Regioselective inter- and intramolecular formal [4+2] cycloaddition of cyclobutanones with indoles and total synthesis of (±)-aspidospermidine

Article abstract of DOI:10.1002/anie.201206734

This way and that way: A formal [4+2] cycloaddition between various cyclobutanones and indoles proceeded efficiently under Lewis acid catalysis (see scheme; PG = protecting group). The regioselectivity of the reaction could be controlled in such a way that each of the two possible regioisomers of a cycloaddition product could be synthesized selectively. The usefulness of this reaction for the total synthesis of hydrocarbazole natural products was demonstrated. Copyright

Full text of DOI:10.1002/anie.201206734

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DOI: 10.1002/anie.201206734
Cycloaddition
Regioselective Inter- and Intramolecular Formal [4+2] Cycloaddition
of Cyclobutanones with Indoles and Total Synthesis of
(ꢀ)-Aspidospermidine**
Mizuki Kawano, Takaaki Kiuchi, Shoko Negishi, Hiroyuki Tanaka, Takaya Hoshikawa,
Jun-ichi Matsuo,* and Hiroyuki Ishibashi
Hydrocarbazoles are found in the skeletons of many alka-
loids, such as strychnine (1),[1] kopsane (2),[2] minfiensine
(3),[3] strictamine (4),[4] and aspidospermidine (5; Scheme 1).
ment of a general, efficient, and conceptually new strategy for
the synthesis of structurally diverse hydrocarbazoles still
remains important and challenging.
We describe herein the first example of a Lewis acid
promoted formal [4+2] cycloaddition of cyclobutanones 6
with indoles (Scheme 2). This reaction enables the selective
Scheme 1. Selected natural products with a hydrocarbazole skeleton.
Alkaloids and synthetic small molecules[5] with a hydrocarba-
zole structure exhibit a broad range of important bioactivi-
ties.[6] For the synthesis of structurally diverse and complex
hydrocarbazoles, [4+2] cycloaddition to the C2–C3 positions
of indoles has high synthetic potential, since two covalent
bonds are formed in one step without the preintroduction of
special substituents (e.g., a vinyl group[3e,7]) on the indole.
Such [4+2] cycloadditions of indoles are categorized into
three types of Diels–Alder reaction (DAR): 1) normal-
electron-demand DARs, in which strongly electron-deficient
indoles that contain two electron-withdrawing groups at their
1- and 3-positions are used,[8] 2) inverse-electron-demand
DARs[9] of highly electron-poor dienes, such as 1,2,4,5-
tetrazine,[9b,c] and 3) DARs of photochemically induced
radical cations with triarylpyrylium salts.[10] In all of these
DARs,[11] the combination of indoles and enophiles (4p
donors) is restricted, and it is also difficult to change the
regioselectivity of the cycloaddition. Therefore, the develop-
Scheme 2. Formal [4+2] cycloaddition between indoles and 3-donor-
substituted cyclobutanones 6. PG=protecting group.
synthesis of both of the two possible regioisomeric hydro-
carbazoles 8 and 9. Thus, we found that the zwitterionic
intermediate 7, which was formed by the activation of 3-
donor-substituted cyclobutanones[12] with a Lewis acid,[13]
reacted efficiently with indoles to give the corresponding
hydrocarbazoles (8 or 9). A special activating group on the
indole nucleus was not required, and a variety of indoles
underwent the reaction, both in an intermolecular and in an
intramolecular manner. The synthesis of a substructure of
strictamine (4) and the total synthesis of (ꢀ)-aspidospermi-
dine (5) by intramolecular cycloaddition reactions are also
described herein.
The screening of Lewis acids for a formal [4+2] cyclo-
addition of indoles 10a–f with cyclobutanone 11a revealed
that TiCl4 was a suitable Lewis acid for indoles 10a–d with an
electron-withdrawing group (EWG) as the N-protecting
group, whereas the use of EtAlCl2 led to the formation of
adducts 12e,f in good yields from the reactive indoles 10e,f
(Scheme 3).[14] Notably, the cycloaddition of indole 10e
without an N-protecting group proceeded smoothly to give
12e. We tested dichloromethane, toluene, and nitroethane as
solvents and found that the use of nitroethane led to better
yields of the cycloadducts derived from the N-arenesulfonyl-
indoles 10a,b and reactive indoles 10e,f, whereas dichloro-
methane was suitable for the reaction of the N-alkoxycarbo-
nylindoles 10c,d.[14] Good endo/exo selectivities were
observed in the reactions of N-arenesulfonylindoles, whereas
almost equal amounts of the endo and exo adducts were
obtained in other cases. As described below, the removal of
[*] M. Kawano, T. Kiuchi, S. Negishi, H. Tanaka, T. Hoshikawa,
Prof. Dr. J. Matsuo, Prof. Dr. H. Ishibashi
School of Pharmaceutical Sciences
Institute of Medical, Pharmaceutical, and Health Sciences
Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: jimatsuo@p.kanazawa-u.ac.jp
[**] We thank Prof. Shuhei Fujinami (Kanazawa University) for X-ray
crystallographic analysis and Mio Hashizume for technical assis-
tance. This study was partially supported by the Kurata Memorial
Hitachi Science and Technology Foundation and JSPS KAKENHI
Grant Number 24590007.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206734.
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to the carbonyl group reacted with N-benzylindoles to afford
compounds 12q–s.
Interestingly, reversed regioselectivity of the cycloaddi-
tion was observed when an indole had an electron-donating
group (EDG) at the 3-position and an EWG on the nitrogen
atom (Scheme 4). Thus, N-benzyloxycarbonyl 3-alkyl indoles
reacted with cyclobutanone 11a to afford hexahydro-3-
Scheme 3. Lewis acid promoted formal [4+2] cycloaddition of indoles
10 with cyclobutanones 11a–e to give hexahydro-2-oxocarbazoles
12a–s. TiCl4 was used as the Lewis acid and EtNO2 as the solvent
unless otherwise mentioned.[14] The structures of the endo product, the
yield of the isolated product, and the endo/exo ratio are given.
[a] CH2Cl2 was used instead of EtNO2. [b] EtAlCl2 was used instead of
TiCl4. [c] Et2AlCl was used as the Lewis acid. [d] For details about the
configuration, see the Supporting Information. Ts=p-toluenesulfonyl,
Ns=o-nitrobenzenesulfonyl, Cbz=benzyloxycarbonyl, Alloc=allyloxy-
carbonyl, Bn=benzyl.
Scheme 4. Inverse regioselectivity in the formal [4+2] cycloaddition of
3-substituted indoles 13 with cyclobutanones 11a–d to give hexahydro-
3-oxocarbazoles 14a–g. The structure of the exo product, the yield of
the isolated product, and the endo/exo ratio are given.[14] The endo/exo
ratio was determined by H NMR spectroscopy. [a] EtAlCl2 was used
instead of TiCl4. TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
1
oxocarbazoles 14a,b without formation of the regioisomeric
hexahydro-2-oxocarbazoles 12. 3-tert-Butyldimethylsilyloxy-
or 3-methylthio-substituted N-p-toluenesulfonylindoles also
reacted with 11a,d to give hexahydro-3-oxocarbazoles 14c–
e.[16] Two contiguous quaternary carbon centers were con-
structed efficiently in the formation of spiro compounds 14 f,g
through the cycloaddition of spirocyclobutanones 11b,c.
A diastereomeric mixture of 12c (endo/exo 54:46) was
transformed smoothly into 15a by the Me3SiOTf-promoted
elimination of ethanol and isomerization (Scheme 5). The
oxidation of 12c with DDQ, followed by treatment with
Me3SiOTf, gave enone 15b in 80% yield over the two steps.
The conjugate addition of Me2CuLi to enone 16a, which was
prepared from 12p, proceeded stereoselectively to afford 16b.
The methylthio group of exo-14e was removed with Raney
nickel at a low temperature to give 17. Thus, we could
synthesize both of the two possible regioisomers 12a and 17
selectively by our cycloaddition approach.
A proposed mechanism for the present cycloaddition is
shown in Scheme 6. The zwitterion 18 generated from the
cyclobutanone (in this case, 11a) reacts with an indole to form
an iminium intermediate 19[17] or a benzylic carbocation 21,
which then cyclizes to 20 (cyclization type A) or 22 (cycliza-
tion type B), respectively.[18] When PG is an electron-donating
group, such as a benzyl group, 19 is formed because the
electron-donating group stabilizes the iminium cation. On the
the ethoxy group in cycloadducts 12 was straightforward. The
stereostructure of exo-12c as a representative exo adduct was
determined unambiguously by X-ray crystallography,
whereas that of an endo adduct was determined by NOE
experiments.[14]
Indoles bearing a methoxy, methyl, or bromo group at the
5-position reacted with 11a to give the corresponding cyclo-
adducts 12g–i in good to high yields (Scheme 3). The
propeller-like cycloadducts 12j,k were obtained from indoles
fused with a five-membered ring. Structures similar to those
of 12j and 12k are found in kopsane (2) and minfiensine (3),
respectively. The mild Lewis acid Et2AlCl was used for the
synthesis of 12k, because the starting indole 10k and the
product 12k were labile under strongly acidic conditions.
Spirocyclobutanones 11b,c with a cyclopentane or cyclohex-
ane ring reacted efficiently to afford spirocycloadducts 12l,m.
The bicyclic cyclobutanone 11e reacted with N-benzylindoles
to give the tetracyclic products 12n (in 67% yield as a single
diastereomer) and 12o (in 31% yield as a 67:33 mixture of
diastereomers).[15] This result suggests that the cyclobutanone
ring of 11e was cleaved selectively to form the zwitterionic
intermediate with the less substituted enolate.[13a] Finally,
cyclobutanone 11d with no alkyl substituents at the a position
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Scheme 5. Transformation of adducts 12c,p and 14e: a) Me3SiOTf,
CH2Cl2, 08C, 1 h, then room temperature, 1 h, 86%; b) 1) DDQ,
toluene, reflux, 45 min; 2) Me3SiOTf, CH2Cl2, 08C, 5 min, 80% (for two
steps); c) 1) Me3SiOTf, Et3N, CH2Cl2, 0!158C, 1.5 h; 2) Me3SiOTf,
CH2Cl2, 08C!RT, 1 h, 83% (for two steps); d) Me2CuLi, BF3·Et2O,
Et2O/THF, ꢁ78!08C, 3.5 h, 92%, single diastereomer; e) Raney
nickel, EtOH/THF, ꢁ208C, 1 h, 70%, d.r. 90:10. DDQ=2,3-dichloro-
5,6-dicyano-p-benzoquinone, Tf=trifluoromethanesulfonyl.
Scheme 7. Synthesis of a substructure of 4: a) 2,2-dichloropropanoyl
chloride, Zn, Et2O, room temperature, 2 h; b) Zn/Cu, NH4Cl, MeOH,
room temperature, 1 h, 60% (for two steps), d.r. 66:34; c) tryptamine,
NaBH(OAc)3, CH2Cl2, room temperature, 14 h, quantitative; d) AllocCl,
10% aqueous Na2CO3, Et2O, room temperature, 12 h, 87%; e) TsCl,
NaOH, TBHSA, CH2Cl2, room temperature, 5 h, quantitative; f) TBAF,
AcOH, THF, room temperature, 24 h; g) DMP, CH2Cl2, room temper-
ature, 4 h, 80% (for two steps), d.r. 83:17; h) BF3·Et2O, CH2Cl2, room
temperature, 2 h, 87%, d.r. 65:35. TBHSA=tetrabutylammonium
hydrogen sulfate, TBAF=tetrabutylammonium fluoride, DMP=Dess–
Martin periodinane.
Scheme 6. Proposed mechanism for the formal [4+2] cycloaddition of
3-ethoxycyclobutanones with indoles.
other hand, the presence of an electron-withdrawing group on
the nitrogen atom to disfavor 19 (compare 12p and 14a) and
an electron-donating R group to favor 21 (compare 12c and
14a) promotes type B cyclization.
Scheme 8. Total synthesis of (ꢀ)-5: a) CbzCl, CH2Cl2, room temper-
=
ature, 15 h, 99%; b) Zn/Cu, Cl3C(C O)Cl, Et2O, sonication, 08C, 0.5 h,
then room temperature, 14 h; c) Zn/Cu, NH4Cl, MeOH, room temper-
ature, 2 h, 85% (for two steps); d) ethylene glycol, TsOH/H2O,
benzene, reflux, 12 h, 95%; e) H2, Pd/C, EtOH, room temperature, 3 h,
quantitative; f) 3-indoleacetic acid, EDC, 08C, 5 h, 89%; g) BnBr, NaH,
DMF, room temperature, 2.5 h, 95%; h) 1n HCl, EtOH, reflux, 3 h,
93%; i) Me3SiOTf, toluene, reflux, 10 min, 46% (+ C22 epimer, 32%);
j) N2H4·H2O, Na, (CH2OH)2, 160–2108C, 18 h; k) LiAlH4, THF, room
temperature, 1 h, 71% (for two steps); l) H2, Pd(OH)2, EtOH, room
temperature, 46 h, 93%. EDC=1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride.
An intramolecular cyclization between a cyclobutanone
and an indole was employed for the synthesis of a substructure
28 of (ꢀ)-strictamine (4; Scheme 7).[19] Compound 26, the
indole nitrogen atom of which was protected with an electron-
withdrawing group (Ts), was used for the intramolecular
formal [4+2] cycloaddition, since type-B cyclization was
expected to give 28. A [2+2] cycloaddition between the TBS
enol ether 23 and methyl chloro ketene was followed by
reductive removal of the chloro group with a zinc–copper
couple to give cyclobutanone 24. The reductive amination of
24 with tryptamine afforded 25, the secondary amino group
and indole nitrogen atom of which were protected with an
Alloc and a Ts group, respectively. Deprotection and
oxidation of the hydroxy group gave the cycloaddition
precursor 26. The key intramolecular [4+2] cycloaddition of
26 proceeded smoothly in the presence of the Lewis acid
BF3·Et2O, and the desired product 28 was obtained in 87%
yield. It was assumed that an intermediate 27 was formed by
regioselective ring cleavage[13a] of the a-methylcyclobutanone
ring of 26 and that type-B intramolecular addition then gave
28.
benzyl group of enamine 29, which was readily prepared in
five steps according to a procedure described by Norman and
Heathcock,[22] was exchanged for an N-Cbz group by treat-
ment with benzyloxycarbonyl chloride.[23] A [2+2] cyclo-
addition with dichloroketene, followed by reductive de-
chlorination, gave cyclobutanone 30 in 85% yield over two
steps. Protection of the carbonyl group of cyclobutanone 30 as
an acetal and removal of the N-Cbz group afforded the
piperidine derivative 31. It was necessary to protect the
carbonyl group of 30 because the 3-aminocyclobutanone that
should be formed by removal of the N-Cbz group of 30 was
too unstable to be isolated. Amine 31 was coupled with 3-
indoleacetic acid to give the corresponding amide, the indole
nitrogen atom of which was protected with a benzyl group.
Hydrolysis of the acetal group then gave the cycloaddition
We used a type-A intramolecular cyclization for the total
synthesis of (ꢀ)-aspidospermidine (5;[20] Scheme 8).[21] The N-
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precursor 32.[24] After extensive screening of Lewis acids and
optimization of the reaction conditions, the intramolecular
[4+2] cycloaddition of 32 proceeded to give the desired
pentacyclic compound 34 in 46% yield along with the C22
epimer of 34 (32%). The cyclobutanone ring of 32 was
cleaved regioselectively as observed for the bicyclic cyclo-
butanone 11e, and an intramolecular type-A cyclization of 33
gave 34. Wolff–Kishner reduction[20i,25] of 34, followed by
reduction of the amide group with LiAlH4 and removal of the
N-Bn group with Pd(OH)2,[20k] gave (ꢀ)-5. Notably, in this
synthesis, the C and E rings of 5, with an angular C22 ethyl
substituent, were constructed in a single step.
In conclusion, we have developed a new formal [4+2]
cycloaddition between indoles and cyclobutanones that can
proceed in both an intra- and an intermolecular manner, and
we have shown that cyclobutanones were excellent four-
carbon-atom donors for various indoles. The regioselectivity
of the cycloaddition was controlled by the indole substituents,
and it was demonstrated that the two possible regioisomers of
a cycloaddition product could be synthesized selectively. The
wide reaction scope and unique orientation control were
applied to the synthesis of a tetracyclic substructure of (ꢀ)-
strictamine (4) and the total synthesis of (ꢀ)-aspidospermi-
dine (5). We believe that this regioselective method offers
rapid and reliable access to structurally diverse hydrocarba-
zoles from abundant indoles.
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Received: August 20, 2012
Revised: October 30, 2012
Published online: November 26, 2012
Keywords: alkaloids · cycloaddition · Lewis acids ·
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regioselectivity · total synthesis
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[15] N-Benzylindoles bearing a 2-(triisopropylsilyloxy)ethyl group,
a 2-bromoethyl group, or an ethoxycarbonylmethyl group at the
3-position did not react with 11e.
[16] An attempted cycloaddition of 11e with 3-tert-butyldimethylsi-
lyloxy-substituted N-p-toluenesulfonylindole did not proceed.
[17] The stepwise mechanism was suggested by the formation of an
open-chain by-product in the synthesis of 12 f (Scheme 3).[14]
[18] Similar regioselectivity was reported previously: Z. Song, Y.-M.
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