Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b] benzothiazole-based isothioureas as enantioselective acylation catalysts

Article abstract of DOI:10.1039/c0ob00515k

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ～50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

Full text of DOI:10.1039/c0ob00515k

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PAPER
Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b]-
benzothiazole-based isothioureas as enantioselective acylation catalysts†
Dorine Belmessieri,a Caroline Joannesse,a Philip A. Woods,a Callum MacGregor,a Caroline Jones,a Craig D.
Campbell,a Craig P. Johnston,a Nicolas Duguet,a Carmen Concello´n,a Ryan A. Braggb and Andrew D. Smith*a
Received 29th July 2010, Accepted 16th September 2010
DOI: 10.1039/c0ob00515k
The catalytic activity and enantioselectivity in the kinetic resolution of ( )-1-naphthylethanol with a
range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of
the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving
good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to
>100 at ~50% conversion). Low catalyst loadings (0.10–0.25 mol%) of the optimal isothiourea can be
used to generate enantiopure alcohols (>99% ee) in good yields.
Introduction
In recent years a range of synthetic small molecule catalysts
have been developed that promote efficient kinetic resolution of
racemic alcohols via derivatisation with anhydrides and related
electrophiles.1 Among these catalysts, those based upon the parent
archetypal DMAP or PPY scaffolds are among the most common,
with catalysts 1, 2 and 3, developed by Fu,2 Spivey3 and Campbell4
respectively, representative of the aminopyridine class (Fig. 1).5
A number of alternative catalyst architectures have also been
introduced, such as proline-derived diamine 4 used by Oriyama,6
peptides such as 5 introduced by Miller,7 and chiral phosphine 6
utilised by Vedejs.8,9
Building upon this success, Birman and co-workers have
elegantly shown that amidines and isothioureas can efficiently
promote a range of alcohol acylation protocols. In this area,
Birman first introduced a range of dihydroimidazo[1,2-a]pyridine
(DHIP) derivatives (such as CF3-PIP 7 and Cl-PIQ 8) for
kinetic resolutions,10 before showing that isothioureas such as
Fig. 1 Selected small molecule catalysts for the kinetic resolution of
alcohols.
commercially available tetramisole 9 and its benzannulated ana-
logue (benzotetramisole, BTM) 10 could promote efficient kinetic
resolution11 and desymmetrisation reactions.12 Independent stud-
ies by Okamoto and Birman showed that achiral 3,4-dihydro-2H-
pyrimido[2,1-b]benzothiazole (DHPB) 11 was an efficient catalyst
for O-acylation,13 with subsequent work by Birman utilising
homobenzotetramisole (HBTM) 12 for the kinetic resolution of
aryl-cycloalkanols14 and a-aryl, a-aryloxy and a-arylthioalkanoic
acids (Fig. 2).15 The high levels of selectivity observed with
aEastCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews, Fife, UK. E-mail: ads10@st-andrews.ac.uk; Fax: +44 (0)1333
4639808; Tel: +44 (0)1333 4639896
bAstraZeneca UK Ltd, Mereside, Alderley Park, Macclesfield, Cheshire,
SK10 4TG, UK
† Electronic supplementary information (ESI) available: Experimental
procedures, HPLC data and spectroscopic data for all new products is
available. See DOI: 10.1039/c0ob00515k
Fig. 2 Amidines and isothiourea catalysts for alcohol acylation.
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these isothiourea catalysts in kinetic resolution reactions
has prompted the use of BTM for the kinetic resolution
of 2-hydroxyalkanoates,16 2,2,2-trifluoro-1-arylethanols,17 and
tetramisole derivatives for the resolution of carboxylic acids.18
As part of our interest in the development of synthetic
methods employing Lewis bases19 as catalysts,20 we have employed
isothiourea DHPB 11 as an efficient achiral catalyst for the
Steglich rearrangement of oxazolyl carbonates.21 Our further
recent studies have shown that enantiomerically pure isothioureas
such as HBTM 12, as well as alternative 3,4-dihydropyrimido[2,1-
b]benzothiazole-based isothioureas 13 and 14, are efficient asym-
metric catalysts of this reaction, giving C-carboxyazlactones in
high ee. Notably, variation in catalytic activity with the stere-
odirecting unit of the isothiourea was observed in this model
study, with isothiourea 13 giving the highest enantioselectivity
at rt, but proving less catalytically active than either HBTM 12 or
14 (Fig. 3).22
We delineate herein our complementary studies within this area,
focusing on the effects upon catalytic efficiency and selectivity
with variation in stereodirecting unit within a series of isothiourea
derivatives of generic structure 16 (Fig. 5). The utility of the
optimal catalyst identified from these studies is subsequently used
to promote the kinetic resolution of a number of simple aryl-alkyl
alcohols.
Fig. 5 Probing structure-enantioselectivity relationships using isoth-
ioureas in the kinetic resolution of alcohols.
Results and Discussion
Synthesis of isothiourea catalysts
The preparation of a series of bespoke isothiourea catalysts that
varied in the nature of the stereodirecting group(s), substitu-
tion pattern and conformational constraints within the catalyst
framework required synthetic routes to the corresponding enan-
tiomerically pure g-amino alcohols. g-Amino alcohol 21 was
prepared following the literature procedure from methionine,24
while alcohols 22–24 were synthesised by reduction of the corre-
sponding enantiomerically pure b-amino acids 18–20 respectively,
which are commercially available25 or made following literature
procedures.26 Reduction of diastereo- and enantiomerically pure
b-amino aldehydes 25 and 26, readily available following List’s
proline-catalysed asymmetric Mannich protocol on multi-gram
scale, gave alcohols 28 and 29.27 Deprotection of 27, prepared
following Gellman’s asymmetric aminomethylation procedure,
gave alcohol 30 (Fig. 6).28
Commercially available (S)-3-amino-3-phenylpropan-1-ol hy-
drochloride, and the synthesised g-amino alcohols 21–24, 28–30
were each condensed with 2-chlorobenzothiazole to give 31–39,
with subsequent cyclisation giving the desired isothioureas. To
probe the effect of a substituent upon the benzothiazole ring,
amino alcohol 28 was condensed with 2,6-dichlorobenzothiazole
and cyclised to give isothiourea 43 (Table 1).
Fig. 3 Previous work: isothiourea mediated O- to C-carboxyl transfer.
Building upon these precedents, we were intrigued to probe the
effect of integrating alternative stereodirecting groups within the
tetrahydropyrimidine unit of isothioureas such as HBTM, and
to examine the consequence of these changes upon the efficiency
and stereoselectivity of kinetic resolution reactions. Birman and
co-workers have conducted an analogous study within the DHIP
structural class, with a C(2)-aryl substituent shown to be essential
for high levels of stereocontrol.10c While this work was ongoing,
Birman and co-workers showed that the incorporation of a methyl
group within the HBTM-skeleton had a dramatic effect upon
both catalytic activity and stereoselectivity in kinetic resolutions of
aryl-cycloalkanols,23 with catalyst 15 (HBTM 2) proving optimal
(Fig. 4).
Model studies: structure-enantioselectivity relationships in the
kinetic resolution of ( )-1-naphthylethanol with isothioureas
The reactivity and stereoselectivity of these 3,4-
dihydropyrimido[2,1-b]benzothiazole-based
isothioureas
in
kinetic resolutions was next evaluated in order to probe the
effects of variation in stereodirecting unit within these systems.
As a model system, the resolution of ( )-1-naphthylethanol 46
with propionic anhydride (0.5 eq) in CHCl3 using (i-Pr)2NEt
(0.6 eq) as an auxiliary base was studied (Table 2).29 As a
benchmark standard, isothiourea HBTM 12 (0.75 mol%) was
Fig. 4 Evolution of HBTM.
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Table 1 Synthesis of isothioureas
Alcohol
(yield)
Isothiourea
(yield)
Entry
R1
R2
R3
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
H
H
Cl
H
H
31 (80%)
32 (62%)
33 (60%)
34 (51%)
35 (61%)
36 (86%)
37 (79%)
38 (85%)
39 (59%)
12 (61%)
40 (74%)
13 (97%)
41 (78%)
42 (quant)
14 (83%)
43 (81%)
44 (88%)
45 (51%)
CHPh2
i-Pr
t-Bu
CH2CH2CH2CH2
Ph
i-Pr
i-Pr
i-Pr
i-Pr
Ph
2-Naphthyl
H
the incorporation of an a-branched sterically encumbered
C(2)-alkyl stereodirecting unit (as in isothioureas 13, 40 and 41)
is detrimental to catalyst activity (in comparison to HBTM 12
or 14) for this kinetic resolution, although isothiourea 40 shows
equivalent enantioselectivity to HBTM 12. 2,3-Disubstitution of
the isothiourea leads to improved catalytic activity, with a C(2)-
phenyl unit within the tetrahydropyrimidine structure leading to
high enantioselectivity and reactivity. Interestingly, this contrasts
the trends in stereoselectivity observed in our previous studies on
O- to C-carboxyl transfer reactions of oxazolyl carbonates, where
isothiourea C(2)-i-Pr 13 gave the highest enantioselectivity at rt,22
but is consistent with Birman’s previous structural investigations
upon the DHIP class of Lewis bases in kinetic resolution
reactions.10c In direct comparison to HBTM 12, isothiourea 14,
containing an additional C(3)-i-Pr unit gives enhanced selectivity;
as C(3)-i-Pr isothiourea 45 gives poor enantioselectivity and
catalytic activity, the 2,3-disubstitution within 14 appears to exert
a synergistic effect upon the enantioselectivity in this process.
Further reaction optimisation studies used the most effective
isothiourea (2S,3R)-14 and focused upon solvent and temperature
variation (Table 3). At 0 ◦C, good reaction conversion was
observed within 1 h, with best selectivity observed in either toluene
(S = 34) or CHCl3 (S = 36) rather than CH2Cl2 or THF (entries 2–
5). In toluene and CHCl3 the kinetic resolution could be performed
at -40 ◦C, giving ~40% conversion within 1 h but with similar levels
of enantioselectivity to that observed at 0 ◦C (entries 7–8). Further
reduction in catalyst loading to 0.1 mol% proved possible, giving
36% conversion at 0 ◦C within 1 h, although further reduction
in catalyst loading gave only modest product conversion (entries
9–11). Alternatively, using 0.6 eq of propionic anhydride and a
Fig. 6 Synthesis of enantiomerically pure g-amino alcohols.
used, giving good levels of conversion within 1 h and good
levels of stereoselectivity (S = 18). C(2)-Benzhydryl (CHPh2)
substituted isothiourea 40 showed only modest catalytic activity
at 0.75 mol% loading (<10% conversion to propionate 47
within 1 h), requiring extended reaction times and increased
catalyst loading for acceptable reaction conversions, although
delivering approximately equivalent levels of stereoselectivity
to HBTM 12 (S~20, entries 2–4). Similarly, C(2)-isopropyl
and C(2)-tert-butyl substituted isothioureas 13 and 41 required
extended reaction times at 2.5 mol% loading to give good product
conversions, albeit with only modest enantioselectivity (S = 12 and
8 respectively, entries 5–6). C(3)-i-Pr substituted isothourea 45
showed only modest catalytic activity and enantioselectivity in this
process (entry 7), although increased reaction rates were observed
using 2,3-disubstituted isothioureas 14 and 42–44, with good
conversion (47–50%) reached within 1 h at rt using 0.75 mol%
of the respective isothiourea. Among these disubstituted
isothioureas, the highest enantioselectivity was observed using
isothiourea 14 (S = 30, entry 9) containing an additional cis-
i-Pr substituent in comparison to HBTM 12, consistent with
Birman’s work with HBTM-2 15. Reduced stereoselectivity was
observed using the constrained tetracyclic isothiourea 42 or the
C(2)-2-naphthyl substituted isothiourea 44 (entries 8 and 11).
The incorporation of a Cl-substituent into the benzothiazole ring
had a negligible effect, with isothiourea 43 giving approximately
equivalent stereoselectivity to its parent catalyst 14 (entry 10).
Taken together, these structure–activity studies indicate that
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Table 2 Model studies for the kinetic resolution of ( )-1-naphthylethanol
Table 3 Optimisation studies: kinetic resolution of ( )-1-naphthylethanol
Entry Isothiourea
1
eealcohol(%)a
57
eeester(%)a
81
c (%)b
S
Entry 14 (mol%) T/◦C solvent eealcohol(%)a eeester(%)a c (%)b
S
41
18
1
2
3
4
5
6
7
8
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.25
0.10
0.025
0.05
rt
0
0
0
CHCl3 84
CHCl3 86
84
86
85
80
84
86
90
91
87
88
86
76
50
50
48
49
47
50
37
39
47
36
10
55
30
36
34
20
24
40
33
38
33
24
21
23
PhMe
CH2Cl2 77
THF 74
80
2
8
22
70
87
84
86
8
20
20
26
19
19
0
3c
-20
-40
-40
0
0
0
CHCl3 87
CHCl3 53
4c,d
PhMe
57
9
CHCl3 77
CHCl3 49
CHCl3 10
CHCl3 92
5c,e
6c,e
7
60 (ent)
72 (ent)
67 (ent)
15
45
45
27
50
50
47
12
8
10
11
12c
rt
a Determined by chiral HPLC analysis. b Reaction conversion was deter-
mined using cHPLC = 100 ¥ eealcohol/(eeester+ eealcohol).30 c Reaction conditions:
isothiourea 14 (0.05 mol%), (EtCO)2O (0.6 eq), i-Pr2NEt (0.75 mol%),
alcohol ( )-46 (1 mmol), 28 h, rt; purification gave alcohol (S)-46 in 39%
yield (92% ee) and ester 47 in 40% yield (76% ee).
54 (ent)
5
1.3
11
30
28
50%) to the corresponding ester was observed within 1 h for
all substrates, with ( )-2-naphthylethanol 48 resolved with high
selectivity at either rt or -20 ◦C (entries 3–4). ( )-Arylethanols
49–51 were competently resolved (entries 5–10), with resolution
of ( )-52 proceeding with high selectivity (S>100, entries 11–
12). The ( )-cinnamyl and ( )-propargylic alcohols 53 and 54
were also resolved with lower, but still acceptable, levels of
enantiodiscrimination (S>17, entries 13–17).
8
70
84
75
69
9
84
Comparison of 3,4-dihydropyrimido[2,1-b]benzothiazole-based
isothiourea catalysts
10
86
Having shown that isothiourea 14 is able to operate in kinetic
resolution reactions at relatively low catalyst loadings, a direct
assessment of its reactivity and stereoselectivity in comparison
with the literature studies of the related 3,4-dihydropyrimido[2,1-
b]benzothiazole-based catalysts HBTM 12 and HBTM 2 15 was
carried out. In our hands, employing 14 as the acylation catalyst
under the experimental conditions employed by Birman for the
kinetic resolution of ( )-2-naphthylethanol 48 using HBTM 12,
and propargylic alcohol 54 using HBTM 2 15, indicated that
isothiourea 14 gave comparable reactivity but improved selectivity
to the literature in both cases (Tables 5 and 6). Although the
levels of asymmetric induction using isothiourea 14 are useful
in these reactions, BTM 10 has been shown to catalyse highly
enantioselective kinetic resolutions of ( )-48 (S = 108)11a and ( )-
54 (S = 31)11c using 4 mol% of the acylation catalyst using related
reaction conditions.
11
73
79
48
19
a Determined by chiral HPLC analysis. b Reaction conversion was deter-
mined using cHPLC = 100 ¥ eealcohol/(eeester+ eealcohol).30 c Isothiourea loading
of 2.5 mol%. d Reaction time 63 h. e Reaction time 44 h.
catalytic amount of Hu¨nig’s base (0.75 mol%), the resolution of
( )-46 could be effected using only 0.05 mol% of isothiourea 14,
giving ~5% conversion to propionate 47 within 28 h at rt (entry 12).
Reaction generality – kinetic resolutions of model secondary
alcohols
Model for asymmetric induction
Further studies probed the utility of isothiourea 14 (0.75 mol%)
to catalyse the kinetic resolution of a series of model secondary
aryl-alkyl alcohols in CHCl3 (Table 4). Good conversion (34–
The high levels of enantiodiscrimination observed in these kinetic
resolutions, with a consistent preference for the (R)-enantiomer
of the racemate to undergo esterification, resulting in isolation
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Table 4 Kinetic resolutions using isothiourea 14
Table 5 Comparison of HBTM 12 and isothiourea 14 for the kinetic
resolution of ( )-48
Entry substrate
T/◦C eealcohol(%)a eeester(%)a c (%)b
S
1
2
rt
-40
84
57
84
91
50
39
30
38
3
4
rt
81
71
91
94
47
43
55
65
-20
Entry
1
Isothiourea
eealcohol(%)
76a
eeester(%)
83a
c (%)
S
48a
25a
5
6
rt
0
77
75
84
87
52
46
14
35
88b
91b
50c
67
7
8
rt
0
78
74
71
76
52
45
14
17
2
9
10
rt
0
65
47
84
89
44
34
23
35
a Literature values taken from reference 14; b Determined by chiral HPLC
analysis. c Reaction conversion was determined using cHPLC = 100 ¥
eealcohol/(eeester+ eealcohol).30
11
12
rt
0
82
98
96
99
46
50
>100
>100
system of the alcohol with the acetylated isothiouronium catalyst
intermediate (shown in Fig. 7 for the kinetic resolution of ( )-1-
naphthylethanol for simplicity).34 Although this model accounts
for the sense of asymmetric induction in these kinetic resolutions,
the apparent beneficial effect of the adjacent C(3)-i-Pr substituent
within isothiourea 14 is not immediately clear, although we
currently speculate this substituent acts as a conformational
lock within the N-acyl intermediate. Computational analysis is
underway to probe the origin of this effect.
13
14
rt
0
70
73
65
83
52
47
10
22
15
16
17
rt
0
-20
50
55
43
67
83
84
42
40
34
9
18
17
a Determined by chiral HPLC analysis. b Reaction conversion was deter-
mined using cHPLC = 100 ¥ eealcohol/(eeester+ eealcohol).30
of the resolved enantioenriched (S)-alcohol, is consistent with
the following simplistic model. Based upon a combination of
previous modelling studies from Birman and Houk on the origin
of CF3-PIP catalysed kinetic resolutions,31 and our own modelling
studies upon the behaviour of HBTM in asymmetric Steglich
reactions,22 we postulate that the N-acylated catalyst preferentially
adopts a conformation that places the adjacent Ph substituent in
a pseudoaxial position in order to minimise 1,2-strain.32 In this in-
termediate, the N-propionyl group is assumed to lie preferentially
approximately co-planar with the isothiourea heterocycle, with the
syn-rotamer (C O group syn to C N) preferred.22,31 Preferential
reaction of the (R)-enantiomer of the alcohol, presumably with
the propionate counterion hydrogen bonded to the hydroxyl of
the substrate following the calculations of Mayr and co-workers,33
is favoured due to p–p and/or cation-p interactions of the p-
Fig. 7 Simplistic model for enantiodiscrimination in the kinetic resolu-
tion of secondary alcohols using catalyst 14.
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Table 6 Comparison of HBTM 2 15 and isothiourea 14 for the kinetic
resolution of ( )-54
Table 7 Preparative scale resolutions using isothiourea 14
eealcohol Yield eeester Yield
Entry substrate
1c
(%)a
(%)
(%)a (%)
c (%)b
S
>99
30
74
50
57
35
Entry
1
Isothiourea
eealcohol(%)
86a
eeester(%)
76a
c (%)
S
53a
21a
2c
3d
4c
5c
>99
>99
95
30
44
24
27
67
99
66
57
50
44
54
44
60
50
59
63
30
99b
76b
55c
39
>100
17
2
a Literature values taken from reference 23; b Determined by chiral HPLC
analysis. c Reaction conversion was determined using cHPLC = 100 ¥
eealcohol/(eeester+ eealcohol).30
>99
18
Preparative scale kinetic resolutions of secondary alcohols
To further demonstrate the synthetic utility of isothiourea catalyst
14, its ability to deliver alcohols of high enantiopurity in a selection
of kinetic resolution reactions at low catalyst loadings (0.10–
0.25 mol%) on a ~3 mmol scale was investigated. Based upon the
selectivity factors observed in the reactions above, judicious choice
of propionic anhydride stoichiometry (0.60–0.65 eq) allowed the
reactions to proceed to 50–63% conversion. In each case the
resolved alcohols and the corresponding esters were isolated by
chromatography, giving the alcohols in 24–44% isolated yield and
95%->99% ee (Table 7).
a Determined by chiral HPLC analysis. b eaction conversion was deter-
mined using cHPLC = 100 ¥ eealcohol/(eeester+ eealcohol).30 c Isothiourea loading of
0.10 mol% and reaction temperature rt. d Isothiourea loading of 0.25 mol%
and reaction temperature 0 ◦C.
Experimental
For general experimental details see ESI.† The ESI also contains
spectroscopic and HPLC data for isothioureas 12, 13, 40–45,
products 29–35, resolved alcohols 46 and 48–54 as well as the
corresponding propionate esters. The ee for catalysts 40 and 45
has been unambigously determined by chiral HPLC analysis while
the ee for catalysts 41–44 is assumed to be >98%.
Conclusion
In conclusion, we have demonstrated that variation of the
stereodirecting group and conformational constraints within the
tetrahydropyrimidine skeleton of a series of chiral isothioureas
leads to dramatic changes in catalytic efficiency and stereoselec-
tivity in the kinetic resolution of secondary alcohols. (2S,3R)-2-
Phenyl-3-isopropyl substituted isothiourea 14 proved optimal of
those tested in this study, allowing low catalyst loadings (<1 mol%)
to be used to generate good reaction conversion within 1 h with
good enantioselectivities (S up to >100) for a series of aryl-alkyl
alcohols. The application of isothiourea 14 to prepare alcohols
with ees of up to >99% has also been demonstrated utilising low
catalyst loadings (0.10–0.25 mol%). Current studies are focused
upon developing alternative applications of enantiomerically pure
isothioureas in asymmetric catalysis.
Preparation of isothioureas: Preparation of
(R)-3-amino-4,4-dimethylpentanol 23
LiAlH4 (2.0 M in THF, 5.20 mL, 10.3 mmol, 3.0 eq) was added
dropwise to a solution of (3R)-3-amino-4,4-dimethylpentanoic
ac◦id 1925 (500 mg, 3.44 mmol, 1.0 eq) in dry THF (10 mL) at
0 C. The reaction mixture was then refluxed for 2 h, cooled to
0
◦C and quenched by dropwise addition of H2O. The mixture
R
was filtered through Celiteꢀ and concentrated under vacuum to
give 23 as a white solid (330 mg, 73%); mp 70–74 ◦C; [a]D20 +1.5 (c
1.1 in CHCl3); nmax (KBr) 3400–2700, 3348, 2955; dH (400 MHz;
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CDCl3) 0.86 (9H, s), 1.32–1.42 (1H, m), 1.64–1.70 (1H, m), 2.51
(1H, dd, J 11.3, 2.1), 2.81 (2H, br s) 3.76–3.86 (1H, m), 3.84
(1H, dt, J 10.4, 4.0); dC (75 MHz, CDCl3) 25.9, 31.7, 34.7,
63.0, 63.8; m/z (ES+) 132 ([M+H]+, 29%), 97.1 ([M–NH2–OH]+,
100%).
Preparation (S)-2-(aminomethyl)-3-methylbutan-1-ol
hydrochloride 30
A stirred solution of alcohol 27 (709 mg, 2.30 mmol, 1.0 eq) in
MeOH (11 mL), distilled H2O (1 mL) and acetic acid (1 mL)
was degassed for 30 min before 20% palladium hydroxide on
carbon (272 mg) was added. The resulting suspension was stirred
for 3 days under 1 atm of hydrogen. The reaction mixture was
then diluted with CH2Cl2 (8 mL) and Boc2O (608 mg, 2.74 mmol,
1.2 eq) was added followed by i-Pr2NEt (0.97 mL, 5.47 mmol,
2.4 eq). The mixture was stirred overnight then filtered through
Preparation of ((1S,2R)-2-aminocyclohexyl)methanol 24
An oven-dried three-necked flask equipped with a magnetic stirrer,
a condenser and a nitrogen-inlet tube was flushed with N2 and
charged with THF (10 mL) and LiAlH4 (2.0 M in THF, 5.24 mL,
10.5 mmol, 1.5 eq). The reaction mixture was cooled to 0 ◦C and
20 (1.00 g, 6.99 mmol, 1.0 eq)26 was added in portions. After the
addition was complete the ice bath was removed and the mixture
was warmed to rt and refluxed overnight. The mixture was cooled
again to 0 ◦C and diluted with Et2O (8 mL). The reaction was
quenched with H2O (0.40 mL), 15% aq. NaOH (0.40 mL), and
H2O (1.19 mL). The mixture was stirred vigorously for 30 min
and the white precipitate was filtered. The filter cake was washed
with Et2O and the organic filtrates combined, dried (Na2SO4), and
concentrated in vacuo to give 24 (689 mg, 76%) as a colourless oil;35
[a]D20 -14.0 (c 0.5 in CH2Cl2);36 dH (400 MHz, CDCl3) 1.22–1.37
(2H, m), 1.39–1.49 (2H, m), 1.51–1.64 (4H, m), 1.67–1.78 (1H, m),
3.27 (1H, dd, J 8.1, 3.8), 3.72 (1H, dd, J 11.0, 3.5), 3.80 (1H, dd,
J 11.1, 6.7).
R
Celiteꢀ and washed with MeOH. The solvent was then removed
in vacuo to afford a colourless liquid. After partitioning between
CH2Cl2 (20 mL) and sat. aq. NaHCO3 (20 mL) the organic phase
was separated and the aqueous phase was extracted with CH2Cl2
(3 ¥ 20 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo to give alcohol (S)-tert-butyl-2-
(hydroxymethyl)-3-methylbutylcarbamate 63 (457 mg, 92%) as a
pale yellow solid; mp 57–59 ◦C; {lit.28 mp 68–69 ◦C}; [a]2D0 +8.6 (c
0.8 in MeOH); {lit.28 [a]D20 +11.4 (c 0.5 in MeOH)}; dH (300 MHz,
CDCl3) 0.92 (3H, d, J 6.8), 0.94 (3H, d, J 6.8), 1.25–1.34 (1H,
m), 1.44 (9H, s), 1.58–1.69 (1H, m), 3.13–3.23 (1H, m), 3.33–3.41
(1H, m), 3.51 (1H, ABX, JBA 11.7, JBX 7.0), 3.68 (1H, ABX, JAB
11.7, JAX 4.0), 4.82 (1H, s). A solution of HCl (4.0 M in dioxane,
5.80 mL, 23.0 mmol, 11.8 eq) was added to alcohol (S)-63 (423 mg,
1.95 mmol, 1.0 eq) and stirred at rt for 4 h. The reaction was
concentrated and dried in vacuo to afford amino alcohol (S)-30
(248 mg, 83%) as a colourless oil; [a]2D0 -4.7 (c 0.5 in MeOH); nmax
(film) 3385, 2926; dH (400 MHz, CD3OD) 0.96 (6H, d, J 6.7), 1.67–
1.80 (2H, m), 2.98–3.10 (2H, m), 3.63 (1H, dd, J 10.5, 8.5), 3.81
(1H, dd, J 10.5, 3.4); dC (75 MHz, CD3OD) 19.8, 20.0, 28.5, 42.5,
45.3, 63.9; m/z (ES+) 118 ([M], 100%); HRMS (ES+) C6H16NO,
([M]) requires 118.1232; found 118.1236 (+3.6 ppm).
Preparation of (1S,2S)-2-(hydroxymethyl)-3-methyl-1-
(naphthalen-2-yl)butan-1-aminium chloride 29
2627 (5.80 g, 17.0 mmol, 1.0 eq) was dissolved in MeOH (133 mL).
NaBH4 (964 mg, 25.5 mmol, 1.5 eq) was added portion-wise and
the reaction mixture was allowed to stir for 2 h. The mixture was
quenched with sat. aq. NaHCO3 and MeOH was removed in vacuo.
The product was extracted with CH2Cl2 (¥3) and the combined
organic extracts were dried (MgSO4), filtered and concentrated
in vacuo to give tert-butyl (1S,2S)-2-(hydroxymethyl)-3-methyl-1-
(naphthalen-2yl)butylcarbamate 57 (5.75 g, 99%) as a white solid;
Preparation of (S)-3-(benzo[d]thiazol-2-ylamino)-4,4-
diphenylbutan-1-ol 32
A mixture of (S)-3-amino-4,4-diphenylbutan-1-ol24 (500 mg,
2.07 mmol, 1.0 eq), 2-chlorobenzothiazole (0.28 mL, 2.28 mmol,
1.1 eq) and i-Pr2NEt (0.72 mL, 4.14 mmol, 2.0 eq) was heated at
135 ◦C in a sealed tube for 40 h. After cooling to 40 ◦C, CH2Cl2
(4 mL) was added and the reaction mixture was cooled to rt. The
crude product was transferred to a flask and concentrated in vacuo.
The residue was purified via flash column chromatography (silica;
99 : 1 to 98 : 2 CH2C◦l2–MeOH) to give 32 (480 mg, 62%) as a yellow
solid; mp 170–172 C; [a]2D0 -110.1 (c 1.0 in CHCl3); nmax (KBr)
3449, 3024, 1570, 1546, 1529; dH (400 MHz, CDCl3) 1.39 (1H, t,
J 12.6), 1.90–1.98 (1H, m), 3.51–3.63 (2H, m), 4.02 (1H, d, J 9.3),
4.84 (1H, br s), 5.08 (1H, br s), 7.07 (1H, t, J 7.6), 7.12–7.19 (2H,
m), 7.19–7.30 (9H, m), 7.47 (1H, d, J 7.9), 7.52 (1H, d, J 8.1);
dC (100 MHz, CDCl3) 38.4, 54.2, 57.6, 58.1, 119.2, 120.9, 122.3,
126.2, 127.0, 127.1, 128.3, 128.4, 129.0 (2¥), 130.2, 141.5, 142.1,
151.5, 167.5; m/z (CI+) 375 ([M+H]+, 100%), 207 ([M–Ph2CH]+,
13%); HRMS (CI+) C23H23N2OS+, ([M+H]+) requires 375.1531;
found, 375.1526 (-1.4 ppm).
◦
mp 124-126 C; [a]D20 -48.0 (c 0.5 in CH2Cl2); nmax (KBr) 3308,
2964, 1677, 1545; dH (400 MHz, CDCl3) 0.85 (3H, d, J 6.9), 1.03
(3H, d, J 6.4), 1.44 (9H, s), 1.68–1.84 (1H, m), 1.97 (1H, br s),
2.31 (1H, br s), 3.53 (1H, dd, J 11.1, 9.0), 3.70 (1H, br d, J 9.2),
5.21 (1H, br s), 5.82 (1H, br s), 7.43–7.51 (3H, m), 7.77 (1H, s),
7.79–7.85 (3H, m); dC (100 MHz, CDCl3) 19.3, 22.8, 26.6, 28.5,
51.3, 55.3, 61.1, 79.8, 125.3, 125.8, 125.9, 126.2, 127.7, 128.0, 128.3,
132.7, 133.3, 138.8, 155.9; m/z (NSI+) 344 ([M+H]+, 75%); HRMS
(NSI+) C21H30NO3 , ([M+H]+) requires 344.2220; found 344.2226
+
(+1.7 ppm). HCl (4.0 M in dioxane, 45.9 mL, 184 mmol, 12.6
eq) was added to 57 (5.00 g, 14.6 mmol, 1.0 eq) and stirred at rt
for 4 h. The reaction mixture was concentrated in vacuo to afford
◦
29 (3.68 g, 90%) as a white solid; mp 190–196 C; [a]2D0 -36.0 (c
0.5 in MeOH); nmax (KBr) 3273, 2875, 2163, 1602; dH (400 MHz,
CD3OD) 0.84 (3H, d, J 5.8), 1.18 (3H, d, J 4.2), 1.54–1.69 (1H,
m), 2.09–2.21 (1H, m), 3.54 (1H, t, J 10.1), 3.73–3.82 (1H, m),
4.77 (1H, s), 7.54 (2H, d, J 3.2), 7.66 (1H, d, J 5.1), 7.87–8.01
(3H, m), 8.05 (1H, s); dC (100 MHz, CD3OD) 19.7, 22.5, 28.1,
49.8, 58.5, 61.4, 126.4, 127.8, 127.9, 128.7, 128.9, 129.2, 129.7,
133.3, 134.5, 134.8; m/z (NSI+) 244 ([M+H]+, 100%); HRMS
(NSI+) C16H22NO+, ([M]+) requires 244.1696; found 244.1698
(+0.9 ppm).
Preparation of (R)-3-(benzothiazol-2-ylamino)-3-tert-
butylpropanol 34
A pressure tube charged with amino alcohol (R)-3-amino-
4,4-dimethylpentanol 23 (360 mg, 2.74 mmol, 1.0 eq),
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2-chlorobenzothiazole (0.37 mL, 3.01 mmol, 1.1 eq) and i-Pr2NEt
(1.42 mL, 8.22 mmol, 3.0 eq) was flushed with N2 several times,
then heated at 130 ◦C for 3 days. After cooling to 40 ◦C, the
reaction mixture was treated with CH2Cl2 (3 mL) then further
cooled to rt. The diluted reaction mixture was applied directly to a
chromatographic column (silica; 1 : 1 : 98 i-PrOH/NEt3/hexanes)
to give 34 as a white solid (374 mg, 51%), which was shown by chiral
HPLC {Daicel CHIRALCEL OD-H, 4.6 mm ¥ 250 mm, 10 : 90
i-PrOH/hexane, 1 mL min-1, retention times of enantiomers:
6.3 min (R), 8.6 min (S)} to have >99% ee; mp 160–164 ◦C;
[a]2D0 -78.7 (c 0.3 in CHCl3); nmax (KBr) 3291–2700, 2960, 1542; dH
(300 MHz; CDCl3) 1.02 (9H, s), 1.88 (1H, ddt, J 14.1, 11.7, 2.6),
2.07 (1H, dddd, J 13.8, 10.9, 5.6, 2.8), 3.73–3.59 (2H, m), 4.01
(1H, ddd, J 11.8, 9.5, 2.4), 4.49 (1H, br s), 4.87 (1H, br d, J 9.0),
7.08 (1H, td, J 7.7, 1.1), 7.28 (1H, td, J 7.2, 1.2), 7.49 (1H, dd, J
8.1, 0.7), 7.54 (1H, dd, J 8.0, 0.9); dC (75 MHz, CDCl3) 26.8, 33.5,
34.6, 58.7, 60.7, 118.9, 120.8, 122.0, 126.1, 130.0, 151.7, 168.1; m/z
(ES+) 265 ([M+H]+, 100%); HMRS (ES+) C14H21N2OS+, ([M+H]+)
requires 265.1369; found 265.1372 (+1.1 ppm).
120.7, 126.6, 126.7, 127.9, 128.2, 128.6, 130.9, 138.7, 149.6, 168.3;
m/z (ESI+) 361 ([M+H]+, 100%); HRMS (ESI+) C19H2ClN2OS+,
([M+H]+) requires 361.1136; found 361.1137 (+0.2 ppm).
Preparation of (S)-2-((S)-(benzo[d]thiazol-2-ylamino)(naphthalen-
2-yl)methyl)-3-methylbutan-1-ol 38
A pressure tube charged with 29 (400 mg, 1.43 mmol, 1.0 eq) was
flushed with Ar several times. i-Pr2NEt (0.97 mL, 5.57 mmol, 3.9
eq) was added, the reaction mixture was heated to 135 ◦C and
2-chlorobenzothiazole (0.21 mL, 1.57 mmol, 1.1 eq) was added.
After 3 days and cooling to rt CH2Cl2 was added and the mixture
was transferred to a flask and concentrated in vacuo. The residue
was purified via flash column chromatography (silica; 2 : 98 EtOH–
CH2Cl2) to give 38 (458 mg, 85%) as an orange solid; mp 80–86 ◦C;
[a]2D0 -74.0 (c 0.5 in CH2Cl2); nmax (KBr) 3296, 2959, 1600, 1545;
dH (400 MHz, CDCl3) 0.81 (3H, d J 6.8), 1.18 (3H, d, J 6.7), 1.70
(1H, dq, J 13.6, 6.8), 2.28 (1H, ddt, J 10.2, 6.9, 3.6), 3.75 (1H, t,
J 10.5), 3.97 (1H, dd, J 10.8, 3.9), 5.08 (1H, d, J 3.8), 6.96–7.03
(1H, m), 7.18–7.24 (1H, m), 7.38–7.44 (3H, m), 7.48 (1H, d, J 7.8),
7.70 (1H, dd, J 8.5, 1.5), 7.77 (3H, dd, J 8.8, 4.7), 7.95 (1H, s); dC
(100 MHz, CDCl3) 19.8, 22.8, 27.0, 51.1, 60.6, 62.4, 118.2, 121.0,
121.4, 126.0, 126.1, 126.1, 126.3, 127.4, 127.7, 128.1, 128.4, 129.8,
133.0, 133.2, 136.6, 151.2, 168.4; m/z (NSI+) 377 ([M+H]+, 100%);
HRMS (NSI+) C23H25N2OS+, ([M+H]+) requires 377.1682; found
377.1683 (+0.2 ppm).
Preparation of ((1S,2R)-2-(benzo[d]thiazol-2-ylamino)cyclohexyl)-
methanol 35
24 (400 mg, 3.10 mmol, 1.0 eq), 2-chlorobenzothiazole (0.45 mL,
3.41 mmol, 1.1 eq), i-Pr2NEt (1.08 mL, 6.20 mmol, 2.0 eq)
and MeCN (3 mL) were placed in a sealed microwave tube.
The reaction mixture was heated to 145 ◦C for 1 h in a
microwave reactor. The mixture was transferred to a flask and
concentrated in vacuo. Purification of the residue via automated
flash column chromatography (silica; NEt3/i-PrOH/isohexane)
Preparation of (S)-2-((S)-benzo[d]thiazol-2-ylamino)methyl)-3-
methylbutan-1-ol 39
A sealed tube was charged with amino alcohol (S)-30 (240 mg,
1.57 mmol, 1.0 eq) and i-Pr2NEt (1.09 mL, 6.28 mmol, 4.0 eq). The
reaction mixture was heated to 135 ◦C and 2-chlorobenzothiazole
(0.21 mL, 1.73 mmol, 1.1 eq) was added. The mixture was left
at 135 ◦C for 3 days then allowed to cool to rt. The mixture was
diluted with CH2Cl2 (2 mL) and purified via column chromatog-
raphy (0 : 100 to 2 : 98 EtOH–CH2Cl2) to give the alcohol (S)-39
(233 mg, 59%) as a white solid; mp 126–128 ◦C; [a]D20 +28.1 (c 0.6 in
CHCl3); nmax (KBr) 3252, 2952, 1581; dH (300 MHz, CDCl3) 0.99
(3H, d, J 6.8), 1.00 (3H, d, J 6.8), 1.51 (1H, app tq, J 7.2, 3.7), 1.75
(1H, dq, J 14.0, 7.2), 3.57–3.63 (2H, m), 3.74–3.80 (2H, m), 4.28
(1H, br s), 5.47 (1H, s), 7.08 (1H, app dt, J 7.6, 1.0), 7.25–7.31 (1H,
m), 7.49–7.56 (2H, m); dC (75 MHz, CDCl3) 20.4, 28.1, 44.8, 48.2,
62.0, 118.8, 121.8, 122.6, 126.9, 131.1, 153.0, 169.6; m/z (ES+) 251
([M+H]+, 100%); HRMS (ES+) C13H19N2OS+, ([M+H]+) requires
251.1218; found 251.1218 (-0.1 ppm).
◦
gave 35 (496 mg, 61%) as a white solid;37 mp 154–164 C; [a]2D0
+92.0 (c 0.3 in CH2Cl2); nmax (KBr) 3254, 2925, 1531; dH (400 MHz,
CDCl3) 1.00–1.13 (1H, m), 1.32–1.45 (3H, m), 1.66–1.80 (3H, m),
1.81–1.91 (1H, m), 1.92–1.99 (1H, m), 3.31 (1H, t, J 11.3), 3.39
(1H, dd, J 11.9, 4.7), 4.54 (1H, br s), 5.30–5.45 (1H, m), 5.67 (1H,
br s), 7.06–7.11 (1H, m), 7.27 (1H, ddd, J 8.2, 7.2, 1.1), 7.48 (1H,
ddd, J 8.1, 1.1, 0.5), 7.50–7.54 (1H, m); dC (100 MHz, CDCl3) 21.1,
23.6, 25.2, 31.0, 44.2, 50.7, 63.7, 119.0, 120.8, 122.2, 126.2, 130.0,
151.5, 167.5; m/z (ESI+) 263 ([M+H]+, 100%); HRMS (ESI+)
C14H19N2OS+, ([M+H]+) requires 263.1213; found 263.1213 (-0.1
ppm).
Preparation of (2S,3R)-2-(((6-chlorobenzo[d]thiazol-2-
yl)amino)(phenyl)methyl)-3-methylbutan-1-ol 37
28 (500 mg, 2.17 mmol, 1.0 eq), 2,6-dichlorobenzothiazole
(488 mg, 2.39 mmol, 1.1 eq), i-Pr2NEt (1.13 mL, 6.52 mmol,
3.0 eq) and MeCN (2 mL) were placed in a sealed microwave
tube. The reaction mixture was heated to 145 ◦C for 1 h in a
microwave reactor. The reaction was transferred to a flask and
concentrated in vacuo. Purification of the residue via automated
flash column chromatography (silica; NEt3/i-PrOH/isohexane)
gave 37 (618 mg, 79%) as a white solid; mp 56–62 ◦C; [a]D20 -84.0 (c
0.5 in CH2Cl2); nmax (KBr) 3290, 2960, 1599, 1543; dH (400 MHz,
CDCl3) 0.83 (3H, d, J 6.8), 1.15 (3H, d, J 6.7), 1.67 (1H, dq, J
13.4, 6.7), 2.18 (1H, ddt, J 10.0, 6.9, 3.6), 3.68 (1H, t, J 10.4),
3.91 (1H, dd, J 10.8, 3.7), 4.90 (1H, d, J 3.8), 7.21 (1H, dd, J
8.6, 2.0), 7.26–7.38 (4H, m), 7.47 (1H, d, J 2.1), 7.49–7.54 (2H,
m); dC (100 MHz, CDCl3) 19.8, 22.7, 27.0, 51.0, 60.6, 62.3, 118.8,
Preparation of (S)-2-benzhydryl-3,4-dihydro-2H-pyrimido[2,1-b]-
benzothiazole 40
Et3N (0.50 mL, 3.60 mmol, 3.0 eq) was added to a solution of (S)-3-
(benzo[d]thiazol-2-ylamino)-4,4-diphenylbutan-1-ol 32 (450 mg,
1.20 mmol, 1.0 eq) in CH2Cl2 (15 mL) at 0 ◦C under N2, followed
by methanesulfonyl chloride (0.10 mL, 1.32 mmol, 1.1 eq). The
reaction mixture was stirred at 0 ◦C for 1 h and was then allowed
to warm to rt. Once a few drops of MeOH had been added to
quench excess methanesulfonyl chloride, Et3N (2 mL) was added
and the mixture refluxed for 16 h. After cooling to rt, water was
added and the layers were separated. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was purified
566 | Org. Biomol. Chem., 2011, 9, 559–570
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via flash column chromatography (silica; 99 : 1 to 95 : 5 CH2Cl2–
MeOH) to give 40 as a yellow solid (310 mg, 74%), which was
shown by chiral HPLC {Daicel CHIRALCEL AD-H, 4.6 mm ¥
250 mm, 30 : 70 i-PrOH/hexane, 1 mL min-1, retention times of
enantiomers: 14.0 min (R), 24.2 min (S)} to have >99% ee; mp
176–177 ◦C; [a]D20 +54.4 (c 0.5 in CHCl3); nmax (KBr) 2925, 1624,
1586; dH (300 MHz, CDCl3) 1.59 (1H, dtd, J 13.8, 8.6, 5.3),
1.82 (1H, app dq, J 13.6, 4.4), 3.53–3.71 (2H, m), 3.88 (1H, d,
J 9.5), 4.26 (1H, td, J 8.9, 4.0), 6.61 (1H, dd, J 7.9, 0.5), 6.87 (1H,
td, J 7.6, 1.1), 7.06–7.27 (10H, m), 7.33 (2H, dd, J 8.1, 1.0); dC
(100 MHz, CDCl3) 23.7, 41.0, 57.6, 57.7, 107.3, 121.6, 121.8, 122.9,
125.8, 126.3, 126.5, 128.4, 128.5, 128.7, 128.9, 140.8, 142.8, 143.6,
157.1; m/z (ES+) 357 ([M+H]+, 100%); HRMS (ES+) C23H21N2S+,
([M+H]+) requires 357.1420; found 357.1420 (0.0 ppm).
(ESI+) 245 ([M+H]+, 100%); HRMS (ESI+) C14H17N2S+, ([M+H]+)
requires 245.1107; found 245.1108 (+0.3 ppm).
Preparation of (2S,3R)-8-chloro-3-isopropyl-2-phenyl-3,4-dihydro-
2H-pyrimido[2,1-b]benzothiazole 43
Thionyl chloride (0.11 mL, 1.52 mmol, 2.2 eq) was added to a
stirred solution of 37 (250 mg, 0.693 mmol, 1.0 eq) in PhMe
(3 mL) and the reaction mixture was heated at 120 ◦C. Once
complete, the mixture was allowed to cool to rt and MeOH was
added. After evaporation of the solvent, 10% aq. NaOH was
added to the residue followed by extraction with CH2Cl2 (¥3). The
combined organic extracts were washed with brine, dried (Na2SO4)
and concentrated in vacuo to afford 43 (192 mg, 81%) as a gold
◦
solid; mp 140–144 C; [a]2D0 +194.0 (c 0.5 in CH2Cl2); nmax (KBr)
2959, 2864, 1629; dH (400 MHz, CDCl3) 0.76 (3H, d, J 6.7), 1.05
(3H, d, J 6.5), 1.16–1.28 (1H, m), 1.88 (1H, ddt, J 11.2, 9.3, 4.7),
3.28 (1H, t, J 11.5), 3.78 (1H, ddd, J 11.7, 5.2, 1.6), 4.84–4.87
(1H, m), 6.67 (1H, d, J 8.5), 7.07–7.14 (3H, m), 7.16–7.26 (4H,
m); dC (100 MHz, CDCl3) 20.0, 22.1, 26.9, 40.8, 42.2, 60.9, 108.5,
121.9, 124.8, 126.1, 127.4, 127.5, 128.0, 128.5, 139.2, 140.2, 158.3;
m/z (NSI+) 343 ([M+H]+, 100%); HRMS (NSI+) C19H20ClN2S+,
([M+H]+) requires 343.1030; found 343.1034 (+1.1 ppm).
Preparation of (R)-2-tert-butyl-3,4-dihydro-2H-pyrimido[2,1-b]-
benzothiazole 41
Et3N (0.71 mL, 5.10 mmol, 3.0 eq) was added to a solution of
(R)-3-(benzothiazol-2-ylamino)-3-tert-butylpropanol 34 (450 mg,
1.70 mmol, 1.0 eq) in CH2Cl2 (18 mL) at 0 ◦C under N2 atmosphere,
followed by methanesulfonyl chloride (0.26 mL, 3.40 mmol, 2.0
eq). The reaction mixture was stirred at 0 ◦C for 1 h and was
then allowed to warm to rt. Once MeOH (0.5 mL) had been
added to quench excess methanesulfonyl chloride, Et3N (1.8 mL)
was added and the mixture refluxed for 16 h. After cooling to
rt, H2O was added and the layers were separated. The organic
layer was dried (MgSO4) and concentrated in vacuo. The residue
was purified via flash column chromatography (silica; 2 : 1 : 97 i-
PrOH/NEt3/hexanes) to give 41 (325 mg, 78%) as a white solid;
Preparation of (2S,3R)-3-isopropyl-2-(2-naphthyl)-3,4-dihydro-
2H-pyrimido[2,1-b]benzothiazole 44
Thionyl chloride (0.20 mL, 2.79 mmol, 2.1 eq) was added to a
stirred solution of 38 (500 mg, 1.33 mmol, 1.0 eq) in PhMe (6 mL)
and the reaction mixture was heated at 120 ◦C. Once complete,
the mixture was allowed to cool to rt and MeOH was added.
After evaporation of the solvent, 10% aq. NaOH was added to the
residue followed by extraction with CH2Cl2 (¥3). The combined
organic extracts were washed with brine, dried (Na2SO4) and
concentrated◦in vacuo to afford 44 (420 mg, 88%) as a brown solid;
mp 108–112 C; [a]D20 +250.0 (c 0.5 in CH2Cl2); nmax (KBr) 3057,
2959, 1624, 1587; dH (400 MHz, CDCl3) 0.75 (3H, d, J 6.7), 1.09
(3H, d, J 6.5), 1.22–1.34 (1H, m), 1.97 (1H, ddt, J 10.7, 9.3, 4.7),
3.37 (1H, t, J 11.4), 3.84 (1H, ddd, J 11.7, 5.3, 1.6), 5.03 (1H, dd, J
4.3, 1.1), 6.77 (1H, d, 7.7), 6.99 (1H, td, J 7.7, 1.0), 7.15–7.21 (1H,
m), 7.26 (1H, dd, J 8.5, 1.8), 7.29 (1H, dd, J 7.7, 1.0), 7.35–7.39
(2H, m), 7.62 (1H, s), 7.69–7.75 (3H, m); dC (100 MHz, CDCl3)
20.1, 22.3, 27.1, 41.2, 42.2, 61.5, 107.8, 122.1, 122.1, 123.3, 125.8,
126.1, 126.1, 126.1, 126.2, 127.0, 127.6, 128.1, 132.8, 133.4, 138.2,
140.8, 158.7; m/z (NSI+) 359 ([M+H]+, 100%); HRMS (NSI+)
C23H23N2S+, ([M+H]+) requires 359.1576; found 359.1574 (-0.7
ppm).
◦
mp 114–116 C; [a]D20 -148.7 (c 0.5 in CHCl3); nmax (KBr) 2948,
1625; dH (300 MHz; CDCl3) 0.99 (9H, s), 1.58–1.72 (1H, m), 2.08
(1H, dddd, J 13.2, 4.8, 3.3, 1.2), 3.08 (1H, dd, J 11.1, 3.3), 3.62
(1H, dt, J 11.4, 1.8), 3.84 (1H, ddd, J 11.4, 5.7, 2.1), 6.68 (1H, app
d, J 7.5), 6.95 (1H, dt, J 7.7, 0.9), 7.16 (1H, dt, J 7.8, 1.2), 7.26
(1H, dd, J 7.6, 1.2); dC (75 MHz, CDCl3) 20.5, 26.6, 34.4, 42.0,
64.6, 107.1, 121.3, 121.8, 122.7, 125.7, 141.0, 156.4; m/z (ES+) 247
([M+H]+, 100%); HMRS (ES+) C14H19N2S+, ([M+H]+) requires
247.1263; found 247.1265 (+0.6 ppm).
Preparation of (6aR,10aR)-(7,8,9,10,10a,11)-hexahydro-6aH-
benzothiazolo[2,3-b]quinazoline 42
Thionyl chloride (0.12 mL, 1.66 mmol, 2.2 eq) was added to a
stirred solution of 35 (198 mg, 0.756 mmol, 1.0 eq) in PhMe
(3 mL) and the reaction mixture was heated at 120 ◦C. Once
complete the mixture was allowed to cool to rt and MeOH was
added. After evaporation of the solvent, 10% aq. NaOH was
added to the residue followed by extraction with CH2Cl2 (¥3). The
combined organic extracts were washed with brine, dried (Na2SO4)
and concentrated in vacuo to afford 42 (186 mg, quantitative yield)
as a brown solid; mp 100–102 ◦C; [a]D20 +146.0 (c 0.5 in CH2Cl2);
Preparation of (S)-3-isopropyl-3,4-dihydro-2H-pyrimido[2,1-b]
benzothiazole 45
A flask was charged with alcohol (S)-39 (233 mg, 0.930 mmol,
1.0 eq), thionyl chloride (0.150 mL, 2.05 mmol, 2.2 eq) and
toluene (5 mL). The reaction mixture was refluxed for 6 h, cooled
to rt and concentrated in vacuo. The residue was dissolved in
MeOH (9 mL), KOH (131 mg, 2.33 mmol, 2.5 eq) was added
and the mixture was refluxed for 3 h. After cooling to rt, H2O
(9 mL) was added and the product extracted with CH2Cl2 (3 ¥
15 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), filtered and concentrated in vacuo. (S)-45 was
n
max (KBr) 2932, 2848, 1615; dH (400 MHz, CDCl3) 1.25–1.67 (7H,
m), 1.72–1.82 (1H, m), 2.01 (1H, tt, J 8.8, 4.3), 3.46 (1H, dd, J
11.4, 4.4), 3.55–3.60 (1H, m), 3.65 (1H, dd, J 11.4, 5.0), 6.62 (1H,
d, J 8.0), 6.89 (1H, td, J 7.6, 1.0), 7.09 (1H, td, J 7.8, 1.1), 7.18
(1H, dd, J 7.8, 0.9); dC (100 MHz, CDCl3) 21.9, 24.6, 26.6, 30.6,
32.3, 46.4, 54.6, 107.2 121.5, 121.8, 122.8, 125.8, 141.1, 156.5; m/z
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obtained as a brown oil (110 mg, 51%), which was shown by chiral
HPLC {Daicel CHIRALCEL AD-H, 4.6 mm ¥ 250 mm, 20 : 80
i-PrOH/hexane, 1 mL min-1, retention times of enantiomers: 7.6
(R), 9.0 (S)} to have >98% ee; [a]2D0 -64.0 (c 0.6 in CHCl3); nmax
(KBr) 2961,1631; dH (300 MHz, CDCl3) 1.03 (3H, d, J 6.3), 1.04
(3H, d, J 6.3), 1.65–1.79 (2H, m), 3.22 (1H, ABX, JAB 14.8, JBX
10.2), 3.36 (1H, app t, J 10.7), 3.67–3.71 (1H, m), 3.82–3.86 (1H,
m), 6.75 (1H, d, J 8.0), 6.98 (1H, app. t, J 7.6), 7.18 (1H, app
t, J 7.6), 7.26–7.27 (1H, m); dC (75 MHz, CDCl3) 157.7, 140.8,
125.8, 122.7, 121.8, 121.6, 107.2, 49.4, 45.1, 35.9, 29.2, 20.2, 20.0;
m/z (ES+) 233 ([M+H], 100%); HRMS (ES+) C13H17N2S, ([M+H])
requires 233.1112; found 233.1105 (-3.2 ppm).
LiAlH4 reduction of ester (entries 11 and 12; Table 4)
To a solution of the propionate ester of 52 (40 mg, 0.180 mmol,
1.0 eq) in anhydrous Et2O (2.5 mL) was added LiAlH4 (2.0 M
in hexanes, 0.14 mL, 0.290 mmol, 1.6 eq). The reaction mixture
was stirred at rt for 2 h then quenched with MeOH. The resulting
mixture was filtered through a cotton wool bud, dried (Na2SO4)
and concentrated in vacuo to furnish the corresponding alcohols.
Characterisation data for (R)-1-(4-fluorophenyl)ethyl propionate
59
76% ee; [a]2D0 +76.4 (c 0.3 in CHCl3); dH (300 MHz, CDCl3): 1.13
(3H, t, J 7.6), 1.51 (3H, d, J 6.6), 2.33 (2H, qd, J 7.6, 1.5),
5.86 (1H, q, J 6.6), 6.99-7.05 (2H, m), 7.26-7.34 (2H, m); dC
(75 MHz, CDCl3), 9.7, 22.9, 28.5, 72.1, 115.9 (d, J 21.5), 128.5
(d, J 8.2), 138.3, 161.3 (d, J 166.1), 174.3; nmax (film) 2983, 1735;
m/z (EI+) 196 ([M]+, 12%), 123 ([M–CO2Et]+, 100%); HRMS (ES+)
C11H17FNO2 ([M+NH4]+) requires 214.1238; found 214.1239 (+0.5
ppm).
General procedure for the kinetic resolution of secondary alcohols
(Table 4)
The requisite secondary alcohol (1.00 mmol, 1.0 eq) was added to
0.5 mL of the stirred catalyst stock solution (see below for prepa-
ration) at the required temperature. Once the reaction mixture
was homogenous, propionic anhydride (0.60 mL, 0.500 mmol,
0.5 eq) was added and timing was initiated. After 1 h, MeOH
(2 mL) was added and the mixture was diluted with EtOAc. The
mixture was washed with 1.0 M aq. HCl, sat. aq. NaHCO3, dried
(MgSO4) and concentrated in vacuo. Purification of the residue
via flash column chromatography {silica; 5 : 95 EtOAc/hexanes
(entries 3–6 and 13–17; Table 4) 2 : 98 EtOAc/hexanes (entries
1,2 and 7–12, Table 4)} gave the corresponding alcohol and
ester. The alcohols were directly analysed by chiral HPLC. The
esters were derivatised (see below for derivatisation procedures)
and then analysed by chiral HPLC. All propionate esters have
previously been characterised in the literature, except (R)-1-(4-
fluorophenyl)ethyl propionate 59.
General procedure for the preparative scale kinetic resolution of
secondary alcohols (Table 7)
The requisite secondary alcohol (1.0 eq) was added to 2 mL of the
stirred stock solution of catalyst 14 at the required temperature.
Once the reaction mixture was homogenous, propionic anhydride
(0.6 eq) was added and timing was initiated. After the specified
time, MeOH (5 mL) was added and the mixture was diluted
with EtOAc. The mixture was washed with 1.0 M aq. HCl,
sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo.
Purification of the residue via flash column chromatography gave
the corresponding alcohol and ester.
Preparation of catalyst stock solution
Preparative scale kinetic resolution of 1-(naphtalen-1-yl)ethanol 46
Chiral isothiourea 14 (3 mol%), i-Pr2NEt (0.42 mL, 2.40 mmol,
2.4 eq) and the requisite solvent (1 mL) were placed in a 2 mL
volumetric flask. Once the mixture was homogeneous the requisite
solvent was added until the total volume of the mixture had
reached 2 mL.
Following the general procedure, alcohol 46 (500 mg, 2.90 mmol,
1.0 eq) and 2 mL of the catalyst stock solution {14 (4.4 mg,
0.0140 mmol, 0.5 mol%) and i-Pr2NEt (0.30 mL, 1.74 mmol,
0.6 eq) in CHCl3 (10 mL)} were stirred and propionic anhydride
(0.22 mL, 1.74 mmol, 0.6 eq) was added. The reaction was stirred
at rt for 18 h. Purification via flash column chromatography gave
the alcohol as a beige solid (144 mg, 30%, >99% ee) and the ester
as a pale yellow oil (333 mg, 50%, 74% ee). The alcohol and ester
were directly analysed by chiral HPLC {Daicel CHIRALCEL
OD-H, 4.6 mm ¥ 250 mm, 10 : 90 i-PrOH/hexane, 1 mL min-1,
retention times of alcohol enantiomers: 16.1 min (R), 9.9 min (S)
and ester enantiomers 4.8 min (R), 5.9 min (S)}.
Derivatisation procedures DMAP-catalysed esterification of
alcohols (entries 3 and 4; Table 4)
A flask was charged with DMAP (0.7 mg, 0.00600 mmol,
10 mol%), CH2Cl2 (0.2 mL) and alcohol 48 (11 mg, 0.0660 mmol,
1.0 eq). Once homogeneous, propionic anhydride (0.10 mL,
0.0850 mmol, 1.3 eq) was added and the reaction mixture was
stirred for 3 h at rt. The mixture was then diluted with EtOAc,
washed with 1.0 M aq. HCl and sat. aq. NaHCO3, dried (MgSO4)
and concentrated in vacuo. The corresponding esters were then
analysed by chiral HPLC.
Preparative scale resolution of 1-(naphtalen-2-yl)ethanol 48
Following the general procedure, alcohol 48 (500 mg, 2.90 mmol,
1.0 eq) and 2 mL of catalyst stock solution {14 (4.4 mg,
0.0140 mmol, 0.5 mol%), i-Pr2NEt (0.30 mL, 1.74 mmol, 0.6 eq) in
CHCl3 (10 mL)} were stirred and propionic anhydride (0.22 mL,
1.74 mmol, 0.6 eq) was added. The reaction was stirred at rt
for 18 h. Purification via flash column chromatography gave the
alcohol as a white powder (154 mg, 30%, >99% ee) and the ester
as brown oil (332 mg, 50%, 67% ee). The alcohol was derivatised
and analysed by chiral HPLC {Daicel CHIRALCEL OD-H,
KOH hydrolysis of ester (entries 5–10, 13–17; Table 4)
To a solution of the requisite ester in MeOH was added aq. 2.0 M
KOH. The reaction mixture was stirred for 2 h at 65 ◦C then
extracted with EtOAc (¥2) and concentrated in vacuo. The alcohols
obtained were then analysed by chiral HPLC.
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4.6 mm ¥ 250 mm, 1 : 99 i-PrOH/hexane, 1 mL min-1, reten-
tion times of enantiomers: 7.2 min (R), 8.7 min (S)}.
Guerin, S. J. Miller and T. Lectka, Chem. Rev., 2003, 103, 2985–3012;
A. C. Spivey, A. Maddaford and A. J. Redgrave, Org. Prep. Proced. Int.,
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2731–2733.
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3 A. C. Spivey, T. Fekner and S. E. Spey, J. Org. Chem., 2000, 65,
3154–3159; A. C. Spivey, A. Maddaford, D. Leese and A. J. Redgrave,
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T. Fekner, A. Maddaford and D. P. Leese, Tetrahedron, 2006, 62, 295–
301.
Preparative scale resolution of 2,2-dimethyl-1-phenylpropan-1-ol
52
Following the general procedure, alcohol 52 (500 mg, 3.05 mmol,
1.0 eq) and 5 mL of the catalyst stock solution {14 (4.7 mg,
0.0150 mmol, 0.5 mol%), i-Pr2NEt (0.31 mL, 1.83 mmol, 0.6 eq) in
CHCl3 (10 mL)} were stirred and propionic anhydride (0.25 mL,
1.98 mmol, 0.65 eq) was added. The reaction was stirred at 0 ◦C
for 60 h. Purification via flash column chromatography gave the
alcohol as a white powder (220 mg, 44%, >99% ee) and the ester as
a pale yellow oil (298 mg, 44%, 99% ee) The ester was hydrolysed
and analysed by chiral HPLC analysis {Daicel CHIRALCEL
OD-H, 4.6 mm ¥ 250 mm, 15 : 85 i-PrOH/hexane, 1 mL min-1,
retention times of enantiomers: 5.9 min (R), 4.7 min (S)}.
4 G. Priem, B. Pelotier, S. J. F. Macdonald, M. S. Anson and I. B.
Campbell, J. Org. Chem., 2003, 68, 3844–3848.
5 For reviews that highlight alternative applications of planar chiral PPY
derivatives in asymmetric catalysis see: G. C. Fu, Acc. Chem. Res., 2000,
33, 412–420; G. C. Fu, Acc. Chem. Res., 2004, 37, 542–547. For select
recent applications of PPY derivatives in asymmetric catalysis see; M.
Dochnahl and G. C. Fu, Angew. Chem. Int. Ed., 2009, 48, 2391–2393;
J. M. Berlin and G. C. Fu, Angew. Chem., Int. Ed., 2008, 47, 7048–
7050.
6 T. Sano, K. Imai, K. Ohashi and T. Oriyama, Chem. Lett., 1999, 265–
266; T. Sano, H. Miyata and T. Oriyama, Enantiomer, 2000, 5, 119–123;
D. Terakado, H. Koutaka and T. Oriyama, Tetrahedron: Asymmetry,
2005, 16, 1157–1165; D. Terakado and T. Oriyama, Org. Synth., 2006,
83, 70–79.
Preparative scale resolution of (E)-4-phenylbut-3-en-2-ol 53
Following the general procedure, alcohol 53 (500 mg, 3.37 mmol,
1.0 eq) and 2 mL of the catalyst stock solution {14 (5.2 mg,
0.0170 mmol, 0.5 mol%), i-Pr2NEt (0.34 mL, 2.02 mmol, 0.6 eq) in
CHCl3 (10 mL)} were stirred and propionic anhydride (0.26 mL,
2.02 mmol, 0.6 eq) was added. The reaction was stirred at rt
for 24 h. Purification via flash column chromatography gave the
alcohol as a colourless oil (120 mg, 24%, 95% ee) and the ester as
a pale yellow oil (354 mg, 54%, 66% ee) The ester was hydrolysed
and analysed by chiral HPLC analysis {Daicel CHIRALCEL
OD-H, 4.6 mm ¥ 250 mm, 10 : 90 i-PrOH/hexane, 1 mL min-1,
retention times of enantiomers: 10.1 min (R), 15.3 min (S)}.
7 For reviews see: S. J. Miller, Acc. Chem. Res., 2004, 37, 601–610; E.
Colby Davie, S. M. Mennen, Y. Xu and S. J. Miller, Chem. Rev.,
2007, 107, 5759–5812. For specific applications see; S. J. Miller, G. T.
Copeland, N. Papaioannou, T. E. Horstmann and E. M. Ruel, J. Am.
Chem. Soc., 1998, 120, 1629–1630; E. R. Jarvo, G. T. Copeland, N.
Papaioannou, P. J. Bonitatebus Jr and S. J. Miller, J. Am. Chem. Soc.,
1999, 121, 11638–11643; E. R. Jarvo, M. M. Vasbinder and S. J. Miller,
Tetrahedron, 2000, 56, 9773–9779; G. T. Copeland and S. J. Miller,
J. Am. Chem. Soc., 2001, 123, 6496–6502; E. R. Jarvo, C. A. Evans,
G. T. Copeland and S. J. Miller, J. Org. Chem., 2001, 66, 5522–5527;
M. C. Angione and S. J. Miller, Tetrahedron, 2006, 62, 5254–5261.
8 E. Vedejs and O. Daugulis, J. Am. Chem. Soc., 1999, 121, 5813–5814;
E. Vedejs, O. Daugulis and S. T. Diver, J. Org. Chem., 1996, 61, 430–
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125, 4166–4173; E. Vedejs and J. A. MacKay, J. Org. Chem., 2004, 69,
6934–6937.
9 For selected other kinetic resolution procedures using small molecule
catalysts see: (a) M.-H. Lin and T. V. RajanBabu, Org. Lett., 2002,
4, 1607–1610; (b) K.-S. Jeong, S.-H. Kim, H.-J. Park, K.-J. Chang and
K. S. Kim, Chem. Lett., 2002, 1114–1115; (c) Y. Matsumura, T. Maki, S.
Murakami and O. Onomura, J. Am. Chem. Soc., 2003, 125, 2052–2053;
(d) S. Mizuta, M. Sadamori, T. Fujimoto and I. Yamamoto, Angew.
Chem., Int. Ed., 2003, 42, 3383–3385; (e) Y. Suzuki, K. Yamauchi, K.
Muramatsu and M. Sato, Chem. Commun., 2004, 2770–2771; (f) K.
Ishihara, Y. Kosugi and M. Akakura, J. Am. Chem. Soc., 2004, 126,
12212–1243; (g) C. O. Dalaigh, S. J. Hynes, D. J. Maher and S. J.
Connon, Org. Biomol. Chem., 2005, 3, 981–984; (h) T. Kano, K. Sasaki
and K. Maruoka, Org. Lett., 2005, 7, 1347–1349; (i) S. Yamada, T.
Misono and Y. Iwai, Tetrahedron Lett., 2005, 46, 2239–2242. For an
interesting approach to the kinetic resolution of quaternary and tertiary
b-hydroxy esters see: D. J. Schipper, S. Rousseaux and K. Fagnou,
Angew. Chem., Int. Ed., 2009, 48, 8343–8347.
Preparative scale resolution of 4-phenylbut-3-yn-2-ol 54
Following the general procedure, alcohol 54 (500 mg, 3.42 mmol,
1.0 eq) and 2 mL of the catalyst stock solution {14 (5.2 mg,
0.0170 mmol, 0.5 mol%), i-Pr2NEt (0.34 mL, 2.02 mmol, 0.6 eq) in
CHCl3 (10 mL)} were stirred and propionic anhydride (0.26 mL,
◦
2.05 mmol, 0.6 eq) was added. The reaction was stirred at 0 C
for 18 h. Purification via flash column chromatography gave the
alcohol as a colourless oil (134 mg, 27%, >99% ee) and the ester as
a pale yellow oil (300 mg, 44%, 57% ee) The ester was hydrolysed
and analysed by chiral HPLC analysis {Daicel CHIRALCEL
OD-H, 4.6 mm ¥ 250 mm, 15 : 85 i-PrOH/hexane, 1 mL min-1,
retention times of enantiomers: 5.9 min (R), 11.3 min (S)}.
Acknowledgements
The authors would like to thank the Royal Society for a University
Research Fellowship (ADS), AstraZeneca (PAW), the EPSRC
(CJ), The Carnegie Trust for the Universities of Scotland (CDC
and CJ) and the Nuffield Foundation (Bursary to CM). The
EPSRC mass spectrometry facility is also acknowledged.
10 (a) V. B. Birman, E. W. Uffman, H. Jiang, X. Li and C. J. Kilbane,
J. Am. Chem. Soc., 2004, 126, 12226–12227; (b) V. B. Birman and H.
Jiang, Org. Lett., 2005, 7, 3445–3447; (c) V. B. Birman, X. Li, H. Jiang
and E. W. Uffman, Tetrahedron, 2006, 62, 285–294.
Notes and references
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12 V. B. Birman, H. Jiang and X. Li, Org. Lett., 2007, 9, 3237–3240.
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13 M. Kobayashi and S. Okamoto, Tetrahedron Lett., 2006, 47, 4347–4350;
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26 J. Matsuo, M. Okano, K. Takeuchi, H. Tanaka and H. Ishibashi,
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29 Throughout this manuscript, the level of reaction conversion was calcu-
lated by HPLC measurement of the reaction products using the method
of Kagan outlined in reference 30. The reaction conversions can also be
readily determined by 1H NMR spectroscopy and indicate a consistent
level of conversion to that observed from HPLC calculation. Duplicate
reactions were carried out, with equivalent levels of conversion and
enantioselectivity observed. The absolute configuration of the products
was confirmed by specific rotation calculation and comparison with the
literature in each case (see ESI† for further details).
17 Q. Xu, H. Zhou, X. Geng and P. Chen, Tetrahedron, 2009, 65, 2232–
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19 For an excellent recent review of Lewis-base mediated reaction
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20 (a) J. E. Thomson, K. Rix and A. D. Smith, Org. Lett., 2006, 8, 3785–
3788; (b) J. E. Thomson, C. D. Campbell, C. Concello´n, N. Duguet,
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and A. D. Smith, Tetrahedron: Asymmetry, 2010, 21, 601–616. For a
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30 H. B. Kagan, J. C. Fiaud, in “Topics in Stereochemistry”, E. L. Eliel
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32 All attempts to prepare authentic N-acyl intermediates and to analyse
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33 S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich and H. Zipse, Chem.–
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34 Within the series of arylethanols tested for their reactivity in kinetic
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35 Several work-up procedures for LiAlH4 reductions are available that
avoid the difficulties of separating by-products of the reduction. The
Fieser work-up employed here provides a granular inorganic precipitate
that is easy to rinse and filter; (a) L. A. Paquette, in Handbook of
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36 Although this species and its enantiomer have been reported in the
literature, no specific rotation values have been reported.
37 Automated flash column chromatography was performed on a Teledyne
Isco CombiFlashꢀR System.
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25 Enantiomerically pure b-amino acids 18 and 19 are commercially
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570 | Org. Biomol. Chem., 2011, 9, 559–570
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