Four-directional synthesis of adamantane derivatives

1-Adamantanemethanol, 1,3-adamantanedimethanol and 1,3,5,7-adamantanetetramethanol were converted into adamantanes functionalized with one or four (2 R ,1 S )-2-formyl-1-cyclopropyl residues using Charette enantioselective cyclopropanation reactions and with one, two or four 4-ethoxy-(or 4-t -butoxy)-3-diazo-2,4-dioxobutyl residues from aldehyde and diazo-acetate ester condensation reactions by 1-directional, 2-directional or 4-directional syntheses. The synthesis of adamantane fused to cyclopentadiene is also reported


Introduction
Fuchs introduced the concept of the Intricacy Quotient (IQ) as a measure of the efficiency of natural product total synthesis. 1One of the natural product examples highlighted in this study, was the total synthesis of the CETP inhibitor U-106305 (5) independently by Barrett and Charette. 2,3This synthesis was scored at an IQ of 1.83 by Fuchs and the reason for this high value was due to the use of an iterative two-directional synthesis with late stage desymmetrization (Scheme 1) which, for example in the conversion of tercyclopropane 3 into quinquecyclopropane 4 generated two rings and controlled four stereocenters in an absolute sense.There is an added benefit with two-directional introduction of stereocenters by enantioselective synthesis and that is Horeau amplification of enantioselectivities. 4 It is clear, based on the Fuchs' analysis, that a total synthesis that depends on a four-directional synthesis is likely to score highly on the Fuchs IQ scale.Four-directional transformations of adamantanes bearing identical tertiary substituents at C1, C3, C5 and C7 are well precedented.In a general sense, reaction of the adamantane derivative 6 with various reagents have been used to synthesize other adamantanes 7 bearing four identical substituents Y thereby conserving the symmetry.Most of these known transformations involve the construction of four carbon−heteroatom bonds or the quadruple derivatization of adamantanes functionalized by four identical tertiary aromatic rings.These are illustrated in Table 1 and the paragraph thereafter.

Results and Discussion
Four-directional homologation of 1,3,5,7-adamantanetetracarboxylic acid derivatives Tetramethyl 1,3,5,7-adamantanetetracarboxylate (18) was synthesized from 1,3-adamantanedicarboxylic acid (16) by a modification of Bashir-Hashemi and Li's method. 30Since dicarboxylic acid 16 is of low solubility in oxalyl chloride, the dicarboxylic acid 16 was first converted into the more soluble dichloride 17 31 with thionyl chloride.This was dissolved in oxalyl chloride and irradiated at 20 o C using a medium pressure mercury-vapor lamp (450 Watts) in a quartz vessel to provide, on methanolysis, the tetra-ester 18 in variable yield (25% on a 10 g scale to 43% on a 2 g scale) depending on the efficiency of irradiation decreasing with scale.Reduction of © AUTHOR(S) tetra-ester 18 using lithium aluminum hydride gave the corresponding tetraol 13 (91%).Attempted oxidation of the tetraol 13 to the corresponding tetra-aldehyde 19 was complicated due to its poor solubility in nonpolar solvents.Nonetheless it was soluble in solvents such as MeOH, THF or DMSO.Dess-Martin oxidation of tetraol 13 (50 mg scale) in a mixed-solvent system (dichloromethane/DMSO, 2:1), which was necessary to dissolve the substrate, gave tetra-aldehyde 19 (45%, 40 mg scale) but this yield was not reproductible on a larger scale (32%, 80 mg scale).Swern oxidation of tetraol 13 in the same mixed-solvent system (dichloromethane/DMSO) 17 gave tetra-aldehyde 19 in a significantly better yield (70%, 1 g scale).
(Z)-Selective Horner-Emmons reaction of tetra-aldehyde 19 under Still-Gennari conditions 32 at −78 o C provided an inseparable mixture of the desired product 20 and the incomplete olefination products, however reaction at −20 o C gave the tetra-alkene 20 as the sole product in 64% yield.From 1 H NMR spectroscopy, the coupling constant between two olefinic protons was J 13.1 Hz, which is consistent with all four alkenes possessing the cis geometry. 33Finally, DIBAl-H reduction of tetra-ester 20 gave the tetra-(Z)-allylic alcohol 21 in excellent yield (98%) (Scheme 5).The cis-geometry and constitution were unambiguously confirmed by a single crystal X-ray structure determination (see Supplementary Material: Appendix-1).Scheme 5. Synthesis of tetraol 21 using photochemical substitution and (Z)-selective Horner-Emmons reaction.
The tetra-(Z)-allylic alcohol 21 was of low solubility and this caused significant problems in attempted tetra-cyclopropanation reactions.Prolonged reactions using samarium amalgam or samarium(II) iodide with diiodomethane or chloroiodomethane 34 failed to provide any identifiable cyclopropanated products.Additionally, the tetra-(Z)-allylic alcohol 21 was recovered unchanged on attempted tetra-cyclopropanation using the Charette's procedure. 35Although, in this reaction, the tetra-(Z)-allylic alcohol 21 has very low solubility in the solvent CH2Cl2, it was anticipated that the intermediate zinc-alkoxide species formed from Zn(CH2I)2 and tetraol 21 would result in desymmetrization and enhanced solubility.This proved incorrect and the Charette reaction gave only unreacted starting material.Attempted transient desymmetrization of tetra- Since direct cyclopropanation of tetra-cis-alkene 21 had failed to produce any desired tetra-cyclopropane, the corresponding reactions with allylic alcohol 25 were examined to underscore that the failure in the tetracyclopropanation reaction was solely due to poor solubility.Thus, Swern oxidation of commercially available 1-adamantanemethanol (22) gave rise to aldehyde 23 (82%).This product 23 was subject to the (Z)-selective Horner-Emmons olefination of aldehyde 23 under Still-Gennari conditions, 32 which provided the desired cis-olefin 24 in low but unoptimized yield (30%), owing to the low solubility of 23 in THF.DIBAl-H reduction of ester 24 gave allylic alcohol 25 (90% ), which smoothly underwent Charette cyclopropanation to produce the cyclopropyl alcohol 27 (87%).Oxidation of alcohol 27 by Dess-Martin periodinane gave the corresponding aldehyde 28 (Scheme 6).These results clearly indicated that the failure in our attempted tetracyclopropanation of tetra-cis-alkene 21 under Charette conditions was only the result of low solubility.In order to overcome the reactivity issues with the four-directional approach, desymmetrization and a three-directional strategy was examined.Mono-protection of tetraol 21 with t-butyldiphenylsilyl chloride in pyridine at room temperature gave the mono-silyl derivative 29 (44%, 66% allowing for 33% recovered starting material).To our delight, triol 29 was soluble in dichloromethane and smoothly underwent triple Charette 35 cyclopropanation to produce tricyclopropane 30 (90%) and this was desilylated using tetra-nbutylammonium fluoride in THF to give the tetraol 31 (94%) (Scheme 7).Unfortunately, this tetraol 31 being insoluble in dichloromethane was inert to the Charette reagent.This solubility problem associated with tetraol 31 was circumvented by triple pivaloylation.Thus, acylation of triol 30 with pivaloyl chloride in pyridine gave the triester 32 (95%), which was desilylated to give the allylic alcohol 33 (95%).Charette cyclopropanation of the dichloromethane soluble allylic alcohol 33 gave the tetra-cyclopropane 34 (63%).Finally, the key intermediate tetra-syn-cyclopropyl alcohol 35 (90%) was obtained by DIBAl-H reductive deacylation of the tri-pivaloate 34 (Scheme 8).The constitution of the tetrasyn-cyclopropyl alcohol 35 was confirmed by a single crystal X-ray structure determination (see Supplementary Material: Appendix-2).We were unable to define the absolute stereochemistry due to the lack of heavy atoms in the molecule.Perhaps unsurprisingly, the structure is disordered and actually shows an inversion of chirality in one of the four cyclopropyl arms.The figures in Appendix-2 show both diastereoisomers individually and overlapped, with the major diastereoisomer 35A being ca.64% occupancy, and the minor diastereoisomer 35B ca.36% occupancy and with each diastereoisomer possessing greater than 95% optical purity.Presumably, the final cyclopropanation reaction showed significantly lower diastereoselectivity than expected with the Charette chiral boronate 26 additive and/or recrystallization enhanced the percentage of the minor diastereoisomer.The 13  Swern oxidation of tetraol 35 was carried out in DMSO and dichloromethane solution due to poor solubility in dichloromethane alone.This gave the tetra-aldehyde 14 and subsequent condensation with ptoluenesulfonylhydrazine gave the derived tetra-tosylhydrazone 36 (82%) (Scheme 9).Attempts to generate tetra-carbene C−H insertion or fragmentation products from the tetra-tosylhydrazone 36 by conversion to the derived tetra-potassium salt, generated with either potassium tert-butoxide or potassium hexamethyldisilazide, and aprotic Bamford Stevens thermolysis at 138 C or reaction with dirhodium tetraacetate in the presence of the phase transfer catalysts benzyltriethylammonium chloride or 18-crown-6 36 in dioxane or dichloromethane gave only intractable materials.Evidence for the formation of potassium salt from tetra-tosylhydrazone 36 was seen in the IR spectum with shifts of the sulfone stretches from 1332 and 1162 cm -1 to 1228 and 1126 cm -1 on reaction with the two bases.Four-directional homologation of 1,3,5,7-adamantanetetraacetic acid derivatives In the light of the difficulties with the four-directional reactions to synthesize the adamantane derivatives 35 and 14, studies on four-directional rhodium catalyzed C−H insertion reactions of adamantanes functionalized with four tertiary -diazo--keto-ester units were carried out.Three model adamantane systems with one diazo--keto-ester unit and two -diazo--keto-ester units were also synthesized.The known aldehyde 38 was synthesized from the commercially available alcohol 37 by Swern oxidation. 37Interestingly, upon standing overnight at room temperature, the aldehyde 38 underwent hydration to give the corresponding geminal diol very easily.Therefore aldehyde 38 was used in the next step immediately following its purification.Treatment of freshly prepared aldehyde 38 with ethyl diazoacetate in the presence of a catalytic amount of tin(II) chloride 38 smoothly gave -keto-ester 39a as a 4:1 mixture of enol and keto tautomers.Finally, diazo transfer reaction of β-keto ester 39a with 4-acetamidobenzenesulfonyl azide (40) 39 gave the -diazo--keto-ester 41a (99%).The aldehyde 38 was converted by the same method via -keto-ester 39b (61%) into the -diazo-keto-ester 41b (90%) (Scheme 10).
Dirhodium tetraacetate catalyzed carbene insertion of -diazo--keto-esters 41a and 41b proceeded smoothly at room temperature to generate the cyclized products 47a (90%) and 47b (91%) both as single undetermined racemic stereoisomers.Respective Krapcho deethoxycarbonylation 41 and TFA catalyzed t-butyl ester cleavage and decarboxylation in chlorobenzene at 120 C gave the same fused cyclopentanone 49 42  Double dirhodium tetraacetate catalyzed carbene insertion of di--diazo--keto-ester 46 gave the doubly cyclized product 50 (52%) along with minor unidentified by-products.Subsequent de-t-butylation and decarboxylation catalyzed by TFA in chlorobenzene at 115 o C proceeded smoothly and gave the di-cyclopentanone 51 (97%) as an unidentified racemic stereoisomer (Scheme 13).It should be noted that there are many possible stereo-and regio-isomers arising from the double carbene insertion reaction of di-diazo--keto-ester 46.For example, the final diketone 51 could either have the syn-51 and/or the anti-51 constitution and each of these could have the meso-and/or ()-stereochemistry (Figure 1).Wittig reaction 17 of tetra-aldehyde 19 with excess of methoxymethyl-triphenylphosphonium chloride and sodium hexamethyldisilazane gave tetra-enol ether 52 (79%) as a mixture of (E)-and (Z)-olefins.Hydrolysis using triflic acid in aqueous dichloromethane and iso-propanol gave the tetra-aldehyde 53 (60%).The yield of tetra-aldehyde 53 was inferior if the intermediate enol ether 52 was not isolated due to greater difficulty in purification.Pinnick oxidation 43 of tetra-aldehyde 53 smoothly gave the desired tetra-acid 54a (83%), which was converted via the tetra-acyl chloride (IR 1802 cm -1 ) into the tetramethyl ester 54b (42%).Attempts to convert the tetra-acid 54a via its derived tetra-acyl chloride or via its tetra-mixed anhydride with ethyl chloroformate to the derived tetra-diazo-ketone by reaction with diazomethane gave only intractable mixtures of products.In contrast tetra-aldehyde 53 was smoothly converted into the tetra--keto-ester 15a (82%), which was obtained as a mixture of enol and keto-tautomers (ca 3 : 1), by reaction with ethyl diazoacetate in the presence of tin(II) chloride 38 and subsequently into the tetra--diazo--keto-ester 55a (97%) by diazo transfer from 4-acetamidobenzenesulfonyl azide (40). 39In the same way, the tetra-aldehyde 53 was readily converted into the tetra--keto-ester 15b (81%), which was obtained as a mixture of enol and keto-tautomers (ca 4 : 1), and thence into the tetra--diazo--keto-ester 55b (99%) (Scheme 14).A range of catalysts were examined for the attempted quadruple C−H insertion reaction of tetra-diazo--keto-ester 55a.Reactions using dirhodium tetraacetate in dilute solution (0.01 M) in dichloromethane at room temperature, copper sulfate or copper iodide in toluene at room temperature or reflux all were unsuccessful.In contrast, catalysis using dirhodium tetra-carboxylate (acetate, trifluoroacetate, perfluorobutyrate, octanoate) salts at reflux in toluene or trifluoromethylbenzene gave an isolable fraction by chromatography that may have contained carbene insertion products.For example, catalysis with dirhodium tetra-octanoate in toluene at reflux with slow addition of the tetra--diazo--keto-ester 55a gave a complex product mixture that may have contained the tetra--keto-ester 56a.The 1 H and 13 C NMR spectra of the product was complex presumably due to the presence of multiple isomers and the molecular ion could not be detected in the mass spectrum, although the IR spectrum was consistent with the presence of ester and ketocarbonyl groups (keto-ester 47a at 1755 and 1724 cm -1 and tetra--keto-ester 56a at 1753 and 1725 cm -1 ).Attempted Krapcho deethoxycarbonylation 41 of the product mixture failed to produce identifiable products.

© AUTHOR(S)
Reaction of the tetra--diazo--keto-ester 55b with dirhodium tetra-octanoate in toluene (0.01M) at reflux with slow addition of the substrate gave a complex product mixture that may have contained the tetra--keto-ester 56b.Again, this structural assignment was tentative since the 1 H and 13 C NMR spectra of the product was complex presumably due to the presence of multiple isomers and the molecular ion could not be detected in the mass spectrum, although the IR spectrum was consistent with the presence of an ester and keto-carbonyl groups (1747 and 1722 cm -1 ) (Scheme 15).Attempted global de-t-butylation and decarboxylation catalyzed by TFA using the one step or two step methods in Scheme 12, failed to provide any isolable material although the t-butyl esters were cleaved.

Synthesis of and Dimerization of Adamantanocyclopentadiene 59
Ketone 49 was synthesized by the methods in Scheme 12 and additionally by sequential reaction of 1adamantaneacetic acid with thionyl chloride, diazomethane in diethyl ether and copper sulfate in toluene at reflux. 42Conversion to the cyclopentenone 57 was carried out in modest yield (23% with 32% recovery of starting material) by enol silane formation with lithium 2,2,6,6-tetramethylpiperidide (LiTMP), trimethylsilyl chloride and triethylamine and Saegusa oxidation with palladium acetate.DIBAl-H reduction of the cyclopentenone 57 at −78 o C gave the allylic alcohol 58 (90%) and this delicate compound underwent complete dehydration, presumably DCl catalyzed, in deuterated chloroform over 2 hours during the recording of NMR spectra to produce diene 59 (82% isolated yield) (Scheme 16).Diene 59 underwent a Diels-Alder reaction with maleic anhydride (60) to produce the adduct 61 (23% unoptimized).Whilst diene 59 did not undergo dimerization by a self-Diels-Alder reaction on standing for 23 days, it did undergo an alternative dimerization reaction in the presence of tris(p-bromophenyl)aminium hexachloroantimonate (62), a known SET acceptor for mediating Diels-Alder reactions via diene cation radicals. 44Of particular interest in this context is the known Diels-Alder rapid dimerization of 1,3cyclohexadiene mediated by an SET pathway with aminium cation radical modulators, although 1,3cyclohexadiene in known not to be normally reactive towards such self-Diels-Alder reactions below 200 C.Attempted SET-Diels-Alder reaction of diene 59 gave an adduct that was assigned as dimer 63 (40%).Clearly a product this unexpected requires some further discussion with regard to its assignment.
The proposed structure 63 was elucidated based on the following key facts and explanations: (1) the dimer 63 has the molecular formula of C26H32 as confirmed by MS and high resolution MS; (2) there are three vinyl protons ( 6.30, 5.93, 5.21 ppm) in the 1 H NMR spectrum; (3) there are three quaternary olefinic carbons ( 162.2, 157.9 and 153.0 ppm) and three tertiary olefinic carbons ( 123.9, 117.4,114.6 ppm) in 13 C NMR and 13 C DEPT spectra (see Supplementary Material: Appendix-3); (4) there are two adjacent vinyl protons ( 6.30 and 5.93 ppm), which are correlated to each other have the coupling constant of 1.9 Hz in the 1 H NMR and 1 H COSY spectra and this coupling constant is consistent with bonding B and not bonding A below (Figure 2); (5)  there are three relatively low-field proton signals ( 3.74 ppm, 2.98 ppm and 2.75 ppm) and these protons must be positioned next to a carbon-carbon double bond (HD, HE and HF in the structure 63 in Scheme 16); (6)  there is one proton ( 3.72 ppm) next to a carbon-carbon double bond has the correlation with one vinyl proton and two protons in a CH2 unit from the 1 H COSY and 1 H/ 13 C correlation spectra (see Appendix-3) (HE in the structure 63 in Scheme 16); (7) the max in the UV spectrum is at 262 nm (log ) 262 (3.76) is inconsistent with the alkene and cyclopentadiene units being in conjugation since 1,4,5,5-tetramethylcyclopentadiene shows a max of 258 nm 45 and if the third double bond was conjugated with the cyclopentadiene unit, the absorption maximum should be significantly red shifted.In spite of these considerations, the structural assignment for the dimer 63 must, in the absence of an X-ray crystallographic structure determination, be considered tentative.

Bonding A Bonding B
big coupling costant small coupling constant

Experimental Section
General.Melting points were obtained on a hot stage melting point apparatus and are uncorrected.Infrared spectra were recorded as thin films on sodium chloride plates with absorptions reported in wavenumbers (cm - 1 ). 1 H NMR spectra were recorded at 300 MHz, 400 MHz and 500 MHz with chemical shifts () quoted in parts per million (ppm) and referenced to the residual solvent peak, 7.27 for CDCl3, 7.15 for C6D6, 3.34 for methanol-d4, 2.52 for DMSO-d6. 13C NMR spectra were recorded at 75 MHz, 100 MHz and 125 MHz with chemical shifts () quoted in parts per million (ppm) and referenced to the residual solvent peak, 77.0 for CDCl3, 128.6 for C6D6, 49.9 for methanol-d4, 39.7 for DMSO-d6.Coupling constants (J) are quoted in Hertz (Hz) for both 1 H and 13 C NMR spectra.All reactions were carried out in oven or flame-dried glassware under an inert atmosphere of nitrogen or argon.Reaction temperatures other than room temperature were recorded as bath temperatures unless otherwise stated.CH2Cl2, MeOH, pyridine and Et3N were distilled from calcium hydride under a nitrogen atmosphere.Et2O and THF were distilled from sodium benzophenone ketyl under a nitrogen atmosphere.PhMe was distilled from sodium under a nitrogen atmosphere.Column chromatography was performed on silica gel 60, particle size 20-63 m or particle size 33-70 m.TLC was performed on silica gel 60 F254 glassbacked plates with visualization under ultraviolet light 254 nm and/or by chemical staining using a potassium permanganate dip and drying with a heat gun.
Tetramethyl 1,3,5,7-Adamantanetetracarboxylate (18).1,3-Adamantanedicarboxylic acid 16 (10.0g, 44.6 mmol) and freshly distilled thionyl chloride (60 mL) were heated at reflux with vigorous stirring for 2 h and the excess thionyl chloride was removed in vacuo.The mixture was cooled to room temperature and dry PhH (50 mL) was added which was further removed in vacuo to give an off-white solid, which was stored under vacuum for 12 h to leave crude 1,3-adamantanedicarbonyl chloride 17 (11.7 g) as an off-white solid.This material showed spectroscopic data consistent with the reported values. 31

Scheme 1 .
Scheme 1. Barrett and Charette two directional homologation in the total synthesis of U-106305(5).

Table 2 .
Four-directional synthesis by carbon−carbon construction or change at sp 3 centers -allylic alcohol 21 by alkoxide exchange using trimethyl borate and subsequent Charette reaction also gave unreacted tetraol 21.

Figure 2 .tetra-ester 20 ,
Figure 2. Vinyl coupling constants in the 1 H NMR relevant to the constitution of dimer 63.