Vitamin D: A concise synthesis of the C19 hydroxylated enyne A-ring, an interesting precursor for the preparation of C19 substituted vitamin D analogues

Article abstract of DOI:10.1016/j.tetlet.2004.01.121

A new C₁₉ hydroxylated enyne 15, as potential A-ring building block of vitamin D analogues, was synthesized in enantiomerically pure form in nine steps from (-)-(S)-limonene. This short synthesis involved ozonolyzis of 1,2-limonene oxide followed by a Criegee rearrangement, epoxide trans diaxial ring opening by lithium acetylide, elimination, epoxidation and syn β-elimination of the resulting homopropargylic oxirane.

Full text of DOI:10.1016/j.tetlet.2004.01.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2289–2292
Vitamin D: a concise synthesis of the C19 hydroxylated enyne
A-ring, an interesting precursor for the preparation
of C19 substituted vitamin D analogues
*
*
€
Raphael Rodriguez, Cyril Ollivier and Maurice Santelli
Laboratoire de Synthꢀese Organique associꢁe au CNRS, Facultꢁe des Sciences de Saint Jꢁer^ome,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 21 January 2004; accepted 23 January 2004
Abstract—Anew C
hydroxylated enyne 15, as potential A-ring building block of vitamin D analogues, was synthesized in
19
enantiomerically pure form in nine steps from ())-(S)-limonene. This short synthesis involved ozonolyzis of 1,2-limonene oxide
followed by a Criegee rearrangement, epoxide trans diaxial ring opening by lithium acetylide, elimination, epoxidation and syn
b-elimination of the resulting homopropargylic oxirane.
Ó 2004 Elsevier Ltd. All rights reserved.
Over the last decades, chemical and biochemical
researches on vitamin D 1 have steadily increased and
became of significant interest with the discovery of
1a,25-dihydroxy vitamin D3 or calcitriol 2, the hor-
monally active metabolite of vitamin D. Compound 2 is
well known as a strong calcium and phosphorus regu-
lator, but it also plays an important role in the regula-
tion of malignant cell proliferation, implied in cancers
and other hyperproliferation diseases, cellular differen-
tiation and immunology.1 Unfortunately, doses required
in treatments cause hypercalcaemia side effects that limit
its application as a valuable therapeutical agent. Owing
to these properties, preparation of vitamin D analogues
has attracted the interest of numerous synthetic groups.
Derivatives with modified side chains, Arings and CD
bicyclic systems variously substituted have gained
attention as potential new drugs, due to their higher
efficacy and lower toxicity.2 To date, few modifications
have been reported on the trienic unit except, for
example, the replacement of the C10–C19 methylene by a
10,10-dimethyl group,3 the synthesis of 19-nor-1a,25-
stituents in C19 position.5 Otherwise, p-electron-donat-
ing substituents such as alkoxy groups directly branched
on the triene moiety should influence the1;7 sigmatropic
process (a crucial step required in the transformation of
4 to 3) and then, the biological activity of the compound
should be modified.
R
H
19
10
R = H, 1; R = OH, 2
HO
R
1
3
In order to synthesize vitamin D and its analogues,
several strategies have been elaborated and reported in
~
4
the literature.2 Among these, Mourino proposed an
dihydroxy vitamin D3 and the presence of alkyl sub-
interesting convergent approach based on the con-
struction of a dienyne system 4 via a Sonogashira-type
coupling between the vinyl triflate of the CD-ring
Windaus–Grundmann ketone 5 with the A-ring enyne
type 6.6 Asimilar synthetic plan was chosen for the
preparation of C19 substituted vitamin D analogues as
depicted in the following retrosynthetic format (Scheme
1).
Keywords: Vitamin D; Limonene; Criegee rearrangement; Epoxide ring
opening.
* Corresponding authors. Tel.: +33-4-91-28-80-03; fax: +33-4-91-28-
38-65 (C.O.). Tel.: +33-4-91-28-88-25; fax: +33-4-91-98-38-65 (M.S.);
e-mail addresses: cyril.ollivier@univ.u-3mrs.fr; m.santelli@univ.
u-3mrs.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.121

2290
R. Rodriguez et al. / Tetrahedron Letters 45 (2004) 2289–2292
H
TfO
5
H
H
+
OR
OR
OR
BnO
BnO
R = H, PG
3
4
OBn
6
Scheme 1.
In the present work, we report the synthesis of the
C19 hydroxylated enyne A-ring enantiomerically
enriched in only nine steps starting from ())-(S)-limo-
nene (puriss.) or the commercially available cis and trans
mixture of 1,2-limonene oxide 7.7 Conversion of 7a and
7b to secondary alcohols 8a and 8b was easily achieved
in three steps and 56% overall yield via sequential
ozonolyzis of the isopropylidene moiety followed by a
Baeyer–Villiger rearrangement and saponification of the
resulting acetate. However, the same transformation can
be performed in better yields (>74%) via ozonolyzis
followed by Criegee rearrangement as a ꢀone potꢁ pro-
cess.8 Then, the generated secondary alcohol 8 was
protected with a benzyl group under classical condi-
tions, leading to 9 (Scheme 2). Amixture of trans and cis
epoxides 9a/b9 treated with an excess of lithium acetyl-
ide––ethylenediamine complex in DMSO at room tem-
perature during 3 days gave the trans diaxial
homopropagylic alcohol 10a10 in 58% yield, which
results from the selective ring opening of trans epoxide
as depicted in Scheme 2.11 The cis isomer remained
almost completely unchanged whatever the conditions
used.12 Akinetic separation, where one of both diastereo-
isomers is more reactive than the other one, was oper-
ating (Scheme 3).
Dehydration of tertiary alcohol 10a promoted by action
of POCl3 in pyridine at 0 °C delivered the required exo
methylene adduct 11 as well as the expected endo olefin
12 in a 7:3 ratio and in quantitative yield. Arange of
reaction conditions (p-TSA, Burgesꢁs reagent, BF3ÆEt2O,
CuSO4, PBr3/pyridine, Ac2O/pyridine) were tested to
improve the selectivity in favour of one of both elimi-
nation products but without success. Then, the crude
mixture was oxidized quantitatively by m-CPBA/
CH2Cl2 into epoxides 13 and 14 as a single diastereo-
isomer (Scheme 4). The regioisomers can easily be sep-
arated by flash chromatography.
According to Crandallꢁs procedure on simple cyclic
oxiranes, treatment of each homopropargylic epoxides
13 and 14 with lithium diethyl amide liberates the pri-
mary allylic alcohol 15 and the secondary allylic alcohol
16 in 42% and 48% yields, respectively. Lithium amide
promotes the b-elimination of 13 and 14, which occurs
via a syn pathway.13 Compound 1514 and related pro-
tected derivatives are ready to be engaged in palla-
dium(0) catalyzed-Sonogashira coupling reactions with
CD-ring fragments for the preparation of C19 substi-
tuted vitamin D derivatives. Compound 16 as well as the
ketone 17, easily obtained by oxidation of 16 with
O
O
O
a
b, c, d
56%
h
80%
95%
7a/7b
OH
OBn 9a/9b
trans/cis 3:2
(−)-(S)-Limonene
7a/7b
8a/8b
trans/cis 3:2
O
> 98%
10a/9b 3:2
i
e, f
g
(74%)
OH
O-OAc
OMe
O
+
OBn
OBn
10a
9b
Scheme 2. Reagents and conditions: (a) m-CPBA/CH2Cl2, rt, 7a/7b (80%, trans/cis 3:2); (b) O3, CH2Cl2/MeOH (10:1), )78 °C then Me2S (89%); (c)
m-CPBA/CH2Cl2, rt, 3 days, (80%); (d) K2CO3, MeOH/H2O (1:1), rt, 8a/8b (79%) and (56% over three steps); (e) O3, CH2Cl2/MeOH (10:1), )78 to
15 °C; (f) Ac2O (7 equiv)/Et3N (7 equiv)/DMAP (0.15 equiv), )25 to )8 °C then quenched by MeOH; (g) NaOAc (0.2 equiv)/MeOH, 37 °C (74% over
three steps in a one pot process); (h) NaH/TBAI/PhCH2Br/THF (95%); (i) lithium acetylide––EDA/DMSO, 3 days, 10a/9b (>98%, 10a/9b 3:2).

R. Rodriguez et al. / Tetrahedron Letters 45 (2004) 2289–2292
2291
BnO
HO
O
BnO
BnO
BnO
O
10a
OH
Trans-diaxial ring opening:
Chair product
cis-9b
trans-9a
Trans-diaxial ring opening:
Twist-boat product
Scheme 3.
O
OH
OBn
OBn
OBn 13
11
POCl3
m-CPBA
+
+
Pyridine, 0 °C
95%
CH2Cl2, rt
O
95%
13/14 7:3
OBn
10a
11/12 7:3
14
12
OBn
Scheme 4.
OH
O
MeLi/Et2NH
Et
Et
H
N
BnO
Et2O, 0 ˚C
42 %
Li
OBn
O
OBn
OH
15
13
14
O
O
BnO
MeLi/Et2NH
MnO2
H
PhH, rt
72 %
Et O,
0 ˚C
2
O
Et
Et
48 %
OBn
OBn
OBn
Li
N
16
17
Scheme 5.
MnO2, can also be useful building blocks for the syn-
thesis of vitamin D3 analogues (Scheme 5).
Nationale for the financial support. R.R. thanks the
ꢀ
Ministere de lꢁEducation Nationale for a MESR fel-
lowship. We are indebted to Dr. B. Vacher (Pierre Fabre
ꢁ
Medicaments, Castres, Fr) for helpful comments.
In conclusion, we have developed a short and practical
approach to the preparation of the enantiomerically
enriched alcohols 15 (7.5% yield), 16 (3.5% yield) and
the ketone 17 (2.6%) from the natural substrate ())-(S)-
limonene. Further investigations extended to the syn-
thesis of vitamin D analogues using these new building
blocks and studies on the influence of C19 alkoxide
groups on the1;7 hydrogen sigmatropic shift, that follows
the cross-coupling step between the A-ring enyne and
the enol triflate of the CD-ring Windaus–Grundmann
ketone, are being pursued in our laboratory.
References and notes
1. (a) Bouillon, R.; Okamura, W. H.; Norman, A. W.
Endocr. Rev. 1995, 16, 200–257; (b) Vitamin D, Chemistry,
Biology and Clinical Applications of the Steroid Hormone;
Norman, A. W., Bouillon, R., Thomasset, M., Eds.;
University of California Riverside: Riverside, CA, 1997;
(c) Vitamin D Endocrine System: Structural, Biological,
Genetic and Clinical Aspects; Norman, A. W., Bouillon,
R., Thomasset, M., Eds.; University of California River-
side: Riverside, CA, 2000.
2. For reviews, see: (a) Pardo, R.; Santelli, M. Bull. Soc.
Chim. Fr. 1985, 98–114; (b) Dai, H.; Posner, G. H.
Synthesis 1994, 1383–1398; (c) Zhu, G.-D.; Okamura, W.
H. Chem. Rev. 1995, 95, 1877–1952; (d) Posner, G. H.;
Kahraman, M. Eur. J. Org. Chem. 2003, 3889–3895.
Acknowledgements
We are grateful to the Centre National de la Recherche
ꢀ
Scientifique (CNRS) and the Ministere de lꢁEducation

2292
R. Rodriguez et al. / Tetrahedron Letters 45 (2004) 2289–2292
3. Linclau, B.; Vandewalle, M. Synlett 1995, 1063–1064.
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F. Org. Lett. 2001, 3975–3977.
5. Addo, J. K.; Swamy, N.; Ray, R. Bioorg. Med. Chem.
Lett. 2002, 12, 279–281.
6. The dienyne approach was first developed by Lythgoe,
11. In a pioneer work, Inhoffen reported that the addition of
lithium acetylide to 4-(tetrahydropyran-2-yloxy)-methyl-
cyclohexene oxide proceeds in just 33% yield. No expla-
nation of the origin of this low yield and no structure of
side products were proposed: Inhoffen, H. H.; Weissem-
erel, K.; Quinkert, G.; Bartling, D. Chem. Ber. 1956, 89,
853–861; For other studies on ring opening of methyl-
cyclohexene oxide by lithium acetylide, see: (a) Hanack,
M.; Kunzmann, E.; Schumacher, W. Synthesis 1978, 26–
27; (b) Hopf, H.; Kirsch, R. Angew. Chem., Int. Ed. Engl.
1985, 24, 783–786.
12. Various examples reported in the literature showed that
nucleophilic attacks of cis- and trans-4-substituted methyl-
cyclohexene oxides initiate the selective ring opening of
trans isomers, exclusively. For recent references, with
nitrogen centred nucleophiles: Chrisman, W.; Camara,
J. N.; Marcellini, K.; Singaram, B.; Goralski, C. T.;
Hasha, D. L.; Rudolf, P. R.; Nicholson, L. W.; Borody-
chuk, K. K. Tetrahedron Lett. 2001, 42, 5805–5807, with
phosphorus centred nucleophiles: Muller, G.; Sainz, D.
J. Organomet. Chem. 1995, 495, 103–111.
~
and later improved by Mourino: (a) Dixon, J.; Littlewood,
P. S.; Lythgoe, B.; Saksena, A. K. J. Chem. Soc., Chem.
~
Commun. 1970, 993–994; (b) Castedo, L.; Mourino, A.;
Sarandeses, L. A. Tetrahedron Lett. 1986, 27, 1523–1526;
~
~
(c) Castedo, L.; Mascarenas, J. L.; Mourino, A.;
Sarandeses, L. A. Tetrahedron Lett. 1988, 29, 1203–
1206.
7. Epoxidation of ())-(S)-limonene by m-CPBAgave a 3:2
trans/cis mixture of 1,2-limonene oxide in 80% yield. The
ratio was determined by GC analysis and confirmed by
Cane and Coates: Cane, D. E.; Yang, G.; Coates, R. M.;
Pyun, H.-J.; Hohn, T. M. J. Org. Chem. 1992, 57, 3454–
3462.
8. (a) Criegee, R.; Kaspar, R. J. Liebigs Ann. Chem. 1948,
560, 127; (b) Criegee, R. Angew. Chem., Int. Ed. Engl.
1975, 14, 745–752; (c) Muralidharan, K. R.; Lera, A. R.;
Isaeff, S. D.; Norman, A. W.; Okamura, W. H. J. Org.
Chem. 1993, 58, 1895–1899; (d) Daniewski, A. R.;
Garofalo, L. M.; Hutchings, S. D.; Kabat, M. M.; Liu,
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Chem. 2002, 67, 1580–1587.
13. (a) Crandall, J. K.; Chang, L. J. Org. Chem. 1967, 32, 435–
439; (b) Crandall, J. K.; Chang, L. J. Org. Chem. 1968, 33,
2375–2378; (c) Miginiac, P.; Zamlouty, G. Bull. Soc. Chim.
Fr. 1975, 1740–1744.
25
D
14. Spectral data of 15: ½aŠ À 20:5° (c 2.26, CHCl3); IR (film)
mmax 3419, 3304, 3011, 1637, 1216, 1068, 1025 cmÀ1
;
1H
9. The relative configuration of each diastereoisomers was
assigned by comparison with the spectrum of the cis- and
trans-4-hydroxy-methylcyclohexene oxides reported in the
literature, and also the integration of each signal: Delay,
D.; Ohloff, G. Helv. Chim. Acta 1979, 62, 2168–2173.
10. The stereochemistry was supported by NOESY experi-
ments, that showed correlation between propargylic H-2
and methyl-1 in compound 10a, but not between H-2 and
H-4.
NMR (CDCl3, 300 MHz) d 1.74 (ddt, J ¼ 13:1, 8.3,
5.7 Hz, 1H), 1.85–1.94 (m, 1H), 1.96–2.10 (m, 1H), 2.15
(s, 1H), 2.23–2.54 (m, 3H), 3.08 (s, 1H), 3.63–3.70 (m, 1H),
4.29 (s, 2H), 4.55 (s, 2H), 7.26–7.33 (m, 5H); 13C NMR
(CDCl3, 75 MHz) d 24.9, 26.9, 35.7, 64.5, 70.1, 72.3, 80.4,
82.5, 113.7, 127.6 (3CH), 128.4 (2CH), 138.7, 145.6; MS
(EI, 70 eV) m=z 243 ([Mþ+1], 10), 242 ([Mþ], 45), 151 (40),
136 (19), 123 (16), 109 (100), 91 (49), 81 (21), 79 (24), 77
(20), 65 (21), 43 (11).