Recent Advances and Applications of Reductive Desulfurization In&Nbsp

Tetrahedron 70 (2014) 8983e9027

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Tetrahedron

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Tetrahedron report number 1054 Recent advances and applications of reductive desulfurization in organic synthesis

Jana Rentner, Marko Kljajic, Lisa Offner, Rolf Breinbauer *

Institute of Organic Chemistry, NAWI Graz, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria article info

Article history: Received 28 March 2014 Available online 5 July 2014

Keywords: Desulfurization Radical reaction Raney-nickel Synthon Thiol Total synthesis

Contents

1. Introduction ...... 8983 2. Mechanistic considerations ...... 8984 3. Thiophenes as masked carbon synthons ...... 8986 4. Saturated S-heterocycles as masked carbon-synthons ...... 8995 5. Linchpin strategy for the assembly of building blocks ...... 8997 6. S-heterocycles for deoxygenation of carbonyl groups ...... 8999 7. S-containing functional groups for tuning reactivity ...... 9003 8. S-heterocycles for improved selectivity and molecular recognition ...... 9006 9. Acyclic S-compounds for improved selectivity and molecular recognition ...... 9009 10. Other applications in organic synthesis ...... 9015 11. Reductive desulfurization in peptide chemistry ...... 9021 12. Conclusions ...... 9024 Acknowledgements ...... 9024 13. Abbreviations ...... 9024 References and notes ...... 9025 Biographical sketch ...... 9027

1. Introduction tungsten, or nickel sulfide catalysts, the true potential of this reaction in the lab scale total synthesis of natural products, bi- While the reductive desulfurization of thiols, thioethers, and S- ologically active compounds, or new materials has not been containing heterocycles is performed on a multi-million ton scale in exploited yet. down-stream oil processing in the production of gasoline, kerosene In this report we want to give a summary about the opportu- and Diesel fuel using heterogeneous molybdenum, cobalt, nities offered by reductive desulfurization as a synthetic tool in organic synthesis and highlight its applications as carbon-synthons or for tuning the reactivity and selectivity of reactions. There have * Corresponding author. E-mail address: [email protected] (R. Breinbauer). been comprehensive reviews about the desulfurization of thio http://dx.doi.org/10.1016/j.tet.2014.06.104 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved. 8984 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 compounds with Raney-nickel by van Tamelen1 and Hauptmann2 the 1940’s establishing Raney-Ni as a reagent for reductive de- from 1962 and a book chapter by Gol’dfarb3 from 1986. This re- sulfurization. Soon the desulfurization of thioketals (e.g., 5)16 and view article builds on these earlier review articles to describe the thiophenes (e.g., 6)17,18 was realized by other groups (Scheme 2). current state of this subject and complements review articles about reductive desulfonylation,4,5 which will not be covered in this report, as this article focuses on non-oxidized sulfur species, such as 2. Mechanistic considerations thiols, thioethers, and thiophenes. This review also will not discuss the metal-catalyzed C(sp2)-SR cleavage as it has found numerous As listed in Scheme 2 Raney-Ni has historically been the first applications for the removal of RS-substituents as a strategic reagent, which enabled the desulfurization of thiophenes and thi- transformation in heterocyclic chemistry and can be reliably ac- oethers and is until today the reagent of choice for these trans- e complished by a variety of methods.6 10 We have structured the formations. Activated Raney-Ni can be categorized into seven material according to the fields of application, using the following different generations W-1 up to W-7, all types differing in reaction e categories: 1) thiophenes and saturated S-heterocycles as carbon time for Raney-Ni synthesis and workup conditions.19 23 Murray fragments, 2) assembly of organic frameworks using the linchpin Raney reported the first Raney-Ni catalyst in 1927 without immo- strategy, 3) deoxygenation of carbonyl groups via thioketalization, bilization of the metal on a surface.24 W-2 to W-7 type Raney-nickel 4) increasing the reactivity of reactions by tuning the electronic catalysts are advancements of this first catalyst and show in general properties of reagents, 5) increasing the selectivity of reactions by increased reactivity mainly to varying functional groups. In parallel, conformational restriction, and 6) as functional handles in peptide its stability decreases. These catalyst generations must be synthe- chemistry (Scheme 1). Naturally, certain applications would fit into sized shortly before use and cannot be stored over a longer period. more than one category, so we arbitrarily classified such application Another very important fact is their extremely high inflammability into a single category to avoid overlap. increasing with the catalyst generation. All Raney-nickel catalysts The first examples of desulfurization of thioethers (e.g., 1),11 S- incorporate emerging hydrogen during its synthesis from nickel- containing amino acids (e.g., 2e3),11,12 or biotin methyl ester ealuminium alloy under basic conditions. Due to the highly pyro- e (4)13 15 have been reported by Mozingo et al. from Merck & Co in phoric properties of all Raney-nickel catalysts they are only stored

Scheme 1. Key transformation using reductive desulfurization. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8985

Scheme 2. Historically ﬁrst examples of reductive desulfurizations.

and handled as suspension. Stating the exact amount of catalyst for thiophene25 and thioether26 on Raney-Ni and thiophene on a reaction is therefore impossible. Ni(111),27 X-ray absorption spectroscopy of dibenzothiophene on Because of its complex nature as a skeletal catalyst resulting Ni/ZnO28 and more recently of computational DFT calculations of from alkaline leaching of a NiAl-alloy the investigation of the re- thiophene adsorption and dissociation on various Ni crystal faces.29 action mechanism is complicated by various Ni crystal faces and the From these studies a consensual mechanistic proposal can be de- surface decoration with adsorbed hydrogen or oxygen species. lineated (Scheme 3). Adsorption of thiophene on the Ni surface Therefore, our current knowledge about the mechanism of de- results in the geometric distortion of the adsorbed molecule and sulfurization on Ni surfaces is based on studies on model systems, the loss of aromaticity of the thiophene ring. Donation from the such as X-ray photoelectron spectroscopy studies (XPS) under ul- sulfur lone pair to the Ni-atoms is paralleled by back donation from trahigh vacuum (UHV) conditions of the chemisorption of Ni d-orbitals to the p-electrons of the carbon framework.29

Scheme 3. Plausible mechanism for desulfurization of thiophenes on Ni surfaces. 8986 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Depending on the crystal face several mechanistic pathways are transformations for thioether cleavage enabled by lithium/ethyl- discussed for the following CeS dissociation step, which very likely amine or LiDBB. involves a metallocycle intermediate. The CeS dissociation step has a surprisingly low activation barrier. Under UHV conditions CeS 3. Thiophenes as masked carbon synthons cleavage occurs on Raney-Ni for thiophene25 and dipropylsulfide26 at around 170 K. The hydrogenation of the olefins of the formed Building on the first historic precedence described above in olefin species is believed to have a higher activation barrier. While Scheme 2 Gol’dfarb et al. have extensively studied in a series of it is well known that saturated S-heterocycles and thioethers are publications in the 1960’s (mostly written in Russian) the use of more reactive than thiophene in the desulfurization reaction with thiophene as a C -building block. In Scheme 5 an elegant synthetic Raney-Ni and industrial HDS catalysts, such as Mo and Co, current 4 sequence is depicted, in which thiophenes are transformed to ali- evidence suggests that the S from thiophene is removed directly phatic amino acids. For example, thiophene 13 can be converted without prior hydrogenation as this process would be energetically into a-aminoenanthic acid 14 in 53% yield. 5-Acetamidothiophene- unfavourable.30 2-carboxylic acid (15) was desulfurized into d-acetamidovaleric While the spectroscopic proof of a postulated metallathiacycle acid (16) in formidable 96% yield, whereas bicyclic derivative 17 on a Ni surface is still awaited, there are several homogeneous was transformed into ε-ethyl-ε-caprolactam (18) in 82% yield metal complexes known, which make these species very plausi- (Scheme 5).34 ble.31 Jones et al. have for example, shown that [(dippe)NiH] (I) 2 Gol’dfarb’s strategy was applied by Mandolini et al. in an early readily reacts with thiophene to form the nickelthiacycle II, which synthesis of (rac)-muscone (21)(Scheme 6).35 The macrocycle was has been characterized by X-ray crystallography (Scheme 4).32 formed via an intramolecular FriedeleCrafts acylation of thiophene-carboxylic acid 19 to form 14-membered structure 20, which upon reductive desulfurization expanded to 15-ring ketone muscone (21). Stetter et al. could show that cyanide ions catalyze the addition of aromatic aldehydes across Michael-acceptors. An elegant way to formally extend the scope of this reaction to aliphatic aldehydes is the use of thiophene aldehydes, which offer the advantage of being non-enolizable, but after 1,4-addition and reductive desulfurization give access to g-ketocarboxylic acids. In Scheme 7 the conversion of Scheme 4. Reaction of a nickelhydride precursor with thiophene. dialdehyde 22 into diketocarboxylic acid 25 illustrates this strategy, in which the solvent ethylmethylketone (EMK) prevents reduction of the keto group.36 In a second line of mechanistic reasoning Eisch et al. have pos- Gronowitz et al. took advantage of the fruitful combination of tulated that homogeneous hydrideeNi(0) complexes induce CeS flexible thiophene substitution reactions with a subsequent re- cleavage via single electron transfer (SET),33 which parallels similar ductive desulfurization with Raney-Ni to produce a series of

Scheme 5. Reductive desulfurization of thiophenes by Gol’dfarb.

Scheme 6. Synthesis of (rac)-muscone (21). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8987

Scheme 7. Stetter reaction with thiophene aldehydes.

branched fatty acids. In Scheme 8 this approach is demonstrated for As a tool compound for mechanistic enzymatic investigations the synthesis of 4-ethylhexanoic acid (30). Metallation of 3-ethyl-2- Boland et al. prepared the partially deuterated analogue of palmitic methylthiophene (28) and electrophilic quench with dry ice pro- acid 35 as a mechanistic probe.40 2,2-Bithienyl (31) functioned as duced thiophene carboxylic acid 29, which upon reductive de- aC8-building block, which after lithiation is reacted with enzy- sulfurization with Raney-Ni generated branched fatty acid 30 in matically prepared chiral building block 32 to furnish 33, which is transformed into ester 34 via a lithiation/electrophilic quench sequence. Desulfurization of 34 was accomplished with nickel boride prepared from NiCl2 and NaBD4 in deuterated MeOH/THF to war- rant a high degree of isotopic labelling. Subsequent saponiﬁcation of the ester delivered the desired deuterated palmitic acid 35 (Scheme 9). Similarly, perdeuterated heptanoic acid ester 38 was prepared by the dehalogenation and desulfurization of methyl 3-chloro-5,6- dibromothieno[3,2-b]thiophene-2-carboxylate (37) with Raney-Ni 41 in 10% NaOD/D2O(Scheme 10). The multifold use of thiophene as C4-building block has also been shown by Cantor et al. in the preparation of a series of poly- hydroxyalkanes 42 as anaesthetics by using thiophene as a template to position the carbinol groups between C4-tethers (Scheme 11).42 For the synthesis of long chain alkane derivatives the sequence of FriedeleCrafts acylation of thiophenes, followed by Wolf- feKishner-reduction and reductive desulfurization has proven to Scheme 8. Synthesis of branched fatty acids. be a very useful method, which only recently has seen competition by oleﬁn cross metathesis. Knapp Jr. et al. used the desulfurization of such a thiophene linker in the synthesis of the myocardial im- 37 77% yield. Branched fatty acids could also be synthesized using aging agent 46 (Scheme 12).43 38 a similar strategy. Similarly, Sargent et al. produced the u-phenylalkylcatechol 50, Analogous strategies have been pursued for the synthesis of ir- which occurs in the Burmese lac tree Melanorrhoea usitata 39 regular isoprenoid and extended phytane carbon skeletons. (Scheme 13).44

Scheme 9. Synthesis of a selectively deuterated fatty acid. 8988 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 10. Synthesis of perdeuterated heptanoic acid (38).

Scheme 11. Cantor’s synthesis of anaesthetics 42.

Scheme 12. Synthesis of a myocardial imaging agent.

Noe et al. showed that alkoxy-substituted thiophenes can be by reaction of acid chloride 55 with enantiomerically pure thio- partially reduced to the corresponding enolethers, which upon phene 56. WolffeKishner-reduction and reductive desulfurization acidic hydrolysis can be transformed to the corresponding ketones, with Raney-Ni produced alkylpyridine 59, which through func- such as 52 (Scheme 14). Based on this rationale they succeeded in tional group transformation furnished niphatesine C (60) the racemic synthesis of the antiaggression pheromone 54 of the (Scheme 15).46 wasp (Paravespula vulgaris) by reductive desulfurization of 53.45 In their synthesis of dimethoxy[8]paracyclophane (65) Tashiro Niphatesine C (60) is an alkaloid isolated from a marine sponge et al. ﬁrst assembled the dithia[3.3]paracyclothiophenophane 63 by found near Okinawa Island, which shows moderate antimicrobial reaction of bisbenzylthiol 62 with bis(chloromethyl)thiophene 61. activity. In the total synthesis of 60 Bracher set the carbon skeleton Photolytic desulfurization of the thioether groups in 63 in neat J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8989

Scheme 13. Synthesis of u-phenylalkylcatechol 50.

Scheme 14. Preparation of enolethers and their conversion into pheromones.

Scheme 15. Synthesis of niphatesine C (60). 8990 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

P(OMe)3 as solvent produced thienophenophane 64, which after The synthesis of meso-trialkyl-substituted subporphyrins 71 treatment with Raney-Ni was debrominated and desulfurized to 65 could not be achieved by the condensation of pyridine-tri-N-pyr- (Scheme 16).47 rolyl-borane with aliphatic aldehydes despite considerable exper- Sone et al. prepared a series of crown ethers 66 containing imentation, while this protocol has proven useful to produce thiophene units and tested their binding afﬁnity against alkali subporphyrins with aromatic aldehydes. Therefore, Osuka et al. metal cations.48 Reductive desulfurization with Raney-Ni afforded synthesized the meso-trithienyl-subporphyrins 70aec in 0.9e3.7%

Scheme 16. Synthesis of dimethoxy[8]paracyclophane (65). the corresponding crown ethers 67 having two adjacent sub- yields. Reductive desulfurization with Raney-Ni converted the stituents as a cis/trans mixture of isomers (Scheme 17). thiophenes into alkyl groups, but also led to overreduction prod- For the synthesis of the largest so far known bicyclo[n.n.n] ucts, which could be easily oxidized back with chloranil to furnish alkane the group of Oda has ﬁrst produced trithienylmethano- the trialkyl-subporphyrins 71aec (Scheme 19).50 The desulfurization of thiophenes has also been used in the synthesis of highly substituted 1,2-azaborines.51,52 Jones et al. presented a short stereoselective synthesis of estradiol and its 6,6-dimethyl analogue 75 starting from readily accessible 1,11-epithiosteroids.53 72 was desulfurized with Raney-Ni, which established the natural 9a-H-conﬁguration but was accompanied with reduction of the benzylic carbonyl group. Reoxidation with BaMnO4 set the stage for a BaeyereVilliger-oxidation to produce 74. Twofold reductive ester cleavage delivered 6,6- dimethylestradiol (75) (19% overall yield from 2-methylcylo Scheme 17. Preparation of crown ethers 67. pentenone) (Scheme 20). Jacobi has recognized that the reductive desulfurization of 3- methylthiophenes produces an isoprenyl-unit and applied this in- phane 68 by McMurry-coupling of tris(5-formyl-2-thienyl) sight in a synthesis of the terpenoid natural product 7a-eremo- 54 methane. Subsequent reductive desulfurization of 68 with Raney- philane (79)(Scheme 21). Starting from thiazole A an Ni produced bicyclo[10.10.10]dotriacontane 69 in 82% yield intramolecular DielseAlder-reaction between thiazole and alkyne (Scheme 18).49 moieties followed by a retro-[4þ2]-reaction under the release of

Scheme 18. Synthesis of bicyclo[10.10.10]dotriacontane 69. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8991

Scheme 19. Synthesis of subporphyrins 71aec.

Scheme 20. Synthesis of the estradiol analogue 75.

Scheme 21. Synthesis of the terpenoid natural product 7a-eremophilane (79). 8992 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

HCN produced substituted thiophene 77, which was converted to crystallized in 52% isolated yield. Interestingly, the reductive de- sesquiterpene 78 by desulfurization with Raney-Ni. Removal of the sulfurization was accompanied by reduction of the carbonyl group, CO-group via a reduction followed by a BartoneMcCombie-de- which is in contrast to the general functional group tolerance of this oxygenation of the resulting alcohol produced 79. transformation for other substrates. Reduction of 82 with LiAlH4 The group of Daich has developed a synthetic sequence of bi- produced ethyl-indolizidinol 83. ologically interesting substituted indolizidinols based on reductive When using benzo[b]thiophenes the corresponding phenyl- desulfurization of thiophenes (Scheme 22).55 Starting from thio- indolizidines were produced.56,57 In the course of these studies the

Scheme 22. Synthesis of ethyl-indolizidinol 83.

phene-2-carboxaldehyde (80) and L-glutamic acid intermediate 81 diastereoselectivity of the reduction process was carefully studied, was produced in 55% yield over three steps. Reductive de- revealing that in general hydrogen is delivered from the sterically sulfurization of 81 occurred in 90% yield to produce a mixture of more accessible face, but that polar substituents lead to secondary four possible diastereomers (68:12:10:10), from which 82 could be effects (Scheme 23).56

Scheme 23. Diastereoselectivity in the reaction benzothiophenes. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8993

More recently, Honda et al. have presented a spectacular total thioaroylketene S,N-acetal 99 with silylenolethers. Reaction of 99 synthesis of the natural cholestane diglycoside OSW-1 (95), which with 100 produced ring enlarged thienolactam 101, which upon exhibited extremely high cytotoxic activity against human malig- desulfurization delivers 102 (Scheme 26).60 The authors stated that nant cancer cells. The thiophene moiety was introduced by alkyl- desulfurization with Raney-Ni produced partially hydrogenated ation of alcohol 90 with 91. Base-induced Wittig-rearrangement product containing olefin, therefore a second hydrogenation with converted 92 into alcohol 93, which was then elaborated into ad- PtO2 was necessary to produce the alkyl-substituted product 102. vanced intermediate 94. Despite the structural and functional However, hydrogenation with PtO2 alone did not convert 101, complexity of 94, featuring free hydroxyl groups, ester groups and confirming the observation that Ni is necessary to induce the an isolated olefin, the reductive desulfurization with deactivated desulfurization. Raney-Ni W2 and hydrogen at rt occurred in very good 79% yield to Viner et al. from Syngenta prepared the nanomolar acting ace- deliver OSW-1 (95)(Scheme 24).58 tylcholinesterase inhibitors 105aeb, which have been designed as

Scheme 24. Synthesis of cholestane diglycoside OSW-1 (95).

Krishna et al. used thiophenes for the production of C-glyco- chimeras of tacrine and 3-(N,N,N-trimethylammonio)tri- sides.59 2-Lithiothiophene adds to lactol 96, which under fluoroacetophenone.61 Thiophene 103 was lithiated with LDA and Mitsunobu-conditions furnishes C-aryl glycoside 97. Reductive reacted with the trifluoroacetic Weinreb amide forming 104.Re- desulfurization produces C-butyl glycoside 98 (Scheme 25). ductive desulfurization produced the aliphatic trifluoromethyl Kim et al. have developed a versatile method for the production ketones 105aeb as the corresponding hydrates due to the stabi- of 2-substituted 3-alkylamino-5-arylthiophenes by reaction of lizing effect of the trifluoromethyl group. The Raney-Ni reaction led

Scheme 25. Synthesis of C-glycosides. 8994 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 26. Reductive desulfurization of a thienolactam.

to partial dechlorination of the arene leading to a product mixture, For chemical proteomics purposes to identify the protein targets which could be separated by ﬂash chromatography (Scheme 27). of small molecule drugs, the small molecule needs to be attached to Fang et al. have developed a method, in which methyl thio- a solid support. As very often the functional groups available at the phene-2-carboxylates or methyl-3-(thien-2-yl)acrylate (107)are drug molecule prove essential for the biological activity, Rentner transformed with SmI2 into carbanion equivalents, which can react and Breinbauer have developed a labelling strategy for drug-like

Scheme 27. Synthesis of acetylcholinesterase inhibitors.

with electrophiles, such as 106 to produce CeC-coupling products, molecules taking advantage of the less relevant but abundant CH- such as 108. Reductive desulfurization of the dihydrothiophene arene bonds of the small molecule via Pd(II)-catalyzed dehydro- intermediates with Raney-Ni produces aliphatic hydroxy-alkanoic genative coupling. As the methodology for Csp2eCsp3 coupling is acid esters, as has been exempliﬁed for the spore germination in- not satisfyingly developed yet, they used a two-step sequence, in hibitor 109 (Scheme 28).62 which ﬁrst a Csp2eCsp2 coupling with functionalized thiophenes

Scheme 28. Synthesis of aliphatic hydroxyl-alkanoic esters via thienyl carbanions. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8995 was performed.63 For example, modified caffeine 110 was first 4. Saturated S-heterocycles as masked carbon-synthons reacted via dehydrogenative cross-coupling with various thiophene derivatives 111 followed by subsequent reductive desulfurization While thiophenes can be excellently decorated with substituents with Raney-Ni producing the desired flexible alkyl chain taking advantage of the full repertoire of arene substitution and (Scheme 29). A benefit of this hydrodesulfurization is the simul- functionalization reactions their application is limited as a mere C4- taneous cleavage of appropriate protecting groups. The obtained building block. Using various partially saturated or completely sat- alkylated caffeine 113 can finally be attached directly to a solid urated S-heterocycles overcomes this limitation and expands the support or markers for further studies (Table 1). scope of this reaction strategy to other Cn-building blocks.

Scheme 29. Labelling of drug-like molecules via dehydrogenative coupling of functionalized thiophenes.

Palumbo et al. reported an approach, in which 5,6-dihydro-1,4-

Table 1 dithiins were used as C2-building blocks, which upon reductive Screening of thiophenes in drug tethering desulfurization produced not the expected alkane but alkene product. Coupling of lithiated dithiin 114 with chiral aldehydes Entry FG1 of 111 Yield FG2 of 113 115e117 and subsequent reduction enabled access to poly- 112 113 hydroxylated compounds. The intermediates 118 were desulfurized 1CH3 98% 85% CH3 according to their previous report on sulfur removal from dithiins a 2CH2NHBoc 99% 83% CH2NHBoc 64 b (Scheme 30). While reductive desulfurization of 118 with Raney- 3CH2NHCbz 97% 40% CH2NH2 fi 4CHOH 63% 40% CH OH Ni produced the (Z)-ole n 119 the desulfurization of 118a with 2 2 5CH2OBn 89% 99% CH2OH LiAlH4/Ti(OiPr)4/quinoline (16:8:0.15) in ethanol at 50 C led to 72% 119a as an exclusive (E)-olefin isomer.65 a Addition of 0.2 equiv CuCl. b Addition of 0.1 equiv 1,10-phenanthroline. In subsequent publications from the Palumbo group the coupling of phenylic and O-allylic dithiins was successfully tested with several other electrophiles.66,67 Iodomethane, benzylbromide, ep- In conclusion, thiophene is a very functional C4-building block, oxides, aldehydes, and even D-galactono-d-lactones were efficiently which requires the use of Raney-Ni as a desulfurization agent, as Ni coupled. Reductions were always performed with optimized has proven to be instrumental to break the SeC bond. The func- Raney-Ni conditions mostly in THF. The remaining double bond tional group tolerance is rather high, but olefins and halogens are after desulfurization offers opportunities for further de- usually also subjected to hydrogenation resp. hydrogenolysis, al- rivatizations. For example, this double bond served for the total though exceptions are known and have been described in this synthesis of several modified sugars like alloses, L-(and D-) hexoses 68e71 chapter. Nickel boride (in situ prepared from NiCl2,NaBH4) has and L-hexopyranose analogues. A very interesting example of been demonstrated to be milder than Raney-Ni. this strategy is highlighted in Scheme 31 with their synthesis of 1-

Scheme 30. Control of oleﬁn geometry in the stereoselective reductive desulfurization of dithiins. 8996 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 31. Dithiins as a reagent for iminosugar synthesis.

deoxy-L-iminosugars starting from non-carbohydrate materials the inorganic base NaH2PO4. Reduction with NaBH4 affords the dithiin 120 and Garner aldehyde 121.72 Central intermediate 123 benzodithiol derivative 128, which yields the alcohol 129 after re- could either be desulfurized to unsaturated piperidine 124 under ductive desulfurization with Raney-Ni. Cozzi et al. published this controlled conditions with Raney-Ni in 76% yield, whereas harsher methylation strategy with a variety of aldehydes, where they re- conditions in THF led to complete reduction of the oleﬁn to produce ceived high ee-values of 92e97%. saturated product 125 in 83% yield. Benzodithiol derivative 128a can be further transformed after Sulfur heterocycles can also be used to serve as a C1-building benzyl-protection by subsequent lithiation and treatment with an block. Cozzi et al. described a new approach to a-alkylated alde- electrophile (MeI or BnBr) (Scheme 33).73 After ﬁnal reductive hydes by stereoselective organocatalysis and subsequent reductive desulfurization with Raney-Ni the differently substituted alcohols desulfurization (Scheme 32).73 1,3-Benzodithiolylium tetra- 132 were produced.

Scheme 32. Benzodithiolylium tetraﬂuoroborate (127) as an alkylating agent in enantioselective organocatalysis.

Scheme 33. Preparation of chiral alcohols 132.

fluoroborate (127) was used as an alkylating agent. The optimized By using 1,3-benzodithiolylium tetrafluoroborate 127 with al- reaction conditions were found to be the MacMillan catalyst and dehydes in the presence of the amine catalyst 134 and ()-CSA benzoic acid in the presence of a 1:1 mixture of H2O and CH3CN and Cozzi et al. formed quaternary stereocentres under mild reaction J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8997 conditions and without using transition metals.74 The enamine Corey and Seebach successfully reintroduced the term, defining mediated alkylation of a-substituted aldehydes was complemented umpolung as the inversion of polarity and hence of reactivity of by reduction and removal of the benzene-1,2-dithiol activating a functional group by chemical modification. Umpolung-based group with Raney-Ni. This synthetic strategy was demonstrated in strategies are of great significance for organic synthesis. Espe- the synthesis of chiral alcohol 138 starting from 2-phenylpropanal cially the synthetic potential of 1,3-dithiane linchpins serving as (A133). It should be noted that Raney-Ni reduction did not effi- sulfur-stabilized acyl and alkyl anion synthons has been recognized ciently deprotect the benzyl group, which made a second reduction leading to their application in the synthesis of complex natural and step with Pd/C necessary (Scheme 34). unnatural products.76

Scheme 34. Organocatalytic synthesis of alcohols with quaternary stereogenic centres.

Analogously, Cozzi et al. functionalized directly a variety of These nucleophilic acylating and alkylating agents are prepared aryltetrafluoroborate salts via 1,3-benzodithiolylium tetra- by Lewis or Brønsted acid catalyzed conversion of aldehyde 144 fluoroborate reaction.75 By using 2.5 equiv of the benzodithiolylium with 1,3-propanedithiol and deprotonation of dithiane 145 with salt 127, 140 is formed via hydride shift. 140 is stable in the presence alkyllithium yielding 2-lithio-1,3-dithiane (146). After reaction of air and can be easily isolated and purified. NaBH4 reduction af- with an electrophile the dithioketal moiety may be hydrolysed to fords the neutral 141 in high yields. These benzodithiolylium de- give ketone 148 or it could be converted by reductive derivatives can either be desulfurized directly or further sulfurization yielding alkane 149 (Scheme 36).77 functionalized with an electrophile followed by reductive de- The ability to react with a wide range of electrophiles including sulfurization. Cozzi et al. demonstrated this exemplarily with alkyl halides, aldehydes and ketones, epoxides and aziridines, acyl phenyltetrafluoroborate 139 producing ester 143 (Scheme 35). halides and a,b-unsaturated carbonyl compounds makes 1,3-

Scheme 35. Benzoditholylium salt (127) in the coupling with aryl-nucleophiles.

5. Linchpin strategy for the assembly of building blocks dithianes a valuable tool for complex molecule synthesis (Scheme 37).76 When the concept of umpolung was ﬁrst introduced by Wittig Other reports reviewing the application of 1,3-dithianes in the in the 1920’s describing the inversion of charge, it was not imme- total syntheses of natural products cover the literature until diately accepted by the scientiﬁc community. About 50 years later 2004.76,77 Therefore, we will focus on the review of some of 8998 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 36. Opportunities in 1,3-dithiane chemistry.

dideoxy-60-hydroxycarbauridine via convergent or linear nucleobase introduction was achieved by the group of Linclau. Since their strategy does not start from natural sugars but from arabitoldwith both enantiomers equally availabledD- and L-carbanucleosides are accessible. The synthesis of carbafuranose 157 was accomplished via a Brook rearrangement mediated stereoselective linchpin cyclization reaction of silyl 1,3-dithiane 150 and chiral epoxide 156. Having the correct relative stereochemistry (anti-configuration of the 10-OTBS and the 40-hydroxymethyl group) the dithioketal group of carbafuranose 157 was removed by desulfurization with Raney- Ni. After acylation of the hydroxymethyl group and desilylation of the secondary hydroxy group, 158 was converted to the desired carbanucleoside 160 via a Mitsunobu reaction with nucleobase 159 as nucleophile (Scheme 39).80,81 By 1,3-dithiane bi-alkylation Dai et al. accomplished the total synthesis of two diastereomeric butenolide alcohols, (4S,10S,11S)- and (4S,10R,11R)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide (168)(Scheme 40). The syn-aldol subunit was synthesized by a syn-selective aldol reaction and converted to chiral iodide 162. Together with the iodinated chiral building block 164, 162 was used Scheme 37. Diversity generation through linchpin strategy. in the three-component linchpin coupling with 1,3-dithiane 161. Reductive desulfurization of the coupling product 165 with Raney- the most recent reports on the subject of dithiane based Ni yielded 166 in excellent 93% yield. Selective deprotection of the chemistry. primary alcohol and its oxidation gave the aldehyde, which was Smith et al. achieved the total synthesis of the alkaloid transformed to the alkene in a Wittig olefination. The secondary ()-indolizidine 223AB (155) by one-pot three-component linch- alcohol was deprotected yielding the allyl alcohol, which was ac- pin coupling of silyl 1,3-dithiane 150 with epoxide 151 anddafter ylated to give the acrylate 167. The desired butenolide 168 was Brook rearrangementdwith N-toluenesulfonyl aziridine 152. Lith- achieved by a ring-closing metathesis reaction applying a Grubbs iation of dithiane 150 followed by the addition of epoxide 151 and second generation catalyst and the removal of the THP ether. The aziridine 152 in HMPA yielded 153, the carbon backbone of linchpin coupling constitutes a flexible strategy for the synthesis of ()-indolizidine 223AB. Deprotection and one-pot activation of the the other diastereomers.82 alcohols and deprotection of the amine gave the double cyclization Similar to the linchpin strategy is the dilithiomethane equiva- product 154, which was transformed to the desired ()-indolizi- lent 170 introduced by Cohen and applied in their synthesis of dine 223AB (155) by reductive desulfurization with Raney-Ni (rac)-hirsutene (177).83,84 2-Methyl-2-cyclopentenone (169) reac- (Scheme 38). This synthetic strategy exploits the potential of the ted with lithiated species 170 in a 1,4-addition to form 171, which 1,3-dithiane as a linchpin in carbon backbone formation and as an was thiolithiated in situ with s-BuLi to furnish reagent 172, again auxiliary accelerating the cyclization reaction. undergoing 1,4-addition with 5,5-dimethylcyclopentenone (173). Due to the flexibility of the available epoxide and the aziridine By addition with FeCl3 the enolates were coupled oxidatively to reagents, the three-component linchpin coupling is a promising triquinane 175 in excellent diastereoselectivity, which is rational- strategy for the total syntheses of other indolizidine, quinolizidine ized by reversible bond cleavage and bond formation of the in- and quinolizine alkaloids.78,79 termediate radical species. Desulfurization with Raney-Ni The synthesis of carbafuranoses and their conversion to the produced 177, which was elaborated to hirsutene (177) carbanucleosides 20,30-dideoxycarbathymidine (160) and 20,30- (Scheme 41). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8999

Scheme 38. Synthesis of ()-indolizidine 223AB (155).

Scheme 39. Synthesis of carbanucleoside 20,30-dideoxycarbathymidine (160).

In conclusion, the use of geminal thioacetals offers a variable C1- WolffeKishner-reduction, the Clemmensen-reduction, etc. As synthon, which has found widespread application for the assembly many of these methods involve quite harsh reaction conditions of carbon framework. In the case of 1,3-dithiane reductive de- requiring strong bases, acids or elevated temperature, a two-step sulfurization results in a CH2-unit, which nicely complements the procedure, in which the keto group is ﬁrst transformed into a thi- typical oxidative or hydrolytic workup delivering a C]O functional oketal and in a second step desulfurized with Raney-Ni has become group. very popular in the synthesis of natural products. In the literature this transformation is sometimes named as the ‘Wolf- 6. S-heterocycles for deoxygenation of carbonyl groups romeKarabinos-method’ after the inventors of this protocol.16 Sometimes also the name ‘Mozingo-reaction’ can be found, which The deoxygenation of keto groups to methylene units can in our opinion is better used as a general term for reductive de- be accomplished by a variety of methods, including the sulfurization of thioether bonds. 9000 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 40. Synthesis of butenolide 168 via linchpin strategy.

Scheme 41. Synthesis of (rac)-hirsutene (177).

In their synthesis of the triquinane sesquiterpenoid methyl Maguire et al. applied this two-step sequence in their synthesis cantabrenonate 181, Piers et al. converted the more reactive alde- of the daucane sesquiterpene analogue 187.88 Ketone 185 was hyde group in intermediate 178 into thioacetal 179, while leaving transformed into the thioketal 186, which was desulfurized with the keto group unreacted. Deoxygenation with Raney-Ni in- Raney-Ni to furnish 187 letting the oleﬁn moiety intact (Scheme 44). troduced the methyl substituent in 180, which was transformed Kuwahara et al. used the transformation of a formyl group into ultimately into the desired target structure 181 (Scheme 42).85 a methyl group for their synthesis of the olfactory compound Lasiol

Scheme 42. Synthesis of synthesis of the triquinane sesquiterpenoid methyl cantabrenonate 181.

Fukumoto et al. reduced thioketal 182 with Raney-Ni to form (190)(Scheme 45).89 Lactol 188 was converted into a thioketal, lactone 183, which was further elaborated to D9(12)-capnellene 184 which was converted into ethoxyethyl (EE) ether 189 more suitable (Scheme 43).86,87 for the subsequent desulfurization. Reductive cleavage of the J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9001

Scheme 43. Synthesis of D9(12)-capnellene 184.

Scheme 44. Synthesis of daucane sesquiterpene analogue 187.

Scheme 45. Synthesis of the olfactory compound Lasiol (190).

thioketal with Li/EtNH2 and deprotection of the EE ether produced reaction with the vinylsulﬁde moiety to assemble the structure 199, 190 (Scheme 45). which upon desulfurization of the phenylthio group and the tran- Wakamatsu et al. used the deoxygenation of carbonyl groups via sition state stabilizing thioketal produced target compound 200 thioketalization in their synthesis of decan-9-olide (193)da natural (Scheme 48). product, which ﬁrst has been isolated from the metasternal gland For their research on biomimetic polyene cyclizations the group 90 secretion of Phoracantha synonyma (Scheme 46). of Zeelen aimed at the synthesis of DL-19-nor-4-pregnen-20-one

Scheme 46. Synthesis of decan-9-olide (193).

Similarly Ayer et al. transformed 194 into (rac)-geosmin (196) (203).93 This reference compound was synthesized by ﬁrst form- (Scheme 47).91 ing the thioketal with the more reactive a,b-unsaturated ketone in Fukumoto et al. presented a fascinating synthesis of the des-A B- 201 to 202 with subsequent reduction via Li/NH3 (Scheme 49). aromatic steroid 200.92 Thermolysis of 197 resulted in ortho-qui- The total synthesis of ()-stypoldione (206) was achieved by the nodimethane 198, followed by intramolecular DielseAlder- group of K. Mori. This cyto- and ichthyotoxic diterpenic metabolite

Scheme 47. Synthesis of (rac)-geosmin (196). 9002 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 48. Synthesis of des-A B-aromatic steroid 200.

Scheme 49. Synthesis of DL-19-nor-4-pregnen-20-one (203). of Lamouroux papenfus was synthesized in 17 steps encompassing enabled via thioketalization of 204 with ethane-1,2-dithiol and a critical deoxygenation of a keto-group in one of the last steps of boron triﬂuoride followed by subsequent hydrogenolysis with the synthetic sequence.94 Reduction of the C-4 carbonyl was Raney-Ni to produce 205 in 67% (Scheme 50).

Scheme 50. Total synthesis of ()-stypoldione (206). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9003

Pedro et al. managed a synthesis of herbolide I, in which a two- of the keto group was accomplished by thioketalization of 217 step deoxygenation through the thioketal intermediate 208 was delivering 218, which was desulfurized to 219 with Raney-Ni used. Desulfurization was achieved with Raney-Ni in very good 89% (Scheme 53).98 yield without overreduction of the oleﬁn moiety (Scheme 51).95 In conclusion, the reductive desulfurization of thioketals and The ﬁnal sesquiterpene lactones (210, 211) led to the conclusion acetals has been well studied, and can be easily achieved with that for herbolide I an erroneous structure has been published in Raney-Ni, Li/EtNH2, or Li/NH3(liq) as the preferred reducing agents. a preceding paper.96

Scheme 51. Selective desulfurization in the presence of an oleﬁn.

The deoxygenation of ketones via desulfurization of thioketals 7. S-containing functional groups for tuning reactivity has been especially popular for total syntheses of sesquiterpenes. Srikrishna et al. elegantly used this approach for the regioselective As thiosubstituents can be removed via reductive de- thioketalization of dione 213 towards (þ)-seychellene (216). The sulfurization in a ‘traceless’ manner leaving a hydrogen behind, more sterically demanding ketone remained untouched. Sub- such substituents have been used to activate (or tune the reactivity sequent desulfurization of 214 with Raney-Ni led quantitatively to of) reagents and reaction partners. bis-norseychellenone (215). Similar results were achieved in the In this respect, a paradigm changing strategic application of same work towards ent-seychellene (þ)-(216)(Scheme 52).97 a desulfurization reaction was the classic synthesis of cantharidin

Scheme 52. Total synthesis of (þ)-seychellene (216).

Fadel et al. presented a synthesis of (þ)-b-cuparenone (220) (223) by Dauben.99 Cantharidin is the active ingredient of the using chiral precursor 217 as a central intermediate, whose qua- aphrodisiac ‘Spanish Fly’. The attempted DielseAlder-reaction be- ternary stereogenic centre has been prepared by speciﬁc hydrolysis tween dimethylmaleic anhydride and furan did not proceed of an a,a-disubstituted malonic ester substrate with PLE. Removal even at 40 kbar pressure. In contrast, 2,5-dihydrothiophene-3,4- 9004 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 53. Synthesis of (þ)-b-cuparenone (220). dicarboxylic anhydride (221) reacted smoothly to 222, which is Ishibashi et al. have developed a Ru-catalyzed chlorine atom believed to result from the less electron-donating character of the transfer cyclization of N-allylic a-chloro-a-thioacetamides. In thioalkyl substituents and reduced steric demand. Reaction of 222 one example they used substrate 230, which was cyclized to with Raney-Ni reduced the oleﬁnic double bond and removed the 231 with RuCl2(PPh3)2 as a catalyst. Treatment with Raney-Ni sulfur bridge to produce cantharidin (223)(Scheme 54). led to desulfurization and dehalogenation producing the

Scheme 54. Dauben’s synthesis of cantharidine (223).

In their formal total synthesis of the pyrrolizidine alkaloid bicyclic lactam 232 in excellent diastereoselective purity (þ)-retronecine (229), Kametani et al. used an intermolecular car- (Scheme 56).101 benoid displacement reaction of optically active sulﬁde 224 with Kodama et al. used an anion-induced intramolecular cyclization diazomalonate 225 under Rh(II)-catalysis (Scheme 55).100 De- for the synthesis of the diterpenoid (rac)-cubitene (236), which has sulfurization of 226 with Raney-Ni led to 227 without cleaving the been isolated from the defence secret of the East African termite

Scheme 55. Synthesis of (þ)-retronecine (229).

Scheme 56. Chlorine atom transfer cyclization.

benzylesters, which was later achieved with Pd/C allowing the Cubitermes umbratus. Deprotonation of allylic sulﬁde 233 with n- conversion into lactone 228, from which an earlier synthesis of BuLi produced an anion, which attacked the epoxide moiety in- (þ)-retronecine (229) had been reported. tramolecularly leading to 12-membered ring 234. Desulfurization J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9005 of 234 with Na in n-BuOH led to 235 in excellent 93% yield without Building on their observation that b-alkylthio substituents ac- compromising the oleﬁn geometries. Dehydration of the tertiary celerate the Rh-catalyzed intermolecular hydroacylation of alkenes alcohol furnished 236 (Scheme 57).102 and alkynes, Willis et al. exploited this chelation-effect by studying

Scheme 57. Stabilized allyl anion cyclization in the synthesis of (rac)-cubitene (236).

A similar type of intramolecular cyclization was used by Li et al. b-thioketal (ﬁve- and six-membered rings) substituted aldehydes in their synthesis of (rac)-sarcophytol M (239). Allylsulﬁde 237 was as substrates, for which intermediates, such as 247 are postulated. deprotonated with LDA forming an allyl carbanion, which attacked In one application of this reaction aldehyde 244 reacts with the carbonyl group of the ketone intramolecularly to furnish 14- methylacrylate to CeC-fused product 245, which by reductive de- 106 membered ring 238, which upon desulfurization with Li/EtNH2 sulfurization can be converted into g-ketoester 246 (Scheme 60). produced 239 in 78% yield (Scheme 58).103 A similar strategy was In their elegant enantioselective total synthesis of ()-strych- used for the synthesis of isoprenoid chains.104 nine (252) Shibasaki et al. prepared thioacetal 248. In the presence

Scheme 58. Synthesis of (rac)-sarcophytol M (239).

In their synthesis of the ionophore lasalocid A (X537A) Ireland of 5 equiv DMTSF a thionium ion is formed, which reacts as an et al. required the intermediate 243, which they planned to achieve electrophile with the nucleophilic indole producing the C-ring of by opening the epoxide 240 with a methyl anion synthetic equiv- 249. Functional group manipulation furnished 250, which was set alent.105 When using lithium dimethyl cuprate, the attack occurred for reductive desulfurization to produce 251. The classic protocol at the more hindered C-17 position producing 241, which was ra- even with deactivated Raney-Ni W-2 proved unsatisfactory as it tionalized by precomplexation of the organometallic reagent by the promoted considerable migration of the exocyclic (C19eC20) oleﬁn adjacent MOM-protecting group. With lithiated 1,3-dithiane, attack to the endocylic (C20eC21) alkene. Fortunately, nickel boride in occurred at the sterically more accessible C-16 position of 240. a carefully optimized solvent mixture (EtOH:MeOH 4:1), which Reductive desulfurization with Raney-Ni transformed the dithiane suppressed overreduction, produced desired 251 in 61% yield. 251 242 into the corresponding methyl substituent furnishing 243 could be transformed into target compound ()-strychnine (252)in (Scheme 59). four steps (Scheme 61).107,108

Scheme 59. Regioselective ring opening of epoxides by methyl anion equivalents. 9006 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 60. Thiodirected hydroacylation.

Scheme 61. Shibasaki’s synthesis of ()-strychnine (252).

Knapp et al. enabled ring expansion of cyclic ketones to 1,2-keto 8. S-heterocycles for improved selectivity and molecular thioketals. This two-step procedure was successfully used to recognition shorten the total synthesis of ()-coriolin intermediate 260 as well as selective introduction of a methyl group during this synthesis The traceless removal of sulfur from molecular frameworks not (Scheme 62).109 The final step in their synthesis towards the only allows to use such substituents to control the reactivity in ()-coriolin BC rings 260 involved reduction of the thioketal 259 reagents, but also to fix conformational orientations or to impose via Raney-Ni. a steric bias, which has a favourable influence on the selectivity of Schreiber et al. reported desulfurization with Raney-Ni W-4 that reagents. has been activated by sonication. The thioacetal in the a,a-di- Stotter et al. have developed a very useful method to fix the substituted lactone was incorporated to ease the ring-expansion of geometry of acyclic olefins through the formation of the olefins as 261, which produced a mixture of 262a and 262b. This mixture part of sulfur-containing heterocycles.111 4-Thiacylcohexanone was used in the following reduction with the sonicated Raney-Ni (266) is reacted with carbanion reagents, which after dehydration towards the spore germination autoinhibitor gloeosporone produces cyclic olefin 267. The allylic CH in a-position to sulfur can (Scheme 63).110 be deprotonated and reacted with generic electrophiles to produce J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9007

Scheme 62. Ring expansion in the synthesis coriolin intermediate (260).

Scheme 63. Ring expansion in Schreiber’s synthesis towards gloeosporone.

268. Reductive desulfurization ultimately furnishes Z-oleﬁn 269 sitophilure (278).112 As cyclic 1,3-diketones are more opportune (Scheme 64). They have applied this strategy in the formal total substrates than acyclic 1,3-diketones 3-propionyltetrahydrothio synthesis of the Cecropia juvenile hormone 275. Starting from 270 pyran-4-one (276) was reduced by bakers’ yeast in very good and 271 the dithiopyran structure 272 was assembled, which was enantio- and excellent diastereoselectivity to chiral b-hydrox- further elaborated to 273. For the crucial desulfurization a two-step yketone 277. Reductive desulfurization using Raney-Ni furnished protocol was developed. First the allylic CeS bond was cleaved be pheromone 278 (Scheme 65). reduction with lithium in ethylamine at 78 C, immediately fol- Griengl et al. observed only moderate enantioselectivity of 54% lowed by desulfurization of the resulting mercaptans using Raney- ee in the cyanohydrin formation of ethyl methyl ketone 279 cata- Ni in reﬂuxing EtOH. This protocol is superior to a protocol using lyzed by the hydroxynitrilase (HNL) from Hevea brasiliensis. Con- Raney-Ni alone, which suffers from overreduction and double bond sidering a ‘docking/protecting group’ technique the spatial isomerization. similarity of the vicinity in the carbonyl group should be abolished Fujisawa et al. used a chemoenzymatic approach for the syn- (Scheme 66). Indeed substrates 281 and 285 proved to be excellent thesis of rice and weevils aggregation pheromone ()-(4R,5S)- substrates for the HNL-reaction, producing the cyanohydrins 282 9008 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 64. Synthesis of juvenile hormone (275).

Scheme 65. Chemoenzymatic synthesis pheromone 278.

Scheme 66. Selectivity improvement in HNL-biocatalytic transformation by removable thiosubstituents. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9009 and 286 in 99% ee each, which after hydrolysis and reductive de- absolute configuration in the asymmetric autocatalytic reaction of sulfurization could be converted into the chiral disubstituted a- substrate 311 leading to product and autocatalyst 312. hydroxycarboxylic acid 284.113 Schmalz reported about an elegant synthesis of the marine Another application, in which an enzymatic reaction is followed natural product (þ)-ptilocaulin (318) with the chiral h6-arene- by a reductive desulfurization has been given by Haufe et al. Cr(CO)3 complex 313 as a synthetic building block. Lithiated 1,3- 114 (Scheme 67). Diene 288 is first reacted with dichlorosulfane to dithiane (314) served as a C1-building block attacking 313 to pro- deliver the dichloro-thioadamantane 290 in a transannular S-het- duce cyclohexenone 315 in 99% ee. Functional group manipulation erocyclization via episulfonium ion 289. Favoured by anchimeric led to 316, which upon reductive desulfurization with Raney-Ni assistance of sulfur, nucleophilic displacement resulted in diol furnished 317, which was elaborated to 318 (Scheme 70).120 (rac)-291. Kinetic resolution of the racemic mixture by acetylation Taking together the work of Ward et al. provides convincing with Candida rugosa lipase left behind unreacted enantiomer showcases, which illustrate the efficiency of using the combination (þ)-291 consistent with Kazlauskas’ rule of enantiomeric recogni- of S-heterocycles/reductive desulfurization as a strategic tool to tion. Reductive desulfurization produced enantiopure 9-oxybicyclo improve the selectivity of reactions. This methodology has already [3.3.1]nonane-2,6-diol (þ)-292. shown its value in the synthesis of complex natural products.

Scheme 67. Synthesis of enantiopure 9-oxybicyclo[3.3.1]nonane-2,6-diol ((þ)-292).

Ward et al. influenced significantly the synthetic methods to 9. Acyclic S-compounds for improved selectivity and molec- polypropionate derivatives by developing a thiopyran based strat- ular recognition egy.115 The main strength of this template based synthesis is the thiopyran induced establishment of stereocentres followed by In a similar manner to the strategy described in Chapter 7 also simple desulfurization to obtain complex natural products and acyclic S-compounds have found application as a control element analogues. With this strategy, Ward et al. were able to synthesize in stereoselective reactions. for example, serricornin (298), siphonarin B (306) and baconipyr- The selective a-alkylation of ketones is an important tool in the e ones A (307) and C (308)(Scheme 68).116 118 All syntheses start synthesis of polycyclic natural products. Ireland and Marshall have with two functionalized thiopyranes 293 and 294 or 299, which introduced in 1962 a viable strategy to this problem by introducing undergo an enantioselective aldol reaction. After desired func- the n-butylthiomethylene blocking group, which after serving its tionalization of the resulting thiopyran motif 295, desulfurization function can be either removed by basic hydrolysis or converted takes place in 82% yield followed by deprotection to obtain serri- into a methyl group via reductive desulfurization. Using 2- cornin (298). In the synthesis of baconipyrone A (307) and C (308) methylcyclohexanone as a model substrate they could convert and siphonarin B (306), the protected aldol product 300 was the central intermediate 321 into the differently methylated cy- desulfurized directly in 86% yield. The subsequent functionalization clohexanones 323e325 (Scheme 71).121 gave 302, which underwent another aldol reaction with thiopyran Using the methodology developed earlier by Paterson and motif 303. Treatment with Raney-Ni resulted in double reductive Fleming,122 Tamura et al. reported an efficient synthesis of methyl desulfurization and deprotection in one step. After selective dihydrojasmonate (321) starting from cyclopentenone (326). transformations either siphonarin B (306), baconipyrone A (307)or Reaction with silylketene acetal 327 introduced the ester side baconipyrone C (308) were obtained. chain with concomitant formation of the silylenolate 328. 328 Soai et al. have used a twofold reductive desulfurization of reacted in the presence of TiCl4 with the highly electrophilic thiophene substituents at a quaternary stereogenic centre for the chlorosulfide 329 resulting in a-substituted 330. The ancillary production of the chiral but optically inactive (‘cryptochiral’) nat- phenylthio group was removed by reductive desulfurization with urally occurring alkane (R)-310.119 The differently substituted Raney-Ni producing the dihydrojasmonate first as a mixture of thiophene rings were essential for resolution of the racemic mix- cis/trans diastereomers, which was easily transformed into ture (rac)-309 via HPLC on a chiral stationary phase (Scheme 69). pure trans-product 331 via epimerization with triethylamine 310 does not show a measurable optical resolution, but controls the (Scheme 72).123 9010 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 68. Ward’s syntheses of polypropionate natural products using his tetrahydropyran methodology.

Scheme 69. Asymmetric autocatalysis triggered by cryptochiral alkane 310. J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9011

Scheme 70. Schmalz’ synthesis of (þ)-ptilocaulin (318).

Scheme 71. Regioselective alkylation through n-butylthiomethylene blocking groups.

Scheme 72. Synthesis of dihydrojasmonate 331. 9012 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Schaumann et al. reported about an elegant and efficient syn- (arylsulfanyl)propanals exploiting the chelating property of the thesis of (þ)-artemeseole, a compound identified in the essential phenylthio group. Reaction of aldehyde 357 with Me2Zn in from Artemisia tridentata. Deprotonation of allylphenylsulfide with thepresenceofTiCl4 furnished alcohol 358 with high anti-Cram n-BuLi generated an allyl anion, which reacted with epoxide 332 to selectivity. Reductive desulfurization produced the pine produce among other isomers homoallylic alcohol 333. Functional sawfly pheromone component 359 by converting the phenyl- group manipulation furnished key intermediate 334. Anion gen- thiomethyl substituent into a methyl group (Scheme 77).128 It eration via the radical anion lithium di-tert-butylbiphenyl (LiDBB) should be noted that the methyl group itself could not have instantaneously led to cyclopropane ring closure providing 335, been introduced with the desired diastereoselectivity in the which under acid catalysis was transformed into (þ)-artemeseole organozinc addition as it would lack the chelating ability (336)(Scheme 73).124 and also exerts only a small steric influence, again showcasing

Scheme 73. Synthesis of (þ)-artemeseole (336).

Nicolaou et al. have developed a universal strategy for the the stereoselectivity gain made possible by using thioether stereocontrolled construction of 2-deoxy glycosides. The anomeric groups. 129 centre is controlled by the stereoconfiguration of a phenylthio Mikami et al. used their BINOL/TiCl2(Oi-Pr)2 catalyst system substituent, which is subsequently removed (Scheme 72).125 An for a two directional asymmetric ene reaction with fluoral (360) impressive application of this strategy is the synthesis of Sialyl LeX and enesulfide 361 to produce a mixture of isomers of double (345). Glycosylation of 342 with intermediate 341 furnishes tetra- reacted products with anti,Z-363 and anti,E-363 as main products, saccharide 343. Reductive desulfurization was achieved with which upon reductive desulfurization and hydrogenation with Ph3SnH/AIBN in refluxing toluene in 77% accompanied with for- Raney-Ni convergently reacted to diol 364, which found use mation of the d-lactone 344. Protecting group manipulation led to as tether in antiferroelectronic liquid crystalline molecules Sialyl LeX (345)(Scheme 74). (Scheme 78).130 This strategy was also used by Roush et al. in their synthesis of In their synthesis of corynantheine (368) Autrey and Scullard the C-D-E trisaccharide subunit of the natural product olivomy- used the methylthio substituent in 365 to guide the Beckmann cin.126 After assembly of the trisaccharide 346 the tosyl groups of fragmentation to produce 366. In order to convert 366 to olefin 367 346 were first converted into iodides via SN2 displacement. Sub- they faced the challenge to desulfurize a vinylsulfide in the pres- sequent treatment with Raney-Ni not only reductively removed the ence of a nitrile and without reducing the desired olefin. It required phenylthio group but also dehalogenated the iodides to produce considerable optimization to identify the optimal conditions with the C-D-E trisaccharide subunit of olivomycin 347 protected as the Raney-Ni in refluxing MeOH to produce the desired compound 367 trimethylsilylethylether (Scheme 75). in excellent 82% yield (Scheme 79).131 Nakayama et al. used a thioether linkage to turn a notoriously The enantioselective protonation of enolates represents a highly unselective intermolecular pinacol coupling between ketones into desirable transformation for creating new stereogenic centres. a highly selective intramolecular pinacol coupling of easily pre- However, current methodology faces selectivity problems. Tomioka pared diketosulfides 348, in which the cis-diol intermediates 349 et al. have reported about a very interesting two-step procedure, are produced.127 Depending on the alkyl substituents, de- which combines a 1,4-addition of a bulky thiolate 371 to the ac- sulfurization with Raney-Ni furnishes the erythro-orthreo-1,2-diols rylate 369 in the presence of chiral modifier 370 resulting in an 350 (Scheme 76). With this approach also unsymmetrical diols 353 enolate 372, which is immediately protonated by the correspond- are accessible, which otherwise would produce mixtures in the ing thiol 373. Reductive desulfurization of the thioether 374 with intermolecular pinacol coupling. If thiophenes are introduced as Raney-Ni produced chiral esters 375 without any epimerization substituents in the substrate 354, then the subsequent de- (Scheme 80).132 sulfurization delivers the corresponding alkyl products 356. Singh et al. showed a similar reaction but with the advantage of Hogberg€ et al. identified conditions, which allow the highly using just 1% chiral thiourea catalyst 377 instead of a chiral reagent diastereoselective addition of organozinc reagents to 2-alkyl-3- for the enantioselective thia-Michael addition. As an application of J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9013

Scheme 74. Phenylthio-controlled glycosylation in the synthesis of Sialyl LeX (345).

Scheme 75. Synthesis of the C-D-E trisaccharide subunit of olivomycin.

their highly selective reaction they showed a synthesis of (S)-ibu- positions the hydrogen of the isoborneol for an 1,7-hydride shift in profen (379). Thia-Michael reaction of PhSH to acrylamide 376 analogy to an intramolecular MVP-reduction to produce 383. The under catalysis with 377 occurred in 92% ee. Reductive de- authors comment that with aromatic substituents at position R1 sulfurization with Raney-Ni and saponification led to 379 in 52% and R2 desulfurization with Raney-Ni to 384 occurred without ra- yield (Scheme 81).133 cemization of the secondary alcohol in hypophosphite buffered Node et al. developed a domino-Michael addition/Meer- EtOH solution, whereas this method did not proceed for aliphatic weinePonndorfeVerley (MVP) reduction, which formally repre- substituents. For these the secondary alcohol had first to be pro- sents a highly enantioselective reduction of a,b-unsaturated tected as benzoate esters and then Raney-Ni W-2 in EtOH produced ketones to secondary alcohols.134 a,b-Unsaturated ketone 380 re- 384 to avoid epimerization (Scheme 82). acts first in a thia-Michael addition with chiral camphor-derived ()-Pyrimidoblamic acid (389) was a central intermediate in the thiol 381 under Me2AlCl-mediation. Intermediate 382 ideally synthesis of deglycobleomycin A2 by the Boger group. The tin 9014 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 76. Selectivity gain via thio-tethered intramolecule pinacol coupling.

Scheme 77. Phenylthio-substituents enabling a switch to chelate controlled addition selectivity.

Scheme 78. Improved selectivity in asymmetric ene reaction.

enolate 386 reacted with imine 385 to furnish coupling product Nagao et al. have developed a method, in which under soft 387. The methylthio group, which had served its purpose as a se- enolization conditions chiral tin enolates are formed from 390, lectivity improving group in the previous step, was removed under which react with iminium species generated from precursor 391 to radical conditions using Bu3SnH/AIBN in reﬂuxing benzene to form coupling product 392. Reductive desulfurization with Raney- produce 388 (Scheme 83).135 Ni in reﬂuxing EtOH occurred under concomitant cleavage of the J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9015

Scheme 79. Thiosubstituent directed Beckmann-fragmentation.

Scheme 80. Enantioselective protonation of acrylates induced by a thia-Michael addition.

auxiliary to furnish 393, which upon saponification produced addition of H2S to the a,b-unsaturated enone forming a b-mer- 136 (þ)-ecgoninic acid (394)(Scheme 84). captoenone 396, which was desulfurized with n-Bu3P under photolytic conditions via a C-radical to give 397 in 65% overall yield 10. Other applications in organic synthesis (Scheme 85). In their total synthesis of a-berbatene (402) Ito et al. trans- In their attempt to synthesize the major metabolite 398 of formed the dimesylate 399 into tetrahydrothiophene 400, which prostaglandin D2 Corey et al. faced the challenge to reduce the a,b- was desulfurized with lithium in ethylamine in the presence of 2- unsaturated enone of 395 in the presence of a thioketal and propanol leaving the olefin moiety intact. 401 was then trans- 138 a nonconjugated olefin.137 This was accomplished by first 1,4- formed into 402 via skeletal rearrangement (Scheme 86). 9016 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 81. Synthesis of (S)-ibuprofen (379) via enantioselective organocatalytic thia-Michael addition.

Scheme 82. Intramolecular MVP-reduction.

Scheme 83. Synthesis of ()-pyrimidoblamic acid (389). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9017

Applying a transformation introduced by Djerassi et al.139 for steroids Masjedizadeh from Syntex succeeded in the desulfurization of thiazolidinone 404 into enamide 405, which ultimately could be transformed into chiral (S)-2-aminoquinuclidine (406)(Scheme 87). This synthesis sequence was applicable to prepare tritiated variants of 406.140 Reductive desulfurization can also be used for the deoxygenation of alcohols, if the alcohol is ﬁrst converted into a thiol or thioether. Fukumoto et al. used a clever arrangement of Sharp- less asymmetric epoxidation of 407 to produce a highly strained oxaspiropentane, which readily converts into cyclobutanone 408 upon acid-catalyzed 1,2-rearrangement. Removal of the hydroxy group was achieved in a two-step procedure involving the desulfurization of the phenylthio group producing 410. 410 was converted into (þ)-a-cuparenone (411) in an one-pot reaction following a previously established protocol (Scheme 88).141 For their synthesis of the marine natural product avarol (418) Theodorakis et al. developed a fascinating radical CeC coupling reaction. Starting from carboxylic acid 412 the Barton ester 413 was synthesized, which upon photolysis produced radical 414. 414 im- Scheme 84. Synthesis of (þ)-ecgoninic acid (394). mediately reacted in conjugate type addition with benzoquinone 415 resulting in 416, which with an excess of 415 furnished the

Scheme 85. Chemoselective reduction of a,b-unsaturated ketone.

Scheme 86. Synthesis of a-berbatene (402). 9018 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 87. Synthesis of enamide via reductive desulfurization.

Scheme 88. Synthesis of (þ)-a-cuparenone (411).

isolable derivative 417 in 81% yield. Reductive desulfurization re- anionic cascade reaction, which involves an S/O group transfer moved the 2-pyridylthio substituent and reduced the quinone reaction. By reacting 419 with vinyl-Grignard reagent in the pres- 142 moiety producing avarol (418) in very good yield (Scheme 89). ence of CeCl3 the C]O group is nucleophilically attacked to give the Steroid scaffolds were synthesized by Njardarson et al. by using divinyl carbinol, that is, treated with KOtBu creating an oxyanion, thiopyran building blocks, which were synthesized via one-pot which reacts with the phosphorous atom furnishing a thiolate

Scheme 89. Synthesis of avarol (418). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9019 anion, which undergoes a 6-endo-trig cyclization to produce 420.A For their synthesis of (rac)-18-noraspidospermidine (434) the DielseAlder reaction of 420 with dienophile 421 produced 422, group of Rodriguez used a Pummerer rearrangement of acylsulﬁnyl which either upon reductive desulfurization with Raney-Ni resul- derivative 431 to form cyclization product 432. The reaction ted in descarba-steroid 423 or could be ring contracted to steroid mechanism is believed to proceed through a sulfenium in- derivative 424 (Scheme 90).143 termediate, which electrophilically attacks the electron rich indole

Scheme 90. Synthesis of steroid analoga.

Oleﬁns can be activated by reaction with sulfenium reagents, for ring. Reductive desulfurization of 432 with Raney-Ni furnished nucleophilic attack, which results in products with an RS- 433 in 82% yield. 433 was then reduced with LiAlH4 to 434 substituent, which can later be removed by reductive (Scheme 93).146 desulfurization. Magnusson et al. synthesized a series of enantiomerically pure In a synthetic study towards the antiimmunosuppressive lignans by diastereoselective 1,4-addition of the dithioacetal anion agent FR901483 Weinreb et al. accomplished the PhSCl 436 to a,b-unsaturated ketone 435. In this example reductive de- induced cyclization of homoallylic amine 424 to tricyclic structure sulfurization of 437 with Raney-Ni followed by deoxygenation 425, which was smoothly desulfurized to product 426 with Pd/C in AcOH led to (þ)-burseran (438) in 52% yield (Scheme 91).144 (Scheme 94).147

Scheme 91. PhSCl-induced cyclization of homoallylamines.

Livinghouse et al. converted the acyclic precursor 427 via In a study aiming at the synthesis of lactones of tyrosine a sulfenium ion promoted cascade annulation into tricycle 428. and other amino acids Rao et al. needed intermediate 442, Efforts towards the selective desulfurization of the phenylthio which should be prepared by reductive desulfurization of 441. substituents in 428 with Raney-Ni or lithium amalgam led to The standard reagent Raney-Ni in various solvents as well partial reductive cleavage of the benzylic cyano substituent. The as a variety of hydride reducing agents proved to be inefficient. transformation of 428 to 429 was finally accomplished in 94% Ultimately either radical desulfurization with Bu3SnH or overall yield by protecting first the nitrile function as its lithio refluxing with Hantzsch ester produced 442 in good yields derivative, allowing the reductive desulfurization with lithium (Scheme 95).148 naphthalenide and final oxidative decyanation to deliver Saito et al. have developed a stereoselective hetero-DielseAlder 429. Dealkylation with BBr3 furnished (rac)-nimbidiol (430) reaction between thiochalcones, such as 443 with dimenthylfu- (Scheme 92).145 marate 444 to furnish 3,4-dihydrothiopyranes, which upon 9020 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 92. Synthesis of (rac)-nimbidiol (430).

Scheme 93. Synthesis of (rac)-18-noraspidospermidine (434).

Scheme 94. Synthesis of the lignan (þ)-burseran (438). J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9021

Scheme 95. Selective desulfurization methods in the presence of sensitive functional groups.

reduction of the ester groups produced 445. Reductive de- The desulfurization of alkylthio-DNA adducts with Raney-Ni has sulfurization with Raney-Ni resulted in optically pure diol 446 recently been used for the development of an assay of 1,2- (Scheme 96).149 dibromoethane-derived DNA crosslinks formed with O6-alkylgua- In a study towards the synthesis of pseudoguainolides McKer- nine-DNA alkyltransferase.152 vey et al. treated 447 with Raney-Ni, which led to desulfurization of

Scheme 96. Diastereoselective DielseAlder reaction.

the butylthio group, debromination and hydrogenation of the oleﬁn 11. Reductive desulfurization in peptide chemistry delivering 448 in 68% yield (Scheme 97).150 In a study aiming at the synthesis of carbapenems Natsugari Recent developments in peptide chemistry have allowed the et al. had to investigate the desulfurization of intermediate 449. total synthesis of proteins. Instrumental for this amazing de- They observed an interesting case of stereoselective control velopment was an efﬁcient assembly strategy with which un-

Scheme 97. Desulfurization producing lactone 448.

depending on the used desulfurization agent. With Raney-Ni they protected peptide fragments (resulting from solid phase peptide isolated trans-azetidinone 450 as the major product (47% isolated synthesis or recombinant expression) are connected via native yield) together with 21% of cis-azetidinone 451. In contrast Bu3SnH chemical ligation (NCL) developed by Kent et al. In NCL a peptide with AIBN as a radical initiator yielded preferentially cis-azetidi- fragment with a C-terminal thioester 452 undergoes ﬁrst a trans- none 451 in 72%, with 450 as a by-product in 22% yield thioesteriﬁcation with a peptide fragment 453 exhibiting an N- (Scheme 98).151 terminal cysteine (Cys) resulting in thioester 454, which in an 9022 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 98. Diastereoselective control in the synthesis of azetidinones via desulfurization.

intramolecular S-toN-acyl shift furnishes the thermodynamically extending the scope of NCL in converting the introduced Cys of more stable peptide 455 (Scheme 99).153 coupled peptide 455 into an alanine (Ala) of 456 via reductive de- Due to its efﬁciency the NCL has soon found application in the sulfurization (Scheme 100).155 They showcased this strategy in total synthesis of proteins, such as HIV-protease, Ras, and others. A a synthesis of the peptide antibiotic microcin J25 (459). Intra-

Scheme 99. Native chemical ligation (NCL) of peptide fragments.

considerable limitation however was the requirement to have a Cys molecular NCL of the acyclic precursor 457 furnished cyclization at the ligation site, because Cys is the least abundant of all protei- product 458 in 50% isolated yield, which could be quantitatively nogenic amino acids. By building on earlier work by Perlstein et al. transformed into 459 by reductive desulfurization with either who have demonstrated that proteins can be desulfurized with Raney-Ni or Pd/Al2O3. When using other peptide substrates the Raney-Ni,154 Dawson and Yan have found a very convenient way of authors noted that prolonged treatment with Raney-Ni is J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9023

Scheme 100. Synthesis of microcin J25 (459) via NCL and reductive Cys-to-Ala conversion.

accompanied with desulfurization of methionine (M), whereas Pd/ In the optimization process for this reaction Danishefsky re- Al2O3 can lead to hydrogenation of tryptophan (W). alized that yields and selectivity are best, if the water-soluble As the desulfurization with Raney-Ni or Pd/C imposes tris(2-carboxyethyl)phosphine (TCEP) and the water-soluble rad- some restrictions on the use of protecting or activating groups, ical initiator VA-044 is used, which has the additional advantage of Danishefsky et al. developed a homogeneous radical desulfuri having a very low temperature of decomposition.160 With this zation method with triethylphosphite (or trialkylphosphine) and reaction combination it is possible to perform the Cys/Ala a radical initiator for peptides and proteins, by adapting method- transformation in the presence of Met, biotin, Cys(Acm), thiazoli- ology developed earlier for small molecule synthesis dines, and many other functionalities. The unique selectivity of e (Scheme 101).156 159 their new method proved instrumental for Danishefsky’s suc- cessful total synthesis of a homogeneous erythropoietin (EPO) with the native sequence of 166 amino acids and chitobioseglycan residues.161 Over the last years, several b-thio and g-thio substituted amino acids have been synthesized, which offer new opportunities for identifying other ligation sites, which after radical desulfurization produce natural amino acids. As this topic has been reviewed by Dawson162 and Seitz163 only a few examples are named here. The groups of Seitz164 and Danishefsky165 have introduced the amino acids 460 and 461, which serve as N-terminal ligating units delivering peptides, which upon radical desulfurization are converted into peptide 464 with Val at the ligation site (Scheme 102). In addition thiolated amino acid 465 enables the proline (Pro)- ligation,166 466 the phenylalanine (Phe)-ligation,167 and 467 the lysine (Lys)-ligation in combination with radical desulfurization (Scheme 103).168 Very recently Payne et al. have reported an aspartate (Asp)-ligation, which tolerates unprotected Cys as the desulfurization occurs without an added initiator because the homolytic cleavage of the CeS bond at the thiolated Asp should be two orders of mag- nitudes faster than in the Cys. An example is given in Scheme 104 Scheme 101. Catalytic cycle for the radical desulfurization of thiols. for the ligation of peptides 468 and 469 and the in situ initiator- 9024 J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027

Scheme 102. Amino acids for the Val-peptide ligation.

strategic use of such elements in synthetic planning. For the future we hope that an even more efficient and milder reagent than Raney-Ni (ideally in the form of a catalyst) will be identified, which allows the reductive desulfurization of thiophenes and thioethers.170 Currently, Raney-Ni is without alternative as a reagent for thiophenes. For thioethers it can be complemented with Li in amine solvents, which itself has its limitations as a reagent. The recent Scheme 103. Amino acids used for Pro-, Phe-, and Lys-ligation. discovery of the reagent combination TCEP/VA-044, which has revolutionized the desulfurization of thiols due to its efficiency and

Scheme 104. Asp-ligation and initiator-free desulfurization.

free desulfurization with TCEP furnishing peptide 470 in 63% functional group tolerance, shows that such innovations are still yield.169 possible. These selected examples show that new ligation strategies enabled by several new thiol-substituted amino acids in combination Acknowledgements with TCEP/VA-044 as a very mild and highly efficient desulfurization reagent are making an enormous impact in the syn- Our own research in this field was supported by grants of thesis of peptides, proteins and posttranslationally modified PLACEBO (Platform for Chemical Biology) project as part of protein structures. the Austrian Genome Project GEN-AU funded by the For- schungsforderungsgesellschaft€ (FFG) and Bundesministerium fur€ Wissenschaft und Forschung (BMWF) and NAWI Graz. 12. Conclusions

In this review we have shown that S-containing compounds Abbreviations have found widespread application in organic synthesis as they can be used as Cn-building blocks, are able to regulate the reactivity of reagents, help to control the stereochemical outcome of reactions, Acm acetamidomethyl or are reactive handles to stitch reaction partners together. Once ACN acetonitrile such elements have served its purpose they can be removed by AIBN 2,20-azobis(isobutyronitrile) reductive desulfurization in a traceless manner, leaving only a hy- Bn benzyl drogen atom behind, which offers tremendous ﬂexibility in the Bz benzoyl J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 9025

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Biographical sketch

Jana Rentner was born in Halle/Saale (Germany) in 1983. In 2007 she ﬁnished her master thesis in chemistry at the University of Leipzig (Germany) in Organic Synthesis in the group of Prof. Rolf Breinbauer. In 2008 she followed Rolf to Graz University of Lisa Offner was born in Leoben (Austria) in 1989. In 2008 she started studying chem- Technology (Austria) where she received her PhD in 2012. After brief post-doctoral istry at the Graz University of Technology where she received her MSc degree being work in 2012 in the group of Dr. Mandana Gruber in Graz (Austria), she accepted a po- mentored by Dr. Mandana Gruber and Prof. Rolf Breinbauer at the Institute of Organic sition in pharmaceutical development in industry. Chemistry. Currently she is studying the Master’s program in Biotechnology at the Graz University of Technology, starting her master thesis in the ﬁeld of synthetic biology in Dr. Birgit Wiltschi’s group.

Marko Kljajic was born in Derventa (Bosnia and Herzegovina) in 1988. After ﬁnishing his BSc in Chemistry, he continued his Master studies at the Graz University of Tech- nology in Graz (Austria). He ﬁnished his MSc thesis on the topic of Pd-catalyzed ally- lations of phenols under the guidance of Prof. Rolf Breinbauer. At the moment he is working on the synthesis of covalent binding inhibitors for activity-based proteomics. Rolf Breinbauer was born in Scharding€ (Austria) in 1970. He studied chemistry at the Vienna University of Technology and the University of Heidelberg and received his PhD under the guidance of Prof. Manfred T. Reetz at the Max-Planck-Institut fur€ Kohlenfor- schung in Mulheim/Ruhr€ (Germany) in 1998. After working as a Post-Doc with an Er- win-Schrodinger-Fellowship€ in the laboratory of Prof. Eric N. Jacobsen (Harvard University), he moved in 2000 to Dortmund (Germany) as a group leader at the Max-Planck-Institute of Molecular Physiology (Department Head: Prof. Herbert Wald- mann) and as a Junior Professor at the University of Dortmund. From 2005 to 2007 he was a Professor of Organic Chemistry at the University of Leipzig. Since 2007 he is Full Professor of Organic Chemistry at the Graz University of Technology in Graz (Austria). The research focus of his group is the design and synthesis of molecular probes for Chemical Biology and the development of new synthetic methods.