Total Synthesis of (+)-Alsmaphorazine C and Formal Synthesis of (+)-Strictamine: A Photo-Fries Approach

Article abstract of DOI:10.1002/anie.202101752

A bioinspired photo-Fries/imine capture cascade reaction was developed in continuous-flow mode, which facilitated the rapid construction of a series of diversely functionalized 2,7-heterocycle-fused tetrahydrocarbazoles, the ubiquitous core structures emb

Full text of DOI:10.1002/anie.202101752

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Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 10603–10607
International Edition: doi.org/10.1002/anie.202101752
German Edition: doi.org/10.1002/ange.202101752
Natural Products
Total Synthesis of (+)-Alsmaphorazine C and Formal Synthesis of
+)-Strictamine: A Photo-Fries Approach
(
+
+
Beiling Gao, Fengjie Yao , Zhaodong Zhang , and Hanfeng Ding*
Abstract: A bioinspired photo-Fries/imine capture cascade
reaction was developed in continuous-flow mode, which
facilitated the rapid construction of a series of diversely
functionalized 2,7-heterocycle-fused tetrahydrocarbazoles, the
ubiquitous core structures embedded in strychnos and akuam-
miline-type monoterpene indole alkaloids. The synthetic utility
of this novel method has been preliminarily explored by the
first total synthesis of (+)-alsmaphorazine C and formal
synthesis of (+)-strictamine in a concise and efficient manner.
F
or decades, the monoterpene indole alkaloids continued to
attract the attention from medicinal chemists as high-profile
targets due to their broad spectrum of potential biological
[
1]
activities. Among them, an array of strychnos and akuammi-
line alkaloids possess an intricate common core structure,
namely the 2,7-heterocycle-fused tetrahydrocarbazole skele-
ton (1) bearing two adjacent quaternary stereocenters (Sche-
me 1a). Over the past fifteen years, aims to address the
synthetic challenges posed by these complex molecules have
resulted in numerous innovations in methodologies toward
[
2]
the core structure and stunning achievements in total
[
3]
synthesis. However, despite these elegant advances, the
concise and efficient cascade approaches for the direct
assembly of 1 bearing a functional group (N or O) at C16,
which is prevasive in a variety of akuammiline alkaloids such
as aspidophylline A (3), corymine (4) and echitamine (5),
[
2e,3n,u]
remain limited and in urgent demand.
Scheme 1. a) Representative monoterpene indole alkaloids and their
common core structure. b) Plausible biogenetic pathways of alsma-
phorazines C–E and evolution of the bioinspired photo-Fries/imine
capture strategy.
Alsmaphorazine C (6), an indole alkaloid possessing
a similar pentacyclic ring system but displaying opposite
absolute stereochemistry to minfiensine (2), was isolated by
Morita and co-workers from the leaves of Alstonia pneuma-
tophore (Apocynaceae). Our interests in this molecule arose
from the proposed biogenetic relationship with the other two
congeners alsmaphorazines D (7) and E (8), in which these
alkaloids were proposed to be derived from preakuammicine
[4]
has been known and used as efficient strategies for syn-
[
5]
thesis. However, whether both directions of the CO migra-
tion between N1 and C7 occur in Nature for the generation of
structural diversity are still not clear. To provide more insights
into the biogenetic pathways and offer a distinct bond-
disconnection strategy for the synthesis of natural alkaloids
(such as 6), we envisioned that a chemically reverse C3(N1!
C7) rearrangement would also be likely to proceed on the
(
9) as the same precursor via oxidative skeletal rearrange-
ments with the attachment of CO at C7 and N1, respectively
Scheme 1b). The chemical migration of CO from C7 to N1
(
readily available dihydropyrido[1,2-a]indolone (DHPI) 10
[
+]
[+]
[
*] B. Gao, F. Yao, Z. Zhang, Prof. Dr. H. Ding
Department of Chemistry, Zhejiang University
Hangzhou 310058 (China)
ꢀ1
(
BDE(
ca. 84.3 kcalmol ) under photo-Fries condi-
C(O)-N)
[6]
tions. Upon selective capture of the resultant imine in
indolenine intermediate 11 through a cascade sequence, the
E-mail: hfding@zju.edu.cn
[3q]
“
akuammiline ketone” 12 could be accessed in short steps.
Prof. Dr. H. Ding
Furthermore, by pre-installing the chiral center at C16 of 10
with a suitable substituent, a diastereoselective control might
be expected, which would circumvent the tough challenges
associated with a productive late-stage functionalization at
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101752.
[
3o,q,s]
this position in complex systems.
Herein, we describe our
efforts culminating in the first and asymmetric total synthesis
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10603

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of (+)-alsmaphorazine C, as well as a formal synthesis of
+)-strictamine based on a continuous-flow photo-Fries/
imine capture strategy.
(
Our syntheses commenced with exploration on the
feasibility of the photo-Fries/imine capture cascade. A series
of DHPIs with distinct types of protecting groups on N4
[
7]
atom were investigated (Table 1; see the Supporting Infor-
mation, Table S1 for a detailed conditional screening). In our
Table 1: Optimization of the photo-Fries/imine capture cascade.
[
c]
Entry
R
Solvent
MeOH
Product (Yield)
[
[
[
[
a]
a]
b]
b]
1
2
3
4
H, Me or Bn
CO Me
CO Me
CO Me
13a–c (21–65%)
Et O
12d (25%), 14d (38%)
12d (54%), 14d (20%)
12d (77%), 14d (<5%)
2
2
Et O
2
2
t-BuOH
2
[a] Batch conditions: 10a–d (0.5 mmol, c=0.1 M), rt, 6 h. [b] Flow
conditions: 10d (c=0.1 M), rt, residence time 20 min. [c] Yields of
isolated product.
initial trials, by irradiating a solution of 10a–c in quartz tube
with a 300 W high pressure mercury lamp (maximum at
Scheme 2. Scope of the continuous-flow photo-Fries/imine capture
cascade. Conditions: 10i–aj (c=0.1 M in t-BuOH), hn, rt, residence
time 15–60 min.
3
65 nm) at room temperature for 6 h, an unexpected intra-
molecular ring-enlargement reaction occurred exclusively to
[
8]
give lactams 13a–c, respectively (entry 1). The above out-
comes implied that once indolenine intermediates 11a–c were
formed through photo-Fries rearrangement, their C3-ketone
would be more susceptible to be attacked by the alkylamine
nucleophiles. Therefore, we conceived that the replacement
fused product 12z was obtained with slightly reduced
efficiency, probably owing to the lack of the Thorpe–Ingold
effect during the photo-rearrangement step. Furthermore, the
tryptophol derivative 10aa also afforded 12aa in 56% yield,
along with lactone 13aa as a minor product. However, indole-
3-acetic acid 10ab gave merely cycloheptanone 13ab, which
was originated from a photo-induced radical decarboxyla-
with an electron-withdrawing group, such as CO Me, Boc, Ac,
2
Ts, or o-Ns (10d–h, respectively), on N4 atom by decreasing
its nucleophilicity should offer an opportunity to achieve the
reversal of site-selectivity. Indeed, the CO Me group turned
2
[
13]
out to be a promising choice, albeit providing the anticipated
tion. More importantly, DHPIs bearing substitution at C6,
C14, and C16 were found compatible as well, again resulting
in good yields and satisfactory diastereoselectivities (45–
65%, up to > 20:1 d.r.; 12ac–aj). The favored formation of
the major diastereomers in the cases of 12ag–aj probably
arises from minimization of the 1,3-diaxial interactions in
a six-membered chairlike transition state (TS-1 vs. TS-2).
Encouraged by these outcomes, we turned to the asym-
metric total synthesis of (+)-alsmaphorazine C (Scheme 3).
Amidation of 7-methoxytryptamine (15) followed by Friedel–
Crafts acylation with methyl succinyl chloride (16) through
optimizing a procedure from Tokuyama and co-workers
successfully afforded keto-acid 17 in 43% yield over two
product 12d in 25% yield together with substantial gener-
[9,10]
ation of 14d (entry 2).
To reduce the amount of latter side
product by competitively accelerating the desired reaction,
we designed and assembled a continuous-flow photochemi-
[
11]
cal reactor based on the methods developed by Booker-
[
12a]
[12b]
Milburn
and Li
(for the setup, see the Supporting
Information). To our pleasure, performing the reaction under
the same conditions as entry 2 but in continuous-flow mode
with a residence time of 20 min afforded 12d in a dramatically
improved yield (entry 3). Further switching the solvent to t-
BuOH led to effective inhibition of 14d and delivering 12d in
7
7% yield (entry 4).
[
14]
With optimized conditions in hand, the generality and
steps. After conversion into 18, a Noyori–Ikariya catalyst
19 (2 mol%) promoted asymmetric reduction gave alcohol 20
scope of the continuous-flow photo-Fries/imine capture
cascade was explored (Scheme 2). Various DHPIs with
different electronic and steric parameters on the phenyl
ring, including 9-, 10-, and 11-substituted, were converted into
the corresponding products in moderate to good yields (40–
[
15]
with excellent efficiency and enantioselectivity. By com-
parison, the much lower yield and poorer ee value were
observed when catalytic amount of (R)-2-methyl-CBS-oxa-
[
16]
zaborolidine was used. Delightfully, under the optimized
8
0%; 12i–x). Compared with 12h and 12y, the cycloheptane-
continuous-flow conditions, irradiating a solution of 20
1
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Scheme 3. Total synthesis of (+)-alsmaphorazine C (6). 4-DMAP=N,N-dimethylpyridin-4-amine, EDC·HCl=1-(3-dimethyl aminopropyl)-3-ethyl-
carbodiimide hydrochloride, NMO=N-methylmorpholine N-oxide, PDC=pyridinium dichromate, TosMIC=4-toluenesulfonylmethyl isocyanide,
TPAP=tetrapropylammonium perruthenate.
smoothly produced tetracyclic ketone 21 (> 99% ee) and its
Upon hydrolysis, a labile acid was obtained, which immedi-
ately underwent methylation to afford ester 29 in 70% yield
over two steps. The substrate-controlled stereoselective
[9]
C2,C7-diepimer (99% ee) as a 3.7:1 mixture in a combined
yield of 70%. This process can be scaled up by using a non-
commercial continuous-flow reactor, in which a flow rate of
1
9,20
hydroboration of the trisubstituted D -olefin occurred
well at 508C. Finally, a chemoselective oxidation was realized
by PDC to furnish (+)-alsmaphorazine C (6) in 60% yield
over two steps, whose absolute stereochemistry was deter-
mined unambiguously through X-ray crystallographic analy-
ꢀ
1
0
.75 mLmin afforded ca. 1.0 g of 21 every hour (for details,
see the Supporting Information). Notably, by exposure to
BF ·Et O, the undesired C2,C7-diepi-21 could be recycled by
3
2
conversion back to 20 in 85% yield without decrease in
enantioselectivity. After N1-methylation and oxidation state
[
9]
sis (ORTEP drawing, Scheme 3).
adjustment, the removal of the CO Me group took place with
To further demonstrate synthetic utility of the continuous-
flow photo-Fries/imine capture cascade reaction, the formal
2
the aid of C16-ketone under mild conditions through the
intermediacy of carbamate 22, delivering secondary amine 23
in 63% yield over two steps. Alkylation of 23 with (E)-1-
bromo-2-iodobut-2-ene (24) provided vinyl iodide 25, which
[22]
synthesis of akuammiline alkaloid (+)-strictamine (30) was
also pursued (Scheme 4). Structurally, this molecule contains
a unique methanoquinolizidine cage (6/6/6 ring system)
decorated with four stereocenters. Combined with its signifi-
cant NF-kB inhibitory effects, (+)-30 serves as an excellent
testing ground for novel synthetic methods and tactics. A
substantial progress has been made over the past five
[17]
underwent an enolate mediated cross-coupling to afford
pentacycle 26 on gram scale in 69% yield over two steps. Slow
addition of t-BuOK to maintain its low concentration is
critical to the reaction, otherwise a quick decomposition of 26
would be observed. The ensuing subjection to TosMIC
[3t,23]
years.
closed by the groups of Garg,
Notably, five asymmetric approaches were dis-
[18]
[23a,i]
[23e]
[23f,g,j]
resulted in a Van Leusen homologation and gave rise to
7 in 79% yield (12:1 d.r. at C16). However, subsequent
Snyder
and Qin,
2
respectively. Our synthesis began with the preparation of (ꢀ)-
12ag from commercially available imine 31. After subjection
of the latter to a one-pot process involving Boc protection,
hydrolysis of the nitrile was problematic. Attempts to perform
the nitrile hydration under various conditions such as alkali
I [19a]
II
[19b]
[24]
hydroxide, alkoxide, Rh
or Cu -mediated
and in the
saponification and enamine hydrolysis, an intramolecular
[20]
presence of Ghaffar-Parkins catalyst either gave a rather
stable lactone or caused decomposition of the starting
material. On the basis of exhaustive experimentation, we
found by treatment of 27 with RuCl ·nH O, K S O and KOH
amidation gave 32 in 78% yield over two steps.
Subsequent Noyori reduction with catalytic ent-19
afforded (+)-10ag in 92% yield (> 99% ee), which then
underwent a continuous-flow photo-Fries/imine capture cas-
cade to deliver (ꢀ)-12ag (> 99% ee) in 52% yield. Dis-
appointingly, attempts of the N4(C2!C16) rearrangement on
(ꢀ)-12ag or its acetate failed to provide any desired
3
2
2
2
8
(
1.0 M aq.) to produce potassium ruthenate (K RuO ) in
2 4
[21]
situ,
the C3-ketone was formed in advance and then
engaged in the addition of the epimerized nitrile to yield 28.
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“
National Young Top-Notch Talent Support Program”. We
thank Prof. Pengfei Li (FIST, Xiꢀan Jiaotong University) for
helpful suggestions on the continuous-flow setup.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cascade reactions · monoterpene indole alkaloids ·
natural products · total synthesis
[
1] a) Atta-ur-Rahman, A. Basha, Indole Alkaloids, Harwood
Academic Publishers, Amsterdam, 1999; b) G. W. Gribble in
Second Supplements to the 2nd ed. of Roddꢀs Chemistry of
Carbon Compounds, Vol. 4 (Ed.: M. Sainsbury), Elsevier,
Amsterdam, 1991, pp. 69 – 164; c) U. Anthoni, C. Christo-
phersen, P. H. Nielsen in Alkaloids: Chemical and Biological
Perspecties, Vol. 13 (Ed.: S. W. Pelletier), Elsevier, Amsterdam,
1999, pp. 163 – 236; d) V. Saraswathi, V. Mathuram, S. Subrama-
nian, S. Govindasamy, Cancer Biochem. Biophys. 1999, 17, 79;
e) A. Ramꢁrez, S. Garcꢁa-Rubio, Curr. Med. Chem. 2003, 10,
1891.
Scheme 4. Formal synthesis of (+)-strictamine (30). cod=1,5-cyclo-
octadiene, KHMDS=potassium bis(trimethylsilyl)amide, LDA=
lithium diisopropylamide, Tf=trifluoromethanesulfonyl, TFA=tri-
fluoroacetic acid.
[2] a) Y. Liu, W. Xu, X. Wang, Org. Lett. 2010, 12, 1448; b) Q. Li, G.
Li, S. Ma, P. Feng, Y. Shi, Org. Lett. 2013, 15, 2601; c) Z.-W.
Zhang, J. Yang, Tetrahedron Lett. 2014, 55, 761; d) Y. Yu, J. Li, L.
Jiang, J.-R. Zhang, L. Zu, Angew. Chem. Int. Ed. 2017, 56, 9217;
Angew. Chem. 2017, 129, 9345; e) Q. Wang, J. Hu, N. Zheng, Org.
Lett. 2019, 21, 614; f) J. A. Rossi-Ashton, A. K. Clarke, R. J. K.
Taylor, W. P. Unsworth, Org. Lett. 2020, 22, 1175; g) K. Hosoya,
K. Iida, M. Odagi, K. Nagasawa, J. Org. Chem. 2020, 85, 11980.
3] Syntheses of minfiensine: a) A. B. Dounay, L. E. Overman,
A. D. Wrobleski, J. Am. Chem. Soc. 2005, 127, 10186; b) A. B.
Dounay, P. G. Humphreys, L. E. Overman, A. D. Wrobleski, J.
Am. Chem. Soc. 2008, 130, 5368; c) L. Shen, M. Zhang, Y. Wu, Y.
Qin, Angew. Chem. Int. Ed. 2008, 47, 3618; Angew. Chem. 2008,
120, 3674; d) S. B. Jones, B. Simmons, D. W. C. MacMillan, J.
Am. Chem. Soc. 2009, 131, 13606; e) G. Li, A. Padwa, Org. Lett.
[
25]
products.
As an alternative solution, (ꢀ)-12ag was first
transformed into enoate 34 through a three-step sequence
including aminal formation, vinyl triflation, and palladium-
catalyzed CO insertion. At this point, a variety of bases such
as DBU, DABCO, TBAF, LDA, NaH, K CO , t-BuOK and
[
2
3
KHMDS were evaluated to trigger the ring-opening elimi-
nation of 34 and the following 1,2-N4 rearrangement via the
[23f]
intermediacy of 35.
Fortunately, KHMDS turned out to be
effective, furnishing indolenine 36 in 55% yield on gram scale.
The spectroscopic data of 36 are fully consisted with those
2
2
011, 13, 3767; f) P. Liu, J. Wang, J. Zhang, F. G. Qiu, Org. Lett.
011, 13, 6426; g) Y. Yu, G. Li, L. Jiang, L. Zu, Angew. Chem. Int.
[23b]
reported by Zhu,
thus completing a concise formal syn-
Ed. 2015, 54, 12627; Angew. Chem. 2015, 127, 12818; h) W. Ji, L.
Yao, X. Liao, Org. Lett. 2016, 18, 628; i) C. A. Leverett, G. Li, S.
France, A. Padwa, J. Org. Chem. 2016, 81, 10193; j) Z.-X. Zhang,
S.-C. Chen, L. Jiao, Angew. Chem. Int. Ed. 2016, 55, 8090;
Angew. Chem. 2016, 128, 8222; k) K. Du, H. Yang, P. Guo, L.
Feng, G. Xu, Q. Zhou, L. W. Chung, W. Tang, Chem. Sci. 2017, 8,
thesis of (+)-strictamine (30).
In conclusion, we have described a novel continuous-flow
photo-Fries/imine capture cascade for the assembly of
diversely functionalized 2,7-heterocycle-fused tetrahydrocar-
bazoles, the core structures found in a number of strychnos
and akuammiline-type monoterpene indole alkaloids. As
a preliminary utilization of this efficient transformation, the
first total synthesis of (+)-alsmaphorazine C and formal
synthesis of (+)-strictamine have been achieved with good
enantio- and diastereoselective control. Of note, our synthetic
efforts offered new insight into the biogenetic pathways of
monoterpene indole alkaloids. In view of the high efficiency
in building structural complexity, we anticipate that the
described methodologies and strategies will find wide appli-
cation in the syntheses of other relavent natural products.
6247; l) C. Zhang, W. Ji, Y. A. Liu, C. Song, X. Liao, J. Nat. Prod.
2018, 81, 1065; syntheses of aspidophylline A: m) L. Zu, B. W.
Boal, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 8877; n) M. Teng,
W. Zi, D. Ma, Angew. Chem. Int. Ed. 2014, 53, 1814; Angew.
Chem. 2014, 126, 1845; o) W. Ren, Q. Wang, J. Zhu, Angew.
Chem. Int. Ed. 2014, 53, 1818; Angew. Chem. 2014, 126, 1849;
p) J. Moreno, E. Picazo, L. A. Morrill, J. M. Smith, N. K. Garg, J.
Am. Chem. Soc. 2016, 138, 1162; q) S.-Z. Jiang, X.-Y. Zeng, X.
Liang, T. Lei, K. Wei, Y.-R. Yang, Angew. Chem. Int. Ed. 2016,
55, 4044; Angew. Chem. 2016, 128, 4112; r) T. Wang, X. Duan, H.
Zhao, S. Zhai, C. Tao, H. Wang, Y. Li, B. Cheng, H. Zhai, Org.
Lett. 2017, 19, 1650; syntheses of corymine and deformylcor-
ymine: s) B. Zhang, X. Wang, C. Cheng, D. Sun, C. Li, Angew.
Chem. Int. Ed. 2017, 56, 7484; Angew. Chem. 2017, 129, 7592;
t) X. Xie, B. Wei, G. Li, L. Zu, Org. Lett. 2017, 19, 5430; u) B.
Zhang, X. Wang, C. Li, J. Am. Chem. Soc. 2020, 142, 3269;
synthesis of echitamine: v) X. Zhang, B. N. Kakde, R. Guo, S.
Yadav, Y. Gu, A. Li, Angew. Chem. Int. Ed. 2019, 58, 6053;
Angew. Chem. 2019, 131, 6114; syntheses of vincorine: w) M.
Acknowledgements
Financial support was provided by the National Natural
Science Foundation of China (21871230, 21622205) and the
1
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Zhang, X. Huang, L. Shen, Y. Qin, J. Am. Chem. Soc. 2009, 131,
013; x) W. Zi, W. Xie, D. Ma, J. Am. Chem. Soc. 2012, 134, 9126;
y) B. D. Horning, D. W. C. MacMillan, J. Am. Chem. Soc. 2013,
35, 6442; syntheses of picrinine: z) J. M. Smith, J. Moreno, B. W.
Boal, N. K. Garg, J. Am. Chem. Soc. 2014, 136, 4504; aa) J. M.
Smith, J. Moreno, B. W. Boal, N. K. Garg, J. Org. Chem. 2015, 80,
c) M. B. Plutschack, B. Pieber, K. Gilmore, O. H. Seeberger,
6
Chem. Rev. 2017, 117, 11796; d) M. Di Filippo, C. Bracken, M.
Baumann, Molecules 2020, 25, 356; e) T. H. Rehm, Chem. Eur. J.
2020, 26, 16952; for recent application in natural product
synthesis, see: f) Y. Que, H. Shao, H. He, S. Gao, Angew.
Chem. Int. Ed. 2020, 59, 7444; Angew. Chem. 2020, 132, 7514;
g) D. Jiang, K. Xin, B. Yang, Y. Chen, Q. Zhang, H. He, S. Gao,
CCS Chem. 2020, 2, 800.
1
8954; syntheses of aspidodasycarpine and lonicerine: ab) Y. Li,
S. Zhu, J. Li, A. Li, J. Am. Chem. Soc. 2016, 138, 3982; syntheses
of scholarisine K and alstolactine A: ac) D. Wang, M. Hou, Y. Ji,
S. Gao, Org. Lett. 2017, 19, 1922.
[12] a) B. D. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B.
Berry, K. I. Booker-Milburn, J. Org. Chem. 2005, 70, 7558; b) K.
Chen, S. Zhang, P. He, P. Li, Chem. Sci. 2016, 7, 3676.
[13] For a study on the photooxidative decarboxylation of indole-3-
acetic acid, see: Y. Maki, I. Oyabu, S. Ohara, M. Sako, Y. Kitade,
K. Hirota, Chem. Pharm. Bull. 1989, 37, 3239.
[
4] For isolation, see: a) K. Koyama, Y. Hirasawa, A. E. Nugroho, T.
Kaneda, T. C. Hoe, K.-L. Chan, H. Morita, Tetrahedron 2012, 68,
1
502; for a total synthesis of alsmaphorazine D, see: b) C. Zhu,
Z. Liu, G. Chen, K. Zhang, H. Ding, Angew. Chem. Int. Ed. 2015,
4, 879; Angew. Chem. 2015, 127, 893.
5] a) H.-J. Teuber, D. Cornelius, E. Worbs, Tetrahedron Lett. 1964,
, 331; b) S. D. Edmondson, A. Mastracchio, E. R. Parmee, Org.
5
[14] H. Tokuyama, K. Okano, H. Fujiwara, T. Noji, T. Fukuyama,
Chem. Asian J. 2011, 6, 560.
[
5
[15] ꢆ. Dilek, S. Patir, E. Ertꢃrk, Synlett 2019, 30, 69.
[16] a) M. C. Hillier, J.-F. Marcoux, D. Zhao, E. J. J. Grabowski, A. E.
McKeown, R. D. Tillyer, J. Org. Chem. 2005, 70, 8385; b) G. Liu,
C. S. Lancefield, M. M. Lorion, A. M. Z. Slawin, N. J. Westwood,
Synthesis 2014, 46, 2808.
[17] a) H. Cao, J. Yu, X. Z. Wearing, C. Zhang, X. Liu, J. Deschamps,
J. M. Cook, Tetrahedron Lett. 2003, 44, 8013; b) C. R. Edwankar,
R. V. Edwankar, J. R. Deschamps, J. M. Cook, Angew. Chem.
Int. Ed. 2012, 51, 11762; Angew. Chem. 2012, 124, 11932.
[18] O. H. Oldenziel, D. van Leusen, A. M. van Leusen, J. Org.
Chem. 1977, 42, 3114.
[19] a) J. Lee, M. Kim, S. Chang, H.-Y. Lee, Org. Lett. 2009, 11, 5598;
b) P. Marcꢄ, J. Lynch, A. J. Blacker, J. M. J. Williams, Chem.
Commun. 2016, 52, 1436.
[20] T. Ghaffar, A. W. Parkins, Tetrahedron Lett. 1995, 36, 8657.
[21] a) E. J. Corey, A. G. Myers, J. Am. Chem. Soc. 1985, 107, 5574;
b) L. J. Nannini, S. J. Nemat, E. M. Carreira, Angew. Chem. Int.
Ed. 2018, 57, 823; Angew. Chem. 2018, 130, 831.
Lett. 2000, 2, 1109; c) N. Voꢂte, D. Philp, A. M. Z. Slawin, N. J.
Westwood, Org. Biomol. Chem. 2010, 8, 442; d) Z. Dong, X.-W.
Zhang, W. Li, Z.-M. Li, W.-Y. Wang, Y. Zhang, W. Liu, W.-B. Liu,
Org. Lett. 2019, 21, 1082; e) W. Li, Z. Dong, Y. Zhang, Z. Zeng,
M. Usman, W.-B. Liu, J. Org. Chem. 2019, 84, 7995.
[
6] Computational level: M06-2X/def2-TZVPP//M06-2X/def2-
TZVP. For photochemical rearrangements of indoles, see:
a) M. Somei, M. Natsume, Tetrahedron Lett. 1973, 14, 2451;
b) H. Takechi, M. Machida, Y. Kanaoka, Chem. Pharm. Bull.
1
988, 36, 2853; c) M. A. Mirande in Organic Photochemistry and
Photobiology (Eds.: W. Horspool, F. Lenci), CRC, Boca Raton,
003, chap. 42, pp. 1 – 11; d) A. Weedon in Advances in Photo-
2
chemistry, Vol. 22 (Eds.: D. C. Neckers, D. H. Volman, G.
von Bꢃnau), Wiley, New York, 1997, pp. 229 – 277.
[
7] DHPIs 10a – h were readily prepared within two steps from
commercially available tryptamines according to the protocol by
Bach and co-workers: L. Jiao, E. Herdtweck, T. Bach, J. Am.
Chem. Soc. 2012, 134, 14563.
[22] H. K. Schnoes, K. Biemann, J. Mokry, I. Kompis, A. Chatterjee,
G. Ganguli, J. Org. Chem. 1966, 31, 1641.
[
8] a) Y. Ban, K. Yoshida, J. Goto, T. Oishi, J. Am. Chem. Soc. 1981,
1
03, 6990; b) Y. Ban, K. Yoshida, J. Goto, T. Oishi, E. Takeda,
[23] a) Ref. [3p]; b) W. Ren, Q. Wang, J. Zhu, Angew. Chem. Int. Ed.
2016, 55, 3500; Angew. Chem. 2016, 128, 3561; c) D. Nishiyama,
A. Ohara, H. Chiba, H. Kumagai, S. Oishi, N. Fujii, H. Ohno,
Org. Lett. 2016, 18, 1670; d) R. Eckermann, M. Breunig, T.
Gaich, Chem. Commun. 2016, 52, 11363; e) M. W. Smith, Z.
Zhou, A. X. Gao, T. Shimbayashi, S. A. Snyder, Org. Lett. 2017,
19, 1004; f) T. Xiao, Z.-T. Chen, L.-F. Deng, D. Zhang, X.-Y. Liu,
H. Song, Y. Qin, Chem. Commun. 2017, 53, 12665; g) Z.-T. Chen,
T. Xiao, P. Tang, D. Zhang, Y. Qin, Tetrahedron 2018, 74, 1129;
h) K. Sato, N. Takanashi, N. Kogure, M. Kitajima, H. Takayama,
Heterocycles 2018, 97, 365; i) E. Picazo, L. A. Morrill, R. B.
Susick, J. Moreno, J. M. Smith, N. K. Garg, J. Am. Chem. Soc.
2018, 140, 6483; j) W. Li, Z. Chen, D. Yu, X. Peng, G. Wen, S.
Wang, F. Xue, X.-Y. Liu, Y. Qin, Angew. Chem. Int. Ed. 2019, 58,
Tetrahedron 1983, 39, 3657.
[
9] Deposition Numbers 2058581 (for 12d), 2058554 (for 14d),
2
058575 (for C2,C7-diepi-21), and 2058577 (for (+)-6) contain
the supplementary crystallographic data for this paper. These
data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[
10] It was found that 14d could be obtained from 12d in 86% yield
under the same photo-conditions. The conversion presumably
proceeded through a Norrish-type I cleavage of the C3-C7 bond,
followed by [1,3]-H shift and radical-radical coupling between
C3 and N1.
6059; Angew. Chem. 2019, 131, 6120.
[
[
24] Atta-ur-Rahman, J. Chem. Soc. Perkin Trans. 1 1972, 736.
25] a) G. Massiot, C. Lavaud, J. Vercauteren, L. Le Men-Olivier, J.
Lꢄvy, J. Guilhem, C. Pascard, Helv. Chim. Acta 1983, 66, 2414;
b) H. Ishikawa, M. Kitajima, H. Takayama, Heterocycles 2004,
63, 2597.
[
11] For selected reviews on flow photochemistry, see: a) J. P.
Knowles, L. D. Elliott, K. I. Booker-Milburn, Beilstein J. Org.
Chem. 2012, 8, 2025; b) D. Cambiꢄ, C. Bottecchia, N. J. W.
Straathof, V. Hessel, T. Noꢅl, Chem. Rev. 2016, 116, 10276;
Manuscript received: February 4, 2021
Accepted manuscript online: March 4, 2021
Version of record online: April 6, 2021
Angew. Chem. Int. Ed. 2021, 60, 10603 –10607
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10607