VOL. 48, NO. 3 • 2015

Ynamides: Powerful and Versatile Reagents for Chemical Synthesis

Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products Spiral into 3D with spirocyclic building blocks

O

N Boc S N S O O O O Spirocyclic modules containing four-membered rings 797154 are currently of growing interest to discovery chemists. Spirocyclic molecule

Aldrich offers a suite of spirocyclic building blocks and starting materials in collaboration with Professor Dr. Erick Carreira. The use of these products allows Starting Materials Spirocyclic Building Blocks the synthesis of spirocycles with spatially well-defined exit vectors to creatively exploit three dimensions. In addition, spirocyclic building blocks provide access O O O CH3 Ts N to improved physicochemical properties through O N N Boc functionalization, innovative scaffolds in medicinal O N chemistry, and a useful collection of unprecedented Boc HO inputs for fragment-based libraries. 792586 795895 797502

O H2N N Boc Boc N O O O 797464 797545 N Ts O O O 793868 S N Boc N Boc O HO Professor Dr. Erick Carreira 797456 797561

References: (1) Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66. Venture farther into 3D and learn more: (2) Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2013, 15, 4766. (3) Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2011, 13, 6134. Aldrich.com/spirocycles (4) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014, 114, 8257.

84031-a 57 VOL. 48, NO. 3 • 2015

Aldrich Chemical Co. LLC. “PLEASE BOTHER US.” 6000 N. Teutonia Ave. Milwaukee, WI 53209, USA Dear Fellow Chemists, To Place Orders Professor Shannon S. Stahl of the Department of Chemistry at the Telephone 800-325-3010 (USA) University of Wisconsin-Madison, kindly suggested that we consider offering KetoABNO, an N-oxyl radical that is a less sterically demanding FAX 800-325-5052 (USA) and more electron-deficient redox mediator than TEMPO and ABNO. It or 414-438-2199 has been employed to catalyze the efficient aerobic oxidation (oxygen Mail P.O. Box 2060 or air) of secondary alcohols to ketones at ambient temperature.1 The Milwaukee, WI 53201, USA reaction is compatible with substrates containing diverse functional groups. KetoABNO also 2 Customer & Technical Services catalyzes a general, mild, and chemoselective aerobic oxidation of amines to imines. Customer Inquiries 800-325-3010 (1) Lauber, M. B.; Stahl, S. S. ACS Catal. 2013, 3, 2612. (2) Sonobe, T.; Oisaki, K.; Kanai, M. Chem. Sci. 2012, 3, 3249. Technical Service 800-325-5832 O SAFC® 800-244-1173 Custom Synthesis 800-244-1173 N Flavors & Fragrances 800-227-4563 O• International 314-771-5765 791814 24-Hour Emergency 314-776-6555 791814 KetoABNO (9-azabicyclo[3.3.1]nonan-3-one-N-oxyl) 250 mg Website sigma-aldrich.com 1 g Email [email protected] We welcome your product ideas. Do you need a product that is not featured on our website or in General Correspondence our catalog? Ask Aldrich! For more than 60 years, your research needs and suggestions have shaped the Aldrich product offering. Email your suggestion to [email protected]. Editor: Sharbil J. Firsan, Ph.D. P.O. Box 2060, Milwaukee, WI 53201, USA [email protected]

Subscriptions Scott Batcheller Manager Request your FREE subscription to the Chemistry R&D and Product Management Aldrichimica Acta, through: iPad® App: Aldrich.com/acta-app Web: Aldrich.com/acta TABLE OF CONTENTS Email: [email protected] Ynamides: Powerful and Versatile Reagents for Chemical Synthesis...... 59 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte, Université Libre de Bruxelles (ULB) Phone: 800-325-3010 (USA) Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Mail: Attn: Marketing Services Products...... 71 Sigma-Aldrich Corporation R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma,* U.S. Environmental Protection 3050 Spruce Street Agency St. Louis, MO 63103

ABOUT OUR COVER Tamaca Palms (oil on canvas, 67.9 × 91.3 cm) was painted in 1854 by the famed American landscape artist Frederic Edwin Church (1826–1900). Born to a wealthy family, Church took up art studies at an early age and apprenticed for two years with the renowned British landscape painter Thomas Cole, who had relocated to The entire Aldrichimica Acta archive is available at Aldrich.com/acta. the U.S. and co-founded the Hudson River School of landscape painting. Church began his artistic career soon after by painting Aldrichimica Acta (ISSN 0002-5100) is a publication of Aldrich, scenes from the northeastern U.S. in the style of the Hudson a member of the Sigma-Aldrich Group. River School. He won artistic acclaim and achieved commercial success early in his career and, unlike many posthumously Detail from Tamaca Palms. Photo courtesy National ©2015 Sigma-Aldrich Co. LLC. All rights reserved. SIGMA, famous artists, had assembled a small fortune from the sale of Gallery of Art, Washington, DC. SAFC, SIGMA-ALDRICH, ALDRICH, and SUPELCO are trademarks his works by the time he died. of Sigma-Aldrich Co. LLC, registered in the US and other Inspired by the writings of the distinguished naturalist and explorer Alexander von Humboldt, Church countries. Add Aldrich is a trademark of Sigma‑Aldrich Co. travelled extensively in South America, Jamaica, the North Atlantic, the Middle East, Italy, and Greece. It LLC. Aldrich brand products are sold through Sigma-Aldrich, was upon his return from a trip to Colombia in 1853 that Church painted Tamaca Palms in his New York studio based on meticulous sketches and observations he had made during the trip.* He often painted Inc. Purchaser must determine the suitability of the products stunning, large, brightly lit, and detailed panoramas that documented the natural features, plants, and for their particular use. Additional terms and conditions may animals of exotic locales. Reminiscent of the romantic tradition in European art, Church’s awe of the beauty apply. Please see product information on the Sigma-Aldrich and majesty of the natural world is unmistakable in his works, where natural features and phenomena are website at www.sigmaaldrich.com and/or on the reverse given prominence over the human element. side of the invoice or packing slip. Sigma-Aldrich Corp. is a This painting is part of the Corcoran Collection at the National Gallery of Art, Washington, DC. subsidiary of Merck KGaA, Darmstadt, Germany. * Could Church have used the sketches that he based Tamaca Palms on as an inspiration for later compositions, iPad is a registered trademark of Apple Inc. especially in his later years? To find out, visit Aldrich.com/acta483 Dynamize your chemistry with ynamides

Versatile synthetic handle Electrophiles

EWG EWG R N • N R' R R' Ynamide Nucleophiles Despite their huge potential, the inaccessibility and instability of highly reactive nitrogen-substituted alkynes such as ynamines impede numerous synthetic routes. • Total synthesis • Functionalization In collaboration with Professor Gwilherm Evano, • Medicinal chemistry • Asymmetric synthesis Aldrich offers a selection of ynamides—stable surrogates • Heterocyclic chemistry • Organometallic chemistry for ynamines due to the presence of the electron- O withdrawing group (EWG). These strikingly reactive yet O O N stable building blocks are ideal for a multitude of chemo-, O regio-, and stereoselective transformations. Their utility N Ph is extended since the EWG furnishes a versatile chelating 805564 805580 or directing site. Significant scaffolds and reagents in total synthesis and medicinal chemistry, ynamides are O also excellent precursors of highly reactive keteniminium N ions, carbenoids, and many other useful intermediates for the development of new and innovative chemical 805599 O transformations. S N O O O n-C6H13 N

805572 805602

Professor Gwilherm Evano, Cédric Theunissen, and Morgan Lecomte (left to right)

References: (1) Evano, G.; Theunissen, C.; Lecomte, M. Aldrichimica Acta 2015, 48, 59. Learn more about Evano ynamides: (2) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (3) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, Aldrich.com/ynamides 110, 5064.

84031-b 59 VOL. 48, NO. 3 • 2015 Ynamides: Powerful and Versatile Reagents for Chemical Synthesis

Prof. G. Evano Mr. C. Theunissen Mr. M. Lecomte

Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte Laboratoire de Chimie Organique Service de Chimie et PhysicoChimie Organiques Université Libre de Bruxelles (ULB) Avenue F. D. Roosevelt 50, CP160/06 1050 Brussels, Belgium Email: [email protected]

Keywords. ynamides; alkynes; organic synthesis; heterocyclic 4. Ynamides as Precursors of Metallated Ketenimines chemistry; reactivity; reactive intermediates. 5. Ynamides as Radical Acceptors 6. Ynamides in Cycloaddition Reactions: Diversity-Oriented Abstract. Ynamides have recently emerged as particularly useful Syntheses of Heterocycles building blocks for chemical synthesis. Their remarkable reactivity has 6.1. [2 + 2] Cycloadditions been exploited in the design of a number of novel synthetic processes 6.2. [3 + 2] Dipolar Cycloadditions and for the generation of otherwise inaccessible reactive intermediates. 6.3. [4 + 2] Cycloadditions The state of the art of the chemistry of ynamides and its impact on 6.4. [2 + 2 + 1] Pauson–Khand Cycloadditions organic synthesis are highlighted in this review, which has been 6.5. [2 + 2 + 2] Cycloadditions structured according to the nature of both the reactive intermediates 7. Cycloisomerization of Ynamides: Rapid Approaches to Diverse generated and the types of reaction they undergo. Nitrogen Heterocycles 8. Polycyclizations of Ynamides: Straightforward Routes to Complex Outline Nitrogen Heterocycles 1 Introduction 9. Ynamides as Building Blocks for the Synthesis of Natural 2. Ynamides as User-Friendly Precursors Products: Enabling New and Original Bond Disconnections 2.1. Of Otherwise Inaccessible Keteniminium Ions 10. Conclusion and Outlook 2.1.1. By Protonation 11. Acknowledgments 2.1.2. By Reaction with Electrophiles 12. References 2.1.3. By Reaction with Electrophilic Metal Complexes 2.2. Of a-Oxo- or a-Imidocarbenes and Carbenoids 1. Introduction 2.2.1. a-Oxocarbenes by Gold-Catalyzed Reaction of Organic synthesis is today clearly a central science with significant Ynamides with Mild Oxidants contributions to, and impact on, various other scientific disciplines 2.2.2. a-Imidocarbenes by Gold-Catalyzed Reaction of such as biology, medicine, and materials science. As a consequence, Ynamides with Pyridine N-Aminidines and Isoxazoles the high and growing demand for efficient synthetic routes to assemble 3. Carbometallation of Ynamides: New Paradigms in Asymmetric complex molecules or pharmaceuticals from simple building blocks, as Synthesis and Heterocyclic Chemistry well as the quest for molecular diversity, will continue to challenge the 3.1. Intermolecular Carbometallation: Easy Access to Metallated resourcefulness of organic chemists for years to come. In this context, the Enamides and Beyond development of original and versatile starting materials, together with 3.2. Intramolecular Carbometallation: New Perspectives in the design of new strategies, will contribute to the selective syntheses of Heterocyclic Chemistry ever larger and more complex systems with increased efficiency. Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 60 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

The need for cleaner, environmentally benign, and more sustainable donating ability of the ynamide nitrogen strongly polarizes the triple chemical practices also poses new challenges and requires new ways of bond, which allows for exceptionally high levels of reactivity and carrying out chemical synthesis. Hence, in addition to the development regio- and/or stereoselectivities. This reactivity is yet tempered by of new reactions, reagents, and catalysts, novel ways to assemble the electron-withdrawing group, which provides enhanced stability molecules in a more sustainable manner are presently an important when compared to the highly sensitive ynamines,4,5 and can also act factor to consider. as an efficient directing group, chiral auxiliary, or can even participate The chemistry of ynamides clearly falls into this category: they in the reaction (Figure 1). These characteristics, coupled with recent display an exceptionally fine balance of stability and reactivity, offer breakthroughs in their synthesis,6–16 have allowed for the increased unique and multiple opportunities for the inclusion of nitrogen-based application of ynamides in synthesis and for their involvement in new functionalities into organic molecules,1 and have recently emerged as and remarkably efficient sequences that are difficult to accomplish especially useful and versatile building blocks.2,3 Indeed, the electron- otherwise. This short review highlights the remarkable reactivity of these building blocks through selected and representative examples of new (a) Overview of the Reactivity of Ynamides reactions that have been designed on the basis of the unique behavior of 17 stabilization triple bond polarization ynamides and other electron-deficient ynamines, which are now also directing group strong differentiation commonly referred to as “ynamides”. chiral auxiliary of the two sp carbons potential internal precursors of highly reactive site reactive intermediates 2. Ynamides as User-Friendly Precursors 2.1. Of Otherwise Inaccessible Keteniminium Ions Two characteristic features that are crucial to the reactivity of ynamides EWG EWG R1 N • N are the activation of the triple bond and its strong polarization due to 2 1 2 R R R the conjugation of the amine group with the alkyne. Recent studies have ynamides shown that ynamides react with electrophiles between 103 to 105 times 18 (b) Most Common Classes of Ynamides (Electron-Deficient Ynamines) faster than regular alkynes (Figure 2). The resulting keteniminium ions O can participate in a number of transformations including the trapping O O O R3 of these highly reactive and otherwise inaccessible intermediates with R3 OR3 NR3R4 R1 N R1 N R1 N R1 N R2 nucleophiles. Many electrophile–nucleophile combinations have been R2 R2 R2 O employed to access diverse building blocks from ynamides; selected O O OR3 OR3 EWG O O 1 examples will be presented in the next paragraphs. S P P R N 1 3 4 4 5 R N R R1 N OR R1 N NR R N R2 2 R R2 R2 EWG 2.1.1. By Protonation R2 R2 R2 1 O O Brönsted acids have been widely utilized for the generation of R N R3 S S R3 NR3R4 R1 N R1 N R1 N keteniminium ions by protonation of ynamides. Depending on the type of acid used and the presence or absence of an additional nucleophile, Figure 1. “Ynamides”: Structural Types and Chemical Properties. the conjugated base can act as a nucleophile that traps the keteniminium ion. This yields polysubstituted enamides in a highly stereocontrolled manner, which are valuable building blocks in chemical synthesis and (a) Nucleophilicity Parameters N of Ynamides medicinal chemistry. The regio- and stereoselective hydrohalogenation N of ynamides is certainly the most representative example of this type of 19–21 ON 12 reactivity (Scheme 1, Part (a)). Me Ts Provided that a strong acid is utilized for the protonation of 11 ON Et N ynamides—which allows the generation of keteniminium ions Ph Bn 7 Ts associated with weakly nucleophilic counterions—additional 6 N nucleophiles such as arenes can be used to trap the intermediate NHAc Bn keteniminium intermolecularly (Scheme 1, Part (b))22 or even 5 OMe Ts intramolecularly (which would correspond to a keteniminium version of 4 Ph N the Pictet–Spengler cyclization), as exemplified in Scheme 1, Part (c).23 Bn 3 The generation of highly reactive keteniminium ions by protonation of O ynamides, followed by their reaction with a nucleophile, has also been 2 Ph N employed to generate intermediate species which can then undergo H 1 a [3,3]-sigmatropic rearrangement. Indeed, the protonation of chiral Ph 0 H Ph ynamides with para-nitrobenzenesulfonic acid, followed by addition of allylic alcohols and subsequent rearrangement of the intermediate allyl (b) Ynamides as Precursors of Keteniminium Ions vinyl ethers, yields highly substituted homoallylic amides with good EWG E E 1 EWG R N • N 2 levels of diastereoselectivity, which illustrates well the use of chiral 2 1 R R R ynamides in asymmetric synthesis (Scheme 1, Part (d)).24 In a similar Figure 2. (a) Comparison of the Nucleophilicity Parameters N of Ynamides fashion, the use of arylsulfoxides instead of allylic alcohols provides with Those of Related p-Nucleophiles (Mayr Reactivity Scale). (b) Generation an efficient (excellent yields within minutes at room temperature) entry of Keteniminium Ions from Ynamides. (Ref. 18) into a-arylamides, when catalytic amounts of triflic acid are utilized (Scheme 1, Part (e)).25 61 VOL. 48, NO. 3 • 2015

2.1.2. By Reaction with Electrophiles CuIII complexes—generated by (formal) oxidative addition of Pd0 or The use of other electrophilic reagents for the generation of keteniminium CuI precursors to aryl triflates and diaryliodonium salts respectively— ions from ynamides is much more challenging since they need to react readily with ynamides, as exemplified by the palladium-catalyzed selectively react with the triple bond and not the electron-withdrawing arylative cyclization of hydroxy-ynamides (Scheme 3, Part (a))32 and group, which would result in a loss of the stabilization of the ynamides. the copper-catalyzed carbocyclization of homobenzylic ynamides In addition, the counteranion needs to be a weak nucleophile to avoid (Scheme 3, Part (b)).33 trapping the keteniminium ion, which can be circumvented by using In addition to these electrophilic palladium and copper complexes, an internal nucleophile. The halo-26 and carbocyclizations27 of ortho- the metal that is probably the most suitable for the activation of the triple anisole-substituted ynamides yielding highly substituted benzofurans bond of ynamides is gold. Indeed, gold complexes have been shown (Scheme 2, Part (a)) are representative of this strategy. Other examples over the years to be excellent electrophilic catalysts for the activation of that nicely illustrate both the synthetic potential of ynamides and the alkynes, and their use with ynamides, which are more electron-rich than exceptional reactivity of keteniminium ions generated from these regular alkynes, is therefore ideal. In addition, the polarization of the building blocks include the reaction of ynamides with aldehydes, triple bond ensures high levels of chemoselectivity, as demonstrated by ketones, or enones in the presence of a Lewis acid catalyst. Indeed, the gold-catalyzed hydroamination of ynamides which proceeds readily 34 upon activation with boron trifluoride or a combination of CuCl2 and at room temperature (Scheme 3, Part (c)).

AgSbF6, the activated carbonyl derivatives are electrophilic enough Perhaps more importantly than its use for the regioselective addition to react with ynamides to give intermediate keteniminium ions which of nucleophiles to ynamides, this exceptional affinity between gold can be converted into conjugated amides (Scheme 2, Part (b))28,29 or complexes and ynamides has found a number of applications in the design into formal [2 + 2] cycloaddition products (Scheme 2, Part (c)).30 An of new reactions based on the interception of the auro-keteniminium enantioselective version of the last reaction, now commonly known as ions with certain nucleophiles, giving rise to intermediates that can be the Ficini cycloaddition, has been reported recently.31 further elaborated into carbenoid species. Representative examples of such transformations will be discussed in the next section. 2.1.3. By Reaction with Electrophilic Metal Complexes Besides strong acids and other electrophiles; such as halonium ions, EWG carbocations, or activated carbonyl derivatives; electrophilic metal Y N R2 I2 or NBS or complexes can also be employed for the generation of transient NCS Y + EWG EWG (a) • N 2 N keteniminium ions that can then be trapped by a nucleophile, generally or ZnBr2/Ar2CHOH R O R2 CH Cl , rt 1 II 2 2 OMe R in an intramolecular fashion. In this respect, electrophilic Pd and OMe R1 Y = I, Br, Cl, Ar CH R1 2 54–97%

3 4 – R R C=O R3 O O EWG MgX 3 2 EWG BF3•OEt2 4 + EWG R N EWG wet CH2Cl2 + EWG H X (b) 1 R 2 1 – R N • N 2 R (a) R 2 o 1 R N • N X R CH2Cl2, –78 C R 4 1 2 or (i) TMSX, R2 1 R R R R1 R N EWG CH2Cl2; (ii) H2O 2 14–92% or HF•Py R O X = I, Br, Cl, F E:Z 3 4 – 15–99%; = 66:34 to >99:1 R R O O CuCl2 (20 mol %) 3 3 R4 R R4 EWG AgSbF6 (60 mol %) R EWG X (c) 1 R N • N 2 2 o 1 R EWG Tf2NH (10 mol %) H R CH2Cl2, 0 C R + 1 EWG 1 R N (b) R N + 4 Å MS o 1 2 R2 X CH2Cl2, –35 C R N EWG R 2 R 21–75% X = O, NR 29–94% Z:E = 10:1 to >25:1 Scheme 2. Remarkably Reactive Keteniminium Ions by Reaction of n-Bu Ynamides with Electrophiles. (Ref. 26–30) O O

O Tf2NH (5 mol %) N (c) n-Bu N O o CH2Cl2, 30 C ArOTf EWG Bn Ar N R2 84% Pd2(dba)3 (2.5 mol %) EWG XantPhos (5 mol %) 2 O O O R O (a) R1 N O 2 2 1 2 Ph R R K2CO3 (2.0 equiv) R O HO R 1 N O (d) 1 R OH DMA, 80 oC R N N 1 51–94% 4-O2NC6H4SO3H Ph R O Ph Ph (10–20 mol %) O Ts o Ph Ph PhMe, 70–125 C Ph IOTf, DTPB Ph N Bn 60–86% 2 Ts CuCl (2.5 mol %) O (b) N o Bn DCE, 50 C S 2 O O O R O Ph R3 2 + OR N 1 68% S R 1 O N O (e) R N O 2 ArNH2 1 R S ArN EWG TfOH (10 mol %) R EWG (Ph3P)AuNTf2 (1 mol %) 3 1 CH2Cl2, rt R (c) R N N R2 CH2Cl2, rt R1 R2 R3 37–96% 89–98% Scheme 1. Keteniminium Ions by Protonation of Ynamides and Their Scheme 3. Cyclization and Functionalization of Ynamides via Keteniminium Subsequent Transformations. (Ref. 19–25) Ions Promoted by Electrophilic Metal Complexes. (Ref. 32–34) Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 62 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

2.2. Of a-Oxo- or a-Imidocarbenes and Carbenoids external oxidant (LG+-O–) a to the nitrogen atom, while the presence of a-Oxocarbenes and carbenoids are versatile intermediates that are a leaving group in the oxidant enables the generation of the carbenoid. extensively employed for the development of a wide array of useful transformations. They are, however, typically generated by metal- 2.2.1. a-Oxocarbenes by Gold-Catalyzed Reaction of promoted decomposition of the corresponding potentially hazardous Ynamides with Mild Oxidants diazo derivatives, which is clearly a severe limitation in terms of This strategy turned out to be especially fruitful by allowing the efficiency, flexibility, and safety (Scheme 4, Part (a)). In an attempt to generation of a-oxocarbenoids under remarkably mild conditions (gold address this drawback, recent studies have shown that such carbenoids complexes as catalysts and pyridine N-oxides as oxidants) from readily can be readily generated by metal-promoted activation of ynamides available starting materials. In addition, these transformations proceed in the presence of a suitable mild oxidant. This approach provides an with impressive levels of chemoselectivity, since the ynamide can be interesting and user-friendly alternative to the use of diazo derivatives selectively activated in the presence of a wide number of potentially (Scheme 4, Part (b)). oxidizable functional groups such as alkenes, alkynes, or even sulfides. Both the inherent reactivity of ynamides and the nature of the Once generated, the a-oxocarbenoids can participate in a number oxidant are critical in this approach, since the polarization of the of inter- and intramolecular transformations. Representative examples triple bond of the ynamide ensures a total regiocontrol of the p-acidic involving an intermolecular reaction of a-oxocarbenoids include activation by the metal, and therefore the addition of the nucleophilic their trapping with allylic sulfides followed by a [2,3]-sigmatropic rearrangement, which leads to highly functionalized a-thioamides (Scheme 5, Part (a)),35 or their reaction with indoles (Scheme 5, Part (b)).36 Alternatively, the presence of an internal functional group which O O EWG 1 [M] 1 [M] R R R1 N R R can react with the intermediate carbenoid can be utilized to access (a) mild oxidant R2 N2 [M] (b) various cyclic and polycyclic molecules. For example, intramolecular 2 [M] cyclopropanation of an appended alkene provides a straightforward R = NR (EWG) + – LG –O entry to fused cyclopropyl-lactams (Scheme 5, Part (c)),37 while a 5-exo-

O LG+ dig cyclization involving an internal styryl group yields functionalized O R1 + EWG indenes (Scheme 5, Part (d)).38 In all cases, the advantage of using N R1 EWG N [M]– R2 ynamides rather than the corresponding diazo compounds as precursors LG – 2 [M] R of carbenoids is quite obvious. Following these studies, the use of 39 40 Scheme 4. Ynamides as Precursors of a-Oxocarbenoids. other oxidants such as sulfoxides or nitrones and the use of rhodium complexes instead of gold catalysts have been reported.41

2.2.2. a-Imidocarbenes by Gold-Catalyzed Reaction of 1 (1.3 equiv) Ynamides with Pyridine N-Aminidines and Isoxazoles (ArO)3PAuNTf2 O EWG (5 mol %) In all examples mentioned in the previous paragraphs, the pyridine 1 EWG (a) R N + SR3 N 2 3 1 N-oxide derivatives only transfer their oxygen atom to generate R CH2Cl2, rt R S R 2 1.2 equiv R the oxocarbenoid that is then trapped by a nucleophile, either Ar = 2,4-(t-Bu)2C6H3 53–77% intramolecularly or intermolecularly. An extension of this strategy O 2 (2 equiv) relies on the use of nitrogen nucleophiles possessing both a leaving R1 EWG IPrAuNTf2 N EWG group and a nucleophilic site, masked or not, enabling the generation (5 mol %) 2 (b) R1 N + R3 R a o R3 of electrophilic gold -imidocarbenes that can react with the internal R2 N H2O, 80 C 4 N nucleophile. The gold-catalyzed, formal [3 + 2] cycloaddition between R 4 1.5 equiv R ynamides and pyridine N-aminidines is a remarkable application of 70–97% 3 (2 equiv) this reactivity: Reaction of the ynamides with dichloro(pyridine- O IMesAuCl/AgBF4 1 carboxylato)gold triggers the addition of the pyridine N-aminidine EWG (4 mol %) R 1 2 EWG (c) R N R 3 N ylide to the ynamide. This is followed by cleavage of the pyridine MsOH (1.2 equiv) R 4 3 DCE, rt R N-aminidine N–N bond—generating the key a-imidocarbene—and R R2 4 R 26–99% cyclization involving the N-acyl group to yield highly substituted oxazoles (Scheme 6, Part (a)).42 Similarly, isoxazoles can be employed EWG 4 (1.2 equiv) O N in place of the pyridine N-aminidine ylide to give 2-aminopyrroles that JohnPhosAuCl/AgNTf2 2 43 1 R result from a formal [3 + 2] cycloaddition (Scheme 6, Part (b)). R EWG (5 mol %) (d) N R1 R3 As evidenced by all the examples described up to this point, ynamides 2 DCE, rt R have evolved as remarkably useful building blocks which act as efficient 12–92% R3 precursors of highly reactive intermediates such as keteniminium ions or carbenoids that can hardly be accessed from other reagents. This + + + + exceptional reactivity, which has ultimately led to the design of original N CO2Me N Br N N O– O– O– O– Me reactions, is mostly based on the electron-rich nature of the ynamides 1 2 3 4 and the polarization of the alkyne. Another facet of their reactivity that has been explored recently is based on their anionic chemistry and, here Scheme 5. Gold a-Oxocarbenoids from Ynamides and Their Subsequent too, ynamides act as unique building blocks, notably as substrates for Inter- and Intramolecular Reactions. (Ref. 35–38) carbometallation reactions. These reactions, and the impressive input of ynamides in this chemistry, will be presented in the next section. 63 VOL. 48, NO. 3 • 2015

3. Carbometallation of Ynamides: New Paradigms in 3.2. Intramolecular Carbometallation: New Perspectives in Asymmetric Synthesis and Heterocyclic Chemistry Heterocyclic Chemistry The carbometallation of ynamides is certainly the most straightforward The unique reactivity of ynamides towards organometallic reagents way to generate, with high levels of regio- and stereoselectivities, has also been exploited for the design of new syntheses in heterocyclic metallated enamides. Except in the case where the metal employed is chemistry based on intramolecular carbometallation reactions. In this palladium, the presence of the electron-withdrawing group (EWG)— context, the capacity of the electron-withdrawing group to control which is also an excellent coordinating group—usually overcomes the the regioselectivity of an intramolecular carbolithiation has been polarization of the triple bond (the two effects acting in opposite ways), used to prepare highly functionalized 1,4-dihydropyridines from and controls the regioselectivity of the carbometallation. This results N-allylynamides by a totally selective deprotonation and 6-endo-dig in the selective formation of a-metallated enamides rather than their cyclization sequence (Scheme 8, Part (a)).50 b-metallated isomers, regardless of the inter- or intramolecular nature Other heterocycles that can be readily prepared by intramolecular of the reaction. carbometallation of ynamides include functionalized indoles—easily

3.1. Intermolecular Carbometallation: Easy Access to Metallated Enamides and Beyond (a) Cis Carbometallation [Rh(cod)(MeCN)2]BF4 H Various organometallic reagents have been employed for the EWG (8 mol %) 3 1 3 R EWG carbometallation of ynamides in the presence or absence of a R N + R B(OH)2 N R2 THF:H2O (20:1) 1 2 44,45 R R 2 equiv µw, 90 oC catalyst. For example, the carbocupration and rhodium-catalyzed 25–89% carbozincation46 of these building blocks afford straightforward rr = 6:1 to >19:1 entries to a-metallated enamides, which can be trapped by an array of (b) Trans Carbometallation with Switch in Regioselectivity 3 electrophiles, with total control of both the regio- and stereoselectivities. Pd(OAc)2 (5 mol %) R EWG P(3-Tol)3 (10 mol %) 1 1 3 R EWG The carbometallation of ynamides with organoboron reagents is a good R N + R B(OH)2 N 2 N , EtOH, 70 oC illustration of the switch of regioselectivity that can be achieved by R 1.5 equiv 2 H R2 70–92% the proper choice of the catalytic system. Indeed, while the use of a E:Z = 83:17 to 92:8 b rhodium catalyst provides the -functionalized enamides resulting from (c) Application in Asymmetric Synthesis a cis carbometallation that places the metal next to the nitrogen atom 1. Me2CuLi•LiBr•SMe2 47 O o (Scheme 7, Part (a)), switching to palladium catalysts reverses both (1.2 equiv), Et2O, –40 C OH O O t o 48 O 2. -BuO2H (1.2 equiv), –80 C the regio- and stereoselectivity of the reaction (Scheme 7, Part (b)). R N Ar N o O Besides providing one of the most efficient entries to multisubstituted 3. ArCHO (1.2 equiv), –80 C RMe + enamides, the carbometallation of ynamides has had a dramatic Bn 4. H3O Bn 45–62% impact in asymmetric synthesis. One of the most striking examples is dr = 90:2:5:3 to 95:2:2:1 the carbocupration of chiral ynamides and oxidation of the resulting vinylcopper species. This sequence, the success of which is clearly Scheme 7. Intermolecular Carbometallation of Ynamides, Highlighting based on the unique reactivity of ynamides, enables the generation of Control of the Regioselectivity and Remarkable Application in Asymmetric stereodefined trisubstituted enolates—compounds that are especially Synthesis. (Ref. 47–49) challenging to generate otherwise—which are then trapped with aldehydes to yield aldol adducts possessing all-carbon quaternary Boc stereocenters (Scheme 7, Part (c)).49 1. s-BuLi (1.2 equiv) Boc TMEDA (1.1 equiv) N (a) R1 N R2 o THF, –78 C R1 R2 R3 2. NH4Cl(aq) R3 78–95%

EWG O N EWG (A) or (B) N Cl 2 Au O R3 (b) R1 N E R Cl + 3 E (0.9 equiv) EWG R (5 mol %) 1 1 O N Br R (a) R N + 2 N o R R2 O N + PhMe, 90 C 34–93% R1 N EWG 1.5 equiv t o R2 (A) (i) -BuLi (1.5 equiv), Et2O, –78 C; (ii) CuCN•2LiCl (1.0 equiv), –78 oC to rt. (B) (i) i-PrMgCl•LiCl (1.1 equiv), THF, –20 to 0 oC; (ii) 68–98% CuCN•2LiCl (0.3–1.0 equiv), rt to 50 oC.

R3 4 3 R 4 R4 R R (ArO)3PAuNTf2 (HO)2B EWG (5 mol %) 1 NH (1.5 equiv) (b) R N + 3 N O 1 2 R o R Ts R O DCE, 80 C Pd(PPh3)4 (5 mol %) R1 N EWG R3 Ts Cs2CO3 (1.5 equiv) N 2.0 equiv t 2 1 2 Ar = 2,4-( -Bu)2C6H3 R (c) R N R o 4 n DME, 85 C R n 58–96% 2 R 55–87% Br n = 1–3 dr = 1:1 to 3:1

Scheme 6. Gold-Catalyzed, Formal [3 + 2] Cycloaddition of Ynamides via Scheme 8. Synthesis of Heterocycles by Intramolecular Carbometallation of a-Imidocarbenoids. (Ref. 42,43) Ynamides. (Ref. 50–53) Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 64 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

obtained by carbocupration of readily available N-arylynamides (Scheme 8, Part (b))51,52—or their tetrahydro derivatives. Higher ring systems R1 N can be accessed from bromoenynamides by a palladium-catalyzed R2 cyclization–cross-coupling–electrocyclization sequence (Scheme 8, R3 Part (c)).53 R1 R5 (i) or (ii) TMS N • N 2 R3 5 R 1 R 4. Ynamides as Precursors of Metallated Ketenimines 2 R 1 = TMS 3 R4 R (i), (iii) R (i), (iii) R R4 • N If organometallic reagents and palladium catalysts can be utilized 40–72% – 2 58–99% + R (ii) M R (i), (iv) to generate metallated enamides from ynamides, as discussed in the alkanenitriles 3 4 1 ketenimines R R = TMS previous paragraphs, they can also be employed to generate metallated R2 R1 O R2 R4 ketenimines in situ, another useful class of reactive intermediates that 3 Ar N R3 R H are quite challenging to prepare despite their interesting reactivity. N The first strategy to generate these metallated ketenimines involves 17–33% 45–62% alkenenitriles conjugated amides either the addition of an organolithium to ynimines or the deprotonation of the latter with a strong base. The metallated ketenimines can then (i) R4Li, THF, –78 oC. (ii) KHMDS, THF, –78 oC. (iii) R5X, –78 oC to rt. (iv) ArCHO, –78 oC to rt. be trapped with electrophiles, which provides a highly divergent and efficient entry to various building blocks, including highly substituted alkanenitriles, alkenenitriles, ketenimines, and conjugated amides Scheme 9. Generation and Reactivity of Metallated Ketenimines from (Scheme 9).54 Ynimines. (Ref. 54) The second strategy for the generation of metallated ketenimines is based on the palladium-catalyzed oxidative addition to the C–N bond of N-allylynamides. The products resulting from this oxidative addition are in equilibrium with the palladated ketenimine, which can EWG then proceed down a number of reaction pathways including reductive 1 N R elimination and reaction with amines yielding homoallyl amidines,55 (i) (ii) or an aza-Rautenstrauch rearrangement affording cyclopentenimines56 EWG EWG (Scheme 10). The reductive elimination represents a straightforward N N R1 EWG R1 and efficient entry to ketenimines, while the intermediate palladated NHR2 • N II R1 [Pd ] ketenimines have found various elegant applications in the synthesis of 57,58 52 to ≥95% 34 to ≥95% complex heterocyclic systems. homoallyl amidines cyclopentenimines 5. Ynamides as Radical Acceptors 2 o (i) Pd(PPh3)4 (5 mol %), K2CO3 (1.0 equiv), R NH2 (3.0 equiv), THF, 65 C Ynamides are also excellent radical acceptors and their use in free o (ii) Pd(PPh3)4 (5 mol %), PhMe, 70 C radical reactions provides many opportunities for the synthesis of nitrogen-containing molecules. There are still only few examples of intermolecular addition of radical intermediates to ynamides, the Scheme 10. Generation and Reactivity of Palladated Ketenimines from most notable being the addition of the electrophilic thiyl radicals. One N‑Allylynamides. (Ref. 55,56) equivalent of thiol in tert-butyl alcohol in the presence of AIBN as the radical initiator provides within 10 minutes the corresponding Z b-thioenamide—a moiety that is found in various natural products—as the main product. Employing an excess of thiol and longer reaction R2SH (1 equiv) EWG 59 2 times affords mainly the E isomer (Scheme 11, Parts (a) and (b)). EWG AIBN (0.5 equiv) R SN R1 (a) N The beneficial use of ynamides as radical acceptors is even more t o R1 -BuOH, 85 C 33–76% evident in the intramolecular counterparts, since they afford efficient E:Z = 1:2.9 to 1:11 10 min and original entries to nitrogen heterocycles of various sizes. The size R2SH (4 equiv) of the heterocyclic ring is controlled simply by the length of the tether 2 EWG AIBN (1 or 2 equiv) R S 60,61 (b) N between the radical center and the ynamide (Scheme 11, Part (c)). t o EWG R1 -BuOH, 85 C N 2.5–6 h R1 6. Ynamides in Cycloaddition Reactions: Diversity- 68–97% E:Z = 8.4:1 to 33:1 Oriented Syntheses of Heterocycles The main problem of cycloadditions involving alkynes is that they O F3C O (n-Bu)3SnH (2 equiv) often yield mixtures of regioisomers due to a poor differentiation of CF3 AIBN (0.5 equiv) TMS N the two sp carbon atoms of the triple bond. This issue can be easily (c) TMS N n PhH, reflux overcome by using ynamides since the inherent polarization of the n triple bond ensures that high levels of regioselectivity are typically n = 1–3 Br 29–78% reached. Another clear advantage of ynamides in cycloaddition reactions lies in the intramolecular variants, which lead to the direct assembly of a wide range of heterocyclic scaffolds. These reactions are Scheme 11. Ynamides as Excellent Radical Acceptors. (Ref. 59–61) efficiently catalyzed by various metals, and representative examples are covered in this section. 65 VOL. 48, NO. 3 • 2015

6.1. [2 + 2] Cycloadditions 3 The most notable example of a formal [2 + 2] cycloaddition involving MeCN, CH2Cl2, R 3 O 4 EWG R THF, or Et2O–DME R ynamides is the Ficini cycloaddition, which is actually a stepwise (a) R1 N + O • o o 2 R4 0 C to 40 C process involving the generation of an intermediate keteniminium R R1 N EWG ion followed by ring closure as described in Section 2.1.2 (Scheme R2 2, Part (c)). [2 + 2] cycloadditions with ynamides, which efficiently 65–94% yield aminocyclobutenes, also include their highly regioselective R3 R3 62 3 3 thermal reaction with ketenes (Scheme 12, Part (a)). This variant R R Cp*RuCl(cod) was recently extended to the use of ynesulfoximines,63 iodoynamides,64 EWG (5–10 mol %) X (b) R1 N + X 65 o and vinylketenes, and is now a robust method for the synthesis of R2 THF, 25–65 C R1 N EWG 3-aminocyclobutenones. Other examples of [2 + 2] cycloadditions with X = CH2, O, NBoc R2 ynamides are the Ru- or Rh-catalyzed reactions with bicyclic alkenes 25–97% (Scheme 12, Part (b))66 and nitrostyrenes.67 Scheme 12. [2 + 2] Cycloadditions with Ynamides. (Ref. 62,66) 6.2. [3 + 2] Dipolar Cycloadditions While most alkynes typically afford mixtures of regioisomers in RN3 (1.0 equiv) dipolar [3 + 2] cycloaddition reactions, cycloadditions of ynamides Cu(OAc) (20 mol %) N 2 R N N with dipoles usually proceed with high levels of regioselectivity, and Bn Na ascorbate (0.4 equiv) (a) H N t Bn can therefore be employed for the preparation of an array of amino- Ts -BuOH–CHCl3 N substituted carbocycles and heterocycles (Scheme 13).68–71 In addition, H2O, rt Ts 3 38–96% terminal ynamides are also remarkably efficient reaction partners for R N3 (1.2 equiv) Cp*Ru(PPh3)2Cl N 3 2 R the copper-catalyzed Kinugasa reaction, an iconic route to b‑lactams R (2.5 mol %) N N (b) R1 N 2 in which the first step involves a [3 + 2] cycloaddition with a nitrone. o R EWG PhMe, rt to 80 C R1 N The use of an ynamide in this reaction offers two main advantages: it EWG can introduce a nitrogen atom on the final b‑lactam, or it can control 65–95% the stereochemistry of the two stereocenters formed by starting from R2ClC=NOH 2 N 1 R O 72 R CuSO •5H O (10 mol %) chiral ynamides. (c) 4 2 H N R1 EWG K2CO3, Na ascorbate N t 6.3. [4 + 2] Cycloadditions -BuOH, H2O, rt EWG 22–86% The intramolecular [4 + 2] cycloadditions of ynamides can be a H straightforward entry to various nitrogen heterocycles, and can be +– N EtO2C N R EtO2CCH=N=N (d) conducted either in the presence of a cationic rhodium catalyst from H N R diene-ynamides (Scheme 14, Part (a)),73 or thermally from enyne- EWG PhMe, 110 oC N EWG containing ynamides (Scheme 14, Part (b)).74,75 43–52% 2 An interesting extension—which increases the range of heterocyclic R CO2Me 2 3 R CO2Me systems that can be conveniently synthesized from ynamides using a R CO2Me 3 Me (0.5 equiv) R CO2Me [4 + 2] cycloaddition strategy—was recently reported, and is based on (e) 1 N R Me a hexadehydro-Diels–Alder reaction of diyne-ynamides. This reaction, Ts Sc(OTf)3 (10 mol %) R1 N CH2Cl2 (anhyd), rt which can be performed either thermally76 or in the presence of Ts catalytic amounts of silver triflate (Scheme 14, Part (c)),77 generates an 53 to >99% intermediate aryne which can then be trapped by various nucleophiles Scheme 13. Formal, [3 + 2] Dipolar Cycloadditions with Ynamides. (Ref. 68–71) to generate highly functionalized indolines. In addition to their remarkable [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions, ynamides have been elegantly utilized in [2 + 2 + x] reactions, EWG R EWG [RhCl(PPh3)3] (5 mol %) providing entries to other molecular architectures. Here again, the R N AgSbF6 (5 mol %) N (a) success and the high levels of selectivity of these processes lie in most PhMe (anhyd) cases in the exceptional reactivity of ynamides. These reactions will be DCE, 20 oC 70–89% described in the following paragraphs. EWG R1 EWG R1 N BHT (1 or 3 equiv) R3 N 6.4. [2 + 2 + 1] Pauson–Khand Cycloadditions (b) R3 PhMe, 110–210 oC 2 [2 + 2 + 1] reactions of ynamides are mostly associated with the Pauson– R2 R Khand reaction. As a gross simplification, the use of ynamides in this 40–76% venerable reaction can be beneficial mostly in two cases: either in an Ts Ar–H Ts 1 intermolecular reaction in which the ynamide is utilized to introduce an R N AgOTf (0–10 mol %) Ar N 78 (c) 2 o exocyclic amine (Scheme 15, Part (a)), or in intramolecular processes R 90 C R1 in which the nitrogen is incorporated into one of the rings formed during R2 the cycloaddition. This latter case results in the diastereoselective 52–65% formation of cyclopentapyrrol-5-one derivatives (Scheme 15, Part (b)).79 In both cases, the reaction conditions are based on Schreiber’s Scheme 14. [4 + 2] Cycloadditions with Ynamides. (Ref. 73,74,77) protocol and rely on the use of [Co2(CO)8] and trimethylamine N-oxide. Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 66 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

6.5. [2 + 2 + 2] Cycloadditions The metal-catalyzed [2 + 2 + 2] cycloaddition of ynamides with alkynes Co2(CO)8 (1.1 equiv) O 2 Me3NO•2H2O (6–9 equiv) EWG and/or nitriles provides original entries to polysubstituted anilines, EWG R or NMO (6 equiv) R2 N aminopyridines, and aminopyrimidines. These reactions have been (a) N + R R R1 THF or CH2Cl2, MeOH extensively studied over the past decade and, in most cases, at least two –30 to 40 oC R1 6–10 equiv 41–98% reactants are tethered to ensure high levels of selectivity. Representative examples include the rhodium-catalyzed reaction of yne-ynamides with alkynes yielding polysubstituted carbazoles (Scheme 16, Part (a)),80 EWG EWG Co2(CO)8 (1.1 equiv) the enantioselective cyclization of ynamides with diynes leading to N Me3NO or NMO (6 equiv) N axially chiral anilides (Scheme 16, Part (b)),81 and the cobalt-catalyzed (b) CO2Me O CO2Me THF, CH2Cl2, rt cyclotrimerization of yne-ynamides with nitriles affording bicyclic H 82 35–69% 3‑aminopyridines (Scheme 16, Part (c)). NMO = N-methylmorpholine N-oxide de >95 to 97% While monomolecular versions of these reactions where all reactants are tethered together—which leads to the formation of Scheme 15. Pauson–Khand Reactions with Ynamides. (Ref. 78,79) one additional cycle—have also been reported, the corresponding trimolecular processes, in which serious issues with selectivity often arise, are still rare. One isolated example of such cyclotrimerization was reported in 2014, and is based on the gold-catalyzed, formal Ts Ts 4 1 R [RhCl(PPh3)3] R [2 + 2 + 2] cycloaddition of an ynamide with two equivalents of a nitrile R1 N N (3–5 mol %) 4 83 (a) + R (Scheme 16, Part (d)). 4-Aminopyrimidines, which are commonly PhMe, rt R3 R2 5 2 R 5 found in many bioactive molecules, are formed in high yields and with R R 3 5–6 equiv R 68–98% remarkable efficiency. The selectivity of this reaction was attributed to the electron-rich nature of the ynamide triple bond, which can be [Rh(cod)2]BF4 (10 mol %) selectively activated by the gold catalyst. TMS Bz R R (S)-xylyl-BINAP Bz R N (10 mol %) Bn (b) TMS N + 7. Cycloisomerization of Ynamides: Rapid Approaches to CH2Cl2, rt Bn R 1.0 equiv X Diverse Nitrogen Heterocycles X 15–79% 1.0 equiv 79–97% ee Heterocyclic scaffolds that are at the core structures of various natural and/or biologically relevant molecules can be accessed by R1 cycloisomerization of ynamides possessing other reactive moieties Ts CpCo(CO)(dmfu) Ts 1 N N R (10 mol %) N N such as an alkene or an allene. The cycloisomerization of homoallylic (c) n + n o 2 ynesulfonamides and their higher homologues is quite representative H R2 PhMe, 110 C R n = 1–3 1.5 equiv dmfu = dimethyl fumarate 36–100% of the advances recently made in this area, and showcases the dramatic effect that both the metal catalyst and the substitution pattern of the EWG 1 2 starting ynamide can have on the outcome of the reaction. Indeed, [Ph3PAuNTf2] R N R EWG N (5 mol %) upon reaction with a catalytic amount of PtCl2, a 1,6-enynamide (d) 1 3 R N + 2 R N 84 2 o R R3 DCE, 28 or 75 C N produced a vinyl-substituted dihydropyrrole (Scheme 17, Part (a)), 3 4.0 equiv R a compound which can also be obtained from the same enynamide 45–92% using a ring-closing metathesis reaction.85 Under the exact same conditions, a 1,7-enynamide exhibited a different behavior and Scheme 16. [2 + 2 + 2] Cyclotrimerizations with Ynamides. (Ref. 80–83) led to the selective formation of a strained 2‑azabicyclo[4.2.0]oct- 1(6)-ene (Scheme 17, Part (b)).84 A skeletal rearrangement of the 1,6‑enynamide to an aminoethylcyclobutanone was promoted by a 86 Ts Ts gold catalyst (Scheme 17, Part (c)). The presence of a propargylic N PtCl2 (5 mol %) PtCl2 (5 mol %) N (a) (b) alcohol in the starting enynamide had a dramatic influence on the PhMe, 80 oC PhMe, 80 oC cycloisomerization reaction pathway, which led to the formation n = 1, R = H n = 2, R = H 98% 34% of a fused cyclopropylpyrrolidine (Scheme 17, Part (d)).86 The Ts O O combination of a 1,6-enynamide and a palladium(II) catalyst resulted AuCl (5 mol %) R N AuCl (5 mol %) Ts (c) n H N (d) in a cycloisomerized product possessing both a five-membered-ring CH Cl , rt CH Cl , rt NH 2 2 2 2 87 n = 1, R = H n = 1, R = CH2OH heterocyclic core and an exocyclic diene (Scheme 17, Part (e)). The Ts 40–50% 40% ruthenium-catalyzed cycloisomerization of the 1,7‑analogue afforded 87 n-Hex Ts a 2-azabicyclo[4.2.0]oct-1(8)-ene (Scheme 17, Part (f)). Since Pd(OAc) , bbeda [Cp*Ru(cod)Cl] 2 n-Hex (2.5 mol %) (5 mol %) N the outcome of these cycloisomerizations is now well understood, (e) N Ts (f) PhMe, 60 oC MeCN, 80 oC they clearly provide excellent opportunities for diversity-oriented 81% n = 1, R = n-Hex n = 2, R = n-Hex 90% synthesis in heterocyclic chemistry. Z:E = 97:3 bbeda = N,N'-bis(benzylidene)ethylenediamine If enynamides clearly are ideal substrates in cycloisomerization reactions, the cycloisomerizations are not restricted to this subclass of ynamides. Other functional groups on the starting ynamides can be Scheme 17. Examples of Cycloisomerizations of Enynamides. (Ref. 84,86,87) employed to access other types of cycloisomerization products. The silver-catalyzed cycloisomerization of allenynamides (Scheme 18, 67 VOL. 48, NO. 3 • 2015

Part (a))88 and the gold-catalyzed transformation of furanyl-ynamides robust and reliable methods can be employed.94 Figure 3 showcases (Scheme 18, Part (b))89 are two examples of this approach. a few of the natural and/or biologically relevant molecules that are The reliability of the ynamide reactions described up till now, and readily obtained using an ynamide in a key step of the synthesis.23,95–104 the possibility of predicting the regioselectivity in most of them, have Importantly, ynamides are not only utilized for the introduction of a recently led to the design of more complex processes in which more than nitrogen atom, they can also be employed to access key intermediates in one cycle are formed in a single operation. These efficient polycyclization a synthetic sequence or to control the regio- and/or stereoselectivity of reactions from ynamides will now be briefly discussed. a reaction. In this latter case, the nitrogen atom of the starting ynamides can be sacrificial and does not necessarily have to be incorporated into 8. Polycyclizations of Ynamides: Straightforward Routes to the target molecule. Complex Nitrogen Heterocycles Most reactions involving ynamides can be taken one step further by 10. Conclusion and Outlook carefully tuning the nature and position of substituents to promote The unique reactivity of ynamides has made them into powerful cascade processes, leading to the selective formation of complex reagents for chemical synthesis. They are convenient precursors of heterocyclic frameworks. In most cases, the activation of the ynamide highly reactive intermediates such as keteniminium ions or carbenoid triggers the polycyclization, and its presence typically controls the species. They offer general, reliable, and often straightforward routes to regioselectivity of the process. many molecules ranging from simple building blocks and heterocycles The first cationic cascade involving ynamides was reported in 2014, to complex polycyclic structures and natural products. Chiral ynamides and is based on a keteniminium ion initiated cascade polycyclization offer new opportunities in asymmetric synthesis, and various long- of N-benzyl- or N-allyl-ortho-tolylynamides. Upon reaction with excess triflic acid or catalytic amounts of bistriflimide, these ynamides are transformed into the corresponding highly reactive keteniminium 1 Ts R Ts 1 ions. This induces a [1,5]-shift of hydrogen, an electrocyclization, R N AgOTf (10 mol %) N and a Friedel–Crafts-type reaction (Scheme 19, Part (a)).90 Polycyclic (a) R2 CH2Cl2, rt nitrogen heterocycles possessing up to three stereocenters and seven • R3 R2 fused cycles can be easily obtained in a single operation: the comparison R3 53–99% of this route with previously reported ones for accessing similar Me molecular architectures in more than ten steps clearly demonstrates the Ts OH Ts R2 N AuCl3 (3–5 mol %) N advantages of using ynamides. 1 1 (b) R2 O R R The gold-catalyzed activation of ynamides can also be employed to n MeCN, rt, or n o promote polycyclization reactions via gold carbenoids. Treatment of CDCl3, 0 C n = 1,2 17–88% an N-styryl ortho-azidophenyl ynamide with a cationic gold catalyst at room temperature generates the key carbenoid (by activation Scheme 18. Other Cycloisomerizations of Ynamides. (Ref. 88,89) of the ynamide, nucleophilic attack of the azide, and extrusion of dinitrogen), which is trapped by the appended alkene to generate a cyclopropanindoloquinoline with remarkable efficiency (Scheme 19, Part (b)).91 4 TfOH(xs) R o H EWG The vinylpalladium complex formed after an initial oxidative EWG CH Cl , 0 C 2 2 N addition–carbopalladation sequence of a bromoenynamide (see (a) N R2 R1 R2 or Tf2NH 1 (20 mol %) R Scheme 8, Part (c)) can also be utilized in a cascade polycyclization H CH Cl , rt by further intramolecular carbopalladation of a second alkyne group in R4 2 2 3 3 26–95% R the starting acyclic precursor (Scheme 19, Part (c)).92 Reactive aryne R

N3 intermediates—which are conveniently generated by a silver-catalyzed (4-CF3C6H4)3PAuCl Ts N Ts (5 mol %) N formal [4 + 2] cycloaddition from diyne-ynamides as discussed (b) N AgOTf (5 mol %) in Section 6.3 (see Scheme 14, Part (c))—can also trigger a second DCE, rt 3 R1 cyclization by insertion into a C(sp )–H bond, affording multisubstituted 1 H R R2 93 2 cyclopentaindoles in excellent yields (Scheme 19, Part (d)). R 74–94%

Y Ts Pd(PPh ) Ts 3 4 Y 9. Ynamides as Building Blocks for the Synthesis of N (5–10 mol %) N Natural Products: Enabling New and Original Bond (c) Br R n Et3N (6 equiv) R n o Disconnections MeCN, 80 C 49–90% Previous sections demonstrated the tremendous advances recently R1 reported in the chemistry of ynamides. Capitalizing on the remarkable R2 Ts 3 R2 N reactivity of ynamides, a number of robust, reliable, and efficient R Ts R1 R4 N AgOTf (10 mol %) processes have been developed over the past 15 or so years. Simple (d) R5 R3 R6 PhMe, 90 oC building blocks, heterocycles, reactive intermediates, as well as complex R4 R5 molecular architectures can efficiently be obtained from various 62–96% R6 ynamides. The attractiveness and reliability of some of these processes, which often also provide shorter and more efficient synthetic routes as compared to other approaches, have been exploited in the synthesis Scheme 19. Cascade Polycyclizations of Ynamides. (Ref. 90–93) of various natural products, an area of chemistry where only the most Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 68 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

standing synthetic challenges—such as the generation of stereodefined substituted alkynes” or “N-alkynylamides”, but their reactivity is in trisubstituted enolates,49 the catalytic and stereocontrolled generation of fact a subtle combination of both functional groups, and the ynamide dienolates,105 and the preparation of an azacyclohexyne derivative106— moiety should in general be considered as a whole. Ynamides have have been, at least partially, solved by taking advantage of ynamide been used recently in coordination chemistry, where they behave as chemistry. In most cases, they do not only react as “nitrogen- stable equivalents of unstable oxazol-4-ylidenes.107 Ynamides are also starting to find applications in medicinal chemistry. In spite of the widespread studies of ynamides, many aspects of their reactivity remain largely unexplored. Further understanding and quantification of the exact influence of the electron-withdrawing groups and other N N Me N N substituents on the reactivity of ynamides will facilitate the choice of N N H N a class of ynamides for a given application. In any case, this field is H N N NH2 H HO N anticipated to continue to rapidly expand and mature, and interesting 10-desbromo- 11-desbromo- aplidiopsamine A95 breakthroughs can be expected. arborescidine A23 arborescidine C23 keteniminium–arene keteniminium Pictet– keteniminium Pictet– cyclization Spengler cyclization Spengler cyclization 11. Acknowledgments The authors gratefully acknowledge financial support from the N Université Libre de Bruxelles, the Université de Versailles Saint- OH O O N H Quentin-en-Yvelines, the ANR (project VINFLUSUP ANR-11- Me N 9 Ar O JS07-003-01), and the FNRS (Incentive Grant for Scientific Research tanikolide96 n° F.4530.13). C. T. and M. L. thank Les Fonds pour la Formation à la 97 Rh-catalyzed carbozincation sarizotan (Ar = 4-FC6H4) Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.) for graduate (followed by dihydroxylation of intramolecular carbolithiation–oxidation the resulting enamide) fellowships. We also thank all of our co-workers and collaborators, who have contributed to some of the chemistry described in this review.

O OH N OCONH2 12. References OH HO OH O H (1) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. N L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560. MeO O NH O HO R N OH (2) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. MeO O HO (3) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; lennoxamine98 pauciflorol F99 FR900482 (R = CHO) Hsung, R. P. Chem. Rev. 2010, 110, 5064. 65 carbopalladation– Pd-catalyzed FR66979 (R = CH2OH) Suzuki–Miyaura hydrostannylation–acylation [2 + 2] cycloaddition with (4) Ficini, J. Tetrahedron 1976, 32, 1449. vinylketene–electrocyclic ring (5) Zificsak,C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. opening–6-π electrocyclization Tetrahedron 2001, 57, 7575. (6) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17. (7) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; AcN Me R OH N Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. Me N H (8) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011. Me O N N (9) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. H n-C H H 5 11 Me Lett. 2004, 6, 1151. OH (10) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. 100 102 antiostatin A1 herbindole perlolyrine Rh-catalyzed [2 + 2 + 2] A (R = Me), B (R = Et) Ru-catalyzed [2 + 2 + 2] (11) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. cyclotrimerization C (R = CH=CHEt)101 cyclotrimerization 2009, 48, 4381. Rh-catalyzed [2 + 2 + 2] (12) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000. cyclotrimerization (13) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272. (14) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996. HO CO2Me Me H H (15) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756. O N O H H O n (16) Mansfield, S. J.; Campbell, C. D.; Jones, M. W.; Anderson, E. A. Chem. N O -Bu HO N Commun. 2015, 51, 3316. NH N N NH2 H N O (17) Lu, T.; Hsung, R. P. ARKIVOC 2014, i, 127. H O 103 (18) Laub, H. A.; Evano, G.; Mayr, H. Angew. Chem., Int. Ed. 2014, 53, 4968. isoperlolyrine102 lavendamycin methyl ester geralcin A104 Ru-catalyzed [2 + 2 + 2] Ru-catalyzed [2 + 2 + 2] hydrogenation (19) Mulder , J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.; Frederick, cyclotrimerization cyclotrimerization M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547. (20) Sato, A. H.; Ohashi, K.; Iwasawa, T. Tetrahedron Lett. 2013, 54, 1309. Figure 3. Natural and/or Biologically Relevant Molecules Synthesized from (21) Metayer , B.; Compain, G.; Jouvin, K.; Martin-Mingot, A.; Bachmann, Ynamides (Bonds and Atoms Shown in Red Were Initially Part of the Starting C.; Marrot, J.; Evano, G.; Thibaudeau, S. J. Org. Chem. 2015, 80, 3397. Ynamides. In the Case Where the Nitrogen Atom of the Ynamide Was Not (22) Zhang, Y. Tetrahedron 2006, 62, 3917. Incorporated in the Final Product, Its Initial Position Is Indicated by a Grey, (23) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Italic, and Upper-Case N. Key Bond Disconnections Involving the Ynamides Org. Lett. 2005, 7, 1047. Are Shown in Blue). (24) Mulder , J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383. 69 VOL. 48, NO. 3 • 2015

(25) Peng, B.; Huang, X.; Xie, L.-G.; Maulide, N. Angew. Chem., Int. Ed. Courillon, C. Tetrahedron Lett. 2011, 52, 2876. 2014, 53, 8718. (62) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. (26) Kong, Y.; Yu, L.; Fu, L.; Cao, J.; Lai, G.; Cui, Y.; Hu, Z.; Wang, G. Tetrahedron 2006, 62, 3815. Synthesis 2013, 45, 1975. (63) Pirwerdjan, R.; Priebbenow, D. L.; Becker, P.; Lamers, P.; Bolm, C. Org. (27) Kong, Y.; Jiang, K.; Cao, J.; Fu, L.; Yu, L.; Lai, G.; Cui, Y.; Hu, Z.; Wang, Lett. 2013, 15, 5397. G. Org. Lett. 2013, 15, 422. (64) Wang, Y.-P.; Danheiser, R. L. Tetrahedron Lett. 2011, 52, 2111. (28) You, L.; Al-Rashid, Z. F.; Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; (65) Mak, X. Y.; Crombie, A. L.; Danheiser, R. L. J. Org. Chem. 2011, 76, 1852. Hsung, R. P. Synlett 2007, 1656. (66) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823. (29) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. (67) Smith, D. L.; Chidipudi, S. R.; Goundry, W. R.; Lam, H. W. Org. Lett. (30) Li, H.; Hsung, R. P.; DeKorver, K. A.; Wie, Y. Org. Lett. 2010, 12, 3780. 2012, 14, 4934. (31) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072. (68) IJsselstijn, M.; Cintrat, J.-C. Tetrahedron 2006, 62, 3837. (32) Fujino, D.; Yorimitsu, H.; Osuka, A. J. Am. Chem. Soc. 2014, 136, 6255. (69) Oppilliart, S.; Mousseau, G.; Zhang, L.; Jia, G.; Thuéry, P.; Rousseau, B.; (33) Walkinshaw, A. J.; Xu, W.; Suero, M. G.; Gaunt, M. J. J. Am. Chem. Soc. Cintrat, J.-C. Tetrahedron 2007, 63, 8094. 2013, 135, 12532. (70) Li, H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung, R. P. (34) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottländler, M.; Heterocycles 2007, 74, 553. Skrydstrup, T. Org. Lett. 2009, 11, 4208. (71) Mackay, W. D.; Fistikci, M.; Carris, R. M.; Johnson, J. S. Org. Lett. 2014, (35) Dos Santos, M.; Davies, P. W. Chem. Commun. 2014, 50, 6001. 16, 1626. (36) Li, L.; Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W. Chem. Sci. (72) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa, R. 2014, 5, 4057. Org. Lett. 2008, 10, 3477. (37) Wang, K.-B.; Ran, R.-Q.; Xiu, S.-D.; Li, C.-Y. Org. Lett. 2013, 15, 2374. (73) Witulski, B.; Lumtscher, J.; Bergsträβer, U. Synlett 2003, 708. (38) Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. (74) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. Angew. Chem., Int. Ed. 2011, 50, 6911. (75) Martínez-Esperón, M. F.; Rodríguez, D.; Castedo, L.; Saá, C. Org Lett. (39) Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011, 13, 1556. 2005, 7, 2213. (40) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad, S. N.; (76) Karmakar, R.; Yun, S. Y.; Wang, K.-P.; Lee, D. Org. Lett. 2014, 16, 6. Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372. (77) Lee, N.-K.; Yun, S. Y.; Mamidipalli, P.; Salzman, R. M.; Lee, D.; Zhou, (41) Liu, R.; Winston-McPherson, G. N.; Yang, Z.-Y.; Zhou, X.; Song, W.; T.; Xia, Y. J. Am. Chem. Soc. 2014, 136, 4363. Guzei, I. A.; Xu, X.; Tang, W. J. Am. Chem. Soc. 2013, 135, 8201. (78) Witulski, B.; Göβmann, M. Synlett 2000, 1793. (42) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem., Int. Ed. (79) Witulski, B.; Göβmann, M. Chem. Commun. 1999, 1879. 2011, 50, 8931. (80) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281. (43) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, (81) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, X.; Ye, L.-W. Chem. Sci. 2015, 6, 1265. 4586. (44) Minko, Y.; Pasco, M.; Chechik, H.; Marek, I. Beilstein J. Org. Chem. (82) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; 2013, 9, 526. Aubert, C.; Gandon, V. Org. Lett. 2011, 13, 2030. (45) Basheer, A.; Marek, I. Beilstein J. Org. Chem. 2010, 6 (77); DOI: (83) Karad, S. N.; Liu, R.-S. Angew. Chem., Int. Ed. 2014, 53, 9072. 10.3762/bjoc.6.77. (84) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria, M. (46) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802. Org. Lett. 2004, 6, 1509. (47) Gourdet, B.; Smith, D. L.; Lam, H. W. Tetrahedron 2010, 66, 6026. (85) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. (48) Yang, Y.; Wang, L.; Zhang, J.; Jin, Y.; Zhu, G. Chem. Commun. 2014, 50, 2347. (86) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726. (49) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature (87) W alker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.; Anderson, E. A. 2012, 490, 522. Angew. Chem., Int. Ed. 2013, 52, 9139. (50) Gati, W.; Rammah, M. M.; Rammah, M. B.; Couty, F.; Evano, G. J. Am. (88) Garcia, P.; Harrak, Y.; Diab, L.; Cordier, P.; Ollivier, C.; Gandon, V.; Chem. Soc. 2012, 134, 9078. Malacria, M.; Fensterbank, L.; Aubert, C. Org. Lett. 2011, 13, 2952. (51) Gati, W.; Couty, F.; Boubaker, T.; Rammah, M. M.; Rammah, M. B.; (89) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.; Evano, G. Org. Lett. 2013, 15, 3122. Oeser, T. Chem.—Eur. J. 2008, 14, 6672. (52) Frischmuth, A.; Knochel, P. Angew. Chem., Int. Ed. 2013, 52, 10084. (90) Theunissen, C.; Métayer, B.; Henry, N.; Compain, G.; Marrot, J.; Martin- (53) Greenaway, R. L.; Campbell, C. D.; Holton, O. T.; Russell, C. A.; Mingot, A.; Thibaudeau, S.; Evano, G. J. Am. Chem. Soc. 2014, 136, 12528. Anderson, E. A. Chem.—Eur. J. 2011, 17, 14366. (91) Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2014, 16, 3138. (54) Laouiti, A.; Couty, F.; Marrot, J.; Boubaker, T.; Rammah, M. M.; (92) Campbell, C. D.; Greenaway, R. L.; Holton, O. T.; Chapman, H. A.; Rammah, M. B.; Evano, G. Org. Lett. 2014, 16, 2252. Anderson, E. A. Chem. Commun. 2014, 50, 5187. (55) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.; Huang, J.; (93) Y un, S. Y.; Wang, K.-P.; Lee, N.-K.; Mamidipalli, P.; Lee, D. J. Am. Hsung, R. P. Org. Lett. 2009, 11, 899. Chem. Soc. 2013, 135, 4668. (56) Wang, X.-N.; Winston-McPherson, G. N.; Walton, M. C.; Zhang, Y.; (94) Evano, G.; Theunissen, C.; Pradal, A. Nat. Prod. Rep. 2013, 30, 1467. Hsung, R. P.; DeKorver, K. A. J. Org. Chem. 2013, 78, 6233. (95) Y amaoka, Y.; Yoshida, T.; Shinozaki, M.; Yamada, K.; Takasu, K. J. Org. (57) Huang, P.; Chen, Z.; Yang, Q.; Peng, Y. Org. Lett. 2012, 14, 2790. Chem. 2015, 80, 957. (58) DeKorver, K. A.; Hsung, R. P.; Song, W.-Z.; Wang, X.-N.; Walton, M. C. (96) Gourdet, B.; Lam, H. W. Angew. Chem., Int. Ed. 2010, 49, 8733. Org. Lett. 2012, 14, 3214. (97) Gati, W.; Rammah, M. M.; Rammah, M. B.; Evano, G. Beilstein J. Org. (59) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L. Org. Chem. 2012, 8, 2214. Lett. 2010, 12, 2650. (98) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2006, 47, 767. (60) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095. (99) Kerr , D. J.; Miletic, M.; Manchala, N.; White, J. M.; Flynn, B. L. Org. (61) Balieu, S.; Toutah, K.; Carro, L.; Chamoreau, L.-M.; Rousselière, H.; Lett. 2013, 15, 4118. Ynamides: Powerful and Versatile Reagents for Chemical Synthesis 70 Gwilherm Evano,* Cédric Theunissen, and Morgan Lecomte

(100) Alayrac, C.; Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464. and his research group focuses on copper catalysis and the synthesis of (101) Saito, N.; Ichimaru, T.; Sato, Y. Org. Lett. 2012, 14, 1914. heteroatom-substituted alkynes and natural products. (102) Dassonneville, B.; Witulski, B.; Detert, H. Eur. J. Org. Chem. 2011, Cédric Theunissen was born in Brussels in 1989 and studied 2836. chemistry at the Université Libre de Bruxelles. In 2012, he obtained (103) Nissen, F.; Detert, H. Eur. J. Org. Chem. 2011, 2845. his master’s degree under the supervision of Prof. Cécile Moucheron. (104) Beveridge, R. E. Ph.D. Thesis, University of Toronto, ON, November His master’s thesis research focused on the synthesis of new ruthenium 2014. complexes designed to interact with DNA in an anticancer approach. (105) Jadhav, A. M.; Pagar, V. V.; Huple, D. B.; Liu, R.-S. Angew. Chem., Int. He then obtained an F.R.I.A. fellowship, and started his Ph.D. level Ed. 2015, 54, 3812. research in the group of Prof. Gwilherm Evano. This research focuses (106) Tlais, S. F.; Danheiser, R. L. J. Am. Chem. Soc. 2014, 136, 15489. on the development of new copper-mediated synthetic transformations (107) Ung, G.; Mendoza-Espinosa, D.; Bertrand, G. Chem. Commun. 2012, 48, 7088. and on the study of the reactivity of ynamides. Morgan Lecomte was born in 1988 in Arlon, Belgium, and studied About the Authors chemistry at the Université Libre de Bruxelles. In 2012, he joined the Gwilherm Evano studied chemistry at the École Normale Supérieure in Laboratory of Organic Chemistry as a master’s student, working under Paris, and received his Ph.D. degree from the Université Pierre et Marie the supervision of Professors Ivan Jabin and Gwilherm Evano on the Curie in 2002 under the supervision of Professors François Couty and use of hetero-substituted alkynes for the selective functionalization Claude Agami. After postdoctoral studies with Prof. James S. Panek of calixarenes. He obtained an F.R.I.A. fellowship in 2013 to work at Boston University, he joined the Centre National de la Recherche toward his Ph.D. degree in the group of Prof. Gwilherm Evano, where Scientifique (CNRS) at the Université de Versailles in 2004. He then he focuses on the study of the reactivity of ynamides and other hetero- moved to the Université Libre de Bruxelles as associate professor in substituted alkynes and on the development of new reactions and 2012. He has coauthored over 80 publications and 10 book chapters, processes from these building blocks.

PRODUCT HIGHLIGHT

Bobbitt’s Salt Safe and Reliable Oxidation Reagent

Bobbitt’s Salt (745537) is a recyclable stoichiometric oxidant capable of converting alcohols into the corresponding carbonyl species (aldehyde, carboxylic acid, ketone, O etc.) under mild conditions. Recent developments by Prof. Nicholas Leadbeater and HN CH Prof. James Bobbitt have expanded the scope of this highly effective reagent. 3 - Benefits BF4 Environmentally benign oxidant void of chromium H3C CH3 • N H3C CH3 • Easily handled and stored at room temperature O • Highly selective and functional-group tolerant Bobbitt's745537 Salt • Applications beyond alcohol oxidation, including C–H bond activation 745537

Reference: For more information or to order this product, visit Leadbeater, N. E.; Bobbitt, J. M. Aldrichimica Acta Aldrich.com/bobbitts-salt 2014, 47, 65.

84031-c 71 VOL. 48, NO. 3 • 2015 Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products

Dr. R. B. Nasir Baig Dr. M. N. Nadagouda Dr. R. S. Varma

R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma* Sustainable Technology Division National Risk Management Research Laboratory U.S. Environmental Protection Agency, MS 443 Cincinnati, OH 45268, USA Email: [email protected]

Keywords. regiospecific; stereospecific; ring-opening; unnatural 5.1. (+)-Saxitoxin amino acid; chiral building block; natural product; cyclic sulfamidate. 5.2. (S)-(+)- and (R)-(–)-Dapoxetines 5.3. Antifungal Glucan Synthase Inhibitors Abstract. This article reviews the emergence of cyclic sulfamidates 5.4. (+)-Tetraponerine T-3 as versatile intermediates for the synthesis of unnatural amino acids, 5.5. Pyrrolidinones and Piperidinones chalcogen peptides, modified sugars, drugs and drug candidates, and 5.6. Thiomorpholinones and Piperazinones important natural products. 5.7. 1,4-Benzoxazines, Benzothiazines, and Quinoxalines 5.8. Carbohydrates Outline 5.9. Unnatural Amino Acids 1. Introduction 6. Conclusion 2. Structural Analysis and Reactivity of Cyclic Sulfamidates 7. Acknowledgments 3. Synthesis of Cyclic Sulfamidates 8. References 3.1. From 1,2-Amino Alcohols 3.2. From Diols and Epoxides Using the Burgess Reagent 1. Introduction 3.3. Via Metal-Catalyzed C–H Amination Cyclic sulfamidates are synthetic intermediates that are readily 3.4. Through Cascade Metathesis accessible from both amino acids and amino alcohols, and form a 3.5. By Hydrogenation and Transfer Hydrogenation versatile set of electrophiles that can undergo facile and regiospecific 3.6. By Arylation of Cyclic N-Sulfamidate Alkylketimines nucleophilic substitution at the O-bearing carbon center. Synthetically, 3.7. Through Aminohydroxylation of Sulfamate Esters five- and six-membered-ring sulfamidates are equivalent to aziridines 4. Ring-Opening Reactions of Cyclic Sulfamidates and azetidines. However, cyclic sulfamidates have several advantages 4.1. Heteroatom Nucleophiles over aziridines and azetidines in terms of reactivity and selectivity 4.1.1. Sulfur Nucleophiles (Figure 1, Part (a)). The present article reviews exciting recent advances 4.1.2. Nitrogen Nucleophiles in organic synthesis enabled by cyclic sulfamidates. 4.1.3. Oxygen Nucleophiles 4.1.4. Phosphorus Nucleophiles 2. Structural Analysis and Reactivity of Cyclic Sulfamidates 4.1.5. Selenium Nucleophiles Cyclic sulfites (1,3,2-dioxathiolane 2-oxides, 1) and cyclic sulfates 4.1.6. Halogen Nucleophiles (1,3,2-dioxathiolane 2,2-dioxides, 2) are the sulfite and sulfate esters of 4.2. Carbon Nucleophiles diols, and are the synthetic equivalents of epoxides. Cyclic sulfamidites 4.2.1. Hard Carbon Nucleophiles (1,2,3-oxathiazole 2-oxide, 3) and sulfamidates (1,2,3-oxathiazole 4.2.2. Soft (Stabilized) Carbon Nucleophiles 2,2-dioxides, 4) are the corresponding sulfite and sulfate esters of amino 5. Applications of Cyclic Sulfamidates in Heterocycle and Natural alcohols, and are the synthetic equivalents of aziridines (Figure 1, Part Product Synthesis (b)). Although compound classes 1–4 have been known for a long time, Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products 72 R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma*

their general application in synthesis became possible only after the 3. Synthesis of Cyclic Sulfamidates development of efficient methods for their synthesis. Derivatives3 and McCombie and Parkes discovered cyclic sulfamidites by accident in 4 can be better alternatives to aziridines, since they are not encumbered 1912.1 However, they remained little used until 1969, when Deyrup with regioselectivity issues; sulfamidates (4), an activated form of and Moyer’s unsuccessful attempt to prepare aziridines from 1,3-amino sulfamidites (3), have a great potential as nitrogenous electrophiles for alcohols led to the formation of cyclic sulfamidites instead.2 While this regioselective ring-opening under mild conditions. became thereafter a practical method for their synthesis,3 the sluggish reactivity of sulfamidites, and the need to employ drastic conditions in their reactions, prevented their wider use in organic synthesis.4 The sluggish reactivity of sulfamidites has been overcome by converting them into the corresponding sulfamidates.5–7 (a) Nu– 3 O O – O O R Nu 2 R3 3 3 S R R S N R N O N N O 3.1. From 1,2-Amino Alcohols 2 1 2 1 R 221 R 1 1 1 R R Cyclic sulfamidates can be prepared directly in one step from 1,2-amino R2 R – R Nu – 8 Nu alcohols by treatment with SO2Cl2 or SO2Im2. This method, however, aziridines 1,2-sulfamidates azetidines 1,3-sulfamidates found limited success in the case of conformationally constrained 9 (b) 1,2-amino alcohols, such as 2-aminophenols and prolinols, and – – O O O O O O cannot be utilized as a general preparative method due to competitive + + S S R3 S R3 S O O O O N O N O aziridination and/or azitidation. Consequently, a two-step approach that 10 n n n n mirrors the synthesis of cyclic sulfates has been developed, whereby R2 R1 R2 R1 R2 R1 R2 R1 treatment of 1,2- or 1,3-amino alcohols with SOCl2 leads to the efficient sulfites (1) sulfates (2) sulfamidites (3) sulfamidates (4) formation of cyclic 1,2- and 1,3-sulfamidites2 that are then oxidized to the sulfamidates (Scheme 1, Part (a)).11 Figure 1. (a) Preferred Sites of Nucleophilic Attack in Aziridines, Azetidines, and Cyclic Sulfamidates. (b) Cyclic Sulfite and Sulfate Derivatives of Diols and 3.2. From Diols and Epoxides Using the Burgess Reagent Amino Alcohols. The Burgess reagent is prepared from chlorosulfonyl isocyanate and triethylamine in a simple, two-step procedure.12 Nicolaou and co- workers have shown that this reagent can be utilized to synthesize cyclic sulfamidates from diols via a double alcohol activation mechanism,13 and applied this approach to the synthesis of functionalized chiral 14 (a) From 1,2-Amino Alcohols (Ref. 11) sulfamidates from allyl epoxides (Scheme 1, Part (b)). This method – O O O allows the direct conversion of diols (1,2-diols, 1,3-diols, etc.) into + R S S the corresponding sulfamidates, with the regioselectivity being RHN OH N O R N O SOCl2 [O] dependent on the stereoelectronic preferences of the diols. Hudlicky 2 R1 R2 Base R1 R R1 R2 and co-workers have also demonstrated that cyclic sulfamidates can be 15 (b) Using the Burgess Reagent (Ref. 14) accessed from epoxides by treatment with the Burgess reagent.

O O S 3.3. Via Metal-Catalyzed C–H Amination Et N CO2Me O O 3 N O O 16 + – MeO C S Capitalizing on the discovery by Breslow and Gellman, Che and co- OH S 2 N O O (1.3 equiv) MeO2C N 1 – O R workers demonstrated that intermolecular nitrogen insertion into an THF–DCM (4:1) O R1 R HO R unactivated C–H bond is possible via Ru- or Mn-catalyzed nitrene reflux, 3 h or R1 R insertion.17 This strategy was applied to cyclic sulfamidates by using 81–87% O O MeO2C S N O the enantioselective intramolecular amidation of saturated C–H bonds 18 (Ref. 19) catalyzed by a Ru-porphyrin chiral complex. Du Bois and co-workers (c) Via Metal Catalyzed C–H Amination R HO R1 reported a similar protocol using a Rh-catalyzed reaction (Scheme O O O O 19 S Rh2(oct)4 (2 mol %) S 1, Part (c)). Che’s and Du Bois’s methods involved intramolecular H2N O HN O PhI(OAc)2 (1.1 equiv) cyclization of sulfamate ester wherein the cyclization results most of Ph CO2Et MgO (2.3 equiv) Ph CO2Et the time in the formation of six-membered-ring cyclic sulfamidates.20,21 o CH2Cl2, 40 C, 2 h 91%, syn:anti = 13:1 8 other examples: 60–90% Some sluggish substrates give five- or even seven-membered-ring 20 (d) Through Cascade Metathesis (Ref. 31) sulfamidates. This study led to the development of a modular method O 22 H2NSO3 O for the synthesis of sulfamidates from sulfamate esters. Cui and He S O HN have employed silver metal in combination with phenyliodonium 1. Rh2(esp)4 (2 mol %) 23 PhI(OAc)2 (1.1 equiv) acetate for the intramolecular cyclization of sulfamate esters. There

O CH2Cl2, rt, 0.5 h O have been other strategies utilizing Rh, Cu, and Au metal salts or 2. NaBH4, MeOH complexes for the formation of seven-membered-ring sulfamidates, esp = (α,α,α',α'-tetramethyl- 98% where the nitrogen is also a part of an aziridine ring system.24–25 1,3-benzenedipropionate) 8 other examples: 21–81% Although the metal-catalyzed synthesis of cyclic sulfamidates has been well established using C–H activation, the asymmetric variant has not been generalized. Che26 employed chiral manganese(III) Scheme 1. Syntheses of Cyclic Sulfamidates. Schiff-base complexes, while Müller27,28 attempted the use of rhodium chiral complexes as catalysts for the enantioselective synthesis of 73 VOL. 48, NO. 3 • 2015 cyclic sulfamidates. However, moderate asymmetric inductions were would result in racemization.3–5 The free thiol group is not a suitable observed in both cases. In contrast, Du Bois’s use of a chiral rhodium nucleophile for the opening of five-membered-ring sulfamidates carboxamidate complex29 and Blakey’s demonstration of cationic bearing an a-carbonyl group; in combination with a base it leads to the ruthenium(II)-pybox systems30 have provided a reasonable, practical formation of dehydro amino acids. Thioacetates, a stabilized form of synthesis of chiral cyclic sulfamidates. thiol nucleophiles, serve as masked thiols in reactions with sulfamidates to give amino thioacetate derivatives.41 Our group has demonstrated 3.4. Through Cascade Metathesis the usefulness of in situ generated dithiocarbamates, another type of Blakey and co-workers disclosed an unconventional method for stabilized sulfur nucleophile, in sulfamidate chemistry (Scheme 3, Part the synthesis of cyclic sulfamidates using a cascade metallonitrene– (b)).42 The addition of in situ generated dithiocarbamate anion to cyclic alkyne metathesis process.31 Their study was based on the hypothesis sulfamidates leads to stereo- and regioselective ring-opening to form that the metallonitrene species would react with an alkyne, leading to a zwitterionic intermediate; this would be followed by a metal shift that precipitates a cascade cyclization coupled with a concerted imine (Ref. 33) reduction. The method has been very useful for the synthesis of six- and (a) By Hydrogenation 31–32 seven-membered-ring sulfamidates (Scheme 1, Part (d)). O O H2 (600 psi) O O S Pd(CF3CO2) (2 mol %) S N O (S,S)-f-binaphane (2.4 mol %) HN O 3.5. By Hydrogenation and Transfer Hydrogenation R CF3CH2OH, rt, 12 h R Treatment of a-hydroxy ketones with sulfamoyl chloride (H2NSO2Cl) R = Me, t-Bu, n-Hex, XC6H4 (X = H, 94–99% affords the corresponding cyclic imines which can be hydrogenated 2-Me, 4-Me, 3-MeO, 4-F) 94–97% ee to sulfamidates. The asymmetric variant gives direct access to enantioenriched cyclic 1,2-sulfamidates as in the case of the Pd/ (b) By Arylation of Cyclic N-Sulfamidate Alkylketimines (Ref. 36) 33 binaphane one (Scheme 2, Part (a)). The reaction proceeds efficiently O O Ar O O and gives quantitative yields in almost all cases. Lee and co-workers, S B [Rh(OH)diene]2 S N O O O (3 mol %) HN O reported that RhCl(R,R)-TsDPEN]Cp* catalyzes an asymmetric + Me Me R transfer hydrogenation using formic acid and triethyl amine as the R Me Me MeOH (4 equiv) Ar dioxane, 80 oC, 48 h hydrogen source.34,35 2 equiv 20 examples 19–99% R = Me, n-Bu, n-Hex, i-Pr, Bn, Cy, BnO(CH ) 2 2 92–99% ee Ar = 1-Np, Ph, monosubstituted benzene 3.6. By Arylation of Cyclic N-Sulfamidate Alkylketimines Feng, Lin, and co-workers developed a new route for the enantioselective (c) Through Aminohydroxylation of Sulfamate Esters (Ref. 38) synthesis of sulfamidates by 1,2-arylation of cyclic N-sulfamidate O O O O K2OsO4•2H2O (4 mol %) S t S alkylketimines with arylboronate esters. A range of enantiomerically H2N O -BuOCl (1.0 equiv) HN O pure substituted cyclic sulfamidates have been prepared in 19–99% EtN(i-Pr)2 (5 mol %) HO yield by this method in the presence of a chiral rhodium–diene complex R R' NaOH (0.92 equiv) R R' n-PrOH–H2O as a catalyst (Scheme 2, Part (b)) These sulfamidates provide access 5 examples: 50–68% to biologically interesting and enantiomerically pure b-alkyl-b-aryl amino alcohols.36 Scheme 2. Additional Syntheses of Cyclic Sulfamidates.

3.7. Through Aminohydroxylation of Sulfamate Esters Inspired by the intramolecular aminohydroxylation of carbamates derived from allylic alcohols,37 Kenworthy and Taylor employed the O O S NCS Bn N O aminohydroxylation of sulfamate esters derived from homoallylic NH4SCN (2 equiv) (a) o HO3SN CO2t-Bu alcohols for the synthesis of six-membered-ring sulfamidates (Scheme t-BuO2C DMF, 20 C,12 h 2, Part (c)).38 Bn 91% 4. Ring-Opening Reactions of Cyclic Sulfamidates S – The main driving force in aziridine and azetidine chemistry comes O O NS S Cbz S R from the ring strain, which is lacking in five- and higher-membered- N O (1 equiv) (b) CO2Me ring nitrogen heterocycles. In contrast, the reactivity in sulfamidate DMF, rt, 8–24 h N S MeO2C R NHCbz ring-opening reactions is attributed to the activation of the C–O bond – – SO3 15 examples: 84–95% by the SO2 group, which makes them good electrophiles that can react = 1o or 2o acyclic or cyclic amine with a variety of heteroatom and carbon nucleophiles. Moreover, their N ability to undergo regioselective ring-opening reactions augments their O O 1. [BnNEt ] MoS (1.2 equiv) synthetic value. Bn S 3 2 4 NHBn N O MeCN, 28 oC, 0.5–18 h (c) R S S R R 2. HCl(aq), rt 4.1. Heteroatom Nucleophiles 3. NH4OH, 10 min NHBn 4.1.1. Sulfur Nucleophiles 8 examples: 70–95% The ring-opening of sulfamidates with ammonium thiocyanate gives 3-thiocyanate alanine derivatives (Scheme 3, Part (a)).39,40 Lubell and Scheme 3. Ring-Opening of Sulfamidates with Sulfur Nucleophiles. (Ref. 39,40,42,43) co-workers were able to confirm that the stereoselectivity of the reaction is not compatible with an elimination–addition mechanism which Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products 74 R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma*

the optically pure products in high yield (84–95%). Chandrasekaran instead of b-amino disulfides.44 This regio- and stereoselective ring- and co-workers have effected the ring-opening of sulfamidates using opening of sulfamidates provides an efficient, direct, and altenative

[BnEt3N]2MoS4, which acts as a sulfur-transfer reagent via disulfide route to conventional methods for the synthesis of b-amino thiols via bond formation. The reaction proceeds efficiently in acetonitrile to give the acid-catalyzed ring-opening of aziridines with hydrogen sulfide the N-alkyl-b-amino disulfides directly (Scheme 3, Part (c)).43 or with the sodium or potassium salt of thioacetic acid, followed by 45 Interestingly, [BnEt3N]2MoS4 exhibited anomalous behavior in the deprotection of masked thiols. Five-membered-ring sulfamidates give reaction with sulfamidates derived from diols by using the Burgess b-amino thiols, whereas the reaction of six-membered-ring sulfamidates reagent. Its reaction with sulfamidates under conditions similar to those forms g-amino thiols.44 shown in Scheme 3, Part (c), resulted in the formation of b-amino thiols 4.1.2. Nitrogen Nucleophiles The nucleophilic nitrogen can be that of a primary amine, secondary amine, azide, or even that of a heterocyclic system such as imidazole or O O related scaffold. Sodium azide reacts with cyclic sulfamidates to give S 1. PMBNH (1.5 equiv) 2 BnHN BnN O MeCN, rt, 7 h H the corresponding amino azide derivatives, with no apparent restriction (a) N 46 2. F B•OEt (4 equiv) MeO2C PMB on substrate structure and substituents. Primary and secondary amines MeO2C 3 2 n-PrSH (5 equiv) 63% react efficiently with cyclic sulfamidates to give the corresponding 5 CH Cl , rt, 1 h 2 2 diamine derivatives (Scheme 4, Part (a)).47 The ring-opening with a 1. 5, MeCN PMB o heterocyclic system nitrogen has been employed effectively to prepare peraza BnHN NHBn 60 C, 7 h N 48 macrocycles 2. F B•OEt (4 equiv) chiral 2,3-diaminopropanoate derivatives. CO Me CO Me 3 2 2 2 n-PrSH (5 equiv) 55% CH2Cl2, rt, 1 h 4.1.3. Oxygen Nucleophiles The ring-opening of sulfamidates has been unsuccessful with most O 1. NaNO2, DMF O o O 70 C, 27 h HO strong oxygen nucleophiles (e.g., sodium methoxide). The possible O NH N S 2. HOAc H (b) O hydrolysis of serine- or threonine-derived cyclic sulfamidates with N Ph NH 3. Amberlyst®-15 Ph NTs sodium bicarbonate in deuterated water (D O) has been disappointing,49 Ts 2 N MeOH, 0.5 h and the ring-opening of a-methylserine-derived sulfamidates gave a 70% 4. NH4OH, 0.33 h 40 inversion of configuration very poor yield of ring-opened products. The first successful ring- opening of sulfamidates was achieved with weakly basic oxygen nucleophiles, and was further exemplified using stabilized phenoxy Scheme 4. Ring-Opening of Cyclic Sulfamidates with (a) Nitrogen and (b) 50 Oxygen Nucleophiles. (Ref. 47,51) ions. Khanjin and Hesse utilized NaNO2 for the ring-opening of sulfamidates, which was followed by hydrolysis to give macrocyclic alcohols (Scheme 4, Part (b)).51

4.1.4. Phosphorus Nucleophiles O O The introduction of phosphorus has been very difficult due to its S OBocN Li sensitivity to the reaction conditions and substrate structure. Although (a) + P many N–P chiral ligands have been synthesized, severe problems have R1 R2 BH 3 52 1. THF, –60 oC, 1 h been encountered in terms of byproduct formation and purification. 2. rt, 24 h Chiral 1-isopropylamino-2-(diphenylphosphino)ethanes can be R1 = H, Me, Ph; R2 = H, Ph 3. H2SO4, 1 h synthesized through ring-opening of chiral, cyclic sulfamidates with 4. Na2CO3, NaCl, H2O 53,54 R1 R2 5. DABCO®, PhMe potassium diphenylphosphide (KPPh2). This method has been 90–95 oC, overnight extended to the synthesis of protic aminophosphines with multiple H2N P 6. TFA, CH2Cl2, rt chiral centers by the nucleophilic ring-opening of N-protected cyclic overnight 65–75% sulfamidates. The introduction of another chiral center into the 7. Na2CO3, NaCl, H2O aminophosphine backbone using nucleophilic phosphide—derived 1. KSeCN (2 equiv) from the reaction of butyllithium and the respective phosphine– O O acetone, reflux, 2 h borane—was a significant finding that was extended to the synthesis of S 2. [BnNEt3]2MoS4 NHBn OBnN (1.5 equiv) 53,54 Se Ph a wide range of multicenter phosphine ligands (Scheme 5, Part (a)). (b) Ph Se Bn MeCN, rt, 8 h 3. HCl(aq), rt, 12 h NHBn 4. NH4OH 23 other examples: 30–99% 4.1.5. Selenium Nucleophiles Chandrasekaran and co-workers reported the synthesis of chiral O O N-benzyl-b-aminodiselenides in moderate-to-good yields via a regio- S 1. (n-Bu)4NF, MeCN OBnN rt, 0.5 h FBnNH and steroselective ring-opening of sulfamidates with potassium (c) 55 Me 3. 20% H2SO4–Et2O (1:1) Me selenocyanates (Scheme 5, Part (b)). The reaction proceeds rt, 2 h 4. NaOH(aq) 77% through selenocyanate intermediates, which, on dimerization with tetrathiomolybdate, afford the N-benzyl-b-aminodiselenide products.

Scheme 5. Ring-Opening of Cyclic Sulfamidates with (a) Phosphorus, (b) 4.1.6. Halogen Nucleophiles Selenium, and (c) Halogen Nucleophiles. (Ref. 54–56) Among halogens, fluoride ion has been employed for the nucleophilic ring-opening of sulfamidates to afford, in the case of five-membered-ring 75 VOL. 48, NO. 3 • 2015

sulfamidates, b-amino fluorides. KF/CaF2 or ammonium fluorides have been used as sources of nucleophilic fluorines (Scheme 5, Part (c)).56 O O S 1. NCCH2Li CN 4.2. Carbon Nucleophiles OBnN –78 oC to rt, overnight BnHN (a) 4.2.1. Hard Carbon Nucleophiles Me 2. H2SO4(aq) Me The ring-opening of sulfamidates with aryllithium reagents (e.g., phenyl-, 73% 3,4-dimethoxyphenyl-, and 2-thienyllithium) has been reported.57 While O 58 O O the reaction of cyclic sulfamidates with alkyllithiums failed initially, 1. H2C(CO2Et)2, NaH S CO2Et the reaction of alaninol-derived sulfamidates with alkyllithiums such OMeN DMF, 100 oC, 14 h MeN (b) as di(n-butyl)lithium cuprate, lithiated acetonitrile, and lithiated Me Ph 2. HCl(aq) Me Ph 3. NaHCO3(aq) 1,3-dithiane afforded the corresponding amines (Scheme 6, Part (a)).59 60%

The same reaction with PhLi or n-BuLi gave a mixture of products, O O OO 1. cat (10 mol %) OO presumably due to competitive attack at the electrophilic C-5 and S S Cs2CO3 BocN O MeN Ot-Bu (1.5 equiv) MeN Ot-Bu centers. Similarly, the reaction of hard carbon nucleophiles (such as (c) + O xylene, 0 oC O alkyllithium, Grignard reagents, etc.) with serine- and threonine- NHBoc 16–120 h derived sulfamidates consistently led to mixtures of products due to 86%, 85% ee cat = cinchona-derived 2. HCl (1 M) 4 other examples: competitive attack at the reactive carbonyl group. phase-transfer catalyst 59–89%, 70–93% ee

4.2.2. Soft (Stabilized) Carbon Nucleophiles It is believed that the softening of carbon nucleophiles through Scheme 6. Ring-Opening of Cyclic Sulfamidates with (a) Hard Carbon conjugation or stabilization would result in increased selectivity. Nucleophiles and (b, c) Soft Carbon Nucleophiles. (Ref. 59,61,63) Cyanide ion is the most stable of carbon nucleophiles; it can react with any type of sulfamidates to give the corresponding aminonitrile derivatives.60 Cyclic sulfamidates react with most of the stabilized carbon nucleophiles (e.g. β-keto esters, diethyl malonates, aryl- 1. 2,4,6-Me3C6H2NHBoc NaH, DMF, TFA, DCM substituted enolates, and phosphonate-stabilized enolates) to give the 80%, 99% ee cyclized product in the presence of a proximate ester, ketone, or amine N 2. HC(OEt)3, HCO2H N NH BF , PhMe – + functional group (Scheme 6, Part (b)).61 O S O 4 4 BF4 N O 92% Mes Many natural products bearing aminoethylene and aminopropylene 6 7 scaffolds at a quaternary stereocenter are known in the literature.62 These Me aminoalkenes can be incorporated at quaternary centers through the N N Me enantioselective ring-opening of aziridines and azetidines. However, Cl Me t these electrophiles require activation at nitrogen, and, typically, a wide Ru 1. KO -Bu, hexane [(PCy3)2Cl2Ru=CHPh] range of activating groups need to be screened along with asymmetric Cl 82% i -PrO i induction. In contrast, the reaction of cyclic sulfamidates with tert- 2. 2-( -PrO)C6H4CH=CH2 DCM 8 butyl 1-methyl-2,6-dioxopiperidine-3-carboxylate in the presence 56% of a cinchona-derived phase-transfer catalyst readily gives the ring- opened product (Scheme 6, Part (c)). The variation in ring size and Scheme 7. Cyclic Sulfamidates for the Synthesis of Asymmetric Ligands of protecting group at the nitrogen atom in the sulfamidates does not alter Chiral Olefin-Metathesis Catalysts. (Ref. 64) the reaction outcome.63

5. Applications of Cyclic Sulfamidates in Heterocycle and Natural Product Synthesis MbsN O O MbsN Blechert and co-workers utilized cyclic sulfamidates for the synthesis S of asymmetric ligands that are incorporated into highly active, chiral H2N NO H2N NH OBn olefin-metathesis catalysts (Scheme 7).64,65 Cyclic sulfamidate 6 BnOH N3 o N3 was converted into chiral diamine 7, in high yield and with high MbsN MeCN, 75 C MbsN enantioselectivity, through a regioselective ring-opening with Boc- MeS N MeS N H H mesidine. Chiral diamine 7 was then elaborated into chiral ruthenium 75% catalyst 8 in two straightforward steps. + H2N H NH O 5.1. (+)-Saxitoxin HO N HO O NH2 Neurotoxic agents are important pharmacological scaffolds used for NNH

+ understanding protein function associated with the ionic mechanisms NH2 of electrical transmission in cells. The guanidinium toxins such as (+)-saxitoxin Mbs = p-methoxybenzenesulfonyl (+)-saxitoxin and (–)-tetrodotoxin are exemplary in this regard, and have been employed for the study of voltage-gated sodium channels along with their identification and characterization. The basic saxitoxin Scheme 8. Cyclic Sulfamidate Ring-Opening as a Key Step in the Synthesis of (+)-Saxitoxin. (Ref. 66) skeleton was assembled from cyclic sulfamidate, and converted into (+)-saxitoxin and its derivatives (Scheme 8).66 Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products 76 R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma*

5.2. (S)-(+)- and (R)-(–)-Dapoxetines (S)-(+)-Dapoxetine hydrochloride is a potent and selective serotonin O O O O Rh (R-nap) (2 mol %) reuptake inhibitor, and is used specifically for the treatment of S 2 4 S H2N O PhI=O (1.2 equiv) HN O premature ejaculation. It is obtained from racemic dapoxetine

Ph 4 Å MS, CH2Cl2 Ph by tartaric acid promoted chiral resolution, or from chiral amino rt, 2 h 85%, 91.7% ee alcohols through enzymatic synthesis. In contrast, Du Bois’s method,

employing Rh2(S-nap)4 or Rh2(R-nap)4, provides both enantiomers 1. MeI (2.1 equiv), K2CO3 (1.2 equiv) (n-Bu)4NI (cat), DMF, rt, 6 h of the cyclic 1,3-sulfamidate precursors, which are easily converted 81%, 92.0% ee 2. NaH (2.0 equiv), 1-NpOH (2.0 equiv) into (S)-(+)- and (R)-(–)-dapoxetines using a straightfoward reaction DMF, rt, 1 h; 84%, 91.2% ee sequence (Scheme 9).67 3. HCO2H (5.3 equiv), H2CO(aq) (5.3 equiv) reflux, 8 h; 75%, 91.8% ee

Me2N O(1-Np) 5.3. Antifungal Glucan Synthase Inhibitors Enfumafungin, isolated from a fermentation of a Hormonema Ph (S)-(+)-dapoxetine species, is capable of inhibiting fungal glucan synthase, and two R novel enfumafungin derivatives have been identified as potent ( )-(–)-dapoxetine was prepared in 79% yield 68 by using Rh2(S-Nap)4 and a similar reaction sequence glucan synthase inhibitors. The installation of the side chain was

accomplished by SN2 ring-opening of an N-tosylated aziridine by the in situ generated potassium alkoxide of the starting material.69 The Scheme 9. (S)-(+)- and (R)-(–)-Dapoxetines from Cyclic Sulfamidates. (Ref. 67) replacement of aziridine with its synthetic equivalent, a five-membered- ring sulfamidate, allows the direct incorporation of the side chain under milder condition (Scheme 10).70

5.4. (+)-Tetraponerine T-3 O O The tetraponerines constitute a family of alkaloids that pseudomyrmecine O OBn S Me MeN O Me Me ants of the genus Tetraponera deploy as paralyzing venoms in chemical Me Me warfare. Their challenging tricyclic skeleton and biological activities i-Pr H MeO 71 MeO Me (1.2 equiv) O make them attractive targets for total synthesis. Mann and co-workers O Me Me KOCMe Et (1.2 equiv) i O reported the synthesis of (+)-tetraponerine T-3 starting from chiral HO 2 -Pr H H PhMe, DMAc, rt, 24 h N Me Me Me SO3K (R)-piperidine ethanol and using sulfamidate as a key intermediate en enfumafungin derivative route to the strategically important diamine. The diamine was directly (2.711 kg, 4.573 mol) converted into (+)-tetraponerine T-3 in a one-pot hydroformylation and cyclization process (Scheme 11).71

glucan synthase inhibitors 5.5. Pyrrolidinones and Piperidinones The reactions of five- and six-membered-ring sulfamidates with enolates Scheme 10. Cyclic Sulfamidate Allows a Direct and Milder Incorporation of derived from malonate afford access to C–3 carboxylated lactams, such the Side Chain en Route to a Large-Scale Semisynthesis of Enfumafungin as pyrrolidinone and piperidinone derivatives, in excellent yields.61,72 It Derivatives. (Ref. 70) is important to note that the lactamization is dependent on the ring size: formation of six-membered rings is slower than that of five-membered rings. The reaction of cyclic sulfamidates with phosphonate-stabilized enolates gives a-phosphono lactams,73 which are amenable to double- O O bond installation through a Wadsworth–Emmons olefination. Elevated S N O temperatures are required to achieve C–O bond cleavage, which leads N OH to the competitive decomposition of the enolate component possibly H Me 74 (R)-piperidine ethanol due to nucleophilic attack on phosphorus. Gallagher and co-workers

H2C=CHCH2NH2 have demonstrated the use of a-sulfinyl-substituted nucleophiles in µw, 100 oC, 12 h sulfamidate ring-opening reactions, which lead upon hydrolysis to the lactamization product.75 The strategy could not be extended to other cyclic sulfamidates due to competing sulfoxide elimination at higher RhCl(CO)(PPh3)2 (2 mol %) XantPhos (8 mol %) temperatures, leading to the formation of complex mixtures. Switching N H2:CO (1:1; 7 bar) NH HN to the a-phenylsulfenyl group [PhS(=O)–] on the enolate component Me µ o N THF, w, 100 C, 1 h Me helped generate an array of a-sulfenylated lactams in good-to- 63% Me excellent yields. The sulfenylated lactams can be easily converted into (+)-tetraponerine T-3 unsaturated lactams by a Pummerer rearrangement. The strategy was 80% employed for the synthesis of alkylidene pyrrolidines and piperidines starting with cyclic sulfamidates, which undergo ring-opening with the dianion of ethyl acetoacetates, followed by in situ N-sulfate hydrolysis Scheme 11. Cyclic Sulfamidate as Key Intermediate in the Synthesis of and intramolecular condensation onto the intermediate ketone.76 The most (+)-Tetraponerine T-3 Alkaloid. (Ref. 71) important application of sulfamidate chemistry in this regard has been the enantioselective total synthesis of (–)-paroxetine (Scheme 12, Part (a)) 77 VOL. 48, NO. 3 • 2015 and (+)-laccarin.76 Gallagher also utilized sulfamidates in the synthesis and gram-negative bacteria. The crucial step in its preparation was of (–)-aphanorphine, a natural product isolated from the freshwater the asymmetric synthesis of the chiral benzoxazine core from the blue-green algae, Aphanizomenon flos-aquae (Scheme 12, Part (b)).77–81 sulfamidate. The benzoxazine intermediate was then easily converted These syntheses proceed through pyrrolidinone or piperidinone into (–)-levofloxacin in a few simple steps.81,82 The seven-membered- intermediates, which have also been utilized in the synthesis of natural ring variants of benzoxazine are important in pharmaceutical products and their heterocyclic analogues.76–81 applications.83 Tetrahydro-1,4-benzothiazepines S107 and JTV519 are being evaluated for treating conditions linked to the stabilization 5.6. Thiomorpholinones and Piperazinones of cardiac ryanodine receptors (RyR1) that leak Ca2+ when subjected Cyclic 1,2-sulfamidates, even sluggish ones possessing both primary to stress.84,85 The usefulness of cyclic sulfamidates in this area was and secondary electrophilic centers, react with methyl thioglycolate proven by the synthesis of relevant seven- and eight-membered-ring to give chiral thiomorpholinones in excellent yields (Scheme 13, Part heterocycles (Scheme 14, Part (b)).85 (a)).79 Gallagher’s group extended this methodology to the synthesis of piperazinones, wherein phenylalanine-derived cyclic sulfamidates 5.8. Carbohydrates provide the corresponding piperazinones (Scheme 13, Part (b)).79 A wide range of diols on different carbohydrate scaffolds (e.g., d-Glc, Bicyclic systems such as praziquantel can be constructed by employing d-Gal, l-Rha, d-Rib, etc.) can be converted into the corresponding different amino-based nucleophiles;6 a phenylalanine-derived cyclic sulfamidates by using the Burgess reagent.86 Nucleophilic ring- sulfamidate reacts efficiently with enantiotopic proline ethyl esters to opening of these sulfamidates with sodium azide permits the synthesis afford bicyclic piperazinones.79 The ring-opening of an enantiopure of a-glycosylamines.86 The ring-opening of carbohydrate-derived cyclic sulfamidate with the indole nitrogen of indolecarboxylic acid sulfamidates with non-carbon strong nucleophiles of low basicity methyl ester provides the corresponding pyrazino-indole with 98% ee.80 proceeds efficiently, while the use of carbohydrate-derived soft

5.7. 1,4-Benzoxazines, Benzothiazines, and Quinoxalines

The ring-opening of sulfamidates with aromatic amines, phenols, or O O O thiophenols under basic conditions, in combination with a Pd-catalyzed S 1. NaHCO3,THF:H2O (1:1) R N O O or Cs2CO3, THF Buchwald-type amination, opens a new avenue for the synthesis of (a) + R N S R1 R2 MeOSH 2. HCl (5 M), rt 1,4-benzoxazines, benzothiazines, and quinoxalines. For example, 3. NaHCO 3 R1 R2 4. PhMe, reflux, 3 h when the ring-opening of cyclic sulfamidates with 2-bromophenols 4 examples: 35–98% is followed by N-sulfate hydrolysis and Pd-catalyzed amination, O O 4 substituted and enantiopure 1,4-benzoxazines are obtained in good-to- O R 3 R S R 81 N O O NHTs high yields (Scheme 14, Part (a)). 1. NaH or Cs2CO3, DMF (b) + R N NTs 1 2 4 2. HCl (5 M), rt (–)-Levofloxacin is one of the major antibiotic drugs used to treat R R R'ORR3 3. NaHCO 3 R1 R2 a wide range of infections, and is active against both gram-positive 4. PhMe, reflux, 18 h 5 examples: 25–90%

Scheme 13. Thiomorpholinones and Piperazinones by Ring-Opening of O O O S CO2Me Cyclic Sulfamidates. (Ref. 79) BnN O 1. H2C(CO2Me)2 BnN H NaH, DMF, 60 oC H (a) 2. HCl (5 M) 3. PhMe, reflux O O F 70% F OH R3 S 1 3 O Br o R N O O R N 1. NaH, DMF, rt to 60 C (a) + R4 1 2 O R 2. Pd(OAc)2 (5 mol %) 2 HCl•HN O R 4 R O H R XantPhos (7.5 mol %) 2 equiv NaOt-Bu, PhMe, 100 oC 8 examples: 42–86%

F R1 = Me, R2 = H O 3 4 (–)-paroxetine hydrochloride R = Boc, R = 2,3-F2 F COOH O O O O 1. (EtO) OPCH CO Et S 2 2 2 P(OEt)2 N N MeN O KOt-Bu, THF, 40 oC MeN MeN O (b) Me 2. HCl (5 M) Br Br (–)-levofloxacin O O XH OH 84% S H TsN O 1. NaH, DMF TsN OMe OMe (b) + H NMe Bn 2. HCl (5%) Bn 3. DEAD, PPh X HO 3 Me X = O (50%), S (55%), NTs (35%) (–)-aphanorphine

Scheme 12. Cyclic Sulfamidates in the Synthesis of Piperidinones and Scheme 14. Cyclic Sulfamidates as Convenient Precursors of Pyrrolidinones en Route to (–)-Paroxetine and (–)-Aphanorphine. (Ref. 76,77) 1,4-Benzoxazines, Benzothiazepines, and Benzodiazepines. (Ref. 81,85) Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products 78 R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma*

nucleophiles results in the successful synthesis of di- and trithio- the nucleophilic ring-opening of sulfamidates with azide, followed by saccharide analogues.87 Chandrasekaran and co-workers effected azido–alkyne cycloaddition.89 the synthesis of carbohydrate-fused triazole heterocycles in a one- Lubell and co-workers synthesized N-(9-(9-phenylfluorenyl))- pot tandem process. The reaction proceeds via azido ring-opening homoserine-derived cyclic sulfamidates, and showed that they could be propargylation and subsequent intramolecular cycloaddition of the used for the synthesis of functionalized, enantiopure g-amino acids. The alkyne and azide to deliver the carbohydrate-fused triazole derivative reactions were successful with nitrogen, sulfur, and stabilized oxygen (Scheme 15).46 The same group also reported that the reaction of nucleophiles, providing the corresponding unnatural, g-substituted d-glucose-derived sulfamidates with bis(benzyltriethylammonium) amino acids in >97% ee’s.90 Peregrina’s group reported that the five-

tetrathiomolybdate {[BnNEt3]2MoS4} results in the formation of membered-ring, a-methylisoserine-derived (R)-sulfamidate could 2-thiolglucosamine derivatives.44,88 be used as an excellent chiral building block that undergoes ring- opening with sulfur nucleophiles at the quaternary carbon.91 They 5.9. Unnatural Amino Acids developed a protocol for the synthesis of (2S,2'R)- and (2R,2'R)-a- Interest in unnatural amino acids has been growing due to their methylnorlanthionines (a-Me-nor-Lan) in diastereomerically pure application in peptide research.89 Cyclic sulfamidates provide a forms by using the corresponding a-methylisoserine-derived cyclic unique opportunity to modify natural amino acids into a wide range of sulfamidate as a chiral building block (Scheme 16).92 unnatural analogues by simple reaction sequences and in fewer steps. Chandrasekaran’s group converted serine and threonine derivatives into 6. Conclusion unnatural cystine and selenocystine amino acids via cyclic sulfamidate This review highlighted the important role cyclic sulfamidates intermediates.43,55 Our group has demonstrated that the reaction of cyclic are playing in natural product synthesis and method development. sulfamidates with in situ generated dithiocarbamate anions can be used Their reactions are highly regioselective and stereospecific with for the synthesis of unnatural amino acids containing dithiocarbamate inversion of configuration at the reaction center. Even though cyclic side chains.42a We have also utilized sulfamidates for the synthesis of sulfamidates had not been extensively studied because of their triazole-modified unnatural amino acids in 71–86% yields through reactions with carbon nucleophiles had led to complex mixtures and/or decomposition products, recent investigations have overcome most of these limitations by softening the carbon nucleophiles. This approach has resulted in new synthetic strategies in organic chemistry with no CO2Me CO Me 1. NaN3 (3 equiv) 2 limitations in terms of reactivity. We believe that cyclic sulfamidates O N o O BnO O DMF, 80 C, 6 h BnO NH S offer a unique synthetic potential, and can provide practical solutions O 2. citric acid (sat), 4 h BnO O BnO N3 to the synthesis of challenging drug targets that are sought after by OBn OBn both academia and industry. 85% COOMe 1. NaH (1.3 equiv) O N ≡ 7. Acknowledgments BnO BrCH2C CH o R. B. Nasir Baig was supported by the Postgraduate Research Program BnO N DMF, 0 C, 2 h 2. 80 oC, 8 h at the National Risk Management Research Laboratory administered OBn N N by the Oak Ridge Institute for Science and Education through an 80% (from D-glucose) interagency agreement between the U.S. Department of Energy and the U.S. Environmental Protection Agency. Scheme 15. Carbohydrate-Derived Fused Heterocycles Through the Intermediacy of Cyclic Sulfamidates. (Ref. 46) 8. References (1) McCombie, H.; Parkes, J. W. J. Chem. Soc. 1912, 101, 1991. (2) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175. (3) Wei, L.; Lubell, W. D. Can. J. Chem. 2001, 79, 94. R CO2Me (4) Gautun, H. S. H.; Carlsen, P. H. J. Tetrahedron: Asymmetry 1995, 6, 1667. HS (5) Meléndez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581. O O NHBoc S 1. DBU, DMF (6) Bower, J. F.; Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem. 2010, 8, 1505. Me NHCO2Me MeO2C N O 50 oC, 1 h Me N CO2Me (7) Megia-Fernandez, A.; Morales-Sanfrutos, J.; Hernandez-Mateo, F.; Me 2 S 2'R Me 2. HCl (2 N):DCM (1:1) MeO N Santoyo-Gonzalez, F. Curr. Org. Chem. 2011, 15, 401. O 25 oC, 10 h O NHBoc MeO (8) Andersen, K. K.; Bray, D. D.; Chumpradit, S.; Clark, M. E.; Habgood, G. R or S 98 or 95% J.; Hubbard, C. D.; Young, K. M. J. Org. Chem. 1991, 56, 6508.

1. LiOH•H2O (9) Aguilera, B.; Fernández-Mayoralas, A.; Jaramillo, C. Tetrahedron 1997, MeOH:H2O (3:2) Me NH2•HCl 53, 5863. 25 oC, 24 h HO CO2H (10) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538. 2 S 2'R 2. HCl (12 N) (11) Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J. Org. Chem. 2002, 67, 5164. O NH2•HCl reflux, 12 h (12) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. α-Me-nor-Lan hydrochloride (2S,2'R), 80%; (2R,2'R), 78% (13) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834. (14) Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Scheme 16. Diastereomerically Pure (2S,2'R)- and (2R,2'R)-a-Methyl- Huang, X. Chem.—Eur. J. 2004, 10, 5581. norlanthionines (a-Me-nor-Lan) from Chiral Cyclic Sulfamidates. (Ref. 92) (15) Leisch, H.; Saxon, R.; Sullivan, B.; Hudlicky, T. Synlett 2006, 445. (16) Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728. 79 VOL. 48, NO. 3 • 2015

(17) Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett. 2000, 2, 2233. (59) Pound, M. K.; Davies, D. L.; Pilkington, M.; de Pina Vaz Sousa, M. M.; (18) Lin, X.; Che, C.-M.; Phillips, D. L. J. Org. Chem. 2008, 73, 529. Wallis, J. D. Tetrahedron Lett. 2002, 43, 1915. (19) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. (60) Guziec, F. S., Jr.; SanFilippo, L. J. J. Org. Chem. 1991, 56, 3178. 2001, 123, 6935. (61) Bower, J. F.; Švenda, J.; Williams, A. J.; Charmant, J. P. H.; Lawrence, R. (20) Toumieux, S.; Compain, P.; Martin, O. R.; Selkti, M. Org. Lett. 2006, 8, M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727. 4493. (62) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (21) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron (63) Moss, T. A.; Alonso, B.; Fenwick, D. R.; Dixon, D. J. Angew. Chem., Int. 2009, 65, 3042. Ed. 2010, 49, 568. (22) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558. (64) Kannenber g, A.; Rost, D.; Eibauer, S.; Tiede, S.; Blechert, S. Angew. (23) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210. Chem., Int. Ed. 2011, 50, 3299. (24) Wehn, P. M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 3802. (65) Tiede, S.; Berger, A.; Schlesiger, D.; Rost, D.; Lühl, A.; Blechert, S. (25) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du Bois, J. Tetrahedron Angew. Chem., Int. Ed. 2010, 49, 3972. 2006, 62, 11331. (66) Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, (26) Zhang, J.; Chan, P. W. H.; Che, C.-M. Tetrahedron Lett. 2005, 46, 5403. 129, 9964. (27) Fruit, C.; Müller, P. Helv. Chim. Acta 2004, 87, 1607. (67) Kang, S.; Lee, H.-K. J. Org. Chem. 2010, 75, 237. (28) Fruit, C.; Müller, P. Tetrahedron: Asymmetry 2004, 15, 1019. (68) Peláez, F.; Cabello, A.; Platas, G.; Díez, M. T.; González del Val, A.; (29) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220. Basilio, A.; Martán, I.; Vicente, F.; Bills, G. F.; Giacobbe, R. A.; (30) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825. Schwartz, R. E.; Onishi, J. C.; Meinz, M. S.; Abruzzo, G. K.; Flattery, A. (31) Thornton, A. R.; Blakey, S. B. J. Am. Chem. Soc. 2008, 130, 5020. M.; Kong, L.; Kurtz, M. B. Syst. Appl. Microbiol. 2000, 23, 333. (32) Thornton, A. R.; Martin, V. I.; Blakey, S. B. J. Am. Chem. Soc. 2009, (69) Balkovec, J. M.; Bouffard, F. A.; Tse, B.; Dropinski, J.; Meng, D.; 131, 2434. Greenlee, M. L.; Peel, M.; Fan, W.; Mamai, A.; Liu, H.; Li, K. Antifungal (33) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou,Y.-G. Org. Agents. World Patent WO2007127012, Nov 8, 2007. Lett. 2008, 10, 2071. (70) Zhong, Y.-L.; Gauthier, D. R., Jr.; Shi, Y.-J.; McLaughlin, M.; Chung, J. (34) Lee, H.-K.; Kang, S.; Choi, E. B. J. Org. Chem. 2012, 77, 5454. Y. L.; Dagneau, P.; Marcune, B.; Krska, S. W.; Ball, R. G.; Reamer, R. A.; (35) Kang, S.; Han, J.; Lee, E. S.; Choi, E. B.; Lee, H.-K. Org. Lett. 2010, 12, 4184. Yasuda, N. J. Org. Chem. 2012, 77, 3297. (36) Chen, Y.-J.; Chen, Y.-H.; Feng, C.-G.; Lin, G.-Q. Org. Lett. 2014, 16, 3400. (71) Airiau, E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei, M.; Mann, A. J. (37) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem. Org. Chem. 2010, 75, 8670. Soc. 2002, 124, 12934. (72) Bower, J. F.; Williams, A. J.; Woodward, H. L.; Szeto, P.; Lawrence, R. (38) Kenworthy, M. N.; Taylor, R. J. K. Org. Biomol. Chem. 2005, 3, 603. M.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 2636. (39) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron: Asymmetry (73) Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67, 5709. 1990, 1, 881. (74) Bower , J. F.; Chakthong, S.; Švenda, J.; Williams, A. J.; Lawrence, R. M.; (40) Boulton, L. T.; Stock, H. T.; Raphy, J.; Horwell, D. C. J. Chem. Soc., Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2006, 4, 1868. Perkin Trans. 1 1999, 1421. (75) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 4909. (41) Aguilera, B.; Fernández-Mayoralas, A. Chem. Commun. 1996, 127. (76) Bower, J. F.; Riis-Johannessen, T.; Szeto, P.; Whitehead, A. J.; Gallagher, (42) (a) Saha, A.; Nasir Baig, R. B.; Leazer, J.; Varma, R. S. Chem. Commun. T. Chem. Commun. 2007, 728. 2012, 48, 8889. (b) Nasir Baig, R. B.; Varma, R. S. Curr. Org. Chem. (77) Bower, J. F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005, 5793. 2013, 17, 2323. (78) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143. (43) Nasir Baig, R. B.; Kanimozhi, C. K.; Sai Sudhir, V.; Chandrasekaran, S. (79) W illiams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.; Gallagher, Synlett 2009, 1227. T. Org. Lett. 2003, 5, 811. (44) Nasir Baig, R. B.; Phani Kumar, N. Y.; Mannuthodikayil, J.; (80) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chandrasekaran, S. Tetrahedron 2011, 67, 3111. Chem., Int. Ed. 2008, 47, 3238. (45) Nasir Baig, R. B.; Sai Sudhir, V.; Chandrasekaran, S. Synlett 2008, 2684. (81) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 3283. (46) Sai Sudhir, V.; Phani Kumar, N. Y.; Nasir Baig, R. B.; Chandrasekaran, S. (82) Atarashi, S.; Yokohama, S.; Yamazaki, K.; Sakano, K.; Imamura, M.; J. Org. Chem. 2009, 74, 7588. Hayakawa, I. Chem. Pharm. Bull. 1987, 35, 1896. (47) Kim, B. M.; So, S. M. Tetrahedron Lett. 1999, 40, 7687. (83) Reid, T. S.; Beese, L. S. Biochemistry 2004, 43, 6877. (48) Kim, B. M.; So, S. M. Tetrahedron Lett. 1998, 39, 5381. (84) Bellinger , A. M.; Reiken, S.; Carlson, C.; Mongillo, M.; Liu, X.; (49) Cohen, S. B.; Halcomb, R. L. J. Am. Chem. Soc. 2002, 124, 2534. Rothman, L.; Matecki, S.; Lacampagne, A.; Marks, A. R. Nat. Med. (50) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585. 2009, 15, 325. (51) Khanjin, N. A.; Hesse, M. Helv. Chim. Acta 2003, 86, 2028. (85) Rujirawanich, J.; Gallagher, T. Org. Lett. 2009, 11, 5494. (52) Malkov, A. V.; Hand, J. B.; Kočovsky, P. Chem. Commun. 2003, 1948. (86) Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D. A. J. (53) Rönnholm, P.; Södergren, M.; Hilmersson, G. Org. Lett. 2007, 9, 3781. Am. Chem. Soc. 2004, 126, 6234. (54) Guo, R.; Lu, S.; Chen, X.; Tsang, C.-W.; Jia, W.; Sui-Seng, C.; Amoroso, (87) Aguilera, B.; Fernández-Mayoralas, A. J. Org. Chem. 1998, 63, 2719. D.; Abdur-Rashid, K. J. Org. Chem. 2010, 75, 937. (88) Nasir Baig, R. B.; Sai Sudhir, V.; Chandrasekaran, S. Tetrahedron: (55) Nasir Baig, R. B.; Chandrakala, R. N.; Sai Sudhir, V.; Chandrasekaran, S. Asymmetry 2008, 19, 1425. J. Org. Chem. 2010, 75, 2910. (89) Nasir Baig, R. B.; Varma, R. S. Chem. Commun. 2012, 48, 5853. (56) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 766. (90) Atfani, M.; Wei, L.; Lubell, W. D. Org. Lett. 2001, 3, 2965. (57) Cooper, G. F.; McCarthy, K. E.; Martin, M. G. Tetrahedron Lett. 1992, (91) Avenoza, A.; Busto, J. H.; Jiménez-Osés, G.; Peregrina, J. M. J. Org. 33, 5895. Chem. 2006, 71, 1692. (58) Alker, D.; Doyle, K. J.; Harwood, L. M.; McGregor, A. Tetrahedron: (92) A venoza, A.; Busto, J. H.; Jiménez-Osés, G.; Peregrina, J. M. Org. Lett. Asymmetry 1990, 1, 877. 2006, 8, 2855. Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products 80 R. B. Nasir Baig,* Mallikarjuna N. Nadagouda, and Rajender S. Varma*

Trademarks. Amberlyst® (Rohm and Haas Co.); DABCO® (Air postdoctoral fellow with Prof. R. S. Varma at NRMRL, U.S. EPA, where Products and Chemicals, Inc.). he conducted research on nanocatalysis and on greener methods for synthesizing bioactive compounds. Disclaimer Mallikarjuna N. Nadagouda received his Ph.D. degree in 2003 from U.S. Environmental Protection Agency (EPA), through its Office Gulbarga University while working with Prof. J. Gopalakrishnan (retired) of Research and Development, partially funded and collaborated in at IISc. After working for 2 years at General Electric, Bangalore, India, the research described herein. It has been subjected to the Agency’s he joined Prof. Alan G. MacDiarmid’s group at the University of Texas administrative review and has been approved for external publication. at Dallas. He then accepted an appointment as an ORISE postdoctoral Any opinions expressed in this paper are those of the author(s) and do fellow (with Prof. Varma) at NRMRL, U.S. EPA, where he is currently not necessarily reflect the views of the Agency, therefore, no official working as a physical scientist at NRMRL, Ohio. endorsement should be inferred. Any mention of trade names or Rajender S. Varma is a recognized authority on Green Chemistry, commercial products does not constitute endorsement or recommendation and is a senior scientist in the Sustainable Technology Division at the for use. U.S. EPA. He has a Ph.D. degree in Natural Products Chemistry from Delhi University (India), and, after postdoctoral research at Robert About the Authors Robinson Laboratories, Liverpool, U.K., he became a faculty member at R. B. Nasir Baig received his M.Sc. degree in chemistry from Baylor College of Medicine and Sam Houston State University. He has Amravati University and his Ph.D. degree in 2009 from the Indian over 40 years of research experience in multidisciplinary technical areas, Institute of Science (IISc), Bangalore, under the supervision of Prof. especially the development of environmentally friendlier alternatives for S. Chandrasekaran. He has worked on the synthesis of functionalized synthetic methods by using microwaves and ultrasound. He is a member buckybowls (triformylsumanene) with Prof. H. Sakurai and as an ORISE of the editorial advisory boards of several international journals.

PRODUCT HIGHLIGHT

Stahl Aerobic Oxidation Solutions Easy as 1–2–3 at room Alcohol oxidation is one of the most frequently performed oxidation reactions in temperature OH O organic chemistry. In collaboration with Professor Shannon Stahl, Aldrich offers the and in air 1 2 1 2 Stahl Aerobic Oxidation Solutions: 796549 and 796557. R R R R [Cu(MeCN)4]OTf Both solutions contain 1-methylimidazole (NMI), 2,2΄-bipyridyl (bpy), and either 685038 TEMPO or ABNO; all you have to do is add the copper catalyst and your substrate! Features • Easy reaction setup and workup procedures • Most reactions proceed at room temperature open to the air • TEMPO offers chemoselective oxidation of primary alcohols • ABNO offers rapid oxidation of both primary and secondary alcohols • Broad substrate scope and high functional group tolerance

For more information on these solutions, visit Aldrich.com/aerobic-oxidation 84031-d Building blocks for SuFEx, the next click reaction Monofunctional

O O O F S CF2CF2CF2CF3 S F F S O O O

319732 ALD00118 ALD00136

F F O S O In collaboration with Professor K. Barry Sharpless, O S O N N Aldrich offers sulfonyl fluorides for rapid installment O S O O F S of building blocks onto lead compounds. Sulfonyl O fluorides react predictably with nucleophiles, but remain ALD00150 ALD00152 ALD00168 inert to oxidation, reduction, thermolysis, and other 1 reactive conditions. Bifunctional

O Functionalization of your lead compound can be achieved O O O O F S OH S F S F with potent Michael-acceptor ethenesulfonyl fluoride (ESF, F O F O O 746959) to covalently link nucleophiles to a pendant SO2F 746959 group. A recent review by Sharpless and co-workers details 531413 ESF ALD00024 opportunities provided by Sulfur(VI) Fluoride Exchange 2 O (SuFEx) chemistry. Like its alkyne–azide predecessor, this F O S O O F F S O S click chemistry reaction is fast and quantitative. Thus, OH O O Br the sulfonyl fluoride group is a promising tool for drug O S O F Cl O discovery and chemical biology applications. F ALD00172 ALD00204 ALD00364

Professor K. Barry Sharpless

To learn more about our extensive References: (1) Dong, J.; Sharpless, K. B.; Kwisnek, L.; Oakdale, J. S.; Fokin, V. V. Angew. portfolio of sulfonyl fluorides, visit Chem., Int. Ed. 2014, 53, 9466. (2) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. Aldrich.com/sufex 2014, 53, 9430.

84031-e EU

SEARCH FOR ANSWERS, NOT JUST STRUCTURES

INTRODUCING BUILDING BLOCK EXPLORER A comprehensive collection of building blocks backed by scientific expertise, accurate inventory and reliable shipping — all in one place.

START EXPLORING | sigma-aldrich.com/explore

84031-g RVO 84031-512740 1115