Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• configurationally labile amino aldehyde intermediates [55][56]. Basically any carbamate or amide protecting group (= PG) orthogonal to the benzyl moiety would be suitable for this strategy. Furthermore, we decided to surrender protection of the OH functions in the synthesis of intermediates D and C in order to

• , phenylalanine, phenylglycine and methionine 1a–d were converted to their N-benzyl-N-carbamate-protected derivatives 2a–d (PG = Cbz, Boc) in a practical one pot procedure through combination of Quitt´s reductive benzylation protocol [61] and a Schotten–Baumann acylation [62][63] in 70–95% yield (Scheme 1). While

• carbamate protected amino acid derivatives 3 (remaining as impurity in the isolated products 2), quantitative benzylation (1→I) was ensured by successive addition of three portions of benzaldehyde/NaBH4 (Quitt´s procedure [61] → two portions) and by maintaining the pH at a value of 10–11. The extractive

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• easy reaction of this electron-rich benzylamine with CO2 to give an insoluble carbamate. Skipping the extractive purification and directly using the crude amine in the ensuing sequence gave again erratic yields and was troublesome because of the difficult separation of the Ugi adducts 9 from

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• Curtius rearrangement, upon heating the intermediate isocyanate was trapped with EtOH to yield ethyl carbamate protected amine 141. Deprotection of the Alloc-group [126] and chloro carbamate formation furnished 142. Exposure of this compound to a silver source led to the formation of the five-membered

• (see Scheme 21), followed by the formation of an acid-azide. Shiori version [146][147] of the Curtius rearrangement with concomitant addition of MeOH to the intermediate isocyanate afforded carbamate 171. Oxetane 171 was then opened under Lewis-acidic conditions. The deprotected alcohol was protected

• demercurization [128][129] sequence (through intermediate 177) yielding 178. The oxindole protecting group was then removed, followed by reduction of the carbamate to the remaining missing methyl group [151] to finish gelsemine (146). The total synthesis of the monoterpenoid-indole alkaloid gelsemoxonine (197

Synthesis of novel derivatives of 5-hydroxymethylcytosine and 5-formylcytosine as tools for epigenetics

• Anna Chentsova,
• Era Kapourani and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 7–11, doi:10.3762/bjoc.10.2

• the corresponding carbamates 7a–c. The reaction of aldehyde 4 and vinylmagnesium bromide yielded directly carbamate 7d. Surprisingly, the reaction of derivative 5 bearing a N-(TCBoc)2 group with organometallic compounds (methylmagnesium bromide, THF, 0 °C → room temperature, lithium (trimethylsilyl

Oligomeric epoxide–amine adducts based on 2-amino-N-isopropylacetamide and α-amino-ε-caprolactam: Solubility in presence of cyclodextrin and curing properties

• Julian Fischer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 2803–2811, doi:10.3762/bjoc.9.315

• pressure and the product dried in vacuo. 11.9 g (62.9 mmol = 87.8%) of a colorless oil was obtained. FTIR (diamond) ν (cm−1): 3500–3200 (br, NH), 1753 (s, ester), 1695 (vs, carbamate); 1H NMR (300 MHz, CDCl3) δ 5.22 (s, 1H, NH), 3.78 (d, J = 5.9 Hz, 2H, CH2), 3.62 (s, 3H, OCH3), 1.33 (s, 9H, RC(CH3)3); 13C

• 102 °C) were obtained. FTIR (diamond) ν (cm−1): 3292, 3222 (br, NH), 1692 (vs, carbamate), 1657, 1548 (vs, amide); 1H NMR (300 MHz, CDCl3) δ 6.41 (s, 1H, RC(O)-NH-R), 5.57 (s, 1H, R-NH-C(O)OR), 3.98 (m, 1H, CH-Me2), 3.66 (d, J = 5.7 Hz, 2H, CH2), 1.36 (s, 9H, RC(CH3)3), 1.06 (d, J = 6.6 Hz, 6H, RHC

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• density from the reaction center toward nitrogen. In cases where syn-selectivity is observed, the Cram’s chelation control model provides an explanation [56][57]. Chelating metal coordinates between the two carbonyls (the aldehyde and the carbamate), thus forcing the nucleophile to attack from the si-side

• syn-selectivities were achieved with vinylZnCl in Et2O (1:6 anti/syn). Coleman also noticed that the addition of excess ZnCl2 did not increase the syn-selectivity at all. They attributed this to the mono-coordination of the metal to the carbamate instead of the usual “bidentate” chelation control

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• hydroamination of alkenes. Detailed computational studies on the addition of benzyl carbamate to dienes revealed the protodeauration as the rate-determining step of the reaction [34]. Mechanistically, the initial stage was determined dealing with the energetically favourable substitution of the TfO− ligand from

• the gold coordination sphere with the diene (Figure 4). Preferred coordination geometry is the η2-type, with the gold cation coordinating to a single double bond. Either direct coordination of the nucleophile to the gold cation, or reaction of the PH3AuOTf with the carbamate to deliver TfOH and

• [38]. Although prolonged reaction times were required (up to 68 h in refluxing dioxane), remarkable tolerance in terms of carbamate protecting groups (Scheme 7a) and substituents at the carbon chain was recorded (Scheme 7b,c). Soon after the same team disclosed that the titled transformation could be

One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger–aza-Wittig reaction

• Diego Carnaroglio,
• Katia Martina,
• Giovanni Palmisano,
• Andrea Penoni,
• Claudia Domini and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2013, 9, 2378–2386, doi:10.3762/bjoc.9.274

• [1]. Isocyanates play a relevant role as chemical intermediates in the manufacturing of thermoplastic foams, elastomers, adhesives, agrochemicals and pharmaceuticals. The isocyanate group is also widely used as a precursor to several bioactive compounds and drugs that contain urea and carbamate

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• ) is hydrogenated to the vinylogous carbamate 2.53 in the presence of acetic anhydride. Then the intermediate 2.53 can be subjected to an asymmetric hydrogenation utilising rhodium-based catalyst systems at elevated hydrogen pressures rendering the desired ethyl (R)-nipecotate 2.54 [75]. Uniting the

• scientists and consists of a chiral hydroisoquinoline linked to a (R)-quinuclidinol unit through a carbamate linkage (Figure 6). Upon protonation the tertiary amine of the quinuclidine is expected to resemble the ammonium substructure of muscarine (2.58) [76]. This molecule can be prepared by direct coupling

• of the (R)-quinuclidinol and tetrahydroisoquinoline carbamate partner (Scheme 28). The (R)-quinuclidinol (2.59) itself can be accessed from quinuclidone (2.60), and is most conveniently prepared by alkylation of ethyl isonicotinate (2.61) with ethyl bromoacetate (2.62) followed by full reduction of

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• carbamate formation of the starting material. Upon exposure of 223 to phosphorus pentoxide, the desired isoindolinone 224 was formed in 75% yield. Deprotection led to lactonamycinone (214), which was the substrate for a ytterbium triflate-catalyzed glycosylation to give 215 and 217, respectively

Natural products in synthesis and biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 1897–1898, doi:10.3762/bjoc.9.223

• aminosugar, a hydroxylamine linkage between two sugar subunits, a carbamate, an aromatic iodide, a thioester, and a trisulfide [4]. Natural products have also been used by humankind since ancient times and are part of our traditions and culture, as is evident from the widespread consumption of coffee, tea

A Lewis acid-promoted Pinner reaction

• Dominik Pfaff,
• Gregor Nemecek and
• Joachim Podlech

Beilstein J. Org. Chem. 2013, 9, 1572–1577, doi:10.3762/bjoc.9.179

• were observed, when ester or carbamate groups were present in the substrates (Table 2, entries 8 and 9). The Lewis acid trimethylsilyl triflate possibly cleaves the benzyloxycarbonyl (Z) group, since the similar trimethylsilyl iodide (TMSI) is known to cleave Z protecting groups [17]. Poor yields are

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

• Willmen Youngsaye,
• Cathy L. Hartland,
• Barbara J. Morgan,
• Amal Ting,
• Partha P. Nag,
• Benjamin Vincent,
• Carrie A. Mosher,
• Joshua A. Bittker,
• Sivaraman Dandapani,
• Michelle Palmer,
• Luke Whitesell,
• Susan Lindquist,
• Stuart L. Schreiber and
• Benito Munoz

Beilstein J. Org. Chem. 2013, 9, 1501–1507, doi:10.3762/bjoc.9.171

• tert-butyl carbamates 5 prior to undergoing palladium-mediated Suzuki reactions with various boronic acid partners. Under the reaction conditions, the carbamate-protecting group was also cleaved to afford the desired 3-arylindazoles, albeit as the unprotected systems 6. Alkylation with methyl

Formal synthesis of (−)-agelastatin A: an iron(II)-mediated cyclization strategy

• Daisuke Shigeoka,
• Takuma Kamon and
• Takehiko Yoshimitsu

Beilstein J. Org. Chem. 2013, 9, 860–865, doi:10.3762/bjoc.9.99

• -hydroxycarbamate 7 in 67% yield [36]. Thereafter, N-hydroxycarbamate 7 was reacted with TsCl and triethylamine in THF to furnish N-tosyloxycarbamate 8 in 92% yield. With this carbamate 8, we examined the iron(II)-mediated cyclization under various conditions (Table 1). The application of FeBr2 (0.5 equiv)/Bu4NBr

• (1.5 equiv) in EtOH effected cyclization, but the yield of 5a was poor due to the concomitant formation of carbamate 9 (39%) and enone 10 (30%) (Table 1, entry 1). This was in marked contrast to the observation that the same reagent system, i.e., FeBr2 (0.5 equiv)/Bu4NBr (1.2 equiv), allowed the

• provided evidence that these byproducts were generated by the intramolecular cyclization of enone 10 with TMSCl in EtOH, suggesting that the FeCl2/TMSCl system also gave enone 10 in ca. 30% yield [37]. The present study on the aminohalogenation reaction of carbamate 8 has inspired mechanistic insights that

Gold-catalyzed oxycyclization of allenic carbamates: expeditious synthesis of 1,3-oxazin-2-ones

• Benito Alcaide,
• Pedro Almendros,
• M. Teresa Quirós and
• Israel Fernández

Beilstein J. Org. Chem. 2013, 9, 818–826, doi:10.3762/bjoc.9.93

• ][53][54][55], we decided to examine the gold-catalyzed cyclization of N-Boc-allenes with the aim of establishing a protocol for the synthesis of 1,3-oxazin-2-one derivatives in which the carbamate group should serve as the source of CO2. Results and Discussion To explore the effects of various

• by treatment with paraformaldehyde in the presence of diisopropylamine and copper(I) bromide (Crabbé reaction) [59][60]. We employed three different gold salts in our initial screening of catalysts for the model system, allenic carbamate 2a. Initially, the use of AuCl3 and AuCl were tested, but both

• failed to catalyze the reaction. Fortunately, we found that [AuClPPh3]/AgOTf was an excellent catalyst for our purpose. To our delight, the reaction of allenic carbamate 2a at room temperature afforded 3-benzyl-6-methylene-1,3-oxazinan-2-one (3a) bearing an exocyclic double bond as the sole product

Intramolecular carbonickelation of alkenes

• Rudy Lhermet,
• Muriel Durandetti and
• Jacques Maddaluno

Beilstein J. Org. Chem. 2013, 9, 710–716, doi:10.3762/bjoc.9.81

• gives the same good yield added to an attractive (2c + 2c’)/3c ratio of 87/13 (Table 1, entry 3). Formation of the 3-methylindoline 3 is therefore disfavored when a mesyl protecting group is used instead of a carbamate. When this reaction is run with stoichiometric amounts of nickel, the reductive

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

• Julien Lefranc,
• Alberto Minassi and
• Jonathan Clayden

Beilstein J. Org. Chem. 2013, 9, 628–632, doi:10.3762/bjoc.9.70

• products that may be deprotected in situ to provide a new connective route to hindered amines. Keywords: carbamate; carbolithiation; carbometallation; organolithium; stereospecificity; styrene; urea; Introduction Enamines and N-acyl enamines are in general nucleophiles, reacting with electrophiles at the

• manipulated carbamate products bearing a standard Boc protecting group, providing they too could be carbolithiated and trapped without rearrangement. Related carbamates are reactive towards carbolithiation–rearrangement reactions [6]. Thus, Boc-protected carbamates 9–11 were synthesised by acylation of the

• imines 7 and 8 with di-tert-butyl dicarbonate or with (−)-menthylchloroformate (Scheme 4). The N-alkenylcarbamates 10 and 11 were formed exclusively as their E isomers, and the X-ray crystal structure of E-10 is shown in Figure 2. Vinyl carbamate 9 was treated with primary, secondary or tertiary

End-labeled amino terminated monotelechelic glycopolymers generated by ROMP and Cu(I)-catalyzed azide–alkyne cycloaddition

• Ronald Okoth and
• Amit Basu

Beilstein J. Org. Chem. 2013, 9, 608–612, doi:10.3762/bjoc.9.66

• used to terminate polymers prepared by ring-opening metathesis polymerization of norbornenes bearing an activated ester. The terminating agent is a cis-butene derivative bearing a Teoc (2-trimethylsilylethyl carbamate) protected primary amine. Post-polymerization modification of the polymer was

• reaction as well as subsequent polymer modifications, and that can also be removed under mild conditions for the subsequent functionalization of an amine-terminated polymer. We report here the development of the terminating agent 3, which caps a ROMP-derived polymer with a 2-trimethylsilylethyl carbamate

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• bond with the correct stereochemistry and the introduction of the pendant isopropyl group present in the target. The intermediate cyclic carbamate 2 is not isolated but cleaved into aminoalcohol 3 to simplify purification. The conversion of aminoalcohol 3 into (–)-dendrobine (4), hinges on the use of

Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

• Yury Minko,
• Morgane Pasco,
• Helena Chechik and
• Ilan Marek

Beilstein J. Org. Chem. 2013, 9, 526–532, doi:10.3762/bjoc.9.57

• organometallic species (i.e., copper) with a polar functional group in the vicinity of the reactive center should be able to reverse the regioselectivity of the carbometallation, as we have shown for the carbocupration of ethynyl carbamate (XR = OCONR2, Path C, Scheme 1) [24]. Herein we describe our results for

• the carbocupration of an N-alkynylsulfonamide could be easily achieved, we were interested to see whether such a carbocupration reaction could be extended to ynamide 4 bearing an acyclic carbamate moiety. We were pleased to find that this reaction could also be performed on N-alkynylcarbamate 4 with

• carbamate moiety. Molecular structure of 9f (hydrogen atoms except of H9 and H10 are omitted for clarity). Possible regioisomers obtained in the carbocupration reaction of α-heterosubstituted acetylenes 1. Regioselective carbometallation of N-alkynylsulfonamide 2. Regioselective carbometallation of ynamide

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• reaction of chiral imines with enolates derived from Weinreb amides [13][14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone

• preparation of chiral 2,6-disubstituted piperidines, we wish to report here a facile synthetic route to various β’-carbamate-α,β-unsaturated ketones in good overall yields and good enantioselectivities. Results and Discussion In a preliminary approach, preparation of β-amino ketones was envisaged through a

• ester moiety to a Weinreb amide [18] followed by changing the nitrogen protecting group to a carbamate furnished the key intermediate 6, which could be further alkylated with Grignard reagents to give β’-amino protected α,β-enone 1 in good overall yield and high enantiomeric excess. As Grignard reagents

Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation

• Kei Murakami and
• Hideki Yorimitsu

Beilstein J. Org. Chem. 2013, 9, 278–302, doi:10.3762/bjoc.9.34

• alkynes generally gives the vicinal product 2D (copper locates at the β-position to the O or N) (Scheme 13, path A) [14][70][71][72][73]. On the other hand, the reversed regioselectivity was observed in the carbocupration of O-alkynyl carbamate and N-alkynyl carbamate, in which carbonyl groups worked as a

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• +] calcd for C28H30N4O6, 518.2165; found, 518.2178. Benzyl (((3S,6S,12aS)-3-methyl-2-(2-(methylamino)-2-oxoethyl)-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-6-yl)methyl)carbamate (1a): Compound 6 (165 mg, 0.32 mmol, 518 g/mol) was dissolved in EtOH (3 mL). Aqueous LiOH (0.5

An improved synthesis of a fluorophosphonate–polyethylene glycol–biotin probe and its use against competitive substrates

• Hao Xu,
• Hairat Sabit,
• Gordon L. Amidon and
• H. D. Hollis Showalter

Beilstein J. Org. Chem. 2013, 9, 89–96, doi:10.3762/bjoc.9.12

• by a different procedure [17]; MS m/z: 456.1 [M + H]+. 2-(2-(2-(2-(Diethoxyphosphoryl)ethoxy)ethoxy)ethoxy)ethyl (5-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)pentyl)carbamate (8): A solution of in situ synthesized 5-(biotinamido)pentaneamine, trifluoroacetic acid salt

• [M + H]+. 2-(2-(2-(2-(Ethoxy(hydroxy)phosphoryl)ethoxy)ethoxy)ethoxy)ethyl (5-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)pentyl)carbamate (9): A mixture of lithium azide (200 mg, 4.1 mmol), diethyl phosphonate polyether carbamate 8 (150 mg, 0.22 mmol), and 2 mL of DMF

• ,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)pentyl)carbamate (FP–PEG–biotin; 1): To a solution of monoethyl phosphonate polyether carbamate 9 (46 mg, 0.072 mmol) in 1 mL of anhydrous dichloromethane at −42 °C was added (diethylamino)sulfur trifluoride (DAST; 26.4 μL, 0.022 mmol). The

A chemist and biologist talk to each other about caged neurotransmitters

• Graham C.R. Ellis-Davies

Beilstein J. Org. Chem. 2013, 9, 64–73, doi:10.3762/bjoc.9.8

• expense of another property, such as the rate of release [7]. For example, GABA caged directly as an ester with coumarin chromophores is photoreleased quickly, but is quite unstable in (frozen) solution [60]. However, when caged via a carbamate, its release is orders of magnitude slower, but the compounds