Synthesis of Chiral 1,3-Dienes through Ring-Closing Metathesis of Enantioenriched Enynes: Potential Precursors of Morphane Analogs

A simple methodology for the synthesis of enynes by indium mediated diastereoselective allylation of aromatic N-tert-butanesulfinylimines bearing alkenyl groups at ortho-position with allyl bromide has been developed. The addition of the allyl indium intermediate to the chiral imine took place with excellent diastereoselectivity. Ruthenium-catalyzed ring-closing metathesis of the resulting enynes provided the expected cyclic 1,3-dienes in good to moderate yields. These chiral dienes are potential precursors of biologically and pharmacologically active morphane derivatives.


INTRODUCTION
Ring closing metathesis (Schmalz 1995) is an important tool in organic synthesis because cyclic unsaturated compounds could be accessed from linear hydrocarbons with double or triple bonds at the terminal positions.When the ring closing metathesis is performed on an enyne system, the resulting cyclic 1,3-dienes with one exocyclic double bond are of special interest (Kaliappan 2005).These dienes are versatile synthetic intermediates and could be involved in a wide variety of process, such as cycloaddition reactions, electrophilic additions, etc.The first ring closing metathesis of enynes was performed by Katz and Sivavec in 1985 by means of a tungsten Fischer carbene complex (Katz and Sivavec 1985).More recently, Grubbs developed more efficient catalysts of ruthenium to perform olefin metathesis in different types of solvents (Vougioukalakis and Grubbs 2010).In addition, these catalysts were air-tolerant, avoiding the tedious work under inert atmospheres, and also compatible with a wide range of functional groups (Hoveyda et al. 2004).In 2010, Tan and co-workers studied the ring-closing metathesis of chiral propargyl amines bearing allyl and tert-butanesulfinyl groups bonded to the nitrogen atom, using a second generation ruthenium catalyst (Bauer et al. 2010).In this way, vinylpyrrolines were obtained as reaction products

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MARÍA JESÚS GARCIA-MUÑOZ et al. in high yields (Figure 1a).The group of Fustero reported the synthesis of enantiopure cyclic dienes through the ring-closing metathesis of homoallylic benzylic alcohols with an alkenyl group at orthoposition of the aromatic ring (Rodriguez et al. 2016), using Grubbs second generation catalyst in the presence of 1,7-octadiene as additive (Figure 1b).More recently, the same group performed the ring-closing metathesis of structural related N-tertbutanesulfinyl amino derivatives under similar reaction conditions (Lazaro et al. 2017), producing the expected dienes in high yields (Figure 1c).On the other hand, our research group reported the stereoselective allylation (Foubelo and Yus 2004) and propargylation (Garcia-Muñoz et al. 2013) of N-tert-butanesulfinyl aldimines and ketimines (Sirvent et al. 2012) with brominated precursors by means of indium metal, leading to homoallylic and homopropargylic amine derivatives, respectively, with high diastereoselectivity.These compounds were used as precursors in the synthesis of natural products (Foubelo and Yus 2014) and other structurally diverse nitrogen-containing compounds (Garcia-Muñoz et al. 2016).Continuing our interest in this topic, and prompted by the latest results from the group of Fustero, we report herein our approach to the synthesis enantioenriched 1,3-dienes with a N-tert-butanesulfinamide group through an enyne ring-closing metathesis.

SYNTHESIS OF 2-[2-(OCT-1-YL)PHENYL] ACETALDEHYDE (13)
A 1 M solution of potassium hexamethyldisilazide (KHMDS, 2.0 mL, 2.0 mmol) was added to a suspension of (methoxymethyl) triphenylphosphonium chloride (0.684 g, 2.0 mmol) in THF (4 mL) at -78 ºC.The reaction mixture was stirred at the same temperature for 1 h.After that, a solution of aldehyde 9b (0.214 g, 1.0 mmol) in THF (8 mL) and stirring was maintained for 3 h allowing the system to reach 0 ºC.The resulting mixture was filtered through a short plug of celite, washed with hexane (3×15 mL) and concentrated (15 Torr).The residue was dissolved in THF (1.5 mL), treated with a 3 M solution of HCl (0.25 mL, 0.75 mmol) and the resulting solution was stirred at 78 ºC for 18 h.After that, the reaction mixture was cooled down to room temperature, basified with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (3×15 mL).The organic layer was washed with brine (2×10 mL), dried over anhydrous magnesium sulfate and evaporated (15 Torr) to yield aldehyde 16 which was used in the next step without purification.

GENERAL PROCEDURE FOR THE PREPARATION OF N-TERT-BUTANESULFINYL ALDIMINES 4A AND 14
To a solution of (R)-tert-butanesulfinamide (1, 0.601 g, 5.0 mmol) and the corresponding aldehyde (5.5 mmol) in THF (20 mL) was added Ti(OEt) 4 (2.28 g, 2.08 mL, 10.0 mmol) at room temperature under argon.The resulting mixture was stirred for 5 h at the same temperature, and after that, quenched with brine (3.0 mL), and diluted with ethyl acetate (50.0 mL).The resulting suspension was filtered through a short plug of Celite and concentrated Then, the reaction mixture was filtered through a short plug of Celite and the solvent was evaporated (15 Torr).The residue was purified by column chromatography (hexane/EtOAc) to yield pure compounds 4a and 14.Yields for compounds 4a and 14 are given in Figures 2 and 4, respectively.Physical and spectroscopic data follow.

RESULTS AND DISCUSSION
Homopropargylamine derivatives 6a and 6b were prepared first starting from ortho-bromostyrene 2a.The reaction of 2a with n-BuLi in THF (an aromatic organolithium compound is formed through a bromine-lithium exchange), followed by reaction with N,N-dimethylformamide (DMF) and final hydrolysis with water gave ortho-vinylbenzaldehyde (3a) in 89% yield.Condensation of aldehyde 3a with (R)-N-tert-butanesulfinamide (1) in the presence of Ti(OEt) 4 led to N-tert-butanesulfinyl imine 4a in 75% yield.Further indium promoted propargylation of 4a with trimethylsilylpropargyl bromide (5) gave rise to the expected compound 6a with high diastereoselectivity (>98:2) and yield (70%).Finally, treatment of 6a with potassium carbonate in a mixture of THF and methanol for 12 hours led to the formation of terminal alkyne 6b in 89% yield (Figure 2).
Unfortunately, all the attempts to perform a ring-closing metathesis in enynes 6a and 6b, under the reaction conditions described by Bolm in the synthesis of cyclic sulfoximines with Grubbs second generation catalyst failed to produce the desired cyclic dienes 7 (Furger and Bolm 2009).Instead of that, starting compounds were recovered unaltered (Figure 3).
We decided to study the enyne ring-closing metathesis in other compounds different to 6a and 6b.These compounds were prepared in two synthetic operations starting from orthobromobenzaldehyde (3b, R 2 = H) and 2-bromo-5methoxybenzaldehyde (3c, R 2 = OMe).First, the palladium catalyzed Sonogashira coupling reaction of aromatic aldehydes 3 with terminal alkynes 8 led to ortho-alkynyl aldehydes in high yields.After that, enynes 11 were obtained by aminoallylation of aldehyde 9 by successive reaction with (R)-N-tert-butanesulfinamide (1) in the presence of Ti(OEt) 4 at room temperature for 1 hour, followed by addition of indium metal and allyl bromide (10), and further reaction of the resulting mixture at 60 ºC for 6 hours, in a one-pot process.The reaction was monitorized by TLC and it was not necessary to isolate the imine intermediate.The expected enynes 11 were obtained in good to moderate yields.The aminoallylation of aldehyde 9d with an electron-donating substituent at the aromatic ring took place in only 30% yield, leading to enyne 11d.On the other hand, enyne 11f was obtained in quantitative yield by desilylation of 11a (Table I).
The treatment of compounds 11 with a catalytic amount of Grubbs second generation catalyst in toluene a 110 ºC for 1 hour led to the expected cyclic dienes 12 in variable yields, but for silylated derivative 11a (R 1 = SiMe 3 ) which did not undergo ring-closing metathesis and was recovered at the end of the reaction.The highest yields were obtained for enynes 11b [R 1 = (CH 2 ) 5 Me] and 11f (R 1 = H), which derived from aliphatic alkynes 8, leading to dienes 12b and 12f, in 70 and 69% yield, respectively.On the other hand, lower yields were found for enynes 11d and 11e with electrondonating methoxy groups in one of the aromatic rings (Table II).
Ring-closing metathesis of all enynes 11 shown on Table I produced six-membered cycles.With the aim of widen the scope of this reaction, we prepared an enyne system which after ring-closing metathesis would generate a seven-membered ring.For this purpose, aromatic aldehyde 9b was transformed into aldehyde 13.This homologation process was carried out through a Wittig reaction with methoxymethyl triphenylphosphonium chloride, followed by acidic hydrolysis.After that, the imine 14 was prepared in 64% yield by condensation with (R)-N-tert-butanesulfinamide    a Isolated yield after column chromatography purification.
(1) in the presence of Ti(OEt) 4 .Allylation of this imine with allyl bromide (10) in the presence of indium metal gave the expected enyne 15 in 50% yield.Finally, the ring-closing metathesis of 15 under the reactions conditions depicted on Table II led to diene 16 upon formation of a sevenmembered ring.Surprisingly this metathesis took place in higher yield (78%) than for compounds 12, in spite of the higher stability of six-membered rings (Figure 4).Importantly, two stereogenic centers are present in dienes 12 and 16 (the carbon atom bonded to the nitrogen, and the sulfur atom), and are of potential interest in Diels-Alder reactions with different dienophiles, because high levels of regio-and stereoselectivity could be achieved in these transformations.
In conclusion, second generation Grubbs catalyst demonstrated to be effective in the ring-closing metathesis of N-tert-butanesulfinyl homoallylamine derivatives bearing ortho-alkynyl substituted aryl groups.The resulting dienes 12 and 16 are of potential interest in Diels-Alder reactions with different dienophiles, because high levels of regio-and stereoselectivity could be achieved in these transformations due to the presence of two stereogenic centers (the sulfur atom and the carbon atom bonded to the nitrogen).These chiral dienes are interesting precursors for the asymmetric synthesis of the skeleton present in some alkaloids, such as 17 (Foubelo andYus 2014, 2016), and particularly in morphane derivatives (see, e.g.morphine; Figure 5) (Abate et al. 2012).

ACKNOWLEDGMENTS
We thank the continued financial support from our Ministerio de Ciencia e Innovación (MCINN;

TABLE I Synthesis of enynes 11.
a Isolated yield after column chromatography purification.b Compound 11f was obtained by desilylation of 11a under basis conditions.