N-Methyl Pratensilin B分子的首次全合成

doi:10.6023/cjoc202509002

摘要/Abstract

(±)-Pratensilin是一类从链霉菌中分离得到的天然产物, 因具有显著的抗菌与抗肿瘤活性, 在天然产物化学领域受到了人们的关注, 但其分子结构包含A、B、C、D、E五个环系, 且C环与E环共同构成特征性(5,5)-(N,O)-螺缩酮骨架, 合成难度较大, 迄今尚未见化学合成相关报道. 针对N-Methyl Pratensilin B分子开展全合成研究: 首先以三氟甲磺酸铜(Cu(OTf)₂)为催化剂, 外消旋噁唑啉为配体, 通过催化反应高效构建目标分子关键的(5,5)-(N,O)-螺缩酮骨架; 随后在催化量氢氧化锂(LiOH)作用下, 利用分子内Aldol环化反应顺利构建B环系. 通过上述关键步骤的设计与优化, 最终完成N-Methyl Pratensilin B分子的首次全合成. 本研究为(±)-Pratensilin类天然产物的合成化学研究提供了可行策略, 也为其后续生物活性深入探究奠定物质基础.

关键词: (N,O)-螺缩酮, Aldol环化, Pratensilin, 全合成

(±)-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

引用此文

程文富, 赵明豪, 杨宇晨, 王丽佳. N-Methyl Pratensilin B分子的首次全合成[J]. 有机化学, 2026, 46(2): 670-677.

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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图/表 9

图1. 天然产物Pratensilin分子结构及其生物活性

Figure 1. Molecular structure and biological activity of the natural product of Pratensilins

图式1. N-Methyl Pratensilin B分子逆合成分析

Scheme 1. Retrosynthetic analysis of N-methyl Pratensilin B

图式2. 化合物5的合成

Scheme 2. Synthesis of compound 5

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

表1. 化合物10的合成中碱的优化a

Table 1. Optimization of the base in the synthesis of compound 10

图式3. 螺环化合物3的构建

Scheme 3. Construction of spirocyclic compound 3

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

表2. 化合物11的合成条件优化a

Table 2. Optimization of the synthesis conditions for compound 11

图式4. N-Methyl Pratensilin B的全合成

Scheme 4. Total synthesis of N-methyl Pratensilin B

图式5. 螺手性中心构型翻转

Scheme 5. Inversion of the configuration of spiro chiral center

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

表3. Aldol缩合环化反应条件优化

Table 3. Optimization of reaction conditions for Aldol condensation cyclization

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