Construction of the tricyclic A-B-C core of the veratrum alkaloids

Article abstract of DOI:10.1021/jo401158d

Organocatalyzed enantioselective allylation of 2-iodocyclohexenone followed by methylation and oxy-Cope rearrangement delivered enantiomerically enriched 2-methyl 3-allyl cyclohexanone, which engaged in acid-catalyzed Robinson annulation to give the bicyclic enone. Subsequent elaboration of the pendant allyl group into an α-diazo β-keto ester set the stage for Rh-mediated cyclization to deliver the tricyclic A-B-C core of the Veratrum alkaloids.

Full text of DOI:10.1021/jo401158d

Article
pubs.acs.org/joc
Construction of the Tricyclic A‑B‑C Core of the Veratrum Alkaloids
Douglass F. Taber* and James F. Berry
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: Organocatalyzed enantioselective allylation of
2-iodocyclohexenone followed by methylation and oxy-Cope
rearrangement delivered enantiomerically enriched 2-methyl 3-
allyl cyclohexanone, which engaged in acid-catalyzed Robinson
annulation to give the bicyclic enone. Subsequent elaboration
of the pendant allyl group into an α-diazo β-keto ester set the
stage for Rh-mediated cyclization to deliver the tricyclic A-B-C
core of the Veratrum alkaloids.
To date, no direct synthetic route to the 6−6−5 tricyclic core
system of the Veratrum alkaloids has been described. We
envisoned (eq 1) an approach to the β-keto ester 5 by way of
the key enone 6.
INTRODUCTION
The Veratrum alkaloids (Figure 1) contain a 6−6−5−6
carbocyclic scaffold connected to either a piperidine system
■
RESULTS AND DISCUSSION
■
The Wieland−Miescher ketone 8 (Figure 2), both in racemic3
and enantiomerically pure4 form, has been a workhorse for
Figure 2. Chirons for polyalicyclic synthesis.
Figure 1. Members of the Veratrum family of alkaloids.
polyalicyclic synthesis. We hypothesized that the enantiomeri-
cally pure enone 6 and the deconjugated ether 9 could be
similarly versatile chirons.
or a 5−6 tetrahydrofuran/piperidine system.1 Members of this
family of natural products include veratramine 1, cyclopamine
2, jervine 3, and cycloposine 4. In particular, cyclopamine has
been investigated for its activity against certain cancers,
especially basal cell carcinoma, pancreatic cancer, medullo-
blastoma, and small cell lung cancer.2 These cancers propagate
via the Hedgehog pathway, of which cyclopamine 2 is a known
inhibitor.
Preparation of the Enone 6. The preparation (Scheme 1)
of the enone 6 began with the crystalline α-iodo enone 10.5 As
we have reported,6 asymmetric allylation proceeded smoothly
using the Schaus7 protocol, allyl borane 11 in the presence of
catalytic R-Br2BINOL, to deliver the alcohol 12 in high yield
Received: May 27, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401158d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1
Scheme 2
and 95% ee. For this conversion to be practical, the catalyst
($200/g) needed to be recycled. We were pleased to find that
an aqueous extraction using 5% NaOH enabled 90−95%
catalyst separation and recovery.
A Kumada coupling8 was employed to convert 12 to 13. The
oxy-Cope rearrangement of 13 in toluene using KH in paraffin9
initially presented some difficulty, due to the low molecular
weight of 14. Extractive workup with low boiling diethyl ether
reduced the amount of volatile product lost during the
purification. Direct filtration of the concentrated toluene extract
through silica gel then delivered the pure ketone 14.
Scheme 3
Rounding out the synthesis was a Robinson annulation with
methyl vinyl ketone to give the enantiomerically pure enone 6.
The acid-mediated Robinson annulation proceeded to ∼35%
conversion before decomposition set in. Attempts to increase
conversion through additional equivalents of methyl vinyl
ketone were not successful. However, the unreacted ketone 14
was readily recovered in the course of the purification of 6.
Preparation of the Ether 9. Many polyalicyclic natural
products, including 1−4, have an equatorial hydroxyl group in
the A ring with the alkene beginning at C-5. We therefore
applied (Scheme 2) the classic deconjugating protocol10 to the
enone 6. The crude enol acetate 15 was reduced11 with NaBH4
to give the alcohol 16 as a 4:1 mixture of diastereomers. A
survey of protecting groups led to the crystalline 3-
bromobenzoate 17, the structure, including absolute config-
uration, of which was confirmed by X-ray crystallography
(Supporting Information).
Exposure of the recrystallized 17 to CH3OH/K2CO3
liberated the pure equatorial alcohol 18, which was carried on
to the benzyl ether 9. The protection of 18 with BnBr and NaH
gave incomplete conversion, even at elevated temperatures.
Alternatively, with KH in paraffin,12 the alcohol was converted
to the benzyl ether 9 smoothly at room temperature.
Preparation of a Tricyclic β-Keto Ester. The alkaloids 1−
4 each have a trans-fused five-membered C-ring. Given the
literature precedent,13 it seemed likely that the α-diazo β-keto
ester 20 (Scheme 3) would, under Rh catalysis, cyclize to 5.
In a preliminary investigation, the terminal alkene of racemic
9 was selectively converted to the methyl ketone 19 using the
modified Wacker oxidation developed by Sigman,14 tert-butyl
hydroperoxide in the presence of a Pd(quinox)Cl2 complex.
Diazo transfer15 on the derived β-keto ester delivered the
desired α-diazo β-keto ester 20.
In the event, cyclization proceeded smoothly, to give the
crystalline tricyclic ketone 5 as a single diastereomer. The
assignment of the relative configuration of 5 was supported by
the ring methines at δ 62.3, 48.5, and 37.7 in the 13C NMR, as
well as by the 12.0 Hz coupling constant of the β-keto ester
1
methine in the H NMR.
CONCLUSION
We have developed a scalable, enantioselective route to the
bicyclic chirons 6 and 9 and to the tricyclic β-keto ester 5. We
■
B
dx.doi.org/10.1021/jo401158d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(0.750 g, 1.689 mmol), t-BuOH (4.65 g, 62.83 mmol), and the
allylborane 11 (6.861 g, 54.46 mmol). This mixture was stirred for 10
min at room temperature, then 2-iodocyclohex-2-enone 10 (9.3 g,
41.89 mmol) was added all at once, and the mixture was stirred for 24
h at room temperature. The mixture was then diluted with PE and
extracted with 5% aqueous NaOH solution × 3. The aqueous phase
was then back extracted once with diethyl ether, and the combined
organics were dried (Na2SO4) and concentrated. The residue was
passed through a small plug of silica gel to give alcohol 1218 (10.6 g,
96% yield) as a light yellow oil. [α]20D = −34.6 (c 1.00, CH2Cl2), 95%
ee; TLC Rf (MTBE/PE, 1:4) 0.54; 1H NMR (CDCl3) δ 6.57 (m, 1H),
5.78 (m, 1H), 5.19 (d, J = 6.0 Hz, 1H), 5.15 (s, 1H), 2.44 (d, J = 7.2
Hz, 2H), 2.04 (m, 4H), 1.89 (m, 1H), 1.72 (m, 2H); 13C NMR δ (u)
119.0, 111.8, 73.0, 47.2, 34.2, 29.7, 18.9; (d) 141.9, 132.9; IR 3435,
1638, 1436, 1329, 1171, 1081, 981, 918, 764 cm−1; HRMS calcd for
C9H12I (M − OH) 246.9984, obsd 246.9992. Recovery of catalyst.
The basic aqueous phase was acidified with conc aqueous HCl until
the pH was ∼1. The aqueous layer was extracted × 3 with Et2O, and
the combined organics were dried (Na2SO4), rotovaped to silica gel,
and purified through a silica plug to give recovered (R)-BINOL-Br2
(0.690 g, 92% recovered).
believe that these now readily available chirons will have wide
applicability in target-directed synthesis.16
EXPERIMENTAL SECTION
■
1
General Procedures. H NMR and 13C NMR were measured at
400 MHz for 1H and 90 and 100 MHz for 13C in CDCl3. 13C
multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as
“d”, from methylene and quaternary carbon as “u”. The infrared (IR)
spectra were determined as neat oil. High resolution mass spectra
(HRMS) were obtained by electron impact (EI) or chemical
ionization (CI). Rf values indicated refer to thin layer chromatography
(TLC) on 2.5 cm × 10 cm, 250 μm analytical plates coated with silica
gel GF, developed in the solvent system indicated. Flash
chromatography was performed using silica gel 60 (40−60 μm).
Solvents are referred as vol/vol mixtures. All air- and moisture-
sensitive reactions were performed in oven-dried glassware under a
positive pressure of nitrogen. All solvents were purified immediately
prior to use. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from sodium metal/benzophenone under nitrogen. Dichloro-
methane, toluene, and acetonitrile (MeCN) were distilled from CaH2
under nitrogen. All reaction mixtures were stirred magnetically under
nitrogen atmosphere. MTBE is tert-butyl methyl ether, PE is 30−60
petroleum ether, DME is dimethoxyethane, and MeOH is methanol.
HRMS were recorded in EI mode on a double-focusing instrument.
2-Iodocyclohex-2-enone 10. Following the reported procedure,5
2-cyclohexenone (35.0 g, 0.365 mol) was dissolved in a 1:1 mixture of
THF/H2O and stirred at 0 °C for 5 min. Next, K2CO3 (60.375 g,
0.438 mol) was added, followed by DMAP (8.893 g, 7.29 mmol). The
reaction mixture turned a series of colors before finally turning brown.
The solution was stirred for 10 min. I2 (111.1 g, 0.437 mol) was then
added slowly to avoid forming a solid mass at the bottom of the flask.
The reaction turned black and was stirred overnight open to the
atmosphere at room temperature. The mixture was then partitioned
between EtOAc and, sequentially, 0.1 M aqueous HCl, saturated
aqueous Na2S2O3, and brine. The combined organic layers were dried
(Na2SO4) and concentrated. The residue was filtered through a silica
plug to give enone 10 (72.89 g, 90% yield) as a yellow crystalline solid.
The spectral data matched that of the previously synthesized
material.5b TLC Rf (MTBE/PE, 1:4) 0.40; 1H NMR (CDCl3) δ
7.77 (t, J = 4.4 Hz, 1H), 2.67 (t, J = 6.8 Hz, 2H), 2.44 (m, 2H), 2.09
(m, 2H); 13C NMR δ (u) 192.2, 103.9, 37.3, 30.0, 22.9; (d) 159.5.
B-Allyl-1,3,2-dioxaborinane 11. Following the reported proce-
dure,17 a solution of trimethyl borate (22.76 mL, 200 mmol) was
dissolved in 200 mL of Et2O at −78 °C, and allylmagnesium bromide
(1.0 M in Et2O, 200 mL, 200 mmol) was added. The resulting white
suspension was stirred at this temperature for 2 h before the dry ice
bath was removed and the solution allowed to warm to −20 °C.
Aqueous HCl (3 M, 200 mL) was added, and the mixture turned clear
as the solids dissolved. The solution was stirred for 20 min at room
temperature. The layers were separated, and the aqueous layer was
extracted × 3 with Et2O. The organic layers were dried and
concentrated to about 200 mL on a rotovap with the bath set no
higher than 30 °C. Then 100 mL of dry Et2O was added along with
1,3-propanediol (15.2 g, 200 mmol) and activated 4 Å molecular sieves
(36 g). The reaction mixture was stirred at room temperature for 20 h.
The reaction mixture was filtered through glass wool, and the
molecular sieves were washed × 2 with Et2O. The reaction mixture
was concentrated without having the water bath exceed 30 °C. The
resulting clear solution was dissolved in 200 mL of pentane, and the
excess 1,3-propanediol (bottom layer) was removed via pipet. The
solution was filtered through Celite and concentrated under reduced
pressure to give compound 11 (17.1 g, 68% yield) as a clear oil. The
spectra matched that of the previously synthesized compound.7 1H
NMR (CDCl3) δ 5.86 (m, 1H), 4.92 (m, 2H), 3.99 (t, J = 5.6 Hz, 4H),
1.95 (m, 2H), 1.64 (d, J = 7.2 Hz, 2H); 13C NMR δ (u) 113.9, 61.8,
27.3; (d) 135.5.
Determination of Enantiomeric Excess. An HPLC was used,
along with a UV−vis detector and a Chiracel OD column (150 mm ×
20 mm). A 20-μL portion of a 1 mg/mL sample of alcohol 12 in PE
was injected, and a linear run (1 mL/min) was employed ranging from
0.2% isopropanol in hexane at 0 min to 0.3% isopropanol in hexane at
70 min. The detector was set at a wavelength of 254 nm. The retention
time of the major enantiomer was 19.012 min, and that of the minor
enantiomer was 21.062 min.
(R)-1-Allyl-2-methylcyclohex-2-enol 13.6 To a slurry of
NiCl2·dppp (23 mg, 0.5 mol %) in dry Et2O (40 mL) was added
MeMgBr (3.0 M in Et2O, 6.7 mL, 20.04 mmol) via syringe, and the
mixture was then stirred at room temperature for 10 min under N2.
Iodide 12 (2.30 g, 8.71 mmol) was slowly added in 10 mL of Et2O.
The reaction was stirred overnight at room temperature. Once the
reaction was complete by TLC, Na2SO3 (5 g) was added, and the
mixture stirred vigorously for 5 min. The atmosphere was purged
completely with N2, and the solution was sparged with N2. The
solution was then rapidly quenched with saturated aqueous Na2S2O3
under N2 atmosphere. PE was then immediately added to dilute the
solution. The layers were separated and the aqueous layer was
extracted × 3 with Et2O. The solution was then dried (Na2SO4 and
Na2SO3) and concentrated. The solution was filtered through a small
plug of silica gel to give alcohol 13 (1.196 g, 90% yield) as a light
yellow oil. [α]20D = −34.9 (c 1.00, CH2Cl2); TLC Rf (MTBE/PE, 1:4)
1
0.46; H NMR δ 5.78 (m, 1H), 5.64 (m, J = 1.6 Hz, 1H), 5.15 (m,
1H), 5.11 (t, J = 1.2 Hz, 1H), 2.40 (dt, J = 7.2, 1.2 Hz, 2H), 1.98 (m,
2H), 1.78 (m, 4H), 1.64 (m, 4H); 13C NMR δ (u) 137.0, 118.2, 71.6,
43.6, 35.7, 25.6, 19.1; (d) 134.1, 126.6, 17.8; IR 1639, 1440, 1174, 973,
912 cm−1; HRMS calcd for C10H15 (M − OH) 135.1174, obsd
135.1173.
(R)-3-Allyl-2-methylcyclohexanone 14. Following the literature
procedure,6,19 18-crown-6 (4.113 g, 15.58 mmol) was dissolved in dry
toluene (80 mL), t-BuOK (3.489 g, 31.16 mmol) was added, and the
mixture was stirred under N2 for 5 min at room temperature. Alcohol
13 (3.383 g, 22.26 mmol) in 15 mL of dry toluene was added dropwise
over 5 min. The mixture was then heated to 85 °C (bath temperature)
for 1 h, cooled to room temperature, and quenched with saturated
aqueous NH4Cl. The aqueous layer was extracted × 3 with PE, and the
combined organic layers were dried (Na2SO4). The toluene/PE
solution was then diluted with more PE and placed directly on a
column for purification by silica gel chromatography to afford ketone
14 (2.162 g, 64% yield, mixture of trans/cis diastereomers) as a light
yellow oil. [α]20 = +10.0 (c 1.00, CH2Cl2, 2:1 mixture of trans/cis
D
diastereomers); TLC Rf (MTBE/PE, 1:4) 0.67; 1H NMR δ 5.85−5.73
(m, 1H, trans diastereomer), 5.75−5.63 (m, 1H, cis diastereomer),
5.11−5.03 (m, 2H, trans diastereomer), 5.03−4.98 (m, 2H, cis
diastereomer), 2.66−2.00 (m, 6H), 1.93−1.41 (m, 4H), 1.05 (d, J =
12.8 Hz, 3H, trans diastereomer), 1.02 (d, J = 12.8 Hz, 3H, cis
diastereomer); 13C NMR (trans diastereomer) δ (u) 213.4, 117.1,
(R)-1-Allyl-2-iodocyclohex-2-enol 12. Following the reported
procedure,7 to a round-bottom flask were added (R)-BINOL-Br2
C
dx.doi.org/10.1021/jo401158d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
41.5, 38.2, 30.3, 25.7; (d) 135.5, 49.4, 45.2, 11.9; (cis diastereomer) δ
(u) 214.5, 116.3, 39.8, 33.7, 26.7, 23.7; (d) 136.5, 48.7, 41.9, 11.5; IR
1711, 1640, 1447, 1221, 999, 914 cm−1; HRMS calcd for C10H17O (M
+ H) 153.1279, obsd 153.1283.
129.9, 128.2, 124.1, 75.1, 46.0, 18.2; IR 1719, 1285, 1255, 1123, 987,
747 cm−1.
Enantioenriched Alcohol 18. Ester 17 was recrystallized by
dissolving in a minimal amount of boiling MeOH and allowing the
solution to stand and cool until crystals formed. The diastereomeric
(4aR,5R)-5-Allyl-4a-methyl-4,4a,5,6,7,8-hexahydronaphtha-
len-2(3H)-one 6. To a solution of ketone 14 (1.360 g, 8.95 mmol) in
dry toluene (30 mL) were added p-toluenesulfonic acid monohydrate
(0.170 g, 0.89 mmol) and a small amount of methylene blue dye as a
free radical inhibitor. The mixture was stirred for 5 min at room
temperature, then methyl vinyl ketone (1.565 g, 22.37 mmol) was
added, and the mixture was heated to reflux overnight. The reaction
was then cooled to room temperature and quenched with saturated
aqueous NaHCO3. The layers were separated, and the aqueous layer
was extracted × 3 with Et2O. The combined organic layers were then
dried (Na2SO4), and the ether was removed (setting the rotovap bath
no higher than 30 °C). The toluene solution was diluted with PE and
placed directly on a column for purification by silica gel
chromatography to afford enone 6 (417 mg, 66% brsm, 23% overall)
ratio of the isolated crystals ranged from 9:1 to 20:1. [α]20 = −39.2
D
(14:1 ratio), mp = 77−79 °C. After recrystallization, ester 17 (103 mg,
0.264 mmol) was stirred in 4 mL of MeOH. Then K2CO3 (146 mg,
1.059 mmol) was added, and the suspension was stirred at room
temperature for 2.5 h. The MeOH was removed under reduced
pressure, and the residue was rotovaped to silica gel and chromato-
graphed to give enantioenriched alcohol 18 (50 mg, 92% yield) [α]20
D
= −92.8 (c 1.00, CH2Cl2, 20:1 diastereomeric ratio) as a clear oil. The
spectra matched those of alcohol 16.
(1R,6S,8aR)-1-Allyl-6-(benzyloxy)-8a-methyl-1,2,3,5,6,7,8,8a-
octahydronaphthalene 9. The alcohol 18 (90 mg, 0.44 mmol) was
dissolved in 5 mL of THF and KH(P) (70 mg at 50% w/w in paraffin,
0.874 mmol) was added. The mixture was stirred at room temperature
for 30 min, and then tetrabutylammonium iodide (16 mg, 0.044
mmol) was added, followed by BnBr (75 mg, 0.437 mmol). The
reaction mixture was stirred for 1 h at room temperature and then
rotovaped to silica gel and chromatographed to give benzyl ether 9
(110 mg, 85% yield) as a clear oil. TLC Rf (MTBE/PE, 1:4) 0.82; 1H
NMR δ 7.39−7.22 (m, 5H), 5.76 (m, 1H), 5.38 (m, 1H), 5.00 (m,
2H), 4.56 (s, 2H), 3.29 (m, 1H), 2.44 (m, 1H), 2.35−1.00 (m, 12H),
0.95 (s, 3H); 13C NMR δ (u) 140.9, 139.0, 115.6, 70.0, 39.1, 37.3,
36.8, 34.6, 28.4, 26.0, 23.0; (d) 138.8, 128.4, 127.6, 127.5, 122.7, 78.6,
46.1, 18.2; IR 1451, 1357, 1094, 909, 735 cm−1; HRMS calcd for
C14H21 (M − OBn) 189.1643, obsd 189.1647.
as an orange oil along with 887 mg of ketone 14. [α]20 = +69.8 (c
D
1.00, CH2Cl2); TLC Rf (MTBE/PE, 1:4) 0.35; 1H NMR δ 5.86−5.66
(m, 2H), 5.08−4.98 (m, 2H), 2.50−2.08 (m, 6H), 1.92−1.71 (m, 4H),
1.43−1.25 (m, 3H), 1.13 (s, 3H); 13C NMR δ (u) 199.5, 171.8, 116.2,
39.2, 35.4, 34.1, 33.9, 33.5, 26.8, 26.3; (d) 137.7, 124.2, 48.4, 16.8; IR
1673, 1615, 1441, 995, 912 cm−1; HRMS calcd for C14H21O (M + H)
205.1592, obsd 205.1588.
(4aR,5R)-5-Allyl-4a-methyl-1,2,3,4,4a,5,6,7-octahydronaph-
thalen-2-ol 16. The enone 6 (0.400 g, 1.96 mmol) was dissolved in
acetic anhydride (5 mL), and acetyl chloride (0.769 g, 9.80 mmol) was
then added. The mixture was heated to 65 °C for 4 h. The acetic
anhydride and acetyl chloride were removed via bulb to bulb
distillation under vacuum (heating no higher than 40 °C). The
residue was then dissolved in CH2Cl2, rotovaped to silica gel, and
purified by column chromatography to afford (4aR,5R)-5-allyl-4a-
methyl-3,4,4a,5,6,7-hexahydronaphthalen-2-yl acetate 15 along with
unidentified contaminants (0.320 g total weight). This crude mixture
(which included acetate 15) was dissolved in 13 mL of a 1:1 mixture of
THF/t-BuOH. The solution was cooled to 0 °C and stirred for 5 min.
NaBH4 (0.395 g, 10.41 mmol) in a 1:1 mixture of H2O/THF (3 mL)
was then added dropwise at 0 °C. The reaction mixture was placed in
the freezer (−20 °C) for 48 h and then stirred at room temperature for
48 h. The solvent was removed under reduced pressure, and 0.5 M
aqueous HCl was added to the residue. The aqueous layer was
extracted × 3 with Et2O. The combined organic layers were dried
(Na2SO4) and concentrated. The residue was purified via column
chromatography to afford alcohol 16 (206 mg, 50% yield from 6) as a
1-((1R,6S,8aR)-6-(Benzyloxy)-8a-methyl-1,2,3,5,6,7,8,8a-oc-
14
tahydronaphthalen-1-yl)propan-2-one 19. Pd(quinox)Cl2 (14
mg, 8.5 mol %) and AgSbF6 (40 mg, 24 mol %) were stirred with 3 mL
of CH2Cl2 for 10 min at room temperature in the dark. tert-Butyl
hydroperoxide (70% in H2O, 677 mg, 5.27 mmol) was added at room
temperature, and the mixture was stirred for 10 min. The solution was
then cooled to 0 °C and stirred for 5 min. Benzyl ether 9 (130 mg,
0.439 mmol) in 1 mL of CH2Cl2 was then added slowly over 5 min.
The reaction mixture was stirred until the starting material was
consumed, as monitored by TLC. The excess TBHP was reduced by
adding saturated aqueous Na2S2O3 and stirring for 30 min. The
aqueous layer was extracted × 3 with CH2Cl2. The combined organics
were washed with brine, dried (Na2SO4), and concentrated. The
residue was chromatographed to afford ketone 19 (130 mg, 61% yield)
1
as a clear oil. TLC Rf (MTBE/PE, 1:4) 0.42; H NMR δ 7.39−7.25
4:1 mixture of diastereomers (clear oils). [α]20 = −71.0 (c 1.00,
(m, 5H), 5.42 (s, 1H), 4.59 (s, 2H), 3.36−3.25 (m, 1H), 2.59−2.40
(m, 2H), 2.30−2.20 (m, 2H), 2.17 (s, 3H), 2.10−1.09 (m, 9H), 0.98
(s, 3H); 13C NMR δ (u) 208.2, 139.2, 137.9, 69.0, 43.7, 38.0, 35.7,
35.6, 27.2, 24.6, 23.5; (d) 127.4, 126.6, 126.4, 121.7, 77.4, 40.6, 29.6,
17.5; IR 1714, 1453, 1359, 1274, 1094, 738 cm−1; HRMS calcd for
C21H29O2 (M + H) 313.2168, obsd 313.2176.
D
CH2Cl2, 4:1 mixture of diastereomers); TLC Rf (MTBE/PE, 1:4)
0.28; 1H NMR (CDCl3) δ 5.77 (m, 1H), 5.40 (m, 1H), 5.01 (m, 2H),
3.54 (m, 1H), 2.35−1.07 (m, 14H), 0.95 (s, 3H); 13C NMR δ (u)
140.7, 115.5, 42.2, 36.9, 34.6, 31.6, 25,9, 23.0; (d) 138.7, 122.8, 71.9,
46.1, 18.2; IR 1641, 1439, 1357, 1049, 906 cm−1; HRMS calcd for
C14H21 (M − OH) 189.1643, obsd 189.1640.
Methyl 2-Diazo-4-((1R,6S,8aR)-6-(benzyloxy)-8a-methyl-
1,2,3,5,6,7,8,8a-octahydronaphthalen-1-yl)-3-oxobutanoate
20. NaH (60% in mineral oil, 50 mg, 1.25 mmol) and dimethyl
carbonate (187 mg, 2.08 mmol) were stirred in 3 mL of dry DME. The
solution was heated to reflux (bath temperature = 95 °C, condenser
attached), and 2 drops of MeOH were added. Ketone 19 (65 mg,
0.208 mmol) in 2.5 mL of DME was added, and the mixture was
heated to reflux for 12 h. The solution was cooled, and 10% aqueous
HCl was added. The aqueous layer was extracted × 3 with Et2O. The
combined organics were dried (Na2SO4) and concentrated. The
residue was chromatographed to give methyl 4-((1R,6S,8aR)-6-
(benzyloxy)-8a-methyl-1,2,3,5,6,7,8,8a-octahydronaphthalen-1-yl)-3-
oxobutanoate (59 mg) as a clear oil. TLC Rf (MTBE/PE, 1:4) 0.39;
1H NMR δ 7.31 (m, 5H), 5.40 (m, 1H), 4.56 (s, 2H), 3.74 (s, 3H),
(4aR,5R)-5-Allyl-4a-methyl-1,2,3,4,4a,5,6,7-octahydronaph-
thalen-2-yl 3-Bromobenzoate 17. Alcohol 16 (0.227 g, 1.10
mmol), m-Br benzoic acid (0.244 g, 1.21 mmol), and DMAP (34 mg,
0.275 mmol) were combined in a round-bottom flask along with 5 mL
of CH2Cl2. The solution was cooled to 0 °C and stirred for 5 min.
DCC in 2 mL of CH2Cl2 was added slowly. The ice bath was removed,
and the reaction was stirred overnight at room temperature. The solids
were filtered out and washed with CH2Cl2. The filtrate was
concentrated, and the residue was rotovaped to silica gel and
chromatographed to give ester 17 (353 mg, 94% yield) as a clear oil
(4:1 mixture of diastereomers). [α]20 = −39.2 (c 1.00, CH2Cl2, after
D
crystallization, 14:1 mixture of diastereomers); TLC Rf (MTBE/PE,
5:95) 0.69; 1H NMR (CDCl3) δ 8.19 (t, J = 1.6 Hz, 1H), 8.00 (dt, J =
7.6, 1.2 Hz, 1H), 7.70 (dt, J = 8.0, 1.2 Hz, 1H), 7.34 (t, J = 8.0 Hz,
1H), 5.80 (m, 1H), 5.50 (s, 1H), 5.05 (m, 2H), 4.88 (m, 1H), 2.47 (m,
2H), 2.34 (dd, J = 12.4, 1.2 Hz, 1H), 2.02 (m, 4H), 1.76 (m, 3H), 1.26
(m, 3H), 1.03 (s, 3H); 13C NMR δ (u) 164.7, 139.4, 132.7, 122.4,
115.6, 38.0, 37.0, 36.6, 34.5, 27.8, 26.0, 23.0; (d) 138.6, 135.7, 132.6,
3.46 (s, 2H), 3.30 (m, 1H), 2.65 (dd, J = 16.8, 2.4 Hz, 1H), 2.45 (m,
1H), 2.33 (dd, J = 16.8, 10.4 Hz, 1H), 2.24 (m, 1H), 2.10−1.06 (m,
9H), 0.96 (s, 3H); 13C NMR δ (u) 202.7, 167.6, 140.1, 138.9, 70.1,
49.5, 44.2, 39.0, 36.8, 36.6, 28.3, 25.6, 24.5; (d) 128.4, 127.6, 127.5,
122.7, 78.4, 52.4, 41.4, 18.5; IR 1742, 1712, 1442, 1314, 1241, 1079
D
dx.doi.org/10.1021/jo401158d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
cm−1; HRMS calcd for C23H30O4Na: 393.2042 (M + Na), obsd
393.2037.
(4) For recent preparations of the Wieland−Miescher ketone, see:
(a) Bradshaw, B.; Extebarria-Jardi, G.; Bonjoch, J.; Viozquez, S. F.;
Guillena, G.; Najera, C. Adv. Synth. Catal. 2009, 351, 2482−2490 and
references therein. (b) Guillena, G.; Najera, C.; Viozquez, S. F. Synlett
2008, 3031−3035.
(5) (a) Krafft, M. E.; Cran, J. W. Synlett 2005, 1263−1266.
(b) Pandey, G.; Balakrishnan, M. J. Org. Chem. 2008, 73, 8128−8131.
(6) Taber, D. F.; Gerstenhaber, D. A.; Berry, J. F. J. Org. Chem. 2011,
76, 7614−7617.
(7) (a) Schaus, S. E.; Lou, S.; Moquist, P. N. J. Am. Chem. Soc. 2006,
128, 12660−12661. (b) Barnett, D. S.; Moquist, P. N.; Schaus, S. E.
Angew. Chem., Int. Ed. 2009, 48, 8679−8682.
(8) Kiso, Y.; Yamamoto, K.; Tamao, K.; Kumada, M. J. Am. Chem.
Soc. 1972, 94, 4374−4376.
The β-keto ester (55 mg, 0.149 mmol) was dissolved in 3 mL of dry
MeCN, and MsN315(36 mg, 0.297 mmol) was added. The solution
was stirred for 5 min at 0 °C, and NEt3 (45 mg, 0.445 mmol) was
added in 1 mL of MeCN. The solution was stirred overnight at room
temperature. The solution was evaporated directly onto silica gel and
chromatographed to give diazo ester 20 (50 mg, 65% yield from 19) as
a light yellow oil. TLC Rf (MTBE/PE, 1:4) 0.44; 1H NMR δ 7.34 (m,
5H), 5.42 (m, 1H), 4.59 (s, 2H), 3.86 (s, 3H), 3.38−3.26 (m, 1H),
2.97 (dd, J = 16.0, 2.4 Hz, 1H), 2.75 (dd, J = 16.0, 10.8 Hz, 1H), 2.51−
1.12 (m, 11H), 1.04 (s, 3H); 13C NMR δ (u) 193.0, 161.8, 140.4,
139.0, 74.2, 70.0, 41.0, 39.0, 37.0, 36.7, 28.3, 25.7, 24.3; (d) 128.4,
127.6, 127.5, 122.6, 78.5, 52.2, 42.2, 18.6; IR 2061, 1748, 1718, 1447,
1319, 1247, 1088 cm−1; HRMS calcd for C23H28O4N2Na (M + Na)
419.1947, obsd 419.1942.
(3aR,7S,9aR,9bS)-Ethyl 7-(Benzyloxy)-9a-methyl-2-oxo-
2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-cyclopenta[a]-
naphthalene-3-carboxylate 5. Rhodium(II) octanoate (2 mg) was
stirred in 2.5 mL of CH2Cl2 that had been filtered through anhydrous
K2CO3. Diazo ester 20 (50 mg, 0.126 mmol) was dissolved in 3 mL of
CH2Cl2 (filtered through anhydrous K2CO3) and added dropwise
under N2. The solution was stirred for 1 h at room temperature. The
reaction mixture was evaporated onto silica gel and chromatographed
to afford tricyclic ketone 5 (32 mg, 70% yield) as an off white solid.
TLC Rf (MTBE/PE, 1:4) 0.20; mp = 107−110 °C (recrystallized from
MeOH); 1H NMR δ 7.37−7.29 (m, 5H), 5.43 (m, 1H), 4.59 (s, 2H),
3.77 (s, 3H), 3.33 (m, 1H), 2.91 (d, J = 12.0 Hz, 1H), 2.58−2.18 (m,
6H), 2.05−1.17 (m, 6H), 1.10 (s, 3H); 13C NMR δ (u) 210.1, 169.3,
141.2, 138.7, 70.1, 38.9, 38.7, 38.2, 36.5, 31.4, 27.9; (d) 128.4, 127.6,
127.6, 120.8, 78.1, 62.3, 52.5, 48.5, 37.7, 18.4; IR 1756, 1728, 1438,
1264, 1128, 1094, 736 cm−1; HRMS calcd for C23H29O4 (M + H)
369.2066, obsd 369.2060.
(9) Taber, D. F.; Nelson, C. G. J. Org. Chem. 2006, 71, 8973−8974.
(10) (a) Mase, T.; Ichita, J.; Marino, J. P.; Koreeda, M. Tetrahedron.
Lett. 1989, 30, 2075−2078. (b) Moon, S. S.; Stuhmiller, L. M.;
McMorris, J. C. J. Org. Chem. 1989, 54, 26−28. (c) Moon, S. S.;
Stuhmiller, L. M.; Chadha, R. K.; McMorris, J. C. Tetrahedron 1990,
46, 2287−2306.
(11) Hua, Z.; Carache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J.
Org. Chem. 2005, 70, 9849−9856.
(12) Huang, H.; Nelson, C. G.; Taber, D. F. Tetrahedron. Lett. 2010,
51, 3545−3546.
(13) Taber, D. F.; Ruckle, R. E. J. Am. Chem. Soc. 1986, 108, 7686−
7693.
(14) (a) Michel, B. W.; Carmelio, A. M.; Cornell, C. N.; Sigman, M.
S. J. Am. Chem. Soc. 2009, 131, 6076−6077. (b) Cornell, C. N.;
Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796−2797.
(15) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem.
1986, 51, 4077−4078.
(16) For a complementary preparation of an angularly substituted
trans-antitrans 6−6−5 chiron, see: (a) Taber, D. F.; Taluskie, K. V. J.
Org. Chem. 2006, 71, 2797−2801. (b) Taber, D. F.; Joerger, J.-M. J.
Org. Chem. 2008, 73, 4155−4159.
(17) Brown, H. C.; Rachela, P. J.; Pellechia, J. J. Org. Chem. 1990, 55,
1868−1874.
(18) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127,
14556−14557.
(19) For rate acceleration of the oxy-Cope rearrangement using 18-
crown-6, see: Evans, D.; Golob, A. M. J. Am. Chem. Soc. 1975, 97,
4765−4766.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds as well
as 50% probability figures and CIR files for 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: taberdf@udel.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank John Dykins for high resolution mass spectrometry
under the financial support of NSF 054117, Dr. Shi Bai for
NMR spectra financially supported by NSF CRIF:MU, CHE
080401, Glenn Yap for X-ray crystallography, and the National
Institutes of Health (GM060287) for financial support of this
work.
REFERENCES
(1) Keeler, R. F. Phytochemistry 1968, 7, 303−306.
(2) For a review on the topic of cyclopamine, including its chemistry,
biology and medicinal relevance, see: Heretsch, P.; Tzagkaroulaki, L.;
Giannis, A. Angew. Chem., Int. Ed. 2010, 49, 3418−3427 and references
therein.
■
(3) For the initial preparation of the Wieland−Miescher ketone, see:
(a) Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215−2228.
(b) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623 (July 29,
1971) and USP 3,975,440 (Aug 17, 1976) Example 21. (c) Hajos, Z.
G.; Parrish, D. R. Organic Synthesis; Wiley: New York, 1990; Collect.
Vol. VII, pp 368−372. (d) Bui, T.; Barbas, C. F. Tetrahedron Lett.
2000, 41, 6951−6954.
E
dx.doi.org/10.1021/jo401158d | J. Org. Chem. XXXX, XXX, XXX−XXX