Total syntheses of ainsliadimer B and gochnatiolides A and B

Article abstract of DOI:10.1002/chem.201204292

Oh my goch: The total syntheses of ainsliadimer B and gochnatiolides A and B from α-santonin have been accomplished in 25 steps with approximately 1 % overall yield. A Diels-Alder reaction of natural dehydrozaluzanin C with a monomeric guaianolide derivative allows stereoselective assembly of a dimeric gochnatiolide-type skeleton with the required stereochemistry and preinstalled functionalities for the synthesis of dimeric ainsliadimer B and gochnatiolides A and B (see scheme). Copyright

Full text of DOI:10.1002/chem.201204292

COMMUNICATION
DOI: 10.1002/chem.201204292
Total Syntheses of Ainsliadimer B and Gochnatiolides A and B
Dongliang Xia,[a] Yu Du,[a] Zhi Yi,[a] Hao Song,[a] and Yong Qin*[a, b]
Dedicated to Professor Zhitang Huang on the occasion of his 85th birthday
The genus Ainsliaea is an important herbal resource in
traditional Chinese medicine for treating various diseases,
including rheumatism, traumatic injuries, edema, stomach
ache, and anorexia.[1] Phytochemistry studies in recent dec-
B[8,9] and gochnatiolides A–C[9] by the Lei group by using a
Diels–Alder reaction of monomeric guaianolide units. How-
ever, efficiently assembling a dimeric skeleton and precisely
controlling the regio- and stereoselectivity of individual syn-
theses of dimeric gochnatiolides remains challenging.
In this communication, we report the total syntheses of
ainsliadimer B and gochnatiolides A and B by using a path-
way in which the key reaction is a cross Diels–Alder cyclo-
addition of dehydrozaluzanin C with its analogues. Precise
modification of the monomeric guaianolide unit for the
Diels–Alder reaction allows highly regio- and stereoselective
assembly of the skeletons of di-
ACHTUNGTRENNUNGades have shown that the major secondary metabolites iso-
lated from these plant species are monomeric, dimeric and
trimeric guaianolides,[2] such as dehydrozaluzanin C (1),[3]
ainsliadimer B (2b),[4] the gochnatiolides A (3),[5] B (4),[5,6]
and C (5),[5] and the ainsliatrimers A (6) and B (7;[4]
Figure 1). These compounds exhibit micro- to nanomolar ac-
tivity against a variety of human cancer cell lines.[4]
meric guaianolides.
The retrosynthetic analysis of
dimeric guaianolides is shown
in Scheme 1. We envisioned
ꢀ
that the double bond at C4’
C15’ of gochnatiolides A and B
(3 and 4) could be derived from
10’-epi-ainsliadimer B (2a) and
ainsliadimer B (2b), respective-
ly, by C15’-b-hydroxyl elimina-
tion.
10’-epi-Ainsliadimer B
(2a) and ainsliadimer B (2b), in
turn, could be synthesized from
intermediate 8 by regio- and
stereoselective epoxidation on
Figure 1. Structures of dimeric and trimeric guaianolides.
These dimeric and trimeric guaianolides were proposed to
be accessible through the biosynthetic assembly of the
ꢀ
the C1’ C10’ double bond, followed by a base-catalyzed ep-
oxide ring-opening reaction. Compound 8 could be con-
structed by a regio- and stereoselective intermolecular
Diels–Alder reaction between the precisely modified elec-
tron-rich diene 9 and the electron-deficient dienophile dehy-
drozaluzanin C (1). Both monomeric diene 9 and dienophile
1 could be synthesized from the same intermediate 10 by
multi-step functional transformation. Intermediate 10 could
be readily derived from the known intermediate 11, which
itself could be produced by the photoirradiation-induced re-
arrangement of naturally abundant a-santonin.
monoACHTUNGTRENNUNGmeric guaianolide unit of dehydrozaluzanin C ana-
logues by Diels–Alder cycloaddition.[4,7] This approach has
guided biomimetic syntheses of dimeric ainsliadimers A and
[a] D. Xia,+ Y. Du,+ Z. Yi, H. Song, Prof. Dr. Y. Qin
Key Laboratory of Drug Targeting and Drug Delivery Systems of the
Ministry of Education, West China School of Pharmacy
and State Key Laboratory of Biotherapy
Sichuan University, Chengdu, 610041 (P.R. China)
Fax : (+86)28-85503842
E-mail: yongqin@scu.edu.cn
The total syntheses of dimeric guaianolides commenced
with the preparation of 14 from 11. The alkene 12 was pre-
pared in approximately 40% yield by using a known five-
step procedure (Scheme 2).[10] Regioselective epoxidation of
the double bond within the cyclopentene ring was realized
by using meta-chloroperbenzoic acid (mCPBA) in CHCl3 to
provide epoxide 13 in 84% yield. Epoxide ring opening in
[b] Prof. Dr. Y. Qin
Innovative Drug Research Centre and
College of Chemistry and Chemical Engineering
Chongqing University, Chongqing, 401331 (P.R. China)
Fax : (+86)23-65678750
E-mail: qinyong@cqu.edu.cn
[+] These authors contributed equally to this work
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204292.
13 with AlACHTUNGRTNENG(U OiPr)3 in toluene at high temperature gave inter-
Chem. Eur. J. 2013, 19, 4423 – 4427
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4423

mediate 10 in 65% yield. Oxi-
dation of 10 with Dess–Martin
reagent provided 14 in excellent
yield.
With 14 in hand, we tested
the feasibility of a proposed
bioACTHNUTRGNEUGmN imetic Diels–Alder reac-
tion[4,7] of 14 with its oxidized
enol 15 or diene 16, to directly
yield a gochnatiolide-type skel-
eton (Scheme 2). Oxidation of
14 with (PhSeO)2O,[11] followed
by removal of the excess oxi-
dant (PhSeO)2O by using rapid
flash chromatography, gave a
crude mixture of the unstable
oxidized product 15 and partial-
ly oxidized diene 16. When this
mixture was treated with
2 equivalents of 14 under vari-
ous conditions, dimer 18 was
always isolated as the sole de-
tectable dimer in approximately
10% yield. This dimer most
Scheme 1. Retrosynthetic analysis of dimeric guaianolides.
likely resulted from
a cross
Diels–Alder reaction of enol 15
with diene 16, followed by a
1,3-hydroxyl migration in the
resulting adduct 17. We suspect-
ed that the reaction of 14 with
its oxidized enol 15 or diene 16
failed to yield a gochnatiolide-
type skeleton because these
ꢀ
compounds lack
a C11 C13
double bond, leading to an un-
favorable conformation that
prevents the desired Diels–
Alder reaction between them.
To test this idea, compound
10 was converted to natural za-
luzanin C (19)[12] by a two-step
procedure of phenylselenation
and dephenylselenation. Zalu-
zanin C (19) was further oxi-
dized with Dess–Martin reagent
to give dehydrozaluzanin C (1),
ꢀ
which possesses
a C11 C13
double bond. As before, in the
case of oxidation of by
1
(PhSeO)2O, excess oxidant
(PhSeO)2O was removed by
using rapid flash chromatogra-
phy and 2 equivalents of 1 were
added. Only adduct 23,[9] rather
Scheme 2. Model reactions to assemble a dimeric skeleton. Reagents and conditions: a) mCPBA, CHCl3,
ꢀ208C to 08C, 2 h, 84%; b) Al
ACHTUNGTRENNUN(G OiPr)3, toluene, sealed, 1408C, 5 h, 65%; c) Dess–Martin reagent, CH2Cl2,
than
a
gochnatiolide-type
08C, 1 h, 90%; d) (PhSeO)2O, PhCl, 708C, 0.5 h; e) neat, 258C, 24 h, 10% for 14 to 18 over two steps, 19%
for 1 to 23 over two steps; f) lithium diisopropyl amide (LDA), (PhSe)2, hexamethylphosphoramide (HMPA),
THF, ꢀ788C to ꢀ308C, 2.5 h, 75%; g) H2O2, AcOH, THF, 08C!258C, 0.5 h, 82%.
adduct, was isolated in 19%
yield. Analogously to 18, com-
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Total Syntheses of Ainsliadimer B and Gochnatiolides A and B
COMMUNICATION
pound 23 should form through a cross Diels–Alder reaction
between the two oxidized intermediates enol 20 and diene
21, followed by 1,3-hydroxyl migration of the adduct 22
(Scheme 2).
hydration at a later stage to generate a b-hydroxyl group for
synthesizing ainsliadimer B (2) is quite challenging.[9,13] Tem-
ꢀ
porarily protecting the C4’ C15’ double bond with a 15’-
silyl
A
Because both the dienophile functionality in 1 and the
diene functionality in 20 and 21 are electron-deficient, the
number of reactive sites and therefore the risk of undesired
reaction pathways other than the planned Diels–Alder reac-
tion of 9 with 1.
ꢀ
Diels–Alder reaction of 1 at the C4 C15 double bond with
20 or 21 is theoretically unfavorable because it requires
overcoming a high energy barrier. In order to force the
Diels–Alder reaction of 1 to occur at the electron-deficient
As shown in Scheme 3, the diene 9 was prepared from
compound 14. The enone group in 14 was subjected to a Mi-
chael addition of (PhMe2Si)2Cu(CN)Li2 to give silane 24.[14]
After fluoridation of the silyl group with HBF4·Et2O and ox-
idation with H2O2 to convert the silyl group to a hydroxyl
group, the resulting hydroxyl group was protected with a
TBS group to afford compound 26. Both phenylselenation
(26 to 27) and reduction of the ketone functionality (27 to
28) proceeded in high yield
ꢀ
C4 C15 double bond and thereby form a gochnatiolide-type
adduct, we prepared a precisely modified electron-rich
diene functionality at C14’, C10’, C1’, and C2’ in a guaiano-
lide unit such as 9 (Scheme 3). We also preinstalled a 15’-si-
lyloxy substituent in 9 because performing a direct enone
with excellent stereoselectivity,
with each step yielding a single
stereomer. After converting the
phenylselenyl group to a double
bond (28 to 29) without protec-
tion of the hydroxyl group, the
lactone ring in 29 was modified
ꢀ
with a C11’ C13’ double bond
by two steps of phenylselena-
tion and dephenylselenation to
provide compound 30. Protec-
tion of the hydroxyl group in 30
with TMS afforded the diene 9
in high yield. As expected,
when 1 equivalent of
9 was
mixed with 2 equivalents of 1
under neat conditions at 608C
for 10 h, an electron-demanding
Diels–Alder reaction occurred
to provide the desired adduct 8
in 66% yield (Scheme 3). Al-
though the Diels–Alder reac-
tion of 9 with 1 could theoreti-
cally occur via several path-
ways, 8 was isolated as the sole
gochnatiolide-type adduct, indi-
cating that the reaction pro-
ceeds through
a
dominant
endo-addition transition state
(Ts-31a) rather than through an
exo-addition transition state
(Ts-31b). This is probably be-
cause the bottom face of the
diene in 9 is completely blocked
by two silyloxy groups, and the
upper face of the dienophile in
1 is completely blocked by the
seven-membered ring. The re-
action had to be conducted in a
solid phase in order to obtain
reasonable yields. In the pres-
Scheme 3. Synthesis of gochnatiolide A. Reagents and conditions: a) PhMe2SiLi, CuCN, THF, ꢀ788C, 2.5 h,
88%; b) HBF4·Et2O, CH2Cl2, 08C, 5 min; c) H2O2, KF, NaHCO3, MeOH/THF (1:1), 08C to 308C, 1.5 h, 96%
over two steps; d) tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), 2,6-lutidine, CH2Cl2, 08C, 0.5 h,
95%; e) lithium hexamethyldisilazide (LiHMDS), PhSeBr, THF, ꢀ788C to ꢀ558C, 2.5 h, 78%; f) NaBH4,
CeCl3·7H2O, MeOH, 08C, 1.5 h, 83%; g) H2O2, THF, 08C to 258C, 1.5 h, 94%; h) LDA, (PhSe)2, HMPA, THF,
ꢀ788C to ꢀ308C, 1.5 h; i) H2O2, AcOH, THF, 08C to 258C, 1.5 h, 73% over two steps; j) TMSCl, Et3N,
CH2Cl2, 08C to 108C, 92%; k) neat, 608C, 10 h, 66%; l) mCPBA, CH2Cl2, 08C, 0.5 h, 97%; m) TBAF, THF,
08C, 0.5 h, 97%; n) PCC, CH2Cl2, 08C, 1 h; o) Et3N, CH2Cl2, 258C, 3 h, 85% over two steps; p) DCC, CuCl,
CH2Cl2, reflux, 4 h, 92%.
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Y. Qin et al.
ence of a variety of solvents,
the Diels–Alder reaction pro-
ceeded very slowly to give 8 in
less than 15% yield. The addi-
tion of weak acids, such as ceric
ammonium sulfate (CAS), pyri-
dinium
(PPTS), TsOH, and AcOH, to
the Diels–Alder reaction
p-toluenesulfonate
caused the decomposition of 1,
exclusively.
Compound
8
possesses
a
gochnatiolide-type skeleton and
suitable functionalities at C10’
and C15’, allowing us to begin
Scheme 4. Syntheses of ainsliadimer B and gochnatiolide B. Reagents and conditions: a) TBAF, THF, 08C to
258C, 0.5 h, 99%; b) mCPBA, CH2Cl2, 08C, 1 h, 95%; c) PCC, CH2Cl2, 08C, 1 h; d) iPr2NEt, CH2Cl2, 258C,
3 h, 88% over two steps; e) DCC, CuCl, CH2Cl2, reflux, 5 h, 83%.
synthesizing
gochnatiolide A
(3). To our delight, treating 8
with 2 equivalents of mCPBA
in CH2Cl2 at 08C for 0.5 h
regio- and stereoselectively created an a-epoxide ring,
giving compound 32 in 97% yield as a single stereomer.
After the removal of both silyl protecting groups in 32, the
secondary hydroxyl group at C3’ in 33a was selectively oxi-
dized with pyridinium chlorochromate (PCC) to yield a
ketone functionality without affecting the primary hydroxyl
group at C15’. The epoxide ring was then opened with Et3N
to give 10’-epi-ainsliadimer B (2a) in 85% yield over two
steps (33a to 2a). Dehydration of 2a with N,N’-dicyclo-
ulation of functionalities. The successful synthesis of dimeric
gochnatiolides provides the starting material for further syn-
thesis of complex trimeric ainsliatrimers.
Acknowledgements
We are grateful for financial support from the NSFC (20825207,
20972100, 21021001, and 21132006) and the National Basic Research Pro-
gram of China (973 program, 2010CB833200). We thank Prof. Weidong
Zhang, Second Military University, Shanghai, China, for providing NMR
spectra for comparison.
ACHTUNGTRENNUNGhexylACHTUNGTRENNUNGcarbodiimide (DCC)/CuCl in CH2Cl2 completed the
synthesis of gochnatiolide A (3; Scheme 3).
The tertiary hydroxyl group at C10’ in both ainsliadimer B
(2b) and gochnatiolide B (4) has an inverted configuration
relative to the same group in gochnatiolide A (3), and direct
epoxidation of 8 provides only an a-epoxide ring. Thus, it
would be advantageous to find an alternative way to gener-
ate the b-epoxide ring necessary for the syntheses of ainslia-
dimer B (2b) and gochnatiolide B (4; Scheme 4). Fortunate-
ly, after removing both silyl groups in 8 with tert-butyl am-
monium fluoride (TBAF), epoxidation of the resulting 34
with mCPBA provided separable a-epoxide 33a and
b-epoxide 33b in 95% yield in a 1:1 ratio. Selective oxida-
tion of the secondary hydroxyl group in 33b with PCC, fol-
lowed by epoxide ring opening with the Hꢁnig base, gave
ainsliadimer B (2b) in 88% yield over two steps. Dehydra-
tion of ainsliadimer B (2b) with DCC/CuCl in CH2Cl2 com-
pleted the total synthesis of gochnatiolide B (4; Scheme 4).
In summary, the total syntheses of dimeric ainsliadimer B
(2b), and gochnatiolides A and B (3 and 4) from a-santonin
have been accomplished in 25 steps with approximately 1%
overall yield. A well-designed Diels–Alder reaction of natu-
ral dehydrozaluzanin C (1) with the precisely modified
Keywords: Diels–Alder reactions · dimeric guaianolides ·
natural products · regioselectivity · stereoselectivity · total
synthesis
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Total Syntheses of Ainsliadimer B and Gochnatiolides A and B
COMMUNICATION
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Received: December 3, 2012
Published online: February 28, 2013
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