Asymmetric aziridination of cyclic enones using chiral diamine catalysts and its application to the total synthesis of (-)-agelastatin A

Article abstract of DOI:10.1021/ol2023054

The asymmetric aziridination of cyclic enones with N-tosyloxycarbamates, using N-neopentyl 1,2-diphenylethylenediamine as a catalyst, and its application to the formal total synthesis of (-)-agelastatin A, using a one-pot silylation-selenylation procedure

Full text of DOI:10.1021/ol2023054

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5744–5747
Asymmetric Aziridination of Cyclic
Enones Using Chiral Diamine Catalysts
and Its Application to the Total Synthesis
of (À)-Agelastatin A
Yasuhiro Menjo, Akinari Hamajima, Neri Sasaki, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received August 25, 2011
ABSTRACT
The asymmetric aziridination of cyclic enones with N-tosyloxycarbamates, using N-neopentyl 1,2-diphenylethylenediamine as a catalyst, and its
application to the formal total synthesis of (À)-agelastatin A, using a one-pot silylation-selenylation procedure and the regioselective aziridine-
opening by an azide anion as key steps, are described.
The chiral amine-catalyzed asymmetric reaction is one
of the most studied areas of modern organic synthesis.1
Many enantioselective reactions by various chiral amines
have been developed to date. We have demonstrated that
N-tosyloxycarbamates as a nitrogen source can be efficiently
used for the asymmetric aziridination of enones using R,R-
diphenylprolinol trimethylsilyl ether.2À4 Chiral aziridines
are useful synthetic intermediates with one or two stereo-
genic centers. They are effectively used for the synthesis of
amino acids, natural products, and pharmaceuticals.5,6 As
part of such research, we examined the asymmetric aziri-
dination of cyclic enones using new catalysts and found an
efficient method.
stated that the level of enantioselection depends on the
structure of the N-tosyloxy alkylcarbamates and is mode-
rate for 2-cyclopenten-1-one. We now describe an efficient
asymmetric aziridination of cyclic enones using the N-
neopentyl 1,2-diphenylethylenediamine catalyst 4 and its
application in a formal total synthesis of (À)-agelastatin A.
(3) For the aziridinations using N-arenesulfonyloxycarbamates, see:
(a) Lwowski, W.; Mairich, T. J. J. Am. Chem. Soc. 1965, 87, 3630–3637.
(b) Banks, M. R.; Blake, A. J.; Cadogan, J. I. G.; Dawson, I. M.;
Gosney, I.; Grant, K. J.; Gaur, S.; Hodgson, P. K. G.; Knight, K. S.;
Smith, G. W. Tetrahedron 1992, 48, 7979–8006. (c) Fioravanti, S.;
Morreale, A.; Pellacani, L.; Tardella, P. A. Synthesis 2001, 13, 1975–
1978. (d) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Eur.
J. Org. Chem. 2003, 23, 4549–4552. (e) Fioravanti, S.; Morreale, A.;
Pellacani, L.; Tardella, P. A. Synlett 2004, 1083–1085. (f) Fioravanti, S.;
Colantoni, D.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 2005, 70,
3296–3298. (g) Mohr, F.; Binfield, S. A.; Fettinger, J. C.; Vedernikov,
A. N. J. Org. Chem. 2005, 70, 4833–4839. (h) Lebel, H.; Huard, K.;
Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198–14199. (i) Lebel, H.;
Lectard, S.; Parmentier, M. Org. Lett. 2007, 9, 4797–4800. (j) Pesciaioli,
F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.;
Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703–
8706. (k) De Vincentiis, F.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.;
Bartoli, G.; Galzerano, P.; Melchiorre, P. Chem. Asian J. 2010, 5, 1652–
1656. (l) Deiana, L.; Zhao, G.; Lin, S.; Dziedzic, P.; Zhang, Q.;
The asymmetric aziridination of cyclic enones with N-
tosyloxy tert-butylcarbamate (pTsONHBoc) using the
cinchona alkaloid derivatives as organocatalysts has al-
ready beenreportedbyMelchiorreandco-workers.3k They
(1) For reviews of organocatalysts, see: (a) Pellissier, H. Tetrahedron
2007, 63, 9267–9331. (b) Kotsuki, H.; Ikishima, H.; Okuyama, A.
Heterocycles 2008, 75, 493–529. Heterocycles 2008, 75, 757–797.
(c) Xu, L.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807–1821. (d) Enders,
D.; Wang, C.; Liebich, J. X. Chem.;Eur. J. 2009, 15, 11058–11076.
(2) Arai, H.; Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.;
Hamada, Y. Tetrahedron Lett. 2009, 50, 3329–3332.
ꢀ
Leijonmarck, H.; Cordova, A. Adv. Synth. Catal. 2010, 352, 3201–
3207. (m) Deiana, L.; Dziedzic, P.; Zhao, G.; Vesely, J.; Ibrahem, I.;
ꢀ
Rios, R.; Sun, J.; Cordova, A. Chem.;Eur. J. 2011, 17, 7904–7917.
r
10.1021/ol2023054
Published on Web 10/03/2011
2011 American Chemical Society

The presence of benzoic acid and sodium hydrogen carbo-
nate were essential for a smooth reaction, preventing
decomposition of the N-tosyloxy alkylcarbamates. To our
delight, the primary-secondary diamine 4,7 which can be
easily prepared from the commercially available chiral 1,2-
diphenyethylenediamine (DPEN) 5, exhibited an excellent
enantioselectivity. The chiral aziridine 1a was obtained in
75% yield with 95% ee, if the reaction was performed in
chloroform in the presence of benzoic acid.8 We have
examined the scope of this new asymmetric aziridination.
pTsONHCbz and pTsONHBoc as a nitrogen source were
equally effective for this aziridination and produced the
corresponding keto aziridines in good yields and with high
enantioselectivities. Interestingly, in contrast to Mel-
chiorre’s case,3k the use of pTsONHCbz resulted in a
somewhat higher enantioselectivity than pTsONHBoc.
The introduction of the N-neopentyl group to DPEN
was essential for high enantioselection. The reaction of
2-cyclohexen-1-one and 2-cyclohepten-1-one also effi-
ciently proceeded to afford the corresponding aziridines
with high enantioselectivity. The absolute configurations
of the product were assigned by comparison of the known
1b and ent-1b with the reported retention time in HPLC
analysis.3k
Next, we turned our attention to application of this
efficient asymmetric aziridination tothe total synthesis of a
natural product. (À)-Agelastatin A9 isolated by Pietra and
co-workers in 1993 from the Coral Sea sponge Agelas
dendromorpha has received much attention because of its
potent cytotoxicity against a wide range of cancer cell
lines.10 It is also known as an inhibitor of osteopontin-
mediated adhesion, invasion, colony formation,11 and
glycogen synthase kinase-3β,10a a potential target for
Alzheimer’s disease, diabetes, and bipolar disorder. These
remarkable biological activities coupled with its highly
complex structure have made (À)-agelastatin A an attrac-
tive target for total synthesis. The structure comes from the
5,6,5,5-tetracyclic system that contains 4 contiguous chiral
centers on the C-ring, and each of them is substituted with
a nitrogen atom. To date, 11researchgroupshave reported
racemic,12,13a,1 and asymmetric12,13bÀ13k,13mÀ13p total
syntheses of agelastatin A.
Table 1. Chiral Diamine-Catalyzed Aziridination of Cyclic En-
ones
entrya cat.
n
product (R = Cbz)
product (R = Boc)
1b,c
2b
3
4
5
4
4
1
1ad
75% yielde
95% eef
1b
89% yield
88% ee
1
2
3
ent-1a
2a
59% yield
59% ee
ent-1b
2b
81% yield
71% ee
84% yield
97% ee
80% yield
97% ee
4
3a
83% yield
94% ee
3b
91% yield
92% ee
a Reaction was carried out with pTsONHR (0.20 mmol), a cyclic
enone (0.24 mmol), benzoic acid (0.20 mmol), sodium hydrogen carbo-
nate (1.0 mmol), diamine 4 or 5 (0.04 mmol) in chloroform (2 mL) at
room temperature for 24 h. b Three equivalents of 2-cyclopenten-1-one
were used. c Reaction time was 40 h. d Scale = 10 mmol. e Isolated yield.
f Enantiomeric excess was determined by HPLC analysis.
First, some simple chiral 1,2-diamines for the aziridina-
tion of 2-cyclopenten-1-one, using N-tosyloxy benzylcar-
bamate (pTsONHCbz), were evaluated. Table 1 depicts
selected examples of the diamine-catalyzed aziridination.
The reaction was carried out with pTsONHR (1 equiv), a
cyclic enone (1.2 equiv), benzoic acid (1 equiv), sodium
hydrogen carbonate (5 equiv), and the diamine catalyst
(20 mol %) in solvent at room temperature for 24 h.
Among them, are stereoselective syntheses based on
transition metal-catalyzed asymmetric reactions, transfor-
mations from naturally occurring chiral substances, or the
enzymatic resolution of a racemic substrate. On the other
(4) For a review of R,R-diarylprolinol ethers, see: (a) Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922–948. (b) Lattanzi, A. Chem.
Commun 2009, 1452–1463. (c) Palomo, C.; Mielgo, A. Angew. Chem.,
Int. Ed. 2006, 45, 7876–7880.
(5) For reviews of aziridines, see: (a) Sweeney, J. B. Chem. Soc. Rev.
2002, 32, 247–258. (b) Halfen, J. A. Curr. Org. Chem. 2005, 9, 657–669.
(c) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2920. (d) Osborn,
H. M. I.; Sweeney, J. B. Tetrahedron: Asymmetry 1997, 8, 1693–1715.
(e) Pellissier, H. Tetrahedron 2010, 66, 1509–1555.
(7) Wang, M.; Lin, L.; Shi, J.; Liu, X.; Kuang, Y.; Feng, X. Chem.À
Eur. J. 2011, 17, 2365–2368.
(8) In our preliminary experiments, the addition of sodium benzoate
instead of benzoic acid and sodium hydrogen carbonate produced in
somewhat the decreased yield and with enantiomeric excess (50%, 88%
ee). Therefore, we employed a mixture of benzoic acid and sodium
hydrogen carbonate.
(9) (a) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.;
Pusset, J.; Leroy, S.; Pietra, F. J. Chem. Soc. Chem. Commun 1993,
1305–1306. (b) D’Ambrosio, M.; Guerriero, A.; Chiasera, G.; Pietra, F.
Helv. Chim. Acta 1994, 77, 1895–1902.
(10) (a) Meijer, L.; Thunnissen, A. M.; White, A. W.; Garnier, M.;
Nikolic, M.; Tsai, L. H.; Walter, J.; Cleverley, K. E.; Salinas, P. C.; Wu,
Y. Z.; Biernat, J.; Mandelkov, E. M.; Kim, S. H.; Pettit, G. R. Chem.
Biol. 2000, 7, 51–63. (b) Pettit, G. R.; Ducki, S.; Herald, D. L.; Doubek,
D. L.; Schmidt, J. M.; Chapuis, J. C. Oncol. Res. 2005, 15, 11–20.
(6) For recent examples of the enantioselective aziridination, see:
(a) Hashimoto, T.; Nakatsu, H.; Yamamoto, K.; Watanabe, S.; Mar-
uoka, K. Chem. Asian J. 2011, 6, 607–613. (b) Larson, S. E.; Li, G.;
Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C.
ꢀ
Org. Lett. 2011, 13, 2188–2191. (c) Arroyo, Y.; Meana, A.; Sant-Tejedor,
M. A.; Alonso, I.; Garcıa Ruano, J. L. Chem.;Eur. J. 2010, 16, 9874–
´
ꢀ
ꢀ
9883. (d) Bonifacio, V. D. B.; Gonzalez-Bello, C.; Rzepa, H. S.;
Prabhakar, S.; Lobo, A. M. Synlett 2010, 1, 145–149. (e) Huang, L.;
Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892–8895. (f) Hashimoto, T.;
Nakatsu, H.; Yamamoto, T.; Maruoka, K. J. Am. Chem. Soc. 2011, 133,
9730–9733. (g) Murakami, Y.; Takeda, Y.; Minakata, S. J. Org. Chem.
2011, 76, 6277–6285.
Org. Lett., Vol. 13, No. 21, 2011
5745

hand, organocatalytic reactions have never been applied
for the total synthesis of (À)-agelastatin A.
TMSCl) failed due to its extreme sensitivity to hydrolysis,
and the R-phenylselenylation of 1a by the standard proce-
dure (LDA in THF at À78 °C, then PhSeCl) produced an
inseparable mixture of 9 and 10. After several experiments,
we found that Tanabe’s procedure14 for the preparation
of silyl enol ethers was efficient for our case. Thus, 1a
was treated with N,O-bis(trimethylsilyl)acetamide
(BSA) in the presence of DBU (0.2 equiv). The clean
conversion of 1a to the corresponding trimethylsilyl enol
Scheme 1. Retrosynthetic Analysis of 6
1
ether 8 was confirmed by the H NMR analysis of the
reaction mixture. The reaction mixture was directly
treated with phenylselenyl chloride at À78 °C to give 9
in a satisfactory yield.15
Figure 1. Enone 7 and enone’s precursors 8À10.
In designing a synthetic plan to (À)-agelastatin A, we
focused on Ichikawa’s intermediate 6 for the construction
of a B ring of agelastatin A.13h We envisioned that
regioselective aziridine-opening of 1a by a nitrogen nu-
cleophile and dehydrogenation to the enone should pro-
duce Ichikawa’s key intermediate 6 (Scheme 1).
With the chiral keto aziridine 1a in hand, we attempted
the synthesis of enone 7 by the phenylselenylation or
Ito-Saegusa oxidation of 2a (Figure 1). However, formation
of the trimethylsilyl enol ether 8 from 1a by the standard
procedure (LDA or LiHMDS in THF at À78 °C, then
Several attempts at effecting the direct ring-opening of
the keto aziridine 1a or 9 with an azide anion were
unsuccessful and resulted in decomposition of the start-
ing materials. Finally, we found that the ring-opening
reaction, after reduction of the ketone function of 9,
regioselectively proceeded to produce the corresponding
product. Thus, 9 was reduced with sodium borohydride
at À78 °C to give 11, which was treated with sodium
azide to produce the azide 12 in a good yield as a single
isomer.16 The nickel boride-catalyzed reduction of the
azide, and the acylation of the resulting amine 13
with 4,5-dibromo-1H-pyrrole-2-carboxylic acid 14 gave
15. Finally, oxidative elimination of the phenylsel-
enyl group furnished the chiral intermediate 6 of (À)-
agelastatin A in a nearly quantitative yield (Scheme 2).
Its spectroscopic data were identical with the reported
values for 6. The absolute configuration of the keto
aziridine 1a was unambiguously confirmed by comparison
(11) Mason, C. K.; McFarlane, S.; Johnston, P. G.; Crowe, P.;
Erwin, P. J.; Domostoj, M. M.; Campbell, F. C.; Manaviazar, S.; Hale,
K. J.; El-Tanani, M. Mol. Cancer Ther. 2008, 7, 548–558.
(12) For reviews of agelastatins, see: (a) Weinreb, S. M. Nat. Prod.
Rep. 2007, 24, 931–948. (b) Dong, G. Pure Appl. Chem. 2010, 82, 2231–
2246.
(13) (a) Stien, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.; Weinreb,
S. M. J. Am. Chem. Soc. 1999, 121, 9574–9579. (b) Feldman, K. S.;
Saunders, J. C. J. Am. Chem. Soc. 2002, 124, 9060–9061. (c) Feldman,
K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096–
7109. (d) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving, E.;
Scheinmann, F. Org. Lett. 2003, 5, 2927–2930. (e) Domostoj, M. M.;
Irving, E.; Scheinmann, F.; Hale, K. J. Org. Lett. 2004, 6, 2615–2618.
(f) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621–623. (g) Trost, B. M.;
Dong, G. J. Am. Chem. Soc. 2006, 128, 6054–6055. (h) Ichikawa, Y.;
Yamaoka, T.; Nakano, K.; Kotsuki, H. Org. Lett. 2007, 9, 2989–2992.
(i) Yoshimitsu, T.; Ino, T.; Tanaka, T. Org. Lett. 2008, 10, 5457–5460.
(j) Davis., F. A.; Zhang, J.; Zhang, Y.; Qiu, H. Synth. Commun. 2009, 39,
1914–1919. (k) Yoshimitsu, T.; Ino, T.; Futamura, N.; Kamon, T.;
Tanaka., T. Org. Lett. 2009, 11, 3402–3405. (l) Dickson, D. P.; Wardrop,
D. J. Org. Lett. 2009, 11, 1341–1344. (m) Wehn, P. M.; Du Bois, J.
Angew. Chem., Int Ed. 2009, 48, 3802–3805. (n) Hama, N.; Matsuda, T.;
Sato, T.; Chida, N. Org. Lett. 2009, 11, 2687–2690. (o) Trost, B. M.;
Dong, G. Chem.;Eur. J. 2009, 15, 6910–6919. (p) Movassaghi, M.;
Siegel, D. S.; Han., S. Chem. Sci. 2010, 561–566.
23
of the optical rotation of 6 ([R]D = À200.9, c 1.62,
15
chloroform) with the reported data ([R]D = À223.4, c
0.56, chloroform).13h
In summary, we have discovered an asymmetric aziridi-
nation of cyclic enones catalyzed by a primary-secondary
chiral diamine 4, which can be readily prepared from the
commerciallyavailableDPEN. The chiralketo aziridine1a
(14) Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A.; Nishii, Y. Chem.
Commun 2002, 1628–1629.
(15) This phenylselenylation occurred from the less hindered face to
afford trans-phenylselenide 9 as a single diastereomer.
5746
Org. Lett., Vol. 13, No. 21, 2011

Scheme 2. Formal Total Synthesis of (À)-Agelastatin A
was efficiently transformed into the known intermediate 6
of (À)-agelastatin A, in seven steps, and 30% overall yield,
which represents a new formal total synthesis of (À)-
agelastatin A.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Scientific Research (B) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.).
(16) In the aziridine ring-opening reaction, the high regioselectivity
can be explained by the steric interaction of the adjacent hydroxy group.
Then, the azide anion attacks regioselectively at the remote position
from the hydroxyl group to give 12.
Supporting Information Available. Supplemental infor-
mation and spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 21, 2011
5747