DIPEA equiv
2.2.4 Synthesis of 3-Acyl Tetramic Acids
4-Benzyloxy-5-substituted-pyrrolidine-2-ones 69c and 69d were transformed to 4-hydroxy-pyrrol-2-ones 51b and 51c by hydrogenolysis using palladium on charcoal:
Excellent yields were obtained and the double bond of the heterocycle remained intact.
A methanolic solution of 51c produced a tautomeric mixture i.e. a combination of 3-enol (α) and 2,4-diketo (β) tautomers, in a 1:2.3 ratio respectively. While tetramic acid 51b in d-MeOH produced an α:β ratio of 1:2.8, with each tautomer consisting of a 50:50 mixture of diastereoisomers. The diastereoisomers present are (5S,1'S)- and
(5R,1'S)-4-hydroxy-5-sec-butyl-pyrrol-2(5H)-one and (5S,1'S)- and (5R,1'S)-5-sec-butyl-pyrrolidine-2,4-dione.
The tautomers of 51b were easily separated due to their differences in solubility;
the 2,4-diketo tautomer (β) was readily soluble in ethyl acetate while the enol tautomer (α) was only sparingly soluble in methanol. The 13C-NMR spectrum of the diketo (β) tautomer of 51b in Fig.8 clearly shows two signals for each carbon atom which are characteristic of the diastereoisomers present. The further away the carbon atom is from the chiral centres, the closer the signals of the diastereoisomers e.g. the signals for C-2 downfield in the spectrum are relatively close, almost merging as one signal, in comparison to the pair of signals for C-1':
Fig.8 13C-NMR spectrum of the tautomer mixture of 51b
The final step of the total synthesis of 54b involves 3-acylation of 51b. It was not possible to 3-acylate benzyl tetramate 69c because the 4-O protecting group 'ties up' the electrons of the 3-double bond, hindering reactivity at the 3-position. Therefore, removal of the protecting group induces keto-enol tautomerisation, rendering C-3 available for reaction with electrophiles.
A number of acylation procedures available involve the use of a strong base, usually BuLi, and the corresponding acyl chloride. This is not suitable for use with tetramic acids such as 51b because of the possibility of competing reactions at 1-H and 4-OH. If the preparation of 51b was stereoselective, this acylation procedure would also induce racemisation at position-5 of the heterocycle. Attempts by other groups to acylate pyrrolidine-2,4-diones using these base-mediated procedures led predominantly to
formation of the 4-O acylated product or exceptionally low yields of the desired 3-acyl tetramic acid. Such procedures include the use of various metal enolate derivatives and the corresponding chloride/fluoride[81] or triethylamine and an active ester[82]. Therefore, only acid-mediated acylation procedures were considered here.
Acylation was achieved in reasonable yields (54%) by treating 5-sec-butyl-pyrrolidine-2,4-dione 51b with BF3.OEt2 and acetyl chloride in the absence of solvent[83], while acylation using titanium tetrachloride in nitrobenzene (50oC, 2.5 h) also generated product 54b but lower yields (41%) were obtained[60].
NH
The BF3-etherate method, a Lewis acid-mediated acylation, generates a neutral boron difluoride complex similar to 73[83]:
NH
73 has been isolated as a neutral compound and characterised[83], but generally an aqueous work-up or immediate treatment with methanol directly generates the 3-acyl tetramic acid.
3-Acetyl-5-sec-butyl-pyrrolidine-2,4-dione 54b possesses a β-tricarbonyl system and exists in several tautomeric forms, namely two pairs of 'internal' tautomers a↔b and c↔d, and 'external' tautomers ab↔cd. Rapid interconversion occurs between the internal tautomers by an intramolecular proton transfer along the hydrogen bond, while external tautomers interchange much more slowly due to necessary rotation of the C-3 acyl residue[84]. Therefore, on an NMR-timescale, internal tautomers are not detected
separately but as one signal, whereas the comparatively slower external tautomerisation can be measured by NMR spectroscopy with a separate signal for each tautomer pair (ab and cd) and the ab:cd ratio determined.
Proton δ Multiplicity Intensity Ratio J/Hz
1-H 6.44, 6.25 2 x s 3:1
5-H 3.76, 3.95 2 x d 2.86:1 3.7, 4.21 2'-H 2.43, 2.48 2 x s 3.55:1
1''-H 1.9 m
2''-H 1.23 m
3''-H,
1'''-H 0.9-1.0 m
Average ratio = 3.1:1
Table 4 1H-NMR data of 54b in CDCl3. See Scheme 32 for numbering key
NB for simplicity, the chemical shifts and multiplicity patterns quoted in Table 4 are averages of the diastereomers present. For precise values, see P.91.
The 1H-NMR spectrum of 3-acetyl-5-sec-butyl-pyrrolidine-2,4-dione 54b was recorded in deuteriochloroform and only some protons gave two clear sets of peaks: N-H, 5-H and 2'-H corresponding to the two sets of external tautomers. Comparison of the integrations of these signals revealed an average ratio of 3.1:1, which is largely concentration independent. The more intense peaks are thought to arise from the cd external tautomer pair while the smaller signals result from the ab pair i.e. ab:cd 1:3.1. This has been proven in literature[85] and is also based on the fact that diamagnetic anisotropy of the carbonyl groups causes deshielding of the neighbouring protons positioned in the same plane as the double bond and shields protons out of that plane[84,85]. Therefore, the 5-H peak of the cd tautomers appears higher field (3.76 ppm) in relation to 5-H of the ab tautomers (3.95 ppm). This significant difference in chemical shift, coupled with the two sets of peaks corresponding to N-H and 2'-H, allows calculation of the ratios of external tautomers from the intensities of the individual peaks.
The individual diastereoisomers were also identified in the 1H-NMR spectrum of 54b in a 1:1 ratio, from the 1-H and 5-H signals. The peaks corresponding to the diastereoisomers appeared within 0.02 ppm of each other in the spectrum e.g. 5-H of the ab tautomer pair displayed two doublet signals at 3.94 and 3.96 ppm and so it is safe to assume that these signals do not result from tautomers. Signals arising from the two
external tautomer pairs have a larger separation, see Table 4. Comparison of the 1 H-NMR spectrum of 54b with that of the non-acylated precursor 51b also allows assignment of the peaks corresponding to the diastereomers.
13C-NMR spectroscopy was more advantageous for the study of tautomerisation, as the chemical shift of the carbon atom is hugely dependant on the hybridisation of the carbon atom itself and is hardly affected by the anisotropy of nearby substituents. Again, a CDCl3 solution of 54b produced a double set of signals for some carbons in the 13 C-NMR spectrum: Table 5 13C-NMR data of 3-acetyl-5-sec-butyl-pyrrolidine-2,4-dione 54b in CDCl3
* more intense signal for specified carbon atom
The external tautomers, ab and cd, are clearly represented by two peaks for each of C-2 and C-4. The difference in chemical shifts of the two signals for each carbon atom is attributed to the enol-keto tautomerisation of that carbon atom and hydrogen-bonding with the 3-acetyl residue. Hydrogen-bonded carbonyls are thought to resonate lower field in comparison to the corresponding free carbonyl[84], therefore C-2 of the cd tautomer pair should resonate at a higher frequency than in ab while the C-4 signal of cd should occur higher field than ab.
Four signals are observed for C-4, C-5 and C-1''' which correspond to the diastereoisomers present; two diastereomers for each external tautomer pair. Assignment of the diastereoisomers and tautomers was based on theory outlined above, comparisons with 1H-NMR and 13C-NMR spectra of the non-acylated precursor 51b and experimental data from previous research in this area[85]. It was deduced that the more intense peaks in the 13C-NMR spectrum (*, Table 5) of 54b result from the cd tautomeric forms.
Carbon δ ablit δ cdlit δexpt 2 169.9 175.6 175.0 3 105.7 102.5 100.3 4 201.0 195.5 194.8 1' 188.4 184.0 184.2
Table 6 Lit.[85] and current experimental values for the 13C-NMR chemical shifts of 54b in a CHCl3 solution
Enolic carbon atoms resonate at a lower frequency than their keto carbon counterparts[84], therefore from the more intense, lower frequency signal for an enolic C-1' atom and with the predominance of the higher frequency, hydrogen-bonded C-2 (Table 6), it appears that, with respect to 54b, tautomer d is the main tautomeric form. Steyn and Wessels[85]
have supported this theory with the X-ray crystallographic structure determination.
The predominance of the d tautomer of 54b over its geometric isomer b and internal isomer c is due to the greater ability of the C-2 carbonyl, over the 4-oxo function, to form an intramolecular hydrogen bond with the 3-acetyl residue. Nitrogen, as part of an amide structure, donates electrons to the C-2 carbonyl moiety, thereby enhancing its proton accepting ability. Research has shown that when the nitrogen atom is acylated, the major external tautomer pair is ab because the nitrogen lone pair can no longer enhance the proton-accepting ability of the C-2 carbonyl, which in turn increases the possibility of hydrogen-bonding at C-4[86].
In conclusion, the total synthesis of 3-acetyl-4-hydroxy-5-s-butyl-pyrrol-2(5H)-one 54b was established with few intermediate steps and reasonable yields. The versatility of the individual steps introduces flexibility to the synthesis, enabling a number of amino acids to be used as starting materials, generating a range of tetramic acids. These intermediate compounds are further functionalised by a simple 3-acylation.
NH2 O OH
NH2 O OBn
NH O O
NH O HO
O
60b 52d
(i), (ii), (iii)
51b
54b
(vi)
85% 68%
54%
(iv),(v)
Scheme 33 Total synthesis of 54b: Reagents and conditions (i) BnOH, PTSA 61, PTSCl 62, 80oC, 2 h. (ii) 2M HCl in Et2O, CHCl3, 0oC, 30 min. (iii) NH3/DCM, CHCl3, r.t., 60 min. (iv) 1.3 1a, benzoic acid, THF, reflux, 24 h. (v) H2, 5% Pd/C, MeOH, r.t., 12 h. (vi) AcCl, BF3.OEt2, 80oC, 8 h.
Further work:
• Investigation of inorganic reagents to complex phosphine oxide, aiding its removal from crude tetramate mixtures.