The First Total Synthesis of N-Methyl Pratensilin B

doi:10.6023/cjoc202509002

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (2): 670-677.DOI: 10.6023/cjoc202509002 Previous Articles Next Articles

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N-Methyl Pratensilin B分子的首次全合成

程文富^a, 赵明豪^a, 杨宇晨^a, 王丽佳^a^,^b^,^*()

^a 华东师范大学化学与分子工程学院上海市分子治疗与新药研发工程技术研究中心上海 200062
^b 上海市分子智造前沿科学基地上海 200062

收稿日期:2025-09-03 修回日期:2025-09-17 发布日期:2025-10-09
通讯作者: 王丽佳
基金资助:
国家自然科学基金重大研究计划培育项目(91956103); 面上项目(22571088)

The First Total Synthesis of N-Methyl Pratensilin B

Wenfu Cheng^a, Minghao Zhao^a, Yuchen Yang^a, Lijia Wang^a^,^b^,^*()

^a Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062
^b Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, Shanghai 200062

Received:2025-09-03 Revised:2025-09-17 Published:2025-10-09
Contact: Lijia Wang
Supported by:
Major Research Plan(91956103); General Program(22571088)

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Abstract

(±)-Pratensilins are a class of natural products isolated from Streptomyces. Owing to their notable antibacterial and antitumor activities, they have been identified as research focus in the field of natural product chemistry. However, their molecular structure comprises five ring systems (A, B, C, D, and E) with the C and E rings jointly forming a characteristic (5,5)-(N,O)-spiroketal scaffold, which poses substantial synthetic challenges. To date, no reports on their chemical synthesis have been documented. To address this gap in the synthetic research of such natural products, this study undertook a total synthesis study targeting the N-methyl Pratensilin B molecule. Firstly, using copper trifluoromethanesulfonate [Cu(OTf)₂] as the catalyst and a racemic oxazoline as the ligand, the key (5,5)-(N,O)-spiroketal scaffold of the target molecule was efficiently constructed via a catalytic reaction. Subsequently, under the action of a catalytic amount of lithium hydroxide (LiOH), the B ring system was successfully constructed through an intramolecular Aldol cyclization reaction. Through the design and optimization of the aforementioned key steps, the first total synthesis of the N-methyl Pratensilin B molecule was ultimately accomplished. This study provides a viable strategy for the synthetic chemistry research of (±)-Pratensilin-type natural products and also lays a material foundation for the in-depth investigation of their subsequent biological activities.

Key words: (N,O)-spiroketal, aldol cyclization, pratensilin, total synthesis

Cite this article

Wenfu Cheng, Minghao Zhao, Yuchen Yang, Lijia Wang. The First Total Synthesis of N-Methyl Pratensilin B[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 670-677.

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References 15

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Entry	Base	t/°C	Yield^b /%
1	NaOEt (1.2 equiv.)	70	N.D.
2	K₂CO₃ (2.0 equiv.)	r.t.	N.R.
3	n-BuLi (1.2 equiv.)	－78 to r.t.	N.R.
4	LHMDS (1.2 equiv.)	－78 to r.t.	N.R.
5	TBAF (5 equiv.)	60	30
6^c	TBAF (3 equiv.)	70	70

Entry	Base	t/°C	Yield^b /%
1	NaOEt (1.2 equiv.)	70	N.D.
2	K₂CO₃ (2.0 equiv.)	r.t.	N.R.
3	n-BuLi (1.2 equiv.)	－78 to r.t.	N.R.
4	LHMDS (1.2 equiv.)	－78 to r.t.	N.R.
5	TBAF (5 equiv.)	60	30
6^c	TBAF (3 equiv.)	70	70

Entry	Conditions	Yield^b/%
1	Tf₂O, Py, DMAP, DCM, 24 h	29
2	Et₃N, PhNTf₂, DMAP, DCM, 24 h	46
3	K₂CO₃, PhNTf₂, THF, 7 h	96
4^c	K₂CO₃, PhNTf₂, THF, 7 h	97

Entry	Conditions	Yield^b/%
1	Tf₂O, Py, DMAP, DCM, 24 h	29
2	Et₃N, PhNTf₂, DMAP, DCM, 24 h	46
3	K₂CO₃, PhNTf₂, THF, 7 h	96
4^c	K₂CO₃, PhNTf₂, THF, 7 h	97

Entry	Conditions	t/°C	Yield^a/%
1	TsOH (20 mol%), DCE, 24 h	80	N.R.
2	L-Proline (30 mol%), CH₃CN, 24 h	r.t.	N.R.
3	Pyrrolidine (30 mol%), DCM, 48 h	r.t.	N.R.
4	LDA (1.5 equiv.), THF, 48 h	－78 to r.t.	Messy
5	K₂CO₃ (3.0 equiv.), THF, 48 h	r.t. to 40	N.R.
6	LHMDS (3.0 equiv.), THF, 24 h	－78 to r.t.	N.D.
7	LiOH (10 mol%), i-PrOH, 24 h	r.t.	34

N-Methyl Pratensilin B分子的首次全合成

The First Total Synthesis of N-Methyl Pratensilin B

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