Catalytic asymmetric aminolactonization of 1,2-disubstituted alkenoic acid esters: Efficient construction of aminolactones with an all-carbon quaternary stereo-centre

Article abstract of DOI:10.1039/c4cc01944j

Chiral BOX-Cu(OTf)₂ catalyzed enantioselective aminolactonization of the tert-butyl ester of alkenoic acids has been developed via in situ aziridination using PhINNs as the nitrene source. It provides exclusively trans-γ- and δ-amino lactones including an additional all-carbon quaternary stereo-centre with up to 98% ee in good to excellent yields. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01944j

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Catalytic asymmetric aminolactonization of
1,2-disubstituted alkenoic acid esters: Efficient
construction of aminolactones with an all-carbon
quaternary stereo-centre†‡
Cite this: Chem. Commun., 2014,
50, 6913
Received 16th March 2014,
Accepted 4th May 2014
Saumen Hajra,* Sk Md Samim Akhtar and Sk Mohammad Aziz
DOI: 10.1039/c4cc01944j
www.rsc.org/chemcomm
Chiral BOX–Cu(OTf)2 catalyzed enantioselective aminolactonization of
the tert-butyl ester of alkenoic acids has been developed via in situ
aziridination using PhINNs as the nitrene source. It provides exclusively
trans-c- and d-amino lactones including an additional all-carbon
quaternary stereo-centre with up to 98% ee in good to excellent yields.
The oxidative intramolecular reaction of carboxylic acid and its
derivatives with pendant olefins is an efficient tool for the
construction of synthetically useful compounds like g- and
d-lactones. Among the oxidative cyclization reactions of alkenoic
acids/derivatives, halolactonization is an age-old reaction that has
been widely used in organic synthesis for the installation of a
remote chiral functionality.1 Recently catalytic asymmetric halo-
lactonization of prochiral alkenoic acids has progressed and
matured significantly with excellent diastereo- and enantio-
Scheme 1 Proposed aminolactonization via aziridination.
selectivity.2 Asymmetric hydroxylactonization via epoxidation is also Herein we report the catalytic and enantioselective aminolacto-
known in the literature and has proven to be a versatile transfor- nization of internal b,g- and g,d-alkenoic acid esters that provides
mation too.3 However, synthetically useful, conceptually related g and d-lactones, respectively, containing internal amino function-
asymmetric aminolactonization via aziridination has not yet been ality with high diastereo- (dr 4 99 : 1) and enantio-selectivity
explored, though asymmetric aziridination4 and subsequent ring (ee upto 94%) and also synthesis of aminolactones having an
opening reactions5 have been extensively studied. Our research all-carbon quaternary stereo-centre with excellent diastereo- (dr 4
interest towards asymmetric aminocyclization6 via catalytic and 99 : 1) and enantioselectivity (ee upto 98%).
enantioselective in situ aziridination prompted us to investigate the
One of the more convenient ways for the direct and stereo-
aminolactonization of alkenoic acids/derivatives. Recently Dodd selective conversion of alkenes to aziridines is by the action of
et al. reported the aminolactonization of a terminal alkenoic acid iodinane ylides (ArI = NSO2Ar) under copper catalyzed reaction
ester and one entry of a non-racemic reaction with 48% ee.7
conditions.11 Recently, copper catalyzed iminoiodinane mediated
It was hypothesized that alkenoic acid esters 1 upon aziridina- stereoselective aminoarylation reactions have been extensively studied
tion would generate aziridine 2 with a tethered carboxylic acid in our laboratory.6 Cu(OTf)2 was found to act as an efficient dual
ester and g-aryl substitution of the in situ generated aziridine may catalyst for aziridination and subsequent Friedel–Crafts cyclization
facilitate the fused-5-endo-cyclization to produce g-lactones 3, reaction of the in situ generated aziridine and combination of the
containing internal amino-functionality (Scheme 1). The amino- same with chiral bis-oxazoline (BOX) ligand led to high enantio-
lactones are valued enough to access several synthetic targets.8–10 induction. In the allied studies PhINSO2(4-NO2C6H4) [PhINNs]
was recognized as the better nitrene precursor compared to
Department of Chemistry, Indian Institute Technology Kharagpur,
PhINSO2(4-MeC6H4) [PhINTs]. It is also observed that the
PhINSO2Ar species undergoes decomposition in the presence
of carboxylic acid. So aminolactonization of alkenoic carboxylic
Kharagpur 721302, India. E-mail: shajra@chem.iitkgp.ernet.in;
Fax: +91 3222 255303; Tel: +91 3222 283340
† Dedicated with respect to Professor Ganesh Pandey on the occasion of his
acid via in situ aziridination was not successful. Accordingly the
60th birthday.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01944j tert-butyl ester of alkenoic acid is used where the tert-butyl
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Table 1 Optimization of asymmetric aminolactonization of alkenoic acid
ester 1a
with the cyclised product 3a. The enantioselectivity (ee) and yield of
the cyclized product 4-nosylamido-5-phenylbutyrolactone 3a on silica
gel was not affected. So we opted for silica gel (60–120 mesh)
mediated lactonization instead of additional Cu(OTf)2.
To optimize the yield and enantioselectivity, the reaction was
studied with different BOX ligands in a variety of solvents and with
variation of the reaction temperature as well. For the reaction of 1a
in the presence of BOX ligands 4b–4d, the dissolution of the nitrene
reagent was found to be incomplete even after 24 h and resulted in
poor yields and ee (entries 2–4). Extra chelation due to the Py-BOX
ligand 4e led to the complete erosion of enantioselectivity (entry 5).
The same result was also obtained for the phenyl BOX ligand 4f with
cyclo-propyl unit (entry 6). At last the indanolamine derived BOX
ligand 4g was found to work well. The extra bulk of the indanol-
amine derived BOX ligand 4g, compared to the phenyl BOX ligand 4a
may hinder the copper ion from undergoing good chelation, which is
ultimately manifested in better enantioselectivity (ee 63%; entry 7).
The effect of the solvent on this reaction was very substantial. In
CH2Cl2, ClCH2CH2Cl, CHCl3 and CH3CN, the yields were comparable
but the corresponding selectivities were quite decisive (entries 7–11).
Chlorinated solvents resulted in comparatively higher chiral induc-
tion and CHCl3 emerged as the best choice for the solvent with an ee
of 90% under the same reaction conditions (entry 9).
The aziridination was also found to be very sensitive toward
temperature. The reaction slowed down significantly upon
lowering the temperature and at 10 1C there was no reaction even
after 48 h. When temperature was raised to 40 1C, the yield
increased from 68% to 80% with reduced enantioselectivity (87%),
which was quite acceptable (entries 9 and 12). Both silica gel as
well as the additional amount of Cu(OTf)2 facilitate the cyclization
step. Enantioselectivity and yield in both cases were the same.
Thus the results are best explained by aziridine formation and
cyclization, where the enantioselectivity originates in an aziridina-
tion step which is carried over through the lactonization step and
there is no erosion of enantioselectivity. To support this further,
instead of the tert-butyl ester, the corresponding methyl ester was
subjected to the reaction conditions in the presence of the BOX
ligand 4g and the corresponding aziridine was isolated in 72% ee.
Entry Ligand Solvent
T (1C) t (h) Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4g
4g
4g
4g
4g
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl 30
CHCl3
C6H6
30
30
30
30
30
30
30
12
24
24
24
24
24
18
24
24
24
18
20
81
26
39
Trace
31
44
72
64
68
43c
15c
12c
NDd
0
0
63
41
90
53
21
87
9
30
30
30
40
10
11
12
15
70
80
CH3CN
CHCl3
a
b
Isolated yield after flash column chromatography. Enantiomeric
c
excess was determined by HPLC. The other enantiomer was predomi-
d
nantly formed. ND = not determined.
group serves to mask the carboxylic acid. It was assumed that The lower ee value of the aziridine from methyl alkenoic acid ester
chelation of the Lewis acid with the N-nosyl moiety of aziridine compared to amino lactone 3a obtained from the corresponding
would generate a partial positive charge on the benzylic carbon of tert-butyl ester 1a may be due to steric-demand.
the aziridine, which would facilitate the subsequent lactonization
Having set the optimized reaction conditions, we explored the
with the release of the tert-butyl group as butylene (Scheme 1). scope of this catalytic asymmetric aminolactonization reaction
Thus the tert-butyl ester of homocinnamic acid 1a was reacted using a panel of substituted phenyl analogous substrates. For
with PhINNs in the presence of a BOX–Cu(OTf)2 catalyst and substrates 1b and 1c having halogen substituents at the para-
showed encouraging results (Table 1). It is to be noted that there position of the aromatic ring, the reaction went through smoothly
was no reaction in the absence of the BOX ligand.
to provide the aminolactones 3b and 3c with very good ee values of
Reaction of 1a (5.0 equiv.) with PhINNs (1.0 equiv.) was carried 90% and 86%, respectively (Table 2; entries 2 and 3). Aziridination
out in the presence of Cu(OTf)2 (0.1 equiv.) and the phenyl-BOX of an ortho-substituted styrene is always a challenge. Substrate 1d
ligand 4a (0.12 equiv.) derived from L-phenyl glycine in CH2Cl2 at having ortho-chloro substituent afforded the highest ee of 94%
30 1C. After complete dissolution of PhINNs (12 h), the reaction (entry 4). ortho- and meta-bromo substrates 1e and 1f underwent
mixture was treated with an additional amount of Cu(OTf)2 the reaction easily and provided satisfactory yields with compar-
(0.1 equiv.). Within 10 min, the intermediate compound transformed able enantioselectivities (entries 5 and 6). Very fast aziridination
exclusively into trans-aminolactone 3a (dr 4 99 : 1) with 43% ee in was observed for substrate 1g containing a para-electron donating
81% yield (Table 1; entry 1). Every attempt to isolate the intermediate substituent and the product aminolactone 3g exhibited 77% ee
aziridine 2a by column chromatography failed; we always ended up (entry 7). It is worth mentioning that for electron rich substrates a
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Table 2 Generalisation of the one pot aminolactonization reaction for
b,g-unsaturated carboxylic acid esters 1a
Entry Ar
1
3
tb (h)
Yieldc (%) eed (%)
1
2
3
4
5
6
7
8
9
Ph
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
20
22
24
30
30
24
5 min
80
63
68
57
56
62
87
83
87
90
86
94
80
82
77
88
84
4-FC6H4
4-ClC6H4
2-ClC6H4
2-BrC6H4
3-BrC6H4
4-MeOC6H4
4-MeC6H4
1g
3g
1h 3h 20
3,4-OCH2OC6H4 1i
3i
15 min 82
a
Substrate 1 (5 equiv.) and PhINNs (1.0 equiv.) was employed with the
BOX–Cu(II) complex, derived from 10 mol% Cu(OTf)2 and 12 mol% BOX
ligand 4g in CHCl3. The suspension was stirred at 40 1C. After dissolution
of all the nitrenoid reagents, 0.2 g of silica gel (60–120 mesh) was added.
Scheme 2 One pot aminolactonization reaction of g,d-unsaturated ester 5.
b
Total time including aziridine formation and subsequent lactonization.
c
d
Isolated yield after flash column chromatography. Enantiomeric
excess was determined by HPLC using a chiralcel IA column.
silica gel or an additional Lewis acid for lactonization was not
necessary as it directly produced the desired aminolactone. Our
attempt to control the reaction by lowering the temperature did
not improve the results. At 20 1C, the yield was similar, but the ee
fell to 58%. At 0 1C the reaction of 1g was very slow with
incomplete consumption of the nitrenoid reagent even after 24 h
and resulted in poor yield and ee. Substrate 1h showed similar
reactivity to that of 1a and provided high yields of aminolactone 3h
with good enantioselectivity (entry 8). Like substrate 1g, 1i also
underwent fast reaction and provided directly amino lactone 3i
with good yield and ee (entry 9). The absolute stereochemistry of
the aminolactone 3 produced in the presence of indanolamine
BOX ligand 4g was assigned as (4R, 5S) by analogy with the
literature reports (Table 2).6,11
Scheme 3 One pot aminolactonization reaction in spiro-5-exo-tet ring
opening fashion.
stereoselective cyclization and lead to the generation of an all-carbon
The novel aminolactonization reaction was also employed to quaternary chiral centre. Thus substrate 11a was reacted with
higher homologous alkenoic acid esters 5 towards the synthesis PhINNs in the presence of the Cu(OTf)2–BOX 4g catalyst under
of amino-d-lactones 7. Substrates 5a–d reacted smoothly in the standard reaction conditions (Scheme 4). We are delighted to report
presence of the indanolamine based BOX ligand 4g under the same that it exclusively provided only one isomer of amino-d-lactone 12a
reaction conditions and afforded exclusively trans-products 6a–d having an all-carbon quaternary stereo-centre in high yield and
(dr 4 99 : 1) with high enantioselectivity and yields (Scheme 2).
enantioselectivity. This strategy is also generalized using a few
The aminolactonization is also implemented in styrene 8, substrates 11b–11d, which afforded excellent enantioselectivity
where carboxylic ester functionality is tethered at the ortho- (ee up to 98%) and yields (Scheme 4). The stereochemistry of the
position of the arene moiety (Scheme 3). Substrate 8 (E : Z = all-carbon quaternary centre is assigned by the nOe experiment.
82 : 18) underwent smooth aminolactonization under the same
The aminolactones are important structural motifs that are
reaction conditions via spiro-5-exo-tet ring opening of aziridine present in, or are precursors to, many biologically important
9 and afforded exclusively lactone 10 with 79% ee in good yield. compounds.8,9 For example, aminolactones 3 can be easily trans-
Asymmetric construction of all-carbon quaternary stereo-centre is formed into b-benzyl-b-amino acids (Scheme 5), which are the key
of great interest and challenge to organic chemists.12 This prompted precursors to many compounds.9 As an application, aminolactone
us to investigate the aminolactonization of alkene having the pro- 3g was converted to b-amino acid by reductive lactone opening.
chiral gem-dicarboxylic acid ester 11. It was hypothesized that during However, Pd/C-catalyzed direct hydrogenation of 3g to the corre-
lactonization one of the tert-butyl ester moieties would be involved in sponding N-nosyl-b-amino acid was not successful. So it was
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represents an elegant route to the formation of exclusively
trans-g- and d-lactones containing the amino-functionality with
synthetically useful yields and enantioselectivities (ee of up to
94%). Aminolactonization of olefin with tethered pro-chiral
gem-diester efficiently afforded amino lactones with an all-carbon
quaternary stereo-centre in very high yields with excellent diastereo-
(499 : 1) and enantioselectivity (ee: 94 to 98%). Further application
of the method is exemplified by transforming the amino g-lactone 3
to N-Boc-b-benzyl-b-amino acid.
We thank DST, New Delhi for providing financial support.
SMSA and SMA thank the UGC and CSIR, New Delhi, respec-
tively, for their fellowships. The authors are thankful to the
referees for constructive scientific comments and suggestions.
Notes and references
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Scheme 4 Synthesis of d-aminolactones with all-carbon quaternary
stereo-centre.
4 Reviews on asymmetric aziridination: (a) P. Muller and C. Fruit,
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Scheme 5 Synthesis of N-Boc b-benzyl-b-amino acid 16.
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converted to N-Boc-aminolactone 15 upon treatment with
4-methoxythiophenol and subsequent Boc-protection. Com-
pound 15 upon hydrogenation in the presence of Pd/C gave
the desired N-Boc-b-amino acid 16 in excellent yield. The
26
optical rotation of 16 {[a]D = À17.4 (c 1.1, EtOH)} was
compared with the literature data13 {[a]D20 = À18.7 (c 1, EtOH)},
and the absolute stereochemistry of amino acid 16 was con-
firmed to be (S). In turn it further confirmed the absolute
stereochemistry of aminolactone 3 as (4R, 5S).
In summary, we have developed an efficient enantioselective
aminolactonization of internal alkenoic acid esters via in situ
aziridination using a chiral BOX–Cu(OTf)2 catalyst. This report
13 L. Lankiewicz, D. Glanz, Z. Grzonka, J. Slaninova, T. Barth and
F. Fahrenholz, Bull. Pol. Acad. Sci., Chem., 1989, 37, 45.
6916 | Chem. Commun., 2014, 50, 6913--6916
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