Chiral recognition with silicon-stereogenic silanes: Remarkable selectivity factors in the kinetic resolution of donor-functionalized alcohols

Article abstract of DOI:10.1002/anie.200703847

(Chemical Equation Presented) Slick silicon: A low-molecular-weight silane (C₁₃H₂₀Si, 204.38 g mol^-1) with silicon-centered chirality is capable of discriminating enantiomeric rhodium-substrate complexes in dehydrogenative Si-O coupling reactions with outstanding selectivity factors (see scheme, s = selectivity factor).

Full text of DOI:10.1002/anie.200703847

Angewandte
Chemie
DOI: 10.1002/anie.200703847
Kinetic Resolution
Chiral Recognition with Silicon-Stereogenic Silanes: Remarkable
Selectivity Factors in the Kinetic Resolution of Donor-Functionalized
Alcohols**
Hendrik F. T. Klare and Martin Oestreich*
Non-enzymatic kinetic resolution is an important technique
in asymmetric synthesis to access optically active materials.[1]
A useful parameter for expressing the efficiency of resolution
is the selectivity factor s, which is the ratio of the rate
constants for the reaction of a chiral catalyst or a chiral
reagent with the different enantiomers.[2] In order to at the
same time obtain high chemical yield, ideally 50% for both
the slow- andthe fast-reacting enantiomer, andperfect
enantioselectivity, selectivity factors must be extremely high
(s > 200). Such numbers are, however, far from the norm; for
example, Vedejs et al. identified an exceptional chiral phos-
phine-basedcatalyst for the nucleophilic acylation of benzylic
alcohols (s ꢀ 350).[3,4]
and Moreau showed that these species mediate dehydrogen-
[13]
ꢁ
ative Si O coupling of reactive diorganosilanes. However,
when using our sterically hindered triorganosilanes,[5] these
catalysts were largely unreactive.[14] The Wilkinson catalyst
[RhCl(Ph3P)3] showedpromising levels of conversion. Facile
[15]
variation of the liganditself andthe metal-to-ligandratio
was ensuredby employing the cationic precursor rhodium( i)
complex [Rh(cod)2]OTf. To test these rhodium–ligand com-
binations (Table 1), we chose the reaction of the privileged[16]
silane rac-1[17] with donor-functionalized alcohol rac-2, which
[6]
hadproven to be a goodsubstrate in our earlier study.
As
the process is diastereoselective by nature, the diastereomeric
ratio of silyl ether 3 correlates directly with the selectivity
factor of the relatedkinetic resolution; thus, these catalysts
were assessedwith racemic silane.
Our screening commencedwith three monoedntate
phosphine ligands (Table 1, entries 1–3). These ligands pro-
As part of our research program on silicon-stereogenic
silanes in asymmetric catalysis,[5] in 2005 we introduced a
[6]
novel reagent-controlledstrategy for the kinetic resolution
of donor-functionalized alcohols[7] by means of diastereose-
[8]
[9]
ꢁ
ꢁ
lective Cu H-catalyzed dehydrogenative Si O coupling.
In this unique stereoselective alcohol silylation,[10] asymmetry
at the silicon atom enables discrimination of enantiomeric
alcohols with promising selectivity (s ꢀ 10).[6] We then set out
to identify transition-metal–ligand combinations that would
catalyze the kinetic resolution with substantially improved
selectivity factors and, as a future prospect, that would be
capable of alcohol racemization,[11] thereby resulting in
dynamic kinetic resolution.[12] Herein, we report on an
Table 1: Ligand screening in the diastereoselective rhodium(I)-catalyzed
dehydrogenative coupling.[a]
ꢁ
intriguing rhodium-catalyzed dehydrogenative Si O cou-
pling, in which a silicon-stereogenic silane kinetically selects
one of the two enantiomeric transition-metal–substrate com-
plexes with outstanding preference (s ꢀ 900). This chiral
recognition originates from a single stereocenter in a low-
molecular-weight (204.38 gmolꢁ1) chiral reagent that is
almost a pure hydrocarbon (C13H20Si) without any further
binding sites.
Entry
L
t [h]
Conv [%][b]
d.r.[c]
70:30
80:20
85:15
82:18
>99:1
99:1
1
2
3
Ph3P
Mes3P
tBu3P
24
12
12
16
12
4
44
55
54
100
100
100
4[d]
5[d]
6[d]
IMes·HCl
IPr·HCl
In light of the above considerations, we decided to use
rhodium(I)- and ruthenium(II)-based catalysts, since Corriu
IPr·HCl/Mes3P[e]
[a] Unless otherwise noted, all reactions were conducted using [Rh-
(cod)2]OTf (5.0 mol%)and the indicated ligand (10 mol%)with a
substrate concentration of 0.1m in toluene at 508C; when using carbene
ligand precursors IMes·HCl and IPr·HCl, slightly less than twice the
equimolar amount of KOtBu (relative to the precursor)was added.
[b] Monitored by 1H NMR spectroscopy and determined by integration of
the baseline-separated resonance signals of 2 at d=5.16 ppm and 3 at
d=4.93/5.02 ppm. [c] Determined by GC analysis using an SE-54
column. [d] The generation of the catalytically active carbene complexes
displayed a marked sensitivity towards the temperature of the deproto-
nation step; maintaining the reaction mixture at room temperature for
1 h prior to substrate addition was critical to success. [e] 1:1 mixture.
IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, Mes=2,4,6-tri-
methylphenyl, IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
[*] H. F. T. Klare, Prof. Dr. M. Oestreich
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
Fax: (+49)251-83-36501
E-mail: martin.oestreich@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/research/
oestreich/oe_welcome.html
[**] The research was supported by the Deutsche Forschungsgemein-
schaft (Oe 249/4-1). M.O. is indebted to the Aventis Foundation
(Karl-Winnacker-Stipendium, 2006–2008). The authors thank Bar-
bara Hildmann for skillful technical assistance.
Angew. Chem. Int. Ed. 2007, 46, 9335 –9338
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
duced unreactive (poor conversion) and unselective (poor
necessary vacant site for silane coordination, which stems
from a weak interaction.
diastereomeric ratio) catalysts. Yet these parameters
improvedwith increasing steric bulk and s-donor strength
of the phosphine (tBu3P > Mes3P > Ph3P). Therefore, we
turnedto N-heterocyclic carbene ligansd (preparedfrom
IMes·HCl andIPr·HCl), which generatedsufficiently reactive
catalysts (Table 1, entries 4 and5). The latter system afforded
3 with perfect stereocontrol (d.r. > 99:1) as determined by GC
analysis. When one of the carbene ligands was replaced by a
phosphine, the reaction rate increased, and very high levels of
diastereoselectivity were maintained (Table 1, entry 6). We
believe that the carbene ligandremains at the rhodium center,
while the phosphine dissociates rapidly, thereby providing the
With this relatively unpretentious catalyst system, we
startedto perform kinetic resolution of different nitrogen-
donor-containing alcohols rac-2 and rac-4 to rac-10, which
have the requiredarray of functional groups, using highly
enantioenrichedsilane ( SiR)-1[17a] (Table 2). Importantly, the
data summarized in Table 2 also includes the diastereomeric
ratios of the silyl ethers obtainedin the racemic experiment
(reaction with rac-1, column 7), because in this case, diaster-
eoselection is independent of the degree of conversion.
Accordingly, the stereoselectivity factor s is the critical
parameter in the enantiomeric case (reaction with (SiR)-1,
Table 2: Variation of the donor in the kinetic resolution of donor-functionalized secondary alcohols.[a]
Entry
Racemic alcohol
Donor
Silyl ether
Yield [%][b]
Recovered alcohol
Conv [%][f]
s[g,h]
d.r.[c]
96:4
d.r.[c,d]
Yield [%][b]
ee [%][e]
1[i]
2
rac-2
rac-4
rac-5
rac-6
rac-7
rac-8
rac-9
(SiS,S)-3
–
>99:1
(R)-2
(R)-4
(R)-5
(R)-6
(R)-7
(R)-8
(R)-9
–
>99
98
–
50.8[k]
52
900
[j]
[j]
(SiS,S)-11
(SiS,S)-12
(SiS,S)-13
(SiS,S)-14
(SiS,S)-15
(SiS,S)-16
40
–
94:6
–
98:2
96:4
97:3
96:4
98:2
98:2
38
–
>50
–
3
–
4
46
47
50
46
94:6
95:5
94:6
97:3
39
42
45
41
96
90
93
90
52
>50
>50
>50
>50
5
50
6
51
7
49
8
rac-10
(SiS,S)-17
48
95:5
97:3
(R)-10
39
92
51
>50
[a] Unless otherwise noted, all reactions were conducted using [Rh(cod)2]OTf (5.0 mol%), IPr·HCl (10 mol%), and KOtBu (20 mol%)with a substrate
concentration of 0.1m in toluene at 508C; Do=donor. [b] Yield of analytically pure product isolated by flash chromatography on silica gel.
[c] Determined by 1H NMR spectroscopy prior to purification by integration of the baseline-separated resonance signals of the diastereomers. [d] The
diastereomeric ratio in the racemic series is not biased by conversion. [e] Determined by HPLC analysis using Daicel Chiralcel columns providing
baseline separation of enantiomers. [f] Monitored by 1H NMR spectroscopy and determined by integration of the baseline-separated resonance
signals. [g] The selectivity factor was calculated by the following equation:[2,18] s=ln[(1-C)(1ꢁee)]/ln[(1ꢁC)(1+ee)] where ee=ee/100 and C=
conversion/100; for almost all substrates, s is almost certainly larger than 50. [h] Uncorrected selectivity factor.[20] [i] Final data point in Figure 1. [j] A
routine kinetic resolution with yields of isolated product is provided in Table 3, entry 1. [k] Determined by GC analysis (SE-54 column)using decane a s
an internal standard.
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Angewandte
Chemie
column 12). However, the accuracy of the analytical methods
usedis not sufficient for its exact calculation
Consequently, we carefully determined s in a single example
(rac-2!(R)-2, Table 2, entry 1) by the linear regression
depicted in Figure 1; for this approach, conversion was
The success with the 2-pyridyl donor ligand prompted us
if s > 50.[1,3]
to employ relatedheteroarenes rac-4 to rac-10[22] (Table 2).
Heteroarenes rac-4 to rac-7, containing two nitrogen donors,
produced invariably high diastereomeric ratios (d.r. = 96:4) in
the racemic andexcellent selectivity factors ( s > 50) in the
enantioselective experiment (Table 2, entries 2–5); interest-
ingly, the 4-pyrimidyl donor, unlike its 2-pyrimidyl counter-
part, failed to undergo the dehydrogenative coupling with
sufficient conversion (Table 2, entries 3 and 5). An additional
substituent in the proximity of the donor was tolerated; rac-8,
which has a synthetically useful 6-methyl-2-pyridyl unit,[23]
reactedwith excellent efficiency (Table 2, entry 6). Similarly,
1-isoquinolinyl- and2-quinolinyl-functionalizedalcohols rac-
9 and rac-10, respectively, were resolvedwith considerable
selectivity (Table 2, entries 7 and8).
[2,18]
After variation of the nitrogen donor, the steric and
electronic properties of the substituent R attachedto the
hydroxylated carbon atom (Table 3) were systematically
varied. Naphthyl-substituted alcohols rac-18 and rac-19
comparedwell with model system rac-2 (Table 3, entries 1–
3). Electron-rich anisyl-substitutedsubstrates rac-20 to rac-22
reactedas expected(Table 3, entries 4–6). Conversely, a nitro
group at the arene retarded the reaction, thereby preventing
sufficient conversion for a resolution; however, the level of
Figure 1. Determination of the selectivity factor by linear regression
based on recovered (R)-2 (C=conv/100, ee=ee/100, s=900).
ꢁ
diastereoselection in the Si O coupling of rac-23 was still high
(Table 3, entry 7). Alcohol rac-24 with an ortho-chloro
substituent was prone to racemization at prolongedreaction
times (Table 3, entry 8). Kinetic resolution of the arene-
monitored by GC analysis using an internal standard, and
enantiomeric excess was measuredby HPLC analysis of
recovered, slow-reacting (R)-2. The slope (= selectivity
factor) of the linear regression is approximately 900.[19] In
order to corroborate this exceptional result, we also deter-
minedthe enantiomeric excess of the fast-reacting enantio-
mer (S)-2 after stereospecific reductive cleavage[6,17] of
diastereoenriched (SiS,S)-3 (d.r. ꢀ 96:4 at 51% conversion).
Treatment of (SiS,S)-3 with diisobutylaluminum hydride
quantitatively yielded (S)-2 in 93% ee along with recovered
(SiR)-1 (> 99% ee).[1a,2]
substitutedalcohols was accomplishedwith
s > 50. For
comparison, we subjectedmethyl-substituted rac-25 to the
standard procedure. Although this resolution was less effi-
cient, a goodenantiomeric excess of 90% at a conversion of
54% (s = 20) was achieved(Table 3, entry 9).
In summary, we developed a rhodium-catalyzed dehydro-
ꢁ
genative Si O coupling using a chiral silane. This reaction
proceeds with remarkable levels of diastereoselectivity, and
its application to the kinetic resolution of nitrogen-donor-
Table 3: Variation of the substituent in the kinetic resolution of donor-functionalized secondary alcohols.[a]
Entry
Racemic alcohol
R
Silyl ether
Yield [%][b]
Recovered alcohol
Conv [%][f]
s[g]
d.r.[c]
d.r.[c,d]
Yield [%][b]
ee [%][e]
1
2
3
4
5
6
7
8
9
rac-2
Ph
(SiS,S)-3
50
48
53
52
50
52
–
95:5
96:4
91:9
93:7
93:7
91:9
–
99:1
96:4
97:3
97:3
98:2
98:2
98:2
96:4
90:10
(R)-2
45
45
41
41
42
44
–
>99
93
>99
>99
98
>99
–
–
52
50
54
54
53
54
–
>50
>50
>50
>50
>50
>50
–
rac-18
rac-19
rac-20
rac-21
rac-22
rac-23
rac-24
rac-25
1-naphtyl
2-napthyl
2-anisyl
3-anisyl
4-anisyl
4-nitrophenyl
2-chlorophenyl
Me
(SiS,S)-26
(SiS,S)-27
(SiS,S)-28
(SiS,S)-29
(SiS,S)-30
(SiS,S)-31
(SiS,S)-32
(SiS,R)-33
(R)-18
(R)-19
(R)-20
(R)-21
(R)-22
(R)-23
(R)-24
(S)-25
41
51
92:8
85:15
34
41
48
54
–
20
90
For footnotes [a]–[g], see Table 2.
Angew. Chem. Int. Ed. 2007, 46, 9335 –9338
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Communications
[9] a) C. Lorenz, U. Schubert, Chem. Ber. 1995, 128, 1267 – 1269;
b) D. R. Schmidt, S. J. OꢀMalley, J. L. Leighton, J. Am. Chem.
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[10] a) T. Isobe, K. Fukuda, Y. Araki, T. Ishikawa, Chem. Commun.
2001, 243 – 244; b) Y. Zhao, J. Rodrigo, A. H. Hoveyda, M. L.
Snapper, Nature 2006, 443, 67 – 70.
functionalizedalcohols producedextremely high selectivity
factors (s = 900, s > 50). In contrast to our previously reported
ꢁ
Cu H catalysis, this process might also enable racemization
of the slow-reacting alcohol[11] prior to Si O coupling.
ꢁ
Development of a relateddynamic kinetic resolution on this
basis is currently underway.
[11] J. S. M. Samec, J.-E. Bäckvall, P. G. Andersson, P. Brandt, Chem.
Soc. Rev. 2006, 35, 237 – 248.
Received: August 21, 2007
Revised: September 24, 2007
Publishedonline: November 7, 2007
[12] a) O. Pamies, J.-E. Bäckvall, Chem. Rev. 2003, 103, 3247 – 3261;
b) R. Stürmer, Angew. Chem. 1997, 109, 1221 – 1222; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1173 – 1174.
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Organomet. Chem. 1976, 114, 135 – 144; d) R. J. P. Corriu,
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[14] H. F. T. Klare, Diploma Thesis, Westfälische Wilhelms-Univer-
sität Münster (Germany), 2007.
Keywords: asymmetric catalysis · dehydrogenation ·
kinetic resolution · rhodium · silicon
.
[1] a) For an excellent review, see: E. Vedejs, M. Jure, Angew.
Chem. 2005, 117, 4040 – 4069; Angew. Chem. Int. Ed. 2005, 44,
3974 – 4001; b) For a brief summary of kinetic resolutions of
alcohols, see: P. Somfai, Angew. Chem. 1997, 109, 2849 – 2851;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2731 – 2733.
[2] H. B. Kagan, J. C. Fiaudin Topics in Stereochemistry, Vol. 18
(Eds.: E. L. Eliel, S. H. Wilen), Wiley, New York, 1988, pp. 249 –
330.
[3] E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 2003, 125, 4166 – 4173.
[4] Extremely high values were reportedby Matsumura et al. for the
catalyst-controlledcopper(II)-catalyzedkinetic resolution of
1,2-diols (s > 645);[7] these were, however, not validated by
rigorous determination of enantiomeric excess of unreacted
starting material andconversion: Y. Matsumura, T. Maki, S.
Murakami, O. Onomura, J. Am. Chem. Soc. 2003, 125, 2052 –
2053.
[15] Rhodium-to-ligand ratios other than 1:2 (1:1, 1:3, and 1:4)
completely eliminatedcatalytic turnover. [14]
[16] a) M. Oestreich, Chem. Eur. J. 2006, 12, 30 – 37; b) S. Rendler, M.
Oestreich, Beilstein J. Org. Chem. 2007, 3, 9.
[17] a) S. Rendler, G. Auer, M. Keller, M. Oestreich, Adv. Synth.
Catal. 2006, 348, 1171 – 1182; b) M. Oestreich, G. Auer, M.
Keller, Eur. J. Org. Chem. 2005, 184 – 195; c) M. Oestreich, U. K.
Schmid, G. Auer, M. Keller, Synthesis 2003, 2725 – 2739.
[18] J. M. Goodman, A.-K. Köhler, S. C. M. Alderton, Tetrahedron
Lett. 1999, 40, 8715 – 8718.
[19] As we are using an enantioimpure reagent (less than 100% ee) in
our kinetic resolution,[20,21] s shouldbe correctedusing the
mathematical description introduced by Ismagilov.[20] We
decided against this option for the resolution of rac-2
(99.7% ee for (SiR)-1) because of the high numerical value of s.
[20] R. F. Ismagilov, J. Org. Chem. 1998, 63, 3772 – 3774.
[21] T. O. Luukas, C. Girard, D. R. Fenwick, H. B. Kagan, J. Am.
Chem. Soc. 1999, 121, 9299 – 9306.
[5] M. Oestreich, Synlett 2007, 1629 – 1643.
[6] S. Rendler, G. Auer, M. Oestreich, Angew. Chem. 2005, 117,
7793 – 7797; Angew. Chem. Int. Ed. 2005, 44, 7620 – 7624.
[7] For the kinetic resolution of pyridyl alcohols (s = 125), see: C.
Mazet, S. Roseblade, V. Köhler, A. Pfaltz, Org. Lett. 2006, 8,
1879 – 1882.
ꢁ
[22] Variation of the donor was also investigated in our Cu H-
ꢁ
catalyzedSi O coupling: O. Plefka, Diploma Thesis, Albert-
Ludwigs-Universität Freiburg (Germany), 2006.
[23] This unit serves as a precursor for 1,5-dicarbonyl compounds
(“pyridine route”): S. Danishefsky, A. Zimmer, J. Org. Chem.
1976, 41, 4059 – 4064.
[8] S. Rendler, M. Oestreich, Angew. Chem. 2007, 119, 504 – 510;
Angew. Chem. Int. Ed. 2007, 46, 498 – 504.
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