Total synthesis of (±)-lycoposerramine-R, a novel skeletal type of Lycopodium alkaloid

Tetrahedron 71 (2015) 51e56

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Total synthesis of (
)-lycoposerramine-R, a novel skeletal type of Lycopodium alkaloid Hiroaki Ishida y, Shinya Kimura y, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama * Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 October 2014 Received in revised form 13 November 2014 Accepted 14 November 2014 Available online 20 November 2014

The total synthesis of (
)-lycoposerramine-R, a novel skeletal type of Lycopodium alkaloid, was accomplished via the DielseAlder reaction, the stereoselective introduction of a methyl group, the regioand stereoselective reductive amination, and the construction of a pyridone ring. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Lycopodium Lycoposerramine-R Pyridone

1. Introduction Plants from the genus Lycopodium (Lycopodiaceae) have long been studied because of the immense number of alkaloids, the socalled Lycopodium alkaloids,1 isolated from them. Those alkaloids have unique structures and biological activities, such as acetylcholine esterase (AchE) inhibitory activity,2 and are anticipated to treat Alzheimer’s disease and to improve geriatric memory loss. Because of this, Lycopodium alkaloids have continued to attract the attention of researchers in natural product chemistry, synthetic chemistry, and medicinal chemistry.3 In the course of our chemical and synthetic studies on Lycopodium alkaloids,4 we have reported the isolation and structure elucidation of a novel skeletal type of Lycopodium alkaloid, lycoposerramine-R (1), from Lycopodium serratum in 2009.4e Lycoposerramine-R (1) possesses a unique tetracyclic ring system containing a pyridone ring, a 5/6 cis fused ring, and four asymmetric centers (Fig. 1). To date, only the racemic total synthesis of lycoposerramine-R (1) by Bisai and Sarpong has been reported.3s Herein we report the second and independent total synthesis of lycoposerramine-R (1).

stage by transformation of tricyclic key intermediate 2, which could be derived from diketone 3 by regioselective reductive amination. Diketone 3 could be obtained from enone 4 via a stereoselective addition of a methyl group and the Wharton rearrangement. Enone 4 could be synthesized via the DielseAlder reaction of dienophile 5 with diene 6.5 We embarked on the synthesis of key intermediate 2 (Scheme 2). The DielseAlder reaction of dienophile 5, which was prepared by reacting benzyl N-allylcarbamate with 2-iodo-2-cyclopentenone6 under the SuzukieMiyaura coupling conditions, with aminosiloxydiene 6 in the presence of dibutylhydroxytoluene (BHT) followed by acid hydrolysis afforded enone 4 in a quantitative yield. Our next task was the diastereoselective introduction of a methyl group at C-15. Enone 4 was treated with hydrogen peroxide to give an epoxide, which was then subjected to Wharton rearrangement conditions.7 IBX oxidation of the resultant allylic alcohol produced enone 7. The stereoselective introduction of a methyl group at C-15

O 1

HN

2. Results and discussion Our synthetic plan for lycoposerramine-R (1) is shown in Scheme 1. The pyridone ring in 1 could be constructed at the last * Corresponding author. E-mail address: [email protected] (H. Takayama). y H. Ishida and S. Kimura contributed equally to this work. http://dx.doi.org/10.1016/j.tet.2014.11.038 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

5 8

H

7

12

N 9 13 H H Me H lycoposerramine-R (1) 15

Fig. 1. Structure of lycoposerramine-R (1).

52

H. Ishida et al. / Tetrahedron 71 (2015) 51e56

O 1

HN 4

5 7

H

5

construction of pyridone ring

allylMgBr

12

7 15

H Me

N

H H Me H lycoposerramine-R (1)

H Me

Cbz

H

N

H

N

13

O

4

H

THF, rt 85%

Cbz

H

H 8

O

O 4

5

2) NaBH(OAc) 3 AcOH, THF, rt Me

13 12

7

H

rearrangement

15

H Me

N Cbz

3) allylMgBr THF, rt N

H

3

Me

H

O

4

1) Pd-C, H 2 MeOH, rt

O

O

4

H 2) CbzCl H Na 2CO3 Me H CH 2Cl 2, H 2O rt 9 63% (2 steps)

NHCbz

stereoselective introduction of methyl group

OH

1) KOH, EtOH rt to reflux

O

N H Me

2

2 NHCbz

reductive amination

O

4

H

12

15

O

4

4) CbzCl, Na 2CO3 CH2Cl 2, H 2O, rt 45% (4 steps)

H

H 10

Scheme 3. Synthesis of allyl compound 9.

3 O NHCbz

NHCbz Diels-Alder reaction

O

5 OTBS

O

H

Me 2N

4

6

Scheme 1. Retrosynthetic analysis of lycoposerramine-R (1).

BHT, neat 40 °C ; 1N HCl, THF

NMe 2

O NHCbz

O 4

quant.

7

OTBS 5

NHCbz

9

NHCbz

MeMgCl, CuI LiBr·H 2O TMSCl, –78 °C

O

O

O

13

89% dr = 7:1

3) IBX, AcOEt, 60 °C 98%

Me

H

7

84% (3 steps)

15

7

H

1) Pd-C, H 2, MeOH, rt 2) NaBH(OAc) 3, AcOH THF, rt 3) CbzCl, Na 2CO3 CH2Cl 2, H 2O, rt

O 4

NHCbz O

15

H

6

1) H 2O 2 aq, NaOH aq MeOH, rt, quant. 2) NH 2NH 2·H 2O, AcOH MeOH, reflux, 59%

12

bromide in THF gave unexpected carbamate 8, which was formed by the cyclization between the resultant alkoxide and the carbonyl group of the carbobenzyloxy (Cbz) group on the nitrogen function. Thus obtained carbamate 8 was treated with KOH in EtOH followed by Cbz re-protection of the secondary amine to afford allyl compound 9. To shorten the synthetic route to 9, diketone 3 was subjected to reductive amination to give tricyclic amine 10, which was directly allylated followed by Cbz protection to yield allyl compound 9 in 45% yield in four steps from 3. To construct the pyridone ring, we next introduced oxygen functions at C-1 and C-5 positions in 9 (Scheme 4). Allyl compound 9 was converted into diene 11 via regioselective dehydration with SOCl2 in pyridine.9 The hydroboration reactions of terminal (C-1eC-2) and endo (C-4eC-5) olefins in 11 were, respectively, achieved by treating 11 with 9-BBN and then with BH3$THF in THF. Subsequent oxidation afforded diol 12 as a single diastereomer.10 The construction of the pyridone ring was accomplished by Jones’ oxidation of diol 12 followed by treatment of resultant 5-oxocarboxylic acid 13 with NH2OMe$HCl in AcOH to produce pyridone 14. Finally, deprotection of the Cbz group in 14 gave lycoposerramine-R (1). Synthetic 1 was identified by directly comparing its chromatographic behavior and UV, 1H NMR, 13C NMR, and mass spectra with those of the natural compound except for the optical property.

dif. NOE

3

OH

5 4

N

O 5

5

Cbz

13 7

12

7 15

Me

H

H

15

H Me

H Me

2

H

HO

dif. NOE

Cbz

2

CH 2Cl 2 0 °C to rt 65%

N

H H Me

Cbz

H

O OH 1) CrO3, H 2SO 4 H 2O

N

O 54

1

H Me

H

Cbz

13

O 1

HN

HN 5

H 2, Pd/C

H

N H Me

OH

N

H

acetone, 0 °C

12

O

3) H 2O 2 aq, 2N NaOH aq 25 °C 39% (3 steps)

Cbz

H

1

Scheme 2. Synthesis of tricyclic key intermediate 2.

H Me

1) 9-BBN, THF, rt 2) BH 3· THF, rt

11

5 4

H

1

2

4

9

Cbz

was achieved by treating enone 7 with the organocuprate prepared from MeMgCl, CuI, and LiBr$H2O8 to afford separable diketone 3 and its 15-epimer in 89% total yield with dr¼7:1. The relative stereochemistry at C-15 in 3 was confirmed by NOE correlation of the methyl protons to H-7. Reductive amination of diketone 3 followed by Cbz protection afforded tricyclic key intermediate 2 in a regioand stereoselective manner. The desired stereochemistry at C-13 in 2 was confirmed from NOE correlation of the methyl protons to H-13. Having succeeded in the synthesis of tricyclic intermediate 2, we attempted to introduce a C-3 unit at C-4 position in 2 to construct the pyridone ring (Scheme 3). Treatment of 2 with allylmagnesium

5

SOCl2, py

H

N

13

1

N

H

O 12

2

3

H 14

Cbz

MeOH, rt quant

H

N H Me

H

H

lycoposerramine-R (1) Scheme 4. Synthesis of lycoposerramine-R (1).

2) NH 2OMe·HCl AcOH sealed tube 12% (2 steps)

H. Ishida et al. / Tetrahedron 71 (2015) 51e56

In conclusion, we have achieved the total synthesis of lycoposerramine-R (1) in 15 steps, including the DielseAlder reaction, the stereoselective introduction of a methyl group, the regio- and stereoselective reductive amination, and the construction of a pyridone ring. The asymmetric total synthesis of lycoposerramine-R to establish its absolute configuration is under way in our laboratory.

53

d 7.38e7.34 (5H, overlapped, eNHCO2CH2C6H5), 6.32 (1H, d,

3. Experimental section

J¼10.3 Hz, H-13), 6.05 (1H, d, J¼10.0 Hz, H-14), 5.09 (2H, s, -NHCO2CH2C6H5), 4.88 (1H, br s, eNHCO2CH2C6H5), 3.19 (2H, t, J¼6.5 Hz, H2-9), 2.68 (2H, overlapped), 2.47 (2H, overlapped), 2.26 (1H, m), 2.09 (1H, m), 1.70 (4H, overlapped), 1.46 (1H, m). 13C NMR (CDCl3, 100 MHz) d 216.8, 196.8, 156.3, 147.5, 136.4, 130.2, 128.5, 128.2, 128.1, 66.7, 54.8, 41.0, 38.3, 38.2, 37.8, 32.5, 25.5, 25.4. IR (ATR) nmax cm1 3333, 2933, 1715, 1672, 1627, 1244, 1207. HRESIMS m/z 364.1543 [MþNa]þ (calcd for C20H23NO4Na 364.1525).

3.1. General experimental procedures

3.3. Synthesis of enone 7

IR: recorded on a JASCO FT/IR-230 spectrophotometer. UV: recorded in MeOH on a JASCO V-560 instrument. 1H and 13C NMR spectra: recorded on JEOL JNM ECP-400, JNM ECP-600, JNM ECS400, and ECA-600. J values are given in Hz. EIMS: direct probe insertion at 70 eV recorded on a JEOL GC-mate. ESIMS and HRESIMS: recorded on a Thermo Fisher Scientific Exactive spectrometer and JEOL JMS-T100LP. TLC: precoated silica gel 60 F254 plates (Merck, 0.25 mm thick). Column chromatography: silica gel 60 [Kanto Chemical, 40e50 mm (for flash column chromatography)] and Chromatorex NH [Fuji Silysia Chemical Ltd., 100e200 mesh (for amino-silica gel open column chromatography)]. Medium pressure liquid chromatography (MPLC): C. I. G. prepacked column CPS-HS221-05 (Kusano Kagakukikai, SiO2).

3.3.1. Synthesis of epoxide. To a stirred solution of 4 (20.0 mg, 0.059 mmol) in MeOH (0.2 mL) were slowly added 30% aqueous H2O2 solution (26 mL, 0.234 mmol) and 1.5 M aqueous NaOH solution (12 mL, 0.018 mmol) at 0  C under argon atmosphere. After stirring for 3 h at room temperature, ice and brine were successively added to the reaction mixture and the resultant mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine and then with saturated aqueous Na2S2O3 solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc) and then by MPLC (SiO2, EtOAc/nhexane¼1:1) to afford epoxide (21.7 mg, quant.) as a pale yellow oil. Epoxide: 1H NMR (CDCl3, 400 MHz) d 7.37e7.30 (5H, overlapped, eNHCO2CH2C6H5), 5.08 (2H, s, eNHCO2CH2C6H5), 4.87 (1H, br s, eNHCO2CH2C6H5), 3.50 (1H, d, J¼3.8 Hz) and 3.30 (1H, d, J¼3.8 Hz) (H-13, H-14), 3.17 (2H, q, J¼5.9 Hz, H2-9), 2.72 (1H, dd, J¼15.0, 9.2 Hz), 2.60 (1H, q, J¼7.2 Hz, H-7), 2.51 (1H, m), 2.36e2.27 (2H, overlapped), 2.11 (1H, m), 1.85 (1H, m), 1.63e1.56 (3H, overlapped), 1.43 (1H, m). 13C NMR (CDCl3, 100 MHz) d 218.3, 206.4, 156.3, 136.4, 128.5, 128.2, 128.1, 66.7, 63.0, 54.6, 50.5, 40.9, 40.8, 38.4, 36.9, 31.3, 27.1, 25.0. IR (ATR) nmax cm1 1709, 1524. HRESIMS m/z 380.1482 [MþNa]þ (calcd for C20H23NO5Na 380.1474).

3.2. Synthesis of enone 4 3.2.1. Synthesis of dienophile 5. To a stirred solution of benzyl Nallylcarbamate (1.30 g, 6.80 mmol) in degassed THF (14 mL) was added a degassed solution of 9-BBN (0.5 M in THF, 18.1 mL, 9.04 mmol) at room temperature under argon atmosphere. After stirring for 4 h at the same temperature, degassed H2O (2.8 mL) was added to the reaction mixture. The resultant mixture was transferred via a cannula to a solution of 2-iodo-2-cyclopentenone (929 mg, 4.46 mmol), PdCl2(dppf) (181 mg, 0.223 mmol), Ph3As (70 mg, 0.223 mmol), and Cs2CO3 (2.18 g, 6.69 mmol) in degassed DMF (46 mL) at room temperature under argon atmosphere. After stirring for 17 h at the same temperature, saturated aqueous NH4Cl solution was added and the resultant mixture was diluted with EtOAc. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc/n-hexane¼1:1) to afford 5 (781 mg, 77%) as a pale yellow oil. Compound 5: 1H NMR (CDCl3, 400 MHz) d 7.36e7.29 (6H, overlapped, eNHCO2CH2C6H5, H-3), 5.09 (2H, s, eNHCO2CH2C6H5), 5.04 (1H, br s, eNHCO2CH2C6H5), 3.18 (2H, q, J¼6.6 Hz, H2-8), 2.56 (2H, m), 2.40 (2H, m), 2.22 (2H, t, J¼7.1 Hz), 1.70 (2H, quin, J¼7.2 Hz). 13C NMR (CDCl3, 100 MHz) d 210.2, 158.5, 156.4, 145.3, 136.5, 128.5, 128.1, 128.0, 66.5, 40.3, 34.5, 28.1, 26.5, 21.8. IR (ATR) nmax cm1 3331, 1686. EIMS m/z (%) 273 (Mþ, 4), 91 (100). 3.2.2. Synthesis of enone 4. To a stirred mixture of 5 (50 mg, 0.183 mmol) and 6 (125 mg, 0.551 mmol) was added BHT (40 mg, 0.183 mmol) at room temperature under argon atmosphere, and the mixture was stirred for 38 h at 40  C. After cooling to room temperature, the reaction mixture was dissolved in THF (0.9 mL) and 1 N aqueous HCl solution (0.45 mL) was added to the mixture at 0  C. After stirring for 3 h at room temperature, saturated aqueous NaHCO3 solution was added to the reaction mixture and the resultant mixture was diluted with EtOAc. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (SiO2, EtOAc/CHCl3¼1:4) to afford 4 (64.5 mg, quant) as a yellow oil. Compound 4: 1H NMR (CDCl3, 400 MHz)

3.3.2. Synthesis of allyl alcohol. To a stirred solution of the above epoxide (8.9 mg, 0.025 mmol) in MeOH (1.0 mL) were added NH2NH2$H2O (1.2 mL, 0.025 mmol) and AcOH (1.4 mL, 0.025 mmol) at 0  C under argon atmosphere. After stirring for 3 h at 100  C, H2O was added to the reaction mixture and the resultant mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by MPLC (SiO2, EtOAc/n-hexane¼3:2) to afford allyl alcohol (5.1 mg, 59%) as a pale yellow oil. Allyl alcohol: 1H NMR (CDCl3, 400 MHz) d 7.38e7.29 (5H, overlapped, eNHCO2CH2C6H5), 5.83 (2H, s, H-14, H-15), 5.09 (2H, s, eNHCO2CH2C6H5), 4.85 (1H, br s, eNHCO2CH2C6H5), 3.90 (1H, d, J¼6.3 Hz, H-13), 3.14 (2H, m, H2-9), 2.34e2.30 (3H, overlapped), 2.20e2.09 (2H, overlapped), 1.96e1.90 (2H, overlapped), 1.65e1.31 (4H, overlapped). 13C NMR (CDCl3, 100 MHz) d 223.2, 156.4, 136.6, 128.5, 128.09, 128.05, 127.7, 127.4, 68.7, 66.6, 54.1, 41.2, 38.5, 35.4, 29.8, 26.2, 26.1, 25.2. IR (ATR) nmax cm1 3350, 1696, 1527. HRESIMS m/z 366.1678 [MþNa]þ (calcd for C20H25NO4Na 366.1681). 3.3.3. Synthesis of enone 7. To a stirred solution of the above allyl alcohol (115.1 mg, 0.335 mmol) in EtOAc (2.4 mL) was added IBX (187.7 mg, 0.670 mmol) at 0  C under argon atmosphere. After stirring for 8.5 h at 60  C, the reaction mixture was diluted with EtOAc. The resultant mixture was filtered through a pad of CeliteÒ, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc) and then by MPLC (SiO2, EtOAc/n-hexane¼7:3) to afford 7 (111.9 mg, 98%) as a pale yellow oil. Compound 7: 1H NMR (CDCl3, 400 MHz) d 7.38e7.30 (5H, overlapped, eNHCO2CH2C6H5), 6.86 (1H, m, H-15), 6.05 (1H, d, J¼10.5 Hz, H-14), 5.08 (2H, s,

54

H. Ishida et al. / Tetrahedron 71 (2015) 51e56

eNHCO2CH2C6H5), 4.87 (1H, br s, eNHCO2CH2C6H5), 3.15 (2H, m, H2-9), 2.71 (1H, m), 2.62 (1H, m), 2.42e2.34 (2H, overlapped), 2.21e2.05 (2H, overlapped), 1.90e1.77 (3H, overlapped), 1.58 (1H, m), 1.40 (1H, m). 13C NMR (CDCl3, 100 MHz) d 212.4, 193.5, 156.4, 147.3, 136.5, 128.5, 128.1, 66.6, 64.4, 40.9, 38.3, 35.9, 29.8, 26.8, 25.2, 24.6. IR (ATR) nmax cm1 1699, 1673, 1526. HRESIMS m/z 364.1521 [MþNa]þ (calcd for C20H23NO4Na 364.1525). 3.4. Synthesis of diketone 3 A round-bottomed flask was charged with CuI (42.9 mg, 0.409 mmol) and LiBr$H2O (77.8 mg, 0.409 mmol), fitted with a rubber septum, evacuated on heating with stirring, and then backfilled with argon. THF (0.4 mL) was added to the flask and the mixture was cooled to 78  C. MeMgCl (3 M in THF, 128 mL, 0.383 mmol) was slowly added to the cooled mixture at 78  C. After adding a solution of 7 (43.6 mg, 0.128 mmol) in dry THF (2.0 mL) at 78  C, TMSCl (45 mL, 0.358 mmol) was immediately added dropwise at the same temperature, and the reaction mixture was stirred for 2 h at 78  C. After adding H2O at 0  C, the resultant mixture was stirred for 30 min at the same temperature. Then, saturated aqueous NH4Cl solution was added and the resultant mixture was stirred for 5 min at room temperature. The mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc) to afford 3 and its 15-epimer (total 40.7 mg, 89%, dr¼7:1), which was purified by MPLC (SiO2, EtOAc/n-hexane¼9:11) to give pure 3 as a colorless oil. Compound 3: 1H NMR (CDCl3, 400 MHz) d 7.38e7.29 (5H, overlapped, eNHCO2CH2C6H5), 5.09 (2H, s, eNHCO2CH2C6H5), 4.91 (1H, br s, eNHCO2CH2C6H5), 3.18 (2H, q, J¼6.3 Hz, H2-9), 2.51 (1H, m), 2.39 (1H, ddd, J¼19.4, 9.2, 2.7 Hz), 2.30e2.07 (4H, overlapped), 1.94 (1H, m), 1.80e1.66 (5H, overlapped), 1.34e1.24 (2H, m), 1.04 (3H, d, J¼6.1 Hz). 13C NMR (CDCl3, 100 MHz) d 215.2, 208.9, 156.4, 136.5, 128.5, 128.1, 128.0, 66.6, 60.4, 46.9, 42.1, 40.9, 35.9, 32.8, 30.2, 28.3, 25.0, 23.8, 21.6. IR (ATR) nmax cm1 1742, 1695, 1523. HRESIMS m/z 380.1822 [MþNa]þ (calcd for C21H27NO4Na 380.1838). 3.5. Synthesis of tricyclic key intermediate 2 To a solution of 3 (899.3 mg, 2.516 mmol) in MeOH (25 mL) was added 10% PdeC (267.8 mg) at room temperature. The reaction mixture was stirred under 1.0 atm pressure of hydrogen atmosphere for 1.5 h at room temperature. The reaction mixture was diluted with EtOAc and the resultant mixture was filtered through a pad of CeliteÒ. The filtrate was concentrated to afford the crude product of tricyclic imine, which was used for the next reaction without further purification. Tricyclic imine (crude): 1H NMR (CDCl3, 400 MHz) d 3.81 (1H, dd, J¼17.5, 5.1 Hz, H-9), 3.49 (1H, ddd, J¼16.5, 11.3, 5.2 Hz, H-9), 2.48e2.32 (3H, overlapped), 2.32e2.20 (4H, overlapped), 1.94 (1H, m), 1.72e1.63 (3H, overlapped), 1.59 (1H, m), 1.55e1.46 (2H, overlapped), 0.94 (3H, d, J¼6.9 Hz). 13C NMR (CDCl3, 100 MHz). d 215.8, 167.2, 56.4, 48.7, 43.4, 42.5, 35.5, 32.4, 29.3, 28.6, 24.0, 17.9, 17.5. IR (ATR) nmax cm1 1731, 1651. To a stirred solution of the above crude product of tricyclic imine in THF (11 mL) were added NaBH(OAc)3 (800.0 mg, 3.774 mmol) and AcOH (144 mL, 2.516 mmol) at 0  C under argon atmosphere. After stirring for 11 h at room temperature, 1 N aqueous NaOH solution was added to the reaction mixture. The resultant mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material thus obtained was dissolved in CH2Cl2 (79 mL) and then a solution of Na2CO3 (2.667 g, 25.16 mmol) in H2O (63 mL) was added to the mixture. After vigorously stirring for 10 min at room temperature,

CbzCl (1.1 mL, 7.548 mmol) was added to the mixture at 0  C and the reaction mixture was stirred for 4 h at room temperature. After adding CHCl3 and saturated aqueous NaHCO3 solution, the organic phase was separated. The aqueous phase was extracted three times with CHCl3. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc/CHCl3¼1:5) to afford 2 (721.9 mg, 84% in 3 steps) as a pale yellow oil. Compound 2: 1H NMR (CDCl3, 400 MHz) d 7.40e7.26 (5H, overlapped, eNHCO2CH2C6H5), 5.24 (1H, d, J¼12.6 Hz, eNHCO2CH2C6H5), 5.10 (1H, d, J¼12.6 Hz, eNHCO2CH2C6H5), 4.35 (1H, m, H-9), 3.37 (1H, dd, J¼13.5, 3.7 Hz, H-13), 2.74 (1H, ddd, J¼13.0, 13.0, 2.6 Hz, H-9), 2.42 (1H, ddd, J¼13.5, 13.5, 4.0 Hz), 2.36e2.30 (2H, overlapped), 2.17e2.06 (3H, overlapped), 2.04 (1H, m), 1.94 (1H, m), 1.71 (1H, m), 1.52e1.24 (5H, overlapped), 1.01 (3H, d, J¼7.3 Hz, H3-16). 13C NMR (CDCl3, 100 MHz) d 217.5, 155.9, 137.5, 128.3, 127.8, 127.5, 66.5, 58.1, 53.1, 48.5, 40.6, 34.72, 34.68, 34.6, 33.4, 27.8, 23.2, 21.5, 16.6. IR (ATR) nmax cm1 1731, 1711, 1683. HRESIMS m/z 364.1871 [MþNa]þ (calcd for C21H27NO3Na 364.1889). 3.6. Synthesis of carbamate 8 To a stirred solution of 2 (61.7 mg, 0.181 mmol) in THF (0.6 mL) was slowly added allylmagnesium bromide (1.0 M in Et2O, 0.22 mL, 0.217 mmol) at 0  C under argon atmosphere, and the resultant mixture was stirred for 1.5 h at room temperature. After adding saturated aqueous NH4Cl solution at 0  C, the resultant mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc/n-hexane¼0:1e3:7) to yield 8 (42.2 mg, 85%) as a colorless solid. Compound 8: 1H NMR (CDCl3, 400 MHz) d 6.05 (1H, m, H-2), 5.20 (1H, ddd, J¼10.1, 1.6, 1.6 Hz, H-1), 5.12 (1H, dd, J¼16.9, 0.9 Hz, H-1), 3.96 (1H, dd, J¼13.1, 6.6 Hz, H-9), 3.12 (1H, ddd, J¼12.7, 12.7, 3.8 Hz, H-9), 2.94 (1H, dd, J¼13.3, 6.7 Hz, H-13), 2.60 (1H, ddd, J¼14.2, 4.6, 1.8 Hz), 2.26 (2H, overlapped), 2.05e1.94 (4H, overlapped), 1.93e1.82 (2H, overlapped), 1.81e1.68 (2H, overlapped), 1.62 (1H, m), 1.47 (1H, dd, J¼13.7, 8.2 Hz), 1.40e1.37 (2H, overlapped), 1.30 (1H, m), 1.01 (3H, d, J¼6.4 Hz, H3-16). 13C NMR (CDCl3, 150 MHz) d 161.6, 133.2, 118.8, 95.1, 60.9, 54.6, 45.6, 43.4, 40.3, 37.3, 34.12, 34.06, 31.1, 27.2, 24.6, 24.5, 23.0. IR (ATR) nmax cm1 2923, 1696, 1474, 1344, 1245, 1218. ESIMS m/z 298 [MþNa]þ, 254 [M-CO2þNa]þ. HRESIMS m/z 254.1877 [M-CO2þNa]þ (calcd for C16H25NNa 254.1885). 3.7. Synthesis of allyl compound 9 from carbamate 8 Compound 8 (4.0 mg, 0.015 mmol) was dissolved in a solution of KOH (47.4 mg, 0.726 mmol) in EtOH (1.0 mL) at 0  C under argon atmosphere. The reaction mixture was stirred for 1.5 h at room temperature and for 2 h at 40  C, and then refluxed for 12 h. After the reaction mixture was concentrated, the resultant crude material was dissolved in CH2Cl2 (0.6 mL) and then H2O (0.4 mL) was added and the mixture was stirred vigorously for 10 min at room temperature. CbzCl (2.6 mL, 0.017 mmol) was added to the stirred mixture at 0  C and the reaction mixture was stirred for 2 h at room temperature. After adding CHCl3 and saturated aqueous NaHCO3 solution, the resultant mixture was extracted three times with CHCl3. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc/n-hexane¼2:25) to give 9 (3.5 mg, 63% in 2 steps) as a colorless oil. Compound 9: 1H NMR (CDCl3, 400 MHz) d 7.40e7.28 (5H, overlapped, eNHCO2CH2C6H5), 5.95 (1H, dddd, J¼19.2, 10.3, 6.9, 6.9 Hz, H-2), 5.16 (1H, d, J¼12.4 Hz,

H. Ishida et al. / Tetrahedron 71 (2015) 51e56

55

-NHCO2CH2C6H5), 5.11 (1H, d, J¼12.4 Hz, eNHCO2CH2C6H5), 5.01 (1H, dd, J¼10.1, 1.6 Hz, H-1), 4.91 (1H, dd, J¼17.0, 1.6 Hz, H-1), 4.29 (1H, dd, J¼13.5, 5.9 Hz, H-9), 4.00 (1H, br s, OH), 3.36 (1H, dd, J¼13.5, 5.1 Hz, H-13), 3.16 (1H, ddd, J¼13.2, 13.2, 6.6 Hz, H-9), 3.03 (1H, ddd, J¼13.0, 13.0, 4.0 Hz), 2.26 (1H, m), 2.20 (2H, d, J¼6.6 Hz), 1.98e1.71 (7H, overlapped), 1.51e1.21 (5H, overlapped), 1.01 (3H, d, J¼7.0 Hz, H3-16). 13C NMR (CDCl3, 150 MHz) d 156.0, 136.5, 135.9, 128.6, 128.1, 127.9, 116.4, 84.9, 67.0, 61.8, 51.4, 49.9, 47.4, 46.6, 38.0, 37.8, 34.5, 33.2, 27.0, 26.6, 24.3, 19.6. IR (ATR) nmax cm1 3413, 1672. HRESIMS m/z 406.2311 [MþNa]þ (calcd for C24H33NO3Na 406.2358).

5.01e4.92 (2H, overlapped, H2-1), 4.47 (1H, m, H-9), 3.35 (1H, dd, J¼13.7, 3.2 Hz, H-13), 3.03 (1H, m), 2.84 (1H, ddd, J¼13.0, 13.0, 2.9 Hz, H-9), 2.45 (1H, m), 2.26 (1H, ddd, J¼3.5, 13.5, 5.0 Hz), 2.06 (1H, m), 2.01e1.92 (3H, overlapped), 1.77 (1H, m), 1.62 (1H, m), 1.55e1.21 (4H, overlapped), 0.97 (3H, d, J¼7.3 Hz, H3-16). 13C NMR (CDCl3, 150 MHz) d 154.5, 147.5, 137.1, 136.7, 128.4, 128.0, 127.8, 125.5, 115.4, 66.5, 59.8, 53.3, 48.6, 44.6, 39.9, 35.6, 35.3, 34.5, 34.1, 27.6, 23.6,18.1. IR (ATR) nmax cm1 1682. ESIMS m/z 388 [MþNa]þ. HRESIMS m/z 366.2416 [MþH]þ (calcd for C24H32NO2 366.2433).

3.8. Synthesis of allyl compound 9 from diketone 3

To a stirred solution of 11 (39.1 mg, 0.107 mmol) in THF (0.4 mL) was added 9-BBN (0.5 M in THF, 0.64 mL, 0.321 mmol) at 0  C under argon atmosphere. After stirring for 4 h at room temperature, the mixture was treated with an additional amount of BH3$THF (1 M in THF, 0.68 mL, 0.642 mmol), and the resultant mixture was stirred for 10 h at room temperature. After adding 30% aqueous H2O2 solution (0.7 mL, 6.418 mmol) and 2 N aqueous NaOH solution (2.41 mL, 4.818 mmol), the resultant mixture was stirred for 6 h at 25  C. Saturated aqueous Na2S2O3 solution was added to the mixture. After stirring for 40 min at 25  C, the mixture was extracted five times with 10% MeOH/CHCl3. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOEt) and then by MPLC (SiO2, MeOH/ CHCl3¼1:9) to give 12 (16.6 mg, 39%) as a colorless oil. Compound 12: 1H NMR (CDCl3, 400 MHz) d 7.36e7.29 (5H, overlapped, -NHCO2CH2C6H5), 5.07 (2H, s, -NHCO2CH2C6H5), 4.38 (1H, m, H-9), 4.26 (1H, ddd, J¼7.5, 7.5, 3.8 Hz, H-5), 3.54 (2H, m, H2-1), 3.30 (1H, ddd, J¼13.7, 4.1 Hz, H-13), 2.82 (1H, ddd, J¼13.0, 13.0, 2.9 Hz, H-9), 2.65 (1H, ddd, J¼13.7, 13.7, 5.0 Hz), 2.16 (2H, overlapped), 2.03 (1H, m), 1.92e1.61 (8H, overlapped), 1.51e1.23 (5H, overlapped), 0.99 (3H, d, J¼7.3 Hz, H3-16). 13C NMR (CDCl3, 150 MHz) d 154.4, 137.1, 128.4, 127.9, 127.8, 80.8, 66.5, 62.8, 61.5, 54.0, 49.4, 48.6, 43.0, 41.7, 39.2, 35.6, 34.1, 32.1, 30.1, 27.8, 22.9, 17.3. IR (ATR) nmax cm1 3428, 1684. HRESIMS m/z 424.2423 [MþNa]þ (calcd for C24H35NO4Na 424.2464).

To a solution of 3 (10.0 mg, 0.028 mmol) in MeOH (0.5 mL) was added 10% PdeC (3.0 mg) at room temperature. The reaction mixture was stirred under 1.0 atm pressure of hydrogen atmosphere for 2 h at room temperature. Then, the reaction mixture was diluted with MeOH and the resultant mixture was filtered through a pad of CeliteÒ. The filtrate was concentrated to afford the crude product of tricyclic imine. To a stirred solution of the above crude product of tricyclic imine in THF (0.5 mL) were added NaBH(OAc)3 (9.2 mg, 0.042 mmol) and AcOH (1.6 mL, 0.028 mmol) at 0  C under argon atmosphere. After stirring for 3.5 h at room temperature, NaBH(OAc)3 (30.6 mg, 0.140 mmol), AcOH (4.8 mL, 0.084 mmol), and THF (0.5 mL) were added to the reaction mixture at 0  C, and the resultant mixture was stirred for 10.5 h at room temperature. 1 N aqueous NaOH solution was added to the reaction mixture. The resultant mixture was diluted with EtOAc and then extracted five times with 10% MeOH/CHCl3. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the crude product of 10. To a stirred solution of the above crude product of 10 in THF (0.5 mL) was slowly added allylmagnesium bromide (1.0 M in Et2O, 33.6 mL, 0.034 mmol) at 0  C under argon atmosphere, and the reaction mixture was stirred for 2 h at room temperature. After adding saturated aqueous NH4Cl solution at 0  C, the resultant mixture was extracted five times with 10% MeOH/CHCl3. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product of allyl amine. To a stirred solution of the above crude product of allyl amine in CH2Cl2 (0.9 mL) were added H2O (0.7 mL) and Na2CO3 (29.7 mg, 0.279 mmol) at room temperature. CbzCl (4.9 mL, 0.034 mmol) was added to the mixture at 0  C and the reaction mixture was stirred for 4 h at room temperature. After adding CHCl3 and saturated aqueous NaHCO3 solution, the organic phase was separated. The aqueous phase was extracted two times with CHCl3. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (EtOAc/ n-hexane¼7:93) to give 9 (4.8 mg, 45% in 4 steps) as a colorless oil. 3.9. Synthesis of diene 11 To a stirred solution of 9 (40.3 mg, 0.105 mmol) in CH2Cl2 (1.1 mL) were added pyridine (127 mL, 1.576 mmol) and SOCl2 (16 mL, 0.210 mmol) at 0  C under argon atmosphere. After stirring for 1.5 h at 0  C and for 1.5 h at room temperature, the reaction mixture was concentrated. The crude material was purified by silica gel flash column chromatography (EtOAc/n-hexane¼7:93) to afford 11 (25.0 mg, 65%) as a colorless oil. Compound 11: 1H NMR (CDCl3, 400 MHz) d 7.35e7.27 (5H, overlapped, eNHCO2CH2C6H5), 5.87 (1H, dddd, J¼16.9,10.1, 6.9, 6.9 Hz, H-2), 5.35 (1H, br s, H-5), 5.12 (1H, d, J¼12.4 Hz, eNHCO2CH2C6H5), 5.05 (1H, d, J¼12.8 Hz, eNHCO2CH2C6H5),

3.10. Synthesis of diol 12

3.11. Synthesis of pyridone 14 To a stirred solution of 12 (16.3 mg, 0.041 mmol) in acetone (0.5 mL) was added Jones’ reagent* at 0  C until the color (orange) of the reagent persisted under argon atmosphere, and the reaction mixture was stirred for 45 min at the same temperature. After adding i-PrOH at 0  C to destroy excess reagent, the reaction mixture was concentrated. The resultant mixture was extracted five times with 10% MeOH/CHCl3. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (MeOH/CHCl3¼1:4) to give the crude product of 5oxocarboxylic acid 13, which was used for the next reaction without further purification. To a stirred solution of the above crude product of 13 in AcOH (2.0 mL) was added NH2OMe$HCl (33.9 mg, 0.406 mmol) at room temperature under argon atmosphere, and the reaction mixture was stirred for 7 h at 160  C in a sealed tube. The solvent was removed as an azeotrope with n-hexane. The crude material was purified by silica gel flash column chromatography (MeOH/CHCl3¼1:4) and then by MPLC (SiO2, MeOH/CHCl3¼1:19) to yield 14 (1.5 mg, 12% in 2 steps) as a colorless oil. Compound 14: 1H NMR (CDCl3, 400 MHz) d 7.39e7.23 (6H, overlapped, H-3, eNHCO2CH2C6H5), 6.15 (1H, d, J¼9.2 Hz, H-2), 5.15 (1H, d, J¼12.4 Hz, eNHCO2CH2C6H5), 5.07 (1H, d, J¼11.9 Hz, eNHCO2CH2C6H5), 4.52 (1H, br d, J¼11.9 Hz), 3.41 (1H, dd, J¼13.1, 3.0 Hz), 3.09 (1H, dd, J¼16.9, 6.4 Hz), 2.90 (1H, m), 2.33 (1H, d, J¼16.9 Hz, H-6), 2.26 e2.18 (2H, overlapped), 2.05 (1H, br s), 1.92

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(1H, br d, J¼13.7 Hz), 1.76 (1H, m), 1.72e1.52 (2H, overlapped), 1.45e1.31 (3H, overlapped), 1.01 (3H, d, J¼6.7 Hz, H3-16). 13C NMR (CDCl3, 150 MHz) d 165.5, 154.9, 150.2, 140.6, 136.9, 128.5, 128.3, 128.1, 122.0, 116.1, 66.7, 59.9, 50.9, 48.7, 42.5, 38.8, 35.5, 34.2, 33.0, 27.0, 22.8, 18.1. IR (ATR) nmax cm1 1654. ESIMS m/z 415 [MþNa]þ. HRESIMS m/z 393.2162 [MþH]þ (calcd for C24H29N2O3 393.2178). UV (MeOH) lnm 320.5, 234.0, 203.0. *Preparation of Jones’ reagent: To a solution of CrO3 (133.0 mg) in H2O (0.4 mL) were slowly added H2SO4 (120 mL) and H2O (0.1 mL) at 0  C. 3.12. Synthesis of lycoposerramine-R (1) To a solution of 14 (1.9 mg, 0.005 mmol) in MeOH (0.5 mL) was added 10% PdeC (1.0 mg) at room temperature. The reaction mixture was stirred for 9 h at room temperature under 1.0 atm pressure of hydrogen atmosphere. The reaction mixture was concentrated and the crude material was purified by amino-silica gel open column chromatography (MeOH/EtOAc¼1:9) to afford 1 (1.8 mg, quant) as a colorless oil. Synthetic 1 was completely identical in all respects (chromatographic behavior and UV, 1H NMR, 13C NMR, and mass spectra) with the natural compound except for the optical property.

4.

Acknowledgements This work was supported by JSPS KAKENHI Grant Numbers 25293023 and 25460005. References and notes 1. For recent reviews on Lycopodium alkaloids, see: (a) Murphy, R. A.; Sarpong, R. Chem. Eur. J. 2014, 20, 42e56; (b) Siengalewicz, P.; Mulzer, J.; Rinner, U. In The €lker, H.-J., Ed.; Elsevier: Amsterdam, 2013; Vol. 72, pp 1e151; (c) Alkaloids; Kno € lker, H.-J., Ed.; Kitajima, M.; Takayama, H. In Topics in Current Chemistry; Kno Springer: Berlin, 2012; Vol. 309, pp 1e31; (d) Nakayama, A.; Kitajima, M.; Takayama, H. Synlett 2012, 2014e2024; (e) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679e729; (f) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.; Academic: New York, 2005; Vol. 61, pp 1e57; (g) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752e772; (h) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A., Brossi, A., Eds.; Academic: New York, 1994; Vol. 45, pp 233e274. €ckmantel, W. Acc. Chem. Res. 1999, 32, 641e650; (b) Liu, 2. (a) Kozikowski, A. P.; Tu J.-S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu, F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837e839. 3. For some recent examples of the total synthesis of Lycopodium alkaloids, see: (a) Yang, Y.; Haskins, C. W.; Zhang, W.; Low, P. L.; Dai, M. Angew. Chem., Int. Ed.

5. 6. 7. 8. 9. 10.

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