Reagent-controlled asymmetric homologation of boronic esters by enantioenriched main-group chiral carbenoids

Article abstract of DOI:10.1021/ol053055k

Putative enantioenriched carbenoid species, (R)-1-chloro-2- phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generated in situ by sulfoxide ligand exchange from (-)-(R_s,R)-1- chloro-2-phenylethyl p-tolyl sulfoxide (8), effected the stereocontrolled homologation of boronic esters. sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approaching that of sulfoxide 8 in examples employing Li-carbenoid 26.

Full text of DOI:10.1021/ol053055k

Supporting Information: CONTENTS
Reagent Controlled Asymmetric Homologation of Boronic Esters by
Enantioenriched Main-Group Chiral Carbenoids
Paul R. Blakemore,*,† Stephen P. Marsden,‡ and Huw D. Vater‡
†Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003
‡School of Chemistry, University of Leeds, Leeds, West Yorkshire, LS2 9JT, U.K.
Experimental Procedures
S2-S20
General techniques
S2
S3-S4
S5
Preparation of enantioenriched chlorosulfoxide 8
Sulfoxide ligand exchange study from 8
Repetition of Hoffmann's benzaldehyde trapping experiment
Preparation of boronic esters 13-19
S5-S7
S8-S10
S11-S17
Preparation of racemic carbinol standards 20-24, HPLC
resolution methods, and configurational assignment for 22 and 23
Asymmetric homologation procedures
S18-S21
1H NMR Spectra
S22-S37
S1

Supporting Information: EXPERIMENTAL PROCEDURES
Reagent Controlled Asymmetric Homologation of Boronic Esters by
Enantioenriched Main-Group Chiral Carbenoids
Paul R. Blakemore,*,† Stephen P. Marsden,‡ and Huw D. Vater‡
†Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003
‡School of Chemistry, University of Leeds, Leeds, West Yorkshire, LS2 9JT, U.K.
General techniques: All reactions requiring anhydrous conditions were conducted in flame-dried glass apparatus
under an atmosphere of N2. Tetrahydrofuran (THF) and diethyl ether were freshly distilled from sodium
benzophenone ketyl prior to use. Preparative chromatographic separations were performed on silica gel 60 (35-
75 µm) and reactions followed by TLC analysis using silica gel 60 plates (2-25 µm) with fluorescent indicator
(254 nm) and visualized with UV, phosphomolybdic acid, or p-anisaldehyde. All commercially available
reagents were used as received unless otherwise noted.
Melting points were recorded on a melting point stage and are uncorrected. Specific optical rotation data were
recorded under the indicated conditions using 1 mL cells with either 0.25 dm or 1.00 dm path length. Infra-red
spectra were recorded in Fourier transform mode using a thin film supported between NaCl plates for liquid
1
samples and an ATR probe for solids. H, 13C, 11B, and 19F NMR spectra were recorded in Fourier transform
mode at the field strength specified and from the indicated deuterated solvents in standard 5 mm diameter tubes.
1
13
Chemical shift for H and C nuclei is quoted in ppm relative to residual solvent signals calibrated as follows:
CDCl3 δH (CHCl3) = 7.26 ppm, δC = 77.2 ppm. Chemical shift in 11B NMR spectra are reported in ppm with
19
external calibration to a BF3•OEt2 standard (δB = 0.00 ppm). Chemical shift in F NMR spectra are reported in
1
ppm with external calibration to a CFCl3 standard (δF = 0.00 ppm). Multiplicities in the H NMR spectra are
described as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Numbers in parentheses
following carbon atom chemical shifts refer to the number of attached hydrogen atoms as revealed by the DEPT
spectral editing technique. Low (MS) and high resolution (HRMS) mass spectra were obtained using either
electron impact (EI), electrospray (ES), or fast atom bombardment (FAB) ionization techniques. Ion
mass/charge (m/z) ratios are reported as values in atomic mass units.
S2

Blakemore, Marsden, and Vater
– Preparation of enantioenriched chlorosulfoxide 8 –
Chlorosulfoxide 8 was prepared essentially as previously described by Hoffmann and co-workers1 according to
the following scheme:–
(a) SOCl (119.0), 0 °C
2
(b) (–)-menthol (156.3)
MgBr
O
S
Ph
SO Na
2
p-Tol
C
O
PhMe, –78 °C, 1.5 h
95%
Py (79.1), Et O
2
0 °C ! rt, 16 h
C H NaO S•2.6H O
7
H
O S (S1)
2
43%
7
2
(225.0)
2
17 26
(294.5)
NCS (135.5), K CO (138.2)
2
CH Cl , rt, 6 d
3
O
S
O
S
2
2
"
p-Tol
Ph
p-Tol
Ph
64%, dr(") = 5:1
Cl
x3 recrys. Et2O
C
H
OS (S2)
C H ClOS (8)
15 15
(278.8)
15 16
16%, dr(") > 99:1
%ee > 98%
(244.4)
(SS)-Menthyl p-toluenesulfinate (S1): The Andersen menthyl sulfinate (S1)2 was prepared according to the
following slight modification of Solladie's procedure.3 Thus, sodium toluenesulfinate 2.6 hydrate (45.1 g, 200
mmol) was added portionwise to thionyl chloride (51.0 mL, d = 1.63, 83.1 g, 699 mmol) at 0 °C during 30 min.
After cessation of the ensuing effervescence, PhMe (50 mL) was added to the resulting sulfinyl chloride and the
mixture concentration in vacuo. The residue was dissolved in PhMe (50 mL) and again concentrated in vacuo.
Following repetition of this dissolution/concentration operation, the sulfinyl chloride was dissolved in
anhydrous Et2O (160 mL) and added to a solution of (–)-menthol (39.0 g, 250 mmol) and pyridine (36.0 mL, d =
0.98, 35.2 g, 445 mmol) in Et2O (90 mL) at 0 °C. A voluminous colorless precipitate appeared immediately. The
mixture was stirred at rt for 16 h and then poured into H2O (50 mL) and the layers separated. The organic phase
was washed with 1.5 M aq. HCl (3x50 mL), dried (Na2SO4) and concentrated in vacuo. The residue was
recrystallized three times from acetone to yield the title compound (S1, 25.4 g, 86.2 mmol, 43%) as colorless
needles: mp 107-109 °C (acetone) [lit.4 mp 106-108 °C (acetone)]; [α]D23 = –204 (c = 2.24, acetone) [lit.5 [α]D =
–201 (c = 1.5, acetone)]; IR (neat) 2907, 1594, 1492, 1451, 1128, 958 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.60
(2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 4.12 (1H, td, J = 10.7, 4.5 Hz), 2.42 (3H, s), 2.28 (1H, dm, J = 12.8
Hz), 2.13 (1H, qm, J = 7.2 Hz), 1.73-1.64 (2H, m), 1.55-0.79 (5H, m), 0.96 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J =
7.2 Hz), 0.71 (3H, d, J = 7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 143.3 (0), 142.6 (0), 129.8 (2C, 1), 125.1
(2C, 1), 80.3 (1), 48.0 (1), 43.1 (2), 34.2 (2), 31.9 (1), 25.4 (1), 23.5 (2), 22.5 (3), 21.9 (3), 21.3 (3), 15.9 (3)
ppm; MS (EI+) m/z 294 (15, M+•), 139 (100). Spectroscopic data were in agreement with those previously
reported by Watanabe et al.4
(RS)-2-Phenylethyl p-tolyl sulfoxide (S2): A vigorously stirred suspension of mechanically activated Mg-
turnings (2.04 g, 83.9 mmol) in anhydrous THF (50 mL) under N2 was treated with neat phenethyl bromide
(11.4 mL, d = 1.35, 15.4 g, 83.2 mmol) at a rate sufficient to first initiate, and then subsequently sustain, a gentle
1. Hoffmann, R. W.; Nell, P. G.; Leo, R.; Harms, K. Chem. Eur. J. 2000, 6, 3359.
2. Andersen, K. K. Tetrahedron Lett. 1962, 93.
3. Solladie, G. Synthesis 1981, 185.
4. Watanabe, Y.; Mase, N.; Tateyama, M.-A.; Toru, T. Tetrahedron:Asymmetry 1999, 10, 7337.
5. Hajipour, A.; Mallakpour, S.; Afrousheh, A. Tetrahedron 1999, 55, 2311.
S3

Blakemore, Marsden, and Vater
reflux. After the addition was complete, the exotherm ceased and the reaction mixture returned to rt. The THF
solvent was then removed in vacuo and the residual Grignard reagent taken up in PhMe (50 mL). The resulting
solution was cooled to –78 °C and treated with (SS)-menthyl p-toluenesulfinate (S1, 20.4 g, 69.2 mmol) in PhMe
(100 mL) during 13 min. After stirring at –78 oC for 1.5 h, the reaction mixture was poured into sat. aq. NH4Cl
(50 mL) and the layers separated. The organic phase was washed with 1.5 M aq. HCl (30 mL) and the combined
aqueous phases were extracted with Et2O (5x30 mL). The combined organic phases were then washed
succesively with H2O (2x30 mL) and brine (2x30 mL), dried (Na2SO4) and concentrated in vacuo. The residue
was purified by filtration through a plug of SiO2 (∅ = 6.5 cm, depth = 3 cm) eluting with 33% EtOAc in
hexanes (200 mL) followed by EtOAc (150 mL). The title compound (S2, 16.1 g, 65.9 mmol, 95%) was
21
obtained as a pale yellow oil which solidified upon standing: mp 47-51 °C (acetone); [α]D = +99 (c = 2.06,
1
acetone) [lit.6 [α]D = +125 (c = 2.24, acetone)]; IR (neat) 3021, 1599, 1492, 1451, 1039, 803, 702 cm—1; H
NMR (300 MHz, CDCl3) δ 7.53 (2H, d, J = 8.2 Hz), 7.37-7.15 (7H, m), 3.14-2.84 (4H, m), 2.42 (3H, s) ppm;
13C NMR (75 MHz, CDCl3) δ 141.7 (0), 140.5 (0), 139.0 (0), 130.1 (2C, 1), 128.9 (2C, 1), 128.7 (2C, 1), 126.8
(1), 124.2 (2C, 1), 58.5 (2), 28.3 (2), 21.6 (3) ppm; MS (EI+) m/z 244 (50, M+°), 105 (100). NMR spectral data
were in agreement with those previously reported by Yoshimura et al.7
HPLC analysis of S2 performed with a Daicel Chiralcel® OD-H column, eluting with 1% i-PrOH in hexanes at
1.0 mL min–1 and monitored by UV at 210 nm, gave peaks: tret. (S2) = 60.4 min, tret. (ent-S2) = 69.1 min, which
integrated to reveal 96% ee (as compared to a racemic standard).
(RS,R)-1-Chloro-2-phenylethyl p-tolyl sulfoxide (8): According to the method of Satoh and Yamakawa8 and as
applied previously by Hoffmann and co-workers.1 A solution of (RS)-2-phenylethyl p-tolyl sulfoxide (S2,
5.62 g, 23.0 mmol, 96% ee) in CH2Cl2 (50 mL) was treated with K2CO3 (1.91 g, 13.8 mmol) and N-
chlorosuccinimide (15.3 g, 115 mmol). The resulting suspension was stirred vigorously at rt for 140 h.
After this time, the mixture was poured into Et2O (100 mL) and washed successively with 5 wt.% aq.
NaI (2x200 mL), sat. aq. Na2S2O3 (35 mL), and brine (2x50 mL), then dried (Na2SO4) and concentrated
in vacuo. The crude residue was purified by column chromatography to afford sulfoxide 8 (4.11 g, 14.7 mmol,
64%) as a 5.5:1 respective mixture of syn and anti diastereoisomers (epimeric about C∗; ratio determined by
integration of 1H NMR spectrum). After three recrystallation cycles from Et2O (conducted at 4 °C), sulfoxide 8
(1.03 g, 3.69 mmol, 16%) was obtained as colorless needles which were diastereoisomerically pure as adjudged
1
23
by H NMR spectroscopy: mp 81-82 °C (Et2O) [lit.1 mp 77-78 °C (acetone)]; [α]D = –89.8 (c = 0.62, acetone)
20
1
[lit.1 [α]D = –91.8 (c = 2.0, acetone)]; IR (neat) 2945, 1604, 1454, 1086, 943, 803, 699 cm–1; H NMR (300
MHz, CDCl3) δ 7.58 (2H, d, J = 8.2 Hz), 7.39-7.21 (7H, m), 4.67 (1H, dd, J = 9.7, 4.4 Hz), 3.64 (1H, dd, J =
14.3, 4.4 Hz), 2.72 (1H, dd, J = 14.3, 9.7 Hz), 2.44 (3H, s) ppm; 13C NMR (75 MHz, CDCl3) δ 142.7 (0), 135.6
(0), 135.5 (0), 129.8 (2C, 1), 129.6 (2C, 1), 128.9 (2C, 1), 127.5 (1), 125.8 (2C, 1), 76.7 (1), 37.1 (2), 21.7 (3)
ppm; MS (EI+) m/z 280 (30, M(37Cl)+•) 278 (90, M(35Cl)+•), 103 (100). NMR spectral data recorded for 8 were in
complete agreement with those previously reported by Hoffmann et al.1
HPLC analysis of recrystallized 8 performed with a Daicel Chiralcel® OD-H column, eluting with 5% i-PrOH
in hexanes at 1.0 mL min–1 and monitored by UV at 250 nm, gave peaks: tret. (ent-8) = 15.3 min, tret. (8) = 23.5
min, which integrated to reveal 98.7% ee (as compared to a racemic standard).
6. Hoffmann, R. W.; Nell, P. G. Ang. Chem. Int. Ed. 1999, 38, 338.
7. Yoshimura, T.; Yoshizawa, M.; Tsukurimichi, E. Bull. Chem. Soc. Jpn. 1987, 60, 2491.
8. Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. Tetrahedron Lett. 1988, 29, 313.
S4

Blakemore, Marsden, and Vater
– Sulfoxide ligand exchange study from 8 (Scheme 2) –
EtMgCl (1.0 eq)
THF, –78 °C
O
S
O
S
T (°C) X (min)
10
11
D
+
Ph
91% 74%
96% 64%
100% 19%
–78
–50
–20
10
90
p-Tol
p-Tol
Ph
Cl
! T, X min
then, CD OD
Cl
C H ClOS (8) (278.8)
3
C H OS (10)
9
C H DCl (11)
8
195
12
(168.3)
8
(141.6)
15 15
A stirred solution of sulfoxide 8 (195 mg, 0.70 mmol) in anhydrous THF (2 mL) at –78 °C under N2 was treated
with EtMgCl (0.61 mL, 1.18 M in THF, 0.72 mmol). The mixture was allowed to warm steadily to the indicated
temperature (T) during the prescribed time period (X min) at which point d4-MeOH (0.16 mL, d = 0.89, 142 mg,
3.84 mmol) was added. After warming to rt, the mixture was treated with sat. aq. NH4Cl (10 mL) and extracted
successively with Et2O (2x10 mL) and EtOAc (2x10 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column chromatography (eluting with 50% EtOAc in
1
hexanes) to yield, in order of elution, deuterated chloride 11 (%D ≥ 91% by H NMR analysis) and ethyl
sulfoxide 10 (%D = 0% by 1H NMR analysis), both as colorless oils.
1
Ethyl p-tolyl sulfoxide (10): IR (neat) 2928, 1596, 1492, 1454, 1086, 1045, 1012, 812 cm—1; H NMR (300
MHz, CDCl3) δ 7.50 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 2.87 (1H, dq, J = 13.4, 7.4 Hz), 2.76 (1H, dq,
J = 13.4, 7.4 Hz), 2.42 (3H, s), 1.19 (3H, t, J = 7.4 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 141.6 (0), 140.2 (0),
130.0 (2C, 1), 124.4 (2C, 1), 50.5 (2), 21.6 (3), 6.2 (3) ppm; MS (ES+) m/z 169 [100, (M+H)+]. 1H and 13C NMR
spectral data were in agreement with those previously reported by Evans et al.9
1
(2-Chloro-2-deuteroethyl)benzene (11): IR (neat) 2950, 1728, 1478, 1412, 1349, 1259, 1097 cm–1; H NMR
(300 MHz, CDCl3) δ 7.36-7.20 (5H, m), 3.70 (1H, t of 1:1:1 triplet, J = 7.2, 1.5 Hz), 3.07 (2H, br d, J = 7.2 Hz)
ppm; 13C NMR (75 MHz, CDCl3) δ 138.2 (0), 129.0 (2C, 1), 128.8 (2C, 1), 127.1 (1), 44.9 (1, 1:1:1 triplet, J =
46.3 Hz), 39.3 (2) ppm; MS (EI+) m/z 143 (6, M(37Cl)+•), 141 (19, M(35Cl)+•), 91 (100). Data for 11 were in
agreement with those previously reported by Namavari et al.10
– Repetition of Hoffmann's carbenoid trapping experiment with benzaldehyde (Equation 1) –
(a)
(b)
EtMgCl, THF, –78 °C
PhCHO (106.1)
KOH (56.1), EtOH
0 °C
Ph
O
S
Ph
OH Ph
O
O
+
Ph
!
p-Tol
Ph
Me AlCl (92.5)
2
80%
cis:trans = 94:6
Cl
Cl
Ph
Ph
63%, dr(!) = 93:7
C H O (cis-12) (trans-12)
15 14
C H ClOS (8)
15 15
(278.8)
C H ClO (S3)
15 15
(246.7)
cis = 98.4% ee
trans > 98% ee
(210.3)
(210.3)
(1R,2R)-2-Chloro-1,3-diphenylpropan-1-ol (S3): The method of Hoffmann and co-workers1 was
followed with slight modification (EtMgCl in place of EtMgBr). Thus, the experiment was conducted
in a two compartment reaction vessel fabricated from two single-necked 25 mL RB flasks connected about
their equators by way of a short horizontal glass tube (ca. 20 mm length, ∅ (int.) = 4 mm). Each compartment
was provided with a magnetic stir bar. The apparatus was maintained under an atmosphere of N2 and one
compartment charged with a solution of isomerically homogenous sulfoxide 8 (59 mg, 0.21 mmol, %ee > 98%)
in anhydrous THF (3.5 mL). The other compartment was similarly charged with EtMgCl (2.65 mL, 0.11 M in
9. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am. Chem. Soc. 1992, 114,
5977.
10. Namavari, M.; Satyamurthy, N.; Barrio, J. R. J. Fluorine Chem. 1995, 72, 89.
S5

Blakemore, Marsden, and Vater
THF, 0.29 mmol) and the entire apparatus was cooled by submergence in a –78 °C cold bath. After allowing a
suitable time period for the attainment of thermal equilibrium (ca. 20 min, with stirring), the apparatus was
gently tilted to effect the portionwise addition (six portions) of the solution of sulfoxide 8 to the Grignard
reagent during 17 min. The connecting tube remained submerged in the cooling bath throughout this operation.
The reaction mixture was afforded 30 min to stir at –78 °C during which time the compartment previously
occupied by the sulfoxide was charged with a mixture of benzaldehyde (36 µL, d = 1.04, 37 mg, 0.35 mmol) and
Me2AlCl (0.35 mL, 1.0 M in hexanes, 0.35 mmol) in THF (2.5 mL). The apparatus was tilted as before to add
the now chilled mixture of benzaldehyde/Me2AlCl to the carbenoid solution in four portions during 15 min. The
reaction mixture was then allowed to warm steadily to –30 oC over the following 13.5 h before being quenched
by the addition of sat. aq. NH4Cl (1 mL). The layers of the resulting biphasic mixture were separated and the
aqueous phase was extracted with t-BuOMe (3x10 mL). The combined organic phases were then washed
successively with H2O (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated in vacuo. The residue was
purified by column chromatography (eluting with 10% EtOAc in hexanes) to afford the title compound (S3, 33
mg, 0.134 mmol, 63%, dr(∗) = 93:7 as adjudged by 1H NMR spectral analysis) as a colorless oil: IR (neat) 3423,
1
3027, 1602, 1495, 1454, 1064, 1028, 746, 696 cm–1; H NMR (300 MHz, CDCl3, signals attributable to major
isomer only) δ 7.47-7.12 (10 H, m), 4.77 (1H, t, J = 5.4 Hz), 4.34 (1H, dt, J = 9.2, 5.4 Hz), 3.11 (1H, dd, J =
13
14.2, 5.4 Hz), 2.94 (1H, dd, J = 14.2, 9.2 Hz), 2.72 (1H, d, J = 5.4 Hz, OH) ppm; C NMR (75 MHz, CDCl3,
signals attributable to major isomer only) δ 140.3 (0), 137.6 (0), 129.4 (2C, 1), 128.8 (2C, 1), 128.7 (2C, 1),
1
128.5 (1), 127.1 (1), 126.7 (2C, 1), 76.0 (1), 70.1 (1), 41.1 (2) ppm. H and 13C NMR data were in agreement
with those previously reported by Hoffmann et al.1
(2S,3R)-cis-2-Benzyl-3-phenyloxirane (cis-12) and (2S,3S)-trans-2-benzyl-3-phenyloxirane (trans-12):
Following the method of Hoffmann and co-workers,1 a solution of chlorohydrin S3 (16 mg, 0.065 mmol, dr(∗) =
93:7) in EtOH (1.5 mL) at 0 °C was treated with an ethanolic solution of KOH (0.32 mL, 0.40 M in EtOH, 0.13
mmol) during 30 s. The resulting mixture was stirred at rt for 19 h and was then treated with NH4Cl (115 mg,
2.15 mmol) and concentrated in vacuo. The residue was partitioned between t-BuOMe (10 mL) and sat. aq.
NH4Cl (5 mL) and the layers well shaken and separated. The aqueous phase was extracted with t-BuOMe (3x10
mL) and the combined organic phases were washed with brine (2x5 mL), dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatography (eluting with 10% EtOAc in hexanes) to afford the
title compounds (cis-12 and trans-12, 11 mg, 0.052 mmol, 80%) as an inseparable mixture of colorless oils (cis:
1
1
trans = 94:6 as adjudged by H NMR spectral analysis): IR (neat) 3027, 1602, 1495, 1454, 743, 696 cm–1; H
NMR (300 MHz, CDCl3, signals attributable to cis-12 only) δ 7.43-7.16 (8H, m), 7.04 (2H, d, J = 6.4 Hz), 4.17
(1H, d, J = 4.1 Hz), 3.44 (1H, td, J = 6.4, 4.1 Hz), 2.77 (1H, dd, J = 14.6, 6.4 Hz), 2.56 (1H, dd, J = 14.6, 6.4
Hz) ppm; 13C NMR (75 MHz, CDCl3, signals attributable to cis-12 only) δ 137.6 (0), 135.5 (0), 129.0 (2C, 1),
128.7 (2C, 1), 128.3 (2C, 1), 127.9 (1), 126.8 (2C, 1), 126.7 (1), 59.9 (1), 57.8 (1), 33.4 (2) ppm; MS (ES+) m/z
211 [42, (M+H)+], 115 (100). H and 13C NMR data were in agreement with those previously reported by
1
Hoffmann and Schulze.11
HPLC analysis of the mixture of cis-12 and trans-12 obtained in the above experiment using two different chiral
stationary phases permitted determination of %ee for both diastereoisomers. Thus, analysis of a racemic sample
of 12 exhibiting cis:trans ~ 3:1 with a Daicel Chiralcel® AS-RH column, eluting with 40-55% MeCN in H2O
(over 30 min) at 1.0 mL min–1 and monitored by UV at 210 nm, gave resolved peaks tret. (cis-12 + ent-cis-12) =
19.0 min, tret. (trans-12) = 20.4 min, and tret. (ent-trans-12) = 26.0 min (Figure S1). Analysis of the same sample
with a Daicel Chiralcel® OD-RH column, eluting with 40-55% MeCN in H2O (over 30 min) at 1.0 mL min–1
11. Schulze, V.; Hoffmann, R. W. Chem. Eur. J. 1999, 5, 337.
S6

Blakemore, Marsden, and Vater
and monitored by UV at 210 nm, gave resolved peaks tret. (ent-cis-12) = 26.4 min, tret. (ent-trans-12) = 27.6 min,
and tret. (cis-12 + trans-12) = 28.6 min (Figure S2). Examination of integration values for chromatograms
similarly obtained from the enantioenriched sample of cis-12 and trans-12 obtained in the above experiment,
revealed %ee (cis-12) = 98.4% and %ee (trans-12) > 98% (Figures S3 and S4). Absolute stereochemical
configurations for these compounds were previously established by Hoffmann and co-workers.1
HV7 31B#4[modified byGRIGG]
mAU
HV7 31BOD-RH
UV_VIS_1
WVL:210 nm
HV7 31B#6[modified byGRIGG]
mAU
HV7 31BAS-RH
UV_VIS_1
WVL:210 nm
450
450
%D: 0.0 %
%C: 0.0 %
%D: 0.0 %
%C: 0.0 %
1 - 19.033
3 - 28.600
98.0
55.0
1 - 26.440
300
200
100
300
200
100
2 - 27.627
2 - 20.373
3 - 25.960
55.0
%B: 47.5 %
%B: 51.0 %
Flow: 1.000 ml/min
Flow: 1.000 ml/min
min
min
-50
-50
Figure S1. HPLC chromatogram (AS-RH)
for rac-12 (cis:trans ~ 3:1)
Figure S2. HPLC chromatogram (OD-RH)
for rac-12 (cis:trans ~ 3:1)
Peak 1 - 19.0 min (74.27%)
Peak 2 - 20.4 min (12.82%)
Peak 3 - 26.0 min (12.90%)
Peak 1 - 26.4 min (36.86%)
Peak 2 - 27.6 min (12.99%)
Peak 3 - 28.6 min (50.15%)
HV7 31B #9 [modified by GRIGG]
mAU
HV6 93D AS-RH
UV_VIS_1
WVL:210 nm
HV7 31B#10[modifiedbyGRIGG]
mAU
HV6 93D OD-RH
UV_VIS_1
WVL:210 nm
160
50.0
40.0
30.0
20.0
10.0
3 - 28.853
3´
2 - 28.500
%D: 0.0 %
%D: 0.0 %
%C: 0.0 %
1 - 18.980
%C: 0.0 %
55.0
98.0
125
100
75
50
3
25
2 - 20.440
55.0
1 - 26.627
%B: 47.5 %
%B: 51.0 %
Flow: 1.000 ml/min
Flow: 1.000 ml/min
min
min
-20
-5.0
Figure S3. HPLC chromatogram (AS-RH)
Figure S4. HPLC chromatogram (OD-RH)
for enantioenriched 12 (cis:trans = 94:6)
for enantioenriched 12 (cis:trans = 94:6)
Peak 1 - 19.0 min (93.53%)
Peak 2 - 20.4 min (6.47%)
Peak 3 - 26.0 min (< 0.05%)
Peak 1 - 26.6 min (0.71%)
Peak 2 - absent (< 0.05%)
Peaks 3,3´ - 28.5-28.9 min (99.29%)
S7

Blakemore, Marsden, and Vater
– Preparation of boronic esters 13-19 (Tables 1 and 2) –
100 °C, 2 h
57%
O
O
O
B
+
HB
Ph
C H
O
Ph
C H BO
C H BO (13)
14 13 2
8
8
6
5
2
(104.2)
(119.9)
(224.1)
2-(2-Phenylethyl)benzo-1,3,2-dioxaborole (13): A stirred mixture of styrene (1.15 mL, d = 0.91, 1.05 g, 10.0
mmol) and catecholborane (1.17 mL, d = 1.13, 1.32 g, 11.0 mmol) was heated at 100 °C under N2 for 2 h. After
this time, distillation in a Kugelrohr oven (200 °C, 4.5 mmHg) afforded the title boronic ester 13 (1.28 g, 5.71
mmol, 57%) as a colorless air-sensitive oil which was stored under N2 and used promptly: IR (neat) 3214, 1602,
1471, 1380, 1235, 1065, 1004, 922, 862, 807, 741, 700 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.15 (7H, m), 7.13-
7.05 (2H, m), 2.99 (2H, t, J = 8.2 Hz), 1.67 (2H, t, J = 8.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 148.3 (2C, 0),
128.6 (2C, 1), 128.1 (2C, 1), 126.1 (1), 122.8 (2C, 1), 112.5 (2C, 1), 29.8 (2) ppm [O-C (x2) and B-CH2 not
11
observed]; MS (EI+) m/z 224 (65, M+•), 91 (100). B NMR spectral data for this compound have been reported
by Burgess and van der Donk.12
(104.2)
100 °C, 2 h
O
OH OH
O
B
O
B
+
HB
Ph
C H
!, 17 h
70%
O
O
Ph
Ph
O
C H BO
6 2
(119.9)
C H BO (13)
14 13 2
(224.1)
C
H BO (14)
13 19 2
(218.1)
5
8
8
(104.2)
5,5-Dimethyl-2-(2-phenylethyl)-1,3,2-dioxaborinane (14): A stirred mixture of styrene (1.15 mL, d = 0.91,
1.05 g, 10.0 mmol) and catecholborane (1.17 mL, d = 1.13, 1.32 g, 11.0 mmol) was heated at 100 °C under N2
for 2 h. After cooling to rt, the resulting boronate (13) was added directly to a solution of 2,2-dimethyl-1,3-
propanediol (2.60 g, 25.0 mmol) in anhydrous THF (13 mL) and heated to reflux for 17 h. After this time, the
mixture was concentrated in vacuo and the residue purified by column chromatography (eluting with 10%
EtOAc in hexanes) to afford the title compound (14, 1.53 g, 7.02 mmol, 70%) as a colorless oil: bp 204-206 °C
1
(4.5 mmHg); IR (neat) 2959, 1602, 1475, 1346, 1287, 1250, 1172, 696 cm–1; H NMR (300 MHz, CDCl3) δ
7.30-7.11 (5H, m), 3.59 (4H, s), 2.71 (2H, t, J = 8.2 Hz), 1.08 (2H, t, J = 8.2 Hz), 0.93 (6H, s); 13C NMR (75
MHz, CDCl3) δ 145.1 (0), 128.3 (2C, 1), 128.1 (2C, 1), 125.5 (1), 72.1 (2C, 2), 31.7 (0), 30.2 (2), 21.9 (2C, 3),
16.7 (2) ppm; MS (FAB+) m/z 218 (100, M+•); HRMS (ES+) m/z 219.1568 (calcd. for C13H20BO2: 219.1556).
Boronate 14 was previously reported by Kakiuchi et al without characterization data.13
pentane, rt, 3 min
66%
OH
B
O
B
+
Me
OH
OH OH
C H O
Me
O
CH BO
C H BO (15)
6 13 2
5
2
5
12
2
(59.9)
(104.2)
(128.0)
2,5,5-Trimethyl-1,3,2-dioxaborinane (15): Prepared by analogy to Brown's synthesis of 2-tert-butyl-1,3,2-
dioxaborinane from tert-butylboronic acid and 1,3-propanediol.14 Thus, a mixture of methaneboronic acid (104
mg, 1.74 mmol), 2,2-dimethyl-1,3-propanediol (200 mg, 1.92 mmol), and pentane (1.8 mL) was stirred at rt
12. Burgess, K.; van der Donk, W. A. Organometallics 1994, 13, 3616.
13. Kakiuchi, F.; Usui, M., Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706.
14. Srebnik, M.; Cole, T. E.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1989, 54, 6085.
S8

Blakemore, Marsden, and Vater
under N2 for 3 min. After this time, the layers of the resulting biphasic mixture were separated. Careful removal
of the pentane solvent by evaporation under one atmosphere of N2 afforded the title boronate (15, 147 mg, 1.15
mmol, 66%) as a colorless oil: IR (neat) 2923, 1714, 1473, 1336, 1248, 1034 cm–1; 1H NMR (300 MHz, CDCl3)
δ 3.59 (4H, s), 0.96 (6H, s), 0.20 (3H, s) ppm; 13C NMR (75 MHz, CDCl3) δ 72.2 (2C, 2), 31.7 (0), 22.0 (2C, 3)
11
ppm [B-CH3 not observed]; B NMR (160 MHz, CDCl3) δ 30.3 ppm. Boronate 15 was previously reported by
Kakiuchi et al without characterization data.13
(104.2)
Oi-Pr
B
O
B
n-BuLi, Et O
2
OH OH
(i-PrO) B
3
Oi-Pr
O
–78 °C, 1.5 h
rt, 14 h, 65%
C H BO
9 21 3
(188.1)
C H BO (16)
9
19
(170.1)
2
2-Butyl-5,5-dimethyl-1,3,2-dioxaborinane (16): A solution of n-butyllithium (6.60 mL, 1.52 M in hexanes,
10.0 mmol) in Et2O (27 mL) at –78 °C under N2 was treated with triisopropyl borate (2.30 mL, d = 0.818, 1.88
g, 10.0 mmol) during 1 h. After 20 min at –78 °C, the cold bath was removed and the reaction mixture allowed
to warm to rt. Once at rt, the reaction mixture was treated with 2,2-dimethyl-1,3-propanediol (830 mg, 7.97
mmol) and stirred for 14 h. The mixture was then partitioned between Et2O (100 mL) and sat. aq. NH4Cl (50
mL) and the layers separated. The organic phase was washed successively with H2O (2x50 mL) and brine (50
mL), dried (Na2SO4) and concentrated in vacuo. The residue was distilled at reduced pressure to yield the title
boronate (16, 876 mg, 5.15 mmol, 65%) as a colorless oil: bp 51-52 oC (1.5 mmHg); IR (neat) 2956, 2928, 1476,
1412, 1330, 1248, 1179, 1075 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.59 (4H, s), 1.41-1.24 (4H, m), 0.96 (6H, s),
13
0.88 (3H, t, J = 7.0 Hz), 0.71 (2H, t, J = 7.4 Hz) ppm; C NMR (75 MHz, CDCl3) δ 72.1 (2C, 2), 31.8 (0), 26.6
(2), 25.7 (2), 22.0 (2C, 3), 14.8 (2), 14.1 (3) ppm; MS (ES+) m/z 209 [100, (M+K)+].
(104.2)
O
B
100 °C, 4 h
O
O
O
OH OH
+
B
HB
O
!, 19 h
86%
O
C H BO
6 2
(119.9)
C H BO (17)
11 21 2
(196.09)
C H
6 10
(82.1)
5
C H BO (202.1)
12 15 2
2-Cyclohexyl-5,5-dimethyl-1,3,2-dioxaborinane (17): A stirred mixture of cyclohexene (1.01 mL, d = 0.81,
819 mg, 9.97 mmol) and catecholborane (1.17 mL, d = 1.13, 1.32 g, 11.0 mmol) was heated at 100 °C under N2
for 4 h. After cooling to rt, the resulting boronate was added directly to a solution of 2,2-dimethyl-1,3-
propanediol (2.60 g, 25.0 mmol) in anhydrous THF (13 mL) and heated to reflux for 19 h. After this time, the
mixture was concentrated in vacuo and the residue purified by column chromatography (eluting with 10%
EtOAc in hexanes) to afford the title compound (17, 1.68 g, 8.57 mmol, 86%) as a colorless air-sensitive oil: IR
(neat) 2923, 1476, 1410, 1314, 1253, 1179 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.58 (4H, s), 1.72-1.55 (5H, m),
1.34-1.17 (5H, m), 0.94 (6H, s), 0.91-0.79 (1H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 72.1 (2C, 2), 31.8 (0),
28.4 (2C, 2), 27.6 (2C, 2), 27.1 (2), 25.8 (br), 21.9 (2C, 3) ppm.
S9

Blakemore, Marsden, and Vater
(104.2)
PhMgCl, Et O
2
Oi-Pr
Oi-Pr
O
O
OH OH
(i-PrO) B
3
B
B
–78 °C !
–15 °C, 4 h
rt, 16 h, 54%
C H BO
9 21 3
(188.1)
C
H BO (18)
11 15 2
(190.1)
C
H
12 19
BO (206.1)
2
5,5-Dimethyl-2-phenyl-1,3,2-dioxaborinane (18): A solution of phenylmagnesium bromide (14.6 mL, 1.37 M
in THF, 20.0 mmol) in Et2O (52 mL) at –78 °C was slowly treated with triisopropyl borate (4.60 mL, d = 0.82,
3.76 g, 20.0 mmol) during 2 h. The solution was allowed to warm to –15 °C over 4 h and then 2,2-dimethyl-1,3-
propanediol (2.19 g, 21.0 mmol) was added in one portion. The resulting mixture was stirred at rt for 16 h and
then partitioned between Et2O (200 mL) and sat. aq. NH4Cl (100 mL). The layers were separated and the organic
phase washed successively with H2O (2x100 mL) and brine (100 mL), dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatography (eluting with 5% EtOAc in hexanes) to yield the
title boronate (18, 2.05 g, 10.8 mmol, 54%) as colorless plates: mp 61-63 °C (hexanes) [lit.15 mp 65-66 °C
(hexanes)]; IR (neat) 2956, 1599, 1314, 1133, 696, 642 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.80 (2H, d, J = 6.7
Hz), 7.48-7.31 (3H, m), 3.77 (4H, s), 1.02 (6H, s) ppm; 13C NMR (75 MHz, CDCl3) δ 134.0 (2C, 1), 130.9 (1),
11
127.8 (2C,1), 72.5 (2C, 2), 32.1 (0), 22.1 (2C, 3) ppm [C-B not observed]; B NMR (160 MHz, CDCl3) δ 26.8
ppm. 1H and 11B NMR spectral data were in agreement with those previously reported by Davis et al.16
(104.2)
80 °C, 3 h
O
O
B
OH OH
O
B
+
HB
Ph
C H
rt, 41 h
41%
O
Ph
O
O
Ph
C
C H BO
C
H BO (19)
13 17 2
(216.1)
8
6
6
5
(119.9)
2
(102.1)
H BO (222.0)
14 11 2
(E)-5,5-Dimethyl-2-(2-phenylethenyl)-1,3,2-dioxaborinane (19): A mixture of phenylacetylene (0.55 mL, d =
0.93, 512 mg, 5.01 mmol) and catecholborane (0.59 mL, d = 1.13, 667 mg, 5.56 mmol) were stirred at 80 °C
under N2 for 3 h. After cooling to rt, the resulting orange solid was dissolved in Et2O (50 mL). Exactly one half
of the ethereal solution was treated with 2,2-dimethyl-1,3-propanediol (1.30 g, 12.5 mmol) and stirred at rt
under N2 for 41 h. After this time, the reaction mixture was washed with H2O (10 mL), dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chromatography (eluting with 10% EtOAc in
hexanes) to afford the title unsaturated boronate (19, 220 mg, 1.02 mmol, 41%) as a colorless solid: mp 41-44
°C (pentane, colorless prisms); IR (neat) 2956, 1622, 1478, 1256, 1190, 1078, 998, 749, 693 cm–1; 1H NMR (300
MHz, CDCl3) δ 7.49 (2H, d, J = 7.2 Hz), 7.38-7.23 (4H, m), 6.11 (1H, d, J = 18.4 Hz), 3.70 (4H, s), 1.01 (6H, s)
13
ppm; C NMR (75 MHz, CDCl3) δ 147.2 (1), 137.9 (0), 128.6 (2C, 1), 127.1 (2C, 1), 121.0 (1), 72.3 (2C, 2),
31.9 (0), 22.0 (2C, 3) ppm. IR and NMR spectral data were in agreement with those previously reported by
Kobayashi et al.17
15. Bowie, R.; Musgrave, O. J. Chem. Soc. 1963, 3945.
16. Davis, F.; Turchi, I.; Maryanoff, B.; Hutchins, R. J. Org. Chem. 1972, 37, 1583.
17. Kobayashi, Y.; Nakayama, Y.; Mizojiri, R. Tetrahedron 1998, 54, 1053.
S10

Blakemore, Marsden, and Vater
– Preparation of standards (±)-20-24, HPLC resolution, and configurational assignment for 22 and 23 –
Ph
MgBr
Ph
C
Ph
Ph
C H O
OH
THF, 0 °C ! rt
O
53%
H
O (rac-20)
16 18
8
8
(226.3)
(120.1)
(±)-1,4-Diphenylbutan-2-ol (rac-20): A vigorously stirred suspension of mechanically activated Mg-turnings
(270 mg, 11.1 mmol) in anhydrous THF (10 mL) under N2 was treated with neat phenethyl bromide (1.37 mL, d
= 1.35, 1.85 g, 10.0 mmol) at a rate sufficient to first initiate, and then subsequently sustain, a gentle reflux.
Shortly after the addition was complete, the exotherm ceased and the reaction mixture returned to rt. The
solution of the so-formed Grignard reagent was cooled to 0 °C and treated with phenylacetaldehyde (1.17 mL, d
= 1.03, 1.21 g, 10.0 mmol) in anhydrous THF (5 mL) during 6 min. The reaction mixture was stirred at 0 °C for
10 min and then allowed to warm to rt. After stirring for 15 h at rt, the mixture was poured into sat. aq. NH4Cl
(10 mL) and the resulting layers well shaken and separated. The aqueous phase was extracted with EtOAc (3x10
mL) and the combined organic phases washed successively with H2O (10 mL) and brine (10 mL), dried
(Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (eluting with 6%
EtOAc in hexanes) to afford the title carbinol (rac-20, 1.19 g, 5.26 mmol, 53%) as a viscous oil which
crystallized upon standing: mp 43-44 °C (Et2O-hexanes (1:1), colorless needles) [lit.18 mp 44 °C]; IR (neat)
1
3357, 2918, 1602, 1492, 1451, 1084, 1029, 749, 697 cm–1; H NMR (300 MHz, CDCl3) δ 7.35-7.15 (10H, m),
3.90-3.75 (1H, m), 2.92-2.64 (4H, m), 1.94-1.75 (2H, m), 1.53 (1H, d, J = 4.1 Hz, OH) ppm; 13C NMR (75
MHz, CDCl3) δ 142.2 (0), 138.5 (0), 129.6 (2C, 1), 128.8 (2C, 1), 128.63 (2C, 1), 128.57 (2C, 1), 126.7 (1),
1
126.0 (1), 72.1 (1), 44.3 (2), 38.6 (2), 32.3 (2) ppm; MS (EI+) m/z 226 (8, M+•), 208 (25), 91 (100). H NMR
data were in agreement with those reported previously by Lambert et al.19
HPLC resolution of rac-20 was achieved with a Daicel Chiralcel® OD-H column, eluting with 5% i-PrOH in
hexanes at 1.0 mL min–1 and monitored by UV at 210 nm, which gave peaks: tret. (20) = 10.9 min, tret. (ent-20) =
17.6 min (Figure S5). Assignment of enantiomorphs to the peaks as indicated below was based on the outcome
of asymmetric homologation of boronate 14 by carbenoids ent-9 and 26 (Table 1, Entry 7, Figure S15, p. S19
and Table 2, Entry 2, Figure S19, p. S21) and the analogy of these results to those obtained from boronates 16
and 17 for which absolute configuration of product carbinols was established (vide infra).
HV6 54J RAC #3
mAU
HV6 54J RAC OD-H
UV_VIS_1
WVL:210 nm
300
250
200
150
100
50
Figure S5. Chromatogram for HPLC
1 - 10.940
resolution of rac-20.
Peak 1 - 10.9 min (50.33%)
S
Ph
2 - 17.627
Ph
20
OH
Peak 2 - 17.6 min (49.67%)
R
Ph
Ph
%D: 0.0 %
ent-20 OH
%C: 0.0 %
0
%B: 95.0 %
Flow: 1.000 ml/min
min
-50
18. Cornubert, R.; Eggert, H. Bull. Soc. Chim. Fr. 1954, 21, 522.
19. Lambert, J. B.; Mark, H. W.; Magyar, E. S. J. Am. Chem. Soc. 1977, 99, 3059.
S11

Blakemore, Marsden, and Vater
MeLi
Ph
C H O
Ph
O
OH
THF, 0 °C ! rt
65%
8
8
C H O (rac-21)
9
12
(136.2)
(120.1)
(±)-1-Phenylpropan-2-ol (rac-21): A stirred solution of MeLi (12.5 mL, 1.60 M in Et2O, 20.0 mmol) in
anhydrous THF (16 mL) at 0 °C was treated with phenylacetaldehyde (2.30 mL, d = 1.03, 2.36 g, 19.7 mmol)
during 23 min. The resulting mixture was stirred at 0 °C for 30 min and then for a further 3 h at rt. After this
time, the mixture was poured into sat. aq. NH4Cl (50 mL) and the layers separated. The aqueous phase was
extracted with Et2O (3x50 mL) and the combined organic phases were washed successively with H2O (25 mL)
and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column
chromatography (eluting with 10% EtOAc in hexanes) to yield the title carbinol (rac-21, 1.78 g, 13.1 mmol,
65%) as a pale yellow liquid: bp 71-72 °C (2 mmHg) [lit.20 bp 65-66 oC (1 mmHg)]; IR (neat) 3358, 2964, 1599,
1451, 1077, 938, 741, 698 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.19 (5H, m), 4.05-3.95 (1H, m), 2.80 (1H,
dd, J = 13.6, 4.9 Hz), 2.69 (1H, dd, J = 13.6, 7.9 Hz), 1.54 (1H, d, J = 3.6 Hz, OH), 1.25 (3H, d, J = 6.1 Hz)
ppm; 13C NMR (75 MHz, CDCl3) δ 138.7 (0), 129.6 (2C, 1), 128.8 (2C, 1), 126.7 (1), 69.1 (1), 46.0 (2), 23.0 (3)
ppm. Spectroscopic data were in agreement with those previously reported by Besse et al.21
HPLC resolution of rac-21 was achieved with a Daicel Chiralcel® AD column, eluting with 1% i-PrOH in
hexanes at 0.5 mL min–1 and monitored by UV at 210 nm, which gave peaks: tret. = 33.7 min, tret. = 36.2 min
(Figure S6). Peaks within this chromatogram have not been assigned to particular enantiomorphs because a pure
sample of enantioenriched carbinol 21 could not be obtained from asymmetric homologation of 15 by carbenoid
9 (Table 1, Entry 8).
HV4 92C #12 [modified byGRIGG]
mAU
HV5 20C AD
UV_VIS_2
WVL:210 nm
900
Figure S6. Chromatogram for HPLC
1 - 33.727
2 - 36.227
resolution of rac-21.
600
400
200
Peak 1 - 33.7 min (49.57%)
Peak 2 - 36.2 min (50.43%)
%D: 0.0 %
%C: 0.0 %
%B: 99.0 %
Flow: 0.500 ml/min
min
-100
20. Snook, M. E.; Hamilton, G. A. J. Am. Chem. Soc. 1974, 96, 860.
21. Besse, P.; Renard, M. F.; Veschambre, H. Tetrahedron:Asymmetry 1994, 5, 1249.
S12

Blakemore, Marsden, and Vater
BuLi
Ph
C H O
Ph
O
OH
THF, 0 °C ! rt
50%
8
8
C
H O (rac-22)
12 18
(120.1)
(178.3)
(±)-1-Phenylhexan-2-ol (rac-22): A stirred solution of n-BuLi (13.2 mL, 1.51 M in hexanes, 19.9 mmol) in
anhydrous THF (15 mL) at 0 °C was treated with phenylacetaldehyde (2.34 mL, d = 1.03, 2.41 g, 20.1 mmol)
during 7 min. The resulting mixture was stirred at 0 °C for 1 h and then at rt for 20 h. After this time, the
mixture was poured into sat. aq. NH4Cl (50 mL) and the layers were separated. The aqueous phase was extracted
with Et2O (3x50 mL) and the combined organic phases were washed successively with H2O (25 mL) and brine
(25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography
(eluting with 10% EtOAc in hexanes) to yield the title carbinol (rac-22, 1.80 g, 10.1 mmol, 51%) as a pale
o
yellow oil: bp 101-102 °C (1.5 mmHg) [lit.22 bp 100-102 C (1 mmHg)]; IR (neat) 3373, 2928, 1602, 1454,
1
1028, 743, 699 cm–1; H NMR (300 MHz, CDCl3) δ 7.36-7.19 (5H, m), 3.87-3.77 (1H, m), 2.84 (1H, dd, J =
13
13.5, 4.2 Hz), 2.64 (1H, dd, J = 13.5, 8.5 Hz), 1.60-1.25 (6H, m), 0.91 (3H, t, J = 7.2 Hz) ppm; C NMR (75
MHz, CDCl3) δ 138.9 (0), 129.6 (2C, 1), 128.6 (2C, 1), 126.5 (1), 72.8 (1), 44.2 (2), 36.6 (2), 28.1 (2), 22.9 (2),
14.3 (3) ppm. 1H and 13C NMR spectral data were in agreement with those previously reported by Bonini et al.23
HPLC resolution of rac-22 was achieved with a Daicel Chiralcel® OD-H column, eluting with 0.5% i-PrOH in
hexanes at 1.0 mL min–1 and monitored by UV at 210 nm, which gave peaks: tret. (22) = 12.3 min, tret. (ent-22) =
16.1 min (Figure S7).
HV6 52Q#6 [modifiedbyhplc]
mAU
HV6 52QRAC OD-H
UV_VIS_2
WVL:210 nm
100.0
87.5
75.0
62.5
50.0
37.5
Figure S7. Chromatogram for HPLC
1 - Peak 1 - 12.273
resolution of rac-22.
2 - Peak 2 - 16.147
Peak 1 - 12.3 min (50.02%)
S
Et
Ph
22
OH
Peak 2 - 16.1 min (49.98%)
R
Et
Ph
%D: 0.0 %
ent-22 OH
%C: 0.0 %
%B: 95.0 %
Flow: 1.000 ml/min
min
20.0
To establish absolute configuration for enantiomorphs 22 (S) and ent-22 (R), diastereomeric mixtures of MTPA-
esters (S4 and epi-S4) were prepared both from a sample of rac-22 and a sample of enantioenriched 22 (%ee =
70%) obtained from asymmetric homologation of boronate 16 by carbenoid 9 (Table 1, Entry 9). Analysis of 1H
NMR data for the two epimeric components present within the mixtures according to the Mosher
configurational correlation model (Figure S8),24 enabled assignment of (S)-configuration to carbinol 22 as
illustrated.
22. Uguen, D. Bull. Soc. Chim. Fr. 1981, 2, 99.
23. Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J. Org. Chem. 1995, 60, 4803.
24. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
S13

Blakemore, Marsden, and Vater
Figure S8. Mosher analysis
"! < 0
of S4 and epi-S4
!
(Me) 0.87
!
(Me) 0.83
Me
Me
!
(CH2Ph)
2.92
!
(CH2Ph)
2.97
"! > 0
S
MeO
Ph
Ph
O
O
O
O
2.83
2.91
Ph
ent-22
Ph
H
Ph
OMe
S
R
H
22
OH
R
R
F C
CF
3
3
(major enantiomer from
shielding zone of
MTPA Ph-moiety
S4
epi-S4
=
homolog. of 16 by 9)
Preparation of MTPA ester's S4 and epi-S4: Following the method of Li,25 a mixture of (±)-1-phenylhexan-2-
ol (rac-22, 52 mg, 0.29 mmol), dicyclohexylcarbodiimide (DCC, 171 mg, 0.83 mmol), 4-(dimethyl-
amino)pyridine (DMAP, 5 mg, 0.041 mmol) and (R)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (96 mg,
0.41 mmol) was reacted in CH2Cl2 (3 mL) at rt for 92 h. After this time, the mixture was concentrated in vacuo
and the residue purified by column chromatography (eluting with 5% Et2O in hexanes) to afford a 1:1 mixture of
S4 and epi-S4 (82 mg, 0.21 mmol, 71%) as a colorless oil: IR (neat) 2956, 1742, 1454, 1264, 1168, 1023, 993,
696 cm–1; MS (ES+) m/z 417 [90, (M+Na)+], 330 (100); HRMS (ES+) m/z 417.1651 (calcd. for C22H25F3NaO3:
417.1653). A diastereomerically enriched sample of S4/epi-S4 (dr = 85:15) was similarly prepared from 21 with
70% ee (Table 1, Entry 9). NMR data were unambigously attributed to either S4 or epi-S4 by comparison of
spectra obtained from the isomer mixture with S4:epi-S4 = 50:50 to those obtained from the isomer mixture
with S4:epi-S4 = 85:15.
1
(S)-1-Phenylhex-2-yl (R)-α-methoxy-α-(trifluoromethyl)phenylacetate (S4): H NMR (300 MHz, CDCl3) δ
7.42-7.16 (8H, m), 7.10 (2H, d, J = 6.4 Hz), 5.35 (1H, quintet, J = 6.3 Hz), 3.43 (3H, q, 5JHF = 1.0 Hz), 2.92 (1H,
dd, J = 13.9, 7.5 Hz), 2.83 (1H, dd, J = 13.9, 5.8 Hz), 1.70-1.58 (2H, m), 1.41-1.18 (4H, m), 0.87 (3H, t, J = 7.1
Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 166.4 (0), 137.0 (0), 132.4 (0), 129.6 (1), 129.5 (2C, 1), 128.6 (2C, 1),
128.5 (2C, 1), 127.51 (1), 127.49 (1), 126.7 (1), 123.5 (0, q, 1JC-F = 287 Hz), 84.7 (0, q, 2JC-F = 27.4 Hz), 78.1 (1),
4
19
55.5 (3, q, JC-F = 1.7 Hz), 40.2 (2), 33.3 (2), 27.6 (2), 22.6 (2), 14.1 (2) ppm; F NMR (470 MHz, CDCl3) δ –
71.88 (3F, s) ppm.
1
(R)-1-Phenylhex-2-yl (R)-α-methoxy-α-(trifluoromethyl)phenylacetate (epi-S4): H NMR (300 MHz, CDCl3) δ
7.42-7.18 (8H, m), 7.12-7.08 (2H, m), 5.37 (1H, quintet, J = 6.8 Hz), 3.39 (3H, q, 5JHF = 1.0 Hz), 2.97 (1H, dd, J
= 13.3, 6.7 Hz), 2.91 (1H, dd, J = 13.3, 6.7 Hz), 1.69-1.57 (2H, m), 1.43-1.15 (4H, m), 0.83 (3H, t, J = 6.4 Hz)
ppm; 13C NMR (75 MHz, CDCl3) δ 166.5 (0), 137.3 (0), 132.5 (0), 129.6 (1), 129.5 (2C, 1), 128.7 (2C, 1),
128.5 (2C, 1), 127.5 (2C, 1), 126.9 (1), 123.5 (0, q, 1JC-F = 287 Hz), 84.7 (0, q, 2JC-F = 27.4 Hz), 78.1 (1), 55.5 (3,
q, 4JC-F = 1.7 Hz), 40.3 (2), 33.3 (2), 27.1 (2), 22.6 (2), 14.0 (2) ppm; 19F NMR (470 MHz, CDCl3) δ –71.79 (3F,
s) ppm.
c-C H MgBr
6
11
Ph
Ph
O
THF, 0 °C ! rt
OH
C H O (rac-23)
14 20
36%
C H O
8
8
(120.1)
(204.3)
(±)-1-Cyclohexyl-2-phenylethanol (rac-23): A vigorously stirred suspension of mechanically activated Mg-
turnings (270 mg, 11.1 mmol) in anhydrous THF (14 mL) under N2 was treated with neat cyclohexyl bromide
(1.23 mL, d = 1.32, 1.62 g, 9.93 mmol) at a rate sufficient to first initiate, and then subsequently sustain, a gentle
25. Wei, Z.-L.; Li, Z.-Y.; Lin, G.-Q. Tetrahedron: Asymmetry 2001, 12, 229.
S14

Blakemore, Marsden, and Vater
reflux. Shortly after the addition was complete, the exotherm ceased and the reaction mixture returned to rt. The
solution of so-formed Grignard reagent was cooled to 0 °C and treated with phenyacetaldehyde (1.17 mL, d =
1.03, 1.21 g, 10.0 mmol) during 2 min. The reaction mixture was stirred at 0 °C for a further 40 min and then at
rt for 1 h before pouring into sat. aq. NH4Cl (50 mL). The layers were separated and the aqueous phase was
extracted with Et2O (3x50 mL). The combined organic phases were then washed successively with H2O (25 mL)
and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column
chromatography (eluting with 10% EtOAc in hexanes) to yield the title carbinol (rac-23, 731 mg, 3.58 mmol,
36% yield) as colorless solid: mp 55-57 °C (pentane) [lit.26 mp 57.5 °C (hexanes)]; IR (neat) 3302, 2928, 1602,
1492, 1443, 1034, 749, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (5H, m), 3.58 (1H, ddd, J = 9.5, 8.9,
3.6 Hz), 2.89 (1H, dd, J = 13.6, 3.3 Hz), 2.60 (1H, dd, J = 13.6, 9.5 Hz), 1.97-1.63 (5H, m), 1.50-1.36 (2H, m),
1.35-1.02 (5H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 139.4 (0), 129.5 (2C, 1), 128.7 (2C, 1), 126.5 (1), 77.0
(1), 43.3 (1), 40.9 (2), 29.5 (2), 28.1 (2), 26.7 (2), 26.5 (2), 26.3 (2) ppm. Data previously reported for carbinol
1
23 by Ohta et al are believed to be in error [mp 173-174 °C (pentane), H NMR spectrum lists 21H with no
proton resonating in the 3-5 ppm region].27
HPLC resolution of rac-23 was achieved with a Daicel Chiralcel® OD-H column, eluting with 0.38% i-PrOH in
hexanes at 1.0 mL min–1 and monitored by UV at 210 nm, which gave peaks: tret. (23) = 14.0 min, tret. (ent-23) =
20.4 min (Figure S9).
Figure S9. Chromatogram for HPLC resolution of rac-23.
Peak 1 - 14.0 min (50.22%)
HV6 71B #2
mAU
HV6 69B OD-H
UV_VIS_2
WVL:210 nm
300
200
100
R
Ph
23
OH
Peak 2 - 20.4 min (49.98%)
%D: 0.0 %
%C: 0.0 %
%B: 96.2 %
Flow: 1.000 ml/min
S
Ph
min
-20
ent-23 OH
To establish absolute configuration for enantiomorphs 23 (R) and ent-23 (S), an authentic enantioenriched
sample of (R)-1-cyclohexyl-2-phenylethanol was prepared by reduction of benzyl cyclohexyl ketone (S5) with
(S)-Me-CBS-oxazaborolidine S6, as follows:–
Ph
Ph
H
O
C H BNO (S6)
18 20
(277.2)
N
B
K Cr O (294.2)
2 2 7
H SO (98.1), H O
Me
Ph
Ph
Ph
2
4
2
AcOH, PhMe, rt, 19 h
52%
BH •SMe , THF
3
–30 °C, 1 h
2
OH
O (rac-23)
O
OH
C H O (23)
14 20
87%, 72% ee
C
H
14 20
C
H
O (S5)
14 18
(204.3)
(202.3)
(204.3)
26. Perlman, D.; Davidson, D.; Bogert, M. J. Org. Chem. 1936, 1, 288.
27. Ohta, S.; Yamashita, M.; Arita, K.; Kajiura, T.; Kawasaki, I.; Noda, K.; Izumi, M. Chem. Pharm. Bull.
1995, 43, 1294.
S15

Blakemore, Marsden, and Vater
Benzyl cyclohexyl ketone (S5): Following the method of Jones,28 a mixture of rac-23 (137 mg, 0.67 mmol),
K2Cr2O7 (107 mg, 0.36 mmol), H2SO4 (110 µL, d = 1.84, 202 mg, 2.06 mmol), H2O (0.36 mL) and AcOH (35
µL, d = 1.05, 36.7 mg, 0.61 mmol) was stirred vigorously in PhMe (1 mL) at rt for 19 h. After the prescribed
work-up, the crude residue was purified by column chromatography (eluting with 10% EtOAc in hexanes) to
afford the desired ketone (S5, 71 mg, 0.35 µmol, 52%) as a pale yellow oil: IR (neat) 2928, 1706, 1495, 1448,
1
699 cm-1; H NMR (300 MHz, CDCl3) δ 7.36-7.14 (5H, m), 3.73 (2H, s), 2.46 (1H, tt, J = 11.1, 3.3 Hz), 1.88-
1.60 (5H, m), 1.43-1.13 (5H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 211.4 (0), 134.5 (0), 129.6 (2C, 1), 128.7
(2C, 1), 126.9 (1), 50.2 (1), 48.0 (2), 28.6 (2C, 2), 25.9 (2), 25.7 (2C, 2) ppm; MS (ES+) m/z 203 [100, (M+H)+].
IR and 1H NMR data were in agreement with those previously reported by Inaba et al.29
(R)-1-Cyclohexyl-2-phenylethanol (23): Following the method of Corey and co-workers,30 reduction of ketone
S5 (16 mg, 0.079 mmol) was effected by (S)-Me-CBS-oxazaborolidine S6 (0.17 mL, 1.0 M in PhMe, 0.17
mmol) and borane dimethyl sulfide complex (0.20 mL, 2.0 M in Et2O, 0.40 mmol) in anhydrous THF (0.4 mL)
at –30 °C. Following the prescribed work-up procedure, the residue was purified by column chromatography
(eluting with 10% EtOAc in hexanes) to yield the title carbinol (23, 14 mg, 0.069 mmol, 87% yield) as a
colorless solid which gave identical spectral data to those previously obtained for rac-23.
HPLC analysis of this sample according to the protocol identified for resolution of rac-23 (above) revealed an
enantiomeric excess of 72% (Figure S10). Application of the Corey stereocontrol model for reduction of ketone
S5 with catalyst (S)-S6 predicts that the major product from this transformation would be (R)-configurated
(Figure S11).30 Peak 1 in the HPLC trace for rac-23 (Figure S9), which corresponds to the major enantiomer
(23) obtained by asymmetric homologation of boronate 17 by carbenoid 26 (Table 2, Entry 3, Figure S20, p.21),
was therefore assigned as being (R)-1-cyclohexyl-2-phenylethanol. Peak 2, which was obtained as the major
product of asymmetric homologation of boronate 17 by carbenoid ent-9 (Table 1, Entry 10, Figure S17, p. S19),
was necessarily therefore assigned as (S)-1-cyclohexyl-2-phenylethanol.
HV7 9D #2[modifiedbyGRIGG]
mAU
HV7 16D OD-H
UV_VIS_2
WVL:210 nm
1,000
800
600
400
200
1 - 13.173
Ph
Me
O
O
B
S
N
Ph H
H
B
H
most sterically
demanding ketone
flanking group
H
preferential hydride
transfer to si-face
OH
2 - 18.853
%D: 0.0 %
Ph
23
%C: 0.0 %
R
%B: 96.2 %
Flow: 1.000 ml/min
min
-100
Figure S10. HPLC chromatogram (OD-H) for
product of (S)-CBS reduction
Figure S11. Application of Corey stereocontrol
model to ketone S5 (see ref. 30)
Peak 1 - 13.2 min (86.04%)
Peak 2 - 18.9 min (13.96%)
28. Good, R.; Jones, G. J. Chem. Soc. C 1970, 1938.
29. Inaba, S.-I.; Rieke, R. J. Org. Chem. 1985, 50, 1373.
30. Corey, E.; Helal, C. Angew. Chem., Int. Ed. 1998, 37, 1986.
S16

Blakemore, Marsden, and Vater
PhMgCl
Ph
Ph
Ph
O
OH
C H O (rac-24)
14 14
THF, 0 °C ! rt
85%
C H O
8
(120.1)
8
(198.3)
(±)-1,2-Diphenylethanol (rac-24): A stirred solution of PhMgCl (29.0 mL, 0.70 M in THF, 20.3 mmol) at 0 °C
under N2 was treated with phenylacetaldehyde (2.30 mL, d = 1.03, 2.37 g, 19.7 mmol) during 4 min. The
resulting mixture was stirred at 0 °C for a further 30 min and then at rt for 2.5 h before being pouring into sat.
aq. NH4Cl (50 mL). The aqueous phase was extracted with Et2O (3x50 mL) and the combined organic phases
washed successively with H2O (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The
residue was purified by column chromatography (eluting with 10% EtOAc in hexanes) to yield the title carbinol
(rac-24, 3.32 g, 16.7 mmol, 85%) as a pale yellow liquid that crystallized on standing: mp 64-66 °C (hexanes)
[lit.31 mp 66-67 °C (Skellysolve B)]; IR (neat) 3324, 3027, 2862, 1599, 1451, 1316, 1070, 1039, 776, 696 cm–1;
1H NMR (300 MHz, CDCl3) δ 7.38-7.17 (10H, m), 4.90 (1H, ddd, J = 8.2, 5.1, 2.6 Hz), 3.05 (1H, dd, J = 13.6,
5.1 Hz), 2.98 (1H, dd, J = 13.6, 8.2 Hz), 1.96 (1H, br, OH) ppm; 13C NMR (75 MHz, CDCl3) δ 143.9 (0), 138.2
(0), 129.7 (2C, 1), 128.7 (2C, 1), 128.6 (2C, 1), 127.8 (1), 126.8 (1), 126.1 (2C, 1), 75.5 (1), 46.3 (2) ppm; MS
1
13
(ES+) 181 [100, (M–OH)+]. IR, H NMR, and C NMR spectral data were in agreement with those previously
reported by Knochel and co-workers.32
HPLC resolution of rac-24 was achieved with a Daicel Chiralcel® OD-RH column, eluting with 30-45% MeCN
in H2O (over 45 min) at 1.0 mL min–1 and monitored by UV at 210 nm, which gave peaks: tret. (ent-24) = 24.0
min, tret. (24) = 25.6 min (Figure S12). Assignment of enantiomorphs to the peaks as indicated below was based
on the outcome of asymmetric homologation of boronate 18 by carbenoid 9 to yield enantioenriched 24 (Table
1, Entry 11, Figure S18, p. S19) and the analogy of this result to those obtained by asymmetric homologation of
boronates 16 and 17 for which absolute configuration of product carbinols was established (vide supra).
Figure S12. Chromatogram for HPLC
resolution of rac-24.
Peak 1 - 24.0 min (49.18%)
S
Ph
Ph
ent-24 OH
Peak 2 - 25.6 min (50.82%)
R
Ph
Ph
24
OH
31. Meilahn, M. K.; Munk, M. E. J. Org. Chem. 1969, 34, 1440.
32. Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org. Chem. 1993, 58, 2694.
S17

Blakemore, Marsden, and Vater
– Reagent controlled asymmetric homologation procedures (Tables 1 and 2) –
Asymmetric homologation employing a preformed Mg-carbenoid (Table 1, Entries 2-12):
1
(b) R B(OR) (1 eq)
2
2 eq
(a) EtMgCl (2 eq)
solvent
–78 °C ! rt, 17 h
! ", 2 h
1
20 R = PhCH CH
2
2
O
S
Ph
Ph
Ph
1
21 R = Me
1
1
ClMg
R
22 R = n-Bu
1
p-Tol
–78 °C
30 min
(c) aq. NaOH, H O
2
2
23 R = c-hex
1
Cl
C H ClOS (8, 278.8)
Cl
OH
EtOH-THF
0 °C ! rt
24 R = Ph
9
15 15
The following procedure for homologation of boronate 14 by carbenoid 9 in PhMe solvent to yield
enantioenriched carbinol 20 is representative (Table 1, Entry 6, R1 = PhCH2CH2).
(S)-1,4-Diphenylbutan-2-ol (20): A stirred solution of sulfoxide 8 (291 mg, 1.04 mmol, dr > 99:1, %ee > 98%)
in anhydrous PhMe (7 mL) at –78 °C under N2 was treated carefully with EtMgCl (0.59 mL, 1.76 M in THF,
1.04 mmol) during 18 min. A colorless precipitate was observed to form which hindered stirring. After 30 min, a
solution of boronic ester 14 (115 mg, 527 µmol) in PhMe (2 mL) was added during 40 min via a syringe pump.
The reaction mixture was then allowed to warm slowly to rt over 17 h (nb. reaction flask left submerged in cold
Dewar bath, but no further dry ice added) and was observed to become homogenous at ca. –30 °C. Once at rt,
the reaction mixture was heated to a gentle reflux for 2 h and then subsequently cooled to 0 °C. EtOH (1 mL),
THF (1 mL), 3.75 M aq. NaOH (0.5 mL, 1.9 mmol) and 30% w/w aq. H2O2 (1 mL, 8.8 mmol) were then added
successively and the mixture stirred for 3 h before being pouring into sat. aq. NH4Cl (10 mL). The layers were
then separated and the aqueous phase extracted with EtOAc (3x10 mL). The combined organic phases were
washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was
purified by column chromatography (eluting with CH2Cl2) to afford the desired enantioenriched alcohol (20, 57
mg, 252 µmol, 48%) as a colorless oil. Spectral data were identical to those previously obtained for rac-20.
HPLC analysis using a slightly different chiral stationary phase (Daicel Chiralcel® OD vs. OD-H) to that
described above for resolution of rac-20 (p. S11), but under otherwise identical conditions, revealed %ee = 82%
(Figure S13). For control purposes, resolution of rac-20 on the OD column was demonstrated (Figure S14).
HV6 48J#2[modified byGRIGG]
mAU
HV6 54JOD
1 - 12.653
UV_VIS_2
WVL:210 nm
HV6 54J RAC #1
mAU
HV6 54J RAC OD
UV_VIS_1
1,200
1,000
800
600
400
200
0
70.0
WVL:210 nm
2 - 13.587
50.0
37.5
25.0
12.5
3 - 21.827
2 - 19.907
%D: 0.0 %
%D: 0.0 %
%C: 0.0 %
%C: 0.0 %
0.0
%B: 95.0 %
Flow: 1.000 ml/min
%B: 95.0 %
Flow: 1.000 ml/min
min
min
-200
-10.0
Figure S13. HPLC chromatogram (OD) for
enantioenriched 20 (Table 1, Entry 6): 82% ee
Peak 1 - 12.7 min (91.15%)
Figure S14. Chromatogram for HPLC
resolution of rac-20 on OD column
Peak 1 - 13.6 min (50.62%)
Peak 2 - 19.9 min (8.85%)
Peak 2 - 21.8 min (49.38%)
S18

Blakemore, Marsden, and Vater
Other enantioenriched carbinol products listed in Table 1 were similarly prepared. In each case, spectral data
were identical to those obtained from the corresponding racemic sample (pp. S11-S17). HPLC analysis was
applied to determine %ee according to the previously established resolution protcols. Selected chromograms
(Entries 7, 9-11) are presented below (Figures S15–S18). Carbinol 21 (R1 = Me, Table 1, Entry 8) was obtained
as an inseparable mixture with recovered chlorosulfoxide (8) and %ee could not be accurately determined.
HV6 42A#5 [modified byGRIGG]
mAU
HV6 42AOD-H
UV_VIS_2
30.0
25.0
20.0
15.0
10.0
5.0
WVL:210 nm
1 - 13.227
2 - 17.933
%D: 0.0 %
%C: 0.0 %
0.0
%B: 95.0 %
Flow: 1.000 ml/min
min
-5.0
Figure S15. HPLC chromatogram (OD-H) for
enantioenriched ent-20 (Table 1, Entry 7): 75% ee
Peak 1 - 10.6 min (12.51%)
Figure S16. HPLC chromatogram (OD-H) for
enantioenriched 22 (Table 1, Entry 9): 70% ee
Peak 1 - 13.2 min (85.23%)
Peak 2 - 16.8 min (87.49%)
Peak 2 - 17.9 min (14.77%)
HV7 9D #1[modifiedbyGRIGG]
mAU
HV7 9D OD-H
UV_VIS_2
WVL:210 nm
350
300
2 - 19.227
200
100
1 - 13.400
%D: 0.0 %
%C: 0.0 %
0
%B: 96.2 %
Flow: 1.000 ml/min
min
-50
Figure S17. HPLC chromatogram (OD-H) for
Figure S18. HPLC chromatogram (OD-RH) for
enantioenriched 24 (Table 1, Entry 11): 59% ee
Peak 1 - 24.5 min (20.37%)
enantioenriched ent-23 (Table 1, Entry 10): 60% ee
Peak 1 - 13.4 min (19.89%)
Peak 2 - 19.2 min (80.11%)
Peak 2 - 26.1 min (79.63%)
S19

Blakemore, Marsden, and Vater
Asymmetric homologation employing a Li-carbenoid under Barbier conditions (Table 2, Entries 2 and 3):
(a) n-BuLi (2 eq), THF
–78 °C ! 0 °C, 2.5 h
2 eq
1 eq
1
O
O
O
S
R
Ph
1
Ph
R B
+
OH
p-Tol
(b) aq. NaOH, H O
2
2
Cl
ClOS (8, 278.8)
1
1
0 °C !!rt
14 R = PhCH CH
2
20 R = PhCH CH
2
2
2
1
1
C
H
15 15
17 R = c-hex
23 R = c-hex
The following procedure for homologation of boronate 14 by carbenoid 26 to yield enantioenriched carbinol 20
is representative (Table 2, Entry 2, R1 = PhCH2CH2).
(S)-1,4-Diphenylbutan-2-ol (20): A stirred solution of sulfoxide 8 (136 mg, 488 µmol) and boronic ester 14 (54
mg, 248 µmol) in THF (2 mL) at –78 °C under N2 was carefully treated with n-BuLi (0.32 mL, 1.5 M in
hexanes, 480 µmol) (nb. n-BuLi solution introduced to reaction mixture by running it down the cold flask side-
wall during 3 min). The mixture was then allowed to warm to 0 °C with stirring during 2.5 h. After this time, 3.8
M aq. NaOH (0.13 mL, 0.5 mmol) and 8.8 M aq. H2O2 (0.20 mL, 1.8 mmol) were added and the resulting
biphasic mixture allowed to warm to rt during 2.5 h. The mixture was then poured into 1.5 M aq. HCl (10 mL)
and the layers separated. The aqueous phase was extracted with EtOAc (3x10 mL) and the combined organic
phases were washed successively with H2O (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatography (eluting with CH2Cl2) to yield the desired enantio-
enriched alcohol (20, 39 mg, 173 µmol, 70%) as a colorless oil. Phenethyl chloride (7 mg, 50 µmol, 10%), butyl
p-tolyl sulfoxide (51 mg, 260 µmol, 53%), and sulfoxide 8 (32 mg, 115 µmol, 23%, dr (syn:anti) = 48:52) were
also isolated.
Spectral data for 20 were identical to those previously obtained for rac-20 (p. S11). HPLC analysis according to
the protocol given above for rac-20, revealed %ee = 96% (Figure S19, p. S21): [α]D21 = –5.3 (c = 0.6, CHCl3).
1
Phenethyl chloride: H NMR (300 MHz, CDCl3) δ 7.35-7.10 (5H, m), 3.65 (2H, t, J = 7.5 Hz), 3.00 (2H, t, J =
7.5 Hz) ppm. Data were identical with an authentic sample purchased from a commercial supplier.
Butyl p-tolyl sulfoxide: IR (neat) 2958, 1596, 1492, 1462, 1086, 1037, 812 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.52 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 2.79 (1H, dd, J = 6.1, 3.1 Hz), 2.76 (1H, dd, J = 6.9, 3.3 Hz),
2.42 (3H, s), 1.79-1.34 (4H, m), 0.92 (3H, t, J = 7.3 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 141.5 (0), 141.0 (0),
130.1 (2C, 1), 124.3 (2C, 1), 57.3 (2), 24.4 (2), 22.1 (2), 21.6 (3), 13.9 (3) ppm; MS (ES+) m/z 393 [100,
(2M+H)+]. Spectroscopic data were in agreement with those reported by Ohta et al.33
(RS,S)-1-Chloro-2-phenylethyl p-tolyl sulfoxide (anti-8): IR (neat) 3027, 1596, 1492, 1454, 1146, 1050, 809,
696 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.67 (2H, d, J = 8.2 Hz), 7.38-7.22 (7H, m), 4.53 (1H, dd, J = 9.7, 2.9
Hz), 3.61 (1H, dd, J = 14.3, 2.9 Hz), 3.17 (1H, dd, J = 14.3, 9.7 Hz), 2.44 (3H, s) ppm; 13C NMR (75 MHz,
CDCl3) δ 143.1 (0), 137.8 (0), 135.1 (0), 130.01 (2C, 1), 129.97 (2C, 1), 128.8 (2C, 1), 127.6 (1), 126.0 (2C, 1),
77.8 (1), 37.4 (2), 21.7 (3) ppm; MS (ES+) m/z 279 [100, (M+H)+]. An X-ray crystallographic analysis of anti-8
was reported by Hoffmann and co-workers.1
33. Ohta, H.; Okamoto, Y.; Tsuchihashi, G. Agric. Biol. Chem. 1985, 49, 671.
S20

Blakemore, Marsden, and Vater
Enantioenriched carbinol 23 was similarly prepared in 86% yield by asymmetric homologation of boronate 17
by carbenoid 26 (Table 2, Entry 3, R1 = c-hex). HPLC analysis according to the protocol given above for rac-23,
revealed %ee = 87% (Figure S20, p. S21): [α]D21 = +7.0 (c = 1.2, CHCl3).
HV7 64C #5 [modifiedbyGRIGG]
mAU
HV7 66EOD-H25/08
UV_VIS_1
WVL:210 nm
HV7 64C #6
mAU
HV7 67D OD-H25/08
UV_VIS_1
WVL:210 nm
2,200
200
150
100
50
1 - 15.340
1 - 11.260
1,500
1,000
500
%D: 0.0 %
%D: 0.0 %
%C: 0.0 %
%C: 0.0 %
%B: 95.0 %
Flow: 1.000 ml/min
2 - 17.800
%B: 96.2 %
Flow: 1.000 ml/min
2 - 22.127
min
min
-200
-20
Figure S19. HPLC chromatogram (OD-H) for
enantioenriched 20 (Table 2, Entry 2): 96% ee
Peak 1 - 11.3 min (97.96%)
Figure S20. HPLC chromatogram (OD-H) for
enantioenriched 23 (Table 2, Entry 3): 87% ee
Peak 1 - 15.3 min (93.49%)
Peak 2 - 17.8 min (2.04%)
Peak 2 - 22.1 min (6.51%)
S21