Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

Article abstract of DOI:10.1038/nchem.1798

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

Full text of DOI:10.1038/nchem.1798

ARTICLES
PUBLISHED ONLINE: 24 NOVEMBER 2013 | DOI: 10.1038/NCHEM.1798
Biogenetically inspired synthesis and skeletal
diversification of indole alkaloids
Haruki Mizoguchi1, Hideaki Oikawa1 and Hiroki Oguri1,2
*
To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing
a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a
polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic
strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of
scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent
intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties
without structural simplification of naturally occurring alkaloids. Three distinct modes of [412] cyclizations and two types
of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-,
aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from
tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (+)-vincadifformine,
(+)-andranginine and (2)-catharanthine.
atural products often bear a variety of functional groups
In the biosynthetic assembly line, protection of the labile inter-
on a rigid, architecturally complex and sp3-rich skeleton, a mediates in an enzyme catalytic site provides kinetic stabilization
N
configuration that allows specific molecular recognition and regulation of multimodal reactivity, allowing cascade synthesis
through multipoint interactions to modulate the functions of with control of chemo-, regio-, stereo- and even enantioselectivity.
target biomacromolecules. Chemical synthesis of natural products In principle, each evolved enzyme has a tailored fit that contributes
and their analogues could provide optimum screening collections to the catalysis of a particular mode of a skeleton-constructing
for the development of drug candidates with higher hit rates and transformation16. Accordingly, the participation of a series of
lower probabilities of side effects1–3. Although some innovative syn- similar but functionally distinct biomacromolecular catalysts is
thetic approaches have been recently reported to provide efficient required for skeletal diversification. Meanwhile, the chemical
access to such molecules as specific modulators of challenging bio- emulation of divergent biogenic processes without the assistance
logical targets4–11, a potentially general strategy for the development of biomolecular catalysts17 poses challenges in areas including (1)
of divergent synthetic processes to produce assortments of skeletally the stabilization of labile intermediates during handling in
diverse and densely functionalized scaffolds remains elusive and the laboratory, (2) the concise and flexible assembly of building
needs to be formulated.
blocks, and (3) the systematic implementation of various intra-
When working towards the total synthesis of a natural product molecular cyclization reactions through site-selective activation of
composed of complex cyclic arrays, chemists usually develop a polyunsaturated substrates while suppressing competitive reactions.
customized synthetic approach for the individual targeted scaffold. In this study, we aimed to formulate a chemical strategy to not
In contrast, biosynthetic machinery often exploits a common only build a bioinspired assembly line, but also to achieve
intermediate, conducting divergent transformations to furnish systematic diversification of the skeletal and stereochemical
assortments of architecturally distinct skeletons. For example, a properties of multicyclic scaffolds without structural simplification
biogenetic hypothesis for monoterpene indole alkaloids is outlined of the natural products involved. Herein, we report the successful
in Fig. 112, where multistep enzymatic transformations commence development of a divergent synthetic process that generates an
with the assembly of tryptamine 1 and secologanin 2 to produce unprecedented level of skeletal variation of monoterpene
preakuammicine 3. Cleavage of two C–C bonds in the central indole alkaloids.
core of 3 generates the hypothetical key intermediate dehydroseco-
dine 4, composed of a pair of diene units, a dihydropyridine (DHP) Results and discussion
and a vinylindole. Intermediate 4 may undergo divergent Diels– Design of the divergent synthetic process. To explore a
Alder-type reactions in either of two ways, with the DHP group biogenetically inspired synthetic approach, we turned our
serving as a dienophile or diene to form the aspidosperma-type attention to the dehydrosecodine 4. Unfortunately, hypothetical
alkaloid tabersonine 5 (path A) or the iboga-type catharanthine 6 intermediate 4 has not been isolated or synthesized, presumably
(path B)13. In addition, a distinct biosynthetic [4þ2] cyclization is because the DHP unit of 4, which contains an ethyl substituent,
postulated for andranginine 7 (path C), involving an intermediate may be labile to oxidation and oligomerization. In this study,
bearing a cross-conjugated triene with a higher oxidation level we designed the artificial pluripotent intermediate 14 with the
than 4 (ref. 14). The architectural complexity as well as the skeletal intention of stabilizing the polyunsaturated system, by
variation of the cognate alkaloids could be pre-encoded into the installing an electron-withdrawing carbonyl group in place of the
polyunsaturated structure of the achiral intermediate 4, defining ethyl substituent (Fig. 2a). In addition, the attachment of
a branching point of the biogenesis15.
various substituents to the carbonyl group could modify the
1Division of Chemistry, Graduate School of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan, 2Japan Science and
Technology Agency (JST) PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan. e-mail: oguri@sci.hokudai.ac.jp
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
Multistep
enzymatic
N
Me
H
NH2
H
transformations
N
Me
OH
CO2Me
N
H
N
H
H
N
H
Tryptamine: 1
Preakuammicine: 3
Ngouniensine: 8
+
CHO
H
OGlu
Ring-cleavage
H
O
MeO2C
Secologanin: 2
Hypothetical intermediate
N
Me
Path A
Path C
NH
CO2Me
Oxidation?
Dehydrosecodine: 4
Path B
Enzyme A
Enzyme B
Enzyme C
N
N
N
HN
N
H
N
H
Me
CO2Me
Me
CO2Me
MeO2C
[4+2] cyclizations
H
N
N
N
H
Aspidosperma
Me
Iboga
Me
HN
N
H
N
H
CO2Me
CO2Me
MeO2C
Tabersonine: 5
Catharanthine: 6
Andranginine: 7
Figure 1 | Proposed biogenesis of indole alkaloids 5–7 and structure of ngouniensine 8. A hypothetical common intermediate, dehydrosecodine (4) could
be biosynthesized through multistep enzymatic transformations starting from union of tryptamine (1) and secologanin (2). A pair of diene units in 4, DHP
and a vinylindole are thought to be installed through cleavage of two C–C bonds in the central core of an intermediate (3). Divergent [4þ2] cyclizations of 4
would form the aspidosperma-type alkaloid tabersonine (5, path A) or the iboga-type catharanthine (6, path B). A distinct biosynthetic [4þ2] cyclization is
postulated for andranginine (7, path C), involving an intermediate bearing a cross-conjugated triene.
reactivity of the DHP unit for systematic implementation of of tryptamine 1 with methyl 3-bromo-2-oxopropanoate 9 and pro-
intramolecular cyclizations with control of regio- and pargyl bromide 10.
stereoselectivity. We devised three types of bioinspired [4þ2]
cyclizations of 14, leading to 15–17, by manipulating the Development of Cu(I)-catalysed cyclization to form the DHP
DHP unit conjugated with the carbonyl group. Redox activations ring. With this strategic planning in mind, we first sought to
of the DHP unit of 14 were also explored to achieve distinct develop an expedient protocol for the conversion of ene-yne 13 to
modes of annulation to furnish either the tetracyclic framework the DHP–vinylindole intermediate 14 (Fig. 2b). Although
18 of ngouniensine 8 (ref. 18) or the unnatural skeleton 19. We approaches to the synthesis of substituted pyridines via the
also conceived
an auxiliary to the carbonyl group to accomplish explored19–21, protocols for obtaining DHP rings via metal-
enantioselective synthesis.
catalysed 6-endo cyclization of N-propargyl enaminocarbonyls are
a late-stage chiral induction by attaching oxidation of temporarily formed DHPs have been relatively well
The sensitive DHP unit in intermediate 14 should be formed just limited22,23. In our system, rapid construction of the 1,6-DHP ring
before the divergent cyclization reactions. Retrosynthetically, che- was required under very mild conditions so as not to cause
moselective activation of the alkynyl group in ene-yne 13 would further intra- and intermolecular reactions of the elaborate p-
allow 6-endo cyclization to afford 14. With the intention of flexibly conjugated systems in 14. As shown in Fig. 2b, investigation using
incorporating a series of enaminocarbonyl moieties into the precur- the model substrate 20 allowed us to identify the optimum
sors, we devised a union of tricycle 11 with an ethynylcarbonyl com- conditions, which use a cationic Cu(I) catalyst as an efficient
pound 12, accompanied by Hofmann elimination, to generate the alkyne activator. Upon treatment of 20 with a catalytic amount
acyclic intermediate 13 containing a vinylindole unit. Tricyclic 11, (10 mol%)
of
[Cu(dppf)(MeCN)]PF6
(ref.
24)
in
a b-amino-acid derivative, should be readily available by assembly dichloromethane, 6-endo cyclization proceeded smoothly within
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
a
Common intermediate
[4+2] cyclizations
N
N
N
R
R
Cu(I)
O
O
N
R
DHP
synthesis
H
N
H
CO2Me
CO2Me
N
O
CO2Me
H
Iboga-type: 15
13
DHP-vinylindole: 14
Modular assembly
N
H
Redox-mediated cyclizations
N
HN
MeO2C
R
R
O
N
O
H
CO2Me
11
O
N
H
R
N
H
H
Aspidosperma-type: 16
Me
CO2Me
12
Ngouniensine-type: 18
H
O
N
N
R
OR'
O
NH2
N
N
H
H
H
H
CO2Me
CO2Me
Br
CO2Me
N
Andranginine-type: 17
Br
H
Unnatural-type: 19
1
9
10
b
6
[Cu]+
[Cu(dppf)(MeCN)]PF6
(10 mol%)
N
N
1,6-DHP
N
3
CH2Cl2, r.t.
60 min
N
97%
N
H
CO2Me
CO2Me
H
CO2Me
20
21
Figure 2 | Outline of a biogenetically inspired synthetic process to furnish alkaloidal scaffolds. a, Synthetic strategy for a divergent process featuring
reactivity modulation of an achiral polyunsaturated intermediate (14) through manipulation of the carbonyl group conjugated with the DHP unit. Modular
assembly of tryptamine (1) and building blocks (9, 10 and 12) followed by cyclization of ene-yne (13) would allow rapid and flexible access to the common
intermediate (14). Three distinct modes of bioinspired [4þ2] cyclizations could produce assortments of naturally occurring scaffolds (15–17). Distinct modes
of annulations were devised through redox activations of the DHP unit to furnish either the tetracyclic framework 18 of ngouniensine or the unnatural
skeleton (19). b, Rapid formation of 1,6-DHP ring using Cu(I) catalysis. The optimum conditions for the 6-endo cyclization of ene-yne were explored using the
model substrate (20). dppf, 1,1′-bis(diphenylphosphino)ferrocene.
60 min at room temperature to afford the desired 1,6-DHP 21 in was prone to gradual dimerization under concentrated conditions,
97% yield without affecting the non-protected indole or the it was used directly in subsequent conversions, without
resulting DHP ring located in the vicinity.
chromatographic purification in most cases.
Synthesis of a precursor for DHP cyclization, ene-yne 13a. Bioinspired divergent [412] cyclization reactions. The formation
Having developed a sensible approach to the formation of the 1,6- of DHP–vinylindole intermediate 14 and the implementation of a
DHP ring, we synthesized ene-yne 13a, bearing a vinylindole unit, series of [4þ2] cyclization reactions were explored next (Fig. 3).
from tryptamine 1 in five steps (Fig. 3). A Pictet–Spengler Upon treatment of a crude mixture containing 13a with
reaction of 1 with 9 and subsequent ring expansion gave 22, [Cu(dppf)(MeCN)]PF6 (10 mol%) at 60 8C,
a cascade of
based on a reported protocol25. Reduction of 22 with sodium reactions—DHP formation (13a ꢀ 14a) and a subsequent Diels–
cyanoborohydride in acetic acid and subsequent N-propargylation Alder-type reaction—proceeded smoothly in one pot to produce
produced 11a in 61% yield (two steps). Simultaneous installation iboga-type 23 in 48% yield from 11a. The streamlined synthesis
of the enaminoester group and the gem-substituted vinylindole of the iboga skeleton, possessing an additional carbonyl functional
unit was efficiently achieved upon treatment of 11a with methyl group, was achieved in six steps from 1 without protection
propiolate 12a to furnish 13a. Presumably,
a zwitterionic of the indole group. In contrast, for substrates bearing a
intermediate would be capable of causing regioselective Hofmann tert-butoxylcarbonyl (Boc) group or a simple methyl substituent
elimination spontaneously. The use of 2,2,2-trifluoroethanol as a at the indole N1 position, the same conversion produced only
co-solvent with 1,2-dichloroethane was critical in gaining single- trace amounts of the corresponding iboga-type cycloadducts,
step access to 13a in greater than 80% yield. As the ene-yne 13a whereas Cu(I)-catalysed DHP formation took place efficiently
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
1)
O
1) NaBH3CN, AcOH, r.t.
Br
2) 10, Et3N, K2CO3,
acetone, r.t.
MeO2C
MeOH, reflux
2) Pyridine, reflux
NH
9
NH2
· HCl
61% (2 steps)
N
H
N
CO2Me
H
22
1•HCl
O
N
N
N
OMe
O
R2
12a/12b
+
H
COR2
12a
ClCH2CH2Cl
CF3CH2OH
N
R1
O
CO2Me
H
N
R1
CO2Me
CO2Me
Me
11a: R1 = H
11b: R1 = Boc
11c: R1 = Teoc
(Boc)2O
Me3Si
13a: R1 = H, R2 = OMe, 80%
Teoc-Im
12b
13b: R1 = Boc, R2 = OMe, 89% (from 11a)
13c: R1 = Teoc, R2 = Me, 59% (from 11a)
N
N
DHP
One-pot
[Cu(dppf)(MeCN)]PF6
cyclization
N
H
N
H
ClCH2CH2Cl
CO2Me
CO2Me
60 °C
O
OMe
14a
CO2Me
48% (from 11a)
Iboga-type: 23
Common intermediates
in situ generation
5
N
H
4
X
N
1) Pd/C, H2, MeOH,
r.t., 70% (from 13b)
2) Et3N, hydroquinone
N
X
R2
HN
N
CO2Me
O
R1
MeO2C
CO2Me
toluene/ClCH2CH2Cl
180 °C, 61%
MeO2C
N
R1
Aspidosperma-type
CO2Me
24b: R1 = Boc
25a: X = CH, 25b: X = CH2
14a: R1 = H, R2 = OMe
14b: R1 = Boc, R2 = OMe
14c: R1 = Teoc, R2 = Me
H
N
N
1) TBAF, THF, r.t.
O
OSiiPr3
N
H
OTIPS
2) TIPSOTf, iPr2NEt
Me3Si
N
O
N
H
OMe
26c
O
CO2Me
ClCH2CH2Cl, r.t.
N
Teoc-Im
29% (from 13c)
Andranginine-type: 27
Figure 3 | Unified synthetic process for divergent access to 23, 25 and 27 through distinct [412] cyclization reactions. Pictet–Spengler reaction of
tryptamine (1) with 9 and subsequent ring expansion produced 22. Reduction followed by N-propargylation gave 11a. Assemblies of 11 with ethynylcarbonyl
unit (12) could generate a zwitterionic intermediate effecting Hofmann elimination to afford ene-yne (13). Cu(I)-catalysed cyclization of 13a followed by
[4þ2] cyclization allowed a streamlined synthesis of iboga-type scaffold 23. The aspidosperma-type scaffold 25b was synthesized through regioselective
hydrogenation of 14b and a different [4þ2] cyclization. A distinct [4þ2] cyclization was realized through conversion of 14c into silylenol
ether (26c) to produce andranginine-type scaffold (27). Boc, t-butoxycarbonyl; Teoc, 2-(trimethylsilyl)ethoxycarbonyl; Im, imidazole; dppf,
1,1′-bis(diphenylphosphino)ferrocene; DHP, dihydropyridine; TBAF, tetra-n-butylammonium fluoride; TIPSOTf, triisopropylsilyl trifluoromethanesulfonate.
regardless of the indole substituent (see Supplementary (TBSOTf) at low temperature (see Supplementary Information).
Information). It is likely that the contribution of hydrogen To suppress the formation of the iboga-skeleton as well as oxidation
bonding between the indole NH and the carbonyl oxygen of the of the DHP ring, we were obliged to protect the indole nitrogen and
a,b-unsaturated methylester in 14a not only increased the also to reduce the C4–C5 double bond in the DHP ring. Protection
electrophilicity of the dienophile but also fixed the conformation of 11a with a Boc group and subsequent assembly of 11b with 12a
appropriately for cyclization to form the iboga-skeleton 23.
via Hofmann elimination gave ene-yne 13b in good yields.
We next aimed to achieve a distinct mode of [4þ2] cyclization Cu(I)-catalysed DHP formation and subsequent site-selective
leading to the aspidosperma-skeleton 25 (Fig. 3). Despite extensive hydrogenation of the resulting 14b provided isolable tetrahydropyr-
efforts to activate 14a with various Lewis/Brønsted acids and idine 24b in 70% yield (two steps). Microwave-assisted heating of
bases, formation of the iboga-skeleton 23 and oxidation to pyridi- 24b at 180 8C with hydroquinone (a polymerization inhibitor)
nium salts predominantly occurred. The aspidosperma-skeleton and triethylamine26 effected thermal decomposition of the Boc
25a was obtained, in less than 5% yield, only when 14a was carefully group followed by [4þ2] cyclization, giving rise to the aspidosperma
treated with tert-butyldimethylsilyl trifluoromethanesulfonate skeleton 25b in 61% yield.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
O
N
[Ru(bpy)3](BF4)2
N
OMe
2
12a
2BF4
CO2Me
H
CF3CH2OH
ClCH2CH2Cl
N
RuII
N
N
H
CO2Me
N
N
N
N
N
CO2Me
H
13a
11a
[Cu(dppf)(MeCN)]PF6
Common intermediate
in situ generation
One-pot
visible light
CO2Me
CO2Me
CO2Me
One-pot
Me
[Ru(bpy)3](BF4)2
N
N
N
6
ClCH2CH2Cl
120 °C
CH2Cl2/MeNO2
r.t.
N
H
N
OMe
H
N
H
H
CO2Me
CO2Me
14a
O
21% (from 13a)
8-endo
57% (from 11a) 7-endo
120 °C
40–60 °C
N
Retro-Diels–Alder
CO2Me
N
H
CO2Me
N
N
H
N
H
N
H
H
H
CO2Me
CO2Me
Me
CO2Me
CO2Me
Ngouniensine-type: 28
Iboga-type: 23
Unnatural-type: 29
Figure 4 | Redox-mediated activation of the DHP–diene 14a leading to tetracyclic 28 and 29, which contain a DHP ring. The common intermediate (14a)
generated from 11a was subjected to either two- or single-electron oxidation process to produce 28 and 29, respectively. Upon heating at 120 8C,
ngouniensine-type scaffold 28 was obtained as the major product. The involvement of the retro-Diels–Alder reaction (23 ꢀ 14a) and a hydride shift,
followed by 7-endo-cyclization of a zwitterionic intermediate, were postulated in the formation of 28. Single-electron oxidation of 14a provided an
unnatural-type tetracycle 29 presumably via 8-endo-radical cyclization. bpy, 2,2′-bipyridine; dppf, 1,1′-bis(diphenylphosphino)ferrocene.
Our attention then turned to achieving a distinct [4þ2] annula- cyclization of 14a, we first envisaged two-electron oxidation of the
tion via intermediate 26c to yield the andranginine-type compound DHP ring to generate a pyridinium species. Indeed, when the
27 (Fig. 3). To this end, we examined the installation of a methyl- reaction mixture for the conversion of 13a to 14a was heated to
ketone group into the versatile intermediate 14 to generate the 120 8C, a distinct annulation of 14a took place predominantly,
cross-conjugated triene 26c through silylenol ether formation. giving tetracyclic 28 in good yield (57% from 11a). The tetracyclic
Cu(I)-catalysed 6-endo cyclization of the corresponding ene-yne array of 28 is identical to the framework of naturally occurring
13 bearing the methylketone group, however, required gentle ngouniensine (8)27. The relative configuration of 28 was
heating at 45 8C to form the DHP ring. From a practical point of elucidated based on X-ray analysis of the crystalline equivalents
view, protection of the indole nitrogen should be beneficial in sup- (see Supplementary Information). Taking into account the
pressing competitive cyclization leading to the iboga skeleton and experimental results for the conversions of deuterium-labelled 14a
other side reactions. In fact, protection with a 2-(trimethylsilyl)- (Supplementary Schemes 1, 2), 28 could presumably be formed
ethoxycarbonyl (Teoc) group (11a ꢀ 11c) ensured the stabilities through a hydride shift generating a zwitterionic intermediate
of 13c and 14c upon conversion of 11c into 14c. The tricycle 11c composed of a pyridinium cation and an enolate anion, which
and 4-trimethylsilyl-3-butyne-2-one 12b were efficiently assembled would undergo subsequent 7-endo cyclization28. In contrast to the
via Hofmann elimination to give the desired 13c with the loss of a identical conversion of 13a into 14a under gentle heating at 60 8C
trimethylsilyl group. The resulting 13c was subjected to sequential yielding the iboga-skeleton 23 as the major product (Fig. 3), 23
operations—Cu(I)-catalysed DHP formation at 45 8C, producing was not obtained at all at 120 8C. We thus postulated the
14c, and removal of the Teoc group with tetrabutylammonium fluo- involvement of a retro-Diels–Alder reaction. When isolated 23
ride (TBAF), followed by treatment with triisopropylsilyl trifluoro- was heated to 120 8C, as expected, we observed the consumption
methanesulfonate (TIPSOTf) at room temperature—to generate the of 23 and the formation of 28 as the major product (47%, see
silylenol ether 26c. The desired mode of [4þ2] cyclization of 26c Supplementary Information). It seems probable that the retro-
occurred spontaneously to furnish the andranginine-type scaffold Diels–Alder reaction of kinetically formed 23 regenerates the
27 (29% for three steps from 13c). Thus far, we have implemented DHP–vinylindole intermediate 14a at the elevated temperature.
three distinct bioinspired Diels–Alder-type cyclization reactions of Hydride transfer and subsequent cyclization may occur
intermediates (14a, 24b and 26c), leading to a series of alkaloidal irreversibly to furnish ngouniensine-type 28.
scaffolds (23, 25b and 27).
We next envisioned single-electron oxidation of the 1,6-DHP
ring in 14a to generate a carbon-centred radical species. Because
Redox-mediated cyclization reactions leading to 28 and 29. photo-redox synthetic processes often use 1-benzyl-1,4-dihydro-
Further skeletal diversifications were then explored through redox nicotinamide (BNAH) with a 1,4-DHP system as a versatile
activation of the DHP unit (Fig. 4). To achieve an alternative reductant29–31, 14a was treated with a photo-redox catalyst,
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
a
1) SO3·pyridine
DMSO/iPr2NEt
r.t., quant.
N
N
H2
N
N
H
DIBAL
Pd/C
H
H
H
HN
HN
MeO2C
THF
–78 ° to 0 °C
87%
HN
MeO2C
HN
Me
MeOH, r.t.
77%
OH 2) Ph3P CH3Br
NaHMDS, THF
0 °C, 59%
CO2Me
MeO2C
( )-vincadifformine: 32
MeO2C
25b
30
31
b
H
H
H
Pd(PPh3)4
HCO2H
Et3N, DMF
46% (2 steps)
N
N
CsF, PhN(Tf)2
N
OTf
OTIPS
N
MeOCH2CH2OMe
N
H
H
CO2Me
CO2Me
CO2Me
33
27
X-ray: 7
( )-andranginine: 7
Me
Me
c
Me
Me
O
N
O
N
O
O
[Cu(dppf)(MeCN)]PF6
N
AcOH
N
N
N
+
O
CH2Cl2, r.t.
67%
H
ClCH2CH2Cl, 45 °C
48%
O
N
O
N
Me
N
H
H
O
CO2Me
H
O
CO2Me
34
CO2Me
Me
11a
35
12c
N
1) DIBAL, THF
N
N
Fe(acac)3
MeMgBr
O
P
CeCl3
–78 °C, 64%
Me
N
CO2Me
OPh
O
N
H
MeOH, r.t.
80%
N
H
2) (PhO)2P(O)Cl
THF, –60 °C
H
OPh
CO2Me
39%
Et3N, CH2Cl2
r.t., 81%
CO2Me
CO2Me
(–)-catharanthine: (–)-6
36
37
Figure 5 | Total synthesis of three natural products. a, Site-selective reduction of methylester (25b) followed by oxidation of the resulting primary alcohol
and Wittig elongation gave 31. Site-selective hydrogenation of 31 afforded (+)-vincadifformine (32). b, Direct conversion of silylenol ether (27) to vinyl
triflate (33) and subsequent palladium-catalysed reduction furnished (+)-andranginine (7). c, Hofmann elimination triggered by addition of 11a to 12c gave
34. After Cu(I)-catalysed formation of a DHP ring, the critical [4þ2] cyclization reaction proceeded with complete diastereocontrol in one pot to produce 35.
Removal of the chiral auxiliary, site-selective reduction of 36, and conversion into an allylic phosphate 37 followed by Fe-catalysed cross-coupling with
MeMgBr accomplished asymmetric total synthesis of (2)-catharanthine (6). DIBAL, diisobutylaluminium hydride; NaHMDS, sodium hexamethyldisilazide;
Tf, trifluoromethanesulfonyl; dppf,1,1′-bis(diphenylphosphino)ferrocene; acac, acetylacetonate.
[Ru(bpy)3](BF4)2, at 0 8C under irradiation with fluorescent light vinyl group. Site-selective hydrogenation of 31 gave rise to
(12 W). The tetracyclic scaffold 29, not found in naturally occurring vincadifformine 32 in 77% yield.
alkaloids, was obtained, albeit in low yield (21%), which may have
Next, the conversion of pentacycle 27 to andranginine 7 was
been consistent with our intention to conduct a redox-mediated accomplished by trimming an additional functional group in two
8-endo cyclization. Oxidative activations of 14a in either a two-elec- steps (Fig. 5b). Direct conversion of silylenol ether 27 to vinyl triflate
tron or a single-electron process produced tetracycles (28 and 29) 33 (ref. 36) and subsequent palladium-catalysed reduction
bearing a DHP ring in their fused scaffolds, which could provide furnished 7 in good yield. X-ray analysis of crystalline 7 confirmed
a versatile platform for further diversification. In this way, we illus- its relative configuration, which was identical to the proposed
trated the systematic generation of skeletally diverse scaffolds (23, 25 structure of andranginine37. This is the first example of de novo
and 27–29) relevant to naturally occurring indole alkaloids within total synthesis of the almost disregarded natural product 7, in 11
six to nine steps from tryptamine 1.
steps38, which lends experimental support to an alternative mode
of biosynthetic Diels–Alder-type cyclization diverging from the
Total synthesis of three natural products. To highlight the hypothetical intermediate 4.
applicability and efficiency of the divergent synthetic process, we
We then performed enantioselective total synthesis of cathar-
sought to achieve total syntheses of (+)-vincadifformine (32), anthine 6 (Fig. 5c). To illustrate late-stage asymmetric induction
(+)-andranginine (7) and (2)-catharanthine (6) (Fig. 5). Because through attachment of a chiral auxiliary to the DHP ring, ene-yne
the aspidosperma-type scaffold 25b bears the requisite functional 34 with an oxazolidinone group was synthesized by exploiting the
array of (+)-vincadifformine 32 (Fig. 5a), we carried out a total modular nature of the assembly line. Hofmann elimination trig-
synthesis to confirm its structure (see Supplementary Information gered by the addition of 11a to 12c proceeded efficiently under
for precedent total syntheses of 32)5,32–35. The more sterically modified conditions to produce 34 in 67% yield with the loss of a
hindered methyl ester in 25b was reduced site-selectively by stereogenic centre in racemate 11a. Upon treatment of 34 with
simple treatment with diisobutylaluminium hydride (DIBAL) to the Cu(I) catalyst (15 mol%) at 45 8C, a cascade transformation
furnish primary alcohol 30 in 87% yield. Oxidation of 30 and afforded the desired 35 in 48% yield with complete diastereocontrol
subsequent Wittig elongation produced 31, which contains a of the critical [4þ2] cyclization reaction. Removal of the chiral
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1798
ARTICLES
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Received 4 June 2013; accepted 11 October 2013;
published online 24 November 2013
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Acknowledgements
The authors dedicate this manuscript to Masahiro Hirama on the occasion of his 65th
birthday. The authors thank Y. Fujimura (Shionogi & Co.) and T. Matsumoto (Rigaku
Corporation) for performing X-ray analyses. This work was supported by JSPS KAKENHI
(grant no. 23310156 to H. Oguri) and in part by the Naito Foundation and the Science and
Technology Research Partnership for Sustainable Development Program (SATREPS) of the
Japan Science and Technology Agency (JST). The authors acknowledge a fellowship for
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to H. Oguri.
´
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Competing financial interests
The authors declare no competing financial interests.
8
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