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intermittently (one minute ꢁ 40 intervals) in the presence of
catalytic KHSO4 in 2-propanol and 1,4-dioxane provided the
desired indolizinone 18 in satisfactory yield.
Having successfully constructed the highly substituted
indolizinone core by the cascade reaction, we then focused on
the formation of the nine-membered lactam ring to complete
a total synthesis of (À)-rhazinilam (Scheme 5). Because of
a highly reactive nature toward nucleophiles,[20] the N-acyl
Scheme 3. Preparation of the ynamide 13. Reagents and conditions:
a) (S)-(À)-1-phenethylamine, toluene, reflux, 18 h. b) Methyl acrylate,
RT, 7 d; then AcOH, MeOH/H2O (3:5), RT, 3 h, 83% (2 steps), >99%
ee. c) TMSCl, Et3N, DMF, 1008C, 46 h. d) DDQ, 2,6-lutidine, toluene,
RT, 4 d, 80% (2 steps). e) 37% aq. H2O2, 20% NaOH aq., MeOH,
08C, 0.5 h, 92%. f) Semicarbazide hydrochloride, NaOAc·3H2O,
MeOH/H2O (2:1), RT, 10 h. g) Pb(OAc)4, CH2Cl2, À108C, 2 h.
h) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, tBuOH/H2O (3:1),
08C, 2 h, 69% (3 steps). i) Aminoacetoaldehyde dimethylacetal, EDCI,
HOBt, DMAP, CH2Cl2, RT, 3 h, 81%. j) 2-Bromoiodobenzene, [Pd-
(PPh3)2Cl2] (3 mol%), CuI (6 mol%), Et3N, DMF, 508C, 2 h, 88%.
DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone, DMAP=4-(dimethyl-
amino)pyridine, DMF=N,N-dimethylformamide, EDCI=1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride, HOBt=1-hydroxy-
benzotriazole, TMS=trimethylsilyl.
Scheme 5. Total synthesis of (À)-rhazinilam (1). Reagents and condi-
tions: a) NaBH4, CeCl3·7H2O, MeOH, 08C, 2 h. b) NaBH3CN, AcOH,
MeCN, RT, 2 h, 80% (2 steps). c) NaN3, CuI (2 equiv), MeHN-
(CH2)2NHMe (3 equiv), DMSO, 1008C, 48 h, 64%. d) KOH, MeOH,
RT, 30 min; aq. HCl. e) EDCI, HOBt, CH2Cl2, RT, 8 h, 76% (2 steps).
DMSO=dimethyl sulfoxide.
a substantial amount of the ketoaldehyde 18’ (Scheme 4). The
low yield could be due to the steric bulkiness of the
quaternary carbon center adjacent to the triple bond, which
slows the initial cyclization step and causes decomposition of
the acetal. Then, conversion of the triple bond into the ketone
may have occurred by gold-catalyzed methanolysis. We
reasoned that the undesired conversion of the triple bond
would be suppressed by use of an acetal substrate derived
from a sterically demanding alcohol. Thus, we prepared the
diisopropyl acetal 19 and subjected it to the same reaction
conditions. The generation of 18’ was suppressed, however,
we did not observe significant improvement in the yield of 18
(33%). Expecting acceleration effects both on the first and
the second cyclization steps, we then examined microwave
irradiation and additives. After extensive optimization, we
eventually found that reaction with irradiation of microwave
pyrrole functionality was initially reduced in a stepwise
manner by Luche conditions and subsequent NaBH3CN
reduction in acidic media to give 21. The aryl bromide 21 was
then converted into aniline 22 by a one-pot copper-mediated
reaction via an aryl azide.[21] Finally, saponification of the
ester and subsequent lactamization furnished (À)-rhazinilam
(1). All the properties of synthetic 1 were identical to
published data.[2]
In contrast to (À)-rhazinilam (1), it was a difficult
challenge to construct the nine-membered lactam ring of
(À)-rhazinicine (2) and leave the highly reactive N-acyl
pyrrole functionality untouched. Thus, the copper-mediated
conversion into aniline resulted in decomposition of 18. Even
under mild saponification conditions using LiOH in THF, the
ring opening of the six-membered lactam ring occurred to
afford a dicarboxylic acid with loss of chirality. The requisite
conversion of the methyl ester 18 to the corresponding
carboxylic acid was best effected by treatment with TMSI.[22]
Then, the resultant carboxylic acid was converted into an
amide by activation with CDI and subsequent treatment with
ammonium hydroxide. Gratifyingly, crucial formation of the
nine-membered lactam ring proceeded by copper-mediated
intramolecular amidation[23] to furnish (À)-rhazinicine (2;
Scheme 6). The physical and spectral properties, including
optical rotation of synthetic 2, were identical to those
reported for the natural product.[3]
In summary, we have achieved a total synthesis (À)-
rhazinilam (1) and the first asymmetric total synthesis of (À)-
rhazinicine (2) by using the efficient construction of the per-
substituted indolizinone core though a gold-catalyzed cascade
Scheme 4. Construction of 5-indolizinone by gold-catalyzed cascade
cyclization. MWI=microwave irradiation.
4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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