Angewandte
Chemie
ing: Kobayashiꢀs protocol[15] failed to give the desired amines
due to the low reactivity of the allylic boronic esters used. We
made recourse to the free boronic acids.[16] Treatment of
known aldehyde 29[17] with cis boronic acid 30[16] in liquid
[15]
NH3 provided amine 31 (53% yield, ca. 10:1 d.r.), which
underwent desulfonation and thioisocyanate formation to
afford compound 32 (88% overall yield). Exposure of 32 to
DDQ and Sc(OTf)3 at 808C furnished racemic hapalindole Q
(3) in 48% yield. Similarly, amine 33, which was obtained
from 29 and trans boronic acid 34,[16] was further converted to
formamide 35. The oxidative cyclization followed by dehy-
dration proceeded smoothly to give racemic 12-epi-hapalin-
dole Q isonitrile (4) in 51% yield (2 steps). These syntheses
took advantage of the flexible access to the substrates and the
functional group tolerance of the cyclization.
We applied the above strategy and method to the
synthesis of racemic hapalindole H[5b] and hapalonamide H
(Scheme 4). Compound 36 was constructed from 30 and 4-Br-
Scheme 5. Total synthesis of deschloro 12-epi-fischerindole I nitrile.
EDC=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide, TMP=2,2,6,6-
tetramethylpiperidine, TMS=trimethylsilyl, HOBt=1-hydroxybenzotri-
azole.
octadien-1-ol) afforded ester 39, which underwent an Ireland–
Claisen rearrangement (LiTMP, TMSCl) to give acid 40 as
a major diastereomer. This compound was converted to nitrile
41 (66% overall yield) as the cyclization substrate. The C11
stereocenter was used transiently for directing the stereo-
chemical outcome at C15 of the product and then vanished.
Treatment of 41 with DDQ (3 equiv) in DCE at 508C
furnished racemic deschloro 12-epi-fischerindole I nitrile (7)
in 43% yield in a one-pot reaction, presumably via inter-
mediate 42 (see compound 17 in Scheme 2). The structure of 7
was verified by X-ray crystallographic analysis.[13]
The structure of deschloro 12-epi-fischerindole W
nitrile[4d] (43, Scheme 6) seemed at odds with the presumed
biosynthetic pathway, in which it would arise from an
isopropenyl-containing precursor. On this basis, we proposed
an alternative structure (44), in which the aryl methyl is
moved to C16.[20] Our total synthesis (Scheme 6) confirmed
this to be the correct structure. CrCl2-mediated allylation[21] of
unprotected aldehyde 45 furnished the cyclization substrate
46 (62% yield), which was subjected to the oxidative
cyclization conditions to give 19 (53% yield, see Scheme 2).
Exposure of 19 to Pd(OAc)2 and p-benzoquinone at 808C
provided carbazole 47 in 51% yield through an oxidative
Heck annulation;[22] the structure of 47 was confirmed by X-
ray crystallographic analysis.[13] Treatment of 47 with
BF3·OEt2/TMSCN gave the corresponding benzylnitrile (ca.
3:1 mixture of C11 diastereomers). The spectra of the major
isomer 44 (44% yield after purification) are identical to those
reported for the natural sample. Thus, we revised the
structure of the natural product from 43 to 44.
Scheme 4. Total syntheses of hapalindole H and hapalonamide H.
29[17,18] (39% yield) in a similar fashion to that described
above. The cyclization afforded compound 37 (58% yield),
which was subjected to Baranꢀs conditions for reductive Heck
annulation.[5j] Dehydration of the resultant formamide pro-
vided hapalindole H (5, 66% yield, 2 steps); its structure was
confirmed by X-ray crystallographic analysis.[13] In this syn-
thesis, the stereocenters at C11 and C12 were pre-installed on
the linear precursor, and those at C10 and C15 were secured
by the oxidative cyclization. Thus, no additional redox process
was required for the stereochemical adjustment.[5b] Photo-
sensitized oxidation of 5 (air, Rose Bengal, visible light) gave
hapalonamide H (6) in 87% yield[19] presumably through an
1O2 cleavage mechanism, which represents the first synthesis
of this natural product.
The first synthesis of deschloro 12-epi-fischerindole I
nitrile (7) possessing a tetracyclic framework was accom-
plished (Scheme 5), based on the cyclization cascade
observed leading to compound 17 (Scheme 2). Distinct from
many other members of the hapalindole family, 7 contains
a nitrile rather than an isonitrile or thioisocyanate function.
Condensation of acid 38 with nerol ((Z)-3,7-dimethyl-2,6-
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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