Studies toward a synthesis of C3-epimauritine D: Construction of the macrocycle

Article abstract of DOI:10.1016/S0040-4039(03)00278-8

We successfully synthesized a 14-membered cyclic enamide of C3-epimauritine D from the cis-2,3-pyrrolidinediol derivative. Treatment of the pyrrolidinediol with nitrobenzonitrile in an S_NAr reaction efficiently installed the desired aryl-alkyl ether linkage on the N-heterocyclic system. Macrocyclization was successfully achieved by the use of TFFH as the peptide coupling reagent in the presence of HOAt.

Full text of DOI:10.1016/S0040-4039(03)00278-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2557–2560
Studies toward a synthesis of C3-epimauritine D: construction of
the macrocycle
Young-Ah Kim, Hyo-Nim Shin, Myoung-Soon Park, So-Hye Cho and So-Yeop Han*
Department of Chemistry, Division of Molecular Life Sciences, and Division of Nano Sciences, Ewha Womans University,
Seoul 120-750, Republic of Korea
Received 19 December 2002; revised 28 January 2003; accepted 30 January 2003
Abstract—We successfully synthesized a 14-membered cyclic enamide of C3-epimauritine D from the cis-2,3-pyrrolidinediol
derivative. Treatment of the pyrrolidinediol with nitrobenzonitrile in an SNAr reaction efficiently installed the desired aryl–alkyl
ether linkage on the N-heterocyclic system. Macrocyclization was successfully achieved by the use of TFFH as the peptide
coupling reagent in the presence of HOAt. © 2003 Elsevier Science Ltd. All rights reserved.
Over the past decades, considerable investigations into
the total synthesis of cyclopeptide alkaloids were per-
formed owing to their prominent biological activities as
well as structural interests.1 Numerous efforts have
been specially concentrated on the macrocyclization.2
Recently, the total synthesis of sanjoinine G1 was
reported which utilized an intramolecular SNAr
reaction3 and modified Schmidt protocol4 for the con-
struction of the macrocycle. Herein, we wish to report
our newly developed procedure toward epimauritine D
1 (Fig. 1), which is the C3-epimer of 14-membered
cyclopeptide alkaloid mauritine D that was isolated
from Zizyphus nummularia by Tschesche.5 We reasoned
that unnatural epimer would provide biological activity
relationship as well as synthetic methodology compar-
ing with natural product. In this report, we described
the preparation of the key intermediate 2 of C3-epi-
mauritine D by macrocyclization at the C1–N14 site.
Our retrosynthetic analysis for the enamide 2 is illus-
trated in Scheme 1. We envisioned that macrocycle 2
Figure 1. Structure of C3-epimauritine D 1.
Keywords: cyclopeptide alkaloid; epimer; pyrrolidinone; macrocy-
clization; cyclic enamide; pfp ester; TFFH.
* Corresponding author. Tel.: +82-2-3277-2377; fax: +82-2-3277-2384;
e-mail: syhan@ewha.ac.kr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00278-8

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Y.-A. Kim et al. / Tetrahedron Letters 44 (2003) 2557–2560
An attempted synthesis of linear precursor 14 is out-
lined in Scheme 2. Pyrrolidinone 8 was prepared in five
steps from
-serine6 and then reduced to compound 7
D
by using borane–dimethylsulfide complex. One of the
key steps was the construction of aryl–alkyl ether link-
age to set the C-3 stereocenter of compound 5. We
carried out the SNAr reaction with compound 7 using
various conditions (Table 1).4a,7 Treatment of 7 with
fluorobenzonitrile at room temperature afforded a desi-
lylated by-product (entry 2). Compound 5 could be
achieved in 78% yield by first generating the alkoxide of
7 via NaH which then displaced the nitro group of
p-nitrobenzonitrile. Optimization of 5 required per-
forming the reaction at −30°C (entry 7) since low yields
were obtained at higher temperatures (entries 3 and 5).
Furthermore, replacing NaH with the bases DBU,
Et3N, or LiH resulted in no product (entries 1, 4 and 6).
Compound 5 was converted to 9 by a Swern–Masa-
mune oxidation, followed by protection to methyl ester
10. The cyano group of 10 was treated with Raney Ni
and NaH2PO2 to afford aldehyde 11, which was then
reacted with the anion of nitromethane to give the
expected epimeric benzylic alcohol 12. Treatment of
compound 12 with TBS–Cl and imidazole followed by
reduction of the nitro group using ammonium formate
and Pd/C provided the amine 13 in good yield. Cou-
pling reaction between the amine 13 and Z-isoleucine 6
was achieved by using standard DCC/HOBt methodol-
ogy. We were unexpectedly confronted by the problem
that the hydrolysis of compound 3 to carboxylic acid 14
was unsuccessful with aqueous solutions of bases such
as LiOH, NaOH, and Ba(OH)2. Thus, construction of
macrocycle via route A was hampered due to the failure
of the preparation of the linear precursor 14.
Scheme 2. Reagents and conditions: (a) reflux, BH3SMe2,
THF, 5 h, 88%; (b) nitrobenzonitrile, NaH, DMF, −30°C, 4
h, 78%; (c) AcOH:THF:H2O (3:1:1 v/v/v), 40–45°C, 15 h,
88%; (d) DMSO, TFAA, NEt3, CH2Cl2, −78°C, 3 h; (e) 1 M
KMnO4, 1.25 M NaH2PO4 buffer (pH 4.12), t-BuOH, rt, 1 h,
81% for two steps; (f) DCC, DMAP, MeOH, CH2Cl2, 0°C–rt,
3 h, 96%; (g) Raney Ni, NaH2PO2, py:AcOH:H2O (2:1:1
v/v/v), 40°C, 3 h, 93%; (h) Na, CH3NO2, MeOH, 0°C, 30
min, 93% with recovered starting material; (i) TBDMS–Cl,
imidazole, DMF, 0–25°C, 24 h, 93%; (j) 10% Pd/C,
HCO2NH4, MeOH, 0–25°C, 4 h, 82%; (k) Z-isoleucine 6,
DCC, HOBt, NMM, CH2Cl2, 0°C–rt, 3 h, 94%.
Because of the difficulty encountered in the hydrolysis
of 3, we changed our strategy and planned a different
route via the linear precursor 4 (Scheme 3). Compound
4 was prepared from compound 5 via a similar syn-
thetic protocol as for compound 3. The cyano group of
5 was converted to the aldehyde 15 in 73% yield,
followed by a Henry reaction to produce 16. In order to
differentiate the protecting groups on the secondary
alcohol from the primary alcohol, compound 16 was
silylated with TIPSOTf in the presence of 2,6-lutidine8
to yield, after reduction of the nitro group, amine 17.
could be produced by an intramolecular cyclization of
either intermediate 3 or 4. Compounds 3 and 4 could be
disconnected into 5 and 6. Compound 5 could be
prepared from pyrrolidine 7 and p-nitrobenzonitrile via
an SNAr reaction. Compound 7 could be obtained from
the known pyrrolidinone 8.
Table 1. SNAr reaction under various conditions
Entry
Substratea
Base
Solvent
Reaction time (h)
Reaction temp.
Yieldb
1
2
3
4
5
6
7
A
A
B
B
B
B
B
DBU
NaH
NaH
Et3N
NaH
LiH
CH3CN
HMPA
HMPA
HMPA
DMF
12
1
1
24
2
12
4
rt
rt
rt
rt
n.r.c
Traced
25%
n.r.
34%
n.r.
0°C
rt
−30°C
DMF
DMF
NaH
78%
a A: fluorobenzonitrile; B: nitrobenzonitrile.
b Isolated yield.
c n.r.: no reaction.
d Trace: trace amount of product.

Y.-A. Kim et al. / Tetrahedron Letters 44 (2003) 2557–2560
2559
Scheme 4. Reagents and conditions: (a) pentafluoro phenol,
DCC, CH2Cl2, 0°C–rt, 3 h, 92%; (b) 10% Pd/C, cyclohexene,
EtOH, 4-pyrrolidinopyridine, 1,4-dioxane, 95°C–rt, 4 h; (c)
10% Pd/C, MeOH, rt, 1 h, 87%; (d) TFFH, HOAt, DIEA,
CH2Cl2, 0°C, 2 h, 75%.
Scheme 3. Reagents and conditions: (a) Raney Ni, NaH2PO2,
py:AcOH:H2O (2:1:1 v/v/v), 40–45°C, 3 h, 73%; (b) Na,
CH3NO2, MeOH, 0°C, 30 min, 85% with recovered starting
material; (c) TIPSOTf, 2,6-lutidine, CH2Cl2, 0°C, 3 h, 65%;
(d) 10% Pd/C, HCO2NH4, MeOH, 40°C, 2 h, 81%; (e)
Z-isoleucine 6, DCC, HOBt, NMM, CH2Cl2, 0°C–rt, 3 h,
91%; (f) AcOH:THF:H2O (3:1:1 v/v/v), 45–50°C, 3 h, 87%;
(g) DMSO, TFAA, NEt3, CH2Cl2, −78°C, 3 h; (h) 1 M
KMnO4, 1.25 M NaH2PO4 buffer (pH 4.12), t-BuOH, rt, 1 h,
65% for two steps.
Scheme 5. Reagents and conditions: (a) TBAF, THF, 0°C–rt,
2 h, 60%; (b) MsCl, NEt3, CH2Cl2, −10°C, 30 min; (c)
diphenyldiselenide, NaBH4, EtOH, 80°C, 30 min, 50% for
two steps; (d) NaIO4, MeOH, 40 min; (e) benzene, 60°C, 40
min, 60% for two steps.
Acylation of amine 17 by Z-isoleucine 6 produced
amide 4 which was then selectively deprotected to
alcohol 18 by using
a
mixture of acetic
acid:tetrahydrofuran:water. Subsequently, the Swern–
Masamune oxidation of alcohol 18 afforded the car-
boxylic acid 19.
As shown in Scheme 4, our initial investigation on the
macrocyclization of carboxylic acid 19 was carried out
under modified Schmidt protocol.2f,9 Interestingly, our
attempt to form the macrocycle 22 from the activated
pentafluorophenyl (pfp) ester 20 afforded none of the
desired product. After removal of the Z group of
compound 19, several attempts to cyclize compound 21
to lactam 22 failed using standard reagents such as
BOP-Cl, DPPA, and BOP.10 However, using methodol-
ogy developed by Carpino,11 compound 21 reacted with
tetramethylfluoroformamidinium hexafluorophosphate
(TFFH)/HOAt in CH2Cl2 to give the desired product
22 as a mixture of two diastereomers in 75% yield.
and selenation. Oxidation of compound 24 with sodium
periodate, followed by thermal elimination, afforded
the enamide 2 in 60% yield with a rotation value of
−274 (c 0.69, CHCl3).
In conclusion, the cyclic enamide 212 was efficiently
synthesized from the known pyrrolidinone 8 in 17 steps
and an overall yield of 1.4%. The structure was con-
1
1
1
firmed by H, 13C, H–1H COSY, and H–13C COSY
NMR spectroscopy and HRMS spectrometry. Further
investigations toward the total synthesis of C3-epi-
mauritine D with 2 are now in progress.
Completion of the synthesis of the cyclic enamide 2 is
shown in Scheme 5. Desilylation of the macrocycle 22
using TBAF afforded the alcohol 23, which was then
converted to the selenide 24 by sequential mesylation
Acknowledgements
This research was supported by a Grant from KOSEF
(R14-2002-015-01002-0) and Ministry of Health & Wel-

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Y.-A. Kim et al. / Tetrahedron Letters 44 (2003) 2557–2560
fare (01-PJ1-PG3-21500-0042). YAK, HNS, MSP and
SHC are recipients of a graduate fellowship of Brain
Korea 21 program.
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