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DOI: 10.1055/s-0029-1216862
Synthesis of Highly Functionalized Proline Derivatives via a One-Pot Michael/SN′-Addition/Cyclization Approach
Publication History
Publication Date:
02 June 2009 (online)
Abstract
Chelated enolates undergo Michael addition towards halogenated α,β-unsaturated esters in a highly stereoselective fashion. The enolates formed can be trapped with electrophiles such as Baylis-Hillman-type acrylates in a stereoselective fashion, before subsequent cyclization gives rise to substituted proline derivatives. Up to three stereogenic centers can be formed in this one-pot reaction.
Key words
amino acids - Baylis-Hillman - chelates - cyclization - Michael addition - one-pot reaction
Cyclic amino acids, such as substituted prolines and the family of the kainoids have attracted interest due to their remarkable biological activity. The latter compounds in particular can be regarded as conformationally fixed analogues of the amino acid glutamate, which can interact very strongly and selectively with the metabotropic glutamate receptors in the mammalian central nervous systems. [¹] (-)-Kainic acid (A) exhibits potent anthelmintic properties [²] but is also used as a neuroexcitatory agent [³] by the neuroscience community in modeling afflictions such as epilepsy, [4] Alzheimer’s disease, [5] and Huntington’s chorea. [6]
Prolineglutamic acid (B), a chimera of proline and glutamic acid, is a simplified analogue of kainic acid (Figure [¹] ). Therefore, it is not surprising that this amino acid was the target of several synthetic approaches. Yoo et al. described intramolecular Michael additions providing diastereomeric mixtures of protected cis- and trans-B, [7] while Correira et al. were able to obtain the cis-isomer stereoselectively via a [2+2]-cycloaddition. [8] Further enantioselective syntheses were described by the groups of Sabol [9] and Karoyan. [¹0]
Figure 1
Our group is also involved in the synthesis of unnatural amino acids, mainly by using metal-chelated glycine ester enolates as nucleophiles in a wide range of different reactions. [¹¹] In this context, we used trifluoroacetyl (TFA)-protected glycine ester enolates as nucleophiles in Michael additions towards various α,β-unsaturated esters. [¹²] In general, the Michael adducts are obtained in high yield and diastereoselectivity, while the best results are obtained with Z-configured substrates. If Michael acceptors such as 1 are used, containing leaving groups in suitable positions, the Michael addition can initiate a subsequent ring closure (MIRC). The product distribution can be controlled by the reaction conditions used. If the dianion 2, formed as an intermediate, is directly quenched at -78 ˚C, the expected Michael adduct 3 can be obtained as sole product in high yield and anti-selectivity (>97% ds). In contrast, if the reaction mixture is allowed to warm to room temperature, the carbocyclic product 4 is formed preferentially, especially with substrates containing good leaving groups (X = Br, I). [¹²a] If t-BuOH is added as proton source to quench this enolate, the still-deprotonated amide can attack the leaving group, giving rise to heterocyclic amino acids 5. [¹³ ] If allylic esters are used as Michael acceptors, the Michael addition can be combined with a subsequent Claisen rearrangement/lactamization giving rise to highly substituted pyroglutamates in one step (Scheme [¹] ). [¹4]
Scheme 1 Michael additions and MIRC of chelated enolates
This observation caused the question of whether it would be also possible to quench the enolate with other electrophiles, such as Baylis-Hillman adducts. [¹5] This would provide direct access to even more complex heterocyclic amino acids, bearing side chains which can be subjected to further modifications.
In our first experiment using the brominated Michael acceptor 1a (R = Me, X = Br, n = 2) we tried to trap the Michael adduct with the acetylated Baylis-Hillman product 6a. Acceptor 6a was added at -70 ˚C and the reaction mixture was allowed to warm to room temperature overnight. The expected double addition/cyclization product 7a was obtained in acceptable yield, accompanied by proline derivative 5a and a surprisingly high amount of cyclobutane 4a (Scheme [²] ).
Scheme 2 Double Michael additions and MIRC of chelated enolates
Obviously, the in situ formed enolate 2 (Scheme [¹] ) starts to react with 6a within the same temperature range in which the intramolecular enolate alkylation occurs. To avoid this side reaction, we investigated the reaction in more detail by HPLC analysis. During the warm-up, samples were taken and analyzed to figure out at which temperature the different reactions set in. And indeed, the initiation temperatures were relatively similar. The addition reaction with 6a started around -40 ˚C, while an intramolecular alkylation was observed at temperatures higher than -30 ˚C. This allowed us to suppress this side reaction completely by running the reaction constantly at -40 ˚C. Under these optimized conditions a range of aromatic and aliphatic Baylis-Hillman derivatives 6 could be converted into the corresponding prolines 7 in high yields (Table [¹] ).
Although three stereogenic centers are formed in one reaction, only one diastereomer (out of four) was obtained whose relative configuration could be determined by X-ray crystal structure analysis (Figure [²] ). As expected, the substituents at the pyrrolidine ring (C1/C2) showed a syn-configuration, resulting from a highly diastereoselective addition of the chelated enolate on the Z-configured substrate, [¹²a] [¹4] [¹5] while the exocyclic stereogenic center is anti-oriented (C2/C5). The configuration of the double bond formed in the SN′-addition step was Z, the selectivity slightly depending on the substitution pattern. All proline derivatives 7 could be obtained in isomerically pure form by simple flash chromatography.
Figure 2 X-ray crystal structure of 7c
In the NMR spectra the formation of rotamers was observed, but coalescence occurred at higher temperature, clearly indicating that the second set of signals is the result of a hindered rotation around the secondary amide bond.
In conclusion we could show that Michael additions of chelated enolates can be combined with stereoselective enolate alkylations and subsequent N-heterocyclizations giving rise to complex unusual amino acids in a highly stereoselective fashion. Three stereogenic centers can be generated in this simple one-pot protocol. Further domino processes are currently under investigation.
All reactions were carried out in oven-dried glassware (100 ˚C) under argon. All solvents were dried before use. THF was distilled from LiAlH4. The products were purified by flash chromatography on silica gel. TLC: commercially precoated Polygram® SIL-G/UV 254 plates. Visualization was accomplished with UV-light, I2 and KMnO4 solution. Melting points are uncorrected. Selected signals in the NMR spectra for the minor rotamers are extracted from the spectra of the isomeric mixture.
Double Michael Additions/Cyclizations: General Procedure
In a Schlenk flask hexamethyldisilazane (0.3 mL, 1.42 mmol) was dissolved in THF (2 mL). The solution was cooled to -78 ˚C before n-BuLi (1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath was removed and the solution was allowed to warm up for 15 min, before it was cooled again to -78 ˚C. In a second Schlenk flask ZnCl2 (80 mg, 0.57 mmol) was dried with a heat gun under high vacuum, before it was dissolved in THF (3 mL). After addition of TFA-Gly-Ot-Bu (115 mg, 0.5 mmol) the solution was cooled to -78 ˚C, before the fresh prepared LHMDS solution was added, followed by the Michael acceptor 1 (80 mg, 0.4 mmol) [¹²a] (15 min later) in THF (2 mL). After 2 h the corresponding Baylis-Hillman adduct 6 (0.75 mmol) was added in THF (1 mL) and the mixture was stirred at -40 ˚C for 6 h. After that period of time the mixture was allowed to warm to r.t. overnight, before it was diluted with Et2O (5 mL) and 1 M KHSO4 (2 mL) was added. The layers were separated, the aqueous phase was washed with CH2Cl2 (2 × 10 mL) and the combined organic layers were dried (Na2SO4). After evaporation of the solvent in vacuo the crude product was purified by flash chromatography (silica, hexanes-EtOAc).
(±)-(Z)- N -Trifluoroacetyl-3-[1,3-di(methoxycarbonyl)-4-phenylbut-3-en-1-yl]proline tert -Butyl Ester (7a)
According to the general procedure 7a was obtained from methyl 2-(acetoxy-2-phenylmethyl)acrylate [¹6] 6a (165 mg, 0.70 mmol) after flash chromatography (silica, hexanes-EtOAc, 8:2) in 94% yield (196 mg, 0.38 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.39 (s, 9 H, 7-H), 1.90 (m, 1 H, 3-Ha), 2.03 (m, 1 H, 3-Hb), 2.59-2.84 (m, 4 H, 2-H, 10-H, 13-H), 3.55, 3.78 (2 s, 6 H, 12-H, 16-H), 3.58 (m, 1 H, 4-Ha), 3.95 (dd, J 4b,4a = 9.7 Hz, J 4b,3a = 9.7 Hz, 1 H, 4-Hb), 4.51 (d, J 1,2 = 7.4 Hz, 1 H, 1-H), 7.34 (d, J 19,20 = 7.3 Hz, 2 H, 19-H), 7.29-7.39 (m, 3 H, 20-H, 21-H), 7.76 (s, 1 H, 17-H).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 27.5 (t, C-3), 27.6 (q, C-7), 29.5 (t, C-13), 42.0 (d, C-2), 44.6 (d, C-10), 46.1 (tq, J 4,F = 3.4 Hz, C-4), 51.7, 52.2 (2q, C-12, C-16), 62.8 (d, C-1), 83.1 (s, C-6), 117.1 (q, J 13,F = 287.3 Hz, C-9), 128.6, 128.7 (2d, C-19, C-20), 128.8 (s, C-21), 129.7 (s, C-14), 135.0 (s, C-18), 141.2 (d, C-17), 155.8 (q, J 8,F = 37.6 Hz, C-8), 167.9, 168.4, 173.0 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.38 (s, 9 H, 7-H), 1.76 (m, 1 H, 3-Ha), 3.55, 3.78 (2 s, 6 H, 12-H, 16-H), 4.55 (dd, J 1,2 = 7.4 Hz, J 1,2 = 1.4 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.4 (t, C-3), 29.5 (t, C-13), 44.7 (d, C-2), 45.0 (d, C-10), 47.2 (t, C-4), 61.7 (dq, J 1,F = 2.7 Hz, C-1), 83.4 (s, C-6), 129.6 (s, C-14), 134.9 (s, C-18), 141.2 (d, C-17), 167.9, 168.7, 173.3 (3 s, C-5, C-11, C-15).
HRMS (CI): m/z [M + H]+ calcd for C25H31F3NO7: 514.2053; found: 514.2038.
(±)-(Z)- N -Trifluoroacetyl-3-[1,3-di(methoxycarbonyl)-4-(4-chlorophenyl)but-3-en-1-yl]proline tert -Butyl Ester (7b)
According to the general procedure 7b was obtained from TFA-Gly-Ot-Bu (160 mg, 0.71 mmol), 1a (110 mg, 0.57 mmol) and methyl 2-[acetoxy(4-chlorophenyl)methyl]acrylate [¹7] 6b (484 mg, 1.78 mmol) after flash chromatography (silica, hexanes-EtOAc, 8:2) in 86% yield (268 mg, 0. 49 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.39 (s, 9 H, 7-H), 1.94 (m, 1 H, 3-Ha), 2.06 (m, 1 H, 3-Hb), 2.66 (m, 2 H, 2-H, 10-H), 2.74 (d, J 13,10 = 7.1 Hz, 2 H, 13-H), 3.55, 3.78 (2 s, 6 H, 12-H, 16-H), 3.59 (m, 1 H, 4-Ha), 3.97 (dd, J 4b,4a = 9.8 Hz, J 4b,3a = 9.8 Hz, 1 H, 4-Hb), 4.51 (d, J 1,2 = 7.3 Hz, 1 H, 1-H), 7.18 (d, J 19,20 = 8.4 Hz, 2 H, 19-H), 7.34 (d, J 20,19 = 8.4 Hz, 2 H, 20-H), 7.69 (s, 1 H, 17-H).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 27.5 (t, C-3), 27.6 (q, C-7), 29.6 (t, C-13), 42.1 (d, C-2), 44.5 (d, C-10), 46.1 (tq, J 4,F = 3.4 Hz, C-4), 51.7, 52.2 (2q, C-12, C-16), 62.8 (d, C-1), 83.1 (s, C-6), 117.1 (q, J 13,F = 287.3 Hz, C-9), 128.9, 130.0 (2d, C-19, C-20), 130.3 (s, C-14), 133.3 (s, C-21), 134.7 (s, C-18), 139.7 (d, C-17), 155.8 (q, J 8,F = 37.6 Hz, C-8), 167.6, 168.4, 173.0 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.39 (s, 9 H, 7-H), 1.79 (m, 1 H, 3-Ha), 3.55, 3.78 (2 s, 6 H, 12-H, 16-H), 3.85 (dd, J 4b,4a = 10.0 Hz, J 4b,3a = 10.0 Hz, 1 H, 4-Hb), 4.55 (d, J 1,2 = 7.4 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.4 (q, C-7), 29.5 (t, C-13), 44.6 (d, C-2), 45.1 (d, C-10), 47.1 (t, C-4), 61.7 (dq, J 1,F = 2.7 Hz, C-1), 83.4 (s, C-6), 129.0, 130.0 (2d, C-19, C-20), 130.2 (s, C-14), 133.3 (s, C-21), 134.8 (s, C-18), 140.0 (d, C-17), 167.6, 168.6, 173.3 (3 s, C-5, C-11, C-15).
HRMS (CI): m/z [M + H]+ calcd for C25H30ClF3NO7: 548.1663; found: 548.1727.
Anal. Calcd for C25H29ClF3NO7 (547.95): C, 54.80; H, 5.33; N, 2.56. Found: C, 54.89; H, 5.20; N, 2.44.
(±)-(Z)- N -Trifluoroacetyl-3-[1,3-di(methoxycarbonyl)-4-(4-nitrophenyl)but-3-en-1-yl]proline tert -Butyl Ester (7c)
According to the general procedure 7b was obtained from TFA-Gly-Ot-Bu (176 mg, 0.77 mmol), 1a (123 mg, 0.64 mmol) and methyl 2-[acetoxy(4-nitrophenyl)methyl]acrylate [¹8] 6c (321 mg, 1.15 mmol) after flash chromatography (silica, hexanes-EtOAc,7:3) in 86% yield (307 mg, 0.55 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.40 (s, 9 H, 7-H), 1.95 (m, 1 H, 3-Ha), 2.06 (m, 1 H, 3-Hb), 2.64-2.79 (m, 4 H, 2-H, 10-H, 13-H), 3.57, 3.81 (2 s, 6 H, 12-H, 16-H), 3.60 (m, 1 H, 4-Ha), 3.98 (dd, J 4b,4a = 9.9 Hz, J 4b,3a = 9.9 Hz, 1 H, 4-Hb), 4.50 (d, J 1,2 = 7.1 Hz, 1 H, 1-H), 7.39 (d, J 19,20 = 8.3 Hz, 2 H, 19-H), 7.75 (s, 1 H, 17-H), 8.23 (d, J 20,19 = 8.3 Hz, 2 H, 20-H).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 27.6 (t, C-3), 27.7 (q, C-7), 38.0 (t, C-13), 42.7 (d, C-2), 45.3 (d, C-10), 46.1 (tq, J 4,F = 3.4 Hz, C-4), 51.8, 51.9 (2q, C-12, C-16), 62.9 (d, C-1), 83.2 (s, C-6), 117.1 (q, J 13,F = 287.3 Hz, C-9), 123.4, 129.0 (2d, C-19, C-20), 133.3 (s, C-14), 136.4, 136.5 (2 s, C-18, C-21,), 142.4 (d, C-17), 155.8 (q, J 8,F = 37.6 Hz, C-8), 167.1, 168.4, 172.9 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.39 (s, 9 H, 7-H), 1.81 (m, 1 H, 3-Ha), 3.58, 3.82 (2 s, 6 H, 12-H, 16-H), 4.53 (d, J 1,2 = 6.8 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.6 (q, C-7), 44.7 (d, C-2), 45.5 (d, C-10), 47.1 (t, C-4).
HRMS (CI): m/z [M + H]+ calcd for C25H30F3N2O9: 559.1903; found: 559.1812.
Crystal Data for 7c
C25H29F3N2O9, MW = 558.50, monoclinic, P2(1)/c, a = 12.7767(5) Å, b = 21.6096(8) Å, c = 10.4574(4) Å; δ = 90˚, δ = 111.936(2)˚, δ = 90˚; V = 2678.25(18) ų, Z = 4, D calc. = 1.385 Mg/m³; T = 103(2) K; λ = 0.71073 Å; abs. coeff.: 0.118 mm-¹; Θ-range: 1.72 to 29.66˚; reflections collected: 34863; independent reflections: 7423 [R(int) = 0.0577]; completeness to theta: 98.0%; Goodness-of-fit on F ²: 1.049; final R indices [I > 2σ(I)]: R1 = 0.0807, wR2 = 0.1835, R indices (all data): R1 = 0.1329, wR2 = 0.2080.
Anal. Calcd for C25H29F3N2O9 (558.51): C, 53.76; H, 5.23; N, 5.02. Found C, 53.73; H, 5.21; N, 5.01.
(±)-(Z)- N -Trifluoroacetyl-3-[1,3-di(methoxycarbonyl)-4-(4-methoxyphenyl)but-3-en-1-yl]proline tert -Butyl Ester (7d)
According to the general procedure 7d was obtained from TFA-Gly-Ot-Bu (137 mg, 0.60 mmol), 1a (95 mg, 0.49 mmol) and methyl 2-[acetoxy(4-methoxyphenyl)methyl]acrylate [¹9] 6d (380 mg, 1.44 mmol) after flash chromatography (silica, hexanes-EtOAc, 8:2) in 79% yield (212 mg, 0.39 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.41 (s, 9 H, 7-H), 2.00 (m, 1 H, 3-Ha), 2.12 (m, 1 H, 3-Hb), 2.70 (m, 1 H, 2-H), 2.80-2.90 (m, 3 H, 10-H, 13-Ha, 13-Hb), 3.57, 3.79 (2 s, 6 H, 12-H, 16-H), 3.62 (m, 1 H, 4-Ha), 3.83 (s, 3 H, 22-H), 4.04 (dd, J 4b,4a = 9.7 Hz, J 4b,3a = 9.7 Hz, 1 H, 4-Hb), 4.56 (d, J 1,2 = 7.6 Hz, 1 H, 1-H), 6.91 (m, 2 H, 19-H), 7.26 (m, 2 H, 20-H), 7.72 (s, 1 H, 17-H).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 27.5 (t, C-3), 27.6 (q, C-7), 29.6 (t, C-13), 42.2 (d, C-2), 44.5 (d, C-10), 46.2 (tq, J 4,F = 3.4 Hz, C-4), 51.7, 52.0 (2q, C-12, C-16), 55.3 (q, C-22), 62.9 (d, C-1), 83.1 (s, C-6), 114.1 (d, C-20), 116.1 (q, J 13,F = 287.3 Hz, C-9), 127.3, 127.5 (2 s, C-14, C-18, 130.6 (d, C-19), 140.8 (s, C-17), 155.8 (q, J 8,F = 37.6 Hz, C-8), 160.0 (s, C-21), 168.2, 168.5, 173.2 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.40 (s, 9 H, 7-H), 1.86 (m, 1 H, 3-Ha), 3.57, 3.80 (2 s, 6 H, 12-H, 16-H), 3.85 (dd, J 4b,4a = 10.0 Hz, J 4b,3a = 10.0 Hz, 1 H, 4-Hb), 4.60 (dd, J 1,2 = 7.3 Hz, J 1,3a = 1.3 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.4 (q, C-7), 29.6 (t, C-13), 44.6 (d, C-2), 45.2 (d, C-10), 47.2 (t, C-4), 61.8 (dq, J 1,F = 2.5 Hz, C-1), 83.4 (s, C-6), 114.2 (d, C-20), 127.2, 127.4 (2 s, C-14, C-18), 130.6 (d, C-19), 140.9 (s, C-17), 160.1 (s, C-21), 168.2, 168.7, 173.5 (3 s, C-5, C-11, C-15).
HRMS (CI): m/z [M + H]+ calcd for C26H33F3NO8: 544.2158; found: 544.2139.
(±)-(Z)- N -Trifluoroacetyl-3-(1-methoxycarbonyl-3-ethoxycarbonylpent-3-en-1-yl)proline tert -Butyl Ester (7e)
According to the general procedure 7e was obtained from TFA-Gly-Ot-Bu (134 mg, 0.59 mmol), 1a (103 mg, 0.54 mmol) and methyl 2-[1-acetoxyethyl]acrylate [²0] 6e (283 mg, 1.52 mmol) after flash chromatography (silica, hexanes-EtOAc, 8:2) in 87% yield (219 mg, 0.47 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.26 (t, 3 H, 17-H), 1.41 (s, 9 H, 7-H), 1.71 (d, 3 H, 19-H), 2.02 (m, 1 H, 3-Ha), 2.22 (m, 2 H, 3-Hb, 10-H), 2.51 (m, 2 H, 13-H), 2.72 (m, 1 H, 2-H), 3.60 (s, 3 H, 12-H), 3.63 (m, 1 H, 4-Ha), 4.00 (dd, J 4b,4a = 9.8 Hz, J 4b,3a = 9.8 Hz, 1 H, 4-Hb), 4.15 (q, 2 H, 16-H), 4.51 (d, J 1,2 = 7.9 Hz, 1 H, 1-H), 6.94 (q, J 18,19 = 7.2 Hz, 1 H, 18-H).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 14.1, 14.2 (2q, C-17, C-19), 27.5 (t, C-3), 27.6 (q, C-7), 29.1 (t, C-13), 42.3 (d, C-2), 44.8 (d, C-10), 46.2 (tq, J 4,F = 3.3 Hz, C-4), 51.7 (q, C-12), 60.6 (t, C-16), 62.9 (d, C-1), 83.0 (s, C-6), 117.1 (q, J 13,F = 287.3 Hz, C-9), 129.8 (s, C-14), 139.3 (d, C-18), 155.8 (q, J 8,F = 37.6 Hz, C-8), 166.9, 168.5, 173.5 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.40 (s, 9 H, 7-H), 1.89 (m, 1 H, 3-Ha), 2.82 (m, 1 H, 2-H), 3.61 (s, 3 H, 12-H), 3.85 (dd, J 4b,4a = 9.8 Hz, J 4b,3a = 9.8 Hz, 1 H, 4-Hb), 4.54 (d, J 1,2 = 7.2 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.6 (q, C-7), 29.0 (t, C-13), 45.0 (d, C-2), 47.2 (t, C-4), 61.8 (dq, J 1,F = 2.7 Hz, C-1), 83.4 (s, C-6), 129.8 (s, C-14), 139.2 (d, C-18), 166.8, 168.7, 173.8 (3 s, C-5, C-11, C-15).
Anal. Calcd for C21H30F3NO7 (465.47): C, 54.19; H, 6.50; N, 3.01. Found: C, 54.47; H, 6.38; N, 3.42.
(±)- N -Trifluoroacetyl-3-[1,3-di(methoxycarbonyl)but-3-en-1-yl]proline tert -Butyl Ester (7f)
According to the general procedure 7f was obtained from TFA-Gly-Ot-Bu (129 mg, 0.57 mmol), 1a (100 mg, 0.52 mmol) and methyl 2-(1-acetoxymethyl)acrylate [²¹] 6f (230 mg, 1.47 mmol) after flash chromatography (silica, hexanes-EtOAc, 8:2) in 84% yield (191 mg, 0.44 mmol).
¹H NMR (500 MHz, CDCl3): δ (major rotamer) = 1.41 (s, 9 H, 7-H), 1.98 (m, 1 H, 3-Ha), 2.18 (m, 1 H, 3-Hb), 2.33 (dd, J 13a,13b = 13.8 Hz, J 13a,10 = 9.2 Hz, 1 H, 13-Ha), 2.61 (ddd, J 10,2 = 11.3 Hz, J 10,13a = 9.2 Hz, J 10,13b = 4.0 Hz, 1 H, 10-H), 2.66 (m, 1 H, 2-H), 2.78 (dd, J 13b,13a = 13.8 Hz, J 13b,10 = 4.0 Hz, 1 H, 13-Hb), 3.61, 3.72 (2 s, 6 H, 12-H, 16-H), 3.62 (m, 1 H, 4-Ha), 3.98 (dd, J 4b,4a = 9.8 Hz, J 4b,3a = 9.8 Hz, 1 H, 4-Hb), 4.51 (d, J 1,2 = 7.5 Hz, 1 H, 1-H), 5.51, 6.16 (2 s, 2 H, 17-Ha, 17-Hb).
¹³C NMR (125 MHz, CDCl3): δ (major rotamer) = 27.6 (t, C-3), 27.7 (q, C-7), 35.0 (t, C-13), 41.8 (d, C-2), 45.1 (d, C-10), 46.1 (tq, J 4,F = 3.4 Hz, C-4), 51.5, 52.0 (2q, C-12, C-16), 62.9 (d, C-1), 83.1 (s, C-6), 116.1 (q, J 13,F = 287.4 Hz, C-9), 127.4 (t, C-17), 137.0 (s, C-14), 155.8 (q, J 8,F = 37.3 Hz, C-8), 166.6, 168.4, 173.1 (3 s, C-5, C-11, C-15).
¹H NMR (500 MHz, CDCl3): δ (minor rotamer; selected signals) = 1.40 (s, 9 H, 7-H), 1.84 (m, 1 H, 3-Ha), 2.32 (dd, J 13a,13b = 14.3 Hz, J 13a,10 = 8.9 Hz, 1 H, 13-Ha), 3.62, 3.72 (2 s, 6 H, 12-H, 16-H), 3.83 (dd, J 4b,4a = 10.0 Hz, J 4b,3a = 10.0 Hz, 1 H, 4-Hb), 4.55 (dd, J 1,2 = 7.3 Hz, J 1,3a = 1.3 Hz, 1 H, 1-H).
¹³C NMR (125 MHz, CDCl3): δ (minor rotamer; selected signals) = 24.5 (q, C-7), 35.1 (t, C-13), 44.8 (d, C-2), 45.3 (d, C-10), 47.2 (t, C-4), 61.8 (dq, J 1,F = 2.8 Hz, C-1), 83.4 (s, C-6), 127.4 (t, C-17), 137.0 (s, C-14), 166.6, 168.7, 173.3 (3 s, C-5, C-11, C-15).
Anal. Calcd for C19H26F3NO7 (437.41): C, 52.17; H, 5.99; N, 3.20. Found: C, 52.27; H, 6.02; N, 3.51.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft and by the Fonds der Chemischen Industrie. We also want to thank Dr. Volker Huch for X-ray crystal structure analysis.
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Ciganek E. Org. React. 1997, 51: 201 - 15b
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Watson DG.Yudin A. J. Am. Chem. Soc. 2005, 127: 17516 - 17
Basavaiah D.Krishnamacharyulu M.Hyma RS.Sarma P. J. Org. Chem. 1999, 64: 1197 - 18
Nilov D.Raecker R.Reiser O. Synthesis 2002, 2232 - 19
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Shimamoto K.Ohfune Y. J. Med. Chem. 1996, 39: 407 ; and references cited therein - 1b
Shimamoto K.Ohfune Y. Synlett 1993, 919 - 1c
Ornstein PL.Bleisch TJ.Arnold MB.Wright RA.Johnson BG.Schoepp DD. J. Med. Chem. 1998, 41: 346 - 1d
Pellicciari R.Costantino G. Curr. Opin. Chem. Biol. 1999, 3: 433 - 1e
Moloney MG. Nat. Prod. Rep. 1999, 16: 485 ; and references cited therein - 2
Nitta I.Watase H.Tomiie Y. Nature 1958, 181: 761 - 3 For a recent review, see:
Wang Q.Yu S.Simonyi A.Sun G.Sun A. Mol. Neurobiol. 2005, 31: 3 ; and references cited therein - 4
Sperk G. Prog. Neurobiol. 1994, 42: 1 - 5a
Goodenough S.Schleusner D.Pietrzik C.Skutella T.Behl C. Neuroscience 2005, 132: 581 - 5b
Mohmmad A.Sultana R.Keller J.St. Clair D.Markesbery W.Butterfield D. J. Neurochem. 2006, 96: 1322 - 6a
Coyle JT.Schwarcz R. Nature 1976, 263: 244 - 6b
McGeer EG.McGeer PL. Nature 1976, 263: 517 - 7
Yoo S.Lee S.Kim N. Tetrahedron Lett. 1988, 29: 2195 - 8
Carpes MJS.Miranda P.Correira CR. Tetrahedron Lett. 1997, 38: 1869 - 9
Sabol J.Flynn G.Friedrich D.Huber EW. Tetrahedron Lett. 1997, 38: 3687 - 10
Karoyan P.Chassaing G. Tetrahedron Lett. 2002, 43: 253 - Reviews:
- 11a
Kazmaier U. Amino Acids 1996, 11: 283 - 11b
Kazmaier U. Liebigs Ann./Recl. 1997, 285 - 11c
Bauer M.Kazmaier U. Recent Res. Dev. Org. Chem. 2005, 9: 49 ; and references cited therein - 12a
Pohlman M.Kazmaier U. Org. Lett. 2003, 5: 2631 - 12b
Pohlman M.Kazmaier U.Lindner T. J. Org. Chem. 2004, 69: 6909 - 12c
Mendler B.Kazmaier U.Huch V.Veith M. Org. Lett. 2005, 7: 2643 - 12d
Mendler B.Kazmaier U. Synthesis 2005, 2239 - 13
Schmidt C.Kazmaier U. Eur. J. Org. Chem. 2008, 887 - 14
Schmidt C.Kazmaier U. Org. Biomol. Chem. 2008, 6: 4643 - Reviews:
- 15a
Ciganek E. Org. React. 1997, 51: 201 - 15b
Basavaiah D.Rao AJ.Satyanarayana T. Chem. Rev. 2003, 103: 811 - 16
Watson DG.Yudin A. J. Am. Chem. Soc. 2005, 127: 17516 - 17
Basavaiah D.Krishnamacharyulu M.Hyma RS.Sarma P. J. Org. Chem. 1999, 64: 1197 - 18
Nilov D.Raecker R.Reiser O. Synthesis 2002, 2232 - 19
Hong WP.Lee KJ. Synthesis 2005, 33 - 20
Siegfried E.Emsilie N. J. Chem. Soc., Perkin Trans. 1 1982, 2079 - 21
Vloon W.Bos J.Koomen GJ.Pandit U. Tetrahedron 1992, 48: 8317
References
Figure 1
Scheme 1 Michael additions and MIRC of chelated enolates
Scheme 2 Double Michael additions and MIRC of chelated enolates
Figure 2 X-ray crystal structure of 7c