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A Formal Synthesis of (-)-Perhydrohistrionicotoxin using a Cross Metathesis-Hydrogenation Approach Nicolas Daniel Spiccia, James V. Burnley, Kamani Subasinghe, Christopher Perry, Laurent Lefort, W. Roy Jackson, and Andrea J. Robinson J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01257 • Publication Date (Web): 21 Jul 2017 Downloaded from http://pubs.acs.org on July 21, 2017

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The Journal of Organic Chemistry

A Formal Synthesis of (-)-Perhydrohistrionicotoxin using a Cross Metathesis-Hydrogenation Approach Nicolas D. Spiccia,a James V. Burnley,a Kamani Subasinghe,a Christopher Perry,a Laurent Lefort,b W. Roy Jacksona and Andrea J. Robinsona,* a

School of Chemistry, Monash University, Clayton 3800, Victoria, Australia

b

DS DSM Ahead R&D B.V.-Innovative Synthesis, P.O. Box 18 6160MD, Geleen, The Netherlands

[email protected]

ABSTRACT

The development of an efficient, high yielding six-step convergent synthesis of the semi-synthetic alkaloid ()-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Brønstedacid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalysed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps.

The histrionicotoxin group of spiro-piperidine alkaloids was first isolated from the skin of the Colombian poison dart frog Dendrobates histrionicus by Daly et al. (Figure 1).1 Histrionicotoxin-283A 1 and its more potent synthetic relative, perhydrohistrionicotoxin 2, are analgesic neurotoxins that act by non-competitive inhibition of nicotinic acetylcholine receptors.2-5

Figure 1. Amphibian spirocyclic alkaloids The structure for histrionicotoxin-283A 1 was solved by X-ray crystallography1 and was shown to be comprised of a 1-azaspiro[5.5]undecane core, four stereocentres (three contiguous and one isolated), two unsaturated ene-yne chains at C2 and C7, and a hydroxyl group at C8 (Figure 1). Both 1 and 2 are

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structurally and biologically interesting, and these compact, spirocyclic structures have become popular synthetic targets for organic chemists. Numerous total6-9 and formal syntheses10-14 have been published. Towards this end, several C-C bond forming reactions have been used to construct the aza-spirocyclic core which include a ring closing metathesis reaction to form C4-C515 and C7-C8,16 an intramolecular aldol condensation to form C7-C8,17 and a dipolar [3+2] cycloaddition reaction to form C6-C76 (Figure 1). Formation of the N1-C6 bond using a high yielding acid-catalysed intramolecular aza-Michael cyclisation has also been successfully employed by Winterfeldt and coworkers.14 This latter approach interested us because their spirocyclic precursor, enone 3, could be expediently intercepted by a cross metathesishydrogenation approach providing some key challenges could be met: i) controlling CM selectivity, ii) achieving high yielding metathesis in the presence of a coordinating amine, and iii) regioselective hydrogenation (Scheme 1). These challenges presented an opportunity for us to merge several recent interests of our group, notably the use of CM and acid-catalysed cyclisation to generate spirocyclic pyrrolidines and piperidines,18-19 ii) the use of Brønsted-acid protected alkenylamines to prevent Rualkylidene catalyst poisoning,20-23 and iii) tandem CM+H catalysis,24-25 to achieve a formal synthesis of perhydrohistrionicotoxin 2.

Scheme 1. Retrosynthesis of Winterfeldt’s intermediate 3

Previous work by us had revealed that spiro-piperidines can not be generated via direct CM of homoallylglycine derivatives with methylenecyclohexane.18 However, we postulated that cross metathesis of a suitably protected homoallylic amine 4 with vinyl cyclohexenone 5 would generate the appropriate chain length intermediates for spiro-piperidine alkaloids and provide an expedient way to introduce the C8 hydroxyl group (Scheme 1). With only a few examples of metathesis reactions involving vinyl cyclohexanes in the literature,26-28 and no examples utilising vinyl cyclohexenones, we were interested in investigating the cross metathesis activity of this olefin family (Scheme 1).

Whereas the Winterfeldt synthesis generated racemic amine 3, we aimed to synthesise the chiral amine (+)4 and dienone 5 (Scheme 1), which would be combined using ruthenium-alkylidene catalysed metathesis followed by selective hydrogenation to deliver (+)-3. We hypothesised that homodimerisation of 5 would be minimal as the terminal olefin is electron poor and considered to be a type III olefin according to the Grubbs nomenclature.29

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Numerous methods are available for the synthesis of chiral homoallylic amines.30-34 A substantial number of these methods, however, require sterically demanding or aromatic functional groups adjacent to the prochiral centre to assist chiral induction. Such methods are obviously unsuitable for the synthesis of (+)-4 and we therefore chose to investigate routes employing asymmetric hydrogenation and asymmetric allylation. Asymmetric hydrogenation of prochiral enamides has been exploited extensively for the synthesis of chiral amine containing products such as α- and β-amino acids.35-38 Enamide 6 (R=Et) was subjected to asymmetric hydrogenation using Rh(I)-catalysts bearing chiral phosphine ligands (R,R)-Me-BPE 7, (R,R)-Me-DuPHOS 8 and (R,R)-Et-DuPHOS 9 (Scheme 2).35-36 Unfortunately, excellent conversion was accompanied by poor enantioselectivity (Table 1, entries 1-3) with these catalysts. Chiral phosphoramidite ligand screening,39 however, proved beneficial and use of Rh(I)(COD)OTf and BINOL-derived ligand 10 at low catalyst loading (0.5 mol%) gave the desired β-amido ester 11 in excellent enantioselectivity (97% ee) and good isolated yield (80%) (entry 4). Conversion of 11 to its parent β-amino acid40 facilitated stereochemical assignment and confirmed the installation of the required R-stereochemistry needed for elaboration into (-)perhydrohistrionicotoxin 2. However, reduction of the ester functionality in 11 to the requisite propenyl sidechain was problematic. Under a variety of reaction conditions, hydride reduction of the ester to aldehyde 12 was always accompanied by over-reduction to the primary alcohol (Scheme 2). Furthermore, subsequent Wittig methylenation of 12 was capricious and gave only poor isolated yields (99

18

-

2

Rh(COD)(8).OTf

Et

MeOH

90 psi

>99

38

-

3

Rh(COD)(9).OTf

Et

MeOH

90 psi

>99

50

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4

Rh(COD)(10)2.OTf

Me

350 psi

>99

97

80

i

PrOH

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A viable route to the key chiral amine cross-partner 4 utilised Keck’s asymmetric allylation approach41 and started with the known alcohol (-)-14,42 which in turn was synthesised from hexanal (Scheme 3). The alcohol was converted into its mesylate 15 followed by substitution with sodium azide to give the inverted homoallylic azide 16 in excellent yield. The azide 16 was then reduced using LiAlH4 and the resultant amine (R)-4 (>99% ee)43 was protected as the corresponding tetrafluoroborate salt. Scheme 3. Synthesis of Cross Metathesis Precursors 4 and 5

Once chiral amine 4 was in hand, synthesis of the required enone cross partner, 2-butyl-3-vinylcyclohex-2enone 5, started with 1,3-cyclohexadione. Hantzsch’s ester was used in a proline-catalysed tandem catalytic reaction, where the unstable Knoevenagel condensation product of butyraldehyde and 1,3-cyclohexadione was immediately reduced to the known dione 17 which was isolated by crystallisation on large scale and in high yield (87%) (Scheme 3).44 The diketone 17 was then converted to the 1,3-dione enol 18 in excellent yield (97%) and subsequent reaction with vinyl magnesium bromide, followed by acid-catalysed dehydration using Kishi’s conditions,45 gave the dienone cross-partner 5 in excellent yield. The dienone 5 and homoallylic amide 13, amine 4 and amine salt 4·BF4 were then reacted in a cross metathesis reaction in a 3:1 stoichiometric ratio using 5 mol % Hoveyda-Grubbs second generation catalyst (HGII). The benzamide 13 gave the desired cross partner in 73% isolated yield and only the (E)-isomer was isolated. Commercially available ruthenium catalysts have been shown to be inapplicable to metathesis reactions involving unprotected amine compounds, so it was not surprising to see the free amine 4 fail in the CM reaction. We have recently shown that conversion of free amines into salts allows for crossmetathesis reactions to be carried out in high yield.20-21 A range of salts was examined and consistently high yields were found when using triflate and tetrafluoroborate salts. Accordingly, the tetrafluoroborate salt of the homoallylic amine 4 reacted with dienone 5 using 5 mol% HGII in dry ethyl acetate at 70 oC for 16 hours to give the free amine 19 in 65% yield after basification (Scheme 4).46 All that remained to intercept the Winterfeldt intermediate (+)-3 was to perform a regio and chemoselective reduction of the conjugated γ,δ-alkene of 19 in the presence of the sensitive α,βunsaturated enone moiety (Scheme 4). Gratifyingly, hydrogenation of amine 19 with Pd/BaSO4 provided Winterfeldt’s enone 3 in near quantitative yield (Scheme 4). A cross-metathesis/hydrogenation sequence using the Ru residues from the metathesis step was also investigated to shorten the synthetic sequence and reduce catalyst load. The tandem protocol, while successful, gave amine 3 in 41% yield compared with a

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60% yield for the two step procedure. Unfortunately, the tandem approach was also disadvantaged by preventing the recovery and recycling of excess enone 5 from the metathesis step.

Scheme 4: Synthesis of the Winterfeldt Intermediate 3

Winterfeldt’s reported transformation of the intercepted enone 3 into 2 involves acid-catalysed acetal formation and spirocyclisation, followed by ketal deprotection and base-catalysed epimerisation to give spiro-ketone 20 (Scheme 1).14 Subsequent hydride reduction then yields (2S)-perhydrohistrionicotoxin 2. In the course of our investigation, alternative cyclisation strategies were also investigated, including ketalisation, trans-ketalisation, Lewis acid activations, and Lewis base activations, however no higher yielding chemistry was identified to replace the literature transformation to the semi-synthetic alkaloid 2.

CONCLUSION In conclusion, we have successfully employed highly efficient and selective CM and hydrogenation reactions to generate the advanced Winterfeldt spirocyclic precursor (+)-3 to (-)-perhydrohistrionicotoxin 2. The enone (+)-3 was synthesised in a convergent six step synthesis from dione 17 and alcohol 14 with a longest linear sequence of 5 steps and a total yield of 47%. Key transformations include a one pot Knoevenagel condensation/transfer hydrogenation mediated by Hantzch’s ester, a cross-metathesis reaction of a Brønsted-acid masked primary homoallylic amine, and a palladium-catalysed regioselective hydrogenation. This work constitutes a formal synthesis of the amphibian-derived neurotoxin, perhydrohistrionicotoxin 2.

EXPERIMENTAL SECTION General Experimental Infrared spectra (IR) were recorded on a Fourier Transform infrared spectrophotometer as thin films between sodium chloride plates. IR absorptions (νmax) are reported in wavenumbers (cm-1) with the relative intensities expressed as s (strong), m (medium) or prefixed b (broad). Proton nuclear magnetic resonance (1H-NMR) spectra were recorded on 300, 400 or 600 MHz spectrometers operating at 300, 400 or 600 MHz respectively, as solutions in deuterated solvents as specified. Each resonance was assigned according to the following convention: chemical shift; multiplicity; observed coupling constants (J Hz); number of protons. Chemical shifts (δ), measured in parts per million

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(ppm), are reported relative to the residual proton peak in the solvent used as specified. Multiplicities are denoted as singlet (s), doublet (d), triplet (t), quartet (q), apparent quintet, multiplet (m) or prefixed broad (b), or a combination where necessary. Carbon-13 nuclear magnetic resonance (13C-NMR) spectra were recorded on 300, 400 or 600 MHz spectrometers operating at 75, 100 or 125 MHz respectively, as solutions in deuterated solvents as specified. Chemical shifts (δ), measured in parts per million (ppm), are reported relative to the residual proton peak in the deuterated solvent (as specified). Low resolution electrospray ionisation (ESI) mass spectra were recorded on a quadrupole mass spectrometer as solutions in specified solvents. Spectra were recorded in positive and negative modes (ESI+ and ESI-) as specified. High resolution electrospray mass spectra (HRMS) were recorded on a Bruker BioApex 47e Fourier Transform mass spectrometer (4.7 Tesla magnet) fitted with an analytical electrospray source. The mass spectrometer was calibrated with an internal standard solution of sodium iodide in CH3OH.

(R)-3-(4-Aminononyl)-2-butylcyclohex-2-en-1-one 3. To (R)-3-(4-aminonon-1-en-1-yl)-2-butylcyclohex-2-en1-one 18 (127 mg, 0.48 mmol) in MeOH (5 mL) was added to Pd/BaSO4 (13 mg, 10 mol%). Hydrogen was introduced through a three-way stopcock by means of a balloon and partial vacuum by three purge refill cycles. The suspension was stirred for 0.5 h at which point silica was added and the solvents removed in vacuo. The crude material was purified by column chromatography (95%:4%:1%, CHCl3:MeOH:NH3) to afford 3 (126 mg, 98%) as a yellow oil.47 [ࢻ]૛૛ ࡰ -9.38 (c 0.25, MeOH). IR νmax 2926m, 2858w, 2359w, 1657s, -1 1 1456w, 1373w, 1112w cm . H NMR (400 MHz, CDCl3): δ 2.77 (br s, 1H), 2.35 (t, J 6.0 Hz, 2H), 2.32 (t, J 6.0 Hz, 2H), 2.25 (t, J 7.2 Hz, 4H), (app. quintet, J = 6.0 Hz, 2H), 1.60-1.22 (m, 16 H), 0.92 (t, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 199.2, 158.3, 136.0, 51.4, 38.2, 35.0, 32.0, 32.0, 30.6, 25.7, 25.0, 24.5, 23.0, 22.7, 22.6, 14.1, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H36NO+ 294.2797; Found 294.2796.

(R)-Non-1-en-4-ammonium tetrafluoroborate 4. LiAlH4 (227 mg, 5.99 mmol) was added to (R)-4-azidonon1-ene 15 (1.00 g, 5.99 mmol) in Et2O (10 mL) at 0 oC. The resulting suspension was stirred for 1 h at which point sodium hydroxide (2 M, 0.50 mL) was added carefully, followed by Na2SO4, and then the solution was filtered. Next, HBF4.OEt2 (0.82 mL, 5.99 mmol) was added to the solution which was then concentrated under reduced pressure to afford 4.HBF4 (1.21 g, 88%) as an off white solid. [ࢻ]૛૛ ࡰ 13.6 (c 0.22, DMF). IR νmax -1 1 3257m, 2929m, 1608w, 1499m, 1013s, 993s, 923m cm . H NMR (400 MHz, D2O): δ 5.91-5.82 (m, 1H), 5.325.28 (m, 2H), 3.38 (app. quintet, J = 6.4 Hz, 1H), 2.57-2.51 (m, 1H), 2.42-2.35 (m, 1H), 1.71-1.65 (m, 3H), 1.45-1.33 (m, 8H), 0.92 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, D2O): δ 132.2, 120.0, 51.1, 36.3, 31.6, 30.6, 24.0, 21.7, 13.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H20N+ 142.1596; Found 142.1593. % ee assessment made by conversion of 4.HBF4 to the N-benzoyl derivative 11 via acylation and oxidative ozonolysis: HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR= 22.0 min (>99% area). Racemic N-benzoyl derivative 11 acquired from Pd/C catalysed hydrogenation of enamide 6: HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR= 18.5 and 21.8 min.

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2-Butyl-3-vinylcyclohex-2-en-1-one 5. Vinyl magnesium bromide (3.56 mL, 3.56 mmol, 1M in Et2O) was added to 2-butyl-3-isobutoxycyclohex-2-en-1-one 17 (398 mg, 1.78 mmol) in THF (10 mL) at 0 oC. The reaction was warmed to room temperature and stirred for 16 h. The solution was then cooled to 0 oC and HCl (1 M, 10 mL) was carefully added. Next, the product was extracted with DCM (3x20 mL) and the combined organic extract dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (light petroleum → 10% EtOAc:light petroleum) to aﬀord 5 (485 mg, 99%) as a bright yellow oil. IR νmax 2953m, 2929m, 1661s, 1611w, 1372m, 1189m, 913m cm-1. 1H NMR (400 MHz, CDCl3): δ 6.90 (dd, J 17.6, 10.8 Hz, 1H), 5.65 (d, J 17.6 Hz, 1H), 5.43 (d, J 10.8 Hz, 1H), 2.49 (t, J 6.0 Hz, 2H), 2.42 (q, J 6.0 Hz, 4H), 1.97 (app. quintet, J = 6.8 Hz, 2H), 1.33-1.27 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 199.7, 149.1, 137.5, 134.9, 119.9, 38.2, 32.2, 25.5, 24.3, 22.9, 22.0, 14.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H19O+ 179.1436; Found 179.1430.

(Z)-Methyl 3-benzamidooct-2-enoate 6 (R=Me). Methyl 3-oxooctanoate S1. Methyl acetoacetate (4.23 mL, 39.4 mmol) was added dropwise over 5 mins to a stirred solution of sodium hydride (1.04 g, 43.3 mmol) in dry THF (25 mL) under an atmosphere of nitrogen at 0 °C. The clear solution was warmed to room temperature for 5 mins before cooling to 0 °C and added n-butyllithium (22.8 mL, 43.3 mmol) dropwise over 5 mins. The resulting red/orange solution was warmed to room temperature for 5 mins before cooling to 0 °C and added n-butyl bromide (5.06 mL, 47.3 mmol) in one portion, where the colour dissipated and a precipitate formed. The solution was allowed to stir at 0 °C for 30 mins before warming to room temperature. After 30 mins, the reaction mixture was carefully quenched with 1M HCl (20 mL), diluted with Et2O (20 mL) and the phases were separated. The aqueous phase was further extracted with Et2O (3×20 mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by bulb-to-bulb distillation (100 °C, ~1 mbar) to give methyl 3oxooctanoate S1 (4.54 g, 67%) as a clear colourless oil.48 1H n.m.r. (300 MHz, CDCl3): δ 3.73 (s, 3H, H1’), 3.43 (bs, 2H, H2), 2.52 (t, J = 7.2 Hz, 2H, H4), 1.54 (p, J = 6.6 Hz, 7.5 Hz, 2H, H5), 1.29 (m, 4H, H6 & H7), 0.89 (t, J = 5.7 Hz, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 202.8 (C3), 167.7 (C1), 52.3 (C1’), 49.0 (C2), 43.0 (C4), 31.3, 23.1, 22.3 (C5-C7), 13.8 (C8). LRMS (ESI-TOF) m/z: [M+H]+ Calcd for [C9H17O3]+ 173.1; Found 173.0. Methyl 3-amino-oct-2-enoate S2. Methyl 3-oxooctanoate S1 (2.56 g, 14.9 mmol) was added to a stirred suspension of ammonium acetate (11.5 g, 149 mmol) in methanol (40 mL). The resulting yellow solution was left to stir at room temperature for 48 hours before concentration in vacuo. The reaction mixture was diluted with water (20 mL), EtOAc (50 mL) and the phases were separated. The aqueous phase was further extracted with EtOAc (3×50 mL), washed with water (3×25 mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by via flash chromatography (SiO2; 1:3; EtOAc:hexane) to give methyl 3-amino-oct-2-enoate S2 (2.38 g, 94%) as a mixture of inseparable geometric isomers (A:B ; 86:14).49 1H n.m.r. (300 MHz, CDCl3): δ 4.52 (s, 1H, H2), 3.71 (s, 3H, H1’ isomer B), 3.63 (s, 3H, H1’ isomer A), 2.50 (t, J = 7.5 Hz, 2H, H4 isomer B), 2.10 (t, J = 7.5 Hz, 2H, H4 isomer A), 1.61-1.45 (m, 2H, H5), 1.36-1.20 (m, 4H, H6 & H7), 0.87 (t, J = 6.9 Hz, 3H), NH2 not observed. 13C n.m.r. (100 MHz, CDCl3): δ 170.7 (C1), 164.1 (C4), 82.9 (C2), 50.0 (C1’), 36.4 (C4), 31.1, 27.5, 22.4 (C5-C7), 13.8 (C8). LRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C9H18NO2]+ m/z 172.1; Found 171.9.

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(Z)-Methyl 3-benzamidooct-2-enoate 6 (R=Me). Benzoyl chloride (1.29 mL, 12.3 mmol) in CH2Cl2 (2 mL) was added dropwise over 10 mins to a stirred solution of methyl 3-amino-oct-2-enoate S2 (2.10 g, 12.3 mmol) and pyridine (1.08 mL, 13.4 mmol) in CH2Cl2 (20 mL) under an atmosphere of nitrogen at 0 °C. The resulting solution was warmed to room temperature. After 16 hours the reaction mixture was quenched with sat. NaHCO3 (20 mL), diluted with CH2Cl2 and the phases were separated. The aqueous phase was further extracted with CH2Cl2 (3×50 mL), washed 1M HCl (3×50 mL), sat. NaHCO3 (3×50 mL), water (3×50 mL), dried (MgSO4) and concentrated in vacuo to give crude methyl 3-benzamidooct-2-enoate 6, R=Me. The crude product was purified by via flash chromatography (SiO2; 1:7; EtOAc:hexane) to give (Z)-methyl 3benzamidooct-2-enoate 6 (R=Me) (1.98 g, 59%) as a light yellow oil. Alternatively, a 250 mL round bottom flask was charged with methyl 3-oxooctanoate S1 (2.90 g, 16.8 mmol), benzamide (20.2 g, 167 mmol) and toluene (100 mL) and a catalytic amount of p-toluene sulphonic acid (200 mg). The flask was then heated to reflux in a Dean-Stark apparatus with water separation. After 16 hours the mixture was cooled to 0 °C, filtered and concentrated in vacuo to give crude methyl 3benzamidooct-2-enoate 6 (R=Me). The crude product was purified by via flash chromatography (SiO2; 1:10; EtOAc:hexane) to give (Z)-methyl 3-benzamidooct-2-enoate 6 (R=Me) (3.12 g, 68%) as a light yellow oil. 1H n.m.r. (300 MHz, CDCl3): 12.1 (bs, 1H, NH), 8.03-7.96 (m, 2H, H2’), 7.60-7.45 (m, 3H, H3’), 5.09 (s, 1H, H2), 2.91 (d, J = 7.8 Hz, 2H, H4), 1.70-1.57 (m, 2H, H5), 1.45-1.28 (m, 4H, H6 & H7), 0.91 (t, J = 7.2 Hz, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 170.1 (CONH), 164.8 (C1), 159.8 (C3), 134.1 (C1’), 132.3 (C4’), 128.8 (C2’), 127.7 (C3’), 96.3 (C2), 51.2 (C1”), 34.3 (C4), 31.5, 28.1, 22.4 (C5-C7), 14.0 (C8). LRMS (ESI-TOF) m/z: [M + Na]+ Calcd for [C16H21NNaO3]+ 298.1; Found 298.1. νmax (neat): 2955m, 2931m, 1699s, 1671s, 1630s, 1506m, 1488m, 1468m, 1450m, 1436m, 1375s, 1265s, 1247s, 1174s, 1113m cm-1. HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR=6.8 min (100% area).

(Z)-Ethyl 3-benzamidooct-2-enoate 6 (R=Et). Ethyl 3-oxooctanoate S3. Ethyl acetoacetate (1.85 mL, 14.7 mmol) was added dropwise over 5 mins to a stirred solution of sodium hydride (351 mg, 14.7 mmol) in dry THF (15 mL) under an atmosphere of nitrogen at 0 °C. The clear solution was warmed to room temperature for 10 mins before cooling to 0 °C and added n-butyllithium (6.48 mL, 16.1 mmol) dropwise over 5 mins. The resulting red/orange solution was warmed to room temperature for 10 mins before cooling to 0 °C and added n-butyl bromide (1.88 mL, 17.6 mmol) in one portion, where the colour dissipated and a precipitate formed. The solution was allowed to stir at 0 °C for 2 hours before warming to room temperature overnight. The reaction mixture was carefully quenched with 1M HCl (10 mL), diluted with Et2O and the phases were separated. The aqueous phase was further extracted with Et2O (4×15 mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by bulb-to-bulb distillation (110 °C, ~1 mbar) to give ethyl 3-oxooctanoate S3 (1.98 g, 73%) as a clear colourless oil.50 1H n.m.r. (300 MHz, CDCl3): δ 4.19 (q, J = 7.1 Hz, 2H, H1’), 3.42 (bs, 2H, H2), 2.52 (t, J = 7.5 Hz, 3H, H4), 1.59 (p, J = 7.1 Hz, 2H, H5), 1.42 – 1.16 (m, 4H, H6 & H7), 1.27 (t, J = 7.1 Hz, 3H, H2’), 0.88 (t, J = 6.6 Hz, 3H, H8). Ethyl 3-amino oct-2-enoate S4. Ethyl 3-oxooctanoate S3 (0.98 g, 5.3 mmol) was added to a stirred suspension of ammonium acetate (4.1 g, 53 mmol) in methanol (6 mL). The resulting yellow solution was left to stir at room temperature for 72 hours before concentration in vacuo. The reaction mixture was

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diluted with sat NaHCO3 (30 mL), EtOAc (30 mL) and the phases were separated. The aqueous phase was further extracted with EtOAc (3×30 mL), washed with water (3×30 mL), dried (MgSO4) and concentrated in vacuo to give ethyl 3-amino-oct-2-enoate S4 (856 mg, 88%) as a mixture of inseparable geometric isomers (A:B; 10:90).51 1H n.m.r. (300 MHz, CDCl3): δ 4.54 (s, 1H, H2), 4.20 (q, J = 7.1 Hz, 2H, H1’ isomer A), 4.11 (q, J = 7.1 Hz, 2H, H1’ isomer B), 2.53 (t, J = 7.4 Hz, 2H, H4 isomer A), 2.11 (t, J = 7.5 Hz, 2H, H4 isomer B), 1.63 – 1.47 (m, 4H, H5 & H6), 1.40 – 1.20 (m, 5H, H7 & H2’), 0.92 – 0.85 (m, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 170.6 (C1), 164.0 (C3), 83.6 (C2), 58.7 (C1’), 36.6 (C4), 31.4 (C5), 27.7 (C6), 22.5 (C7’), 14.7 (C2’), 14.1 (C8). (Z)-Ethyl 3-benzamidooct-2-enoate 6 (R=Et). Benzoyl chloride (617 μL, 5.31 mmol) in CH2Cl2 (2 mL) was added dropwise over 10 mins to a stirred solution of ethyl 3-amino-oct-2-enoate S4 (820 mg, 4.43 mmol) and pyridine (430 μL, 5.31 mmol) in CH2Cl2 (15 mL) under an atmosphere of nitrogen at 0 °C. The resulting solution was warmed to room temperature. After 16 hours the reaction mixture was quenched with sat. NaHCO3 (15 mL), diluted with CH2Cl2 (30 mL) and the phases were separated. The aqueous phase was further extracted with CH2Cl2 (3×30 mL), washed 1M HCl (3×30 mL), sat. NaHCO3 (3×30 mL), water (3×50 mL), dried (MgSO4) and concentrated in vacuo to give crude ethyl 3-benzamidooct-2-enoate 6 (R=Et) as a mixture of geometric isomers. The crude product was purified by via flash chromatography (SiO2; 1:8; EtOAc:hexane) to give (Z)-methyl 3-benzamidooct-2-enoate 6 (R=Et) (1.0 g, 78%) as a light yellow oil. 1H n.m.r. (200 MHz, CDCl3): δ 12.09 (s, 1H, NH), 7.98 (dt, J = 13.9 Hz, J = 6.7 Hz, 2H, H2’), 7.76 – 7.36 (m, 4H, H3’ & H4’), 5.08 (s, 1H, H2), 4.21 (q, J = 7.1 Hz, 2H, H1”), 2.98 – 2.78 (m, 2H, H4), 1.62 (m, 2H, H5), 1.52 – 1.13 (m, 7H, H6, H7 & H2”), 0.96 – 0.84 (m, 3H, H8). 13C n.m.r. (75 MHz, CDCl3): δ 169.9 (CONH), 165.0 (C1), 159.8 (C3), 134.4, 132.4, 129.0, 127.8, 96.9 (C2), 60.2 (C1”), 34.5, 31.7, 28.3, 22.6, 14.6 (C2”), 14.1 (C8). LRMS (ESITOF) m/z: [M + H]+ Calcd for [C17H24NO3]+ 290.2; Found 290.1. (R,S)-Methyl 3-benzamidooctanoate ±11 (R=Me). A Fischer-Porter tube was charged with (Z)-methyl 3benzamidooct-2-enoate 6 (R=Me) (535 mg, 1.93 mmol), palladium on carbon 10% w/w (54 mg) and methanol (15 mL). The headspace of the vessel was purged with argon over three cycles, charged with hydrogen (75 psi) and stirred at room temperature for 18 hours. The hydrogen was then vented from the vessel and the reaction mixture was filtered through a short plug of diatomaceous earth and concentrated in vacuo. The crude product was purified by via crystallisation (1:10; CH2Cl2:hexane) to give (R/S)-methyl 3benzamido octanoate 11 (R=Me) (390 mg, 73%) as an off white semi-solid. 1H n.m.r. (400 MHz, CDCl3): δ 7.82 – 7.73 (m , 2H, H2’), 7.54 – 7.37 (m, 4H, H3’ & H4’), 6.88 (bd, J = 8.7 Hz, NH), 4.54 – 4.32 (m, 1H, H3), 3.71 (s, 3H, OMe), 2.66 (qd, J = 16.0 Hz, 4.9 Hz, 2H, H2), 1.74 – 1.48 (m, 2H, H4), 1.48 – 1.17 (m, 6H, H5-H7), 0.87 (t, J = 7.0 Hz, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 172.9 (CONH), 166.9 (C1), 134.8, 131.5, 128.7, 127.1 (C1’-C4’), 51.9 (OMe), 46.5 (C3), 38.2 (C2), 34.3 (C4), 31.7 (C5), 26.1 (C6), 22.6 (C7), 14.11 (C8). LRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C16H24NO3]+ 278.2; Found 278.1. νmax (neat): 3306m, 2957m, 2924m, 2855m, 1737s, 1636s, 1535s cm-1. HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR=17.7 min (50% area, (S)-isomer) tR=21.2 min (50% area, (R)-isomer). (R,S)-Ethyl 3-benzamidooctanoate ±11 (R=Et). A Fischer-Porter tube was charged with (Z)-ethyl 3benzamidooct-2-enoate 6 (R=Et) (66 mg, 0.23 mmol), palladium on carbon 10% w/w (6.5 mg) and methanol (5 mL). The headspace of the vessel was purged with argon over three cycles, charged with hydrogen (75 psi) and stirred at room temperature for 18 hours. The hydrogen was then vented from the vessel and the reaction mixture was filtered through a short plug of diatomaceous earth and concentrated in vacuo. The crude product was purified by via flash chromatography (SiO2; 1:3; EtOAc:hexane) to give (R/S)-ethyl 3benzamido octanoate 11 (R=Et) (48 mg, 73%) as a light yellow oil. 1H n.m.r. (400 MHz, CDCl3): δ 7.82 – 7.74 9



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(m, 2H, H2’), 7.54 – 7.39 (m, 4H, H3’ & H4’), 6.90 (bd, J = 9.1 Hz, NH), 4.50 – 4.39 (m, 1H, H3), 4.17 (qd, J = 7.1 Hz, J = 2.1 Hz, 2H, H1”), 2.64 (qd, J = 15.9 Hz, J = 4.9 Hz, 2H, H2), 1.74 – 1.50 (m, 2H, H4), 1.48 – 1.23 (m, 6H, H5-H7), 1.27 (t, J = 7.2 Hz, 2H, H2”), 0.88 (t, J = 7.1 Hz, 2H). 13C n.m.r. (100 MHz, CDCl3): δ 172.5 (CONH), 170.1 (C1), 134.9, 131.5, 128.7, 127.1 (C1’-C4’), 60.8 (C1”), 46.6 (C3), 38.5 (C2), 34.4 (C4), 31.7 (C5), 26.1 (C6), 22.6 (C7), 14.3 (C2”), 14.1 (C8). LRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C17H26NO3]+ 292.2; Found 292.1. HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR=17.2 min (50% area, (S)-isomer), tR=20.8 min (50% area, (R)-isomer). General procedure for asymmetric hydrogenation of enamides 6. In a nitrogen filled dry box, a FischerPorter tube was charged with degassed substrate (~0.8 mmol), asymmetric hydrogenation catalyst (2-5 mg), solvent (10 mL), sealed and removed from the dry box. The headspace of the vessel was purged with argon over three cycles, charged with hydrogen and stirred at room temperature for 18 hours. The hydrogen was then vented from the vessel and the reaction mixture was concentrated in vacuo. A small sample of the crude product was purified by preparative thin layer chromatography (SiO2; 1:1:0.1; EtOAc:hexane:methanol) for chiral HPLC analysis. HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min. (+)-Methyl 3-benzamidooctanoate (+)-11 (R=Me). In a nitrogen filled dry box, a Fischer-Porter tube was charged with degassed (Z)-methyl 3-benzamidooct-2-enoate 6 (R=Me) (1.7 g, 6.0 mmol), isopropanol (10 mL) and a solution of Rh(COD)(10)OTf (1.4 mL, 30 μmol) prepared from a 21 μM solution of Rh(COD)(10)OTf in dichloromethane (Rh(COD)OTf (18 mg, 41 μmol) and 10 (36 mg, 83 μmol) in DCM (2 mL)). The vessel sealed, removed from the dry box and the headspace of the vessel was purged with argon over three cycles, charged with hydrogen (350 psi) and stirred at room temperature for 16 hours. The hydrogen was then vented from the vessel and the reaction mixture was concentrated in vacuo. The crude material was then purified by gradient flash chromatography (SiO2; 1:6 to 1:1; EtOAc:hexane) to give (+)-methyl 3benzamidooctanoate (+)-11 (1.34 g, 80%, >99% ee) as colourless oil. Spectra for (+)-methyl 3-benzamido octanoate were consistent with previously recorded data. [ࢻ]૛૙ ࡰ 42.2 (c 0.88, CH2Cl2). HPLC (DIACEL CHIRACEL OD 0.46 x 250mm C-048, isocratic elution (98:2; hexane:isopropanol), 1 mL/min: tR=18.4 min (99% area, (R)-isomer). (R)-3-Aminooctanoic acid hydrochloride S5. (+)-Methyl 3-benzamidooctanoate (+)-11 (54 mg, 0.19 mmol, 97% ee) was added to a 25 mL round bottom flask which containing 6M HCl (10 mL). The mixture was heated at reflux for 16 hours before being cooled, diluted with dichloromethane (10 mL) and the phases separated. The aqueous phase was further washed with dichloromethane (3×10 mL) and then concentrated in vacuo to give (R)-3-aminooctanoic acid hydrochloride S5 (38 mg, >99%) as a light yellow coloured oil. Spectral data were consistent with that reported in the literature.52 1H n.m.r. (200 MHz, D2O): δ 3.79 – 3.61 (m, 1H, H3), 2.83 (qd, J = 17.6 Hz, J = 6.4 Hz, 2H, H2), 1.88 – 1.66 (m, 2H, H4), 1.60 – 1.24 (m, 6H, H5-H7), 52 ૛૙ 0.95 (t, J = 6.6 Hz, 3H, H8). [ࢻ]૛૙ ࡰ -19.7° (c 0.80, H2O). Literature optical rotation: [ࢻ]ࡰ -16.6° (c 1.1, H2O). Selected data for 3-benzamidooctanal 12. 1H n.m.r. (400 MHz, CDCl3): δ 9.80 (s, 1H, H1), 7.80 – 7.68 (m, 2H, H2’), 7.54 – 7.36 (m, 3H, H3’ 7 H4’), 6.55 (s, 1H, NH), 4.59 – 4.42 (m, 1H, H3), 2.84 – 2.70 (m, 2H, H2), 1.77 – 1.56 (m, 2H, H4), 1.48 – 1.19 (m, 6H, H5-H7), 0.86 (t, J = 7.0 Hz, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 201.6 (C1), 167.3 (CONH), 134.5, 131.7, 128.7, 127.0 (C1’-C4’), 48.4 (C3), 46.0 (C2), 34.7 (C4) , 31.6 (C5), 26.1 (C6), 22.6 (C7), 14.1 (C8). LRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C15H24NO2]+ 248.2; Found 248.2.

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Selected data for 3-benzamidooctanol S6. 1H n.m.r. (400 MHz, CDCl3): δ 7.77 (d, J = 7.1 Hz, 2H, H2’), 7.51 (t, J = 7.3 Hz, 1H, H4’), 7.43 (t, J = 7.4 Hz, 2H, H3’), 6.20 (d, J = 8.6 Hz, 1H, NH), 4.34 – 4.20 (m, 1H, H3), 3.83 (bs, 1H, OH), 3.72 – 3.54 (m, 2H, H1), 2.05 – 1.86 (m, 2H, H2), 1.72 – 1.51 (m, 2H, H4), 1.51 – 1.35 (m, 2H, H5), 1.35 – 1.21 (m, 4H, H6 & H7), 0.88 (t, J = 6.9 Hz, 3H, H8). 13C n.m.r. (100 MHz, CDCl3): δ 168.7 (CONH), 134.2, 131.8, 128.8, 127.1 (C2’-C4’), 58.8 (C1), 47.1 (C3), 38.6 (C2), 35.6 (C4), 31.7 (C5), 26.2 (C6), 22.7 (C7), 14.1 (C8). LRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C15H24NO2]+ 250.2; Found 250.2. (R)-4-Benzamido-non-1-ene 13. n-Butyllithium (1.41 mL, 2.56 mmol) was added dropwise over five mins to a stirred solution of methyltriphenylphosphonium bromide (953 mg, 2.67 mmol) in dry THF (15 mL) at 0 °C under an atmosphere of nitrogen. After the addition was complete, the bright yellow solution was stirred at 0 °C for 20 mins before being warmed to room temperature and stirred for a further five mins. The mixture was then cooled (0 °C) and (R)-3-benzamidooctanal 12 (550 mg, 66% w/w, 1.48 mmol) was added dropwise as a solution in THF (5 mL). After the addition was complete, the reaction mixture was allowed to stir to room temperature over 16 hours. The mixture was then quenched with the addition of sat. ammonium chloride solution (10 mL), diluted with diethyl ether (30 mL) and the phases were separated. The aqueous layer was further extracted with diethyl ether (3×30 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was then purified by flash chromatography (SiO2; 1:5; EtOAc:hexane) to give (R)-4-benzamido-non-1-ene 13 (107 mg, 29%) as a clear oil. Alternatively, diisobutyl aluminium hydride (2.5 mL, 3.24 mmol) was added dropwise over 10 mins to a Schlenk flask containing a stirred solution of methyl 3-benzamidooctanoate 11 (900 mg, 3.24 mmol) in dry THF (20 mL) at -78 °C under an atmosphere of nitrogen. After the addition was complete, the mixture was stirred for 1 hour at -78 °C. Meanwhile, a solution of methylenetriphenylphosphorane (15 mL, 4.87 mmol) in tetrahydrofuran was prepared in a second Schlenk flask by dropwise addition of n-butyllithium (4.43 mL, 4.87 mmol) to methyltriphenylphosphonium bromide (1.74 g, 4.87 mmol) in dry THF (15 mL) at 0 °C under an atmosphere of nitrogen. After the addition was complete, the bright yellow solution was stirred at 0 °C for 20 mins before being warmed to room temperature and stirred for a further five mins. This ylid mixture was again cooled to 0 °C and was transferred dropwise by nylon cannula to the Schlenk flask containing the methyl (R)-3-benzamidooctanoate 11 and DIBAL-H at -78 °C. The combined mixture was stirred to room temperature overnight before being quenched with 1M HCl (5 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was then purified by flash chromatography (SiO2; 1:3; EtOAc:hexane) to give (R)-4-benzamidonon-1-ene 13 (384 mg, 48%) as a clear oil. 1H n.m.r. (300 MHz, CDCl3): δ 7.78 – 7.70 (m, 2H, H2), 7.53 – 7.38 (m, 3H, H3 & H4), 5.99 – 5.74 (m, 2H, H2 & NH), 5.19 – 5.03 (m, 2H, H1), 4.29 – 4.13 (m, 1H, H4), 2.49 – 2.21 (m, 2H, H5), 1.75 –1.21 (m, 6H, H6-H8), 0.98 – 0.78 (m, 3H, H9). 13C n.m.r. (75 MHz, CDCl3): δ 167.3 (CONH), 135.5, 134.7, 131.6, 128.9, 127.1(C2 & C1’-C4’), 118.3 (C1), 49.4 (C4), 39.5 (C3), 34.8 (C5), 32.1 (C6), 26.0 (C7), 22.9 (C8), 14.3 (C9). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H24NO+ 246.1858; Found 246.1850. (S)-Non-1-en-4-ol 14. Made according to a procedure by Keck et al..41 Ti(OiPr)4 (0.67 mL, 2.27 mmol) was added to (R)-BINOL (650 mg, 2.27 mmol) and 4Å molecular sieves (8.00 g) in DCM (40 mL) at room temperature. The resulting suspension was stirred for 1 h, at which point hexanal (2.00 g, 20 mmol) was added and the mixture was cooled to 0 oC. Next, allyltributyl stannane (7.94 g, 24.0 mmol) was added and the mixture was cooled to -25 oC for 108 h. The reaction was then quenched by addition of aqueous KF (100 mL, 10% w/v) and the biphasic mixture stirred until a clear solution was obtained (0.5 h). The product was extracted with DCM (3x20 mL) and the combined organic extract dried (Na2SO4), filtered and concentrated 11



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under reduced pressure. The crude material was purified by column chromatography (light petroleum → 42 10% EtOAc:light petroleum) to afford 14 (2.27 g, 79%) as a colourless oil. [ࢻ]૛૛ ࡰ -7.7 (c 1.0, CHCl3); lit. -9 (c -1 1 1.5, CHCl3 ). IR νmax 3332b, 1961s, 1450s, 1176s, 1047m, 683s cm . H NMR (400 MHz, CDCl3): δ 5.87-5.77 (m, 1H), 5.14 (br d, J = 4.4 Hz, 1H), 5.10 (br s, 1H), 3.64 (app. quintet, J = 4.4 Hz, 1H), 2.29 (dt, J = 14.0, 5.6 Hz, 1H), 2.13 (dt, J = 14.0, 8.0 Hz, 1H), 1.66 (br s, 1H), 1.47-1.40 (m, 3H), 1.34-1.25 (m, 4H), 0.88 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 135.0, 118.0, 70.7, 42.0, 36.8, 31.9, 25.4, 22.6, 14.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H19O+ 143.1436; Found 143.1435. (R)-4-Azidonon-1-ene 16. Mesyl chloride (0.60 mL, 7.73 mmol) was added to (S)-non-1-en-4-ol 6 (1.00 g, 7.02 mmol) and Hünig’s base (2.44 mL, 14.1 mmol) in DCM (10 mL) at 0 oC. The resulting yellow solution was stirred for 1 h at which point NaHCO3 (sat., 10 mL) was added and the biphasic mixture stirred for 0.5 h. The product was extracted with DCM (3x20 mL) and the combined organic extract dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc) to afford mesylate 15 (1.54 g, 98%) as an unstable colourless oil which was immediately used in the next step. (S)-Non-1-en-4-yl methanesulfonate (1.00 g, 4.54 mmol) was added to sodium azide (650 mg, 10.0 mmol) in DMF (10 mL) at room temperature. The suspension was stirred for 16 h. Water (100 mL) was then added and the product was extracted with Et2O (5x20 mL) and the combined organic extract dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (10% EtOAc:light petroleum) to afford 16 (759 mg, 88% over two steps) as a colourless oil. -1 1 [ࢻ]૛૛ ࡰ +29.1 (c 1.13, CHCl3). IR νmax 2928w, 2361s, 2341m, 1686w, 1218w, 1181w cm . H NMR (400 MHz, CDCl3): δ 5.81 (ddt, J = 27.2, 10.0, 6.8 Hz, 1H), 5.17-5.10 (m, 2H), 5.10 (br s, 1H), 3.32 (app. quintet, J = 6.4 Hz, 1H), 2.32-2.28 (m, 2H), 1.57-1.46 (m, 3H), 1.374-1.24 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 134.1, 118.0, 62.4, 38.8, 33.9, 31.6, 25.7, 22.6, 14.0. HRMS (ESI-TOF) m/z: [M – N2 + H]+ Calcd for C9H18N+ 140.1439; Found 140.1434. 2-Butyl-1,3-cyclohexadione 17. The synthesis of 2-butyl-1,3-cyclohexadione 17 was carried out according to a procedure described by Ramachary et al..44 A solution of 1,3-cyclohexadione (2.07 g, 18.5 mmol) and (S)proline (215 mg, 1.84 mmol) in CH2Cl2 (10 mL) was added dropwise over 5 mins to a stirring suspension of Hantzsch’s ester (4.68 g, 18.5 mmol) and 1-butyraldehyde (2.5 mL, 28 mmol) in CH2Cl2 (30 mL). The resulting bright yellow solution was allowed to stir at room temperature for 1 hour before concentration in vacuo to give bright yellow oil. The crude product was then purified by precipitation (-15 °C; hexane: CH2Cl2; 10:1). The precipitate was collected by vacuum filtration, washed with hexane (3×10 mL) and dried in vacuo to give 2-butyl-1,3-cyclohexadione 17 (2.70 g, 87%) as a colourless solid. Spectral data were consistent with those reported in the literature.44 1H n.m.r. (400 MHz, CDCl3 & d4-MeOH): δ 2.35 (t, J = 6.4 Hz, 4H, H7), 2.232.17 (m, 2H, H3), 1.89 (p, J = 6.8 Hz, 2H, H8), 1.32-1.21 (m, 4H, H4 & H5), 0.89-0.82 (m, 3H, H6), H2 not observed. 13C n.m.r. (75 MHz, CDCl3 & d4-MeOH): δ 116.5 (C2-enol), 67.8 (C2), 39.9 & 39.1 (C7), 31.1, 29.9, 23.0, 22.9 21.7, 20.9 (C3-C5), 18.4 (C8), 14.2 & 14.0 (C6). LRMS (ESI-TOF) m/z: [M-H]-. Calcd for [C10H15O2]167.1; Found 166.7. 2-Butyl-3-isobutoxycyclohex-2-enone 18. A 100 mL round bottom flask was charged with 2-butyl-1,3cyclohexadione 17 (2.10 g, 12.0 mmol), iso-butanol (6.93 mL, 75.0 mmol), benzene (50 mL) and a catalytic amount of p-toluene sulphonic acid (200 mg). The flask was then heated to reflux in a Dean-Stark apparatus with water separation for 16 hours. After cooling, the solution was diluted with Et2O (50 mL), sat. NaHCO3

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(20 mL) and the phases were separated. The aqueous phase was further extracted with Et2O (3×20 mL) and the combined organic extract was washed with water (3×20 mL), dried (MgSO4) and concentrated to give an orange oil. The crude product was purified by bulb-to-bulb distillation (150 °C, 0.2 mbar) to give 2-butyl-3isobutoxycyclohex-2-enone 18 (2.73 g, 97%) as a clear orange oil. 1H n.m.r. (200 MHz, CDCl3): δ 3.73 (d, J = 6.2 Hz, 2H, H1’), 2.52 (t, J = 6.2 Hz, 2H, H10), 2.33-2.21 (m, 4H, H3 & H8), 1.96 (m, 3H, H9 & H2’), 1.34-1.23 (m, 4H, H4 & H5), 0.98 (d, J = 6.8 Hz, 6H, H3’), 0.90-0.82 (m, 3H, H6). 13C n.m.r. (100 MHz, CDCl3): δ 198.4 (C1), 171.6 (C7), 120.0 (C2), 73.9 (C1’), 36.5 (C10), 31.1 (C4), 28.9 (C2’), 25.5 (C8), 22.9 (C5), 21.8 (C9), 21.1 (C3), 19.0 (C3’), 14.1 (C6). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for [C14H25O2]+ 225.1855; Found 225.1848. (R)-3-(4-Aminonon-1-en-1-yl)-2-butylcyclohex-2-en-1-one 19. 2-Butyl-3-vinylcyclohex-2-en-1-one 5 (360 mg, 2.00 mmol) in EtOAc (4 mL) was added to (R)-non-1-en-4-ammonium tetrafluoroborate 4 (154 mg, 0.67 mmol) and HGII (21 mg, 34 μmol) in EtOAc (5 mL) and then heated at 80 oC for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. NaHCO3 (sat., 10 mL) and DCM (10 mL) were added to the residue and the resulting biphasic mixture was then stirred for 0.5 h. The product was extracted with DCM (3x20 mL) and the combined organic extract dried (K2CO3), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (50% EtOAc: light petroleum → 95%:4%:1% CHCl3:MeOH:NH3) to afford 19 (127 mg, 65%) as a yellow oil. The product 19 contained contained ~10% Z-isomer as judged by 1H NMR spectroscopy. 1H NMR (400 MHz, CDCl3): 6.90 (dd, J 17.6, 10.8 Hz, 1H), 5.65 (d, J 17.6 Hz, 1H), 2.87-2.85 (m, 1H), 2.49 (t, J 6.4 Hz, 2H), 2.40 (dd, J 7.6, 6.4 Hz, 5H), 2.23-2.15 (m, 1H), 1.97 (app. quintet, J = 6.8 Hz, 2H), 1.39-1.22 (m, 12H), 0.30 (t, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 199.6, 149.2, 136.1, 134.7, 130.9, 51.2, 42.4, 38.2, 37.8, 32.2, 32.0, 26.4, 25.9, 24.3, 22.9, 22.7, 22.2, 14.1, 14.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H34NO+ 292.2640; Found 292.2639.

Acknowledgements The authors wish to acknowledge the financial assistance of the Australian Research Council (DP120104169) and the award of a postgraduate research award to N.D.S..

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX. Electronic copies of the carbon and proton NMR spectra for compounds 3, 4, 5, 6 (R=Me, Et), 11 (R=Me, Et), 12, 13, 14, 16, 18, 19, S1, S2, S3, S4, S5 and S6.

References

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