Asymmetric Total Synthesis and Structural Revision of Antiangiogenic Natural Product Penduliflaworosin

doi:10.6023/cjoc202409025

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (3): 959-968.DOI: 10.6023/cjoc202409025 Previous Articles Next Articles

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抗血管生成天然产物Penduliflaworosin的不对称全合成及结构修正

斯绪格, 蔡泉^*()

复旦大学化学系上海 200433

收稿日期:2024-09-20 修回日期:2024-10-31 发布日期:2024-12-05
基金资助:
国家自然科学基金(22071030); 国家自然科学基金(22222104); 上海市科学技术委员会(22JC1401102)

Asymmetric Total Synthesis and Structural Revision of Antiangiogenic Natural Product Penduliflaworosin

Xuge Si, Quan Cai()

Department of Chemistry, Fudan University, Shanghai 200433

Received:2024-09-20 Revised:2024-10-31 Published:2024-12-05
Contact: * E-mail: quan_cai@fudan.edu.cn
Supported by:
National Natural Science Foundation of China(22071030); National Natural Science Foundation of China(22222104); Science and Technology Commission of Shanghai Municipality(22JC1401102)

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Abstract

Penduliflaworosin is a diterpenoid natural product isolated from the medicinal plant Croton crassifolius, which demonstrates highly potent antiangiogenic activities. In this work, enantioselective total synthesis of penduliflaworosin and its C4 epimer has been realized for the first time, thus revising the erroneous structure of penduliflaworosin shown in previous literatures. In the synthesis, the main cis-decalin moiety bearing two quaternary stereogenic centers was efficiently constructed by tandem olefin migration/asymmetric inverse-electron-demand Diels-Alder reaction of 2-pyrone with polysubstituted 1,4- cyclohexadiene. From this intermediate, enantioselective synthesis of penduliflaworosin and its epimer was realized by subsequent several key steps, involving the 1,2-addition with 3-furanyl zinc reagent, oxidation, and olefin isomerization.

Key words: penduliflaworosin, antiangiogenic activity, asymmetric total synthesis, inverse-electron-demand Diels-Alder reaction

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Xuge Si, Quan Cai. Asymmetric Total Synthesis and Structural Revision of Antiangiogenic Natural Product Penduliflaworosin[J]. Chinese Journal of Organic Chemistry, 2025, 45(3): 959-968.

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References 14

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Carbon No.	ent-2		Penduliflaworosin		32
Carbon No.	¹H NMR	¹³C NMR	¹H NMR	¹³C NMR	¹H NMR	¹³C NMR
1	2.21 (dd, J=14.0, 8.0 Hz), 2.17~1.86 (m), 1.77~1.52 (m), 1.48 (ddd, J=13.6, 10.4, 3.2 Hz)	24.1	2.06 (m), 1.80 (m)	24.6	2.11~2.04 (m), 1.89~1.78 (m)	24.8
2		19.6	1.70 (m)	19.0	1.76~1.55 (m)	19.1
3		26.8	2.21 (dd, J=13.9, 7.5 Hz), 1.93 (m)	26.5	2.22 (dd, J=14.0, 7.6 Hz), 2.01~1.90 (m)	26.7
4		47.6	—	47. 5	—	47.6
5		135.0	—	134.8	—	135.0
6		26.9	1.82 (m), 1.54 (m)	26.6	1.89~1.78 (m), 1.76~1.55 (m)	26.8
7		35.8	1.97 (m), 1.62 (m)	34.9	2.01~1.90 (m), 1.76~1.55 (m)	35.1
8		38.3	1.71 (m)	37.7	1.76~1.55 (m)	37.9
9	—	53.4	—	53.2	—	53.4
10	—	129.4	—	128.6	—	128.8
11	2.70 (dd, J=14.0, 8.4 Hz), 2.24~2.18 (m)	41.6	2.80 (dd, J=13.9, 8.0 Hz), 2.21 (dd, J=13.9, 8.0 Hz)	41.3	2.81 (dd, J=14.0, 8.8 Hz), 2.22 (dd, J=14.0, 7.6 Hz)	41.4
12	5.44 (t, J=8.0 Hz)	72.1	5.44 (t, J=8.0 Hz)	72.1	5.45 (t, J=8.0 Hz)	72.3
13	—	125.8	—	125.8	—	126.0
14	6.41 (brs)	108.3	6.40 (d, 0.9 Hz)	108.2	6.41 (brs)	108.3
15	7.44 (t, J=1.6 Hz)	144.2	7.43 (brs)	144.0	7.44 (t, J=1.6 Hz)	144.2
16	7.46 (brs)	139.5	7.44 (brs)	139.2	7.45 (brs)	139.4
17	1.05 (d, J=6.8 Hz)	16.5	1.02 (d, J=6.7 Hz)	16.2	1.02 (d, J=6.4 Hz)	16.4
18	1.29 (s)	22.8	1.33 (s)	22.8	1.34 (s)	23.0
19	—	177.9	—	178.1	—	178.3
20	—	177.6	—	177.4	—	177.6
21	3.67 (s)	52.2	3.66 (s)	51.9	3.67 (s)	52.1

Carbon No.	ent-2		Penduliflaworosin		32
Carbon No.	¹H NMR	¹³C NMR	¹H NMR	¹³C NMR	¹H NMR	¹³C NMR
1	2.21 (dd, J=14.0, 8.0 Hz), 2.17~1.86 (m), 1.77~1.52 (m), 1.48 (ddd, J=13.6, 10.4, 3.2 Hz)	24.1	2.06 (m), 1.80 (m)	24.6	2.11~2.04 (m), 1.89~1.78 (m)	24.8
2		19.6	1.70 (m)	19.0	1.76~1.55 (m)	19.1
3		26.8	2.21 (dd, J=13.9, 7.5 Hz), 1.93 (m)	26.5	2.22 (dd, J=14.0, 7.6 Hz), 2.01~1.90 (m)	26.7
4		47.6	—	47. 5	—	47.6
5		135.0	—	134.8	—	135.0
6		26.9	1.82 (m), 1.54 (m)	26.6	1.89~1.78 (m), 1.76~1.55 (m)	26.8
7		35.8	1.97 (m), 1.62 (m)	34.9	2.01~1.90 (m), 1.76~1.55 (m)	35.1
8		38.3	1.71 (m)	37.7	1.76~1.55 (m)	37.9
9	—	53.4	—	53.2	—	53.4
10	—	129.4	—	128.6	—	128.8
11	2.70 (dd, J=14.0, 8.4 Hz), 2.24~2.18 (m)	41.6	2.80 (dd, J=13.9, 8.0 Hz), 2.21 (dd, J=13.9, 8.0 Hz)	41.3	2.81 (dd, J=14.0, 8.8 Hz), 2.22 (dd, J=14.0, 7.6 Hz)	41.4
12	5.44 (t, J=8.0 Hz)	72.1	5.44 (t, J=8.0 Hz)	72.1	5.45 (t, J=8.0 Hz)	72.3
13	—	125.8	—	125.8	—	126.0
14	6.41 (brs)	108.3	6.40 (d, 0.9 Hz)	108.2	6.41 (brs)	108.3
15	7.44 (t, J=1.6 Hz)	144.2	7.43 (brs)	144.0	7.44 (t, J=1.6 Hz)	144.2
16	7.46 (brs)	139.5	7.44 (brs)	139.2	7.45 (brs)	139.4
17	1.05 (d, J=6.8 Hz)	16.5	1.02 (d, J=6.7 Hz)	16.2	1.02 (d, J=6.4 Hz)	16.4
18	1.29 (s)	22.8	1.33 (s)	22.8	1.34 (s)	23.0
19	—	177.9	—	178.1	—	178.3
20	—	177.6	—	177.4	—	177.6
21	3.67 (s)	52.2	3.66 (s)	51.9	3.67 (s)	52.1

抗血管生成天然产物Penduliflaworosin的不对称全合成及结构修正

Asymmetric Total Synthesis and Structural Revision of Antiangiogenic Natural Product Penduliflaworosin

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