Total syntheses of ent-heliespirones A and C

Article abstract of DOI:10.1021/jo201971g

Stereodivergent total syntheses of ent-heliespirone A and C were both completed in 11 vessels and ～24% combined overall yield (A + C). These syntheses employed an identical inverse demand Diels-Alder reaction between a surrogate for an extendedly conjugated γ-δ unsaturated ortho-quinone methide and l-lactic-acid-derived exocyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding p-quinone by argentic oxide (AgO). In addition, an unusual intramolecular etherification of a 3° alcohol caused by cerium ammonium nitrate was observed.

Full text of DOI:10.1021/jo201971g

Article
pubs.acs.org/joc
Total Syntheses of ent-Heliespirones A and C
Wen-Ju Bai, Jason C. Green, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Stereodivergent total syntheses of ent-heliespi-
rone A and C were both completed in 11 vessels and ∼24%
combined overall yield (A + C). These syntheses employed an
identical inverse demand Diels−Alder reaction between a
surrogate for an extendedly conjugated γ−δ unsaturated ortho-
quinone methide and L-lactic-acid-derived exocyclic enol ether.
Novel reactions of special note include a diastereoselective
reduction of a chroman spiroketal by combination of
borontrifluoride etherate and triethyl silane, along with
oxidative rupture of a chroman etherial ring into the corresponding p-quinone by argentic oxide (AgO). In addition, an
unusual intramolecular etherification of a 3° alcohol caused by cerium ammonium nitrate was observed.
heliespirones A (1) and C (2) (Scheme 1). We further chose
this chroman intermediate based upon a hypothesis that the
INTRODUCTION
■
A new family of bioactive spirosesquiterpenes, heliespirones
1−3, was recently isolated from aqueous leaf extracts of the
sunflower Helianthus annus (Figure 1).1 These compounds
Scheme 1. Synthetic Plan
Figure 1. Proposed biosynthesis of the heliespirane family.
display an intriguing oxaspirocyclic motif previously unknown
among sesquiterpenes. The heliespiranes exhibited significant
inhibition in the coleoptile bioassay, suggesting use as novel
allelopathic agrochemicals. Given the previous isolation of
heliannuol C (4) and A (5) from the same species, their
biosynthesis has been envisioned to proceed by oxidative
rupture of their respective benzofused cyclic ethers to the
corresponding quinones, followed by an intramolecular 1,4-
conjugate addition of their respective secondary alcohols. A
synthetic approach along these lines of thinking would be
orthogonal to Liu’s, which had formed the penultimate quinone
from an acyclic hydroquinone precursor.2
benzylic vinyl substituent could guide the reduction of the
intermediate oxonium A that would arise from application of
Lewis acid to the chroman spiroketal 7. If this stereochemical
relay proved diastereoselective, it would then provide us with a
general stereochemical approach to cis-oriented chroma motifs.
We further suspected that the key spiroketal 7 could arise from
a diastereoselective inverse electron demand ortho-quinone
In our strategy, we targeted the chroman 6, a structural
isomer of heliannuol C (4),3 as the penultimate intermediate,
thereby mimicking the supposed divergent biosynthesis of
Received: September 28, 2011
Published: November 10, 2011
© 2011 American Chemical Society
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Article
methide Diels−Alder (o-QMDA) reaction between the
exocyclic enol ether 8 and the intermediate o-QM B generated
from addition of vinylmagnesium bromide to the OBoc
salicylaldehyde 9.4 If all went as planned, then we would arrive
at the heliespirones 1 and 2 in just three pots from the OBoc
salicylaldehyde 9.
vinylmagnesium bromide to the o-QM B rapidly formed by
facile elimination within species D.
When forming species resembling the o-QM B in our prior
studies with vinylmagnesium bromide, we had never encoun-
tered this bromination adduct nor seen more than traces of the
corresponding bis-addition product. Moreover, in all cascades
initiated by addition of an aromatic or aliphatic Grignard
reagent in the presence of enol ether, the cycloaddition reaction
had always predominated, even if excess (>2.0 equiv of RMgBr)
of the organometallic reagent were used to initiate the cascade.
To ensure complete consumption of the Grignard reagent prior
to formation of o-QM B, we added 2 equiv of vinylmagnesium
bromide to the commercially available phenol 15 followed by
the addition of Boc2O.5 While this modified procedure
intercepted intermediate D and eliminated the formation of
the phenol 14, we still observed the brominated product 13 in
49% yield. If no enol ether was added during the course of the
reaction, then the bromide 13 was formed as the major product
(90% yield).
RESULTS AND DISCUSSION
■
In 2002, we reported that addition of vinylmagnesium bromide
to aldehyde 10 triggered an o-QMDA reaction to occur with
ethyl vinyl ether (EVE) to afford the respective chroman acetal
11 in 70% yield (>50:1 d.r.) (Scheme 2i).4c While this specific
Scheme 2. Cascades Triggered by Vinylmagnesium Bromide
However, when our best cycloaddition conditions were
implemented using the aldehyde 15 in combination with
MeMgBr, the chroman acetal 16 arose in better than 80% yield
as a single diastereomer. Suspecting chemical collusion between
the vinyl substituent and this particular aromatic core, which
perhaps resulted in rapid elimination of intermediate D and
subdued reactivity of intermediate B, we reasoned that a
surrogate for the vinyl residue would be required. In the
interest of time, we moved forward to test the diastereose-
lectivity of the desired cycloaddition reaction with some easily
accessible exocyclic enol ethers.
Our first attempt involved addition of methylmagnesium
bromide to aldehyde 9 so as to trigger the o-QMDA reaction
with the enol ether 17, prepared in just two steps from 2-
hydroxyisobutyric acid by condensation with benzaldehyde
and Petasis methylenation (Scheme 3). The desired cyclo-
Scheme 3. Some Early Model Studies with o-QMDA
example used EVE as the solvent, we have also shown that
these cycloadditions proceed with as few as 2 equiv of an enol
ether as the dienophile. Before examining more elaborate
exocyclic enol ethers, we found that application of similar
conditions, using EVE as the solvent for addition of
vinylmagnesium bromide to aldehyde 9, afforded a meager
31% yield of the desired adduct 12, albeit as a single
diastereomer (Scheme 2ii). Isolated alongside the chroman
were two unanticipated side products. We believe the bromide
13 resulted from an intramolecular delivery of a bromide within
intermediate C. On the other hand, the phenol 14 (25% yield)
most likely arose from a 1,4-conjugate addition of residual
addition reaction failed, presumably because of steric
interactions caused by the gem-dimethyl substituent, as related
analogs were known by us to participate in similar reac-
tions.4f We were fortunate to find that the cycloaddition pro-
ceeded with the less sterically congested enol ether 18 derived
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analogously from L-lactic acid.6 Its reaction afforded the desired
spiroketal 19 in 75% yield (>50:1 overall d.r.). As expected for
the subsequent reduction, A-1,3 interactions served to position
the benzylic methyl substituent in a pseudo-axial orientation on
the oxonium intermediate so that the hydride addition
proceeded from the face opposite the methyl residue, affording
chroman 20 as a single diastereomer in a 95% yield. Thus, we
had established a two-step process for the controlled
construction of chromans of interest from OBoc salicylaldehyde
via a chroman spiroketal intermediate.
In light of the problems caused by the vinyl substituent, we
set out to construct its surrogate. The route began by
regioselective acylation of 1,4-dimethoxy-2-methylbenzene 21
with acryloyl chloride mediated by aluminum trichloride
(Scheme 4). The Friedel−Crafts reaction proceeded at 0 °C
Subsequent deprotonation with methylmagnesium bromide
triggered the desired cascade and provided the chroman
spiroketal 25 in 81% yield (>50:1 d.r.). Reduction of ketal
moiety proceeded as before and afforded the alcohol 26 in 94%
yield. Its relative and absolute stereochemistry was secured by a
two-step conversion to the sulfone 27 and X-ray analysis.7
To complete the construction of the vinyl chroman, the
thioether and secondary alcohol in compound 26 were
concurrently oxidized to the corresponding sulfoxide and
ketone in nearly quantitative yield by prolonged exposure to
IBX (2-iodoxybenzoic acid).8 To the best of our knowledge,
this is the first such example of a concurrent oxidation.
Subsequent treatment of the ketone in 28 with methylmagne-
sium bromide followed by thermolysis gave our desired
chroman 29 in 79% yield over the two steps.
We were now poised to test what we suspected to be a very
challenging oxidative rupture of the chroman etherial ring so as
to cede the corresponding p-quinone in the presence of the
unprotected tertiary alcohol appendage. Submission of
compound 29 to cerium ammonium nitrate (CAN), which
was well-known to convert hydroquinone ethers into their
corresponding p-quinones,9 afforded instead the unexpected
tricyclic ether 32 in 81% yield (Table 1, entry a). We suspect
Scheme 4. Enantioselective Synthesis of (+)-29
Table 1. Efforts Toward Oxidative Rupture of the Chroman
Ring
a
b
CAN (1.7 equiv), (MeCN/H2O 3/1), 0 °C, 30 min. CAN
c
(2.5 equiv), (MeCN/H2O 3/1), 0 °C, 30 min. CAN (5.0 equiv),
(MeCN/H2O 3/1), 0 °C, 30 min. AgO (6.0 equiv), 6 M HNO3
(9 equiv), dioxane, rt, 3 min. CAN (2.5 equiv), (MeCN/H2O 3/1),
d
e
over the course of 1 h, whereupon warming to 35 °C for an
additional 2 h resulted in cleavage of the more labile aryl methyl
ether, affording the phenol 22 in 91% yield. The aryl acrylate
moiety in 22 underwent 1,4-conjugate addition with thiophenol
with the aid of DBU (1,8-diazobicycloundec-7-ene) to produce
the thioether 23 in 95% yield. Carbonate formation followed by
reduction of the ketone with sodium borohydride furnished the
o-QMDA precursor 24 in 91% overall yield for the two steps.
0 °C, 30 min. 90% yield.
this etherification starts by formation of a tertiary cerium
alkoxide A followed by fragmentation to the corresponding
alkoxy radical B (Scheme 5). However, because of the
stereochemical positioning of the reacting groups, we speculate
oxidation of the methine between the vinyl and aryl residues
proceeds in an unprecedented fashion, via an intermolecular
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Article
Scheme 5. Proposed Mechanism for Formation of Compound 32
hydrogen transfer, followed by conventional radical oxidation
and ether formation.10 Interested to see whether a vinyl sub-
stituent was necessary for this outcome, we applied similar
conditions to the methyl alcohol analog 20. If the solution of
the alcohol 20 was preheated to 60 °C prior to addition of the
oxidant, then a similar etherification was observed to produce
the cyclic ether 34.
1 and 2, except for the optical rotations, which were equal
and opposite.
CONCLUSION
■
In summary, we have completed the total syntheses of ent-
heliespirone A (35) and ent-heliespirone C (36) from a
chroman spiroketal that was produced in enantiomerically pure
manner from L-lactic acid. Key steps were an o-QMDA reaction
used to set the benzylic stereocenter that subsequently guided a
diastereoselective reduction of oxonium generated from the
chroman spiroketal. The final oxaspirocyclic ethereal bond was
generated via an unusual oxidative rupture of the chroman
ethereal ring mediated by argentic oxide and base-mediated
Michael addition of the freed secondary alcohol.
The desired quinone 30 was obtained along with a few other
products upon increasing the equivalents of the oxidant (Table 1,
entry b). We speculate that the p-quinone 30 and the
p-quinone ketal 31 both formed from the same oxonium
intermediate produced by oxidative dearomatization of 29 but
diverged because of competing intermolecular addition of water
verses intramolecular addition of the tertiary alcohol. On the
other hand, the p-quinone 33 likely emerged from oxidative
hydrolysis of the unusual ether 32. Indeed, we found that upon
resubjecting compound 32 to CAN afforded the p-quinone 33
in nearly quantitative yield (Table 1, e). However, upon adding
more oxidant at the beginning of the reaction and thereby
increasing the water content, the yield of the desired quinone
30 could not be improved (Table 1, entry c). Moreover,
hydrolysis of the ketal 31 to the p-quinone 30 proved
impossible in our hands under a myriad of conditions. After a
rather exhaustive search of oxidative demethylation methods
thought to proceed by different mechanisms, we were fortunate
to find that exposure of the chroman 29 to argentic oxide
(AgO),11 a mixture of AgI and AgIII species (Ag2O·Ag2O3),
afforded the desired p-quinone 30 in a 62% yield (Table 1,
entry d). We speculated that the tertiary alcohol is protected as
its corresponding silver alkoxide, as very little of the benzylic
oxidation products 32 and 33 were observed.
EXPERIMENTAL SECTION
■
General Procedures. In reactions, where water was not present as
solvent, reagent, or byproduct, vented vessels were flame-dried under a
slow nitrogen flow. A slight positive pressure of dry nitrogen was
maintained via rubber septa seal during the course of the reaction.
Reactions were monitored by analytical thin-layer chromatography on
hard layer silica gel 60 F250 plates cut into 1 × 2.5 cm pieces.
Visualization was effected by ultraviolet light (254 nm), followed by
staining (Seebach or permanganate). Removal of solvents was
accomplished using a rotary evaporator. If the product was nonvolatile,
trace solvents were removed at a pressure of approximately 0.03 mmHg.
Ethyl acetate (anhydrous) was utilized directly from the bottle.
Deuterated chloroform was filtered through basic alumina prior to
use. Solvents were distilled before use under a slight positive pressure
of nitrogen. Diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane,
benzene, and toluene were distilled from sodium and benzophenone.
Dichloromethane, 1,2-dichloroethane, and nitromethane were distilled
from CaH2. Chloroform was filtered through alumina before being
fractionally distilled. 1H NMR spectra were recorded on 200, 400, 500,
or 600 MHz instruments. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance of CDCl3 (7.27 ppm).
13C NMR spectra were recorded on 400, 500, 600, and 800 MHz
Treatment of quinone 30 with cesium carbonate furnished
ent-heliespirone A (35) and ent-heliespirone C (36) in 45
and 38% yield, respectively (Scheme 6),12 which could be
Scheme 6. Cesium Carbonate Mediated Conjugate Addition
instruments with a solvent resonance of CDCl3 (77.00 ppm). High
resolution mass spectra (HRMS) were recorded by electrospray
ionization/time-of-flight experiments. Melting points are uncorrected.
tert-Butyl (2-Formyl-4-methoxy-5-methylphenyl) carbonate
(9). Boc2O (646.9 mg, 2.96 mmol, 1.2 equiv) was added in one
portion to a solution of compound 15 (410 mg, 2.47 mmol, 1 equiv),
i-Pr2NEt (0.43 mL, 2.47 mmol, 1 equiv), and DMAP (30.2 mg,
0.25 mmol, 0.1 equiv) in DCM (20 mL, 0.1 M) at room temperature.
The solution was allowed to stir for 30 min and then quenched with
saturated aqueous NH4Cl. The solution was extracted with DCM, and
the combined organic solutions were washed with brine, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, eluent: 90% hexanes, 10% ethyl
easily separated by chromatography. This is a significant
improvement over the Lewis acidic conditions previously
employed for this transformation.2 All spectral data were
identical with the data of the corresponding natural products
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acetate) to afford compound 9 (624 mg, 2.35 mmol, 95%). White
(125 MHz; CDCl3) δ 155.6, 152.1, 141.8, 128.6, 128.1, 126.5, 126.1,
124.3, 107.3, 83.6, 55.7, 33.4, 27.7, 16.2; HRMS (EI) m/z calculated
for C16H21O4Br 356.0623, found 356.0636; IR (neat) cm−1 2980,
2960, 1756, 1505, 1370, 1253, 1203, 1147; Rf = 0.5 (83% hexanes, 17%
ethyl acetate).
1
solid: mp 80−82 °C; H NMR (600 MHz, CDCl3) δ 10.15 (s, 1H),
7.28 (s, 1H), 7.05 (s, 1H), 3.89 (s, 3H), 2.28 (s, 3H), 1.58 (s, 9H); 13C
NMR (150 MHz, CDCl3) δ 188.0, 155.9, 152.0, 146.4, 136.1, 126.4,
125.0, 108.5, 84.4, 55.9, 27.7, 16.9; HRMS (EI) m/z calculated for
C14H18O5Na [M + Na]+ 289.1052, found 289.1044; IR (neat) cm−1
2985, 2870, 1751, 1688, 1609, 1370, 1255, 1144; Rf = 0.35 (90%
hexanes, 10% ethyl acetate).
cis-2-Ethoxy-6-methoxy-4,7-dimethylchroman (16). The
procedure yielding compound 16 was the same as procedure 2.
1
80% yield. Colorless liquid: H NMR (600 MHz; CDCl3) δ 6.66 (s,
cis-2-Ethoxy-6-methoxy-7-methyl-4-vinylchroman (12). Procedure
1 from OBoc salicylaldehyde: Vinylmagnesium bromide (0.53 mL,
0.39 mmol, 0.7 M in THF, 1.05 equiv) was added slowly to a solution
of compound 9 (100 mg, 0.37 mmol, 1 equiv) in ethyl vinyl ether
(3.6 mL, 0.1 M) at −78 °C. The reaction was warmed to room
temperature over 3 h and then quenched with saturated aqueous
NH4Cl. The solution was extracted with EtOAc, and the combined
organic solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: 90% hexanes, 10% ethyl acetate) to
afford compound 12 (29 mg, 0.12 mmol, 31%), compound 14
(19.1 mg, 0.09 mmol, 25%), and compound 13 (trace). Procedure 2
from salicylaldehyde: Vinylmagnesium bromide (0.84 mL, 0.62 mmol,
0.7 M in THF, 2.05 equiv) was added slowly to a solution of compound
15 (50 mg, 0.30 mmol, 1 equiv) in ethyl vinyl ether (3 mL, 0.1 M) at
0 °C. The reaction was stirred at this temperature for 20 min and then
cooled to −40 °C. Boc2O (131 mg, 0.60 mmol, 2 equiv) was added to the
reaction in one portion, and then the reaction was warmed to room
temperature over 3 h and quenched with saturated aqueous NH4Cl.
The solution was extracted with EtOAc, and the combined organic
solutions were washed with brine, dried with MgSO4, and con-
centrated in vacuo. The residue was purified by column chro-
matography (SiO2, eluent: 90% hexanes, 10% ethyl acetate) to afford
chroman acetal 12 (31.4 mg, 0.13 mmol, 44%) and compound 13
(50.1 mg, 0.14 mmol, 49%).
1H), 6.63 (s, 1H), 5.14 (dd, J = 6.6, 2.4 Hz, 1H), 3.98 (dq, J = 9.6,
7.1 Hz, 1H), 3.79 (s, 3H), 3.61 (dq, J = 9.6, 7.1 Hz, 1H), 2.97 (q, J =
7.1 Hz, 1H), 2.17 (s, 3H), 2.17−2.15 (m, 1H), 1.75 (ddd, J = 13.5, 7.9,
6.7 Hz, 1H), 1.39 (d, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 155.2, 145.6, 126.2, 125.0, 119.1, 109.2,
98.8, 64.1, 56.0, 36.0, 28.2, 21.8, 15.9, 15.3; HRMS (EI) m/z calculated
for C14H20O3Na [M + Na]+ 259.1310, found 259.1294; IR (neat)
cm−1 2930, 1496, 1406, 1206, 1137, 1053, 1010, 883; Rf = 0.75 (83%
hexanes, 17% ethyl acetate).
4,4-Dimethyl-5-methylene-2-phenyl-1,3-dioxolane (17)13
.
TsOH (86 mg, 0.5 mmol, 0.05 equiv) was added to a solution of
2-hydroxyisobutyric acid (1.56 g, 15 mmol, 1.5 equiv) and PhCHO
(1.06 g, 10 mmol, 1 equiv) in DCM (58.6 mL, 0.17 M) at room
temperature. The solution was allowed to stir for 15 h under
azeotropic reflux at 45 °C before it was cooled and quenched at room
temperature with saturated aqueous NaHCO3. The solution was then
extracted with DCM, and the combined organic solutions were washed
with saturated aqueous NaHCO3 and brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: 90% hexanes, 10% ethyl acetate) to
afford 5,5-dimethyl-2-phenyl-1,3-dioxolan-4-one14 (1.56 g, 8.1 mmol,
81%). Colorless liquid: 1H NMR (600 MHz; CDCl3) δ 7.52−7.51 (m,
2H), 7.47−7.45 (m, 3H), 6.45 (s, 1H), 1.59 (s, 3H), 1.57 (s, 3H); Rf =
0.4 (90% hexanes, 10% ethyl acetate). Petasis reagent15 (4.3 mL,
1.72 mmol, 0.4 M in Tol, 2.2 equiv) was added to a solution of this
intermediate lactone (150 mg, 0.78 mmol, 1 equiv) in toluene (5 mL,
0.08 M) under N2 at room temperature. The solution was allowed to
stir for 1.5 h at 78 °C and then cooled down to room temperature.
The solution was purified by column chromatography (SiO2, eluent:
first 100% hexanes to remove toluene; then 95% hexanes, 5% ethyl
acetate) to afford the enol ether 17 (115 mg, 0.61 mmol, 78%).
cis-2-Ethoxy-6-methoxy-7-methyl-4-vinylchroman (12). Col-
1
orless liquid: H NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.55 (s,
1H), 6.00−5.93 (m, 1H), 5.21 (ddd, J = 17.0, 1.8, 0.8 Hz, 1H), 5.15
(dd, J = 6.6, 2.5 Hz, 1H), 5.10 (dd, J = 9.9, 1.8 Hz, 1H), 3.98 (dq, J =
9.6, 7.1 Hz, 1H), 3.76 (s, 3H), 3.63 (dq, J = 9.6, 7.1 Hz, 1H), 3.50 (q,
J = 7.8 Hz, 1H), 2.20 (ddd, J = 13.5, 6.7, 2.5 Hz, 1H), 2.17 (s, 3H),
1.92 (ddd, J = 13.5, 7.9, 6.6 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 152.0, 145.5, 141.8, 126.7, 121.3, 119.1,
115.2, 110.3, 98.2, 64.0, 55.8, 39.5, 34.4, 15.9, 15.2; HRMS (EI) m/z
calculated for C15H20O3 248.1412, found 248.1397; IR (neat) cm−1
2975, 2929, 1497, 1404, 1204, 1143, 1061, 1037; Rf = 0.8 (88%
hexanes, 12% ethyl acetate).
1
Colorless liquid: H NMR (600 MHz; CDCl3) δ 7.53−7.51 (m, 2H),
7.43−7.41 (m, 3H), 6.15 (s, 1H), 4.31 (d, J = 2.5 Hz, 1H), 3.90 (d, J =
2.5 Hz, 1H), 1.58 (s, 3H), 1.52 (s, 3H); Rf = 0.75 (96% hexanes, 4%
ethyl acetate).
(2S,4S)-4-Methyl-5-methylene-2-phenethyl-1,3-dioxolane
(18). Sc(OTf)3 (40 mg, 0.08 mmol, 0.001 equiv) was added to a
solution of L-lactic acid (8.1 g, 90 mmol, 1.5 equiv) and
Ph(CH2)2CHO (8.04 g, 60 mmol, 1 equiv) in DCM (350 mL, 0.17
M) at room temperature. The solution was allowed to stir for 10 h
under azeotropic reflux at 45 °C before it was cooled and quenched at
room temperature with saturated aqueous NaHCO3. The solution was
extracted with DCM, and the combined organic solutions were washed
with saturated aqueous NaHCO3 and brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by distillation to
remove Ph(CH2)2CHO (95−98 °C/1 mmHg), followed by column
chromatography (SiO2, eluent: 90% hexanes, 10% ethyl acetate) to
afford (2S,5S)-5-methyl-2-phenethyl-1,3-dioxolan-4-one6 (9.27 g,
4-Methoxy-5-methyl-2-(penta-1,4-dien-3-yl)phenol (14).
1
Colorless liquid: H NMR (500 MHz; CDCl3) δ 6.67 (s, 1H), 6.59
(s, 1H), 6.10 (ddd, J = 17.2, 10.3, 6.2 Hz, 2H), 5.25 (dt, J = 10.3,
1.5 Hz, 2H), 5.17 (dt, J = 17.3, 1.6 Hz, 2H), 4.73 (s, 1H), 4.26−4.24
(m, 1H), 3.78 (s, 3H), 2.18 (s, 3H); 13C NMR (125 MHz; CDCl3) δ
152.0, 147.1, 138.5, 126.5, 124.7, 119.1, 116.3, 111.3, 56.0, 47.8, 15.8;
HRMS (EI) m/z calculated for C13H16O2 204.1150, found 204.1141;
IR (neat) cm−1 3457, 2933, 1756, 1505, 1464, 1407, 1201, 1150; Rf =
0.45 (88% hexanes, 12% ethyl acetate).
(E)-2-(3-Bromoprop-1-en-1-yl)-4-methoxy-5-methylphenyl
tert-Butyl Carbonate (13). Vinylmagnesium bromide (0.84 mL,
0.62 mmol, 0.7 M in THF, 2.05 equiv) was added slowly to a solution
of compound 15 (50 mg, 0.30 mmol, 1 equiv) in diethyl ether (3 mL,
0.1 M) at 0 °C. The reaction was stirred at this temperature for 20 min
and then cooled to −40 °C. Boc2O (78.6 mg, 0.36 mmol, 1.2 equiv)
was added to the reaction in one portion, and then the reaction was
warmed to room temperature over 3 h and quenched with saturated
aqueous NH4Cl. The solution was extracted with EtOAc, and the
combined organic solutions were washed with brine, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, eluent: 90% hexanes, 10% ethyl
acetate) to afford compound 13 (96.1 mg, 0.27 mmol, 90%). Colorless
liquid: 1H NMR (500 MHz; CDCl3) δ 6.91 (s, 1H), 6.89 (s, 1H), 6.70
(d, J = 15.5 Hz, 1H), 6.38 (dt, J = 15.6, 7.8 Hz, 1H), 4.16 (dd, J = 7.8,
1.0 Hz, 2H), 3.85 (s, 3H), 2.21 (s, 3H), 1.56 (s, 9H); 13C NMR
1
45 mmol, 75%%, d.r. = 10:1). Colorless liquid: H NMR (200 MHz;
CDCl3) δ 7.30−7.12 (m, 5H), 5.45 (td, J = 4.8, 1.0 Hz, 1H), 4.29 (qd,
J = 6.7, 1.1 Hz, 1H), 2.79−2.71 (m, 2H), 2.15−2.05 (m, 2H), 1.46 (d,
J = 6.8 Hz, 3H); Rf = 0.45 (93% hexanes, 7% ethyl acetate); [α]23D +5.3
(c = 1.6, CHCl3). The procedure of Petasis methylenation to afford
enol ether (−)-18 is the same as shown above. Colorless liquid
1
(d.r. = 10:1): H NMR (500 MHz; CDCl3) δ 7.32 (t, J = 7.5 Hz,
2H), 7.24 (t, J = 7.9 Hz, 3H), 5.23 (t, J = 4.5 Hz, 1H), 4.57 (dddt, J =
8.2, 6.2, 4.2, 2.0 Hz, 1H), 4.31 (t, J = 2.2 Hz, 1H), 3.84 (t, J = 2.1 Hz,
1H), 2.83−2.79 (m, 2H), 2.12−2.08 (m, 2H), 1.47 (d, J = 6.0 Hz,
3H); 13C NMR (125 MHz; CDCl3) δ 161.3, 141.2, 128.50, 128.45,
126.0, 104.0, 77.4, 74.6, 35.3, 29.5, 18.6; HRMS (EI) m/z calculated
for C13H16O2 204.1150, found 204.1143; IR (neat) cm−1 3027, 2932,
383
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2866, 1685, 1496, 1298, 1241, 1133; Rf = 0.75 (96% hexanes, 4%
ethyl acetate); [α]23 −26.4 (c = 2.5, CHCl3).
benzene (1 mL, 0.22 M). The reaction was stirred for 1 h at room
temperature and quenched with water. The solution was extracted
with EtOAc, and the combined organic solutions were washed with
brine, dried with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, eluent: 87% hexanes, 13%
ethyl acetate) to afford compound 23 (51.6 mg, 0.17 mmol, 95%).
(2R,2′S, 4R,5′DS)-6-Methoxy-4,5′,7-trimethyl-2′-
phenethylspiro[chroman-2,4′-[1,3]dioxolane] (19). Methylmag-
nesium bromide (0.73 mL, 0.73 mmol, 1 M in Et2O, 1.15 equiv) was
added slowly to a solution of compound 9 (168 mg, 0.63 mmol,
1 equiv) and enol ether (−)-18 (642 mg, 3.15 mmol, 5 equiv) in Et2O
(6.3 mL, 0.1 M) at −78 °C. The reaction was warmed to room
temperature over 3 h and then quenched with saturated aqueous
NH4Cl. The solution was extracted with EtOAc, and the combined
organic solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: first 75% hexanes, 25% DCM to
remove excess (−)-18; then 95% hexanes, 5% ethyl acetate) to afford
compound (−)-19 (173 mg, 0.47 mmol, 75%, dr >50:1). Colorless
1
Yellow solid: mp 64−65 °C; H NMR (500 MHz; CDCl3) δ 11.93
(s, 1H), 7.40−7.38 (m, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.23 (t, J = 7.3
Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 3.76 (s, 3H), 3.35−3.27 (m, 4H),
2.24 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 202.9, 157.2, 150.4,
138.7, 135.6, 129.5, 129.1, 126.4, 120.3, 116.4, 108.4, 55.8, 37.9, 28.1,
16.9; HRMS (EI) m/z calculated for C17H18O3NaS [M + Na]+
325.0874, found 325.0869; IR (neat) cm−1 3041, 2934, 1613, 1481,
1368, 1299, 1233, 1027; Rf = 0.3 (90% hexanes, 10% ethyl acetate).
tert-Butyl (2-(1-Hydroxy-3-(phenylthio)propyl)-4-methoxy-
5-methylphenyl) Carbonate (24). Boc2O (646.9 mg, 2.96 mmol,
1.2 equiv) was added slowly to a solution of compound 23 (746 mg,
2.47 mmol, 1 equiv), i-Pr2NEt (0.43 mL, 2.47 mmol, 1 equiv), and
DMAP (30.2 mg, 0.25 mmol, 0.1 equiv) in DCM (20 mL, 0.1 M) at
room temperature. The solution was allowed to stir for 30 min and
then quenched with saturated aqueous NH4Cl. The solution was
extracted with DCM, and the combined organic solutions were washed
with brine, dried with MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, eluent: 84% hexanes,
16% ethyl acetate) to afford the corresponding alcohol 23a: 1H NMR
(500 MHz; CDCl3) δ 7.37−7.35 (m, 2H), 7.31−7.27 (m, 2H), 7.18 (s,
1H), 7.20−7.16 (m, 1H), 6.96 (s, 1H), 3.84 (s, 3H), 3.31−3.22 (m,
4H), 2.24 (s, 3H), 1.53 (s, 9H); 13C NMR (125 MHz; CDCl3) δ
197.2, 155.4, 151.9, 143.0, 136.1, 133.6, 129.00, 128.98, 128.2, 126.0,
125.5, 109.9, 83.9, 55.7, 41.9, 27.80, 27.66, 16.4; HRMS (EI) m/z
calculated for C22H26O5NaS [M + Na]+ 425.1399, found 425.1397; IR
(neat) cm−1 2980, 1759, 1682, 1498, 1397, 1275, 1205, 1148; Rf = 0.28
(90% hexanes, 10% ethyl acetate). NaBH4 (280.8 mg, 7.37 mmol,
0.63 M in H2O, 3 equiv) precooled to 0 °C was then added slowly to a
solution of this alcohol intermediate in THF (23 mL, 0.1 M) at 0 °C.
The reaction was stirred at 0 °C and monitored carefully by TLC.
After the starting material disappeared, the reaction was quenched with
0.5 N HCl. The solution was extracted with EtOAc, and the combined
organic solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: 80% hexanes, 20% ethyl acetate) to
afford compound 24 (910 mg, 2.25 mmol, 91% over two steps).
1
liquid: H NMR (600 MHz; CDCl3) δ 7.29 (t, J = 7.5 Hz, 2H), 7.21
(t, J = 7.5 Hz, 3H), 6.70 (s, 1H), 6.65 (s, 1H), 5.28 (t, J = 4.5 Hz, 1H),
4.27 (q, J = 6.5 Hz, 1H), 3.83 (s, 3H), 3.06 (quintet, J = 7.2, 2.1 Hz,
1H), 2.77 (t, J = 8.4 Hz, 3H), 2.21 (s, 3H), 2.10 (dd, J = 13.7, 7.3 Hz,
1H), 2.04−2.01 (m, 2H), 1.90 (dd, J = 13.7, 2.5 Hz, 1H), 1.52 (d, J =
7.2 Hz, 3H), 1.33 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz; CDCl3) δ
152.5, 145.1, 141.7, 128.48, 128.44, 126.3, 125.9, 124.7, 119.5, 110.0,
104.9, 101.7, 81.1, 56.0, 35.4, 33.1, 29.8, 28.1, 23.5, 16.3, 16.0; HRMS
(EI) m/z calculated for C23H28O4Na [M + Na]+ 391.1885, found
391.1866; IR (neat) cm−1 2957, 2928, 1496, 1409, 1224, 1196, 1139,
1042; Rf = 0.82 (83% hexanes, 17% ethyl acetate); [α]23 −64.4 (c =
D
0.45, CHCl3).
(S)-1-((2R,4R)-6-Methoxy-4,7-dimethylchroman-2-yl)ethanol
(20). BF3·Et2O (0.17 mL, 1.35 mmol, 5 equiv) was added slowly to a
solution of compound (−)-19 (100 mg, 0.27 mmol, 1 equiv) and
Et3SiH (0.22 mL, 1.26 mmol, 5 equiv) in DCM (7 mL, 0.04 M) at
−78 °C. The reaction was stirred for 2 h at 0 °C and then quenched
with saturated aqueous NaHCO3. The solution was extracted with
DCM, and the combined organic solutions were washed with brine,
dried with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, eluent: 87% hexanes, 13%
ethyl acetate) to afford compound (−)-20 (60.5 mg, 0.25 mmol, 95%).
Colorless liquid: 1H NMR (600 MHz; CDCl3) δ 6.69 (s, 1H), 6.64 (s,
1H), 4.03 (qd, J = 6.5, 3.6 Hz, 1H), 3.91 (ddd, J = 11.6, 3.6, 1.8 Hz,
1H), 3.80 (s, 3H), 2.99 (dquintet, J = 12.4, 6.2 Hz, 1H), 2.34 (s, 1H),
2.17 (s, 3H), 2.02 (ddd, J = 13.4, 5.8, 1.8 Hz, 1H), 1.57 (dt, J = 13.3,
11.8 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHz; CDCl3) δ 152.0, 148.0, 126.1, 124.8, 118.7, 108.9,
79.3, 69.3, 56.1, 31.4, 29.4, 20.6, 17.8, 15.9; HRMS (EI) m/z calculated
for C14H20O3Na [M + Na]+ 259.1310, found 259.1298; IR (neat)
cm−1 3437, 2959, 2872, 1509, 1464, 1210, 1176, 1058; Rf = 0.2 (83%
1
Colorless liquid: H NMR (500 MHz; CDCl3) δ 7.36−7.34 (m, 2H),
7.27 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.88 (s,
1H), 4.98 (dd, J = 8.4, 4.7 Hz, 1H), 3.81 (s, 3H), 3.08−2.98 (m, 2H),
2.19 (s, 3H), 2.18−2.11 (m, 1H), 2.05−1.97 (m, 1H), 1.55 (s, 9H);
13C NMR (125 MHz; CDCl3) δ 155.9, 152.8, 140.7, 136.5, 133.8,
hexanes, 17% ethyl acetate); [α]22 −53.4 (c = 0.5, CHCl3).
D
129.1, 128.9, 127.2, 125.9, 124.0, 107.7, 83.6, 67.4, 55.7, 36.8, 30.1,
27.7, 16.0; HRMS (EI) m/z calculated for C22H28O5NaS [M + Na]+
427.1555, found 427.1559; IR (neat) cm−1 3452, 2932, 1754, 1501,
1370, 1255, 1201, 1149; Rf = 0.18 (90% hexanes, 10% ethyl acetate).
(2R,2′S,4S,5′S)-6-Methoxy-5′,7-dimethyl-2′-phenethyl-4-(2-
(phenylthio)ethyl)spiro[chroman-2,4′-[1,3]dioxolane] (25). Methyl-
magnesium bromide (0.52 mL, 0.26 mmol, 0.5 M in Et2O, 1.05 equiv)
was added slowly to a solution of compound 24 (100 mg, 0.25 mmol,
1 equiv) and compound (−)-18 (102 mg, 0.5 mmol, 2 equiv) in
Et2O (2 mL, 0.13 M) at −78 °C. The reaction was warmed to room
temperature over 3 h and then quenched with saturated aqueous
NH4Cl. The solution was extracted with EtOAc, and the combined
organic solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column chro-
matography (SiO2, eluent: first 75% hexanes, 25% DCM to remove
excess (−)-18; then 95% hexanes, 5% ethyl acetate) to afford com-
pound (−)-25 (99 mg, 0.2 mmol, 81%, d.r. > 50:1). Colorless liquid:
1H NMR (500 MHz; CDCl3) δ 7.43−7.41 (m, 2H), 7.32−7.28 (m,
1-(2-Hydroxy-5-methoxy-4-methylphenyl)prop-2-en-1-one
(22). Acryloyl chloride (0.13 mL, 1.64 mmol, 1.1 M in DCM, 1 equiv)
was added slowly to a solution of AlCl3 (440 mg, 3.28 mmol, 2 equiv)
and compound 21 (250 mg, 1.64 mmol, 1 equiv) in DCE (1.5 mL,
1.1 M) at 0 °C. The reaction was stirred for 1 h at 0 °C and then
warmed to 35 °C for 2 h. The reaction was then cooled down to room
temperature and poured into ice water. The solution was then
extracted with DCM, and the combined organic solutions were washed
with water, brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, eluent: 90%
hexanes, 10% ethyl acetate) to afford compound 22 (286.5 mg, 1.49
1
mmol, 91%). Yellow oil: H NMR (500 MHz; CDCl3) δ 12.33 (s,
1H), 7.25 (dd, J = 16.8, 10.5 Hz, 1H), 7.05 (s, 1H), 6.80 (s, 1H), 6.54
(dd, J = 16.8, 1.7 Hz, 1H), 5.93 (dd, J = 10.5, 1.5 Hz, 1H), 3.81 (s,
3H), 2.24 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 193.3, 158.4,
150.3, 138.9, 130.8, 130.2, 120.3, 116.6, 108.8, 55.8, 17.0; HRMS (EI)
m/z calculated for C11H12O3Na [M + Na]+ 215.0684, found 215.0679;
IR (neat) cm−1 3582, 2961, 1645, 1587, 1504, 1408, 1254, 1208; Rf =
0.5 (90% hexanes, 10% ethyl acetate).
1-(2-Hydroxy-5-methoxy-4-methylphenyl)-3-(phenylthio)-
propan-1-one (23). Compound 22 (35 mg, 0.18 mmol, 0.9 M in
benzene, 1 equiv) was added slowly to a solution of DBU (31 μL,
0.22 mmol, 1.2 equiv) and PhSH (22 μL, 0.22 mmol, 1.2 equiv) in
4H), 7.23−7.18 (m, 4H), 6.70 (s, 1H), 6.52 (s, 1H), 5.25 (t, J = 4.5
Hz, 1H), 4.26 (q, J = 6.5 Hz, 1H), 3.74 (s, 3H), 3.23 (ddd, J = 12.9,
7.5, 5.5 Hz, 1H), 3.16 (dt, J = 10.0, 5.0 Hz, 1H), 3.06 (dt, J = 12.8,
7.5 Hz, 1H), 2.76−2.73 (m, 2H), 2.46−2.38 (m, 1H), 2.20 (s, 3H),
2.17−2.10 (m, 1H), 2.06−1.96 (m, 4H), 1.34 (d, J = 6.5 Hz, 3H);
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13C NMR (125 MHz; CDCl3) δ 152.3, 145.1, 141.5, 136.4, 129.5,
128.9, 128.42, 128.39, 126.5, 126.06, 125.89, 122.7, 119.4, 110.1,
104.5, 101.7, 81.3, 55.8, 35.4, 35.1, 31.85, 31.78, 30.0, 28.9, 16.01,
15.95; HRMS (EI) m/z calculated for C30H34O4NaS [M + Na]+
513.2076, found 513.2052; IR (neat) cm−1 3025, 2928, 1497, 1410,
1225, 1195, 1122, 1046; Rf = 0.65 (96% hexanes, 4% ethyl acetate);
0.5 M in Et2O, 1.1 equiv) at 0 °C. The reaction was stirred for 30 min
at 0 °C and then quenched with saturated aqueous NH4Cl. The
solution was extracted with EtOAc, and the combined organic
solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was dissolved in toluene
(7.8 mL), sealed into a tube, and heated for 6 h at 150 °C. Then
the reaction was cooled down to room temperature and quenched
with water. The solution was extracted with EtOAc, and the combined
organic solutions were washed with water, brine, dried with MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: 83% hexanes, 17% ethyl acetate) to
afford compound (+)-29 (17.1 mg, 0.066 mmol, 79% for three steps).
Colorless liquid: 1H NMR (600 MHz; CDCl3) δ 6.67 (s, 1H), 6.59 (s,
1H), 5.73 (dt, J = 17.4, 10.2 Hz, 1H), 5.29 (dd, J = 17.4, 1.2 Hz, 1H),
5.22 (dd, J = 10.2, 1.8 Hz, 1H), 3.82 (dd, J = 11.4, 1.8 Hz, 1H), 3.76
(s, 3H), 3.56−3.51 (m, 1H), 2.17 (s, 3H), 2.05 (ddd, J = 13.2, 6.0, 1.8
Hz, 1H), 1.68 (q, J = 12.4 Hz, 1H), 1.32 (s, 3H), 1.27 (s, 3H); 13C
NMR (150 MHz; CDCl3) δ 151.8, 147.7, 141.0, 126.7, 121.2, 118.6,
116.7, 110.2, 81.5, 71.8, 55.9, 41.3, 30.1, 25.8, 24.3, 15.8; HRMS (EI)
m/z calculated for C16H22O3Na [M + Na]+ 285.1467, found 285.1459;
IR (neat) cm−1 3438, 2928, 2855, 1728, 1497, 1406, 1209, 1120; Rf =
[α]22 −83.3 (c = 0.50, CHCl3).
D
(S)-1-((2R,4S)-6-Methoxy-7-methyl-4-(2-(phenylthio)ethyl)-
chroman-2-yl)ethanol (26). BF3·Et2O (0.63 mL, 5 mmol, 25 equiv)
was added slowly to a solution of compound (−)-25 (100 mg,
0.20 mmol, 1 equiv) and Et3SiH (0.8 mL, 5 mmol, 25 equiv) in DCM
(5 mL, 0.04 M) at −78 °C. The reaction was stirred for 2 h at 0 °C and
then quenched with saturated aqueous NaHCO3. The solution was
extracted with DCM, and the combined organic solutions were washed
with brine, dried with MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, eluent: 87% hexanes,
13% ethyl acetate) to afford compound (−)-26 (67.3 mg, 0.19 mmol,
94%). Colorless liquid: 1H NMR (400 MHz; CDCl3) δ 7.40−7.37 (m,
2H), 7.31 (t, J = 7.6 Hz, 2H), 7.24−7.19 (m, 1H), 6.64 (s, 1H), 6.53
(s, 1H), 4.08−4.01 (m, 1H), 3.83 (ddd, J = 11.5, 3.6, 1.7 Hz, 1H), 3.71
(s, 3H), 3.17−3.11 (m, 1H), 3.11−3.05 (m, 1H), 2.97−2.91 (m, 1H),
2.33−2.24 (m, 1H), 2.15 (s, 3H), 2.09 (td, J = 6.4, 1.6 Hz, 1H), 1.93−
1.82 (m, 1H), 1.58 (q, J = 12.4 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H); 13C
NMR (125 MHz; CDCl3) δ 152.1, 148.5, 136.1, 129.8, 129.0, 128.4,
126.2, 122.5, 119.0, 108.5, 79.0, 69.2, 55.9, 34.4, 33.0, 30.7, 27.7,
17.9, 15.8; HRMS (EI) m/z calculated for C21H26O3NaS [M + Na]+
381.1500, found 381.1497; IR (neat) cm−1 3442, 2926, 1584, 1501,
1408, 1211, 1176, 1043; Rf = 0.35 (75% hexanes, 25% ethyl acetate);
0.55 (75% hexanes, 25% ethyl acetate); [α]23 +34.1 (c = 0.20,
D
CHCl3).
2-((3S,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl)-5-methyl-
cyclohexa-2,5-diene-1,4-dione (30).2 To a solution of compound
(+)-29 (10 mg, 0.038 mmol, 1 equiv) and AgO (28.4 mg, 0.229 mmol,
6 equiv) in 1,4-dioxane (1 mL, 0.04 M), HNO3 (57 μL, 0.342 mmol,
6 N in H2O, 9 equiv) was added. The reaction was stirred at room
temperature for 3 min and then quenched with water. The solution
was extracted with EtOAc, and the combined organic solutions were
washed with brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, eluent: 67%
hexanes, 33% ethyl acetate) to afford compound (+)-30 (6.2 mg,
0.024 mmol, 62%) together with two minor products: compound
(+)-31 (1.8 mg, 0.007 mmol, 18%) and compound (−)-33 (0.9 mg,
0.003 mmol, 9%). Yellow oil: 1H NMR (600 MHz; CDCl3) δ 6.60 (q,
J = 1.6 Hz, 1H), 6.54 (s, 1H), 5.78 (ddd, J = 17.4, 10.2, 8.4 Hz, 1H),
5.22 (dt, J = 17.4, 1.2 Hz, 1H), 5.21 (dt, J = 10.2, 0.6 Hz, 1H), 3.73
(td, J = 9.1, 3.5 Hz, 1H), 3.46 (dd, J = 10.8, 1.2 Hz, 1H), 2.29 (s, 1H),
2.04 (d, J = 1.6 Hz, 3H), 1.74 (ddd, J = 13.8, 10.0, 1.8 Hz, 2H), 1.62
(s, 1H), 1.54 (ddd, J = 13.8, 10.8, 3.6 Hz, 1H), 1.21 (s, 3H), 1.15 (s,
3H); 13C NMR (150 MHz; CDCl3) δ 188.4, 187.2, 151.4, 145.5, 137.3,
133.9, 131.9, 118.2, 75.9, 73.0, 39.5, 35.8, 26.4, 23.6, 15.5; HRMS (EI)
m/z calculated for C15H20O4 264.1362, found 264.1357; IR (neat) cm−1
3445, 2971, 2928, 1652, 1352, 1258, 1232, 915; Rf = 0.35 (50% hexanes,
[α]22 −52.5 (c = 0.50, CHCl3).
D
(S)-1-((2R,4S)-6-Methoxy-7-methyl-4-(2-(phenylsulfonyl)-
ethyl)chroman-2-yl)ethyl Nitro Sulfonate (27). 4-Nitrobenzene-
sulfonyl chloride (26 mg, 0.12 mmol, 4 equiv) was added in one
portion to a solution of compound (−)-26 (10 mg, 0.03 mmol,
1 equiv), Et3N (40 μL, 0.30 mmol, 10 equiv), and DMAP (7 mg,
0.06 mmol, 2.0 equiv) in DCM (0.25 mL, 0.1 M) at room temperature.
The solution was allowed to stir for 30 min and then quenched with
saturated aqueous NH4Cl. The solution was extracted with DCM, and
the combined organic solutions were washed with 1 N HCl, brine,
dried with MgSO4, and concentrated in vacuo. The residue was
dissolved in DCM (0.25 mL), followed by adding mCPBA (14 mg,
0.07 mmol, 70% wet, 2.5 equiv) at 0 °C. The solution was allowed to
stir for 30 min and then quenched with water. The solution was
extracted with DCM, and the combined organic solutions were washed
with saturated aqueous Na2S2O3, brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: 50% hexanes, 50% ethyl acetate) to
afford compound (−)-27 (16.2 mg, 0.028 mmol, 94% for two steps).
Yellow solid: mp 160−162 °C; 1H NMR (600 MHz; CDCl3) δ 8.35 (d,
J = 8.8 Hz, 2H), 8.10 (d, J = 8.9 Hz, 2H), 7.93 (dd, J = 8.2, 1.0 Hz, 2H),
7.70 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 2H), 6.47 (s, 1H), 6.15 (s,
1H), 4.87 (qd, J = 6.6, 3.3 Hz, 1H), 3.83 (ddd, J = 11.5, 3.2, 1.6 Hz,
1H), 3.71 (s, 3H), 3.12−3.08 (m, 1H), 3.07−2.98 (m, 2H), 2.38−2.32
(m, J = 6.4, 3.6 Hz, 1H), 2.11−2.06 (m, 1H), 2.08 (s, 3H), 1.96 (ddd,
J = 13.1, 6.0, 1.5 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H), 1.39 (q, J = 12.4
Hz, 1H); 13C NMR (150 MHz; CDCl3) δ 152.5, 150.6, 147.3,
142.7, 139.0, 133.9, 129.43, 129.29, 128.0, 127.1, 124.2, 119.9,
118.8, 107.7, 81.6, 76.3, 55.9, 52.5, 32.3, 27.5, 26.3, 16.9, 15.7;
HRMS (EI) m/z calculated for C27H29NO9NaS2 [M + Na]+
598.1181, found 598.1160; IR (neat) cm−1 3105, 2925, 1735,
1532, 1350, 1147, 1186, 1087; Rf = 0.5 (50% hexanes, 50% ethyl
50% ethyl acetate); [α]23 +33.1 (c = 0.10, CHCl3).
D
(3R,5S,9aR)-2,2,8-Trimethyl-5-vinyl-4,5-dihydro-2H-3,9a-
epoxybenzo[b]oxepin-7(3H)-one (31). To a solution of com-
pound (+)-29 (10 mg, 0.038 mmol, 1 equiv) in MeCN/H2O (3/1)
(1 mL, 0.04 M), CAN (103.2 mg, 0.11 M in H2O, 0.19 mmol, 5 equiv)
was added at 0 °C. The reaction was stirred at this temperature for
30 min and then quenched with water. The solution was extracted
with EtOAc, and the combined organic solutions were washed with
brine, dried with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, eluent: 83% hexanes, 17%
ethyl acetate) to afford compound (+)-31 (4 mg, 0.015 mmol, 40%)
together with two minor products: compound (+)-30 (2.1 mg,
0.008 mmol, 21%) and compound (−)-33 (2.4 mg, 0.009 mmol,
1
24%). Colorless liquid: H NMR (600 MHz; CDCl3) δ 6.40 (q,
acetate); [α]22 −33.8 (c = 0.26, CHCl3).
J = 1.5 Hz, 1H), 5.85 (d, J = 2.4 Hz, 1H), 5.65 (ddd, J = 17.4, 10.2,
8.4 Hz, 1H), 5.25 (dd, J = 10.2, 1.2 Hz, 1H), 5.18 (d, J = 17.4 Hz,
1H), 4.19 (d, J = 4.2 Hz, 1H), 3.55 (dtd, J = 10.8, 8.0, 2.5 Hz, 1H),
2.08 (ddd, J = 14.2, 7.5, 1.2 Hz, 1H), 1.94−1.91 (m, 1H), 1.90 (d,
J = 1.5 Hz, 3H), 1.52 (s, 3H), 1.42 (s, 3H); 13C NMR (150 MHz;
CDCl3) δ 186.4, 156.9, 138.7, 138.5, 137.0, 121.4, 119.0, 98.0, 82.7,
80.8, 39.6, 32.9, 29.1, 21.9, 15.5; HRMS (EI) m/z calculated for
C15H18O3 246.1256, found 246.1262; IR (neat) cm−1 2925, 1684,
1647, 1292, 1148, 1070, 1053, 971; Rf = 0.75 (50% hexanes, 50%
D
2-((2R,4S)-6-Methoxy-7-methyl-4-vinylchroman-2-yl)-
propan-2-ol (29).3c IBX (143 mg, 0.503 mmol, 6 equiv) was added
to a solution of compound (−)-26 (30 mg, 0.083 mmol, 1 equiv) in
DMF (5 mL, 0.017 M) at room temperature. The reaction was stirred
for 7 h at 80 °C before being cooled down to room temperature and
then quenched with water. The solution was extracted with EtOAc,
and the combined organic solutions were washed with water, brine,
dried with MgSO4, and concentrated in vacuo. The residue was
dissolved in THF (5 mL) and added MeMgBr (0.18 mL, 0.09 mmol,
ethyl acetate); [α]24 +53.2 (c = 0.10, CHCl3).
D
385
dx.doi.org/10.1021/jo201971g | J. Org. Chem. 2012, 77, 379−387

The Journal of Organic Chemistry
Article
(2R,5S)-7-Methoxy-3,3,8-trimethyl-5-vinyl-3,5-dihydro-2H-
2,5-methanobenzo[e][1,4]dioxepine (32). To a solution of
compound (+)-29 (10 mg, 0.038 mmol, 1 equiv) in MeCN/H2O
(3/1) (1 mL, 0.04 M), CAN (35.4 mg, 0.11 M in H2O, 0.065 mmol,
1.7 equiv) was added at 0 °C. The reaction was stirred at this
temperature for 30 min and then quenched with water. The solution
was extracted with EtOAc, and the combined organic solutions were
washed with brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (SiO2, eluent: 90%
hexanes, 10% ethyl acetate) to afford compound (−)-32 (8.0 mg,
238.1205, found 238.1214; IR (neat) cm−1 3405, 2967, 2927, 1653,
1377, 1260, 1072, 912; Rf = 0.36 (50% hexanes, 50% ethyl acetate);
[α]23 +12.6 (c = 0.10, CHCl3).
D
ent-Heliespirone A and C. To a solution of compound 30
(26 mg, 0.098 mmol, 1 equiv) in DCM (1.5 mL, 0.065 M), Cs2CO3
(20 mg, 0.061 mmol, 0.63 equiv) was added at room temperature. The
reaction was warmed to 50 °C and stirred for 8 h before cooled down
to room temperature and quenched with water. The solution was
extracted with DCM, and the combined organic solutions were washed
with brine, dried with MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, eluent: 80% hexanes,
20% ethyl acetate) to afford ent-heliespirone A (35) (11.7 mg, 0.044 mmol,
45%) and ent-heliespirone C (36) (9.8 mg, 0.037 mmol, 38%).
1
0.031 mmol, 81%). Colorless liquid: H NMR (600 MHz; CDCl3) δ
6.60 (s, 1H), 6.57 (s, 1H), 6.29 (dd, J = 17.4, 10.8 Hz, 1H), 5.61 (dd,
J = 17.4, 1.8 Hz, 1H), 5.40 (dd, J = 10.8, 1.8 Hz, 1H), 4.47 (d, J =
2.4 Hz, 1H), 3.74 (s, 3H), 2.43 (d, J = 12.0 Hz, 1H), 2.29 (dd, J = 12.0,
3.2 Hz, 1H), 2.16 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H); 13C NMR
(150 MHz; CDCl3) δ 151.1, 146.3, 136.8, 128.1, 127.0, 117.4, 115.9,
107.3, 86.4, 82.5, 80.5, 55.9, 37.6, 28.3, 24.0, 16.0; HRMS (EI) m/z
calculated for C16H20O3Na [M + Na]+ 283.1310, found 283.1298; IR
(neat) cm−1 2962, 2927, 2855, 1690, 1496, 1405, 1260, 1105; Rf = 0.7
1
ent-Heliespirone A (35). Colorless liquid: H NMR (600 MHz,
CDCl3) δ 6.63 (q, J = 1.4 Hz, 1H), 5.31 (ddd, J = 16.8, 9.6, 9.6 Hz,
1H), 5.08 (d, J = 16.8 Hz, 1H), 4.98 (d, J = 10.2 Hz, 1H), 4.05 (dd, J =
10.8, 5.4 Hz, 1H), 3.25 (d, J = 15.6 Hz, 1H), 2.98 (d, J = 15.6 Hz, 1H),
2.93 (ddd, J = 12.6, 9.6, 6.6 Hz, 1H), 2.15 (ddd, J = 12.6, 12.6,
10.8 Hz, 1H), 1.97 (d, J = 1.4 Hz, 3H), 1.99−1.95 (m, 1H), 1.34 (s, 3H),
1.11 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 201.3, 195.5, 153.6, 137.1,
135.4, 118.5, 87.6, 86.8, 70.2, 57.1, 51.9, 31.9, 28.4, 25.3, 16.0; HRMS (FI)
m/z calculated for C15H20O4 264.1362, found 264.1356; IR (neat) cm−1
3447, 2973, 2924, 1678, 1622, 1242, 1061, 1005; Rf = 0.7 (50% hexanes,
50% ethyl acetate); [α]24 +23.2 (c = 0.09, CHCl3) {lit.2 [α]14.5 +17.6
(83% hexanes, 17% ethyl acetate); [α]22 −116.1 (c = 0.05, CHCl3).
D
2-((2S,4R)-4-Hydroxy-5,5-dimethyl-2-vinyltetrahydrofuran-
2-yl)-5-methylcyclohexa-2,5-diene-1,4-dione (33). To a solu-
tion of compound (−)-32 (10 mg, 0.038 mmol, 1 equiv) in MeCN/
H2O (3/1) (1 mL, 0.04 M), CAN (51.6 mg, 0.11 M in H2O,
0.095 mmol, 2.5 equiv) was added at 0 °C. The reaction was stirred at
this temperature for 30 min and then quenched with water. The
solution was extracted with EtOAc, and the combined organic solutions
were washed with brine, dried with MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography (SiO2, eluent: 75%
hexanes, 25% ethyl acetate) to afford compound (−)-33 (8.9 mg, 0.034
mmol, 90%). Colorless liquid: 1H NMR (600 MHz; CDCl3) δ 7.02 (s,
1H), 6.53 (s, 1H), 6.13 (ddd, J = 17.4, 10.2, 0.6 Hz, 1H), 5.36 (d, J =
17.4 Hz, 1H), 5.04 (d, J = 10.2 Hz, 1H), 4.03 (t, J = 5.4 Hz, 1H), 2.71
(dd, J = 13.6, 6.0 Hz, 1H), 2.25 (dd, J = 13.6, 6.0 Hz, 1H), 2.03 (s, 3H),
1.63 (s, 1H), 1.32 (s, 3H), 1.25 (s, 3H); 13C NMR (150 MHz; CDCl3)
δ 188.9, 187.5, 152.5, 145.4, 141.7, 134.1, 130.4, 113.8, 83.5, 81.2, 77.4,
44.7, 27.4, 22.4, 15.4; HRMS (EI) m/z calculated for C15H18O4
262.1205, found 262.1195; IR (neat) cm−1 3439, 2925, 1652, 1340,
1245, 1095, 1000, 921; Rf = 0.55 (50% hexanes, 50% ethyl acetate);
D
D
(c = 0.09, CHCl3); lit.1a [α]25 −29.0 (c = 0.10, CHCl3)}.
D
1
ent-Heliespirone C (36). Colorless liquid: H NMR (600 MHz,
CDCl3) δ 6.69 (q, J = 1.4 Hz, 1H), 5.63 (ddd, J = 16.8, 10.2, 8.4 Hz,
1H), 5.13 (d, J = 9.6 Hz, 1H), 5.12 (d, J = 18.0 Hz, 1H), 3.96 (dd, J =
10.8, 5.4 Hz, 1H), 3.30 (dt, J = 11.4, 7.8 Hz, 1H), 2.96 (d, J = 16.2 Hz,
1H), 2.85 (d, J = 16.2 Hz, 1H), 2.06 (ddd, J = 12.2, 6.9, 5.3 Hz, 1H),
2.00 (d, J = 1.4 Hz, 3H), 1.98−1.91 (m, 1H), 1.25 (s, 3H), 1.14 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 196.7, 196.3, 151.9, 137.1,
134.6, 119.9, 86.9, 86.7, 70.3, 48.8, 47.1, 32.4, 27.7, 24.5, 16.2; HRMS
(FI) m/z calculated for C15H20O4 264.1362, found 264.1353; IR (neat)
cm−1 3460, 2970, 1738, 1687, 1440, 1365, 1228, 1114; Rf = 0.6 (50%
hexanes, 50% ethyl acetate); [α]23D −24.9 (c = 0.10, CHCl3) {lit.2 [α]14.5
D
−31.8 (c = 0.11, CHCl3); lit.1b [α]25 +14.4 (c = 0.10, CHCl3)}.
D
ASSOCIATED CONTENT
■
[α]24 −52.3 (c = 0.10, CHCl3).
D
S
* Supporting Information
(2R,3S,5R)-7-Methoxy-3,5,8-trimethyl-3,5-dihydro-2H-2,5
methanobenzo[e][1,4]dioxepine (34). To a solution of chroman
(−)-20 (10 mg, 0.04 mmol, 1 equiv) in MeCN/H2O (3:1) (1 mL,
0.04 M), CAN (39.4 mg, 0.07 mmol, 0.11 M in H2O, 1.7 equiv) was
added at 60 °C. The reaction was stirred at this temperature for
10 min, cooled down to room temperature, and quenched with water.
The solution was extracted with EtOAc, and the combined organic
solutions were washed with brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluent: first 90% hexanes, 10% ethyl acetate
and then 67% hexanes, 33% ethyl acetate) to afford compound (−)-34
(5.9 mg, 0.025 mmol, 60%) and the corresponding p-quinone (2.2 mg,
Comparison of 1H and 13C NMR data of synthetic and natural
heliespirone A and C; crystallographic details of 27; and copies
of 1H NMR, 13C NMR, and DEPTNOE spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pettus@chem.ucsb.edu.
1
0.009 mmol, 22%). Colorless liquid: H NMR (600 MHz; CDCl3)
ACKNOWLEDGMENTS
δ 6.71 (s, 1H), 6.60 (s, 1H), 4.51 (d, J = 3.0 Hz, 1H), 4.37 (q, J =
6.6 Hz, 1H), 3.79 (s, 3H), 2.25 (d, J = 12.0 Hz, 1H), 2.16 (s, 3H), 1.96
(dd, J = 12.0, 3.6 Hz, 1H), 1.76 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHz; CDCl3) δ 151.5, 145.8, 128.3, 125.7, 118.2, 106.0,
82.3, 81.5, 77.9, 56.0, 37.2, 20.7, 20.0, 16.0; HRMS (EI) m/z calculated
for C14H18O3 234.1256, found 234.1251; IR (neat) cm−1 2975, 2928,
1496, 1467, 1408, 1277, 1192, 1108; Rf = 0.72 (83% hexanes, 17%
■
TRRP is very grateful for NSF’s prior funding of the group's
o-QM research CHE-0806356.
DEDICATION
■
This paper is dedicated by Wen-Ju Bai to Professor Qi-Lin Zhou
(Nankai University, P. R. China) for his contribution to develop-
ment of privileged chiral spiro ligands and subsequent
applications toward transition metal-catalyzed reactions.
ethyl acetate); [α]22 −110.0 (c = 0.10, CHCl3). The corresponding
D
p-quinone product: 2-((2R,4R,5S)-4,5-dihydroxyhexan-2-yl)-5-methyl-
1
cyclohexa-2,5-diene-1,4-dione. Colorless liquid: H NMR (600 MHz;
CDCl3) δ 6.60 (q, J = 1.2 Hz, 1H), 6.54 (d, J = 1.2 Hz, 1H), 3.78 (qd,
J = 6.3, 3.5 Hz, 1H), 3.68 (d, J = 10.2 Hz, 1H), 3.15−3.09 (m, 1H),
2.37 (s, 1H), 2.04 (d, J = 1.2 Hz, 3H), 1.76 (s, 1H), 1.58 (ddd, J =
13.8, 10.2, 4.8 Hz, 1H), 1.48 (ddd, J = 13.8, 8.4, 2.4 Hz, 1H), 1.18 (d,
J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 2H); 13C NMR (150 MHz;
CDCl3) δ 188.4, 187.6, 154.0, 145.4, 133.8, 131.0, 73.0, 70.6, 38.0,
28.7, 18.6, 17.1, 15.4; HRMS (EI) m/z calculated for C13H18O4
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