2,3-seco-Steroids

5a-dichloro-seco-steroid (396), which could not be prepared directly from the seco-diol (397), was obtained by a two-stage chlorination starting with the 3-acetate of (397). The seco-steroid (398) was the major product (35 %) formed on brief treatment of 5,6a-epoxy-5a-cholestan-3-one ethylene acetal with boron trifluoride etherate in benzene.  

The isolation of the biologically active metabolite of vitamin D3 in a pure state, and the determination of its structure as 25-hydroxycholecalciferol (401) has been rapidly followed by its synthesis via irradiation of 25-hydroxycholesta-5,7-dien-3j -ol by three independent groups. The first synthesis of pre-calciferola (405) has been achieved by reaction of the lithium derivative of the chloro-ketone (402) with the en-yne (403) to give (404) which was treated with bis(ethylenediamine)chromium(ii) and then partially reduced catalytically. The thermal isomerisation of (405) (as 3,5-dinitrobenzoate) to vitamin D3 represents the first non-photochemical synthesis. 

CarbocycUc Steroids.— The Torgov synthesis continues to exhibit its great versatility and was recently employed in the first synthesis of B-homo-oestrone. Condensation of the vinyl alcohol (407) and 2-methy 1-cyclopentane-l,3-dione in the presence of l,4-diazabicyclo[2,2 ]octane and cyclisation with toluene-p-sulphonic acid gave the B-homo-oestrapentaene (409) in 33 % overall yield from 3-methoxybenzosuberone. A three-stage reduction by sodium borohydride, catalytic hydrogenation, and lithium-ammonia afforded 3-methoxy-B-homo- 

Galantay and H. P. Weber, Experientia, 1969, 25, 571. Unless otherwise stated all formulae refer to racemates. 

Further application of the Torgov reaction has been made in the synthesis of oestrone, the 3,16-dimethylether of oestriol, and a series of 4-halogeno-oestrogens. A novel modification involves the use of allylic amine (412) (readily prepared from the enamine of m-methoxytetralone) in place of the usual alcohol 

---

The structure-reactivity relationship between a 19-Me- and 19-nor-5,10-seco-steroid has been investigated using lOOC and intramolecular nitrone cycloaddition taking into account various stereochemical aspects (Schemes 27 and 28) [67]. The E-19-nor-5,10-seco-ketone 255 a, on treatment with hydroxylamine hydrochloride (R = H), undergoes lOOC via 256a to a single isoxazolidine 257... 

Soares MB, Bellintani MC, Ribeiro IM, Tomassini TC, Ribeiro dos Santos R. Inhibition of macrophage activation and lipopolysaccaride-induced death by seco-steroids purified from Physalis angulata L. Eur J Pharmacol 2003 459 107-112. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Other parts of the northeastern Atlantic are more productive indole alkaloids isolated from bryozoans, seco-steroids from a gorgonian, Gersemia fruticosa, from the White Sea, toxic peptides from brackish-water cyanobacteria, and macrolides from dinoflagellates (Chart 7.8.A/P/PO). 

Vitamin D. The term vitamin D refers to a group of seco-steroids that possess a common conjugated triene system of double bonds. Vitamin I), (10a) and vitamin D, (10b) are the best-known examples (Fig. 2). Vitamin D (10a) is found primarily in vertebrates, whereas vitamin 11 (10b) is found primarily in plants. The term vitamin is a misnomer. Vitamin I) is a prohormonc that is converted into physiologically active form, primarily 1.25-dihydroxy vitamin D3 (11), by successive hydroxylalions in the liver and kidney. This active form is part of a hormonal system that regulates calcium and phosphate metabolism in the target tissues. 

Paspalin cannot be regarded as a true alkaloid, its unique structure— a seco-steroid annelated to an indole nucleus—deserves, however, attention as it demonstrates the great versatility of the ergot fungus. 

The chemical structure of vitamin D3 is closely related to its precursor, 7-dehydrocholesterol, from which it is produced by a photochemical reaction. Therefore, vitamin Do is closely related structurally to the four-ring nucleus of steroids derived from the cyclopentanoperhydro-phenanthrene ring system. No vitamin D activity is noticed until the B ring of 7-dehydrocholesterol is opened between C-9 and C-10. Thus, vitamin D3 is a 9,10-seco steroid and its carbon skeleton is numbered accordingly (Scheme I). The important aspects of its chemistry center about the 5,6,7-cis-triene structure. The formula for vitamin D3 is C27H44O and its formula weight is 384.64. 

Vitamin D, along with parathyroid hormone and calcitonin, plays a primary role in calcium and phosphorus homeostasis in the body. Intensive research efforts over the past several years have elucidated a role for vitamin D in many other physiological processes as well. The biological actions of this seco-steroid are mediated primarily through the action of its polar metabolite, 1,25-dihydroxy vitamin D3 (l,25(OH)2D3). There is emerging evidence that l,25(OH)2D3 has many more target tissues than those involved in its classical role in the control of mineral metabolism. In addition, some of the actions of l,25(OH)2D3 may be mediated by mechanisms other than the classical steroid-receptor interaction. In this chapter we will provide a brief overview of the multiple actions of vitamin D3 and the pleiotropic mechanisms by which these actions are accomplished. 

Vitamin D refers to a group of seco-steroids that possess a common conjugated triene system of double bonds. Vitamin [67-97-0] (16a) and vitamin D2... 

Fragmentation of 20-chloro-i6 hydroxypregnanes-->i6,i7-seco-steroids G. Adam, Angew. Chem. Jnt, Ed. Engl., 6 (1967) 631. 

The seco-steroids (327) were obtained by dehydrogenation, cleavage and aro-matization occurring during treatment of oestradiol derivatives with DDQ. Treatment of oestrone (114a), equilenin, and isoequilenin acetates with peracids afforded the lactones (328), (329a), and (329b), respectively. When heated... 

A-Homocholestane derivatives have been obtained by the Demjanov ring-enlargement reaction. Transannular solvolysis reactions have been observed in seco-steroids of type (393) containing a ten-membered ring. Thus, treatment of (393) in aqueous acetone solution produced 5(10—> l H)abeo-5fi-cholest-10(19)-ene 3/8-acetate (394) in high yield. ... 

Compound (80), prepared from 2-methylcyclopentane-l,3-dione and methyl 2-chloroacrylate followed by the sequence (76)-> (77)-> (78)- (79) (resolved)— (80), combined with (71) (prepared from m-methoxyphenylstyrene and diborane) to form the seco-steroid (82)/ Acetic anhydride-toluene-p-sulphonic acid then cyclized this stereoselectively to furnish the triacetate (83) which on saponification gave the triol (84). Interestingly, this compound reacted with toluene-p-sulphonic acid in alcohol to produce, by dehydration and change of configuration at C-14, the compound (85), which served as a source of various 8a-oestrone compounds. Compound (84) on treatment with boron trifluoride etherate underwent pinacol transformation in preference to dehydration to yield the ketone (86) this ketone was correlated with the known compound (87). 

Le Boulch, N., Raoul, Y., and Ourisson, G. 1967. Epoxidation in the seco-steroid series. II. Configuration of the ergocalciferol epoxides. Bulletin de la Societe chimique de France, 2413-2415. 

The 5 -perhydroazulene structure (524) is accessible by solvolysis of a la-mesylate (523)." The comparable reaction in the 5a-series requires solvolysis of a 1 -substituted steroid. In each case the migrating C jj-C o) bond has an onti-periplanar relationship to the leaving group. Related perhydroazulenes (526) are obtained by transannular cyclisation of the 5,10-seco-steroid (525). ... 

In contrast to the usual reaction of aromatic aldehydes with cyclic ketones o-nitrobenzaldehyde condenses with 17-ketones to produce good yields of seco-acids, a reaction which has been applied to the preparation of 16-oxa-steroids. Thus, 3 -hydroxy-5a-androstan-17-one or its acetate affords the seco-steroid (153), which can be oxidised either as the free acid by ozone and alkaline hydrogen peroxide to the diacid (155) or, as its methyl ester (154), with chromium trioxide to the monomethyl ester (156). Diborane reduction of the diacid (155) or lithium aluminium hydride reduction of the dimethyl ester (157) gave the trans-diol (158), cyclised with toluene-p-sulphonic acid to 16-oxa-androstan-3)5-ol (159) or, by oxidation with Jones reagent to the lactone (152) (as 3-ketone) in quantitative yield. This lactone could also be obtained by lithium borohydride reduction of the monomethyl ester (156), whilst diborane reduction of (156) and cyclisation of the resulting (151) afforded the isomeric lactone (150). The diacid (155) reacted with acetic anhydride to afford exclusively the cis-anhydride (161) which was reduced directly with lithium aluminium hydride to the cis-lactone (160) or, as its derived dimethyl ester (162) to the cis-diol (163) which cyclised to 16-oxa-14)5-androstan-3) -ol (164). 

Attempted hydrolysis of the acetate function of the 10a-8jS,9j5-epoxide (303) with dilute methanolic potassium hydroxide afforded, via retro-aldol type cleavage, the 8,9-seco-steroid (304). 

A new, general method is developed for preparation of various 3-substituted carbonyl compounds of high enantiomeric purity. Application of this method is made to asymmetric synthesis of either enantiomer of 3-methylalkanoic acids, of enantiomerically pure 3-methylcyclopentanone, 3-methyl-cyclohexanone, 3-naphthylcyclopentanone and 3-vinylcyclopentanone 18. 9,11-Seco steroid 3 6... 

Few new examples of photorearrangement in six-membered heterocycles have been reported. Irradiation of pentafluoropyridine in the gas phase affords the Dewar isomer with a half-life of 5 days at room temperature. Two transients, thought to be isomers of azafulvene, were detected on flash photolysis. The conversion of the lactam (73) into the seco-steroid (74) on irradiation in t-butyl alcohol is viewed as arising via an electrocyclic ring-opening process, followed by addition of solvent, as shown in Scheme 8. Spectroscopic evidence for the... 

Figure 3.2.5 Two conformers of a seco-steroid, namely 11 P-fluoro-1 a-hydroxyvitamin D3. The s-trans conformer shows less sterical repulsion, but the s-cis conformer may be stabilized by 1-11 hydrogen bonds.

---