Total Syntheses of (-)-Mersicarpine, (-)-Scholarisine G, (+)-Melodinine E, (-)-Leuconoxine, (-)-Leuconolam, (-)-Leuconodine A, (+)-Leuconodine F, and (-)-Leuconodine C: Self-Induced Diastereomeric Anisochronism (SIDA) Phenomenon for Scholarisine G and Leu

Article abstract of DOI:10.1021/jacs.5b03619

(Chemical Equation Presented) Enantioselective total syntheses of title natural products from a common cyclohexenone derivative (S)-18 were reported. Ozonolysis of (S)-18 afforded a stable diketo ester (R)-17 that was subsequently converted to two skeleta

Full text of DOI:10.1021/jacs.5b03619

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Article
Total Syntheses of (-)-Mersicarpine, (-)-Scholarisine G, (+)-Melodinine
E, (-)-Leuconoxine, (-)-Leuconolam, (-)-Leuconodine A, (+)-Leuconodine
F and (-)-Leuconodine C. Self-Induced Diastereomeric Anisochronism
(SIDA) Phenomenon for Scholarisine G, Leuconodines A and C
Zhengren Xu, Qian Wang, and Jieping Zhu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 May 2015
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Page 1 of 15
Journal of the American Chemical Society
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Total Syntheses of (-)-Mersicarpine, (-)-Scholarisine G, (+)-
Melodinine E, (-)-Leuconoxine, (-)-Leuconolam, (-)-
Leuconodine A, (+)-Leuconodine F and (-)-Leuconodine C.
Self-Induced Diastereomeric Anisochronism (SIDA) Phe-
nomenon for Scholarisine G, Leuconodines A and C.
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Zhengren Xu, Qian Wang and Jieping Zhu*
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne (Switzerland)
Supporting Information
ABSTRACT: Enantioselective total syntheses of title natural products from a common cyclohexenone derivative (S)-18
were reported. Ozonolysis of (S)-18 afforded a stable diketo ester (R)-17 that was subsequently converted to two skele-
tally different natural products, ie, (-)-mersicarpine (8) with a [6.5.6.7] fused tetracyclic ring system and (-)-
scholarisine G (9) with a [6.5.6.6.5] fused pentacyclic skeleton, respectively. The post-cyclization diversification was
realized by taking advantage of the facile conversion of (+)-melodinine E (6) to N-acyliminium ion 7, from which a
hydroxy group was selectively introduced to the C6, C7, C10 and the central C21 position of diazafenestrane system,
leading to (-)-leuconodine A (11), (+)-leuconodine F (12), (-)-scholarisine G (9), (-)-leuconodine C (13) and skeletally
different (-)-leuconolam (5). Furthermore, an unprecedented non-natural oxabridged oxadiazafenestrane 68 was
formed by oxidation of (+)-melodinine E (6). During the course of this study, a strong self-induced diastereomeric an-
isochronism (SIDA) phenomenon was observed for scholarisine G (9), leuconodines A (11) and C (13). X-ray structures
of both the racemic and the enantiopure natural products 9, 11, and 13 were obtained. The different crystal packing of
1
these two forms nicely explained the chemical shift differences observed in the H NMR spectra of the racemic and the
enantio-enriched compounds in an achiral environment.
INTRODUCTION
tion/Reduction/Cyclization (iORC) process that com-
pletely re-organized cyclopentene derivatives to the
polycyclic skeletons of targeted natural products. By
imposing certain geometric constraints into the iORC
substrates, we demonstrated that it is possible to con-
trol the chemo- and stereo-selectivity of the complex
domino process to deliver specifically the desired natu-
ral product.
The monoterpene indole alkaloids represent an im-
portant family of natural products for their potent bio-
activities and structural diversities. Until now, over
1
2000 members with more than 42 different skeletons
2
are known. Despite the structural complexity and di-
versity, they are uniformly made by nature’s biosyn-
thetic machineries from strictosidine (1), which is in
turn produced by fragment coupling of two simple
building blocks, tryptamine (2) and secologanin (3) by
To further explore the synthetic potential of this con-
cept in natural product synthesis, we became interested
in addressing following two additional criteria that
nature has used extensively in their biosynthesis ma-
3
way of the Pictet-Spengler reaction (Scheme 1a). In-
spired by nature’s simple logic, namely couple and
divert, for making skeletally diverse alkaloids, we initi-
ated a research program aimed at mimicking the bio-
synthetic philosophy of nature at strategic level by
using the synthetic tools available in the laboratory. As
6
chineries for structural diversification: a) to reach
condition-controlled diversification from the same
intermediate rather than the substrate-controlled cy-
clization; b) to reach structural diversity by selectively
converting one intermediate/natural product to a series
of natural products with different skeletons and/or
different oxidation states. Towards this goal, the group
of leuconolam-leuconoxine-mersicarpine alkaloids
4
a proof-of-concept, we recently accomplished total
synthesis of vincadifformine (4), goniomitine and
5
kopsihainanine A, three polycyclic natural products
with different ring connectivities and stereochemistry,
from readily accessible intermediates. Two key steps
characterized our approaches: a) a Pd-catalyzed decar-
boxylative coupling between phenyl acetate derivatives
and vinyl triflates; b) an integrated Oxida-
7
belonging to the Aspidosperma sub-family was chosen
8
to showcase our strategy.
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Scheme 1. Logic for the Synthesis of Monoterpene Indole Alkaloids: a) Nature’s Strategy; b) Our Ap-
proach
1
2
Fragment Coupling
Cyclization
Post-Cyclization
3
4
5
6
CHO
NH2
+
O
O
OGlc
HO
4
H
N
N
H
O
N
OH
N
7
MeO2C
21
N
1
7
8
N
2 Tryptamine
3 Secologanin
N
O
O
O
H
O
9 (-)-Scholarisine G
(-)-Leuconodine B
9
10 (-)-Leuconoxine
5 (-)-Leuconolam
H+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
OGlc
O
O
N
O
O
HO
H
O
N
H
H
H
N
21
N
N
MeO2C
1 Strictosidine
O
N
H
7
N
N
N
H
7
H
O
O
CO2Me
H+
11 (-)-Leuconodine A
12 (+)-Leuconodine F
4 (+)-Vincadifformine
O
a. Nature's strategy
b. This work
N
O
CO2Me
H
N
N
H
N
O
HO
6 (+)-Melodinine E
N3
N
N
O
O
O
O
oxidative
rearrangement
14 (+)-Arboloscine
13 (-)-Leuconodine C
NO2
O
OMe
N3
NO2
18
O
N
17
H
N
HO
N
OH
N
N
N
O
I
O
O
O
B(OH)2
+
8 (-)-Mersicarpine
15 (-)-Leuconodine D
16 (-)-Leuconodine E
NO2
N3
19
20
Fragment Coupling
Cyclization
Post-Cyclization
(-)-Leuconolam (5), with a fused [6.9.6.5] ring system,
was first isolated from Leuconotis griffithii in 1984 by
Goh and coworkers. Derived from the oxidative rear-
rangement of vincadifformine (4), leuconolam was
proposed to be the first intermediate in the biosynthe-
sis of leuconolam-leuconoxine-mersicarpine class of
ring skeleton were disclosed before the isolation of
these natural products. Thus, treatment of N4-oxide of
1,2-dehydro-aspidospermidine with acetic anhydride
under Polonovski-Potier conditions afforded leucono-
dine D and rhazinilam/leuconolam skeleton. On the
other hand, treatment of leuconolam with a MeOH
solution of HCl provided 6-chloroleuconoxine (initially
named 6-chlorodiazaspiroleuconolam).
first enantioselective total syntheses of (+)-melodinine
E (6), (-)-scholarisine G (9) and (-)-leuconoxine (10),
three racemic total syntheses from the group of To-
kuyama, Dai, Stoltz and Liang and two enantiose-
lective total syntheses from the group of Higuchi and
9
21
10
22
11
12
alkaloids. The group of Banwell and of Hoye has
accomplished total syntheses of this natural product.
10a-b
Since our
(+)-Melodinine E (6, a.k.a. 6,7-dehydroleuconoxine)
has an interesting [6.5.6.6.5] fused pentacyclic ring
system, four of which are arranged around the C21
aminal carbon. The structure of melodinine E was first-
ly reported by Luo and coworkers in 2007. Kam and
coworkers subsequently found that epileuconolam
8
23
24
25
13
26
27
Kawasaki, Gaich, respectively, have been reported.
isolated from Leuconotis eugenifolia by Goh and
Isolated by Kam and coworkers in 2004 from the
Kopsia genus, (-)-mersicarpine (8) was biosynthetical-
ly derived from melodinine E via an oxidative skeletal
10a
coworkers in 1986,
was actually identical to
14
melodinine E. It was proposed that melodinine E was
biogenetically derived from leuconolam via transannu-
lar cyclization of the N-acyl iminium ion intermediate
28
rearrangement. The intriguing [6.5.6.7] fused tetracy-
clic skeleton was characterized by the unique tetrahy-
dro-2H-azepine ring system, and became a popular
target since its isolation. Eight total syntheses have
been achieved by groups of Kerr, Fukuyama, To-
kuyama, Zhu, Liang,
15
7. Related natural products such as (-)-scholarisine G
(9, a.k.a. leuconodine B ), (-)-leuconoxine (10, a.k.a.
diazaspiroleuconolam ), (-)-leuconodine A (11), (+)-
16
17
18
29
30
19
31
8
25,32
33
24
leuconodine
F
(12, a.k.a. 6-oxoleuconoxine ), (-)-
Han, Dai and Higu-
26,34
leuconodine C (13), (-)-leuconodine D (15) and (-)-
leuconodine E (16), as well as the secoleuconoxine,
(+)-arboloscine (14), have also been isolated from
various plants during the past decades. All these natu-
ral products with different oxidation states are biosyn-
thetically derived from melodinine E (6). Interestingly,
structures with the same [6.5.6.6.5] fused pentacyclic
chi/Kawasaki,
16
From vincadifformine (Scheme 1a), nature synthesized
leuconolam (5) as the primary product that was subse-
quently elaborated to melodinine E (6), scholarisine G
(leuconodine B, 9), and leuconodines A, C, D, E. F (11,
13, 15, 16, 12) and mersicarpine (8). In our planned
20
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three-phase synthesis strategy (Scheme 1b), we selected
1. disiamyl borane
THF, 0 oC to rt
O
O
O
1
2
3
4
5
6
7
8
scholarisine G (9) and mersicarpine (8) as our primary
synthetic targets reasoning that the former could be
easily dehydrated to melodinine E (6), which could in
turn be elaborated to other leuconodines in the post-
cyclization phase. In the cyclization phase, both
[6.5.6.7] fused tetracyclic skeleton in (-)-mersicarpine
(8) and [6.5.6.6.5] fused pentacyclic ring system in (-)-
scholarisine G (9) was thought to be obtained by con-
trolling the cyclization mode (6-membered ring vs 7-
membered ring) of the same diketo ester 17, an ozonol-
ysis product of substituted cyclohexenone derivative
18. The latter could be obtained by the Suzuki-Miyaura
cross-coupling reaction between 2-nitrophenyl boronic
acid 19 and vinyl iodide 20 in the fragment coupling
phase. We detail herein the total syntheses of (-)-
mersicarpine (8), (-)-scholarisine G (9) and the suc-
cessful transformation of the latter to (+)-melodinine E
(6), (-)-leuconoxine (10), (-)-leuconolam (5), (-)-
leuconodine A (11), (+)-leuconodine F (12) and (-)-
leuconodine C (13) as well as other non-natural prod-
ucts resulting from unprecedented oxidative transfor-
mations. In addition to the enantiomerically enriched
natural products, we have also synthesized the racemic
form of these alkaloids and document the self-induced
diastereomeric anisochronism (SIDA) phenomenon in
Pd(OAc)2
Ph3P, THF
then NaOH, H2O2
O
65 °C, 92%
2. NaH, TBSCl, THF
75% in 2 steps
21
(±)-22
O
O
1. TMSOTf, Et3N
CH2Cl2, 0 °C
I2, DMAP
CCl4/pyridine
OTBS
2. Pd(OAc)2, O2
DMSO, 80 °C
79%
OTBS
(1:1), 95%
(±)-23
(±)-24
O
9
O
2-NO2C6H4B(OH)2 (19)
Pd2(dba)3, JohnPhos
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NO2
OTBS
Ba(OH)2, THF/H2O
OTBS
(±)-25
(±)-26
NaN3
DMF
O
O
1. AcCl, MeOH
2. TsCl, Et3N
DMAP, CH2Cl2
55% in 3 steps
rt, 95%
NO2
NO2
N3
TsO
(±)-27
(±)-18
Scheme 3. Enantioselective Synthesis of (S)-18
and Its Conversion to Diketo Ester (R)-17
disiamyl boran
THF, 0 oC to rt
Pd2(dba)3
(S)-t-BuPhox
O
O
O
O
THF, 25 °C
90% yield
92% ee
then NaI, NaOAc
Chloramine T
MeOH, H2O, 80%
21
(S)-22
O
O
O
1
the H NMR spectra of scholarisine G (9), leuconodines
IBX, DMSO
NaN3, DMF
A (11) and C (13). The different auto-association modes
80 °C, 12 h
70%
rt, 92%
N3
I
N3
in the solid state of both racemic and enantio-enriched
(S)-28
(S)-29
(S)-33
1
natural products nicely explained the H NMR spectra
O
2-NO2C6H4B(OH)2 (19)
Pd2(dba)3, JohnPhos
O
difference between the racemic mixture and the enan-
tiomer in an achiral solvent.
I2, DMAP
I
CCl4/pyridine
(1:1), 95%
Ba(OH)2, THF/H2O
75%
NO2
N3
(S)-20
N3
(S)-18
RESULTS AND DISCUSSION
N3
N3
NO2
O
NO2
O
O3, NaHCO3
Ac2O, Et3N
Fragment Coupling Phase: Synthesis of Func-
tionalized Cyclohexenone 18. The synthesis of (±)-
18 commenced with palladium-catalyzed decarboxyla-
tive allylation of β-ketoester 21 (Scheme 2). Using the
CH2Cl2/MeOH
(5:1), -78 °C
0 °C to rt
92%
O
O
CO2Me
MeO
34
O2H
O
(R)-17
35
conditions developed by Tsuji and co-workers, the
O
TBSO
keto ester 21 was converted to 2-allyl-2-ethyl cyclohex-
anone 22 in 92% yield. A hydroboration-oxidation
sequence transformed 22 to the corresponding primary
alcohol which, without purification, was directly pro-
tected as its TBS ether to give 23 (NaH, TBSCl, THF).
No attempt was made to purify the primary alcohol as
it readily cyclized to hemiketal upon purification by
column chromatography on silica gel. The hemiketal
was also the major product when the TBS protection
CN
CN
N3
30
31
32
An enantioselective synthesis of (R)-17 is shown in
Scheme 3. Enantioselective decarboxylative allylation
of β-keto ester 21 under Stoltz's conditions provided
enantio-enriched α,α-disubstituted cyclohexanone (S)-
40
22 in 90% yield with 92% ee. Taking advantage of a
41
36
hydroboration-iodination sequence,
the terminal
was performed in DMF in the presence of imidazole.
double bond in (S)-22 was then transformed in one
operation into alkyl iodide (S)-28 which was subse-
quently converted to alkyl azide (S)-29 under standard
conditions (NaN3, DMF). Formation of silyl enol ether
30 followed by dehydrogenation with Pd(OAc)2 in
DMSO at 60 °C for 12 h afforded the desired enone in
Saegusa-Ito oxidation of cyclohexanone 23 [TMSOTf,
Et3N, CH2Cl2, then Pd(OAc)2, O2, DMSO] provided
37
enone 24 in 79% yield. α-Iodination of enone 24 oc-
curred smoothly to afford vinyl iodide 25, which un-
derwent the Suzuki-Miyaura cross-coupling with 2-
38
nitrophenylboronic acid (19) to give 26. Removal of
37
70% yield in 200 mg scale. The reaction needed to be
the TBS silyl ether under mild acidic conditons (AcCl in
39
carefully monitored as prolonged reaction time or over
heating (above 80 °C) produced a significant amount of
nitrile 31 resulting from the palladium-catalyzed dehy-
MeOH), followed by tosylation of the resulting prima-
ry alcohol converted 26 to 27 in 55% overall yield in 3
steps. Reaction of 27 with sodium azide afforded the
desired cyclization precursor (±)-18 in 95% yield.
42
drogenation of alkyl azide. Unfortunately when the
reaction was performed in a gram scale, the reaction
became sluggish affording low yield of the enone 33.
Heating the reaction mixture to 80 °C provided nitrile
32 in 55% isolated yield as the major product indicat-
ing that the dehydrogenation of alkyl azide to nitrile
Scheme 2. Synthesis of (±)-18
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became kinetically competitive relative to the Saegusa- 17 without work-up of the intermediate steps. The or-
1
2
3
4
5
6
7
8
Ito oxidation of the silyl enol ether at this temperature.
On the other hand, either silyl enol ether 30 or cyclo-
der of the reaction sequence is important as attempt to
perform the lactamization after the oxidation of the 3-
amino indole 39 led only to the degradation. Further-
hexanone 29 was recovered when oxidants other than
43,44
O2 were used.
Finally, it was found that oxidation of
more, it was found that Pd/C acted also as a catalyst to
30,31
cyclohexanone 29 with an excess amount of IBX (6.0
accelerate the peroxidation of 40 to 41.
In its ab-
equiv) in DMSO proceeded smoothly in multigram
sence, the same reaction took several days to comple-
tion (see Figure S1 and S2).
30,45
scale to provide enone (S)-33 in 70% yield.
α-
Iodination of (S)-33 followed by Suzuki-Miyaura cross-
coupling of the resulting vinyl iodide with 2-
nitrophenyl boronic acid (19) afforded (S)-18 without
event. Cleavage of the enone double bond with ozone
buffered with NaHCO3 gave peroxide 34 cleanly as a
mixture of 1:1 diastereomers, which was transformed to
Scheme 4. From Linear Diketone (R)-17 to
[6,5,6,7]-Fused Tetracyclic Skeleton: A One-pot
Synthesis of (-)-Mersicarpine (8)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
O
NO2
N
7
N
7
Ph3P, THF
60 °C, 12 h
7
21
21
+
21
NO2
O
NO2
O
O
N3
1
the methyl ester (R)-17 by in situ addition of acetic
4
CO2Me
(R)-17
46
CO2Me
anhydride and triethylamine.
This ozonolysis-
CO2Me
35 94%
36 0%
oxidative workup sequence worked efficiently in multi-
gram scale.
Pd/C, H2 , EtOH
rt, 3 h
NH2
O
O
7
7
Cyclization Phase: Total Syntheses of (-)-
Mersicarpine (8), (-)-Scholarisine G (9) and
(+)-Melodinine E (6). The total synthesis of (-)-
mersicarpine (8) from diketone (R)-17 is shown in
Scheme 4. It is reasonable to assume that after reduc-
tion of both the nitro and the azido groups, the conden-
sation of aniline nitrogen (N1) with the C21 carbonyl
group leading to indolenine structure would be both a
kinetically and thermodynamically favored process,
while the primary amine (N4) could attack either the
C7 or the C21 carbonyl (or transient iminyl) groups
leading to mersicarpine and leuconoxine skeleton,
respectively. The result of a preliminary experiment
under Staudinger conditions was revealing. Treatment
of (R)-17 with Ph3P resulted in the formation of 7-
membered azepino derivative 35 in 94% yield at the
expense of the tetrahydropyridine 36. The reasons for
the preferential formation of 7-membered ring are two
folds. Firstly the C7 carbonyl group is more electro-
philic due to the presence of an electron-withdrawing
2-nitrophenyl group. Secondly, the C7 is also sterically
more accessible than the C21 carbonyl function, the
latter being adjacent to a quaternary carbon. While
compound 35 was certainly an attractive intermediate
for further elaboration to mersicarpine, a more direct
synthesis of natural product from (R)-17 was sought.
Gratefully, simply stirring an ethanol solution of (R)-17
under hydrogen atmosphere in the presence of Pd/C (3
mol% based on Pd) gave, after column chromatog-
raphy, (-)-mersicarpine (8) in 23% yield together with
50% of the hexahydroazepino[3,2-b]indole 39. Reason-
ing that mersicarpine (8) could be formed by a se-
quence of lactamization and facile air-oxidation of 3-
aminoindole 39, a more efficient one-pot protocol
allowing the direct conversion of (R)-17 to (-)-
mersicarpine (8) was developed. Hydrogenation of (R)-
17 in the presence of Pd/C (10 mol% based on Pd) gave
unstable 3-aminoindole derivative 39, which under-
went KOH-promoted lactamization to give tetracyclic
derivative 40 (See Figure S1 and S2 for detailed NMR
studies of this sequence). Purging the reaction mixture
21
NH2
O
21
N
H2N
CO2Me
37
38
CO2Me
HN
HN
7
21
O2, 1 h
KOH, EtOH
30 min
N
H
N
CO2Me
O
39
40
N
N
OH
O2H
Me2S, 2 h
N
N
75% overall
O
O
41
8 (-)-Mersicarpine
For the total synthesis of leuconoxine skeleton from the
same diketone (R)-17, we need to orient the nucleo-
philic addition of N4 to the iminyl carbon C21 instead
of the carbonyl carbon C7 in the hypothetic intermedi-
ate 38 or its synthetic equivalents. To reach this goal,
we thought to proceed by a) reducing the nucleophilici-
ty of the C4 nitrogen by converting the C4 primary
amine to acetamide, inhibiting therefore its spontane-
ous condensation with the C7 carbonyl group; b) en-
hancing the electrophilicity of the C21 iminyl carbon by
its conversion to N-acyliminium taking advantage of
the pendant ester function. While searching for condi-
tions for this individual step, we aimed at finding sim-
ple protocols that are easily integrated into a one-pot
process.
Conversion
of
(R)-diketone
17
to
[6,5,6,6]spirotetracycle of scholarisine G is depicted in
Scheme 5. Hydrogenation of (R)-17 (Pd/C, EtOH) in
the presence of acetic anhydride (5.0 equiv) afforded
indolin-3-one 42 involving a sequence of a) reduction
of both nitro and azido groups; b) selective condensa-
tion of the aniline nitrogen with the C21 ketone and the
reduction of the resulting imine function; c) selective
N-acetylation of the C4-primary amine. Without isola-
tion, compound 42 was spontaneously oxidized to the
unstable indol-3-one 43 upon purging the reaction
mixture with argon followed by oxygen. Addition of
potassium hydroxide into the above reaction mixture
triggered the lactamization leading to δ-lactam N-
acyliminium that was in situ trapped by ethanol to
afford 2-ethoxyindolin-3-one 44 as a mixture of two
with argon followed by oxygen afforded presumably
30,47
peroxide 41
which, upon addition of dimethyl sul-
fide, was reduced to (-)-mersicarpine (8) in 75% overall
yield. We stress that the whole transformation was
realized by sequential addition of reagents (Pd/C, H2;
KOH; O2; Me2S) to the ethanol solution of diketone (R)-
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Journal of the American Chemical Society
diastereomers (dr = 2:1). The lack of diastereoselectivi-
ty in this hemi-aminal formation is of no consequence
O
4
5
6
HO
1
2
3
4
5
6
7
8
t-BuOK (8.0 equiv)
THF, -50 °C
N
O
7
since it will be converted back to N-acyliminium ion in
the next step. To our delight, treatment of the crude
mixture of 44 with TFA in CH2Cl2 afforded the desired
[6,5,6,6] spiro tetracycle 46 as an only diastereomer
whose structure was fully determined by X-ray analy-
sis. The intramolecular nucleophilic addition of amide
NH to the in situ generated N-acyliminium ion 45 took
place therefore from the side opposite to the neighbor-
ing ethyl group. We emphasize that the in situ acetyla-
tion of the primary amine N4 during hydrogenation
was not a redundant step since it introduced the miss-
ing C2 unit needed for the synthesis of leuconoxine
skeleton.
21
1
N
N
15
N
then -78 °C, HOAc
73%
2
O
O
16
O
46
9 (-)-Scholarisine G
O
HO
N
O
N
N
N
9
H
O
NOE
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
HO
HO
49
50
An intramolecular aldolization of 46 completed the
synthesis of (-)-scholarisine G (9, Scheme 6). After
extensive experimentations, it was found that (-)-
scholarisine G (9) could be obtained in 73% yield by
treatment of 46 with an excess amount of t-BuOK (8.0
equiv) at -50 °C, followed by quenching the reaction
with acetic acid at -78 °C. The presence of an excess
amount of base was crucial for the success of the reac-
tion as the desired product could be detected only after
6 equiv of t-BuOK was added. Furthermore, quenching
the reaction with acetic acid at low temperature was
also important as significant degradation was observed
when the reaction was quenched with H2O, MeOH or
sat. aq. NH4Cl. The structure of our synthetic com-
pound was unequivocally confirmed by single crystal X-
ray analysis. Consequently, our synthesis also con-
firmed the absolute configuration of (-)-scholarisine G
(9), previously assigned based on the biosynthetic hy-
pothesis.
Scheme 5. Divert the Cyclization Manifold:
From (R)-Diketone 17 to [6,5,6,6] Spiro-
tetracyclic Skeleton 46.
AcHN
O
O
Pd/C, H2
7
O2
Ac2O, EtOH
21
4
NO2
O
1
rt, 3 h
N3
N
H
CO2Me
CO2Me
(R)-17
42
AcHN
OEt
AcHN
O
O
TFA/CH2Cl2 (1:1)
rt, 18 h
KOH, EtOH
dr = 2:1
N
N
MeO2C
O
43
44
AcHN
4
O
O
7
21
1
N
N
N
A hemiaminal by-product 49 resulting from the attack
of enolate at the C2 amide carbonyl group rather than
the C7 ketone group, was isolated in around 1% yield.
The carbinol structure 49 was unambiguously deter-
mined by X-ray analysis, representing one of the rare
examples of stable tetrahedral intermediates resulting
O
O
O
45
46 (50%)
!
+
AcHN
O
OAc
O
H
O
N
H
from the nucleophilic addition to amide carbonyl func-
O
N
O
14,50
N
tion.
We note here that the C2 amide carbonyl in 46
MeO2C
51
could in fact be considered as a vinylogous imide,
while the C7 ketone could be regarded as a vinylogous
amide, therefore the reactivity difference between the
two carbonyl groups is not very pronounced.
48
47 (3%)
A side product 47 having a pyran ring was isolated in
3% yield from the reaction mixture in some experi-
ments. Only one diastereomer was isolated and the
structure was confirmed by X-ray analysis. Different
from 46 in which the piperidine ring adopted a boat
conformation, the pyran ring in 47 took a chair con-
formation with the C3 acetamido group at the equato-
rial position. A reasonable precursor to 47 would be
hemiaminal 48 which in turn was formed by palladi-
um–catalyzed α-acetoxylation of the azide 17. We be-
lieved that controlled conversion of alkyl azides to
hemiaminals is a synthetically very useful transfor-
It is also interesting to note that 16β-hydroxy-
scholarisine G (50) was isolated in around 5% yield
when an excess of LiHMDS was used as a base. The
formation of 50 could be explained by oxidation of the
in situ generated C16-enolate of 9 by adventurous air
introduced during the TLC monitoring of the reaction.
The absolute configuration of C16 was determined to be
R based on the analysis of the coupling constant of H16
[δ 4.48 (dd, J = 6.8, 11.6 Hz)], and the NOE correlation
between H16 and H15.
Scholarisine G and other leuconodines share an un-
usaual [5.5.6.6]diazafenestrane system that is extreme-
ly rare in nature. Detailed analysis of X-ray structure
mation since they could serve as
a latent N-
42a,48
acyliminium equivalent.
Note that there are only
52
very few methods allowing the generation of N-
49
of scholarisine G (9) indicated that the central carbon
atom of the fenestrane is not particularly distorted. On
the other hand, the bond length of N1-C2 (1.373Å) is
longer than that of N4-C5 (1.352Å), while the pyrami-
dalization angle of N1 (χ = -32) is larger than N4 (χ = -
19.9). In the C NMR spectrum of 9, it was observed
that the C2 carbon resonanced at a lower field (δ 173.6)
than that of C5 (δ 170.0). All these data indicated that
acylimines from aliphatic aldehydes.
Scheme 6. Total Synthesis of (-)-Scholarisine G
(9)
53
13
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the delocalization of N1 lone pair electron to C2 car- diate might be easy to form from melodinine E under
1
2
3
4
5
6
7
8
bonyl is less important than that of N4 to C5. Conse-
quently, the C2 carbonyl carbon is more electrophilic
than C5 and the C2 carbonyl oxygen is less nucleophilic
than the C5 carbonyl oxygen. In line with this analysis,
all our attempts to reduce scholarisine G with different
hydride reducing agent afforded only the C2 carbonyl
mild acidic conditions. This mechanistic assumption
has very important bearing in our subsequent experi-
mental design aimed at converting melodine E to other
leuconodine congeners.
Post-Cyclization Phase: Bio-inspired Diversifi-
cation of (+)-Melodinine E (6). (+)-Melodinine E
(6) was proposed to be the biosynthetic precursor of all
the other leuconoxine group alkaloids with different
oxidation states. With this idea in mind, we set out to
explore these transformations in laboratory settings.
14
reduced product (see supporting information). How-
ever, Dai and co-workers have reported an elegant
solution to this selectivity problem by taking advantage
of the higher nucleophilicity of the C5 carbonyl oxygen.
Thus γ-lactam in leuconoxine (10) was selectively con-
verted to the methyl amidinium salt that was subse-
quently reduced by sodium cyanoborohydride to leuco-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Post-Cyclization Phase: From (+)-
Melodinine E (6) to (-)-Leuconoxine (10).
24
O
nodine D (15).
O
H
N
(±)-Scholarisine G was also synthesized following the
same synthetic route. While there are small discrepan-
Pd/C, H2
N
N
MeOH, 85%
N
1
cies in the H NMR spectrum between synthetic and
O
O
natural (-)-scholarisine
G (9), the synthetic (±)-
6 (+)-Melodinine E
10 (-)-Leuconoxine
scholarisine G (9) did not match that of the natural
1
product. Both Tokuyama and Dai also noted that the H
The transformation of (+)-melodinine E (6) to (-)-
leuconoxine (10) was straightforward. Hydrogenation
of 6 in the presence of catalytic amount of Pd/C in
methanol gave (-)-leuconoxine (10) in 85% yield
(Scheme 8).
NMR spectra of their synthetic (±)-scholarisine G did
not match that of our synthetic (-)-scholarisine G. By
detailed NMR titration experiments and analysis of the
single crystal structures of both (±)- and
(-)-
scholarisine G, we demonstrated that scholarisine G
showed interesting self-induced diastereomeric an-
isochronism (SIDA) phenomenon (vide infra).
Selective hydroxylation of leuconoxine (10) at C6 posi-
tion is difficult to realize due to the easy enolization of
the C2 amide function as we stated earlier. Indeed,
Kam and co-workers have shown that treatment of
leuconoxine (10) with LDA followed by oxygen afford-
ed 16-hydroxyleuconoxine as an only isolable product
in 21% yield together with the recovered starting mate-
Scheme 7. Transformation of (-)-Scholarisine G (9) to
(+)-Melodinine E (6)
O
O
5
6
HO
4
SOCl2, Et3N
CH2Cl2
Cl
E
N
N
7
D
14
rial. Therefore, we thought that melodinine E could be
B
21
C
A
N
N
15
0 oC to rt
80%
1
an appropriate precursor for the synthesis of leucono-
dine A (11). A chemoselective 1,4-reduction of α,β-
unsaturated amide in 6 would generate regioselectively
the C6-enolate or its radical equivalent that could sub-
sequently be oxidized to the leuconodine A (11). After
many unsuccessful trials, it was found that treatment of
2
O
O
16
9 (-)-Scholarisine G
51
MsCl, Et3N
ClCH2CH2Cl, rt
O
O
A
54
MsO
E
6 with Mn(dpm)3 and PhSiH3 under O2 atmosphere
DBU, 75 o
20 h, 75%
C
N
B
N
D
N
afforded cleanly a single product whose structure was
determined to be the (-)-scholarisine G (9) in 90% yield
(Scheme 9). The result is at the first glance unexpected
since α,β-unsaturated amides are known to be trans-
formed regioselectively to α-hydroxy amide under
C
N
O
6 (+)-Melodinine E
O
52
The synthesis of (+)-melodinine
E (6) from (-)-
scholarisine G (9) is shown in Scheme 7. Treatment of
a dichloromethane solution of 9 with thionyl chloride
and triethylamine afforded the chlorinated product 51
in 80% yield whose structure was confirmed by X-ray
diffraction analysis. Although base-promoted elimina-
tion of chloride in 51 did give 6, the reaction was not
very efficient in our hands. Alternatively, O-mesylation
of the tertiary hydroxy group in 9 followed by a DBU-
promoted elimination of the resulting mesylate afford-
ed (+)-melodinine E (6) in 75% isolated yield.
55
Mukaiyama conditions. A possible explanation to the
unexpected regioselectivity is the lability of the central
aminal function. Under Mukaiyama conditions,
melodinine E (6) may be in equilibrium with the N-
acyliminium 7, which could then be reduced to en-
56
amide 53 by the in situ generated Mn hydride species.
Trapping of the enamide 53 by Mn-peroxide or by
molecular oxygen would afford the peroxide 54 that
was subsequently reduced to scholarisine G (9). Alter-
natively, direct hydride transfer from HMn(dpm)2 to
the C6 position in an SN2' manner could also account
for the formation of enamide 53.
In solid state, the D ring (piperidine) of fenestrane
motif of melodinine E adopts a twisted boat confor-
14
mation, rendering it more strained and less stable
Scheme 9. Post-Cyclization Phase: Unexpected
Conversion of (+)-Melodinine E (6) to (-)-
Scholarisine G (9).
relative to scholarisine G whose D ring is in a chair
form. Indeed, while scholarisine G (9) was stable in a
TFA/CH2Cl2 (v/v = 1/1) solution for several days, severe
degradation occurred within 12 h when melodinine E
(6) was dissolved in the same solvent. It is reasonable
to assume that degradation of 6 went through the N-
acyl iminium ion 7 (cf Scheme 1) and that this interme-
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would then furnish 57 which, upon aqueous work-up,
O
6
HO
1
2
3
4
5
6
7
8
afforded two separable diastereomers 11 and 58. When
O
7
Mn(dpm)3, O2
PhSiH3, 0 °C
N
copper(II) triflate (0.1 equiv) was used as a catalyst, the
aniline 59 was isolated in 15% yield in addition to 11
N
N
N
14
2-propanol, 90%
2
O
and 58. By increasing the loading of Cu(OTf)2 (0.6
equiv), the yield of 59 was increased to 70%. We as-
sumed that Cu(OTf)2, due to its increased Lewis acidity,
might be able to activate the six-membered lactam
leading therefore to its hydrolysis. A control experi-
ment showed that in the absence of copper salt, heating
a TFA solution to 70 °C also led to the formation of 11
and 58, albeit in a much lower yield.
O
16
9 (-)-Scholarisine G
6 (+)-Melodinine E
HMn(dpm)2
O
O
O
HOO
N
N
N
9
NH
NH
N
10
11
12
13
O
O
7
53
54
O
Oxidation of (-)-leuconodine A (11) by DMP afforded
14
(+)-leuconodine F (12) in 83% yield. The structure of
the synthetic leuconodine F (12) was confirmed by X-
ray structural analysis.
Scheme 10. Post-Cyclization Phase: From (+)-
Melodinine E (6) to (-)-Leuconodine A (11) and
(+)-Leuconodine F (12).
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Post-Cyclization Phase: From (+)-
Melodinine E (6) to (-)-Leuconolam (5).
O
Cu(2-ethyl hexanoate)2
(10 mol%)
O
N
N
N
NH
O
OH
TFA (20 equiv)
CH2Cl2, rt
D
O
THF/3N H2SO4 (2:1)
40 oC, 2.5 h, 70%
O
N
N
A
C
N
B
6 (+)-Melodinine E
7
N
O
O
O
H
O
F3COCO
H
OCOCF3
OCOCF3
6 (+)-Melodinine E
5 (-)-Leuconolam
H+
H
O
O
N
H+
N
N
N
NH
NH
O
N
O
O
21
N
O
40 °C
55
56
57
1
NH
N
O
N
HO
H
2
O
O
H
O
7
60
N
(-)-Leuconolam (5) was proposed to be the biogenetic
precursor of melodinine E (6), and biomimetic trans-
O
aqueous
NaHCO3
formation of 5 to 6 under acidic conditions has been
58 (-)-6-epi-Leuconodine A (8%)
+
10a-b,14
realized in laboratory settings.
We have reversed
O
HO
H
the process by converting (+)-melodinine E (6) to (-)-
leuconolam (5) as shown in Scheme 11. Treatment of a
solution of 6 in THF/3N H2SO4 (v/v = 2/1) at 40 °C for
2.5 h afforded (-)-leuconolam (5) in 70% isolated yield.
It was noted that the starting material disappeared
rapidly under acidic conditions at room temperature
leading to the presumed N-acyl iminium ion 7. Howev-
er, only melodinine E was recovered upon workup indi-
cating that the transannular cyclization of 7 back to 6 is
a kinetically favored process. In order to promote the
formation of leuconolam, heating the reaction mixture
is the key. We assumed that upon heating to 40°C, the
rotation of C1-N2 bond took place to convert the trans
C1-N2 amide bond to the higher energy cis-isomer as
found in 60. The intramolecular aminal formation was
impossible in 60 due to the geometric constraint as the
nucleophilic N1 atom is too far away from electrophilic
C21 iminium carbon, the intermolecular addition of
water to C21 became therefore competitive leading to
the formation of leuconolam (5). The structure of our
synthetic leuconolam was unambiguously confirmed by
X-ray structural analysis. It is worth noting that the
addition of water to C21 of the N-acyliminium took
place from the same face occupied by the neighboring
ethyl substituent placing therefore both the hydroxy
and the ethyl groups in the convex face defined by the
B-C-D ring. Additionally, an axial chirality was created
in this transformation and only one atropisomer corre-
sponding to the natural product was produced.
N
DMP, CH2Cl2
0 °C to rt, 83%
N
O
11 (-)-Leuconodine A (68%)
O
O
O
NH2
H
N
N
O
N
O
O
59
12 (+)-Leuconodine F
On the basis of above experiment observation and
mechanistic hypothesis, an unusual α-hydroxylation of
the α,β-unsaturated amide in 6 was finally developed
(Scheme 10). Treatment of a CH2Cl2 solution of 6 with
20 equivalents of TFA in the presence of a catalytic
amount of copper(II) 2-ethylhexanoate (0.1 equiv) gave
an unstable trifluroacetate 57 as a mixture of two dia-
stereomers. Without purification, the reaction mixture
was worked up with aqueous NaHCO3 to provide di-
rectly (-)-leuconodine A (11) in 68% yield, together
with 8% of 6-epi-leuconodine A (58). Both structures
were unambiguously confirmed by X-ray analysis. We
hypothesized that the reaction might go through the N-
acyliminium intermediate 7. Conjugate addition of
trifluoroacetate to N-acyliminium 7 would afford en-
amide 55 which upon protonation would provide the
N-acyl iminium salt 56. Transannular cyclization of 56
Scheme 12. Post-Cyclization Phase: From (+)-
Melodinine E (6) to (-)-Leuconodine C (13).
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opened form of (+)-melodinine E (6). Selective meth-
1
2
3
4
5
6
7
8
anolysis of 6 could in principle provide a direct access
to 14 (Scheme 13). However, treatment of 6 with KOH
in MeOH afforded the methyl ester 65 resulting from
the selective ring opening of the δ-lactam. We noted
that the aminal function in 65 was unstable and its
stereogenic center is readily epimerized even under
mild acidic conditions (CDCl3). The equilibrium be-
tween 65 and 66 went through most probably the N-
acyl iminium intermediate 67.
11 Leuconodine A + 58 6-epi-Leuconodine A
PIFA, TFA
70 °C, 5 min
TfO- 10
O
-
CF3CO2
6
O
N
O
N
PIFA
H+
N
O
N
O
N
NH
F3C
I
O
O
Ph
O
9
6 (+)-Melodinine E
7
61
Scheme 13. Base-Promoted Methanolysis of
Melodinine E (6) to Tetracycle 65.
AgOTf, PIFA
TFA, CH2Cl2
rt, 1.5 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
TfO
H
HO
O
TfO
H+
O
N
O
O
KOH in MeOH
TBAF
34%
N
N
N
N
N
NH
N
THF, rt
N
N
O
O
O
O
65
CO2Me
6 Melodinine E
64
63
62
O
O
O
H+
H
N
N
N
CO2Me
Pd/C, H2
91%
N
10
HO
H
H2N
N
CO2Me
O
66
67
13 (-)-Leuconodine C
We have accidentally found that keeping a CH2Cl2 solu-
tion of 6 for several months resulted in the formation
of a complex oxa-bridged polycycle 68, albeit in a very
low conversion (Scheme 14). The structure of 68 was
initially proposed based on detailed NMR studies and
was later confirmed by X-ray analysis.
Direct aromatic hydroxylation of (-)-leuconoxine (10)
at C10 would convert 10 to (-)-leuconodine C (13).
However, all our attempts towards this end were un-
successful. We then thought that it should also be pos-
sible to take advantage of the equilibrium between (+)-
melodinine E (6) and the N-acyl iminium ion interme-
diate 7 to introduce a hydroxy group into the C10 posi-
tion. Our working hypothesis exploiting the transiently
generated secondary amide function is as follows
(Scheme 12). Reaction of the secondary amide function
in 7 with a hypervalent iodine reagent could afford 61
in which the aromatic C10 position was now susceptible
to nucleophilic attack to furnish 62. Rearomatization of
62 followed by tansannular aminal formation would
Scheme 14. Post-Cyclization Phase: From (+)-
Melodinine E (6) to an Oxabridged Polycycle.
6
O
7
CH2Cl2, air
several months
N
N
low conversion
O
6 (+)-Melodinine E
VO(acac)2
isovaleraldehyde
ClCH2CH2Cl, O2
rt, 4 h
57
afford the desired 10-hydroxy derivative (e.g. 63).
While conceptually interesting, the potential complica-
tion was the high electrophilicity of the C6 position of
the intermediate 7 and we have in fact exploited this
latter property for converting melodinine E (6) to leu-
conodine A (11, cf Scheme 10). Indeed, preliminary
experiments using PIFA as an oxidant in neat TFA
afforded, after basic workup, only leuconodine A (11)
and its C6-epimer 58, resulting from the hydroxylation
O
O
O
O
O
O
H
HO
N
O
N
+
+
N
N
N
O
N
O
O
69 (15%)
70 (1%)
68 (35%)
The X-ray structure of melodinine E (6) showed that
the C6-C7 double bond, especially C7 showed similar
character as that of the strained bridgehead double
bond. For example, the value of pyramidalization angle
(χ = 30.5°) of C7 is between that of the bridgehead
carbon of strained double bond in [3,3,1] (χ = 39.0°, τ =
10.8°) and [4,3,1] (χ = 22.7°, τ = 6.4°) bicyclic systems,
while the torsion angle (τ = 21.0°) is larger. Therefore,
we thought that the formation of 68 might be initiated
by the oxidation of the C6=C7 double bond since the
ground-state triplet oxygen is known to oxidize the
angle-strained olefins in a concentration-depending
57b
at the C6 postion. The ratio and yields of 11 and 58
were similar to that obtained using copper(II) 2-ethyl
hexanoate as a catalyst. After many trials, we were
finally able to obtain the desired 10-OTf melodinine E
(63) in 34% yield by treatment of a dichloromethane
solution of 6 in the presence of AgOTf (2.5 equiv), PIFA
(1.5 equiv) and TFA (20 equiv) at room temperature for
1.5 h. Hydrolysis of the sulfonate (TBAF, rt) afforded
58
phenol 64 cleanly, which was unstable and underwent
degradation upon aqueous workup. Therefore, hydro-
genation was performed directly by adding Pd/C to the
above reaction mixture to afford (-)-leuconodine C (13)
in 91% overall yield.
59
manner. However, an attempt to increase the efficien-
cy of this transformation by performing the reaction at
high concentration (c 1.0 M) was unsuccessful.
Post-Cyclization Phase: Conversion of (+)-
Melodinine E (6) to Other Non-Natural Polycy-
clic Compounds. (+)-Arboloscine (14) was the ring-
Intrigued by the molecular structure of 68 and its easy
formation under aerobic conditions from melodinine E
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(6), we thought that such compound, yet unknown, In light of the easy formation of 68 under biomimetic
1
2
3
4
5
6
7
8
could also exist in nature. Therefore, we screened dif-
ferent oxidative conditions in order to increase the
efficiency of this transformation. Interestingly, Mukai-
yama epoxidation using molecular oxygen as a terminal
oxidant turned out to be the most effective. Simply
stirring a dichloroethane solution of 6 and an excess of
isovaleraldehyde in the presence of a catalytic amount
oxidative conditions, we would not be surprised if this
compound would be isolated one day from the natural
sources.
Self-Induced Diastereomeric Anisochronism
1
(SIDA) Phenomenon in H NMR Spectra of
Scholarisine G (9), Leuconodines A (11) and C
(13).
60
of VO(acac)2 under oxygen atmosphere afforded 68 in
It is now well known that enantiomers and racemates
could show different physical and chemical properties
because of the interactions between different enantio-
mers, thus resulting in the nonlinear effects in asym-
35% yield. Epoxide 69 and 7-hydroxy-leuconodine F
(70) were also isolated in yields of 15% and 1%, respec-
tively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 15. Proposed Mechanism for the Oxida-
tion of (+)-Melodinine E (6) to 68, 69 and 70.
62
metric synthesis, and the phenomenon of self-
63
disproportionation of enantiomers (SDE). The self-
O
induced diastereomeric anisochronism (SIDA) phe-
nomenon refers to the fact that in some cases, enanti-
omers and racemic mixtures show different NMR spec-
R
O
M
O
RCHO
O
N
O
O
R
O
O
R
O
71
72
O
tra in achiral solvents, and distinct signals of each en-
O
64-71,72a
antiomer could be obtained.
The extent of spec-
NH
N
N
N
NH
troscopic difference is concentration- and solvent-
dependent indicating an auto-association phenome-
non. However, the SIDA phenomenon is still over-
looked nowadays by many practitioners of organic
synthesis for several reasons. Firstly, there were only
limited examples of SIDA phenomenon reported since
its first disclosure in 1969 by Williams and coworkers
O
73
O
6 (+)-Melodinine E
O
O
7
N
O
R
N
path a
O
O
O
69
O
O
H
O
O
1
N
on the nonequivalence of the H NMR spectra of race-
O
N
R
O
64a
O
mic and enantiopure dihydroquinine.
In addition,
O
74
different terms such as solute-solute interactions of
N
N
64a
65
enantiomers, self-induced anisochrony (SIA), statis-
O
O
O
tically-controlled
(SCAD) self-induced diastereomeric anisochronism,
self-induced nonequivalence, and self-discrimination
of the enantiomers have been proposed to explain the
associate
diastereoisomerism
HO
75
N
66
67
68
path b
path c
N
OH
N
OH
69
O
HO
N
O
O
O
same phenomenon that might complicate the situation.
Secondly, the differences in NMR spectra between
enantiomers and racemates were so small in most of
the cases that they were arbitrarily considered as ‘iden-
tical’. Thirdly, in natural product research, it is often
difficult to obtain both enantiomers and racemates for
comparison. Indeed in nowadays, synthetic chemists
tend to directly investigate the enantioselective ap-
proaches without caring too much about the racemic
version. To the best of our knowledge, only two natural
70
O
N
N
H
O
O
O
O
77
76
O
N
N
68
Resubmitting the epoxide 69 to the Mukaiyama epoxi-
dation conditions resulted in the full recovery of the
starting material. The result of this control experiment
indicated therefore that epoxide 69 is not the interme-
diate on the way to 68 and 70. A possible reaction
pathway accounting for the oxidation of melodinine E
(6) to all the three products is depicted in Scheme 15.
Metal mediated oxidation of aldehyde afforded acyl
radical 71, which was trapped by molecular oxygen to
64a
64p
products, dihydroquinine and spirobrassinin, were
reported to show SIDA phenomenon.
The NMR spectra of our synthetic (-)-scholarisine G (ee
90%) matched with the natural product, although small
discrepancies still exist (Fig. 1E). However, several tiny
‘impurity’ signals were always found in the spectra of
our synthetic (-)-scholarisine G, and the amount of
which varied with the concentration. The ‘impurity’
signals disappeared and only one set of signals corre-
sponding to (-)-scholarisine G was found when CD3OD
61
give acylperoxy radical 72. While 72 could in principle
add to C7, a β position of the α,β-unsaturated amide
unit in 6, we hypothesized that this may not take place
in accordance with our previous experimental observa-
tions. The acylperoxy radical 72 would instead add to
C6 of the in situ generated N-acyliminium ion 7 to
produce the acylperoxide intermediate 73, which is in
equilibrium with the cyclic aminal 74. An intramolecu-
lar radical trapping by the acyl peroxide could give the
epoxide 69 (path a). On the other hand, further oxida-
tion of 74 would afford intermediate 75, which under-
went Grob type fragmentation to give N-acyl iminium
ion intermediate 76. The α-hydroxy ketone in 76 was
in equilibrium with its enol form 77. Cyclization via C-
C bond (path b) formation or via C-O bond (path c)
formation would then give 70 or 68, respectively.
73
1
was added. On the other hand, the H NMR spectrum
of (±)-scholarisine G in CDCl3 (Figure 1A) was not iden-
tical to that of (-)-scholarisine G (Figure 1E), especially
the chemical shift of H16. While two H16 protons of (-)-
scholarisine G appeared normally having chemical
shifts of 2.65 ppm and 2.35 ppm, respectively, one of
the H16 protons of the racemic scholarisine G reso-
nanced at abnormally high field (δ = 0.80 ppm) as it
was positioned beneath an electron rich aromatic ring.
1
Interestingly, the H NMR spectrum shifted significant-
ly when CD3OD was added to the CDCl3 solution of (±)-
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Figure 1. H NMR Spectra of Scholarisine G (9) with Different Enantio-purities in CDCl3
71
74
mathematic models and computational studies have
been published to account for the SIDA phenomenon.
X-ray structures of both racemic and enantiopure SIDA
molecules have, to the best of our knowledge, never
been obtained in order to understand the phenomenon
1
scholarisine G (see Figure S3). The H NMR spectrum
became similar to that reported for (-)-scholarisine G
1
when the H NMR was recorded in a 2.7/1 (v/v) mix-
ture of CDCl3/CD3OD.
72
at molecular level. Fortunately enough, we were able
The aforementioned observation seems to indicate that
hydrogen bond played a key role in the abnormal be-
havior of the NMR spectra of scholarisine G and the
SIDA could be responsible for the observed NMR spec-
tra differences between the (-)- and (±)-scholarisine G.
To further confirm the presence of SIDA phenomenon,
scholarisine G with different enantiomeric purities
were prepared by titration of (-)-scholarisine G with
to grow single crystals of both (±)- and (-)-scholarisine
G suitable for X-ray diffraction analysis. In the solid
state of (±)-scholarisine G (Figure 2a, space group P-1),
heterodimer was formed by two hydrogen bonds be-
tween C2 carbonyl group of one enantiomer and C7
hydroxy group of its antipode, forming a 14-membered
ring. In this dimeric structure, two ethyl substituents
pointed towards two different directions avoiding
therefore the steric repulsion. On the other hand, the
crystal structure of (-)-scholarisine G (space group
P212121) appeared as a helix by the iteratively formed
hydrogen bonds between C2 carbonyl group of one
molecule and C7 hydroxy group of the other having the
same absolute configuration. In addition, one molecule
of methanol formed an additional hydrogen bond with
C5 carbonyl group at the outer sphere of the helix.
1
(±)-scholarisine G and their H NMR spectra were rec-
orded. Some of these spectra are displayed in Figure 1
(see Figure S4 for additional spectra). As expected,
both (±)- and (-)-scholarisine G showed only one set of
signals (Figure 1A and 1E), which were different from
each other. Two sets of peaks, corresponding to each
enantiomer, were found for non-racemic samples (Fig-
ure 1B-1D), and the enantiomeric ratio could be read
out directly by measuring the ratio of the correspond-
ing integrals. Furthermore, when a concentrated solu-
tion of non-racemic sample of scholarisine G in CDCl3
was diluted, the two distinct sets of peaks started to
collapse, and the spectrum became similar to that of (-
)-scholarisine G at high dilution (see Figure S5).
Although the structural information obtained from the
solid state could not be directly transposed into solu-
tion structure, we found that the high field shift of H16
1
observed in the H NMR spectra of (±)-scholarisine G
in CDCl3 was in consistent with its crystalline hetero-
dimeric structure, in which one of the H16 protons was
located at the shielding area of the phenyl ring of the
other enantiomer. Thus we believed that the heterodi-
mer of (±)-scholarisine G formed via hydrogen bond
was the major species responsible for the SIDA phe-
Supramolecular self-association between enantiomers
in solution is generally responsible for the SIDA. Alt-
hough π-π stacking can induce SIDA, hydrogen bond-
ing-induced dimerizaiton/oligomerization is more
frequently associated with this phenomenon. While
70
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nomenon, which could be broken down to monomer Figure 3. a. X-ray Structure of (±)-Leuconodine
1
2
upon addition of CD3OD or by dilution
A (11). b. X-ray Structure of (-)-Leuconodine A
(11)
3
4
5
6
7
8
9
Two other natural products, leuconodines A and C
having a hydroxy group at C6 and C10, respectively,
also displayed the SIDA phenomenon, albeit with dif-
ferent magnitude (Figure S6, S8, and S9). In the cases
of scholarisine G (Figure S4) and leuconodine C (Figure
1
S8 and S9), significantly different H NMR spectra were
obtained for racemates and enantiomers. However,
only small discrepancy in the chemical shift of H6 was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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28
29
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32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
noticed in the H NMR spectra of (±)- and (-)-
leuconodine A (Figure S6), which could be easily con-
sidered as ‘identical’ if no particular attention were
paid (Figure S6). The presence of SIDA phenomenon of
leuconodines A and C was also due to the H-bonding
induced dimer formation as evidenced from the results
of dilution experiments (Figure S7, S10, and S11) as
well as the X-ray structural analysis of both the race-
mates (Figure 3 and 4) and the enantiomers (see Sup-
porting Information). In (±)-leuconodine A, a 10-
membered ring was formed via two H-bonds between
two enantiomers (Figure 3a), while H-bond network in
(-)-leuconodine A need to be relayed by water mole-
cules (Figure 3b). In the case of (±)-leuconodine C, an
18-membered H-bonded macrocycle was generated
between two enantiomers (Figure 4). As it is evident
from our studies, there is no direct correlation between
the ring size of the H-bonding network and the magni-
tude in NMR spectra difference for these SIDA mole-
cules. On the other hand, it was found that the SIDA
phenomenon was configuration-dependent as no obvi-
ous differences were observed between racemates and
enantiomers of epi-leuconodine A, probably because
the formation of heterodimer was hindered in this case.
Finally, no obvious differences between the racemates
and enantiomers were observed in the NMR spectra of
both leuconoxine and melodinine E lacking the 7-
hydroxy group. Obviously, dimer formation was impos-
sible with these two alkaloids due to the lack of a H-
bond donor (7-hydroxy group).
Figure 2. a. X-ray Structure of (±)-Scholarisine
G (9). b. X-ray Structure of (-)-Scholarisine G
(9).
Figure 4. X-ray Structure of (±)-Leuconodine C
(13)
CONCLUSION
In conclusion, we developed a unified strategy for the
enantioselective synthesis of leuconolam-leuconoxine-
mersicarpine subfamily of Aspidosperma alkaloids. A
simple 2,6,6-trisubstituted cyclohexenone derivative
(S)-18, readily accessible by the Suzuki-Miyaura cross-
coupling reaction between enantiomerically enriched
vinyl iodide (S)-20 and 2-nitrophenyl boronic acid
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Page 12 of 15
3. O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23,
532-547.
4. (a) Xu, Z.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2013,
52, 3272-3276. (b) Wagnières, O.; Xu, Z.; Wang, Q.; Zhu, J. J.
Am. Chem. Soc. 2014, 136, 15102-15108 and references cited
therein.
5. Djerassi, C.; Budzikiewicz, H.; Wilson, J. M.; Gosset, J.; Le
Men, J.; Janot, M.-M. Tetrahedron Lett. 1962, 3, 235-239.
6. (a) Fischbach, M. A.; Clardy, J. Nat. Chem. Biol. 2007, 3,
353-355. (b) Austin, M. B.; O’Maille, P. E.; Noel, J. P. Nat.
Chem. Biol. 2008, 4, 217-222.
7. (a) Lopchuk, J. M. Prog. Heterocycl. Chem. 2011, 23, 1-25.
(b) Saxton, J. E. The Alkaloids 1998, 50, 343-376. (c) Saxton,
J. E. Chem. Heterocycl. Compd. 1983, 25, 331-437.
8. For primary communication, see: Xu, Z.; Wang, Q.; Zhu, J.
J. Am. Chem. Soc. 2013, 135, 19127-19130.
(19), served as a common intermediate for all the tar-
1
2
3
4
5
6
7
8
geted natural products. Ozonolysis of (S)-18 afforded
stable diketo ester (R)-17 that was subsequently con-
verted to two skeletally different natural products, (-)-
mersicarpine (8) and (-)-scholarisine G (9), respective-
ly. Key to the success of the structure diversification is
the fine-tuning of nucleophilicity of primary amine
(N4) and the electrophilicity of C7 carbonyl vs C21
carbonyl/iminyl groups in the putative 3H-indol-3-one
intermediate 38. Dehydration of (-)-scholarisine G (9)
afforded (+)-melodinine E (6) that was subsequently
served as springboard to reach (-)-leuconoxine (10), (-
)-leuconodine A (11), (-)-leuconodine C (13), (+)-
leuconodine F (12) and (-)-leuconolam (5). The devel-
opment of all these transformations was based on the
chemical reactivity of the hypothetic N-acyliminium
ion 7, generated in situ from (+)-melodinine E (6).
Indeed, the formation of this intermediate formally
inversed the polarity of the C6=C7 double bond and at
the same time, converted the tertiary amide to the sec-
ondary amide allowing therefore a traceless activation
of the latter function. Fine-tuning the reaction condi-
tions allowed us to introduce regio- and stereo-
selectively a hydroxy group to the C6, C7, C10 and C21
positions of melodinine E leading directly to the related
natural products. A structurally unusual oxabridged
oxadiazafenestrane 68 was formed by slow aerobic
oxidation of melodinine E (6) and conditions were
developed for a more efficient generation of this poly-
cyclic compound. During the course of this study, the
self-induced diastereomeric anisochronism (SIDA)
phenomenon was observed for scholarisine G (9), leu-
conodines A (11) and C (13). We obtained the x-ray
structures of both racemic and enantiopure natural
products. The crystal packing of these two forms nicely
explained the chemical shift difference observed in the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9. Goh, S. H.; Wei, C.; Ali, A. R. M. Tetrahedron Lett. 1984,
25, 3483-3484.
10. (a) Goh, S. H.; Ali, A. R. M. Tetrahedron Lett. 1986, 27,
2501-2504. (b) Goh, S. H.; Ali, A. R. M.; Wong, W. H. Tetra-
hedron 1989, 45, 7899-7920. (c) David, B.; Sévenet, T.; Thoi-
son, O.; Awang, K.; Païs, M.; Wright, M.; Guénard, D. Bioorg.
Med. Chem. Lett. 1997, 7, 2155-2158.
11. Banwell, M. G.; Beck, D. A. S.; Willis, A. C. ARKIVOC
2006, No. iii, 163-174.
12. Izgu, E. C.; Hoye, T. R. Chem. Sci. 2013, 4, 2262-2266.
13. Feng, T.; Cai, X.-H.; Liu, Y.-P.; Li, Y.; Wang, Y.-Y.; Luo,
X.-D. J. Nat. Prod. 2010, 73, 22-26.
14. Low, Y.-Y.; Hong, F.-J.; Lim, K.-H.; Thomas, N. F.; Kam,
T.-S. J. Nat. Prod. 2014, 77, 327-338.
15. Feng, T.; Cai, X.-H.; Zhao, P.-J.; Du, Z.-Z.; Li, W.-Q.; Luo,
X.-D. Planta Med. 2009, 75, 1537-1541.
16. Gan, C.-Y.; Low, Y.-Y.; Thomas, N. F.; Kam. T.-S. J. Nat.
Prod. 2013, 76, 957-964.
17. Abe, F.; Yamauchi, T. Phytochemistry 1994, 35, 169-171.
18. Décor, A.; Bellocq, D.; Thoison, O.; Lekieffre, N.; Chiaroni,
A.; Ouazzani, J.; Cresteil, T.; Guéritte, F.; Baudoin, O. Bioorg.
Med. Chem. 2006, 14, 1558-1564.
19. Lim, S.-H.; Sim, K.-M.; Abdullah, Z.; Hiraku, O.; Hayashi,
M.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1380-
1383.
1
H NMR spectra of racemic and enantiopure com-
20. Lim, K.-H.; Kam, T.-S. Helv. Chim. Acta 2007, 90, 31-35.
21. Numbering for monoterpene indole alkaloids, see: Le
Men, J.; Taylor, W. I. Experientia 1965, 21, 508-510.
22. (a) Hugel, G.; Lévy, J.; Le Men, J. Tetrahedron Lett.
1974, 15, 3109-3112. (b) Croquelois, G.; Kunesch, N.; Poisson,
J. Tetrahedron Lett. 1974, 15, 4427-4430. (c) Rodier, N.;
Céolin, R.; Croquelois, G.; Kunesch, N.; Poisson, J. Acta
Cryst. 1978, B34, 3682-3685.
pounds in an achiral environment.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
spectroscopic and crystallographic data. This material is
available free of charge via the Internet at
http://pubs.acs.org
23. Umehara, A.; Ueda, H.; Tokuyama, H. Org. Lett. 2014,
16, 2526-2529.
24. Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Org. Lett. 2014, 16,
AUTHOR IFORMATION
6216-6219.
Corresponding Author
jieping.zhu@epfl.ch
25. Li, Z.; Geng, Q.; Lv, Z.; Pritchett, B. P.; Baba, K.; Numajiri,
Y.; Stoltz, B. M.; Liang, G. Org. Chem. Front. 2015, 2, 236-
240.
26. Higuchi, K.; Suzuki, S.; Ueda, R.; Oshima, N.; Kobayashi,
E.; Tayu, M.; Kawasaki, T. Org. Lett. 2015, 17, 154-157.
27. Pfaffenbach, M.; Gaich, T. Chem. Eur. J. 2015, 21, 6355-
6357.
28. Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M.
Tetrahedron Lett. 2004, 45, 5995-5998.
29. Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008,
10, 1437-1440.
30. Nakajima, R.; Ogino, T.; Yokoshima S.; Fukuyama, T. J.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank EPFL (Switzerland), the Swiss National Science
Foundation (SNSF) and the Swiss National Centres of
Competence in Research (NCCR) for financial support. We
are grateful to Dr. Rosario Scopelliti for performing X-ray
structural analysis.
Am. Chem. Soc. 2010, 132, 1236-1237.
31. (a) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama, H.
Org. Lett. 2012, 14, 2320-2322. (b) Iwama, Y.; Okano, K.;
Sugimoto, K.; Tokuyama, H. Chem. Eur. J. 2013, 19, 9325-
9334.
32. Lv, Z.; Li, Z.; Liang, G. Org. Lett. 2014, 16, 1653-1655.
33. (a) Zhong, X.; Li, Y.; Han, F.-S. Chem. Eur. J. 2012, 18,
9784-9788. (b) Zhong, X.; Qi, S.; Li, Y.; Zhang, J.; Han, F.-S.
REFERENCES
1. (a) Hájíček, J. Collect. Czech. Chem. Commun. 2011, 76,
2023-2083. (b) Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod.
Rep. 2010, 27, 1630-1680 and references cited therein.
2. Buchingham, J.; Baggaley, K. H.; Roberts, A. D.; Szabó, L.
F. Dictionary of Alkaloids. 2nd ed.; CRC Press, Taylor &
Francis Group, Boca Raton, FL, USA, 2010.
ACS Paragon Plus Environment
12

Page 13 of 15
Journal of the American Chemical Society
Tetrahedron ASAP,
54. Inoki, S.; Kato, K.; Isayama, S.; Mukaiyama, T. Chem.
http://dx.doi.org/10.1016/j.tet.2014.07.095.
Lett. 1990, 19, 1869-1872.
55. Sato, M.; Gunji, Y.; Ikeno, T.; Yamada, T. Chem. Lett.
2004, 33, 1304-1305.
56. Magnus, P.; Payne, A. H.; Waring, M. J.; Scott, D. A.;
Lynch, V. Tetrahedron Lett. 2000, 41, 9725-9730.
57. (a) Pialat, A.; Liégault, B.; Taillefer, M. Org. Lett. 2013,
15, 1764-1767. (b) Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kiku-
gawa, Y. J. Org. Chem. 2002, 67, 7424-7428.
1
2
3
4
5
6
7
8
34. For formal synthesis, see: (a) Biechy, A.; Zard, S. Z. Org.
Lett. 2009, 11, 2800-2803. (b) Pfaffenbach, M.; Gaich, T.
Eur. J. Org. Chem. 2015, ASAP, DOI:
10.1002/ejoc.201500309. For synthetic studies, see: (c) Li,
H.; Cheng, B.; Boonnak, N.; Padwa, A. Tetrahedron 2011, 67,
9829-9836. (d) Li, Z.; Liang, G. Tetrahedron Lett. 2013, 54,
242-244. (e) Li, H.; Bonderoff, S. A.; Cheng, B.; Padwa, A. J.
Org. Chem. 2014, 79, 392-400.
35. Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.;
Shimizu, I. J. Org. Chem. 1987, 52, 2988-2995.
36. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190-6191.
37. Takahashi, K.; Akao, R.; Honda, T. J. Org. Chem. 2009,
74, 3424-3429.
38. (a) Myers, A. G.; Herzon, S. B. J. Am. Chem. Soc. 2003,
125, 12080-12081. (b) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457-2483.
39. Khan, A. T.; Mondal, E. Synlett 2003, 694-698.
40. (a) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.;
Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.;
Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.;
Enquist, Jr. J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.;
Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17,
14199-14223. (b) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem.
2013, 2745-2759.
41. Kabalka, G. W.; Gooch, E. E. J. Org. Chem. 1981, 46,
2582-2584.
42. (a) Hayashi, H.; Ohno, A.; Oka, S. Bull. Chem. Soc. Jpn.
1976, 49, 506-509. (b) Kappe, C. O. Liebigs Ann. Chem.
1990, 505-507.
43. (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011-1013. (b) Lu, Y.; Nguyen, P. L.; Lévaray, N.; Lebel, H. J.
Org. Chem. 2013, 78, 776-779. For a review, see: (c) Muzart,
J. Eur. J. Org. Chem. 2010, 3779-3790.
44. Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566-
14569.
58. Landvatter, S. W.; Katzenellenbogen, J. A. J. Med. Chem.
1982, 25, 1300-1307.
9
59. (a) Bartlett, P. D.; Banavali, R. J. Org. Chem. 1991, 56,
6043-6050. (b) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc.
1993, 115, 2248-2260. (c) Vanderwal, C. D.; Vosburg, D. A.;
Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125,
5393-5407. (d) Michels, T. D.; Dowling, M. S.; Vanderwal, C.
D. Angew. Chem. Int. Ed. 2012, 51, 7572-7576. For a review
on strained double bonds, see: (e) Warner, P. M. Chem. Rev.
1989, 89, 1067-1093.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
60. Inoki, S.; Takai, T.; Yamada, T.; Mukaiyama, T. Chem.
Lett. 1991, 20, 941-944.
61. For mechanistic studies of Mukaiyama epoxidation, see:
(a) Nam, W.; Kim, H. J.; Kim, S. H.; Ho, R. Y. N.; Valentine, J.
S. Inorg. Chem. 1996, 35, 1045-1049. (b) Wentzel, B. B.;
Alsters, P. L.; Feiters, M. C.; Nolte, R. J. M. J. Org. Chem.
2004, 69, 3453-3464.
62. Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37,
2922-2959.
63. (a) Soloshonok, V. A.; Klika, K. D. Helv. Chim. Acta 2014,
97, 1583-1589. (b) Martens, J.; Bhushan, R. Helv. Chim. Acta
2014, 97, 161-187. (c) Klika, K. D. Int. J. Org. Chem. 2012, 2,
224-232.
64. (a) Williams, T.; Pitcher, R. G.; Bommer, P.; Gutzwiller,
J.; Uskoković, M. J. Am. Chem. Soc. 1969, 91, 1871-1872. (b)
Horeau, A.; Guetté, J. P. Tetrahedron 1974, 30, 1923-1931.
(c) Thong, C. M.; Marraud, M.; Néel, J. C. R. Acad. Sci., Ser. C
1975, 281C, 691-694. (d) Harger, M. J. P. J. Chem. Soc.,
Chem. Commun. 1976, 555-556. (e) Harger, M. J. P. J. Chem.
Soc., Perkin II 1977, 1882-1887. (f) Harger, M. J. P. J. Chem.
Soc., Perkin II 1978, 326-331. (g) Arnold, W.; Daly, J. J.;
Imhof, R.; Kyburz, E. Tetrahedron Lett. 1983, 24, 343-346.
(h) Nakao, Y.; Sugeta, H.; Kyogoku, Y. Bull. Chem. Soc. Jpn.
1985, 58, 1767-1771. (i) Hui, R. A. H. F.; Salamone, S.; Wil-
liams, T. H. Pharm. Biochem. Behav. 1991, 40, 491-496. (j)
Jursic, B. S.; Goldberg, S. I. J. Org. Chem. 1992, 57, 7172-
7174. (k) Ouryupin, A. B.; Kadyko, M. I.; Petrovskii, P. V.;
Fedin, E. I. Chirality 1994, 6, 1-4. (l) Tait, A.; Colorni, E.;
Bella, M. D. Tetrahedron: Asymmetry 1997, 8, 2199-2207.
(m) Ghosh, S. K. J. Peptide Res. 1999, 53, 261-274. (n) Kes-
sar, S. V.; Singh, P.; Kaur, A.; Singh, S. ARKIVOC 2003, (iii),
120-124. (o) Nieminen, V.; Murzin, D. Y.; Klika, K. D. Org.
Biomol. Chem. 2009, 7, 537-542. (p) Klika, K. D.; Budovská,
M.; Kutschy, P. J. Fluor. Chem. 2010, 131, 467-476.
65. Giordano, C.; Restelli, A.; Villa, M. J. Org. Chem. 1991,
56, 2270-2272.
66. Kabachnik, M. I.; Mastryukova, T. A.; Fedin, E. I.; Vais-
berg, M. S.; Morozov, L. L.; Petrovsky, P. V.; Shipov, A. E.
Tetrahedron 1976, 32, 1719-1728.
67. Ouryupin, A. B.; Kadyko, M. I.; Petrovskii, P. V.; Fedin, E.
I.; Okruszek, A.; Kinas, R.; Stec, W. J. Tetrahedron: Asym-
metry 1995, 6, 1813-1824.
68. (a) Dobashi, A.; Saito, N.; Motoyama, Y.; Hara, S. J. Am.
Chem. Soc. 1986, 108, 307-308.
69. Huang, S.-H.; Bai, Z.-W.; Feng, J.-W. Magn. Reson.
Chem. 2009, 47, 423-427.
45. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.
J. Am. Chem. Soc. 2002, 124, 2245-2258.
46. (a) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron
Lett. 1982, 23, 3867-3870. (b) Claus, R. E.; Schreiber, S. L.;
Jeong, N.; Semmelhack, M. F. Org. Synth. 1986, 64, 150-156.
47. Hester, Jr. J. B. J. Org. Chem. 1967, 32, 3804-3808.
48. (a) Domanig, R. Munatsh. Chem. 1982, 113, 213-221. (b)
Effenberger, F.; Beisswenger, T. Chem. Ber. 1984, 117, 1497-
1512.
49. (a) Petrini, M. Chem. Rev. 2005, 105, 3949-3977. For
recent examples, see (b) Abermil, N.; Masson, G.; Zhu, J. Adv.
Synth. Catal. 2010, 352, 656-660. (c) George, N.; Bekkaye,
M.; Masson, G.; Zhu, J. Eur. J. Org. Chem. 2011, 3695-3699.
(d) Kano, T.; Yurino, T.; Asakawa, D.; Maruoka, K. Angew.
Chem. Int. Ed. 2013, 52, 5532-5534 and references cited
therein.
50. Examples of isolated tetrahedral intermediates, see: (a)
Kirby, A. J.; Komarov, I. V.; Feeder, N. J. Am. Chem. Soc.
1998, 120, 7101-7102. (b) Arai, E.; Tokuyama, H.; Linsell, M.
S.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 71-74. (c) Cox,
C.; Wack, H.; Lectka, T. J. Am. Chem. Soc. 1999, 121, 7963-
7964. (d) Adler, M.; Marsch, M.; Nudelman, N. S.; Boche, G.
Angew. Chem. Int. Ed. 1999, 38, 1261-1263. (e) Evans, D. A.;
Borg, G.; Scheidt, K. A. Angew. Chem. Int. Ed. 2002, 41,
3188-3191. (f) Szostak, M.; Aubé, J. J. Am. Chem. Soc. 2010,
132, 2530-2531. (g) Szostak, M.; Sautier, B.; Spain, M.; Beh-
lendorf, M.; Procter, D. J. Angew. Chem. Int. Ed. 2013, 52,
12559-12563. For a review, see: (h) Adler, M.; Adler, S.;
Boche, G. J. Phys. Org. Chem. 2005, 18, 193-209.
51. Krueger, P. J. Can. J. Chem. 1973, 51, 1363-1367.
52. (a) Boudhar, A.; Charpenay, M.; Blond, G.; Suffert, J.
Angew. Chem. Int. Ed. 2013, 52, 12786-12798. (b) Keese, R.
Chem. Rev. 2006, 106, 4787-4808.
70. Bergman, S. D.; Kol, M. Inorg. Chem. 2005, 44, 1647-
1654.
71. (a) Horeau, A. Tetrahedron Lett. 1969, 10, 3121-3124. (b)
Kabachnik, M. I.; Fedin, E. I.; Morozov, L. L.; Vaisberg, M. S.;
Petrovskii, P. V.; Shipov, A. E.; Mastryukova, T. A. Russ.
Chem. Bull. 1976, 25, 58-67. (c) Kabachnik, M. I.; Mastryu-
kova, T. A.; Fedin, E. I.; Vaisberg, M. S.; Morozov, L. L.; Pe-
trovskii, P. V.; Shipov, A. E. Russ. Chem. Rev. 1978, 47, 821-
53. (a) Winkler, F. K.; Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-
182. For a review of distorted amide bond, see: (b) Szostak,
M.; Aubé, J. Chem. Rev. 2013, 113, 5701-5765.
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834. (d) Fedin, E. I.; Davankov, V. A. Chirality 1995, 7, 326-
330.
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72. In their total synthesis of (-)-decarbamoylsaxitoxin, Kishi
and Hong have observed the SIDA phenomenon for one of
their synthetic intermediates and obtained an x-ray structure
of the racemic compound, see: (a) Hong, C. Y.; Kishi, Y. J.
Am. Chem. Soc. 1992, 114, 7001-7006. X-ray structure of
homo- and hetero-dimers of proline and Binol-based phos-
phoric acid have been obtained. However, SIDA were not
reported for these molecules, see: (b) Hayashi, Y.; Matsuzawa,
M.; Yamaguchi, J.; Yonehara, S.; Matsumoto, Y.; Shoji, M.;
Hashizume, D.; Koshino, H. Angew. Chem. Int. Ed. 2006, 45,
4593-4597. (c) Li, N.; Chen, X.-H.; Zhou, S.-M.; Luo, S.-W.;
Song, J.; Ren, L.; Gong, L.-Z. Angew. Chem. Int. Ed. 2010,
49, 6378-6381.
73. The 7-hydroxy leuconodine F (70) probably has the same
SIDA phenomenon because two sets signals appeared in the
1H NMR spectra of enantio-enriched sample of 70 in CDCl3.
Upon addition of CD3OD, the tiny peaks disappear, and only
one set peaks could be detected (see supporting information).
However, we did not study the SIDA phenomenon of 70 in
detail because of the limited supply of 70.
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74. Alkorta, I.; Elguero, J. J. Am. Chem. Soc. 2002, 124,
1488-1493.
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9
O
O
O
HO
H
O
H
H
N
N
N
O
N
HO
N
N
N
N
NO2
O
N3
O
O
O
6 (+)-Melodinine E 10 (-)-Leuconoxine 11 (-)-Leuconodine A 13 (-)-Leuconodine C
O
O
O
O
O
N
H
HO
H
OH
N
OH
N
N
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11
12
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O
N
N
N
O
N
N
N
O
O
H
O
O
O
8 (-)-Mersicarpine
9 (-)-Scholarisine G
5 (-)-Leuconolam 12 (+)-Leuconodine F
(-)-68
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