Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• ring [19]. We have now developed this concept further toward a library synthesis of functionalized azepino-isoindolinone derivatives. Results and Discussion N-Alkylation of phthalimide with 4-penten-1-ol under Mitsunobu conditions, followed by NaBH4 reduction and pivaloate protection of the

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• intramolecular conjugate addition. Three of these compounds (1–3) were obtained from the corresponding alcohols [19][20] in three steps: Mitsunobu reaction with NH-Boc-tosylate, followed by tosyl deprotection with magnesium, and finally two-directional cross metathesis with ethyl acrylate to install the desired

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1]. Keywords: diversity oriented synthesis; julocrotine; leishmania; Mitsunobu reaction; Ugi reaction; Introduction Julocrotine (1) is a natural glutarimide alkaloid isolated from several plants of the genus Croton [2][3][4

• chiral center of 4 can be observed even in the presence of weak bases such as potassium carbonate [17]. Thus, we decided to use a base-free N-alkylation protocol, namely the Mitsunobu reaction of 3 and the readily available 2-phenylethanol [18]. This protocol gave the desired optically active product in

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3

• glycosidase inhibitory activity. Keywords: amination; glycomimetics; glycosidases; Mitsunobu; pseudodisaccharides; Introduction We have been interested in synthesising molecules consisting of two monosaccharides linked by formal condensation without using the anomeric position [1]. Such molecules, termed

• investigations into this area [6] we found that the installation of amine linkages between primary–primary carbons of monosaccharides was relatively straightforward; this was achieved by Mitsunobu coupling between carbohydrate C-6 alcohols and carbohydrate C-6 sulfonamides. Primary–secondary linkages were more

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• condensation of 1 with racemic alcohols 2a,b through a Mitsunobu reaction. The moderate yields are due to the consumption of alcohols 2, which undergo side-reactions, resulting in incomplete transformation of 1, even when using 1.3–1.5 equiv of 2. The use of a larger excess of 2 would probably increase the

• noting that the Mitsunobu reaction is not effective on unprotected salicylaldehyde. 2,3-Dihydrobenzo[f][1,4]oxazepines similar to 5a,b have been previously prepared, but through less general routes [22][23][24]. Compounds 5a,b were reacted with a series of isocyanides and carboxylic acids to give, in

High chemoselectivity in the phenol synthesis

• Matthias Rudolph,
• Melissa Q. McCreery,
• Wolfgang Frey and
• A. Stephen K. Hashmi

Beilstein J. Org. Chem. 2011, 7, 794–801, doi:10.3762/bjoc.7.90

• procedure of Fukumoto et al. [38] gave 13. Addition of ethynylmagnesium bromide to 13 led to 14, which reacted with furan 15 [40] under Mitsunobu conditions [39] to afford 8. While the yields were good for the first two steps of the reaction sequence, the yield of the last step was only 32%. With AuCl3 the

• reaction with 15 under Mitsunobu conditions yielded 27. Deprotection of the alkyne 27 and the silyl ether 28, followed by the oxidation of the resulting alcohol 29 finally led to 16. It was not possible to remove both silyl groups simultaneously with TBAF, longer reaction times which would be necessary for

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• regioselective invertive epoxide opening. 1.1.3 Mitsunobu reactions The Mitsunobu reaction offers an operationally straightforward method for activating simple alcohols to invertive substitution, and it is widely used for constructing new stereodefined carbon–heteroatom bonds [24][25]. The Mitsunobu reaction

• proceeds by reaction of a phosphine and DIAD or DEAD with an alcohol 23 to form an O-phosphinite leaving group (Scheme 9). SN2 substitution to yield 24 is accompanied by formation of a phosphine oxide. There are many examples of the use of sulfur nucleophiles in the Mitsunobu reaction [25][26][27]: The

• reaction is successful with a wide range of primary and secondary alcohols, but Mitsunobu-type reactions are very sensitive to steric bulk at the electrophilic carbon atom. For example, reaction of alcohol 25 with a phenol under standard Mitsunobu conditions at 50 °C for 16 hours provides only a trace

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• eletriptan (Scheme 20). A rather ingenious Mitsunobu coupling reaction has been used to create a highly functionalised substrate 96 for an intramolecular Heck reaction resulting in a very short and succinct synthesis of eletriptan and related analogues 97 [29] (Scheme 21). Interestingly, it was found that

Photoinduced homolytic C–H activation in N-(4-homoadamantyl)phthalimide

• Nikola Cindro,
• Margareta Horvat,
• Kata Mlinarić-Majerski,
• Axel G. Griesbeck and
• Nikola Basarić

Beilstein J. Org. Chem. 2011, 7, 270–277, doi:10.3762/bjoc.7.36

• diazomethane, generated in situ from N-methyl-N-nitroso-p-toluenesulfonamide (Diazald®) [56]. Homoadamantanone 3 was first reduced to the alcohol 4 [57][58][59] and subsequently converted to homoadamantyl phthalimide 5 in moderate yield via the Mitsunobu protocol [60] (Scheme 2). To get more insight into the

Carbasugar analogues of galactofuranosides: α-O-linked derivatives

• Jens Frigell and
• Ian Cumpstey

Beilstein J. Org. Chem. 2010, 6, 1127–1131, doi:10.3762/bjoc.6.129

• , our best results were obtained using an oxidation–reduction approach. Attempted SN2 reactions (Mitsunobu reaction or sulfonate displacement) gave inferior results. Hence the C2 alcohols 8 and 11 were oxidised under Swern conditions to give the ketones 15 and 16. Reduction of ketone group in ethyl

Ring-alkyl connecting group effect on mesogenic properties of p-carborane derivatives and their hydrocarbon analogues

• Aleksandra Jankowiak,
• Piotr Kaszynski,
• William R. Tilford,
• Kiminori Ohta,
• Adam Januszko,
• Takashi Nagamine and
• Yasuyuki Endo

Beilstein J. Org. Chem. 2009, 5, No. 83, doi:10.3762/bjoc.5.83

• and appropriate phenol using the classical Mitsunobu procedure [34]. A similar procedure was used for the preparation of tetraester 20B, while 19B was prepared more efficiently using the acid chloride method. Ester 19D has been reported in the literature [35]. Phenol 24 was prepared by acylation of 4

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• sequence using dihydroxylation with osmium tetroxide, mesylation and displacement with azide was used to produce leucoaziridinomitosane 45, whose spectral data matched those of an authentic sample derived from natural mitomycin C. 3.3. Williams. Mitsunobu reaction R.M. Williams successfully used this

• disconnection during the total synthesis of FR-900482 [62][63]. Coupling of nitrotoluene 59 and aldehyde 60 [64] gave the aldol product 61 as a 2:1 mixture of diastereomers (Scheme 17). Manipulation of protecting groups and oxidation states led to compound 62, which cyclised smoothly under Mitsunobu conditions

• leaving group X free for nucleophilic displacement with the nitrogen of the newly formed pyrroline. The synthesis began by Mitsunobu coupling of phenol 76 with allylic alcohol 77 to give ether 78, which was heated in N,N-dimethylaniline to trigger a Claisen rearrangement (Scheme 22). A sequence of

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole- based inhibitors of neuronal nitric oxide synthase

• Graham R. Lawton,
• Haitao Ji,
• Pavel Martásek,
• Linda J. Roman and
• Richard B. Silverman

Beilstein J. Org. Chem. 2009, 5, No. 28, doi:10.3762/bjoc.5.28

• diastereomers was formed, but both were oxidized to α-bromoketone 12. Condensation with thiourea gave the 2-aminothiazole (13). Diprotection of the amine with Boc groups and deprotection of the TBS ether gave trans-alcohol 15. A Mitsunobu reaction was used to install a nitrogen atom in the form of a phthalimide

• does not need to be diprotected to allow the Mitsunobu reaction with phthalimide as the nucleophile to proceed (28a-c). This is presumably because the thiazole nitrogen is less nucleophilic. Cleavage of the phthalimide group gave amines 29a-c. The syntheses of 4a-c were completed by reductive amination

Recent progress on the total synthesis of acetogenins from Annonaceae

• Nianguang Li,
• Zhihao Shi,
• Yuping Tang,
• Jianwei Chen and
• Xiang Li

Beilstein J. Org. Chem. 2008, 4, No. 48, doi:10.3762/bjoc.4.48

• different fluorous PMB tags, was transformed into alkene M-120 and was then followed by two splits. First, each of the two mixtures was subjected to a Shi epoxidation with enantiomeric ketone catalysts. Later, these two mixtures were split again, half being subjected to a Mitsunobu reaction and the other

• ,19S,20S)-cis-murisolin (112), and (15R,16R,19R,20S)-murisolin A (121) (Scheme 18). The mono-THF moieties were synthesized from epoxy alcohol 122 by using Sharpless AD-mix-β for the threo-trans-threo THF moiety 123, a AD-mix-β followed by the Mitsunobu reaction for the erythro-cis-threo THF moiety 125

• ). 130 was obtained by using the Sharpless epoxidation and dihydroxylation of 129. Compound 130 was then subjected to the Mitsunobu inversion to afford 131, which was transformed into 125. Then the THF moiety 125 and γ-lactone moiety 132 were coupled by a Sonogashira cross-coupling, and diimide reduction

C₂-symmetric bisamidines: Chiral Brønsted bases catalysing the Diels- Alder reaction of anthrones

• Deniz Akalay,
• Gerd Dürner,
• Jan W. Bats and
• Michael W. Göbel

Beilstein J. Org. Chem. 2008, 4, No. 28, doi:10.3762/bjoc.4.28

• compounds 2 could be introduced by a Mitsunobu alkylation of maleimide [12]. Alternatively, substituted maleimides were prepared by reaction of maleic anhydride with the corresponding amines followed by ring closure [13][14]. Cycloaddition kinetics of 1a and 2a was examined first by 1H NMR in CD2Cl2 at room

N-1 regioselective Michael- type addition of 5-substituted uracils to (2-hydroxyethyl) acrylate

• Sławomir Boncel,
• Dominika Osyda and
• Krzysztof Z. Walczak

Beilstein J. Org. Chem. 2007, 3, No. 40, doi:10.1186/1860-5397-3-40

• ] Mitsunobu reaction;[8] or reactions that operate through ANRORC-mechanisms that require the presence of strongly electron-withdrawing groups.[9] Recently, we have described an N1- and N3-regioselective Michael-type addition of 5-substituted uracil derivatives to methyl acrylate and acrylonitrile.[10

A convenient allylsilane- N-acyliminium route toward indolizidine and quinolizidine alkaloids

• Roland Remuson

Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32

• hydroxyalkylallylsilane 32 is accomplished in 40% yield following Trost's procedure. [48] Reaction of glutarimide with alcohol 32 under Mitsunobu reaction conditions afforded imide 33 in 67% yield. Reduction of 33 was carried out with an excess of sodium borohydride in methanol at 0°C to give 34 as a mixture of two

• trimethylsilylmethylmagnesium chloride addition to ethyl (S)-3-hydroxybutanoate as we described. [50] The first three steps of the enantioselective synthesis were those previously described for the synthesis of racemic compounds (vide supra). Condensation of alcohol 32 with glutarimide under Mitsunobu conditions led to

• glutarimide under Mitsunobu conditions led to imide 40 in 46% yield. Reduction of 40 with diisobutylaluminium hydride afforded hydroxylactam 41 isolated as a mixture of isomers, a higher yield of a single isomer was obtained when using lithium triethylborohydride as reducing regent. The reduction had to be

The use of silicon- based tethers for the Pauson- Khand reaction

• Adrian P. Dobbs,
• Ian J. Miller and
• Saša Martinović

Beilstein J. Org. Chem. 2007, 3, No. 21, doi:10.1186/1860-5397-3-21

• both for the formation of the silyl ethers and from the Pauson-Khand reaction were the corresponding silanols, we wondered if it would be possible to use these compounds for the preparation of our desired ethers via a Mitsunobu reaction. There are examples in the chemical literature in which silanols

• may be used analogously to alcohols in the Mitsunobu reaction.[29] Unfortunately, neither triisopropylsilanol (synthesised by the hydrolysis of commercially available triisopropylsilyl chloride) or diisopropyl(1-methylallyl)-silanol and but-2-enyldiisopropylsilanol gave any product and quantitative

• allyltrimethylsilane. Preparation of allyldiisopropylsilyl ethers. Pauson-Khand reaction of allyldiisopropylsilyl ethers. Preparation of allyldiisopropylsilanes. Attempted Mitsunobu reactions of diisopropylsilanols. Preparation of alkynic diisopropylsilanes. Preparation of allyldiisopropylsilyl ethers. Preparation of

Pd-catalysed [3 + 3] annelations in the stereoselective synthesis of indolizidines

• Olivier Y. Provoost,
• Andrew J. Hazelwood and
• Joseph P. A. Harrity

Beilstein J. Org. Chem. 2007, 3, No. 8, doi:10.1186/1860-5397-3-8

• smoothly transformed to aziridine 7 after Mitsunobu condensation. Having arrived at the key [3+3] annelation step, we decided to employ our standard conditions for the Pd-catalysed reaction. Indeed, we were pleased to find that the desired piperidine 8 could be furnished in high yield and that this

Reaction of benzoxasilocines with aromatic aldehydes: Synthesis of homopterocarpans

• Míriam Álvarez-Corral,
• Cristóbal López-Sánchez,
• Leticia Jiménez-González,
• Antonio Rosales,
• Manuel Muñoz-Dorado and
• Ignacio Rodríguez-García

Beilstein J. Org. Chem. 2007, 3, No. 5, doi:10.1186/1860-5397-3-5

• with LiAlH4. Under these conditions the pivaloyl protecting group was removed, affording the dihydroxylated derivative 8. Application of the Mitsunobu conditions (DIAD, PPh3) to 9 promoted the cyclization to give the homopterocarpan 8. Therefore, following this five steps route, we have accessed the

Synthesis of coumarin or ferrocene labeled nucleosides via Staudinger ligation

• Ivana Kosiova,
• Andrea Janicova and
• Pavol Kois

Beilstein J. Org. Chem. 2006, 2, No. 23, doi:10.1186/1860-5397-2-23

• synthesised from 5'-tosylated intermediates, [36] whilst 3'-azido-3'-deoxythymidine 6 was prepared via a Mitsunobu type reaction. [37] Staudinger reaction of azidonucleosides 3–6 with triphenylphosphine led to iminophosphorane intermediates 7–10, which reacted subsequently with active esters of coumarin-4

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

• Paul S. Humphries,
• Quyen-Quyen T. Do and
• David M. Wilhite

Beilstein J. Org. Chem. 2006, 2, No. 21, doi:10.1186/1860-5397-2-21

• Paul S. Humphries Quyen-Quyen T. Do David M. Wilhite Pfizer Global R&D, Department of Medicinal Chemistry, 10614 Science Center Drive, San Diego, CA 92121, USA 10.1186/1860-5397-2-21 Abstract A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu

• (Figure 1). Aromatic ethers are structural motifs found in many naturally occurring molecules and compounds of medicinal interest.[13] We envisaged the pyridyl ether moiety of 1 to be efficiently formed via Mitsunobu coupling of the requisite pyridinol and alkyl alcohols.[14][15][16][17] Our first attempt

• at the Mitsunobu reaction between pyridinol 2 and alcohol 3, utilizing a modification of the conditions originally reported by Mitsunobu,[18] afforded pyridyl ether 4 in 54% yield (Scheme 1). Interestingly, the reaction did not reach completion and pyridinol 2 was recovered, despite the fact that it

Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives

• Andrew Kennedy,
• Adam Nelson and
• Alexis Perry

Beilstein J. Org. Chem. 2005, 1, No. 2, doi:10.1186/1860-5397-1-2

• and 18 were epimerised by Mitsunobu[43][44] inversion to yield the anti allylic alcohols 16 and 19. Diastereoselective dihydroxylation of a model system The diastereoselectivity of the dihydroxylation of the model compounds 15 and 17-19 was studied under both Upjohn[45] (cat. OsO4, NMO, acetone-water

• ] although the reducing agent still approaches the ketone from a pseudo-axial direction, the net stereochemical outcome is different (see Figure 6). The configuration of both alcohols in the bis-allylic alcohols trans-27 and cis-27 was cleanly inverted using a Mitsunobu reaction, and the resulting diesters