
==== Front
Org Lett
Org Lett
ol
orlef7
Organic Letters
1523-7060
1523-7052
American Chemical Society

39213514
10.1021/acs.orglett.4c02682
Letter
Cu-Catalyzed Asymmetric Synthesis of γ-Amino Alcohols Featuring Tertiary Carbon Stereocenters
https://orcid.org/0000-0002-9812-9405
Delgado Alejandro ‡¥
Orlando Paolo ‡†
Lanzi Matteo *‡
https://orcid.org/0000-0003-3984-3550
Benet-Buchholz Jordi ‡
https://orcid.org/0000-0001-6180-9581
Passarella Daniele †
https://orcid.org/0000-0002-7402-4764
Kleij Arjan W. *‡§
‡ Institute of Chemical Research of Catalonia (ICIQ-Cerca), the Barcelona Institute of Science and Technology (BIST), 43007 − Tarragona, Spain
¥ Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, 43007 Tarragona, Spain
† Department of Chemistry, Università degli Studi di Milano, Via Camillo Golgi, 19, 20133 Milano, Italy
§ Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain
* Email: akleij@iciq.es
* Email: matteo.lanzi@unipr.it
30 08 2024
13 09 2024
26 36 75967600
22 07 2024
09 08 2024
07 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Alkyne-functionalized oxetanes are presented as versatile substrates that in combination with amine reagents can be transformed into structurally diverse, chiral γ-amino alcohols featuring a tetrasubstituted tertiary stereocenter under Cu catalysis. Control experiments demonstrate the privileged nature of these oxetane precursors in terms of yield and asymmetric induction levels in the developed protocol, and postsynthetic modifications offer an easy way to access more advanced synthons.

UniversitÃ  degli Studi di Milano 10.13039/100012352 NA AgÃ¨ncia de GestiÃ³ d''Ajuts Universitaris i de Recerca 10.13039/501100003030 2021-SGR-00853 Ministerio de Ciencia, InnovaciÃ³n y Universidades 10.13039/100014440 PRE2021-100384 Ministerio de Ciencia, InnovaciÃ³n y Universidades 10.13039/100014440 PID2020-112684GB-100 Ministerio de Ciencia, InnovaciÃ³n y Universidades 10.13039/100014440 CEX2019-000925-S document-id-old-9ol4c02682
document-id-new-14ol4c02682
ccc-price
==== Body
pmcγ-Amino-alcohols are useful building blocks toward a plethora of heterocyclic products including 1,4-oxazepanes, benzo[e][1,4]diazepines and 1,3-oxazinan-2-ones among others.1 There are many natural products containing chiral 1,3-amino alcohol motifs (examples are shown in Scheme 1a), and therefore their (often multistep) synthesis has been on the radar of the community over the past two decades.1a,2 Direct and practical methods for the 1,2-amino alcohol congeners have been reported including propargylic substitution (Scheme 1b, c) of suitable precursors promoted by Cu-catalysis3 and Sharpless amino hydroxylation of alkenes4 achieving the asymmetric synthesis of β-amino alcohols. Despite such basic fragments being present in numerous bioactive and natural compounds, generic and direct methods for chiral γ-amino alcohol featuring bulky stereogenic centers adjacent to the N-atom have only received modest attention, thus creating incentives for new method development. Specifically, the discovery of efficient preparative routes toward γ-amino alcohols that incorporate tertiary carbon centers remains important but also largely unexplored. Efforts to establish asymmetric methods for these latter targets could possibly aid more intensive application of 1,3-amino alcohol synthons.

Scheme 1 (a) Pharma-Relevant γ-Amino Alcohols, (b) Asymmetric Propargylic Substitution, (c) Approaches towards β-Amino Alcohols, and (d) This Work

Catalytic asymmetric propargylic substitution (APS, Scheme 1b, c) has emerged as a robust method to forge sterically congested carbon stereocenters,5 with a recent method standing out reporting the synthesis of α-tertiary ethynyl amines.5e Among the various known approaches, chiral phosphoric acids and transition metal catalysis, particularly copper and ruthenium, have gained prominence.5−7 Cu-catalyzed APS reactions have been particularly versatile, allowing the utilization of a diverse range of nucleophiles though mainly yielding secondary carbon stereocenters. Instructive examples of amination protocols include the work of Nishibayashi8 and van Maarseveen9 who independently described Cu-promoted enantioselective propargylic aminations using anilines in the presence of chiral diphosphine and pybox ligands, respectively. These simple APS processes utilize accessible reagents offering thus a straightforward and effective access for the synthesis of other types of highly functionalized synthons bearing secondary and to a lesser extent tertiary carbon stereocenters.10

Scheme 2 Initial Screening of Ligands and Anilines

In the past decade, we have become increasingly interested in using various alkyne-based precursors and their primarily Cu-catalyzed stereoselective transformation into functionally dense propargylic,11 diene12 and allene13 type products. We surmised that a Cu-catalyzed activation of alkynyl oxetanes compounds14 in the presence of amine pronucleophiles could enable a suitable APS pathway thereby giving highly functionalized γ-amino alcohols. Here we show that such an activation strategy indeed delivers a new range of chiral 1,3-amino alcohol building blocks with elusive tertiary, tetrasubstituted stereogenic centers (Scheme 1).

To test our hypothesis, we selected alkynyl-oxetane 1 and aniline model substrates while contemplating on our previous experience using Cu-catalysts supported by chiral box and pybox ligands providing us a set of initial reaction conditions (Scheme 2).11 Furthermore, a preliminary set of electronically and sterically distinct aromatic amines were tested in this APS manifold leading to products of type 2. The use of various box, pybox, and diphosphine ligands was productive toward formation of product 2 based on p-methyl-aniline as a pronucleophile leading to up to 90% of product [(R,R)-L7; 67:33 er] but with highly modest enantiocontrol. Ortho-substituted anilines, such as those bearing methyl-, methoxy- and i-propyl groups, delivered the desired product in varying yields (36–67%) and, importantly, with an encouraging 89:11 er for the latter substrate.

Bulkier ortho substituents on the aniline (tBu) or the presence of two ortho-substituents (Me) were unproductive under the given reaction conditions demonstrating the delicate effect of steric bulk in both substrates. We continued our screening with the ortho-iPr based aniline and L7 as a structural basis for further ligand investigations (Table 1 and Supporting Information, SI, for further details). The use of ligands L8–L11 did not increase the enantiocontrol (SI) in this model transformation toward 2a. Then, we evaluated the solvent effect, ligand influence, molarity, and relative amount of amine reagent. Various ethers (MTBE, Et2O and 2-Me-THF, Table 1) were all suitable media for the formation of the product 2a in appreciable to excellent yields. The use of ligand L7 proved to be more productive when compared to L8–L11 (entries 4–8). The presence of Et2O as a solvent (entry 3) led to 2a in 87% yield with an enantiomeric ratio of 89:11. The influence of the reaction temperature was also scrutinized, and we found that at −10 °C enantiocontrol improved (up to 94:6 er, entry 11:2-Me-THF as solvent). At −20 °C the protocol was less productive (entry 13) and by increasing the amount of amine (to 3.5 equiv) and DIPEA (1.5 equiv), a virtual quantitative yield of 2a was attained (97%, entry 14). Finally, by switching the configuration of the chiral ligand L7 to (S,S), we obtained the other enantiomer of 2a with a similar process efficiency (entry 15:99%, 5:95 er). This latter result supports the view of having a catalyst-controlled outcome in this coupling manifold with a possible coordinative implication of the ether-type solvents.

Table 1 Screening of other Conditions towards the Preparation of γ-Amino Alcohol 2aa

entry	T (°C), L	Solvent	Yield 2ab	erc	
1d	0, L7	MTBE	67	90:10	
2e	0, L7	Et2O	70	87:13	
3	0, L7	Et2O	87	89:11	
4	0, L7	Et2O	78	84:16	
5	0, L8	Et2O	47	88:12	
6	0, L9	Et2O	48	56:44	
7	0, L10	Et2O	51	14:86	
8	0, L11	Et2O	14	50:50	
9	–10, L7	Et2O	86	87:13	
10f	–10, L7	Et2O	87	91:9	
11	–10, L7	2-Me-THF	81	94:6	
12f	–10, L7	2-Me-THF	94	94:6	
13f,g	–20, L7	2-Me-THF	46	84:16	
14f,g	–10, L7	2-Me-THF	97	94:6	
15f,g,h	–10, L7	2-Me-THF	99	5:95	
a Unless otherwise stated, the reaction conditions are 1a (0.20 mmol), Cu(OTf)2 (5 mol %), L (7.5 mol %), DIPEA (1.2 equiv), ortho-iPr-aniline (3 equiv, for entries 4–8:2 equiv), 48 h; note that (R,R)-L7 was used.

b Yields were determined by 1H NMR (CDCl3) using dibromomethane as internal standard.

c Determined by chiral SFC.

d 2.5 equiv of aniline were used.

e 2 equiv of aniline were used.

f 3.5 equiv of aniline were used.

g 1.5 equiv of DIPEA used.

h In the presence of (S,S)-L7. MTBE = methyl-tert-butyl-ether.

We next compared the performance of alkynyl-oxetane substrate 1a with that of the six-membered cyclic carbonate 3 (Scheme 3), which after decarboxylation would render the same Cu-intermediate. Surprisingly, the participation of carbonate substrate 3 delivered desired product 2a in only 36% yield and virtually as a racemic mixture (53:47 er). To further study the potential influence of the structure of the propargylic precursor, we then compared the performance of alkynyl epoxide 4 and five-membered cyclic carbonate 5 under the same reaction conditions leading to the β-amino alcohol 6 product. Remarkably, the use of both latter substrates gave the product 6 in a similar high yield (99%) and with similar order-of-magnitude enantiocontrol (86:14 vs 93:7 er). The combined observations underline the unique reactivity of the alkynyl oxetane as substrate in the formation of γ-amino alcohols,15 whereas the optimized reaction conditions also seem useful in the context of β-amino alcohol formation.

Scheme 3 Comparison of Alkynyl-Derived Oxetane/Epoxide and Cyclic Carbonate Precursors in the Formation of Amino Alcohols under Optimized Reaction Conditions

With the optimized conditions determined for 1,3-amino alcohols 2, we subsequently investigated the scope of the method using various alkynyl oxetanes 1 and aromatic amines (Scheme 4). First the para position of the aryl-substituent of the alkynyl oxetane was varied (2a–2f) showing that the presence of electron-withdrawing groups such as Cl, Br and CF3 (cf., 2c, 2d and 2f) led to a lower product yield but retaining high enantio-induction comparable to the synthesis of 2a. Ortho-substitution in the aryl of substrate 1 was also tolerated though a more moderate yield (2g: 56%) and enantioselectivity (86:14 er) were noted. Much better performance in terms of enantiocontrol was observed for oxetane substrates with meta-substituted aryls (2h–2j; er values up to and around 95:5). Extending the π-conjugation of the aryl-group in 1 (2k, 94:6 er) was also endorsed though again only a moderate yield of product was attained.16 The use of aliphatic amines was not productive leading to 1,3-enynols as the major reaction components (see the SI for details).16

Scheme 4 Scope of γ-Amino Alcohols 2

To further study the ability of the catalytic process to accommodate sterically and electronically different aromatic amines, we tested various substitutions in combination with other functionalized alkynyl oxetanes 1. In general, we observed that smaller ortho-groups in the aromatic amine substrate led to a good product yield with slightly lower enantiocontrol (e.g., 2l: 70%, 89:11 er). Larger-volume groups in the amine, when coupled with different alkynyl oxetanes (2m and 2n), gave rise to significantly reduced yields (52% and 37%, respectively) though with similar enantio-fidelity as compared to 2l. The installation of electron-withdrawing groups in both substrates (cf., 2o) was relatively unproductive in terms of both yield and stereocontrol. Further variation in the amine reagent using a multiple substitution (2p: 87%, 90:10 er) was fruitful while the presence of a substituted vinylic group (2q: 21%) or an additional fused benzene ring (2r: 1-naphthyl-amine, 28%) led to a low yield of target product.16

Other fused bicyclic ring-based amines (cf., 2s and 2t) were well tolerated, and their coupling delivered the desired products in appreciable yields (64–82%) and er values. On the other hand, aromatic amines with a meta-substituent could be coupled to a para-halogenated aryl-derived alkynyl oxetane 1 giving functional 2u (39%) and 2v (77%) though with lower enantio-discrimination.

Finally, we examined the use of indolines as reagents (synthesis of 2w–2y) to provide synthons of pharmaceutical interest. Their preparation was feasible with different degrees of efficiency (yield: 48–96%) and with enantioselectivities reaching 90:10 er (2w). The ortho-methyl group in the indoline (cf., product 2y) leads to a product with two stereocenters with similar levels of enantio- and diastereocontrol (70:30 er for major diastereomer, 85:15 dr). The absolute configuration of compound 2w was determined by electron diffraction using dynamical refinements on 10 crystals measured for this sample. The absolute configuration for the major fraction of compound 2w was determined to be S at C1 (see Scheme 4; z-score 18.8 σ, P (%): 100%; see for more details the SI).

In order to test the γ-amino alcohols as suitable synthons toward more advanced building blocks, we carried out a series of postsynthetic modifications (Scheme 5). First, the 5-fold scale up of 2b was carried out (using 1.0 mmol of 1b), and the target product was isolated in 56% yield without erosion of the enantioselectivity.17 A Sonogashira type cross-coupling reaction was carried out using 2g affording internal alkyne product 7 in 99% yield. A Pd-catalyzed cascade indole synthesis (cf., 8) was also feasible involving the pendent alkyne group of 2t giving the product containing an elusive heterodiaryl-substituted tertiary stereocenter in 50% yield. The primary alcohol in 2b could be utilized in a Steglich esterification protocol using Isoxepac (an anti-inflammatory agent) furnishing drug-tagged 9 in 74% yield. A combination of triphosgene and pyridine enabled the transformation of the aliphatic alcohol group in 2d to its corresponding alkyl chloride (10, 82%) in a good yield. Product 2q was submitted to a Pd-catalyzed Suzuki coupling producing the product 11 in excellent yield (93%) without affecting the alkyne/alkene functional groups and er value of the starting material. Finally, an intramolecular alkynylation in 2o afforded the dihydro-isoquinoline derivative 12 in 51% yield.5e

Scheme 5 Scale-Up and Diversification Studies

Conditions: (i) [Pd-Cl2(PPh3)4] (5 mol%), Cul (5 mol%), Arl (1 equiv), Et3N (1.1 equiv, CH3CN, r.t., 16 h (ii) [Pd-Cl2(PPh3)4] (5 mol%), Cul (5 mol%), Arl (1 equiv), TMG (3 equiv), DMF, (50 °C, 4 h. (iii) DMAP (10 mol%), Isoxepac (1.05 equiv), DCC (1.1 equiv), DCM, r.t, 16 h; (iv) triphosgene (50 mol%), pyridine (4 equiv), DCM, r.t., 4 h; (v) [Pd-Cl2(PPh3)4] (5 mol%). Ar-Bpin (1.5 equiv), K2CO3 (2 equiv). THF, H2O, 70 °C, 16 h; (vi) IPrAuCl (5 mol%), AgNTf2 (6 mol%), MeOH, r.t., 72 h. See SI for more details.

In conclusion, we herein report the first general, enantioselective synthesis of γ-amino alcohols featuring a tertiary carbon center via a Cu-based propargylic amination reaction. The results attained highlight the privileged nature of the alkynyl oxetanes 1 as precursors compared to their cyclic carbonate analogues. Our protocol combines user-friendly reaction conditions of the first oxidation step, and we have constructed a reasonable scope of both alkynyl oxetanes 1 and (functional) aromatic amines. Further derivatization of selected γ-amino alcohols illustrates the synthetic potential of these chiral building blocks as to further diversify the set of chiral intermediates potentially useful in future drug discovery and development programs.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information (SI).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c02682.Experimental procedures, characterization for all new compounds including copies of NMR spectra and HPLC chromatograms, and crystallographic details (PDF)

Supplementary Material

ol4c02682_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

We thank the Cerca program/Generalitat de Catalunya, ICREA, Ministerio de Ciencia e Innovación (PID2020-112684GB-100, and Severo Ochoa Excellence Accreditation 2020–2023 CEX2019-000925-S) and AGAUR (2021-SGR-00853 and 2021-BP-00162) for support. A.D. thanks MICINN for a predoctoral fellowship (PRE2021-100384), and P.O. acknowledges support from the Università degli Studi di Milano.
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Although the exact reason for the difference in performance when using 1a or 3 as substrates is not known, at this stage a different catalyst speciation proposal seems reasonable.

In various reactions leading to a lower product yield we found a principal byproduct, viz. a 1,3-enyne-5-ol. In some cases these byproducts were isolated and characterized; see the SI for details.

We found that under these conditions more 1,3-enyne-5-ol byproduct was formed, see also ref (16).
