Synthesis of 2,5-Disubstituted Octahydroquinolin-4-ones via an

A route for the preparation of 2,5-disubstituted octahydroquinolin-4-ones, synthetic precursors of the decahydroquinoline-type toxins, is presented. The key steps are an asymmetric epoxidation and an intramolecular hetero Diels-Alder reaction between an activated diene and an imine. The presence of an allylic stereogenic center induces some selectivity and thus only two cycloadducts are obtained in 70:30 ratio and good yield.


Introduction
Interest in the biological activity of the analogs of naturally occurring toxins, such as those isolated from skin extracts of dendrobatid frogs [1], has prompted the development of new synthetic strategies or has led to the improvement of older ones for these targets [2].One of the most powerful strategies is based on intramolecular Diels-Alder reactions, which have been used in different approaches, usually with high selectivity [3].Grieco and Parker [4] have presented a synthesis of (-)-8a-epi-pumiliotoxin based on an hetero Diels-Alder reaction between a diene and an imine carried out under Mannich conditions and they found that the selectivity of the process can be influenced by an allylic substituent.
Within a project aimed at the synthesis of bicyclic alkaloids, we were interested in the development of a synthetic strategy for the preparation of 2,5-disubstituted decahydroquinolines [1], which could allow us to prepare different analogs of the natural toxins.We envisioned that the basic skeleton could be constructed by the intramolecular hetero Diels-Alder reaction of a suitable precursor containing a diene and an imine, in an approach similar to the one used by Grieco and Parker [4].
For our synthesis, and in order to increase the reactivity, we decided to place an activating group such as a tert-butyldimethylsilyloxy moiety on the diene, in such a position as to favor the desired regiochemistry of the process.To achieve the required substitution pattern, a substituent is needed at the allylic position and, in order to have a more flexible synthesis, it must be possible to transform said substituent into the different functional groups present in the natural toxins.Thus, it was decided to place a protected hydroxy group at the allylic position.It was also expected that the 1,3-non-bonded interaction between that substituent and the silyloxy group would increase the selectivity of the process by favoring one of the possible reacting conformations [5].Therefore, the goal of this work was to establish a synthetic route to an activated diene-imine system, such as the one shown in Scheme 1, and to test its reactivity under hetero Diels-Alder reaction conditions.

Results and Discussion
In order to achieve this goal, and to do so in an enantioselective way, we decided to use the Katsuki-Sharpless asymmetric epoxidation reaction [6] as the source of the allylic stereogenic center, and thus the allylic alcohol 1, which can be prepared easily from 1,5-pentanediol [7] was selected as our starting compound.The asymmetric epoxidation gave the expected epoxide 2 in good yield and high enantioselectivity, and in the subsequent steps it was regioselectively opened to give a diol.The secondary hydroxy group was then protected as the corresponding methoxymethyl ether by first masking the primary one as the bulky pivaloyl ester.Finally, the pivaloyl group was removed, yielding 6 (Scheme 2).

Scheme 2
Reagents: (a) (+)-diethyl tartrate, Ti(OiPr) Oxidation of 6 and treatment with the anion of benzyl protected homopropargyl alcohol allowed the construction of 7, which has the carbon skeleton of the target compound.In order to transform 7 into the desired compound, and after several attempts, the following sequence was found to be the most efficient: partial reduction of the triple bond, removal of the silicon protecting group and selective oxidation of the allylic alcohol formed to give the α, β-unsaturated ketone 9, precursor of the activated diene system (Scheme 3).After acetylation of the primary hydroxy group the compound 10 containing the activated diene system was prepared by LDA enolization of the α,β-unsaturated ketone 9, in a process hindered by side reactions such as elimination of the -OMOM group or the abstraction of the γ proton instead of the α one.The last step on the synthesis was the transformation of the acetylated primary hydroxy group into the imine, and this was achieved by reductive deprotection of the acetate and SO 3 •Py oxidation of the free hydroxy group to give the aldehyde 11, which was pure enough to be used without purification.When 11 was subjected to column chromatography, it was obtained pure, but in only a 40% yield (Scheme 4).The cycloaddition reaction was carried out by first converting 11 into an imine by treatment with benzylamine in the presence of anhydrous magnesium sulfate and, without purification, the crude reaction mixture was dissolved in CH 3 CN and indium triflate was added as the Lewis acid.This way, two compounds were isolated in a 70:30 ratio and 79% yield and their structures were established spectroscopically.Both compounds presented the structure expected for the cycloadducts, differing only in the relative stereochemistry at the newly formed stereogenic centers.The major compound 12, results from the exo approach of the imine to the diene portion of the molecule in the most favorable conformation, whereas the minor one 13 arises from the endo approach.The relative stereochemistry was deduced from goesy experiments on 12 and 13 [8] and was confirmed, using also goesy experiments, on the more stable decahydroquinolone 14, prepared from 12 by treatment with tetrabutyl ammonium fluoride (Scheme 5).The isolated yield in our case (79%) was higher than that reported by Grieco and Parker [4] (55%), which may be due to the activation provided by the silyloxy group, but the selectivity of the process is similar to that previously described, affording the two cycloadducts in a 70:30 ratio and with the same relative stereochemistry in both of them.

Conclusions
In summary, an enantioselective route to the octahydroquinolinone skeleton with substitution on the 2 and 5 positions has been described.The key steps are a Katsuki-Sharpless asymmetric epoxidation, used for the introduction of the controlling stereogenic center, and an intramolecular hetero Diels-Alder reaction of a molecule containing an activated diene and an imine.The resulting cycloadducts can be used for the synthesis of analogs of naturally occurring toxins of the 2,5-decahydroquinoline family.

Experimental
General 1 H-NMR and 13 C-NMR spectra were recorded in CDCl 3 or C 6 D 6 at 400 MHz ( 1 H) and 100 MHz ( 13 C) on a Bruker AVANCE 400 instrument.The chemical shifts are quoted in ppm using the residual solvent signal as reference.Multiplicities were determined by DEPT experiments.IR spectra were recorded using a Shimadzu 408 spectrophotometer.Optical rotations were determined using a Perkin-Elmer 241 polarimeter.Mass spectra were run on a VG (Fisons) spectrometer.Flash chromatography was performed on columns packed with Merck silica gel 60 (260-400 mesh).Solvents and reagents were generally distilled prior to use, and purified when necessary according to standard procedures.

(7S)-1-(benzyloxy)-11-(tert-butyldiphenylsilyloxy)-7-(methoxymethoxy)undec-3-yn-5-ol (7)
To a solution of DMSO (0.63 mL, 8.98 mmol) in CH 2 Cl 2 (30 mL) under argon at -78ºC was slowly added a solution of oxalyl chloride (2 M in CH2Cl2, 2.24 mL, 4.48 mmol).After 30 min the alcohol 6 (1.61 g, 3.74 mmol) was added in CH 2 Cl 2 (10 mL).After the mixture was stirred for 1 h, TEA (2.6 mL, 18.7 mmol) was added, and the reaction was allowed to reach to room temperature.Water was added, and the reaction was extracted with CH 2 Cl 2 .The combined organic extracts were washed with 10 mL each of 1 % aqueous solution of HCl, 5 % Na 2 CO 3 , and a saturated solution of NaCl.The solution was dried (MgSO 4 ) and concentrated.The expected aldehyde was obtained and used without further purification.To a solution of ((but-3-ynyloxy)methyl)benzene (658 mg, 4.11 mmol) in THF (15 mL) under argon at -78ºC was added n-BuLi (2.57mL, 4.11 mmol, 1.6 M in hexane), and the mixture was stirred for 30 min.Then, a solution of the previously obtained aldehyde in THF (5 mL) was added.The reaction mixture was allowed to warm to room temperature for 2 h and then it was quenched by the addition of aqueous saturated NH 4 Cl solution and extracted with Et 2 O (3 × 25 mL).The combined organic extracts were washed with brine, dried (MgSO 4 ) concentrated, and chromatographed on silica gel (75:25 Hex-EtOAc) yielding 1.93 g (88%) of an inseparable mixture of diastereomers 7.