[RuCl(p-cymene)-(S)-BINAP]Cl Catalyzed Asymmetric Preparation of trans-3-Amino-bicyclo[2.2.2]octane-2-carboxylic Acid Ethyl Ester

doi:10.6023/cjoc202301029

Abstract

trans-3-Amino-bicyclo[2.2.2]octane-2-carboxylic acid ester is the key common chiral fragment of some novel antiviral drugs (like Pimodivir and ZSP1273), which targets the PB2 subunit of RNA polymerase. Now, the market demand of this molecule is at level of hundreds kilograms to tons, and there are several related innovative drugs in clinical study. Here a asymmetric transfer hydrogenation strategy to directly construct trans-3-amino-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester using [RuCl(p-cymene)-(S)-BINAP]Cl as catalyst with excellent enantioselectivity (over 98% ee) and without tautomerization and protecting/de-protecting process is developed, which holds the potential of scale up production and commercial value.

Key words: influenza, Ru catalysis, asymmetric transfer hydrogenation, β-amino acid ester

Cite this article

Zhangtao Zhou, Yang Wang, Bingxin Cheng, Weiping Ye. [RuCl(p-cymene)-(S)-BINAP]Cl Catalyzed Asymmetric Preparation of trans-3-Amino-bicyclo[2.2.2]octane-2-carboxylic Acid Ethyl Ester[J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2961-2967.

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References 10

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Entry	Hydrogen source	Amine source	GC yield/%				ee/% of 2
Entry	Hydrogen source	Amine source	1	2	3	4	ee/% of 2
1	HCO₂NH₄	aq. NH₃•H₂O	39.4	20.7	14.5	4.3	93.8
2	HCO₂NH₄	aq. NH₄Cl	31.7	38.2	7.3	4.8	92.9
3	HCO₂NH₄	aq. NH₄Ac	32.7	36.2	8.3	5.0	89.9
4	HCO₂NH₄	NH₄Cl	13.9	43.9	3.4	8.9	86.5
5	HCO₂NH₄	NH₄Ac	22.9	25.7	9.4	10.1	88.5
6^b	HCO₂NH₄		1.0	51.1	1.0	4.1	92.7
7^c	HCO₂H/Et₃N	aq. NH₃•H₂O	44.1	21.1	11.8	2.9	58.7
8^d	HCO₂H/Et₃N	aq. NH₄Cl	24.5	52.7	2.1	2.5	79.1
9^d	HCO₂H/Et₃N	aq. NH₄Ac	1.8	53.4	1.0	5.5	70.5
10	HCO₂H/Et₃N	NH₄Cl	39.1	36.2	0.4	0.9	68.1
11	HCO₂H/Et₃N	NH₄Ac	0.4	52.8	0.2	1.4	67.1

Entry	Hydrogen source	Amine source	GC yield/%				ee/% of 2
Entry	Hydrogen source	Amine source	1	2	3	4	ee/% of 2
1	HCO₂NH₄	aq. NH₃•H₂O	39.4	20.7	14.5	4.3	93.8
2	HCO₂NH₄	aq. NH₄Cl	31.7	38.2	7.3	4.8	92.9
3	HCO₂NH₄	aq. NH₄Ac	32.7	36.2	8.3	5.0	89.9
4	HCO₂NH₄	NH₄Cl	13.9	43.9	3.4	8.9	86.5
5	HCO₂NH₄	NH₄Ac	22.9	25.7	9.4	10.1	88.5
6^b	HCO₂NH₄		1.0	51.1	1.0	4.1	92.7
7^c	HCO₂H/Et₃N	aq. NH₃•H₂O	44.1	21.1	11.8	2.9	58.7
8^d	HCO₂H/Et₃N	aq. NH₄Cl	24.5	52.7	2.1	2.5	79.1
9^d	HCO₂H/Et₃N	aq. NH₄Ac	1.8	53.4	1.0	5.5	70.5
10	HCO₂H/Et₃N	NH₄Cl	39.1	36.2	0.4	0.9	68.1
11	HCO₂H/Et₃N	NH₄Ac	0.4	52.8	0.2	1.4	67.1

Entry	Hydrogen source	Additive	Conversation/% of 3	GC yield/% of 2	ee/% 2
1	HCO₂NH₄		98.1	74.4	98.0
2	HCO₂NH₄	NH₄Cl	99.0	86.0	97.4
3	HCO₂H/Et₃N	NH₄Cl	99.0	61.1	96.0
4	HCO₂NH₄	HCO₂H	97.6	71.7	92.5
5	HCO₂NH₄	AcOH	99.0	75.6	82.5
6^b	HCO₂NH₄	HCl	96.1	61.2	88.3
7	HCO₂NH₄	PhCO₂H	91.0	61.2	39.0
8^c	HCO₂NH₄	NH₄Cl	99.0	85.0	97.3

Entry	Hydrogen source	Additive	Conversation/% of 3	GC yield/% of 2	ee/% 2
1	HCO₂NH₄		98.1	74.4	98.0
2	HCO₂NH₄	NH₄Cl	99.0	86.0	97.4
3	HCO₂H/Et₃N	NH₄Cl	99.0	61.1	96.0
4	HCO₂NH₄	HCO₂H	97.6	71.7	92.5
5	HCO₂NH₄	AcOH	99.0	75.6	82.5
6^b	HCO₂NH₄	HCl	96.1	61.2	88.3
7	HCO₂NH₄	PhCO₂H	91.0	61.2	39.0
8^c	HCO₂NH₄	NH₄Cl	99.0	85.0	97.3

Entry	Catalyst loading/mol%	Conversion/% of 3	GC yield/% of 2	ee/% of 2
1^b	5.0	99.0	86.0	98.0
2^b	4.0	84.3	62.3	97.4
3^b	3.0	78.9	57.1	97.5
4^b	2.0	64.6	36.4	99.0
5^c	2.5	99.9	86.3	97.4
6^c	2.0	99.9	86.0	97.4
7^c	1.5	93.1	79.6	97.8
8^c	1.0	91.1	74.8	97.5
9^c	0.5	30.1	5.9	99.0

[RuCl(p-cymene)-(S)-BINAP]Cl催化不对称合成反式-3-氨基-双环[2.2.2]辛烷-2-甲酸乙酯