Synthesis of A-Ring Precursors of 1α,25-Dihydroxyvitamin D3 Analogues Functionalized at C-2

Article abstract of DOI:10.1002/ejoc.201701258

A flexible approach to an A-ring building block for new 1α,25-dihydroxyvitamin D analogues functionalized at C-2 as potential clinical candidates is described. The synthesis of alcohol 5 starts from (R)-carvone, and uses a Criegee rearrangement to selecti

Full text of DOI:10.1002/ejoc.201701258

DOI: 10.1002/ejoc.201701258
Full Paper
Precursor Synthesis
Synthesis of A-Ring Precursors of 1α,25-Dihydroxyvitamin D3
Analogues Functionalized at C-2
Rita Sigüeiro*[
a]
Abstract: A flexible approach to an A-ring building block for alcohol 5 starts from (R)-carvone, and uses a Criegee rearrange-
new 1α,25-dihydroxyvitamin D analogues functionalized at C-2 ment to selectively degrade the isopropenyl side-chain as one
as potential clinical candidates is described. The synthesis of of the key steps.
Introduction
Most known vitamin D analogues modified at C-2 have been
synthesized by convergent strategies such as the Wittig–Horner
1α,25-Dihydroxyvitamin D3 [1α,25(OH) D , 1,25D, calcitriol, 1;
2 3
[11a]
approach or Pd-catalysed processes,
and the corresponding
Scheme 1], the biologically active form of vitamin D , regulates
3
A-ring building blocks have been prepared using the Diels–
Alder reaction, Heck-type cyclization, or fluoride-mediated elim-
mineral metabolism and mediates important biological func-
tions, such as cell differentiation, cell proliferation, and immuno-
[
11f,11g,12]
ination of allyl sulfones.
We have recently developed
[
1,2]
modulation.
The discovery of the VDR in more than 30 tis-
an efficient convergent approach to vitamin D metabolites and
analogues featuring a highly stereoselective intramolecular
cyclization of an enol triflate (A-ring or lower fragment) fol-
lowed by an in-situ Suzuki–Miyaura coupling of the resulting
palladium intermediate with an alkenyl boronic ester (CD-side-
sues including skin, brain, heart, pancreas, kidney, intestine, co-
lon, prostate, ovary, and breast led to the study of the possible
use of 1,25D in the treatment of metabolic bone diseases,
psoriasis, cancers and immune disorders.
crystal structure of 1,25D in complex with VDR (LBD) opens
up the possibility of rational design of 1,25D analogues and
[
6,7]
The solution of the
[
8]
[
13]
chain upper fragment). This paper describes a further poten-
tial application of this strategy: a synthetic approach to A-ring
alcohol 5 as a versatile building block for the synthesis of new
analogues of 1,25D functionalized at C-2 (Scheme 1).
[
9]
mimics as potential therapeutic agents. The availability of
[
10]
space around the A-ring in the binding pocket that could be
used for the introduction of different substituents has led to
the design and synthesis of various biologically active 1,25D
[
11]
analogues functionalized at C-2.
α,25-dihydroxy-2ꢀ-(3-hydroxy-propoxy)vitamin D3 (ED-71,
eldecalcitol) has recently been commercialized by the Chugai
Among these compounds,
Results and Discussion
1
(
R)-Carvone (6) was the starting point for the synthesis of target
[
14,11a,12]
[
11b]
alcohol 5 (Scheme 2).
Treatment of (R)-carvone with
Pharmaceutical Co. for the treatment of osteoporosis.
lithium diisopropylamide (LDA) in the presence of 1,3-dimethyl-
,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) followed by the
3
addition of allyl bromide provided, after flash chromatography,
the desired alkylated product 7a (55 %) together with its
[
15]
epimer and recovered starting material.
The structure of 7a
was proposed on the basis of a comparison of its spectroscopic
1
13
data ( H and C NMR, COSY, and HMQC) with those of (R)-
carvone. The stereoselective formation of epoxide 8 was best
accomplished in 74 % yield by the reaction of 7a with tert-
butylhydroperoxide (TBHP) in the presence of DBU (1,5-diazabi-
[
16]
cyclo[5.4.0]undecane).
Epoxide 8 was then reduced with L-
Selectride in THF to give alcohol 9 in 75 % yield. The stereo-
chemistry of the hydroxy group was assigned by NOE analysis.
An alternative route to alcohol 9 was also explored. The
stereoselective reduction of (R)-carvone was best accomplished
Scheme 1. Structure of target building block 5, and retrosynthetic analysis of
potential 1,25D analogues 2 functionalized at C-2 via intermediates 3 and 4.
TBS = tert-butyldimethylsilyl.
[
17]
[
a] Departamento de Química Orgánica, Laboratorio de Investigación Ignacio
Ribas, Universidad de Santiago de Compostela,
under Luche reaction conditions (NaBH , CeCl ·7H O, MeOH)
4 3 2
to give a mixture of allylic alcohols 10a and 10b (ca. 1.8:1;
Avda. Ciencias s/n, 15782 Santiago de Compostela, Spain
E-mail: rita.sigueiro@usc.es
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701258.
[
18]
9
2 %).
This was then subjected to Sharpless hydroxy-group-
directed epoxidation with tert-butyl hydroperoxide and vanadyl
acetylacetonate in toluene to give, after flash chromatography,
Eur. J. Org. Chem. 2017, 6797–6803
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and 13 (24 %). Lactols 12 were oxidized with pyridinium
dichromate in CH Cl to give lactone 14 in 97 % yield. X-ray
2
2
analysis of compound 14 confirmed the relative configuration
[
19]
of the five stereogenic centres of the molecule.
At this stage, the degradation of the isopropenyl side-chain
[
20]
by Criegee rearrangement was achieved. Ozonolysis of 14 in
MeOH/CH Cl followed by removal of the excess O and acyl-
2
2
3
ation of the resulting α-methoxy hydroperoxide with p-nitro-
benzoyl chloride in pyridine/CH Cl provided acetate 15 in
2
2
7
4 % yield. The structural identity of 15 was established by
comparison with the compound obtained by Baeyer–Villiger
oxidation (mCPBA, CH Cl , KH PO /Na HPO ) of 13a. Problems
2
2
2
4
2
4
associated with the selective hydrolysis of the acetate group
with NaOMe/MeOH led us to study the Criegee rearrangement
of 14 to give the desired alcohol 16a directly. After several ex-
Scheme 2. Synthesis of alcohol 9 from (R)-carvone. DBU = 1,5-diazabi-
cyclo[5.4.0]undecane; DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyr-
imidinone; TBHP = tert-butylhydroperoxide; acac = acetoacetate.
periments, the Hoffmann La Roche reaction conditions (O ,
3
=
[21]
MeOH/CH Cl ; Ac O, Et N, DMAP; NaOAc, MeOH)
provided
2
2
2
3
alcohol 16a in 61 % yield.
Protection (TBSCl, imidazole, DMF) and reduction of the re-
the desired epoxide 9 (55 %) together with epoxide 11 (9 %) sulting lactone 16b with diisobutylaluminum hydride in tolu-
and starting ketone 7a (26 %); this could be recycled through ene gave a mixture of lactols 17 (74 % yield over two steps),
the first route to give additional amounts of 9 (65 % combined which, upon Wittig reaction with Ph P=CH (generated from
3
2
overall yield).
Ph PCH I and KOtBu in toluene), resulted in the formation of
3 3
With alcohol 9 in hand, the synthesis of the target A-ring alkene 18a (96 %). Protection of 18a (TBSCl, imidazole, DMF)
building block 5 (Scheme 3) was undertaken. Oxidative cleav- and hydroboration–oxidation (BH , THF; H O , NaOH) of the re-
3
2 2
age of the double bond in alcohol 9 using catalytic OsO and sulting diprotected alkene 18b gave the desired alcohol 5 (75 %
4
KIO (1 equiv.) in THF/H O gave a mixture of lactols 12 (74 %) over 2 steps; 13.6 % overall yield over 10 steps).
4
2
Scheme 3. Synthesis of building block 5, and X-ray crystal structure of lactone 14. DIBAL-H = diisobutylaluminum hydride; PDC = pyridinium dichromate;
mCPBA = m-chloroperbenzoic acid; TBS = tert-butyldimethylsilyl; tol = toluene; DMAP = 4-dimethylaminopyridine.
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Conclusions
Yields refer to chromatographically purified compounds, unless
otherwise stated. Compound names and signals in the NMR spectra
A flexible route to 1α,25-dihydroxyvitamin D A-ring building have been numbered using IUPAC numbering according to the
block 5 has been developed [11 steps, 7.5 % overall yield from Chemdraw program.
(
R)-carvone]. This compound represents a precursor for the syn-
(
5R,6S)-6-Allyl-2-methyl-5-(prop-1-en-2-yl)-cyclohex-2-en-1-one
thesis of new vitamin D analogues functionalized at C-2 for the (7a): A solution of lithium diisopropylamide was prepared by the
screening of clinical candidates. Key features of the synthetic slow addition of nBuLi (2.44
approach are the formation of lactone 14 from epoxy alcohol 8.8 mmol, 1.2 equiv.) to neat iPr
M
solution in hexanes; 3.6 mL,
NH (1.1 mL, 8 mmol, 1.1 equiv.) at
2
–
78 °C. The cooling bath was removed, and the white slurry was
9
, and the Criegee rearrangement to degrade the (R)-carvone
stirred at room temperature for 15 min. The suspension was cooled
to –78 °C, and THF (12 mL) was added. After 15 min, 1,3-dimethyl-
isopropenyl side-chain.
3
4
1
,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU; 4 mL, 31.5 mmol,
.7 equiv.) was added, and the reaction mixture was stirred for
5 min. Then, a solution of (R)-carvone (6; 1 g, 6.7 mmol, 1 equiv.)
Experimental Section
in THF (5 mL) was added by cannula. The resulting mixture was
stirred for 1 h. Freshly, distilled allyl bromide (distilled from CaH2;
General Remarks: Reagents were purchased from Sigma–Aldrich
or Acros Organics and used without further purification, unless oth-
erwise stated. All reactions involving oxygen- or moisture-sensitive
compounds were carried out under a dry argon atmosphere using
oven-dried or flame-dried glassware and standard syringe/septum
techniques. Liquid reagents or solutions of reagents were added
by syringe or cannula. All dry solvents were distilled under argon
0.72 mL, 7.9 mmol, 1.2 equiv.) was added dropwise. The reaction
mixture was stirred for 14 h at –78 °C, and then for 3 h at –25 °C.
The reaction was quenched with sat. aq. NH Cl (20 mL). The mixture
4
was extracted with Et O (3 × 25 mL). The combined organic layers
2
were washed with brine (30 mL), dried, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography (SiO2,
immediately before use: tetrahydrofuran (THF), Et O, benzene, and
2
3
× 21 cm, hexanes) to give 7a (0.7 g, 55 %) as a colourless oil, and
toluene were distilled from Na/benzophenone; CH Cl and Ac O
2
2
2
also recovered starting material 6 (0.216 g, conversion 71 %). Data
were distilled from P O ; pyridine, iPr NH, and Et N were distilled
2
5
2
3
2
5
for 7a: R = 0.40 (5 % EtOAc/hexanes). [α] = +62.4 (c = 3.5, CHCl3).
f
D
from CaH ; MeOH was distilled from Mg/I ; DMF (ACS reagent), DBU,
2
2
1
H NMR (400 MHz, CDCl ): δ = 6.62 (m, 1 H, 3-H), 5.75 (ddt, J = 17.1,
3
and DMPU were dried with activated molecular sieves (4 Å). Solu-
tions of n-butyllithium in hexanes were titrated with N-benzyl-
benzamide before use. Reaction temperatures refer to external bath
temperatures. Acetone/dry-ice baths were used for reactions at low
temperature. Alternatively, acetone baths were cooled with a
CRYOCOOL immersion cooler equipped with a temperature regula-
tor. Silicone baths with a contact thermometer were used for high-
temperature reactions. Ozonolysis reactions were carried out using
a Trailigaz ozonizer model LABO-5LOX. Reactions were monitored
by thin-layer chromatography (TLC) using aluminium-backed Merck
silica gel 60 plates (0.2 mm thickness). TLC plates were visualized
first with ultraviolet light (254 nm), and then by immersion in solu-
tions of ceric ammonium molybdate or p-anisaldehyde followed by
heating with a heat gun. Organic extracts were dried with
anhydrous Na SO , filtered, and concentrated using a rotary evapo-
1
0.1, 7.0 Hz, 1 H, 2′-H), 4.98 (dm, J = 17.1 Hz, 1 H, 3′-H ), 4.94 (dm,
Z
J = 10.3 Hz, 1 H, 3′-H ), 4.81 (dq, J = 3.0, 1.5 Hz, 1 H, 1′′-H ), 4.75 (d,
J = 1.5 Hz, 1 H, 1′′-H ), 2.65 (ddd, J = 11.4, 9.6, 5.2 Hz, 1 H, 5-H),
E
E
Z
2.49 (dtd, J = 13.2, 7.0, 6.4 Hz, 1 H, 1′-H), 2.43–2.32 (m, 2 H, 6-H and
4-H), 2.27 (dtd, J = 18.0, 5.2, 1.5 Hz, 1 H, 4-H), 2.18 (ddd, J = 13.2,
7.1, 6.1 Hz, 1 H, 1′-H), 1.73 (br. s, 3 H, Me-C-2), 1.67 (s, 3 H, Me-3′)
13
ppm. C NMR (100.6 MHz, CDCl ): δ = 200.4 (C=O, C-1), 145.1 (=C,
C-2′′), 143.1 (=CH, C-3′), 135.9 (=CH, C-2′), 135.0 (=C, C-2), 116.5 (=
CH , C-3′), 113.4 (=CH , C-1′′), 48.7 (CH, C-6), 46.6 (CH, C-5), 31.6
3
2
2
(CH , C-1′), 30.5 (CH , C-4), 18.8 (CH , Me-C-2), 15.9 (CH , C-3′′) ppm.
2 2 3 3
–
1
+
IR (film): ν˜ = 1713 (C=O), 1671 (C=C), 1644 (C=C) cm . MS (CI ):
+
+
m/z (%) = 191.1 (100) [M + H] , 163.1 (19) [M – (CH=CH )] , 149.1
2
+
+
+
(
[
48) [M – iPr] , 109.1 (61) [M – 2iPr] . HRMS (CI ): calcd. for C H O
M + H] 191.1436; found 191.1430.
13 19
+
2
4
rator at aspirator pressure (20–30 Torr). Flash column chromatogra- (1R,3S,4R,6R)-3-Allyl-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo-
phy was carried out with Merck silica gel 60 (230–400 mesh). tert-
[4.1.0]heptan-2-one (8): Dry 1,5-diazabicycle[5.4.0]undecane (DBU;
2.4 mL, 15.8 mmol, 3 equiv.) and tert-butyl hydroperoxide (TBHP;
Butyl methyl ether (TBME) and Et O were used as received for ex-
2
tractions. EtOAc, hexanes, and CH Cl used for extractions or chro-
5 M solution in decane; 31.5 mL, 15.8 mmol, 3 equiv.) were succes-
2
2
matography were previously distilled. NMR spectra were measured sively added dropwise to a solution of enone 7a (1 g, 5.3 mmol,
as solutions in CDCl3 or CD OD with Bruker DPX-250 (250 MHz),
Varian Inova 400 (400 MHz), and Bruker DRX-500 (500 MHz) spec-
trometers. Chemical shifts are reported on the δ scale (ppm) down-
1 equiv.) in dry THF (10 mL). The reaction mixture was stirred at
room temperature for 12 h. Additional amounts of TBHP (1 mL,
5.3 mmol, 1 equiv.) and DBU (0.8 mL, 5.3 mmol, 1 equiv.) were then
added. After a further 12 h, additional TBHP (1 mL, 5.3 mmol,
1 equiv.) and DBU (0.8 mL, 5.3 mmol, 1 equiv.) were again added.
This process was repeated five times. The reaction was then
3
field from tetramethylsilane (δ = 0.0 ppm), and the residual solvent
1
signal was used as an internal standard: δ = 7.26 ppm ( H, CHCl )
3
13
and δ = 77.0 ppm ( C, t, CDCl ); δ = 3.31 ppm (q, 1 H, CD OH) and
δ = 79.0 ppm ( C, hept, CD OD). Coupling constants (J) are re-
3
3
13
quenched with sat. aq. NH Cl (20 mL). The mixture was extracted
3
4
ported in Hz. Distortionless enhancement by polarization transfer
with Et O (3 × 20 mL). The combined organic layers were washed
2
(DEPT-135) was used to assign carbon types. Low- (MS) and High-
with sat. aq. Na S O (40 mL), dried, filtered, and concentrated in
2
2 3
resolution mass spectra (HRMS) were measured with a Micromass
Autospec instrument (CI) or with a Bruker Microtof instrument
vacuo. The residue was purified by flash chromatography (SiO2,
3 × 20 cm, 1 % EtOAc/hexanes) to give epoxide 8 (0.797 g, 74 %) as
2
5
(ESI-TOF). IR spectra were recorded on a silicon disc with a Varian
a yellowish oil. R = 0.35 (6 % EtOAc/hexanes). [α] = +159.6 (c =
f
D
1
FTIR 670 spectrometer. Elemental analysis was carried out with a
Fisons element analyser, model EA 1108. X-ray diffraction was car-
ried out with a Bruker APPEX-II single-crystal diffractometer. Melting
points were measured in open capillary tubes. Optical rotations
were measured with a Jasco DIP-370 polarimeter in a 1 dm cell.
3.5, CHCl ). H NMR (400 MHz, CDCl ): δ = 5.54 (m, 1 H, 2′-H), 4.88
3 3
(dm, J = 15.6 Hz, 1 H, 3′-H ), 4.87 (d, J = 10.3 Hz, 1 H, 3′-H ), 4.75
Z
E
(m, 1 H, 1′′-H ), 4.70 (J = 1.8 Hz, 1 H, 1′′-H ), 3.30 (d, J = 3.3 Hz, 1
E
Z
H, 6-H), 2.63 (td, J = 11.7, 4.4 Hz, 1 H, 4-H), 2.50 (m, 1 H, 1′-H), 2.12
(dt, J = 14.8, 3.7 Hz, 1 H, 5-H), 2.06 (m, 1 H, 1′-H), 1.99 (ddd, J =
11.4, 5.4, 4 Hz, 1 H, 3-H), 1.87 (dd, J = 14.8, 11.1 Hz, 1 H, 5-H), 1.55
3
–1
–1
–3
[
α] and c are given in deg cm g dm and g cm , respectively.
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(
(
d, J = 1.5 Hz, 3 H, Me-3′′), 1.30 (s, 3 H, Me-C-1) ppm. 13C NMR 2), 21.8 (CH , C-3′), 19.0 (CH , Me-C-6b) ppm; (12S, minor com-
3
3
100.6 MHz, CDCl ): δ = 206.8 (C=O, C-2), 144.4 (=C, C-2′′), 134.6 (=
pound) δ = 146.0 (=C, C-2′), 112.6 (=CH , C-1′), 97.9 (CH, C-5), 80.4
3
2
CH, C-2′), 116.8 (=CH , C-3′), 113.4 (=CH , C-1′′), 60.5 (CH, C-6), 58.8 (CH, C-6a), 62.0 (CH, C-1a), 57.2 (C, C-6b), 40.7 (CH, C-3), 37.1 (CH,
2
2
(
5
C, C-1), 48.7 (CH, C-3), 38.9 (CH, C-4), 32.4 (CH , C-1′), 28.8 (CH , C- C-3a), 33.0 (CH , C-4), 28.9 (CH , C-2), 21.8 (CH , C-3′), 19.2 (CH , Me-
2 2 2 2 3 3
–
1
+
), 18.8 (CH , C-3′′), 15.9 (CH , Me-C-1) ppm. IR (film): ν˜ = 1704 (C= C-6b) ppm. IR (film): ν˜ = 3378 (O–H), 1642 (C=C) cm . MS (CI ): m/z
3
3
–1 + + +
O), 1642 (C=C), 1613 (C=C) cm . MS (CI ): m/z (%) = 207.1 (2) [M + (%) = 211.2 (3) [M + H] , 193.1 (75) [M – OH] , 175.0 (88) [M – OH
H] , 165.1 (4) [M – C H ] , 125.1 (6) [M – 2C H – H O] , 97.1 (14) – H O] , 151.0 (25) [M – C H – H O] , 106.7 (100). HRMS (CI ): calcd.
+
+
+
+
+
+
3
5
3
5
2
2
3
5
2
+
+
+
[M – 2C H – OMe] , 19.1 (100). HRMS (CI ): calcd. for C H O [M for C H O [M + H] 211.1334; found 211.1331.
3 5 13 19 2 12 19 3
+
+
H] 207.1385; found 207.1379.
Data for 13:[23] M.p. 85.6–91.4 °C (EtOAc).
1aR,3R,3aS,6aS,6bR)-6b-Methyl-3-(prop-1-en-2-yl)hexa-
hydrooxireno[2,3-g]benzofuran-5(1aH)-one (14): Pyridinium di-
chromate (PDC; 5.9 g, 15.7 mmol, 1 equiv.) was added to a solution
of lactols 12 (1.1 g, 5.24 mmol, 1 equiv.) in dry CH Cl (30 mL). The
(
1S,2S,3S,4R,6R)-3-Allyl-1-methyl-4-(prop-1-en-2-yl)-7-oxabi-
(
[22]
cyclo[4.1.0]heptan-2-ol (9):
1
of ketone 8 (1.45 g, 7.0 mmol, 1 equiv.) in THF (20 mL) at –78 °C.
After 30 min, the reaction was quenched by the slow addition of
MeOH (5 mL) and H O (5 mL). Solutions of NaOH (10 % aq.; 5 mL)
and H O (30 % aq. v/v; 7 mL) were successively and slowly added.
The mixture was allowed to reach room temperature over 12 h. Sat.
aq. NH Cl (15 mL) was added. The mixture was extracted with Et O
L-Selectride® (1 M solution in THF;
0.5 mL, 10.5 mmol, 1.5 equiv.) was added dropwise to a solution
2
2
mixture was stirred in the dark at room temperature for 12 h. The
2
resulting black mixture was diluted with Et O (50 mL), and filtered
2
2
2
through a pad of Celite/silica gel. The solids were washed with Et O
2
(
3 × 20 mL). The solution was concentrated in vacuo, and the result-
4
2
ing oil was purified by flash chromatography (SiO , 2 × 8 cm, 20 %
2
(
3 × 30 mL). The combined organic phases were dried, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (SiO , 3 × 12 cm, 4 % EtOAc/hexanes) to give 9 (1.09 g,
EtOAc/hexanes) to give lactone 14 (1.06 g, 97 %) as a white solid.
25
M.p. 155–156 °C (EtOAc). R = 0.50 (50 % EtOAc/hexanes). [α]
=
f
D
+75.6 (c = 3.5, CHCl3). 1H NMR (400 MHz, CDCl ): δ = 4.78 (d,
2
3
2
5
7
–
2
5 %) as a colourless oil. R = 0.20 (8 % EtOAc/hexanes). [α]
49.8 (c = 3.6, CHCl ). H NMR (400 MHz, CDCl ): δ = 5.77 (m, 1 H,
=
f
D
J = 1.5 Hz, 1 H, 1′-H ), 4.74 (d, J = 6.7 Hz, 1 H, 6-Ha), 4.68 (br. s, 1
E
1
3
3
H, 1′-H ), 3.16 (d, J = 2.5 Hz, 1 H, 1-Ha), 2.54 (dd, J = 17.9, 8.5 Hz, 1
H, 4-H), 2.33–2.18 (m, 3 H, 3-H, 3-Ha and 4-H), 2.05 (dt, J = 14.7,
Z
′-H), 5.02 (d, J = 17.2 Hz, 1 H, 3′-H ), 4.96 (d, J = 10.1 Hz, 1 H, 3′-
Z
H ), 4.72 (br. s, 1 H, 1′′-H ), 4.70 (s, 1 H, 1′′-H ), 3.83 (br. s, 1 H, 2-H),
3
E
E
Z
2.6 Hz, 1 H, 2-H), 1.71 (dd, J = 14.7, 11.2 Hz, 1 H, 2-H), 1.56 (d, J =
.21 (t, J = 2.0 Hz, 1 H, 6-H), 2.10 (s, 1 H, OH), 2.06–1.97 (m, 3 H, 5-
13
0
.7 Hz, 3 H, Me-3′), 1.42 (s, 3 H, Me-C-6b) ppm. C NMR (100.6 MHz,
H, 4-H and 1′-H), 1.85 (m, 1 H, 1′-H), 1.75 (tm, J = 13.5 Hz, 1 H, 5-
H), 1.56 (dq, J = 1.3, 0.8 Hz, 3 H, Me-3′′), 1.38 (s, 3 H, Me-C-1), 1.19
CDCl ): δ = 175.8 (C=O, C-5), 144.3 (=C, C-2′), 113.5 (=CH , C-1′),
3
2
8
0.3 (CH, C-6a), 59.6 (CH, C-1a), 55.1 (C, C-6b), 38.7 (CH, C-3a), 35.3
(
m, 1 H, 3-H) ppm. 13C NMR (100.6 MHz, CDCl ): δ = 145.4 (=C, C-
3
(CH, C-3), 32.8 (CH , C-4), 28.6 (CH, C-2), 21.6 (CH , Me-C-6), 18.8
(CH , C-3′) ppm. IR (film): ν = 1769 (C=O lactone), 1640 (C=C) cm .
3
MS (CI ): m/z (%) = 209.1 (96) [M + H] , 193.1 (23) [M – Me] , 192.1
(47) [M – H O] , 191.1 (97) [M – OH] , 167.0 (64) [M – C H ] , 150.0
2
3
2
′′), 137.0 (=CH, C-2′), 116.1 (=CH , C-3′), 113.2 (=CH , C-1′′), 67.9
–1
2
2
˜
(CH, C-2), 62.5 (CH, C-6), 60.6 (C, C-1), 42.0 (CH, C-3), 36.6 (CH, C-4),
+
+
+
3
1.8 (CH , C-1′), 30.8 (CH , C-5), 22.0 (CH , Me-C-1), 18.1 (CH ,
+
+
+
2
2
3
3
2
3
5
–
1
+
C-3′′) ppm. IR (film): ν˜ = 3314 (O–H), 1661 (C=C) cm . MS (CI ): m/z
+
+
(60) [M – C H O ] , 106.7 (100). HRMS (CI ): calcd. for C H O [M
2 2 2 12 17 3
+
+
(%) = 209.2 (24) [M + H] , 191.2 (53) [M – OH] , 175.1 (16) [M – H O
+
2
+ H] 209.1178; found 209.1173.
(1aR,3R,3aS,6aS,6bR)-6b-Methyl-5-oxooctahydrooxireno-
2,3-g]benzofuran-3-yl Acetate (15): Ozone in oxygen (0.7 bar,
+
+
+
–
Me] , 151.1 (19) [M – C H – OH] , 111.1 (17) [M – 2C H – H O] .
3 5 3 5 2
+
+
HRMS (CI ): calcd. for C H O [M + H] 209.1542; found 209.1545.
1
3 21 2
[
–
1
(
1aR,3R,3aS,6aS,6bR)-6b-Methyl-3-(prop-1-en-2-yl)octa-
0.1 NL h , 50 W) was bubbled through a solution of lactone 14
hydrooxireno[2,3-g]benzofuran-5-ol (12): OsO4 (4 % solution in
water; 10 drops) was added to a suspension of 9 (1.0 g, 4.8 mmol,
1
(1 g, 4.81 mmol, 1 equiv.) in dry MeOH (10 mL) and dry CH Cl
2
2
(50 mL) at –78 °C until the solution turned blue (20 min). The excess
O was removed by bubbling with argon for 30 min at –78 °C. The
3
equiv.) in THF/H O (1:1; 40 mL). The mixture was stirred for 5 min,
2
and then KIO (1.1 g, 4.8 mmol, 1 equiv.) was added. After 5 h, the
reaction mixture was allowed to reach room temperature under a
slow flow of argon (40 min). Then, dry benzene (20 mL) was added
and the mixture was concentrated in vacuo.
4
mixture was filtered through a pad of Celite, and the solids were
washed with EtOAc. The combined organic phase was washed with
sat. aq. Na S O (30 mL), dried, filtered and concentrated in vacuo.
The residue was purified by flash chromatography (SiO , 2 × 14 cm,
2
2
2 3
The residue was dissolved in dry CH Cl2 (50 mL) and pyridine
2
2
(5.5 mL), and the solution was cooled to –78 °C under argon. Then,
0 % EtOAc/hexanes) to give lactols 12 (0.742 g, 74 %; equilibrium
freshly distilled p-nitrobenzoyl chloride (2.4 g, 12.9 mmol, 2.7 equiv.,
Kugelrohr) was added in one portion. The reaction mixture was
allowed to reach room temperature slowly. After 12 h, the mixture
was cooled to –78 °C and filtered through a cold filter plate, wash-
ing with CH Cl (15 mL) precooled to –78 °C. The resulting solution
[
23]
mixture 12R and 12S, 3:1) as a white solid, and ketone 13
(0.245 g, 24 %; equilibrium mixture 13R and 13S, 2:1) as a yellowish
solid.
Data for 12: M.p. 83–89 °C (EtOAc). R = 0.20 (30 % EtOAc/hexanes).
f
2
2
1
H NMR (500 MHz, CDCl ; 12R, major compound): δ = 5.57 (t, J =
was concentrated to dryness, and the residue was dissolved in
3
2
.5 Hz, 1 H, 5-H), 4.72 (br. s, 1 H, 1′-H), 4.70 (br. s, 1 H, 1′-H), 4.42 (d,
J = 7.0 Hz, 1 H, 6-Ha), 3.73 (s, 1 H, OH), 3.12 (d, J = 3.0 Hz, 1 H, 1-
Ha), 2.18–1.88 (m, 4 H), 1.79–1.63 (m, 2 H), 1.60 (s, 3 H, Me-3′), 1.42 concentrated in vacuo. The residue was purified by flash column
s, 3 H, Me-C-6b) ppm; (12S, minor compound) δ = 5.36 (t, J = chromatography (SiO , 3 × 10 cm, 20 % EtOAc/hexanes) to give
CHCl /MeOH (3:1; 20 mL). The solution was washed with HCl (10 %
3
aq.; 2 × 15 mL), and NaOH (3
M aq.; 2 × 15 mL), dried, filtered, and
(
2
5
7
1
.8 Hz, 1 H, 5-H), 4.77 (s, 1 H, 1′-H), 4.76 (s, 1 H, 1′-H), 4.32 (d, J = acetate 15 (0.810 g, 74 %) as a white solid. M.p. 124–126 °C (EtOAc).
2
5
1
.9 Hz, 1 H, 6-Ha), 3.64 (d, J = 6.8 Hz, 1 H, OH), 3.25 (d, J = 3.3 Hz,
R = 0.62 (4 % MeOH/CH Cl ). [α] = +14.5 (c = 2.5, CHCl ). H NMR
f 2 2 3
D
H, 1-Ha), 2.54 (m, 1 H), 2.29 (m, 1 H), 2.18–1.88 (m, 3 H), 1.79–1.63
(400 MHz, CDCl ): δ = 4.98 (m, 1 H, 3-H), 4.81 (d, J = 8.0 Hz, 1 H, 6-
3
(
(
(
m, 1 H), 1.61 (s, 3 H, Me-3′), 1.44 (s, 3 H, Me-C-6b) ppm. 13C NMR
Ha), 3.21 (t, J = 2.1 Hz, 1 H, 1-Ha), 2.64 (m, 1 H, 3-Ha), 2.53 (ddd, J =
17.6, 9.4, 1.3 Hz, 1 H, 4-H), 2.46–2.31 (m, 2 H, 4-H and 3-H), 2.01 (d,
J = 2.0 Hz, 3 H, Me-2′), 1.91 (ddt, J = 15.2, 7.3, 2.0 Hz, 1 H, 2-H), 1.46
125.7 MHz, CDCl ; 12R, major compound): δ = 145.8 (C, C-2′), 112.2
=CH , C-1′), 97.0 (CH, C-5), 77.5 (CH, C-6a), 59.8 (CH, C-1a), 56.5 (C,
3
2
C-6b), 41.0 (CH, C-3), 38.4 (CH , C-4), 37.3 (CH, C-3a), 29.4 (CH , C-
(d, J = 2.2 Hz, 3 H, Me-C-6b) ppm. 13C NMR (100.6 MHz, CDCl ): δ =
2
2
3
Eur. J. Org. Chem. 2017, 6797–6803
www.eurjoc.org
6800
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
5
75.1 (C=O, C-5), 169.9 (C=O, C-1′), 79.9 (CH, C-6a), 69.0 (CH, C-3),
(250 MHz, CDCl ): δ = 4.77 (d, J = 7.3 Hz, 1 H, 6-Ha), 3.83 (dd, J =
11.7, 7.5 Hz, 1 H, 3-H), 3.17 (t, J = 2.3 Hz, 1 H, 1-Ha), 2.57–2.30 (m,
3
9.5 (CH, C-1a), 56.7 (C, C-6b), 37.7 (CH, C-3a), 31.4 (CH , C-4), 27.3
2
(
CH , C-2), 20.9 (CH , C-2′), 20.3 (CH , Me-C-6b) ppm. IR (film): ν =
775 (C=O lactone), 1732 (C=O acetate) cm . MS (CI ): m/z (%) =
3 H, CH -4 and 3-H), 2.23 (ddd, J = 14.9, 4.2, 2.3 Hz, 1 H, 2-H), 1.79
2
3
3
˜
2
–
1
+
1
2
1
–
5
(ddd, J = 14.9, 7.5, 2.3 Hz, 1 H, 2-H), 1.43 (s, 3 H, Me-C-6b), 0.82 (s,
+
+
+
13
27.1 (25) [M + H] , 211.1 (5) [M – Me] , 193.1 (73) [M – H O – Me] ,
9 H, Me CSi), 0.023 (s, 3 H, MeSi), 0.015 (s, 3 H, MeSi) ppm. C NMR
2
3
+
+
93.1 (79) [M – 2H O – Me] , 167.0 (45) [M – OAc] , 148.9 (100) [M (63 MHz, CDCl ): δ = 175.9 (C=O, C-5), 80.7 (CH, C-6a), 66.6 (CH, C-
2
3
+
OAc – H O] . C H O (226.2263): calcd. C 58.40, H 6.24; found C
3), 60.0 (CH, C-1a), 56.4 (C, C-6b), 41.1 (CH, C-3a), 37.1 (CH , C-4),
2
11 14
5
2
8.04, H 6.25.
31.2 (CH , C-2), 25.5 (3 CH , Me CSi), 20.8 (CH , Me-C-6b), 17.7 (C,
2
3
3
3
CSi), –4.5 (CH , MeSi), –5.0 (CH , MeSi) ppm. IR (film): ν = 1768 (C=
3
3
+
˜
(
1aR,3R,3aS,6aS,6bR)-3-Hydroxy-6b-methylhexahydro-
–
1
+
O lactone) cm . MS (ESI-TOF ): m/z (%) = 321.1 (100) [M + Na] ,
oxireno[2,3-g]benzofuran-5(1aH)-one (16a): Ozone in oxygen
+
+
+
–1
299.2 (9) [M + H] , 283.2 (3) [M – Me] , 253.2 (2) [M – OH – CO] ,
(0.7 bar, 0.1 NL h , 50 W) was bubbled through a solution of lact-
+
+
2
39.1 (10) [M – CO – Me] , 167.1 (12) [M – OTBS] , 149.1 (4) [M –
OTBS – H O] 121.0 (5), 105.0 (4). HRMS (ESI-TOF ): calcd. for
C H O Si [M + H] 299.1673; found 209.1674.
2
one 14 (0.5 g, 2.4 mmol, 1 equiv.) in dry MeOH (1 mL) and dry
CH Cl (10 mL) at –78 °C until the solution turned blue (10 min).
The excess O3 was removed by bubbling with argon for 30 min.
The reaction mixture was allowed to reach room temperature
+
+
2
2
2
+
15 27 4
(1aR,3R,3aR,6aS,6bR)-3-[(tert-Butyldimethylsilyl)oxy]-6b-meth-
yloctahydrooxireno[2,3-g]benzofuran-5-ol (17): DIBAL-H (1 so-
lution in CH Cl ; 1.5 mL, 1.51 mmol, 1.2 equiv.) was added to a
(40 min) under a slow flow of argon.
M
2
2
The mixture was then cooled to –35 °C. After 10 min, Et N (4.6 mL,
3
were slowly added. Once the DMAP had dissolved, Ac O (freshly
distilled from P O under argon; 3.2 mL, 33.6 mmol, 14 equiv.) was
added dropwise by syringe. The reaction mixture was allowed to
reach –8 °C, and it was stirred at this temperature for 2 h. The
reaction was quenched by the slow addition of MeOH (5 mL). The
mixture was stirred at room temperature for 5 min, then it was
diluted with EtOAc (30 mL), and successively washed with a solution
3
solution of 16b (0.375 g, 1.26 mmol, 1 equiv.) in dry toluene (10 mL)
at –78 °C. The mixture was stirred for 30 min. The reaction was then
3.6 mmol, 14 equiv.) and DMAP (60 mg, 0.48 mmol, 0.2 equiv.)
2
quenched with sat. aq. NH Cl (10 mL). The mixture was allowed to
4
2
5
reach room temperature, and then it was extracted with EtOAc (2 ×
15 mL). The combined organic extracts were dried, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (SiO , 3 × 8 cm, 15 % EtOAc/hexanes) to give 17 (0.336 g,
2
8
9 %, equilibrium mixture 5.6:1) as a colourless oil. R = 0.7 (50 %
f
1
EtOAc/hexanes). H NMR (250 MHz, CDCl ; major compound): δ =
3
of citric acid (10 % aq.; 2 × 30 mL) and sat. aq. NaHCO (2 × 25 mL).
The organic solution was dried, filtered, and concentrated in vacuo.
3
5.61 (d, J = 4.1 Hz, 1 H, 5-H), 4.48 (d, J = 8.1 Hz, 1 H, 6-Ha), 3.71 (br.
s, 1 H, OH), 3.66 (td, J = 9.3, 4.6 Hz, 1 H, 3-H), 3.12 (d, J = 2.5 Hz, 1
H, 1-Ha), 2.53–1.61 (m, 5 H), 1.41 (br. s, 3 H, Me-C-6b), 0.83 (s, 9 H,
Me CSi), 0.03 (s, 6 H, Me Si) ppm; (minor compound) δ = 5.41 (m,
The residue was dissolved in dry MeOH (10 mL), and NaOAc (40 mg,
0
.48 mmol, 0.2 equiv.) was added. The mixture was heated at 37 °C
3
2
for 12 h, and then it was concentrated to half its volume. The sus- 1 H, 5-H), 4.38 (d, J = 7.6 Hz, 1 H, 6-Ha), 4.01 (td, J = 7.7, 4.9 Hz, 1
pension was diluted with EtOAc (30 mL), and the mixture was
washed with sat. aq. NH Cl (25 mL). The aqueous phase was ex-
tracted with EtOAc (2 × 20 mL). The combined organic extracts
were dried, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (SiO , 2.5 × 8 cm, 50 % EtOAc/
hexanes) to give alcohol 16a (0.265 g, 61 %) as a white solid. M.p.
1
CHCl ). H NMR (500 MHz, CD OD): δ = 4.96 (d, J = 7.7 Hz, 1 H, 6-
Ha), 4.79 (br. s, 1 H, OH), 3.67 (td, J = 9.3, 4.6 Hz, 1 H, 3-H), 3.28 (dd,
H, 3-H), 3.71 (br. s, 1 H, OH), 3.24 (m, 1 H, 1-Ha), 2.53–1.61 (m, 5 H),
1.44 (br. s, 3 H, Me-C-6b), 0.83 (s, 9 H, Me CSi), 0.01 (s, 6 H, Me Si)
4
3
2
ppm. 13C NMR (63 MHz, CDCl ; major compound): δ = 97.5 (CH, C-
3
5), 78.9 (CH, C-6a), 69.5 (CH, C-3), 60.5 (CH, C-1a), 57.1 (C, C-6b), 43.4
(CH, C-3a), 38.1 (CH , C-4), 32.8 (CH , C-2), 25.6 (3 CH , Me CSi), 21.1
2
2
2
3
3
(CH , Me-C-6b), 17.8 (C, CSi), –4.3 (CH , MeSi), –4.8 (CH , MeSi) ppm;
3
3
3
2
5
35–136 °C. R = 0.25 (4 % MeOH/CH Cl ). [α] = +1.31 (c = 1.8, (minor compound) δ = 98.5 (CH, C-5), 80.9 (CH, C-6a), 68.3 (CH, C-
f
2
2
D
1
3
3
3), 62.3 (CH, C-1a), 57.8 (C, C-6b), 43.8 (CH, C-3a), 37.4 (CH , C-4),
2
31.9 (CH , C-2), 25.6 (3 CH , Me C-Si), 21.0 (CH , Me-C-6b), 17.8 (C,
2
3
3
3
J = 2.8, 1.7 Hz, 1 H, 1-Ha), 2.72 (dd, J = 18.0, 9.4 Hz, 1 H, 4-H), 2.48 CSi), –4.4 (CH , MeSi), –4.8 (CH , MeSi) ppm. IR (film): ν = 3371 (O–
3
3
˜
–
1
+
+
(
dd, J = 18.0, 3.9 Hz, 1 H, 4-H), 2.40 (tdd, J = 9.4, 7.7, 3.9 Hz, 1 H, 3-
Ha), 2.33 (ddd, J = 14.7, 4.5, 2.9 Hz, 1 H, 2-H), 1.82 (ddd, J = 14.7,
.2, 1.7 Hz, 1 H, 2-H), 1.49 (s, 3 H, Me-C-6b) ppm. 13C NMR
125.7 MHz, CD OD): δ = 178.7 (C=O, C-5), 83.1 (CH, C-6a), 66.4 (CH,
H) cm . MS (ESI-TOF ): m/z (%) = 301.2 (90) [M + H] , 299.2 (18)
+
+
+
[(MH – OH)] , 283.2 (7) [M – OH] , 283.2 (5) [M – Me] , 269.1 (20)
+
+
+
9
(
[M – CH OH] , 255.1 (23) [M – OH – CO] , 185.0 (23) [M – TBS] ,
137.0 (100) [M – OTBS – Me – OH] 115.1 (36), 109.0 (39). HRMS
2
+
3
+
+
C-3), 62.0 (CH, C-1a), 57.5 (C, C-6b), 42.0 (CH, C-3a), 32.9 (CH , C-4), (ESI-TOF ): calcd. for C H O Si [M + H] 301.1835; found 301.1841.
2
15 29 4
3
1
1
–
1
5
2.4 (CH , C-2), 21.4 (CH , Me-C-6b) ppm. IR (film): ν˜ = 3311 (O–H),
2
3
(
1S,2S,3R,4R,6R)-3-Allyl-4-[(tert-butyldimethylsilyl)oxy]-1-
–
1
+
+
763 (C=O lactone) cm . MS (CI ): m/z (%) = 185.1 (96) [M + H] ,
methyl-7-oxabicyclo[4.1.0]heptan-2-ol (18a): A mixture of
Ph PCH I (1.06 g, 2.96 mmol, 7 equiv.) and dry toluene (15 mL) was
+
+
86.1 (16) [(M + 1) + H] , 167.0 (95) [M – OH] , 153.0 (25) [M – OH
3
3
+
+
+
Me] , 138.9 (92) [M – CO – H O] , 124.8 (98) [M – CO – OH] ,
2
2
vigorously stirred for 5 min, and then KOtBu (0.330 g) was added.
The mixture was heated at 90 °C for 30 min. The oil bath was then
removed, and the yellow suspension was allowed to reach room
temperature. After 15 min, a solution of lactols 17 (0.127 mg,
0.422 mmol, 1 equiv.) in toluene (10 mL) was added by cannula.
The mixture was stirred at room temperature for 35 min. The reac-
06.7 (100). C H O (185.1910): calcd. C 58.69, H 6.57; found C
9
12 4
8.24, H 6.47.
(
1aR,3R,3aR,6aS,6bR)-3-[(tert-Butyldimethylsilyl)oxy]-6b-meth-
ylhexahydrooxireno[2,3-g]benzofuran-5(1aH)-one (16b): Imidaz-
ole (0.67 g, 9.78 mmol, 3 equiv.) and TBSCl (0.74 g, 4.89 mmol,
1
.5 equiv.) were successively added to a solution of alcohol 16a
tion was quenched with sat. aq. NH Cl (50 mL). The resulting mix-
4
(
0.6 g, 3.26 mmol, 1 equiv.) in dry DMF (10 mL). The reaction mixture
ture was extracted with hexanes (2 × 30 mL). The combined organic
extracts were dried, filtered, and concentrated in vacuo. The residue
was stirred for 12 h, and then ice was added. The resulting mixture
was extracted with TBME (2 × 20 mL). The combined organic ex-
was purified by flash chromatography (SiO , 1.5 × 10 cm, 10 %
2
tracts were dried, filtered, and concentrated. The residue was puri- EtOAc/hexanes) to give 18a (0.121 g, 96 %) as a yellowish foam.
1
fied by flash chromatography (SiO , 2 × 10 cm, 10 % EtOAc/hex-
R = 0.7 (40 % EtOAc/hexanes). H NMR (250 MHz, CDCl ): δ = 5.79
2
f
3
anes) to give 16b (0.847 g, 87 %) as a white solid. M.p. 34.1–34.8 °C.
(dq, J = 17.2, 8.7 Hz, 1 H, 2′-H), 5.09 (d, J = 17.2 Hz, 1 H, 3′-H ), 5.02
Z
2
5
1
Rf = 0.7 (40 % EtOAc/hexanes). [α]D = –0.82 (c = 1, CHCl ). H NMR (d, J = 10.0 Hz, 1 H, 3′-H ), 3.92 (dd, J = 8.8, 4.2 Hz, 1 H, 2-H), 3.56
3
E
Eur. J. Org. Chem. 2017, 6797–6803
www.eurjoc.org
6801
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
+
(
(
dt, J = 9.3, 4.2 Hz, 1 H, 4-H), 3.21 (d, J = 0.9 Hz, 1 H, 6-H), 2.45–2.30
m, 2 H), 2.20–1.88 (m, 2 H), 1.66 (dd, J = 14.8, 8.8 Hz, 1 H), 1.40 (s,
[M – OH – OTBS – tBu] . HRMS (ESI-TOF ): calcd. for C H NaO Si
22
45
3
2
+
[M + Na] 453.2832; found 453.2829.
3
H, Me-C-1), 0.85 (s, 9 H, Me CSi), 0.02 (s, 3 H, MeSi), 0.01 (s, 3 H,
3
13
MeSi) ppm. C NMR (63 MHz, CDCl ): δ = 137.2 (=C, C-2′), 116.3
3
Acknowledgments
(
(
=CH , C-3′), 69.4 (CH, C-2), 65.1 (CH, C-4), 63.2 (CH, C-6), 60.7
2
C, C-1), 47.4 (CH, C-3), 34.9 (CH , C-1′), 30.3 (CH , C-5), 25.7 (3 CH ,
2
2
3
A postdoctoral fellowship (Axudas posdoutorais, plan I2C, mod
B) from the Xunta de Galicia, USC-RIADIT (X-ray, NMR spectro-
scopy, and MS sections), and the input given to this work by
Prof. Antonio Mouriño are gratefully acknowledged.
Me C-Si), 21.5 (CH , Me C-1), 17.9 (C, CSi), –4.5 (CH , MeSi), –4.9
3
3
3
3
–
1
(
(
CH , MeSi) ppm. IR (film): ν˜ = 3320 (O–H), 1641 (C=C) cm . MS
3
+
+
ESI-TOF ): m/z (%) = 321.2 (100) [M + Na] , 306.3 (10) [(M – OH) +
+
+
Na] , 301.1 (61), 292.3 (14) [(M – CH – OH) + Na] , 239.0 (22) [M –
C H – H O] , 224.2 (4) [M – OH – tBu] , 118.1 (4). HRMS (ESI-TOF ):
calcd. for C H NaO Si [M + Na] 321.1856; found 321.1856.
2
+
+
+
3
5
2
+
16
30
3
Keywords: Synthesis design · Natural products · Chiral
{
[(1R,2S,3S,4R,6R)-3-Allyl-1-methyl-7-oxabicyclo[4.1.0]heptane- pool · Asymmetric synthesis · Rearrangement
,4-diyl]bis(oxy)}bis(tert-butyldimethylsilane) (18b): Imidazole
0.55 g, 0.8 mmol, 2 equiv.) and TBSCl (0.91 g, 0.6 mmol, 1.5 equiv.)
were successively added to a solution of alcohol 18a (0.120 g,
.4 mmol, 1 equiv.) in dry DMF (2 mL). The reaction mixture was
2
(
[1] D. Feldman, J. W. Pike, J. S. Adam (Eds.), Vitamin D, 3rd ed., Elsevier Aca-
demic Press, San Diego, CA, 2011.
0
[2] L. A. Plum, H. F. DeLuca, Nat. Rev. Drug Discovery 2010, 9, 941–955.
[3] M. J. Campbell, L. Adorini, Expert Opin. Ther. Targets 2006, 10, 735–748.
[4] J. W. Pike, M. B. Meyer, K. A. Bishop, Rev. Endocr. Metab. Disord. 2012, 13,
stirred at room temperature for 12 h, and then ice was added. The
resulting mixture extracted with hexanes (2 × 10 mL). The com-
bined organic extracts were dried, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (SiO2,
4
5–55.
[
[
5] R. M. Evans, Mol. Endocrinol. 2005, 19, 1429–1438.
6] G. Jones, S. A. Strugnell, H. F. DeLuca, Physiol. Rev. 1998, 78, 1193–1231.
1
.5 × 10 cm; 5 % EtOAc/hexanes) to give 18b (0.140 g, 84 %) as a
2
5
colourless oil. R = 0.8 (20 % EtOAc/hexanes). [α] = –23.6 (c = 1,
CHCl ). H NMR (250 MHz, CDCl ): δ = 5.65 (dddd, J = 17.0, 9.6, 8.5,
f
D
[7] D. Feldman, A. V. Krishnan, S. Swami, E. Giovannucci, B. J. Feldman, Nat.
Rev. Cancer 2014, 14, 342–357.
1
3
3
5
1
.7 Hz, 1 H, 2′-H), 4.99 (d, J = 17.0 Hz, 1 H, 3′-H ), 4.94 (d, J = 9.6 Hz,
[8] N. Rochel, J. M. Wurtz, A. Mitschler, B. Klaholz, D. Moras, Mol. Cell 2000,
5, 173–179.
Z
H, 3′-H ), 4.35 (d, J = 5.8 Hz, 1 H, 2-H), 3.89 (m, 1 H, 4-H), 2.98 (d,
E
[
9] a) S. Eduardo-Canosa, R. Fraga, R. Sigüeiro, M. Marco, N. Rochel, D. Moras,
A. Mouriño, J. Steroid Biochem. Mol. Biol. 2010, 121, 7–12; b) C. Carlberg,
F. Molnár, A. Mouriño, Expert Opin. Ther. Pat. 2012, 22, 417–435; c) S.
Yamada, M. Makishima, Trends Pharmacol. Sci. 2014, 35, 324–337; d) M. A.
Maestro, F. Molnár, A. Mouriño, C. Carlberg, Expert Opin. Ther. Pat. 2016,
J = 4.5 Hz, 1 H, 6-H), 2.44 (ddd, J = 15.1, 5.8, 4.2 Hz, 1 H, 3-H), 2.23–
.04 (m, 2 H), 1.82–1.62 (m, 2 H), 1.32 (s, 3 H, Me-C-1), 0.94 (s, 9 H,
Me CSi), 0.87 (s, 9 H, Me CSi), 0.12 (s, 3 H, MeSi), 0.08 (s, 3 H, MeSi),
2
3
3
1
3
0
.02 (s, 6 H, 2 MeSi) ppm. C NMR (63 MHz, CDCl ): δ = 138.6 (=C,
3
C-2′), 115.3 (=CH , C-3′), 70.0 (CH, C-2), 68.2 (CH, C-4), 59.8 (CH, C-
6
2
2
6, 1291–1306.
), 59.0 (C, C-1), 46.4 (CH, C-3), 30.3 (CH , C-5), 29.6 (CH , C-1′), 25.9
2 2
[10] S. Hourai, T. Fujishima, A. Kittaka, Y. Suhara, H. Takayama, N. Rochel, D.
Moras, J. Med. Chem. 2006, 49, 5199–5205.
(3 CH , Me CSi), 25.7 (3 CH , Me CSi), 20.9 (CH , Me-C-1), 18.3 (C,
3 3 3 3 3
CSi), 17.9 (C, CSi), –4.4 (CH , MeSi), –4.7 (CH , MeSi) –4.9 (CH , MeSi),
[11] a) A. Glebocka, G. Chiellini, Arch. Biochem. Biophys. 2012, 523, 48–57; b)
N. Kubodera, Heterocycles 2016, 92, 1013–1029; c) A. Kittaka, Y. Suhara,
H. Takayanagi, T. Fujishima, M. Kurihara, H. Takayama, Org. Lett. 2000, 2,
2619–2622; d) Y. Suhara, K. Nihei, M. Kurihara, A. Kittaka, K. Yamaguchi,
T. Fujishima, K. Konno, N. Miyata, H. Takayama, J. Org. Chem. 2001, 66,
3
3
3
–
1
+
–
5.0 (CH , MeSi) ppm. IR (film): ν˜ = 1639 (C=C) cm . MS (ESI-TOF ):
3
+ +
m/z (%) = 413.3 (38) [M + H] , 395.3 (50) [M – OH] , 281.2 (100) [M
–
2
+
+
+
OTBS] , 263.2 (18) [M – OTBS – H O] , 239.1 (4) [M – C H – H] ,
2 3 5
+
+
24.2 (3) [M – OTBS – tBu] . HRMS (ESI-TOF ): calcd. for C H O Si
2 45 3 2
2
8
760–8771; e) S. Honzawa, K. Hirasaka, Y. Yamamoto, S. Peleg, T. Fuji-
+
[
M + H] 413.2902; found 413.2900.
shima, M. Kurihara, N. Saito, S. Kishimoto, T. Sugiura, K. Waku, H. Takay-
ama, A. Kittaka, Tetrahedron 2005, 61, 11253–11263; f) V. Sikervar, J. C.
Fleet, P. L. Fuchs, J. Org. Chem. 2012, 77, 5132–5138; g) V. Sikervar, J. C.
Fleet, P. L. Fuchs, Chem. Commun. 2012, 48, 9077–9079; h) D. R. Laplace,
M. V. Overschelde, P. J. De Clercq, A. Verstuyf, J. M. Winne, Eur. J. Org.
Chem. 2013, 728–735; i) M. Matsuo, A. Hasegawa, M. Takano, H. Saito, S.
Kakuda, T. Chida, K. Takagi, E. Ochiai, K. Horie, Y. Harada, M. Takimoto-
Kamimura, K. Takenouchi, D. Sawada, A. Kittaka, ACS Med. Chem. Lett.
3
-{(1R,2S,3S,4R,6R)-2,4-Bis[(tert-Butyldimethylsilyl)oxy]-1-
methyl-7-oxabicyclo[4.1.0]heptan-3-yl}propan-1-ol (5): BH (1
M
3
solution in THF; 0.26 mL, 0.255 mmol, 1.5 equiv.) was added to a
solution of 18b (70 mg, 0.170 mmol, 1 equiv.) in dry THF (1.5 mL)
at 0 °C. After 1 h, NaOH (3
M aq.; 1 mL) and H O (30 % aq.; 2 mL)
2 2
were successively added. The mixture was vigorously stirred for 3 h,
and then it was extracted with EtOAc (2 × 10 mL). The combined
organic extracts were dried, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (1.5 × 8 cm; 10 %
2013, 4, 671–674; j) H. Saito, K. Takagi, K. Horie, S. Kakuda, M. Takimoto-
Kamimura, E. Ochiai, T. Chida, Y. Harada, K. Takenouchi, A. Kittaka, J.
Steroid Biochem. Mol. Biol. 2013, 136, 3–8; k) I. K. Sibilska, R. R. Sicinski,
J. T. Ochalek, L. A. Plum, H. F. DeLuca, J. Med. Chem. 2014, 57, 8319–
EtOAc/hexanes) to give 5 (67 mg, 91 %) as a colourless oil. R = 0.2
f
8
331; l) H. Saitoh, H. Watanabe, S. Kakuda, M. Takimoto-Kamimura, K.
1
(
20 % EtOAc/hexanes). H NMR (250 MHz, CDCl ): δ = 4.34 (d, J =
3
Takagi, A. Takeuchi, K. Takenouchi, J. Steroid Biochem. Mol. Biol. 2015,
148, 27–30; m) I. K. Sibilska, M. Szybinski, R. R. Sicinski, L. A. Plum, H. F.
DeLuca, J. Med. Chem. 2015, 58, 9653–9662; n) A. Flores, I. Massarelli,
J. B. Thoden, L. A. Plum, H. F. DeLuca, J. Med. Chem. 2015, 58, 9731–9741;
o) D. Sawada, E. Ochiai, A. Takeuchi, S. Kakuda, M. Kamimura-Takimoto,
F. Kawagoe, A. Kittaka, J. Steroid Biochem. Mol. Biol. 2016, https://doi.org/
5
2
.8 Hz, 1 H, 2-H), 3.91 (m, 1 H, 4-H), 3.56 (t, J = 5.0 Hz, 2 H, CH -1),
.97 (d, J = 4.6 Hz, 1 H, 6′-H), 2.17 (dd, J = 15.1, 5.8 Hz, 1 H), 2.03
2
(br. s, 1 H, OH), 1.83–1.27 (m, 6 H), 1.31 (s, 3 H, Me-C-1′), 0.93 (s, 9
H, Me CSi), 0.88 (s, 9 H, Me CSi), 0.12 (s, 3 H, MeSi), 0.08 (s, 3 H,
3
3
1
3
MeSi), 0.02 (s, 6 H, 2 MeSi) ppm. C NMR (63 MHz, CDCl ): δ = 70.3
3
1
0.1016/j.jsbmb.2016.09.007.
(
CH, C-2′), 68.4 (CH, C-4′), 63.3 (CH , C-1), 59.7 (C, C-1′), 59.0 (CH, C-
2
[
12] For reviews, see: Y. Z. Yin, J. P. Li, C. Liu, L. Q. Tang, Z. P. Liu, Curr. Org.
Synth. 2011, 8, 374–392.
6
′), 47.0 (CH, C-3′), 32.4 (CH , C-2), 30.6 (CH , C-5′), 25.9 (3 CH ,
2 2 3
Me CSi), 25.7 (3 CH , Me CSi), 21.0 (CH , C-3), 20.9 (CH , Me-C-1),
3
3
3
2
3
[
13] P. Gogoi, R. Sigüeiro, S. Eduardo, A. Mouriño, Chem. Eur. J. 2010, 16,
1
8.2 (C, CSi), 17.9 (C, CSi), –4.4 (CH , MeSi), –4.7 (CH , MeSi), –4.9
3 3
1
432–1435.
–
1
(
CH , MeSi), –5.0 (CH , MeSi) ppm. IR (film): ν˜ = 3432 (O–H) cm .
3
3
[14] For previous uses of (R)- or (S)-carvone for the synthesis of A-ring build-
ing blocks of vitamin D, see: a) Y. Chen, T. Ju, Org. Lett. 2011, 13, 86–89;
+ + +
MS (ESI-TOF ): m/z (%) = 453.3 (15) [M + Na] , 431.3 (3) [M + H] ,
+
+
[11a,12]
4
15.3 (100) [M – OH] , 282.2 (10) [M – OH – OTBS] , 225.2 (9)
b) See also refs.
Eur. J. Org. Chem. 2017, 6797–6803
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
[
15] Alkylation attempts using other bases [LDA or NaHMDS (sodium hexa-
methyldisilazide)] in THF or Et O at different temperatures gave mixtures
of products, including the dialkylated compound, which were difficult
to separate by flash chromatography.
2 2
16] The classical method using H O and LiOH gave a mixture of products,
[20] a) R. Criegee, Angew. Chem. Int. Ed. Engl. 1975, 14, 745–752; Angew.
Chem. 1975, 87, 765–771; b) S. L. Schreiber, W. F. Liew, Tetrahedron Lett.
1983, 24, 2363–2366.
[21] A. R. Daniewski, L. M. Garafalo, S. D. Hutching, M. M. Kabat, W. Liu, M.
Okade, R. Radinov, J. Org. Chem. 2002, 67, 1580–1587.
[22] For experimental procedures to obtain alcohol 9 by an alternative route
(Luche–Sharpless), see the Supporting Information.
2
with a low yield of the desired epoxide 8 (22 %).
17] J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227.
18] The use of other reducing agents (DIBAL-H, THF;
[
[
L-Selectride, THF;
[23] For the characterization of this compound, see the Supporting Informa-
tion.
4 2 2 4 3
NaBH /ZnCl , Et O; NaBH /CeCl , MeOH, pyridine) gave the desired prod-
uct in a lower yield (<50 %) with similar stereoselectivity.
19] CCDC 1571570 (for 14) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[
Received: September 7, 2017
Eur. J. Org. Chem. 2017, 6797–6803
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6803
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim