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DOI: 10.1055/s-0028-1083350
Synthesis of (-)-Monomorine I
Publication History
Publication Date:
02 February 2009 (online)
Abstract
(-)-Monomorine I has been synthesized using a stereoselective intramolecular 1,6-conjugate addition of a hydroxylamine to a dienyl ester, followed by a tandem hydrogenation-lactamization reaction.
Key words
Michael addition - tandem reaction - alkaloid - lactam - heterocycle
The synthesis of indolizidine alkaloids remains a field of great interest, not only due to the biological properties of many of these alkaloids, but also due to the challenge of achieving effective and efficient control of the stereochemistry. [¹] Amongst the indolizidine alkaloids, a large number possess alkyl substituents at positions 3 and 5. Amongst these 3,5-dialkylindolizidines, (+)-monomorine I, a pheromone of the pharaoh ant, [²] as well as its enantiomer, (-)-monmorine I (1), and its racemic form, have become frequent targets for synthetic chemists and are widely used to demonstrate the efficacy of synthetic methodology (Figure [¹] ). [³-5]
Figure 1 (-)-Monomorine I
The problem of controlling the relative stereochemistry of the piperidine ring was solved with great elegance by Stevens and Lee in work that has become a classic application of stereoelectronic control. [4] Numerous other methods have been devised for controlling the stereochemistry of the pyrrolidine ring, and the issue of absolute stereochemistry. While there are excellent methods for controlling stereochemistry during five-membered-ring formation, six-membered rings tend to be more reliable and predictable as they can adopt a well-understood chair conformation. With this thought in mind, we set out to apply our recently reported 1,2-oxazine method [6] to the synthesis of (-)-monomorine I (1) and, thus, demonstrate a rapid and efficient route to indolizidines. In particular, we anticipated that the use of tandem reactions would shorten the synthesis and that we would be able to establish the two chiral centers of the pyrrolidine by formation of a six-membered tetrahydro-1,2-oxazine ring 2 (Scheme [¹] ), then relay those stereocenters into the desired five-membered ring by a sequence of a ring-opening and a reclosing reaction.
Scheme 1 (-)-Monomorine I retrosynthesis
Commercially available hex-1-ene oxide was subjected to hydrolytic kinetic resolution using Jacobsen’s catalyst. [7] The unreacted (S)-epoxide 3 (>99% ee by chiral GC) was then treated with allylmagnesium bromide to give secondary alcohol 4. Substitution of the hydroxy group with N-hydroxyphthalimide under Mitsunobu conditions [8] proceeded satisfactorily provided that the reaction was maintained at room temperature. It was also found that this reaction proceeded with complete inversion most reliably when conducted in toluene, rather than tetrahydrofuran. [9] Cross-metathesis of the N-alkoxyphthalide 5 with crotonaldehyde, employing Grubbs’ second-generation catalyst, followed by Wittig reactions with the appropriate ylides yielded the desired dienes 7a and 7b (Scheme [²] ). While the intermediate aldehyde 6 may be isolated, this is not necessary. The ylide may be added to the crude product of the cross-metathesis, provided that the excess crotonaldehyde has been removed in vacuo.
Scheme 2 Diene synthesis
The first of the two planned tandem reactions, deprotection-1,6-conjugate addition, was achieved using the previously reported method. [6] Liberation of the hydroxylamine of 7a on treatment with hydrazine hydrate gave the tetrahydro-1,2-oxazine 8 as a single stereoisomer (Scheme [³] ). The ring stereochemistry was assigned to be trans in accordance with previous studies, [6] although the ¹H NMR signals for the protons at C3 and C6 were not resolved. This assignment was subsequently confirmed by conversion into the natural product. In contrast, when the corresponding methyl ketone 7b was employed in an analogous sequence, attempted liberation of the hydroxylamine under the same conditions yielded a complex mixture, possibly due to competing condensation with the ketone carbonyl.
The second of the two planned tandem reactions was reduction of the N-O bond and the alkene of oxazine 8, accompanied by lactam formation. Hydrogenation proved to be problematic with inconsistent results from palladium-on-carbon. [¹0] In several runs, it was found that alkene reduction-lactamization proceeded to give the bicyclic oxazine 9, [¹¹] rather than the desired lactam 10. After some experimentation, it was found that the use of platinum oxide in the presence of calcium carbonate gave reliable tandem double reduction-lactamization, cleanly delivering lactam 10. Various hydrogenation reactions are frequently carried out under acidic conditions, [¹²] however, in our hands this did not result in a clean reaction.
Scheme 3 Tandem reactions
N-Alkylation of simple amides is usually difficult. [¹³] In contrast, treatment of mesylate 11 with potassium tert-butoxide yielded the indolizidinone 12 (Scheme [4] ), assuming inversion during cyclization. The remaining methyl group was then introduced by the method of Orito, [5] which, presumably, proceeds via reduction of an intermediate iminium ion. The spectroscopic data of the synthetic monomorine thus obtained was in good agreement with that reported by others. [³-5] [¹¹] An optical rotation of -35.5 was obtained for the synthetic compound, which may be compared to +35.1 reported for the natural product. [²]
Scheme 4 Monomorine synthesis
(-)-Monomorine I (1) has been prepared by a flexible route that may be adapted for the synthesis of analogues and the opposite antipode. The overall yield, from resolved hexene oxide, is 26% and the synthesis is complete in just nine steps including a tandem deprotection-intramolecular Michael addition and a tandem double hydrogenation-lactamization. The application of this method to indolizidines with other substitution patterns is under way.
THF was distilled from Na/benzophenone, CH2Cl2 was distilled from CaH2 and Et2O was obtained from a solvent purifier (alumina column). Other reagents and solvents were commercial and used as received. IR spectra were recorded on a Bio-Rad FTS 165 spectrophotometer either neat or as Nujol mulls using NaCl plates. ¹H NMR spectra were recorded on a Bruker Advance DPX300 at 300 MHz with residual protic solvent as the reference. ¹³C spectra were recorded at the corresponding frequency on the same instrument. Mass spectra were recorded on a Finnigan Trace GC Ultra instrument at 70 eV with EI mode. HRMS were recorded on a Finnigan MAT95XP instrument, also using EI mode. Specific rotations, [α]D, were recorded on an Jasco P-1030 polarimeter and are given with units of 10-¹deg˙cm²˙g-¹. Elemental analysis was carried out at Nanyang Technological University.
( S )-Non-1-en-5-ol (4) [¹4]
Allyl bromide (15 mL, 60 mmol) was slowly added dropwise to Mg turnings (2.7 g, 112.8 mmol) in anhyd Et2O. The mixture was stirred for 1.5 h and the resulting Et2O soln was transferred by cannula to a new flask. 1,2-Epoxyhexane (3.0 g, 3.6 mL, 30 mmol) was added slowly. The mixture was stirred for 1 h and then sat. aq NH4Cl (20 mL) and H2O (20 mL) were added. The mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried (MgSO4). The solvent was evaporated to afford 4 (3.6 g, 85%) as a colorless oil, which was used without purification; R f = 0.49 (hexanes-EtOAc, 9:1).
[α]D ²5 -0.9 (c 1.32, CH2Cl2).
¹H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 6.9 Hz, 3 H), 1.32-1.56 (m, 8 H), 2.12-2.21 (m, 2 H), 3.61-3.64 (m, 1 H), 4.97 (ddt, J = 10.1, 2.2, 1.2 Hz, 1 H), 5.05 (ddt, J = 17.2, 1.8, 1.6 Hz, 1 H), 5.84 (ddt, J = 6.7, 10.2, 17.1 Hz, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 138.7, 114.7, 71.5, 37.2, 36.5, 30.1, 27.8, 22.7, 14.0.
( R )-5-[(1,3-Dioxo-1,3-dihydro-2 H -isoindol-2-yl)oxy]non-1-ene (5)
Alcohol 4 (3.6 g, 25 mmol), PhthNOH (4.08 g, 25 mmol), and Ph3P (6.56 g, 25 mmol) were dissolved in toluene (100 mL). DIAD (6.06 g, 5.9 mL, 30 mmol) was added dropwise at 0 ˚C and the mixture was stirred at r.t. overnight. The solvent was evaporated and the residue was purified by flash chromatography (hexane-EtOAc, 90:10) to afford 5 (7.2 g, 99%) as a colorless oil that solidified during refrigeration; R f = 0.3 (hexanes-EtOAc, 9:1).
[α]D ²5 -4.8 (c 1.22, CH2Cl2).
IR (NaCl): 3000, 2954, 2933, 1789, 1732, 1371, 1188, 977 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.34-1.55 (m, 4 H), 1.68-1.85 (m, 4 H), 2.22-2.44 (m, 2 H), 4.28 (q, J = 5.9 Hz, 1 H), 5.01 (ddt, J = 10.2, 1.9, 1.2 Hz, 1 H), 5.10 (ddt, J = 17.2, 1.8, 1.6 Hz, 1 H), 5.88 (ddt, J = 6.6, 10.3, 17.0 Hz, 1 H), 7.73-7.85 (m, 4 H).
¹³C NMR (75 MHz, CDCl3): δ = 164.3, 138.0, 134.4, 129.0, 123.4, 114.9, 87.64. 32.1, 31.6, 29.1, 27.0, 22.7, 14.0.
MS (EI): m/z (%) = 288.11 [M + H]+, 230.11, 125.27, 164.13, 132.15, 83.28, 69.26 (100).
HRMS (EI): m/z [M]+ calcd for C17H21NO3: 287.1516; found: 287.1517.
( R , E )-6-[(1,3-Dioxo-1,3-dihydro-2 H -isoindol-2-yl)oxy]dec-2-enal (6)
Alkene 5 (0.6 g, 2.1 mmol) and Grubbs II catalyst (32 mg, 0.04 mmol) were dissolved in CH2Cl2 (12 mL). Crotonaldehyde (0.42 g, 0.49 mL, 6 mmol) was added and the mixture was heated at reflux for 2 h under N2. The solvent was evaporated and the residue was purified by flash chromatography (hexane-EtOAc, 90:10) to afford 6 (600 mg, 92%) as a colorless oil; R f = 0.38 (hexanes-EtOAc, 3:1).
[α]D ²5 -13.7 (c 1.00, CH2Cl2).
IR (NaCl): 3000, 2954, 2931, 1789, 1693, 1371, 1124, 877 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.19-1.55 (m, 4 H), 1.57-1.72 (m, 2 H), 1.75-1.90 (m, 2 H), 2.52-2.75 (m, 2 H), 4.22 (q, CH, J = 5.7 Hz, 1 H), 6.16 (dd, J = 15.7, 7.9 Hz, 1 H), 6.93 (dt, J = 15.6, 6.7 Hz, 1 H), 7.71-7.81 (m, 4 H), 9.48 (d, J = 7.9 Hz, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 194.1, 164.3, 158.1, 134.5, 133.1, 128.8, 123.4, 87.2, 32.0, 30.5, 27.9, 27.0, 22.6, 13.9.
MS (EI): m/z (%) = 316.11 [M]+, 285.17, 232.98, 153.17, 163.08 (100).
HRMS (EI): m/z [M]+ calcd for C18H21NO4: 316.1530; found: 316.1530.
Methyl (8 R ,2 E ,4 E )-8-[(1,3-Dioxo-1,3-dihydro-2 H -isoindol-2-yl)oxy]dodeca-2,4-dienoate (7a)
One-pot method: Alkene 5 (0.6 g, 2.1 mmol) and Grubbs II catalyst (32 mg, 0.04 mmol) were dissolved in CH2Cl2 (12 mL). Crotonaldehyde (0.42 g, 0.49 mL, 6 mmol) was added and the mixture was heated at reflux for 2 h under N2. The volatiles were evaporated and the residue was taken up in CH2Cl2 (18 mL). Methyl (triphenylphosphoranylidene)acetate (0.78 g, 2.3 mmol) was added and the mixture was stirred at r.t. under N2 overnight. The solvent was evaporated and the residue was purified by flash chromatography (hexane-EtOAc, 75:25) to afford 7a (646 mg, 83% over 2 steps) as a colorless oil.
From isolated aldehyde 6: Aldehyde 6 (310 mg, 0.95 mmol) and methyl (triphenylphosphoranylidene)acetate (403 mg, 1.05 mmol) were dissolved in CH2Cl2 (10 mL). The mixture was stirred overnight. The solvent was evaporated and the residue was purified by flash chromatography (hexane-EtOAc, 75:25) to afford 7a (300 mg, 86%) as a colorless oil; R f = 0.34 (hexanes-EtOAc, 3:1).
[α]D ²5 +18.0 (c 0.5, CH2Cl2).
IR (NaCl): 3000, 2954, 2933, 1732, 1643, 1373, 1215, 977 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.26-1.50 (m, 4 H), 1.63-1.84 (m, 4 H), 2.40-2.56 (m, 2 H), 3.72 (s, 3 H), 4.23 (q, J = 5.6 Hz, 1 H), 5.81 (d, J = 15.8 Hz, 1 H), 6.12-6.31 (m, 2 H), 7.22-7.30 (m, 1 H), 7.74-7.78 (m, 4 H).
¹³C NMR (75 MHz, CDCl3): δ = 167.7, 164.4, 145.1, 143.6, 134.5, 129.0, 128.9, 123.5, 119.1, 87.5, 51.4, 32.2, 31.5, 28.3, 27.1, 22.7, 14.0.
MS (EI): m/z (%) = 195 [M]+, 371.08, 210.15, 176.11, 134.14, 109.17, 67.17 (100).
HRMS (EI): m/z [M]+ calcd for C21H25NO5: 371.1727; found: 371.1721.
(±)-(3 E ,5 E )-9-[(1,3-Dioxo-1,3-dihydro-2 H -isoindol-2-yl)oxy]trideca-3,5-dien-2-one (7b) [¹5]
Aldehyde 6 (103 mg, 0.343 mmol) and (acetylmethylene)triphenylphosphorane (208 mg, 0.66 mmol) were dissolved in MeCN (4 mL) and heated at reflux for 36 h under N2. The mixture was pre-absorbed on silica gel (1 g) and purified by flash chromatography (silica gel, hexane-EtOAc, 99:1) to give 7b (0.07 g, 60%) as a colorless oil; R f = 0.33 (hexanes-EtOAc, 3:1).
IR (NaCl): 3000 (v br s), 2870, 2860, 1730, 1645, 1597, 1447, 1277, 1128 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.1 Hz, 3 H), 1.31-1.42 (m, 8 H,), 2.25 (s, 3 H), 2.41-2.53 (m, 2 H), 4.23 (q, J = 5.8 Hz, 1 H), 6.06 (d, J = 15.6 Hz, 1 H), 6.24-6.27 (m, 2 H), 7.09 (dd, J = 15.6, 9.8 Hz, 1 H), 7.73-7.82 (m, 4 H).
¹³C NMR (75 MHz, CDCl3): δ = 164.4, 162.3, 144.5, 143.8, 134.5, 129.4, 129.1, 129.0, 123.4, 87.4, 32.2, 31.5, 28.4, 27.1, 27.1, 22.8, 14.0.
MS (EI): m/z (%) = 356.07 [M + H]+, 192.2 (100), 163.12, 135.21, 95.24.
HRMS (EI): m/z [M + H]+ calcd for C21H26NO4: 356.1856; found: 356.1849.
Methyl (3 S ,6 R , E )-(6-Butyltetrahydro-2 H -1,2-oxazin-3-yl)but-3-enoate (8)
Dienyl ester 7a (1.2 g, 3.2 mmol) was dissolved in CH2Cl2 (10 mL) and hydrazine hydrate (0.6 mL, 20.2 mmol) was added. The mixture was stirred at r.t. for 10 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was purified by flash chromatography (hexane-EtOAc, 95: 5) to afford 8 (750 mg, 96%) as a colorless oil; R f = 0.39 (EtOAc).
[α]D ²5 -16.6 (c 1.00, CH2Cl2).
IR (NaCl): 3000, 2953, 2933, 1737, 1435, 1195, 1165 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.7 Hz, 3 H, CH3), 1.26-1.89 (m, 11 H), 3.06 (d, J = 7.0 Hz, 2 H), 3.50-3.55 (m, 2 H), 3.68 (s, 3 H), 5.43 (dd, J = 15.6, 7.0 Hz, 1 H), 5.78 (dt, J = 15.4, 7.0 Hz, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 171.8, 132.5, 125.1, 79.4, 59.5, 51.8, 37.7, 34.5, 30.5, 30.2, 27.6, 22.7, 14.0.
MS (EI): m/z (%) = 242.18 [M + H]+, 184.22, 168.30, 144.24, 112.26 (100).
HRMS (EI): m/z [M]+ calcd for C13H23NO3: 241.1672; found: 241.1676.
( R )-6-[( R )-3-Hydroxyheptyl]piperidin-2-one (10)
PtO2 (10 mg, 0.04 mmol) and CaCO3 (10 mg, 0.1 mmol) were added to a soln of oxazine 8 (100 mg, 0.414 mmol) in MeOH (6 mL). The mixture was stirred under H2 (balloon) for 1 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography (EtOAc-MeOH, 95:5) to give 10 (75 mg, 88%) as a low melting point white solid; mp 63-65 ˚C; R f = 0.13 (EtOAc).
[α]D ²5 2.55 (c 1.00, CH2Cl2).
IR (NaCl): 3309, 3269, 3198, 3000, 1658, 1456 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 6.68 Hz, 3 H), 1.32-1.76 (m, 12 H), 1.89-1.92 (m, 2 H), 2.27-2.41 (m, 2 H), 3.31-3.45 (m, 1 H), 3.54-3.67 (m, 1 H), 6.15 (s, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 172.4, 71.6, 53.3, 37.4, 33.1, 32.9, 31.0, 28.6, 27.8, 22.7, 19.8, 14.0.
MS (EI): m/z (%) = 213.16 [M]+, 195.16, 185.12, 156.14, 98.08 (100).
HRMS (EI): m/z [M]+ calcd for C12H23NO2: 213.1723; found: 213.1725.
( R )-6-[( R )-3-(Mesyloxy)heptyl]piperidin-2-one (11)
Et3N (90 µL) was added dropwise to a soln of lactam 10 (70 mg, 0.328 mmol) in CH2Cl2 (3 mL). The soln was cooled to 0 ˚C and MsCl (75 mg, 0.66 mmol) was added slowly. The mixture was stirred for 2 h. Sat. aq NH4Cl (5 mL) was added and then the mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (EtOAc-MeOH, 95: 5) to afford 11 (88 mg, 93%) as a low melting point white solid; R f = 0.22 (EtOAc).
[α]D ²5 +16.0 (c 1.0, CH2Cl2).
IR (NaCl): 3260, 3200, 3000, 2953, 2935, 1658, 1346, 1172, 904 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 6.8 Hz, 3 H), 1.28-1.48 (m, 4 H), 1.64-1.80 (m, 8 H), 1.85-2.0 (m, 2 H), 2.28-2.49 (m, 2 H), 3.02 (s, 3 H), 3.33-3.48 (m, 1 H), 4.72 (s, J = 6.0 Hz, 1 H), 5.71 (s, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 172.5, 83.0, 52.6, 38.6, 34.1, 31.8, 31.2, 30.0, 28.1, 27.1, 22.4, 19.6, 13.8.
MS (EI): m/z (%) = 195.15 [M+ - MsOH], 98.06 (100), 96.13, 55.05.
Anal. Calcd for C13H25NO4S: C, 53.58; N, 4.81; H, 8.65. Found: C, 53.34; N, 4.80; H, 8.53.
(3 S ,8a R )-3-Butylhexahydroindolizin-5(1 H )-one (12)
KOt-Bu (18 mg, 0.16 mmol) was added to a soln of mesylate 11 (160 mg, 0.55 mmol) in THF (3 mL) and the mixture was stirred for 1 h. The solvent was evaporated and distilled H2O (5 mL) was added. The mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated to give 12 (84 mg, 78%) as a colorless liquid; R f = 0.38 (EtOAc).
[α]D ²5 +45.48 (c 1.12, CH2Cl2).
IR (NaCl): 3000, 2953, 2987, 2868, 1643, 1446 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.8 Hz, 3 H), 1.16-1.39 (m, 6 H), 1.60-1.79 (m, 4 H), 1.85-2.08 (m, 4 H), 2.25-2.36 (m, 2 H), 3.29-3.44 (m, 1 H), 3.90-4.00 (m, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 169.2, 59.8, 57.1, 32.3, 31.3, 30.9, 29.2, 28.7, 27.4, 22.6, 21.1, 14.0.
MS (EI): m/z (%) = 195.12 [M]+, 166.16, 152.16, 138.13 (100), 96.22.
HRMS (EI): m/z [M]+ calcd for C12H21NO: 195.1618; found: 195.1616.
(-)-Monomorine I (1)
A 3 M soln of MeMgBr in Et2O (0.1 mL, 0.3 mmol) was added dropwise to a soln of bicyclic lactam 12 (20 mg, 0.1 mmol) in THF. The mixture was heated at reflux for 5 h under N2 and then cooled to r.t. AcOH (0.2 mL, 3.53 mmol) was added dropwise and the mixture was stirred for 1 h. NaBH4 was added to the mixture at 0 ˚C, and the mixture was stirred for 3 h. Sat. aq NaHCO3 (5 mL) was added and the mixture was extracted with CHCl3 (3 × 5 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (alumina, EtOAc-MeOH, 95:5) to afford monomorine I (1) (12 mg, 60%) as a light yellow oil; R f = 0.44 (EtOAc).
[α]D ²5 -35.5 (c 1.00, CH2Cl2).
IR (NaCl): 3000, 2957, 2860, 1612, 1454, 1379 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.6 Hz, 3 H, CH3), 1.12 (d, J = 6.3 Hz, 3 H), 1.17-1.57 (m, 10 H), 1.60-1.88 (m, 6 H), 2.0-2.11 (m, 1 H), 2.13-2.27 (m, 1 H), 2.48-2.53 (m, 1 H).
¹³C NMR (75 MHz, CDCl3): δ = 67.2, 62.9, 60.3, 39.6, 35.7, 30.8, 30.3, 29.7, 29.4, 24.9, 22.9, 22.8, 14.1.
MS (EI): m/z (%) = 196.23 [M + H]+, 180.22, 138.16 (100), 124.29, 98.22.
HRMS (EI): m/z [M]+ calcd for C13H25N: 195.1982; found: 195.1987.
Acknowledgment
We thank the Singapore Ministry of Education Academic Research Fund Tier 2 (grant T206B1220RS) and Nanyang Technological University for generous support of this work.
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Variability in this material has been reported:
Bates RW.Boonsombat J. Org. Biomol. Chem. 2005, 3: 520 - 10b
Ikawa T.Sajiki H.Hirota K. Tetrahedron 2004, 60: 6189 - 11 Oxazine 9,
in its racemic form, is an intermediate in Kibayashi’s
synthesis of monomorine I:
Watanabe Y.Iida H.Kibayashi C. J. Org. Chem. 1989, 54: 4088 ; but carried through to the natural product by a different sequence - 12
Rylander PN. Hydrogenation Methods Academic Press; London: 1985. - 13
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Enantiomeric excess was determined by chiral HPLC on an OD-H column (hexane-i-PrOH, 95:5).
15Model studies were carried out on the racemic compound.
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Nagasaka T.Kato H.Hayashi H.Shioda M.Hikasa H.Hamagichi F. Heterocycles 1990, 30: 561 - (ah)
Ito M.Kibayashi C. Tetrahedron 1990, 31: 5065 - (ai)
Tokuyama T.Jefford CW.Tang Q.Zaslona A. Helv. Chim. Acta 1989, 72: 1749 - (aj)
Yamazaki N.Kibayashi C. J. Am. Chem. Soc. 1989, 111: 1396 - (ak)
Yamaguchi R.Hata EI.Matsuki T.Kawanisi M. J. Org. Chem. 1987, 52: 2094 - (al)
Iida H.Watanabe Y.Kibayashi C. Tetrahedron Lett. 1986, 27: 5513 - (am)
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Royer J.Huson HP. J. Org. Chem. 1985, 50: 670 - (ap)
Sonnet PE.Oliver JE. J. Heterocycl. Chem. 1975, 12: 289 - (aq)
Oliver JE.Sonnet PE. J. Org. Chem. 1974, 39: 2662 - 4
Stevens RV.Lee AWM. J. Chem. Soc., Chem. Commun. 1982, 102 - 5
Yuguchi M.Tokuda M.Orito K. Bull. Chem. Soc. Jpn. 2004, 77: 1031 - 6
Bates RW.Snell RH.Winbush SA. Synlett 2008, 1042 - 7
Tokunaga M.Larrow JF.Kakiuchi F.Jacobsen EN. Science 1997, 277: 936 - 8
Grochowski E.Jurczak J. Synthesis 1976, 682 - We previously reported similar transformations which proceeded satisfactorily with Pd/C:
- 10a The difference is likely
to be due to the different batches and suppliers of Pd/C.
Variability in this material has been reported:
Bates RW.Boonsombat J. Org. Biomol. Chem. 2005, 3: 520 - 10b
Ikawa T.Sajiki H.Hirota K. Tetrahedron 2004, 60: 6189 - 11 Oxazine 9,
in its racemic form, is an intermediate in Kibayashi’s
synthesis of monomorine I:
Watanabe Y.Iida H.Kibayashi C. J. Org. Chem. 1989, 54: 4088 ; but carried through to the natural product by a different sequence - 12
Rylander PN. Hydrogenation Methods Academic Press; London: 1985. - 13
Fones WS. J. Org. Chem. 1949, 14: 1099 - 14a
Janza B.Studer A. J. Org. Chem. 2005, 70: 6991 - 14b
Cooke MP.Houpis N. Tetrahedron Lett. 1985, 26: 4987
References
Enantiomeric excess was determined by chiral HPLC on an OD-H column (hexane-i-PrOH, 95:5).
15Model studies were carried out on the racemic compound.
Figure 1 (-)-Monomorine I
Scheme 1 (-)-Monomorine I retrosynthesis
Scheme 2 Diene synthesis
Scheme 3 Tandem reactions
Scheme 4 Monomorine synthesis