National Sun Yat-sen University Institutional Repository:Item 987654321/32139

行政院國家科學委員會補助專題研究計畫

5 成 果 報 告

□期中進度報告

α-磺酸基乙醯胺的化學(1)異 啉環酮及 啉酮之合成研究(2) 杉喃 D,

塔呾

啉

A58365B 諾瑪倪啶等天然物之合成研究

計畫類別：5 個別型計畫 □ 整合型計畫

計畫編號：NSC 96－2113－M－110－001

執行期間：96 年 08 月 01 日至 97 年 07 月 31 日

計畫主持人：張彥誠

共同主持人：

計畫參與人員： 汪永盛、黃政杰、陳志清、張榮凱、鍾文軒、蘇家誼

成果報告類型(依經費核定清單規定繳交)：□精簡報告 5完整報告

本成果報告包括以下應繳交之附件：

□赴國外出差或研習心得報告一份

□赴大陸地區出差或研習心得報告一份

□出席國際學術會議心得報告及發表之論文各一份

□國際合作研究計畫國外研究報告書一份

處理方式：除產學合作研究計畫、提升產業技術及人才培育研究計畫、

列管計畫及下列情形者外，得立即公開查詢

□涉及專利或其他智慧財產權，□一年□二年後可公開查詢

本精簡報告將研究以下主題：

第一部份

1) 廬葨依嘻嚀 D 及亞羅猶新賓之合成研究

第二部份

1) 2-

啉環酮新合成途徑的開發

第三部份

1) 化合物安咳啅呢克羅嚀的合成研究

2) 門森賁之合成研究

3) Erysotramidine 之合成研究

This report will study the following subjects:

Part I

1) Synthesis of Louisianin D and Alloyohimbane

Part II

1) New Approach to 2-Quinolinones

Part III

1) Synthesis of Anhydrolycorine

2) Synthesis of Mesembrine

3) Synthesis of Erysotramidine

目 錄

Part I

Synthesis of Louisianin D and Alloyohimbane ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥1

Part II

New Approach to 2-Quinolinones ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥1

Part III

Synthesis of Anhydrolycorine ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥6

Synthesis of Mesembrine ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥9

Synthesis of Erysotramidine ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥10

附錄 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥11

Part I Synthesis of Louisianin D and Alloyohimbane

本實驗室近年來利用α-sulfonyl amide 之雙陰離子與具有α,β-unsaturated

ester 官能基的 Michael acceptor 進行 [3+3] 環合加成反應而生成 glutarimide，進

而運用到各種天然物的合成上。

Ts N O R1 R3 R2 O RO2C N Ts R3 R2 O O R1 + Alkaloids

我們認為如果選取具有環狀結構的α,β-不飽和酯類來進行 [3+3] 環合加成

反應，應該可以得到駢雙環醯亞胺化合物，進而運用於 Alloyohimbane (1)、

Louisianin D (2)的合成研究，如 Scheme 1 所示。

Ts N O R1 RO2C O N Ts O O R1 + N N H H H H Alloyohimbane (1) N O Louisianin D (2) Scheme 1

研究成果已發表在 Org. Lett. 2006, 8, 3033-3035.如附錄。

Part II New Approach to 2-Quinolinones

本實驗室能將 glutarimide 3 轉換成雙烯化合物 4，接著利用 Diels-Alder 環合

反應得到化合物 5a-i，如 Table1 所示。並進一步將部分環化產物利用 NaH 以及

N Ts O O Ph Bn N Ts O Ph Bn 1) NaH, THF 2) MeMgBr 3) Ac2O 4) Et3N, MeOH 3 4 N Ts O Bn Ph EWG R dienophile EWG R R = H or EWG 5a-i Table 1.

dienophile products yield %

O O O COOEt COOEt CN COOMe N Ts O Bn Ph COOEt COOEt N Ts O Bn Ph COOMe N Ts O Bn Ph CN N Ts O Bn Ph O O O 66 79 73 5a 5b 5c 5d 70 Entry 1 2 3 4 COOEt COOMe COOMe N Ts O Bn Ph COOEt H N Ts O Bn Ph COOEt H + N Ts O Bn Ph COOMe COOMe 5f-1 5f-2 5e 5f-1 / 5f-2 43 / 21 74 5 6 O O O N Ts O Bn Ph O O N Ts O Bn Ph O O 84 80 N Ts O Bn Ph O O 70 O O 5g 5h 7 8 9

N Ts O Bn Ph CO₂Me CO2Me N Ts O Bn Ph CO2Et N Ts O Bn Ph O O O O N Ts O Ph Bn 1 2 3 4 products yield% Entry 60% 6a 6b 6c 6d 70% 50% Table 2. N Ts O Bn Ph NaOMe, NBS THF, _N Ts O Bn Ph 42%

接著希望能將化合物 6c-d 轉換成 aza-polycyclic aromatic compounds，研究其

是否有類似 pentacene 的光學性質。

為了增加此研究方法的實用性，我們也合成出一系列的雙烯化合物 12-15 來

進行上述的反應，來得到 2-quinolinone 16-27，如 Table3 所示。

N O Ts O R 1) NaH, THF 2) MeMgBr, THF 3) Ac2O 4) Et3N, MeOH 1) dienophile 2) NaOMe, NBS 2-quinolinone derivatives N Ts O R

Table 3.

entry dienelactam

dienophile

2-quinolinone

yield %

註一

1

N Ts O F Bn

12

COOEt N Ts O F Bn COOEt

16

41

2

N Ts O F Bn

12

COOMe COOMe N Ts O F Bn COOMe COOMe

17

60

N Ts O F Bn O O

18a

11

3

N Ts O F Bn

12

O O N O F Bn O O

18b

44

4

N Ts O Br Bn

13

COOEt N Ts O Br Bn COOEt

19

56

5

N Ts O Br Bn

13

COOMe COOMe N Ts O Br Bn COOMe COOMe

20

61

6

N Ts O Br Bn

13

O O N O Br Bn O O

21

51

Table 3.(續)

entry dienelactam

dienophile

2-quinolinone

yield %

註一

7

N Ts O Me Bn

14

COOEt N Ts O Me Bn COOEt

22

57

8

N Ts O Me Bn

14

COOMe COOMe N Ts O Me Bn COOMe COOMe

23

47

9

N Ts O Me Bn

14

O O N Ts O Me Bn O O

24

38

10

N Ts O OMe Bn

15

COOEt N Ts O OMe Bn COOEt

25

56

11

N Ts O OMe Bn

15

COOMe COOMe N Ts O OMe Bn COOMe COOMe

26

55

12

N Ts O OMe Bn

15

O O N O OMe Bn O O Ts

27

57

註一

經管柱層析純化後以環外二烯基的內醯胺化合物為計算基準所得之產率

研究成果已發表在 Org. Lett. 2008, 10, 673-676.如附錄。

Part III

1. Synthesis of Anhydrolycorine

本實驗室先前曾利用α-sulfonyl acetamide 28 與α-bromo esters 進行 [3+2]

annulation 來得到 3-sulfonyl imides 29，雖然此方法可得到不錯的產率，但其上

取代基只能侷限於 Alkyl group 且α-bromo esters 的取得並不容易，因此希望能夠

開發新的方法來改善上述兩各缺點。

Ts O _NH R R' Br CO₂Et NaH, THF N O R'' R Ts O 28 29 R' = R'' = H 29a :78% Me 29b :70% Et 29c :65%

在研究過程中我們發現，如果將α-bromo esters 換成具有醛類官能基的 ester

30，再與α-sulfonyl acetamide 進行 [3+2] annulation 可成功在 4 號位置碳上置入

一個 hydroxy group，此化合物可利用酸性條件下(TFA, MeOH)將 -OH 轉換

成 –OMe 來得到化合物 32。另外，我們可以利用-OMe 的離去性質，使用 Grignard

reagent 來當 Base 及 nuclephile 將其置換成所需要的取代基並且在過量的試劑

下，選擇性的打在 5 號位置的 carbonyl group 上而成功獲得化合物 33，如 Scheme

2 所示。

N O O OH Ts Ts O NH Bn NaH, THF T= -10oC H O OMe O CO2Me MeO2C i) O3, CH2Cl2 -780C ii) DMS, -780C to rt overnight H O OMe O TFA, MeOH reflux 80% for 2 steps O N O OMe Ts Bn _Bn 30 31 32 MgBr THF, rt 74% N O Ts OH Bn 33 2 5 4

Scheme 2

有此成功例子，將 N 上取代基換成含有 Br 官能基的化合物 35，嘗試利用立

障效應以及溫度的控制，在低溫下選擇性只接一個取代基在原先的 methoxy

group 位置而沒有繼續打在 5 號碳的 carbonyl group 上(化合物 38)。同樣地，我

們可以利用 Ts group 的影響，選擇性置入 R

2

group 在 5 號碳上，使得 4、5 號碳

為不同取代基(化合物 39)。另外，將溫度控制在室溫下，則可以得到兩個均為

相同取代基的產物 40，如 Scheme 3 所示。

Ts O _NH Br O O Ts O _NH O O Br₂, CH₂Cl₂ 0oC to rt, 95% NaH, THF T= -10oC H O OMe O N O O Br O O Ts OH N O O Br O O Ts OMe TFA, MeOH reflux, 6h 80% for 2 steps R1MgBr, THF -20oC to rt O N O Br O O Ts R₁ N O Br O O Ts R₁ OH R₂ i) NaH, THF, rt ii) R2MgBr iii) NH₄Cl _(aq), 0oC N O Br O O Ts R₁ OH R₂ R₁MgBr THF, rt R1 = R2 = 40a, Allyl, 73% 40b, Vinyl, 69% 40c, Ph R₁ = Allyl, R₂ = Me, 70.4% R₁ = Allyl, 81% 34 35 36 37 38 39 Schmem 3

接著我們將具有兩個相同取代基的化合物 40a 應用在天然物 Anhydrolycorine

的全合成上，目前已合成至化合物 41，接著再進行 Heck reaction 及官能基修飾

就可以完成其研究，如 Scheme 4 所示。

N O Ts Br O O N O Ts O O N O O MgBr THF, rt 73%

i) 1 mol% 2nd Grubbs' cat CH2Cl2, rt

ii) HOAc, reflux 82% for 2 steps Br O O Ts OMe N O Br O O Ts OH Pd(OAc)2 PPh3, K2CO3 DMF, 100oC 1) Na-Hg, Na2HPO4 MeOH 2) LAH, THF, reflux N O O Anhydrolycorine Scheme 4 40a 41 42

2. Synthesis of Mesembrine

另外，將 N 上的取代基改為甲基的話，同樣可以獲得化合物 44 並且進一步

來合成天然物 Mesembrine，目前已合成到化合物 46，如 Scheme 5 所示。

N O O OMe Ts MgBr N O Ts OH O N Ts N O Ts N O Ts N mesembrine N O O OH Ts Ts O NH NaH, THF T= -10oC H O OMe O TFA, MeOH reflux, 6h 90% for 2 steps THF, rt 74%

i) 1 mol% 2nd Grubbs' cat CH₂Cl₂, rt

ii) HOAc, reflux 88% for 2 steps 1) H2, Pd/C, MeOH-THF 10 min, 95% 2) ICl, NEt3, CH2Cl2 0oC to rt OMe OMe OMe OMe CuI, DMS THF, -78oC OMe OMe MgBr

Scheme 5

43 44 45 46 47

N O O OR1 Ts R2 N O O Anhydrolycorine N O O lycorane N mesembrine OMe OMe N H N HO N H N HO subincanadine A subincanadine B N R1 R N H R1 R₂ N OMe OMe O 3-demethoxyerythratidinone N OMe OMe O OMe erysotramidine R' R'' R' R''

Scheme 6

48 51 53

3. Synthesis of Erysotramidine

本實驗室目前發展出可合成具有-OH 或是-OMe group 化合物 48 的方法，除

了可控制接上不同取代基外，現正將其應用於許多天然物如 Anhydrolycorine、

Mesembrine 的合成研究上，另外，未來也將嘗試置入炔類官能基來合成 Indole

衍生物以及合成具有 spiro 環的天然物如 erysotramidine 等，如 Scheme 6 所示。

Efficient Synthesis of Fused Bicyclic

Glutarimides. Its Application to

(

±

)-Alloyohimbane and Louisianin D

Hung-Wei Chen,

†

_{Ru-Ting Hsu,}

‡

_{Meng-Yang Chang,}

§

_{and Nein-Chen Chang*}

,†

Department of Chemistry, National Sun Yat-Sen UniVersity, Kaohsiung 804, Taiwan, Department of Nursing, Shu-Zen College of Medicine and Management,

Kaohsiung County 821, Taiwan, and Department of Applied Chemistry, National UniVersity of Kaohsiung, Kaohsuing 804, Taiwan

[email protected]

Received April 21, 2006

ABSTRACT

The reaction ofr-sulfonyl acetamide 1 with various cyclic unsaturated esters 2 to fused bicyclic glutarimides is reported. Syntheses of (±)-alloyohimbane (4) and louisianin D (5) have been accomplished.

Bicyclic pyridines, piperidines,δ-lactams, and 2-pyridones

are important core structures that are found in numerous biologically active compounds.1 _{Although many methods}

have been reported for the synthesis of such compounds,2

we envisioned that our previously developed [3+3] annu-lation of R-sulfonyl acetamide with R,β-unsaturated esters

to give polysubstituted glutarimides3 _{would be ideal for}

constructing fused bicyclic glutarimides which could be further converted to nitrogen-containing polycyclic alkaloids.2b,4

Thus, the reaction of R-sulfonyl acetamide 1 with various cyclic unsaturated esters 2 was investigated. The results are shown in Table 1. It is interesting to note that 3a and 3b are both cis-fused bicyclic compounds. The structures of 3a and

3b were unequivocally established by single-crystal X-ray

†_{National Sun Yat-Sen University.}

‡_{Shu-Zen College of Medicine and Management.} §_{National University of Kaohsiung.}

(1) (a) Frederlesen, S. M.; Stermitz, F. R. J. Nat. Prod. 1996, 59, 41. (b) Stefanska, A. L.; Cassel, R.; Ready, S. J.; Warr, S. R. J. Antibiot. 2000,

53, 357. (c) Nakamura, M.; Kido, K.; Kinjo, J.; Nohara, T. Phytochemistry

2000, 53, 253. (d) Nakamura, M.; Chi, Y.-M.; Yan, W.-M.; Yonezawa, A.;

(2) For pyridines, see: (a) Jones, K.; Escudero-Hernandez, M. L.

Tetahedron 1998, 54, 2275. (b) John, K.; Fiumana, A.; Escudero-Hernandez,

M. L. Tetrahedron 2000, 56, 397. For piperidines, see: (c) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2003, 5, 1689. (d) Gunter, M.; Gais, H.-J. J. Org. Chem. 2003, 68, 8037. Forδ-lactams, see: (e) Li, T.-T.; Lesko, P.; Ellison, R. H.; Subramanian, N.; Fried, J. H.

J. Org. Chem. 1981, 46, 111. (f) Gracias, V.; Frank, K. E.; Milligan, G. L.;

Aube, J. Tetrahedron 1997, 48, 16241. For 2-pyridones, see: (g) Yamamoto,

ORGANIC

LETTERS

2006

Vol. 8, No. 14

analysis (Figure 1). The stereochemistries of 3c-e were determined by comparing their1_{H NMR spectra with those}

of 3a and 3b.

To demonstrate the utility of this one-pot process, the formal synthesis of (()-alloyohimbane (4) was investigated. As shown in Scheme 1, regioselective reduction of 3e by sequential addition of triethylamine in THF and LAH reduction at refluxing temperature furnished 6. Treatment of 6 with sodium amalgam gave 4,5-annulated lactam 7. The spectral data of 7 were in agreement with those reported in the literature.4a_{Lactam 7 has been converted to}

alloyohim-bane (4).4a,5_{Thus, the formal synthesis of alloyohimbane (4)}

was accomplished.

For the synthesis of louisianin D (5)4b _{produced by a}

species of Streptomyces,6_{glutarimide 3a was chosen as the}

starting material. Following the procedure developed in our laboratory,7 _{3a was reduced regioselectively to the}

corre-sponding hydroxylactam 8. Treatment of 8 with boron triflouride furnished enlactam 9. Allylation of 9 followed by dehydrosulfonation produced double-bond migrated 2-py-ridone 10. To accomplish the synthesis of louisianin D, 10 was first converted to the corresponding 2-chloropyridine

11, which was then reduced to bicyclic pyridine 12 by

treatment of 11 with zinc in acetic acid.8 _{Regioselective}

hydroxylation of 12 with LHMDS and oxygen yielded 13,9

which was then further oxidized with the swern-oxidation

(5) (a) Sparks, S. M.; Shea, K. J. Tetahedron Lett. 2000, 41, 6721. (b) Aube, J.; Wang, Y. G.; Hammond, M.; Tanol, M.; Takusagawa, F.; Vandervelde, D. J. J. Am. Chem. Soc. 1990, 112, 4879.

(6) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.; Furuhata, K.; Takayanagi, H.; Komiyama, K.; Woodruff, H. B.; Omura, S. J. Antibiot. 1995, 48, 1090. (7) Chang, B.-R.; Chen, C.-Y.; Chang, N.-C. Tetrahedron Lett. 2002, Table 1. Formation of Fused Bicyclic Glutarimides

a_{All yields were based on R-toluenesulfonyl acetamide.}

Scheme 1. Formal Synthesis of (()-Alloyohimbane Figure 1. X-ray structures of (()-3a and (()-3b.

reagent to afford 5 (Scheme 2). The spectral data of 5 were in agreement with those reported in the literature.6

In conclusion, we have developed a one-pot reaction procedure to cis-fused bicyclic glutarimides. Syntheses of (()-alloyohimbane (4) and louisianin D (5) were reported. Further application of fused bicyclic glutarimides to more complicated pentacyclic indole alkaloids is underway in our laboratory.

Acknowledgment. Financial support from the National

Science Council of the Republic of China is gratefully acknowledged.

Supporting Information Available: Additional

spectro-scopic data for all new compounds (1_{H NMR in CDCl} 3) and

X-ray crystallographic data in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org.

OL060958K

(9) (a) Boch, M.; Korth, T.; Nelke, J. M.; Pike, D.; Radunz, H.; Winterfeldt, E. Chem. Ber. 1972, 105, 2126. (b) Tang, C. S. F.; Morrow, C. J.; Rapoport, H. J. Am. Chem. Soc. 1975, 97, 159. (c) Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 611. (d) Ragan, J. A.; Jones, B. P.; Meltz, C. N.; Teixeira, J. J., Jr. Sythesis

2002, 4, 483. (e) Stork, G.; Fujimoto, D. N. A.; Koft, E. R.; Balkovec, J.

M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239. Scheme 2. Total Synthesis of Louisianin D

A facile approach to polysubstituted 2-pyridones. Application

to the synthesis of 3,4-disubstituted isoquinolinone

and total synthesis of oxyisoterihanine

Tsung-Hsiu Tsai,

a

Wen-Hsuan Chung,

a

Jung-Kai Chang,

a

Ru-Ting Hsu

b

and Nein-Chen Chang

a,

*

a

Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan b

Department of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung County 821, Taiwan

Received 5 June 2007; revised 27 June 2007; accepted 29 June 2007 Available online 10 July 2007

Abstract—A facile approach to polysubstituted 2-pyridones from 1-benzyl-5,6-dialkyl-3-(4-toluenesulfonyl)pyridin-2-one was described. A new approach to 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine will also be reported.

Ó 2007 Elsevier Ltd. All rights reserved.

1. Introduction

The 2-pyridone core is an important framework that can be found in numerous biologically active compounds.1 _{It is} a common template utilized for the synthesis of a wide vari-ety of nitrogen heterocycles such as pyridine, piperidine, quinolizidine, and indolizidine alkaloids.2Although a great number of methods have been reported for the synthesis of 2-pyridones,3 _{the development of new and flexible} approach to polysubstituted 2-pyridones is still required. During the course of our study of regioselective introduction of substituent at C-6 carbonyl in 3-sulfonyl glutarimides 1,4 the resulting exo or endo enlactams 2 have been successfully converted to L-733,060 3, CP-99,994 4, and cassine 55 (Fig. 1). We envisioned that this result can be further applied to the synthesis of polysubstituted 2-pyridones.

2. Results and discussion 2.1. Synthesis of polysubstituted 2-pyridones

We first examined the synthesis of 3,6-disubstituted and 3,5,6-trisubstituted 2-pyridones. Alkylation of enlactam 2 at C-3 position followed by dehydrosulfonation with sodium methoxide furnished the desired 2-pyridones 7. Some repre-sentative examples are listed inTable 1.

N H O Ph CF3 CF3 N H H N Ph OCH3 3. L-733,060 4. CP-99,994 N Ts O O R1 R3 N H OH CH3 O 10 5. Cassine N Ts O R4 R1 R3 1 2

Figure 1. The application of exo or endo enlactams toL-733,060 3,

CP-99,994 4 and cassine 5.

Table 1. Synthesis of 3,6-disubstituted and 3,5,6-trisubstituted 2-pyridones 7from 2 N Ts O R4 Bn R3 1) NaH 2) R1_X N Ts O R4 Bn R3 R1 NaOMe N R1 O R4 Bn R3 2 6 7 3 5 6 Entry R1 R3 R4 Yield (%) 7a Me H Et 86 7b Bn H Et 80 7c Me Me Me 85 7d Me Me Et 81 Keywords: 2-Pyridones; Isoquinolinone; Benzo[c]phenanthridine;

Oxyiso-terihanine.

We next investigated the synthesis of 4,5,6-trisubstituted 10and tetrasubstituted 2-pyridone 11. We envisioned that 3-sulfonyl-2-pyridone 8 might be a reasonable precursor for the synthesis of these compounds. 2-Pyridones 8 was easily accomplished by oxidation of enlactam 2 with DDQ (Table 2).

With desired 2-pyridone 8 in hand, we investigated the intro-duction of substituent at C-4 position. Treatment of 8 with 3 equiv of Grignard reagents furnished 1,4-addition product 96b_{in all substrates except 8c (Scheme 1andTable 3).}

N Ts O R4 Bn R3 R2 N R1 O R4 Bn R3 R2 R2_MgBr 1) NaH / R1_X 2) DBU N O R4 Bn R3 R2 9 10 11 8 + 1) Na/Hg 2) DDQ

Scheme 1. Synthesis of 4,5,6-trisubstituted 2-pyridones 10 and tetrasubsti-tuted 2-pyridones 11 from 8.

We were slightly surprised to obtain 10e as the major product during the reaction. It indicated that proton exchange oc-curred after 1,4-addition. The presence of phenyl group at

C-6 position might promote the proton migration and elim-ination (Scheme 2). The synthesis of 4,5,6-trisubstituted 2-pyridone was demonstrated by the conversion of 9a to 10a. Removing the tosyl group on 9a with sodium amalgam followed by oxidation of the resulting enlactam with DDQ yielded 10a in 80%. Alkylation of 9 followed by dehydrosul-fonation with DBU provided the corresponding tetrasubsti-tuted 2-pyridones 11.7 Some examples are listed in Table 4. It is noteworthy that 2-pyridones 11c contained four different substituents.

2.2. A new approach to isoquinolinone skeleton 14 To demonstrate the synthetic potential of these results, a new approach to isoquinolinone skeleton was tested. As shown in Scheme 3, 1,4-addition of an allylmagnesium bromide to 8b followed by allylation furnished diallyl enlactam 12. Per-forming ring-closing metathesis reaction on 12 with first generation Grubbs catalyst followed by dehydrosulfonation produced isoquinolinone 14. Presumably, after dehydrosul-fonation of 12, the resulting 13 oxidized spontaneously to form isoquinolinone 14. N Ts O Bn 1) 2) NaH/ _{O N} Bn 8b 12 Ts N O Bn N O Bn MgBr Br 1) RCM, CH2Cl2 2) t-BnOK, t-BuOH reflux, 81% 67%

Table 2. Synthesis of 5,6-disubstituted 2-pyridone 8 from 2

N Ts O R4 Bn R3 N Ts O R4 Bn R3 DDQ toluene, reflux 2 8 Entry R3 R4 Yield (%) 8a Me Me 85 8b Me Et 90 8c Me Ph 81 8d Bn Me 88

Table 3. Ratio of compounds 9 and 10

Table 4. Synthesis of tetrasubstituted 2-pyridones 11 from 9 Entry R1 R2 R3 R4 Yield (%) 11a Me Me Me Me 95 11b Me Me Me Et 93 11c Allyl Ph Me Et 90 11d Me Et Bn Me 92 All yields are based on compound 9.

N Ts O R4 Bn R3 8 N O R4 Bn R3 10 N R1 O R4 Bn R3 11 R2 R2 N Ts O Ph Bn 10e N Ts O Ph Bn N O Ph Bn 8c H H EtMgBr 70%

Scheme 2. Proposed mechanism for the formation of 8c to 10e. 9826 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

up the core structure of benzo[c]phenanthridine alkaloids distributed in Papaveraceous and Rutaceous plants.8_The al-kaloids have attracted considerable attention from synthetic organic chemists and biochemists over the last two decades due to their unique structure and biological activity.9 Oxy-terihanine 15a, a phenolic benzo[c]phenanthridine, was isolated from Xanthoxylum nitidum (Roxb.) D. C. (Fagara nitida Roxb.) in 1984.9c The structures of 15a and 15b were further confirmed by Ishii et al. (Fig. 2).10b_{Our strategy} for the synthesis of 15 was shown inScheme 4. The core structure of 15b was envisaged to arise from tricyclic pyri-done derivative 16 via the procedures developed above. Pyri-done 16 was predicted to derive from enlactam 17 through Friedel–Crafts reaction. Enlactam 17 was anticipated to arise from [3+3] cycloaddition adduct 18.

To test the strategy toward 15b, we first set out to synthesize tricyclic pyridone derivative 16 (Scheme 5). Following the method developed in our laboratory,4reaction of a-sulfonyl acetamide 19 with Baylis–Hillman adduct 20 furnished [3+3] annulation product glutarimide 18 in 78% yield. Hy-drogenation of 18 in the presence of Ra/Ni gave 21 in 95% yield. Regioselective addition of aryl group at C-6 position in 21 followed by dehydration of the resulting hydroxylac-tam produced enlachydroxylac-tam 17.5 _{Exposure of 17 to boron}

trifluoride yielded Friedel–Crafts reaction and aromatization product 22. Oxidation of 22 with DDQ furnished the desired tricyclic pyridone 16. N O CH3 Ts O O O H2 , Ra/Ni N O CH3 Ts O O O O O Br 1) NaH 2) 3) Ac2O 4) Et3N, MeOH , Mg N CH3 Ts O O O N CH3 O Ts CH2Cl2 DDQ N CH3 O Ts Toluene, reflux. [3+3] NaH, THF BF3 OEt2 THF, r.t. O O O O O O NH O CH3 Ts O O O OAc MeO + 19 20 ₁₈ 21 17 22 16 (78%) (95%) (65%) (93%) (83%) 6

Scheme 5. Synthesis of tricyclic pyridone 16.

With required 16 in hand, the next task was to build the fourth ring on 16. Following the procedures described in Scheme 6, tetracyclic enlactam 256a_{was prepared in 84%} from 16. To accomplish the synthesis of the core skeleton of benzo[c]phenanthridine, enlactam 25 was dehydrosulfo-nated with DBU, and the resulting 26 was oxidized with DDQ, which afforded the desired 27 in 92% yield for two steps sequence.

2.4. Total synthesis of oxyisoterihanine 15b

The synthesis of oxyisoterihanine 15b was carried out as de-picted inScheme 7. Oxidation of 25 with m-CPBA furnished epoxide 286c_{in 94% yield. Exposure of 28 in methanol and} dichloromethane in the presence of boron trifluoride af-forded 29 in 85% yield. The structure of 29 was unequivo-cally established by single-crystal X-ray analysis (Diagram 1).6a_{Finally, Swern oxidation of 29 furnished ketone 30,} which was further dehydrosulfonated with DBU to afford 15bin 65% yield. The spectral data of 15b were in agree-ment with those reported in the literature.10

3. Conclusion

In conclusion, we have disclosed an efficient and regiocon-trolled synthesis of polysubstituted 2-pyridones. Starting from readily available glutarimides, the substituents can be introduced to glutarimides or the corresponding 2-pyridones in different stages at desired positions to form substituted N A B C D 1 2 3 4 5 6 7 8 9 10 11 12 N O OR2 R1O

oxyterihanine 15a R1=H, R2=Me

oxyisoterihanine 15b R1=Me, R2=H

O O

benzo[c]phenanthridine

Figure 2. The core structure of benzo[c]phenanthridine alkaloids.

N CH3 O O O N CH3 O Ts O O N O CH3 Ts O O O NH Ts O O O N CH3 Ts O O O O O OH O OAc + [3+3] 16 17 18 Oxyisoterihanine 15b 9827 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

benzo[c]phenanthridine was developed. Total synthesis of oxyisoterihanine 15b was accomplished. Further application of these results to the synthesis of polysubstituted pyridines, tri and tetracyclicquinoline and isoquinoline alkaloids are underway in our laboratory.

4. Experimental 4.1. General

Melting points were determined with melting point appara-tus and were uncorrected.1H NMR and13C NMR were re-corded on Varian VRX 500 spectrometer. NMR spectra were recorded in CDCl3 (1H NMR at 500 MHz and 13C NMR at 125 MHz), and chemical shifts are expressed in parts per million (d) relative to internal Me4Si.

Tetrahydrofuran was distilled prior to use. All other reagents and solvents were obtained from commercial sources and were used without any further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Solutions of products in organic sol-vents were dried with anhydrous magnesium sulfate before N CH3 O Ts m-CPBA CH2Cl2, r.t. N CH3 O Ts O CH2Cl2, MeOH BF3 OEt2 N CH3 O Ts MeO OH Swern ox. N CH3 O Ts MeO O DBU THF, reflux. N CH3 O MeO OH Oxyisoterihanine 15b O O O O O O O O O O 25 28 29 30 (94%) (85%) (65%, 2 steps) H H _H H

Scheme 7. Completion of the total synthesis of oxyisoterihanine 15b.

N CH3 O N CH3 O Ts MgBr THF N CH3 O Ts Br NaH, THF N CH3 O RCM Ts CH2Cl2 , r.t. DBU THF, 60 °C N CH3 O DDQ THF, reflux. _N CH3 O O O O O O O O O O O O O Ts 16 23 24 25 26 27 (98%) (94%) (96%) (93%) (99%) H

Scheme 6. Synthesis of benzo[c]phenanthridine 27.

N CH3 O Ts MeO OH O O 29

60%) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 15 min, methylmagne-sium bromide (1.3 mmol) was added in one portion and further stirred at room temperature for 30 min, then quenched with acetic anhydride (122.4 mg, 1.2 mmol) and the reaction mixture was stirred for an additional 30 min. After the reaction was completed, the reaction mixture was quenched with a saturated ammonium chloride solution (1 mL), filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 2.

4.2.2. General procedure for the preparation of 3,6-di-substituted pyridin-2-one and 3,5,6-tri3,6-di-substituted pyr-idin-2-one (7).A solution of enlactam 2 (1 mmol) in dry THF (5 mL) was added to a rapidly stirred suspension of sodium hydride (1.5 mmol, 60%) in tetrahydrofuran (20 mL). After the reaction mixture was stirred at room temperature for 15 min, alkyl halide (1.1 mmol) was added. The reaction was completed, the reaction mixture was quenched with a saturated ammonium chloride solution (1 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 6. Sodium methoxide (1.1 mmol) was added to a rap-idly stirred solution of 6 in THF (20 mL) at room tempera-ture. After the reaction was accomplished (monitored by TLC), the reaction mixture was quenched with water (2 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 7.

4.2.2.1. 1-Benzyl-6-ethyl-3-methylpyridin-2-one (7a). Yield 77%; yellow oil;1_{H NMR (500 MHz, CDCl}

3) 7.31– 7.20 (m, 6H), 7.11 (d, J¼8.0 Hz, 2H), 5.99 (d, J¼7.0 Hz, 1H), 5.39 (br s, 2H), 2.55 (q, J¼8.0 Hz, 2H), 2.17 (s, 3H), 1.17 (t, J¼7.5 Hz, 3H); 13_{C NMR (125 MHz, CDCl} 3) 164.1, 148.5, 137.0, 136.5, 128.7 (2C), 127.1, 126.4, 126.3 (2C), 104.0, 46.6, 25.7, 17.3, 12.5; HRMS (ESI, M+₊₁₎ calcd for C15H18NO 228.1388, found 228.1390.

4.2.2.2. 1,3-Dibenzyl-6-ethylpyridin-2-one (7b). Yield 68%; yellow oil;1_{H NMR (500 MHz, CDCl} 3) d 7.31–7.20 (m, 8H), 7.10 (d, J¼7.0 Hz, 2H), 6.99 (d, J¼8.0 Hz, 1H), 5.98 (d, J¼7.0 Hz, 1H), 5.39 (br s, 2H), 3.89 (s, 2H), 2.55 (q, J¼7.5 Hz, 2H), 1.15 (t, J¼7.0 Hz, 3H); 13_{C NMR} (125 MHz, CDCl3) d 163.5, 149.0, 140.0, 136.9, 136.4, 129.9, 128.4 (2C), 128.7 (2C), 128.4 (2C), 127.1, 126.2 (2C), 126.1, 104.0, 46.7, 36.7, 25.7, 12.4; HRMS (ESI, M+_{+1) calcd for C} 21H22NO 304.1701, found 304.1699. 4.2.2.3. 1-Benzyl-3,5,6-trimethylpyridin-2-one (7c). Yield 87%; yellow oil; 1H NMR (500 MHz, CDCl3) d 7.31–7.10 (m, 6H), 5.41 (br s, 2H), 2.18 (s, 2H), 2.17 (s,

4.2.2.4. 1-Benzyl-6-ethyl-3,5-dimethylpyridin-2-one (7d). Yield 89%; yellow oil;1_{H NMR (500 MHz, CDCl}

3) d 7.29–7.22 (m, 5H), 7.10 (s, 1H), 7.09 (d, J¼6.0 Hz, 2H), 5.41 (br s, 2H), 2.56 (q, J¼7.5 Hz, 2H), 2.16 (s, 3H), 2.07 (s, 3H), 1.09 (t, J¼7.5 Hz, 3H);13_{C NMR (125 MHz, CDCl} 3) d 163.4, 144.8, 140.8, 137.5, 128.6 (2C), 127.0, 126.2 (2C), 126.1, 112.0, 76.8, 47.1, 23.0, 17.2, 12.6; HRMS (ESI, M++1) calcd for C16H20NO 242.1545, found 242.1546. 4.2.3. General procedure for the preparation of 5,6-di-substituted pyridin-2-one (8).DDQ (1.2 mmol) was added to a solution of 5,6-disubstituted-D-enlactams 2 (1 mmol) in toluene (20 mL). After the reaction mixture was stirred at re-fluxing temperature for 10 h, 10% NaOH (1 mL) was added to destroy the remaining DDQ and filtered through Celite. The organic layer was extracted with dichloromethane (320 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (dichloro-methane/methanol¼100:1) to afford 8.

4.2.3.1. 1-Benzyl-5,6-dimethyl-3-(4-toluenesulfonyl)-pyridin-2-one (8a). Yield 85%; yellow oil; 1_{H NMR} (500 MHz, CDCl3) d 8.25 (s, 1H), 8.00 (d, J¼7.5 Hz, 2H), 7.3 (d, J¼8.0 Hz, 2H), 7.27–7.23 (m, 3H), 7.02 (d, J¼ 7.5 Hz, 2H), 5.32 (br s, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H);13C NMR (125 MHz, CDCl3) d 157.7, 151.5, 144.5, 144.0, 137.1, 135.3, 129.2 (2C), 128.9 (4C), 127.6, 126.6, 126.4 (2C), 112.5, 47.8, 21.6, 18.2, 17.6; HRMS (ESI, M+_{+1) calcd for C} 21H22NO3S 368.1320, found 368.1318. 4.2.3.2. 1-Benzyl-6-ethyl-5-methyl-3-(4-toluenesulfon-yl)pyridin-2-one (8b). Yield 90%; yellow oil; 1_{H NMR} (500 MHz, CDCl3) d 8.24 (s, 1H), 8.09 (d, J¼7.5 Hz, 2H), 7.30 (d, J¼7.5 Hz, 2H), 7.26–7.20 (m, 3H), 6.98 (d, J¼6.5 Hz, 2H), 5.32 (br s, 2H), 2.61 (q, J¼8.0 Hz, 2H), 2.41 (s, 3H), 2.19 (s, 3H), 1.089 (t, J¼8.0 Hz, 3H); 13_C NMR (125 MHz, CDCl3) d 157.7, 156.4, 145.0, 144.0, 137.0, 135.8, 129.2 (2C), 129.0 (2C), 128.9 (2C), 127.5, 126.8, 126.2 (2C), 112.0, 47.2, 24.0, 21.6, 17.2, 11.8; HRMS (ESI, M++1) calcd for C22H24NO3S 382.1477, found 382.1477.

4.2.3.3. 1-Benzyl-5-methyl-6-phenyl-3-(4-toluenesul-fonyl)pyridin-2-one (8c).Yield 81%; yellow oil;1_{H NMR} (500 MHz, CDCl3) d 8.36 (s, 1H), 8.07 (d, J¼8.5 Hz, 2H), 7.42–7.07 (m, 8H), 6.85 (d, J¼7.0 Hz, 2H), 6.63 (d, J¼7.0 Hz, 2H), 5.01 (br s, 2H), 2.44 (s, 3H), 1.81 (s, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 157.2, 153.6, 144.7, 144.2, 136.9, 136.2 (2C), 133.0, 129.6, 129.2 (2C), 129.1 (2C), 128.9 (2C), 128.3 (2C), 128.0 (2C), 127.2, 126.9 (2C), 113.4, 49.2, 21.7, 17.9; HRMS (ESI, M+_{+1) calcd for} C26H24NO3S 430.1477, found 430.1479.

4.2.3.4. 1,5-Dibenzyl-6-methyl-3-(4-toluenesulfonyl)-pyridin-2-one (8d). Yield 88%; yellow oil; 1_{H NMR} (500 MHz, CDCl3) d 8.30 (s, 1H), 8.01 (d, J¼9.0 Hz, 2H), 7.32–7.25 (m, 8H), 7.07 (d, J¼7.5 Hz, 2H), 7.01 (d, J¼8.0 Hz, 2H), 5.32 (br s, 2H), 3.87 (s, 2H), 2.42 (s, 3H), 2.21 (s, 3H);13_{C NMR (125 MHz, CDCl} 3) d 157.7, 152.6, 9829 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

4.2.4. General procedure for the preparation of 4,5,6-tri-substituted pyridin-2-one (9).Grignard reagent (1.3 mmol) was added to a solution of compound 8 (1 mmol) in dry THF (5 mL) at room temperature. After the reaction was accom-plished (monitored by TLC), the reaction mixture was quenched with water (2 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (3 20 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 9.

4.2.4.1. 1-Benzyl-4,5,6-trimethyl-3-(4-toluenesul-fonyl)-3,4-dihydropyridin-2-one (9a).Yield 70%; yellow oil;1_{H NMR (500 MHz, CDCl} 3) d 7.73 (d, J¼8.5 Hz, 2H), 7.32–7.22 (m, 7H), 5.13 (d, J¼16.0 Hz, 1H), 4.49 (d, J¼ 16.0 Hz, 1H), 3.85–3.84 (m, 1H), 2.96 (dd, J¼6.5, 14.0 Hz, 1H), 2.43 (s, 3H), 1.73 (s, 3H), 1.60 (s, 3H), 1.05 (d, J¼7.5 Hz, 3H);13_{C NMR (125 MHz, CDCl} 3) d 161.4, 144.9, 137.7, 136.1, 129.4 (2C), 128.8 (2C), 128.7 (2C), 128.3, 127.2, 126.9 (2C), 115.1, 72.9, 45.8, 33.4, 21.7, 17.6, 17.5, 14.5; HRMS (ESI, M+_{+1) calcd for} C22H26NO3S 384.1633, found 384.1636.

4.2.4.2. 1-Benzyl-6-ethyl-4,5-dimethyl-3-(4-toluene-sulfonyl)-3,4-dihydropyridin-2-one (9b). Yield 75%; yel-low oil;1H NMR (500 MHz, CDCl3) d 7.75 (d, J¼8.5 Hz, 2H), 7.33–7.23 (m, 7H), 5.20 (d, J¼15.5 Hz, 1H), 4.53 (d, J¼15.5 Hz, 2H), 3.80 (s, 1H), 2.95 (q, J¼7.5 Hz, 1H), 2.42 (s, 3H), 2.32–2.24 (m, 1H), 2.18–2.11 (m, 1H), 1.04–0.98 (m, 6H); 13_{C NMR (125 MHz, CDCl} 3) d 161.8, 144.9, 137.8, 136.4, 133.4, 129.7 (2C), 128.6 (2C), 128.5 (2C), 127.1, 127.0 (2C), 115.4, 72.4, 45.5, 32.9, 21.7, 21.0, 17.5, 17.3, 12.3; HRMS (ESI, M++1) calcd for C23H28NO3S 398.1790, found 398.1792. 4.2.4.3. 1-Benzyl-6-ethyl-5-methyl-4-phenyl-3-(4-tolu-enesulfonyl)-3,4-dihydropyridin-2-one (9c). Yield 70%; yellow oil; 1_{H NMR (500 MHz, CDCl} 3) d 7.80 (d, J¼ 8.5 Hz, 2H), 7.34–7.18 (m, 10H), 7.01–7.00 (m, 2H), 5.22 (d, J¼15.5 Hz, 1H), 4.58 (d, J¼15.5 Hz, 1H), 4.21 (s, 1H), 4.09 (s, 1H), 2.48–2.42 (m, 1H), 2.44 (s, 3H), 2.38–2.33 (m, 1H), 1.82 (s, 3H), 1.11 (t, J¼7.5 Hz, 3H);13_{C NMR} (125 MHz, CDCl3) d 161.3, 145.1, 137.9, 137.4, 136.0, 129.9 (2C), 129.0 (2C), 128.7 (2C), 128.5, 128.4 (2C), 127.6 (2C), 127.5 (2C), 127.3, 126.5, 112.1, 73.1, 45.7, 43.2, 21.7, 21.3, 17.9, 12.5; HRMS (ESI, M+_{+1) calcd for C}

28H30NO3S 460.1946, found 460.1948. 4.2.4.4. 1-Benzyl-6-ethyl-5-methyl-3-(4-toluenesul-fonyl)-4-vinyl-3,4-dihydropyridin-2-one (9d).Yield 73%; yellow oil;1_{H NMR (500 MHz, CDCl} 3) d 7.77 (d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H), 7.29–7.20 (m, 5H), 5.61–5.55 (m, 1H), 5.22 (d, J¼15.5 Hz, 1H), 5.09–5.02 (m, 2H), 4.50 (d, J¼15.5 Hz, 1H), 4.95 (s, 1H), 3.54 (d, J¼5.5 Hz, 1H), 2.44 (s, 3H), 2.36–2.28 (m, 1H), 2.24–2.14 (m, 1H), 1.83 (s, 3H), 1.03 (t, J¼7.5 Hz, 3H); 13 yellow oil; 1H NMR (500 MHz, CDCl3) d 7.83 (d, J¼8.0 Hz, 2H), 7.38–6.92 (m, 12H), 5.05 (d, J¼15.0 Hz, 1H), 3.99 (d, J¼15.0 Hz, 1H), 3.95 (s, 1H), 2.89 (t, J¼7.5 Hz, 1H), 2.47 (s, 3H), 1.66 (s, 3H), 1.59–1.52 (m, 1H), 1.40–1.34 (m, 1H), 0.93 (t, J¼7.5 Hz, 3H);13_{C NMR} (125 MHz, CDCl3) d 161.8, 145.0, 137.4, 136.6, 134.4, 134.2, 129.8 (3C), 128.6 (3C), 128.2, 128.1 (3C), 128.0 (3C), 127.1, 117.6, 70.7, 47.1, 40.0, 25.0, 21.7, 19.3, 11.4; HRMS (ESI, M+_{+1) calcd for C}

28H30NO3S 460.1946, found 460.1950.

4.2.5. General procedure for the preparation of 4,5,6-tri-substituted pyridin-2-one (10).Sodium amalgam (Na/Hg, 3.0 g) and sodium phosphate (40 mg) were added to a stirred solution of 9 (1 mmol) in methanol (20 mL) and vigorously stirred for 2 h at room temperature. The residue was filtered and washed with methanol (210 mL). The combined or-ganic layers were concentrated to obtain the crude product. After the crude product was purified by silica gel chromato-graphy (n-hexane/ethyl acetate¼4:1 to 2:1), to afford the desulfonation product, which then dissolved in toluene (10 mL), DDQ (2 equiv) was added and stirred at refluxing temperature for 10 h. After the reaction was accomplished (monitored by TLC), the reaction mixture was quenched with water (2 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL), dried, filtered, and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 10.

4.2.5.1. 1-Benzyl-4-ethyl-5-methyl-6-phenylpyridin-2-one (10e). Yield 70%; yellow oil; 1_{H NMR (500 MHz,} CDCl3) d 7.37–7.30 (m, 3H), 7.16–7.14 (m, 4H), 6.95 (d, J¼7.0 Hz, 2H), 6.82–6.80 (m, 2H), 5.08 (br s, 2H), 2.67 (q, J¼7.5 Hz, 2H), 1.75 (s, 3H), 1.27 (t, J¼7.5 Hz, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 162.4, 143.3, 138.1, 137.7, 134.5, 133.7, 129.3 (2C), 128.7, 128.5 (2C), 128.1 (2C), 126.9 (2C), 126.7, 113.4, 49.1, 23.8, 17.9, 12.7; HRMS (ESI, M+_{+1) calcd for C}

21H21NO 304.1701, found 304.1698.

4.2.6. General procedure for the preparation of 3,4,5,6-tetrasubstituted pyridin-2-one (11). A solution of com-pound 9 (1 mmol) in dry THF (5 mL) was added to a rapidly stirred suspension of sodium hydride (60 mg, 1.2 mmol, 60%) in THF (20 mL). The resulting mixture was stirred at room temperature for 15 min, iodide methane (1.3 mmol) was added. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (2 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL) and dried with anhy-drous MgSO4, filtered and concentrated. After the crude al-kylated product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1), t-BuOH (15 mL) and t-BuOK (1.1 mmol) were added to a solution of alkylated

4.2.6.1. 1-Benzyl-3,4,5,6-tetramethylpyridin-2-one (11a).Yield 95%; yellow oil;1_{H NMR (500 MHz, CDCl}

3) d 7.30–7.19 (m, 3H), 7.11 (d, J¼7.0 Hz, 2H), 5.43 (br s, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 162.8, 146.3, 138.0, 137.2, 128.6 (2C), 126.9, 126.2 (2C), 123.0, 113.2, 48.0, 17.2, 16.6, 15.1, 13.5; HRMS (ESI, M+_{+1) calcd for C}

16H20NO 242.1545, found 242.1547.

4.2.6.2. 1-Benzyl-6-ethyl-3,4,5-trimethylpyridin-2-one (11b).Yield 93%; yellow oil;1_{H NMR (500 MHz, CDCl}

3) d 7.29–7.20 (m, 3H), 7.09 (d, J¼7.5 Hz, 2H), 5.43 (br s, 2H), 2.61 (q, J¼7.5 Hz, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H), 1.09 (t, J¼7.5 Hz, 3H);13_{C NMR (125 MHz,} CDCl3) d 162.8, 146.7, 143.2, 137.7, 128.7 (2C), 126.9, 126.1 (2C), 123.5, 112.8, 47.5, 23.2, 17.1, 14.5, 13.5, 12.9; HRMS (ESI, M++1) calcd for C17H22NO 256.1701, found 256.1699.

4.2.6.3. 1-Benzyl-6-ethyl-5-methyl-4-phenyl-3-propen-ylpyridin-2-one (11c). Yield 90%; yellow oil; 1_{H NMR} (500 MHz, CDCl3) d 7.47–7.11 (m, 10H), 7.05–6.98 (m, 1H), 5.87 (d, J¼14.0 Hz, 1H), 5.50 (br s, 2H), 2.83 (q, J¼7.5 Hz, 2H), 1.74 (s, 3H), 1.66 (d, J¼1.5 Hz, 3H), 1.15 (t, J¼7.5 Hz, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 161.7, 150.9, 144.9, 139.3, 137.4, 131.1, 128.7 (2C), 128.5 (2C), 128.4 (2C), 127.2, 127.1, 126.2 (2C), 126.0, 122.8, 112.1, 47.4, 23.7, 19.9, 15.6, 12.7; HRMS (ESI, M+_{+1) calcd for} C24H26NO 344.2014, found 344.2017.

4.2.6.4. 1,5-Dibenzyl-4-ethyl-3,6-dimethylpyridin-2-one (11d). Yield 92%; yellow oil; 1_{H NMR (500 MHz,} CDCl3) d 7.31–7.02 (m, 10H), 5.45 (br s, 2H), 3.88 (s, 2H), 2.50 (q, J¼7.5 Hz, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.06 (t, J¼7.5 Hz, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 163.4, 151.9, 140.7, 139.8, 137.1, 128.7 (2C), 128.6 (2C), 127.5 (2C), 127.1, 126.3, 126.2 (2C), 123.3, 114.7, 48.1, 33.9, 23.8, 16.8, 13.3, 13.0; HRMS (ESI, M+_{+1) calcd} for C23H26NO 332.2014, found 332.2012.

4.3. Synthesis of isoquinolinone skeleton 14

4.3.1. 3,4-Diallyl-1-benzyl-6-ethyl-5-methyl-3-(4-tolu-enesulfonyl)-3,4-dihydropyridin-2-one (12). Allylmagne-sium bromide (2.0 mL, 1.3 mmol) was added to a solution of compound 8b (570 mg, 1.5 mmol) in dry THF (15 mL). After the reaction was accomplished (monitored by TLC), the reaction mixture was quenched with water (5 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (320 mL), dried, filtered, and concen-trated. Without purification, the residue in dry THF (5 mL) was added to a suspension of sodium hydride (72 mg, 1.2 mmol, 60%) in THF (10 mL) and stirred at room temper-ature for 15 min. Allyl bromide (270 mg, 1.5 mmol) was added to the solution. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl ace-tate (320 mL) and dried with anhydrous MgSO4, filtered

7.34–7.23 (m, 7H), 5.82–5.74 (m, 1H), 5.72–5.63 (m, 1H), 5.12 (d, J¼15.0 Hz, 1H), 5.06–4.84 (m, 4H), 4.53 (d, J¼15.0 Hz, 1H), 2.97–2.93 (m, 1H), 2.80 (dd, J¼5.0, 10.0 Hz, 1H), 2.64–2.42 (m, 3H), 2.44 (s, 3H), 2.32–2.15 (m, 2H), 1.76 (s, 3H), 0.90 (t, J¼7.5 Hz, 3H); 13_{C NMR} (125 MHz, CDCl3) d 166.8, 144.6, 137.7, 136.5, 135.8, 134.3, 131.3 (2C), 131.2 (2C), 129.1 (2C), 128.6 (2C), 127.3 (2C), 124.5, 119.6, 116.7, 115.0, 74.9, 45.1, 37.2, 29.7, 21.6 (2C), 20.9, 12.4; HRMS (ESI, M+_{+1) calcd for} C28H34NO3S 464.2259, found 464.2256.

4.3.2. 2-Benzyl-3-ethyl-4-methylisoquinolin-1-one (14). Diallyl compound 12 (165 mg, 0.36 mmol) in dry dichloro-methane (40 mL) was added to first generation Grubbs cat-alyst [(C6H11)3P]2Cl2RuC2H3Ph (29.6 mg, 0.036 mmol, 10 mol %), and the mixture was allowed to react for 12 h at room temperature. After the reaction was completed (monitored by TLC), the mixture was quenched with water (20 mL) and extracted with dichloromethane (230 mL) and dried with anhydrous MgSO4, filtered and concentrated. To the solution of the residue in t-BuOH (15 mL) was added t-BuOK (44 mg, 1.1 mmol) and then heated to reflux for 24 h. The organic solvent was evaporated under reduced pressure and the residue was extracted with water (15 mL) and ethyl acetate (320 mL). The combined organic layer was dried with anhydrous MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford isoquinolinone derivative 14 (78 mg, 81%) as a colorless oil. 1_{H NMR} (500 MHz, CDCl3) d 8.52 (d, J¼10.0 Hz, 1H), 7.71–7.69 (m, 2H), 7.50–7.46 (m, 1H), 7.31–7.21 (m, 3H), 7.14 (d, J¼7.5 Hz, 2H), 5.51 (br s, 2H), 2.73 (q, J¼7.5 Hz, 2H), 2.34 (s, 3H), 1.18 (t, J¼7.5 Hz, 3H);13_{C NMR (125 MHz,} CDCl3) d 163.0, 141.0, 137.8, 137.5, 132.3, 128.7 (2C), 128.5, 127.0, 126.0 (2C), 125.9, 124.6, 122.6, 109.1, 47.1, 23.1, 13.5, 13.3; HRMS (ESI, M+_{+1) calcd for C}

19H20NO 278.1545, found 278.1547.

4.4. Synthesis of benzo[c]phenanthridine nucleus 4.4.1. 3-(2,2-Dimethoxyethylidene)-1-methyl-5-(4-tolu-enesulfonyl)piperidine-2,6-dione (18). A solution of a-sulfonyl methylacetamide 19 (3.0 g, 13.2 mmol) in dry THF (30 mL) was added to a rapidly stirred suspension of sodium hydride (1.6 g, 39.6 mmol, 60%) in dry THF (20 mL). After the reaction mixture was stirred at room tem-perature for 30 min, a solution of a,b-unsaturated ester 20 (3.7 g, 15.8 mmol) in dry THF (70 mL) was added. The resulting mixture was stirred for 15 min, quenched with saturated ammonium chloride solution (25 mL) in an ice bath, and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl ace-tate (350 mL). The combined organic layers were washed with brine (240 mL), dried over anhydrous MgSO4, fil-tered and evaporated. Purification on silica gel (n-hexane/ ethyl acetate/triethyl amine¼4:1:0.01 to 2:1:0.01) produced glutarimide 18 (3.8 g, 78%) as a white solid; 1_{H NMR} (500 MHz, CDCl3) d 7.76–7.72 (m, 2H), 7.39–7.37 (m, 2H), 6.99 (dd, J¼2.5, 5.5 Hz, 0.8 H), 5.77 (d, J¼7.0 Hz,

9831 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

d 164.5, 164.4 (0.2C), 164.3 (0.8C), 146.0 (0.8C), 145.9 (0.2C), 142.5 (0.2C), 140.1 (0.8C), 134.6 (0.2C), 134.3 (0.8C), 123.0 (1.6C), 129.9 (0.4C), 129.2 (0.4C), 129.1 (1.6C), 127.0 (0.8C), 124.9 (0.2C), 99.1 (0.8C), 98.9 (0.2C), 66.0 (0.2C), 65.8 (0.8C), 54.7 (0.2C), 53.9 (0.2C), 53.0 (0.8C), 52.2 (0.8C), 28.4 (0.2C), 27.8 (0.8C), 27.4 (0.2C), 22.0 (0.8C), 21.8; HRMS (ESI, M+_{+1) calcd for} C17H21O6NSNa 390.0987, found 390.0985. Mp: 118.6– 119.7C.

4.4.2. 3-(2,2-Dimethoxyethyl)-1-methyl-5-(4-toluenesul-fonyl)piperidine-2,6-dione (21). To a solution of glutar-imide 18 (3.2 g, 8.7 mmol) in dry THF (60 mL) was added 2.1 g of Raney nickel 2800 (H2O). The reaction slurry was stirred at room temperature for 12 h under 40 psi H2. The re-action mixture was filtered over Celite and the solution was concentrated under reduced pressure. Purification on silica gel (hexane/ethyl acetate/triethyl amine¼4:1:0.01 to 2:1:0.01) produced 21 (3.1 g, 95%) as a white solid; 1H NMR (500 MHz, CDCl3) d 7.88 (d, J¼8.0 Hz, 0.4H), 7.76 (d, J¼8.0 Hz, 1.6H), 7.39–7.37 (m, 2H), 4.65 (t, J¼5.5 Hz, 0.2H), 4.61 (t, J¼5.5 Hz, 0.8H), 4.20 (dd, J¼5.5, 13.0 Hz, 0.2H), 4.14 (dd, J¼3.0, 6.0 Hz, 0.8H), 3.40–3.32 (m, 7H), 3.17 (s, 2.4H), 3.08 (s, 0.6H), 2.91–2.87 (m, 0.8H), 2.78– 2.73 (m, 0.2H), 2.47 (s, 2.4H), 2.46 (s, 0.6H), 2.37–2.32 (m, 1H), 2.19–2.13 (m, 1H), 1.80–1.75 (m, 1H);13C NMR (125 MHz, CDCl3) d 173.4 (0.8C), 173.0 (0.2C), 165.2 (0.2C), 164.7 (0.8C), 145.7 (0.8C), 145.4 (0.2C), 135.6 (0.2C), 135.1 (0.8C), 129.9 (1.6C), 129.6 (0.4C), 129.5 (0.4C), 129.0 (1.6C), 103.0 (0.8C), 102.5 (0.2C), 65.8 (0.8C), 65.6 (0.2C), 53.9, 53.5 (0.8C), 53.2 (0.2C), 37.1 (0.2C), 34.9 (0.8C), 34.0 (0.8C), 33.4 (0.2C), 27.5 (0.8C), 27.5 (0.2C), 24.0 (0.8C), 23.7 (0.2C), 21.7 (0.8C), 21.7 (0.2C). Anal. Calcd for C17H23NO6S: C, 55.27; H, 6.28; N, 3.79. Found: C, 55.11; H, 6.43; N, 3.58.

4.4.3. 6-(Benzo[1,3]dioxol-5-yl)-5-(2,2-dimethoxyethyl)- 1-methyl-3-(4-toluenesulfonyl)-3,4-dihydro-1H-pyridin-2-one (17).A solution of glutarimide 21 (890 mg, 2.4 mmol) in dry THF (40 mL) was added to a rapidly stirred suspen-sion of sodium hydride (140 mg, 3.6 mmol, 60%) in THF (10 mL). After the reaction mixture was stirred at room tem-perature for 15 min, the Grignard reagent, which was pre-pared by 4-bromo-1,2-(methylenedioxy)benzene (1.5 mL, 12.0 mmol) with magnesium (410 mg, 16.8 mmol) in dry THF (30 mL) at reflux temperature for 1 h, was added at room temperature in one portion by syringe. The resulting mixture was stirred at room temperature for 60 min. After the reaction was accomplished (monitored by TLC), acetic anhydride (2.3 mL, 24.1 mmol) was added at room temper-ature for 30 min. After the reaction was accomplished (moni-tored by TLC), the reaction mixture was quenched with water (3 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (330 mL) and dried with anhydrous MgSO4, filtered, and concentrated. The residue

(n-hexane/ethyl acetate/triethyl amine¼6:1:0.01 to 4:1:0.01) to afford 17 (733 mg, 65%) as a pale yellow oil; 1_{H NMR (500 MHz, CDCl} 3) d 7.81 (d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 1H), 6.84–6.77 (m, 1H), 6.70–6.66 (m, 1H), 6.58–6.55 (m, 1H), 5.98 (dd, J¼1.5, 3.0 Hz, 2H), 4.40 (t, J¼5.5 Hz, 1H), 4.00 (dd, J¼4.0, 7.0 Hz, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 3.15 (dd, J¼3.5, 17.5 Hz, 1H), 2.95 (dd, J¼7.0, 17.5 Hz, 1H), 2.75 (s, 3H), 2.44 (s, 3H), 2.37– 2.25 (m, 2H); HRMS (ESI, M+_{+1) calcd for C}

24H28NO7S 474.1578, found 474.1585.

4.4.4. 1-Methyl-8,9-methylenedioxy-3-(4-toluenesul-fonyl)-3,4-dihydro-1H-benzo[h]quinoline-2-one (22). To a solution of lactam 17 (1.8 g, 3.3 mmol) and anhydrous MgSO4(2.0 g) in dichloromethane was added boron trifluo-ride diethyl ether complex (0.75 mL, 8.1 mmol) at30_C. The mixture was stirred for 20 h at that temperature. The re-action mixture was filtered and was added saturated sodium bicarbonate solution to neutralize. The mixture was ex-tracted with dichloromethane (350 mL). The combined organic layers were washed with brine (240 mL), dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 22 (1.5 g, 93%) as a white solid; 1_{H NMR (500 MHz, CDCl} 3) d 7.49 (d, J¼8.0 Hz, 2H), 7.42 (d, J¼8.5 Hz, 1H), 7.18 (d, J¼8.5 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J¼8.0 Hz, 2H), 6.75 (s, 1H), 6.05 (d, J¼6.0 Hz, 2H), 4.28 (t, J¼5.5 Hz, 1H), 3.55–3.54 (m, 2H), 3.44 (s, 3H), 2.20 (s, 3H); 13_{C NMR (125 MHz,} CDCl3) d 165.3, 147.4, 147.2, 144.5, 136.6, 135.4, 131.9, 129.0 (2C), 128.7 (2C), 124.8, 124.0, 121.8, 121.1, 104.5, 101.4, 99.9, 67.0, 38.4, 28.0, 21.3; HRMS (ESI, M+_{+1) calcd} for C22H20NO5S 410.1062, found 410.1059. Anal. Calcd for C22H19NO5S: C, 64.53; H, 4.68; N, 3.42. Found C, 64.23; H, 4.39; N, 3.45. Mp: 209.4–211.3C.

4.4.5. 1-Methyl-8,9-methylenedioxy-3-(4-toluenesul-fonyl)-1H-benzo[h]quinoline-2-one (16).To a solution of 22 (610 mg, 1.5 mmol) in toluene (35 mL) was added DDQ (1.0 g, 4.5 mmol). The resulting mixture was refluxed for 1 day. After removal of the precipitates by filtration, a large amount of 5% NaOH was added to the filtrate and the mixture was extracted with dichloromethane (3 30 mL). The combined organic layers were washed with 5% NaOH, dried over anhydrous MgSO4, filtered and evap-orated. Purification on silica gel (dichloromethane/meth-anol¼200:1 to 100:1) produced 16 (500 mg, 83%) as a white solid; 1_{H NMR (500 MHz, CDCl} 3) d 8.78 (s, 1H), 8.06 (d, J¼8.5 Hz, 2H), 7.70 (s, 1H), 7.53 (d, J¼8.5 Hz, 1H), 7.50 (d, J¼8.5 Hz, 1H), 7.33 (d, J¼8.5 Hz, 2H), 7.21 (s, 1H), 3.95 (s, 3H), 2.42 (s, 3H); 13_{C NMR (125 MHz,} CDCl3) d 159.3, 149.6, 147.5, 144.5, 142.9, 142.3, 136.6, 135.3, 129.4 (2C), 129.3 (2C), 129.2, 125.1, 124.2, 119.2, 116.1, 105.5, 103.2, 102.1, 40.5, 21.7; HRMS (ESI, M+₊₁₎ calcd for C22H18NO5S 408.0906, found 408.0903. Anal.

at room temperature for 1.5 h. After the reaction was accom-plished (monitored by TLC), the reaction mixture was quenched with water (2 mL) and filtered through Celite. The organic layer was extracted with ethyl acetate (3 20 mL) and dried with anhydrous MgSO4, filtered, and con-centrated. The crude product was purified by silica gel chro-matography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford 23 (108 mg, 98%), which was crystallized from n-hexane/ethyl acetate as a colorless solid; 1_{H NMR (500 MHz, CDCl}

3) d 7.41 (d, J¼8.5 Hz, 1H), 7.24 (d, J¼8.5 Hz, 2H), 7.13 (d, J¼ 8.5 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J¼8.5 Hz, 2H), 6.63 (s, 1H), 6.05–6.04 (m, 2H), 5.77–5.69 (m, 1H), 5.15 (d, J¼ 10.5 Hz, 1H), 5.07 (d, J¼17.0 Hz, 1H), 4.30 (s, 1H), 3.67 (t, J¼7.0 Hz, 1H), 3.41 (s, 3H), 2.45–2.40 (m, 1H), 2.28– 2.22 (m, 1H), 2.08 (s, 3H);13C NMR (125 MHz, CDCl3) d 164.3, 147.2, 147.1, 144.3, 136.1, 134.8, 133.0, 131.9, 128.8 (2C), 128.2 (2C), 124.9, 124.4, 123.9, 121.8, 119.4, 104.4, 101.4, 100.2, 72.1, 39.2, 39.1, 38.8, 21.1; HRMS (ESI, M++1) calcd for C25H24NO5S 450.1375, found 450.1373. Anal. Calcd for C25H23NO5S: C, 66.80; H, 5.16; N, 3.12. Found C, 66.88; H, 5.24; N, 3.20. Mp: 227.1–228.7C. 4.4.7. 3,4-Diallyl-1-methyl-8,9-methylenedioxy-3-(4-tolu-enesulfonyl)-3,4-dihydro-1H-benzo[h]quinoline-2-one (24). A solution of 23 (108 mg, 0.24 mmol) in dry THF (10 mL) was added to a rapidly stirred suspension of sodium hydride (13 mg, 0.31 mmol, 60%) in dry THF (2 mL). After the reaction mixture was stirred at room temperature for 30 min, the allyl bromide (0.04 mL, 0.48 mmol) was added. The resulting mixture was stirred for 30 h, quenched with water (3 mL), and concentrated under reduced pressure. The residue was diluted with water (3 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (230 mL), dried over anhydrous MgSO4, filtered and evaporated. Purification on silica gel (n-hexane/ethyl acetate¼4:1 to 2:1) produced 24 (111 mg, 94%) as a white solid;1_{H NMR (500 MHz, CDCl} 3) d 8.24 (d, J¼8.0 Hz, 1.2H), 7.45–7.35 (m, 2.8H), 7.12–7.01 (m, 3H), 6.71 (d, J¼7.5 Hz, 0.6H), 6.64 (s, 0.4H), 6.07–6.03 (m, 2H), 5.98–5.90 (m, 0.4H), 5.78–5.67 (m, 1H), 5.39 (d, J¼17.0 Hz, 0.4H), 5.32–5.26 (m, 1.4H), 5.17 (d, J¼10.0 Hz, 0.4H), 4.95 (d, J¼10.0 Hz, 0.6H), 4.87 (d, J¼ 17.0 Hz, 0.6H), 4.73 (d, J¼10.0 Hz, 0.6H), 4.10 (d, J¼17.0 Hz, 0.6H), 3.73–3.70 (m, 0.4H), 3.61–3.58 (m, 0.6H), 3.49–3.44 (m, 3.4H), 3.24–3.14 (m, 1H), 3.04–2.96 (m, 0.8H), 2.74–2.68 (m, 0.6H), 2.44 (s, 1.8H), 2.29 (dd, J¼7.5, 16.0 Hz, 0.6H), 2.16 (dd, J¼7.5, 16.0 Hz, 0.6H), 2.06 (s, 1.2H);13_{C NMR (125 MHz, CDCl} 3) d 168.6 (0.6C), 167.2 (0.4C), 147.8 (0.6C), 147.4 (0.6C), 147.1 (0.4C), 146.9 (0.4C), 144.9 (0.6C), 143.6 (0.4C), 137.4 (0.4C), 136.0 (1.2C), 135.3 (0.8C), 134.5 (0.6C), 131.8 (0.4C), 131.7 (0.4C), 131.6 (0.6C), 131.3 (1.2C), 130.3 (0.6C), 129.3 (1.2C), 128.5 (0.8C), 128.3 (0.8C), 125.7 (0.6C), 124.9 (0.4C), 124.7, 124.4 (0.6C), 122.3 (0.4C), 121.7 (0.6C), 121.1 (0.4C), 121.1 (0.4C), 119.9 (0.6C), 117.6 (0.6C), 116.5 (0.4C), 104.8 (0.6C), 104.2 (0.4C), 101.4 (0.6C), 101.3 (0.4C), 100.3 (0.4C), 99.8 (0.6C), 75.0 (0.6C), 74.7 (0.4C), 44.6 (0.6C), 39.7 (0.4C), 39.3 (0.4C), 38.5 (0.6C), 36.5 (0.6C), 36.1 (0.6C), 34.0 (0.4C), 29.5 (0.4C), 21.6 (0.6C), 4.4.8. 5-Methyl-2,3-methylenedioxy-6a-(4-toluenesul- fonyl)-6a,7,10,10a-tetrahydrobenzo[c]phenanthridin-6(5H)-one (25). First generation Grubbs catalyst (22 mg, 0.02 mmol) was added to a solution of 24 (100 mg, 0.2 mmol) in dichloromethane (10 mL) at room tempera-ture for 7.5 h. The mixtempera-ture was concentrated and purified by flash column chromatography (n-hexane/ethyl acetate¼ 4:1 to 2:1) to yield 25 (91 mg, 96%), which was crystal-lized from n-hexane/ethyl acetate as colorless crystals; 1_H NMR (500 MHz, CDCl3) d 7.52 (d, J¼8.5 Hz, 1H), 7.29 (d, J¼8.5 Hz, 1H), 7.12 (d, J¼8.0 Hz, 2H), 7.07 (s, 1H), 6.78 (d, J¼8.0 Hz, 2H), 6.62 (s, 1H), 6.05 (dd, J¼1.0, 3.5 Hz, 2H), 6.02–5.97 (m, 1H), 5.86–5.82 (m, 1H), 3.66 (dd, J¼6.5, 11.5 Hz, 1H), 3.48–3.43 (m, 1H), 3.41 (s, 3H), 3.31–3.23 (m, 1H), 2.82–2.72 (m, 2H), 2.15 (s, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 166.7, 144.6, 144.6, 141.3, 134.05, 133.8, 129.3, 126.0 (2C), 126.0 (2C), 123.1, 122.27, 122.25, 120.5, 118.8, 117.9, 101.8, 98.7, 97.8, 66.7, 36.4, 35.3, 28.3, 23.6, 18.6; HRMS (ESI, M+_{+1) calcd for C}

26H23NO5S 462.1375, found 462.1377. Anal. Calcd for C26H22NO5S: C, 67.66; H, 5.02; N, 3.03. Found C, 66.25; H, 4.63; N, 2.88. Mp: 203.2–205.1C.

4.4.9. 7,10-Dihydro-5-methyl-2,3-methylenedioxyben-zo[c]phenanthridin-6(5H)-one (26). To a solution of 25 (70 mg, 0.15 mmol) in dry THF (10 mL) was added DBU (0.05 mL, 0.3 mmol). The resulting mixture was heated to 60C for 20 h. After the reaction was accomplished (monitored by TLC), the resulting mixture was concen-trated under reduced pressure. The residue was diluted with water (10 mL) and extracted with dichloromethane (330 mL). The combined organic layers were washed with brine (240 mL), dried over anhydrous MgSO4, fil-tered and evaporated. Purification on silica gel (n-hexane/ ethyl acetate¼2:1 to 1:1) to yield 26 (45 mg, 93%) as a white solid; 1_{H NMR (500 MHz, CDCl} 3) d 7.71 (s, 1H), 7.52 (d, J¼8.5 Hz, 1H), 7.49 (d, J¼8.5 Hz, 1H), 7.18 (s, 1H), 6.11 (s, 2H), 6.05–6.00 (m, 1H), 6.94–6.90 (m, 1H), 3.98 (s, 3H), 3.58–3.54 (m, 2H), 3.34–3.30 (m, 2H); 13_{C NMR (125 MHz, CDCl} 3) d 164.3, 147.7, 146.8, 139.3, 137.5, 132.2, 124.5, 124.1, 122.8, 121.8, 119.9, 119.2, 117.8, 104.8, 102.8, 101.5, 40.5, 27.0, 25.5; HRMS (ESI, M+_{+1) calcd for C}

19H16NO3306.1130, found 306.1129. Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found C, 74.29; H, 5.24; N, 4.46. Mp: 232.6– 233.9C.

4.4.10. 5-Methyl-2,3-methylenedioxybenzo[c]phenan-thridin-6(5H)-one (27). To a solution of 26 (36 mg, 0.1 mmol) in dry THF (10 mL) was added DDQ (79 mg, 0.35 mmol), and the resulting mixture was refluxed for 2 h. The mixture was concentrated and purified by column chro-matography (dichloromethane/methanol¼1:0 to 100:1)) to yield 27 (38 mg, 99%) as a pale yellow oil; 1_{H NMR} (500 MHz, CDCl3) d 8.55 (dd, J¼1.0, 8.0 Hz, 1H), 8.27 (d, J¼8.0 Hz, 1H), 8.12 (d, J¼8.5 Hz, 1H), 7.79–7.76 (m, 1H), 7.64 (s, 1H), 7.60–7.57 (m, 2H), 7.19 (s, 1H), 6.11 (s, 2H), 3.99 (s, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 164.8, 9833 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

4.5. Total synthesis of oxyisoterihanine 15b

4.5.1. 5-Benzyl-8,9-epoxy-8,9-dihydroxy-2,3-methylene- dioxy-6a-(4-toluenesulfonyl)-6a,7,8,9,10,10a-hexahydro-benzo[c]phenanthridin-6(5H)-one (28).To a solution of 25 (30 mg, 0.065 mmol) in dichloromethane (2.0 mL) was added m-CPBA (28 mg, 0.16 mmol) at room temperature for 2 days. After the reaction was accomplished (monitored by TLC), quenched with saturated sodium bicarbonate aque-ous solution, and extracted with dichloromethane (3 20 mL). The combined organic layers were washed with brine (240 mL), dried over anhydrous MgSO4, filtered and evaporated. Purification on silica gel (n-hexane/ethyl acetate¼4:1 to 2:1) produced 28 (29 mg, 94%) as a white solid; 1H NMR (500 MHz, CDCl3) d 7.46 (d, J¼8.5 Hz, 1H), 7.25 (d, J¼8.5 Hz, 1H), 7.18 (d, J¼8.0 Hz, 2H), 7.03 (s, 1H), 6.80 (d, J¼8.0 Hz, 2H), 6.72 (s, 1H), 6.06 (d, J¼9.5 Hz, 2H), 3.64–3.53 (m, 3H), 3.49–3.45 (m, 1H), 3.39 (s, 3H), 2.98–2.86 (m, 2H), 2.54 (d, J¼17.5 Hz, 1H), 2.10 (s, 3H); 13_{C NMR (125 MHz, CDCl} 3) d 168.0, 147.2, 147.2, 144.0, 136.2, 135.4, 131.8, 128.8 (2C), 128.5 (2C), 124.9, 124.1, 121.2, 120.2, 104.3, 101.4, 100.3, 67.2, 53.3, 50.5, 39.3, 34.0, 29.6, 25.2, 21.2; HRMS (ESI, M+_{+1) calcd for C}

26H24NO6S 478.1324, found 478.1321. Mp: 202.6C (dec).

4.5.2. 9-Hydroxy-8-methoxy-5-methyl-2,3-methylene- dioxy-6a-(4-toluenesulfonyl)-6a,7,8,9,10,10a-hexahydro-benzo[c]phenanthridin-6(5H)-one (29).To a solution of 28 (109 mg, 0.23 mmol) in methanol (9 mL) and dichlorome-thane (3 mL) was added boron trifluoride diethyl ether com-plex (0.09 mL, 0.68 mmol) in an ice bath for 1 h and allowed to warm to room temperature for 35 h. After the reaction was accomplished (monitored by TLC), quenched with saturated sodium bicarbonate aqueous solution, and extracted with di-chloromethane (330 mL). The combined organic layers were washed with brine (240 mL), dried over anhydrous MgSO4, filtered and evaporated. Purification on silica gel (dichloromethane/methanol¼40:1) produced 29 (98 mg, 85%), which was crystallized from n-hexane/ethyl acetate as colorless crystals; 1H NMR (500 MHz, CDCl3) d 7.53 (d, J¼8.0 Hz, 1H), 7.29 (d, J¼8.0 Hz, 1H), 7.07 (s, 1H), 6.81 (d, J¼7.5 Hz, 2H), 6.55 (d, J¼7.5 Hz, 2H), 6.25 (s, 1H), 6.02 (dd, J¼1.0, 4.5 Hz, 2H), 4.34–4.32 (m, 1H), 3.80 (dd, J¼4.0, 13.0 Hz, 1H), 3.57–3.55 (m, 1H), 3.54 (s, 3H), 3.37 (dd, J¼3.5, 16.0 Hz, 1H), 3.34 (s, 3H), 3.21 (dt, J¼3.5, 13.5 Hz, 1H), 2.39 (dd, J¼3.5, 16.0 Hz, 1H), 2.21 (td, J¼3.5, 13.5 Hz, 1H), 2.12 (s, 3H); 13_{C NMR} (125 MHz, CDCl3) d 170.4, 147.0, 146.9, 143.5, 138.6, 136.6, 131.7, 128.4 (2C), 127.9 (2C), 125.0, 124.9, 121.7, 120.3, 104.4, 101.2, 100.1, 78.0, 70.2, 67.8, 57.3, 38.8, 35.0, 27.7, 26.8, 21.0; HRMS (ESI, M+_{+1) calcd for} C27H28NO7S 510.1586, found 510.1587. Anal. Calcd for C27H27NO7S: C, 63.64; H, 5.34; N, 2.75. Found C, 63.34; H, 5.21; N, 2.75. Mp: 188.6C (dec).

accomplished and allowed to warm to room temperature, then quenched with water (3 mL), and concentrated under reduced pressure. The residue was diluted with water (3 mL) and extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine (230 mL), dried over anhydrous MgSO4, filtered and evaporated. The residue was dissolved in THF (5 mL) and added DBU (0.02 mL, 0.13 mmol). The resulting mixture was refluxed for 1 h. Af-ter the reaction was accomplished (monitored by TLC), the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with dichloromethane (530 mL). The combined organic layers were washed with brine (240 mL), dried over anhy-drous MgSO4, filtered and evaporated. Purification on silica gel (dichloromethane/methanol¼100:1) to yield 15b (11.7 mg, 65%) as a white solid; 1_{H NMR (300 MHz,} CDCl3) d 7.97 (d, J¼8.4 Hz, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.56 (d, J¼8.4 Hz, 1H), 7.19 (s, 1H), 6.18 (s, 1H), 6.10 (s, 2H), 4.08 (s, 3H), 3.98 (s, 3H); HRMS (FAB, M+_{+1) C} 20H16NO5 350.1028, found 350.1037. Mp: 299.8–302.0C. Acknowledgements

The authors would like to thank the National Science Coun-cil of the Republic of China for financial support.

Supplementary data

Supplementary data associated with this article can be found in the online version, atdoi:10.1016/j.tet.2007.06.101.

References and notes

1. (a) Smith, D. Comprehensive Organic Chemistry; Sammes, P. G., Ed.; Pergamon: Oxford, 1979; Vol. 4, p 3; (b) Bailey, T.; Goe, G.; Scriven, E. Heterocyclic Compounds; Newkome, G. R., Ed.; Wiley: New York, NY, 1984; Vol. 144, p 1, Part 5; (c) McKillop, A.; Boulton, A. Comprehensive Heterocyclic Chemistry; McKillop, A., Boulton, A., Eds.; Pergamon: Oxford, 1984; Vol. 2, p 67.

2. (a) Almqvist, F.; Pemberton, N.; Jakobsson, L. Org. Lett. 2006, 8, 935–938; (b) Scriven, E. F. V. Comprehensive Organic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 2; (c) Elbein, A. D.; Molyneux, R. J. Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, NY, 1981; Vol. 5, p 1; (d) John, G. Comprehensive Organic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 167; (e) Torres, M.; Gil, M. Curr. Org. Chem. 2005, 9, 1757–1779.

3. (a) For a review, see: Rigby, J. Synlett 2000, 1–12; (b)

Chapman and Hall: London, 1989; (g) Daly, J. W. J. Nat. Prod. 1998, 61, 162–172; (h) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett. 2007, 9, 2421–2423 and references cited therein.

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6. (a) The configuration of 23, 25 and 29 were established by their single-crystal X-ray analysis and1H NMR; (b) The stereo-chemistry of 9 was based on the related compound 23; (c) The stereochemistry of 24 and 28 were based on the structures of 25 and 29.

7. Takahashi, T.; Tsai, F.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M,; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059–5067 and references cited therein.

8. (a) Ninomiya, I.; Naito, T. Recent Developments in the Chemistry of Natural Carbon Compounds; Bognar, R., Szantay, Cs., Eds.; Akademiai Kiado: Budapest, 1984; Vol. 10, p 11; Simanek, V. The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1985; Vol. 26, p 185; (b) Hanaoka, M. The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1988; Vol. 33, p 141; (c) Bentley, K. W. Nat. Prod. Rep. 1991, 8, 350–352; Bentley, K. W. Nat. Prod. Rep. 1992, 9, 374–375; Bentley, K. W. Nat. Prod. Rep. 1993, 10, 457–

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9835 T.-H. Tsai et al. / Tetrahedron 63 (2007) 9825–9835

New Approach to 2-Quinolinones

Cheng-Chieh Huang and Nein-Chen Chang*

Department of Chemistry, National Sun Yat-Sen UniVersity, Kaohsiung 804, Taiwan [email protected]

Received December 17, 2007

ABSTRACT

An efficient approach to 2-quinolinone derivatives 1 via Diels−Alder cyclization ofexo-diene lactams 5 and dienophiles is reported.

Polysubstituted quinolinones, dihydroquinolines, tetrahyd-roquinolines, and quinolines are common motifs found in

natural products and pharmaceutical agents.1 _Furthermore,

2-quinolinone derivatives have been paid considerable at-tention in organic chemistry due to their use as

anti-inflammatories, antihypertensives, and analgesics2_{and in the}

preparation of antipsychotic agents.3 _{As such, a common}

(1) For examples, see the following. Quinolin-2-ones: (a) Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, I. M.; Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36, 3397. (b) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.; Stevenson, G. I.; Carling, R. W.; Baker, R.; Marshell, G. R.; Kemp, J. A.; Foster, A. C.; Grimwood, S.; Hargreaves, R.; Hurley, C.; Saywell, K. L.; Tricklebank, M. D.; Leeson, P. D. J. Med. Chem. 1997, 40, 4053. (c) Foucaud, B.; Laube, B.; Schemm, R.; Kreimeyer, A.; Goeldner, M.; Betz, H. J. Biol. Chem. 2003, 278, 24011. Tetrahydroquinolines: (d) Katritzky, A.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. Dihydroquino-lines: (e) Michne, W. F.; Guiles, J. W.; Treasurywala, A. D.; Castonguay,

Scheme 1 Scheme 2 Scheme 3

ORGANIC

LETTERS

2008

Vol. 10, No. 4

673-676

Although many methods have been developed for the synthesis of quinolines and their derivatives, most are not

the development of novel synthetic approaches remains an active research area.5_{2-Quinolinones, reasonable precursors}

of quinoline, are useful intermediates in organic synthesis.6

In general, the synthesis of quinolinone starts with benzene and then builds up to the second ring. Following this strategy, the presence of deactivated electron-withdrawing substituents at benzene ring normally will give low yields of quinolinone.

(4) (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett. 1999, 40, 1499. (b) Zhou, L.; Zhang, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2899. (c) Larock, R. C.; Kero, M.-Y. Tetrahedron Lett. 1991, 32, 569. (d) Zhou, L.; Tu, S.; Shi, D.; Dai, G.; Chen, W. Synthesis 1988, 851. (e) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291. (f) Ozawa, F.; Yanagihara, H.; Yamamoto, A. J. Org. Chem. 1986, 51, 415.

(5) Wang, G. W.; Jia, C. S.; Dong, Y. W. Tetrahedron Lett. 2006, 47, 1059.

(6) (a) Holzapfel, C. W.; Dwyer, C. Heterocycles 1998, 48, 215. (b) Cortese, N. A.; Ziegler, C. B.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem.

1978, 43, 2952. (c) Chorbadjiev, S. Synth. Commun. 1990, 20, 3497. (d)

Kobayashi, K.; Kitamura, T.; Yoneda, K.; Morikawa, O.; Konishi, H. Chem. Lett. 2000, 798. (e) Hino, K.; Furukawa, K.; Nagai, Y.; Uno, H. Chem. Pharm. Bull. 1980, 28, 2618. (f) Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110. (g) Ferrer, P.; Avendano, C.; Soellhuber, M. Liebigs Ann. Chem. 1995, 1895. (h) Scheme 4

Table 1. Diels-Alder Reaction of Diene 8 with Various Dienophiles

Here, we wish to report a new approach to 2-quinolinones 1 in which the construction of benzene ring was at the last stage.

Recently, we developed a one-pot procedure which converted readily available glutarimide 2 to the correspond-ing ene lactams 3 (Scheme 1).7_{We envisioned that these}

results can be applied to the synthesis of exo-diene lactams

5. Diels-Alder cyclization of 5 with dienophiles and then

aromatization of the resulting products 6 will give 2-quino-linones 1 (Scheme 2).

We first studied the synthesis of diene lactam 8. Sequential reaction of readily available 78_{with sodium hydride,}

meth-ylmagnesium bromide, and then acetic anhydride furnished diene lactam 8 in 55% yield. Diene 8 is very stable and can be stored at room temperature for several months.

With diene 8 in hand, we then focused our attention on the Diels-Alder reaction of 8 with various dienophiles (Table 1). The reactions of diene 8 with alkene dienophiles provide regioselectively the corresponding bicyclic ene lactams in reasonable yield (entries 1-3).9_{Dienophiles with}

triple bonds similarly undergo Diels-Alder reaction (entries 4 and 5) (Table 1). In the case of ethyl propiolate, a mixture of 13a and 13b in a 2:1 ratio was observed. Presumably, part of 13a was air oxidized to 13b during the reaction. Aza-polycyclic aromatic compounds have been shown in recent