Convergent Route to ent-Kaurane Diterpenoids: Total Synthesis of Lungshengenin D and 1α,6α-Diacetoxy-ent-kaura-9(11),16-dien-12,15-dione

Article abstract of DOI:10.1021/jacs.7b00140

The Hoppe’s homoaldol reaction of a cyclo-hexenyl carbamate with an aldehyde followed by an unprecedented BF₃·OEt₂ mediated intramolecular Mukaiyama-Michael-type reaction affords the tetracyclic core structure of ent-kaurane diterpenoids. The usage of this convergent approach for assembling these natural products is demonstrated by the first asymmetric total syntheses of two highly oxidized ent-kaurane diterpenoids: Lungshengenin D and 1α,6α-diacetoxy-ent-kaura-9(11),16-dien-12,15-dione.

Full text of DOI:10.1021/jacs.7b00140

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A Convergent Route to ent-Kaurane Diterpenoids: Total Synthesis of
Lungshengenin D and 1a,6a-Diacetoxy-ent-kaura-9(11),16-dien-12,15-dione
xiangbo zhao, Wu Li, Junjie Wang, and Dawei Ma
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Feb 2017
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A Convergent Route to ent-Kaurane Diterpenoids: Total Synthesis of
Lungshengenin D and 1α,6α-Diacetoxy-ent-kaura-9(11),16-dien-
12,15-dione
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Xiangbo Zhao,† Wu Li,† Junjie Wang† and Dawei Ma†*
†State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
Supporting Information Placeholder
ABSTRACT: The Hoppe’s homoꢀaldol reaction of a cycloꢀ
hexenyl carbamate with an aldehyde followed by an unpreceꢀ
dented BF3•OEt2 mediated intramolecular Mukaiyamaꢀ
Michaelꢀtype reaction affords the tetracyclic core structure of
entꢀkaurane diterpenoids. The usage of this convergent apꢀ
proach for assembling these natural products is demonstrated
by the first asymmetric total syntheses of two highly oxidized
entꢀkaurane diterpenoids: Lungshengenin D and 1α,6αꢀ
diacetoxyꢀentꢀkauraꢀ9(11),16ꢀdienꢀ12,15ꢀdione.
Since the first discovery of entꢀkaurene (1) (Scheme 1) from
the leaf essential oil of the New Zealand kauri in 1961,1 more
than a thousand entꢀkaurane diterpenoids have been isolated
and identified from different plants species, especially Isodon
genus.2 These natural products are assumed to share the same
biogenic precursor, entꢀkaurene (1), and generate through difꢀ
ferent oxygenations, CꢀC bond cleavages, or fragmentaꢀ
tions.2,3a In the preliminary biological studies, these diterpeꢀ
noids have been found to possess a broad range of bioactivities
spanning from antiꢀtumor, antiꢀinfective and immunosuppresꢀ
sive actions to inhibition of vascular smooth muscle contracꢀ
Scheme 1. Structures of some entꢀKaurane Diterpenoids and
Their Retrosynthetic Analysis
tion.2 During the past half century, their intriguing structures
and interesting biological activities have piqued the interest of
As shown in Scheme 1, we envisaged that some highly oxiꢀ
a number of research groups, whose studies culminated severꢀ
dized entꢀkaurane diterpenoids like 2 and 3 could be elaboratꢀ
al elegant synthesis of their core structures and target moleꢀ
ed from the same intermediate 4 via lateꢀstage functional
cules.3ꢀ5 However, more efficient and general strategies for asꢀ
group manipulations. A unique retrosynthetic design of the
sembling the entꢀkaurane diterpenoids remain highly desirable
core 4 was to forge the central B ring featuring two key strateꢀ
to accelerate the process of syntheses and biological studies.
gic connections at the C5/C6 and C9/10 junctures with two
To date, eight diterpenoids with the basic structure of entꢀ
relatively simple fragments 6 and 7. We assumed that the
preparation of 4 could be achieved through generation of the
kaurane have been synthesized.4 Interestingly, the reported
synthetic strategies for installing the [3.2.1] bicyclic motif
C9ꢀC10 bond by an unprecedented MukaiyamaꢀMichaelꢀtype
were all set up at late stages, which maximized functional
reaction of 5,8 which could be installed by a signature Hoppe’s
homoꢀaldol reaction9 of cyclohexenyl carbamate 6 and aldeꢀ
group manipulations and lengthened their overall linear synꢀ
thetic steps in some cases.4aꢀi,4l,m,o This problem prompts us to
hyde 7 to forge C5ꢀC6 bond. If these two CꢀC bond formation
reactions work well, we would be able to develop a converꢀ
gent and efficient route to the core structure of a number of
entꢀkaurane diterpenoids. The required building block 6 could
develop a more convergent protocol to entꢀkaurane diterpeꢀ
noids, in which the [3.2.1] bicyclic unit is established at the
early stage. The strategy has enabled the first total syntheses
of 1α,6αꢀdiacetoxyꢀentꢀkauraꢀ9(11),16ꢀdienꢀ12,15ꢀdione (2)6
be easily obtained from 2,4,4ꢀtrimethylꢀ2ꢀcyclohenenꢀ1ꢀone,
and Lungshengenin D (3).7
while the [3.2.1] bicyclic motif 7 could be assembled using
Toyota’s Pdꢀcatalyzed cycloalkenylation10 of a silyl enol ether
generated from olefin 8 and Stoltz’s Pdꢀcatalyzed asymmetric
allylic alkylation reaction11,12 of 10 as the key steps.
With the idea in mind, we started our investigation by preparꢀ
ing two building blocks 6 and 7 (Scheme 2). Asymmetric reꢀ
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duction of enone 11 under the typical CoreyꢀBakshiꢀShibata’s
Page 2 of 6
O
conditions13 provided alcohol 12 in 90% yield with 99% ee,
which was treated with NaH in THF and then trapped the reꢀ
sultant sodium alkoxide with N,Nꢀdiisopropyl chloroformaꢀ
mide to afford the carbamate 6. In a parallel procedure, deproꢀ
tonation of enone 13 followed by carbamoylation delivered a
βꢀketo ester, which was subjected to alkylation with an iodide
to give 10. Under the catalysis of Pd2(dba)3 and (S)ꢀtꢀBuꢀ
Phox,14 intramolecular allylation proceeded smoothly in an enꢀ
antioselective manner to furnish enol ether 9 in 82% yield with
87% ee. Next, DIBALꢀH reduction of 9 and subsequent hyꢀ
drolysis with 5% HCl produce enone 8 upon elimination of the
resultant hydroxyl group. After converting 8 to the correꢀ
sponding enol silyl ether, Pdꢀcatalyzed cycloalkenylation was
conducted to give bicyclic enone 14.10a Finally, protection the
ketone moiety in 14 followed by cleavage of the silyl ether
and oxidation with TPAP and NMO yielded the aldehyde 7.
O
OCb
1
2
3
4
5
6
7
8
s-BuLi, rac-TMCDA,
Me
78 °C Et2O
BF3—OEt2, 20 °C
then aq NaHCO3
80 %
gram scale
6
7
+
5
then Ac2O, DMAP
82%
gram scale
6
H
Me
Me
dr = 1.3:1
OAc
5
LA
O
O
O
R2N
LA
HO
O
O
O
OCb
O
O
H
Me
H
Me
Me
9
10
9
9
9
6
+H2O
10
10
5
10
11
12
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ꢀCbOH
H
Me
H
H
OAc
Me
Me Me
OAc
Me
Me
OAc
B
(R = iꢀPr)
A
C
O
12
O
12
O
O
O
1. K2CO3
MeOH
2. IBX, DMSO
O
O
O
H
Me
H
H
Me
H
Me
1
+
O
OH
OCb
3. DBU, THF
70%
5
6
6
(R)ꢀ2ꢀmethylꢀCBSꢀ
oxazaborolidine
Me
Me
Me
H
NaH, THF
H
Me
Me OAc
Me
Me
OAc
Me
Me
O
boraneꢀtetrahydrofuran
complex
toluene, 40 C, 90%
ClCON(Prꢀi)2
4
15
(67%, dr = 1.3:1)
16
(13%, dr = 1.3:1)
85%
Me Me
Me Me
12
Me Me
(CH2OH)2, PPTs
6
(99% ee)
11
78%
OEt
LA
O
R
O
OEt
OCb
1. LDA, THF, 78 °C, then allyl chlorformate
N
Li
A
H
9
O
O
O
5
2. ICH2CH2OTBDPS, Cs2CO3, CH3CN
C
B
N
H
AcO
O
8
6
65%
OEt
O
13
O
O
OTBDPS
E
16
Xꢀray of
10
D
N(Prꢀi)2
5 mol % Pd2(dba)3
12.5 mol % (S)ꢀtꢀBuꢀPhox
THF, 40
DIBALꢀH, toluene
Scheme 3. Homoꢀaldol Reaction of 6 and 7 and Subsequent
Cyclization
O
C
then 5% HCl, MeOH
78%
82% yield, 87% ee
Since the discovery of Hoppe’s homoꢀaldol reaction, further
transformations of its alkenyl cabamate products mainly foꢀ
cused on the formation of polysubstituted tetrahydrofurans
through an intramolecular addition of the carbamoylꢀprotected
enolate unit to the oxonium moiety that was in-situ formed by
condensation of the alcohol part with an aldehyde.8,15 We
speculated that the ketal moiety in our homoꢀaldol product 5
might deliver an vinylogous oxonium intermediate A upon
treatment with a Lewis acid, in which the alkenylcabamates
unit might attack the extremely polar CꢀC double bond at C9
and therefore produce MukaiyamaꢀMichaelꢀtype reaction
intermediate B. Treatment of B with water would cleave its
carbamate part to form ketone intermediate C, which would
undergo hydrolysis or cyclization to afford 15 and 4,
respectively. Based on this consideration, we explored the
reaction of the ketal 5 under the action of different Lewis
acids, and were pleased to find that BF3·OEt2 mediated
OTBDPS
9
O
O
1. (CH2OH)2, PPTs
benzene, reflux
O
O
1. TBSOTf, Et3N
2. Pd(OAc)2, O2
DMSO
2. TBAF, THF
3. TPAP, NMO
82%
58%
OTBDPS
CHO
OTBDPS
8
14
7
Scheme 2. Synthesis of Building Blocks 6 and 7
With the cyclohexenyl carbamate 6 and the aldehyde 7 in
hand, we attempted their homoꢀaldol reaction under Hoppe’s
conditions (Scheme 3). Accordingly, stereospecific deprotonaꢀ
tion of 6 with the retention of the configuration15 in the presꢀ
ence of sꢀBuLi and racemic transꢀN,N,N’N’ꢀtetramethyl 1,2ꢀ
diaminoꢀcyclohexane (TMCDA) followed by addition of 7
produced an alcohol, which was trapped with acetic anhydride
to give the ester 5. In the homoꢀaldol reaction, the stereochemꢀ
istry of C5 in 5 was fully controlled by configurationally staꢀ
ble allyllithiums, proceeding in a strict suprafacial manner
through a possible transition state D,15a,b in which the lithiated
species attacked the aldehyde 7 from the back side of the carꢀ
bamate group. However, another newly created stereogenic
center C6 in 5 was poorly induced so that a diastereomeric
mixture of 1.3:1 was obtained. Since this stereogenic center
would be inconsequential in the subsequent transformation, we
decided to use this mixture 5 to carry out the crucial cyclizaꢀ
tion through an unprecedented MukaiyamaꢀMichaelꢀtype reacꢀ
tion.
o
reaction proceeded well at −20 C to provide a mixture of 15
and 4 with a ratio of 13:67 by quenching the reaction with
aqueous NaHCO3. When aqueous NH4Cl was added to quench
the reaction, 15 was isolated as a single product. Interestingly,
the dione 15 could be selectively protected to give 4,
presumably because of the relative steric hindrance of the
carbonyl at the C1 position. As we expected, the cyclization
took place in a highly stereoselective manner and only the
formation of two isomers 15 and 4 was observed. This result
can be rationalized that the cyclization proceeded via a favored
transition state E, in which the C10 stereochemistry was fully
controlled by the C5 stereogenic center, while the
alkenylcabamate unit attacked the vinylogous oxonium moiety
from the sterically less hindered convex face of the [3.2.1]
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bicyclic unit to give the desired C9 stereochemistry. At this After installation of the requisite ether linkage, our next chalꢀ
1
2
3
4
5
6
7
8
moment, only the C5 stereochemistry was undesired for the
synthesis of the target molecules.16 We planned to epimerize
the compound at this position after oxidation of the liberated
alcohol to ketone. To this end, deprotection of 4 followed by
oxidation with IBX reagent produced a dione, which was
treated with DBU in THF to deliver the desired dione 16
exclusively.
lenging task was reduction of C12 carbonyl group in the presꢀ
ence two other carbonyl groups. After some attempts, we
found that C12 ketone moiety was still more reactive than the
other two ketone units, and could be selectively reduced with
NaBH4 in ethanol. The resultant alcohol was reacted with meꢀ
syl chloride to provide 22. Next, LiAlH4ꢀreduction of 22 to
remove the mesylate group and subsequent reoxidation of two
resultant hydroxyl groups with IBX produced enone 23 in
75% yield. Finally, stereoselective epoxidation of 23 with t-
BuO2H followed by reduction of the resultant epoxide with
NaSePh furnished alcohol 24 as a single product.20 After hyꢀ
droxylꢀdirected reduction of 24 with Me4NBH(OAc)3 to conꢀ
trol the C1 stereochemistry, regioselective acetylation of the
resultant diol delivered 3 in 60% yield.
Having completed the assembly of the core structure 16, we
turned our attention to its further conversion to the highly oxiꢀ
dized entꢀkaurane diterpenes. In 2008, Lou group discovered
diterpene 26 from Chinese liverwort, an aquatic habituated livꢀ
erwort Jungermannia atrobrunnea. Structurally, 2 has close
oxygenation pattern with 16, and therefore was chosen as the
first target molecule. The conversion of 16 to 2 is depicted in
Scheme 4. We found that the C1 ketone part is sterically less
hindered and could be regioselectively and stereoselectively
9
10
11
12
13
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15
16
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O
O
O
11
O
1. KHMDS, 78
TBSCl (4.0 eq)
C
tꢀBuOK
THF, 78
O
o
H
H
Me
Me
reduced with Lꢀselectride at −78 C to give a monoꢀalcohol,
C
1
which was further reduced with DIBALꢀH in oneꢀpot to afford
diol 17. It is notable that direct reduction of two ketone units
with DIBALꢀH was possible, but gave two isomers because of
poor seteroselectivity at the C1 position. Esterification of 17
with NaH/AcCl followed by deprotection of the ketal moiety
with HCl provided ketone 18. After 18 was transformed into
the corresponding enone according to Saegusa’s procedure,17
SeO2ꢀoxidation of the C15 methylene and subsequent oxidaꢀ
tion of the resultant allyl alcohol were conducted to furnish 2.
2
then
(PhSeO)2O
40%
2. DDQ, MeCN,
DTBMP
3. 2 N HCl, THF
65%
6
H
H
Me
Me
O
19
Me
Me
O
(57% brsm)
16
O
H
O
12
HO
11
H
O
Me
16
O
Me
Me
O
2 N HCl
MeOH/THF
H
50 o
C
82%
H
H
Me
Me
Me
Me
O
O
O
O
20
12
21
O
O
OMs
12
O
H
OH
Me
1
12
Lꢀselectride
then
DIBAlꢀH,
H
H
H
Me
O
Me
O
O
Me
Me
1. NaBH4, 10 o
EtOH/CH2Cl2
C
Me
O
1. LiAlH4, THF
2. IBX, DMSO
H
6
toluene
H
78 oC, 82%
2. MsCl, DMAP
CH2Cl2
H
H
Me
Me
Me
O
16
Me
OH
H
75%
Me
17
H
O
Me
23
Me
O
O
O
Me
22
O
55%
OAc
Me
OAc
Me
H
H
1. NaH, AcCl
DMAP
H
Me
1. TMSOTf, 20
15 2. Pd(OAc)2, MeCN
C
HO
1. tꢀBuOOH
Triton B
Me
O
Me
Me
O
1
1. Me4NBH(OAc)3
2. 2 N HCl
75%
H
O
3. SeO2, tꢀBuOOH
4. IBX, DMSO
66%
3
2. (PhSe)2
NaBH4
80%
H
H
2. Ac2O
DMAP, AcO
Py, 0
60%
H
HO
Me
Me
OAc
Me
Me
OAc
H
Me
H
O
18
2
Me
24
C
Me
O
Me
3
Scheme 4. Total Synthesis of entꢀKaurane Diterpenoid 2
Scheme 5. Total Synthesis of Lungshengenin D
Lungshengenin D is a pentacyclic entꢀkaurane diterpenoid that
was isolated from a medicinal herb for treatment of hepatitis.7
It contains an ether link between C11 and C16. We planned to
install this unit by creating a hydroxyl group at the C11
position of 16. Before it more reactive C2 position must be
blocked, and we therefore decided to increase the oxygenation
state of the Aꢀring first. As depicted in Scheme 5, after 16 was
converted into disilyl enol ether, selective oxidation of the less
sterically hindered Aꢀring with DDQ and DTBMP produced
an enone,18 which was treated with HCl to cleavage the
remained silyl enol ether unit and the ketal moiety to provide
enone 19 in 65% yield. Selective deprotonation at C11 was
In conclusion, we have developed a convergent and concise
approach for assembling the core structure of some entꢀ
kaurane diterpenoids. The key elements of this synthesis inꢀ
clude implementation of a Hoppe’s homoꢀaldol reaction to
connect two conveniently accessible building blocks as well as
an unprecedented intramolecular MukaiyamaꢀMichaelꢀtype
reaction to install the Bꢀring. By using this strategy, we have
accomplished the first total syntheses of 1α,6αꢀdiacetoxyꢀentꢀ
kauraꢀ9(11),16ꢀdienꢀ12,15ꢀdione and Lungshengenin D. In
lateꢀstage functional group manipulations, several regioselecꢀ
tive and stereospecific transformations were applied to estabꢀ
lish the densely functionalized structure. The present strategy
should be applicable for assembling more entꢀkaurane diterpeꢀ
noids by finely tuning the homoꢀaldol condensation partners.
These investigations are actively pursued in our laboratory and
will be disclosed in due course.
o
achieved by treatment of 19 with tꢀBuOK at −78 C, and the
resulting carbanion was oxidized to afford alcohol 20 as a
single isomer in 40% yield, along with the recovery of 19 in
30% yield.19 Attempts to push this reaction to full conversion
failed (see SI); mainly because overꢀoxidation of the product
to the C11/12 enone was observed. After exposing of 20 on 2
N HCl in mixed methanol and THF, intramolecular ether
formation occurred directly to provide 21 in 82% yield.
ASSOCIATED CONTENT
Supporting Information.
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AUTHOR INFORMATION
Corresponding Author
*madw@sioc.ac.cn
ACKNOWLEDGMENT
9
The authors are grateful to Chinese Academy of Sciences (supꢀ
ported by the Strategic Priority Research Program, grant
XDB20020200 & QYZDJꢀSSWꢀSLH029) and the National Natuꢀ
ral Science Foundation of China (grant 21132008) for their finanꢀ
cial support.
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