Pd-allylic substitution mediated synthesis of 25-amino vitamin D 3 derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.04.019

Vitamin D₃ analogues with a nitrogen atom linked to C-25 have been synthesized. The key step involves an allylic substitution with 2-nitropropane using catalytic species of Pd(0). This optimized procedure gave the desired compound with complete regioselectivity and high yields and was used for the successful preparation of targeted vitamin D derivatives. The chosen strategy for the construction of the triene unit was totally compatible with the new functional groups.

Full text of DOI:10.1016/j.tetlet.2013.04.019

Tetrahedron Letters 54 (2013) 3164–3166
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-allylic substitution mediated synthesis of 25-amino vitamin D3 derivatives
⇑
⇑
Marcos L. Rivadulla, Xenxo Pérez-García, Manuel Pérez , Generosa Gómez, Yagamare Fall
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Vitamin D3 analogues with a nitrogen atom linked to C-25 have been synthesized. The key step involves
an allylic substitution with 2-nitropropane using catalytic species of Pd(0). This optimized procedure
gave the desired compound with complete regioselectivity and high yields and was used for the success-
ful preparation of targeted vitamin D derivatives. The chosen strategy for the construction of the triene
unit was totally compatible with the new functional groups.
Received 11 March 2013
Revised 4 April 2013
Accepted 5 April 2013
Available online 12 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Vitamin D
Pd-allylic substitution
Azavitamin D3
Wittig–Horner
Introduction
Results and discussion
1
a
,25-Dihydroxyvitamin D3 (3, calcitriol) is the hormonally ac-
The synthesis of nitro derivative 6 started from Inhoffen-Lyth-
goe diol 5, which was obtained by reductive ozonolysis of commer-
cially available vitamin D2.5 Treatment of 5 with TESCl and
subsequent selective deprotection of the primary silyl ether affor-
ded alcohol 8 in 92% yield. The hydroxyl group was oxidized to the
corresponding aldehyde and treated with a Wittig reagent giving
the unsaturated ester 9 in 93% yield. The reduction of the ester
with Dibal-H and acetylation furnished in high yields the ideal sub-
strate 11 for Pd-allylic substitution.
tive metabolite of vitamin D3. The importance of calcitriol resides
in its activity in a multitude of biological processes related to cal-
cium and phosphorus homeostasis, cell proliferation, differentia-
tion, and apoptosis.1
One current target in organic chemistry is the design and syn-
thesis of new analogues of 3 having a relatively weak systemic ef-
fect on calcium metabolism while maintaining potent regulatory
effects on cell differentiation and proliferation.
Tryingtoachievethisgoal,manygroupswerefocusedinthestudy
ofstructuralmodificationsofvitaminD. DeLucaandco-workers syn-
thesizedandtested25-azavitaminD3 42 (Fig.1).Theyfoundthatitisa
competitor for the biological site of 25 hydroxylation,3 showing an
important effect of nitrogen in this position. Also, previous reports
displayed that the hydroxyl group in 25 position of vitamin D is
essential due to the affinity for the transporter protein DBP in blood.4
Here, we report the synthesis of new analogues of vitamin D3 1
and 2, with amine and amide groups linked to C25. Our retrosyn-
thetic analysis for 1 and 2 is depicted in Scheme 1. We anticipated
that the side chains of analogues 1 and 2 could result from the
reduction of nitroderivate 6 which could be prepared from Inhof-
fen-Lythgoe diol 5 using the allylic substitution catalyzed by Pd
(Pd-AS) strategy. The triene system would then be installed using
the Wittig–Horner coupling between the A ring synthon (7) and
the corresponding Grundmann ketone derived from 6, with the
hope that the nitro functional group would be compatible with
the coupling conditions (Scheme 1).
The homoallylic nitro compound 12 was obtained in high yield by
treatment of allylic acetate 11 with 2-nitropropane in the presence
of Pd(PPh3)4 as the catalyst. Catalytic hydrogenation of 12 afforded
almost quantitatively nitro-derivative 6. It is remarkable that the
synthesis of this intermediate is easily scalable to gram quantities
and with the use of highly efficient catalytic procedures (Scheme 2).
The key step of the first part of the synthesis was the Pd-AS of
allylic acetate 11. The Pd-AS is an outstanding procedure in the
synthesis of natural products.6 This particular case is an example
of the Tsuji–Trost reaction.7 Compound 6 was thus easily obtained
in high overall yield (eight steps, 71% from 5).
Once the nitroderivate 6 was prepared, the synthesis of ana-
logue 1 was performed. The desilylation of compound 6 and pos-
terior oxidation with PDC afforded ketone 14 in excellent yields.
The coupling of ketone 14 with phosphine oxide 78 afforded ana-
logue 15 in 96% yield. The conditions for the reduction of the nitro
group in 15 should be compatible with the triene system. After
much experimentation the optimized reaction conditions were
found to be LiAlH4 in Et2O, affording the amine derivative 16 in
high yields. This advanced intermediate was transformed into
compound 19 by treatment with TBAF in 83% yield (Scheme 3).
⇑
Corresponding authors. Tel.: +34 986 81 23 20; fax: +34 986 81 22 62.
E-mail addresses: manuperez@uvigo.es (M. Pérez), yagamare@uvigo.es (Y. Fall).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.019

M. L. Rivadulla et al. / Tetrahedron Letters 54 (2013) 3164–3166
3165
H
N
25
25
O
This work
(1)
R = H
(2)
NH2
C D
OH
O
25
1α,25-Dihydroxyvitamin D3 (Calcitriol) (3)
R = OH
R = H
OH
A
25
N
HO
R
25-azavitamin D3 (DeLuca analogue) (4)
Figure 1.
25
OH
R
NO2
6
5
Pd-allylic alkylation
pathway
OTES
OH
Inhoffen-Lythgoe
diol
O
PPh2
HO
R=
NH2 (1)
"A"ringsynthon
(7)
O
(2)
OH
H
N
TBSO
Scheme 1. Retrosynthetic scheme.
1) TEMPO, IBD
O
O
1) TESCl, Imid,
DMF
OH
OH
CH2Cl2
OEt
5
9
8
2) TBAF (1.0M)
2) Ph3PCHCO2Et
THF
THF
OH
OTES
93%
OTES
92%
NO2
Ac2O, Py
DMPA
Dibal-H
Pd(PPh3)4, Cs2CO3
OH
OAc
10
11
DMSO
99%
THF, -78°C
97%
CH2Cl2
87%
OTES
OTES
H2, Pd/C (5%)
NO2
NO2
AcOEt
99%
12
6
OTES
OTES
Scheme 2. Synthesis of nitro derivative 6.
PDC
TBAF
NO2
THF
NO2
NO2
CH2Cl2
92%
6
14
13
80%
OTES
OH
O
O
PPh2
7
n-BuLi
96%
THF
-78ºC
TBSO
NH2
NH2
NO2
LiAlH4
TBAF
1
16
15
THF
83%
Et2O
95%
HO
TBSO
TBSO
Scheme 3. Synthesis of analogue 1.

3166
M. L. Rivadulla et al. / Tetrahedron Letters 54 (2013) 3164–3166
O
O
Cl
MeO
MeO
O
LiAlH4
18
O
NO2
NH2
NH
CH2Cl2, Et3N, 0ºC
98%
THF
98%
6
17
19
OTES
TBAF
OTES
OTES
O
N
O
N
PDC
CH2Cl2
85%
THF
94%
O
O
20
21
OH
O
O
PPh2
7
n-BuLi
97%
THF
-78ºC
TBSO
O
HO
O
O
NH
N
LiOH·H2O
O
23
22
THF/H2O 1:1
98%
TBSO
TBSO
TBAF
THF
70%
H
N
O
O
OH
2
HO
Scheme 4. Synthesis of analogue 2.
The synthesis of analogue
2 was carried out as follows
Supplementary data
(Scheme 4): reaction of nitroderivate 6 with LiAlH4 afforded amine
17 in 97% yield. Amine 17 gave amide 19 on reaction with acyl
chloride 18 in almost quantitative yield. Amide 19 reacted with
TBAF resulting in the removal of the silyl protecting group and
the concomitant formation of a pyrrolidine derivative 20 in 94%
yield. Pyrrolidine 20 was successfully oxidized with PDC and the
resulting ketone 21 was coupled with phosphine oxide 7,8 afford-
ing 97% yield of compound 22. The subsequent pyrrolidine opening
with LiOH afforded the desired functionalization of targeted com-
pound 23 in 98% yield. The last step was the deprotection of the si-
lyl ether 23 with TBAF, giving vitamin D3 analogue 29 in 70% yield.
In summary, we have developed a very efficient synthesis of
two new 25-amino vitamin D3 analogues, the key step of the syn-
thesis being an allylic substitution catalyzed by Pd (Pd-AS). Work is
now in progress for the synthesis of other aza analogues of calci-
triol with a view to their biological evaluation.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
019.
References and notes
1. (a) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocrinol. Rev. 1995, 16, 200–
257; (b) Jones, G.; Strugnell, S. A.; DeLuca, H. F. Physiol. Rev. 1998, 78, 1193–
1231; (c) Eelen, G.; Verlinden, L.; De Clercq, P.; Vandewalle, M.; Bouillon, R.;
Verstuyf, A. Anticancer Res. 2006, 26, 2717–2721.
2. Onisko, B. L.; Schnoes, H. F.; DeLuca, H. F. Tetrahedron Lett. 1977, 13, 1107–
1108.
3. (a) Onisko, B. L.; Schnoes, H. K.; DeLuca, H. F. J. Biol. Chem. 1979, 254, 3493–3496;
(b) Onisko, B. L.; Schnoes, H. K.; DeLuca, H. F. Bioorg. Chem. 1980, 9, 187–198.
4. Cooke, N.E., Haddad, J.G., Feldman, D., Glorieux, F., Pike, J.W., Eds.; Vitamin D,
Elsevier Academic Press: New York, NY, 1997; pp 73–94.
5. Fernández, B.; Martínez Pérez, J. A.; Granja, J. R.; Castelo, L.; Mouriño, A. J. Org.
Chem. 1992, 57, 3173–3178.
6. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2943.
7. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143–1145.
8. (a) Sardina, F. J.; Mouriño, A.; Castedo, L. J. Org. Chem. 1986, 51, 1264–1269; (b)
Mascareñas, J. L.; Mouriño, A.; Castedo, L. J. Org. Chem. 1986, 1269–1272.
9. To the best of our knowledge these are new vitamin D3 analogues. The
analogous 25-carbamate is known: Jones, H.; Yang, S. S.; Jacobus, D. P. U.S.
Patent 4,069,321 A1, 1978.
Acknowledgments
This work was supported financially by the Xunta de Galicia (N°
EXPTE. 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.