4.3 Synthesis of E,E,E-trienes for IMDA cycloadditions
4.3.2 Organocatalytic asymmetric IMDA
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lactol 460. The five membered lactol ring appeared to be more favorable than the aldehyde formation under O-silylating conditions.
O HO
460a/b
O
TBDPSO +
O HO
467 468
a
1.5:1
Scheme 88. Reagents and conditions: a) TBDPSCl, imidazole, DMF, +50 °C, 22 h (65
%).
The chiral auxiliary 41 can be removed to yield hydroxyl sulfones by using sulfur anions (55). However, such a cleavage of auxiliaries leads to a longer synthesis route due to extra steps for the introduction and removal of the sulfur containing moiety. At this point, I decided to consider other methods to prepare bicyclo[4.3.0]nonane aldehydes and the results of these experiments are presented in the following chapter.
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89). In order to achieve this, triene ester 443 was reduced with DIBAL-H to triene alcohol 469, which was oxidized preferably without isolation to the corresponding aldehyde 470 with MnO2. Oxidation required excess of MnO2 to be completed. The triene aldehyde 470 was susceptible for polymerization and it was preferably stored in a freezer.
The linear triene aldehyde 470 was accompanied with inseparable branched aldehyde 471, which formed in the chain elongation step (see 439→440+441). The ratio of 470 to 471 depended on the chain elongation step as stated before.
a BnO OH
BnO O
BnO CO2Me
b
469
470 443
BnO O +
471
Scheme 89. Reagents and conditions: a) DIBAL-H, CH2Cl2, -78 °C; b) MnO2, CH2Cl2, r.t., 24 h (89 % over 2 steps).
Imidazolidinone catalysts 474-476 (Scheme 90) were prepared according to published procedures (135). The stereochemistries of the catalysts 474-476 were confirmed by NOE-NMR measurements. The cyclization of the amide 473 produced a diastereomeric mixture of imidazolidinones 474a/b (1:3.1). Unfortunately, the cyclization favored the trans-cycloadduct, which was lower in energy. The NOE-NMR showed coupling between the protons H2 and H5 in imidazolidinone ring of 474a. It was interesting to note that the cis-product 474a did not racemize notably during the long reaction time.
However, the trans-product 474b was prone to racemization and cycloadduct 474b was found to be entirely racemic by chiral HPLC analysis.
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472 NH3Cl O NH
NH2 O NH
473
NH O N
474a
a b
NH O N +
474b 1:3.1
H H
NOE
NH O N
H H
NH O N
475 476
5
2
2
Scheme 90. Reagents and conditions: a) NaHCO3, CHCl3; b) BnCHO, PTSA, MeOH, + 75 °C, 4 days (44 %).
I decided to replace the N-methyl group of the organocatalyst 475 with an N-benzyl group, because I though that it would make the catalyst more rigid. By rigidifying the catalyst structure, the catalyst should give better enantioselectivity by favoring the desired reaction path to the cycloadduct.
2-Amino-3-phenyl-propionic acid methyl ester hydrochloride salt 477 was directly amidated with benzylamine in high yield (88 %). The cyclization of 478 produced 18 % of the correct diastereomer 479a. The stereochemistry of the catalyst 479a was confirmed by NOE-NMR measurement. Consequently, H2 and H5 protons of the imidazolidinone ring showed NOE between them. Notable racemization was not observed for the cis- cycloadduct 479a, however, the trans-cycloadduct 479b was accompanied with racemization.
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477 NH3Cl O O
NH2 O NH
478
NH O N
479a
NH O N
479b +
a b
1:2 H
H NOE
5
2
Scheme 91. Reagents and conditions: a) BnNH2, EtOH, r.t., 23 h (88 %); b) (Me)3CCHO, PTSA, MeOH, rfx, 46 h (56 %).
The starting materials of IMDA cycloadditions were mixtures of linear triene aldehyde 470 and the inseparable branched triene aldehyde 471 (Scheme 92). The linear triene aldehyde 470 was more inclined for polymerization and thus some of the experiments were performed with starting materials containing more of the branched triene aldehyde 471. However, both aldehydes 470 and 471 are capable of forming the iminium ion with the amine catalyst. The catalyst loadings were calculated according to the total aldehyde amount. The cycloadduct aldehyde 480 was reduced to the corresponding alcohol 481 for analytical purposes. The branched triene aldehyde 471 was unable to cycloaddition and was thus easily separated from the cycloadduct 480 by flash chromatography. The endo/exo selectivities were determined by 1H NMR from the crude product mixtures. The chemical shifts of the carbonyl protons of the endo-and exo-cycloadduct aldehydes 480 differed by about 0.08 ppm’s.
BnO O
OBn O
a b
OBn HO
470 480 481
+ 471 + 471
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Scheme 92. Reagents and conditions: a) organocatalyst, solvent mixture, acid; b) NaBH4, EtOH, r.t.
The results of the organocatalytic IMDA cycloadditions are presented in the Table 4.
Catalyst 475 gave highest enantioselectivities (Entry 2, 74 %ee), yields (entry 3, 99 %) and endo-selectivities (entries 2, 3, 4 and 7, >99:1) compared to other organocatalysts 474a, 476 and 474a. Trimethyl oxazolidinone 476, which was chiral only at the C5- position was found to give low stereoselectivities (Entry 1), although oxazolidinone 476 is an excellent catalyst for Diels-Alder cycloaddition (135a). The IMDA cycloaddition of triene aldehyde 470 was noticed to be solvent dependent. Acetonitrile appeared to be the best of the examined solvents for this cycloaddition. However, MeOH afforded somewhat higher enantioselectivity (Entries 2 and 3), but an extra step was required for acetal cleavage, which was formed from the aldehyde 480 during the reaction. Also, the yield of the cycloadduct 480 was lower in MeOH than in acetonitrile. The enantioselectivities did not improve significantly using lower temperature (Entries 9 and 10). Furthermore, the low temperature (-20 °C) retarded the reaction significantly, so that the reaction was not complete even after several days of standing. Surprisingly, the enantioselectivity was decreased at lower temperature in the reaction catalyzed by 475 (Entry 3 and 4). In comparison, the enantioselectivity increased slightly, but the endo:exo ratio became worse when the reaction was catalyzed by 479a at low temperature (-20
°C). Although a direct comparison between the co-acids can not be made, because the solvent system was also changed, it can be inferred that p-toluene sulphonic acid in dichloromethane/iso-propanol afforded worse endo:exo selectivities and enantioselectivities than other solvent/acid systems examined (Entries 5 and 11).
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Table 4. The conditions and results of IMDA reaction of the triene aldehyde 470 catalyzed by the organocatalysts 474a, 475, 476 and 479a.
Entry Catalysta Temperature Solvent Acid Endo:Exob Yieldc (%) %e.ed
1 474a r.t. H2O/CH3CN 0.1 M
HCl >99:1 59 10
2 475 r.t. H2O/MeOH 0.4 M
HCl >99:1 54 74
3 475 r.t. H2O/CH3CN 0.1 M
HCl >99:1 99e 72 4 475 -20 → +6 °C H2O/CH3CN 0.1 M
HCl >99:1 54 66
5 475 -20 → +6 °C CH2Cl2/i- PrOH
PTSA 25:1 45 41
6 475 -20 → +6 °C H2O/THF TFA - - -
7 475f r.t. H2O/CH3CN 0.1 M
HCl >99:1 79 72
8 476 0 °C → r.t. H2O/MeOH 0.4 M HCl
3.3:1 28 -
9 479a -20 → +6 °C H2O/CH3CN 0.1 M
HCl 17:1 40 56
10 479a r.t. H2O/CH3CN 0.1 M
HCl >99:1 54 47
11 479a -20 → +6 °C CH2Cl2/i- PrOH
PTSA 14:1 38 12
12 479a -20 → +6 °C H2O/THF TFA - - -
a 20 mol-% of the catalyst was used compared to the calculated sum of total moles of aldehydes 470 and 471. b endo:exo ratios were determined by 1H NMR from the aldehyde
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product mixture. c Yields of isolated pure aldehydes. The yields were correlated to the amount of linear aldehyde 470 in the beginning of the reaction. d For determination of the ee values, the aldehyde products were first reduced to alcohols with excess NaBH4 in EtOH, and the resulting alcohols were analyzed by HPLC using chiral Daicel OD column. Absolute and relative configurations were assigned by chemical correlation to compounds obtained by known methods for Diels-Alder reactions or by analogy. e The ratio of the linear triene aldehyde 470 to the branched triene aldehyde 471 was 1:3.76 in this reaction. f A 5.6 mol-% of the catalyst was used in this reaction.
The proposed mechanism of the organocatalytic IMDA cycloaddition is shown in the Scheme 93. Condensation of triene aldehyde 470 with enantiopure amine 482 leads to the formation of an iminium ion 483. The iminium ion 483 is active enough to enable asymmetric IMDA cycloaddition with the diene part of the molecule. After the cycloadduct 484 has formed, the amine catalyst 482 is recovered by hydrolysis and the aldehyde cycloadduct 480 is produced. After this, a new catalytic cycle can begin.
O
OBn NH
R1 R2 Acid
OBn R2 N
R1 OBn
R2 N R1
H3O+ OBn O
480 470
482
483
484 IMDA
Hydrolysis Condensation 4
5 6
Scheme 93. Mechanism of organocatalytic IMDA cycloaddition. The represented stereochemistry of the cycloadduct 480 is obtained with organocatalyst with (S,S)- stereochemistry.
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The different catalytic activity of the catalyst 476 in Diels-Alder reactions compared to intramolecular Diels-Alder reactions are propably due to steric hindrance between trans- methyl group at position 2 of the imidazolidinone ring (see Scheme 90, methyl group at position 2 of 476) of the catalyst 476 and the aldehyde 470 -CH2- groups (see Scheme 93, carbons (4-6) of 470).