Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin

Article abstract of DOI:10.1002/chem.201504343

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. Sm^II-mediated radical cyclization cascades of dialdehydes, prepared using a new

Full text of DOI:10.1002/chem.201504343

DOI: 10.1002/chem.201504343
Communication
&
Organic Synthesis
Copper-Catalyzed Double Additions and Radical Cyclization
Cascades in the Re-Engineering of the Antibacterial Pleuromutilin
Rebecca E. Ruscoe, Neal J. Fazakerley, Huanming Huang, Sabine Flitsch, and
David J. Procter*[a]
Abstract: A general synthetic sequence involving simply
prepared starting materials provides rapid access to di-
verse, novel tricyclic architectures inspired by pleuromuti-
lin. SmII-mediated radical cyclization cascades of dialde-
hydes, prepared using a new, one-pot, copper-catalyzed
double organomagnesium addition to b-chlorocyclohexe-
none, proceed with complete sequence selectivity and
typically with high diastereocontrol to give analogues of
the target core. Our expedient approach (ca. 7 steps)
allows non-traditional, de novo synthetic access to ana-
logues of the important antibacterial that can’t be pre-
pared from the natural product by semisynthesis.
Cascade processes have the potential to assemble complex
molecular architectures in a single synthetic operation.[1] If
such processes can be mediated by simple, commercial re-
agents and can be harnessed to deliver structures possessing
important biological or physical properties they become even
more desirable. We have recently exploited carbonyl reduction
[2]
by the well-known electron-transfer reductant SmI2 to trigger
cascade processes that deliver natural and unnatural product
structural motifs.[3,4] For example, we have prepared novel or-
ganic materials and bioactive targets using cascades involving
phase-tag removal and cyclization.[3b–d] In addition, we have
developed radical cyclization cascades of dialdehydes[4] and
have used such a cascade[4c,e] in the first enantiospecific total
synthesis of the antibacterial natural product pleuromutilin
(Scheme 1A).[4e] Electron-transfer reduction of dialdehyde 2
using SmI2 gives 3 with complete diastereocontrol and excel-
lent yield.[4c,e] A dialdehyde cascade has since been employed
by Reisman in an elegant synthesis of (À)-maoecrystal Z.[5]
The natural product pleuromutilin is an important lead for
the development of new antibacterials[6,7] and much synthetic
Scheme 1. A) Radical cyclization cascade of a dialdehyde in the first enantio-
specific synthesis of (+)-pleuromutilin. B) Industrially-important pleuromuti-
lin analogues and the traditional method of analogue synthesis. C) This
work: CuI and SmII in a short route to re-engineered pleuromutilin cores.
[a] R. E. Ruscoe, Dr. N. J. Fazakerley, H. Huang, Prof. Dr. S. Flitsch,
Prof. Dr. D. J. Procter
School of Chemistry University of Manchester
effort has been focused on the synthesis of analogues with in-
creased activity and a more favourable pharmacokinetic pro-
file. A handful of compounds are widely used in veterinary
medicine, a single analogue has been licensed for topical use
on humans, and others are currently undergoing clinical evalu-
ation. Crucially, all of the analogues licensed or in clinical trials
are prepared from the natural product and vary only in the
Oxford Rd, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504343.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Chem. Eur. J. 2016, 22, 116 – 119
116
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
C14 side chain (Scheme 1B). As many of the undesirable prop-
erties of the pleuromutilins (e.g. poor solubility and poor phar-
macokinetic properties) are associated with the core of the an-
tibacterial natural product[6,7] re-engineering of the pleuromuti-
lin core is a crucial but long-neglected approach to analogues
that is orthogonal to traditional approaches involving variation
of the C14 side chain only (Scheme 1B). Importantly, our radi-
cal cascade approach to pleuromutilin allows us to consider
the rapid de novo synthesis of simplified analogues that
cannot be prepared from the natural product by semisynthe-
sis—the approach universally adopted by industry in the pur-
suit of pleuromutilin analogues for use in humans.[6,7]
Scheme 3. Sakurai coupling in the synthesis of a cascade substrate bearing
an oxygenated tether. DMP=Dess–Martin periodinane; TBAT=tetrabutylam-
monium difluorotriphenylsilicate. [a] 1:1 mixture of diastereoisomers.
Here we describe the development of a general synthetic se-
quence that rapidly converts simply prepared starting materials
to diverse, novel tricyclic architectures inspired by pleuromuti-
lin[8] but that cannot be prepared from the natural product.
Our studies have resulted in a new, one-pot, copper-catalyzed
double organomagnesium addition to b-chlorocyclohexenone
and have also allowed us to evaluate the scope of the radical
cyclization cascade of dialdehydes.
enone bearing a b-leaving group is unprecedented.[10] Products
of homo-double addition were not isolated. After partial purifi-
cation of 5, palladium-catalyzed methoxycarbonylation gave
unsaturated esters 6a–g.
Unsaturated esters 6a–f were then converted to dialdehydes
7a–f in two straightforward steps (bis-desilylation and -oxida-
tion—see Scheme 3 for illustrative conditions).[11] Thus, cascade
cyclization substrates 7a–f were accessible in only four steps
from 4. A cascade substrate bearing an oxygenated tether was
constructed from 6g by Sakurai coupling[12] with 3-[(tert-butyl-
dimethylsilyl)oxy]propanal, protection of the resulting secon-
dary alcohol as the pivaloate, followed by bis-desilylation and
-oxidation to give dialdehyde 9 in good overall yield (6 steps
from 4) (Scheme 3).
Pleasingly, in all cases, complete sequence integrity was ob-
served in the cascade cyclizations of 7a–f,9 and synthetic
pleuromutilin scaffolds containing 6, 7, 8, and even 9-mem-
bered right-hand rings (10a–g) were obtained in moderate to
good yield (Scheme 4). In all but one case, the cascades pro-
ceeded with complete diastereocontrol at the four newly-
formed stereocentres. It is important to note that general ap-
proaches to such scaffolds from the natural product pleuromu-
tilin would be impossible.[6,7]
We began our studies by developing a route to simplified
analogues of dialdehyde substrate 2. In our pursuit of an expe-
dient route to re-engineered pleuromutilin cores, we devel-
oped a one-pot, sequential addition of two organomagnesi-
ums to b-chlorocyclohexenone
4 catalyzed by CuSPh·LiI
(10 mol%). In situ trapping of the enolate intermediate with
Comins’ reagent[9] gave vinyl triflates 5 in good overall yield
(Scheme 2). Thus, the framework of the cascade substrates 2
could be assembled in one-pot. To the best of our knowledge,
the one-pot addition of two organometallic species to an
Remarkably, in the cascade cyclization of 7a, a substrate in
which both aldehydes are attached to three-carbon tethers,
complete sequence integrity was observed in the dialdehyde
cyclization cascade: the aldehyde on the tether containing the
sp2-hybridized alkene carbon atom undergoes initial coupling
(Scheme 5).[4] This most likely results from the restricted confor-
mation (‘Thorpe–Ingold Effect’) of the alkene-containing tether
resulting in more facile cyclization. Thus reversible formation
of radical anion 11[13] leads selectively to a SmIII-enolate[14] that
undergoes aldol cyclization through closed transition structure
12 to give major product 10a. The minor diastereoisomer 10a’
may arise from open aldol transition-structure 12’. The low dia-
stereoselectivity observed in the second stage of this particular
cascade may result from unfavorable 1,3-trans-diaxial interac-
tions in the closed transition-structure 12 leading to the rela-
tive stereochemistry typically formed in the cascades (vide
infra). The relative stereochemistry of 10a and 10a’ was deter-
mined by X-ray crystallographic analysis (Scheme 4).[15]
Pleasingly, cascade substrate 7b, designed to deliver a 5,6,7-
tricyclic architecture, underwent highly selective reaction with
SmI2 to give 10b as a single diastereoisomer in 63% yield
(Scheme 4). Remarkably, efficient cascade cyclization was also
Scheme 2. One-pot, copper-catalyzed, double conjugate addition of organo-
magnesiums with enolate trapping in the expedient synthesis of unsaturat-
ed esters 6. Comins’ reagent=N-(5-chloro-2-pyridyl)bis(trifluoromethanesul-
fonimide); P=TBS, tert-butyl dimethylsilyl.
Chem. Eur. J. 2016, 22, 116 – 119
www.chemeurj.org
117
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
yl-substituted 5,6,8-tricyclic cascade product 10d was formed
in 81% yield while products possessing less-substituted eight-
membered rings 10e and 10g were isolated as single diaste-
reoisomers in 42 and 44% yields, respectively. In a bid to iden-
tify the limits of the dialdehyde cascade process, we attempted
to construct a nine-membered ring in the final stage of the
cascade. The construction of nine-membered carbocycles is
challenging and, to our knowledge, the formation of nine-
membered carbacycles by using a SmI2-mediated aldol reac-
tion is unprecedented.[16] Impressively, treatment of substrate
7 f with SmI2 gave the 5,6,9-tricyclic architecture and 10 f was
isolated as a single diastereoisomer in 26% yield. The relative
stereochemistry in the cascade products was determined by X-
ray crystallographic analysis of 10a,a’, 10b, and 10e and a de-
rivative of 10d[15] and inferred for the remainder.
To illustrate the potential of our concise route to pleuromuti-
lin analogues, diol 10d, possessing a 5,6,8-tricyclic scaffold,
was treated with one equivalent of Dess–Martin periodinane[17]
to give C3 ketone 11. Installation of the C14 glycolate ester[8b]
gave 12 and completed a seven-step synthesis of a model
pleuromutilin analogue (Scheme 6).
Scheme 6. Concluding a seven-step synthesis of pleuromutilin analogue 12.
DCC=N,N-dicyclohexylcarbodiimide; DMAP=4-dimethylaminopyridine.
Scheme 4. Selective cascade cyclizations to six-, seven-, eight-, and nine-
membered ring-containing analogues of the pleuromutilin scaffold. [a] 2:1
mixture of diastereoisomers. [b] 1:1 mixture of diastereoisomers at the
centre bearing the OPiv group.
In summary, a general synthetic sequence involving simply
prepared starting materials provides rapid access to diverse,
novel tricyclic architectures inspired by pleuromutilin. At the
heart of the short route, SmII-mediated radical cyclization cas-
cades of dialdehydes, prepared using a new one-pot, copper-
catalyzed double organomagnesium addition to b-chlorocyclo-
hexenone, proceed with complete sequence selectivity and
typically with high diastereocontrol. Our expedient approach
(ca. 7 steps) allows non-traditional, de novo synthetic access to
analogues of the important antibacterial natural product that
can’t be prepared from the natural product by semisynthesis.
Acknowledgements
We thank the BBSRC (DTP Studentship to R.E.R.), EPSRC (Estab-
lished Career Felllowship to D.J.P. and DTA Studentship to
N.J.F.), and the University of Manchester (President’s Scholar-
ship to H.H.). We also thank Miles Aukland for his help optimiz-
ing the route to 10a/a’.
Scheme 5. Challenging the sequence integrity of the dialdehyde cascade:
Cyclization of 7a using SmI2.
observed for related substrate 7c despite significant steric
crowding adjacent to the second aldehyde group, and 10c
was isolated in 50% yield as a single diastereoisomer. gem-Di-
substitution in the longer tether of cascade substrates resulted
in more efficient cascade cyclization. For example, gem-dimeth-
Keywords: cyclization · domino reactions · electron-transfer ·
radical reactions · samarium
Chem. Eur. J. 2016, 22, 116 – 119
www.chemeurj.org
118
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[1] For selected reviews on cascade reactions, see: a) E. A. Anderson, Org.
Biomol. Chem. 2011, 9, 3997; b) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134; Angew. Chem. 2006, 118,
7292; c) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993; d) L. F.
Tietze, Chem. Rev. 1996, 96, 115.
[2] For recent reviews of SmI2, see: a) X. Just-Baringo, D. J. Procter, Acc.
Chem. Res. 2015, 48, 1263; b) M. Szostak, N. J. Fazakerley, D. Parmar,
D. J. Procter, Chem. Rev. 2014, 114, 5959; c) M. Szostak, M. Spain, D. J.
Procter, Chem. Soc. Rev. 2013, 42, 9155; d) M. Szostak, M. Spain, D.
Parmar, D. J. Procter, Chem. Commun. 2012, 48, 330; e) M. Szostak, D. J.
Procter, Angew. Chem. Int. Ed. 2012, 51, 9238; Angew. Chem. 2012, 124,
9372; f) C. Beemelmanns, H.-U. Reißig, Chem. Soc. Rev. 2011, 40, 2199;
g) C. Beemelmanns, H.-U. Reißig, Pure Appl. Chem. 2011, 83, 507; h) K. C.
Nicolaou, S. P. Ellery, J. S. Chen, Angew. Chem. Int. Ed. 2009, 48, 7140;
Angew. Chem. 2009, 121, 7276; i) D. J. Procter, R. A. Flowers II, T.
loud, F. Vicente) RSC, 2012, pp. 326; d) R. Novak, Annals New York Acad.
Sci. 2011, 1241, 71; e) R. Jarvest in Functional Molecules from Natural
Sources (Eds.: S. K. Wrigley, R. Thomas, N. Nicholson, C. Bedford), RSC,
2010, pp. 106; f) R. Novak, D. M. Shlaes, Curr. Opin. Investig. Drugs 2010,
11, 182; g) C. Hu, Y. Zou, Mini-Rev. Med. Chem. 2009, 9, 1397; h) M. S.
Butler, A. D. Buss, Biochem. Pharmacol. 2006, 71, 919; i) E. Hunt, Drugs
Future 2000, 25, 1163; for studies on pleuromutilin binding to the ribo-
some; j) F. Schlünzen, E. Pyetan, P. Fucini, A. Yonath, J. M. Harms, Mol.
Microbiol. 2004, 54, 1287; k) C. Davidovich, A. Bashan, T. Auerbach-
Nevo, R. D. Yaggie, R. R. Gontarek, A. Yonath, Proc. Natl. Acad. Sci. USA
2007, 104, 4291.
[7] For a recent review of the synthesis of pleuromutilin analogues from
the natural product, see: N. J. Fazakerley, D. J. Procter, Tetrahedron
2014, 70, 6911.
[8] For an alternative approach to pleuromutilin analogues, see: a) J. Liu,
S. D. Lotesta, E. J. Sorensen, Chem. Commun. 2011, 47, 1500; b) S. D. Lo-
testa, J. Liu, E. V. Yates, I. Krieger, J. C. Sacchettini, J. S. Freundlich, E. J.
Sorensen, Chem. Sci. 2011, 2, 1258.
[9] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299.
[10] For the addition of bis-organocuprates to b-halocyclohexenones to
give spirocycles, see: a) P. A. Wender, A. M. White, J. Am. Chem. Soc.
1988, 110, 2218; b) P. A. Wender, A. W. White, F. E. McDonald, Org. Synth.
1992, 70, 204.
Skrydstrup, Organic Synthesis using Samarium Diiodide:
A Practical
Guide, RSC Publishing, Cambridge, 2009; j) D. J. Edmonds, D. Johnston,
D. J. Procter, Chem. Rev. 2004, 104, 3371; k) H. B. Kagan, Tetrahedron
2003, 59, 10351; l) A. Krief, A.-M. Laval, Chem. Rev. 1999, 99, 745;
m) G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307.
[3] a) I. Yalavac, S. E. Lyons, M. R. Webb, D. J. Procter, Chem. Commun. 2014,
50, 12863; b) M. T. Levick, I. Grace, S.-Y. Dai, N. Kasch, C. Muryn, C. Lam-
bert, M. L. Turner, D. J. Procter, Org. Lett. 2014, 16, 2292; c) M. T. Levick,
S. C. Coote, I. Grace, C. Lambert, M. L. Turner, D. J. Procter, Org. Lett.
2012, 14, 5744; d) S. C. Coote, S. Quenum, D. J. Procter, Org. Biomol.
Chem. 2011, 9, 5104; e) D. Parmar, H. Matsubara, K. Price, M. Spain, D. J.
Procter, J. Am. Chem. Soc. 2012, 134, 12751; f) B. Sautier, S. E. Lyons,
M. R. Webb, D. J. Procter, Org. Lett. 2012, 14, 146; g) D. Parmar, K. Price,
M. Spain, H. Matsubara, P. A. Bradley, D. J. Procter, J. Am. Chem. Soc.
2011, 133, 2418.
[4] a) M. D. Helm, D. Sucunza, M. Da Silva, M. Helliwell, D. J. Procter, Tetrahe-
dron Lett. 2009, 50, 3224; b) M. D. Helm, M. Da Silva, D. Sucunza, M. Hel-
liwell, D. J. Procter, Tetrahedron 2009, 65, 10816; c) M. D. Helm, M. Da
Silva, D. Sucunza, T. J. K. Findley, D. J. Procter, Angew. Chem. Int. Ed.
2009, 48, 9315; Angew. Chem. 2009, 121, 9479; d) T. J. K. Findley, D. Su-
cunza, L. C. Miller, M. D. Helm, M. Helliwell, D. T. Davies, D. J. Procter,
Org. Biomol. Chem. 2011, 9, 2433; e) N. J. Fazakerley, M. D. Helm, D. J.
Procter, Chem. Eur. J. 2013, 19, 6718.
[11] See the Supporting Information.
[12] a) A. Hosomi, M. Endo, H. Sakurai, Chem. Lett. 1976, 5, 941; b) A.
Hosomi, H. Sakurai, Tetrahedron Lett. 1976, 17, 1295; for a recent exam-
ple in target synthesis using BF3·OEt2, see: c) M. J. Wanner, N. P. Willard,
G.-J. Koomen, U. K. Pandit, J. Chem. Soc. Chem. Commun. 1986, 396.
[13] For a discussion of reversible radical formation from aldehydes/ketones
using SmI2, see: P. R. Chopade, E. Prasad, R. A. Flowers, J. Am. Chem.
Soc. 2004, 126, 44.
[14] I. M. Rudkin, L. C. Miller, D. J. Procter, Organomet. Chem. 2008, 34, 19.
[15] See the Supporting Information for CCDC numbers.
[16] For alternative methods for nine-membered carbocycle formation using
SmI2, see: a) J. Saadi, D. Lentz, H.-U. Reissig, Org. Lett. 2009, 11, 3334;
b) E. Nandanan, C. U. Dinesh, H.-U. Reissig, Tetrahedron 2000, 56, 4267;
c) H. Tamiya, K. Goto, F. Matsuda, Org. Lett. 2004, 6, 545; d) G. A. Mo-
lander, G. A. Brown, I. S. de Garcia, J. Org. Chem. 2002, 67, 3459; e) G. A.
Molander, Y. Le HuØrou, G. A. Brown, J. Org. Chem. 2001, 66, 4511.
[17] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[5] a) J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J. Am. Chem. Soc. 2011, 133,
14964; b) J. T. S. Yeoman, J. Y. Cha, V. W. Mak, S. E. Reisman, Tetrahedron
2014, 70, 4070.
[6] For selected, recent reviews on pleuromutilin analogues, see: a) R.
Shang, J. Wang, W. Guo, J. Liang, Current Topics Med. Chem. 2013, 13,
3013; b) Y.-Z. Tang, Y.-H. Liu, J.-X. Chen, Mini-Rev. Med. Chem. 2012, 12,
53; c) R. Novak in Drug Discovery from Natural Products (Eds.: O. Genil-
Received: October 29, 2015
Published online on November 26, 2015
Chem. Eur. J. 2016, 22, 116 – 119
www.chemeurj.org
119
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim