Synthesis of two 6-s-cis locked stereoisomeric analogues of the steroid hormone 1α,25-dihydroxyvitamin D3: 1 α,25-dihydroxy-19-nor-previtamin D3 and 1β,25-dihydroxy- 19-nor-previtamin D3

Article abstract of DOI:10.1016/S0040-4039(99)02152-8

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 synt

Full text of DOI:10.1016/S0040-4039(99)02152-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 775–779
Synthesis of two 6-s-cis locked stereoisomeric analogues of the
steroid hormone 1α,25-dihydroxyvitamin D3:
1α,25-dihydroxy-19-nor-previtamin D3 and 1β,25-dihydroxy-
19-nor-previtamin D3
Mónica Díaz, Miguel Ferrero, Susana Fernández and Vicente Gotor ∗
Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, 33071- Oviedo, Spain
Received 22 October 1999; accepted 17 November 1999
Abstract
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-D3: 1α,25-(OH)2-19-nor-pre-D3 (3) and novel 1β,25-(OH)2-19-nor-pre-D3 (4). © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: previtamin D3 analogues; quinic acid.
1. Introduction
It is well established that 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2-D3] (1, Scheme 1), in addition
to its classical role in calcium homeostasis, affects the human immune system, inhibits cell proliferation,
and promotes cellular differentiation,1 via genomic mechanisms2 by interaction with a nuclear/cytosol
vitamin D receptor (n-VDR) to regulate gene transcription. However, not all actions of 1α,25-(OH)2-
D3 are mediated by genome activation. There is clear evidence that this secosteroid can also generate
biological responses via non-genomic pathways3 by interaction with a membrane vitamin D receptor
(m-VDR), which generates rapid biological responses believed to be independent of direct interaction
with the genome.
∗
Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es (V. Gotor)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02152-8
tetl 16080

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Scheme 1.
The array of biological responses include both non-genomic and genomic effects, and there is
considerable promise for the efficacy of 1α,25 analogues as chemotherapeutic agents in a variety of
human disease states.4
1α,25-(OH)2-D3 exists as two conformationally equilibrating forms (6-s-trans 1 and a minor form 6-s-
cis 10), which exist in slow chemical equilibrium (5–10%) with 1α,25-dihydroxyprevitamin D3 [1α,25-
(OH)2-pre-D3] (2). It was found that whereas 1α,25 (1) is significantly more active than pre-1α,25 (2)
(in a penta-deuterated form)5 in assays reflecting genomic responses, the latter was equally as active as
1α,25 in assays for measuring non-genomic effects.6 It was proposed that 6-s-cis-1α,25 (10) is the active
conformer for eliciting non-genomic effects, with pre-1α,25 (2) simply behaving as an excellent analogue
of this conformer.7 There is a significant influence from stereochemistry in mediating these non-genomic
responses.8 Different analogues can induce different shapes of protein folding resulting in different
conformations of the protein–analogue complex, each leading to different biological responses. It became
of interest to prepare locked analogues of the 6-s-cis conformer of 1α,25 incapable of isomerizing to the
6-s-trans conformation of 1α,25, which is thermodynamically more stable.
Given the importance of A-ring stereochemistry for binding the ligand to the hormone receptor, we
decided (in our framework on vitamin D3 A-ring analogues9) to synthesize stable previtamin analogues 3
and 4 (Scheme 2), which are unable to undergo rearrangement to the respective vitamin D form by virtue
of the absence of the C-19 methyl group.
Scheme 2.

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2. Results and discussion
These analogues (3 and 4, Scheme 2) were synthesised by a convergent route10 from the protected A-
ring synthons 8 or 9 and the known CD-triflate 7,5,10b,11 as shown in the retro-synthetic route in Scheme
2.
The preparation of the A-ring precursors started with the synthesis of compound 1112 from (−)-quinic
acid (10). Dehydration of the hydroxy ester 11 with POCl3 afforded 12 (Scheme 3). Transformation of the
ester into the aldehyde was best carried out through a two-step sequence: reduction of the ester to alcohol
with DIBAL-H gave rise to alcohol 13, and then oxidation of the latter with pyridinium chlorochromate
yielded aldehyde 14. Formation of enyne 8 was accomplished by reaction with trimethylsilyldiazome-
thane in good yield. We obtained A-ring synthon 8 through a short sequence (eight steps) in high overall
yield (30%) and using an inexpensive, commercially available starting material.13
Scheme 3. a: Ref. 14 (57%, four steps). b: POCl3, Py (80%). c: DIBAL-H, toluene (96%). d: PCC, CH2Cl2 (98%). e: TMSCHN2,
nBuLi, THF (70%). f: 1 equiv. TBAF, THF (84%). g: PPh3, DIAD, p-NO2PhCO2H, THF (98%). h: MeONa, MeOH (83%). i:
TBDMSCl, imidazole, CH2Cl2 (95%)
The key step to prepare A-ring precursor 9 was the selective deprotection of compound 12. The
process was performed by dropwise addition of only 1 equivalent of TBAF at 0°C. Under these
conditions, selective desilylation of the C-3 hydroxyl group was achieved with 84% yield of mono-
deprotected alcohol 15, after purification by flash chromatography. Traces of starting material 12 and
the corresponding diol were isolated. A slight excess of TBAF decreased the yield of 15 due to the total
deprotection of both silyl protecting groups. The next step was the inversion of secondary alcohol 15, for
which we used Mitsunobu’s method.14 The reaction took place with total inversion, giving 16 in almost
quantitative yield (98%). After methanolysis of the p-nitrobenzoic ester 16, compound 17 was obtained
in high isolated yield (83%). This was performed using MeONa in MeOH followed by neutralization
with ammonium chloride; if an acid is used undesired silyl deprotection is produced simultaneously.
It is noteworthy that the Mitsunobu reaction on the diol from the di-deprotection of compound 12,
although only C-3 inversion took place selectively, gave a poor yield of inverted derivative and we
isolated appreciable amounts of starting material. Hence the importance of this selective deprotection, of
which just a few examples are reported in the literature is apparent.15 The previously described reaction
sequence from 12 to 8 was followed to obtain compound 9 from 18.
A-Ring synthons 8 or 9 were coupled with 25-OTMS protected triflate 7 using Pd(PPh3)2(OAc)2-CuI
catalyst and Et2NH in DMF (Scheme 4). The resulting silyloxy dienynes were deprotected with TBAF

778
to afford the trihydroxydienynes 5 or 6. Careful catalytic hydrogenation of triols 5 or 6 in MeOH, in the
presence of Lindlar catalyst and quinoline poison, generated previtamins 3 or 4.16
Scheme 4. a: Pd(PPh3)2(OAc)2-CuI, Et2NH, DMF. b: TBAF, THF (85%, two steps). c: Lindlar, quinoline, H2, MeOH (70%)
In summary, we have developed an efficient synthesis of A-ring precursors 8 and 9 from inexpensive
(−)-quinic acid. Key features of these approaches are the selective deprotection of a silyl ether derivative
and the excellent yield of the Mitsunobu reaction, which takes place with total inversion of configuration.
Coupling of these synthons with the appropriate CD-rings/side chain fragment provides access to the
important 6-s-cis locked analogues 3 and 4. Synthesis of other possible previtamin stereoisomers is now
in progress in our laboratory.
Acknowledgements
Financial support from Comisión Interministerial de Ciencia y Tecnología (Spain; Project BIO98-
0770) and Fundación Príncipe de Asturias (Dr. Severo Ochoa Award to M.F.) is gratefully acknowledged.
We also thank the Ministerio de Educación y Cultura (Spain) for postdoctoral fellowships (S.F. and M.F.)
and Solvay-Duphar (Wesp, Holland) for the generous gift of vitamin D3 which was used for preparation
of Grundmann’s ketone.
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