Diastereoselective intramolecular carbamoylketene/alkene [2 + 2] cycloaddition: Enantioselective access to pyrrolidinoindoline alkaloids

Article abstract of DOI:10.1021/ol303204v

A novel and highly diastereoselective intramolecular carbamoylketene/alkene [2 + 2] cycloaddition has been developed, and the methodology was successfully applied to the enantioselective syntheses of (-)-esermethole and Takayama's intermediate for (+)-psychotrimine.

Full text of DOI:10.1021/ol303204v

ORGANIC
LETTERS
2013
Vol. 15, No. 1
200–203
Diastereoselective Intramolecular
Carbamoylketene/Alkene [2 þ 2]
Cycloaddition: Enantioselective Access
to Pyrrolidinoindoline Alkaloids
Takaaki Araki, Tsukasa Ozawa, Hiromasa Yokoe, Makoto Kanematsu,
Masahiro Yoshida, and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima 770-8505, Japan
shishido@ph.tokushima-u.ac.jp
Received November 28, 2012
ABSTRACT
A novel and highly diastereoselective intramolecular carbamoylketene/alkene [2 þ 2] cycloaddition has been developed, and the methodology
was successfully applied to the enantioselective syntheses of (ꢀ)-esermethole and Takayama’s intermediate for (þ)-psychotrimine.
In previous papers, we have described the syntheses of
alkaloids with tetrahydrofuro[2,3-b]indole and hexahy-
dropyrrolo[2,3-b]indole skeletons employing an intramo-
lecular carbamoylketene/alkene [2 þ 2] cycloaddition re-
action as the key step.1 The chemical yield obtained in the
cycloaddition is uniformly high, and the subsequent trans-
formations proceed smoothly and selectively to give the
alkaloids or the key intermediates.
which contains the but-3-ene-1,2-diol moiety with a ter-
tiary stereogenic center at the allylic position (C2). The
chiral auxiliary would serve to induce chirality at the newly
generated benzylic quaternary stereogenic center, and we
anticipated that the substituent (R at C1 in 1) would play
an important role in obtaining higher diastereoselectivity
in 2. In addition, the 1,2-diol functionality would facilitate
the transformation to a variety of functional groups, e.g.,
via an oxidative cleavage of the diol moiety (Scheme 1).
We thought it important to make the reaction asymmetric.
Accordingly we designed a substrate-controlled diastereose-
lective process.2 We chose the optically active substrate 1,
Scheme 1. Substrate for Diastereoselective Cycloaddition
(1) (a) Shishido, K.; Azuma, T.; Shibuya, M. Tetrahedron Lett. 1990,
31, 219–220. (b) Ozawa, T.; Kanematsu, M.; Yokoe, H.; Yoshida, M.;
Shishido, K. J. Org. Chem. 2012, 77, 9240–9249. (c) Ozawa, T.;
Kanematsu, M.; Yokoe, H.; Yoshida, M.; Shishido, K. Heterocycles
2012, 85, 2927–2932.
(2) For related reports on the diastereoselective intramolecular [2 þ 2]
cycloadditions of the substrates with a tertiary stereogenic center on
the alkenyl part, see: (a) Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh,
A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 645–651. (b)
Cholerton, T. J.; Collington, E. W.; Finch, H.; Williams, D. Tetrahedron
Lett. 1988, 29, 3369–3372. (c) Corey, E. J.; Rao, K. S. Tetrahedron Lett.
1991, 32, 4623–4626. (d) Monache, G. D.; Misiti, D.; Salvatore, P.;
Zappia, G.; Pierini, M. Tetrahedron: Asymmetry 2000, 11, 2653–2659.
In this report, we describe a highly diastereoselective intra-
molecular carbamoylketene-alkene [2 þ 2] cycloaddition of
r
10.1021/ol303204v
Published on Web 12/19/2012
2012 American Chemical Society

the substrate with a chiral auxiliary on the alkenyl unit and
application of the methodology to the enantioselective
syntheses of (ꢀ)-esermethole1c,3 and the key intermediate
for the trimeric indole alkaloid (þ)-psychotrimine.4 Our
retrosynthetic analysis of the ketene precursors 3aꢀd
chosen to evaluate the diastereoselection during the cy-
cloaddition is outlined in Figure 1. The aniline derivatives
4aꢀd, which can be converted to 3aꢀdin the usual manner,1
would be prepared by the SuzukiꢀMiyaura coupling5 of the
aminophenylboronates 5a,b6 and the corresponding opti-
cally active vinyl bromides 6aꢀd, among which 6a,c are
known in the literature.7
of 78 provided the enantiomerically pure diol 8,9 which was
treated with cyclopentanone under acidic conditions, fol-
lowed by desilylation to give the alcohol 9. On exposure to
NishizawaꢀGrieco conditions, it afforded 10 which was
converted to the vinyl bromide (R)-6d by bromination and
then dehydrobromination.10 The (R)-6b was derived from
6d by sequential deacetalization and acetonide formation
(Scheme 2).
Scheme 2. Preparation of Optically Pure Dioxolanes (6b,d)
Preparation of the carboxylic acids 3aꢀd is shown in
Scheme 3. Thus, treatment of 5a with 6a,b in the presence
of (Ph3P)4Pd and K2CO3 in aqueous THF provided 4a,b.
These were sequentially subjected to carbomethoxylation,
alkylation, and alkaline hydrolysis1 to produce (S)-3a,b.
The dimethylated analogs (S)-3c,d were prepared effi-
ciently via a similar sequence of reactions as that for the
preparation of 3a,b (Scheme 3).
Figure 1. Retrosynthesis of the ketene precursors (3aꢀd).
The optically active dimethylated dioxolanes 6b,d were
prepared as shown in Scheme 2. Asymmetric dihydroxylation
Scheme 3. Syntheses of Carboxylic Acids 3aꢀd
(3) For asymmetric syntheses, see: (a) Takano, S.; Goto, E.; Hirama,
M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641–2643. (b)
Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett.
1990, 109–112. (c) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K.
Heterocycles 1990, 31, 411–414. (d) Takano, S.; Moriya, M.; Ogasawara,
K. J. Org. Chem. 1991, 56, 5982–5984. (e) Lee, T. B. K.; Wong, G. S. K.
J. Org. Chem. 1991, 56, 872–875. (f) Node, M.; Itoh, A.; Masaki, Y.;
Fuji, K. Heterocycles 1991, 32, 1705–1707. (g) Yu, Q.; Luo, W.; Li, Y.;
Brossi, A. Heterocycles 1993, 36, 1279–1285. (h) Ashimoto, A.;
Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58, 6949–
6951. (i) Pallavicini, M.; Valoti, E.; Villa, L.; Lianza, F. Tetrahedron:
Asymmetry 1994, 5, 111–116. (j) Pallavicini, M.; Valoti, E.; Villa, L.;
Resta, I. Tetrahedron: Asymmetry 1994, 5, 363–370. (k) Fuji, K.;
Kawabata, T.; Ohmori, T.; Shang, M.; Node, M. Heterocycles 1998,
47, 951–964. (l) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6500–6503. (m) Ashimoto, A.; Bachand, B.; Calter,
M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc.
1998, 120, 6488–6499. (n) Kawabata, M.; Nishida, A.; Nakagawa, M.
Org. Lett. 2000, 2, 675–678. (o) Tanaka, K.; Taniguchi, T.; Ogasawara,
K. Tetrahedron Lett. 2001, 42, 1049–1052. (p) Huang, A.; Kodanko,
J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043–14053. (q)
Nishida, A.; Ushigome, S.; Sugimoto, A.; Arai, S. Heterocycles 2005, 66,
181–185. (r) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590–
4591. (s) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314–
6315. (t) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.;
Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874–12875. (u) Bui, T.; Syed,
S.; Barbas, C. S., III. J. Am. Chem. Soc. 2009, 131, 8758–8759. (v) Trost,
B. M.; Zhang, Y. Chem.;Eur. J. 2011, 17, 2916–2922. (w) Schammel,
A. W.; Chiou, G.; Garg, N. K. J. Org. Chem. 2012, 77, 725–728.
(4) For the isolation, see: (a) Takayama, H.; Mori, I.; Kitajima, M.;
Aimi, N.; Lajis, N. H. Org. Lett. 2004, 6, 2945–2948. For the racemic
syntheses, see: (b) Matsuda, Y.; Kitajima, M.; Takayama, H. Org. Lett.
2008, 10, 125–128. (c) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 10886–10887. For the enantioselective syntheses, see: (d)
Takahashi, N.; Ito, T.; Matsuda, Y.; Kogure, N.; Kitajima, M.;
Takayama, H. Chem. Commun. 2010, 46, 2501–2503. (e) Newhouse,
T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010,
132, 7119–7137.
(5) For a review, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483.
Org. Lett., Vol. 15, No. 1, 2013
201

With the ketene precursors 3aꢀd in hand, we advanced
to the key [2 þ 2] cycloaddition. Treatment of 3a with
oxalyl chloride in benzene followed by triethylamine pro-
vided the cycloadduct 2a as an inseparable mixture of
diastereoisomers in a ratio of 9:1 in 45% yield (entry 1).
However, we anticipated, and indeed found, that the
cycloaddition of the alkenyl ketene generated from 3b
resulted in 2b as a single product in 71% yield (entry 2).
In the case of 3c,d, which possess a cyclic acetal moiety,
similar diastereoselections were observed and the cycload-
ducts 2c,d were obtained in higher yields of 81% and 89%,
respectively (entries 3 and 4). Thus, we were able to
establish a novel diastereoselective process for obtaining
the optically pure tricyclic compound (Table 1).
Figure 2. Presumed mechanism for diastereoselection.
Table 1. [2 þ 2] Cycloaddition
examined the conversion of 2d to (ꢀ)-esermethole (16).
Treatment of 2d with N-methylhydroxylamine hydrochloride,
NaHCO3, and 3 A molecular sieves in ethanol at 50 °C
provided the nitrone,11 which, without purification, was
immediately reacted with p-TsCl and 4-pyrrolidinopyri-
dine (PPY) in refluxing chloroform to give 12. After acidic
hydrolysis, the resulting diol 13 was exposed to oxidative
cleavage conditions to produce the aldehyde 14, which was
reduced with NaBH4 to give the alcohol 15. Tosylation
followed by reduction with LiAlH4 provided (ꢀ)-esermet-
hole (16), whose spectral properties and optical rotation
were identical with those reported in the literature.3b Thus,
the absolute configuration of the cycloadduct obtained
diastereoselectively was firmly established to be (R,R,S) as
we had expected (Scheme 4).
carboxylic
entry
acid
product R1
R2
H
R3
Me
yield (%) dra
1
2
3
4
3a
3b
3c
3d
2a
2b
2c
2d
H
45
71
81
89
9:1
1:0
5:1
1:0
H
Me Me
-(CH2)4ꢀ
OMe
H
OMe Me -(CH2)4ꢀ
a Determined by 1H NMR
The mechanism for the exclusive formation of the cyclo-
adducts 2b,d could be explained by considering the transi-
tion states T1 and T2, in which the alkenyl moiety with a
chiral auxiliary would take the conformation (HaꢀC3ꢀ
C2ꢀC1 is in the same plane) minimizing the allylic strain.
As we expected, the bulkiness of the substituent R on the
dioxolane ring played an important role in the transition
state T2, in which the R group significantly interacts with
the ketene moiety. Therefore, the cycloadditions of the
alkenyl ketenes generated from (S)-3b,d resulted in the
predominant formation of 2b,d with the (R,R,S) config-
uration (Figure 2). The absolute configurations of the
cycloadducts were confirmed by the following transforma-
tion of 2d to (ꢀ)-esermethole (16) as shown in Scheme 4.
To test the applicability of this methodology and to
confirm the absolute configuration of the cycloadduct, we
Scheme 4. Synthesis of (ꢀ)-Esermethole (16)
(6) Sun, K.; Liu, S.; Bec, P. M.; Driver, T. G. Angew. Chem., Int. Ed.
2011, 50, 1702–1706.
(7) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.;
Kishi, Y. J. Am. Chem. Soc. 2006, 128, 7463–7465.
(8) Zheng, Y. F.; Oehlschlager, A. C.; Georgopapadakou, N. H.;
Hartman, P. G.; Scheliga, P. J. Am. Chem. Soc. 1995, 117, 670–680.
(9) Vidari, G.; Lanfranchi, G.; Sartori, P.; Serra, S. Tetrahedron:
Asymmetry 1995, 6, 2977–2990.
(10) (a) Ohgiya, T.; Nishiyama, S. Chem. Lett. 2004, 33, 1084–1085.
(b) Ohgiya, T.; Kutsumura, N.; Nishiyama, S. Synlett 2008, 3091–3105.
(11) (a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. M.
J. Chem. Soc. D, Chem. Commun. 1971, 945–946. (b) Jeffs, P. W.;
Molina, G.; Cortesst, N. A.; Hauck, P. R.; Wolfram, J. J. Org. Chem.
1982, 47, 3876–3881. (c) Hoffman, R. V.; Salvador, J. M. Tetrahedron
Lett. 1989, 30, 4207–4210.
202
Org. Lett., Vol. 15, No. 1, 2013

Scheme 5. Synthesis of Takayama’s Intermediate 18
Figure 3. Retrosynthesis of the Takayama’s intermediate 18.
We also applied this method to the synthesis of the
alkaloid (þ)-psychotrimine (17), which was isolated from
Psychotria rostrata by Takayama et al. in 2004,4a and
which exhibits antibacterial activity against Gram-positive
bacteria and acts via membrane disruption.12 Several
synthetic reports have been published so far,4bꢀe including
the first enantioselective total synthesis by Takayama et al.4d
that established the absolute structure. In the Takayama’s
enantioselective synthesis, the 3a-indole-substituted pyrro-
lidinoindoline (18) was shown to be a key intermediate,
which was converted via an eight-step sequence to (þ)-
psychotrimine (17) uneventfully. Therefore, we attempted
the transformation of (S,S,R)-19, which can be derived
from (R)-20, to (ꢀ)-(3aS, 8aS)-18 (Figure 3).
has been developed and the methodology was successfully
applied to the enantioselective syntheses of (ꢀ)-esermet-
hole and Takayama’s intermediate of (þ)-psychotrimine.
The diastereoselective cycloaddition methodology devel-
oped here permitted access to both enantiomeric products,
in which the chiral dioxolane moiety can efficiently serve
for further transformations and functionalization, and it
could also be applied to the enantioselective synthesis of
other related alkaloids with more complicated molecular
structures.
The carboxylic acid (R)-20 was subjected to ketene-
forming conditions to provide exclusively the (S,S,R)-19.
This was then converted to the aldehyde 23 via 21 and
22 through the same sequence of reactions described in
Scheme 4. Oxidation followed by the ShioiriꢀCurtius
rearrangement of 24 gave the amine 25, which was exposed
to the indole-forming conditions13 with 1-bromo-2-(2-bro-
movinyl)benzene (26)14 to furnish the indole 27. Finally,
reduction followed by Boc-protection produced (ꢀ)-18,
whose spectral properties and optical rotation were iden-
tical with those reported4d (Scheme 5).
Acknowledgment. This work was supported financially
by a Grant-in-Aid for the Program for Promotion of Basic
and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN).
In summary, a novel and highly diastereoselective intra-
molecular carbamoylketene/alkene [2 þ 2] cycloaddition
(12) Schallenberger, M. A.; Newhouse, T.; Baran, P. S.; Romesberg,
F. E. J. Antibiot. 2010, 63, 685–687.
(13) (a) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes, I. P.
Adv. Synth. Catal. 2006, 348, 851–856. (b) Ueno, A.; Kitawaki, T.;
Chida, N. Org. Lett. 2008, 10, 1999–2002.
(14) (a) Tietze, L. F.; Nobel, T.; Spescha, M. L. J. Am. Chem. Soc.
1998, 120, 8971–8977. (b) Tadd, A. C.; Matsuno, A.; Fielding, M. R.;
Willis, M. C. Org. Lett. 2009, 11, 583–586.
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
203