Cross-Coupling Attempts

With building blocks 50 and 64 in hand, several cross-coupling conditions used successfully for sterically hindered aryl coupling partners as well as for electron-rich heteroatom-bearing vinyl halides were screened.[87,103–105]

The formation of 76 could not be observed, and protodeborylated 64 was the major byproduct (Table 3). Iodide 50 was completely consumed in every instance, indicating that oxidative addition proceeded well, but the subsequent transmetallation step, even in the presence of alcoholic solvents and water that activate the boron center through formation of a boronate complex, did not proceed at all.^[106]

Table 3. Suzuki cross-coupling of iodoenamine 50 with aldehyde 64.

Entry Pd Source^a Ligand^b Base Solvent System Temp. (°C) Time (h) Yield^c

1 Pd(PPh3)4 - K2CO3 Benzene/MeOH/H2O 70 14 -

2 Pd(PPh3)4 - Na2CO3 Toluene/EtOH 105 16 -

3 Pd(PPh₃)₄ - KOH Toluene/H₂O 105 16 -

4 Pd(dppf)Cl₂ - K₂CO₃ DMSO 80 16 -

5 Pd(OAc)2 CyJohnPhos Ba(OH)2 1,4-Dioxane 80 2 -

6 Pd(OAc)2 CyJohnPhos K3PO4 1,4-Dioxane 80 2 -

7 Pd(OAc)2 SPhos K3PO4 Toluene/H2O 80 5 -

a) 10 mol%; b) 20 mol%; c) decomposition of 50 observed, protodeboronation of 64 as determined by LCMS.

Similar results were observed in the attempted coupling of iodoenamine 50 with isopropoxy-protected aldehyde 66 (Table 4) as well as styrene 70 (Table 5). Using potassium tetrafluoroborate 71 in conjunction with iodide 50 was not successful either (Table 6).^[107–110] These results suggest that steric hindrance, and not electronic bias, might be the culprit for the failure of this cross-coupling.

Additionally, since 66 had been reported to undergo cross-coupling with aryl bromides, the halogenated enamine seems to be the main problem for the unsuccessful reaction outcomes. In fact, using this building block, only one example of cross-coupling can be found in literature.^[87]

Table 4. Suzuki cross-coupling of iodoenamine 50 with isopropoxy-protected aldehyde 66.

Entry Pd Source^a Ligand^b Base Solvent System Temp (°C) Time (h) Yield^c

1 Pd(PPh3)4 - K2CO3 benzene/MeOH/H2O 70 14 -

2 Pd(PPh₃)₄ - Na₂CO₃ toluene/EtOH 105 16 -

3 Pd(PPh₃)₄ - K₃PO₄ 1,4-dioxane 80 7 -

4 Pd(OAc)2 CyJohnPhos Ba(OH)2 1,4-dioxane 60 48 -

5 Pd(OAc)2 SPhos K3PO4 toluene/H2O 100 5 -

a) 10 mol%; b) 20 mol%; c) decomposition of 50 observed, protodeboronation of 66 as determined by LCMS.

Table 5. Suzuki cross-coupling of iodoenamine 50 with isopropoxy-protected styrene 70.

Entry Pd Source^a Ligand^b Base Solvent System Temp (°C) Time (h) Yield^c

1 Pd(PPh3)4 none K2CO3 benzene/MeOH/H2O 70 14 -

2 Pd(PPh3)4 none Na2CO3 toluene/EtOH 105 16 -

3 Pd(PPh₃)₄ none K₃PO₄ 1,4-dioxane 80 16 -

4 Pd(OAc)₂ CyJohnPhos Ba(OH)₂ 1,4-dioxane 80 16 -

5 Pd(OAc)2 SPhos K3PO4 toluene/H2O 100 5 -

a) 10 mol%; b) 20 mol%; c) decomposition of 50 observed, protodeboronation of 70 as determined by LCMS.

Table 6. Suzuki cross-coupling of iodoenamine 50 with potassium tetrafluoroborate 71.

Entry Pd Source^a Ligand^b Base Solvent System Temp (°C) Time (h) Yield^c

1 Pd(dppf)Cl2 none Ag2O toluene 100 18 -

2 PdCl2(PhCN)2 none K2CO3 1,4-dioxane/H2O 80 16 -

3 PdCl2 none K2CO3 1,4-dioxane/H2O 80 16 -

4 Pd(PPh₃)₄ none K₂CO₃ DMF/H₂O 100 12 -

5 Pd(dppf)Cl2 none CsCO3 toluene 100 18 -

We attempted to overcome the lack of reactivity in the cross-coupling by substituting the boronic ester-based Suzuki reaction with a Negishi reaction of organozinc reagents, which have been shown to participate in cross-coupling reactions even at ambient temperature.^[111] Styrene 69 was chosen as the substrate this study. After Br/Li exchange with t-BuLi, lithiated 69 was treated with ZnCl2 and subjected to various Pd-mediated cross-coupling protocols (Table 7).^[112] Although 50 was completely consumed in the reaction, no desired product was formed, and the main side-product was dehalogenated 69 resulting from protolysis of the intermediate organozinc species.

Table 7. Negishi cross-coupling of 50 and 69 to form enamine 79.

Entry Pd Source^a Ligand^b Solvent Temp (°C) Time (h) Yield^c

1 Pd2dba3 SPhos THF 60 16

-2 Pd₂dba₃ RuPhos THF 60 16

-3 Pd₂dba₃ XPhos THF 60 16

-a) 5 mol%; b) 20 mol%; c) decomposition of 50, protodemetalation of 69 observed.

Next, the brominated enamine was examined as cross-coupling partner, as it was believed to be less reactive than the iodide which was evidently too unstable under the reaction conditions (see Table 8, next page). Despite using the very general systems reported by Buchwald and co-workers, the Negishi cross-coupling reaction of 55 and 69 did not lead to product formation.^[113,114] Examination of H2O-quenched reaction aliquots after 2 h indicated only the Br/H exchange of 69 and traces of 55.

After 16 h, 55 was completely consumed and only the Br/H exchange product could be identified in the crude reaction mixture. These disappointing results on the cross-coupling of halogenated enamines 50 and 55 led us to reverse the polarity of the coupling partners.

Table 8. Negishi cross-coupling reaction of bromoenamine 55 and styrene 69.

Entry Pd Source^a Ligand^b Solvent Temp. (°C) Time (h) Yield^c

1 SPhos G2 SPhos THF 60 16

-2 XPhos G3 XPhos THF 60 16

-3 RuPhos G2 RuPhos THF 60 16

-4 PEPPSI-IPr none THF 60 16

-5 Pd(P(o-tolyl)3)2Cl2 none THF 60 16 -

6 Pd(dppf)Cl2 none THF 60 16

-a) 10 mol%; b) 10 mol%; c) decomposition of 55, protodemetalation of 69 observed.

2.1.4. Alternative Fragment Union

Placement of the halogen on the isovanillin building block, rendered electron-poor by the presence of the aldehyde moiety, should favor oxidative addition during the Pd-catalyzed cross-coupling process (Scheme 14). In fact, similar compounds have shown to engage in cross-cross-coupling reactions.^[115–117] The electron-rich nature of the enamine should facilitate the introduction of a boron atom and the subsequent Suzuki cross-coupling. Furthermore, we decided to employ unprotected 2-bromo isovanillin 67 in the cross-coupling. The benzyl group was left out to remove any possible steric hindrance during oxidative addition.

Scheme 14. Envisioned building blocks for the formation of aldehyde 80.

For the synthesis of borylated enamine 81 conditions similar to the Pd-catalyzed borylation of

Table 9. Formation of borylated enamine 81 using palladium catalysis.

Entry Pd Source^a Ligand^b Base Solvent Temp. (°C) Time (h) Yield^d

1^c Pd(OAc)2 CyJohnPhos Et3N 1,4-dioxane 80 1

-2^d Pd(dppf)Cl2 none K2CO3 1,4-dioxane 80 16 -

3^d Pd(dppf)Cl₂ none KOAc DMSO 80 3 -

4^d Pd(OAc)₂ none KOAc DMF 80 5 -

a) 10 mol%; b) 20 mol%; c) HBPin was used as the boron source; d) B₂pin₂ was used as the boron source;

d) decomposition of 50 was observed.

Therefore, a microwave accelerated C–H borylation of enamine 54 was investigated using the conditions reported by Steel and co-workers for the borylation of pyrrole (Scheme 15).^[122] This reaction formed the desired borylated enamine in moderate yield and gram-quantities of 81 could be synthesized using sequential reactions on 1 mmol scale. Brominated isovanillin 67 was prepared following a literature procedure (Scheme 15).^[123]

Scheme 15. Synthesis coupling partners with reversed polarity.

With borylated enamine 81 and bromoisovanillin 67 in hand, another screening of conditions for the Suzuki cross-coupling was performed using catalytic systems known to engage boronic esters containing free phenols (Table 10).[52,82,124]

While reactions carried out at 100 °C resulted in complex mixtures (Entries 1 and 2), a reaction carried out at room temperature did not show appreciable conversion (Entry 3). The use of microwave irradiation, which is routinely used to accelerate challenging Suzuki coupling, also resulted in a complex mixture of products despite the moderate temperature and short reaction time (Entries 5 and 6).^[125,126]

Table 10. Suzuki cross-coupling of boronate 81 and bromoisovanillin 67.

Entry Pd Source^a Ligand^b Base Solvent System Temp. (°C) Time(h) Yield^d

1 Pd(PPh3)4 none K2CO3 1,4-dioxane/H2O 100 2 -

2 Pd(PPh3)4 none K3PO4 DMF 100 18 -

3 Pd(OAc)2 SPhos K3PO4 DMC r.t. 48

-4 Pd(OAc)₂ SPhos K₃PO₄ n-BuOH/H₂O 100 1

-5^c Pd(OAc)₂ SPhos K₃PO₄ MTBE/H₂O 100 0.15

-6^c Pd(dppf)Cl2 none KOH MTBE/H2O 80 0.15

-a) 10 mol%; b) 20 mol%; c) reaction performed in the microwave; d) decomposition of 81 was observed.

2.1.5. Stepwise Construction of the Pyrroline Ring

Our unsuccessful attempts at a convergent cross-coupling of an aromatic building block with a pyrroline unit prompted us to devise a stepwise construction of the pyrroline ring from a substrate that already incorporates the o,o-disubstituted aromatic ring. Previous work conducted by Andreas Bellan showed that that a high-yielding Negishi coupling of acetal 82 with bromoacrylate 83 could afford α,β-unsaturated ester 84 (Scheme 16).^[127] Subsequent 1,4-addition of nitromethane followed by reduction and cyclization gave lactam 85 after N-methylation. Efforts to reduce this compound to the desired enamine 86, or effect enolization to form a vinyl triflate or vinyl phosphonate, remained unsuccessful. Steric hindrance due to the flanking ortho-substituents on the aromatic ring severely obstructs productive reactivity of the five-membered ring and forced us to revise our synthetic approach.

2.2. Revised Retrosynthesis

Failure to synthesize a pyrrolidine ring in the sterically hindered position of an o,o-disubstituted arene led us to modify our synthetic approach and focus on the introduction of a less bulky substituent, thereby postponing the formation of the pyrrolidine ring at a later stage in the synthesis. As shown in Scheme 17, the ring closure was planned to be performed on ketone 86 bearing a pendant amine following treatment with an amination agent. Pertinent examples for this reaction, that constitutes a formal umpolung of the -position of a ketone, have been employed in total synthesis (Scheme 17).^[128–134]

Scheme 17. Proposed α-amination of 86 and relevant literature precedents.

Formation of the crucial benzylic quaternary stereocenter could be achieved by a [3,3]-sigmatropic rearrangement, i.e. the oxy-Cope rearrangement, in which alkene 87 could be formed in high stereoselectivity after the addition of allylmagnesium bromide to ketone 88 (Scheme 18).^[56]

Alternatively, a 1,4-addition of an allyl or vinyl nucleophile could allow the introduction of the C2-unit after appropriate functional group manipulations. In any case, the required tricycle bearing

accessed from isovanillin following Sonogashira coupling and allylation. As put forth in Section 2.1, the allylic alcohol may serve as a stereocontrolling element to enable a diastereoselective Pauson–

Khand reaction and therefore an enantioselective synthesis of sinoracutine. The rigidity of the formed tricycle should allow for the stereoselective introduction of the allyl group required for the projected oxy-Cope rearrangement and stereochemical relay from 88 to the final product.^[135]

Scheme 18. Full retrosynthetic plan for sinoracutine starting from isovanillin.

2.2.1. Synthesis of the Isovanillin Portion

Isovanillin was regioselectively iodinated to give 62, whose free hydroxyl group was benzylated to afford 63 (shown in Scheme 10).^[136] Sonogashira cross-coupling of 63 with trimethylsilyl-acetylene and subsequent allylation with allylmagnesium bromide afforded enyne 91 (Scheme 19).^[137] Cleavage of the terminal TMS group with K2CO3 in MeOH proceeded smoothly on small scale, but side products and lower yields were observed during scale-up. Instead, deprotection of 91 using TBAF proceeded in excellent yield and Pauson–Khand precursor 93 was obtained after treatment with TBSCl and imidazole.

Im Dokument Total synthesis and racemization of (-)-sincoracutine and studies towards the total synthesis of herqulines A and B (Seite 36-44)