A Short, Efficient Copper-Mediated Synthesis of 1α,25-Dihydroxyvitamin D2 (1α,25-Dihydroxyergocalciferol) and C-24 Analogs

Article abstract of DOI:10.1021/jo970604u

Two synthetic routes to the nonnatural hormone 1α,25-dihydroxyergocalciferol [2b, 1α,25-(OH)₂D₂] and analogs modified at C-24 have been developed both starting from aldehyde 7b. Key steps in route A (eight steps, ≈38% overall yield f

Full text of DOI:10.1021/jo970604u

6344
J . Org. Chem. 1997, 62, 6344-6352
A Sh or t, Efficien t Cop p er -Med ia ted Syn th esis of
1r,25-Dih yd r oxyvita m in D2 (1r,25-Dih yd r oxyer goca lcifer ol) a n d
C-24 An a logs1,2
Mercedes Torneiro, Yagamare Fall, Luis Castedo, and Antonio Mourin˜o*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de
Santiago de Compostela, 15706 Santiago de Compostela, Spain
Received April 2, 1997X
Two synthetic routes to the nonnatural hormone 1R,25-dihydroxyergocalciferol [2b, 1R,25-(OH)2-
D2] and analogs modified at C-24 have been developed both starting from aldehyde 7b. Key steps
in route A (eight steps, ≈38% overall yield from 7b) are (1) stereoselective addition of (E)-
vinyllithium reagent 8c to aldehyde 7b; and (2) SN2′ anti-displacement of the allylic phosphate of
5e by organocuprates derived from Grignard reagents and CuCN in the presence of LiCl. Key
steps in route B (eight steps from 7b, 48% overall yield) are (1) Wittig-Horner type coupling between
ketone 22, which bears an allylic phosphate group on the side chain, and the ylide derived from
the Lythgoe-Roche phosphine oxide to form the vitamin D triene unit; and (2) efficient SN2′ anti-
displacement of the phosphate group of 23 by the organocuprate derived from MeMgCl, CuCN,
and LiCl, without affecting the labile vitamin D triene system, to give, after deprotection, 1R,25-
(OH)2-D2. Route B is particularly attractive as an approach to diverse C-24 vitamin D analogs for
biological screening.
In tr od u ction
Vitamin D3 (1a , colecalciferol, Figure 1) is hydroxylated
in the liver and the kidney to its hormonally active form
1R,25-dihydroxyvitamin D3 [1b, calcitriol, 1R,25-(OH)2-
D3], which regulates calcium homeostasis and bone
mineralization.3 Calcitriol also promotes cell-differentia-
tion and inhibits the proliferation of malignant cells,
suppresses tumor growth, inhibits metastasis, and pro-
longs survival4 in cancer patients.5 It has also been used
in the treatment of several other human diseases, includ-
ing osteoporosis,6 psoriasis,7 and AIDS.8 For some years,
the nonnatural vitamin D2 (2a , ergocalciferol) has been
administered to humans and domestic animals3,9 on the
assumption that its metabolism and biological activity
parallel those of vitamin D.10 There is now strong
evidence that vitamin D2 also undergoes a double hy-
F igu r e 1.
droxylation to produce 1R,25-dihydroxyvitamin D2 [2b,
1R,25-(OH)2-D2],10-13 although other metabolites can be
formed as a result of hydroxylations at C-24, C-26, and
C-28.14 1R,25-Dihydroxyvitamin D2 also induces cell-
differentiation and inhibits the proliferation of a number
of tumor cell lines, including leukemic cells.15 Unfortu-
nately, 1b and 2b cause hypercalcemia in treated pa-
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) This paper is dedicated to Professor Dieter Seebach in honor of
his 60th birthday.
(2) This work was taken in part from the doctoral thesis of Mercedes
Torneiro (University of Santiago de Compostela, J anuary 1994).
(3) Norman, A. W. Vitamin D, The Calcium Homeostatic Steroid
Hormone; Academic Press: New York, 1979.
(4) (a) Honma, Y.; Hozumi, M.; Abe, E.; Konno, K.; Fukushima, M.;
Hata, S.; Nishii, Y.; DeLuca, H. F.; Suda, T. Proc. Natl. Acad. Sci.
U.S.A. 1983, 80, 201. (b) Sato, T.; Takuagawa, K.; Asoo, N.; Konno, K.
Br. J . Cancer 1984, 50, 123. (c) Eisman, J . A.; Barkla, D. H.; Tutton,
J . M. Cancer Res. 1987, 47, 21. (d) Uskokovic, M. R. Recent Advances
in Vitamin D Chemistry and Pharmacological Activity. Bioorg. Med.
Chem. Lett. 1993, 3, 1783. (e) Vitamin D, A Pluripotent Steroid
Hormone: Structural Studies, Molecular Endocrinology and Clinical
Applications; Norman, A. W., Bouillon, R., Thomasset, M., Eds.; Walter
de Gruyter: Berlin, 1994.
(10) J ones, G.; Schnoes, H. K.; DeLuca, H. F. Biochemistry 1975,
14, 1250.
(11) (a) Norman, A. W.; Roth, J .; Orci, L. Endocr. Rev. 1982, 3, 331.
(b) Reddy, G. S.; Tserng, K. Biochemistry 1986, 25, 5328 and references
therein. (c) Koszewski, N. J .; Reinhardt, T. A.; Napoli, J . L.; Beitz, D.
C.; Horst, R. L. Biochemistry 1988, 27, 5785.
(12) It has been reported that vitamin D2 and some of its metabolites
are less toxic than the corresponding compounds of the vitamin D3
series: (a) Tjellesen, L.; Gotfredsen, A.; Christiansen, C. Calcif. Tissue
Int. 1985, 37, 218. (b) Sjoden, G.; Smith, C.; Lindgren, U.; DeLuca, H.
F. Proc. Soc. Exp. Biol. Med. 1985, 178, 432.
(5) (a) Leukemia: Inaba, M.; Koyama, H.; Hino, M.; Okuno, S.;
Terada, M.; Nishizawa, Y.; Nishino, T.; Morii, H. Blood 1993, 82, 53.
(b) Breast: Wijngaarden, T. V.; Pols, H. A. P.; Buurman, C. J .;
Birkenha¨ger, J . C.; van Leeuwen, J . P. T. M. Breast Cancer Res. Treat.
1994, 29, 161 and refs therein. (c) Prostate: Skowronski, R. J .; Peehl,
D. M.; Feldman, D. Endocrinology 1995, 136, 20.
(6) (a) DeLuca, H. F. FASEB 1987, 224. (b) Nodin, B. E. C.; Morris,
H. A. J . Cell. Biochem. 1992, 49, 19.
(7) (a) Kragballe, K. J . Cell. Biochem. 1992, 49, 46. (b) van de
Kerkhof, P. C. M. Br. J . Dermatol. 1995, 132, 675 and references
therein.
(13) In humans, vitamin D2 and vitamin D3 (or their corresponding
metabolites) have similar biological potencies, whereas in avians
vitamin D3 is about 10 times as active as vitamin D2: Drescher, D.;
DeLuca, H. F.; Imrie, H. H. Arch. Biochem. Biophys. 1969, 130, 657.
(14) (a) Reddy, G. S.; Tseng, K.-Y. Biochem. 1986, 25, 5328. (b) Clark,
J . W.; Reddy, G. S.; Santos-Moore, A.; Wankadiya, K. F.; Reddy, G.
P.; Eil, C.; Lasky, S.; Tserng, K.-Y., Horst, R. L.; Uskokovic′, M. R.
Bioorg. Med. Chem. Lett. 1993, 3, 1873.
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Biophys. 1989, 273, 64. (b) Norman, A. W.; Koeffler, H. P.; Bishop, J .
E.; Collins, E. D.; Sergeev, I.; Zhou, L. X.; Nemer, I.; Zhou, J .; Henry,
H. L.; Okamura, W. H. In Vitamin D: Gene Regulation, Structure-
function Analysis and Clinical Application; Norman, A. W., Bouillon,
R., Thomasset, M., Eds; Walter de Gruyter: Berlin, 1991; p 146.
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(9) DeLuca, H. F. Handb. Physiol. 1978, 7, 265.
S0022-3263(97)00604-X CCC: $14.00 © 1997 American Chemical Society

Copper-Mediated Synthesis of 1R,25-Dihydroxyvitamin D2
J . Org. Chem., Vol. 62, No. 18, 1997 6345
Sch em e 1
tients, making the therapeutic window of efficacy quite
narrow. For this reason, there is increasing interest in
the development of new vitamin D analogs with strong
cell-differentiating and weak calcemic effects. Most
analogs examined to date belong to the natural vitamin
D3 series rather than the vitamin D2 series,16 although
analogs have been reported that preserve structural
features of vitamin D2 such as the C22-C23 double bond17
or both this double bond and the C-24 methyl group.18,19
Interest in the biological evaluation of vitamin D2
metabolites and analogs has led to the development of
several synthetic approaches to these compounds. Among
the methods that have been used for the introduction of
vitamin D2 and 25-OH-D2 side chains20 are the Wittig
reaction,21 the J ulia olefination,7b,19a,22 the solvolysis of
cyclopropylcarbinyl precursors,23 the chemistry of Zr(C5H5)2
on vinylcyclopropanes,24 the chemistry of isoxazolidines
derived from nitrones,25 the Ramberg-Ba¨cklund reac-
tion,26 and the Claisen rearrangement.27 During the last
decade we have synthesized 25-hydroxyvitamin D2 (2c)28a
and 1R,25-dihydroxyvitamin D2 (2b),28b introducing the
24-methyl group by SN2′ syn-displacement of Z-allylic
phenyl carbamates by Li2Cu3Me5 (Scheme 1). Drawbacks
to this approach are (1) the need to use chiral reducing
agents or to open chiral dioxanones or acetal templates
in order to introduce the allylic 22R-hydroxy configura-
tion; and (2) difficulties with the introduction of alkyl
groups other than methyl by SN2′ syn-displacement of the
carbamate by an alkyl cuprate.29
(16) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. Rev.
1995, 16, 200.
(17) Some interesting analogs of this type are (a) Calcipotriol (MC-
903), which is used for the topical treatment of psoriasis; see Calverley,
M. J .; J ones, G. Vitamin D. In Antitumor Steroids; Blickenstaff, R. T.,
Ed., Academic Press: San Diego, 1992. (b) (22E,25R)-1R,25,26-(OH)3-
Here we describe two short, practical synthetic routes
to 1R,25-dihydroxyvitamin D2 and its analogs modified
at C-24.
∆
22-D3, which has been identified as a potential antiosteoporotic agent;
see Drezner, M. K.; Nesbitt, T. In Vitamin D: Gene Regulation,
Structure-function Analysis and Clinical Application; Norman, A. W.,
Bouillon, R., Thomasset, M., Eds.; Walter de Gruyter: Berlin, 1991; p
816. (c) EB-1089, which inhibits the growth of breast cancer cells in
vitro and in vivo; see Binderup, L. Bioorg. Med. Chem. Lett. 1993, 3,
1891.
Syn th etic P la n
As an extension of our previous work on the synthesis
of vitamin D2 metabolites and analogs, we initially
envisaged the synthesis of the target 1R,25-(OH)2-D2
analogs modified at C-24 by the retrosynthetic analysis
depicted in route A of Scheme 2. This approach takes
advantage of the ready availability of aldehyde 7 by
degradation of commercially available vitamin D2
(2a ).27,28b,c A key step in this approach is the SN2′ anti-
alkylation by cuprates30 of (E)-allylic systems of type 5,
which would be derived from stereoselective reaction of
aldehyde 7 with the appropriate vinyl carbanion31 fol-
lowed by esterification. In preliminary studies using
semirigid allylic systems, similar regio- and stereochem-
ical results were obtained for the alkylation of simple
secondary allylic phosphate esters, pivalates, and ben-
zoates under Goering conditions (RMgX with a catalytic
amount of CuCN),32 phosphates giving higher yields on
reaction products.33 This result, combined with the fact
that Yamamoto and co-workers have also reported that
(18) (a) 1R,25-(OH)2-24-methyl-D2: Sai, H.; Takatsuto, S.; Chem.
Pharm. Bull. 1985, 33, 4815. (b) 1R,25-Dihydroxy-24-epivitamin D2 is
biotransformed to biologically potent 1R,25-(OH)2-∆22-26-homo-D3:
Tanaka, Y.; Sicinski, R. R.; DeLuca, H. F.; Ikekawa, N. Biochemistry
1986, 29, 5512. (c) Dihydrotachysterol D2 (DHT2) is still used in the
treatment of hypoparathyroidism and to prevent bone disorders
attending renal failure: Cota, J . G.; Meilan, M. C.; Mourin˜o, A.;
Castedo, L. J . Org. Chem. 1988, 53, 6094 and references therein. (d)
Kutner, A.; Perlman, K. L.; Lago, A.; Sicinski, R. R.; Schnoes, H. K.;
DeLuca, H. F. J . Org. Chem. 1988, 53, 3450. (e) 25-OH-DHT2 is
biologically more potent than DHT2, but its therapeutical utility has
not yet been studied: Maestro, M. A.; Castedo, L.; Mourin˜o, A. J . Org.
Chem. 1992, 57, 5208.
(19) 1R,25,28-Trihydroxyvitamin D2 inhibits the proliferation of
keratinocytes and sebocytes with low calcium liability, and stimulates
renal vitamin D receptor without causing hypercalcemia: (a) Choudhry,
S. C.; Belica, P. S.; Coffen, D. L.; Foella, A.; Maehr, H.; Manchand, P.
S.; Serico, L.; Yang, R. T. J . Org. Chem. 1993, 8, 1496. (b) Goff, J . P.;
Horst, R. L.; Uskokovic′, M. R. Bioorg. Med. Chem. Lett. 1993, 3, 1825.
(20) (a) Piatak, D. M.; Wicha, J . Chem. Rev. 1978, 78, 199. (b)
Lythgoe, B. Chem. Soc. Rev. 1980, 9, 449. (c) Redpath, J .; Zeele, E. J .
J . Chem. Soc. Rev. 1983, 12, 75-98. (d) Pardo, R.; Santelli, M. Bull.
Soc. Chim. Fr. 1985, 98. (e) Quinkert, G. Vitamin D Active Compounds.
Part I. Synform 1985, 3, 41. (f) Part II. Ibid. 1986, 4, 131. (g) Part III.
Ibid. 1987, 5, 1. (h) Wilson, S. R.; Yasmin, A. Stereoselective Synthesis
of Vitamin D. In Studies in Natural Products Chemistry; Atta-ur-
Rahman., Ed.; Elsevier: Amsterdam, 1992, Vol. 10, p 43. (i) Dai, H.;
Posner, G. H. Synthesis 1994, 1383. (j) Schmalz, H.-G. Nachr. Chem.
Tech. Lab. 1994, 42, 397. (k) Zhu, G.-D.; Okamura, W. H. Chem. Rev.
1995, 95, 1877.
(26) Schmittberger, T.; Uguen, D. Tetrahedron Lett. 1996, 37, 29.
(27) Lythgoe, B.; Roberts, D. A.; Waterhouse, I. J . Chem. Soc., Perkin
Trans. 1 1977, 2608.
(28) (a) Sardina, F. J .; Mourin˜o, A.; Castedo, L. Tetrahedron Lett.
1983, 24, 4477. (b) Sardina, F. J .; Mourin˜o, A.; Castedo, L. J . Org.
Chem. 1986, 51, 1264. (c) Granja, J . R.; Castedo, L.; Mourin˜o, A. J .
Org. Chem. 1993, 58, 124.
(29) Maestro, M. A. Doctoral Thesis, Santiago de Compostela, 1989.
(30) For examples of subsitution reactions at an allylic carbon, see:
(a) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett
1991, 251 and references therein. (b) Yanagisawa, A.; Nomura, N.;
Yamamoto, H. Synlett 1993, 689. (c) Flemming, S.; Kabbara, J .;
Nickisch, K.; Westermann, J .; Mohr, J . Synlett 1995, 183. (d) Persson,
S. M., Klaveen, M. v.; Grove, D. M.; Ba¨ckvall, J . E.; Koten, G. v. Chem.
Eur. J . 1995, 1, 351 and references therein.
(31) It is known that simple vinyl carbanions react with steroidal
22-aldehydes with poor stereoselectivity to give the Cram (R)-allylic
alcohol as the major product. For a few examples, see: ref 20, and (a)
Khripach, V. A.; Zhabinskiy, V. N.; Olkhovick, V. K. Tetrahedron Lett.
1990, 31, 4937. (b) Back, T. G.; Blazecka, P. G.; Krishna, M. V.
Tetrahedron Lett. 1991, 32, 4817.
(21) Hanekamp, J . C.; Rookhuizen, R. B.; v. d. Heuvel, H. L. A.; Bos,
H. J . T.; Brandsma, L. Tetrahedron Lett. 1991, 32, 5397.
(22) Although the overall yield of the J ulia olefination method is
generally lower than that of the Wittig approach, high yields have been
obtained in some cases. For examples of the J ulia olefination, see: (a)
Yamada, S.; Shiraishi, M.; Ohmori, M.; Takayama, H. Tetrahedron
Lett. 1984, 25, 3347. (b) Wicha, J .; Bal, K.; Piekut, S. Synth. Commun.
1977, 7, 215. (c) Perlman, K. L.; Sicinski, R. R.; Phelps, M. E.; Schnoes,
H. K.; DeLuca, H. F. Tetrahedron Lett. 1987, 28, 6129. (d) Sicinski, R.
R.; DeLuca, H. F.; Schnoes, H. K.; Tanaka, Y.; Smith, C. M. Bioorg.
Chem. 1987, 15, 15. (e) Perlman, K. L.; DeLuca, H. F. Tetrahedron
Lett. 1992, 33, 2937. (f) Kutner, A.; Chodynski, M.; Halkes, S. J .;
Brugman, J . Bioorg. Chem. 1993, 21, 13.
(23) Wilson, S. R.; Davey, A. E.; Guazzaroni, M. E. J . Org. Chem.
1992, 57, 2007.
(24) Harada, S.; Kiyono, H.; Taguchi, T.; Hanzawa, Y.; Shiro, M.
Tetrahedron Lett. 1955, 36, 9489.
(25) (a) Baggiolini, F. G.; Iacobelli, J . A. ; Hennessy, B. M.; Batcho,
A. D.; Sereno, J . F.; Uskokovic′, M. R. J . Org. Chem. 1986, 51, 3098.
(b) Batcho, A. D.; Sereno, J . F.; Hennessy, B. M.; Baggioloni, E. G.;
Uskokovic′, M. R,; Horst, R. L. Bioorg. Med. Chem. Lett. 1993, 3, 1821.
(32) (a) Tseng, C. C.; Paisley, S. D.; Goering, H. L. J . Org. Chem.
1986, 51, 2884. (b) Tseng, C. C.; Yen, S.-J ., Goering H. L. ibid. 1986,
51, 2892 and references therein.
(33) Torneiro, M. Doctoral Thesis, Santiago de Compostela, 1994.

6346 J . Org. Chem., Vol. 62, No. 18, 1997
Torneiro et al.
Sch em e 2
Sch em e 3
major product in only moderate yield led us to replace
the potentially labile benzoate protecting group with a
silyl group. In order to selectively remove this silyl
protecting group before introducing the vitamin D triene
system by the Wittig-Horner olefination method,20b it
was also necessary to replace the protecting group at C-25
(Scheme 4). To this end, the requisite lithium reagent
8c was conveniently prepared in two steps from the
protected propargylic alcohol 11.28c Irradiation of 11 in
the presence of Bu3SnH and AIBN led to the formation
of the vinyltin reagent 8b, which was converted to the
desired vinyllithium reagent 8c by treatment with n-
butyllithium. After some experimentation, we found that
addition of 8c (3.3 mmol) to a solution of aldehyde 7b35
(0.3 g, 0.94 mmol) in Et2O at -78 °C afforded a chro-
matographically separable 7:1 mixture of epimeric alco-
hols 5c and 5d in 88% yield. The stereochemistry of 5c
and 5d at C-22 was established by comparison of their
1H NMR spectra with those of 5a and 5b. Attempts to
scale up this procedure to 1.5 g (4.6 mmol) of aldehyde
7b resulted in lower yields; however, this setback was
easily overcome by adding a cooled (-85 °C) solution of
the aldehyde to a -78 °C cooled solution of the lithium
reagent. With the (22R)-alcohol 5c in hand, we next
attempted the preparation of the phosphate 5e, using
Murahashi reaction conditions [(EtO)2POCl, py, CH2Cl2].36
This procedure gave unexpectedly low yields (≈40%) due
to elimination of the phosphate group. However, depro-
tonation of alcohol 5c with n-butyllithium in Et2O at -78
°C, followed by reaction of the resulting lithium alkoxide
with diethyl chlorophosphate at -78 °C, led to the
formation of the desired phosphate 5e in 93% yield.
The stage was now set for studying the reaction of
allylic phosphate 5e with organocuprates. For construc-
tion of 25-OH-D2 side chain, we first tried Goering
reaction conditions [MeMgCl (20 equiv), CuCN (2 equiv),
Et2O, 0 °C f rt].32 Under these conditions alkylation was
not regioselective, affording an inseparable roughly 1:1
allylic phosphates react efficiently in an SN2’ anti fashion
with cuprates derived from magnesium reagents,30a led
us to examine the utility of a phosphate leaving group
first. The synthetic plan also includes a second approach
(route B), in which the copper chemistry is carried out
on an allylic system of type 6, which contains the fully
assembled vitamin D triene unit. This approach has the
advantage that it would allow for the preparation of
several vitamin D2 analogs modified at C-24 in a short
period of time simply by reacting different cuprates with
6, albeit with the risk of destroying the labile vitamin D
triene unit. Since synthesis of vitamin D2 analogs 3 by
both routes was envisaged to pass through 5, this
compound was our first synthetic target.
Resu lts a n d Discu ssion
1. F or m a tion of th e CD Sid e Ch a in F r a gm en t
(Rou te A). Our experiments started from aldehyde
7a 27,28b,c which was treated with the vinyllithium reagent
8a prepared using methodology developed by Salomon
and co-workers34 (Scheme 3). At best, slow addition of
8a (4.5 mmol) to aldehyde 7a (3.2 mmol, THF, -78 °C)
led to a chromatographically separable 6.7:1 mixture of
allylic alcohols 5a and 5b in 61% yield. The stereochem-
istry of these alcohols at C-22 was established by
comparison of the 1H and 13C NMR spectra of the
corresponding deprotected, saturated compounds 9a and
9b with authentic samples prepared from the known
propargylic alcohols 10a and 10b.28c
(35) (a) Wovkulich, P. M.; Barcelos, F.; Batcho, A. D.; Sereno, J . F.;
Baggiolini, E. G.; Hennessy, B. B.; Uskokovic′, M. R. Tetrahedron 1984,
40, 2283. (b) Dauben, W. G.; Ollman, R. R.; Funhoff, A. S.; Neidlein,
R. Tetrahedron Lett. 1989, 30, 677. (c) Ferna´ndez, B.; Mart´ınez-Pe´rez,
J . A.; Granja, J . R.; Castedo, L.; Mourin˜o, A. J . Org. Chem. 1992, 57,
3173.
The fact that reaction of vinyllithium reagent 8a with
aldehyde 7a provided the desired Cram alcohol 5a as the
(34) Salomon, R. G.; Basu, B.; Roy, S.; Sachinvala, N. D. J . Am.
Chem. Soc. 1991, 113, 3096.
(36) Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J . Org.
Chem. 1989, 54, 3292.

Copper-Mediated Synthesis of 1R,25-Dihydroxyvitamin D2
J . Org. Chem., Vol. 62, No. 18, 1997 6347
Sch em e 4
Sch em e 5. Goer in g’s Mech a n ism for th e Rea ction
of Cu p r a tes w ith Allylic Ester s
yield. This type of behavior in the reactions of sp2-
organocopper reagents with allylic systems was also
described by other authors.30b,31a,b,40,41
The above results can be rationalized by the mecha-
nism proposed by Goering,41a in which the allylic ester
and alkyl cuprate initially form a σ-allylic copper complex
B (Scheme 5) that can undergo reductive elimination to
the SN2′ product C faster than it isomerizes to the
π-allylic complex D. By contrast, aryl and vinyl cuprates
form the π-allylic complex D from which both SN2 product
E and the SN2′ product C may be formed.
2. Syn th esis of Vita m in D An a logs. For assembly
of the triene unit of the target vitamin D2 analogs
modified at C-24, we chose the Lythgoe-Roche phosphine
oxide approach.20b,25 This mild, convergent and direct
method requires ketones 15, corresponding to the CD-
side chain fragments, and the phosphine oxide 17,
corresponding to the A-ring fragment (Scheme 6). The
requisite ketones 15b-f were prepared in 92-98% yields
from the corresponding 8â-hydroxy-precursors 12b-f.
Treatment of the phosphine oxide 1720i-k,42 with phenyl-
lithium at -78 °C,43 followed by Lythgoe-type coupling20b,25
of the resulting anion with each of the CD side chain
ketone fragments, provided the corresponding protected
vitamin D analogs 18c-f. Cleavage of the protecting
groups using the cationic ion-exchange resin AG50 WX4
in MeOH afforded a complex mixture of partially depro-
tected products, resulting in the desired vitamin D
analogs in low yield after long reaction times. However,
cleavage of the tert-butyldimethylsilyl groups of 18c-f
by reaction with tetrabutylammonium fluoride, followed
by treatment of each of the resulting crude diols with
AG50 WX4 resin in MeOH, afforded the vitamin D
analogs 19c,d ,f in high yield (≈55%, in three steps from
ketones 15). The formation of 19e as a mixture of
diastereomers can be inferred to be due to transketal-
ization following deprotection. In a similar manner
ketones 16f,g, prepared from 14f,g, were converted to
protected analogues 20f,g. Desilylation followed by
methanolysis of the OMOM group of 20f,g in the presence
of the acidic resin afforded the 25-methoxyvitamin D
analogs 21f,g.44
mixture of the SN2′ and SN2 products 4a and 13a ,
respectively, in 86%. However, under Yamamoto condi-
tions [MeMgCl (10 equiv), CuCN‚2LiCl (10 equiv), THF,
-78 °C],30a,37 the alkylation was highly regioselective,
affording, after deprotection (Bu4NF, THF, 60 °C), the
SN2′ anti-product 12a 28b in 85% yield (Scheme 4). En-
couraged by this result, we examined the reaction of 5e
with sp3-organocopper reagents bearing other alkyl groups.
Introduction of the n-butyl group under the same reaction
conditions occurred with a high degree of regioselectivity
to give, after deprotection,38 compound 12b (78%). Like-
wise, the use of Grignard reagents [c-PrMgBr, i-PrMgCl,
and (OCH2CH2O)CHCH2CH2MgBr]39 gave 4c (87%), 4d
(88%), and 4e (98%), respectively, as the only compounds
detectable by 1H and 13C NMR. However when phos-
phate 5e was treated with sp2-copper reagents under the
same reaction, partial or total loss of SN2′ regioselectivity
occurred. Thus, treatment of 5e with the cuprate derived
from PhMgCl gave a separable 1:3.4 mixture of 4f (SN2′
anti) and 13f (SN2) in 98% yield, and reaction of 5e with
CH2dCHMgBr gave only the SN2 product 13g in 58%
3. Exp lor a tion of Rou te B. Syn th esis of 1r,25-
d ih yd r oxyvita m in D2 (Sch em e 7). Route A allowed
(40) Marino, J . P.; Ferna´ndez de la Pradilla, R.; Laborde, E. J . Org.
Chem. 1987, 52, 4898.
(41) (a) Underiner, T. L.; Paisley, S. D.; Schmitter, J .; Lesheski, L.;
Goering, H. L. J . Org. Chem. 1989, 54, 2369. (b) Underiner, T. L.;
Goering, H. L. Ibid. 1991, 56, 2563.
(37) While this work was in progress, a catalytic version of the
Yamamoto reaction appeared. See ref 30b.
(38) Small amounts of SN2 regioisomers and other stereoisomers
with Z configuration at the double bond were chromatographically
removed after desilylation.
(42) Mourin˜o, A.; Torneiro, M.; Vitale, C.; Ferna´ndez, S.; Pe´rez-
Sestelo, J .; Anne´, S.; Gregorio, C. Efficient and Versatile Synthesis of
A-Ring Precursors of 1R,25-Dihydroxyvitamin D3 and Analogues.
Application to the Synthesis of Lythgoe-Roche Phosphine Oxide.
Tetrahedron Lett. 1997, 38, 4713.
(39) The compound with
a
3,3-(ethylendioxy)propyl group was
(43) Posner, G. H.; J ohnson, N. J . Org. Chem. 1994, 59, 7855.
(44) Efforts to drive the reaction to the desired 1R,25-dihydroxyvi-
tamin D analogs using MeOH-H2O or THF-H2O have not been
carried out.
prepared as a precursor for the preparation of affinity columns for the
purification of the receptor of 1R,25-dihydroxyvitamin D3 hormone
receptor.

6348 J . Org. Chem., Vol. 62, No. 18, 1997
Torneiro et al.
Sch em e 6
Sch em e 7
group by alkyl cuprates. To test the feasibility of this
step we chose 1R,25-dihydroxyergocalciferol (2b) as the
synthetic target. Treatment of phosphate 23 with the
cuprate derived from MeMgCl and CuCN in the presence
of LiCl afforded 24 as the only product (92% yield).
Removal of the silyl groups with tetra-n-butylammonium
fluoride, and the MOM protecting-group with AG50 WX4
resin in methanol, gave the nonnatural hormone 1R,25-
dihydroxyergocalciferol (2b) (89%, two steps).
the efficient preparation of several 1R,25-dihydroxyvita-
min D2 analogs modified at C-24, but required individual
preparation of each CD-side chain vitamin D fragment
prior to Wittig-Horner coupling with the A-ring phos-
phine oxide.45 In route B, the use of a ready-assembled
vitamin D triene moiety with a (22R)-phosphate group
on the side chain (23) should serve for the preparation
of numerous 1R,25-dihydroxyvitamin D2 analogs modified
at the side chain, simply by reacting it with different
cuprates. To test the feasibility of the Wittig-Horner
coupling step, a THF solution of ketone 22 prepared from
5e in 97% was treated at -78 °C with a THF solution of
the ylide resulting from metalation of phosphine oxide
17. We were pleased to find that this reaction afforded
the desired phosphate 23 in 76% yield. Next, we exam-
ined the possibility of incorporating alkyl groups in the
side chain by SN2′ anti-displacement of the phosphate
In summary, we have developed two short, efficient
approaches to the synthesis of 1R,25-dihydroxyergocal-
ciferol and its analogs modified at C-24. In route A, an
allylic phosphate bearing the CD-ring fragment of vita-
min D undergoes SN2′ anti-displacement by an organo-
cuprate and is then coupled with the A-ring fragment by
the Horner-Wittig olefination method, affording analogs
of 1R,25-dihydroxyergocalciferol with an alkyl substituent
at C-24 (eight steps and ≈38% average overall yield from
aldehyde 7b). In route B, an allylic phosphate bearing
the ready-assembled vitamin D triene unit undergoes
SN2′ anti-displacement by an organocuprate. As an
example, the organocuprate derived from MeMgCl af-
forded 1R,25-dihydroxyergocalciferol in eight steps and
48% overall yield from aldehyde 7b. Route B is particu-
larly attractive since it offers the possibility of preparing,
from a single starting allylic phosphate (23), a variety of
C-24 analogs of vitamin D2 for biological screening.
(45) Previous experiments carried out in our laboratory indicate that
the Wittig-Horner type coupling gives the vitamin D triene unit in
low yield when the amount of CD-side chain fragment used is lower
than 50 mg.

Copper-Mediated Synthesis of 1R,25-Dihydroxyvitamin D2
J . Org. Chem., Vol. 62, No. 18, 1997 6349
(22S)-8â-(Ben zoyloxy)-d es-A,B-ch olest a n e-22,25-d iol
(9a ). A mixture of diol 10a (40 mg, 0.10 mmol), Pd/C (10%, 5
mg), and NaHCO3 (12 mg, 0.14 mmol) in dioxane was
hydrogenated at balloon pressure for 12 h. EtOAc (10 mL)
was added, and the mixture was filtered through a short path
of Celite. Concentration in vacuo and flash chromatography
of the concentrate (1 × 15 cm; eluent, 30-50% EtOAc-
hexanes), afforded diol 9a [35 mg, Rf ) 0.2 (40% EtOAc-
hexanes), white solid, mp 35-37 °C]. 1H NMR: 8.07-7.40
(5H, m, Ar), 5.41 (1H, br s, H-8), 3.65 (1H, m, H-22), 1.24 (3H,
s, CH3-26), 1.23 (3H, s, CH3-27), 0.95 (3H, s, CH3-18), 0.94 (3H,
d, J ) 6.29, CH3-21). 13C NMR: 166.56 (CdO), 13 2.72 (Ar),
130.98 (Ar), 129.59 (Ar), 128.38 (Ar), 73.99, 72.19, 70.72, 52.96,
51.57, 41.79, 40.75, 40.50, 39.95, 30.51, 30.18, 29.90, 28.98,
26.57, 22.52, 17.98, 13.41, 11.57. HRMS calcd for C25H38O4
402.2770, found 402.2766.
(22R)-8â-(Ben zoyloxy)-d es-A,B-ch olest a n e-22,25-d iol
(9b). Procedure as above. 9b [81%, Rf ) 0.25 (50% EtOAc-
hexanes), white solid]. 1H NMR: 8.07-7.41 (5H, m, Ar), 5.42
(1H, br s, H-8), 3.65 (1H, m, H-22), 1.25 (3H, s, CH3-26), 1.24
(3H, s, CH3-27), 1.05 (3H, s, CH3-18), 0.96 (3H, d, J ) 6.73,
CH3-21). 13C NMR: 166.56 (CdO), 132.73 (Ar), 130.94 (Ar),
129.59 (Ar), 128.40 (Ar), 74.13, 71.98, 70.74, 53.68, 51.31,
42.16, 41.95, 42.01, 39.95, 30.56, 29.97, 29.15, 26.30, 24.43,
22.65, 17.96, 13.43, 12.27. HRMS: calcd for C25H38O4 402.2770,
found 402.2771.
P r ep a r a tion of 9a a n d 9b fr om a Mixtu r e of 5a a n d
5b. A mixture of 5a and 5b (50 mg, 0.097 mmol), Pd/C (10%,
5 mg), and NaHCO3 (12 mg, 0.14 mmol) in dioxane (2.5 mL)
was hydrogenated at balloon pressure for 24 h. EtOAc (10
mL) was added, and the mixture was filtered through a short
path of Celite. After concentration in vacuo, the residue was
dissolved in THF (1 mL). Tetrabutylammonium fluoride
(TBAF, 0.5 mL, 0.55 mmol, 1.1 M in THF) was added. After
stirring for 24 h, the mixture was concentrated in vacuo. The
residue was extracted with Et2O. The combined organic
phases were washed with saturated NaCl, dried, filtered, and
concentrated in vacuo. Comparison of the spectral data of the
mixture (1H NMR and 13C NMR) with those obtained above
for 9a and 9b shows that 9a is the major component.
(1E)-3-[(Meth oxym eth yl)oxy]-3-m eth yl-1-(tr ibu tylsta n -
n yl)-1-bu ten e (8b). A mixture of compound 11 (0.50 g, 3.90
mmol), Bu3SnH (1.51 g, 1.4 mL, 5.20 mmol), and AIBN (20
mg) was irradiated with a 300 W tungsten lamp at rt for 15
min and at 95 °C for 6 h. The mixture was slowly cooled to
rt. Flash chromatography (1.5 × 15 cm; eluent, 0-0.7%
EtOAc-hexanes) gave tin derivative 8b [1.36 g, 83%, Rf ) 0.4
(10% EtOAc-hexanes), colorless liquid, bp 120 °C/1 mmHg].
1H NMR: 6.02 (2H, AB, J ) 19.5, HCdCH), 4.63 (2H, s,
OCH2O), 3.35 (3H, s, OCH3), 1.47 [6H, m, Sn(CH2-)3], 1.30 (6H,
s, 2 CH3), 1.29 [6H, m, Sn(CH2CH2-)3], 0.91-0.85 [15H, m,
(-CH2CH3)3]. 13C NMR: 153.26 (CHd), 126.58 (CHd), 91.97
(OCH2O), 77.76 (COMOM), 54.98 (OCH3), 29.01 [Sn(CH2-)3],
27.12 [Sn(CH2CH2-)3], 26.75 [C(CH3)2], 13.55 [(-CH3)3], 9.42
[(-CH2CH3)3]. Anal. Calcd for C19H40O2Sn: C, 54.44; H, 9.62.
Found: C, 54.16; H, 9.25.
(22R,23E)-8â-[(ter t-Bu tyld im eth ylsilyl)oxy]-25-[(m eth -
oxym eth yl)oxy]-d es-A,B-ch olest-23-en -22-ol (5c). n-Bu-
tyllithium (3 mL, 2.38 M in hexanes, 7.11 mmol) was slowly
added to tin compound 8b (2.98 g, 7.11 mmol, freshly bulb to
bulb distilled) in Et2O (19 mL) at -78 °C. After stirring for 4
h, the reaction mixture was cooled to -85 °C. A solution of
aldehyde 7b (1.49 g, 4.59 mmol) in Et2O (36 mL) was
cannulated over 15 min. After stirring for 2 h, the reaction
was quenched by dropwise addition of MeOH. The mixture
was allowed to warm to rt and then was poured into a mixture
of saturated NaCl and HCl (10%) and extracted with Et2O.
The combined organic extracts were dried, filtered, and
concentrated in vacuo. Medium pressure liquid chromatog-
raphy (5 × 45 cm; eluent 10% EtOAc-hexanes) gave alcohol
5c [1.58 g, 76%, Rf ) 0.61 (30% EtOAc-hexanes)] as a colorless
oil which crystallizes upon standing in the refrigerator during
several days (mp 49 °C), and 5d [0.24 g, 11%; Rf ) 0.57 (30%
EtOAc-hexanes); colorless oil]. 5c. 1H NMR: 5.66 (1H, d, J
) 16.1, H-24), 5.58 (1H, dd, J ) 16.1, 3.5, H-23), 4.62 (2H, s,
OCH2O), 4.25 (1H, br s, H-22), 3.98 (1H, br s, H-8), 3.33 (3H,
Exp er im en ta l Section
Gen er a l. All reactions involving oxygen- or moisture-
sensitive compounds were carried out under a dry argon
atmosphere. Reaction temperatures refer to external bath
temperatures. All dry solvents were distilled under argon
immediately prior to use. Tetrahydrofuran (THF) and ether
(Et2O) were distilled from Na/benzophenone. Dichloromethane
(CH2Cl2) was distilled from P2O5. The concentrations of
commercially available solutions of organolithium reagents
(Aldrich) were checked by titration using diphenylacetic acid.47
Liquid reagents or solutions of reagents were added by syringe
or cannula. The analytical grade cation exchange resin AG50
WX4 was supplied by BioRad. Organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated with a
rotary evaporator at aspirator pressure (20-30 mmHg). Reac-
tions were monitored by thin layer chromatography (TLC)
using aluminum Merck 60 silica gel plates (0.2 mm thickness).
After ultraviolet illumination at 254 nm, the plates were
visualized by immersion in a solution of phosphomolybdic acid
in MeOH (5%), followed by heating. Column chromatography
was performed with Merck 60 (230-400 mesh) silica gel.48 All
NMR spectra were measured as solutions in CDCl3 unless
otherwise stated. Chemical shifts are reported as δ units
(ppm) downfield from tetramethylsilane (δ 0.0) using residual
solvent signal as an internal standard: δ 7.26 (1H), 77.0 triplet
(13C). All coupling constants are measured in hertz units (Hz).
DEPT was used to assign carbon types. Unless otherwise
noted, mass spectra were measured using electron impact
ionization at 70 eV.
(22R,23E)-8â-(Ben zoyloxy)-25-[(tr ieth ylsilyl)oxy]-d es-
A,B-ch olest-23-en -22-ol (5a ) a n d (22S,23E)-8â-(Ben zoyl-
oxy)-25-[(tr ieth ylsilyl)oxy]-des-A,B-ch olest-23-en -22-ol (5b).
n-Butyllithium (1.83 mL, 2.46 M in hexanes, 4.50 mmol) was
slowly added to a solution of (1E)-3-methyl-1-(tributylstannyl)-
3-[(triethylsilyl)oxy]-1-butene34 (2.21 g, 3.21 mmol) in tetrahy-
drofuran (10 mL) at -78 °C. After stirring for 4 h, the solution
was slowly cannulated into a solution of aldehyde 7a (1.01 g,
3.21 mmol) in tetrahydrofuran (10 mL) at -78 °C. After 2 h,
the reaction was quenched by dropwise addition of MeOH.
After warming to rt, the mixture was concentrated in vacuo.
Flash chromatography (2.5 × 20 cm; eluent, 6-8% EtOAc-
hexanes) afforded a 6.7:1 mixture of 5a and 5b (1 g, 60%
combined yield). HPLC separation of an aliquot (Phenomenex
Zorbasil 10 × 250 mm column; eluent 1% 2-propanol-hexanes,
Φ ) 1.5 mL/min) gave 5a [tR ) 25.2 min, Rf ) 0.69 (30%
EtOAc-hexanes), colorless oil], and 5b [tR ) 22.1 min, Rf )
0.70 (30% EtOAc-hexanes), colorless oil]. 5a . 1H NMR:
8.07-7.41 (5H, m, Ar), 5.74 (1H, d, J ) 15.7, H-24), 5.68 (1H,
dd, J ) 15.7, 4.51, H-23), 5.42 (1H, br s, H-8), 4.26 (1H, br s,
H-22), 1.31 (3H, s, CH3-26), 1.30 (3H, s, CH3-27), 1.06 (3H, s,
CH3-18), 0.94 [9H, t, J ) 7.9, Si(CH2CH3)3], 0.91 (3H, d, J )
6.04, CH3-21), 0.57 [6H, q, J ) 7.9, Si(CH2CH3)3]. 13C NMR:
166.52 (CdO), 138.88 (CH-23 or 24), 132.68 (CHd), 131.00
(Cd), 129.59 (CHd), 128.78 (CH-23 or 24), 128.36 (CHd),
73.54, 72.79 (C-25), 72.17, 52.85, 51.56, 42.79 (C-13), 41.11,
39.86 (CH2), 30.75 (C-26), 30.51 (CH2), 30.43 (C-27), 26.61
(CH2), 22.57 (CH2), 17.96 (CH2), 13.38, 11.86, 6.93 [Si(CH2CH3)3],
6.65 [Si(CH2CH3)3]. Anal. Calcd for C31H50O4Si: C, 72.33; H,
9.79. Found: C, 72.40; H, 9.55. 5b. 1H NMR: 8.07-7.41 (5H,
m, Ar), 5.78 (1H, d, J ) 15.5, H-24), 5.63 (1H, dd, J ) 15.5,
7.0, H-23), 5.41 (1H, br s, H-8), 4.19 (1H, dd, J ) 7.0, 3.6, H-22),
1.32 (3H, s, CH3-26), 1.31 (3H, s, CH3-27), 1.07 (3H, s, CH3-
18), 0.97 (3H, d, J ) 6.14, CH3-21), 0.96 [9H, t, J ) 7.8,
Si(CH2CH3)3], 0.59 [6H, q, J ) 7.8, Si(CH2CH3)3]. 13C NMR:
166.56 (CdO), 141.65 (CH-23 or 24), 132.75 (CHd), 130.99
(Cd), 129.62 (CHd), 128.42 (CHd), 124.58 (CH-23 or 24),
74.00, 72.90 (C-25), 72.01, 53.49, 51.39, 42.16 (C-13), 41.78,
39.95 (CH2), 30.84 (C-26 or 27), 30.59 (CH2), 30.48 (C-26 or
27), 26.51 (CH2), 22.76 (CH2), 17.96 (CH2), 13.53, 12.29, 7.03
[Si(CH2CH3)3], 7.73 [Si(CH2CH3)3]. HRMS calcd for C31H50O4Si
514.3478, found 514.3478.
(46) Attempts to carry out this type of transformation using other
cuprates have not been pursued although similar results are expected.
(47) Kofron, W. G.; Badawski, L. M. J . Org. Chem. 1976, 41, 1879.
(48) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

6350 J . Org. Chem., Vol. 62, No. 18, 1997
Torneiro et al.
s, OCH3), 1.31 (6H, s, CH3-26 and 27), 0.90 (3H, s, CH3-18),
0.86 [9H, s, SiC(CH3)3], 0.82 (3H, d, J ) 5.93, CH3-21), -0.01
(3H, s, SiCH3), -0.03 (3H, s, SiCH3). 13C NMR: 135.00 (CHd),
132.58 (CHd), 91.75 (OCH2O), 75.88 (C-25), 73.35 (69.41),
54.95 (OCH3), 53.13, 52.98, 41.95 (C-13), 40.81, 40.60 (CH2),
34.35 (CH2), 27.32, 27.24 (C-26 and 27), 26.81 (CH2), 25.74
[SiC(CH3)3], 22.93 (CH2), 17.94 [SiC(CH3)3], 13.57, 11.78, -4.89
(SiCH3), -5,26 (SiCH3). Anal. Calcd for C26H50O4Si: C, 68.67;
H, 11.08. Found: C, 68.62; H, 10.86.
trated in vacuo. Flash chromatography gave ketones 15b-f
or 16f,g in high yields (92-99%).
(22E,24S)-24-n -Bu tyl-25-[(m eth oxym eth yl)oxy]-des-A,B-
ch olest-22-en -8-on e (15b): 95%, Rf ) 0.4 (25% EtOAc-
hexanes), colorless viscous oil. 1H NMR: 5.24 (1H, dd, J )
15.2, 8.8, H-22 or 23), 5.11 (1H, dd, J ) 15.2, 9.2, H-22 or 23),
4.70 (2H, AB, J ) 7.0, OCH2O), 3.36 (3H, s, OCH3), 1.18 (3H,
s, CH3-26), 1.13 (3H, s, CH3-27), 1.06 (3H, d, J ) 6.9, CH3-21),
0.88 [3H, t, J ) 6.9, (CH2)3CH3], 0.66 (3H, s, CH3-18). 13C
NMR: 211.69 (CdO), 138.63 (CH-23), 128.99 (CH-22), 90.87
(OCH2O), 78.16 (C-25), 62.02 (CH-14), 56.41 (CH-17), 55.12
(OCH3), 53.20 (CH-24), 49.73 (C-13), 40.96 (CH2-9), 40.07 (CH-
20), 38.88 (CH-12), 30.23 (CH2), 28.23 (CH2), 27.94 (CH2-16),
25.53 (CH3-26), 24.07 (CH2-11), 23.21 (CH3-27), 22.67 (CH2),
20.94 (CH3-21), 19.15 (CH2-15), 14.14 [CH3(CH2)3], 12.68 (CH3-
18). HRMS calcd for C24H42O3 - CH3 363.2899, found 363.2897.
(22R,23E)-22-P h en yl-25-[(m eth oxym eth yl)oxy]-des-A,B-
ch olest-23-en -8-on e (16f): 96%, Rf ) 0.4 (25% EtOAc-
hexanes), colorless oil. 1H NMR: 7.32-7.27 (m, 2H, Ar), 7.20-
7.16 (3H, m, Ar), 5.95 (1H, dd, J ) 15.7, 10, H-23), 5.66 (1H,
d, J ) 15.7, H-24), 4.50 (2H, AB, J ) 7.0, OCH2O), 3.53 (1H,
dd, J ) 10, 2.6, H-22), 3.37 (3H, s, OCH3). 13C NMR: 211.65
(CdO), 144.65 (Cd), 138.64 (CH-23), 128.22 (2CHd), 127.86
(2CHd),126.77 (CHd), 125.88 (CH-24), 91.88 (CH2), 76.24 (C),
61.99 (CH), 55.10 (CH3), 54.89 (CH), 50.22 (CH), 49.81 (C),
42.28 (CH), 40.95 (CH2), 39.07 (CH2), 28.14 (CH3), 27.66 (CH2),
27.18 (CH3), 24.03 (CH2), 19.24 (CH2), 13.60 (CH3), 12.59 (CH3).
HRMS: calcd for C26H38O3 - CH3 383.2586, found 383.2594.
Gen er a l P r oced u r e for th e Cou p lin g Rea ction be-
tw een th e CD Rin g Keton e a n d th e P h osp h in e Oxid e A
Rin g. Phosphine oxide 17 (1 g, 1.718 mmol) was purified by
flash chromatography (3 × 30 cm; eluent, HPLC grade Et2O).
After concentration in vacuo, the phosphine oxide was trans-
ferred to a 100 mL round bottomed flask with hexanes (15 mL).
Concentration in vacuo gave a solid which was dissolved in
hexanes (30 mL). After concentration in vacuo, the phosphine
oxide was vacuum dried over P2O5 for 12 h. The round
bottomed flask containing pure 17 (0.907 g, 1.558 mmol) and
activated molecular sieves (4 Å) was fitted with a septum cap.
Dry THF (15 mL, distilled under argon) was added. This
freshly prepared 0.104 M solution of phosphine oxide in THF
was used in the next experiments.
(22R,23E)-8â-[(ter t-Bu tyld im eth ylsilyl)oxy]-25-[(m eth -
oxym eth yl)oxy]-des-A,B-ch olest-23-en -22-ol Dieth yl P h os-
p h a te (5e). n-Butyllithium (1.26 mL, 2.38 M in hexanes, 3.0
mmol) was slowly added to alcohol 5c (1.24 g, 2.71 mmol) in
Et2O (25 mL) at -78 °C. After stirring for 15 min, diethyl
chlorophosphate (0.43 mL, 0.52 g, 3.0 mmol, freshly distilled
twice from P2O5 under vacuum) was added. After stirring for
3 h, the reaction mixture was poured into a mixtured of
saturated NaCl and ice. The mixture was extracted with Et2O.
The combined ethereal extracts were dried, filtered, and
concentrated in vacuo. Flash chromatography of the concen-
trate (2 × 20 cm; eluent 15-30% EtOAc-hexanes) afforded
phosphate 5e (1.50 g, 93%; Rf ) 0.3 (30% EtOAc-hexanes)]
as a colorless liquid. 1H NMR: 5.71 (1H, d, J ) 15.95, H-24),
5.60 (1H, dd, J ) 15.95, 5.0, H-23), 4.89 (1H, br t, J ) 6.0,
H-22), 4.64 (2H, s, OCH2O), 4.14-3.97 (4H, m, J ) 7.2,
P(OCH2CH3)2], 1.32 (6H, s, CH3-26 and 27), 0.91 (3H, d, J )
6.33, CH3-21), 0.90 (3H, s, CH3-18), 0.87 [9H, s, SiC(CH3)3],
-0.01 (3H, s, SiCH3), -0.02 (3H, s, SiCH3). 13C NMR: 137.50
(CHd), 128.04 (CHd), 91.74 (OCH2O), 81.16 (d, J ) 6.9, C-22),
75.50 (C-25), 69.23, 63.23 (q, J ) 2.8, P(OCH2CH3)2], 54.85
(OCH3), 52.92, 52.53, 41.91 (C-13), 41.83, 40.49 (CH2), 34.18
(CH2), 27.06 (C-26 and 27), 26.75 (CH2), 25.59 [SiC(CH3)3],
22.84 (CH2), 17.79 [SiC(CH3)3], 17.41 (CH2), 15.95 [q, J ) 3.5,
P(OCH2CH3)2], 13.32, 12.16, -5.04 (SiCH3), -5.40 (SiCH3).
Anal. Calcd for C30H59O7PSi: C, 60.99; H, 10.06. Found: C,
61.42; H, 10.07.
(22E,24S)-[(ter t-Bu tyld im eth ylsilyl)oxy]-25-[(m eth oxy-
m et h yl)oxy]-24-m et h yl-d es-A,B-ch olest -22-en -8â-ol (4a )
a n d (22E,24S)-25-[(Meth oxym eth yl)oxy]-24-m eth yl-d es-
A,B-ch olest-22-en -8â-ol (12a ). A mixture of CuCN (63 mg,
0.70 mmol, Aldrich) and LiCl (59 mg, 1.4 mmol) in THF (2
mL) was stirred to effect solution. After cooling to -78 °C,
methylmagnesium chloride (0.235 mL, 3 M in THF, 0.7 mmol)
was added dropwise. The cooling bath was removed, and the
mixture was stirred for 10 min. After cooling to -78 °C, a
solution of phosphate 5e (43 mg, 0.073 mmol, dried over P2O5)
in THF (1.5 mL) was cannulated into the cuprate suspension.
After stirring for 6 h, the reaction mixture was slowly warmed
to rt (12 h). The reaction was quenched dropwise with
saturated aqueous NH4Cl. After stirring for 10 min, the
mixture was extracted with hexanes. The combined organic
extracts were dried, filtered, and concentrated in vacuo to
afford 4a [30 mg, 91%; Rf ) 0.8 (10% EtOAc-hexanes)] as a
viscous oil which was treated with tetrabutylammonium
fluoride (2.3 mL, 1.1 M in THF, 2.5 mmol). The reaction
mixture was stirred for 8 days at rt, and for 20 h at 60 °C,
and was then poured into a saturated NaHCO3 solution and
extracted with Et2O. The ethereal extracts were dried, filtered,
and concentrated in vacuo. Flash chromatography of the
concentrate (1 × 10cm; eluent 12% EtOAc-hexanes) afforded
alcohol 12a 28b,c [21 mg, 0.062 mmol, 85%, Rf ) 0.35 (10%
EtOAc-hexanes)] as a viscous oil which crystallizes on stand-
ing for several days in the refrigerator (mp 56-57 °C).
Phenyllithium (0.416 mmol, 0.231 mL, 1.8 M in cyclohex-
ane-Et2O) was cannulated dropwise into a THF solution of
phosphine oxide 17 (0.395 mmol, 3.8 mL, 0.104 M) at -78 °C.
The deep red solution was stirred at -78 °C for 10 min.
A
cooled (-78 °C) solution of the CD ring ketone (15c-f and
16f,g, 0.208 mmol, dried over P2O5 for 12 h in vacuo) in THF
(1.4 mL) was cannulated dropwise. The red solution was
stirred in the dark at -78 °C for 3 h and then warmed to -65
°C over 30 min. The reaction was quenched with aqueous
sodium and potassium tartrate (0.9 mL, 2 M) and aqueous
potassium carbonate (5 mL). The mixture was allowed to
warm to rt and extracted with CH2Cl2. The organic layer was
dried, filtered, and concentrated in vacuo. Flash chromatog-
raphy of the concentrate (2 × 20 cm; eluent, 1% EtOAc-
hexanes) afforded the protected vitamin D analog (18c-f and
20f,g) which was treated with tetrabutylammonium fluoride
(3.5 mL, 2.887 mmol, 0.83 M in THF). The mixture was stirred
in the dark overnight at rt and concentrated in vacuo. The
concentrate was dissolved in Et2O, washed with brine, dried,
filtered, and concentrated in vacuo. Flash chromatography of
the concentrate (2 × 20 cm; eluent, Et2O) gave the correspond-
ing desilylated vitamin D analog, which was dissolved in
MeOH and treated with resin AG50 WX4 (1.76 g, previously
washed with MeOH). The mixture was stirred in the dark at
rt overnight and filtered. The solids were washed with EtOAc.
The combined liquids were concentrated in vacuo. Flash
chromatography of the concentrate (1.5 × 10 cm; eluent, 20%
Et2O-hexanes) afforded the vitamin D analog (19c-f and
21f,g) (49-64%, three steps from ketones 15 and 16).
Com p ou n d s 4c, 4d , 4e, 12c, 12d , 12e. These compounds
were prepared as above. The starting alkylmagnesium bro-
mides were prepared from bromocyclopropane, 2-bromopro-
pane, and 2-(2-bromoethyl)-1,3-dioxolane, respectively.
Gen er a l P r oced u r e for th e P r ep a r a tion of Keton es
15b-f a n d 16f,g. A mixture of alcohols 12b-f or 14f,g (0.28
mmol), pyridinium dichromate49 (314 mg, 0.84 mmol), and a
crystal of pyridinium tosylate in dry CH2Cl2 (6 mL) were
stirred at rt for 5 h. After adding Et2O (20 mL), the mixture
was stirred for 30 min, filtered through Celite, and concen-
(24S)-24-Cyclop r op yl-1r,25-d ih yd r oxy-28-n or vita m in
D2 (19c): 56%, Rf ) 0.1 (60%, Et2O-hexanes), mp 145 °C. 1H
NMR (CD2Cl2): 6.34 and 6.00 (2H, AB, J ) 11.2, H-6 and 7),
5.30-5.27 (2H, m, H-22 and 23), 5.26 (1H, s, H-19), 4.94 (1H,
(49) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.

Copper-Mediated Synthesis of 1R,25-Dihydroxyvitamin D2
J . Org. Chem., Vol. 62, No. 18, 1997 6351
s, H-19), 4.36 (1H, dd, J ) 6.5, 4.4, H-1), 4.15 (1H, m, H-3),
2.82 (1H, d, J ) 12.5), 2.53 (1H, dd, J ) 13.3, 2.66), 2.25 (1H,
dd, J ) 13.3, 6.5), 1.19 (3H, s, CH3-26), 1.16 (3H, s, CH3-27),
1.02 (3H, d, J ) 6.6, CH3-21), 0.73 (1H, m, c-Pr), 0.55 (3H, s,
CH3-18), 0.53 (1H, m, c-Pr), 0.36 (1H, m, c-Pr), 0.22 (1H, m,
c-Pr), 0.02 (1H, m, c-Pr). 13C NMR (CD2Cl2): 148.41 (Cd),
143.12 (Cd), 140.28 (CHd), 133.90 (Cd), 127.22 (CHd), 124.83
(CHd), 117.49 (CHd), 111.74 (CH2-19), 73.29 (C), 71.04, 67.06,
58.89, 56.72, 56.48, 46.11 (C), 45.66 (CH2), 43.28 (CH2), 40.94
(CH2), 40.72, 29.34 (CH2), 28.24 (CH2), 27.84, 27.41, 23.93
(CH2), 22.63 (CH2), 21.23, 12.33, 11.67, 6.11 (CH2), 2.54 (CH2).
HRMS calcd for C30H46O3 454.3447, found 454.3461.
Aceta l 19e: 49%, Rf ) 0.2 (60% Et2O-hexanes), mp 120
°C. 1H NMR (CD2Cl2): 6.33 and 5.99 (2H, AB, J ) 11.2, H-6
and 7), 5.30-5.26 (1H, m, H-22 or 23), 5.27 (1H, s, H-19), 5.12
(1H, dd, J ) 15.3, 8.4, H-22 or 23), 4.93 (1H, s, H-19), 4.60
(0.4H, d, J ) 1.4, OCHO), 4.44 (0.6H, dd, J ) 9.5, 2.4, OCHO),
4.35 (1H, m, H-1), 4.14 (1H, m, H-3), 3.34 (1.9H, s, OCH3),
3.32 (1.1H, s, OCH3), 2.82 (1H, d, J ) 12.4), 2.52 (1H, dd, J )
13.4, 3.5), 2.25 (1H, dd, J ) 13.4, 6.6), 1.17 (3H, s, CH3-26),
1.12 (1.1H, s, CH3-27), 1.08 (1.9H, s, CH3-27), 0.99 (3H, d, J )
6.6, CH3-21), 0.53 (3H, s, CH3-18). 13C NMR (CD2Cl2): 148.45
(Cd), 143.01 (Cd), 142.98 (Cd), 138.77 (CHd), 138.19 (CHd),
134.02 (Cd), 133.99 (Cd), 129.05 (CHd), 128.46 (CHd), 124.76
(CHd), 117.53 (CHd), 111.70 (CH2-19), 99.08 (CH), 98.41 (CH),
76.26 (C), 75.47 (C), 70.95, 67.03, 56.70, 56.65, 55.59, 55.14,
49.12, 48.68, 46.13 (C), 45.63 (CH2), 43.32 (CH2), 40.77, 40.72
(CH2), 40.69, 31.53 (CH2), 30.40 (CH2), 29.74, 29.70, 29.35
(CH2), 28.05 (CH2), 25.91 (CH2), 23.92 (CH2), 23.35, 22.58
(CH2), 22.11 (CH2), 20.99, 19.66, 12.34. HRMS calcd for
C31H48O4 484.3553, found 484.3580.
(22S,23E)-1r-Hyd r oxy-25-m eth oxy-22-p h en yl-23-d eh y-
d r ovita m in D3 (21f): 55%, Rf ) 0.2 (40% EtOAc-hexanes),
mp 90 °C. 1H NMR (CD2Cl2): 7.27-7.14 (5H, m, Ar), 6.35 and
6.03 (2H, AB, J ) 11.2, H-6 and 7), 5.89 (1H, dd, J ) 15.8,
10.3, H-23), 5.55 (1H, d, J ) 15.8, H-24), 5.29 (1H, d, J ) 1.4,
H-19), 4.96 (1H, s, H-19), 4.36 (1H, m, H-1), 4.15 (1H, m, H-3),
3.5 (1H, d, J ) 10.3, H-22), 3.14 (3H, s, OCH3), 2.80 (1H, d, J
) 12), 2.52 (1H, d, J ) 13), 2.25 (1H, dd, J ) 13.0, 6.5), 1.29
(3H, s, CH3-26), 1.27 (3H, s, CH3-27), 0.80 (3H, d, J ) 6.8, CH3-
21), 0.57 (3H, s, CH3-18). 13C NMR (CD2Cl2): 148.43 (Cd),
145.66 (Cd), 142.99 (Cd), 138.69 (CHd), 133.96 (Cd), 128.33
(CHd), 128.27 (CHd), 127.51 (CHd), 125.92 (CHd), 124.84
(CHd), 117.61 (CHd), 111.76 (CH2-19), 75.20 (C), 71.08, 67.08,
56.74, 55.13, 50.67, 50.50, 46.14 (C), 45.68 (CH2), 43.34 (CH2),
43.20, 40.90 (CH2), 29.32 (CH2), 27.97 (CH2), 26.78, 25.77,
23.89 (CH2), 22.64 (CH2), 13.69, 12.11. HRMS calcd for
C34H48O3 504.3603, found 504.3632.
(22R,23E)-8â-H yd r oxy-25-[(m et h oxym et h yl)oxy]-d es-
A,B-ch olest-23-en -22-yl Dieth yl P h osp h a te (5f). Tetrabu-
tylammonium fluoride (695 mg, 2.66 mmol) was added to a
solution of phosphate 5e (157 mg, 0.266 mmol) in THF (2.5
mL). The mixture was refluxed for 48 h and then allowed to
reach rt. The reaction was quenched with saturated NH4Cl.
The mixture was extracted with Et2O. The combined organic
extracts were dried, filtered, and concentrated in vacuo. Flash
chromatography of the concentrate (1.5 × 10 cm; eluent 70%
EtOAc-hexanes) afforded phosphate 5f [117 mg, 97%; Rf )
0.4 (50% Et2O-hexanes)] as a colorless oil. 1H NMR: 5.76
(1H, d, J ) 15.99, H-24), 5.60 (1H, dd, J ) 15.99, 5.24, H-23),
4.85 (1H, br t, J ) 6.0, H-22), 4.63 (2H, s, OCH2O), 4.14-3.99
[4H, m, J ) 7.2, P(OCH2CH3)2], 4.04 (1H, br s, H-8), 3.33 (3H,
s, OCH3), 1.35-1.23 [6H, m, P(OCH2CH3)2], 1.32 (6H, s, CH3-
26 and 27), 0.92 (3H, s, CH3-18), 0.91 (3H, d, J ) 6.28, CH3-
21). 13C NMR: 137.65 (CHd), 127.72 (CHd), 91.56 (OCH2O),
81.14 (d, J ) 5.7, C-22), 75.31 (C-25), 68.19, 63.13 [q, J ) 3.08,
P(OCH2CH3)2], 54.61 (OCH3), 52.67, 52.48, 41.74 (C-13), 41.58,
40.43 (CH2), 33.61 (CH2), 26.91 (CH3-26 and 27), 26.61 (CH2),
22.37 (CH2), 17.28 (CH2), 15.79 [q, J ) 3.9, P(OCH2CH3)2],
13.03, 12.05. HRMS FAB calcd for C24H45O7PNa 499.2800,
found 499.2796.
mixture was diluted with Et2O, stirred at rt for 30 min, filtered
through Celite, and concentrated in vacuo. Flash chromatog-
raphy of the concentrate (1 × 8 cm; eluent, 40% EtOAc-
hexanes) afforded ketone 22 [68 mg, 99%, Rf ) 0.5 (70%
EtOAc-hexanes)] as a colorless viscous oil. 1H NMR: 5.73
(1H, d, J ) 16.0, H-24), 5.61 (1H, dd, J ) 5.40, 16.0, H-23),
4.86 (1H, br t, H-22), 4.62 (2H, AB, OCH2O), 4.06 [4H, m,
P(OCH2CH3)2], 3.32 (3H, s, OCH3), 1.30 (6H, s, CH3-26 and
27), 1.28 [6H, m, P(OCH2CH3)2], 0.74 (3H, d, J ) 6.74, CH3-
21), 0.61 (3H, s, CH3-18). 13C NMR: 211.41 (CdO), 137.93
(CHd), 127.46 (CHd), 91.69 (OCH2O), 80.82 (d, CH2-22), 75.49
(C-25), 63.41 [m, P(OCH2CH3)2], 61.69, 54.91, 52.48, 49.47 (C-
13), 42.04, 41.95, 40.75 (CH2), 38.75 (CH2), 27.05, 23.80 (CH2),
18.96 (CH2), 15.95 [t, P(OCH2CH3)2], 12.41, 12.19. HRMS FAB
calcd for C24H43O7PNa 497.2644, found 497.2631.
Dieth yl P h osp h a te 23. Phenyllithium (1.05 mmol, 0.526
mL, 2 M in cyclohexane-Et2O) was cannulated dropwise into
a solution of phosphine oxide 17 (1.25 mmol, 6.13 mL, 0.204
M in THF) at -78 °C. The deep red solution was stirred at
-78 °C for 1 h. A cooled (-78 °C) solution of the CD ring
ketone 22 (300 mg, 0.660 mmol) in THF (5 mL) was cannulated
dropwise. The red solution was stirred in the dark at -78 °C
for 3 h and then warmed to -30 °C for 1 h. The reaction was
quenched with saturated NH4
Cl. The mixture was extracted
with Et2O. The combined organic phases were dried, filtered,
and concentrated. The concentrate was purified by flash
chromatography (2.5 × 15 cm, eluent, 0-10% EtOAc-hexanes)
to give 23 [420 mg, 76%, Rf
) 0.7 (60% EtOAc-hexanes)] as a
colorless oil. 1H NMR: 6.25 and 6.03 (2H, AB, J ) 11.21, H-6
and 7), 5.72 (1H, d, J ) 15.95, H-24), 5.64 (1H, dd, J ) 5.69,
15.95, H-23), 5.18 (1H, s, H-19), 4.87 (1H, br t, H-22), 4.84
(1H, d, J ) 2.33, H-19), 4.61 (2H, AB, OCH2O), 4.37 (1H, m),
4.18 (1H, m), 4.11-3.97 [4H, m, P(OCH2CH3)2], 3.30 (3H, s,
OCH3), 1.30 (6H, s, CH3-26 and 27), 1.32-1.26 [6H, m,
P(OCH2CH3)2], 0.95 (3H, d, J ) 6.67, CH3-21), 0.86 [18H, s,
2SiC(CH3)3], 0.53 (3H, s, CH3-18), 0.05 [12H, 3s, 4Si(CH3)2].
13C NMR: 148.90 (Cd), 141.21 (Cd), 138.21 (CHd), 135.75
(Cd), 128.42 (CHd), 123.43 (CHd), 118.45 (CHd), 111.51
(CH2-19), 91.21 (OCH2O), 81.59 (d, CH-22), 75.90 (C-25), 72.43,
67.99, 63.83 [m, P(OCH2CH3)2], 56.74, 55.19, 53.00, 46.43
(CH2), 46.02 (C-13), 45.29 (CH2), 43.13, 43.08, 40.98 (CH2),
29.25 (CH2), 27.69 (CH2), 27.44, 27.41, 26.16, 26.03 [2SiC(CH3)3],
23.90 (CH2), 22.61 (CH2), 18.53 (SiC), 18.42 (SiC), 16.43 [t,
P(OCH2CH3)2], 12.87, 12.00, -4.54 (SiCH3), -4.58 (SiCH3),
-4.67 (SiCH3), -4.88 (SiCH3). HRMS FAB calcd for C45H83
O8Si2PNa 861.5261, found 861.5241.
-
1r-[(ter t-Bu th yld im eth ylsilyl)oxy]-25-[(m eth oxym eth -
yl)oxy]-vita m in D2 ter t-Bu th yld im eth ylsilyl Eth er (24).
A mixture of CuCN (323 mg, 3.61 mmol, Aldrich) and LiCl
(306 mg, 7.2 mmol) in THF (20 mL) was stirred to effect a
homogeneous solution. After cooling to -78 °C, MeMgCl (1.2
mL, 3 M in THF, 3.61 mmol) was added dropwise. After
stirring for 15 min, a solution of phosphate 23 (303 mg, 0.361
mmol) in THF (7 mL) was added via cannula. The mixture
was stirred for 10 h at -78 °C and then allowed to reach for
12 h. The reaction was quenched with drops of saturated
NH4Cl. The mixture was diluted with Et2O and saturated
NH4Cl. The aqueous phase was extracted with Et2O. The
combined organic phases were dried, filtered, and concen-
trated. Flash chromatography of the concentrate (2.5 × 15
cm; eluent, 1% EtOAc-hexanes) afforded protected vitamin
D2 2428c [232 mg, 92%, Rf ) 0.7 (80% EtOAc-hexanes)]. 1H
NMR: 6.25 and 6.02 (2H, AB, J ) 11.23, H-6 and 7), 5.32 (1H,
dd, J ) 15.2, 7.9, H-22 or H-23), 5.24 (1H, dd, J ) 15.2, 8.25,
H-22 or H-23), 5.18 (1H, d, J ) 1.79, H-19), 4.84 (1H, d, J )
2.44, H-19), 4.66 (2H, AB, OCH2O), 4.37 (1H, m), 4.18 (1H,
m), 3.31 (3H, s, OCH3
27), 1.01 (3H, d, J ) 6.53, CH3-21), 0.96 (3H, d, J ) 7.01, CH3-
)3], 0.54 (3H, s, CH3-18), 0.06-0.05
), 1.14 (3H, s, CH3-26), 1.10 (3H, s, CH3-
28), 0.87 [18H, s, SiC(CH3
)2].
[12H, 3s, 4Si(CH3
1r,25-d ih yd r oxyvita m in D2 (2b). Tetrabutylammonium
fluoride (4 mmol, 4 mL, 1 M in THF) was added to a solution
of 24 (102 mg, 0.146 mmol) in THF (2 mL). The mixture was
stirred in the dark for 12 h. Saturated NH4Cl was added, and
the mixture was extracted with Et2O. The combined organic
phases were dried, filtered, and concentrated. The residue was
(22R,23E)-25-[(Meth oxym eth yl)oxy]-8-oxo-d es-A,B-ch o-
lest-23-en -22-yl Dieth yl P h osp h a te (22). A mixture of
alcohol 5f (69 mg, 0.151 mmol), pyridinium dichromate (171
mg, 0.453 mmol), and a crystal of pyridinium p-toluene-
sulfonate in CH2Cl2 (1.5 mL) was stirred at rt for 3 h. The

6352 J . Org. Chem., Vol. 62, No. 18, 1997
Torneiro et al.
dissolved in MeOH (10 mL) and treated with resin AG50 WX4
(3 g, previously washed with MeOH). The mixture was stirred
in the dark at rt for 5 h, filtered, and concentrated. The
residue was flash chromatographed (1 × 10 cm; eluent, 50%
EtOAc-hexanes) to afford 1R,25-dihydroxyvitamin D2 (2b)28c
[55 mg, 89%, Rf ) 0.2 (50% EtOAc-hexanes)]. 1H NMR: 6.34
and 5.99 (2H, AB, J ) 11.27, H-6 and 7), 5.36-5.29 (2H, m,
H-22 and 23), 5.26 (1H, br s, H-19), 4.94 (1H, br s, H-19), 4.35
(1H, m), 4.14 (1H, m), 3.31 (3H, s, OCH3), 1.10 (3H, s, CH3-
26), 1.08 (3H, s, CH3-27), 1.01 (3H, d, J ) 6.51, CH3-21), 0.96
(3H, d, J ) 6.70, CH3-28), 0.54 (3H, s, CH3-18).
Duphar B.V. (Weesp, The Netherlands) for financial
support. M.T. thanks the Spanish Ministry of Educa-
tion and Science for an FPI fellowship.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra of all compounds, and experimental details for the
preparation of compounds 4b, 12b, 4c, 12c, 4d , 12d , 4e, 12e,
4f, 12f, 13f, 14f, 13g, 14g, 15c, 15d , 15e, 15f, 16g, 19d , 19f,
21g (50 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. We are grateful to the DIGICYT
(Spain, projects SAF 92-0572 and 95-0878) and Solvay-
J O970604U