Directed C-H Bond Oxidation of (+)-Pleuromutilin

Article abstract of DOI:10.1021/acs.joc.8b00462

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C-H silylation, followed by Tamao-Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure-activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C-H silylation reaction.

Full text of DOI:10.1021/acs.joc.8b00462

Subscriber access provided by UNIV OF DURHAM
Directed C–H bond oxidation of (+)-pleuromutilin.
Xiaoshen Ma, Roman Kucera, Olivia F. Goethe, Stephen K Murphy, and Seth B Herzon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00462 • Publication Date (Web): 17 Apr 2018
Downloaded from http://pubs.acs.org on April 18, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Title: Directed C–H bond oxidation of (+)ꢀpleuromutilin.
1
1
1
1
Authors: Xiaoshen Ma, Roman Kucera, Olivia F. Goethe, Stephen K. Murphy, and Seth B.
1,2
Herzon*
1
Affiliations: Department of Chemistry, Yale University, New Haven, Connecticut 06520,
2
United States.
Department of Pharmacology, Yale School of Medicine, New Haven,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Connecticut 06520, United States
Email: seth.herzon@yale.edu
Abstract.
Antibiotics derived from the diterpene fungal metabolite (+)ꢀpleuromutilin (1) are useful agents
for the treatment Gramꢀpositive infections in humans and farm animals. Pleuromutilins elicit
slow rates of resistance development and minimal crossꢀresistance with existing antibiotics.
Despite efforts aimed at producing new derivatives by semisynthesis, modification of the
tricyclic core is underexplored, in part due to a limited number of functional group handles.
Herein, we report methods to selectively functionalize the methyl groups of (+)ꢀpleuromutilin (1)
by hydroxylꢀdirected iridiumꢀcatalyzed C–H silylation, followed by Tamao–Fleming oxidation.
These reactions provided access to C16, C17, and C18 monooxidized products, as well as
C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared
from the protected C17 oxidation product. Additionally, C6 carboxylic acid, aldehyde, and
normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences
are carried out on gram scales. The efficiency and practicality of these routes provides an easy
method to rapidly elucidate structure–activity relationships that were previously beyond reach.
This study will inform the design of fully synthetic approaches to novel pleuromutilins and
underscores the power of the hydroxylꢀdirected iridiumꢀcatalyzed C–H silylation reaction.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
Introduction.
1
(+)ꢀPleuromutilin (1) is a diterpene antibiotic that inhibits protein synthesis by binding
2
to the peptidyl transferase center (PTC) of the bacterial ribosome (Scheme 1). Kilogram
quantities of (+)ꢀpleuromutilin (1) are accessible by fermentation. Many pharmaceutical
companies optimized the potency, metabolic stability, and spectrum of activity of 1 by
3
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
semisynthesis. The large majority of these analogs were prepared by sulfonylation of the C22
hydroxyl group (1→2, Scheme 1), followed by displacement with thiolꢀbased nucleophiles.
Tiamulin (3) and valnemulin (4) are two C14 derivatives in veterinary use since the 1990s.
Retapamulin (5) was approved for human use in 2007 as a topical ointment for the treatment for
skin infections. Lefamulin (6) recently passed a Phase III clinical trial for the treatment of
communityꢀacquired pneumonia. Slow rates of resistance development and minimal crossꢀ
4
5
3
c, 3g
resistance with other ribosomeꢀbinding antibiotics are defining features of this class.
2
a
2b
2c
The structures of tiamulin (3), retapamulin (5), lefamulin (6) and two additional
2
b
semisynthetic derviatives bound to the large ribosomal subunits of D. radiodurans or S. aureus
have been determined. Each molecule binds the peptidyl transferase center (PTC) with the
glycolic acid residue directed into the Pꢀsite and the hydrophobic tricyclic core positioned in the
Aꢀsite. The key hydrogen bonding contacts involve the glycolic acid ester and G2061, and a
weak interaction between the C11 hydroxyl group and G2505. The tricyclic core is largely
devoid of polar interactions with the PTC.
Scheme 1. Structures of (+)ꢀpleuromutilin (1), the C22 sulfonate 2, the semisynthetic C14 derivatives 3–6, and
the 12ꢀepiꢀmutilins 7 and 8.
Most pleuromutilins possessing the native tricyclic architecture have selective activity
against Gramꢀpositive pathogens. In 1986, Heinz Berner and colleagues, working at the Sandoz
Research Institute, discovered a process to epimerize the C12 quaternary position of 2 by an
2
ACS Paragon Plus Environment

Page 3 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6
unusual retroallylation–allylation pathway, to provide 12ꢀepiꢀpleuromutilin 22ꢀOꢀtosylate (7).
Recently, researchers at Nabriva explored functionalization of the pseudoequatorial alkene
formed in this isomerization. An oxidative cleavage–reductive amination sequence followed by
displacement of the C22 sulfonate provided 12ꢀepiꢀmutilin derivatives such as 8. These
derivatives have extended spectra of activities. They possess MIC values in the 0.125–8 ꢁg/mL
range against Gramꢀnegative and drug resistant bacteria such as carbapenemꢀresistant
7
7
g
7d, 7e
7e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Enterobacteriaceae (CRE), Klebsiella pneumoniae,
and Citrobacter freundii. This
7b
improvement in activity is due in part to decreased resistance from AcrAB–TolC efflux.
Collectively, these reports provide a strong case for further development of this class.
Because alterations to the tricyclic skeleton are underexplored, we targeted derivatives with
modified ring sizes, exocyclic substituents at sites other than C12 and C14, and atomic
substitution. As the first step of this research program, we developed a fullyꢀsynthetic route to
(+)ꢀpleuromutilin (1) and 12ꢀepiꢀmutilin (11) that proceeds by the convergent union of the
8
eneimide 9 with the C11–C13 synthon 10 (Scheme 2).
Scheme 2. Convergent fragment coupling en route to 12ꢀepiꢀmutilin (11).
CH
3
CH
3
CH
3
I
13
11 OPMB
O
CH
3
OH CH
3
CH
O
3
1
0
12
13
N
Boc
O
9
steps
OH
11
O
CH
3
H
H
9
(+)-12-epi-mutilin (11)
Many different annulation reagents and cyclization strategies can be envisioned to access
pleuromutilins with nonꢀnatural skeletons. To guide synthetic planning, we sought to rapidly
evaluate substituent effects at sites on the periphery of the tricyclic skeleton. To achieve this, we
have focused on identifying methods to functionalize the C–H bonds of the C15, C16, C17, and
C18 methyl substituents of (+)ꢀpleuromutilin (1). We hypothesized that these might be artifacts
1eꢀh
of the biosynthesis, which proceeds from geranylgeranyl diphosphate,
and may not be fully
optimized for binding to the ribosome. These efforts were inspired by recent successes in the
9
controlled, siteꢀselective modification of complex natural products.
Other researchers have examined direct functionalization of (+)ꢀpleuromutilin (1) or its
derivatives. These studies include microbial oxidation of C7 and C8, vinylic hydrogen–
deuterium exchange at C20, silverꢀcatalyzed C13–H amination, and ironꢀcatalyzed C7–H
oxidation. To our knowledge, only a single study describes methyl group oxidation and
involves a manganeseꢀcatalyzed C16–H amination, using a nonꢀnatural C7ꢀhydroxyl group to
direct the oxidation. The antimicrobial activity of this derivative was not evaluated, to our
knowledge.
1
0
11
12
13
1
4
Results and Discussion
C18 Oxidation.
Following an initial evaluation of several C–H oxidation protocols, the powerful
1
5
hydroxylꢀdirected iridiumꢀcatalyzed C–H silylation developed by Hartwig and coꢀworkers
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
emerged as the most general and practical method to modify the methyl groups of (+)ꢀ
pleuromutilin (1). In this approach, treatment of a dialkyl silyl ether with a catalyst derived from
(1,5ꢀcyclooctadiene)(methoxy)iridium(I) dimer and the bidentate ligand 3,4,7,8,ꢀtetramethylꢀ
1
,10ꢀphenanthroline (this combination is abbreviated hereafter as [Ir]), and norbornene (nbe) as
hydrogen acceptor results in dehydrogenative C–H activation to generate a silacycle
intermediate. Typically, the dehydrogenation occurs at the γꢀposition to generate a fiveꢀ
membered silacycle. Tamao–Fleming oxidation then provides a 1,3ꢀdiol product.
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
We first used the C11 hydroxyl group to direct oxidation. Selective protection of the C22
primary alcohol with tert-butyl(chloro)diphenylsilane (TBDPSCl) followed by hydrogenation of
the C19–C20 alkene with palladium on carbon (Pd/C) afforded 12 (98%, two steps, Scheme 3A).
The C22 alcohol was protected to prevent competitive silylation, and it was necessary to saturate
the C19–C20 alkene to avoid iridiumꢀcatalyzed hydrosilylation (Scheme S1). The C19–C20
hydrogenolysis product 16 (Scheme 3B) has been prepared and shown to be equipotent to (+)ꢀ
16
15a
pleuromutilin (1). In the original report, the silane was installed by an iridiumꢀ or rutheniumꢀ
catalyzed dehydrogenative silylation. However, these conditions failed to generate 13, even at
elevated temperatures (Table S1). The failure was most likely due to the steric hindrance created
Scheme 3. A. Synthesis of the C18 oxidation product 15a. B. Ball and stick representation of the Xꢀray
structure of 19,20ꢀdihydropleuromutilin (16). The C17–C10–C11–O11 and O11–C11–C12–C18 dihedral
angles are 0.95° and 49.9°, respectively. The C17, C10, C11, C12, and C18 atoms are shown in blue, all other
carbon atoms are shown in grey. Oxygen atoms are shown in red. Hydrogen atoms are omitted for clarity.
4
ACS Paragon Plus Environment

Page 5 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
by the C10 and C12 substituents. After some experimentation, we found that use of
chlorodimethylsilane [HSi(CH ) Cl] and triethylamine (NEt ) as base at 0 °C provided the silyl
ether 13 in 99% yield on a multigram scale. The silyl ether 13 was stable toward flashꢀcolumn
chromatography. The analogous diphenylsilyl derivative (not shown) was obtained using
chlorodiphenylsilane, with heating to 50 °C (97%, entry 7, Table S1).
3
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Iridiumꢀcatalyzed dehydrogenative C–H silylation of 13 proceeded smoothly to provide a
4:1 mixture of the C11–C18ꢀsilacycle 14a and the C11–C17ꢀsilacycle 14b, respectively. The
silacycles were unstable to purification by flashꢀcolumn chromatography. Efforts to implement
the Tamao–Fleming oxidation with the TBDPS ether in place were complicated by poor
substrate solubility (Table S2). Consequently, the TBDPS ether was removed [tetraꢀnꢀ
butylammonium fluoride (TBAF)] and the resulting product was oxidized with hydrogen
peroxide (H O ) in the presence of potassium bicarbonate (KHCO ). Following purification, the
2
2
3
C18 oxidation product 15a and the C17 oxidation product 15b were obtained separately in 73%
and 6% yields, respectively. Beginning with 4.2 g of the hydrogenolysis product 12, 2.0 g of the
C18 oxidation product 15a was obtained in one pass (Table S2, entry 10). Overall, the sequence
proceeds in 6 steps, 73% yield, and requires only two flashꢀcolumn purifications.
Although the rateꢀdetermining step of the iridiumꢀcatalyzed silylation of primary C–H
bonds γ to a silyl ether is not known, competition experiments suggested the C–H activation step
is rateꢀdetermining in the iridiumꢀcatalyzed silylation of secondary C–H bonds γ to a silyl
1
5b
ether.
endothermic and rateꢀdetermining in the rhodiumꢀcatalyzed silylation of primary C–H bonds γ to
Additionally, computational studies indicated that the C–H activation step is
1
7
a silyl ether. These data and the crystal structure of 19,20ꢀdihydropleuromutilin [16, Scheme
B; synthesized in 99% yield by hydrogenation of (+)ꢀpleuromutilin (1), see the Supporting
3
Information] provides some insight into the positional selectivity of the process. The crystal
structure reveals that the C17–C10–C11–O11 dihedral angle is close to 0° (0.95°). Thus, absent
any distortion of the tricyclic skeleton, C17–H activation would generate a 6ꢀatom metallacycle
that is forced to adopt a higher energy boat or twistꢀboat conformation. By comparison, the
O11–C11–C12–C18 dihedral angle is 49.9°. The 6ꢀatom metallacycle derived from C18–H
activation may adopt a lower energy chairꢀlike conformation.
The C18 oxidation product 15a was transformed to the aldehyde 17 by twoꢀstep sequence
comprising selective sulfonylation of the C22 alcohol, followed by oxidation of the C18 alcohol
1
8
[
Dess–Marin Periodinane (DMP), 65%, Scheme 4). The product 17 presents three orthogonal
functional groups for manipulation. This intermediate is identical to the Nabriva aldehyde 18,
7
h
save for the presence of a C12 ethyl substituent (vs. a C12 methyl substituent in 18). The
6
Nabriva route to 18 relies on Berner’s C12 epimerization, which provides a 1:1 mixture of C12
diastereomers, and requires a difficult chromatographic separation.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
Scheme 4. Synthesis of the aldehyde 17.
OH
2
OTs
2
CH
3
O
CH
3
O
CH
OH
3
1. TsCl
. DMP
65% (two steps)
O
CH
3
O
R
CH
3
O
18
12
2
O
O
OH
OH
CH
3
CH
3
H
H
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
15a
17 R = Et
3
(Nabriva intermediate)
18 R = CH
C17 Oxidation
1
5b
As C–H activation of a methyl substituent is more facile than a methylene position, we
reasoned that by inverting the C12 stereocenter we could overcome the torsional bias discussed
6
above and direct activation to C17. The 12ꢀepi-pleuromutilin derivative 20 was obtained in 94%
yield after four epimerization–separation cycles of the Oꢀ22ꢀsilyl ether 19, using diethylzinc to
promote the epimerization (Scheme 5). Reduction of the C19–C20 alkene and installation of the
dialkylsilyl ether proceeded in 98% yield. The silane 21 underwent C–H functionalization to
afford an 11:1 mixture of the C11–C17ꢀsilacycle 22a and the C11–C20ꢀsilacycle 22b.
Subjecting the unpurified mixture to Tamao–Fleming oxidation, followed by removal of the
TBDPS protecting group and chromatographic purification, afforded separately the C17
oxidation product 23a and the C20 oxidation product 23b in 81% and 5% yields, respectively.
The C17 oxidation product could be functionalized by selective sulfonylation of the C22
hydroxyl group, followed by oxidation of the C17 hydroxyl group (68%, Scheme 6).
Scheme 5. Synthesis of the C17 oxidation product 23a.
OTBDPS
O
OTBDPS
O
OTBDPS
CH
3
O
CH
3
2. Pd/C, H
3. HSi(CH ) Cl, NEt
2
CH
3
1
. ZnEt
94% (4 cycles)
2.9 g scale
2
4. [Ir], nbe
3
2
3
CH
O
CH
O
CH
3
CH
3
O
3
CH
3
3
12
20
CH
3
CH
OH
3
98% (two steps)
11:1 22a:22b
O
O
O
OH
O
CH
3
CH
3
CH
20
3
CH
3
Si
1
900 mg scale
H
H
CH
3
H
H
19
21
OH
OH
OTBDPS
CH
3
O
OTBDPS
CH
3
O
CH
3
O
CH3
O
5
3 2 2
. KHCO , 30% H O
CH
3
O
CH
3
20
O
CH
3
O
CH
3
CH
3
O
CH
3
CH3
CH3
CH
3
+
CH
3
+
20
OH
6. TBAF
O
O
O
11
O
11
OH
OH
OH
O
Si CH
O
CH
3
Si
CH
3
3
CH
3
1
7
17
CH
3
H
H
H
H
CH
3
23a 81%
23b 5%
22a
22b
Scheme 6. Synthesis of the aldehyde 24.
6
ACS Paragon Plus Environment

Page 7 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OH
OTs
2
2
CH
3
O
CH
3
O
1
2
. TsCl
CH
3
O
CH
3
CH
3
O
CH3
CH
3
CH
3
. DMP
O
O
OH
OH
OH
O
1
7
68% (two steps)
H
H
2
3a
24
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
C17 and C18 dioxidation
We recognized that the selectivity of the iridiumꢀcatalyzed C–H functionalization
reaction for primary C–H bonds provided an opportunity to obtain the C17, C18 dioxidized
derivative 28 (Scheme 7). Sequential silylation of the C22 and C18 hydroxyl substituents of 15a
98%, two steps), followed by silylation of the C11 alcohol in the product 25 generated the silane
6 (99%). The silane 26 underwent smooth C–H functionalization to form the expected C17–
C11 silacycle (not shown); Tamao–Fleming oxidation afforded the triol 27 in 76% yield (two
steps). Removal of the TBDPS ether [hydrogen fluoride–pyridine complex (HF•py)] provided
the tetraol 28 in 75% yield.
(
2
Scheme 7. Synthesis of the C17, C18 dioxidized product 28.
C16 Oxidation
We then examined the possibility of using the C14 oxygen to access either the C15 or
C16 methyl substituents. Treatment of (+)ꢀpleuromutilin (1) with excess benzyl chloromethyl
ether (BOMCl) afforded the ether 29 (99%, Scheme 8). Saponification of the glycolic ester
(
sodium hydroxide) followed by selective reduction of C19–C20 alkene under Shenvi’s
1
9
hydrogen atom transfer conditions provided the dihydromutilin derivative 30 (79%, two steps).
The C14 alcohol within 30 was converted to a silyl ether intermediate (not shown) using
chlorodiphenylsilane (HSiPh Cl, 71%). This silyl ether intermediate was subjected to the
2
iridiumꢀcatalyzed C–H silylation to afford the C14–C16 silacycle 31 in 69% yield. The silyl
ether 31 could be converted to the desired diol under slightly modified Tamao–Fleming
oxidation conditions (see Table S3 for optimization experiments) involving in situ opening of the
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
silacycle with TBAF, followed by oxidation of the silylfluoride intermediate (not shown) with mꢀ
chloroperbenzoic acid (mꢀCPBA, 80%).
Scheme 8. Synthesis of the C16ꢀoxidized derivative 32 using the C14 hydroxyl substituent as a directing
group.
OH
OBOM
O
1
CH
6
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
O
3
CH
3
20
1
CH
5
1. BOMCl
O
CH
O
3
3
14
CH
OH
3
DIPEA, NaI
CH
3
O
O
OBOM
CH
3
CH
29
, TBHP,
3
99%
H
H
(
+)-pleuromutilin (1)
2
. NaOH. 3. Mn(dpm)
3 3
, PhSiH
79% (two steps)
16 Ph
Si Ph
CH
3
4. HSiPh
2
Cl
CH
3
CH
3
CH
3
OH
NEt , 71%
3
CH
3
O
14
1
4
CH
OBOM
O
3
CH
3
O
5. [Ir], nbe, 69%
OBOM
CH
3
CH
3
H
H
31
30
6
. TBAF; then m-CPBA, 80%
OH
16
CH
3
CH
3
OH
CH
OBOM
3
O
CH
3
H
32
To reꢀinstall the glycolic ester fragment, the C16 alcohol within 32 was selectively
protected as a benzyloxymethyl (BOM) ether (68%, Scheme 9). The C14 hydroxyl group was
then acylated with benzyloxyacetic acid (88%). High pressure hydrogenolysis of the BOM and
benzyl ether protecting groups [palladium hydroxide on carbon, Pd(OH) /C] afforded 16ꢀ
2
hydroxyꢀ19,20ꢀdihydropleuromutilin (35, 77%). Surprisingly, 35 was unstable toward migration
of the glycolic ester residue to the C16 hydroxyl group. This isomerization occurred
quantitatively when the sample was allowed to stand in chloroformꢀd for 5 days at ambient
temperature, or could be promoted by treatment with trifluoroacetic acid (TFA) in
dichloromethane. This migration process can be explained by the proximity of the C14 and C16
hydroxyl groups. The Xꢀray structure of 16ꢀhydroxyꢀ19,20ꢀdihydromutilin (37) shows that these
two substituents are oriented toward each other, which would be expected to facilitate the acyl
shift (Figure 1). The structure of the isomerization product 36 was confirmed by independent
synthesis from the diol 32 via selective esterification of the C16 alcohol with benzyloxyacetic
acid, followed by hydrogenolysis with Pd(OH) /C (90% yield, two steps).
2
Scheme 9. Synthesis of the C16ꢀoxidized derivatives 35 and 36.
8
ACS Paragon Plus Environment

Page 9 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OH
OBOM
OBn
16
BOMO
CH
CH
3
CH
3
O
CH
3
CH
3
OH
1. NaH; then BOMCl, TBAI
8%
CH
3
OH
14
2. BnOCH
2
CO
2
H, EDCI, DMAP
O
CH
OBOM
3
CH
OBOM
3
3
O
O
88%
6
CH3
OBOM
O
CH
3
CH
3
H
H
CH
3
3
2
HO
33
H
3
4
O
OH
HO 16
O 16
5
. BnOCH
EDCI, DMAP
2 2
CO H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
O
4. CDCl
or TFA, CH
95%
3
CH
2
3. Pd(OH) /C
CH
3
3
OH
CH
CH
3
O
CH
3
14
6. Pd(OH)
2
/C
2
Cl
2
CH
OH
H
2
(800 psi)
77%
CH
OH
3
O
3
H
2
(800 psi)
O
>
CH
3
3
H
9
0% (two steps)
H
36
35
OH
1
6
CH
3
CH
3
OH
CH
CH
OH
3
O
3
H
37
Figure 1. Ball and stick representation of the Xꢀray structure of 16ꢀhydroxyꢀ19,20ꢀdihydromutilin (37). The
C14 and C16 carbon atoms are shown in blue. All other carbon atoms are shown in grey. Hydrogen atoms are
omitted for clarity.
Although the sequence shown in Scheme 8 was efficient, the alkene reduction step
Scheme 8, step 3) was highly exothermic, rendering scaleꢀup difficult. Furthermore, the
(
protecting group scheme did not allow for modulation of the C11 substituent. To address these
issues, an alternative strategy was developed (Scheme 10). Starting with 10 g of (+)ꢀ
pleuromutilin (1), saponification of the C14 ester and reduction of the C19–C20 alkene provided
dihydromutilin (38, 8.0 g, 92%, two steps). Selective protection of the C11 hydroxyl group with
trifluoroacetic anhydride (TFAA) followed by silylation of the C14 hydroxyl group (one flask)
afforded the silyl ether 39 (99%). Iridiumꢀcatalyzed C–H functionalization proceeded in 55%
yield on a 15 g scale. Selective removal of the C11 trifluoroacetate then generated the C16–C14
silacycle 41 (89%, 6.0 g). The C11 hydroxyl group in 41 was readily protected as a BOM ether
(
31, 99%, 6 g scale) or acetate ester (42, 99%).
Scheme 10. Alternative route to the C16 silylation product 31.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
OH
CH
3
SiHPh
2
3
CH
CH
3
CH
3
O
20
CH
3
1
. NaOH
CH
3
OH
3. TFAA, NEt
3
; then HSiPh
2
Cl
CH3
O
14
CH
3
O
1
4
CH
11OH
3
CH
OTFA
O
3
O
CH
OH
3
2. Pd/C, H
2
99%
O
CH
3
CH3
CH
3
H
9
2% (two steps)
8.0 g scale
H
H
(
+)-pleuromutilin (1)
10 g scale
38
39
Ph
Si Ph
16
Ph
Ph
Si Ph
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
Si Ph
CH
3
CH
3
CH
3
6. BOMCl, NaI, DIPEA, 99%
or Ac O, DMAP, pyr, 99%
O
5. NaOH
89%
O
4. [Ir], nbe
55%
CH
3
O
CH
3
CH
3
1
4
CH
OR
3
CH
OH
3
CH
OTFA
3
O
O
O
2
CH
3
CH
3
CH
40
3
H
H
8.0 g scale
H
15 g scale
3
1, R = BOM (6 g scale)
4
1
4
2, R = Ac
Functionalization of the 16ꢀhydroxylꢀ19,20ꢀdihydromutilin derivative 32 was then
investigated (Scheme 11). Sequential protection of the primary C16 alcohol and the secondary
C14 alcohol in 32 provided the orthogonally protected triol derivative 43 (80%, two steps,
Scheme 11). Removal of the silyl ether (TBAF) generated the primary alcohol 44 (99%).
Oxidation of the C14 alcohol then formed the carboxylic acid 45 (98%, two steps).
Scheme 11. Synthesis of the C6 carboxylic acid 45.
OH
OTES
OR
1
6
CH
3
CH
3
CH
3
OH
1
. TESCl, NEt
3
CH
3
14
CH
OBOM
3
CH
OBOM
3
O
2. MOMCl
NaI, DIPEA
O
CH
3
CH
3
H
H
8
0% (two steps)
32
43 R = MOM
3. TBAF, 99%
OH
CO
2
H
6
CH
3
CH
3
OR
CH
3
4
. DMP
OR
CH
3
CH
OBOM
3
O
CH
OBOM
3
5
. NaClO
-methyl-2-butene
NaH PO
2
O
CH
3
2
CH3
H
2
4
H
4
5 R = MOM
44 R = MOM
9
8% (two steps)
Berner and coꢀworkers reported the synthesis of structure 46, which was given the trivial
name 4ꢀepiꢀpleuromutilin, by treatment of (+)ꢀpleuromutilin (1) with sulfuric acid and
2
3
trimethylorthoformate (Scheme 12). The mechanism of this transformation is thought to
involve the acidꢀcatalyzed epimerization of the C4 position of 1 followed by condensation of
methanol to the C3 ketone to generate an oxocarbenium ion. 1,5ꢀHydride shift from C11 to C3
then provides 46. Saponification of the glycolic acid ester of 46 followed by reduction of the
alkene provided the alcohol 47 (98%, two steps). C16 silylation could then be achieved by an
alternative threeꢀstep sequence comprising silyl ether formation, dehydrogenative silylation, and
Tamao–Fleming oxidation, to generation the diol 49 (35% overall). This approach provides a
second route to C16 oxidized derivatives.
1
0
ACS Paragon Plus Environment

Page 11 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 12. C16 functionalization via 4ꢀepiꢀpleuromutilin (46).
OH
OH
CH
3
O
CH
3
O
1. (CH
SO , CH
5%
3
O)
3
CH
CH
H
O
3
4
CH
3
O
CH
3
CH
OH
11
3
H
2
4
3
OH
O
4
CH3
O
3
CH
3
8
3
CH O
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
(+)-pleuromutilin (1)
46
2. NaOH. 3. Pd/C, H
2
.
98% (two steps)
SiPh
O
2
CH
3
CH
3
CH
3
4. HSiPh
2
Cl
CH
H
3
CH
H
3
OH
CH
NEt , 99%
3
CH
3
CH
3
5. [Ir], nbe, 60%
CH
3
O
3 O
CH
3
O
3
CH O
48
47
6. TBAF; then m-CPBA, 59%
HO 1
6
CH
3
CH
H
3
OH
CH
CH
3
3
O
3
CH O
49
C15 Oxidation
Selective functionalization of the C15 methyl substituent proved more challenging. Attempts to
employ the C3 silyl ether derivatives 50 and 51 (Scheme 13A, obtained by reduction of the C3
ketone, see the Supporting Information) or the C16 hydroxyl groups (Scheme 13B) as directing
groups failed to afford any productive results. However, following protection of the C16
hydroxyl group in 32 [acetic anhydride (Ac O), 99%, Scheme 13C], the C14 hydroxyl group
2
could be used as the directing group to achieve C15 C–H functionalization. The diol 56 was
obtained in 26% yield over three steps.
Scheme 13. A. C3 silyl ether derivatives and B. C16 silyl ether derivatives employed in attempted C15
oxidation. C. Successful use of the C14 hydroxyl to direct C15 oxidation.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
OTBDPS
OTBDPS
CH3
O
A.
CH
3
O
1
5
CH
CH
15
CH3
3
CH3
CH
3
O
O
O 3
3
H 3
CH
3
H(CH
3
)
2
Si
OMOM
OMOM
CH
3
H(CH ) Si
CH3
H
3
2
O
H
H
50
51
3 2
Si(CH ) H
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
Si(CH
3
)
2
H
O
B.
O
16
MOM
O
1
6
CH
CH
MOM
15
3
1
CH
5
CH
3
CH
3
O
3
H
3
CH
OBOM
3
O
CH
3 O
CH
3
3
CH O
H
5
2
53
HO
AcO
C.
16
CH
CH
3
3
CH
3
3
OH
1
. Ac
2
O
CH
3
OH
CH
3
1
4
CH
OBOM
O
DMAP, pyr.
99%
O
OBOM
CH
3
CH
3
H
H
32
54
, 91%
AcO
2
2 3
. HSiPh Cl, NEt
AcO
2
SiPh H
1
5
CH
CH
3
3
CH
3
3
OH
3. [Ir], nbe, 49%;
CH
O
HO
3
1
4
CH
O
4. TBAF;
O
OBOM
OBOM
CH
3
then m-CPBA, 58%
CH
55
3
H
H
5
6
Derivatization.
As discussed in the introduction, the Nabriva scientists disclosed that functionalization of
the pseudoequatorial position in 12ꢀepiꢀmutilins with polar diamine substituents resulted in7
extended spectrum activity, including activity against drugꢀresistant Gramꢀnegative pathogens.
These findings are consistent with a recent study by Hergenrother and coꢀworkers which
suggested that primary alkyl amines can increase the accumulation of antibiotics in Gramꢀ
20
negative bacteria. Accordingly, we sought to demonstrate the feasibility of using our oxidized
derivatives to access analogs with polar diamine substituents.
Starting from the 17ꢀhydroxypleuromutilin derivative 57, we prepared four pleuromutilin
analogs bearing primary or secondary amine substituents at C17. The analogs 58a–d were
obtained via the fourꢀstep sequence depicted in Table 1 (34–69% overall).
a
Table 1. Installation of diamine substituents at the C17 position.
12
ACS Paragon Plus Environment

Page 13 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OH
OH
CH
3
O
CH
3
O
CH
3
O
CH
3
CH
3
O
CH3
CH
3
CH
3
O
O
OH
NH
OH
NH
1
7
17
H
H
–
CF CO2–
3
CF
3
CO
2
+H
N
+
3
3
H N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
5
8a, 34%
58a, 34%
OH
OH
CH
3
O
CH
3
CH
3
O
CH3
O
CH
3
CH3
O
CH3
O
OH
CH3
17
O
H
OH
NH
17
H
CF3CO2–
N
–
3 2
CF CO
N
H2
+
+
NH
3
5
8d, 67%
5
8c, 68%
a
For detailed conditions, see the Supporting Information. Isolated yields over four steps.
Additionally, we sought to access C6ꢀnormethylꢀ19,20ꢀdihydropleuromutilin (62,
Scheme 14) to probe the influence of the C16 methyl substituent on activity and demonstrate the
ability of this chemistry to access derivatives with modified carbon skeletons. Beginning with
the C16 oxidation product 32, Dess–Martin oxidation provided the aldehyde 59 (66%).
Rhodiumꢀmediated decarbonylation afforded the 16ꢀdesmethylmutilin derivative 60b (33%)
and the lactone 60a (34%). Esterification of 60b followed by global deprotection generated C6ꢀ
normethylꢀ19,20ꢀdihydropleuromutilin (62, 45%, two steps).
21
Scheme 14. Synthesis of C6ꢀnormethylꢀ19,20ꢀdihydropleuromutilin (62).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Conclusion.
In conclusion, we have demonstrated the application of Hartwig’s hydroxylꢀdirected iridiumꢀ
catalyzed C–H silylation reaction toward the functionalization of the diterpene fungal metabolite
(+)ꢀpleuromutilin (1). These investigations provided the first access to C16, C17, and C18
monooxidized derivatives as well as C15/C16 and C17/C18 dioxidized products. The initial
conversion of these structures to novel pleuromutilins was demonstrated. This work provides a
platform to rapidly modify (+)ꢀpleuromutilin (1) at sites that have not been extensively
investigated (C16, C18) or at sites that were completely unexplored (C15, C17). The efficiency
and practicality of these routes provides a foundation for the rapid production of new derivatives,
which will ultimately inform fully synthetic approaches to new pleuromutilins.
Experimental Section.
General Experimental Procedures. All reactions were performed in singleꢀneck, flameꢀdried, roundꢀ
bottomed flasks fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Airꢀ
and moistureꢀsensitive liquids were transferred via syringe or stainless steel cannula, or were handled in a
nitrogenꢀfilled drybox (working oxygen level <5 ppm). Organic solutions were concentrated by rotary
evaporation at 30–33 °C. Intermediates were purified using a Biotage Isolera system, employing
polypropylene cartridges preloaded with silica gel (60 Å, 40–63 µm particle size, purchased from
Silicycle, Quebec City, Canada) or neutral aluminium oxide (60 Å, 50–200 µm particle size, purchased
from Acros Organics, New Jersey, USA). Samples were eluted using a flow rate of 12–50 mL/min, with
detection by UV (254 nm). Analytical thinꢀlayered chromatography (TLC) was performed using glass
plates preꢀcoated with silica gel (0.25 mm, 60 Å pore size) impregnated with a fluorescent indicator (254
nm). TLC plates were visualized by exposure to ultraviolet light (UV) and/or submersion in aqueous
14
ACS Paragon Plus Environment

Page 15 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ceric ammonium molybdate solution (CAM), acidic pꢀanisaldehyde solution (PAA), or aqueous
potassium permanganate solution (KMnO ), followed by brief heating on a hot plate (120 °C, 10–15 s).
4
Materials. Commercial solvents and reagents were used as received with the following exceptions.
22
Toluene were purified according to the method of Pangborn et al. Dichloromethane was purified
22
according to the method of Pangborn et al, degassed by three freeze–pump–thaw cycles, and stored
under an atmosphere of argon over 4 Å molecular sieves before use. 1,2ꢀDichloroethane, acetone,
chloroform, and pyridine were distilled from calcium hydride under an atmosphere of nitrogen
immediately before use. Commercial anhydrous N,Nꢀdimethylformamide (SigmaꢀAldrich Corporation,
St. Louis, MO) was degassed by three freeze–pump–thaw cycles and stored over activated 4Å MS under
an atmosphere of nitrogen before use. Tetrahydrofuran was distilled from sodium–benzophenone under
an atmosphere of nitrogen immediately before use. Triethylamine and N,Nꢀdiisopropylethylamine was
distilled from calcium hydride under an atmosphere of nitrogen immediately before use. Methanol was
distilled from magnesium under an atmosphere of nitrogen immediately before use.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
1
Instrumentation. Instrumentation. Proton nuclear magnetic resonance spectra ( H NMR) were
recorded at 400, 500, or 600 MHz at 24 °C, unless otherwise noted. Chemical shifts are expressed in
parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to residual protium
in the NMR solvent (CHCl , δ 7.26; CD HOD, δ 3.30; CDHCl , δ 5.33; C HD , δ 7.16). Data are
3
2
2
6
5
represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sep =
septet, m = multiplet and/or multiple resonances, br = broad), integration, coupling constant in Hertz, and
13
assignment. Protonꢀdecoupled carbon nuclear magnetic resonance spectra ( C NMR) were recorded at
100, 125, or 150 MHz at 24 °C, unless otherwise noted. Chemical shifts are expressed in parts per
million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the carbon resonances of
the solvent (CDCl , δ 77.0; CD OD, δ 49.0; CD Cl , δ 54.0; C D , δ 128.1). Distortionless enhancement
3
3
2
2
6
6
by polarization transfer spectra [DEPT (135)] were recorded at 100, 125, or 150 MHz at 24 °C, unless
1
3
otherwise noted. C NMR and DEPT (135) data are combined and represented as follows: chemical
shift, carbon type [obtained from DEPT (135) experiments]. Protonꢀdecoupled fluorine nuclear magnetic
19
resonance spectra ( F NMR) were recorded at 375 MHz or 470 MHz at 24 °C, unless otherwise noted.
Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from fluorotrichloromethane.
Attenuated total reflectance Fourier transform infrared spectra (ATRꢀFTIR) were obtained using a
Thermo Electron Corporation Nicolet 6700 FTIR spectrometer referenced to a polystyrene standard. Data
–1
are represented as follows: frequency of absorption (cm ), intensity of absorption (s = strong, m =
medium, w = weak, br = broad). Highꢀresolution mass spectrometry (HRMS) were obtained on a Waters
UPLC/HRMS instrument equipped with a dual API/ESI ionizer and quadrupole timeꢀofꢀflight (Qꢀ
TOF) mass detector. Unless otherwise noted, samples were eluted over a reverseꢀphase C18 column
(1.7 ꢁm particle size, 2.1 × 50 mm) with a linear gradient of 5% acetonitrile–water containing 0.1%
formic acid→95% acetonitrile–water containing 0.1% formic acid over 1.6 min, followed by 100%
acetonitrile containing 0.1% formic acid for 1 min, at a flow rate of 600 ꢁL/min.
Synthetic Procedures.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Synthesis
of
O-tert-butyldiphenylsilylpleuromutilin
(19,
Scheme
3):
tertꢀ
Butyl(chloro)diphenylsilane (3.43 mL, 13.2 mmol, 1.10 equiv) was added dropwise via syringe to a
solution of pleuromutilin (1, 4.54 g, 12.0 mmol, 1 equiv) and imidazole (1.63 g, 24.0 mmol, 2.00 equiv)
in N,N-dimethylformamide (90 mL) at 0 °C. The reaction mixture was stirred for 50 min at 0 °C. The
product mixture was transferred to a separatory funnel that had been charged with ether (200 mL). The
layers that formed were separated and the organic layer was washed with water (3 × 25 mL). The organic
layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated.
The residue obtained was purified by automated flashꢀcolumn chromatography (eluting with hexanes
initially, grading to 50% ethyl acetate–hexanes, linear gradient) to afford Oꢀtertꢀ
butyldiphenylsilylpleuromutilin (19) as an amorphous white solid (7.40 g, 99%). R = 0.48 (5% ether–
dichloromethane; UV, CAM, PAA). H NMR (400 MHz, CD Cl ) δ 7.68–7.65 (m, 4H, 2 × H , 2 × H ),
.56–7.36 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 6.53 (dd, J = 17.6, 11.2 Hz, 1H, H ), 5.78 (d, J =
f
1
2
2
27
31
7
8
6
1
2
6
28
30
32
19
.4 Hz, 1H, H ), 5.35 (d, J = 11.2 Hz, 1H, 1 × H ), 5.22 (d, J = 17.6 Hz, 1H, 1 × H ), 4.14 (dd, J = 22.8,
1
4
20
20
.0 Hz, 2H, H ), 3.35 (dd, J = 10.0, 3.6 Hz, 1H, H ), 2.39–2.32 (m, 1H, H ), 2.26–2.00 (m, 5H, 2 × H ,
2
2
11
10
2
× H , 1 × H , OH), 1.81–1.75 (m, 1H, 1 × H ), 1.67–1.52 (m, 3H, 1 × H , 1 × H , 1 × H ), 1.50–1.44
4
13
8
1
6
7
(m, 2H, 1 × H , 1 × H ), 1.36 (s, 3H, H ), 1.25–1.19 (m, 1H, 1 × H ), 1.16–1.12 (m, 4H, 1 × H , 3 × H ),
1
7
15
8
13
18
13
1.07 (s, 9H, H ), 0.87 (d, J = 6.8 Hz, 3H, H ), 0.60 (d, J = 6.8 Hz, 3H, H ). C NMR (100 MHz,
2
4
17
16
CD Cl ) δ 317.4 (C), 170.3 (C), 140.1 (CH), 136.1 (CH), 133.4 (C), 130.4 (CH), 128.3 (CH), 128.3 (CH),
2
2
1
(
(
17.8 (CH ), 75.1 (CH), 69.0 (CH), 63.4 (CH ), 58.6 (CH), 46.0 (C), 45.3 (C), 44.5 (CH ), 42.4 (C), 37.4
2
2
2
CH), 36.6 (CH), 35.0 (CH ), 30.9 (CH ), 27.5 (CH ), 27.0 (CH ), 26.7 (CH ), 25.4 (CH ), 19.6 (C), 17.0
2 2 2 3 3 2
–1
CH ), 15.2 (CH ), 11.8 (CH ). IR (ATRꢀFTIR), cm : 2932 (w), 1735 (m), 1462 (w), 1140 (m). HRMSꢀ
3
3
3
+
ꢄꢅ
ESI (m/z): [M + Na] calcd for C H NaO Si, 639.3482; found, 639.3486. ꢀꢁꢂ = +27⁰ (c = 1.0,
3
8
52
5
ꢃ
CHCl3).
Synthesis of O-tert-butyldiphenylsilyl-19,20-dihydropleuromutilin (12, Scheme 3): Palladium on
carbon (5 wt. % loading, 1.28 g, 600 ꢀmol, 0.05 equiv) was added to a solution of Oꢀtertꢀ
butyldiphenylsilylpleuromutilin (19, 7.40 g, 12.0 mmol, 1 equiv) in ethanol (75 mL) at 24 °C. The
reaction vessel was evacuated and reꢀfilled using a balloon of dihydrogen. This process was repeated four
times. The reaction mixture was stirred for 12 h at 24 °C. The product mixture was filtered through a
16
ACS Paragon Plus Environment

Page 17 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
short column of celite and the short column was rinsed with dichloromethane (250 mL). The filtrates
were combined and the combined filtrates were concentrated to afford Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀ
dihydropleuromutilin (12) as an amorphous white solid (7.43 g, 99%). R = 0.54 (20% ethyl acetate–
f
1
hexanes; UV, CAM, PAA). H NMR (400 MHz, CDCl ) δ 7.68–7.66 (m, 4H, 2 × H , 2 × H ), 7.45–
3
27
31
7
2
1
.35 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 5.68 (d, J = 8.4 Hz, 1H, H ), 4.15 (dd, J = 23.2, 6.8 Hz,
2
6
28
30
32
14
H, H ), 3.40 (t, J = 5.8 Hz, 1H, H ), 2.48–2.41 (m, 1H, H ), 2.25–2.08 (m, 2H, H ), 2.15 (s, 1H, H ),
22
11
10
2
4
.84–1.75 (m, 2H, 1 × H , 1 × H ), 1.69–1.52 (m, 6H, 1 × H , 1 × H , 1 × H , 1 × H , 1 × H , 1 × OH),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
8
13
1
6
7
13
19
1.49–1.43 (m, 1H, 1 × H ), 1.40 (s, 3H, H ), 1.35–1.29 (m, 1H, 1 × H ), 1.15–1.10 (m, 1H, 1 × H ), 1.07
7
15
1
8
(s, 9H, H ), 0.97–0.93 (m, 6H, 3 × H , 3 × H ), 0.90–0.83 (m, 1H, 1 × H ), 0.76 (t, J = 7.4 Hz, 3H,
2
4
17
18
19
1
3
H ), 0.63 (d, J = 6.4 Hz, 3H, H ). C NMR (100 MHz, CDCl ) δ 217.2 (C), 170.0 (C), 135.5 (CH),
20
16
3
1
32.8 (C), 129.9 (CH), 127.8 (CH), 76.6(CH), 68.7 (CH), 62.8 (CH ), 58.6 (CH), 45.8 (C), 41.8 (C), 41.1
2
(
(
(
CH ), 40.9 (C), 36.7 (CH). 34.5 (CH), 34.3 (CH ), 30.3 (CH ), 26.8 (CH ), 26.6 (CH ), 26.3 (CH ), 24.9
2 2 2 2 3 3
–1
CH ), 20.8 (CH ), 19.2 (C), 16.5 (CH ), 14.9 (CH ), 11.0 (CH ), 8.3 (CH ). IR (ATRꢀFTIR), cm : 2933.
2
2
3
3
3
3
+
w), 2860 (w), 1734 (m), 1462 (w), 1428 (w), 1215 (w). HRMSꢀESI (m/z): [M + Na] calcd for
ꢄꢅ
C H NaO Si, 641.3638; found, 641.3631. ꢀꢁꢂ = +32⁰ (c = 1.0, CHCl3).
38
54
5
ꢃ
Synthesis of silane 13 (Scheme 3 and Table S1, entry 6): Dimethylchlorosilane (1.50 mL, 13.5
mmol, 2.00 equiv) was added dropwise via syringe to a solution of Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀ
dihydropleuromutilin [12, 4.17 g, 6.74 mmol, 1 equiv, dried by azeotropic distillation with benzene (50
mL)] and triethylamine (3.75 mL, 27.0 mmol, 4.00 equiv) in dichloromethane (42 mL) at 0 °C. The
reaction mixture was stirred for 30 min at 0 °C. The product mixture was diluted sequentially with
pentane (50 mL) and aqueous potassium phosphate buffer solution (pH 7, 0.10 M, 15 mL) at 0 °C
.
The diluted mixture was transferred to a separatory funnel and the layers formed were separated.
The aqueous layer was extracted with dichloromethane (3 × 50 mL). The organic layers were
combined and the combined organic layers were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated to dryness to afford silane 13 as an amorphous white solid
(
4.57 g, 99%). The silane 13 prepared this way was analytically pure and was used in the next step
1
without further purification. R = 0.57 (10% ether–hexanes; UV, CAM, PAA). H NMR (400 MHz,
f
C D ) δ 7.77–7.73 (m, 4H, 2 × H , 2 × H ), 7.21–7.16 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 5.67
6
6
27
31
26
28
30
32
(
d, J = 8.0 Hz, 1H, H ), 4.80 (sep, J = 2.8 Hz, 1H, SiꢀH), 4.16 (s, 2H, H ), 3.22 (d, J = 6.0 Hz, 1H, H ),
14 22 11
2
.41–2.34 (m, 1H, H ), 1.96–1.89 (m, 1H, 1 × H ), 1.85–1.80 (m, 2H, H ), 1.78–1.72 (m, 2H, 1 × H , 1 ×
1
0
19
2
4
H ), 1.70–1.63 (m, 1H, H ), 1.61 (s, 3H, H ), 1.57–1.45 (m, 2H, 1 × H , 1 × H ), 1.41–1.24 (m, 3H, 1 ×
19
6
15
7
13
H , 1 × H , 1 × H ), 1.16 (s, 9H, H ), 1.10–0.99 (m, 2H, 1 × H , 1 × H ), 0.86–0.77 (m, 6H, 3 × H , 3 ×
1
8
13
24
1
7
18
H ), 0.77–0.72 (m, 4H, 1 × H , 3 × H ), 0.66 (d, J = 7.2 Hz, 3H, H ), 0.12 (app d, 6H, 3 × H , 3 × H ).
2
0
8
17
16
33
34
13
C NMR (100 MHz, C D ) δ 214.8 (C), 169.4 (C), 135.7 (CH), 133.0 (C), 129.8 (CH), 127.8 (CH), 127.8
6
6
(
CH), 80.1 (CH), 68.4 (CH), 62.9 (CH ), 58.0 (CH), 45.0 (C), 41.9 (C), 41.4 (C), 40.9 (CH ), 36.6 (CH),
2
2
3
1
5.0 (CH), 34.0 (CH ), 30.2 (CH ), 27.1 (CH ). 26.8 (CH ), 26.5 (CH ), 25.0 (CH ), 21.1 (CH ), 19.1 (C),
2 2 2 3 3 2 2
–1
6.4 (CH ), 14.8 (CH ), 11.9 (CH ), 8.3 (CH ), –0.82 (CH ), –0.84 (CH ). IR (ATRꢀFTIR), cm : 2969
3
3
3
3
3
3
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
+
(
6
w), 1738 (s), 1366 (m), 1218 (m). HRMSꢀESI (m/z): [M – Si(CH ) + Na] calcd for C H NaO Si,
3 2 38 54 5
41.3638; found, 641.3643. ꢀꢁꢂꢃ = +34⁰ (c = 1.0, CHCl3).
ꢄꢅ
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
Attempted synthesis of silane S1 (Table S1, entry 1): A solution of diethylsilane (2.5 ꢀL, 19.4
mmol, 1.20 equiv) in toluene (50 ꢀL) was added dropwise via syringe to a solution of Oꢀtertꢀ
butyldiphenylsilylꢀ19,20ꢀdihydropleuromutilin [12, 10.0 mg, 16.2 ꢀmol, 1 equiv, dried by azeotropic
distillation with benzene (500
0
ꢀ
L)] and tris(triphenylphosphine)ruthenium(II) dichloride (0.300 mg,
.300 mol, 2.00 mol%) in toluene (100 ꢀ
ꢀ
L) at 24 °C in the glovebox. The reaction vessel was sealed
and the sealed vessel was removed from the glovebox. The reaction vessel was placed in an oil bath that
had been previously heated to 50 °C. The reaction mixture was stirred and heated for 12 h at 50 °C. The
product mixture was concentrated to dryness and the residue obtained was purified by automated flashꢀ
column chromatography (eluting with hexanes initially, grading to 50% ethyl acetate–hexanes, linear
gradient) to afford the recovered starting material 12 as an amorphous white solid (9.9 mg, 99%).
Attempted synthesis of silane S1 (Table S1, entry 2): A solution of diethylsilane (2.5 ꢀL, 19.4
mmol, 1.20 equiv) in toluene (50 ꢀL) was added dropwise via syringe to a solution of Oꢀtertꢀ
butyldiphenylsilylꢀ19,20ꢀdihydropleuromutilin [12, 10.0 mg, 16.2 ꢀmol, 1 equiv, dried by azeotropic
distillation with benzene (500
0
ꢀ
L)] and tris(triphenylphosphine)ruthenium(II) dichloride (0.300 mg,
.300 mol, 2.00 mol%) in toluene (100 ꢀ
ꢀ
L) at 24 °C in the glovebox. The reaction vessel was sealed
and the sealed vessel was removed from the glovebox. The reaction vessel was placed in an oil bath that
had been previously heated to 110 °C. The reaction mixture was stirred and heated for 12 h at 110 °C.
The product mixture was concentrated to dryness and the residue obtained was purified by automated
flashꢀcolumn chromatography (eluting with hexanes initially, grading to 50% ethyl acetate–hexanes,
linear gradient) to afford the recovered starting material 12 as an amorphous white solid (10.0 mg, >
9
9%).
Attempted synthesis of silane 13 (Table S1, entry 3): Bis(dimethylsilyl)amine (4.6 ꢀL, 26.0
mmol, 2.00 equiv) was added dropwise via syringe to a solution of Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀ
dihydropleuromutilin [12, 8.1 mg, 13.0 ꢀmol, 1 equiv, dried by azeotropic distillation with benzene
(300 ꢀL)] in dichloromethane (200 ꢀL) at 24 °C. The reaction mixture was stirred for 12 h at 24 °C.
The product mixture was concentrated to dryness and the residue obtained was purified by automated
flashꢀcolumn chromatography (eluting with hexanes initially, grading to 50% ethyl acetate–hexanes,
linear gradient) to afford the recovered starting material 12 as an amorphous white solid (8.1 mg, > 99%).
Attempted Synthesis of silane 13 (Table S1, entry 4): A catalytic amount of ammonium chloride
was added to a solution of Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀdihydropleuromutilin [12, 8.1 mg, 13.0 ꢀmol,
equiv, dried by azeotropic distillation with benzene (300 ꢀL)] in bis(dimethylsilyl)amine (200 ꢀL)
at 24 °C. The reaction vessel was placed in an oil bath that had been previously heated to 50 °C. The
reaction mixture was stirred and heated for 12 h at 50 °C. The product mixture was concentrated to
dryness and the residue obtained was purified by automated flashꢀcolumn chromatography (eluting with
hexanes initially, grading to 50% ethyl acetate–hexanes, linear gradient) to afford the recovered starting
material 12 as an amorphous white solid (8.1 mg, > 99%).
1
18
ACS Paragon Plus Environment

Page 19 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of silane 13 (Table S1, entry 6): Dimethylchlorosilane (5.8 ꢀL, 52.0 mmol, 2.00 equiv)
was added dropwise via syringe to a solution of Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀdihydropleuromutilin
[
12, 16.1 mg, 26.0 ꢀmol, 1 equiv, dried by azeotropic distillation with benzene (500
ꢀL)] and
triethylamine (14.5 L, 104 mol, 4.00 equiv) in dichloromethane (300 L) at 0 °C. The reaction
ꢀ
ꢀ
ꢀ
mixture was stirred for 30 min at 0 °C. The product mixture was diluted sequentially with pentane (1.0
mL) and an aqueous potassium phosphate buffer solution (pH 7, 0.10 M, 1.0 mL) at 0 °C. The diluted
mixture was transferred to a separatory funnel and the layers formed were separated. The aqueous
layer was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layers were dried over sodium sulfate. The dried solution was filtered and the
filtrate was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 25% ether–hexanes, linear gradient) to afford
silane 13 as an amorphous white solid (15.4 mg, 87%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Synthesis of silane S2 (Table S1, entry 7): A 10ꢀmL roundꢀbottomed flask fused to a Teflonꢀ
coated valve was charged with Oꢀtertꢀbutyldiphenylsilylꢀ19,20ꢀdihydropleuromutilin (12, 50.0 mg, 80.8
ꢀmol, 1 equiv). Benzene (1.0 mL) was added and the solution was concentrated to dryness. This process
was repeated twice. The reaction vessel was evacuated and refilled using a balloon of argon. This
process was repeated two times. Dichloromethane (300 ꢀL), triethylamine (45.0 ꢀL, 323 ꢀmol, 4.00
equiv), and (chloro)diphenylsilane (25.0 ꢀL, 121 ꢀmol, 2.00 equiv, 95% purity) were added sequentially
to the reaction vessel. The reaction vessel was sealed and the sealed vessel was placed in an oil bath that
had been previous heated to 50 °C. The reaction was stirred and heated for 3 h at 50 °C. The reaction
vessel was allowed to cool over 30 min to 24 °C. The product mixture was diluted sequentially with
pentane (1.0 mL) and an aqueous potassium phosphate buffer solution (pH 7, 0.10 M, 1.0 mL). The
diluted mixture was transferred to a separatory funnel and the layers formed were separated. The
aqueous layer was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined
and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and
the filtrate was concentrated to dryness. The residue obtained was purified by automated flashꢀ
column chromatography (eluting with hexanes initially, grading to 25% ether–hexanes, linear gradient)
to afford silane S2 as an amorphous white solid (64.0 mg, 97%). R = 0.39 (10% ethyl acetate–hexanes;
f
1
UV, CAM, PAA). H NMR (400 MHz, C D ) δ 7.80–7.77 (m, 4H, 2 × H , 2 × H ), 7.75–7.72 (m, 2H,
6
6
27
31
H ), 7.68–7.66 (m, 2H, H ), 7.25–7.14 (m, 12H, 2 × H , 1 × H , 2 × H , 1 × H , 2 × H , 1 × H , 2 ×
35
39
26
28
30
32
34
36
H , 1 × H ), 5.82 (d, J = 8.0 Hz, 1H, H ), 5.72 (s, 1H, SiꢀH), 4.19 (s, 2H, H ), 3.56 (d, J = 5.6 Hz, 1H,
38
40
14
22
H ), 2.53–2.50 (m, 1H, H ), 2.13–1.98 (m, 2H, H ), 1.85–1.80 (m, 2H, H ), 1.77 (s, 1H, H ), 1.71–1.64
11
10
19
2
4
(m, 1H, H ), 1.56 (s, 3H, H ), 1.54–1.48 (m, 2H, 1 × H , 1 × H ), 1.40–1.35 (m, 1H, 1 × H ), 1.23–1.19
6
15
7
13
8
(
m, 10H, 1 × H , 9 × H ), 1.11–1.07 (m, 1H, 1 × H ), 1.03–0.97 (m, 1H, 1 × H ), 0.95–0.89 (m, 6H, 3 ×
1
3
24
7
1
H , 3 × H ), 0.87 (d, J = 6.8 Hz, 3H, H ), 0.84–0.71 (m, 2H, 1 × H , 1 × H ), 0.68 (d, J = 7.2 Hz, 3H,
1
8
20
17
1
8
13
H ). C NMR (100 MHz, C D ) δ 215.1 (C), 169.8 (C). 136.1 (CH), 136.1 (CH), 135.6 (CH), 135.5
16
6
6
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
(
(
(
(
CH), 135.1 (C), 134.7 (C), 134.5 (C), 133.5 (CH), 130.8 (CH), 130.7 (CH), 130.5 (C), 130.2 (CH), 128.6
CH). 128.4 (CH), 128.2 (CH), 128.2 (CH), 80.1 (CH), 68.8 (CH), 63.3 (CH ), 58.3 (CH), 45.3 (C), 42.4
2
C), 42.2 (C), 41.3 (CH ), 37.0 (CH), 35.7 (CH), 34.5 (CH ), 30.7 (CH ), 28.0 (CH ), 27.2 (CH ), 27.0
2
2
2
3
2
CH ), 25.1 (CH ), 21.7 (CH ), 19.5 (C), 16.8 (CH ), 15.1 (CH ), 12.7 (CH ), 8.8 (CH ). IR (ATRꢀFTIR),
3
–1
2
2
3
3
3
3
+
cm : 2933 (w), 1736 (m), 1428 (m), 1214 (w). HRMSꢀESI (m/z): [M + K] calcd for C H KO Si ,
8
50
64
5
2
ꢄꢅ
39.3929; found, 839.3955. ꢀꢁꢂꢃ = +32⁰ (c = 1.0, CHCl3).
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
Synthesis of silacycles 14a and 14b (Scheme 3): This experiment was adapted from the work of
2
3
Hartwig and coꢀworkers. A 50ꢀmL pressure tube with a Teflonꢀcoated valve was charged with 3,4,7,8ꢀ
tetramethylꢀ1,10ꢀphenanthroline (199 mg, 843 ꢁmol, 12.5 mol%) and norbornene (952 mg, 10.1 mmol,
1.50 equiv) in the glovebox. A 100ꢀmL pearꢀshaped flask was charged with silane 13 [4.57 g, 6.74 mmol,
1
equiv, dried by azeotropic distillation with benzene (3 × 50 mL)]. The vessel containing the silane
was evacuated and refilled using a balloon of argon. This process was repeated two times.
Tetrahydrofuran (10 mL) was transferred into the vessel containing the silane and the resulting solution
was added to the vessel containing the ligand and norbornene in the glovebox. The vessel containing the
silane was rinsed with tetrahydrofuran (3 × 2.0 mL) and the combined rinses were transferred to the
reaction vessel. Methoxy(cyclooctadiene)iridium(I) dimer (233 mg, 337 ꢁmol, 5.0 mol%) was added to
an ovenꢀdried 20ꢀmL vial. Tetrahydrofuran (2.0 mL) was added into the vial containing the catalyst and
the resulting solution was transferred dropwise via syringe to the reaction vessel in the glovebox. The
vial containing the catalyst was rinsed with tetrahydrofuran (3 × 1.0 mL) and the combined rinses were
transferred into the reaction vessel. The reaction vessel was sealed and the reaction mixture was
stirred for 1 h at 24 °C in the glovebox. The sealed reaction vessel was then removed from the glovebox
and placed in an oil bath that had been preheated to 120 °C. The reaction mixture was stirred and heated
for 2 h at 120 °C. The reaction vessel was allowed to cool over 30 min to 24 °C and the cooled product
mixture was concentrated to dryness. The residue obtained was filtered through a pad of silica gel (2.5
×
4.5 cm). The filter cake was washed with a mixture of ether and hexanes (1:1, v/v, 500 mL). The
filtrate were combined and the combined filtrates were concentrated to dryness. The residue obtained
contained a mixture of C11ꢀC18ꢀsilacycle 14a and C11ꢀC17ꢀsilacycle 14b (4.56 g, 99%) and was used in
the next step without further purification. H NMR study of the unpurified mixture revealed an
approximate 4:1 mixture of 14a:14b. An analytically pure sample of 14a and 14b were obtained for
characterization by automated flashꢀcolumn chromatography (eluting with hexanes initially, grading to
2
(
H ), 7.45–7.37 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 5.61 (d, J = 8.0 Hz, 1H, H ), 4.15 (dd, J =
2
1
1.60–1.55 (m, 1H, 1 × H ), 1.55–1.52 (m, 2H, 1 × H , 1 × H ), 1.52–1.38 (m, 3H, 1 × H , 1 × H , 1 ×
H ), 1.36 (s, 3H, H ), 1.17–1.11 (m, 2H, 1 × H , 1 × H ), 1.07 (s, 9H, H ), 0.92 (d, J = 9.0 Hz, 3H, H ),
0.89–0.86 (m, 1H, 1 × H ), 0.71 (t, J = 7.3 Hz, 3H, H ), 0.91 (d, J = 6.0 Hz, 3H, H ), 0.23 (s, 3H, H ),
1
5% ethyl acetate–hexanes, linear gradient). C11ꢀC18ꢀsilacycle 14a: Amorphous white solid. R = 0.51
f
1
10% ethyl acetate–hexanes; UV, CAM). H NMR (500 MHz, CD Cl ) δ 7.68–7.66 (m, 4H, 2 × H , 2 ×
2
2
27
31
26
28
30
32
14
7.0, 16.5 Hz, 2H, H ), 3.49 (d, J = 6.5 Hz, 1H, H ), 2.40–2.34 (m, 1H, H ), 2.17–2.08 (m, 3H, 2 × H ,
2
2
11
10
2
× H ), 2.04–2.00 (m, 1H, 1 × H ), 1.75 (d, J = 14.5 Hz, 1H, 1 × H ), 1.68–1.60 (m, 2H, 1 × H , 1 × H ),
4
19
8
7
13
1
7
13
1
7
19
15
8
18
24
17
1
8
20
16
33
20
ACS Paragon Plus Environment

Page 21 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
0
1
4
2
.16 (s, 3H, H ). C NMR (125 MHz, CD Cl ) δ 218.0 (C), 170.3 (C). 136.1 (CH), 133.5 (C). 133.5 (C),
34 2 2
30.4 (CH), 128.3 (CH), 128.3 (CH), 82.2 (CH), 69.5 (CH), 63.5 (CH ), 59.1 (CH), 47.3 (C), 46.3 (C),
2
2.5 (C), 41.9 (CH ), 37.5 (CH), 35.0 (CH ), 33.7 (CH), 30.6 (CH ), 27.6 (CH ), 27.0 (CH ), 26.2 (CH ),
2
2
2
2
3
2
5.6 (CH ), 19.9 (CH ), 19.7 (C), 16.9 (CH ), 15.3 (CH ), 12.1 (CH ), 8.7 (CH ), 0.53 (CH ), 0.47 (CH ).
IR (ATRꢀFTIR), cm : 2933 (w), 1736 (m), 1428 (m). HRMSꢀESI (m/z): [M + K] calcd for
C H KO Si , 713.3460; found, 713.3488. ꢀꢁꢂ = +28⁰ (c = 0.5, CHCl ). C11ꢀC17ꢀsilacycle 14b:
morphous white solid. R = 0.48 (10% ethyl acetate–hexanes; UV, CAM). H NMR (400 MHz,
CD Cl ) δ 7.69–7.66 (m, 4H, 2 × H , 2 × H ), 7.46–7.36 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 5.68
(d, J = 8.0 Hz, 1H, H ), 4.17 (dd, J = 20.8, 4.4 Hz, 2H, H ), 3.73 (d, J = 5.2 Hz, 1H, H ), 2.86–2.80 (m,
1H, H ), 2.23–2.09 (m, 3H, 2 × H , 1 × H ), 1.76–1.50 (m, 7H, 2 × H , 1 × H , 1 × H , 1 × H , 1 × H , 1
H ), 1.47–1.40 (m, 1H, 1 × H ), 1.36 (s, 3H, H ), 1.29–1.25 (m, 1H, 1 × H ), 1.23–1.20 (m, 1H, 1 ×
2
2
–1
3
3
3
3
3
3
+
ꢄꢅ
40
58
5
2
ꢃ
3
1
A
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
2
2
27
31
26
28
30
32
1
4
22
11
10
2
4
1
6
7
8
13
×
19
19
15
13
H ), 1.18–1.12 (m, 1H, 1 × H ), 1.07 (s, 9H, H ), 1.00–0.96 (m, 1H, 1 × H ), 0.92 (s, 3H, H ), 0.79–
8
7
24
17
18
0
(
1
4
.73 (m, 1H, 1 × H ), 0.69 (t, J = 7.4 Hz, 3H, H ), 0.62 (d, J = 7.2 Hz, 3H, H ), 0.24 (s, 3H, H ), 0.17
1
7
20
16
33
13
s, 3H, H ). C NMR (100 MHz, CD Cl ) δ 217.1 (C), 170.5 (C), 136.1 (CH), 133.5 (C), 1334 (C),
34 2 2
30.4 (CH), 128.3 (CH), 128.3 (CH), 87.3 (CH), 69.2 (CH), 63.5 (CH ), 59.6 (CH), 46.1 (C), 42.4 (C),
2
1.2 (C), 40.4 (CH ), 39.5 (CH), 37.2 (CH), 34.8 (CH ), 31.9 (CH ), 27.4 (CH ), 27.0 (CH ), 25.7 (2 ×
2
2
2
2
2
CH ), 21.2 (CH ), 19.6 (C), 16.8 (CH ), 12.1 (CH ). 13.5 (CH ), 8.5 (CH ), 0.85 (CH ), 0.79 (CH ). IR
3
2
3
3
2
3
3
3
–
1
+
(
ATRꢀFTIR), cm : 2958 (w), 1738 (m), 1462 (w), 1251 (w). HRMSꢀESI (m/z): [M + K] calcd for
ꢄꢅ
C H KO Si , 713.3460; found, 713.3444. ꢀꢁꢂ = +15⁰ (c = 0.5, CHCl3).
40
58
5
2
ꢃ
Tamao—Fleming oxidation of a mixture of 14a and 14b to afford a mixture of S3a and S3b
Scheme 3): Tetrahydrofuran (150 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 168 ꢁL,
.48 mmol, 20.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two
silacycles 14a and 14b (50.0 mg, 74.1 ꢁmol, 1 equiv) and potassium bicarbonate (44.4 mg, 444 ꢁmol,
.00 equiv) in methanol (150 ꢁL) at 24 °C in a 4ꢀmL vial. The vial was sealed with a Teflonꢀlined cap
and the sealed vial was placed in an oil bat that had been preheated to 80 °C. The reaction mixture was
stirred and heated for 3 h at 80 °C. The product mixture was diluted sequentially with dichloromethane
2.0 mL) and saturated aqueous sodium thiosulfate (1.0 mL). The diluted product mixture was transferred
to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with
dichloromethane (3 × 5 mL). The organic layers were combined and the combined organic layers were
dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness.
The residue obtained contained a mixture of diols S3a and S3b (47.1 mg, 99%) and was used in the next
step without further purification. An analytically pure sample of S3a and S3b were obtained for
characterization by automated flashꢀcolumn chromatography (eluting with dichloromethane initially,
grading to 100% ether–dichloromethane, linear gradient; then eluting with 10% methanol–
dichloromethane). Diol S3a:
H NMR (400 MHz, CD Cl ) δ 7.68–7.64 (m, 4H, 2 × H , 2 × H ), 7.45–7.35 (m, 6H, 2 × H , 1 × H , 2
H , 1 × H ), 5.70 (d, J = 8.4 Hz, 1H, H ), 4.16 (dd, J = 24.8, 8.4 Hz, 2H, H ), 3.83 (d, J = 6.4 Hz, 1H,
H ), 3.51 (d, J = 11.2 Hz, 1H, 1 × H ), 3.39 (d, J = 11.2 Hz, 1H, 1 × H ), 3.00–3.65 (br m, 2H, 2 × OH),
(
1
6
(
Amorphous white solid. R = 0.42 (40% ethyl acetate–hexanes; UV, CAM).
f
1
2
2
27
31
26
28
×
30
32
14
22
11
18
18
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
2
1
.47–2.40 (m, 1H, H ), 2.22–2.08 (m, 2H, H ), 2.06 (s, 1H, H ), 1.86–1.75 (m, 3H, 1 × H , 2 × H ),
1
0
2
4
8
19
.68–1.62 (m, 1H, 1 × H ), 1.60–1.53 (m, 3H, 1 × H , 1 × H , 1 × H ), 1.48–1.41 (m, 1H, H ), 1.36–1.30
1
3
1
6
7
1
(
(
m, 5H, 1 × H , 1 × H , 3 × H ), 1.14–1.04 (m, 10H, 1 × H , 9 × H ), 0.92 (d, J = 7.2 Hz, 3H, H ), 0.74
t, J = 7.4 Hz, 3H, H ), 0.60 (d, J = 6.4 Hz, 3H, H ). C NMR (100 MHz, CD Cl ) δ 217.2 (C), 169.9
20 16 2 2
7
13
15
8
24
17
13
(
C), 135.5 (CH), 132.9 (C), 132.8 (C), 129.9 (CH), 127.8 (CH), 75.5 (CH), 70.4 (CH ), 67.9 (CH), 62.9
2
(
CH ), 58.3 (CH), 45.4 (C), 43.8 (C), 41.9 (C), 36.8 (CH), 35.4 (CH ), 34.5 (CH), 34.4 (CH ), 30.2 (CH ),
2 2 2 2
2
6.9 (CH ), 26.4 (CH ), 25.0 (CH ), 19.1 (C), 16.9 (CH ), 16.4 (CH ), 14.6 (CH ), 10.7 (CH ), 7.5 (CH ).
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
2 3 2 2 3 3 3 3
–
1
IR (ATRꢀFTIR), cm : 3265 (br w), 2927 (w), 1759 (m), 1738 (w), 1462 (w). HRMSꢀESI (m/z): [M +
H] calcd for C H O Si, 635.3768; found, 635.3768. ꢀꢁꢂ = +32⁰ (c = 0.33, CHCl ). Diol S3b:
A
+
ꢄꢅ
3
8
55
6
ꢃ
3
1
morphous white solid. R = 0.33 (40% ethyl acetate–hexanes; UV, CAM). H NMR (400 MHz,
f
CD Cl ) δ 7.68–7.66 (m, 4H, 2 × H , 2 × H ), 7.47–7.38 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 5.64
2
2
27
31
26
28
30
32
(
d, J = 8.0 Hz, 1H, H ), 4.18 (dd, J = 26.4, 10.0 Hz, 2H, H ), 3.91–3.88 (m, 1H, 1 × H ), 3.82–3.79 (m,
1
4
22
17
1
H, 1 × H ), 3.60–3.57 (m, 1H, H ), 3.24 (d, J = 7.2 Hz, 1H, C11ꢀOH), 2.62 (t, J = 5.6 Hz, 1H, C17ꢀ
17
11
OH), 2.43 (t, J = 6.4 Hz, 1H, H ), 2.26–2.14 (m, 2H, 2 × H ), 2.08 (s, 1H, 1 × H ), 1.89–1.82 (m, 2H, 1 ×
H , 1 × H ), 1.80–1.65 (m, 3H, 1 × H , 1 × H , 1 × H ), 1.54–1.44 (m, 1H, 1 × H ), 1.42–1.39 (m, 2H, 1
1
0
2
4
8
19
1
7
13
19
×
H , 1 × H ), 1.37 (s, 3H, H ), 1.27–1.25 (m, 1H, 1 × H ), 1.20–1.12 (m, 1H, 1 × H ), 1.08 (3, 9H, H ),
1
7
15
13
8
24
13
0.94 (s, 3H, H ), 0.72 (t, J = 7.4 Hz, 3H, H ), 0.63 (d, J = 6.4 Hz, 3H, H ). C NMR (100 MHz,
1
8
20
16
CD Cl ) δ 216.3 (C), 169.9 (C), 135.5 (CH), 132.9 (C), 129.8 (CH), 127.8 (CH), 127.7 (CH), 77.8 (CH),
68.4 (CH), 62.9 (CH ), 61.4 (CH ), 58.6 (CH), 44.1 (C). 42.7 (CH), 41.9 (C), 40.5 (C), 4.2 (CH ), 36.7
(CH), 34.4 (CH ), 30.4 (CH ), 26.9 (CH ), 26.4 (CH ), 26.0 (CH ), 25.6 (CH ), 20.9 (CH ), 19.1 (C), 16.3
(CH ), 14.6 (CH ), 7.9 (CH ). IR (ATRꢀFTIR), cm : 2932 (w), 1735 (m), 1461 (w). HRMSꢀESI (m/z):
2
2
2
2
2
2
2
2
3
3
2
2
–
1
3
3
3
+
ꢄꢅ
[
M + H] calcd for C H O Si, 635.3768; found, 635.3772. ꢀꢁꢂ = +31⁰ (c = 0.33, CHCl3).
3
8
55
6
ꢃ
Silyldeprotection of a mixture of S3a and S3b to afford a mixture of 15a and 15b (Scheme 3): A
solution of tetrabutylammonium fluoride in tetrahydrofuran (1.00 M, 148 ꢁL, 148 ꢁmol, 2.00 equiv) was
added dropwise via syringe to a solution of the unpurified mixture of the diols S3a and S3b (47.1 mg,
7
4.1 ꢁmol, 1 equiv) in tetrahydrofuran (1.5 mL) at 24 °C. The reaction mixture was stirred for 2 h at 24
°
C. The product mixture was diluted sequentially with dichloromethane (3.0 mL) and saturated aqueous
sodium bicarbonate (2.0 mL). The diluted product mixture was transferred to a separatory funnel and the
layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The
organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried
solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by
automated flashꢀcolumn chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–
hexanes, linear gradient) to afford separately 18ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin (15a) as an
amorphous white solid (21.4 mg, 73%) and 17ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin (15b) as an
amorphous white solid (1.8 mg, 6%). 18ꢀHydroxyꢀ19,20ꢀdihydropleuromutilin (15a): R = 0.33 (75%
ethyl acetate–hexanes; PAA, CAM). H NMR (400 MHz, CD Cl ) δ 5.77 (d, J = 8.4 Hz, 1H, H ), 4.04
(dd, J = 31.2, 14.4 Hz, 2H, H ), 3.87 (d, J = 6.4 Hz, 1H, H ), 3.63 (br s, 1H, C18ꢀOH), 3.56 (d, J = 10.8
Hz, 1H, 1 × H ), 3.43 (d, J = 10.8 Hz, 1H, 1 × H ), 2.69 (br s, H, C11ꢀOH), 2.47–2.40 (m, 1H, H ),
f
1
2
2
14
2
2
11
1
8
18
10
2
×
×
.29–2.13 (m, 2H, H ), 2.11 (s, 1H, H ), 1.87–1.74 (m, 4H, 1 × H , 1 × H , 2 × H ), 1.65–1.54 (m, 3H, 1
2
4
8
13
19
H , 1 × H , 1 × H ), 1.51–1.42 (m, 1H, 1 × H ), 1.42–1.36 (m, 4H, 1 × H , 3 × H ), 1.20–1.07 (m, 2H, 1
1
6
7
1
7
15
H , 1 × H ), 0.95 (d, J = 7.2 Hz, 3H, H ), 0.77 (t, J = 7.4 Hz, 3H, H ), 0.69 (d, J = 6.4 Hz, 3H, H ).
8
13
17
20
16
22
ACS Paragon Plus Environment

Page 23 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
C NMR (100 MHz, CD Cl ) δ 216.7 (C), 172.3 (C), 75.2 (CH), 70.3 (CH ), 69.1 (CH), 61.3 (CH ), 58.1
2
2
2
2
(
2
2
CH), 45.4 (C), 43.9 (C), 41.9 (C), 36.6 (CH), 35.4 (CH ), 34.4 (CH), 34.3 (CH ), 30.2 (CH ), 26.8 (CH ),
4.9 (CH ), 17.0 (CH ), 16.2 (CH ), 14.4 (CH ), 10.6 (CH ), 7.4 (CH ). IR (ATRꢀFTIR), cm : 3373 (m),
2 2 3 3 3 3
944 (m), 1728 (s), 1461 (w), 1385 (w),. HRMSꢀESI (m/z): [M + H] calcd for C H O , 397.2590;
2 2 2 2
–1
+
22
37
6
ꢄꢅ
found, 397.2603. ꢀꢁꢂꢃ = +33⁰ (c = 1.0, CHCl ). 17ꢀHydroxyꢀ19,20ꢀdihydropleuromutilin (15b): R =
0
H ), 4.05 (t, J = 16 Hz, 2H, H ), 3.94 (t, J = 10.0 Hz, 1H, 1 × H ), 3.81 (d, J = 10.4 Hz, 1H, 1 × H ),
3
2.07 (s, 1H, H ), 1.93–1.83 (m, 1H, 1 × H ), 1.79–1.72 (m, 2H, 1 × H , 1 × H ), 1.70–1.59 (m, 3H, 1 ×
H , 1 × H , 1 × H ), 1.54–1.46 (m, 1H, 1 × H ), 1.44–1.36 (m, 5H, 1 × H , 1 × H , 3 × H ), 1.26–1.22 (m,
1
1
(
3
(
+
3
1
f
.11 (75% ethyl acetate–hexanes; PAA, CAM). H NMR (400 MHz, CDCl ) δ 5.71 (d, J = 7.6 Hz, 1H,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
14
22
17
17
.61 (d, J = 6.4 Hz, 1H, H ), 3.10 (br s, H, C11ꢀOH), 2.48–2.40 (m, 1H, H ), 2.29–2.13 (m, 2H, H ),
11 10 2
4
19
8
13
1
6
7
19
1
7
15
H, 1 × H ), 1.21–1.13 (m, 1H, 1 × H ), 0.97 (s, 3H, H ), 0.87 (br m, 1H, C17ꢀOH), 1.26–1.22 (m, 6H,
1
3
8
18
13
× H , 1 × H ). C NMR (100 MHz, CDCl ) δ 216.3 (C), 172.2 (C), 78.01 (CH), 69.7 (CH), 61.6
16
20
3
CH ), 61.3 (CH ), 58.7 (CH), 44.1 (C), 42.7 (CH), 41.9 (C), 40.6 (C), 40.2 (CH), 36.5 (CH ), 34.4 (CH ),
0.4 (CH ), 26.8 (CH ), 26.3 (CH ), 25.7 (CH ), 20.9 (CH ), 16.4 (CH ), 14.7 (CH ), 8.0 (CH ). IR
2 2 3 2 2 3 3 3
ATRꢀFTIR), cm : 3385 (br w), 2930 (s), 2870 (w), 1734 (s), 1458 (m), 1376 (w). HRMSꢀESI (m/z): [M
2
2
2
2
–1
+
H] calcd for C H O , 397.2590; found, 397.2591.
22 37 6
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 1): Tetrahydrofuran
277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol, 20.0 equiv) were
added sequentially to a suspension of the unpurified mixture of the two silacycles 14a and 14b (100.0 mg,
(
1
2
48 ꢁmol, 1 equiv) and potassium bicarbonate (88.9 mg, 889 ꢁmol, 6.00 equiv) in methanol (277 ꢁL) at
4 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was sealed and the sealed tube was
placed in an oil bat that had been preheated to 80 °C. The reaction mixture was stirred and heated for 3 h
at 80 °C. The product mixture was diluted sequentially with dichloromethane (2.0 mL) and saturated
aqueous sodium thiosulfate (1.0 mL). The diluted product mixture was transferred to a separatory funnel
and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 ×
5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium
sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained
was purified by automated flashꢀcolumn chromatography (eluting with hexanes initially, grading to 100%
ethyl acetate–hexanes, linear gradient) to afford separately the silacycle 14a as an amorphous white solid
(
66.9 mg, 67%) and the diol S3a as an amorphous white solid (8.4 mg, 9%).
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 2): Tetrahydrofuran
(
277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol, 20.0 equiv) were
added sequentially to a suspension of the unpurified mixture of the two silacycles 14a and 14b (100.0 mg,
48 ꢁmol, 1 equiv), potassium bifluoride (23.1 mg, 111 ꢁmol, 2.00 equiv), and potassium bicarbonate
88.9 mg, 889 ꢁmol, 6.00 equiv) in methanol (277 ꢁL) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀ
coated valve. The tube was sealed and the sealed tube was placed in an oil bat that had been preheated to
0 °C. The reaction mixture was stirred and heated for 3 h at 80 °C. The product mixture was diluted
1
(
8
sequentially with dichloromethane (2.0 mL), saturated aqueous sodium thiosulfate (1.0 mL), and saturated
aqueous sodium bicarbonate (500 ꢁL). The diluted product mixture was transferred to a separatory funnel
and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 ×
5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium
sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained
was purified by automated flashꢀcolumn chromatography (eluting with hexanes initially, grading to 100%
ethyl acetate–hexanes, linear gradient) to afford separately the silacycle 14a as an amorphous white solid
(
51.7 mg, 52%), the diol S3a as an amorphous white solid (14.3 mg, 15%), and 18ꢀhydroxylꢀ19,20ꢀ
dihydropleuromutilin as an amorphous white solid (15a, 9.7 mg, 17%).
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 3): Dimethylsulfoxide
277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol, 20.0 equiv) were
(
added sequentially to a suspension of the unpurified mixture of the two silacycles 14a and 14b (100.0 mg,
48 ꢁmol, 1 equiv) and potassium bicarbonate (88.9 mg, 889 ꢁmol, 6.00 equiv) in tetrahydrofuran (277
L) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was sealed and the sealed tube
was placed in an oil bat that had been preheated to 80 °C. The reaction mixture was stirred and heated for
h at 80 °C. The product mixture was diluted sequentially with dichloromethane (2.0 mL) and saturated
1
ꢁ
3
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
aqueous sodium thiosulfate (1.0 mL). The diluted product mixture was transferred to a separatory funnel
and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 ×
5.0 mL). The organic layers were combined and the combined organic layers were dried over sodium
1
sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. H NMR analysis of
the unpurified mixture showed complex decompositions.
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 4):
Nꢀ
Methylpyrrolidone (277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol,
20.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two silacycles 14a
and 14b (100.0 mg, 148 ꢁmol, 1 equiv) and potassium bicarbonate (118 mg, 1.18 mmol, 8.00 equiv) in
tetrahydrofuran (277 ꢁL) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was
sealed and the sealed tube was placed in an oil bat that had been preheated to 80 °C. The reaction mixture
was stirred and heated for 3 h at 80 °C. The product mixture was diluted sequentially with
dichloromethane (2.0 mL) and saturated aqueous sodium thiosulfate (1.0 mL). The diluted product
mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous
layer was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear gradient)
to afford separately the silacycle 14a as an amorphous white solid (22.5 mg, 23%) and the diol S3a as an
amorphous white solid (52.3 mg, 56%).
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 5): 1,3ꢀDimethylꢀ
3,4,5,6ꢀtetrahydroꢀ2ꢀpyrimidinone (277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336
ꢁL, 2.96 mmol, 20.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two
silacycles 14a and 14b (100.0 mg, 148 ꢁmol, 1 equiv) and potassium bicarbonate (118 mg, 1.18 mmol,
8
.00 equiv) in tetrahydrofuran (277 ꢁL) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The
tube was sealed and the sealed tube was placed in an oil bat that had been preheated to 80 °C. The
reaction mixture was stirred and heated for 3 h at 80 °C. The product mixture was diluted sequentially
with dichloromethane (2.0 mL) and saturated aqueous sodium thiosulfate (1.0 mL). The diluted product
mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous
layer was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear gradient)
to afford separately the silacycle 14a as an amorphous white solid (22.6 mg, 23%) and the diol S3a as an
amorphous white solid (63.7 mg, 67%).
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 6): N,Nꢀ
Dimethylformamide (277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol,
0.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two silacycles 14A
and 14B (100.0 mg, 148 ꢁmol, 1 equiv) and potassium bicarbonate (118 mg, 1.18 mmol, 8.00 equiv) in
tetrahydrofuran (277 ꢁL) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was
sealed and the sealed tube was placed in an oil bat that had been preheated to 80 °C. The reaction mixture
2
24
ACS Paragon Plus Environment

Page 25 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
was stirred and heated for 3 h at 80 °C. The product mixture was diluted sequentially with
dichloromethane (2.0 mL) and saturated aqueous sodium thiosulfate (1.0 mL). The diluted product
mixture was transferred to a separatory funnel and the layers that formed were separated. The aqueous
layer was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layers were washed with water (5 × 1.0 mL). The washed organic layer was dried over
sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue
obtained was purified by automated flashꢀcolumn chromatography (eluting with hexanes initially, grading
to 100% ethyl acetate–hexanes, linear gradient) to afford separately the silacycle 14A as an amorphous
white solid (18.0 mg, 18%) and the diol S3A as an amorphous white solid (65.3 mg, 70%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 7): N,Nꢀ
Dimethylformamide (277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol,
2
0.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two silacycles 14a
and 14a (100.0 mg, 148 ꢁmol, 1 equiv), 18ꢀcrownꢀ6 (19.6 mg, 74.1 ꢁmol, 0.500 equiv), and potassium
bicarbonate (118 mg, 1.18 mmol, 8.00 equiv) in tetrahydrofuran (277 ꢁL) at 24 °C in a 4ꢀmL pressure
tube with a Teflonꢀcoated valve. The tube was sealed and the sealed tube was placed in an oil bat that had
been preheated to 80 °C. The reaction mixture was stirred and heated for 3 h at 80 °C. The product
mixture was diluted sequentially with dichloromethane (2.0 mL) and saturated aqueous sodium
thiosulfate (1.0 mL). The diluted product mixture was transferred to a separatory funnel and the layers
that formed were separated. The aqueous layer was extracted with dichloromethane (3 × 5.0 mL). The
organic layers were combined and the combined organic layers were washed with water (5 × 1.0 mL).
The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear gradient)
to afford separately the silacycle 14a as an amorphous white solid (18.8 mg, 19%) and the diol S3a as an
amorphous white solid (59.6 mg, 63%).
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 8): N,Nꢀ
Dimethylformamide (277 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336 ꢁL, 2.96 mmol,
2
0.0 equiv) were added sequentially to a suspension of the unpurified mixture of the two silacycles 14a
and 14b (100.0 mg, 148 ꢁmol, 1 equiv), tetramethylammonium chloride (20.6 mg, 74.1 ꢁmol, 0.500
equiv), and potassium bicarbonate (118 mg, 1.18 mmol, 8.00 equiv) in tetrahydrofuran (277 ꢁL) at 24 °C
in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was sealed and the sealed tube was placed
in an oil bat that had been preheated to 80 °C. The reaction mixture was stirred and heated for 3 h at 80
°
C. The product mixture was diluted sequentially with dichloromethane (2.0 mL) and saturated aqueous
sodium thiosulfate (1.0 mL). The diluted product mixture was transferred to a separatory funnel and the
layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 × 5.0 mL).
The organic layers were combined and the combined organic layers were washed with water (5 × 1.0
mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the
filtrate was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear gradient)
to afford separately the silacycle 14a as an amorphous white solid (37.2 mg, 37%) and the diol S3a as an
amorphous white solid (46.3 mg, 49%).
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
Tamao—Fleming oxidation of a mixture of 14a and 14b (Table S2, entry 9): A solution of
tetrabutylammonium fluoride in tetrahydrofuran (1.00 M, 156 ꢁL, 156 ꢁmol, 1.05 equiv) was added
dropwise via syringe to a solution of the unpurified mixture of the two silacycles 14a and 14b (100.0 mg,
1
48 ꢁmol, 1 equiv) in tetrahydrofuran (1.0 mL) at 0 °C. The reaction was stirred at 0 °C for 25 min. The
reaction was diluted sequentially with pentane (1.5 mL) and an aqueous potassium phosphate buffer
solution (pH 7, 0.10 M, 1.0 mL). The diluted mixture was transferred to a separatory funnel that had
been charged with a mixture of ethyl acetate and hexanes (1:1, v/v, 50 mL). The layers that formed were
separated and the organic layer obtained was washed with water (3 × 5.0 mL). The washed organic layer
was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to
dryness. The residue obtained containing the highly unstable primaryl alcohol intermediate S16 was used
immediately in the next step without purification.
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
N,NꢀDimethylformamide (667 ꢁL) and an aqueous hydrogenperoxide solution (30% w/w, 336
ꢁL, 2.96 mmol, 20.0 equiv) were added sequentially to a suspension of the unpurified intermediate S16
(148 ꢁmol, 1 equiv) and potassium bicarbonate (326 mg, 3.26 mmol, 22.0 equiv) in tetrahydrofuran (333
ꢁ
L) at 24 °C in a 4ꢀmL pressure tube with a Teflonꢀcoated valve. The tube was sealed and the sealed tube
was placed in an oil bat that had been preheated to 80 °C. The reaction mixture was stirred and heated for
h at 80 °C. The product mixture was diluted sequentially with dichloromethane (2.0 mL) and saturated
3
aqueous sodium thiosulfate (1.0 mL). The diluted product mixture was transferred to a separatory funnel
and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 ×
5
×
.0 mL). The organic layers were combined and the combined organic layers were washed with water (5
1.0 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and
the filtrate was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear gradient)
to afford 18ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin 15a as an amorphous white solid (47.1 mg, 80%, two
steps).
Tamao—Fleming oxidation of a mixture of 14a and 14b (Scheme 3 and Table S2, entry 10): A
solution of tetrabutylammonium fluoride in tetrahydrofuran (1.00 M, 6.91 mL, 6.91 mmol, 1.05 equiv)
was added dropwise via syringe to a solution of the unpurified mixture of the two silacycles 14a and 14b
(6.58 ꢁmol, 1 equiv) in tetrahydrofuran (45 mL) at 0 °C. The reaction was stirred for 30 min at 0 °C. The
reaction was diluted sequentially with pentane (45 mL) and an aqueous potassium phosphate buffer
solution (pH 7, 0.10 M, 20 mL). The diluted mixture was transferred to a separatory funnel that had
been charged with a mixture of ethyl acetate and hexanes (1:1, v/v, 300 mL). The layers that formed
were separated and the organic layer obtained was washed with water (3 × 25 mL). The washed organic
layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to
dryness. The residue obtained containing the highly unstable primaryl alcohol intermediate S16 was used
immediately in the next step without purification.
N,NꢀDimethylformamide (28 mL) and an aqueous hydrogenperoxide solution (30% w/w, 14.9
mL, 145 mmol, 20.0 equiv) were added sequentially to a suspension of the unpurified intermediate S16
(
6.58 mmol, 1 equiv) and potassium bicarbonate (14.5 g, 145 mmol, 22.0 equiv) in tetrahydrofuran (14
mL) at 24 °C in a 1ꢀL roundꢀbottomed flask equipped with a reflux condenser. The reaction vessel was
placed in an oil bat that had been preheated to 80 °C and the reaction mixture was stirred and heated for 3
h at 80 °C. The product mixture was diluted sequentially with dichloromethane (200 mL) and saturated
aqueous sodium thiosulfate (50 mL). The diluted product mixture was transferred to a separatory funnel
and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 ×
100 mL). The organic layers were combined and the combined organic layers were washed with water
(10 × 20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered
and the filtrate was concentrated to dryness. The residue obtained was purified by automated flashꢀ
column chromatography (eluting with hexanes initially, grading to 100% ethyl acetate–hexanes, linear
26
ACS Paragon Plus Environment

Page 27 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
gradient) to afford 18ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin 15a as an amorphous white solid (1.98 g,
7
4%, two steps).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Synthesis of 19,20-dihydropleuromutilin (16, Scheme 3): Palladium on carbon (5 wt. % loading,
38 mg, 159 ꢀmol, 0.05 equiv) was added to a solution of pleuromutilin (1, 1.20 g, 3.17 mmol, 1 equiv)
3
in ethanol (15 mL) at 24 °C. The reaction vessel was evacuated and reꢀfilled using a balloon of
dihydrogen. This process was repeated four times. The reaction mixture was stirred for 12 h at 24 °C.
The product mixture was filtered through a short column of celite and the short column was rinsed with
dichloromethane (200 mL). The filtrates were combined and the combined filtrates were concentrated to
afford 19,20ꢀdihydropleuromutilin (16) as an amorphous white solid (1.15 g, 96%).
19,20ꢀ
1
dihydropleuromutilin (16): R = 0.34 (50% ethyl acetate–hexanes; CAM, PAA). H NMR (400 MHz,
f
CDCl ) δ 5.68 (d, J = 8.0 Hz, 1H, H ), 4.02 (q, J = 16.0 Hz, 2H, H ), 3.90 (d, J = 6.0 Hz, 1H, H ), 2.79
3
14
22
11
(
br s, 1H, C22ꢀOH), 2.41–2.33 (m, 1H, H ), 2.28–2.12 (m, 2H, H ), 2.08 (s, 1H, H ), 1.80–1.66 (m, 4H, 1
10 2 4
×
H , 1 × H , 1 × H , 1 × C11ꢀOH), 1.65–1.49 (m, 4H, 1 × H , 1 × H , 1 × H , 1 × H ), 1.45 (dt, J =
8
13
19
1
6
7
19
1
2.4, 3.8 Hz, 1H, 1 × H ), 1.41–1.33 (m, 4H, 1 × H , 3 × H ), 1.32–1.26 (m, 1H, 1 × H ), 1.09 (td, J =
1
7
15
13
1
4.0, 4.8 Hz, 1H, 1 × H ), 0.95–0.87 (m, 6H, 3 × H , 3 × H ), 0.72 (t, J = 7.4 Hz, 3H, H ), 0.65 (d, J =
8
17
18
20
1
3
6.8Hz, 3H, H ). C NMR (100 MHz, CDCl ) δ 217.1 (C), 172.2 (C), 76.3 (CH), 69.9 (CH), 61.2 (CH ),
1
6
3
2
58.3 (CH), 45.4 (C), 41.8 (C), 40.9 (C), 40.8 (CH ), 36.5 (CH), 34.3 (CH ), 34.3 (CH), 30.1 (CH ), 26.7
2
2
2
(CH ), 26.2 (CH ), 24.8 (CH ), 20.5 (CH ), 16.4 (CH ), 14.7 (CH ), 11.0 (CH ), 8.1 (CH ). IR (ATRꢀ
2
3
2
2
3
3
3
3
–
1
+
FTIR), cm : 3485 (br w), 2937 (w), 2879 (w), 1727 (s), 1460 (w), 1375 (w). HRMSꢀESI (m/z): [M + H]
calcd for C H O , 381.2641; found, 381.2640. ꢀꢁꢂ = +27⁰ (c = 1.0, CHCl3).
ꢄꢅ
2
2
37
5
ꢃ
A portion of 16 was further purified by recrystallization from methanol to afford a sample of 16 ·
H O for Xꢀray analysis. 16 · H O: mp 140–142 °C.
2
2
Synthesis of O-(p-tolylsulfonyl)-18-hydroxy-19,20-dihydropleuromutilin (S17, Scheme 4):
Triethylamine (76.7 ꢁL, 550 ꢁmol, 1.10 equiv) was added dropwise via syringe to a solution of 18ꢀ
hydroxyꢀ19,20ꢀdihydropleuromutilin [15a, 198 mg, 500 ꢁmol, 1 equiv, dried by azeotropic distillation
with benzene (2.0 mL)] and p-tolylsulfonyl chloride (105 mg, 550 ꢁmol, 1.10 equiv) in methyl ethyl
ketone (9.0 mL) at 24 °C. The reaction mixture was stirred at 24 °C for 12 h. The product mixture was
diluted with saturated aqueous sodium bicarbonate solution (2.0 mL). The diluted mixture was
transferred to a separatory funnel and the layers that formed were separated. The aqueous layer
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
obtained was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 40% acetone–hexanes, linear gradient) to
afford Oꢀ(pꢀtolylsulfonyl)ꢀ18ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin S17 as an amorphous white solid (274
1
mg, 99%). R = 0.56 (50% acetone–dichloromethane; UV, CAM). H NMR (400 MHz, CDCl ) δ 7.82
f
3
(
d, J = 8.0 Hz, 2H, H ), 7.35 (d, J = 8.0 Hz, 2H, H ), 5.70 (d, J = 8.0 Hz, 1H, H ), 4.49 (s, 2H, H ), 3.85
24 25 14 22
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
(
d, J = 6.4 Hz, 1H, H ), 3.57 (d, J = 10.8 Hz, 1H, 1 × H ), 3.42 (d, J = 11.2 Hz, 1H, 1 × H ), 2.45 (s, 3H,
11
18
18
H ), 2.42–2.35 (m, 1H, 1 × H ), 2.29–2.13 (m, 2H, H ), 2.06 (s, 1H, H ), 1.80–1.66 (m, 4H, 1 × H , 1 ×
27
10
2
4
8
H , 2 × H ), 1.63–1.54 (m, 2H, 1 × H , 1 × H ), 1.52–1.41 (m, 2H, 1 × H , 1 × H ), 1.40–1.32 (m, 4H, 1
13
19
1
6
1
7
×
H , 3 × H ), 1.14–1.06 (m, 2H, 1 × H , 1 × H ), 0.94 (d, J = 6.8 Hz, 3H, H ), 0.73 (t, J = 7.4 Hz, 3H,
7
15
8
13
17
13
H ), 0.60 (d, J = 6.8 Hz, 3H, H ). C NMR (100 MHz, CDCl ) δ 216.6 (C), 165.1 (C), 145.3 (C), 132.6
20
16
3
(
C), 129.9 (CH), 128.0 (CH), 75.1 (CH), 70.4 (CH ), 69.7 (CH), 64.9 (CH ), 58.2 (CH), 45.4 (C), 43.9
2
2
(
(
2
C), 41.9 (C), 36.4 (CH), 35.2(CH ), 34.3 (CH), 34.2 (CH ), 30.1 (CH ), 26.7 (CH ), 25.0 (CH ), 21.6
2 2 2 2 2
–1
CH ), 17.0 (CH ), 16.4 (CH ), 14.7 (CH ), 10.7 (CH ), 7.4 (CH ). IR (ATRꢀFTIR), cm : 3333 (br w),
3 2 3 3 3 3
+
942 (w), 2881 (w), 1732 (m), 1598 (w), 1448 (w), 1371 (m). HRMSꢀESI (m/z): [M + H] calcd for
ꢄꢅ
C H O S, 551.2679; found, 551.2681. ꢀꢁꢂ = +25⁰ (c = 1.0, CHCl3).
29
43
8
ꢃ
Synthesis of O-(p-tolylsulfonyl)-18-oxo-19,20-dihydropleuromutilin (17, Scheme 4): Six equal
portions of DessꢀMartin periodinane (16.9 mg, 39.9 ꢁmol, 1.10 equiv) was added over 1 h to a solution of
Oꢀ(pꢀtolylsulfonyl)ꢀ18ꢀhydroxyꢀ19,20ꢀdihydropleuromutilin S17 (20.0 mg, 36.3 ꢁmol, 1 equiv) and
pyridine (29.4 ꢁL, 363 ꢁmol, 10.0 equiv) in dichloromethane (400 ꢁL) at 24 °C. The resulting mixture
was stirred for 30 min at 24 °C. The product mixture was diluted sequentially with ether (1.0 mL), a
saturated aqueous sodium bicarbonate solution (500 ꢁL) and a saturated aqueous sodium thiosulfate
solution (500 ꢁL). The resulting mixture was stirred for 5 min at 24 °C. The resulting mixture was
transferred to a separatory funnel and the layers that formed were separated. The aqueous layer
obtained was extracted with dichloromethane (3 × 5.0 mL). The organic layers were combined and the
combined organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate
was concentrated to dryness. The residue obtained was purified by automated flashꢀcolumn
chromatography (eluting with hexanes initially, grading to 40% ethyl acetate–hexanes, linear gradient) to
afford Oꢀ(pꢀtolylsulfonyl)ꢀ18ꢀoxoꢀ19,20ꢀdihydropleuromutilin (17) as an amorphous white solid (13.1
1
mg, 66%). R = 0.46 (33% ethyl acetate–hexanes; UV, CAM). H NMR (400 MHz, CD Cl ) δ 9.68 (s,
f
2
2
1
4
H, H ), 7.79 (d, J = 8.0 Hz, 2H, H ), 7.39 (d, J = 8.0 Hz, 2H, H ), 5.90 (d, J = 9.2 Hz, 1H, H ), 4.56–
18 24 25 14
.47 (m, 2H, H ), 3.36 (dd, J = 13.2, 6.4 Hz, 1H, H ), 2.46 (s, 3H, H ), 2.33–2.22 (m, 2H, H ), 2.17–
22
11
27
2
2.06 (m, 3H, 1 × H , 1 × H , 1 × H ), 1.68–1.52 (m, 4H, 1 × H , 1 × H , 2 × H ), 1.48–1.40 (m, 5H, 1 ×
4
10
13
1
8
19
H , 1 × H , 3 × H ), 1.32–1.17 (m, 3H, 2 × H , 1 × H ), 1.14 (d, J = 6.8 Hz, 3H, H ), 0.90–0.85 (m, 1H,
1
6
15
7
13
17
13
1
× H ), 0.80 (t, J = 7.4 Hz, 3H, H ), 0.69 (d, J = 6.8 Hz, 3H, H ). C NMR (100 MHz, CDCl ) δ 216.9
8
20
16
3
(
(
C), 215.8 (C), 201.7 (CH), 165.9 (C), 146.4 (C), 133.0 (C), 130.6 (CH), 128.6 (CH), 69.9 (CH), 65.8
CH ), 64.7 (CH), 59.2 (CH ), 46.0 (C), 44.3 (C), 42.6 (C), 37.6 (CH), 34.9 (CH ), 32.7 (CH), 30.3 (CH ),
2
2
2
2
28
ACS Paragon Plus Environment

Page 29 of 101
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
7.2 (CH ), 24.9 (CH ), 24.2 (CH ), 22.0 (CH ), 17.2 (CH ), 15.2 (CH ), 12.9 (CH ), 8.8 (CH ). IR
3
2
2
3
2
3
3
3
–1
(
ATRꢀFTIR), cm : 2925 (m), 1735 (s), 1686 (m), 1454 (w), 1373 (m), 1289 (w). HRMSꢀESI (m/z): [M
+
ꢄꢅ
+
H] calcd for C H O S, 549.2522; found, 549.2522. ꢀꢁꢂ = +24⁰ (c = 0.25, CHCl3).
ꢃ
2
9
41
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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
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
Synthesis of silane S6 (Scheme S1): Dimethylchlorosilane (18.0 ꢁL, 162 ꢁmol, 2.00 equiv) was
added dropwise via syringe to a solution of Oꢀtertꢀbutyldiphenylsilylpleuromutilin [19, 50 mg, 81.1 ꢁmol,
1
equiv, dried by azeotropic distillation with benzene (500
ꢁL)] and triethylamine (45.2 ꢁL, 324
ꢁ
mol, 4.00 equiv) in dichloromethane (500 L) at 0 °C. The reaction mixture was stirred at 0 °C for 30
ꢁ
min. The product mixture was diluted sequentially with pentane (1.0 mL) and aqueous potassium
phosphate buffer solution (pH 7, 0.10 M, 1.0 mL). The diluted mixture was transferred to a
separatory funnel and the layers formed were separated. The aqueous layer was extracted with
dichloromethane (3 × 5 mL). The organic layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to
dryness to afford silane S6 as an amorphous white solid (51.2 mg, 94%). The silane S6 prepared this
way was analytically pure and was used in the next step without further purification. R = 0.60 (15%
ethyl acetate–hexanes; UV, CAM). H NMR (400 MHz, C D ) δ 7.82–7.77 (m, 4H, 2 × H , 2 × H ),
7.25–7.21 (m, 6H, 2 × H , 1 × H , 2 × H , 1 × H ), 6.58 (dd, J = 17.6, 11.2 Hz, 1H, H ), 5.87 (d, J =
f
1
6
6
27
31
2
6
28
30
32
19
8
6
1
×
.0 Hz, 1H, H ), 5.37–5.29 (m, 2H, H ), 4.84 (sep, J = 2.8 Hz, 1H, SiꢀH), 4.18 (s, 2H, H ), 3.29 (d, J =
.0 Hz, 1H, H ), 2.41–2.34 (m, 1H, H ), 1.89–1.85 (m, 2H, H ), 1.82–1.75 (m, 2H, 1 × H , 1 × H ),
.74–1.68 (m, 1H, H ), 1.65 (s, 3H, H ), 1.58–1.51 (m, 1H, 1 × H ), 1.44–1.28 (m, 3H, 1 × H , 1 × H , 1
14 20 22
1
1
10
2
4
13
1
15
7
6
8
H ), 1.07 (s, 9H, H ), 1.14–1.02 (m, 5H, 1 × H , 1 × H , 3 × H ), 0.92–0.75 (m, 4H, 1 × H , 3 × H ),
13
24
1
7
18
8
17
13
0
.70 (d, J = 6.8 Hz, 3H, H ), 0.17–0.14 (m, 6H, 3 × H , 3 × H ). C NMR (100 MHz, C D ) δ 214.8
1
6
33
34
6
6
(
(
(
(
C), 169.1 (C), 139.9 (CH), 135.7 (CH), 133.0 (C), 133.0 (C), 129.8 (CH), 128.2 (CH), 127.8 (CH), 128.8
CH), 127.5 (CH), 116.3 (CH ), 78.9 (CH), 68.9 (CH), 62.9 (CH ), 58.0 (CH), 45.0 (C), 44.6 (CH ), 44.5
C), 42.0 (C), 37.0 (CH), 36.6 (CH), 34.0 (CH ), 30.1 (CH ), 29.2 (CH ), 26.6 (CH ), 26.5 (CH ), 26.1
2
2
2
2
2
3
2
3
–1
CH ), 19.1 (C), 16.2 (CH ), 14.8 (CH ), 12.0 (CH ), –0.93 (CH ), –1.00 (CH ). IR (ATRꢀFTIR), cm :
2
3
3
3
3
3
+
2955 (w), 2861 (w), 1755 (w), 1734 (m), 1457 (w). HRMSꢀESI (m/z): [M – Si(CH ) + Na] calcd for
C H NaO Si, 639.3482; found, 639.3486. ꢀꢁꢂ = +30⁰(c = 0.20, CHCl3).
3
2
ꢄꢅ
38
52
5
ꢃ
Synthesis of 18-hydroxypleuromutilin (S7) and 19-oxo-20-hydropleuromutilin (S8): This
23
experiment was adapted from the work of Hartwig and coꢀworkers. A 4ꢀmL pressure tube with a Teflonꢀ
coated valve was charged with 3,4,7,8ꢀtetramethylꢀ1,10ꢀphenanthroline (2.3 mg, 9.9 ꢁmol, 12.5 mol%)
29
ACS Paragon Plus Environment