Synthesis of chinensines A-E

Article abstract of DOI:10.1021/jo070527v

(Chemical Equation Presented) Short and efficient syntheses of coronarin E (4) and chinensines A-E (5-9) have been accomplished. The use of two different types of reaction of singlet oxygen (¹O₂) lies at the heart of the synthetic st

Full text of DOI:10.1021/jo070527v

Synthesis of Chinensines A-E
Ioannis Margaros and Georgios Vassilikogiannakis*
Department of Chemistry, UniVersity of Crete, Vasilika Vouton, 71003 Iraklion, Crete, Greece
Vasil@chemistry.uoc.gr
ReceiVed March 14, 2007
Short and efficient syntheses of coronarin E (4) and chinensines A-E (5-9) have been accomplished.
The use of two different types of reaction of singlet oxygen (1O2) lies at the heart of the synthetic strategy.
The syntheses have facilitated the clarification of certain previously unknown, or unconfirmed,
stereochemical details (the relativity stereochemistries of chinensines D and E and the absolute
stereochemistries for all the synthesized family members).
In 1997 a family of related compounds (1-5 and 7-9, Figure
1) were isolated from extracts of the aerial parts of a perennial
shrub named Alpinia chinensis.1 This plant, native to Hong
Kong, has long been used in Chinese medicine to treat asthma
and as an analgesic. Compound 6 (a 4-hydroxybutenolide that
is regioisomeric with compound 5) was isolated more recently,
and independently of the other chinensine family members, in
2005 from extracts of the Southeast Asian plant species
Etlingera elatior.2 E. Elatior extracts have been shown to have
interesting biological activities2 among which cytotoxicity
against the HeLa tumor cell line3 and antitumor-promoting
activity4 stand out especially. These natural products (1-9)5
all bear a variably oxidized northern portion attached to a decalin
anchor of the labdane type. Certain characteristics of the former
feature immediately attracted our attention because they bore
all the hallmarks of singlet oxygen-mediated assemblage. It
should be remembered that in Nature four essential prerequisites
necessary for the production and reaction of singlet oxygen (1O2)
are readily met. These criteria are the following: (a) natural
sunlight providing visible spectrum radiation; (b) a proliferation
of photosensitizers (e.g., tannins, porphyrins, and chlorophyll);
(c) pervasive molecular dioxygen (≈20% of atmospheric air);
and (d) an abundance of oxidizable substrates, such as terpenes.
1
Our experience in using O2 in the laboratory to achieve the
biomimetic syntheses of a diverse range of natural products
(particularly starting from naturally occurring furans6)7,8 led us
to propose and investigate such a strategy for synthesizing key
members of the chinensine family. Herein we report our success
in converting our blueprint into reality by accomplishing the
total syntheses of six members of the family, namely coronarin
E (4) and chinensines A-E (5, 6, 7, 8, and 9, respectively).
It is our belief that Nature relies heavily on singlet oxygen
when synthesizing the chinensine family members and this
postulate informed our retrosynthetic analysis. It followed that
the obvious starting point for these syntheses was the already
well-known natural product,1,9 bearing a furan moiety, named
(1) Sy, L.-K.; Brown, G. D. J. Nat. Prod. 1997, 60, 904-908.
(2) Mohamad, H.; Lajis, N. H.; Abas, F.; Ali, A. M.; Sukari, M. A.;
Kikuzaki, H.; Nakatani, N. J. Nat. Prod. 2005, 68, 285-288.
(3) Mackeen, M. M.; Ali, A. M.; El-Sharkawy, S. H.; Manap, M. Y.;
Salleh, K. M.; Lajis, N. H.; Kawazu, K. Int. J. Pharmaogn. 1997, 35, 174-
178.
(6) (a) Vassilikogiannakis, G.; Stratakis, M. Angew. Chem, Int. Ed. 2003,
42, 5465-5468. (b) Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.
Org. Lett. 2004, 6, 2039-2042. (c) Vassilikogiannakis, G.; Margaros, I.;
Montagnon, T.; Stratakis, M. Chem.-Eur. J. 2005, 11, 5899-5907.
(7) Sofikiti, N.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G.;
Stratakis, M. Org. Lett. 2005, 7, 2357-2359.
(4) Murakami, A.; Ali, A. M.; Mat-Salleh, K.; Koshimizu, K.; Ohigashi,
H. Biosci., Biotechnol., Biochem. 2000, 64, 9-16.
(8) Margaros, I.; Montagnon, T.; Tofi, M.; Pavlakos, E.; Vassilikogian-
nakis, G. Tetrahedron 2006, 62, 5308-5317.
(5) We have assigned the names chinensine A, B, C, D, and E to
compounds 5, 6, 7, 8, and 9, respectively, for ease of discussion. Please
note that coronarin E (4) was known and named prior to the isolation of
the chinensine family, see refs 1 and 9 and references therein.
(9) (a) Singh, S.; Gray, A. I.; Skelton, B. W.; Waterman, P. G.; White,
A. H. Aust. J. Chem. 1991, 44, 1789-1793. (b) Sirat, H. M.; Masri, D.;
Rahman, A. A. Phytochemistry 1994, 36, 699-701. (c) Zhao, Q.; Hao,
X.-J.; Chen, Y.-Z.; Zou, C. Chem. J. Chin. UniV. 1995, 16, 64-68.
10.1021/jo070527v CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/27/2007
4826
J. Org. Chem. 2007, 72, 4826-4831

Synthesis of Chinensines A-E
FIGURE 1. Selected members of the chinensine family of natural products.
SCHEME 1. Synthesis of Coronarin E (4)
coronarin E (4). It has been established for some time that furans
can undergo a [4+2]-cycloaddition upon treatment with 1O2 to
yield an endoperoxide10,11 that may then suffer either one of
two fates: (a) nucleophilic opening by, for example, H2O,
followed by a reduction/elimination process to furnish the
corresponding dialdehyde,10 herein, we account for the formation
of dialdehyde 3, or (b) formation of a 4-hydroxybutenolide12
in the presence of a mild base (e.g., naturally occurring amines),
thus, we may also explain the formation hydroxybutenolides 5
and 6 from coronarin E (4). In turn, reduction of hydroxy-
butenolide 5 might be expected to furnish the hemiketal 7, which
we propose is the precursor to diastereomeric endoperoxides 8
and 9 (via a second [4+2]-cycloaddition). The latter stages of
this sequence (7 f 8 and 9) represent a very minor adjustment
to the biogenetic proposal delineated in the isolation paper,1
which we hoped to justify through synthesis. In particular, the
isolation chemists had proposed that the origin of endoperoxides
8 and 9 was diene 2 (itself the product of the extract’s major
component epoxide 1). We preferred to propose diene 7 over
diene 2 as precursor to the endoperoxides 8 and 9 for the
following reasons: first, to participate in the [4+2]-cycloaddi-
tion, the E,Z-diene of 2 would be required to adopt an
unfavorable s-cis configuration (in comparison to E,E-diene 7
where the s-cis configuration is easily adopted), and second,
diene 2 is undoubtedly more electron deficient than diene 7, a
characteristic that might reasonably be expected to impact
negatively its chances of undergoing a [4+2]-cycloaddition of
this sort. It seemed highly probable to us then that the
endoperoxides 8 and 9 in reality arose via a [4+2] reaction
between the E,E-diene moiety of hemiketal 7 and 1O2. It would
be simple to differentiate between the two postulates by close
examination of the stereochemistry of the endoperoxides, a
structural feature not yet deconvoluted. The reaction between
dienes and 1O2 is concerted13 meaning that if E,Z-diene 2 is the
cycloaddition substrate then the endoperoxide products would
be expected to exhibit trans stereochemistry; on the other hand,
our modified hypothesis with E,E-diene 7 as the cycloaddition
substrate would translate to the corresponding cis-endoperoxides.
With its intact labdane skeleton, the commercially available
lactone 10, known as (+)-sclareolide, made an ideal starting
point for the investigation. Furthermore, since sclareolide (10)
is enantiomerically pure it provided the perfect tool with which
to validate the absolute stereochemistry of certain chinensine
family members whose stereochemistry had been tentatively
assigned based on comparisons to other biogenetically close
relatives.1 (+)-Sclareolide (10) was converted into coronarin E
(4) in five steps (Scheme 1). First, 3-lithiofuran, obtained from
3-bromofuran upon treatment with n-BuLi, was used to open
(10) (a) Feringa, B. L. Recl. TraV. Chim. Pays-Bas 1987, 106, 469-488
and references therein. (b) For mechanistic work see: Clennan, E. L.;
Mehrsheikh-Mohammadi, M. E. J. Am. Chem. Soc. 1984, 106, 7112-7118.
(11) For the first isolation of reasonable quantities of highly sensitive
furan endoperoxides see: (a) Gollnick, K.; Griesbeck, A. Tetrahedron 1985,
41, 2057-2068. (b) Gollnick, K.; Griesbeck, A. Angew. Chem., Int. Ed.
Engl. 1983, 22, 726-727.
(12) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773-
2776.
(13) (a) Clennan, E. L. Tetrahedron 1991, 47, 1343-1382. (b) Adam,
W.; Prein, M. Acc. Chem. Res. 1996, 29, 275-283.
J. Org. Chem, Vol. 72, No. 13, 2007 4827

Margaros and Vassilikogiannakis
1
SCHEME 2. Use of O2 to Synthesize Chinensine Family Members
sclareolide 10’s lactone moiety giving hydroxyketone 11 (yield
85%, 11 is itself a natural product14). After much experimenta-
tion, the best conditions to affect the dehydration of 11 and
maximize the exocyclic:endocyclic double bond ratio were
found to be the combination of SOCl2 and pyridine (yield
95%). These reagents gave an exocyclic:endocyclic ratio of 14:1
(∆8,17:∆7,8, Scheme 1), a ratio that represented a vast improve-
ment on those obtained from the initial methods15 investigated.
The furylic ketone 12 was then reduced to the corresponding
diastereomeric mixture (that was equimolar and separable by
column chromatography) of alcohols 13 (also natural products16)
with LiAlH4 in 97% yield. Once again, finding suitable
dehydration conditions demanded our attention because the
standard acidic conditions generally employed for such trans-
formations, when applied to alcohols 13, prompted an undesired
double bond (∆8,17) migration from exocyclic to endocyclic. For
example, use of PTSA furnished dehydrated material in a yield
of 73%, but the exocyclic:endocyclic ratio dropped from 14:1
to 4.5:1. Finally, we settled upon conversion of alcohols 13 to
the corresponding bromides followed by elimination under basic
conditions (DBU), thus affording coronarin E (4) in a lower
yield (57% over two steps), but without contamination from
double bond migration.
The stage was now almost set for the testing of the first key
1O2-mediated cascade reaction sequence that lay at the heart of
our synthetic strategy. First, however, a synthetic trick had to
be employed both to improve the yield and to bias the
regiochemical outcome of this reaction sequence. Although the
[4+2] reaction between 1O2 and furans is well-known,10
transformation of the resultant endoperoxide into the corre-
sponding 4-hydroxybutenolide by the action of base12 has been
shown to proceed only in very low yields. Careful placement
of a silicon group at the C-16 (for synthesis of chinensines A
and C-E), or C-15 (for chinensine B, Scheme 2) should affect
a stabilizing influence and would thus alleviate such prob-
lems.7,17 Fortunately, we had earlier developed a protocol for
achieving the regioselective ortholithiation of furans bearing an
unsaturated 3-position substituent at the more hindered 2-posi-
tion of the furan (in preference to the alternative 5-position).18
This procedure was now applied to accomplish the silylation
(14) Zdero, C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1991,
30, 1597-1601.
(15) For reports of similar failures with these methods see: Kolympadi,
M.; Liapis, M.; Ragoussis, V. Tetrahedron 2005, 61, 2003-2010.
(16) (a) Jung, M.; Ko, I.; Lee, S. J. J. Nat. Prod. 1998, 61, 1394-1396.
(b) Villamizar, J.; Fuentes, J.; Salazar, F.; Tropper, E.; Alonso, R. J. Nat.
Prod. 2003, 66, 1623-1627.
(17) For the silyl stabilization concept, see: Adam, W.; Rodriguez, A.
Tetrahedron Lett. 1981, 22, 3505-3508. For direct comparisons between
the photoxygenations of silyl-substituted and unsubstituted furans, see: (a)
Bury, P.; Hareau, G.; Kocien´ski, P.; Dhanak, D. Tetrahedron 1994, 50,
8793-8808. (b) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. J. Org.
Chem. 1996, 61, 2845-2852.
(18) Tofi, M.; Georgiou, T.; Montagnon, T.; Vassilikogiannakis, G. Org.
Lett. 2005, 7, 3347-3350.
4828 J. Org. Chem., Vol. 72, No. 13, 2007

Synthesis of Chinensines A-E
was quenched with brine (2 mL). The layers were separated and
the aqueous phase was extracted with EtOAc (3 × 6 mL). The
combined organic layers were dried over MgSO4 and filtered. After
evaporation of the solvent under reduced pressure, the solid residue
was pulverized and washed 3 to 5 times with small quantities of
hexanes/EtOAc (20:1 v/v) thus providing 11 (146 mg, 85%), which
was directly used in the next step.
of coronarin E (4) affording a 1:3 mixture of regioisomers 14:
15 (15 being required for synthesis of chinensines A and C-E
and 14 only for chinensine B, Scheme 2). Following this
silylation, the newly secured substrates 14 and 15 were subjected
to the 1O2-reaction conditions, namely, bubbling oxygen through
the reaction solution containing 10-4 M Methylene Blue as
sensitizer while irradiating with visible spectrum light (2 min).
The desired 4-hydroxybutenolides 5 and 6, chinensines A and
B, respectively, were separated from the reaction mixture (15
f 5 and 14 f 6, 5:6 ) 3:1 after purification, 80% overall for
two steps). Hydroxybutenolide 5 was produced as a single
11: [R]24 +21.3 (c 2.50, CHCl3) [lit.14 [R]24 +20.0 (c 0.49,
D
D
CHCl3)]; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.43 (d, J )
1.3 Hz, 1H), 6.78 (d, J ) 1.3 Hz, 1H), 2.85 (dd, J1 ) 17.2 Hz, J2
) 4.9 Hz, 1H), 2.80 (dd, J1 ) 17.2 Hz, J2 ) 4.9 Hz, 1H), 2.13 (t,
J ) 4.9 Hz, 1H), 1.95 (td, J1 ) 12.5 Hz, J2 ) 3.1 Hz, 1H), 1.70
(br d, J ) 14.0 Hz, 2H), 1.60-1.25 (m, 6H), 1.15 (s, 3H), 1.13
(m, 1H), 1.04 (dd, J1 ) 12.3 Hz, J2 ) 2.1 Hz, 1H), 0.92 (dt, J1 )
13.4 Hz, J2 ) 3.9 Hz, 1H), 0.87 (s, 3H), 0.85 (s, 3H), 0.79 (s, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 196.3, 147.0, 144.1, 127.7,
108.9, 73.0, 55.9, 55.8, 44.6, 41.7, 39.4, 38.6, 36.3, 33.3, 33.2, 23.3,
21.4, 20.6, 18.3, 15.7 ppm; HRMS (ESI+) calcd for C20H30O3Na
341.2087 [M + Na+], found 341.2090.
1
diastereomer (by H and 13C NMR) in accordance with the
isolation where only one diastereomer was found.1 In contrast,
hydroxybutenolide 6 was produced as an equimolar mixture of
diastereoisomers. Hydroxybutenolide 6 was isolated as a mixture
of diastereoisomers.2 After the failure of our attempts to reduce
hydroxybutenolide 5 (chinensine A) directly to the lactol 7
(chinensine C), we opted to take a stepwise approach. Thus,
sodium borohydride was used to obtain lactone 1619 from
hydroxybutenolide 5 in 92% yield. Lactone 16 was then further
reduced with Dibal-H to furnish the desired diastereomeric
lactols 7 (chinensines C, Scheme 2) in 96% yield. In the
investigation’s denouement, chinensine C (7) was transformed
to the desired diastereomeric mix (1.3:1) of cis-endoperoxides
8 and 9 (chinensines D and E, respectively) upon relatively
15,16-Epoxylabda-8(17),13(16),14-triene-12-one (∆8,17-12). To
a solution of 11 (144 mg, 0.45 mmol) in dry dichloromethane (3
mL) at room temperature was added dry pyridine (73 µL, 0.91
mmol, 2.0 equiv).20 After the mixture was cooled to -78 °C, a
solution of thionyl chloride (164 µL, 2.26 mmol, 5.0 equiv) in dry
dichloromethane (1.5 mL) and dry pyridine (302 µL, 3.74 mmol,
8.25 equiv) was added over a period of ca. 15 min. The reaction
mixture was stirred for 30 min at the same temperature before being
quenched with saturated aqueous NaHCO3 (10 mL). The reaction
mixture was then allowed to warm to room temperature and the
layers were separated. The aqueous phase was extracted with
dichloromethane (3 × 8 mL). The combined organic layers were
dried over MgSO4 and filtered. The crude 12 obtained after
evaporation of the solvent under reduced pressure was directly used
for the next reaction (129 mg, 95%, ∆8,17-12:∆7,8-12 ) 14:1).
1
prolonged treatment (20 min) with O2 in 60% isolated yield.
The spectral data for synthetic samples of compounds 4-9
(coronarin E and chinensines A-E, respectively) matched
exactly with the data reported for the natural products.1,2 That
the data for the natural and synthetic diastereomeric endoper-
oxides matched exactly was important because it established
the relative stereochemistry of the endoperoxides as being cis
for the first time. Furthermore, it would appear to validate our
proposal that Nature synthesizes these compounds from chin-
ensine C (7), and not from diene 2. In addition, the absolute
stereochemistry has been confirmed since the optical rotations
of the synthetic compounds, with known absolute stereochem-
istry, are in agreement with the values reported for the natural
products.
In summary, short and efficient syntheses of chinensines A-E
have been achieved that allowed the determination of the relative
stereochemistry of the endoperoxide rings of chinensines D an
E and the absolute stereochemistries for all the synthesized
family members. Singlet oxygen has been shown to be a
powerful synthetic tool whose mode of reaction (i.e., a concerted
[4+2]-cycloaddition with a diene) has, in this case, helped to
clarify some biogenetic details for the chinensine family of
secondary metabolites.
∆
8,17-12: [R]24 -65.1 (c 1.25, CHCl3) [lit.21 [R]24 -63.1 (c
1
D
D
0.13, CHCl3)]; H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 7.42
(d, J ) 1.4 Hz, 1H), 6.77 (d, J ) 1.4 Hz, 1H), 4.71 (s, 1H), 4.37
(s, 1H), 2.94 (dd, J1 ) 16.7 Hz, J2 ) 9.7 Hz, 1H), 2.75 (dd, J1 )
16.7 Hz, J2 ) 3.6 Hz, 1H), 2.65 (br d, J ) 9.9 Hz, 1H), 2.38 (ddd,
J1 ) 13.0 Hz, J2 ) 4.1 Hz, J3 ) 2.3 Hz, 1H), 2.14 (dt, J1 ) 13.0
Hz, J2 ) 5.2 Hz, 1H), 1.74 (qd, J1 ) 12.7 Hz, J2 ) 2.7 Hz, 1H),
1.60-1.10 (m, 8H), 0.89 (s, 3H), 0.82 (s, 3H), 0.76 (s, 3H) ppm;
13C NMR (125 MHz, CDCl3) δ 194.2, 148.9, 146.5, 143.8, 127.9,
108.5, 106.2, 54.8, 50.9, 41.7, 39.0, 38.7, 37.2, 36.1, 33.3, 33.2,
23.7, 21.5, 19.0, 14.5 ppm; HRMS (ESI+) calcd for C20H28O2Na
323.1982 [M + Na+], found 323.1982.
Diastereomeric 15,16-epoxy-12-hydroxylabda-8(17),13(16),-
14-triene (13a/13b). To a solution of LiAlH4 (16 mg, 0.43 mmol,
4.0 equiv) in dry THF (1.5 mL) was added dropwise a solution of
ketone 12 (129 mg, 0.43 mmol, 1.0 equiv) in dry THF (3.0 mL).
The reaction mixture was stirred for 30 min before being quenched
with brine (2 mL). The reaction mixture was diluted with EtOAc
(10 mL) and stirred for 30 min with a solution of Rochelle’s salt
(10 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (2 × 4 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude diastereomeric alcohols were used without
further purification (126 mg, 97%). For the purposes of full
spectroscopic characterization the two diastereomers were separated
by flash column chromatography (silica gel, hexanes:EtOAc ) 10:1
f 4:1, v/v).
Experimental Section
8r-Hydroxy-15,16-epoxylabda-13(16),14-diene-12-one (11).
To a solution of 3-bromofuran (118 µL, 1.24 mmol, 2.3 equiv) in
dry THF (2 mL) at -78 °C was added slowly n-BuLi (743 µL,
1.18 mmol, 2.2 equiv). After 5 min of stirring at -78 °C, the
solution was added dropwise (using a precooled cannula) to a
solution of (+)-sclareolide (10, 135 mg, 0.54 mmol, 1.0 equiv) in
dry THF (2 mL) at -78 °C. The mixture was allowed to warm
from -78 to -40 °C over a ca. 20 min period before the reaction
13a (less polar diastereomer): [R]24 +43.3 (c 2.15, CHCl3)
D
[lit.15 [R]24D +45.9 (c 0.49, CHCl3)]; 1H NMR (500 MHz, CDCl3)
δ 7.38 (s, 1H), 7.38 (s, 1H), 6.41 (s, 1H), 4.87 (d, J ) 1.3 Hz, 1H),
(19) Compound 16 is also a natural product: (a) Nakatani, N.; Kikuzaki,
H.; Yamaji, H.; Yoshio, K.; Kitora, C.; Okada, K.; Padolina, W. G.
Phytochemistry 1994, 37, 1383-1388. (b) Xiao, P.; Sum, C.; Zahid, M.;
Ishrud, O.; Pan, Y. Fitoterapia 2001, 72, 837-838.
(20) Boukouvalas, J.; Wang, J.-X.; Marion, O.; Ndzi, B. J. Org. Chem.
2006, 71, 6670-6673.
(21) De la Torre, M. C.; Garcia, I.; Sierra, M. A. J. Org. Chem. 2003,
68, 6611-6618.
J. Org. Chem, Vol. 72, No. 13, 2007 4829

Margaros and Vassilikogiannakis
4.68 (dd, J1 ) 9.6 Hz, J2 ) 2.1 Hz, 1H), 4.48 (s, 1H), 2.42 (ddd,
J1 ) 12.7 Hz, J2 ) 3.9 Hz, J3 ) 2.4 Hz, 1H), 2.12-2.01 (m, 2H),
1.85-1.71 (m, 3H), 1.62-1.46 (m, 2H), 1.43-1.29 (m, 2H), 1.24-
1.07 (m, 2H), 0.93-0.75 (m, 2H), 0.89 (s, 3H), 0.81 (s, 3H), 0.69
(s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 148.9, 143.1, 138.4,
130.2, 108.5, 106.4, 65.2, 55.3, 52.3, 42.0, 39.2, 38.9, 38.2, 33.53,
33.50, 32.6, 24.3, 21.6, 19.3, 14.5 ppm; HRMS (ESI+) calcd for
C20H30O2Na 325.2138 [M + Na+], found 325.2136.
Chinensine A (5) and Chinensine B (6). To a stirred solution
of coronarin E (4, 71 mg, 0.25 mmol, 1.0 equiv) in dry THF (5
mL) at -15 °C was added n-BuLi (1.6 M in hexane, 390 µL, 0.63
mmol, 2.5 equiv) dropwise. After 10 min of stirring at -15 °C,
TMS-Cl (670 µL, 0.58 mmol, 2.3 equiv) was added and the reaction
mixture allowed to warm to ambient temperature and then quenched
with brine (2.0 mL). The layers were separated and the aqueous
phase was extracted with Et2O (5 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo. The
resulting crude mixture of 14 and its regioisomer 15 (14:15, 1:3)
was used without further purification.
13b (more polar diastereomer): [R]24D +10.8 (c 1.35, CHCl3)
[lit.15 [R]24D +8.50 (c 0.50, CHCl3)]; 1H NMR (500 MHz, CDCl3)
δ 7.40 (s, 1H), 7.33 (s, 1H), 6.41 (d, J ) 1.0 Hz, 1H), 4.88 (d, J
) 1.3 Hz, 1H), 4.72 (d, J ) 1.3 Hz, 1H), 4.70 (dd, J1 ) 9.6 Hz, J2
) 4.8 Hz, 1H), 2.37 (ddd, J1 ) 12.7 Hz, J2 ) 3.9 Hz, J3 ) 2.4 Hz,
1H), 1.98-1.13 (m, 9H), 1.10 (dt, J1 ) 13.5 Hz, J2 ) 3.9 Hz, 1H),
0.97 (dd, J1 ) 12.6 Hz, J2 ) 2.6 Hz, 1H), 0.94-0.75 (m, 2H),
0.82 (s, 3H), 0.78 (s, 3H), 0.69 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 148.8, 143.4, 139.6, 128.7, 108.2, 106.6, 65.9, 55.2, 52.8,
41.9, 39.4, 38.7, 38.1, 33.5, 33.4, 31.8, 24.3, 21.6, 19.3, 14.5 ppm;
HRMS (ESI+) calcd for C20H30O2Na 325.2138 [M + Na+], found
325.2140.
A solution of the mixture of 14 and 15 (116 mg, 0.32 mmol) in
CH2Cl2 (8 mL) containing Methylene Blue (10-4 M) was placed
in a test tube with oxygen bubbling gently through it. The solution
was cooled to 0 °C and irradiated with a xenon 300 W lamp for 2
min after which complete transformation of the starting material
was observed (based on TLC). The solvent was removed in vacuo
and the liquid residue was purified by flash column chromatography
(silica gel, hexanes:EtOAc ) 8:1 to 2:1 v/v) to afford chinensine
A (5, 47 mg, 60% over two steps) and chinensine B (6, 16 mg,
20% over two steps).
Coronarin E (4): Method A. To a preheated solution (100 °C)
of the diastereomeric alcohols (126 mg, 0.42 mmol, 1.0 equiv) in
toluene (8 mL) in a sealed tube was added PTSA (2 mg, 0.01 mmol,
0.024 equiv) portionwise. After 11/2 h at the same temperature the
reaction was quenched by addition of saturated aqueous NaHCO3
(4 mL). The layers were separated. The organic layer was dried
over MgSO4 and concentrated under reduced pressure to afford a
Chinensine A (5): [R]24 +7.88 (c 3.40, CHCl3) [lit.1 [R]24
D
D
+33.7 (c 0.35, CHCl3)]. The optical rotation of a very pure sample
1
of compound 5 (see H and 13C-spectrum) was measured many
times; 1H NMR (500 MHz, CDCl3) δ 6.93 (dd, J1 ) 15.8 Hz, J2 )
10.3 Hz, 1H), 6.86 (br s, 1H), 6.12 (br s, 1H), 6.08 (d, J ) 15.8
Hz, 1H), 4.75 (br s, 1H), 4.46 (br s, 1H), 4.34 (br s, -OH), 2.43
(qd, J1 ) 13.5 Hz, J2 ) 1.8 Hz, 1H), 2.38 (br d, J ) 10.1 Hz, 1H),
2.07 (dt, J1 ) 13.0 Hz, J2 ) 4.8 Hz, 1H), 1.70 (br d, J1 ) 13.0 Hz,
1H), 1.56-1.13 (m, 6H), 1.08 (dd, J1 ) 12.5 Hz, J2 ) 2.2 Hz,
1H), 0.99 (br t, J ) 12.9 Hz, 1H), 0.89 (s, 3H), 0.86 (s, 3H), 0.83
(s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.2, 149.2, 140.9,
139.5, 132.4, 120.2, 108.4, 96.3, 62.2, 54.6, 42.2, 40.8, 39.3, 36.7,
33.5 (2C), 23.3, 21.9, 19.0, 15.0 ppm; HRMS (ESI+) calcd for
C20H28O3Na 339.1931 [M + Na+], found 339.1932.
mixture of coronarin E:∆7,8-isomer ) 4.5:1 (starting material, ∆8,17
-
13:∆7,8-13 ) 14:1). Purification by column chromatography (silica
gel, hexanes) afforded pure coronarin E (71 mg of ∆7,8-isomer,
60%).
Coronarin E (4): Method B. To a solution of PPh3 (245 mg,
0.93 mmol, 1.5 equiv) in DCM (3.5 mL) at 0 °C was added
dropwise Br2 (48 µL, 0.93 mmol, 1.5 equiv). After a further 5 min,
Et3N (234 µL, 1.68 mmol, 2.7 equiv) was added and then the
mixture was stirred for 5 min.22 A solution of the diastereomeric
alcohols 13 (188 mg, 0.62 mmol, 1.0 equiv) in CH2Cl2 (1.8 mL)
was then added dropwise and the mixture was allowed to warm to
room temperature. After 2 h the mixture was concentrated in vacuo
and purified by flash column chromatography on silica gel, with
hexanes-EtOAc (30:1, v/v) to afford the corresponding bromides
as orange oil. A solution of these diastereomeric bromides (192
mg, 0.53 mmol) in DBU and toluene (2.5 mL, 1:4) was heated to
reflux overnight. The mixture was then allowed to cool, diluted
with Et2O, and washed with brine. The layers were separated and
the organic layer was dried over MgSO4, filtered, and concentrated
in vacuo to afford a mixture: coronarin E:∆7,8-isomer ) 12:1
(starting material, ∆8,17-alcohols:∆7,8-alcohols ) 14:1). Purification
by flash column chromatography (silica gel, hexanes:EtOAc ) 60:1
v/v) afforded coronarin E (101 mg, 57%, over 2 steps) as a colorless
oil.
1
Chinensine B (6): H NMR (500 MHz, CDCl3) δ )6.58 (br
dd, J1 ) 16.0 Hz, J2 ) 10.4 Hz, 1H + 1H), 6.30 (d, J ) 16.0 Hz,
1H + 1H), 6.26 (br s, 1H + 1H), 5.85 (s, 1H + 1H), 4.78 (s + s,
1H + 1H), 4.46 (s, 1H), 4.38 (s, 1H), 4.10 (br s, 2 × OH), 2.46 (d
+ d, J ) 10.4 Hz, 1H + 1H), 2.44 (m, 1H + 1H), 2.09 (dt, J1 )
13.8 Hz, J2 ) 5.3 Hz, 1H + 1H), 1.75-1.00 (m, 9H + 9H), 0.90
(s, 3H + 3H), 0.87 (s, 3H + 3H), 0.84 (s, 3H + 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 171.6 (2C), 161.3 (2C), 148.9, 148.6,
144.0 (2C), 122.7 (2C), 115.4 (2C), 108.9, 108.5, 97.8 (2C), 62.1
(2C), 54.7, 54.6, 42.2 (2C), 41.0, 40.9, 39.6, 39.5, 36.6 (2C), 33.5
(4C), 23.2 (2C), 21.9 (2C), 19.0 (2C), 15.1 (2C) ppm; HRMS
(ESI+) calcd for C20H28O3Na 339.1931 [M + Na+], found
339.1932.
Labda-8(17),11,13-trien-15(16)-olide [E] (16). To a solution
of chinensine A (5, 47 mg, 0.15 mmol, 1.0 equiv) in MeOH (1.5
mL) was added NaBH4 (7.7 mg, 0.20 mmol, 1.5 equiv) at ambient
temperature. After 15 min of stirring, a few drops of a solution
containing concentrated H2SO4/MeOH (1/10, v/v) was added until
the reaction mixture became clear. After being stirred for 1 min
more the mixture was diluted with EtOAc (6 mL) and washed with
brine. The layers were separated and the aqueous phase was
extracted with EtOAc (3 × 4 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The
crude lactone 16 was used without further purification (41 mg,
92%).
Coronarin E (4): [R]24 +21.6 (c 1.3, CHCl3) [lit.16a,23 [R]24
D
1
D
+21.3 (c 0.44, CHCl3)]; H NMR (500 MHz, CDCl3) δ 7.36 (s,
1H), 7.35 (s, 1H), 6.55 (s, 1H), 6.21 (d, J ) 15.7 Hz, 1H), 5.98
(dd, J1 ) 15.7 Hz, J2 ) 9.8 Hz, 1H), 4.74 (d, J ) 1.8 Hz, 1H),
4.54 (d, J ) 1.8 Hz, 1H), 2.45 (qd, J1 ) 13.5 Hz, J2 ) 2.1 Hz,
1H), 2.40 (ddd, J1 ) 9.7 Hz, J2 ) 4.2 Hz, J3 ) 2.1 Hz, 1H), 2.13
(dt, J1 ) 13.1 Hz, J2 ) 4.9 Hz, 1H), 1.73 (qd, J1 ) 10.3 Hz, J2 )
2.7 Hz, 1H), 1.60-1.37 (m, 5H), 1.22 (dt, J1 ) 13.9 Hz, J1 ) 4.0
Hz, 1H), 1.14 (dd, J1 ) 12.6 Hz, J2 ) 2.5 Hz, 1H), 1.06 (dt, J1 )
13.3 Hz, J2 ) 3.1 Hz, 1H), 0.93 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H)
ppm; 13C NMR (125 MHz, CDCl3) δ 150.1, 143.2, 139.6, 128.2,
124.5, 121.7, 108.0, 107.6, 61.4, 54.8, 42.3, 40.7, 39.1, 36.7, 33.55,
33.53, 23.4, 21.9, 19.1, 15.0 ppm; HRMS (ESI+) calcd for C20H28-
ONa 307.2032 [M + Na+], found 307.2032.
16: [R]24D +15.5 (c 2.00, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.15 (br s, 1H), 6.89 (dd, J1 ) 15.8 Hz, J2 ) 10.2 Hz, 1H), 6.11
(d, J ) 15.8 Hz, 1H), 4.80 (br s, 2H), 4.76 (d, J ) 1.5 Hz, 1H),
4.50 (d, J ) 1.5 Hz, 1H), 2.44 (ddd, J1 ) 13.5 Hz, J2 ) 4.2 Hz, J3
) 2.2 Hz, 1H), 2.37 (br d, J ) 10.0 Hz, 1H), 2.08 (m, 1H), 1.74-
1.35 (m, 6H), 1.18 (dt, J1 ) 13.6 Hz, J2 ) 3.5 Hz, 1H), 1.09 (dd,
J1 ) 12.5 Hz, J2 ) 2.7 Hz, 1H), 1.00 (br t, J1 ) 13.6 Hz, 1H),
0.89 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ 172.3, 149.3, 142.4, 136.8, 129.4, 120.6, 108.4, 69.6,
(22) Anderson, J. C.; Headley, C.; Stapleton, P. D.; Taylor, P. W.
Tetrahedron 2005, 61, 7703-7711.
(23) Itokawa, H.; Morita, H.; Takeya, K.; Motidome, M. Chem. Pharm.
Bull. 1988, 36, 2682-2684.
4830 J. Org. Chem., Vol. 72, No. 13, 2007

Synthesis of Chinensines A-E
62.1, 54.7, 42.2, 40.8, 39.2, 36.7, 33.5 (2C), 23.3, 21.9, 19.0, 15.0
ppm; HRMS (ESI+) calcd for C20H28O2Na 323.1982 [M + Na+],
found 323.1983.
mg, 0.13 mmol) in CH2Cl2 (4 mL) containing Methylene Blue
(10-4 M) was placed in a test tube with O2 gently bubbling through
it. The solution was cooled to 0 °C and irradiated with a xenon
300 W lamp for ca. 20 min after which time complete con-
Chinensine C (7). To a solution of 16 (41 mg, 0.14 mmol, 1.0
equiv) in dry CH2Cl2 (1 mL) at -78 °C was added dropwise
Dibal-H (1.0 M in hexane, 246 µL, 0.25 mmol, 1.8 equiv) over a
period of 15 min.24 The reaction was stirred for a further 30 min at
-78 °C and quenched at the same temperature by adding MeOH
(1.5 mL). The homogeneous mixture was allowed to warm to room
temperature over a period of 1 h until a white precipitate appeared.
The cloudy solution was filtered through a pad of celite that was
washed copiously with Et2O. The filtrate was concentrated under
reduced pressure to give the crude diastereomeric lactols 7 in 1:1
ratio (40 mg, 96%), which were used directly in the next step.
Chinensine C (7): [R]24 +24.2 (c 2.0, CHCl3) [lit.1 [R]24
1
sumption of the starting material was observed by H NMR. The
solvent was removed in vacuo and the residue was purified
by flash column chromatography (silica gel, hexanes:EtOAc
) 6:1 to 2:1 v/v) to afford the inseparable diastereomeric endop-
eroxides (27 mg, 60%, major diastereomer:minor diastereomer )
1.3:1).
1
Chinensines D and E (8 and 9): H NMR (500 MHz, CDCl3)
δ 9.51 (s, 1H major), 9.50 (s, 1H minor), 7.23 (t, J ) 1.4 Hz, 1H
major), 6.94 (t, J ) 1.4 Hz, 1H minor), 5.39 (t, J ) 1.7 Hz, 1H
minor), 5.33 (d, J ) 5.5 Hz 1H major), 4.99 (br s, 1H major), 4.81
(s + s, 1H major + 1H minor), 4.74 (m, 1H major + 1H minor),
4.65 (s, 1H minor), 3.93 (m, 2H major + 2H minor), 2.41 (m, 1H
major), 2.33 (m, 1H minor), 2.25-1.07 (m, 12H major + 12H
minor), 0.97 (s, 3H minor), 0.95 (s, 3H major), 0.88 (s, 3H minor),
0.87 (s, 3H major), 0.84 (s, 3H minor), 0.82 (s, 3H major) ppm;
13C NMR (125 MHz, CDCl3) δ 190.4, 190.2, 152.78, 152.73, 147.0,
144.4, 137.2, 136.8, 110.7, 109.4, 80.0, 79.3, 79.0, 78.6, 62.8, 62.3,
62.2, 59.5, 55.8, 55.6, 42.0, 41.9, 41.5, 41.0, 40.0, 39.0, 38.1 (2C),
33.8, 33.7 (2C), 33.6, 24.1, 24.0, 21.7, 21.6, 19.2, 19.2, 16.9, 16.4
ppm; HRMS (ESI+) calcd for C20H30O4Na 357.2036 [M + Na+],
found 357.2037.
D
D
1
+17.6 (c 0.23, CHCl3)]; H NMR (500 MHz, CDCl3) δ 6.18-
6.04 (m, 6H, 3H for each diastereomer), 5.91 (br s, 2H, 1H for
each diastereomer), 4.80 (d, J ) 15.0 Hz, 2H, 1H for each
diastereomer), 4.75 (br s, 2H, 1H for each diastereomer), 4.57 (d,
J ) 15.0 Hz, 2H, 1H for each diastereomer), 4.51 (d, J ) 1.6 Hz,
1H), 4.45 (d, J ) 1.6 Hz, 1H), 2.68 (m, 2H, 1H for each
diastereomer), 2.44 (br d, J ) 11.7 Hz, 2H, 1H for each
diastereomer), 2.34 (br d, J ) 9.2 Hz, 2H, 1H for each diastere-
omer), 2.07 (m, 4H, 2H for each diastereomer), 1.75-1.33 (m, 10H,
5H for each diastereomer), 1.18 (br t, J ) 13.3 Hz, 2H, 1H for
each diastereomer), 1.09 (br d, J ) 12.5 Hz, 2H, 1H for each
diastereomer), 1.00 (br t, J ) 11.8 Hz, 2H, 1H for each diastere-
omer), 0.89 (br s, 6H, 3H for each diastereomer), 0.833 (br s, 6H,
3H for each diastereomer), 0.827 (s, 3H), 0.82 (s, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 149.8, 149.7, 138.90, 138.86, 133.6,
133.4, 125.4, 125.3, 123.7, 123.6, 108.3, 108.0, 102.7, 102.6, 73.56,
73.55, 61.81, 61.78, 54.7 (2C), 42.3 (2C), 40.83, 40.80, 39.2, 39.1,
36.7 (2C), 33.55 (2C), 33.54 (2C), 23.3 (2C), 21.9 (2C), 19.11,
19.09, 15.0 (2C) ppm; HRMS (ESI+) calcd for C20H28O2Na
323.1982 [M - 2 + Na+], found 323.1984.
Acknowledgment. We thank Dr. Tamsyn Montagnon for
helpful discussions. The project was co-funded by the European
Social Fund and National Resources (B EPEAEK, Pythagoras
program) and with a National Fellowship Institute (IKY)
fellowship (I.M.). We also thank ELKE of University of Crete
for financial support. We thank Prof. A. Giannis and Dr. V.
Sarli for their help with HRMS.
1
Supporting Information Available: Copies of H NMR and
Chinensines D and E (8 and 9). A solution of lactols 7 (40
13C NMR spectra for all relevant compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2006,
8, 3441-3443.
JO070527V
J. Org. Chem, Vol. 72, No. 13, 2007 4831