[3,3]-Sigmatropic rearrangement mediated synthesis of chiral building blocks for the preparation of Gemini and its analogs

Article abstract of DOI:10.1039/c6ra08789b

A novel synthetic methodology for the preparation of Gemini Vitamin D₃ analogs has been developed. Our procedure uses a key sigmatropic rearrangement which allows control over the C-20 stereochemistry, providing a versatile method to introduce

Full text of DOI:10.1039/c6ra08789b

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[3,3]-Sigmatropic rearrangement mediated
synthesis of chiral building blocks for the
Cite this: RSC Adv., 2016, 6, 61073
preparation of Gemini and its analogs†
*
*
Gonzalo Pazos, Manuel Perez, Zoila Gandara, Generosa Gomez and Yagamare Fall
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Received 5th April 2016
Accepted 17th June 2016
A novel synthetic methodology for the preparation of Gemini vitamin D3 analogs has been developed. Our
procedure uses a key sigmatropic rearrangement which allows control over the C-20 stereochemistry,
providing a versatile method to introduce novel side-chains to the vitamin D scaffold giving access to
new analogs with potentially interesting biological properties.
DOI: 10.1039/c6ra08789b
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indirect effects on the immune system.1 However the ther-
apeutical utility of 1 is hampered by the effective doses leading
Introduction
to calcemic side effects and this has stimulated the search for
analogues having a relatively weak systemic effect on calcium
metabolism while maintaining potent regulatory effects on cell
differentiation and proliferation. Therefore, numerous
synthetic vitamin D analogs have been developed for better
efficacy with decreased calcemic toxicity. Among the many new
calcitriol analogs, worth mentioning those in which the C-21
methyl group was extended to form a second side-chain giving
rise to new class of derivatives, known as Gemini (Fig. 1). The
rst example of this type of compounds featured a calcitriol
analog with two identical side chains and was coined Gemini.2
With the two side chains in Gemini, the possibility of chain
modication is increased and the new class of Gemini analogs
has signicantly enlarged the biological spectrum of calcitriol.3
In spite of the obvious interest of the pharmaceutical industry
and the vitamin D research groups for the Gemini analogs, the
current methodologies for the preparation of these analogs lack
exibility and efficiency in the incorporation of molecular
diversity. To the best of our knowledge the only known meth-
odology to access Gemini analogs was described by Uskokovic
and co-workers.2,3
Next to its classical activities, 1a,25-dihydroxyvitamin D3 (1,
calcitriol) (Fig. 1) has been shown to inhibit cellular prolifera-
tion, to induce cellular differentiation and to have numerous
Their procedure relies on an ene reaction for the non-
selective generation of the double side precursor and the
subsequent separation of isomers.
Results and discussions
Fig. 1 Structures of 1a,25(OH)2D3, Gemini and some of its analogs.
We anticipated that we could easily access chiral C-20 epimeric
esters 5 and 6 from ketone 2 (ref. 4) through a [3,3]-sigmatropic
rearrangement of allylic alcohols 3 and 4 as depicted in
Scheme 1.
Accordingly, chiral ester 5 was prepared as outlined in
Scheme 2.
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Departamento de Quımica Organica, Facultad de Quımica and Instituto de
´
Investigacion Biomedica (IBI), University of Vigo, Campus Marcosende, 36310 Vigo,
Spain. E-mail: ggomez@uvigo.es; yagamare@uvigo.es
† Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data of all new compounds. CCDC 1017390. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ra08789b
Stereoselective Horner–Wadsworth–Emmons reaction with
the anion of triethylphosphonoacetate provided the (E)-a,b-
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Scheme 4 Synthesis of diol 14.
Scheme 1 Retrosynthetic analysis of C-20 epimeric esters 5 and 6.
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rearrangement when heated in toluene at 185 C, giving alde-
hyde 11 in 90%.
Both [3,3]-sigmatropic rearrangements proceed with high
stereocontrol and only one diastereomer could be detected by
NMR spectroscopy.
To conrm the C-20 stereochemistry, diol 14 was prepared
(Scheme 4) hoping that it might be a crystalline compound.
Catalytic hydrogenation of alkene 5 followed by Dibal-H
reduction of the ester group afforded alcohol 13 in 71% over-
all yield. TBAF deprotection of the silyl ether group of 13 gave
the diol 14 in 96% yield. To our delight, diol 14 could be
recrystallized from a mixture of hexane and ethyl ether and its
structure conrmed unambiguously as that shown in Fig. 2, by
X-ray crystallographic analysis.7
For the synthesis of compound 6 we considered the same
synthetic sequence using the (Z)-isomer of the allylic alcohol 8.
Thus, the isomerization of the C17–C20 double bond in 8 was
performed by stereoselective epoxidation of 8 [t-BuOOH,
VO(acac)2] and subsequent treatment of the resulting epoxide
with LiPPh2 followed by MeI.5,8 (Scheme 5). The epoxide was
isolated as a single isomer and its formation occurred through
the less hindered steroidal a-face.
The (Z)-allylic alcohol 15 was then uneventfully transformed
unto target compound 6 following the same synthetic sequence
used for 5 (Scheme 6).
We have thus synthesized chiral building blocks 5 and 6,
synthons for the synthesis of C-20 epimeric Gemini analogs.9
We now set up to demonstrate the usefulness of our method by
Scheme 2 Synthesis of ester 5.
unsaturated ester 7 in 94% yield as the only stereoisomer iso-
lated from the reaction mixture.5 Dibal-H reduction of ester 7,
followed by protection of the primary alcohol gave the
compound 9 in good yields. Compound 9 on reaction with
selenium dioxide afforded allylic alcohol 3 in 90% yield. The
ene-like SeO2 oxidation occurs exclusively on the a face of the D
ring due to the steric hindrance of the b-C-18 methyl group and
b-C-8 dimethyl tert-butylsiloxy group. A Johnson-orthoester
Claisen rearrangement6 was performed by reaction of 3 with
trimethylorthoacetate in the presence of catalytic amount of
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2,4,6-trimethylbenzoic acid (TMBA) at 140 C, affording ester 5
in 83% yield.
We thought that instead of carrying out a Johnson-orthoester
Claisen rearrangement on allylic alcohol 3 we could also use
a Claisen rearrangement and get another useful building block
such as aldehyde 11 (Scheme 3).
Reaction of allylic alcohol 3 with ethyl vinyl ether and
Hg(OAc)2 afforded the desired enol ether, which aer purica-
tion by column chromatography underwent
a Claisen
Scheme 3 Synthesis of aldehyde 11.
61074 | RSC Adv., 2016, 6, 61073–61076
Fig. 2 X-ray structure (ORTEP) of 14.
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Scheme 5 Isomerization of the C17–C20 double bond of 8.
Scheme 6 Synthesis of ester 6.
synthesizing Gemini. Our retrosynthetic analysis for Gemini is
depicted in Scheme 7.
We anticipated that Gemini could result from a Wittig–
Horner coupling of phosphine oxide 17 and ketone 16 with the
double side chain. Ketone 16 could be easily prepared from
ester 5 by side chain elaboration as shown in Scheme 8.
Catalytic hydrogenation of alkene 5 followed by Dibal-H
reduction of the ester group afforded alcohol 13 in 71% over-
all yield. TPAP oxidation of alcohol 13 gave 90% yield of alde-
hyde 18 which underwent a Wittig reaction to afford alkene 19
(90%). Catalytic hydrogenation of alkene 19 gave 43% of the
expected compound 20 together with alcohol 21 (48%).
Compounds 20 and 21, on reaction with methyllithium afforded
alcohol 22 (94%) and diol 23 (90%) respectively. Alcohol 22
reacted with TBAF to give diol 23 (94%). Iodination of the
primary hydroxyl group of diol 23 gave iodide 24 in 93% yield.
Nickel-mediated conjugate addition of iodide 24 to methyl
acrylate10 afforded ester 25 in 92% yield. Reaction of 25 with
methyllithium afforded 99% yield of diol 26. HF deprotection of
the silyl ether with TBAF gave the triol 27 which upon TPAP
oxidation afforded ketone 28 in 88% overall yield. TMS
Scheme 8 Synthesis of ketone 16.
protection of the hydroxyl groups of 28 gave 91% yield of the
target ketone 16. With ketone 16 in hand, the stage was now set
for the Wittig–Horner reaction with phosphine oxide 17 (ref. 11)
and the nal desilylation to afford uneventfully the target
Gemini compound (Scheme 9).
Scheme 9 Synthesis of Gemini.
Scheme 7 Retrosynthetic analysis of Gemini.
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A. Conney, L. Cai, F. Liu and N. Suh, Mol. Pharmacol.,
2011, 79, 360–367; (d) H. Maehr and M. R. Uskokovic, Eur.
J. Org. Chem., 2004, 8, 1703–1713; (e) P. S. Manchand and
M. R. Uskokovic, US Pat., US 6008209, 1999, p. 13; (f)
P. S. Manchand and M. R. Uskokovic, WO 9849138, 1998,
p. 35; (g) P. S. Manchand and M. R. Uskokovic, WO
9912894, 1999, p. 60; (h) T. Huet, H. Maehr, H. J. Lee,
M. R. Uskokovic, N. Suh, D. Moras and N. Rochel, Med.
Chem. Commun., 2011, 2, 424–429.
Conclusion
In conclusion, we developed a new and highly exible approach
to the synthesis of chiral building blocks, useful synthons for
the synthesis of Gemini analogs. Current methodologies
described by Uskokovic and co-workers lack exibility and
efficiency. Our synthetic procedure uses key sigmatropic rear-
rangement, providing a versatile method to introduce novel side
chains to the vitamin D scaffold giving access to a variety of
analogs with potentially interesting biological properties. Work
is now in progress for the synthesis of a series of new Gemini
analogs with a view to their biological evaluation.
´
4 For a recent synthesis of ketone 2, see: Z. Gandara,
´
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M. L. Rivadulla, M. Perez, G. Gomez and Y. Fall, Eur. J. Org.
Chem., 2013, 5678–5682.
˜
5 R. Riveiros, A. Rumbo, L. A. Sarandeses and A. Mourino, J.
Org. Chem., 2007, 72, 5477–5485.
6 M. A. Hatcher and G. A. Posner, Tetrahedron Lett., 2002, 43,
5009–5012.
Acknowledgements
This work was supported nancially by the Xunta de Galicia (CN
2012/184). The work of the NMR and MS divisions of the
research support services of the University of Vigo (CACTI) is
also gratefully acknowledged. Z. G. and M. P. thank the Xunta
7 Crystallographic data were collected on a Bruker Smart 1000
CCD diffractometer at CACTI (Universidade de Vigo) at 20 ꢀC
using graphite monochromated Mo Ka radiation (l ¼
˚
˜
de Galicia for Angeles Alvarino contracts.
0.71073 A), and were corrected for Lorentz and polarisation
effects. The frames were integrated with the Bruker SAINT
soware package and the data were corrected for
absorption using the program SADABS. The structures
were solved by direct methods using the program
SHELXS97. All non-hydrogen atoms were rened with
anisotropic thermal parameters by full-matrix least-squares
calculations on F2 using the program SHELXL97.
Hydrogen atoms were inserted at calculated positions and
constrained with isotropic thermal parameters. The
structural data have been deposited with the Cambridge
Crystallographic Data Centre (CCDC) with reference
number CCDC 1017390.†
Notes and references
1 (a) H. F. DeLuca, J. Burmester, H. Darwish and J. Krisinger,
in Comprehensive Medicinal Chemistry, ed. C. Hansch, P. G.
Sammes and J. B. Taylor, Pergamon Press, Oxford, 1991,
vol. 3, pp. 1129–1143; (b) H. Dai and G. H. Posner,
Synthesis, 1994, 12, 1383–1398; (c) G.-D. Zhu and
W. H. Okamura, Chem. Rev., 1995, 95, 1877–1952; (d)
G. Jones, S. A. Strugnell and H. F. DeLuca, Physiol. Rev.,
1998, 78, 1193–1231; (e) Vitamin D, ed. D. Feldman, J. W.
Pike and F. H. Glorieux, Elsevier Academic Press,
Burlington, MA, 2nd edn, 2005; (f) Vitamin D, ed. D.
Feldman, J. W. Pike and J. S. Adams, Elsevier Academic
Press, San Diego, CA, 3rd edn, 2011; (g) G. H. Posner and
M. Kahraman, Eur. J. Org. Chem., 2003, 20, 3889–3895.
2 A. W. Norman, P. S. Manchand, M. R. Uskokovic,
W. H. Okamura, J. A. Takeuchi, J. E. Bishop, J.-I. Hisatake,
H. P. Koeffler and S. Peleg, J. Med. Chem., 2000, 43, 2719–
2729.
8 (a) E. Vedejs and P. L. Fuchs, J. Am. Chem. Soc., 1971, 93,
4070–4072; (b) E. Vedejs and P. L. Fuchs, J. Am. Chem. Soc.,
1973, 95, 822–825.
´
´
´
´
9 Y. Fall, G. Gomez, M. Perez, Z. Gandara, X. Perez, G. Pazos
and G. Kurz, PCT Int. Appl. WO 2011121152 A1 20111006,
2011.
10 S. Sinishtaj, H. B. Jeon, P. Dolan, T. W. Kensler and
G. H. Posner, Bioorg. Med. Chem., 2006, 14, 6341–6348.
3 (a) H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic and
N. Suh, Cancer Res., 2007, 67, 11840–11847; (b) H. J. Lee,
S. Paul, N. Atalla, P. E. Thomas, X. Lin, I. Yang, B. Buckley,
G. Lu, X. Zheng, Y. R. Lou, A. H. Conney, H. Maehr,
L. Adorini, M. Uskokovic and N. Suh, Cancer Prev. Res.,
2008, 1960, 1–9; (c) J. Y. So, H. J. Lee, A. K. Smolarek,
S. Paul, C.-X. Wang, H. Maehr, M. Uskokovic, X. Zheng,
˜
´
´
11 (a) A. Mourino, M. Torneiro, C. Vitale, S. Fernandez, J. Perez-
Sestelo, S. Anne and C. Gregorio, Tetrahedron Lett., 1997, 33,
4713–4716; (b) A. R. Daniewski, L. M. Garofalo,
S. D. Hutchings, M. M. Kabat, W. Liu, M. Okabe,
R. Radinov and G. P. Yiannikour, J. Org. Chem., 2002, 67,
1580–1587.
61076 | RSC Adv., 2016, 6, 61073–61076
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