Kinetic resolution of donor-functionalised tertiary alcohols by Cu-H-catalysed stereoselective silylation using a strained silicon-stereogenic silane

Article abstract of DOI:10.1039/b802186d

A series of propargylic tertiary alcohols decorated with an sp ²-hybridised nitrogen donor were kinetically resolved by reagent-controlled dehydrogenative Si-O coupling with a strained, highly reactive silicon-stereogenic cyclic silane. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802186d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Kinetic resolution of donor-functionalised tertiary alcohols by
Cu–H-catalysed stereoselective silylation using a strained
silicon-stereogenic silane†
Betu¨l Karatas, Sebastian Rendler, Roland Fro¨hlich‡ and Martin Oestreich*
Received 7th February 2008, Accepted 11th February 2008
First published as an Advance Article on the web 29th February 2008
DOI: 10.1039/b802186d
A series of propargylic tertiary alcohols decorated with an sp2-hybridised nitrogen donor were
kinetically resolved by reagent-controlled dehydrogenative Si–O coupling with a strained, highly
reactive silicon-stereogenic cyclic silane.
Introduction
Results and discussion
Non-enzymatic kinetic resolution1,2 of alcohols by stereoselective
silylation—as opposed to the related asymmetric acylation3—
was disregarded entirely until it very recently became the focus
of attention.4 Initiated by a seminal contribution by Ishikawa
et al.,5 Hoveyda and Snapper et al. developed notable catalyst-
controlled asymmetric silylation processes.6 At the same time, we
had devised a conceptually different, reagent-controlled silylation7
by using privileged silicon-stereogenic silane (SiR)-18,9 (Fig. 1) as
a chiral resolving reagent. Our diastereoselective strategy is based
on transition metal-catalysed dehydrogenative Si–O couplings, in
which (SiR)-1 kinetically selects either of the enantiomeric transi-
tion metal–alkoxide complexes. The selectivity factors2 s obtained
in the Cu–H-catalysed etherification10,11 of donor-functionalised
secondary alcohols (s ≈ 10)7a were substantially improved by
employing a Rh(I)–carbene complex as catalyst (s ≈ 900).7b
In our work on the kinetic resolution of secondary alcohols
(vide supra),7 the sterically encumbered tertiary silane (SiR)-1
was sufficiently reactive. Conversely, attempts to accomplish its
dehydrogenative coupling with a tertiary alcohol failed without
exception. We then reasoned that conversion might be, if at all,
achieved by using a silane with enhanced Lewis acidity. The pivotal
step in dehydrogenative Si–O couplings is likely to be a r-bond
metathesis of a transition metal–alkoxide and a Si–H bond,11
which involves a Lewis acid–Lewis base interaction of silicon and
oxygen. Aware of the concept of strain-release Lewis acidity,18 we
prepared (SiR)-2,17 which was accessed following a protocol similar
to that for (SiR)-1.9 Gratifyingly, strained (SiR)-2 was significantly
more reactive than (SiR)-1 in the Cu–H catalysis;7a no conversion
was seen in the Rh(I)-catalysed process, which had emerged as so
effective for secondary alcohols.7b
A brief screening of several 1-substituted (alkyl, aryl, alkenyl
and alkynyl groups) 1-phenyl-2-(2-pyridinyl) ethanols quickly
showed that merely a slender alkynyl substituent is tolerated at the
tertiary carbon atom. Propargylic alcohol rac-3 was chosen for op-
timisation of the reaction conditions (rac-3 → rac-14, Scheme 1).
As the success is reflected in the diastereoselectivity, rac-2 was
used for this.7 Removal of any traces of water by molecular
sieves greatly improved chemical yields. We had learned in our
previous study that electron-rich monophosphines are markedly
superior to electron-poor congeners in terms of reactivity.7 This
held true of this transformation as well (Table 1): poor r-donor
Fig. 1 Privileged silicon-stereogenic silanes.
We then entertained the idea to extend this technique to
tertiary alcohols, for which a stereoselective silylation had not
been reported so far. In fact, examples of their kinetic resolution
are scarce, with only a handful enzymatic12–14 (including catalytic
antibodies15) as well as a single chemical method16 known to date.
In this paper, we report an unprecedented stereoselective silylation
of (again donor-functionalised) tertiary alcohols through the use
of the novel strained silicon-stereogenic silane (SiR)-217 (Fig. 1).
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t, Cor-
rensstrasse 40, D-48149, Mu¨nster, Germany. E-mail: martin.oestreich@uni-
muenster.de; Fax: +49 (0)251 83-36501; Tel: +49 (0)251 83-33271
† Electronic supplementary information (ESI) available: Characterisation
data of 14–24, 26 and 28, 1H and 13C NMR spectra of all new compounds
as well as all four molecular structures; crystal structure data. See DOI:
10.1039/b802186d
Scheme 1 Optimisation of the reaction conditions and diastereoselectiv-
‡ X-Ray crystal structure analysis.
ity in the racemic series.
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Table 1 Assessment of phosphine ligands in Cu–H-catalysed Si–O coupling of rac-2 (0.65 equiv.) and rac-3 (1.0 equiv.). Diastereoselectivity as the
pivotal parameter for the subsequent kinetic resolution
Entry
Ligand R3P
T/◦C
Conv.a (%)
dr of (SiS*,R*)-14b
1
2
3
4
5
(3,5-CF3-C6H3)3P
Ph3P
(3,5-Xylyl)3P
(4-t-Bu-C6H4)3P
t-BuPh2P
L1
L2
L3
L4
L5
40
20
20
20
20
<5
60
65
65
65
53:47
88:12
87:13
92:8
89:11
a Determined by 1H NMR analysis and based on alcohol rac-3 (65% corresponds to quantitative conversion using 0.65 equiv. of silane rac-2).
b Diastereomeric ratio determined by GLC analysis using an SE-54 column.
L1 formed an unreactive and unselective catalyst (entry 1) whereas
moderately r-donating L2–5 combined good reactivity with
reasonable diastereocontrol (entries 2–5). L4 was routinely used
from then on.
Lastly, we exemplarily tested a 2-(6-picolinyl) and a 2-quinolinyl
group as donors (Scheme 3). Among other hetarenes, these had
proven successful in the recently developed Rh(I)-catalysed Si–
O coupling.7b The selectivity factors for both rac-25 → (SiS,R)-
26 and rac-27 → (SiS,R)-28 (Scheme 3) compared well with
rac-3 → (SiS,R)-14 (Table 2, entry 1). The chemical yield of
(S)-27 was lowered by competing retro-1,2-addition affording 2-
methylquinoline.
This protocol was subsequently applied to the kinetic resolution
of a series of aryl-substituted propargylic alcohols rac-3-rac-
10 (Scheme 2 and Table 2, entries 1–8). Diastereoselectivity is
dependent on conversion in the enantiomeric series (columns
10–12, Table 2), which is why we also provide the unbiased
diastereomeric ratios and theoretical selectivity factors s from
experiments in the racemic series (columns 7–9 and 17, Table 2).
Diastereomeric ratios were generally within 90:10 (s = 19–45);
there appears to be a minor influence of the electronic nature of
the arene on its exact values: electron-withdrawing groups at the
arene favour marginally higher numbers, e.g., dr = 94:6 for R2 =
4-chlorophenyl (entry 6) versus dr = 90:10 for R2 = 4-anisyl (entry
4). The relative configuration of the racemic ethers 14–21 was
assigned by X-ray crystal stucture analyses of 15, 16 and 19. In
the enantiomeric series, the resolutions were performed either with
(SiR)-2 or (SiS)-2 of 87–92% ee. The apparent selectivity factors,
sꢀ, using the enantioimpure20 resolving reagent range from 4.6–
9.0,2,19 which corresponds to enantiomeric excesses of 72–92% ee
for the slow-reacting alcohols (S)-3, (S)-5, (S)-8 and (S)-9 as well as
(R)-4, (R)-6 and (R)-7 at approximately 65% conversion. Absolute
configurations were deduced from crystallographic analysis of (S)-
8 and the assigned relative configurations (vide supra).
Conclusion
In summary, we have presented, for the first time, a kinetic
resolution of tertiary (propargylic) alcohols, for which asymmetric
syntheses are less prevalent,21 by stereoselective silylation. The
slow-reacting alcohols were isolated in 13–34% yield (at 65%
conversion) with 72–94% ee; the fast-reacting alcohols might
be liberated from the silyl ether in high chemical yield by
chemoselective reductive cleavage of the Si–O bond.22 These results
bode well for the further development of chiral silanes as resolving
reagents.
Experimental†
General procedure for the preparation of the donor-functionalised
tertiary alcohols
In a flame-dried Schlenk flask, a solution of freshly destilled i-
Pr2NH (1.82 mL, 1.32 g, 13.0 mmol, 1.30 equiv.) in anhydrous
THF (40 mL) was cooled to −78 ◦C followed by slow addition
of n-BuLi (4.80 mL, 12.0 mmol, 1.20 equiv., 2.5 M solution
in hexane).23 The reaction mixture was then allowed to warm
to room temperature and maintained at ambient temperature
In contrast, when replacing the aryl group by an alkyl
substituent such as methyl (in rac-11), 2-propyl (in rac-12) or
cyclohexyl (in rac-13), the diastereoselection completely collapsed
(Table 2, entries 9–11). The steric bulk of the branched alkyl
residues in rac-12 and rac-13 also retarded conversion, requiring
extended reaction times.
Scheme 2 Kinetic resolution of 2-pyridinyl-substituted tertiary alcohols by diastereoselective alcohol silylation.
1436 | Org. Biomol. Chem., 2008, 6, 1435–1440 This journal is The Royal Society of Chemistry 2008
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for 30 minutes. After recooling to −78 ◦C, a solution of the
respective methyl substituted N-hetarene (10.0 mmol, 1.00 equiv.)
in anhydrous THF (10 mL) was added in one portion and stirred
at this temperature for further 30 minutes. Subsequently, the
appropriate ketone24 (12.0 mmol, 1.20 equiv.) was added dropwise
◦
to the deeply coloured mixture. After 30 minutes at −78 C, the
reaction mixture was quenched with H2O (10 mL) and diluted
with tert-butyl methyl ether (10 mL). The pH was adjusted to
7–8 by adding aqueous HCl (2 M), and the organic phase was
separated. Extraction of the aqueous phase with dichloromethane
(3 × 25 mL) and washing of the combined organic extracts with
brine (20 mL) was followed by drying of the organic phases over
Na2SO4. The solvents were evaporated under reduced pressure
affording the desired alcohol as a crystalline solid or colourless oil.
Representative procedure for the Cu–H-catalysed Si–O coupling
˚
A Schlenk tube was charged with molecular sieves (4 A), CuCl
(2.0 mg, 20 lmol, 5.0 mol%), tris(4-tert-butyl)phosphine (17.2 mg,
40.0 lmol, 10.0 mol%) and degassed toluene (1.5 mL) followed
by addition of solid NaOt-Bu (1.9 mg, 20 lmol, 5.0 mol%).
At room temperature, the pre-catalyst was then successively
treated with a solution of alcohol rac-3 (118.2 mg, 400.0 lmol)
in toluene (2.0 mL) and a solution of silane (SiR)-2 (49.5 mg,
260 lmol, 0.65 equiv., 92% ee) in toluene (0.5 mL). The reaction
mixture was maintained at 40 ◦C until GC analysis of an
aliquot indicated complete conversion (after approximately 24 h)
of (SiR)-2 into (SiS,R)-14 (dr = 76:24). The crude mixture was
transferred to a round-bottomed flask and silica gel was added;
the solvent was evaporated under reduced pressure. Purification by
flash chromatography on silica gel (cyclohexane–tert-butyl methyl
ether = 95:5 → 75:25) gave (SiS,R)-14 (110.0 mg, 58%, dr = 76:24)
as well as enantioenriched alcohol (S)-3 (34.6 mg, 34%, 88% ee)
as colourless oils.
2-Phenyl-1-pyridin-2-yl-4-(trimethylsilanyl)but-3-yn-2-ol (3)
Analytical data for rac-3: Yield: 88%. Rf = 0.58 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 92 ◦C. 1H NMR (300 MHz,
CDCl3): d 0.03 (s, 9H), 3.18 (d, J = 14.2 Hz, 1H), 3.32 (d, J =
14.2 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.22 (ddd, J = 7.7, 5.0,
0.6 Hz, 1H), 7.25–7.39 (m, 3H), 7.65 (ddd, J = J = 7.7 Hz, J =
1.8 Hz, 1H), 7.72–7.76 (m, 2H), 8.53 (ddd, J = 5.0, 1.8, 0.8 Hz,
1H). 13C NMR (75 MHz, CDCl3): d 0.03, 51.6, 73.2, 90.0, 108.0,
122.2, 124.8, 125.7, 127.7, 128.3, 137.1, 144.2, 148.2, 158.7. IR
(film) 3255 (br, O–H), 2168 (w, C≡C) cm−1. HRMS (ESI) calcd
for C18H21NOSi (M + Na+): 318.1285; found: 318.1289. Anal.
calcd for C18H21NOSi (295.46): C, 73.17; H, 7.16; N, 4.74; found:
C, 73.08; H, 7.24; N, 4.69.
Analytical data for (S)-3 (88% ee, Entry 1, Table 2): Yield: 34%.
[a]20 = +32.6, [a]20 = +34.8, [a]20 = +42.4, [a]20 = +102.1
D
578
546
436
(c 0.450, CHCl3). HPLC (Daicel Chiralcel IB column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 90 : 10, flow
rate 0.80 mL min−1, k = 230 nm): tR = 5.94 min for (R)-3, tR
6.86 min for (S)-3.
=
1-Pyridin-2-yl-2-(4-tolyl)-4-(trimethylsilanyl)but-3-yn-2-ol (4)
Analytical data for rac-4: Yield: 94%. Rf = 0.58 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 61 ◦C. 1H NMR (300 MHz,
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Scheme 3 Variation of the donor: 2-(6-picolinyl) and 2-quinolinyl substitution.
CDCl3): d 0.02 (s, 9H), 2.34 (s, 3H), 3.16 (d, J = 14.2 Hz, 1H),
2-(4-Methoxyphenyl)-1-pyridin-2-yl-4-(trimethylsilanyl)but-
3-yn-2-ol (6)
3.31 (d, J = 14.2 Hz, 1H), 7.11–7.22 (m, 4H), 7.60–7.66 (m, 3H),
8.51 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d −0.1, 21.2, 51.6, 73.0, 89.7, 108.2, 122.1, 124.8, 125.5, 128.9,
137.0, 137.2, 141.4, 148.2, 158.8. IR (film) 3271 (br, O–H), 2168
(w, C≡C) cm−1. HRMS (ESI) calcd for C19H23NOSi (M + H+):
310.1622; found: 310.1620. Anal. calcd for C19H23NOSi (309.48):
C, 73.74; H, 7.49; N, 4.53; found: C, 73.70; H, 7.52; N, 4.45.
Analytical data for (R)-4 (84% ee, Entry 2, Table 2): Yield: 34%.
[a]20 = −26.4, [a]20 = −28.4, [a]20 = −33.8, [a]20 = −81.5
Analytical data for rac-6: Yield: 85%. Rf = 0.42 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 77 ◦C. 1H NMR (400 MHz,
CDCl3): d 0.02 (s, 9H), 3.14 (d, J = 14.2 Hz, 1H), 3.30 (d, J =
14.2 Hz, 1H), 3.81 (s, 3H), 6.88–6.91 (m, 2H), 7.13 (d, J = 7.4 Hz,
1H), 7.22 (dd, J = 7.4, 4.9 Hz, 1H), 7.62–7.67 (m, 3H), 8.53 (ddd,
J = 4.9, 1.6, 0.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 0.0,
51.7, 55.5, 72.9, 86.9, 108.3, 113.6, 122.1, 124.8, 127.0, 136.6, 137.0,
148.4, 159.0, 159.2. IR (film) 3253 (br, O–H), 2167 (w, C≡C) cm−1.
HRMS (ESI) calcd for C19H23NO2Si (M + Na+): 348.1390; found:
348.1396. Anal. calcd for C19H23NO2Si (325.48): C, 70.11; H, 7.12;
N, 4.30; found: C, 69.79; H, 7.23; N, 4.29.
D
578
546
436
(c 0.580, CHCl3). HPLC (Daicel Chiralcel IA column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 98 : 2, flow
rate 0.80 mL min−1, k = 230 nm): tR = 14.27 min for (S)-4, tR =
15.80 min for (R)-4.
Analytical data for (R)-6 (84% ee, Entry 4, Table 2): Yield:
34%. [a]20 = −22.6, [a]20 = −24.2, [a]20 = −29.0, [a]20
=
D
578
546
436
2-(2-Methoxyphenyl)-1-pyridin-2-yl-4-(trimethylsilanyl)but-
3-yn-2-ol (5)
−67.8, [a]20 = −164 (c 0.545, CHCl3). HPLC (Daicel Chiralcel
365
IA column, column temperature 20 ◦C, solvent n-heptane–
isopropanol = 95 : 5, flow rate 0.80 mL min−1, k = 230 nm):
tR = 13.83 min for (S)-6, tR = 15.47 min for (R)-6.
Analytical data for rac-5: Yield: 85%. Rf = 0.32 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 89 ◦C. 1H NMR (300 MHz,
CDCl3): d 0.05 (s, 9H), 3.52 (d, J = 13.8 Hz, 1H), 3.61 (d, J =
13.8 Hz, 1H), 3.91 (s, 3H), 6.91–6.95 (m, 2H), 7.13–7.18 (m, 2H),
7.25 (m, 1H), 7.58 (ddd, J = J = 7.6 Hz, J = 1.8 Hz, 1H), 7.72
(dd, J = 8.0, 1.8 Hz, 1H), 8.47 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H).
13C NMR (75 MHz, CDCl3): d −0.2, 47.4, 55.7, 71.3, 87.6, 107.8,
112.0, 120.6, 121.7, 124.8, 127.0, 128.7, 131.6, 136.4, 147.8, 156.4,
158.5. IR (film) 3254 (br, O–H), 2170 (w, C≡C) cm−1. HRMS (ESI)
calcd for C19H23NO2Si (M + H+): 326.1571; found: 326.1569. Anal.
calcd for C19H23NO2Si (325.48): C, 70.11; H, 7.12; N, 4.30; found:
C, 69.51; H, 7.23; N, 4.07.
Analytical data for (S)-5 (72% ee, Entry 3, Table 2): Yield: 32%.
[a]20D = +97.4, [a]20578 = +103.2, [a]20546 = +121.2, [a]20436 = +257.5
(c 0.740, CHCl3). HPLC (Daicel Chiralcel IA column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 98 : 2, flow
rate 0.80 mL min−1, k = 230 nm): tR = 14.05 min for (R)-5, tR =
15.27 min for (S)-5.
2-(4-Fluorophenyl)-1-pyridin-2-yl-4-(trimethylsilanyl)but-
3-yn-2-ol (7)
Analytical data for rac-7: Yield: 93%. Rf = 0.52 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 59 ◦C. 1H NMR (400 MHz,
CDCl3): d 0.03 (s, 9H), 3.16 (d, J = 14.4 Hz, 1H), 3.30 (d, J =
14.4 Hz, 1H), 7.01–7.07 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.25
(m, 1H), 7.65–7.73 (m, 3H), 8.53 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H).
13C NMR (100 MHz, CDCl3): d 0.1, 51.5, 72.8, 90.3, 107.8, 115.0
(d, JC–F = 21.3 Hz), 122.3, 124.9, 127.5 (d, JC–F = 8.1 Hz), 137.2,
140.1 (d, JC–F = 2.9 Hz), 148.2, 158.5, 162.4 (d, JC–F = 243.9 Hz).
IR (film) 3264 (br, O–H), 2169 (w, C≡C) cm−1. HRMS (ESI) calcd
for C18H20FNOSi (M + Na+): 336.1190; found: 336.1206. Anal.
calcd for C18H20FNOSi (313.45): C, 68.97; H, 6.43; N, 4.47; found:
C, 68.80; H, 6.49; N, 4.34.
1438 | Org. Biomol. Chem., 2008, 6, 1435–1440
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Analytical data for (R)-7 (86% ee, Entry 5, Table 2): Yield:
calcd for C22H19NO2 (329.40): C, 80.22; H, 5.81; N, 4.25; found:
C, 79.99; H, 5.90; N, 4.19.
32%. [a]20 = −21.1, [a]20 = −22.6, [a]20 = −27.2, [a]20
=
D
578
546
436
−68.0, [a]20 = −177 (c 0.715, CHCl3). HPLC (Daicel Chiralcel
365
IA column, column temperature 20 ◦C, solvent n-heptane–
isopropanol = 98 : 2, flow rate 0.80 mL min−1, k = 230 nm):
tR = 11.96 min for (S)-7, tR = 12.81 min for (R)-7.
2-Methyl-1-pyridin-2-yl-4-(trimethylsilanyl)but-3-yn-2-ol (11)
Analytical data for rac-11: Yield: 82%. Rf = 0.30 (cyclohexane–
tert-butyl methyl ether = 1 : 1). Colourless oil. 1H NMR (300 MHz,
CDCl3): d 0.00 (s, 9H), 1.57 (s, 3H), 3.06 (d, J = 14.1 Hz, 1H),
3.13 (d, J = 14.1 Hz, 1H), 6.36 (br s, 1H), 7.20 (d, J = 7.6 Hz,
1H), 7.21 (m, 1H), 7.66 (ddd, J = J = 7.6 Hz, J = 1.8 Hz, 1H),
8.49 (m, 1H). 13C NMR (75 MHz, CDCl3): d 0.2, 29.7, 48.9, 67.9,
86.7, 109.6, 121.8, 124.5, 136.7, 148.1, 158.8. IR (film) = 3323 (br,
O–H), 2167 (w, C≡C) cm−1. HRMS (ESI) calcd for C13H19NOSi
(M + Na+): 256.1128; found: 256.1121.
2-(4-Chlorophenyl)-1-pyridin-2-yl-4-(trimethylsilanyl)but-
3-yn-2-ol (8)
Analytical data for rac-8: Yield: 91%. Rf = 0.55 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 86 ◦C. 1H NMR (400 MHz,
CDCl3): d 0.03 (s, 9H), 3.16 (d, J = 14.2 Hz, 1H), 3.28 (d, J =
14.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.23 (ddd, J = 7.6, 4.9,
0.8 Hz, 1H), 7.31–7.34 (m, 2H), 7.64–7.68 (m, 3H), 8.52 (ddd,
J = 4.9, 1.9, 0.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): d −0.3,
51.1, 72.5, 90.1, 107.4, 122.1, 124.6, 127.0, 128.1, 133.2, 137.0,
142.7, 148.0, 158.2. IR (film) 3254 (br, O–H), 2169 (w, C≡C) cm−1.
HRMS (ESI) calcd for C18H20ClNOSi (M + Na+): 352.0895;
found: 352.0899. Anal. calcd for C18H20ClNOSi (329.90): C, 65.53;
H, 6.11; N, 4.25; found: C, 65.58; H, 6.27; N, 4.19.
4-Methyl-3-pyridin-2-ylmethyl-1-(trimethylsilanyl)pent-1-yn-
3-ol (12)
Analytical data for rac-12: Yield: 76%. Rf = 0.58 (cyclohexane–
tert-butyl methyl ether = 1:1). Colourless oil. 1H NMR (400 MHz,
CDCl3): d −0.08 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H), 1.00 (d, J =
6.8 Hz, 3H), 1.80 (qq, J = J = 6.8 Hz, 1H), 2.97 (s, 2H), 7.10 (d,
J = 7.7 Hz, 1H), 7.11 (m, 1H), 7.57 (ddd, J = J = 7.7 Hz, J =
1.9 Hz, 1H), 8.39 (m, 1H). 13C NMR (100 MHz, CDCl3): d 0.04,
17.3, 17.9, 37.7, 44.8, 74.8, 88.8, 107.7, 121.8, 124.7, 136.8, 148.1,
159.4. IR (film) 3318 (br, O–H), 2165 (m, C≡C) cm−1. HRMS
(ESI) calcd for C15H23NOSi (M + H+): 262.1622; found: 262.1628.
Anal. calcd for C15H23NOSi (261.44): C, 68.91; H, 8.87; N, 5.36;
found: C, 68.50; H, 8.87; N, 5.72.
Analytical data for (S)-8 (92% ee, Entry 6, Table 2): Yield: 24%.
[a]20 = +13.5, [a]20 = +14.7, [a]20 = +17.9, [a]20 = +43.9
D
578
546
436
(c 1.11, CHCl3). HPLC (Daicel Chiralcel IA column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 98 : 2, flow
rate 0.80 mL min−1, k = 230 nm): tR = 12.57 min for (S)-8, tR =
14.11 min for (R)-8.
2,4-Diphenyl-1-pyridin-2-ylbut-3-yn-2-ol (9)
Analytical data for rac-9: Yield: 88%. Rf = 0.42 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 97 ◦C. 1H NMR (300 MHz,
CDCl3): d 3.34 (d, J = 14.4 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H),
7.21–7.36 (m, 8H), 7.40–7.46 (m, 2H), 7.52 (br s, 1H), 7.70 (ddd,
J = J = 7.7 Hz, J = 1.8 Hz, 1H), 7.82–7.86 (m, 2H), 8.59 (ddd,
J = 4.9, 1.8, 0.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 51.5,
73.3, 85.5, 92.0, 122.3, 123.0, 124.7, 125.7, 127.7, 128.3, 128.3,
128.4, 131.8, 137.2, 144.7, 148.5, 158.9. IR (film) 3254 (br, O–H),
2229 (w, C≡C) cm−1. HRMS (ESI) calcd for C21H17NO (M + H+):
300.1383; found: 300.1380. Anal. calcd for C21H17NO (299.37): C,
84.25; H, 5.72; N, 4.68; found: C, 84.11; H, 5.79; N, 4.58.
2-Cyclohexyl-4-phenyl-1-pyridin-2-ylbut-3-yn-2-ol (13)
Analytical data for rac-13: Yield: 89%. Rf = 0.51 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 98–99 ◦C. 1H NMR
(400 MHz, C6D6): d 1.29 (m, 3H), 1.60 (m, 3H), 1.83 (m, 3H),
2.21 (d, J = 12.7 Hz, 1H), 2.54 (d, J = 13.0 Hz, 1H), 2.99 (d,
J = 14.1 Hz, 1H), 3.13 (d, J = 14.1 Hz, 1H), 6.52 (dd, J = 7.5,
4.9 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.87–6.90 (m, 3H), 6.99
(ddd, J = J = 7.5 Hz, J = 1.8 Hz, 1H), 7.09 (s, 1H), 7.18–7.22 (m,
2H), 8.09 (ddd, J = 4.9, 1.8, 0.8 Hz, 1H). 13C NMR (100 MHz,
C6D6): d 27.3, 28.1, 28.8, 45.8, 49.1, 74.8, 85.4, 93.7, 122.0, 124.3,
125.0, 128.3, 128.7, 132.2, 136.8, 148.8, 160.6. IR (film) = 3301
(br, O–H), 2226 (w, C≡C) cm−1. HRMS (ESI) calcd for C21H23NO
(M + H+): 306.1852; found: 306.1845. Anal. calcd for C21H23NO
(305.42): C, 82.59; H, 7.59; N, 4.59; found: C, 82.38; H, 7.68; N,
4.56.
Analytical data for (S)-9 (92% ee, Entry 7, Table 2): Yield: 25%.
[a]20 = +40.8, [a]20 = +43.2, [a]20 = +51.5, [a]20 = +116
D
578
546
436
(c 0.820, CHCl3). HPLC (Daicel Chiralcel IB column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 90 : 10, flow
rate 0.80 mL min−1, k = 230 nm): tR = 10.04 min for (R)-9, tR =
11.00 min for (S)-9.
1-(6-Methylpyridin-2-yl)-2,4-diphenylbut-3-yn-2-ol (25)
2-(4-Methoxyphenyl)-4-phenyl-1-pyridin-2-ylbut-3-yn-2-ol (10)
Analytical data for rac-25: Yield: 96%. Rf = 0.61 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 72–73 ◦C. 1H NMR
(400 MHz, CDCl3): d 2.58 (s, 3H), 3.26 (d, J = 14.3 Hz, 1H),
3.34 (d, J = 14.3 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 7.08 (d, J =
7.7 Hz, 1H), 7.22–7.25 (m, 5H), 7.30 (dd, J = J = 7.6 Hz, 1H),
7.40 (dd, J = J = 7.6 Hz, 2H), 7.55 (dd, J = J = 7.7 Hz, 1H),
7.82 (d, J = 7.6 Hz, 2H), 7.86 (br s, 1H). 13C NMR (100 MHz,
CDCl3): d 24.5, 51.4, 73.2, 85.4, 92.1, 121.6, 121.9, 123.1, 125.7,
127.7, 128.2, 128.3, 128.4, 131.8, 137.4, 144.9, 157.4, 158.2. IR
(film) 3242 (br, O–H), 2228 (w, C≡C) cm−1. HRMS (ESI) calcd
for C22H19NO (M + H+): 314.1539; found: 314.1534. Anal. calcd
Analytical data for rac-10: Yield: 92%. Rf = 0.30 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 101–102 ◦C. 1H NMR
(400 MHz, CDCl3): d 3.28 (d, J = 14.4 Hz, 1H), 3.40 (d, J =
14.4 Hz, 1H), 3.81 (s, 3H), 6.90–6.94 (m, 2H), 7.18–7.25 (m, 7H),
7.40 (br s, 1H), 7.66 (ddd, J = J = 7.7 Hz, J = 1.7 Hz, 1H),
7.70–7.74 (m, 2H), 8.55 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 51.6, 55.5, 72.9, 85.4, 92.1, 113.7, 122.2,
123.0, 124.7, 127.0, 128.2, 128.3, 131.8, 137.0, 137.2, 148.5, 159.0,
159.2. IR (film) 3254 (br, O–H), 2230 (w, C≡C) cm−1. HRMS (ESI)
calcd for C22H19NO2 (M + H+): 330.1489; found: 330.1487. Anal.
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for C22H19NO (313.40): C, 84.31; H, 6.11; N, 4.47; found: C, 84.04;
H, 6.35; N, 4.22.
4 S. Rendler and M. Oestreich, Angew. Chem., Int. Ed., 2008, 47, 248–250.
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Analytical data for (S)-25 (90% ee, Scheme 3): Yield: 25%.
[a]20D = +97.4, [a]20578 = +103.2, [a]20546 = +121.2, [a]20436 = +257.5
(c 0.740, CHCl3). HPLC (Daicel Chiralcel IB column, column
temperature 20 ◦C, solvent n-heptane–isopropanol = 90 : 10, flow
rate 0.80 mL min−1, k = 230 nm): tR = 7.83 min for (R)-25, tR =
10.61 min for (S)-25.
2,4-Diphenyl-1-quinolin-2-ylbut-3-yn-2-ol (27)
Analytical data for rac-27: Yield: 90%. Rf = 0.62 (cyclohexane–
tert-butyl methyl ether = 1 : 1). M.p. 107 ◦C. 1H NMR (400 MHz,
CDCl3): d 3.52 (d, J = 14.4 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H),
7.18–7.22 (m, 5H), 7.30–7.34 (m, 2H), 7.39–7.44 (m, 2H), 7.54 (m,
1H), 7.74 (m, 1H), 7.76 (br s, 1H), 7.81–7.88 (m, 3H), 8.12 (d,
J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 52.1, 73.2, 85.4, 92.1, 122.9, 123.0, 125.8, 126.6, 127.2,
127.8, 128.2, 128.3, 128.4, 129.0, 130.2, 131.8, 137.2, 144.8, 147.0,
159.6. IR (film) = 3232 (br, O–H), 2228 (w, C≡C) cm−1. HRMS
(ESI) calcd for C25H19NO (M + H+): 350.1539; found: 350.1542.
Anal. calcd for C25H19NO (349.43): C, 85.93; H, 5.48; N, 4.01;
found: C, 85.86; H, 5.45; N, 3.84.
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Analytical data for (S)-27 (94% ee, Scheme 3): Yield: 13%.
[a]20 = +173, [a]20 = +183, [a]20 = +216 (c 0.535, CHCl3).
D
578
546
◦
HPLC (Daicel Chiralcel IB column, column temperature 20 C,
solvent n-heptane–isopropanol = 98 : 2, flow rate 0.80 mL min−1,
k = 230 nm): tR = 20.61 min for (S)-27, tR = 23.23 min for (R)-27.
Acknowledgements
The research was supported by the Deutsche Forschungs-
gemeinschaft (Oe 249/4–1), the Fonds der Chemischen Industrie
(predoctoral fellowship to S.R., 2005–2007) and the Aventis
Foundation (Karl Winnacker fellowship to M.O., 2006–2008).
The authors thank Oliver Plefka for elaborating the resolution
of the strained silane17 and Eduard Hartmann for skilful technical
assistance in the substrate identification.
19 J. M. Goodman, A.-K. Ko¨hler and S. C. M. Alderton, Tetrahedron
Lett., 1999, 40, 8715–8718.
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Soc., 1999, 121, 9299–9306.
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22 Standard reaction conditions:7a,9 Dibal (1.0 equiv.), CH2Cl2, 0 ◦C. It
is important to avoid prolonged reaction times, as partial reduction of
the alkyne is then seen.
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References and notes
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3 E. J. Jarvo and S. J. Miller, in Comprehensive Asymmetric Catalysis-
Supplement 1, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto,
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1440 | Org. Biomol. Chem., 2008, 6, 1435–1440
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©