A Concise Enantioselective Total Synthesis of (?)-Deoxoapodine

Article abstract of DOI:10.1002/anie.202010759

We have established a highly convergent 10-step route for the total synthesis of (?)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid

Full text of DOI:10.1002/anie.202010759

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Accepted Article
Title: A Concise Enantioselective Total Synthesis of (–)-Deoxoapodine
Authors: Kei Yoshida, Kosuke Okada, Hirofumi Ueda, and Hidetoshi
Tokuyama
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10.1002/anie.202010759
Angewandte Chemie International Edition
COMMUNICATION
A Concise Enantioselective Total Synthesis of (–)-Deoxoapodine
Kei Yoshida,+ Kosuke Okada,+ Hirofumi Ueda, and Hidetoshi Tokuyama*
Abstract: We established a highly convergent 10-step route for total
synthesis of (–)-deoxoapodine, which is a hexacyclic aspidosperma
alkaloid. The quaternary carbon center at C5 on the characteristic
tetrahydrofuran ring was constructed via a chiral phosphoric acid-
We designed a convergent route by dissecting 1 into two
segments through a quebrachamine type precursor (6 or 7).
During this process, disconnection of C12–C19 bond gave the
quebrachamine analog (6 or 7). Then, this analog broke down
into indole-3-acetic acid (8) and a bicyclic THF-fused piperidine
segment 9 (Scheme 1A). To realize this highly convergent route
to 1, three major synthetic challenges should be addressed:
oxidative transannular reaction to form C12–C19 bond,[10]
assembly of the quebrachamine skeleton possessing highly
strained bridged 9-membered ring,[11] and asymmetric synthesis
of bicyclic THF-fused piperidine segment.
catalyzed enantioselective bromocycloetherification in
a 5-endo
fashion and subsequent allylation by using Keck’s protocol. The
aspidosperma skeleton was constructed featuring the formation of 9-
membered lactam by catalytic C–H palladation/alkylation cascade at
the indole 2-position and the iron-catalyzed oxidative transannular
reaction at the late-stage of synthesis.
With these considerations in mind, we conducted
a
Over the last decades, aspidosperma alkaloids possessing
fused pentacyclic skeleton have attracted significant attention
from the synthetic community[1] as this family of compounds
displays remarkable structural diversity and constitutes clinically
retrosynthetic analysis of 1 (Scheme 1B). To realize the oxidative
transannular Mannich reaction at the indole C3 position of 6, a
broad range of oxidation protocols, such as the conditions of
using
a
stoichiometric oxidant,[10,12a] recently developed
important antitumor bisindole alkaloids, such as vinblastine.[2]
A
photoredox reactions,[12b] and the reaction in presence of non-
heme type iron catalyst,[13] were extensively screened. We
designed a cascade process to connect indole C2 position and
halogenated alkyl chain of substrate 13 for the formation of the
several congeners, including (–)-deoxoapodine (1) and (–)-
apodine (2), among these alkaloids, have oxygenated structure
at the C21 position. (–)-Deoxoapodine (1), isolated first from
Tabernae armeniaca and then from Hazunta modesta, has the
characteristic tetrahydrofuran (THF) ring fused to aspidosperma
skeleton.[3] Two bisindole alkaloids, vobtusine (4) and
voacandimine A (5), isolated from Voacanga africana Stapf
(Apocynaceae), are composed of two deoxoapodine segments
with two different modes of connectivity (Figure 1).[4] An
enantioenriched total synthesis[5] and two enantioselective total
syntheses[6,7] have so far been reported after the first racemic
total synthesis of 1 by Overman et al.[8] In this paper, we report a
Scheme 1. Retrosynthetic Analysis.
CO2H
A. Outline of Convergent Retrosynthesis
X
N
8
9
N
H
N
H
19
O
O
12
3
HN
2
N
H
N
H
CO2Me
(–)-deoxoapodine (1)
O
6, X = H2
7, X = O
X
convergent 10-step total synthesis of
enantioselective construction of contiguous C5 and C6 centers
via catalytic enantioselective 5-endo
bromocycloetherification,[9] formation of a highly strained bridged
9-membered ring through Pd-catalyzed C–H activation/alkylation
cascade at indole C2 position, and an iron-catalyzed oxidative
transannular reaction to form an aspidosperma skeleton.
1 by featuring an
B. Retrosynthetic Analysis
Late-Stage Oxidative
Transannular Reaction
a
(–)-deoxoapodine (1)
6
Reductive
Elimination
O
O
Oxidative
Addition
N
N
O
O
Figure 1. Aspidosperma Family Alkaloids
Ln
Pd
Ln
Pd
9
N
N
N
N
N
X
X
H
H
H
19
6
11
15
10
5
O
O
12
21
2
N
H
N
H
N
H
O
CO2Me
CO2Me
CO2Me
Ortho C-H
Palladation
(–)-deoxoapodine (1)
(–)-apodine (2)
(–)-tabersonine (3)
O
N
H
O
N
N
Amino
Palladation
O
O
MeO
O
N
N
H
N
2
H
HO
HO
N
H
N
H
3
13
N
H
N
H
X
H
H
X
H
PdXLn
O
O
O
8
N
H
N
H
5-endo
Bromo-
cyclization
CO2Me
vobtusine (4)
CO2Me
voacandimine A (5)
Keck
Allylation
HN
CbzN
CbzN
Br
H
[*]
Dr. K. Yoshida, M. K. Okada, Dr. H. Ueda, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba 6-3, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
H
6
5
O
O
OH
16
15
14
[+]
These authors contributed equally to this work.
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10.1002/anie.202010759
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Studies on Asymmetric Bromocyclization
highly strained bridged 9-membered ring in the quebrachamine
skeleton by applying Bach’s intermolecular C–H alkylation
condition of indole[14a] to the intramolecular version. This process
would start from nitrogen-assisted norbornene mediated ortho
C–H palladation at indole 2-position, followed by ring closure of
the highly strained bridged 9-membered ring via less strained
B1 18 (1.3 eq)
Cat (10 mol%)
Na2CO3 (4 eq)
CbzCl
NaHCO3
HN
CbzN
CbzN
H
O
solvent
temp., 24 h
1,4-dioxane/H2O
0 °C
Br
OH
OH
16
17
(–)-15
10-membered
palladacycle
and
subsequent
reductive
84%
Temp. Yield[a]
(°C)
ee
(%)
elimination. Substrate 13 would be assembled from indole-3-
acetic acid (8) and THF-fused piperidine segment 14. For an
asymmetric synthesis of the THF-fused piperidine segment, we
planned development of an enantioselective 5-endo
bromocycloetherification and subsequent quaternarization of C5
tertiary bromide by radical-mediated Keck allylation with
retention of the configuration.[15]
Our research commenced with studies on the asymmetric
bromocycloetherification using homoallylic alcohol 17. In
general, asymmetric halocycloetherification is difficult and rare
because coordination of alcohols to chiral Lewis bases by
formation of hydrogen bonding or ion pairing is relatively poorer
than that of carboxylic acids.[16] Moreover, almost all the cases
are using activated olefin such as a styrene derivative as
substrate and there are few examples of using a non-activated
olefin. Upon selection of a catalytic system, we focused on the
Toste’s chiral anion concept in phase-transfer catalytic reactions
and its application to bromocyclization of tryptophol by Ma and
Xie et al.[17] Thus, we treated substrate 17, which was derived
from the commercially available alcohol 16, with chiral anion
bromonium ion complex generated from a combination of (R)-
Entry
Catalyst
Solvent
(%)
1
2
(R)-Cat 1
(R)-Cat 2
(R)-Cat 3
(R)-Cat 4
(R)-Cat 5
(R)-Cat 6
(R)-Cat 7
(R)-Cat 8
(R)-Cat 9
(R)-Cat 7
(R)-Cat 7
(R)-Cat 7
(R)-Cat 7
(R)-Cat 7
(R)-Cat 7
(S)-Cat 7
PhMe
PhMe
0
14
–9
31
0
24
22
14
77
59
75
72
46
61
62
52
57
64
71
76
3
PhMe
0
–14
–3
4
PhMe
0
5
PhMe
0
52
6
PhMe
0
64
7
PhMe
0
70
8
PhMe
0
65
9
PhMe
0
–70
74
10
11
12
13
14
15[b]
16[c]
PhCl
0
PhF
0
74
PhF/n-hexane
PhF/n-hexane
0
79
–20
–20
–30
–30
80
PhF/n-heptane
PhF/n-heptane
PhF/n-heptane
81
84
–86
[a] Isolated yield. [b] Reaction time was 72 h. [c] The reaction was conducted
in two gram-scale and the reaction time was 120 h. Cbz
benzyloxycarbonyl.
a
=
binaphthyl-phosphoric acid (R)-Cat
1 and B1 (18) as a
Cat 1: R = R’ = H
Cat 2: R = SiPh3, R’ = H
6
3
R'
R'
R
bromonium ion source in toluene at 0 °C (Table 1, entry 1).
While the desired 5-endo bromocycloetherification product (–)-
15 was obtained, the yield and enantiomeric excess (ee) were
low. Cat 2-4 having bulky substituents at 3 and 3′ positions, were
not effective (entries 2–4). On the other hand, both chemical
yield and ee were dramatically improved by using Cat 5 and Cat
6 having bulkier 2,4,6-trisubstituted phenyl groups (entries 5 and
6) and were further improved by using Cat 7 having linear alkyl
chains at 6 and 6′ positions to afford 15 in 75% yield and 70% ee
(entry 7). Cat 8, having different scaffold than BINOL motif, gave
parallel result with that obtained with Cat 7 (entry 8). On the
other hand, Cat 9, which has a (R)-1,1′-spirobiindane skeleton,
provided (+)-15 with the opposite stereochemistry (entry 9).
Given the best result with Cat 7, further optimizations on solvent
and reaction temperature were carried out (entries 10–14).
Eventually, the desired bicyclic bromoether 15 was obtained at
best in 71% yield and 84% ee by the reaction in a 1:1 (v/v)
mixture of fluorobenzene and heptane at −30 °C (entry 15).
Conversion of (–)-15 into the final deoxoapodine revealed that
the absolute stereochemistry of (–)-15 was determined to be
opposite to that required for the synthesis of natural (–)-
deoxoapodine (1). Finally, reliability and scalability of this
catalytic enantioselective process was proved by a two-gram
scale reaction with excellent reproducibility (entry 16). Moreover,
we can recover Cat 7 in 90% yield and reuse without losing its
enantioselectivity.[18]
Cat 3: R = 2-naphthyl, R’ = H
Cat 4: R = anthracenyl, R’ = H
Cat 5: R = 2,4,6-i-Pr3C6H2, R’ = H
Cat 6: R = 2,4,6-Cy3C6H2, R’ = H
Cat 7: R = 2,4,6-Cy3C6H2, R’ = n-C8H17
O
O
O
P
OH
R
CF3
R
R
O
O
O
CF3
O
O
O
P
P
OH
N
OH
Cl
B1 (18)
R
R
N
Br2
Cat 8: R = 2,4,6-Cy3C6H2 Cat 9: R = 2,4,6-Cy3C6H2
mediated C–H activation/cyclization cascade. First, bromoether
(+)-15, which was obtained under the established optimal
conditions using (S)-Cat 7, was subjected to Keck’s allylation
condition[15] (Scheme 2). Desired allylation reaction proceeded
uneventfully with the retention of the configuration to produce 14
possessing the C5 quaternary carbon center. Ozonolysis of the
terminal alkene, followed by a reductive treatment, afforded
primary alcohol 19. After removal of benzyloxycarbonyl (Cbz)
group, the resultant secondary amine was condensed with
indole-3-acetic acid (8) produced amide 20. Finally, the desired
bromide 21 and iodide 22 were obtained by the corresponding
Appel reaction of primary alcohol 20.
With the indole substrate in hand, we examined the
formation of the highly strained bridged 9-membered lactam ring
by palladium catalyzed C–H activation/intramolecular alkylation
cascade (Scheme 2). First, bromide 21 was subjected to the
Bach’s intermolecular alkylation condition with PdCl2 and K2CO3
in the presence of norbornene at 80 °C.[14] Gratifyingly, the
Having established the catalytic enantioselective 5-endo
bromocycloetherification of non-activated olefin, we then
assembled the substrates 21 and 22 for testing the palladium-
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10.1002/anie.202010759
Angewandte Chemie International Edition
COMMUNICATION
designed cascade reaction proceeded to provide 9-membered
lactam 7 in 9% yield along with a formation of bromo-chloro
substitution product (entry 1). Use of PdBr2 was effective to
suppress the substitution reaction and significantly accelerate
the reaction to provide 7 in higher yield (entry 2). Switching
K2CO3 to K3PO4 further accelerated conversion of 21 (entry 3).
Afterwards, we found that iodide 22 was better substrate and the
reaction of 22 with PdI2 proceeded at 60 °C to give 7 in 38%
yield (entry 5). Extensive optimization led us to find that halide
scavengers, such as NaOTf,[19] NaNTf2, and KNTf2, were crucial
or high yielding reaction (entries 6–8). Thus, the yield of 7 was
dramatically improved up to 67% when iodide 22 was treated
with PdI2, K3PO4, KNTf2, and norbornene at 60 °C.[20] A control
experiment without norbornene did not gave the desired product
7
(entry 9), supporting that this reaction started from a
norbornene-induced amino palladation as shown in Scheme 1.
At this stage, the optical purity of lactam 7 was improved up to
>99% ee by recrystallization. Finally, reduction of lactam 7 by
alane furnished pentacyclic
quebrachamine skeleton.
We then focused our attention on the oxidative
transannular reaction. First, Kutney’s conditions[10] by using
Hg(OAc)2 was tested. However, the reaction only gave a
complex mixture and the expected aspidosperma skeleton was
not formed (Table 2, entry 1). Stephenson’s photoredox
condition[12b] by using Ru catalyst and bromomalonate resulted
in a decomposition of the starting material 6 (entry 2). The
reaction with iodine and sodium bicarbonate in acetonitrile[12a]
6 possessing the THF-fused
Scheme 2. Synthesis of 9-Membered Tertiary Amine
Table 2. Examination of Oxidative Transannular Mannich Reaction
O3
MeOH
–78 °C;
AIBN
allyl-SnBu3
MS4Å
N
N
19
H
CbzN
Br
CbzN
CbzN
HO
H
O
H
O
H
O
conditions
O
O
12
NaBH4
84%
PhH, reflux
92%
N
H
N
6
23
(+)-15
14
19
Temp. Time Yield[a]
Entry
Reagent (equiv)
Hg(OAc)2 (2.2)
Solvent
O
H2 (1 atm)
Pd(OH)2/C
THF/MeOH;
(°C)
(h)
(%)
N
CBr4, PPh3, CH2Cl2
rt to
reflux
1
2
3
AcOH
DMF
24
0
O
or
CO2H
I2, PPh3
imidazole, CH2Cl2
N
H
N
8
Ru(bpy)3Cl2 (0.10)
bromomalonate (3.0)
H
OH
50
0
24
0
6
20
DMT-MM, 99%
I2 (3.0)
sat. aq. NaHCO3
MeCN
0.5
Pd catalyst (30 mol%)
Base (2 equiv)
norbornene (2.2 equiv)
Additive (3.0 equiv)
O
X
N
N
t-BuOH
/H2O
4
5
K3Fe(CN)6 (10)
0
2
1
6
0
O
O
DMF/DMSO/H2O
80 °C (X = Br) or
60 °C (X = I);
N
N
H
n-Bu4NBF4
2.5 F/mol, 30 mA
H
X
MeOH
rt
AlCl3
LiAlH4
THF, 99%
7 (X = O)
6 (X = H2)
X = Br 21 (88%)
then recrystallization
I
22 (90%)
Schrodi-Grubbs
Catalyst (0.10)
6
7
8
EtOAc
DCE
70
60
rt
24
2
0
Additive
Pd
catalyst
Time Yield[a]
Entry
X
Base
(h)
(%)
AcOH (10), O2 (1 atm)
13
22
1
2
Br
Br
PdCl2 K2CO3
PdBr2 K2CO3
–
–
120
9
Fe(R,R-PDP) (0.15)
H2O2 (3.6)
t-BuOH
3
28
28
3
Br
PdBr2 K3PO4
PdBr2 K3PO4
–
20
23
17
48
48
10
10
27
31
38
48
55
67
Fe(S,S-PDP) (0.15)
H2O2 (3.6)
9
t-BuOH
t-AmOH
t-AmOH
rt
rt
rt
0.3
3
38
4[b]
5[b]
6[b]
7[b]
8[b]
9[b,c]
I
I
I
I
I
I
–
Fe(S,S-PDP) (0.03)
H2O2 (3.0)
35
(42)[b]
10
11
PdI2
PdI2
PdI2
PdI2
PdI2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
NaOTf
NaNTf2
KNTf2
KNTf2
Fe(S,S-PDP) (0.03)
TBHP (3.0)
0.5
33
[a] Isolated yield. [b] Based on recovered 6 (16%). bpy = bipyridine, DCE =
1,2-dichloroethane, PDP = bis(2-pyridinylmethyl)-2,2’-bipyrrolidine.
2+
2Cl
2+
2SbF6
0[d]
N
Ru
N
N
Fe
N
N
N
N
N
N
N
NCMe
NCMe
[a] Isolated yield. [b] DMA was used instead of DMF. [c] Norbornene was not
used. [d] The starting material 22 was recovered in 61% yield. AIBN =
azobisisobutyronitrile, MS = molecular sieves, DMT-MM = 4-(4,6-dimethoxy-
o-tolN
No-tol
Cl
Cl
Ru
PCy3
Ph
1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride,
DMF
=
N,N-
dimethylformamide, DMSO = dimethyl sulfoxide, Tf = trifluoromethanesulfonyl,
DMA = N,N-dimethylacetamide.
Schrodi-Grubbs
Catalyst
Fe(S,S-PDP)
Ru(bpy)3Cl2
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10.1002/anie.202010759
Angewandte Chemie International Edition
COMMUNICATION
and oxidation conditions by using potassium ferricyanide[21] gave
the desired product 23, although the yield was only 6% (entries
3 and 4). Next, an electrochemical condition[22] and the aerobic
oxidation with Grubbs catalyst developed by our group[23] were
examined. In both cases, the starting material 6 was completely
consumed, however, the desired product 23 was not obtained
(entries 5 and 6). Interestingly, acetic acid-promoted aerobic
oxidation of 6 provided 23 in 13% yield (entry 7).[24] Furthermore,
non-heme type iron catalyst, such as Fe(R,R-PDP) and H2O2, as
oxidant was effective to promote the oxidative intramolecular
Mannich reaction to provide aspidosperma skeleton 23 in 22%
yield (entry 8).[25] Interestingly, we observed the match–
mismatch combination between substrate and catalyst. Thus,
Fe(S,S-PDP) improved the yield of 23 up to 38% and
substantially shortened the reaction time (entry 9). The catalyst
loading of Fe(S,S-PDP) could be reduced to 3 mol% by using t-
AmOH as solvent without losing the chemical yield of 23 (entry
10). Use of tert-butyl hydroperoxide (TBHP) instead of H2O2
accelerated the reaction (entry 11). The established optimal
conditions (entry 10) were applicable to a half gram-scale
reaction.[26] Finally, methoxy carbonyl group was introduced via a
metalloenamine as intermediate to afford a sub-gram quantity
(260 mg) of (–)-deoxoapodine (1) (Scheme 3).
JP18H04642 in Hybrid Catalysis, a Grant-in aid for Scientific
Research (B) (18H02549) and (C) (17K08204).
Keywords: total synthesis · alkaloid · haloetherification · C-H
functionalization · oxidation
[1]
For selected examples of total synthesis of aspidosperma alkaloids,
see: a) G. Stork, J. E. Dolfini, J. Am. Chem. Soc. 1963, 85, 2872–2873;
b) J. Harley-Mason, M. A Kaplan, Chem. Commun. 1967, 915–916; c)
J. P. Kutney, N. Abdurahman, C. Gletsos, P. Le Quesne, E. Piers, I.
Vlattas, J. Am. Chem. Soc. 1970, 92, 1727–1735; d) F. E. Ziegler, G.
Bennett, J. Am. Chem. Soc. 1971, 93, 5930–5931; e) Y. Ban, T.
Ohnuma, M. Nagai, Y. Sendo, T. Oishi, Tetrahedron Lett. 1972, 13,
5023-5026; f) T. Gallagher, P. Magnus, J. Huffman, J. Am. Chem. Soc.
1982, 104, 1140–1141; g) M. E. Kuehne, D. E. Podhorez, J. Org. Chem.
1985, 50, 924–929; h) S. A. Kozmin, V. H. A Rawal, J. Am. Chem. Soc.
1998, 120, 13523–13524; i) S. Kobayashi, G. Peng, T. Fukuyama,
Tetrahedron Lett. 1999, 40, 1519–1522; j) G. D. Wilkie, G. I. Elliott, B.
S. J. Blagg, S. E. Wolkenberg, D. R. Soenen, M. M. Miller, S. Pollack,
D. L. Boger, J. Am. Chem. Soc. 2002, 124, 11292–11294; k) I.
Coldham, A. J. M. Burrell, L. E. White, H. Adams, N. Oram, Angew.
Chem., Int. Ed. 2007, 46, 6159–6162; l) S. B. Jones, B. Simmons, A.
Mastracchio, D. W. C. MacMillan, Nature 2011, 475, 183–188; m) L.
McMurray, E. M. Beck, M. J. Gaunt, Angew. Chem. Int. Ed. 2012, 51,
9288–9291; n) S .Zhao, R. B. Andrade, J. Am. Chem. Soc. 2013, 135,
13334–1337; o) O. Wagnières, Z. Xu, Q. Wang, J. Zhu, J. Am. Chem.
Soc. 2014, 136, 15102–15108; p) P. W. Tan, J. Seayad, D. J. Dixon,
Angew. Chem., Int. Ed. 2016, 55, 13436–13440; q) For a selected
review, see: J. M. Saya, E. Ruijter, R. V. A. Orru, Chem. Eur. J. 2019,
25, 8916–8935.
Scheme 3. Total Synthesis of (–)-Deoxoapodine
N
N
sec-BuLi;
H
H
NCCO2Me
10 steps
(8.6%)
O
O
[2]
a) “The Aspidosperma Alkaloids”: G. A. Cordell, in The Alkaloids,
Chemistry and Physiology, Vol. 17 (Eds.: R. H. F. Manske, R. G. A.
Rodrigo,), Academic Press, New York, 1979, pp. 199–384; b) “Alkaloids
of the Aspidospermine Group”: J. E. Saxton, in The Alkaloids,
Chemistry and Biology, Vol. 51 (Ed.: G. A. Cordell,), Academic Press,
San Diego, 1998, pp. 1–197. For selected reviews on synthetic studies,
see: c) “Synthesis of the Aspidosperma Alkaloids”: J. E. Saxton, in The
Alkaloids, Chemistry and Biology, Vol. 50 (Ed.: G. A. Cordell,),
Academic Press, San Diego, 1998, pp. 343–376.
THF
–78 °C to rt
N
N
H
260 mg
CO2Me
(–)-deoxoapodine (1)
23
86%
synthetic 1: [α]D26 = –497 (c = 0.56, CHCl3)
natural 1: [α]D25 = –432 (c = 0.76, CHCl3)Ref. 3
In summary, we accomplished a concise total synthesis of
(–)-deoxoapodine (1) in overall 10 steps[26] and with 8.6% yield.
This successful synthesis relied on the design of a highly
convergent route by utilizing direct formation of C12–C19 bond
and C2–C3 bond based on the development of two C–H
functionalization protocols and the early-stage construction of
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Acknowledgements
This work was supported by the Drug Discovery and Life
Science Research (BINDS) from AMED under Grant Number
JP19am0101100 and JSPS KAKENHI Grant Numbers
JP18H04379 in Middle Molecular Strategy, JP18H04231 in
Precisely Designed Catalysts with Customized Scaffolding, and
[10] For construction of aspidosperma skeleton by transannular Mannich
reaction via oxidation of C12 position was only limited to Kutney’s
protocol using highly toxic Hg(OAc)2, which resulted in a low yield and
Ziegler’s preliminary experiment (Ref. 1d) using Pt/O2 (yield not
reported). No alternative method has been developed over the half
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besides the desired product. Other oxidation conditions gave trace
amount of side products due to oxidation of indole skeleton of the
substrate and over-oxidation of the tertiary amine moiety or indole
moiety of the desired product. These observations indicated that Fe-
PDP conditions promoted further oxidative degradations triggered by
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[26] See, the Supporting Information.
[27] The efficiencies of our total synthesis (10 total steps: 10 steps in
longest linear sequence (LLS)) could be recognizable by comparison
with those in the previous total syntheses, i.e., Overman’s synthesis (24
total steps: 21 steps in LLS), Boger’s synthesis (23 total steps: 19 steps
in LLS), Movassaghi’s synthesis (22 total steps: 17 steps in LLS),
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[20] When the reaction was conducted on a gram scale, the yield was
decreased to a modest yield, see the Supporting Information.
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Entry for the Table of Contents
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Dr. Kei Yoshida, M. Kosuke Okada, Dr.
Hirofumi Ueda, and Prof. Dr. Hidetoshi
Tokuyama*
Page No. – Page No.
Title: A Concise Enantioselective Total
Synthesis of (–)-Deoxoapodine
A highly convergent 10-step route for total synthesis of (–)-deoxoapodine was
established. The quaternary carbon center at C5 on the characteristic
tetrahydrofuran ring was constructed via
a chiral phosphoric acid-catalyzed
enantioselective bromocycloetherification in a 5-endo fashion and subsequent
allylation by using Keck’s protocol. The aspidosperma skeleton was constructed
featuring the formation of 9-membered lactam by catalytic C–H palladation/alkylation
cascade at the indole 2-position and the iron-catalyzed oxidative transannular
reaction at the late-stage of the synthesis.
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