' .
`
`r.-
`
`PROGRESS
`IN
`HETEROCYCLIC
`CHEMISTRY
`
`. V
`
`0
`
`L
`
`U
`
`. M
`
`E
`
`12
`
`EDITORS
`G. W. Gribble & T. L. Gilchrist
`
`PERGAMON
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 1 of 31
`
`

`
`••
`
`PROGRESS
`IN
`
`HETEROCYCLIC CHEMISTRY
`
`Volume 12
`
`I
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 2 of 31
`
`

`
`v "
`
`Related Titles of Interest
`
`Books
`
`CARRUTHERS: Cycloaddition Reactions in Organic Synthesis
`CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry
`FINET: Ligand Coupling Reactions with Heteroatomic Compounds
`GAWLEY & AUBE: Principles of Asymmetric Synthesis
`HASSNER & STUMER: Organic Syntheses Based on Name Reactions and
`Unnamed Reactions
`LEVY & TANG: The Chemistry of C-Glycosides
`LI & GRIBBLE: Palladium in Heterocyclic Chemistry
`McKILLOP: Advanced Problems in Organic Reaction Mechanisms
`OBRECHT & VILLALGOROO: Solid Supported Combinatorial and Parnllel Synthesis
`of Small-Molecular-Weight Compound Libraries
`PELLETIER: Alkaloids; Chemical and Biological Perspectives
`PERLMUTIER: Conjugate Addition Reactions in Organic Synthesis
`SESSLER & WEGHORN: Expanded, Contracted and Isomeric Porphyrins
`WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry
`
`Major Reference Works
`
`BARTON, NAKANISHI & METH-COHN: Comprehensive Natural Products Chemistry
`BARTON & OLLIS: Comprehensive Organic Chemistry
`KA TRITZKY & REES: Comprehensive Heterocyclic Chemistry I CO-Rom
`KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry 11
`KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group
`Transformations
`SAINSBURY: Rodd's Chemistry.of.Carbon Compounds
`TROST & FLEMING: Comprehensive Organic Synthesis
`
`Journals
`
`BIOORGANIC & MEDICINAL CHEMISTRY
`BIOORGANIC & MEDICINAL CHEMISTRY LETIERS
`CARBOHYDRATE RESEARCH
`HETEROCYCLES (distributed by Elsevier)
`PHYTOCHEMISTRY
`TETRAHEDRON
`TETRAHEDRON: ASYMMETRY
`TETRAHEDRONLETIERS
`
`Full details o; all Elsevier Science publications are available on www.elsevier.com or
`from your nearest Elsevier Science office.
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 3 of 31
`
`

`
`' •
`
`~ ,.
`
`PROGRESS
`
`IN
`HETEROCYCLIC
`CHEMISTRY
`Volume 12
`
`A critical review of the 1999 literature
`preceded by three chapters on current
`heterocyclic topics
`
`Editors
`
`GORDON W. GRIBBLE
`Department of Chemistry, Darmouth College,
`Hanover, New Hampshire, USA
`
`and
`
`THOMAS L. GILCHRIST
`Department of Chemistry, University of Liverpool,
`Liverpool, UK
`
`ic Synthesis
`)rganic Chemistry
`nic Compounds
`iesis
`on Name Reactions and
`
`y
`)n Mechanisms
`nbinatorial and Parallel Synthesis
`
`rspectives
`rganic Synthesis
`nd Isomeric Porphyrins
`anic Chemistry
`
`1Sive Natural Products Chemistry
`;try
`• Chemistry I CD-Rom
`ieterocyclic Chemistry II
`•e Organic Functional Group
`
`nds
`iesis
`
`:s
`
`·aifable on www.elsevier.com or
`
`PERGAMON
`An Imprint of Elsevier Science
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 4 of 31
`
`

`
`t
`"
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`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 5 of 31
`
`

`
`Contents
`
`Foreword
`
`Editorial Advisory Board Members
`
`Chapter 1: Boron Heterocycles as Platforms for Building New Bioactive Agents
`
`Michael P. Groziak, SRI International, Menlo Park, CA, USA
`
`Chapter 2: Heterocyclic Pbosphoru~ Ylides
`R. Alan Aitken and Tracy Massil, University of St. Andrews, UK
`
`Chapter 3: Palladium Chemistry in Pyridine Alkaloid Synthesis
`
`Jie Jack Li, Pfizer Global R&D, 2800 Plymouth Road, Ann Arbor, Ml, USA
`
`Chapter 4: Three- and Four-Membered Ring Systems
`
`Part 1.
`Albert PadWa, Emory University, Atlanta, 6A, USA and S. "Shilun Murphree, Allegheny College,
`
`Three-Membered Ring Systems
`
`Meadville, PA, USA
`
`F'art 2.
`
`Four·Membered Ring Systems
`
`L. K. Mehta and J. Parrick, Brunel University, Uxbridge, UK
`
`Chapter 5: Five-Membered ;Ring Systems
`
`Part 1.
`
`Thiophenes & Se, Te, Analogs
`
`Erin T. Pelkey, Stanford University, Stanford. .CA, USA
`
`Part 2.
`
`Pyrroles and Benzo Derivatives
`
`Daniel M. Ketcha, Wright State University, Dayton, OH, USA
`
`Part3.
`
`Furans and Benzofurans
`
`Stefan Greve and Willy Friedrichsen, UniverSity of Kiel, Germany
`
`~ '.
`
`v
`
`vii
`
`viii
`
`22
`
`37
`
`57
`
`77
`
`92
`
`114
`
`134
`
`1s and conditions apply to its use:
`
`tational copyright laws. Permission of the Publisher
`or systematic copying, copying for advertising or
`ailable for educational institutions that wish to make
`
`. PO Box 800, Oxford OX5 1 DX, UK; phone: (+44)
`may also contact Global Rights directly through
`
`ght Clearance Center, Inc., 222 Rosewood Drive,
`in the UK through the Copyright Licensing Agency
`>,UK; phone: (+44) 207 631 5555; fax: (+44) 207
`.ts.
`
`Elsevier Science is required for external resale or
`
`npilations and translations.
`
`·ntaincd in this work, including any chapter or part
`
`ieval system or transmitted in any form or by any
`·written permission of the Publisher.
`: mail, fax and e-mail addresses noted above.
`
`-sons or property as a matter of products liability,
`truc1ions or ideas contained in the material herein.
`ion of diagnoses and drug dosages should be made.
`
`.Q 239.48-1992 (Permanence of Paper).
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 6 of 31
`
`

`
`vi
`
`Part 4.
`
`With More than One N Atom
`
`Larry Yet, Albany Molecular Research, Inc., Albany, NY, USA
`
`Part 5.
`
`With N & S (Se) Atoms
`
`Paul A. Bradley a~d David J. Wilkins, Kno/f Pharmaceuticals. No11ingham. UK
`
`Part 6.
`
`With 0 & S (Se, Te) Atoms
`
`R. Alan Aitken, The University of Sr Andrews, UK
`
`Pi1rt 7.
`
`With 0 & N Atoms
`
`Thomas L. Gilchrist, The University of Liverpool, UK
`
`Chapter 6: Six-Membered Ring Systems
`
`· Pyridincs and Benzo Derivatives
`Part 1.
`'
`Robert D. Larsen and Jean-Francois Marcoux, Merck Research Laboratories, Merck & Co., Inc.,
`
`Rahway, NJ, USA
`
`Part2.
`Brian R. Lahue and John K. Snyder, Boston University. Boston, MA, USA
`
`Diazines and Benzo Derivatives
`
`Part 3.
`
`Triazincs, Tetrazines and Fused Ring Polyaza Systems
`
`Carmen Ochoa and Pil<l! Goya, Jnstitura de QuiJ?lfca Medi'ca (CSIC), Madrid, Spain
`
`Part 4.
`
`With 0 and/or S Atoms
`
`John D. Hepworth, University of Hull, UK and B. Mark Heron, University of Leeds, UK
`
`Chapter 7: Seven-Membered Rings
`David J. LeCount, Formerly o/Zeneca Pharmaceuticals, UK: /-Vernon Avenue, Congleton, Cheshire, UK
`
`Chapter 8: Eight-Membered and Larger Rings
`George R. Newkome, UniversityofSouth Florida, Tompa, Fl, USA
`
`Index
`
`161
`
`185
`
`204
`
`219
`
`237
`
`263
`
`294
`
`317
`
`339
`
`352
`
`369
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 7 of 31
`
`

`
`' ''
`
`vii
`
`Foreword
`
`This volume of Progress in Heterocyclic Chemistry (PHC) is the twelfth annual review of
`
`the literature, covering the work published on most of the important heterocyclic ring systems
`
`during 1999, with inclusions of earlier material as appropriate. As in PHC-11, there are also
`
`three specialized reviews in this year's volume. In the inaugural chapter, Michael Groziak
`
`revitalizes the field of boron heterocycies, a relatively obscure class of hetei'ocycles, but with a
`
`promising future. Heterocyclic phosphorus ylides are similarly a little known but useful class of
`
`compounds and Alan Aitken and Tracy Massil have provided a comprehensive review of them in
`
`Chapter 2. In Chapter 3 Jack Li discusses the remarkably versatile palladium chemistry in
`
`pyridine alkaloid synthesis.
`
`The subsequent chapters deal with recent advances in the field ofheterocyclic chemistry
`
`arranged by increasing ring size and with emphasis on synthesis and reactions. The reference
`
`format follows the journal cocj.e sySterµ empioyed in Comprehensive Heterocyclic Chemistry.
`
`We thank all authors for providing cariiera-ready scripts and disks, and we are grateful to Adrian
`
`Shell of Elsevier S9ience fQr his continuing assistance in producing this volume.
`
`'We hope that our readers will fin_d PHC-12 to be a useful and efficient guide to the field of
`
`modem heterocyclic chemistry and that this volume will inspire new ideas and directions in this
`
`vital field of chemistry. The editors welcome suggestions on how to improve upon PHC and are
`
`always seeking topics for future reviews.
`
`Gordon W. Gribble
`
`Tom Gilchrist
`
`gham, UK
`
`atories, Merck & Co., Inc.,
`
`!SA
`
`stems
`
`\Jadrid, Spain
`
`·sity of Leeds, UK
`
`m Avenue, Congleton, Cheshire, UK
`
`161
`
`185
`
`204
`
`219
`
`237
`
`263
`
`294
`
`'
`
`317
`
`339
`
`352
`
`369
`
`I
`
`I
`
`II
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 8 of 31
`
`

`
`j . '
`
`viii
`
`Editorial Advisory Board Members
`Progress in Heterocyclic Chemistry
`
`2000 - 2001
`
`PROFESSOR Y YAMAMOTO (CHAIRMAN)
`Tokyo University, Sendai, Japan
`
`PROFESSOR D. P. CURRAN
`University of Pittsburg, USA
`
`PROFESSOR C.J. MOODY
`University of Exeter, UK
`
`PROFESSOR A. DONDONI
`University of Ferrara, Italy
`
`PROFESSOR K. FUJI
`Kyoto University, Japan
`
`PROFESSOR T.C. GALLAGHER
`University of Bristol, UK
`
`PROFESSOR A.D. HAMIL TON
`Yale University, CT, USA
`
`PROFESSOR M. IHARA
`Tohoku University,
`Send?i, Japan
`
`PROFESSOR G.R. NEWKOME
`University of South Florida,
`USA
`
`PROFESSOR R. PRAGER
`Flinders University
`South Australia
`
`PROFESSOR R.R. SCHMIDT
`University of Konstanz,
`Germany
`
`PROFESSOR S.M. WEINREB
`Pennsylvania State University
`University Park, PA, USA
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 9 of 31
`
`

`
`Board Members
`cyclic Chemistry
`
`Information about membership and activities of the International
`Society of Heterocyclic Chemistry can be found on the World Wide
`Web; the address of the Sbciety's Home Page is:
`
`• '
`
`'
`
`ix
`
`b.!1p://euch6f,chem.emory.edulhetsoc html
`
`~001
`
`AOTO (CHAIRMAN)
`Sendai, Japan
`
`PROFESSOR C.J. MOODY
`University of Exeter, UK
`
`PROFESSOR G.R. NEWKOME
`University of South Florida,
`USA
`
`PROFESSOR R. PRAGER
`Flinders University
`South Australia
`
`PROFESSOR R.R. SCHMIDT
`University of Konstanz,
`Germany
`
`PROFESSOR S.M. WEINREB
`Pennsylvania State University
`University Park, PA, USA
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 10 of 31
`
`

`
`••
`
`Chapter 1
`
`Boron Heterocycles as Platforms for Building New Bio;ictive Agents
`
`Michael P. Groziak
`Pharmaceutical Discovery Division, SRI International, Menlo Park, CA, USA
`michaeLgror.iak@sri:com
`
`Chemists working to develop new bioactive compounds try to be a1ert for new stable
`heterocycle platforms, but they can easily overlook some of the more, shall we say, exotic ones.
`When one thinks about the utility of boron in heterocyclic chemistry, the Suzuki cross-eoupling
`reaction typically first comes to mind.
`In this valuable synthetic reaction <95CRV2457>, a
`boronic acid group is discarded under basic conditions during a Pd-catalyzed C-C bond
`formation. There are exceptions, of course, but few chemists appreciate that boron is an element
`that can be valuable to retain in a molecule so that its unique properties can be utilized.
`This contribution first surveys some of the attractive properties of boron, briefly describing
`applications that have been developed mostly with non-aromatic boron-containing compounds. It
`then examines many Of the iaab)e, formally aromatic boron heterocycles that have been repOrtOO t0
`date, covering much of the pertinent literature through the end of 1999. With the sµm of these
`two parts, I hope the reader will gain an appreciation of the untapped potential held by boron
`heterocycles, especially for constructing new bioactive agents.
`
`I.I WHY BORON?
`
`When selecting atom substitutions for new molecule design, chemists usually look only to the
`right of carbon in the periodic table. The contrarian looks to the left and finds boron-commonly
`viewed as a metal, but in fact quite nonmetallic in many respects. Jn his excellent review of boron
`analogues of biomolecules, Morin showed why working with boron is so attractive <94Ti2521>.
`Here are some of the unique potential applications for any new boron compound:
`
`1.1.1 "B NMR and MRI
`
`Naturally occurring boron is comprised of the "B (80.22%) and 10B (19.78%) isotopes. The
`former is NMR active and fast-relaxing, since it is a quadrupole (angular momentum 312 h/2n).
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 11 of 31
`
`

`
`,,.
`
`2
`
`MP. Groziak
`
`The detennination of the charge, and thereby the valency, of a boron atom in an organic
`compound is usually straightforward if its 11B NMR. chemical shift within the 300+ ppm spectral
`window is compared to that of a close standard with a finnly established solution structure. But,
`there is a need for caution: The structure of many boron-containing compounds depends on the
`nature of the solvent, and so multisolvent (i.e.,·aprotic vs. protic) analyses are ofteri essential for a
`definitive characterization. Sadly, aqueous soliltion 11B NMR spectral" analyses are seldom
`reported-even, surprisingly, for compounds clearly prepared for their poteritial biological value.
`In biochemical applications like enzyme inhibition, 11B NMR spectroscopy <B-78MI14, B-
`83tv:U49> has proven to be an exceptionally useful tool for detailing the interaction of boron(cid:173)
`containing compounds with biomacromolecules <88JA309, 91BMCL9, 93B12651>. Any study
`of new potential boron-based enzyme inhibitors would likely benefit from using this diagnostic
`tool. There is a great potential utility for 11B NMR in the more biological and medicinal
`applications as well. Although likely essential in trace amounts <96.l\.1I2441> for proper bone
`development <90Ml61, 99M1335>, boron is not present to any great extent in living tissues, and
`so there is no background to compete with the detection of the signal from an administered
`boron-containing compound. The great rapidity of the 11B nuclear relaxation presents some
`problems in signal acquisition and the spatial resolution may be limited <95W48>, but clearly
`11B MRS (magnetic resonance spectroscopy) and 11B MRI (magnetic resonance imaging) are two
`of the very exciting potential NMR-based applications for any new boron-based compound.
`Advances in these fields <88Ml231, 90JMR369, 97M1153> have emerged primarily in step with
`efforts to develop boron neutron capture therapy (BNCT), described next.
`
`1.1.2 "B Neutron Capture Therapy (BNCT)
`
`The 1°B isotope is one Of only a handful of nuclides that interact strongly with thermal (slow(cid:173)
`moving) neutrons. It has a large capture cross section for them due to a fortuitous resonance
`between the ene~y of the thermal neutron "falling" ·into the lowest un~cc~.Pied neu~on s.~ate in .
`1°B ind tlie energy needed to promote ·one of the nliCleOns tO ltil.. excitea"state·: . once· the'."lix:Cited ...... .
`state 11B atom is produced, thC powerful nuclear fission reaction 1°B(n,o:)7Li occurs, ejecting a
`ganuna photon together with a 0.87 MeV 'Li particle and a 1.52 MeV 'He particle. These heavy,
`fast moving particles travel along a mean-free path whose length is close to that of a red blood
`cell's diameter (5 µm tor the 7Ll and 9 µm for the 4He), and while so doing can destroy cellular
`structures like membranes, organelles, and even DNA. There are three separate areas where
`technological advances are needed to one day make BNCT a routine binary radiation therapy for
`treating cancer. The first is a high tumor uptake of a boron-containing compound relative to
`nonnal tissue. The second is a sufficiently high concentration of boron 1'target" atoms dispersed
`within the tumor cell (idea1ly in the nucleus). It has been estimated th~t 30 µ.g of 10B per g of
`tumor will suffice. The third is the characteristics and quality of the neutron beam. Epithennal
`(ca. Ike V) neutrons are attractive for BNCT, since these readily pass through living tissue without
`incident as they slow down to become thennal neutrons.
`Many review articles highlighting role of chemistiy in BNCT are available <93AC{B)950,
`94M1119, 94MI849, 97M141, 98Mli74, 98CR!515>. Most of the agents currently under
`investigation are based on an o-carborane (C1H11B10) unit because of its. 10 boron atoms. Of
`course, these IO atoms are not evenly distributed inside the cell, but there are advantages to the use
`of carboranes-not the least of which is their virtual lack of reactivity and toxicity. Nucleosi4es,
`nucleic acids, amino acids, poiyamines, liposomes, and even antibodies equipped with carboranyl
`units are being developed as BNCT agents. One of the more recent classes of compounds under
`investigation is the boronated protoporphyrins (BOPP) <99Ml761>.
`·
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 12 of 31
`
`

`
`••
`
`Boron Heterocycles as Platfornis for Building New Bioaclive Agents
`
`3
`
`Although attractive, acarborane unit is not required. p-Boronophenylalanine (BPA, 1) has but
`one boron atom and yet is one of the lead clinical compounds as a BNCT agent to treat
`glioblastoma multifonne (a form of brain cancer) <99Mll>. BPA, behaving in vivo as an
`analogue of the melanin precursor tyrosine, shows a remarkable selective uptake within these
`tumor cells. Thus, as long as a boron-containing compound can be delivered selectively and in
`sufficient quantity to the target group of cells. it has the potential of being a BNCT agent.
`
`~0,H
`(HO),B~ NH, 1
`
`1.1.3 Boron Heterocycle-Based Fluorescence
`
`4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (2) is the central fluorophore unit of the so-called
`BODJPY® fluorescent dye compounds <94JA7801>. This boron heterocycle is relatively
`nonpolar, since with no net ionic charge it is electrically neutral. Useful bioconjugatable dyes
`with fluorescence emissions spanning the entire visible spectrum were developed by varying the
`pattern and nature of ring substituents. The extinction coefficients are large (>80,000 cm· 1M·1
`)
`and the quantum yields are close to l.0--even, importantly, in water. The emission spectra are
`generally insensitive to solvent polarity and pH and they have a narrow bandwidth. A large two(cid:173)
`photon cross section permits multiphoton excitation. New boron-based compounds exhibiting
`good fluorescence properties like these certainly have the potential to be quite useful as probes in
`biochemical, biological, or even medical diagnostic applications.
`
`~
`~/.J. ,/.JJ
`'E\ F F
`'
`
`1.1.4 Boronic Acid-Based Enzyme Inhibition
`
`Because boronic acids interconvert with ease between the neutral sp2 (trigonal planar.
`substituted) and the anionic spJ (tetrahedral substituted) hybridization states, the B-OH unit has
`found a unique role as a useful replacement for the C=O one at a· site where an acyl group
`transfer takes place. Boronic acid-based inhibition of proteases and other hydrolytic enzymes
`capitalizes on the fact that a tetrahedral boronate molecular fragment is an exceptionally close
`structural mimic of the tetrahedral intermediate of acyl group hydrolysis. Boronic acid-based
`protease inhibition first emerged in the early 1970s, when phenethylboronic acid (3) was found to
`be a good inhibitor of chymotrypsin <70MI23, 71B2477, 74Mli35:>.
`
`VB~H),
`
`Some boronic acid-based enzyme inhibitors undergo strong yet. reversible covalent attachment
`t9 a nucleophile at the enzyme's active site, while others simply act as competitive inhibitors in
`their borate conjugate base fonn. Boronic acid-based inhibition of thrombin has been achieved
`<93Ml109>, and that of ~Iactamases has been partic!Jlarly effective <95n..8399, 96fvll688>.
`When compared to other covalent transition-state analog inhibitors of (3-lactamases like phos-
`
`' ,.
`I· i ,.
`I
`I·
`I l
`
`i,
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 13 of 31
`
`

`
`••
`
`4
`
`M.P. Groziak
`
`phonates, silane triols·, aldehydes, and o:-keto carbonyl compounds, the boronic acids display
`superior characteristics <97JA1529>. If its structure targets it properly to a hydrolytic enzyme's
`active site, a new boronic acid-based compound can be a potent enzyme inhibitor.
`
`1.1.S Bioactlve Boron Compounds
`
`It has been known for about two decades that benzo- and hetero-fused 2-alkyl- and
`arylsulfonylated 2,3,l-diazaborines 4 possess antibacterial properties, particularly against gram
`negative organisms <84JMC947>. The early indication was that th~se compounds affected
`lipopolysaccharide biosynthesis <80AAC549, 81NAT662, 87M137, 89Ml6555, 94Ml1937,
`94JBC5493, 94MI771, 96EJB689, 97JBC27091>. More recent structural studies have shown
`that the biomacromolecular target is enoyl acyl carrier protein reductase (ENR), the NAD(P)H(cid:173)
`dependent enzyme which catalyzes a latter step of fatty acid biosynthesis <96AX(D)1181,
`96SCl2107, 98BPl541, 99MI443, 99JBC30811>. Interestingly, this enzyme is the very same
`target of the broad-spectrum {bacteria, fungi, viruses) bacteriostatic germicide
`triclosan
`<98NAT531, 99JBC11110, 99JMB527, 99JMB859> and the antituberculosis drug isoniazid.
`
`.'
`
`'
`
`c
`
`~Jl~,NH,
`~~ .
`
`lsonlazid
`
`trlclosan
`
`"'
`
`er
`
`w ""
`
`Perhaps because boric acid is a well-known insecticide for cockroaches, boron compounds
`have been examined as insect chemosterilants <69?vfi1472, 70JMC128>. Besides this, boron(cid:173)
`based compounds have been identified as antivirals <96Ml108> and as antituberculosis agents
`<98BMCL843>. This demonstrates how new boron-based compounds have the potential of
`·exhibiting useful medicinal .pro~rties even if the~Js q.o .predete_nni~~ biocheinical target or
`mechanism of action. No boron-based phannaceutical has yet been developed, hut this tilerely
`signifies a great opportunity for chemists working with boron compounds <72PHA1>.
`Only a few boron-based natural products are known. The ionophoric macrodiolide antibiotics
`boromycin (5) <67HCAl533, 96Mll036>, aplasmomycin (6) <76JANIOl9, 77JAN7!4,
`80JAN1316>, and tartrolon B (7) <94LA283, 95JAN26, 99JA8393> are such potent K' earners
`that they are highly toxic to both bacteria and to mammalian eel~.
`
`7
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 14 of 31
`
`

`
`..
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`Boron Heterocycles as Platforms for Building New Bioactive Agents
`
`5
`
`1.1.6 Relative Low Toxicity
`
`Most of the boronic acids and other low molecular-weight synthetic boron compounds that
`have been e'xamined have been found to be relatively nontoxic. The chemistry and biology of
`simple (mostly inorganic and acyclic organic) boron compounds have been reviewed <92Jv11229,
`98M12>. Boric acid and borates have been studied in great detail and posC no toxicity tlueat
`<98Mll-02>. The published contributions to the International Symposia on the Health Effects of
`Boron and its Compounds <94MI1, 98MI1-01> are a rich source of health-related information on
`boric acid and simple organoboron compounds.
`There is typically little or no toxicology or metabolism data available for even moderately
`complicated boron-based compounds. An interesting exception is the collection of tetrahydro-
`3a,4a,4-diazabora-s-inclacenes (8) <71SRl83> structurally related to the BODIPY® fluorescent
`dyestuffs. Rather well characterized, these compounds are stable to both water and alcohols at 23
`•c and undergo reversible salt fonnation with HCI and NaOH. Compound Sb, tenned Myborin,
`was evaluated for its toxicity <75Ml434>. The LD,, values of 69.S mg/kg i.p., 180 mg/kg p.o.,
`and 420 mg/kg s.c. in the mouse reveal it to have moderate toxicity.
`
`When compared to tin compounds, boronic acids are considerably less toxic. This is
`particularly striking when one compares the by-products produced by Stille and Suzuki coupling
`reactions. A Stille coupling generates highly toxic trialkyltin halides which pose a sedous waste
`problem, but a Suzuki coupling generates the comparatively nontoxic boric acid. A look at the
`MSDS-derived LD,0 values of two coupling by-products shows the huge difference in toxicity.
`Tiie LD~I) of Bu3SnCI is 60 mg/kg p.o. in the mouse and 129 mg/kg p.o. in the rat. Those of
`·
`·
`B(OH)3 are 3450 mg/kg iri. the mouse and 2660 inglkg in the rat.
`
`L2 AROMATIC BORON HETEROCYCLES
`
`When a boron atom is connected to the ends of hexatriene, the resulting borepine molecule has
`circuit of p-orbitals containing a HUckel 4n+2 number of n: electrons. Isoelectronic with the
`tropylium cation, borepine has been shown to exhibit aromatic properties <930M3225>. Equally
`fascinating boron heterocycles are produced when the p·electron deficient boron atom is paired
`with a p--electron excessive one in a ring. In endocyclic and potentially aromatiC settings, B-0 and
`B-N single bonds are excellent replacement moieties for O=N and C=C units, respectively. They
`are isovalent, isoelectronic, and isosteric with these units and maintain enough stability within
`4n+2 n:-electron circuitry to help establish at least some degree of aromaticity.
`
`T l
`
`(j
`I ""' :
`
`lsovalent, Jsoelectronic,
`and lsostericwlth:
`
`C?
`0.,, : _ I "~ : _
`!.'..
`
`T
`
`B··
`,,...,,...
`(ma/or)
`
`//
`.
`
`.
`
`[
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 15 of 31
`
`

`
`..
`
`6
`
`MP. Groziak
`
`lsovalent !soelectronlc,
`and lsosterlc with:
`
`Much of the early literature, reviewed quite well by others <62CRV223, B-64MI227, B-
`64Ml235, B-70Mlll7, 77HC381, 84CHEC-1(1)629, 96CHEC-11(6)1155>, names
`these
`"boroaromatic" compounds using replacement nomenclature (e.g., borazaropyridil'le instead of
`diazaborine) and depicts them as zwitterionic species with an endocyclic double-bond from the .
`heteroatom to the boron. However, as the body of ua NMR chemical shift data has grown
`<68JA706, 76JOM123, 94JA7597, 97JA78!7>, it has become apparent that these species are not
`major players on the resonance continua. Indeed, except possibly for the borazines (described
`next), these types of compounds are likely best depicted as nonzwitterionic heteroaromatics with
`single B-X bonds. Despite the negligible amount of p-electron diffusion from the heteroatom to
`the boron, though, these compounds display the stability and other attributes expected of them by
`virtue of their HUckel heteroaromaticity.
`
`1.2.1 Borazines and Boroxins
`
`It is helpful to examine the benzene analogue borazine (B3N3~, 9) and the s-triazine analogue
`boroxin (B3~03) so that we caR know better what to expect when replacing C=C units with B-N
`ones or C=N units with B-0 ones in more complicated molecules. A direct comparison of the
`crystal· strOctures of benzene <58PRS1> with 9 <94CB1887> and of 2,4,6-triphenyl-s-triazine
`<84ZSK!80> with triphenylboroXin (10) <87AX(C)l775> reveals that the B-X replacement
`bonds are longer by ca. 0.05 A in each case.
`·
`.
`
`>· '
`
`Hi;tH *""'~' \l *
`10 A B~1.385A
`
`H
`
`-"' H
`~~ AC-N1.337A
`~N' Ph
`
`H
`
`H,~,B,fH
`H"8'N .... 8'H
`I
`9
`H
`
`B-N 1.429 A
`
`fh
`
`18'?
`
`Plf'8-a,.B,Ph
`
`In general, 9 and its derivatives <70JOM323> are known to exhibit less aromatic character than
`their benzene -counterparts <98TI4913>, but the electronic excitation and p-electron interaction
`have very benzene-like features <86JA3602> and the gas phase ion chemistry is remarkably
`similar to that of benzene <99JA11204>. 1H N.MR spectral comparisons of various methylated
`versions of 9 have been made <730MR585>, and 14N and 11B NMR spectra] analyses of
`borazines have been conducted as well <76CB3480>.
`In a study of a series of B(cid:173)
`monosubstituted (NMe,,, OMe, OAc, and Cl) borazines, it was concJuded that their NH units
`either do not act as hydrogen bond donors or do so only very weakly <771C2935>. Highly
`substituted borazines have been analyzed by X-ray <;!!'stallography <95CB 1037>.
`·
`
`CFAD v. Anacor, IPR2015-01776, EXHIBIT 1049 - Page 16 of 31
`
`

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`..
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`Boron Heterocyc/es as Platforms for Building New Bioactive Agents
`
`7
`
`The electronic structure of benzene, 9, and 10 have been compared in detail <89JCS(P2)719>.
`A MNDO semiempirical investigation of 10 concluded that it likely cannot exist in monomeric
`Ph-B=O fonn<94JOM31>. B-N for C=C replacement analogs of aromatic hydrocarbons have
`been the subject of electronic spectral <71CCC1233> and semiempirical <71CCC1248>
`investigations, and a recent ab iiiitio calculation of the various isomers of tandem B-N for C=C
`replacement analogs of benzene and naphthalene showed that the greatest stability is achieved
`when the B and N atoms are juxtaposed <97lvll65>; Ab iltitio calculations of a collection of 70
`known and unknown 67C-electron monocycles containing B and N-including 26 pyridine
`isosteres-showed that the most stable isomers were those constructed upon the XBHNH unit,
`whereX =N, NH, orO <99JPC(A)2141>.
`
`1.2.2 Relevant Properties of Arylboronic Acids
`
`The properties of phenylboronic acid (11) and some of its simple derivatives deserve comment,
`since boroaromatics are often constructed using these frameworks.
`In the solid st.ate, 11 self(cid:173)
`associates, resembling a carboxylic acid dimer <77CJC3071>. Crystal packing forces can
`produce some peculiar structures, though, like the one for 2-nitro-4-carboxyphenylboronic acid
`(12) that appears to show an intramolecular association between the N02 and B(OH)2 groups
`<93AX(C)690>. Upon close inspection, however, one finds that little or no concornlt.ant
`rehybridization of the boron has taken place in response to this apparent interact~on.
`
`By contrast, the X-ray crystal structures of both 2-fonnylbenzeneboronic acid (13) and its 0-
`methyl oxime (14) reveal an intramolecular hydrogen bond in which one hydroxyl of the B(OHh
`unit truly acts as a hydrogen bond donor to a h~teroa~m of the ortho .side chain <.94MI621>.
`The hydrogen bond distance in the seven-membered rin'g~is i".562·A in 13" a