Catalytic enantioselective addition of alkyl grignard reagents to aliphatic aldehydes

Article abstract of DOI:10.1002/adsc.201201117

Herein, we report an efficient catalytic system for the enantioselective addition of alkyl Grignard reagents to a broad range of aliphatic aldehydes with good yields and enantioselectivities. Remarkably, the challenging methylmagnesium bromide (MeMgBr) can also be added to a variety of aliphatic aldehydes, providing versatile chiral methyl carbinol units with unprecedented yields and enantioselectivities in a simple one-pot procedure under mild conditions. Copyright

Full text of DOI:10.1002/adsc.201201117

Supporting Information
© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2013

SUPPORTING INFORMATION
Catalytic enantioselective addition of alkyl Grignard reagents to aliphatic
aldehydes
Emilio Fernández-Mateosa, Beatriz Maciáb,* and Miguel Yusa,*
a Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica,
Alicante University. Aptdo. 99. E-03080, Alicante, Spain.
b Department of Chemistry and the Environment,
Manchester Metropolitan University, Oxford Road, M1 5GD, Manchester, UK.
beatriz.macia@mmu.ac.uk, yus@ua.es
Table of contents
Page
General Procedure
1
1
4
8
1. Synthesis of Ligands L1–7 and (8H)‐L1
2. Synthesis of chiral secondary alcohols 2a–m
3. Additional data – Mechanistic studies
4. Spectra of compounds (1H NMR, 13C NMR)………………………………………………………………..11
5. Chromatograms (GC, HPLC) 32

General Procedures: Chromatography: Panreac silica gel 60, 40‐63 microns RE, TLC: Machery‐Nagel silica gel 60, 0.20 mm. Components were
visualized by UV and phosphomolibdic acid staining. Progress of the reaction and conversion were determined by GC analysis (Agilent
Technologies 7820A GC System) with a CP‐Chiralsil‐DEX CB (Varian, 25 m × 0.25 mm) or HP‐CHIRAL‐20β (Agilent Technologies, 30 m × 0.25 mm)
column; injector and detector temperatures: 250 °C. Mass spectra were recorded on a GC‐MS spectrometer (Agilent Technologies 6890N Network
GC System) with a HP‐5MS column (Agilent technologies, 30 m × 0.25 mm), including an Agilent Technologies 5973 Network Mass Selective
Detector. 1H‐ and 13C‐NMR were recorded on a Bruker AC‐300 (300 and 75 MHz, respectively) or a Bruker Avance‐400 (400 and 101 MHz,
respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with TMS as internal standard (CDCl3: δ 7.26 for 1H‐NMR, δ 77.0 for
13C‐NMR). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quintuplet = quin, sextuplet =
sext, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured on a Jasco P‐1030 Polarimeter with a 5
cm cell (c given in g/100 mL). IR Spectra were recorded on Jasco FT/IR – 4100 Fourier Transform Infrared Spectrometer. Melting points were
measured in a Reichtert Thermovar hot plate apparatus and are corrected. Enantioselectivities were determined by HPLC analysis (Agilent 1100
Series HPLC) equipped with a G1315B diode array detector and a Quat Pump G1311A or GC analysis (Agilent technologies 7820A GC System) using
N2 as a carrier gas.
All reactions were carried out under argon atmosphere unless noted, using flame dried glassware. Ti(OPri)4 not dry was purchase from
Aldrich and was stored under argon atmosphere. MeMgBr (3 M in Et2O) and EtMgBr (3M in Et2O), were purchased from Aldrich and were used
without further purification. n‐BuMgBr (3.0 M in Et2O) was prepared from 1‐bromobutane and magnesium turnings in Et2O following standard
procedures. Grignard reagents were titrated using s‐BuOH and catalytic amounts of 1,10‐phenanthroline in THF. Aldehydes were purified by
washing with 10% aq. NaHCO3 (3 × 5 mL), dried over hot magnesium sulfate and finally were distilled by Kugelrohr aparatus (Büchi Glass Oven B‐
585) and used immediately. Racemic alcohols were synthesized by reaction of the corresponding aldehyde (1.0 mmol) and RMgX (1.5 mmol) in
THF at 0 °C.
1. Synthesis of ligands L1–7
1.1 Step 1: Synthesis of monobenzylated (S)‐BINOL derivatives (S)‐P1–7
The intermediates (S)‐P1–7 were prepared starting from commercially available (S)‐BINOL or (S)‐8H‐BINOL according to two different procedures:
Scheme 1
Procedure A:1 Synthesis of (S)‐P1, (S)‐P4, (S)‐P5, (S)‐P6, (S)‐P7 and (S)‐(8H)‐P1
(S)‐BINOL (2 g, 7 mmol) or (S)‐8H‐BINOL (2.1 g, 7.0 mmol) was dissolved in 50 mL of acetone in a round bottom flask, then K2CO3 (1.45
g, 10.5 mmol, 1.5 eq.) and the corresponding benzyl bromide derivative (ArCH2Br, 7 mmol, 1 eq) were added and the mixture was heated at 60 °C
during 6 h. The reaction crude was concentrated under vacuum and was extracted with EtOAc (3 × 15 mL). The combined organic layers were
dried over magnesium sulfate and concentrated under vacuum. Synthetic intermediates P were used in the next step without further purification,
Data of the products were in accordance with the previously reported in literature.2
1 Bremmer, J. B.; Keller, P. A.; Pyne, S. G.; Boyle, T. P.; Brkic, Z.; Morgan, J.; Rhodes, D. I. Bioorgan. Med. Chem. 2010, 18, 4793–4800.
2 (a) Fernández‐Mateos, E.; Maciá, B.; Ramón, D. J.; Yus, M. Eur. J. Org. Chem., 2011, 34, 6851−6855. (b) Gao, G.; Gu, F.‐L.; Jiang, J.‐X.; Jiang, K.; Sheng, C.‐Q.; Lai, G.‐Q.;
Xu, L.‐W. Chem. Eur. J., 2011, 17, 2698.
1

Procedure B: Synthesis of (S)‐P2 and (S)‐P3.
(S)‐BINOL (2 g, 7 mmol) was dissolved in 40 mL of acetone in a round bottom flask and a solution of K2CO3 (2.9 g, 21.0 mmol, 3 eq.) in 4 mL of
water was added. Next, the corresponding (bromomethyl)pyridinium bromide (7 mmol, 1 eq.) was added and the mixture was heated at 65 °C
during 12 h. The reaction crude was filtered under vacuum over celite, washing the cake with EtOAc (3 × 50 mL) and solvent was evaporated
under vacuum. The hydroxyether (S)‐P2 was purified by flash silica gel chromatography while the synthetic intermediate (S)‐P3 was used in the
next step without further purification.
1.2 Data of the precursor (S)‐P2
(S)‐2'‐(pyridin‐4‐ylmethoxy)‐(1,1'‐binaphthalen)‐2‐ol [(S)‐P2]: Compound (S)‐P2 was obtained after purification
on flash silica gel chromatography from 100:0 till 0:100 (Hexane/EtOAc) as a white powder (66% yield) and was
O
1
recrystallized in Hexane/EtOAc , m.p. 182–184 °C, [α]D20= ‐17.5 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 8.26
OH
N
(br d, J = 4.5 Hz, 2H), 7.97 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.42 – 7.34 (m, 3H),
7.34 – 7.26 (m, 3H), 7.21 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.85 (br d, J = 5.2 Hz, 2H), 5.08 (d,
J = 13.9 Hz, 1H), 5.03 (d, J = 13.8 Hz, 1H), 3.18 (br s, 1H). 13C NMR (101 MHz, CDCl3) δ 154.3, 151.6, 148.9, 146.9, 134.0, 133.8, 130.9, 129.9, 129.1,
128.2, 127.5, 126.5, 125.2, 124.7, 123.3, 121.2, 117.7, 115.4, 114.8, 69.4. IR (ATR): ν (cm‐1): 3064, 1610, 1504, 1325, 1264, 1044, 798. LRMS (EI)
m/z: 379 (M++2, 5), 378 (M++1, 28), 377 (M+, 100), 286 (14), 285 (47), 284 (10), 269 (11), 268 (38), 257 (15), 255 (19), 240 (17), 239 (42), 229 (28),
228 (37), 227 (20), 226 (37), 93 (22), 80 (49). HRMS calculated for C26H19NO2 377.1416, found 377.1404.
1.3 Step 2: Synthesis of Ar‐BINMOLs derivatives L1–7
Two different procedures were used to synthesize compounds L1–7 through a [1,2]‐Wittig rearrangement from the corresponding hydroxyethers
(S)‐P1–7.
Procedure A: Synthesis of (S)‐L1 and (S)‐L4–7
n‐BuLi (2.5 M in hexane, 2.5 eq) was slowly added to a solution of the corresponding precursor (S)‐P1 or (S)‐P4–7 (4 mmol) in dry THF
(30 mL) at ‐78 °C. The mixture was stirred for 2 h at ‐78 °C and then quenched with water at 0 °C. The resulting mixture was extracted with EtOAc
(3 × 10 mL), and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude
product was purified by chromatography on flash silica gel to give the desired products. Data of the products was in accordance with the
previously reported in the literature.
Procedure B: Synthesis of (S)‐L2–3 and (S)‐(8H)‐L1
n‐BuLi (2.5 M in hexane, 5.0 eq) was slowly added to a solution of the corresponding precursor (S)‐P2–3 or (S)‐(8H)‐P1 (4 mmol) in dry
THF (40 mL) at room temperature. The mixture was stirred for 12 h at 70 °C and then the reaction was quenched with water at 0 °C. The resulting
mixture was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried over magnesium sulfate and concentrated under
vacuum. The crude product was purified by chromatography on flash silica gel to give the desired products (Sa,R)‐L2–3 and (Sa,R)‐(8H)‐L1.
Ar
n-BuLi (2.5 - 5.0 eq.)
O
Ar
OH
OH
OH
THF, -78 ºC, 2 h
or
THF, 70 ºC, 12 h
Ar = C6H5,
Ar
(Sa,R)-L1
Ar
P1
= C6H5,
Ar = 4-C5H4N,
(S)-
(S)-P2
(S)-
L2
= 4-C5H4N,
Ar = 2-C5H4N,
Ar
(Sa,R)-
(Sa,S)-L3
L4
Ar
Ar
P3
P4
= 2-C5H4N,
= o-OMe-C6H5, (S)-
= o-OMe-C6H5,
(Sa,S)-
Ar = m-OMe-C6H5, (Sa,R)-L5
Ar = p-OMe-C6H5, (Sa,R)-L6
Ar L7
Ar = m-OMe-C6H5,(S)-P5
Ar
Ar
P6
P7
= p-OMe-C6H5, (S)-
= 1-Naphtyl, (S)-
= 1-Naphtyl,
(Sa,R)-
Scheme 2
2

1.4 Data of the ligands L2–3, (Sa,R)‐L7 and (Sa,R)‐(8H)‐L1
(Sa)‐2'‐[(R)‐hydroxy(pyridin‐4‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol [(Sa,R)‐L2]: Compound (Sa,R)‐L2 was obtained
N
after purification on flash silica gel chromatography from 100:0 till 20:80 (Hexane/EtOAc) as a yellow foamy solid
(48% yield), m.p. 100–103 °C, [α]D20 = +252 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.20 (br d, J = 6.1 Hz, 2H), 7.93
– 7.78 (m, 4H), 7.44 (ddd, J = 8.1, 6.6, 1.4 Hz, 1H), 7.39 – 7.23 (m, 4H), 7.23 – 7.15 (m, 2H), 6.99 (br d, J = 5.8 Hz, 2H),
6.89 (d, J = 8.4 Hz, 1H), 5.65 (s, 1H), 3.56 (br s, 2H). 13C NMR (75 MHz, CDCl3) δ 152.9, 151.8, 148.3, 139.9, 134.2,
OH
OH
133.5, 132.9, 131.5, 130.3, 129.6, 128.9, 128.2, 128.1, 126.9, 126.7, 126.6, 125.0, 124.7, 123.7, 121.5, 118.2, 117.2, 72.1. IR (ATR): ν (cm‐1): 3297,
3055, 1606, 1506, 1342, 813, 747. LRMS (EI) m/z: 378 (M++1, 3), 377 (M+, 9), 360 (27), 359 (100), 358 (36), 282 (21), 281 (91), 279 (25), 252 (25),
239 (16), 140 (9), 78 (5). HRMS calculated for C26H19NO2 377.1416, found 377.1386.
(Ra)‐2'‐[(S)‐hydroxy(pyridin‐4‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol [(Ra,S)‐L2]: Compound (Ra,S)‐L2 was obtained
N
after purification on flash silica gel chromatography from 100:0 till 20:80 (Hexane/EtOAc) as a yellow foamy solid
(33% yield, two steps), m.p. 100–103 °C, [α]D20 = ‐273 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 6.2 Hz,
OH
OH
2H), 7.95 – 7.73 (m, 4H), 7.42 (ddd, J = 8.1, 6.5, 1.6 Hz, 1H), 7.36 – 7.26 (m, 3H), 7.25 – 7.13 (m, 3H), 6.97 (d, J = 5.8
Hz, 2H), 6.90 (d, J = 8.3 Hz, 1H), 5.64 (s, 1H), 3.56 (br s, 2H). 13C NMR (75 MHz, CDCl3) δ 152.8, 152.0, 148.3, 139.8,
134.2, 133.4, 132.9, 131.8, 130.2, 129.4, 128.9, 128.2, 128.1, 126.8, 126.8, 126.5, 125.0, 124.8, 123.6, 121.5, 118.3, 117.3, 72.1. IR (ATR): ν (cm‐1):
3297, 3055, 1606, 1506, 1342, 813, 747. LRMS (EI) m/z: 378 (M++1, 3), 377 (M+, 9), 360 (27), 359 (100), 358 (36), 282 (21), 281 (90), 279 (26), 252
(25), 239 (16), 140 (9), 78 (4). HRMS calculated for C26H19NO2 377.1416, found 377.1435.
(Sa)‐2'‐[(S)‐hydroxy(pyridin‐2‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol [(Sa,S)‐L3]: Compound (Sa,S)‐L3 was obtained
N
after purification on flash silica gel chromatography from 100:0 till 20:80 (Hexane/EtOAc) as a yellow foamy solid
(40% yield), m.p. 83–85 °C, [α]D20 = +251 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.50 (br d, J = 4.6 Hz, 1H), 7.96 –
OH
OH
7.84 (m, 4H), 7.45 (m, 3H), 7.39 – 7.30 (m, 2H), 7.29 – 7.16 (m, 3H), 7.15 – 7.09 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.68
(d, J = 7.9 Hz, 1H), 5.66 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.5, 152.1, 147.2, 140.7, 137.0, 134.2, 133.5, 133.0,
130.8, 130.2, 129.7, 129.0, 128.3, 128.1, 126.9, 126.7, 126.6, 125.2, 124.9, 123.4, 122.5, 122.0, 118.8, 116.9, 71.7. IR (ATR): ν (cm‐1): 3248, 3057,
1594, 1434, 1038, 816, 746. LRMS (EI) m/z: 378 (M+ + 1, 26), 377 (M+, 90), 360 (16), 359 (54), 358 (11), 332 (22), 331 (96), 330 (100), 329 (11), 328
(16), 282 (19), 281 (79), 280 (11), 279 (30), 268 (15), 254 (14), 253 (45), 252 (53), 250 (19), 240 (11), 239 (36), 237 (11), 164 (10), 109 (14), 80 (24),
79 (12), 78 (19). HRMS calculated for C26H19NO2 377.1416, found 377.1441.
(Sa)‐2'‐[(R)‐hydroxy(naphthalen‐1‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol [(Sa,R)‐L7]: Compound (Sa,R)‐L7 was
obtained after purification on flash silica gel chromatography from 100:0 till 80:20 (Hexane/EtOAc) as a yellow
foamy solid (72% yield), m.p. 105–108 °C, [α]D20 = +330 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.87 (t, J = 6.8 Hz,
2H), 7.81 (t, J = 6.9 Hz, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.48 – 7.41 (m, 2H), 7.37 (ddd, J = 8.1,
6.9, 1.1 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.27 – 7.21 (m, 4H), 7.13 (d, J = 8.3 Hz, 1H), 6.91 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H),
6.40 (s, 1H), 3.45 (br s, 1H), 1.60 (br s, 1H). 13C NMR (101 MHz, CDCl3) δ 151.9, 140.1, 137.5, 133.8, 133.6, 133.4,
OH
OH
133.2, 131.4, 130.4, 129.8, 129.4, 128.4, 128.3, 128.1, 127.9, 126.8, 126.7, 126.5, 126.4, 125.6, 125.4, 125.3, 125.2, 124.9, 123.8, 123.7, 123.4,
118.6, 118.1, 71.6. IR (ATR): ν (cm‐1): 3227, 3051, 1621, 1508, 1268, 783, 748. LRMS (EI) m/z: 426 (M+, 2), 409 (33), 408 (100), 407 (15), 380 (27),
379 (14), 282 (18), 281 (80), 280 (10), 279 (18), 252 (19), 239 (16), 127 (14). HRMS calculated for C31H22O2 426.1620, found 426,1609.
(Sa)‐2'‐[(R)‐hydroxy(phenyl)methyl]‐5,5',6,6',7,7',8,8'‐octahydro‐(1,1'‐binaphthalen)‐2‐ol
[(Sa,R)‐(8H)‐L1]:
Compound (Sa,R)‐(8H)‐L1 was obtained after purification on flash silica gel chromatography from 100:0 till 80:20
(Hexane/EtOAc) as a yellow foamy solid (53% yield), m.p. 74–77 °C, [α]D20 = +90 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 7.30 (d, J = 8.0 Hz, 1H), 7.24 – 7.17 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 – 7.06 (m, 2H), 7.01 (d, J = 8.3 Hz,
1H), 6.81 (d, J = 8.3 Hz, 1H), 5.43 (s, 1H), 4.96 (br s, 1H), 2.80 (t, J = 6.0 Hz, 3H), 2.69 (dd, J = 13.3, 6.7 Hz, 2H), 2.19
OH
OH
(dd, J = 14.2, 6.1 Hz, 2H), 1.99 – 1.89 (m, 1H), 1.80 – 1.50 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 149. 8, 142.7, 139.9, 137.8, 136.5, 136.1, 133.6,
129.8, 129.7, 129.6, 128.1, 127.3, 126.8, 124.7, 124.3, 113.1, 73.5, 29.9, 29.2, 27.4, 27.2, 23.2, 22.9, 22.8, 22.7. IR (ATR): ν (cm‐1): 3337, 2927,
3

1591, 1448, 1018, 808, 698. LRMS (EI) m/z: 384 (M+, <1), 367 (28), 366 (100), 365 (11), 338 (9), 289 (36), 275 (27), 235 (8), 105 (11), 77 (7). HRMS
calculated for C27H28O2 384.2089, found 384, 2057.
2. Synthesis of chiral secondary alcohols 2a–m
2.1 Methodology
In a flame dried Schlenk tube, (Sa,R)‐L2 (22.6 mg, 0.06 mmol) was dissolved in dry Et2O (2.5 mL) under argon atmosphere. The solution
was cooled down to ‐20 °C and Ti(OPri)4 (915 μL, 3.0 mmol, 10 eq.) was added. Five minutes later, RMgBr (0.75 mmol, 2.5 eq.) was added. After
stirring the mixture for additional 15 min, the corresponding previously purified aldehyde (0.3 mmol) was added and the reaction mixture was
stirred at ‐20 °C for 3 h. The reaction was quenched with water (5 mL), and HCl(aq) 2M (5 mL). The mixture was extracted with Et2O (3 × 10 mL), the
combined organic layers were neutralized with NaHCO3(aq) solution (15 mL), dried over magnesium sulfate and concentrated under vacuum. The
crude product was purified by chromatography on flash silica gel to give the desired products 2a–m.
Scheme 3
Ligand (Sa,R)‐L2 could be recovered by acid‐base extraction (60% yield) and reused in the reaction of MeMgBr with 3‐Phenylpropanal
(1g) to give compound 2g without any loss of activity (80% yield, 85% ee).
2.2 Data of the products 2a–m
(S)‐1‐cyclohexylpentan‐1‐ol (2a):3 Compound 2a was obtained after purification on flash silica gel chromatography
OH
from 100:0 till 92:8 (Hexane/EtOAc) as a yellow oil (97% yield, 90% ee); [α]D20 = ‐15.4 (c 1.0, CHCl3) {Lit [α]D20 = +14.3 (c
1
1.9, CHCl3) for 90% ee of R enantiomer}. H NMR (300 MHz, CDCl3) δ 3.41 – 3.29 (m, 1H), 1.86 – 1.71 (m, 3H), 1.71 –
1.57 (m, 3H), 1.55 – 0.96 (m, 12H), 0.91 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 76.2, 43.5, 33.8, 29.3, 28.1, 27.7,
26.6, 26.4, 26.2, 22.8, 14.1. LRMS (EI) m/z: 170 (M+, <1), 152 (8), 113 (44), 95 (100), 87 (45), 82 (17), 69 (90), 67 (19), 57 (13), 55 (22). Ee
determination by chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 120 °C, P = 14.3 psi, retention times: tr(S) = 21.6 min (major enantiomer), tr(R)
= 23.3 min.
(‐)‐3‐ethyloctan‐4‐ol (2b):3 Compound 2b was obtained after purification on flash silica gel chromatography from 100:0
OH
till 94:6 (Hexane/EtOAc) as a colorless oil (97% yield, 80% ee); [α]D20 = ‐10.6 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ
3.61 (dt, J = 8.1, 4.0 Hz, 1H), 1.44 (m, 6H), 1.38 – 1.24 (m, 5H), 1.23 – 1.14 (m, 1H), 0.96 – 0.86 (m, 9H). 13C NMR (101
MHz, CDCl3) δ 73.2, 46.8, 33.7, 28.5, 22.8, 22.1, 21.1, 14.1, 11.9, 11.8. LRMS (EI) m/z: 158 (M+, <1), 101 (17), 87 (47), 86
(15), 83 (11), 70 (17), 69 (100), 59 (18), 57 (15), 55 (15). Ee was determined by chiral GC analysis on the derivative 3b.
(S)‐hept‐1‐en‐3‐ol (2c):4 Compound 2c was obtained after purification on flash silica gel chromatography from 100:0 till
OH
90:10 (Pentane/Et2O) as a colorless oil (53% yield, 96% ee); [α]D20 = +14.2 (c 0.9, CHCl3) {Lit [α]D20 = +9.0 (c 1.0, CHCl3) for
99% ee}. 1H NMR (300 MHz, CDCl3) δ 5.94 – 5.80 (ddd, J = 16.7, 10.4, 6.3 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.13 – 5.06 (dd, J = 10.4, 1.4 Hz,
1H), 4.14 – 4.04 (qt, J = 6.3, 1.1 Hz, 1H), 1.90 (br s, 1H), 1.65 – 1.43 (m, 2H), 1.43 – 1.24 (m, 4H), 0.98 – 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 141.3, 114.5, 73.2, 36.7, 27.5, 22.6, 14.0. LRMS (EI) m/z: 114 (M+, <1), 85 (9), 81 (7), 72 (21), 58 (6), 57 (100), 55 (8). Ee determination by
chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 70 °C, P = 14.3 psi, retention times: tr(S) = 18.1 min (major enantiomer), tr(R) = 19.7 min.
3
Seebach, D.; Kalinowski, H. O.; Bastani, B.; Crass, G.; Daum, H.; Doerr, H.; DuPreez, N. P.; Ehrig, V.; Langer, W. Helv. Chim. Acta 1977, 60, 301–325.
4
Gawas, D.; Kazmaier, U. Org. Biomol. Chem. 2010, 8, 457–462.
4

(+)‐1‐cyclopentylpropan‐1‐ol (2d):5 Compound 2d was obtained after purification on flash silica gel chromatography from
100:0 till 90:10 (Pentane/Et2O) as a colorless oil (80% yield, 86% ee); [α]D20 = +3.7 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3) δ
OH
3.40 – 3.30 (td, J = 8.0, 3.5 Hz, 1H), 1.99 – 1.75 (m, 2H), 1.73 – 1.49 (m, 8H), 1.48 – 1.32 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13
C
NMR (75 MHz, CDCl3) δ 77.4, 45.9, 29.1, 28.9, 28.5, 25.7, 25.6, 10.0. LRMS (EI) m/z: 128 (M+, <1), 99 (42), 82 (8), 81 (100), 79 (10), 69 (10), 68 (20),
67 (14), 59 (81), 58 (21), 57 (13), 55 (9). Ee was determined by chiral GC analysis on the derivative 3d.
(3S,4R)‐4‐methylheptan‐3‐ol (2ea) and (3S,4S)‐4‐methylheptan‐3‐ol (2eb):6 Compounds 2ea and 2eb were obtained as a
OH
diastereomeric mixture 43/57 after purification on flash silica gel chromatography from 100:0 till 90:10 (Pentane/Et2O) as
a colorless oil (78% yield, 77% ee and 87% ee, respectively). 1H NMR (400 MHz, CDCl3) δ 3.42 (m, 1H), 3.35 (m, 1H), 1.05 –
anti
OH
1.60 (m, 16H), 0.87– 0.97 (m, 18H). 13C NMR (101 MHz, CDCl3) δ 78.3, 77.6, 38.5, 35.5, 35.6, 34.1, 27.2, 26.2, 20.4, 20.3,
14.4, 14.3, 13.9, 13.5, 10.6, 10.4. LRMS (EI) m/z: 130 (M+, <1), 101 (16), 83 (22), 70 (8), 59 (100), 58 (21), 57 (11), 55 (18).
syn
Ee was determined by chiral GC analysis on the derivatives 3ea and 3eb.
(S)‐decan‐2‐ol (2f):7 Compound 2f was obtained after purification on flash silica gel chromatography from 100:0
OH
till 94:6 (Hexane/EtOAc) as a colorless oil (98% yield, 88% ee); [α]D20 = +6.2 (c 1.0, CHCl3) {Lit [α]D20 = +6.1 (c 1.0,
CHCl3) for 99% ee}. 1H NMR (400 MHz, CDCl3) δ 3.86 – 3.73 (sext, J = 6.2 Hz, 1H), 1.72 (s, 1H), 1.53 – 1.37 (m, 3H), 1.36 – 1.22 (m, 11H), 1.19 (d, J =
6.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 68.2, 39.3, 31.9, 29.6, 29.5, 29.3, 25.8, 23.4, 22.6, 14.1. LRMS (EI) m/z: 158 (M+,
<1), 143 (24), 140 (23), 112 (47), 111 (31), 98 (22), 97 (41), 85 (26), 84 (35), 83 (72), 82 (15), 71 (28), 70 (51), 69 (100), 67 (10), 57 (58), 56 (45), 55
(80). Ee was determined by chiral GC analysis on the derivative 3f.
(S)‐4‐phenylbut‐2‐ol (2g):8 Compound 2g was obtained after purification on flash silica gel chromatography from 100:0 till
OH
90:10 (Hexane/EtOAc) as a colorless oil (81% yield, 86% ee); [α]D20 = +13.5 (c 1.0, CHCl3) {Lit [α]D20 = +13.8 (c 1.7, CHCl3) for
79% ee}. 1H NMR (300 MHz, CDCl3) δ 7.33 – 7.13 (m, 5H), 3.88 – 3.75 (sext, J = 6.2 Hz, 1H), 2.83 – 2.59 (m, 2H), 1.83 – 1.72
(m, 2H), 1.70 (s, 1H), 1.22 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 142.0, 128.4, 125.8, 67.4, 40.8, 32.1, 23.6. LRMS
(EI) m/z: 151 (M++1, 1), 150 (M+, 10), 132 (52), 131 (9), 118 (10), 117 (100), 115 (9), 105 (10), 92 (34), 91 (75), 78 (20), 77 (13), 65 (12), 51 (7). Ee
determination by chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 110 °C, P = 14.3 psi, retention times: tr(S) = 27.0 min (major enantiomer), tr(R)
= 29.7 min.
(+)‐3‐ethylpentan‐2‐ol (2h):9 Compound 2h was obtained after purification on flash silica gel chromatography from 100:0 till
OH
90:10 (Pentane/Et2O) as a colorless oil (99% yield, 83% ee); [α]D20 = +2.6 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 3.84 (qd, J =
6.4, 5.1 Hz, 1H), 1.93 (br s, 1H), 1.48 – 1.19 (m, 5H), 1.15 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ
69.3, 48.1, 21.6, 21.5, 20.0, 11.7, 11.6. LRMS (EI) m/z: 116 (M+, <1), 101 (10), 83 (9), 71 (16), 70 (100), 69 (14), 59 (17), 57 (13),
55 (42), 53 (6). Ee determination by chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 70 °C, P = 14.3 psi, retention times: tr(R) = 20.4 min, tr(S) =
21.0 min (major enantiomer).
(S)‐1‐cyclohexylethanol (2i):10 Compound 2i was obtained after purification on flash silica gel chromatography from 100:0 till
OH
94:6 (Hexane/EtOAc) as a yellow oil (61% yield, 92% ee); [α]D20 = +2.8 (c 1.0, CHCl3) {Lit [α]D20 = +3.5 (c 3.1, CHCl3) for 95% ee}. 1H
NMR (300 MHz, CDCl3) δ 3.54 (quin, J = 6.2 Hz, 1H), 1.92 – 1.59 (m, 6H), 1.34 – 1.09 (m, 7H), 1.09 – 0.87 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 72.2, 45.1, 28.6, 28.3, 26.5, 26.2, 26.1, 20.3. LRMS (EI) m/z: 128 (M+, <1), 113 (16), 110 (37), 95 (42), 84 (24), 83
(35), 82 (100), 81 (18), 69 (16), 67 (61), 56 (25), 55 (76), 54 (14), 53 (9). Ee was determined by chiral GC analysis on the derivative 3i.
5
Xin, S.; Harrod, J. F. Can. J. Chemistry 1995, 73, 999–1002.
6
Zada, A.; Ben‐Yehuda, S.; Dunkelblum, E.; Harel, M.; Assael, F.; Mendel, Z. J. Chem. Ecol. 2004, 30, 631–641.
7
Keinan, E.; Hafeli, E. K.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 162–169.
8
Li, D. R.; He, A.; Falck, J.R. Org. Lett. 2010, 12, 1756–1759.
9
Rawson. D.; Meyers, A. I. J. Chem. Soc., Chem. Commun. 1992, 6, 494–496.
10
Li, G.; Kabalka, G. W. J. Organomet. Chem., 1999, 581, 66–69.
5

(S)‐3,3‐dimethylbutan‐2‐ol (2j):11 Compound 2j was obtained after purification on flash silica gel chromatography from 100:0 till
90:10 (Pentane/Et2O) as a colorless oil (58% yield, 99% ee); [α]D20 = ‐8.0 (c 1.7, EtOAc) {Lit [α]D20 = +31.0 (c 1.0, CHCl3) for 60% ee}. 1H
NMR (300 MHz, CDCl3) δ 3.47 (q, J = 6.4 Hz, 1H), 1.76 (br s, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 75.6,
OH
34.8, 25.4, 17.8. LRMS (EI) m/z: 136 (M+, 1), 118 (23), 117 (35), 115 (15), 92 (100), 91 (94), 65 (19), 51 (9). Ee determination by chiral GC analysis,
HP‐CHIRAL‐20β column, T = 60 °C, P = 6.0 psi, retention time: tr(S) = 29.8 min (major enantiomer), tr(R) = 31.9 min.
(S)‐3,3‐dimethylhex‐5‐en‐2‐ol (2k):12 Compound 2k was obtained after purification on flash silica gel chromatography from
OH
100:0 till 92:8 (Pentane/Et2O) as a colorless oil (60% yield, 98% ee); [α]D20 = +2.8 (c 1.0, CHCl3) {Lit [α]D20 = ‐7.2 (c 1.1, CHCl3) for
76% ee of R enantiomer}. 1H NMR (300 MHz, CDCl3) δ 5.95 – 5.79 (dddd, J = 15, 12.6, 9.4, 7.5 Hz, 1H), 5.10 – 5.05 (m, 1H), 5.05
– 5.01 (m, 1H), 3.55 (q, J = 6.1 Hz, 1H), 2.11 (ddt, J = 13.6, 7.6, 1.1 Hz, 1H), 1.99 (ddt, J = 13.6, 7.4, 1.1 Hz, 1H)., 1.70 (br s, 1H), 1.13 (d, J = 6.4 Hz,
3H), 0.88 (s, 3H), 0.86 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 135.5, 117.0, 74.2, 43.5, 37.8, 22.9, 22.1, 17.6. LRMS (EI) m/z: 128 (M+, <1), 110 (16), 95
(16), 87 (70), 86 (10), 84 (44), 83 (22), 82 (14), 71 (12), 69 (100), 67 (28), 56 (11), 55 (79), 53 (9). Ee was determined by chiral GC analysis on the
derivative 3k.
(S,E)‐4‐phenylbut‐3‐en‐2‐ol (2l):13 Compound 2l was obtained after purification on flash silica gel chromatography from
OH
20
20
100:0 till 85:15 (Hexane/EtOAc) as a yellow oil (>99% yield, 82% ee); [α]D = ‐25.4 (c 1.0, CHCl3) {Lit [α]D = ‐14.6 (c 1.0,
CHCl3) for 60% ee}. 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 5.3, 3.2 Hz, 2H), 7.34 – 7.27 (m, 2H), 7.27 – 7.20 (m, 1H), 6.55
(d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.4 Hz, 1H), 4.47 (p, J = 6.3 Hz, 1H), 1.99 (br s, 1H), 1.36 (d, J = 6.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 136.6, 133.5, 129.3, 128.5, 127.6, 126.4, 68.8, 23.3. LRMS (EI) m/z: 149 (M++1, 1), 148 (M+, 9), 131 (11), 130 (87), 129 (100),
128 (63), 127 (25), 115 (63), 105 (14), 91 (11), 77 (15), 51 (13). Ee determination by chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 110 °C, P =
10.0 psi, retention times: tr(R) = 60.8 min, tr(S) = 61.8 min (major enantiomer).
(S)‐4‐phenylbut‐3‐yn‐2‐ol (2m):14 Compound 2m was obtained after purification on a flash silica gel chromatography from
OH
100:0 till 90:10 (Hexane/EtOAc) as a colorless oil (80% yield, 60% ee); [α]D20 = −21.5 (c 1.0, CHCl3) {Lit [α]D20 = −33.0 (c 0.9,
CHCl3) for 98% ee}. 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 2H), 7.31 (m, 3H), 4.76 (m, 1H), 2.14 (br s, 1H), 1.56 (d, J = 6.6 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 131.6, 128.3, 128.2, 122.5, 90.9, 84.0, 58.8, 24.4. LRMS (EI) m/z: 147 (M++1, 3), 146 (M+,
33), 145 (50), 132 (10), 131 (100), 129 (11), 128 (12), 127 (10), 103 (65), 102 (14), 77 (32), 51 (11). Ee determination by chiral HPLC analysis,
Chiralcel OJ column, Hexane/PriOH 97:3, flow rate = 1.0 mL/min, λ=210 nm, retention times: tr(R) = 15.6 min, tr(S) = 18.0 min (major enantiomer).
2.3 Derivatization of chiral alcohols
Two different procedures were used to derivatize chiral aliphatic alcohols into the corresponding p‐nitrobenzoate (Procedure A) and acetate
(Procedure B) products.
Procedure A:
The corresponding aliphatic alcohol 2b (31.7 mg, 0.2 mmol) was dissolved in dry DCM (1 mL) at 0 °C and Et3N (56 μL, 0.4 mmol, 2 eq),
DMAP (2.5 mg, 0.02 mmols, 0.1 eq) and p‐nitrobenzoyl chloride (55.7 mg, 0.3 mmol, 1.5 eq) were added. The reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with water (1 mL), extracted with Et2O (3 × 5 mL) and the combined organic layers were dried
over magnesium sulfate and concentrated under vacuum. The crude product was purified by chromatography on flash silica gel to give the desired
product 3b.
11
Gilmore, N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805–2808.
12
Cozzi, P. G.; Kotrusz, P. J. Am. Chem. Soc. 2006, 128, 4940–4941.
13
Inagaki, T.; Ito, A.; Ito, J.; Nishiyama, H. Angew. Chem., Int. Ed. Engl. 2010, 49, 9384–9387.
14
Zhang, X.; Lu, Z.; Fu, C.; Ma, S. Org. Biomol. Chem. 2009, 7, 3258–3263.
6

Procedure B:
The corresponding aliphatic alcohol [2d, 2e, 2f, 2i or 2k (0.1 mmol)] was dissolved in dry DCM (1 mL) at 0 °C and Et3N (28 μL, 0.2 mmol,
2 eq), DMAP (1.3 mg, 0.01 mmol, 0.1 eq) and acetic anhydride (22 μL, 0.2 mmol, 2 eq) were added. The reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with water (1 mL), extracted with Et2O (3 × 5 mL) and the combined organic layers were dried
over magnesium sulfate and concentrated under vacuum. The crude product was purified by Kugelrohr distillation to give the desired products 3d,
3e, 3f, 3i and 3k.
2.4 Data of the products 3b, 3d, 3e, 3f, 3i, and 3k
(S)‐1‐[(3‐ethyloctan‐4‐yl)oxy]‐4‐nitrobenzene (3b): Compound 3b was obtained after purification on flash silica gel
chromatography from 100:0 till 98:2 (Hexane/EtOAc) as a yellow viscous oil (>99% yield). 1H NMR (400 MHz, CDCl3)
NO2
O
δ 8.29 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 5.27 (dt, J = 8.5, 4.2 Hz, 1H), 1.80 – 1.58 (m, 2H), 1.58 – 1.46 (m,
2H), 1.45 – 1.21 (m, 7H), 0.97 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 164.4, 150.4, 136.2, 130.6, 123.5, 77.8, 44.5, 30.7, 28.0, 22.6, 22.2, 21.93, 14.0, 11.8, 11.7. IR (ATR): ν (cm‐
1): 2960, 1719, 1527, 1271, 1101, 718. LRMS (EI) m/z: 307 (M+, <1), 236 (9), 151 (13), 150 (100), 140 (7), 104 (13), 92 (5), 76 (6), 55 (4). HRMS
calculated for C16H25NO3 307.1784, found 250.1119 (M+‐Bu∙). Ee determination by chiral HPLC analysis, Chiralcel ASH column, Hexane/PriOH 99:1,
flow rate = 0.8 mL/min, λ=254 nm, retention times: tr(R) = 7.5 min, tr(S) = 8.7 min (major enantiomer).
(S)‐1‐cyclopentylpropyl acetate (3d): Compound 3d was obtained after purification by Kugelrohr distillation as a colorless oil
(>99% yield). 1H NMR (300 MHz, CDCl3) δ 4.77 (td, J = 7.8, 4.1 Hz, 1H), 2.06 (s, 3H), 1.76 – 1.41 (m, 9H), 1.36 – 1.11 (m, 2H),
O
O
0.88 (t, J = 7.4 Hz, 4H). 13C NMR (75 MHz, CDCl3) δ 171.1, 78.8, 43.3, 29.0, 28.6, 26.2, 25.5, 25.2, 21.2, 9.6. LRMS (EI) m/z: 170
(M+, <1), 141 (17), 112 (33), 110 (35), 101 (69), 97 (11), 95 (14), 82 (17), 81 (100), 71 (16), 68 (16), 67 (39), 55 (11). Ee
determination by chiral GC analysis, CP‐Chiralsil‐DEX CB column, T = 110 °C, P = 14.3 psi, retention time: tr(S) = 6.6 min (major
enantiomer), tr(R) = 7.3 min.
O
(3S,4R)‐4‐methylheptan‐3‐yl acetate (3ea) and (3S,4S)‐4‐methylheptan‐3‐yl acetate (3eb):¡Error! Marcador
O
no definido. Compounds 3ea and 3eb were obtained after Kugelrohr distillation as a colorless oil (>99% yield).
LRMS (EI) m/z: 172 (M+, <1), 143 (9), 130 (9), 112 (22), 101 (100), 83 (47), 72 (50), 71 (14), 70 (26), 69 (25), 57 (13), 55 (29).
anti
O
Ee determination by chiral GC analysis, HP‐CHIRAL‐20β column, T = 70 °C, P = 14.3 psi, retention time for anti
O
diastereoisomers: tr(3S,4R) = 27.9 min (major enantiomer), tr(3R,4S) = 31.2 min, and for syn diastereoisomers: tr(3S,4S) =
29.4 min (major enantiomer), tr(3R,4R) = 32.3 min.
syn
(S)‐decan‐2‐yl acetate (3f):15 Compound 3f was obtained after purification by Kugelrohr distillation as a
colorless oil (>99% yield). 1H NMR (300 MHz, CDCl3) δ 4.95 – 4.79 (sext, J = 6.3 Hz, 1H), 2.04 – 1.95 (s, 3H), 1.66
O
O
– 1.36 (m, 2H), 1.35 – 1.21 (m, 11H), 1.18 (d, J = 6.3 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
170.8, 71.1, 35.9, 31.8, 29.5, 29.4, 29.2, 25.4, 22.6, 21.3, 19.9, 14.0. LRMS (EI) m/z: 200 (M+, <1), 140 (43), 112
(16), 111 (26), 102 (12), 98 (22), 97 (34), 96 (11), 87 (100), 85 (11), 84 (21), 83 (24), 82 (10), 71 (16), 70 (36), 69 (37), 58 (16), 57 (24), 56 (37), 55
(42). Ee determination by chiral GC analysis, Chiralsil‐DEX CB column, T = 130 °C, P = 14.3 psi, retention time: tr(S) = 6.5 min (major enantiomer),
tr(R) = 7.4 min.
(S)‐1‐cyclohexylethyl acetate (3i):16 Compound 3i was obtained after purification by Kugelrohr distillation as a colorless oil
(>99% yield). 1H NMR (400 MHz, CDCl3) δ 4.72 (quin, J = 6.4 Hz, 1H), 2.04 (s, 3H), 1.80 – 1.61 (m, 5H), 1.43 (m, 1H), 1.27 – 1.09
O
O
(m, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.07 – 0.90 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 171.0, 74.7, 42.5, 28.4, 26.3, 26.0, 25.9,
15
Mallmann, A. S.; Ethur, E. M.; da Silva, U. F.; Dalcol, I. I.; Morel, A. F. J. Brazil. Chem. Soc. 2010, 21, 2005–2011.
16
Taglieber, A.; Hobenreich, H.; Carballeira, J. D.; Mondiere, R. J. G.; Reetz, M. T. Angew. Chem., Int. Ed. Engl. 2007, 46, 8597–8600.
7

20.92, 17.0. LRMS (EI) m/z: 128 (M+, <1), 113 (16), 110 (37), 95 (42), 84 (24), 83 (35), 82 (100), 81 (18), 69 (16), 67 (61), 56 (25), 55 (76), 54 (14), 53
(9). Ee determination by chiral GC analysis, HP‐CHIRAL‐20β column, T = 130 °C, P = 14.3 psi, retention time: tr(S) = 8.1 min (major enantiomer),
tr(R) = 8.5 min.
(S)‐3,3‐dimethylhex‐5‐en‐2‐yl acetate (3k):17 Compound 3k was obtained after purification by Kugelrohr distillation as a
colorless oil (>99% yield). 1H NMR (300 MHz, CDCl3) δ 5.80 (ddt, J = 17.6, 10.2, 7.5 Hz, 1H), 5.10 – 4.95 (m, 2H), 4.72 (q, J =
6.4 Hz, 1H), 2.04 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 7.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 170.7, 134.6, 117.4,
76.4, 43.3, 36.8, 22.8, 22.5, 21.2, 14.5. LRMS (EI) m/z: 170 (M+, <1), 129 (27), 110 (17), 95 (19), 87 (100), 83 (20), 69 (29), 67
(13), 55 (29). Ee determination by chiral GC analysis, Chiralsil‐DEX CB column, T = 90 °C, P = 14.3 psi, retention time: tr(S) = 7.2 min (major
enantiomer), tr(R) = 8.5 min.
3. Additional data ‐ Mechanistic studies
3.1 Non‐Linear effect study (NLE)
In a flame dried Schlenk tube, (Sa,R)‐L2 (x mmol) and (Ra,S)‐L2 (y mmol) were dissolved in dry Et2O (1.5 mL) under argon atmosphere.
The solution was cooled down to −20 °C and Ti(OPri)4 (305 μL, 1.0 mmol, 10 eq.) was added. Five minutes later, MeMgBr (3.0 M in Et2O, 83 μL,
0.25 mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, freshly distilled 3‐phenylpropanal (0.1 mmol) was added and the
reaction mixture was stirred at −20 °C for 3 h. The reaction was quenched with water (2 mL), and 2 M HCl(aq) (2 mL). The mixture was diluted with
Et2O (2 mL) and dried over magnesium sulfate. Ee and conversions were determined by chiral GC analysis (see reported data of 2g for further
details). Results are summarized in Table S1:
Table S1. Study of the non‐linear effect with 2g and L2
mg (Sa,R)‐L2
3.77
mg (Ra,S)‐L2
3.77
ee L2 (%)
ee 2g (%)
Conversion (%)
0
20
40
60
80
100
0
82
85
75
78
72
81
4.53
5.28
6.04
6.79
3.02
2.26
1.51
0.75
19
39
60
76
88
7.55
0
NLE study
100
90
80
70
60
50
40
30
20
10
0
0
20
40
60
80
100
ee 2g (%)
Figure 1. Linear plot of ee values of L2 vs ee values of 2g
17
Dillenberger, Z.; Schmid, H.; Hansen, H. Helv. Chim. Acta 1978, 61, 1856–18902.
8

3.2 Kinetic study
(A): In a flame dried Schlenk tube, (Sa,R)‐L2 (22.6 mg, 0.06 mmol) was dissolved in dry Et2O (2.5 mL) under argon atmosphere. The
solution was cooled down to −20 °C and Ti(OPri)4 (915 μL, 3.0 mmol, 10 eq.) was added. Five minutes later, MeMgBr (3.0 M in Et2O, 250 μL, 0.75
mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, freshly distilled 3‐phenylpropanal (0.3 mmol) was added and the
reaction mixture was stirred at −20 °C. Samples were taken at different times during 3h and analyzed by chiral GC. Results are shown in Table S2:
Table S2. Conversion and ee of 2g vs time with (Sa,R)‐L2
Time (min)
Conversion (%)
ee 2g (%)
88
0.5
1
3
32
32
36
42
50
58
66
75
77
85
88
88
88
88
88
88
88
88
5
10
15
25
45
60
180
88
(B): In a flame dried Schlenk tube, (S)‐BINOL (17.2 mg, 0.06 mmol) was dissolved in dry Et2O (2.5 mL) under argon atmosphere. The
solution was cooled down to −20 °C and Ti(OPri)4 (915 μL, 3.0 mmol, 10 eq.) was added. Five minutes later, MeMgBr (3.0 M in Et2O, 250 μL, 0.75
mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, freshly distilled 3‐phenylpropanal (0.3 mmol) was added and the
reaction mixture was stirred at −20 °C. Samples were taken at different times during 3h and analyzed by chiral GC. Results are shown in Table S3:
Table S3. Conversion and ee of 2g vs time with (S)‐BINOL
Time (min)
Conversion (%)
ee 2g (%)
0.5
1
3
14
17
21
23
27
29
41
48
7
7
7
7
7
7
7
7
5
10
15
45
180
(C): In a flame dried Schlenk tube, Ti(OPri)4 (915 μL, 3.0 mmol, 10 eq.) was dissolved in dry Et2O (2.5 mL) under argon atmosphere at
−20 °C . Then, MeMgBr (3.0 M in Et2O, 250 μL, 0.75 mmol, 2.5 eq.) was added. After stirring the mixture for additional 15 min, freshly distilled 3‐
phenylpropanal (0.3 mmol) was added and the reaction mixture was stirred at −20 °C. Samples were taken at different times during 3h and
analyzed by chiral GC. Results are shown in Table S4:
Table S4. Conversion and ee of 2g vs time without ligand
Time (min)
Conversion (%)
ee 2g (%)
0.5
1
3
22
25
27
30
0
0
0
0
5
9

10
15
25
45
60
32
35
39
46
51
64
0
0
0
0
0
0
180
Kinetic experiments
100
80
60
40
20
0
(Sa,R)‐L2
Without ligand
(S)‐BINOL
0
30
60
90
120
150
180
Time (min)
Figure 2. Comparative graphs on the rate of the reaction with (Sa,R)‐L2, (S)‐BINOL and without ligand.
10

4. Spectra of compounds (1H NMR, 13C NMR)
(S)‐P2: (S)‐2'‐(pyridin‐4‐ylmethoxy)‐(1,1'‐binaphthalen)‐2‐ol
11

(Sa,R)‐L2: (Sa)‐2'‐[(R)‐hydroxy(pyridin‐4‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol
12

(Sa,S)‐L3: (Sa)‐2'‐[(S)‐hydroxy(pyridin‐2‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol
13

(Sa,R)‐L7: (Sa)‐2'‐[(R)‐hydroxy(naphthalen‐1‐yl)methyl]‐(1,1'‐binaphthalen)‐2‐ol
OH
OH
(Sa,R)-L7
14

(Sa,R)‐(8H)‐L1: (Sa)‐2'‐[(R)‐hydroxy(phenyl)methyl]‐5,5',6,6',7,7',8,8'‐octahydro‐(1,1'‐binaphthalen)‐2‐ol:
15

(2a): (S)‐1‐cyclohexylpentan‐1‐ol
16

(2b): (‐)‐3‐ethyloctan‐4‐ol
17

(2c): (S)‐hept‐1‐en‐3‐ol
18

(2d): (+)‐1‐cyclopentylpropan‐1‐ol
19

(2f): (S)‐decan‐2‐ol
20

(2g): (S)‐4‐phenylbutan‐2‐ol
21

(2h): (+)‐3‐ethylpentan‐2‐ol
22

(2i): (S)‐1‐cyclohexylethanol
OH
2i
23

(2j): (S)‐3,3‐dimethylbutan‐2‐ol
24

(2k): (S)‐3,3‐dimethylhex‐5‐en‐2‐ol
25

(2l): (S,E)‐4‐phenylbut‐3‐en‐2‐ol
26

(2m): 4‐phenyl‐3‐butin‐2ol
27

(3b): (S)‐1‐[(3‐ethyloctan‐4‐yl)oxy]‐4‐nitrobenzene
28