Total synthesis of gonytolides C and G, lachnone C, and formal synthesis of blennolide C and diversonol

Article abstract of DOI:10.1039/c4ob00950a

The first stereoselective total synthesis of gonytolide C, which is a monomeric unit of an innate immune promoter gonytolide A, has been accomplished from the aldol reaction between acetophenone derived from orcinol and butyrolactone containing α-keto ester followed by the excellent diastereoselective intramolecular cyclization. The first total synthesis of gonytolide G has been achieved by the oxidation of benzylic methyl in gonytolide C. Additionally, total synthesis of lachnone C and a formal synthesis of blennolide C and diversonol have been achieved by this synthetic method. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00950a

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Total synthesis of gonytolides C and G, lachnone
C, and formal synthesis of blennolide C and
diversonol†
Cite this: Org. Biomol. Chem., 2014,
12, 5601
Gangarajula Sudhakar,*a,b Shruthi Bayya,a,b Vilas D. Kadama,b and
Jagadeesh Babu Nanuboluc
The first stereoselective total synthesis of gonytolide C, which is a monomeric unit of an innate immune
promoter gonytolide A, has been accomplished from the aldol reaction between acetophenone derived
from orcinol and butyrolactone containing α-keto ester followed by the excellent diastereoselective intra-
molecular cyclization. The first total synthesis of gonytolide G has been achieved by the oxidation of
benzylic methyl in gonytolide C. Additionally, total synthesis of lachnone C and a formal synthesis of blen-
nolide C and diversonol have been achieved by this synthetic method.
Received 8th May 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4ob00950a
www.rsc.org/obc
that of gonytolide C by one oxygen atom (benzylic methyl
group is replaced by a hydroxymethyl group) (Fig. 1). Apart
Introduction
Chromanones substituted with the γ-lactone moiety are, as from gonytolides, chromanones substituted with the γ-lactone
subunits, monomeric and dimeric units (symmetrical and moiety as a monomeric unit were found earlier in several other
unsymmetrical, homo and hetero), encountered in a vast array
of synthetically challenging and biologically significant natural
products. They are found as subunits in ergoxanthin,1 xantho-
quinodins A32 and B3,3 chaetomanone,4 blennolide G;5
unsymmetrical heterodimers in noduliprevenone,6 mono-
dictyochromes A and B;7 as homodimers in paecilin A,8 and
phomopsis-H76 A.9 Recently, Kikuchi et al. reported the iso-
lation of gonytolides A–G bearing both monomeric and
dimeric chromanones substituted with the γ-lactone moiety
(symmetrical, unsymmetrical and as a subunit) from the fungus
Gonytrichum sp. during a screen for innate immune regulators
from natural sources.10 Gonytolide A (1) and its derivatives have
been identified as innate immune promoters. This axially chiral
dimeric chromanone 1, which also increased TNF-α-stimulated
production of IL-8 in human umbilical vein endothelial cells, is
composed of two monomeric units of gonytolide C (2). Gonyto-
lide B10a is an unsymmetrical dimer while gonytolides D–F are
unsymmetrical hetero dimers.10b Gonytolide G (3) differs from
aDivision of CPC (Organic Chemistry-II), CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India. E-mail: gsudhakar@iict.res.in;
Tel: +914027191435
bAcademy of Scientific and Innovative Research, New Delhi, India
cCenter for X-Ray Crystallography, CSIR-IICT, India
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all new compounds, comparison tables, NMR data of synthetic and natural
compounds and X-ray crystallographic information. CCDC 974676. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00950a
Fig. 1 Gonytolides A (1), C (2), G (3), lachnones C–E (4–6), microdi-
plodiasone (7), paecilin B (8), and blennolides D–F (9–11).
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natural products such as lachnones C–E (4–6),11 microdiplo-
Substrates 13 and 14 required for cross-metathesis reaction
diasone (7),12 paecilin B (8),8 and blennolides D–F (9–11)5 were prepared as shown in Scheme 1A. The synthesis of 13 was
(Fig. 1).
easily achieved in 85% yield from the Friedel–Crafts acylation
Synthetic approaches towards this biologically important reaction between orcinol and crotonoyl chloride. Methylene
and synthetically challenging framework are very limited, and γ-butyrolactone 1416 was derived from 17 which was syn-
only two syntheses are available. The first one, en route to the thesized from methyl 4-oxobutanoate.16 With both fragments
synthesis of blennolide C by Porco et al.,13 reported the in hand, however, all attempts to effect cross-metathesis reac-
mixture of ( )-gonytolide C and ( )-epi-gonytolide C in racemic tion between 13 and 14 under various conditions (Grubbs I, II
form before the isolation of gonytolides. The second approach and Grubbs–Hoveyda I, II (0.05 equiv. to 0.3 equiv.) in CH2Cl2,
for this framework has been reported by Bräse et al. for the toluene, and xylene at rt and reflux) failed, and no reaction
synthesis of lachnone C.14 Herein, we disclose the total syn- was observed. Starting materials were recovered quantitatively,
thesis of gonytolides C (2),12 G (3), and lachnone C (4) and the but ester 14 was decomposed at higher temperatures.
formal synthesis of blennolide C and diversonol by developing
a short and efficient novel synthetic strategy.
We then decided to adopt the synthesis of 12 from an alter-
nate approach (Fig. 2), aldol condensation of acetophenone 15
and α-keto-ester 16. Accordingly, 15 was synthesized in a single
step from orcinol using the Friedel–Crafts acylation reaction
reported in the literature,13 while 16 in 86% yield was derived
1
from 14 under the ozonolysis conditions (Scheme 1B). The H
Results and discussion
and 13C NMR spectra of 16 have shown two set of peaks: a
mixture of ketone 16 and its dihydroxy derivative 16a in the
ratio 1 : 1, and the structure of 16a was confirmed by the X-ray
crystallographic analysis.17
We envisioned that developing a synthetic strategy for mono-
meric chromanone substituted with the γ-lactone framework
would not only allow the synthesis of gonytolides C and G, etc.,
but also the synthesis of dimeric chromanones of this class
from late-stage biaryl coupling of appropriately halogenated
monomeric units. Additionally, it can also be utilized in the
synthesis of biogenetically related tetrahydroxanthones, which
are a larger class of mycotoxins with interesting biological
activities,15 from “retrobiomimetic” synthesis.13
Our plan for the synthesis of monomeric gonytolide C
focused on the oxa-Michael addition of enone 12 (Fig. 2) by
activation with an acid or a base. Enone 12 was expected to
derive from cross-metathesis reaction of crotonophenone 13
and methylene γ-butyrolactone 14, and/or alternatively from
aldol condensation between acetophenone 1513 and α-keto
ester 16. While 13 and 15 can, in turn, be synthesized from
orcinol by the Friedel–Crafts acylation reaction, α-keto ester 16
can be synthesized from γ-butyrolactone 14 by ozonolysis.
With access to both 15 and 16/16a, it was expected that the
synthesis of 12 from 15 and 16/16a by aldol condensation may
also effect an in situ intramolecular oxa-Michael addition to
give the target molecule (2 and/or 2a), directly, in one pot.
Unfortunately, attempts to a one-pot tandem aldol conden-
sation/oxa-Michael addition reaction failed under several reac-
tion conditions and only the decomposition of the ketone 16
was observed under forced conditions such as pyrrolidine as a
base in different solvents: CH3CN, toluene, MeOH, and EtOH
and at various temp.: rt to reflux.18 However, much to our satis-
Fig. 2 Synthetic plan for gonytolide C (2) and retrosynthetic analysis of
12.
Scheme 1 (A) Synthesis of 13 and 14 and attempts to synthesize 12
from cross-metathesis reaction; (B) synthesis of 15 and 16 and 16a.
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faction, the stepwise synthesis such as aldol reaction followed (3) TFA neat as well as in benzene. Only isomerization (major
by an intramolecular cyclization produced the desired product aldol product to minor) was observed with SOCl2, Et3N in
(Scheme 2). Interestingly, we found tunable diastereoselectivity CH2Cl2 at rt for 36 h.22 Gratifyingly, reaction with SOCl2 and
at the cyclization step (Table 1). After several experimentations, an Py in toluene at 65 °C23 provided the desired 2 along with 2a,
aldol reaction between acetophenone 15 and ketone 16/16a was which were easily separated by column chromatography. Thus,
achieved using TiCl4, DIPEA in CH2Cl2 at −78 °C (Scheme 2)19 to total synthesis of the ( )-gonytolide C and ( )-epi-gonytolide C
afford column chromatographically separable diastereomers also became the formal synthesis of ( )-blennolide C and
18 and 18a (dr 2.5 : 1) in 49% combined yield (83%, brsm).
( )-epi-blennolide C, respectively.13 Interestingly, the diastereo-
With the aldol products 18 and 18a in hand, the next task selectivity and yields at the cyclization stage are manoeuvred
was to achieve intramolecular cyclization to obtain the target by the time and temp. as shown in Table 1. Importantly, 18
molecule 2. Initially, no expected cyclization was effected and 18a either individually or together provided the same
under a variety of conditions such as (1) PTSA in toluene/ mixture of 2 and 2a with respect to the dr and yield. Reaction
benzene at rt and reflux,20 (2) DIAD, TPP, Et3N in THF,21 and at rt for 2 h resulted in 2 and 2a in the ratio of 1.3 : 1 in 47%
combined yield (Table 1, entry 1). Increasing the temp. up to
65 °C decreased the reaction time (1 h) and increased the yield
(66%) as well as dr (1.7 : 1) (entry 2). Increasing the temp.
further decreased the reaction time considerably (10 min) with
no significant change in yield (67%) and dr (1.6 : 1) (entry 3).
Running the reaction for a long time also greatly improved the
diastereoselectivity towards the desired product 2. At rt for
24 h, 2 and 2a were obtained in the ratio of 8 : 1 with 40% yield
(entry 4). Within 3 h at 65 °C, 2 and 2a were obtained in 66%
yield and with a dr of 6 : 1 (entry 5). However, the maximum
diastereoselectivity (2 and 2a, dr 18 : 1) was achieved despite a
moderate yield (51%) when the reaction was heated to 110 °C
for 3 h (entry 6). No reaction was observed at a lower temp. of
−78 °C and the reaction at 0 °C gave some unidentified com-
pounds (entries 7 and 8).
It is noteworthy monitoring the reaction at different inter-
vals,24 formation of 2 and 2a are equal or 2a is major at the
beginning of the reaction (immediately after the addition of
thionyl chloride to a solution of 18 and/or 18a, and Py in
toluene) but with time, formation of 2 predominates. Further,
we ascertained25 that the initially formed kinetic product 2a is
converted to the thermodynamic product 2 and the conversion
rate becomes faster at higher temperature with time. The
diastereoselectivity of 2 over 2a and epimerization of 2a to 2 at
Scheme 2 Synthesis of ( )-gonytolide C (2) and ( )-epi-gonytolide C
(2a) and formal synthesis of ( )-blennolide C and ( )-epi-blennolide C.
higher temperatures with time are in line with the vinylogous
addition of siloxyfurans to benzopyryliums reported by Porco
and co-workers.13 In the same report, the diastereoselectivity
was assessed by employing the density functional theory
Table 1 Screening of reaction conditions: temp. and time to give ( )-2
method and the epimerization at higher temperature was pro-
and ( )-2a from ( )-18 and/or ( )-18a
posed based on butenolide enolization.13
Mechanistically in our protocol, the aldol product 18 and/or
18a with a dehydrating agent (thionyl chloride and Py) may
give 12 which would affect the oxa-Michael addition to give 2
and 2a, wherein the diastereoselectivity is governed by the
Entry
Temp.
Time
2 and 2a (dr)a
Yieldb
asymmetric center present in γ-butyrolactone. Unlike epimeri-
zation by butenolide enolization proposed in Porco’s protocol,
here the epimerization of the kinetic product 2a to the thermo-
dynamic product 2 is presumably via 12 by retro-oxa-Michael
addition and followed by oxa-Michael addition. As no loss of
chirality in butyrolactone occurs in this method, it is advan-
tageous and can be valuable in constructing the stereoselective
synthesis of gonytolide C by taking enantiomerically pure
butyrolactone 16/16a.
1
2
3
4
5
6
7
8
rt
2 h
1 h
10 min
24 h
3 h
3 h
24 h
24 h
1.3 : 1
1.7 : 1
1.6 : 1
8 : 1
6 : 1
18 : 1
47%
66%
67%
40%
66%
51%
nrc
65 °C
110 °C
rt
65 °C
110 °C
−78 °C
0 °C
ucd
a Diastereomeric ratio of 2 and 2a is based on the 1H NMR. b Isolated
yields of combined 2 and 2a. c No reaction. d Unidentified compounds.
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Having developed a diastereoselective synthesis of ( )-gony- of (+)-16/16a to (+)-gonytolides C (2) and G (3) was achieved
tolide C, gonytolide G (3) could be synthesized by applying this from the steps developed for their racemic synthesis. The
protocol: taking the hydroxymethyl derivative of 15 and 16/16a spectroscopic data of synthesized gonytolide C (2), epi-gonyto-
as starting materials. However, we envisaged that the oxidation lide C (2a) and gonytolide G (3) are in full agreement with
of benzylic methyl in ( )-gonytolide C (2) would also provide those of reported compounds.10,13 The specific rotations of
the ( )-gonytolide G (3).26 Towards this end, acetylation of the gonytolide C (2): [α]D23 = +23.1 (c 0.39, CHCl3) (synthetic) and
phenolic group in 227 afforded 20 in nearly quantitative yield. [α]D = +25.1 (c 0.184, CHCl3) (natural);10a and gonytolide G (3):
Subsequent two-step transformation: oxidation–hydrolysis28 [α]D23 = +18.0 (c 0.19, CHCl3) (synthetic) and [α]D = +19.7
afforded the acetyl derivative of gonytolide G 21 in 49% yield (c 0.315, CHCl3) (natural),10b are also well matched.
based on the recovery of 20. Selective hydrolysis of the acetyl
Having achieved a stereoselective synthesis of gonytolides C
group of 21 under mild conditions29 helped accomplish the and G from lactone 22, we expected that the same starting
first total synthesis of ( )-gonytolide G (3) in 71% yield and material can be used in the synthesis of lachnone
with 35% overall yield in four steps from 2 (Scheme 3).
C. Accordingly, conversion of acid 22 to the diazoketone 24
Having achieved a diastereoselective synthesis of ( )-gony- was achieved using isobutylchloroformate, diazomethane and
tolide C and ( )-gonytolide G, we considered that synthesis of Et3N in THF in 80% yield (Scheme 5). Methyl ketone 2532 in
16 and 16a in an enantiomerically pure form can provide 83% yield was obtained by the reduction of 24 with hydroiodic
access to the first stereoselective total synthesis of gonytolide acid. The reaction of 25 with 15 under aldol reaction conditions
C and gonytolide G. Then it was commenced from the activation developed for gonytolide C (TiCl4, DIPEA in CH2Cl2), except at
of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (22)30 with EDCI higher temperature (−25 °C) in this case furnished an inseparable
followed by coupling with (cyanomethylene)triphenyl-
phosphorane, giving β-keto cyanophosphorane 23 which upon
ozonolysis in MeOH–CH2Cl2 (3 : 7) provided (+)-16/16a in 1 : 1
ratio with 45% yield over two steps31 (Scheme 4). Conversion
Scheme 3 Synthesis of ( )-gonytolide G (3) from ( )-gonytolide C (2).
Scheme 4 Stereoselective synthesis of (+)-gonytolide C (2) and (+)
gonytolide G (3).
Scheme 5 Synthesis of (+)-lachnone C (4).
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1
mixture of 26 and 26a (dr 1 : 1, based on the H NMR) in 67% 3H), 1.98 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
yield. Intramolecular cyclization of 26 and 26a to give 27 and δ 164.8, 151.3, 147.5, 140.5, 122.2, 120.0, 112.9, 21.7, 18.5;
27a was achieved only after the use of neat trifluoroacetic acid HRMS (ESI): calcd for C11H13O3 [M + H]+ 193.0859; found
at 80 °C. However, column chromatographically separable 27 193.0856
and 27a in 72% yield were obtained but with no diastereo-
selectivity in this case.
Methyl 2-(5-oxotetrahydrofuran-2-yl)acrylate (( )-14)
To know the absolute stereochemistry of cyclized products, To a stirred solution of hydroxyl ester 17 (ref. 16) (12.46 g,
27 and 27a were individually converted to the corresponding 61.68 mmol) in toluene (120 mL) at rt was added p-toluene-
methyl ethers 28 (95%) and 28a (93%), respectively, using MeI sulfonic acid (3.51 g, 18.50 mmol) and allowed the reaction
and potassium carbonate in DMF.14 Comparison of spectral mixture to stir at rt for 3 h. The reaction mixture was quenched
data and specific rotation with the data reported,14 shows that by addition of H2O and extracted with EtOAc. The organic
27 is the required diastereomer for achieving lachnone C and layer was washed with brine, dried over Na2SO4, filtered and
also it accomplishes the formal synthesis of (+)-diversonol (29). concentrated under reduced pressure. The residue was purified
Therefore, compound 27 was subjected to acetylation using by column chromatography to furnish lactone ( )-14 (10.43 g,
Ac2O and pyridine in CH2Cl2 to afford 30. Benzylic bromination 99.5%) as a colorless liquid. Rf = 0.5 (30% EtOAc–hexane);
of the methyl group with NBS and AIBN in CCl4 under heating IR (neat): νmax 2956, 2924, 1779, 1721, 1441, 1276, 1185, 1146,
1
at 80 °C gave benzylic bromide. Hydrolysis of the benzylic 1044 cm−1; H NMR (300 MHz, CDCl3): δ 6.33 (s, 1H), 5.93 (d,
bromide with CaCO3 in aqueous dioxane at 80 °C furnished the J = 1.5 Hz, 1H), 5.29 (t, J = 7.1 Hz, 1H), 3.79 (s, 3H), 2.72–2.52
acetyl derivative of lachnone C 31.28 Deacetylation29 of 31 in (m, 3H), 2.03 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 176.6,
MeOH–Et3N provided lachnone C (4) in 70% yield. Comparison 165.0, 138.4, 125.1, 77.6, 52.0, 28.2, 27.7; HRMS (ESI): calcd for
of spectral data, including specific rotation (synthetic: [α]D28
=
C8H10O4Na [M + Na]+ 193.0471; found 193.0476.
+39.0 (c 0.065, MeOH); natural: [α]2D9 = +43.4 (c 0.13, MeOH)) is
Synthesis of ( )-16/16a
in full agreement with the literature.11,33
The solution of lactone ( )-14 (4 g, 23.52 mmol) in CH2Cl2 was
cooled to −78 °C and O3 gas was bubbled through the solution
until a blue color had been persisted, followed by oxygen gas
to remove the excess of O3. Dimethyl sulfide was added to the
Conclusions
In conclusion, a concise, protecting group free, and stereo- reaction mixture and the solution was warmed to rt and stirred
selective synthetic strategy was developed for the synthesis of for additional 1.5 h. The reaction mixture was taken up in
gonytolide C. Oxidation of the benzylic methyl group in gony- EtOAc and it was washed with water and brine, dried over
tolide C provided the first total synthesis of gonytolide G. Total Na2SO4, filtered, and concentrated. The residue was purified
synthesis of lachnone C and formal synthesis of blennolide C by flash column chromatography to give ( )-16/16a as a white
and diversonol were also accomplished from this synthetic solid (3.5 g, 86%). Rf = 0.25 (50% EtOAc–hexane); mp
method. Application of this method in the synthesis of further 90–93 °C; IR (neat): νmax 3357, 2972, 1756, 1737, 1353, 1209,
monomeric and dimeric chromanones of this class of mole- 1107, 1013 cm−1
;
1H NMR (500 MHz, CDCl3): δ 5.49 (dd, J =
cules as well as biogenetically related tetrahydroxanthones is 9.0, 5.0 Hz, 0.5H), 4.84 (dd, J = 8.0, 5.0 Hz, 0.5H), 3.93 (s,
in progress in our lab and will be reported in due course.
1.5H), 3.90 (s, 1.5H), 2.68 (m, 1H), 2.58 (m, 1H), 2.46
(m, 0.5H), 2.41–2.28 (m, 1.5H), 1.78 (br, 2H); 13C NMR
(75 MHz, CDCl3): δ 188.6, 177.6, 175.7, 171.0, 162.8, 93.4, 80.1,
78.9, 53.5, 53.3, 27.6, 26.2, 24.2, 21.0; HRMS (ESI): calcd for
C7H9O5 [M + H]+ 173.0444; found 173.0442.
Experimental section
(E)-1-(2,6-Dihydroxy-4-methylphenyl)but-2-en-1-one (13)
Synthesis of ( )-18 and ( )-18a
To a mixture of anhydrous aluminium chloride (9.67 g,
72.58 mmol) and orcinol (3 g, 24.19 mmol), chlorobenzene TiCl4 (1 M in CH2Cl2, 34.88 mL, 34.88 mmol) and diisopropyl-
(20 mL) was added at rt. Upon heating to 40 °C, crotonoyl ethyl amine (7.08 mL, 40.69 mmol) were successively added to
chloride (3.27 mL, 33.87 mmol) was added carefully. The reac- a stirred solution of 15 (ref. 13) (1.60 g, 9.68 mmol) in CH2Cl2
tion mixture was stirred at 70 °C for 2 h. After cooling to rt, the (143 mL) at −78 °C under an argon atmosphere. After 30 min
reaction mixture was poured into ice and stirred for 30 min. α-ketoester ( )-16/16a (2 g, 11.6279 mmol) in CH2Cl2 (230 mL)
The aq. phase was extracted twice with EtOAc. The combined was added to the reaction mixture, which was stirred at −78 °C
organic layer was washed with brine, dried over Na2SO4, fil- for 3 h. The reaction mixture was quenched with water at
tered, and concentrated to give the crude product which was −78 °C and extracted twice with EtOAc. The organic phase was
purified by column chromatography to give 13 (3.97 g, 85%) as washed with water, brine, dried over Na2SO4, filtered, and con-
a yellow oil. Rf = 0.5 (15% EtOAc–hexane); IR (neat): νmax 3457, centrated. The obtained crude oil was purified by silica gel
2919, 1740, 1655, 1441, 1287, 1235, 1153, 1098, 973, 837, column chromatography to give separable aldol products
1
769 cm−1; H NMR (500 MHz, CDCl3): δ 7.14 (m, 1H), 6.79 (d, ( )-18 and ( )-18a in a dr of 2.5 : 1 (1.63 g, 49%) (83% brsm,
J = 2.0 Hz, 1.4H) 6.73 (d, J = 2.0 Hz, 0.4H), 6.0 (m, 1H), 2.38 (s, 650 mg of 15 was recovered).
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Minor: as a brown solid; Rf = 0.35 (50% EtOAc–hexane); mp 105.5, 84.6, 79.7, 53.6, 40.3, 27.7, 22.6, 21.7; HRMS (ESI): calcd
178–182 °C; IR (neat): νmax 3482, 3249, 2923, 2854, 1748, 1644, for C16H17O7 [M + H]+ 321.0968; found 321.0966.
1603, 1418, 1376, 1207, 1176, 1081, 1012, 821, 792 cm−1 1H
;
NMR (300 MHz, CDCl3): δ 9.90 (brs, 1H), 6.19 (s, 2H), 4.72 (dd,
J = 8.1, 4.1 Hz, 1H), 4.03 (d, J = 18.8 Hz, 1H), 3.98 (brs, 1H),
3.82 (s, 3H), 3.73 (d, J = 18.8 Hz, 1H), 2.78 (m, 1H), 2.49 (m,
1H), 2.31 (m, 1H), 2.21 (s, 3H), 2.15 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 202.9, 178.7, 173.5, 161.5, 149.0, 108.8,
107.8, 82.7, 77.3, 53.3, 50.0, 28.2, 21.9, 21.7; HRMS (ESI): calcd
for C16H18O8Na [M + Na]+ 361.0893; found 361.0888.
Methyl 5-acetoxy-7-methyl-4-oxo-2-(5-oxotetrahydrofuran-2-yl)-
chroman-2-carboxylate (20)
To a solution of ( )-gonytolide C (2) (50 mg, 0.15 mmol) in dry
CH2Cl2 (1 mL) were added Ac2O (0.045 mL, 0.47 mmol), py
(0.075 mL, 0.94 mmol) and DMAP (3.8 mg, 0.03 mmol) and
the resulting solution was stirred at rt for 4 h. Water was
added to the reaction, and stirred for another 30 min. The
reaction mixture was then extracted with CH2Cl2, washed with
1 N HCl, saturated aq. NaHCO3, and brine, dried over Na2SO4,
and filtered. The organic layer was concentrated on a rotary
evaporator to give the crude product which was purified by
silica gel column chromatography to give the compound ( )-20
(54 mg, 99%) as a white solid. Rf = 0.45 (50%, EtOAc–hexane);
mp 135–138 °C; IR (neat): νmax 2924, 2853, 1775, 1736, 1687,
Major: as a liquid; Rf = 0.25 (50% EtOAc–hexane); IR (neat):
νmax 3446, 2925, 2855, 1746, 1635, 1426, 1379, 1208, 1080,
1
1041, 828, 764 cm−1; H NMR (300 MHz, CDCl3): δ 9.88 (brs,
1H), 6.20 (s, 2H), 4.71 (dd, J = 7.5, 5.2 Hz, 1H), 3.99 (brs, 1H),
3.84 (s, 3H), 3.68 (d, J = 17.9 Hz, 1H), 3.54 (d, J = 17.9 Hz, 1H),
2.65 (m, 1H), 2.54 (m, 1H), 2.49–2.29 (m, 2H), 2.21 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 201.4, 177.3, 173.8, 161.2, 149.0,
109.1, 108.1, 82.6, 76.3, 53.5, 48.4, 28.0, 21.9, 21.8; HRMS
(ESI): calcd for C16H18O8Na [M + Na]+ 361.0893; found
361.0902.
1624, 1422, 1326, 1199, 1153, 1072, 1017 cm−1 1H NMR
;
(500 MHz, CDCl3): δ 6.84 (d, J = 1.5 Hz, 1H), 6.54 (d, J = 1.5 Hz,
1H), 4.86 (dd, J = 8.0, 5.8 Hz, 1H), 3.72 (s, 3H), 2.98 (d, J =
16.6 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 2.71 (ddd, J = 18.0, 9.9,
7.0 Hz, 1H), 2.59 (ddd, J = 18.0, 10.2, 6.5 Hz, 1H), 2.49–2.27
(m, 2H), 2.36 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 185.8, 175.6, 169.4, 168.8, 160.5, 149.6, 148.7, 118.1, 116.3,
111.2, 84.2, 80.9, 53.5, 40.9, 27.6, 22.0, 21.9, 21.0; HRMS (ESI):
calcd for C18H19O8 [M + H]+ 363.1079, found 363.1057.
Synthesis of gonytolide ( )-(2) and ( )-epi-gonytolide (2a)
To a solution of ( )-18 and/or ( )-18a (210 mg, 0.62 mmol) in
dry toluene (6 mL) and py (0.2 mL, 2.60 mmol), thionyl chlor-
ide (0.09 mL, 1.30 mmol) in dry toluene (2 mL) was cannulated
dropwise under N2 at 65 °C. The reaction was stirred for 3 h at
65 °C, allowed to come to rt and then poured into crushed ice
and extracted with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concen-
trated under vacuum. The residue was purified by column
chromatography to give ( )-2 as a white solid & ( )-2a as a
white solid (131 mg, 66%) in the combined yield in the ratio
(6 : 1) respectively.
Methyl-5-acetoxy-7-(hydroxymethyl)-4-oxo-2-(5-
oxotetrahydrofuran-2-yl)chroman-2-carboxylate (21)
A solution of compound ( )-20 (42 mg, 0.12 mmol) in CCl4
(1.5 mL) was heated at 80 °C, and then AIBN (3.8 mg,
0.023 mmol) and NBS (23 mg, 0.13 mmol) were added. The
reaction mixture was heated to 80 °C for 7 h. The reaction was
cooled to rt, H2O was added and extracted with CH2Cl2,
washed with 1 N HCl and brine, dried over Na2SO4, and fil-
tered. Concentration in a vacuum afforded the crude product
which was used in the next reaction without further purifi-
cation. Crude benzyl bromide was taken in 1 mL of 1,4-
dioxane–H2O (1 : 1). Then CaCO3 (7 mg, 0.07 mmol) was added
and heated at 70 °C for 17 h. The reaction was cooled, added
H2O, extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography to give the com-
pound ( )-21 (12 mg, 49% brsm and 18.5 mg of ( )-20 was
recovered) as colorless foam. Rf = 0.2 (50%, EtOAc–hexane); IR
(neat): νmax 2925, 2855, 1774, 1743, 1690, 1625, 1433, 1196,
( )-Gonytolide C (2)
Rf = 0.45 (1% EtOAc–CH2Cl2); mp 136–138 °C; IR (neat): νmax
2924, 2854, 1786, 1743, 1645, 1570, 1455, 1368, 1201, 1138,
835, 751 cm−1; 1H NMR (600 MHz, CDCl3): δ 11.38 (s, 1H), 6.40
(s, 1H), 6.37 (s, 1H), 4.86 (dd, J = 7.9, 6.0 Hz, 1H), 3.74 (s, 3H),
3.11 (d, J = 16.9 Hz, 1H), 2.95 (d, J = 16.9 Hz, 1H), 2.70 (ddd, J =
18.0, 10.1, 7.1 Hz, 1H), 2.59 (ddd, J = 18.0, 10.1, 6.7 Hz, 1H),
2.50–2.36 (m, 2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3):
δ 193.0, 175.5, 168.9, 161.7, 159.0, 151.6, 111.0, 108.4, 105.6,
84.0, 80.9, 53.6, 39.4, 27.6, 22.6, 22.0; HRMS (ESI): calcd for
C16H17O7 [M + H]+ 321.0968; found 321.0967.
1048 cm−1; H NMR (500 MHz, CDCl3): δ 7.05 (s, 1H), 6.73 (s,
( )-epi-Gonytolide (2a)
1
Rf = 0.5 (1% EtOAc–CH2Cl2); mp 174–178 °C; IR (neat): νmax 1H), 4.88 (dd, J = 7.9, 5.8 Hz, 1H), 4.73 (s, 2H), 3.72 (s, 3H),
2924, 1787, 1752, 1646, 1571, 1456, 1367, 1202, 1163, 836, 3.01 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.5, 1H), 2.72 (ddd, J =
1
747 cm−1; H NMR (600 MHz, CDCl3): δ 11.41 (s, 1H), 6.37 (s, 18.0, 9.8, 7.2 Hz, 1H), 2.60 (ddd, J = 18.0, 10.2, 6.7 Hz, 1H),
1H), 6.36 (s, 1H), 4.77 (dd, J = 8.2, 4.1 Hz, 1H), 3.74 (s, 3H), 2.50–2.38 (m, 2H), 2.35 (s, 3H), 1.89 (brs, 1H); 13C NMR
3.45 (d, J = 17.3 Hz, 1H), 3.06 (d, J = 17.3 Hz, 1H), 2.81 (ddd, J = (125 MHz, CDCl3): δ 185.8, 175.5, 169.4, 168.7, 160.8, 151.0,
18.0, 10.5, 8.3 Hz, 1H), 2.57 (ddd, J = 18.0, 10.5, 5.3 Hz, 1H), 150.0, 114.6, 113.2, 112.5, 84.4, 80.9, 63.8, 53.6, 40.9, 27.6,
2.49 (m, 1H), 2.34 (m, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, 21.9, 21.0; HRMS (ESI): calcd for C18H18O9Na [M + Na]+
CDCl3): δ 194.0, 175.9, 169.1, 161.7, 158.9, 151.2, 111.0, 108.3, 401.0843, found 401.0830.
5606 | Org. Biomol. Chem., 2014, 12, 5601–5610
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( )-Synthesis of gonytolide G (3)
Minor: [α]2D3 = +8.7 (c 0.33, CHCl3); major: [α]2D3 = +33.4
(c 0.21, CHCl3);
Compound ( )-21 (8 mg, 0.021 mmol) was taken in MeOH–
Et3N (3 : 1, 0.8 mL) and stirred at rt for 7 h. The reaction
mixture was quenched with 1 N HCl, extracted with EtOAc,
and washed with brine. The organic layer was filtered after
drying over Na2SO4, concentrated in vacuo to give a crude
product which was purified by silica gel column chromato-
graphy to give ( )-gonytolide G (3) (4.9 mg, 71%) as a colorless
(+)-Gonytolide C (2) and (−)-epi-gonytolide C (2a): Same as
its racemic synthesis.
Gonytolide C (2): [α]2D3 = +23.1 (c 0.39, CHCl3);
epi-Gonytolide C (2a): [α]2D3 = −6.4 (c 0.4, CHCl3).
Methyl (R)-5-acetoxy-7-methyl-4-oxo-2-((S)-5-
oxotetrahydrofuran-2-yl)chromane-2-carboxylate (20)
solid. Rf
= 0.25 (50%, EtOAc–hexane); mp 120–122 °C;
Same as its racemic synthesis; and specific rotation is [α]D23
+10.5 (c 0.18, CHCl3).
=
=
IR (neat): νmax 2924, 2854, 1781, 1746, 1645, 1440, 1190,
1051 cm−1; 1H NMR (500 MHz, CDCl3): δ 11.43 (s, 1H), 6.60 (s,
1H), 6.56 (s, 1H), 4.87 (dd, J = 7.9, 5.9 Hz, 1H), 4.67 (s, 2H),
3.74 (s, 3H), 3.14 (d, J = 17.0, 1H), 2.98 (d, J = 17.0 Hz, 1H),
2.72 (ddd, J = 17.8, 9.7, 7.3 Hz, 1H), 2.60 (ddd, J = 17.8, 10.0,
6.4 Hz, 1H), 2.49–2.39 (m, 2H); 13C NMR (125 MHz, CDCl3):
δ 193.3, 175.5, 168.9, 162.1, 159.4, 153.8, 107.7, 106.6, 105.1,
84.2, 80.9, 64.4, 53.7, 39.5, 27.6, 22.0; HRMS (ESI): calcd for
C16H15O8 [M − H]+ 335.0761, found 335.0765.
Methyl (R)-5-acetoxy-7-(hydroxymethyl)-4-oxo-2-((S)-5-
oxotetrahydrofuran-2-yl)chromane-2-carboxylate (21)
Same as its racemic synthesis; and specific rotation is [α]D23
+4.2 (c 0.2, CHCl3).
(+)-Gonytolide G (3): Same as its racemic synthesis; and
specific rotation is [α]2D3 = +18.0 (c 0.19, CHCl3).
(S)-3-Oxo-3-(5-oxotetrahydrofuran-2-yl)-2-
(triphenylphosphoranylidene)propane nitrile (23)
(S)-5-(2-Diazoacetyl)dihydrofuran-2(3H)-one (24)
To a solution of carboxylic acid 2230 (5 g, 38.5 mmol) in dry
THF (12 mL) were added triethylamine (9 mL, 65.4 mmol) and
isobutylchloroformate (7.5 mL, 57.7 mmol) at −20 °C and
stirred for 45 min at −20 °C. Excess of diazomethane was
added to the reaction mixture at −20 °C. The reaction mixture
was warmed to rt and stirred overnight. Excess of diazo-
methane was quenched using acetic acid and washed with sat.
aq. NaHCO3 solution and extracted with EtOAc. The organic
layer was washed with aq. NH4Cl, and brine solution, dried
over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography to give com-
pound 24 (4.4 g, 80%) as a yellow oil. Rf = 0.3 (50%, EtOAc–
hexane), [α]2D2 = −80.0 (c 0.2 CHCl3); IR (neat): νmax 2956, 2116,
1785, 1636, 1379, 1144, 1049 cm−1; 1H NMR (300 MHz, CDCl3):
δ 5.76 (s, 1H), 4.82 (m, 1H), 2.61–2.48 (m, 3H), 2.36 (m, 1H);
13C NMR (75 MHz, CDCl3): δ 191.7, 175.7, 80.4, 53.9, 27.1,
25.5; HRMS (ESI): calcd for C6H6N2O3Na [M + Na]+ 177.0270;
found 177.0260.
To a solution of carboxylic acid 2230 (5 g, 38.5 mmol) in dry
CH2Cl2 (200 mL) were added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) (9.6 g, 50.0 mmol)
and DMAP (470 mg, 3.8 mmol) under a nitrogen atmosphere
at 0 °C. After 2 min stirring, Ph3PvCHCN (12.7 g, 42.3 mmol)
was added and the reaction mixture was stirred at rt for 15 h.
Water (15 mL) was added and the organic layer was separated
and washed with sat. aq. NaHCO3 solution and brine. The
organic layer was dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The residue was purified by
column chromatography to give compound 23 as a colorless
solid (10.3 g, 65%). Rf
= 0.3 (50%, EtOAc–hexane); mp
245–247 °C; [α]2D3 = + 26.0 (c 0.41, CHCl3); IR (neat): νmax 2975,
2946, 2175, 1784, 1603, 1436, 1387, 1256, 1157, 1103, 750, 720,
693 cm−1 1H NMR (600 MHz, CDCl3): δ 7.66–7.61 (m, 3H),
;
7.60–7.54 (m, 6H), 7.54–7.49 (m, 6H), 5.56 (dd, J = 7.9, 4.5, 1H),
2.59–2.47 (m, 2H), 2.41 (m, 1H), 2.29 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 190.5, 176.8, 133.3, 133.2, 129.1, 129.0,
122.2, 121.4, 120.5, 120.4, 78.4, 78.3, 47.7, 46.7, 27.0, 25.9; HRMS
(ESI): calcd for C25H21O3NP [M + H]+ 414.1253; found 414.1244.
(S)-5-Acetyldihydrofuran-2(3H)-one (25)
To a solution of compound 24 (4 g, 25.9 mmol) in chloroform
(150 mL) was added hydriodic acid (57%, 6.8 mL, 51.9 mmol)
dropwise at room temperature with vigorous stirring. After
10 min, the solution was washed with aqueous 10% sodium
thiosulphate, the organic layer was separated, the aqueous
layer was washed with chloroform and the combined organic
layers were dried over Na2SO4, filtered and concentrated
in vacuo. The residue was purified by column chromatography
to give the compound 25 (2.75 g, 83%) as a yellow oil. Rf = 0.3
(50%, EtOAc–hexane); [α]2D3 = +12.6 (c 0.46, MeOH); IR (neat):
Synthesis of (+)-16/16a
Compound 23 (10 g, 24.2 mmol) was dissolved in CH2Cl2
(168 mL) and methanol (72 mL) and cooled to −78 °C. Ozone
was then bubbled through the solution until the reaction
mixture turned blue. Oxygen was then passed through the
solution to remove the excess ozone. The solution was warmed
to room temperature and concentrated in vacuo. The crude
product was purified by column chromatography (60%, EtoAc–
hexane) to give compound (+)-16/16a (2.9 g, 70%) as a white
solid. [α]2D3 = +41.4 (c, 0.67, CHCl3).
νmax 2925, 1784, 1726, 1170, 1064 cm−1 1H NMR (500 MHz,
;
CDCl3): δ 4.80 (m, 1H), 2.54–2.43 (m, 3H), 2.23 (s, 3H),
2.22–2.15 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 205.2, 175.9,
81.8, 27.1, 26.0, 24.3; HRMS (ESI): calcd for C6H9O3 [M + H]+
129.0546 found 129.0542.
Synthesis of (+)-18 and (+)-18a
Same as its racemic synthesis.
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Synthesis of 26 and 26a
1769, 1647, 1575, 1460, 1373, 1213, 1172, 1090, 1014, 790; H
NMR (500 MHz, CDCl3): δ 11.52 (s, 1H), 6.33 (s, 1H), 6.22 (s,
1H), 4.45 (dd, J = 8.0, 5.9 Hz, 1H), 3.30 (d, J = 16.9 Hz, 1H),
2.72 (ddd, J = 16.9, 10.5, 6.7 Hz, 1H), 2.58 (ddd, J = 17.7, 10.3,
7.0 Hz, 1H), 2.49 (d, J = 16.9 Hz, 1H), 2.47 (m, 1H), 2.36 (m,
1H), 2.27 (s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 196.2, 176.1, 161.5, 158.3, 150.6, 110.1, 108.5, 105.2, 82.7,
80.6, 43.1, 28.2, 22.4, 21.5, 19.5; HRMS (ESI): calcd for
C15H15O5 [M − H]+ 275.0914; found 275.0922.
TiCl4 (1 M solution in CH2Cl2, 46.8 mL) and diisopropylethyl
amine (9.51 mL, 54.6 mmol) were successively added to a
stirred solution of 1513 (2.1 g, 13.0 mmol) in CH2Cl2 (60 mL) at
−25 °C under an argon atmosphere. After 30 min methyl
ketone 25 (500 mg, 3.9 mmol) in CH2Cl2 (30 mL) was added to
the reaction mixture, which was stirred at −25 °C for 3 h. The
reaction mixture was quenched with water and was extracted
twice with ethyl acetate. The organic phase was washed with
water and brine, dried over Na2SO4, filtered and concentrated.
The obtained crude oil was purified by silica gel column
chromatography to give an inseparable mixture of aldol
products 26 and 26a as brown foam in the yield (770 mg,
67%). Rf = 0.35 (50%, EtOAc–hexane); IR (neat): νmax 3448,
(R)-5-Methoxy-2,7-dimethyl-2-((S)-5-oxotetrahydrofuran-2-yl)-
chroman-4-one (28)
To a solution of compound 27 (10 mg, 0.036 mmol) in dry
DMF, at 0 °C were added K2CO3 (10 mg, 0.072 mmol) and
iodomethane (1 M, 0.043 mL, 0.043 mmol). The reaction
mixture was stirred for 24 h at room temperature. After com-
pletion of the starting material, water was added and the reac-
tion mixture was extracted with ethyl acetate and washed with
cold water and brine, dried over Na2SO4, filtered and concen-
trated in vacuo. The obtained crude oil was purified by silica
gel column chromatography to give the compound 28 (10 mg,
95%) as an oil. Rf = 0.3 (50%, EtOAc–hexane); [α]2D7 = +38.5
(c 0.3, CHCl3); IR (neat): νmax 2925, 1777, 1677, 1614, 1567,
1
2925, 2855, 1749, 1634, 1417, 1376, 1208, 766 cm−1; H NMR
(500 MHz, CDCl3): δ 6.23 (s, 2H), 6.20 (s, 2H), 4.60 (t, J =
7.4 Hz, 1H), 4.48 (dd, J = 7.6, 6.5 Hz, 1H), 3.74 (d, J = 15.5 Hz,
1H), 3.57 (d, J = 16.0 Hz, 1H), 3.11 (d, J = 16.0 Hz, 1H), 3.09 (d,
J = 15.5 Hz, 1H), 2.68 (m, 1H), 2.61–2.51 (m, 3H), 2.37 (m, 1H),
2.31–2.21 (m, 3H), 2.19–2.17 (m, 6H), 1.35 (s, 3H), 1.31 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 205.2, 205.0, 178.8, 178.1, 161.5,
161.3, 149.0, 148.8, 132.5, 132.5, 132.0, 132.0, 128.8, 128.7,
109.2, 109.1, 85.8, 84.9, 73.7, 73.7, 49.2, 48.7, 28.8, 28.8, 22.4,
22.4, 22.0, 21.9, 21.9, 21.7; HRMS (ESI): calcd for C15H18O6Na
[M + Na]+ 317.0995; found 317.0982.
1465, 1228, 1154, 1112 cm−1 1H NMR (500 MHz, CDCl3):
;
δ 6.34 (s, 1H), 6.30 (s, 1H), 4.50 (t, J = 7.3 Hz, 1H), 3.87 (s, 3H),
2.85 (d, J = 16.0 Hz, 1H), 2.67–2.51 (m, 2H), 2.44 (d, J =
16.0 Hz, 1H), 2.28 (s, 3H), 2.31–2.25 (m, 2H), 1.39 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 188.7, 176.3, 160.3, 160.1, 148.0,
110.6, 108.3, 105.0, 83.1, 80.4, 56.0, 44.3, 28.2, 22.3, 22.2, 18.9;
HRMS (ESI): calcd for C16H19O5 [M + H]+ 291.1227; found
291.1225.
Synthesis of 27 and 27a
To the mixture of aldol products 26 and 26a (310 mg,
1.0 mmol) was added trifluoroacetic acid (8.3 mL,
105.6 mmol) and the reaction mixture was heated to 80 °C.
The reaction was monitored by checking thin layer chromato-
graphy, after completion of the starting material, quenched
with sat. aq. NaHCO3 solution and extracted with ethyl acetate
and washed with water and brine, dried over Na2SO4, filtered
and concentrated. The obtained products were separated by
silica gel column chromatography to give 27 and 27a as solids
(210 mg, 72%) in the combined yield in the ratio (1 : 1).
(S)-5-Methoxy-2,7-dimethyl-2-((S)-5-oxotetrahydrofuran-2-yl)-
chroman-4-one (28a)
Compound 28a was prepared from compound 27a following
the same procedure as outlined for the preparation of com-
pound 28. The residue was purified by silica gel column
chromatography to give compound 28a (9.8 mg, 93%) as an
oil. Rf = 0.3 (50%, EtOAc–hexane); [α]2D4 = −24.0 (c 0.3, CHCl3);
1H NMR (500 MHz, CDCl3): δ 6.34 (s, 1H), 6.31 (s, 1H), 4.45
(dd, J = 7.9, 6.2 Hz, 1H), 3.89 (s, 3H), 3.18 (d, J = 15.7 Hz, 1H),
2.71 (ddd, J = 17.7, 10.0, 6.2 Hz, 1H), 2.57 (ddd, J = 17.8, 10.2,
7.1 Hz, 1H), 2.44 (d, 15.7, 1H), 2.48–2.39 (m, 1H), 2.38–2.31
(m, 1H), 2.30 (s, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3):
δ 189.5, 176.3, 160.1, 160.1, 147.7, 110.6, 108.3, 105.0, 82.8,
80.4, 56.0, 45.1, 28.3, 22.3, 21.6, 18.7; IR (neat): νmax 2924,
1774, 1618, 1462, 1164, 1109, 1019, 944 cm−1; HRMS (ESI):
calcd for C16H18O5Na [M + Na]+ 313.1046; found 313.1043.
(R)-5-Hydroxy-2,7-dimethyl-2-((S)-5-oxotetrahydrofuran-2-yl)-
chroman-4-one (27)
(White solid); Rf = 0.35 (40%, EtOAc–hexane); mp 254–258 °C;
[α]2D2 = +30.0 (c 0.48 CHCl3); IR (neat): νmax 3449, 2923, 2853,
1
1775, 1630, 1440, 1250, 1150, 1034 cm−1; H NMR (300 MHz,
CDCl3): δ 11.51 (s, 1H), 6.34 (s, 1H), 6.23 (s, 1H), 4.56 (t, J =
7.3 Hz, 1H), 2.95 (d, J = 16.8 Hz, 1H), 2.62 (m, 2H), 2.57 (d, J =
16.8 Hz, 1H), 2.37–2.29 (m, 2H), 2.27 (s, 3H), 1.44 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 195.4, 176.1, 161.6, 158.4, 150.9,
110.1, 108.5, 105.3, 82.5, 80.6, 42.7, 28.1, 22.5, 22.2, 19.1;
HRMS (ESI): calcd for C15H17O5 [M + H]+ 277.1070; found
277.1057.
(R)-2,7-Dimethyl-4-oxo-2-((S)-5-oxotetrahydrofuran-2-yl)-
chroman-5-yl acetate (30)
To a solution of compound 27 (50 mg, 0.18 mmol) in anhy-
drous CH2Cl2 (1 mL) were added acetic anhydride (0.05 mL,
0.54 mmol), pyridine (0.09 mL, 1.08 mmol) and DMAP
(S)-5-Hydroxy-2,7-dimethyl-2-((S)-5-oxotetrahydrofuran-2-yl)-
chroman-4-one (27a)
(White solid); Rf = 0.30 (40%, EtOAc–hexane); mp 105–108 °C; (4.4 mg, 0.036 mmol) and the resulting solution was stirred at
[α]2D3 = −42.0 (c 0.25 CHCl3); IR (neat): νmax 3423, 2923, 2853, rt for 4 h. Water was added to the reaction, and the mixture
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was stirred for another 30 min. The reaction mixture was then 4.63 (s, 2H), 4.58 (t, J = 7.3 Hz, 1H), 2.98 (d, J = 17.1 Hz, 1H),
extracted with CH2Cl2, washed with 1 N HCl, saturated aq. 2.61 (d, J = 17.1 Hz, 1H), 2.71–2.55 (m, 2H), 2.38–2.27 (m, 2H),
NaHCO3 solution, and brine, dried over Na2SO4, and filtered. 1.45 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 195.7, 176.1, 161.9,
The organic layer was concentrated in a rotary evaporator to 158.8, 153.1, 106.8, 106.3, 105.2, 82.5, 80.8, 64.4, 42.8, 28.1,
give the crude that was purified by silica gel column chromato- 22.3, 19.1, 195.7, 176.1, 161.9, 158.8, 153.1, 106.8, 106.3, 105.2,
graphy to give the compound 30 (57 mg, 99%) as an oil. Rf = 82.5, 80.8, 64.4, 42.8, 28.1, 22.3, 19.1; HRMS (ESI): calcd for
0.4 (50%, EtOAc–hexane); [α]2D2 = +21.0 (c 0.4 CHCl3); IR (neat): C15H16O6Na [M + Na]+ 315.0839; found 315.0828.
νmax 2924, 2853, 1776, 1687, 1624, 1564, 1341, 1199, 1151,
1076, 1017, 899 cm−1 1H NMR (500 MHz, CDCl3): δ 6.68 (s,
;
1H), 6.49 (s, 1H), 4.52 (t, J = 7.3 Hz, 1H), 2.86 (d, J = 16.0 Hz,
1H), 2.70–2.54 (m, 2H), 2.46 (d, J = 16.0 Hz, 1H), 2.35 (s, 3H),
2.32 (s, 3H), 2.34–2.26 (m, 2H), 1.42 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 188.3, 176.1, 169.6, 159.7, 149.5, 148.1,
117.1, 116.4, 110.9, 82.7, 80.9, 44.0, 28.2, 22.2, 21.8, 21.0, 18.8;
HRMS (ESI): calcd for C17H18O6Na [M + Na]+ 341.0995; found
341.0979.
Acknowledgements
We thank CSIR, New Delhi, India for the award of research fel-
lowships (S. B. and V. D. K.) as well as for financial support as
part of XII Five Year Plan programme under title ORIGIN
(CSC-0108).
(R)-7-(Hydroxymethyl)-2-methyl-4-oxo-2-((S)-5-
oxotetrahydrofuran-2-yl)chroman-5-yl acetate (31)
Notes and references
A solution of compound 30 (80 mg, 0.25 mmol) in CCl4 (1 mL)
was heated at 80 °C, and then AIBN (8.2 mg, 0.05 mmol) and
NBS (49 mg, 0.27 mmol) were added. The reaction mixture was
heated at 80 °C for 6 h. The reaction was cooled to rt, water
was added and extracted with CH2Cl2, washed with 1 N HCl
and brine, dried over Na2SO4 and filtered. Concentration on a
rotatory evaporator gave the crude compound which was used
for the next reaction without further purification. Crude benzyl
bromide was taken in 1 mL of 1,4-dioxane–H2O (1 : 1) and
CaCO3 (15.4 mg, 0.15 mmol) was added and heated at 80 °C
for 16 h. The reaction was cooled, water was added, extracted
with EtOAc, washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by silica gel
column chromatography to give compound 31 (15.5 mg, 49%
brsm, 50 mg of 30 recovered) as a yellow oil. Rf = 0.3 (50%,
1 B. Franck and H. Flasch, Fortschr. Chem. Org. Naturst.,
1973, 30, 151.
2 N. Tabata, H. Tomoda, K. Matsuzaki and S. Ōmura, J. Am.
Chem. Soc., 1993, 115, 8558.
3 N. Tabata, H. Tomoda, Y. Iwai and S. Ōmura, J. Antibiot.,
1996, 49, 267.
4 S. Kanokmedhakul, K. Kanokmedhakul, N. Phonkerd,
K. Soytong, P. Kongsaeree and A. Suksamrarn, Planta Med.,
2002, 68, 834.
5 W. Zhang, K. Krohn, Z. -Ullah, U. Flörke, G. Pescitelli, L. Di
Bari, S. Antus, T. Kurtán, J. Rheinheimer, S. Draeger and
B. Schulz, Chem. – Eur. J., 2008, 14, 4913.
6 A. Pontius, A. Krick, S. Kehraus, S. E. Foegen, M. Müller,
K. Klimo, C. Gerhäuser and G. M. König, Chem. – Eur. J.,
2008, 14, 9860.
7 A. Pontius, A. Krick, R. Mesry, S. Kehraus, S. E. Foegen,
M. Müller, K. Klimo, C. Gerhäuser and G. M. König, J. Nat.
Prod., 2008, 71, 1793.
8 Z. Guo, Z. She, C. Shao, L. Wen, F. Liu, Z. Zheng and Y. Lin,
Magn. Reson. Chem., 2007, 45, 777.
EtOAc–hexane); [α]D27
νmax 3478, 2956, 2924, 1787, 1740, 1639, 1441, 1377, 1264,
1170, 1069 cm−1 1H NMR (500 MHz, CDCl3): δ 6.88 (t, J =
= +37.8 (c 0.3, CHCl3); IR (neat):
;
0.76 Hz, 1H), 6.66 (t, J = 0.76 Hz, 1H), 4.66 (s, 2H), 4.54 (t, J =
7.3 Hz, 1H), 2.88 (d, J = 16.1 Hz, 1H), 2.69–2.54 (m, 2H), 2.48
(d, J = 16.1 Hz, 1H), 2.35 (s, 3H), 2.34–2.26 (m, 2H), 1.72 (brs,
1H), 1.42 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 188.4, 176.2,
169.7, 159.9, 150.6, 149.8, 113.6, 113.4, 112.0, 82.7, 81.0, 63.7,
9 J. Yang, F. Xu, C. Huang, J. Li, Z. She, Z. Pei and Y. Lin,
Eur. J. Org. Chem., 2010, 3692.
43.9, 28.2, 22.2, 21.0, 18.8; HRMS (ESI): calcd for C17H18O7Na 10 (a) H. Kikuchi, M. Isobe, M. Sekiya, Y. Abe, T. Hoshkawa,
[M + Na]+ 357.0944; found 357.0947.
K. Ueda, S. Kurata, Y. Katou and Y. Oshima, Org. Lett.,
2011, 13, 4624; (b) H. Kikuchi, M. Isobe, S. Kurata, Y. Katou
and Y. Oshima, Tetrahedron, 2012, 68, 6218.
(+)-Lachnone C (4)
A solution of compound 31 (10 mg, 0.03 mmol) in CH3OH– 11 V. Rukachaisirikul, S. Chantaruk, W. Pongcharoen,
Et3N (3 : 1, 0.4 mL) was stirred at rt for 5 h. The solution was M. Isaka and S. Lapanun, J. Nat. Prod., 2006, 69, 980.
washed with 1 N HCl, extracted with EtOAc, washed with satu- 12 I. N. Siddiqui, A. Zahoor, H. Hussain, I. Ahmed,
rated aq. NaHCO3 and brine, dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography to give lachnone C (4) (6 mg, 70%) as a yellow
V. U. Ahmad, D. Padula, S. Draeger, B. Schulz, K. Meier,
M. Steinert, T. Kurtán, U. Flörke, G. Pescitelli and
K. Krohn, J. Nat. Prod., 2011, 74, 365.
oil. Rf = 0.2 (50%, EtOAc–hexane); [α]2D8 = +39.0 (c 0.065, 13 T. Qin, R. P. Johnson and J. A. Porco Jr., J. Am. Chem. Soc.,
MeOH); IR (neat): νmax 3428, 2924, 2853, 1772, 1642, 1569,
2011, 133, 1714.
1439, 1375, 1266, 1153, 1087, 1057, 755 cm−1 1H NMR 14 M. C. Bröhmer, E. Bourcet, M. Nieger and S. Bräse, Chem. –
;
(500 MHz, CDCl3): δ 11.56 (s, 1H), 6.51 (s, 1H), 6.45 (s, 1H),
Eur. J., 2011, 17, 13706.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5601–5610 | 5609

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Paper
Organic & Biomolecular Chemistry
15 (a) G. Eglinton, F. E. King, G. Lloyd, J. W. Loder, 22 J. N. Chakor, L. Merlini and S. Dallavalle, Tetrahedron,
J. R. Marshall, A. Robertson and W. B. J. Whalley, J. Chem. 2011, 67, 6300.
Soc., 1958, 1833; (b) M. Isaka, A. Jaturapat, K. Rukseree, 23 G. D. Annis and B. T. Smith, Method for preparing
K. Danwisetkanjana, M. Tanticharoen and 5-haloalkyl-4,5-dihydroisoxazole derivatives, WO,
Y. Thebtarannonth, J. Nat. Prod., 2001, 64, 1015;
2009025983 A2 – published on 26th Feb, 2009.
(c) B. Proksa, D. Uhrin, T. Liptaj and M. Sturdikova, Phyto- 24 Disappearing of starting material can be monitored by
chemistry, 1998, 48, 1161; (d) D.-M. Yang, N. Takeda,
Y. Iitaka, U. Sankawa and S. Shibata, Tetrahedron, 1973, 29,
TLC, but the formation of 2 and 2a is known only after the
work-up.
519; (e) J. W. Hopper, W. Marlow, W. B. Whalley, 25 Samples have been drawn and worked up at different inter-
A. D. Borthwick and R. J. Bowden, Chem. Soc. C, 1973, vals (5 min to 1 h) to assess the conversion of 2a to 2.
3580; (f) D. J. Aberhart, Y. S. Chen, P. De Mayo and 26 The reverse transformation (reduction of benzylic hydroxy-
J. B. Stothers, Tetrahedron, 1965, 21, 1417.
16 (a) M. A. Wijdeven, R. Wijtmans, R. J. F. van den Berg,
W. Noorduin, H. E. Schoemaker, T. Sonke, F. L. van Delft,
methylene to methyl) was performed by Kikuchi et al. to
further confirm the structure of gonytolide G by compari-
son with gonytolide C: see ref. 10b.
R. H. Blaauw, R. W. Fitch, T. F. Spande, J. W. Daly and 27 In our attempts to perform benzylic methyl oxidation of
F. P. J. T. Rutjes, Org. Lett., 2008, 10, 4001; (b) P. Perlmutter
and T. D. McCarthy, Aust. J. Chem., 1993, 46, 253.
17 (a) CCDC 974676 contains the supplementary crystallo-
graphic data for the compound 16a (b) See the ESI.†
model substrates without any protection of the phenolic
hydroxyl groups, we observed bromination only in the aro-
matic ring.
28 Q. Zhou and B. B. Snider, J. Org. Chem., 2010, 75, 8224.
18 (a) S. Rapposelli, D. F. Settimo, M. Digiacomo, C. L. Motta, 29 (a) K. Mori and A. Gupta, Tetrahedron, 1985, 41, 5295;
A. Lapucci, S. Sartini and M. Vanni, Arch. Pharm. Chem. Life
Sci., 2011, 11, 372; (b) F. A. G. E1-Essawy, S. M. Yassin,
(b) J. Barbier, K. Gerth, R. Jansen and A. Kirschning, Org.
Biomol. Chem., 2012, 10, 8298.
I. A. E1-Sakka, A. F. Khattab, I. Sotofte, J. Ø. Madsen and 30 (a) O. H. Gringore and F. P. Rouessac, Org. Synth., 1985, 63,
A. Senning, J. Org. Chem., 1998, 63, 9840.
19 (a) Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T. Itoh,
121; (b) S. Hanessian and P. J. Murray, Tetrahedron, 1987,
43, 5055.
M. Yamamoto, K. Mitarai and Y. Nishii, Tetrahedron, 2002, 31 (a) H. H. Wasserman, A. K. Petersen and M. Xia, Tetra-
58, 8269; (b) A. G. Moiseev and D. C. Neckers, Synthesis,
2005, 2901.
hedron, 2003, 59, 6771; (b) A. Sutherland and C. L. Willis,
J. Org. Chem., 1998, 63, 7764.
20 T. S. Khlebnikova, Y. A. Piveń, N. B. Khripach and 32 G. Berti, P. Caroti, G. Catelani and L. Monti, Carbohydr.
F. A. Lakhvich, Chem. Nat. Compd., 2011, 47, 33. Res., 1983, 124, 35.
21 P.-Y. Chen, T.-P. Wang, M. Y. Chiang, K.-S. Huang, 33 The specific rotation of the synthetic compound is very
C.-C. Tzeng, Y.-L. Chen and E.-C. Wang, Tetrahedron, 2011,
67, 4155.
close to the natural product even though the earlier syn-
thetic compound has reported higher αD value (ref. 14).
5610 | Org. Biomol. Chem., 2014, 12, 5601–5610
This journal is © The Royal Society of Chemistry 2014