Total Synthesis of Notoamides F, I, and R and Sclerotiamide

Article abstract of DOI:10.1002/anie.201604754

The total synthesis of the natural indole alkaloids (+)-notoamide F, I, and R and (?)-sclerotiamide is described. The four heptacyclic compounds were synthesized in 10–12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza-Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt-catalyzed radical cycloisomerization to create the cyclohexenyl ring.

Full text of DOI:10.1002/anie.201604754

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International Edition: DOI: 10.1002/anie.201604754
German Edition: DOI: 10.1002/ange.201604754
Indole Alkaloids
Total Synthesis of Notoamides F, I, and R and Sclerotiamide
Benxiang Zhang+, Weifeng Zheng+, Xiaoqing Wang, Deqian Sun,* and Chaozhong Li*
Abstract: The total synthesis of the natural indole alkaloids
(+)-notoamide F, I, and R and (À)-sclerotiamide is described.
The four heptacyclic compounds were synthesized in 10–12
steps in a convergent and highly stereoselective manner from
the readily available Seebach acetal. Key steps of the synthesis
include a stereoselective oxidative aza-Prins cyclization to
construct the bicyclo[2.2.2]diazaoctane, and a cobalt-catalyzed
radical cycloisomerization to create the cyclohexenyl ring.
T
he structural complexity and diverse biological activities of
prenylated indole alkaloids continue to encourage the devel-
opment of new methods for their efficient and rapid syn-
thesis.[1] A number of secondary metabolites produced by
various fungi of the genera Aspergillus and Penicillium,
including brevianamide B,[2] the stephacidins,[3–6] notoami-
de B,[5,6] malbrancheamide B,[7] marcfortine B,[8] and the cit-
rinalins,[9] have been synthetic targets of many research
groups. For example, Baran et al. accomplished the first total
synthesis of stephacidin A[3] on the basis of a stereoselective
intramolecular oxidative ester–amide coupling developed by
the same group.[10] Williams and co-workers nicely introduced
the biomimetic synthesis of stephacidin A by using an
azadiene intramolecular Diels–Alder reaction and also suc-
ceeded in the biomimetic oxidation of stephacidin A to
notoamide B.[5] More recently, Simpkins et al. also reported
the synthesis of stephacidin A with a tandem radical cycliza-
tion as the key step.[6]
The extra functionality at the C10 position in 1–3 causes
unexpected difficulties in their synthesis, and the reported
strategies for the synthesis of stephacidin A are not readily
applicable to 1–3, as demonstrated by our initial endeavors to
construct the hexacyclic skeleton, namely, compound 7, as
a simplified model of notoamide I (Scheme 1). An oxidative
Notoamides I (1), R (2), and F (3) are three new members
of this family isolated from marine-derived Aspergillus sp. by
the Tsukamoto group.[11] They can be regarded as oxygenated
metabolites of stephacidin A (4). Notoamide R may also
serve as the biosynthetic precursor to sclerotiamide (5),[12]
another member of the family that was isolated two decades
ago but has never been synthesized, despite the significant
interest in spirooxindoles of this type,[5–9] such as notoamide B
(6). Herein we report the first total synthesis of natural
(+)-notoamides F, I, and R and (À)-sclerotiamide.
Scheme 1. Attempts to synthesize 7 as a simplified model of notoami-
de I. DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone.
[*] B. Zhang,[+] Dr. W. Zheng,[+] Dr. X. Wang, Dr. D. Sun, Prof. Dr. C. Li
Key Laboratory of Organofluorine Chemistry and Collaborative
Innovation Center of Chemistry for Life Sciences
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
tandem radical cyclization pathway similar to the strategy
used by Simpkins and co-workers[6] was first tested. Unfortu-
nately, under various conditions, the attempted MnIII-, CuII-,
FeIII-, or CeIV-mediated oxidative radical cyclization[13] of
b-ketoamide 8 failed to give any of the desired product (see
below and Table S1 in the Supporting Information).[14]
Instead, we found that direct UV photolysis of 8 in CH2Cl2
led to the monocyclization products 9a and 9b, both with the
R rather than the desired S configuration at C21. Further-
345 Lingling Road, Shanghai 200032 (P.R. China)
E-mail: sundeqian@sioc.ac.cn
clig@mail.sioc.ac.cn
Prof. Dr. C. Li
School of Chemical Engineering, Ningbo University of Technology
89 Cuibai Road, Ningbo 315016 (P.R. China)
[+] These authors contributed equally.
À
more, formation of the C2 C22 bond through intramolecular
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604754.
Friedel–Crafts alkylation or a formal ene reaction of alkene
10 (the strategy described by Baran et al.)[3] was also
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unsuccessful, probably because of the conjugation of the
electron-withdrawing carbonyl group (see Table S3). The
attempted introduction of the carbonyl moiety by the
oxidation of compound 11[5c] with DDQ or SeO2 also failed:
The starting material either remained unchanged or under-
went rupture of the skeleton (see Table S4).
Our successful retrosynthetic design of notoamide I is
outlined in Scheme 2. We decided to construct the 2H-pyranyl
Scheme 3. Synthesis of the key intermediate 13. Reagents and con-
ditions: a) LDA (1.2 equiv), prenyl bromide (1.8 equiv), THF, À788C,
1.5 h; then aqueous H2SO4, 258C, 24 h; then (Boc)2O (5 equiv), NaOH
(30 equiv), 1,4-dioxane, 258C, 24 h, 58% overall; b) ClH3NCH-
(CO2Me)2 (1.1 equiv), HATU (1.1 equiv), DIEA (2.5 equiv), CH3CN,
258C, 12 h, 96%; c) TFA/CH2Cl2 (1:5), 08C, 5 h; d) AcOH/toluene
(1:9), reflux, 5 h, 90% overall; e) FeCl3 (3 equiv), CH2Cl2/CH3CN (1:4),
258C, 3 h, 67%. LDA=lithium diisopropylamide, HATU=N,N,N’,N’-
tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate,
DIEA=diisopropylethylamine, TFA=trifluoroacetic acid.
Scheme 2. Retrosynthesis of notoamide I. Bn=benzyl, Boc=tert-
butoxycarbonyl.
above FeCl3-mediated reaction of 14 is better classified as an
oxidative aza-Prins cyclization via imine 18.
ring last to avoid any possible complication in the early stages
À
of the synthesis. We envisioned that the C2 C22 linkage could
The reaction of 13 with the Grignard reagent derived from
3-iodoindole 12 and iPrMgCl provided ketone 19 in 47%
yield, thus setting the stage for the desired cycloisomerization
(Scheme 4). The treatment of 19 with catalytic amounts of the
cobalt–salen complex 20a and phenylsilane according to the
method described by Shenvi and co-workers[15] did not give
be created by cobalt-catalyzed radical cycloisomerization as
described by Shenvi and co-workers,[15] and that the C3 C10
À
bond could be formed by a Grignard reaction between iodide
12 and ester 13. The bicyclo[2.2.2]diazaoctane ring of 13 could
in turn be generated by an oxidative aza-Prins cyclization[16] of
dipeptide 14.
Thus, our synthetic route to 1–3 and 5 started with the
known and readily available Seebach acetal[17] 15 (Scheme 3).
The prenylation of 15, followed by acid quenching and
subsequent N-Boc-protection, gave acid 16 in 58% overall
yield. Compound 16 underwent condensation with dimethyl
2-aminomalonate to give the corresponding amide 17 in
nearly quantitative yield. The deprotection of 17 with
trifluoroacetic acid, followed by treatment with acetic acid,
afforded the expected cyclic dipeptide 14. Various conditions
for the oxidative cyclization of 14 were then screened (see
below and Table S5). Gratifyingly, the reaction of 14 with
FeCl3 in a CH3CN/CH2Cl2 solvent mixture at room temper-
ature furnished bicyclo[2.2.2]diazaoctane 13 in 67% yield as
the only stereoisomer. Note that the Mn(OAc)3-mediated[13a]
radical reaction of 14 failed to give any cyclization products;
instead the substrate underwent decomposition. On the other
hand, the copper(II)-promoted reaction of 14 in MeOH
produced the a-methoxylated product in 65% yield, presum-
ably through oxidation (to give imine 18) followed by the
addition of methanol to the imine. Upon treatment with
BF3·Et2O and FeCl3, the methoxylated compound could be
converted into 13 in a highly stereoselective manner, albeit in
low yield (30%). These results in combination with the
experiments with ketoamide 8 (see above) indicate that the
Scheme 4. Cobalt-catalyzed radical cyclization. Reagents and condi-
tions: a) 12 (2.0 equiv), iPrMgCl (2.2 equiv), THF, 08C, 30 min, 47%;
b) 20b (0.2 equiv), PhSiH3 (1.2 equiv), C6H6, 608C, 5 h; then DMP
(2.5 equiv), 258C, 5 h, 82%. DMP=1,1,1-tris(acetyloxy)-1,1-dihydro-
1,2-benziodoxol-3-(1H)-one.
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the expected product, but instead most of 19 was recovered.
The reduction of 1 with DIBAL-H gave (+)-notoamide R
Switching of the cobalt catalyst to complex 20b resulted in the
formation of the desired product 22 along with 2,3-dihydroin-
dole product 21, both in low yields. However, when the
reaction was carried out with a slight excess of phenylsilane,
the yields of 21 and 22 were both significantly increased. The
concurrent formation of 21 and 22 indicate that reductive
cyclization[18] competes well with cycloisomerization. Never-
theless, it was envisioned that 21 could be further converted
into 22 by oxidation. Thus, 19 was treated with phenylsilane
under the catalysis of cobalt complex 20b, and the reaction
was then quenched with Dess–Martin periodinane (DMP).
Compound 22 was obtained cleanly in 82% yield by this one-
pot procedure.
(2) as the only stereoisomer in 85% yield with an [a]D22 value
of + 39.1 (c = 0.23, MeOH), consistent with the reported
value of + 38.0 (c = 0.50, MeOH).[11b] Further treatment of 2
with AcOH in methanol produced (+)-notoamide F (3)
exclusively with complete retention of configuration. The
22
[a]D value of 3 was found to be + 4.7 (c = 0.23, MeOH),
which is comparable with the previously reported value
([a]D21 =+ 1.9 (c = 0.27, MeOH)).[11a] Finally, the conversion
of 2 into (À)-sclerotiamide (5) with oxaziridines[5,21] was
investigated. We screened a number of oxaziridines (see
Table S6) and found that, with oxaziridine 25 as the oxidant,
the rearrangement of 2 proceeded smoothly at room temper-
ature to furnish 5 in 55% yield. The measured [a]D22 value of
À57.4 (c = 0.073, MeOH) matches the reported value[12] well
([a]D = À55.1 (c = 0.1, MeOH)). The 1H and 13C spectra of 1–3
and 5 thus synthesized were identical to those reported
previously.
With intermediate 22 in hand, we went on to complete the
total synthesis of 1–3 and 5 (Scheme 5). The debenzylation of
22, followed by copper-catalyzed propargylation[19] with
propargyl carbonate 23, afforded ether 24 in 65% yield over
In summary, the first total synthesis of 1–3 and 5 from the
Seebach acetal 15 was completed in only 10–12 steps. The
synthesis is efficient and highly stereoselective, and features
an oxidative aza-Prins cyclization to construct the bicyclo-
[2.2.2]diazaoctane in a highly stereoselective manner, and
a cobalt-catalyzed radical cycloisomerization to generate the
cyclohexenyl ring.
Acknowledgements
This project was supported by the NSFC (Grants 21272259,
21290180, 21421002, 21472220, 21502210, 21532008, and
21361140377) and by the CAS (Grant XDB20020000).
Keywords: cyclization · indole alkaloids · natural products ·
radicals · total synthesis
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Received: May 16, 2016
Published online: && &&, &&&&
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Communications
Indole Alkaloids
B. Zhang, W. Zheng, X. Wang, D. Sun,*
C. Li*
&&&& — &&&&
Total Synthesis of Notoamides F, I, and R
and Sclerotiamide
Just a hop, skip, and a jump: The title
compounds were synthesized in only 10–
12 steps from the Seebach acetal. The
synthetic approach features an oxidative
aza-Prins cyclization to construct the
bicyclo[2.2.2]diazaoctane in a highly ste-
reoselective manner and a cobalt-cata-
lyzed radical cycloisomerization to build
the cyclohexenyl ring.
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www.angewandte.org
5
These are not the final page numbers!