Efficient Synthesis of (-)-Hanishin, (-)-Longamide B, and (-)-Longamide B Methyl Ester through Piperazinone Formation from 1,2-Cyclic Sulfamidates

Article abstract of DOI:10.1055/s-0035-1560988

We describe a simple chiral-pool synthesis of (-)-longamide B, (-)-longamide B methyl ester, and (-)-hanishin. The key feature of the total synthesis is the formation of a piperazinone from a 1,2-cyclic sulfamidate and methyl 2-pyrrolecarboxylate, which permits efficient construction of the pyrrolopiperazinone core scaffold.

Full text of DOI:10.1055/s-0035-1560988

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 616–620
letter
616
Z. Shiokawa et al.
Letter
Synlett
Efficient Synthesis of (–)-Hanishin, (–)-Longamide B, and (–)-Lon-
gamide B Methyl Ester through Piperazinone Formation from 1,2-
Cyclic Sulfamidates
Zenyu Shiokawaa,b
Shinsuke Inukib
Koichi Fukase*a
Yukari Fujimoto*b
Br
CO2Me
O
O
O
N
H
O
Br
S
N
R1
N
O
N
NH
NH
a Department of Chemistry, Graduate School of Science,
Osaka University, 1-1 Machikaneyama-cho, Toyonaka,
Osaka 560-0043, Japan
piperazinone
formation
R2
R2
CO2R
b Department of Chemistry, Faculty of Science and
Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama, Kanagawa 223-8522, Japan
R = H: longamide B
R = Me: longamide B methyl ester
R = Et: hanishin
1,2-cyclic
sulfamidate
75%
for 3 steps
4-substituted
pyrrolopiperazinone
fujimotoy@chem.keio.ac.jp
Received: 14.09.215
Accepted after revision: 20.10.2015
Published online: 09.12.2015
Br
O
DOI: 10.1055/s-0035-1560988; Art ID: st-2015-u0727-l
Br
N
NH
Abstract We describe a simple chiral-pool synthesis of (–)-longamide
B, (–)-longamide B methyl ester, and (–)-hanishin. The key feature of
the total synthesis is the formation of a piperazinone from a 1,2-cyclic
sulfamidate and methyl 2-pyrrolecarboxylate, which permits efficient
construction of the pyrrolopiperazinone core scaffold.
CO2R
R = H: longamide B
(1)
R = Me: longamide B methyl ester (2)
R = Et: hanishin
(3)
Key words heterocycles, hanishin, longamide B, asymmetric synthe-
sis, piperazinones, sulfamidates
Figure 1 Structures of the bromopyrrole alkaloids
Longamide B (1),1 longamide B methyl ester (2),2 and
hanishin (3)3 are bromopyrrole alkaloids isolated from Age-
las dispar, Homaxinella sp., and Acdanthella carteri, respec-
tively (Figure 1). Each of these alkaloids has a broad range of
interesting biological activities. For example, longamide B
exhibits antibiotic activity against Gram-positive bacteria,1
longamide B methyl ester exhibits cytotoxic activity against
P388 lymphocytic leukemia cells,2 and hanishin exhibits
cytotoxicity against NSCLC-N6 human non-small-cell lung
carcinoma.3 Because of their biological importance, several
enantioselective syntheses have been described for these
three compounds.4 Patel et al. reported a chiral-pool syn-
thesis of these alkaloids from L-aspartic acid methyl ester.4a
Trost and co-workers have completed an enantioselective
total synthesis of longamide B, based on the construction of
the core structure by a palladium-catalyzed asymmetric
annulation.4b,c Cheng et al. also reported a total synthesis of
these alkaloids through construction of an N-substituted
pyrrole-2-carboxylate.4d
sulfamidates, causing the ring to open to form esters 5
(Scheme 1). When the resulting intermediate contains an
ester or other electrophilic functional group, intramolecu-
lar cyclization proceeds smoothly under basic conditions to
give the functionalized heterocycle 6. The advantage of this
heterocycle formation is that all reactions proceed in a ste-
reocontrolled manner. Consequently, this strategy has been
applied within the last decade in syntheses of various sub-
stituted stereodefined heterocycles,6 including biologically
active natural products7 and drug leads.8
Here, we report the first example of the formation of a
pyrrolopiperazinone moiety of a natural product that uses a
cyclic sulfamidate as the key intermediate. We had expect-
ed that this type of piperazinone-formation reaction from a
1,2-cyclic sulfamidate might provide ready access to the
pyrrolopiperazinone core structure of bromopyrrole alka-
loids, and we describe a novel and efficient total synthesis
of longamide B (1), longamide B methyl ester (2), and han-
ishin (3) by using the piperazinone-formation reaction of a
1,2-cyclic sulfamidate derivative.
In this study, we used a cyclic sulfamidate as a key inter-
mediate to synthesize the target bromopyrrole alkaloids.
Cyclic sulfamidates have recently become recognized as im-
portant precursors for substituted heterocycles.5 Various
nucleophiles can attack the oxygen-bearing carbon in cyclic
Our retrosynthetic analysis of longamide B is shown in
Scheme 2. Nucleophilic substitution of pyrrole 8 to give the
1,2-cyclic sulfamidate 9 is followed by intramolecular lac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 616–620

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Z. Shiokawa et al.
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R3
R3
CO2Me
O
O
S
N
O
R3
X
O
X
MeO2C
X
base
PG
H
N
N
R1
PG
R1
PG
R1
R2
R2
R2
4
5
6
PG = protective group, X = NH2 or S
Scheme 1 Heterocycle-formation reactions using 1,2-cyclic sulfamidates
tamization to generate the pyrrolopiperazinone scaffold 7.
The 1,2-cyclic sulfamidate 9 can, in turn, be prepared from
the amino alcohol derivative 10. This synthetic route might
also be applicable to divergent syntheses of other deriva-
tives by using various nitrogen-containing heterocycles.
Our approach began with the preparation of the cyclic
sulfamidates 11 and 15 (Scheme 3). The amino alcohol 10
was easily prepared by a reported procedure.9 Next, we at-
tempted to convert 10 into the corresponding sulfamidate
11 by the usual method. When thionyl chloride was added
to a mixture of alcohol 10 and pyridine in the sulfamidite-
formation step, a significant amount of the undesired dimer
12 was obtained after oxidation. To prevent the formation
of this dimer, we added a dilute solution of 10 in dichloro-
methane dropwise to a mixture of thionyl chloride and pyr-
idine in dichloromethane to produce the desired sulfami-
date 11 in high yield (82%) after the oxidation. We also pre-
pared the other cyclic sulfamidate 15. The ester derivative
10 was reduced with sodium borohydride; subsequent pro-
tection of the resulting primary alcohol as the correspond-
ing tert-butyl(dimethyl)silyl ether gave the intermediate 14
in 81% yield (two steps). Formation of the cyclic sulfamidate
from 14 in the same manner as for 11 gave compound 15 in
low yield. However, the addition of saturated aqueous
K2HPO4 to the mixture in the oxidation step improved the
yield to give 15 in 90% yield (two steps).
Br
CO2Me
O
O
N
O
NH
H
O
Br
S
Boc
OH
N
8
N
N
O
EtO2C
NHBoc
NH
CO2H
R
R
longamide B (1)
7
9
10
Scheme 2 Retrosynthesis of longamide B
O
O
BocHN
CO2Et
S
(1) SOCl2, pyridine
CH2Cl2, 0 °C
O
O
O
O
Boc
N
OH
S
O
EtO2C
NHBoc
(2) RuCl3, NaIO4
MeCN–H2O (1:1)
0 °C to r.t.
EtO2C
NHBoc
CO2Et
11
10
NaBH4
12
82% (2 steps)
EtOH, reflux
87%
O
S
N
O
Boc
(1) SOCl2, pyridine
CH2Cl2, 0 °C
O
TBSCl
imidazole
OH
OH
NHBoc
NHBoc
HO
TBSO
DMF
0 °C to r.t.
(2) RuCl3, NaIO4
K2HPO4
14
TBSO
13
MeCN–H2O (1:1)
0 °C to r.t.
93%
15
90% (2 steps)
Scheme 3 Synthesis of the key 1,2-cyclic sulfamidates 11 and 15
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 616–620

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Table 1 Optimization of the Nucleophilic Substitution Reaction of Pyrrole 8 with 1,2-Cyclic Sulfamidates 11 and 15a
O
O
CO2Me
S
Boc
conditions
O
N
EtO2C
NHBoc
CO2Me
N
R
+
NHBoc
N
H
R
11 (R = CO2Et)
8
16 (R = CO2Et)
19
15 (R = CH2OTBS)
17 (R = CH2OTBS)
18 (R = CH2OH)
Entry
1
Substrate
Base
Solvent
Product
Yield (%)
11
t-BuOK
DMF
5b
16
19
24b
2
3
4
5
6
15
15
15
15
15
t-BuOK
DMF
18
46
K2CO3
DMF
NDd
ND
ND
ND
ND
ND
c
DIPEAc
t-BuOK
t-BuOK
DMF
CH2Cl2
MeCN
17
18
74
13b
7
15
t-BuOK
THF
ND
ND
a Reaction conditions: 8 (1.2–1.5 equiv), base (1.1–1.5 equiv), solvent, r.t., 1–1.5 h.
b Isolated yield.
c 2.0 equiv.
d ND = not detected.
With the desired sulfamidates in hand, we next investi-
gated the nucleophilic substitution reaction of pyrrole 8
with the 1,2-cyclic sulfamidates 11 and 15 (Table 1). The re-
action of sulfamidate 11 with pyrrole 8 in the presence of
potassium tert-butoxide in N,N-dimethylformamide pro-
duced the desired compound 16 in 5% yield, and the unde-
sired side-product 19 was mainly formed (entry 1). Forma-
tion of 19 can be rationalized in terms of an elimination re-
action resulting from the relatively high acidity of the
α-proton adjacent to the carbonyl group. To suppress this
elimination reaction, we performed the reaction by using
substrate 15, which has a protected hydroxy group instead
of an ester group. As predicted, the reaction of pyrrole 8
with sulfamidate 15 produced the desired product 18 in
moderate yield; the tert-butyl(dimethyl)silyl group was re-
moved in the workup operation. This result encouraged us
to optimize the base and solvent to improve the yield. The
reaction failed to proceed when a weaker base such as po-
tassium carbonate or N,N-diisopropylethylamine was used
instead of potassium tert-butoxide (Table 1, entries 3 and
4). Among the solvents tested (entries 5–7), acetonitrile
was the most effective (74% yield, entry 6).
O
O
O
(1) 4 M HCl in 1,4-dioxane
MeOH, r.t.
CO2Me
S
O
Boc
N
8, t-BuOK
N
N
NH
NHBoc
OTBS
MeCN
(2) Et3N, MeOH, 50 °C
75% (3 steps)
0 °C to r.t.
HO
TBSO
15
17
20
TEMPO
PhI(OAc)2
Br
O
NBS
DMF
ref. 10
longamide B
methyl ester (2)
hanishin (3)
NaHCO3
N
NH
longamide B (1)
Br
CH2Cl2
r.t.
–20 °C to r.t.
HO
55%
87%
21
Scheme 4 Synthesis of the target bromopyrrole alkaloids 1–3
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Letter
Synlett
Having optimized the conditions for the nucleophilic
substitution reaction, we next investigated the intramolec-
ular lactamization (Scheme 4). Removal of the tert-butoxy-
carbonyl and tert-butyl(dimethyl)silyl groups from 17 by
using a 4 M solution of hydrogen chloride in 1,4-dioxane,
followed by intramolecular cyclization of the resulting ami-
no ester with triethylamine, gave the pyrrolopiperazinone
derivative 20 (75% yield, three steps).11 Bromination of
compound 20 produced compound 21. Finally, the hydroxy
group of compound 21 was oxidized to a carboxylic acid
with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and
(diacetoxyiodo)benzene to give longamide B.4c Longamide B
was converted into longamide B methyl ester and hanishin
by the reported procedures.10 Physical data were in agree-
ment with the reported values for the natural products.
In conclusion, we have achieved a short synthesis of lon-
gamide B, longamide B methyl ester, and hanishin that
highlights the utility of 1,2-cyclic sulfamidates in forming
complex piperazinones. This approach should be applicable
to divergent syntheses of pyrrolopiperazinone derivatives
with various substituents on the ring system.
(7) (a) Bower, J. F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005,
793. (b) Bower, J. F.; Riis-Johannessen, T.; Szeto, P.; Whitehead,
A. J.; Gallagher, T. Chem. Commun. 2007, 728.
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J.; Bentley, J. M.; Blench, T. J.; Cliffe, I. A.; Dourish, C.; Hebeisen,
P.; Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mattei, P.; Misra,
A.; Mizrahi, J.; Monck, N. J. T.; Plancher, J. M.; Roever, S.; Roffey,
J. R. A.; Taylor, S.; Vickers, S. P. Bioorg. Med. Chem. Lett. 2006, 16,
1207. (b) Boyer, S. J.; Burke, J.; Guo, X.; Kirrane, T. M.; Snow, R.
J.; Zhang, Y.; Sarko, C.; Soleymanzadeh, L.; Swinamer, A.;
Westbrook, J.; DiCapua, F.; Padyana, A.; Kugler, S.; O’Neill, M. M.
Bioorg. Med. Chem. Lett. 2012, 22, 733. (c) Shiokawa, Z.;
Hashimoto, K.; Saito, B.; Oguro, Y.; Sumi, H.; Yabuki, M.;
Yoshimatsu, M.; Kosugi, Y.; Debori, Y.; Morishita, N.; Dougan, D.
R.; Snell, G. P.; Yoshida, S.; Ishikawa, T. Bioorg. Med. Chem. 2013,
21, 7938.
(9) Nishiguchi, S.; Sydnes, M. O.; Taguchi, A.; Regnier, T.; Kajimoto,
T.; Node, M.; Yamazaki, Y.; Yakushiji, F.; Kiso, Y.; Hayashi, Y. Tet-
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(10) Banwell, M. G.; Bray, A. M.; Willis, A. C.; Wong, D. J. New J. Chem.
1999, 23, 687.
(11) (4S)-4-(2-Hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-
1(2H)-one (20)
t-BuOK (33 mg, 0.29 mmol) was added to a mixture of sulfami-
date 15 (101 mg, 0.27 mmol) and methyl pyrrole-2-carboxylate
(8) (33 mg, 0.32 mmol) in MeCN (5.0 mL) at 0 °C, and the
mixture was stirred at r.t. for 1.5 h. The reaction was quenched
with 10% aq citric acid, and the mixture was extracted with
EtOAc. The extracts were washed with sat. aq NaHCO3 and
brine, then dried (MgSO4) and concentrated under reduced
pressure. To a mixture of the residue in MeOH (2.0 mL) was
added 4 M HCl in 1,4-dioxane (2.0 mL) at r.t., and the mixture
was stirred at r.t. for 1 h. The mixture was evaporated under
reduced pressure and the residue was washed with Et2O and
dried under reduced pressure. A mixture of the residue and Et3N
(0.22 mL, 1.6 mmol) in MeOH (7.0 mL) was stirred at r.t. for 1.5
h and then overnight at 50 °C. The mixture was the concen-
trated under reduced pressure and the residue was purified by
column chromatography (silica gel, 10% MeOH–EtOAc) to give
20 as an off-white solid. Yield: 36 mg (75%); mp 130–134 °C;
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific Re-
search (No. 26282211) from the Japan Society for the Promotion of
Science and by the Keio Gijuku Academic Development Funds, the Ya-
mada Science Foundation, and the Sumitomo Foundation.
References and Notes
(1) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O. J. Nat. Prod.
1998, 61, 122.
(2) Umeyama, A.; Ito, S.; Yuasa, E.; Arihara, S.; Yamada, T. J. Nat.
Prod. 1998, 61, 1433.
(3) Mancini, I.; Guella, G.; Amade, P.; Roussakis, C.; Pietra, F. Tetra-
hedron Lett. 1997, 38, 6271.
(4) (a) Patel, J.; Pelloux-Léon, N.; Minassian, F.; Vallée, Y. J. Org.
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Chem. Soc. 2010, 132, 15800. (c) Trost, B. M.; Dong, G. Org. Lett.
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N.; Hu, Y. Org. Lett. 2012, 14, 1062. (e) Adhikary, N. D.; Kwon, S.;
Chung, W.-J.; Koo, S. J. Org. Chem. 2015, 80, 7693.
27
[α]D –76.8 (c 0.59, MeOH). 1H NMR (400 MHz, CD3OD): δ =
6.93 (dd, J = 2.8, 1.6 Hz, 1 H), 6.75 (dd, J = 4.0, 1.2 Hz, 1 H), 6.11
(dd, J = 3.6, 2.4 Hz, 1 H), 4.34–4.38 (m, 1 H), 3.72 (dd, J = 13.2, 4.4
Hz, 1 H), 3.51–3.57 (m, 1 H), 3.35–3.42 (m, 2 H), 1.81–1.94 (m, 2
H). 13C NMR (100 MHz, CD3OD): δ = 163.38, 125.33, 123.94,
114.84, 110.27, 59.06, 52.47, 45.43, 36.43. HRMS-ESI: m/z [M +
Na] calcd for C9H12N2NaO2: 203.0791; found: 203.0794.
(4S)-6,7-Dibromo-4-(2-hydroxyethyl)-3,4-dihydropyr-
rolo[1,2-a]pyrazin-1(2H)-one (21)
(5) Bower, J. F.; Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem.
2010, 8, 1505.
NBS (87 mg, 0.49 mmol) was added to a solution of 20 (44 mg,
0.24 mmol) in DMF (4.0 mL) at –20 °C, and the mixture was
stirred at the 20 °C for 15 min then at r.t. overnight. The reac-
tion was then quenched with sat. aq NaHCO3 and extracted
with EtOAc. The extracts were washed with H2O and brine then
dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, 5%
MeOH–EtOAc) to give a colorless solid. Yield: 72 mg (87%); mp
(6) (a) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.;
Gallagher, T. Org. Lett. 2003, 5, 811. (b) Bower, J. F.; Švenda, J.;
Williams, A. J.; Charmant, J. P.; Lawrence, R. M.; Szeto, P.;
Gallagher, T. Org. Lett. 2004, 6, 4727. (c) So, S. M.; Yeom, C.-E.;
Cho, S. M.; Choi, S. Y.; Chung, Y. K.; Kim, B. M. Synlett 2008, 702.
(d) Hirschhäuser, C.; Parker, J. S.; Perry, M. W.; Haddow, M. F.;
Gallagher, T. Org. Lett. 2012, 14, 4846. (e) Bandini, M.;
Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem. Int.
Ed. 2008, 47, 3238.
27
139–142 °C; [α]D –25.6 (c 0.23, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 6.91 (s, 1 H), 4.57–4.60 (m, 1 H), 3.80 (ddd, J = 13.8,
4.4, 0.8 Hz, 1 H), 3.63–3.69 (m, 3 H), 1.94–2.02 (m, 1 H), 1.80–
1.87 (m, 1 H). 13C NMR (100 MHz, CD3OD): δ = 159.72, 124.63,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 616–620