Organocatalytic diastereo- And enantioselective Michael addition reactions of 5-aryl-1,3-dioxolan-4-ones

Article abstract of DOI:10.1021/ol070532l

5-Aryl-1,3-dioxolan-4-one heterocycles derived from mandelic acid derivatives and hexafluoroacetone have been identified as new and effective pro-nucleophiles in highly diastereo- and enantioselective Michael addition reactions to nitro olefins catalyzed

Full text of DOI:10.1021/ol070532l

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2107-2110
Organocatalytic Diastereo- and
Enantioselective Michael Addition
Reactions of 5-Aryl-1,3-dioxolan-4-ones
Peter S. Hynes,† Daniela Stranges,‡ Paul A. Stupple,§ Antonio Guarna,‡ and
Darren J. Dixon*,†
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester,
M13 9PL, United Kingdom, Dipartimento di Chimica Organica “U. Schiff”,
UniVersita` di Firenze, Via della Lastruccia, 13, I-50019, Sesto Fiorentino, Italy,
and Pfizer Global Research & DeVelopment, Ramsgate Road, Sandwich, Kent,
CT13 9NJ, United Kingdom
darren.dixon@man.ac.uk
Received March 2, 2007
ABSTRACT
5-Aryl-1,3-dioxolan-4-one heterocycles derived from mandelic acid derivatives and hexafluoroacetone have been identified as new and effective
pro-nucleophiles in highly diastereo- and enantioselective Michael addition reactions to nitro olefins catalyzed by bifunctional epi-9-amino-
9-deoxy cinchona alkaloid derivatives. Diastereoselectivities up to 98% and enantioselectivities up to 89% for a range of nitro olefins and
5-aryl-1,3-dioxolan-4-ones under mild reaction conditions are reported.
Single enantiomer bifunctional organocatalysts derived from
cinchona alkaloids or cyclohexane diamine have emerged
as powerful tools for the enantioselective formation of
carbon-carbon and carbon-heteroatom bonds.1 Their ready
preparation and ability to impart high enantiocontrol in the
addition of carbon- and heteroatom-centered nucleophiles to
a variety of electrophiles have all contributed to the pace of
the field.2,3 While most efforts have concentrated on the
development of the range of electrophilic components, less
attention has been devoted to expanding the pool of carbon-
centered pro-nucleophiles attuned to this type of catalysis.
To address this, we have been searching for new and syn-
thetically Versatile pro-nucleophilic entities that would
partake in highly stereoselective reactions mediated by metal-
free bifunctional catalysts that our group, and others, have
developed. One family of heterocycles, the 1,3-dioxolan-4-
ones, was particularly attractive owing to the simplicity of
their structure combined with their ready synthesis (Scheme
1). We postulated that the tunability arising from pos-
sible structural and electronic variations to the group at the
5-position and the acetal function could provide the nec-
essary acidity/nucleophilicity profile for some derivatives to
partake in enantioselective Lewis base/Brønsted acid bifunc-
tional organocatalyst mediated additions to electrophiles
† The University of Manchester.
‡ Universita` di Firenze.
§ Pfizer Global Research & Development.
(1) For seminal work, see: (a) Hiemstra, H.; Wynberg, H. J. Am. Chem.
Soc. 1981, 103, 417. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672. (c) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am.
Chem. Soc. 2004, 126, 9906. For recent examples, see: (d) Inokuma, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413. (e) Li, H.;
Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063.
(2) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (b) Shreiner, P. R. Chem. Soc. ReV. 2003, 32, 289. (c)
Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem.
Res. 2004, 37, 621. (d) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(e) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(f) Connon, S. J. Chem. Eur. J. 2006, 12, 5418.
10.1021/ol070532l CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/04/2007

Scheme 1. 1,3-Dioxolan-4-ones as Potential Pro-nucleophiles
in Enantioselective Organocatalytic Additions to Electrophiles
Figure 1. DABCO and cinchonine derived organocatalysts.
encouraging; heterocycle 2a, derived from mandelic acid and
acetone,5 reacted with trans-â-nitrostyrene with DABCO
(10%) as catalyst in THF at 30 °C but the conversion was
<5% after 14 days (Table 1, entry 1). Ascribing this to an
(X ) Y). Additionally, the use of such pro-nucleophiles
would provide adducts with an activated ester moiety, which
could undergo hydrolysis, aminolysis, and alcoholysis reac-
tions to yield a range of useful chiral building blocks
containing up to two adjacent, and possibly fully substituted,
stereocenters.4
Table 1. Catalyst Screen and Reaction Condition
Optimizationa
Here, we present our findings on the use of 5-aryl-1,3-
dioxolan-4-ones as pro-nucleophiles in the enantioselective
organocatalytic Michael addition to nitro olefins. The
subsequent manipulation of the adducts, exploiting the natural
reactivity of the carbonyl group, is also reported.
Proof of reactivity studies were required to assess whether
the acidity/nucleophilicity profile of selected 1,3-dioxolan-
4-ones was sufficient for the direct organocatalyzed Michael
addition to nitro olefins. A preliminary study was partially
temp
(°C)
de
ee
entry cat.
R
solvent
convn (%)b (%)b (%)c
1
2
1ad Me
1ad CF3
THF
THF
30
30
0
0
0
0
0
0
0
<5e
>98f
>60g
>98h
>98g
>80g
>98g
>40g
>40g
>85g
>98
>80
>98
>85
>98
>95
>90
>90
>80
3
4
5
6
7
8
9
1c
1c
1c
1b
1d
1e
1f
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
DCM
PhMe
TBME
DCM
DCM
DCM
DCM
DCM
65
76
57
43
70
51
26
56
(3) For recent applications of epi-9-amino-9-deoxy cinchona alkaloid
derivatives as bifunctional organocatalysts, see: (a) Li, B.; Jiang, L.; Liu,
M.; Chen, Y.; Ding, L.; Wu, Y. Synlett 2005, 603. (b) Vakulya, B.; Varga,
S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967. (c) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (d) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256. (e)
To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.;
Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086. (f) Ye,
J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. (g) Tillman, A.
L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (h) Song, J.; Wang,
Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (i) Wang, Y. Q.; Song,
J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. (j) Wang,
J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem.
Soc. 2006, 128, 12652. (k) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli,
A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew.
Chem., Int. Ed. 2006, 45, 4966. (l) Bode, C. M.; Ting, A.; Schaus, S. E.
Tetrahedron 2006, 62, 11499. (m) Liu, T.; Cui, H.; Long, J.; Li, B.; Wu,
Y.; Ding, L.; Chen, Y. J. Am. Chem. Soc. 2007, 129, 1878. (n) Song, J.;
Shih, H.; Deng, L. Org. Lett. 2007, 9, 603. (o) McCooey, S. H.; Connon,
S. J. Org. Lett. 2007, 4, 599. (p) Wang, B.; Wu, F.; Wang, F.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (q) Chen, W.; Du, W.; Yue,
L.; Li, R.; Wu, Y.; Ding, L.; Chen, Y. Org. Biomol. Chem. 2007, 5, 816.
(r) Xie, J.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.; Wu,
Y.; Zhu, J.; Deng, J. Angew. Chem., Int. Ed. 2007, 46, 389. (s) Xie, J.;
Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.; Chen, Y. Org. Lett. 2007, 3,
413. (t) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J.
Am. Chem. Soc. 2006, 128, 3830. (u) Biddle, M. M.; Lin, M.; Scheidt, K.
A. J. Am. Chem. Soc. 2007, 129, 3830. For mechanistic studies utilizing
the cinchona alkaloids, see: (v) Kumar, A.; Salunkhe, R. V.; Rane, R. A.;
Dike, S. Y. Chem. Commun. 1991, 485. (w) Li, H.; Wang, Y.; Tang, L.;
Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105. (x) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I. J. Am. Chem.
Soc. 2006, 128, 13151.
10
1g
0
a Reaction was carried out with 2 (1.0 equiv), 3a (0.5 equiv), and 1b-g
(0.05 equiv) in solvent (1.0 M in 3). b Determined by 1H NMR. c Determined
by HPLC analysis with a chiral column. d 0.1 equiv used. e After 14 days.
f After 96 h. g After 72 h. h After 48 h.
insufficiently low pKa of 2a, we then investigated the
analogous heterocycle 2b where the methyl groups had been
substituted by trifluoromethyl groups.6 This switch was
necessary to lower the pKa sufficiently to allow enolization
and hence activation by the amine base; Michael adduct 4b
was formed smoothly and efficiently with DABCO in THF
at 30 °C for 96 h. In addition, the diastereoselectivity of
this tertiary amine catalyzed process was excellent (>98%;
Table 1, entry 2).
Having established a good reactivity profile with 2b and
trans-â-nitrostyrene, a screen of a small library of cincho-
(4) For examples of the use of chiral dioxolan-4-ones in stereoselective
Michael reactions, see: (a) Blay, G.; Ferna´ndez, I.; Monje, B.; Pedro, J.
R.; Ruiz, R. Tetrahedron Lett. 2002, 43, 8463. (b) Blay, G.; Ferna´ndez, I.;
Monje, B.; Pedro, J. R. Tetrahedron 2004, 60, 165. (c) Aitken, R. A.;
McGill, S. D.; Power, L. A. ARKIVOC 2006, 7, 292.
(5) Coote, S. J.; Davies, S. G.; Middlemass, D.; Naylor, A. J. Chem.
Soc., Perkin Trans. 1 1989, 2223.
(6) Radics, G.; Koksch, B.; El-Kousy, S. M.; Spengler, J.; Burger, K.
Synlett 2003, 1826.
2108
Org. Lett., Vol. 9, No. 11, 2007

nine-derived bifunctional organocatalysts then followed.
Other typical reaction parameters such as solvent and
temperature were systematically varied and a selection of
the findings are detailed in Table 1. Interestingly, catalyst
1c, which we found to be optimal in enantioselective
dimethyl malonate Michael additions3f and Mannich reac-
tions,3g was also found to be optimal in this study. In toluene
at 0 °C for 48 h, catalyst 1c afforded Michael adduct 4b in
76% ee and >98% de (Table 1, entry 4).
mandelic acids and hexafluoroacetone. These were subse-
quently treated with trans-â-nitrostyrene and catalyst 1c in
dichloromethane at 0 °C. In all three cases the adducts 6a-c
were formed in high yield and diastereoselectivity. Reaction
rates varied considerably with the fastest belonging to the
most electron poor derivative 6a. Enantioselectivities were
moderate to good in all cases (Table 3).
With the optimal conditions established, the scope of the
Michael addition reaction was surveyed by initially probing
changes to the Michael acceptor. A range of heteroaromatic
and aromatic nitro olefins bearing electron-donating or
-accepting substituents in the ortho, meta, and para positions
were treated with 5-phenyl-1,3-dioxolan-4-one 2b in toluene
at 0 °C in the presence of 1c. Enantioselectivities ranged
from 60% to 89% ee (Table 2). Substituents in the ortho
Table 3. Scope with Respect to the Dioxolanone
Pro-nucleophilea
time
(h)
yield
(%)b
de
(%)c
ee
(%)d
entry
R
1
2
3
6a
6b
6c
p-CF3-Ph
p-Br-Ph
p-OMe-Ph
2
24
48
71
92
77
>98
>98
>98
60
60
70
Table 2. Scope of the Michael Addition Reaction of 2ba
a Reaction was carried out with 5a-c (1.0 equiv), 3a (0.5 equiv), and
1c (0.05 equiv) in CH2Cl2 (1.0 M in 3). b Isolated yield. c Determined by
1H NMR. d Determined by HPLC analysis with a chiral column.
time yield
(h)
de
ee
With the scope of the reaction established, the synthetic
utility of the Michael adducts was investigated. A selected
adduct rac-4b was synthesized on a gram scale and subjected
to routine alcoholysis, hydrolysis, and aminolysis conditions
(Scheme 2).
entry
R
solvent
PhMe
(%)b (%)c (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4c
4c
4d
4e
4e
4f
4g
4g
4h
4i
o-Br-Ph
o-Br-Ph
m-Br-Ph
p-Br-Ph
p-Br-Ph
o-OMe-Ph
m-OMe-Ph PhMe
m-OMe-Ph CH2Cl2
p-OMe-Ph
m-Me-Ph
p-Me-Ph
o-Cl-Ph
336
CH2Cl2 288
58
72
71
59
85
65
50
70
81
70
67
52
62
69
88
>98
>98
>98
>98
>97
>97
>97
>98
>97
>98
>97
>97
>97
>93
>98
89
79
68
73
68
74
71
68
73
69
70
82
75
60
66
PhMe
PhMe
CH2Cl2
PhMe
30
72
48
72
24
48
72
40
40
264
72
24
48
Scheme 2. Reactions Demonstrating the Synthetic Utility of
the Michael Adducts and X-ray Structure of (R,R,R)-11
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
4j
4k
4l
2-naphth
4m 2-furyl
4n 2-thienyl
a Reaction was carried out with 2b (1.0 equiv), 3b-n (0.5 equiv), and
1c (0.05 equiv) in solvent (1.0 M in 3). b Isolated yield. c Determined by
1H NMR. d Determined by HPLC analysis with a chiral column.
position on the ring increased reaction time and gave rise to
the highest enantioselectivities (entries 1 and 12, 89% and
82% ee, respectively). Despite conditions being optimal for
enantioselectivity, the reaction yields occasionally fell into
the 50s when toluene was used as solvent. In such cases,
yields could be enhanced by switching to dichloromethane
as solvent where only a small decrease in enantioselectivity
was observed (Table 2, entries 2, 5, and 8 vs entries 1, 4,
and 7, respectively).
Attention then moved to the aryl group of the pro-
nucleophile; three derivatives of 2b, bearing electron-
donating or electron-withdrawing groups in the para position
of the phenyl ring, 5a-c, were prepared from the parent
Potassium carbonate mediated methanolysis at room
temperature gave a quantitative yield of methyl ester 7
whereas treatment with aqueous potassium carbonate solution
afforded the R-hydroxy acid 8 in unoptimized 51% yield.
Aminolysis with propylamine in dichloromethane afforded
the propylamide 9 in quantitative yield after stirring for 15
Org. Lett., Vol. 9, No. 11, 2007
2109

min at room temperature. A zinc/aqueous hydrochloric acid
reduction of the nitro group yielded the γ-lactam 10 in 98%
yield.4b,7
products contain two contiguous stereogenic centers, one of
which is a fully substitued carbinol, and are formed with
near-perfect diastereocontrol and in good enantiomeric
excess. The efficient transformation of the Michael adducts
into R-hydroxy acid derivatives has also been demonstrated.
Work to expand further the pro-nucleophile pool and to
exploit 5-aryl-1,3-dioxolan-4-ones in other addition reactions
is underway and will be reported in due course.
In a further aminolysis reaction with (R)-1-(4-methoxy-
phenyl)ethylamine, the absolute and relative stereochem-
istry of one (11) of the two diastereomeric products (11 +
12) was unambiguously determined by single-crystal X-ray
diffraction as (R,R,R).7 In a repeat of this aminolysis reaction
with enantioenriched 4b (76% ee, >98% de) from Table 1,
11 was found to be the major diastereoisomeric product. This
result confirmed the preferential addition of the dioxolan-
4-one nucleophile to the Re face of trans-â-nitrostyrene
mediated by bifunctional catalyst 1c, in agreement with our
previous studies using dimethyl malonate.3f
Acknowledgment. We gratefully acknowledge the EPSRC
and Pfizer Global Research and Development for a student-
ship (to P.S.H.). A.G. is grateful for a Ph.D. fellowship
assigned to D.S. from MIUR (Italy). We are also indebted
to Dr. Cheryl Doherty for the X-ray structure determination.
In conclusion, racemic 5-aryl-1,3-dioxolan-4-ones have
proven effective as pro-nucleophiles in stereoselective Michael
addition reactions to nitro olefins catalyzed by bifunctional
cinchona alkaloid-derived organocatalysts. The reaction
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for products 2a,b, 4b-n,
5a-c, 6a-c, and 7-12. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) Diastereoisomers 11 and 12 were separated by preparative HPLC
with use of an OJ column (see the Supporting Information for details).
OL070532L
2110
Org. Lett., Vol. 9, No. 11, 2007