Highly enantioselective intramolecular aza-spiroannulation onto indoles using chiral rhodium catalysis: Asymmetric entry to the spiro-β-lactam core of chartellines

Article abstract of DOI:10.1039/b913770j

A versatile, highly enantiocontrolled entry to the spiro-β-lactam core of chartellines has been developed by expanding the scope of oxidative nitrogen atom transfer methodology based on chiral Rh-nitrenoid species.

Full text of DOI:10.1039/b913770j

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Highly enantioselective intramolecular aza-spiroannulation onto indoles
using chiral rhodium catalysis: asymmetric entry to the spiro-b-lactam
core of chartellinesw
Shigeki Sato, Masatoshi Shibuya, Naoki Kanoh and Yoshiharu Iwabuchi*
Received (in Cambridge, UK) 9th July 2009, Accepted 13th August 2009
First published as an Advance Article on the web 2nd September 2009
DOI: 10.1039/b913770j
A versatile, highly enantiocontrolled entry to the spiro-b-lactam
core of chartellines has been developed by expanding the scope of
oxidative nitrogen atom transfer methodology based on chiral
Rh-nitrenoid species.
Table 1 Spirocyclization of indolyl carbamates with Rh2(OAc)4
Bryozoans living in the marine environment inspire the synthetic
community by presenting secondary metabolites with exquisitely
complicated architectures. Chartellines (1a–c, Fig. 1),1 the
small group of unique, indole–imidazole alkaloids isolated
from Chartella papyracea have received considerable attention
as targets for total synthesis,2–5 regardless of there being no
reports to suggest their pharmaceutical applicability. Synthetic
routes to the chartellines have yet to be achieved, except for
the insightful biomimetic approach conducted by Baran and
Shenvi, which culminated in the first total synthesis of racemic
chartelline C.4b Exploring the synthesis of the chartellines
should offer ample opportunity for the discovery and develop-
ment of new chemistry.
Substrate
Yielda
Spiro-
C–H
R1
R2
R3
cyclization insertion
Entry
Time/h
1
2
3
4
2a
2b
2c
2d
H
Boc
H
H
CO
CO
CO
CO
2
10
10
18
Complex mixtures
8b (61%)
8c (91%)
9b (26%)
ND
Boc Me
Boc Et
8d (85%)b 9d (10%)
5
2e
2f
Boc
Boc
CO
CO
24
12
ND
ND
9e (47%)
6
ND
7c
8c
2g
2h
Boc H
Boc Me
SO2
SO2
2
2
10b (24%) ND
10c (44%) ND
a
b
c
Yield of isolated product. E or Z ratio was 1 : 0.9. The reaction
was conducted with 2 mol% Rh2(OAc)4, 1.1 equiv. PhI(OAc)2, and
2.3 equiv. MgO at rt.
Our synthetic conception, centering on the asymmetric
generation of the nitrogen-substituted spirocenter, is depicted
in Scheme 1. In light of the continued development of Du
Bois’s C–H amidation chemistry,6 we envisioned that a metal
nitrenoid 3 tethered with a 3-indolylethyl pendant generated
from 2 would produce a spirocycle 6 via aziridine 4 or
betain 5.7–9 The subsequent sequence including hydrolytic
detachment of the tether moiety, oxidation, and lactamization
would provide the chiral spiro-b-lactam 7. For this approach
to be successful, the discovery of a modular combination of
R1, R2, tethering R3 groups, and a chiral ligand that realises a
practical level of asymmetric induction as well as an efficient
merger with the right-half portion of chartellines is required.
We describe herein the first enantiocontrolled entry to the
spiro-b-lactam core of chartellines, featuring a highly enantio-
selective, oxidative intramolecular nitrogen atom transfer to
an indole nucleus by chiral rhodium catalysis.
Fig. 1 The structure of chartellines.
Scheme 1 The plan for enantioselective synthesis of the spiro-b-lactam.
First, we explored the possibilities of catalytic spirocyclization
using a panel of 3-indolylethyl carbamates with Rh2(OAc)4
(Table 1). Although the reaction of indolylethyl carbamate
2a10 under Du Bois/Espino conditions11 using 5 mol%
Rh2(OAc)4 in the presence of PhI(OAc)2 and MgO resulted
in complex mixtures due to oxidative decomposition of the
indole moiety, the N-Boc-protected indole substrate 2b gave
Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University, 6-3Aobayama,
Sendai 980-8578, Japan. E-mail: iwabuchi@mail.pharm.tohoku.ac.jp;
Fax: +81-22-795-6845; Tel: +81-22-795-6846
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/b913770j
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Table 2 Enantioselective spirocyclization
Scheme 2 Optimization of the enantioselective spirocyclization.
Yieldb (ee)c
Catalyst (5 mol%)a
Time/h
8c
9c
11e
Entry
1
2
3
4
12
13
14
15
16
16
30
22
19
27
16
48
93 (10)
34 (67)
62 (90)
36 (94)
35 (94)
53 (93)
ND
46
19
ND
ND
ND
ND
3
3
10
11
20
5
6d
.
Scheme 3 Synthesis of chiral spiro-b-lactam 23.
a
Reactions were conducted using 5 mol% catalyst in the presence
of 1.4 equiv. PhI(OAc)2, 2.5 equiv. MgO, in boiling 0.1 M CH2Cl2.
reaching to 90% ee and 94% ee, respectively, although
chemical yields were low (entries 3, 4).
b
c
Isolated yield. Enantiomeric excess was determined after 8c was
transformed to the di-Boc derivative, followed by chiral HPLC
d
analysis using a Chiralpak AD-H column. The reaction was run in
0.01 M CH2Cl2. Yields were determined by 1H NMR integration of
the crude mixture.
The use of Rh2(S-TCPTAD)4 1515 resulted in similar yields
of products and enantioselectivity as with Rh2(S-TCPTTL)4
(entry 5). An important clue was obtained from the high
dilution reaction (0.01 M) using 16: the yield was improved
to 53% accompanied by 20% yield of aldehyde 11 as a
by-product, indicating possible hydrogen abstraction at the
a-position of the carbamoyloxy group in 2c.16 To suppress this
non productive pathway to 11,17 we synthesized the deuterated
substrate 2i.10 The reaction of 2i with 7 mol% Rh2(S-TCPTTL)4
afforded 8i in 70% yield with complete suppression of the
formation of 11 (Scheme 2). The absolute configuration of 8i
was determined to be R by its conversion to the known
compound AG-041R18 and the subsequent comparison of its
optical rotation with the reported value.19
e
the desired spirocyclization product 8b in 61% yield along
with a considerable amount of the C–H insertion product 9b in
26% yield (entries 1, 2). Importantly, when the 2-methylindolyl
substrate 2c was employed, the reaction gave the product 8c
exclusively in 91% yield (entry 3). In the case of the
2-ethylindolyl substrate 2d, similar spirocyclized products
were produced in a regioisomeric mixture (E or Z = 1.0/0.9)
in 85% yield accompanied by the C–H insertion product 9d in
10% yield. Unfortunately, the reaction of the 2-alkynylindolyl
carbamate 2e did not produce the spirocyclization product but
gave only the C–H insertion product 9e in moderate yield
(entry 5). The reaction of 2-alkenylindolyl carbamate 2f gave
intractable mixtures of unidentifiable products (entry 6). These
results highlighted the role of the 2-alkyl group in donating
electron density to the indole moiety to overcome the competing
C–H insertion at the benzylic position. We next examined the
catalytic spirocyclization of sulfamate esters 2g and 2h, both of
which resulted in low yields due to accompanying decomposition.
It is interesting to point out that the reaction of (N-Boc-2-
methylindol-3-yl)acetamide gave N-(N-Boc-2-methylindol-3-
ylmethyl)acetamide10 quantitatively.
Having identified appropriate conditions for the highly
enantioselective aza-spiroannulation onto the indole ring, we
attempted transformation of the carbamate 8i into the spiro-b-
lactam of the chartellines 23, which the Nishikawa/Isobe team
had synthesized in the racemic form3a (Scheme 3). The exo-
methylene moiety of 8i was cleaved via ozonolysis, and N-Boc
protection led to the bis-Boc carbamate 17. 17 was treated
with K2CO3 in methanol to afford the b-amino alcohol, which
was N-methylated with Me2SO4 to give 18. Oxidation of the
primary alcohol 18 to the corresponding carboxylic acid 20
was achieved in a one-pot manner employing a catalytic
ammount of 1-MeAZADO+ClÀ (19) in the presence of
NaClO2 in MeCN and sodium phosphate buffer.20 The resulting
product 20 was deprotected to give the b-amino acid 21. Upon
treatment with tris(2-oxo-3-benzoxazolinyl)phosphine oxide
(22),21 21 furnished the chiral spiro-b-lactam 23 in 47% yield.
The versatility of the spiro-carbamate 8 was confirmed by its
conversion to the indolenine–imidazole merger 28 via an
efficient Sonogashira coupling (Scheme 4). Thus, the alcohol
25, prepared from 8c via the same sequence as depicted in
Scheme 3, was protected as the TBS ether, and the lactam
Screening of a chiral ligand was conducted concurrently
with the aforementioned studies (Table 2). Treatment of
carbamate 2c with 5 mol% Rh2(S-PTPA)4 1212 in the presence
of PhI(OAc)2 and MgO gave 8c in 93% yield but in 10% ee
(Table 2, entry 1). Use of 5 mol% Rh2(S-PTTL)4 1313 gave 8c
with 67% ee, but the chemical yield was decreased to 34%,
and the C–H insertion product 9c was produced in 46%
yield (entry 2). It was found that Rh2(S-TFPTTL)4 14 and
Rh2(S-TCPTTL)4 1614 afforded high levels of enantioselectivity
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62, 11331–11342; (j) K. W. Fiori and J. Du Bois, J. Am. Chem.
Soc., 2007, 129, 562–568; (k) J. J. Fleming, M. D. McReynolds and
J. Du Bois, J. Am. Chem. Soc., 2007, 129, 9964–9975;
(l) R. M. Conrad and J. Du Bois, Org. Lett., 2007, 9, 5465–5468;
(m) Z. D. Zalatan and J. Du Bois, J. Am. Chem. Soc., 2008, 130,
9220–9221; (n) D. E. Olson and J. Du Bois, J. Am. Chem. Soc.,
2008, 130, 11248–11249; (o) J. V. Mulcahy and J. Du Bois, J. Am.
Chem. Soc., 2008, 130, 12630–12631; (p) Z. D. Zalatan and J. Du
Bois, Synlett, 2009, 143–146; (q) T. Kurokawa, M. Kim and J. Du
Bois, Angew. Chem., Int. Ed., 2009, 48, 2777–2779; (r) P. M. Wehn
and J. Du Bois, Angew. Chem., Int. Ed., 2009, 48, 3802–3805.
7 (a) A. Padwa and T. Stengel, Org. Lett., 2002, 4, 2137–2139;
(b) A. Padwa, A. C. Flick, C. A. Leverett and T. Stengel, J. Org.
Chem., 2004, 69, 6377–6386.
8 J.-L. Liang, S.-X. Yuan, H. P. W. Chan and C.-M. Che,
Tetrahedron Lett., 2003, 44, 5917–5920.
9 For other metal-catalyzed preparations of the spiro-oxindole and
spiro-b-lactam moieties, see: (a) B. Alcaide, P. Almendros and
Scheme 4 Synthesis of indolenine–imidazole merger 28.
R. Rodrı
(b) B. Alcaide, P. Almendros and R. Rodrı
Chem., 2006, 71, 2346–2351; (c) B. Alcaide, P. Almendros,
T. M. del Campo and R. Rodrıguez-Acebes, Adv. Synth. Catal.,
2007, 349, 749–758.
´
guez-Acebes, Chem.–Eur. J., 2005, 11, 5708–5712;
moiety was triflated to give 26. Upon treatment with 10 mol%
Pd(PPh3)4 and 30 mol% CuI in the presence of 10 equiv of
Et3N in THF, the coupling reaction between 26 and the alkyne
27 proceeded smoothly to furnish the indolenine 28 in 90% yield.
In summary, we have described a highly enantioselective
nitrogen atom transfer reaction of 2-(N-Boc-2-alkylindol-3-yl)-
ethyl carbamates based on rhodium nitrenoid chemistry that
provides a reliable platform for enantiocontrolled synthesis of
the spiro-b-lactam core of chartellines. Several novel aspects
disclosed in this study will stimulate further development of
metal nitrenoid chemisty. Efforts toward the synthesis of
chartelline alkaloids are now ongoing.
´
guez-Acebes, J. Org.
´
10 See Supporting Information for detailsw.
11 C. G. Espino and J. Du Bois, Angew. Chem., Int. Ed., 2001, 40, 598–600.
12 (a) S. Hashimoto, N. Watanabe and S. Ikegami, Tetrahedron Lett.,
1990, 31, 5173–5174; (b) S. Hashimoto, N. Watanabe, T. Sato,
M. Shiro and S. Ikegami, Tetrahedron Lett., 1993, 34, 5109–5112;
(c) S. Hashimoto, N. Watanabe and S. Ikegami, Synlett, 1994,
353–355; (d) N. Watanabe, M. Anada, S. Hashimoto and
S. Ikegami, Synlett, 1994, 1031–1033; (e) N. Watanabe,
Y. Ohtake, S. Hashimoto, M. Shiro and S. Ikegami, Tetrahedron
Lett., 1995, 36, 1491–1494.
13 (a) N. Watanabe, T. Ogawa, Y. Ohtake, S. Ikegami and
S. Hashimoto, Synlett, 1996, 85–86; (b) M. Anada and
S. Hashimoto, Tetrahedron Lett., 1998, 39, 79–82; (c) M. Anada,
N. Watanabe and S. Hashimoto, Chem. Commun., 1998,
1517–1518; (d) Y. Natori, M. Anada, S. Nakamura, H. Nambu
and S. Hashimoto, Heterocycles, 2006, 70, 635–647.
14 (a) M. Yamawaki, H. Tsutsui, S. Kitagaki, M. Anada and
S. Hashimoto, Tetrahedron Lett., 2002, 43, 9561–9564;
(b) M. Yamawaki, M. Tanaka, T. Abe, M. Anada and
S. Hashimoto, Heterocycles, 2007, 72, 709–721; (c) M. Anada,
M. Tanaka, T. Washio, M. Yamawaki, T. Abe and S. Hashimoto,
Org. Lett., 2007, 9, 4559–4562; (d) M. Tanaka, Y. Kurosaki,
K. Washio, M. Anada and S. Hashimoto, Tetrahedron Lett.,
2007, 48, 8799–8802; (e) M. Yamawaki, S. Kitagaki, M. Anada
and S. Hashimoto, Heterocycles, 2006, 69, 527–537.
15 R. P. Reddy and H. M. L. Davies, Org. Lett., 2006, 8, 5013–5016.
16 (a) C. G. Espino and J. Du Bois, in Modern Rhodium-Catalyzed
Organic Reactions, ed. P. A. Evans, Wiley-VCH, Weinheim, 2005,
pp. 379–416; (b) R. Gupta, K. M. Sogi, S. E. Bernard,
J. D. Decatur and C. M. Rojas, Org. Lett., 2009, 11, 1527–1530.
17 The use of deuterium isotope effects in natural product synthesis,
see: (a) D. L. J. Clive, M. Cantin, A. Khodabocus, X. Kong and
Y. Tao, Tetrahedron, 1993, 49, 7917–7930; (b) D. L. J. Clive,
Y. Tao, A. Khodabocus, Y.-J. Wu, A. G. Angoh, S. M. Bennett,
C. N. Boddy, L. Bordeleau, D. Kellner, G. Kleiner,
D. S. Middleton, C. J. Nichols, S. R. Richardson and
P. G. Vernon, J. Am. Chem. Soc., 1994, 116, 11275–11286;
(c) E. Vedejs and J. Little, J. Am. Chem. Soc., 2002, 124,
748–749; (d) M. Miyashita, M. Sasaki, I. Hattori, M. Sakai and
K. Tanino, Science, 2004, 305, 495–499.
This work was supported by a Grant-in-Aid for the Research
Fellowship for Young Scientists (S. S), and a Grant-in-Aid
for the Global COE Program of the ‘‘International Center of
Research & Education for Molecular Complex Chemistry’’
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Notes and references
1 (a) L. Chevolot, A. M. Chevolot, M. Gajhede, C. Larsen,
U. Anthoni and C. Christophersen, J. Am. Chem. Soc., 1985, 107,
4542–4543; (b) U. Anthoni, L. Chevolot, C. Larsen, P. H. Nielsen
and C. Christophersen, J. Org. Chem., 1987, 52, 4709–4712;
(c) U. Anthoni, K. Bock, L. Chevolot, C. Larsen, P. H. Nielsen
and C. Christophersen, J. Org. Chem., 1987, 52, 5638–5639.
2 (a) X. Lin and S. M. Weinreb, Tetrahedron Lett., 2001, 42,
2631–2633; (b) C. Sun, X. Lin and S. M. Weinreb, J. Org. Chem.,
2006, 71, 3159–3166.
3 (a) T. Nishikawa, S. Kajii and M. Isobe, Chem. Lett., 2004, 33,
440–441; (b) T. Nishikawa, S. Kajii and M. Isobe, Synlett, 2004,
2025–2027; (c) S. Kajii, T. Nishikawa and M. Isobe, Tetrahedron
Lett., 2008, 49, 594–597; (d) S. Kajii, T. Nishikawa and M. Isobe,
Chem. Commun., 2008, 3121–3123.
4 (a) P. S. Baran, R. A. Shenvi and C. A. Mitos, Angew. Chem., Int.
Ed., 2005, 44, 3714–3712; (b) P. S. Baran and R. A. Shenvi, J. Am.
Chem. Soc., 2006, 128, 14028–14029.
5 P. J. Black, E. A. Hecker and P. Magnus, Tetrahedron Lett., 2007,
48, 6364–6367.
6 (a) C. G. Espino, P. M. Wehn, J. Chow and J. Du Bois, J. Am.
Chem. Soc., 2001, 123, 6935–6936; (b) J. J. Fleming, K. W. Fiori
and J. Du Bois, J. Am. Chem. Soc., 2003, 125, 2028–2029;
(c) A. Hinman and J. Du Bois, J. Am. Chem. Soc., 2003, 125,
11510–11511; (d) P. M. Wehn, J. Lee and J. Du Bois, Org. Lett.,
2003, 5, 4823–4826; (e) C. G. Espino, K. W. Fiori, M. Kim and
J. Du Bois, J. Am. Chem. Soc., 2004, 126, 15378–15379;
(f) M. Kim, J. V. Mulcahy, C. G. Espino and J. Du Bois, Org.
Lett., 2006, 8, 1073–1076; (g) J. J. Fleming and J. Du Bois, J. Am.
Chem. Soc., 2006, 128, 3926–3927; (h) B. H. Brodsky and J. Du
Bois, Chem. Commun., 2006, 4715–4717; (i) K. Guthikonda,
P. M. Wehn, B. J. Caliando and J. Du Bois, Tetrahedron, 2006,
18 (a) T. Chiba, Y. Kinoshita, M. Sawada, K. Kishi, A. Baba and
E. Hoshino, Yale J. Bio. Med., 1998, 71, 247; (b) E. Lindstrom,
M. Bjorkqvist and R. Hakanson, Br. J. Pharmacol., 1999, 127, 530;
(c) X.-Q. Ding, E. Lindstrom and R. Hakanson, Pharmacol.
Toxicol., 1997, 81, 232; (d) T. Emura, T. Esaki, K. Tachibana
and M. Shimizu, J. Org. Chem., 2006, 71, 8559.
19 S. Sato, M. Shibuya, N. Kanoh and Y. Iwabuchi, J. Org. Chem.,
DOI: 10.1021/jo901352u.
20 M. Shibuya, T. Sato, M. Tomizawa and Y. Iwabuchi, Chem.
Commun., 2009, 1739–1741.
21 T. Nagamatsu and T. Kunieda, Chem. Pharm. Bull., 1988, 36,
1249–1251.
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