25-Hydroxy vitamin synthesis

The stereospecific synthesis of an A ring synthon of la-hydroxy vitamin D has been carried out. The ( )-allcene is cyclized to give the (E -c.xo-diene 155, and the (Z)-allcene affords the (Z)-e,xo-diene 156 stereospecifically[125,126]. These results can be understood by the cis addition and syn elimination mechanism. 

The equivalent intramolecular Heck-type vinylation of a a>-vinyl-(Z)-iodoalkene has been used as the key step in the synthesis of A-ring synthons for 1 at,25-di hydroxy vitamin D3 and its analogues403. The reaction takes place under reflux in acetonitrile in the presence of one equivalent of triethylamine404 and gives a 81% yield (equation 102). 

Attempts to demonstrate 25-hydroxy-vitamin D3-l-hydroxylase activity in vitro with rat kidney homogenates have been unsuccessful, although chick kidney preparations exhibit such activity. A heat-labile and very potent inhibitor of the hydroxylase has now been found in the rat preparation 322 all fractions of the kidney homogenate contained the factor, but the microsomes were the richest source, and they released the inhibitor during incubation. A similar inhibitor is also present in rat intestine and serum and in pig kidney, and it may well play a regulatory role in the synthesis of 1,25-dihydroxy-vitamin D3.323 Direct spectroscopic and inhibitory evidence for the presence of cytochrome P450 in kidney mitochondria and of its... 

Reduction.—la,2a-Epoxycholesta-4,6-dien-3-one (63) has been reduced by lithium-liquid ammonia under strictly controlled conditions to give a mixture which included 45% of the la,3/3-dihydroxy-5a-6-ene (64), and 20% of the A5-isomer.88 The A6-compound was used in the preparation of la,3/3-dihydroxycholesta-5,7-diene, required for the synthesis of la-hydroxy-vitamin D3. 

Irradiation of the 5,7-diene gave the previtamin, which was isomerized and saponified to give la-hydroxy-vitamin D3. For the last synthesis of la-hydroxy-7-dehydrocholesterol recorded here, cholesta-l,4,6-triene-3-one was again used as starting steroid.122 Deconjugation of this trienone with strong base followed by immediate reduction with calcium borohydride led to the unstable 3/3-hydroxycholesta-l,5,7-triene which, without isolation, was converted into the 1,4-addition product (265) upon reaction with 4-phenyl-l,2,4-triazoline-3,5-dione. 

As discussed in Sect. 2, a-selanylalkyllithiums, generated from selenoacetals, can react with various electrophilic reagents, i. e. chloromethyl isopropyl ether for the synthesis of la-hydroxy vitamin D analogues [25] and with propargylic chloride derivatives for the preparation of alkynols [26]. A synthesis of vinyl-cyclopropane derivatives from l,4-dichloro-but-2-ene was achieved with trans stereoselectivity (>93%) in 68-89% yield. This one-pot cyclization, via an intramolecular allylic substitution, required the presence of two equivalents of u-BuLi [26] (Scheme 23). 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

An alternative strategy for achieving asymmetric control may be by covalent attachment of a chiral auxiliary to the carbenoid. This strategy has so far met with rather limited success in cyclopropanation reactions (see eq. (3) for a similar palladium-catalyzed reaction). However, the use of a-hydroxy esters as chiral auxiliaries with stabilized rhodium(II) vinylcarbenoids allowed entry into both series of enantiomeric vinylcyclopropanes with predictable stereochemistry. Optical yields are fair to excellent [14] and the outcome of the reaction was rationalized on the basis of interactions between the carbonyl oxygen of the chiral auxiliary and the carbenoid carbon. The strategy led to an efficient synthesis of optically active hydroxy vitamin D3 ring A [28]. 

A new synthesis of la-hydroxycholecalciferol (la-hydroxy-vitamin D3) from cholesterol employs transformations in rings A and B which differ only in detail from an earlier sequence for introduction of the la-hydroxy-group the la,2a-epoxy-3j8,6j8-diol derivative (382) was the key intermediate, allowing regeneration of... 

Lead interferes with vitamin D metabolism, since it inhibits hydroxylation of 25-hydroxy-vitamin D to produce the active form of vitamin D. The effect has been reported in children, with blood levels as low as 10-15 pg/lOO cm3 (WHO, 1986). Measurements of the inhibitory effects of lead on heme synthesis are widely used in screening tests to determine whether medical treatment for lead toxicity is needed for children in high-risk populations who have not yet developed overt symptoms of lead poisoning. 

In a recent elegant synthetic application of this methodology, Vande-walle and co-workers have prepared some vitamin D3 derivatives.60 Scheme 6-VI shows a synthesis of 12-hydroxy vitamin D3 from 7-dehy-drocholesterol. The key feature of this route is the protection of the sensitive triene moiety as its Diels-Alder adduct with jV-phenyltriazoline-3,5-dione. 

J. Yanagisawa, and S. Kato (1997). 25-Hydroxy vitamin Dj la-hydroxylase and vitamin D synthesis. Science 111, 1827-1830. 

The synthesis of 5,6-trans-25-hydroxycholecalciferol (376), a new vitamin D analogue, has been achieved. Treatment of 25-hydroxy-vitamin D3 (375) with iodine in light petroleum ether, followed by addition of Ne2S203 and chromatography, afforded 5,6-rra/j5-25-hydroxy-D3 (376), which has been shown to stimulate intestinal calcium transport. 

Metabolites, 25-hydroxy vitamin D (13) and la,25-dihydroxyvitamin D (14), are produced enzymatically, mainly in the liver and kidneys [49]. Their existence and hormonal activity were discovered after the successful synthesis of radioactively labelled vitamin D3. The synthesis of vitamin D (and its metabolites) is the next item on the agenda. 

Kaneko, C., S. Yamada, A. Sugimoto, Y. Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki Synthesis and Biological Activity of la-Hydroxy vitamin D3. Steroids 23,75 (1974). 

Morisaki, M., A. Saika, K. Bannai, M. Sawamura, J. Rubio-Lightbourn, and N. Ikekawa. Synthesis of Active Forms of Vitamin D. X. Synthesis of la-Hydroxy-vitamin D3. Chem. Pharm. Bull. 23, 3272 (1975). 

Barton DHR, Hesse RH, Pechet, MM, Rizzardo E. Convenient synthesis of la-hydroxy-vitamin D3. J. Am. Chem. Soc. 1973 95 2748-2749. 

The synthesis of vitamin Dj from a sensitive dienone was another etu-ly success of phosphorus ylide synthesis (H.H. Inhoffen, 1958 A). This Wittig reaction could be carried out without any isomerization of the diene. An excess of the ylide was needed presumably because the alkoxides formed from the hydroxy group in the educt removed some of the ylide. 

The chemical syntheses of l,24(R),25-trihydroxy-vitamiQ [56142-94-0] and l,24(3),25-trihydroxy-vitamiQ D [56142-95-1] were reported (131,132) ki 1975. The chemical synthesis of 25,26-dihydroxy-vitamin [29261 -12-9] has also been described, and it has been determined that the biologically occurring epimer is 25(R),26-dihydroxy-vitamin (117,133—135). The 23,25-dihydroxy-24-oxo metabohte has been isolated (136) as well. 1 a-Hydroxycalcitroic acid (l-hydroxy-24-nor-9,10-secochola-5,7-10(19)-ttien-23-oic acid) [71204-89-2], 25-hydroxy-26,23-lactone vitamin [71203-34-6],... 

The literature on basic- and acid-catalyzed alkylation of phenol and of its derivatives is wide [1,2], since this class of reactions finds industrial application for the synthesis of several intermediates 2-methylphenol as a monomer for the synthesis of epoxy cresol novolac resin 2,5-dimethylphenol as an intermediate for the synthesis of antiseptics, dyes and antioxidants 2,6-dimethylphenol used for the manufacture of polyphenylenoxide resins, and 2,3,6-trimethylphenol as a starting material for the synthesis of vitamin E. The nature of the products obtained in phenol methylation is affected by the surface characteristics of the catalyst, since catalysts having acid features address the electrophilic substitution in the ortho and para positions with respect to the hydroxy group (steric effects in confined environments may however affect the ortho/para-C-alkylation ratio), while with basic catalysts the ortho positions become the... 

An obvious way to target chiral compounds is to start with a compound in which the chiral center is already present. Here natural products and derivatives offer a rich pool of generally inexpensive starting materials. Examples include L-hydroxy and amino adds. Sometimes, just one out of many chiral centers is predestined to remain, as in the synthesis of vitamin C from D-glucose, or in the preparation of (S)-3-hydroxy-y-butyrolactone from ladose. 

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