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Article

Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes

by
Jade Vaccari
,
María José González-Soria
,
Nicholas Carter
and
Beatriz Maciá
*
Division of Chemistry & Environmental Science, Manchester Metropolitan University, Oxford Road, Manchester M1 5GD, UK
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(15), 4471; https://doi.org/10.3390/molecules26154471
Submission received: 29 June 2021 / Revised: 20 July 2021 / Accepted: 20 July 2021 / Published: 24 July 2021
(This article belongs to the Special Issue Stereogenic Centers II)
Browse Figure
Versions Notes

Abstract

:
A catalytic methodology for the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes is reported here. The versatile and readily accessible chiral Ph-BINMOL ligand, in the presence of Ti(OiPr)4 and a zinc salt, facilitates the reaction, which proceeds under mild conditions and is compatible with functionalized nucleophiles. The alkylzirconium reagents are conveniently generated in situ by hydrozirconation of alkenes with the Schwartz reagent. This work is a continuation of our previous work on aromatic aldehydes.

1. Introduction

Chiral aliphatic secondary alcohols—ubiquitous (sub)structures in natural products—play a very important role in chemical communication among living organisms, serving as sex, aggregation, alarm and trail pheromones, attractants or repellents. Chiral aliphatic alcohols are very valuable organic materials with applications from pharmaceutical and agricultural to food additives, fragrances and cosmetics [1].
The enantioselective synthesis of aliphatic alcohols has been recognized as a long-term interest in the chemistry community, and a wide variety of catalytic asymmetric methodologies [2,3] allow access to these relevant moieties in high enantiomeric excess, including reduction or hydrogenation of prochiral aliphatic ketones [4,5] and addition of alkyl organometallic reagents to aliphatic aldehydes [6,7]. The addition of alkylzinc [8,9,10,11], alkylaluminum [12,13,14], alkyltitanium [15,16,17] and, more recently, alkyl Grignard reagents [18,19,20,21,22,23,24,25,26] to aliphatic aldehydes has been extensively studied. However, the implementation of these methodologies in industrial processes and large scale reactions, is often hampered by the high reactivity, and sometimes pyrophoric character, of these premade, non-stabilized organometallic nucleophiles [27]. The use of less reactive nucleophiles, such as organozirconium compounds, circumvents some of the negative implications associated with these premade organometallic reagents; such as the need for cryogenic temperatures (needed to obtain high levels of enantioselectivity) and the incompatibilities with several functional groups [28]. In addition, organozirconium reagents are readily accessible via (in-situ) hydrozirconation of alkenes using the Schwartz reagent (Cp2ZrHCl) [29,30,31], and alkenes are classed as inexpensive, abundant and easy to handle precursors [32].
Organozirconium reagents [33,34,35] are relatively inert toward carbonyl compounds [36], but their nucleophilic character can be enabled by different catalysts or stoichiometric mediators [37,38,39,40,41,42]. Thus, the addition of organozirconium reagents to aldehydes [43,44,45,46,47,48,49], ketones [50,51], enones [52,53,54], epoxides [55] and isocyanates [56] is possible in the presence of Ag(I), ZnBr2 or Me2Zn; although these protocols are rarely enantioselective [57,58,59,60,61,62,63]. The addition of alkenylzirconocenes to aldehydes and ketones, reported by Wipf [45,64,65] and Walsh [66], respectively; together with our recent work on the addition of alkylzirconium reagents to aromatic aldehydes [67], are, to the best of our knowledge, the only catalytic asymmetric methodologies for the addition of organozirconium reagents to carbonyl compounds.
Here, we report the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes, using a chiral titanium-(Ph-BINMOL) complex as catalyst in the presence of a zinc salt, under industrially relevant reaction conditions. The in-situ preparation of the alkylzirconium nucleophile allows the synthesis of chiral secondary aliphatic alcohols bearing functional groups that are not compatible with other premade organometallic reagents. This work is an extension of our previous, recently published work [67], where only aromatic aldehydes were employed as substrates.

2. Results and Discussion

The large number of aliphatic secondary alcohols in natural products and pharmaceutical compounds makes enantioselective routes to these materials important [68]. The catalytic enantioselective 1,2-addition reaction of alkyl carbon nucleophiles to aliphatic aldehydes is one of the most efficient and straightforward strategies to chiral aliphatic alcohols. This approach, however, is often challenging, due to the highly enolizable character of aliphatic aldehydes, together with their multiple conformations and lack of π-stacking interactions with the catalysts.
Our investigations started by assessing the use of (Ra,S)-Ph-BINMOL ligand L1 [69,70,71] in the addition of 1-hexene (2a) to cyclohexanecarboxaldehyde (1a, Table 1). The corresponding alkylzirconium reagent was prepared by treatment of 1-hexene (2a, 2.2 eq) with 2.0 eq. of Schwartz reagent (Cp2ZrHCl); a change from a white suspension to a clear yellow solution suggested that the nucleophile had successfully formed [29,30,31]. This was then added to a solution of cyclohexanecarboxaldehyde (1.0 eq., 0.125 M), Ti(OiPr)4 (1.5 eq) and Ph-BINMOL (L1, 20 mol %) in DCM at 35 °C (Table 1, entry 1), following known procedures for the enantioselective addition of different organometallic reagents to carbonyl compounds using Ph-BINMOL ligands [72,73,74,75,76,77,78]. Unfortunately, under these reaction conditions, only the alcohol 4a was obtained (Table 1, entry 1), presumably formed by the reduction of aldehyde 1a by the metal-bonded hydride produced after a β-hydride elimination process in the organozirconium reagent.
Our previous work on the addition of organozirconium reagents to aromatic aldehydes [67] demonstrates that the use of a zinc salt as an additive facilitates the enantioselective nucleophilic addition. Under the initial reaction conditions, different amounts (from 0.025 to 1.5 eq) of ZnBr2 were tested (Table 1, entries 2–5). While the use of 0.025 (entry 2) and 1.0 eq (entry 4) of ZnBr2 provided the reduced product 4a exclusively, the reaction proceeded well with 0.5 eq of ZnBr2 (entry 3), providing the desired chiral secondary alcohol 3aa in 99% conversion and 86% ee. The use of 1.5 eq of ZnBr2 afforded 3aa in slightly lower conversion and enantioselectivity (95% conv and 18% ee, entry 5). Next, we performed a screening of different amounts of titanium isopropoxide (entries 6–9). Increasing the Ti(OiPr)4 loading from 1.5 to 2 eq., resulted in 75% conversion to the reduced product 4a, as well as lower enantioselectivity for the desired product 3aa (Table 1, entry 6). Lowering the equivalents of Ti(OiPr)4 to 1 eq. resulted in >99% conversion to the reduced product 4a (Table 1, entry 7). Varying the ratios between Ti(OiPr)4 and ZnBr2 to 2:1 and 2:2 (Table 1, entries 8 and 9) showed no improvement in enantioselectivity or conversion when compared with the original ratio of 3:1 (Table 1, entry 3).
Having found the optimal ratio between the zinc additive and the titanium source, we explored the reaction at room temperature, in the hope of increasing the enantioselectivity and making the reaction more sustainable. Unfortunately, the conversion to the by-product 4a substantially increased under these conditions (Table 1, entry 10).
The use of CuCl as additive, instead of ZnBr2, was also evaluated (Table 1, entries 11 and 12), but provided slightly lower enantioselectivity at both 35 °C and room temperature (64 and 40% ee, respectively) than the zinc salt.
We have previously reported that 4-Py-BINMOL (L2) is the most effective ligand for the catalytic enantioselective 1,2-addition of Grignard reagents to aliphatic aldehydes [26]. However, when L2 was employed as the ligand for the addition of 1-hexene (2a) to cyclohexanecarboxaldehyde (1a), only 32% conversion was observed for the desired 3aa with lower ee (8%), while the formation of the by-product 4a substantially increased (Table 1, entry 13).
There are multiple mechanistic pathways in which this catalytic enantioselective 1,2-addition reaction of organozirconium reagents could proceed. We hypothesize that the in situ generated organozirconium reagents undergo transmetallation with the zinc bromide, followed by a second transmetallation with the excess of titanium isopropoxide to provide catalytic intermediate/species similar to those proposed by Seebach and Walsh on the Ti(OiPr)4 assisted addition of organozinc reagents to aldehydes (Scheme 1) [15,16]. It cannot be ignored, however, that the activation of aldehydes via a zinc-halide complexation is a well-known effect [79]. It is worth noting that control reactions performed in the absence of Ti(OiPr)4 and (Ra,S)-Ph-BINMOL (L1) resulted in no conversion to our desired product 3aa but 11% and >99% conversion to the reduced product 4a, respectively (Table 1, entries 14 and 15).
With the now optimised conditions [2.2 eq. of alkene, 2 eq. of Cp2ZrCl, 1.5 eq. of Ti(OiPr)4, 0.5 eq. of ZnBr2, 20 mol % of L1, at 35 °C in DCM; Table 1, entry 3], the scope of the reaction with different aliphatic aldehydes was investigated (Table 2). The addition of 1-hexene (2a) to isobutyraldehyde (1b) and 2-ethylbutanal (1c) afforded the corresponding products 3ba and 3ca with excellent conversions (>99%) and enantioselectivities of 76 and 70%, respectively (entries 1 and 2). The isolated yields (42% and 54%, respectively) were moderate, due to the high volatility of the products, but the reduced by-products 4b and 4c were not observed in any case. Similar results were obtained for the reaction with pivaldehyde (1d), which afforded 3da with 93% conversion (7% reduced product), moderate yield (50%, due to volatility of the product) and good enantioselectivity of 84% (entry 3). The use of octanal (1e) as the substrate resulted in excellent conversion to the desired product 3ea (91%, along with 4% conversion to the reduced product 3e), good enantioselectivity (74%, determined on the corresponding benzoate) and 48% isolated yield (entry 4). The addition of 1-hexene (2a) to both 3-phenylpropionaldehyde (1f) and cinnamaldehyde (1g) led to the desired products 3fa and 3ga with 40% and 35% isolated yields, respectively, and high enantiomeric excesses (74% and 78%, entries 5 and 6). The use of phenylpropargyl aldehyde (1h) as substrate, provided 3ha in moderate isolated yield (40%) and moderate enantioselectivity (56%, entry 7). The configuration of alcohols 3 was assigned as (R) after comparison with the optical rotation values in the literature for the known compounds. For unknown compounds, where comparison was not possible, the (R) configuration was assumed by analogy.
Next, we evaluated the use of a variety of alkenes as nucleophiles (Table 3). The reaction with cyclohexanecarboxaldehyde (1a) and 4-phenyl-1-butene (2b) provided moderate yield (33%) and 68% enantioselectivity (entry 1). We were pleased to observe that the methodology is also compatible with functionalised alkenes (entries 2–4). The use of 4–[(tert-butyldimethylsilyl)oxy]-1-butene (2c) as a nucleophile, afforded 3ac with 27% isolated yield and 58% enantioselectivity (entry 2). The reactions with 4-halo-1-butenes 2d and 2e as nucleophiles, provided the desired alcohols 3ad and 3ae in 51 and 36% yield, and 84 and 60% ee (determined on the corresponding benzoates), respectively. It is worth noting that the majority of the yields are low to moderate as a result of the secondary alkyl alcohols being volatile. Alkenes bearing a nitrile or a thioester group (pent-4-enenitrile and but-3-en-1-yl(phenyl)sulfane, respectively) did not provide any conversion under these reaction conditions. It is worth noting that, although the alkene scope is a bit narrow, it includes halogenated alkenes. The presence of halogens is not compatible with premade organometallic reagents [6,7]; so this is a clear advantage of this methodology. Alkenes bearing a protected alcohol are also suitable with our methodology; their analogous premade organometallic reagents would also be of difficult access [18].

3. Conclusions

In conclusion, we have successfully developed an enantioselective 1,2-addition of alkylzirconium reagents to aliphatic aldehydes, using catalytic amounts of the very versatile (Ra,S)-Ph-BINMOL ligand L1, in the presence of titanium isopropoxide and zinc bromide as additives. The alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with Schwartz reagent, thus avoiding the use of premade organometallic reagents. The one-pot reaction proceeds under mild conditions, with enantioselectivities in the range 56–86%, good to high conversions (53–99%) and moderate yields (27–54%). This methodology allows the synthesis of very valuable chiral secondary alcohols, difficult to access by the addition of classical premade organometallic reagents to carbonyls. In addition, the scope of the reaction includes a range of functionalised nucleophiles.

4. Materials and Methods

General Considerations: 1H-NMR, 13C-NMR, and 31P-NMR spectra were recorded on a JEOL® ECS-400 NMR spectrometer (400, 100.6 and 162 MHz, respectively) using CDCl3 as solvent. The chemical shift values were recorded in ppm with the residual CDCl3 referenced to 7.26 and 77.00 for 1H NMR and 13C NMR respectively. Data is reported as follows: chemical shift, multiplicity (singlet = s, doublet = d, triplet = t, quartet = q, multiplet = m), coupling constants (J) in Hz and integration. Infrared Spectra were recorded on a Nicolet® 380 Fourier Transform Infrared Spectrometer and only the most significant frequencies have been reported (in cm−1) for characterisation. Optical rotation measurements were performed on Bellingham + Stanley® ADP220 Polarimeter with a 0.5 cm cell (c given in g/100 mL) using DCM as a solvent. Melting point measurements were performed on Stuart® SMP10 melting point apparatus and were not corrected. Conversion and low resolution mass spectra were recorded on either Agilent 6850 Series connected to an Agilent 5973 mass selective detector using a HP-5ms (30 m × 0.25 mm × 0.25 μm) or on an Agilent Technologies® 7890B GC connected to an Agilent Technologies® 5977b MSD using a HP-5MS (30 m × 0.25 mm × 0.25 μm). Helium was used as the carrier gas at 10 psi, and the samples were ionized by an electronic impact (EI) source at 70 ev. Gas chromatography analysis was performed on an Agilent Technologies® 7890A GC System and a Hewlett Packard® 5890 Series II GC System, with a CycloSil-β (Agilent Technologies, 30 m × 0.25 mm) and a CP-Chirasil-DEX CB (Varian, 25 m × 0.25 mm) column, respectively; injector and detector temperatures: 250 °C. HPLC analysis was carried out on an Agilent 1100 series HPLC equipped with a G1313B diode array detector and a G1311A Quat pump, using the chiral column Lux 5µ Cellulose-1. High resolution mass spectra were obtained on a 6540 LC-QToF spectrometer and the samples were ionized with ESI techniques and introduced through a high pressure liquid chromatography (HPLC) using an Agilent Technologies® 1260 Infinity Quaternary LC system, an Agilent 7200 Accurate Mass Q-ToF GC-MS system or a Waters Xevo G2-S, where the samples were ionized usingASAP techniques. Thin layer chromatography (TLC) was performed on Sigma Aldrich silica gel 60 F254 aluminium plates and visualised by UV light and/or by a staining solution of phosphomolybdic acid. Purification by column chromatography was performed using Geduran® Silica gel 60 in a Biotage® IsoleraTM System, using the eluents mentioned below. All reactions were carried out under inert conditions, using flame dried glassware and argon as the inert gas. All commercially available reagents were purchased from Acros, Alfa Aesar, Manchester Organics, Fisher, Fluorochem and Sigma-Aldrich and were used without further purification, except for all liquid aldehydes, which were freshly distilled before use. Anhydrous, THF, DCM, Et2O and toluene were obtained from Pure SolvTM Solvent Purification Systems. Ligands (Ra,S)-Ar-BINMOLs L1 and L2 were prepared according to literature procedures [44] from (R)-BINOL, purchased from Manchester Organics. Racemic alcohols 3aa–3fa (Table 1) were synthesised from the addition of hexylmagnesium bromide to the corresponding aldehyde. Racemic alcohols 3ab–3ae (Table 2) were prepared using the general procedure below for the catalytic enantioselective 1,2-addition of alkenes to aliphatic aldehydes using racemic L1 as ligand. 4–[(tert-Butyldimethylsilyl)oxy]-1-butene (2c) was prepared according to literature [80]. Spectroscopic data for new compounds and chiral GC and HPLC chromatograms are available as Supplementary Material.
General procedure for the catalytic enantioselective 1,2-addition of alkenes to aliphatic aldehydes: To a stirred suspension of Cp2ZrHCl (154 mg, 0.6 mmol, 2 eq.) in dry DCM (0.3 mL) under argon at RT, the corresponding alkene (2a–e, 0.66 mmol, 2.2 eq.) was added dropwise and the solution was stirred for 30 min. The mixture turned to a clear yellow solution, indicating the successful formation of the alkylzirconium reagent. Next, flame dried ZnBr2 (34 mg, 0.15 mmol, 0.5 eq.) was added to the solution at RT and stirred for 2 min. Next, a solution of Ti(OiPr)4 (134 μL, 0.45 mmol, 1.5 eq.) and (Ra,S)-Ph-BINMOL (L1, 23 mg, 20 mol %) in dry DCM (0.1 mL) was added and stirred for an additional 2 min at RT. Finally, the freshly distilled aldehyde (1a–h, 0.3 mmol) was added and the solution was stirred at 35 °C for 12 h. The reaction was quenched with water (2 mL) and the layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure. The corresponding products were purified by flash silica gel chromatography.
(R)-1-cyclohexylheptan-1-ol (3aa): [81] Obtained as a yellow oil after purification by column chromatography (Et2O/hexane 3:7). 60% yield, 86% ee. [α]D23 = +17.4 (c 1.5, CH2Cl2). {Lit [α]D25 = −10.5 (c 0.2, CHCl3) for 84% ee of S enantiomer}. 1H NMR (400 MHz, CDCl3) δ: 3.39–3.29 (m, 1H), 1.81–1.70 (m, 3H), 1.70–1.60 (m, 2H), 1.51–1.42 (m, 2H), 1.36–0.93 (m, 15H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 76.1, 43.8, 34.0, 33.3, 33.0, 29.4, 27.8, 26.6, 26.5, 26.3, 24.8. m/z: 180 (M+-H2O, 11), 115 (26), 114 (14), 113 (47), 97 (76), 96 (21), 95 (100), 83 (10), 82 (14), 81 (10), 69 (14), 67 (16), 57 (12), 55 (59). HRMS (ASAP): m/z calculated for C13H25O [M-H]+: 197.1905, found: 197.1904. ee determination by chiral GC analysis, CP Chirasil-DEX CB column, T = 95 °C retention times: tr = 42.1 min, tr = 42.8 min (major enantiomer).
(R)-2-methylnonan-3-ol (3ba): [82] Obtained as a yellow oil after purification by column chromatography (Et2O/hexane 3:7). 42% yield, 76% ee. [α]D23 = +13.3 (c 0.6, CH2Cl2). {Lit [α]D25 = −14.1 (c 0.7, CHCl3) for 96% ee of S enantiomer}. 1H NMR (400 MHz, CDCl3) δ: 3.41–3.30 (m, 1H), 1.64 (m, 1H), 1.50–1.41 (m, 2H), 1.41–1.22 (m, 9H), 0.93–0.82 (m, 9H). 13C NMR (101 MHz, CDCl3) δ: 76.9, 34.3, 33.6, 32.0, 29.6, 26.2, 22.8, 19.0, 17.2, 14.3. m/z: 140 (M+-H2O, 11), 115 (26), 97 (82), 73 (47), 69 (20), 57 (14), 55 (100). HRMS (+ESI): m/z calculated for C10H21O [M-H]+: 157.1592, found: 157.1587. ee determination by chiral GC analysis, CP Chirasil-DEX CB column, T = 120 °C, retention times: tr(S) = 43.3 min, tr(R) = 42.5 min (major enantiomer).
(R)-3-ethylnonan-4-ol (3ca): Obtained as a yellow oil after purification by column chromatography (Et2O/hexane 2:8). 54% yield, 70% ee. [α]D23 = +6.7 (c 0.4, CH2Cl2). FTIR (neat) Vmax: 3373, 2958, 2925, 2873, 2858, 1461, 1379, 1143 cm−1. 1H NMR (400 MHz, CDCl3) δ: 3.69–3.52 (m, 1H), 1.45–1.16 (m, 16H), 1.06–0.81 (m, 9H). 13C NMR (101 MHz, CDCl3) δ: 73.3, 46.9, 34.2, 32.0, 29.6, 26.4, 22.8, 22.2, 21.3, 14.3, 12.1, 12.0. m/z: 168 (M+-H2O, 1), 115 (28), 101 (23), 97 (98), 83 (15), 70 (15), 69 (21), 59 (24), 57 (19), 55 (100). HRMS (+ESI): m/z calculated for C12H25O [M-H]+: 185.1905, found: 185.1909. ee determination by chiral GC analysis, CP Chirasil-DEX CB column, T = 95 °C, retention times: tr(S) = 75.1 min, tr(R) = 75.2 min (major enantiomer).
(R)-2,2-dimethylnonan-3-ol (3da): [83] Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 3:7). 50% yield, 84% ee. [α]D23 = +8.9 (c 0.9, CH2Cl2). {Lit [α]D25 = +15.0 (c 5.1, benzene) for 84% ee}. FTIR (neat) Vmax: 3392, 2954, 2925, 2859, 1479, 1466, 1393, 1364, 1075, 1009, 957, 734, 703, 566, 543 cm−1. 1H NMR (400 MHz, CDCl3) δ: 3.17 (d, J = 7.4 Hz, 1H), 1.64–1.40 (m, 3H), 1.36–1.18 (m, 8H), 0.87 (br s, 12H). 13C NMR (101 MHz, CDCl3) δ: 80.1, 35.1, 32.1, 31.6, 29.6, 27.2, 25.8, 22.8, 14.3. m/z: 154 (M+-H2O, 0.18), 115 (31), 114 (13), 97 (100), 87 (28), 69 (31), 57 (40), 56 (12), 55 (80). HRMS (+ESI): m/z calculated for C11H23O [M-H]+: 171.1749, found: 171.1743. ee determination by chiral GC analysis, CP Chirasil-DEX CB column, T = 100 °C, retention times: tr(S) = 38.6 min, tr(R) = 40.2 min (major enantiomer).
(R)-tetradecan-7-ol (3ea): Obtained as a white solid after purification by column chromatography (Et2O/cyclohexane 3:7). 48% yield, 74% ee (determined on the corresponding benzoate 3ea’). [α]D22 = +13.3 (c 0.7, CH2Cl2). Mp = 36–39 °C. FTIR (neat) Vmax: 3343, 2956, 2929, 2872, 1470, 1381, 1045, 952, 817 cm−1. 1H NMR (400 MHz, CDCl3) δ: 3.55 (s, 1H), 1.40 (br s, 7H), 1.26 (br s, 16H), 0.86 (t, J = 6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ: 72.2, 37.6, 32.0, 30.0, 30.0, 29.5, 27.0, 25.8, 25.8, 22.9, 22.8, 14.3. m/z: 196 (M+-H2O, 8), 129 (36), 115 (38), 111 (41), 97 (100), 83 (11), 69 (94), 57 (20), 55 (74). HRMS (+ESI): m/z calculated for C14H29O [M-H]+: 213.2219, found: 213.2213.
(R)-1-phenylnonan-3-ol (3fa): [84] Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 3:7). 40% yield, 74% ee. [α]D26 = −10.5 (c 3.8, CH2Cl2). {Lit [α]D21 = −8.2 (c 0.3, CHCl3) for 72% ee}. 1H NMR (400 MHz, CDCl3) δ: 7.26–7.07 (m, 5H), 3.65–3.49 (m, 1H), 2.78–2.56 (m, 2H), 1.78–1.61 (m, 2H), 1.51 (s, 1H), 1.45–1.12 (m, 10H), 0.81 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 142.4, 128.6, 128.5, 125.9, 71.6, 39.2, 37.7, 32.2, 32.0, 29.5, 25.7, 22.8, 14.2. m/z: 202 (M+-H2O, 32), 131 (50), 117 (47), 115 (18), 105 (22), 104 (92), 92 (23), 91 (100), 69 (17), 55 (13). HRMS (+ESI): m/z calculated for C15H23O [M-H]+: 219.1754, found: 219.1755. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 98:2, flow = 1 mL/min, T = RT, retention times: tr(R) = 16.1 min (major enantiomer), tr(S) = 27.6 min.
(E,R)-1-phenylnon-1-en-3-ol (3ga): [84] Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 2:8). 35% yield, 78% ee. [α]D26 = −66.7 (c 1.2, CH2Cl2). {Lit [α]D21 = −5.6 (c 1.07, CHCl3) for 91% ee}. 1H NMR (400 MHz, CDCl3) δ: 7.40–7.36 (m, 2H), 7.33–7.28 (m, 2H), 7.24–7.20 (m, 1H), 6.56 (d, J = 15.8 Hz, 1H), 6.21 (dd, J = 15.9, 6.8 Hz, 1H), 4.35–4.18 (m, 1H), 1.76–1.51 (m, 3H), 1.42–1.17 (m, 7H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 136.9, 132.7, 130.4, 128.7, 127.8, 126.6, 73.3, 37.5, 31.9, 29.4, 25.6, 22.8, 14.2. m/z: 218 (M+, 3), 148 (14), 134 (11), 133 (100), 131 (17), 130 (29), 129 (16), 128 (16), 115 (64), 113 (14), 105 (47), 104 (21), 103 (31), 91 (45) 79 (17), 78 (18), 77 (46), 55 (55), 51 (14). HRMS (ASAP) m/z calculated for C15H23O [M+H]+: 219.1749, found: 219.1749. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 98:2, flow = 1 mL/min, T = RT, retention times: tr(R) = 20.4 min (major enantiomer), tr(S) = 37.8 min.
(R)-1-phenylnon-1-yn-3-ol (3ha): [85] Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 2:8). 43ae’0% yield, 56% ee. [α]D23 = −22.2 (c 3.6, CH2Cl2). {Lit [α]D23 = −1.5 (c 0.69, CHCl3) for 92% ee). 1H NMR (400 MHz, CDCl3) δ: 7.46–7.40 (m, 2H), 7.35–7.28 (m, 3H), 4.60 (t, J = 6.6 Hz, 1H), 2.18 (br s, 1H), 1.85–1.73 (m, 2H), 1.56–1.43 (m, 2H), 1.40–1.25 (m, 6H), 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 131.8, 128.4, 122.8, 90.4, 84.9, 63.1, 38.0, 31.9, 29.1, 25.3, 22.7, 14.2. m/z: 216 (M+, 4), 198 (58), 155 (40), 154 (14), 152 (10), 142 (15), 141 (67), 139 (12), 129 (69), 128 (100), 127 (11), 115 (65), 105 (15), 103 (21), 102 (86), 91 (16), 77 (20), 76 (18), 75 (10), 74 (10), 70 (14), 55 (12). HRMS (+ESI): m/z calculated for C15H19O [M-H]+: 215.1436, found: 215.1445. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 97:3, flow = 1 mL/min, retention times: tr(R) = 15.0 min, (major enantiomer). tr(S) = 44.5 min.
(R)-1-cyclohexyl-6-phenylhexan-1-ol (3ab): Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 2:8). 33% yield, 68% ee. [α]D23 = +40 (c 0.4, CH2Cl2). FTIR (neat) Vmax: 3368, 3026, 2922, 2852, 1603, 1496, 1450, 1077, 977, 745, 697 cm−1. 1H NMR (400 MHz, CDCl3) δ: 7.23–7.17 (m, 2H), 7.15–7.08 (m, 3H), 3.36–3.19 (m, 1H), 2.55 (t, J = 7.7 Hz, 2H), 1.77–1.63 (m, 3H), 1.64–1.51 (m, 4H), 1.49–0.86 (m, 11H). 13C NMR (101 MHz, CDCl3) δ: 142.8, 128.5, 128.4, 125.7, 76.2, 43.7, 36.1, 34.0, 31.7, 29.3, 27.8, 26.6, 26.4, 26.3, 25.8. m/z: 228 (M+, 21) 145 (27), 128 (16), 132 (23), 117 (29), 105 (16), 104 (100), 95 (29), 92 (19), 91 (89) 83 (10), 81 (14), 67 (17), 55 (23). HRMS (+ESI): m/z calculated for C17H26O [M+Na]+: 269.1876, found: 269.1883. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 97:3 flow = 1 mL/min, T = RT, tr(S) = 9.67 min, tr(R) = 10.12 min (major enantiomer).
(R)-5-(tert-butyl-dimethyl-silanyloxy)-1-cyclohexylheptan-1-ol (3ac): Obtained as a brown oil after purification by column chromatography (Et2O/cyclohexane 3:7). 27% yield, 58% ee. [α]D23 = +10.81 (c 3.7, CH2Cl2). FTIR (neat) Vmax: 3369, 2927, 2854, 1428, 1106, 823, 699, 613, 503, 187 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 4.2, 3.4 Hz, 4H), 7.44–7.34 (m, 6H), 3.67 (t, J = 6.1 Hz, 2H), 3.36–3.29 (m, 1H), 1.83–1.70 (m, 3H), 1.70–0.88 (m with s at 1.05, 25H). 13C NMR (101 MHz, CDCl3) δ: 135.7, 134.2, 129.6, 127.7, 76.2, 63.9, 43.6, 33.9, 32.7, 29.4, 27.8, 27.0, 26.7, 26.5, 26.3, 22.2, 19.3. HRMS (ASAP): m/z calculated for C27H41O2Si [M+H]+: 425.2876, found: 425.2876. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 97:3, flow = 1 mL/min, T= RT retention times: tr(R) = 5.92 min (major enantiomer), tr(S) = 7.41 min.
(R)-5-bromo-1-cyclohexylpentan-1-ol (3ad): Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 1:1). 51% yield, 84% ee (determined on the corresponding benzoate 3ad’). [α]D25 = +12 (c 1, CH2Cl2). FTIR (neat) Vmax: 3368, 2928, 2851, 1450, 1237, 1087, 1064, 1047, 975, 893, 562 cm−1. 1H NMR (400 MHz, CDCl3) δ: 3.41 (t, J = 6.9 Hz, 2H), 3.37–3.32 (m, 1H), 1.94–1.83 (m, 2H), 1.83–1.69 (m, 3H), 1.69–1.57 (m, 3H), 1.57–0.89 (m, 10H). 13C NMR (101 MHz, CDCl3) δ: 76.1, 43.8, 34.0, 33.3, 33.0, 29.4, 27.8, 26.6, 26.5, 26.3, 24.8. m/z: 230 (M+-H2O, 1), 167 (41), 165 (40), 113 (62), 96 (12), 95 (100), 85 (85), 84 (20), 83 (19), 82 (13), 68 (10), 67 (48), 57 (25), 55 (51). HRMS (+ESI): m/z calculated for C11H21O [M+Na]+: 271.0673, found: 271.0668.
(R)-5-chloro-1-cyclohexylpentan-1-ol (3ae): Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 1:1). 36% yield, 60% ee (determined on the corresponding benzoate 3ae’). [α]D25 = +20 (c 0.8, CH2Cl2). FTIR (neat) Vmax: 3369, 2923, 2851, 1449, 1309, 1088, 1065, 977, 892, 734, 651 cm−1. 1H NMR (400 MHz, CDCl3) δ: 3.57–3.48 (m, 2H), 3.39–3.27 (m, 1H), 1.84–1.70 (m, 5H), 1.70–1.55 (m, 4H), 1.53–0.90 (m, 9H). 13C NMR (101 MHz, CDCl3) δ: 76.1, 45.2, 43.8, 33.4, 32.8, 29.4, 27.8, 26.6, 26.4, 26.3, 23.5. m/z: 186 (M+-H2O, 2), 123 (21), 121 (62), 120 (13), 113 (44), 101 (13), 96 (13), 95 (100), 85 (62), 84 (17), 82 (14), 81 (15), 67 (47), 57 (22), 55 (49). HRMS (+ESI): m/z calculated for C11H20OCl [M-H]+: 203.1197, found: 203.1206.
General procedure for the synthesis of benzoate derivatives 3ea’, 3ad’ and 3ae’: [67] The corresponding chiral aliphatic alcohol (3ea, 3ad or 3ae, 0.10 mmol) was dissolved in anhydrous DCM (1 mL, 0.1 M). Sequentially, at 0 °C, Et3N (28 μL, 0.2 mmol, 2.0 eq), benzoyl chloride (12 μL, 0.1 mmol) and DMAP (1.3 mg, 0.20 mmol, 2.0 eq) were added. The reaction mixture was stirred overnight at RT. The reaction was quenched with water (1 mL), extracted with Et2O (3 × 5 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The crude material was purified by flash silica gel chromatography.
(R)-tetradecan-7-yl benzoate (3ea’): Obtained as a white solid after purification by column chromatography (Et2O/cyclohexane 2:8). 55% yield, 74% ee. [α]D23 = +20 (c 1.2, CH2Cl2). Mp = 42–45 °C. FTIR (neat) Vmax: 3349, 2926, 2855, 190, 1723, 1211, 1936, 1014, 703 cm−1. 1H NMR (400 MHz, CDCl3) δ: 8.17 (d, J = 8.1 Hz, 2H), 7.76–7.57 (m, 1H), 7.53 (t, J = 7.7 Hz, 2H), 3.63–3.53 (m, 1H), 1.50–1.36 (m, 6H), 1.28 (br s, 16H), 0.88 (t, J = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ: 162.5, 134.7, 130.7, 129.0, 72.2, 37.6, 32.0, 29.8, 29.5, 29.5, 25.8, 25.8, 22.8, 22.8, 14.3. m/z: 281 (14), 208 (15), 207 (100), 105 (68), 77 (11). HRMS (+ESI): m/z calculated for C21H35O2 [M+H]+: 319.2637, found: 319.2630. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hexane 100, flow = 1 mL/min, T = RT. retention times: tr(S) = 9.97 min, tr(R) = 10.27 min (major enantiomer).
(R)-5-bromo-1-cyclohexylpentyl benzoate (3ad’): Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 3:7). 19% yield, 84% ee. FTIR (neat) Vmax: 2927, 2854, 1716, 1450, 1273, 1113, 712 cm−1. [α]D23 = +24 (c 0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ: 8.09–8.01 (m, 2H), 7.58–7.53 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.08–4.97 (m, 1H), 3.38 (t, J = 6.8 Hz, 1H), 1.95–1.00 (m, 5H). 13C NMR (101 MHz, CDCl3) δ: 166.5, 133.0, 130.7, 129.7, 128.5, 78.3, 45.0, 41.5, 32.6, 30.7, 29.3, 28.3, 26.5, 26.3, 26.2, 23.0. m/z: 313 (1), 232 (12), 230 (13), 122 (17), 109 (18), 105 (100), 96 (19), 95 (24), 82 (11), 81 (29), 79 (13), 77 (37) 67 (26), 55 (14). HRMS (+ESI): m/z calculated for C18H25O2Br [M+Na]+: 375.0936, found: 375.0952. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 99:1, flow = 1 mL/min, T = RT, retention times: tr(S) = 16.34 min, tr(R) = 17.40 min (major enantiomer).
(R)-5-chloro-1-cyclohexylpentyl benzoate (3ae’): Obtained as a yellow oil after purification by column chromatography (Et2O/cyclohexane 3:7). 27% yield, 60% ee. [α]D23 = +10 (c 0.4, CH2Cl2). FTIR (neat) Vmax: 2929, 2854, 1717, 1450, 1279, 1113, 1027, 801, 712 cm−1. 1H NMR (400 MHz, CDCl3) δ: 8.09–8.00 (m, 2H), 7.59–7.52 (m, 1H), 7.47–7.41 (m, 2H), 5.07–4.93 (m, 1H), 3.50 (t, J = 6.7 Hz, 2H), 1.88–1.57 (m, 10H), 1.54–1.42 (m, 2H), 1.36–0.98 (m, 5H). 13C NMR (101 MHz, CDCl3) δ: 166.5, 133.0, 130.8, 129.7, 128.5, 78.3, 44.9, 41.5, 32.6, 30.7, 29.9, 29.3, 28.2, 26.5, 26.3, 23.0. m/z: 281 (0.4), 186 (17), 109 (10), 105 (100), 96 (16), 81 (15), 77 (24) 67 (15), 55 (10). HRMS (+ESI): m/z calculated for C18H25O2Cl [M+Na]+: 331.1441, found: 331.1425. ee determination by chiral HPLC analysis, Phenomenex® LUX Cellulose-1, Hex/i-PrOH 97:3, flow = 1 mL/min, T = RT, retention times: tr(S) = 15.64 min, tr(R) = 16.12 min (major enantiomer).

Supplementary Materials

The Supplementary Materials are available online. Spectroscopic data (IR, 1H and 13C NMR) for new compounds 3ca, 3ea, 3ab, 3ac, 3ad, 3ae, 3ea’, 3ad’, 3ae’, and chiral GC and HPLC chromatograms for all compounds 3.

Author Contributions

J.V. and B.M. conceived and designed the experiments and wrote the paper; J.V. performed the experiments and analyzed the data. M.J.G.-S. and N.C. performed preliminary experiments. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Marie Curie Career Integration Career Scheme (PCIG12-GA-2012-333834), EPSRC First Grant Scheme (EP/M000028/1) and the Royal Societ International Exchange Scheme (IE150375).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

J.V. thanks MMU for a studentship. MMU Scientific Facilities Chemistry, University of Swansea and University of Sheffield are thanked for HRMS analysis.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 are available from the authors.

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Molecules 26 04471 sch001 550
Scheme 1. Proposed titanium-L1 complex (A) and proposed active intermediate (B) containing both aldehyde (RCOH) and nucleophile (CH2CH2R’).
Scheme 1. Proposed titanium-L1 complex (A) and proposed active intermediate (B) containing both aldehyde (RCOH) and nucleophile (CH2CH2R’).
Molecules 26 04471 sch001
Table
Table 1. Optimisation for the synthesis of 3aa a.
Table 1. Optimisation for the synthesis of 3aa a.
Molecules 26 04471 i001
EntryLT (°C)Ti(OiPr)4
(eq)		ZnBr2 (eq)Conv. 3aa (%) bConv. 4a (%) bee (%) c
1.L1351.500>99-
2.L1351.50.0250>99-
3.L1351.50.599186
4.L1351.510>99-
5.L1351.51.595118
6.L13520.5247548
7.L13510.50>99-
8.L1352197158
9.L1352294252
10.L1r.t.1.50.5366470
11.L1351.5- d99164
12.L1r.t.1.5- d851540
13.L2351.50.532628
14.L135-0.5011-
15. 351.50.50>99-
a Reaction conditions: 1a (0.3 mmol), 2a (2.2 eq., 0.66 mmol), Cp2Zr(H)Cl (2.0 eq, 0.60 mmol), L1 or L2 (20 mol %), Ti(OiPr)4 (x eq), ZnBr2 (x eq), DCM (0.3 + 0.1 mL), T, 12 h. b Determined by GC-MS. c Determined by Chiral GC (see experimental section for further details). d Reaction carried out with CuCl (1.5 eq) instead of ZnBr2.
Table
Table 2. Catalytic enantioselective addition of 1-hexene (2a) to aliphatic aldehydes (1b–g) a.
Table 2. Catalytic enantioselective addition of 1-hexene (2a) to aliphatic aldehydes (1b–g) a.
Molecules 26 04471 i002
EntryProductConv. to 3 (%) bConv. to by-Product 4 (%) bYield (%) cee (%) d
1. Molecules 26 04471 i003>9904276(R) e
2. Molecules 26 04471 i004>9905470(R) e
3. Molecules 26 04471 i0059375084(R) e
4. Molecules 26 04471 i0069144874(R) f,g
5. Molecules 26 04471 i007>9904074(R) f
6. Molecules 26 04471 i00887133578(R) f
7. Molecules 26 04471 i00953494056(R) f
a Reaction conditions: 1b–f, (0.3 mmol), 2a (2.2 eq), L1 (20 mol%), Cp2Zr(H)Cl (2.0 eq), Ti(OiPr)4 (1.5 eq), ZnBr2 (0.5 eq), DCM (0.3 + 0.1 mL) 35 °C, 12 h. b Determined by GC-MS. c Isolated yield after flash chromatography. d Configuration in brackets assigned by comparison with optical rotation values in literature (see experimental section for further details). e Determined by Chiral GC (see experimental section for further details). f Determined by Chiral HPLC (see experimental section for further details). g Determined on the corresponding benzoate derivative (see experimental section for further details).
Table
Table 3. Catalytic enantioselective addition of alkenes (2b–e) to cyclohexanecarboxaldehyde (1a) a.
Table 3. Catalytic enantioselective addition of alkenes (2b–e) to cyclohexanecarboxaldehyde (1a) a.
Molecules 26 04471 i010
EntryProductConv. (%) bConv. to Reduced Product 4a (%) bYield (%) cee (%) d
1 Molecules 26 04471 i01160393368(R) e
2 Molecules 26 04471 i012n.dn.d.2758(R) e
3 Molecules 26 04471 i01373205184(R) e,f
4 Molecules 26 04471 i01466343660(R) e,f
a Reaction conditions: 1a (0.3 mmol), 2b–e (2.2 eq), L1 (20 mol %), Cp2Zr(H)Cl (2.0 eq), Ti(OiPr)4 (1.5 eq), ZnBr2 (0.5 eq), DCM (0.3 + 0.1 mL) 35 °C, 12 h. b Determined by GC-MS. c Isolated yield after flash chromatography. d Configuration in brackets assigned by comparison of the optical rotation values in the literature (see experimental section for further details). e Determined by chiral HPLC (see experimental section for further details). f Determined on the corresponding benzoate derivative (see experimental section for further details).
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Vaccari, J.; González-Soria, M.J.; Carter, N.; Maciá, B. Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes. Molecules 2021, 26, 4471. https://doi.org/10.3390/molecules26154471

AMA Style

Vaccari J, González-Soria MJ, Carter N, Maciá B. Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes. Molecules. 2021; 26(15):4471. https://doi.org/10.3390/molecules26154471

Chicago/Turabian Style

Vaccari, Jade, María José González-Soria, Nicholas Carter, and Beatriz Maciá. 2021. "Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes" Molecules 26, no. 15: 4471. https://doi.org/10.3390/molecules26154471

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