Enantioselective synthesis of Wieland-Miescher ketone through bimorpholine-catalyzed organocatalytic aldol condensation

Article abstract of DOI:10.1055/s-2006-947321

Novel bimorpholine-derived organocatalysts have been used for highly enantioselective intramolecular aldol reaction affording Wieland-Miescher ketone in high yield and enantioselectivity (up to 92% and 95%, respectively). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947321

LETTER
1699
Enantioselective Synthesis of Wieland–Miescher Ketone through
Bimorpholine-Catalyzed Organocatalytic Aldol Condensation
O
rganocatalysisby
a
Bimorpho
d
line ri Kriis,a Tõnis Kanger,*a Marju Laars,a Tiiu Kailas,a Aleksander-Mati Müürisepp,a Tõnis Pehk,b Margus Loppa
a
Faculty of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
Fax +3726202828; E-mail: kanger@chemnet.ee
b
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
Received 2 March 2006
O
Abstract: Novel bimorpholine-derived organocatalysts have been
used for highly enantioselective intramolecular aldol reaction af-
fording Wieland–Miescher ketone in high yield and enantioselec-
tivity (up to 92% and 95%, respectively).
O
O
COOH
L-proline
N
– H2O
H
O
O
( )
n
O
n
O
( )
OH
n
1: n = 2, ee 76%
2: n = 1, ee 93%
Key words: asymmetric catalysis, organocatalysis, diamines,
stereoselective synthesis, aldol reactions
Scheme 1 Proline-catalyzed synthesis of Wieland–Miescher ketone
(1) and its nor-analogue 2
Proline-catalyzed asymmetric intramolecular aldol con-
densation of triketones was one of the first reactions
where organocatalysis was used.1 It took several decades
to rediscover the concept of organocatalysis. Today bio-
mimetic metal-free reactions catalyzed by small enantio-
meric molecules have become a powerful tool for creating
of the C–C and the C–heteroatom bond in an asymmetric
way.2 Enamine-based catalysis is a specific example of
this strategy.3 The five-membered ring natural amino acid
proline is still the most widely used catalyst in organo-
catalysis.4
It is well recognized that amine functionality and carbox-
ylic acid functionality both play a crucial role in proline-
catalyzed aldol reactions to control stereoselectivity and
reactivity.11 Substitution of the carboxylic group with an-
other acidic group (like tetrazole)12 has led to a principally
new approach to acid–base catalyzed aldol reactions.13
We assumed that mono salts of bimorpholine 314 or its de-
rivative 4 would act similarly to proline possessing both
basic and acidic properties (Figure 1). Additional donor
sites in the morpholine rings (O-atoms) may give rise to
the formation of a strictly arranged hydrogen bond net-
work. These C2-symmetric compounds represent a new
class of bifunctional organocatalysts, which might pro-
vide high enantioselectivity toward aldol reaction.
Wieland–Miescher ketone (1) and its nor-analogue 2 have
proven to be remarkably important starting compounds
for numerous targeted syntheses.5 The first published
asymmetric synthesis protocol of these compounds1 is
still a landmark, and only a few improvements that in-
volve a modest modification of the main procedure have
been reported.6 Under optimized conditions, enantiomeri-
cally pure ketone 1 was obtained in 57% yield after three
recrystallizations.6a The one-pot reaction starting from 2-
methyl 1,3-cyclohexanedione and methyl vinyl ketone
(35 °C, 89 h, 35 mol% of proline was used) afforded ke-
tone 1 in 49% yield with 76% of ee.7a The synthesis of
diketone 2 was more selective as only 3 mol% of catalyst
was sufficient to achieve ee of 93% with the quantitative
yield of the intermediate bicyclic hydroxy diketone
(Scheme 1).1b
O
O
O
O
N
N
H
N
H
N
H
.
.
H–X
H–X
4a: H–X = – (free base)
4b: H–X = CF3COOH
4c: H–X = CF3SO3H
3a: H–X = – (free base)
3b: H–X = CF3COOH
Figure 1
So far, the C2-symmetric 1,2-diamine 3a has been used
only as a chiral ligand in the transition metal-mediated
hydrogenation reactions.15 Herein we describe the use of
bimorpholines 3 and 4 in the highly stereoselective syn-
thesis of Wieland–Miescher ketone (1) and its analogue 2.
Proline derivatives or other amino acids were found to be
less efficient in this reaction.7,8 There are only two reports
that describe a more enantioselective cyclization reaction.
Barbas has used the antibody-catalyzed Robinson annula-
tion that affords ketone 1 in >95% of ee.9 Davies has ob-
tained ketone 1 in 86% of ee in the presence of b-amino
acid cispentacin.10
High solubility of the bimorpholine salt 4b (as compared
to proline) allows us to use various solvents for the
intramolecular cyclization of triketone 5. The results are
presented in Table 1.
The bimorpholine salt was found to be an efficient cata-
lyst of aldol condensation. Under reflux conditions, high
conversion of the starting ketone was achieved in almost
SYNLETT 2006, No. 11, pp 1699–1702
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947321; Art ID: G08106ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.0
7
.2
0
0
6

1700
K. Kriis et al.
LETTER
Table 1 Cyclization of Triketone 5 in Different Solventsa
Table 2 Organocatalytic Cyclization of Ketones 5 and 6a
O
O
O
O
catalyst
O
O
4b (5 mol%)
O
O
MeCN, reflux
( )
n
O
( )
reflux
O
n
5
1
5: n = 2
6: n = 1
1: n = 2
2: n = 1
Entry Solvent
Time (h)
Ratio of 1:5c ee of 1d,e
Entry Ketone Catalyst (mol%) Time (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
THF
70
70
66
68
45
144
5
77:17
74
85
85
91
87
rac
36
1
2
5
5
5
5
5
5
5
5
6
6
6
4a (5)
4b (1)
4b (5)
4b (10)
4c (5)
4c (20)
3a (5)
3b (5)
3b (5)
4b (5)
4c (5)
69
188
69
45d
55
rac
87
MeOH
56:32
83:11
91:6
i-PrOH
CH3CN
MeCN–H2Of
DMFb
3
84
91
4
48
86
90
79:14
43:21
82:9
5
96
60
95
6
94
82
95
Toluene
7
94
<10
92
n.d.
79
a In a typical experiment 0.5 mmol of triketone was refluxed in 1 mL
of solvent.
8
45
b Reaction temperature 100 °C.
c Chromatographic ratio was determined by GC.
d The ee was determined by chiral HPLC (column Chiralcel OD-H).
e The absolute configuration of the main enantiomer was determined
by the (+) sign of the optical rotation of the isolated product corre-
sponding to S-enantiomer.
9
24
87
58e
80
10
11
71
83
216
68
87
f H2O (10 equiv) was used as a co-solvent.
a In a typical experiment 1 mmol of triketone was refluxed in 2 mL of
MeCN.
b Isolated yield after column chromatography.
c The ee was determined by chiral HPLC (column Chiralcel OD-H).
d The reaction stopped at ca. 60% conversion.
e The absolute configuration of the main enantiomer was determined
by the (+) sign of the optical rotation of the isolated product corre-
sponding to S-enantiomer.
every solvent screened and only a trace of intermediate
hydroxy diketone (depicted in Scheme 1) was detected by
GC. Most intriguingly, in the majority of cases, the enan-
tioselectivity of the reaction exceeds considerably the se-
lectivity obtained with proline (Table 1, entries 2–5).
There are two exceptions: these were the cases when
DMF and toluene were used as solvents (entries 6, 7). The
reaction in DMF at 100 °C was sluggish and the obtained
product was racemic. We assume that too high reaction
temperature (boiling toluene) is probably responsible for
the low selectivity when the reaction is carried out in
toluene. The highest conversion and enantioselectivity
(91%) were obtained in MeCN (entry 4). It has been re-
ported that water has unique properties in the organocata-
lytic aldol reaction.12,16 In our case, water decreased the
stereoselectivity of the reaction (from 91% to 87%, entry
5).
O
H
N+
CH2
H
N
CH2
O
H
H
Figure 2 Proposed hydrogen-bonded structure of the bimor-
pholine–acid catalyst
In this chelated intermediate, the N atom becomes a ste-
reogenic center and an additional stereodiscrimination
takes place.18 The hypothesis is supported by the fact that
catalysts 3a and 4a (free base of unsubstituted and i-Pr-bi-
morpholine) gave either a racemic product or revealed a
very low activity (entries 1, 7). The influence of the iso-
propyl group attached to the nitrogen atom is also evident.
i-Pr-bimorpholine-catalyzed (4b) reaction afforded ke-
tone 1 with much higher ee than unsubstituted catalyst 3b,
(ee 91% and 79% and isolated yields of ketone 1 84% and
92%, respectively; entries 3, 8).
According to the results obtained, MeCN was the solvent
for the following reactions carried out under reflux using
various bimorpholine derivatives as organocatalysts
(Table 2).17
We assumed that acid has a dual role in this reaction.
Firstly, acid catalyzes the enamine formation and acceler-
ates the following cyclization. Secondly, in a preferential
staggered conformation (the dihedral angle of 180° be-
tween the hydrogens), the fixed conformation of bimor-
pholine is formed via hydrogen bonding (Figure 2).
The strength of the acid used for the preparation of the cat-
alyst salt is also an important factor that determines the
stereoselectivity of the reaction and the reactivity of the
Synlett 2006, No. 11, 1699–1702 © Thieme Stuttgart · New York

LETTER
Organocatalysis by Bimorpholine
1701
catalyst. A comparison of triflic acid salt 4c and trifluoro- We may conclude that a new class of organocatalysts –
acetic acid salt 4b showed that the former was a more se- i-Pr-substituted bimorpholine mono salts – for highly
lective but less reactive catalyst than was the latter (entries enantioselective intramolecular aldol reactions have been
3, 5). A stronger acid reduces the nucleophilicity of amine introduced. The efficiency of the organocatalyst has been
via protonation and probably retards the formation of demonstrated on the important synthetic intermediate
enamine. At the same time, a more strongly chelated Wieland–Miescher ketone (1), which was synthesized in
structure of bimorpholine favors higher enantioselectivi- high yield and ee (up to 92% and 95%, respectively).
ty. Indeed, the highest ee (95%, entries 5, 6) was obtained Further investigation of the scope of the aldol reaction and
when the reaction was catalyzed with triflic salt 4c al- other possible applications of the novel organocatalysts 4
though the reaction time was longer than in the case of tri- is under way.21
fluoroacetic acid salt 4b. The prolonged reaction time led
to the formation of side-product 7 as 2:1 mixture of dias-
Acknowledgment
tereoisomers (Scheme 2).19 When water was used as an
The authors thank Estonian Science Foundation (grants nos 6662,
5628 and 6778) and Estonian Ministry of Education and Science
(grant no 0142725s06) for financial support.
additive (10 equiv), Wieland–Miescher ketone (1) and
lactone 7 were formed in almost equal amounts. In the tri-
fluoroacetic acid salt catalyzed (4b) reactions the forma-
tion of lactone 7 was not detected.
References and Notes
(1) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org.
Chem. 1974, 39, 1615.
(2) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim Germany, 2005.
O
O
N
O
O
N
H
.
CF3SO3H
O
O
O
O
+
(3) For recent review, see: List, B. Acc. Chem. Res. 2004, 37,
548.
MeCN–H2O reflux
(5 mol%)
O
H
5
O
7
(4) (a) For a review, see: List, B. Tetrahedron 2002, 58, 5573.
Some recent examples: (b) Tokuda, O.; Kano, T.; Gao, W.-
G.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103.
(c) Suri, J. T.; Steiner, D. D.; Barbas, C. F. III Org. Lett.
2005, 7, 3885. (d) Pan, Q.; Zou, B.; Wang, Y.; Ma, D. Org.
Lett. 2004, 6, 1009. (e) Storer, R. I.; MacMillan, D. W. C.
Tetrahedron 2004, 60, 7705. (f) Hayashi, Y.; Yamaguchi,
J.; Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69,
5966. (g) Enders, D.; Grondal, C. Angew. Chem. Int. Ed.
2005, 44, 1210.
1
O
O
OH
O
O
O
HO
O
O
O
O
OH
Scheme 2 Formation of side-product 7
(5) (a) Shah, N.; Scanlan, T. S. Bioorg. Med. Chem. Lett. 2004,
14, 5199. (b) Kende, A. S.; Deng, W.-P.; Zhong, M.; Guo,
X.-C. Org. Lett. 2003, 5, 1785. (c) Aav, R.; Kanger, T.;
Pehk, T.; Lopp, M. Synlett 2000, 529. (d) Di Filippo, M.;
Izzo, I.; Vece, A.; De Riccardis, F.; Sodano, G. Tetrahedron
Lett. 2001, 42, 1155.
(6) (a) Buchschacher, P.; Fürst, A.; Gutzwiller, J. Org. Synth.,
Coll. Vol. VII; Wiley: New York, 1990, 368. (b) Hajos, Z.
G.; Parrish, D. R. Organic Synthesis, Coll. Vol. VII; Wiley:
New York, 1990, 363.
(7) (a) Bui, T.; Barbas, C. F. III Tetrahedron Lett. 2000, 41,
6951. (b) Cheong, P. A.-Y.; Houk, K. N.; Warrier, J. S.;
Hanessian, S. Adv. Synth. Catal. 2004, 346, 1111.
(8) Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057.
(9) Zhong, G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.;
Barbas, C. F. III J. Am. Chem. Soc. 1997, 119, 8131.
(10) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E.
Chem. Commun. 2005, 3802.
The formation of the by-product 7 can be explained ac-
cording to Coates et al., who found that similar d-lactones
are formed via the enolization of the carbonyl group in the
ring, giving bridged ketol by aldol condensation followed
by intramolecular hemiacetal formation and retro-Claisen
transformation.20
We obtained optimal results while using 5–10 mol% of
the trifluoroacetic acid salt 4b of bimorfoline (entries 3,
4). The reaction with 5 mol% of the catalyst was complet-
ed within 69 hours, affording ketone 1 in 84% of isolated
yield and 91% of ee (entry 3). The reduction of the amount
of the catalyst to 1 mol% resulted in the prolonged reac-
tion time and in the lower stereoselectivity (entry 2).
The same tendencies were observed in the case of tri-
ketone 6. Triflic acid salt 4c was found to be the most
selective but the least reactive organocatalyst. Also, i-Pr-
substituted derivatives 4b and 4c were more selective cat-
alysts than unsubstituted bimorpholine salt 3b (entries 9–
11). Unfortunately, in these cases the enantioselectivity
was lower than with ketone 5, reaching 87% at most.
(11) (a) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.
A.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558.
(b) Clemente, F. R.; Houk, K. N. Angew. Chem. Int. Ed.
2004, 43, 5766.
(12) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem. Int. Ed. 2004, 43, 1983.
(13) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
Synlett 2006, No. 11, 1699–1702 © Thieme Stuttgart · New York

1702
K. Kriis et al.
LETTER
mL/min); tR (S)-1 = 19.4 min, tR (R)-1 = 21.6 min, tR (S)-
(14) (a) Kanger, T.; Kriis, K.; Pehk, T.; Müürisepp, A.-M.; Lopp,
M. Tetrahedron: Asymmetry 2002, 13, 857. (b) Kanger, T.;
Laars, M.; Kriis, K.; Kailas, T.; Müürisepp, A.-M.; Pehk, T.;
Lopp, M. Synthesis 2006, 1853.
(15) (a) Kriis, K.; Kanger, T.; Müürisepp, A.-M.; Lopp, M.
Tetrahedron: Asymmetry 2003, 14, 2271. (b) Kriis, K.;
Kanger, T.; Lopp, M. Tetrahedron: Asymmetry 2004, 15,
2687.
2 = 25.6 min, tR (R)-2 = 28.3 min.
(18) Converting stereogenic N atoms via chelation is described
by: Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron
Lett. 2003, 44, 8893.
(19) (4aS*,8aS*)-6,8a-Dimethylhexahydro-2H-chromene-2,5
(3H)-dione (7).
A 2:1 mixture of two isomers with differing orientations of
the 6-methyl group. Main isomer with 6R* configuration: 1H
NMR (500 MHz, CDCl3): d = 2.73 (m, 1 H, H-3), 2.54 (m, 1
H, H-4a), 2.49 (m, 1 H, H-3), 2.43 (m, 1 H, H-6), 2.42 (m, 1
H, H-4), 2.15 (m, 1 H, H-8), 1.97 (m, 1 H, H-8), 1.94 (m, 1
H, H-7), 1.93 (m, 1 H, H-4), 1.71 (m, 1 H, H-7), 1.54 (s, 3 H,
8a-Me), 1.03 (d, J = 6.5 Hz, 3 H, 6-Me). 13C NMR (125
MHz, CDCl3): d = 209.33 (C-5), 171.24 (C-2), 86.19 (C-8a),
49.52 (C-4a), 44.32 (C-6), 37.48 (C-8), 29.83 (C-7), 28.39
(C-8a-Me), 25.54 (C-3), 15.69 (C-4), 14.19 (C-6 Me).
Minor isomer with 6S* configuration: 1H NMR (500 MHz,
CDCl3,): d = 2.68 (m, 1 H, H-3), 2.66 (m, 1 H, H-4a), 2.57
(m, 1 H, H-6), 2.45 (m, 1 H, H-3), 2.27 (m, 1 H, H-4), 2.10
(m, 2 H, H-7), 2.08 (m, 2 H, H-8), 1.95 (m, 1 H, H-4), 1.44
(s, 3 H, 8a-Me), 1.13 (d, J = 6.5 Hz, 3 H, 6-Me). 13C NMR
(125 MHz, CDCl3): d = 211.33 (C-5), 169.97 (C-2), 85.27
(C-8a), 51.49 (C-4a), 41.53 (C-6), 33.14 (C-8), 27.90 (C-7),
27.81 (C-8a-Me), 27.56 (C-3), 19.53 (C-4), 15.23 (C-6 Me).
MS (EI): m/z (%) = 196 (3) [M+], 181 (2), 168 (4), 112 (86),
84 (29), 43 (100).
(16) (a) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org.
Lett. 2005, 7, 4185. (b) Mase, N.; Nakai, Y.; Ohara, N.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. III J. Am.
Chem. Soc. 2006, 128, 734. (c) Chimni, S. S.; Mahajan, D.;
Babu, V. V. S. Tetrahedron Lett. 2005, 46, 5617.
(d) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958.
(17) General Method for the Organocatalytic Aldol
Condensation of Ketones 5 and 6.
Organocatalyst 3 or 4 (0.05 mmol) was added to a stirred
solution of triketone 5 or 6 (1.0 mmol) in anhyd MeCN (2.0
mL). The reaction mixture was refluxed for an appropriate
time. The reaction was monitored by capillary GC. After
completion of the reaction, toluene (5 mL) was added, the
mixture was concentrated under vacuum and the crude
product was purified by chromatography on silica gel (30%
EtOAc in PE). The obtained ketones 1 and 2 are known
compounds and our spectroscopic and chromatographic data
are in agreement with published data. The ee was determined
by HPLC (Daicel Chiralcel OD-H (250 × 4.6 mm), detection
at l = 254 nm, eluent: 4% of i-PrOH in hexane, flow rate 0.8
(20) Muskopf, J. W.; Coates, R. M. J. Org. Chem. 1985, 50, 69.
(21) Mossé, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A.
Org. Lett. 2006, 8, 2559.
Synlett 2006, No. 11, 1699–1702 © Thieme Stuttgart · New York