Preparation of benzannulated spiroketals by gold(III) catalyzed spirocyclization of alkynyl diols

The first gold(III)-oxazoline catalysed intramolecular tandem dihydroalkoxylations of alkynyl diols to give benzannulated 5,6-spiroketal products is reported. The results showed that Au(III)-bisoxazoline (BOX) and Au(III)-pyridine-oxazoline complexes are highly efficient catalysts for such spirocyclizations. The mono-and dibenzannulated 5,6-spiroketals were obtained in high yields (> 90 %) by rapid conversion of symmetrical and nonsymmetrical alkynyl diols, respectively. The Au(III)-BOX-BF 4 catalyst generated minor spirocyclization enantioselectivity (up to 6 % ee). The choice of solvent was important for the outcome of the reactions.


Introduction
Spiroketals are cyclic ketals in which two rings are joined via two ketal oxygens to a quaternary carbon, the spirocentre.The chiral spiroketal ring system is a structural motif found in a wide variety of densely functionalised natural products which exhibit a broad spectrum of biological activity.Examples of 5,5-, 5,6and 6,6-spiroketals include okadaic acid (1) 1,2 , cephalostatin 1 (2) 3,4 and spongistatin 1 (3) 3,5 (Scheme 1), which have all shown cytotoxic activity, as well as rutamycin which also displays antifungal behaviour. 6The presence of the particular spiroketal fragment was correlated to increased inhibition of human telomerase by the rubromycin family of natural products.The specific chemistry of chiral benzannulated spiroketals has received much attention because they are common key substructures in bioactive natural products 7 such asrubromycin (4), a 5,6-spiroketal comprised of an oxygenated naphthoquinone moiety linked with an isocoumarin fragment.The synthesis of spiroketals has received considerable attention.Most progress has been made on systems that include at least one six-membered ring.][10] However, this poses some challenges due to the reactive nature of the carbonyl group.2][13][14] This method offers specific advantages, as the alkyne acts as a masked carbonyl group, and the non-polar alkyne π-bonds being more compatible than ketones towards a number of common reaction conditions. 15old catalysis has been a rapidly emerging field within transition metal catalysis in the past decade.Gold has a high affinity towards carbon-carbon multiple bonds, especially alkynes, which may be activated towards nucleophilic attack.The combination of high functional group tolerance and usually mild reaction conditions, allow a great diversity of gold catalysed transformations, also including enantioselective reactions. 168][19][20] This transformation has been achieved by simple gold salts such as AuCl [19][20][21] and AuCl 3 12 , as well as Au(I) phosphine complexes 4,12,22 , a Au(I) NAC complex 23 and Au(I/III) NHC complexes. 24s most naturally occurring spiroketals are chiral molecules with a stereogenic spirocentre, the syntheses of chiral spiroketals has attracted attention, targeting at high yields and high diastereo-and enantioselectivities under mild conditions.It is essential to avoid epimerization of the sterogenic spirocentre, which may easily take place under mild acidic conditions.5,6-and 6,6-Spiroketals generally equilibrate toward a particular diastereoisomer under acidic conditions, due to anomeric or substituent stabilization in the sixmembered rings. 257][28][29][30][31][32] Highly enantioselective condensation reactions of unsaturated ketones to afford spiroketals (>99 % ee) have been performed with Ir(I) complexes of chiral phosphine-oxazoline ligands 29 , while catalytic enantioselective spiroketalizations by single OH attack on cyclic enol substrates 27 are reported with both BINOL-derived chiral phosphoric acids (92 % ee) 26 and chiral BINOL-based imidodiphosphoric acid (>99 % ee). 32Benzannulated spiroacetals are successfully formed by intramolecular tandem dihydroalkoxylation of alkynyl diols by binary systems of both gold(I) complexes with chiral Brønsted acids (up to 93 % ee) 30 and chiral gold(I)-phosphine complexes with chiral silver phosphate (74 % ee). 31n contrast to general broad studies based on gold(I) species, comprehensive studies of gold(III) are scarce.Thus, the limited experience of the chemistry of Au(III)-ligand species has inspired us to study the formation of new stable Au(III) complexes with a series of polydentate heterocyclic ligands.We have previously prepared and demonstrated the catalytic activity of Au(III) bisoxazoline (BOX) as well as Au(III) pyridyl/quinolinyl-oxazoline complexes in the cyclopropanation of propargyl acetates followed by cis-to-trans cyclopropyl isomerisation. 33,34Furthermore, pyridyl-oxazoline (PYR-OX) Au(III) complexes are also catalytically active in the alkoxycyclisation reaction of 1,6-enynes. 35Herein we report the first known study on spiroketalization based on Au(III)-BOX and -PYR-OX catalysed tandem dihydroalkoxylation of alkynyl diols to give benzannulated 5,6-spiroketal products.Regio-and stereoselectivity issues are included in the study.
Addition of a silver salt with a weakly coordinating anion is often necessary in gold catalysed reactions to abstract one or more gold bound chlorides, thus generating the catalytically active species. 36,37The Au(III) BOX complexes have been shown to be highly active without silver salt anion exchange, presumably due to decoordination of an oxazoline or pyridine moiety. 33However, the addition of 10 mol% AgBF 4 accelerated the reaction with complex 11a and gave increased yield, but no ee (86 %, 2h, entry 7).The formation of a black solution immediately after silver salt addition indicated decomposition of the gold catalyst and that the reaction, in this case, might be gold(0) catalysed.As gold catalysed dihydroalkoxylation of alkynyl diols with chiral phosphoric acid co-catalysts has been successful 30,38,39 , a reaction with 10 mol% S-camphorsulfonic acid was performed.The addition of acid sped up the reaction up significantly and gave excellent yield of product 14, but did not afford stereoselectivity (93 %, 1h, entry 8).

Mechanism
The mechanism of the gold catalysed intramolecular tandem dihydroalkoxylation of alkynyl diol 7 to spiroketal 14 is postulated 31 to start by π-coordination of the gold catalyst to the alkyne (7) by forming Au(III) activated alkyne A (Scheme 4).The first cyclisation may proceed via either a 6-endo-dig or a 5-exo-dig process to give endo-B and exo-B monocyclic intermediates, respectively.Two alternative pathways a) and b) may describe the final spiroketalization.Proton shift would yield the prochiral cyclic oxocarbenium Au(III) species endo-C and exo-C, which may readily undergo spirocyclization by the second nucleophilic attack of the pendant alcohol group to form gold-coordinated spiroketal D from both intermediates (Scheme 4a).Formation of the stereogenic spirocentre takes place in this step and potential enantioselective ring closure may be induced by the chiral Au(III) coordinated unit.Protodeauration yields the target spiroketal product 14.An alternative mechanism 54 (Scheme 4b) is based on the opposite order of the two steps from intermediates endo-/exo-B, which may undergo direct protodeauration to form vinyl ethers 17 and 18.Indeed, vinyl ethers 17 and 18 could be detected by NMR analysis of reaction samples and vinyl ether 18 was isolated from incomplete reaction mixtures.Protonation of the vinyl ethers leads to the oxocarbenium ions 19 and 20, which would quickly undergo nucleophilic attack and 6-/5-exo-dig spirocyclization to give spiroketal 14 with no expected enantioselectivity, due to the absence of a stereocontrolling gold moiety.In previous studies of similar Au(I)-NHC catalysed reactions, the final step is suggested to be entirely acid catalysed. 40he experimental results do not fully confirm either of the mechanistic pathways a), b). 40,45Complete conversion of the alkynyl diol 7 gave a mixture of spiroketal 14 and vinyl ether 18 (NMR) within minutes for all Au(III)-BOX catalysts 11a-e, but further conversion of vinyl ether 18 to spiroketal 14 was slow and indicates that the final cyclisation to form spiroketal 14 is the rate limiting step of these tandem reactions.No increase of reaction rate was seen by addition of more catalyst to the mixture, which could indicate that the final step might be catalysed by trace amounts of acid.Contradictory results were obtained, applying Au(III)-PYR-OX complex 13, as full tandem conversion of the original diol substrate 7 to target product 14 was seen within 30 min (Table 1, entry 13, Scheme 5b), while, in contrast, a test cyclization reaction of purified vinyl ether 18 only gave 61 % conversion to spiroketal 14 (0 % ee, Scheme 5a) and a complex mixture of new minor products.
As the final cyclisation is the enantiodetermining cyclization step, a completely racemic spiroketal product would be expected if a gold adduct is not involved (e.g. 19, 20; mechanism b).The gold catalysed test reaction of the final cyclization of vinyl ether 18 did actually afford full racemization (Scheme 5a), possibly due to de-coordination of an oxazoline or pyridine moiety, as observed and discussed in our previous catalytic studies with catalyst 13. 33 The fact that some enantioselectivity (up to 5 % ee) was observed through the complete tandem spirocyclization pathway from diol substrate 7 to target product 14, may indicate that the spirocyclization mechanism, catalyzed by Au(III)-oxazoline complexes, is more complex than previously suggested. 31,40heme 5. Spiroketalization of vinyl ether 18 and alkynyl diol 7 to form 5,6-spiroketal 14 by a) mono-and b) dihydroalkoxylation, respectively.

Experimental Section
General.Commercial grade reagents were used without any additional purification.Dry solvents were collected from an MB SPS-800 solvent purification system.Reactions were monitored by NMR and/or thinlayer chromatography (TLC) using silica gel 60 F254 (0.25 mm thickness).TLC plates were developed using UVlight and/or phosphomolybdic acid stain.Flash chromatography was performed with Merck silica gel 60 (0.040-0.063 mm). 1 H and 13 C NMR spectra were recorded with a Bruker Avance DPX 400 MHz spectrometer.Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane (TMS) as an internal standard.Accurate mass determination was performed on a "Synapt G2-S" Q-TOF instrument from Waters.Samples were ionized with an ASAP probe with no chromatography separation performed before mass analysis.Chiral HPLC was used for enantio-determination (% ee) with CHIRALPAK AD-H and OJ-H columns with i-PrOH:hexane eluents and flow rate 0.800 mL/min.

General procedure for Sonogashira cross-coupling
A dried two-neck flask was charged with (2-iodophenyl)methanol 4 (1 eq), the appropriate alkyne (1 eq), (PPh 3 ) 2 PdCl 2 (0.05 eq) and CuI (0.10 eq) under an N 2 -atmosphere.Dry, de-gassed THF was then added, followed by Et 3 N (2 eq).The solution was stirred at room temperature for 16h.The reaction mixture was filtered through celite and added EtOAc.The organic phase was washed twice with sat.NH Cl solution, followed by brine.After drying over anhydrous Na 2 SO 4 and filtration, silica gel was added to the crude product solution, followed by drying in vacuo.Purification by column chromatography (pentane:EtOAc) yielded the final products.

Table 2 .
Synthesis of 5,6-spiroketal regioisomers 15 and 16 by gold(III) catalysed dihydroalkoxylation of alkynyl diol 9 a a All reactions were performed with 0.10 mmol substrate and 5 mol% gold(III) catalyst in 5 mL solvent at room temperature.b Isolated combined yield of 15 and 16. c Determined by chiral HPLC.