Addition of Heteroatom Nucleophiles to Ketene Dimers

An investigation of the reaction of heteroatom nucleophiles with ketene dimers, with an emphasis on a discussion of diastereoselectivity where applicable, is described. During this study we focused on the reaction of nitrogen-centred nucleophiles (Weinreb amine, lithiated Weinreb amide, and an amino acid derivative), and oxygen-centred nucleophiles (alkoxides). Simple Weinreb amide derivatives of ketene heterodimers were formed in moderate to excellent yield (up to 89%) and excellent retention of chirality (ee up to 91%), albeit with poor diastereoselectivity. The 2-pyridone-catalysed amine ring-opening was also applied to the asymmetric synthesis of a cinnabaramide A intermediate. Finally, the use of amide and alkoxide ring-opening nucleophiles enabled the development of a sequential one-pot reaction with benzaldehyde to afford  -lactones in moderate yields (up to 47%) but with good diastereoselectivity (dr up to 24:1).


Introduction
2][23][24][25][26] Herein, we describe our studies investigating the reaction of heteroatom nucleophiles with ketene dimers, with an emphasis on a discussion of scope and diastereoselectivity wherever applicable.During this study we focused on the reaction of nitrogen-centered nucleophiles (Weinreb amine, lithiated Weinreb amide, and an amino acid derivative), and oxygen-centered nucleophiles (metal alkoxides).Scheme 1.Our previous work.

Results and Discussion
During our initial studies we investigated the reaction of Weinreb amine with a variety of ketene heterodimers to access synthetically useful enantioenriched Weinreb amides. 19,20,27The reaction conditions chosen, 1-2 equiv Weinreb amine and ca.5-10 mol% 2-pyridone, were originally introduced by Calter's group for the synthesis of dipropionate synthons. 9The ketene heterodimer test substrates (2a-2d and 2f) were prepared through the alkaloid-catalyzed ketene heterodimerization reaction, as previously described by our group. 19,20Reaction with methylphenylketene homodimer ()-2e was also examined and this was produced through the phosphinecatalyzed homodimerization reaction. 17,18n most cases, Weinreb amide formation proceeded in good to excellent yields (Table 1, entries 1,2, 5-7).Moderate yields were only observed in those cases (entries 3 and 4) where ketene dimerization did not proceed in very good yield (yield is for two steps from ketene in most cases).Enantiomeric excess for each Weinreb amide was good to excellent (76-95% ee) owing to the highly enantioselective nature of the alkaloidcatalyzed ketene heterodimerization process. 19,20However diastereoselectivity for the formation of 3c-3e was poor due to the lack of selectivity in the protonation/proton transfer step of the 2-pyridone-catalyzed reaction. 9a SM = starting material (ketene heterodimer or ketoketene homodimer).b ee for 2 not determined in most cases as 2 was not isolated but instead was directly converted to 3. c % yield = isolated yield for both diastereomers of 3. Excepting entries 5-7, yield for two steps from acyl chloride.d dr determined by GC-MS or 1 H NMR analysis of crude 3. e % ee determined by chiral HPLC analysis.
The ring-opening conditions utilized in Table 1 were then applied to the synthesis of a cinnabaramide A precursor from a silyl-substituted ketene heterodimer.We determined that heterodimer (−)-2f, derived from TMS-ketene and n-hexylketene, can be used to access a precursor to cinnabaramide A (Table 2). 15,16(−)-2f was subjected to reaction with protected serine derivative 4 under 2-pyridone catalysis conditions.A number of variations on the standard reaction conditions of Table 1 were then explored.Ultimately, the reaction proceeded in good yield (82%) and with moderate diastereoselectivity (dr 3:1), after heating (50 °C) with serine derivative 4 (2 equiv) and excess 2-pyridone (2 equiv), and following desilylation with TBAF (Table 2, entry 1).Since enantioenriched reactants were used it was necessary to determine whether erosion of enantiomeric integrity of (−)-2f under the reaction conditions was leading to moderate diastereoselectivity.After running the reaction for 55 h, some 2f was isolated and HPLC analysis was performed on a prepared Weinreb amide derivative 3f.It was determined that the ee of heterodimer 2f did not undergo erosion under the reaction conditions.A series of control experiments were then performed to investigate whether any of the reactants were acting as a base and causing epimerization of 5 under the reaction conditions.5 (dr = 24:1) in THF was heated at 50 °C for 24 h, but after this time there was no change in dr observed.Next a mixture of 5 and 4 in THF was heated at 50 °C for 20.5 h.But again, there was no change in dr observed.Then 2-pyridone (2 equiv) was added to a solution of 4 and 5 in THF, and the reaction mixture was heated at 50 °C for 22 h.However, there still was no observable change in dr.This left the possibility that carbanion generated through desilylation of 2f was causing epimerization of 5. To eliminate epimerization, we introduced KF, to aid desilylation of 2f, along with acetic acid to act as a mild proton source which would help quench the resulting carbanion (Table 2 entries 2-4).In experiments conducted in the presence of acetic acid, diastereoselectivity improved dramatically (Table 2, entries 3 and 4), albeit at the cost of lower conversion to 5 and increased decomposition of 2f.We surmise that the mild proton source protonates desilylated 2f, effectively inhibiting it from acting as a base.a % yield = isolated yield for both diastereomers of 5. b dr determined by 1 H NMR analysis of crude 5.
Having observed that the 2-pyridone-catalyzed amine ring-opening proceeded effectively, from conversion standpoint, for a number of diversely substituted ketene dimers, we then proceeded to investigate the possibility of sequential reactions of ketene heterodimer-derived lithium enolates with an aldehyde (Table 3). 28,29Such a reaction would allow for assembly of complex polyketide derivatives with potentially up to three stereogenic centers, with two being set in the aldol reaction.Lithiated Weinreb amine was utilized as the preferred nucleophile, as Calter's group had success with it in the ring-opening of methylketene homodimer. 10The ketene heterodimer β-lactone 2a was converted to a lithium enolate using LiN(OMe)Me (prepared by the reaction of N,O-dimethylhydroxylamine with n-butyllithium in 2.5 M hexane) as ring-opening agent.The lithium enolate derived from 2a was subjected to reaction with benzaldehyde, and surprisingly led to the formation of δ-lactone 6a (29%, dr = 24:1) along with the acyclic aldol product 7a (20%, dr = 1:1).When the concentration of the heterodimer in THF was increased to 0.2 M only the δ-lactone was formed in 40% yield and with high diastereoselectivity (dr = 24:1).However, the ee of 6a was determined to be only 40% (compared to starting ee of 95% for 2a), which suggested that significant racemization of 2a, or an enolate intermediate, occurred under the reaction conditions.The reaction of silyl-substituted ketene heterodimers (e.g.2f) were also examined under these reaction conditions but led to the formation of a complex mixture rather than the desired acyclic aldol or δ-lactone product.
We then investigated the reaction of methylphenylketene homodimer ()-2e with lithiated Weinreb amine and a number of lithiated alkoxides, and a sequential one-pot reaction of the enolate intermediate with various aldehydes (Table 4).Methylphenylketene homodimer ()-2e was prepared through the PBu3-LiIcatalyzed homodimerization of pre-prepared methylphenylketene. 17,18Disappointingly, ring-opening with lithiated Weinreb amine, and sequential reaction with benzaldehyde was unsuccessful leading to a complex product mixture.Subsequently, optimization studies involving ring-opening with MeOLi were more successful and revealed that the optimal temperature for enolate intermediate formation was ca.0 C.Quenching of the enolate at room temperature led to the ketoester ()-8e being obtained in quantitative yield and with moderate diastereoselectivity (dr 1.6:1).The low diastereoselectivity in the latter transformation was understandable given the lack of diastereofacial bias possible in protonation of the acyclic enolate intermediate.This contrasted with the results of our study involving ring-opening of ketoketene homodimers with alkyllithiums where good levels of diastereoselectivity were observed (dr up to 9:1) due to quenching of a putative cyclic intermediate. 21,23ttempts to carry out a sequential aldol reaction by addition of an aldehyde to the enolate intermediate solution required a considerable amount of optimization.For the sequential one-pot enolate formation-aldol reaction, benzaldehyde was chosen as the test substrate (Table 4).Interestingly, ring-opening with MeOLi, followed by enolate trapping with benzaldehyde led to the formation of product as the δ-lactone ()-6e rather than the acyclic ester product derived from straightforward aldol reaction. 10,13We surmised that cyclization, with loss of MeO -, occurred following aldol reaction (Scheme 2).From Table 4, it is clear that MeOLi was the most effective ring-opening nucleophile, with sterically bulky alkoxides (i-PrOLi and t-BuOLi) failing to provide reasonable levels of conversion.Increasing the number of equivalents of benzaldehyde beyond ca.1.5 equiv led to less clean reactions and slightly lower yield of the desired -lactone (Table 4 entry 5). a NucLi = nucleophile.b Conv = conversion as determined by GC-MS analysis of crude product.c % Yield = isolated yield for both diastereomers of 6e.d dr determined by GC-MS analysis of crude product.
Other aldehydes (valeraldehyde and cyclohexanecarboxaldehyde) were also examined under the reaction conditions but provided less impressive results (42% for valeraldehyde-derived -lactone 6f, but with poor dr 4:2:1).Ethylphenylketene homodimer was also exposed to the optimized reaction conditions (with ZnCl2 as additive) but underwent incomplete conversion to -lactone (up to 32% conv) and with poor diastereoselectivity (dr 2:2:2:1).The proposed mechanism for the δ-lactone forming reaction is shown in Scheme 2. The lithiated nucleophile (Weinreb amide or alkoxide) would add to the carbonyl of ketene dimer 2. Ring-opening would provide lithium enolate 9 as an intermediate.Enolate 9 would then engage in a diastereoselective aldol reaction with added aldehyde to access aldolate 10.Diastereoselectivity would be achieved through a closed Zimmerman-Traxler transition state, in which the phenyl substituent at the chiral center of enolate 9e (R 1 = Ph, from methylphenylketene dimer 2e) is the large substituent, forcing the aldehyde to react with the -face of the enolate anti to the phenyl substituent.We propose that this transition state assembly would favor formation of the syn,syn-diastereomer (Scheme 2), in agreement with the outcome of Calter's results on the aldol reaction of methylketene dimer-derived enolates. 10,13,28,296-Exo-trig cyclisation of aldolate alkoxide 10 onto pendant amide or ester carbonyl would then furnish δ-lactone 6. Scheme 2. Proposed mechanism for the formation of δ-lactone 6.

Conclusions
In conclusion, we report that a range of ketene dimers (heterodimers and ketoketene homodimer) undergo 2pyridone-catalyzed ring-opening reaction with Weinreb amine to access simple Weinreb amides in moderate to excellent yields and with good enantiomeric excesses.Optimization of the 2-pyridone-catalyzed asymmetric synthesis of a cinnabaramide A intermediate was reported.A one-pot transformation of ketene dimers into lactones through a sequential Weinreb amide or alkoxide-mediated ring-opening/aldol reaction/cyclization was also accomplished in moderate yields (40-47%) but with very good diastereoselectivity for select examples.

Experimental Section
General.THF was freshly distilled from benzophenone ketyl radical under nitrogen prior to use, while Hünig's base (diisopropylethylamine) was distilled from calcium hydride and N,N-dimethylethylamine was distilled from potassium hydroxide under nitrogen. 30Most anhydrous solvents (CH2Cl2 and Et2O) were obtained by passing through activated alumina columns on a solvent purification system.2-Pyridone and O-benzyl-D-serine was purchased from Aldrich Chemical Co.Octanoyl chloride and trimethylsilyl chloride were purchased from Aldrich Chemical Co. and distilled prior to use. 30Iatrobeads (Bioscan, 6RS-8060, 60µM particle size), and TLC plates (Sorbent Technologies, UV254, 250 μM) were used as received.2][33][34][35] TMS-quinine, Mequinidine and Me-quinine were synthesized according to literature procedure. 7,36MR spectra were recorded on a Bruker DPX Avance 200 spectrometer (200 MHz for 1 H and 50 MHz for 13 C) and on a Bruker Biospin AG 400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C).NMR chemical shifts were reported relative to TMS (0 ppm) for 1 H and to CDCl3 (77.23 ppm) for 13 C spectra.High resolution mass spectra were obtained on an Agilent Technologies 6520 Accurate Mass Q-TOF LC-MS instrument at Oakland University (with ESI as the ionization method).Low resolution mass spectra were recorded on a GC/MS Hewlett Packard HP 6890 GC instrument with a 5973 mass selective detector, and using a Restek Rtx-CL Pesticides2 GC column (30 m, 0.25 mm ID).IR spectra were recorded on a Bio Rad FTS-175C spectrometer.Optical rotations were measured on a Rudolph DigiPol 781 TDV automatic polarimeter.
The layers were separated and the aqueous layer was washed with CH2Cl2dichloromethane (2 × 5 mL).The combined organics were dried over anhydrous Na2SO4 and then concentrated to about 10 mL.The solution was diluted with pentane (10 mL) and passed through a plug of neutral silica (10 g), eluting with 50% CH2Cl2dichloromethane/pentane (80 mL).The heterodimer product was converted to Weinreb amide derivative (+)-3a prior to isolation due to the volatile nature of the heterodimer.The resulting solution (from plug column) was concentrated to about 7 mL and then N,O-dimethylhydroxylamine (89 mg, 1.46 mmol) was added, followed by 2-pyridone (4 mg, 0.04 mmol) and the reaction was stirred for 3 h at room temperature.The reaction was quenched by the addition of water (5 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2dichloromethane (2 × 5 mL).The combined organics were dried over Na2SO4, concentrated and purified by column chromatography over neutral silica to afford (+)-3a as a colorless oil (107 mg, 79%); HPLC analysis: 91% ee [Daicel Chiralpak AS-H column; 1 mL/min; solvent system: 2% isopropanol in hexane; retention times: 13.3 min (minor), 16 ) was added over 1 h to the above solution, and the mixture was stirred for 3 h at -25 °C.The reaction was quenched by the addition of water (5 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).The combined organics were dried over anhydrous Na2SO4, and the solution was then concentrated to about 15 mL before being diluted with pentane (15 mL) and passed through a plug of neutral silica (18 g), eluting with 50% CH2Cl2/pentane (180 mL).The heterodimer product was converted to Weinreb amide derivative (−)-3a prior to isolation due to the volatile nature of the heterodimer.

(R)-1-[Methoxy(methyl)amino]-4-methyl-1,3-dioxopentan-2-yl acetate ((R)-3b
). Dimethylketene (57 mg, 0.81 mmol) in THF (1.2 mL) was added to a solution of Me-quinine (27 mg, 0.08 mmol) in CH2Cl2 (6 mL) at room temperature, and then Hünig's base (105 mg, 0.81 mmol) was added.Acetoxyacetyl chloride (110 mg, 0.81 mmol) in CH2Cl2 (0.9 mL) was added to the above solution at room temperature over 4 h, and in the third hour of the addition the reaction was cooled down to -25 °C.The reaction was stirred for 20 h at -25 °C and was then quenched by the addition of HCl (1 M, 5 mL).The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).The combined organics were washed with saturated sodium bicarbonate solution (5 mL) and then dried over anhydrous Na2SO4.The heterodimer product was converted to Weinreb amide derivative (+)-3b prior to isolation due to the acid-sensitive nature of the heterodimer.N,O-Dimethylhydroxylamine (50 mg, 0.81 mmol) was added to the heterodimer solution, followed by 2-pyridone (4 mg, 0.04 mmol) and the reaction was stirred for 3 h at room temperature.The reaction was quenched by the addition of water (5 mL).The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).The combined organics were dried over anhydrous Na2SO4, concentrated and purified by column chromatography over neutral silica with a gradient elution (EtOAc/hexane 10 to 30%) to afford (+)-3b as a colorless oil (98 mg, 52%); HPLC analysis: 76% ee [Daicel Chiralcel OD-H column; 1 mL/min; solvent system: 5% isopropanol in hexane; retention times: 11.7 min (major), 12.9 min (minor)]; []  23  temperature, and Hünig's base (105 mg, 0.81 mmol) was then added.Acetoxyacetyl chloride (110 mg, 0.81 mmol) in CH2Cl2 (0.9 mL) was added to the above solution at room temperature over 4 h, and in the third hour of the addition the reaction was cooled down to -25 °C.The reaction was stirred for 20 h at -25° C and was then quenched by the addition of HCl (1M, 5 mL).The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).The combined organics were washed with saturated sodium bicarbonate solution (5 mL) and then dried over anhydrous Na2SO4.The heterodimer product was converted to Weinreb amide derivative (−)-3b prior to isolation due to the acid-sensitive nature of the heterodimer.N,O-Dimethylhydroxylamine (50 mg, 0.81 mmol) was added to the heterodimer solution followed by 2-pyridone (4 mg, 0.04 mmol) and the reaction was stirred for 3 h at room temperature.The reaction was quenched by the addition of water (5 mL).The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).The combined organics were dried over Na2SO4, concentrated and purified by column chromatography over neutral silica with a gradient elution (EtOAc/hexane 10 to 30%) to afford (−)-3b as a colorless oil (106 mg, 57%); HPLC analysis: 91%

(R)-O-Benzyl serine allyl ester (4).
To a suspension of O-benzyl-D-serine (1.19 g, 6.12 mmol) in distilled MeOH (22 mL) was added triethylamine (1.01 mL, 7.96 mmol) and p-anisaldehyde (1.25 g, 9.18 mmol) at 23 °C.The resulting suspension was stirred until the solution became homogeneous (~ 30 min).The solution was then cooled to 0 °C, followed by addition of anhydrous MgSO4 (3.7 g, 30.8 mmol).After 7 h, the MgSO4 was filtered via fritted funnel and washed with MeOH (40 mL).The combined filtrate was cooled to 0 °C for 15 min and then NaBH4 (300 mg, 7.96 mmol) was added portionwise.After stirring at 0 °C for 2 h, the solidified reaction mixture was left in a freezer (~ -10 °C) for 12 h.All volatiles were removed under reduced pressure and the remaining solid was resuspended in water (15 mL) and acidified to pH 3 with 2 N HCl.The precipitated colorless solid was filtered via a Büchner funnel, washed with ice-cold water (2 × 10 mL) and ice-cold Et2O (2 × 10 mL), and dried under vacuum to give O-benzyl-N-PMB serine as a colorless solid.To O-benzyl-N-PMB serine (2.04 g, 6.47 mmol) and p-TsOH (1.34 g, 7.76 mmol) was added allyl alcohol (6 mL) and toluene (40 mL).The solution was stirred at reflux (~ 124 °C) over molecular sieves for ~ 8 h.The resulting solution was concentrated, resuspended in 5% aqueous NaHCO3 (36 mL), and extracted with EtOAc (150 mL).The pH was adjusted to 10.0 (until pH of aqueous solution maintained at 10 after extraction) with 2 M NaOH solution.The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure.The residue was purified by flash column chromatography (20% EtOAc/hexanes) on silica to give the desired allyl ester 4 (907 mg, 42%) as a yellow oil.

Table 2 .
Synthesis of cinnabaramide A precursor from ketene heterodimer 2f