Diastereocontrolled Formal Syntheses of (±)-Lepadiformines A, B, and C and the Divergent Synthesis of 2- epi-Lepadiformine C through Unexpected Double Consecutive Epimerizations

Article abstract of DOI:10.1021/acs.joc.0c00964

We describe here the diastereocontrolled formal racemic syntheses of tricyclic marine alkaloids, lepadiformines A, B, and C as well as their C2 epimers, featuring divergent and stereoselective syntheses of the N-acetyl-8a-cyanodecahydroquinoline frameworks and the base-mediated intramolecular cyclization to establish the spiral quaternary center of the tricyclic framework from sterically well-defined α-aminonitrile 2. The approach allows us to accomplish the tricyclic core structure efficiently from readily available starting materials through simple operations. An unexpected pair of consecutive epimerizations at two contiguous stereocenters is observed on the basis of single-crystal X-ray analyses of the intermediates and derivatives. The findings have been successfully applied to the total synthesis of 2-epi-lepadiformine C. The epimerization mechanism has been elucidated through a series of deuterium-labelling-controlled experiments.

Full text of DOI:10.1021/acs.joc.0c00964

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Article
Diastereocontrolled formal syntheses of (±)-lepadiformine A,
B, and C and the divergent synthesis of 2-epi-lepadiformine
C through unexpected double consecutive epimerizations
Jui-Lin Wu, and Wen-Hua Chiou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00964 • Publication Date (Web): 25 Jun 2020
Downloaded from pubs.acs.org on June 25, 2020
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Page 1 of 24
The Journal of Organic Chemistry
Title: Diastereocontrolled formal syntheses of (±)-lepadiformine A, B, and C and the divergent synthesis of
2-epi-lepadiformine C through unexpected double consecutive epimerizations
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Authors: Jui-Lin Wu and Wen-Hua Chiou*
Address: Department of Chemistry, National Chung-Hsing University, Taichung 402 Taiwan, R.O.C.
Corresponding Author's E-mail address: wchiou@dragon.nchu.edu.tw.
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Abstract: We describe here the diastereocontrolled formal racemic syntheses of tricyclic marine alkaloids
lepadiformine A, B and C and their C2 epimers, featuring divergent and stereoselective syntheses of the
N-acetyl-8a-cyanodecahydroquinoline frameworks and the base-mediated intramolecular cyclization to
establish the spiral quaternary center of the tricyclic framework from sterically well-defined α-aminonitrile
2. The approach allows us to accomplish the tricyclic core structure efficiently from readily available
starting materials through simple operations. An unexpected pair of consecutive epimerizations at two
contiguous stereocenters is observed on the basis of single-crystal X-ray analyses of the intermediates and
derivatives. The findings have been successfully applied to the total synthesis of 2-epi-lepadiformine C. The
epimerization mechanism has been elucidated through a series of deuterium-labelling controlled
experiments.
CN
Lepadiformine A (1a), R1 = n-Hex, R2 = CH OH
2
R1
Lepadiformine B (1b), R1 = n-Bu, R2 = CH OH
2
R2
R1
R1
N
R1
Lepadiformine C (1c), R1 = n-Bu, R2 = H
perhydropyrrolo[2,1-j]quinolone (1), R1 = R2 = H
CN
Ac N
N
O
H
5
4
H
H
H
R1
H H
N
R1
Cbz NH
2
C2-epi-Lepadiformine C, R = n-Bu
N
N
H
H
H
15
NC
18
Ac
O
Introduction:
In 1994, Biard and Clardy reported the isolation of a tricyclic alkaloid Lepadiformine A (1a), from the
1
marine ascidian Clavelina lepadiformis Müller in Tunisia. The correct stereochemistry of lepadiformine A
2
(1a) was established through total synthesis by Kibayashi and coworkers in 2000. The absolute
3
configuration was determined by Weinreb's enantioselective total synthesis in 2002, confirmed shortly
afterwards by the Kibayashi group4,5 in the same year. In 2006, the analogues lepadiformine B (1b) and C
(
1c) were isolated from C. moluccensis by Sauviet and coworkers in Djibouti waters (Figure 1).6
7
8
9
6
A
10
H
A
H
5
11
5
4
10
12
B
B
1
C
C
R2
2
3
N
R1
N
N
13
13
1
NCS
H
R2
14
2
H
H
H
H
R1
n-Hex
1
2
Lepadiformine A (1a), R = n-Hex, R = CH OH
2
1
2
Fasicularin
Lepadiformine B (1b), R = n-Bu, R = CH OH
2
1
2
Lepadiformine C (1c), R = n-Bu, R = H
1
2
perhydropyrrolo[2,1-j]quinolone (1), R = R = H
Figure 1. The structures of lepadiformine A, B, C and fasicularin.
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Sauviat and coworkers reported lepadiformines A ~ C show strong cardiovascular effects in vitro and in
vivo. Lepadiformine A blocks the inward rectifier K current (IK1) with the K of 1.4 µM. The research
results reveal that the length of the aliphatic chain at the C2 position is involved with the blockage degree.
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D
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Compared to lepadiformine A, lepadiformine B ihibits IK1 by 54%. In addition, these alkaloids exhibit
cytotoxicity against several tumor cell lines as well as antiarrhythmic and antihypertensive properties. 1,7 The
unique perhydropyrrolo[2,1-j]quinolone structure (1) and the promising biological activities have prompted
chemists to develop various intellectual and elegant strategies toward their synthesis. 8, 9
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As one of the special and interesting bifunctional compounds, the α-aminonitrile is a versatile
intermediate for a wide range of synthetic applications and receives an enormous amount of attention since
9
the first discovery by Strecker in 1850. The reactivity modes of α-aminonitriles can be classified in to four
types, briefly described as follows (Scheme 1):
Scheme 1. Reactivity modes of α-aminonitriles
R2
R3
R2
R3
N
N
-
CN
+ R-M
+ E
(1)
(2)
C
R1
C
R1
R
A
R2
R3
R2
R3
N
N
C
B
+2e
CN
C
R1
-
R2
R3
R1
R3
E
N
R2
R2
R3
C
R1
CN
N
C
C
N
C
E
+B
R1 = H
+ E
(3)
(4)
CN
CN
R2
R3
R2
R3
+Nuc
N
+ H O
N
2
C
R1
N
C
R1
O
C
C
Nuc
Nuc
(1) Dissociation of the nucleofugal cyanide group under suitable conditions produces iminium
intermediate A for further transformations. The process is also known as the Bruylants reaction. Weinreb
and coworkers demonstrated the elegant manipulation of α-aminonitriles in the synthesis of enantiopure
3
lepadiformine A (–)-(1).
(2) Treatment with a strong reducing agent like LiDBB (lithium
4,4’-di-tert-butylbiphenylide) generates a stabilized carbanion B. (3). The base-mediated α deprotonation
allows for the formation of a nitrile-stablized anion C. Both carbanion B and carbanion C can be
transformed to various adducts. Rychnovsky and coworkers adroitly employed type 2 and type 3 reactions,
1
0
to achieve a variety of spirocyclic ring systems, including lepadiformine B. (4) The electrophilic nature of
the nitrile group permits nucleophilic reactions, and constitutes many synthetic transformations to valuable
chemicals.
Recently, we serendipitously found a convenient access to quaternary α-aminonitrile 2 with good
stereoselectivity on a decagram scale, with the configurations of which are related to those of the quaternary
center and the AB junction of the lepadiformine family (Scheme 2).
a
Scheme 2. Our synthetic plan for lepadiformines using α-aminonitrile 2
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H
O
1
CN
(
a)
A
B
2
3
4
A
R
R
R1
N
Cbz NH
, 91% CCDC1934698 3, R1 = H
2 R = CH=CH
2
NC
Cbz
3
a, R1 = n-Hex
R = CH=CH
R = C≡CH
2
1
5
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9
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3b, R = n-Bu
2' R = C≡CH, 74%
H
A
H
H
ref 13
R1
C
N
B
N
N
NC
H C
R2
0
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O
R1
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R1
H
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4
5
aReagents and conditions: (a) (i) NH3(l), MeOH, -50 °C to 0 °C, (ii)
KCN, NH Cl, NH (aq), rt, (iii) CbzCl, K CO , THF, H O, 0 °C to rt.
4
3
2
3
2
The B ring was established by intramolecular condensation with an aldehyde derived from the allyl
group of 2, and completed the 8a-cyanodecahydroquinoline (8a-CDHQ) framework 3. At this stage, an alkyl
side chain was introduced by Lewis-acid mediated reductive alkylation with excellent diastereoselectivity to
give a syn adduct.11 We envisioned that direct manipulations of the angular nitrile to other carbonyl
derivatives may be difficult due to the sterically demanding nature. Therefore, we considered an
intramolecular addition on the nitrile, inspired by an amide group assisted hydrolysis of
12
α-amino-adamantane-2-carbonitrle, a very steric hindered nitrile group. With a carbon nucleophile in the
framework, the C-ring was established via an intramolecular condensation, thus we turned our attention to
the acetamide 4 instead. Assembly of the C ring as a γ-lactam proceeded by base-mediated condensation of
the acetamide with the angular nitrile to furnish the tricyclic lactam core as the Renaud's intermediate 5,13
which therefore constituted a formal synthesis of lepadiformine alkaloids.
We wish to present here our divergent approach to the syntheses of the lepadiformine alkaloids as well
as their C2 epimers from readily available α-aminonitrile 2, and the clear experimental and theoretical
explanations for the unexpected pair of epimerizations. The discovery of these epimerizations allowed a
synthetic route to the C2-epimers of the alkaloids, the configurations of which are identical with those in the
A and B rings of marine alkaloid fasicularin.
Results and Discussion:
Our synthesis started from readily available quaternary α-aminonitriles 2 and 2’, which were
1
4
synthesized by the Strecker reaction of 2-allylcyclohexanone or 2-propargylcyclohexanone with cyanide in
ammonia (Scheme 2). The unstable free α-aminonitriles were immediately protected with CbzCl to yield 2
and 2’ in good yields. The reaction proved highly diastereoselective, providing a single stereoisomer whose
15
stereochemistry was established by X-ray crystallographic analysis (CCDC no. 1934698). Both the cyano
group and the methine proton are at the axial positions of the chair cyclohexane ring.
After extensive surveys on hydroboration conditions (e.g., B
workup conditions to effect an efficient anti-Markovnikov hydration of the terminal alkene to alcohol 6, we
found that the use of Sia BH followed by the sodium perborate workup was the best combination giving 6 in
3% yield (Scheme 3). Dess-Martin Periodinane (DMP) oxidation of 6 led to an inseparable isomeric
2
H
6
, 9-BBN, Sia
2
BH and Cy
2
BH) and
2
9
mixture 7 of an acyclic aldehyde and the cyclic hemiaminal (~ 1 : 2) in 82% yield along with enamide 3’
15
(
CCDC no. 1911886), which formed from dehydration of the cyclic hemiaminal. But it did not concern us
unduly because subsequent boron trifluoride mediated triethylsilane reduction could produce the 8a-CDHQ
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3
in 78% yield. Another short cut was hydration of α-aminonitriles 2’, through the Sia BH protocol followed
2
1
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9
1
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2
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2
2
2
2
3
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5
5
5
5
5
5
5
5
5
5
6
by the silane reduction of the crude product, to afford 3 in 53% yield over two steps (unoptimised).
Although removal of the Cbz group was easily accomplished by treating 3 with Pd/C in methanol under
atmosphere, the followed acetylation to acetamide 4 proved more difficult than we originally anticipated.
H
2
1
6
The acetylation was successfully performed by treatment with a reactive acetylating agent, generated by
15
mixing acetyl chloride and Et
3
N in dichloromethane at -78 ℃, to yield 4 (CCDC no. 1911884) in 74 %
0
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9
0
yield over two steps. To our delight, simple treatment of N-acetyl-8a-CDHQ (4) with LiHMDS at -78 ℃
followed by an acidic workup delivered the tricyclic ketone 8 in 90% yield.17 Obviously, the enolate
moiety could engage the axial nitrile group to construct the C ring. The resulting iminium moiety was
hydrolyzed to the ketone 8 during the acidic workup.
After reduction of 8 with NaBH , the resulting secondary alcohol was converted to a mesylate, which
4
was treated with DBU to afford conjugated lactam 9 in 86% overall yield for the three-step sequence.
Meanwhile, direct esterification of the crude alcohol with para-nitrobenzoyl chloride yielded benzoate 10 as
a single isomer in 84% yield over two steps, the structure of which was established unequivocally by X-ray
15
analysis (CCDC no. 1911885). The X-ray structure confirmed the present tricyclic structure, and disclosed
the hydride reduction proceeds to the C11 carbonyl group with excellent diastereoselectivity, through the
space of the B ring side. Catalytic hydrogenation of 9 furnished the tricyclic lactam core 5 in 94% yield, a
versatile intermediate to other alkaloids. LiAlH
6% yield.
Scheme 3. Synthesis of perhydropyrrolo[2,1-j]quinolone (1) a
4
reduction afforded perhydropyrrolo[2,1-j]quinolone (1) in
7
Ar COO
H
CN
CN
CN
CN
CN
(
a)
(b)
+
Cbz N
N
Cbz NH
Cbz NH
Cbz NH
Cbz N
O
N
93%
3', 9%
CCDC1911886
10, 84%. two steps
CCDC1911885
Ar = 4-NO C H -
1
2
6
O
OH
OH
CN
7, 82%
CCDC1934698
(
c), 78%
(k) 76%
2
6 4
O
CN
CN
(g), (h)
(g), (j)
(
a), (c)
53%
(
d), (e)
(f)
0%
(d)
Ac N
N
Cbz N
94%
9
N
O
N
Cbz NH
3
4, 74%, two steps
O
O
two steps
9, 86%. two steps
5
2
'
8
CCDC1911884
a
Reagents and Conditions: (a) (i) Sia BH, THF, rt, (ii) NaBO , H O, 0 °C to rt; (b) DMP, CH Cl , 0 °C to rt; (c) Et SiH, BF -OEt , CH Cl , -78
2
3
2
2
2
3
3
2
2
2
°C to 0 °C; (d) Pd/C, H , MeOH, rt; (e) AcCl, Et N, CH Cl -78 °C to 0 °C; (f) (i) LiHMDS , THF, -78 °C to 0 °C, (ii) HCl EtOAc, reflux; (g)
(aq)
2
3
2
2
NaBH , MeOH, 0 °C; (h) p-NO C H COCl, pyridine, reflux; (j) (i) MsCl, Et N, CH Cl , 0 °C, (ii) DBU, CH Cl , reflux; (k). LiAlH . THF, reflux.
4
2
6
4
3
2
2
2
2
4
Having demonstrated that perhydropyrrolo[2,1-j]quinolone (1) could be readily achieved based on the
developed transformation sequence, we sought to apply the strategy to our goal (Scheme 4). Since the
lepadiformine targets differ in a linear side chain, our approach is to introduce an allyl group at the C2
position as a common intermediate, and then extend to either a four or six carbon appendage afterwards,
according to appropriate functional group transformations.18 Thus, direct treatment of 7 with
trimethylallylsilane and BF
3
∙OEt yielded 11 in 77% yield as a single isomer. Subsequent hydration to
2
alcohol 12 was achieved in 94% yield according to the hydroboration–oxidation conditions. DMP oxidation
of 12 generated aldehyde 13 in 96% yield. The aldehyde 13 was allowed to react with the Wittig
phosphoranes, either Ph
3
P=CHCH
2
CH
3
or Ph
3
P=CH
2
, to produce 14a in 84% yield (cis/trans ~ 10:1) and
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The Journal of Organic Chemistry
1
4b in 77% yield, respectively. The structure of 14b is confirmed unequivocally by X-ray analysis (CCDC
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
no. 1920894, Scheme 4), which discloses the syn relationship between the nitrile group and the C2
substituent, and suggests that the silyl addition proceeds in a syn manner.19
a
Scheme 4. Syntheses of 2-substituted 8a-CDHQ 14a and 14b, and the X-ray structure of 14b
R
OH
O
CN
CN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN
CN
(
a)
(b)
2
(c)
96%
2
(d)
2
7
C4a
77%
Cbz N
94%
C2
N
Cbz N
Cbz
N
C2
Cbz
H
H
H
H
C8a
1
1
12
13
14a, R = Et, 84% cis/trans ~ 10:1
4b, R = H, 77% CCDC1920894
1
a
Reagents and Conditions: (a) CH =CHCH SiMe , BF -OEt , CH Cl , -90 °C to 0
2
2
3
3
2
2
2
X-ray structure of 14b
°C; (b) (i) Sia BH, THF, rt, (ii) NaBO , H O, 0 °C to rt; (c) DMP, CH Cl , 0 °C to rt;
2
3
2
2
2
(d) Ph PCH R-Br, LiHMDS, 0 °C, THF, 0 °C then 13 -78 °C to rt.
3
2
Exposure of alkene 14a under the catalytic hydrogenation conditions reduced the double bond and
remove the Cbz group in one pot, acetylation then afforded acetamide 15a in 69% yield for the two-step
sequence, while the identical transformation for n-butyl analogue 14b afforded 15b in 78% yield (Scheme 5).
The acetamide 15b was treated with LiHMDS at low temperature, and then hydrolyzed under acidic
conditions, affording the ketone 16b in 84% yield. This tactic was employed for the formation of 16a in
9
0% yield. The ketone 16a and 16b were subjected to the reduction–mesylation–elimination sequence to
yielded 17a in 67% overall yield and 17b in 94% overall yield, respectively. Catalytic hydrogenation of 17a
and 17b yielded the tricycle 18a and 18b in good yield, respectively. However, there are non-negligible
1
3
20
differences in the C-NMR spectrum of 18b from the reported data (See the spectrum comparison in the
Figure S2 in the Supporting Information). In addition, subsequent LiAlH reduction of 18b afforded 98%
yield of the tricyclic amine 19b, which was expected to be lepadiformine C. But the C NMR spectrum was
4
1
3
2
1
not consistent with that reported in literature (see the comparison in the Figure S3). Therefore, impeccable
evidence for the structure determination is necessary to account for the inconsistency.
a
Scheme 5. Syntheses of C2-epi tricyclic lactam 18a, 18b, and C2-epi-lepadiformine C (19b) and the X-ray
structure of 20b
R
H
H
R1
R1
H
R1
CN
(c)
(d), (f)
Ar COO
(
a), (b)
2
N
N
H
H
N
H
O
Cbz N C2
NC
O
O
H
O
15a, 69% R1 = n-Hex, two steps 16a, 90%
1
4a, R = Et
20a, 40%, CCDC1920877
20b, 79%, CCDC1920876
C5
1
4b, R = H
1
5b, 78% R1 = n-Bu, two steps
16b, 84%
(d), (e)
H
Ar = 4-NO C H -
2
6 4
C10
C2
H
H
R1
R1
R1
(
a)
(g)
N
N
H
H
N
H
9
8%
O
O
1
1
7a, 67%, two steps
18a, 95%
18b, 95%
C2-epi-Lepadiformine C
(19b), R1 = n-Bu
X-ray structure of 20b
7b, 94%, two steps
a
Reagents and Conditions: (a) Pd/C, H , MeOH, rt; (b) AcCl, Et N, CH Cl -78 °C to 0 °C; (c) (i) LiHMDS, THF, -78 °C to 0 °C,
2
3
2
2
(ii) HCl(aq) EtOAc, reflux; (d) NaBH , MeOH, 0 °C; (e) (i) MsCl, Et N, CH Cl , 0 °C , (ii) DBU, CH Cl , reflux; (f)
4
3
2
2
2
2
p-NO C H COCl, pyridine reflux; (g) LiAlH , THF, reflux.
2
6
4
4
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1
5
Gratifyingly, the X-ray crystal structures of the benzoate derivatives 20a (CCDC no. 1920877) and
20b (CCDC no. 1920876, Scheme 5), obtained through the aforementioned reduction-esterification protocol,
unambiguously established the trans relationship between the C2 methine and the bridged methine (C5), and
the trans disposed alkyl chain with respect to the C-ring. It is surprising to learn that unexpected
configuration changes occurred during transformations from 14a to 20a and those from 14b to 20b. Among
three relative configurations between the C2, C4a and C8a stereocenters in the 2-substituted 8a-CDHQ
framework, except one configuration between C4a and C8a retains the original trans configuration, the other
two configurations, i.e. that between C2 and C4a and that between C2 and C8a, have been switched to the
opposite ones (See the relative stereochemistry among C2, C5 and C10 in the X-ray structure of 20b). In
light of the results, there are two possible causes for the observation: One is the epimerization proceeds only
at the C2 position, and the relationships to C2 changes accordingly. The other is that the epimerizations take
place at both the C4a and the C8a positions. Therefore, their mutual relationship retains while their
relationships to C2 is inverted. Thus, a series of isotope experiments are carried out to find the cause.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Figure 2. The C-NMR spectra of the crude free amine product from isotope labelling experiments in the
Pd-catalyzed hydrogenation conditions.
When DCl/D O were added in the hydrolysis stage after LiHMDS treatment of 4 and 15a, there was no
2
deuterium incorporation. The results excluded the possibility of base-mediated epimerization(s) at the labile
methine position(s), and suggested the epimerization occurred at an early stage. We therefore considered the
last reaction, i.e. H
2
and Pd/C in CH OH, in which the olefin hydrogenation and the Cbz deprotection
3
proceeded concurrently. Analyses on the 13C and DEPT spectra of the crude free amine product after
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The Journal of Organic Chemistry
treatment of 14a under the conditions provided valuable information for peak assignments (a, in Figure 2).
As H was replaced by D (b, in Figure 2), two methine peaks remained intact and two peaks in the upper
region changed, which showed that only saturation of the olefin with deuterium occurred. When the reaction
was carried out in CD OD under D , it was surprising to find that the resonances of C4a, C8 and two peaks
in the upper region disappeared (c, in Figure 2). Moreover, replacement with CD OD under H resulted in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
3
2
3
2
the absence of both peaks of C4a and C8a, but two peaks at the upper region came out again (d, in Figure 2).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Miyazawa and coworkers reported a Pd/C catalyzed retro reductive amination process via the
2
2
corresponding imine. The process might allow for the epimerization at the C2 position. However, based on
the observation that the C2 methine keeps intact in the four conditions, the C2 configuration needs to be
retained in the reaction. Moreover, one can conclude that the presence of methanol triggers the observed
epimerization process because the peaks of C4a and C8 disappear only in CD
3
OD. The resulting epimerized
8
a-CDHQ is then acetylated to the epimerized acetamide 15a, instead of 4a as we anticipate. Such an
epimerization process is probably driven thermodynamically by product stability. Thus, we propose a
mechanism as shown in Scheme 6:
Scheme 6. The proposed mechanism for the consecutive double epimerizations
H
CN
R
Pd/C / H2 /MeOH
H
-
PhMe, -CO2
N
H
R
2
Cbz N
2
NC
I
H
1
4b R = 3-butenyl CCDC 1920894
-CN
H
H
H+
-
4
a
H
R
+
H
R
H
N
H
N
H
N
H
R
8
a
8
H
III-a
III-b
II
+H+
H
R
H
H
+CN
N
2
H
H
H
R
Ar COO
N
H
R
N
H
O
NC
IV
V
20b CCDC1920876
Ar = 4-NO C H -, R = n-Bu
2
6 4
Removal of the Cbz group of 14 in methanol produces free amine I. The free α-aminonitrilie I can
undergo a retro-Strecker reaction to form an iminium intermediate II through release of the cyanide in a
locally basic environment. Subsequent loss of a β hydrogen at either the C4a or C8 positions of iminium
intermediate II produces two possible enamine intermediates III-a and III-b. Protonation of the enamine
intermediate III with solvent affords other stable iminium IV, and then cyanide addition follows to generate
another stable amine epimer V.
To verify the hypothesis, we performed DFT calculations to find the relative energies of all six possible
conformers of both trans- and cis-8a-CDHQ, with a methyl group at the C2 position (Figure 3). The
calculations were carried out at the level of B3LYP/6-311++G (d, p) as well as those in methanol using the
CPCM model. To minimize the calculation cost, we substituted a methyl group at the C2 position. The
results shows that the epimerized amine V bearing with an equatorial methyl group is more stable than the
amine I bearing with an axial methyl group by 4.7 kcal/mol. The values in gas phase are consistent with
those in methanol. Moreover, the compound is also the most stable product among all six possible
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conformers.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 3. Relative energies of the free trans- and cis 2-methyl-8a-CDHQs. The values (kcal/mol) in the
parenthesis are their relative energies in methanol
Me
CN
CN
Me
Me
H
H
N
NC
H
N
H
N
H
H
H
H
H
I : +4.7 (+4.7)
I
cis-1: +6.4 (+6.4)
I
cis-2: +8.8 (+9.5)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
H
H
H
NC
N
Me
N
H
N
H
Me
H
H
NC
H
CN
H
Vcis-2 : +1.9 (+1.9)
V : 0.0 (0.0)
V
cis-1: +4.3 (+5.0)
Having confirmed the unexpected epimerizations were attributed to the conditions of Pd-catalyzed
hydrogenation in methanol , we employed an acidic method to remove the protecting group, rather than
neutral conditions. Thus, the acid-labile olefin group was supposed to be saturated before removal of the
Cbz group (Scheme 7). The saturation of the C=C bond in the side chain of 14b was successfully achieved
2
3
by the Naota's aerobic hydrogenation conditions, i.e. in situ generation of diimide by flavin mediated
aerobic oxidation of hydrazine, to furnish 3b in 98% yield. Treatment within a HBr solution containing
acetic acid 24 as the co-solvent at 60 ℃ cleaved the Cbz group smoothly, followed by the acetylation to
give 4b in 86% yield. The structures of both 4b and 3b were determined by X-ray analyses, which disclosed
25
the cis relationship between the cyano group and the n-butyl group continued from 14b to 4b (CCDC no.
15
1
952224 for 3b; CCDC no. 1947629 4b). Obviously, the acidic conditions prevented the epimerization
effectively. Meanwhile, the acetamide 4a could be achieved using the three-step sequence from 14a. As the
cyclization conditions mentioned above, treatment of 4b with base and then an acidic workup furnished 21b
in 66% yield, while that of 21a in 54% yield (Scheme 7).
Scheme 7. Syntheses of lepadiformine A (1a), B (1b), and C (1c) a
R
O
CN
CN
R1
R1
CN
(
b), (c)
(d)
(e), (f)
(g)
(a)
2
Ac N
N
R1
N
R1
Cbz N
N
R1
O
O
Cbz N
H
H
O
H
H
H
4a, R = Et, cis/trans ~ 10:1 3a, R1 = n-Hex, 96%
4b, R = H, CCDC1920894 3b, R1 = n-Bu, 98%, CCDC1952224 4b, 86%, two steps
4a, 53%, two steps
H
1
1
21a, 54%
21b, 66%
22a, 84%, two steps
5a, 100%
5b, 100%
22b, 26%, two steps
CCDC1947269
R2
ref 13, 20a
N
a
R
Reagents and Conditions: (a) H NNH , riboflavin tetrabutyrate, O , CH CN, rt; (b)
2
2
2
3
H
Lepadiformine A (1a), R1 = n-Hex, R2 = CH OH
Lepadiformine B (1b), R1 = n-Bu, R2 = CH
Lepadiformine C (1c), R1 = n-Bu, R2 = H
HBr(aq), AcOH, 60 °C; (c) AcCl, Et N, CH Cl , -78 °C to 0 °C; (d) (i) LiHMDS, THF,
3
2
2
2
2
OH
-78 °C to 0 °C, (ii) HCl(aq), EtOAc, reflux; (e) NaBH
, MeOH, 0 °C. (f) (i) MsCl, Et N,
4 3
CH Cl , 0 °C, (ii) DBU, CH Cl , reflux; (g) Pd/C, H , MeOH, rt.
2
2
2
2
2
The ketone 21a was subjected to the reduction–mesylation–elimination protocol as stated above to
produce 22a in 84% overall yield, which was hydrogenated to 5a in quantitative yield. The synthesis of
other analogue, 5b was achieved from 21b by using the same protocol. The spectral data of 5a and 5b were
in good agreement with those reported in the literature (See the Figure S1 in the Supporting Information for
5
b).13, 20 As the intermediate to the syntheses of the lepadiformine family, the lactam 5a can be further
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converted into lepadiformine A (1a) according to the Renaud's protocol,13 which can be applied to
transformation of lactam 5b to lepadiformine B (1b). Moreover, while the synthesis of epi-lepadiformine C
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
19b) was accomplished in 98% yield by LiAlH reduction of lactam 18b (Scheme 4), lepadiformine C (1c)
4
could be obtained by the same reduction of the lactam 5b, as demonstrated by Aubé and coworkers. 20a
Conclusion:
In conclusion, concise, divergent and parallel formal racemic syntheses of marine alkaloids
lepadiformine A, B and C have been developed, as well as their C2 epimers from the facile preparation of
α-aminonitrile 2. The approach highlights the fully diastereoselective syntheses of the α-aminonitriles and
the 2-substituted 8a-cyanodecahydroquinoline frameworks, and the base-mediated intramolecular
cyclization, crafting the tricyclic core structure with the spiral quaternary carbon. Subsequent functional
group transformations afford the tricyclic lactam 5; this constitutes a formal synthesis of lepadiformine A, B
and C. Perhydropyrrolo[2,1-j]quinolone core (1) can be accomplished in nine steps with 22% overall yield
from α-aminonitrile 2’. These reactions are ligand-free, readily scalable, and operationally simple, not
requring expensive chemicals.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
An unexpected epimerizations at two contiguous stereocenters observed by single-crystal X-ray
analyses, has been elucidated to occur at two bridged stereocenters of the 8a-CDHQ framework. Controlled
experiments with deuterated reagents clearly demonstrate that the epimerizations originate in the
thermodynamically driven isomerism through the retro-Strecker/ imine-enamine interchange /Strecker
sequence when the free amine has been formed. Such a finding provides a supplementary route to syntheses
of the C2-epimers of lepadiformine alkaloids, demonstrated by the synthesis 2-epi-lepadiformine C. The
application of this methodology in the synthesis of other azatricyclic ring systems and the computational
details are currently under investigation within our laboratory.
Experimental Section:
All reactions were performed under an argon atmosphere and in anhydrous solvent, unless otherwise
stated. An oil bath was used for the heat source. The solvents and reagents have been dried or refined
according to the literature procedures. The reaction flasks were dried in a 110 °C oven and allowed to cool to
room temperature in a desiccator with drying agents and assembled under argon atmosphere. TLC analyses
were visualized with UV light, iodine chamber, 10% sulfuric acid or 10% PMA solution. The crude product
were purified by flash column chromatography on silica gel to give isolated yield. IR spectra were recorded
on an ATR-FTIR apparatus. Melting points were recorded on a melting apparatus. X-ray crystal structure
determination have been carried out on an X-ray apparatus and the results have been checked to obtain the
1
13
corresponding CCDC number. All NMR spectra, i.e., H, C, DEPT, gCOSY, gHSQC, and gHMBC were
recorded on a 400 MHz or 600 MHz NMR spectrometer, which provided all necessary data for the full
assignment of each compound. Chemical shifts (δ) are reported in ppm using residual undeuterated solvent
as an internal standard. Coupling constants are described in hertz (Hz). Mass spectra were recorded on a
mass spectrometer with a magnetic sector, using the electrospray ionization (ESI) or fast atom bombardment
(FAB).
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Preparation of E-2-Alkyl-1-benzyloxycarbonylamino-1-cyanocyclohexane: To a 250 mL three-necked
flask equipped with a cold finger condenser at -50 ℃ in a well-ventilated hood, ammonia gas is slowly
passed through the system until ca. 40 mL of liquid ammonia has been formed. Under slow flow rate of
ammonia atmosphere, the condenser is replaced with an addition funnel containing 2-allylcyclohexanone
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(10.0 g, 72.4 mmol) dissolved in ca. 30 ml. of methanol. The solution is added to the liquid ammonia, and
the funnel is rinsed with a little methanol. The resulting ammonia-methanol solution is warmed up to 0 ℃
and stirred for 1 h. To the solution is added potassium cyanide (6.13 g, 94.1 mmol, 1.3 eq), ammonia
chloride (8.90 g, 166 mmol, 2.3 eq) and aqueous ammonia (28%, 64 mL) in sequence. After addition has
been complete, the outlets of the reaction flask are equipped with a drying tube, and the solution is stirred at
room temperature overnight. Small amount of water is added to dissolve the solid precipitate, and the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
resulting reaction mixture is extracted with CH
2
Cl
2
(30 mL × 4). The combined organic layers are washed
with brine (30 mL), dried over anhydrous MgSO
4
, filtered and concentrated in vacuo to give a crude
2
6
α-aminonitrile product. The crude product is used directly without further purification.
To a THF solution (96 mL) of crude α-aminonitrile, K CO (28.0 g, 203 mmol, 2.8 eq) in water (48 mL)
2
3
was added and the solution is stirred for 10 min in an ice bath. CbzCl (15.5 mL, 109 mmol, 1.5 eq) is added
slowly via a syringe. After the addition has been finished, the ice bath is removed and the solution is stirred
at room temperature overnight. Separated from the reaction mixture, the aqueous layer was subjected to
extraction with EtOAc (30 mL × 4). The combined organic layers are washed with brine (30 mL), dried
over anhydrous MgSO , filtered and concentrated in vacuo to give a crude α-aminonitrile product.
4
Purification of the crude product by flash chromatography on silica gel, using EtOAc/n-Hex as the eluant
afforded the titled product.
E-2-(2-Propenyl)-1-benzyloxycarbonylamino-1-cyanocyclohexane (2): White solid, (19.8 g, 66.2 mmol,
1
91%): mp = 68-70 ℃, recrystallized from CH
NMR (400 MHz, CDCl
1H), 2.00 – 2.13 (m, 1H), 2.46 – 2.59 (m, 1H), 2.73 (d, J = 12.5 Hz, 1H), 5.03 – 5.19 (m, 4H), 5.29 (brs, 1H),
2
Cl
2
, CCDC no. 1934698; R
f
= 0.29 (EtOAc/Hex = 1 : 5); H
3
) δ 1.14 – 1.29 (m, 1H), 1.29 – 1.43 (m, 1H), 1.46 – 1.78 (m, 5H), 1.86 – 1.96 (m,
1
3
1
5
.65 – 5.80 (m, 1H), 7.21 – 7.45 (m, 5H); C{ H} NMR (101 MHz, CDCl
(CH ), 35.5 (CH ), 36.1 (CH ), 43.8 (CH), 57.4 (C), 67.2 (CH ), 117.7 (CH
CH), 128.5 (CH), 135.3 (CH), 135.7 (C), 154.1 (C); IR (cm , film): max = 3319, 3068, 3035, 2939, 2863,
3
) δ 22.5 (CH
2
), 24.4 (CH ), 28.3
2
2
2
2
2
2
), 118.0 (C), 128.2 (CH), 128.3
-1
(
+
+
1703, 1642, 1524, 1453, 1256, 1025, 915; EI-HRMS (m/z) : [M] calcd for C18
98.1685 (Δ = -3.0 ppm).
H
22
N
2
O
2
298.1676, found
2
E-2-(2-Propynyl)-1-benzyloxycarbonylamino-1-cycanocyclohexane (2’): White solid (3.05 g, 10.3 mmol,
1
7
1
2
1
4%), mp = 100-102 ℃; R
f
= 0.43 (EtOAc/Hex = 1 : 3); H NMR (400 MHz, CDCl
3
) δ 1.17 – 1.33 (m, 1H),
.35 – 1.66 (m, 3H), 1.66 – 1.80 (m, 2H), 1.80 – 1.94 (m, 1H), 1.97 – 2.11 (m, 2H), 2.15 – 2.31 (m, 1H),
13
1
.56 – 2.79 (m, 2H), 5.01 – 5.18 (m, 2H), 5.80 (s, 1H), 7.17 – 7.49 (m, 5H); C{ H} (101 MHz, CDCl
3
) δ
54.3 (C), 135.8 (C), 128.6 (CH), 128.3 (CH), 128.2 (CH), 117.5 (C), 81.9 (C), 71.0 (CH), 67.2 (CH
2
), 57.6
-1
(
C), 43.8 (CH), 36.2 (CH
2
), 29.0 (CH
2
), 24.5 (CH
2
), 22.5 (CH
2
), 21.4 (CH
2
); IR (cm , film): max = 3305,
+
+
2
2
941, 2864, 2241, 2120, 1704, 1522, 1256; EI-HRMS (m/z) : [M] calcd for C18
96.1517 (Δ = 0.7 ppm).
H
20
N
2
O
2
296.1519, found
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General Procedure for the Hydroboration-Oxidation: To a BH
1.8 eq) in an ice bath, was slowly added 2-methyl-2-butene (5.1 mL, 48 mmol, 3.6 eq) via a syringe. The
solution was stirred for 2 h in an ice bath. To the freshly prepared Sia BH solution, was transferred by
3
-Me
2
S solution (2 M, 12 mL, 24 mmol,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
cannulation into a THF solution (26 mL) of the olefin substrate (2, 4.00 g 13.4 mmol). After the addition has
been finished, the ice bath was removed and the reaction mixture was stirred for 1 h. The reaction was
quenched with water (40 mL), followed by a sodium perborate tetrahydrate (NaBO
.4 eq), and the resulting solution was stirred overnight. Separated from the reaction mixture, the aqueous
layer was subjected to extraction with EtOAc (30 mL × 4). The combined organic layers are washed with
brine (30 mL), dried over anhydrous MgSO , filtered and concentrated in vacuo to give a crude product.
3
-4H O, 11.1 g, 72 mmol,
2
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
Purification of the crude product by flash chromatography on silica gel, using EtOAc/n-Hex as the eluant
afforded the titled product.
E-2-(3-Hydroxypropyl)-1-benzyloxycarbonylamino-1-cycanocyclohexane (6): Light Colorless oil, (3.96
1
g, 12.5 mmol, 93%), R
f
= 0.21 (EtOAc/Hex = 1 : 1); H NMR (400 MHz, CDCl
3
) δ 1.10 – 1.47 (m, 6H),
1
5
2
.48 – 1.62 (m, 2H), 1.62 – 1.76 (m, 3H), 1.80 – 1.93(m, 2H), 2.73 (d, J = 12.3 Hz, 1H), 3.53 – 3.65 (m, 2H),
13
1
.00 – 5.16 (m, 2H), 6.22 (brs, 1H), 7.17 – 7.43 (m, 5H); C{ H} NMR (101 MHz, CDCl
3
) δ 22.4 (CH
2
),
),
4.5 (CH ), 26.8 (CH ), 28.3 (CH ), 28.9 (CH ), 36.1 (CH ), 43.4 (CH), 57.2 (C), 61.8 (CH
2
2
2
2
2
2
), 66.9 (CH
2
-1
1
18.2 (C), 128.0 (CH), 128.1 (CH), 128.4 (CH), 135.8 (C),154.6 (C),; IR (cm , film): max = 3479, 3318,
+
+
2
939, 2865, 2240, 1705, 1528, 1454, 1254, 1027; EI-HRMS (m/z) : [M] calcd for C18
H
24
N
2
O
3
316.1781,
found 316.1788 (Δ = -2.2 ppm).
rel-(2S,4aS,8aR)-N-Benzyloxycarbonyl-8a-cyano-2-(3-hydroxypropyl)decahydroquinoline (12): White
1
solid (2.227 g, 6.20 mmol, 94%) mp = 86-88 ℃; R
f
= 0.22 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
)
δ 1.22 – 1.42 (m, 5H), 1.42 – 1.55 (m, 3H), 1.55 – 1.83 (m, 9H), 1.83 – 2.03 (m, 3H), 3.42 – 3.54 (m, 3H),
1
3
1
4.21 – 4.29 (m, 1H), 5.08 (d, J = 12.1 Hz, 1H), 5.21 (d, J = 12.1 Hz, 1H), 7.45 – 7.28 (m, 5H); C{ H}
NMR (101 MHz, CDCl
3
) δ 23.3 (CH
2
× 2), 25.0 (CH
2
), 26.4 (CH
2
), 28.5 (CH
2
), 30.2 (CH
2
), 30.5 (CH
2
),
36.0 (CH ), 46.5 (CH), 55.8 (CH), 58.6 (C), 62.0 (CH
2
2
), 67.6 (CH
2
), 119.9 (C), 128.3 (CH), 128.5 (CH × 2),
-
1
1
35.7 (C), 157.0 (C); IR (cm , film) max = 2938, 2865, 1709, 1456, 1383, 1276, 1261, 1152, 1112 ;
+
EI-HRMS (m/z) : [M] calcd for C21
H
28
N
2
3
O 356.2094, found 356.2104 (Δ = -2.8 ppm).
General Procedure for the Dess-Martin Periodinane Oxidation: To a CH
2
Cl
(3.01 g, 9.5 mmol, 1.0 eq) in an ice bath under argon, was added Dess-Martin reagent (4.44 g, 10.5 mmol,
.1 eq) in portions. The ice bath was removed and the reaction mixture was stirred at room temperature for 3
2
solution (47 mL) of alcohol
6
1
h. Upon completion of the reaction monitored by TLC analysis, the reaction was quenched with saturated
NaHCO solution (30 mL). After filtration with a short celite pad and separation of the organic layer, the
aqueous layer was extracted with CH Cl (20 mL × 4). The combined organic layers were washed with brine,
dried over anhydrous Na SO , filtered and concentrated in vacuo to give a crude product. The crude product
3
2
2
2
4
was purified by flash chromatography on silica gel, using ethyl acetate/n-hexane as the eluant, afforded the
products as followed:
E-2-(3-Oxopropyl)-1-benzyloxycarbonylamino-1-cycanocyclohexane (7): Colorless oil, (2.45 g, 7.8
1
mmol, 82%), aldehyde as major: R
f
= 0.23 (EtOAc/Hex = 1 : 3); H NMR (400 MHz, CDCl
3
) δ 1.11 – 1.42
(m, 4H), 1.45 – 1.86 (m, 7H), 1.93 – 2.08 (m, 2H), 2.10 – 2.31 (m, 1H), 2.44 – 2.60 (m, 1H), 2.60 – 2.75 (m,
11
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1
H), 2.88 (d, J = 12.1 Hz, 1H), 3.09 (d, J = 12.9 Hz, 1H), 5.07 – 5.33 (m, 2H), 5.77 (dd, J = 15.9, 13.1 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
) 27 δ 18.4, 19.7, 21.0,
1H), 7.25 – 7.50 (m, 5H), 9.74 (d, J = 12.3 Hz, 1H); C{ H} NMR (101 MHz, CDCl
2.1, 22.3, 22.9, 23.0, 23.1, 23.3, 24.6, 24.7, 24.8, 25.0, 26.6, 28.9, 29.5, 29.6, 29.9, 30.1, 30.4, 30.8, 36.0,
36.1, 38.4, 41.0, 41.1, 43.5, 46.0, 56.9, 57.3, 58.4, 58.5, 66.8, 68.0, 68.2, 75.7, 76.6, 78.5, 118.0, 118.4,
3
2
-1
119.5, 128.1, 128.3, 128.4, 128.6, 135.4, 154.5, 154.8, 156.8, 203.1; IR (cm , film) max = 3483, 3330, 2940,
+
2864, 2237, 1711, 1523, 1454,1399, 1309, 1277, 1260, 1116, 1044, 1010; EI-HRMS (m/z) : [M] calcd for
+
C
18
H
22
N
2
O
3
314.1628, found 314.1637 (Δ = -2.9 ppm).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
trans-N-Benzyloxycarbonyl-8a-cyano-2,3-didehydrodecahydroquinoline (3’): White solid, (261 mg, 0.9
mmol, 9%), mp = 82-84 ℃, recrystallized from CH Cl , CCDC no. 1911886; R = 0.44 (EtOAc/Hex = 1 : 5)
1H NMR (400 MHz, CDCl
) δ 1.24 – 1.45 (m, 2H), 1.47 – 1.61 (m, 1H), 1.63 – 1.88 (m, 5H), 1.88 – 1.98 (m,
H), 2.00 – 2.11 (m, 1H), 3.48 (d, J = 12.4 Hz, 1H), 5.01 (ddd, J = 8.5, 6.5, 2.1 Hz, 1H), 5.14 – 5.30 (m, 2H),
2
2
f
3
1
6
1
3
1
.67 – 6.81 (m, 1H), 7.22 – 7.51 (m, 5H); C{ H} NMR (101 MHz, CDCl
3
) δ 23.1 (CH
2
), 24.9 (CH
2
), 26.2
(CH
2
), 30.0 (CH ), 34.7 (CH ), 42.2 (CH), 59.2 (C), 68.2 (CH ), 106.1 (CH), 117.8 (C), 125.3 (CH), 128.1
2
2
2
-1
(CH), 128.2 (CH), 128.4 (CH), 128.6 (CH), 129.8 (CH), 135.4 (C), 152.9 (C); IR (cm , film) max = 2932,
+
2
861, 1720, 1664, 1454, 1384, 1307, 1256, 1159, 1117, 1011, 750; EI-HRMS (m/z) : [M] calcd for
+
C
18
H
20
N
2
O
2
296.1519, found 296.1528 (Δ = -3.0 ppm).
rel-(2S,4aS,8aR)-N-Benzyloxycarbonyl-8a-cyano-2-(3-oxypropyl)decahydroquinoline (13): White solid
1
(988 mg, 2.8 mmol, 96%), mp = 80-82 ℃; R
f
= 0.28 (EtOAc/Hex = 1 : 3); H NMR (400 MHz, CDCl
3
) δ
1.23 – 1.36 (m, 2H), 1.37 – 1.44 (m, 1H), 1.45 – 1.55 (m, 1H), 1.56 – 1.83 (m, 8H), 1.85 – 1.95 (m, 1H),
.09 – 2.31 (m, 3H), 3.46 – 3.56 (m, 1H), 4.21 – 4.30 (m, 1H), 5.09 (d, J = 12.0 Hz, 1H), 5.23 (d, J = 12.0
2
1
3
1
Hz, 1H), 7.25 – 7.46 (m, 5H), 9.48 (s, 1H); C{ H} NMR (101 MHz, CDCl
3
) δ 23.3 (CH
2
× 2), 24.6 (CH
2
),
),
2
5.0 (CH ), 26.6 (CH ), 30.5 (CH ), 36.0 (CH ), 41.1 (CH ), 46.5 (CH), 55.1 (CH), 58.7 (C), 67.7 (CH
2
2
2
2
2
2
-1
119.7 (C), 128.5 (CH), 128.6 (CH × 2), 135.6 (C), 156.7 (C), 201.1 (CH); IR (cm , film) max = 2938, 2864,
+
+
2
725, 2229, 1711, 1497, 1456, 1384, 1283, 1242, 1153, 1112; EI-HRMS (m/z) : [M] calcd for C21
H
26
N
2
O
3
354.1938, found 354.1938 (Δ = 0 ppm).
trans-N-Benzyloxycarbonyl-8a-cyanodecahydroquinoline (3): To a CH
2
Cl
Cl
(99 µL, 0.80 mmol, 1.2 eq). As the addition has
been finished, the cooling bath was removed and the reaction mixture was stirred at room temperature. Upon
2
solution (7 mL) of aldehyde 7
o
(210 mg, 0.67 mmol, 1 eq) at -78 C, was added dropwise a CH
2
2
solution (0.8 mL) containing
triethylsilane (128 µL, 0.80 mmol, 1.2 eq) and BF
3
OEt
2
completion of the reaction monitored by TLC analysis, a saturated NaHCO solution was slowly added into
3
o
the reaction mixture at 0 C, and then warmed up to room temperature. After separation of the organic layer,
the aqueous layer was extracted with CH
2
Cl
2
. The combined organic extracts were dried over Na SO4. After
2
removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to give a
crude product. Purification of the crude product by flash chromatography on silica gel, EtOAc/n-Hex as the
eluant to give the titled product. Colorless oil (155 mg, 0.52 mmol, 78%), R
1H NMR (400 MHz, CDCl
) δ 1.20 – 1.36 (m, 1H), 1.42 – 1.60 (m, 4H), 1.61 – 1.73 (m, 4H), 1.74 – 1.89 (m,
H), 3.14 (d, J = 13.1 Hz, 1H), 3.53 – 3.69 (m, 2H), 5.16 (s, 2H), 7.20 – 7.46 (m, 5H); C{ H} NMR (101
MHz, CDCl ) δ 22.5 (CH ), 23.3 (CH ), 24.9 (CH ), 25.7 (CH ), 30.2 (CH ), 35.0 (CH ), 41.9 (2C, CH and
CH), 61.1 (C), 67.5 (CH ), 118.3 (C), 128.0 (CH), 128.1 (CH), 128.4 (CH), 136.0 (C), 155.3 (C); IR (cm ,
f
= 0.33 (EtOAc/Hex = 1 : 5);
3
1
3
1
3
3
2
2
2
2
2
2
2
-1
2
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film) max = 2937, 2863, 2232, 1705, 1497, 1454, 1404, 1352, 1255, 1239, 1166, 1002 ; EI-HRMS (m/z) :
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
[M] calcd for C18
H
22
N
2
O 298.1676, found 298.1686 (Δ = -3.4 ppm).
2
General Procedure for Preparation of the trans-acetamides:
Catalytic hydrogenation: To a 25 mL flask containing freshly activated Pd/C catalyst (10%, 342 mg, 10
mol%) was added MeOH solution (5 mL) of carbamate 3 (959 mg, 3.2 mmol, 1.0 eq). The reaction
suspension was stirred overnight under a hydrogen balloon. Upon completion of the reaction monitored by
TLC analysis, the suspension was filtered through celite and the filtrate was concentrated under reduced
pressure to give a crude product (525 mg, 3.2 mmol, quantitative).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Acetylation: The crude product was used directly without further purification. To a CH
2
Cl solution (17 mL)
2
o
of acetyl chloride (430 μL, 6.1 mmol, 1.0 eq) at -78 C, was slowly added Et
3
N (850 μL, 6.1 mmol, 3.5 eq),
and the solution was stirred for another 10 min at the low temperature. To the freshly prepared acetylating
reagent, was cannulated the crude amine (287 mg, 1.7 mmol) in CH
2
Cl solution (2 mL). The solution was
2
o
stirred for 1.5 h at -78 C. Upon completion of the reaction monitored by TLC analysis, a saturated NaHCO
3
solution was slowly added. After separation of the organic layer, the aqueous layer was extracted with
CH Cl . The combined organic extracts were dried over Na SO4. After removal of the solid dehydrating
2
2
2
agent, the organic layer was concentrated under reduced pressure to give a crude product. Purification of the
crude product by flash chromatography on silica gel, EtOAc/n-Hex as the eluant to give the titled product.
trans-N-Acetyl-8a-cyanodecahydroquinoline (4): Yellow solid, (260 mg, 1.3 mmol, 74%), mp = 62-64 ℃,
1
recrystallized from CH
2
Cl
2
, CCDC no. 1911884; R
f
= 0.43 (pure EtOAc); H NMR (400 MHz, CDCl
3
) δ
1
1
.22 – 1.32 (m, 1H), 1.32 – 1.43 (m, 1H), 1.50 – 1.62 (m, 2H), 1.62 – 1.69 (m, 2H), 1.70 – 1.82 (m, 4H),
1
3
1
.82 – 1.93 (m, 2H), 2.13 (s, 3H), 3.15 – 3.23 (m, 1H), 3.46 (dd, J = 7.8, 4.4 Hz, 2H); C{ H} NMR (101
) δ 22.1 (CH ), 22.9 (CH ), 23.8 (CH), 24.0 (CH ), 24.9 (CH ), 29.7 (CH ), 33.6 (CH ), 40.4
CH), 41.8 (CH ), 60.1 (C), 117.9 (C), 170.7 (C); IR (cm , film) max = 2936, 2864, 2233, 1653, 1410 ;
EI-HRMS (m/z) : [M] calcd for C12
MHz, CDCl
3
2
2
2
2
2
2
-1
(
2
+
+
H
18
N O 206.1414, found 206.1425 (Δ = -5.3 ppm).
2
rel-(2R,4aR,8aS)-N-Acetyl-2-butyl-8a-cyanodecahydroquinoline (15a): Yellow oil, (259 mg, 0.89 mmol,
1
69%), R
f
= 0.44 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.87 (t, J = 6.6 Hz, 3H), 1.04 – 1.16 (m,
1
H), 1.18 – 1.36 (m, 9H), 1.45 – 1.58 (m, 2H), 1.58 – 1.77 (m, 7H), 1.79 – 1.90 (m, 1H), 2.00 – 2.10 (m,
13
1
2H), 2.13 (s, 3H), 3.32 (d, J = 12.6 Hz, 1H), 3.63 – 3.75 (m, 1H); C{ H} NMR (101 MHz, CDCl
CH ), 21.4 (CH ), 22.5 (CH ), 23.1 (CH × 2), 23.7 (CH), 25.1 (CH ), 27.4 (CH ), 29.2 (CH ), 30.5 (CH
31.6 (CH ), 35.3 (CH ), 37.9 (CH ), 39.0 (CH), 54.2 (CH), 58.2 (C), 118.4 (C), 171.4 (C); IR (cm , film)
3
) δ 14.0
(
3
2
2
2
2
2
2
2
),
-1
2
2
2
+
+
max = 2933, 2861, 2230, 1657; EI-HRMS (m/z) : [M] calcd for C18
H
30
N O 290.2353, found 290.2359 (Δ =
2
-2.1 ppm).
rel-(2R,4aR,8aS)-N-Acetyl-2-butyl-8a-cyanodecahydroquinoline (15b): Yellow oil, (143 mg, 0.54 mmol,
1
7
1
2
2
8%), R
f
= 0.28 (EtOAc/Hex = 1 : 3); H NMR (400 MHz, CDCl
3
) δ 0.91 (t, J = 6.8 Hz, 3H), 1.04 – 1.17 (m,
H), 1.17 – 1.41 (m, 5H), 1.47 – 1.58 (m, 2H), 1.58 – 1.79 (m, 7H), 1.79 – 1.92 (m, 1H), 1.98 – 2.11 (m, 2H),
1
3
1
.13 (s, 3H), 3.32 (d, J = 12.9 Hz, 1H), 3.63 – 3.75 (m, 1H); C{ H} NMR (101 MHz, CDCl
1.3 (CH ), 22.6 (CH ), 23.1 (CH × 2), 23.8 (CH), 25.1 (CH ), 29.6 (CH ), 30.5 (CH ), 35.3 (CH
), 38.9 (CH), 54.2 (CH), 58.2 (C), 118.4 (C), 171.4 (C); IR (cm , film) max = 2936, 2864, 2231, 1656,
3
) δ 14.0 (CH
3
),
2
2
2
2
2
2
2
), 37.6
-1
(CH
2
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+
+
1
452, 1400, 1340, 1166; EI-HRMS (m/z) : [M] calcd for C16
H
26
N O 262.2040, found 262.2048 (Δ = -3.1
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ppm).
Procedure for the Intramolecular Cyclization: To a THF solution (47 mL) of acetamide 4 (1.930 g, 9.4
mmol, 1.0 eq) at -78 ℃ was slowly added LiHMDS solution (1 M, 28 mL, 28 mmol, 3.0 eq) via a syringe.
The reaction mixture was stirred at the low temperature for 1 h, and warmed up gradually to room
temperature in 2 h. After slow addition of hydrochloric acid (1 N, 47 mL) and EtOAc (47 mL), the reaction
was heated at reflux for 24 h. After separation of the organic layer, the aqueous layer was extracted with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EtOAc. The combined organic layers were dried over Na SO4. After removal of the solid dehydrating agent,
2
the organic layer was concentrated under reduced pressure to give a crude product. Purification of the crude
product by flash chromatography on silica gel, EtOAc/n-Hex as the eluant to give the titled product.
2
8
rel-(5S,10R)-11,13-Dioxodecahydro-H-pyrrolo[2,1-j]quinoline (8): Yellow solid (2.060 g, 9.9 mmol,
1
9
0%), mp = 120-122 ℃; R
f
= 0.59 (pure EtOAc); H NMR (400 MHz, CDCl
3
) δ 0.96 – 1.14 (m, 1H), 1.25 –
1.40 (m, 1H), 1.40 – 1.54 (m, 2H), 1.54 – 1.75 (m, 6H), 1.75 – 1.85 (m, 1H), 1.85 – 1.99 (m, 1H), 2.18
dddd, J = 12.8, 12.7, 12.7, 4.0 Hz, 1H), 2.77 (d, J = 20.9 Hz, 1H), 2.86 (ddd, J = 13.6, 11.5, 6.8 Hz, 1H),
(
1
3
1
3.30 (d, J = 20.9 Hz, 1H), 4.20 (dd, J = 13.8, 8.4 Hz, 1H); C{ H} NMR (101 MHz, CDCl
3
) δ 21.3 (CH
2
),
2
2.4 (CH ), 23.7 (CH ), 25.8 (CH ), 26.6 (CH ), 33.8 (CH ), 34.6 (CH ), 42.0 (CH and CH
2
2
2
2
2
2
2
), 71.3 (C),
-
1
+
169.7 (C), 208.4 (C); IR (cm , film) ν = 1759, 1691, 1276, 1261; EI-HRMS (m/z) : [M] calcd for
+
C
12
H17NO
2
207.1254, found 207.1250 (Δ = 1.9 ppm).
rel-(2R,5R,10S)-2-Hexyl-11,13-dioxodecahydro-H-pyrrolo[2,1-j]quinoline (16a): Yellow oil (249 mg,
1
0
1
1
.85 mmol, 90%), R
f
= 0.25 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J = 6.8 Hz, 3H),
.10 – 1.16 (m, 1H), 1.16 – 1.39 (m, 9H), 1.39 – 1.49 (m, 3H), 1.49 – 1.60 (m, 2H), 1.60 – 1.77 (m, 3H),
.77 – 1.94 (m, 3H), 2.09 – 2.22 (m, 1H), 2.26 – 2.42 (m, 1H), 2.77 (d, J = 20.7 Hz, 1H), 3.34 (d, J = 20.7
1
3
1
Hz, 1H), 4.66 – 4.52 (m, 1H); C{ H} NMR (101 MHz, CDCl
CH ), 26.0 (CH ), 26.7 (CH ), 26.8 (CH ), 29.0 (CH ), 29.4 (CH
2.0 (CH and CH ), 47.0 (CH), 71.7 (C), 169.9 (C), 207.8 (C); IR (cm , film) max = 2931, 2862, 1760,
692, 1450, 1402; EI-HRMS (m/z) : [M] calcd for C18
3
) δ 14.0 (CH
3
), 21.8 (CH
2
), 22.5 (CH
2
), 25.1
(
2
2
2
2
2
2
), 31.7 (CH
2
), 37.1 (CH
2
), 38.8 (CH
2
),
-
1
4
1
2
+
29NO +
291.2193, found 291.2199 (Δ = -2.1 ppm).
H
2
rel-(2R,5R,10S)-2-Butyl-11,13-dioxodecahydro-H-pyrrolo[2,1-j]quinoline (16b): Yellow oil (173 mg,
1
0.66 mmol, 84%), R
f
= 0.35 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.91 (t, J = 7.1 Hz, 3H),
1
.02 – 1.18 (m, 1H), 1.26 – 1.42 (m, 5H), 1.42 – 1.52 (m, 3H), 1.52 – 1.63 (m, 2H), 1.63 – 1.79 (m, 3H),
1.79 – 1.96 (m, 3H), 2.08 – 2.25 (m, 1H), 2.36 (dddd, J = 12.7, 12.7, 12.7, 4.0 Hz, 1H), 2.79 (d, J = 20.7 Hz,
1
3
1
1
H), 3.35 (d, J = 20.7 Hz, 1H), 4.55 – 4.68 (m, 1H); C{ H} NMR (101 MHz, CDCl
(CH ), 22.4 (CH ), 25.1 (CH ), 26.0 (CH ), 26.7 (CH ), 29.0 (CH ), 29.4 (CH ), 37.1 (CH
2.0 (CH and CH ), 47.0 (CH), 71.7 (C), 169.8 (C), 207.8 (C); IR (cm , film) max = 2933, 2867, 1760,
3
) δ 14.0 (CH
3
), 21.8
2
2
2
2
2
2
2
2
), 38.4 (CH
2
),
-
1
4
2
+
25NO +
263.1880, found 263.1889 (Δ = -3.4
1693, 1459, 1401, 1293; EI-HRMS (m/z) : [M] calcd for C16
H
2
ppm).
rel-(2R,5S,10R)-2-Hexyl-11,13-dioxodecahydro-H-pyrrolo[2,1-j]quinoline (21a): colorless oil (44 mg,
1
0
.15 mmol, 54%), R
f
= 0.53 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J = 6.2 Hz, 3H),
1
.05 – 1.19 (m, 1H), 1.22 – 1.37 (m, 8H), 1.37 – 1.55 (m, 3H), 1.62 – 1.78 (m, 6H), 1.78 – 1.90 (m, 3H),
14
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2
.24 (dddd, J = 12.5, 12.3, 12.3, 3.2 Hz, 1H), 2.45 – 2.58 (m, 1H), 2.70 (d, J = 21.0 Hz, 1H), 3.17 – 3.31 (m,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
2H); C{ H} NMR (101 MHz, CDCl
3
) δ 14.0 (CH
3
), 21.2 (CH
2
), 22.6 (CH
2
), 24.5 (CH
2
), 25.9 (CH
2
), 26.3
), 52.8
(CH ), 27.6 (CH ), 29.1 (CH ), 30.0 (CH
2
2
2
2
), 31.8 (CH
2
), 32.8 (CH
2
), 33.9 (CH
2
), 42.5 (CH), 43.0 (CH
2
-1
(CH), 73.7 (C), 170.2 (C), 209.0 (C); IR (cm , film) max = 2930, 2858, 1759, 1695, 1462, 1332, 1283;
+
29NO +
291.2193, found 291.2204 (Δ = -3.8 ppm).
EI-HRMS (m/z) : [M] calcd for C18
H
2
rel-(2R,5S,10R)-2-Butyl-11,13-dioxodecahydro-H-pyrrolo[2,1-j]quinoline (21b): Yellow oil (76 mg, 0.29
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mmol, 66%), R
f
= 0.50 (EtOAc/Hex =1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.90 (t, J = 7.0 Hz, 3H), 1.04 –
1
3
.19 (m, 1H), 1.26 – 1.55 (m, 7H), 1.60 – 1.78 (m, 7H), 1.78 – 1.89 (m, 2H), 2.24 (dddd, J = 12.6, 12.6, 12.6,
13
1
.9 Hz, 1H), 2.46 – 2.58 (m, 1H), 2.69 (d, J = 21.0 Hz, 1H), 3.17 – 3.32 (m, 2H); C{ H} NMR (101 MHz,
CDCl
3
) δ 14.1 (CH
3
), 21.2 (CH
2
), 22.5 (CH
2
), 24.5 (CH
2
), 25.9 (CH
2
), 26.3 (CH
2
), 29.9 (CH
2
), 30.0 (CH ),
2
-1
3
2.5 (CH ), 33.9 (CH
2
2
), 42.4 (CH), 43.0 (CH
2
), 52.8 (CH), 73.7 (C), 170.2 (C), 209.0 (C); IR (cm , film)
+
25NO +
263.1880, found
max = 3008, 1758, 1695, 1277, 1261; EI-HRMS (m/z) : [M] calcd for C16
63.1887 (Δ = -2.7 ppm).
H
2
2
General Derivation Procedure of the β-oxo tricyclic lactams:
Reduction: To a MeOH solution (5 mL) of ketone 8 (218 mg, 1.1 mmol, 1.0 eq) at an ice bath, was added
NaBH (99 mg, 2.6 mmol, 2.5 eq) in portions. The reaction mixture was stirred in the ice bath for 1 h, and
quenched with saturated NH Cl solution. After evaporation of the volatile substance, the resulting solution
was partitioned with EtOAc. The combined organic extracts were dried over Na SO4. After removal of the
4
4
2
solid dehydrating agent, the organic solution was concentrated under reduced pressure to give a crude
product. The crude alcohol product was used directly without further purification.
Mesylation: To a solution of the crude alcohol from sodium borohydride reduction in CH
cooled in an ice bath, was added Et N (320 µL, 2.6 mmol, 2.5 eq) via a syringe followed by MsCl (170 µL,
.2 mmol, 2.0 eq). The reaction was stirred in the ice bath for 1.5 h. Upon completion of the reaction
monitored by TLC analysis, a saturated NaHCO solution was slowly added. After separation of the organic
layer, the aqueous layer was extracted with CH Cl . The combined organic extracts were dried over Na SO4.
2
Cl
2
(5 mL),
3
2
3
2
2
2
After removal of the solid dehydrating agent, the extracts were concentrated under reduced pressure to give
a crude product. The crude product was used directly without further purification.
Elimination: The crude mesylate was diluted with CH
µL, 2.8 mmol, 2.5 eq). The reaction mixture was stirred and heated at reflux for 8 h. Upon completion of the
reaction monitored by TLC analysis, the reaction was quenched with saturated NH Cl solution. After
separation from the organic extracts, the aqueous solution was extracted with CH Cl . The combined organic
extracts were dried over Na SO4. After removal of the solid dehydrating agent, the organic layer was
2
Cl
2
(8.5 mL) followed by the addition of DBU (0.4
4
2
2
2
concentrated under reduced pressure to give a crude product. Purification of the crude product by flash
chromatography on silica gel, EtOAc/n-Hex as the eluant to give the titled product.
rel-(5S,10R)-11,12-Didehydro-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (9): Yellow oil (181 mg, 0.95
1
mmol, 86% over three steps), R
f
= 0.29 (EtOAc/Hex = 1 : 1); H NMR (400 MHz, CDCl
3
) δ 0.60 – 0.79
(m, 1H), 1.18 – 1.32 (m, 1H), 1.32 – 1.70 (m, 6H), 1.77 – 1.93 (m, 4H), 1.93 – 2.03 (m, 1H), 2.92 (ddd, J =
1
3.9, 10.9, 6.9 Hz, 1H), 3.92 (dd, J = 13.9, 8.6 Hz, 1H), 6.17 (d, J = 5.9 Hz, 1H), 7.36 (d, J = 5.9 Hz, 1H);
1
3
1
C{ H} NMR (101 MHz, CDCl
3
) δ 22.2 (CH
2
), 23.8 (CH
2
), 24.5 (CH
2
), 26.6 (CH
2
), 29.3 (CH
2
), 35.5 (CH ),
2
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-
1
3
6.6 (CH ), 43.2 (CH), 71.2 (C), 127.6 (CH), 151.0 (CH), 176.2 (C); IR (cm , film) max = 2935, 2864,
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
1683, 1456, 818, 764 ; EI-HRMS (m/z) : [M] calcd for C12H17NO 191.1305, found 191.1306 (Δ = -0.5
ppm).
rel-(2R,5R,10S)-2-Butyl-11,12-didehydro-13-oxodecahydro-H-pyrrolo[2,1-j]-quinoline (17a): Yellow oil
1
(157 mg, 0.57 mmol, 67%) R
f
= 0.23 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.62 – 0.78 (m,
1
2
H), 0.84 (s, 3H), 1.12 – 1.38 (m, 8H), 1.38 – 1.52 (m, 3H), 1.52 – 1.69 (m, 4H), 1.69 – 1.86 (m, 2H), 1.86 –
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.09 (m, 4H), 2.09 – 2.24 (m, 1H), 4.25 – 4.44 (m, 1H), 6.15 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 5.6 Hz, 1H);
1
3
1
C{ H} (101 MHz, CDCl
3
) δ 14.0 (CH
), 31.6 (CH ), 31.7 (CH
CH), 150.7 (CH), 175.7 (C); IR (cm , film) max = 2931, 2862, 1742, 1690, 1460, 1390, 1345; EI-HRMS
3
), 22.5 (CH
2
), 23.4 (CH
2
), 24.3 (CH
2
), 26.7 (CH
2
), 27.0 (CH ), 29.0
2
(
(
(
CH
2
), 29.5 (CH
2
2
2
), 38.0 (CH
2
), 39.2 (CH
2
), 43.7 (CH), 48.8 (CH), 71.7 (C), 127.0
-1
+
+
m/z) : [M] calcd for C18H29NO 275.2244, found 275.2245 (Δ = -0.4 ppm).
rel-(2R,5R,10S)-2-Butyl-11,12-didehydro-13-oxodecahydro-H-pyrrolo[2,1-j]-quinoline (17b): Yellow
1
oil (178 mg, 0.72 mmol, 94%) R
f
= 0.32 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.64 – 0.78 (m,
1
H), 0.87 (t, J = 6.9 Hz, 3H), 1.13 – 1.25 (m, 2H), 1.25 – 1.38 (m, 3H), 1.40 – 1.53 (m, 3H), 1.53 – 1.69 (m,
4H), 1.71 – 1.85 (m, 2H), 1.87 – 2.05 (m, 3H), 2.17 (ddd, J = 13.3, 10.5, 7.3 Hz, 1H), 4.31 – 4.42 (m, 1H),
1
3
1
6
.17 (d, J = 6.0 Hz, 1H), 7.37 (d, J = 6.0 Hz, 1H); C{ H} NMR (101 MHz, CDCl
(CH ), 23.4 (CH ), 24.3 (CH ), 26.8 (CH ), 29.2 (CH ), 29.5 (CH ), 31.7 (CH ), 37.6 (CH
3.7 (CH), 48.8 (CH), 71.8 (C), 127.1 (CH), 150.8 (CH), 175.7 (C); IR (cm , film) max = 2934, 2864, 1685,
3
) δ 14.0 (CH
3
), 22.4
2
2
2
2
2
2
2
2
), 39.2 (CH
2
),
-
1
4
+
+
1276, 1261; EI-HRMS (m/z) : [M] calcd for C16H25NO 247.1931, found 247.1937 (Δ = -2.4 ppm).
rel-(2R,5S,10R)-2-Hexyl-11,12-didehydro-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (22a): Yellow oil
1
(24 mg, 0.09 mmol, 84%), R
f
= 0.53 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.80 – 0.88 (m,
3
1
H), 1.18 – 1.36 (m, 8H), 1.37 – 1.52 (m, 3H), 1.55 – 1.74 (m, 4H), 1.76 – 1.93 (m, 5H), 2.42 – 2.54 (m,
13
1
H), 3.15 – 3.27 (m, 1H), 6.06 (d, J = 5.9 Hz, 1H), 7.25 (d, J = 6.0 Hz, 1H); C{ H} NMR (101 MHz,
) δ 14.1 (CH ), 22.6 (CH × 2), 23.8 (CH ), 26.7 (CH ), 27.4 (CH ), 29.1 (CH ), 29.4 (CH ), 31.7
), 32.2 (CH ), 35.6 (CH ), 43.6 (CH), 52.2 (CH), 72.3 (C), 129.1 (CH), 149.3 (CH), 176.5
CDCl
3
3
2
2
2
2
2
2
(CH
2
), 31.9 (CH
2
2
2
-1
+
+
(C); IR (cm , film) max = 2932, 2859, 1688; EI-HRMS (m/z) : [M] calcd for C18
H29NO 275.2244, found
2
75.2259 (Δ = -5.5 ppm).
rel-(2R,5S,10R)-2-Butyl-11,12-didehydro-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (22b): Yellow oil
1
(13 mg, 0.05 mmol, 26%), R
f
= 0.48 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.88 (t, J = 6.7 Hz,
3H), 1.19 – 1.51 (m, 8H), 1.56 – 1.74 (m, 4H), 1.74 – 1.94 (m, 6H), 2.42 – 2.55 (m, 1H), 3.14 – 3.28 (m,
1
3
1
1
H), 6.07 (d, J = 5.9 Hz, 1H), 7.26 (d, J = 5.9 Hz, 1H); C{ H} NMR (101 MHz, CDCl
(CH ), 22.7 (CH ), 23.8 (CH ), 26.8 (CH ), 29.5 (CH ), 29.7 (CH ), 31.8 (CH ), 32.0 (CH
3.7 (CH), 52.2 (CH), 72.4 (C), 129.1 (CH), 149.3 (CH), 176.6 (C); IR (cm , film) max = 2935, 2865, 1689;
3
) δ 14.1 (CH
3
), 22.5
2
2
2
2
2
2
2
2
), 35.6 (CH
2
),
-
1
4
+
+
EI-HRMS (m/z) : [M] calcd for C16H25NO 247.1931, found 247.1941 (Δ = -4.0 ppm).
Preparation of the 4-Nitrobenzoate derivatives: To the crude alcohol (300 mg, 0.84 mmol, 1 eq) from
sodium borohydride reduction of ketone 8, diluted within CH Cl (8.4 mL) cooled in an ice bath, was added
pyridine (280 µL, 3.4 mmol, 4.0 eq) via a syringe followed by addition of 4-nitrobenozoyl chloride (342 mg,
.84 mmol, 2.2 eq) in one portion. The reaction was stirred under reflux conditions for 4 h. Upon completion
2
2
1
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of the reaction monitored by TLC analysis, HCl solution (1 N, 5 mL) was added to quench the reaction.
After separation of the organic layer, the aqueous layer was extracted with CH Cl . The combined organic
extracts were dried over Na SO . Removal of the solid dehydrating agent, followed by concentration of the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
4
extracts under reduced pressure gave a crude product, which was purified by flash chromatography on silica
gel, EtOAc/n-Hex as the eluant to give the titled product.
rel-(5S,10R,11S)-11-(4-Nitrobenzoyloxy)-13-oxodecahydro-H-pyrrolo[2,1-j]-quinoline (10): Yellow
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solid (252 mg, 0.70 mmol, 84%), mp = 160-162 ℃ (decomposed), recrystallized from CHCl , CCDC no.
3
1
1
1
1
911885; H NMR (400 MHz, CDCl
3
) δ 1.12 – 1.26 (m, 1H), 1.36 – 1.57 (m, 4H), 1.57 – 1.74 (m, 3H),
.74 – 1.91 (m, 3H), 1.97 – 2.13 (m, 1H), 2.25 (dd, J = 13.4, 4.8 Hz, 1H), 2.66 – 2.94 (m, 3H), 3.99 (dd, J =
1
3
1
3.8, 8.1 Hz, 1H), 5.78 (dd, J = 10.3, 8.3 Hz, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.31 (d, J = 8.9 Hz, 2H); C{ H}
) δ 21.0 (CH ), 22.2 (CH ), 22.4 (CH ), 25.8 (CH ), 27.1 (CH ), 31.5 (CH ), 33.3
NMR (101 MHz, CDCl
3
2
2
2
2
2
2
(
CH
2
), 36.7 (CH
2
), 42.0 (CH), 64.4 (C), 71.9 (CH), 123.8 (CH), 130.8 (CH), 134.8 (C), 150.7 (C), 163.9 (C),
-1
1
70.3 (C); IR (cm , film) max = 2935, 2869, 1726, 1697, 1607, 1528, 1274, 1102, 750, 719; ESI-HRMS
+
+
(
m/z) : [M] calcd for C19
H
22
N
2
O
5
358.1523, found 358.1537 (Δ = -3.9 ppm).
rel-(2R,5R,10S,11R)-2-hexyl-11-(4-Nitrobenzoyloxy)-13-oxodecahydro-H-pyrrolo-[2,1-j]quinoline (20a):
Yellow solid, (86 mg, 0.19 mmol, 40%), mp = 166-168 ℃ (decomposed), recrystallized from CH
2
Cl ,
2
1
CCDC no. 1920877; R
f
= 0.15 (EtOAc/Hex = 1 : 4) H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J = 6.8 Hz, 3H),
1
.14 – 1.39 (m, 9H), 1.39 – 1.61 (m, 6H), 1.61 – 1.83 (m, 4H), 1.88 – 2.01 (m, 1H), 2.05 – 2.23 (m, 2H),
2.39 (dd, J = 13.1, 5.1 Hz, 1H), 2.75 (dd, J = 15.9, 10.6 Hz, 1H), 2.89 (dd, J = 15.9, 8.0 Hz, 1H), 4.27 – 4.40
1
3
1
(
m, 1H), 5.72 (dd, J = 10.3, 8.3 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.9 Hz, 2H); C{ H} NMR
(101 MHz, CDCl ) δ 14.0 (CH ), 22.2 (CH × 2), 22.6 (CH ), 25.9 (CH ), 26.7 (CH ), 27.4 (CH ), 29.0 (CH
2), 31.7 (CH ), 33.8 (CH ), 36.6 (CH ), 39.1 (CH ), 42.2 (CH), 46.6 (CH), 65.1 (C), 72.2 (CH), 123.8
(CH), 130.7 (CH), 135.0 (C), 150.7 (C), 163.9 (C), 170.8 (C); IR (cm , film) max = 2940, 2872, 1723, 1694,
3
3
2
2
2
2
2
2
×
2
2
2
2
-1
+
+
1
526, 1275 ; EI-HRMS (m/z) : [M] calcd for C25
H
34
N
2
O
5
442.2462, found 442.2474 (Δ = -2.7 ppm).
rel-(2R,5R,10S,11R)-2-Butyl-11-(4-nitrobenzoyloxy)-13-oxodecahydro-H-pyrrolo-[2,1-j]quinoline (20b):
Yellow solid, (121 mg, 0.29 mmol, 79%), mp = 194-198 ℃ (decomposed), recrystallized from CHCl ,
3
1
CCDC no. 1920876; R
f
= 0.72 (EtOAc/Hex = 2 : 1); H NMR (400 MHz, CDCl
3
) δ 0.90 (t, J = 6.9 Hz, 3H),
1
2
.19 – 1.39 (m, 5H), 1.41 – 1.59 (m, 5H), 1.62 – 1.83 (m, 5H), 1.91 – 2.01 (m, 1H), 2.06 – 2.24 (m, 2H),
.39 (dd, J = 13.0, 5.2 Hz, 1H), 2.75 (dd, J = 15.8, 10.6 Hz, 1H), 2.90 (dd, J = 15.9, 8.0 Hz, 1H), 4.29 – 4.40
13
1
(
m, 1H), 5.73 (dd, J = 10.4, 8.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 8.4 Hz, 2H); C{ H} NMR
101 MHz, CDCl ) δ 14.1 (CH ), 22.2 (CH × 2), 22.5 (CH ), 25.9 (CH ), 27.5 (CH ), 29.0 (CH ), 29.1
CH ), 33.8 (CH ), 36.7 (CH ), 38.8 (CH ), 42.2 (CH), 46.6 (CH), 65.2 (C), 72.2 (CH), 123.8 (CH), 130.7
CH), 135.0 (C), 150.7 (C), 164.0 (C), 170.8 (C); IR (cm , film) max = 2934, 2868, 2360, 1726, 1694, 1528,
(
3
3
2
2
2
2
2
(
2
2
2
2
-1
(
+
+
1
407,1347, 1273, 1101 ; EI-HRMS (m/z) : [M] calcd for C23
H
30
N
2
O
5
414.2149, found 414.2148 (Δ = 0.2
ppm).
Preparation of the tricyclic lactams: The conjugated tricyclic lactams were hydrogenated to the saturated
tricyclic products according to the mentioned catalytic hydrogenation procedure.
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rel-(5S,10R)-13-Oxodecahydro-H-pyrrolo[2,1-j]quinoline (5): Yellow oil (201 mg, 1.0 mmol, 94%), R
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
= 0.18 (EtOAc/Hex = 1 : 1); H NMR (400 MHz, CDCl
3
) δ 1.08 – 1.23 (m, 1H), 1.23 – 1.38 (m, 3H), 1.40 –
1
.49 (m, 2H), 1.49 – 1.59 (m, 2H), 1.59 – 1.70 (m, 3H), 1.70 – 1.85 (m, 3H), 1.86 – 1.98 (m, 1H), 2.15 –
1
3
1
2.27 (m, 1H), 2.40 – 2.56 (m, 1H), 2.68 – 2.84 (m, 1H), 3.88 (dd, J = 13.7, 8.5 Hz, 1H); C{ H} NMR (101
MHz, CDCl ) δ 21.3 (CH ), 22.5 (CH ), 23.5 (CH ), 24.9 (CH ), 26.0 (CH ), 27.3 (CH ), 30.6 (CH ), 33.3
(CH ), 33.8 (CH ), 42.1 (CH), 64.0 (C), 175.8 (C); IR (cm , film) max = 3475, 2934, 2863, 1684, 1460,
417 ; EI-HRMS (m/z) : [M] calcd for C12
3
2
2
2
2
2
2
2
-1
2
2
+
+
1
H19NO 193.1461, found 193.1456 (Δ = 2.6 ppm).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
rel-(2R,5S,10R)-2-Hexyl-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (5a): Yellow oil (25 mg, 0.09
1
mmol, 100%), R
f
= 0.45 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.84 (t, J = 6.7 Hz, 3H), 1.08 –
1
8
.20 (m, 1H), 1.21 – 1.52 (m, 13H), 1.53 – 1.79 (m, 9H), 1.85 (dd, J = 12.4, 8.2 Hz, 1H), 2.08 (dd, J = 16.1,
13
1
.9 Hz, 1H), 2.36 – 2.51 (m, 2H), 3.09 – 3.19 (m, 1H); C{ H} NMR (101 MHz, CDCl
), 22.6 (CH ), 23.5 (CH ), 24.4 (CH ), 26.1 (CH ), 27.2 (CH ), 27.7 (CH ), 29.1 (CH
1.5 (CH ), 31.8 (CH × 2), 33.2 (CH ), 42.4 (CH), 51.6 (CH), 66.1 (C), 176.3 (C); IR (cm , film) max
3
) δ 14.0 (CH
3
), 22.1
(CH
2
2
2
2
2
2
2
2
), 30.4 (CH
2
),
=
-1
3
2
2
2
2
+
+
931, 2858, 1685; EI-HRMS (m/z) : [M] calcd for C18
H31NO 277.2400, found 277.2404 (Δ = -1.4 ppm).
13
13,20b
The C NMR data are in agreement with those reported in the literature.
rel-(2R,5S,10R)-2-Butyl-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (5b): Colorless oil (13 mg, 0.05
1
mmol, 100%), R
f
= 0.38 (EtOAc/Hex = 1 : 2); H NMR (400 MHz, CDCl
3
) δ 0.89 (t, J = 7.0 Hz, 3H), 1.09 –
1
.24 (m, 2H), 1.24 – 1.39 (m, 6H), 1.39 – 1.53 (m, 3H), 1.54 – 1.72 (m, 6H), 1.72 – 1.82 (m, 2H), 1.83 –
1
3
1
1.91 (m, 1H), 2.06 – 2.15 (m, 1H), 2.38 – 2.54 (m, 2H), 3.10 – 3.22 (m, 1H); C{ H} NMR (101 MHz,
CDCl
30.4 (CH
933, 2862, 1684; EI-HRMS (m/z) : [M] calcd for C16
3
) δ 14.1 (CH
3
), 22.1 (CH
2
), 22.6 (CH
2
), 23.5 (CH
2
), 24.4 (CH
2
), 26.1 (CH
2
), 27.2 (CH
2
), 30.0 (CH
2
),
=
-1
2
), 31.6 (CH
2
× 2), 33.2 (CH
2
), 42.5 (CH), 51.7 (CH), 66.2 (C), 176.3 (C); IR (cm , film) max
+
+
2
H
27NO 249.2087, found 249.2096 (Δ = -3.6 ppm).
1
3
20a,20b
The C NMR data are in agreement with those reported in the literature.
rel-(2R,5R,10S)-2-Hexyl-13-oxodecahydro-H-pyrrolo[2,1-j]-quinoline (18a): Yellow oil (124 mg, 0.45
1
mmol, 95%), R
f
= 0.14 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.83 (t, J = 6.4 Hz, 3H), 1.10 –
1
2
1
2
.34 (m, 11H), 1.34 – 1.52 (m, 5H), 1.52 – 1.62 (m, 2H), 1.62 – 1.87 (m, 5H), 1.87 – 1.98 (m, 1H), 1.98 –
1
3
1
.10 (m, 1H), 2.10 – 2.26 (m, 1H), 2.39 – 2.54 (m, 1H), 4.13 – 4.28 (m, 1H); C{ H} (101 MHz, CDCl
4.0 (CH ), 22.5 (CH ), 22.6 (CH ), 23.9 (CH ), 25.4 (CH ), 26.1 (CH ), 26.6 (CH ), 27.7 (CH ), 29.1 (CH
), 30.6 (CH ), 31.7 (CH ), 36.2 (CH ), 39.3 (CH
3
) δ
3
2
2
2
2
2
2
2
2
),
9.4 (CH
2
2
2
2
2
), 42.5 (CH), 46.5 (CH), 64.9 (C), 176.1 (C); IR
-1
+
31NO+
(
cm , film) max = 2931, 2861, 1689, 1459, 1403, 1355; EI-HRMS (m/z) : [M] calcd for C18
H
2
77.2400, found 277.2413 (Δ = -4.7 ppm).
rel-(2R,5R,10S)-2-Butyl-13-oxodecahydro-H-pyrrolo[2,1-j]quinoline (18b): Yellow oil (164 mg, 0.66
1
mmol, 95%), R
f
= 0.12 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.84 (t, J = 6.8 Hz, 3H), 1.15 –
1.36 (m, 9H), 1.38 – 1.52 (m, 4H), 1.53 – 1.63 (m, 1H), 1.65 – 1.83 (m, 5H), 1.94 (dd, J = 12.1, 7.6 Hz, 1H),
1
3
1
1
.99 – 2.10 (m, 1H), 2.19 (dd, J = 16.5, 8.8 Hz, 1H), 2.42 – 2.55 (m, 1H), 4.16 – 4.26 (m, 1H); C{ H}
NMR (101 MHz, CDCl ) δ 14.0 (CH ), 22.4 (CH ), 22.6 (CH ), 23.9 (CH ), 25.4 (CH ), 26.1 (CH ), 27.7
CH ), 28.8 (CH ), 29.4 (CH ), 30.6 (CH ), 36.1 (CH ), 38.9 (CH
3
3
2
2
2
2
2
(
2
2
2
2
2
2
), 42.5 (CH), 46.5 (CH), 64.9 (C), 176.2
-
1
+
(C); IR (cm , film) max = 2935, 2864, 1686, 1458, 1403, 1261; EI-HRMS (m/z) : [M] calcd for
+
C
16
H
27NO 249.2087, found 249.2099 (Δ = -4.8 ppm).
18
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Page 19 of 24
The Journal of Organic Chemistry
The LiAlH
4
reduction: To a solution of lactam (9, 180 mg, 0.93 mmol, 1.0 eq.) in THF (9.3 mL) in an ice
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bath under argon, was slowly added LiAlH (141 mg, 3.7 mmol, 4.0 eq) in portions. The reaction mixture
4
was stirred under reflux conditions overnight. Upon completion of the reaction monitored by TLC analysis,
the reaction mixture was cooled down in an ice bath. Addition of water (1 mL), NaOH (15%, 1 mL), and
water (1 mL) in sequence resulted in the formation of white solid precipitates, which were filtered off by a
short celite pad to give a filtrate. The filtrate was concentrated under reduced pressure to give a crude
product. The crude product was purified by a short chromatography on silica gel, using EtOAc/n-hex as the
eluant to give the titled product.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
rel-(5S,10R)-Decahydro-H-pyrrolo[2,1-j]quinoline (1): Yellow oil (126 mg, 0.70 mmol, 76%), H NMR
(400 MHz, CDCl
3
) δ 0.96 – 1.11 (m, 2H), 1.11 – 1.25 (m, 1H), 1.25 – 1.35 (m, 2H), 1.35 – 1.47 (m, 2H),
1
1
.48 – 1.72 (m, 8H), 1.87 – 2.02 (m, 1H), 2.24 – 2.37 (m, 1H), 2.46 – 2.58 (m, 1H), 2.64 (d, J = 12.3 Hz,
1
3
1
H), 2.99 – 3.14 (m, 1H), 3.61 (s, 1H); C{ H} NMR (101 MHz, CDCl
3
) δ 20.1 (CH
2
), 21.6 (CH
2
), 23.5
), 67.5
(
CH
2
), 26.2 (CH
2
), 26.4 (CH
2
), 27.0 (CH
2
), 30.8 (CH
2
), 35.9 (CH
2
), 43.2 (CH), 51.1 (CH
2
), 51.4 (CH
2
-
1
+
21N+
(C); IR (cm , film) max = 2930, 2859, 1447, 1274, 1082, 765; EI-HRMS (m/z) : [M] calcd for C12
H
1
79.1669, found 179.1675 (Δ = -3.3 ppm).
rel-(2R,5R,10S)-2-Butyl-decahydro-H-pyrrolo[2,1-j]quinoline (C2-epi-Lepadiformine C, 19b): Yellow
1
oil (153 mg, 0.65 mmol, 98%), H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J = 6.9 Hz, 3H), 0.98 – 1.20 (m, 5H),
1
.20 – 1.35 (m, 6H), 1.35 – 1.47 (m, 2H), 1.47 – 1.68 (m, 7H), 1.68 – 1.76 (m, 1H), 1.76 – 1.91 (m, 2H),
1
3
1
1.91 – 2.02 (m, 1H), 2.86 – 3.00 (m, 2H); C{ H} NMR (101 MHz, CDCl
CH ), 23.0 (CH ), 23.6 (CH ), 26.3 (CH ), 26.7 (CH ), 28.9 (CH ), 31.1 (CH
37.2 (CH
3
) δ 14.0 (CH
3
), 20.1 (CH
2
), 22.5
),
(
2
2
2
2
2
2
2
), 32.6 (CH
2
), 36.4 (CH
2
-
1
2
), 43.4 (CH), 47.7 (CH
2
), 57.7 (CH), 68.1 (C); IR (cm , film) max = 2930, 2860, 1450, 1275 ;
+
+
EI-HRMS (m/z) : [M] calcd for C16
H
29N 235.2295, found 235.2301 (Δ = -2.6 ppm).
rel-(2R,4aS,8aR)-N-Benzyloxycarbonyl-8a-cyano-2-(2-propenyl)decahydroquinoline (11): To a CH
2
Cl
2
solution (33 mL) of allyltrimethylsilane (2.6 mL, 16.4 mmol, 2.4 eq) and BF
3
OEt
2
(1.0 mL, 8.2 mmol, 1.2
o
o
eq) at -90 C was added dropwise CH
2
Cl solution (7 mL) of aldehyde 7 (2.143 g, 6.8 mmol, 1 eq) at -78 C.
2
The cooling bath was removed and the reaction mixture was stirred at room temperature. Upon completion
of the reaction monitored by TLC analysis, a saturated NaHCO solution was slowly added into the reaction
3
o
mixture at 0 C, and then warmed up to room temperature. After separation of the organic layer, the aqueous
layer was extracted with CH
2
Cl
2
. The combined organic layers were dried over Na SO4. After removal of the
2
solid dehydrating agent, the organic layer was concentrated under reduced pressure to give a crude product
as an inseparable mixture with encarbamate 3’ (~ 4 : 1). The crude product can be used directly for the
subsequent transformations. For the purpose of isolation of the title product, the crude product was allowed
to stand at room temperature for several days, for encarbamate 3’ is prone to be gradually decomposed at
room temperature. Subsequent flash chromatography on silica gel, EtOAc/n-Hex as the eluant gave the pure
1
product as white solid (1.766 g, 77%) mp = 58-60 ℃; R
CDCl
H), 2.57 – 2.69 (m, 1H), 3.49 – 3.58 (m, 1H), 4.26 – 4.34 (m, 1H), 4.97 – 5.06 (m, 2H), 5.11 (d, J = 12.1
f
= 0.44 (EtOAc/Hex = 1 : 5); H NMR (400 MHz,
3
) δ 1.24 – 1.42 (m, 3H), 1.44 – 1.54 (m, 1H), 1.56 – 1.73 (m, 5H), 1.73 – 1.86 (m, 3H), 2.27 – 2.38 (m,
1
13
1
Hz, 1H), 5.18 (d, J = 12.1 Hz, 1H), 5.50 – 5.63 (m, 1H), 7.28 – 7.43 (m, 5H); C{ H} NMR (101 MHz,
CDCl ) δ 23.2 (CH ), 23.3 (CH ), 25.1 (CH ), 26.1 (CH ), 30.5 (CH ), 35.9 (CH ), 36.6 (CH ), 49.5 (CH),
3
2
2
2
2
2
2
2
19
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The Journal of Organic Chemistry
Page 20 of 24
5
5.3 (CH), 58.7 (C), 67.6 (CH
2
), 117.8 (CH
2
), 119.9 (C), 128.3 (CH × 2), 128.5 (CH), 134.9 (CH), 135.7
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
(C), 156.9 (C); IR (cm , film) max = 2938, 2864, 1712, 1641, 1456, 1383, 1273, 1152, 1112, 1000, 915;
+
+
EI-HRMS (m/z) : [M] calcd for C21
H
26
N
2
O 338.1989, found 338.1984 (Δ = 1.5 ppm).
2
General Procedure for the Wittig Olefination: To a THF solution (40 mL) of methyltriphenyl-
phosphonium bromide (1.774 g, 5.0 mmol, 3.0 eq) at an ice bath, was slowly added NaHMDS solution (1 M,
4
.1 mL, 4.1 mmol, 2.5 eq) via a syringe. The reaction mixture was stirred at the low temperature for 1 h. To
the freshly prepared Wittig reagent at the ice bath was added a THF solution (2 mL) of aldehyde 13 (592 mg,
.7 mmol, 1.0 eq), and warmed up gradually to room temperature in 2 h. Upon completion of the reaction
monitored by TLC analysis, the reaction was quenched with saturated NH Cl. After separation of the organic
layer, the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
2
SO4.
After removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to
give a crude product. Purification of the crude product by flash chromatography on silica gel, EtOAc/n-Hex
as the eluant to give the titled product.
cis-rel-(2R,4aS,8aR)-N-Benzyloxycarbonyl-8a-cyano-2-(3-hexenyl)decahydroquinoline (14a): Yellow
1
oil (477 mg, 1.3 mmol, 84% )， cis/trans = 10:1, cis-14a : R
CDCl
4H), 1.99 – 2.11 (m, 1H), 3.53 (d, J = 13.3 Hz, 1H), 4.19 – 4.27 (m, 1H), 5.08 – 5.20 (m, 3H), 5.23 – 5.33
f
= 0.56 (EtOAc/Hex = 1 : 3); H NMR (400 MHz,
3
) δ 0.87 – 0.95 (m, 3H), 1.24 – 1.42 (m, 3H), 1.44 – 1.55 (m, 2H), 1.59 – 1.81 (m, 8H), 1.85 – 1.98 (m,
1
3
1
(
m, 1H), 7.27 – 7.43 (m, 5H); C{ H} NMR (101 MHz, CDCl
(CH ), 24.8 (CH ), 25.1 (CH ), 26.1 (CH ), 30.5 (CH ), 31.9 (CH
C), 67.6 (CH ), 119.8 (C), 127.5 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 132.2 (CH), 135.8 (C), 157.0
3
) δ 14.3 (CH
3
), 20.4 (CH
2
), 23.3 (CH ), 23.4
2
2
2
2
2
2
2
), 36.1 (CH
2
), 46.6 (CH), 55.6 (CH), 58.7
(
2
-1
(C); IR (cm , film) max = 3008, 2937, 2864, 2229, 1711, 1457, 1383, 1283, 1242, 750, 698; EI-HRMS
+
+
(m/z) : [M] calcd for C24
H
32
N
2
O
2
380.2458, found 380.2468 (Δ = -2.6 ppm).
rel-(2R,4aS,8aR)-N-Benzyloxycarbonyl-8a-cyano-2-(3-butenyl)decahydroquinoline (14b): White solid
(462 mg, 1.3 mmol, 77%), mp = 93-95 ℃, recrystallized from CH
2
Cl
2
, CCDC no. 1920894; R = 0.58
f
1
(EtOAc/Hex = 1 : 3); H NMR (400 MHz, CDCl
3
) δ 1.23 – 1.42 (m, 3H), 1.44 – 1.56 (m, 2H), 1.57 – 1.89
(m, 9H), 1.92 – 2.13 (m, 2H), 3.53 (d, J = 13.2 Hz, 1H), 4.18 – 4.27 (m, 1H), 4.82 – 4.97 (m, 1H), 5.09 (d, J
1
3
1
=
12.1 Hz, 1H), 5.21 (d, J = 12.1 Hz, 1H), 5.53 – 5.66 (m, 1H), 7.25 – 7.47 (m, 5H); C{ H} NMR (101
) δ 23.3 (CH × 2), 25.1 (CH ), 26.0 (CH ), 30.5 (CH ), 31.2 (CH ), 31.5 (CH ), 36.0 (CH ),
6.6 (CH), 55.5 (CH), 58.7 (C), 67.6 (CH ), 115.0 (CH ), 119.8 (C), 128.3 (CH), 128.5 (CH × 2), 135.8 (C),
37.3 (CH), 157.0 (C); IR (cm , film) max = 2938, 2864, 2363, 1711, 1641, 1455, 1382, 1283, 1242, 998,
MHz, CDCl
3
2
2
2
2
2
2
2
4
1
9
2
2
-1
+
+
13 ; EI-HRMS (m/z) : [M] calcd for C22
H
28
N
2
O 352.2145, found 352.2155 (Δ = -2.8 ppm).
2
General Procedure for the Aerobic Hydrogenation: To a 25 mL flask charged with the alkene (14a, 216
mg, 0.61 mmol, 1.0 eq) and riboflavin tetrabutyrate (8 mg, 12 µmol, 2 mol%), was added acetonitrile (4.9
mL), hydrazine hydrate (N
2
H
4
-H O, 60 µL, 1.2 mmol, 2.0 eq). The solution was stirred under an oxygen
2
balloon at room temperature overnight. Evaporation of the volatile substance afforded the resulting crude
reside, which was purified by flash chromatography on silica gel, EtOAc/n-Hex as the eluant to give the
titled product.
20
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Page 21 of 24
The Journal of Organic Chemistry
rel-(2R,4aS,8aR)-N-Benzyloxycarbonyl-2-hexyl-8a-cyanodecahydroquinoline (3a): Colorless oil (625
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
mg, 1.63 mmol, 96%) R
f
= 0.51 (EtOAc/Hex =1 : 6); H NMR (400 MHz, CDCl
3
) δ 0.85 (t, J = 6.9 Hz, 3H),
0
.99 – 1.09 (m, 1H), 1.17 (brs, 5H), 1.20 – 1.27 (m, 3H), 1.27 – 1.38 (m, 3H), 1.45 – 1.52 (m, 1H), 1.56 –
1.69 (m, 4H), 1.69 – 1.81 (m, 4H), 1.87 – 2.00 (m, 1H), 3.52 (d, J = 13.1 Hz, 1H), 4.14 – 4.24 (m, 1H), 5.08
1
3
1
(
d, J = 12.2 Hz, 1H), 5.21 (d, J = 12.1 Hz, 1H), 7.25 – 7.44 (m, 5H); C{ H} NMR (101 MHz, CDCl
14.0 (CH ), 22.5 (CH ), 23.3 (CH ), 23.4 (CH ), 25.1 (CH ), 26.4 (CH ), 27.5 (CH ), 29.0 (CH ), 30.5 (CH
1.7 (CH ), 32.3 (CH ), 36.1 (CH ), 46.6 (CH), 56.3 (CH), 58.7 (C), 67.5 (CH ), 119.8 (C), 128.2 (CH),
128.4 (CH), 128.5 (CH), 135.9 (C), 157.1 (C); IR (cm , film) max = 2933, 2861, 2229, 1712, 1457, 1382,
3
) δ
3
2
2
2
2
2
2
2
2
),
3
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
+
1
284, 1244; EI-HRMS (m/z) : [M] calcd for C24
H
34
N
2
O
2
382.2615, found 382.2612 (Δ = 0.8 ppm).
rel-(2R,4aS,8aR)-N-Benzyloxycarbonyl-2-butyl-8a-cyanodecahydroquinoline (3b): White solid (211 mg,
0
1
1
3
.60 mmol, 98%), mp = 96-98 ℃, recrystallized from CH
2
Cl
2
, CCDC no. 1952224; R = 0.47 (EtOAc/Hex =
f
1
: 6); H NMR (400 MHz, CDCl
3
) δ 0.81 (t, J = 7.1 Hz, 3H), 0.96 – 1.09 (m, 1H), 1.09 – 1.24 (m, 3H),
.24 – 1.40 (m, 3H), 1.40 – 1.53 (m, 2H), 1.54 – 1.69 (m, 4H), 1.69 – 1.82 (m, 4H), 1.86 – 2.00 (m, 1H),
.46 – 3.56 (m, 1H), 4.14 – 4.24 (m, 1H), 5.08 (d, J = 12.1 Hz, 1H), 5.21 (d, J = 12.1 Hz, 1H), 7.24 – 7.44
13
1
(
m, 5H); C{ H} (101 MHz, CDCl
3
) 14.0 (CH
3
), 22.3 (CH
2
), 23.3 (CH
2
), 23.4 (CH
2
), 25.1 (CH
2
), 26.3
(
CH ), 29.6 (CH ), 30.5 (CH ), 32.0 (CH
2
2
2
2
), 36.0 (CH
2
), 46.6 (CH), 56.2 (CH), 58.6 (C), 67.5 (CH
2
), 119.8
-1
(
C), 128.2 (CH), 128.4 (CH × 2), 135.9 (C), 157.1 (C); IR (cm , film) max = 2936, 2864, 2229, 1711, 1457,
+
+
1
382, 1281, 1242; EI-HRMS (m/z) : [M] calcd for C22
H
30
N
2
O 354.2302, found 354.2303 (Δ = -0.3 ppm).
2
General Procedure for Preparation of the syn-acetamides:
A mixed solution of carbamate (3b, 182 mg, 0.51 mmol, 1.0 eq) in HBr(aq) (48%, 2.5 mL) and acetic acid (10
mL) was stirred at 60 ℃ for 6 h. Upon completion of the reaction monitored by TLC analysis, the solution
was concentrated under reduced pressure to give a crude residue. The crude product was acetylated
according to the mentioned procedure directly without further purification.
rel-(2R,4aS,8aR)-N-Acetyl-2-hexyl-8a-cyanodecahydroquinoline (4a): Colorless oil (81 mg, 0.28 mmol,
1
5
3%), R
f
= 0.51 (EtOAc/Hex = 1 : 4); H NMR (400 MHz, CDCl
3
) δ 0.85 (t, J = 6.6 Hz, 3H), 1.08 – 1.20 (m,
2H), 1.20 – 1.34 (m, 8H), 1.34 – 1.52 (m, 3H), 1.57 – 1.78 (m, 7H), 1.78 – 1.86 (m, 1H), 2.10 – 2.18 (m,
1
3
1
4
H), 3.54 (d, J = 13.3 Hz, 1H), 3.81 – 3.90 (m, 1H); C{ H} NMR (101 MHz, CDCl
(C), 57.9 (C), 56.4 (CH), 46.6 (CH), 35.5 (CH ), 32.9 (CH ), 31.7 (CH ), 30.4 (CH ), 28.9 (CH
6.3 (CH ), 25.2 (CH ), 24.7 (CH), 23.3 (CH ), 23.2 (CH ), 13.9 (CH
3
) δ 175.4 (C), 119.5
2
2
2
2
2
), 27.8 (CH ),
2
-1
2
2
2
2
2
), 22.5 (CH
2
3
); IR (cm , film) max
=
+
2935, 2863, 2229, 1674, 1458, 1367, 1274; EI-HRMS (m/z) : [M] calcd for C18
H
30
N
2
O 290.2353, found
2
90.2357 (Δ = -1.4 ppm).
rel-(2R,4aS,8aR)-N-Acetyl-2-butyl-8a-cyanodecahydroquinoline (4b): Yellow solid (115 mg, 0.44
mmol, 86%), mp = 78-80 ℃, recrystallized from CH
2
Cl
2
, CCDC no. 1947269; R = 0.31 (EtOAc/Hex = 1 :
f
1
5
1
3
2
5
); H NMR (400 MHz, CDCl
3
) δ 0.87 (t, J = 7.0 Hz, 3H), 1.08 – 1.20 (m, 2H), 1.20 – 1.54 (m, 7H), 1.54 –
.65 (m, 3H), 1.65 – 1.78 (m, 4H), 1.78 – 1.92 (m, 1H), 2.05 – 2.20 (m, 4H), 3.53 (d, J = 13.1 Hz, 1H),
1
3
1
.78 – 3.90 (m, 1H); C{ H} NMR (101 MHz, CDCl
4.7 (CH), 25.2 (CH ), 26.3 (CH ), 30.0 (CH ), 30.4 (CH
7.9 (C), 119.5 (C), 175.3 (C); IR (cm , film) max = 2935, 2864, 2362, 1673, 1457, 1382, 1277; EI-HRMS
3
) δ 14.0 (CH
3
), 22.4 (CH
2
), 23.1 (CH
2
), 23.3 (CH
2
),
2
2
2
2
), 32.7 (CH
2
), 35.4 (CH
2
), 46.5 (CH), 56.3 (CH),
-1
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Page 22 of 24
+
+
(
m/z) : [M] calcd for C16
H
26
N O 262.2040, found 262.2047 (Δ = -2.7 ppm).
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Supporting Information:
The Supporting Information is available free of charge on the ACS Publications website.
1
13
H and C-NMR spectra of all compounds (PDF)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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3
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2
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0
The X-ray Crystallographic Data of 2, 3’, 3b, 4, 4b, 10 14b, 20a, and 20b (CIF)
All calculated geometry coordinates from DFT calculation for stability comparison.
AUTHOR INFORMATION
Corresponding Author
Wen-Hua Chiou, ORCID ID: 0000-0003-3805-0225
*
E-mail: wchiou@dragon.nchu.edu.tw.
Notes
The authors declare no competing financial interest.
th
Dedicated to Professor Iwao Ojima on occasion of his 75 birthday.
■
ACKNOWLEDGMENTS
The research funding from the ministry of science and technology of Republic of China is greatly
acknowledged,
(MOST
105-2113-M-005-002,
MOST
106-2113-M-005-002
and
MOST
1
07-2113-M-005-020) as well as the support from National Chung Hsing University and the National center
for High-performance computing.
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The Journal of Organic Chemistry
References
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(
8) For excellent reviews for synthesis of the lepadiformine family and references cited therein, see: (a) Weinreb, S. M. Studies
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1
06, 2531. (b) Schär, P.; Cren, S.; Renaud, P., Tricyclic Marine Alkaloids: Synthetic Approaches to Cylindricines,
Lepadiformine, and Fasicularin. Chimia 2006, 60, 131. (c) Kaga, A.; Chiba, S. Synthesis of Tricyclic Marine Alkaloids,
Cylindricines, Lepadiformines, Fasicularin, and Polycitorols: A Recent Update. Synthesis 2018, 50, 685.
(9) For recently excellent reviews for α-aminonitrile, see: (a) Otto, N.; Opatz, T., Heterocycles from α-Aminonitriles. Chem. Eur.
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chemistry, synthesis, and biological properties. Tetrahedron 2018, 74, 773.
(
10) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D., Total Synthesis of Lepadiformine Alkaloids using N-Boc
α-Amino Nitriles as Trianion Synthons. J. Org. Chem. 2012, 77, 3390.
(
11) (a) Luker, T.; Hiemstra, H.; Speckamp, W. N., Total Synthesis of Desoxoprosophylline: Application of a Lactam-Derived
Enol Triflate to Natural Product Synthesis. J. Org. Chem. 1997, 62, 3592. (b) Ojima, I.; Vidal, E. S., Rhodium-Catalyzed
Cyclohydrocarbonylation: Application to the Synthesis of (+)-Prosopinine and (-)-Deoxoprosophylline. J. Org. Chem. 1998,
63, 7999. For the excellent review for trimethylsilyl nucleophile, see (c) Gawronski, J.; Wascinska, N.; Gajewy, J., Recent
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Rev. 2008, 108, 5227.
(
(
(
12) Paventi, M.; Chubb, F. L.; Edward, J. T., Assisted hydrolysis of the nitrile group of 2-aminoadamantane-2-carbonitrile. Can.
J. Chem. 1987, 65, 2114.
13) Schar, P.; Renaud, P., Total Synthesis of the Marine Alkaloid (±)-Lepadiformine via a Radical Carboazidation. Org. Lett.
2006, 8, 1569.
14) Preparation of 2-allylcyclohexnone and 2-propargylcyclohexnone, see (a) Stork, G.; Brizzolara, A.; Landesman, H.;
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Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207; for the preparation of enantiopure 2-allylcyclohexanone, see
(b) Braun, M.; Meletis, P.; Fidan, M., (S)-(-)-2-allylcyclohexanone. Org. Synth. 2009, 86, 47.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
15) See the Supporting Information for the ORTEP representation of the X-ray structure.
(16) The addition sequence was important in this reaction. As long as the free aminonitrile was mixed with a base, it usually
suffered with low yields. Such a phenomenon also suggested possible spontaneous dissociation of the nitrile group,
especially in the basic conditions.
(
17) As we anticipated, despite intense efforts to convert the angular nitrile group of CDHQ 3, attempts to attain the carbonyl
functionality from the nitrile for further transformations were unsuccessfully. These efforts included basic or
peroxide-mediate hydrolysis, reducing agents, Rh-mediated hydrolysis and organolithiums. These reactions led either to
recovery of the starting materials, low yield of the aldehyde product, or to complete destruction if in forcing conditions.
18) For synthesis of a certain 3-substituted trimethylallylsilane to save the additional efforts on the appendage, see: Hoshi, M.;
Masuda, Y.; Arase, A., The Hydroboration of 3-Chloro-1-trimethylsilyl-1-propyne with Dialkylboranes and Its Application
to the Syntheses of (E)-3-Trimethylsilyl-2-alkenes and 3-Trimethylsilyl-1-alkenes. Bull. Chem. Soc. Jpn. 1992, 65, 685.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(19) For the detailed DFT calculation discussions on the observed syn selectivity of silane additions, see: Chiou, W.-H.; Chen,
H.-Y., Synthesis of dendrobatid alkaloid (+)-167B and (+)-209D and the investigation of diastereoselectivity using DFT
calculations. RSC Adv. 2017, 7, 684.
(
20) (a) Meyer, A. M.; Katz, C. E.; Li, S.-W.; Velde, D. V.; Aube, J., A Tandem Prins/Schmidt Reaction Approach to Marine
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D.; Gouda, H.; Toyooka, N., Formal Syntheses of (−)-Lepadiformines A, C, and (−)-Fasicularin. J. Org. Chem. 2019, 84,
5222.
(
21) Nishikawa, K.; Yamauchi, K.; Kikuchi, S.; Ezaki, S.; Koyama, T.; Nokubo, H.; Matsumura, K.; Kodama, T.; Kumagai, M.;
Morimoto, Y., Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)2-Catalyzed
Cycloisomerization Reaction and their Cytotoxic Activities. Chem. Eur. J. 2017, 23, 9535.
(22) Miyazawa, A.; Tanaka, K.; Sakakura, T.; Tashiro, M.; Tashiro, H.; Prakash, G. K. S.; Olah, G. A., Microwave-assisted direct
transformation of amines to ketones using water as an oxygen source. Chem. Commun. 2005, 2104.
(23) Imada, Y.; Kitagawa, T.; Ohno, T.; Iida, H.; Naota, T., Neutral Flavins: Green and Robust Organocatalysts for Aerobic
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(24) Addition of the co-solvent is necessary because of the poor solubility of the substrates in HBr. Employment of ethereal
solvents will result in the decomposition of the solvents.
(25) The catalytic hydrogenation over Pd/C proceeded very slowly in ethyl acetate.
(
26) The crude product is prone to be decomposed at room temperature.
(27) Two sets of the 13C-NMR peaks have been reported due to the observation of equilibrium between acyclic form (i.e.
aldehyde) as the major contributor and cyclic form as the minor one (i.e. aminal).
(28) The numbering method follows the lepadiformine system for convenience.
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