Catalytic enantioselective addition of alkylzirconium reagents to aliphatic aldehydes

Article abstract of DOI:10.3390/molecules26154471

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.

Full text of DOI:10.3390/molecules26154471

molecules
Article
Catalytic Enantioselective Addition of Alkylzirconium
Reagents to Aliphatic Aldehydes
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; JADE.VACCARI@stu.mmu.ac.uk (J.V.); mariajo.gonzalez.s@gmail.com (M.J.G.-S.);
ncarter1990@gmail.com (N.C.)
* Correspondence: b.macia-ruiz@mmu.ac.uk; Tel.: +44-(0)161-247-1416
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.
Keywords: alkenes; Schwartz reagent; enantioselective catalysis; titanium-diol complex;
aliphatic aldehydes
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
1. Introduction
Citation: Vaccari, J.; González-Soria,
M.J.; Carter, N.; Maciá, B. Catalytic
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
Enantioselective Addition of
Alkylzirconium Reagents to Aliphatic
Aldehydes. Molecules 2021, 26, 4471.
https://doi.org/10.3390/molecules
agricultural to food additives, fragrances and cosmetics [1].
26154471
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
Academic Editor: Alejandro
methodologies [
cess, including reduction or hydrogenation of prochiral aliphatic ketones [
dition of alkyl organometallic reagents to aliphatic aldehydes [ ]. The addition of
alkylzinc [8–11], alkylaluminum [12 14], alkyltitanium [15 17] and, more recently, alkyl
2,
3] allow access to these relevant moieties in high enantiomeric ex-
Baeza Carratalá
4,5] and ad-
6,7
Received: 29 June 2021
Accepted: 20 July 2021
Published: 24 July 2021
–
–
Grignard reagents [18–26] to aliphatic aldehydes has been extensively studied. However,
the implementation of these methodologies in industrial processes and large scale reac-
tions, 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 incom-
patibilities with several functional groups [28]. In addition, organozirconium reagents
are readily accessible via (in-situ) hydrozirconation of alkenes using the Schwartz reagent
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
(Cp2ZrHCl) [29
precursors [32].
–31], and alkenes are classed as inexpensive, abundant and easy to handle
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Organozirconium reagents [33
but their nucleophilic character can be enabled by different catalysts or stoichiometric me-
diators [37 42]. Thus, the addition of organozirconium reagents to aldehydes [43–49],
ketones [50 51], enones [52 54], epoxides [55] and isocyanates [56] is possible in the pres-
ence of Ag(I), ZnBr2 or Me2Zn; although these protocols are rarely enantioselective [57 63].
The addition of alkenylzirconocenes to aldehydes and ketones, reported by Wipf [45 64 65
–35] are relatively inert toward carbonyl compounds [36],
–
,
–
–
,
,
]
Molecules 2021, 26, 4471. https://doi.org/10.3390/molecules26154471
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4471
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and Walsh [66], respectively; together with our recent work on the addition of alkylzir-
conium reagents to aromatic aldehydes [67], are, to the best of our knowledge, the only
catalytic asymmetric methodologies for the addition of organozirconium reagents to car-
bonyl 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 pharma-
ceutical 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 alco-
hols. This approach, however, is often challenging, due to the highly enolizable character
of aliphatic aldehydes, together with their multiple conformations and lack of
interactions with the catalysts.
π-stacking
Our investigations started by assessing the use of (Ra,S)-Ph-BINMOL ligand L1 [69–71]
in the addition of 1-hexene (2a) to cyclohexanecarboxaldehyde (1a, Table 1). The corre-
sponding 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 [29–31]. 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
–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 aldehy-
des [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).

Molecules 2021, 26, 4471
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Table 1. Optimisation for the synthesis of 3aa a.
Ti(OiPr)4
◦
Conv. 3aa (%) b
Conv. 4a (%) b
Entry
L
T ( C)
ZnBr2 (eq)
ee (%) c
(eq)
1.
2.
3.
4.
5.
6.
7.
8.
9.
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L1
35
35
35
35
35
35
35
35
35
r.t.
35
r.t.
35
35
35
1.5
1.5
1.5
1.5
1.5
2
1
2
2
1.5
1.5
1.5
1.5
-
0
0.025
0.5
1
1.5
0.5
0.5
1
0
0
99
0
>99
>99
1
>99
1
75
>99
1
2
64
1
15
62
11
>99
-
-
86
-
18
48
-
58
52
70
64
40
8
95
24
0
97
94
36
99
85
32
0
2
10.
11.
12.
13.
14.
15.
a
0.5
d
-
-
d
0.5
0.5
0.5
-
-
1.5
0
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. Determined by GC-MS. c Determined by Chiral GC (see experimental section for further details).
b
d
Reaction carried out with CuCl (1.5 eq) instead of ZnBr2.
The use of CuCl as additive, instead of ZnBr2, was also eva◦luated (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 cyclo-
hexanecarboxaldehyde (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

Molecules 2021, 26, 4471
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3aa but 11% and >99% conversion to the reduced product 4a, respectively (Table 1, entries
14 and 15).
Scheme 1. Proposed titanium-L1 complex (A) and proposed active intermediate (B) containing both aldehyde (RCOH) and
nucleophile (CH2CH2R’).
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.

Molecules 2021, 26, 4471
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Table 2. Catalytic enantioselective addition of 1-hexene (2a) to aliphatic aldehydes (1b–g) a.
Conv. to 3 (%) b
Conv. to by-Product 4 (%) b
ee (%) d
Entry
Product
Yield (%) c
1.
>99
0
42
76(R) e
70(R) e
2.
>99
0
54
3.
4.
5.
93
91
7
4
0
50
48
40
84(R) e
74(R) f,g
74(R) f
>99
78(R) f
56(R) f
6.
87
53
13
49
35
40
7.
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. Determined by GC-MS. c Isolated yield after flash chromatography. Configuration in brackets assigned by comparison with
optical rotation values in literature (see experimental section for further details). Determined by Chiral GC (see experimental section for
further details). Determined by Chiral HPLC (see experimental section for further details). Determined on the corresponding benzoate
derivative (see experimental section for further details).
b
d
e
f
g
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 mod-
erate 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 bear-

Molecules 2021, 26, 4471
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ing a protected alcohol are also suitable with our methodology; their analogous premade
organometallic reagents would also be of difficult access [18].
Table 3. Catalytic enantioselective addition of alkenes (2b–e) to cyclohexanecarboxaldehyde (1a) a.
Conv. to Reduced
Conv. (%) b
ee (%) d
Entry
Product
Yield (%) c
Product 4a (%) b
1
60
39
33
68(R) e
2
3
n.d
73
n.d.
20
27
51
58(R) e
84(R) e,f
60(R) e,f
4
66
34
36
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. Determined by GC-MS. c Isolated yield after flash chromatography. Configuration in brackets assigned by comparison of
the optical rotation values in the literature (see experimental section for further details). Determined by chiral HPLC (see experimental
section for further details). Determined on the corresponding benzoate derivative (see experimental section for further details).
b
d
e
f
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: H-NMR, 13C-NMR, and 31P-NMR spectra were recorded on
1
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 refer-
enced 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

Molecules 2021, 26, 4471
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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 Ag-
ilent 5973 mass selective detector using a HP-5ms (30 m
an Agilent Technologies® 7890B GC connected to an Agilent Technologies® 5977b MSD
using a HP-5MS (30 m 0.25 mm 0.25 m). Helium was used as the carrier gas at
×
0.25 mm
×
0.25 µm) or on
×
×
µ
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, respec-
tively; 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 usin-
gASAP 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 ar-
gon 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
L1, 23 mg, 20 mol %) in dry DCM (0.1 mL) was added and stirred for an additional 2 min
µL, 0.45 mmol, 1.5 eq.) and (Ra,S)-Ph-BINMOL
(
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
organic layers were dried with MgSO4, filtered and concentrated under reduced pressure.
The corresponding products were purified by flash silica gel chromatography.
×
10 mL) and the combined
(R)-1-cyclohexylheptan-1-ol (3aa):
[
81] Obtained as a yellow oil after purification by
23
column chromatography (Et2O/hexane 3:7). 60% yield, 86% ee. [
α
]
= +17.4 (c 1.5,
D
25
1
CH2Cl2). {Lit
[α
]
=
−
10.5 (c 0.2, CHCl3) for 84% ee of S enantiomer}. H NMR (400 MHz,
D
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,

Molecules 2021, 26, 4471
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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):
umn chromatography (Et2O/hexane 3:7). 42% yield, 76% ee. [
[
82] Obtained as a yellow oil after purification by col-
23
α
]
D
= +13.3 (c 0.6, CH2Cl2).
Lit
25
1
{
[
α
]
D
=
−
14.1 (c 0.7, CHCl3) for 96% ee of S enantiomer}. H 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
23
chromatography (Et2O/hexane 2:8). 54% yield, 70% ee. [
α
]
D
= +6.7 (c 0.4, CH2Cl2). FTIR
(neat) Vmax: 3373, 2958, 2925, 2873, 2858, 1461, 1379, 1143 cm−1. H NMR (400 MHz, CDCl3)
1
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
]
23 = +8.9 (c 0.9,
D
25
CH2Cl2). {Lit
[
α
]
= +15.0 (c 5.1, benzene) for 84% ee}. FTIR (neat) Vmax: 3392, 2954,
D
2925, 2859, 1479, 1466, 1393, 1364, 1075, 1009, 957, 734, 703, 566, 543 cm−1
400 MHz, CDCl3) : 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)
: 80.1, 35.1, 32.1, 31.6, 29.6, 27.2, 25.8, 22.8, 14.3.
.
1H NMR
(
δ
δ
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 chro-
matography (Et2O/cyclohexane 3:7). 48% yield, 74% ee (determined on the corresponding
◦
benzoate 3ea’). [
α
]
22 = +13.3 (c 0.7, CH2Cl2). Mp = 36–39 C. FTIR (neat) Vmax: 3343, 2956,
D
2929, 2872, 1470, 1381, 1045, 952, 817 cm−1. H NMR (400 MHz, CDCl3)
δ: 3.55 (s, 1H), 1.40
1
(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
26
chromatography (Et2O/cyclohexane 3:7). 40% yield, 74% ee. [
α
]
D
=
−
10.5 (c 3.8, CH2Cl2).
: 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,
: 142.4, 128.6, 128.5, 125.9, 71.6,
Lit
21
1
{
[
α
]
=
−
8.2 (c 0.3, CHCl3) for 72% ee}. H NMR (400 MHz, CDCl3)
δ
D
10H), 0.81 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ
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
26
column chromatography (Et2O/cyclohexane 2:8). 35% yield, 78% ee. [
α
]
=
−
66.7 (c
D
21
1
1.2, CH2Cl2). {Lit
[
α
]
=
−
5.6 (c 1.07, CHCl3) for 91% ee}. H NMR (400 MHz, CDCl3)
D

Molecules 2021, 26, 4471
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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
23
column chromatography (Et2O/cyclohexane 2:8). 43ae’0% yield, 56% ee. [
α
]
=
−
22.2 (c
D
3.6, CH2Cl2). {Lit
: 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)
: 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+,
[
α
]
D
=
−
1.5 (c 0.69, CHCl3) for 92% ee). H NMR (400 MHz, CDCl3)
23
1
δ
δ
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
23
by column chromatography (Et2O/cyclohexane 2:8). 33% yield, 68% ee. [
α
]
= +40 (c
D
0.4, CH2Cl2). FTIR (neat) Vmax: 3368, 3026, 2922, 2852, 1603, 1496, 1450, 1077, 977, 745,
1
697 cm−1. H 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,
23
58% ee. [
α
]
= +10.81 (c 3.7, CH2Cl2). FTIR (neat) Vmax: 3369, 2927, 2854, 1428, 1106,
D
823, 699, 613, 503, 187 cm−1. H NMR (400 MHz, CDCl3)
δ 7.67 (dd, J = 4.2, 3.4 Hz, 4H),
1
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
25
corresponding benzoate 3ad’). [
α
]
= +12 (c 1, CH2Cl2). FTIR (neat) Vmax: 3368, 2928,
D
2851, 1450, 1237, 1087, 1064, 1047, 975, 893, 562 cm−1. H NMR (400 MHz, CDCl3)
δ: 3.41 (t,
1
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
25
the corresponding benzoate 3ae’). [
α
]
= +20 (c 0.8, CH2Cl2). FTIR (neat) Vmax: 3369,
D
2923, 2851, 1449, 1309, 1088, 1065, 977, 892, 734, 651 cm−1. H NMR (400 MHz, CDCl3)
δ:
1

Molecules 2021, 26, 4471
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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’
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
L, 0.2 mmol, 2.0 eq),
benzoyl chloride (12 L, 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
, 3ad’ and 3ae’: [67]
,
µ
µ
×
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
23
column chromatography (Et2O/cyclohexane 2:8). 55% yield, 74% ee. [
α
]
= +20 (c 1.2,
D
CH2Cl2). Mp = 42–45 ◦C. FTIR (neat) Vmax: 3349, 2926, 2855, 190, 1723, 1211, 1936, 1014,
1
703 cm−1. H 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 pu-
rification by column chromatography (Et2O/cyclohexane 3:7). 19% yield, 84% ee. FTIR
1
(neat) Vmax: 2927, 2854, 1716, 1450, 1273, 1113, 712 cm−1. [
α
]
D
23 = +24 (c 0.5, CH2Cl2). H
NMR (400 MHz, CDCl3)
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)
: 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.
δ: 8.09–8.01 (m, 2H), 7.58–7.53 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H),
δ
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 purifi-
cation by column chromatography (Et2O/cyclohexane 3:7). 27% yield, 60% ee. [
(c 0.4, CH2Cl2). FTIR (neat) Vmax: 2929, 2854, 1717, 1450, 1279, 1113, 1027, 801, 712 cm−1
1H NMR (400 MHz, CDCl3)
: 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)
: 166.5, 133.0, 130.8, 129.7, 128.5, 78.3, 44.9, 41.5, 32.6,
α]
D
23 = +10
.
δ
δ
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.

Molecules 2021, 26, 4471
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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, Uni-
versity 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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