Total Synthesis of (-)-Carinatine A and (+)-Lycopladine A

Article abstract of DOI:10.1021/acs.joc.6b01435

An efficient synthesis of two Lycopodium alkaloids, (-)-carinatine A and (+)-lycopladine A, is achieved in eight steps. The synthesis features an intramolecular aldol reaction for assembling the 6,5-fused ring system, a subsequent Tsuji-Trost allylation for generating a quarternary carbon center, and a 6π-electrocyclization to form the pyridine ring.

Full text of DOI:10.1021/acs.joc.6b01435

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Article
Total Synthesis of (-)-Carinatine A and (+)-Lycopladine A
Lingxing Meng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01435 • Publication Date (Web): 02 Aug 2016
Downloaded from http://pubs.acs.org on August 2, 2016
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Total Synthesis of (-)-Carinatine A and (+)-Lycopladine A
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Lingxing Meng*
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai
200032, China
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menglx@sioc.ac.cn
Abstract
An efficient synthesis of two Lycopodium alkaloids, (ꢀ)ꢀcarinatine A and
(+)ꢀlycopladine A is achieved in eight steps. The synthesis features an intramolecular
aldol reaction for assembling the 6,5ꢀfused ring system, a subsequent TsujiꢀTrost
allylation for generating a quarternary carbon center, and a 6πꢀelectrocyclization to
form the pyridine ring.
Introduction
Carinatine A (1) is a tetracyclic alkaloid isolated from Phlegmariurus carinatus, a
plant that has been used as a traditional Chinese medicine for the treatment of
rheumatism, swelling and pain.1 This compound, together with the structurallyꢀrelated
lycopladine A (2)2 and lycoposerramine R (3)3, belongs to the growing Lycopodium
alkaloid family (Figure 1). The family contains at least 300 members with a wide
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range of biological activities, such as antiꢀtumor and acetylcholine esterase (AChE)
inhabition.4 During the past decades, these alkaloids have piqued the interest of a
large number of research groups, whose studies have culminated in elegant total
syntheses of some Lycopodium alkaloids and new synthetic methodologies for
assembling their core structures.5
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To date, four groups have disclosed their results on the total synthesis of
lycopladine A. In 2006, Toste group achieved the first total synthesis of
(+)ꢀlycopladine A by taking advantage of goldꢀcatalyzed cyclization of silylenol ether
with alkyne to install the key quaternary center of hydrindanone intermediate.6a Four
years later, Martin and coꢀworkers reported their synthesis of (±)ꢀlycopladine A, in
which the key tricyclic framework was elaborated via sequential conjugate addition
and enolate arylation reactions of 3ꢀchloroꢀ2ꢀmethylpyridine and an unsaturated
βꢀketoester.6b In 2011, Hiroya et al. accomplished their total synthesis of
(+)ꢀlycopladine A by utilizing diastereoselective protection of carbonyl group in a
1,3ꢀcyclohexanedione derivative as the key step.6c Recently, Yang group described
another route for total synthesis of (+)ꢀlycopladine A, in which Helquist annulation
was employed as the key step.6d In this paper, we wish to report the total synthesis of
(ꢀ)ꢀcarinatine A and (+)ꢀlycopladine A by using the same intermediate.
Figure 1. Structures of carinatine A, lycopladine A and lycoposerramine R
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Scheme 1 depicts our retrosynthetic analysis for carinatine A and lycopladine A. We
believed that these two alkaloids could be assembled from common intermediate 4 via
suitable transformations. The pyridine ring in the oxime 4 is traced back to diallyl
compound 5 via transformation and subsequent 6πꢀelectrocyclozation. This cisꢀ6,5
fused ring system bearing the key quarternary C12 may generate from the
corresponding allyl ester 6 via TsujiꢀTrost allylation, 6 could be formed by
intramolecular aldol reaction of tricarbonyl compound 7. 7 is disassembled into
known ketone 9 and diazo ester 8.
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Scheme 1. Retrosynthetic analysis of carinatine A and lycopladine A
Results and Discussion
As shown in Scheme 2, our synthesis started from the diastereoselective Michael
addition of silylenol ether 8 to known unsaturated ketone 9 under the activation of
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zinc trifluoromethanesulfonate, which generated diazo compound 10 in 91% yield
with 2:1 diastereomeric ratio.7 The transformation of diazo group in 10 to the
corresponding carbonyl group proved to be problematic. Initial attempts by using
oxidative reagents (eg. mꢀCPBA, tꢀBuOCl or DMDO) failed to give the tricarbonyl
compound 7 because of easy epoxidation of CꢀC double bond. This problem forced us
to consider applying Ganem’s deoxygenation method to accomplish the desired
transformation.8 To our delight, treatment of 10 with substoichiometric amount of
rhodium(II) acetate dimer and 2.0 equiv. of 1,2ꢀepoxycyclohexene delivered the
tricarbonyl compound 7 in 33% yield (isolated as its monoꢀhydrate form, see
experiental section). It was found that major side reaction was the cyclopropanation of
resultant rhodium carbene with the olefin moiety, we decided to inhibit this side
reaction by introducing more epoxide reagent and increasing concentration of the
reaction. Yield could be increased to 73% if 10 equiv. of 1,2ꢀepoxycyclohexene was
used when the reaction was carried out at 0.5 M. Although tricarbonyl form of 7 was
not isolated directly, we attempted the intramolecular aldol reaction of 7. Yb(OTf)3
was a suitable catalyst,9 leads to the formation of 11 in moderate yield (53% at 0.5
mmol scale, 45% at 4 mmol scale) with 1.5:1 diastereoselectivity at C4 position.10
Subsequent protection of tertiary alcohol with TMS group gave allyl carboxylate ester
12.
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Scheme 2. Construction of cisꢀ6,5 fused bicyclic intermediate 12
With 12 in hand, we tried TsujiꢀTrost allylation under the conditions developed by
Stoltz and coworkers.11 It was found that under the catalysis of Pd2(dba)3 and
(R)ꢀtꢀBuꢀPHOX, decarboxylative allylation of 12 proceeded smoothly to afford
product 13 as a single isomer. After oximation of 13, unexpected hemiꢀketal
compound 14 was isolated, whose structure was established via Xꢀray structural
analysis (Scheme 3). The formation of 14 indicated that the decarboxylative allylation
took place at C5 position of 13 rather than the desired C4. This result implied that
enolate 15 generated in the decarboxylative step might undergo TMS migration to
produce the more stable enolate 16, for its less steric repulsion between the enolate
anion (smaller than ꢀOTMS) and the quarternary center.
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PdL+
PdL+
OSiMe3
Me
Me
TMS
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5
Oꢀ
migration
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Oꢀ
OSiMe3
O
O
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16
[PdL]
ꢀCO2
ꢀPdL
Me
5
Pd2(dba)3, (R)ꢀtꢀBuꢀPHOX
OTMS
12
4 O
THF, 50 °C, 52%
O
13
H2NOH—HCl
NaOAc
EtOH, reflux
50%
Me
5
OTMS
OH
4
N
O
ORTEP of 14
14
Scheme 3. Decarboxylative allylationof silyl ether 12
Since trimethylsilyl protecting group underwent migration, we decided to change
the protecting group of tertiary alcohol 11 (Scheme 4). After the intramolecular aldol
reaction of 7, acetyl anhydride was added to quench the reaction to give ester 17.12
Surprisingly, the ester 17 was inert under the previous decarboxylative allylation
conditions. After some trials, we found that under the catalysis of 10 mol % Pd(PPh3)4,
the decarboxylative allylation occurred at room temperature to provide the desired
product 18 and 18’ in 55% yield with 10:1 diastereoselectivity. It is notable that
addition of 1.0 equiv. of CO(OAllyl)2 and 4Å molecular sieves were necessary to
suppress the protonation side product. After treatment of 18 with 6 N HCl in MeCN,
elimination took place to provide dienone 19 in 63% yield as a mixture of sꢀtrans and
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sꢀcis conformational isomers, together with simple hydrolysis product 20 in 35% yield.
The structure of alcohol 20 was confirmed by Xꢀray crystallographic analysis, which
was subjected to SOCl2/pyridine mediated elimination to give the dienone 19 in 61%
yield.
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Scheme 4. Synthesis of dienone 19
Starting from the dienone 19, we completed the total syntheses of carinatine A and
lycopladine A (Scheme 5). Treatment of 19 with 2.5 equiv of NH2OH⋅HCl and 2.5
equiv. of K2CO3 in EtOH/CHCl3 under microwave irradiation gave the cyclization
product 4 in 67% yield.13 This process might go through four cascade steps:
oximation, isomerization of the sꢀtransꢀdiene to form the intermediate 21,
6πꢀelectrocyclization
of
21
and
dehydrative
aromatization.
Finally,
hydroborationꢀoxidation of terminal olefin moiety in 4 produced alcohol 22, which
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was subjected to reductive removal of oxime with TiCl3 to furnish (+)ꢀlycopladine A
(2).14 We also observed the isomeric lactol form 23 coexisting with 2 as reported
previously.6b,d In a parallel procedure, intramolecular Mitsunobu reaction of 22 with
nꢀBu3P and 1,1’ꢀ(azodicarbonyl)dipiperidine (ADDP) afforded (ꢀ)ꢀcarinatine A (1).15
The analytical data of these two synthetic compounds were identical with those
reported.
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Me
OH
N
6 -electro
cyclozation
H2NOH—HCl, K2CO3
19
ꢀH2O
67%
EtOH, CHCl3, 140 °C
microwave
N
HO
21
Me
Me
9ꢀBBN, THF, 60 °C
N
N
then H2O2, 30% NaOH
89%
N
N
HO
Me
HO
OH
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TiCl3
acetone, H2O, r.t.
74%
nꢀBu3P, ADDP
THF, 60 °C
80%
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N
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N+
O
O
ꢀO
OH
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Scheme 5. Completion of the synthesis of (ꢀ)ꢀcarinatine A and (+)ꢀlycopladine A
In summary, we have achieved the first total synthesis of (ꢀ)ꢀcarinatine A (1) and
developed another synthetic route to (+)ꢀlycopladine A (2). Only 8 steps were required
for synthesizing both alkaloids from the known enone 9. The synthesis features an
intramolecular aldol reaction, a TsujiꢀTrost allylation and a 6πꢀelectrocyclization as
the key steps. This strategy may be applicable for assembling other related alkaloids.
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General methods. Tetrahydrofuran was freshly redistilled from sodium under
argon when using. Thin layer chromatography was performed on TLC silica gel 60
F254. Flash column chromatography was performed using normal phase silica gel.
Preparative thin layer chromatography separations were carried out on 0.50 mm silica
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1
gel plates (60 F254) In H NMR spectra, chemical shifts were given in relative to
tetramethylsilane (δ 0.00 ppm) in CDCl3 or the undeuterated solvent residual signals.
In 13C NMR spectra, chemical shifts were internally referenced to the deuterated
solvent signals. Mass spectra and high resolution mass spectra were recorded on an
ESI, ESIꢀFTMS or EI type spectrometer.
(R)-2-allyl-5-methylcyclohex-2-enone (9). The procedure was modified from
Caine’s method.16 To a solution of (R)ꢀpulegone (54 mL, 92% pract. from Acros, 0.33
mol) in 260 mL MeOH was added H2O2 (61 mL, 30% aq., 0.60 mol). A solution of
LiOH⋅H2O (1.38 g, 0.033 mol) in 20 mL deionized water was added dropwise. The
flask was immerged in water bath to maintain the reaction temperature at rt. After
stirring for 6 hours, 260 mL saturated NaCl solution was added to quench, and MeOH
was removed under reduced pressure. The solution was extracted by EtOAc (250
mL×3), washed with brine and dried over Na2SO4. Removal of the solvent under
reduced pressure gave epoxide product as colorless liquid, which was used without
any further purification.
To a suspension of NaH (16.4 g, 60% in oil, 0.41 mol) in 300 mL dry THF at 0 °C
was added 4ꢀmethylbenzenethiol (51.0 g, 0.41 mol, in 200 mL THF). The solution
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was slowly warmed to rt and stirred for 30 min. After no gas released, epoxide (from
previous step) in 80 mL THF was added slowly. The solution was heated to reflux for
8 hours. After slightly cooled, allyl bromide (41 mL, 0.48 mol) in 100 mL THF was
added dropwise. The solution was maintained at 50 °C for 6 hours and cooled to rt.
The suspension was filtered through a pad of celite, washed with EtOAc and filtrate
was concentrated under reduced pressure. 300 mL NH4Cl solution was added to
quench, followed by extracted with EtOAc (250 mL×3), washed with brine. Removal
of the solvent under reduced pressure gave crude sulfide as yellow oil, which was
used directly in next step.
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To a solution of sulfide (from previous step) in 400 mL EtOAc was added HOAc
(95 mL, 1.6 mol), NaBO3⋅4H2O (152 g, 1.0 mol), H2O (80 mL). The suspension was
heated to 60 °C and stirred on a mechanical stirrer overnight. After cooling, the
suspension was filtered through a pad of celite and concentrated under reduced
pressure. Na2CO3 solution was slowly added to quench until no gas evolved. The
solution was extracted by EtOAc (250 mL×3), washed with brine and dried over
Na2SO4. The solvent was concentrated to give crude product, which was purified by
vaccum distillation (88ꢀ90 °C, 10 mbar). Unsaturated ketone 9 (20.0 g, 44% for 3
steps) was a light yellow liquid. The spectrum data were identical with those
reported.16
1H NMR (400 MHz, CDCl3) δ 6.74ꢀ6.64 (m, 1H), 5.85ꢀ5.75 (m, 1H), 5.11ꢀ4.94 (m,
2H), 2.93 (d, J = 6.5 Hz, 2H), 2.55ꢀ2.33 (m, 2H), 2.26ꢀ1.96 (m, 3H), 1.04 (d, J = 6.3
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 199.3, 145.2, 137.8, 136.0, 116.3, 46.6, 34.5,
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33.4, 30.7, 21.3. HRMS (ESI) calcd. for C10H15O (M + H)+ 151.1118, found
151.1117.
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Allyl-4-((1S,5R)-2-allyl-5-methyl-3-oxocyclohexyl)-2-diazo-3-oxobutanoate (10).
To a solution of zinc trifluoromethanesulfonate (129 mg, 0.36 mmol) in 15 mL dry
CH2Cl2 under argon atmosphere was added 9 (1.07 g, 7.1 mmol, in 5.0 mL CH2Cl2).
The solution was cooled to 0 °C and 8 (10.6 mmol, crude, in 8.0 mL CH2Cl2)7 was
added. The reaction was warmed to rt and stirred overnight. After concentration and
reꢀdissolved in 25 mL THF, HCl (25 mL, 6.0 N) was added and then the solution was
stirred for 6 hours. The solution was extracted by EtOAc (50 mL×3), washed with
NaHCO3, brine and dried over Na2SO4. Purification by column chromatography (SiO2,
230ꢀ400 mesh, eluting with hexane/EtOAc, 15:1 to 10:1) gave epimer mixture 10
(2.06 g, 91%, ca. 2.0:1 d.r.) as yellow liquid. Futher purification by preparative thin
layer chromatography gave individual isomers for NMR analysis.
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Major isomer. 1H NMR (400 MHz, CDCl3) δ 5.97ꢀ5.90 (m, 1H), 5.82ꢀ5.67 (m, 1H),
5.40ꢀ5.25 (m, 2H), 5.06ꢀ4.92 (m, 2H), 4.71 (dt, J = 5.8, 1.3 Hz, 2H), 2.95ꢀ2.86 (m,
1H), 2.79 (dd, J = 16.4, 4.4 Hz, 1H), 2.64ꢀ2.56 (m, 2H), 2.47 (ddd, J = 14.1, 7.6, 6.3
Hz, 1H), 2.39 (ddd, J = 12.6, 4.2, 1.8 Hz, 1H), 2.18ꢀ2.07 (m, 1H), 2.05ꢀ1.91 (m, 2H),
1.85ꢀ1.76 (m, 1H), 1.61ꢀ1.50 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 211.3, 191.4, 160.8, 136.3, 131.4, 119.4, 116.3, 76.4, 66.0, 53.4, 50.1, 38.2,
38.0, 36.3, 30.6, 30.4, 22.3. HRMS (ESI) calcd. for C17H22N2NaO4 (M + Na)+
341.1476, found 341.1472.
Minor isomer. 1H NMR (400 MHz, CDCl3) δ 5.97ꢀ5.89 (m, 1H), 5.76ꢀ5.66 (m, 1H),
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5.39ꢀ5.24 (m, 2H), 5.08ꢀ4.96 (m, 2H), 4.74ꢀ4.66 (m, 2H), 2.96 (dd, J = 17.0, 7.1 Hz,
1H), 2.82 (dd, J = 17.0, 6.9 Hz, 1H), 2.65ꢀ2.55 (m, 1H), 2.43ꢀ2.23 (m, 4H), 2.19ꢀ2.05
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(m, 2H), 1.76ꢀ1.68 (m, 1H), 1.64ꢀ1.54 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H). C NMR
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(101 MHz, CDCl3) δ 213.1, 191.1, 160.9, 135.4, 131.4, 119.3, 116.8, 76.3, 65.9, 54.2,
47.2, 43.9, 34.8, 34.7, 34.5, 29.8, 21.5. HRMS (ESI) calcd. for C17H22N2NaO4 (M +
Na)+ 341.1476, found 341.1472.
Allyl-4-((1S,5R)-2-allyl-5-methyl-3-oxocyclohexyl)-2,2-dihydroxy-3-oxobutanoa
te (7, hydrate form). To a solution of 10 (6.36 g, 20 mmol) in 20 mL dry toluene was
added 1,2ꢀepoxycyclohexene (20 mL, 200 mmol) and rhodium(II) acetate dimer (44
mg, 0.10 mmol). The reaction was heated to 50 °C and stirred for 1 hour until no gas
evolved. The solution was concentrated and purified by column chromatography
(SiO2, 230ꢀ400 mesh, eluting with hexane/acetone, 6:1 to 4:1), which produced
mixture 7 (4.64 g, 73%) as dark yellow liquid.
Tricarbonyl compound 7 reacted with residual water in silica column and deuterated
solvents so NMR spectra were recorded as hydrate form. Further efforts for
purification such as heating caused complex mixture.9
1H NMR (400 MHz, CDCl3) δ 6.02ꢀ5.84 (m, 1H), 5.74ꢀ5.65 (m, 1H), 5.46ꢀ5.21 (m,
2H), 5.12ꢀ4.88 (m, 2H), 4.83ꢀ4.60 (m, 2H), 2.94ꢀ2.69 (m, 1H), 2.47ꢀ2.00 (m, 7H),
13
1.91ꢀ1.55 (m, 3H), 0.99 (d, J = 6.2 Hz, 3H). C NMR (126 MHz, CDCl3) δ 212.9,
211.5, 202.3, 202.1, 168.5, 168.5, 135.7, 135.1, 130.5, 130.3, 120.5, 120.3, 117.1,
116.7, 92.8, 92.7, 67.7, 67.7, 54.0, 52.7, 50.2, 47.1, 39.8, 37.6, 35.6, 34.5, 34.1, 34.04,
33.9, 30.5, 30.5, 29.8, 22.3, 21.4. IR (neat, cmꢀ1) ν 3439, 2955, 1745, 1733, 1705,
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1455, 1275. HRMS (ESI) calcd. for C17H23O5 (M + H – H2O)+ 307.1540, found
307.1538.
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(3aS,5R,7aS)-allyl-7a-allyl-1-hydroxy-5-methyl-2,7-dioxooctahydro-1H-indene-
1-carboxylate (11). To a solution of 7 (918 mg, 3.0 mmol) in 30 mL dry CH2Cl2 was
added ytterbium(III) trifluoromethanesulfonate (186 mg, 0.30 mmol). The solution
was heated to 60 °C (bath temp.) for 24 hours. After cooling to rt, NaHCO3 solution
was added to quench the reaction. The mixture was filtered through celite and
extracted by CH2Cl2 (30 mL×3), washed with brine and dried over Na2SO4.
Purification by column chromatography (SiO2, 230ꢀ400 mesh, eluting with
hexane/acetone, 10:1 to 6:1) gave 11 (413 mg, 45%, ca. 1.5:1 d.r.) as yellow liquid.
Futher purification by preparative thin layer chromatography gave individual isomers
for NMR analysis.
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Major isomer. 1H NMR (400 MHz, CDCl3) δ 5.89ꢀ5.80 (m, 1H), 5.77ꢀ5.68 (m, 1H),
5.36ꢀ5.24 (m, 2H), 5.14ꢀ5.05 (m, 2H), 4.69ꢀ4.60 (m, 1H), 4.56 (dd, J = 12.7, 6.3 Hz,
1H), 3.83 (s, br, 1H), 2.85 (dd, J = 16.5, 12.4 Hz, 1H), 2.76ꢀ2.66 (m, 1H), 2.56 (dd, J
= 13.7, 7.5 Hz, 1H), 2.52ꢀ2.43 (m, 2H), 2.38 (dd, J = 13.7, 7.3 Hz, 1H), 2.31ꢀ2.20 (m,
1H), 2.00 (dd, J = 16.9, 11.2 Hz, 1H), 1.95ꢀ1.86 (m, 1H), 1.68 (ddd, J = 14.1, 10.7,
13
5.9 Hz, 2H), 1.06 (d, J = 6.6 Hz, 3H). C NMR (126 MHz, CDCl3) δ 212.2, 209.4,
170.6, 133.6, 130.8, 120.3, 119.5, 84.4, 67.5, 61.1, 48.8, 42.5, 41.6, 37.4, 34.4, 25.9,
21.8. HRMS (ESI) calcd. for C17H23O5 (M + H)+ 307.1540, found 307.1539.
Minor isomer. 1H NMR (400 MHz, CDCl3) δ 6.12ꢀ6.03 (m, 1H), 5.96ꢀ5.87 (m, 1H),
5.55 (s, 1H), 5.40ꢀ5.26 (m, 2H), 5.12ꢀ5.03 (m, 2H), 4.74ꢀ4.66 (m, 2H), 3.06 (ddd, J =
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2.49ꢀ2.37 (m, 2H), 2.30ꢀ2.22 (m, 1H), 2.20ꢀ2.04 (m, 2H), 1.85ꢀ1.76 (m, 2H), 1.10 (d,
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J = 6.4 Hz, 3H). C NMR (126 MHz, CDCl3) δ 217.3, 210.0, 167.7, 131.9, 130.9,
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120.2, 118.4, 88.5, 66.8, 60.2, 47.7, 38.9, 37.9, 37.8, 31.7, 31.7, 22.1. HRMS (ESI)
calcd. for C17H23O5 (M + H)+ 307.1540, found 307.1539.
(3aS,5R,7aS)-allyl-7a-allyl-5-methyl-2,7-dioxo-1-((trimethylsilyl)oxy)octahydro
-1H-indene-1-carboxylate (12). To a solution of 11 (675 mg, 2.2 mmol) in 22 mL dry
CH2Cl2 was added 2,6ꢀlutidine (0.41 mL, 3.5 mmol) and trimethylsilyl
trifluoromethanesulfonate (0.60 mL, 3.3 mmol). The reaction was stirred at rt for 30
minutes, quenched by NaHCO3 solution, extracted by CH2Cl2 (30 mL×3), washed
with brine and dried over Na2SO4. Purification by column chromatography (SiO2,
230ꢀ400 mesh, eluting with hexane/EtOAc, 20:1) gave a mixture of 12 (675 mg, 81%,
ca. 1.5:1 d.r.) as colorless liquid. Futher purification by preparative thin layer
chromatography gave individual isomers for NMR analysis.
Major isomer. 1H NMR (400 MHz, CDCl3) δ 5.95ꢀ5.90 (m, 1H), 5.72ꢀ5.68 (m, 1H),
5.33 (ddd, J = 13.8, 11.5, 1.2 Hz, 2H), 5.12ꢀ4.99 (m, 2H), 4.75ꢀ4.70 (m, 1H),
4.61ꢀ4.49 (m, 1H), 2.85ꢀ2.70 (m, 2H), 2.65 (dd, J = 13.8, 4.8 Hz, 1H), 2.51 (dd, J =
15.1, 5.8 Hz, 1H), 2.38ꢀ2.21 (m, 3H), 2.13 (dd, J = 13.8, 9.7 Hz, 1H), 1.98ꢀ1.92 (m,
13
1H), 1.72ꢀ1.64 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H), 0.13 (s, 9H). C NMR (101 MHz,
CDCl3) δ 210.0, 209.0, 168.7, 133.8, 131.1, 119.6, 119.1, 86.6, 66.3, 60.6, 48.7, 41.2,
37.3, 34.9, 34.0, 29.4, 20.7, 1.4. HRMS (ESI) calcd. for C20H31O5Si (M + H)+
379.1935, found 379.1933.
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Minor isomer. 1H NMR (400 MHz, CDCl3) δ 5.97ꢀ5.74 (m, 2H), 5.37ꢀ5.21 (m, 2H),
5.08ꢀ4.97 (m, 2H), 4.70ꢀ4.65 (m, 1H), 4.55ꢀ4.50 (m, 1H), 2.76ꢀ2.64 (m, 2H),
2.64ꢀ2.53 (m, 1H), 2.43ꢀ2.26 (m, 3H), 2.25ꢀ2.13 (m, 1H), 2.03 (dd, J = 15.7, 11.3 Hz,
1H), 1.87ꢀ1.81 (m, 1H), 1.76ꢀ1.69 (m, 1H), 1.02 (d, J = 6.5 Hz, 1H), 0.16 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 210.4, 209.3, 170.7, 134.3, 131.5, 119.3, 118.1, 85.4, 66.4,
63.5, 48.6, 41.6, 40.3, 38.1, 33.3, 26.9, 21.7, 1.7. HRMS (ESI) calcd. for C20H31O5Si
(M + H)+ 379.1935, found 379.1933.
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(2R,3aS,5R,7aR)-2,7a-diallyl-5-methyl-2-((trimethylsilyl)oxy)hexahydro-1H-ind
ene-1,7(7aH)-dione (13). To a hot air gun dried Schlenk bottle, charged with
bis(dibenzylideneacetone)palladium(0) (85 mg, 93 ꢁmol) and (R)ꢀ4ꢀtertꢀbutylꢀ2ꢀ[2ꢀ
(diphenylphosphino)phenyl]ꢀ2ꢀoxazoline (89 mg, 0.23 mmol) under Ar atmosphere
was added 12 (700 mg, 1.9 mmol, in 19 mL THF) via syringe. The solution was
bubbled under argon for 5 minutes and heated to 50 °C. After 2 hours, the solvent was
removed under reduced pressure, which was chromatographed (SiO2, 230ꢀ400 mesh,
eluting with hexane/EtOAc, 15:1), single isomer product 13 (322 mg, 52%) was got
as light yellow liquid.
1H NMR (400 MHz, CDCl3) δ 5.84ꢀ5.75 (m, 1H), 5.64ꢀ5.56 (m, 1H), 5.20ꢀ4.99 (m,
4H), 2.56 (dd, J = 13.6, 6.6 Hz, 1H), 2.47ꢀ1.98 (m, 8H), 1.85ꢀ1.61 (m, 3H), 1.05 (d, J
= 6.2 Hz, 3H), 0.13 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 212.3, 205.9, 132.6, 132.6,
119.6, 118.9, 80.6, 65.0, 47.4, 40.5, 38.5, 37.9, 35.8, 32.5, 28.9, 22.2, 2.1. HRMS (ESI)
calcd. for C19H31O3Si (M + H)+ 335.2039, found 335.2037.
(2a1R,4R,5aS,7R,7aS)-2a1,7-diallyl-4-methyl-7-((trimethylsilyl)oxy)-2a1,3,4,5,5a,
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6,7,7a-octahydroindeno[7,1-cd]isoxazol-7a-ol (14). To a solution of 13 (67 mg, 0.20
mmol) in 2.0 mL ethanol was added NH2OH⋅HCl (15 mg, 0.22 mmol) and NaOAc
(25 mg, 0.30 mmol). The solution was heated to reflux for 2 hours and cooled, diluted
by water (10 mL), extracted by EtOAc (5 mL×3), washed with brine and dried over
Na2SO4. Purification by column chromatography (SiO2, 230ꢀ400 mesh, eluting with
hexane/EtOAc, 8:1) gave 14 (36 mg, 50%) as white solid.
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1H NMR (400 MHz, CDCl3) δ 5.88ꢀ5.76 (m, 2H), 5.18ꢀ5.08 (m, 4H), 2.93 (s, br,
1H), 2.57ꢀ2.47 (m, 3H), 2.38 (dd, J = 14.7, 8.4 Hz, 1H), 2.07ꢀ1.99 (m, 2H), 1.78ꢀ1.65
(m, 3H), 1.65ꢀ1.54 (m, 2H), 1.46ꢀ1.37 (m, 1H), 1.01 (d, J = 6.0 Hz, 3H), 0.17 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 163.3, 134.5, 134.1, 119.0, 117.9, 115.2, 85.4, 59.7,
40.8, 40.4, 35.6, 34.2, 32.8, 32.6, 31.7, 22.1, 2.7. HRMS (ESI) calcd. for
C19H32NO3Si (M + H)+ 350.2148, found 350.2146. m.p. 94ꢀ96 °C (recrystallized from
ethanol).
(3aS,5R,7aS)-allyl-1-acetoxy-7a-allyl-5-methyl-2,7-dioxooctahydro-1H-indene-
1-carboxylate (17). To a solution of 7 (1.22g, 4.0 mmol) in 40 mL dry CH2Cl2 was
added ytterbium(III) trifluoromethanesulfonate (248 mg, 0.40 mmol). The solution
was stirred at 60 °C (bath temp.) for 24 hours (TLC monitored). After cooling to rt,
Ac2O (1.2 mL, 12 mmol) was added and the mixture was stirred for 3 hours. Then 30
mL saturated NaHCO3 solution was added to quench and stirred for 30 minutes. The
mixture was filtered and filtrate was extracted by CH2Cl2 (40 mL×3), washed with
brine and dried over Na2SO4. Purification by column chromatography (SiO2, 230ꢀ400
mesh, eluting with hexane/EtOAc, 10:1 to 6:1) gave mixture 17 (630 mg, 45%, ca.
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1.5:1 d.r.) as yellow liquid. Futher purification by preparative thin layer
chromatography gave individual isomers for NMR analysis.
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Major isomer. 1H NMR (400 MHz, CDCl3) δ 5.94ꢀ5.86 (m, 1H), 5.84ꢀ5.73 (m, 1H),
5.39ꢀ5.25 (m, 2H), 5.15ꢀ5.05 (m, 2H), 4.75ꢀ4.62 (m, 2H), 2.85ꢀ2.54 (m, 4H),
2.43ꢀ2.35 (m, 1H), 2.34ꢀ2.16 (m, 3H), 2.15 (s, 3H), 1.83ꢀ1.67 (m, 2H), 1.05 (d, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 208.1, 203.1, 169.5, 165.9, 132.5, 131.0,
119.9, 118.9, 88.9, 66.8, 59.3, 48.2, 39.2, 38.7, 37.7, 33.2, 29.8, 21.8, 21.0. HRMS
(ESI) calcd. for C19H25O6 (M + H)+ 349.1648, found 349.1646.
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The minor isomer decomposed smoothly (acetyl removed) in column
chromatography, preparative thin layer chromatography or HPLC so no clear NMR
data were recorded.
18 and 18’. To a hot air gun dried Schlenk bottle charged with 4 Å molecular sieves
(200 mg) and Pd(PPh3)4 (116 mg, 0.10 mmol) under Ar atmosphere was added 6.0 mL
dry THF. 17 (348 mg, 1.0 mmol, in 4.0 mL THF) and diallyl carbonate (0.14 mL, 1.0
mmol) was added via syringe. The solution was bubbled under argon for 5 minutes
and stirred at rt for 12 h. After completion of the reaction, the mixture was filtered by
celite and filtrate was concentrated. Purification by column chromatography (SiO2,
230ꢀ400 mesh, eluting with hexane/EtOAc, 12:1 to 8:1) gave 18 (151 mg, 50%) as
yellow semiꢀsolid and its epimer 18’ (15 mg, 5%) as yellow oil.
(1S,3aS,5R,7aS)-1,7a-diallyl-5-methyl-2,7-dioxooctahydro-1H-inden-1-yl
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acetate (18). H NMR (400 MHz, CDCl3) δ 5.96ꢀ5.83 (m, 1H), 5.64ꢀ5.49 (m, 1H),
5.15ꢀ4.98 (m, 4H), 2.81 (dd, J = 13.2, 5.4 Hz, 1H), 2.71ꢀ2.58 (m, 3H), 2.56ꢀ2.48 (m,
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2H), 2.43 (dd, J = 14.4, 8.4 Hz, 1H), 2.34ꢀ2.25 (m, 1H), 2.20ꢀ2.12 (m, 1H), 2.00 (s,
3H), 1.88ꢀ1.81 (m, 1H), 1.79ꢀ1.71 (m, 1H), 1.68ꢀ1.59 (m, 1H), 0.98 (d, J = 7.0 Hz,
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3H). C NMR (101 MHz, CDCl3) δ 210.6, 207.7, 169.3, 133.0, 132.0, 120.0, 119.4,
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88.4, 56.3, 49.5, 40.0, 39.1, 37.2, 34.8, 33.0, 27.1, 21.4, 20.6. HRMS (ESI) calcd. for
C18H24NaO4 (M + Na)+ 327.1565, found 327.1567.
(1R,3aS,5R,7aS)-1,7a-diallyl-5-methyl-2,7-dioxooctahydro-1H-inden-1-yl
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acetate (18’). H NMR (400 MHz, CDCl3) δ 6.00ꢀ5.86 (m, 1H), 5.78ꢀ5.67 (m, 1H),
5.20ꢀ4.99 (m, 4H), 3.20 (ddt, J = 14.6, 6.1, 1.4 Hz, 1H), 2.86ꢀ2.76 (m, 2H), 2.72ꢀ2.58
(m, 3H), 2.34ꢀ2.19 (m, 2H), 2.13ꢀ1.98 (m, 2H), 2.04 (s, 3H), 1.78ꢀ1.61 (m, 2H), 1.02
(d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 211.0, 207.6, 169.7, 133.5, 132.9,
119.1, 119.0, 88.3, 61.5, 48.9, 39.4, 38.9, 37.0, 36.9, 32.8, 29.3, 22.0, 20.7. HRMS
(ESI) calcd. for C18H24NaO4 (M + Na)+ 327.1565, found 327.1567.
19 and 20. To a solution of 18 (548 mg, 1.8 mmol) in 18 mL MeCN was added HCl
(18 mL, 6.0 N). The reaction was allowed to stir at rt for 24 hours and MeCN was
removed under vaccum. The solution was extracted by EtOAc (30 mL×3), washed
with NaHCO3, brine and dried over Na2SO4. Purification by column chromatography
(SiO2, 230ꢀ400 mesh, eluting with hexane/EtOAc, 15:1 to 6:1) gave dienone 19 (277
mg, 63%, conformational isomers mixture, which converts into its sꢀtrans isomer
smoothly) as light yellow oil and alcohol 20 (163 mg, 35%) as light yellow solid.
(3aS,6R,7aS)-3a-allyl-3-allylidene-6-methylhexahydro-1H-indene-2,4-dione (19,
s-trans isomer). 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 12.0 Hz, 1H), 6.45 (ddd, J
= 16.7, 12.0, 10.1 Hz, 1H), 5.81ꢀ5.66 (m, 2H), 5.62 (d, J = 10.1 Hz, 1H), 5.13ꢀ5.01 (m,
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2H), 2.77ꢀ2.59 (m, 3H), 2.54 (dd, J = 14.3, 5.0 Hz, 1H), 2.37 (dd, J = 14.0, 7.7 Hz,
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1H), 2.19–2.08 (m, 4H), 1.61 (t, J = 5.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 3H). C NMR
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(101 MHz, CDCl3) δ 211.8, 205.6, 137.2, 136.2, 133.8, 130.6, 130.2, 119.1, 59.8, 46.3,
43.2, 39.9, 36.9, 36.6, 28.6, 20.2. HRMS (ESI) calcd. for C16H21O2 (M + H)+
245.1536, found 245.1537.
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(3S,3aS,6R,7aS)-3,3a-diallyl-3-hydroxy-6-methylhexahydro-1H-indene-2,4-dione
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(20). [α]D +143 (c 1.0, CHCl3).1H NMR (400 MHz, CDCl3) δ 6.05ꢀ5.84 (m, 2H),
5.14ꢀ5.01 (m, 4H), 4.99 (d, J = 2.2 Hz, 1H), 2.82ꢀ2.65 (m, 3H), 2.55 (dd, J = 14.2, 6.2
Hz, 1H), 2.43ꢀ2.20 (m, 4H), 2.14ꢀ1.97 (m, 2H), 1.86ꢀ1.73 (m, 2H), 1.08 (d, J = 6.4 Hz,
13
3H). C NMR (126 MHz, CDCl3) δ 218.3, 214.2, 132.4, 131.9, 118.6, 118.0, 85.2,
59.5, 47.7, 38.3, 36.9, 36.5, 35.8, 32.4, 31.3, 22.1. HRMS (ESI) calcd. for C16H23O3
(M + H)+ 263.1643, found 263.1642. m.p. 122ꢀ124 °C (recrystallized from
hexane/EtOAc).
Conversion of 20 to 19. To a solution of 20 (156 mg, 0.59 mmol) in 5.9 mL dry
MeCN under Ar atmosphere was added pyridine (0.19 mL, 2.4 mmol) and distilled
SOCl2 (68 ꢁL, 0.94 mmol). The reaction was stirred at rt for 16 hours and quenched
by NaHCO3 solution, extracted by EtOAc (30 mL×3), brine and dried over Na2SO4.
Purification by column chromatography (SiO2, 230ꢀ400 mesh, eluting with
hexane/EtOAc, 15:1) gave 19 (87 mg, 61%) as light yellow oil. The spectra data were
identical with previous.
(4bS,7R,8aS,E)-4b-allyl-7-methyl-7,8,8a,9-tetrahydro-4bH-indeno[2,1-b]pyridi
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n-5(6H)-one oxime (4). To a solution of 19 (57 mg, 0.23 mmol) in 1.5 mL CHCl3 and
3.1 mL ethanol in a microwave vial was added NH2OH⋅HCl (40 mg, 0.58 mmol) and
K2CO3 (80 mg, 0.58 mmol). The sealed vial was heated to 140 °C in a microwave
reactor (Biotage Initiator+, High abs., 15 bar) and stirred for 2 hours. After cooling,
the solution was diluted with 20 mL water and 5 mL saturated K2CO3 solution,
extracted by CH2Cl2 (10 mL×3), brine and dried over Na2SO4. Purification by column
chromatography (SiO2, 230ꢀ400 mesh, eluting with CH2Cl2/MeOH/Et3N, 30:1:0.3)
gave 4 (39 mg, 67%) as white solid.
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[α]D +28.1 (c 1.0, CHCl3). H NMR (500 MHz, CD3OD) δ 8.24 (dd, J = 5.1, 1.5
Hz, 1H), 7.65 (dd, J = 7.7, 1.5 Hz, 1H), 7.18 (dd, J = 7.7, 5.1 Hz, 1H), 5.79ꢀ5.67 (m,
1H), 5.14ꢀ4.99 (m, 2H), 3.05ꢀ2.95 (m, 1H), 2.86 (ddd, J = 15.1, 4.3, 1.7 Hz, 1H),
2.82ꢀ2.70 (m, 3H), 2.62 (dd, J = 14.2, 6.6 Hz, 1H), 1.88 (dt, J = 18.2, 9.1 Hz, 1H),
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1.81ꢀ1.67 (m, 2H), 1.62ꢀ1.55 (m,1H), 1.32 (s, br, 1H), 1.02 (d, J = 6.5 Hz, 3H). C
NMR (101 MHz, CD3OD) δ 164.1, 161.1, 148.0, 142.5, 135.9, 135.8, 122.5, 118.6,
54.1, 43.2, 42.2, 38.4, 35.3, 30.3, 27.8, 22.0. HRMS (ESI) calcd. for C16H21N2O (M +
H)+ 257.1648, found 257.1648.
(4bS,7R,8aS,E)-4b-(3-hydroxypropyl)-7-methyl-7,8,8a,9-tetrahydro-4bH-inden
o[2,1-b]pyridin-5(6H)-one oxime (22). To a solution of 4 (20 mg, 0.078 mmol) in 1.1
mL dry THF under Ar atmosphere was added 9ꢀBBN (0.47 mL, 0.5 M in THF, 0.23
mmol). The solution was heated at 60 °C overnight and then cooled to 0 °C. NaOH
solution (2.0 mL, 10% aq.) was added to the solution and then H2O2 (1.0 mL, 30% aq.)
was added dropwise. The mixture was stirred at rt for 2 hours, extracted by EtOAc (8
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mL×3), brine and dried over Na2SO4. Purification by column chromatography (SiO2,
230ꢀ400 mesh, eluting with CH2Cl2/MeOH/Et3N, 25:1:0.25) gave 22 (19 mg, 89%) as
white solid.
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[α]D +47.8 (c 1.0, MeOH). H NMR (400 MHz, CD3OD) δ 8.23 (dd, J = 5.1, 1.5
Hz, 1H), 7.63 (dd, J = 7.7, 1.5 Hz, 1H), 7.18 (dd, J = 7.7, 5.1 Hz, 1H), 3.59ꢀ3.47 (m,
2H), 3.04ꢀ2.89 (m, 2H), 2.85ꢀ2.67 (m, 2H), 2.08ꢀ1.97 (m, 1H), 1.95ꢀ1.86 (m, 1H),
1.85ꢀ1.71 (m, 3H), 1.68ꢀ1.56 (m, 2H), 1.43ꢀ1.32 (m, 1H), 1.03 (d, J = 5.9 Hz, 3H).
13C NMR (101 MHz, CD3OD) δ 164.1, 161.7, 147.8, 142.9, 135.9, 122.5, 63.1, 54.4,
43.8, 38.3, 35.3, 33.7, 30.3, 29.3, 27.8, 22.1. HRMS (ESI) calcd. for C16H23N2O2 (M
+ H)+ 275.1758, found 275.1754.
Lycopladine A (2). To a solution of 22 (26 mg, 0.095 mmol) in 2.0 mL acetone was
added TiCl3 (0.20 mL, 20% in HCl aq.) under Ar atmosphere. The reaction was stirred
at rt for 1 hour and quenched by 10 mL Na2CO3 solution. The mixture was filtered by
celite, filtrated was extracted with EtOAc (8 mL×3), brine and dried over Na2SO4.
Purification by column chromatography (SiO2, 230ꢀ400 mesh, eluting with
CH2Cl2/MeOH/Et3N, 30:1:0.3) gave 2 (18 mg, 74%) as white solid. The spectrum
data were identified with those reported.2
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[α]D +137 (c 0.50, MeOH) lit.2 [α]D23 +102 (c 1.0, MeOH). H NMR (500 MHz,
CD3OD) δ 8.31 (dd, J = 5.1, 1.4 Hz, 1H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H), 7.25 (dd, J =
7.7, 5.1 Hz, 1H), 3.57ꢀ3.51 (m, 2H), 3.09 (dd, J = 16.4, 8.2 Hz, 1H), 2.99ꢀ2.94 (m,
1H), 2.83 (dd, J = 16.4, 9.0 Hz, 1H), 2.29 (dd, J = 5.3, 4.1 Hz, 2H), 2.16ꢀ2.03 (m, 2H),
1.92ꢀ1.79 (m, 3H), 1.61ꢀ1.52 (m, 1H), 1.39ꢀ1.32 (m, 1H), 1.09 (d, J = 6.5 Hz, 3H).
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13C NMR (126 MHz, CD3OD) δ 214.6, 164.3, 148.7, 140.0, 136.2, 123.1, 62.8, 62.7,
47.8, 43.5, 38.6, 34.8, 33.4, 29.6, 29.1, 22.0. HRMS (ESI) calcd. for C16H22NO2 (M +
H)+ 260.1646, found 260.1645.
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Carinatine A (1). To a solution of 22 (13 mg, 0.048 mmol) in 2.5 mL dry THF was
added nꢀBu3P (26 ꢀL, 0.092 mmol) and 1,1'ꢀ(azodicarbonyl)dipiperidine (23 mg,
0.090 mmol). The reaction was heated to 60 °C and stirred for 3 h. The mixture was
concentrated and purificated by thin layer chromatography, which gave 1 (10 mg,
80%) as colorless oil. The spectra were identified with isolated product.1
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[α]D ꢀ127 (c 0.50, MeOH) lit.1 [α]D ꢀ94.4 (c 1.2, MeOH). 1H NMR (500 MHz,
CD3OD) δ 8.40 (dd, J = 5.1, 1.4 Hz, 1H), 7.53 (dd, J = 7.7, 1.4 Hz, 1H), 7.28 (dd, J =
7.7, 5.1 Hz, 1H), 4.00 (m, 2H), 3.58 (dd, J = 17.2, 7.5 Hz, 1H), 3.04 (dd, J = 16.8, 6.7
Hz, 1H), 2.77ꢀ2.73 (1H, m), 2.70 (d, J = 17.2 Hz, 1H), 2.16ꢀ2.07 (m, 1H), 2.04ꢀ1.83
(m, 4H), 1.73ꢀ1.67 (m, 1H), 1.63ꢀ1.56 (m, 1H), 1.48ꢀ1.42 (m, 1H), 0.94 (d, J = 6.8 Hz,
13
3H). C NMR (126 MHz, CD3OD) δ 165.0, 156.3, 149.6, 141.8, 134.2, 123.3, 59.1,
52.6, 45.3, 40.7, 38.5, 33.9, 32.9, 27.9, 20.1, 19.5. HRMS (EI) calcd. for C16H20N2O
(M)+ 256.1576, found 256.1577.
Acknowledgment
This work is supported by National Natural Science Foundation of China (grant
21132008 & 20921091). The author is grateful to Prof. Dawei Ma’s guidance and
helpful advice, to Prof. Qinshi Zhao and Fei Liu’s original NMR data of isolated
(ꢀ)ꢀcarinatine A.
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Associated content
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Supporting Information available. Copies for NMR data of new compounds, (ꢀ)ꢀ1
and (+)ꢀ2. Comparison spectrum of natural product and synthetic (ꢀ)ꢀ1 and (+)ꢀ2.
Xꢀray crystal data for 14 and 20. These materials are available free of charge via the
Internet at http://pubs.acs.org.
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References and Notes
(1) Liu, F.; Liu, Y.ꢀC.; Jiang, W.ꢀW.; He, J.; Wu, D.ꢀX.; Peng, L.ꢀY.; Jia, S.; Cheng,
X.; Zhao, Q.ꢀS. Nat. Prod. Bioprospect. 2014, 4, 221ꢀ225.
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