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Tetrahedron 69 (2013) 3437e3443
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Synthesis of 1,5-diazaspiro[2.3]hexanes, a novel diazaspirocyclic system Asta Zukauskait e_ a, b, Sven Mangelinckx a, Gert Callebaut a, Clarence Wybon a, Algirdas Sa ckus b, Norbert De Kimpe a, * a
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium _ ˛ pl. 19, LT-50270 Kaunas, Lithuania Institute of Synthetic Chemistry, Kaunas University of Technology, Radvilenu
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 September 2012 Received in revised form 14 February 2013 Accepted 19 February 2013 Available online 26 February 2013
The convenient synthesis of 1,5-diazaspiro[2.3]hexanes, as new structurally challenging strained diazaspirocyclic compounds, was developed starting from easily accessible ethyl 2-(bromomethyl)-1tosylaziridine-2-carboxylate. The key transformations in the developed four-step sequence involved a chemoselective reduction of the functionalized ethyl 1-tosylaziridine-2-carboxylate to the corresponding b-bromo aldehyde and an aza-Payne-type rearrangement of intermediate N-tosyl 2-(aminomethyl)aziridines into N-alkyl 2-(aminomethyl)aziridines. A final base-mediated cyclization of the formed bromo amines gave efficient access to the new diazaspirocyclic system. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Aziridines Azetidines Azaspirocycles Aza-Payne rearrangement
1. Introduction Recently, there has been a growing interest in the field of spirocyclic chemistry. Spirocycles comprise an interesting class of compounds, both from a chemical and a biological point of view. Azaspiro scaffolds are present in a number of natural products, such as halichlorine,1 sibirine,2 nitramine,3 and families of histrionicotoxins.4 Heteroatom-containing azaspirocycles, in particular, are considered to be surrogates for other saturated heterocycles, such as piperazines, morpholines, thiomorpholines, and piperidines,5 in some cases even being stable alternatives of their labile monocyclic analogues6 with applications as valuable building blocks in the field of drug discovery and for tuning of drugs or druglike structures.7 For example, 5-azaspiro[2.4]heptyl substituents were reported to enhance the antibacterial activity of quinolone antibiotics8 or highly potent oxazolidinone antibacterial agents.9 1,6-Diazaspiro[3.4]octanes possess (partial) agonist potencies for nicotinic acetylcholine receptors.10 3,9-Diazaspiro[5.5]undecanes,11 3-azaspiro[5.5]undecanes,12 and 2,8-diazaspiro[4.5]decanes13 were found to be spirocyclic nonpeptide glycoprotein IIbeIIIa antagonists and antiplatelet agents for inhibition of thrombus formation, while several diazaspiro sulfonamides were described as potent
Akt inhibitors.14 Series of potent muscarinic antagonists bear 3,9diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane and 2,9-diazaspiro[5.5]undecane moieties.15 The 2,8-diazaspiro[4.5] decane moiety was used to replace piperidine in a series of soluble, selective neuropeptide YeY2 receptor antagonists,16 while appropriately substituted 2,8-diazaspiro[4.5]decanones were found to be potent and selective T-type calcium channel antagonists.17 7Azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane were reported as lead scaffolds for novel spirocyclic inhibitors of fatty acid amide hydrolase.18 Several 3,9-diazaspiro[5.5]undecanes were disclosed as chemokine receptor antagonists,19 while 1,7diazaspiro[4.5]decanes were used as ligands for metal complexation with ZnCl2.20 Despite the significant interest and development in this field, some areas of this challenging chemistry are still un- or underexplored. Up to now, 1,5-diazaspiro[2.3]hexanes 1 (Fig. 1) are unknown in the well documented area of spirocyclic diamines, with the exception of some spirocyclic aziridine-azetidinones.21 In order
R1 N N 1
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 21; e-mail address:
[email protected] (N. De Kimpe). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.02.065
R2
Fig. 1. General structure of 1,5-diazaspiro[2.3]hexanes 1.
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group,23 a transformation, which was foreseen to provide synthetic access to the structurally challenging 1,5-diazaspiro[2.3]hexanes. All initial attempts to directly form aziridine-2-carboxaldehyde 10 by the use of DIBAL-H,24 in diethyl ether ( 78 Cdreflux) failed as each time no reaction occurred. When LiAlH4 in diethyl ether at 0 C was used, a mixture of bromo alcohol 8 and alcohol 9 was obtained, in 36% and 41% yield, respectively (Table 1, entry 1). In order to avoid the formation of 2-methylaziridine 9, as side product resulting from dehalogenation of aziridine 8, a smaller amount of LiAlH4 was used and the reaction time was shortened to 15 min. However, even under these conditions, dehalogenation could not be avoided (Table 1, entry 2). Surprisingly, when the reaction was performed at 78 C with 1 mol equiv of LiAlH4 for 1 h, no formation of the corresponding alcohol was observed and instead b-bromo aldehyde 10 was directly obtained in 88% yield (Table 1, entry 3). As shown by several groups, halogenated aldehydes7b,25,26,27 and aldimines28 can be used as attractive substrates for the synthesis of spiro derivatives. Inspired by these examples, several attempts were made to access the novel class of structurally challenging 1,5-diazaspiro[2.3]hexanes. Initially, it was expected that the reaction of b-bromo aldehyde 10 with an amine and reducing agent would give the corresponding 1,5-diazaspiro[2.3] hexane directly via the intermediate imine.29 However, even though treatment of bromo aldehyde 10 with benzylamine in the presence of HOAc in methanol at 50 C for 4 h gave intermediate
to fill this important gap, the synthesis of 1,5-diazaspiro[2.3]hexanes 1 was investigated starting from previously reported ethyl 2(bromomethyl)-1-tosylaziridine-2-carboxylate 7.22 2. Results and discussion In view of the initially reported low yield of aziridine 7 (17% yield over three steps),22 and the high price of the starting ethyl 2-(bromomethyl)acrylate 2, a new synthetic pathway for this functionalized aziridine was developed (Scheme 1). As the original synthesis suffered from undesired diallylation in the amination step using Ntosylamide, it was envisioned that this side reaction could be avoided if instead of a primary amine, an appropriate secondary amine was used. For this reason, ethyl 2-(hydroxymethyl)acrylate 3 was treated with BocNHTos under Mitsunobu conditions, efficiently affording N,N-diprotected allylamine 4 in 91% yield. The carbamate function in allylamine 4 was cleaved with TFA in CH2Cl2 at room temperature for 1 h, yielding N-allyl-N-tosylamide 5 in 98% yield. The low yield of 57% of the subsequent bromination, as previously reported,22 was improved by simply prolonging the reaction time to 24 h (instead of 4.5 h). Thus, after optimizing reaction conditions, and final cyclization of dibromo b-amino ester 6, ethyl 2-(bromomethyl)-1-tosylaziridine-2-carboxylate 7 was synthesized from commercially available ethyl 2-(hydroxymethyl)acrylate 3 by a fourstep procedure in 79% overall yield.
OH
COOEt
COOEt
2
Tos N Boc
1.1 equiv DIAD 1.1 equiv PPh3
Br
1.1 equiv BocNHTos THF, r.t., 24 h
3
COOEt 4 (91%) TFA CH2Cl2, r.t., 1 h
Ref. 22 17% over 3 steps Tos N
1.5 equiv K2CO3
Br COOEt 7 (95%)
CH3CN, 60 °C, 2 h
Br
Tos NH Br COOEt 6 (93%)
Tos NH
1.1 equiv Br2 CH2Cl2, r.t., 24 h
COOEt 5 (98%)
Scheme 1. Synthesis of ethyl 2-(bromomethyl)-1-tosylaziridine-2-carboxylate 7.
imine 11a, the addition of 2 equiv of sodium cyanoborohydride did not result in a 4-exo-tet-cyclization toward the corresponding 1,5diazaspiro[2.3]hexane. Instead, a ring transformation, similar to an aza-Payne rearrangement, during which activated 2-(hydroxymethyl)aziridines are transformed into the corresponding epoxy
It was envisioned that reduction of aziridine 7 with the appropriate reducing agent and, if necessary, subsequent oxidation of the corresponding alcohol 8, would give b-bromo aldehyde 10. Aziridine-2-carboxaldehydes have recently proven to be good substrates in reductive aminations for the introduction of an aminomethylene Table 1 Synthesis of 2-bromomethyl-1-tosylaziridine-2-carboxaldehyde 10
Tos N
Tos N
Reaction conditions Br COOEt
Br
+
Tos N
+
Tos N
Br
Et2O OH 8
7
OH
O H
9
10
Entry
Reducing agent
Temperature
Reaction time
Resulta,b
1 2 3
1 mol equiv LiAlH4 0.6 mol equiv LiAlH4 1 mol equiv LiAlH4
0 C 0 C 78 C
30 min 15 min 1h
8 (36%)þ9 (41%) 7/8/9 2:2:1 10 (88%)
a b
Yields in parentheses indicate isolated yields after flash chromatography. Ratio of reaction products determined by 1H NMR analysis of the crude reaction mixture.
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amines under basic conditions,30 occurred (Scheme 2). This rearrangement involved regioselective ring opening of in situ formed activated 2-(aminomethyl)aziridine 12a by intramolecular nucleophilic substitution to afford aziridine 13a in 10% yield.
10
Tos N
Br
HN
Tos
Br
Br
=
2) 2 equiv NaCNBH3 MeOH, ∆, 15 h
O H
Tos N
rearrangement involved ring opening of the intermediate 2-(aminomethyl)aziridines (like 12a) by intramolecular nucleophilic substitution (Scheme 2). Subsequently, the synthesis of 1,5-diazaspiro [2.3]hexanes 14 was completed by cyclization of the bromo amines
=
1) 1 equiv BnNH2 1 equiv HOAc MeOH, 50 °C, 4 h Br
Tos N
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H
H 11a
N Bn
NH Bn
Bn
12a
N
13a (10%)
Scheme 2. Unexpected rearrangement of b-bromo aldehyde 10 to aziridine 13a.
Even though the desired azaspiro product was not formed, the reaction outcome was promising, as after optimization of reaction conditions, bromo amines 13 could be suitable substrates for intramolecular ring closure under basic conditions. Therefore, several N-alkyl- and N-aryl-b-bromo imines 11 were prepared through condensation of 2-bromomethyl-1-tosylaziridine-2carboxaldehyde 10 with 1.1e1.5 equiv of the corresponding amine in CH2Cl2 at reflux in the presence of MgSO4 (Table 2).31 The strategy chosen gave nearly quantitative amounts of imines 11 that were obtained in high purity (imines 11bed). Only in case of benzyl derivative 11a, the purity of the crude product was lower due to the presence of excess unreacted benzylamine, which could be removed in a subsequent step. Table 2 Synthesis of (aziridin-2-yl)carboxaldimines 11
Tos N
Br O
Tos N
1.1-1.5 equiv RNH2 MgSO4, CH2Cl2, ∆, 2 h
H 10 Entry
R
Amine
1 2 3 4 5
Bn Allyl i-Pr i-Pr c-Hex
1.1 1.1 1.1 1.5 1.1
equiv equiv equiv equiv equiv
Br
N H R 11a-d Result
13 with 2 equiv of K2CO3 and heating at 60 C in acetonitrile for 24 h, affording spiro compounds 14aed in 88e96% yield. To further demonstrate the usefulness of the developed synthetic procedure, the deprotection of the tosyl group of 1,5diazaspiro[2.3]hexane 14a was attempted (Scheme 4). Analogous to the detosylation of a related 1,6-diazaspiro[3.3]heptane,6 tosylamide 14a was treated with a large excess of Mg in methanol for 26 h at room temperature, leading to the formation of the desired crude amine 15 without ring opening of the strained spirocyclic system (LC-MS and NMR analysis). The 1H NMR spectrum of the crude amine 15 showed the characteristic singlets for the protons of the methylene function of the aziridine at 1.43 and 2.05 ppm, together with the partially overlapping signals of the methylene protons of the azetidine and benzyl moiety in the range 3.16e3.71 ppm. The corresponding 13C NMR spectrum contained signals of the aziridine methylene carbon, spiro-carbon, azetidine methylene carbons and benzylic methylene carbon at 37.1, 40.9, 56.5, 61.4, and 59.2 ppm, respectively. Further efforts to isolate an analytically pure product via column chromatography, or via precipitation as the corresponding oxalate salt,6 failed however.
Bn N
a,b
11a (97%)c 11b (95%) 10/11c 1:1 11c (96%) 11d (99%)
BnNH2 allylNH2 i-PrNH2 i-PrNH2 c-HexNH2
N
Upon reduction of imines 11 with 1.1 equiv of NaBH4 in methanol at reflux for 2 h, the rearranged amines 13aed were obtained in high yields (85e90%) (Scheme 3). As discussed above, this heterocyclic
Tos N
Br
1.1 equiv NaBH4
R N
a
H
11a (R = Bn) 11b (R = allyl) 11c (R = i-Pr) 11d (R = c-Hex)
Bn N NH 15 (89%)a
Yield of crude product
Scheme 4. Deprotection of the tosyl group of 1,5-diazaspiro[2.3]hexane 14a.
3. Conclusion In conclusion, an efficient synthesis of 1,5-diazaspiro[2.3]hexanes, as new structurally challenging strained diazaspirocyclic compounds, was developed starting from ethyl 2-(bromomethyl)-
Br
MeOH, ∆, 2h N R
MeOH, 0 °C - r.t., 26 h Tos
14a
a
Yields in parentheses indicate crude yields. b Ratio of reaction products determined by 1H NMR analysis of the crude reaction mixture. c The crude imine 11a contained excess benzylamine.
15 equiv Mg
2 equiv K2CO3 CH3CN, 60 °C, 24 h
NH Tos 13a (90%) 13b (85%) 13c (88%) 13d (90%) Scheme 3. Synthesis of 1,5-diazaspiro[2.3]hexanes 14.
R N N
Tos
14a (88%) 14b (93%) 14c (96%) 14d (90%)
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1-tosylaziridine-2-carboxylate, the synthesis of which was optimized. The key transformations in the developed short sequence involved a chemoselective reduction of the functionalized ethyl 1tosylaziridine-2-carboxylate to the corresponding b-bromo aldehyde and an aza-Payne-type rearrangement occurring upon reduction of the subsequently formed b-bromo aldimines leading to non-activated 2-(aminomethyl)-2-(bromomethyl)aziridines. A final base-mediated cyclization of the latter bromo amines gave efficient access to the new diazaspirocyclic system. 4. Experimental 4.1. General Flame-dried glassware was used for all non-aqueous reactions. Commercially available solvents and reagents were purchased from common chemical suppliers and used without further purification, unless stated otherwise. Tetrahydrofuran and diethyl ether were distilled from sodium and sodium benzophenone ketyl. Dichloromethane was distilled over calcium hydride. Methanol was dried with magnesium and distilled. Flash chromatography was carried out using a glass column filled with silica gel (Acros, particle size 0.035e0.070 mm, pore diameter ca. 6 nm). TLC was performed on glass-backed silica plates (Merck Kieselgel 60 F254, precoated 0.25 mm), which were developed using standard visualization techniques or agents: UV fluorescence (254 nm and 366 nm), coloring with iodine vapor, permanganate solution/D. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were run with a Jeol Eclipse FT 300 NMR spectrometer at room temperature. The compounds were diluted in deuterated chloroform, quoted in parts per million (ppm) and referenced to tetramethylsilane (TMS, d¼0) or the appropriate residual solvent peak. IR spectra were obtained from a Perkin Elmer Spectrum BX spectrometer from samples in neat form with an ATR (Attenuated Total Reflectance) accessory. Only selected absorbances (ymax/cm 1) are reported. LC-MS was performed with Agilent 1100 Series VL (ES, 4000 V) equipment or Agilent 1100 Series SL (ES, 4000 V) equipment, performing electron-spray ionization at 4 kV (positive mode) or 3.5 kV (negative mode) and fragmentation at 70 eV, with only molecular ions (MþHþ), and major peaks being reported with intensities quoted as percentage of the base peak, using either an LC-MS coupling or a direct inlet system. HRMS analysis was performed using an Agilent 1100 series HPLC coupled to an Agilent 6220 TOF-Mass Spectrometer equipped with ESI/APCI-multimode source. Melting € chi 540 points of crystalline compounds were measured with a Bu apparatus and were not corrected. 4.2. Synthetic procedures 4.2.1. Synthesis of ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4sulfonyl]amino}methyl)prop-2-enoate 4. Ethyl 2-(hydroxymethyl)acrylate 3 (1470 mg, 11.31 mmol), triphenylphosphine (3259 mg, 12.44 mmol) and BocNHTos (3360 mg, 12.44 mmol) were dissolved in dry THF (110 mL). Diisopropyl azodicarboxylate (2512 mg, 12.44 mmol) was slowly added at 0 C and the reaction mixture was stirred at room temperature for 24 h. Evaporation of the solvent and purification by flash chromatography on silica gel (petroleum ether/EtOAc 9:1) afforded pure compound 4. 4.2.2. Ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4-sulfonyl]amino} methyl)prop-2-enoate 4. Colorless viscous oil, yield 91%, Rf¼0.31 (petroleum ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): d 1.31 (3H, t, J¼7.2 Hz), 1.35 (9H, s), 2.45 (3H, s), 4.24 (2H, q, J¼7.2 Hz), 4.72 (2H, dd, J¼1.7, 1.7 Hz), 5.75 (1H, t, J¼1.7 Hz), 6.37 (1H, t, J¼1.7 Hz), 7.31 (2H, d, J¼8.3 Hz), 7.81 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 14.3, 21.8, 27.9, 47.3, 61.1, 84.7, 124.9, 128.3, 129.4, 136.4, 137.1, 144.6,
150.7, 165.6. IR (neat, cm 1): yC]O¼1726, yC]C¼1640, yO]S]O¼1169. MS (ES, pos. mode): m/z (%): 384 (MþHþ, 100). 4.2.3. Synthesis of ethyl 2-{[(N-toluene-4-sulfonyl)amino]methyl}acrylate 5. Ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4-sulfonyl] amino}methyl)prop-2-enoate 4 (1935 mg, 5.1 mmol) was dissolved in CH2Cl2 (36 mL), and trifluoroacetic acid (15 mL) was slowly added at 0 C, and then the reaction mixture was warmed up to room temperature. After 1 h, the reaction mixture was cooled down to 0 C, quenched by slowly adding aqueous saturated NaHCO3 and extracted with CH2Cl2 (315 mL). Drying of the combined organic extracts with MgSO4, filtration of the drying agent, evaporation of the solvent under reduced pressure and purification by flash chromatography on silica gel (petroleum ether/EtOAc 7:3) afforded pure title compound 5. Note: the sufficiently pure crude product can also be used in the next step without purification. 4.2.4. Ethyl 2-{[(N-toluene-4-sulfonyl)amino]methyl}acrylate 5. Orange oil, yield 98%, Rf¼0.27 (petroleum ether/EtOAc 7:3). 1H NMR (300 MHz, CDCl3): d 1.26 (3H, t, J¼7.2 Hz), 2.43 (3H, s), 3.81 (2H, d, J¼6.6 Hz), 4.16 (2H, q, J¼7.2 Hz), 5.02 (1H, t, J¼6.6 Hz), 5.76 (1H, d, J¼0.7 Hz), 6.17 (1H, d, J¼0.7 Hz), 7.29 (2H, d, J¼8.3 Hz), 7.72 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 14.1, 21.5, 44.7, 61.1, 127.1, 127.7, 129.7, 135.5, 137.2, 143.5, 165.8. IR (neat, cm 1): yNH¼3277, yC]O¼1708, yC]C¼1636 (weak), yO]S]O¼1155. MS (ES, pos. mode): m/z (%): 284 (MþHþ, 100). 4.2.5. Synthesis of ethyl 2,3-dibromo-2-[(tosylamino)methyl]propanoate 6. To a solution of ethyl 2-{[(N-toluene-4-sulfonyl)amino]methyl}acrylate 5 (3320 mg, 11.7 mmol) in CH2Cl2 (230 mL), a solution of Br2 (2065 mg, 0.67 mL, 12.9 mmol) in CH2Cl2 (100 mL) was added dropwise at 0 C and the reaction mixture was left stirring upon warming to room temperature for 24 h. Subsequently, the resulting reaction mixture was poured into saturated NaHCO3 solution and extracted with EtOAc (350 mL). Drying of the combined organic extracts with MgSO4, filtration of the drying agent, evaporation of the solvent under reduced pressure and purification by flash chromatography on silica gel (petroleum ether/EtOAc 7:3) afforded pure title compound 6. 4.2.6. Ethyl 2,3-dibromo-2-{[(toluene-4-sulfonyl)amino]methyl}propanoate 6. Pink oil, yield 93%, Rf¼0.40 (petroleum ether/EtOAc 7:3). 1 H NMR (300 MHz, CDCl3): d 1.32 (3H, t, J¼7.2 Hz), 2.44 (3H, s), 3.61 (1H, dd, J¼14.3 Hz, 5.2 Hz), 3.71 (1H, dd, J¼14.3 Hz, 9.2 Hz), 3.90 (1H, d, J¼10.3 Hz), 4.07 (1H, d, J¼10.3 Hz), 4.27 (1H, dq, J¼10.7 Hz, 7.2 Hz), 4.31 (1H, dq, J¼10.7 Hz, 7.2 Hz), 5.07 (1H, dd, J¼9.2, 5.2 Hz), 7.34 (2H, d, J¼8.3 Hz), 7.79 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 13.8, 21.6, 33.2, 47.5, 58.7, 63.2, 127.2, 129.9, 136.5, 144.0, 167.2. IR (neat, cm 1): yNH¼3279, yC]O¼1735, yO]S]O¼1155. MS (ES, pos. mode): m/z (%): 442/444/446 (MþHþ, 100). 4.2.7. Synthesis of ethyl 2-(bromomethyl)-1-(toluene-4-sulfonyl)aziridine-2-carboxylate 7. To a solution of ethyl 2,3-dibromo-2-[(tosylamino)methyl]propanoate 6 (618 mg, 1.39 mmol) in CH3CN (30 mL) was added powdered K2CO3 (289 mg, 2.09 mmol) and the reaction mixture was stirred at 60 C for 2 h. Then the solvent was removed under reduced pressure and Et2O (30 mL) was added. The resulting solution was filtered and the filter cake was washed with small portions of Et2O. Evaporation of the solvent under reduced pressure and purification by flash chromatography on silica gel (petroleum ether/Et2O 7:3) afforded pure title compound 7. 4.2.8. Ethyl 2-(bromomethyl)-1-(toluene-4-sulfonyl)aziridine-2carboxylate 7. Yellow oil, yield 95%, Rf¼0.52 (petroleum ether/ EtOAc 7:3). 1H NMR (300 MHz, CDCl3): d 1.34 (3H, t, J¼7.2 Hz), 2.45 (3H, s), 2.75 (1H, s), 3.19 (1H, d, J¼1.1 Hz), 3.70 (1H, d, J¼10.5 Hz),
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4.23 (1H, dd, J¼10.5 Hz, 1.1 Hz), 4.30 (2H, q, J¼7.2 Hz), 7.34 (2H, d, J¼8.3 Hz), 7.83 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 14.0, 21.8, 29.3, 38.9, 49.9, 63.0, 127.9, 129.8, 136.1, 145.1, 165.5. IR (neat, cm 1): yC]O¼1740, yO]S]O¼1162. MS (ES, pos. mode): m/z (%): 362/364 (MþHþ, 100). 4.2.9. Synthesis of [2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2yl]-methanol 8 and [2-methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]methanol 9. Ethyl 2-bromomethyl-1-(toluene-4-sulfonyl)aziridine2-carboxylate 7 (140 mg, 0.39 mmol) was dissolved in dry Et2O (5 mL), after which LiAlH4 (15 mg, 0.39 mmol) was added in small portions at 0 C. The resulting mixture was stirred at 0 C for 30 min. Afterward, water was added dropwise and the quenched reaction mixture was extracted with Et2O (310 mL). Drying of the combined organic extracts with MgSO4, filtration of the drying agent, evaporation of the solvent under reduced pressure and purification by flash chromatography on silica gel (petroleum ether/EtOAc 3:1e1:1) afforded pure [2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol 8 and [2-methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol 9. Caution: strict safety measurements have to be applied for LiAlH4promoted reactions to avoid risk of violent reactions or explosions. 4.2.10. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol 8. White crystals (mp¼126.4e126.6 C), yield 36%, Rf¼0.52 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 2.46 (3H, s), 2.50 (1H, s), 2.72 (1H, dd, J¼9.9, 5.0 Hz), 2.85 (1H, s), 3.27 (1H, dd, J¼10.5,1.1 Hz), 4.00 (1H, ddd, J¼13.2, 5.0, 1.1 Hz), 4.13 (1H, dd, J¼10.5, 1.1 Hz), 4.39 (1H, dd, J¼13.2, 9.9 Hz), 7.35 (2H, d, J¼8.3 Hz), 7.83 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.8, 32.4, 39.3, 54.0, 61.1, 127.6, 129.9, 136.4, 144.9. IR (neat, cm 1): yOH¼3526, yO]S]O¼1154. MS (ES, pos. mode): m/z (%): 320/322 (MþHþ, 100). HRMS Calcd for C11H14BrNO3S: 319.9951 [MþH]þ. Found: 319.9954 [MþH]þ. 4.2.11. [2-Methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol 9. Yellow oil, yield 41%, Rf¼0.31 (petroleum ether/EtOAc 1:1). All spectroscopic data were in good agreement with reported data.32 IR (neat, cm 1): yOH¼3501, yO]S]O¼1154. MS (ES, pos. mode): m/z (%): 242 (MþHþ, 100). 4.2.12. Synthesis of 2-bromomethyl-1-(toluene-4-sulfonyl)aziridine2-carboxaldehyde 10. Ethyl 2-bromomethyl-1-(toluene-4-sulfonyl)aziridine-2-carboxylate 7 (400 mg, 1.1 mmol) was dissolved in dry Et2O (40 mL), after which LiAlH4 (42 mg, 1.1 mmol) was added in small portions at 78 C. The resulting mixture was stirred at 78 C for 1 h. Afterward, water was added dropwise and the quenched reaction mixture was extracted with Et2O (320 mL). Drying of the combined organic extracts with MgSO4, filtration of the drying agent, evaporation of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (petroleum ether/EtOAc 3:2) afforded pure title compound 10. Caution: strict safety measurements have to be applied for LiAlH4promoted reactions to avoid risk of violent reactions or explosions. 4.2.13. 2-Bromomethyl-1-(toluene-4-sulfonyl)aziridine-2-carboxaldehyde 10. White crystals (mp¼112.9e113.1 C), yield 88%, Rf¼0.45 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 2.47 (3H, s), 2.91 (1H, s), 3.37 (1H, s), 3.65 (1H, d, J¼11.0 Hz), 3.83 (1H, d, J¼11.0 Hz), 7.38 (2H, d, J¼8.3 Hz), 7.86 (2H, d, J¼8.3 Hz), 9.38 (1H, s). 13 C NMR (75 MHz, CDCl3): d 21.8, 27.0, 40.0, 54.4, 127.9, 130.0, 135.3, 145.5, 191.7. IR (neat, cm 1): yC]O¼1726, yO]S]O¼1162. MS (ES, pos. mode): m/z (%): 318/320 (MþHþ, 100). HRMS Calcd for C11H12BrNO3S: 317.9794 [MþH]þ. Found: 317.9801 [MþH]þ. 4.2.14. Synthesis of 2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2yl-carboxaldimines 11. The synthesis of N-benzyl 2-bromomethyl-1(p-toluene-4-sulfonyl)aziridin-2-yl-carboxaldimine 11a is
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representative. To a slurry of MgSO4 (480 mg) in CH2Cl2 (10 mL) was added benzylamine (57 mg, 0.53 mmol) followed by 2-bromomethyl1-(p-toluene-4-sulfonyl)aziridine-2-carboxaldehyde 10 (154 mg, 0.48 mmol). The resulting suspension was refluxed for 2 h and cooled to room temperature. Then, the reaction mixture was filtered and the filter cake was washed with small portions of CH2Cl2. The solvent was evaporated under reduced pressure to afford the title compound 11a, which was used in the next step without further purification. 4.2.15. [2-Bromomethyl-1-(toluene-4-sulfonyl)-aziridin-2-ylmethylene]benzylamine 11a. Light yellow oil, yield 97% (75% purity), Rf¼0.33 (petroleum ether/EtOAc 4:1) 1H NMR (300 MHz, CDCl3): d 2.44 (3H, s), 2.79 (1H, s), 3.19 (1H, s), 3.58 (1H, d, J¼10.5 Hz), 4.11 (1H, d, J¼10.5 Hz), 4.78 (1H, d, J¼14.3 Hz), 4.79 (1H, d, J¼14.3 Hz), 7.25e7.38 (7H, m), 7.81 (2H, d, J¼8.3 Hz), 7.83 (1H, s). 13C NMR (75 MHz, CDCl3): d 21.8, 31.5, 40.4, 52.0, 64.4, 127.2, 127.8, 128.0, 128.6, 129.8, 136.0, 138.3,144.9,158.0. IR (neat, cm 1): yCH]N¼1659, yO]S]O¼1160. MS (ES, pos. mode): m/z (%): 407/409 (MþHþ, 100). 4.2.16. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]allylamine 11b. Yellow oil, yield 95%, Rf¼0.63 (petroleum ether/ EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 2.45 (3H, s), 2.77 (1H, s), 3.16 (1H, s), 3.58 (1H, d, J¼10.5 Hz), 4.09 (1H, d, J¼10.5 Hz), 4.12e4.28 (2H, m), 5.17 (1H, dq, J¼10.5, 1.7 Hz), 5.24 (1H, dq, J¼17.1, 1.7 Hz), 6.00 (1H, ddt, J¼17.1, 10.5, 5.5 Hz), 7.34 (2H, d, J¼8.3 Hz), 7.71 (1H, s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.8, 31.4, 40.4, 52.0, 62.7, 116.6, 127.8, 129.8, 134.8, 136.1, 144.9, 158.0. IR (neat, cm 1): yCH]N¼1660, yC]C¼1642, yO]S]O¼1161. MS (ES, pos. mode): m/z (%): 357/359 (MþHþ, 100). 4.2.17. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]isopropylamine 11c. Yellow oil, yield 96%, Rf¼0.36 (petroleum ether/ EtOAc 4:1) 1H NMR (300 MHz, CDCl3): d 1.20 (6H, d, J¼6.1 Hz), 2.44 (3H, s), 2.73 (1H, s), 3.14 (1H, s), 3.53 (1H, d, J¼10.5 Hz), 3.55 (1H, sept, J¼6.1 Hz), 4.08 (1H, d, J¼10.5 Hz), 7.33 (2H, d, J¼8.3 Hz), 7.71 (1H, s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.8, 23.6, 23.7, 31.9, 40.3, 52.0, 61.2, 127.7, 129.8, 136.3, 144.8, 153.8. IR (neat, cm 1): yCH]N¼1656, yO]S]O¼1161. MS (ES, pos. mode): m/z (%): 359/361 (MþHþ, 100). 4.2.18. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]cyclohexylamine 11d. Yellow oil, yield 99%, Rf¼0.63 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 1.14e1.86 (10H, m), 2.44 (3H, s), 2.73 (1H, s), 3.15 (1H, s), 3.17e3.30 (1H, m), 3.52 (1H, d, J¼10.5 Hz), 4.08 (1H, d, J¼10.5 Hz), 7.33 (2H, d, J¼8.3 Hz), 7.73 (1H, s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.8, 24.5, 25.7, 32.0, 33.7, 33.9, 40.3, 52.1, 69.0, 127.7, 129.8, 136.4, 144.8, 154.0. IR (neat, cm 1): yCH]N¼1656, yO]S]O¼1161. MS (ES, pos. mode): m/z (%): 399/401 (MþHþ, 100). 4.2.19. Synthesis of rearranged aziridines 13. The synthesis of N-[1benzyl-2-(bromomethyl)aziridin-2-ylmethyl]-4-methylbenzenesulfonamide 13a is representative. [2-Bromomethyl-1-(toluene-4sulfonyl)aziridin-2-ylmethylene]benzylamine 11a (197 mg, 0.48 mmol), dissolved in MeOH (10 mL) and cooled down to 0 C, was treated with NaBH4 (20 mg, 0.53 mmol) in small portions, and the resulting reaction mixture was stirred at reflux for 2 h. The reaction mixture was then cooled to room temperature and concentrated to 2/ 3 of the initial volume. Ice was added and the product was extracted with CH2Cl2 (310 mL). The combined organic extracts were dried with MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 3:1e2:1) to afford pure compound 13a. 4.2.20. N-(1-Benzyl-2-(bromomethyl)aziridin-2-ylmethyl)-4-methylbenzenesulfonamide 13a. Yellow oil, yield 90%, Rf¼0.15 (petroleum
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ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): d 1.53 (1H, s), 2.12 (1H, s), 2.42 (3H, s), 3.11 (1H, dd, J¼12.9, 3.9 Hz), 3.24 (1H, dd, J¼12.9, 7.2 Hz), 3.41 (1H, d, J¼13.2 Hz), 3.51 (1H, d, J¼11.3 Hz), 3.76 (1H, d, J¼11.3 Hz), 4.01 (1H, d, J¼13.2 Hz), 5.00 (1H, br s), 7.17e7.40 (7H, m), 7.72 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.7, 32.6, 39.2, 41.8, 46.4, 56.1, 127.2, 127.5, 127.9, 128.7, 129.9, 136.7, 138.7, 143.6. IR (neat, cm 1): yNH¼3279, yO]S]O¼1157. MS (ES, pos. mode): m/z (%): 409/411 (MþHþ, 100). 4.2.21. N-(1-Allyl-2-(bromomethyl)aziridin-2-ylmethyl)-4-methylbenzenesulfonamide 13b. Colorless oil, yield 85%, Rf¼0.44 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 1.40 (1H, s), 2.07 (1H, s), 2.43 (3H, s), 2.87 (1H, dd, J¼14.3, 6.1 Hz), 3.09 (1H, dd, J¼13.2, 4.4 Hz), 3.22 (1H, dd, J¼13.2, 7.2 Hz), 3.46 (1H, dd, J¼14.3, 5.5 Hz), 3.51 (1H, d, J¼11.6 Hz), 3.71 (1H, d, J¼11.6 Hz), 5.00e5.28 (3H, m), 5.81e5.95 (1H, m), 7.31 (2H, d, J¼8.3 Hz), 7.74 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.6, 32.4, 38.8, 41.6, 46.5, 54.8, 116.8, 127.2, 129.9, 135.0, 136.8, 143.6. IR (neat, cm 1): yNH¼3276, yC]C¼1644, yO]S]O¼1156. MS (ES, pos. mode): m/z (%): 359/361 (MþHþ, 100). 4.2.22. N-(2-Bromomethyl-1-isopropylaziridin-2-ylmethyl)-4-methylbenzenesulfonamide 13c. Yellow oil, yield 88%, Rf¼0.40 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 1.08 (3H, d, J¼6.1 Hz), 1.09 (3H, d, J¼6.1 Hz), 1.40 (1H, s), 1.91 (1H, s), 2.24 (1H, sept, J¼6.1 Hz), 2.43 (3H, s), 2.88 (1H, dd, J¼12.7, 5.0 Hz), 3.31 (1H, dd, J¼12.7, 5.5 Hz), 3.48 (1H, d, J¼11.0 Hz), 3.71 (1H, d, J¼11.0 Hz), 4.94 (1H, br s), 7.31 (2H, d, J¼7.7 Hz), 7.74 (2H, d, J¼7.7 Hz). 13C NMR (75 MHz, CDCl3): d 21.6, 22.6, 23.6, 31.8, 37.7, 43.0, 47.0, 52.5, 127.2, 129.8, 136.8, 143.6. IR (neat, cm 1): yNH¼3284, yO]S]O¼1157. MS (ES, pos. mode): m/z (%): 361/363 (MþHþ, 100). 4.2.23. N-(2-Bromomethyl-1-cyclohexylaziridin-2-ylmethyl)-4-methylbenzenesulfonamide 13d. Yellow oil, yield 90%, Rf¼0.31 (petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3): d 1.09e1.37 (4H, m), 1.42 (1H, s), 1.52e1.88 (7H, m), 1.90 (1H, s), 2.43 (3H, s), 2.84 (1H, dd, J¼12.7, 5.5 Hz), 3.33 (1H, dd, J¼12.7, 6.1 Hz), 3.46 (1H, d, J¼11.0 Hz), 3.72 (1H, d, J¼11.0 Hz), 4.88 (1H, br s), 7.31 (2H, d, J¼8.3 Hz), 7.74 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.6, 24.5, 24.8, 25.8, 32.0, 32.8, 34.2, 37.3, 42.5, 47.0, 60.3, 127.2, 129.8, 136.8, 143.6. IR (neat, cm 1): yNH¼3280, yO]S]O¼1157. MS (ES, pos. mode): m/z (%): 401/403 (MþHþ, 100). 4.2.24. Synthesis of 1,5-diazaspiro[2.3]hexanes 14. The synthesis of 1-benzyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14a is representative. To a solution of N-(1-benzyl-2-(bromomethyl)aziridin-2-ylmethyl)-4-methylbenzenesulfonamide 13a (90 mg, 0.22 mmol) in CH3CN (9 mL) was added powdered K2CO3 (46 mg, 0.33 mmol). The reaction mixture was stirred at 60 C for 24 h. Then the solvent was removed under reduced pressure and Et2O (10 mL) was added. The mixture was filtered and the filter cake was washed with small portions of Et2O. The combined filtrates were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 4:1e1:1) to afford compound 14a. 4.2.25. 1-Benzyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14a. Yellow solid (120.6e120.8 C), yield 88%, Rf¼0.09 (petroleum ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): d 1.36 (1H, s), 1.97 (1H, s), 2.46 (3H, s), 3.18 (1H, d, J¼13.8 Hz), 3.36 (1H, d, J¼13.8 Hz), 3.95 (1H, d, J¼8.8 Hz), 4.00 (1H, d, J¼8.8 Hz), 4.07 (1H, d, J¼8.8 Hz), 4.12 (1H, d, J¼8.8 Hz), 7.15e7.30 (5H, m), 7.33 (2H, d, J¼8.3 Hz), 7.72 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.8, 36.4, 38.6, 54.3, 58.9,
59.4, 127.2, 127.4, 128.5, 128.6, 130.0, 131.4, 138.3, 144.3. IR (neat, cm 1): yO]S]O¼1156. MS (ES, pos. mode): m/z (%): 329 (MþHþ, 100). HRMS Calcd for C18H20N2O2S: 329.1318 [MþH]þ. Found: 329.1332 [MþH]þ. 4.2.26. 1-Allyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14b. Light yellow crystals (56.0e56.2 C), yield 93%, Rf¼0.25 (Et2O 100%). 1H NMR (300 MHz, CDCl3): d 1.23 (1H, s), 1.92 (1H, s), 2.48 (3H, s), 2.66 (1H, dd, J¼14.9, 5.0 Hz), 2.75 (1H, ddt, J¼14.9, 5.0, 1.7 Hz), 3.93 (1H, d, J¼8.8 Hz), 3.97 (1H, d, J¼8.8 Hz), 4.04 (1H, d, J¼8.8 Hz), 4.06 (1H, d, J¼8.8 Hz), 4.97 (1H, dq, J¼10.5, 1.7 Hz), 5.06 (1H, dq, J¼17.8, 1.7 Hz), 5.72 (1H, ddt, J¼17.8, 10.5, 5.0 Hz), 7.39 (2H, d, J¼8.3 Hz), 7.76 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.7, 36.0, 38.0, 54.1, 57.3, 59.4, 116.3, 128.6, 129.9, 131.5, 134.5, 144.4. IR (neat, cm 1): yC]C¼1643, yO]S]O¼1159. MS (ES, pos. mode): m/z (%): 279 (MþHþ, 100). HRMS Calcd for C14H18N2O2S: 279.1162 [MþH]þ. Found: 279.1172 [MþH]þ. 4.2.27. 1-Isopropyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14c. Light yellow amorphous solid, yield 96%, Rf¼0.25 (Et2O 100%). 1 H NMR (300 MHz, CDCl3): d 0.83 (3H, d, J¼6.1 Hz), 1.01 (3H, d, J¼6.1 Hz), 1.18 (1H, s), 1.46 (1H, sept, J¼6.1 Hz), 1.84 (1H, s), 2.46 (3H, s), 3.91 (1H, d, J¼8.8 Hz), 3.95 (1H, d, J¼8.8 Hz), 4.05 (2H, s), 7.40 (2H, d, J¼8.3 Hz), 7.78 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.7, 22.1, 22.4, 35.1, 38.0, 54.1, 55.1, 59.9, 128.6, 129.9, 131.3, 144.4. IR (neat, cm 1): yO]S]O¼1155. MS (ES, pos. mode): m/z (%): 281 (MþHþ, 100). HRMS Calcd for C14H20N2O2S: 281.1318 [MþH]þ. Found: 281.1324 [MþH]þ. 4.2.28. 1-Cyclohexyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14d. Yellow oil, yield 90%, Rf¼0.11 (petroleum ether/EtOAc 1:1). 1 H NMR (300 MHz, CDCl3): d 0.80e1.75 (11H, m), 1.17 (1H, s), 1.82 (1H, s), 2.47 (3H, s), 3.93 (1H, d, J¼8.8 Hz), 3.96 (1H, d, J¼8.8 Hz), 4.00 (1H, d, J¼8.8 Hz), 4.05 (1H, d, J¼8.8 Hz), 7.39 (2H, d, J¼8.3 Hz), 7.78 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3): d 21.7, 24.3, 24.6, 25.8, 32.1, 33.2, 34.3, 37.5, 54.2, 60.1, 62.7, 128.7, 129.9, 131.3, 144.4. IR (neat, cm 1): yO]S]O¼1160. MS (ES, pos. mode): m/z (%): 321 (MþHþ, 100). HRMS Calcd for C17H24N2O2S: 321.1631 [MþH]þ. Found: 321.1636 [MþH]þ. 4.2.29. Detosylation of 1,5-diazaspiro[2.3]hexane 14a. A mixture of magnesium powder (74 mg, 3.0 mmol) in dry MeOH (1 mL) was stirred at room temperature for 10 min. The reaction mixture was cooled down to 0 C and a solution of 1-benzyl-5-(toluene-4sulfonyl)-1,5-diazaspiro[2.3]hexane 14a (100 mg, 0.3 mmol) in dry MeOH (0.6 mL) was added dropwise. Subsequently, the resulting suspension was allowed to warm slowly to room temperature. The reaction was monitored by LC-MS and after 22 h, a second portion of magnesium powder (37 mg, 1.5 mmol) was added. The suspension was stirred for another 4 h at room temperature. Subsequently, the reaction mixture was concentrated under reduced pressure to afford a gray suspension. This was suspended in CH2Cl2 (10 mL), filtered and the filter cake was washed with small portions of CH2Cl2. The solvent was evaporated under reduced pressure to afford the detosylated compound 15. Caution: strict safety measurements have to be applied for Mgpromoted reactions to avoid risk of violent reactions, fires or explosions. 4.2.30. 1-Benzyl-1,5-diazaspiro[2.3]hexane 15. Colorless oil, yield of crude product 89%, Rf¼0.40 (CH2Cl2/MeOH 9:1). All spectroscopic data were obtained from the crude product. 1H NMR (300 MHz, CDCl3): d 1.43 (1H, s), 1.81 (1H, br s), 2.05 (1H, s), 3.18 (1H, d, J¼13.8 Hz), 3.46e3.55 (3H, m), 3.66e3.71 (2H, m), 7.20e7.40 (5H, m). 13C NMR (75 MHz, CDCl3): d 37.1, 40.9, 56.5, 59.2, 61.4, 126.9,
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127.7, 128.4, 139.4. IR (neat, cm m/z (%): 175 (MþHþ, 100).
1
): yNH¼3365. MS (ES, pos. mode):
Acknowledgements The authors are indebted to the Research Foundation-Flanders (FWO-Flanders), Ghent University (BOF), the Lithuanian State Studies Foundation, the Research Council of Lithuania and Kaunas University of Technology for financial support. Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.065. These data include MOL files and Intake’s of the most important compounds described in this article. References and notes 1. Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867e3870. 2. Osmanov, Z.; Ibragimov, A. A.; Yunusov, S. Y. Chem. Nat. Compd. 1982, 18, 206e208. 3. (a) Keppens, M.; De Kimpe, N. J. Org. Chem. 1995, 60, 3916e3918; (b) Alonso, E. R.; Tehrani, K. A.; Boelens, M.; De Kimpe, N. Synlett 2005, 1726e1730; (c) Keppens, M.; De Kimpe, N. Synlett 1994, 285e286. 4. (a) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J. A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870e1875; (b) Alex Sinclair, A.; Stockman, R. A. Nat. Prod. Rep. 2007, 24, 298e326. € ller, K.; Carreira, E. M. 5. (a) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Mu Angew. Chem., Int. Ed. 2010, 49, 3524e3527; (b) Wuitschik, G.; Carreira, E. M.; € ller, K. J. Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Mu Med. Chem. 2010, 53, 3227e3246. rot, C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 6. Burkhard, J. A.; Gue 2010, 12, 1944e1947. 7. (a) Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514e5533; (b) Stocks, M. J.; Wilden, G. R. H.; Pairaudeau, G.; Perry, M. W. D.; Steele, J.; Stonehouse, J. P. ChemMedChem 2009, 4, 800e808; (c) Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2011, 13, 6134e6136; (d) Methot, J. L.; Hamblett, C. L.; Mampreian, D. M.; Jung, J.; Harsch, A.; Szewczak, A. A.; Dahlberg, W. K.; Middleton, R. E.; Hughes, B.; Fleming, J. C.; Wang, H.; Kral, A. M.; Ozerova, N.; Cruz, J. C.; Haines, B.; Chenard, M.; Kenific, C. M.; Secrist, J. P.; Miller, T. A. Bioorg. Med. Chem. Lett. 2008, 18, 6104e6109; (e) Kattar, S. D.; Surdi, L. M.; Zabierek, A.; Methot, J. L.; Middleton, R. E.; Hughes, B.; Szewczak, A. A.; Dahlberg, W. K.; Kral, A. M.; Ozerova, N.; Fleming, J. C.; Wang, H.; Secrist, P.; Harsch, A.; Hamill, J. E.; Cruz, J. C.; Kenific, C. M.; Chenard, M.; Miller, T. A.; Berk, S. C.; Tempest, P. Bioorg. Med. Chem. Lett. 2009, 19, 1168e1172; (f) Jonckers, T. H. M.; Lin, T.-I.; Buyck, C.; Lachau-Durand, S.; Vandyck, K.; Van Hoof, S.; Vandekerckhove, L. A. M.; Hu, L.; Berke, J. M.; Vijgen, L.; Dillen, L. L. A.; Cummings, M. D.; De Kock, H.; Nilsson, M.; Sund, C.; Rydeg ard, C.; Samuelsson, B.; Rosenquist, A.; Fanning, G.; Van Emelen, K.; Simmen, K.; Raboisson, P. J. Med. Chem. 2010, 53, 8150e8160. 8. Takahashi, Y.; Masuda, N.; Otsuki, M.; Miki, M.; Nishino, T. Antimicrob. Agents Chemother. 1997, 41, 1326e1330. 9. Kim, S.-Y.; Park, H. B.; Cho, J.-H.; Yoo, K. H.; Oh, C.-H. Bioorg. Med. Chem. Lett. 2009, 19, 2558e2561.
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