Organocatalytic asymmetric mannich reactions of 5H-oxazol-4-ones: Highly enantio- and diastereoselective synthesis of chiral α-alkylisoserine derivatives

Article abstract of DOI:10.1002/adsc.201300135

The first organocatalytic Mannich reaction of 5H-oxazol-4-ones with various readily prepared aryl- and alkylsulfonimides has been developed. Two commercially available pseudoenantiomeric Cinchona alkaloids-derived tertiary amine/ureas have been demonstrated as the most efficient catalysts to access the opposite enantiomers of the Mannich products with equally excellent enantio- and diastereoselectivities. From the Mannich adducts, important α-methyl-α-hydroxy-β-amino acid derivatives, such as the α-methylated C-13 side chain of taxol and taxotere, can be conveniently prepared. Copyright

Full text of DOI:10.1002/adsc.201300135

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DOI: 10.1002/adsc.201300135
Organocatalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-
ones: Highly Enantio- and Diastereoselective Synthesis of Chiral
a-Alkylisoserine Derivatives
Zhiqiang Han,+a Wenguo Yang,+a Choon-Hong Tan,a,b and Zhiyong Jianga,b,*
a
Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan
475004, Peopleꢀs Republic of China
E-mail: chmjzy@henu.edu.cn
Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, 637371, Singapore
b
+
Z. Han and W. Yang made equal contributions to this work.
Received: February 8, 2013; Published online: May 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300135.
Abstract: The first organocatalytic Mannich reac-
tion of 5H-oxazol-4-ones with various readily pre-
pared aryl- and alkylsulfonimides has been devel-
oped. Two commercially available pseudoenantio-
meric Cinchona alkaloids-derived tertiary amine/
ureas have been demonstrated as the most efficient
catalysts to access the opposite enantiomers of the
Mannich products with equally excellent enantio-
and diastereoselectivities. From the Mannich ad-
ducts, important a-methyl-a-hydroxy-b-amino acid
derivatives, such as the a-methylated C-13 side
chain of taxol and taxotere, can be conveniently
prepared.
Non-proteinogenic a-hydroxy-b-amino acids (isoser-
ines) are probably the most important members of
the b-amino acid family that are essential scaffolds to
a large number of well-known, naturally occurring
products endowed with potent biological activity
(Figure 1).[1] A prime example is (2R,3S)-phenyliso-
serine at the C-13 side chain of taxol, taxotere and de-
rivatives, which are currently considered to be among
the most promising drugs used in cancer chemothera-
py for breast and ovarian cancer.[2] Following numer-
ous synthetic efforts, biological assays carried out
with the C-2’-methylated a-hydroxy-b-amino acids,
namely a-hydroxy-a-methyl-b-amino acids, revealed
significant enhancement of potency and reduction in
toxicity compared with the parent drug.[3] Concurrent-
ly, Turos and co-workers disclosed that the incorpora-
tion of methyl group into the C-3 position of N-thio-
lated C-3-oxygenated b-lactams should increase the
Keywords: a-alkyl-a-hydroxy b-amino acids; asym-
metric catalysis; Mannich reaction; 5H-oxazol-4-
ones; N-triisopropylbenzenesulfonylimines
Figure 1. Representative biologically active molecules containing a-hydroxy-b-amino acids.
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Zhiqiang Han et al.
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Figure 2. Retrosynthetic analysis of a-methyl-a-hydroxy-b-amino acids (Pg=protecting group).
anti-Bacillus activity (Figure 1).[4] The improved activ- access various a-hydroxy-a-methyl/alkyl-b-amino
ities exhibited by these potential drug candidates acids with excellent enantio- and diastereoselectivity
have stimulated the development of preparative and a broad substrate scope. Herein, we would like to
methods for a-hydroxy-a-methyl-b-amino acids.[5] report the first organocatalytic Mannich reaction of
However, the asymmetric strategy to access a-hy- 5H-oxazol-4-ones with the readily prepared and
droxy-a-methyl-b-amino acids with aryl and alkyl b- modified aryl- as well as alkylsulfonimides in excel-
substituted groups simultaneously, is still not reported lent enantio- and diastereoselectivities, leading to the
and represents a formidable task, coupled with the favorable preparation of enantiopure a-methyl/alkyl-
challenge to construct a chiral tertiary alcohol.[6]
a-hydroxy-b-amino acid derivatives. Furthermore, this
On retrosynthetic analysis, it is easy to reveal that protocol is applicable to access the opposite enantio-
the Mannich reaction is plausible to construct the b- mers of the Mannich adducts with equally excellent
amino acid with a-hydroxy esters as nucleophiles stereoselectivities by replacing the catalyst with its
(Figure 2). However, the construction of a chiral terti- pseudoenantiomeric pair.
ary alcohol using the Mannich reaction demands
To achieve the stereoselective Mannich reaction of
a highly reactive system for the sterically hindered 5H-oxazol-4-ones with sulfonimides, a bifunctional
donor substrates. We turned our attention to the tertiary amine catalyst with a properly installed
Mannich reaction of 5H-oxazol-4-one 1a bearing Brønsted acid moiety is pertinent. Therefore, we
a methyl group at the C-5 position as the pronucleo- began our investigation by examining a number of
phile, by which the Mannich adduct could be readily thiourea and urea bifunctional catalysts derived from
converted into chiral a-hydroxy acids with a quaterna- commercially available Cinchona alkaloids (I–VI)
ry stereocenter.
(Figure 3).[11] The results are summarized in Table 1.
5H-Oxazol-4-ones were first introduced by Trost Initially, we selected the Mannich reaction of 5H-
and co-workers as useful pronucleophiles in asymmet- oxazol-4-one 1a with N-Ts-imine 2a as a model reac-
ic allylic alkylation with chiral diphosphine-molybde- tion in CH2Cl2 at 258C in the presence of 10 mol%
num catalysts.[7] Subsequently, Misaki and Sugimura cinchonine-derived thiourea I (Table 1, entry 1). We
et al. described an asymmetric aldol reaction of 5H- found that the reaction could proceed smoothly
oxazol-4-ones with aldehydes and 1,4-addition with within 12 h in excellent yield with good enantioselec-
terminal alkynyl carbonyl compounds catalyzed by tivity but poor diastereoselectivity. When the reaction
chiral guanidine catalysts.[8] Ye and co-workers pre- was conducted at À108C (Table 1, entry 2), the ee
sented a 1,4-addition of 5H-oxazol-4-ones to a,b-un- value of the product 3a increased to 94%. Further op-
saturated ketones using a new thiourea-tertiary amine timizations of the reaction conditions were done by
bifunctional catalyst derived from l-tert-leucine.[9] screening and examination of solvents with I as cata-
Trost and co-workers reported a 1,4-addition of 5H- lyst at À108C (Table 1, entries 3–5). Et2O proved op-
oxazol-4-ones to nitroolefins to prepare a-alkyl-a-hy- timal with regards to both diastereo- and enantiose-
droxy carboxylic acid derivatives catalyzed by a dinu- lectivity (Table 1, entry 4). We further prepared sever-
clear zinc complex.[10]
al sulfonimides[12] and explored the effects of the N-
Very recently, Wang and co-workers disclosed the protective group of imines under the same reaction
first report on the asymmetric Mannich reaction be- conditions (Table 1, entries 6–8). It was found that the
tween 5H-oxazol-4-ones with N-diphenylphophinoyl- steric tuning of the protective groups enhanced the
protected imines catalyzed by a zinc complex with diastereoselectivity greatly and sulfonimide 2c with
good to excellent enantioselectivities.[5c] Notably, the N-triisopropylbenzenesulfonyl (TIPBs)[13] as the bulk-
presented results with 5H-oxazol-4-one 1a as nucleo- iest group gave the best results (3c, 96% ee and
phile were rare, and only one example of an alkyl- >19:1 dr). Since the adduct 3c was very unstable in
ACHTUNGTRENNUNGimine was reported with a good enantioselectivity. In the presence of traces of moisture, the hydrolyzed
this context, it is still highly desirable and represents product 4a without compromising ee and dr was con-
a formidable task to develop an asymmetric catalysis veniently obtained by adding 5.0 equiv. of water into
to afford an efficient and economical approach to the reaction system at room temperature after the
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Organocatalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-ones
Figure 3. Structures of various Cinchona alkaloid-derived bifunctional organocatalysts I–VI.
Table 1. Screening studies.[a]
Entry
2
Catalyst
Solvent
Temp. [oC]
Time [h]
3/4
Yield [%][b]
ee [%][c]
dr[d]
1
2
3
4
2a
2a
2a
2a
2a
2b
2c
2d
2c
2c
2c
2c
2c
I
I
I
I
I
I
I
I
II
III
IV
V
VI
CH2Cl2
CH2Cl2
toluene
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
25
12
12
12
12
12
28
28
28
72
72
72
72
72
3a
3a
3a
3a
3a
3b
4a
3d
ent-4a
4a
4a
4a
ent-4a
90
43
87
82
39
76
87
76
80
79
76
87
83
77, 31
94, 48
96, 74
96, 57
82, 45
96, 87
96
99, 99
96
98
1.5:1
2.5:1
2.0:1
4.0:1
3.0:1
13:1
>19:1
1:1
>19:1
>19:1
>19:1
>19:1
>19:1
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
5
6
7[e]
8
9[e]
10[e]
11[e]
12[e,f]
13[e,h]
Et2O
Et2O
Et2O
95
99[g]
97
[a]
The reaction was carried out with 0.02 mmol of 1a, 0.03 mmol of 2, and 0.002 mmol of catalyst in 0.2 mL solvent.
Isolated yield.
Determined by HPLC methods.
Determined by H NMR analysis.
After 1a was exhausted, 5 equiv. of H2O was added at room temperature and the hydrolyzed product 4a was obtained
within 30 min.
0.1 mmol of 1a, 0.15 mmol of 2, and 0.01 mmol of V in 1.0 mL Et2O at À108C.
Temp. =08C, time=48 h, yield=93%, ee=93%, dr=19:1; temp.=258C, time=12 h, yield=85%, ee=79%, dr=19:1.
0.1 mmol of 1a, 0.15 mmol of 2, and 0.01 mmol of VI in 1.0 mL Et2O at À108C. Bz=benzoyl.
[b]
[c]
[d]
[e]
1
[f]
[g]
[h]
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Zhiqiang Han et al.
Table 2. Asymmetric Mannich reaction of 5H-oxazol-4-ones 1 with N-TIPBs-arylimines 2 catalyzed by V.[a]
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Entry
R
Ar
Time [h]
4
Yield [%][b]
ee [%][c]
dr[d]
1
2
3
4
5
6
7
8
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Et (1b)
n-Bu (1c)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Et (1b)
4-CF3C6H4 (2e)
4-ClC6H4 (2f)
3-FC6H4 (2g)
4-MeC6H4 (2h)
4-iPrC6H4 (2i)
4-MeOC6H4 (2j)
2-MeOC6H4 (2k)
1-naphthyl (2l)
2-furyl (2m)
2-thienyl (2n)
Ph (2c)
82
72
92
78
89
84
82
88
72
79
94
96
89
86
92
86
88
88
96
96
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
ent-4c
ent-4e
ent-4f
ent-4g
ent-4i
ent-4k
ent-4l
ent-4m
87
81
83
84
78
87
72
83
81
80
69
77
81
90
81
78
83
80
72
82
99
96
99
96
99
96
94
98
94
94
97
99
95
96
98
96
97
90
99
98
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
9
10
11
12
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
19[e]
20[e]
Ph (2c)
4-ClC6H4 (2f)
4-MeC6H4 (2h)
4-iPrC6H4 (2i)
4-MeOC6H4 (2j)
1-naphthyl (2l)
2-thienyl (2n)
Ph (2c)
n-Bu (1c)
Ph (2c)
[a]
The reaction was carried out with 0.1 mmol of 1, 0.15 mmol of 2, and 0.01 mmol of V in 1.0 mL Et2O at À108C.
[b]
[c]
[d]
[e]
Isolated yield.
Determined by HPLC methods.
1
Determined by H NMR analysis.
The reaction was carried out with 0.1 mmol of 1, 0.15 mmol of 2, and 0.01 mmol of VI in 1.0 mL Et2O at À108C. Bz =
benzoyl.
5H-oxazol-4-one 1a had been exhausted (Table 1, of the reaction were not affected by the electronic ef-
entry 7). fects of substituted groups on the aromatic rings of
We next utilized other Cinchona alkaloids-derived imines (Table 2, entries 1–7). Excellent ees were also
thioureas and ureas (II–VI) to catalyze the Mannich obtained when the phenyl group of imines is replaced
reaction of 5H-oxazol-4-one 1a with N-TIPBs-imine by other aromatic groups such as furyl and thienyl
2c in Et2O at À108C (Table 1, entries 9–13). The (Table 2, entries 9 and 10). Other 5H-oxazol-4-ones
survey revealed that both of enantio- and diastereose- 1b and 1c, containing 5-substituted n-butyl and ethyl,
lectivities were excellent in all of the reaction condi- also gave the corresponding adducts 3l and 3m in
tions, and cinchonine-derived urea V was the best cat- good yields with 97% and 99% ee in >19:1 dr
alyst (Table 1, entry 12). We were delighted to find (Table 2, entries 11 and 12), indicating that more hin-
that cinchonidine-derived urea VI, the pseudoenan- dered substituent at the C-5 position of 5H-oxazol-4-
tiomeric pair of V, provided ent-4a, the enantiomer of one should help increase the enantioselectivity of the
4a, with 97% ee and >19:1 dr (Table 1, entry 13).
reaction. Subsequently, we evaluated the generality of
With a set of optimized reaction conditions on the reaction by utilizing the catalyst VI to generate
hand (10 mol% V in Et2O at À108C, then 5.0 equiv. the enantiomers of 4 (ent-4, Table 2, entries 13–20). It
of H2O at room temperature for 30 min), as shown in was found that the desired enantiomers could be ob-
Table 2, the Mannich reaction with 5H-oxazol-4-ones tained in 72–90% yield and 90–99% ee with >19:1 dr.
1a as the nucleophiles could be extended to a wide
Next we endeavored to prepare the equally impor-
variety of N-TIPBs-arylimines (2e–n) to afford the tant b-alkyl-substituted a-hydroxy-b-amino acid deriv-
desired products 4b–k in 72–87% yield with 94–99% atives via Mannich reaction of 5H-oxazol-4-ones
ee and >19:1 dr (Table 2, entries 1–10). The results 1 with N-TIPBs-alkylimines 5 under the established
disclosed that the reaction rate and enantioselectivity reaction conditions. We believe that it is difficult to
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Organocatalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-ones
Table 3. Asymmetric Mannich reaction of 5H-oxazol-4-ones 1 with N-
TIPBs-alkylimines 5 catalyzed by VI.[a]
[a]
The reaction was carried out with 0.1 mmol of 1, 0.15 mmol of 5, and
0.01 mmol of V in 1.0 mL Et2O at À208C; yield of isolated product; ees
1
were determined by HPLC methods; drs were determined by H NMR
analysis.
[b]
The reaction was conducted at À108C. Bz=benzoyl, TMG=1,1,3,3-tet-
ramethylguanidine.
introduce both aryl- and alkylimines under the same (1,1,3,3-tetramethylguanidine) were necessary for the
conditions,[14] but by lowering the temperature to hydrolysis process. Moreover, the enantiomer of 6
À208C, the Mannich reactions could be accomplished (ent-6) could be obtained with similar enantio- and
with good to excellent diastereoselectivities and excel- diastereoselectivities (Table 3, entries 8 and 9).
lent enantioselectivities (6:1 to 19:1 dr and 90–95%
To verify the synthetic value of this work, we at-
ee, Table 3, entries 1–7). Since the Mannich adducts tempted to prepare the Mannich adducts on a gram
are stable in the presence of H2O, 2.0 equiv. of TMG scale (Scheme 1). From commercially available 1,3,5-
Scheme 1. Gram-scale preparation of Mannich adduct 4a: a) ClSO3H (4.0 equiv.), CH2Cl2, 08C to room temperature, 45 min;
b) NH3 (aq.), CH2Cl2, room temperature, 12 h, 74% yield (two steps); c) PhCHO (1.0 equiv.), neat, 1608C, 16 h, 83% yield.
Bz=benzoyl.
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Zhiqiang Han et al.
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Scheme 2. Synthesis of a-methyl-a-hydroxy-b-amino acids: a) NaOH (aq., 5.0 equiv.), EtOH, 08C to room temperature,
98% yield; b) Na/NH3, À788C, 0.5 h, 81% yield; c) BzCl (1.1 equiv.), Et3N (4.0 equiv.), CH2Cl2, room temperature, 12 h,
84% yield; d) TsOH (2.0 equiv.), MeOH, 958C in sealed tube, 7 d, 66% yield, 99% ee. Bz=benzoyl.
tris(1-methylethyl)-benzene 7 (5.0 g), the correspond- acid derivatives with an extensive scope and excellent
ing sulfonamide 8 could be readily prepared with results. Further work is ongoing to prepare another
74% yield (5.2 g) after reaction with chlorosulfuric pair of diastereomers through this protocol and will
acid and ammonia.[12] 5.7 g of N-TIPBs-phenylimine be reported in due course.
2c were then obtained from 8 and benzaldehyde with
83% yield. In the presence of catalyst V at À108C
after 96 h, the Mannich reaction of 2c with 1a afford- Experimental Section
ed the adduct 4a in a 4.63 g (80%) yield in 98% ee
and >19:1 dr.
Representative Procedure for the Synthesis of 4a
Subsequently, we prepared a-methyl-a-hydroxy-b-
amino acids from the Mannich adducts (Scheme 2). In
the presence of NaOH in EtOH, 4a could be hydro-
lyzed to afford the corresponding tertiary alcohol 9 in
excellent yield. After treating compound 9 with Na/
NH3 at À788C, a-methylated (2R, 3S)-phenylisoserine
10 was conveniently attained. The amine group of 10
was then protected by a benzoyl group (Bz) to furnish
compound 11a. The absolute configurations of the
Mannich products were assigned based on X-ray crys-
tallographic analysis of a single crystal of 11b, pre-
pared from 10 and 2-chlorobenzoyl chloride.[15] Next,
the esterification of 11a by using 2.0 equiv. of p-tolu-
5H-Oxazol-4-one 1a (1.79 g, 10.23 mmol, 1.0 equiv.) and N-
TIPBs-phenylimine 2c (5.7 g, 15.34 mmol, 1.5 equiv.) were
dissolved in diethyl ether (90 mL). After stirring at À108C
for 30 min, a pre-cooled solution of catalyst V (1.023 mmol,
0.1 equiv., 561 mg in 10 mL Et2O) was added. The reaction
mixture was stirred at À108C and monitored by TLC. After
96 h, the reaction was completed and warmed up to room
temperature. H2O (0.92 mL, 51.15 mmol, 5.0 equiv.) was
added and monitored by TLC. For about 30 min, the hydrol-
ysis was completed. After extraction using Et2O and brine
for three time, flash chromatography afforded product 4a as
a colorless oil; yield: 4.63 g (80%).
Supporting Information
ACHTUNGTRENNUNGenesulfonic acid successfully generated the optical
pure compound 12, which is the a-methylated C-13
side chain of taxol and taxotere.
Experimental procedures, characterization and spectroscopic
data (PDF) are available in the Supporting Information.
In summary, we have developed the first organoca-
talytic Mannich reaction of 5H-oxazol-4-ones with
easily prepared N-TIPBs-aryl- and alkylimines in ex-
cellent enantio- and diastereoselectivities. A pair of
bifunctional tertiary amine/ureas, derived from two
commercially available pseudoenantiomeric Cinchona
alkaloids provide the optimal catalyst to access the
opposite enantiomers of the Mannich products with
equally excellent stereoselectivities. The Mannich re-
action could be conveniently scaled up to the gram
scale without compromising the enantioselectivity.
Demonstrating the synthetic utility, we have success-
fully prepared an important a-methyl-a-hydroxy-b-
amino acid derivative, the a-methylated C-13 side
chain of taxol and taxotere, from the Mannich adduct.
We believe that this protocol can be applied to pre-
pare a variety of a-methyl/alkyl-a-hydroxy-b-amino
Acknowledgements
We are grateful for financial support from the NSFC
(21072044), Excellent Youth Foundation of Henan Scientific
Committee (114100510003), Specialized Research Fund for
the
Doctoral
Program
of
Higher
Education
(20104103120002) and International Cooperation Foundation
of Henan Province (104300510062).
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Organocatalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-ones
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[15] In the presence of 2-Cl-BzCl (1.1 equiv.) and Et3N
(4.0 equiv) in CH2Cl2 at room temperature within 12
hours, 84% yield of 11b was obtained. CCDC 917270
(11b) contains the supplementary crystallographic data
for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Adv. Synth. Catal. 2013, 355, 1505 – 1511
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