Studies on aldol reactions of nortropinone derivatives in solution and on solid phase

Article abstract of DOI:10.2174/157017810790533887

Polymer-anchored (Merrifield, trityl chloride, Wang p-nitrophenyl carbonate and triazene supports) nortropinone, or N-protected nortropinone derivatives in solution, were subjected to deprotonation with LDA or chiral lithium amides, and the resulting lith

Full text of DOI:10.2174/157017810790533887

Letters in Organic Chemistry, 2010, 7, 21-26
21
Studies on Aldol Reactions of Nortropinone Derivatives in Solution and on
Solid Phase
Ryszard Lazny*, Aneta Nodzewska and Michal Sienkiewicz
Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland
Received September 01, 2009: Revised November 16, 2009: Accepted November 17, 2009
Abstract: Polymer-anchored (Merrifield, trityl chloride, Wang p-nitrophenyl carbonate and triazene supports)
nortropinone, or N-protected nortropinone derivatives in solution, were subjected to deprotonation with LDA or chiral
lithium amides, and the resulting lithium enolates were trapped with an aldehyde. The aldols were obtained with moderate
to good yields (44-84%) and enantioselectivities (44-86% ee).
Keywords: Aldol reaction, polymer support, solid-phase synthesis, chiral lithium amide, nortropinone.
O
INTRODUCTION
Solid-phase Organic Synthesis (SPOS) has taken an
important place among small molecule synthesis methods,
mostly because of its capacity for process simplification and
parallel or combinatorial syntheses [1]. The aldol reaction is
one of many C–C bond-forming transformations
implemented in polymer-supported synthesis [2]. However,
scope of aldol reactions of many, polymer supported,
building block molecules is very limited [3]. Nortropinone
(8-azabicyclo[3.2.1]octan-3-one, 1, Fig. 1) [4] or its N-
alkylderivatives (notably tropinone) [5] are interesting
scaffolds, from a medicinal chemistry point of view. It has
been shown that diverse tropane derivatives of potential
pharmacological importance [6] can be prepared using
deprotonation with lithium amides and the aldol reaction of
tropinone (2) as the key step [7]. Some approaches to
tropane (8-azabicyclo[3.2.1]octane) derivatives by parallel
solution synthesis [8] and solid-phase synthesis [9] have
been published, none of them, however, are based on enolate
chemistry of an immobilized tropane derivative. Therefore,
we tested the aldol reaction of nortopinone (1), anchored on
selected, available, polymeric supports. In our earlier
communication we have reported a solid-phase aldol reaction
of nortropinone anchored via spacer-modified triazene
linkers [3e]. Herein, we report results of testing of the aldol
reaction on the Merrifield, Wang carbamate, para-C3-T2
triazene, and trityl polymers.
N
X
nortropinone 1, X = H
tropinone 2, X = Me
benzyl resin 3, X =
trityl resin 4, X =
Ph
Ph
triazene
resin 5, X =
N
N
O
O
3
O
Wang
carbamate
resin 6, X =
O
O
= polystyrene-divinylbenzene co-polymer
Fig. (1).
carbamate linker and one triazene linker. From the reactions
in solution, it was known that the N-alkyl derivatives give
typically higher yields and better stereoselectivities in
deprotonation reactions with lithium amides followed by
trapping with various electrophiles including aldehydes [10].
For that reason, we wanted to probe the deprotonations on
the trityl gel and the Merrifield gel. Nortropinone was
immobilized on the polymers under standard conditions [3e,
11]. All the reactions of the immobilized nortropinone with
benzaldehyde (Scheme 1) were performed under previously
reported conditions [3e]. The polymer bound ketone was
deprotonated with LDA in THF at –78 ºC. After the excess
of lithium amide was washed out, the polymer supported
lithium enolate was reacted with benzaldehyde.
RESULTS AND DISCUSSION
Polymer Supported Aldol Reactions
Nortropinone (1) could be most obviously immobilized
on solid supports via the secondary amine functionality. Four
polymers capable of amine binding through linkers stable to
strong bases were chosen for testing: two of them giving N-
alkyl linker (trityl chloride and Merrifield gels); one
*Address correspondence to this author at the Institute of Chemistry,
University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland; Tel: +48-
85-745-7834; Fax: +48-85-747-0113; E-mail: lazny@uwb.edu.pl
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Lazny et al.
OH
O
O
O
R
HO
HB
1. LDA
2. RCHO
HN
R
R
N
H
N
H
N
3. cleavage: TFA/DCM
4. NH3
HA
O
exo-anti
second isomer
9a R = Ph
trityl resin 4
7a R = Ph
8a R = Ph
triazene resin 5
carbamate Wang resin 6
9b R = i-Pr
9c R = 4-NO2-Ph
9d R = 1-Napht
7b R = i-Pr
7c R = 4-NO2-Ph
7d R = 1-Napht
8b R = i-Pr
8c R = 4-NO2-Ph
8d R = 1-Napht
Scheme 1.
The reactions were quenched by addition of acetic acid in
the released products were N-metylated [14] to furnish the
known N-methyl analogues. The NMR spectrum of the
product from the reaction of nortropinone with
benzaldehyde, cleaved from the Merrifield support,
compared favorably to benzylidenetropinone 11, obtained in
solution from aldol 10 under conditions of cleavage with 1-
chloroethyl chloroformate (ACE-Cl) in 1,2-dichloropropane
(DCP) or dichloromethane (Scheme 2). This observation
suggested that the formed, polymer-bound aldol, most likely
underwent elimination during the acidic conditions of
cleavage and work-up to give the product of condensation
9a. Not surprisingly, the reaction on the Merrifield polymer
followed by ACE-Cl cleavage gave solely the product of
elimination with 75% conversion (Table 1, entry 1). A
related elimination of the AcOH molecule, under weakly
acidic conditions (SiO2), from the acetyl derivative of aldol
12 to give enone 11, is known [7c]. Interestingly, the
reaction of aldol 10 with 1-chloroethyl chloroformate gave
the product of elimination 11 without concomitant
demethylation at the nitrogen atom, which is a known
reaction of tropanes [15].
THF. The standard quench method, i.e. addition of a
saturated aqueous ammonium chloride solution, typically
gave worse conversions of substrates to aldols. The aldol
products were cleaved using conditions optimized for
cleavage of the substrate, i.e., nortropinone from used
supports.
Proton NMR analysis of the cleaved product mixtures
revealed varying degrees of conversion (Table 1). In addition
to the expected aldol product 7a, and its diastereomer 8a (5-
30% for polymers 4, 5, 6), the cleaved product mixtures
contained varying amounts of elimination-product (the aldol
condensation product 9a) and the unreacted nortropinone.
The amount of product 9a varied depending on cleavage
time, TFA concentration and work-up conditions from 7-
20% for polymers 4, 5, 6, but reached virtually 100% for
polymer 3. The relative configuration of the major products
7a (the exo-anti diastereomer), and ꢀ-benzylidene
nortropinone (the E-isomer), was inferred from the
comparison of their NMR data, especially coupling constants
[12] of signals corresponding to CH-OH (2-4 Hz) and
chemical shifts of vinylic hydrogens, with NMR data of their
N-methyl analogues of known relative configurations [7c,
13]. To make a positive identification, the crude mixtures of
The extent of elimination varied with the concentration
of TFA, and with the time required for the cleavage
procedure. It seemed that the elimination was the
Table 1. Results of Aldol Reactions of Immobilized Nortropinone on Various Solid Supports
Products
Ratio
Loading of
Nortropinonea
[mmol/g] ([%])b
Support
Yield
[%]
Conversion in Aldol
Reactionc [%]
Entry
Cleavage Reagent
RCHO
(Linker Type)
7 : 8
3
i) ACE-Cl/ DCP,
ii) MeOH
d
d
d
1
0.40 (37)
PhCHO
-
-
-
(Merrifield; benzyl)
4 (trityl)
2
20% TFA/DCM
10% TFA/DCM
1.55 (100)
0.71 (78)
PhCHO
PhCHO
37
77
44
52
72:28
90:10
5 (p-C3-T2
triazene)
3e
4
5
6
7
PhCHO
i-PrCHO
64
67
65
72
58
55
53
57
78:12
69:31
85:15
67:33
6 (Wang
carbamate)
20% TFA/DCM
0.87 (100)
4-NO2-PhCHO
1-naphtylCHO
aloading of nortropinone on starting polymer determined from mass of nortropinone hydrochloride obtained after cleavage [11a].
b% of theoretical value.
csum of major and minor isomers.
donly aldol condensation product (75% conversion and 55% yield).
eresults previously reported3e and shown for comparison.

Studies on Aldol Reactions of Nortropinone Derivatives in Solution
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
23
OH
O
N
OAc
O
N
O
N
H
H
ACE-Cl, DCM or DCP
Silica Gel
Ph
Ph
Ph
Me
Me
Me
10
11
12
Scheme 2.
consequence of the acidic cleavage. A high total conversion
of substrate to products was generally observed on the para-
C3-T2 5 (77%) and the Merrifield support 3 (75%, Table 1).
Aldol reaction gave moderate conversions on the Wang
carbamate polymer 6 (64%) and low on the trityl polymer 4
(37%). The hindered reactivity of the bound amino ketone on
the trityl gel may stem from the enlarged steric demand of
the trityl linker group. The model reaction of N-trityl
nortropinone in solution was also rather low yielding (47%)
compared with the reaction of other N-protected
nortropinone derivatives. The solution aldol reaction of
benzaldehyde with N-Cbz nortropinone (51% yield), N-Bn
nortropinone (85% yield), and N-phenyldiazo nortropinone
(triazene, 86% yield) were significantly more effective. The
best, in terms of yield and diastereoselectivity, were the
reactions of N-alkyl derivatives (N-benzyl and N-methyl,
yield 91% [7c]). However, the analogous N-alkyl linkers
(Merrifield gel, Wang gel) turned out to be impractical.
Unfortunately, no method for cleavage of such linkers, mild
enough for the acid and base sensitive aldols, could be
found.
amounts of their diastereomers (8, Table 1, entry 5-7). The
relative configuration of diastereomer 8 remains, at present,
unknown. Similarly to experiments with benzaldehyde, the
products of elimination 9 were also observed in small
quantities (<10%).
Enantioselective Aldol Reactions of Nortropinone
Derivatives in Solution and on Solid Phase
A highly enantioselective aldol reaction of tropinone can
be realized through enantioselective deprotonation of
tropinone with chiral, optically pure, lithium amides [7c, 16].
By the same token, we wanted to probe the enantioselective
aldol reaction of polymer immobilized nortropinone
derivatives. Firstly, the model reactions of nortropinone
derivatives corresponding to triazene linker, carbobenzyloxy
linker and benzyl amine linker (Merrifield gel bound amine)
were deprotonated with two proven lithium amides (17 and
18, Scheme 3) derived from chiral secondary amines. The
chiral deprotonating reagents were used under roughly
optimized conditions and in the presence of optimized
amounts of lithium chloride additive, which is known to
increase the enantioselectivity [17] (compare entry 2 and 3,
Table 2). The lithium chloride – lithium amide 17 mixture
was most conveniently prepared from the corresponding
amine hydrochloride and n-BuLi [7c]. The N-benzyl
derivative 15 gave the best enantioselectivity, regardless of
chiral amide used (82 and 86%). On the other hand, the N-
Cbz derivative showed distinctly different but rather low ee
of the aldol obtained with both chiral reagents (8 and 45%).
The most enantioselective reagents for the solution models
Taking into account overall performance, simplicity of
preparation, and higher loadings and purity of cleavage
products from triazene gel 5 [3e] and Wang carbamate (a
carbobenzyloxy analogue linker) gel 6, the latter was chosen
as the optimal support for further testing. The aldol reactions
on gel 6, with three other aldehydes, showed performance
comparable to benzaldehyde (Table 1). The yields were
moderately good with moderate conversion. The cleavage
gave the major aldol products 7, admixed with noticeable
OH
OH
O
O
O
H
H
Deprotection
or Cleavage
1.Lithium Amide
Ph
Ph
17 or 18
N
H
N
X
N
X
2. PhCHO
X = PhN2 (13)
X = Cbz (14)
X = Bn (15)
16a X = PhN2
16b X = Cbz
16c X = Bn
7a
ee = 8-86% (in solution)
ee = 44-48% (on solid phase)
X = triazene resin (5)
X = Wang carbamate resin (6)
16d X = triazene resin
16e X = Wang carbamate resin
NLi
N
N
Li
17
18
Scheme 3.

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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Lazny et al.
Table 2. Results of Enantioselective Aldol Reactions of Nortropinone in Solution and on Solid Support
Additive
Chiral
Amine
Time of
Time of Reaction with
PhCHO
Entry
X
Yield [%]
ee [%]b
Deprotonation
(LiCl) [equiv.]
1
2
3
4
5
6
7
PhN2 (13)
PhN2 (13)
PhN2 (13)
Cbz (14)
Cbz (14)
Bn (15)
17·HCl
18
1.1
0.7
-
4a+120 min
4a+120 min
4a+120 min
4a+120 min
4a+120 min
30a+150 min
30a+150 min
10 min
10 min
10 min
15 min
15 min
15 min
15 min
81
82
80
45
44
84
74
72
63
53
8
18
17·HCl
18
1.1
0.7
1.1
0.7
45
82
86
17·HCl
18
Bn (15)
Resin 5
(p-C3-T2 triazene)
8
17·HCl
0.7
300 min
90 min
55
57
48
44
Resin 6
(Wang carbamate)
9
18
0.7
300 min
90 min
atime of addition of the ketone.
bee of the major isomer (present in the reaction mixture admixed with the other isomer 8) was measured by 1H-NMR in the presence of (+)-TFAE.
were then used for deprotonations on solid phase. Despite
optimization efforts, a disappointing drop in selectivity was
observed for the triazene linker support (from 72 to 48% ee).
The ee for the Wang carbamate linker remained also
virtually unchanged and low (44%). Regrettably, aldol of the
most promising benzyl amine derivative could not be
cleaved cleanly and, as a consequence, the ee of the product
could not be measured.
sodium/benzophenone. Magnetic resonance spectra (1H
NMR and 13C NMR) were recorded on a Bruker 200
spectrometer in CDCl3. Chemical shifts are reported in ppm
downfield of tetramethylsilane. Merrifield gel, and trityl
chloride gel were purchased from Novabiochem or Aldrich.
The Wang 4-nitrophenylcarbonate polymer was prepared
from the Wang gel (Fluka) according to the literature
procedure [11d]. The aldol reactions in solution were
performed as described before [7c, 19].
CONCLUSIONS
Typical Procedure for the Aldol Reaction of Polymer
Supported Nortropinone
The polymer anchored nortropinone could be
deprotonated with LDA to give lithium enolates, which in
turn reacted, as expected, with benzaldehyde giving aldols
[18]. This was demonstrated by cleavage of the aldol
products from the polymeric supports. The degree of
conversion of the ketone to aldols depended on the
polymeric support used for immobilization. The best
supports were the Merrifield polymer and the triazene
polymer (conversions 75-77%). The reactions reached
medium conversions (64-72%) on the polymer with the
Wang carbamate linker and low (37%) on the trityl linker.
Overall, the enantioselectivity of the aldol reaction on solid
phase was low to moderate. The supported enantioselective
reaction showed usually lower enantioselectivities compared
to the analogous reaction in solution. A dramatic drop was
observed for the triazene linker. The reaction in solution, and
the supported reaction on the Wang carbamate linker,
showed virtually the same low enantioselectivity (45, 44%
ee). Although the most promising supports with benzyl
linkers could be the Wang and the Merrifield polymers, so
far no suitable cleavage method for aldol nortropinone has
been found. The presented study indicated that several
problems, such as linker, cleavage and low enantioselectivity
remain to be addressed before highly stereoselective aldol
reactions of polymer immobilized tropanone derivatives can
be developed.
A dry polymer (0.30 g) with an anchored nortropinone 6
(0.26 mmol) was washed with dry THF (3 ꢀ 4 mL), and
cooled to ꢀ78°C over 20 min. A cold (ꢀ78°C) solution of
lithium amide (1.31 mmol, 5 equiv, prepared from n-
butyllithium in hexane, 2.5M, and diisopropylamine) in THF
(4 mL) was then added. The suspension was intermittently
shaken at ꢀ78°C for 5 h and washed with dry THF (3 ꢀ 4
mL). PhCHO (2.61 mmol, 0.27 mL, 10 equiv) was added,
and the mixture was intermittently shaken at ꢀ78°C for 45
min. Subsequently, AcOH (0.39 mmol, 0.024 g, 1.5 equiv) in
THF (0.5 mL) was added and the mixture was shaken for 5
min. The mixture was then allowed to warm to rt and was
subjected to typical washing (THF, DCM and methanol) and
cleavage.
General Procedure for the Analysis of Products from the
Polymer Supported Aldol Reaction
The polymers were subjected to cleavage procedures
depending on the type of employed linker: 3 (first ACE-Cl/
DCP, at rt for 24h and then MeOH, 12h, reflux), 4 and 6
(20% TFA/DCM for 15 min, at rt,), 5 (10% TFA/DCM at 0
°C for 10 min). The resulting crude mixtures of cleavage
products in the form of trifluoroacetates (from polymers 4, 5,
and 6) or hydrochlorides (from polymer 3) were washed with
aq. NH3, and backwashed with DCM (2 ꢀ 3mL). The organic
layer was dried (Na2SO4), concentrated under vacuum, and
EXPERIMENTAL
1
subjected to H-NMR analysis in CDCl3. Conversion and
All air sensitive reactions were carried out under argon.
Tetrahydrofuran was distilled under argon from

Studies on Aldol Reactions of Nortropinone Derivatives in Solution
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
25
derivatives by solid-phase synthesis. Tetrahedron Lett., 1996, 37,
2757.
(a) Lounasmaa, M. In The Alkaliods; Brossi, A., Ed.; Academic
Press: New York, 1988; Vol. 33, pp. 1-81. (b) Lounasmaa, M.;
Tamminen, T. In The Alkaloids; Cordell, G.A., Ed.; Academic
Press: New York, 1993; Vol. 44, pp. 1-113.
ratio of aldol products was inferred from integration of
characteristic nortropinone and carbinol –CH–OH signals:
[4]
[5]
Nortropinone aldol: ꢀH major isomer 7a: 5.25 (d, J=3.2
Hz, 1H, –CH–OH), minor isomer 8a: 4.97 (d, J 2.4 Hz).
(a) Singh, S. Chemistry, design, and structure-activity relationship
of cocaine antagonists. Chem. Rev., 2000, 100, 925. (b) Hoepping,
A.; George, C.; Flippen-Anderson, J.; Kozikowski, A.P. Radical
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Kozikowski, A.P.; Roberti, M.; Xiang, L.; Bergmann, J.S.;
Callahan, P.M.; Cunningham, K.A.; Johnson, K.M. Structure-
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Clercq, E.; Balzarini, J.; Kawase, M.; Sakagami, H.; Quail, J.W.;
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preferential toxicity to tumour cells displayed by some 2,4-
bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-ones and 3,
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Nortropinone aldol: ꢀH major isomer 7b: 3.52 (dd, J1=2.0
Hz, J2=9.2 Hz, 1H, –CH–OH), minor isomer 8b: 3.27 (dd,
J1=2.8 Hz, J2=9.1 Hz).
Nortropinone aldol: ꢀH major isomer 7c: 5.33 (d, J=2.4
Hz, 1H, –CH–OH), minor isomer 8c: 5.10 (d, J 1.9 Hz).
Nortropinone aldol: ꢀH major isomer 7d: 6.00 (d, J=2.5
Hz, 1H, –CH–OH), minor isomer 8d: 5.37 (d, J 3.3 Hz).
ACKNOWLEDGEMENTS
The authors are grateful to the University of Bialystok
(BST-125 and BW-173) for financial support and to Dr. L.
Siergiejczyk for assistance in recording NMR spectra.
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