Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy

Article abstract of DOI:10.1002/anie.201607832

A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exo hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring-forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22-hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural-product-like molecules. We believe that this method and the small-molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products.

Full text of DOI:10.1002/anie.201607832

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607832
German Edition: DOI: 10.1002/ange.201607832
Cascade Reactions
Hot Paper
Total Synthesis of Camptothecin and Related Natural Products by
a Flexible Strategy
Ke Li, Jinjie Ou, and Shuanhu Gao*
Abstract: A flexible strategy for constructing natural products
containing indolizinone or quinolizinone scaffolds and their
analogues was developed, which was based on a cascade
exo hydroamination followed by spontaneous lactamization.
This method was applied in the total synthesis of camptothecin
in nine steps in a new ring-forming approach. It was also used
to efficiently prepare five biogenetically or structurally related
natural alkaloids, including 22-hydroxyacuminatine, oxypal-
matine, norketoyobyrine, naucleficine, and nauclefine, as well
as 35 natural-product-like molecules. We believe that this
method and the small-molecule library prepared with it can
open new avenues for studying the bioactivity of camptothecin
and Nauclea natural products.
munity and the pharmaceutical industry have made signifi-
cant efforts in chemical synthesis[3] as well as bioactivity and
mechanistic studies[2,3au,4] of CPT for cancer chemotherapy.
However, initial drug development studies with CPT failed
because of its poor solubility and severe, unpredictable
toxicity.[5] Subsequent structural modifications of CPT have
led to the commercially available anticancer drugs topotecan
(Hycamtin, 3; Figure 1a),[6] belotecan (4),[7] and irinotecan
(Camptosar, 5)[8] as well as several CPT analogues that are
anticancer drug candidates.
We herein report the development of a flexible strategy
for the efficient synthesis of CPT and biogenetically or
structurally related natural products, including 22-hydroxy-
acuminatine (6),[9] oxypalmatine (8),[10] norketoyobyrine
(11),[11] naucleficine (12),[12] and nauclefine (13).[13] This
strategy is based on a cascade cyclization reaction for the
construction of the indolizinone or quinolizinone scaffold (B/
C or C/D rings). We thus generated a small library of natural-
product-like molecules for future bioactivity studies.
CPT (1; Figure 1a) contains a highly conjugated pentacy-
clic skeleton with quinoline (A/B rings), indolizinone (C/D
rings), and a-hydroxylactone moieties (E ring).[14] 22-Hy-
droxyacuminatine (6) and CPT differ in the E ring, which is
a substituted arene ring in 6. We reasoned that taking the
indolizinone scaffold (C/D rings) as a point cut and expanding
the C ring by one carbon atom should lead to a large family of
alkaloid-containing quinolizinones (Figure 1b) differing pri-
marily in the various fused aromatic or heteroaromatic rings
connected to the quinolizinone moiety (7–14). Compounds
11–14 belong to a large family of indoloquinolizidine-type
alkaloids isolated from Nauclea latifolia plants, which are
traditionally used in ethnomedicine.[15] Extracts and com-
pounds isolated from different parts of this plant, most likely
indoloquinolizidine alkaloids,[13,16] exhibit a broad spectrum
of bioactivities.
Camptothecin (CPT, 1; Figure 1a) was isolated by Wani and
Wall in 1966[1] from the bark and stem of Camptotheca acu-
minata (“Xi Shu”), a plant native to China. This natural
alkaloid potently inhibits tumor growth by binding to top-
oisomerase I, preventing DNA religation. The resulting DNA
damage leads to cell apoptosis.[2] Both the academic com-
We reasoned that both indolizinone (5/6-membered ring
system, I) and quinolizinone (6/6-membered ring system, II)
scaffolds could be effectively constructed from substrate III
by cascade cyclization (Scheme 1). This process would involve
Figure 1. The camptothecin family and structurally related natural
products.
À
a key hydroamination (C N bond formation) followed by
À
lactamization. We envisioned that C N bond formation could
be achieved by two pathways: 1) alkyne group activation with
p-Lewis acids or 2) alkyne group polarization by introduction
of conjugated electron-withdrawing groups. We predicted
that this cascade reaction would present two major chal-
lenges: 1) controlling the endo/exo regioselectivity of the
cyclization and 2) controlling the geometry of the cyclized
product to ensure subsequent lactamization. We aimed to use
a convergent approach in which III would be prepared from
the coupling components IV and V and ethynylsilane in
[*] K. Li, J. Ou, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical Pro-
cesses, School of Chemistry and Molecular Engineering
East China Normal University
3663N Zhongshan Road, Shanghai 200062 (China)
E-mail: shgao@chem.ecnu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607832.
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electron-withdrawing ester in 15b may polarize the alkyne
group through a conjugative effect, facilitating the desired
5-exo hydroamination.
To test this hypothesis, we treated 15a with TFA in DCM
at 08C, which afforded the primary amine trifluoroacetate.
This salt was dissolved in DCE, and K2CO3 (3 equiv) was
added to neutralize the excess TFA. Gold(I) catalysis using
PPh3AuNTf2 led to full consumption of the substrate but low
yields of the cyclized products rosettacin (18) and 19 (entry 7).
In the absence of gold catalyst, cyclization products were not
detected, even after 18 h (entry 8). In strong contrast, treating
the trifluoroacetate salt 15b with K2CO3 in methanol at 408C
generated rosettacin (18) in 74% yield (entry 9). The
cyclization proceeded with good regioselectivity; the
Scheme 1. Synthetic plan. EDG=electron-donating group, EWG=elec-
tron-withdrawing group.
Table 1: Optimization of the reaction conditions.[a]
Sonogashira coupling reactions. We predicted that
changing the coupling components IV and V would
allow for the facile preparation of various polycyclic
rings, making this synthetic strategy quite flexible.
With these considerations in mind, we began by
investigating the key cyclization reaction using 15a
and 15b as model substrates. These substrates were
efficiently prepared in four steps (see the Supporting
Information). We initially focused on pathway 1 by
taking advantage of previous reports on gold-cata-
lyzed carbon–heteroatom bond-forming reactions.[17]
As soft and carbophilic Lewis acids, Au complexes
have emerged as some of the strongest activators of
Entry Substrate Catalyst
Base
Solvent
t
Conv. Yield
[h] [%][b] [%][b]
1
2
3
4
5
6
15a
15a
15a
15a
15a
15a
PPh3AuNTf2
AgNTf2
[RhCl(cod)]2
Pt(NTf2)2
Cu(OTf)2
InBr3
–
–
–
–
–
–
DCE
DCE
DCE
DCE
toluene
DCE
18
18
20
18
6
20
8
32
16 (12), 17 (8)
16 (4), 17 (4)
16 (7)
À
C C triple bonds; they effectively coordinate to
53
100
100
16 (3), 17 (47)
16 (22), 17 (27)
17 (8), 18 (27)
19 (7)
À
various C C p-bonds, facilitating nucleophilic attack
by diverse functional groups.[18] We first screened
various cationic gold(I) complexes with different
phosphine ligands and anions for their ability to
promote the intramolecular hydroamination of 15a.
PPh3AuNTf2 (generated in situ from PPh3AuCl and
AgNTf2) gave the best result, furnishing a mixture of
regioisomers 16 (5-exo-cyclized product) and 17
(6-endo-cyclized product) in respective yields of
12% and 8% (Table 1, entry 1; see the Supporting
Information for more screening results). We inves-
tigated various transition-metal-based catalysts in
the hydroamination reaction, including AgNTf2,
[RhCl(cod)]2, Pt(NTf2)2, and Cu(OTf)2 (entries 2–
5).[19] The results were similar to those obtained with
gold catalysts.
6
7[c,d] 15b
8[c,d] 15b
9[d] 15b
10[d] 15b
11[d] 15b
12[d] 15b
PPh3AuNTf2 K2CO3
DCE
DCE
2
100
18 (6), 19 (3)
ND
–
–
–
–
–
K2CO3
K2CO3
18 100
MeOH 18 100
18 (74)
18 (43)
18 (10)
18 (77)
Na2CO3 MeOH 18 100
DBU MeOH 18 100
Cs2CO3 MeOH 18 100
[a] Conditions: Starting material (0.05 mmol, c=0.05 molLÀ1), 408C. [b] Deter-
mined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as the
internal standard. [c] With EtOH (5 equiv). [d] Conditions: 1) 15a, TFA, DCM, 08C,
2 h; 2) base, solvent, 408C. Boc=tert-butoxycarbonyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DCE=1,2-dichloroethane, DCM=dichloromethane, Tf=tri-
fluoromethanesulfonyl.
Based on these results, we postulated that the low reaction
conversion may be due to the Boc protecting group decreas-
ing the nucleophilicity of the primary amine, and that the low
regioselectivity of the cyclization might be due to the
interaction of the metal catalyst with the nitrogen atom of
the quinoline moiety. Interestingly, treatment of 15a with
InBr3 in DCE at 808C yielded the desired cyclized product
rosettacin (18)[20] in 27% yield (entry 6), together with the 6-
endo-cyclized products 17 (8% yield) and 19 (7% yield). We
realized that deprotection and lactamization occurred spon-
taneously after poorly regioselective hydroamination. We
concluded that substrate 15b (R = H) might be more suitable
than 15a for the formation of indolizinones. The ortho
6-endo-cyclized product was not detected. We further opti-
mized the reaction conditions by screening different bases
and solvents. Using the weaker base Na2CO3 or the stronger
base DBU reduced the yield (entries 10 and 11; see the
Supporting Information for more screening results). In the
end, we selected Cs2CO3 as the base for the cyclization
because of its better solubility in methanol (entry 12).
We then explored the scope and generality of the reaction
under the optimized conditions to obtain a library of
polycyclic indolizinones, including related natural products
such as 6 and their derivatives. We focused on the functional-
group tolerance and the properties of the two fragments (A
and B) that are connected to the alkyne. With a quinoline ring
2
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as fragment A and an arene ring as fragment B, we first tested
particular interest because it contains the basic skeleton of
the effect of the electron density of fragment B on the
reaction. The reaction was not affected by electron-donating
substituents (-OMe, -Me, -OCH2O-) and electron-withdraw-
ing substituents (-CO2Me, -F, -CF3) on the aryl ring (20–28,
Scheme 2). The desired cyclized products were obtained in
CPT at a lower oxidation state, making it potentially useful as
a synthetic precursor. When fragment B was a cyclohexene
ring, the regioselectivity of the cyclization changed, generat-
ing 33’ and 34’ as the major products by 6-endo cyclization.
When both fragments A and B were arene rings, substrates
bearing electron-donating or -withdrawing substituents
worked well in the cascade cyclization, yielding the corre-
sponding annulated products 35–38 in yields of 74–92%. It is
noteworthy that 22-hydroxyacuminatine (6) could be pre-
pared in a one-pot operation from its alkyne precursor
through the key cascade cyclization and deprotection in 70%
yield over three steps.
Next, we turned our attention to constructing natural
products with a quinolizinone scaffold, as well as analogues of
such molecules (Scheme 3). Cascade cyclization by 6-exo
hydroamination followed by spontaneous lactamization usu-
ally furnished the desired products smoothly in yields of 49–
98% under the optimized conditions. Oxypalmatine (8) was
efficiently prepared in a four-step sequence, and some
analogues with various substituents (40–44) were also pro-
duced. When fragment A was an indole, norketoyobyrine
(11), nauclefine (13), and related structures (45–48) were
generated in excellent yields through the same one-pot
cyclization. The cyclized product 47 could be transformed
into naucleficine (12) in 75% yield over two steps.[21] The
structures of these analogues were confirmed by X-ray
diffraction analysis of single crystals of 41 and 48. We also
tested reaction compatibility with substrates bearing quino-
line rings that are one-carbon homologues of the substrates
shown in Scheme 2. The corresponding cyclized products 49–
52 were obtained in acceptable yields. In a few cases,
cyclization proceeded mainly through the 7-endo pathway,
generating unusual 7-5 fused skeletons (53’–55’). The struc-
tures of these compounds were confirmed by X-ray analysis of
single crystals of 53’.[22]
Scheme 2. Scope of the cascade cyclization for the preparation of
polycyclic indolizinones. MOM=methoxymethyl.
good yields as single regioisomers. A naphthyl-substituted
substrate also reacted smoothly to give the desired product 29
in excellent yield. We then changed fragment B to a cyclo-
pentene or dihydropyran ring, and obtained the desired
products 30–32 in acceptable yields. The structure of 30 was
confirmed by X-ray analysis. The cyclized product 32 is of
Studies of the generality of the cascade cyclization showed
that in all cases, lactamization occurred spontaneously after
Scheme 3. Scope of the cascade cyclization for the preparation of polycyclic quinolizinones. DMS=dimethyl sulfide.
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intramolecular hydroamination. The regioselectivity of the
cyclization in most cases reflected the 5- or 6-exo pathway.
Based on these results, we postulate a mechanism for the
reaction (Scheme 4). The alkyne group is effectively polarized
by the ortho electron-withdrawing ester group, facilitating
reagent (NCCO2Et) to afford the b-keto ester intermediate,
which was efficiently transformed into enol triflate 58 in 73%
yield over two steps. Sonogashira coupling[24] between
2-chloroquinoline 59 and (trimethylsilyl)acetylene followed
by removal of the TMS group afforded terminal alkyne 61 in
88% over two steps. A second Sonogashira reaction was used
to couple fragments 58 and 61, which furnished the densely
functionalized alkyne 62 on large scale and in good yield.
Then the key cascade cyclization was tested to build the basic
skeleton of CPT. Treatment of compound 62 with trifluoro-
acetic acid in dichloromethane for 4 h yielded the Boc-
deprotected product. After azeotropic dehydration with
toluene, the free primary amine was dissolved in anhydrous
methanol and treated with cesium carbonate in the dark,
affording the desired pentacyclic structure 63 as a single
regioisomer in 76% yield. Compound 63 was transformed
into CPT through two pathways. Treatment of 63 with
trifluoromethanesulfonic acid (TfOH) in acetonitrile at
room temperature resulted in the formation of the known
advanced intermediate 64 in 95% yield. 64 was efficiently
converted into (+)-1 by Sharpless asymmetric dihydroxyla-
tion using (DHQD)2PYR as the ligand, followed by I2/
CaCO3-based hemiacetal oxidation, which was developed by
Chavan[3al] and Yao.[3ap] In the second pathway, acetal 63 was
hydrolyzed to semiacetal 66 under weakly acidic conditions at
408C, and 66 was easily obtained by Dess–Martin periodinane
oxidation to generate deoxycamptothecin (67) in 83% yield.
67 can be easily converted into (+)-1 by asymmetric
a-hydroxylation of the lactone as previously reported.[3ae]
In summary, we have developed a flexible strategy for
constructing indolizinone- or quinolizinone-containing skel-
etons. These intramolecular cyclizations involve a cascade
exo-type hydroamination followed by spontaneous lactam-
ization. This rationally designed cascade reaction occurs
under extremely mild conditions in the absence of transition
metals, and it provides good
À
C N bond formation through primary amine addition under
basic conditions. The resulting enamine adduct VI can
theoretically form with Z or E geometry. We speculate that
the Z olefin easily cyclizes to afford the desired indolizinone
or quinolizinone while the enamine with E geometry may
undergo lactamization through E/Z isomerization to form the
final products via imine intermediate VII.
Scheme 4. Proposed reaction process.
To further demonstrate the synthetic potential of this
method, we used this cascade cyclization as a key ring-
forming step in the total synthesis of CPT (1). The synthesis
commenced with the preparation of the coupling fragments,
vinyl triflate 58 and quinoline 61 (Scheme 5). Treatment of
the known b-hydroxyketone 56 with LDA and TMSCl
followed by SnCl4-promoted cyclization with triethyl ortho-
formate gave rise to acetal 57 in 39% yield over two steps.[23]
The resulting acetal 57 was treated with LDA and Manderꢀs
regioselectivity. The reac-
tion precursors can be effi-
ciently prepared from easily
available building blocks
through
a
convergent
approach, enabling the
divergent synthesis of vari-
ous substrates simply by
changing the coupling frag-
ments. This method also
provides a reliable, unified
approach for synthesizing
CPT and Nauclea natural
alkaloids, as shown by the
synthesis of six natural
products and 35 analogues.
Using this method, we ach-
ieved the total synthesis of
CPT (1) in nine steps in
Scheme 5. Total synthesis of camptothecin. a) LDA, TMSCl, THF, À788C to 258C; b) HC(OEt)3, SnCl4, CH2Cl2,
À788C, 39% over 2 steps; c) LDA, NCCO2Et, THF, À788C; d) KHMDS, THF, Comins reagent, À788C to
258C, 73% over 2 steps; e) Pd(PPh3)2Cl2, PPh3, CuI, Et3N, toluene, 258C; f) K2CO3, MeOH, 08C, 88% over
2 steps; g) Pd(PPh3)2Cl2, PPh3, CuI, Et3N, toluene, 608C, 91% brsm; h) TFA, CH2Cl2, 08C; then Cs2CO3,
MeOH, 258C, 76%; i) TfOH, MeCN, 258C, 95%; j) K2OsO2(OH)4, (DHQD)2PYR, K3Fe(CN)6, K2CO3,
CH3SO2NH2, t-BuOH, H2O, 08C; k) I2, CaCO3, MeOH, H2O, 408C, 81% over 2 steps; l) HCO2H, H2O, 408C,
82% brsm; m) DMP, CH2Cl2, 258C, 83%. brsm=based on recovered starting material, DMP=Dess–Martin
periodinane, KHMDS=potassium bis(trimethylsilyl)amide, LDA=lithium diisopropylamide, TFA=trifluoro-
acetic acid, TMS=trimethylsilyl.
a
novel
ring-forming
approach. We believe that
this approach, together with
the small-molecule library
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these studies will be reported in due course.
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Acknowledgements
We thank the National Basic Research Program of China (973
Program 2015CB856600) and the National Natural Science
Foundation of China (21272076, 21422203) for generous
financial support.
Keywords: camptothecin · hydroamination · indolizinones ·
quinolizinones · total synthesis
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(53’) contain the supplementary crystallographic data for this
Received: August 11, 2016
Published online: && &&, &&&&
6
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Communications
Cascade Reactions
K. Li, J. Ou, S. Gao*
&&&& — &&&&
Total Synthesis of Camptothecin and
Related Natural Products by a Flexible
Strategy
Natural products containing indolizinone
or quinolizinone moieties and analogues
thereof were obtained by a cascade exo
hydroamination followed by spontaneous
lactamization. This method was applied
to the total synthesis of camptothecin in
nine steps and to efficiently prepare five
biogenetically or structurally related nat-
ural alkaloids.
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7
These are not the final page numbers!