Yankun
Zhao
,
Hongya
Yan
,
Yulian
Zhang
,
Tao
Zhou
,
Mengxing
Tian
,
Chongzhou
Zhang
,
Shan
Yuan
,
Hanyue
Qiu
*,
Ling
He
and
Min
Zhang
*
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China. E-mail: hanyue.qiu@cqu.edu.cn; minzhang@cqu.edu.cn
First published on 13th June 2024
The catalytic asymmetric propargylation of enol(ate) intermediates is a well-established method for the synthesis of α-propargyl-substituted carbonyl compounds. However, the propargylation of homo-enol(ate) or its equivalents for the synthesis of β-propargyl-substituted carbonyl compounds remains underdeveloped. A catalytic enantioselective decarboxylative intramolecular propargylation of cyclopropanols has been developed using a PyBox-complexed copper catalyst. This reaction offers an effective approach to assemble a cyclopentanone skeleton bearing an all-carbon quaternary stereogenic center and an adjacent quaternary gem-dimethyl carbon center, which is the core scaffold of the naturally occurring cuparenoids. Key to the success of this protocol is the use of a new structurally optimized PyBox ligand. This study represents the first example of catalytic asymmetric intramolecular propargylation of cyclopropanols.
At the outset of the present study, the feasibility and challenges of propargylation of cyclopropanol were first considered. The great advances made in the area of catalytic asymmetric propargylic substitutions of propargylic electrophiles with an array of nucleophiles in the past few years indicate the feasibility of this reaction.2–8,24 Despite that, there are inherent issues that need to be addressed. In Cha,18 Yoshikai,19 Yin,15 and Trost's16 ring-opening allylation of cyclopropanol, preactivation of the cyclopropanol unit as a zinc or potassium alkoxide salt is essential prior to the transmetallation with copper or nickel for the subsequent allylic substitution.15–22 These studies together with our experience25–30 and others' reports31–36 on ring-opening reactions of cyclopropanols indicate that how to activate the cyclopropanol unit is key to the success of the ring-opening reactions of cyclopropanols and thus should be identified primarily. Furthermore, an asymmetric catalytic system applicable to the reaction of cyclopropanol remains underdeveloped,9–14,37–43 which highlights the need to establish an effective asymmetric catalytic system for this new reaction.
To address the aforementioned issues, we have developed the first and highly enantioselective intramolecular propargylation of cyclopropanol, which was enabled by a new structurally optimized pybox ligand-complexed copper catalyst.44 The cyclopropanol and propargyl units were simultaneously activated as cyclopropoxide and copper allenylidene respectively by decarboxylation. This protocol furnishes a series of cyclopentanones bearing an all-carbon quaternary stereogenic center adjacent to a quaternary gem-dimethyl carbon center (Fig. 1B). This sterically congested motif is the cuparane core shared by a number of naturally occurring cuparenoids, an eminent family of sesquiterpenes which were isolated from a culture broth of a mushroom (Flammulina velutipes) and other natural sources and exhibited a series of antimicrobial activities (Fig. 1C).45–52
Entry | Metal salt | Ligand | Base | Yieldb (%) | ee (%) |
---|---|---|---|---|---|
a Typical reaction conditions unless otherwise noted: 1a (0.1 mmol), metal salt (10 mol%), ligand (12 mol%), base (1 equiv.), DCE (4 mL), 80 °C, 48 h. b Isolated yield of 2a. c Determined by chiral HPLC analysis. d Reaction was conducted at 60 °C. | |||||
1 | Cu(OTf)2 | L1 | DIPEA | 35 | 20 |
2 | Cu(MeCN)4PF6 | L1 | DIPEA | 75 | 66 |
3 | Cu(MeCN)4PF6 | L1 | NaHCO3 | 86 | 68 |
4 | Cu(MeCN)4PF6 | L2 | NaHCO3 | 86 | 64 |
5 | Cu(MeCN)4PF6 | L3 | NaHCO3 | 19 | 40 |
6 | Cu(MeCN)4PF6 | L4 | NaHCO3 | 67 | 15 |
7 | Cu(MeCN)4PF6 | L5 | NaHCO3 | 57 | −22 |
8 | Cu(MeCN)4PF6 | L6 | NaHCO3 | 48 | 6 |
9 | Cu(MeCN)4PF6 | L7–L10 | NaHCO3 | 0 | — |
10 | Cu(MeCN)4PF6 | L11 | NaHCO3 | 85 | 90 |
11 | Cu(MeCN)4PF6 | L12 | NaHCO3 | 90 | 94 |
12 | Cu(MeCN) 4 PF 6 | L12 | NaHCO 3 | 95 | 95 |
13d | Cu(MeCN)4PF6 | L13 | NaHCO3 | 85 | 95 |
14d | Cu(MeCN)4PF6 | L14 | NaHCO3 | 85 | 86 |
15d | Cu(MeCN)4PF6 | L15 | NaHCO3 | 20 | 70 |
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Having established the optimized catalytic system, we then explored the generality of this enantioselective propargylation of cyclopropanols (Table 2). A broad range of substrates, possessing both electro-donating and -withdrawing groups at the para-position of the phenyl ring, were well tolerated to furnish the desired products in high yields with excellent enantioselectivies (2b–2j). The variation of the substituent pattern has a subtle impact on the reaction outcome. For instance, the substrates 1k, 1l, 1m, 1n, 1o, and 1p, which possess MeO-, F-, Cl-, Br-, and Me- substituents at the meta- or ortho-position of the phenyl ring, all participated in the transformations and thus provided cyclopentanones (2k–2p) in high enantioselectivities with handles for further derivations. Furthermore, substrates with two or three substituents of different nature at the phenyl ring were tolerated as well (2q–2v). 1w and 1x bearing a bicyclic aromatic substituent also proved to be viable substrates. The substrate scope was further expanded to include substrates substituted with heteroaryl groups, including furyl, thienyl, and indolyl groups (2y–2ab). Notably, replacing the phenyl group with a methyl group also produced product 2ac with good enantioselectivity in synthetically useful yield. Moreover, 1ad with a spiropentyl group was also a suitable substrate. The relative and absolute configurations of 2n were determined by single-crystal X-ray crystallographic analysis (see the ESI† for details), and the same configurations were analogously assigned to the other products.
a Reaction conditions: 1 (0.1 mmol), Cu(MeCN)4PF6 (10 mol%), L12 (12 mol%), NaHCO3 (1 equiv.), DCE (4 mL), 60 °C, 24–48 h; isolated yields were reported and ee values were determined by chiral HPLC analysis. |
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Since the products generated by this new protocol bear a naturally occurring cuparane core, introduction of such a fragment into therapeutic molecules would be of pharmaceutical significance.53 To demonstrate the potential synthetic utility of this protocol in drug development, derivations of drugs were carried out (Fig. 2). The fructose with two acetal groups, core scaffold of the anticonvulsant drug topiramate, was introduced with cuparane cores having different absolute configurations in high diastereoselectivities under the typical reaction conditions with L12 or ent-L12 (2ae and 2ae′) as the ligand. The same manipulation was also applied to the anti-inflammatory drugs naproxen and indomethacin (2af, 2af′, and 2ag).
Besides the high yields and enantioselectivity, this key cyclization reaction boasts good scalability. Grams of 2h were conveniently accumulated by the reaction conducted at the gram scale without affecting the reaction efficiency and enantioselectivity (Fig. 3). Further elaborations at the alkynyl-substituted cuparane core of 2h were carried out. Saturation of the alkynyl group of 2h delivered the natural product analogue 6-methyl-α-cuparenone (4) in 95% yield. The click reaction of 2h and azide 5 possessing a biotin segment provided 6, which could serve as a chemical probe to investigate the biological properties of the cuparenoids. Taking advantage of the alkynyl group, a reaction of Larock indole synthesis delivered indolyl-substituted product 7. Furthermore, a sequence of partial saturation of the alkyne, allyl addition to the ketone group, and ring closing metathesis with the Grubbs II catalyst furnished the bridged product 8 in a synthetically useful yield.
To gain more mechanistic insights into the current reaction, several experiments were conducted (Fig. 4). Substrate 1ah with an additional PMB group at the cyclopropane moiety generated product 2ah with the cleavage of the less substituted bond (Fig. 4A). This result indicates that an ionic cyclopropanol ring-opening mechanism might operate since it is generally accepted that the radical cyclopropanol ring-opening process favors breaking the more substituted to produce a more stable radical intermediate, while the ionic ring-opening process tends to break the less substituted one.9–14 The reaction of 1a proceeded well in the presence of the radical scavenger TEMPO or BHT, further confirming that this is a non-radical process (Fig. 4B). Non-linear effect experiments were carried out with ee-varied chiral L12 (Fig. 4C). The results clearly showed the linear relationship between the ee value of L12 and the ee value of product 2a, indicating that a monomeric complex may work as a catalyst in the reaction.8 On the basis of our mechanistic experiments and the literature precedents,2–8,24 a plausible catalytic cycle and stereoinduction model were proposed (Fig. 4D). First, deprotonation of 1a generated the copper acetylide intermediate 9. The monocopper allenylidene complex 3 with the cyclopropanol segment activated as a cyclopropoxide is then formed by decarboxylation. Ring-opening cyclization of the cyclopropoxide unit to the copper allenylidene affords intermediate 11. The asymmetric induction may be rationalized by a spatial repulsion exerted by the cyclohexyl group, in which re-face attack on the copper allenylidene occurs preferentially. Finally, protodemetalation occurs to furnish product 2a and to release the L12-complexed copper species, which re-enters the catalytic cycle.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2321372, 2321373, 2321374 and 2321378. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc02504k |
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