Stereoselective convergent synthesis of 24,25-dihydroxyvitamin D3 metabolites: a practical approach.

Article abstract of DOI:10.1002/1521-3765(20020617)8:12<2747::AID-CHEM2747>3.0.CO;2-J

Vitamin D3 active metabolites 24R,25-(OH)2-D3, 24S,25-(OH)2-D3, and 1 alpha, 24R,25-(OH)3-D3 were synthesized by a convergent and stereoselective approach. In the synthetic route, the stereogenic center at C-24 was generated through ultrasonically induced aqueous conjugate addition of iodide 6 to Seebach's dioxolanone 5, and the vitamin D triene system was constructed using the Lythgoe approach. The synthesis, which is both short (seven steps from iodide 6) and efficient (32-40% overall yield), allows the preparation of large quantities of the metabolites and provides a novel example of a highly stereoselective reaction promoted by the zinc-copper couple in aqueous media.

Full text of DOI:10.1002/1521-3765(20020617)8:12<2747::AID-CHEM2747>3.0.CO;2-J

FULL PAPER
Stereoselective Convergent Synthesis of 24,25-Dihydroxyvitamin D3
Metabolites: A Practical Approach
Jose¬ P¬erez Sestelo,*[a] Iva¬n Cornella,[a] Olga de Una,[a] Antonio Mourino,[b] and
ƒ
ƒ
Luis A. Sarandeses*[a]
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
Abstract: Vitamin D3 active metabo-
lites 24R,25-(OH)2-D3, 24S,25-(OH)2-
D3, and 1a,24R,25-(OH)3-D3 were syn-
thesized by a convergent and stereo-
selective approach. In the synthetic
route, the stereogenic center at C-24
was generated through ultrasonically
induced aqueous conjugate addition of
iodide 6 to Seebach×s dioxolanone 5, and
the vitamin D triene system was con-
structed usingthe Lythoge approach.
The synthesis, which is both short (seven
steps from iodide 6) and efficient (32
40% overall yield), allows the prepara-
tion of large quantities of the metabo-
lites and provides a novel example of a
highly stereoselective reaction promot-
ed by the zinc-copper couple in aqueous
media.
Keywords: asymmetric synthesis
Michael addition ¥ vitamins
¥
R3
24
Introduction
25
R1
Vitamin D3 (1a, Figure 1) produces biological responses after
transformation by successive stereospecific enzymatic hy-
droxylations into the major active metabolites 1a,25-(OH)2-
D3 (1b, calcitriol) and 24R,25-(OH)2-D3 (1c, secalciferol).[1]
These metabolites interact with specific protein vitamin D
receptors (VDRs) in the cell nucleus (VDRnuc) or in the
membrane (VDRmen), and give rise to the biological responses
through genomic or non-genomic pathways.[2] Calcitriol and
secalciferol are involved in a wide range of biological
functions such as calcium homeostasis, cellular differentiation
and proliferation processes, and other functions related to the
immune system. Once the biological responses have been
produced, the metabolites are deactivated by further oxida-
tions of the side-chain that lead to more polar metabolites.[3]
The major factor in the biological activity of vitamin D3 has
generally been attributed to calcitriol, while the functions of
secalciferol have been relatively unexplored. In the last two
H
1α
HO
R2
1a: R1 = R2 = R3 = H; vitamin D3
1b: R1 = R2 = OH, R3 = H; 1α,25-(OH)2-D3
1c: R1 = R3 = OH, R2 = H; 24R,25-(OH)2-D3
Figure 1. Vitamin D3 (1a), calcitriol (1b), and secalciferol (1c).
decades,[4] intensive research aimed at elucidatingthe precise
biological function of secalciferol and the utility of 24-hydroxy
derivatives has been undertaken. As a consequence, a non-
nuclear receptor specific for this vitamin D metabolite was
discovered.[5] Secalciferol participates, in association with
calcitriol, in the intestinal and bone absorption of calcium and
phosphorus, but its role in cellular differentiation or prolif-
eration processes is still not understood.[6] Nevertheless, 24-
hydroxylated vitamin D analogues such as calcipotriol,[7]
tacalcitol (24R-OH-D3), and secalciferol itself, have been
found to be effective as antipsoriatic or calcium-regulating
agents.[8] The importance of the 24-hydroxy side-chain is also
recognized by its presence in natural steroids.[9]
¬
[a] Dr. J. Perez Sestelo, Prof. Dr. L. A. Sarandeses,
ƒ
Dr. I. Cornella, O. de Una
Departamento de QuÌmica Fundamental
ƒ
ƒ
Universidade da Coruna, 15071 A Coruna (Spain)
Fax : (‡34)981-167-065
E-mail: qfsarand@udc.es
ƒ
[b] Prof. Dr. A. Mourino
¬
Departamento de QuÌmica Organica y Unidad Asociada al C.S.I.C.
Universidade de Santiago de Compostela
15706 Santiago de Compostela (Spain)
In response to the extraordinary biological activity of
vitamin D, the synthesis of metabolites and analogues with
Supportinginformation for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author.
Chem. Eur. J. 2002, 8, No. 12
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2747

J. Pÿrez Sestelo, L. A. Sarandeses et al.
FULL PAPER
specific biological responses
has been widely pursued.[10] In
this sense, calcitriol and numer-
ous 25-hydroxy analogues have
been efficiently prepared fol-
lowingconvergent synthetic ap-
proaches. However, the synthe-
sis of secalciferol and its ana-
logues has thus far involved low
yieldinglinear approaches that
use steroids as startingmateri-
als (biomimetic approach).[11]
The resolution of complex dia-
stereomeric mixtures is always
necessary except in cases in
R1 R2
O
*
O
R1 R2
I
OH
OH
5
O
2a: R1 = OH; R2 = H
2b: R1 = H; R2 = OH
H
H
HO
O
H
6
Conjugate
Addition
P(O)Ph2
HO
R3
1c: R1 = OH, R2 = R3 = H; 24R, 25-(OH)2-D3
1d: R1 = R3 = H; R2 = OH; 24S, 25-(OH)2-D3
1e: R1 = R3 = OH; R2 = H; 1α,24R, 25-(OH)3-D3
TBSO
R3
3: R3 = H
4: R3 = OH
Scheme 1. Retrosynthetic analysis.
which the C-24 stereogenic center is present in a synthetic
intermediate.[12]
Michael addition between the known iodide 6 and Seebach×s
dioxolanone 5.
As part of our long-term program devoted to the synthesis
of vitamin D analogues and metabolites, and to the rational
understandingof related biological functions, we focused our
attention on the development of an efficient and stereo-
selective approach to 24-hydroxyvitamin D3 metabolites.
Several years ago we reported an efficient synthesis of the
calcitriol side-chain by means of an ultrasonically induced
zinc-copper conjugate addition to a,b-unsaturated systems in
aqueous media,[13] by application of reaction conditions
developed by Luche in the eighties [Eq. (1)].[14] The method
was employed for the synthesis of calcitriol and 25-dialkyl
analogues. Herein we report the use of this methodology for
the stereoselective synthesis of 24-hydroxyvitamin D metab-
olites.
The synthesis starts with iodide 6, which contains the CD
rings of the vitamin D structure and can be obtained on a
multigram scale from vitamin D2 via the Inhoffen Lythgoe
diol.[18] Seebach×s dioxolanone 5 was prepared as both
enantiomers, (‡)-5 and (À)-5, from enantiomerically pure
lactic acid accordingto the literature procedure. [16] To test our
retrosynthetic analysis, we performed the aqueous zinc/
copper sonochemically-induced conjugate addition of iodide
6 to the dioxolanone enantiomer (‡)-5. Remarkably, the 1,4-
conjugate addition product 7 was obtained as a cis:trans
mixture of diastereomers in an 11:1 ratio (83% de) and 70%
yield (Scheme 2). The stereochemistry of the major diaster-
O
H
Zn(Cu)
R'
R
R'
R
X
O
ꢀ1†
EtOH/H2O
ultrasound
I
O
O
O
O
Zn, CuI
O
EtOH/H2O (7:3)
ultrasound
70%, 83% de
H
H
O
HO
HO
The application of Luche×s methodology in stereoselective
synthesis is practically unknown, beinglimited to addition to a
prochiral carbon in a very electron-deficient olefin.[15] For our
synthesis, we envisioned the use of a chiral a-hydroxy Michael
acceptor such as Seebach×s dioxolanone 5,[16] in this kind of
reaction to obtain the required diastereoselectivity [Eq. (2)].
6
(+)-5
7
O
H
O
I
O
O
Zn, CuI
O
EtOH/H2O (7:3)
ultrasound
74%, 86% de
H
H
O
HO
HO
6
(–)-5
8
O
O
Scheme 2. Diasteroselective Michael addition.
*
O
*
O
ꢀ2†
R
R
X
*
O
O
eomer was assigned cis (24R) on the basis of the NMR
assignments described by Beckwith[19] for radical conjugate
additions to chiral dioxolanones such as 5. This stereochem-
ical outcome is consistent with the results found in other 1,4-
conjugate additions under classical radical conditions
(nBu3SnH/AIBN)[19] and with those obtained by Seebach for
dioxolanone enolate alkylations.[20] Accordingto the mecha-
nism proposed by Luche for the zinc-copper conjugate
addition, the final step occurs through the protonation of an
enolate.[14]
Results and Discussion
For the stereoselective synthesis of 24,25-dihydroxyvit-
amin D3 metabolites (1c e), we considered the retrosynthet-
ic analysis depicted in Scheme 1. Accordingto this scheme,
the conjugated vitamin D triene system should be constructed
followingthe Lythgoe approach [17] from 24,25-dihydroxylated
ketone 2 and the known phosphane oxides 3 or 4. The 24,25-
dihydroxyketone 2 would be prepared by stereoselective
In an effort to determine whether the stereoselectivity of
the reaction was due to the chirality of the iodide, the
2748
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0947-6539/02/0812-2748 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 12

Vitamin D3 Metabolites
2747 2752
dioxolanone, or both (double stereodifferentiation), we
performed the reaction with the dioxolanone enantiomer
(À)-5. Under the same experimental conditions, the conjugate
addition product 8 was obtained in similar yield (74%) and
with a similar stereoselectivity (diastereomeric ratio of 13:1,
86% de), and the cis diastereomer was again the major
product. This result proves that the stereoselectivity of the
reaction is independent of the chirality of the iodide and that a
remarkable, highly diastereoselective protonation of the
enolate in aqueous media occurs.
At this point we studied the cleavage of the protected a-
hydroxyacid in 7 and 8, and the introduction of the C-26 and
C-27 methyl groups of the vitamin D side-chain. Both
objectives were achieved in one step. The reaction of
dioxolanone 7 with methylmagnesium bromide afforded the
triol 9 as a mixture of C-24 epimers in an 11:1 ratio
(Scheme 3). At this point, the major stereoisomer (24R) was
separated by chromatography (90% yield).[21] In a similar
way, triol 10 (24S) (epimer of 9 at C-24) was obtained from 8
by reaction with MeMgBr and subsequent purification by
crystallization (86% yield).
same synthetic sequence (seven steps from iodide 6, 33%
overall yield). 24S,25-(OH)2-D3 (1d) is a naturally occurring
vitamin D3 metabolite that results from the enzymatic reduc-
tion of 24-oxo-25-hydroxyvitamin D3. This metabolite (1d)
exhibits lower affinity for the VDR and its biological activity
is, in general, a few orders of magnitude below calcitriol and
secalciferol.[5, 24] Nevertheless, its utility as an antitumor agent
is patented.[25]
To further exploit the synthetic utility of this approach, we
also synthesized the vitamin D3 metabolite 1a,24R,25-(OH)3-
D3 (1e). This is an active metabolite, generated in vivo from
calcitriol and in vitro from secalciferol, that has preferential
biological action in the transport of calcium in the intestine.[26]
A Wittig Horner reaction between ketone 13 and the anion
of the 1a-hydroxylated phosphane oxide 4,[27] generated at
low temperature with nBuLi, afforded the protected metab-
olite 17 in 92% yield (Scheme 4). Deprotection with TBAF,
followed by treatment with the resin AG 50W-X4 yielded the
desired metabolite 1a,24R,25-(OH)3-D3 (1e) in 80% overall
yield.
With the two optically pure triols 9 and 10 in hand, we
turned our attention to their conversion into the 24R,25-
(OH)2-vitamin D3 metabolite (1c, secalciferol) and its 24S
epimer (1d). We first attempted the synthesis of secalciferol.
Protection of the 24,25-diol unit as a ketal with acetone was
achieved with the aid of ultrasound[22] (9 ! 11), and subse-
quent oxidation of the hydroxyl group at the C-8 position
afforded the ketone 13 in 87% overall yield. A Wittig
Horner reaction between ketone 13 and the anion of the
phosphane oxide 3,[23] which contained the A ringof
vitamin D, generated by treatment with nBuLi at low temper-
ature, yielded the protected vitamin 15 in 73% yield.
Subsequent deprotection of 15 with tetrabutylammonium
fluoride (TBAF) and the cationic resin AG 50W-X4 afforded
the 24R,25-(OH)2-D3 (1c, secalciferol) in seven steps from
iodide 6 and in 32% overall yield. The synthesis of 24S,25-
(OH)2-D3 (1d) was achieved from triol 10 by followingthe
O
O
O
O
1) TBAF
4, nBuLi
H
1e
2) AG 50W-X4
80%
92%
H
O
13
17
TBSO
OTBS
Scheme 4. Synthesis of 1a,24R,25-(OH)3-D3 (1e).
In summary, we describe here the first stereoselective
convergent synthesis of the 24,25-dihydroxyvitamin D3 me-
tabolites 24R,25-(OH)2-D3 (1c), 24S,25-(OH)2-D3 (1d), and
1a,24R,25-(OH)3-D3 (1e). The synthetic approach is both
short and efficient (seven steps
from known iodide 6 and 32
40% overall yield) and is a
practical method for the syn-
thesis of these natural metabo-
*
OH
24
O
O
O
O
24
24
OH
MeMgBr
Me2CO, H+
O
lites. A novel diastereoselective
conjugate addition promoted
by zinc/copper-assisted cou-
plingin aqueous media was
employed. This reaction should
be of general use in organic
chemistry, not only for the syn-
thesis of other 24-vitamin D
analogues, but also for many
other chiral compounds such as
a-hydroxyacids. Efforts to ex-
plore the scope of this reaction
and the synthesis of new 24-
vitamin D derivatives by using
other chiral a,b-unsaturated
systems are in progress.
H
H
H
HO
HO
HO
7: 24R (cis:trans = 11:1)
8: 24S (cis:trans = 13:1)
11: 24R (89%)
9: 24R (90%)
10: 24S (86%)
12: 24S (90%)
R1 R2
PDC
O
O
24
O
OH
O
24
1) TBAF
2) AG 50W-X4
3, nBuLi
H
H
H
O
13: 24R (99%)
14: 24S (97%)
HO
TBSO
1c: 24R, R1 = OH, R2 = H (79%)
1d: 24S, R1 = H, R2 = OH (82%)
15: 24R (73%)
16: 24S (72%)
Scheme 3. Synthesis of 24R,25-(OH)2-D3 (1c) and 24S,25-(OH)2-D3 (1d).
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J. Pÿrez Sestelo, L. A. Sarandeses et al.
FULL PAPER
CHCl3); IR (neat): nÄ ˆ 3390, 2922, 1377, 1071 cmÀ1
;
1H NMR (200 MHz,
Experimental Section
CDCl3, 258C): d ˆ 0.92 (d, J ˆ 6.5 Hz, 3H), 0.94 (s, 3H), 1.18 (s, 3H), 1.20 (s,
3H), 3.33 (brs, 1H), 4.08 (brs, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ
13.5 (CH3), 17.4 (CH2), 18.4 (CH3), 22.5 (CH2), 23.2 (CH3), 26.6 (CH3), 27.2
(CH2), 28.1 (CH2), 32.6 (CH2), 33.5 (CH2), 35.1 (CH), 40.4 (CH2), 41.9 (C),
52.6 (CH), 56.6 (CH), 69.4 (CH), 73.2 (C), 78.8 (CH); MS (EI): m/z (%):
General materials and methods: Unless otherwise stated, all reactions were
conducted in flame-dried glassware under a positive pressure of argon.
Reaction temperatures refer to external bath temperatures. All dry
solvents were distilled under argon immediately prior to use. Tetrahydro-
furan (THF) was distilled from the sodium/benzophenone. Dichloro-
methane (CH2Cl2) was distilled from P2O5. Absolute MeOH and EtOH
were distilled from Mgturninsg. Methyl acrylate was distilled under
vacuum prior use. Zinc was purified as described in the literature.[28]
Copper iodide was purified by recrystallization from saturated potassium
iodide solution.[29] Sonications were carried out in a Kerry Pulsatron KC6
(38 kHz, 110 W) cleaningbath, filled with water and thermostated (18
208C) by running tap water through a stainless steel coil. Organic extracts
were dried over anhydrous MgSO4, filtered, and concentrated usinga
rotary evaporator at aspirator pressure (20 30 mmHg). Thin-layer chro-
matography was carried out on Merck silica gel coated aluminium plates
60F254 (layer thickness 0.2 mm) and components were located by observa-
tion under UV light and/or by treating the plates with a phosphomolybdic
acid or p-anisaldehyde reagent followed by heating. Flash column
chromatography was performed on Merck silica gel 60 (230 400 mesh)
by Still×s method.[30] [a]D: Jasco DIP-1000. UV: Kontron Uvikon941. IR:
‡
‡
298 (3) [M ], 280 (10) [M À H2O], 135 (100); HRMS (EI): m/z: calcd for
‡
C18H34O3: 298.2508 [M ]; found: 298.2512; elemental analysis calcd (%)
for C18H34O3 (298.5): C 72.44, H 11.48; found: C 72.15, H 11.63.
(8b,24S)-De-A,B-cholesta-8,24,25-triol (10):[21] Followingthe same exper-
imental procedure used for 9, dioxolanone 8 (120 mg, 0.35 mmol) afforded,
after purification by flash chromatography (40% EtOAc/hexanes), 10
(90 mg, 86%) as a white solid. Rf ˆ 0.40 (70% EtOAc/hexanes); m.p. 89
918C (Et2O/hexanes); [a]2D1 ˆ ‡19.3 (c ˆ 0.47 in CHCl3); IR (neat): nÄ ˆ
3410, 2950, 1360, 1085 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.91
(d, J ˆ 5.9 Hz, 3H), 0.93 (s, 3H), 1.18 (s, 3H), 1.20 (s, 3H), 3.27 (dd, J ˆ 9.8,
2.0 Hz, 1H), 4.06 (d, J ˆ 2.0 Hz, 1H); 13C NMR (50 MHz, CDCl3, 258C):
d ˆ 13.5 (CH3), 17.4 (CH2), 18.7 (CH3), 22.5 (CH2), 23.1 (CH3), 26.5 (CH3),
27.1 (CH2), 28.3 (CH2), 33.1 (CH2), 33.5 (CH2), 35.5 (CH), 40.4 (CH2), 41.8
(C), 52.5 (CH2), 56.6 (CH), 69.3 (CH), 73.2 (C), 79.5 (CH); MS (EI): m/z
‡
‡
(%): 298 (4) [M ], 270 (8) [M À C2H4], 71 (100); HRMS (EI): m/z: calcd
‡
for C18H34O3: 298.2508 [M ]; found: 298.2505; elemental analysis calcd
(%) for C18H34O3 (298.5): C 72.44, H 11.48; found: C 72.70, H 11.57.
Matson FTIR. H NMR: 200 MHz, Bruker AC-200F. 13C NMR: 50 MHz,
1
(8b,24R)-De-A,B-cholesta-8,24,25-triol cyclic 24,25-(1-methylethylidene
acetal) (11): A solution of 9 (100 mg, 0.33 mmol) in acetone (10 mL)
Bruker AC-200F (DEPTwas used to assign carbon types). MS: Fisons VG-
Quattro. HRMS: VG Autospec M. The AG 50W-X4 resin was purchased
from Bio-Rad, Hercules (California, USA) and used as received.
containingone drop of conc. H SO4 was sonicated for 2.5 h. The mixture
2
was concentrated to a small volume and the residue was dissolved in
CH2Cl2 (20 mL). The organic phase was washed with water (15 mL), dried,
filtered, and concentrated to afford 11 (100 mg, 89%) as a colorless oil.
(2S,5R,8'b)-2-(tert-Butyl)-5-(de-A,B-8'-hydroxy-24'-norcholan-23'-yl)-1,3-
dioxolan-4-one (7): CuI (182 mg, 0.96 mmol) and Zn (188 mg, 2.88 mmol)
were added to a solution of dioxolanone (‡)-5[16] (100 mg, 0.64 mmol) and
6[13d] (310 mg, 0.96 mmol) in aqueous EtOH (5 mL, 70%). The resulting
black mixture was sonicated for 90 min until consumption of (‡)-5 was
complete (by TLC). The mixture was diluted with EtOAc (8 mL) and
filtered through a short pad of Celite, washing the solids with EtOAc (3 Â
15 mL). The organic phase was washed with saturated NH4Cl (30 mL) and
NaCl (30 mL), dried, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (20% EtOAc/hexanes) to afford, after
concentration and high vacuum drying, 7 (158 mg, 70%, 24R/24S 11:1) as a
white foam. Rf ˆ 0.34 (30% EtOAc/hexanes); IR (neat): nÄ ˆ 3525, 2935,
1796, 1197 cmÀ1; 1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.93 (d, J ˆ 4.5 Hz,
3H), 0.95 (s, 3H), 0.98 (s, 9H), 4.07 (brs, 1H), 4.25 (m, 1H), 5.12 (d, J ˆ
1.4 Hz, 0.915H), 5.26 (d, J ˆ 1.4 Hz, 0.085H); 13C NMR (50 MHz, CDCl3,
258C): d ˆ 13.5 (CH3), 17.4 (CH2), 18.3 (CH3), 22.5 (CH2), 23.5 (3CH3), 27.0
(CH2), 27.1 (CH2), 30.5 (CH2), 33.6 (CH2), 34.3 (C), 34.7 (CH), 40.3 (CH2),
41.8 (C), 52.6 (CH), 56.1 (CH), 69.3 (CH), 75.2 (CH), 109.2 (CH), 173.6
1
Rf ˆ 0.70 (70% EtOAc/hexanes); H NMR (200 MHz, CDCl3, 258C): d ˆ
0.93 (s, 3H), 0.93 (d, J ˆ 5.6 Hz, 3H), 1.11 (s, 3H), 1.26 (s, 3H), 1.37 (s, 3H),
1.42 (s, 3H), 3.64 (dd, J ˆ 8.6, 3.5 Hz, 1H), 4.09 (brs, 1H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 13.5 (CH3), 17.4 (CH2), 18.4 (CH3), 22.5
(CH2), 22.8 (CH3), 25.9 (CH2), 26.2 (CH3), 26.8 (CH3), 27.2 (CH2), 28.6
(CH3), 32.7 (CH2), 33.6 (CH2), 35.4 (CH), 40.4 (CH2), 41.8 (C), 52.6 (CH),
56.4 (CH), 69.3 (CH), 80.2 (C), 83.7 (CH), 106.3 (C); MS (FAB): m/z (%):
‡
‡
337 (12) [M À H], 323 (100) [M À CH3]; HRMS (EI): m/z: calcd for
‡
C21H38O3: 338.2821 [M ]; found: 338.2828.
(24R)-De-A,B-24,25-dihydroxycholestan-8-one cyclic 24,25-(1-methyl-
ethylidene acetal) (13): A mixture of 11 (96 mg, 0.28 mmol) and PDC
(319 mg, 0.85 mmol) in CH2Cl2 (17 mL) was stirred for 6 h. Et2O (10 mL)
was added and the resultingmixture was stirred for 15 min. The mixture
was filtered through Celite, and the solid was washed with Et2O (5 Â
10 mL). The filtrate was concentrated in vacuo and the residue was
purified by flash chromatography (30% EtOAc/hexanes) to afford, after
concentration and high vacuum drying, 13 (94 mg, 99%) as a colorless oil.
‡
‡
(C); MS (FAB): m/z (%): 352 (8) [M ], 334 (9) [M À H2O], 111 (100);
‡
HRMS (EI): m/z: calcd for C21H36O4: 352.2614 [M ]; found: 352.2618.
Rf ˆ 0.70 (50% EtOAc/hexanes); IR (neat): nÄ ˆ 2950, 1725, 1120 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.65 (s, 3H), 0.99 (d, J ˆ 5.4 Hz,
3H), 1.10 (s, 3H), 1.25 (s, 3H), 1.33 (s, 3H), 1.42 (s, 3H), 3.63 (dd, J ˆ 8.4,
3.4 Hz, 1H); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 12.5 (CH3), 18.6 (CH3),
19.0 (CH2), 22.9 (CH3), 24.0 (CH2), 26.0 (CH2), 26.2 (CH3), 26.8 (CH3), 27.5
(CH2), 28.5 (CH3), 32.7 (CH2), 35.6 (CH), 39.0 (CH2), 40.9 (CH2), 49.9 (C),
56.5 (CH), 61.9 (CH), 80.1 (C), 83.6 (CH), 106.4 (C), 211.9 (C); MS (FAB):
(2R,5S,8'b)-2-(tert-Butyl)-5-(de-A,B-8'-hydroxy-24'-norcholan-23'-yl)-1,3-
dioxolan-4-one (8): Followingthe same experimental procedure used for 7,
dioxolanone (À)-5[16] (101 mg, 0.65 mmol) afforded, after purification
(20% EtOAc/hexanes), 8 (168 mg, 74%, 24R/24S 1:13) as a white foam.
Rf ˆ 0.36 (30% EtOAc/hexanes); IR (neat): nÄ ˆ 3520, 2946, 1749,
1194 cmÀ1
;
1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.92 (d, J ˆ 4.4 Hz,
‡
‡
3H), 0.94 (s, 3H), 0.98 (s, 9H), 4.08 (d, J ˆ 2.9 Hz, 1H), 4.22 (m, 1H), 5.12
(d, J ˆ 1.5 Hz, 0.93H), 5.25 (d, J ˆ 1.5 Hz, 0.07H); 13C NMR (50 MHz,
CDCl3, 258C): d ˆ 13.5 (CH3), 17.4 (CH2), 18.3 (CH3), 22.5 (CH2), 23.4
(3CH3), 27.0 (CH2), 27.2 (CH2), 30.9 (CH2), 33.5 (CH2), 34.2 (C), 43.9 (CH),
40.3 (CH2), 41.8 (C), 52.5 (CH), 56.1 (CH), 69.2 (CH), 75.6 (CH), 109.2
m/z (%): 337 (22) [M ‡H], 321 (100) [M À CH3]; HRMS (EI): m/z calcd
‡
for C21H36O3: 336.2664 [M ]; found: 336.2659.
(3b,5Z,7E,24R)-3-[(tert-Butyldimethylsilyl)oxy]-9,10-secocholesta-
5,7,10(19)-triene-24,25-diol cyclic 24,25-(1-methylethylidene acetal) (15):
nBuLi in hexanes (0.125 mL, 2.39m, 0.30 mmol) was added dropwise to a
solution of phosphane oxide 3 (142 mg, 0.31 mmol) in THF (7 mL) at
À788C. The red solution was warmed to 08C and, after 20 min, cooled
again to À788C. A solution of 13 (43 mg, 0.13 mmol) in THF (3 mL) was
then added by cannula. The mixture was warmed to RT and stirred for a
further 5 h. The reaction was quenched with saturated aqueous NH4Cl
‡
‡
(CH), 173.7 (C); MS (EI): m/z (%): 352 (5) [M ], 334 (38) [M À H2O],
‡
111 (100); HRMS (EI): m/z: calcd for C21H36O4: 352.2614 [M ]; found:
352.2611.
(8b,24R)-De-A,B-cholesta-8,24,25-triol (9):[21] MeMgBr in Et2O (1.40 mL,
3.0m, 4.20 mmol) was slowly added a solution of to a solution of 7 (178 mg,
0.50 mmol) in THF (10 mL) at À788C. The mixture was warmed to RTand
stirred for 5 h. The reaction was quenched with few drops of MeOH, and
the resultingmixture was concentrated to a small volume. The residue was
dissolved in EtOAc (15 mL) and washed with saturated NaHCO3 (15 mL)
and NaCl (15 mL), dried, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography (75% EtOAc/hexanes) to
afford, after concentration and high vacuum drying, 9 (134 mg, 90%) as a
colorless oil. Rf ˆ 0.10 (30% EtOAc/hexanes); [a]1D9 ˆ ‡35.1 (c ˆ 0.35 in
(1 mL) and then poured into a separatingfunnel with Et O (20 mL). The
2
organic layer was washed successively with saturated solutions of NH4Cl
(10 mL) and NaCl (10 mL). The organic layer was dried, filtered, and
concentrated, all with protection from light. The residue was purified by
flash chromatography (45% EtOAc/hexanes) to afford, after concentration
and high vacuum drying, 15 (54 mg, 73%) as a colorless oil. Rf ˆ 0.65 (50%
EtOAc/hexanes); IR (neat): nÄ ˆ 3031, 2930, 1462, 1097 cmÀ1
;
1H NMR
(200 MHz, CD2Cl2, 258C): d ˆ 0.06 (s, 3H), 0.07 (s, 3H), 0.56 (s, 3H), 0.87
2750
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Chem. Eur. J. 2002, 8, No. 12

Vitamin D3 Metabolites
2747 2752
(s, 9H), 0.95 (d, J ˆ 5.9 Hz, 3H), 1.05 (s, 3H), 1.20 (s, 3H), 1.28 (s, 3H), 1.35
EtOAc/hexanes); [a]2D6 ˆ ‡30.6 (c ˆ 0.7 in CHCl3); IR (neat): nÄ ˆ 3410,
3070, 2930, 1625, 1050 cmÀ1; UV (MeOH): lmax ˆ 265, 215 nm; 1H NMR
(200 MHz, CD2Cl2, 258C): d ˆ 0.54 (s, 3H), 0.93 (d, J ˆ 5.9 Hz, 3H), 1.11 (s,
3H), 1.16 (s, 3H), 3.22 (m, 1H), 3.87 (m, 1H), 4.79 (brs, 1H), 5.03 (brs,
1H), 6.02, 6.23 (2d, AB, J ˆ 11.2 Hz, 2H); 13C NMR (50 MHz, CD2Cl2,
258C): d ˆ 12.1 (CH3), 19.1 (CH3), 23.4 (CH3), 23.9 (CH2), 26.6 (CH3), 27.9
(CH2), 28.7 (CH2), 29.3 (CH2), 30.0 (CH2), 32.4 (CH2), 33.6 (CH2), 35.7
(CH2), 36.7 (CH), 40.9 (CH2), 46.1 (CH2), 46.3 (C), 56.6 (CH), 56.8 (CH),
69.5 (CH), 73.3 (C), 79.9 (CH), 112.4 (CH2), 117.9 (CH), 122.5 (CH), 135.8
(s, 3H), 3.61 (m, 1H), 3.86 (m, 1H), 4.76 (brs, 1H), 5.00 (brs, 1H), 6.01, 6.18
‡
(2d, AB, J ˆ 11.2 Hz, 2H); MS (EI): m/z (%): 570 (28) [M ], 555 (36)
‡
[M À CH3], 193 (100); HRMS (EI): m/z: calcd for C36H62O3Si: 570.4468
‡
[M ]; found: 570.4468.
(3b,5Z,7E,24R)-9,10-Secocholesta-5,7,10(19)-triene-3,24,25-triol [24R,25-
dihydroxyvitamin D3] (1c):[31] nBu4NF ¥ 3H2O (45 mg, 0.14 mmol) was
added to a solution of 15 (33 mg, 0.06 mmol) in THF (10 mL), with
protection from the light. The solution was stirred for 23 h, poured into a
separatingfunnel with EtOAc (30 mL), and the organic layer was washed
with a saturated solution of NH4Cl (10 mL), dried, filtered, and concen-
trated in vacuo. The residue was dissolved in deoxygenated MeOH
(10 mL), and AG 50W-X4 resin (175 mg) was added. The mixture was
stirred for 24 h, filtered, the solids were washed with MeOH (4 Â 5 mL),
and concentrated in vacuo. The residue was purified by flash chromatog-
raphy (85% EtOAc/hexanes) to afford, after concentration and high
‡
‡
(C), 142.4 (C), 145.8 (C); MS (EI): m/z (%): 416 (18) [M ], 398 (3) [M
H2O], 136 (100); HRMS (EI): m/z: calcd for C27H44O3: 416.3290 [M ];
À
‡
found: 416.3290.
(1a,3b,5Z,7E,24R)-1,3-Di[(tert-butyldimethylsilyl)oxy]-9,10-secocholesta-
5,7,10(19)-triene-24,25-diol cyclic 24,25-(1-methylethylidene acetal) (17):
Followingthe same experimental procedure used for 15, treatment of
ketone 13 (50 mg, 0.15 mmol) with the anion formed from phosphane oxide
4 (128 mg, 0.22 mmol) and nBuLi in hexanes (0.10 mL, 2.13m, 0.21 mmol)
afforded, after purification by flash chromatography (40% EtOAc/
hexanes), 17 (96 mg, 92%) as a colorless oil. Rf ˆ 0.76 (50% EtOAc/
hexanes); 1H NMR (200 MHz, CD2Cl2, 258C): d ˆ 0.06 (s, 12H), 0.53 (s,
3H), 0.87 (s, 18H), 0.95 (d, J ˆ 5.9 Hz, 3H), 1.05 (s, 3H), 1.20 (s, 3H), 1.28
(s, 3H), 1.35 (s, 3H), 3.61 (dd, J ˆ 8.8, 2.9 Hz, 1H), 4.18 (m, 1H), 4.38 (t, J ˆ
5.4 Hz, 1H), 4.84 (d, J ˆ 2.4 Hz, 1H), 5.18 (d, J ˆ 2.0 Hz, 1H), 6.02, 6.26
(2d, AB, J ˆ 11.2 Hz, 2H); 13C NMR (50 MHz, CD2Cl2, 258C): d ˆ À4.9
(CH3), À4.7 (CH3), À4.64 (CH3), À4.61 (CH3), 11.1 (CH3), 12.1 (CH3), 18.4
(C), 18.9 (CH3), 22.5 (CH2), 23.1 (CH3), 23.9 (CH2), 26.0 (6CH3), 26.4
(CH), 27.0 (CH3), 28.0 (CH2), 28.8 (CH3), 29.2 (CH2), 33.3 (CH2), 36.6
(CH), 39.2 (C), 40.9 (CH2), 45.2 (CH2), 46.1 (C), 46.3 (CH2), 56.7 (CH), 67.9
(CH), 72.3 (CH3), 80.4 (C), 84.0 (CH), 106.5 (C), 111.4 (CH2), 118.2 (CH),
123.4 (CH), 135.5 (C), 141.5 (C), 148.8 (C); MS (FAB): m/z (%): 701 (29)
vacuum drying, 1c (20 mg, 79%) as a white solid. Rf ˆ 0.5 (EtOAc); [a]D24
ˆ
‡20.4 (c ˆ 0.1 in CHCl3); IR (neat): nÄ ˆ 3410, 3081, 2927, 1639, 1048 cmÀ1
;
UV (MeOH): lmax ˆ 264, 215 nm; 1H NMR (200 MHz, CD3OD, 258C): d ˆ
0.56 (s, 3H), 0.95 (d, J ˆ 5.9 Hz, 3H), 1.12 (s, 3H), 1.15 (s, 3H), 3.21 (d, J ˆ
9.3 Hz, 1H), 3.75 (m, 1H), 4.74 (brs, 1H), 5.02 (brs, 1H), 6.02, 6.21 (2d,
AB, J ˆ 11.2 Hz, 2H); 13C NMR (50 MHz, CD3OD, 258C): d ˆ 12.3 (CH3),
19.2 (CH3), 23.2 (CH3), 24.5 (CH2), 24.9 (CH3), 25.6 (CH2), 28.7 (CH2), 29.9
(CH2), 30.7 (CH2), 33.6 (CH2), 34.2 (CH2), 36.6 (CH2), 37.2 (CH), 41.9
(CH2), 46.9 (C), 47.0 (CH2), 57.5 (CH), 58.0 (CH), 70.5 (CH), 73.8 (C), 79.7
(CH), 112.6 (CH2), 118.9 (CH), 122.6 (CH), 137.3 (C), 142.5 (C), 147.0 (C);
‡
‡
MS (EI): m/z (%): 416 (100) [M ], 398 (22) [M À H2O]; HRMS (EI): m/z:
‡
calcd for C27H44O3: 416.3290 [M ]; found: 416.3288.
(8b,24S)-De-A,B-cholesta-8,24,25-triol cyclic 24,25-(1-methylethylidene
acetal) (12): Followingthe same experimental procedure used for 11, triol
10 (62 mg, 0.21 mmol) afforded 12 (63 mg, 90%) as a colorless oil. Rf ˆ 0.75
(70% EtOAc/hexanes); 1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.93 (s,
3H), 0.93 (d, J ˆ 5.4 Hz, 3H), 1.10 (s, 3H), 1.25 (s, 3H), 1.33 (s, 3H), 1.41 (s,
3H), 3.61 (dd, J ˆ 7.3, 5.3 Hz, 1H), 4.08 (d, J ˆ 2.4 Hz, 1H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 13.5 (CH3), 17.4 (CH2), 18.6 (CH3), 22.5
(CH2), 22.8 (CH3), 25.9 (CH2), 26.3 (CH3), 26.8 (CH3), 27.1 (CH2), 28.6
(CH3), 32.7 (CH2), 33.5 (CH2), 35.3 (CH), 40.4 (CH2), 41.8 (C), 52.6 (CH),
56.4 (CH), 69.3 (CH), 80.1 (C), 84.0 (CH), 106.3 (C); MS (EI): m/z (%): 337
‡
‡
[M ], 686 (24) [M À H2O], 568 (100); HRMS (EI): m/z: calcd for
‡
C42H76O4Si2: 700.5282 [M ]; found: 700.5288.
(1a,3b,5Z,7E,24R)-9,10-Secocholesta-5,7,10(19)-triene-1,3,24,25-tetrol
[1a,24R,25-trihydroxyvitamin D3] (1e):[31] nBu4NF ¥ 3H2O (171 mg,
0.54 mmol) was added to a solution of 17 (95 mg, 0.13 mmol) in THF
(10 mL), with protection from the light. The solution was stirred for 22 h,
poured into a separatingfunnel with EtOAc (30 mL), and the organic layer
was washed with a saturated solution of NH4Cl (10 mL), dried, filtered, and
concentrated in vacuo. The residue was dissolved in deoxygenated MeOH
(10 mL) and AG 50W-X4 resin (370 mg) was added. The mixture was
protected from light and stirred for 22 h. The solids were filtered, washed
with MeOH (4 Â 6 mL), and the resultingsolution was concentrated in
vacuo. The crude product was purified by flash chromatography (5%
MeOH/EtOAc) to afford, after concentration and high vacuum drying, 1e
‡
‡
(1) [M À H], 323 (58) [M À H2O], 111 (100); HRMS (EI): m/z: calcd for
‡
C21H38O3: 338.2821 [M ]; found: 338.2825.
(24S)-De-A,B-24,25-dihydroxycholestan-8-one cyclic 24,25-(1-methylethyl-
idene acetal) (14): Followingthe same experimental procedure used for 13,
alcohol 12 (111 mg, 0.33 mmol) afforded, after purification (30% EtOAc/
hexanes), 14 (107 mg, 97%) as a colorless oil. Rf ˆ 0.70 (50% EtOAc/
(47 mg, 80% over two steps) as a white solid. Rf ˆ 0.3 (EtOAc); [a]D18
ˆ
hexanes); IR (neat): nÄ ˆ 2950, 1720, 1120 cmÀ1
;
1H NMR (200 MHz,
‡38.2 (c ˆ 0.85 in MeOH); IR (neat): nÄ ˆ 3426, 2924, 1639, 1364,
1046 cmÀ1; UV (MeOH): lmax ˆ 266, 215 nm; 1H NMR (200 MHz, CD3OD,
258C): d ˆ 0.57 (s, 3H), 0.96 (d, J ˆ 5.9 Hz, 3H), 1.12 (s, 3H), 1.15 (s, 3H),
3.21 (d, J ˆ 9.3 Hz, 1H), 4.11 (m, 1H), 4.35 (t, J ˆ 5.9 Hz, 1H), 4.89 (d, J ˆ
2.0 Hz, 1H), 5.28 (d, J ˆ 1.0 Hz, 1H), 6.08, 6.32 (2d, AB, J ˆ 11.2 Hz, 2H);
13C NMR (50 MHz, CD3OD, 258C): d ˆ 12.4 (CH3), 19.3 (CH3), 23.3 (CH2),
24.6 (CH2), 25.0 (CH3), 25.6 (CH3), 28.7 (CH2), 30.0 (CH2), 30.7 (CH2), 34.2
(CH2), 37.2 (CH), 41.9 (CH2), 43.7 (CH2), 46.1 (CH2), 46.7 (C), 57.6 (CH),
58.1 (CH), 67.4 (CH), 71.4 (CH), 73.9 (C), 79.7 (CH), 112.0 (CH2), 119.0
(CH), 124.9 (CH), 135.6 (C), 142.5 (C), 149.8 (C); MS (EI): m/z (%): 432
CDCl3, 258C): d ˆ 0.64 (s, 3H), 0.98 (d, J ˆ 5.8 Hz, 3H), 1.08 (s, 3H), 1.24 (s,
3H), 1.31 (s, 3H), 1.40 (s, 3H), 3.60 (dd, J ˆ 6.1, 1.0 Hz, 1H); 13C NMR
(50 MHz, CDCl3, 258C): d ˆ 12.5 (CH3), 18.6 (CH3), 19.0 (CH2), 22.8
(CH3), 24.0 (CH2), 25.9 (CH2), 26.2 (CH3), 26.8 (CH3), 27.5 (CH2), 28.5
(CH3), 32.8 (CH2), 35.6 (CH), 39.0 (CH2), 40.9 (CH2), 49.9 (C), 56.5 (CH),
61.9 (CH), 80.1 (C), 83.9 (CH), 106.3 (C), 211.9 (C); MS (EI): m/z (%): 337
‡
‡
(3) [M ‡H], 321 (100) [M À CH3]; HRMS (EI): m/z: calcd for C21H36O3:
‡
336.2664 [M ]; found: 336.2667.
(3b,5Z,7E,24S)-3-[(tert-Butyldimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19)-
triene-24,25-diol cyclic 24,25-(1-methylethylidene acetal) (16): Following
the same experimental procedure used for 15, treatment of ketone 14
(46 mg, 0.14 mmol) with the anion formed from phosphane oxide 3 (81 mg,
0.18 mmol) and nBuLi in hexanes (0.092 mL, 2.24m, 0.20 mmol) afforded,
after purification by flash chromatography (40% EtOAc/hexanes), 16
(57 mg, 72%) as a colorless oil. Rf ˆ 0.74 (30% EtOAc/hexanes); IR (neat):
‡
‡
(9) [M ], 414 (100) [M À H2O]; HRMS (EI): m/z: calcd for C27H44O4:
‡
432.3240 [M ]; found: 432.3240.
Acknowledgements
nÄ ˆ 3030, 2940, 1450, 1100 cmÀ1
;
1H NMR (200 MHz, CD2Cl2, 258C): d ˆ
We are grateful to the Xunta de Galicia (XUGA 10305A98 and
PGIDT01PXI10307PR), DGES (Spain, PM97-0166), and the University
0.06 (s, 6H), 0.54 (s, 3H), 0.88 (s, 9H), 0.95 (d, J ˆ 5.9 Hz, 3H), 1.05 (s, 3H),
1.20 (s, 3H), 1.27 (s, 3H), 1.35 (s, 3H), 3.59 (m, 1H), 3.84 (m, 1H), 4.76 (d,
J ˆ 1.9 Hz, 1H), 5.01 (d, J ˆ 1.0 Hz, 1H), 6.01, 6.18 (2d, AB, J ˆ 11.2 Hz,
ƒ
of A Coruna for financial support. I.C. also acknowledges a predoctoral
‡
‡
ƒ
fellowship from the University of A Coruna.
2H); MS (EI): m/z (%): 570 (32) [M ], 555 (45) [M À CH3], 193 (100);
‡
HRMS (EI): m/z: calcd for C36H62O3Si: 570.4468 [M ]; found: 570.4465.
(3b,5Z,7E,24S)-9,10-Secocholesta-5,7,10(19)-triene-3,24,25-triol [24S,25-
dihydroxyvitamin D3] (1d):[31] Followingthe same experimental procedure
used for 1c, compound 16 (40 mg, 0.07 mmol) afforded, after purification
(90% EtOAc/hexanes), 1d (24 mg, 82%) as a white solid. Rf ˆ 0.46 (70%
[1] a) Vitamin D (Eds.: D. Feldman, F. H. Glorieux, J. W. Pike), Academ-
ic Press, New York, 1997; b) M. J. Calverley, J. Jones in Antitumor
Steroids (Ed.: R. T. Blickenstaff), Academic Press, San Diego, 1992,
Chem. Eur. J. 2002, 8, No. 12
¹ WILEY-VCH VerlagGmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0812-2751 $ 17.50+.50/0
2751

J. Pÿrez Sestelo, L. A. Sarandeses et al.
FULL PAPER
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Received: February 5, 2002 [F3852]
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