Optically pure bulky (hetero)arylalkyl carbinols via kinetic resolution

Article abstract of DOI:10.1039/c1cc14591f

Planar chiral nucleophilic catalyst Fc-PIP was employed in the kinetic resolution of bulky (hetero)arylalkyl carbinols delivering unreacted alcohols with extremely high enantiomeric excess (>99.0% ees) in ideal conversions ranging from 50.4-56.7%.

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COMMUNICATION
Optically pure bulky (hetero)arylalkyl carbinols via kinetic resolutionw
Bin Hu,a Meng Meng,a John S. Fossey,ab Weimin Mo,c Xinquan Huc and Wei-Ping Deng*a
Received 27th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1cc14591f
Planar chiral nucleophilic catalyst Fc-PIP was employed in the
kinetic resolution of bulky (hetero)arylalkyl carbinols delivering
unreacted alcohols with extremely high enantiomeric excess
(499.0% ees) in ideal conversions ranging from 50.4–56.7%.
Chiral bulky (hetero)arylalkyl carbinols are versatile synthetic
building blocks that can be found in biologically active units,1
in the synthesis of natural products and their analogs,2 as chiral
auxiliaries3 and as chiral ligands.4 Bulky alcohol 1 can be
converted into useful chiral bipyridine ligand 2 (Fig. 1),4a,f which
has been employed in catalytic asymmetric transformations,4a–f,5
including the asymmetric ring-opening of meso-epoxides,5d,e
asymmetric Michael additions.5c,f 9-Anthryl-tert-butyl carbinol 3
has been used as a chiral auxiliary3 and has been incorporated
into a dihydroxylation catalyst by Corey and Zhang.4g
Fig. 2 Representative nonenzymatic nucleophilic catalysts.
The synthesis of such bulky (hetero)arylalkyl carbinols
often relies upon oxidative kinetic resolution6 or asymmetric
ketones either by hydrogenation or hydrogen transfer, affording
the corresponding chiral carbinols in moderate ee.8 As such
the development of new methods capable of delivering hetero-
arylalkyl carbinols in high ee continues to be an important
challenge in synthetic chemistry.
reduction protocols.4a,d,g Noyori and coworkers reported that
asymmetric hydrogenation of tert-alkyl ketones using homo-
geneous chiral RuCl2[(S)-tolbinap](pica) complexes delivered
bulky arylalkyl carbinols in excellent yields and enantio-
selectivities (up to 98% ee),7a although heteroaryl substrates
were not quite so well tolerated, presumably due to the
deactivation of catalyst by potential coordination of hetero-
atoms to the ruthenium catalyst.7b Subsequently ruthenium
complexes bearing chiral tridenate ligands were developed by
Clarke et al. for the enantioselective reduction of bulky
Catalytic kinetic resolution (KR) of secondary alcohols
through acyl transfer using nonenzymatic nucleophilic catalysts
is one of the effective approaches for the generation of chiral
alcohols.9–14 Over the past two decades, significant progress
has been made in the development of new families of chiral
nonenzymatic acylation catalysts, including chiral phosphines,10
2,3-dihydroimidazo derivatives11 and 4-(dimethylamino) pyridine
(DMAP) equivalents with central,12 axial,13 helical14 and planar
chirality (Fig. 2).15 Whilst such catalysts were effective for the
kinetic resolution of a range of secondary alcohols, it is notable
that catalysts for the acylative KR of heteroarylalkyl carbinols
have, to the best of our knowledge, not yet been reported.
Our own planar chiral ferrocene derivative (Fc-PIP) for
nucleophilic catalysis (Fig. 2),16,17 that combines two inspirational
catalyst systems of Fu et al.15 and Birman et al.11 into a hybrid
chiral nucleophilic catalyst, showed extraordinary selectivity
factors S of up to 1892 in the kinetic resolution of phenyl
tert-butyl carbinol.16 In light of our good results we turned our
attention to the kinetic resolution of bulky secondary alcohols
including heteroarylalkyl carbinols. Therefore, a series of
chiral racemic bulky (hetero)arylalkyl carbinols 1, 3–15 were
prepared and subjected to our developed catalytic KR system
(Scheme 1).
Fig. 1 Bulky (hetero)arylalkyl carbinols.
a Shanghai Key Laboratory of Functional Materials Chemistry,
East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, China. E-mail: weiping_deng@ecust.edu.cn
b School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, B15 2TT, UK. E-mail: j.s.fossey@bham.ac.uk
c College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou 310014, China.
E-mail: mowm@zjut.edu.cn
w Electronic supplementary information (ESI) available: CIF file for
(R,RP)-Fc-PIP and general experimental procedure, HPLC data ana-
lysis for all kinetic resolution of rac-alcohols. CCDC 837133. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc14591f
In our previous study, phenyl tert-butyl carbinol 4 underwent
catalytic KR using 2 mol% of Fc-PIP in toluene at 0 1C to
c
10632 Chem. Commun., 2011, 47, 10632–10634
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(499.0%) and in good to excellent yields (43–48%) (Table 1,
entries 7–17). 9-Anthryl-tert-butyl carbinol 3 was resolved
very slow with only a moderate selectivity factor S = 37
(Table 1, entry 9, 499.0% ee, 4 days). Synthetically useful
bulky alcohols 9–1118 underwent catalytic KR reactions with
selectivity factors S ranging from 68 to 86 delivering the
corresponding unreacted alcohols in 499.0% ees with recovery
445% (Table 1, entries 10–12).
Heteroaryl-tert-butyl carbinols (1, 12–15), which have not
yet been studied in nonenzymatic acyl transfer catalysis, worked
well in the catalytic KR reaction with Fc-PIP and allowed
isolation of the corresponding unreacted alcohols in 499.0% ees
(Table 1, entries 13–17, S value ranging from 37–74). Among
them, 6-(2-bromopyridinyl)-tert-butyl alcohol 1 and TBS pro-
tected 3-indolyl-tert-butyl 14 were relatively inert, and either
15 mol% of catalyst loading or increased temperatures (room
temperature) were necessary to achieve acceptable resolution
results (Table 1, entries 15–16). Interestingly, relatively electron-
deficient 4-(2-chloro-pyridinyl)-tert-butyl alcohol 15 was much
more reactive than 1 with a higher S value (74 versus 39). By
contrast catalytic KR of 15 using Birman’s Cl-PIQ catalyst
gave a selectivity factor S = 13 after 48 h (Table 1, entry 18).
To further demonstrate the utility of this process, a reasonable
scale (800 mg) catalytic KR of bulky alcohol 15 was per-
formed,19 using 3 mol% of Fc-PIP as a catalyst. This reaction
Scheme 1 Kinetic resolution of bulky arylalkyl carbinols using Fc-PIP.
give the corresponding ester and unreacted alcohol in 499.0% ee
and 81.1% ee, respectively, with a selectivity factor S = 534 at
45% conversion, notably the low reactivity of these substrates
meant 50% conversion was not readily accomplished, even
with a prolonged time of 24 h.
Herein an increase of catalyst loading to 5 mol% improved
the conversion (48.5% at 11 h) to give the corresponding ester
and unreacted alcohol in 499.0% and 93.2% ees, with an
improved S value of 690 (Table 1, entry 1). As expected, the
percentage recovery and the ee of unreacted alcohol was
improved to 50.4% and 499.0%, respectively, accompanied
by a slightly reduced ee of ester due to the slight over-acylation
(98.2% ee, S = 683) when a longer reaction time was used,
24 h (Table 1, entry 2). Next the bulky carbinols 3–15 were
exposed to the newly optimised reaction conditions. Surprisingly
aryl tert-butyl carbinols 5 and 6, with substituents in the para
position, suffered from reduced S values affording unreacted
alcohols in 98.0% and 96.0% ees respectively (Table 1, entries
3 and 4, S = 118 for 5 and 61 for 6). Next a variety of bulky
secondary alcohols including aryl-tert-butyl alcohols with
extended aromatic systems (3, 7–8), phenyl-tert-butyl gem
dimethyl derivatives (9–11), and heteroaryl-tert-butyl carbinols
(1, 12–15) were investigated under optimal reaction conditions.
Catalyst Fc-PIP worked well to afford the corresponding
unreacted alcohols in extraordinarily high enantiomeric excess
Scheme 2 Larger scale catalytic KR of racemic 15.
Table 1 Kinetic resolution of bulky (hetro)arylalkyl carbinols using Fc-PIP
Sc
a
eeE (%)
b
eeA (%)
c
CHPLC (%)
Entry
Substrate
t/h
1
2
3
4
5
6
7
8
4
4
5
6
5
6
7
8
11
24
7
499.0
98.2
92.5
88.0
91.6
79.8
85.2
92.6
75.8
83.8
85.4
88.6
80.6
86.2
76.8
75.6
86.8
53.6
93.2
499.0
98.0
48.5
50.4
51.4
52.2
51.9
55.6
53.8
51.7
56.6
54.3
53.9
52.8
55.1
53.5
56.3
56.7
53.7
64.6
690
683
118
61
120
59
71
142
37
68
85
86
48
73
39
37
74
10.5
11
93
48
19
96
93
36
93
93
48
78
72
15.5
48
96.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
499.0
97.6
9
3
9
10
11
12
13
14
15
16
17
18
10
11
12
13
1d
14e
15
15f
13
a
b
c
The ee of the ester product. The ee of the unreacted alcohol, which was tested at least three times for the ees 499.0%. Calculated from the ee
of the ester and unreacted alcohol. Using 15 mol% of catalyst Fc-PIP. Room temperature. Using 5 mol% of catalyst Cl-PIQ.
d
e
f
c
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proceeded smoothly to afford unreacted alcohol 15 in 499.0%
ee with good selectivity factor S = 46 and in 44.3% yield
(Scheme 2). After routine work-up the catalyst was readily
recovered (95%).
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In summary, we have demonstrated that planar-chiral
Fc-PIP can catalyse the acyl transfer kinetic resolution of a wide
range of bulky alcohols with remarkable efficiency, affording
unreacted alcohols in extremely high enantiomeric excess
(499.0%) and in good yields (43.3–49.6%; ideal conversion
50%). Importantly a practical method for accessing a range of
bulky carbinols, including synthetically important heteroaryl
carbinols in excellent ees (499.0%), was demonstrated.
WPD thanks the ‘‘Shu Guang’’ project of Shanghai Education
Development Foundation (No. 09SG28); JSF and WPD thank
the NSFC (No. 21050110426 and 21172068) and Catalysis and
Sensing for our Environment network. JSF thanks ECUST, the
University of Birmingham and ERDF AWM II; WMM thanks
the NSFC (No. 20876149)
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