg
,
de
,
d
f
O2 level headspace
(%)
[6]
11
cyclic oligomers
(A %)
linear oligomers
(A %)
10
assay yield (10)
a
entry conditions
(mL/g)
(A %)
(A %)
(%)
1
2
3
4
5
6
7
8
A
A
B
B
B
B
B
B
<0.01
<0.01
<0.01
12
500
12
12
12
12
12
50
0
0
0
11
2
2
2
2
2
1
2
0
0
0
68
95
91
66
53
48
44
95
30
78
70
37
28
21
16
88
h
0.5−1
6
6
h
5
10
21
10
15
25
0
14
14
10
0
h
h
<0.01
a
Conditions A: To a solution of 6 (12 mmol, 1.0 equiv) in CH3CN (8 mL/g)/ H2O (4 mL/g) was added catalyst (2 mol %) and the mixture was
heated to 60 °C for 1 h. Conditions B: 6 (9.0 mmol, 0.75 equiv) of in CH3CN (4 mL/g) was added to the solution of the catalyst (2 mol %) and 6
b
(3.0 mmol, 0.25 equiv) in CH3CN/H2O (8 mL/g; 1:1, v/v) over 1 h at 60 °C. Headspace O2 levels were monitored employing a headspace
c
d
oxygen probe sensitive to a 0.01% limit. Concentration is expressed as mL of solvent (CH3CN/H2O) per gram of 6. Results reported as HPLC A
e
f
% in the crude reaction mixture. Observed linear oligomers did not contain boron moieties. Assay yields determined by HPLC analysis of the
crude mixture. The amount of cyclic oligomers represents only dimers and trimers; higher order oligomers were omitted for simplicity. O2 level
g
h
was controlled by an initial sparge with N2 to achieve levels below 0.01% followed by backfilling with O2.
Scheme 2. End-Game Chemistry to GDC-5338 (1)
However, even under the optimized conditions using [(t-
Bu3P)Pd(crotyl)]Cl as precatalyst, a significant discrepancy
was observed between the isolated yields of 10 and the clean
reaction profile observed by HPLC analysis. Further HPLC
method development indicated that the missing mass balance
was associated with a late eluting mixture of linear and cyclic
oligomers of the tripeptide precursor 6, as elucidated by mass
spectrometric (MS) analysis.15
To suppress the undesired cyclic oligomers, we first
examined the effect of concentration (Table 2). Not
surprisingly, when the substrate concentration was lowered,
the amount of the undesired cyclic oligomer was minimized
(cf. entries 1 and 2). To mimic these high dilution conditions
but maintain practical reaction volumes, the linear precursor 6
was introduced as a solution in CH3CN over 2 h to a solution
of catalyst and base, which afforded a clean reaction profile
with 70% assay yield as determined by quantitative HPLC
analysis (entry 3).
To further improve the yield, we aimed to suppress the
formation of linear oligomers. Interestingly, we only observed
the protodeborylated linear peptide 11 and its corresponding
oligomers via mass spectrometric analysis of the crude reaction
mixtures but no detectable level of uncyclized oligomers
containing the boronates. This observation led us to
hypothesize that the linear precursor underwent protodebor-
ylation before the intramolecular coupling and that the oxygen
level in the reaction could be one of the critical process
parameters.16 Indeed, when the reaction was run at 0.5−1.0%
C
DOI: 10.1021/acs.orglett.9b03481
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O2, both the reaction conversions and assay yields were
diminished, with a concomitant formation of 11 as well as the
linear oligomer side products (entry 4). Additional increase of
the headspace O2 level led to even higher amounts of the
undesired side products (cf. entries 5−7). Thus, a very strict
degassing protocol was implemented to ensure consistent
reaction performance. Finally, running a reaction at higher
overall dilution (50 mL/g) accompanied by a slow addition of
6 led to further improvement in isolated yield (entry 8).
Consequently, this represents >60% increase in yield compared
to the sole example of this type of the Suzuki−Miyaura
macrocyclization previously described on decagram scale.4
After successful execution of the very challenging Suzuki−
Miyaura macrocyclization, we proceeded to complete the
synthesis of 1 (Scheme 2). Alkylation of macrocycle 10 with
tert-butyl N-bromoethyl carbamate17 led to functionalized
macrocycle 218 in a 76% yield after crystallization. The
absolute stereochemistry of 2 was unambiguously assigned by
single-crystal X-ray diffraction.
The Cbz group on macrocycle 2 was removed via Pd/C
hydrogenolysis in DMA. Initial evaluation of typical amide
coupling conditions for the attachment of diaminobutyric acid
(Dab) 3 to the macrocycle led to 18% epimerization at the
Dab stereocenter. After careful examination, the combination
of HATU19 and i-Pr2NEt was identified as the optimal
conditions to minimize the level of epimer (<0.05%), affording
the desired product in 99 A % purity by HPLC analysis after
crystallization from CH3CN/THF.
5338 was isolated in 75% yield over four steps as the bis-
mesylate salt from ester 15, with high chemical (>99 A %
HPLC) and stereochemical (>99:1 dr) purity.
In conclusion, we have developed an efficient, practical, and
stereocontrolled synthesis of GDC-5338 that proceeds in 17
steps and 15% overall yield. Central to our approach was the
strategic C- to N-terminus assembly of the linear tripeptide
backbone as well as the in-depth reaction understanding that
resulted in a high-yielding Suzuki−Miyaura macrocyclization,22
leading to a >4-fold yield improvement (from 20% to 88%)
compared to the sole previously described approach on
decagram scale.4 The final chemoselective deprotection and
salt formation afforded a stable, crystalline, pharmaceutical
grade GDC-5338, with high stereochemical integrity (>99:1
dr). We are confident that this practical entry into the
arylomycin core and synthetic analogues will accelerate further
development of new Gram-negative antibiotics.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03481.
Experimental details and spectroscopic data (PDF)
Accession Codes
CCDC 1959253 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Fmoc deprotection using TBAF20 allowed for a simple
aqueous workup to purge the corresponding byproduct. Biaryl
acid 4, obtained through a condensation of amidine 12 and
ketoester 13 followed by ester hydrolysis in 61% yield over two
steps (Scheme 2),21 was then introduced through an EDCI/
HOAt coupling to give the desired functionalized macrocycle
14 in 80% yield over four steps after precipitation from i-
PrOAc/n-heptane from compound 2.
Initial investigations of the ester hydrolysis in 14 proved to
be challenging due to competing epimerization at the Hpg
stereocenter (2.6−4.0 A % HPLC). Ultimately, we found that
using 2.5 equiv of LiOH in THF/H2O at 0 °C afforded the
corresponding acid with >98.5:1.5 dr as ascertained by HPLC
analysis. The resulting acid was then activated with HATU in
MeTHF and coupled with aminoacetonitrile hydrochloride in
the presence of i-Pr2NEt as base in DMF. Subsequent
crystallization from DMF/H2O afforded the complete frame-
work of 1.
Identifying suitable conditions for the global deprotection
and salt formation of the penultimate macrocycle proved
especially difficult due to the inherent reactivity of the nitrile
warhead in the presence of the nucleophilic free amine side
chains. Various acids and solvents combinations were
evaluated; however, due to high aqueous solubility of the
ammonium salts, significant loss upon aqueous workup was
observed. Attempts to obtain free base 1 by neutralization of
the ammonium salts resulted in competing hydrolysis of the
nitrile warhead. The combination of MsOH in THF and
CH3CN at 70 °C led to the formation of crude 1 as the
corresponding bis-methanesulfonate salt, which readily crystal-
lized from the solution and thus avoided an aqueous workup. A
subsequent recrystallization from n-PrOH/H2O was essential
to ensure high purity API and remove several impurities
including amide hydrolysis, nitrile hydrolysis, partial Boc
deprotection, dimer, and Ritter reaction side products. GDC-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wong.nicholas@gene.com.
*E-mail: petronijevic.filip@gene.com.
*E-mail: hong.allen@gene.com.
ORCID
Nicholas Wong: 0000-0001-9830-3541
Allen Y. Hong: 0000-0002-4691-548X
Xin Linghu: 0000-0002-8095-3244
Ngiap-Kie Lim: 0000-0002-3760-4874
Chong Han: 0000-0002-2863-3921
Francis Gosselin: 0000-0001-9812-4180
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Colin Masui, Dr. David Russell, and Dr.
Antonio DiPasquale (Genentech, Inc.) for experimental
assistance and Dr. Michael Koehler (Genentech, Inc.) for
insightful discussions.
REFERENCES
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