Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy★

doi:10.6023/cjoc202502033

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (9): 3478-3485.DOI: 10.6023/cjoc202502033 Previous Articles Next Articles

ARTICLES

地屈孕酮的形式合成: 一种温和的去芳构化策略^★

姚宏淼^b, 王少东^b, 元鑫鑫^b, 曾乾定^a, 江海^c, 邹义勇^c, 任江萌^b^,^*(), 张宇松^d^,^*(), 曾步兵^a^,^*()

^a 华东理工大学药学院化学生物学上海市重点实验室上海 200237
^b 华东理工大学药学院上海 200237
^c 台州仙琚药业有限公司浙江台州 317016
^d 浙江仙琚制药股份有限公司浙江台州 317300

收稿日期:2025-02-26 修回日期:2025-03-30 发布日期:2025-04-16

Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy^★

Hongmiao Yao^b, Shaodong Wang^b, Xinxin Yuan^b, Qianding Zeng^a, Hai Jiang^c, Yiyong Zou^c, Jiangmeng Ren^b^,^*(), Yusong Zhang^d^,^*(), Bu-Bing Zeng^a^,^*()

^a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237
^b School of Pharmacy, East China University of Science and Technology, Shanghai 200237
^c Taizhou Xianju Pharmaceutical Co. Ltd., Taizhou, Zhejiang 317016
^d Zhejiang Xianju Pharmaceutical Co. Ltd., Taizhou, Zhejiang 317306

Received:2025-02-26 Revised:2025-03-30 Published:2025-04-16
Contact: *E-mail: renjm@ecust.edu.cn; cjq@xjpharma.com; zengbb@ecust.edu.cn
About author:
^★ Academic Papers of the 27^th Annual Meeting of the China Association for Science and Technology.

1. .pdf(1452KB)

Abstract

A dearomatization strategy using dicetolic acid (6) as the starting material to synthesize the core intermediate (10R,13S,14S)-10,13-dimethyl-7,10,11,12,13,14,15,16-octahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione (20) for the formal synthesis of dydrogesterone is presented, achieving a total yield of 21% over nine steps. This approach features an environmentally friendly carbonyl protection strategy and efficient Heck coupling, while avoiding harsh conditions and hazardous reagents throughout the entire process.

Key words: dydrogesterone, dearomatization, steroid, Heck coupling

Cite this article

Hongmiao Yao, Shaodong Wang, Xinxin Yuan, Qianding Zeng, Hai Jiang, Yiyong Zou, Jiangmeng Ren, Yusong Zhang, Bu-Bing Zeng. Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy^★[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3478-3485.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

References 17

[1]	(a) Mirza, F. G.; Patki, A.; Pexman-Fieth, C. Gynecol. Endocrinol. 2016, 32, 97.
	(b) Koren, G.; Gilboa, D. Arch. Dis. Child. 2019, 104, e2.
	(c) Zeyneloglu, H. B.; Tohma, Y. A.; Gunakan, E.; Onalan, G.; Eryılmaz, T. Gynecol. Endocrinol. 2021, 37, 1000.
	(d) Ott, J.; Egarter, C.; Aguilera, A. Gynecol. Endocrinol. 2022, 38, 279.
[2]	(a) Podzolkova, N.; Tatarchuk, T.; Doshchanova, A.; Eshimbetova, G.; Pexman-Fieth, C. Gynecol. Endocrinol. 2016, 32, 246. doi: 10.3109/09513590.2015.1115832 pmid: 26613278
	(b) Stute, P. Gynecol. Endocrinol. 2021, 37, 683. pmid: 26613278
	(c) Sukhikh, G. T.; Adamyan, L. V.; Dubrovina, S. O.; Baranov, I. I.; Bezhenar, V. F.; Kozachenko, A. V.; Radzinsky, V. E.; Orazov, M. R.; Yarmolinskaya, M. I.; Olofsson, J. I. Fertil. Steril. 2021, 116, 1568. pmid: 26613278
	(d) Ashraf, S.; Hussain, T.; Bajwa, S. Z.; Mujahid, A.; Afzal, A. J. Mater. Chem. B 2024, 12, 6905. pmid: 26613278
[3]	(a) El-Zibdeh, M. Y.; Yousef, L. T. Maturitas 2009, 65, 43.
	(b) Carp, H. Gynecol. Endocrinol. 2012, 28, 983.
	(c) Lee, H. J.; Park, T. C.; Kim, J. H.; Norwitz, E.; Lee, B. BioMed. Res. Int. 2017, 2017, 3616875.
[4]	(a) Yalçın Bahat, P.; Yücel, B.; Yuksel Ozgor, B.; Kadiroğulları, P.; Topbas Selçuki, N. F.; Çakmak, K.; Üreyen Özdemir, E. J. Obstet. Gynaecol. 2022, 42, 1276.
	(b) Tang, W.; Zhu, X.; Bian, L.; Zhang, B. Eur. J. Obstet. Gynecol. Reprod. Biol. 2024, 296, 120.
[5]	Taniguchi, F.; Ota, I.; Iba, Y.; Toda, T.; Tagashira, Y.; Ohata, Y.; Kurioka, H.; Endo, Y.; Sunada, H.; Noma, H.; Azuma, Y.; Harada, T. J. Obstet. Gynaecol. Res. 2019, 45, 168. doi: 10.1111/jog.13807
[6]	Colombo, D.; Ferraboschi, P.; Prestileo, P.; Toma, L. J. Steroid Biochem. Mol. Biol. 2006, 98, 56. pmid: 19193503
	(b) Queisser-Luft, A. Early Hum. Dev. 2009, 85, 375. doi: 10.1016/j.earlhumdev.2008.12.016 pmid: 19193503
[7]	Bai, H.; Gu, W.; Zhao, D.; Xu, G.; Tang, W. Green Synth. Catal. 2023, https://doi.org/10.1016/j.gresc.2023.12.001.
[8]	(a) Samir, N.; Suresh, V.; Sachin, S.; Abraham, T.; Pramod, P.; Bhaskar, B. S. WO 2018109622, 2018. pmid: 7616875
	(b) Rappoldt, M. P.; Westerhof, P. Recl. Trav. Chim. Pays-Bas 1961, 80, 43. pmid: 7616875
	(c) Engbert, H. R.; Westerhof, P.; Frederik, L. S. H. US 3198792, 1965. pmid: 7616875
	(d) Rappoldt, M. P.; Rix, T. H. R. Recl. Trav. Chim. Pays-Bas 1971, 90, 27. pmid: 7616875
	(e) Bout, B.; Voorhaar, R.EP 0558119, 1993. pmid: 7616875
	(f) de Lignieres, B.; Dennerstein, L.; Backstrom, T. Maturitas 1995, 21, 251. pmid: 7616875
	(g) Schindler, A. E.; Campagnoli, C.; Druckmann, R.; Huber, J.; Pasqualini, J. R.; Schweppe, K. W.; Thijssen, J. H. H. Maturitas 2003, 46, 7. pmid: 7616875
	(h) Zhang, J.; Wang, C.; Chen, J.WO 2013078575, 2013. pmid: 7616875
	(i) Dong, J.; Wu, Z.; Chen, J.WO 2016154772, 2016. pmid: 7616875
	(j) Pan, C.; Su, G.; Yu, C.; Qin, J.; Li, Y.; Yang, Q.; Fang, S.WO 2021093494, 2021. pmid: 7616875
	(k) Li, X.; Zhang, R.; Li, J.; Liu, N.; Chen, X.; Liu, Y.; Zhao, G.; Ding, K.; Yao, P.; Feng, J.; Wu, Q.; Zhu, D.; Ma, Y. JACS Au 2024, 4, 1356. pmid: 7616875
[9]	Pan, C.; Su, G.; Yu, C.; Qin, J.; Li, Y.; Yang, Q.; Fang, S.CN 110818760, 2019.
[10]	(a) Chen, X.-B.; Yuan, Q.-J.; Wang, J.; Hua, S.-K.; Ren, J.; Zeng, B.-B. J. Org. Chem. 2011, 76, 7216.
	(b) Xiao, X.; Chen, T.; Zhang, F.; Cheng, J.; Wu, P.; Ren, J.; Zeng, B. Chin. J. Chem. 2015, 33, 643.
	(c) Xiao, X.; Xu, Z.; Zeng, Q.-D.; Chen, X.-B.; Ji, W.-H.; Han, Y.; Wu, P.; Ren, J.; Zeng, B.-B. Chem.-Eur. J. 2015, 21, 8351.
	(d) Ren, J.; Zhao, P.; Xiao, X.; Chen, T.; Zeng, B.-B. Synthsis 2016, 48, 4161.
[11]	Donova, M. V.; Egorova, O. V. Appl. Microbiol. Biotechnol. 2012, 94, 1423.
[12]	Nakamatsu, T.; Beppu, T.; Arima, K. Agric. Biol. Chem. 1983, 47, 1449.
	(b) Zhao, A.; Zhang, X.; Li, Y.; Wang, Z.; Lv, Y.; Liu, J.; Alam, M. A.; Xiong, W.; Xu, J. Biotechnol. Adv. 2021, 53, 107860.
	(c) Jin, Y.; Peng, J.; Tian, W.; Chang, Z. Chem. Biodiversity 2023, 20, e202200800.
[13]	Rigby, J. H.; Warshakoon, N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237.
[14]	(a) House, H. O.; Kramar, V. J. Org. Chem. 1963, 28, 3362. pmid: 12431074
	(b) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S. E.; Clarke, M. O.; Horan, J. C.; Kan, C.; Lacôte, E.; Lippa, B.; Nell, P. G.; Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648. pmid: 12431074
[15]	(a) Delidovich, I.; Palkovits, R. Green Chem. 2016, 18, 590.
	(b) Wu, H.; Wang, L. New J. Chem. 2020, 44, 10428.
	(c) Gupta, A.; Sidhwani, I. T.; Gupta, R.; Monga, Y.; Sharma, R. K. New J. Chem. 2023, 47, 17229.
	(d) Xu, Q.; Liu, H.; Li, Z.; Zang, Y.; Li, G.; Zhu, F.; Ma, S.; Ma, Y.; Liao, M. React. Chem. Eng. 2024, 9, 2411.
[16]	Wang, X.; Huang, G.; Wang, Y.; Gui, J. J. Am. Chem. Soc. 2023, 145, 9354.
[17]	Wang, D.; Cao, F. R.; Lu, G.; Ren, J.; Zeng, B. B. Tetrahedron 2021, 92, 132250.

Entry	Solvent	Catalyst (Dosage/mol%)	EG/equiv.	T/℃	Yield^b/%
Entry	Solvent	Catalyst (Dosage/mol%)	EG/equiv.	T/℃	9	10	11
1	—	PTSA^c (3)	60	r.t.	35.1	29.9	24.3
2	CH₃CN	PTSA^c (3)	3	r.t.	37.4	19.2	32.2
3	CH₃CN	Oxalic acid (50)	2	80	11.4	6.7	N.D.
4	CH₃CN	Oxalic acid (50)	8	80	33.2	19.3	N.D.
5	CH₃CN	Oxalic acid (50)	25	80	59.6	23.5.	Trace
6	CH₃CN	PVP-I (3)	2	60	9.8	N.D.	N.D.
7	CH₃CN	PVP-I (3)	3	60	68.3	23.4	N.D.
8	CH₃CN	PVP-I (3)	8	60	42.6	29.7	Trace
9	CH₃CN	PVP-I (3)	30	60	26.5	42.3.	54.2
10	—	PVP-I (3)	60	60	Trace	N.D.	N.D.
11	EtOAc	PVP-I (3)	3	60	15.8	Trace	N.D.
12	THF	PVP-I (3)	3	60	25.7	Trace	N.D.
13	CH₃CN	PVP-I (3)	3	r.t.	39.5	9.5	N.D.
14	CH₃CN	PVP-I (3)	3	80	45.3	21.3	29.4

Entry	Solvent	Catalyst (Dosage/mol%)	EG/equiv.	T/℃	Yield^b/%
Entry	Solvent	Catalyst (Dosage/mol%)	EG/equiv.	T/℃	9	10	11
1	—	PTSA^c (3)	60	r.t.	35.1	29.9	24.3
2	CH₃CN	PTSA^c (3)	3	r.t.	37.4	19.2	32.2
3	CH₃CN	Oxalic acid (50)	2	80	11.4	6.7	N.D.
4	CH₃CN	Oxalic acid (50)	8	80	33.2	19.3	N.D.
5	CH₃CN	Oxalic acid (50)	25	80	59.6	23.5.	Trace
6	CH₃CN	PVP-I (3)	2	60	9.8	N.D.	N.D.
7	CH₃CN	PVP-I (3)	3	60	68.3	23.4	N.D.
8	CH₃CN	PVP-I (3)	8	60	42.6	29.7	Trace
9	CH₃CN	PVP-I (3)	30	60	26.5	42.3.	54.2
10	—	PVP-I (3)	60	60	Trace	N.D.	N.D.
11	EtOAc	PVP-I (3)	3	60	15.8	Trace	N.D.
12	THF	PVP-I (3)	3	60	25.7	Trace	N.D.
13	CH₃CN	PVP-I (3)	3	r.t.	39.5	9.5	N.D.
14	CH₃CN	PVP-I (3)	3	80	45.3	21.3	29.4

Entry	Catalyst	Base	Additive	T/℃	Yield^b/%
1	Pd(OAc)₂	K₃PO₄	—	140	52
2	PdCl₂	K₃PO₄	—	140	49
3	PdCl₂(PPh₃)₂	K₃PO₄	—	140	43
4	Pd(PPh₃)₄	K₃PO₄	—	140	25
5	Pd/C	K₃PO₄	—	140	29
7	Pd(OAc)₂	K₂CO₃	—	140	46
8	Pd(OAc)₂	NaHCO₃	—	140	43
9	Pd(OAc)₂	Na₂CO₃	—	140	61
10	Pd(OAc)₂	Na₂CO₃	PPh₃	140	69
11^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃^c	140	85
12^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃	150	78
13^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃	100	67

Entry	Catalyst	Base	Additive	T/℃	Yield^b/%
1	Pd(OAc)₂	K₃PO₄	—	140	52
2	PdCl₂	K₃PO₄	—	140	49
3	PdCl₂(PPh₃)₂	K₃PO₄	—	140	43
4	Pd(PPh₃)₄	K₃PO₄	—	140	25
5	Pd/C	K₃PO₄	—	140	29
7	Pd(OAc)₂	K₂CO₃	—	140	46
8	Pd(OAc)₂	NaHCO₃	—	140	43
9	Pd(OAc)₂	Na₂CO₃	—	140	61
10	Pd(OAc)₂	Na₂CO₃	PPh₃	140	69
11^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃^c	140	85
12^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃	150	78
13^d	Pd(OAc)₂	Na₂CO₃	P(o-Tol)₃	100	67

地屈孕酮的形式合成: 一种温和的去芳构化策略^★

Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy^★

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 8

References 17

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Jingjing Zhang, Huiqiong Li, Xingjie Zhang, Yongpeng Wang, Xuemei Zhou, Weilie Xiao, Lijun Cheng, Xiaoli Li. A New Steroid from Armillaria gallica [J]. Chinese Journal of Organic Chemistry, 2025, 45(4): 1411-1416.
[2]	Jie Chen, Jun Li, Xianwen Long, Haixiang Shen, Jun Deng. Recent Advances of Wagner-Meerwein Rearrangement in Natural Product Synthesis [J]. Chinese Journal of Organic Chemistry, 2025, 45(3): 896-912.
[3]	Xiaofeng Zhang, Aggeliki Roumana, Haikang Mao, Jing Xu. Synthesis of the AB Ring System of Daphniphyllum Alkaloid Daphniglaucin C [J]. Chinese Journal of Organic Chemistry, 2025, 45(3): 925-932.
[4]	Qian Chen, Zhaobin Han, Kuiling Ding. Transition Metal Catalyzed Carbocycle-Selective Asymmetric Hydrogenation of Aromatic Rings [J]. Chinese Journal of Organic Chemistry, 2024, 44(7): 2063-2076.
[5]	Jing Tang, Wenkun Luo, Jun Zhou. Advances in the Synthesis of Azaspiro[4.5]trienones [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3006-3034.
[6]	Jun Lu, Qichuang Li, Renxiao Liang, Yixia Jia. Nickel-Catalyzed Intramolecular Dearomative Arylation of Pyridiniums and Quinoliniums [J]. Chinese Journal of Organic Chemistry, 2023, 43(5): 1875-1882.
[7]	Mingyang Pang, Honghong Chang, Zhang Feng, Juan Zhang. Recent Advances in Transition-Metal-Catalyzed Tandem Dearomatization of Indoles [J]. Chinese Journal of Organic Chemistry, 2023, 43(4): 1271-1291.
[8]	Peng Liu, Fuming Zhong, Lihao Liao, Weiqiang Tan, Xiaodan Zhao. Progress in the Construction of Spirocyclohexadienones via Alkyne-Involving Dearomatization [J]. Chinese Journal of Organic Chemistry, 2023, 43(12): 4019-4035.
[9]	Huaiyuan Zhang, Nuo Xu, Rongping Tang, Xingli Shi. Recent Advances in Asymmetric Dearomatization Reactions Induced by Chiral Hypervalent Iodine Reagents [J]. Chinese Journal of Organic Chemistry, 2023, 43(11): 3784-3805.
[10]	Junxiu Liang, Yazhou Liu, Amu Wang, Yanchao Wu, Xiaofeng Ma, Huijing Li. Dearomatization of Halonaphthols via an Intermolecular [4＋1] Spiroannulation with in situ Formed Aza-ortho-quinone Methides [J]. Chinese Journal of Organic Chemistry, 2023, 43(11): 3888-3899.
[11]	Rong Wang, Lichen Xu, Yi Lu, Bo Jiang, Wenjuan Hao. Sc(OTf)₃-Catalyzed Dearomatization of Indoles for the Synthesis of 3,3'-Bisindoles [J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1582-1590.
[12]	Qiang Yan, Rong Fan, Binbin Liu, Shuaisong Su, Bo Wang, Tuanli Yao, Jiajing Tan. Recent Progress in Aryne Participated Dearomatization Reactions [J]. Chinese Journal of Organic Chemistry, 2021, 41(2): 455-470.
[13]	Yuchao Wang, Jinbiao Liu, Guanyinsheng Qiu, Yu Yang, Hongwei Zhou. Metal-Free Selenizative spiro-Tricyclization of N-Hydroxylethyl-N-arylpropiolamides [J]. Chinese Journal of Organic Chemistry, 2021, 41(12): 4798-4807.
[14]	Yinjun Huang, Jinshan Li, Shen Li, Junan Ma. Cobalt-Catalyzed Aerobic Oxidative Dearomatization of 2-Aryl Indoles and in situ [3+2] Annulation with Enamides [J]. Chinese Journal of Organic Chemistry, 2021, 41(10): 4028-4038.
[15]	Jun Lu, Renxiao Liang, Yixia Jia. Copper-Catalyzed Intramolecular Dearomative Arylation of Naphthylamines [J]. Chinese Journal of Organic Chemistry, 2021, 41(10): 4007-4013.

地屈孕酮的形式合成: 一种温和的去芳构化策略★

Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy★

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 8

References 17

Related Articles 15

Recommended Articles

Metrics

Comments

地屈孕酮的形式合成: 一种温和的去芳构化策略^★

Formal Synthesis of Dydrogesterone: A Milder Dearomatization Strategy^★