Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts : Synthesis of Biologically Active Acyloins and Vicinal Aminoalcohols

Um rearranjo de Curtius, utilizando adutos de Morita-Baylis-Hillman como substrato, foi realizado em uma sequência que permitiu a síntese de várias hidroxi-cetonas (aciloínas) com uma grande diversidade estrutural e com bons rendimentos globais. Por sua vez, essas aciloínas foram transformadas em 1,2-amino-alcoóis de configuração relativa anti, através de uma etapa de aminação redutiva altamente diastereosseletiva. A utilidade sintética dessas abordagens foi demonstrada através das sínteses totais da (±)-bupropiona, fármaco utilizado no tratamento na síndrome de abstinência de fumantes e da (±)-espisulosina, um potente agente anti-tumoral isolado inicialmente de uma fonte marinha.


Introduction
The formation of new C-N bonds by incorporation of a nitrogen atom into a molecule is a fundamental transformation in organic chemistry, since it allows accessing many valuable compounds. 1Basically, this can be achieved by nucleophilic substitution reactions or by electrophilic amination reactions. 2 C-N bond can also be built through rearrangement reactions.For instance, Lossen, 3 Beckman, 4 Schmidt 5 and Curtius 6 rearrangements are processes which allow the efficient formation of a new C-N bond from carbonyl containing derivative compounds.
The Curtius rearrangement is a thermal decomposition of a carbonyl azide leading to an isocyanate.This stereospecific rearrangement provides carbamates or amines in good overall yields and selectivities.Unfortunately, this rearrangement has the drawback that low molar mass acyl azides present an explosion hazard. 7This safety issue has limited the industrial use of this transformation until recently, when Am Ende et al. 8 reported a new experimental protocol, which enabled the use of this reaction under safer conditions even when conducted on a large scale.This and other protocols have revived interest in this rearrangement, particularly for industrial purposes. 9egarding the potential of this rearrangement, our group has recently reported the preparation of some carbamates from Morita-Baylis-Hillman (MBH) adducts. 10Curtius rearrangement would be the best way to achieve our target, since the carboxyl group in this structure is needed to perform this rearrangement.Thus, when an acid derived from a MBH adduct was treated with sodium azide, heated at reflux and treated subsequently with t-butanol, the corresponding ene-carbamate was formed in good overall yield.However, in some examples it was observed the occurrence of a byproduct (ca.12-15%) which was characterized as being an acyloin (Scheme 1).
The acyloin formation was easily explained by the presence of water (tiny amount) in the t-BuOH used to transform the intermediate ene-isocyanate into the corresponding ene-carbamate.This undesirable side reaction caught our attention, since a-hydroxyketones (acyloins) are structural motifs present in several biologically active compounds, in which the activity is closely associated with the presence of this structural pattern.Due to the synthetic and biological relevance of acyloins, several synthetic approaches have already been developed in order to prepare them.Conventionally, a-hydroxy ketones are prepared by the acyloin condensation reaction, 11 oxidation of enolates or double bonds, 12 or reduction of a-diketones or esters. 13Recently, a method based on ketohydroxylation of alkenes was developed to give acyloins. 14Alternatively, radical oxidation of a 1,3-dicarbonyl compound with cerium salts could also be used for the preparation of acyloins. 15Most recently, a skeletal rearrangement of symmetrically a,a-disubstituted a-amino aldehyde has been reported as a new strategy for preparing acyloins. 16eyond its biological importance, a-hydroxyketones are also an interesting synthetic platform that allows further chemical transformations.For instance, a a-hydroxyketone can be easily transformed into a a-aminoketone.This structural pattern is present in some commercial drugs, such as bupropion [(±)-a-t-butylamino-3-chloropropiophenone] (1, Figure 1), a potent synthetic inhibitor of dopamine reuptake with subtle noradrenergic reuptake. 17Bupropion is an atypical antidepressant, which has been licensed by FDA to treat the abstinence syndrome of smokers. 18cinal aminoalcohols (or 1,2-aminoalcohols) are structural units that currently occur in several biologically active compounds.They are also part of several chiral catalysts and new materials.
The biological and synthetic importances of this structural motif have stimulated the development of several methods to synthesize it, both in racemic and enantiomerically pure forms. 19Classically, syn-1,2-aminoalcohols can be prepared in their racemic or asymmetric versions using the aminohydroxylation strategy developed by Sharpless et al. 20 Another efficient way to prepare vicinal aminoalcohols is by the opening of an epoxide ring with a suitable nitrogen source, such as amines or azide ions, to provide aminoalcohols or azidoalcohols, respectively. 21,22y using simple chemical transformations, a-hydroxyketones (acyloins) can also be used as substrates for the stereoselective preparation of 1,2-aminoalcohols. 23pisulosine (2, Figure 1) is a sphingoid-type base which presents a long unsaturated alkyl chain (C 15 ) and a 1,2-aminoalcohol motif in an anti relationship. 24This compound was isolated from extracts obtained from the clam Spisula polynyma and exhibits a promising activity against prostate cancer. 25n a research program directed towards the total synthesis of drugs from Morita-Baylis-Hillman adducts, 26 we describe herein the synthesis of a-hydroxyketones and their diastereoselective transformations into anti-1,2-aminoalcohols.To exemplify the synthetic utility of this approach, we also describe the syntheses of the drugs (+/-)-bupropion and (+/-)-spisulosine.

Results and Discussion
The present work began by preparing the MBH adducts, according to a procedure previously developed in our laboratory. 27The strategy provides the corresponding adducts in good to high yields.The results are summarized in Table 1.
Initially, the Curtius rearrangement without protection of the secondary hydroxyl group was of interesting in this  work.So, adduct 3 was hydrolysed in the presence of LiOH in an acetonitrile:H 2 O (1:1) mixture to give a hydroxyacid in almost quantitative yield (> 98%).When this acid was treated with ethyl chloroformate, extensive degradation of our starting material was observed by TLC analysis.
In an attempt to circumvent this issue, the secondary hydroxyl group of the MBH adducts was protected, before ester hydrolysis.Thus, adducts 3-12 were treated with TBSCl or TBSOTf in DMF or dichloromethane, in the presence of imidazole or triethylamine, respectively.The silylated adducts (13-22) were obtained in good to excellent yields.Soon after, ester hydrolysis was carried out with LiOH, in an acetonitrile:H 2 O mixture at 60 °C to produce acids 23-32 in excellent yields.The results of these steps are summarized in Table 2.
The Curtius rearrangement was initiated using diphenylphosphoryl azide (DPPA). 28This reagent is supposed to react with a carboxylic acid to provide an isocyanate in a single step.A solution of silyl-acid 23 in toluene was therefore treated with DPPA at reflux for 20 h.Unfortunately, it was unable to isolate any isocyanate.Instead, a complete destruction of the silylated acid was observed.
Because of this result, it was decided to perform the Curtius rearrangement by using a classical experimental protocol.Thus, an acetone solution of silylated acids was treated with ethyl chloroformate in the presence of triethylamine at 0 °C for 5 min.After that, sodium azide was added to the reaction mixture and this mixture was vigorously stirred for 2 h.The crude products were refluxed in dry toluene for 2 h to give the corresponding isocyanates, which finally were refluxed in water to furnish a set of acyloins in good overall yield (ranging from 35 to 50% for 3 steps).The results are summarized in Table 3.
Acyloins were obtained in good overall yield in three steps from Morita-Baylis-Hillman adducts.The strategy is simple and requires no special conditions such as low temperature, dry solvents or special catalysts.Moreover, it uses reagents which are routinely found in organic synthesis laboratories.The bifunctional identity (one eletrophilic group and another nucleophilic) makes acyloins an important building block in organic synthesis.They can be converted into several different functional groups, such as alcohols, diols, epoxides, amines, hydroxylamines and haloketones.This synthetic versatility explains the frequent use of acyloins as building blocks for the synthesis of pharmaceutical compounds. 29 ketone carbonyl group can be promptly transformed into an amine by a reductive amination reaction.][32] Recently, Cabral et al. 33 have developed a simple method to perform a reductive amination, based on in situ formation of an iminium, followed by reduction with LiBH 4 .Thus, this was viewed in the present work as an attractive opportunity to test this method to prepare vicinal aminoalcohols from our acyloins.
A methanol solution of 35 was treated with LiBH 4 in the presence of an excess of benzylamine (3 equiv.) at −72 °C to give aminoalcohol 46 in 83% yield and excellent 1,2-anti diastereoselectivity (97:3 d.r., anti:syn).This simple sequence has allowed the development of a highly diastereoselective synthesis of several different aminoalcohols in good yields.The results are summarized in Table 4.
For all cases examined, the vicinal aminoalcohols were obtained in good yields and with excellent diastereoselectivities.To confirm the 1,2-anti relative stereochemistry, the silyl protecting group of aminoalcohol 44 was removed by treatment with TBAF.The unprotected vicinal aminoalcohol 55 was reacted with triphosgene to Yields refer to isolated and purified products; b diastereoisomeric ratio was determined by analysis of the 1 H NMR spectra of the crude reaction mixture.
The carbinolic proton shows a doublet with a coupling constant of 5 Hz for the anti relationship, while the syn product shows a coupling constant of 8.2 Hz.
afford oxazolidinone 56, in 70% yield (Scheme 2).The coupling constant between hydrogens H a and H b was found to be 8.2 Hz, which it is in agreement with typical coupling constants for a cis relationship in oxazolidinones formed from a 1,2-anti aminoalcohol (Scheme 2). 34he presence of a bulky protecting group on the secondary hydroxyl group might play an important role in the iminium reduction step.Most likely the hydride attack occurs at the opposite side from the protecting group.To experimentally validate this hypothesis, silylated acyloin 35 was treated with TBAF in methanol to provide acyloin 57 in 80% yield.A methanol solution of 57 at −72 °C was treated with LiBH 4 to afford aminoalcohol 58 in 70% yield and moderate diastereoselectivity (87:13 d.r.; anti:syn) (Scheme 3).
This result shows the effect of the silyl protecting group on the diastereoselectivity of the reduction step.Besides, the lithium atom could be complexed both with the nitrogen and the oxygen lone pairs (Figure 2).This arrangement allows the hydride to approach only from the less hindered side.The oxygen atom attached to the silicon of the TBS group has a low basicity, however it is still able to establish intramolecular hydrogen bonds in order to control stereoselectivities of reactions. 35he Curtius rearrangement carried out with MBH adducts has allowed the development of a new approach to prepare a-hydroxyketones, which have been used to prepare diastereoselective 1,2-anti vicinal aminoalcohols.
Searching to demonstrate the synthetic utility of these approaches, the total synthesis of two pharmacologically active compounds is now described.(±)-Bupropion (1, Figure 1) is an aminoketone acting on CNS. 36This compound is commmercialized in its racemic form, since it racemizes very quickly in the body when administered in its enantiomerically pure form.Our target compound could be prepared from acyloin 34 (Figure 3).A 1,2-carbonyl transposition reaction is required to provide 59, which can be converted uneventfully to (±)-1. 37 direct way to perform the required 1,2-carbonyl transposition was using the Lobry-de Bruyn-van Ekenstein transformation. 38This reaction, currently used in carbohydrate chemistry, is essentially an enolization of a sugar having a hydrogen at the a-carbon to the carbonyl group and proceeds via an enediol intermediate.Some acyloins rearrange with positions exchanged under the influence of base in this transformation.To test this alternative, the TBS group of acyloin 34 was removed by treatment with TBAF in methanol for 12 h to give the corresponding unprotected acyloin in  75% yield.A methanol solution of this acyloin was reacted with a 30% solution of NaOH at room temperature.As a result, an extensive acyloin degradation was observed even at lower temperatures (−5 and −10 °C).We also tested the Voight amination (formation of ketoamine by treatment of an acyloin with P 2 O 5 in the presence of a primary amine), however this reaction also failed. 39ue to these results, the synthetic approach towards the synthesis of bupropion was changed.As an alternative, the required transposition could be done in three steps.Thus, carbonyl reduction of the acyloin (±)-34 directly led to a monoprotected diol (±)-60 in almost quantitative yield.TBS removal was performed in the presence of TBAF to afford diol (±)-61 in 97% yield, as a mixture of diastereoisomers.Selective benzylic oxidation of (±)-61 with IBX in DMSO expectedly led to the 1,2-carbonyl transposition product (±)-59, as the sole product, in 85% yield (3 steps, 81% overall yield, Scheme 4).
Bupropion, in its racemic version, was obtained in 7 steps from Morita-Baylis-Hillman 4, in 27% overall yield.The sequence is facile to execute and can be scaled-up without problems.
The synthetic methods described in this paper can be combined in order to synthesize spisulosine (2, Figure 1) as a racemate.This natural anti-tumoral compound can be prepared from acyloin 42, using a diastereoselective reductive amination step (Scheme 5).
The diastereoselective total synthesis of spisulosine was accomplished from acyloin (±)-42 using a very simple and direct sequence.Reductive amination of acyloin (±)-42 was performed with an excess of benzylamine to give vicinal aminoalcohol (±)-62, with high anti diastereoselectivity (> 95:5, anti:syn), in 68% yield (Scheme 6).To quickly finish the synthesis, it was only necessary to remove the protecting groups (TBS and benzyl).For thus, a solution of (±)-62 in methanol was acidified with some drops of concentrated HCl and the mixture was poured into a hydrogenating bottle containing 10% Pd on charcoal (10 mol%).To our surprise, after several hours at 60 psi, neither of the protecting groups was removed.Perhaps, the long carbon chain favoured the formation of mycelles, which could interact with the solid catalyst.
To solve this unexpected issue, a mixture of solvents for the hydrogenation reaction was used.Thus, a mixture of (±)-62 in dichloromethane:acetic acid (1.5:1) in the presence of 10% Pd/C at 60 psi and 50 °C was shaken for 20 h to furnish the debenzylated aminoalcohol (±)-63 in 87% yield.
Finally, the TBS group of (±)-63 was removed by the treatment with concentrated HCl (0.1 mL) in a solution of dichoromethane:methanol (1:1; 1 mL) to give (±)-spisulosine (2) in 98% yield.All spectroscopic and physical data are identical to those described in literature for natural and synthetic spisulosine (Scheme 6). 24,40pisulosine was synthetized in 7 steps from hexadecanal with an overall yield of 10%.The strategy is very simple and requires no special conditions such as low temperature or dry solvents.If the sequence begins with adduct 12 in its enantiomerically pure form, it would allow the enantioselective synthesis of spisulosine.By using this strategy, spisulosine derivatives can also be synthesized using the sequence described herein.

Conclusions
In summary, the Curtius rearrangement coupled with Morita-Baylis-Hillman adducts as substrate has proven to be an alternative for the preparation of interesting building blocks for organic syntheses.This combination allowed the synthesis of a set of acyloins in good overall yields for three steps.Reductive amination of these acyloins gave vicinal aminoalcohols in good overall yields and with high diastereoselectivities, in favor of the 1,2-anti isomer.Moreover, we have demonstrated that these methods can be used in the synthesis of important pharmacologically active compounds.Thus, (±)-bupropion was prepared in 7 steps from a MBH adduct, in 27% overall yield.Using this strategy we also showed a highly diastereoselective total synthesis of (±)-spisulosine which was accomplished in 7 steps from hexadecanal with an overall yield of 10%.

General procedure
The 1 H and 13 C NMR spectra were recorded on a Bruker at 250 and 62.5 MHz, respectively, or on an Inova instrument at 500 and 125 MHz, respectively.High resolution mass (HRMS) spectra were recorded using a Q-TOF Micromass equipment (Waters, UK).Manipulations and reactions were not performed under dry atmospheres or employing dry solvents, unless otherwise specified.In those cases CH 2 Cl 2 , DMF and triethylamine were dried over CaH 2 and distilled.Purification and separations by column chromatography were performed on silica gel, using normal or flash chromatography.Thin layer chromatography (TLC) was detected by spraying with 5% ethanolic phosphomolybdic acid and heating.All the Morita-Baylis-Hillman reactions were sonicated in an ultrasonic cleaner (81 W, 40 MHz).

General procedure for the silylation of Morita-Baylis-Hillman adducts
A mixture of MBH adduct (1-3 mmol), imidazole (2.5 equiv.),TBSCl (1.5 equiv.)and a few drops of DMSO (to facilitate stirring), under argon atmosphere, was stirred at room temperature.After 2-4 h, the crude residue was diluted in ethyl acetate (25 mL).The organic layer was washed with distilled water (15 mL), brine (2 × 15 mL), dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.The crude mixture was filtered through silica gel (ethyl acetate:hexanes, 30:70) to provide the silylated compounds in good to excellent yields.

General procedure for hydrolysis of silylated esters
To a solution of silylated MBH adduct (1-3 mmol) in a mixture of water:acetonitrile (1:1) was added LiOH (10 equiv.).The resulting solution was stirred for 4 h at 50-60 o C.Then, the solvents were removed under reduced pressure and the crude mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.The residue was filtered through silica gel (ethyl acetate as solvent) to provide the corresponding carboxylic acids in almost quantitative yields, for most cases > 99%.(23)

General procedure for the preparation of a-hydroxyketones (acyloins)
To a stirred 0.2 mol L -1 solution of carboxylic acid in acetone at 0 ºC was added triethylamine (2 equiv.)and ethyl chloroformate (1.5 equiv.).The mixture was stirred at 0 ºC and carbonate formation was observed by TLC after 5 min.After that, NaN 3 was added (2.5 equiv.).The resulting mixture was vigorously stirred for 2 h until the formation of a slightly apolar layer (acylazide formation).Then, the crude mixture was diluted in cold dichloromethane and washed with cold water.The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.To this crude material, under an argon atmosphere, dry toluene (0.1 mol L -1 ) was added and the mixture was refluxed for 2 h.The solvent was then removed under reduced pressure and the resulting product was diluted in water.The mixture was refluxed for 12 h.Then, the reaction mixture was coolled to room temperature and extracted with ethyl acetate.The organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.The residue was purified by flash silica gel column chromatography (ethyl acetate:hexanes, up to 25:75) to provide the required acyloins.Yields refer to 3 steps from MBH adducts.

General procedure for the diastereoselective preparation of vicinal alcohols
To a 0.2 mol L -1 methanolic solution of acyloins was added an amine (3 equiv.).The resulting solution was vigorously stirred at room temperature for 1 h.After, the solution was cooled to −78 o C and LiBH 4 (1.2 equiv.) was added.The mixture was then warmed to room temperature and stirred for 12 h.Then, the medium was diluted with ethyl acetate (15 mL) and the organic phase was washed with water (5 × 7 mL), brine (10 mL), dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.The residue was purified through silica gel (solvent: hexanes:ethyl acetate, up to 65:35) to provide the corresponding vicinal aminoalcohols, in good yields and in high diastereoselectivities.

Synthesis of (±)-1-(3-chlorophenyl)propane-1,2-diol (61)
To a solution of alcohol (±)-60 (100 mg, 0.34 mmol) in THF (6 mL) at 0 o C was added a solution of TBAF (0.41 mL, 1 mol L -1 in toluene).The mixture was stirred for 5 min and was warmed to room temperature.After 2 h, a mixture of water (5 mL) and ethyl acetate (15 mL) was added to the reaction medium.The organic phase was separated, washed with brine (5 mL), dried over anhydrous Na 2 SO 4 and the solvent was removed under vacuum.The residue was filtered through silica gel (solvent: ethyl acetate) to provide the diol (±)-61, in 97% yield.Colorless oil; IR (film) n max /cm

Table 1 .
Morita-Baylis-Hillman adducts a Yields refer to isolated and purified products; b MBH reaction was performed with excess of methyl acrylate in the presence of [bmim]PF 6 at 0 °C; c prepared by oxidation of commercial hexadecanol with PCC in refluxing dichloromethane in 95% yield.

Table 2 .
Silylation and hydrolysis of Morita-Baylis-Hillman adducts a Yields refer to isolated and purified products; b methanol used as solvent and NaOH used as base instead of LiOH.Vol.22,No. 8, 2011