Total synthesis of a CD-ring: Side-chain building block for preparing 17-epi-calcitriol derivatives from the Hajos-Parrish dione

Article abstract of DOI:10.1021/jo201083w

An efficient synthesis of the key building block for 17-epi-calctriol from the Hajos-Parrish dione involving a sequence of diastereoselective transformation of the azulene core and the side-chain construction is presented.

Full text of DOI:10.1021/jo201083w

NOTE
pubs.acs.org/joc
Total Synthesis of a CD-Ring: Side-Chain Building Block for
Preparing 17-epi-Calcitriol Derivatives from the HajosÀParrish Dione
Karol Michalak and Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
S Supporting Information
b
ABSTRACT: An efficient synthesis of the key building block for 17-epi-calctriol from the
HajosÀParrish dione involving a sequence of diastereoselective transformation of the azulene
core and the side-chain construction is presented.
Scheme 1. Calcitriol, Its 17-Epi Derivative, and the Planned
Synthetic Transformations
he total synthesis of calcitriol (1R,25-dihydroxy-vitamin D3,
1, Scheme 1) and its congeners attracts a great deal of
T
attention owing to the present and pending medical applications
of these compounds.1 In search for a modification of the
calcitriol structure that would improve selectivity of action, we
have recently synthesized 17-epi-calcitriol (2).2,3 The synthesis
commenced from 3β-hydroxyandrost-5-en-17-one and, in
part, followed the classical vitamin D route through 17-epi-
cholestane intermediates and a photolytic opening of the
ring B. Although some improvements were developed, the
synthesis included notoriously ineffectual steps (brominationÀ
dehydrobromination, photolysis) that diminished the overall
yield (4.80%, 23 steps).
The promising biological activity of 2, which proved to be
more active in inhibiting proliferation human breast cancer
MCF-7 than 1, and the progress in the total synthesis of trans-
hydrindan derivatives prompted us to revisit the synthesis. It was
thought that 2, and eventually other 17-epi-calicitriol analogues,
could be efficiently synthesized from the HajosÀParrish dione4
3. Diastereoselective transformations of 3 are of interest on their
own rights since this optically active 10-carbon compound,
readily obtained by an organocatalytic route, provides an im-
portant augment of the natural chiral pool.5
The dione 3 was selectively reduced and the hydroxy group in
the five-membered ring was protected as a tert-butyl ether to give
5 (Scheme 2), following the well-known procedure.6 The trans-
hydrindan intermediate 6 was then prepared from 5 by a sequence
of reactions previously reported from this laboratory7,8 amended
to gram-scale operations (eight steps, 52% overall yield).
The usual modus operandi for cyclopropanation of alkene 11
would involve its reaction with ethyl diazoacetate induced by a
rhodium12 or palladium catalyst2,13 [often Pd(OAc)2 or Rh2-
(AcO)4]. After some experimentation, we have found that an
inexpensive and easy to prepare copper catalyst,14 CuI P-
3
(OMe)3, gives the best results with regard to both the product
purity and the yield. Thus, slow addition of ethyl diazoacetate (ca.
5 equiv) to a mixture of 11 and CuI P(OMe)3 (10 mol %) in
3
The benzoate 7 was subjected to an action of CeCl3 7H2O
3
benzene, at reflux temperature, afforded the cyclopropane deri-
vative 12 (as a mixture isomers, Scheme 3). A brief heating of the
crude product with sodium methoxide in methanol affected
trans-esterification, epimerization at the R-position to the alkox-
ycarbonyl group, and a cleavage of the benzoate linkage to
and NaI in acetonitrile9 to provide alcohol 8 that was subse-
quently oxidized into ketone 9 (74% from 6).
All our attempts to transform ketone 9 via its hydrazone into
the respective vinyl iodide10 which could be reduced into alkene
11 failed, presumably, because of inherent instability of the iodide.
Eventually, the ketone 9 was transformed into enol triflate 10, and
this derivative was treated with tributylammonium formate in the
presence of Pd(PPh3)2(OAc)2 to afford 11 (86% in two steps).11
Received: May 30, 2011
Published: July 04, 2011
r
2011 American Chemical Society
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afforded 13 (80% yield from 11). The hydroxy group in 13 was
protected as a tert-butyldimethylsilyl derivative in the usual way
to give 14. The cyclopropane carboxylic ester moiety in 14 was
then reduced with lithium in liquid ammoniaÀTHF in the
presence of tert-butyl alcohol.15 The crude reduction product
was reoxidized with the Jones’ reagent to afford carboxylic acid 15
contaminated with a side product (less than 10% by 1H NMR).
Since the contamination could not be removed by chromatog-
raphy at this stage, the crude acid was treated with diazomethane,
and the ester 16 containing a side product (less than 10%) was
used for a sterol side chain construction. Thus, treatment of 16
with LDA in THFÀhexanes, at À78 °C, and then with methyl
iodide (3.5 equiv) and HMPA (3.5 equiv) afforded selectively the
methyl derivative (95% yield) to which the structure 17 was
assigned16 contaminated with a side product (less than 10%).
The crude ester 17 was reduced with lithium aluminum hydride
in THF and the product was purified by a careful chromatogra-
phy on a silica gel column to give alcohol 18 (91% yield).
The alcohol 18 was converted into its tosylate, and the latter
was allowed to react with a lithium acetylide, prepared from 19
and BuLi.17 The derivative 20 was subjected to exhaustive
catalytic hydrogenation to afford 21. The protective TBS group
in a sterically congested environment and the THP group were
then removed by treatment of 21 with 40% HF in acetonitrile.18
The diol 22 thus obtained, after column chromatography, was
shown to be 97.5% pure by HPLC. Oxidation of 22 with PDC19
afforded the hydroxy ketone 4 identical in all respects with the
product obtained previously from a steroid starting material.2
In conclusion, the trans-hydrindan derivative 4, being a key
building block for the synthesis of 17-epi-calcitriol 2, has been
prepared from the HajosÀParrish dione 3 in 24 steps, 14.97%
overall yield. The method for transforming of 3 into 6 has been
improved and amended to a gram-scale operations. The side
chain has been attached to the olefin 11 using a cyclopropanation
reaction induced by a Cu complex. The developed methods may
serve for economic synthesis of 17-epi-calcitriol and analogues.
Scheme 2. Transformation of the HajosÀParrish Dione (3)
into the trans-Hydrindan Intermediate 11a
’ EXPERIMENTAL SECTION
NMR spectra were recorded in CDCl3 solutions, 1H at 200 MHz and
13C at 50 MHz; chemical shifts are quoted on the δ scale, ppm, with the
1
solvent signal as the internal standard (CHCl3, H NMR 7.26 ppm;
CDCl3, 13C NMR 77.00 ppm). In the 13C NMR spectra multiplicities of
signals were assigned using the DEPT technique. High-resolution mass
spectra (HRMS) were taken using EI technique, electrospray ionization
(ESI), or liquid secondary ion mass spectroscopy (LSIMS). Column
chromatography was performed on Merck silica gel 60, 230À400 mesh.
TLC was performed on aluminum sheets, Merck 60F 254. Anhydrous
solvents were obtained by distillation from benzophenone ketyl (THF),
calcium hydride (CH2Cl2), or lithium aluminum hydride (ether). Com-
mercially available hexanes (a mixture of isomers) was used. Air-sensitive
a Key: (a) refs 7 and ref.;8 (b) BzCl, DMAP, Py, reflux, 1 h (52% from 3);
(c) CeCl3 7H2O, NaI, MeCN, reflux, 2 h (100%); (d) Jones’ reagent,
3
acetone (86%); (e) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2,
rt, 6 h, 91%; (f) Pd(PPh3)2(OAc)2, Bu3N, HCO2H, DMF, rt f
60 °C, 95%.
Scheme 3. Side-Chain Constructiona
a Key: (a) N2CH2CO2Et (added dropwise), CuI P(OMe)3 (10 mol %); (b) MeONa, MeOH, reflux, 1.5 h (80% from 11); (c) TBSCl, DMAP,
3
imidazole, DMF, 80 °C, 16 h (99%); (d) Li, t-BuOHÀTHFÀliquid NH3 and then Jones’ oxidation (98% yield, ca. 90% pure, see the text); (e) CH2N2,
Et2O (89% yield, ca. 90% pure); (f) LDA, À78 °C and then MeI and HMPA, À78 °C, 16 h, 95%; (g) LiAlH4, THF, chromatography (91%); (h) (1)
TsCl, Py, (2) 19, BuLi, 5 °C and then reflux, 4 days; (i) H2, 10% Pd-on-carbon, NaHCO3, reflux, 5 days; (j) 40% HF, MeCN, rt, 8 h, 72% from 18; (k)
PDC, CH2Cl2 (96%).
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reactions were performed in flame-dried glassware under argon.
Organic solutions were evaporated in a rotary evaporator. Reagents
were used as purchased. Microanalyses were performed at our ana-
lytical laboratory.
water and brine, dried (Na2SO4), and filtered through a pad of silica
gel (ca. 3 g). The silica gel was washed with hexanesÀEtOAc (7:3,
50 mL). The combined filtrate was evaporated to give 8 (1.230 g,
100%). 1H NMR: 1.0À2.1 (m, 11H) overlapping 1.01 (s, 3H), 3.65 (t,
1H, J = 8.0 Hz), 5.40 (br d, 1H, J = 2.2 Hz), 7.60À7.36 (m, 3H),
8.12À8.02 (m, 2H). 13C NMR: 12.4, 17.6, 21.9, 29.3, 30.5, 36.6, 42.0,
46.6, 71.7, 81.5, 128.3, 129.5, 130.6, 132.7, 166.4. MS EI (m/z): 274
(M+, 6), 230 (3), 169 (12), 152 (54), 134 (30), 108 (50), 105 (100).
HRMS: calcd for C17H22O3 274.15689, found 274.15572.
(3aR,4S,7aS)-4-Hydroxy-7a-methyloctahydro-1H-inden-
1-one Benzoate (9). Jones’ reagent was added dropwise to a stirred
solution of 8 (1.201 g, 4.38 mmol) in acetone (20 mL) at rt until the
reagent color persisted. The mixture was stirred for a few additional min,
and then the reagent excess was destroyed with i-PrOH (0.25 mL). The
solution was diluted with hexanes (60 mL), and then Na2SO4 was added
in portions until a well-separated greenish granulate solid was formed.
The solution was decanted, and the solvent was evaporated. The residue
was chromatographed on silica gel (25 g, hexanesÀEtOAc, 9:1) to give 9
(1.031 g, 86%). 1H NMR: 2.2À1.1 (m, 10H) overlapping 1.21 (s, 3H),
2.42À1.34 (m, 1H), 5.53 (br d, 1H, J = 1.6 Hz), 7.60À7.38 (m, 3H),
7.78À8.06 (m, 2H). 13C NMR: 16.2, 17.3, 21.2, 30.5, 31.6, 35.1, 47.0,
47.4, 71.9, 128.4, 129.4, 130.3, 132.9, 166.1, 219.5. MS EI (m/z): 272
(M+, 4), 244 (4), 167 (7), 150 (26), 122 (14), 108 (14), 105 (100).
HRMS: calcd for C17H20O3 272.14124, found 272.14216.
(3aR,7S,7aR)-3a-Methyl-3a,4,5,6,7,7a-hexahydro-1H-in-
den-7-ol Benzoate (11). Tf2O (0.81 mL, 4.9 mmol) was added
dropwise to a mixture of 9 (1.021 g, 3.75 mmol), 2,6-di-tert-butyl-4-
methylpyridine (1.154 g, 5.6 mmol), and CH2Cl2 (20 mL) and stirred at
rt. After 6 h, Et3N (1.55 mL, 11 mmol) and hexanes (40 mL) were
added. The mixture was stirred briefly and concentrated to a volume of
ca. 10 mL. The upper layer was separated and transformed to a silica gel
column (25 g). The column was eluted with hexanes (300 mL) to
recover 2,6-di-tert-butyl-4-methylpyridine (1.132 g) and then with
hexanesÀEtOAc, 97:3 (400 mL) to give triflate 10 (1.372 g, 91%). A
mixture of 10 (1.372 g, 3.40 mmol), Pd(PPh3)2(OAc)2 (52 mg, 0.068
mmol, 2 mol %), Bu3N (2.43 mL, 10.2 mmol), HCO2H (g99%,
0.32 mL, 8.5 mmol), and DMF (10 mL) was stirred at rt, the
temperature was warmed to 60 °C (bath) in ca. 10 min, and stirring
was continued for 20 min. After cooling, the mixture was diluted with
EtOAc (30 mL) and poured into water. The product was extracted with
hexanes (100 mL). The extract was washed with 1 N HCl, water, and
brine and dried (Na2SO4). The solvent was evaporated, and the reside
was chromatographed on silica gel (20 g, hexanesÀEtOAc, 98:2) to give
11 (829 mg, 95%). 1H NMR: 2.2À1.0 (m, 9H) overlapping 1.15 (s, 3H),
5.50 (br d, 1H, J = 2.4 Hz), 5.76À5.68 (m, 1H), 5.84À5.78 (m, 1H),
7.60À7.38 (m, 3H), 9.10À8.02 (m, 2H). 13C NMR: 18.5, 19.6, 30.9,
31.4, 36.00, 44.8, 71.3, 128.3, 128.6, 129.5, 130.8, 132.6, 143.3, 166.4. MS
LSIMS (m/z): 535 [(2M + Na)+, 12], 279 [(M + Na)+, 100]. HRMS:
calcd for C17H20O2Na 279.13555, found 279.13681.
Gram-Scale Preparation of (1S,3aR,4S,7aS)-1-tert-butoxy-
7a-methyloctahydro-1H-inden-4-ol benzoate (7) from the
HajosÀParrish Dione (3). The HajosÀParrish dione (3, 3.00 g,
18.2 mmol) was transformed6 into (1S,7aS)-1-tert-butoxy-7a-methyl-
1,2,3,6,7,7a-hexahydro-5H-inden-5-one (5), and this product, without
purification, was reduced following the Luche protocol.7,20 Thus obtained
(1S,5S,7aS)-1-tert-butoxy-7a-methyl-2,3,5,6,7,7a-hexahydro-1H-inden-5-
ol21 was epoxidized with m-CPBA7 to afford (1aS,2S,4aR,5S,7aR)-1-tert-
butoxy-4a-methyloctahydroindeno[3a,4-b]oxiren-2-ol. This crude pro-
duct was dissolved in Et2O (140 mL), and NaBH3CN (3.0 g, 47.8 mmol)
was added. The mixture was stirred at rt while BF3 Et2O (3.6 mL, 29.2
3
mmol) was added dropwise over 1 h. Stirring was continued for 1 h and
then the mixture was poured into brine and satd aq NaHCO3 (1:1,
100 mL). The organic layer was separated, washed consecutively with 2%
aq NaOH (100 mL) and brine (50 mL), and dried (Na2SO4). The
solvent was evaporated, and the residue was chromatographed on silica
gel (60 g, hexaneÀEtOAc, 3:1) to give (1S,3aR,4R,5S,7aS)-1-tert-butoxy-
7a-methyloctahydro-1H-indene-4,5-diol (2.764 g, 63% yield from 3). A
mixture of this diol (2.764 g, 11.4 mmol), thiocarbonyldiimidazole
(TCDI, 4.15 g, 23.3 mmol), and THF (20 mL) was heated under reflux
for 3 h. After cooling, the solvent was evaporated, and the residue
was chromatographed on silica gel (50 g, hexanesÀEtOAc, 9:1) to give
(3aS,5aS,6S,8aR,8bR)-6-tert-butoxy-5a,8a-dimethyloctahydro-3aH-
indeno[4,5-d]dioxole-2-thione (2.909 g, 90%, 57% from 3). A mixture of
the latter product (2.909 g, 10.2 mmol), MeI (12 mL, 193 mmol),
NaHCO3 (0.5 g), and some Cu turnings was stirred and heated in a
sealed ampule at 45 °C (an oil bath temperature) for 40 h. After cooling,
the solid material was filtered off, and the filtrate was evaporated to
dryness. The residue was chromatographed on silica gel (50 g, hexa-
nesÀEtOAc, 93:7) to give O-[(1S,3aR,4R,5R,7aS)-1-tert-butoxy-5-iodo-
7a-methyloctahydro-1H-inden-4-ol] S-methyl thiocarbonate (4.062 g).
This product was dissolved in THF (20 mL), and the solution was added
dropwise, over ca. 15 min, to a suspension of LiAH4 (1.40 g, 36.8 mmol)
in THF (100 mL) heated under reflux. Heating was continued for15 min,
and then the mixture was allowed to cool to rt. The reagent excess was
destroyed with concd aq Na2SO4. The solid was filtered off and washed
with EtOAc. The combined filtrate was evaporated to dryness to give
alcohol 67 containing a side product, ca. 5% by 1H NMR (2.152 g), that
was used for the next step without purification.
A mixture of crude 6 (1.026 g, ca. 4.53 mmol), pyridine (10 mL),
DMAP (5 mg), and benzoyl chloride (0.785 mL, 6.8 mmol) was heated
under reflux for 1 h. Water (0.5 mL) was then added, and the mixture was
cooled to rt and diluted with EtOAc (30 mL). The solution was
partitioned between water (100 mL) and hexanes (100 mL). The hexane
layer was collected and washed consecutively with water, 5% HCl, water,
and brine. After drying (Na2SO4), the solution was filtered through a pad
of silica gel (ca. 3 g). The silica gel was washed with hexanesÀEtOAc, 8:2
(15 mL), and the solvent was evaporated to give benzoate 7 (1.490 g,
52% from 3). 1H NMR: 2.1À1.0 (m, 11H) overlapping 1.09 (s, 3H), 1.15
(s, 9H), 3.40 (br t, 1H, J = 8.0 Hz), 5.40 (br d, 1H, J = 2.0 Hz), 7.60À7.36
(m, 3H), 8.12À8.02 (m, 2H). 13C NMR: 13.1, 17.8, 22.3, 28.7, 30.1, 30.8,
37.2, 41.6, 46.7, 72.00, 72.2, 80.5, 128.3, 129.5, 130.8, 132.6, 166.4. MS EI
(m/z): 330 (M+, 1), 274 (18), 152 (89), 134 (57), 108 (41), 105 (100).
HRMS: calcd for C21H30O3 330.21950, found: 330.22049.
Methyl (1S,1aS,1bR,5S,5aR,6aR)-5-Hydroxy-1b-methyldo-
decahydrocycloprop[a]indene-1-carboxylate (13). To a mix-
ture of 11 (428 mg, 1.67 mmol) and CuI P(OMe)3 (52 mg, 0.17 mmol,
3
10 mol %) in benzene (15 mL), heated under reflux, was added freshly
distilled ethyl diazoacetate (0.87 mL, 8.4 mmol) in benzene (15 mL)
over 5.5 h by means of a syringe pump via a cannula inserted through the
condenser in such a manner that the reagent solution was dropping
directly onto the surface of the mixture from the cold part of the
condenser. After an additional 0.5 h, the mixture was allowed to cool, and
then the solvent was evaporated. The residue was transferred with
hexanes to a silca gel column (30 g, in hexanes). The column was eluted
with hexanesÀEtOAc 99:1 (500 mL) to recover the starting material
contaminated with nonpolar side products (48 mg) and then with
hexanesÀEtOAc 94:6 (500 mL) to give ethyl ester 12 (616 mg). This
product consisted of exo- and endo-isomers in a ratio of ca. 7:1 and ethyl
(1S,3aR,4S,7aS)-1,4-Dihydroxy-7a-methyloctahydro-1H-
indenyl 4-benzoate (8). A mixture of 7 (1.485 g, 4.49 mmol),
CeCl3 7H2O (2.01 g, 5.4 mmol), NaI (0.81 g, 5.4 mmol), and MeCN
3
(20 mL) was heated under reflux for 2 h. After the mixture was cooled
to rt, a few crystals of Na2SO3 were added and the mixture was diluted
with hexanes (100 mL). The solution was washed consecutively with
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NOTE
diazoacetate decomposition products (ca. 15%) by 1H NMR analysis. An
analytical sample was prepared by stirring of a solution of a sample of this
product in EtOH with palladium on carbon (5%) in hydrogen atmo-
sphere (90 atm, rt, 20 h) and rechromatography. 12 (Main Isomer). 1H
NMR: 1.12 (dt, 1H, J = 2.8, 7.8 Hz), 2.1À1.2 (m, 11H) overlapping 1.25
(s, 3H) overlapping 1.26 (t, 3H, J = 7.2 Hz), 4.01 (q, 2H, J = 7.2 Hz), 5.44
(br.s, 1H), 7.62À7.36 (m, 3H), 8.10À7.97 (m, 2H). 13C NMR: 14.3,
18.5, 20.2, 22.3, 23.5, 26.4, 30.7, 35.2, 37.8, 40.3, 43.3, 60.4, 71.3, 128.3,
129.5, 130.5, 132.8, 166.3, 173.7. MS LSIMS (m/z): 707 [(2M + Na]+,
13), 365 [(M + Na]+, 100). HRMS: calcd for C21H26O4Na 365.17233,
found 365.17084. Minor Isomer, the Diagnostic Signal. 1H NMR: 4.18
(q, 1H, J = 6.6 Hz). The crude 12 (582 mg) was dissolved in a solution of
MeONa in MeOH, prepared from MeOH (5 mL) and sodium (140 mg).
The mixture was heated under reflux for 1.5 h, cooled, and transferred
with Et2O (30 mL) into 3% aq HCl (80 mL). The product was extracted
with a mixture of hexanes and EtOAc (1:1, 100 mL). The organic extract
was washed with water and brine and dried (Na2SO4). The solvent was
evaporated, and the residue was chromatographed on silica gel (15 g,
hexanesÀEtOAc, 85:15) to give 13 (304 mg, 80% from 11). 1H NMR:
0.87 (ddd, 1H, J = 12.2, 6.2, 2.2 Hz), 1.9À1.1 (m, 11H) overlapping 1.14
(s, 3H), 3.64 (s, 3H), 4.14 (br s, 1H). 13C NMR: 18.0, 20.1, 22.1, 23.7,
26.2, 34.0, 35.5, 38.4, 40.2, 43.9, 51.6, 68.7, 174.3. MS EI (m/z): 224 (M+,
4), 206 (32), 191 (52), 175 (17), 147 (100). HRMS: calcd for C13H20O3
224.14124, found 224.14196.
Methyl [(1S,3aR,4S,7aR)-4-(tert-Butyldimethylsilyloxy)-7a-
methyloctahydro-1H-inden-1-yl]acetate (16). Diazomethane in
Et2O was added dropwise to a stirred solution of 15 (432 mg, 1.32 mmol)
in Et2O (15 mL) until a yellow color persisted. The reagent excess and
the solvent were evaporated, and the residue was chromatographed on
silica gel (4 g, hexaneÀEtOAc, 97:3) to give 16 contaminated with a side
product, less than 10% (by 1H NMR) (399 mg, 89%). 1H NMR: À0.01
(s, 3H), 0.00 (s, 3H), 0.87 (s, 9H), 2.1À10.9 (m, 13H) overlapping 1.02
(s, 3H), 2.50À2.24 (m, 1H), 3.65 (s, 3H), 4.08 (br.d, 1H, J = 2.2 Hz). 13C
NMR: À5.1, À4.8, 17.5, 18.0, 23.1, 24.2, 25.8, 27.4, 34.5, 34.6, 37.8, 42.4,
45.2, 47.4, 51.4, 69.1, 174.2. MS EI (m/z): 340 (M+, 1), 325 (1), 309 (3),
297 (5), 283 (56), 209 (38), 207 (22), 177 (28), 149 (53), 135 (100),
133 (67), 107 (14). HRMS: calcd for C19H36O3Si 340.24337, found
340.24347. Minor Side Product. 1H NMR: 4.04À3.98 (m, 1H).
Methyl (2S)-2-[(1S,3aR,4S,7aR)-4-(tert-Butyldimethylsily-
loxy)-7a-methyloctahydro-1H-inden-1-yl]propanoate (17).
Ester 16 (386 mg, 1.14 mmol) in THF (5 mL) was added dropwise to a
stirred at À78 °C solution of LDA in THF prepared from (i-Pr)2NH
(0.19 mL, 1.37 mmol), BuLi (2.17 M in hexanes, 0.63 mL, 1.37 mmol),
and THF (5 mL). The mixture was stirred at À78 °C for 0.5 h, and then
MeI (0.085 mL, 1.37 mmol) and HMPA (0.24 mL, 1.38 mmol) were
consecutively added. Stirring was continued for 16 h (at À78 °C), and
the solution was diluted with hexanes (20 mL) and poured into water.
The mixture was extracted with hexanes (40 mL). The organic extract
was washed consecutively with water and brine and dried (Na2SO4).
The solvent was evaporated, and the residue was chromatographed on
silica gel (4 g, hexanesÀEtOAc, 97:3) to give 17 contaminated with a
side product, less than 10% (by 1H NMR) (380 mg, 95%). 1H NMR:
À0.02 (s, 3H), À0.01 (s, 3H), 0.86 (s, 9H), 2.0À0.9 (m, 12H)
overlapping 1.01 (s, 3H), 1.07 (d, 3H, J = 6.8 Hz), 2.19 (dq, 1H, J =
10.4, 6.8 Hz). 3.63 (s, 3H), 4.06 (br.d, 1H, J = 2.6 Hz). 13C NMR: À5.1,
À4.8, 17.1, 17.7, 18.1, 23.9, 24.7, 24.8, 25.8, 34.3, 34.6, 41.7, 42.9, 48.6,
51.2, 51.3, 69.2, 178.0. MS EI (m/z): 354 (M+, 1), 339 (1), 323 (2), 311
(4), 297 (64), 223 (76), 221 (27), 191 (21), 163 (100), 135 (79), 133
(34), 107 (24). HRMS: calcd for C20H38O3Si 354.25902, found
354.25811.
Methyl (1S,1aS,1bR,5S,5aR,6aR)-5-(tert-Butyldimethylsily-
loxy)-1b-methyldodecahydrocyclopropa[a]indene-1-car-
boxylate (14). A mixture of 13 (304 mg, 1.36 mmol), TBSCl (409 mg,
2.71 mmol), imidazole (369 mg, 5.43 mmol), DMAP (3 mg), and DMF
(3 mL) was stirred at 80 °C (bath) for 16 h. After cooling, the mixture
was diluted with Et2O (25 mL) and poured into brine. The product was
extracted with hexanes (50 mL). The extract was washed with water
(2 Â 25 mL) and brine and dried (Na2SO4). The solvent was evaporated,
and the residue was chromatographed on silica gel (10 g, hexa-
1
nesÀEtOAc, 99:1) to give 14 (456 mg, 99%). H NMR: À0.01 (s,
3H), 0.00 (s, 3H), 0.87 (s, 9H) partly overlapping 0.86 À 0.72 (m, 1H),
1.11 (s, 3H), 1.7À1.1 (m, 11H), 3.63 (s, 3H), 4.06 (d, 1H, 0.8 Hz). 13C
NMR: À5.1, À4.8, 18.1, 18.2, 20.1, 22.6, 23.9, 25.8, 26.6, 34.6, 35.8, 38.6,
40.4, 44.2, 51.5, 68.8, 174.5. MS EI (m/z): 338 (M+, 6), 323 (3), 281
(100), 206 (23), 175 (32), 147 (52), 133 (21), 105 (31). HRMS: calcd
for C19H34O3Si 338.22772, found 338.22865.
Minor Side Product. 1H NMR: 3.66 (s, 3H), 4.05À3.96 (m, 1H).
(1S,3aR,4S,7aR)-1-[(1S)-2-Hydroxy-1-methylethyl]-4-(tert-
butyldimethylsilyloxy)-7a-methyloctahydro-1H-indene (18).
LiAlH4 (76 mg, 2 mmol) was added to a stirred solution of crude 17 (380
mg, 1.07 mmol) in THF (15 mL). After 15 min, the reagent excess was
destroyed with satd aq Na2SO4, and the mixture was diluted with Et2O
(30 mL). Thesolidwasfiltered offandwashed with Et2O. Thefiltrate was
evaporated to dryness, and the residue was chromatographed on silica gel
(40 g, hexaneÀEtOAc, 96:4, (ca. 1200 mL) to give 18 (319 mg, 91%). 1H
NMR: À0.01 (s, 3H), 0.00 (s, 3H), 0.84 (d, 3H, J = 6.6 Hz), 0.87 (s, 9H),
1.00 (s, 3H), 2.0À1.1 (m, 13H), 3.25 (dd, 1H, J = 10.2, 7.2 Hz), 3.43 (dd,
1H, J = 10.2, 6.2 Hz), 4.06 (br.d, 1H, J = 2.2 Hz). 13C NMR: À5.1, À4.7,
13.8, 17.7, 18.0, 21.2, 24.9, 24.9, 25.8, 34.9, 34.7, 36.1, 43.1, 49.1, 49.2,
68.4, 69.1. MS EI (m/z): 326 (M+, 1), 311 (1), 283 (3), 269 (45), 193
(35), 177 (15), 175 (11), 135 (44), 121 (23), 109 (18), 107 (22), 95
(46), 93 (22), 83 (31), 81 (28), 75 (100). HRMS: calcd for C19H38O2Si
326.26411, found 326.26282.
[O-[2ξ-Tetrahydro-2H-pyranyl)oxy]-1-[(1R)-5-hydroxy-1,5-
dimethylhex-3-ynyl]]-(1S,3aR,4S,7aR)-4-(tert-butyldimethy-
lsilyloxy)-7a-methyloctahydro-1H-indene (20). TsCl (373 mg,
1.96 mmol) was added to a solution of 18 (319 mg, 0.98 mmol) in
pyridine (8 mL) stirred at rt. After 16 h, the mixture was cooled to 0 °C,
and water (0.5 mL) was added. The mixture was allowed to warm to rt
(in ca. 20 min) and then diluted with Et2O (20 mL) and poured into
water. The product was extracted with hexanes (80 mL). The extract was
washed with water and brine and dried (Na2SO4). The solvent was
evaporated to give the crude tosylate (471 mg) that was used further
without purification. This product was dissolved in dry dioxane (8 mL),
[(1S,3aR,4S,7aR)-4-(tert-Butyldimethylsilyloxy)-7a-methy-
loctahydro-1H-inden-1-yl]acetic Acid (15). A mixture of t-
BuOHÀTHF (3: 4, 7 mL) and a solution of 14 (456 mg, 1.35 mmol)
in tert-BuOHÀTHF (1: 1, 8 mL) were consecutively added to a solution
of Li (188 mg, 27 mg atom) in liquid NH3 (25 mL) at reflux. After 30
min, an excess of Li was destroyed with solid NH4Cl, and then ammonia
was allowed to evaporate. The residue was dissolved in Et2O (60 mL)
and poured into water. The product was extracted with hexanes (60 and
30 mL). The combined extract was washed with water and brine and
dried (Na2SO4). The solvent was evaporated, and the residue was
dissolved in acetone (15 mL). The solution was stirred at rt while Jones’
reagent (2.67 M, 2 mL) was added in two portions. After 0.5 h, the
reagent excess was destroyed with i-PrOH (1 mL), and some Na2SO4
was added. The solid was filtered off and washed with EtOAc. The
combined filtrate was evaporated to dryness, and the residue was
chromatographed on silica gel (15 g, hexanesÀEtOAc, 8:2) to give 15
contaminated with a side product, less than 10% (by 1H NMR)(432 mg,
98%). 1H NMR: 0.00 (s, 3H), 0.01 (s, 1H), 0.88 (s, 9H), 1.04 (s, 3H),
2.1À1.1 (m, 13H), 2.50À2.30 (m, 1H), 4.01 (dd, 1H, J = 4.4, 2.0 Hz).
13C NMR: À5.1, À4.8, 17.5, 18.1, 23.1, 24.2, 25.8, 27.5, 34.5, 34.7, 37.8,
42.4, 45.00, 47.4, 69.1, 180.3. MS EI (m/z): 326 (M+, 2), 293 (2), 269
(64), 251 (25), 193 (36), 149 (53), 135 (100), 107 (11). HRMS: calcd
for C18H34O3Si 326.22772, found 326.22752. Minor Side Product. 1H
NMR: 4.04À3.99 (m, 1H)
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The Journal of Organic Chemistry
NOTE
and the solution was combined with a solution of a lithium acetylenide
prepared as follows: butyllithium (2.17 M in hexanes, 4.1 mL, 8.9 mmol)
was added to a mixture of 2-[(1,1-dimethylprop-2-ynyl)oxy]tetrahydro-
2H-pyran (19) (1.65 g) and dioxane (8 mL) stirred at 5 °C, and the
mixture was allowed to warm to rt in ca. 20 min. The combined solution
was heated under reflux for 4 days, cooled, and diluted with hexanes
(100 mL). The solution was washed consecutively with water (100 mL)
and brine, dried (Na2SO4), and clarified by filtration through a pad of
silica gel (1 g). The silica gel was washed with hexanesÀEtOAc (90:10,
30 mL). The filtrates were combined, and the solvent was evaporated.
The residue was dried at 40 °C under vacuum (2 mmHg) for a few hours
to give 20 (1.00 g). An analytical sample was purified by a repeated
chromatography on silica gel (100 g per 1 g) eluting with hexa-
nesÀEtOAc (100:0.5). 1H NMR: À0.01 (s, 3H), 0.00 (s, 3H), 0.87 (s,
9H) overlapping0.89 (d, 3H, J = 7.4 Hz), 1.00 (s, 3H), 1.9À1.2(m, 19H)
overlapping1.46 (s, 3H), 1.49 (s, 3H), 2.04 (t, 2H, J = 6.6 Hz), 3.40À3.54
(m, 1H), 4.02À3.88 (m, 1H), 4.06 (br.d, 1H, J = 2.0 Hz), 5.05 (dd, 1H,
J = 6.0, 3.2 Hz). 13C NMR: À5.1, À4.76, 16.80, 17.7, 18.0, 20.8, 21.6, 24.9
br, 25.5, 25.8, 27.0, 30.2, 31.1, 32.1, 33.5, 34.7, 34.8, 43.1, 48.9, 52.7, 63.4,
69.2, 71.4, 83.4, 84.0, 96.2. MS EI (m/z): 476 (M+, 1), 475 (4), 317 (3),
265 (1), 251 (2), 243 (30), 187 (14), 161 (34), 159 (100), 147 (14), 135
(19), 133 (15), 121 (11), 119 (11), 109 (23), 107 (16), 105 (12).
HRMS: calcd for C29H52O3Si 476.36857, found 476.36729.
O-[[2ξ-(Tetrahydro-2H-pyranyl)oxy]-1-[(1R)-5-hydroxy-1,5-
dimethylhexyl]]-(1S,3aR,4S,7aR)-4-(tert-butyldimethylsily-
loxy)-7a-methyloctahydro-1H-indene (21). A mixture of crude
20 (1.0 g), EtOAc (10 mL), 10% palladium-on-carbon (45 mg), and
NaHCO3 (0. 1 g) was stirred under hydrogen atmosphere for 5 days at
reflux temperature. The mixture was cooled and filtered through a pad of
Celite, and the solid was washed with EtOAc. The filtrates were
combined, and the solvent was evaporated to give 21 (1.031 g).
Hydrogenation of the previously prepared analytical sample of 20 under
an analogous conditions provided an analytical sample of 21. 1H NMR:
À0.01 (s, 3H), 0.00 (s, 3H), 2.0À0.7 (m, 23H) overlapping 0.78 (d, 3H,
J = 6.6 Hz), 0.87 (s, 9H), 0.98 (s, 3H), 1.18 (s, 3H), 1.19 (s, 3H),
3.50À3.36 (m, 1H), 4.02À3.88 (m, 1H), 4.05 (s, 1H), 4.74À4.66 (m,
1H). 13C NMR: À5.1, À4.7, 16.8, 17.8, 18.1, 21.0, 21.4, 22.0, 25.0, 25.2,
25.5, 25.9, 26.3, 26.9, 32.6, 33.0, 33.1, 34.6, 34.6, 38.4, 42.2, 43.1, 49.0,
53.4, 53.5, 63.5, 69.3, 76.3, 93.9. MS LSIMS (m/z): 983 [(2M + Na]+,
8), 503 [(M + Na)+, 100]. HRMS: calcd for C29H56O3SiNa 503.3891,
found 503.38751.
(1S,3aR,4S,7aR)-1-[(1R)-5-Hydroxy-1,5-dimethylhexyl]-
7a-methyloctahydro-1H-inden-4-ol (22). HF (40%, 4 mL) was
added to a solution of crude 21 (351 mg) in MeCN (20 mL) in a plastic
container, and the mixture was stirred vigorously for 8 h at rt. The
mixture was then partitioned between EtOAc (100 mL) and water
(100 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (2 Â 30 mL). The combined organic extracts
were washed with satd aq NaHCO3 and then with brine and dried
(Na2SO4). The solvent was evaporated, and the residue was chromato-
graphed on silica gel (20 g, hexanesÀEtOAc, 85:15) to give 22 (68 mg,
72% yield from 18). HPLC analysis (Nucleosil 50/5 column, hexaneÀ
EtOAc, 3:1, RI detector) indicated that this product was 97.5% pure
(tR = 13.60 min) with two contaminants: tR = 15.32 min, 2.0% and tR =
16.04 min, 0.5%. 21. 1H NMR: 0.79 (d, 3H, J = 6.4 Hz) partly
overlapping 1.9À0.8 (m, 19H), 1.00 (s, 3H), 1.20 (s, 6H), 4.13 (br s,
1H). 13C NMR: 16.7, 17.5, 21.2, 22.2, 24.3, 24.7, 29.2, 33.0, 32.6, 34.2,
38.2, 42.7, 44.2, 48.5, 53.3, 69.1, 71.0. MS LSIMS (m/z): 305 [(M +
Na)+, 85], 303 (100), 247 (65), 209 (70). HRMS: calcd for
C18H34O2Na 305.2451, found 305.24584.
Et2O (10 mL) and filtered through a pad of Celite. The filtrate was
evaporated to dryness, and the residue was chromatographed on silica
gel (1 g, hexanesÀEtOAc, 80:20) to give 4 (7.8 mg, 96%) identical with a
sample reported earlier.2
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of all
S
b
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jwicha@icho.edu.pl.
’ ACKNOWLEDGMENT
We thank the Institute of Organic Chemistry, the Polish
Academy of Sciences, for financial support.
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