Readily accessible 9-epi-amino cinchona alkaloid derivatives promote efficient, highly enantioselective additions of aldehydes and ketones to nitroolefins

Article abstract of DOI:10.1021/ol0628006

Simple cinchona alkaloid derivatives, available via a one-pot procedure from commercially available starting materials, have been shown to promote highly enantio- and diastereoselective Michael-type addition reactions between enolizable carbonyl compounds

Full text of DOI:10.1021/ol0628006

ORGANIC
LETTERS
2
007
Vol. 9, No. 4
99-602
Readily Accessible 9-epi-amino
Cinchona Alkaloid Derivatives Promote
Efficient, Highly Enantioselective
Additions of Aldehydes and Ketones to
Nitroolefins
5
S e´ amus H. McCooey and Stephen J. Connon*
Centre for Synthesis and Chemical Biology, School of Chemistry, UniVersity of Dublin,
Trinity College, Dublin 2, Ireland
connons@tcd.ie
Received November 17, 2006
ABSTRACT
Simple cinchona alkaloid derivatives, available via a one-pot procedure from commercially available starting materials, have been shown to
promote highly enantio- and diastereoselective Michael-type addition reactions between enolizable carbonyl compounds and nitroalkenes of
broad scope. The influence of both the absolute and relative stereochemistry at C-9 on catalyst performance has also been assessed.
Recent years have witnessed a dramatic upsurge in awareness
among chemists of the potential utility of asymmetric
organocatalysis as a tool for the synthesis of enantiopure
Existing organocatalysts for these nitro-Michael processes
can be (ad hoc) categorized as promoting the addition of
3
,4
either acidic pronucleophilies or enolizable carbonyl
1
5-7
molecules under mild, environmentally benign conditions.
compounds. Since the first reports of an amine-catalyzed
2
5a-c
The Michael addition of nucleophiles to nitrolefins is
asymmetric addition of ketones to nitroalkenes in 2001,
proving a particularly attractive target for organocatalyst
design, due largely to (a) the ready availability and high
reactivity of nitroalkenes, (b) the ability of the nitro
functionality to accept hydrogen bonds from suitably de-
signed catalyst systems, and (c) the high synthetic utility of
the nitroalkane adducts.
extraordinary progress has been made with respect to both
5,6
stereoselectivity and substrate scope using both secondary
7
and primary chiral amine catalysts. However, latitude for
further development remains, in particular with regard to the
design of readily accessible and inexpensive (in both
antipodal forms) catalyst systems capable of promoting
efficient, enantio/diastereoselective nitro-Michael additions
involving both ketones and aldehydes (both straight-chain
and R,R-disubstituted) of general utility.
(1) Recent general reviews: (a) List, B. Chem. Commun. 2006, 819. (b)
Berkessel, A.; Gr o¨ ger, H. In Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim,
2
005. (c) Jayasree, S.; List, B. Org. Biomol. Chem. 2005, 3, 719. (d) Dalko,
(2) Recent reviews: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877. (b) Krause, N.; Hoffmann-R o¨ der, A. Synthesis
2001, 171. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e) Houk, K. N.;
List, B. Acc. Chem. Res. 2004, 37, 487.
1
0.1021/ol0628006 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/23/2007

With this in mind, we wished to design simple, readily
available, and tunable 1,2-diamine catalyst templates based
on the cinchona alkaloid backbone as mediators of asym-
metric “enamine” organocatalysis for the first time (Figure
Table 1. Initial Catalyst Screening and Optimization
1). Such a strategy was appealing primarily for two rea-
entry
catalyst
DHQA
9-epi-DHQA
9-epi-DHQBA CH3COOH
9-epi-DHQA
acid
mol % H2O t (d) conv (%)a,b
1
2
3
4
5
6
7
CH3COOH
CH3COOH
100
100
100
0
5.8
5.8
5.8
7 (19)
24
0
3.8 >98c
9-epi-DHQBA
9-epi-DHQA
0
100
0
0
0
0
0
0
0
3.8
0
3.8 >98c
9-epi-DHQA
9-epi-DHQA
9-epi-DHQA
9-epi-DHQA PhCOOH
DHQA PhCOOH
9-epi-DHQBA PhCOOH
9-epi-DHQDA PhCOOH
9-epi-DHQDA PhCOOH
9-epi-DHQDA PhCOOH
CH3COOH
CH3COOH
CF3COOH
3.8
3.7
3.7
3.7
3.8
3.8
3.8
3.8
6.9
31 (63)
24
15
68 (45)
12
d
8
d
9
d
1
1
1
1
1
1
0
1
2
3
4
5
d
d
d
d
d
Figure 1. Novel cinchona alkaloid-derived catalysts.
0
91 (-49)
90 (-59)
73 (-71)
e
0
0
sons: (a) availability - the alkaloid starting materials are
inexpensive and available in both pseudoenantiomeric forms,
thereby avoiding reliance on either amino-acid-derived
f
a
Determined by 1H NMR spectroscopy. b Enantioselectivity (% ee,
c
d
determined by CSP-HPLC) in parentheses. Multiple products. 10 equiv
of acetone used. Isolated yield: reaction at 8 °C with 20 mol % catalyst.
Isolated yield:reaction at 0 °C with 20 mol % catalyst
e
f
(3) (a) Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (b) Li, H.;
Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (c)
Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185.
(
d) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119. (e) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (f) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481. (g) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W.
Org. Lett. 2005, 7, 4713. (h) Herrera, R. P.; Sgarzani, V.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576. (i) Zhuang, W.; Hazell,
R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566. (j) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105. (k) McCooey, S. H.; McCabe, T.; Connon,
S. J. J. Org. Chem. 2006, 71, 7494. (l) Fleming, E. M.; McCabe, T.; Connon,
S. J. Tetrahedron Lett. 2006, 47, 7037. (m) Wang, J.; Li, H.; Zu, L.; Wang,
W. Org. Lett. 2006, 8, 1391. (n) Li, H.; Wang, J.; Zu, L.; Wang, W.
Tetrahedron Lett. 2006, 47, 2585. (o) Hamza, A.; Schubert, G.; So o´ s, T.;
Papai, I. J. Am. Chem. Soc. 2006, 128, 13151. (p) Poulsen, T. B.; Bell, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63.
stereogenicity or resolution techniques; in addition the
catalysts would be accessible from available alkaloid deriva-
3e,k
tives in a one-pot procedure, and (b) tunability - we and
3f,8
others have recently demonstrated the potential advantages
associated with tuning the chiral evironment of modified
cinchona alkaloid organocatalysts through the inversion of
configuration at C-9; this together with an ability to design
both primary and secondary prototype amine catalysts affords
an exceptional degree of scope for catalyst optimization from
9
simple starting materials. We therefore prepared the 9-amino
(
4) For selected recent reviews on the use of hydrogen bonding in
derivative of dihydroquinine quinidine (DHQA) together
with C-9 inverted and N-benzylated analogues (Figure 1)10
and evaluated them as organocatalysts of a challenging (from
catalysis, see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal.
006, 348, 999. (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
006, 45, 1520. (c) Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (d) Connon,
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (e) Takemoto, Y. Org. Biomol.
Chem. 2005, 3, 4299. (f) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2
2
2
062. (g) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
(6) (a) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077. (b)
Moss e´ , S.; Alexakis, A. Org. Lett. 2006, 8, 3577. (c) Mase, N.; Watanabe,
K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 4966. (d) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng,
J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093. (e) Luo, S.; Mi, X.; Zhang,
L.; Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006, 3687. (f) Almai,
D.; Alonso, D. A.; N a´ jera, C. Tetrahedron: Asymmetry 2006, 17, 2064.
(g) Li, Y.; Liu, X.-Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2034.
(h) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z.
Tetrahedron: Asymmetry 2006, 17, 491. (i) Cao, C.-L.; Ye, M.-C.; Sun,
X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901. (j) Palomo, C.; Vera, S.; Mielgo,
A.; G o´ mez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984. (k) Pansare,
S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624. (l) Moss e´ , S.; Laars,
M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559. (m) Wang,
J; Li, H; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J. 2006, 12,
4321.
(
5) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (b)
Betancourt, J. M.; Saktivel, K.; Thayumanavan, R.; Barbas, C. F., III. J.
Am. Chem. Soc. 2001, 123, 5260. (c) Betancourt, J. M.; Barbas, C. F., III.
Org. Lett. 2001, 3, 3737. (d) Enders, D.; Seki, A. Synlett 2002, 26. (e)
Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (f) Andrey, O.; Alexakis,
A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147.
(
(
g) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559.
h) Martin, H. J.; List, B. Synlett 2003, 1901. (i) Ishii, T.; Fujioka, S.;
Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558. (j) Cobb,
A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun.
2004, 1808. (k) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka,
F.; Barbas, C. F., III. Synthesis 2004, 9, 1509. (l) Mase, N.; Thayumanavan,
R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (m) Kotrusz,
P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem. 2004, 1577.
(n) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (o)
Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
Huthmacher, K. Eur. J. Org. Chem. 2005, 4995. (p) Hayashi, Y.; Gotoh,
T.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (q) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84.
(7) (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (b) Huang,
H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (c) Yalonde, M.
P.; Chen. Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366. (d)
Xu, Y.; Zou, W.; Sund e´ n, H.; Ibrahem, I.; C o´ rdova, A. AdV. Synth. Catal.
2006, 348, 418. (e) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460.
600
Org. Lett., Vol. 9, No. 4, 2007

1
1
an asymmetric catalysis standpoint ) Micheal reaction, the
addition of acetone to (E)-â-nitrostyrene 1.
riority of acyclic to cyclic ketone substrates and the isolation
of 3 and 4 in >95% ee (the highest enantioselectivity for
these substrates thus far reported) is gratifying. Although
several amine catalysts capable of promoting the enantiose-
The results of this preliminary study (Table 1) were
instructive. Initial experiments demonstrated that the primary
amine derivatives of DHQ (DHQA and 9-epi-DHQA) were
capable of promoting the reaction when utilized at 10 mol
5
-7
lective addition of 5-7 to 1 are known, to the best of our
6m
knowledge only one report detailing a syn-selective catalyst
12
%
loading. Although the employment of a Brønsted acid
system has thus far appeared for the analogous transforma-
additive resulted in clean reactions (which gave multiple
products otherwise), contrary to recent reports concerning
primary amine catalysts for this reaction, we did not find
the use of water as an additive to be beneficial in this system
tion of more challenging, acyclic ketones such as 3-4 with
>80% ee.
Aldehyde substrates (both R-substituted and R,R-disub-
stituted analogues) were also found to be compatible with
7
a-c
(entries 1-7).
Interestingly, inversion of the “natural”
9
-epi-DHQDA (Table 3), allowing the isolation of adducts
alkaloid stereochemistry at C-9 (i.e., 9-epi-DHQA) resulted
in a catalyst considerably more active than DHQA (entries
1
, 2, 10, and 11) without alteration of the sense of
stereoinduction observed (i.e., both DHQA and 9-epi-DHQA
promote the formation of (R)-2), whereas the secondary
amine analogue of this material (9-epi-DHQBA) proved
completely inactive (entries 3, 5, and 12). Further experi-
mentation allowed the identification of optimal, solvent-free
conditions under which the quinidine derivative 9-epi-
DHQDA (Figure 1) could promote the efficient formation
of (S)-2 with good enantioselectivity11 in the presence of
benzoic acid (entries 7-15).
Table 3. Addition of Aldehydes to 1
With an active catalyst system in hand, attention was now
turned to the key question of reaction scope. 9-epi-DHQDA
promoted the smooth, high-yielding addition of a variety of
ketones to 1 to give syn adducts 3-7 in good to outstanding
enantio- and diastereoselectivity (Table 2). The clear supe-
Table 2. Addition of Ketones to 1
a
Isolated yield. b Determined by H NMR spectroscopy; the syn dias-
1
c
teromer is preferentially formed in all cases (where relevant). Determined
by CSP-HPLC; see Supporting Information. d At 0 °C. e Repetition of the
reaction at 0 °C had no effect on enantioselectivity.
8
-13 in high yield and excellent enantoselectivity (with one
exception, entry 5) using only 10 mol % of catalyst. While
as expected) the sense of stereoinduction in these reactions
is the opposite to that observed using ketone substrates (Table
), high levels (up to >95% de) of syn-diastereoselectivity
are preserved, with even 2-methyl butanal, a substrate with
minimal steric differentiation between R-substituents), pro-
viding a 2:1 ratio of diastereomers in excellent yield (entry
(
1
a
Isolated yield. b Determined by 1H NMR spectroscopy; the syn dias-
c
teromer is preferentially formed in all cases. Determined by CSP-HPLC;
see Supporting Information. 23% yield of the regioisomer also isolated.
At 0 °C. 100 µL of toluene added, reaction on 0.4 mmol scale.
d
e
f
4
).
Org. Lett., Vol. 9, No. 4, 2007
601

We propose that the observed enantio- and diastereose-
lectivity can be rationalized in terms of a synclinal transition
state (Figure 2). In this case the in situ formed (E)-enamine
Table 4. Reaction Scope with Respect to the Nitroolefin
13
Figure 2. Rationale for the observed stereoselectivity in the
formation of 3 (A) and 13 (B) promoted by 9-epi-DHQDA.
directs its bulkier substituent (the alkyl group for ketones
(A) and the olefinic moiety for aldehydes (B) away from
the catalyst, resulting in a single enamine rotamer, one face
of which is shielded by the catalyst’s quinoline ring. Given
the low steric requirement of the catalyst’s tertiary amine
moiety and the necessity of an acidic cocatalyst for efficient,
clean reactions,14 it seems likely that a hydrogen bonding
interaction between the nitroolefin electrophile and the
protonated quinuclidine nitrogen atom contributes to the high
levels of catalyst activity and selectivity observed.
Finally, investigation of the reaction scope with respect
to the electrophile was examined. We were pleased to find
that isobutryaldehyde could be efficaciously added to ni-
troolefins of variable steric and electronic characteristics in
the presence of 9-epi-DHQDA with the highest levels of
enantioselectivity reported thus far for this aldehyde substrate
a
Isolated yield. b Determined by CSP-HPLC; see Supporting Information.
c
Product isolated before complete consumption of starting material. Longer
reaction times lead to side reactions and reduced yield.
metric syn-selective addition reactions of enolizable carbonyl
compounds to nitroolefins. The catalysts are readily available
in both pseudoenantiomeric forms and have been found (at
relatively low loadings) to catalyze highly enantio- and
diastereoselective nitro-Michael addition reactions of excep-
tionally broad scope: ketones (cyclic/acyclic), aldehydes
(Table 4, entries 1-5).
In summary, cinchona alkaloid derived catalysts such as
9-epi-DHQDA are capable of promoting efficient asym-
(
8) (a) Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005,
6
1
03. (b) Vakulya, B.; Varga, S.; Cs a´ mpai, A.; So o´ s, T. Org. Lett. 2005, 7,
967. (c) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, Li. J. Am. Chem.
(
straight-chain/R,R-disubstitued), and a variety of nitrolefins
Soc. 2006, 126, 8156. (d) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem.
Commun. 2006, 1191. (e) Wang, J.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.;
Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (f) Song, J.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
are tolerated. Studies aimed at the further investigation of
the potential utility of these amine catalysts of “unnatural”
configuration at C-9 are in progress.
(9) As this manuscript was being reviewed, a report appeared online
detailing the use of 9-epi-DHQA as an organocatayst for promotion of
Michael addition reactions via “iminium ion” catalysis: Xie, J.-W.; Chen,
W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng,
J.-G. Angew. Chem., Int. Ed. 2006, 45, early view.
Acknowledgment. We thank the Irish Research Council
for Science Engineering and Technology and Trinity College
Dublin for generous financial support.
(
10) See Supporting Information for details.
11) Only Tsogoeva (91% ee, ref 7a) and Jacobsen (99% ee, ref 7b)
(
have reported amine-based catalysts capable of promoting this reaction with
55% ee.
12) Tsogoeva (ref 7a) and Jacobsen (ref 7b) have recently reported
bifunctional thiourea-based catalysts that promote highly enantioselective
reactions with this substrate class with anti diastereoselectivity.
Supporting Information Available: General experimen-
>
1
13
(
tal procedures, H and C NMR spectra, characterization
data, HPLC assays. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
13) For discussion, see ref 5e and references therein.
(14) Polymerization was the major fate of the nitroolefin substrate in
the absence of a Brønsted acid co-catalyst.
OL0628006
602
Org. Lett., Vol. 9, No. 4, 2007