Synthesis and Configuration of Natural Dracaenones

Article abstract of DOI:10.1021/acs.orglett.8b03965

Several dracaenones were synthesized in enantiopure forms for the first time. The key chiral center at C-7 was installed with well-defined stereochemistry using either an Evans aldol condensation or a chiral oxidant-mediated asymmetric epoxidation, while

Full text of DOI:10.1021/acs.orglett.8b03965

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis and Configuration of Natural Dracaenones
Mei-Mei Li,†,‡ Yikang Wu,*,‡ and Bo Liu*,†
†School of Materials Science and Engineering, Harbin University of Science and Technology, Harbin 150040, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Several dracaenones were synthesized in enantiopure
forms for the first time. The key chiral center at C-7 was installed with
well-defined stereochemistry using either an Evans aldol condensation
or a chiral oxidant-mediated asymmetric epoxidation, while and the
critical oxidative coupling was achieved under the PIFA/PTA
conditions. Comparison of optical rotations for the synthetic and
natural samples allowed for unequivocal assignment of the absolute
configurations of the natural dracaenones.
racaenones are a group of bridged compounds with an
of 1 should be opposite to that of 2 and 3. It is noteworthy that
compound 2 was also isolated5 (by Li and Hou, in 2014) from
the resin of D. cochinchinensis. However, the optical rotation
was reported to be +0.51 (c 0.4, MeOH), radically different
from the data ([α]D −411 (c 0.0258, MeOH)) reported2 by
Cordell.
D
uncommon homoisofavane skeleton. The first one ever
known in this family was caesalpin J1a (1, Figure 1, with
Compound 4 was isolated by Zhang and Yang6 (from fresh
stems of D. cochinchinensis) with the gross structure and
relative configuration assigned on the basis of the spectro-
scopic data. The absolute configuration was deduced through
comparison of the sign of optical rotation with those of 1−3.
Compounds 5 and 6 were isolated by Tu7 (from heartwood
of Caesalpinia sappan L.). The NMR data for 5 were very
similar to those for 1. With the aid of 2D NOE data, 5 was
assigned as the C-13 epimer of 1. Similarly, the structure of 6
was deduced according to the high resemblance between the
NMR for 6 and 3. In both cases, the absolute configuration was
assigned by comparison of the optical rotation with that for 1−
3.
While the assignments of the gross structures and relative
configurations of those natural dracaenones seem to be
impeccable, the absolute configurations were not beyond all
doubtthe octant rule was originally established for cyclo-
hexanone systems, with only a very limited number of known
precedents of semiquinone systems. Besides, 1 and 3 are not
exactly mirror images to one another. Therefore, assignment of
the configuration of the bridge system of 1 by comparison of
its sign of optical rotation with that of 3 was not really
convincing; the contribution of the chiral center at C-13
should not be overlooked. To verify the absolute configuration
of dracaenones, we performed the syntheses described below.
Construction of the bridged ring is apparently a critical step
in the whole synthesis of dracaenones. A survey of the
literature revealed that the only precedent (racemic, Scheme 1)
Figure 1. Structures of 1 (caesalpin J), 2, 3, 4, 5 (epicaesalpin J), and
6 with the atom-numbering system adopted from ref 2.
relative configuration determined by X-ray crystallographic
analysis1b of its triacetate), which was isolated (from dried
heartwood of Caealpinia sappan L.) in 1985 by Nohara and co-
workers. Shortly afterward, the closely related 2 and 3 (both
were isolated from Dracaena loureiri) were reported2 by
Cordell. The name dracaenone was then introduced and
adopted in all subsequent publications on this family of natural
products.
On the basis of their analysis of the CD data (using the
octant rule3), Cordell2 also proposed the absolute config-
urations of 2 and 3 as depicted in Figure 1.4 Because the sign
of optical rotation for 1 was opposite to that for 2 and 3, they
suggested that the absolute configuration of the bridge system
Received: December 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03965
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Construction of the Bridged Ring System
Scheme 2. Synthesis of ent-4
was that reported by Cordell8 in the late 1980s, which relied
on a TTFA-mediated oxidative coupling to construct the C−C
bond between the two quaternary carbon atoms. Although the
yields were not really satisfactory (12−37%), the lack of any
other existing choices prompted us to examine this protocol
first.
As shown in Table 1, the TTFA conditions were apparently
not applicable to our substrates. Fortunately, the PIFA/PTA9
a
Table 1. Results of Synthesis of 8 (cf. Scheme 1)
entry
7
R1
R2
R3
reagents
8 (yield, %)
b
d
1
2
3
4
5
6
7
8
a
a
b
c
c
d
d
e
f
H
H
Me
H
H
H
H
H
Me
Me
H
H
H
Me
Me
TTFA
a (0%)
c
PIFA/PTA
PIFA/PTA
TTFA
PIFA/PTA
TTFA
PIFA/PTA
PIFA/PTA
TTFA
PIFA/PTA
TTFA
a (traces)
a (10%)
e
c (0%)
c (0%)
e
e
H
H
−CH2−
−CH2−
−CH2−
d (0%)
d (0%)
e
Me
Me
Me
H
Me
Me
Me
d (60%)
e
9
Me
Me
H
H
TBS
Me
Me
Me
Me
Me
Me
f (0%)
10
11
12
13
14
f
f (89%)
g (28%)
g (12%)
g (40%)
g (62%)
g
h
i
PIFA/PTA
PIFA/PTA
PIFA/PTA
f
g
j
MOM
Scheme 3. Conversion of 12 into 16
a
Cf. also the Supporting Information; 7f = ( )-15, 7i = ( )-22a, 7j =
b
c
( )-22b. TTFA = thallium trifluoroacetate. PIFA = phenyliodine
bis(trifluoroacetate) or bis(trifluoroacetoxy)iodo)benzene (in old
documents), PTA = H3[PW12O40] (phosphotungstic acid). Affords
an unidentified (main) product. A complex mixture. Isolated yield
after cleavage of the TBS group. Isolated yield after cleavage of the
d
e
f
g
MOM group.
conditions, which were broadly exploited by Kita and co-
workers in the synthesis of other ring systems with great
success, proved to be satisfactory (Table 1, entries 8, 10, 13,
and 14) if the phenolic OHs were protected in proper forms.
With the key step secured, we next performed the
enantioselective total synthesis shown in Scheme 2. An
Evans aldol condensation of 9 with 10, followed by reductive
cleavage of the auxiliary and tosylation, gave 11. Removal of
the TBS groups with n-Bu4NF led to concurrent etherification,
giving 12. Direct deoxygenation of 12 failed completely.
However, its diacetate (13) could be smoothly converted into
1510 by treatment with Et3SiH/TFA followed by saponification
and methylation. Finally, PIFA/PTA-mediated9f cyclization
and the cleavage9f of the OMe groups afforded the end product
ent-4.
It is noteworthy that direct exposure of 12 to PIFA/PTA led
to a 1:1 mixture of 17a and 17b (Scheme 3).11 However,
because only 17a could be acetylated and deoxygenated
(leading to a rather low total yield), this route was abandoned.
The NMR and optical rotation for natural 4 were reported6
to be determined in CD3OD and MeOH, respectively.
However, ent-4 turned out to be insoluble in either CD3OD
or MeOH. We tested a range of commonly used organic
solvents and found that only DMSO (and DMSO-d6) could
dissolve ent-4.
1
The H and 13C NMR of ent-4 recorded in DMSO-d6 were
fully consistent with those for natural 4, showing that the
corresponding data of natural 4 must be measured in DMSO-
d6. The optical rotation for ent-4 in DMSO (c = 0.7) had a sign
opposite to that for natural 4, with a magnitude of
approximately half of that for natural 4 (increased slightly
with dilution, Table 2). The absolute configuration of 15 was
clearly defined by the Evans aldol condensation. Therefore, it
can be concluded beyond all doubts that the absolute
configuration of ent-4 must be as depicted. Consequently,
natural 4 must have the absolute configuration as shown in
Figure 1.
Using ent-9 instead of 9 as the starting material, natural 4
was also synthesized in a similar fashion (detailed in the
Supporting Information).
B
DOI: 10.1021/acs.orglett.8b03965
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
later increased to +100 (detailed in the Supporting
Information). The [α]D +0.51 (c 0.4, MeOH) for natural 2
reported by Li and Hou5 thus could be reasonably explained.
Synthesis of 5 was first attempted as shown in Scheme 5.
The known 23 was converted into 25 as reported by Davis.12
Table 2. Optical Rotation of ent-4
b
c
entry
[α]D
c
T (°C)
SD
CV (%)
1
2
3
4
+139.9
+253.4
+256.4
+273.1
0.7
0.1
0.07
0.05
17.9
18.3
18.4
18.4
3.6693
4.1173
3.9581
4.9927
+2.62
+1.63
+1.54
+1.83
Scheme 5. Synthesis of ent-6
a
Measured in DMSO, with no detectable changes with time observed.
Standard deviation. Coefficient of variation.
b
c
The synthesis of 2 is outlined in Scheme 4. The key C-7
stereogenic center was installed using the same strategy as in
Scheme 4. Synthesis of 2
Reduction of 25 with NaBH4 in MeOH−THF led to 26.
Methylation of the C-13 OH was unexpectedly complicated by
concurrent formation of 28. For instance, treatment of 26 with
t-BuOK/MeI led to both the desired 29 (42%) and the
unwanted 28 (34%). Use of NaHMDS/THF to replace t-
BuOK/MeCN gave more or less the same results. Conversion
of 29 into 31 was feasible (cyclization of 28 to give 30 also
occurred smoothly). However, deprotection of 31 led to a
complex mixture rather than the expected 5.
Conversion of 26 into 27 under the NaBH4/THF−TFA
conditions was successful. The resulting 27 underwent
cyclization readily on exposure to PIFA/PTA and, after
cleavage of the methoxy groups, afforded ent-6 (the antipode
of natural 6).
the synthesis of 4. However, removal of the redundant OH at
C-8 of the intermediate aldol after formation of the
benzodihydrofuran ring in this case was unsatisfactory (12−
27%). Fortunately, deoxygenation immediately after reductive
removal of the chiral auxiliary proved feasible, which led to 20
in 79% yield. Tosylation and TBAF-mediated desilylation−
cyclization gave 21, which could be converted into 2 directly
(but only in 12% yield). Performing the oxidative coupling
after protection of the phenolic OH in 21 with TBS or MOM
remarkably improved the formation of the bridged ring system,
affording 2 (40% from 22a or 62% from 22b, respectively),
1
which showed H and 13C NMR identical to those for natural
The difficulty associated with cleavage of the methoxy
groups in 31 later was circumvented by using MOM as the
protecting group. As shown in Scheme 6, asymmetric
epoxidation of 32 installed the C-7 OH (86% ee). Subsequent
reduction with NaBH4/THF−MeOH afforded 34. Methyl-
ation of 34 was achieved using KOH (instead of t-BuOK) as
the base. Slightly improved selectivity was thus obtained (i.e.,
37% of the desired 36 and 28% of 35, along with 16% of
recovered 34, which could be recycled). Treatment of 36 with
PIFA/PTA led to the expected 37. Finally, exposure of 37 to
2.
The optical rotation of 2 had the same sign as that originally
reported2 (−411 (c 0.0248, MeOH)) for natural 2. However,
the magnitude was substantially smaller (than natural 2). We
examined the time-dependence of the [α]D (with ent-2 as the
substrate, synthesized using the same approach as detailed in
the Supporting Information) and found that the [α]D did not
change much with time at c = 0.025. However, at c = 0.4, the
time dependence was very obvious: The [α]D measured
immediately after preparation of the sample solution was −6.9.
Three minutes later, it changed to +7.6. The data recorded 1 h
1
F3CCO2H gave the desired end product 5, which showed H
and 13C NMR identical to those for natural 5.
C
DOI: 10.1021/acs.orglett.8b03965
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Organic Letters
Letter
ORCID
Scheme 6. Synthesis of 5
Mei-Mei Li: 0000-0001-5492-3263
Yikang Wu: 0000-0003-4501-5401
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSF of China (21532002,
21672244) and the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20020200).
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03965.
■
Org. Chem. 2014, 79, 8481−8485.
S
(10) Deprotection of the antipode of 15 (i.e., ent-15) led to a natural
product, which has not been synthesized to date (cf. the Supporting
Information).
(11) It is noteworthy that the optical rotations for 17a and 17b were
radically different (+225.6 for 17a vs −8.4 for 17b, cf. the Supporting
Information). Therefore, the hidden presumption in the assignment
of absolute configuration in previous studies (i.e., the sign of optical
rotation of dracaenones is mainly decided by the absolute
configuration of the bridged ring system) might not be always
correct; the presence of an additional stereogenic center might have
an unexpectedly strong influence on the magnitude and the sign of
optical rotation.
Scanned NMR and IR spectra, HPLC, experimental
details, time-dependence of [α]D for ent-2, and tabular
comparison of 1H and 13C NMR for natural and
synthetic samples (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(12) Davis, F. A.; Chen, B.-C. J. Org. Chem. 1993, 58, 1751−1753.
*E-mail: yikangwu@sioc.ac.cn.
*E-mail: liubo@hrbust.edu.cn.
D
DOI: 10.1021/acs.orglett.8b03965
Org. Lett. XXXX, XXX, XXX−XXX