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Research ArticleClinical Studies

Development of Efficient Chemical Syntheses of Vitamin D Degradation Products

LARS KATTNER, DAN BERNARDI and ERIK RAUCH
Anticancer Research February 2015, 35 (2) 1205-1210;
LARS KATTNER
Endotherm Life Science Molecules, Saarbrücken, Germany
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DAN BERNARDI
Endotherm Life Science Molecules, Saarbrücken, Germany
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ERIK RAUCH
Endotherm Life Science Molecules, Saarbrücken, Germany
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Abstract

In recent years it has been recognized that vitamin D deficiency is associated with a wide range of diseases, including various types of cancers. Due to the enormous medical importance of vitamin D and its metabolites, their status in blood serum has to be accurately measured. Thus, the metabolites actually used as reference standards and also others of relevant biological activity have to be provided for validation and continuous improvement of appropriate diagnostic devices. Efficient chemical syntheses of vitamin D derivatives described in the literature are herein proven in a comparative study and applied to the synthesis of some of the most relevant natural metabolites as representative examples.

  • Vitamin D metabolites
  • assay development
  • stereoselective synthesis

Vitamin D and its metabolites are known for many distinguished roles in human physiology and pharmacology (1-4). Vitamin D is responsible for intestinal absorption of calcium and phosphate, and is thus particularly critical to the process of bone mineralization. Vitamin D deficiency is considered to be associated with a wide range of diseases (5), such as rickets, osteoporosis, psoriasis, leukemia, breast and prostate cancer, Alzheimer disease, AIDS, cardiovascular diseases, as well as autoimmune disorders, such as multiple sclerosis. On the other hand, vitamin D toxicity, caused by high-dose supplementation, may lead to calcemia and presumably also other disorders.

Due to this enormous medical importance for disease prevention, and therapy (6), and because it has become obvious in recent years that approximately 60% of all citizens in industrialized countries suffer from vitamin D deficiency, the status of vitamin D and its natural metabolites in human serum has to be carefully and regularly analyzed and monitored. However, the biological role of more than 40 natural vitamin D metabolites (1) known to date is still not fully understood although the metabolic pathways involved are quite well-established (1, 4). Vitamin D (1), generated either from 7-dehydrocholesterol in the skin by sunlight irradiation or supplied by food ingredients, is hydroxylated in the liver to 25-hydroxyvitamin D3 (2), and then in the kidney (and also other tissues) to the most relevant metabolite 1,25-dihydroxyvitamin D3 (calcitriol) (3) (Figure 1). Compounds 2 and 3 are degraded separately following two pathways, usually by successive oxidation and degradation of their side-chains, respectively. In both pathways, the same enzyme 24-hydroxylase (CYP24) is mainly involved, as also in the metabolism of vitamin D analogs.

In most common assays for determining a vitamin D status (7-10) in blood serum or plasma, the inactive metabolite 2 is measured instead of 1 or 3, because the concentration of 2 is considered to correlate well to that of 1 and 3 (1000-fold to 3) and is maintained in the serum for many days at comparably high concentrations (18-36 μg/l, half life 4-6 h). However, other metabolites, such as 4-6 and their corresponding 1α-hydroxylated as well as D2 derivatives should not be neglected, mainly due to their interference with metabolites assayed (7, 8), and also due to their potential, but widely uncertain, biological activity.

We have proven and optimized various alternative approaches described in the literature towards the synthesis of metabolites 2-6, as well as their corresponding 1α-hydroxylated and partly D2 derivatives, and review herewith the most efficient chemical syntheses of the naturally occurring vitamin D degradation products 4-6 as representative examples, particularly because the metabolites 2-6 are all actually measured in currently available clinical assays. The aim of our work was mainly to explore the most efficient approach for the synthesis of these metabolites, to make them available in gram quantities to be employed either as reference standards, as starting materials or building blocks for the synthesis of further metabolites or analogs, or to be used for biological studies.

Materials and Methods

Although a wide variety of chemical syntheses of vitamin D metabolites and their analogs are described in the literature (1, 11, 12), not all of them are suitable for producing gram quantities of the desired target molecule. In Figure 2, three general synthetic strategies are outlined: The first one (route A) is the biosynthetic pathway (also technically applied for the synthesis of vitamin D3 and D2). In this approach, a 7-dehydrocholesterol derivative is irradiated by UV light, and the intermediate product (previtamin D) is isomerized thermally to a corresponding vitamin D derivative. By application of the second strategy (routes B-E), an A-ring and a CD-ring precursor are synthesized independently, which are finally connected after appropriate chemical modifications in the course of a convergent synthesis. In the third approach (routes F-G) a vitamin D3 or D2 molecule is appropriately modified in the course of a linear synthesis, leaving the vitamin D skeleton intact. We applied all three approaches in order to explore the most efficient one for the synthesis of each metabolite of interest.

Figure 1.
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Figure 1.

Metabolites of vitamin D3.

Results

Synthesis of 24R,25-dihydroxyvitamin D3 (4) (Figure 3). The most feasible synthesis of this metabolite, which is described in detail in (13) and references therein, follows a convergent approach (route D in Figure 2). It starts with readily available vitamin D2 7. KMnO4 oxidation and silylation of the 3-OH group with tert-butyldimethylsilyl chloride yielded 8. Oxidative cleavage of 8 with Pb(IV) acetate, and subsequent reductive workup with sodium borohydride (NaBH4) gave separately appropriate precursors of A-ring (9) and CD-ring (10). 9 was treated with N-chlorosuccinimide to yield 11, which was converted to 12 by adding lithium diphenylphosphide and hydrogen peroxide. 10 was submitted to an ozonolysis, to yield after reductive workup with NaBH4 diol 13. In order to produce sufficient quantities of diol 13, vitamin D2 was preferentially directly submitted to an ozonolysis, followd by reductive workup with NaBH4. Subsequently, 13 was converted into iodide 14, which was added in a Zn/Cu-mediated coupling, supported by ultrasound, to enone 15. 15 was obtained by addition of pivaldehyde to lactic acid, in turn available in both enantiomeric configurations, either one or the other to be employed depending on the desired configuration at the later 24 position in the product, and subsequent bromination and elimination. The resulting coupling product 16 was treated with methylmagnesium bromide in the course of a Grignard reaction, and the resulting 1,2 diol moiety of the resulting triol 17 was protected as an isopropylidene ketal. The remaining free alcohol group was oxidized with pyridinium dichromate to yield ketone 18, which was coupled in the course of a Wittig reaction with A-ring phosphine oxide 12 to give 19. Removal of the silyl protective group with tetra-n-butylammonium fluoride and acidic hydrolysis of the ketal finally led to production of 4.

Synthesis of (23S,25R)-25-dihydroxyvitamin D3 26,23-lactone (5) (Figure 4) (14-23). Analogously to the successful previously described synthesis of 4, a convergent approach appeared to be most suitable, using A-ring precursor 12 and CD-ring building block 10, both obtained by oxidative degradation from vitamin D2 (7). In order to introduce the appropriate side chain, isopentenol 22 was submitted to a stereoselective Sharpless dihydroxylation (20). The resulting 1,2 diol moiety was protected as an isopropylidene ketal, yielding 23, which was transformed into sulfone 24 by successive treatment of 23 with p-toluene sulfonyl chloride, thiophenol/potassium t-butoxide and m-chloroperoxybenzoic acid. In the course of a Julia olefination (23), 24 was added to the corresponding CD-ring aldehyde 21, in turn available from 10 by silylation and oxidative degradation of 20 by ozonolysis. Surprisingly, a Wittig reaction of a phosphine oxide corresponding to 24, with 21 was not successful. The isopropylidene ketal at 25 was removed under acidic conditions using pyridinium p-toluenesulfonate, and the primary alcohol moiety was oxidized to yield 26, which was submitted to an iodolactonization, yielding after removal of the iodo substituent at 27 by tributyltin hydride to a mixture of diastereomers 28, which were employed in the next steps without further purification. Desilylation of 28 and oxidation of the resulting alcohol 29 with pyridinium dichromate gave 30, which was coupled as previously described in the course of a Wittig reaction with A-ring phoshine oxide 12 to yield 31. Final desilylation and submission of the resulting product mixture to preparative High Pressure Liquid Chromatography (HPLC) led to diastereomerically pure (23S,25R) diastereomer 5.

Figure 2.
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Figure 2.

Approaches towards the synthesis of vitamin D metabolites.

Synthesis of 3-epi-25-hydroxyvitamin D3 (6) (Figure 5). For the synthesis of this metabolite, a linear, non-convergent approach, corresponding to a well-established technical calcitriol (3) synthesis (24-29) was chosen. By contrast, in the first step the 3-OH group was inverted under Mitsunobu conditions by treatment with diethyl azodicarboxylate and -nitrobenzoic acid, followed by lithium aluminium hydride, leading to 32, although obtained in poor yield (21%). Protection of the 3-OH group as a tert-butyldimethylsilyl ether, conversion in a SO2 adduct and subsequent degradation of the side-chain by ozonolysis and reductive workup with NaBH4 gave 33. Tosylation and removal of the SO2 protective group led to 34, which was coupled by a Grignard reaction with 35, leading to 36 after prior desilylation of the coupling product. Alternatively, 33 was converted into the iodide 37, which was added in a Ni/Zn-mediated Michael-type reaction to ethyl acrylate. The resulting ethyl ester was treated with methyl magnesium bromide to give 36 in comparably good yields. 36 was finally isomerized photochemically (25, 26) to give 6.

Discussion

Although the synthesis according to the biosynthetic pathway, starting from a 7-dehydrocholesterol derivative, is technically applied, at least for the synthesis of vitamin D3 and analogously for vitamin D2, this approach turned-out to be less favorable for the synthesis of their metabolites, because the two-step transformation (photochemical ring opening and thermal isomerization), a synthesis sequence to be performed rather at the end than at the beginning of a suitable synthesis, led to very low yields (i.e. 20%). All most feasible syntheses successfully applied on laboratory scale started from readily available vitamin D2. Depending on substituents to be introduced and transformations necessary, the most straightforward approach appeared to be the option leaving the vitamin D skeleton intact, and to employ an SO2 adduct as an intermediate, as established for the technical calcitriol synthesis and analogously for the described synthesis of 3-epi-25-hydroxyvitamin D3 (6). However, because the SO2 adduct does not tolerate strong bases, acids, elevated temperatures or otherwise harsh reaction conditions, which have to be applied to synthesize most other metabolites, this approach has its limitations. Consequently, the most flexible, although more lengthy route involves the cleavage of vitamin D2 into an A-ring and a CD-ring, appropriate modification of the CD-ring precursor and subsequent coupling with accordingly modified A-ring phoshine oxide 12. Finally it should be noted that the corresponding 1α-hydroxylated derivatives of 2 and 4-6 can easily be synthesized by allylic selenium dioxide oxidation at an appropriate synthesis step (29).

Figure 3.
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Figure 3.

Synthesis of 24R,25-dihydroxyvitamin D3. TBDMSCl: tert-butyldimethylsilyl chloride, NCS: N-chlorosuccinimide, LiPPh2: lithium diphenylphosphide, PDC: pyridinium dichromate, n-BuLi: n-butyllithium, TBAF: tetra-n-butylammonium fluoride.

Conclusion

Efficient chemical syntheses of vitamin D degradation products in gram quantities are favorably carried-out successfully starting from vitamin D2, either in a convergent or linear approach, depending on substitution pattern and structural elements to be envisaged.

Figure 4.
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Figure 4.

Synthesis of (23S,25R)-25-dihydroxyvitamin D3 26,23-Lactone. TBDMSTf: Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester, TsOH: p-toluenesulfonic acid, TsCl: p-toluenesulfonyl chloride, Py: pyridine, PhSH: thiophenol, KOtBu: potassium tert-butoxide, MCPBA: meta-chloroperoxybenzoic acid, LDA: lithium diisopropylamide, PPTS: pyridinium p-toluenesulfonate, DMSO: dimethyl sulfoxide, Bu3SnH: tributyltin hydride, TBAF: tetra-n-butylammonium fluoride, PDC: pyridinium dichromate.

Figure 5.
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Figure 5.

Synthesis of 3-epi-25-hydroxyvitamin D3. DEAD: Diethyl azodicarboxylate, TBDMSCl: tert-butyldimethylsilyl chloride, TsCl: p-toluenesulfonyl chloride, Py: pyridine, TES: triethylsilyl, TBAF: tetra-n-butylammonium fluoride.

Acknowledgements

This work was generously supported by the Ministry of Economics and Science of the Saarland, and Roche Diagnostics GmbH (Penzberg, Germany).

  • Received October 21, 2014.
  • Revision received November 5, 2014.
  • Accepted November 10, 2014.
  • Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

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