Synthetic approaches towards alkaloids bearing a -tertiary amines

Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classi ﬁ ed along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the a -tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed.

Methods used for the installation of a-tertiary amines 2.1 A C,C-bond is formed in the step that generates the ATA 2.2 A C,N-bond is formed in the step that generates the ATA 3 Homotropane alkaloids 4 Histrionicotoxins 5 Lycopodium alkaloids 6 Hasubanan alkaloids 7 Stemona alkaloids 8 Indole alkaloids 9 Cephalotaxines 10 Erythrina alkaloids 11 Indolizidine and quinolizidine alkaloids 12

Introduction
Alkaloids have played an important role in the development of synthetic organic chemistry, pharmacology and medicine. Once considered to be metabolic waste products, they are now known to benet their producers in various ways, e.g. as antimicrobials, antifeedants or as mediators of ecologically benecial interactions. 1 Though a limited number of amino acids are involved in their biosynthesis, alkaloids exhibit enormous structural variability, which is oen increased through the incorporation of terpenoid and polyketide components and late-stage oxidative transformations. 2 Reecting their structural diversity and relatively weak basicity, alkaloids interact with a large variety of biological targets and have found many uses in human medicine. 3,4 In addition, they have provided inspiration for countless synthetic drugs that borrow structural motifs from their natural counterparts.
The a-tertiary amine (ATA) stands out among the structural features frequently found in alkaloids. [5][6][7][8] For the purposes of this review and in keeping with the literature, we dene an ATA as a nitrogen atom bound to a sp 3 -hybridized carbon that bears three additional carbon-carbon bonds. The nitrogen itself can be sp 3 -hybridized as part of a primary, secondary and tertiary amine. Broadening our denition, it can also be sp 2 -or sphybridized, e.g. in an amide or isonitrile. The tetrasubstituted carbon from which the C,N-bond branches out is oen stereogenic, which makes ATAs particularly interesting from a synthetic point of view. Our denition puts emphasis on this particular C,N-bond and avoids the confusion that is oen associated with the term 'quaternary stereocenter', which, strictly speaking, refers only to a carbon atom surrounded by four other carbons. Fig. 1 shows some alkaloids and drugs with alkaloid-like properties that illustrate our denition and demonstrate that the nitrogen in ATAs (highlighted in red) can be substituted to various degrees. Memantine and huperzine A contain primary ATAs, whereas ketamine, MK-801 and histrionicotoxin 283A (HTX 283A) feature secondary ATAs, and lycopodine is representative of molecules containing a tertiary ATA. 2,2,6,6-Tetramethylpiperidine (TMP) and the alkaloid porantherine are examples for molecules featuring a twofold ATA. The dimeric alkaloid stephacidin B contains no fewer than four ATAs. Notably, the acarbons are stereogenic in the majority of these compounds.
In this review, we wish to provide a brief survey of synthetic methods used to install the ATA motif and discuss their application in the total synthesis of alkaloids. The syntheses included here have been selected based on their historical signicance, the intriguing structure of their target molecule, and the elegance and efficiency of the method used. The order of their presentation is somewhat arbitrary, mixing biosynthetic and taxonomic categories (such as Lycopodium alkaloids), with purely structural ones (such as quinolizidine alkaloids). Generally, we have aimed to proceed from simpler target molecules to more complex ones. While our review is by no means comprehensive, we hope to feature the most instructive examples for the establishment of ATAs and thus provide inspiration and valuable lessons for future work. We also hope that this review will benet the design of synthetic pathways toward drugs and synthetic building blocks that contain a-tertiary amines.

Methods used for the installation of a-tertiary amines
Many approaches toward the installation of ATAs have been developed but only a relatively small subset of these has proven popular in alkaloid total synthesis. Here, we provide a brief survey of these methods, discussing them in general terms. We classify them according to the bond that is formed in the key step and the electronic nature of the nitrogen and carbon, respectively. However, it should be noted that not all of the syntheses discussed in this review fall into this simplied organizational scheme.

A C,C-bond is formed in the step that generates the ATA
The a-carbon is electrophilic. Some of the most commonly encountered methods involve the addition of carbon nucleophiles to activated imines and iminium ions (Scheme 1). They include Mannich reactions, Strecker reactions, aza-Prins reactions and the 1,2-addition of organometallic reagents to C,Ndouble bonds. N-Acyliminium ions are particularly powerful electrophiles in reactions of this type. A variant of the Heck olenation that involves enamines also falls into this category.
The a-carbon is nucleophilic. In an Umpolung of the above situation, the a-carbon can also serve as a nucleophile (Scheme 2). For instance, the alkylation of branched nitroalkanes or of deprotonated amino acid derivatives can be used to establish ATAs. Insertions of carbons into nucleophilic C,H-bonds next to a C,N-bond are a member of this general category as well.
Radical reactions. Radical reactions establishing ATAs are relatively rare, but not unprecedented (Scheme 4). 5-endo-Trig and 6-endo-trig cyclizations as well as radical transfer allylations belong to this category.

A C,N-bond is formed in the step that generates the ATA
The nitrogen is electrophilic. Rearrangements that involve electron-decient nitrogen atoms are oen encountered in the formation of ATAs (Scheme 5).
They include the Curtius, Schmidt, Hofmann, Beckmann and Stieglitz rearrangements. 5 Oen, these reactions can be classied as [1,2] sigmatropic rearrangements. Related nucleophilic substitutions involving N-haloamines have been used as well. An electron-decient nitrogen atom also plays a role in the insertion of nitrenes into C,H-bonds.
The nitrogen is nucleophilic. The formation of ATAs through nucleophilic additions or substitutions involving nitrogen is fairly common (Scheme 6). The classical Michael addition falls into this category, as do S N 2 0 reactions and haloaminations. For obvious reasons, S N 2 reactions are rare and mostly conned to intramolecular cases. Carbocations that react with a nucleophilic nitrogen occur in the aza-Prins reaction and the Ritter reaction. Oxidative dearomatizations have also been used in a few cases to establish ATAs.
Pericyclic reactions. Pericyclic reactions in which a C,Nbond is formed provide powerful means to establish ATAs (Scheme 7). Overman, Kazmaier-Claisen and [3,3] sigmatropic rearrangements of allylic isocyanides belong to this category. Divinyl cyclopropane rearrangements have also been used to establish ATAs. 5 Many more methods have emerged in recent years that can be used to create ATAs, such as reactions proceeding via C,Hactivation 9 and hydroaminations. 10 Since they have not yet been employed in the total synthesis of alkaloids, they are not featured in this review. Other methods, such as the Mannich reaction, Curtius rearrangement and Michael reaction, have proven to be so popular in the total synthesis of alkaloids that we cannot include all instances where they have been employed in this review.

Homotropane alkaloids
One of the rst applications of Mannich reactions in the construction of ATAs occurred during the synthesis of certain homotropane alkaloids. Three representatives, euphococcinine, N-methyl euphococcine and adaline, feature an ATA in the bridgehead position of a bicyclic framework (Fig. 2). These simple natural products are excreted by lady beetles (coccinellids) when threatened. 11,12 In 1959, Alder synthesized N-methyl-euphococcinine using a protocol analogous to the famous tropinone syntheses of Robinson 13,14 and Schöpf 15 (Scheme 8a). 16 Dehydropyrane 1 was converted into ketoaldehyde 2, which was then transformed into N-methyl-euphococcinine in a one-pot process (via iminium-intermediate 3). [17][18][19] A similar strategy was later adopted to synthesize the structurally related alkaloid adaline. 20 Throughout the years, this biomimetic Mannich strategy was adopted in other syntheses of euphococcinine and adaline. [21][22][23] Alternative approaches involved a 1,3-dipolar cycloaddition, 24 addition to an N-acyliminium ion, 25 Michael addition 26,27 and allylic rearrangement of a cyanate to an isocyanate. 28,29 In 2010, Davis published a biomimetic synthesis of (À)-euphococcinine and (À)-adaline in enantiopure form (Scheme 8b). 30 The key steps of these syntheses involved the stereoselective formation of piperideine 6 and 7 from the enantiomerically pure N-sulnyl aminoketones 4 and 5, respectively. 31 An ensuing intramolecular Mannich reaction afforded the azabicyclononane natural products.

Histrionicotoxins
In 1971, Daly isolated six different alkaloids, termed histrionicotoxins (HTXs), from skin extracts of the Colombian poison arrow frog Dendrobates histrionicus (Fig. 3). 32,33 They all contain a unique spirocyclic piperidine core and differ mostly in the length and the degree of saturation of the two side chains. Several histrionicotoxins were identied as inhibitors of nicotinic acetylcholine receptors, [34][35][36][37][38] which, together with their attractive structures, prompted signicant attention from the synthetic community. 39 The low natural abundance of these alkaloids and the fact that the frogs do not secrete HTXs in captivity made an efficient synthetic approach all the more desirable.
The rst total synthesis of histrionicotoxin alkaloids was reported by Kishi in 1975 (Scheme 9a). [40][41][42] His synthesis of octahydrohistrionicotoxin (oHTX) utilized an intramolecular acid-catalyzed aza-Michael addition to set the ATA. Amide 8 was converted to a 2 : 1 mixture of epimeric spiroketolactams 9 and 10. It was possible to transform 9 into the desired diastereoisomer 10 upon treatment with sodium methoxide.
Heathcock established one of the most elegant and inuential routes to lycopodine in 1982 (Scheme 13a). [80][81][82] In a remarkable sequence, intermediate 28 underwent deprotection, condensation and intramolecular Mannich reaction to yield secondary amine 30, presumably via iminium ion 29. The installation of the a-tertiary amine and the formation of two out of four rings thus occurred in a single step, mimicking the proposed biosynthesis of this natural product. Subsequent optimization led to the shortest synthesis of lycopodine to date, consisting of only eight steps. 82 Using a similar sequence, lycodine and lycodoline were prepared as well. 82 Variations of Heathcock's strategy have been used in other synthetic approaches toward Lycopodium alkaloids, e.g. in syntheses of clavolonine by Evans (2005) 84 and Fujioka (2011). 83 One drawback of intramolecular Mannich reactions, however, is the need to simultaneously form an iminium ion and an enol. Thus, long reaction times of up to 18 days were needed. 82 Recently, this problem was solved in an elegant way by Carter (Scheme 13b). 85,86 Using an aza-Wittig approach, Carter was able to prepare and isolate the TBS-enol ether imine 31. Treatment of 31 with zinc triate furnished the ATA and concomitantly resulted in the rearrangement of the sulnyl residue yielding lycopodine precursor 32.
In 1985, Kraus published a route towards lycopodine that was based on the formation of a bridgehead olen (Scheme 14a). 87 Tertiary alkyl bromide 33 was treated with DBU and 3-amino-1-propanol to install amino ketone 34, which could be further transformed into the natural product in two additional steps using Heathcock's protocol. An equally unusual approach was reported by Grieco, who employed a Stieglitz rearrangement (Scheme 14b). 88 To effect the reaction, N-chloroamine 35 was treated with silver tetrauoroborate followed by cyanoborohydride. Many other syntheses of lycopodine have been accomplished utilizing different strategies, such as Michael additions, for the assembly of the ATA. [89][90][91] Members of the lycodine class of natural products feature an ATA and a pyridine or pyridone moiety. The parent compound, lycodine, 92 was rst isolated from L. annotinum in 1958. 93 Apart from the Heathcock synthesis mentioned above, 82 several additional syntheses of lycodine have been achieved to date. [94][95][96][97] Schumann used a classical Mannich strategy to access racemic lycodine, a-obscurine and N-acetylabellidine (Scheme 15). [98][99][100] The mechanism of the key double Mannich reaction cascade was further explored almost 30 years later by Sarpong. 94 He used the same cascade as an opening sequence in an asymmetric synthesis of enantiomerically pure (+)-complanadine A, a lycodine dimer, which was shown to enhance expression of nerve growth factor in human cells. 101 It was found that cyclic enamide 36 opens to ketone 37 or enol 38 under acidic conditions, which adds to the unsaturated bicyclic imine 39. Protonation of the resulting enamine 40 triggers a second, intramolecular Mannich reaction to afford tricycle 42 via the iminium ion 41. Finally, an intramolecular enamide formation furnished tetracyclic des-N-methyl-a-obscurine, containing the entire lycodine framework.
In an unusual approach, Tsukano and Hirama applied an intramolecular palladium-mediated Heck reaction between enecarbamate and pyridine triate 43 to form the ATA, which yielded lycodine precursor 44 (Scheme 16a). 95 Recently, another very short synthesis of (À)-lycodine as well as the closely related (+)-abellidine was accomplished by Takayama (Scheme 16b). 97 Starting from a linear precursor 45, he was able to assemble the whole tetracyclic skeleton 48 of both alkaloids in a cascade reaction involving a double condensation (45 / 46), a conjugate addition (46 / 47) followed by a Mannich reaction (47 / 48). In addition, Shair published an approach towards several members of the 7membered-ring-containing Lycopodium alkaloids using a transannular Mannich reaction (not shown). 102,103 One of the rare cases of a S N 2 reaction in ATA formation can be found in Lei's recent synthesis of (À)-8-deoxyserratinine (Scheme 17). 104 Tertiary alcohol 49 was converted into chloride 50, which was attacked intramolecularly by the free secondary amine (50 / 51). In 2014, Lei extended his strategy to a synthesis of the oxidised congener (À)-serratinine. 105 Other approaches towards 8-deoxyserratinine and related alkaloids include a Schmidt rearrangement and an intramolecular epoxide opening. [106][107][108] In contrast to the multiple strategies used for the installation of ATAs in the Lycopodium alkaloids mentioned above, the Scheme 16 Syntheses of various Lycopodium alkaloids by Tsukano (2010) and Takayama (2014 Scheme 17 Lei's synthesis of (À)-8-deoxyserratinine (2014). Boc ¼ tert-butyloxycarbonyl. Kozikowski (1989).

Scheme 19
Huperzine A syntheses by Sun/Lin (2012) and White (2013). Boc ¼ tert-butyloxycarbonyl, p-TsCl ¼ para-toluenesulfonic acid. methods used to access the medicinally important acetylcholine esterase inhibitor huperzine A are less diverse. Since the ATA in huperzine A is primary, it can be efficiently installed using a Curtius rearrangement. Indeed, synthetic efforts towards huperzine A were almost exclusively focused on carboxylic acid precursors, such as 52. [109][110][111][112][113][114][115][116] The rst synthesis of huperzine A was published by Kozikowski in 1989 (Scheme 18). 109 First, he completed the core 52 wherein the primary amine is replaced by a methyl ester. Aer saponication, Curtius rearrangement (52 / 53) followed by double deprotection provided racemic huperzine A. In the following years, many huperzine A syntheses and several semisyntheses were published. 117,118 All of them featured a racemic or enantiomerically pure carboxylic acid derivative of precursor 53, keeping the Curtius rearrangement as the key step for the formation of the ATA. [109][110][111][112][113][114][115][116] These efforts culminated in the recently published large-scale asymmetric synthesis of huperzine A. 119 A few groups, however, have been able to avoid Curtius rearrangements in the synthesis of huperzine A. Sun and Lin accessed the alkaloid using an intramolecular Heck reaction (54 / 55) (Scheme 19a), 120 whereas the White group performed an elegant tandem intramolecular aza-Prins cyclization/cyclobutane fragmentation (56 / 53) to set the ATA in 53 (Scheme 19b). 121 Two Lycopodium alkaloids recently isolated from Lycopodium hamiltonii, viz. the nankakurines A and B, have attracted broad interest in the synthetic community (Fig. 4). 122,123 So far, two syntheses of these natural products have been reported. In 2008, Overman published an enantioselective synthesis of the misassigned original structure of nankakurine A (61) (Scheme 20a) followed by the syntheses of the reassigned structures of nankakurine A and B in 2010 (Scheme 20b). 124,125 In the case of 5-epi-nankakurine (61), an aza-Prins reaction (59 / 60) was used, which allowed for the direct formation of both piperidine rings in 61 in one step starting from bicycle 59. 124 This strategy, however could not be applied for the formation of actual nankakurine A. Its synthesis was accomplished utilizing an intramolecular 1,3-dipolar cycloaddition of an azomethine imine 63, formed in situ via condensation of 62 with formaldehyde. This reaction provided access to tetracyclic pyrazolidine 64, which, aer SmI 2 mediated N,N-bond cleavage, gave rise to nankakurines A and B. 125 Two years later, Waters reported a racemic synthesis of nankakurines A and B using a Grignard addition to an iminium species derived from luciduline, which is easily accessible by total synthesis (not shown). 126 Porantherine, the major alkaloid of the poisonous woody shrub Poranthera corymbosa, is structurally similar to the Lycopodium alkaloids, although not a member of the family (Fig. 4). 127,128 Possessing two tertiary carbons attached to the same amine (twofold ATA), porantherine is a considerable synthetic challenge that has been met only twice thus far. 129,130 Both syntheses are racemic and based on similar strategies for the assembly of the ATA motif, namely an addition to a ketimine followed by Mannich reaction. Corey published his synthesis of the natural product in 1974 (Scheme 21), 129 only three years aer its isolation. The rst ATA was installed through addition of an organolithium compound to imine 65 to form 66, which then cyclized to the corresponding enamine 67 upon treatment with acid. The formation of the second ATA center through an intramolecular Mannich addition (via iminium ion 68) furnished ketone 69, which was eventually converted to the natural product.
A second synthesis of porantherine, published by Stevens in 1987, involved the addition of two alkyllithium compounds to an iminoether (not shown). 130

Hasubanan alkaloids
The hasubanan alkaloids, isolated from various plant sources, are structurally related to the better-known morphine alkaloids but feature a pyrrolidine ring instead of a piperidine ring. They are comprised of over 40 family members, all of which share the same aza-propellane skeleton (Fig. 5). 131 Scheme 20 Overman's syntheses of misassigned nankakurine A (2008) and revised nankakurines A and B (2010). Bn ¼ benzyl, Bz ¼ benzoyl, TFA ¼ trifluoroacetic acid, Ts ¼ para-toluenesulfonyl.
In contrast to this approach, which sets the ATA at a relatively late stage in the synthesis, Reisman installed it at the beginning (Scheme 23a). 144 Reaction of the chiral N-tert-buta-nesulnimine 78 with phenethyl Grignard 77 provided sulnamide 79 with a high degree of diastereoselectivity. Subsequently, 79 was converted into a series of hasubanan alkaloids such as (À)-8-demethoxyrunanine.
The rst enantioselective synthesis of hasubanonine was published by Herzon (Scheme 23b). 143 Methylation of iminoquinone Diels-Alder adduct 80 (80 / 81), followed by addition of alkynyl lithium 82 gave amine 83, which was eventually transformed into optically pure (À)-hasubanonine. This strategy proved to be versatile, as many more hasubanan alkaloids, including (À)-runanine, (À)-delavayine, (+)-periglaucine B and (À)-acutumine, could be accessed by variation of the alkynyl species. 143,145,146 7 Stemona alkaloids Plants belonging to the family Stemonaceae, which are mostly found in Southeast Asia, have been used for centuries as insecticides and for the treatment of respiratory diseases. [148][149][150] Phytochemical investigations led to the isolation of a variety of natural products known as Stemona alkaloids (Fig. 6). 151,152 These polycyclic natural products possess highly complex structures weaving together pyrrolidines and butenolides, oen through spiro fusions that contain ATAs. The structural beauty of these molecules generated considerable interest in the synthetic community and stimulated the development of new synthetic methods for the installation of ATAs. 151,152 The strategies employed range from classical additions to imines, 153,154 to radical cyclization cascades, 155,156 radical allylations, 157 semipinacol-Schmidt cascades, 158,159 Schmidt reactions, 160 aza-Cope-Mannich reactions, 161 cyclopropane-Cope rearrangements 162 and catalytic 1,3-dipolar cycloadditions. 163 The rst synthesis of a Stemona alkaloid, viz. isostemofoline, was published by Kende in 1999 and employed a highly unusual and elegant approach. 162 The ATA was formed via rhodiumcatalyzed reaction of pyrrole 84 with vinyl diazoester 85. The resultant divinyl cyclopropane 86 underwent Cope rearrangement in situ to afford bicycle 87, which was then used as a key intermediate in the further assembly of the natural product (Scheme 24a).
More recently, two synthetic approaches aimed at members of the stemonamine group were published. Ishibashi developed an entry to racemic stemonamide and isostemonamide as well as their reduced derivatives stemonamine and isostemonamine, based on a radical cascade as the key step for the formation of the ATA (Scheme 24b). 155,156 Treatment of the achiral precursor 88 with tributyltin hydride and 1,1 0 -azobis(cyclohexanecarbonitrile) (ABCN) at elevated temperatures effected a 7-endo-trig cyclization that likely yielded radical 89 as the proposed intermediate, which in turn underwent an unusual 5-endo-trig cyclization providing access to a separable mixture of isomers 90 and 91. Further transformations of these tricyclic compounds furnished stemonamide and some of its congeners.
An alternative approach to stemonamide and related Stemona alkaloids was published by Zhang (Scheme 24c). 159 Based on his systematic studies on the reactivity of a-hydroxy epoxides such as 92, 164 he developed a powerful cascade that combines a semipinacol rearrangement with an Aubé-Schmidt reaction (92/94). The resulting amide 94 was obtained as a 5 : 1 mixture of diastereomers, reecting the diastereomeric mixture of propargylic azides employed as substrates. Using this strategy and variations thereof, Zhang was able to synthesize stemonamide and three additional Stemona alkaloids, viz. maistemonine, stemonamine, and isomaistemonine. [158][159][160] The only synthesis of asparagamine A, an unsaturated derivative of stemonamide, was achieved by Overman in 2003. 161 He installed the ATA using his signature aza-Cope-Mannich cascade (Scheme 25a). The synthesis of a precursor molecule

Indole alkaloids
Indole alkaloids are a structurally and biosynthetically heterogeneous class of natural products characterized by an indole nucleus or derivative thereof. Several of them, albeit not the best known ones, contain ATAs (Fig. 7). Kopsine, the rst member of the so-called Kopsia alkaloids, was isolated as early as 1890, 165 but it took several decades before its complex structure, and those of its congeners, could be elucidated. [166][167][168][169][170][171][172][173] All members of this family possess an ATA incorporated in a bicyclo[2.2.2]octane system. Thus, the kopsanes seem predestined for Diels-Alder reactions, and few syntheses fail to employ a [4+2] cycloaddition strategy. [174][175][176] The routes used can be divided into two main categories: (a) intermolecular Diels-Alder reactions 177-180 and (b) intramolecular Diels-Alder reactions. [181][182][183][184][185] The very rst synthesis of (AE)-aspidofractinine, completed in 1976, introduced an intermolecular Diels-Alder reaction to set the ATA using nitroethylene as a dienophile (not shown). 177 Over time, phenyl vinyl sulfone emerged as a more practical dienophile 178,179 and in 2009 the rst enantioselective synthesis of (+)-aspidofractinine was reported by Spino using this reagent (Scheme 26a). 180 In this case, imine 101 thermally isomerized to diene 102, which then underwent cycloaddition from the sterically more accessible convex side to afford sulfone 103.
The rst successful intramolecular Diels-Alder approach to (AE)-kopsanone and (AE)-10,22-dioxokopsane was reported in 1983 by Magnus (Scheme 26b). 181,182 They synthesized sulde 104 as a suitable precursor, with the dienophile placed in the concave position. The cycloaddition reaction proceeded at 100 C and provided intermediate 105, which was transformed into (AE)-kopsanone in a few steps. Using a similar strategy, other indole alkaloids, (AE)-kopsijasmine and (AE)-kopsine, were prepared as racemates, 184,185 as well as (À)-kopsinilam and (À)-kopsinine in enantiomerically pure form. 183 In a recent example for an alternative approach by Boger, a powerful radical transannular cyclization was applied to install the ATA of kopsinine (Scheme 26c). 176 Upon treatment of xanthate 106 with SmI 2 , ATA 108 was formed as a single diastereomer. Presumably, a primary radical intermediate 107 is formed, which undergoes a radical cyclization followed by reduction and diastereoselective protonation of the ester enolate.
Lapidilectine B and lundurine A are two structurally related Kopsia alkaloids that contain two ATAs. Although not originating from the same organism, they show a similar scaffold with a bridged 8-membered ring fused to an indoline on one side and a 5-membered ring on the other. Lapidilectine A was isolated by Awang from the leaves of the tree Kopsia lapidilecta in 1992. 186,187 Lundurines A-D were isolated from the Malaysian tree Kopsia tenuis, 188 and shown to be effective at bypassing multidrug resistance in vincristine-resistant KB cells. 189 Qin accomplished the rst enantioselective synthesis of (À)-lundurine A in 2014 (Scheme 27a). 190 The rst ATA was established via the addition of allylmagnesium bromide to an iminium ion generated by in situ alkylation of imine 109 to form tetracycle 110. In order to establish the two fully substituted stereocenters on the indoline of 112, Qin resorted to an unusual intramolecular Simmons-Smith cyclopropanation of diiodide

111.
Two other racemic syntheses of lundurine A and B have been reported by Nishida. [191][192][193] He employed a Curtius rearrangement and a 1,2-addition to an iminium ion for lundurine B 193 and a Tsuji-Trost amination and an indoxyl bisalkylation for the synthesis of lundurine A (not shown). 191,192 In 2001, Pearson employed a Smalley cyclization of aryl ketone azide 113 to furnish the spiroindoxyl 114 (Scheme 27b). 194,195 In the nal steps of his lapidilectine B synthesis, he then used his trademark azaallyl anion [3+2] cycloaddition to establish the pyrrolidine ring (115 / 116) as an inconsequential mixture of regioisomers.
The cycloaddition approach has not been limited to the kopsane alkaloids. Other indole alkaloids, such as stephacidin A and the notoamides, which bear two ATAs, were prepared by a presumably biomimetic [4+2] cycloaddition.
Williams synthesized stephacidin A and notoamide B starting from imidate 117, which underwent base-mediated isomerization to 118 followed by intramolecular Diels-Alder reaction to afford diazabicyclo[2.2.2]octane 119 (Scheme 28). 196 This remarkable reaction sets both ATAs in a single step. Later that year, stephacidin B was accessed via avrainvillamide using the same strategy. 197 In 2005, Baran used the a-alkylation of proline derivative 120 with complete chirality transfer, a method developed by Seebach, 198 to set the rst ATA of stephacidin A in 121 (Scheme 29). 199 The second ATA present in 123 was installed by an intramolecular, stereocontrolled oxidative enolate coupling starting from diketopiperazine 122. Baran was then able to convert stephacidin A into avrainvillamide and stephacidin B following a biosynthetic proposal. 200 A second synthesis of avrainvillamide and stephacidin B was accomplished concurrently by Myers (Scheme 30). 201 In this case, the rst ATA was installed by a Strecker-type addition of TMS cyanide to enamine 124 to form the N-Boc amino nitrile 125. The second ATA was then set by a very unusual radical transfer cyclization. Abstraction of a hydrogen atom in 126, followed by loss of toluene, generates an aminoacyl radical which attacks the enamide double bond and ejects a phenylthiyl radical to form the diketopiperazine 127.

Scheme 27 Syntheses of Kopsia alkaloids by Qin (2014) and Pearson (2001). Bn
In the case of citrinadin A, epoxide 128 was heated in the presence of methylamine to provide 1,2-amino alcohol 129 (Scheme 31a). 205 Wood's approach employed an azide-mediated opening of epoxide 130 to establish the ATA in 131 (Scheme 31b). 206 Both reactions are rare examples where an ATA has been set through a S N 2 reaction.
More recently, Sarpong published his entry to the prenylated indole alkaloids cyclopiamine B and ent-citrinalin B (Scheme 32). The rst ATA was set via a Hofmann rearrangement (132 / 133). 207 The second, not asymmetric, ATA center was established by treating ent-citrinalin B with sodium hydride to effect the rearrangement of the chromanone to the tetrahydroquinolone moiety present in cyclopiamine via retro-Michael/Michael addition. Using a similar approach, he was then able to synthesize the structurally related alkaloids stephacidin A and notoamide B. 208 Two alkaloids closely related to notoamide B, marcfortine B and C, were synthesized by Trost using a Michael addition and a radical cyclization to set the two ATAs (not shown). 209,210 Gelsemoxonine is an indole alkaloid with an ATA that is part of a azetidine, a rare structural motif. It is also a member of the Scheme 28 Synthesis of prenylated indole alkaloids by .
Scheme 29 Synthesis of prenylated indole alkaloids by . acac ¼ acetylacetonate, Boc ¼ tert-butyloxycarbonyl, t-Bu ¼ tertbutyl, LDA ¼ lithiumdiisopropylamide. Gelsemium spirooxindole family, a large alkaloid family with highly compact, strained and complex structures, which have attracted considerable synthetic activity. [211][212][213] In 2011, Fukuyama accomplished a total synthesis of gelsemoxonine that employed an intramolecular epoxide opening of 134 to install the ATA (Scheme 33a). 214 Recently, Carreira published an elegant entry to gelsemoxonine, setting the ATA 136 via a diastereoselective propynyllithium addition to isoxazoline 135 (Scheme 33b). 215 The welwitindolinones are another class of indole alkaloids with an ATA that is not part of the indole-derived moiety itself. The rst welwitindolinone natural products (Fig. 7) were isolated by Moore in 1994 from the cyanobacteria Hapalosiphom welwitschii and Westiella intracta. 216 All welwitindolinones known so far feature a [4.3.1] bicyclic framework, which, in some cases, contains a modied ATA that bears an isothiocyanate or isonitrile functional group. 217,218 Being a considerable challenge for total synthesis, the welwitindolinones have become popular targets. 219 The rst total synthesis of N-methylwelwitindolinone D isonitrile was accomplished by Rawal in 2011 220-222 using Kim's oxime rearrangement to install the isothiocyanide (137 / 138, Scheme 34a). 223,224 Desulfuration of 138 then gave the naturally occuring isonitrile. Martin completed a synthesis that intercepts Rawal's synthesis in 2012. 225 Garg's total synthesis of N-methylwelwitindolinone C isothiocyanate used an intramolecular Ag-mediated nitrene C,Hinsertion of amide 139 as the critical step, which furnished carbamate 140 (Scheme 34b). 226,227 To improve the regioselectivity and yield of this late stage transformation, the authors beautifully exploited the deuterium kinetic isotope effect. 228 Both Rawal and Garg were able to subsequently synthesize several members of the welwitindolinone family by varying their initial strategies. 222,[228][229][230] In addition, Hatakeyama recently accomplished another synthesis of (À)-N-methylwelwitindolinone C isothiocyanate using an endgame similar to Rawal's. 231 Two examples of reactions which have been specically developed to set an ATA, both explored by the Baran laboratory, are shown in Scheme 35.
In the synthesis of chartelline C, the ATA was set via a cascade reaction initiated by the bromination of indole 141 at 185 C resulting in 142 (Scheme 35a). Amide attack furnished intermediate 143, which then rearranged in a 1,5-shi to give the ring contracted spiro-b-lactam 144. 232,233 For the synthesis of psychotrimine, a coupling of indole 147 with 2-iodoaniline (146) was developed to yield 148, which then underwent further cyclization to give 149 (Scheme 35b). 234 This method was also used for the syntheses of psychotetramine, 235 kapakahine B and kapakahine F. 236,237 Another interesting way to install an ATA in a structurally complex indole alkaloid was published by Danishefsky (Scheme 36). 238 In his synthesis of the furanobisindole alkaloid phalarine, amino acid derivative 150 was treated with formaldehyde and acid to set the ATA in a diastereoselective fashion (150 / 152). It is not clear, however, whether this reaction proceeds via

Cephalotaxines
Due to their interesting chemical structure and antileukemic activities, the cephalotaxines, isolated from the Japanese plum yew (Cephalotaxus harringtonii), have emerged as popular targets for natural product synthesis (Fig. 8). 239 The rst synthesis of cephalotaxine itself was reported by Weinreb in 1972 (Scheme 37a). 240 Conversion of enamine 155 into diketone 156 set the stage for a Lewis-acid catalyzed cyclization to yield tertiary amine 158 (via intermediate 157). Weinreb was able to synthesize cephalotaxine in six additional steps with an overall yield of 20%, setting a high bar for the following syntheses.
In 1988, Fuchs utilized an intramolecular [4+2] nitroso-Diels-Alder cycloaddition to assemble the benzazepine 161 from hydroxamic acid 159 (via intermediate 160, Scheme 37b). 241 Tietze published a formal asymmetric synthesis of (À)-cephalotaxine in 1999 that is based on palladium catalysis   244 A rather unusual approach for the asymmetric synthesis of (À)-cephalotaxine was pursued by Royer, who introduced the ATA on key intermediate 169 via semipinacol rearrangement of chiral a-hydroxyiminium 168. The latter was generated by acidcatalyzed isomerization and protonation of pyrrolinone 167 (Scheme 39a). 245 Another synthesis was developed by Gin, who transformed vinylogous amide 170 into azomethine ylide 171 which then underwent 1,3-dipolar cycloaddition with phenyl vinyl sulfone to yield 172 (Scheme 39b). 246,247 The unexpected yet advantageous stereochemical outcome of this cycloaddition was conrmed by X-ray analysis.

Scheme 40 Syntheses of cephalotaxine by Mariano (2006), Hayes (2008) and Ishibashi (2008). ABCN
reaction, 257 addition to an imine, 258 transannular cyclization 259 and oxidative rearrangement. 251 10 Erythrina alkaloids Erythrina alkaloids were discovered at the end of the 19 th century, when extracts of Erythrina trees were found to possess curare-like neuromuscular activities. 260 Due to their biological activities and interesting structures (Fig. 9), several total syntheses of these natural products have been carried out and many creative ways to install ATAs have been developed in this context. 261 In 1990, the group of Ishibashi published the synthesis of (AE)-3-demethoxyerythratidinone using an intramolecular Pummerer-like rearrangement of the enamine 180, setting the stage for a Pictet-Spengler-type reaction (181 / 182) to furnish the ATA (Scheme 41a). 262 Thirteen years later, the same group published an oxidative radical cyclization starting from enamine 183 to obtain the skeleton of 3-demethoxyerythratidinone 182 (Scheme 41b). 263 Tsuda's approach featured an intermolecular photochemical [2+2] cyclization to install the ATA, starting from bicycle 184 and diene 185 (Scheme 41c). In the following steps, a ring expansion of the four-membered ring in 186 furnished the six-membered ring by a formal 1,3-migration of a vinylcyclobutane, affording the scaffold of erysotrine. 264 Funk accomplished the synthesis of isophellibiline via an approach that relies on pericyclic reactions (Scheme 42a). 265 Heating of dioxine 187 resulted in retro-Diels-Alder reaction to afford dehydroalanine derivative 188, which then underwent intramolecular [4+2] cycloaddition to yield lactam 189. The latter was converted into isophellibinine in a few steps.
Recently, Sarpong developed a new methodology to furnish ATAs and applied it to the synthesis of cocculolidine (Scheme 42b). 266 Propargylic alcohol 190 underwent cycloisomerization upon heating to form benz[g]indolizinone 191 which was then transformed to cocculidine in two additional steps.

Indolizidine and quinolizidine alkaloids
A range of alkaloids that belong to the indolizidine and quinolizidine structural class feature an ATA in their carbon skeleton. 280 They include natural products as diverse as the cylindricines, 280,281 FR901483, 282 himandrines, lepadiformines 283 and halichlorine 284 (Fig. 10).
The rst synthesis of cylindricine alkaloids (viz. cylindricine A, D and E) was accomplished by Snider utilizing a double Michael addition of ammonia to divinylketone 198 which gave the ATA 199, a direct precursor of cylindricine A (Scheme 44a). 285 Variations of this approach have been used several times in the synthesis of cylindricines. 286 In 2003, Padwa published a synthesis featuring a Michael addition/dipolar cycloaddition cascade between butadiene 201 and oxime 200 to form 203 via intermediate 202 (Scheme 44b). 287 The Hsung synthesis of enantiomerically pure cylindricine C relies on a nucleophilic attack of a diene on N-acyliminium ion 205 starting from ketone 204 (Scheme 45). 288,289 This vinylogous aza-Prins approach was based on a synthesis published by Kibayashi in 2005. 290 Additional strategies to synthesize the ATA in cylindricine alkaloids involve mainly Michael additions, 286,291,292 Grignard additions to an imine, 293 a cycloaddition of an alkyne to a pyrrole derivative, 294 and carboazidation. 295 FR901483, an alkaloid isolated from the fermentation broth of a Cladobotryum species with an intricate tricyclic structure, 282 proved to be an equally popular synthetic target. A biomimetic approach was employed by Sorensen in his enantioselective synthesis (Scheme 46a). 296 The oxidative azaspiroannulation of amine 207 promoted by (diacetoxyiodo)benzene resulted in the formation of spiroamine 208, an intermediate on the way to the natural product. The same year, Ciufolini set the ATA via a closely related oxidative spiroannulation (not shown, for an example of the methodology see Scheme 43b). 297 An alternative to this strategy was found by Wang. 298 In this case, an Aubé-Schmidt reaction of azide 209 provided access to lactam 212, featuring the ATA of FR901483 (209 / 212, Scheme 46b). Additional synthetic strategies to set the ATA in FR901483 include a triple Michael addition, 299 a one-pot bisalkylation, 300,301 an aza-Cope rearrangement/Mannich cyclization 302,303 and an oxidative dearomatization. 297 The members of the galbulimima alkaloid family, such as himgaline and himandrine, also possess an ATA-containing quinolizidine core (Fig. 10). Exploring a biosynthetic hypothesis, Chackalamannil used an intramolecular Michael addition to convert GB 13 to himgaline via ketone 213 (Scheme 47a). 304,305 In an interesting variation of this apporach, Movassaghi converted enone 214 via its a-chloroester 215 to hexacyclic amine 216, which could then be transformed into himandrine. (Scheme 47b). 304 In 1996, Uemura disclosed a small series of unusual marine alkaloids featuring ATAs. One of these compounds,  halichlorine, was isolated from the marine sponge Halichondria okadai and was found to selectively inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1). 306 Pinnaic acid and tauropinnaic acid were recovered from bivalve Pinna muricata. 307,308 All three molecules present a challenging 6-aza-spiro [4.5]decane core containing the ATA. The latter two lack a quinolizidine moiety, but are included in this chapter due to their close structural relationship. Danishefsky and Trauner were the rst to report the synthesis of (+)-halichlorine in 1999 309 followed by a synthesis of pinnaic acid in 2001 (Scheme 48). 310,311 They used Meyers' lactam 217 as a chiral precursor, which was combined with allyltrimethylsilane in a Sakurai reaction to install the ATA in 218. Intermediate 219 could be diversied to reach both halichlorine and pinnaic acid. These syntheses established the absolute conguration of halichlorine and conrmed the stereochemistry at C-14 and C-17 of pinnaic acid.
A related apporach employing a different type of N-acyl iminium ion was used by Heathcock in 2004 for the synthesis of halichlorine, pinnaic acid and tauropinnaic acid (Scheme 49a). 312 Treatment of carbamate acetal 220 with allyl trimethylsilane and titanium tetrachloride furnished ATA-bearing carbamate 221 with a high degree of stereoselectivity. This key intermediate could be transformed into all three natural products.
In 2007, Arimoto reported his version of an asymmetric synthesis of pinnaic acid using a Beckmann rearrangement to install the ATA (Scheme 49b). 313 The enantiomerically pure bicyclic ketone 222 was treated with a bulky hydroxylamine Scheme 44 Synthesis of cylindricines by Snider (1997) and Padwa (2003 reagent to afford the desired lactam 223, which was then converted into the natural product.

Lactacystine and salinosporamide
In 1991, Omura isolated the unusual natural product lactacystin from Streptomyces sp. OM-6519 and identied it as a proteasome inhibitor (Fig. 11). 314,315 A structurally related b-lactone, salinosporamide A, which shows similar biological activity, was subsequently isolated from a marine bacterium, Salinispora tropica. 316 Both compounds possess a densely functionalized g-lactam core with three contiguous stereocenters, one of which is of the ATA type. Their signicant biological activity has stimulated a large number of total syntheses, 317 and a variety of methods for the installation of the ATA motif have been applied.  In pioneering work, Corey reported ve total syntheses of lactacystin between 1992 and 1998. [318][319][320]326,327 The Corey group showed that the ATA can be installed using an aldol addition of a-amino acid derivative 224 (via intermediate 225, Scheme 50a). Other groups also contributed to this eld in the 1990s. [321][322][323][324][325]328 In most cases, the strategy applied for the installation of the ATA motif involved an alkylation or aldol reaction of an a-amino acid derivative. [318][319][320][321][322]324,[326][327][328] By contrast, Shibasaki introduced the ATA with a catalytic enantioselective Strecker reaction (Scheme 50b). 317,334 In this work, phosphinoylimine 226 was converted to aminonitrile 227 using a gadolinium catalyst and the chiral ligand A.
Another unusual approach was taken by Wardrop 346 in his formal synthesis and Hayes 338 in his total synthesis of lactacystin (Scheme 50c). Both groups explored an intramolecular carbene insertion into a C,H-bond to form the ve-membered heterocyclic core. Hayes converted the enantiomerically pure Scheme 48 Synthesis of halichlorine and pinnaic acid by Danishefsky and Trauner (1999). TBDPS ¼ tert-butyldiphenylsilyl, TMS ¼ trimethylsilyl.
vinyl bromide 229 to the corresponding vinylidene carbene, which underwent cyclization to afford 230 in high yield.
The rst synthesis of salinosporamide was reported by Corey in 2004. 330,331 In this case, the ATA was installed by alkylation of threonine-derived oxazoline 231 with chloromethyl benzyl ether (via intermediate 232, Scheme 51a).
A more recent synthesis of salinosporamide A published by Sato and Chid uses a stereoselective Overman rearrangement to install the ATA (Scheme 51b). 343 Heating of the highly functionalized trichloroacetimidate 233 provided trichloroacetamide 234 as a key intermediate.

Manzacidins
The manzacidins, a small family of bromopyrrole alkaloids, have attracted considerable attention from the synthetic community despite, or maybe because of their relatively simple structures. Manzacidins A-C (Fig. 12) were rst isolated form the Okinawan sponge Hymeniacidon sp. by Kobayashi in 1991, 348 followed by the isolation of manzacidin D from the 'living fossil' sponge Astrosclera willeyana 349 and N-methylmanzacidin C from Axinella brevistyla. 350 In 2000, Ohfune reported the synthesis of manzacidins A and C via a Strecker reaction and assigned the absolute conguration of these natural products (not shown). 351 In 2002, DuBois synthesized manzazidin C using an elegant oxidative C,Hinsertion that involved sulfamate 235 (via intermediate 236, Scheme 52a). 352 One year later, he used a similar strategy to set the ATA in tetrodotoxin (see chapter 14, Scheme 54c). 353 Leighton accomplished the synthesis of manzacidin C employing their asymmetric silane-promoted [3+2] cycloaddition methodology (Scheme 52b). 354 Exposure of alkene 237 and hydrazone 238 to chiral silane R,R-B gave pyrazolidine 239, thus setting both stereocenters of the target molecule, including the ATA, in a single step. Intermediate 239 was subsequently converted to manzacidin C via reductive N,Nbond cleavage. A more recent formal synthesis of manzacidins A and C, published by Ichikawa, features a rare allyl cyanate/isocyanate rearrangement as the key step (Scheme 53). 355 To this end, he synthesized carbamate 240, which was converted to allyl cyanate 241 by in situ dehydration. The subsequent rearrangement with chirality transfer gave isocyanate 242, which was then transformed into manzacidin A. The synthesis of manzacidin C was accomplished analogously from a diastereoisomer of carbamate 240. 355 Several other synthetic approaches toward these molecules have been reported. These strategies for the installation of the ATA moiety involve diastereoselective nitrene insertion, 352 1,3dipolar cycloaddition, 356,357 Hofmann rearrangement, 358 diastereoselective iodocyclization, 359,360 Grignard addition to an imine 361 and a variety of other methods. [362][363][364][365][366] Indeed, manzacidines remain targets of great interest for synthetic chemists. In 2015, Inoue published a synthesis of manzacidin A using a radical-based decarbonylative coupling (not shown). 367 Recently the relative stereochemistry of manzacidin B, which possesses an additional stereocenter, was revised using total synthesis. 362,363,365 Scheme 51 Syntheses of salinosporamide A by Corey (2004) and Sato (2011). Bn ¼ benzyl, LDA ¼ lithium diisopropylamide, TMS ¼ trimethylsilyl.

Tetrodotoxin
Tetrodotoxin (TTX) was rst isolated from the Fugu puffer sh in 1909. 368,369 Its structure was independently reported by Hirata-Goto, 370 Tsuda 371 and Woodward 372 in the 1960s. Their assignment was conrmed by X-ray crystallography, which also established the absolute conguration of the molecule. 373,374 TTX features a highly functionalized heteroadamantane framework that contains an ortho-acid and is fused to a cyclic guanidinium moiety via an ATA motif. The molecule is an extremely powerful and selective blocker of voltage-gated sodium channels and is widely used as a research tool in neuroscience. [375][376][377][378][379] Due to its intriguing structure and bioactivity, attempts to synthesize TTX have been made from an early stage and activity in this eld has recently increased signicantly. 380 The rst total synthesis of TTX was accomplished by Kishi in 1972 (Scheme 54a). [381][382][383][384] In his approach, the ATA was formed using a Beckmann rearrangement of oxime 243, which was synthesized using a regioselective Diels-Alder reaction. The resulting key intermediate 244 was converted into TTX using a series of stereoselective redox transformations, ring cleavage and the installation of the cyclic guanidine with newly developed methodology. Although the Kishi synthesis was not enantioselective, it still stands as one of the strategically most elegant approaches to a natural product featuring an ATA motif.
Aer a 30 year lull, Isobe published the rst enantioselective synthesis of TTX wherein the ATA motif was installed with a stereoselective Overman rearrangement (Scheme 54b). [385][386][387] To this end, an allylic alcohol was converted to trichloroacetimidate 245, which underwent rearrangement to yield trichloroacetamide 246. Compound 246 bears all the carbon atoms of TTX and could be converted into the natural product in a series of steps.
Shortly thereaer, DuBois developed an enantioselective approach to TTX that involved his signature nitrene insertion chemistry (Scheme 54c). 353 Exposure of the key intermediate, carbamate 247, to a hypervalent iodine reagent and magnesium oxide in the presence of a rhodium catalyst led to the formation of oxazolidinone 248, which bears the ATA motif. Insertion into other possible C,H-bonds was largely avoided through careful engineering of the substrate.

Miscellaneous alkaloids
ATA's occur in many other alkaloids that cannot easily be categorized along the biosynthetic and structural lines shown above. An example is gracilamine, which was isolated in 2005 bÿ Unver and Kaya from the Amaryllidacae species Galanthus gracilis. 388 In 2012, the rst synthesis of gracilamine was disclosed by Ma (Scheme 55a). 389 It relies on a potentially biomimetic, stereoselective and intramolecular [3+2] cycloaddition, transforming 249 into the highly functionalized pyrrolidine 250.
In a recent synthesis, Gao set the ATA via an intramolecular Mannich annulation (Scheme 55b). 390 First, a-ketoester 252 was condensed with amine 251. The resulting iminium ion 253 then underwent a diastereoselective Mannich reaction to furnish the hexacyclic scaffold 254 of gracilamine.
The amathaspiramides A-F are a family of marine alkaloids isolated from the bryozoan Amathia wilsoni in 1999 (Fig. 13). 391 They feature an unusual spirocyclic core consisting of a pyrrolidine fused to a pyrrolidinone moiety. 391 The rst total synthesis of a member of this family, viz. amathaspiramide F, was disclosed by Trauner in 2002 (Scheme 56a). 392 In this work, the proline-derived N,N-acetal 255 was converted to the corresponding silyl ketene acetal, which underwent a diastereoselective Michael addition to the nitro olen 256, establishing the ATA of 257. Subsequently, Ohfune published his approach to amathaspiramide F which utilizes an enolate Claisen rearrangement for the same purpose (not shown). 393 In 2012, Fukuyama reported the asymmetric synthesis of the entire amathaspiramide family (Scheme 56b). 394 In their work, the benzyl ester 258 bearing a quaternary stereocenter was rst deprotected and the resulting acid converted to the corresponding amine via Curtius rearrangement. Aer hydrolysis of the resulting isocyanate, the intermediate amino ester underwent cyclization to afford the pyrrolidinone 259, which could be converted into all members of the family.
More recently, Lee used a formal [3+2] cycloaddition between lithium(trimethylsilyl)diazomethane 266 and a,bunsaturated ester 265 to set the ATA in amanthaspiramide C (via intermediate 267, Scheme 57b). 396 The N,N-bond in pyrazoline 268 was cleaved by treatment with p-TsOH and additional transformations led to the total synthesis of amathaspiramide C and the formal synthesis of all the other amathaspiramides.
Scheme 55 Syntheses of gracilamine by Ma (2012) and Gao (2014). TBDPS ¼ tert-butyldiphenylsilyl, Troc ¼ 2,2,2-trichlorethoxycarbonyl, TFA ¼ trifluoroacetic acid. Fig. 13 The amathaspiramides A-F. Herein, we have provided a survey of syntheses that feature the installation of an a-tertiary amine (ATA) as a common thread. This structural motif is widespread amongst alkaloids and has physicochemical consequences, such as increased lipophilicity and chromatographic mobility that distinguishes its bearers from other basic amines. Since ATAs also occur in drug candidates and building blocks for functional materials, our review is intended to provide a useful reference for medicinal chemists and colleagues active in the material sciences. It may also provide a baseline for the development of additional and hopefully more efficient methods for the synthesis of target molecules containing a-tertiary amines.

Acknowledgements
We thank the Deutsche Forschungsgemeinscha (SFB 749) for nancial support. We are also grateful to the Deutsche Telekom Foundation (Ph.D. Scholarship to N. V.). We thank Felix Hartrampf, Benjamin Williams, Daniel W. Terwilliger, Dr Henry Toombs Ruane and David Konrad for helpful discussions and for proofreading the manuscript.
18 Notes and references