Syntheses of cis - And trans -Jamtine and Their N -Oxides via a Benzyl Configuration-Inversion Approach

Article abstract of DOI:10.1055/s-0037-1610745

A novel synthesis of the tetrahydroisoquinoline alkaloid jamtine and its epimer is reported. The synthetic strategy hinges on a one-pot conjugate reduction/Robinson cyclization sequence and an efficient benzyl configuration inversion by an oxidation/reduction approach. The N -oxide derivatives of the jamtine isomers were also synthesized and identified by X-ray crystallographic analysis. Additionally, a density functional theory calculation for the four possible N -oxide structures was exploited to gain further insight into the structure of the natural product in comparison to those of the synthetic N -oxides, because the NMR data of the synthetic derivatives did not match those reported for natural jamtine N -oxide.

Full text of DOI:10.1055/s-0037-1610745

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, 339–342
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Z. Liu et al.
Letter
Synlett
Syntheses of cis- and trans-Jamtine and Their N-Oxides via a
Benzyl Configuration-Inversion Approach
◊
Zhigang Liu
0
0
0
0-
0
0
0
3-4
9
1
7-7
3
8
7
MeO
MeO
O
Zhengshen Wang◊
N
H
Yujie Li
MeO2C
MeO
MeO
MeO
MeO
Conjugate reduction/
Robinson cyclization
Qiang Zhang
Jin-Ming Gao
N
N
(trans,cis)-jamtine N-oxide
O
O
O
H
H-
MeO2C
MeO
MeO2C
one-pot
Huaiji Zheng*
0
0
0
0-0
0
0
3-1
6
7
4-
7
5
8
2
O
N
O
MeO
H
Shaanxi Key Laboratory of Natural Products and Chemical Biology,
College of Chemistry and Pharmacy, Northwest A&F University,
Yangling, 712100, P. R. of China
MeO2C
O
(cis,cis)-jamtine N-oxide
hjzheng@nwsuaf.edu.cn
◊These authors contributed equally to this work.
Received: 22.11.2019
Accepted after revision: 20.12.2019
Published online: 28.01.2019
MeO
MeO
MeO
O
14 N
14 N
MeO
H
H
DOI: 10.1055/s-0037-1610745; Art ID: st-2019-l0629-l
MeO2C
MeO2C
Abstract A novel synthesis of the tetrahydroisoquinoline alkaloid jam-
tine and its epimer is reported. The synthetic strategy hinges on a one-
pot conjugate reduction/Robinson cyclization sequence and an efficient
benzyl configuration inversion by an oxidation/reduction approach. The
N-oxide derivatives of the jamtine isomers were also synthesized and
identified by X-ray crystallographic analysis. Additionally, a density
functional theory calculation for the four possible N-oxide structures
was exploited to gain further insight into the structure of the natural
product in comparison to those of the synthetic N-oxides, because the
NMR data of the synthetic derivatives did not match those reported for
natural jamtine N-oxide.
jamtine N-oxide (1)
jamtine (2)
HO
HO
HO
MeO
MeO
MeO
O
N
N
N
H
H
H
MeO2C
MeO2C
MeO2C
haiderine (3)
hirsutine (4)
jamtinine (5)
Figure 1 Jamtine N-oxide (1) and related tetrahydroisoquinoline alkaloids
Key words natural products, jamtine, total synthesis, one-pot reac-
tion, conjugate reduction, Robinson cyclization
Pummerer/Pictet–Spengler cyclization, asymmetric de-
symmetrization of a meso-imide, and a Castagnoli conden-
sation approach.8 However, the NMR data for the synthetic
jamtine N-oxide disagreed with those reported for the nat-
ural product. It is observed that all the synthetic jamtine
derivatives possess a trans-configuration between the
methyl ester and H-14 atom, as proposed at the time of
their isolation. Actually, the relative configuration of these
two groups could not be determined, even after a detailed
analysis of the NOESY spectra of all related natural com-
pounds.2a,5–7 In a further exploration of the total synthesis
and structural elucidation of jamtine isomers and their N-
oxides, we set out to devise a flexible synthetic strategy to
access both cis- and trans-jamtine and their N-oxides.
Alkaloid N-oxides are known to be readily available
from the corresponding amines through appropriate oxida-
tion. Thus, our retrosynthetic analysis began from the cis-
and trans-jamtines, as outlined in Scheme 1. trans-Jamtine
(2) might be derived by a consecutive benzyl oxidation/re-
duction sequence from cis-jamtine (6), which would in turn
be obtained from the amide cis-7 through reduction of the
two carbonyl groups. The characteristic ,-unsaturated
Tetrahydroisoquinoline alkaloids are an important class
of biologically and pharmacologically active candidates for
use as antibiotics and antitumor agents.1 Jamtine N-oxide
(1), as a novel tetrahydroisoquinoline alkaloid, was isolated
from the leaves of the climbing shrub Cocculus hirsutus
from Pakistan,2 the extracts of which have been used as a
folk medicine to treat rheumatism and diarrhea.3 Moreover,
a previously reported in vitro study revealed that an aque-
ous extract of the leaves of C. hirsutus exhibited significant
antihyperglycemic activity in mice.4 Although jamtine (2),
in the form of the free amine, has not been isolated previ-
ously, it is envisaged also to be a natural metabolite as the
biogenic precursor of jamtine N-oxide, based on the fact
that other related free amines such as haiderine (3),5 hirsu-
tine (4),6 and jamtinine (5)7 have been reported to be isolat-
ed from the same plant species (Figure 1).
Considerable efforts toward the total synthesis of jam-
tine N-oxide (1) or jamtine (2) have been reported by sever-
al groups, whose key synthetic strategies included tandem
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 339–342
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

340
Z. Liu et al.
Letter
Synlett
cyclohexenone group of 7 might be constructed through a
Robinson cyclization between the 1,3-dicarbonyl com-
pound 8 and methyl vinyl ketone (9; MVK), whereas 8
might be derived from the known precursor 10 through a
conjugate reduction.
cis-12 was almost quantitatively converted into a thioamide
under Lawesson’s conditions, followed by reduction to the
free amine cis-13 with Meerwein’s salt and NaBH4. Finally,
desulfurization of cis-13 with Raney-nickel resulted in the
successful formation of cis-jamtine (6). The configuration of
these compounds was confirmed by the X-ray crystallo-
graphic analysis of cis-13.
MeO
MeO
MeO
MeO
MeO
N
O
Reduction
Oxidation
MeO
Reduction
N
N
H
MeO
MeO
H
H
MeO2C
MeO
MeO2C
MeO2C
HS
1) Lawesson's reagent
SH
N
N
O
O
MeO
H
BF3⋅Et2O
PhMe, 120 °C, 95%
H
O
MeO2C
MeO2C
trans-jamtine (2)
cis-jamtine (6)
cis-7
2) Me3OBF4, THF
CH2Cl2, 0 °C to rt
82%
then NaBH4, MeOH
73%
S
S
O
MeO
MeO
MeO
MeO
Conjugate
reduction
cis-7
cis-12
Robinson cyclization
O
N
N
O
OH
O
H
MeO2C
MeO
MeO
MeO
MeO2C
N
O
H
Raney-Ni
N
9 (MVK)
8
10
MeO
H
MeO2C
MeO2C
EtOH, rt
77%
Scheme 1 Retrosynthetic analysis
S
S
cis-13
ORTEP of cis-13
cis-jamtine (6)
Our synthesis started from 2-(3,4-dimethoxyphe-
nyl)ethylamine (11), which was converted into the known
compound 10 in moderate yield over three steps by using
dimethyl malonate and oxalyl chloride (Scheme 2).9 Reduc-
tion of compound 10 with Hantzsch ester10 in refluxing
CH2Cl2 resulted in the formation of enol 8; this reaction was
effectively catalyzed by L-proline at r.t. with the reduction
in the reaction time from 15 to 3 hours. Gratifyingly, we
successfully conducted the conjugate reduction and subse-
quent Robinson cyclization11 in one-pot under Hantzsch es-
ter/L-proline/CHCl3 conditions, followed with sequentially
addition of MVK and PTSA, affording the cyclohexenone cis-
7. Although chiral proline was used in this reaction, no en-
antiomeric excess of cis-7 was observed. X-ray crystallo-
graphic analysis of this tetracyclic compound 7 unambigu-
ously confirmed the cis-configuration between the ester
group and H-14. The nearly planar structure of compound 8
rendered H-14 sterically significant in preventing approach
of MVK from the same side.
Scheme 3 Synthesis of cis-jamtine (6)
MeO
MeO
MeO
MeO
MeO
MeO
N
N
O
N
TFA
NaBH4
O
O
H
H
DDQ
HO
MeO2C
MeO2C
MeO2C
1,4-dioxane, rt
92%
CH2Cl2, rt
98%
S
S
S
S
S
S
cis-12
14
trans-12
MeO
MeO
MeO
MeO
1) Lawesson's reagent
PhMe, 120 °C, 94%
N
H
N
Raney-Ni
MeO2C
H
MeO2C
EtOH, rt
75%
2) Me3OBF4, THF
then NaBH4, MeOH
70%
S
S
trans-13
trans-jamtine (2)
+
+
MeO
MeO
N
O
MeO2C
S
Conversion of cis-7 into cis-jamtine (6) was achieved in
four steps (Scheme 3). The enone carbonyl group was selec-
tively protected as a 1,3-dithiane, and the resulting amide
S
ORTEP of trans-12
TS 1
Scheme 4 Synthesis of trans-jamtine (2)
MeO
MeO
Hantzsch ester MeO
L-proline
As hydroisoquinolines can be easily oxidized to
imines,12 the desired inversion of the configuration at H-14
of cis-12 was conducted through an oxidation/reduction ap-
proach (Scheme 4). DDQ oxidation of cis-12 delivered alco-
hol 14 in 92% yield; this was then reduced with NaBH4/TFA
to afford trans-12 in quantitative yield. These two transfor-
mations might proceed via a common iminium intermedi-
ate (TS 1), in which both the nucleophilic OH and the nega-
tive H react separately with the iminium TS 1 by approach-
ing from the opposite side of the ester group to facilitate
the formation of the trans-product. The structure of trans-
12 was further confirmed by X-ray crystallographic analy-
MeO
MeO
3 steps
N
N
O
O
MeO
NH2
H
CHCl3, rt
MeO2C
MeO2C
O
OH
11
10
8
MeO
MeO
N
9
O
PTSA
H
MeO2C
80 °C
80 °C
58% from 10
O
cis-7
ORTEP of cis-7
Scheme 2 One-pot synthesis of cis-7 by conjugate reduction/Robinson
cyclization
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 339–342

341
Z. Liu et al.
Letter
Synlett
sis. Next, following the same procedures as used in the syn-
thesis of cis-jamtine (6), trans-jamtine (2) was successfully
generated from trans-12 in 49% overall yield. The NMR data
of trans-jamtine (2) was in full agreement with those of
synthesized samples reported by other research groups.8a–d
With both cis- and trans-jamtines in hand, our attention
then turned to the nitrogen oxidation to access the required
jamtine N-oxides. Two jamtine N-oxides were synthesized
readily by exposing the corresponding free amines to mCP-
BA at room temperature (Scheme 5), whereby the products
15 and 16 appeared as solids (not oils or gums as previously
reported), and both were obtained as single diastereoiso-
mers. The structures of the two stereoisomers were unam-
biguously confirmed as (trans,cis)-jamtine N-oxide (15) and
(cis,cis)-jamtine N-oxide (16) by X-ray crystallography; the
oxygen of the N–O bond and H-14 have a cis configuration.
A complete comparison of the spectroscopic data of N-ox-
ides 15 and 16 with those of the natural N-oxide revealed a
considerable discrepancy (see Supporting Information),
probably due to the diastereochemistry of the N–O bond.
15
(trans,cis)
16
(cis,cis)
0.00a (0.07b) kcal/mol
0.17a (0.00b) kcal/mol
17
18
(cis,trans)
(trans,trans)
2.34a (2.38b) kcal/mol
4.60a (4.68b) kcal/mol
Figure 2 Relative free energies of the four relative configurations of
jamtine N-oxide calculated in CH2Cl2 or H2O solvent. a ΔE calculated in
CH2Cl2. b ΔE calculated in H2O.
MeO
O
mCPBA, CH2Cl2, rt
N
MeO
2
H
In summary, we have accomplished syntheses of cis-
and trans-jamtine14 and their N-oxides. The assembly of the
core of these four tetrahydroisoquinoline compounds relied
on a one-pot conjugate reduction/Robinson cyclization se-
quence followed by an efficient benzyl configuration inver-
sion (by an oxidation/reduction approach). The synthetic
jamtine N-oxides 15 and 16 were confirmed to be the non-
natural isomers. Development of an alternative oxidation
methodology to access the natural N-oxide, as well as bio-
logical evaluations of our synthetic jamtine N-oxides, are
currently underway and will be reported in due course.
MeO2C
93%
(trans,cis)-jamtine N-oxide (15)
ORTEP of 15
MeO
O
mCPBA, CH2Cl2, rt
N
MeO
6
H
MeO2C
90%
(cis,cis)-jamtine N-oxide (16)
ORTEP of 16
Scheme 5 Syntheses of (trans,cis)- and (cis,cis)-jamtine N-oxides (15
and 16)
To gain further insight into the structures of jamtine N-
oxides, we performed preliminary conformational re-
search13 on the four relative configurations of jamtine N-ox-
ide including the synthetic (trans,cis)- and (cis,cis)-products
15 and 16 and their N–O epimers (trans,trans)-17 and
(cis,trans)-18, as shown in Figure 2. DFT calculations
showed that both our synthetic isomers 15 and 16 exhibit-
ed lower free energies in a solvent model of CH2Cl2 or H2O,
whereas isomers 17 and 18 possessed higher free energies.
However, whether or not the natural product is one of the
N–O epimers 17 and 18 is yet to be determined by their to-
tal synthesis. Our late-stage oxidation facilitated a sub-
strate-dependent diastereoselective formation of the N-ox-
ide with a cis-configuration relative to H-14. However, an
early installation of the N-oxide functionality or enzymati-
cally mediated epimerization might be involved in the bio-
synthesis of the isomer 17 or 18.
Funding Information
We are grateful for generous financial support from the National Nat-
ural Science Foundation of China (21702167 to Z.L., 21772156 and
21502151 to H.Z., and 21702168 to Z.W.) and the Natural Science
Foundation of Shaanxi Province (S2016YFJQ0080 to Z.L.).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610745.
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References and Notes
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, 339–342

342
Z. Liu et al.
Letter
Synlett
Chopra’s Indigenous Drugs of India, 2nd ed; U. N. Dahr: Calcutta,
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(13) The conformational research was carried out using DFT method
in Gaussian 09 software (for details see the Supporting Informa-
tion).
362. For
a review of natural isoquinoline N-oxides, see:
(e) Dembitskya, V. M.; Gloriozova, T. A.; Poroikov, V. V. Phyto-
medicine 2015, 22, 183.
(14) Methyl cis-2,3-Dimethoxy-5,8,10,11,12,12b-hexahydroisoin-
dolo[1,2-a]isoquinoline-12a(6H)-carboxylate (cis-Jamtine) (6)
To a solution of cis-13 (355 mg, 0.82 mmol) in absolute EtOH
(10 mL) was added excess Raney-Ni (W-2 type, newly reacti-
vated), and the mixture was vigorously stirred at rt for 2 h. The
mixture was then filtered through a plug of Celite that was
washed with EtOAc. The filtrate was concentrated, and the
residue was purified by chromatography [silica gel, CH2Cl2–
MeOH (50:1)] to give a white solid; yield: 218 mg (77%); mp
95.2–98.0 °C.
(3) Rao, K. V. J.; Rao, L. R. C. J. Sci. Ind. Res. 1981, 20B, 125.
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1991, 54, 582.
(7) Ahmad, V. U.; Iqbal, S. Phytochemistry 1993, 33, 735.
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Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003,
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2003, 59, 9213. (e) Pérard-Viret, J.; Souquet, F.; Manisse, M.-L.;
Royer, J. Tetrahedron Lett. 2010, 51, 96. For synthetic efforts
toward jamtine and methodological researches, see: (f) Tang, Y.;
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I.; Ershova, J. D.; Orlova, A. A.; Zaytsev, V. P.; Nikitina, E. V.;
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N.; Maharramov, A. M.; Varlamov, A. V. Tetrahedron 2009, 65,
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1H NMR (500 MHz, CDCl3):  = 6.98 (s, 1 H), 6.56 (s, 1 H), 5.70 (s,
1 H), 4.36 (s, 1 H), 3.88 (s, 3 H), 3.90–3.82 (m, 1 H), 3.84 (s, 3 H),
3.78 (s, 3 H), 3.35 (d, J = 12.8 Hz, 1 H), 2.94–2.85 (m, 1 H), 2.73–
2.57 (m, 3 H), 2.16 (dt, J = 12.8, 3.1 Hz, 1 H), 2.12–2.04 (m, 1 H),
2.04–1.94 (m, 1 H), 1.68–1.60 (m, 1 H), 1.44–1.33 (m, 1 H), 0.70
(td, J = 13.6, 3.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3):  = 176.8,
147.6, 147.0, 138.8, 126.9, 125.0, 121.8, 110.9, 110.6, 68.2, 61.5,
55.8, 55.7, 54.3, 52.2, 46.5, 29.9, 28.6, 23.5, 19.4. HRMS (ESI):
m/z [M + H]+ calcd for C20H26NO4: 344.1856; found: 344.1854.
Methyl trans-2,3-Dimethoxy-5,8,10,11,12,12b-hexahydroisoin-
dolo[1,2-a]isoquinoline-12a(6H)-carboxylate (trans-Jamtine)
(2)
To a solution of trans-13 (180 mg, 0.42 mmol) in absolute EtOH
(8 mL) was added excess Raney-Ni (W-2 type, newly reacti-
vated), and the mixture was vigorously stirred at rt for 2 h. The
mixture was then filtered through a plug of Celite that was
washed with EtOAc. The filtrate was concentrated, and the
residue was purified by chromatography [silica gel, CH2Cl2–
MeOH (50:1)] to give a white solid; yield: 108 mg (75%); mp
104.0–106.3 °C.
(9) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem.
Pharm. Bull. 1987, 35, 479.
(10) Selected examples of transfer hydrogenation with Hantzsch
ester: (a) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc.
2006, 128, 13074. (b) Martin, N. J. A.; List, B. J. Am. Chem. Soc.
2006, 128, 13368; corrigendum: Org. Lett. 2007, 9, 2753.
(c) Yang, J. W.; List, B. Org. Lett. 2006, 8, 5653.
(11) For a review of natural products syntheses using Robinson
cyclization: (a) Gallier, F.; Martel, A.; Dujardin, G. Angew. Chem.
Int. Ed. 2017, 56, 12424. For selected examples, see:
(b) Yamashita, S.; Naruko, A.; Nakazawa, Y.; Zhao, L.; Hayashi,
Y.; Hirama, M. Angew. Chem. Int. Ed. 2015, 54, 8538. (c) Dethe, D.
H.; Sau, S. K. Org. Lett. 2019, 21, 3799. (d) Li, H.; Chen, Q.; Lu, Z.;
Li, A. J. Am. Chem. Soc. 2016, 138, 15555.
(12) For selected examples for the oxidation of hydroisoquinolines to
imine intermediates, see: (a) Boess, E.; Schmitz, C.; Klussmann,
M. J. Am. Chem. Soc. 2012, 134, 5317. (b) Kumaraswamy, G.;
Murthy, A. N.; Pitchaiah, A. J. Org. Chem. 2010, 75, 3916.
1H NMR (500 MHz, CDCl3):  = 6.79 (s, 1 H), 6.56 (s, 1 H), 5.71 (s,
1 H), 3.98 (dq, J = 12.0, 2.8 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 1 H),
3.84 (s, 3 H), 3.42 (d, J = 11.2 Hz, 1 H), 3.29 (s, 3 H), 3.11 (dt, J =
11.9, 4.3 Hz, 1 H), 2.90 (ddd, J = 15.1, 10.1, 4.9 Hz, 1 H), 2.82 (dd,
J = 8.9, 3.7 Hz, 1 H), 2.78–2.72 (m, 1 H), 2.52 (dt, J = 15.3, 3.3 Hz,
1 H), 2.14–2.08 (m, 2 H), 1.89–1.82 (m, 1 H), 1.56–1.51 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 173.3, 147.4, 146.6, 137.8,
128.4, 126.9, 121.1, 111.1, 110.0, 71.3, 57.1, 56.8, 56.0, 55.7,
51.4, 47.8, 31.9, 27.2, 24.3, 19.8. HRMS (ESI): m/z [M + H]+ calcd
for C20H26NO4: 344.1856; found: 344.1855.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 339–342