Kinetic resolution of chiral secondary alcohols by dehydrogenative coupling with recyclable silicon-stereogenic silanes

Article abstract of DOI:10.1002/anie.200502631

(Chemical Equation Presented) Fishing for enantiomers: A novel kinetic resolution of racemic alcohols capable of two-point binding makes use of silanes with silicon-centered chirality. This strategy is based on a diastereoselective dehydrogenative silicon-oxygen coupling under copper catalysis (see scheme). The resolving silane is completely recovered without erosion of stereochemical information at silicon.

Full text of DOI:10.1002/anie.200502631

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Communications
Kinetic Resolution
antipode (R)-B would remain in enantioenriched form.
Moreover, stereospecific reductive cleavage of the silicon–
oxygen bond in C would allow complete recovery of the
resolving reagent A. Importantly, both silicon–oxygen bond
formation and cleavage would have to proceed without any
erosion of stereochemical information at the silicon atom.
Herein, we describe this novel concept of utilizing silicon-
stereogenic silanes A in a kinetic resolution reaction.
DOI: 10.1002/anie.200502631
Kinetic Resolution of Chiral Secondary Alcohols
by Dehydrogenative Coupling with Recyclable
Silicon-Stereogenic Silanes**
We initially sought suitable reaction conditions for silane
alcoholysis with a particular emphasis on the stereochemical
course at the silicon atom. Several heterogeneous and
homogeneous catalysts are available,[5,6] and we selected the
copper(i)-catalyzed dehydrogenative coupling introduced by
Lorenz and Schubert.[7] Oxygen-sensitive [{(Ph3P)CuH}6][8] is
effectively replaced by a robust precatalyst (CuCl, Ph3P,
NaOtBu) reported by Buchwald and co-workers[9] which also
enables simple variation of the phosphine ligand.
Sebastian Rendler, Gertrud Auer, and Martin Oestreich*
Non-enzymatic kinetic resolution[1] of racemic mixtures is a
competitive strategy in asymmetric synthesis for the prepa-
ration of chiral building blocks.[2,3] The general approach
relies on either a chiral reagent to undergo or a chiral catalyst
to promote a stereoselective reaction of one enantiomer over
the other. Within the theme of the former scenario, we
devised a novel concept based on an unprecedented diaster-
eoselective transition-metal-catalyzed dehydrogenative sili-
con–oxygen coupling of silicon-stereogenic silanes A and
racemic alcohols rac-B (Scheme 1).[4]
We then screened this catalyst in the methanolysis of
several asymmetrically substituted silanes[10] 1–3 (Figure 1)
followed by stereoretentive reduction with aluminum
We envisioned that if a preferential reaction of Awith (S)-
B to produce diastereoenriched C were viable, the optical
Figure 1. Silanes with silicon-centered chirality.
hydrides.[11] To our delight, 1–3 were invariably recovered
with complete retention of configuration, thereby verifying
the stereospecificity of the copper(i)-catalyzed dehydrogen-
ative silicon–oxygen coupling at the asymmetrically substi-
tuted silicon atom.[12] These experiments secured the pivotal
preservation of the stereochemical integrity at silicon
throughout this two-step process.[13]
We then addressed the stereoselectivity of the dehydro-
genative silicon–oxygen coupling of racemic alcohols with
privileged silane (SiR)-1.[14] A selected experiment (rac-4!
(SiS,S)-5, Scheme 2) showed that unfunctionalized secondary
alcohols are essentially ineffective (d.r. ꢀ 60:40). These dis-
couraging observations led us to consider the introduction of
a pendant donor (Do) in the substrate (Do = CH in 4, Do = N
in 6), which provides a temporary residence site for the
copper catalyst. We reasoned that alcohols capable of two-
point binding would create more rigidity around the copper
center, which in turn could be beneficial to diastereoselectiv-
ity. Consistent with our hypothesis, we were pleased to find
that dehydrogenative coupling of rac-6 and (SiR)-1 proceeded
with substantially improved diastereoselectivity and
enhanced reaction rate (rac-6!(SiS,S)-7, Scheme 2).
Scheme 1. Kinetic resolution with recyclable silicon-stereogenic silanes
(R1 ¼R2 ¼R3, RL =large R, and RS =small Rgroups).
[*] Dipl.-Chem. S. Rendler, Dipl.-Chem. G. Auer, Dr. M. Oestreich
Institut für Organische Chemie und Biochemie
Albert-Ludwigs-Universität
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
Fax: (+49)761-203-6100
E-mail: martin.oestreich@orgmail.chemie.uni-freiburg.de
[**] Financial support was provided by the Deutsche Forschungsge-
meinschaft (Emmy Noether Progamme, 2001–2006), the Fonds der
Chemischen Industrie (predoctoral fellowship to S.R., 2005–2007),
and the Dr. Otto Röhm Gedächtnisstiftung. The authors thank Ilona
Hauser for skillful technical assistance and Gerd Fehrenbach for
HPLC analyses. M.O. is indebted to Professor Reinhard Brückner for
his continuous encouragement. Generous donation of Buchwald
biaryl phosphine ligands by Lanxess AG (Germany) is gratefully
acknowledged.
The ideal phosphine ligand for this transformation, tri(3,5-
xylyl)phosphane (L1 f), was identified in an extensive screen-
ing of mono- and bidentate phosphine and N-heterocyclic
carbene ligands (L1, L2, and L3, Table 1). We aimed to
elucidate the influence of the ligand on the reaction rate and
diastereoselectivity of the dehydrogenative coupling of rac-6
7620
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7620 –7624

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Angewandte
Chemie
point binding. The exact mecha-
nism of the actual silicon–oxygen
bond formation is still not com-
pletely understood, but is likely
to involve—at least in a transi-
tion state—a pentacoordinated
silicon of unknown configura-
tion. Remarkably, a conceivable
pseudorotation[17] and, hence,
racemization are not observed,
which indicates a concerted s-
bond metathesis.[10c]
Scheme 2. Control of diastereoselectivity: Beneficial two-point binding. L1 f=tri(3,5-xylyl)phosphane.
We conducted our investiga-
tions with rationally yet empiri-
and (SiR)-1.[15] A ligand/copper(i) ratio of 2:1 is usually needed
to stabilize the catalyst. We began with triphenylphosphane
(L1a), which gave (SiS,S)-7 under mild conditions with good
diastereoselectivity (Table 1, entry 1). The reactivity
decreased significantly in the presence of electron-poor
phosphines L1b–d,[4a] yet the diastereoselectivity remained
almost unaffected (Table 1, entries 2–4). Steric hindrance was
not tolerated, and 2-tolyl-substituted phosphine L1e failed to
stabilize the catalyst (Table 1, entry 5). Conversely, 3,5-xylyl-
substituted phosphine L1 f combined high reactivity with
excellent diastereoselectivity at complete conversion
(Table 1, entry 6). Electron-rich phosphines L1g and L1h
(Table 1, entries 7 and 8), N-hetereocyclic carbene ligands[16]
L2a and L2b (Table 1, entries 9 and 10), and Buchwald biaryl
phosphines (not shown) were less effective. Interestingly,
bidentate phospines L3a–d generated unreactive catalysts
and led merely to moderate levels of diastereoselectivity
(Table 1, entries 11–14).
cally designed (SiR)-1.[14] A comparison with less sterically
encumbered cyclic or even acyclic silanes (SiR)-2 and (SiR)-3
impressively demonstrated once again the importance of
steric demand and of three truly different substituents at the
silicon atom (Scheme 4).[10c] Whereas less-hindered silanes
were expectedly more reactive, diastereoselectivity collapsed
in the case of cyclic (SiR)-2 (d.r. = 66:34) and was hardly
observed with (SiR)-3 (d.r. = 57:43).
These findings can be roughly rationalized by the model
outlined in Scheme 3. In the rate-determining step, one of the
ligands L at the copper(i) center is replaced by the weakly
Scheme 4. Probing the steric demand and substitution pattern at the
silicon atom.
This preliminary insight set the stage for an investigation
of the kinetic resolution itself. As a starting point, we resolved
our standard substrate rac-6 by using optically enriched (SiR)-
1 (96% ee). Both silyl ether (SiS,S)-7 and alcohol (R)-6[18] were
isolated in quantitative yields, the latter with an encouraging
84% ee at 56% conversion (Table 2, entry 1). Importantly,
the diastereomeric ratio of (SiS,S)-7 decreases with increasing
conversion (d.r. = 92:8 at 50% conversion versus d.r. = 86:14
at 56% conversion). The stereoselectivity factor s[1] can only
be estimated at larger than 10,[19] as this kinetic resolution
involves an enantiomerically impure resolving reagent.[20]
Indeed, we were able to verify experimentally this interesting
Scheme 3. Model for the postulated rate-determining step.
coordinating silane. This requires ligands with distinctly tuned
s-donor and p-acceptor strength as well as steric demand at
electron-rich copper(i). In the case of monodentate ligands, a
ligand must dissociate to generate a vacant coordination site
(D!E). In the case of bidentate ligands, one of the chelates
must open in an energetically clearly unfavorable step: 1) F!
G, leaving the N,O-chelate intact, or 2) F!H, without two-
Angew. Chem. Int. Ed. 2005, 44, 7620 –7624
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7621

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Communications
Table 1: Identification of effective ligands for the conversion 6!7.[a]
Entry
Ligand L
R
L/CuCl
T [8C]
t [h]
d.r.[b]
Conv. [%][c]
L1
1
2
3
L1a
2:1
2:1
2:1
20
50
70
48
48
60
90:10
89:11
83:17
42
37
38
L1b
L1c
4
5
6
L1d
L1e
L1 f
2:1
2:1
2:1
70
20
20
60
–
86:14
–
34[d]
[e]
–
20
92:8
50
7
8
L1g
L1h
1:1[f]
2:1
20
50
24
6
81:19
75:25
33
21[e]
L2
R
9[g]
L2a
1:1
1:1
85
60
2
2
55:45
76:24
10
40
10[g]
L2b
L3[h]
L3a
L3b
L3c
L3d
n
1
2
3
4
11
12
13
14
(dppm)
1:1
1:1
1:1
1:1
45
45
45
45
48
48
48
48
82:18
87:13
80:20
79:21
32
20
20
18
(dppe)
(dppp)
(dppb)
[a] Unless otherwise noted, all reactions were conducted with CuCl (5.0 mol%), L1 (10 mol%) or L2/L3 (5.0 mol%), NaOtBu (5.0 mol%) with a
substrate concentration of 0.1m in toluene. [b] Determined from the 1H NMRspectra of the crude reaction mixtures by integration of the baseline-
separated resonance signals of diastereomeric (SiS,S)-7 at d=4.93 ppm and (SiS,R)-7 at d=5.02 ppm. [c] Monitored by 1H NMRspectroscopic
analysis and determined by integration of the baseline separated resonance signals of 6 at d=5.16 ppm and 7 at d=4.93/5.02 ppm. [d] Extremely
slow conversion. [e] Unstable catalyst. [f] Sterically demanding L1g allowed an equimolar ratio of ligand and CuCl. [g] Substoichiometric amounts of
NaOtBu (30 mol%) were required. [h] dppm=1,1-bis(diphenylphosphanyl)methane, dppe=1,2-bis(diphenylphosphanyl)ethane, dppp=1,3-bis(di-
phenylphosphanyl)propane, dppb=1,4-bis(diphenylphosphanyl)butane.
example of mutual kinetic resolution.[1] For this purpose, we
resolved rac-6 with (SiR)-1 (32% ee). The optical purity of
(R)-6 (25% ee) as well as of (SiR)-1 (48% ee) increased as the
reaction proceeded until 50% conversion was reached.[1,20]
An investigation of the substrate scope demonstrated
some generality for the class of 2-pyridyl-substituted secon-
dary alcohols (Table 2, entries 2–7). Replacement of a phenyl
group (rac-6) by 1-naphthyl (rac-10) only had a marginal
7622 www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7620 –7624

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Angewandte
Chemie
Table 2: Copper-catalyzed dehydrogenative kinetic resolution.[a]
Entry
Alcohol
rac-6
RSilane (
SiR)-1
Silyl ether
Yield [%][d]
Conv. [%][f]
Alcohol
ee [%][b]
Product[c]
d.r.[e]
Product[c]
Yield [%][d]
ee [%][g] ([a]D)[h]
84 (+)
1
2
96
(SiS,S)-7
99
97
86:14
56
58
(R)-6
99
99
rac-10
93
(SiS,S)-16
84:16
(R)-10
80 (+)
3
4
rac-11
rac-12
95
93
(SiS,S)-17
(SiS,S)-18
92
99
88:12
87:13
50
57
(R)-11
(R)-12
99
99
70 (+)
74 (ꢁ)
5[i]
rac-13
93
(SiS,S)-19
99[i]
74:26
64[j]
(R)-13
84[i]
89 (ꢁ)
6
rac-14
rac-15
93
94
(SiS,R)-20
(SiS,S)-21
98
87
76:24
94:6[l]
58
46
(S)-14
(R)-15
98
99
73 (+)
7[k]
68 (ꢁ)[l]
[a] Unless otherwise noted, all reactions were conducted with CuCl (5.0 mol%), L1 f (10 mol%), NaOtBu (5.0 mol%) with a substrate concentration
of 0.1m in toluene at 258C. [b] HPLC analysis using a Daicel Chiralcel OJ-Rcolumn (EtOH/H O 80:20 at 208C) provided baseline separation of
2
enantiomers. [c] Absolute configurations of (SiR)-1[10c] and (R)-6[18] and, therefore, 7 are known. The absolute configurations of enantioenriched
alcohols 10–15 as well as silyl ethers 16–21 were assigned by analogy. [d] Yield of analytically pure product isolated by flash chromatography on silica
gel. [e] Determined from the 1H NMRspectra of the crude reaction mixtures by integration of the baseline-separated resonance signals of the
diastereomers. [f] Monitored by 1H NMRanalysis and determined by integration of the baseline-separated resonance signals of the alcohol and silyl
ether. [g] HPLC analysis using a Daicel Chiralcel OD-H column (n-heptane/iPrOH 90:10 for 6, 10, 12, and 13 and 98:2 for 11 at 208C) or Daicel
Chiralcel AD-H column (n-heptane/iPrOH=98:2 for 14 and 15 at 208C) provided baseline separation of enantiomers. [h] c=0.22–0.55 in CHCl3 at
208C. [i] Reaction accompanied by partial Z-selective alkyne reduction: (SiS,S)-19 contaminated with 7% Z alkene and (R)-13 contaminated with 21%
Z alkene in 57% ee. [j] (SiR)-1: 0.65 equiv. [k] The reaction was performed with CuCl (10 mol%), L1 f (20 mol%), NaOtBu (20 mol%), and (SiR)-1
(1.2 equiv) at 1108C. [l] High diastereomeric ratio at conversion below 50% and, therefore, moderate enantiomeric excess.
effect (Table 2, entry 2), whereas the efficiency decreased
with less sterically demanding vinyl (rac-11) and cinnamyl
groups (rac-12) (Table 2, entries 3and 4). For alkynyl
substitution (rac-13), we probed the efficiency at higher
conversion and obtained good enantiomeric purity; how-
ever, this reaction was accompanied by partial reduction of
the triple bond (Table 2, entry 5). When methyl derivative
rac-14 was employed, the kinetic resolution was least
efficient (Table 2, entry 6). Dehydrogenative coupling of
branched, tBu-substituted alcohol rac-15 was highly diaster-
eoselective, but conversion did not proceed beyond 50%,
even at elevated temperatures (Table 2, entry 7).
Scheme 5. Recycling of the resolving reagent. DIBAL-H=diisobutylaluminum
hydride.
Finally, our concept would only come full circle with
complete recovery of the resolving reagent without race-
mization at the silicon atom. Reductive cleavage of the
silicon–oxygen linkage in (SiS,S)-7 in quantitative yield
liberated (SiR)-1 with an unchanged 96% ee (Scheme 5).
In conclusion, we have developed a novel kinetic reso-
lution based on a diastereoselective dehydrogenative cou-
pling of racemic alcohols and asymmetrically substituted
silanes. Two-point binding of the substrates emerged as the
pivotal feature for stereoselectivity. The efficiency of this
strategy was exemplified by resolving a family of 2-pyridyl-
substituted alcohols. Apart from the recyclability of the
silicon-stereogenic silane, this two-step reaction sequence
Angew. Chem. Int. Ed. 2005, 44, 7620 –7624
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7623