ll

Previews
Dimerization approach stage of the synthesis, the diketopiper-
azines were assembled. Compound
to (+)-asperazine A 5 was coupled to N-Boc-D-phenylala-
nine with propylphosphonic anhydride
(T3P) and Hünig’s base. The amino
Yiwei Zhang1 and Chi P. Ting1,*
group (N4) and the pyrrolidine (N2) re-
acted chemoselectively over the indo-
Tryptophan-linked dimeric diketopiperazine alkaloids possess great line (N3) to form compound 6. The Boc
molecular diversity and bioactivity. In this issue of Chem, Jiang and groups were removed by treatment
co-workers report an oxidative approach to those alkaloids contain- with hydrochloric acid in dioxane, and
ing an unsymmetrical C3-N10 linkage. In their concise synthesis of the resulting product (7) treated with
(+)-asperazine, they successfully dimerized a designer tryptophan- 7M ammonia in methanol furnished
alternative building block through the sustained release of electro- (+)-asperazine A in 46% yield over four
philic iodine. steps. In a separate sequence, 5 was
converted to 15,150 -epi-asperazine A
by coupling with N-Boc-L-phenylala-
Tryptophan-based dimeric alkaloids Optimal conditions involved subjecting
nine. Moreover, 22 different 2N sub-
are a large class of bioactive natural 1,3-dicarbonyl iodomethylcycloprop-
strates were amenable to dimerization,
products, and their molecular diversity ane (3) to catalytic nickel (II) perchlorate
enabling the synthesis of asperazine
stems from the numerous isomers that hexahydrate as a Lewis acid to achieve
analogs.
can be generated by dimerization of the sustained release of iodine cation.
the tryptophan indole.1 Perhaps un- Density functional theory (DFT) and
From Chapman’s classic synthesis of
surprisingly, many syntheses of these mechanistic studies suggest that the re-
carpanone9 to Shair’s synthesis of lon-
indole alkaloids utilize L-tryptophan or action occurs by the initial formation of
githorone A,10 chemists have long ex-
its derivatives as the starting material.2 a N-iodoaniline. The electrophilic N-io-
ploited the hidden symmetry of natural
Although this strategy has been widely doaniline (N1) reacts with the enamine
products as an efficient strategy toward
successful, as shown by Movassaghi,3 (N2) of another monomer to form the
their synthesis. In this issue of Chem,
Baran,4 MacMillan,5 and others,6,7 C3-N10 linkage. Afterward, the result-
Jiang and co-workers contribute to
several indole alkaloids formed from ing iminium ion reacts with the pendant
this area with a remarkable domino
unsymmetric dimerization are not easily aniline (N3) to form the pyrroloindoline.
cyclization that exploits the latent sym-
accessible. In the case of asperazine (1; The unreacted enamine (N4) undergoes
metry of asperazine A for its assembly.
Scheme 1), the core of the natural prod- acid-mediated tautomerization to form
Moreover, their work highlights the ad-
uct possesses an unusual C3-N10 link- an iminium ion that undergoes cycliza-
vantages of monomer design in biomi-
age between the two indole moieties. tion by the secondary aniline (N1).
metic synthesis and raises several
Although the C3-N10 linkage was Ring opening and aromatization form
exciting questions. What other dimeric
previously accessed by indole-aniline the indole ring and generate the pro-
natural products can be accessed with
coupling, as reported by Baran,6 a gen- duct containing four different nitro-
the use of synthetic surrogates of na-
eral method of accessing this linkage gen-containing functional groups (4N
ture’s building blocks? Are there syn-
from direct dimerization of tryptophan dimer, 4; Scheme 1). This methodology
thetic substitutes for other amino
remains elusive. In this issue of Chem, enables the synthesis of the core of as-
acids? With reagent-controlled dimer-
Jiang and co-workers report a domino perazine in a single step.
ization used in combination with the
cyclization approach to accessing C3-
design of custom monomers, one can
N10 cross-linked compounds by utiliz- For the synthesis of (+)-asperazine, a
only envision the opportunities that
ing an unconventional 2N monomer nosyl-protected 2N monomer (2) was
await in the area of biomimetic total
(2) as a chemical surrogate for trypto- subjected to domino dimerization con-
synthesis.
phan.8 This strategy enabled an expe- ditions to form 4 in 78% yield on a
dient synthesis of (+)-asperazine (1) gram scale (Scheme 1). The dimeriza-
and analogs thereof (Scheme 1). tion occurred with endo selectivitity to
form a single diastereomer. The nosyl 1Departmentof Chemistry, Brandeis University,
Monomeric 2N building blocks (2) groups were removed with thiophenol Waltham, MA 02453, USA
were first subjected to different electro- and potassium carbonate to form the *Correspondence: [email protected]
philic iodine sources for dimerization. unprotected pyrroloindoline 5. At this https://doi.org/10.1016/j.chempr.2023.01.015

258 Chem 9, 258–265, February 9, 2023 ª 2023 Elsevier Inc.

Scheme 1. Synthesis of (+)-asperazine A

DECLARATION OF INTERESTS 3. Kim, J., Ashenhurst, J.A., and 7. Tadano, S., Sugimachi, Y., Sumimoto, M.,
Movassaghi, M. (2009). Total synthesis of Tsukamoto, S., and Ishikawa, H. (2016).
The authors declare no competing (+)-11,11’-dideoxyverticillin A. Science Collective synthesis and biological evaluation
324, 238–241. of tryptophan-based dimeric
interests. diketopiperazine alkaloids. Chem. Eur. J. 22,
4. Newhouse, T., and Baran, P.S. (2008). Total 1277–1291.
synthesis of (G)-psychotrimine. J. Am. Chem.
Soc. 130, 10886–10887. 8. Bai, L., Li, J., and Jiang, X. (2023). Total
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