Development of a Modular Synthetic Route to (+)-Pleuromutilin, (+)-12-epi-Mutilins, and Related Structures

Article abstract of DOI:10.1021/jacs.7b09869

We describe the development of an enantioselective synthetic route to (+)-pleuromutilin (1), (+)-12-epi-mutilin, and related derivatives. A key hydrindanone was prepared in three steps and 48% overall yield from cyclohex-2-en-1-one. 1,4-Hydrocyanation provided a nitrile (53%, or 85% based on recovered starting material) that was converted to the eneimide 57 in 80% yield by the 1,2-addition of methyllithium to the nitrile function, cyclization, and in situ acylation with di-tert-butyldicarbonate. The eneimide 57 was employed in a 2-fold neopentylic coupling reaction with an organolithium reagent derived from the alkyl iodides (R)- or (S)-30, which contain the C11-C13 atoms of the target, to provide diastereomeric diketones in 60% or 48% yield (for coupling with (R)- or (S)-30, respectively). The diketone derived from (S)-30 contains the (S)-C12 stereochemistry found in pleuromutilin and was elaborated to an alkynylaldehyde. Nickel-catalyzed reductive cyclization of this alkynylaldehyde, to construct the eight-membered ring of the target, unexpectedly provided a cyclopentene (67%), which arises from participation of the C12-α-olefin in the transformation. The diketone derived from the enantiomeric C12-fragment (R)-30 underwent reductive cyclization to provide the desired product in 60% yield. This was elaborated to 12-epi-mutilin by a four-step sequence (39% overall). Installation of the glycolic acid residue followed by C12 epimerization (Berner et al. Monatsh. Chem. 1986, 117, 1073) generated (+)-pleuromutilin (1). (+)-12-epi-Pleuromutilin and (+)-11,12-di-epi-pleuromutilin were prepared by related sequences. This work establishes a convergent entry to the pleuromutilins and provides a foundation for the production of novel antibiotics to treat drug-resistant and Gram-negative infections.

Full text of DOI:10.1021/jacs.7b09869

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Article
Development of a modular synthetic route to (+)-
pleuromutilin, (+)- 12-epi-mutilins, and related structures.
Mingshuo Zeng, Stephen K Murphy, and Seth B Herzon
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09869 • Publication Date (Web): 19 Oct 2017
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Journal of the American Chemical Society
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Development of a modular synthetic route to (+)-pleuromutilin, (+)-
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1,2,*
Mingshuo Zeng, Stephen K. Murphy, and Seth B. Herzon
1
2
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States. Department of Pharmacology,
Yale School of Medicine, New Haven, Connecticut 06520, United States.
ABSTRACT: We describe the development of an enantioselective synthetic route to (+)-pleuromutilin (1), (+)-12-epi-mutilin, and
related derivatives. A key hydrindanone was prepared in three steps and 48% overall yield from cyclohex-2-en-1-one. 1,4-
Hydrocyanation provided a nitrile (53%, or 85% based on recovered starting material) that was converted to the eneimide 57 in
8
0% yield by the 1,2-addition of methyllithium to the nitrile function, cyclization, and in situ acylation with di-tert-
butyldicarbonate. The eneimide 57 was employed in a two-fold neopentylic coupling reaction with an organolithium reagent de-
rived from the alkyl iodides (R)- or (S)-30, which contain the C11–C13 atoms of the target, to provide diastereomeric diketones in
6
0% or 48% yield (for coupling with (R)- or (S)-30, respectively). The diketone derived from (S)-30 contains the (S)-C12 stereo-
chemistry found in pleuromutilin, and was elaborated to an alkynylaldehyde. Nickel-catalyzed reductive cyclization of this al-
kynylaldehyde, to construct the eight-membered ring of the target, unexpectedly provided a cyclopentene (67%), which arises from
participation of the C12-α-olefin in the transformation. The diketone derived from the enantiomeric C12-fragment (R)-30 under-
went reductive cyclization to provide the desired cyclization product in 60% yield. This was elaborated to 12-epi-mutilin by a four-
step sequence (39% overall). Installation of the glycolic acid residue, followed by C12 epimerization (Berner et. al Monatsh.
Chem. 1986, 117, 1073) generated (+)-pleuromutilin (1). (+)-12-Epi-pleuromutilin and (+)-11,12-di-epi-pleuromutilin were pre-
pared by related sequences. This work establishes a convergent entry to the pleuromutilins and provides a foundation for the pro-
duction of novel antibiotics to treat drug-resistant and Gram-negative infections.
Introduction
+)-Pleuromutilin (1) was isolated in 1951 by Kavanagh,
The derivatives 3–5 (and other C14 analogs) are active
against primarily Gram-positive pathogens. Functionalization
of the cyclooctane ring has the potential to significantly im-
prove the spectrum of activity. For example, epimerization of
the C12 position (by an unusual retroallylation–allylation reac-
(
Hervey, and Robbins from Pleurotus mutilus and Pleurotus
passeckerianus and shown to inhibit the growth of Gram-
1
2
3
4
15
positive bacteria (Figure 1). Anchel, Arigoni, and Birch
tion discovered by Berner, vide infra), followed by function-
established the structure of 1, which was confirmed by X-ray
crystallographic analysis. (+)-Pleuromutilin (1) is comprised
of a densely-functionalized eight-membered carbocycle fused
to a cis-hydrindanone core and contains eight contiguous ste-
reocenters, three of which are quaternary. The biosynthesis of
alization of the transposed alkene provides 12-epi-
pleuromutilin derivatives such as 6, which possess activity
5
1
6
against Gram-negative pathogens. This improved activity is
16b
due in part to decreased AcrAB-TolC efflux, a common
resistance mechanism in Gram-negative strains. Pleuromu-
tilins inhibit the three bacterial strains recently classified as
urgent threats by the Centers for Disease Control and Preven-
(
+)-pleuromutilin (1), from geranylgeranyl pyrophosphate, has
4,6
been elucidated.
1
7
18
tion: Clostridium difficile, carbapenem-resistant Enterobac-
The antibacterial properties of pleuromutilins derive from
the inhibition of bacterial protein synthesis. The tricyclic core
and the C14 glycolic acid residue bind the A- and P-sites, re-
1
6h
teriaceae
gonorrhoeae.
(6Ca RE),
and
drug-resistant
Neisseria
1
7
8
spectively, of the peptidyl transferase center. The C14 gly-
colic acid residue is essential for antibacterial activity; by
comparison, the deacylated derivative (+)-mutilin (2) is not
As outlined, semisynthesis has primarily enabled modifica-
tion of C14 and, to a lesser extent, C12. Although a limited
1
0
number of changes to other positions have been made, much
of the chemical space surrounding the carbon skeleton remains
unexplored. A fully synthetic route to pleuromutilins would
enable access to a greater diversity of antibiotics with poten-
tially expanded activity spectra and improved pharmacological
properties. Herein we describe in full detail our synthetic
studies toward (+)-pleuromutilin (1), culminating in the devel-
opment of a convergent, enantioselective, 16-step route to the
(+)-12-epi-mutilin scaffold as well as a 19-step route to (+)-
9
active against Gram-positive bacteria. Thousands of C14 ana-
10
logs have been prepared from natural (+)-pleuromutilin (1).
Tiamulin (3) and valnemulin (not shown) are C14 analogs
used in veterinary applications since the 1980s. Retapamulin
(
4) was approved in 2007 for the treatment of impetigo in hu-
11
mans.
Most pleuromutilins tested to date elicit very low
12
mutational frequencies, and as of 2014 clinical resistance to
1
3
retapamulin (4) therapy has not been recorded. Lefamulin (5)
recently passed a Phase III clinical trial for the treatment of
community-acquired bacterial pneumonia (IV-to-oral admin-
1
9,20,21
pleuromutilin (1) itself.
We believe this work provides a
1
4
istration).
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Figure 1. Structures of natural (+)-pleuromutilin (1) and the deacylated derivative (+)-mutilin (2), structures of the semisynthetic C14
derivatives tiamulin (3), retapamulin (4), and lefamulin (5), and the structure of a representative 12-epi-mutilin derivative 6. Natural (+)-
pleuromutilin (1) and the semisynthetic C14 derivatives 3–5 are active primarily against Gram-positive pathogens. 12-Epi-mutilin
derivatives possess extended spectrum activity against Gram-negative and drug-resistant pathogens.
2
7
28
foundation to leverage the wealth of existing target binding
and structure–activity data toward the production of improved
fully synthetic analogs. Successes in the development of fully
synthetic routes to other clinical classes of antibiotics, such as
Scheme 1. Key steps in the Gibbons (A), Boeckman (B),
29
and Procter (C) syntheses of pleuromutilin (1).
22
23
24
25
β-lactams, vancomycins, tetracyclines, and macrolides,
underscore the potential for antibiotic development through
2
6
chemical synthesis.
Results
Three syntheses of pleuromutilin (1) have been reported,
and the key transformations used to construct the eight-
membered ring in each are summarized in Scheme 1. Gib-
bons, working in the laboratory of the late R. B. Woodward,
introduced this ring by a bromonium ion-induced Grob frag-
27
mentation (7®8, Scheme 1A, step 13 of 31 linear steps).
This transformation was discovered while attempting to form
an epoxide from 7 via a bromohydrin intermediate. Boeckman
and co-workers employed an anionic oxy-Cope rearrangement
to construct the eight-membered ring (9®10, Scheme 1B, step
2
8
7 of 27 linear steps). Finally, Procter and co-workers utilized
a samarium diiodide-mediated cyclization cascade to construct
the five- and eight-membered rings simultaneously (11®12,
2
9
Scheme 1C, step 9 of 34 linear steps). This last work consti-
tutes the first enantioselective route to (+)-pleuromutilin (1).
These syntheses are timeless achievements in their own right
that feature important strategic and methodological advances,
1
0
and have been reviewed. Several synthetic studies toward
(
Scheme 2A depicts the key elements of our retrosynthetic
analysis. As with all routes to pleuromutilin, the glycolic acid
3
0
+)-pleuromutilin (1) have also been reported.
2
9
residue was installed in the final steps of the synthesis. The
eight-membered ring was deconstructed via the hypothetical
bond disconnections (shown in structure 13) to the hy-
drindanone 14, a two-carbon (C10–C17) fragment, and the
bridging synthon 15. In the forward sense, construction of the
C9–C10 and C13–C14 bonds would afford the aldehyde 16
Our strategy-based design was informed by the challenges
encountered by Gibbons, Boeckman, and Procter in the steps
of their syntheses following formation of the 8-membered
carbocycle. Each synthesis constructs the core relatively early
(
steps 7, 9, or 13) and follows with 18–25 further transfor-
mations. We sought to limit the number of reactions after
formation of the 8-membered ring to achieve a more step-
(
Scheme 2B). We envisioned many possible modes of C10–
31
C11 bond formation from 16 including a Nozaki–Hiyama–
economic and convergent synthesis. Working within these
3
2
Kishi cyclization through a C10–C17 vinyl triflate or a re-
constraints, we aimed to close the 8-membered ring towards
the end of our synthesis using only the innate functionality of
the pleuromutilins and with all quaternary centers and func-
tional groups in place. This goal forced us to target powerful
transformations for the construction of carbon–carbon bonds
in sterically-congested settings.
3
3
34
ductive cyclization of an enal or ynal via a C10–C17 alkene
or alkyne, respectively. The design of this cyclization strategy
was informed by well-known physical organic properties of
3
5
medium-sized rings (Scheme 2C). When using flexible, fully
saturated cyclization precursors, entropic and enthalpic penal-
ties arising from substrate reorganization and syn-pentane
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Scheme 2. A. The outlines of our strategy to access (+)-mutilin (2). B. The cyclization substrate 16 targeted. C. Destabiliz-
ing syn-pentane and transannular interactions arising from a more flexible and saturated cyclization precursor.
1
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5
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9
1
1
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5
6
A.
CH3
OH
CH3
CH3
OH
CH3
CH3
CH3
O
I
1
4
13
14
C10–C17
fragment
CH3
OH
CH3
OH
+
+
CH3
9
OCH3
13
O
O
10
9
11
11
CH3
(+)-mutilin (2)
O
O
7CH3
H
H
1
1
4
15
13
B.
C.
CH
3
CH
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
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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
H
H
O
1
O
14
CH
3
5-out-of-8 atoms fixed in place
CH
3
4
5
CH3
CH3
OH
O
4
O
11
9
10
17
non-bonding interactions
relieved by C10/C14 sp/sp2 centers
10
O
flexible substrate
multiple syn-pentane
transannular
interactions
H
H
interactions
1
6
17
Key design criteria and challenges: maximize convergency, minimize post-macrocyclization reactions, utilize innate functionality, develop neopentylic bond constructions
Scheme 3. Stereoselective synthesis of the hydrindanone 14.
Zn(CH3)2
Cu(OTf)2, L1;
O
O
OTf
O
NaOt-Bu, CH3I
CH O C
3
2
LHMDS, Tf NPh
2
3 2
CH O C
CH3O2C
CH3
CH3
CH3
CH3
CH3
CH3Li, electrophile
>20:1 dr
88%
>
20:1 dr, 97:3 er
18
19
20
21
OCH3 i-PrMgCl
4
-component coupling
0%, >20:1 dr, 97:3 er
9
7%
7
OCH3
1. Pd(PPh3)4, LiCl
Sn(C2H3)4, CO
yield of 20
electrophile (from 18, two steps)
HO
CH3O2C
Ph
2. Cu(OTf)2
CH3
CH3
O
O
CH3
CH3OCOCN
O
71%
73% (two steps)
P
N
CH3
22
Ph
7
5%
CH3O
N
CH3SO3H
N
L1
CH3O
CH3
CH3
O
CH3O
CH3
CH3
O
CH3O
CH3
CH3
O
O
O
71%
O
(from 22)
OCH3
1
4
1
9
interactions, respectively, result in a high kinetic barrier to
ring formation. For example, C–O bond forming ring closures
action that comprises copper-catalyzed enantioselective 1,4-
addition of dimethyzinc to cyclohex-2-en-1-one (18), in situ
activation of the resulting alkyl zinc enolate with methyllithi-
5
to make 8-membered cyclic ethers are ~10 times slower than
3
6
37
for 5-membered cyclic ethers. Repulsive non-bonded interac-
tions in the cyclization transition state manifest transannular
interactions in the eight-membered ring product. By compari-
son, the cyclization strategy we designed breaks the 8-
membered ring into two shorter fragments (C10–C17 and
C11–C14) thereby more effectively exploiting the preorgani-
zation afforded by the rigid cis-hydrindanone. This strategy
locks 5-out-of-8 atoms (C4, C5, C9, C10, C14) in the develop-
um, and C-acylation with methyl cyanoformate (Mander’s
3
8
reagent). Diastereoselective methylation of the resulting β-
ketoester 19 provided the α-methyl-β-ketoester 20 in 71%
overall yield, >20:1 dr, and 97:3 er. Due to the high cost and
safety concerns associated with the use of Mander’s reagent,
we sought a safe and inexpensive alternative. Methyl 1H-
imidazole-1-carboxylate was identified as a superior reagent
that afforded the product 20 in comparable yield (75% overall,
two steps). Ultimately, the conjugate addition–acylation and
alkylation steps were carried out in one flask to access the a-
methyl-b-ketoester 20 in one step (70%). Deprotonation of
the α-methyl-β-ketoester 20 and trapping of the resulting eno-
late with N-phenyltriflimide afforded the vinyl triflate 21
(88%). The triflate 21 was subjected to a carbonylative Stille
3
9
2
ing ring in place. Furthermore, utilizing sp- or sp -hybridized
carbons at C10 and C14 alleviates transannular interactions in
the cyclization product 17. Overall, we anticipated that the 8-
membered ring formation (C10–C11 bond construction) and
the fragment coupling (C13–C14 bond construction) steps,
both of which are two-fold neopentylic couplings, would be
the most challenging transformations of this synthesis.
2
1
40
coupling with tetravinyl tin; the resulting dienone (not
Initially, we prepared the hydrindanone 14 from cyclohex-2-
en-1-one (18) by a five-step sequence (Scheme 3). The route
began with a stereoselective conjugate addition–acylation re-
shown) underwent selective Nazarov cyclization on treatment
with copper triflate to provide the hydrindanone 14 in 73%
4
1
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Scheme 4. A. Attempted synthesis of the diketone 25 via the acid chloride 23 or the lactone 27. B. Synthesis of the alkyl io-
dide (S)-30.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
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2
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2
2
2
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4
4
4
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5
5
5
5
5
5
5
5
6
A.
[M]
OPMB
OPMB
CH
3
CH
3
CH
CH
CH
3
O
O
14
Cl
CH
CH
O
14
2
4
O
1. NaOH
. SOCl
46% (two steps)
O
3
3
O
3
3
CH
CH3
3
O
2
2
1
4
23
25
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
(S)-30, t-BuLi
then Nazarov cyclization
OCH
Pd(PPh
3
OCH
3
OCH
3
OTf
3 4
)
O
14
CH
3
O
2
C
CuI, Et
3
N
1. Ba(OH)
2. PPh
24% (two steps)
2
O
CH
CH
3
3
CH
3
O
2
C
93%
3
AuNTf
2
CH
CH
3
3
CH
CH
3
3
2
1
2
6
27
B.
O
O
NaHMDS
O
O
1
3
11
PMBOCH
2
Cl
1. LiAlH
4
, 40%
I
OPMB
O
N
CH
3
O
N
CH
i-Pr
OPMB
CH
3
CH
3
56 %
3
2. PPh
imidazole
71%
3
, I
2
i-Pr
6
:1 dr
(
S)-28
(S,S)-29
(S)-30
4
4
yield from 21 (five steps, 48% overall yield from 18). Alt-
hough the Nazarov cyclization was in some instances efficient,
tin-based impurities carried over from the Stille coupling led
to variable yields of 14. To address this and to avoid using
toxic alkenylstannane reagents, an alternative cyclopentannu-
ganozinc reagent 24 ([M] = ZnI) derived from (S)-30 or
45
cross-electrophile coupling with (S)-30 directly, the addition
product 25 was never detected. Strongly basic or nucleophilic
reagents appeared to enolize or add to the enone, while at-
tempts to activate the acid chloride using many transition met-
als resulted in rapid decarbonylation, presumably due to the
stability of the resulting allylic metal intermediate.
2
1
lation was developed. 1,2-Addition of the magnesium acety-
30b,42
lide derived from methyl propargyl ether
provided the
alcohol 22 in 97% yield and 10:1 dr (stereoselectivity of addi-
tion not determined). Treatment with methanesulfonic acid
We then targeted the enelactone 27 as a fragment coupling
partner (Scheme 4A). This species possesses a fused bicyclic
skeleton which was expected to facilitate C14-addition by
releasing ring strain on opening, and the cyclopentanone func-
tionality is masked as an acyl enol ether, thereby removing
any complications arising from deprotonation or 1,2-addition.
The enelactone 27 was obtained in three steps and 22% yield
from the vinyl triflate 21. Sonogashira coupling of 21 with
induced
cascade
a
Rupe rearrangement–Nazarov cyclization
to generate the hydrindanone 14 directly in 71%
30b,42
yield (from 22; three steps, 48% overall yield from 18).
We then focused on developing conditions to functionalize
the C14 carbonyl group (Scheme 4). Saponification of the
ester (sodium hydroxide) followed by treatment of the result-
ing carboxylic acid with thionyl chloride afforded the acid
chloride 23 in 46% yield (two steps, Scheme 4A). The acid
chloride 23 was surprisingly resistant to hydrolysis and could
be purified by flash-column chromatography. This stability
may be due to the pseudoaxial disposition of the C14 carbonyl
and the presence of an α-quaternary center. These factors, and
the observation that the enone function of 23 was readily-
enolizable, presaged the difficulties we would encounter in the
fragment coupling.
4
6
methyl propargyl ether afforded the enyne 26 (93%). Sapon-
ification of the methyl ester (barium hydroxide) followed by
4
7
gold-catalyzed 5-exo-dig cyclization generated the enelac-
tone 27 (24%, two steps). Unfortunately, addition of the al-
kyllithium reagent derived from (S)-30 (formed by lithium–
halogen exchange) did not proceed, and unreacted 27 was
recovered. The addition of methyllithium to 27 successfully
opened the lactone to afford the desired dienone (not shown),
suggesting the combined steric hindrance of the two neopentyl
reagents 27 and 30 as the likely cause of failure.
The alkyl iodide fragment (S)-30 contains the C11–C13 at-
oms of the target and was prepared in three steps from the
chiral tigloyl derivative (S)-28 (Scheme 4B). Site- and stere-
oselective a-alkylation of the imide (S)-28 with para-
methoxybenzyl chloromethyl ether afforded the imide (S,S)-29
We also pursued an entirely distinct fragment coupling that
relied on a Claisen condensation to install the C14 ketone ear-
4
8
ly in the route and a Tsuji–Trost reaction to forge the C12–
C13 bond (Scheme 5). Claisen condensation of benzylacetate
with the acid chloride derived from the enyne 26 (not shown)
provided the b-ketoester 31 in 29% yield (two steps), thereby
providing the key C13–C14 bond. Palladium-catalyzed allylic
alkylation of the b-ketoester 31 using rac-2-methyl-2-
4
3
in 56% yield (6:1 dr). Reduction of the imide and deoxy-
iodination generated the alkyl iodide (S)-30 in 28% yield (two
steps).
We envisioned accessing the diketone 25 by coupling the
alkyl iodide (S)-30 with the acid chloride 23. However, de-
spite extensive efforts including cross-coupling with an or-
48
vinyloxirane afforded the lactone 32 (59%). Unfortunately,
we were not able to obtain the hydrindanone 33 from the
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
4
9
Scheme 5. Attempted synthesis of the hydrindanone 33.
iso-propylmagnesium chloride. Swern oxidation of the re-
sulting primary alcohol (not shown) generated the amido alde-
hyde 36 (93%, two steps). Protection of the aldehyde function
and reduction of the Weinreb amide (di-iso-butylaluminum
hydride, DIBALH) provided 37 (79%, two steps).
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
OCH
3
BnO
O
1
3
14
O
1
. Ba(OH)
2
CH3
CH3
OCH3
CH
3
O
2
C
2. oxalyl chloride;
Copper-catalyzed stereoselective 1,4-addition of dimethyl-
zinc to cyclohex-2-en-1-one (18), followed by addition of the
aldehyde 37, afforded the b-hydroxyketone 38 in 78% yield
LHMDS–
benzyl acetate
CH
CH
3
3
2
6
29% (two steps)
31
5
0
and as a mixture of diastereomers (Scheme 6B). The b-
hydroxyketone 38 was oxidized with 2-iodoxybenzoic acid
(IBX) and the resulting β-diketone (not shown) was treated
with iodomethane and tetra-n-butylammonium fluoride
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
Ph
Ph
O
CH
3
O
O
(
TBAF), to provide the α-methyl-β-diketone 39 (69%, two
NH HN
Pd
2
(dba)
2
L , DBU
2
steps, >20:1 dr). Advancement of this material via the usual
route involving Nazarov cyclization was not possible due to
the acid-sensitivity of the acetal group. Instead, we imple-
mented a strategy involving site-selective deprotonation of the
α-methyl-β-diketone 39 (potassium hexamethyldisilazide,
KHMDS) and treatment of the resulting enolate with acetalde-
hyde to afford a b-hydroxyketone (not shown). Activation of
the hydroxyl group with trifluoroacetic anhydride (TFAA) and
elimination of the resulting trifluoroacetate ester (1,8-
PPh
2
2
Ph P
5
9%
L
2
O
O
O
O
12
1
3
O
O
CH
3
CH
3
O
CH
CH
3
CH
CH
3
OCH
3
3
3
5
1
diazabicyclo[5.4.0]undec-7-ene, DBU) provided the enone
0 (76%, two steps). Extended enolate formation and trapping
4
3
3
32
5
2
with N-(5-chloro-2-pyridyl)triflimide (Comins' reagent) af-
forded the dienyl triflate 41 in 78% yield. The dienyl triflate
41 was transformed to the hydrindanone 42 in 84% yield by a
enyne 32. Extensive attempts to hydrate the alkyne within 32
by inter- or intramolecular addition) were unsuccessful.
(
5
3
palladium-catalyzed carbonylative cyclization.
Given these difficulties, we temporarily set aside our goal of
Our attention then turned toward functionalization of the C9
position to install C10–C17 fragment required for eight-
membered ring construction. The hydrindanone 14 (Scheme
3) was employed as a model substrate since it was more acces-
sible than 42. In line with Paquette’s attempted intramolecular
a convergent synthesis and focused on appending the C11–
C14 fragment at the outset. Strategically, this allowed us to
advance material to the cyclization reaction and elucidate key
aspects of that transformation that would be necessary in the
final route. To enable this, we prepared the aldehyde 37,
which contains the C11–C14 atoms of the target (Scheme 6A).
Allylic alkylation of ethyl benzoylacetate (34), followed by in
situ benzoyl migration, generated the diester 35 (43%, 99:1
er). Cleavage of both esters was effected by treatment with
excess N,O-dimethylhydroxylamine hydrogen chloride and
3
0b
additions to the C9 position, 1,4-addition to the tetrasubsti-
tuted enone functionality within 14 proved challenging
(Scheme 7).
4
8
Scheme 6. A. Synthesis of the C11–C14 aldehyde 37. B. Synthesis of the hydrindanone 42.
A.
CH3
O
1
. CH3NH2(OCH3)Cl
1. ethylene glycol
PTSA•H2O
O
O
CH3
O
i-PrMgCl
CH3
CH3
O
O
Pd2(dba)3
L2, TBAT
43%
Ph
O
O
CH3
O
11
OEt
N
14 H
Ph
OEt
2. (COCl) , DMSO
2. DIBALH
2
O
3
Et N
OCH3
O
79% (two steps)
3
4
35
36
37
9
3% (two steps)
B.
Zn(CH3)2
Cu(OTf)2, L1;
1. KHMDS, ZnBr2
acetaldehyde
O
CH3 OH
O
CH3
O
O
1. IBX
O
O
3
7
2. TBAF, CH3I
CH3
CH3
2. pyridine, TFAA; DBU
76% (two steps)
O
O
CH3
7
8%
69% (two steps)
18
38
39
O
Pd(OAc)2
CH3 O
14
CH3 O
OTf
CH3 O
O
n-Bu4NCl, CO
t-BuOK,
O
11
O
O
CH3
9
CH3
CH3
pyridine
84%
CH3
CH3
Comins' reagent
78%
CH3
CH3
O
O
O
4
2
41
40
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
Scheme 7. A. 1,4-Addition of lithium divinylcuprate and hydrogen cyanide to the hydrindanone 14. B. Improved procedure
for the 1,4-hydrocyanation of 14 involving recycling of the undesired diastereomer 50.
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
O
A.
CH
3
O
O
H
CH
3
O
O
O
O
CH
CH
3
O
2 4 3
Sn(CHCH ) , CH Li;
NaOH
82%
CH
3
3
H
CH
3
3
3
CH
OH
CH
CuBr•S(CH
3 2
)
BF •Et O
3
2
1
4
38–60%
43
44
44
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
Inset:
[Cu]
2
Et AlCN (3:1 45:46)
O
OCH
3
CH
3
OCH
3
O
OCH
3
CH O
O
H
3
CH O
O
H
N
3
vs.
O
O
CH3
O
O
CH
3
CH
3
CH
CH
3
CH
CH
O
3
CH
3
3
3
[M]
9
CH
3
9
9
[Cu]
OAlEt
2
CN
CN
4
5
47
49 (65% from 14)
DIBALH
then H
NaOH
+
+
+
O
CH
3
2
OAlEt
2
O
O
CH
CH
3
H
CH
3
H
O
OH
OH
3
CH
3
OCH
3
9
9
9
CH
3
CN
CN
N
4
6
48
48
4
9
B.
CH
CH
CH
CH3
3
O
O
CH
3
O
O
H
CH
CH
CH3
3
O
O
CH
3
O
O
3
O
O
O
O
O
O
O
3
H
CH3
3
3
H
CH3
CH
3
H
CH
3
Et AlCN
2
CH
NaOH
CH
3
+
+
9
9
9
9
2
then H O
CN
CN
CN
CN
14
47
50
49
53% from 14)
50
(
NaOH
38% recovery of 14
54
55
Attempted addition of acetylide- or alkenyl-based nucle-
ophiles generally resulted in recovery of unreacted 14 or the
production of 1,2-addition products. Boron trifluoride–diethyl
face was formed exclusively as the cis-diastereomer and was
configurationally-stable (see 50, Scheme 7B). Unfortunately,
separation of the three diastereomers 47, 49, and 50 was diffi-
cult on preparative scales. Accordingly, we investigated
methods to resolve them in situ. We found that the undesired
C9 addition intermediate 46 could be selectively reduced (at
the ester function) by introduction of DIBALH directly. The
desired addition intermediate 45 was unreactive, presumably
due to the reduced accessibility of the axial ester substituent.
The reduction of 46 proceeded to the alcohol oxidation state;
upon neutralization this species cyclized to the hemiketal 48,
which facilitated its separation from 47. After additional ex-
perimentation, we found that 47 could be quantitatively epi-
merized to 49 by treatment with dilute sodium hydroxide
(65% yield of 49 from 14). The relative stereochemistry of 49
was confirmed by X- ray analysis (see inset, Scheme 7A).
Alternatively, subjecting the mixture of trans-hydrindanone 47
and the undesired addition product 50 to epimerization using
aqueous sodium hydroxide provided the cis-diastereomers 49
and 50, which could be separated by flash-column chromatog-
raphy (Scheme 7B). Although the yield of the desired product
49 is somewhat lower in this approach (53%) the undesired
isomer could be
5
6
etherate-promoted addition of lithium divinylcuprate was
successful and provided the addition product 43 in variable
yields (38–60%) as a single detectable diastereomer (Scheme
7A). Unfortunately, X-ray crystallographic analysis of the
hemiketal 44, obtained by saponification of 43, revealed that
the addition proceeded with the undesired facial selectivity.
Based on NOE analysis, we believe the ester substituent occu-
pies the pseudoaxial orientation. Therefore, we expected ni-
trile addition syn to the ester substituent, which would corre-
spond to pseudoaxial attack, in accord with the Fürst–Plattner
rule. We hypothesize that metal chelation by the 1,4-ketoester
may drive the ester into the pseudoequatorial position (as
shown in the inset), thereby making addition anti to the ester
substituent now the pseudoaxial, and more favorable, mode of
approach.
57
Fortunately, we found that 1,4-hydrocyanation of 14 pro-
ceeded with 3:1 selectivity in favor of the desired C9 diastere-
omer. Careful analysis of the product mixture revealed that
the desired C9-addition product underwent kinetic protonation
to the trans diastereomer 47, and that this slowly converted to
the desired cis isomer 49 upon concentration and purification.
By comparison, the C9 adduct arising from addition to the Si-
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
Scheme 8. Synthesis of the cyclopentene 53 from the enone 42.
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
1
.
O
O
P
OCH
O
OCH3
O
CH3
3
N2
CH3
O
CH3
O
CH3
1. Et AlCN;
2
O
CH3
DIBALH
O
H
K2CO3
O
CH3
CH3
O
CH3
CH3
CH3
O
O
2. KHMDS;
DIBALH
2. PTSA
O
H
5
2
10% (two steps)
CHO
4
2
51
Ni(cod) , L , Et SiH
2
3
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
34% (three steps)
CH3
CH3
CH3
i-Pr
i-Pr
O
O
CH3
O
CH3
N
N
CH3
CH3
OTES
O
OTES
i-Pr i-Pr
H
H
L3
54
not formed
53
5
3
Scheme 9. Synthesis of the alkynylaldehyde 62 from the hydrocyanation product 49.
CH
3
CH3O 14 O
CH3O
CH3
CH3
O
H
relative to 49, 57 has
O
O
methyllithium
addition,
CH3
O
CH3
CH3
H
O
14
O
N
R
ketalization
acidic C–H bonds α to ketone removed
10
one electrophilic site
O
cyclization, and
an accessible and e– deficient C14-site
acylation (for 57)
H
1
0
enhanced ring strain
5
6 R = H
57 R = Boc
N
N
4
9
55
1
2
I
OPMB
CH3O
CH3
CH3
O
H
CH
3
CH
3
O
CH3
Boc
N
O
O
CH
O
3
O
CH
O
3
(HOCH2)2
CH3Li
(S)-30
1
4
4
9
N
R
CH3
12
PTSA
then Boc2O (for 57)
t-BuLi
O
O
CH3
OPMB
H
H
8
3%
N
64% for 56
80% for 57
(for 57)
5
5
56 R = H
57 R = Boc
58
then HCl, 60% (from 57)
CH
3
CH
3
CH
3
CH
3
O
O
O
O
CH
O
3
CH
O
3
TBAF
CH
O
3
KHMDS
CH
O
3
1
. DDQ
. DMP
O
CH3
CH3
CH3
OPMB
12
CH3
Comins'
reagent
2
O
O
O
O
O
OPMB
CH3
OPMB
H
H
H
OTf
H
6
2% (three steps)
62
61
60
73%
59
efficiently recycled by elimination of hydrogen cyanide using
concentrated sodium hydroxide to regenerate 14 (38% recov-
ery based on 14), ultimately allowing higher material through-
put (85% yield of 49 based on recovered 14).
from those developed by Montgomery and co-workers to pro-
60
mote the exo-selective reductive cyclization of ynals, a single
product was obtained from the aldehyde 52 (34% over three
steps). Although limitations in sample size impeded full char-
1
acterization of this product at this time, the expected H NMR
1
,4-Hydrocyanation of the fully-elaborated hydrindanone 42
resonances for the vinyl group in the desired product 54 were
conspicuously absent. Subsequently, the structure of this
product was identified as the tetracycle 53 by comparison to a
related cyclization product (see 66, Scheme 10) and, ultimate-
ly, single crystal X-ray analysis (see inset).
and reduction (DIBALH) of the resulting nitrile (with in situ
5
8
protection of the ketone as its corresponding enolate) provid-
ed the aldehyde 51 in 10% yield over two steps (Scheme 8).
5
9
Homologation with the Ohira–Bestmann reagent followed by
aldehyde deprotection generated the cyclization precursor 52.
With the alkynyl aldehyde 52 in hand, conditions to effect the
The poor yields and linear nature of our route to the ynal 52
motivated us to explore other pathways to cyclization precur-
sors. Recognizing that access to nitrile 49 provided new ave-
nues for fragment coupling, we applied lessons learned from
our prior studies to transform 49 into a viable coupling
3
4,60
exo-selective reductive cyclization were examined.
presence of bis(1,5-cyclooctadiene)nickel (Ni(cod)
In the
2
), 1,3-
bis(2,6-di-iso-propylphenyl)-1,3-dihydro-2H-imidazol-2-
ylidene (L ), and triethylsilane, conditions slightly modified
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Scheme 10. Divergent cyclization pathways of the alkynyl aldehyde 62.
Page 8 of 13
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
Cl
Cl
CH3
40% Ni(cod)2
40% L4
equiv (i-Pr)3SiH
40% Ni(cod)2
40% L4
5 equiv Et3SiH
i-Pr
CH3
CH3
CH3
i-Pr
O
CH3
O
O
O
CH3
O
CH3
O
N
N
5
CH3
CH3
CH3
OTES
O
55%
67%
i-Pr
O
O
i-Pr
O
H
H
H
O
L4
6
3
62
66
[Ni0]
C–H reductive
elimination
electrocyclic
ring opening
oxidative cyclization
CH3
CH3
CH3
CH3
[NiII]–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
O
O
[NiII]
O
O
CH3
O
CH3
O
CH3
[NiII]
CH3
C–O reductive
elimination
Et3SiH
H
insertion
CH3
O
CH3
O
CH3
CH3
OTES
O
O
O
O
O
TES
H
H
H
H
65
64
67
68
partner (see top, Scheme 9). First, we planned to address the
acidity of the ketone function of 49 by protection as a ketal
(55). Second, we needed strategies to enhance the electro-
philicity of the C14 carbonyl group while mitigating the addi-
tional steric hindrance imparted by the axial nitrile group.
Conversion to an eneamide 56 or eneimide 57 was an attrac-
tive strategy as it was expected to alleviate C10–C14 diaxial
interactions and make C14 more accessible to nucleophiles.
Use of this strategy also introduced ring strain and electronic
activation of C14 for fragment coupling. These modifications
were envisioned to work together to make the key
bis(neopentylic) fragment coupling more favorable. In addi-
tion, we anticipated production of a methyl ketone function
following eneamine (amide) hydrolysis after ring opening.
This would help us to realize our strategy (Scheme 2B, C) to
break the 8-membered ring into two short fragments (C10–
C17 and C11–C14) and effectively exploit the preorganization
afforded by the rigid cis-hydrindanone.
bond reductive elimination (64→65), and electrocyclic ring
opening (65→63). Although 63 was not the desired product,
this result demonstrated the feasibility of the oxidative cycliza-
tion step, and suggested that tri-iso-propylsilane was too bulky
to engage the metalacycle 64. Consistent with this, when tri-
ethylsilane was used as reductant, the pentacycle 66 was ob-
tained in 67% yield. This compound was prepared in suffi-
cient quantities for complete characterization, and provided a
basis for elucidating the structure of 53 (Scheme 8). A logical
mechanism for the generation of 66 involves s-bond metathe-
sis of triethylsilane and the metallacyclopentene 64 to generate
67, 1,2-insertion of the α-olefin into the nickel–carbon bond to
generate 68, and carbon–hydrogen bond reductive elimination.
15
As discussed above, Berner had reported that the C12 po-
sition of pleuromutilin could be epimerized by a retroallyla-
tion–allylation reaction on heating with ethylzinc iodide
(
Scheme 11). The mechanism of this transformation is be-
lieved to comprise formation of the zinc alkoxide 70, retroal-
lylation to generate the allylzinc species 71, isomerization to
72, allylation to 73, and protonolysis. An approximately
equimolar mixture of 69 and the 12-epi-derivative 74 was
obtained, suggesting they are nearly equal in energy. With
this in mind, we recognized that the undesired alkene insertion
(responsible for the formation of 66) could be avoided by plac-
ing the alkene in the pseudoequatorial position; following ring
closure, the C12 position could be epimerized by the reverse
of the pathway shown in Scheme 11. From the standpoint of
In practice, protection of the ketone [ethylene glycol, p-
toluenesulfonic acid (PTSA)] proceeded smoothly to afford
the ketal 55 (81%, Scheme 9). Treatment of 55 with methyl-
lithium provided the eneamide 56 (64%), resulting from 1,2-
addition to the nitrile and in situ cyclization. In order to pro-
tect the acidic amide functionality and enhance the electro-
philicity of C14, we synthesized the eneimide 57 by introduc-
2
ing di-tert-butyldicarbonate (Boc O) directly to the reaction
mixture following the cyclization step (80% yield). Generation
of the organolithium reagent derived from (S)-30 (tert-
butyllithium) followed by introduction of the eneimide 57
resulted in 1,2-addition to provide an intermediate acylimine
Scheme 11. C12 epimerization of pleuromutilin 22-O-
tosylate (69) reported by Berner.
15
(
58) that was hydrolyzed (hydrochloric acid) to the methyl
ketone 59 (60%). This key fragment coupling served to forge
one of the bis(neopentylic) carbon–carbon bonds in the target.
The methyl ketone 59 was dehydrated to the alkyne 61 via the
vinyl triflate 60. Removal of the p-methoxybenzyl ether (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone, DDQ) followed by
6
1
oxidation (Dess–Martin periodinane, DMP) generated the
alkynyl aldehyde 62 (45%, four steps).
With an efficient route to the alkynyl aldehyde 62, we were
positioned to fully investigate the key Ni-catalyzed reductive
cyclization step. Using tri-iso-propylsilane as a reductant and
4,5-dichloro-1,3-bis(2,6-di-iso-propylphenyl)-1,3-dihydro-2H-
imidazol-2-ylidene (L ) as the ligand, as recommended by
4
60b
Montgomery and co-workers, the enal 63 was obtained un-
expectedly (55%, Scheme 10). We speculate that 63 is formed
by oxidative cyclization to the metallacyclopentene 64, C–O
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Journal of the American Chemical Society
kyne 77 by conversion to the vinyl triflate 76, followed by
antibiotic development, this approach could be more useful.
6
2
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
As discussed in the introduction, 12-epi-mutilin derivatives
bearing polar functionality in the pseudoequatorial C12 posi-
tion (such as 6, Figure 1) possess extended spectrum activity,
including activity against drug-resistant and Gram-negative
pathogens. Synthesis of pleuromutilins with a pseudoequato-
rial alkene substituent (as in 12-epi-mutilins) would allow for
direct functionalization at this position and could capitalize on
these known improvements in activity.
elimination with TBAF (69%, two steps), or more conven-
iently in one step by vinyl triflate formation in the presence of
excess base (81%). Removal of the p-methoxylbenzyl ether
with DDQ afforded a primary alcohol (not shown) that was
oxidized to the aldehyde 78 (95%, two steps). When the ynal
78 was subjected to the nickel-catalyzed reductive cyclization
using L
success of this transformation),
was not observed, and the allylic alcohol 79 was obtained in
0% yield after removal of the silyl ether. As discussed in the
3
(the chlorinated ligand L
4
was not essential to the
3
4,60
participation of the α-olefin
Our approach to the alkyl iodide (S)-30 relied on the stere-
oselective alkylation of the Evans imide (S)-28 (Scheme 4B).
Because both enantiomers of the Evans auxiliary are commer-
cially-available, this approach to the C11–C13 fragment al-
lowed us to easily obtain the alternate enantiomer (R)-30 by an
identical pathway (see Supporting Information). The eneimide
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
introduction and shown in Schemes 2B and 2C, preorganiza-
tion by the cis-hydrindanone skeleton, as well as the presence
2
of sp centers at C10 and C14 in the product 79 (which allevi-
ate transannular interactions) may facilitate this transformation.
2
Substrate organization by formation of a nickel h -carbonyl-
5
7 successfully underwent ring opening upon addition of the
alkyllithium derived from (R)-30 to provide the diketone 75 in
8% yield after hydrolysis of the acylimine intermediate
Scheme 12). The methyl ketone 75 was converted to the al-
2
h -alkyne complex may be another contributing factor.
4
(
Scheme 12. Synthesis of the tetracycle 79.
CH3
CH3
CH3
O
CH
3
O
CH3
O
O
CH
3
CH3
O
CH3
O
t-BuLi
KHMDS
Comins' reagent
75%
1
2
O
N
Boc
I
OPMB
1
2
+
CH
3
then HCl
O
O
O
CH
3
OPMB
OPMB
H
H
H
OTf
76
4
8%
5
7
(R)-30
75
KHMDS (3.5 equiv)
Comins' reagent
TBAF, 92%
81%
CH
3
CH3
CH3
O
CH
3
O
CH
3
O
CH
3
CH
O
3
CH3
O
1. DDQ
2. DMP
CH3
O
Ni(cod)
2 3
, L
1
4
1
0
OH
3
Et SiH; TBAF
O
O
O
O
OPMB
H
H
H
6
0%,
95% (two steps)
79
78
77
>
20:1 dr, >20:1 rr
Scheme 13. A. Attempted Nozaki–Hiyama–Kishi cyclization of the vinyl triflate 80 and attempted reductive cyclization of
the alkenyl aldehyde 81. B. Attempted aldol–dehydration ring closure of the dialdehyde 84. C. Attempted ring-closing
metathesis of the diene 86. D. Proposed mechanism for the reductive cleavage of 81.
A.
CH3
CH3
CH3
CH3
O
CH
3
O
CH
3
O
CH
3
O
CH3
O
1. DDQ
. DMP
2% (two steps)
CH3
O
CrCl
NiCl
71%
CH3
O
Cp
2
Ti[P(CH
Ph SiH
24%
)
]
2
CH3
O
2
3
3
CH
3
2
2
2
2
O
O
O
O
O
O
OPMB
O
O
H
Tf
H
Tf
80
H
H
6
7
6
81
82
B.
CH3
CH3
CH3
CH3
O
CH
3
O
CH
3
CH3
O
O
CH
3
O
CH
3
CH3
O
CH3
O
[CpRu(CH
,5´-(CF -2,2´-bipyridine
85%
CN)
]PF
1. DDQ
2. PCC
CH3
O
3
3
6
5
3
)
2
O
O
O
O
OPMB
OPMB
O
H
H
H
O
H
O
O
68% (two steps)
7
7
83
84
85
C.
CH3
D.
CH3
O
CH3
CH3
OPMB
CH
CH
3
O
CH3
O
Pd(OAc)
HCO
2%
(PPh
)
CH3
O
O
CH
3
CH3
CH3
O
O
2
3
2
O
3
CH
3
2
H
O
O
O
O
OPMB
OPMB
O
TiCp
2
OTf
H
H
H
H
5
7
6
86
87
88
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Journal of the American Chemical Society
Page 10 of 13
Scheme 14. Synthesis of (+)-pleuromutilin (1), (+)-12-epi-pleuromutilin (97), and (+)-11,12-di-epi-pleuromutilin (93).
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
OTr
OH
CH
3
CH
3
H
CH
3
O
CH
3
O
O
CH
3
O
CH
3
CH
O
3
CH
O
3
SmI2
96%
CH3
2
Et Zn
14
CH
CH3
O
3
CH3
O
OH
OH
1
0
then HCl
CH
OH
3
O
O
O
O
OH
H
H
CH3
96
CH3
33% (+97, 56%)
H
H
7
9
89
(+)-pleuromutilin (1)
O
1
. DMP. 2. SmI
2
EDC, DMAP;
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
TFA
TrO
1
.
N
N
2.
OH, CH
3
OH, NaHCO
3
9
8%, >20:1 dr (two steps)
64% (two steps)
OH
CH
3
CH
3
CH
3
TFA
N
N
O
CH
3
O
O
CH
3
OH CH
3
OH CH
3
1.
2.
CH
3
Na
CH
O
3
HCl
CH
3
14
14
12
CH
3
O
CH3
O
O
12
11
EtOH
OH
96%
OH
O
O
O
CH
3
CH
3
11
CH
3
OH
O
TFAO
EDC, DMAP;
CH OH, NaHCO
H
H
H
OH
CH3
H
3
3
(+)-12-epi-pleuromutilin (97)
9
0
91 (42%)
(+)-12-epi-mutilin (94)
59% (two steps)
+
OH
1.
TrO
EDC, DMAP
O
CH
3
CH
3
CH
3
O
OH
OH CH
OH
CH3
CH
O
3
3
HCl
CH3
CH
3
14
12
CH
3
O
1
2
O
2. HCl
6% (two steps)
11
81%
11
O
O
CH
3
CH
3
1
1
CH
3
H
OH
H
OH
6
H
OH
(
+)-11,12-di-epi-
92 (10%)
(+)-11,12-di-epi-mutilin (95)
9
0
pleuromutilin (93)
We also investigated other ring closure strategies. The vinyl
triflate 80, obtained from 76 in two steps (p-
methoxybenzylether cleavage and oxidation of the resulting
alcohol, 62%, Scheme 13A), could conceivably undergo a
pseudoaxial hydrogen atom abstraction to deliver the desired
C10 and C14 pseudoequatorial diastereomers. Attempted
samarium diiodide-mediated reduction of the C14 carbonyl of
79 provided the pentacycle 89 (96%), presumably by 5-exo-
trig cyclization of a C14 ketyl radical. To prevent this, we
investigated reduction of the C10 alkene first in the presence
of the C12 olefin. Attempts to effect a net redox-neutral one-
step isomerizationof the C10–C11 allylic alcohol were unsuc-
cessful. Accordingly, the allylic alcohol within 79 was oxi-
dized to an enone (not shown) that was treated with samarium
3
2
Nozaki–Hiyama–Kishi cyclization, but under a variety of
conditions only the reduction product 81 was obtained. The
alkene 81 could undergo a titanium(II)-mediated reductive
3
3
cyclization; however, only the methyl ketone 82 was ob-
tained (24%) when 81 was treated with bis(cyclopentadienyl)-
bis(trimethylphosphine)titanium(II). We speculate that 82 is
formed by reductive cleavage of the 1,4-dicarbonyl functional
group to afford the corresponding enolates (see 88, Scheme
6
7
diiodide to afford the diketone 90 with the expected pseudo-
equatorial stereochemistry at C10. The relative stereochemis-
try of 90 was confirmed by X-ray analysis (see inset). The
1
3D). Alternatively, radical cleavage (to generate the a-keto
2
7
radical corresponding to 82), followed by reduction to a titani-
diketone 90 was reduced with sodium in ethanol to provide
the diol 91 (42%) and the C11 diastereomer 92 (10%). Each
product could be separately deprotected (hydrochloric acid) to
access 12-epi-mutilin (94, 96%) or 11,12-di-epi-mutilin (95,
81%). (+)-11,12-Di-epi-pleuromutilin (93) was obtained by
site-selective acylation of 11,12-di-epi-mutilin (95), followed
by deprotection (66%, two steps). To access (+)-pleuromutilin
(1), 12-epi-mutilin (94) was treated with trifluoroacetylimid-
um enolate, may be the operative pathway. In a separate strat-
6
3
egy, anti-Markovnikov hydration of the terminal alkyne 77
provided the aldehyde 83 (85%, Scheme 13B). The dialde-
hyde 84 was obtained after p-methoxybenzylether cleavage
and oxidation of the resulting alcohol (68%, two steps). Un-
fortunately, the dialdehyde 84 did not undergo aldol condensa-
64
tion to 85. The terminal alkene 86, obtained in 52% yield by
6
5
29
reduction of the vinyl triflate 76, was subjected to ring-
azole and the resulting C11 ester (not shown) was coupled
closing metathesis using the Grubbs second-generation cata-
lyst, but did not provide the desired product 87 (Scheme
with O-tritylglycolic acid to afford 96 (64%, two steps). Epi-
merization of the C12 position, followed by acidification, pro-
6
6
13C).
vided (+)-pleuromutilin (1, 33%).
Finally, (+)-12-epi-
pleuromutilin (97) was obtained by stepwise acylation of the
C11 and C14 alcohols with trifluoroacetylimidazole and O-
trifluoroacetylglycolic acid, respectively, followed by meth-
anolysis of the trifluoroacetyl esters (59%, two steps).
To complete the synthesis, the C14 and C10 positions of the
cyclization product 79 needed to be reduced with stereocontrol
(Scheme 14). Given the boat–chair conformation of the sub-
strate, hydridic reagents were expected to approach from the
exterior of the 8-membered ring, which would provide the
undesired pseudoaxial stereochemical outcome. Accordingly,
we focused on single-electron reductions that may proceed by
Conclusion
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Journal of the American Chemical Society
We have described the development of modular and effi-
8. The positional numbering introduced by Arigoni (ref. 3) is used
for all synthetic intermediates.
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
cient enantioselective synthetic routes to (+)-pleuromutilin (1),
(+)-12-epi-pleuromutilin (97), (+)-11,12-di-epi-pleuromutilin
(93), 12-epi-mutilin (94) and 11,12-di-epi-mutilin (95). Ob-
stacles we faced during the study were overcome with several
9
1
. Egger, H.; Reinshagen, H. J. Antibiot. 1976, 29, 923.
0. For a review of synthetic and semisynthetic studies of (+)-
pleuromutilin (1), see: Fazakerley, N. J.; Procter, D. J. Tetrahedron
014, 70, 6911.
1. Daum, R. S.; Kar, S.; Kirkpatrick, P. Nat. Rev. Drug Discovery
2
notable breakthroughs.
Nagata hydrocyanation of the
1
tetrasubstituted hydrindanone 14 established a handle for in-
stallation of a variety of C10–C17 fragments to develop a
method for construction of the ehtig-membered ring. The
identification of the eneimide 57 was essential to realize the
key fragment coupling involving two neopentylic reagents.
Finally, nickel-catalyzed reductive cyclization provided the
desired eight-membered ring, and unusual reaction pathways,
such as rearrangement to the enal 63 and double cyclization to
the cyclopentenes 53 and 66, were discovered.
2007, 6, 865.
12. Paukner, S.; Riedl, R. Cold Spring Harbor Perspect. Med.
2017, 7, a027110.
1
1
3. Walsh, C. T.; Wencewicz, T. A. J. Antibiot. 2014, 67, 7.
4. https://globenewswire.com/news-
0
1
2
3
4
5
6
7
8
9
0
1
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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
release/2017/09/18/1124000/0/en/Nabriva-Therapeutics-Announces-
Positive-Topline-Results-from-Global-Phase-3-Clinical-Trial-
Evaluating-IV-and-Oral-Lefamulin-for-the-Treatment-of-
Community-Acquired-Bacterial-Pneumo.html accessed 10/09/2017
1
5. Berner, H.; Vyplel, H.; Schulz, G.; Schneider, H. Monatsh.
Chem. 1986, 117, 1073.
6. (a) Paukner, S.; Gruss, A.; Fritsche, T. R.; Ivezic-Schoenfeld,
The work herein provides a blueprint for the preparation of
novel pleuromutilins by total synthesis. In order to maximally
capitalize on this work, methods to shorten the annulation
strategy, incorporate heteroatoms into the eight-membered,
and modulate the structure of the hydrindanone residue are
being pursued. These studies will be guided by the well-
characterized interaction of pleuromutilins with the bacterial
1
Z.; Jones, R. N., In Vitro Activity of the Novel Pleuromutilin BC-
3781 Tested Against Bacterial Pathogens Causing Sexually
Transmitted Diseases (STD). In 53rd Interscience Conference on
Antimicrobial Agents and Chemotherapy, Denver, CO, 2013. (b)
Paukner, S.; Strickmann, D. B.; Ivezic-Schoenfeld, Z., Extended
Spectrum Pleuromutilins: Mode-of-action Studies. In 24th European
Congress of Clinical Microbiology and Infectious Diseases
(ECCMID), Barcelona, Spain, 2014. (c) Wicha, W. W.; Ivezic-
Schoenfeld, Z., In Vivo Activity of Extended Spectrum Pleuromutilins
in Murine Sepsis Model. In 24th European Congress of Clinical
Microbiology and Infectious Diseases (ECCMID), Barcelona, Spain,
7
ribosome and are envisioned to allow access to positions of
the molecule that have previously been inaccessible by sem-
isynthetic or fully synthetic approaches.
ASSOCIATED CONTENT
Supporting Information
2
014. (d) Thirring, K.; Heilmayer, W.; Riedl, R.; Kollmann, H.;
Ivezic-Schoenfeld, Z.; Wicha, W.; Paukner, S.; Strickmann, D.
Preparation of 12-epi-pleuromutilin derivatives as antimicrobial
agents. Patent WO2015110481A1, 2015. (e) Paukner, S.; Kollmann,
H.; Riedl, R.; Ivezic-Schoenfeld, Z., Kill curves of the Novel
Extended-Spectrum Pleuromutilin Antibiotic BC-9529. In 25th
European Congress of Clinical Microbiology and Infectious Diseases
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures and NMR spectroscopic data
for all new compounds are included in the Supporting Information
PDF).
(
ECCMID), Copenhagen, Denmark, 2015. (f) Paukner, S.; Wicha, W.
(
W.; Heilmayer, W.; Thirring, K.; Riedl, R., Extended Spectrum
Pleuromutilins: Potent Translation Inhibitors with Broad-Spectrum
Antibacterial Activity In Vitro an In Vivo. In Interscience Conference
of Antimicrobial Agents and Chemotherapy/International Congress of
Chemotherapy and Infection (ICAAC/ICC), San Diego, CA, 2015.
(g) Paukner, S.; Wicha, W. W.; Thirring, K.; Kollmann, H.; Ivezic-
Schoenfeld, Z., In Vitro and In Vivo Efficacy of Novel Extended
Spectrum Pleuromutilins Against S. aureus and S. pneumoniae. In
AUTHOR INFORMATION
Corresponding Author
*
seth.herzon@yale.edu
Author Contributions
2
5th European Congress of Clinical Microbiology and Infectious
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Diseases (ECCMID), Copenhagen, Denmark, 2015. (h) Wicha, W.
W.; Paukner, S.; Strickmann, D. B.; Thirring, K.; Kollmann, H.;
Heilmayer, W.; Ivezic-Schoenfeld, Z., Efficacy of Novel Extended
Spectrum Pleuromutilins Against E. coli In Vitro and In Vivo. In 25th
European Congress of Clinical Microbiology and Infectious Diseases
ACKNOWLEDGMENT
Financial support from Yale University, the National Institute of
General Medical Sciences (R01GM110506), and the National
Sciences and Engineering Research Council of Canada (postdoc-
toral fellowship to S.K.M.) is gratefully acknowledged.
(
ECCMID), Copenhagen, Denmark, 2015.
17. https://www.cdc.gov/drugresistance/biggest_threats.html,
accessed May 13, 2017.
18. Post, K. W.; Songer, J. G. Anaerobe 2004, 10, 47.
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