D3 is the driving force for the development of new synthetic
strategies. Current synthetic methodologies can be classified
into three main types. The classical approach involves
photochemical ring opening of a steroid precursor,6 a route
that does not work well for the synthesis of 1R-hydroxyvi-
tamin D analogues. More efficient approaches are based on
convergent methodologies in which a preformed ring-A
fragment is attached to a CD fragment.4,7 A wide variety of
routes to this ring-A synthon have been reported.4,5a More
recently, Trost and co-workers have developed a new
convergent route in which the ring-A and triene unit are
formed by Pd(0)-catalyzed alkylation-cyclization reactions
starting from an acyclic unit and a vinyl bromide8 (route A,
Scheme 1). This approach is being successfully employed
and triene unit are constructed by one-pot Pd-catalyzed
tandem cyclization-Negishi coupling process involving an
alkenyl zinc intermediate (3) and a vinyl triflate (4) (route
B, Scheme 1).9
On the basis of the results of previous work,7e we
envisioned that the triene system of 1R,25-(OH)2-D3 and its
1-hydroxylated analogues could be formed by a palladium-
catalyzed cascade involving a carbometalation-cyclization
process starting from vinyl triflate 4 followed by cross-
coupling of the resulting Pd(II) intermediate 210 with the
alkenyl zinc derivative 3.
Calcidiol (1b) was selected as our initial target (Scheme
2) to assess the viability of the new convergent strategy and
Scheme 2. Convergent Synthesis of Calcidiol (1b)
Scheme 1. Trost Approach (A) and New Retrosynthetic
a
Analysis (B) of 1R,25-(OH)2-D3
for synthetic simplicity. The bromoolefin 3a was prepared
from Grundmann’s ketone (5a) according to Trost’s proce-
dure.8
Vinyl triflate 4a was prepared in 45% yield from l-carvone
as described previously.11 Metalation of the alkenyl bromide
3a with tert-butyllithium and subsequent transmetalation with
zinc dibromide provided the organozinc derivative 3b. The
carbometalation-cyclization-Negishi cross-coupling cas-
cade to the vitamin D triene unit was performed as follows.
A solution of vinyl triflate 4a (1 equiv), triethylamine (3
equiv), and a catalytic amount of tetrakis(triphenylphos-
phine)palladium(0) was added to a solution of the organozinc
derivative 3b (2 equiv) in THF at -40 °C. The reaction
mixture was stirred for 15 min and then allowed to reach
room temperature. The residue was purified by flash chro-
matography (SiO2) to provide, after desilylation, the desired
calcidiol (1b) (75% from 3a).
a Si ) Protecting group. SD ) Side chain.
for the preparation of 1R-hydroxyvitamin D analogues
modified at the ring-A.
We wish to report a new, highly efficient convergent
strategy to 1R,25-(OH)2-D3 and its analogues in which ring-A
(5) (a) Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877-1952.
(b) Krause, S.; Schmalz, H.-G. Organic Synthesis Highlights; Schmalz, H.-
G., Ed.; Wiley and VCH: Weinheim, Germany, 2000, pp 212-217. (c)
Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003, 3889-3895.
(6) (a) Schmalz, H.-G.; Walzer, E. Vitamin D ActiVe Compounds;
Quinkert, G., Ed.; VCH Verlagsgesellschaft mbH: Weinheim, Germany,
1985, Vol. 3, pp 41-122. (b) Schmalz, H.-G.; Walzer, E. Vitamin D ActiVe
Compounds Part II; Quinkert, G., Ed.; VCH Verlagsgesellschaft mbH:
Weinheim, Germany, 1986, Vol. 4, pp 131-258. (c) Schmalz, H.-G.;
Walzer, E. Vitamin D ActiVe Compounds Part III; Quinkert, G., Ed.; VCH
Verlagsgesellschaft mbH: Weinheim, Germany, 1987, Vol. 5, pp 1-86.
(7) For selected examples, see: (a) Baggiolini, E. G.; Iacobelli, J. A.;
Hennessy, B. M.; Uskokovic´, M. R. J. Org. Chem. 1986, 51, 3098-3108.
(b) Mascaren˜as, J. L.; Sarandeses, L. A.; Castedo, L.; Mourin˜o, A.
Tetrahedron 1991, 20/21, 3485-3489. (c) Pe´rez-Sestelo, J.; Mascaren˜as,
J. L.; Castedo, L.; Mourin˜o, A. J. Org. Chem. 1993, 58, 118-123. (d)
VanAlstyne, E. M.; Norman, A. W.; Okamura, W. H. J. Am. Chem. Soc.
1994, 116, 6207-6216. (e) Garc´ıa, A. M.; Mascaren˜as, J. L.; Castedo, L.;
Mourin˜o, A. J. Org. Chem. 1997, 62, 6353-6358. (f) Hanazawa, T.;
Koyama, A.; Wada, T.; Morishige, E.; Okamoto, S.; Sato, F. Org. Lett.
2003, 5, 523-525.
(9) For a related 5-exo-dig cyclocarbopalladation-Stille cross-coupling
process, see: Salem, B.; Delort, E.; Klotz, P.; Suffert, J. Org. Lett. 2003,
5, 2307-2310.
(10) Previous work in our laboratory led to an efficient approach to
3-deoxy-1-hydroxyvitamin D3 analogues employing a Pd(0)-catalyzed
coupling between an alkenyl iodide and an alkenyl zinc intermediate. This
process presumably proceeds via palladium intermediates of type 2.
Unfortunately, the formation of the vinyl iodide corresponding to ring A
of 1R,25-(OH)2-D3 through metal-induced cyclization on the 3-hydroxyl-
protected enyne precursor was unsuccessful.
(11) The corresponding tert-butyldimethyl silyl-protected vinyl triflate
was used in our laboratories for the construction of Lythgoe Ring-A
phosphine oxide. Mourin˜o, A.; Torneiro, M.; Vitale, C.; Ferna´ndez, S.;
Pe´rez-Sestelo, J.; Anne´, S.; Gregorio, C. Tetrahedron Lett. 1997, 38, 4713-
4716.
(8) (a) Trost, B. M.; Dumas, J. J. Am. Chem. Soc. 1992, 114, 1924-
1925. (b) Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114,
9836-9845.
5886
Org. Lett., Vol. 7, No. 26, 2005