Divergent Total Syntheses of (?)-Huperzine Q, (+)-Lycopladine B, (+)-Lycopladine C, and (?)-4-epi-Lycopladine D

Article abstract of DOI:10.1002/asia.201700364

We report herein our synthetic efforts towards the divergent syntheses of (?)-huperzine Q (1), (+)-lycopladine B (2), (+)-lycopladine C (3), and (?)-lycopladine D (4). The 10-step total synthesis of (?)-huperzine Q (1) and the first total syntheses of (+)

Full text of DOI:10.1002/asia.201700364

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Accepted Article
Title: Divergent Total Syntheses of (-)-Huperzine Q, (+)-Lycopladine B,
(+)-Lycopladine C and (-)-4-epi-Lycopladine D
Authors: Xiaoguang Lei, Benke Hong, Dachao Hu, Jinbao Wu, Jing
Zhang, and Houhua Li
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Divergent Total Syntheses of (-)-Huperzine Q, (+)-Lycopladine B,
(+)-Lycopladine C and (-)-4-epi-Lycopladine D
Benke Hong,[a] Dachao Hu,[b] Jinbao Wu,[c] Jing Zhang,[c] Houhua Li,[d] Yingming Pan,[b] Xiaoguang
Lei*[a]
Dedication ((optional))
Abstract: We report herein our synthetic efforts towards the divergent syntheses of (-)-huperzine Q (1), (+)-lycopladines B (2), C (3) and (-)-
lycopladine D (4). The 10-step total synthesis of (-)-huperzine Q (1) and the first total syntheses of (+)-lycopladines B (2) and C (3) have been
accomplished via a series of cascade reactions. Our approach features a Michael addition/aldol/intramolecular C-alkylation sequence to forge
the 6/9 spirocycle ring followed by an ethylene-accelerated carbonyl-olefin metathesis to construct the common 6/5/9 ring system. Finally, a
late-stage enamine bromofunctinalization enables us to access (-)-huperzine Q (1), (+)-lycopladines B (2), C (3) and a tandem C4-
epimerization/retro-Claisen condensation furnished (-)-4-epi-lycopladine D (63).
Introduction
carbinolamine lactone core. In 2013, Zhao and co-workers
achieved the first total synthesis of (-)-lycopladine D (4).[7] Herein,
we describe a full account of our divergent syntheses of (-)-
huperzine Q (1), (+)-lycopladines B (2) and C (3)[8] as well as our
synthetic efforts towards (-)-lycopladine D (4).
The Lycopodium alkaloids are a large family of complex natural
product. Nearly 300 compounds have been isolated so far.[1]
Owing to their intricate polycyclic skeletons and diverse
bioactivities, the total syntheses of these alkaloids have attracted
broad attention from the synthetic community in recent years. [2]
Among these compounds, (-)-huperzine Q (1), (+)-lycopladines B
(2), C (3) and (-)-lycopladine D (4) are four structurally related
fawcettimine-type alkaloids (Figure 1). Huperzine Q (1) was
isolated from Huperzia serrata by Zhu and co-works in 2002 and
possess an unprecedented pentacyclic ring system and an aminal
moiety.[3] The Takayama group[4] and the Zhao group[5] reported
the total syntheses of 1 in 2011 and 2015, respectively. (+)-
Lycopladines B (2), C (3) and (-)-lycopladine D (4) were isolated
from Lycopodium complanatum by Kabayashi and co-workers in
2006.[6] Whereas both (+)-lycopladines B (2) and C (3) contain a
Figure 1. Huperzine Q (1), lycopladines B (2), C (3) and D (4).
Results and Discussion
unique tetracyclic skeleton with
a dienamine moiety, (-)-
lycopladine D (4) consists of a pentacyclic core structure with a
Retrosynthetic analysis
[a]
Dr. B. Hong, Prof. Dr. X. Lei
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)
E-mail: xglei@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/leigroup/
D. Hu, Prof. Dr. Y. Pan
[b]
State Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, School of Chemistry and Pharmaceutical
Science, Guangxi Normal University, Guilin 541004(China)
J. Wu, J. Zhang
School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072 (China)
Dr. H. Li
[c]
[d]
Scheme 1. Retrosynthetic analysis
Department of Chemical Biology, Max Planck Institute of Molecular
Physiology, 44227 Dortmund, Germany
Our retrosynthetic analysis for (-)-huperzine
lycopladines B (2), C (3) and (-)-lycopladine D (4) is outlined in
Q (1), (+)-
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Scheme 2. Sythesis of diketone 7 via MIcheal/aldol/C-alkylation and SmI2-mediated pinacol coupling; Bn = benzyl, Boc = tert-butyl carbamate, DABCO = 1,4-
diazabicyclo[2.2.2]octane, DBU = 1,8-diazabicycloundec-7-ene, DCM = dichloromethane, DMF = dimethylformamide, DMP = Dess-Martin periodinane, DMSO =
dimethyl sulfoxide, Ms = mesityl, pTsOH = para-toluenesulfonic acid. NMO = N-methylmorpholine-N-oxide, nOe = nuclear Overhauser effect, THF = tetrahydrofuran,
TPAP = tetrapropylammonium perruthenate,
Scheme 1. We envisioned that the aminal moiety in 1 and the
dienamine moiety in 2 and 3 could be derived from enamine inter-
mediates 5 and 6, respectively. While both 5 and 6 could arise
from 7 via a C4-epimerization/cyclization sequence, diketone 7
could also potentially serve as a common synthetic intermediate
for the synthesis of (-)-lycopladine D (4) through aldehyde 10. The
cyclopentanone ring in 7 could be constructed from spirocyclic
diketone 8, which could be readily accessed from enone 9 through
our previously developed Michael addition/aldol/C-alkylation
method.
regioselectively reduce to equatorial hydroxyl product 17 in 52%
yield by using NaBH4 in DCM/MeOH. The stereochemistry of 17
was determined by NOE analysis. Lemieux-Johnson oxidation of
17 afford aldehyde precursor 18 and subsequent treatment of 18
with SmI2 in THF afford two coupling products 4,5-trans diol 19
and 4,5-cis diol 20 in 32% and 30% yields, respectively. Oxidation
of 19 and 20 by Ley oxidation and Swern oxidation[11] respectively
provide the same α-hydroxy ketone 21 exclusively without any
diol oxidative cleavage byproduct.[12] Deoxygenation of 21 with
SmI2 using t-BuOH as proton source furnished tricyclic ketone 7
in 89% yield.
Initial synthetic strategy to construct the 6/5/9 tricyclic
skeleton
Second generation synthetic strategy to construct the 6/5/9
tricyclic skeleton
As show in Scheme 2, our synthesis commenced with the
synthesis of enone 9 via lipase-mediated kinetic resolution.
Esterification of both the carboxyl and vinylogous acid groups in
commercial available 11 followed by LiAIH4 reduction and acid
hydrolysis afforded racemic enone 12.[9] Kinetic resolution of 12
with Lipase-PS gave (R)-12 in 95% ee, subsequent benzyl
protection afforded enone 9 in 94% yield.[10] The tandem Michael
addition/aldol reaction was occured smoothly via minor
modification of our previous protocol.[2h] Treatment of enone 9
with freshly prepared allylcuprate followed by aldehyde 13 to
afford desired alcohol 14 as a mixture of two diastereoisomers in
82% yield, which was converted to C-alkylation precursor diketo
iodide 15 in four steps (desilylation, selective primary mesylation,
oxidation and iodination) in 53% yield. After reaction conditions
optimization, the desired C-alkylation product 8 was obtained in
51% isolated yield using DBU under dilute conditions in DMF
(0.008 M) along with O-alkylation product 16 in 23% yield.
While the key tricyclic intermediate 7 can be successfully
synthesized using aforementioned strategy, it requires totally 15
With spiro-diketone 8 in hand, we then focused on the
construction of the 6/5/9 tricyclic skeleton using SmI2-mediated
pinacol coupling.[2h] Owing to the steric hindrance of the axial
allylic group at C7 position, carbonyl at C13 position can be
Scheme 3. Second generation Michael addition/aldol/C-alkylation.
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steps starting from commercial available 3,5-dioxocyclohexa-
necarboxylic acid 11, among which most are functional group
interconversions. We thus tried to develop a more efficient
strategy to synthesize the 6/5/9 tricyclic framework.
lecular C-alkylation to afford diketone 8 in only 5 steps from the
commercially available aldehyde 22.
With 8 in hand, we attempted to construct the 6/5/9 skeleton
directly via a regioselective carbonyl-olefin metathesis between
the alkene and carbonyl at C4 position. As shown in the literature,
carbonyl-olefin metathesis can be achieved by various
apporaches via photochemical promoted Paternò-Büchi reaction
[15], transition metal alkylidene[16], or cationic cyclization[17]. Initially,
after irradiation of 8 with ultraviolet light (300 nm) for 1 h, starting
material was decomposed (Table 1, Entry 1). We then turned our
attention to transition metal mediated methods. Upon treatment of
8 with Tebbe reagent, no reaction occurred (Table 1, Entry 2).
From a mechanistic point of view, Tebbe reagent might be very
difficult to interact with steric hindered carbonyl group at C4
position in order to initiate the reaction[16f]. In sharp contrast,
transition metal species derived from both Rainier’s and Grubbs’
methods react firstly with the alkene group, which may offer an
opportunity to proceed the reaction and furnish the desired result.
To our delight, our previous hypothesis was confirmed upon
treatment of 8 with Rainier’s protocol,[16g,16h] where desired
product 27 was formed in 10% yield (Table 1, Entry 3). However,
further extensive reaction optimization did not provide optimal
results. We finally turned our attention to carbonyl-olefin
metathesis mediated by Schrock complex reported by Grubbs
group.[16d, 18] Under the original conditions, no reaction occurred
and the starting material 8 was recovered (Table 1, Entry 4).
Our new synthetic plan began with the preparation of
enantiopure enone 9 via a catalytic enantioselective approach
(Scheme 3). The α,β-unsaturated aldehyde 23 was prepared from
benzyloxyacetaldehyde 22 through Horner-Wadsworth-Emmons
reaction in 85% yield.[13] Subsequent organocatalytic Robinson
annulation reaction[14] with tert-butyl acetoacetate, provided 9 in
93 % ee and 70% yield. Similar to our previous protocol, enone 9
was then treated with allylcuprate and the resulting enolate was
trapped with aldehyde 25 to afford alcohol 26 in 73% yield.
Oxidation of 26 with Dess-Martin periodinane followed by intramo-
Table 1. Carbonyl-olefin metathesis. [a]
Entry
Condition
Additi
ve
T [oC] / t [h]
rt /1 h
Yield
Decomposed
NR
1
2
3
hv (300 nm),
benzene
none
none
none
o
When the reaction temperature increased to 80 C, the desired
product 27 was obtained in 32% yield (Table 1, Entry 5). The yield
was only increased to 38% upon full consumption of 8 after 10 h
Tebbe reagent [b]
toluene
,
110 oC/12 h
TiCl4, Zn, PbCl2,
rt to reflux/
12 h
10%
CH3CHBr2, THF,
TMEDA, DCM
4
5
Schrock complex [b]
(1.0 eq), benzene
none
none
none
none
rt /22 h
80 oC /5 h
80 oC /10 h
80 oC /10 h
80 oC /5 h
80 oC /6 h
rt /22 h
NR
Schrock complex
(1.0 eq), benzene
32%
(36% brsm)
6
Schrock complex
(1.0 eq), benzene
38%
7
Schrock complex
(1.0 eq), DCE
16%
(36% brsm)
8
Schrock complex
(1.0 eq), benzene
1 atm
C2H4
48%
(75% brsm)
9
Schrock complex
(1.0 eq), benzene
1 atm
C2H4
41%
10
Schrock complex
(1.0 eq), benzene
1 atm
C2H4
23%
(73% brsm)
[a] atm = atmosphere, NR = no reaction. brsm = based on recovered starting
material. DCE = 1,2-dichloroethane, TMEDA = N, N, N', N'-Tetramethylet -
hylenediamine. [b] Structure of Tebbe reagent and Schrock complex.
Scheme 4. Proposed mechanism of ethylene-accelerated carbonyl olefin
metathesis
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(Table 1, Entry 6). Surprisingly, the yield was increased to 48%
and 75% based on recovered starting material under 1 atm
ethylene atmosphere (Table 1, Entry 8). We also observed a
dramatic accelerating effect even at room temperature, where
23% yield was obtained in the presence of ethylene (Table 1,
Entry 10).
the axial radical followed by protonation to afford the equatorial
alcohol.[23] The spectroscopic data of synthetic (-)-huperzine Q
fully matched the previously reported.[3]
As aforementioned, cyclization product 36 can be obtained in
43% yield along with enamine 5 in 1:1 ratio from alcohol 33. the
same mixture of 5 and 36 (1:1.2) was obtained upon treatment of
either enamine 5 or 36 with (+)-CSA at 160 oC for 30 min (Table
2), which indicated that 5 existed in equilibrium with 36 under the
acidic conditions presumably via an iminium ion intermediate 35.
Based on these findings, our proposed mechanism for
ethylene promoted carbonyl olefin metathesis is depicted in
Scheme 4. In the presence of ethylene, Schrock complex was
converted into more active species 28,[19] which will react with 8
to afford molybdenum alkylidene intermediate 30 via olefin
metathesis. Ethylene also can convert 30 back to starting material
8 to avoid the formation of side product. 30 would then undergo
intramolecular carbonyl olefination with C4 carbonyl group to
produce target product 27. In all cases, only desired product 27
was observed, without any C13 carbonyl olefination product 33.
This was probably due to the formation of a high torsional strained
anti-bredt bridge[20] double bond for 33.
Table 2. Equilibrium between enamine 5 and aminal 36.
Entry
Substrate
Ratio of 5 and 36[a]
1 : 1
Total synthesis of (-)-huperzine Q (1)
1
2
3
33
5
With cyclopentene product 27 in hand, the diketone 7 was
obtained as a diastereoisomeric mixture through a one-pot
hydroboration/oxidation process.[21] Hydrogenolysis of 7 with
Pd(OH)2/C in the presence of H2 afforded alcohol 33 in 91% yield
(Scheme 5). Inspired by the landmark work done by Heathcock
group during their fawcettimine synthesis,[22] we envisaged that
the aminal moiety of (-)-huperzine Q (1) could be accessed from
33 through C4-epimerazation/cyclization sequence. Gratifyingly,
upon treatment of 33 with (+)-CSA at 160 oC a mixture of desired
aminal product 36 and enamine 5 was obtained in 1:1 ratio. At this
point, we only need to install the C5 hydroxyl group by reducing
carbonyl group at C5 position to complete the synthesis of (-)-
1 : 1.2
36
1 : 1.2
[a] Determined by 1H-NMR of crude reaction mixture.
After extensive screening with different electrophiles, we
were finally pleased to obtain bromide 40 in 96% yield upon
treatment of 5 with NBS in the presence of (+)-CSA (Scheme 6).
Enamine 5 might firstly form a bromonium ion 38 reversibly,
followed by bromonium ion ring opening to afford iminium ion 39,
which underwent further cyclization to generate 40. The structure
of 40 was confirmed by 2D NMR spectroscopy and X-ray
diffraction analysis.[24] Bromide 40 was reduced to (-)-huperzine
Q (1) in one step through SmI2 mediated debromination and
ketone reduction in the presence of Et3N and H2O.[25] Additionally,
enamine 5 can be accessed directly from diketone 7 in 84% yield
through one-pot C4-epimerization/cyclization/debenzylation seq-
uence. Thus, the synthesis of (-)-huperzine Q was accomplished
in 10 steps starting from commercial available 22.
huperzine
Q (1). However, treatment of 36 with bulky
Superhydride resulted in the exclusively formation of 5-epi-
huperzine Q 37 via hydride attack from a convex face. Finally, 36
was converted into (-)-huperzine Q (1) quantitatively using SmI2
in the presence of H2O, presumably due to the initial formation of
Scheme 5. Total synthesis of (-)-huperzine Q (1). CSA = camphorsulfonic acid,
oDCB = ortho-dichlorobenzene.
Scheme 6. Synthesis of (-)-huperzine Q (1) via enamine bromofunctinalization.
NBS = N-bromosuccinimide.
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Total syntheses of (+)-lycopladine B (2) and C (3)
Table 3. Unsuccessful attempts to synthesize dienamine 41.[a]
After the synthesis of (-)-huperzine Q (1), we then focused on the
syntheses of (+)-lycopladine B (2) and C (3), which required the
construction of the challenging dienamine moiety. We initially
envisaged that dienamine 41 could be accessed from enamine 6
via oxidation (Scheme 7). Our synthesis commenced with the
preparation of the key precursor enamine 6. Unfortunately,
attempts to synthesize 6 from alcohol 5 via various oxidative
conditions were unsuccessful, and all led to byproduct enone 42.
The formation of 42 presumably occurred via initial oxidation of 5
followed by enolization to provide enol 43, which was attacked by
another equivalent of oxidant to form the intermediate 44. Next,
oxidative cleavage of 44 occurred to provide enone 42.[26] Of note,
we also failed to convert 42 into vinyl triflate or vinyl iodide 45
which could potentially be converted to dienamine 41 upon
carbonylation. Finally, a one-pot oxidation[27] of alcohol 33
provided ester 46 in 86% yield, followed by C4-epimerization
/cyclization to yield enamine 6 smoothly as a diastereoisomeric
mixture (15α/β = 3.2/1).
Entry
Condition
DDQ, THF-H2O(5/1), 0 oC
DDQ ,THF, rt to reflux
IBX, DCM, rt
Result
1
2
3
4
5
6
7
NR
ND
NR
Decomposed
ND
IBX, toluene/DMSO(2/1), rt to 75 oC
Pd(OAc)4, O2, DCM, rt
MnO2, benzene, rt
NR
K2CO3 , air, acetone, rt
NR
[a] DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, NR = no reaction,
ND = No desired product, TBAF = tetra-n-butylammonium fluoride.
Finally, an alternative elimination strategy was developed to
construct the dienamine structure. Inspired by our (-)-huperzine Q
(1) synthesis, we hypothesized that 6 could react with NBS to form
α-bromoiminium ion 48, followed by subsequent elimination to
establish diiminium ion 47. Tautomerization of 47 would then yield
dienamine 41 (Scheme 8). Upon treatment of 6 with NBS in the
presence of Et3N or DBU, we just recovered starting material.
After reaction conditions screening, bromide 49 and epoxyamine
50 were obtained instead of dienamine 41 upon treating with NBS
in THF/H2O/HOAc at 0 oC. The structure of 49 and 50 were
unambiguously confirmed by single crystal X-ray diffraction
analysis.[29] Of note, epoxidation reagents such as meta-
chloroperoxybenzoic acid (mCPBA) or oxone provided merely a
complex mixture.
Scheme 7. Attempts to synthesize dienamine 41 via oxidation strategy. IBX =
2-iodoxybenzoic acid. PCC = pyridinium chlorochromate.
With 6 in hand, we hypothesized that enamine 6 could be
oxidized to diiminium ion intermediate 47, which could then
undergo tautomerization to the dienamine 41. Unfortunately, upon
treatment of 6 with various oxidants such as DDQ[28a, 28b], IBX[28c,
[28e]
28d], MnO2[28c], Pd(OAc)2
and air[28f], no desired dienamine 41
was observed (Table 3).
Scheme 8. Discovery of epoxyamine 50.
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To further rationalize the C15 stereochemistry and also the
formation of 49 and 50, a dynamic kinetic epimerization
mechanism was proposed as shown in Scheme 9. Under acid
conditions, α-6 is in facile equilibrium with β-6, which are
converted into corresponding bromonium ions 51 and 52
respectively in the presence of NBS. Subsequent ring opening
and hydration formed ketone amines 53, which underwent ring-
chain tautomerization[30] to afford hemiaminals 54 and 55. Finally,
dehydration of 54 yield bromide 49, while 55 underwent an
intramolecular SN2 substitution to afford epoxyamine 50.
med that 50 would undergo epoxide ring opening to afford 56, the
C16 ester group could accelerate the dehydration instead of
polymerization to form the desired diiminium ion 47. Additionally,
based on the X-ray structure of 50, the bond length of C13-N bond
is much shorter (1.431 Å) than C9-N bond (1.471 Å) and C1-N
bond (1.479 Å), which indicates that C13-N bond might have a
more sp2-hybrized character and thus favours to form a iminium
ion during the epoxide ring opening. With this hypothesis in mind,
various conditions were screened. And we were pleased to find
that dienamine 41 was obtained in 62% yield with pTsOH•H2O in
o
120 C in the presence of 4 Å molecular sieves. Ketone 41 was
further converted into (+)-lycopladine B (2) via Luche reduction,
and subsequent acetylation of 2 yielded (+)-lycopladine C (3)
smoothly. The spectroscopic data of synthetic (+)-lycopladine B
(2) and C (3) fully matched previous reported data.[6] Thus, the
first total syntheses of lycopladine B (2) and C (3) were achieved
in 12 and 13 steps respectively and the absolute configurations
were therefore confirmed.
Study towards the synthesis of (-)-lycopladine D (4)
We finally turned our attention to (-)-lycopladine D (4), which
bears a challenging carbinolamine lactone motif. Our synthesis
began with the oxidation of alcohol 33 with Dess-Martin
periodinane to afford corresponding aldehyde 10 in 96% yield
(Scheme 11). Next, treatment of 10 with potassium carbonate in
methanol resulted in C15 epimerization and concomitant intramol-
ecular aldol reaction and provided 58. The stereochemistry of
C16 hydroxyl group was not determined, which was directly
oxidized to 1,3-diketone 59 in 53% yield over 2 steps. The
structure of 59 was confirmed by 2D NMR spectroscopy. Upon
Scheme 9. Proposed mechanism for the syntheses of 49 and 50.
As shown in the literature, epoxyamines were initially isolated
and characterized by Stevens and co-workers.[31] Only few stable
epoxyamines have been documented[32] and have been
underexplored in organic synthesis, mostly owing to the
decomposition or polymerization via nitrogen-assisted epoxide
ring opening (Scheme 10). Epoxyamine 50 could be obtained in
53% yield in one-pot from ester 46 along with 33% bromide 49.
Inspired by the decomposition pathway of epoxyamines, we assu-
Scheme 10. Total syntheses of (-)-lycopladines B (2) and C (3). DMAP =
Scheme 11. Study towards the synthesis of (-)-lycopladine D (4).
dimethylaminopyridine.
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Scheme 12. Summary of syntheses of (-)-huperzine Q (1), (+)-lycopadine B (2), C (3) and (-)-4-epi-lycopladine D (63).
treatment of 59 with pTsOH, the desired carbinolamine lactone
core 62 was formed in excellent yield. 59 might first undergo Boc
deprotection and C4 epimerization to form ketone amine 60,
which then underwent ring-chain tautomerization to provide
hemiaminal 61. Finally, triggered by the formation of -hydroxyl
ketone through the hydroxyl attack of C16 carbonyl group, a retro-
Claisen condensation occurred and delivered the carbinolamine
lactone 62 in 82% yield. Despite the efficiency of this cascade, the
stereochemistry at C4 position in 62 is opposite to natural (-)-
lycopladine D (4). Unfortunately, tremendous efforts to epimerize
C4 position were unsuccessful. Moreover, many attempts to
install the C4 stereogenic center at late stage via either
hydroboration/ oxidation or directed hydrogenation were also
failed. These results indicated that the current strategy was not
suitable to achieve the desired stereochemistry at C4 position
presumably due to the disfavored conformation issue. Ultimately,
ketone 62 was converted into (-)-4-epi-lycopladine D (63)
exclusively in 83% yield via selective reduction from a convex face.
epoxiamine 50 was obtained and applied to the complex nature
product synthesis for the first time. Further investigations towards
the synthetic application of epoxyamines in other nature products
synthesis are currently underway in our lab and will be reported
in due course.
Experimental Section
Synthesis of enone (R)-9
Tert-butyl acetoacetate (5.15 g, 32.5 mmol) was added to a
mixture of catalyst 24 (1.94 g, 3.25 mmol) and unsaturated
aldehyde 23 (8.6 g, 48.81 mmol). The resulting mixture was
stirred at rt until the complete the consumption of tert-Butyl
acetoacetate. Then diluted with 45 mL toluene and pTsOH•H2O
(1.12 g, 6.51 mmol) was added. After stirring at 80 oC for 5 h, the
solvent was removed and purified on silica gel (petroleum ether
/EtOAc = 20/1) to afford enone (R)-9 (4.90 g, 70%) in 93% ee.
The spectroscopic data are in accordance with literature reported
values.[33] The ee value was determined by HPLC analysis with a
Chiralcel AD-H column, hexane/i-propanol = 99/1, 1.0 mL/min, λ
= 214 nm. tR (minor) = 14.7 min, tR (major) = 15.8 min. See SI.
Conclusions
In summary, we have accomplished the total synthesis of (-)-
huperzine Q in 10 steps from the commercially available 22, and
the first total syntheses of (+)-lycopladines B (2) and C (3) in 12
steps and 13 steps, respectively (Scheme 12). Our syntheses
features: 1) an evolved Michael addition/aldol/C-alkylation
sequence to form the 6/9 spirocycle; 2) an ethylene-accelerated
carbonyl-olefin metathesis to construct 6/5/9 tricyclic skeleton; 3)
a C4-epimerization followed by NBS induced functionalization to
access (-)-huperzine Q (1) and (+)-lycopladines B (2) and C (3);
4) an unusual retro-Claisen condensation allowed for the
construction of carbinolamine lactone core of (-)-lycopladine D (4).
Of particular note, an X-ray crystal structure of an unusual
Synthesis of alcohol 14
To a stirred solution of methyl sulfide-THF (10 mL/100 mL) was
added CuI (3.70 g, 19.4 mmol) at rt. After 20 minutes, the mixture
o
was cooled to -78 C, and then AllMgBr (1 M in Et2O, 19.4 mL,
19.4 mmol) was added dropwise. After 1 h at this temperature, a
solution of enone 9 (2.00 g, 9.24 mmol) in 5 mL of THF was added,
and the mixture was stirred for additional 1 h at -78 oC. A solution
of aldehyde 13 (9.40 g, 19.4 mmol) in 20 mL of THF was added.
o
The final mixture was stirred at -78 C for additional 3 h before
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quenched by adding saturated aqueous NH4Cl solution (150 mL)
at -78oC and then warmed to rt. The aqueous layer was extracted
with CH2Cl2 (3 x 200 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc = 10/1) to afford two diastereomeric
mixtures 14 (5.60 g, 82%) as a slightly yellow oil.
138.0, 136.3, 135.7, 135.0, 128.3, 128.2, 127.5, 127.4, 127.3,
117.7, 116.9, 116.6, 111.2, 79.6, 74.6, 73.3, 73.1, 73.0, 72.9, 69.8,
67.7, 47.5, 43.7, 43.6, 39.9, 39.7, 38.5, 38.2, 35.6, 35.2, 34.5,
34.2, 33.0, 32.4, 32.3, 30.7, 30.5, 29.8, 28.5, 28.3, 23.6, 22.9,
21.7; IR (neat) νmax 2917, 2849, 1687, 1590, 1413, 1160, 910, 734
cm-1; HRMS (ESI) [M + H]+ calculated for C29H43INO5: 612.2180,
found: 612.2195.
Rf = 0.2 (petroleum ether/EtOAc = 4/1); 1H NMR (400 MHz,
CDCl3) δ 7.75-7.54 (m, 4H), 7.49-7.26 (m, 11H), 5.76-5.66 (m,
1H), 5.07-5.02 (m, 2H), 4.50 (s, 2H), 3.88 (br s, 1H), 3.68 (t, J =
5.9 Hz, 2H), 3.35 (d, J = 4.0 Hz, 2H) 3.28-3.14 (m, 5H), 2.47-2.33
(m, 3H), 2.21-2.06 (m, 4H), 1.86-1.77 (m, 6H), 1.56-1.53 (m, 2H),
1.41 (s, 9H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 213.7,
155.9, 138.2, 135.5, 133.7, 129.6, 128.3, 127.6, 127.6, 127.5,
117.3, 105.0, 79.3, 73.7, 73.1, 70.9, 61.6, 60.3, 46.5, 44.2, 43.7,
37.9, 36.9, 34.9, 32.6, 31.7, 29.5, 28.4, 26.8, 24.6, 19.2; IR (neat)
νmax 3429, 2929, 2857, 1692, 1472, 1364, 1106, 701 cm-1; HRMS
(ESI) [M + H]+ calculated for C45H64NO5Si: 742.4497, found:
742.4486.
Synthesis of diketone 8
To a solution of diketone iodide 15 (1.80 g, 2.94 mmol) in
anhydrous DMF (370 mL) was added DBU (1.79 mL, 11.76 mmol)
at rt, The reaction mixture was stirred for 72 h until the reaction
was complete. The reaction mixture was concentrated in vacuo
and purified on silica gel (petroleum ether/EtOAc = 10/1 to 4/1) to
afford diketone 8 (725 mg, 51%) and 16 (327 mg, 23%) both as
colorless oil.
Diketone 8: Rf = 0.45 (petroleum ether/EtOAc = 4/1); [α]25D -4.6 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.75-
5.66 (m, 1H), 4.98 (d, J = 11.2 Hz, 2H), 4.50 (s, 2H), 3.50-3.25 (m,
2H), 3.25-2.81 (m, 4H), 2.82-2.51 (m, 2H), 2.51-2.17 (m, 6H), 2.10
(m, 1H), 2.00 (m, 1H), 1.95-1.78 (m, 2H), 1.76-1.52 (m, 4H), 1.47
(s, 9H); 13C NMR (100MHz, CDCl3) δ 211.3, 157.1, 138.2, 137.1,
128.4, 127.6, 127.4, 116.18, 116.1, 79.8, 73.5, 73.1, 70.5, 49.0,
47.6, 44.8, 41.9, 39.3, 37.7, 34.9, 33.5, 33.0, 29.7, 28.5, 26.1,
25.6, 23.3 , 20.7; IR (neat) νmax 2974, 2930, 1692, 1410, 1165,
736 cm-1; HRMS (ESI) [M + H]+ calculated for C29H42NO5:
484.3057, found: 484.3061.
Synthesis of diketo iodide 15
The substrate 14 (14.0 g, 18.87 mmol) were dissolved in 125 mL
of anhydrous CH3CN, and Et3N·3HF (15.7 mL, 94.4 mmol) was
added at rt. After stirred for 72 h at rt, the reaction mixture was
quenched with saturated aqueous NH4Cl solution (200 mL) and
extracted with EtOAc (200 mL x 3). The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated in
vacuo. The residual used directly in the next step. To a solution
of above crude in CH2Cl2 (280 mL) was added collidine (7.56 mL,
56.61 mmol) at rt. The solution was cooled to 0 oC, and
methanosulfonyl chloride (1.50 mL, 18.87 mmol) was added
dropwise. After stirring at 4-7 oC for 24 h, the reaction mixture was
quenched with water (300 ml) and extracted with CH2Cl2 (200 mL
x 3), the combined organic extracts were washed with 0.5%
aqueous HCl (200 mL), dried over Na2SO4 and concentrated in
vacuo to provide a crude residue, which was used directly in the
next step. The crude compound was redissolved in CH2Cl2 (100
mL) and the solution was cooled to 0 oC. Dess-Martin periodinane
(8.02 g, 18.87 mmol) was added, and the reaction mixture was
warmed to room temperature and stirred at rt for 3 h. Then
saturated aqueous NaHCO3 (100 mL) and saturated aqueous
Compound 16: Rf = 0.2 (petroleum ether/EtOAc = 4/1); [α]25
-
D
1
39.6 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m,
5H), 5.86-5.68 (m, 1H), 5.01-4.90 (m, 2H), 4.56-4.44 (m, 2H),
4.16-3.94 (m, 2H), 3.46 (dd, J = 9.1, 4.8 Hz, 1H), 3.40-3.17 (m,
5H), 3.00-2.89 (m, 1H), 2.79-2.52 (m, 3H), 2.29-1.96 (m, 5H),
1.90-1.76 (m, 1H), 1.71 (m, 4H), 1.45 (s, 9H), 1.12 (td, J = 12.9,
5.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 201.8, 201.5, 163.8,
163.1, 156.4, 156.1, 138.2, 137.9, 128.3, 127.5, 127.4, 120.0,
119,7, 115.5, 79.4, 75.0, 73.0, 67.8, 67.1, 48.9, 48.2, 47.0, 42.1,
42.0, 38.7, 32.0, 30.0, 29.7, 29.6, 28.5, 28.4, 28.3, 27.6, 25.9,
25.4; IR (neat) νmax 2972, 2925, 1685, 11635, 1599, 1414, 1150,
736 cm-1; HRMS (ESI) [M + H]+ calculated for C29H42NO5:
484.3057, found: 484.3055.
o
Na2S2O3 (100 mL) were added to the mixture at 0 C and the
Synthesis of alcohol 17
solution was stirred for additional 1 h. The aqueous phase was
separated and extracted with CH2Cl2 (100 mL x 3), the combined
organic extracts were dried over Na2SO4, concentrated in vacuo
and used directly in the next step. The crude was dissolved in
anhydrous acetone (100 mL), and sodium iodide (19.8 g, 132.1
mmol) was added in one portion at rt. After stirring for 24 h at 60
oC, the reaction mixture was concentrated in vacuo and purified
on silica gel (petroleum ether/EtOAc = 4/1) to afford inseparable
diastereomeric mixtures 15 (6.10 g, 53% for 4 steps) as a yellow
oil.
Rf = 0.4 (petroleum ether/EtOAc = 4/1); 1H NMR (400 MHz,
CDCl3) δ 7.39-7.27 (m, 5H), 5.70 (m, 1H), 5.11-4.98 (m, 2H), 4.48
(s, 2H), 3.40-3.29 (m, 2H), 3.24 (t, J = 6.8 Hz，2H), 3.20-3.14 (m,
2H), 3.14 (t, J = 6.8 Hz, 2H) 2.58-2.45 (m, 2H), 2.40 (d, J = 7.0
Hz, 2H), 2.37-2.28 (m, 2H), 2.12-1.97 (m, 4H), 1.97-1.82 (m, 1H),
1.77 (t, J = 7.2 Hz, 2H), 1.72-1.59 (m, 2H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 207.5, 199.9, 182.4, 155.4, 140.5, 138.2,
The C-alkylation product 8 (4.60 g, 9.5 mmol) was dissolved in
240 mL of anhydrous CH2Cl2, sodium borohydride (734 mg, 19.02
mmol) and anhydrous methanol (24 mL) were added sequentially.
The reaction mixture was stirred at rt for 1 h before quenched by
saturated aqueous NaHCO3 (200 mL). The aqueous phase was
separated and extracted with CH2Cl2 (200 x 3 mL), and the
combined organic extracts were dried over Na2SO4, concentrated
in vacuo and purified on silica gel (petroleum ether/EtOAc = 10/1
to 1/1) to afford hydroxyl ketone 17 (2.40 g, 52%) as a colorless
oil.
Rf = 0.2 (petroleum ether/EtOAc = 4/1); [α]26D -6.8 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.71-5.53 (m, 1H),
5.06-4.95 (m, 1H), 4.50 (s, 1H), 4.24 (d, J = 11.2 Hz, 1H), 3.61 (t,
J = 11.7 Hz, 1H), 3.38-3.12 (m, 5H), 3.07-2.76 (m, 4H), 2.43-2.37
(m, 1H), 2.30-2.08 (m, 3H), 2.04-1.88 (m, 4H), 1.84-1.56 (m, 3H),
1.47 (s, 9H), 1.45-1.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
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219.7, 157.1, 138.5, 136.5, 128.3, 127.5, 127.4, 116.4, 79.6, 75.2,
73.0, 69.2, 69.1, 60.3, 49.5, 48.3, 45.3, 43.6, 40.9, 34.2, 32.6,
32.2, 31.8, 31.2, 28.5, 27.3, 25.4, 23.8, 23.3, 23.2, 22.4; IR (neat)
νmax 3556, 2974, 2928, 1690, 1411, 1364, 1168, 737 cm-1; HRMS
(ESI) [M + H]+ calculated for C29H44NO5: 486.3214, found:
486.3222.
for 2 h. After the reaction was complete, the reaction mixture was
directly purified on silica gel (petroleum ether/EtOAc = 2/1) to
afford 21 (100 mg, 73%) as a slightly yellow power.
Method B: To a stirred solution of (COCl)2 (673 L, 7.66 mmol)
in 10 mL of CH2Cl2 was added anhydrous DMSO (1.21 mL, 15.3
o
mmol) at -78 C and stirred for 10 min, then 20 (150 mg, 0.306
mmol) in 5 mL CH2Cl2 was added. After stirring for 1.5 h, Et3N
o
(4.89 mL, 35.19 mmol) was added and stirred at 0 C for 30min
Synthesis of 19 and 20
before quenching by water (10 mL). The aqueous phase was
separated and extracted with CH2Cl2 (10 mL x 3), the combined
organic extracts were dried over Na2SO4, concentrated in vacuo
and purified on silica gel (petroleum ether/EtOAc = 4/1) to afford
To s solution of 17 (464 mg, 0.294 mmol) in dioxane/water (v/v =
2/1, totally 66 mL) were added DABCO (552.0 mg, 4.78 mmol),
NaIO4 (2.08 g, 9.55 mmol), and OsO4 (9.70 mL, 0.0955 mmol,
0.00984 M in tert-butanol) sequentially, the reaction was stirred at
rt and monitored by TLC. After the reaction was complete, ethyl
acetate (20 mL) and saturated aqueous Na2S2O3 (20 mL) were
added, the aqueous phase was separated and extracted with
EtOAc, and the combined organic extracts were dried over
Na2SO4, concentrated in vacuo to provide a crude residue, which
was used directly in the next step. The crude compound was
redissolved in anhydrous THF (degassed, 30 mL) at -78 oC was
added SmI2 (0.1 M in THF, freshly prepared, 38 mL, 3.8 mmol).
The resulting mixture was quickly warmed to room temperature
and stirred for additional 7 h. The reaction mixture was quenched
with saturated aqueous Rochelle’s salt (20 ml) at 0 oC and
extrated with EtOAc (20 mL x 3), combined organic extracts were
dried over Na2SO4, concentrated in vacuo and purified with silica
gel column chromatography (petroleum ether/EtOAc = 3/1 to 1/1)
to afford triol 19 (148 mg, 32% for 2 steps) and triol 20 (139 mg,
30% for 2 steps) both as a slightly yellow powder.
Compound 19: Mp: 47-48 oC; Rf = 0.2 (petroleum ether/EtOAc =
1/1); [α]23D -1.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39-
7.26 (m, 5H), 4.84 (s, 1H), 4.48 (s, 2H), 4.42-4.25 (m, 1H), 3.57-
3.01 (m, 9H), 2.91 (br s, 1H), 2.13-1.50 (m, 12H), 1.45 (s, 9H),
1.30 (q, J = 12 Hz 1H), 1.13 (td, J = 13.4, 4.5 Hz, 1H), 0.97-0.82
(m, 1H); 13C NMR (100 MHz, CDCl3)δ 156.7, 138.4, 128.3, 127.5,
127.5, 83.7, 79.9, 79.3, 75.4, 73.1, 71.34, 51.6, 51.0, 47.5, 46.6,
46.0, 37.7, 34.9, 34.8, 33.6, 33.1, 31.6, 29.7, 28.5, 27.0, 23.2,
22.8, 22.2, 21.7; IR (neat) νmax 3362, 2926, 2861, 1718, 1685,
1565, 1418, 1365, 1169, 734 cm-1; HRMS (ESI) [M + H]+
calculated for C28H44NO6: 490.3163, found: 490.3168;
Compound 20: Mp: 80-82 oC; Rf = 0.1 (petroleum ether/EtOAc =
1/1); [α]23D 8.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-
7.26 (m, 5H), 4.49 (s, 2H), δ 4.17 (dd, J = 11.6, 3.7 Hz, 1H), 4.06-
3.41 (m, 3H), 3.31 (d, J = 6.1 Hz, 2H), 3.25-2.66 (m, 3H), 2.24-
1.78 (m, 8H), 1.67-1.62 (m, 2H), 1.54-1.36 (s, 11H), 1.30-1.25 (m,
1H), 1.08 (td, J = 13.5, 4.9 Hz, 1H), 0.98-0.81 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 157.3, 157.0, 138.4, 128.3, 127.5, 127.5,
105.0, 86.9, 79.6, 75.2, 73.1, 65.6, 60.4, 51.2, 48.7, 47.5, 45.8,
44.6, 39.1, 38.4, 33.1, 32.1, 31.9, 30.5, 29.7, 29.3, 28.6, 24.6,
23.2, 22.7, 21.8, 21.0, 20.4, 19.1, 14.2, 14.1, 13.7; IR (neat) νmax
3389, 2924, 2857, 1718, 1666, 1453, 1414, 1365, 1241, 1170,
773 cm-1; HRMS (ESI) [M + H]+ calculated for C28H44NO6:
490.3163, found: 490.3165.
21 (144 mg, 97%) as a yellow power.
o
Mp: 148-150 C; Rf = 0.8 (petroleum ether/EtOAc = 1/1); [α]26
D
1
98.2 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.40-7.26 (m,
5H), 5.25-5.20 (m, 1H), 4.51 (s, 2H), 3.82 (td, J = 13.2, 4.2 Hz,
1H), 3.64-3.50 (m, 1H), 3.45-3.35 (m, 2H), 3.29-3.02 (m, 1H), 2.84
(d, J = 13.4 Hz, 1H), 2.74 (t, J = 13.8 Hz, 1H), 2.53-2.24 (m, 5H),
2.18-1.83 (m, 6H), 1.81-1.71 (m, 2H), 1.47 (s, 9H), 1.37-1.11 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 220.6, 216.7, 157.5, 138.0,
129.5, 128.5, 127.8, 127.5, 83.2, 79.5, 73.5, 73.2, 59.7, 46.4, 44.6,
42.0, 39.2, 36.6, 34.9, 28.6, 26.3, 25.9, 24.4, 23.3, 18.8; IR (neat)
νmax 3455, 2923, 1753, 1683, 1485, 1409, 1365, 1169, 738 cm-1;
HRMS (ESI) [M + H]+ calculated for C28H40NO6: 486.2850, found:
486.2860.
Synthesis of diketone 7
To a solution of 21 (47.0 mg, 0.0968 mmol) in THF/tBuOH (10
mL/2.5 mL) was added SmI2 (2.90 mL, 0.290 mmol, 0.1 M in THF,
freshly prepared) at -78 oC and the reaction mixture was warmed
to rt and stirred at rt for 30 min. Then the reaction was opened to
air and quenched with saturated aq. NaHCO3 solution. The
mixture was extracted with ether (10 ml x 3) and the combined
organic extracts were dried over Na2SO4, concentrated in vacuo
and purified on silica gel (petroleum ether/EtOAc = 10/1) to afford
diketone 7 (40.0 mg, 89%) as slight yellow oil.
Rf = 0.82 (petroleum ether/EtOAc = 1/1); [α]25 +80.5 (c 0.4,
D
CHCl3); 1H NMR (400 MHz,CDCl3) δ 7.40-7.27 (m, 5H), 4.60-4.43
(m, 2H), 3.84-3.57 (m, 2H), 3.50-3.32 (m, 2H), 3.09-2.70 (m, 2H),
2.69-2.49 (m, 2H), 2.49-2.31 (m, 2H), 2.31-2.13 (m, 4H), 2.13-
1.95 (m, 1H), 1.95-1.84 (m, 1H), 1.79 (m, 4H), 1.72-1.52 (m, 3H),
1.52-1.40 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 218.7, 215.0,
214.4, 213.4, 156.8, 156.6, 138.1, 128.4, 127.7, 127.5, 127.5,
79.8, 79.6, 74.0, 73.9, 73.2, 60.4, 60.3, 50.2, 49.5, 47.3, 44.7,
41.8, 41.8, 41.6, 38.8, 38.6, 38.2, 36.7, 35.4, 31.1, 28.5, 28.4,
27.9, 27.0, 25.7, 25.6, 25.4, 23.6, 23.4, 22.0, 21.6, 21.0; IR (neat)
νmax 2926, 1742, 1691, 1412, 1365, 1165, 668 cm-1; HRMS (ESI)
[M + NH4]+ calculated for C28H43N2O5: 487.3166, found: 487.3166.
Synthesis of aldehyde 10
To a solution of alcohol 33 (94.0 mg, 0.248 mmol) in CH2Cl2 (9
mL) was added Dess-Martin periodinane (158 mg, 0.372 mmol)
at 0 oC and the reaction mixture was warmed to rt and stirred at rt
for 1.5 h. Then saturated aqueous NaHCO3 (5 mL) and saturated
aqueous Na2S2O3 (5 mL) were added to the reaction mixture at 0
oC and the solution was stirred for additional 1 h. The aqueous
phase was separated and extracted with CH2Cl2 (5 mL x 3), the
combined organic extracts were dried over Na2SO4, concentrated
Synthesis of α-hydroxy ketone 21
Method A: To a stirred solution of triol 19 (139 mg, 0.284 mmol)
in anhydrous CH2Cl2 (7 mL) at rt was added 4-methylmorpholine
N-oxide monohydrate (196 mg, 1.42 mmol) and TPAP (5.10 mg,
0.0142 mmol) sequentially. The resulting mixture was stirred at rt
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in vacuo and purified on silica gel (petroleum ether/EtOAc = 1/1)
to aldehyde 10 (90.0 mg, 96%) as a brown oil.
1H), 2.51 (dd, J = 17.3, 14.8 Hz, 1H), 2.40-2.25 (m, 2H), 2.24-2.07
(m, 3H), 2.07-1.96 (m, 3H), 1.91-1.70 (m, 3H), 1.69-1.50 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 217.2, 176.9, 101.1, 60.4, 52.8,
49.5, 48.1, 45.5, 41.1, 39.9, 39.7, 39.3, 30.8, 30.4, 27.2, 23.5; IR
(neat) νmax 2926, 2865, 1779, 1737, 1455, 1368, 1223, 1200, 802
cm-1; HRMS (ESI) [M + H]+ calculated for C16H22NO3: 276.1594,
found: 276.1581.
Rf = 0.2 (petroleum ether/EtOAc = 1/1); [α]18D 45.2 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 3.83-3.30 (m, 2H), 3.07-
2.63 (m, 5H) 2.52 (dd, J = 13.6, 4.1 Hz, 1H), 2.42-2.01 (m, 5H),
1.95-1.74 (m, 4H), 1.72-1.50 (m, 3H), 1.43 (d, J = 16.2 Hz, 9H),
1.27-1.11 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 217.3, 217.0,
211.6, 200.0, 199.9, 156.7, 156.2, 79.7, 60.5, 60.4, 49.4, 47.8,
47.6, 47.3, 46.6, 44.8, 41.3, 38.2, 37.7, 37.6, 37.3, 28.5, 28.4,
27.7, 26.8, 25.3, 23.5, 22.3, 22.0, 21.7, 21.1; IR (neat) νmax 2972,
2929, 1739, 1726, 1687, 1481, 1413, 1366, 1243, 1163, 731 cm-
1; HRMS (ESI) [M + Na]+ calculated for C28H31NO6Na: 400.2094,
found: 400.2096;
Synthesis of 4-epi-lycopladine D (63)
To a stirred solution of 62 (6.00 mg, 0.0218 mmol) in 2 mL MeOH
was added NaBH4 (1.65 mg, 0.0436 mmol) at 0 oC and the
resulting solution was warmed to rt and stirred for an additional 2
h, then quenched with saturated aqueous NaHCO3 (1 mL) and
extracted with CH2Cl2 (2 mL x 3), the combined organic extracts
were dried over Na2SO4, concentrated in vacuo and purified on
silica gel (CH2Cl2/MeOH = 40/1) to afford 4-epi-lycopladine D (63)
Synthesis of triketone 59
To a stirred solution of 10 (55.0 mg, 0.146 mmol) in 5 mL MeOH
was added K2CO3 (65.0 mg, 0.469 mmol) at rt and the reaction
mixture was stirred at rt for 12 h. Then another portion K2CO3
(45.0 mg, 0.325 mmol) was added and stirred for additional 12 h.
Then the reaction was quenched with saturated aqueous NH4Cl
solution (5 mL). The mixture was extracted with CH2Cl2 (5 ml x 3)
and the combined organic extracts were dried over Na2SO4,
concentrated in vacuo and used directly in next step. The crude
residue was redissolved in 5 mL CH2Cl2 and the solution was
cooled to 0 oC. Dess-Martin periodinane (132 mg, 0.31 mmol) was
added, and the reaction mixture was warmed to room temperature
and stirred at rt for 1 h. Then saturated aqueous NaHCO3 (5 mL)
and saturated aqueous Na2S2O3 (50 mL) were added to the
mixture at 0 oC and the solution was stirred for additional 1 h. The
aqueous phase was separated and extracted with CH2Cl2 (5 mL x
3), the combined organic extracts were dried over Na2SO4,
concentrated in vacuo and purified on silica gel (petroleum
ether/EtOAc = 2/1) to afford triketone 59 (29.0 mg, 53% for 2
steps) as a brown oil.
Rf = 0.3 (petroleum ether/EtOAc = 1/1); [α]18D 11.0 (c 0.65, CHCl3);
1H NMR (400 MHz, CDCl3) δ 3.97-3.76 (m, 2H), 3.26 (d, J = 7.7
Hz, 1H), 3.04-2.99 (m, 1H), 2.90-2.85 (m, 1H), 2.74-2.61 (m, 3H),
2.40-2.26 (m, 2H), 2.24-2.17 (m, 1H), 2.14-2.07 (m, 1H), 2.05-
1.92 (m, 4H), 1.86-1.73 (m, 2H), 1.43-1.40 (m, 9H), 1.28-1.35 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 210.0, 207.4, 204.8, 155.5,
80.1, 60.7, 60.5, 57.5, 50.9, 49.5, 43.5, 43.2, 40.2, 33.5, 28.3,
27.5, 24.6, 23.6, 21.4; IR (neat) νmax 2968, 2931, 2872, 1765,
1720, 1687, 1467, 1415, 1367, 1279, 731 cm-1; HRMS (ESI) [M +
H]+ calculated for C21H30NO5: 376.2118, found: 376.2115.
(5.00 mg, 83%) as a colorless oil.
1
Rf = 0.2 (CH2Cl2/MeOH = 10/1); [α]17 - 8.0 (c 0.05, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 4.07 (br s, 1H), 3.53-3.41 (m, 1H), 3.24-
3.11 (m, 1H), 2.97 (dd, J = 15.0, 5.2 Hz, 1H), 2.89-2.79 (m, 1H),
2.73 (dd, J = 8.9, 3.6 Hz, 1H), 2.65 (d, J = 11.6 Hz, 1H), 2.25-2.19
(m, 1H), 2.03-1.94 (m, 1H), 1.97-1.83 (m, 6H), 1.82-1.67 (m, 3H),
1.62-1.44 (m, 3H), 1.35-1.27 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 177.4, 101.4, 72.2, 53.0, 52.3, 49.3, 48.6, 42.3, 41.2, 40.1, 40.0,
39.8, 31.9, 26.7, 24.6, 23.8; IR (neat) νmax 3367, 2924, 2853, 1778,
1451, 1260, 1101, 1020, 798 cm-1; HRMS (ESI) [M + H]+
calculated for C16H24NO3: 278.1751, found: 278.1753.
Acknowledgements
We thank Ms. Mingyan Zhao (NIBS) for NMR and HPLC-MS
analysis, Dr. Jiang Zhou (Peking University) for HRMS analysis,
Prof. Wen-xiong Zhang and Prof. Nengdong Wang (Peking
University) for X-ray analysis. Financial support from NNSFC
(21625201, 21561142002, and 21472010), and National High
Technology Projects 973 (2015CB856200) is gratefully
acknowledged.
Keywords: Carbonyl olefin metathesis • epoxyamine • enamine
bromofunctionalization
synthesis
• retro-Claisen condensation • total
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Synthesis of carbinolamine lactone 62
To a stirred solution of 59 (2.00 mg, 0.00533 mmol) in 1mL
toluene was added p-TsOH•H2O (5.50 mg, 0.0289 mmol) then
o
stirred at 110 C additional 1 h. Then quenched with saturated
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40/1) to afford carbinolamine lactone 62 (1.20 mg, 82%) as a
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Rf = 0.6 (CH2Cl2/MeOH = 10/1); [α]17 56.4 (c 0.12, CHCl3); H
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3.4 Hz, 1H), 2.81 (dd, J = 8.9, 3.4 Hz, 1H), 2.74 (d, J = 11.9 Hz,
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Divergent Total Syntheses of (-)-
Huperzine Q, (+)-Lycopladine B, (+)-
Lycopladine C and (-)-4-epi-Lycopladine
D
Structurally complex lycopodium alkaloids have been achieved by employing a
unified synthetic strategy featuring Michael/aldol/C-alkylation, ethylene-
accelerated carbonyl-olefin metathesis, late-stage enamine bromofunctionaliza-
tion and C4-epimerization/retro-Claisen condensation.
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