Divergent total synthesis of the lycopodium alkaloids huperzine A, huperzine B, and huperzine U

Article abstract of DOI:10.1021/jo402419h

Huperzine A, huperzine B, and huperzine U are congeners isolated from the Chinese herb Huperzia serrata (=Lycopodium serratum) in minuscule amounts. The most efficient total synthesis of huperzine A, the first asymmetric total syntheses of huperzine B, and the first total synthesis of huperzine U have been achieved efficiently in overall yields of 17%, 10%, and 9%, respectively, each spanning 10-13 steps from (R)-pulegone. The featured steps include palladium-catalyzed Buchwald-Hartwig coupling and Heck cyclization reactions and an Ir-catalyzed olefin isomerization reaction. This work has established the absolute configurations of huperzine B and huperzine U and revealed that natural huperzine A, huperzine B, and huperzine U possess the same set of absolute stereochemistries, thus providing support for the potential role of huperzine B and huperzine U in the biosynthesis of huperzine A.

Full text of DOI:10.1021/jo402419h

Article
pubs.acs.org/joc
Divergent Total Synthesis of the Lycopodium Alkaloids Huperzine A,
Huperzine B, and Huperzine U
Rui Ding,† Jian-Guo Fu,† Guang-Qiang Xu, Bing-Feng Sun,* and Guo-Qiang Lin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Huperzine A, huperzine B, and huperzine U are congeners isolated from the Chinese herb Huperzia serrata
(=Lycopodium serratum) in minuscule amounts. The most efficient total synthesis of huperzine A, the first asymmetric total
syntheses of huperzine B, and the first total synthesis of huperzine U have been achieved efficiently in overall yields of 17%, 10%,
and 9%, respectively, each spanning 10−13 steps from (R)-pulegone. The featured steps include palladium-catalyzed Buchwald−
Hartwig coupling and Heck cyclization reactions and an Ir-catalyzed olefin isomerization reaction. This work has established the
absolute configurations of huperzine B and huperzine U and revealed that natural huperzine A, huperzine B, and huperzine U
possess the same set of absolute stereochemistries, thus providing support for the potential role of huperzine B and huperzine U
in the biosynthesis of huperzine A.
INTRODUCTION
■
The Lycopodium alkaloids are a family of architecturally diverse
natural products with various biological activities that have
attracted broad attention from both the chemical and medicinal
communities.1 Notably, huperzine A (1), the most significant
Lycopodium alkaloid, has aroused tremendous interest because
of its nootropic effects.2 Huperzine A (1),3 huperzine B (2),3
and huperzine U (3)4 are congeners isolated from the Chinese
herb Huperzia serrata (=Lycopodium serratum) in minuscule
amounts (200, 100, and 0.38 ppm for 1, 2, and 3, respectively,
from the dry plant). Huperzine A is the most potent natural
product possessing acetylcholinesterase (AChE) inhibition
activity. It is clinically used as a symptomatic treatment of
early to moderate Alzheimer’s disease (AD) with comparable
efficacy to tacrine, galantamine, and donepezil.1a In comparison
Figure 1. Structures of huperzine A (1), huperzine B (2), and
huperzine U (3) from Huperzia serrata (=Lycopodium serratum) and
to huperzine A, huperzine B (2) displays weaker AChE
FS0311.
inhibition activity but a higher therapeutic index.5 The
bis(huperzine B) derivative FS0311 (4) exhibits similar AChE
hypothetically being cleaved by late-stage enzymatic oxidation-
s.1a Huperzine U (3) contains a rare dihydropyridone motif and
a tertiary hydroxyl substituent at C12.
Biosynthetic studies of Lycopodium alkaloids have been
limited to the feeding experiments conducted by Hemscheidt
and Spenser, which established pelletierine metabolized from
lysine as the basic building block of all Lycopodium alkaloids
(Scheme 1).7 Notably, phlegmarine was previously proposed to
inhibition potency as donepezil but higher potency than
huperzine A. Meanwhile, this derivative antagonizes cognitive
deficits induced by scopolamine or transient brain ischemia.6
The biological activities of huperzine U (3), however, have not
been reported, possibly as a result of the scarceness of this
natural product.
Structurally, huperzine A (1), huperzine B (2), and
huperzine U (3) belong to the lycodine subgroup, which
features a bicyclo[3.3.1]nonane core flanked by two piperidine
rings at various oxidation levels (Figure 1). For huperzine A,
only one piperidine ring exists, with the missing one
Received: October 30, 2013
© XXXX American Chemical Society
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Scheme 1. Proposed Biosynthesis of 1, 2, and 3
Scheme 2. Retrosynthetic Analysis for 1, 2, and 3
olefinic bond in 1 and the piperidine ring in 2 and 3 could be
traced back to an α-amino ketone function, and all of the Δ15(8)
double bonds in 1−3 could stem from olefin isomerization of a
Δ14(15) double bond, thus reducing targets 1−3 to a common
precursor 6. The subsequent bond disconnection would allow 6
to be produced from 7 via an intramolecular Heck reaction,
which entails a trans relative stereochemistry in 7. This defined
stereochemistry could be created via diastereoselective
alkylation of the key intermediate 9 with bromide 8. An
unprecedented Buchwald−Hartwig coupling reaction of the
simple α-trifloxy enone 10 with Boc-NH2 would generate 9.
The chiral compound 10 was envisaged to stem from (R)-
pulegone in a chiral-pool synthetic strategy.
be the second general intermediate to Lycopodium alkaloids.1a
Nevertheless, compound 5 could in principle be the general
intermediate to all Lycopodium alkaloids, including phlegmarine,
considering that 5 is more properly functionalized (Scheme 1).
Accordingly, deacetylflabellidine,8 a known alkaloid that might
stem from 5 via a Mannich-type cyclization, could reasonably
be proposed as the common biosynthetic precursor to 1, 2, and
3 (Scheme 1). Importantly, the proposed biosynthetic
pathways structurally correlate these molecules and intrinsically
entail the stereochemical coherence among them (specifically,
the absolute stereochemistry at C7), but this has yet to be
verified. Considering the impact this issue may have on the
biogenesis of these significant natural products, a conclusive
vindication would be of paramount importance. Actually, to
date the absolute configuration has been established only for
huperzine A (1). Particularly noteworthy is that huperzine U
(3) was originally considered to be a racemic compound
because of its reported zero optical rotation.4 Although
huperzine A has been the topic of numerous synthetic papers,9
to date only two racemic total syntheses of huperzine B (2)
have been accomplished,10 and no total synthesis of huperzine
U (3) has been reported.
Synthesis of 9. The synthetic journey commenced with the
elaboration of (R)-pulegone into 10 (Scheme 3). (R)-Pulegone
Scheme 3. Synthesis of 10
(100% ee) was triflated with LDA/PhNTf2 to give a mixture of
1
11 and 12 in a ratio of 6/1, as determined by H NMR
spectroscopy. Subsequent exposure to ozonolysis generated 10
in 69% yield over the two steps.
Previously we communicated the most efficient total
synthesis of (−)-huperzine A (1) to date.9s In this paper, we
present a full account of the divergent total synthesis of
huperzine A (1), huperzine B (2), and huperzine U (3) and the
absolute configuration assignments of the latter two natural
products with biosynthetic implications.
We next focused on the synthesis of 9, which entails a
Buchwald−Hartwig coupling reaction.11 With Pd2(dba)3 as the
catalyst and t-Bu-XPhos as the ligand, the conditions were
briefly examined (Table 1). The optimal conditions involved
potassium carbonate as the base and toluene as the solvent,
which delivered 9 in 91% yield with complete conservation of
the optical purity (100% ee). With cesium carbonate as the
base, 9 was obtained with slightly diminished yield (83%) and
optical purity (96% ee). The ligand tBu-XPhos could be mostly
RESULTS AND DISCUSSION
Retrosynthetic Analysis. The retrosynthetic analysis is
illustrated in Scheme 2. We envisioned that both the exocyclic
■
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Table 1. Buchwald−Hartwig Coupling Reaction of 10 with
Boc-NH2
Scheme 5. Rationale for the Racemization in the Alkylation
Reaction
entry
base
solvent
yield (%)
ee (%)
1
2
3
K2CO3
K2CO3
Cs2CO3
t-BuOH
toluene
toluene
43
91
83
−
100
96
recovered (ca. 90%) and reused. Noticeably, prior to our
investigations, the Buchwald−Hartwig coupling reaction of
simple α-trifloxy enones, which provides facile access to α-
amino enones, has never been reported.
Synthesis of 7. The alkylation reaction between 9 and
bromide 8 was investigated next (Scheme 4). This is a dianion-
Scheme 4. Alkylation of 9 and 13
Figure 2. Structures of 15a, 15b, and 16a−e.
Scheme 6. Pd-Catalyzed Intramolecular γ-Arylation of 14
Ketone 7 was reduced to a 1/1 mixture of 18a and 18b in
quantitative yield. Both 18a and 18b could successfully undergo
the intramolecular Heck reaction to furnish 19a and 19b in
yields of ca. 40%. The structure of 19a was established through
X-ray crystallographic analysis.35 Both 19a and 19b were found
to undergo Ley−Griffith oxidation to afford 6 in nearly
quantitative yield (Scheme 7).35 The three-step sequence was
further optimized with the mixture being directly used (Table
2). Under the optimal conditions (entry 8), ketone 6 could be
isolated in 63% yield with 96% ee over three steps from 7. This
procedure allowed the multigram-scale synthesis of 6 in a
consistent yield.
powered alkylation reaction since it was found to be necessary
to use 2−3 equiv of base (vs 9) to achieve a good yield of the
alkylation product. Thus, the α-alkylation of 9 with 8 was
realized with 2.5 equiv of LDA at −70 °C, furnishing 7 in 75%
yield (83% brsm) with 96% ee and >20/1 dr. In contrast, the
reaction of 13 with 8 generated 14 in only 25% yield.
Maintaining the reaction mixture at a low temperature was
critical to achieve a high enantiomeric excess of the product.
When the alkylation reaction was conducted with 2.2 equiv of
LDA at −25 °C, the product was obtained in 83% yield with
75% ee and 10/1 dr. The rationale for the racemization at
elevated temperature is depicted in Scheme 5. Racemization of
9 under the reaction conditions was not deemed possible since
recovered 9 completely retained its optical purity (100% ee).
This enabled us to conclude that the racemization occurred on
the alkylation product 7-Li, stemming from alkylation of 9-Li2
by 8. The monolithiated species 7-Li might transform into ent-
7-Li through stepwise epimerizations via α-epi-7-Li and/or γ-
epi-7-Li.
Scheme 7. Synthesis of 6 via Heck Cyclization
Synthesis of 6. The Heck cyclization has gained wide-
spread acceptance in natural product synthesis,12 including
Mann’s formal racemic synthesis of 1.9n Nevertheless, it has
rarely been applied to enamine-type substrates.13 Actually, none
of the attempted substrates 7, 14, 15a, 15b, and 16a−e (Figure
2) succeeded in producing a Heck cyclization product.
Interestingly, 14 underwent an unprecedented intramolecular
γ-arylation to give 17 in good yield (Scheme 6).14 The structure
of 17 was confirmed by X-ray crystallographic analysis.35
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Table 2. Optimization of the Heck Cyclization in the Three-
Step Sequence
Table 3. Optimization of the Grignard Addition Reaction of
6
a
a
entry
base
solvent
conc. (mol/L)
yield (%)
entry
method
A
T (°C)
result
1
2
3
4
5
6
7
8
Et3N
DMA
DMA
DMA
DMA
DMF
toluene
DMA
DMA
0.03
0.03
0.03
0.03
0.03
0.03
0.01
0.005
40
<5
<5
23
25
<5
53
63
1
2
3
4
5
−65
−65
−65
−25
0
6 (80%), 21 (17%)
6 (>95%)
b
K2CO3
Ag3PO4
DIPEA
Et3N
A
B
B
B
6 (55%), 21 (37%)
21 (74%), 19 (20%)
21 (45%), 19 (38%)
a
b
Et3N
Method A: EtMgBr added to 6. Method B: 6 added to EtMgBr. A
Lewis acid (CeCl3, BF3·Et2O, MgCl2, or LiCl) was used.
Et3N
Et3N
a
detailed mechanism could be elusive, the N-Boc group did play
a role in determining the facial selectivity of the Grignard
addition reaction.
With the addition products in hand, we sought to realize the
dehydration reaction. Interestingly, when 22a was treated with
TfOH in toluene, a cagelike pentacyclic ether 23 was isolated in
79% yield (Scheme 10). In contrast, under the same conditions,
Yields of 6 over the three steps from 7.
Attempted Installation of the Exocyclic Double Bond
on 6. Ketone 6 with a proper level of functionalization could
serve as a perfect synthetic precursor for various lycodine-type
alkaloids. For the synthesis of huperzine A, we needed to install
an exocyclic double bond onto 6. Despite appearing deceptively
simple, the construction of the exocyclic double bond was
actually quite challenging. Attempted Wittig reaction, Julia
olefination, and Takai−Utimoto olefination15 were unsuccess-
ful. Treatment of 6 with TsOH gave 20, which was unstable,
probably because of its propensity to undergo dimerization
and/or oligomerization. Olefination of 20 was also unsuccessful
(Scheme 8).
Scheme 10. Total Synthesis of Huperzine A from 22b
Scheme 8. Attempted Olefinations of 6 and 20
22b successfully underwent a dehydration reaction to give 24,
which after demethylation with TMSI and concomitant olefin
isomerization delivered huperzine A (1) in 72% yield over two
steps. This synthesis of huperzine A was plagued by the low
yield of 22b in the Grignard addition reaction.
Total Synthesis of Huperzine A. An addition−elimi-
nation-based protocol was then developed to meet the
challenge (Scheme 9). Thus, the addition reaction between 6
Dehydration of 21a was next investigated (Scheme 11).
Exposure of 21a to Burgess reagent or Martin sulfurane
generated olefin 25 in low yield. Treatment of 21a with SOCl2
in the presence of pyridine furnished 26 in 80% yield, which
failed to produce 25 under various conditions. When 21a was
Scheme 9. Grignard Addition Reaction of 6
Scheme 11. Attempted Dehydration of 21a
and ethylmagnesium bromide was investigated (Table 3).
Under the optimized conditions (entry 4), 21a/21b in a ratio
of 7/1 were isolated in an overall yield of 74% along with a 20%
yield of 19, which could be completely recycled by the Ley−
Griffith oxidation. The structure of 21a was confirmed by X-ray
crystallographic analysis.35 When 6 was first converted to 20
and the latter was treated with EtMgBr, 22a and 22b could be
isolated in yields of 55% and 31%, respectively. Although the
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exposed to concentrated HBr in refluxing toluene, pentacycle
27 was isolated.
Scheme 14. Synthesis of 35 and 38
Eventually it was discovered that SOCl2 in toluene in the
absence of pyridine could effect a slow dehydration of 21a/21b
to form 25 as a sole isomer along with a trace amount of 24
(Scheme 12); a minor amount of Wagner−Meerwein
Scheme 12. Total Synthesis of Huperzine A from 21
rearrangement product 28 was also isolated. In toluene, the
(25 + 24)/28 ratio was 2.6/1, while in DMF or DMA, 28 could
be isolated as the major product along with 29, which exhibited
high propensity toward hydrolysis to give 28 (Table 4). The
Table 4. Dehydration and Wagner−Meerwein
Rearrangement of 21
a
entry
solvent
temp
result
1
2
3
4
toluene
DMF
RT
25/24 (59%), 28 (23%)
25 (37%), 28/29 (50%)
25 (43%), 28/29 (48%)
25 (32%), 28/29 (55%)
4), could be attributed to the enhanced reactivity of the allyl
Grignard reagent. The major diastereomer 30 along with its
stereochemistry was established through X-ray crystallographic
analysis.35 Maintaining the reaction mixture at low temperature
was necessary. When the reaction was conducted at −25 °C,
the formation of a significant amount of 32 was observed.
The hydroboration/oxidation of 30 proceeded uneventfully
at 0 °C to produce 33 in good yield (86%). With 33 in hand,
the focus shifted to the construction of the piperidine ring
(Scheme 14). When 33 was exposed to MsCl in the presence of
Et3N, the O-alkylation product 34 was formed predominantly
(91% yield) without detection of any N-alkylation product.
This result could be explained by the steric preference for the
C12-OH group as well as the weak nucleophilicity of the
carbamate nitrogen atom. In line with this rationale, after the
conversion of 33 to its mesylate derivative, the reaction mixture
was immediately treated with TsOH. Once the deprotection of
the carbamate was completed, Et3N was added, since prolonged
exposure to acidic conditions would trigger the cyclo-
etherification of the C12-OH group (vide infra). This
procedure provided 35 and 36 in a ratio of 1/1.4. Further,
employment of TfOH as the amine liberating agent enhanced
the selectivity to 5/1, affording 35 in a satisfactory yield of 80%.
Delightfully, by means of the identical sequence, 31 could be
converted to 38 via the intermediacy of 37 in a similarly good
yield.
RT
DMA
DMA
RT
60 °C
a
1
Yields determined by H NMR analysis.
structure of 28 was originally assigned as 28-A on the basis of
MS and 2D-NMR techniques,9s but 28-B could not be
excluded, and the real structure of 28 needs further
investigation (Scheme 13). Olefin isomerization of 25 with
Scheme 13. Dehydration of 21 Leading to 25/24 (Path a)
and Two Possible Structures of 28 (28-A and 28-B) Derived
via Wagner−Meerwein Rearrangement of 21 (Paths b and c)
Total Synthesis of Huperzine B. Deoxygenative reduction
of 35 and 38 was investigated in an attempt to set up the C12
stereocenter directly. Unfortunately, neither could give the
desired product under various tested conditions. Exposure of
35/38 to Et3SiH in the presence of BF3 or TiCl4 gave either no
reaction or (for 35) cyclization product (vide infra). The
Barton−McCombie deoxygenation protocol (NaH/CS2/MeI,
then Bu3SnH/AIBN) was also attempted but proved to be
unsuccessful (Scheme 15).16
A three-step sequence was then developed to complete the
total synthesis of huperzine B (2) (Scheme 16). The
dehydration reaction performed separately on 35 and 38 with
SOCl2 furnished 39 in similarly good yields (84% from 35, 81%
HBr and concomitant demethylation delivered huperzine A (1)
in 57% yield over two steps. This synthesis of huperzine A
covers 10 steps from (R)-pulegone with 17% overall yield.
Construction of the Lycodine Framework. For the
synthesis of huperzine B and huperzine U, 6 needs first to have
the piperidine ring installed. The allylation of 6 performed at
−78 °C with allylmagnesium chloride proceeded smoothly to
deliver the addition products 30 and 31 (which were separable
by regular chromatography) in a nearly quantitative combined
yield with a diastereoselectivity of 1.6/1 (Scheme 14). The
decreased diastereoselectivity (1.6/1 at −78 °C) compared
with that for ethylation of 6 (dr 7/1 at −25 °C; Table 3, entry
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Scheme 15. Attempted Direct Deoxygenative Reduction of
35/38
Scheme 17. Attempted Olefin Isomerization of 35 Leading
to 42
Scheme 16. Total Synthesis of Huperzine B (2)
investigation. Upon exposure of 35 to the catalyst in CH2Cl2
under inert (nitrogen) or high-pressure hydrogen (80 atm)
atmosphere, no reaction was observed (Table 5, entries 1 and
Table 5. Ir-Catalyzed Olefin Isomerization of 35
entry
pressure of H2
result
1
2
3
0
no reaction
no reaction
98% yield
80 atm
1 atm
2). Interestingly, when 35 was placed in a hydrogen atmosphere
at normal pressure in the presence of the catalyst, the reaction
proceeded slowly to provide 43 in a nearly quantitative yield
(entry 3). The structure of 43 was confirmed by 2D NMR
analysis. To the best of our knowledge, this represents the first
example where a trisubstituted olefin was isomerized by a
transition-metal catalyst. In addition, it demonstrates the
strategic application of olefin isomerization in natural product
synthesis with a readily available catalyst. By contrast, previous
examples of olefin isomerization in total synthesis have
generally been limited to allyl ethers in protecting group
manipulations.24
from 38). Compound 39 was further subjected to olefin
migration by HBr with concomitant demethylation, affording
40 in quantitative yield. Subsequent catalytic hydrogenation
with Pd/C proceeded in a regio- and stereoselective manner to
selectively saturate the Δ11(12) olefin, furnishing 2 in 57% yield
along with a minor amount of 41. Intriguingly, it was found to
be critical to have the Δ15(8) double bond in position before the
hydrogenation since the reaction performed on 39 was found
1
to be non-regioselective. The H and 13C NMR spectroscopic
data of synthetic 2 matched those reported for huperzine B.
Comparison of the specific optical rotation data {[α]2D5 −46.6 (c
0.16, MeOH); lit.3 [α]D26 −54.2 (c 0.20, MeOH)} enabled us to
establish the absolute configuration of natural huperzine B as
identical to that of synthetic 2. Consequently, natural huperzine
B and huperzine A possess the same set of absolute
stereochemistries.
Total Synthesis of Huperzine U. Olefin isomerization
(Δ14(15) → Δ15(8)) is the critical step in our planned total
synthesis of huperzine U. There is a strong propensity for this
isomerization reaction to take place, as evidenced by the
conversion of 24/25 to 1 (Schemes 10 and Scheme 12) and the
conversion of 39 to 40 (Scheme 16), suggesting a
thermodynamic driving force. In all of these cases, the Δ11(12)
olefinic bond appeared to be compatible with the C15
carbocation intermediate formed under acidic conditions. In
the presence of the C12-OH group, however, the carbocation-
based processes were not regarded as viable methods since the
OH group could readily capture the carbocation intermediate.
This was evidenced by the quantitative conversion of 21a to 27
under acidic conditions (Scheme 11). As expected, treatment of
35 with TfOH (1.0 equiv) afforded 42 along with the recovered
starting material (Scheme 17). No olefin isomerization product
was observed.
In view of the fact that no reaction occurred in the absence of
either the catalyst or hydrogen, the complex [Ir](H)2 formed
should be the operative catalyst.25 This was validated by the
observed success of olefin isomerization catalyzed by preformed
[Ir](H)2 under an argon atmosphere. On the basis of this
evidence, two mechanistic scenarios were proposed (Scheme
18). In the hydride addition mechanism (catalytic cycle A),
[Ir](H)2 would undergo addition of Ir−H across the olefin
double bond of 35 to give 44, which would advance to 43 via β-
H elimination.18,20 In the π-allyl mechanism (catalytic cycle B),
35 would combine with [Ir](H)2 via allylic C−H insertion to
form an Ir(V) species, η3-allyl complex 45, which would
decompose to 43 through reductive elimination.22b In view of
the presence of Ir−H bonds in the catalyst, the first scenario
was the preferred one.17 The exact reason that no isomerization
occurred under a high-pressure hydrogen atmosphere could be
elusive. Presumably, H2 saturated the metal center by forming a
tetrahydride Ir(V) complex26 and impeded further coordination
with the substrate, thus precluding the desired reaction.
The total synthesis of huperzine U was then accomplished
from 43 (Scheme 19). Demethylation of the methoxypyridine
ring was explored. Treatment of 43 with NaSEt in DMF gave
no reaction at lower temperatures (80−110 °C) and
decomposed products at a higher temperature (120 °C).27
To address this challenge, we resorted to transition-metal-
catalyzed olefin isomerization.17−23 Crabtree’s catalyst, [Ir-
(COD)(PCy3)(Py)]PF6 (denoted as [Ir]) was recruited for the
28
29
The use of BBr3 or BCl3 in CH2Cl2 at room or refluxing
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to the possibility that the originally reported optical rotation of
huperzine U may have been mistaken.
Scheme 18. Proposed Mechanisms for the Ir-Catalyzed
Olefin Isomerization of 35
CONCLUSION
■
In summary, by employing a unified synthetic strategy, the
most efficient total synthesis of huperzine A (1) to date, the
first asymmetric total synthesis of huperzine B (2), and the first
total synthesis of huperzine U (3) were collectively
accomplished in overall yields of 17%, 10%, and 9%,
respectively, each spanning 10−13 steps from (R)-pulegone.
The synthetic routes feature (1) the first example of a
Buchwald−Hartwig coupling reaction with a simple α-trifloxy
enone substrate, (2) a rare example of Heck cyclization of an
enamine-type substrate, and (3) the first example of Ir-
catalyzed isomerization of a trisubstituted olefin. This work has
for the first time established the absolute configurations of
huperzine B and huperzine U and revealed that natural
huperzine A, huperzine B, and huperzine U possess the same
set of absolute stereochemistries. This provides support for the
proposed biosynthetic pathways depicted in Scheme 1. The
concise and efficient nature of the synthetic routes renders
them highly valuable for supplying sufficient amount of these
sparse natural products for biological and medicinal purposes.
Scheme 19. Total Synthesis of Huperzine U (3)
EXPERIMENTAL SECTION
■
General Methods. All nonaqueous reactions were run under a
positive pressure of nitrogen. Anhydrous solvents were obtained using
standard drying techniques. Commercial-grade reagents were used
without further purification unless stated otherwise. Flash chromatog-
raphy was performed on 300−400 mesh silica gel with the indicated
solvent systems. 1H NMR spectra were recorded on a 400 MHz
spectrometer using TMS (0.00 ppm) or residual chloroform (7.26
ppm) as an internal standard. Chemical shifts (δ) are reported in parts
per million downfield from TMS. Data are reported as chemical shift
(s = singlet, br = broad, d = doublet, t = triplet, q = quartet, hept =
heptet, m = multiplet; J = coupling constant in Hz, integration.). 13C
NMR spectra were recorded on a 100 MHz spectrometer using proton
decoupling, unless otherwise noted. Chemical shifts are reported in
parts per million downfield from TMS. The central resonance of
CDCl3 (77.00 ppm) was used as the internal standard. [α]D values are
given in units of 10−1 deg cm2 g−1. HRMS was performed using either
an FTMS-ESI or FTMS-MALDI spectrometer.
tert-Butyl ((5S,9S,11S)-11-Allyl-11-hydroxy-2-methoxy-7-
methyl-5,8,9,10-tetrahydro-5,9-methanocycloocta[b]pyridin-
5-yl)carbamate (30) and tert-Butyl ((5S,9S,11R)-11-Allyl-11-
hydroxy-2-methoxy-7-methyl-5,8,9,10-tetrahydro-5,9-
methanocycloocta[b]pyridin-5-yl)carbamate (31). To a solution
of ketone 6 (689 mg, 2.0 mmol) in THF (10 mL) was added a
solution of allylmagnesium chloride (3.0 mL, 2.0 M in THF) slowly at
−78 °C. After the mixture was stirred at that temperature for 3 h, the
reaction was quenched with saturated aqueous NH4Cl (10 mL). (If the
reaction was conducted at −25 °C, the byproduct 32 could be
obtained as a dense colorless liquid.) The resulting mixture was then
allowed to warm to room temperature, extracted with CH2Cl2 (20 mL
× 3), dried over Na2SO4, concentrated, and purified by chromatog-
raphy (hexane/EtOAc = 30/1) to give 30 (467 mg, 60%) and 31 (298
mg, 38%) as dense colorless liquids. Data for 30: mp 185−187 °C;
[α]2D7 +12.5 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.52 (d,
J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 6.20−6.08 (m, 1H), 5.45 (s,
1H), 5.12 (d, J = 10.0 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H), 4.97 (br s,
1H), 4.48 (br s, 1H), 3.89 (s, 3H), 3.17 (dd, J1 = 19.4 Hz, J2 = 7.2 Hz,
H-6), 2.72 (d, J = 19.4 Hz, H-6), 2.72 (dd, J1 = 18.3 Hz, J2 = ca. 5 Hz,
H-8), 2.51−2.42 (m, 2H), 2.10 (dd, J1 = 14.0 Hz, J2 = 8.5 Hz, 1H),
1.82 (d, J = 18.3 Hz, H-8), 1.63 (s, 3H), 1.49 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 162.1, 157.0, 154.0, 134.9, 134.0, 133.7, 130.1, 127.4,
117.3, 107.7, 80.7, 76.1, 61.8, 53.4, 39.3, 39.1, 37.2, 35.2, 28.4, 22.8; IR
(thin film): 3264, 2976, 2935, 2906, 1678, 1598, 1533, 1475, 1424,
temperature proved abortive. When 43 was subjected to AlCl3
in DCE at RT, 42 was isolated as the major product.30
Employment of the original Harrison’s conditions was
unsuccessful.31 Nevertheless, by modifying Harrison’s con-
ditions we were able to obtain the demethylation product.
Thus, exposure of 43 to LiI in refluxing toluene resulted in a
mixture of 46 and 47 with a ratio of ca. 2/1. Compound 47 was
derived from 46 via N-methylation by the byproduct MeI. The
use of Et3N as a scavenger of MeI successfully enhanced the
ratio. When 20 equiv of Et3N was added, the reaction offered
46 and 47 in a ratio of 36/1 as determined by 1H NMR analysis
of the crude mixture, and the desired product 46 was isolated in
83% yield. Finally, semihydrogenation of the pyridone ring was
accomplished by employing Kamochi’s procedure, furnishing
huperzine U (3) in 83% yield.32 Other conditions such as H2/
Pd33 or Mg/MeOH34 were futile.
1
The H and 13C NMR spectroscopic data for synthetic 3
matched those reported for huperzine U. The value of the
specific optical rotation of synthetic 3, albeit small {[α]D +8.6
(c 0.85, MeOH)}, was not equal to zero as originally reported.
Fortunately, comparison of the CD data {synthetic 3 (c 2.0 ×
10−4 mol/L, CH3OH): [θ]245 +1.1 × 104, [θ]319 −1.4 × 102;
natural huperzine U (c 1.8 × 10−3 mol/L, CH3OH): [θ]240 +1.7
× 104, [θ]313 −6.4 × 102}4 enabled us to establish the absolute
stereochemistry of huperzine U as identical to that of synthetic
3. Consequently, natural huperzine U and huperzine A possess
the same set of absolute stereochemistries. Meanwhile, it points
G
dx.doi.org/10.1021/jo402419h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1365, 1310, 1289, 1254, 1170, 1091, 1041, 918, 822, 673, 631, 573
cm−1; LRMS (ESI): 387 (M + H)+; HRMS (MALDI-ESI): calcd for
C22H31N2O4 (M + H)+: 387.2278, found: 387.2289. Data for 31: mp
161.9, 155.4, 153.4, 136.2, 132.8, 130.0, 127.3, 106.8, 86.1, 79.3, 68.6,
60.4, 53.3, 39.8, 37.3, 36.2, 31.8, 28.4, 26.0, 23.0; IR (thin film): 3393,
2974, 2910, 1725, 1594, 1475, 1424, 1366, 1309, 1251, 1163, 1073,
1038, 1005, 977, 935, 911, 878, 819, 776, 737, 703, 616 cm−1; LRMS
(ESI): 387 (M + H)+; HRMS (ESI): calcd for C22H31N2O4 (M + H)+:
387.2278, found: 387.2282.
1
173−175 °C; [α]2D7 +47.6 (c = 1.47, CHCl3); H NMR (400 MHz,
CDCl3): δ 7.33 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.24−
6.12 (m, 1H), 5.76 (br, 1H), 5.15 (d, J = 8.0 Hz, 1H), 5.12 (d, J = 16.1
Hz, 1H), 4.99 (s, 1H), 4.90−5.00 (br s, 1H), 3.87 (s, 3H), 3.52 (dd, J1
= 18.6 Hz, J2 = 8.1 Hz, H-6), 2.55−2.45 (m, 3H), 2.40−2.31 (m, 2H),
1.94 (d, J = 18.5 Hz, H-8), 1.59 (s, 3H), 1.46 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 161.8, 157.0, 156.6, 135.3, 134.6, 133.7, 128.5, 127.6,
117.2, 106.7, 81.2, 74.9, 63.2, 53.4, 40.1, 38.7, 37.7, 34.7, 28.3, 22.5; IR
(thin film): 3327, 2977, 2914, 1686, 1593, 1522, 1474, 1426, 1368,
1307, 1285, 1255, 1166, 1078, 1038, 983, 915, 823, 738, 618 cm−1;
LRMS (ESI): 387 (M + H)+; HRMS (MALDI-ESI): calcd for
C22H31N2O4 (M + H)+: 387.2278, found: 387.2272. Data for 32: [α]2D5
(4aS,5S,10bS)-8-Methoxy-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-10b,5-prop[1]eno-1,7-phenanthrolin-4a-ol (35) and
(2′S,5S,9S)-2-Methoxy-7-methyl-4′,5,5′,8,9,10-hexahydro-3′H-
spiro[5,9-methanocycloocta[b]pyridine-11,2′-furan]-5-amine
(36). To a solution of 33 (574 mg, 1.42 mmol) in DCM (14 mL) were
added triethylamine (0.59 mL, 4.26 mmol) and methanesulfonyl
chloride (0.165 mL, 2.13 mmol) at room temperature. After
consumption of the starting material, trifluoromethanesulfonic acid
(0.38 mL, 4.26 mmol) was added to the reaction mixture. After the
mixture was stirred at room temperature for 30 min, triethylamine
(1.18 mL, 8.52 mmol) was added. After 3 h of further reaction, 1 N
NaOH (10 mL) was added, and the resulting solution was vigorously
stirred overnight, extracted with CH2Cl2 (20 mL × 3), dried over
Na2SO4, concentrated, and purified by chromatography (EtOAc) to
give 35 (325 mg, 80%) and 36 (64 mg, 16%) as dense colorless
1
+48.2 (c = 0.4, CHCl3); H NMR (400 MHz, CDCl3): δ 7.55 (d, J =
8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.20−6.08 (m, 1H), 6.10−5.98
(m, 1H), 5.40 (s, 1H), 5.21−4.95 (m, 5H), 4.42 (br s, 1H), 3.53 (d, J
= 7.0 Hz, 2H), 3.27 (dd, J1 = 19.2 Hz, J2 = 7.5 Hz, H-8), 2.84 (d, J =
19.2 Hz, H-8), 2.74 (dd, J1 = 18.4 Hz, J2 = 6.2 Hz, H-6), 2.52 (t, J = 7.0
Hz, 1H), 2.46 (dd, J1 = 14.1 Hz, J2 = 5.7 Hz, 1H), 2.07 (dd, J1 = 14.1
Hz, J2 = 8.6 Hz, 1H), 1.84 (d, J = 18.4 Hz, H-6), 1.63 (s, 3H), 1.49 (s,
9H); 13C NMR (100 MHz, CDCl3): δ 157.6, 157.0, 155.9, 135.7,
134.9, 134.6, 134.2, 131.5, 127.1, 120.0, 117.5, 116.9, 80.7, 75.9, 62.1,
42.4, 39.4, 39.2, 37.1, 35.2, 28.4, 22.8; IR (thin film): 3285, 2981, 2922,
1678, 1527, 1457, 1368, 1289, 1252, 1166, 1062, 988, 912, 831, 646
cm−1; LRMS (ESI): 397 (M + H)+; HRMS (MALDI-ESI): calcd for
C24H33N2O3 (M + H)+: 397.2486, found: 397.2483.
liquids. Data for 35: [α]D25 +56.3 (c = 1.0, CHCl3); H NMR (400
1
MHz, CDCl3): δ 7.65 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H),
5.11 (s, 1H), 3.88 (s, 3H), 3.20 (dd, J1 = 18.8 Hz, J2 = 7.0 Hz, H-6),
2.83 (dd, J1 = 13.2 Hz, J2 = 4.8 Hz, 1H), 2.79 (d, J = 18.8 Hz, H-6),
2.67 (dd, J1 = 18.8 Hz, J2 = 7.0 Hz, H-8), 2.57 (td, J1 = 13.1 Hz, J2 =
3.3 Hz, 1H), 2.74−2.42 (br, 2H), 2.34 (t, J = 7.1 Hz, 1H), 2.08−1.96
(m, 1H), 1.92 (d, J = 18.8 Hz, H-8), 1.73 (td, J1 = 13.1 Hz, J2 = 4.5 Hz,
1H), 1.67−1.61 (m, 1H), 1.60 (s, 3H), 1.39−1.31 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 161.8, 153.4, 135.8, 135.2, 129.4, 129.3, 107.9,
69.1, 59.0, 53.3, 40.6, 40.1, 37.7, 37.5, 29.4, 22.6, 22.0; IR (thin film):
3146, 2957, 2933, 1595, 1576, 1475, 1449, 1314, 1254, 1176, 1103,
1027, 959, 884, 870, 834, 792, 641, 622, 559 cm−1; LRMS (ESI): 287
(M + H)+; HRMS (ESI): calcd for C17H23N2O2 (M + H)+: 287.1754,
tert-Butyl ((5S,9S,11S)-11-Hydroxy-11-(3-hydroxypropyl)-2-
methoxy-7-methyl-5,8,9,10-tetrahydro-5,9-methanocycloocta-
[b]pyridin-5-yl)carbamate (33). To a solution of 30 (638 mg, 1.65
mmol) in THF (16 mL) was added borane tetrahydrofuran complex
solution (3.30 mL, 1.0 M in THF) at 0 °C. After consumption of the
starting material, 1 N NaOH (8 mL) and H2O2 (5 mL, 30%) was
added to the reaction mixture. After the mixture was stirred at room
temperature for 3 h, the reaction was quenched with saturated aqueous
Na2S2O3 (2 mL), and the resulting mixture was extracted with CH2Cl2
(20 mL × 3), dried over Na2SO4, concentrated, and purified by
chromatography (hexane/EtOAc = 3/1) to give 33 (574 mg, 86%) as
found: 287.1758. Data for 36: [α]2D6 +88.3 (c = 0.435, CHCl3); H
1
NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 8.5
Hz, 1H), 5.57 (s, 1H), 4.24−4.15 (m, 1H), 3.96−3.87 (m, 1H), 3.86
(s, 3H), 3.31 (dd, J1 = 19.3 Hz, J2 = 8.6 Hz, H-6), 2.81 (d, J = 19.3 Hz,
H-6), 2.68 (dd, J1 = 18.1 Hz, J2 = 5.4 Hz, H-8), 2.55−2.47 (m, 1H),
2.12−1.93 (m, 3H), 1.88 (d, J = 18.1 Hz, H-8), 1.79−1.69 (m, 1H)
1.64 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.4, 154.0, 135.4,
134.7, 128.3, 126.5, 107.5, 84.2, 69.7, 59.8, 53.4, 39.5, 37.5, 35.2, 31.0,
26.1, 22.8; IR (thin film): 2918, 1675, 1595, 1500, 1475, 1424, 1378,
1309, 1260, 1190, 1068, 1033, 895, 823, 736, 702, 651, 614, 524 cm−1;
LRMS (ESI): 309 (M + Na)+; HRMS (ESI): calcd for C17H22N2NaO2
(M + Na)+: 309.1574, found: 309.1576.
a white solid: mp 174−176 °C; [α]2D3 −16.3 (c = 1.27, CHCl3); H
1
NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 8.5
Hz, 1H), 5.46 (s, 1H), 5.07 (s, 1H), 4.99 (br, 1H), 3.87 (s, 3H), 3.74−
3.58 (m, 2H), 3.12 (dd, J1 = 19.0 Hz, J2 = 7.0 Hz, 1H), 3.18−3.06 (br,
1H), 2.76 (d, J = 19.0 Hz, 1H), 2.74 (dd, J1 = 18.1 Hz, J2 = 7.0 Hz,
1H), 2.65 (t, J = 7.0 Hz, 1H), 1.85 (d, J = 18.1 Hz, 1H), 1.91−1.80 (m,
1H), 1.75−1.66 (m, 2H), 1.63 (s, 3H), 1.60−1.54 (m, 1H), 1.49 (s,
9H); 13C NMR (100 MHz, CDCl3): δ 162.0, 157.2, 153.6, 134.0,
133.9, 130.2, 127.4, 107.9, 80.9, 76.0, 63.4, 62.1, 53.4, 39.5, 37.1, 34.2,
31.2, 28.4, 26.7, 22.7; IR (thin film): 3527, 4277, 2951, 2922, 1665,
1597, 1534, 1474, 1422, 1298, 1255, 1165, 1086, 1035, 993, 920, 838,
696, 680, 617 cm−1; LRMS (ESI): 405 (M + H)+; HRMS (MALDI-
ESI): calcd for C22H33N2O5 (M + H)+: 405.2384, found: 405.2392.
tert-Butyl ((2′S,5S,9S)-2-Methoxy-7-methyl-4′,5,5′,8,9,10-
hexahydro-3′H-spiro[5,9-methanocycloocta[b]pyridine-11,2′-
furan]-5-yl)carbamate (34). To a solution of 33 (30 mg, 0.074
mmol) in DCM (1.5 mL) were added triethylamine (31 μL, 0.22
mmol) and methanesulfonyl chloride (8.6 μL, 0.11 mmol) at room
temperature, and the mixture was stirred for 48 h. Then the reaction
was quenched with H2O (1 mL), and the mixture was extracted with
CH2Cl2 three times. The combined organic layers were dried over
anhydrous Na2SO4 before the solvent was removed under reduced
pressure. The residue was purified via flash chromatography on silica
gel (hexane/EtOAc = 20/1) to give 34 (26 mg, 91%) as a colorless oil:
[α]2D7 +76.2 (c = 0.665, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.56
(d, J = 8.5 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.68 (br s, 1H), 4.96 (br
s, 1H), 4.09−4.01 (m, 1H), 3.95−3.88 (m, 1H), 3.86 (s, 3H), 3.28
(dd, J1 = 19.1 Hz, J2 = 8.3 Hz, H-6), 2.77 (d, J = 19.1 Hz, H-6), 2.68
(dd, J1 = 17.4 Hz, J2 = 4.6 Hz, 1H), 2.42−2.36 (m, 1H), 2.19−2.09 (m,
1H), 2.00−1.85 (m, 2H), 1.82 (d, J = 17.7 Hz, 1H), 1.68−1.59 (m,
1H), 1.64 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
tert-Butyl ((5S,9S,11R)-11-Hydroxy-11-(3-hydroxypropyl)-2-
methoxy-7-methyl-5,8,9,10-tetrahydro-5,9-methanocycloocta-
[b]pyridin-5-yl)carbamate (37). To a solution of 31 (120 mg, 0.31
mmol) in THF (3 mL) was added borane tetrahydrofuran complex
solution (0.62 mL, 1.0 M in THF) at 0 °C. After consumption of the
starting material, 1 N NaOH (2 mL) and H2O2 (1 mL, 30%) were
added to the reaction mixture. After the mixture was stirred at room
temperature for 3 h, saturated aqueous Na2S2O3 (2 mL) was added,
and the resulting mixture was extracted with CH2Cl2 (10 mL × 3),
dried over Na2SO4, concentrated, and purified by chromatography
(hexane/EtOAc = 3/1) to give 37 (115 mg, 92%) as a white solid: mp
177−179 °C; [α]2D7 79.2 (c = 1.10, CHCl3); H NMR (400 MHz,
1
CDCl3): δ 7.32 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 6.16 (br,
1H), 5.02 (s, 1H), 4.95 (br, 1H), 3.87 (s, 3H), 3.72 (m, 1H), 3.65 (m,
1H), 3.52 (dd, J1 = 18.8 Hz, J2 = 8.3 Hz, H-6), 3.46 (br, 1H), 2.70 (t,
1H), 2.52 (d, J = 18.8 Hz, H-6), 2.32 (dd, J1 = 18.6 Hz, J2 = 4.0 Hz, H-
8), 1.99 (d, J = 18.6 Hz, H-8), 2.07 (d, J = 17.8 Hz, 1H), 1.94−1.87
(m, 2H), 1.76−1.63 (m, 2H), 1.58 (s, 3H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 161.9, 157.2, 156.5, 134.2, 133.6, 128.6, 127.4,
106.7, 81.4, 74.7, 63.8, 63.6, 53.4, 38.5, 38.0, 33.8, 32.7, 28.3, 27.3,
22.4; IR (thin film): 3328, 3051, 2931, 1686, 1593, 1525, 1474, 1426,
1368, 1342, 1062, 1039, 982, 887, 737, 703, 619 cm−1; LRMS (ESI):
405 (M + H)+; HRMS (ESI): calcd for C22H33N2O5 (M + H)+:
405.2384, found: 405.2393.
H
dx.doi.org/10.1021/jo402419h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4aR,5S,10bS)-8-Methoxy-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-10b,5-prop[1]eno-1,7-phenanthrolin-4a-ol (38) and
(2′R,5S,9S)-2-Methoxy-7-methyl-4′,5,5′,8,9,10-hexahydro-3′H-
spiro[5,9-methanocycloocta[b]pyridine-11,2′-furan]-5-amine
(12-epi-36). To a solution of 37 (161 mg, 0.40 mmol) in DCM (4
mL) were added triethylamine (0.16 mL, 1.20 mmol) and
methanesulfonyl chloride (46.2 μL, 0.60 mmol) at room temperature.
After consumption of the starting material, trifluoromethanesulfonic
acid (0.11 mL, 0.60 mmol) was added. The mixture was stirred at
room temperature for 30 min, and triethylamine (0.32 mL, 2.40
mmol) was added. After 3 h of further reaction, the resulting solution
was vigorously stirred with 1 N NaOH (3 mL) overnight, extracted
with CH2Cl2 (10 mL × 3), dried over Na2SO4, concentrated, and
purified by chromatography (hexane/EtOAc = 2/1) to give 38 (90
mg, 79%) as a white dense liquid and 12-epi-36 (18 mg, 16%) as a
afford 40 (22 mg, 100%) as a white solid: mp 230−232 °C; [α]D28
1
−73.0 (c = 1.34, CHCl3); H NMR (400 MHz, CDCl3): δ 13.26 (br,
1H), 7.76 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 5.66 (t, J = 3.8
Hz, 1H), 5.41 (d, J = 3.7 Hz, 1H), 3.07 (t, J = 3.7 Hz, 1H), 2.96 (m,
2H), 2.85 (m, 1H), 2.74 (d, J = 16.8 Hz, 1H), 2.51 (d, J = 16.8 Hz,
1H), 2.03 (br s, 2H), 2.01 (d, J = 16.8 Hz, 1H), 1.56 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 165.4, 143.2, 139.5, 139.1, 133.8, 124.6,
122.2, 117.5, 116.5, 53.0, 46.7, 39.4, 39.2, 36.7, 26.3, 22.7; IR (thin
film): 3278, 2962, 1873, 1656, 1613, 1553, 1462, 1377, 1303, 1263,
1165, 1120, 1095, 1009, 807, 738, 703, 659 cm−1; LRMS (ESI): 255
(M + H)+; HRMS (ESI): calcd for C16H19N2O (M + H)+: 255.1492,
found: 255.1494.
(4aR,5R,10bR)-12-Methyl-2,3,4,4a,5,6-hexahydro-1H-5,10b-
prop[1]eno-1,7-phenanthrolin-8(7H)-one (Huperzine B, 2) and
(4aR,5S,10bR,12S)-12-Methyl-2,3,4,4a,5,6-hexahydro-1H-
5,10b-propano-1,7-phenanthrolin-8(7H)-one (41). To a solution
of 40 (5.6 mg, 22 μmol) in EtOH (1 mL) was added Pd/C (10%)
catalyst (2.3 mg, 22 μmol). Then the mixture was allowed to stir at
room temperature under balloon pressure of H2 for 12 h. The
insoluble solid was filtered, and the solvent was removed under
reduced pressure. The residue was purified via flash chromatography
on silica gel (DCM/MeOH = 10/1) to give huperzine B (2) (3.2 mg,
57%) as a white solid, along with minor amount of 41 (ca. 0.6 mg,
10%). Data for 2: mp 268−270 °C; [α]2D5 −46.6 (c = 0.16, CH3OH);
1H NMR (400 MHz, CDCl3): δ 12.71 (br, 1H), 7.71 (d, J = 9.3 Hz,
colorless oil. Data for 38: [α]2D6 104.8 (c = 2.00, CHCl3); H NMR
1
(400 MHz, CDCl3): δ 7.67 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 8.5 Hz,
1H), 5.32 (s, 1H), 3.89 (s, 3H), 3.42 (dd, J1 = 18.8 Hz, J2 = 7.8 Hz, H-
6), 3.01 (ddd, J1 = 13.3 Hz, J2 = 2.3 Hz, J3 = 2.0 Hz, 1H), 2.87 (td, J1 =
13.3 Hz, J2 = 3.0 Hz, 1H), 2.67 (d, J = 18.8 Hz, H-6), 2.50 (dd, J1 =
18.6 Hz, J2 = 6.0 Hz, H-8), 2.31 (t, J = 7.3 Hz, 1H), 2.09 (d, J = 18.6
Hz, H-8), 2.02 (dd, J1 = 13.6 Hz, J2 = 4.8 Hz, 1H), 1.84 (qt, J1 = 13.3
Hz, J2 = 4.2 Hz, 1H), 1.61 (s, 3H), 1.60 (m, 1H), 1.50 (br d, J = 13.1
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 161.8, 154.4, 134.5, 134.3,
130.2, 129.4, 107.3, 69.4, 59.4, 53.3, 41.4, 39.9, 38.5, 37.8, 30.5, 22.5,
21.2; IR (thin film): 3301, 2914, 1594, 1474, 1426, 1338, 1306, 1267,
1248, 1174, 1107, 1036, 898, 824, 737, 704 cm−1; LRMS (ESI): 287
(M + H)+; HRMS (ESI): calcd for C17H23N2O2 (M + H)+: 287.1754,
found: 287.1765. Data for 12-epi-36: [α]2D6 53.2 (c = 0.82, CHCl3); 1H
NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 8.5
Hz, 1H), 5.26 (s, 1H), 3.93 (m, 1H), 3.86 (s, 3H), 3.83 (m, 1H), 3.39
(dd, J1 = 18.3 Hz, J2 = 7.8 Hz, H-6), 2.64 (d, J = 18.3 Hz, H-6), 2.55−
2.46 (m, 1H), 2.48 (d, J = 6.1 Hz, 1H), 2.16−2.10 (m, 1H), 2.09 (d, J
= 17.4 Hz, 1H), 2.03−1.91 (m, 2H), 1.83−1.76 (m, 1H), 1.54 (s, 3H),
1.51 (br, 2H); 13C NMR (100 MHz, CDCl3): δ 161.6, 154.1, 135.9,
133.6, 132.9, 132.0, 107.1, 87.0, 68.2, 56.6, 53.3, 39.8, 39.0, 36.0, 31.1,
27.0, 22.4; IR (thin film): 3385, 3315, 2926, 1727, 1593, 1471, 1438,
1424, 1343, 1306, 1248, 1188, 1068, 1036, 921, 826, 735 cm−1; LRMS
(ESI): 287 (M + H)+; HRMS (ESI): calcd for C17H23N2O2 (M + H)+:
287.1754, found: 287.1763.
1H), 6.46 (d, J = 9.3 Hz, 1H), 5.47 (d, J = 4.7 Hz, 1H), 2.86 (dd, J1 =
17.8 Hz, J2 = 5.3 Hz, 1H), 2.74 (d, J = 13.3 Hz, 1H), 2.42 (d, J = 18.3
Hz, 1H), 2.37 (m, 1H), 2.30 (dd, J1 = 13.3 Hz, J2 = 1.5 Hz, 1H), 2.06
(d, J = 17.9 Hz, 1H), 1.87 (d, J = 17.1 Hz, 1H), 1.69 (m, 1H), 1.54 (s,
3H), 1.66−1.50 (m, 2H), 1.47 (m, 1H), 1.26 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 165.1, 143.1, 140.5, 132.3, 126.0, 118.0, 118.0, 53.2,
47.8, 41.6, 40.4, 34.4, 29.5, 27.9, 25.2, 22.9; IR (thin film): 3296, 2925,
2854, 1655, 1614, 1553, 1456, 1406, 1376, 1310, 1123, 1097, 836, 736,
652 cm−1; LRMS (ESI): 257 (M + H)+; HRMS (ESI): calcd for
C16H21N2O (M + H)+: 257.1648, found: 257.1653. Data for 41: mp
252−254 °C; [α]2D5 −88.6 (c = 0.33, CHCl3); H NMR (400 MHz,
1
CDCl3): δ 7.64 (d, J = 9.6 Hz, 1H), 6.48 (d, J = 9.6 Hz, 1H), 2.98 (dd,
J1 = 18.6 Hz, J2 = 6.5 Hz, 1H), 2.74 (br d, J = 13.3 Hz, 1H), 2.48 (d, J
= 18.6 Hz, 1H), 2.38 (t, J = 12.3 Hz, 1H), 2.11−1.99 (m, 3H), 1.67−
1.41 (m, 8H), 1.32−1.28 (m, 1H), 0.61 (d, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 165.0, 144.0, 140.5, 119.2, 117.8, 52.9, 46.9,
43.6, 41.1, 38.7, 32.5, 30.4, 27.9, 26.0, 25.6, 22.6; IR (thin film): 3302,
2922, 2851, 1660, 1621, 1552, 1464, 1325, 1261, 1135, 1097, 967, 866
cm−1; LRMS (ESI): 259 (M + H)+; HRMS (ESI): calcd for
C16H23N2O (M + H)+: 259.1805, found: 259.1810.
(5S,10bR)-8-Methoxy-12-methyl-2,3,5,6-tetrahydro-1H-
10b,5-prop[1]eno-1,7-phenanthroline (39). To a solution of 35
(30 mg, 104 μmol) in N,N-dimethylacetamide (1 mL) was added
SOCl2 (30 μL, 0.42 mmol) at room temperature. The mixture was
stirred at this temperature for 9 h and then poured into a saturated
aqueous solution of Na2CO3 and extracted with CH2Cl2 three times.
The combined organic layers were dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The residue was
purified via flash chromatography on silica gel (hexane/EtOAc = 3/1)
to give 39 (24 mg, 84%) as a colorless oil: [α]2D7 148.5 (c = 1.05,
(4aS,6R,7aR,12bS)-10-Methoxy-6-methyl-1,2,3,4,6,7,7a,8-oc-
tahydro-6,12b-methanofuro[2,3-e][1,7]phenanthroline (42).
To a solution of alkene 35 (10 mg, 0.035 mmol) in CH2Cl2 (0.5
mL) was added trifluoromethanesulfonic acid (3.1 μL, 0.035 mmol).
The mixture was allowed to stir at room temperature for 20 h and then
poured into a saturated aqueous solution of Na2CO3 and extracted
with CH2Cl2 three times. The combined organic layers were dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The residue was purified via flash chromatography on silica
gel (EtOAc) to give ether 42 (2.0 mg, 20%) as a colorless solid along
with recovered starting material 35 (7.0 mg, 70%): mp 153−154 °C;
1
CHCl3); H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.2 Hz, 1H),
6.50 (d, J = 8.2 Hz, 1H), 5.59 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 1H), 5.28
(s, 1H), 3.86 (s, 3H), 3.28 (dd, J1 = 18.6 Hz, J2 = 8.3 Hz, H-6), 2.95
(m, 2H), 2.79 (d, J = 18.6 Hz, H-6), 2.65 (ddd, J1 = 13.6 Hz, J2 = 10.0
Hz, J3 = 4.2 Hz, 1H), 2.50 (dd, J1 = 17.8 Hz, J2 = 6.3 Hz, H-8), 2.11
(m, 1H), 2.07 (d, J = 17.8 Hz, H-8), 1.88 (m, 1H), 1.59 (s, 3H), 1.50
(br, 1H); 13C NMR (100 MHz, CDCl3): δ 162.0, 155.6, 140.8, 133.8,
133.4, 133.0, 131.0, 115.4, 107.2, 54.3, 53.3, 42.7, 42.2, 39.3, 36.2, 26.2,
22.8; IR (thin film): 2908, 2829, 1590, 1578, 1471, 1422, 1325, 1308,
1269, 1189, 1114, 1073, 944, 828, 665 cm−1; LRMS (ESI): 269 (M +
H)+; HRMS (ESI): calcd for C17H21N2O (M + H)+: 269.1648, found:
269.1646.
(5R,10bR)-12-Methyl-2,3,5,6-tetrahydro-1H-5,10b-prop[1]-
eno-1,7-phenanthrolin-8(7H)-one (40). Alkene 39 (24 mg, 88
μmol) was dissolved in 1.0 M aqueous HBr (2 mL), and the solution
was refluxed for 10 h and then cooled to room temperature. Saturated
aqueous NaHCO3 was added, and the mixture was extracted with
dichloromethane three times. After drying over anhydrous Na2SO4,
the solution was concentrated under reduced pressure, and the residue
was purified by flash chromatography (DCM/MeOH = 10/1) to
1
[α]2D4 −36.8 (c = 0.7, CHCl3); H NMR (400 MHz, CDCl3): δ 8.00
(d, J = 8.6 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.07−2.92
(m, 2H), 2.81−2.72 (m, 1H), 2.35−2.25 (m, 1H), 2.18−2.08 (m, 1H),
2.03 (td, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H), 2.02−1.93 (m, 1H), 1.75−1.57
(m, 4H), 1.52−1.43 (m, 2H), 1.43 (s, 3H), 1.33 (dd, J1 = 12.0 Hz, J2 =
5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 162.6, 150.8, 137.6,
128.3, 108.7, 81.3, 80.5, 62.4, 59.2, 53.2, 44.3, 41.7, 41.6, 33.5, 26.4,
24.1, 21.1; IR (thin film): 2928, 2862, 1598, 1576, 1473, 1421, 1342,
1316, 1135, 1116, 1033, 1002, 876, 828, 739, 637 cm−1; LRMS (ESI):
287 (M + H)+; HRMS (ESI): calcd for C17H23N2O2 (M + H)+:
287.1754, found: 287.1751.
(4aS,5R,10bS)-8-Methoxy-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-5,10b-prop[1]eno-1,7-phenanthrolin-4a-ol (43). To a
solution of alkene 35 (260 mg, 0.91 mmol) in CH2Cl2 (5 mL) was
I
dx.doi.org/10.1021/jo402419h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
added Crabtree’s catalyst (36 mg, 0.045 mmol). Then the mixture was
allowed to stir at room temperature under balloon pressure of H2 for 5
days. The solvent was removed under reduced pressure, and the
residue was subjected to column chromatography on silica gel
(EtOAc/MeOH = 5/2) to give alkene 43 (255 mg, 98%) as a
CD3OD): δ 173.0, 134.7, 132.2, 123.8, 107.8, 68.2, 63.6, 42.3, 41.7,
38.2, 33.0, 31.0, 30.0, 22.7, 20.2, 20.0; IR (thin film): 3225, 2924, 2852,
1691, 1663, 1559, 1436, 1384, 1330, 1304, 1266, 1209, 1112, 1040,
1008, 816, 732, 697 cm−1; LRMS (ESI): 275 (M + H)+; HRMS (ESI):
calcd for C16H23N2O2 (M + H)+: 275.1754, found: 275.1756.
colorless oil: [α]2D6 +40.0 (c = 0.7, CHCl3); H NMR (400 MHz,
1
CDCl3): δ 7.81 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 5.41 (d, J
= 5.0 Hz, 1H), 3.90 (s, 3H), 3.10 (dd, J1 = 18.0 Hz, J2 = 5.7 Hz, 1H),
2.82−2.72 (m, 2H), 2.46 (t, J = 5.4 Hz, 1H), 2.36 (td, J1 = 13.1 Hz, J2
= 2.9 Hz, 1H), 2.33 (br s, 2H), 2.26 (d, J = 17.8 Hz, 1H), 1.91 (qt, J1 =
12.9 Hz, J2 = 4.5 Hz, 1H), 1.79 (d, J = 17.3 Hz, 1H), 1.68 (td, J1 = 13.1
Hz, J2 = 4.3 Hz, 1H), 1.64−1.57 (m, 1H), 1.55 (s, 3H), 1.42−1.34 (m,
1H); 13C NMR (100 MHz, CDCl3): δ 162.6, 152.7, 137.1, 132.6,
128.7, 123.5, 108.8, 68.0, 57.6, 53.3, 44.8, 41.7, 40.9, 37.1, 29.7, 22.9,
22.8; IR (thin film): 3396, 2927, 2849, 1599, 1571, 1482, 1428, 1325,
1266, 1099, 1029, 823, 760, 625, 558 cm−1; LRMS (ESI): 287 (M +
H)+; HRMS (ESI): calcd for C17H23N2O2 (M + H)+: 287.1754, found:
287.1758.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of related compounds, X-
ray structure for 30, and CD spectrum for huperzine U (3).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: bfsun@sioc.ac.cn.
*E-mail: lingq@sioc.ac.cn.
(4aS,5R,10bS)-4a-Hydroxy-12-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-5,10b-prop[1]eno-1,7-phenanthrolin-8(7H)-one (46).
An oven-dried sealed tube under an atmosphere of Ar was charged
with alkene 43 (108 mg, 0.378 mmol), LiI (355 mg, 1.89 mmol), TEA
(1.04 mL, 7.55 mmol), and toluene (4 mL). The mixture was allowed
to stir at 140 °C for 7 h. Then the solvent was removed under reduced
pressure, and the residue was dissolved in MeOH. The insoluble solid
was filtered, and the MeOH was removed under reduced pressure. The
residue was purified via flash chromatography on silica gel (EtOAc/
MeOH = 5/1) to give pyridone 46 (85 mg, 83%) as a colorless oil. (If
the starting material reacted with LiI without TEA, the byproduct 47
Author Contributions
†R.D. and J.-G.F. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (21172246, 21290180), the National Basic Research
Program of China (973 Program, 2010CB833206), and the
State Key Laboratory of Bioorganic and Natural Products
Chemistry is greatly appreciated. We also thank Prof. Chang-
Heng Tan (Shanghai Institute of Materia Medica, CAS) and
Prof. Hao-Yang Wang and Prof. Jing-Wu Kang (Shanghai
Institute of Organic Chemistry, CAS) for helpful discussions.
could be formed.) Data for 46: [α]2D4 −14.8 (c = 1.25, MeOH); H
1
NMR (400 MHz, CD3OD): δ 7.79 (d, J = 9.5 Hz, 1H), 6.41 (d, J = 9.5
Hz, 1H), 5.35 (d, J = 5.1 Hz, 1H), 2.91 (dd, J1 = 17.9 Hz, J2 = 5.5 Hz,
1H), 2.73 (dt, J1 = 13.5 Hz, J2 = 2.1 Hz, 1H), 2.48 (d, J = 17.7 Hz,
1H), 2.38−2.23 (m, 3H), 1.94 (qt, J1 = 13.1 Hz, J2 = 4.3 Hz, 1H), 1.69
(d, J = 16.6 Hz, 1H), 1.66 (dd, J1 = 13.3 Hz, J2 = 4.3 Hz, 1H), 1.56 (s,
3H), 1.52 (d, J = 13.6 Hz, 1H), 1.42−1.34 (m, 1H); 13C NMR (100
MHz, CD3OD): δ 165.5, 143.9, 141.9 133.6, 132.9, 121.1 118.2, 68.3,
57.7, 44.2, 42.1, 41.7, 33.2, 31.0, 23.3, 22.7; IR (thin film): 3277, 2923,
2852, 1656, 1611, 1553, 1456, 1377, 1261, 1188, 1091, 1014, 801, 736,
626 cm−1; LRMS (ESI): 273 (M + H)+; HRMS (ESI): calcd for
C16H21N2O2 (M + H)+: 273.1598, found: 273.1604. Data for 47: [α]2D5
−10.5 (c = 0.25, CHCl3); 1H NMR (400 MHz, CD3OD): δ 7.67 (d, J
= 9.5 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H), 5.35 (d, J = 5.0 Hz, 1H), 2.97
(dd, J1 = 17.9 Hz, J2 = 5.5 Hz, 1H), 2.91 (br s, 1H), 2.84 (s, 3H),
2.63−2.52 (m, 4H), 2.38 (t, J = 5.3 Hz, 1H), 2.05−1.90 (m, 1H), 1.91
(d, J = 16.7 Hz, 1H), 1.71−1.59 (m, 1H), 1.61 (s, 3H), 1.51 (d, J =
13.1 Hz, 1H), 1.37−1.29 (m, 1H); 13C NMR (100 MHz, CD3OD): δ
165.0, 142.7, 141.0, 132.0, 122.5, 121.3, 117.3, 68.8, 60.2, 49.5, 41.0,
39.6, 39.5, 32.7, 30.6, 23.1, 20.3; IR (thin film): 3374, 2961, 2923,
2851, 1656, 1611, 1552, 1459, 1376, 1261, 1097, 1023, 864, 800, 735,
703, 617 cm−1; LRMS (ESI): 287 (M + H)+; HRMS (ESI): calcd for
C17H23N2O2 (M + H)+: 287.1754, found: 287.1761.
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J
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