Modular, Scalable Synthesis of Group A Streptogramin Antibiotics

Article abstract of DOI:10.1021/jacs.7b08577

Streptogramin antibiotics are used clinically to treat multidrug-resistant bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their utility. New methods to chemically modify streptogramins would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Here we report a modular, scalable synthesis of group A streptogramin antibiotics that proceeds in 6-8 linear steps from simple chemical building blocks. We have applied our route to the synthesis of four natural products in this class including two that have never before been accessed by fully synthetic routes. We anticipate that this work will lead to the discovery of new streptogramin antibiotics that overcome previous limitations of the class.

Full text of DOI:10.1021/jacs.7b08577

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Communication
Modular, Scalable Synthesis of Group A Streptogramin Antibiotics
Qi Li, and Ian B. Seiple
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08577 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
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Modular, Scalable Synthesis of Group A Streptogramin Antibiotics
Qi Li and Ian B. Seiple*
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Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco,
San Francisco, California 94158, United States
Supporting Information Placeholder
ABSTRACT: Streptogramin antibiotics are used clinicalꢀ
ly to treat multidrugꢀresistant bacterial infections, but
their poor physicochemical properties and narrow specꢀ
tra of activity have limited their utility. New methods to
chemically modify streptogramins would enable strucꢀ
tural optimization to overcome these limitations as well
as to combat growing resistance to the class. Here we
report a modular, scalable synthesis of group A streptoꢀ
gramin antibiotics that proceeds in 6ꢀ8 linear steps from
simple chemical building blocks. We have applied our
route to the synthesis of four natural products in this
class including two that have never before been accessed
by fully synthetic routes. We anticipate that this work
will lead to the discovery of new streptogramin antibiotꢀ
ics that overcome previous limitations of the class.
Streptogramin antibiotics (also known as virginiamyꢀ
cins, madumycins, pristinamycins) are produced by sevꢀ
eral species of Streptomyces and comprise two structurꢀ
ally distinct subgroups: group A (23ꢀmembered macroꢀ
cyclic polyketide/nonꢀribosomal peptide hybrids) and
group B (19ꢀmembered macrocyclic depsipeptides).
Streptogramins have been used as livestock feed addiꢀ
1
tives for decades, but were not approved by the FDA
until the introduction of quinupristin–dalfopristin (Synꢀ
ercid®, a 30:70 combination of 7 and 2) in 1999. The
therapeutic use of this combination therapy is limited by
its IVꢀonly formulation and its narrow spectrum of activꢀ
ity, and it is reserved for hospitalized patients with mulꢀ
tidrugꢀresistant skin and skinꢀstructure infections or with
bacteremia caused by vancomycinꢀresistant Enterococ-
Figure 1. Selected natural and semisynthetic group A and
group B streptogramin antibiotics. Semisynthetic modificaꢀ
tions are shown in blue.
2
are in turn obtained from the fermentation broth of
cus faecium. An orally bioavailable combination of
2
Streptomyces pristinaespiralis. This semisynthetic apꢀ
semisynthetic streptogramins known as NXLꢀ103
(flopristin–linopristin, not depicted) underwent phaseꢀII
clinical trials in 2011, but has not progressed further in
proach has enabled commercialꢀscale production of this
waterꢀsoluble combination therapy but does not permit
broad exploration of structure–activity relationships of
3
the clinic.
4
each component. New methods to modify streptoꢀ
Quinupristin (7) and dalfopristin (2) are derived from
virginiamycin S1 (6) and virginiamycin M1 (1), which
gramins, informed by recent crystallographic data of
5
6
several streptogramins bound to bacterial and archaeal
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Scheme 1. Synthesis of madumycins I (4) and II (5) by the convergent assembly of 7 simple building blocks.
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a
Reagents and conditions: (a) 10 (0.5 equiv), TfOH (0.45 equiv), DCM, –78 ºC, 1 h, then a solution of isopropanol (1.1
equiv), 8 (1 equiv), 9 (1.25 equiv) in DCM (slow addition over 2 h), 1.5 h, 94%, 87% ee; (b) propargylamine (4 equiv), Alꢀ
Me (4 equiv), 0 ºC to 23 ºC, then 11, DCM, 40 ºC, 3 h, 90%; (c) CuCN (2 equiv), nꢀBuLi (4.2 equiv), Bu SnH (4.2 equiv), 1
3
3
h, –78 ºC, 100%, ≥20:1 E:Z; (d) 12 (1 equiv), 13 (1.5 equiv), DCC (1.6 equiv), DMAP (0.2 equiv), 6 h, then Et NH (480
equiv), DCM, 23 ºC, 3 h, 88%; (e) 16 (1.1 equiv), TiCl (1.2 equiv), Pr EtN (1.2 equiv), 2 h, 15 (1 equiv, slow addition over
0 min), 10 min, 64%; (f) 17 (1 equiv), 2,6ꢀlutidine (2 equiv), TBSOTf (1.2 equiv), DCM, 0 ºC, 30 min, 92%; (g) 19 (2
equiv), nꢀBuLi (4 equiv), 30 min, then 18 (1 equiv, slow addition over 30 min), THF, –78 ºC, 30 min, 71%; (h) 14 (1 equiv),
2
i
4
2
3
i
2
0 (1.1 equiv), Pr EtN (2 equiv), HATU (1.5 equiv), DCM, 23 ºC, 5 h, 88%; (i) 21 (1 equiv), JackiePhos (0.2 equiv),
2
Pd dba (0.1 equiv), toluene, 50 ºC, 3 h, 64%; (j) Bu NF (10 equiv), Im•HCl (10 equiv), THF, 23 ºC, 12 h, 91%; (k) 4 (1
2
3
4
equiv), Et BOMe (1.2 equiv), 15 min, then NaBH (2 equiv), THF:MeOH 4:1 (v/v), –78 ºC, 3 h, 72%. DCC = dicyclohexylꢀ
carbodiimide, DCM = dichloromethane, dba = dibenzylideneacetone, DMAP = 4ꢀdimethylaminopyridine, Fmoc = 9ꢀ
fluorenylmethoxycarbonyl, HATU 1ꢀ[Bis(dimethylamino)methylene]ꢀ1Hꢀ1,2,3ꢀtriazolo[4,5ꢀb]pyridiniumꢀ3ꢀ
oxidhexafluorophosphate, Im = imidazole, TBS = tertꢀbutyldimethylsilyl, TfO = trifluoromethanesulfonate, THF = tetrahyꢀ
drofuran, TMS = trimethylsilyl.
2
4
=
ribosomes, would enable further optimization to overꢀ
come the limitations of this class. Chemical syntheses of
group A streptogramins, the major components of comꢀ
bination therapies in the class, have appeared in the litꢀ
erature. Three routes to virginiamycin M2 (3) have been
demonstrably scalable route to facilitate access to gram
quantities of intermediates for analog development.
Herein we describe an efficient, modular, and scalable
synthesis of group A streptogramins.
Our route to madumycins I (4) and II (5) from seven
simple building blocks is depicted in Scheme 1 (building
blocks in bold color). The synthesis of the left half
commences with a Mukaiyamaꢀtype vinylogous aldol
reaction between silyl dienol ether 9 (available in one
step from methyl 2ꢀpentenoate) and isobutyraldehyde (8)
catalyzed by 10 to provide enoate 11 in 94% yield and
7
disclosed (see Figure 1) including an elegant synthesis
by Wu and Panek that represents the shortest and most
efficient fully synthetic route to a streptogramin reported
toꢀdate (6% overall yield over 10 linear steps from an
7
c,7d
allylsilane precursor).
Syntheses of madumycin II
8
9
(5) and of closely related streptogramins have also
been disclosed. To the best of our knowledge, fully synꢀ
thetic routes madumycin I (4) and virginiamycin M1 (1)
have not been developed. We were particularly interestꢀ
ed in access to 1, as its dehydroproline function serves
as a handle for the installation of sidechains (e.g., 1ꢀ2)
that increase water solubility and are permitted in its
1
0
8
7% ee. This step serves to set two of the stereocenters
found in the final product and is readily performed on
11
multigramꢀscale. Amidation of 11 with propargylamine
in the presence of trimethylaluminum followed by hyꢀ
drostannylation of the resulting terminal alkyne producꢀ
es 12 in 90% yield (2 steps). Notably, these two steps are
carried out in the presence of an unprotected
5
a,5b
binding pocket.
Additionally, we were interested in a
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Scheme 2: Syntheses of virginiamycins M1 (1) and M2 (3).
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Reagents and conditions: (a) 22 (1.5 equiv), 12 (1 equiv), DCC (1.6 equiv), DMAP (0.2 equiv), 6 h, then Et NH (480
2
i
equiv), DCM, 23 ºC, 3 h, 88%; (b) 23 (1 equiv), 20 (1.1 equiv), Pr EtN (2 equiv), HATU (1.5 equiv), DCM, 23 ºC, 5 h,
7%; (c) JackiePhos (0.2 equiv), Pd dba (0.1 equiv), toluene, 50 ºC, 3 h, 59%; (d) 24 (1 equiv), Bu NF (10 equiv), Im•HCl
10 equiv), THF, 23 ºC, 12 h, 82%; (e) PhIO (1.1 equiv), DCM, 23 ºC, 30 min, 92%; (f) 20 (1.25 equiv), Ghosez reagent (1.3
equiv), 2,6ꢀlutidine (2.5 equiv), 2 h, then 25 (1 equiv), DCM, 23 ºC, 12 h, 65%; (g) JackiePhos (0.3 equiv), Pd dba (0.15
equiv), toluene, 80 ºC, 24 h, 43%; (h) 26 (1 equiv), Bu NF (10 equiv), Im•HCl (10 equiv), THF, 23 ºC, 12 h, 80%. DCC =
dicyclohexylcarbodiimide, DCM = dichloromethane, dba = dibenzylideneacetone, DMAP = 4ꢀdimethylaminopyridine, Fmoc
2
8
(
2
3
4
2
3
4
=
9ꢀfluorenylmethoxycarbonyl, HATU
=
1ꢀ[Bis(dimethylamino)methylene]ꢀ1Hꢀ1,2,3ꢀtriazolo[4,5ꢀb]pyridiniumꢀ3ꢀ
oxidhexafluorophosphate, Im = imidazole, TBS = tertꢀbutyldimethylsilyl, TfO = trifluoromethanesulfonate, THF = tetrahyꢀ
drofuran, TMS = trimethylsilyl.
secondary alcohol, obviating the need for additional proꢀ
tection/deprotection steps. Dꢀalanine was introduced as
its Fmocꢀcarbamate (13) using DCC in the presence of
catalytic DMAP followed by the addition of diethylaꢀ
mine to cleave the Fmoc group in a single operation in
8% yield. The synthesis of left half 14 proceeds in 4
steps in 74% overall yield from building blocks 8 and 9
5 steps from commercially available materials), and has
been conducted on multigramꢀscale. It is important to
note that three of the steps in the sequence incorporate
building blocks that are amenable to structural diversifiꢀ
cation, as we will demonstrate (vide infra).
from 15 and 16 and has enabled the preparation of over
10 grams of 20.
The coupling of left half 14 to right half 20 is accomꢀ
plished using HATU in the presence of diisopropylethylꢀ
amine to provide macrocycle precursor 21 in 88% yield.
We next explored macrocyclization by means of an inꢀ
tramolecular Stille cross coupling reaction. Macrocyꢀ
clization reactions are often challenging steps in fully
8
(
7ꢀ9
synthetic approaches to streptogramins; indeed, Patꢀ
tenden and coworkers found a Stille macrocyzliation to
be a limiting step (30% yield with Pd dba and Ph As) in
2
3
3
9a,9b
their synthesis of 14,15ꢀanhydrovirginiamycin M2.
Our synthesis of right half 20 commences with the
aldol coupling of (E)ꢀ3ꢀbromobutꢀ2ꢀenal (15, available
in 3 steps from crotyl alcohol) and acetyl thiazoliꢀ
dinethione 16, providing 17 in 64% yield as a single
diastereomer. We found that the ßꢀhydroxycarbonyl in
Optimization of the Stille macrocyclization reaction on a
related substrate (see Supporting Information) revealed
that sterically hindered phosphine ligands provided the
highest isolated yields. Buchwald's JackiePhos, a ligand
designed to facilitate challenging transmetallations, was
1
3
1
7 was too labile for the subsequent steps in the syntheꢀ
found to be optimal. Thus, intramolecular Stille macꢀ
rocyclization of 21 proceeds at 50 ºC in 4 h with 20%
catalyst loading to provide protected macrocycle in 64%
yield. Highly dilutive conditions, which frequently
plague macrocyclization reactions, were not required:
this reaction proceeds without appreciable amounts of
dimeric or polymeric byproducts even at 0.005ꢀ0.01 M.
Removal of the silyl groups is accomplished with buffꢀ
ered tetrabutylammonium fluoride to provide maꢀ
dumycin I (4) with an overall yield of 38% from 8 and 9
or 21% from 15 and 16. Treatment of 4 with sodium
sis, and thus the secondary alcohol is shielded as its tertꢀ
butyldimethylsilyl ether in 92% yield to provide ßꢀ
silyloxyimide 18. Treatment with the dianion of oxazole
19, which contains a trimethylsilyl function at C5 to
prevent deprotonation of the oxazole ring, directly
provides right half acid 20 in 71% yield. This enabling
step allows the carboxylic acid to be directly introduced,
obviating the need for a subsequent deprotection step.
The route to the right half proceeds in 42% overall yield
12
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borohydride in the presence of diethylmethoxyborane
The Supporting Information is available free of charge on
the ACS Publications website.
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provides madumycin II (5) in 72% yield as a single diaꢀ
stereomer, and represents the first reported interconverꢀ
sion of these natural products.
Procedures for each step in Schemes 1 and 2, summary of
conditions screened for Stille macrocyclization, and characꢀ
terization of all intermediates and final compounds. (PDF)
To demonstrate the modularity of our route, we next
applied it to the synthesis of virginiamycin M2 (3) as
depicted in Scheme 2 (top sequence). DCC/DMAPꢀ
mediated esterification of alcohol 12 with Fmocꢀ
protected Dꢀproline (22) followed by the addition of
AUTHOR INFORMATION
Corresponding Author
Et NH provides proline ester 23 in 88% yield. Coupling
0
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with the right half (20), macrocyclization, and desilylaꢀ
tion provides virginiamycin M2 (3) in yields comparable
to those in Scheme 1. Overall, the route proceeds in 31%
yield from 8 and 9 (7 steps) or 18% overall yield from
15 and 16 (6 steps). This represents the shortest and
most efficient route to 2 reported to date.
*ian.seiple@ucsf.edu
Funding Sources
This work was supported by the National Center for Adꢀ
vancing Translational Sciences, National Institutes of
Health,
through UCSFꢀCTSI
Grant
Number UL1
TR001872 and UCSF Catalyst Award #A127552. Its conꢀ
tents are solely the responsibility of the authors and do not
necessarily represent the official views of the NIH.
Access to virginiamycin M1 (1) proved to be more
challenging due to its 2,3ꢀdehydroproline function
(Scheme 2). Coupling of 12 and 22 proceeds as above,
and the resulting secondary amine 23 is oxidized effiꢀ
ciently and selectively to imine 25 in the presence of
ACKNOWLEDGMENT
15
iodosylbenzene. We found that several amide bondꢀ
We thank Dr. Ziyang Zhang, Prof. Tim Newhouse, and
Prof. Tom Maimone for helpful discussions. We are in debt
to Dr. Mark Kelly (UCSF NMR Lab) for assistance with
the analysis of intermediate 12.
forming reagents were ineffective at coupling 25 to right
half 20, potentially due to the comparatively lower nuꢀ
cleophilicity of the 1,2ꢀdehydroproline function relative
to other amines. Successful coupling is achieved by iniꢀ
tial conversion of 20 to an acid chloride with Ghosez’s
16
Notes
reagent followed by treatment with imine 25, which
reliably provides macrocycle precursor in 65% yield on
multigram scale. Macrocyclization requires increased
catalyst loading (30%) and slightly increased temperaꢀ
ture (80 ºC) and provides 26 in 43% yield. Desilylation
efficiently provides virginiamycin M1 (1). This is the
first time this natural product has been accessed by a
fully synthetic route.
The authors declare no competing financial interest.
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(
(
1)
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nation. The left (14, 23, 25) and right (20) halves are
obtained in linear sequences of 3ꢀ5 steps from the simple
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(a) Entwistle, D. A.; Jordan, S. I.; Montgomery, J.;
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3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1996, 1315ꢀ1317; (b)
Entwistle, D. A.; Jordan, S. I.; Montgomery, J.; Pattenden, G.
Synthesis 1998, 1998, 603ꢀ612; (c) Dvorak, C. A.; Schmitz, W. D.;
Poon, D. J.; Pryde, D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I.
Angew. Chem. Int. Ed. 2000, 39, 1664ꢀ1666.
(
10) Simsek, S.; Kalesse, M. Tetrahedron Lett. 2009, 50, 3485ꢀ
3488.
(14) Chen, K.ꢀM.; Hardtmann, G. E.; Prasad, K.; Repič, O.;
Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155ꢀ158.
(15) Ochiai, M.; Inenaga, M.; Nagao, Y.; Moriarty, R. M.; Vaid,
R. K.; Duncan, M. P. Tetrahedron Lett. 1988, 29, 6917ꢀ6920.
(16) Devos, A.; Remion, J.; FrisqueꢀHesbain, A.ꢀM.; Colens,
A.; Ghosez, L. J. Chem. Soc., Chem. Comm. 1979, 1180ꢀ1181.
(
11) Although it is required in high loading, it is important to
note that catalyst 10 is readily prepared in a single step from α,αꢀRꢀ
diphenylprolinol and boric acid, and the α,αꢀRꢀdiphenylprolinol can
be recovered after use (see Supporting Information).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
12) Wood, R. D.; Ganem, B. Tetrahedron Lett. 1983, 24, 4391ꢀ
4392.
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O
a.
Ph
SnBu3
SnBu3
H
Ph
NH2
Me
Me
H
O
O
O
O
O
b.
, AlMe3
N
H
B
90%
.2-g scale
OMe
N
H
d. DCC, DMAP;
N
8
TfO–
O
Ph
H
3
Et NH
2
1
0
Me
Me
Me
Me
Me
NHFmoc
Me
13
OTBS
HO
9
4%, 87% ee
88%
c. CuCN, n-BuLi, Me
NH2
OH
11
OH
12
O
MeO
Bu SnH
1
.4-g + 5.7-g
3
2.6-g scale
Me
Me
Me
Me
Me
scale
1
00%
9
Left Half (14)
(
1 step from methyl
3.1-g scale
(≥20:1 E:Z)
2
-pentenoate)
Br
OH
O
Br
OTBS
O
Br
OTBS
O
e. TiCl4,
f. TBSOTf,
2,6-lutidine
O
Me
Me
Me
S
Me
Me
Me
Me
Me
N
Me
O
Br
O
i
g. n-BuLi
71%
PrEt N
2
N
O
O
6
4%
N
S
92%
N
S
HO
N
Me
H
S
TMS
19
5
.3-g + 8.0-g
Me
6.7-g scale
Me
3.0-g scale
S
S
HO
O
scale
1
5
16
17
18
TMS
(3 steps from
(2 steps from
(R)-valinol)
Right Half (20)
crotyl alcohol)
SnBu3
Br
O
O
O
i. Pd (dba)
JackiePhos
2
3
OH
OH
N
H
N
H
OTBS
N
6
4%
Me
Me
O
OH k. NaBH4,
Me
Me
O
O
H
h. HATU,
O
O
Me
Me
Me
O
O
Et BOMe
2.4-g scale
O
i
2
Pr EtN
2
Me
N
O
Me
N
O
N
O
N
H
O
N
H
7
2%
j. Bu NF,
88%
4
O
N
H
Me
Me
Me
Me
Im•HCl
Me
Me
O
2.8-g + 2.7-g
scale
1.0-g scale
madumycin II (5)
From 8 and 9: 8 steps, 27% yield
From 15 and 16: 7 steps, 15% yield
madumycin I (4)
From 8 and 9: 7 steps, 38% yield
From 15 and 16: 6 steps, 21% yield
91%
TMS
1.7-g scale
21

a.
O
SnBu3
Fmoc
N
O
O
HO
O
b. Right Half 20,
OTBS
O
OH
2
2
i
HATU, PrEt N
N
2
d. Bu NF,
Im•HCl
N
H
4
N
H
H
DCC, DMAP; Et NH
2
87%
Me
Me
Me
Me
Me
Me
O
Me
Me
O
O
O
O
O
H
8
8%
c. JackiePhos
Pd2(dba)3
H
82%
H
H
N
N
N
O
N
O
N
2.2-g scale
O
5
9%
O
Me
O
Me
O
Me
TMS
N
H
SnBu3
virginiamycin M2 (3)
From 8 and 9: 7 steps, 31% yield
23
24
f. Right Half 20,
Me
Me
From 15 and 16: 6 steps, 18% yield
NMe2
Me
Cl
OH
O
SnBu3
Me
Me
,6-lutidine
1
2
OH
O
O
O
2
N
H
a. 22, DCC, DMAP;
OTBS
O
Et NH
65%
Me
Me
Me
O
2
N
H
h. Bu NF,
Im•HCl
4
O
O
N
H
8
8%
e. PhIO
2%
3.0-g scale
Me
Me
Me
N
Me
Me
O
O
O
N
g. JackiePhos
Pd2(dba)3
80%
N
Me
O
N
O
9
N
1
.0-g scale
O
4
3%
1.2-g scale
Me
O
virginiamycin M1 (1)
From 8 and 9: 8 steps, 15% yield
From 15 and 16: 6 steps, 9% yield
Me
2
.3-g scale
TMS
2
5
26

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