An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R)‐1‐(4‐Hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol via Asymmetric Aldol Reaction

An efficient stereoselective total synthesis of (3R,5R)‐1‐(4‐hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol ( 1 ) is reported based on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight steps from commercially available trans‐cinnamaldehyde.     

Efficient Synthesis of 1,2,3,4,6‐Penta‐O‐acetyl‐L‐idopyranose

An efficient synthesis of 1,2,3,4,6‐penta‐O‐acetyl‐L ‐idopyranose 2 from 3,5‐O‐benzylidene‐1,2‐O‐isopropylidene‐α‐D ‐glucofuranose in five steps in 45% overall yield via hydroboration of enol ether, hydrolysis of L ‐idofuranosyl sugar and acetolysis of 1,6‐anhydro‐β‐L ‐idopyranose as key steps is described here.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Improved Synthesis of Phytosphingosine and Dihydrosphingosine from 3,4,6‐Tri‐O‐benzyl‐D‐galactal

An efficient and facile synthesis of phytosphingosine and dihydrosphingosine derivatives is described with less steps and in improved overall yield (66–72%) starting from commercially available tri‐O‐benzyl‐D ‐galactal. The key steps include Wittig reaction, Mitsunobu transformation, reduction, and deprotection.     

(-)-（3S, 6R）-3, 6-羟基-10-甲基十一酸及其三聚体的全合成

以廉价易得的异戊基溴为起始原料,以烯丙基二异松莰烷基硼烷参与的不对称烯丙基化反应和Yamaguchi酯化反应为关键步骤,实现了对(-)-(3S,6R)-3,6-二羟基-10-甲基十一酸(总收率27.5％)及其三聚体(总收率24.5％)的不对称全合成。     

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).     

Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol

The first total synthesis of the natural product (?)‐(19R)‐ibogamin‐19‐ol ((?)‐ 1 ) is reported (biogenetic atom numbering). Starting with L ‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (?)‐ 1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).     

Total Synthesis of (−)‐Morphine

We have developed an efficient total synthesis of (?)‐morphine in 5 % overall yield with the longest linear sequence consisting of 17 steps from 2‐cyclohexen‐1‐one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki–Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6‐addition. Furthermore, mild deprotection conditions to remove the 2,4‐dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N‐methyl‐DNs‐amide moiety.     

Photochemistry of Tricyclo[5.2.2.02,6]undeca‐4,10‐dien‐8‐ones: An Efficient General Route to Substituted Linear Triquinanes from 2‐Methoxyphenols. Total Synthesis of (±)‐Δ9(12)‐Capnellene

An efficient and short entry to polyfunctionalized linear triquinanes from 2‐methoxyphenols is described by utilizing the following chemistry. The Diels–Alder reactions of masked o‐benzoquinones, derived from 2‐methoxyphenols, with cyclopentadiene afford tricyclo[5.2.2.0^2,6]undeca‐4,10‐dien‐8‐ones. Photochemical oxa‐di‐π‐methane (ODPM) rearrangements and 1,3‐acyl shifts of the Diels–Alder adducts are investigated. The ODPM‐rearranged products are further converted to linear triquinanes by using an O‐stannyl ketyl fragmentation. Application of this efficient strategy to the total synthesis of (±)‐Δ⁹⁽¹²⁾‐capnellene was accomplished from 2‐methoxy‐4‐methylphenol in nine steps with 20 % overall yield.     

Total Synthesis of (2Z)‐[(4R,5R,6S)‐6‐(β‐D‐Glucopyranosyloxy)‐4,5‐dihydroxycyclohex‐2‐en‐1‐ylidene]ethanenitrile,a Cyanoglucoside from Ilex warburgii

The total synthesis of the noncyanogenic cyanoglucoside 1 , originally isolated from Ilex warburgii, was achieved in nine steps (9% overall yield), starting from an optically pure Diels–Alder adduct ((+)‐ 3 ). The key step of the synthesis, the glycosidation, was carried out under Koenigs–Knorr conditions closely related to those developed for the total syntheses of (?)‐lithospermoside and (?)‐bauhinin. We had to tune the protecting groups used for the two free cis‐configured OH groups of the aglycone, which afforded the desired β‐d‐ glucoside intermediate 15 in very good yield (62%).     

Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin

A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps).     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

An Alternative Synthesis of the Dopaminergic Drug 2‐Amino‐1,2,3,4‐tetrahydronaphthalene‐5,6‐diol (5,6‐ADTN)

Racemic 2‐amino‐1,2,3,4‐tetrahydronaphthalene‐5,6‐diol (5,6‐ADTN; 4 ) was synthesized from 5,6‐dimethoxynaphthalene‐2‐carboxylic acid ( 14 ) in four steps (60% overall yield; Scheme). The crucial steps of the synthesis are Birch reduction of 14 to the valuable synthon 15 , Curtius reaction and carbamate formation ( 16 ), hydrogenolysis ( 17 ), and demethylation to the biologically active hydrobromide salt 18 of 4 .     

Enantiospecific Synthesis of (R)‐3‐Amino‐4‐(2,4,5‐trifluorophenyl)butanoic Acid Using (S)‐Serine as a Chiral Pool

Starting from (S)‐serine, a new method was developed for the synthesis of the β‐amino acid part of sitagliptin in ten steps and with an overall yield of 30%. The crucial step of the synthesis was the ring opening of N‐ and O‐protected (R)‐aziridin‐2‐methanol with (2,4,5‐trifluorophenyl)magnesium bromide to give N‐ and O‐protected (R)‐2‐amino‐3‐(2,4,5‐trifluorophenyl)propan‐1‐ol.     

1H‐Azepine‐4‐amino‐4‐carboxylic Acid: A New α,α‐Disubstituted Ornithine Analogue Capable of Inducing Helix Conformations in Short Ala‐Aib Pentapeptides

A very efficient synthesis of orthogonally protected 1H‐azepine‐4‐amino‐4‐carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1‐amino‐4‐oxo‐cyclohexane‐4‐carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5‐mer peptides showed that the (R)‐Azn isomer possesses a marked helicogenic effect.     

Synthesis of (±)‐Trinervitadiene‐2,3‐diol

The first synthesis of trinervita‐1(15),8(19)‐dien‐2β,3α‐diol ( 2a ) and its 2α‐isomer 2b , which have been isolated from termite soldiers, where they are used as defense chemicals, is documented starting from geranylgeranioic acid in 33 steps. The route for construction of the key intermediate of the trinervitane skeleton 8 has been developed previously (Scheme 1). Noteworthy features include the efficient construction of the trinervitane framework from the corresponding bicyclic 7(16)‐secotrinervitane skeleton and Me₃SiCl (TMSCl)‐induced ring‐opening of tetrasubstituted epoxide to give the corresponding allyl alcohols (Scheme 7). The synthetic route developed in the present study seems applicable to the syntheses of other trinervitane‐type natural products.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

An Efficient Synthesis of 5,6‐Dimethoxy 1‐ and 2‐Naphthols via Teuber Reaction

Based on the oxidation of 1,5‐naphthalenediol ( 4 ) and 6‐bromo‐2‐naphthol ( 9 ) via Teuber reaction, an efficient synthesis of 5,6‐dimethoxy‐1‐naphthol ( 1 ) and 5,6‐dimethoxy‐2‐naphthol ( 2 ) was achieved with high overall yield (16% for 1 and 25% for 2 ). The key steps of the synthetic strategy involved the oxidation of naphthols ( 4 and 9 ) to the corresponding naphthoquinones ( 5 and 10 ) and the conversion of 5,6‐dimethoxy‐2‐naphthaldehyde to 5,6‐dimethoxy‐2‐naphthol formate through Baeyer‐Villiger oxidation‐rearrangement.     

Asymmetric Syntheses of 2‐(1‐Aminoethyl)phenols

Three different routes were probed for the synthesis of enantiomerically enriched 2‐(1‐aminoethyl)phenols and their methyl ethers. The first route centers on diastereoselective nucleophile addition to chiral imines. The second route has as key steps the enantioselective reduction of a ketone followed by nucleophilic substitution, and the third route involves a diastereoselective imine reduction. The efficiency of the approach depends on the substrate substitution pattern. All three methods work well for the parent compound 2‐(1‐aminoethyl)phenol ( 1 ) but the third route is the most efficient, providing the compound with >96% enantiomer excess in three steps with an overall yield of 71%. Conversely, for the ortho‐methyl analogue 2 , the first method is best. For the t‐Bu‐substituted analogue 3 , only moderate enantiomeric enrichment was achieved.     

不对称合成(+)-(11R, 12S)-盐酸甲氟喹

疟疾药物、(+)-(11R, 12S)-盐酸甲氟喹的不对称合成,由购买得到的2－三氟甲基苯胺、三氟乙酰乙酸乙酯,环戊酮为起始原料经过7步反应以14％的收率得到。关键步骤为脯氨酸催化的不对称aldol反应和贝克曼重排,绝对构型由Mosher的方法确定。