A-ring Synthon Research Articles

Novel approach to A-ring synthon for Pd-catalyzed synthesis of 1α-hydroxylated vitamin D metabolites

A novel approach to an A-ring synthon for Pd-catalyzed synthesis of 1α-hydroxylated vitamin D metabolites is described. Key step is an asymmetric glyoxylate ene reaction to access a highly diastereomerically pure α-hydroxy ester. Subsequent stereospecific transformation to an anti-1,3-diol and appropriate chemical modifications at both ends of the acyclic precursor leads to a diastereomerically and enantiomerically pure silylated anti-1,3-diol enyne, serving as a versatile A-ring synthon for its use in vitamin D synthesis.

Large-Scale Synthesis of Eldecalcitol

Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman’s ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.

Synthesis of Diastereomers of 1,3-cis-25-Dihydroxy-19-norvitamin D3.

1β,3β,25-Dihydroxy-19-norvitamin D3 (4a) and 1α,3α,25-dihydroxy-19-norvitamin D3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3-((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia-Kocienski olefination to construct the diene unit. The structures of the products were confirmed by (1)H-NMR and nuclear Overhauser effect (NOE) experiments.

A route to the 9,10-secosteroid astrogorgiadiol featuring a key sp2–sp3 Suzuki type cross-coupling

The described semi-synthetic route differs from the previously published approaches by an original C-7–C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challenging sp2–sp3 cross-coupling. A range of A-ring synthons was synthesized to allow the investigations of various conditions of metal-catalyzed couplings. Suzuki-type chemistry provided a useful (89% yield) answer. Whereas the last step of the designed route—a regioselective opening of the epoxide obtained from the alkene, product of the coupling reaction—proved more challenging than expected, a hydroboration endgame route completed a formal synthesis of (−)-astrogorgiadiol.

Synthesis of (−)-astrogorgiadiol

Astrogorgiadiol is a naturally occurring Vitamin D analogue that, in cell culture, downregulates the production of the cytokine osteopontin (OPN). OPN has been implicated in virulent asthma, and OPN knockout mice do not develop osteoporosis. As we have pursued whole animal studies with astrogorgiadiol, we have increased the scale of the synthesis. We report an improved preparation of the A-ring synthon and the scale-up of the diasteromerically pure D-ring/sidechain chiron.

ChemInform Abstract: A New Efficient Synthesis of Taxol A-Ring Synthon via Two Aldol Condensations.

Abstract An efficient stereocontrolled synthesis of a taxol A-ring synthon using two aldol reactions as key steps is presented.

Synthesis and biological evaluation of new 6- s- cis locked 1,2,25-trihydroxyprevitamin D 3 analogues

An efficient synthesis of several diastereomers of 2-hydroxy substituted 1α,25-dihydroxyprevitamin D 3 derivatives was accomplished utilizing a practical route to the A-ring synthon. The biological activity of the analogues was evaluated in vitro. All the synthesized derivatives demonstrated low affinity for the vitamin D receptor and vitamin D-binding protein compared with 1α,25-dihydroxyvitamin D 3, the natural hormone. 1α,2β,25-trihydroxy-19- nor-pre-D 3 was the most potent of the analogues in inhibiting proliferation of MCF-7 cells but requires higher EC 50 concentrations than 1α,25-dihydroxyvitamin D 3.

2,2-Functionalized analogues of 1α,25-dihydroxyvitamin D 3, the potent inducers of cell differentiation

All four possible A-ring stereoisomers of 2,2-dimethyl-1,25-dihydroxyvitamin D 3 ( 4) were designed and convergently synthesized. Nine-step conversion of methyl hydroxypivalate 6 provided the desired A-ring enyne synthon ( 13a,b) in good overall yield. Cross-coupling reaction of the A-ring synthon 13a,b with the CD-ring portion in the presence of palladium catalyst, followed by deprotection, gave the vitamin analogues ( 4a–d). We also synthesized four stereoisomers of 2,2-ethano-1,25-dihydroxyvitamin D 3 ( 5), as novel spiro-ring analogues having cyclopropane fused at the C2 position. Biological potencies of the synthesized compounds were assessed in terms of the vitamin D receptor (VDR) binding affinity, as well as the HL-60 cell differentiation-inducing activity. The 2,2-ethano analogue 5a showed a comparable activity to the natural hormone 1, while the 2,2-dimethyl analogue 4a exhibited one-third of the activity of 1 in cell differentiation, with the reduced VDR binding affinity.

A concise enantioselective synthesis of a key A-ring synthon for 1 alpha-hydroxyvitamin D3 compounds.

[figure: see text] This report describes a concise enantioselective synthesis of the A-ring synthon for the synthesis of 1 alpha-hydroxyvitamin D3 compounds. The synthesis involves two notable transformations: (I) stereoselective construction of the enol triflate from the vinyl ketone by Michael addition of Ph2P(O)Li followed by in situ triflation of the resulting enolate and (II) palladium-catalyzed Heck type cyclization of the enol triflate.

Construction of the A-ring of cylindrospermopsin via an intramolecular oxazinone- N-oxide dipolar cycloaddition

The efficient synthesis of an A-ring synthon for the marine hepatatoxin cylindrospermopsin has been achieved. The key step features an intramolecular oxazinone N-oxide/alkene dipolar cycloaddition resulting in the establishment of the three contiguous stereogenic centers in the A-ring from one pre-existing stereogenic center in a single step.

Synthesis of two 6- s- cis locked stereoisomeric analogues of the steroid hormone 1α,25-dihydroxyvitamin D 3: 1α,25-dihydroxy-19- nor-previtamin D 3 and 1β,25-dihydroxy-19- nor-previtamin D 3

An efficient synthesis of A-ring precursors 8 and 9 from inexpensive commercially available (−)-quinic acid has been developed. A-Ring synthon 8 has been obtained through a short sequence (eight steps) in high overall yield (30%). One key step in the synthesis of A-ring precursor 9 is the selective deprotection of a silyl ether in an α,β-unsaturated ester 12. However, of note is the excellent yield of the Mitsunobu process on derivative 15, which takes place with the total inversion of configuration, giving ester 16. Coupling of A-ring synthons 8 and 9 with the appropriate CD-rings/side chain fragment 7, provides access to 6- s- cis locked analogues of the steroid hormone 1α,25-(OH) 2-D 3: 1α,25-(OH) 2-19- nor-pre-D 3 ( 3) and novel 1β,25-(OH) 2-19- nor-pre-D 3 ( 4).

Efficient synthesis and biological evaluation of all a-ring diastereomers of 1α,25-dihydroxyvitamin D3 and its 20-epimer

An improved synthesis of the diastereomers of 1α,25-dihydroxyvitamin D3 (1) was accomplished utilizing our practical route to the A-ring synthon. We applied this procedure to synthesize for the first time all possible A-ring diastereomers of 20-epi-1α,25-dihydroxyvitamin D3 (2). Ten-step conversion of 1-(4-methoxyphenoxy)but-3-ene (6), including enantiomeric introduction of the C-3 hydroxyl group to the olefin by the Sharpless asymmetric dihydroxylation, provided all four possible stereoisomers of A-ring enynes (3), i.e., (3R,5R)-, (3R,5S)-, (3S,5R)- and (3S,5S)-bis[(tert-butyldimethylsilyl)oxy]oct-1-en-7-yne, in good overall yield. Palladium-catalyzed cross-coupling of the A-ring synthon with the 20-epi CD-ring portion (5), (E)-(20S)-de-A,B-8-(bromomethylene)cholestan-25-ol, followed by deprotection, afforded the requisite diastereomers of 20-epi-1α,25-dihydroxyvitamin D3 (2). The biological profiles of the synthesized stereoisomers were assessed in terms of affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), HL-60 cell differentiation-inducing activity and in vivo calcium-regulating potency in comparison with the natural hormone.

Synthesis and pharmacokinetics of 1 alpha-hydroxyvitamin D3 tritiated at 22 and 23 positions showing high specific radioactivity.

A novel synthesis of a radioactive compound of 1 alpha-hydroxyvitamin D3 (1 alpha OHD3) (1) and its pharmacokinetics are described. Radioactive 1 alpha OHD3 tritiated at 22 and 23 positions ([22,23-(3)H4]1 alpha OHD3) (5) was prepared via key reactions of the reduction of acetylenic side chain in the ketone (12) with tritium gas in the presence of palladium-charcoal and the subsequent Wittig reaction with the A-ring synthon (16). [22,23-(3)H4]1 alpha OHD3 (5) showed high specific radioactivity (111.5 Ci/mmol) and was used successfully in pharmacokinetics studies with rats. In the pharmacokinetics studies, the plasma concentration level of the active form of vitamin D3, 1 alpha,25-dihydroxy-vitamin D3 [1 alpha,25(OH)2D3], after oral or intravenous administration of [22,23-(3)H4]1 alpha OHD3 (5), showed longer half-life, lower maximum concentration, and lower area under the curve than those after treatment of 1 alpha,25(OH)2D3 tritiated at 26 and 27 positions (4). These results might suggest a beneficial therapeutic utility of 1 alpha OHD3 (1) over the treatment of 1 alpha,25(OH)2D3 (2).

1α,25-Dihydroxyvitamin D3 A-Ring Precursors: Studies on Regioselective Enzymatic Alkoxycarbonylation Reactions of Their Stereoisomers. Chemoenzymatic Synthesis of A-Ring Synthon Carbamate Derivatives, Including Carbazates and Polyamino Carbamates

The stereoisomers of 1α,25-dihydroxyvitamin D3 A-ring synthon 3a, named 3b−d, were subjected to a very comprehensive regioselective enzymatic study with Candida antarctica lipase (CAL). From this, it emerged that 3b, the enantiomer of the natural A-ring synthon, was a very good substrate for CAL in toluene, dioxane, or THF, showing in all cases conversions close to 100% and regioselectivities between 95% and 99% toward the C-5-(S) hydroxyl group. The best results for the regioselective enzymatic transformation of stereoisomer 3c were achieved with toluene at 30 °C or with THF at 60 °C. The regioselectivity displayed a preference toward the C-5-(S) hydroxyl group. The 1:10 ratio (3c:4) was mandatory so as to obtain an acceptable degree of conversion (in dioxane or THF). The A-ring synthon 3d has a surprising conduct, suffering C-5-(R) enzymatic alkoxycarbonylation, whereas in the acylation process with Chromobacterium viscosum lipase, it showed behavior opposite to that observed for 3a−c. In addition to th...

A new efficient synthesis of taxol A-ring synthon via two aldol condensations

An efficient stereocontrolled synthesis of a taxol A-ring synthon using two aldol reactions as key steps is presented.

Asymmetric synthesis of a key ring A synthon for 1α-hydroxy-19-nor vitamin D

A diasteroselective carbonyl ene reaction on a substrate obtained from a regioselective propiolate ene reaction is described for the synthesis of 19-nor A-ring synthon 3.

Enantioselective Synthesis of the Enyne A-Ring Synthon of the 1α-Hydroxy Vitamins D

Enantioselective Synthesis of the Enyne A-Ring Synthon of the 1α-Hydroxy Vitamins D

Synthesis of 1α, 25-Dihydroxyvitamin D3 A-Ring Synthon by Pd-Catalyzed Cyclization

Synthesis of 1α, 25-Dihydroxyvitamin D₃ A-Ring Synthon by Pd-Catalyzed Cyclization

Enantioselective synthesis of calcitriol a-ring fragments

Commercial ( S)-(+)-carvone is transformed to a calcitriol A-ring synthon in 24% overall yield by a highly efficient 11-step sequence. The route is designed to enable the large scale production of enantiopure A-ring precursors for the synthesis of calcitriol analogues

Toward a general synthesis of A-ring trihydroxylated vitamin D analogs: Synthesis of an A-ring synthon of ED-71 from d-arabinose

(3 R, 4 S, 5 R)-3, 4-( O-isopropylidene)-5-(tert-butyldimethylsiloxy)-1-octene-7-yne was synthesized from d-arabinose in 9 steps and 28% yield and coupled via the Trost-Dumas carbopalladation method to a steroidal CD-ring fragment to yield 1α, 2β-dihydroxyvitamin D 3.