As 4a and 4b could not be separated from this mixture, access to pure samples of the predicted stereoisomers of JBIR-22 (4a-d) would require an asymmetric synthesis of 68. The critical step in the synthetic strategy involved an enantioselective IMDA cyclisation of trienal 69 to provide either enantiomer of aldehyde 78,[(2S,3S, 6R, 7S)-78a or (2R,3R, 6S, 7R)-78b] which could be elaborated to furnish a single enantiomer of the desired intermediate 68 (Scheme 3.23, Route B). The trienal 69
could be accessed via chain elongation of our previously synthesised dienal 75 (Scheme 3.29).
Scheme 3.29. Retrosynthetic analysis of 78a. 78a could be accessed by an enantioselective IMDA cycloaddition of 69 which would arise from a chain elongation of dienal 75.
Extensive research has been carried out into the development of enantioselective IMDA routes to 78
due to its occurrence in natural products with potent biological activities such as the antiproliferative agent (+)-UCS1025A (79)220 and the phytotoxic polyketide solanapyrone D (80).221 Studies towards these and related natural products have centred around the use of either an organocatalytic IMDA developed by MacMillan222 or a chiral auxiliary mediated IMDA pioneered by Evans.223
Scheme 3.30. Examples of the utilisation of the chiral auxiliary approach in the synthesis of (+)-UCS1025A (79)218 and tetrodecamycin (83).224
Examples using the chiral auxiliary methodology include the use of (+)-camphor sultam (81) in the synthesis of (+)-UCS1025A (79)218 and (R)-4-benzyl-2-oxazolidinone (82) in the synthesis of the
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decalin ring of tetrodecamycin (83) (Scheme 3.30).224 MacMillan and co-workers are pioneers in the field of organocatalytic IMDA reactions with the development of a range of chiral imidazolidinone organocatalysts which displayed excellent enantio- and diastereocontrol with good yields and substrate scope.225 This methodology has been used in the total synthesis of (+)-UCS1025A (79),220 solanapyrone D (80)221 and related natural products such as amaminol A (84)226 and B227 (Scheme 3.31).
Scheme 3.31. Utilisation of imidazoline organocatalyst (R,R)-85 in the total synthesis of solananpyrone D (80)221 and amaminol A (84).226 Reagents and conditions: (a) 20 mol% 85.TfOH, CH3CN (2% H2O), 5 C, 48 hours, 71%. (b) 20 mol% 85.TFA, CH3CN (2% H2O), -20 C.
Based on literature precedent, an organocatalytic IMDA methodology was selected for the conversion of 69 to 78 (Scheme 3.29), due to the high levels of diastereo- (>20:1) and enantiocontrol (90% ee) reported for this transformation without the extra synthetic steps required to introduce and remove a chiral auxiliary.221
Scheme 3.32. Chain elongation of 75 to 87. Reagents and conditions: (a) Diisopropyl(ethoxycarbonylmethyl) phosphonate (86), LiHMDS, THF, -78 C r.t., 4 h, 88%. (b) DIBAL-H, DCM, -78 C, 30 mins, 97%.
Trienal 69 was prepared using a route adapted from MacMillan’s approach in the synthesis of solanapyrone D (80).221 This involved an olefination of dienal 75 to furnish 87 which was subsequently reduced by DIBAL-H to provide alcohol 88 in excellent yield (Scheme 3.32). The final step in MacMillan’s route involved a catalytic tetrapropylammonium perruthenate (TPAP) oxidation
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of alcohol 88 to the corresponding aldehyde 69 in a 59% yield. In an attempt to improve on this yield, a screen of oxidation conditions was carried out (Table 3.5). Conditions that removed the need for purification facilitating the direct use of the trienal 69 in the next step were considered highly valuable due to the instability of 69.
Table 3.5. Optimisation of the oxidation of 88 to 78.
Entry
Oxidant
Solvent
Time
69
(isolated yield, %)
1
cat. TPAP/NMO
DCM
50 mins
59
2212
DDQ
DCM
12 h
-
3
PCC
DCM
12 h
63
4
PCC
DCM
3 h
78
5
Dess-Martin
DCM
30 mins
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Dess-Martin periodinane was identified from the screen as the optimal oxidant for this transformation providing quantitative conversion to 69 in 30 minutes. In addition, a simple aqueous work-up furnished pure trienal 69 which could be directly used in the IMDA reaction without further chromatographic purification. Although this optimised route provides 69 in excellent yield (85% over 3 steps; Scheme 3.33, Route A) from 75, it was not an ideal approach as it contained two concession steps.228 In an “ideal synthesis”,228–232 nonstrategic redox manipulations such as the reduction of ester 87 to the alcohol 88, followed by subsequent oxidation to the aldehyde 69 are regarded as concession steps. A strategic redox manipulation is defined as a reaction which establishes the correct functionality found in the target product.228 As our desired polyene 69 is in the aldehyde oxidation state, an ideal synthesis would transform 75 to the desired aldehyde 69 in one-step, without any nonstrategic redox manipulations. This was achieved by reacting 75 with the commercially available Wittig reagent 89, which after a simple acidic deprotection of the acetal provided the desired aldehyde 69 in good yield (64%) and in just one-step (Scheme 3.33, Route B).
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Scheme 3.33. Optimised chain elongation strategy. Reagents and conditions: Route A: (a) LiHMDS, THF, diisopropyl(ethoxycarbonylmethyl) phosphonate (86), -78 C r.t., 4 h, 88%. (b) DIBAL-H, DCM, -78 C, 30 mins, 97%. (c) Dess-Martin periodinane, DCM, H2O, r.t., 1 h, quantitative. Route B: (a) (i) (1,3-dioxolan-2-ylmethyl)triphenylphosphonium
bromide (89), tBuOK, THF, 0 C, 3.5 h. (ii) 10% aq. oxalic acid, r.t., 1 h, 64%.
In contrast with our previously synthesised triene 66 (Scheme 3.26), it was not possible to remove the undesired minor Z-isomer of trienal 69 (C8-C9 double bond). However, this was not an issue as it has been shown that Z,E-dienes are uniformly inert to this catalytic IMDA, resulting in a kinetic purification.221,226 Trienal 69 was subjected to the catalytic IMDA conditions (20 mol% imidazolidinone (S,S)-85/(R,R)-85.TfOH) which afforded the desired decalins 78a and 78b
respectively, in good yields (78a, 65%; 78b, 68%; based on consumed E,E,E-trienal) and moderate diastereoselectivity (dr 4:1) (Scheme 3.34). This moderate diastereoselectivity was surprising when compared to the selectivity reported by MacMillan and co-workers (dr >20:1). However, it was in agreement with the findings of Christmann et al.233 for the same transformation. This reduction in diastereoselectivity may be due to epimerisation of the C2 position which was also observed by MacMillan for similar substrates.221 The removal of the minor diastereomer was not possible until the final step of the synthesis. A portion of the aldehydes 78a and 78b were converted to the corresponding alcohols 90a and 90b via NaBH4 mediated reduction for determination of their
enantiomeric purity (Scheme 3.34). A racemic standard was obtained by a BF3.OEt2 catalysed
cycloaddition of 69 to provide (±)-78 as a single diastereomer, which was subsequently reduced to the corresponding alcohol (±)-90 (Scheme 3.34A). Enantiomeric excesses were obtained by chiral GC analysis using an Agilent Cyclosil-B (isotherm, 140 C, Scheme 3.34B). The determined enantiomeric purity of 78a (87% ee) and 78b (84% ee) are in agreement with the reported values for this reaction (80-90% ee).221,233,234 The enantiomeric purity could be improved if required by recrystallisation at the alcohol oxidation state.235
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Scheme 3.34. (A) Synthesis of racemic decalin (±)-78 and enantiomerically enriched decalins (2S,3S, 6R, 7S)-78a and (2R,3R, 6S, 7R)-78b. Reagents and conditions: (a) BF3.Et2O, DCM, -78 C 0 C, 3 h, 74%. (b) 20 mol% imidazolidinone
(S,S)-85.TfOH, MeCN (2% H2O), -5 C, 48 h, 65%, dr 4:1, 87% ee. (c) 20 mol% imidazolidinone (R,R)-85.TfOH, MeCN (2%
H2O), -5 C, 48 h, 68%, dr 4:1, 84% ee. (d) NaBH4, EtOH, 0 C, 1 h, (±)-90 - 86%; 90a – 88%; 90b – 91%. (B) Determination of the enantiomeric purity of decalins 90a (middle) and 90b (bottom) via chiral GC analysis. Only section corresponding to the major diastereomer of 90a and 90b is shown, see Appendix G for full chromatograms.
The expected relative and absolute configuration of 78a and 78b were confirmed by analysis of the X-ray crystallographic structures of the corresponding carboxylic acid derivatives 91a and 91b
(Scheme 3.35). The crystalline acids 91a and 91b were obtained by rapid air oxidation (at 4 C) of aldehydes 78a and 78b respectively.
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Scheme 3.35. Confirmation of the expected absolute configuration of 78a and 78b by analysis of the small molecule X- ray crystal structures of the corresponding carboxylic acids 91a and 91b. X-ray crystallographic data provided by Dr David Cordes.