Enantioselective intramolecular AZA-spiroannulation onto benzofurans using chiral rhodium catalysis

Article abstract of DOI:10.3987/COM-14-12941

The development of efficient and enantioselective intramolecular aza-spiroannulation onto benzofurans using chiral rhodium catalysis is described. The optimized reaction conditions [Rh₂(S-TCPTAD) ₄ (3 mol %), PhIO (1.6 equiv), MeOH (10 equiv) in PhCF₃, 0°C] brought about oxidative aza-spiroannulation of 3-(carbamoylmethyl) benzofuran (3) resulting in (2R,3S)-2-methoxy-2H-spiro- [benzofuran-3,4′- oxazolidin]-2′-one (15a) in 69% yield with 86% ee, the absolute structure of which was determined by a combination of X-ray crystallography and vibrational circular dichroism (VCD) spectroscopy. The reaction is applicable to the asymmetric construction of various 2,3-dihydrobenzofuran derivatives bearing a nitrogen-containing tetrasubstituted carbon stereocenter at C3 (up to 92% ee).

Full text of DOI:10.3987/COM-14-12941

HETEROCYCLES, Vol. 89, No. 3, 2014
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HETEROCYCLES, Vol. 89, No. 3, 2014, pp. 631 - 639. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 13th January, 2014, Accepted, 24th January, 2014, Published online, 30th January, 2014
DOI: 10.3987/COM-14-12941
ENANTIOSELECTIVE INTRAMOLECULAR AZA-SPIROANNULATION
ONTO BENZOFURANS USING CHIRAL RHODIUM CATALYSIS
Takuro Shibuta,1 Shigeki Sato,1 Masatoshi Shibuya,1 Naoki Kanoh,1 Tohru
Taniguchi,2 Kenji Monde,2 and Yoshiharu Iwabuchi*1
1 Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan; E-mail:
y-iwabuchi@m.tohoku.ac.jp
2 Frontier Research Center for Post-Genome Science and Technology, Faculty of
Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo
001-0021, Japan
Abstract – The development of efficient and enantioselective intramolecular
aza-spiroannulation onto benzofurans using chiral rhodium catalysis is described.
The optimized reaction conditions [Rh2(S-TCPTAD)4 (3 mol %), PhIO (1.6 equiv),
MeOH (10 equiv) in PhCF3, 0 °C] brought about oxidative aza-spiroannulation of
3-(carbamoylmethyl)benzofuran (3) resulting in (2R,3S)-2-methoxy-2H-spiro-
[benzofuran-3,4'-oxazolidin]-2'-one (15a) in 69% yield with 86% ee, the absolute
structure of which was determined by a combination of X-ray crystallography and
vibrational circular dichroism (VCD) spectroscopy. The reaction is applicable to
the asymmetric construction of various 2,3-dihydrobenzofuran derivatives bearing
a nitrogen-containing tetrasubstituted carbon stereocenter at C3 (up to 92% ee).
2-Oxindoles and 2,3-dihydrobenzofurans, furnished with a nitrogen-containing tetrasubstituted chiral
center at the C3 positions,1,2 are structural motifs found in a variety of potential medicines,
pharmaceutically relevant and/or structurally intriguing natural products (Figure 1),3-8 thus attracting
considerable attention from the synthetic community.
Despite its structural similarity to 3-amino-2-oxindole, for which several synthesis strategies have been
developed,3-5,9 few reliable methods capable of constructing 3-amino-2,3-dihydrobenzofurans in an
enantiocontrolled manner have been reported to date.6b,6c,7,10 In the light of successful applications of
Rh(II)-catalyzed intramolecular nitrene transfer11-13 onto indole substrates (Scheme 1),14-16 an analogous
aza-spiroannulation onto benzofuran substrates was envisaged, due to the recent discovery of

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(–)-fumimycin (1)6a as a novel class of antibiotic agents based on its inhibition of peptide deformylase
activity.17 Notwithstanding the rather discouraging precedents of aza-spiroannulation onto benzofuran
Figure 1. Representative biologically active 3-amino-2-oxindoles and 3-aminodihydrofurans
Scheme 1. Selected precedents of aza-aspiroannulation onto indole and benzofuran

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(Scheme 1, a),15a,18 the modular nature of the chiral rhodium-15c,16 or iron17-nitrene complex encouraged us
to identify useful conditions for installing the intended nitrogen-containing tetrasubstituted carbon at C3
with high enantioselectivity (Scheme 1, b and c). Herein, we describe the first diastereo- and
enantiocontrolled aza-spiroannulation onto benzofurans using chiral rhodium catalysis.
The investigation commenced with the inspection of the reactivity and enantioselectivity of simple
benzofuran 3 under typical reaction conditions, using the Rh2(S-TCPTTL)4(cat.)19/PhI(OAc)2/MgO
system.12 As anticipated, the desired spirocycle 920 was only obtained in 39% yield as a diastereomeric
mixture (dr = 1.2:1), which is in line with the result of Padwa et al15b (Scheme 2).
Scheme 2. Our initial attempt of asymmetric aza-spiroannulation onto a simple benzofuran 3 and the
plausible reaction mechanisms
The enantioselectivity was also disappointingly low (20% ee). Furthermore, the undesired compound
1020 was produced in 30% yield. On the basis of these results, it was speculated that this particular
rhodium-catalyzed reaction of the benzofuran 3 proceeded in the following manner (Scheme 2), namely:
(i) the initial generation of the rhodium nitrenoid 11 is followed by an intramolecular aziridination to
yield aziridine 12; (ii) 12 can equilibrate with betaine 13, and this equilibrated species can be isomerized
to 14 under given conditions; (iii) AcOH, generated in situ, attacks 12 at C2 from the convex face to yield
the !–acetoxy anomer of 9; (iv) the nucleophilic attack of AcOH with betaine 13 proceeds in a less
diastereoselective manner to produce a diastereomeric mixture of 9, while the nucleophilic attack of
betaine 14 by AcOH yields the undesired by-product 10. The desired spirocyclic compounds were
predicted to form efficiently and in a stereospecific manner when aziridine intermediate 12 is quickly

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attacked by stronger nucleophiles prior to its isomerization to betaine 13. The choice of alcohol as a
nucleophile seemed to be suitable for this purpose.21,22 As expected, the treatment of carbamate 8 with
Rh2(S-TCPTTL)4 (3 mol %), 1.6 equiv of PhIO, 50 equiv of MeOH, and PhCF3 as the solvent afforded
the spirocycle 15a in 71% yield as a single diastereomer (Table 1, entry 1). However, the
enantioselectivity of 15a was still low, that is, 36% ee. As the desired spirocycle was successfully
obtained, the focus shifted to the improvement in enantioselectivity (Table 1). When the amount of
MeOH was decreased to 10 equiv, a slightly higher level of ee was observed (entry 2). The use of 3
mol % Rh2(S-TCPTAD)423 as a chiral catalyst provided 15a in 68% ee (entry 3). Screening of
nucleophiles was then undertaken to examine their influence on enantioselectivity using EtOH, allyl alcohol,
Table 1. Optimization of reaction conditions

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and AcOH (entries 4–6). As a result, spirocycles 15b and 15c were respectively obtained as a single
diastereomer though they exhibited a lower ee than 15a (entries 4 and 5 vs entry 3). When 10 equiv of
AcOH was added, the result got worse: spirocycle 9 resulted as a diastereomeric mixture with quite a low
enantioselectivity along with undesired compound 10 (entry 6). Ultimately, it was elucidated that
lowering the reaction temperature is critical for good enantioselectivity. When this aza-spirocyclization
reaction using MeOH was carried out at 0 °C, spirocycle (–)-15a was obtained in good yield with good
enantioselectivity characterized by 69% yield and 86% ee (entry 7).
The absolute stereostructure of the product (–)-15a was determined by a combination of X-ray
crystallography and vibrational circular dichroism (VCD) spectroscopy.24,25 The relative configuration
of 15a was established as shown in Table 1 by X-ray crystallographic study (Figure 2, a). To determine
the absolute configuration of (–)-15a, calculations for conformational analysis were carried out using
arbitrarily selected (2R,3S)-15a (Figure 2, b). Theoretical IR and VCD calculations were then performed
for each conformer using density functional theory (DFT) with the B3LYP/6-311+G(d,p) level of theory,
and the final calculated IR and VCD spectra were obtained based on the Boltzmann population average of
each spectrum. The population-weighted theoretical VCD spectra were shown to be in good agreement
Figure 2. Experiments for determining absolute configuration of the obtained spirocycle 15a

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with the experimental VCD spectra (Figure 2, c). As the result, the absolute configuration of (–)-15a was
elucidated to be (2R,3S). The determined absolute stereostructure of (–)-15a indicates that spirocycle
15a was generated through an SN2-type ring opening of the aziridine intermediate 12.
The scope of the asymmetric aza-spiroannulation conditions optimized for the benzofuran 8 was
investigated by applying them to a diverse range of benzofurans (Figure 3). The introduction of oxygen
functional groups and a phenyl group at C5 was tolerated and the corresponding spirocycles were
obtained in good yield with reasonable enantioselectivity (73"80% ee) (16a–16d).26
The
halogen-substituted benzofurans were found to be suitable substrates in this particular
aza-spirocyclization reaction. The spirocyclic compounds 16e–16h showed good level of ee (84–92% ee).
Although bromo-substituted 16h was obtained in low yield, unreacted benzofuran substrate was
recovered without severe decomposition. Spirocycle 16i, in which an allyl group was introduced at C4
directed for fumimycin (1) synthesis, was obtained in good yield but with moderate enantioselectivity,
implying that modification of the aromatic moiety should be conducted after construction of the C3
stereocenter.
Figure 3. Scope of chiral Rh(II)-catalyzed asymmetric aza-spiroannulation onto benzofurans

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In summary, an efficient asymmetric aza-spiroannulation onto benzofurans was developed based on chiral
rhodium catalysis. This procedure provides a reliable platform for the construction of enantio-enriched
3-amino-2,3-dihydrobenzofurans in particular non-substituted and mono-substituted ones. A concise
synthesis of the core structure of fumimycin has also been achieved. Efforts toward total synthesis of
(–)-fumimycin based on this methodology are now ongoing.27
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysis” from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
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Supporting Information.
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aza-spiroannulation.