New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

Article abstract of DOI:10.1016/j.tet.2008.12.034

Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (+)-4 and (-)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectivel

Full text of DOI:10.1016/j.tet.2008.12.034

Tetrahedron 65 (2009) 1235–1240
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New A-ring analogs of the hormone 1
a
,25-dihydroxyvitamin D3:
(20-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3
,
,
Heung Bae Jeon a b, Gary H. Posner a
*
a Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
b Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (þ)-4
and (ꢀ)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-bu-
tyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (20-hydroxymethyl)tetrahy-
drofuro[1,2-a]-25-hydroxyvitamin D3 3a and 3b as new A-ring-modified analogs of the natural hormone
Received 1 November 2008
Received in revised form 8 December 2008
Accepted 8 December 2008
Available online 24 December 2008
1
a,25-dihydroxyvitamin D3 were readily synthesized by using Lythgoe-type coupling of the A-ring
phosphine oxides (þ)-4 and (ꢀ)-4 with C,D-ring ketone (þ)-5.
Keywords:
Vitamin D3 analogs
Ó 2009 Elsevier Ltd. All rights reserved.
A-Ring-modified analogs
Bicyclic A-ring phosphine oxide
Lythgoe-type coupling
1. Introduction
moiety in 1a,25-dihydroxyvitamin D3 analog was never introduced
until now. Herein, we describe the stereoselective synthesis of the
The natural hormone 1
a
,25-dihydroxyvitamin D3 (1, calcitriol),
conceptually new analogs 3a and 3b.
regulates diverse biochemical functions, such as immunomodula-
tion, control of hormonal systems, inhibition of cell growth, and
induction of cell differentiation.1–3 This hormone and some of its
synthetic analogs are currently used as efficacious drugs for che-
motherapy of patients having secondary hyperthyroidism, osteo-
porosis, and psoriasis.3,4 Currently, more than six analogs are
regularly used as drugs that promote healthier living.4 Although
most synthetic analogs feature changes in the side chain of the
molecule,3,5 some A-ring-modified analogs have potent biological
activities and potential for chemotherapy of cancer.6
OH
OH
H
H
1
2
HO
OH
HO
OH
O
OH
1
Crystallizing the modified vitamin D receptor (VDR) containing
calcitriol (1) has allowed X-ray determination to show that the
relatively large ligand-binding pocket can accommodate much
structural variation in potential calcitriol analog ligands.7 On this
1α,25-Dihydroxyvitamin D3
(calcitriol)
2
ED-71
basis and on some structural similarity to 2
b-(3-hydroxypropoxy)-
OH
OH
1
a,25-dihydroxyvitamin D3 (2, ED-71), which was developed from
the Chugai Pharmaceutical Co. as a promising candidate for the
treatment of osteoporosis,8 enantiomerically pure analogs 3a and
3b having the bicyclic A-ring moiety attached with a 2-hydroxy-
methyltetrahydrofuran ring at C1 and C2 of natural A-ring were
designed to mimic the terminal –OH in the 3-hydroxypropoxy
group at C2 of ED-71 (2). As far as we know, the bicyclic A-ring
H
H
1
2
1
2
HO
HO
O
O
OH
1,2-β-THF-α−CH2OH
OH
3a
3b
* Corresponding author. Tel.: þ1 410 516 4670; fax: þ1 410 516 8420.
E-mail address: ghp@jhu.edu (G.H. Posner).
1,2-α-THF-β-CH2OH
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.034

1236
H.B. Jeon, G.H. Posner / Tetrahedron 65 (2009) 1235–1240
3b
ring ketone (þ)-59 and bicyclic tetrahydrofuro[1,2-a]-A-ring phos-
3a
phine oxide (þ)-4 and (ꢀ)-4.
Our approach to the tetrahydrofuro[1,2-a] (THF)-attached
bicyclic A-ring phosphine oxide (þ)-4 commenced with
commercially available methyl 2-pyrone-3-carboxylate (6) and
tert-butyldimethylsilyl (TBS)-protected (S)-2-hydroxymethyl-2,3-
dihydrofuran (S)-7, which was prepared according to a previously
reported procedure,10 as shown in Scheme 2. Inverse-electron-de-
mand Diels–Alder cycloaddition of 2-pyrone-3-carboxylate 6 with
2 equiv of dihydrofuran (S)-7 to allow isolation of the bridged tri-
cyclic adduct 8a without loss of CO2 by cycloreversion was ac-
complished by various different reaction conditions with various
solvents, catalysts, temperatures, times, and pressures. The results
are shown in Table 1. Thus, the desired tricyclic adduct 8a was
obtained in good yield via high pressure (w10 kbar) cycloaddition
with a catalytic amount of BaCO3 at room temperature, although
the reaction gave a mixture of endo and exo isomers as 4:1 ratio
(entry 17 in Table 1). Chemospecific allyloxide opening of the lac-
tone ring in tricyclic lactone ester 8a and subsequent protection of
the resultant alcohol 10 with tert-butyldimethylsilyl triflate
OTMS
+
P(O)Ph2
P(O)Ph2
+
H
O
(+)-5
TBSO
TBSO
O
O
OTBS
OTBS
(+)-4
(-)-4
Scheme 1.
2. Results and discussion
Synthesis of the tetrahydrofuro[1,2-a] (THF) attached hybrid
analogs 3a and 3b can be envisioned retrosynthetically through the
disconnections shown in Scheme 1. Analogs 3a and 3b can be
prepared through Horner–Wadsworth–Emmons coupling of C,D-
O
CO2Me
n-BuLi
O
cat. BaCO3
O
CO2Me
O
CH2=CHCH2OH
~10 kbar
OTBS
O
+
O
CH2Cl2, 3days
58%
CH2Cl2
OTBS
72%
(S)-7
8a
6
Pd(OAc)2
PPh3
HCO2H, NEt3
CO2Allyl
CO2Me
CO2Me
CO2Allyl
CO2Me
TBSOTf
2,6-lutidine
+
O
TBSO
O
Dioxane
TBSO
CH2Cl2
94%
HO
O
O
OTBS
OTBS
OTBS
OTBS
13
(-)-12
11
10
69%
11%
Scheme 2.
Table 1
Diels–Alder cycloaddition of 6 and (S)-7 in various conditionsa
CO2Me
O
CO2Me
O
CO2Me
O
O
O
O
O
O
+
CO2Me
O
OTBS
O
+
+
OTBS
OTBS
OTBS
(S)-7
8a
(+)-9
6
8b
Entry
Solvent
Catalyst
Temp
Time
Yield [8a/8b/(þ)-9]b
1
2
3
4
5
6
7
8
CH2Cl2
THF
THF
CH2Cl2
Benzene
ClCH2CH2Cl
DMSO
ZnBr2
ZnBr2
ZnBr2
BaCO3
rt
rt
Reflux
Sealed tube (80–85 ꢁC)
Reflux
Sealed tube (85–90 ꢁC)
Sealed tube (85–90 ꢁC)
Sealed tube (80–85 ꢁC)
Sealed tube (80–85 ꢁC)
rt
Sealed tube (80–85 ꢁC)
Sealed tube (80–85 ꢁC)
Sealed tube (40–45 ꢁC)
Sealed tube (55–60 ꢁC)
Sealed tube (55–60 ꢁC)
High pressure
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
20% (only 8a)
No reaction
No reaction
12% (9:2:2)
<5% (2:1:1)
15% (1:1:2)
15% (1:1:2)
32% (2:1:1)
12% (2:1:1)
<5% (only 8a)
91% (1:3:10)
89% (1:7:25)
11% (4:1:0)
26% (4:1:2)
27% (3:1:1)
43% (10:1:0)
63% (4:1:0)
61% (4:1:0)
BaCO3
CHCl3
BaCO3
BaCO3
9
Benzene
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24 h
3 h
10
11
12
13
14
15
16
17
18
Yb(OTf)3
BaCO3
BaCO3
BaCO3
BaCO3
4 days
4 days
4 days
4 days
4 days
3 days
3 days
3 days
ZnBr2
BaCO3
High pressure
High pressure
a
Compound 6 (1 equiv) and 2 equiv of (S)-7 were used for all reactions.
b
The yield and the ratio of 8a, 8b, and (þ)-9 were measured by 1H NMR, compared to the remaining starting material 6.

H.B. Jeon, G.H. Posner / Tetrahedron 65 (2009) 1235–1240
1237
CO2Me 0.2 eq. (R, R)-Jacobsen cat.
O
cat. BaCO3
CHCl3
5 eq. NMO
O
CO2Me
2.5 eq. m-CPBA
O
OTBS
+
O
sealed tube
80 °C, 4 days
65%
CH2Cl2, rt
57%
(S)-7
OTBS
6
(+)-9
CO2Me
Pd2(dba)3.CHCl3
CO2Me
CO2Me
n-Bu3P
TBSOTf
O
2,6-lutidine
HCOOH, NEt3
dioxane, rt
55%
HO
TBSO
O
O
O
CH2Cl2
95%
OTBS
OTBS
OTBS
(+)-14
(-)-12
(-)-15
DIBAL-H
CH2Cl2
96%
P(O)Ph2
OEt
OEt
OEt
O
S
CO2Et
O
OH
O
1. DIBAL-H
Ph
2. NCS, Me2S
cat. TMBA
CH2Cl2
sealed tube
TBSO
3. Ph2PLi
4. H2O2
40%
TBSO
TBSO
O
OTBS
110 °C, overnight
(-)-16
OTBS
54%
OTBS
(+)-17
(+)-4
Scheme 3.
(TBSOTf) afforded bicyclic allyl methyl malonate 11 in good yield
(Scheme 2). Deallyloxycarbonylation of allyl ester 11 under reflux in
dioxane using formic acid and a catalytic amount of palladium
acetate,11 however, provided the desired conjugated enoate ester
(ꢀ)-1212 in only 10% yield, along with undesired dihy-
drobenzofuran 13 in 69% yield as a major product.
For the synthesis of enantiomerically pure A-ring phosphine
oxide (ꢀ)-4, the enantiomer of (þ)-4, Diels–Alder reaction of
methyl 2-pyrone-3-carboxylate (6), and dihydrofuran (R)-7 was
accomplished by heating in a sealed tube to give bicyclic adduct
(ꢀ)-9 in 65% yield (Scheme 4). Stereoselective epoxidation of (ꢀ)-9
with m-CPBA in the presence of a catalytic amount of (S,S)-Jacobsen
catalyst and excess NMO gave epoxide (ꢀ)-14 in 60% yield. Then,
the A-ring phosphine oxide (ꢀ)-4 was readily obtained from ep-
oxide (ꢀ)-14 in several steps in similar yields according to the same
procedure to (þ)-4 from (þ)-14 as shown in Scheme 3.
The low yield in the deallyloxycarbonylation of 11 led us to
examine other synthetic routes to intermediate (ꢀ)-12. We en-
visaged that the decarboxylated bicyclic adduct (þ)-9 of 8a would
give the enoate ester (ꢀ)-12 by introducing a hydroxyl group
stereoselectively at C3. Thus, heating 2-pyrone-3-carboxylate 6
and dihydrofuran (S)-7 along with a catalytic amount of BaCO3 in
a sealed tube at 80–85 ꢁC for 4 days afforded the desired bicyclic
adduct (þ)-9 in 65% yield (entry 12 in Table 1 and Scheme 3).
Reaction of (þ)-9 with m-chloroperoxybenzoic acid (m-CPBA) in
the presence of a catalytic amount of the (R,R)-Jacobsen catalyst
and excess N-methylmorpholine-N-oxide (NMO) gave epoxide
(þ)-14 stereoselectively in 57% yield.13 Epoxide ring opening of
(þ)-14 using formic acid and a catalytic amount of tris(dibenzyli-
deneacetone)dipalladium(0) [Pd2(dba)3]14 followed by O-silylation
of the resulting alcohol (ꢀ)-15 provided the desired enoate ester
(ꢀ)-12 in good yield. Reduction of the conjugated methyl ester
functionality in (ꢀ)-12 by diisobutylaluminum hydride (DIBAL-H)
produced allylic alcohol (ꢀ)-16 in 96% yield. The [3,3]-sigmatropic
Claisen rearrangement using 1-(phenylsulfinyl)-2,2,2-triethoxy-
ethane in the presence of a catalytic amount of 2,4,6-trime-
thylbenzoic acid (TMBA) allowed allyl alcohol (ꢀ)-16 to undergo
efficient, regiospecific formation of two-carbon-extended conju-
gated dienoate ester (þ)-17 as the desired Z-isomer in 54% yield,
along with the E-isomer as a side product in 10% yield.15 On the
basis of the literature precedent9 and our own experience, dien-
oate ester (þ)-17 was reduced by DIBAL-H, chlorinated by
N-chlorosuccimide (NCS), converted into the corresponding
phosphine by lithium diphenylphosphide (Ph2PLi), generated from
diphenylphosphine (Ph2PH) and n-BuLi, and finally oxidized by
H2O2 to give tetrahydrofuro[1,2-a]-A-ring phosphine oxide (þ)-4
in good yield.
Finally, Lythgoe-type coupling16 of the bicyclic A-ring phosphine
oxides (þ)-4 and (ꢀ)-4 with enantiomerically pure C,D-ring ketone
(þ)-5 was followed by fluoride-promoted desilylation using tetra-
butylammonium fluoride (TBAF) to afford diastereomerically pure
1a,25-dihydroxyvitamin D3 analogs 3a and 3b, respectively
(Scheme 5). The lack of any significant in vitro antiproliferative
activity of new analogs 3a and 3b, however, was disappointing.
CO2Me
cat. BaCO3
CHCl3
O
+
6
OTBS
O
sealed tube
80 °C, 4 days
65%
(R)-7
OTBS
(-)-9
0.25 eq.
(S,S)-Jacobsen cat.
5 eq. NMO
2.5 eq. m-CPBA
CH2Cl2, rt
P(O)Ph2
60%
CO2Me
O
O
TBSO
O
OTBS
(-)-14
OTBS
(-)-4
Scheme 4.

1238
H.B. Jeon, G.H. Posner / Tetrahedron 65 (2009) 1235–1240
P(O)Ph2
2.4 Hz, 1H), 5.98 (dd, J¼9.6, 7.8 Hz, 1H), 4.85 (d, J¼8.0 Hz, 1H), 3.84
P(O)Ph2
(m, 1H), 3.77 (s, 3H), 3.71 (dd, J¼10.8, 4.0 Hz, 1H), 3.65 (dd, J¼10.8,
5.6 Hz, 1H), 3.19 (m, 1H), 2.34 (dt, Jd¼12.4 Hz, Jt¼8.4 Hz, 1H), 2.12
(ddd, J¼12.4, 6.4, 2.0 Hz, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).
13C NMR (100 MHz, CDCl3)
d 167.4, 137.6, 134.3, 126.1, 121.9, 77.2,
TBSO
TBSO
O
O
71.2, 65.4, 51.7, 39.8, 35.3, 25.9, 18.3, ꢀ5.39, ꢀ5.42. HRMS
([MþNa]þ) calcd 324.1757, found 324.1750.
OTBS
OTBS
(+)-4
(-)-4
4.3. Methyl 1a,3a,5,6,6a(S),6b(S)-hexahydro-5(S)-(tert-
butyldimethylsilyloxy)methyl-7-oxa-bicyclo[4.1.0]hepta-
1(6),2-dieno[4,5-b]furan-3-carboxylate [(D)-14]
1. n-BuLi
THF
1. n-BuLi
OTMS
THF
21%
50%
2. TBAF
93%
2. TBAF
92%
H
To a solution of cycloadduct (þ)-9 (0.80 g, 2.47 mmol), (R,R)-
Jacobsen catalyst (0.34 g, 0.50 mmol), NMO (1.44 g, 12.3 mmol) in
CH2Cl2 (25 mL) was added m-CPBA (0.85 g, 4.94 mmol) at rt. After
stirring for overnight at rt, the reaction mixture was quenched with
water. After addition of CH2Cl2 (60 mL), the organic layer was
washed with water, saturated aqueous Na2SO3, and saturated
aqueous NaHCO3, then dried over MgSO4, and concentrated. The
residue was subjected to column chromatography with EtOAc–
O
(+)-5
OH
HO
OH
H
O
H
hexanes (1:5) as eluent to give the desired
(0.48 g, 57%) and the b-epoxide diastereomer (0.10 g, 12%). Com-
a
-epoxide (þ)-14
HO
O
pound (þ)-14: [
a]
þ52.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
22
D
d
6.94 (d, J¼4.0 Hz, 1H), 4.74 (d, J¼8.8 Hz, 1H), 4.03 (ddd, J¼9.6, 8.8,
OH
OH
3b
3a
4.0 Hz, 1H), 3.76 (s, 3H), 3.62 (dd, J¼10.4, 4.0 Hz, 1H), 3.56 (dd,
J¼10.4, 5.2 Hz, 1H), 3.47 (dd, J¼3.6, 2.0 Hz, 1H), 3.40 (t, J¼4.0 Hz,
1H), 3.25 (qd, Jq¼9.2 Hz, Jd¼1.6 Hz, 1H), 2.13 (ddd, J¼12.8, 9.2,
4.0 Hz, 1H), 1.80 (m, 1H), 0.88 (s, 9H), 0.046 (s, 3H), 0.040 (s, 3H). 13C
Scheme 5.
3. Conclusion
NMR (100 MHz, CDCl3)
d 166.2, 135.8, 133.0, 78.6, 72.0, 65.3, 52.8,
52.0, 45.4, 36.2, 31.1, 25.8, 18.2, ꢀ5.37, ꢀ5.43. IR (neat, cmꢀ1) 2952,
2929, 2856, 1726, 1472, 1435, 1256, 1114, 1090, 837, 778. HRMS
([MþNa]þ) calcd 363.1598, found 363.1594.
In conclusion, the diastereomerically pure (20-hydroxy-
methyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3 3a and 3b as
new A-ring-modified analogs of the hormone 1a,25-dihydroxy-
vitamin D3 have been successfully synthesized by Lythgoe-type
coupling of the conceptually new bicyclic (20-hydroxymethyl)te-
trahydrofuro[1,2-a]-A-ring phosphine oxides (þ)-4 and (ꢀ)-4 with
enantiomerically pure C,D-ring ketone (þ)-5.
4.4. Methyl 2,3,3a(S),4,5,7a(S)-hexahydro-4(R)-hydroxy-2(S)-
(tert-butyldimethylsilyloxymethyl)benzofuran-7-carboxylate
[(L)-15]
4. Experimental
4.1. General
To
a
solution of Pd2(dba)3CHCl3 (62 mg, 0.06 mmol) and
L, 0.12 mmol) in dioxane (6 mL) was added a solution
n-Bu3P (30
m
of formic acid (0.6 mL, 12.5 mmol) and NEt3 (0.69 mL) in dioxane
(5 mL). After the resulting solution stirring for 10 min at rt, a so-
lution of epoxide (þ)-14 (0.71 g, 2.09 mmol) in dioxane (5 mL)
was added. The mixture solution was stirred for overnight at rt,
and then quenched with water. The solution was extracted ether.
The organic layer was washed with brine, dried over MgSO4, and
concentrated. The residue was subjected to column chromato-
All reactions were conducted under a positive pressure of dry
argon with dry, freshly distilled solvents unless otherwise noted. All
reagents were purchased from commercial suppliers and used
without further purification unless otherwise noted. Flash column
chromatography was performed by employing 230–400 mesh silica
gel. Thin-layer chromatography was performed using silica gel 60
F254 precoated plates (0.25 mm thickness) with a fluorescent in-
dicator. Infrared spectra were recorded on a Perkin–Elmer 1600 FT-
IR spectrometer using NaCl plates. 1H and 13C NMR spectra were
obtained in CDCl3 solution and were referenced to CHCl3 (7.26 and
77.0 ppm, respectively) using a Varian XL 400 MHz NMR spec-
trometer. Optical rotations were measured with a JASCO, P-100
model polarimeter.
graphy with EtOAc–hexanes (2:3) as eluent to give the desired
25
alcohol (ꢀ)-15 (0.39 g, 55%). [
a
]
D
ꢀ50.8 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3)
d
7.01 (dd, J¼6.0, 2.8 Hz, 1H), 4.76 (d, J¼4.8 Hz,
1H), 4.15 (ddd, J¼12.0, 7.6, 4.4 Hz, 1H), 3.76 (s, 3H), 3.66–3.76 (m,
3H), 2.64 (dt, Jd¼18.8 Hz, Jt¼5.6 Hz, 1H), 2.13–2.25 (m, 3H), 2.04
(dt, Jd¼13.6 Hz, Jt¼7.6 Hz, 1H), 1.69 (br s, 1H), 0.90 (s, 9H), 0.09 (s,
3H), 0.07 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 166.6, 140.1, 130.1,
77.5, 74.4, 66.5, 65.8, 51.8, 45.5, 34.2, 30.0, 25.9, 18.3, ꢀ5.4. IR
(neat, cmꢀ1) 3437, 2952, 2928, 2856, 1723, 1652, 1472, 1436, 1252,
1134, 1090, 1033, 1005, 837, 779. HRMS ([MþNa]þ) calcd 365.1755,
found 365.1767.
4.2. Methyl 2,3,3a(S),7a(S)-tetrahydro-2(S)-(tert-butyldi-
methylsilyloxymethyl)benzofuran-7-carboxylate [(D)-9]
In a sealed tube, a solution of methyl-2-oxo-2H-pyran-3-car-
boxylate (6, 1.08 g, 7.01 mmol), dihydrofuran (S)-7 (2.74 g,
12.8 mmol), and catalytic amount (0.10 g) of BaCO3 in CHCl3
(14 mL) was heated to 80 ꢁC for 4 days. The reaction mixture was
concentrated. The residue was subjected to column chromatogra-
4.5. Methyl 2,3,3a(S),4,5,7a(S)-hexahydro-4(R)-(tert-butyl-
dimethylsilyloxy)-2(S)-(tert-butyldimethylsilyloxymethyl)-
benzofuran-7-carboxylate [(L)-12]
To a solution of alcohol (ꢀ)-15 (0.14 g, 0.41 mmol) and 2,6-
lutidine (0.14 mL, 1.23 mmol) in CH2Cl2 (20 mL) was added TBSOTf
(0.19 mL, 0.82 mmol) at ꢀ78 ꢁC. After stirring for 1 h at ꢀ78 ꢁC, the
reaction mixture was warmed to rt. The solution was quenched
phy with EtOAc–hexanes (1:7) as eluent to give the desired cyclo-
22
adduct (þ)-9 (1.48 g, 65%). [
a
]
þ35.7 (c 1.0, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
7.15 (d, J¼6.0 Hz, 1H), 6.10 (ddd, J¼9.6, 6.0,

H.B. Jeon, G.H. Posner / Tetrahedron 65 (2009) 1235–1240
1239
with aqueous 1 N HCl (1 mL) and extracted with CH2Cl2. The or-
ganic layer was washed with brine, dried over MgSO4, and con-
centrated. The residue was subjected to column chromatography
and aqueous 1 N HCl (3 mL). The solution was extracted with
CH2Cl2. The organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was subjected to column
chromatography with EtOAc–hexanes (1:3) as eluent to give the
desired allyl alcohol (0.19 g, 55%).
To a solution of N-chlorosuccinimide (0.17 g, 1.27 mmol) in
CH2Cl2 (15 mL) was added dimethylsulfide (95 mL, 1.29 mmol) at
0 ꢁC. After stirring for 15 min at 0 ꢁC, and then 10 min ꢀ20 ꢁC, the
resulting allyl alcohol (0.17 g, 0.37 mmol) in CH2Cl2 (5 mL) was
added dropwise via cannula. After stirring for 1.5 h at ꢀ20 ꢁC, the
reaction mixture was quenched with water, extracted with CH2Cl2,
dried over MgSO4, and concentrated. The residue was passed over
a plug of silica gel (60% hexanes, 40% EtOAc), concentrated, and
azeotropically dried with benzene. The resulting allyl chloride was
immediately carried on to the next step.
with EtOAc–hexanes (1:7) as eluent to give the desired TBS-pro-
25
tected alcohol (ꢀ)-12 (0.18 g, 95%). [
a
]
D
ꢀ42.6 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3)
d
6.97 (dd, J¼5.6, 2.4 Hz, 1H), 4.72 (d,
J¼4.8 Hz, 1H), 4.10 (ddd, J¼12.4, 8.4, 4.4 Hz, 1H), 3.74 (s, 3H), 3.66–
3.72 (m, 3H), 2.51 (dt, Jd¼18.8 Hz, Jt¼5.2 Hz, 1H), 2.10–2.21 (m, 3H),
1.93 (dt, Jd¼13.6 Hz, Jt¼7.6 Hz, 1H), 0.894 (s, 9H), 0.888 (s, 9H), 0.08
(s, 3H), 0.07 (s, 6H), 0.06 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 166.7,
140.6, 129.9, 77.5, 74.5, 66.8, 65.9, 51.7, 46.0, 34.8, 30.1, 25.9, 25.8,
18.3, 17.9, ꢀ4.2, ꢀ4.8, ꢀ5.4. IR (neat, cmꢀ1) 2953, 2929, 2857, 1725,
1654, 1472, 1463, 1436, 1386, 1361, 1311, 1251, 1102, 1034, 1006, 921,
836, 776. HRMS ([MþNa]þ) calcd 479.2619, found 479.2613.
4.6. 2,3,3a(S),4,5,7a(S)-Hexahydro-4(R)-(tert-butyldi-
methylsilyloxy)-2(S)-(tert-butyldimethylsilyloxymethyl)-7-
(hydroxymethyl)benzofuran [(L)-16]
Totheallyl chloride inTHF(10 mL) at ꢀ78 ꢁC was added a solution
of lithium diphenylphosphide, prepared by the addition of n-butyl-
lithium (1.6 M in hexanes, 1.37 mL, 2.2 mmol) to a solution of
diphenylphosphine (0.38 mL, 2.2 mmol) in THF (8 mL) at 0 ꢁC, via
cannula and the orange solution was stirred for 1.5 h at ꢀ78 ꢁC. The
mixture was slowly diluted with 5 mL of water and evaporated. The
residue was diluted with CH2Cl2 (15 mL) and water (10 mL) and the
vigorously stirred mixture was treated with hydrogen peroxide (30%,
4.0 mL) and stirring was continued overnight. The reaction mixture
was extracted with CH2Cl2 and water, dried over MgSO4, and con-
centrated. The residue was subjected to silica gel column chroma-
To a solution of ester (ꢀ)-12 (0.18 g, 0.39 mmol) in CH2Cl2
(25 mL) was added DIBAL-H (1.5 M in Tol., 0.66 mL, 0.99 mmol) at
ꢀ78 ꢁC. After stirring for 1 h at ꢀ78 ꢁC, the reaction mixture was
quenched with aqueous 1 N HCl (2 mL). The solution was extracted
with CH2Cl2. The organic layer was washed with brine, dried over
MgSO4, and concentrated. The residue was subjected to column
chromatography with EtOAc–hexanes (1:4) as eluent to give the
24
desired alcohol (ꢀ)-16 (0.16 g, 96%). [
a
]
ꢀ38.4 (c 1.0, CHCl3). 1H
tography with EtOAc–hexanes (2:1) as eluent to give the pure
D
23
NMR (400 MHz, CDCl3)
d
5.72 (m, 1H), 4.43 (d, J¼12.4 Hz, 1H), 4.10
phosphine oxide (þ)-4 (0.15 g, 63%). [
a
]
þ16.5 (c 1.00, CHCl3). 1H
D
(m, 1H), 4.05 (d, J¼12.4 Hz, 1H), 3.59–3.66 (m, 3H), 2.52 (s, 1H), 2.31
(dt, Jd¼17.2 Hz, Jt¼5.6 Hz, 1H), 2.22 (m, 1H), 2.10 (ddd, J¼13.2, 6.8,
2.0 Hz, 1H), 1.99 (m, 1H), 1.84 (dt, Jd¼13.2 Hz, Jt¼7.6 Hz, 1H), 0.883
(s, 9H), 0.879 (s, 9H), 0.056 (s), 0.047 (s)dtotal 12H. 13C NMR
NMR (400 MHz, CDCl3) d 7.65–7.78 (m, 4H), 7.40–7.53 (m, 6H), 5.49
(q, J¼7.2 Hz,1H), 5.29 (d, J¼2.0 Hz,1H), 5.08 (d, J¼2.0 Hz,1H), 4.31 (d,
J¼4.8 Hz, 1H), 4.06 (m, 1H), 3.65 (d, J¼4.4 Hz, 2H), 3.48 (ddd, J¼10.0,
8.4, 4.0 Hz,1H), 3.27–3.34 (m, 2H), 2.37 (dd, J¼12.8, 4.0 Hz,1H), 2.12–
2.22 (m, 2H), 1.98 (ddd, J¼12.8, 7.6, 3.2 Hz, 1H), 1.84 (m, 1H), 0.90 (s,
9H), 0.83 (s, 9H), 0.075 (s, 3H), 0.070 (s, 3H), ꢀ0.014 (s, 3H), ꢀ0.028 (s,
(100 MHz, CDCl3)
d 135.9, 124.7, 78.1, 77.8, 68.0, 66.1, 65.9, 46.2,
33.9, 30.2, 25.83, 25.77, 18.2, 18.0, ꢀ4.2, ꢀ4.8, ꢀ5.3. IR (neat, cmꢀ1
)
3389, 2955, 2929, 2857, 1472, 1461, 1349, 1255, 1102, 1002, 838, 773.
3H). 13C NMR (100 MHz, CDCl3)
d
142.1 (d, J¼2.3 Hz), 140.1 (d,
HRMS ([MþNa]þ) calcd 451.2670, found 451.2664.
J¼12.2 Hz), 131.7 (d, J¼3.0 Hz), 131.6 (d, J¼2.3 Hz), 131.6
(d, J¼74.3 Hz), 131.5 (d, J¼75.1 Hz), 131.4 (d, J¼9.1 Hz), 130.8 (d,
J¼9.1 Hz), 128.6 (d, J¼1.5 Hz), 128.5 (d, J¼1.5 Hz), 117.5, 116.2
(d, J¼7.6 Hz), 82.2, 77.7, 70.7 (d, J¼1.2 Hz), 66.0, 49.7, 44.3, 31.5 (d,
J¼69.8 Hz), 31.1, 25.9, 25.8,18.3,17.9, ꢀ4.2, ꢀ4.8, ꢀ5.2, ꢀ5.3. IR (neat,
cmꢀ1) 2955, 2931, 2856,1472,1438,1254,1192,1120,1102,1073, 836,
775, 744, 718, 695. HRMS([MþNa]þ)calcd 638.3376, found 638.3368.
4.7. (Z)-Ethyl 2-[hexahydro-4(R)-(tert-butyldimethylsilyloxy)-
2(S)-(tert-butyldimethylsilyloxymethyl)-7-methylenebenzo-
furan-6(2H)-ylidene]acetate [(D)-17]
A sealed tube, equipped with a stirring bar, was charged with allyl
alcohol (ꢀ)-16 (0.16 g, 0.35 mmol), 2,4,6-trimethylbenzoic acid
(5 mg),
1-(phenylsulfinyl)-2,2,2-triethoxyethane
(0.20 g,
4.9. (20-Hydroxymethyl)tetrahydrofuro[1,2-a]-25-
0.70 mmol), and CH2Cl2 (5 mL). The mixture was sealed with argon
and heated to 110 ꢁC overnight. The reaction mixture was cooled to rt
and concentrated. The residue was subjected to column chroma-
hydroxyvitamin D3 3a (1,2-a-THF-b-CH2OH)
A solution of 35 mg (0.055 mmol) of A-ring phosphine oxide
tography with EtOAc–hexanes (1:15) as eluent to give desired dien-
(þ)-4 in 1.5 mL of anhydrous THF was cooled to ꢀ78 ꢁC and treated
25
oate (þ)-17 (94 mg, 54%). [
a
]
þ2.97 (c 1.0, CHCl3). 1H NMR
with 34 mL (0.055 mmol, 1.6 M in hexanes) of n-BuLi under argon
D
(400 MHz, CDCl3)
d
5.68(s,1H), 5.32(t, J¼1.6 Hz,1H), 5.24 (t, J¼1.2 Hz,
atmosphere. The mixture turned deep reddish and was stirred for
15 min at ꢀ78 ꢁC. To the solution was added dropwise a precooled
(ꢀ78 ꢁC) solution of 12 mg (0.034 mmol) of the C,D-ring ketone
(þ)-5 in 1.5 mL of anhydrous THF via cannula. The reaction kept
going until the reddish orange color faded to yellow (about 6.5 h).
The reaction was quenched by adding 1.0 mL of pH 7 buffer (com-
mercially available from ALDRICH) at ꢀ78 ꢁC, then warmed to room
temperature, extracted with EtOAc (20 mLꢂ2), washed with brine,
dried over MgSO4, and concentrated. The residue was subjected to
column chromatography with EtOAc–hexanes (1:15) as eluent to
afford 5.5 mg (21%) of the coupled product as a colorless oil.
The coupled product (5.5 mg, 0.0071 mmol) was dissolved in
1H), 4.55 (d, J¼5.2 Hz, 1H), 4.08–4.15 (m, 3H), 3.83 (ddd, J¼8.0, 6.8,
3.6 Hz,1H), 3.60–3.67 (m, 2H), 2.50 (m,1H), 2.23–2.35 (m, 2H),1.91 (t,
J¼6.8 Hz, 2H),1.23 (t, J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.057 (s),
0.051 (s), 0.048 (s)dtotal 12H. 13C NMR (100 MHz, CDCl3)
d 166.0,
152.0, 142.0, 118.0, 116.5, 81.5, 77.5, 70.3, 65.7, 59.9, 49.2, 43.9, 30.4,
25.9, 25.7, 18.3, 17.9, 14.0, ꢀ4.37, ꢀ4.82, ꢀ5.31, ꢀ5.35. IR (neat, cmꢀ1
)
2954, 2929, 2857, 1729, 1641, 1472, 1361, 1255, 1178, 1092, 1038, 836,
776. HRMS ([MþNa]þ) calcd 519.2932, found 519.2952.
4.8. (20-tert-Butyldimethylsilyloxymethyl)tetrahydrofuro-
[1,2-a]-A-ring phosphine oxide (D)-4
2 mL of anhydrous THF, and to the solution was added 78 mL
To a solution of dienoate (þ)-17 (0.38 g, 0.76 mmol) in toluene
(10 mL) was added DIBAL-H (1.5 M in Tol., 1.27 mL, 1.91 mmol) at
ꢀ78 ꢁC. After stirring for 1 h at ꢀ78 ꢁC, the reaction mixture was
quenched with aqueous 2 N potassium, sodium-tartrate (2 mL),
(0.078 mmol) of a 1.0 M solution of TBAF in THF. The resulting
mixture was stirred in darkness overnight at room temperature,
then quenched with 2 mL of water. The solution was extracted with
EtOAc (20 mLꢂ3), washed with brine, dried over MgSO4, and

1240
H.B. Jeon, G.H. Posner / Tetrahedron 65 (2009) 1235–1240
P. M.; Kensler, T. W.; Posner, G. H. Bioorg. Med. Chem. 2006, 14, 6341–6348; (d)
Posner, G. H.; Kim, H. J.; Kahraman, M.; Jeon, H. B.; Suh, B. C.; Li, H.; Dolan, P. M.;
Kensler, T. W. Bioorg. Med. Chem. 2005, 13, 5569–5580; (e) Kahraman, M.;
Sinishtaj, S.; Dolan, P. M.; Kensler, T. W.; Peleg, S.; Saha, U.; Chuang, S. S.;
Bernstein, G.; Korczak, B.; Posner, G. H. J. Med. Chem. 2004, 47, 6854–6863; (f)
Suh, B.-C.; Jeon, H. B.; Posner, G. H.; Silverman, S. M. Tetrahedron Lett. 2004, 45,
4623–4626; (g) Sussman, F.; Rumbo, A.; Vilaverde, M. C.; Mourino, A. J. Med.
Chem. 2004, 47, 1613–1616; (h) Posner, G. H.; Halford, B. A.; Peleg, S.; Dolan, P.;
Kensler, T. W. J. Med. Chem. 2002, 45, 1723–1730; (i) Posner, G. H.; Crawford, K.;
Siu-Caldera, M.-L.; Reddy, G. S.; Sarabia, S. F.; Feldman, D.; van Etten, E.;
Mathieu, C.; Gennaro, L.; Vouros, P.; Peleg, S.; Dolan, P. M.; Kensler, T. W. J. Med.
Chem. 2000, 43, 3581–3586; (j) Posner, G. H.; Wang, Q.; Han, G.; Lee, J. K.;
Crawford, K.; Zand, S.; Berm, H.; Peleg, S.; Dolan, P.; Kensler, T. W. J. Med. Chem.
1999, 42, 3425–3435; (k) Yamada, S.; Yamamoto, K.; Masuno, H.; Ohta, M.
J. Med. Chem. 1998, 41, 1467–1475.
6. (a) Saito, N.; Honzawa, S.; Kittaka, A. Curr. Top. Med. Chem. 2006, 6, 1273–1288;
(b) Peleg, S.; Petersen, K. S.; Suh, B. C.; Dolan, P.; Agoston, E. S.; Kensler, T. W.;
Posner, G. H. J. Med. Chem. 2006, 49, 7513–7517; (c) Hatcher, M. A.; Peleg, S.;
Dolan, P.; Kensler, T. W.; Sarjeant, A.; Posner, G. H. Bioorg. Med. Chem. 2005, 13,
3964–3976; (d) Sicinska, W.; Rotkiewicz, P.; DeLuca, H. F. J. Steroid Biochem. Mol.
Biol. 2004, 89, 107–110; (e) Sicinski, R. R.; Rotkiewicz, P.; Kolinski, A.; Sicinska,
W.; Prahl, J. M.; Smith, C. M.; DeLuca, H. F. J. Med. Chem. 2002, 45, 3366–3380;
(f) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681–694; (g) Zhou, X.; Zhu, G.-D.;
Van Haver, D.; Vandewalle, M.; DeClercq, P. J.; Verstuyf, A.; Bouillon, R. J. Med.
Chem. 1999, 42, 3539–3556; (h) Sicinski, R. R.; Prahl, J. M.; Smith, C. M.; DeLuca,
H. F. J. Med. Chem. 1998, 41, 4662–4674; (i) Posner, G. H.; Nelson, T. D.; Guyton,
K. Z.; Kensler, T. W. J. Med. Chem. 1992, 35, 3280–3287; (j) Perlman, K. L.;
Swenson, R. E.; Paaren, H. E.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett. 1991,
32, 7663–7666.
7. Rochel, N.; Wurtz, J. M.; Mitschler, A.; Klaholz, B.; Moras, D. Mol. Cell 2000, 5,
173–179.
8. (a) Matsumoto, T.; Miki, T.; Hagino, H.; Sugimoto, T.; Okamoto, S.; Hirata, T.;
Yanagisawa, Y.; Hayashi, Y.; Fukunaga, M.; Shiraki, M.; Nakamura, T. J. Clin. En-
docrinol. Metab. 2005, 90, 5031–5036; (b) Miyamoto, K.; Murayama, E.; Ochi, K.;
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9. (a) Nagasawa, K.; Matsuda, N.; Noguchi, Y.; Yamanashi, M.; Zako, Y.; Shimizu, I.
J. Org. Chem.1993, 58,1483–1490; (b) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B.
M.; Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098–3108.
10. Takle, A.; Kocienski, P. Tetrahedron 1990, 46, 4503–4516.
11. Mandai, T.; Imaji, M.; Takada, H.; Kawata, M.; Nokami, J.; Tsuji, J. J. Org. Chem.
1989, 54, 5395–5397.
12. The structure of (ꢀ)-12 can be explained as following: due to the steric issue of
the large group, –CH2OTBS, in dienophile (S)-7, only two possible cycloadducts,
endo-8a and exo-8b, can be obtained from the lower approach of (S)-7 to diene
6 in Diels–Alder cycloaddition. Under high pressure, that the major product is
endo-cycloadduct 8a can be explained by the various products generated from
the following reaction steps as shown in Scheme 2. For example, after several
reaction steps with the major cycloadduct, deallyloxycarbonylation afforded
a conjugated enoate ester product. If this product was generated from 8a, it
should be (ꢀ)-12. Or, if this product was generated from 8b, it should be
compound A. Herein, the coupling constant of H at C3 (see the circled H below
in structures (ꢀ)-12 and A) in 1H NMR showed a trans, trans, cis coupling
constant of ddd (J¼12.4, 8.4, 4.4 Hz) pattern. From this fact, it was concluded
that product (ꢀ)-12 was generated from the cycloadduct 8a. In addition, the
other intermediates shown in Schemes 2 and 3 also showed that the coupling
constant of H at C3 matched with the trans, trans, cis type. In case of (þ)-9,
although its stereochemistry was not clear at first, the same compound (ꢀ)-12
with the same physical data after several reaction steps was obtained.
concentrated. The residuewas subjectedtocolumn chromatography
with EtOAc as eluent to give 3.4 mg (92%) of the desired product 3a.
24
[
a]
þ11.9 (c 0.072, CHCl3). 1H NMR (300 MHz, CDCl3)
d 6.38 (d,
D
J¼10.8 Hz, 1H), 6.04 (d, J¼11.2 Hz, 1H), 5.41 (s, 1H), 5.15 (s, 1H), 4.49
(d, J¼5.6 Hz, 1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H), 3.54 (m,
1H), 2.82 (dd, J¼12.3, 2.6 Hz,1H), 2.64 (dd, J¼13.2, 3.0 Hz,1H),1.22 (s,
6H), 0.87 (d, J¼7.3 Hz, 3H), 0.55 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
143.4,142.5,131.9,125.1,117.4,116.7, 81.3, 71.1, 69.9, 65.4, 56.5, 56.4,
48.9, 45.9, 44.4, 42.7, 40.5, 36.4, 36.1, 30.4, 29.4, 29.2, 29.1, 27.6, 23.6,
22.3, 20.8, 18.8, 12.1. IR (neat, cmꢀ1) 3389, 2928, 2872, 1655, 1455,
1378, 1261, 1214, 1096, 1044, 914, 797, 761. UV (MeOH) lmax 270 (
3
1831). HRMS ([MþNa]þ) calcd 495.3445, found 495.3433.
4.10. (20-Hydroxymethyl)tetrahydrofuro[1,2-a]-25-
hydroxyvitamin D3 3b (1,2-b-THF-a-CH2OH)
A solution of 70 mg (0.11 mmol) of A-ring phosphine oxide
(ꢀ)-4 in 1.5 mL of anhydrous THF was cooled to ꢀ78 ꢁC and treated
with 68 mL (0.11 mmol, 1.6 M in hexanes) of n-BuLi under argon
atmosphere. The mixture turned deep reddish and was stirred for
15 min at ꢀ78 ꢁC. To the solution was added dropwise a precooled
(ꢀ78 ꢁC) solution of 18 mg (0.055 mmol) of the C,D-ring ketone
(þ)-5 in 1.5 mL of anhydrous THF via cannula. The reaction kept
going for 7 h with the reddish orange color at ꢀ78 ꢁC, and then kept
going at ꢀ55 ꢁC for overnight (changed to colorless). The reaction
was quenched by adding 1.0 mL of pH 7 buffer (commercially
available from ALDRICH) at ꢀ78 ꢁC, then warmed to room tem-
perature, extracted with EtOAc (25 mLꢂ2), washed with brine,
dried over MgSO4, and concentrated. The residue was subjected to
column chromatography with EtOAc–hexanes (1:15) as eluent to
afford 20 mg (50%) of the coupled product as a colorless oil.
The coupled product (20 mg, 0.026 mmol) was dissolved in 2 mL
of anhydrous THF, and to the solution was added 0.31 mL
(0.31 mmol) of a 1.0 M solution of TBAF in THF. The resulting mix-
ture was stirred in darkness overnight at room temperature, then
quenched with 2 mL of water. The solution was extracted with
EtOAc (20 mLꢂ3), washed with brine, dried over MgSO4, and con-
centrated. The residue was subjected to column chromatography
with EtOAc as eluent to give 11 mg (93%) of the desired product 3b.
25
[
a]
ꢀ3.88 (c 0.35, MeOH). 1H NMR (400 MHz, CDCl3)
d 6.39 (d,
D
J¼10.8 Hz,1H), 6.07 (d, J¼11.2 Hz,1H), 5.42 (d, J¼1.6 Hz,1H), 5.20 (d,
J¼2.0 Hz, 1H), 4.44 (d, J¼4.8 Hz, 1H), 4.23 (m, 1H), 3.66–3.76 (m,
2H), 3.53 (dd, J¼11.6, 6.0 Hz, 1H), 2.82 (dd, J¼12.4, 4.0 Hz, 1H), 2.61
(dd, J¼13.6, 4.0 Hz, 1H), 1.21 (s, 6H), 0.93 (d, J¼6.4 Hz, 3H), 0.55 (s,
3H). 13C NMR (100 MHz, CDCl3)
d 143.5, 142.2, 132.1, 124.9, 117.9,
117.3, 81.9, 71.1, 70.2, 65.2, 56.5, 56.4, 49.1, 45.9, 44.3, 43.6, 40.4,
36.3, 36.1, 30.7, 29.3, 29.2, 29.0, 27.6, 23.6, 22.3, 20.8, 18.8, 12.0. IR
(neat, cmꢀ1) 3389, 2928, 2872, 1655, 1455, 1378, 1261, 1214, 1096,
CO2Me
O
CO2Me
O
O
CO2Me
O
O
O
O
1044, 914, 797, 761. UV (MeOH) lmax 270 (
3
6629). HRMS ([MþNa]þ)
OTBS
OTBS
calcd 495.3445, found 495.3422.
OTBS
8a
(+)-9
8b
Acknowledgements
CO2Me
We thank the NIH for financial support (CA 93547) and
T. Kensler and P. Dolan (Johns Hopkins University) for in vitro
antiproliferative testing, and Lindsey Hess (Johns Hopkins Univer-
sity) for measuring the UV spectrum.
CO2Me
(-)-12
TBSO
TBSO
O
O
H
H
OTBS
OTBS
(-)-12
A
References and notes
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16. Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Tideswell, J.; Wright, P. W.
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