Collective Total Syntheses of Atisane-Type Diterpenes and Atisine-Type Diterpenoid Alkaloids: (±)-Spiramilactone B, (±)-Spiraminol, (±)-Dihydroajaconine, and (±)-Spiramines C and D

Article abstract of DOI:10.1002/anie.201508996

The first total syntheses of the architecturally complex atisane-type diterpenes and biogenetically related atisine-type diterpenoid alkaloids (±)-spiramilactone B, (±)-spiraminol, (±)-dihydroajaconine, and (±)-spiramines C and D are reported. Highlights

Full text of DOI:10.1002/anie.201508996

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International Edition: DOI: 10.1002/anie.201508996
German Edition: DOI: 10.1002/ange.201508996
Total Synthesis
Collective Total Syntheses of Atisane-Type Diterpenes and Atisine-
Type Diterpenoid Alkaloids: (Æ)-Spiramilactone B, (Æ)-Spiraminol,
(Æ)-Dihydroajaconine, and (Æ)-Spiramines C and D
Hang Cheng, Fan-Hao Zeng, Xue Yang, Yin-Juan Meng, Liang Xu,* and Feng-Peng Wang
Dedicated to Professor Guo-Qiang Lin
Abstract: The first total syntheses of the architecturally
complex atisane-type diterpenes and biogenetically related
atisine-type diterpenoid alkaloids (Æ)-spiramilactone B, (Æ)-
spiraminol, (Æ)-dihydroajaconine, and (Æ)-spiramines C
and D are reported. Highlights of the synthesis include a late-
stage biomimetic transformation of spiramilactone B, a facile
formal lactone migration from the pentacyclic skeleton of
spiramilactone E, a highly efficient and diastereoselective 1,7-
enyne cycloisomerization to construct the functionalized
tetracyclic atisane skeleton, and a tandem retro-Diels–Alder/
intramolecular Diels–Alder sequence to achieve the tricyclo-
[6.2.2.0] ring system.
Wnt/b-catenin signaling and colon-cancer-cell tumorigen-
esis.[3c–e] The structures of spiramines C and D show an
unprecedentedly complex heptacyclic ring framework that
contains three bridged ring units (A/E, B/F, and C/D). One of
the distinctive structural characteristics of spiramines C
and D is a C7–C20 oxygen-bridge linkage that distinguishes
them from other atisine-type members, such as isoatisine (4)
and dihydroajaconine (3).[4] This unusual structural motif is
also found in a few members of the atisane-type diterpenes,
such as spiraminol (5)[5a] and spiramilactone B (6),[5b] which
surprisingly were isolated from the same Spiraea plants.
Compounds 5 and 6 are closely related to spiramines C and D
and only differ in the constitution of ring E. It has been
proven that spiraminol (5) can be transformed into spirami-
nes C and D by reaction with ethanolamine, indicating that
the spiraminol could be regarded as the potential biosynthetic
precursor of Spiraea alkaloids.[3a,6]
Despite the intriguing biosynthetic and structural proper-
ties of these Spiraea atisine-type alkaloids and related
diterpenes, there are no reports on their total syntheses. To
date, successful total syntheses towards atisane diterpenes
and atisine diterpenoid alkaloids have been limited to some
relatively uncomplicated compounds, such as methyl atise-
noate,[7a–d] antiquorin,[7e] atisine or isoatisine (4),[7d,f–k] and
azitine.[7l] In continuation of our long-standing interest in the
chemistry of diterpenoid alkaloids,[8] we wish to describe
herein the first total syntheses of several atisane- and atisine-
type compounds with more highly oxidized skeletons includ-
ing spiramilactone B (6), spiraminol (5), spiramines C and D
(1,2), and dihydroajaconine (3), using a unified synthetic
strategy that is distinctly different from previous approaches.
In view of the chemical and biogenetic relationships of
atisine-type diterpenoid alkaloids and atisane-type diterpenes
proposed by Hao and co-workers,[3a,b] it is obvious that
spiramines C and D could be generated from spiramilacto-
ne B (6) via spiraminol (5) by a biomimetic reduction of the
lactone group followed by condensation with ethanolamine.[6]
Moreover, reduction of the C15-OH epimer of spiramines C
and D would deliver dihydroajaconine (3).
A
tisine-type diterpenoid alkaloids and atisane-type diter-
penes are widely distributed in the plant world and have long
been attractive targets for synthetic chemists because of their
physiological and architectural properties.[1] Spiramines C
and D (1, 2; Figure 1), representative alkaloids for the Spiraea
japonica complex, were first isolated by Hao and co-workers
in 1987.[2] These compounds and their derivatives have been
shown to exhibit anti-platelet aggregation, anti-inflammatory,
and neuroprotective effects,[3a,b] and are capable of inhibiting
Figure 1. Representative members of the series of atisane-type
diterpenes and atisine-type diterpenoid alkaloids.
[*] H. Cheng, F.-H. Zeng, X. Yang, Y.-J. Meng, Prof. L. Xu,
Prof. F.-P. Wang
Thus, spiramilactone B (6) was chosen as the first natural
product target in our synthetic route. By retrosynthetic
analysis (Scheme 1), we envisioned that hexacyclic 6 could
be formed from the pentacyclic d-lactone 8, which might be
generated by a formal lactone migration[9] from the g-lactone
9. Interestingly, the pentacyclic core structure of 9 is common
to another naturally occurring atisane diterpene named
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)
E-mail: liangxu@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508996.
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Scheme 1. Retrosynthetic analysis of spiramilactone B (6). D–A=
Diels–Alder.
spiramilactone E (7; Figure 1).[10] Subsequently, the bridged g-
lactone 9 could be prepared from the functionalized tetracy-
clic atisane skeleton 10, which itself could be formed by
installation of the trans-fused ring A by using a pivotal
ruthenium-catalyzed cycloisomerization reaction[11] on the
tricyclic intermediate 11. In turn, 11 could be obtained by
means of an oxidative dearomatization of phenol 12 followed
by intramolecular Diels–Alder reaction developed previously
by us and Liao and co-workers.[8b, 12]
Scheme 2. Construction of the functionalized tetracyclic atisane skele-
ton 21. Reagents and conditions: a) PhI(OAc)2, MeOH, RT, 2 h, 95%;
b) mesitylene, reflux, 3 h, 91%; c) SmI2, THF/MeOH (5:1 v/v), RT, 5 h,
72%; d) (CH2OH)2, CAS (5 mol%), toluene, reflux, 5 h, 90%; e) DMP,
Na2CO3, CH2Cl2, 08C to RT, 2 h, 92%; f) H2, 10% Pd/C, MeOH, 308C,
4 h, 96%; g) NaHMDS, Tf2NPh, THF, À788C, 3 h; h) [Pd(PPh3)4],
Et3N, CO, MeOH/DMF (2:3 v/v), 708C, 10 h, 89% over two steps;
i) LDA, DMPU, 18, THF, 08C, 3.5 h, 75%; j) K2CO3, MeOH, RT, 2 h,
95%; k) nBuLi, ClCO2Me, THF, À788C to 08C, 1.5 h, 83%; l) [CpRu-
(CH3CN)3]PF6 (10 mol%), DMF, acetone, RT, 1 h; then TsOH, RT, 1 h,
91%. CAS=L(À)-camphorsulfonic acid; DMP=Dess–Martin period-
inane; NaHMDS=sodium bis(trimethylsilyl)amide; Tf=trifluoro-
methanesulfonyl; TsOH=p-toluenesulfonic acid; DMF=N,N-dimethyl-
formamide; LDA=lithium diisopropylamide; DMPU=1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone; Cp=cyclopentadienyl.
Our synthetic efforts commenced with the preparation of
the required tricyclic intermediate 11 with an optimized
procedure based on a previously reported method.[12] As
shown in Scheme 2, dearomatization of the readily available
phenol 12[8b] with PhI(OAc)2 in MeOH at room temperature
generated masked ortho-benzoquinone 13 which dimerized
spontaneously to 14.[12] Upon heating 14 to reflux in
mesitylene, a retro Diels–Alder/intramolecular Diels–Alder
cascade process proceeded efficiently to give the desired
cycloadduct 11 as a single diastereomer in 86% yield over two
steps. Notably, by using this improved reaction sequence, 11
could be efficiently and reliably accessed on the decagram
scale from 12. With the tricyclo[6.2.2.0] ring precursor 11 in
hand, the installation of trans-fused six-membered ring A was
next addressed (Scheme 2). After sequential reductive
be attributed to the relatively more congested endo-side of
the allylic ester anion. Subsequent desilylation followed by
a straightforward acylation furnished the enyne ester 20,
setting the stage for the crucial Ru-catalyzed cycloisomeriza-
tion. Gratifyingly, with a slightly modified version of the
conditions of Trost et al.,[11] 1,7-enyne cycloisomerization of
20 by employing 10 mol% [CpRu(CH3CN)3]PF6 in the
presence of 1.5 equivalents of DMF as additive, followed by
removal of the ethylene ketal group in a one-pot step,
proceeded efficiently to furnish the tetracyclic ketone 21 as
a single diastereomer in excellent yield.
With the functionalized tetracyclic atisene skeleton in
hand, the next challenging task was to install the bridged
lactone moieties on the molecules. As shown in Scheme 3,
stereoselective reduction of ketone 21 with Super-Hydride
(LiBHEt3) at À788C followed by epoxidation of C6–C7 olefin
using m-chloroperoxybenzoic acid (m-CPBA)[18] furnished 22
as the major hydroxy isomer. After protection of the hydroxy
group of 22 with a methoxymethyl (MOM) group, regiose-
lective ring-opening of the epoxide in the presence of the
catalytic [Ti(OiPr)2Cl2] led to exclusive formation of the
[13]
removal of the two methoxy groups of 11 with SmI2 and
protection of the ketone with glycol alcohol, oxidation of the
hydroxy group of the resulting ethylene ketal 15 with Dess–
Martin periodinane (DMP)[14] followed by hydrogenation of
the double bond afforded ketone 16 in 57% overall yield.
Subsequently, vinyl triflate formation[15] followed by palla-
dium-catalyzed carboxymethylation[16] converted ketone 16
into a,b-unsaturated methyl ester 17 in 75% yield. Moving
forward, the elaboration of the requisite side-chain for
eventual construction of ring A called for a stereoselective
alkylation occurring at the C10 position in enoate 17 to an
exo orientation. To our delight, the deconjugative alkyla-
tion[17] of 17 was effected on treatment with LDA/DMPU
(LDA = lithium diisopropylamide; DMPU = 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone) then iodide deriva-
tive 18, delivering the desired 19 as a single diastereomer in
75% yield. The exclusive stereochemistry of alkylation could
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Scheme 4. Construction of the hexacyclic skeleton 30. Reagents and
conditions: a) O3, CH2Cl2, À788C, 45 min, 95%; b) PbCl2, Zn, TiCl4,
CH2Br2, THF/CH2Cl2 (5:2 v/v), 08C to RT, 2.5 h, 72%; c) DIBAL-H,
CH2Cl2, À788C, 1 h; d) PPTS, MeOH, RT to 458C, 5 h, 85% over two
steps; e) BH3·Me2S (1m in THF), THF, 08C, 1 h; then 30% H2O2, 3N
NaOH, 30 min, 75%; f) DMP, NaHCO3, CH2Cl2, RT, 1 h; g) tBuOK,
CH3I, À208C, 40 min; h) NaClO2, NaH2PO4, 2-methyl-2-butene,
t-BuOH/H2O (3:1 v/v), À58C, 78% over three steps. DIBAL-H=di-
isobutylaluminium hydride; PPTS=pyridinium p-toluenesulfonate.
Scheme 3. Installation of the lactone moieties. Reagents and condi-
tions: a) LiBHEt3, THF, À788C, 30 min, 85%; b) m-CPBA, NaHCO3,
CH2Cl2, 08C, 2 h, 71%; c) MOMCl, iPr2NEt, CH2Cl2, 08C, 3.5 h, 89%;
d) [Ti(OiPr)2Cl2], CH2Cl2, À208C, 1 h, 83%; e) DMP, NaHCO3, CH2Cl2,
RT, 1 h, 90%; f) SmI2, THF/MeOH (10:1 v/v), À788C, 2 h; g) NaBH4,
CeCl3·7H2O, THF:MeOH (5:1 v/v), 1 h; h) DIC, HOBt, toluene, 458C,
3 h, 75% over three steps. m-CPBA=m-chloroperoxybenzoic acid;
MOMCl=chloromethyl methyl ether; DIC=N,N’-diisopropylcarbo-
diimide; HOBt=1-hydroxybenzotriazole.
hydroxy g-lactone 23, completing the core pentacyclic struc-
ture of spiramilactone E (7). Next, the formal lactone
migration from g-lactone 23 to d-lactone 25 was achieved by
a straightforward four-step sequence.[19] First DMP oxidation
of the hydroxy group of 23 gave ketone 24 in 90% yield, then
sequential reductive a-deoxygenation of ketone 24 with
SmI2,[13] stereoselective reduction of the carbonyl group with
NaBH4, and lactonization of the resulting hydroxy acid with
N,N’-diisopropylcarbodiimide and 1-hydroxybenzotriazole
ultimately furnished the desired d-lactone 25 (characterized
by X-ray crystallography)[20] in 75% overall yield (over three
steps). Notably, the crude acid intermediates in the reaction
sequence could be directly used in the next steps without
purification.
With the requisite pentacyclic lactone 25 in hand, we
focused our attention on constructing the hexacyclic skeleton
of spiramilactone B (Scheme 4). Ozonolysis of the conjugated
enoate 25 followed by Takai olefination[21] of the resulting
ketone using CH2Br2 in the presence of TiCl4/Zn afforded
terminal olefin 26 in 72% yield. Conversion of lactone 26 to
aldolactol 27 was achieved in 85% yield by reduction with
diisobutylaluminium hydride (DIBAL-H) followed by con-
densation with MeOH in the presence of catalytic pyridinium
p-toluenesulfonate (PPTS). Hydroboration–oxidation[22] of
olefin 27 gave the primary alcohol 28. DMP oxidation of 28
afforded a labile aldehyde, which was immediately subjected
to an exclusive alkylation on treatment with potassium tert-
butoxide and methyl iodide, delivering the methyl group to
the b-face to give 29 in 87% yield.[8d] Pleasingly, attempt to
oxidize aldehyde to acid using Pinnick oxidation[23] resulted in
direct formation of lactone 30 in 90% yield, completing the
whole hexacyclic skeleton of spiramilactone B.
Scheme 5. Total syntheses of (Æ)-spiramilactone B (6), (Æ)-spiraminol
(5), (Æ)-spiramines C and D (1,2), and (Æ)-dihydroajaconine (3).
Reagents and conditions: a) CH2Cl2, ZnBr2, n-PrSH, 3 h; b) DMP,
NaHCO3, CH2Cl2, 08C to RT, 1 h, 81% over two steps; c) LiHMDS,
N,N-dimethylmethyleneiminium iodide, THF, À788C, 3.5 h; CH3I,
CH2Cl2, RT, 8 h; DBU, CH2Cl2, RT, 2 h, 71%; d) NaBH4, MeOH/CH2Cl2
(2:1 v/v), À208C, 1 h, 95% (b:a=5:1); e) PhSCl, Et3N, Et2O, 08C to
RT, 1.5 h, 99%; f) P(OMe)3, MeOH, 508C, 72 h, 64% (91% yield
based on recovered 33); g) DIBAL-H, CH2Cl2, À788C, 1.5 h, 90% for
5; h) H2N(CH2)2OH, THF, reflux, 3 h; silica gel, MeOH, 8 h, 60% for
(Æ)-spiramine C (1), 36% for (Æ)-spiramine D (2); i) NaBH4, MeOH,
RT, 5 h, 85% for three steps from 33. DBU=1.8-diazabicyclo-
[5.4.0]undec-7-ene.
The synthetic steps involved in the final stage of the
synthesis are summarized in Scheme 5. Removal of the MOM
protecting group of 30 under mild conditions (ZnBr2/n-
PrSH)[24] followed by DMP oxidation of the resulting alcohol
led cleanly to the ketone 31 (characterized by X-ray
crystallography).[20] The subsequent Eschenmoser a-methe-
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nylation of ketone 31 proceeded smoothly by means of
[1] a) A. M. Hamlin, J. K. Kisunzu, R. Sarpong, Org. Biomol. Chem.
a successive three-step sequence to provide exocyclic enone
32 in 71% yield.[25] However, for the synthesis of spiramilac-
tone B, reduction of enone 32 with NaBH4 unfortunately gave
the undesired b-OH isomer 33 as the major product (b:a =
5:1). After an unsuccessful attempt to invert the configuration
of the b-OH isomer with Mitsunobu reaction, the stereo-
chemistry of the allylic alcohol of 33 was inverted, for the
most part, by a Mislow–Evans rearrangement[26] via an allylic
sulfoxide intermediate (see the Supporting Information for
the detailed description), to provide (Æ)-spiramilactone B (6)
in 64% yield (after separation and purification)). Next,
reduction of the lactone moiety with DIBAL-H at À788C
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successfully gave (Æ)-spiraminol (5) as
a single C-19
epimer,[27] which condensed with ethanolamine in THF to
deliver (Æ)-spiramine C (1) and (Æ)-spiramine D (2) in 60%
and 36% yield, respectively.[6] Additionally, another naturally
occurring atisine-type diterpenoid alkaloid (Æ)-dihydro-
ajaconine (3) bearing a C15 positioned b-OH group was
smoothly synthesized by complete reduction of the C15-OH
epimers 34 of spiramines C/D. Compound 34 itself was
prepared by applying the same reduction/condensation
sequence to epimer 33 of spiramilactone B.
In summary, we have achieved the collective total
syntheses[28] of several members of the structurally complex
atisane-type diterpenes and related atisine-type diterpenoid
alkaloids, namely (Æ)-spiramilactone B, (Æ)-spiraminol, (Æ)-
spiramines C and D, and (Æ)-dihydroajaconine, characterized
by late-stage biomimetic transformations of (Æ)-spiramilac-
tone B. The synthesis of spiramilactone B features the effec-
tive construction of the hexacyclic system from the pentacy-
clic core structure 23 of spiramilactone E by means of
a straightforward formal lactone migration. In the construc-
tion of the pentacyclic skeleton of spiramilactone E bearing
a g-lactone moiety, a unique retro Diels–Alder/intramolecu-
lar Diels–Alder cascade sequence allowed rapid access to the
tricyclo[6.2.2.0] ring system 11. Subsequently, a diastereose-
lective Ru-catalyzed 1,7-enyne cycloisomerization was used
to achieve the highly functionalized tetracyclic atisane
skeleton 21. Further development of the asymmetric synthetic
route as well as application of this new strategy for
construction of functionalized atisane skeletons to synthesize
architecturally more complex hetidine- or hetisine-type
diterpenoid alkaloids[1c] are currently underway in our
laboratory.
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Financial support for this work was provided by the National
Natural Science Foundation of China (Grant Numbers
21472129 and 21272163).
Keywords: alkaloids · cycloisomerization · ruthenium ·
terpenoids · total synthesis
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Received: September 25, 2015
Published online: November 6, 2015
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