Stereoselective total synthesis of nemorosone

Article abstract of DOI:10.1021/jo300646j

The highly stereoselective total synthesis of nemorosone via a new approach to the bicyclo[3.3.1]nonane-2,4,9-trione core which features intramolecular cyclopropanation of an α-diazo ketone, stereoselective alkylation at the C8 position, and regioselectiv

Full text of DOI:10.1021/jo300646j

Article
pubs.acs.org/joc
Stereoselective Total Synthesis of Nemorosone
Masahiro Uwamori, Aya Saito, and Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
S
* Supporting Information
ABSTRACT: The highly stereoselective total synthesis of nemorosone via a new approach to the bicyclo[3.3.1]nonane-2,4,9-
trione core which features intramolecular cyclopropanation of an α-diazo ketone, stereoselective alkylation at the C8 position,
and regioselective ring-opening of cyclopropane is described. The total synthesis of nemorosone includes chemo- and
stereoselective hydrogenation directed by the internal alkene.
structure, we started to develop an approach to the synthetic
intermediate 4 that is common for PPAPs (Scheme 1).7
Our approach features intramolecular cyclopropanation
(IMCP) of 1 (step I),8 subsequent stereoselective alkylations
of 2 (step II), and regioselective ring-opening of the cyclo-
propane ring in 3 (step III). As step I is the desymmetrization
step, it would be made sufficiently enantioselective through the
use of a chiral catalyst. Step II would enable the introduction of
two different substituents at the C8 position to generate an all-
carbon quaternary stereogenic center because the alkylation
proceeds from the less hindered convex side. Hence, this
approach allows for the stereoselective total synthesis of hyper-
forin. Step III regioselectively affords 4 because the electron-
donating methoxy group on the cyclopropane and the electron-
withdrawing ketone cooperatively enhance the ring-opening
reaction.
Scheme 2 shows the retrosynthetic analysis of nemorosone
to 4. The C1 benzoyl and C2 hydroxyl groups of nemorosone
were planned to be added at the last stage because the C1
benzoyl group basically suffers from nucleophilic addition and
the C2 enol hydroxyl is reactive. Hence, the set precursor, 5,
could be obtained by the introduction of prenyl groups at the
C3 and C5 positions of 6. Alternatively, conversion of all the
allyl groups at the C3, C5, and C7 positions to prenyl groups
via cross-metathesis would also be possible if the introduction
of prenyl groups proves difficult.5c,6c,d,9 Compound 6 was
thought to be obtained by allylic oxidation at the C4 position of
7, which could be derived from 4 via the stereoselective
construction of the C7 stereogenic center.
INTRODUCTION
■
Polycyclic polyprenylated acylphloroglucinols (PPAPs) feature
complex and diverse structures, including a highly oxygenated
and densely substituted bicyclo[3.3.1]nonane-2,4,9-trione or
bicyclo[3.2.1]octane-2,4,8-trione core complete with prenyl or
geranyl side chains, among others (Figure 1).1 The family of
PPAPs consists of more than 110 members, and their number
continues to increase. Interestingly, PPAPs having closely related
structures show different and wide-ranging biological activities.
For example, nemorosone exhibits anti-HIV and antitumor activi-
ties,2 hyperforin shows antidepressant and antitumor activities,3
and garsubellin A has anti-Alzheimer activity,4 while the dif-
ferences in their structures lie only in the substituents.
Consequently, development of a synthetic approach to the
bicyclo[3.3.1]nonane-2,4,9-trione core would contribute to
structure−activity relationship studies of PPAPs, with the
potential of finding new artificial compounds that show signifi-
cant biological activity. The intriguing structures and biological
activities of PPAPs described above have made them attractive
synthetic targets, and many synthetic studies,5 as well as total
syntheses,6 have been reported thus far. Regarding nemor-
osone, two total syntheses were reported.6c,e However, most of
these syntheses have been accomplished via cyclohexenone
derivatives as the synthetic intermediates. We herein report the
total synthesis of nemorosone via a new approach to the
bicyclo[3.3.1]nonane-2,4,9-trione core, which can be applied to
the synthesis of other PPAPs.
RESULTS AND DISCUSSION
Scheme 3 shows the preparation of α-diazo-β-ketone 1 from
2,6-dimethoxybenzoic acid methyl ester 8. Compound 8 was
■
Nemorosone and some PPAPs share the bicyclo[3.3.1]nonane-
2,4,9-trione core, which incorporates stereogenic centers as well
as oxygen functionalities at the same positions. Considering
these structural features and the hidden symmetry in the
Received: March 31, 2012
Published: May 7, 2012
© 2012 American Chemical Society
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Figure 1. Structures of nemorosone, hyperforin, garsubellin A, and bicyclo[3.3.1]nonane-2,4,9-trione.
Scheme 1. New Approach to 4 via Cyclopropane 2
Scheme 2. Retrosynthetic Analysis of Nemorosone to 4
Scheme 3. Attempted Preparation of 13
subjected to Birch reduction, followed by a one-pot reaction
with allylbromide, reduction of the methyl ester with lithium
aluminum hydride, and protection of the primary hydroxyl
group as a TIPS ether to afford 9. Selective dihydroxylation of 9
and the following 1,2-diol cleavage afforded aldehyde 10,10
which was subjected to the reaction with a methyllithium to
afford 11. Since compound 11 was acid-sensitive, 12 was
formed from 11 when it was subjected to the purification by
silica gel chromatography.
Hence, we explored the one-pot procedure for converting 10
to methyl ketone 13 and found that 10 was converted to 13 by
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the one-pot methylation11−Oppenauer oxidation12 protocol
developed in this study (Scheme 4). That is, the reaction of 10
treatment with acid afforded 3′ as the single product with
excellent overall yield, which is a potential intermediate for the
total synthesis of hyperforin (Scheme 6).
Scheme 4. Preparation of 1 via Two One-Pot Procedures
Scheme 6. Highly Stereoselective Preparation of 3′ from 2
To generate the C7 stereogenic center, chemo- and
stereoselective reduction of the C6−C7 alkene in 14 was
examined. Compound 14 has a methoxy group on the electron-
rich C2−C3 alkene and an ester group on the electron-deficient
C6−C7 alkene. Hence, the C6−C7 alkene of 14 was expected
to be selectively reduced under suitable conditions. However,
the reduction of 14 with common reagents that have been used
for the reduction of α,β-unsaturated esters did not proceed,
most probably owing to steric hindrance.
Fortunately, we found that hydrogenation of 14 with
Crabtree’s catalyst (0.5 mol %)14 proceeded smoothly at
room temperature to afford 15 as the single isomer (Scheme 7).
with trimethylaluminum afforded the alkoxide, which was
subsequently treated with 3-nitrobenzaldehyde in a one-pot
manner to afford 13 in 85% yield. Methyl ketone 13 was
successfully converted to 1 according to Danheiser’s protocol.13
Initially, we isolated the trifluoroacetyled methyl ketone, which
was prepared from 13, and used it for the next diazotransfer
reaction to prepare 1, but soon found that the two reactions
were able to carry out in a one-pot manner with high yield.
IMCP of 1 was carried out under conditions optimized by us
(Scheme 5).7,8 Since the IMCP of 1 with a chiral ligand was
Scheme 7. Highly Stereoselective Hydrogenation of 14 To
Afford 15
1
Interestingly, extensive H NMR studies suggested that 15 has
Scheme 5. Preparation of 14 via IMCP of 1
the desired C7 configuration. More usually, hydrogenation of
the alkene in a bridge-ring system such as 14 selectively
proceeds at the less hindered convex face. However, the
structure of 15 indicated that hydrogenation of 14 exclusively
occurred at the more hindered concave face. Therefore, we
speculated that hydrogenation of 14 was directed by the C2−
C3 alkene.
To confirm the directing effect of the C2−C3 alkene,
hydrogenation of 14′, which was prepared by acidic hydrolysis
of 14, was examined (Scheme 8). As the result, no reactions
Scheme 8. Preparation and Attempted Hydrogenation of 14′
planned to be examined separately, IMCP of 1 was carried
out with achiral ligand A to afford 2. Since compound 2 is
acid-sensitive, crude 2 was subjected to a reaction with excess
methyl iodide and potassium tert-butoxide to afford a dimethyl-
ated compound, which was then treated with acid. The ring-
opening reaction of cyclopropane proceeded regioselectively to
afford diketone 4 as the single isomer (58%, three steps). Con-
version of 4 to the corresponding enol triflate and subsequent
palladium-mediated carbonylation afforded 14.
occurred under the same conditions in Scheme 7, suggesting
the directing effect by the C2−C3 alkene. To the best of our
knowledge, stereoselective hydrogenation directed by the
internal alkene has not been reported in the literature thus far.
We also found that the sequential allylation and methylation
of 2 proceeded at the less-hindered convex face and subsequent
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Reduction of 15 with DIBAL-H, subsequent selective
acetylation of the primary hydroxyl group, and oxidation of
the secondary hydroxyl group afforded 16 (Scheme 9). Allylic
Scheme 11. Introduction of Allyl Groups at C5 and C3
Positions
Scheme 9. Preparation of Triflate 18
Alternatively, although the overall yield was reduced, one-pot
allylation at the C5 and C3 positions was found to be possible
(Scheme 12). Thus, reaction of 20 with excess LTMP, followed
Scheme 12. One-Pot Introduction of Allyl Groups at C5 and
C3 Positions
oxidation at the C4 position of 16 successfully afforded 17.5t,15
The acetate of 17 was removed, and the resultant alcohol was
converted to triflate 18 so as to introduce a prenyl group at the
C7 position via a coupling reaction.
However, coupling reaction of 18 with the organocopper
reagent derived from 2-methyl-1-propenyllithium did not take
place (Scheme 10). To our delight, the coupling reaction of 18
by the reaction with allylbromide, and subsequent addition of
thienylcuprate afforded 22 in 50% yield.
Scheme 10. Coupling Reactions of 18 with Cuprates
Removal of the TIPS group of 22, Dess−Martin oxidation,
reaction with phenylmagnesium bromide, and further Dess−
Martin oxidation afforded 23 (Scheme 13). The intermediate
Scheme 13. Total Synthesis of Nemorosone
with divinyl cuprate smoothly afforded 20 without involv-
ing 1,4-addition in the enone system. Thereafter, the allyl
group at the C7 position was planned to be converted to a
prenyl group by cross-metathesis at a later stage of the
synthesis.
Since the cross-metathesis had to be carried out at the later
stage, allylations at the C5 and C3 positions were carried out
because all of the allyl groups at the C3, C5, and C7 positions
were expected to be simultaneously converted to prenyl groups
via the cross-metathesis. Allylation at the C5 position of 20
using LDA resulted in reduction of the C9 ketone, but use of
LTMP solved this problem, successfully affording the C5-
allylated product (Scheme 11).5o,p,6e,16 Subsequent allylation at
the C3 position did not take place under the same conditions as
those used for the C5 allyation. However, as has been reported,
use of thienylcuprate as the additive provided 22 in good
yield.5p,6c,17
aldehyde was suspected to be not so reactive because it was a
sterically hindered neopentyl type aldehyde having a successive
quaternary carbon center, but the addition of a phenyl-
magnesium bromide to the aldehyde selectively took place with
high yield. The high yield could be attributed to the C2−C3
alkene and C9 ketone that would inductively activate the
aldehyde. In addition, oxygen atoms of the C2 methoxy group
and C9 ketone could act as directing groups that accelerate
the addition of a phenylmagnesium bromide. The three allyl
groups of 23 were cleanly converted to prenyl groups by cross-
metathesis with Grubbs II catalyst and 2-methylpropene at
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washed with brine (350 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude ester 8a (ca. 40.8 g)
was used for the next step without further purification.
60 °C in a sealed tube. Finally, the methyl group on the C2
hydroxyl group was successfully removed under Krapcho
conditions.5p,6d,e The final product proved to be identical to
nemorosone in all respects (1H and 13C NMR, IR, and
HRMS),2 confirming the total synthesis of nemorosone.
In summary, we have established a new synthetic route to the
bicyclo[3.3.1]nonane-2,4,9-trione core of PPAPs via the
intramolecular cyclopropanation (IMCP) (step I), subsequent
stereoselective alkylations (step II), and regioselective ring-
opening of cyclopropane (step III). The IMCP (step I) can
be made enantioselective through the use of a chiral catalyst,
and stereoselective alkylations (step II) enable the construction
of the C8 all-carbon quaternary stereogenic center for the total
synthesis of hyperforin. The total synthesis of nemorosone fea-
tures the successful application of this new approach developed
by us, wherein chemo- and stereoselective hydrogenation,
which is directed by the internal alkene, precedes palladium-
mediated allylic oxidation at the C4 position, one-pot allylations
at the C5 and C3 positions, and global cross-metathesis with
Grubbs II catalyst and 2-methyl-1-propene. Further synthetic
studies of PPAPs on the basis of this research are underway and
will be reported in due course.
To a stirred suspension of LiAlH4 (8.74 g, 187 mmol, 1.1 equiv) in
Et2O was added a solution of 8a (ca. 40.8 g) in Et2O (93 mL) at 0 °C.
After the reaction was completed, to the mixture was added saturated
aqueous Na2SO4 (20 mL), and the reaction mixture was stirred for 1 h.
Then the mixture was filtered through a plug of Celite, and the filtrate
was concentrated under reduced pressure. The crude alcohol 8b (ca.
37.0 g) was used for the next step without further purification.
To a stirred solution of 8b (ca. 37.0 g) in CH2Cl2 (180 mL) were
added Et3N (62.7 mL, 450 mmol, 2.6 equiv) and TIPSOTf (53.2 mL,
198 mmol, 1.2 equiv) successively at 0 °C. After the reaction was
completed, saturated aqueous NaHCO3 solution (180 mL) was added
to the reaction mixture, and the aqueous layer was extracted with
CH2Cl2 (150 mL × 2). The combined organic layer was washed with
brine (400 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexane/ethyl acetate = 50/1) to afford 9 (49.6 g, 79%) as an oil: Rf =
1
0.85 (hexane/ethyl acetate = 4/1); H NMR (500 MHz, CDCl3) δ
5.68−5.50 (1H, m), 4.95−4.87 (2H, m), 4.79 (2H, t, J = 4.0 Hz), 3.73
(2H, s), 3.49 (6H, s), 2.78−2.71 (2H, m), 2.20 (2H, d, J = 7.0 Hz),
1.00 (21H, brs); 13C NMR (125 MHz, CDCl3) δ 152.9 (Cq), 135.0
(CH), 115.6 (CH2), 93.8 (CH), 65.1 (CH2), 54.1 (CH3), 50.2 (Cq),
34.7 (CH2), 24.1 (CH2), 17.9 (CH3), 12.0 (CH); IR (neat) νmax 2942,
2865, 1698, 1464, 1225, 1208, 1137 cm−1; HRMS (FAB-DFMS) [M +
H]+ calcd for C21H39O3Si 367.2668, found 367.2682.
2-[2,6-Dimethoxy-1-((triisopropylsilyloxy)methyl)cyclohexa-2,5-
dienyl]acetaldehyde (10). To a stirred solution of K2OsO4·2H2O
(118 mg, 0.320 mmol, 0.3 mol %) in H2O (305 mL) were added
(DHQD)2PHAL (623 mg, 0.800 mmol, 0.75 mol %), K2CO3 (44.2 g,
319.7 mmol, 3.0 equiv), and K3Fe(CN)6 (105 g, 320 mmol, 3.0 equiv)
successively at room temperature. Then, to the reaction mixture was
added a solution of 9 (39.1 g, 106.6 mmol) in t-BuOH (305 mL) at
room temperature. After the reaction was completed, saturated aque-
ous Na2SO3 solution (200 mL) was added to the reaction mixture, and
the aqueous layer was extracted with Et2O (300 mL × 3). The
combined organic layer was washed with brine (500 mL × 1), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude diol 9a (ca. 44.9 g) was used for the next step without further
purification.
To a stirred solution of 9a (ca. 44.9 g) in MeOH (373 mL) was
added a solution of NaIO4 (26.3 g, 123.2 mmol) in H2O (373 mL) at
0 °C, and the reaction mixture was warmed to room temperature.
After the reaction was completed, water (746 mL) was added to
the reaction mixture, and the aqueous layer was extracted with Et2O
(500 mL × 3). The combined organic layer was washed with brine
(700 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexane/ethyl acetate = 10/1) to afford 10 (31.9 g, 81%) as a white
powder: Rf = 0.35 (hexane/ethyl acetate = 10/1); 1H NMR (500
MHz, CDCl3) δ 9.58 (1H, t, J = 3.0 Hz), 4.85 (2H, t, J = 4.0 Hz), 3.77
(2H, s), 3.50 (6H, s), 2.85−2.75 (2H, m), 2.44 (2H, d, J = 3.0 Hz),
0.99 (21H, brs); 13C NMR (125 MHz, CDCl3) δ 203.0 (Cq), 152.0
(Cq), 94.3 (CH), 64.5 (CH2), 54.3 (CH3), 47.3 (Cq), 43.9 (CH2),
24.0 (CH2), 17.7 (CH3), 12.0 (CH); IR (neat) νmax 2941, 2865, 1720,
1695, 1205, 1125, 1065 cm−1; HRMS (FAB-DFMS) [M + H]+ calcd
for C20H37O4Si 369.2461, found 369.2449; mp 58−59 °C.
EXPERIMENTAL SECTION
■
1
General Methods. H and 13C NMR spectra were recorded on
400 or 500 MHz spectrometers. 1H and 13C chemical shifts are
reported in ppm downfield from tetramethylsilane (TMS, δ scale) with
the solvent resonances as internal standards. The following
abbreviations are used to explain the multiplicities: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; band, several overlapping
signals; brs, broad; Cq, quaternary carbon; CH, methine carbon; CH2,
methylene carbon; CH3, methyl carbon. IR spectra were recorded on a
FT/IR spectrometer. To confirm the 1H and 13C NMR peak
1
assignments (Supporting Information) and carbon multiplicities, H
NMR, BCM, DEPT, COSY, HMQC, HMBC, and NOESY methods
were used. All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous conditions, unless
otherwise noted. All reactions were monitored by thin-layer
chromatography carried out on 0.25 mm silica gel plates using UV
light as visualizing agent and phosphomolybdic acid and heat as
developing agents. Silica gel (60, particle size 0.040−0.063 mm) was
used for flash chromatography. Preparative thin-layer chromatography
(PTLC) separations were carried out on self-made 0.3 mm silica gel
plates. THF and Et2O were distilled from sodium/benzophenone
ketyl. Toluene was distilled from sodium. MeOH was distilled with a
small amount of magnesium and I2. Benzene and MeCN were distilled
from CaH2, and all commercially available reagents were used without
further purification. Optical rotations were measured on a polar-
imeterat a wavelength of 589 nm. High resolution mass spectra
(HRMS) were obtained by either an electronspray ionization (ESI)
recorded in a TOF mass spectrometer (Time-of-Flight mass spectro-
meter) or a fast atom bombardment (FAB) recorded in a DFMS
(double-focusing mass spectrometer), and theoretical monoisotopic
molecular masses were typically ≤5 ppm. Melting point was uncor-
rected. TLC Rf's of purified compounds are included.
1-[2,6-Dimethoxy-1-((triisopropylsilyloxy)methyl)cyclohexa-2,5-
dienyl]propan-2-one (13). To a stirred solution of 10 (33.5 g, 90.8
mmol) in toluene was added a solution of Me3Al in toluene (50 mL,
100 mmol, 1.1 equiv) at 0 °C, and the reaction mixture was stirred at
0 °C for 4 h. To the reaction mixture was added 3-nitrobenzaldehyde
(62.1 g, 272 mmol, 3.0 equiv) at 0 °C, and the resulting mixture was
warmed to room temperature. After the reaction was completed,
CH2Cl2 (200 mL) and saturated aqueous Rochelle salt solution (200
mL) were added to the reaction mixture, and the resultant mixture was
stirred for 1 h. Then the mixture was filtered through a plug of Celite,
and the aqueous layer was extracted with CH2Cl2 (200 mL × 2). The
combined organic layer was washed with saturated aqueous NaHCO3
[(1-Allyl-2,6-dimethoxycyclohexa-2,5-dienyl)methoxy]-
triisopropylsilane (9). To a stirred solution of methyl 2,6-
dimethoxybenzoate (33.6 g, 171 mmol) in Et2O (114 mL) was
added t-BuOH (18.0 mL, 189 mmol, 1.1 equiv) at room temperature,
and then the mixture was cooled to −78 °C. To the mixture was added
liquid NH3 (230 mL), which was introduced via a dry ice condenser,
and with stirring, sodium (9.46 g, 411 mmol, 2.4 equiv) was added in
portions. After 30 min, allyl bromide (46.0 mL, 531 mmol, 3.1 equiv)
was added dropwise. When the reaction was completed, NH3 was
allowed to evaporate overnight, and Et2O (150 mL) and H2O (150
mL) were added to the reaction mixture. The aqueous layer was
extracted with Et2O (100 mL × 2). The combined organic layer was
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(400 mL) and then washed with brine (500 mL × 1), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate = 10/1) to
afford 13 (29.6 g, 85%) as an oil: Rf = 0.50 (hexane/ethyl acetate =
(hexane) to afford 4 (4.52 g, 58% (three steps)) as a white powder:
Rf = 0.60 (hexane/ethyl acetate = 4/1); 1H NMR (500 MHz, CDCl3)
δ 4.74 (1H, dd, J = 5.5, 1.5 Hz), 4.25 (1H, d, J = 8.5 Hz), 3.95 (1H, d,
J = 8.5 Hz), 3.46 (3H, s), 3.02 (1H, dd, J = 16.5, 7.5 Hz), 2.94−2.85
(1H, brs), 2.56 (1H, ddd, J = 16.5, 5.5, 2.0 Hz), 2.42 (1H, d, J = 16.5
Hz), 2.27 (1H, ddd, J = 16.5, 5.5, 1.5 Hz), 1.17 (3H, s), 1.10−1.01
(21H, brs), 0.99 (3H s); 13C NMR (125 MHz, CDCl3) δ 209.5 (Cq),
207.3 (Cq), 154.6 (Cq), 93.4 (CH), 60.9 (Cq), 57.5 (CH2), 54.5
(CH3), 53.7 (Cq), 45.1 (CH2), 44.7 (CH), 30.7 (CH2), 23.4 (CH3),
19.4 (CH3), 17.9 (CH3), 12.0 (CH); IR (neat) νmax 2956, 2940, 2864,
1729, 1708, 1656, 1458, 1241, 1217, 1105, 1089, 1063 cm−1; HRMS
(FAB-DFMS) [M + H]+ calcd for C22H39O4Si 395.2618, found
395.2632; mp 106−107 °C.
(1R*,5S*,8S*)-1-[(Triisopropylsilyloxy)methyl]-8-allyl-8-methyl-2-
methoxybicyclo[3.3.1]non-2-ene-7,9-dione (3′). To a stirred solution
of 2 (ca. 1.46 g), which was prepared from 1 (1.40 g, 3.43 mmol), in
THF (16.0 mL) and HMPA (14.0 mL) was added KHMDS in toluene
(23.0 mL, 11.5 mmol, 3.0 equiv) at −78 °C. After 30 min, to the
reaction mixture was added allyl iodide (2.10 mL, 23.0 mmol, 6.0
equiv) at −78 °C. The resultant solution was warmed to 0 °C. After
the reaction was completed, saturated aqueous NaHCO3 solution (50
mL) was added to the reaction mixture, and the aqueous layer was
extracted with Et2O (50 mL × 3). The combined organic layer was
washed with brine (200 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude allylated cyclo-
propane 2b (ca. 3.57 g) was unstable under acidic conditions.
Therefore, it was used for the next step without further purification.
To a stirred solution of 2b (ca. 3.57 g) in THF (35.3 mL) and
HMPA (7.1 mL) was added KHMDS in toluene (67.8 mL, 33.9 mmol,
4.0 equiv) at −78 °C. After 30 min, to the reaction mixture was added
methyl iodide (4.22 mL, 67.8 mmol, 8.0 equiv) at −78 °C. After
the reaction was completed, saturated aqueous NaHCO3 solution
(100 mL) was added to the reaction mixture, and the aqueous layer
was extracted with Et2O (100 mL × 3). The combined organic layer
was washed with brine (400 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude cyclopropane 2c
(ca. 3.21 g) was unstable under acidic conditions. Therefore, it was
used for the next step without further purification.
1
4/1); H NMR (500 MHz, CDCl3) δ 4.80 (2H, t, J = 4.0 Hz), 3.70
(2H, s), 3.50 (6H, s), 2.77 (2H, brs), 2.56 (2H, s), 2.00 (3H, s), 0.99
(21H, s); 13C NMR (125 MHz, CDCl3) δ 207.6 (Cq), 152.3 (Cq),
94.0 (CH), 65.3 (CH2), 54.1 (CH3), 48.4 (Cq), 44.7 (CH2), 30.9 (CH3),
24.0 (CH2), 17.7 (CH3), 11.9 (CH); IR (neat) νmax 2941, 2865, 1710,
1698, 1663, 1464, 1385, 1352, 1225, 1211, 1077 cm−1; HRMS (FAB-
DFMS) [M + H]+ calcd for C21H39O4Si 383.2618, found 383.2625.
1,3-Dimethoxy-2-[(triisopropylsilyloxy)methyl]-2-(3-diazo-2-oxo-
propyl)-1,3-cyclohexadiene (1). To a stirred solution of LHMDS in
THF (72.3 mL, 76.6 mmol, 1.1 equiv) was added a solution of 13
(27.7 g, 72.3 mmol) in THF (145 mL) at −78 °C, and the reac-
tion mixture was stirred for 30 min at the same temperature. Then, to
the reaction mixture was added 2,2,2-trifluoroethyl trifluoroacetate
(10.7 mL, 79.6 mmol, 1.1 equiv) in one portion at −78 °C, and then
was added water (3.9 mL, 217 mmol, 3.0 equiv) at 0 °C. The resulting
mixture was warmed up to room temperature and stirring was
continued for additional 1 h. To the reaction mixture was added Et3N
(101 mL, 723 mmol, 10 equiv) and p-NO2PhSO2N3 (49.5 g, 217
mmol, 3.0 equiv), and the mixture was warmed up to 40 °C. After the
reaction was completed, the reaction mixture was diluted with Et2O
(400 mL × 1), and washed with 10% NaOH aqueous solution (100
mL × 3). The organic layer was washed with brine (500 mL × 1),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (CH2Cl2) to afford
1 (24.7 g, 84%) as a yellow powder: Rf = 0.30 (hexane/ethyl acetate =
4/1); 1H NMR (500 MHz, CDCl3) δ 5.21 (1H, brs), 4.83 (2H, t, J =
4.0 Hz), 3.70 (2H, brs), 3.53 (6H, s), 2.78 (2H, t, J = 4.0 Hz), 2.50
(2H, brs), 0.96 (21H, s); 13C NMR (125 MHz, CDCl3) δ 193.0 (Cq),
151.9 (Cq), 94.5 (CH), 65.3 (CH2), 54.5 (Cq), 54.2 (CH3), 48.8
(Cq), 42.0 (CH2), 24.0 (CH2), 17.7 (CH3), 11.9 (CH); IR (neat) νmax
2942, 2865, 2098, 1698, 1643, 1464, 1386, 1355, 1206, 1133 cm−1;
HRMS (FAB-DFMS) [M + H]+ calculated for C21H37O4N2Si
409.2523, found 409.2522; mp 60−61 °C.
(1R*,5S*)-1-[(Triisopropylsilyloxy)methyl]-8,8-dimethyl-2-
methoxybicyclo[3.3.1]non-2-ene-7,9-dione (4). To a stirred solution
of [CuOTf]2·PhMe (161 mg, 0.311 mmol, 2 mol %) in toluene (6.2
mL) was added a solution of ligand A18 (112 mg, 0.623 mmol, 4 mol %)
in toluene (6.2 mL) at room temperature, and the reaction mixture
was stirred at the same temperature for 30 min. Then, to the reaction
mixture was added a solution of 1 (6.35 g, 15.6 mmol) in toluene
(31.1 mL) at room temperature. After the reaction was com-
pleted, saturated aqueous NaHCO3 solution (50 mL) was added to
the reaction mixture, and the aqueous layer was extracted with Et2O
(100 mL × 3). The combined organic layer was washed with brine
(400 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude cyclopropane 2 (ca. 6.52 g) was unstable
under acidic conditions. Therefore, it was used for the next step
without further purification.
To a stirred solution of 2c (ca. 3.21 g) in THF (36.9 mL)
was added 2 N HCl (7.4 mL) at 0 °C. After the reaction was
completed, saturated aqueous NaHCO3 solution (100 mL) was added
to the reaction mixture, and the aqueous layer was extracted with Et2O
(200 mL × 3). The combined organic layer was washed with brine
(300 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexane/ethyl acetate = 20/1) to afford 3′ (1.26 g, 88% (three steps))
1
as a white powder: Rf = 0.50 (hexane/ethyl acetate = 4/1); H NMR
(500 MHz, CDCl3) δ 5.92−5.81 (1H, m), 5.05−4.95 (2H, m), 4.76
(1H, dd, J = 5.5, 2.0 Hz), 4.20 (1H, d, J = 8.5 Hz), 4.08 (1H, d, J =
8.5 Hz), 3.48 (3H, s), 3.01 (1H, dd, J = 15.5, 6.5 Hz), 2.89 (1H, t, J =
6.5 Hz), 2.83 (1H, dd, J = 14.5, 4.5 Hz), 2.60 (1H, ddd, J = 16.5, 6.5,
2.0 Hz), 2.37 (1H, dd, J = 15.5, 1.0 Hz), 2.29 (1H, ddd, J = 16.5, 5.5,
1.0 Hz), 2.12 (1H, dd. J = 14.5, 9.5 Hz), 1.11−0.98 (21H, brs), 0.99 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 209.0 (Cq), 206.8 (Cq), 154.3
(Cq), 136.1 (CH), 117.3 (CH2), 93.8 (CH), 61.9 (Cq), 57.6 (CH2),
55.6 (CH3), 54.5 (Cq), 45.1 (CH), 44.9 (CH2), 37.4 (CH2), 30.5
(CH2), 19.7 (CH3), 17.9 (CH3), 12.0 (CH); IR (neat) νmax 2941,
2865, 1715, 1659, 1463, 1426, 1238, 1164, 1129, 1109, 1011 cm−1;
HRMS (FAB-DFMS) [M + H]+ calcd for C24H41O4Si 421.2774, found
421.2788; mp 59−60 °C.
(1R*,5S*)-1-[(Triisopropylsilyloxy)methyl]-8,8-dimethyl-2-me-
thoxy-9-oxobicyclo[3.3.1]nona-2,6-diene-7-carboxylic Acid Methyl
Ester (14). To a stirred solution of 4 (6.40 g, 16.2 mmol) and Comins’
reagent (2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyri-
dine)19 (7.00 g, 17.8 mmol, 1.1 equiv) in THF (66.5 mL) was
added KHMDS in toluene (35.6 mL, 17.8 mmol, 1.1 equiv) dropwise
at −78 °C. The resultant solution was warmed to room temperature.
After the reaction was completed, saturated aqueous NaHCO3
solution (100 mL) was added to the reaction mixture, and the
aqueous layer was extracted with Et2O (200 mL × 3). The combined
To a stirred solution of crude 2 (ca. 6.52 g) in THF (71.5 mL) and
HMPA (14.3 mL) was added t-BuOK (5.78 g, 51.5 mmol, 3.3 equiv)
at 0 °C. After 30 min, to the reaction mixture was added MeI (6.41
mL, 17.2 mmol, 6.6 equiv) at 0 °C. After the reaction was completed,
saturated aqueous NaHCO3 solution (50 mL) was added to the
reaction mixture, and the aqueous layer was extracted with EtOAc
(100 mL × 3). The combined organic layer was washed with brine
(300 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude dimethyl cyclopropane 2a (ca. 11.3 g)
was unstable under acidic conditions. Therefore, it was used for the
next step without further purification.
To a stirred solution of 2a (ca. 11.3 g) in THF (23.0 mL) was
added 2 N HCl (4.6 mL) at 0 °C. After the reaction was completed,
saturated aqueous NaHCO3 solution (100 mL) was added to the
reaction mixture, and the aqueous layer was extracted with Et2O
(100 mL × 3). The combined organic layer was washed with brine
(200 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by recrystallization
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organic layer was washed with 10% NaOH (300 mL) and brine (300
mL × 1), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (hexane/
ethyl acetate = 15/1) to afford 4a (7.33 g, 86%) as a white powder:
Rf = 0.70 (hexane/ethyl acetate = 5/1); 1H NMR (500 MHz, CDCl3)
δ 5.67 (1H, d, J = 5.5 Hz), 4.81 (1H, dd, J = 5.5, 2.0 Hz), 4.27 (1H, d,
J = 8.5 Hz), 3.92 (1H, d, J = 8.5 Hz), 3.52 (3H, s), 3.07−2.98 (1H, m),
2.57 (1H, ddd, J = 16.5, 5.5, 2.0 Hz), 2.35 (1H, ddd, J = 16.5, 5.5, 1.5
Hz), 1.23 (3H, s), 1.07−1.00 (21H, brs), 0.95 (3H, s); 13C NMR (125
MHz, CDCl3) δ 204.4 (Cq), 155.2 (Cq), 154.3 (Cq), 118.3 (Cq),
116.9 (CH), 93.7 (CH), 61.1 (Cq), 57.9 (CH2), 54.4 (CH3), 47.1
(Cq), 43.8 (CH), 28.4 (CH2), 22.4 (CH3), 21.7 (CH3), 17.9 (CH3),
12.1 (CH); IR (neat) νmax 2943, 2866, 1741, 1659, 1465, 1417, 1246,
1209, 1140, 1004, 983 cm−1; HRMS (FAB-DFMS) [M + H]+ calcd for
C23H38F3O6SSi 527.2110, found 527.2117; mp 46−47 °C.
crude ester 15 (ca. 1.03 g) was used for the next step without further
purification.
To a stirred solution of crude 15 (ca. 1.03 g) in CH2Cl2 (11.7 mL)
was added a solution of DIBAL-H in toluene (7.40 mL, 1.01 M, 7.47
mmol, 3.3 equiv) at −78 °C. After the reaction was completed,
saturated aqueous Rochelle salt (50 mL) was added to the reaction
mixture, and the resultant mixture was stirred for 1 h. Then the
mixture was filtered through a plug of Celite, and the aqueous layer
was extracted with EtOAc (100 mL × 3). The combined organic layer
was washed with brine (200 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude diol 15a (ca. 997.5
mg) was used for the next step without further purification.
To a stirred solution of 15a (ca. 997.5 mg) in CH2Cl2 (24.2 mL)
were added Et3N (1.01 mL, 7.25 mmol, 3.2 equiv), DMAP (29.5 mg,
0.242 mmol, 0.11 equiv), and Ac2O (0.25 mL, 2.66 mmol, 1.2 equiv)
successively at room temperature. After the reaction was completed,
saturated aqueous NaHCO3 solution (20 mL) was added to the
reaction mixture, and the aqueous layer was extracted with Et2O (40
mL × 3). The combined organic layer was dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude acetate 15b (ca.
1.08 g) was used for the next step without further purification.
To a stirred solution of 15b (ca. 1.08 g) in CH2Cl2 (23.8 mL) were
added Dess−Martin periodinane (3.04 g, 7.13 mmol, 3.1 equiv) and
NaHCO3 (2.00 g, 27.8 mmol, 12 equiv) at room temperature. After
the reaction was completed, Et2O (50 mL) and a mixture of saturated
aqueous NaHCO3 solution (60 mL) and saturated aqueous Na2S2O3
solution (60 mL) were added to the reaction mixture. The aqueous
layer was extracted with Et2O (50 mL × 2). The combined organic
layer was washed with brine (20 mL × 1), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/ethyl acetate = 10/1) to afford 16 (832
mg, 80% (4 steps)) as a white powder: Rf = 0.25 (hexane/ethyl
A solution of 4a (5.79 g, 11.0 mmol), Et3N (4.60 mL, 33.0 mmol,
3.0 equiv), Pd(OAc)2 (113.6 mg, 0.506 mmol, 0.046 equiv), and dppf
(560 mg, 1.01 mmol, 0.092 equiv) in MeOH/DMF (1/1, 110 mL)
was stirred under an atmosphere of CO at 50 °C. After the reaction
was completed, saturated aqueous NH4Cl solution (100 mL) was
added to the reaction mixture, and the aqueous layer was extracted
with Et2O (200 mL × 2). The combined organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/ethyl acetate =
15/1) to afford 14 (4.50 g, 94%) as a white powder: Rf = 0.45
1
(hexane/ethyl acetate = 10/1); H NMR (500 MHz, CDCl3) δ 6.59
(1H, d, J = 5.0 Hz), 4.76 (1H, dd, J = 5.5, 2.0 Hz), 4.31 (1H, d, J = 8.5
Hz), 3.97 (1H, d, J = 8.5 Hz), 3.70 (3H, s), 3.48 (3H, s), 2.97 (1H, dt,
J = 5.0, 2.0 Hz), 2.55 (1H, ddd, J = 16.5, 5.0, 2.0 Hz), 2.34 (1H, ddd,
J = 16.5, 5.5, 2.0 Hz), 1.32 (3H, s), 1.10 (3H, s), 1.08−1.00 (21H, m);
13C NMR (125 MHz, CDCl3) δ 207.1 (Cq), 167.1 (Cq), 155.1 (Cq),
140.0 (Cq), 137.9 (CH), 93.4 (Cq), 62.4 (Cq), 58.1 (CH2), 54.4
(CH3), 51.5 (CH3), 47.7 (Cq), 46.0 (CH), 28.3 (CH2), 23.5 (CH3),
22.7 (CH3), 17.9 (CH3), 12.1 (CH); IR (neat) νmax 2943, 2865, 1737,
1720, 1656, 1463, 1330, 1245, 1230, 1155, 1127, 1106, 1045 cm−1;
HRMS (ESI-TOF) [M + Na]+ calcd for C24H40NaO5Si 459.2543,
found 459.2535; mp 111−113 °C.
1
acetate=10/1); H NMR (500 MHz, CDCl3) δ 5.03−4.95 (1H, m),
4.22 (1H, d, J = 8.0 Hz), 4.18 (1H, dd, J = 11.0, 4.0 Hz), 4.00 (1H, d,
J = 8.0 Hz), 3.74 (1H, dd, J = 11.0, 8.5 Hz), 3.50 (3H, s), 2.67−2.53
(2H, m), 2.43−2.33 (1H, m), 2.24 (1H, dd, J = 15.5, 4.5 Hz), 2.04
(3H, s), 1.93 (1H, ddd, J = 13.5, 4.5, 2.0 Hz), 1.79−1.68 (1H, m), 1.08
(3H, s), 1.06−1.00 (21H, m), 0.68 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 210.5 (Cq), 171.1 (Cq), 153.1 (Cq), 97.4 (CH), 65.8
(CH2), 62.9 (Cq), 58.0 (CH2), 54.3 (CH3), 44.2 (CH), 43.7 (Cq),
40.6 (CH), 36.8 (CH2), 29.9 (CH2), 24.3 (CH3), 21.0 (CH3), 17.9
(CH3), 17.8 (CH3), 12.1 (CH); IR (neat) νmax 2942, 2864, 1743,
1726, 1663, 1464, 1365, 1236, 1211, 1102, 1033 cm−1; HRMS (ESI-
TOF) [M + Na]+ calcd for C25H44NaO5Si 475.2856, found 475.2838;
mp 93−94 °C.
(1R*,5S*)-1-[(Triisopropylsilyloxy)methyl]-8,8-dimethyl-2,9-
dioxobicyclo[3.3.1]non-6-ene-7-carboxylic Acid Methyl Ester (14′).
A solution of 14 (11.0 mg, 0.0252 mmol) in acetone/H2O (40/1, 1.0
mL) was added p-toluene sulfonic acid monohydrate (9.6 mg, 0.0504
mmol, 2.0 equiv) at room temperature. The reaction mixture was
stirred at room temperature for 48 h before being quenched with
saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was
extracted with Et2O (10 mL × 3). The combined organic layer was
washed with brine (20 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/ethyl acetate = 10/1) to afford 14′
(3.5 mg, 33%) as an oil: Rf = 0.45 (hexane/ethyl acetate = 4/1);
1H NMR (400 MHz, CDCl3) δ 6.65 (1H, d, J = 7.0 Hz), 4.25 (1H, d,
J = 10.5 Hz), 4.11 (1H, d, J = 10.5 Hz), 3.73 (3H, s), 3.26 (1H, dd, J =
10.5, 4.5 Hz), 2.62−2.41 (2H, m), 2.10−1.98 (1H, m), 1.97−1.85
(1H, m), 1.25 (3H, s), 1.18 (3H, s), 1.06−1.02 (21H, brs); 13C NMR
(100 MHz, CDCl3) δ 206.9 (Cq), 206.0 (Cq), 166.0 (Cq), 140.8
(Cq), 136.4 (CH), 75.3 (Cq), 59.1 (CH2), 51.8 (CH3), 48.0 (Cq),
46.5 (CH), 36.7 (CH2), 24.1 (CH2), 22.0 (CH3), 21.5 (CH3), 17.9
(CH3), 11.9 (CH); IR (neat) νmax 2943, 2867, 1743, 1721, 1705, 1462,
1435, 1316, 1239, 1113, 1039 cm−1; HRMS (FAB-DFMS) [M + H]+
calcd for C23H39O5Si 423.2567, found 423.2576.
(1R*,5S*,7S*)-7-Acetoxymethyl-1-[(triisopropylsilyloxy)methyl]-
8,8-dimethyl-2-methoxybicyclo[3.3.1]non-2-en-9-one (16). To a
stirred solution of 14 (1.00 g, 2.29 mmol) in CH2Cl2 (11.4 mL)
was added Crabtree’s catalyst (9.2 mg, 11.5 μmol, 0.5 mol %) at room
temperature under an atmosphere of Ar, and the reaction mixture was
stirred under an atmosphere of H2 at room temperature. After the
reaction was completed, saturated aqueous NH4Cl solution (30 mL)
was added to the reaction mixture, and the aqueous layer was extracted
with CH2Cl2 (50 mL × 2). The combined organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
(1R*,5R*,7S*)-7-Acetoxymethyl-1-[(triisopropylsilyloxy)methyl]-
8,8-dimethyl-2-methoxybicyclo[3.3.1]non-2-ene-4,9-dione (17). To
a stirred solution 16 (17.3 mg, 0.0382 mmol) in CH2Cl2 (0.55 mL)
was added Pd(OH)2/C (2.0 mg, 3.77 μmol, 0.099 equiv), Cs2CO3
(62.2 mg, 0.191 mmol, 5.0 equiv), and TBHP in decane (34.8 μL,
0.191 mmol, 5.0 equiv) successively at room temperature. After the
reaction was completed, the reaction mixture was filtered through a
plug of Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography (hexane/
ethyl acetate = 3/2) to afford 17 (12.4 mg, 70%) as a white powder:
Rf = 0.45 (hexane/ethyl acetate = 1/1); 1H NMR (500 MHz, CDCl3)
δ 5.88 (1H, s, H-3), 4.35 (1H, d, J = 8.5 Hz), 4.16 (1H, dd, J = 11.0,
3.5 Hz), 4.05 (1H, d, J = 8.5 Hz), 3.77 (3H, s), 3.71 (1H, dd, J = 11.0,
9.0 Hz), 3.25 (1H, dd, J = 5.0, 2.5 Hz), 2.21 (1H, ddd, J = 13.5, 5.0, 2.5
Hz), 2.13−2.03 (1H, m), 1.98 (3H, s), 1.76 (1H, dt, J = 13.5, 5.0 Hz),
1.09 (3H, s), 1.07−0.92 (21H, m), 0.74 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 204.4 (Cq), 194.5 (Cq), 176.9 (Cq), 170.8 (Cq), 108.0
(CH), 65.5 (Cq), 64.4 (CH2), 60.5 (CH), 57.5 (CH2), 56.4 (CH3),
42.8 (Cq), 40.2 (CH), 32.5 (CH2), 24.3 (CH3), 20.8 (CH3), 17.8
(CH3), 17.1 (CH3), 11.9 (CH); IR (neat) νmax 2942, 2865, 1737,
1658, 1592, 1463, 1379, 1367, 1343, 1237, 1218, 1202, 1108 cm−1;
HRMS (ESI-TOF) [M + Na]+ calcd for C25H42NaO6Si 489.2648,
found 489.2637; mp 130−131 °C.
(1R*,5R*,7S*)-7-Allyl-1-[(triisopropylsilyloxy)methyl]-8,8-dimethyl-
2-methoxybicyclo[3.3.1]non-2-ene-4,9-dione (20). To a solution of
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17 (514.6 mg, 1.10 mmol) in MeOH (22.0 mL) was added K2CO3
(304.6 mg, 2.20 mmol, 2.0 equiv) at room temperature. After the
reaction was completed, the reaction mixture was concentrated under
reduced pressure. The residue was diluted with Et2O (30 mL) and
H2O (30 mL). The aqueous layer was extracted with Et2O (50 mL ×
2). The combined organic layer was washed with brine (100 mL × 1),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude alcohol 17a (ca. 535.1 mg) was used for the next step
without further purification.
To a stirred solution of 17a (ca. 535.1 mg) in CH2Cl2 (11 mL) was
added 2,6−lutidine (0.38 mL, 3.30 mmol, 3.0 equiv) and Tf2O (0.28
mL, 1.65 mmol, 1.5 equiv) successively at −78 °C. After the reaction
was completed, saturated aqueous NaHCO3 solution (60 mL) was
added to the reaction mixture. The aqueous layer was extracted with
Et2O (50 mL × 2). The combined organic layer was washed with
saturated aqueous CuSO4 solution (100 mL), brine (20 mL × 1),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude triflate 18 (ca. 645.0 mg) was unstable. Therefore, it was
used for the next step without further purification.
stirring was continued for 30 min at the same temperature. Then to
the reaction mixture was added (2-Th)Cu(CN)Li16 (2.9 mL, 0.1 M,
0.289 mmol, 5.5 equiv), and after the resulting mixture was stirred for
30 min at the same temperature, allyl bromide (22.8 μL, 0.263 mmol,
5.0 equiv) was added to the reaction mixture. After the reaction was
completed, 30% aqueous NH4OH solution (10 mL) was added to the
reaction mixture, and the aqueous layer was extracted with Et2O (10
mL × 3). The combined organic layer was washed with brine (20 mL ×
1), dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography (hexane/
ethyl acetate = 20/1) to afford 22 (26.6 mg, 99%) as a white powder:
Rf = 0.20 (hexane/ethyl acetate = 15/1); 1H NMR (500 MHz, CDCl3)
δ 5.97−5.82 (1H, m), 5.72−5.61 (1H, m), 5.61−5.50 (1H, m), 5.08−
4.85 (6H, m), 4.43 (1H, d, J = 8.5 Hz), 4.10 (1H, d, J = 8.5 Hz), 4.02
(3H, s), 3.34 (1H, ddt, J = 16.0, 5.5, 2.0 Hz), 3.27 (1H, ddt, J = 16.0,
5.5, 2.0 Hz), 2.54 (1H, dd, J = 14.0, 7.0 Hz), 2.49 (1H, dd, J = 14.0, 7.0
Hz), 2.22−2.12 (1H, m), 1.93 (1H, dd, J = 13.0, 4.5 Hz), 1.75−1.63
(1H, m), 1.60−1.50 (1H, m), 1.24 (1H, t, J = 12.5 Hz), 1.17−0.98
(24H, m), 0.67 (3H, s); 13C NMR (125 MHz, CDCl3) δ 206.6 (Cq),
197.0 (Cq), 174.1 (Cq), 136.7 (CH), 136.2 (CH), 134.1 (CH), 124.7
(Cq), 117.6 (CH2), 116.6 (CH2), 115.3 (CH2), 67.5 (Cq), 63.1 (Cq),
62.6 (CH3), 59.4 (CH2), 44.2 (Cq), 42.5 (CH2), 40.6 (CH), 35.3
(CH2), 33.8 (CH2), 28.5 (CH2), 24.4 (CH3), 18.1 (CH3), 18.0 (CH3),
16.3 (CH3), 12.3 (CH); IR (neat) νmax 2944, 2867, 1731, 1655, 1640,
1601, 1464, 1376, 1239, 1100 cm−1; HRMS (ESI-TOF) [M + Na]+
calcd for C31H50NaO4Si 537.3376, found 537.3351.
(1R*,5R*,7S*)-3,5,7-Triallyl-1-[(triisopropylsilyloxy)methyl]-8,8-di-
methyl-2-methoxybicyclo[3.3.1]non-2-ene-4,9-dione (22) (One-Pot
Procedure). To a stirred solution of 21 (21.8 mg, 0.0502 mmol) in
THF (1.5 mL) was added LTMP (0.50 mL, 0.5 M in THF, 0.25
mmol, 5.0 equiv) at −78 °C, and stirring was continued at the same
temperature for 2 h. Then, to the reaction mixture were added HMPA
(0.19 mL) and allyl bromide (21.7 μL, 0.251 mmol, 5.0 equiv). After
30 min, to the reaction mixture was added LTMP (0.50 mL, 0.5 M in
THF, 0.25 mmol, 5.0 equiv) at −78 °C, and stirring was continued at
the same temperature for 1 h. Then, to the reaction mixture was added
(2-Th)Cu(CN)Li (2.5 mL, 0.1 M, 0.25 mmol, 5.0 equiv) at the same
temperature, and after 30 min, allyl bromide (21.7 μL, 0.251 mmol, 5.0
equiv) was added. After the reaction was completed, 30% aqueous
NH4OH solution (10 mL) was added to the reaction mixture, and the
aqueous layer was extracted with Et2O (10 mL × 3). The combined
organic layer was washed with brine (20 mL × 1), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate = 20/1) to
afford 22 (13.0 mg, 50%) as a white powder.
(1S*,5R*,7S*)-3,5,7-Triallyl-1-benzoyl-8,8-dimethyl-2-
methoxybicyclo[3.3.1]non-2-ene-4,9-dione (23). To a stirred sol-
ution of 22 (50.8 mg, 0.0987 mmol) in THF (3 mL) was added TBAF
(0.49 mL, 1.0 M in THF, 0.49 mmol, 5.0 equiv) at room temperature.
After the reaction was completed, saturated aqueous NH4Cl (3 mL)
was added to the reaction mixture, and the aqueous layer was extracted
with Et2O (10 mL × 2). The combined organic layer was washed with
brine (10 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude 22a (ca. 55.9 mg) was used for the next
step without further purification.
To a stirred solution of crude 22a (ca. 55.9 mg) in CH2Cl2 (3.0
mL) were added Dess−Martin periodinane (62.4 mg, 0.148 mmol, 1.5
equiv) and NaHCO3 (41.5 mg, 0.494 mmol, 5.0 equiv) at room
temperature. After the reaction was completed, Et2O (15 mL) and a
mixture of saturated aqueous NaHCO3 solution (10 mL) and
saturated aqueous Na2S2O3 solution (10 mL) were added to the
reaction mixture. The aqueous layer was extracted with Et2O (10 mL ×
2). The combined organic layer was washed with brine (20 mL × 1),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude 22b (ca. 53.5 mg) was used for the next step without
further purification.
To a solution of 18 (ca. 645.0 mg) in THF (4.4 mL) was added
(vinyl)2Cu(CN)Li2 (7.92 mL, 0.25M, 1.98 mmol, 2.0 equiv)20 at −40 °C.
After the reaction was completed, 30% aqueous NH4OH solution
(30 mL) was added to the reaction mixture. The aqueous layer was
extracted with Et2O (30 mL × 3). The combined organic layer was
washed with brine (80 mL × 1), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/ethyl acetate = 10/1) to afford 20
(408.2 mg, 88% (three steps)) as a white powder: Rf = 0.25 (hexane/
1
ethyl acetate = 2/1); H NMR (500 MHz, CDCl3) δ 5.87, 5.65−5.51
(1H, m), 4.97 (1H, s), 4.95 (1H, d, J = 4.5 Hz), 4.37 (1H, d, J = 8.5
Hz), 4.07 (1H, d, J = 8.5 Hz), 3.77 (3H, s), 3.22 (1H, brs), 2.28−2.22
(2H, m), 1.83−1.67 (1H, m), 1.65−1.51 (2H, m), 1.07−0.95 (21H,
m), 1.04 (3H, s), 0.71 (3H, s); 13C NMR (125 MHz, CDCl3) δ 205.2
(Cq), 195.0 (Cq), 177.2 (Cq), 136.5 (CH), 116.8 (CH2), 107.8 (CH),
65.8 (Cq), 61.1 (CH), 57.9 (CH2), 56.3 (CH3), 43.6 (Cq), 40.4
(CH), 34.1 (CH2), 33.9 (CH2), 24.2 (CH3), 17.8 (CH3), 16.4 (CH3),
11.9 (CH); IR (neat) νmax 2942, 2864, 1736, 1657, 1592, 1463, 1341,
1249, 1213, 1198, 1131, 1101 cm−1; HRMS (FAB-DFMS) [M + H]+
calcd for C25H43O4Si 435.2931, found 435.2910; mp 136−137 °C.
(1R*,5R*,7S*)-5,7-Diallyl-1-[(triisopropylsilyloxy)methyl]-8,8-di-
methyl-2-methoxybicyclo[3.3.1]non-2-ene-4,9-dione (21). To a
stirred solution of 20 (17 mg, 0.0391 mmol) in THF (1 mL) was
added LTMP (0.78 mL, 0.5 M, 0.391 mmol, 10 equiv) at −78 °C, and
stirring was continued for 1 h at the same temperature. Then, to the
reaction mixture were added HMPA (0.25 mL) and allyl bromide
(0.05 mL, 0.587 mmol, 15 equiv). After the reaction was completed,
saturated aqueous NH4Cl solution (10 mL) was added to the reaction
mixture and the aqueous layer was extracted with Et2O (10 mL × 3).
The combined organic layer was washed with brine (20 mL × 1), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/ethyl acetate =
5/1) to afford 21 (17.9 mg, 96%) as a white powder: Rf = 0.25
1
(hexane/ethyl acetate = 2/1); H NMR (500 MHz, CDCl3) δ 5.89
(1H, s), 5.77−5.65 (1H, m), 5.64−5.53 (1H, m), 5.08−4.88 (4H, m),
4.43 (1H, d, J = 8.0 Hz), 4.10 (1H, d, J = 8.0 Hz), 3.77 (3H, s), 2.55
(1H, dd, J = 14.0, 7.0 Hz), 2.50 (1H, dd, J = 14.0, 7.0 Hz), 2.25−2.12
(1H, m), 1.95 (1H, dd, J = 13.0, 4.0 Hz), 1.82−1.70 (1H, m), 1.65−
1.51 (1H, m), 1.25 (1H, t, J = 13.0 Hz), 1.09−0.97 (24H, m), 0.69
(3H, s); 13C NMR (125 MHz, CDCl3) δ 206.1 (Cq), 196.3 (Cq),
175.9 (Cq), 136.6 (CH), 134.1 (CH), 117.6 (CH2), 116.8 (CH2),
108.1 (CH), 65.8 (Cq), 63.2 (Cq), 58.3 (CH2), 56.1 (CH3), 43.6
(Cq), 41.8 (CH2), 40.9 (CH), 34.9 (CH2), 33.9 (CH2), 24.3 (CH3),
17.89 (CH3), 17.88 (CH3), 16.3 (CH3), 12.0 (CH); IR (neat) νmax
2941, 2865, 1731, 1655, 1600, 1463, 1376, 1342, 1240, 1214, 1105
cm−1; HRMS (FAB-DFMS) [M + H]+ calcd for C28H47O4Si 475.3244,
found 475.3225; mp 58−59 °C.
To a stirred solution of 22b (ca. 53.5 mg) in THF (3 mL) was
added a solution of PhMgBr in THF (0.22 mL, 0.50 M, 0.109 mmol,
1.1 equiv) at −78 °C. Stirring was continued at −78 °C for 30 min.
After the reaction was completed, saturated aqueous NH4Cl (10 mL)
(1R*,5R*,7S*)-3,5,7-Triallyl-1-[(triisopropylsilyloxy)methyl]-8,8-di-
methyl-2-methoxybicyclo[3.3.1]non-2-ene-4,9-dione (22). To a
stirred solution of 21 (24.9 mg, 0.0525 mmol) in THF (2 mL) was
added LTMP (0.53 mL, 0.5 M, 0.263 mmol, 5.0 equiv) at −78 °C, and
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The Journal of Organic Chemistry
Article
was added to the reaction mixture, and the aqueous layer was extracted
with Et2O (10 mL × 2). The combined organic layer was washed with
brine (10 mL × 1), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude 22c (ca. 63.5 mg) was used for the next
step without further purification.
(1H, dd, J = 13.0, 3.5 Hz), 1.79−1.71 (2H, m), 1.69 (3H, s), 1.66 (3H,
s), 1.65 (9H, s), 1.59 (3H, s), 1.43 (1H, t, J = 13.0 Hz), 1.34 (3H, s),
1.11 (3H, s); 13C NMR (125 MHz, CD3OD) δ 209.7 (Cq), 195.2
(Cq), 138.4 (Cq), 135.2 (Cq), 134.3 (Cq), 133.5 (Cq), 133.2 (CH),
129.7 (CH), 128.9 (CH), 124.2 (CH), 122.5 (CH), 121.10 (Cq),
121.07 (CH), 78.3 (Cq), 62.1 (Cq), 49.1 (Cq), 44.7 (CH2), 42.4
(CH), 30.6 (CH2), 28.3 (CH2), 26.4 (CH3), 26.17 (CH3), 26.15
(CH3), 24.5 (CH3), 23.9 (CH2), 18.4 (CH3), 18.3 (CH3), 18.1 (CH3),
16.4 (CH3). Because of tautomerism C-2 and C-4 carbons could not
be identified in the 13C NMR spectrum.; IR (neat) νmax 3297, 2964,
2923, 2855, 2359, 2342, 1723, 1699, 1581, 1446, 1372, 1220, 1186
cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for C33H42NaO4 525.2981,
found 525.2991.
To a stirred solution of 22c (ca. 63.5 mg) in CH2Cl2 (3.0 mL) were
added Dess−Martin periodinane (103.9 mg, 0.247 mmol, 2.5 equiv)
and NaHCO3 (62.2 mg, 0.720 mmol, 7.5 equiv) at room temperature.
After the reaction was completed, Et2O (10 mL) and a mixture of
saturated aqueous NaHCO3 solution (10 mL) and saturated aqueous
Na2S2O3 solution (10 mL) were added to the reaction mixture. The
aqueous layer was extracted with Et2O (10 mL × 2). The combined
organic layer was washed with brine (20 mL × 1), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/ethyl acetate = 15/1) to
afford 23 (34.1 mg, 80% (four steps)) as an oil: Rf = 0.40 (hexane/
ethyl acetate = 4/1); 1H NMR (500 MHz, CDCl3) δ 7.61 (2H, d, J =
7.5 Hz,), 7.44 (1H, d, J = 7.5 Hz), 7.31 (2H, d, J = 7.5 Hz), 5.92−5.81
(1H, m), 5.81−5.70 (1H, m), 5.65−5.51 (1H, m), 5.18−5.10 (1H, m),
5.09−5.03 (2H, m), 5.03−4.93 (3H, m), 3.45 (3H, s), 3.30 (2H d, J =
6.0, 1.8 Hz), 2.64 (1H, dd, J = 14.0, 7.5 Hz), 2.57 (1H, dd, J = 14.0, 7.5
Hz), 2.35−2.26 (1H, m), 1.98 (1H, dd, J = 13.0, 4.5 Hz), 1.84−1.72
(1H, m), 1.71−1.61 (1H, m), 1.47 (1H, t, J = 13.0 Hz), 1.34 (3H, s),
1.19 (3H, s); 13C NMR (125 MHz, CDCl3) δ 207.3 (Cq), 196.3 (Cq),
193.0 (Cq), 170.9 (Cq), 137.0 (Cq), 136.6 (CH), 135.7 (CH), 133.8
(CH), 132.2 (CH), 128.2 (CH), 128.1 (CH), 121.2 (Cq), 119.0
(CH2), 116.8 (CH2), 115.9 (CH2), 74.2 (Cq), 64.8 (Cq), 61.8 (CH3),
47.7 (Cq), 42.9 (CH2), 41.4 (CH), 34.4 (CH2), 33.6 (CH2), 28.2
(CH2), 24.4 (CH3), 16.2 (CH3); IR (neat) νmax 3078, 2922, 2851,
1721, 1702, 1656, 1600, 1445, 1393, 1242, 1217 cm−1; HRMS (ESI-
TOF) [M + Na]+ calcd for C28H32NaO4 455.2198, found 455.2180.
(1R*,5R*,7S*)-1-Benzoyl-4-hydroxy-8,8-dimethyl-3,5,7-tris(3-
methylbut-2-enyl)bicyclo[3.3.1]non-3-ene-2,9-dione (Nemorosone).
Compound 23 (19.4 mg, 0.0448 mmol) and Grubbs II catalyst (0.38
mg, 4.48 μmol, 1 mol %) were added to a sealed tube. Liquid
isobutene (5 mL) was added via a dry ice condenser to the sealed tube
cooled at −78 °C. The closed sealed tube was slowly warmed to
60 °C. After being stirred for 4 h, the sealed tube was cooled to −78 °C,
opened, and warmed to room temperature to vent off the excess
isobutene. The residue was purified by flash chromatography (hexane/
ethyl acetate = 15/1) to afford 23a (21.1 mg, 91%) as an oil: Rf = 0.40
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR assignments and spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone and Fax: +813-5286-3240. E-mail: mnakada@waseda.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported in part by a Grant-in-Aid
for Scientific Research on Innovative Areas “Organic Synthesis
based on Reaction Integration” (No. 2105) and the Global
COE program “Center for Practical Chemical Wisdom” by
MEXT and a Waseda University Grant for Special Research
Projects.
REFERENCES
■
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(hexane/ethyl acetate = 10/1); H NMR (500 MHz, CDCl3) δ 7.61
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