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 Nalkylderivatives (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. 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 Nalkyl 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: +4885-745-7834; Fax: +48-85-747-0113; E-mail:
[email protected]
1570-1786/10 $55.00+.00
N X nortropinone 1, X = H
tropinone 2, X = Me
benzyl resin 3, X = Ph
Ph
trityl resin 4, X = triazene resin 5, X =
N
N
O Wang carbamate resin 6, X =
O
O 3
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.
© 2010 Bentham Science Publishers Ltd.
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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Lazny et al.
O
HO R 1. LDA 2. RCHO
HN
O HB
HA
O
R
N
N
H
H
second isomer
exo-anti trityl resin 4 triazene resin 5 carbamate Wang resin 6
O R
N 3. cleavage: TFA/DCM 4. NH3
OH
7a R = Ph 7b R = i-Pr 7c R = 4-NO2-Ph 7d R = 1-Napht
9a R = Ph 9b R = i-Pr 9c R = 4-NO2-Ph 9d R = 1-Napht
8a R = Ph 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 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 (530% 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 720% 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 Table 1.
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
Results of Aldol Reactions of Immobilized Nortropinone on Various Solid Supports Support
Entry
Cleavage Reagent (Linker Type) 3
Loading of Nortropinonea [mmol/g] ([%])b
RCHO
Conversion in Aldol Reactionc [%]
7:8
0.40 (37)
PhCHO
-d
-d
-d
2
4 (trityl)
20% TFA/DCM
1.55 (100)
PhCHO
37
44
72:28
3e
5 (p-C3-T2 triazene)
10% TFA/DCM
0.71 (78)
PhCHO
77
52
90:10
4
PhCHO
64
58
78:12
5
i-PrCHO
67
55
69:31
4-NO2-PhCHO
65
53
85:15
1-naphtylCHO
72
57
67:33
7
6 (Wang carbamate)
20% TFA/DCM
0.87 (100)
loading of nortropinone on starting polymer determined from mass of nortropinone hydrochloride obtained after cleavage [11a]. % of theoretical value. sum of major and minor isomers. d only aldol condensation product (75% conversion and 55% yield). e results previously reported3e and shown for comparison. c
[%]
Products Ratio
i) ACE-Cl/ DCP, ii) MeOH
6
b
Yield
(Merrifield; benzyl)
1
a
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 1chloroethyl 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].
Studies on Aldol Reactions of Nortropinone Derivatives in Solution
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
O H OH
O H OAc
O Ph
ACE-Cl, DCM or DCP
Silica Gel
Ph
N
23
Ph
N
N
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 paraC3-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. 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
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 (
