Enantioselective organocatalytic addition of azlactones to maleimides: A highly stereocontrolled entry to 2,2-Disubstituted-2H-oxazol-5-ones

Article abstract of DOI:10.1002/chem.201000239

The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to maleimides is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol.

Full text of DOI:10.1002/chem.201000239

DOI: 10.1002/chem.201000239
Enantioselective Organocatalytic Addition of Azlactones to Maleimides:
A Highly Stereocontrolled Entry to 2,2-Disubstituted-2H-oxazol-5-ones
Andrea-Nekane R. Alba,[a] Guillem Valero,[a] Teresa Calbet,[b] Mercꢀ Font-Bardꢁa,[b]
Albert Moyano,*[a] and Ramon Rios*[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
Abstract: The first highly diastereo- and enantioselective organocatalytic synthesis
Keywords:
Michael addition · organocatalysis ·
oxazolones
maleimides
·
of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to
maleimides is promoted by bifunctional thiourea catalysts, which afford the corre-
sponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol.
Introduction
dent on the substitution pattern of the azlactone. When 2-
aryl-substituted azlactones were used only C-2 addition was
observed, whereas the use of 2-tert-butylazlactones exclu-
sively afforded the C-4-substituted regioisomer (Scheme 1).
The enantioselective construction of quaternary stereocen-
ters is a challenging goal in organic synthesis and this topic
has received considerable attention from the synthetic com-
munity.[1] In this context, the alkylation of azlactones (4H-
oxazol-5-ones) has emerged as one of the most useful ways
to build quaternary stereocenters, due to their high reactivi-
ty and easy transformation into quaternary a-substituted a-
amino acid derivatives.[2] In 2008, Jørgensen and co-workers
reported the first asymmetric oxazolone addition to a,b-un-
saturated aldehydes, catalyzed by chiral secondary amines,
with excellent results.[3] Subsequently, Jørgensen and co-
workers[4] and ourselves[5] almost simultaneously disclosed
the tertiary-amine-catalyzed azlactone addition to nitrostyr-
enes, which proceeded with high diastereoselectivities. One
of the most interesting points to emerge from both papers
was the regioselectivity of the reaction, which was depen-
Scheme 1. Regioselectivity of the addition of azlactones to nitrostyrenes.
However, it should be highlighted that the nature of the
electrophile also plays an important role in the regiochemis-
try of the addition. As first demonstrated by Steglich
et al.,[6] in several cases the regiochemistry is totally directed
by the nature of electrophile. Thus, a,b-unsaturated alde-
hydes appear to give C-4-substituted azlactones independent
of the nature of C-2 substituent.[3] Very recently, we have
found that the addition of azlactones to 1,1-bis(phenylsulfo-
nyl)ethene also takes place with complete C-4 regioselectivi-
ty (Scheme 2).[7]
With these results in mind, and in the context of a re-
search program devoted to the development of new asym-
metric methodologies based on organocatalysis,[8] we decid-
ed to study the behavior of azlactones towards other electro-
philes, such as maleimides. Maleimides have been used ex-
tensively in metal-mediated asymmetric synthesis as dieno-
[a] A.-N. R. Alba, G. Valero, Prof. Dr. A. Moyano, Dr. R. Rios+
Department of Organic Chemistry, Universitat de Barcelona
Martꢀ i Franquꢁs 1-11, 08028 Barcelona (Spain)
Fax : (+34)933397878
E-mail: amoyano@ub.edu
rios.ramon@icrea.cat
[b] T. Calbet, M. Font-Bardꢀa
Departament de Cristalografia, Mineralogia i Dipꢂsits Minerals
Universitat de Barcelona, Martꢀ i Franquꢁs s/n
08028 Barcelona (Spain)
[+] ICREA Researcher at UB
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000239.
9884
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Chem. Eur. J. 2010, 16, 9884 – 9889

FULL PAPER
enantioselectivity were reduced,
whereas chloroform (Table 1,
entry 2) provided results only
marginally inferior to those ob-
tained with toluene. When
polar solvents ethanol and
DMF were used, no reaction
was observed (Table 1, entries 4
and 5).
Scheme 2. Regioselectivity of the addition of azlactones to a,b-unsaturated aldehydes and vinyl sulfones.
philes[9] or dipolarophiles[10] in cycloadditions, or as Michael
acceptors.[11] Following the landmark 1989 paper of Riant
Table 1. Optimization of reaction conditions with Takemotoꢄs thiourea.[a]
and Kagan,[12] maleimides have been employed in enantiose-
lective Diels–Alder cycloadditions with anthrones[13] and,
more recently, in asymmetric Michael reactions with 1,3-di-
carbonyl compounds,[14] aldehydes,[15] and 2-mercaptobenzal-
dehydes.[16] Their use in vinylogous Michael reactions with
a,a-dicyanoolefins has also been reported.[17] To the best of
our knowledge, the asymmetric conjugate addition of azlac-
tones to maleimides had not yet been studied and should
provide a practical route to synthetically and biologically
important chiral a-succinimidates.[18]
Entry
Solvent
Conversion (1 h) [%][b]
T [8C]
d.r.[b]
e.r.[c]
1
2
3
4
5
6
7
toluene
CHCl3
AcOEt
EtOH
DMF
toluene
toluene
100
100
100
–
–
100
20
RT
RT
RT
RT
RT
4
20:1
18:1
13:1
–
–
25:1
25:1
84:16
82:12
71:29
–
Results and Discussion
–
Our initial investigations revealed that 4H-oxazol-5-one 1a
underwent a Et3N-catalyzed Michael addition to N-phenyl-
maleimide (2a) in toluene at room temperature (Scheme 3)
to afford compound 3a as mixture of diastereomers (2.4:1
diastereomeric ratio (d.r.)) in 92% isolated yield, with com-
plete C-2 regioselectivity.
87:13
94:6
À20
[a] Maleimide 2a (1 equiv) was added to a mixture of 1a (1.2 equiv) and
catalyst I (10 mol%). [b] Determined by 1H NMR spectroscopy of the
crude reaction mixture. [c] Major diastereomer e.r., determined by chiral
HPLC.
Next, we screened catalysts other than (S,S)-I, which in-
cluded chiral thioureas and bases derived from Cinchona al-
kaloids, in toluene at room temperature (Table 2). The reac-
tion was efficiently catalyzed by quinidine-derived thiourea
II, although with reduced enantioselectivity (Table 2, entry 2
versus 1). Quinine-derived thiourea III also catalyzed the
addition but, surprisingly, with a very low reaction rate
(Table 2, entry 3). When chiral bases quinine (VII), quini-
dine (VIII), and Sharplessꢄ ligands IV–VI were used no re-
action was observed (Table 2, entries 4–8). This shows that
the hydrogen-bond-donating thiourea moiety is crucial in
the catalysis of this new reaction (see Scheme 5 below).
Once the reaction conditions were optimized with respect
to catalyst (Takemotoꢄs thiourea I) and solvent (toluene),
we performed a screening of substituted azlactones. The
scope of the reaction with C-2-substituted valine-derived
azlactones 1a–d is summarized in Table 3. As previously no-
ticed by Jørgensen and co-workers[3] and ourselves,[7] when
fluorine atoms were located in positions 2,4 on the phenyl
ring the enantioselectivities increased up to 95:5 e.r. in rela-
tion to entry 1, Table 3. It should be noted that when 2-
alkyl-substituted oxazolones were treated with maleimides
in the presence of catalyst I, a 3.5:1 regioisomeric mixture
of C-4 and C-2 adducts was obtained. The major C-4 ad-
Scheme 3. Addition of azlactone 1a to N-phenylmaleimide (2a).
We turned our attention to an asymmetric version of the
same reaction. To this end, we tested Takemotoꢄs thiourea
catalyst (S,S)-I[19] in different solvents, with the intention to
take advantage of the bifunctional nature of the catalyst to
improve the diastereoselectivity of the process[7] (Table 1).
To our delight, the reaction afforded optically active adduct
3a (84:16 enantiomeric ratio (e.r.)) when run in toluene at
room temperature, with excellent diastereoselectivity (20:1
d.r.) and total conversion after 1 h (Table 1, entry 1). When
the reaction was performed at À208C both the diastereose-
lectivity (25:1 d.r.) and the enantioselectivity (94:6 e.r.) in-
creased, although the reaction rate was appreciably reduced
(Table 1, entry 7). When the reaction was run in ethyl ace-
tate (Table 1, entry 3) both the diastereoselectivity and the
Chem. Eur. J. 2010, 16, 9884 – 9889
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9885

A. Moyano, R. Rios et al.
Table 2. Catalyst screening.[a]
Table 4. C-4 substituent screening: Addition of 2-(2,4-difluorophenyl)-
azlactones to N-phenylmaleimide.[a]
Entry
R
Compound
Yield [%][b]
d.r.[c]
4.4:1
8:1
25:1
e.r.[d]
95:5
96:4
95:5
1
2
3
4
Me
iBu
iPr
3g
3 f
3c
3e
73
87
99
99
tBu
>25:1
99.5:0.5
[a] Maleimide 2a (1 equiv) was added to a mixture of 1 (1.2 equiv) and
catalyst I (10 mol%) in toluene and stirred for 14 h at À208C. [b] Isolat-
Conversion (14 h) [%][b] d.r.[b] e.r.[c]
1
Entry Catalyst
ed yield after column chromatography. [c] Determined by H NMR spec-
troscopy of the crude reaction mixture. [d] Major diastereomer e.r., de-
termined by chiral HPLC.
1
2
3
4
5
6
7
8
G
100
100
<10
0
20:1
20:1
84:16
68:32
n.d.[e] n.d.
–
–
–
–
–
–
–
–
–
–
0
0
0
0
chromatographic purification, the essentially stereoisomeri-
cally pure adduct 3e (>25:1 d.r. and 99.5:0.5 e.r.) was ob-
tained in 99% yield.
Finally, we studied the scope of the reaction with malei-
mides 2a–e with azlactones derived from tert-leucine
(Table 5). In all cases, the reactions were very stereoselec-
[a] Maleimide 2a (1 equiv) was added to a mixture of 1a (1.2 equiv) and
catalyst I (10 mol%) in toluene at RT [b] Determined by 1H NMR spec-
troscopy of the crude reaction mixture. [c] Major diastereomer e.r., deter-
mined by chiral HPLC. [d] After 24 h, traces of the product were detect-
ed by NMR analysis. [e] n.d.=none detected. [f] (DHQD)2AQN =hydro-
quinidine(anthraquinone-1,4-diyl) diether. [g] (DHQD)2PHAL=1,4-bis-
(dihydroquinidinyl)-phthalazine. [h] (DHQD)2PYR=hydroquinidine-2,5-
diphenyl-4,6-pyrimidinediyl diether.
Table 5. Reaction scope: Addition of 2-aryl-4-tert-butylazlactones to N-
aryl maleimides.[a]
Table 3. C-2 substituent screening: Addition of 2-aryl-4-isopropylazlac-
tones to N-phenylmaleimide.[a]
Entry Ar
R
3
Yield [%][b] d.r.[c]
99
e.r.[d]
1[e]
2
2,4-F2C6H3 Ph
2,4-F2C6H3 4-MeOC6H4 3h 84
2-FC6H4
2,4-F2C6H3 3-ClC6H4
2,4-F2C6H3 4-CF3C6H4
2,4-F2C6H3 6-ClC6H4
3e
>25:1 99.5:0.5
>25:1 97.5:2.5
>25:1 96:4
>25:1 96:4
>25:1 97:3
>25:1 98:2
>25:1 96:4
3[f]
4
Ph
3i
3j
3k 92
3l 94
3m 95
85
62
5
6
Entry Ar
Compound Yield [%][b] T [8C] d.r.[c] e.r.[d]
7
Ph
Ph
1
2
3
4
Ph
3a
76
76
99
85
À20
À20
4
20:1
20:1
25:1
20:1
94:6
92:8
95:5
84:16
2,6-F2C6H3 3b
2,4-F2C6H3 3c
2-FC6H4
[a] Maleimide 2 (1 equiv) was added to a mixture of 1 (1.2 equiv) and
catalyst I (10 mol%) in toluene and stirred for 14 h at 48C. [b] Isolated
yield after column chromatography. [c] Determined by 1H NMR spectros-
copy of the crude reaction mixture. [d] Major diastereomer e.r., deter-
mined by chiral HPLC. [e] Reaction run at À208C. [f] Reaction run at
RT.
3d
RT
[a] Maleimide 2a (1 equiv) was added to a mixture of 1 (1.2 equiv) and
catalyst I in toluene. [b] Isolated yield after column chromatography.
[c] Determined by 1H NMR spectroscopy of the crude reaction mixture.
[d] Major diastereomer e.r., determined by chiral HPLC.
tive and afforded diastereomerically pure (>25:1 d.r.) 2-
aryl-2-(3-succinimidyl)-2H-oxazol-5-ones of high enantio-
meric purity (>96:4 e.r.). It should be noted that product 3e
precipitated from the solution in toluene and as a result
could be isolated in enantiopure form (only one enantiomer
detected by HPLC) and in 99% yield by simple filtration of
the reaction mixture.
The relative and absolute configuration of compound 3n,
obtained from the reaction of azlactone 1i (derived from
(S)-isoleucine) with N-phenylmaleimide (2a) (Scheme 4),
were ascertained by X-ray diffraction analysis of a single
crystal of the major diastereomer (Figure 1).
ducts were produced with low diastereoselectivities and with
moderate enantioselectivities.[20]
We retained the 2-(2,4-difluorophenyl) substituent in
azlactones 1e–g to investigate the effect of the C-4 alkyl
substituent (Table 4). Both the yields and the enantiomeric
purities were good in all instances. The diastereoselectivity
of the process was clearly dependent on the a-branching
degree of the C-4 alkyl substituent and increased along the
series methyl<isobutyl<isopropyl<tert-butyl (Table 4, en-
tries 1–4, respectively). This last example (reaction with tert-
leucine-derived azlactone 1e) was remarkable in that, after
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Chem. Eur. J. 2010, 16, 9884 – 9889

Organocatalytic Addition of Azlactones to Maleimides
FULL PAPER
and suitability for large-scale reactions for practical industri-
al preparations.[22]
Experimental Section
General procedure for azlactone addition to maleimides: In a small flask,
oxazolone 1a–i (0.30 mmol, 1.2 equiv), maleimide 2a–e (0.25 mmol,
1.0 equiv), and catalyst I (0.025 mmol, 0.1 equiv) in toluene (1 mL) were
stirred at the temperature described in Tables 3–5 or Scheme 4. The
crude products 3a–n were purified by flash column chromatography.
Scheme 4. Reaction of azlactone 1i with maleimide 2a.
Compound 3a: The reaction was run with (R,R)-I. Colorless oil, 88%
enantiomeric excess (ee). [a]2D5 =À20.5 (c=0.7, CHCl3); 1H NMR
(400 MHz, CDCl3, TMSint): d=7.61–7.56 (m, 2H), 7.47–7.42 (m, 5H),
7.41–7.36 (m, 1H), 7.20–7.15 (m, 2H), 3.89 (dd, J=9.7, 5.4 Hz, 1H), 3.02
(h, J=6.8 Hz, 1H), 2.93 (dd, J=18.6, 5.4 Hz, 1H), 2.75 (dd, J=18.6,
9.7 Hz, 1H), 1.30 (d, J=6.8 Hz, 3H), 1.24 ppm (d, J=6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=173.5, 172.7, 171.6, 163.2, 136.4, 131.3,
130.0, 129.3, 129.2, 129.1, 129.0, 128.9, 126.4, 126.2, 125.9, 104.7, 47.6,
31.7, 29.7, 28.3, 19.3, 19.1 ppm; HRMS (ESI): m/z: calcd for C22H21N2O4:
377.1496 [M+H]+; found: 377.1487; HPLC (Chiralpak IC, 1 mLminÀ1
,
hexane/iPrOH 80:20, 254 nm): retention times (tR) for major diastereo-
mer=17.8, 28.7 min.
Compound 3b: The reaction was run with (S,S)-I. Colorless oil, 84% ee.
[a]2D5 =+10.0 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3, TMSint): d=
7.48–7.38 (m, 4H), 7.23–7.20 (m, 2H), 7.02–6.96 (m, 2H), 4.41 (dd, J=
8.9, 6.0 Hz, 1H), 3.03 (h, J=6.7 Hz, 1H), 2.97 (dd, J=18.5, 9.7 Hz, 1H),
2.89 (dd, J=9.5, 7.2 Hz, 1H), 1.29 (d, J=6.9 Hz, 3H), 1.23 ppm (d, J=
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.3, 172.6, 171.0, 163.4,
161.7 (d, J=6.5 Hz), 159.2 (d, J=7.3 Hz), 132.3, 132.2, 132.0, 131.3, 129.3,
129.2, 128.9, 128.9, 126.6, 126.2, 113.3 (d, J=3.4 Hz), 113.0 (d, J=2.7 Hz),
45.5, 31.5, 28.1, 19.1, 18.8 ppm; 19F NMR (376 MHz, CDCl3): d=À105.3
(m), À107.3 ppm (m); HRMS (ESI): m/z: calcd for C22H19F2N2O4:
Figure 1. X-ray structure of 3n.[21]
Based on these data, we tentatively propose a bifunctional
transition state in which the tertiary amine of the catalyst
deprotonates the azlactone and the thiourea moiety acti-
vates the maleimide, as shown in Scheme 5.
413.1307 [M+H]+; found: 413.1305; HPLC (Chiralpak IC, 1 mLminÀ1
,
hexane/iPrOH 80:20, 254 nm): tR for major diastereomer=18.2, 30.0 min.
Compound 3c: The reaction was run with (R,R)-I. Colorless oil, 90% ee.
[a]2D5 =À17.0 (c=2.1, CHCl3); 1H NMR (300 MHz. CDCl3, TMSint): d=
7.47–7.35 (m, 4H), 7.20–7.16 (m, 2H), 6.99–6.89 (m, 2H), 4.28 (dd, J=
9.7, 5.6 Hz, 1H), 3.05 (h, J=6.8 Hz, 1H), 2.86 (dd, J=18.4, 9.7 Hz, 1H),
2.72 (dd, J=18.4, 5.6 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.24 ppm (d, J=
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.3, 172.8, 172.5, 165.2
(d, J=11.9 Hz), 163.0, 162.7 (d, J=12.3 Hz), 161.8 (d, J=12.7 Hz), 159.3
(d, J=11.9 Hz), 131.2, 129.6 (dd, J=10.0, 4.2 Hz), 129.2, 128.9, 126.2,
111.6 (dd, J=21.1, 21.2 Hz), 105.8, 105.5, 105.3, 102.5 (d, J=3.8 Hz), 44.9
(d, J=4.6 Hz), 31.5, 28.4, 19.3, 19.0 ppm; 19F NMR (376 MHz. CDCl3):
d=À105.3 (m), À106.9 ppm (m); HRMS (ESI): m/z: calcd for
C22H19F2N2O4: 413.1307 [M+H]+; found: 413.1304; HPLC (Chiralpak IC,
1 mLminÀ1, hexane/iPrOH 75:25, 254 nm): tR major diastereomer=13.3,
19.5 min.
Scheme 5. Proposed transition state for azlactone addition to maleimides.
Compound 3d: The reaction was run with (S,S)-I. Colorless oil, 67% ee.
[a]2D5 =À10.5 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.47–7.56 (m, 5H), 7.26–7.17 (m, 4H), 4.35 (dd, J=9.4, 5.9 Hz, 1H), 3.06
(h, J=6.9 Hz, 1H), 2.85 (dd, J=18.6, 9.7 Hz, 1H), 2.79 (dd, J=18.2,
5.6 Hz, 1H), 1.32 (d, J=6.9 Hz, 3H), 1.24 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=173.4, 172.9, 172.3, 163.1, 161.4, 158.9,
135.4 (d, J=9.9 Hz), 132.1 (d, J=8.8 Hz), 129.2, 128.9, 128.4 (d, J=
2.7 Hz), 126.5, 126.2, 124.5 (d, J=4.2 Hz), 123.7 (d, J=11.9 Hz), 116.9 (d,
J=116.9 Hz), 102.9 (d, J=3.4 Hz), 44.9 (d, J=4.9 Hz), 31.7, 28.4, 19.3,
19.1 ppm; 19F NMR (376 MHz, CDCl3): d=À111.4 ppm (t, J=16.0 Hz);
HRMS (ESI): m/z: calcd for C22H19FN2NaO4: 417.1221 [M+Na]+; found:
Conclusion
We have reported a new, organocatalytic, easily executed,
and highly enantioselective entry to 2H-oxazol-5-ones with
quaternary stereocenters. The addition of 4-alkyl-azlactones
1 to maleimides 2 is efficiently catalyzed by bifunctional thi-
ourea–amine I (both enantiomers of which are commercially
available) with complete C-2 regioselectivity and with good
to excellent diastereoselectivity. The resulting adducts are
obtained with good yields and enantioselectivities. The pro-
cedure presented herein has distinct advantages in terms of
operational simplicity, environmentally friendly conditions,
417.1222; HPLC (Chiralpak IA, 1 mLminÀ1
, hexane/iPrOH 90:10,
254 nm): tR major diastereomer=67.7, 70.5 min.
Compound 3e: The reaction was run with (R,R)-I. Colorless oil, 99% ee.
[a]2D5 =À13.8 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.48–7.37 (m, 4H), 7.21–7.19 (m, 2H), 6.99–6.91 (m, 2H), 4.27 (dd, J=
9.7, 5.5 Hz, 1H), 2.85 (dd, J=18.3, 9.7 Hz, 1H), 2.73 (dd, J=18.4, 5.6 Hz,
1H), 1.34 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=173.8, 173.3,
Chem. Eur. J. 2010, 16, 9884 – 9889
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A. Moyano, R. Rios et al.
172.7, 165.2 (d, J=11.2 Hz), 162.7 (d, J=11.9 Hz), 161.9, 159.3 (d, J=
11.9 Hz), 134.2, 131.2, 129.6 (dd, J=9.9, 4.2 Hz), 129.2, 129.1, 128.9,
126.4, 126.2, 111.6 (dd, J=21.1, 3.5 Hz), 105.1 (dd, J=25.3, 25.4 Hz),
101.2 (d, J=4.2 Hz), 44.9 (d, J=5.0 Hz), 35.0, 31.5, 26.8 ppm; 19F NMR
(376 MHz, CDCl3): d=À106.3 (m), À107.8 ppm (m); HRMS (ESI): m/z:
calcd for C23H24F2N3O4: 444.1729 [M+NH4]+; found: 444.1731; HPLC
(Chiralpak IB, 1 mLminÀ1, hexane/iPrOH 80:20, 254 nm): tR major dia-
stereomer = 26.7, 28.6 min.
(m); HRMS (ESI): m/z: calcd for C23H20ClF2N2O4: 461.1074 [M+H]+;
found: 461.1073; HPLC (Chiralpak IB, 1 mLminÀ1, hexane/iPrOH 80:20,
254 nm): tR major diastereomer = 11.7, 12.2 min.
Compound 3k: The reaction was run with (R,R)-I. Colorless oil, 94% ee.
[a]2D5 =À6.6 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.75–7.70 (m, 2H), 7.42–7.35 (m, 3H), 7.00–6.90 (m, 2H), 4.30 (dd, J=
9.7, 5.5 Hz, 1H), 2.89 (dd, J=18.5, 9.7 Hz, 1H), 2.74 (dd, J=18.5, 5.5 Hz,
1H), 1.33 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=173.9, 172.7,
172.3, 165.3 (d, J=11.9 Hz), 162.8 (d, J=11.9 Hz), 161.9, 161.9, 159.3,
134.3, 130.7 (d, J=33.7 Hz), 129.5 (dd, J=9.5, 3.4 Hz), 126.4, 126.3, 120.0,
111.75 (dd, J=21.1, 2.7 Hz), 105.8, 105.6, 105.3, 101.1 (d, J=3.1 Hz), 45.0
(d, J=4.2 Hz), 35.0, 31.5, 26.9 ppm; 19F NMR (376 MHz, CDCl3): d=
À62.4 (s, 3F), À105.2 (m, 1F), À107.3 ppm (m, 1F); HRMS (ESI): m/z:
calcd for C24H20F5N2O4: 495.1338 [M+H]+; found: 495.1337; HPLC
(Chiralpak IB, 1 mLminÀ1, hexane/iPrOH 80:20, 254 nm): tR major dia-
stereomer=8.7, 14.7 min.
Compound 3 f: The reaction was run with (S,S)-I. Colorless foam,
92% ee. [a]2D5 =+9.5 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3,
TMSint): d=7.50–7.35 (m, 4H), 7.21–7.16 (m, 2H), 7.00–6.89 (m, 2H),
4.29 (dd, J=9.7, 5.8 Hz, 1H), 2.86 (dd, J=18.3, 9.7 Hz, 1H), 2.73 (dd, J=
18.3, 5.8 Hz, 1H), 2.59–2.54 (m, 2H), 2.21 (h, J=6.7 Hz, 1H), 0.99 (d, J=
6.7 Hz, 3H), 0.96 ppm (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=173.1, 172.8, 167.7, 165.2 (d, J=11.9 Hz), 163.7, 162.8, 162.6, 161.7 (d,
J=12.3 Hz), 159.2 (d, J=12.3 Hz), 134.2, 131.2, 129.5 (dd, J=4.2,
10.0 Hz), 129.2, 129.1, 128.9, 128.8, 127.9, 126.4, 126.2, 126.0, 111.7 (dd,
J=21.5, 3.4 Hz), 105.8, 105.5, 105.3, 103.0 (d, J=3.8 Hz), 44.9 (d, J=
4.2 Hz), 36.8, 31.4, 26.0, 22.6, 22.5 ppm; 19F NMR (376 MHz, CDCl3): d=
À105.4 (m, 1F), À106.8 ppm (m, 1F); HRMS (ESI): m/z: calcd for
C23H21F2N2O4: 427.1464 [M+H]+; found: 427.1464; HPLC (Chiralpak IA,
1 mLminÀ1, hexane/iPrOH 90:10, 254 nm): tR major diastereomer=25.8,
27.3 min.
Compound 3l: The reaction was run with (R,R)-I. Colorless oil, 96% ee.
[a]2D5 =À8.6 (c=1.4, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.45–7.35 (m, 3H), 7.20–7.14 (m, 2H), 7.00–6.90 (m, 2H), 4.27 (dd, J=
9.7, 5.6 Hz, 1H), 2.86 (dd, J=18.5, 9.7 Hz, 1H), 2.71 (dd, J=18.5, 5.6 Hz,
1H), 1.33 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=173.9, 173.0,
172.5, 165.3 (d, J=11.9 Hz), 162.7 (d, J=12.7 Hz), 161.0, 159.3 (d, J=
12.3 Hz), 134.7, 129.4, 127.4, 119.9 (d, J=11.1 Hz), 111.8, 111.6, 105.8,
105.6, 105.3, 101.2, 44.9, 35.0, 31.5, 26.9 ppm; 19F NMR (376 MHz,
CDCl3): d=À105.3 (m), À107.0 ppm (m); HRMS (ESI): m/z: calcd for
C23H20ClF2N2O4: 461.1074 [M+H]+; found: 461.1072; HPLC (Chiralpak
IB, 1 mLminÀ1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer=
9.2, 17.2 min.
Compound 3g: The reaction was run with (R,R)-I. Colorless foam,
90% ee. [a]2D5 =À12.4 (c=1.5, CHCl3); 1H NMR (400 MHz, CDCl3,
TMSint): d=7.48–7.36 (m, 4H), 7.21–7.15 (m, 2H), 7.00–6.88 (m, 2H),
4.27 (dd, J=9.7, 5.6 Hz, 1H), 2.86 (dd, J=18.3, 9.7 Hz, 1H), 2.67 (dd, J=
18.3, 5.6 Hz, 1H), 2.37 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
173.1, 165.1, 163.7, 162.8, 161.8, 159.2, 131.2, 129.7, 129.2, 128.9, 126.2,
119.8, 111.8, 105.5, 45.0, 31.4, 14.1 ppm; 19F NMR (376 MHz, CDCl3): d=
À105.4 (m), À107.1 ppm (m); HRMS (ESI): m/z: calcd for
C20H14F2KN2O4: 423.0553 [M+K]+; found: 423.0553; HPLC (Chiralpak
IA, 1 mLminÀ1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer=
16.1, 17.6 min.
Compound 3m: The reaction was run with (R,R)-I. Colorless foam,
92% ee. [a]2D5 =À12.6 (c=0.9, CHCl3); 1H NMR (300 MHz, CDCl3,
TMSint): d=7.61–7.56 (m, 2H), 7.50–7.38 (m, 6H), 7.21–7.14 (m, 2H),
3.87 (dd, J=9.7, 5.2 Hz, 1H), 2.93 (dd, J=18.6, 5.3 Hz, 1H), 2.74 (dd, J=
18.6, 9.7 Hz, 1H), 1.33 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
173.5, 172.9, 172.7, 162.1, 136.5, 134.0, 129.9, 129.2, 129.0, 128.8, 126.4,
103.5, 47.6, 34.9, 31.7, 26.9 ppm; HRMS (ESI): m/z: calcd for
C23H23N2O4: 391.1652 [M+H]+; found: 391.1653; HPLC (Chiralpak IB,
1 mLminÀ1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer=9.9,
26.4 min.
Compound 3h: The reaction was run with (R,R)-I. Yellow oil, 95% ee.
[a]2D5 =À12.0 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.42–7.36 (m, 1H), 7.12–7.08 (m, 2H), 6.99–6.91 (m, 4H), 4.26 (dd, J=
9.7, 5.6 Hz, 1H), 3.81 (s, 3H), 2.84 (dd, J=18.4, 9.7 Hz, 1H), 2.71 (dd,
J=18.4, 5.4 Hz, 1H), 1.34 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
173.8, 173.6, 173.0, 165.6 (d, J=11.6 Hz), 162.0, 159.7, 158.9 (d, J=
11.8 Hz), 129.5 (dd, J=10.1, 4.5 Hz), 127.4, 123.8, 120.1 (dd, J=12.1,
4.0 Hz), 114.6, 111.6 (dd, J=21.1, 3.8 Hz), 105.5 (dd, J=25.9, 26.0 Hz),
101.2 (d, J=4.0 Hz), 55.5, 44.9 (d, J=4.5 Hz), 35.0, 31.4, 26.9 ppm;
19F NMR (376 MHz, CDCl3): d=À106.3 (m), À107.8 ppm (m); HRMS
(ESI): m/z: calcd for C24H26F2N3O5: 474.1835 [M+NH4]+; found:
Compound 3n: The reaction was run with (S,S)-I. White solid, 10:1 d.r.
[a]2D5 =+24.4 (c=1.9, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.60–7.55 (m, 2H), 7.46–7.41 (m, 5H), 7.40–7.35 (m, 1H), 7.19–7.15 (m,
2H), 3.91 (dd, J=9.7, 5.5 Hz, 1H), 2.93 (dd, J=18.5, 5.5 Hz, 1H), 2.87–
2.10 (m, 1H), 2.75 (dd, J=18.5, 9.7 Hz, 1H), 1.89–1.77 (m, 1H), 1.55–
1.45 (m, 1H), 1.26 (d, J=6.9 Hz, 3H), 0.89 ppm (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=173.5, 172.7, 170.9, 163.3, 136.5, 131.3,
129.8, 129.1, 129.0, 128.8, 126.4, 126.2, 104.8, 47.4, 35.0, 31.7, 26.6, 16.5,
11.6 ppm; HRMS (ESI): m/z: calcd for C23H23N2O4: 391.1652 [M+H]+;
found: 391.1651.
474.1837; HPLC (Chiralpak IA, 1 mLminÀ1
, hexane/iPrOH 90:10,
254 nm): tR major diastereomer=29.0, 36.4 min.
Compound 3i: The reaction was run with (R,R)-I. Colorless oil, 84% ee.
[a]2D5 =À20.1 (c=1.5, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.47–7.37 (m, 5H), 7.23–7.17 (m, 4H), 4.33 (dd, J=9.3 Hz, 5.8 Hz, 1H),
2.85 (dd, J=18.3, 9.3 Hz, 1H), 2.78 (dd, J=18.7, 5.9 Hz, 1H), 1.35 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3): d=173.6, 173.5, 172.9, 162.0, 161.4,
158.9, 132.1 (d, J=9.9 Hz), 131.3, 129.2, 128.8, 128.4 (d, J=2.3 Hz), 126.5,
125.2, 124.5 (d, J=3.4 Hz), 123.7 (d, J=11.5 Hz), 116.9 (d, J=21.8 Hz),
101.7 (d, J=3.4 Hz), 44.9 (d, J=4.9 Hz), 34.9, 31.7, 26.9 ppm; 19F NMR
(376 MHz, CDCl3): d=À111.5 ppm (m); HRMS (ESI): m/z: calcd for
C23H22FN2O4: 409.1558 [M+H]+; found: 409.1564; HPLC (Chiralpak IA,
1 mLminÀ1, hexane/iPrOH 95:5, 254 nm): tR major diastereomer=65.5,
69.6 min.
Acknowledgements
We thank the Spanish Ministry of Science and Innovation (MICINN) for
financial support (Project AYA2009-13920-C02-02). A.N.R.A is also
grateful to MICINN for a Predoctoral fellowship.
Compound 3j: The reaction was run with (R,R)-I. Colorless oil, 92% ee.
[a]2D5 =À7.5 (c=0.4, CHCl3); 1H NMR (400 MHz, CDCl3, TMSint): d=
7.41–7.36 (m, 3H), 7.25–7.24 (m, 1H), 7.14–7.12 (m, 1H), 6.99–6.91 (m,
2H), 4.28 (dd, J=9.7, 5.6 Hz, 1H), 2.86 (dd, J=18.5, 9.8 Hz, 1H), 2.73
(dd, J=18.5, 5.5 Hz, 1H), 1.35 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=173.9, 173.6, 172.8, 172.5, 172.3, 161.8, 134.7, 132.2, 130.2,
129.5 (dd, J=8.4, 4.2 Hz), 129.2 (d, J=5.6 Hz), 129.1, 126.5, 124.3, 111.7
(d, J=21 Hz), 105.6 (dd, J=26.6, 26.7 Hz), 101.1 (d, J=8 Hz), 44.9, 35.0,
31.4, 26.8 ppm; 19F NMR (376 MHz, CDCl3): d=À105.4 (m), À107.1 ppm
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Received: January 27, 2010
Published online: May 18, 2010
Chem. Eur. J. 2010, 16, 9884 – 9889
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9889