Enantioselective total syntheses of Kuwanon X, Kuwanon Y, and Kuwanol A

Article abstract of DOI:10.1021/acs.orglett.5b03285

The first enantioselective total syntheses of (a)-kuwanon X, (+)-kuwanon Y, and (+)-kuwanol A have been accomplished by using asymmetric Diels-Alder cycloaddition promoted by chiral VANOL or VAPOL/boron Lewis acid. The biosynthesis-inspired asymmetric Diels-Alder cycloaddition shows high exo selectivity (exo/endo = 13/1), which was unprecedented in the previous total syntheses of related prenylflavonoid Diels-Alder natural products. An acid catalyzed intramolecular ketalization process enabled a biomimetic transformation to construct the polycyclic skeleton of kuwanol A efficiently.

Full text of DOI:10.1021/acs.orglett.5b03285

Letter
pubs.acs.org/OrgLett
Enantioselective Total Syntheses of Kuwanon X, Kuwanon Y, and
Kuwanol A
Lei Gao,†,‡ Jianguang Han,‡ and Xiaoguang Lei*,†,‡,§
†Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
‡National Institute of Biological Sciences (NIBS), Beijing 102206, China
§Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional
Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: The first enantioselective total syntheses of
(−)-kuwanon X, (+)-kuwanon Y, and (+)-kuwanol A have
been accomplished by using asymmetric Diels−Alder cyclo-
addition promoted by chiral VANOL or VAPOL/boron Lewis
acid. The biosynthesis-inspired asymmetric Diels−Alder cyclo-
addition shows high exo selectivity (exo/endo = 13/1), which was
unprecedented in the previous total syntheses of related
prenylflavonoid Diels−Alder natural products. An acid catalyzed
intramolecular ketalization process enabled a biomimetic trans-
formation to construct the polycyclic skeleton of kuwanol A
efficiently.
bout 50 kinds of optically active Diels−Alder type natural
Aproducts have been isolated from the moraceous plant
whose root bark has been used as a traditional Chinese medicine
for antiphlogistic, expectorant, antipyretic, and diuretic pur-
poses.1 Some of them, as bioactive plant constituents, showed
promising biological activities such as antibacterial, hypotensive,
antiphlogistic activities, etc.2 Structurally, these molecules share
the same chalcone dienophile moiety but differ in the
dehydroprenyl diene moiety. Based on the structure of diene,
the Diels−Alder type adducts from the moraceous plant can be
divided into five structural categories.1b,3,4 Due to their
promising biological activities and striking chemical structures,
the Diels−Alder type natural products represent very attractive
synthetic targets, and efforts have been made toward the total
syntheses of three categories of the adducts.4
Figure 1. Representative Diels−Alder type adducts of a chalcone and a
dehydroprenylstilbene.
to construct the desired cyclohexene skeleton by our group.12a,b
In our continuous efforts to synthesize the different Diels−Alder
type adducts from different categories, herein we would like to
report the first enantioselective total syntheses of kuwanons X
and Y, and kuwanol A.
As depicted in Scheme 1, the kuwanol A (4) could be derived
from the endo-kuwanon Y (2) through a biomimetic acid
catalyzed ketalization.6 The kuwanons X (1) and Y (2) could be
generated through asymmetric Diels−Alder cycloadditions from
the known dienophile 613 and diene 7. For the synthesis of diene
7, the dehydroprenyl group could be introduced by palladium
catalyzed cross-coupling reaction from iodide 8 in which C−C
double bond could be constructed by Horner−Wadsworth−
Emmons reaction from phosphonate 9 and aldehyde 10.
Representative Diels−Alder type adducts of a chalcone and a
dehydroprenylstilbene, one group of adducts from the mora-
ceous plant, are shown in Figure 1: kuwanon X (1),5 kuwanon Y
(2),6 kuwanol E (3),7 and the related ketalized adducts kuwanol
A (4)8 and sorocein I (5).9 To date no total syntheses of this type
of natural products have been reported, although some of them
have shown promising biological activities.10 For example, the
kuwanol E is one of the most potent natural compound inhibitors
of Mycobacterium tuberculosis protein tyrosine phosphatase B (Ki
= 1.6 0.1 μM) discovered by far.10c
Although many methods11 have been developed to synthesize
Diels−Alder type adducts or their derivatives, the enantiose-
lective total syntheses of these natural products are very limited.
Recently, an asymmetric Diels−Alder cycloaddition, catalyzed by
chiral VANOL or VAPOL-boron Lewis acid, has been reported
Received: November 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03285
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Organic Letters
Letter
With diene 7 and dienophile 6 in hand, attention was turned to
the asymmetric Diels−Alder cycloaddition. As shown in Table 1,
Scheme 1. Retrosynthetic Analysis of Kuwanon X, Kuwanon
Y, and Kuwanol A
Table 1. Screening of Chiral Ligands for the Asymmetric
Diels−Alder Cycloaddition
a
b
entry
ligands
time (h)
yield (%)
endo/exo
ee (%) endo/exo
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
23
24
21
21
22
20
28
95
70
69
79
60
42
80
1:4.2
1:5.3
1:11.4
1:13.0
1:3.1
1:7.0
1:3.5
70/13
94/81
50/96
53/97
0/1
81/63
96/63
As shown in Scheme 2, the synthesis of diene 7 commenced
with iodination of methyl 3,5-dihydroxy-benzoate 11 to give
Scheme 2. Synthesis of the Diene 7
a
b
1
Based on H NMR analysis. Determined by chiral HPLC analysis.
(R)-BINOL (L1), (R)-VANOL (L2), and (R) and (S)-VAPOL
(L3 and L4) were initially used to catalyze the reaction. All of
these chiral boron complexes showed unexpected exo
selectivity15 (entries 1−4). Among them, L4 effectively catalyzed
the Diels−Alder cycloaddition with very high exo selectivity
(exo/endo = 13/1) and ee value (97%), which could be used
directly for the enantioselective total synthesis of 1 (entry 4). For
the enantioselective synthesis of 2, using L2 as chiral ligand gave
a satisfying ee value but not a good endo-selectivity (entry 2).
Then several VANOL derivatives were used to improve the endo-
selectivity (entries 5−7). The (S)-4,4′-dibromo-VANOL (L5)
had the biggest negative impact on the enantioselectivity, which
was consistent with the previous results.12a,16 (entry 5).
Compared with L2, the (R)-7,7′-ditrifluoromethyl-VANOL
(L6) gave worse endo-selectivity and enantioselectivity (entry
6), while (R)-6,6′-dibromo-VANOL (L7) exhibited satisfying
enantioselectivity and improved endo-selectivity (entry 7). A
proposed transition state to explain the Diels−Alder selectivity
has been reported by our previous study12b and is also included in
the Supporting Information.
The corresponding exo-17 and endo-18 were treated with
K2CO3 in the mixture of THF and MeOH to give 1 and 2 in
yields of 67% and 49%, respectively, as shown in Scheme 3. The
spectroscopic data for synthetic 1 and 2 were in agreement with
those reported for the natural products. With 1 and 2 in hand,
sulfuric acid was employed to catalyze the biomimetic intra-
molecular ketalization of exo-1 and endo-2, but only endo-2
formed a ketalized product (see Supporting Information for
detailed mechanism), which was confirmed as kuwanol A (4).
Although the enantioselective total synthesis of the ketalized
compound 4 was accessible by using R-VANOL as a chiral ligand,
iodide 12 in 95% yield. Compound 12 was protected with TBS
group to give 13, then reduced by DIBAL to afford alcohol 14,
iodinated to give iodide 15 and followed by reacting with triethyl
phosphite to afford 9 in high yield over four steps. Iodide 8 was
obtained in 57% yield over three steps by Horner−Wadsworth−
Emmons reaction followed by deprotection of the silyl protecting
groups and reprotection with acetyl groups. With iodide 8 in
hand, first we tried to prepare diene 7 by Heck reaction with 2-
methylbut-3-en-2-ol and dehydration11f (not shown). Unfortu-
nately, only a mixture was obtained. Alternatively, Suzuki
reaction was used to synthesize diene 7.11c,14 Diene 7 could
not be obtained in satisfying yield by Suzuki reaction in one step,
though acetyl reprotection of the crude mixture gave diene 7 in
89% yield.
B
DOI: 10.1021/acs.orglett.5b03285
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Organic Letters
Letter
Scheme 3. Syntheses of Kuwanon X, Kuwanon Y, and
Kuwanol A
Scheme 5. Synthesis of Kuwanol A from MOM Protected
Diene 19
transition state, and so the subtle improvement to 1.2/1 was
possible.19
In the next step, several acidic conditions such as 0.8 M HCl in
THF/i-PrOH and 0.8 M sulfuric acid in EtOH were evaluated for
one-pot deprotection and ketalization of endo-22 but all failed.
Ultimately we found deprotection/ketalization of 22 could be
achieved in one step to afford 4 by using 10% sulfuric acid/EtOH.
By changing the protecting group in the diene moiety, the total
yield of kuwanol A (4) increased from 3.6% to 17.6% from the
same dienophile 6 with one step shorter and no significant
change in enantioselectivity.
In summary, the first enantioselective total syntheses of
kuwanons X and Y and kuwanol A have been accomplished by
employing a chiral ligand/boron Lewis acid promoted
asymmetric Diels−Alder cycloaddition in 12 and 11 steps,
respectively. The asymmetric Diels−Alder reaction featured high
exo-selectivity. The synthesis also featured a biomimetic acid-
catalyzed intramolecular ketalization process to furnish the
striking polycyclic framework of kuwanol A in one step.
Demonstrated by total syntheses of kuwanons X and Y and
kuwanol A, the chiral ligand/boron Lewis acid catalyzed
asymmetric Diels−Alder cycloaddition will have a broad
application in the total syntheses of other related complex
natural products isolated from moraceous plants.
the total yield from dienophile 6 was very low (3.7% over three
steps) due to the low endo-selectivity and moderate yield in the
subsequent two steps. As previously reported,11c,f,g when the two
phenolic hydroxyl groups in the ortho position of the
dehydroprenyl group were protected by MOM or Me group
instead of acetyl group, no obvious exo/endo stereoselectivity was
observed in the Diels−Alder cycloaddition. This inspired us to
further investigate whether the two acetyl groups near the
dehydroprenyl group played a key role in the exo-selectivity.
MOM-protected diene 19 was synthesized from phosphonate 9
and aldehyde 10 as shown in Scheme 4. Iodide 21 was obtained
Scheme 4. Syntheses of the MOM Protected Diene
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03285.
from precursors 9 and 10 after three steps. With iodide 21 in
hand, commercially available 2-methyl-but-3-en-2-ol was again
tested to synthesize diene 19 by Heck reaction and
dehydration.17 After screening several conditions, diene 19
could be obtained in 76% yield directly from 2-methylbut-3-en-2-
ol.
With MOM protected diene 19 in hand, the asymmetric
Diels−Alder cycloaddition promoted by (R)-VANOL (L2)/
boron Lewis acid was achieved as shown in Scheme 5. Compared
with the acetyl protected diene 7 (Table 1, entry 2), when diene
19 was used, the endo/exo stereoselectivity was changed from 1/
5.3 to 1/1.2 without losing the enantioselectivity (from 94% to
90%). This indicates that different substitution in diene may
contribute to different stereoselectivity in the asymmetric Diels−
Alder cycloaddition.15k,18 With the raised HOMO in diene 19,
the cycloaddition transition state occurs earlier in the reaction
pathway; hence, there is less steric demand one would need to
overcome for the endo transition state in comparison to the exo
Experimental procedures, product characterizations, and
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xglei@pku.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Alexander X. Jones (Peking University) for helpful
discussions, Prof. Guangzhong Tu (Beijing Institute of Micro-
chemistry) for NMR analysis, Dr. Jiang Zhou (Peking
University) for HRMS analysis, and Prof. William D. Wulff
(Michigan State University) for generously offering us three
C
DOI: 10.1021/acs.orglett.5b03285
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Letter
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Diels−Alder reactions, see: (e) Ahrendt, K.; Borths, C. J.; MacMillan, D.
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VANOL derivatives. Financial support from the National High
Technology Project 973 (2015CB856200) and NNSFC
(21222209, 91313303, 21472010, and 21561142002) is grate-
fully acknowledged.
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