NIS-PPh3: A selective reagent for the spiroannulation of o-allyl phenols. total synthesis of corallidictyal D

Article abstract of DOI:10.1021/jo4014047

Treatment of o-allyl phenols with catalytic NIS-PPh₃ affords the corresponding spirodihydrobenzofuran derivatives in high yield with high regio- and total stereoselectivity under mild conditions. These results were utilized to achieve the first

Full text of DOI:10.1021/jo4014047

Article
pubs.acs.org/joc
NIS−PPh3: A Selective Reagent for the Spiroannulation of o‑Allyl
Phenols. Total Synthesis of Corallidictyal D
M. Jose Cano,† Hanane Bouanou,† Ruben Tapia,† Esteban Alvarez,† Ramon Alvarez-Manzaneda,‡
́
́
́
Rachid Chahboun,*,† and Enrique Alvarez-Manzaneda*,†
†Departamento de Química Organ
́
ica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
‡
́
Area de Química Organ
́
ica, Departamento de Química y Física, Universidad de Almería, 04120 Almería, Spain
S
* Supporting Information
ABSTRACT: Treatment of o-allyl phenols with catalytic
NIS−PPh3 affords the corresponding spirodihydrobenzofuran
derivatives in high yield with high regio- and total stereo-
selectivity under mild conditions. These results were utilized to
achieve the first total synthesis of the protein kinase C
inhibitor corallidictyal D starting from α-ionone.
Intramolecular hydroalkoxylations of alkenylphenols similar
to compounds 25 and 26, catalyzed by Lewis acids9,10 and by
Bronsted acids,10 have been reported previously. In all cases,
the corresponding benzopyran derivatives were obtained as a
mixture of C8 epimers, with the C8β-Me isomer being the
major constituent (see Table 1, entry 110). As indicated above,
Corey and Das2b and McMurry and Erion2c reported having
obtained the corresponding spirodihydrobenzofurans when the
cyclization was accomplished with hydrochloric acid and
cationic resin, respectively. However, when drimenyl phenol
26 was subjected to these reaction conditions in our laboratory,
benzopyran derivatives 30 and 3210 were obtained again (Table
1, entries 2 and 3). At this point it is important to emphasize
that decalinic structures of this type are prone to undergo
rearrangement under some acidic conditions.11
Recently, while continuing our studies on the use of PPh3
and iodine derivatives,12 we found that some alkenyl phenols,
after treatment with NIS and PPh3, undergo cyclization to
provide the corresponding spirodihydrobenzofuran derivatives.
Table 1 shows the results of reactions of several o-(β-
cyclogeranyl) phenols (16−18) (entries 4−6) and o-drimenyl
phenols (25 and 26) (entries 7−9) with catalytic NIS−PPh3 in
dichloromethane at room temperature. As can be seen, in the
worst case a 3.5:1 mixture of spirodihydrobenzofuran and
benzopyran derivative was obtained. The relative stereo-
chemistry of cyclized products was established on the basis of
NOE experiments. The NOESY spectra of spiro compounds
19−21, 27, and 28 show correlations between each benzylic
proton and its nearest methyl groups (Figure 2). Interestingly,
the proportion of spirane derivative increased considerably
when a greater amount of unsaturated phenol was utilized;
thus, phenol 26 (approx. 1 g) (entry 9) was transformed into
compound 28 almost entirely.
INTRODUCTION
■
During the last few decades, a variety of spirodihydrobenzo-
furan derivatives and related compounds, characterized by their
wide-ranging, potent biological activities, have been isolated
from different natural sources. Representative examples (Figure
1) are corallidictyal B (1) and D (2), two spirosesquiterpene
aldehydes isolated from the marine sponge Aka coralliphaga,
with protein kinase C inhibitory activity;1 the complement
inhibitor K-76 (4);2 the antiviral stachybotrydial (5);3 and the
myoinositol monophosphatase (IMPase) inhibitor L-671,776
(6).4 Various spirodihydrobenzofuran lactams have been
isolated from the cultures of different Stachybotrys species,
such as compounds 7−11, with pancreatic cholesterol esterase
inhibitor activity,5 and lactams 12−15, antagonists of
endothelin and inhibitors of HIV-1 protease.6 More recently,
liphagal (3), a metabolite with selective PI3K kinase inhibitory
activity that is structurally related to compounds 1 and 2, has
also been reported.7
Despite the significant biological activities and the interesting
sterically constrained spiro structure of the above-mentioned
compounds, only a few syntheses for some of these compounds
have been reported. In all cases, the key step is the
spiroannulation of the suitable drimane (bicyclic sesquiterpene)
phenol. Corey and Das2b synthesized K-76 (4) after cyclization
utilizing a THF/ethylene glycol/2 N hydrochloric acid mixture.
Three years latter, McMurry and Erion2c described a synthesis
of compound 4 utilizing cationic resin as the cyclizing agent.
More recently, Kende et al.8 reported the synthesis of
stachybotrylactam (12), also utilizing cationic resin. In all
cases, a mixture of spirodihydrobenzofuran and benzopyran in a
1.7−3.5:1.0 ratio was obtained.
RESULTS AND DISCUSSION
■
The interest of the metabolites mentioned above encouraged us
to investigate alternative methods to achieve the spiroannula-
tion process.
Received: July 5, 2013
Published: August 28, 2013
© 2013 American Chemical Society
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Figure 1. Bioactive spirodihydrobenzofurans and related metabolites.
Table 1. Cyclization of Some o-Allyl Phenols under Acidic Conditions or after Reaction with NIS−PPh3
entry
o-allyl phenol
reaction conditions
products
a
1
2
26
26
26
16
17
18
25
26
26
26
26
26
26
acid
30 (minor) + 32 (major) (76−93%)
30 + 32 (1:5) (93%)
32 (92%)
b
HCl(conc), ethylene glycol/THF, 60 °C, 1 h
Amberlyst A-15, DCM, reflux, 60 h
c
3
d
4
NIS, PPh3, DCM, rt, 15 h
19 + 22 (4:1) (87%)
20 + 23 (4:1) (89%)
21 + 24 (3.5:1) (86%)
27 + 2913 (5:1) (85%)
28 + 30 (6:1) (90%)
28 + 30 (10:1) (90%)
32 (89%)
d
5
NIS, PPh3, DCM, rt, 12 h
d
6
NIS, PPh3, DCM, rt, 14 h
d
7
NIS, PPh3, DCM, rt, 12 h
d
8
NIS, PPh3, DCM, rt, 10 h
e
9
NIS, PPh3, DCM, rt, 14 h
10
11
12
13
I2, DCM, rt, 15 min
d
NIS, PPh3, DCM/H2O, rt, 30 h
no reaction
HI/H2O, DCM, rt, 10 min
anhydrous HI, DCM, rt, 5 min14
28 + 30 + 32 (1:3:10) (83%)
28 + 30 + 32 (1:3:5) (91%)
a
b
BF3·OEt2, TsOH, H2SO4(conc), and β-naphthalenesulfonic acid were utilized (see ref 10). Corey’s method.2b No reaction occurred at room
temperature. McMurry’s method.2c NIS (0.1 equiv) and PPh3 (0.1 equiv) were utilized. 1 g of compound 26 was cyclized.
c
d
e
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These results are consistent with those of previously reported
acidic cyclizations. These cyclizations take place through an
intermediate carbocation and can be summarized as follows:
the most favorable carbocation on C8 leads to the mixture of
benzopyran epimers, whereas the carbocation on C9 can
provide the spirane derivative together with other side reaction
products (rearrangement, etc.).
Figure 2. Observed NOEs for spiro compounds.
The behavior of acyclic o-allyl phenols was also investigated.
o-Allylphenol and 2-allyl-6-methylphenol remained unaltered
after treatment with NIS−PPh3 at room temperature for 12 h.
After longer reaction times, partial isomerization of the
carbon−carbon double bond was observed, but no cyclization
reaction took place.
The use of other phosphines was also investigated. When
tributylphosphine was utilized instead of triphenylphosphine,
the cyclization proceeded in a similar way but resulted in a
lower proportion of spiro compound. Therefore, compound 26
was transformed into a 4:1 mixture of compounds 28 and 30
(89%), after treatment with NIS−PBu3 at room temperature
for 16 h. This result shows the influence of the bulky phenyl
substituents of PPh3 in the regiochemistry of the cyclization
process.
A first fact to be considered in accounting for the results
obtained with the NIS−PPh3 system is the complete anti
stereoselectivity of the addition process, which is unprece-
dented in this type of reaction. Under the conditions previously
described in the literature, the hydroalkoxylation process is not
stereoselective, and the products obtained result from syn and
anti addition.
In order to rule out the participation of hydroiodic acid in the
NIS−PPh3-mediated process, other cyclization reactions were
investigated. The most representative essays were those
involving drimenyl phenols, shown in Table 1 (entries 10−
12). Thus, the treatment of phenol 26 with I2 in DCM gave
benzopyran 32 almost exclusively (entry 10). No reaction was
observed when o-allyl phenol 26 was treated with NIS−PPh3 in
DCM saturated with H2O (entry 11). The same results were
obtained after prolonged reaction times and when 1 equiv of
NIS and PPh3 were utilized. When the cyclization was
performed in the presence of aqueous HI in DCM, the
benzopyran derivative was again the main product (entry 12).
Similar behavior was observed when the reaction was carried
out utilizing anhydrous HI, which was prepared following the
procedure reported by Koreeda and co-workers.14 Treatment of
compound 26 with this reagent in dichloromethane at room
temperature for 5 min gave a 1:3:5 mixture of compounds 28,
30, and 32 (91%). The same result was obtained when the O-
tert-butyldimethylsilyl derivative of phenol 26 was reacted
under these conditions. However, when this compound was
treated with NIS−PPh3, the starting material was recovered
after 24 h of reaction time.
Scheme 1. Possible Mechanism for the NIS−PPh3-Mediated Cyclization of o-Allyl Phenols
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Scheme 2. Synthesis of o-Allyl Phenol 26 from α-Ionone (33)
When the NIS−PPh3 system is utilized, an anti concerted
process, precluding the formation of an intermediate
carbocation, must take place. A possible mechanism consistent
with the experimental results is postulated in Scheme 1. The
phenolic hydroxyl group acts as a nucleophile and a proton
donor simultaneously. The OH group, activated by the
successfully. It should be noted that all of the previously
reported processes utilized to attain the trans-decalone skeleton
from α-ionone (33) were not stereoselective. Instead, they
afforded a mixture of the desired A/B trans-fused β-keto ester
and its cis-fused stereoisomer, among other compounds.19
Treatment of compound 36 with red-Al at 0 °C gave
hydroxyketone 37.20 This ketone was directly arylated by
reaction with benzyl ether 38,21 easily prepared from
commercial sesamol, in the presence of cationic resin Amberlyst
A-15, affording ketone 39. Methenylation of the latter,
isomerization of the new carbon−carbon double bond, and
hydrogenation finally resulted in the desired phenol 26.
Eventually, the synthesis of corallidictyal D (2) from phenol
26 via spirodihydrobenzofuran compound 28 was tackled
(Scheme 3). Treatment of 28 with BuLi in THF at −78 °C
followed by the addition of DMF and further reaction for 2 h
gave aldehyde 42 (72% after column chromatography).
Imakura’s method,22 which we successfully utilized for the
cleavage of the methylenedioxy group in our synthesis of
liphagal (3),7c failed with aldehyde 42. Instead, this cleavage
was achieved using Goodman’s method.23 Treatment of
aldehyde 42 with AlCl3 in dichloromethane at −40 °C for 10
min and subsequent refluxing of a methanolic solution of the
crude product in the presence of catalytic concentrated HCl led
to corallidictyal D (2). Alternatively, an enantiospecific
synthesis of compound 2 was accomplished utilizing
enantiomerically pure drimenyl phenol 26 synthesized starting
from the commercial diterpene (−)-sclareol.10 The optical
rotation of synthetic corallidictyal D (2) {[α]2D5 = −21.8 (c 14.8,
CHCl3)} did not allow us to confirm the absolute stereo-
chemistry of natural compound 2, as this was isolated from its
natural source as a mixture of C9 epimers.1
+
phosphonium ion PPh3I, transfers the proton by the β face
of the olefinic bond of the adjacent molecule. The latter
undergoes simultaneous intramolecular nucleophilic O-attack at
C9, affording intermediate I, the precursor of the spirane
compound (Scheme 1a). Alternatively, when the proton is
transferred by the α face of the olefinic bond, the O-
nucleophilic attack takes place C8, providing intermediate II,
the precursor of the benzopyran derivative (Scheme 1b). The
preference for the β-face attack could be attributed to the steric
hindrance that the phenolic moiety exerts on the α-face in the
most favored conformation.
Similar behavior was previously found in the base-mediated
cyclization of the 8,9-epoxy derivatives of alkenyl phenols
similar to compound 25: the 8β,9β-epoxy derivative undergoes
nucleophilic attack at C9 to provide the corresponding spiro
compound, whereas the 8α,9α-epoxy derivative undergoes C8
attack, affording the benzopyran derivative.10
Spirodihydrobenzofuran compound 28, obtained from o-allyl
phenol 26, is a suitable precursor of corallidictyal D (2). An
efficient synthesis of drimenyl phenol 26 starting from
commercial α-ionone (33), which is also accessible in
enantiomerically pure form,15 has been developed (Scheme
2). Selective 1,4-reduction of dienone 33 was achieved by
treatment with Raney Ni.16 Enol phosphate 35 was obtained in
a one-pot reaction after treatment of methyl ketone 3417 with
an excess of NaH and with dimethyl carbonate and ClPO-
(OEt)2 successively. Compound 35 was transformed with
complete regio- and stereoselectivity into bicyclic enol
phosphate 3618 after treatment with SnCl4 in dichloromethane
at 0 °C. This transformation achieved the trans compound
In summary, a very efficient procedure to achieve the
spiroannulation of o-allyl phenols has been reported. Treatment
of these with catalytic NIS and PPh3 affords the corresponding
spirodihydrobenzofuran derivatives in high yield with high
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time, until TLC showed that no phenol remained. The solvent was
removed under vacuum, and the crude product was directly purified by
flash chromatography on silica gel (ether/hexanes mixture) to give the
desired spirobenzofuran derivative.
Scheme 3. Synthesis of Corallidictyal D (2)
2-((2,6,6-Trimethylcyclohex-1-enyl)methyl)phenol (16). Uti-
lizing β-cyclocitral (0.5 g, 3.22 mmol) and following the general
procedure described for the preparation of monoterpenic phenols
1
afforded 16 (481 mg, 65% global yield) as a brown syrup. H NMR
(CDCl3, 500 MHz) δ: 7.04 (dd, J = 8.0, 7.4 Hz, 1H), 7.03 (d, J = 7.4
Hz, 1H), 6.82 (dd, J = 7.4, 7.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.49
(s, 1H), 3.41 (s, 2H), 2.07 (t, J = 6.3 Hz, 2H), 1.75−1.61 (m, 2H),
1.56 (s, 3H), 1.53−1.46 (m, 2H), 0.94 (s, 6H). 13C NMR (CDCl3, 125
MHz) δ: 154.3 (C), 134.1 (C), 130.9 (C), 129.1 (CH), 126.8 (C),
126.6 (CH), 120.1 (CH), 115.2 (CH), 39.8 (CH2), 35.1 (C), 32.8
(CH2), 28.5 (CH2), 28.4 (2 × CH3), 27.0 (CH), 20.5 (CH3), 19.4
(CH2). IR (film): 3470, 3434, 1589, 1499, 1454, 1336, 1273, 1206,
1087, 1040, 843, 756 cm−1. HRMS (FAB) m/z: calcd for C16H22ONa
(M + Na+) 253.1568, found 253.1570.
4-Methyl-2-((2,6,6-trimethylcyclohex-1-enyl)methyl)phenol
(17). Utilizing β-cyclocitral (0.72 g, 4.73 mmol) and following the
general procedure described for the preparation of monoterpenic
phenols afforded 17 (623 mg, 54% global yield) as a brown syrup. 1H
NMR (CDCl3, 500 MHz) δ: 6.86 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H),
6.65 (d, J = 8.0 Hz, 1H), 5.17 (s, 1H), 3.40 (s, 2H), 2.25 (s, 3H), 2.08
(t, J = 6.3 Hz, 2H), 1.76−1.64 (m, 2H), 1.60 (s, 3H), 1.54−1.45 (m,
2H), 0.96 (s, 6H). 13C NMR (CDCl3, 125 MHz) δ: 151.9 (C), 134.4
(C), 131.2 (C), 129.8 (CH), 129.4 (C), 127.0 (CH), 126.2 (C), 115.0
(CH), 39.9 (CH2), 35.1 (C), 32.8 (CH2), 29.0 (CH2), 28.4 (2 CH3),
20.7 (CH3), 20.5 (CH3), 19.3 (CH2). IR (film): 3410, 1705, 1611,
1505, 1469, 1361, 1259, 1204, 1092, 1041, 929, 807, 759 cm−1. HRMS
(FAB) m/z: calcd for C17H24ONa (M + Na+) 267.1725, found
267.1712.
regioselectivity and complete stereoselectivity. This spiroannu-
lation process seems to be the most suitable procedure reported
to date for achieving a wide variety of spirodihydrobenzofuran
derivatives such as compounds 1, 2, and 4−15, which exhibit
important biological activities. With this new cyclization
procedure, the first total synthesis of the protein kinase C
inhibitor corallidictyal D (2) has been reported. Remarkable
key steps of the synthetic sequence are the Lewis acid-catalyzed
cyclization of the β-keto ester enol phosphate 35, the
chemoselective reduction of enol phosphate 36 to give
hydroxyketone 37, and the direct arylation of the latter leading
to ketone 39.
6-((2,6,6-Trimethylcyclohex-1-enyl)methyl)benzo[d][1,3]-
dioxol-5-ol (18). Utilizing β-cyclocitral (0.39 g, 2.56 mmol) and
following the general procedure described for the preparation of
monoterpenic phenols afforded 18 (428 mg, 61% global yield) as
1
brown syrup. H NMR (CDCl3, 500 MHz) δ: 6.55 (s, 1H), 6.38 (s,
1H), 5.86 (s, 2H), 5.11 (s, 1H), 3.30 (s, 2H), 2.05 (t, J = 6.3 Hz, 2H),
1.75−1.58 (m, 2H), 1.56 (s, 3H), 1.52−1.46 (m, 2H), 0.94 (s, 6H).
13C NMR (CDCl3, 125 MHz) δ: 148.2 (C), 145.5 (C), 141.2 (C),
134.1 (C), 131.2 (C), 118.6 (C), 108.5 (CH), 100.7 (CH2), 98.0
(CH), 39.8 (CH2), 35.0 (C), 32.8 (CH2), 28.4 (CH3), 28.4 (CH3),
28.3 (CH2), 20.4 (CH3), 19.3 (CH2). IR (film): 3446, 1631, 1504,
1477, 1439, 1361, 1295, 1222, 1164, 1040, 937, 860, 761 cm−1. HRMS
(FAB) m/z: calcd for C17H22O3Na (M + Na+) 297.1467, found
297.1471
Cyclization of Phenols with the NIS−PPh3 system. Following
the general cyclization procedure with the NIS−PPh3 system,
monoterpenic phenols 16−18 and sesquiterpenic phenols 25 and 26
were cyclized.
Cyclization of 16 (115 mg, 0.5 mmol) yielded a mixture of isomers
19 and 22 (100 mg) in a 4:1 ratio and 87% yield after 15 h.
Monoterpenic phenol 17 (122 mg, 0.5 mmol) was cyclized in the
same manner, furnishing the corresponding isomeric mixture of 20
and 23 (109 mg) in a 4:1 ratio and 89% yield in 12 h.
Treatment of 18 (135 mg, 0.5 mmol) following the same procedure
provided the corresponding isomeric mixture of 21 and 24 (118 mg)
in a 3.5:1 ratio and 86% yield after 14 h.
Sesquiterpenic phenol 25 (150 mg, 0.28 mmol) was also cyclized in
the same manner, giving access to the corresponding isomeric mixture
of 27 and 29, 31 (121 mg) in a 5:1 ratio and 85% yield in 12 h.
Cyclization of 26 (110 mg, 0.32 mmol) yielded a mixture of isomers
28 and 30, 32 (136 mg) in a 6:1 ratio and 90% yield after 10 h, and up
to a 10:1 ratio and 90% yield were achieved in 14 h when the reaction
was performed on a gram scale.
In each case, after careful separation in silica gel (100% hexanes),
both isomers were isolated and characterized.
4,4,6-Trimethylspiro[benzofuran-5(8H),5(6H)-cyclohexane]
(19). Colorless syrup. 1H NMR (CDCl3, 500 MHz) δ: 7.08 (br d, J =
7.4 Hz, 1H), 7.06 (t, J = 8.3 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.72 (d,
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Monoterpenic
Phenols 16−18. A 1.7 M solution of tert-butyllithium (1.2 mmol)
was added at −78 °C to a solution of the aryl bromide (1.2 mmol) in
Et2O under an argon atmosphere. After the mixture was stirred for 25
min, β-cyclocitral (1 mmol) was added, and the reaction mixture was
further stirred for 40 min at −78 °C, at which time TLC showed that
no starting material remained. Water (10 mL) was then added to
quench the reaction, and the mixture was extracted with ether. The
combined organic phases were dried, filtered, and concentrated to give
a crude product that was used in the next step without purification.
To a solution of the above crude product in CH2Cl2 (10 mL) were
added successively NaBH3CN (5 mmol) and ZnI2 (2 mmol) at 0 °C,
and the mixture was allowed to warm to room temperature and stirred
for 5 h, at which time TLC showed that no starting material remained.
The mixture was then filtered through a silica gel column and washed
with ether (15 mL). The combined filtrate was evaporated to give a
crude product that was used in the next step without purification. This
was dissolved in THF (10 mL), and tetrabutylammonium fluoride (1.5
mmol) was added. After the solution was stirred for 15 min at room
temperature, water was added, and the mixture was extracted with
ether. The combined organic phases were dried, and the solvent was
removed under vacuum to give a crude product that was chromato-
graphed on a silica gel column (20% ether/hexanes) to give phenol
16−18.
General Cyclization Procedure with the NIS−PPh3 System.
N-Iodosuccinimide (0.1 mmol) was added to a solution of
triphenylphosphine (0.1 mmol) in dry CH2Cl2 (4 mL), and the
mixture was stirred at room temperature for at least 15 min. A solution
of phenol (1 mmol) in CH2Cl2 (4 mL) was then added at 0 °C, and
the reaction mixture was stirred at room temperature for the specified
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J = 7.9 Hz, 1H), 3.22 (d, J = 16.3 Hz, 1H), 2.88 (d, J = 16.3 Hz, 1H),
1.87−1.72 (m, 2H), 1.64−1.42 (m, 4H), 1.26 (br d, J = 12.6 Hz, 1H),
1.00 (s, 3H), 0.84 (s, 3H), 0.75 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3,
125 MHz) δ: 161.0 (C), 127.7 (CH), 127.4 (C), 124.1 (CH), 119.2
(CH), 108.2 (CH), 94.0 (C), 38.1 (C), 37.1 (CH), 36.3 (CH2), 34.9
(CH2), 30.7 (CH2), 24.8 (CH3), 22.4 (CH3), 21.4 (CH2), 15.6 (CH3).
NOESY (CDCl3, 500 MHz) observed correlations: 3.22 (d, J = 16.3
Hz, 1H) with 1.00 (s, 3H) and 0.84 (s, 3H); 2.88 (d, J = 16.3 Hz, 1H)
with 0.75 (d, J = 6.6 Hz, 3H). IR (film): 1729, 1600, 1484, 1462, 1387,
1325, 1267, 1244, 1134, 1017, 945, 919, 871, 747, 707 cm−1. HRMS
(FAB) m/z: calcd for C16H22ONa (M + Na+) 253.1568, found
253.1572.
3′,4,4,6-Tetramethylspiro[benzofuran-5(8H),5(6H)-cyclohex-
ane] (20). Colorless oil. 1H NMR (CDCl3, 500 MHz) δ: 6.89 (s, 1H),
6.86 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.18 (d, J = 16.3 Hz,
1H), 2.84 (d, J = 16.3 Hz, 1H), 2.26 (s, 3H), 1.85−1.71 (m, 2H),
1.65−1.49 (m, 2H), 1.44 (m, 1H), 1.35−1.19 (m, 2H), 0.99 (s, 3H),
0.84 (s, 3H), 0.75 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 125 MHz)
δ: 161.7 (C), 130.9 (C), 130.7 (CH), 130.0 (C), 127.4 (CH), 110.3
(CH), 96.6 (C), 40.8 (C), 39.8 (CH), 39.0 (CH2), 37.6 (CH2), 33.4
(CH2), 27.4 (CH3), 25.1 (CH3), 24.1 (CH2), 23.4 (CH3), 18.3 (CH3).
NOESY (CDCl3, 500 MHz) observed correlations: 3.18 (d, J = 16.3
Hz, 1H) with 0.99 (s, 3H) and 0.84 (s, 3H); 2.84 (d, J = 16.3 Hz, 1H)
with 0.75 (d, J = 6.6 Hz, 3H). IR (film): 1730, 1615, 1494, 1469, 1386,
1263, 1243, 1224, 1133, 945, 920, 807 cm−1. HRMS (FAB) m/z: calcd
for C17H24ONa (M + Na+) 267.1725, found 267.1723.
(dd, J = 9.7, 3.5 Hz, 2H), 1.17 (s, 3H), 0.94 (s, 3H), 0.64 (s, 3H). 13C
NMR (CDCl3, 125 MHz) δ: 148.9 (C), 146.2 (C), 141.1 (C), 113.3
(C), 107.7 (CH), 100.6 (CH2), 99.0 (CH), 75.2 (C), 44.4 (CH), 41.8
(CH2), 39.6 (CH2), 34.0 (C), 32.4 (CH3), 26.8 (CH3), 23.9 (CH2),
21.4 (CH3), 18.2 (CH2). IR (film): 1876, 1731, 1631, 1503, 1479,
1438, 1387, 1366, 1235, 1180, 1148, 1040, 941, 915, 868, 845, 775
cm−1. HRMS (FAB) m/z: calcd for C17H22O3Na (M + Na+) 297.1467,
found 297.1472.
4,5-Dimethoxy-2-(((4aS,8aS)-2,5,5,8a-tetramethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methyl)phenol
(25). Phenol 25 (652 mg) was obtained from (4aS,5S)-5-(2-
(benzyloxy)-4,5-dimethoxybenzyl)-1,1,4a-trimethyl-6-methylenedeca-
hydronaphthalene (1.2 g, 2.68 mmol) in 68% global yield following the
same procedure described for the preparation of sesquiterpenic phenol
26.10
1
Colorless syrup. [α]D25 = +54.3 (c 14.9, CHCl3). H NMR (CDCl3,
500 MHz) δ: 6.57 (s, 1H), 6.39 (s, 1H), 5.37 (br s, 1H, OH), 3.82 (s,
3H), 3.79 (s, 3H), 3.35 (d, J = 16.5 Hz, 1H), 3.30 (d, J = 16.5 Hz, 1H),
2.20−2.09 (m, 2H), 1.74 (dd, J = 13.0, 6.9 Hz, 1H), 1.62 (s, 3H),
1.58−1.45 (m, 2H), 1.42−1.31 (m, 2H), 1.29−1.16 (m, 2H), 1.13−
1.01 (m, 2H), 1.00 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H). 13C NMR
(CDCl3, 125 MHz) δ: 148.4 (C), 143.0 (C), 138.4 (C), 135.6 (C),
130.7 (C), 117.0 (C), 114.0 (CH), 101.1 (CH), 57.0 (CH3), 56.1
(CH3), 52.2 (CH), 41.9 (CH2), 39.4 (C), 36.7 (CH2), 33.8 (C), 33.6
(CH2), 33.5 (CH3), 28.4 (CH2), 22.0 (CH3), 20.6 (CH3), 20.5 (CH3),
19.2 (CH2), 19.1 (CH2). IR (film): 3462, 1604, 1521, 1451, 1412,
1366, 1201, 1095, 999, 862, 752 cm−1. HRMS (FAB) m/z: calcd for
C23H34O3Na (M + Na+) 381.2406, found 381.2398.
3′,4′-Methylenedioxy-4,4,6-trimethylspiro[benzofuran-5-
1
(8H),5(6H)-cyclohexane] (21). Colorless syrup. H NMR (CDCl3,
[1′(2)R,2′R,4′aR,8′aS]-5,6-Methoxy-3′,4′,4′a,5′,6′,7′,8′,8′a-
500 MHz) δ: 6.55 (s, 1H), 6.31 (s, 1H), 5.85 (s, 1H), 5.84 (s, 1H),
3.12 (d, J = 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 1.86−1.66 (m,
2H), 1.65−1.37 (m, 4H), 1.22 (m, 1H), 0.96 (s, 3H), 0.84 (s, 3H),
0.76 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ: 155.7 (C),
147.1 (C), 140.6 (C), 118 (C), 104.4 (CH), 100.9 (CH2), 95.1 (C),
91.9 (CH), 38.2 (C), 37.3 (CH), 36.3 (CH2), 35.2 (CH2), 30.7
(CH2), 24.8 (CH3), 22.4 (CH3), 21.5 (CH2), 15.7 (CH3). NOESY
(CDCl3, 500 MHz) observed correlations: 3.12 (d, J = 15.9 Hz, 1H)
with 0.96 (s, 3H) and 0.84 (s, 3H); 2.77 (d, J = 15.9 Hz, 1H) with 0.76
(d, J = 6.6 Hz, 3H). IR (film): 1875, 1730, 1619, 1501, 1479, 1387,
1305, 1268, 1184, 1150, 1040, 942, 920, 844, 766, 743 cm−1. HRMS
(FAB) m/z: calcd for C17H22O3Na (M + Na+) 297.1467, found
297.1475.
1,1,4a-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene (22).
Colorless syrup. 1H NMR (CDCl3, 500 MHz) δ: 7.05 (dd, J = 7.6, 7.6
Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 7.3, 7.3 Hz, 1H), 6.75
(d, J = 8 Hz, 1H), 3.04 (dd, J = 17.6, 8.0 Hz, 1H), 2.77 (d, J = 17.6 Hz,
1H), 2.04 (br d, J = 14.6 Hz, 1H), 1.86 (m, 1H), 1.59−1.36 (m, 4H),
1.27 (t, J = 11.9 Hz or dd, J = 26.0, 15.5 Hz, 1H), 1.21 (s, 3H), 0.97 (s,
3H), 0.65 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ: 154.5 (C), 128.9
(CH), 126.6 (CH), 122.0 (C), 119.8 (CH), 117.1 (CH), 75.2 (C),
44.5 (CH), 41.7 (CH2), 39.6 (CH2), 34.0 (C), 32.3 (CH3), 27.0
(CH3), 23.6 (CH2), 21.4 (CH3), 18.1 (CH2). IR (film): 1610, 1586,
1489, 1455, 1373, 1312, 1239, 1160, 1107, 1057, 1021, 946, 848, 753,
707 cm−1. HRMS (FAB) m/z: calcd for C16H22ONa (M + Na+)
253.1568, found 253.1572.
octahydro-2′,5′,5′,8′a-tetramethylspiro[benzofuran-2-
1
(3H),1′(2′H)-naphthalene] (27). Colorless oil. H NMR (CDCl3,
500 MHz) δ: 6.66 (s, 1H), 6.42 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H),
3.18 (d, J = 15.8 Hz, 1H), 2.74 (d, J = 15.8 Hz, 1H), 1.73 (m, 1H),
1.68−1.23 (m, 10H), 1.18 (ddd, J = 13.6, 13.6, 3.6 Hz, 1H), 0.95 (s,
3H), 0.91 (s, 3H), 0.84 (s, 3H), 0.73 (d, J = 6.5 Hz, 3H).13C NMR
(CDCl3, 125 MHz) δ: 155.8 (C), 149.2 (C), 142.6 (C), 116.9 (C),
108.70 (CH), 96.6 (C), 93.9 (CH), 57.0 (CH3), 56.1 (CH3) 46.7
(CH), 42.6 (C), 41.8 (CH2), 37.4 (CH), 35.0 (CH2), 33.3 (C), 33.3
(CH3), 31.3 (CH2), 31.3 (CH2), 22.1 (CH3), 21.6 (CH2), 18.4 (CH2),
16.3 (CH3), 15.8 (CH3). NOESY (CDCl3, 500 MHz) observed
correlations: 3.18 (d, J = 15.8 Hz, 1H) with 0.95 (s, 3H); 2.74 (d, J =
15.8 Hz, 1H) with 0.73 (d, J = 6.5 Hz, 3H). HRMS (FAB) m/z: calcd
for C23H34O3Na (M + Na+) 381.2406, found 381.2392.
[ 1 ′ ( 2 ) R , 2 ′ R , 4 ′ a R , 8 ′ a S ] - 5 , 6 - M e t h y l e n e d i o x y -
3′,4′,4′a,5′,6′,7′,8′,8′a-octahydro-2′,5′,5′,8′a-tetramethylspiro-
[benzofuran-2(3H),1′(2′H)-naphthalene] (28). Colorless syrup.
[α]2D5 = +2.07 (c 16.5, CHCl3). H NMR (CDCl3, 500 MHz) δ: 6.54
1
(s, 1H), 6.35 (s, 1H), 5.85 (s, 1H), 5.84 (s, 1H), 3.15 (d, J = 16.0 Hz,
1H), 2.71 (d, J = 16.0 Hz, 1H), 1.71 (tt, J = 12.0, 6.5 Hz, 1H), 1.65−
1.44 (m, 5H), 1.43−1.28 (m, 5H), 1.19 (m, 1H), 0.93 (s, 3H), 0.91 (s,
3H), 0.84 (s, 3H), 0.73 (d, J = 6.5 Hz, 3H).13C NMR (CDCl3, 125
MHz) δ: 155.7 (C), 147.0 (C), 140.6 (C), 117.8 (C), 104.3 (CH),
100.9 (CH2), 96.6 (C), 91.9 (CH), 46.5 (CH), 42.5 (C), 41.8 (CH2),
37.3 (CH), 34.8 (CH2), 33.4 (C), 33.3 (CH3), 31.3 (CH2), 31.2
(CH2), 22.1 (CH3), 21.5 (CH2), 18.4 (CH2), 16.2 (CH3), 15.7 (CH3).
NOESY (CDCl3, 500 MHz) observed correlations: 3.15 (d, J = 16.0
Hz, 1H) with 0.93 (s, 3H); 2.71 (d, J = 16.0 Hz, 1H) with 0.73 (d, J =
6.5 Hz, 3H). IR (film): 1618, 1501, 1472, 1458, 1386, 1304, 1263,
1211, 1151, 1041, 1006, 940, 843, 797, 751 cm−1. HRMS (FAB) m/z:
calcd for C22H30O3Na (M + Na+) 365.2093, found 365.2102.
Treatment of 26 with I2: Synthesis of 8-epi-19,20-Di-O-
methylenepuupehenol (32). Iodine (41 mg, 0.16 mmol) was added
to a solution of phenol (37 mg, 0.11 mmol) in dry CH2Cl2 (2 mL),
and the mixture was stirred at room temperature for 15 min until TLC
showed no remaining starting material. After removal of most of the
solvent under reduced pressure, the reaction mixture was filtered over
silica gel and concentrated to give a crude product that was purified by
flash chromatography on silica gel (5% ether/hexanes) to afford 32 as
a colorless syrup (33 mg, 89%).
1,1,4a,6-Tetramethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene
1
(23). Colorless syrup. H NMR (CDCl3, 500 MHz) δ: 6.85 (s, 2H),
6.63 (d, J = 8.8 Hz, 1H), 2.99 (dd, J = 17.6, 8.0 Hz, 1H), 2.72 (d, J =
17.6 Hz, 1H), 2.25 (s, 3H), 2.03 (m, 1H), 1.85 (m, 1H), 1.56−1.36
(m, 5H), 1.19 (s, 3H), 0.95 (s, 3H), 0.66 (s, 3H). 13C NMR (CDCl3,
125 MHz) δ: 154.9 (C), 131.9 (C), 131.5 (CH), 130.0 (CH), 124.3
(C), 119.4 (CH), 77.7 (C), 47.2 (CH), 44.4 (CH2), 42.3 (CH2), 36.6
(C), 34.9 (CH3), 29.6 (CH3), 26.2 (CH2), 24.1 (CH3), 23.2 (CH3),
20.8 (CH2). IR (film): 1730, 1503, 1457, 1372, 1306, 1267, 1237,
1160, 1122, 947, 812 cm−1. HRMS (FAB) m/z: calcd for C17H24ONa
(M + Na+) 267.1725, found 267.1723.
5a,9,9-Trimethyl-6,7,8,9,9a,10-hexahydro-5aH-[1,3]dioxolo-
[4,5-b]xanthene (24). Colorless oil. 1H NMR (CDCl3, 500 MHz) δ:
6.49 (s, 1H), 6.30 (s, 1H), 5.84 (d, J = 8.0 Hz, 2H), 2.92 (dd, J = 17.4,
8.0 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 1.97 (ddd, J = 15.4, 6.3, 3.5 Hz,
1H), 1.82 (m, 1H), 1.47−1.38 (m, 2H), 1.35 (d, J = 8.0 Hz, 1H), 1.25
Treatment of 26 with NIS−PPh3 in CH2Cl2/H2O or CH2Cl2/
THF/H2O. N-Iodosuccinimide (7 mg, 0.03 mmol) was added to a
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solution of triphenylphosphine (8 mg, 0.03 mmol) in CH2Cl2 (4 mL),
and the mixture was stirred at room temperature for at least 15 min.
Water (0.2 mL) and a solution of 26 (83 mg, 0.24 mmol) in CH2Cl2
(4 mL) were then added successively at 0 °C, and the reaction mixture
was stirred at room temperature for 30 h, at which time TLC showed
unaltered 26 and the formation of triphenylphosphine oxide.
Similar results were obtained when 1 equiv of NIS and 1 equiv of
PPh3 were utilized. When the reaction time was prolonged to 6 days,
the unaltered starting material was recovered.
concentrated in vacuo to give the crude product as a pale-yellow oil,
which was purified by chromatography on silica gel (30% ether/
hexanes) to afford pure β-keto ester 35 (2.28 g, 87%) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ: 5.35 (br s, 1H), 5.32 (t, J = 4.1 Hz,
1H), 4.25 (dq, J = 7.3, 1.8 Hz, 2H), 4.23 (dq, J = 7.3, 1.8 Hz, 2H), 3.68
(s, 3H), 2.46 (m, 1H), 1.98−1.88 (m, 2H), 1.75−1.68 (m, 2H), 1.67
(br s, 3H), 1.60 (m, 1H), 1.48 (m, 1H), 1.41 (m, 1H), 1.35 (t, J = 7.1
Hz, 6H), 1.14 (m, 1H), 0.92 (s, 3H), 0.86 (s, 3H). 13C NMR (126
MHz, CDCl3) δ: 164.34 (C), 164.32 (C), 162.6 (C), 121.1 (CH),
104.8 (CH), 64.8 (CH2), 64.7 (CH2), 51.1 (CH3), 48.7 (CH), 35.6
(CH2), 32.6 (C), 31.5 (CH2), 28.0 (CH2), 27.6 (CH3), 27.5 (CH3),
23.5 (CH3), 23.0 (CH2), 16.2 (CH3), 16.1 (CH3). IR (film): 3449,
1732, 1665, 1440, 1276, 1207, 1164, 1032, 986 cm−1. HRMS (FAB)
m/z: calcd for C19H33O6PNa (M + Na+) 411.1912, found 411.1904.
Methyl 2-(diethoxyphosphoryloxy)-5,5,8a-trimethyl-
1,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (36).
To a solution of β-keto ester 35 (2 g, 5.15 mmol) in dry CH2Cl2
(15 mL) was added tin tetrachloride (1.21 mL, 10.30 mmol) at 0 °C.
After the mixture was stirred at the same temperature for 10 min, the
cooling bath was removed. The reaction mixture was allowed to warm
to room temperature for 1 h, at which time TLC showed no remaining
starting material. The mixture was then cooled to 0 °C, and water was
added to quench the reaction. The solvent was removed under
vacuum, and the crude product was fractionated in water/ether
(30:100 mL). The phases were shaken and separated, and the organic
layer was washed with saturated aqueous NaHCO3 (2 × 25 mL), water
(25 mL), and brine (25 mL). The dried organic layers were filtered
and evaporated, and the residue was directly purified by flash
chromatography (30% ether/hexanes) to yield 36 (1.6 g, 81%) as a
colorless syrup.
When the reaction was performed in CH2Cl2/THF/H2O (4:2:1)
utilizing different proportions of reagent, similar results were obtained
even when the reaction time was prolonged for 6 days.
Treatment of 26 with HI/H2O. To a solution of 26 (93 mg, 0.27
mmol) in dichloromethane (2 mL) was added at room temperature a
55% aqueous solution of hydroiodic acid (0.1 mL), and the reaction
mixture was stirred for 10 min, at which time TLC showed no
remaining starting material. Next, water was added, and the reaction
mixture was extracted with dichloromethane (2 × 10 mL). The
combined organic layers were washed with water (3 × 5 mL) and
brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum to give 0.77 mg (83%) of a crude product.
Spectra of this showed an isomeric mixture of 28, 30, and 32 in a
1
1:3:10 ratio as determined by H NMR spectroscopy.
Treatment of 26 with Anhydrous HI. To a solution of 1,3-
propanedithiol (0.75 mL, 0.622 mmol) in dry CH2Cl2 (5 mL) was
added iodine (79 mg, 0.311 mmol), and the mixture was stirred at
room temperature for 30 min. A solution of phenol 26 (73 mg, 0.213
mmol) in dry CH2Cl2 (5 mL) was then added, and the resulting
mixture was stirred at room temperature for 5 min, at which time TLC
showed no remaining starting material. The solvent was then removed
under vacuum, and the residue was diluted with ether/water (30 mL,
3:1), after which the phases were shaken and separated. The organic
layer was washed with saturated aqueous NaHCO3 (10 mL), water (10
mL), and brine. The dried organic layers were filtered and evaporated
to give 66 mg (91%) of a crude product. Spectra of this showed an
isomeric mixture of 28, 30, and 32 in a 1:3:5 ratio as determined by 1H
NMR spectroscopy.
1H NMR (CDCl3, 500 MHz) δ: 5.66 (m, 1H). 4.17−4.04 (m, 4H)
3.66 (s, 3H), 3.21 (br s, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.70 (m,
1H), 1.52 (m, 1H), 1.47−1.39 (m, 3H), 1.32 (t, J = 7.5 Hz, 3H), 1.30
(t, J = 7.4 Hz, 3H), 1.24 (dd, J = 12.0, 4.2 Hz, 1H), 1.18 (m, 1H), 0.96
(s, 3H), 0.90 (s, 3H), 0.88 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ:
170.6 (C). 142.9 (C), 112.0 (CH), 64.4 (CH2), 64.2 (CH2), 60.5
(CH), 51.3 (CH3), 48.9 (CH), 42.0 (CH2), 40.4 (CH2), 37.5 (C),
33.4 (CH3), 33.1 (C), 22.2 (CH3), 22.0 (CH2), 18.6 (CH2), 16.13
(CH3), 16.07 (CH3), 15.35 (CH3). IR (film): 3455, 1739, 1686, 1442,
1273, 1165, 1036, 970 cm−1. HRMS (FAB) m/z: calcd for
C19H33O6PNa (M + Na+) 411.1912, found 411.1923.
1-(Hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-
2(1H)-one (37). Phosphoenol ester 36 (1.5 g, 3.86 mmol) in dry
THF (200 mL) was added dropwise to a solution of sodium aluminum
bis(2-methoxy)hydride in toluene (d = 1.02 g/mL) (1 mL, 5.0 mmol)
at 0 °C under an argon atmosphere. After the mixture was stirred at
the same temperature for 30 min, the reaction was quenched with 0.1
M HCl (10 mL). The mixture was then concentrated under reduced
pressure and diluted with ether/water (80:20 mL), and the phases
were shaken and separated. The organic layer was washed with brine
(15 mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatog-
raphy (35% ether/hexanes) to afford 727 mg of 37 (84%) as a
colorless oil.
Treatment of 26 with the NIS−PBu3 System. N-Iodosuccini-
mide (7 mg, 0.031 mmol) was added to a solution of
tributylphosphine (7 mg, 0.034 mmol) in dry CH2Cl2 (3 mL), and
the mixture was stirred at room temperature for 15 min. A solution of
phenol 26 (106 mg, 0.309 mmol) in CH2Cl2 (3 mL) was then added
at 0 °C, and the reaction mixture was stirred at room temperature for
16 h, until TLC showed no remaining phenol. The solvent was
removed under vacuum, and the crude product was directly purified by
flash chromatography on silica gel (3% ether/hexanes) to give 94 mg
1
(89%) of a mixture of 28 and 30 in a 4:1 ratio as determined by H
NMR spectroscopy.
Dihydro-α-ionone (34). To a solution of α-ionone (33) (2 g, 10.4
mmol) in THF (25 mL) was added Raney Ni solution (50% in water,
3 mL), and the reaction mixture was stirred for 1 h at room
temperature, at which time TLC showed no remaining starting
material. The reaction mixture was then filtered through a silica gel/
Na2SO4 mixture (100 g) and washed with acetone (10 mL), and the
solvent was removed under vacuum to give 34 (1.64 g, 81%) as a
colorless oil.
Methyl (Z)-3-(Diethoxyphosphoryloxy)-5-(2,6,6-trimethylcy-
clohex-2-enyl)pent-2-enoate (35). Sodium hydride (1.65 g, 41.2
mmol, 60% dispersion in mineral oil) was carefully added in portions
to a precooled solution (0 °C) of dihydro-α-ionone (34) (2 g, 10.3
mmol) in dry THF (20 mL) under an argon atmosphere. After the
reaction mixture was stirred at this temperature for 10 min, dimethyl
carbonate (103 mmol, 8.66 mL) was added, and the reaction mixture
was stirred at reflux for an additional 4 h, at which time TLC showed
the disappearance of the starting material. Diethyl chlorophosphonate
(3.1 mL, 20.6 mmol) was then added dropwise, and the mixture was
stirred for another 12 h at room temperature. After this time, the
mixture was poured into ice (50 g) and extracted with ether (2 × 50
mL). The combined organic layers were washed with water (2 × 30
mL) and brine (1 × 30 mL), dried over Na2SO4, filtered, and
1-((6-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)methyl)-5,5,8a-
trimethyloctahydronaphthalen-2(1H)-one (39). Amberlyst 15
ion-exchange resin (0.5 g) and 4 Å molecular sieves (1 g) were
added to a solution of β-hydroxy ketone 37 (0.8 g, 3.57 mmol) and 38
(913 mg, 4 mmol) in dry DCM (20 mL), and the mixture was stirred
at reflux for 6 h, at which time TLC showed no remaining 37. The
mixture was then filtered, and the solvent was removed under vacuum
to give a crude product that was purified by flash chromatography on
silica gel (25% ether/hexanes) to give 39 (1.1 g, 89%) as a colorless
syrup.
1H NMR (CDCl3, 500 MHz) δ: 7.42−7.32 (m, 5H), 6.89 (s, 1H),
6.52 (s, 1H), 5.86 (d, J = 1.5 Hz, 1H), 5.84 (d, J = 1.5 Hz, 1H), 4.95
(d, J = 11.2 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H), 2.72 (dd, J = 13.2, 9.6
Hz, 1H), 2.63 (dd, J = 13.2, 1.9 Hz, 1H), 2.42 (br d, J = 9.6 Hz, 1H),
2.31 (ddd, J = 12.9, 4.7, 2.0 Hz, 1H), 2.16 (m, 1H), 1.98 (m, 1H), 1.65
(br d, J = 13.5 Hz, 1H), 1.60 (ddd, J = 26.4, 13.2, 4.7 Hz, 1H), 1.42
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(ddt, J = 27.4, 13.6, 3.3 Hz, 1H), 1.34 (dd, J = 12.7, 3.0 Hz, 1H), 1.33
(dd, J = 13.2, 1.3 Hz, 1H), 1.22 (m, 1H), 1.06−0.92 (m, 2H), 0.91 (s,
3H), 0.80 (s, 3H), 0.71 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ:
211.9 (C), 151.4 (C), 146.0 (C), 140.9 (C), 137.1 (C), 128.6 (2 CH),
128.5 (2 CH), 128.3 (CH), 123.1 (C), 112.3 (CH), 101.0 (CH2), 95.5
(CH), 71.6 (CH2), 64.5 (CH), 54.4 (CH), 43.3 (C), 42.9 (CH2), 42.0
(CH2), 38.8 (CH2), 33.8 (C), 33.7 (CH3), 24.4 (CH2), 23.2 (CH2),
21.8 (CH3), 19.1 (CH2), 14.7 (CH3). IR (film): 1709, 1622, 1505,
1484, 1389, 1170, 1041, 939, 896, 751, 698 cm−1. HRMS (FAB) m/z:
calcd for C28H34O4Na (M + Na+) 457.2355, found 457.2353.
added 10% Pd/C (500 mg, 10% mmol), and the reaction mixture was
stirred at room temperature under a hydrogen atmosphere (1.5 atm)
for 1 h. Filtration and concentration yielded 1.62 g of 26 (97%) as a
colorless syrup.
[1′(2)R,2′R,4′aR,8′aS]-7-Formyl-5,6-methylenedioxy-
3′,4′,4′a,5′,6′,7′,8′,8′a-octahydro-2′,5′,5′,8′a-tetramethylspiro-
[benzofuran-2(3H),1′(2′H)-naphthalene] (42). To a solution of 28
(420 mg, 1.22 mmol) in THF (12 mL) was added n-butyllithium (2.2
M in hexanes, 1.70 mL, 3.66 mmol) at −78 °C under an argon
atmosphere, and the reaction mixture was stirred at this temperature
for 5 min. It was then allowed to warm to 5 °C and subsequently
cooled to −50 °C. TMEDA (1.13 mL, 0.18 mmol) was added
dropwise at −50 °C, and freshly distilled DMF (0.71 mL, 9.18 mmol)
was also added dropwise to the resultant pale-yellow solution. The
mixture was stirred and allowed to warm to −40 °C over 20 min, at
which time TLC showed no remaining starting material. The reaction
was quenched with water (3 mL), and the solvent was removed. Et2O/
water (40:10 mL) was added to the crude product, and the phases
were shaken and separated. The organic phase was washed with 2 N
HCl (3 × 10 mL) and brine (2 × 10 mL), dried over anhydrous
Na2SO4, and filtered. Removal of the solvent under reduced pressure
afforded a crude product that was directly purified by flash
chromatography (10% ether/hexanes) to give 322 mg of aldehyde
42 (72%) as a yellow syrup.
5-(Benzyloxy)-6-((5,5,8a-trimethyl-2-methylenedecahydro-
naphthalen-1-yl)methyl)benzo[d][1,3]dioxole (40). A 2 M
solution of n-butyllithium in hexanes (0.7 mL, 1.4 mmol) was added
dropwise under an argon atmosphere to a stirred suspension of
methyltriphenylphosphonium bromide (400 mg, 1.12 mmol) in dry
THF (10 mL) at 0 °C, and the reaction mixture was allowed to warm
to room temperature after 15 min of stirring. Next, a solution of 39
(250 mg, 0.58 mmol) in dry THF (10 mL) was added dropwise at 0
°C, and the reaction mixture was further stirred at room temperature
for an additional 4 h. Water (1 mL) was then added to quench the
reaction, and the solvent was removed under vacuum. The crude
product was extracted with ether (2 × 30 mL). The dried organic
layers were evaporated, and the residue was directly purified by flash
chromatography on silica gel (10% ether/hexanes) to yield 40 (181
mg, 72%) as a colorless syrup and 30 mg (12%) of starting material.
1H NMR (CDCl3, 500 MHz) δ: 7.30 (m, 5H), 6.59 (s, 1H), 6.46 (s,
1H), 5.78 (s, 2H), 4.92 (s, 2H), 4.69 (s, 1H), 4.57 (s, 1H), 2.68 (br d,
J = 15.4 Hz, 1H), 2.59 (dd, J = 15.1, 10.5 Hz, 1H), 2.27 (br d, J = 12.8
Hz, 1H), 2.09 (br d, J = 10.0 Hz, 1H), 1.90 (ddd, J = 13.0, 13.0, 5.0
Hz, 1H), 1.71−1.60 (m, 2H), 1.46 (dd, J = 27.7, 13.9 Hz, 1H), 1.34−
1.18 (m, 3H), 1.08−0.98 (m, 2H), 0.95 (ddd, J = 18.7, 16.7, 3.8 Hz,
1H), 0.80 (s, 3H), 0.74 (s, 3H), 0.69 (s, 3H). 13C NMR (CDCl3, 125
MHz) δ: 151.3 (C), 148.9 (C), 145.7 (C), 141.2 (C), 137.4 (C), 128.9
(CH), 128.7 (2 CH), 128.0 (CH), 127.8 (CH), 123.8 (C), 109.8
(CH), 107.7 (CH2), 101.1 (CH2), 96.3 (CH), 71.7 (CH2), 56.3 (CH),
55.8 (CH), 42.3 (CH2), 40.1 (C), 39.1 (CH2), 38.5 (CH2), 33.8
(CH3), 33.7 (C), 24.6 (CH2), 23.9 (CH2), 21.9 (CH3), 19.6 (CH2),
14.7 (CH3). IR (film): 1644, 1585, 1504, 1483, 1434, 1388, 1167,
1040, 1000, 938, 867, 743, 696 cm−1. HRMS (FAB) m/z: calcd for
C29H36O3Na (M + Na+) 455.2562, found 455.2554.
5-(Benzyloxy)-6-((2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a
octahydronaphthalen-1-yl)methyl)benzo[d][1,3]dioxole (41).
Iodine (66 mg, 0.25 mmol) was added to a solution of
triphenylphosphine (78 mg, 0.31 mmol) in dry CH2Cl2 (6 mL), and
the mixture was stirred at room temperature for 10 min. A solution of
alkene 40 (110 mg, 0.25 mmol) in CH2Cl2 (5 mL) was then added at
room temperature. The reaction mixture was stirred at room
temperature for 20 min, at which time an aliquot was checked by
1H NMR spectroscopy, which showed no starting material. After
removal of most of the solvent under reduced pressure, the crude
product was purified by flash chromatography on silica gel (10%
ether/hexanes) to yield 41 (75 mg, 70%) as a colorless syrup.
1H NMR (CDCl3, 500 MHz) δ: 7.44 (br d, J = 7.4 Hz, 2H), 7.38
(br t, J = 7.4 Hz, 2H), 7.32 (br t, J = 7.3 Hz, 1H), 6.60 (s, 1H), 6.56 (s,
1H), 5.89 (d, J = 1.5 Hz, 1H), 5.88 (d, J = 1.5 Hz, 1H), 5.05 (d, J =
12.0 Hz, 1H), 5.02 (d, J = 12.0 Hz, 1H), 3.38 (d, J = 17.4 Hz, 1H),
3.22 (d, J = 17.4 Hz, 1H), 2.17 (m, 1H), 2.06 (dd, J = 17.8, 6.3 Hz,
1H), 1.72 (m, 1H), 1.60−1.50 (m, 2H), 1.48 (s, 3H), 1.45−1.20 (m,
5H), 1.09 (m, 1H), 0.98 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H). 13C NMR
(CDCl3, 125 MHz) δ: 150.8 (C), 145.4 (C), 141.3 (C), 137.7 (C),
137.6 (C), 129.1 (C), 128.7 (2 CH), 128.0 (CH), 127.4 (2 CH),
123.3 (C), 109.0 (CH), 100.9 (CH2), 96.4 (CH), 71.4 (CH2), 52.1
(CH), 41.9 (CH2), 39.1 (C), 36.2 (CH2), 33.7 (CH2), 33.5 (C), 33.4
(CH3), 27.0 (CH2), 21.9 (CH3), 20.5 (CH3), 20.3 (CH3), 19.3 (CH2),
19.1 (CH2). IR (film): 1729, 1626, 1505, 1481, 1387, 1382, 1316,
1174, 1041, 939, 870, 739, 696 cm−1. HRMS (FAB) m/z: calcd for
C29H36O3Na (M + Na+) 455.2562, found 455.2562.
[α]2D5 = −33.5 (c 20.2, CHCl3). H NMR (CDCl3, 500 MHz) δ:
1
10.26 (s, 1H, CHO), 6.77 (s, 1H), 6.023 (s, 1H), 6.018 (s, 1H), 3.15
(d, J = 16.1 Hz, 1H), 2.74 (d, J = 16.1 Hz, 1H), 1.77 (tt, J = 12.1, 6.5
Hz, 1H), 1.66−1.45 (m, 5H), 1.43−1.24 (m, 5H), 1.14 (ddd, J = 13.4,
13.4, 3.7 Hz, 1H), 0.95 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H), 0.75 (d, J =
6.5 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ: 186.7 (CHO), 157.3
(C), 145.5 (C), 141.4 (C), 118.9 (C), 110.7 (CH), 105.5 (C), 102.6
(CH2), 99.1 (C), 46.7 (CH), 42.5 (C), 41.6 (CH2), 37.2 (CH), 33.7
(C), 33.4 (CH2), 33.2 (CH3), 31.3 (CH2), 31.1 (CH2), 21.9 (CH3),
21.3 (CH2), 18.2 (CH2), 16.1 (CH3), 15.6 (CH3). NOESY (CDCl3,
500 MHz) observed correlations: 3.15 (d, J = 16.1 Hz, 1H) with 0.95
(s, 3H); 2.74 (d, J = 16.1 Hz, 1H) with 0.75 (d, J = 6.5 Hz, 3H). IR
(film): 1689, 1637, 1455, 1392, 1310, 1256, 1190, 1091, 1072, 1007,
968, 927, 760, 714, 630 cm−1. HRMS (FAB) m/z: calcd for
C23H30O4Na (M + Na+) 393.2042, found 393.2046.
Corallidictyal D (2). Anhydrous AlCl3 (172 mg, 1.29 mmol, 3
equiv) was added to a cold (−40 °C) solution of 42 (60 mg, 0.43
mmol) in dry dichloromethane (10 mL) under an argon atmosphere,
and the reaction mixture was stirred for 5 min, at which time TLC
showed no remaining starting material. Water (0.5 mL) was then
added, and the organic solvent was removed under vacuum. The
resulting crude product was dissolved in methanol (4 mL).
Concentrated HCl (1 mL) was added, and the mixture was refluxed
for 30 min (until none of the intermediate chloromethyl ether
remained). The reaction mixture was allowed to cool to room
temperature, and the methanol was evaporated. The crude product
was diluted with ether (50 mL) and washed with water (3 × 20 mL)
and brine (2 × 20 mL). The organic phase was dried over anhydrous
Na2SO4 and filtered, and the solvent was removed to give pure
corallidictyal D (2) as a colorless oil (144 mg, 92%).
[α]2D5 = −21.8 (c 14.8, CHCl3). H NMR (CDCl3, 500 MHz) δ:
1
11.09 (br s, 1H, OH), 10.20 (s, 1H, CHO), 6.93 (s, 1H), 5.09 (br s,
1H, OH), 3.14 (d, J = 16.0 Hz, 1H), 2.73 (d, J = 16.0 Hz, 1H), 1.78
(tt, J = 12.4, 6.5 Hz, 1H), 1.67−1.53 (m, 3H), 1.48 (ddd, J = 16.3,
12.7, 3.1 Hz, 1H), 1.42−1.11 (m, 7H), 0.96 (s, 3H), 0.91 (s, 3H), 0.85
(s, 3H), 0.73 (d, J = 6.5 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ:
193.0 (CHO), 157.0 (C), 146.3 (C), 137.0 (C), 119.5 (CH), 117.5
(C), 105.8 (C), 99.5 (C), 47.0 (CH), 42.6 (C), 41.8 (CH2), 37.3
(CH), 33.7 (CH2), 33.6 (CH3), 33.4 (C), 31.5 (CH2), 31.3 (CH2),
22.0 (CH3), 21.5 (CH2), 18.4 (CH2), 16.4 (CH3), 15.8 (CH3).
NOESY (CDCl3, 500 MHz) observed correlations: 3.14 (d, J = 16.0
Hz, 1H) with 0.96 (s, 3H); 2.73 (d, J = 16.0 Hz, 1H) with 0.73 (d, J =
6.5 Hz, 3H). IR (film): 3565, 3419, 1652, 1634, 1470, 1386, 1332,
1299, 1255, 1236, 1213, 1109, 1069, 1032, 1010, 977, 936, 892, 856,
782, 752, 728, 667, 621 cm−1. HRMS (FAB) m/z: calcd for
C22H30O4Na (M + Na+) 381.2042, found 381.2033.
6-((2,5,5,8a-Tetramethyl-3,4,4a,5,6,7,8,8a-octahydro-
naphthalen-1-yl)methyl)benzo[d][1,3]dioxol-5-ol (26). To a
solution of 41 (2.1 g, 4.86 mmol) in dry methanol (20 mL) was
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The Journal of Organic Chemistry
Article
1H NMR (DMSO-d6, 500 MHz) δ: 10.14 (s, 1H, CHO), 6.90 (s,
1H), 3.10 (d, J = 16.2 Hz, 1H), 2.71 (d, J = 16.2 Hz, 1H), 1.77 (m,
1H), 1.60−1.05 (m, 11H), 0.93 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H),
0.67 (d, J = 6.5 Hz, 3H). 13C NMR (DMSO-d6, 125 MHz) δ: 191.9
(CHO), 155.7 (C), 146.9 (C), 137.4 (C), 120.6 (CH), 116.8 (C),
106.1 (C), 98.2 (C), 46.1 (CH), 42.0 (C), 41.3 (CH2), 36.4 (CH),
33.2 (CH2), 32.9 (CH3), 32.8 (C), 30.7 (CH2), 30.7 (CH2), 21.7
(CH3), 20.9 (CH2), 17.8 (CH2), 15.7 (CH3), 15.5 (CH3).
(d) Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 6814−6818.
(8) Kende, A. S.; Deng, W.-P.; Zhong, M.; Guo, X.-C. Org. Lett.
2003, 5, 1785−1788.
(9) Tsujimori, H.; Mori, K. Biosci., Biotechnol., Biochem. 2001, 65,
167−171.
́
(10) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Cortes,
M.; Armstrong, V. Tetrahedron 1999, 55, 15181−15208.
(11) Kuan, K. K. W.; Pepper, H. P.; Bloch, W. M.; George, J. H. Org.
Lett. 2012, 14, 4710−4713 and references cited therein.
(12) (a) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera Torres, E.;
Alvarez, E.; Alvarez-Manzaneda, R.; Haidour, A.; Ramos, J. Tetrahedron
Lett. 2004, 45, 4453−4455. (b) Alvarez-Manzaneda, E.; Chahboun, R.;
Cabrera Torres, E.; Alvarez, E.; Alvarez-Manzaneda, R.; Haidour, A.;
Ramos, J. Tetrahedron Lett. 2005, 46, 1075−1077. (c) Alvarez-
Manzaneda, E.; Chahboun, R.; Cabrera Torres, E.; Alvarez, E.; Alvarez-
Manzaneda, R.; Haidour, A.; Ramos, J. Tetrahedron Lett. 2005, 46,
3755−3759.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 2, 16−25, 27,
28, 35−37, and 39−42; NOESY data for compounds 20 and
27; and HSQC, HMBC, and NOESY data for compound 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.;
Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Tapia, R.; Es-Samti,
H.; Fernandez, A.; Barranco, I. Eur. J. Org. Chem. 2009, 1139−1143.
(14) Chervin, S. M.; Abada, P.; Koreeda, M. Org. Lett. 2000, 2, 369−
372.
(15) Fehr, C.; Guntern, O. Helv. Chim. Acta 1992, 75, 1023−1028.
(16) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
Meneses, R. Synlett 1999, 1663−1666.
(17) (a) Baker, B. A.; Boskovic, Z. V.; Lipshutz, B. H. Org. Lett. 2008,
10, 289−292. (b) Tang, Y.-X.; Suga, T. Phytochemistry 1994, 37, 737−
740.
(18) The only precedent of a similar transformation involves the
cyclization of the enol phosphate of methyl farnesyl acetoacetate to
give the corresponding tricyclic organomercurial β-keto ester (27−
30%) after treatment with mercuric trifluoroacetate. See: (a) Corey, E.
J.; Reid, J. G.; Myers, A. G.; Hahl, R. W. J. Am. Chem. Soc. 1987, 109,
918−919. (b) Corey, E. J.; Hahl, R. W. Tetrahedron Lett. 1989, 30,
3023−3026.
(19) (a) Escher, S.; Giersch, W.; Niclass, Y.; Bernardinelli, G.; Ohloff,
G. Helv. Chim. Acta 1990, 73, 1935−1947. (b) Mori, K.; Aki, S.; Kido,
M. Liebigs Ann. Chem. 1994, 319−324.
(20) For spectroscopic data for ketone 37, see: Furuichi, N.; Hata, T.;
Soetjipto, H.; Kato, M.; Katsumura, S. Tetrahedron 2001, 57, 8425−
8442.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: rachid@ugr.es.
*E-mail: eamr@ugr.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Spanish Ministry of Science and
Innovation (Project CTQ2009-09932) and the Regional
Government of Andalucia (Projects P07-FQM-03101 and
P11-CTS-7651, and assistance for the FQM-348 group) for
financial support. M.J.C and R.T. thank the Spanish Ministry of
Science and Innovation for the predoctoral grants provided.
REFERENCES
■
(1) (a) Chan, J. A.; Freyer, A. J.; Carte, B. K.; Hemling, M. E.;
Hofmann, G. A.; Mattern, M. R.; Mentzer, M. A.; Westley, J. W. J. Nat.
Prod. 1994, 57, 1543−1548. (b) Grube, A.; Assmann, M.; Lichte, E.;
Sasse, F.; Pawlik, J. R.; Kock, M. J. Nat. Prod. 2007, 70, 504−509.
̈
(2) For the isolation of K-76, see: (a) Miyazaki, W.; Tamaoka, H.;
Shinohara, M.; Kaise, H.; Izawa, T.; Nakano, Y.; Kinoshita, T.; Hong,
K.; Inoue, K. Microbiol. Immunol. 1980, 24, 1091−1098. For the
synthesis of K-76, see: (b) Corey, E. J.; Das, J. J. Am. Chem. Soc. 1982,
104, 5551−5553. (c) McMurry, J. E.; Erion, M. D. J. Am. Chem. Soc.
1985, 107, 2712−2720. For a recent review concerning K-76 and
structurally related compounds, see: (d) Larghi, E. L.; Kaufman, T. S.
ARKIVOC 2011, 2011 (vii), 49−102.
(21) For the preparation of benzyl ether 38, see: Bezerra-Netto, H. J.
C.; Lacerda, D. I.; Miranda, A. L. P.; Alves, H. M.; Barreiro, E. J.; Fraga,
C. A. M. Bioorg. Med. Chem. 2006, 14, 7924−7935.
(22) Imakura, Y.; Konishi, T.; Uchida, K.; Sakurai, H.; Kobayashi, S.;
Haruno, A.; Tajima, K.; Yamashita, S. Chem. Pharm. Bull. 1994, 42,
500−511.
(23) Reitz, A.; Avery, M. A.; Verlander, M. S.; Goodman, M. J. Org.
Chem. 1981, 46, 4859−4863.
(3) (a) Ayer, W. A.; Miao, S. Can. J. Chem. 1993, 71, 487−493.
(b) Lin, T.-W.; Chang, W.-W.; Chen, C.-C.; Tsai, Y.-C. Biochem.
Biophys. Res. Commun. 2005, 331, 953−957.
(4) Lam, Y. K. T.; Wichmann, C. F.; Meinz, M. S.; Guariglia, L.;
Giacobbe, R. A.; Mochales, S.; Kong, L.; Honeycutt, S. S.; Zink, D.;
Bills, G. F.; Huang, L.; Burg, R. W.; Monaghan, R. L.; Jackson, R.;
Reid, G.; Maguire, J. J.; McKnight, A. T.; Ragan, C. I. J. Antibiot. 1992,
45, 1397−1403.
(5) Sakai, K.; Watanabe, K.; Masuda, K.; Tsuji, M.; Hasumi, K.;
Endo, A. J. Antibiot. 1994, 48, 447−456.
(6) (a) Roggo, B. E.; Petersen, F.; Sills, M.; Roesel, J. L.; Moerker, T.;
Peter, H. H. J. Antibiot. 1996, 49, 13−19. (b) Roggo, B. E.; Hug, P.;
Moss, S.; Stampfli, A.; Kriemler, H.-P.; Peter, H. H. J. Antibiot. 1996,
̈
49, 374−379.
(7) (a) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.;
Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest, R.;
Andersen, R. J. Org. Lett. 2006, 8, 321−324. (b) George, J. H.;
Baldwin, J. E.; Adlington, R. M. Org. Lett. 2010, 12, 2394−2397.
(c) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Cano, M. J.;
Haidour, A.; Alvarez-Manzaneda, R. Org. Lett. 2010, 12, 4450−4453.
9204
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