Progress in Heterocyclic Chemistry

By Elsevier Science

This is the 26th annual volume of Progress in Heterocyclic Chemistry and covers the literature published during 2013 on most of the important heterocyclic ring systems. This volume opens with two specialized reviews, not restricted to work published in 2013: ‘Recent Developments in the Synthesis of Cyclic Guanidine Alkaloids’ written by Matthew G. Donahue, and ‘Heterocyclic chemistry: a complete toolbox for nanostructured carbon materials’ written by Luisa Lascialfari, Stefano Fedeli, and Stefano Cicchi. The remaining chapters examine the 2013 literature on the common heterocycles in order of increasing ring size and the heteroatoms present.

• Recognized as the premiere review of heterocyclic chemistry
• Contributions from leading researchers in the field
• Systematic survey of the important 2013 heterocyclic chemistry literature

• Language: English
• Publisher: Elsevier Science
• Release date: Oct 27, 2014
• ISBN: 9780081000427

Book preview

Progress in Heterocyclic Chemistry

VOLUME TWENTY SIX

Editors

Gordon W. Gribble

Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA

John A. Joule

The School of Chemistry, The University of Manchester, Manchester, UK

Table of Contents

Cover image

Title page

Copyright

Contributors

Foreword

Editorial Advisory Board Members Progress in Heterocyclic Chemistry

Chapter 1. Recent Developments in the Synthesis of Cyclic Guanidine Alkaloids

1.1. Introduction and Scope of the Review

1.2. Cyclic Guanidines in Organic Chemistry

1.3. Total Synthesis of Cyclic Guanidine Natural Products

1.4. Recently Isolated Natural Products and Medicinal Agents

Chapter 2. Heterocyclic Chemistry: A Complete Toolbox for Nanostructured Carbon Materials

2.1. Introduction

2.2. Three Membered Cycles

2.3. Five-Membered Heterocycles

2.4. Six-Membered Heterocycles

2.5. Seven-Membered Heterocycles

Chapter 3. Three-Membered Ring Systems

3.1. Introduction

3.2. Epoxides

3.3. Aziridines

Chapter 4. Four-Membered Ring Systems

4.1. Introduction

4.2. Azetidines, Azetines, and Related Systems

4.3. Monocyclic 2-Azetidinones (β-Lactams)

4.4. Fused and Spirocyclic β-Lactams

4.5. Oxetanes, Dioxetanes, and 2-Oxetanones (β-Lactones)

4.6. Thietanes and Related Systems

4.7. Silicon and Phosphorus Heterocycles Miscellaneous

Chapter 5.1. Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives

5.1.1. Introduction

5.1.2. Reviews and Books on Thiophene, Selenophene, and Tellurophene Chemistry

5.1.3. Synthesis of Thiophenes, Selenophenes, and Tellurophenes

5.1.4. Elaboration of Thiophenes and Benzothiophenes

5.1.5. Elaboration of Selenophenes and Benzoselenophenes

5.1.6. Synthesis of Thiophenes, Selenophenes, and Tellurophenes for Use in Material Science

5.1.7. Thiophenes, Selenophenes, and Tellurophenes in Medicinal and Environmental Chemistry

5.1.8. Selenophenes

Chapter 5.2. Five-Membered Ring Systems: Pyrroles and Benzo Analogs

5.2.1. Introduction

5.2.2. Synthesis of Pyrroles

5.2.3. Reactions of Pyrroles

5.2.4. Synthesis of Indoles

5.2.5. Reactions of Indoles

5.2.6. Isatins, Oxindoles, Indoxyls, and Spirooxindoles

5.2.7. Carbazoles

5.2.8. Azaindoles

5.2.9. Isoindoles

Chapter 5.3. Five-Membered Ring Systems: Furans and Benzofurans

5.3.1. Introduction

5.3.2. Reactions

5.3.3. Synthesis

Chapter 5.4. Five Membered Ring Systems: With More than One N Atom

5.4.1. Introduction

5.4.2. Pyrazoles and Ring-Fused Derivatives

5.4.3. Imidazoles and Ring-Fused Derivatives

5.4.4. 1,2,3-Triazoles and Ring-Fused Derivatives

5.4.5. 1,2,4- Triazoles and Ring-Fused Derivatives

5.4.6. Tetrazoles and Ring-Fused Derivatives

Chapter 5.5. Five-Membered Ring Systems: With N and S (Se) Atoms

5.5.1. Introduction

5.5.2. Thiazoles

5.5.3. Isothiazoles

5.5.4. Thiadiazoles

5.5.5. Tellurazoles

Chapter 5.6. Five-Membered Ring Systems: With O and S (Se, Te) Atoms

5.6.1. 1,3-Dioxoles and Dioxolanes

5.6.2. 1,3-Dithioles and Dithiolanes

5.6.3. 1,3-Oxathioles and Oxathiolanes

5.6.4. 1,2-Dioxolanes

5.6.5. 1,2-Dithioles and Dithiolanes

5.6.6. Three Heteroatoms

Chapter 5.7. Five-Membered Ring Systems with O & N Atoms

5.7.1. Isoxazoles

5.7.2. Isoxazolines

5.7.3. Isoxazolidines

5.7.4. Oxazoles

5.7.5. Oxazolines

5.7.6. Oxazolidines

5.7.7. Oxadiazoles

Chapter 6.1. Six-Membered Ring Systems: Pyridine and Benzo Derivatives

6.1.1. Introduction

6.1.2. Overview of Pyridine and (Iso)Quinoline Uses

6.1.3. Synthesis of Pyridines

6.1.4. Reactions of Pyridines

6.1.5. Synthesis of (Iso)Quinolines

6.1.6. Reactions of (Iso)Quinolines

Chapter 6.2. Six-Membered Ring Systems: Diazines and Benzo Derivatives

6.2.1. Introduction

6.2.2. Pyridazines and Benzo Derivatives

6.2.3. Pyrimidines and Benzo Derivatives

6.2.4. Pyrazines and Its Benzo Derivatives

Chapter 6.3. Triazines and Tetrazines

6.3.1. Triazines

6.3.2. Tetrazines

Chapter 6.4. Six-Membered Ring Systems: With O and/or S Atoms

6.4.1. Introduction

6.4.2. Heterocycles Containing One Oxygen Atom

6.4.3. Heterocycles Containing One Sulfur Atom

6.4.4. Heterocycles Containing Two or More Oxygen Atoms

6.4.5. Heterocycles Containing Both Oxygen and Sulfur in the Same Ring

Chapter 7. Seven-Membered Rings

7.1. Introduction

7.2. Seven-Membered Systems Containing One Heteroatom

7.3. Seven-Membered Systems Containing Two Heteroatoms

7.4. Seven-Membered Systems Containing Three or More Heteroatoms

7.5. Future Directions

Chapter 8. Eight-Membered and Larger Rings

8.1. Introduction

8.2. Carbon–Oxygen Rings

8.3. Carbon–Nitrogen Rings

8.4. Carbon–Sulfur Rings

8.5. Carbon–Nitrogen–Selenium Rings

8.6. Carbon–Nitrogen–Oxygen Rings

8.7. Carbon–Nitrogen–Sulfur Rings

8.8. Carbon–Oxygen–Sulfur Rings

8.9. Carbon–Sulfur–Phosphorus Rings

8.10. Carbon–Boron–Sulfur–Oxygen Rings

8.11. Carbon–Nitrogen–Oxygen–Sulfur Rings

Index

Copyright

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Contributors

R. Alan Aitken,     School of Chemistry, University of St. Andrews, St. Andrews, Fife, UK

Benito Alcaide,     Departamento de Química Orgánica I, Unidad Asociada al CSIC, Universidad Complutense de Madrid, Madrid, Spain

Pedro Almendros,     Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas, IQOG-CSIC, Madrid, Spain

Edward R. Biehl,     Southern Methodist University, Dallas, TX, USA

Alex C. Bissember,     School of Physical Sciences - Chemistry, University of Tasmania, Hobart, TAS, Australia

Stefano Cicchi,     Università degli Studi di Firenze, Firenze, Italy

Franca M. Cordero,     Università degli Studi di Firenze, Firenze, Italy

Matthew G. Donahue,     Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS, USA

Renhua Fan,     Department of Chemistry, Fudan University, Shanghai, China

Stefano Fedeli,     Università degli Studi di Firenze, Firenze, Italy

Donatella Giomi,     Università degli Studi di Firenze, Firenze, Italy

Christopher Hyland,     School of Chemistry, University of Wollongong, Wollongong, NSW, Australia

Jeremy Just,     School of Physical Sciences – Chemistry, University of Tasmania, Hobart, TAS, Australia

Tara L.S. Kishbaugh,     Chemistry Department, Eastern Mennonite University, Harrisonburg, VA, USA

Dmitry N. Kozhevnikov

Department of Organic Synthesis, Ural Federal University, Ekaterinburg, Russia

I. Postovsky Institute of Organic Synthesis, Ekaterinburg, Russia

David J. Lapinsky,     Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA

Luisa Lascialfari,     Università degli Studi di Firenze, Firenze, Italy

Justin M. Lopchuk,     The Scripps Research Institute, Department of Chemistry, La Jolla, CA, USA

Adam G. Meyer,     CSIRO Division of Materials Science and Engineering, Clayton, VIC, Australia

George R. Newkome,     Departments of Polymer Science and Chemistry, The University of Akron, Akron, OH, USA

Xiao-Shui Peng

Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules & Shenzhen, Center of Novel Functional Molecules, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China

Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China

Lynn A. Power,     Liverpool, UK

Anton M. Prokhorov,     Department of Organic Synthesis, Ural Federal University, Ekaterinburg, Russia

K. Alison Rinderspacher,     Columbia University, New York, NY, USA

John H. Ryan,     CSIRO Division of Materials Science and Engineering, Clayton, VIC, Australia

Clementina M.M. Santos,     Department of Vegetal Production and Technology, School of Agriculture, Polytechnic Institute of Bragança, Bragança, Portugal

Artur M.S. Silva,     Departament of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal

Jason A. Smith,     School of Physical Sciences – Chemistry, University of Tasmania, Hobart, TAS, Australia

Charlotte C. Williams,     CSIRO Division of Materials Science and Engineering, Parkville, VIC, Australia

Jie Wu,     Department of Chemistry, Fudan University, Shanghai, China

Yong-Jin Wu,     Bristol Myers Squibb Company, Wallingford, CT, USA

Bingwei V. Yang,     Bristol Myers Squibb Company, Princeton, NJ, USA

Larry Yet,     Department of Chemistry, University of South Alabama, Mobile, AL, USA

Foreword

Gordon W. Gribble and John A. Joule

This is the 26th annual volume of Progress in Heterocyclic Chemistry and covers the literature published during 2013 on most of the important heterocyclic ring systems. References are incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry and are listed in full at the end of each chapter.

This volume opens with two specialized reviews, not restricted to work published in 2013: ‘Recent Developments in the Synthesis of Cyclic Guanidine Alkaloids’ written by Matthew G. Donahue, and ‘Heterocyclic chemistry: a complete toolbox for nanostructured carbon materials’ written by Luisa Lascialfari, Stefano Fedeli, and Stefano Cicchi. The remaining chapters examine the 2013 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. The Index is not fully comprehensive, however the Contents pages list all the subheadings of the chapters which will assist in accessibility for readers.

We are delighted to welcome some new contributors to this volume, and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are aware that all our Authors produce their chapters while attending to their many other duties and responsibilities. We are also grateful to our colleagues at Elsevier for supervising the publication of this volume and preparing the Index.

We hope that our readers find this series to be a useful guide to the most recent developments in heterocyclic chemistry. As always, we encourage suggestions for improvements, ideas for review topics, and inquiries from interested potential authors.

Editorial Advisory Board Members Progress in Heterocyclic Chemistry

2014 – 2015

Professor Dawei Ma (Chairman)

Shanghai Institute of Organic Chemistry, China

Professor Alan Aitken

University of St. Andrews, UK

Professor Xu Bai

Jilin University, China

Professor Margaret Brimble

University of Auckland, New Zealand

Professor Marco Ciufolini

University of British Columbia, Canada

Professor Stephen Martin

University of Texas, USA

Professor Oliver Reiser

University of Regensburg, Germany

Professor Mark Rizzacasa

University of Melbourne, Australia

Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://www.ishc-web.org/

Chapter 1

Recent Developments in the Synthesis of Cyclic Guanidine Alkaloids

Matthew G. Donahue email address: [e-mail]     Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS, USA

Abstract

The cyclic guanidine motif, present in complex alkaloids, active pharmaceutical ingredients, and organocatalysts, is discussed beginning with amine guanidinylation and proceeding through numerous cyclization methods. The application of such methods is reviewed in the context of complex alkaloid synthesis.

Keywords

Alkaloid; Aminoimidazolidine; Batzelladine; Carboamination; Carbodiimide; Cyanamide; Cycloguanidinylation; Diamination; Electrophile; Guanidine; Guanidinylation; Palau'amine; Saxitoxin; Synthesis; Tetrahydropyrimidine; Thiourea; Urea

1.1. Introduction and Scope of the Review

The cyclic guanidine substructure (typically substituted imidazolin-2-iminium salt or tetrahydropyrimidin-2(1H)-iminium salt) present in complex molecular architectures such as saxitoxin, batzelladines, and palau’amine has enticed synthetic organic chemists to develop new processes to efficiently prepare them. As the field has rapidly evolved, it is now seemingly straightforward for chemists to synthesize such challenging targets. This chapter will provide a broad overview of some of those methods used to construct the cyclic guanidine moiety found in complex alkaloids. A survey of the literature is presented since 2000 and is not meant to be exhaustive in nature, but will serve to introduce the reader to a general background of the various key methods. The first section will provide a brief update on guanidinylation reagents. A recap of cyclization strategies, highlighted in the scheme below, is then presented that demonstrates differential preparations of cyclic guanidines. The second section serves as an illustration of the application of methods used in the total syntheses of three complex molecules. The final section will display some of the unique structures recently isolated from plant material and discovered in medicinal chemistry laboratories.

1.2. Cyclic Guanidines in Organic Chemistry

1.2.1. Amine Guanidinylation Reagents in Organic Chemistry

Cyclic guanidines are typically forged from acyclic precursors, in turn prepared via guanidinylation of amines. The reader is referred to Katritzky and Rogovoy’s 2005 comprehensive review on guanylating agents for a thorough treatment (05ARK49). Following their convention for categorization, reagents of each class are presented: (1) thioureas, (2) isothioureas, (3) aminoiminomethane sulfonic and sulfinic acids, (4) carbodiimides and cyanamides, (5) triflyl guanidines, (6) pyrazole-1-carboximidamides and imidazole-1-yl carboximidamides, and (7) benzotriazole- and benzimidazole-containing reagents. Ansyln’s 2002 review on solid-phase synthesis of guanidinium derivatives is also a beneficial reference (02EJOC3909).

The coupling reagent 2,4,6-trichloro-1,3,5-triazine (TCT, a cyanuric chloride) was found to be an inexpensive way to prepare N,N-di-Boc-protected guanidines using the di-Boc-thiourea (09SL3368). The active guanidinylating agent was determined to be N,N′-di-Boc-carbodiimide upon treatment with N-methylmorpholine.

Maki showed that amines (R¹  =  alkyl, aryl), after conversion to thioureas with N-protected isothiocyanates (R²  =  Cbz, Fmoc, CO2Et), can be converted to differentially protected guanidines using the Burgess reagent (14OL1868).

A 2004 report by Izdebski detailed the preparation of ortho-halogenated N-Cbz S-methylisothioureas (04S37). The presence of the halogen atom is claimed to obviate the need for toxic mercuric chloride, which is required for weakly nucleophilic amines.

Castillo-Meléndez and Golding developed 3,5-dimethyl-N-nitro-1-pyrazole-1-carboxamidine (DMNPC) for the mild (HgCl2-free) preparation of N-nitroguanidines (04S1655). The nitro group can be cleaved via transfer hydrogenation with formic acid in methanol catalyzed by 10% Pd/C. A polymer-bound pyrazole guanidinylating reagent for the preparation of protecting group free guanidines was developed by Kirschning (06S461). Microwave radiation was found to accelerate the process, and the reagent could be regenerated without deleterious effects.

A 2006 report detailed the three-step synthesis of N-hydroxy guanidines from N-Cbz protected thioureas for the synthesis of NG-hydroxy-L-arginine (06OL4035).

Looper developed an in situ protocol for the conversion of the shelf-stable potassium salt of N-Cbz-cyanamide into N-Cbz N-TMS-carbodiimide for the preparation of mono-N-acylguanidines (11JOC6967). The reaction has been demonstrated on a wide variety of aliphatic and aromatic amines without the assistance of an exogenous activating agent.

González and coworkers published a one-pot protocol in which an azide is hydrogenated then trapped in situ with N’,N’’-di-Boc-N-triflyl-guanidine (GN-Tf) (10JOC5371). The reaction was deemed competent on a wide variety of carbohydrate substrates.

1.2.2. Methods for Cyclic Guanidine Formation

Two complete reviews on the synthesis of acyclic guanidines have been published and provide excellent up to date coverage of new methods (12CSR2463, 14CSR3406). Wardrop’s extensive review on alkene deamination methods highlights cycloguanidination methods prior to 2012 (12T4067). The chart below depicts some of the recent strategies developed for synthesizing cyclic guanidines.

A few notable achievements highlighting the use of transition metal catalysis to form cyclic guanidines are discussed in the following vignette. Alper has developed a research program predicated on Pd-catalyzed ring-opening reactions of aziridines and pyrrolidines with heterocumulenes (95JA4700, 00JOC5887, 04T73). The maturity of catalytic palladium cyclization methods is evident in the work by Muñiz (08JA763) and Wolfe (13OL5420). The Muñiz cyclization involves guanidination of an olefin by a pendant bis-protected guanidine. The Wolfe olefin carboamination employs an allylic guanidine for sequential cyclization–cross-coupling. The Shi group discovered the Cu(I)-catalyzed intermolecular cycloguanidination of olefins with diaziridines (08OL1087).

A wide variety of novel methods have been published in recent years signifying the intense interest in this area. Madalengoitia discovered that the azanorbornene scaffold, when treated with an in situ-generated carbodiimide, undergoes a 1,3-diaza-Claisen rearrangement to afford fused cyclic guanidines (04OL3409). A most unique synthesis of cyclic guanidines was published utilizing aminyl radical cyclization onto N-acyl cyanamides (10AG(I)2178). The reaction of β-aminoazides with isocyanates under microwave heating followed by tri-n-butylphosphine effected the formation of 2-aminoimidazolidines in high yield (13JOC5737). The hydrogenation of 2-aminopyrimidines has been shown to be an efficient route to cyclic guanidine-containing amino acids (13TL4526) and substituted 2-anilino 1,4,5,6-tetrahydropyrimidines (14ARK161).

The venerable Mitsunobu reaction has proved its utility in the ring closure of β-guanidinoalcohols for the synthesis of hydroxyenduracididine derivatives (09EJOC6129). N-Heterocyclic carbenes have been employed in nitrogen atom transfer from electrophilic ruthenium (VI) nitride complexes (11IC2501). Xie delineated the mechanistic details of the titanacarborane monoamide catalyzed reaction of carbodiimides (11OL4562). Xi introduced a method for preparing regioisomers in the presence or absence of trimethylaluminum (12OBC6266). The syntheses of 5-, 6-, and 7-membered N-cycloguanidinyl peptides have been carried out using a solid-phase strategy (14TL1733).

1.2.3. Cyclic Guanidines as Organocatalysts

Cyclic guanidines have emerged as a powerful class of organocatalysts due to their increased nucleophilicity and ability to hydrogen bond (09CAJ488, 12CSR2109, 13S703). A few examples are shown to give the reader a flavor of the type of transformations that have been achieved. The organocatalyst 1,5,7-triazabicyclododecene (TBD) has been found to be an efficient catalyst in the amidation of methyl esters (09JOC9490, 12JPC12389, 12OPRD1967). Terada has shown that the nine-membered ring axially chiral guanidine can induce both high diastereo- and enantioselectivities in the vinylogous aldol reaction of furanones (10AG(I)1858).

1.3. Total Synthesis of Cyclic Guanidine Natural Products

1.3.1. Saxitoxin, Decarbamoylsaxitoxin, Saxitoxinol, and Gonyautoxin 3

Marine sponges are a bountiful source of exceedingly complex toxic alkaloids that serve as the organic chemist’s muse (93CRV1897). The total syntheses of one compound in particular, namely saxitoxin (STX), spanning sequential generations of organic chemists, sheds light on the evolution of the art of organic synthesis. Recent reviews by Llewellyn (06NPR200) and Du Bois (14AG(I)2) serve as authoritative sources for the synthetic chemistry and biology of STX. The reader is referred to these sources for an in-depth discussion on this fascinating natural product. The present discussion is meant to be a brief case study in the evolution of cyclic guanidine synthesis over the past four decades.

With the synthesis of (±)-STX in 1977, Kishi laid down the gauntlet for synthetic chemists demonstrating that highly nitrogenous molecules could be synthesized in the laboratory (77JA2818, 80H1477). The campaign commenced with the conversion of butyric acid into lactam 1 over seven steps. The Eschenmoser sulfide contraction was then utilized to prepare vinylogous urethane 2 over three steps. Treatment of 2 with silicon tetraisothiocyanate and benzyloxyacetaldehyde proceeds first with a enamine–aldol reaction and then formation of a Lewis acid-activated thiourea adduct that suffers an electrocyclization affording 3 as a 1:1 mixture. It is noteworthy at this point that no more carbon–carbon bonds will be made in this synthesis. The next sequence of events served to install the C5 nitrogen in 4 via Hofmann rearrangement. Treatment of 4 with trifluoroacetic acid induced protonation at C5, generating an N-thioacyl iminium ion that was trapped by the C5 urea. Subsequent conversion of both the urea and thiourea in 5 to the guanidine functionality was accomplished in two steps by treatment with Meerwein’s reagent then ammonium propionate. This two-step sequence is a standard tactic for not carrying a guanidine through the entire synthesis. The remaining steps involved deblocking of the dithiane and installation of the carbamate.

Reagents and conditions: (i) P2S5, C6H6, 80  °C; (ii) methyl 2-bromo-3-oxobutyrate, NaHCO3, CH2Cl2, Δ; (iii) KOH, MeOH, 50  °C; (iv) BnOCH2CHO, Si(SCN)4, PhH; PhCH3, 110  °C; (v) NH2NH2·H2O, MeOH, H2O; (vi) NOCl, CH2Cl2, −50  °C; (vii) 90  °C, PhH; (viii) NH3, PhH; (ix) 1,3-propanedithiol, BF3·OEt2, CH3CN; (x) AcOH-CF3CO2H 9:1, 50  °C; (xi) Et3O+BF4−, NaHCO3, CH2Cl2; (xii) EtCO2NH4, 135  °C; (xiii) BCl3, CH2Cl2, 0  °C; Ac2O, pyridine; (xiv) NBS, wet CH3CN, 15  °C; MeOH, 100  °C; (xv) ClSO2NCO, HCO2H, 5  °C.

Not long after Kishi’s synthesis was completed, Jacobi published an equally impressive campaign featuring the development of an intramolecular 1,3-dipolar cycloaddition of an azomethine imine to a 2-imidazolone to set the N,N-aminal ring system 9 (81JA239, 84JA5594, 86CCA267). Transfer hydrogenation cleaved the cyclic hydrazine thereby inducing N-thioacylation with expulsion of phenoxide generating the thiourea 11. As with Kishi’s work, the urea to guanidine conversion was employed to access the final form of STX. The complete story was recalled in exciting detail a few years later (B-89MI191).

Reagents and conditions: (i) ClCOCH2CO2Et, SnCl4, CH3NO2; (ii) 1,3-propanedithiol, BF3·OEt2, CH3CN; (iii) KOH, MeOH; (iv) (CF3CO)2O, PhH; (v) BnNHNH2, THF; (vi) MeOCH(OH)CO2Me, BF3·OEt2; (vii) NaBH4, NaOMe, MeOH, PhH; (viii) BH3·SMe2; (ix) Pd, HCO2H; (x) PhOC(S)Cl, pyridine, THF; (xi) Na, NH3, −78  °C; (xii) Ac2O, pyridine; (xiii) Et3O+BF4–, KHCO3, CH2Cl2; (xiv) EtCO2NH4, 130  °C; (xv) NBS, wet CH3CN, 15  °C; MeOH, 100  °C; (xvi) ClSO2NCO, HCO2H, 5  °C.

Nearly three decades after Kishi’s landmark racemic synthesis of STX, the Du Bois group published a phenomenal total synthesis of (+)-STX (06JA3926, 07JA9964, 09JA12524) utilizing rhodium catalyzed CH amination methodology developed in their lab (03JA2028). As with Kishi’s second-generation synthesis (92JA7001), Du Bois started with (R)-glyceraldehyde 2,3-acetonide as the source of chirality. In eight steps, the thiourea 14 containing the carbon backbone of STX was deftly prepared. Typical of all STX syntheses, the only carbon–carbon bond forming reaction was utilized in the entire sequence. This occurred early on with the alkynylation of the iminium ion generated by treatment of oxathiazinane with zinc chloride. The next sequence of events involved installation of the C6 nitrogen by SN2 displacement of the secondary triflate with azide. Silver nitrate forced oxidation of the thiourea to the carbodiimide 15 that was trapped by the pendant secondary amine inducing ring closure of the nine-membered ring to give 16. The allylic amine was treated under oxidative conditions to afford the α-hydroxyketone 17 that suffered ring closure to the N,O-acetal 18. Acetal exchange with boron tris-trifluoroacetate then caused cyclization to the N,N-aminal 19. A final oxidation converted the secondary alcohol to the hydrate of STX. As a consequence of the advancement in guanidine chemistry since Kishi’s synthesis, the Du Bois work avoided the urea to guanidine conversion completely. The efficiency is realized in lower step counts obviating oxidation adjustment issues.

Reagents and conditions: (i) ClSO2NH2, DMA-CH3CN; (ii) Rh2(O2CR)4 (2–4 mol%), PhI(OAc)2, MgO, CH2Cl2; (iii) BF3·OEt2, TsOCH2CH2CCZnCl, THF, 40  °C; (iv) H2, Pd/CaCO3/Pb, THF; (v) NaN3, n-Bu4NI, DMF; (vi) p-MeOC6H4CH2Cl, nNMbs, i-Pr2NEt, CH3CH; (ix) Tf2O, pyridine, DMAP, CH2Cl2; (x) NaN3, DMF, −15  °C; (xi) (NH4)2Ce(NO3)6, tNMbs, KOt-Bu, then (CH3Si)2NH; (xiii) CH3CN-H2O, 70  °C; (xiv) Me3P, THF-H2O; (xv) AgNO3, Et3N, CH3CN; (xvi) Cl3CC(O)NCO, THF-CH3CN, 15  °C; K2CO3, MeOH; (xvii) OsCl3 (10  mol%), oxone, Na2CO3, EtOAc-CH3CN-H2O; (xviii) B(O2CCF3)3, CF3CO2H; (xix) DCC, DMSO, pyridine·HO2CCF3.

The Nagasawa group has developed the cyclic nitrone–alkene cycloaddition reaction as a method for the synthesis of (−)-decarbamoyloxysaxitoxin (doSTX) (07AG(I)8625, 09CAJ277, 10OL2150, 11CEJ12144, 12PAC1445). In this case, the TIPS protected secondary alcohol in 19 dictates the facial selectivity of the cycloaddition thereby setting three contiguous chirality centers with the correct relative stereochemistry. Reminescent of the Kishi approach, a Hofmann rearrangement installed the five-membered ring nitrogen 20 to 21. The Mitsunobu reaction was used to cyclize 21 to the six-membered ring guanidine 22. To cyclize to the five-membered ring guanidine, five steps were required to convert 22 to the N,O-aminal 23. Global hydrogenolysis of the four N-Cbz groups, followed by stirring in THF, lead to tricyclic guanidine 24. The final step involved oxidation of the secondary alcohol to the ketone, which exists as the hydrate due to ring strain.

C(SCH3)NHCbz, HgCl2, Et3N, DMF; (vi) DEAD, PPh3, PhCH3; (vii) nC(SCH3)NHCbz, HgCl2, Et3N, DMF; (xii) H2, Pd(OH)2, CH3OH-EtOAc; (xiii) THF, 50  °C; (xiv) DMSO, iNi-Pr, pyridine·HO2CCF3.

Gonyautoxin 3 (GTX3) was synthesized in enantioselective fashion by Du Bois (08JA12630). The campaign commenced with serine and in four steps produced the fused pyrrole urea 25. It should be noted that the entire synthesis only required one carbon–carbon bond forming reaction depicted in the electrophilic aromatic ring closure. After guanidinylation of the allylic amine to give 26, transformation of 26 to 27 relied on the two-step urea-to-guanidine conversion. A rhodium-catalyzed oxidation of the pyrrole induced formation of the N,N-aminal yielding allylic acetate 27. The next seven steps were spent on oxidation state adjustments featuring deoxygenation of the allylic acetate and dihydroxylation. Selective sulfation of the secondary alcohol then completed the GTX campaign.

Reagents and conditions: (i) Pyrrole-1-carboxylic acid, DCC, Et3N, CH2Cl2; (ii) t-BuPh2SiCl, imidazole, DMF; (iii) iC(SMe)Cl; (vi) EtOSO2CF3, 2,4,6-tri-tert-butylpyrimidine, CH2Cl2, 47  °C; (vii) NH3, NH4OAc, MeOH, 60  °C; (viii) CCl3C(O)Cl, i-Pr2NEt, CH2Cl2, −20  °C; (ix) 5  mol% Rh2(esp)2, PhI(OAc)2, MgO, CH2Cl2, 42  °C; (x) Et3SiH, BF3·OEt2, CH2Cl2; (xi) n-Bu4NF, THF; (xii) Cl3CC(O)NCO, CH2Cl2, −20  °C; MeOH; (xiii) 2  mol% OsO4, NMO, THF/H2O; (xiv) PhC(O)CN, DMAP, CH2Cl2/MeCN, −78  °C; (xv) Dess–Martin Periodinane, CH2Cl2; (xvi) H2, Pd/C, CF3CO2H, MeOH; NH3, MeOH; (xvii) DMF·SO3, 2,6-di-tert-butyl-4-methylpyridine, NMP.

In 2011, Looper demonstrated the competency of electrophile-initiated guanidine–alkyne cyclizations in an efficient synthesis of STX (11JA20172). The synthesis commenced with the known preparation of aldonitrone 30 followed by addition of the magnesiated alkyne that contained the remaining carbon atoms of the molecule. Following requisite oxidation state adjustments 31 was converted into 32. The secondary nitrogens of 32 were guandinylated with isothiourea affording bis-guanidine 33. In a unique one-pot procedure, silver induced geminal diamination of the alkyne 33 followed subsequently by oxazolidinone cyclization by iodide displacement furnished 34. In the last five steps, hydrogenolysis of the benzyl ether gave the primary alcohol that was activated as the mesylate. Following chemoselective hydrolysis of the cyclic carbamate, intramolecular SN2 displacement of the mesylate by the guanidine nitrogen gave the cyclopentane ring.

Reagents and conditions: (i) t-BuPh2SiCl, imidazole, DMF; (ii) i-Bu2AlH, CH2Cl2, −90  °C; (iii) BnHNOH; (iv) homopropargyl benzyl ether, i-PrMgCl, THF, −78  °C  →  −55  °C; (v) Cu(OAc)2, Zn, AcOH, H2O; (vi) 1M HCl in MeOH, 40  °C; (vii) KOCN, MsOH, CH2Cl2; (viii) N,N′-di-Boc-S-methylisothiourea, HgO, Et3N, CH2Cl2; (ix) AgOAc, CH2Cl2; AgOAc, Et2O, I2; AgOAc, CH3CN, AcOH, 60  °C; (x) H2 (80 psi), Pd(OH)2, i-PrOH; (xi) MsCl, Et3N, DMAP, CH2Cl2; (xii) Cs2CO3, EtOH, 0  °C; (xiii) Dess–Martin periodinane, CH2Cl2; (xiv) CF3CO2H, CH2Cl2.

The Nishikawa group employed a strategy of guanidine–alkyne electrophile-initiated cyclization in the synthesis of dcSTX-OH (11AG(I)7176, 11SL651, 12JSOC1178). This route began with Garner’s aldehyde as the source of chirality. It is noteworthy that the only carbon–carbon bond forming reaction is the first step in which the lithium acetylide adds to the aldehyde with 10:1 diastereoselectivity. The next series of steps involve installation of the C5 nitrogen with retention of configuration. This is achieved by double inversion proceeding through the N-guanidinyl aziridine 36. The key step in this synthesis is treatment of alkyne with pyridine hydrobromide perbromide to effect: (1) electrophile-initiated cyclization of the guanidine, (2) a second cyclization to the N,O-acetal, and (3) annulation of the five-membered ring via N displacement of the mesylate. The geminal dibromide, serving as a masked ketone, was transformed into the secondary alcohol 39 via the enol acetate. The azide was reduced via Staudinger reduction and subsequently guanidinylated affording 40. The N,O-acetal was exchanged for the five-membered ring guanidine bearing the N,N-aminal by the method of Du Bois with the boron Lewis acid affording dcSTX-OH.

Reagents and conditions: (i) n-BuLi, HMPA, PhCH3, −78  °C, 2  h; (ii) CH3SO2Cl, Et3N, CH2Cl2, rt, 1  h; (iii) CF3CO2H, CH2Cl2-H2O, rt, 2  h; Amberlite® IRA-410, CH3OH, rt, 30  min; (iv) Et3N, DMF; N,N′-di-Boc-S-methylisothiourea, HgCl2, Et3N, DMF, rt, 30  min; (v) TBSCl, Et3N, CH2Cl2-DMF, rt, 16  h; (vi) Ac2O, Et3N, DMAP, CH2Cl2, rt, 3.5  h; (vii) NaN3, DMF, rt, 4.5  h; (viii) n-Bu4NF, THF, rt, 30  min; (ix) CH3SO2Cl, Et3N, CH2Cl2, 0  °C  →  rt, 40  min; (x) KCN, EtOH, rt, 12  h; (xi) CF3CO2H, CH2Cl2, rt, 2  h; (xii) PyHBr3, K2CO3, CH2Cl2-H2O, rt, 1  h; (xiii) Ac2O, Et3N, CH2Cl2, rt, 15  min; (xiv) NaBH4, CH3OH, rt, 30  min; (xv) Me3P, CH2Cl2, rt, 30  min; 12  M HCl-CH3OH, rt; (xvi) N,N′-di-Cbz-S-methylisothiourea, HgCl2, Et3N, DMF, 60  °C; (xvii) H2, Pd/C, CH3OH-EtOAc, rt, 27  h; (xvii) B(OCOCF3)3, CF3CO2H, rt, 24  h.

1.3.2. Batzelladines, Crambescidins, and Ptilomycalin A

The structural disclosure of ptilomycalin A in 1989 ushered in a new era of aza-annulation strategies to synthesize the core 2,2a,3,4,5,7,8,8a-octahydro-1H-2a¹,5,6-triazaacenaphthylene structure. The subsequent disclosure of batzelladines and crambescidins beckoned research groups to develop new methods for their synthesis. Early work by Snider utilized a biomimetic double Michael addition for the ptilomycalin A core that set the precedent for all subsequent strategies (94JA549).

Overman exploited the Biginelli condensation to efficiently synthesize (−)-ptilomycalin A (95JA2657). The ureido aldehyde 44 was condensed with the β-keto ester 45 giving the bicyclic urea 46. The pentacyclic guanidinium core was sutured via treatment of the keto urea with ammonia in a sealed tube. The remaining steps installed the spermidine side chain in the amide residue. The Overman group’s contribution to cyclic guanidine synthesis is manifest in a portfolio of impressive syntheses including crambescidin 359, 657, and 800 along with batzelladine F (00JA4893, 04CC253, 05JA3380, 06JA2604).

Reagents and conditions: (i) morpholine, CH3CO2H, EtOH, Na2SO4, 70  °C; (ii) PPTS, CH3OH, 50  °C; (iii) p-TsOH, CHCl3, 23  °C; (iv) (COCl)2, DMSO, CH2Cl2, −78  °C; Et3N; (v) CH3OSO2CF3, 2,6-di-tert-butylpyridine, CH2Cl2, 23  °C; (vi) Grignard, THF, −78  °C; morpholinium acetate; (vii) (COCl)2, DMSO, CH2Cl2, −78  °C; Et3N; (viii) n-Bu4NF, THF; (ix) NH3, NH4OAc, t-BuOH, sealed tube, 60  °C; (x) Pd(PPh3)4, pyrrolidine, CH3CN, 23  °C; (xi) bis-Boc spermidine, EDCI, DMAP, CH2Cl2, 23  °C; (xii) Et3N, CH3OH, 65  °C; (xiii) HCO2H; NaOH-NaCl (aq).

Prior to their successful STX work, the Nagasawa group defined the scope of the nitrone–alkene cycloaddition for guanidine synthesis on a batzelladine A campaign (04AG(I)1559, 05CEJ6878). The western cyclic guanidine was synthesized in 15 steps originating from the Goti enantiopure nitrone 19. The route featured a Mitsunobu ring closure to access the bicyclic guanidine 51. The union of the western and eastern fragments was accomplished via ester coupling of alcohol 51 with guanidine acid 52, in turn prepared via the nitrone–alkene cycloaddition route. The bis-guanidine 53 was carried to batzelladine A in four additional steps utilizing a second Mitsunobu ring closure.

Reagents and conditions: (i) PhCH3, 90  °C; (ii) LiAlH4, Et2O, 0  °C; (iii) CsF, EtOH, 90  °C; (iv) TBSCl, pyridine; (v) ClC(S)OPh, pyridine, DMAP; (vi) nC(SCH3)NHBoc, HgCl2, Et3N, DMF; (ix) PPh3, DEAD, PhCH3; (x) n-Bu4NF, THF; (xi) TPAP, NMO, molecular sieves, CH2Cl2; (xii) NaClO4, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O, TMSCHN2; (xiii) n-PrSLi, HMPA; (xiv) BOPCl, Et3N, CH2Cl2; (xv) DDQ, CH2Cl2-H2O; (xvi) EDCI, DMAP, CH2Cl2; (xvii) HF·pyridine, THF; (xviii) H2, Pd/C; (xix) PPh3, DEAD, PhCH3; (xx) CF3CO2H-CH2Cl2.

Gin and coworkers developed an exquisite vinyl carbodiimide–imine annulation method for the synthesis of (−)-batzelladine D (05JA6924). The strategy involved the union of vinyl carbodiimide 54 with imine 55 to access the PMB-protected cyclic guanidine 56 in short order. The core 56 was elaborated to the seco-guanidine 57 over five steps featuring hydrogenation of the convex face of the vinylogous urethane with Crabtree’s catalyst and installation of the eastern arm via Wittig olefination. Electrophile initiated iodoamination of 57 closed the final guanidine ring affording 58 with correct 1,3-syn stereochemistry due to minimization of A¹,³-strain. Necessary deiodination and protecting group removal steps completed the synthesis of batzelladine D. A year later, Gin detailed the total synthesis of (+)-batzelladine A (06JA13255).

Reagents and conditions: (i) (CH3NH)2CN(CH3)2N3, CHCl3; (ii) PPh3, CH2Cl2; (iii) p-CH3OC6H4CH2NCO, PhCH3, 85  °C; (iv) (ClCH2)2, 23  °C; (v) nN(CH2)4OSO2CH3, Cs2CO3, DMF, 40  °C; (xi) I2, K2CO3, DMF; (xii) 10% Pd/C, Et3N, H2 (1  atm), EtOAc; (xiii) CF3CO2H.

Gin returned with an equally impressive synthesis of (−)-crambidine utilizing a variant