The Total Synthesis of Chalcitrin. Biological & Biomedical Sciences Coursework

The Total Synthesis of Chalcitrin
J. Am. Chem. Soc. 2019, 141, 4515−4520
Assessment will be based on:
● the retrosynthesis
● the understanding of the details of the chemistry involved
● its organisation into a coherent form
● the clarity of review
● critique and discussion of the key steps and strategy in the synthesis
The aim is to discuss the critical features of the synthesis; the focus should be:
● the nature (mechanism, i.e. arrow-pushing!) of key C-C bond forming steps
● overall strategy
● stereocontrol 
● and any other novel/interesting components of the published work. 
Detailed chemistry of protection-deprotection sequences and redox chemistry need not be emphasised, but may be necessary in some cases 
Plan for review -- breakdown each scheme and analyse the chemistry for each step
Intro -- Patrick
● Source of Chalcitrin
● Pulvinic acid dimers (analogues of Chalcitrin)
● Interest area of group
● Overview of dimer scaffold
Scheme 1: Retrosynthesis [8 steps] 
● Show general reaction for coupling reaction (heck/stille) with possibilities of switching between the halide and metal partners -- shows great flexibility of the synthesis
Scheme 2: Formation of tricyclic intermediate [10 steps] 
● Preparing the tricyclic intermediate to be the metal (tin) coupling partnerScheme 3: First coupling attempt [6 steps]
● Stille and heck reactions coupled with pulvinic acid as the halide partner because this is the faster route (cannot directly convert pulvinic acid to stannane)
● Stille was determined to be the only successful coupling reaction, so now the target is to have tandem (2x) stille reaction instead of Stille+Heck
● This requires preparing a double vinyl halide intermediate for subsequent conversion to bistannane tricyclic partnerScheme 4: Preparing double vinyl halide intermediate [8 steps] Scheme 5: Second and third coupling attempts [4 steps]● Tandem stille reactions used as planned
● 2nd attempt - Bistannane tricyclic intermediate + halide pulvinic acid = no product
● Switch the partners; have the tricyclic be the halide partner. This is the flexibility of the reaction proving to be advantageous
● 3rd attempt - Double halide tricyclic intermediate + stannane pulvinic acid = productScheme 6: Preparing stannane pulvinic acid [6 Steps] 
Stannane group cannot be directly added/substituted to pulvinic acid commercial source● Therefore the group had to synthesise the stannane pulvinic acid from scratch (tetronic acid)Conclusion
● Overall yield, total steps
● Summarise and highlight some key reactions?
● Interesting bits:
○ In the end, the longest route (everything made from scratch) was the only successful path to product reported○ The flexibility of switching the possible coupling partners contributed to the success of the total synthesis○ Characterisation after product synthesis confirmed that natural isolate exists in carboxylate form, not the protonated form which was initially synthesised----
 
 Intro: [References to be added in later]
Chalcitrin is a yellow pigment that presents a tricyclic core with two pulvinic acid side chains. It is obtained from Chalciporous piperatus (Peppery Bolete) belonging to a group of naturally occurring pulvinic acid dimers. The naturally occuring dimer is found mostly in the stalks of the fungus. In addition, other pigments of structured dimers Sclerocitrin, norbadione A, and xerocomic acid are also present alongside Chalcitrin. The major pigments responsible for the colour in this fungus are found to be chalcitrin and sclerocitrin.  
Dissecting the dimers by structure elucidation has linked back to a common precursor; xerocomic acid. This building block is already present together with the natural dimers in the natural extract, indicating xerocomic acid to be their monomeric precursor. Hence, sclerocitrin and norbadione A are analogues of chalcitrin.
The proposed synthesis undertaken by nature to construct chalcitrin starts with oxidation of xerocomic acid to dehydroxerocomic acid. This creates a quinoid ring that can dimerse with the same building block through enzymatic C-C coupling due to the presence of electrophilic and nucleophilic centres. An enol driven reaction leads to attack of the electrophilic enone on the other side.  
Oxidative cleavage of the alpha-hydroxyketone results in formation of acid which undergoes subsequent decarboxylation to the bicyclic intermediate. Reduction of the 1,2 dione to the diol enables for intramolecular 1,4 conjugate addition to chalcitrin.
 Norbadione A is also found in another fungi; Xerocomus badius (Bay Boletus) and extraction of this pigment was performed using small amounts of hydrochloric acid indicating that norbadione A exists in its salt form. The analysis of the other dimers; sclerocitrin and chalcitrin obtained from Chalciporous piperatus were also found to be existing in the salt form, with potassium ions. Interestingly, norbadione A can complex cesium ions, as this dimer was also isolated from another mushroom species located near the chernobyl incident in an environment high in concentration of radioactive cesium. As a result, the surmised function of these naturally occurring pulvinic acid is to form stable complexes with metal ions in nature.
Chalcitrin has so far been reported to source only from Chalciporous piperatus in sparing amounts, with 6 mg obtained from 300 g of the fungus. As a result, a synthetic call has been made to improve the short supply. This review will report the total synthesis of chalcitrin by Snyder and co-workers.   
Scheme 1: Retrosynthesis [7 steps]
Overall Retrosynthetic Analysis 
Retrosynthetic analysis of chalcitrin begins by performing a C-C disconnection of the two pulvinic acid groups, revealing the tricyclic intermediate. In the forward direction, joining these groups will be done with a palladium-based coupling reaction, presumably stille. This final coupling step proved to be most problematic due to the crowded nature of chalcitrin. However, the flexibility of the reactants to act as either the metal complex or halide partner proved to be instrumental in the success of synthesising the product. The successful combination of reactant partners can only be determined through trial and error, as there are steric interactions that favour one combination of reactive partners over the other, which will be discussed later in this review. At this stage, the substituents are left ambiguously as either metal or halide partner to address the uncertainty of this final coupling step. Next, past experiences of Snyder and co-workers have shown that benzyl ether to be the most effective protecting group on the pulvinic acid group due to the ability for rapid and global deprotection after the coupling step.  
The presence of α-hydroxy ketone in the tricyclic core indicates a viable disconnection. With an acyloin addition envisioned in the forward direction using N-heterocyclic carbene, the next retrosynthetic step entails disconnecting the bond between the alcohol and carbonyl. As a result, the alcohol and carbonyl become the a1 and d1 synthons respectively. Additionally transformation of the ketone in the tricyclic intermediate to the silicon group will provide stereocontrol for the other groups.The next retrosynthetic target from this point is the secondary alcohol at (a). This will require several transformations: first, the aldehyde is converted to the primary alcohol -- with dess-martin oxidation in the forwards direction. Following this, transforming the alcohol to a terminal alkene, with a hydroboration reaction in the forwards direction. Afterwards, disconnecting the allylic side chain therefore projects an allylation in the forwards direction by nucleophilic substitution. After reaching this targeted intermediate -- rearranging the view of the structure presents a potential disconnection of the cyclic structure.
 A conia-ene is envisioned in the forwards direction which results in a C-C disconnect producing d2 and a1 synthon, leading to the reagents: enolate counterpart silyl enol ether, and electrophilic alkyne from electrophilic activation using a Lewis acid[S] for the intramolecular conia-ene reaction in the forwards direction, further discussed later in this review.  Lastly, the presence of β-hydroxy ketone indicates addition by the aldol reaction in the forward direction, hence the retrosynthetic step is disconnecting the bond that separates the groups. At the same time, the silicon group can be disconnected from the cyclopentanone which would arise by nucleophilic addition to a precursor α-β-unsaturated pentanone in the forward direction. Thus, the retrosynthetic analysis of chalcitrin has arrived at α-β-unsaturated pentanone as the starting reactant. 
 Scheme 2: Formation of Tricyclic intermediate [10 steps]The synthesis of chalcitrin begins by constructing the tricyclic intermediate [X]. Firstly, the generation of the silyl cuprate allowed for conjugate 1,4 addition to the commercially available starting material 2-cyclopenten-1-one.  
[Cuprate soft nucleophile] The silyl conjugate addition with copper is employed to enable later functionalization to the carbonyl unit as the silyl group acts as a “masked hydroxyl group”[S]. Furthermore, it traps the adjacent enolate 12 formed in situ, and the enolate becomes more nucleophilic due to the adjacent electron-donating C-Si bond [S] which enables the following d) aldol reaction to occur producing 14 in 91% yield with 1.45:1 diastereomeric ratio at the secondary alcohol. Fortunately, the mixture is not problematic because this chiral centre would be removed in later reactions. Interestingly, 14 was formed as the desired single diastereomer at the chiral centres on the cyclopentane despite not explicitly reacting asymmetrically. 
The secondary alcohol was immediately protected using MOMBr to afford 15 in 85% yield with 1.6:1 diastereomeric ratio. In preparation for the later Conia ene reaction, the TMS-protected alkyne 15 underwent direct one step electrophilic iodination using N-iodosuccinimide and Ag catalyst. The use of the metal catalyst allowed for mild reaction conditions, notably conducted at room temperature. Comparing this to the traditional stepwise method which prepares haloalkynes using a strong base to deprotonate the terminal alkyne and trapping with the halogenating agent [S]. Furthermore, the Ag catalyst improves the reaction efficiency by not forming the intermediary unstable alkyne present in the traditional method [S].  
It is this iodine group in 16 that will participate in the final coupling step, which could also be converted to the stannane partner. The Conia ene reaction: named after Jean Conia back in 1975, and the intramolecular variant of the Ene reaction, involves thermal intramolecular cyclisation between the enol tautomer of a carbonyl compound and alkyne or alkene [S]. However, the keto tautomer is favoured at equilibrium because it is the lower energy form. Therefore, the traditional conia ene reaction requires high temperature conditions over 300°C to access the intramolecular cyclisation [S]. This presents further restrictions to the range of substrates, as many functional groups are susceptible to pyrolysis at these high temperatures. It is possible to utilise metal enolates to overcome the thermal conditions required for the Conia ene cyclisation and therefore expand the range of potential substrates [S]. Additionally, electrophilic activation of the corresponding alkyne using soft carbophilic Lewis acids such as Gold(I) permits Conia ene to be conducted in more mild conditions [S]. Snyder and co-workers followed a similar approach: Toste, who utilised silyl enol ethers as substrates for the required enolate, and a gold (Au) catalyst to overcome the thermal conditions and apply the Conia ene reaction in their synthesis of Lycopladine A [S]. Taking inspiration from this work, Snyder converted 17 to the silyl enol ether 18 in 88% yield.  
Having generated the silyl enol ether 18, the substrate is ready for the Conia ene reaction. The suggested mechanism for Snyder’s bicyclic intermediate below follows a mechanism proposed by Barrault’s Gold-Catalysed total synthesis of Hyperforin [S]. This similar work employed the Conia ene reaction also using a silyl enol (TBS) to fashion the bicyclic framework desired by Snyder’s synthesis of Chalcitrin.
 The gold catalyst was employed in the form CyJohnPhosAuCl which utilises bulky CyJohnPhosphorus ligand to enhance the catalytic activity of the gold catalyst. In similar works, Samawura used bulky phosphorus groups as ligands for gold catalysed Conia ene of alkyne tethered ketoesters [S]. The bulky nature of the phosphorus ligands creates a small cavity, whereby the gold metal centre coordinates to the alkyne for electrophilic activation, causing the substrate to occupy the cavity. It is surmised that occupying this cavity forced the enol into close vicinity to the activated alkyne, thus overcoming the initial entropy barrier created from the many rotational modes of the alkyne[S]. As a result, conversion to the cyclised product improved and allowed for mild reaction conditions to be conducted. Additionally, the silver salt, AgOTf, plays an important role to generate a more reactive gold catalyst in situ through chloride abstraction from the neutral gold catalyst [S] and drive cyclisation. The triflate (-OTf) serves as a counterion [S] and improves overall selectivity of 21 as there are potential undesired side products through the 5-exo-dig pathway discussed by Berrault however Snyder did not make any mentions of selectivity difficulties in making 21.
The reactive gold catalyst is surmised by the Dewar-Chatt-Duncanson model to coordinate with the alkyne in this catalytic transformation thus preparing 19 for electrophilic activation by reducing the electron density caused by the “dominating σ-donation of the olefinic ligand”[S]. As a result, the silyl enol which acts as a “frozen enol equivalent” [S], attacks the activated alkyne in a manner proposed in 19. According to Baldwin rules, the cyclisation occurs in the desired 6-endo dig fashion, a favoured ring closure and one of the possible cyclisation pathways reported in Barrault’s total synthesis of Hyperforin, yielding the vinyl gold(I) intermediate 20. To reach the final cyclised product, 20 undergoes protonolysis using t-BuOH as the proton source, as silyl enol ethers lack the proton source that enol nucleophiles possess [S]. The combinative use of these reagents allowed Snyder to access this key conia ene reaction to employ on substrate 18 in mild conditions, as evident by the reaction temperature of 40°C, to furnish the bicyclic framework 21 as a mixture of both protected and deprotected alcohol due to the acidic conditions. 
 Scheme 3: First coupling attempt [6 steps]
The two pulvinic side chains were incorporated using a variant of Pd-based C-C bond-forming chemistry. The initial approach involved the introduction of one of the side chains via Stille coupling between the stannane variant of the readily synthesised lactone derivative and the vinyl iodide motif of the tricyclic intermediate. Meanwhile, the other side chain would be added via a Heck reaction between the iodolactone and an enone generated on the right-hand ring of the tricyclic intermediate. However, they were never able to directly form a stannane from the iodolactone. Instead, they developed alternate coupling partners by firstly converting the tricyclic intermediate (#) into stannane (#) through a two-step Fleming-Tamao oxidation of the alkyl silane, concomitant alcohol oxidation and enone formation using IBX under acidic conditions. Then, the alkenyl iodide (#) was converted into a stannane (#).  
Figure #. 
The Fleming-Tamao oxidation allows the conversion of a carbon-silicon bond to a carbon-oxygen bond with retention of the configuration (Figure #). The silyl group is used as a functional equivalent of the hydroxyl group, essentially acting as a “masked hydroxy group”. Additionally, the silyl group is a non-planar and relatively unreactive species and therefore can tolerate reaction conditions that are incompatible with alcohols. Hence, organosilicon compounds are often used in the total synthesis of complex natural products and pharmaceutical drugs.  
Figure #. Tamao-Fleming oxidation. (ref)
The term refers to the two slightly different oxidation conditions developed by the research groups of Kohei Tamao and Ian Fleming in the early 1980s.1,2 Tamao’s oxidation condition involves a fluoride atom, provided by a fluoride source such as KF or KHF2, attacking the fluorosilane in a fast and reversible manner. The pentacoordinated species that is generated is more electrophilic than the fluorosilane, thus allowing attack by a nucleophilic oxidant such as H2O2 to yield a negatively charged hexacoordinated transition state. The attack of H2O2trans to the electronegative fluoride group is energetically favoured. The group cis to the peroxide oxygen in the transition state structure then migrates preferentially, thus retaining the configuration at the carbon center. The silicon-oxygen bond that is generated is then hydrolyzed by water. The reaction also occurs in MeOH/THF mixed solvent with a weakly alkaline condition employed by adding NaHCO3 or KHCO3, with no fluoride ions  being required.1 
Figure #. Tamao oxidation mechanism. (ref)
On the other hand, Fleming oxidation uses a more robust silyl group with only carbon atoms attached to the silicon atom. In the total synthesis of chalcitrin, the silyl structure used was dimethylphenylsilyl. An electrophile, such as H+BF4-, attacks the phenyl ring in the ipso position to give a beta-carbocation which is, in turn, stabilised by the silicon group. The elimination of the phenyl group occurs as a heteroatom, such as F, attacks the silicon group. Then, the alkyl group undergoes 1,2-migration from the silicon atom to the oxygen atom. Hydrolysis and subsequent workup yield the desired alcohol.2
 Figure #. Tamao-Fleming oxidation of alkyl silane...