Ynamides in Ring Forming Transformations

Conspectus

The ynamide functional group activates carbon-carbon triple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years.

This Account surveys and assesses new organic transformations involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides.

This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within, or in close proximity to, a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides.

1. Introduction

Over the past 15 years, ynamides have become a modern functional group that has been prominently featured in a variety of synthetic transformations including natural product total syntheses.^1-3 Fueled by preparative access that is efficient and atom economical,^4,5 the field of ynamide chemistry has rapidly expanded. Ynamides provide a means of activating carbon-carbon triple bonds, giving them both electrophilic and nucleophilic properties. The electronic properties of ynamides are tunable based on selection of the electron-withdrawing group attached to nitrogen, thereby rendering them highly versatile synthons. Furthermore, among all heteroatom-substituted alkynes, ynamides are special because nitrogen is one of the most privileged elements in nature. Consequently, many transformations involving ynamides offer a diverse array of novel structural entities that are not only powerful platforms for further transformations, but also prevalent among important pharmacophores. These properties have contributed to a continued and dramatic increase in the number of publications in the last few years.

This Account aims to examine the literature from late 2009 through early 2013 related to the use of ynamides in synthetic transformations that form cyclic and polycyclic manifolds. Consequently, the Account is organized by reaction types used in the ring formation, and representative examples are selected to showcase scope and mechanistic insight of each transformation. The intention here is not to comprehensively review the ynamide chemistry that appeared during this period, but to highlight major advancements in ynamide chemistry through revelation of its utility in rapid assembly of structural complexity. As a result, some beautiful recent works are not presented here. This includes improved ynamide preparations and syntheses of de novo structural analogs of ynamides. Both topics have been the subject of a thorough review published recently by Evano.⁴ In addition, new advances related to in situ generation of ketenimines or metallo-ynamides via Huisgen's azide-[3 + 2] cycloaddition/retro-[3 + 2] are not covered here.⁶

2. Radical Cyclizations

Balieu and Courillon⁷ reported the formation of sixmembered rings 5 and 6, and the eight-membered ring 3 via the radical cyclization of ynamides 1 (Scheme 1). A tandem radical cyclization also took place when R was 3,5-dimethoxyphenyl through vinyl radical 4.

Scheme 1.

Chemla and Perez-Luna⁸ reported synthesis of 3-alkylidenetetrahydrofurans 11 from ynamides 7 through a 1,4-addition/alkyne carbozincation sequence based on a radical zinc-atom transfer process (Scheme 2). The addition of ethyl radical gave enoxy radical 8, which underwent 5-exo-dig cyclization with the ynamide leading to vinyl radical 9 of E-geometry.

Scheme 2.

3. Ring-Closing Metathesis

Wakamatsu and Mori⁹ reported further development of their ring-closing metathesis of ene-ynamides, featuring syntheses of 7-membered heterocycles 13, 15 and 8-membered heterocycles 17 using 2^nd-generation Grubbs catalyst (Scheme 3).

Scheme 3.

4. Non-Transition Metal Mediated Cyclizations

Popik¹⁰ reported acid catalyzed cycloaromatizations of cyclic ynamides 18 (Scheme 4). Protonation of the ynamide followed by addition of the alkyne onto the resulting keteniminium ion 19 provided cation 20, which underwent Friedel-Crafts additions. Alcoholic solvent trapping of 19 competed with cycloaromatization, especially with increasing in ring size.

Scheme 4.

Evano¹¹ developed a general and efficient approach toward 1,4-dihydropyridines 29 and pyridines 30 from readily available N-allyl-ynamides 24 via a tandem lithiation–isomerization–6-endo-dig intramolecular carbolithiation sequence (Scheme 5).

Scheme 5.

Flynn¹² reported a highly torquoselective Nazarov cyclization of 2-amido divinyl ketones 34 derived from chiral oxazolidinone-substituted ynamides 31 (Scheme 6). The diastereoselectivity can be very high, and Nazarov arrested products such as 37a could also be obtained.

Scheme 6.

Cao¹³ described an efficient approach toward 3-allenyl-2-amidobenzofurans 40 and 3-alkyl-2-amidobenzofurans 44 via a novel carbocation-induced electrophilic cyclization of o-anisole-substituted ynamides with 1,1-diaryl-prop-2-yn-1-ol 39 and diarylmethanol 41, respectively (Scheme 7).

Scheme 7.

Later, Cao¹⁴ developed a novel synthesis of 2-amidobenzofurans and 2-amidobenzothiophenes via electrophilic cyclization of o-anisole- and o-thioanisole-substituted ynamides 45 with I₂, NBS, and NCS. This strategy was also used to construct 1-amidonaphthalenes 50 and 1-amidobenzopyrans 52 from ynamides (Scheme 8).

Scheme 8.

Hsung¹⁵ unveiled a novel acid promoted 5-endo-dig cyclization of chiral γ-amino-ynamide 53 concomitant with the loss of the t-Bu group that led to the formation of isothaizole 54 and dihydroisothaizole S-oxide 55. An inversion at the “S” center occurred in 55 (Scheme 9).

Scheme 9.

Hsung¹⁶ featured an aza-variant of a Meyer-Schuster rearrangement of γ-amino-ynamides 56, which involved the formation of azetene intermediate 58 and pericyclic ring-opening (Scheme 10).

Scheme 10.

5. Transition Metal Mediated Cyclizations

5.1. Rhodium

Nishimura and Hayashi¹⁷ disclosed a rhodium-catalyzed asymmetric cycloisomerization of heteroatom-bridged 1,6-enynamides such as 60 to afford 3-aza and oxabicyclo[4.1.0]heptene derivatives such as 61a (Scheme 11). 2-oxazolidinone and 2-azetidinone substituents of the ynamides were critical for high enantioselectivities, as the carbonyl oxygen might coordinate to the metal during the transformation.

Scheme 11.

Tang¹⁸ developed an efficient method for the generation of α-oxo Rh(I) carbenes 63 and 69 from ynamides with 3,5-dichloropyridine N-oxide. The resulting Rh(I) carbenes then react intramolecularly with various alkynes or alkenes affording 2-oxopyrrolidines 66 and 3-azabicyclo[3.1.0]hexanes 71, respectively (Scheme 12).

Scheme 12.

5.2. Palladium

Anderson¹⁹ reported a palladium-catalyzed tandem cascade of cyclization–cross-coupling–6π-electron electrocyclization using bromoenynamides 72 (Scheme 13).

Scheme 13.

Anderson²⁰ subsequently reported a related palladium-catalyzed cascade using bromoenynamides 75 affording cyclic 2-amidodienes 77 that could be used in ensuing Diels-Alder cycloadditions (Scheme 14). An alcohol served as a hydride source to terminate the carbopalladation process.

Scheme 14.

5.3. Platinum

Liu²¹ reported an equivalent of Pt(II)-catalyzed oxo-arylations of ynamide 79 (Scheme 15). This process employs nitrones 80 and provides imines 83 via intermediates 81 and 82, and under reductive conditions using NaBH₃CN, 2-indolones 85 were obtained.

Scheme 15.

5.4. Copper

Chen²² reported a Cu(I)-catalyzed 1,2-aminothiolation of 1,1-dibromoalkenes 86 with 2-thiobenzoimidazole, leading to thiazolines 90 and 91 (Scheme 16). The regiochemistry of the 1,2-aminothiolation depends on whether it is 5-endo dig cyclization of S- or N-alkynylation intermediates (88 or 89).

Scheme 16.

Hashmi²³ reported a copper-mediated domino reaction of three simple components that included propargylcarboxamide 92, protected amine 93, and a chloride source. This cascade provides an efficient construction of highly functionalized oxazines 97 (Scheme 17).

Scheme 17.

Neuville²⁴ developed an efficient and regioselective approach to 1,2,4-trisubstituted imidazoles 103 via a copper-catalyzed oxidative diamination of terminal alkynes 99 by amidines 98 (Scheme 18). This transformation employs oxygen as the co-oxidant and proceeds through a direct N-alkynylation of the terminal acetylenes, thereby rendering the process atom economical.

Scheme 18.

Evano²⁵ reported a modular synthesis of polysubstituted indoles 105 from N-aryl-ynamides 104. A bromine/lithium exchange of N-(2-bromoaryl)ynamides 104, followed by a 5-endo-dig carbocupration afforded the substituted indoles efficiently (Scheme 19).

Scheme 19.

5.5. Silver

Malacria, Fentsterbank, and Aubert²⁶ reported a silver-catalyzed cycloisomerization of de novo allene-ynamides 106, leading to amide-substituted cross-conjugated trienes 108 that are useful for tandem Diels-Alder cycloadditions (Scheme 20).

Scheme 20.

5.6. Gold

Hashimi²⁷ reported a gold-catalyzed cyclization of furanyl-ynamides 109 (Scheme 21). The course of the cyclization depended upon the length of the tether. Benzoanellated heterocycles 114 were produced when n = 1, while cyclopentadiene fused piperidines 118 were obtained when n = 2.

Scheme 21.

Skrydstrup²⁸ reported Au(I)-catalyzed hydroaminations or hydrations of diynamides 119 to access 2,5-diamidopyrroles 121 and 2,5-diamidofurans 122,respectively (Scheme 22). This development represents a clever application of diynamides.

Scheme 22.

Liu²⁹ reported highly regioselective Au(I)-catalyzed oxidative ring-expansions of cyclopropyl-substituted ynamides 123 using Ph₂SO (Scheme 23). The ring expansion is not believed to proceed through an α-keto gold carbenoid intermediate but through 124. Subsequently, Li³⁰ independently reported a similar gold-catalyzed oxidative ring-expansion (details not shown here).

Scheme 23.

Liu³¹ then explored 1,5-enynamides 127, developing a Au(I)-catalyzed oxidative cyclization using 8-methylquinoline N-oxide 128 as the external oxidant to construct 3-carboxyamidoindenes 131 (Scheme 24). The transformation is believed to proceed through α-ketocarbenoid 129.

Scheme 24.

Li³² reported a clever synthesis of 3-aza-bicyclo[3.1.0]hexan-2-one derivatives 135 via Au(I)-catalyzed oxidative cyclopropanations of N-allylynamides 132 using pyridine N-oxide as the external oxidant (Scheme 25).

Scheme 25.

Sueda³³ reported both Ag(I)- and/or Au(I)-catalyzed cyclizations of de novo ynimides 136, which could be accessed for the first time. These cyclizations gave β-ketoimides 140 when using both Au(I) and Ag(I), while providing oxazoles 143 when using only Ag(I) (Scheme 26).

Scheme 26.

Hashmi³⁴ reported synthesis of highly functionalized cyclopentadienes 152 in moderate to good yields via Au(I)-catalyzed intermolecular cyclization of propargylic carboxylates 144 and ynamides 145 (Scheme 27).

Scheme 27.

Sahoo³⁵ developed Au(I)-catalyzed hydrative cyclization of easily accessible 5-yne-ynamides 153, giving substituted 1,6-dihydropyridin-2(3H)ones 157 in good to excellent yields (Scheme 28). A mechanism involving a 6-endo-dig cyclization of intermediate 155 was proposed.

Scheme 28.

Bertrand³⁶ reported that deprotonation of oxazolium salt 159 initiated an interesting ring opening process giving ynamide 160 (Scheme 29). The acyclic ynamide readily reacts with various transition metals affording robust mesoionic carbene complexes 161.

Scheme 29.

6. Cycloadditions and Formal Cycloadditions

6.1 [2 + 1]

Hsung³⁷ reported the first examples of stereoselective intramolecular cyclopropanations via a de novo class of push-pull carbenes derived from DMDO-epoxidations of chiral ynamides 162 (Scheme 30). This tandem epoxidation-cyclopropanation afforded a series of structurally unique amido-cyclopropanes 165.

Scheme 30.

Buono³⁸ reported an unusual palladium catalyzed [2 + 1] cycloaddition of ynamides 166 with norbornene derivatives 167 giving various substituted aminomethylenecyclopropanes 170 (Scheme 31). Based on their previous study in alkyne system,³⁹ this process may involve a [2 + 2] cycloaddition of palladium vinylidene species with the double bonds of norbornene derivatives, followed by reductive elimination to furnish cyclopropanes.

Scheme 31.

6.2 [2 + 2]

Hsung⁴⁰ reported the first successful example of Ficini's [2 + 2] cycloaddition of ynamides 171 with enones 172 using CuCl₂ and AgSbF₆ as catalysts (Scheme 32).

Scheme 32.

Mezzetti⁴¹ subsequently reported Cu(OTf)₂ promoted Ficini [2 + 2] cycloadditions of ynamides with unsaturated β-keto esters in addition to a beautiful asymmetric variant using dicationic ruthenium(II)/PNNP complex (Scheme 33).

Scheme 33.

Danheiser⁴² reported the first examples of thermal [2 + 2] cycloadditions of 2-iodoynamides 181 with ketenes 182, leading to 3-amido-2-iodocyclobutenones 183 (Scheme 34).

Scheme 34.

Lam⁴³ reported a [2 + 2] cycloaddition of ynamides 184 with nitroalkenes 185 catalyzed by a dirhodium complex and sodium tetraphenylborate, leading to nitro-substituted cyclobutenamides 189 and 190 (Scheme 35).

Scheme 35.

Takasu and Takemoto⁴⁴ reported selective syntheses of either syn or anti isomers of α,β-unsaturated amidines 195 and 198 through a tandem cascade of aza-[2 + 2] cycloaddition–4π-electron pericyclic ring-opening by using Tf₂NH or CSA as catalyst, respectively (Scheme 36). The torquoselectivity of ring-opening was controlled by the Brønsted acidity of the catalyst and the polarity of the solvent.

Scheme 36.

Mikami⁴⁵ reported an asymmetric [2 + 2] cycloaddition of ynamide 199 with ethyl trifluoropyruvate 200 using a dicationic (S)-BINAP-Pd catalyst with excellent yield and enantioselectivity. This is also the first enantioselective synthesis of a stable oxetene derivative (Scheme 37).

Scheme 37.

6.3. [3 + 2]

Lam⁴⁶ reported a Rh-catalyzed formal [3 + 2] cycloaddition of ynamides 202 with arylboronic acids or esters 203 containing an electrophilic functional group at the ortho-position. This transformation effectively provides 2-amido-indenols 205 or 2-amido-indenes 206 in good regioselectivities (Scheme 38).

Scheme 38.

Sueda⁴⁷ applied their ynimides 207 to the copper-mediated Huisgen's azide-[3 + 2] cycloaddition giving 4-phthalimido-1-benzyl-1,2,3-triazole 208 (Scheme 39).

Scheme 39.

Davies⁴⁸ reported that 2,4,5-trisubstituted oxazoles 211 could be synthesized from ynamides 210 and 1,3-N,O-dipole equivalents 209 in a gold (III) catalyzed process (Scheme 40).

Scheme 40.

Gagosz and Skrydstrup⁴⁹ reported syntheses of cyclopentadienes 214 or tricycles 215 from dimerizations of ynamides 212 in the presence of a Au(I) complex (Scheme 41). While the divergence in this dimerization depends upon the substitution pattern, its efficiency is directly dependent on the electronic properties of the ynamide, which acts both as the electrophile and the nucleophile in the process.

Scheme 41.

Lai⁵⁰ reported the synthesis of δ-carbolines 220 from 2-iodoanilines 216 and N-tosyl-enynamides 217 via a Pd(0)-catalyzed cascade (Scheme 42). This cascade involves Larock's heteroannulation giving indoles 218 and an electrocyclization of 2-aza-trienes 219 after loss of TsOH.

Scheme 42.

Peng⁵¹ reported a AgOTf/Pd(OAc)₂ co-catalyzed [3 + 2]-cycloaddition of N-allyl-N-sulfonyl ynamides 221 with N’-(2-alkynyl-benzylidene)hydrazides 222 giving 2-amino-H-pyrazolo[5,1-a]isoquinolines 228 (Scheme 43). The transformation proceeds through 6-endo-dig cyclization of 222, [3 + 2] cycloaddition between 224 and 225, 3,3-sigmatropic rearrangement, and aromatization.

Scheme 43.

Batey⁵² reported a series of 1,3-dipole cycloadditions using ynehydrazides 229 that were first synthesized in these authors’ lab. This exercise demonstrates the synthetic potential of these novel ynamides (Scheme 44).

Scheme 44.

6.4. [4 + 1]

Liu⁵³ reported a gold-catalyzed formal [4 + 1]-cycloaddition of ynamides 231 with 8-methylquinoline oxide 128, leading to a series of substituted 2-amido-furans 237 (Scheme 45). Mechanistically, this formal cycloaddition likely proceeded through α–keto carbenoid 234 via an initial gold-catalyzed addition of 8-methylquinoline oxide 128 to ynamides 231 followed by an oxa-Nazarov cyclization.

Scheme 45.

6.5. [4 + 2]

Hoye⁵⁴ disclosed an intramolecular hexadehydro-Diels-Alder cycloaddition reaction of ynamide 238 (Scheme 46). The hexadehydro-Diels-Alder reaction of 238 led to the key benzyne intermediate 240, which was trapped by the pendant silyloxy group, giving the tricycle 242 in 80% yield after an O-to-C silyl migration of the zwitter ionic intermediate 241.

Scheme 46.

Lee⁵⁵ independently reported a similar hexadehydro-Diels-Alder cycloaddition of ynamide 243 catalyzed with silver (Scheme 47). What distinguishes this beautiful work from Hoye's is the alkane C-H insertion of the silver complex aryne to form carbon-carbon bonds.

Scheme 47.

Lee⁵⁶ subsequently reported a clever use of the Alder-ene process to trap the aryne intermediates derived from hexadehydro-Diels-Alder cycloaddition of ynamide 249 (Scheme 48). The metal catalyst was not essential, but increased the reaction's rate.

Scheme 48.

Danheiser⁵⁷ developed an ynamide-benzannulation using cyclobutenones 252 to synthesize highly substituted anilides 257 (Scheme 49). This benzannulation proceeds beautifully via four consecutive pericyclic processes, thereby constituting a formal [4 + 2] annulation. With olefin substitutions in R⁴ and on the nitrogen atom, these anilides could undergo ring-closing metathesis to generate complex N-heterocycles such as 258.

Scheme 49.

6.6. [2 + 2 + 2]

Witulski⁵⁸ reported a ruthenium-catalyzed hetero-[2 + 2 + 2] cycloaddition of yne-ynamides 259 with Mander's reagent giving β- and γ-carbolines 260 and 261 (Scheme 50). The regioselectivity could be controlled by the steric hindrance of substitutions to the alkynes and ynamides. A total synthesis of eudistomin U 263 was achieved using regioselective β-carboline synthesis.

Scheme 50.

Nissen⁵⁹ subsequently reported the total synthesis of lavendamycin by Ru(II)-catalyzed hetero-[2 + 2 + 2] cycloaddition of ynamide 266 and an electron deficient nitrile to prepare the carboline scaffold (Scheme 51).

Scheme 51.

Witulski and Detert⁶⁰ later reported the total syntheses of perlolyrine 275 and isoperlolyrine 276, featuring this Ru(II)-catalyzed hetero-[2 + 2 + 2] cycloaddition using yne-ynamides 271 and 273 (Scheme 52).

Scheme 52.

Malacria, Aubert and Gandon⁶¹ reported a Co(I)-catalyzed regioselective [2 + 2 + 2]-cycloaddition between ynamides 277 and nitriles 278 (Scheme 53). Through adjusting the substituent on the ynamides, regioselectivity of this cycloaddition could be tuned to favor either 3-aminopyridines 279 or 4-aminopyridines 280.

Scheme 53.

Saito and Sato⁶² reported divergent total syntheses of (-)-herbindoles A-C through intramolecular [2 + 2 + 2] cycloaddition of ynamide 281 catalyzed by Wilkinson's catalyst (Scheme 54). All three herbindoles could be constructed from the common indoline intermediate 282.

Scheme 54.

Liu⁶³ reported a Au(I)-catalyzed formal [2 + 2 + 2] cycloaddition of ynamides 286 with two equivalents of enol ethers (Scheme 55). Under activation by gold, two consecutive nucleophilic attacks by the enol ether followed by Prins-type cyclization furnished cyclic enamides 290 stereoselectively.

Scheme 55.

6.7. [3 + 2 + 2]

Saito⁶⁴ unveiled a novel Ni(0)-catalyzed [3 + 2 + 2] cycloaddition of ethyl cyclopropylideneacetate 291 with ynamides 292 (Scheme 56). The desired cycloadducts 293 were obtained in moderate yields with significant amounts of trisubstituted benzenes 294 resulting from trimerizations of the corresponding ynamides.

Scheme 56.

7. Rearrangements

Hsung⁶⁵ communicated the synthesis of azapin-2-one 299 via a sequence of aza-Claisen rearrangement, Pd(0)-catalyzed Overman rearrangement after trapping of ketenimine 296 with allyl alcohol, and ring-closing metathesis (Scheme 57).

Scheme 57.

Hsung⁶⁶ reported a novel synthesis of α,β-unsaturated cyclopentenimine 305 via a Pd-catalyzed aza-Rautenstrauch-type cyclization⁶⁷ (Scheme 58). It was proposed that the ynamido-π-allyl complex 301 derived from the oxidative addition of TIPS-terminated ynamide 295 underwent a Pd-[3,3] sigmatropic rearrangement giving the α-imino palladium carbenoid 302, which is related to the key intermediates proposed in the Rautenstrauch cyclization.

Scheme 58.

Later, Hsung and DeKorver⁶⁸ discovered that the substrate scope for the Pd-catalyzed carbocyclization was quite broad. A variety of functionalized N-allyl-γ-branched ynamides were employed in cyclopentenimine synthesis. With N-sulfonyl ynamides 306, palladium catalysis is required, as facile 1,3-sulfonyl shifts dominate under thermal conditions. However, since no analogous 1,3-phosphoryl shift is operational, N-phosphoryl ynamides 309 were used to prepare similar cyclopentenimines under thermal conditions through zwitter ionic intermediates 311 that underwent N-promoted H-shifts (Scheme 59).

Scheme 59.

DeKorver and Hsung⁶⁹ described a moderately stereoselective Staudinger-type ketenimine-imine [2 + 2] cycloaddition using N-phosphoryl ynamide 313 giving azetidin-2-imine 315 bearing a quaternary carbon center (Scheme 60). The ketenimine intermediate 314 was generated in situ via an aza-Claisen reaction.

Scheme 60.

DeKorver and Hsung⁷⁰ showcased a tandem aza-Claisencarbocyclization of N-phosphoryl-N-allyl-ynamides that included possibilities such as ring-expansion via Meerwein-Wagner rearrangement and polyene-type cyclizations, thereby rapidly building structural complexity leading to fused bi- and tricyclic scaffolds (Scheme 61).

Scheme 61.

Hsung⁷¹ communicated a stereoselective synthesis of bridged or fused bicycloimines through a crossed or fused intramolecular [2 + 2] cycloaddition of ketenimines via palladium-catalyzed aza-Claisen rearrangements of N-allylynamides 330 and 333 (Scheme 62). Preference of cycloaddition pathways depended upon alkene substitutions.

Scheme 62.

Meyer and Cossy⁷² described an interesting Saucey-Marbet rearrangement of ynamide 336 containing an N-Bocglycinate motif, providing stereoselective access to functionalized allenamide 339^73,74 (Scheme 63). These de novo allenamides underwent silver catalyzed cyclization affording 3-pyrrolidine derivatives 340 having 2,5-syn relative stereochemistry.

Scheme 63.

8. Conclusion

This manuscript has highlighted recent advances in ynamide cyclization reactions that are useful in the rapid synthesis of cyclic and polycyclic structural motifs. The transformations presented are significant due to their rapid assembly of structural complexity, and inclusion of nitrogen within, or in close proximity to, the newly formed ring or rings. Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings. We hope this Account will help promote continued interest in the chemistry of ynamides.

Biographies

Xiao-Na Wang received a B.S. in chemistry from Nanyang Normal University in 2006, and her Ph.D. degree in 2011 at Institute of Chemistry, Chinese Academy of Sciences with Professor Song Ye. Currently, she is conducting postdoctoral research with Professor Richard Hsung at the University of Wisconsin.

Hyu-Suk Yeom received a B.S in chemistry from Hanyang University in 2007 and his Ph.D. degree in 2012 with Professor Shin at Hanyang University. Currently, he is conducting postdoctoral research with Professor Richard Hsung at the University of Wisconsin.

Lichao Fang received a B.S. in chemistry from Nankai University in 2007. He carried out doctoral research with Professor Zhen Yang at Peking University and obtained his Ph.D. degree in 2012. Currently, he is conducting postdoctoral research with Professor Richard Hsung at the University of Wisconsin.

Shuzhong He received his B.S. degree from Peking University in 2004. He then joined Professor Chi-Sing Lee's group in Peking University Shenzhen Graduate School and obtained his Ph.D. degree in 2011. Currently, he is a postdoctoral research scholar with Professor Richard Hsung at the University of Wisconsin.

Zhi-Xiong Ma received a B.S. in chemistry from University of Science and Technology of China in 2005, and his Ph.D. degree in 2010 at Shanghai Institute of Organic Chemistry with Professor Gang Zhao. Currently, he is conducting postdoctoral research with Professor Richard Hsung at the University of Wisconsin.

Brant L. Kedrowski obtained a B.S. in chemistry in 1994, and Ph.D. in organic chemistry in 2000 with Professor Wayland Noland at the University of Minnesota. He did postdoctoral work with Professor Clayton Heathcock at the University of California Berkeley before his appointment as an assistant professor at the University of Wisconsin Oshkosh in 2002. He was promoted to associate professor in 2008 and to full professor in 2013.

Richard P. Hsung obtained his B.S. in chemistry and mathematics from Calvin College and attended The University of Chicago for his M.S. and Ph.D. degrees in organic chemistry, respectively, with Professors Jeff Winkler and Bill Wulff. After postdoctoral stays with Professor Larry Sita in Chicago and Professor Gilbert Stork at Columbia University, he moved to University of Minnesota as an assistant professor in 1997. He was promoted to associate professor in 2002 and to full professor after moving to University of Wisconsin in 2006. He has coauthored over 200 publications and supervised over 150 students and postdoctoral fellows with research interests in developing stereoselective methods using allenamides, ynamides, enamides, and cyclic acetals, and applications in natural product syntheses.