Recent advances in the synthesis of taxoids: 2015-2020

Taxol is a highly oxygenated, polycyclic diterpene first isolated from the bark of the Pacific yew tree. The impressive antitumor activity of this compound led to intense synthetic activity over the past 30 years. The first syntheses were reported more than 25 years ago


Introduction
Taxol© or paclitaxel was first isolated in 1964 by Wall and co-workers from the extracts of the bark of Taxus brevifolia, also known as the pacific yew tree. 1 This complex polycyclic molecule belongs to the taxane diterpene family, of which there are now more than 550 known compounds, 2 and was found to have impressive activity against KB cells.In 1992, taxol was approved by the FDA for treatment of recurrent ovarian cancer and in 1994 for the treatment of breast cancer.It was also reported that taxol has a significant effect in the treatment of different types of cancer such as lung and liver cancer. 3,4The anti-cancer activity of taxol results from its ability to inhibit tumor cell proliferation through enhancement of tubulin polymerization and to act as a promotor of microtubule assembly which leads to the stabilization of microtubules.Taxol 1, (Figure 1) is a highly oxygenated diterpene with a unique chemical structure characterized by a distorted eight-membered (B) ring fused with two peripheral 6-membered rings (A and C), referred to as a 6/8/6 skeleton, with an oxetane ring (D) fused with the C ring.It has acetyl groups at C4 and C10, a benzoyl group at C2, free hydroxyl groups at C1 and C7, and a unique -phenylisoserine side chain at C13.The natural supply of taxol is relatively low (0.5-1 kg taxol from 4,500 kg pacific yew tree bark).Methanolysis of 1 leads to baccatin III (2); C7 protected analogs of 2 have been highly utilized in the penultimate steps for the synthesis of taxol.][10][11][12] These Scheme 1. Retrosynthetic analysis of taxol according to Nakada's approach.
Baker's yeast mediated reduction of 2,2-dimethyl-1,3-cyclohexandione 38 gave 10 in good chemical yield and excellent enantioselectivity (Scheme 2).Silylation with chloromethyldimethylsilyl chloride, followed iodination under Finkelstein conditions afforded 11. 39 Lithium-halogen exchange of 11 triggered an intramolecular alkylation to generate the corresponding chiral tertiary bicyclic alcohol 12. Tamao oxidation followed by acetonide formation and Dess-Martin oxidation yielded ketone 13. -Methylation of 13 proceeded via the silyl enol ether, hydrazone generation and oxidation using iodine gave 14. Swapping the cyclic acetonide for a cyclic benzylidene acetal, followed by reductive cleavage at the less hindered oxygen and Dess-Martin oxidation gave (+)-8 (R = I).While Nakata's group developed multiple routes to vinylhalides 8, 37,40 the present route gave the highest overall yield and enantioselectivity.

AUTHOR(S)
Baker's yeast sucrose/H 2 O Triton X-100 10 (87%, 99%ee) Preparation of the C ring fragment 9 commenced with Birch reduction of methyl 2,6dimethoxybenzoate (15); alkylation of the product with LDA followed by methyl iodide gave diene 16 (Scheme 3). 36,37Reduction of the ester with DIBAL, protection of the resulting 1 o alcohol as a benzyl ether and acidcatalyzed vinyl ether hydrolysis led to the achiral 1,3-cyclohexadione 17.As was the case for preparation of the A ring fragment, Baker's yeast reduction of 17 proceeded in good yield and excellent enantioselectivity to give (+)-18.A protecting group swap yielded benzylidene acetal 19.Transformation of 19 into the vinyl iodide 20 followed a procedure similar to previously used for 13 to 14. Similar reductive cleavage of the benzylidene acetal at the less hindered oxygen and protection of the resultant 1 o alcohol gave (+)-9.Lithium-halogen exchange of (+)-9 and reaction with aldehyde (+)-8 (R = I) gave (+)-7 as a single diastereomer (Scheme 4). 36,37The stereochemical outcome was rationalized on the basis of a chelationcontrolled addition (see red insert).Sharpless epoxidation of 7 catalyzed with VO(OEt)3 gave epoxide 21 as a single stereoisomer.Attempted ionic reduction of 21 (BF3-EtO2/NaBH3CN) led surprisingly to the cyclic benzylidene acetal 22; the yield of this product could be improved by using only the Lewis acid.Nakada's group proposed that 22 is formed by a 1,5-hydride shift of the BF3 complexed epoxide, followed by deprotonation of the C2 hydroxyl group and nucleophilic attack on the benzyl cation (see blue insert).A sequence of oxidation of the C9 primary alcohol, protection of the C4 secondary alcohol, addition of methyl Grignard and oxidation afforded the methyl ketone 6. Formation of the eight-membered B ring was achieved by Pd-catalyzed intramolecular alkenylation to give 5.While this C-C bond formation proceeded in excellent yield, the catalyst loading (30%) was relatively high.The C4 exocyclic methylene was constructed by deprotection of the C4 silyl ether, Dess-Martin oxidation and a Takai methenylation (Scheme 5). 36,37Selenium dioxide allylic oxidation of the less substituted exocyclic olefin of 23 proceeded in a stereoselective fashion to give 24.Transformation of 24 to the hydroxyoxetane followed a variation of the methodology utilized in Holton's synthesis. 7Thus, stereoselective dihydroxylation of allylic alcohol with stoichiometric OsO4 and acylation of the 1 o alcohol afforded 25.Mesylation of the C5 secondary alcohol, hydrolysis of the primary acetate and treatment with DBU afforded 26.Treatment of the enolate anion of 26 with 2-(phenylsulfonyl)-3-phenyl-oxaziridine (Davis reagent) introduced a hydroxyl group at C10, however this possessed the opposite stereochemistry to that desired for taxol.Acylation of this alcohol and epimerization with DBN produced 28.Reductive deprotection of the benzylidene acetal and the C7 benzyl ether was achieved using Pearlman's catalyst, reaction with triphosgene generated the cyclic carbonate ring and C7 hydroxyl protection as a TES ether rendered (-)-4, an intermediate in the Nicolaou total synthesis. 12he Nakada synthesis of chiral ABCD tetracyclic core of taxol required 49 steps from the commercially available achiral 2,2-dimethyl-1,3-cyclohexandione and 2,6-dimethoxy methyl benzoate resulting in ~0.91% overall yield.Approximately 1/3 of the steps involved protection or deprotection with approximately 1/6 of the steps utilized for oxidations or reductions.
The preparation of hydrazone 32 from 34 (Scheme 7) followed a modification of Koskinen's procedure. 44To this end, double methylation of 34, followed formation of the mono ketal formation and reaction with tosylhydrazine afforded 36.Alkylation of 36 introduced the requisite methyl group at C12; subsequent Shapiro reaction with protic work up gave the olefin.Deprotection of the ketal followed by hydrazone formation with Ring C fragment 33 was synthesized from tri-O-acetyl-D-glucal 35 by Ferrier rearrangement with methanol, followed by catalytic hydrogenation, according to the literature procedure 45 (Scheme 8).Hydrolysis of the acetate groups, Appel iodination of the primary alcohol, and protection of the secondary alcohol gave 37. Elimination with potassium t-butoxide, a carbo-Ferrier rearrangement, 46 and -elimination with mesyl chloride/NEt3 gave 6(S)-benzyloxy-2-cyclohexenone (38).Carbonyl transposition 47 with methyl lithium followed by PCC oxidation generated 39.Copper catalyzed 1,4-addition of vinyl magnesium chloride occurred on the face of the enone opposite to the 4-benzyloxy substituent.The resultant enolate was trapped in situ as the silyl enol ether; Lewis acid catalyzed aldol condensation with formalin gave a separable mixture of the desired 40 (60%) along with the C3-epimer (41, 23%, taxol numbering).Protection of the major diastereomer (40) as its THP ether, followed by Luche reduction gave an equimolar, but separable mixture of the desired secondary alcohol 43 and the diastereomer 44.Oxidation of 44 under Ley conditions 48 regenerated 42.Finally, protection of the secondary alcohol, regioselective hydroboration/oxidation, protection with tbutyldiphenylsilyl chloride, hydrolysis of the THP mixed acetal and Ley oxidation generated the requisite aldehyde 33.While this route generated an optically pure fragment, drawbacks to this approach include Coupling of 33 with a two-fold excess of the vinyl anion generated from hydrazine 32 gave the allylic alcohol 45 as a single diastereomer (Scheme 9). 42,43The stereochemical outcome is similar to that observed in the syntheses of Nicolaou, 8,11 Danishefsky 13,14 and Kuwajima 17,18 where a Shapiro reaction was utilized to generate the C2-C3 bond.Stereoselective epoxidation catalyzed by VO(acac)2, followed by regioselective reduction gave the vic-diol which was protected as the cyclic carbonate 46.Oxidation of 46 with a large excess of chromium trioxide in the presence of 3,5-dimethylpyrazole proceeded predominantly at both the C13 allylic position as well as at the C7 benzyl ether to generate 48, along with a lesser amount of partially oxidized 47.Subjecting 47 to further treatment with CrO3/DMP gave additional 48.Stereoselective reduction of 48 at C13, protection of the resultant secondary alcohol as the benzoyl ester, deprotection of the silyl ether and oxidation of the primary alcohol afforded 31 and set the stage for the final key step.Cyclization was achieved using an excess of SmI2 to afford a mixture of diastereomeric homoallylic alcohols 30 and 49 (66%, 1:1.5 ratio).The structural assignments of 30 and 49 were confirmed by X-ray crystallography.An additional byproduct (50) resulted from formation of a C-C bond between C10 and C13.Formation of product 50 is reminiscent of the challenges faced by the Nicolaou group in their McMurry coupling to generate the C9-C10 bond. 8,11Chida found that use of HMPA as a co-solvent was crucial for the success of this reaction, as THF alone led to simply reduction of the aldehyde.Oxidation of 49 gave 51; all attempts to isomerize the olefin into conjugation failed.DFT calculations of simplified models of 51 and 52 indicated that the conjugated olefin (52) was less stable than the skipped enone (51).Since isomerization of 51 to 52 failed, an alternative route to converge with Takahashi's intermediate was devised (Scheme 10). 42,43Stereoselective reduction of 51, and protection of the resultant alcohol gave the benzyl ether 53.Dihydroxylation of 53 with an excess of OsO4, followed by reaction with sodium hydride, carbon disulfide and iodomethane gave the bis-xanthate 54.Thermal double elimination of 54 led to the conjugated diene 55.Deprotection of the C4 methoxymethyl ether and oxidation to the ketone set the stage for eventual introduction of a C4 exocyclic methylene via an interrupted Peterson olefination.To this end, addition of the Grignard reagent from (chloromethyl)trimethylsilane yielded the tertiary alcohol 56.Reduction of 56 with hydrogen in the presence of Pearlman catalyst proceeded via addition at the less substituted C13-C14 olefin as well as cleavage of the C10 benzyl ether; the resultant secondary alcohol was oxidized to a ketone, and elimination of the -silylalcohol rendered the exocyclic olefin (57).The C7 benzoate ester was exchanged for a triethylsilyl ether over a three-step sequence to afford 58.Selenium dioxide allylic oxidation of the less substituted exocyclic olefin proceeded in a stereoselective fashion to give 59.Transformation of 59 to the hydroxyoxetane followed a variation of the methodology utilized in Holton's synthesis. 7Thus, mesylation of the C5 hydroxyl, stereoselective dihydroxylation of the exocyclic olefin and treatment with Hunig's base afforded 29.As an intermediate in Takahashi's formal synthesis, 23 the cyclic carbonate present in 29 was opened with phenyl lithium, followed by acetylation of the C4 tertiary alcohol to generate 60, which is itself an intermediate in the Danishefsky total synthesis. 13,14he Chida synthesis of chiral ABCD tetracyclic core of taxol required 31 steps from the commercially available achiral 1,3-cyclohexandione and chiral tri-O-acetyl-D-glucal resulted in ~0.12% overall yield.Approximately 1/3 of the steps involve protection or deprotection while approximately 1/6 of the steps were utilized for oxidations or reductions.

Inoue total synthesis of 1-hydroxytaxinine (A + C > AC -> ABC)
Inoue's group reported the first total synthesis of 1-hydroxytaxinine (61, Scheme 11). 49Their retrosynthetic analysis required the introduction of oxygen functionality at C5, C7 and C13 of a nearly complete carbon skeleton (62).They envisioned generation of the C1-C2 bond in the B ring by a pinacol coupling of the ketoaldehyde 63.This approach is relatively unique, as many of the other syntheses create the C1-C2 bond prior to formation of the central eight-membered ring.Precursor 63 would be accessed by a decarbonylative radical coupling of fragments 64 and 65.The initial steps for preparation of the A ring fragment are similar to those utilized by Nakada 36,37 (c.f.Scheme 2).Thus, mono-protection of 2,2-dimethyl-1,3-cyclohexadione followed by -methylation generated 66; hydrazone formation and treatment with iodine/DBU gave vinyl iodide 67 (Scheme 12).Heck reaction of 67 with an excess of methyl acrylate led to 68.Sharpless asymmetric dihydroxylation of dienoate 68 proceeded at the less substituted, albeit more electron-deficient olefin.Since the diol was not completely separable from methyl sulfonamide, the crude mixture was directly protected as acetonide derivative 69.Conversion of methyl ester 69 to an acyl telluride 64 required saponification, activation with i-butyl chloroformate, and reaction with phenyltelluride (prepared by reduction of diphenyl ditelluride).Reduction of the acyl telluride with triethylborane in an open-air reaction, proceeded with formation of the C8-C9 bond in a stereoselective fashion; oxidation of the product with DDQ restored the 2-cyano-2-cyclohexenone ring (70).The reductive decarbonylation of 64 proceeded via the acyl radical 71, and while decarbonylation of 72 immolated the C9 stereocenter, addition of the -alkoxy radical 72 proceeded from the less sterically hindered face with apparent stereo-retention (see magenta insert).Conjugate addition of methyl Grignard in the presence of CuI to 70 proceeded predominantly on theface (Scheme 13). 49Reduction of the resultant -cyano cyclohexanone, mesylation of the secondary alcohol and elimination with DBU gave the corresponding -unsaturated nitrile 71 as an inseparable mixture of diastereomers at C8. Reduction of the nitrile, followed by aqueous acidic work-up (for hydrolysis of the imine and cyclic ketal) led to a separable mixture of the desired stereoisomer (-)-63 and 72.A TiCl4/Zn mediated pinacol coupling of 63, after work-up with excess acetic anhydride, provided mono-acetate 62 as the major product along with minor amounts of diol 73.The structure of 62 was corroborated by X-ray crystal structure.The stereochemical outcome was rationalized by proposing that the transition state for C1-C2 bond formation on the si-face of C2 would be higher in energy (compared to the re-face) due to steric interactions between the Ti-O moiety with one of the gem-dimethyl groups at C15 as well as with the C5 hydrogen.The undesired diol 73 could be recycled to (-)-63 by glycol cleavage with Pb(OAc)4.Exhaustive allylic oxidation at both C5 and C13 was achieved with CrO3/3,5-dimethylpyrazole to give 74 as the major product along with minor amounts of a product reflecting cleavage of the C1-C15 bond (75).While the oxidation of 62 to 74 introduced oxygen functionality at the desired C5 position, establishment of the C3 stereocenter remained to be accomplished (Scheme 14).To this end, reaction of 74 with tosylhydrazine occurred at the less hindered C5 ketone.Catecholborane reduction took place predominantly on the less hindered re-face to generate an allylic diazine that undergoes [3,3]-sigmatropic rearrangement to afford the desired (3R)-stereocenter present in 76.Catalytic osmium dihydroxylation in a stereofacial fashion, esterification of the more accessible C5 alcohol with cinnamic acid and oxidation of the C4 alcohol yielded ketone 77.Chemo-and stereoselective nucleophilic addition of methyl Grignard to the C4 ketone gave the corresponding tertiary alcohol.Acetonide hydrolysis and chemoselective acetylation of the C9 and C10 secondary alcohols in the presence of the C1 and C4 tertiary alcohols afforded 78.Attempted dehydration of 78 with Burgess reagent was plagued by rearrangement to afford a 5/7/6 skeleton of the abeotaxane family along with 61.In order to avoid this rearrangement, the tertiary C1 alcohol of 78 was protected as the dimethylsilylhydride ether, followed by dehydration of the C4 alcohol with Burgess reagent and cleavage of the silyl ether yielded 1-hydroxytaxinine (+)-61.

Process improvements to the synthesis of taxadienone.
Refinements of the original 58 Baran synthesis of (+)-taxadienone (80) have followed the same sequence of reactions, however with improvements for scaleup (Scheme 16).Due to concern for highly energetic nature for the ring opening/elimination of gemdibromocyclopropane (82) to 3-bromo-2,4-pentadiene (83), the process research group at Albany Molecular Research Institute established a continuous flow process for this transformation with a 12.5 min residence time at 150 o C. 59 Additionally, the AMRI group established a crystallization protocol for separation/purification of (+)-80 (20-22% isolated yield) from the ~2:1 mixture of diastereomers 80 and 85 resulting from the intramolecular Diels-Alder cyclization.
In their recent synthesis of taxol, 56,57 Baran's group reported using n-butyl lithium (in place of s-butyl lithium used in their original 58 synthesis) for the lithium halogen exchange of 83.A further improvement reported in the recent Baran synthesis concerned a telescoping of the cuprate addition/aldol condensation/oxidation sequence from 86 to the Diels-Alder precursor 81a/b.This improvement utilized Nheterocyclic carbene ligand (+)-90 (15 mol%) instead of phophoramidite (+)-88 for the cuprate addition and the in situ aldol condensation with acrolein, followed by a DMP oxidation (in place of Jones reagent).Conducting these reactions also avoided the unstable trimethylsilyl enol ether 87 and shortened overall process time from 3 days to 1 day.Scheme 16.Synthesis of taxadienone (+)-82 (CuTC = copper(I)-thiophene-2-carboxylate, process improvements in red).

Oxidase phase synthesis of taxabaccatin III.
Baran's group utilized taxadienone (+)-82 as the starting point for their oxidase phase synthesis of taxabaccatin III (Scheme 17). 55Bouveault-Blanc reduction of 82 with sodium in isopropanol gave 91 along with a minor amount of the C2-epimer.Directed epoxidation with VO(acac)2 followed by alkaline hydrolysis afforded the triol 92, which was protected as the bis-acetate 93.Introduction of the C13 and C10 oxygen atoms was informed by the lessons which were learned in their synthesis of taxuyunnanine D. 54 Thus, allylic oxidation of 93, using the Cr(V) reagent 94 pioneered in the Baran synthesis of proceeded to give a separable mixture of the desired enone 95 along with minor amounts of the tertiary allylic alcohol 96.Additionally, oxidation at C10 utilized the radical-mediated protocol with NBS/benzoyl peroxide followed by solvolysis with trimethylsilyl alcohol to yield 97. Dehydration of 97 with Burgess reagent and subsequent treatment with excess DIBAL effected reduction at C13 as well as removal of the acetate groups at C2 and C5.The resultant triol was protected as the tris-MOM ether, followed by selective oxidation of the C10 silyl ether to generate the ketone 99.Introduction of the C9 ketone relied on treatment of the enolate anion of 99 with "MoOPh", 60 and CuOAc oxidation of the resultant -hydroxyketone led to 100.A sequential application of LiAlH(Ot-Bu)(s-Bu)2 and sodium amalgam generated diol 101, which embodied all of the oxygen functionality in the correct positions with the correct stereochemistry.The synthesis was completed by acetylation of the C9 and C10 alcohols, mild removal of the three MOM protecting groups and acetylation of the C2, C5 and C13 alcohols.ii) CuOAc (40)  MeOH

Baran oxidase phase synthesis of taxol
While the oxidase phase syntheses of (-)-taxuyunnanine D 54 and (+)-taxabaccatin III 55 proceeded in relatively short order from taxadienone (+)-82 (5 and 13 steps respectively), application of this strategy to the total synthesis of taxol presented considerable challenge.This is due not only to the need to introduce six oxygen atoms but also two of these sites are the secondary neopentyl carbon (C7) and the bridgehead quaternary carbon (C1).The supporting information for the Baran synthesis outlines numerous unsuccessful attempts at directed C-H oxidation at these two positions.Due to these failures, it was necessary to introduce a C5-C6 olefin to facilitate oxidation at C7.
The oxidase phase commenced from the diketone (+)-80 (Scheme 18), 56,57 and utilized oxidation protocols at C13 and C10 similar to those pioneered in the (-)-taxuyunnanine D 54 and (+)-taxabaccatin III 55 syntheses.Thus, allylic oxidation using the Cr(V) oxidant 94 proceeded at both C13 as well as at C11 to generate a mixture of 102 and 103; regio-and enantioselective bromination of this mixture using CuBr2 gave 104 after purification.Radical allylic bromination of 104 followed by silver mediated substitution by triethylsilanol generated 105.Elimination of HBr introduced the C5-C6 olefin which would eventually be crucial for oxidation at C7.The differential reactivity of the three carbonyl groups in 106 allowed for sequential reaction with methylmagnesium bromide, then DIBAL and finally LiAlD4 to give triol 107, which was protected at the secondary allylic alcohol.Oxidation using excess dimethyldioxirane (DMDO) proceeded predominantly at the bridgehead C1 and the less hindered C5-C6 olefin to generate 109, along with minor amounts of the keto epoxide 110.Deuterium labelling at C2 of 108 was necessary, since attempted oxidation of the protioversion of 108 with DMDO proceeded predominantly via C2 alcohol oxidation instead of C1 hydroxylation.Thus, deuterium labelling at C2 suppressed this alcohol oxidation via a kinetic isotope effect.The keto epoxide 110 could be further processed into additional 109 by SmI2 mediated reduction of the C2 ketone, followed by treatment of 111 with excess DMDO.Notably, at this stage the stereochemistry at C2 of 109 is opposite to that desired in taxol.The stereochemistry was corrected by an oxidation/reduction sequence, followed by reaction with triphosgene to give the cyclic carbonate 112 (Scheme 19).Lewis acid activated epoxide opening with tetrabutylammonium iodide, separating the boron salts with 2-fluoropyridine, and protection of the resultant iodohydrin as the TMS ether was followed by iodine oxidation with DMDO leading to a syn-elimination.The resultant C6-C7 olefin was epoxidized with further application of DMDO.Titanium mediated epoxide ring opening of 113 in the presence of triethylsilane proceeded regioselectively at the less hindered C6 carbon to give 114; the C7 alcohol was protected as a BOM ether.Sequential treatment of 115 with Burgess reagent followed by HF-pyridine gave a nearly equimolar, but separable, mixture of ketone 116 along with allylic alcohol 117; this latter product closely resembled an intermediate in the Holton synthesis 7 except that it possessed the opposite stereochemistry at C10. Introduction of the oxetane D ring closely followed the precedent set by the Florida State group (as well as that in the Chida formal synthesis 42,43 ).To that end mesylation, followed by dihydroxylation with stoichiometric OsO4, treatment with Hunig's base and oxidation of the C10 TES ether gave ketone 118.Oxidation at C9 with selenic anhydride in the presence of water, followed by redoxisomerization, regeneration of the cyclic carbonate and exhaustive acetylation yielded the diacetate 119.Finally, cleavage of the C13 TBS ether and opening of the carbonate with phenyl lithium yielded 120.Esterification with lactam 121 followed by hydrogenolysis of the BOM ether completed the total synthesis of taxol [(-)-1].The Baran two phase enantioselective synthesis of taxol required 27 steps from commercially available achiral tetramethylethylene and 3-ethoxy-2-cyclohexenone resulted in ~0.005% overall yield.Approximately 1/3 of the steps involved protection or deprotection with approximately 1/5 of the steps were utilized for oxidations or reductions.At the time of their report, a total of 35.2 mg of (-)-1 was produced, representing a 2.5-fold increase in the next greatest quantity produced by prior total syntheses. 12While the Baran synthesis stands as a significant example of the two-phase approach, there are notable downsides.These include a low yield of the key intramolecular Diels-Alder product (80, 20-22%), low yield for formation of 117 from 115 (32%), and relatively low conversion of 5,6-epoxide 112 to C7-alcohol 114 (29%).

Gaich synthesis of (±)-and (-)-canataxpropellane
Canataxpropellane (122, Scheme 20) is a highly oxidized, heptacyclic diterpene isolated from Taxus canadensis, the Canadian yew. 61It is related to the more common taxoids by virtue of three additional C-C bonds, between C3-C11, C4-C12, and C14-C20.The structure of 122 was assigned on the basis of extensive NMR spectral analysis.The authors proposed 61 that 122 exists as an undefined mixture of interconverting conformers (3:1 ratio), based on an appearance of an additional set of signals in the NMR spectra which they stated showed chemical exchange correlation.No biological data were reported for this compound.Very recently, Gaich's group in Konstanz, Germany reported a total synthesis of both racemic and optically active canataxpropellane. 62,63Their retrosynthetic analysis envisioned generation of the cyclopentane A ring by a pinacol coupling of dialdehyde 123.This dialdehyde can be accessed from 124 by B-ring functionalization at C8 and C5 positions via singlet oxygen cycloaddition.Synthetic intermediate 124 would be generated from an intermediate which resulted from a photochemical [2+2] cyclization of 125 which would itself be constructed via Diels-Alder reaction between isobenzofuran 126 and dienophile 127.Dienophile 127 was prepared in three steps from the terpene safranal, by hydration of the distal olefin and oxidation of the -hydroxyenal 128 to give the 2,5-cyclohexadienone 129 (Scheme 21). 62Reduction with triacetoxyborohydride, and protection of the primary allylic alcohol afforded 127.Benzylic bromination of methyl 3-methoxy-2-methylbenzoate, followed by lactone formation in the presence of CaCO3 led to 130. Treatment of lactone 130 with base followed by quenching with t-butyldimethylsilyl chloride gave the isobenzofuran 126 which was not isolated but instead immediately reacted with 127 to give (±)-125 with excellent endo-selectivity.Irradiation of a degassed solution of 125 at 254 nm afforded (±)-131 along with recovered starting material.Recovered 125 could be recycled to eventually give 71% of the desired 131.While 131 contains six of the required seven rings present in the target structure along with oxygenation at C2 with the appropriate stereochemistry, cleavage of the C20-bridging oxygen bond required a sequence of 6 steps.To this end, treatment of 131 with TBAF initiated a retroaldol reaction cleaving the C14-C20 bond (Scheme 22).Stereoselective reduction of the resultant ketone 132 resulted in a trans-lactonization to give 133; the C2 alcohol was protected as a MOM ether.Reduction of 134 followed by Swern oxidation and base-mediated aldol condensation reinstalled the C14-C20 bond with appropriate stereochemistry at C20. Attention was next turned to elaboration of the methoxycyclohexadiene B ring.Singlet oxygen cycloaddition gave a single endoperoxide (136) which was immediately reduced with 2,6-di-tert-butyl-4-methylphenol (BHT) to yield hydroxyenone 137 in a good yield.Attempted reduction with other standard endoperoxide reducing agents (thiourea; H2, catalyst; L-selectride; HN=NH) resulted in considerably lower yields.Since the stereochemistry at C5 of 137 was opposite to that required for the target molecule, an oxidation/reduction sequence was used to generate the desired hydroxyenone 138, along with a minor amount of the product resulting from reduction of the C6-C7 olefin (139).The structure of 138 was secured by X-ray crystallographic analysis.
Either 138 or 139 could be converted into the benzylidene acetal 140 (Scheme 23).Vinyl triflate formation from 140 using Comin's reagent to convert the carbonyl to an enol triflate, set the stage for Pdcatalyzed carboxymethylation.Reduction of the resultant enoate 141 with Mg in methanol produced a saturated ester which underwent deprotonation and -methylation with iodomethane to afford 142.Reduction of 142 with LiAlH4 and treatment with TBAF led to diol 143.Bisaldehyde 144, generated by Swern oxidation of 143, was subjected to a pinacol coupling with TiCl4/Zn metal to yield diol 145 as a single stereoisomer, which comprises the complete carbon skeleton and oxidation level of the target, cantaxpropellane.To complete the synthesis, 145 was peracetylated, before deprotectection of the MOM ether with 2-bromo-1,3,2-benzodioxaborole gave a separable mixture of alcohol 148 and triol 147; this latter product could be recycled into additional 148 by reintroducing the benzylidene acetal.The less sterically hindered C9 acetate underwent selective methanolysis and the resulting diol was selectively acetylated at the C2 alcohol.Finally reductive removal of the benzylidene acetal gave rac-cantaxpropellane (±)-122.Notably, the NMR spectral data for synthetic 122 matched the major set of signals from the isolation work reported by Kiyota's group. 61For this reason, Graich suggested 62 that the second set of signals found in their isolation product may be due to a related derivative of 122 rather than a conformer.
Since the cycloaddition of achiral components 126 and 127 generates racemic 125, a synthesis of (-)-122 would require either an enantioselective Diels-Alder reaction, or separation of enantiomers or diastereomers at some early stage.Attempts to use Lewis or Bronsted acid catalysts for the Diels-Alder reaction led to decomposition of the cycloadduct 125.Reaction of the anion generated from lactone 130 with a TADDOL based silyl chloride 150 yielded chiral isobenzofuran 151, which upon reaction with the cyclohexadienone 127 generated a separable mixture of diastereomers (-)-152 and (-)-153 (~3:2 ratio) from which pure (-)-152 was isolated in 31% yield (Scheme 24).Photocycloaddition of 152 gave (-)-154 and treatment with TBAF gave the optically active synthetic intermediate (-)-132, which was assessed as >98% ee by chiral HPLC.The absolute configuration of (-)-132 was established by X-ray crystal structure analysis [Flack x = -0.11(7); Hooft y = -0.030(18)] as well circular dichroism.Lactol (-)-132 was processed by the same sequence of reactions as in the racemic synthesis to subsequently yield optically active (-)-canataxpropellane.

5 Scheme 5 .
Scheme 5. Installation of the oxane ring and completion of the formal synthesis.
Scheme 15.Retrosynthetic analysis of tax according to Baran's approach.

Scheme 22 .
Scheme 22. Generation of the cyclic core of cataxpropellane skeleton via cycloaddition.
Final steps of the Chida formal synthesis.