Mimicking the Main Events of the Biosynthesis of Drimentines: Synthesis of Δ8′-Isodrimentine A and Related Compounds

Article abstract of DOI:10.1002/ejoc.201600444

Drimentines are a family of tetracyclic alkaloids biosynthetically originating from the condensation of sesquiterpene units onto cyclic dipeptides. A straightforward assembly of the fused “pyrroloindoline–diketopiperazine” core of drimentines is described herein and used for the synthesis of Δ^8′-isodrimentine A. The strategy involves a bio-inspired indole dearomatization of a tryptophan-containing cyclodipeptide by a drimane-type decaline followed by the intramolecular trapping of the resulting indolenine intermediate in an uninterrupted reactive sequence. The starting diketopiperazine was prepared by classical peptidic coupling and the drimane-type decaline from (+)-sclareolide. A fully biomimetic approach with a linear sesquiterpene unit is also reported and led to farnesylated pyrroloindoline–diketopiperazines, which correspond to the proposed biosynthetic precursors of both drimentines A and D. The end product Δ^8′-isodrimentine A and its congeners were evaluated in vitro for their cytotoxic activities against three human tumor cell lines.

Full text of DOI:10.1002/ejoc.201600444

DOI: 10.1002/ejoc.201600444
Full Paper
Bio-Inspired Synthesis
Mimicking the Main Events of the Biosynthesis of Drimentines:
Synthesis of Δ8′-Isodrimentine A and Related Compounds
Adam Skiredj,[a] Mehdi A. Beniddir,[a] Laurent Evanno,*[a] and Erwan Poupon*[a]
Abstract: Drimentines are a family of tetracyclic alkaloids bio- ive sequence. The starting diketopiperazine was prepared by
synthetically originating from the condensation of sesquiterp- classical peptidic coupling and the drimane-type decaline from
ene units onto cyclic dipeptides. A straightforward assembly of (+)-sclareolide. A fully biomimetic approach with a linear ses-
the fused “pyrroloindoline–diketopiperazine” core of drimen- quiterpene unit is also reported and led to farnesylated pyrrol-
tines is described herein and used for the synthesis of Δ8′-iso- oindoline–diketopiperazines, which correspond to the pro-
drimentine A. The strategy involves a bio-inspired indole dearo- posed biosynthetic precursors of both drimentines A and D.
matization of a tryptophan-containing cyclodipeptide by a dri- The end product Δ8′-isodrimentine A and its congeners were
mane-type decaline followed by the intramolecular trapping of evaluated in vitro for their cytotoxic activities against three hu-
the resulting indolenine intermediate in an uninterrupted react- man tumor cell lines.
Introduction
by the trapping of the indoline nitrogen atom (pathway b) af-
fording drimentine A (1) or D (7), respectively. Hence, we de-
cided to mimic the indole dearomatization/intramolecular
indolenine trapping sequence. Besides biosynthetic considera-
tions, this approach appeared to us to be straightforward lead-
Drimentines are a family of pyrroloindoline–diketopiperazine
alkaloids isolated from Actinomycetes strains[1,2] showing anti-
biotic activities[1] as well as moderate cytotoxicities.[2] Among
the substantial array of prenyl-modified peptides,[3] to date dri-
mentines and the co-isolated indotertines are the sole exam-
ples of pyrroloindoline–diketopiperazines bearing a sesquiter-
pene moiety (Scheme 1).[4] En route to this class of alkaloids,
Joullié et al. reported a seminal total synthesis of roquefort-
ine C.[5] More recently, Li et al. have reported a collective syn-
thesis of drimentines A (1), G, F and indotertine A (2) by a
multistep strategy resting on the radical conjugate addition of
a bromoindoline derivative onto an appropriate Michael ac-
ceptor.[6] Given our long-lasting interest for the biomimetic syn-
thesis[7] of natural products, we have been prompted to take
advantage of a short and straightforward bio-inspired approach
towards this group of alkaloids. When considering their biosyn-
thetic origin (Scheme 1), the enzymatic transfer of a farnesyl
unit (3) on a tryptophan-containing diketopiperazine (4) is likely
to be responsible for the formation of their polycyclic central
skeleton. Indeed, this would generate a transient indolenine in-
termediate (5) subsequently trapped by intramolecular nucleo-
philic attack forming thereby the final diketopiperazino–pyrr-
oloindoline core (6, which could be considered as a “protodri-
mentine”) of drimentines (1 herein).[8] As a final step, an enzy-
matic cationic cascade cyclization leading to the decaline ring
system may end either by a ꢀ-elimination (pathway a), either
[a] BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay,
92290, Châtenay-Malabry, France
E-mail: laurent.evanno@u-psud.fr
erwan.poupon@u-psud.fr
www.biocis.u-psud.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600444.
Scheme 1. Biosynthesis of drimentines A (1) and D (7).
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ing promptly to accessible precursors from the required trypto-
phan-containing dipeptides and electrophilic C15 units. In this
work, we evaluated the introductions of two distinct C15 units:
(i) a farnesyl addition by allylation followed by a cascade cycli-
zation in a completely bio-inspired approach; (ii) a preformed
drimane-type decaline obtained from sclareolide providing di-
rectly the targeted scaffold.
Results and Discussion
Prior to any study of the envisioned reaction sequences, we
prepared unprotected cyclo-Leu-Trp (4) by peptidic coupling in
two steps and good yields.[9] From there, electrophilic C15 do-
nors were needed, and appropriate bromide derivatives had to
be prepared. At first, farnesylation was chosen to initiate the
study with the aim of achieving a fully biomimetic synthesis of
drimentines A (1) and D (7) from protodrimentine (6).
For this purpose, after the sequential exposure of 4 to potas-
sium tert-butoxide and triethylborane (allowing the formation
of an indolyltriethylborate species), farnesyl bromide (8)[10]
served as the electrophile (Scheme 2).[11–13] Under these condi-
tions, complexation of the indole anion is supposed to enhance
the C-3 nucleophilicity by electron enrichment, therefore allow-
ing the C-3 quaternization. The direct trapping of the transitory
Scheme 2. Bio-inspired assembly of “protodrimentine” (6). Reaction condi-
tions: tBuOK, –78 °C, BEt3, then 8 (1.1 equiv.), 50 °C, 12 h, 63 % and after
preparative HPLC (6: 25 %; 9: 25 %).
indolenine by the appended diketopiperazine moiety allowed Resolution by preparative HPLC afforded the two diastereomers
the formation of the tetracyclic ring system of drimentines just 14 and 15 (Δ8′-isodrimentine A) in 14 % isolated yield, each,
as in the biosynthetic proposal. Indeed, under stoichiometric alongside with minute amounts (2 %) of 16 originating from a
conditions the reaction afforded a 1:1 diastereomeric mixture Wagner–Meerwein rearrangement of 15.[22] Owing to its high
of 6/9 in 63 % yield. Further resolution by preparative HPLC structural similarity with 1 and 7, compound 15 represented
gave ꢀ-adduct 6 and α-adduct 9 both in 25 % isolated yield, the opportunity to reach challenging alkaloids of the series.
each.[14] Given the upstream position of ꢀ-adduct 6 in the pro- Indeed, among other possibilities, a supplementary N-6/C-8′
posed biosynthetic pathway of drimentines, numerous at- ring closure after the formation of a C-8′ carbocation could lead
tempts of farnesyl cyclization were carried out in order to reach to drimentine D (7). However, all the experiments carried out
the final drimentine skeleton or even drimentines themselves, to this end led to decomposition of the framework (Table 1).
but without success (Table 1).[15,16]
Compounds 6, 9, 14, 15 and 16 were evaluated in vitro for
The successful synthesis of protodrimentine (6), prompted us their cytotoxic activities against three human tumor cell lines:
to pursue the study with preformed C15 drimane-type decalines colon cancer (HCT-116), lung carcinoma (A549) and myeloge-
(Scheme 3). After the synthesis of the required decalines (i.e., nous leukemia (K562). The results revealed that the non-cy-
with two possible leaving groups: iodide for 10[6,17] and mesyl- clized compounds 6, 9 and α-adduct 14 were inactive (IC50
>
ate for 11[18,19]) in several steps from sclareolide (12),[20] the 100 μ
), while compounds 15 and 16 showed moderate cyto-
M
previously validated conditions (tBuOK, BEt3) proved to be inef- toxic activities against HCT-116 and K562 cell lines (Table 2).
fective with such homoallylic electrophiles. Nonetheless, the re- Those results indicate that both isomers 15 and 16 are active
course to the very similar allylic drimane 13[21] restored the in the same range than natural drimentines.[2] Overall, it could
efficiency of the conditions. Starting from equimolar amounts be postulated that the presence of a decaline group on the
of 4 and 13, the key alkylation provided a 1:1 α/ꢀ-diastereo- ꢀ-position of the tetracyclic alkaloid framework is critical for
meric mixture of the targeted drimentine core in 35 % yield.[14] achieving tumor-cell growth-inhibitory activity.
Table 1. Cyclization attempts of 6 and 15 toward drimentine A/D (2/7).
Substrate
Conditions
Solvent
Temp.
Observations
6
6
6
(R)-BINOL, SnCl4
CH2Cl2
toluene
CH3NO2
CH3NO2
toluene
CH2Cl2
0 °C
50 °C
–20 °C
–25 °C
r.t.
degradation
no reaction
PTSA[a]
[16]
H2SO4
partially cyclised compounds (no exo-methylene group)
6
Et2SBr·SbCl5Br[16]
PTSA
C-9 bromination
degradation
degradation
degradation
15
15
15
Amberlyst®-15
BF3·OEt2
r.t.
0 °C
CH2Cl2
[a] PTSA = p-toluenesulfonic acid.
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form and [D6]DMSO as solvents. The solvent signals were used as
references. Multiplicities are described by the following abbrevia-
tions: s = singlet, d = doublet, t = triplet, q = quadruplet, m =
multiplet, br. = broad. HR ESI MS experiments were conducted with
a Thermoquest TLM LCQ Deca ion-trap spectrometer. XBridge® C18
column (150 × 19 mm i.d.; 5 μm) was used for preparative HPLC
separations using a Waters Delta Prep apparatus equipped with a
binary pump (Waters 2525) and a UV/Vis diode array detector (190–
600 nm; Waters 2996).
General Procedure for the Alkylation of cyclo-Leu-Trp (4): To a
pre-cooled solution (0 °C) of alcohol (farnesol or driman-8-en-11-ol,
163 mg, 0.74 mmol) in diethyl ether (5 mL), PBr3 (100 μL, 1.1 mmol)
was added. After 1 h of stirring, the reaction mixture was washed
with water (5 mL). The organic layer was dried with Na2SO4 and
concentrated under reduced pressure. The corresponding allyl
bromide was used without further purification immediately after its
synthesis. To a pre-cooled solution (–78 °C) of cyclo-Leu-Trp
(200 mg, 0.67 mol) in dioxane (3 mL), a 1
M solution of tBuOK in
THF (670 μL, 0.67 mmol) was added. After 10 min of stirring, a 1
M
solution of triethylborane in hexane (670 μL, 0.67 mmol) was added.
After 10 min of stirring, the appropriate, freshly prepared allyl brom-
ide (0.74 mol) in solution in dioxane (2 mL) was added, and the
reaction mixture was heated to 50 °C for 16 h. After cooling, the
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with water (5 mL). The organic layer was dried with Na2SO4 and
concentrated under reduced pressure. From farnesol: purification
by flash chromatography on silica gel (eluent: dichloromethane/
methanol, 9:1) affordes a mixture of 6/9 (212 mg, 63 %). Resolution
by preparative HPLC (isocratic 85 % MeOH in H2O at 42 mL/min)
afforded 9 (tr = 13.1 min; 85 mg, 25 %) and 6 (tr = 14.6 min; 85 mg,
25 %). From driman-8-en-11-ol: purification by flash chromatogra-
phy on silica gel (eluent: dichloromethane/methanol, 9:1) afforded
mixture of 14/15/16 (118 mg, 35 %). Resolution by preparative
HPLC (isocratic 85 % MeOH in H2O at 42 mL/min) afforded 14 (tr =
11.1 min; 47 mg, 14 %), 16 (tr = 12.3 min; 7 mg, 2 %) and 15 (tr =
13.6 min; 46 mg, 14 %).
Scheme 3. Biomimetic assembly of Δ8′-isodrimentine A (15). Reagents and
conditions: (a) tBuOK, –78 °C, BEt3, then 13 (1.1 equiv.), 50 °C, 12 h, 35 % and
after preparative HPLC (14: 14 %; 15: 14 %; 16: 2 %).
Table 2. IC50 [μM] of compounds 15 and 16 against cell lines HCT116, A549
and K562 cells.[a]
(2S,3S)-cyclo-Leucinyl-(3-farnesyl-N,2-cyclo-2,3-dihydrotrypto-
phyl), Protodrimentine A (6): 1H NMR (400 MHz, [D]chloroform):
δ = 7.11–7.04 (m, 2 H), 6.75 (t, J = 7.2 Hz, 1 H), 6.59 (d, J = 7.7 Hz,
1 H), 6.47 (s, 1 H), 5.29 (s, 1 H), 5.21–5.13 (m, 2 H), 5.12–5.05 (m, 2
H), 3.99 (dd, J = 11.3, 6.2, Hz, 1 H), 3.94 (dd, J = 9.3, 3.9 Hz, 1 H),
2.64 (dd, J = 12.8, 6.2 Hz, 1 H), 2.42 (m, 2 H), 2.29 (dd, J = 12.8,
11.1 Hz, 1 H), 2.09–1.94 (m, 9 H), 1.77 (m, 1 H), 1.67 (s, 3 H), 1.60 (s,
3 H), 1.59 (s, 3 H), 1.55 (m, 1 H), 1.51 (s, 1 H), 0.98 (d, J = 6.5 Hz, 3
H), 0.92 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (101 MHz, [D]chloroform):
δ = 169.9, 166.8, 148.9, 139.3, 135.13, 131.2, 131.0, 128.6, 124.3,
123.9, 123.4, 119.1, 118.2, 109.3, 79.7, 58.7, 55.6, 53.5, 39.9, 39.7,
38.6, 38.0, 35.4, 26.7, 26.5, 25.6, 24.5, 23.2, 21.2, 17.6, 16.3, 16.0 ppm.
HCT-116
A549
K562
15
16
Taxotere®
6.0 0.6
5.0 1.0
0.050 0.002
71
46
6
3
4.5 0.3
16.2 2.8
0.050 0.001
0.20 0.02
[a] Values are mean standard errors of three independent experiments.
Conclusions
In this work, we accessed the drimentine scaffolds in a straight-
forward sequence mimicking the main events of their biosyn-
thesis. cyclo-Leu-Trp was easily alkylated by farnesyl bromide IR (neat): ν = 3305, 2940–2915, 2845, 1675–1658, 1606, 1484,
˜
1293 cm–1. HRMS (ESI): calcd. for C33H47N2O2 [M + H]+ 504.3590;
+
affording a direct biosynthetic precursor. Allylation conditions
found 504.3599. [α]D = –205.3 (c = 0.57 CH2Cl2).
were also effective with bulky drimane-type decalines allowing
the efficient assembly of the alkaloid core. Δ8′-Isodrimentine A
(15) and analogous 16 were synthetized and showed moderate
cytotoxicities but similar to that of drimentine A, while α-ad-
duct 14 and non-cyclized compounds 6 and 9 were inactive.
(2R,3R)-cyclo-Leucinyl-(3-farnesyl-N,2-cyclo-2,3-dihydrotrypto-
phyl) (9): 1H NMR (400 MHz, [D]chloroform): δ = 7.08 (d, J = 7.4 Hz,
1 H), 7.04 (td, J = 7.7, 1.3 Hz, 1 H), 6.72 (td, J = 7.5, 1.0 Hz, 1 H), 6.55
(d, J = 7.8 Hz, 1 H), 6.27 (s, 1 H), 5.37 (s, 1 H), 5.14 (t, J = 7.5 Hz, 1
H), 5.11–5.02 (m, 2 H), 4.28 (t, J = 8.5 Hz, 1 H), 3.96 (dd, J = 9.4,
3.8 Hz, 1 H), 2.52 (s, 1 H), 2.49 (s, 1 H), 2.47–2.44 (m, 2 H), 2.10–1.95
(m, 9 H), 1.74 (m, 1 H), 1.67 (s, 3 H), 1.61 (s, 3 H), 1.59 (s, 3 H), 1.58
(s, 3 H), 1.53 (m, 1 H), 0.95 (d, J = 6.5 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3
Experimental Section
General: IR spectra were recorded with a Vector 22 Bruker spec- H) ppm. 13C NMR (101 MHz, [D]chloroform): δ = 169.9, 168.0, 147.4,
trometer. NMR spectra were recorded with Bruker AM-300 139.3, 135.3, 132.5, 131.3, 128.3, 124.2, 123.8, 123.0, 119.0, 118.5,
(300 MHz) and AM-400 (400 MHz) spectrometers using [D]chloro-
109.2, 81.2, 58.0, 55.6, 53.6, 39.9, 39.7, 38.4, 38.2, 35.2, 26.7, 26.5,
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25.7, 24.5, 23.2, 21.2, 17.7, 16.5, 16.0 ppm. IR (neat): ν = 3315, 2950–
˜
Keywords: Alkaloids · Drimentines · Biomimetic synthesis ·
Pyrroloindoline–diketopiperazines · Indoles
2922, 2852, 1678–1650, 1613, 1487, 1303–1287 cm–1. HRMS (ESI):
calcd for C33H47N2O2 [M + H]+ 504.3590; found 504.3602. [α]D
+82.7 (c = 0.25 CH2Cl2).
=
+
(2R,3R)-cyclo-Leucinyl-[3-(driman-8-en-11-yl)-N,2-cyclo-2,3-di-
hydrotryptophyl] (14): 1H NMR (400 MHz, [D]chloroform): δ = 7.12
(dd, J = 7.5, 1.2 Hz, 1 H), 7.03 (td, J = 7.7, 1.2 Hz, 1 H), 6.74 (t, J =
7.4 Hz, 1 H), 6.51 (d, J = 7.9 Hz, 1 H), 5.87 (s, 1 H), 5.52 (s, 1 H), 4.33
(t, J = 8.3 Hz, 1 H), 3.93 (dd, J = 8.6, 3.5 Hz, 1 H), 2.84 (d, J = 15.2 Hz,
1 H), 2.57 (dd, J = 13.1, 8.5 Hz, 1 H), 2.49 (dd, J = 13.1, 8.5 Hz, 1 H),
2.44 (d, J = 15.2 Hz, 1 H), 2.10 (dd, J = 18.0, 7.1 Hz, 1 H), 2.00 (m, 1
H), 1.95 (m, 1 H), 1.78 (d, J = 12.5 Hz, 1 H), 1.74–1.59 (m, 3 H), 1.55–
1.42 (m, 3 H), 1.44 (s, 3 H), 1.42–1.39 (m, 2 H),1.34 (d, J = 13.0 Hz, 1
H), 1.01 (dd, J = 12.9, 2.3 Hz, 1 H), 1.10–0.97 (m, 2 H), 0.97 (d, J =
6.5 Hz, 2 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.85 (s, 3 H), 0.77 (s, 3 H), 0.62
(s, 3 H); 169.8, 167.8, 147.2, 138.2, 133.9, 131.5, 128.3, 123.6, 119.2,
109.4, 81.3, 58.0, 55.9, 53.5, 51.5, 41.5, 40.8, 38.4, 38.1, 37.7, 33.87,
33.81, 33.5, 33.4, 24.7, 23.3, 21.7, 21.2, 20.8, 20.1, 19.01, 18.89 ppm.
[1] E. Lacey, M. Power, R. W. Rickerds, Z. WU., Patent Int. Appl. 1998, WO
9809968 A1, 19980312.
[2] a) Q. Che, T. Zhu, X. Qi, A. Màndi, T. Kurtàn, X. Mo, J. Li, Q. Gu, D. Li, Org.
Lett. 2012, 14, 3438–3441; b) Q. Che, T. Zhu, R. A. Keyzers, X. Liu, J. Li, Q.
Gu, D. Li, J. Nat. Prod. 2013, 76, 759–763; c) Q. Che, J. Li, D. Li, Q. Gu, T.
Zhu, J. Antibiot. 2016, doi:DOI: 10.1038/ja.2015.133.
[3] a) M. Ishikura, K. Yamada, T. Abe, Nat. Prod. Rep. 2010, 27, 1630–1680; b)
P. M. Scott, M. A. Merrien, J. Polonsky, Experientia 1976, 32, 140–142.
[4] a) M. Okada, H. Yamagushi, I. Sata, F. Tsuji, D. Dubnau, Y. Sakagami, Biosci.
Biotechnol. Biochem. 2008, 73, 914–918; b) F. Tsuji, K. Kobayashi, M.
Okada, H. Yamaguchi, M. Ojika, Y. Sakagami, Bioorg. Med. Chem. Lett.
2011, 21, 4041–4044.
[5] a) D. J. Richard, B. Schiavi, M. M. Joullié, Proc. Natl. Acad. Sci. USA 2004,
101, 11971–11976; b) N. Shangguan, W. J. Hehre, W. S. Ohlinger, M. P.
Beavers, M. M. Joullié, J. Am. Chem. Soc. 2008, 130, 6281–6287.
[6] Y. S. Ruofan, W. Zhang, A. Li, Angew. Chem. Int. Ed. 2013, 52, 9201–9204;
Angew. Chem. 2013, 125, 9371.
IR (neat): ν = 3340, 2930–2920, 2832, 1665–1649, 1600, 1454, 1211,
˜
+
1150 cm–1. HRMS (ESI): calcd. for C33H47N2O2 [M + H]+ 504.3590;
[7] a) F. Senejoux, L. Evanno, E. Poupon, Eur. J. Org. Chem. 2013, 453–455;
b) A. Skiredj, M. A. Beniddir, D. Joseph, K. Leblanc, G. Bernadat, L. Evanno,
E. Poupon, Angew. Chem. Int. Ed. 2014, 25, 6419–6424; Angew. Chem.
2014, 126, 6537; c) A. Skiredj, M. A. Beniddir, D. Joseph, K. Leblanc, G.
Bernadat, L. Evanno, E. Poupon, Org. Lett. 2014, 16, 4980–4983; d) S.
Benayad, M. A. Beniddir, L. Evanno, E. Poupon, Eur. J. Org. Chem. 2015,
1894–1898.
found 504.3584. [α]D = +184.2 (c = 0.19 CH2Cl2).
(2S,3S)-cyclo-Leucinyl-[3-(driman-8-en-11-yl)-N,2-cyclo-2,3-di-
hydrotryptophyl], Δ8′-Isodrimentine A (15): 1H NMR (400 MHz,
[D]chloroform): δ = 7.04 (td, J = 7.6, 1.2 Hz, 1 H), 7.00 (dd, J = 7.6,
1.2 Hz, 1 H), 6.75 (td, J = 7.4, 1.0 Hz, 1 H), 6.54 (d, J = 7.8 Hz, 1 H),
6.00 (s, 1 H), 5.39 (s, 1 H), 3.95 (m, 2 H), 2.79 (t, J = 6.4 Hz, 1 H), 2.76
(d, J = 3.4 Hz, 1 H), 2.39 (d, J = 15.0 Hz, 1 H), 2.38 (t, J = 12.3 Hz, 1
H) 2.10-2.00 (m, 2 H), 1.90 (td, J = 17.2, 6.6 Hz, 1 H), 1.79–1.50 (m,
7 H), 1.50–1.35 (m, 2 H), 1.20–1.14 (m, 3 H), 1.10 (s, 3 H), 0.99 (d, J =
6.5 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.90 (s, 3 H), 0.88 (s, 3 H), 0.82
(s, 3 H) ppm. 13C NMR (101 MHz, [D]chloroform): δ = 169.8, 166.7,
149.3, 137.1, 132.6, 132.3, 128.5, 124.5, 119.5, 109.3, 81.6, 59.7, 56.1,
53.7, 51.41, 42.0, 41.9, 39.0, 38.4, 38.1, 34.2, 33.6, 33.49, 33.43, 24.7,
[8] X. Yu, G. Zocher, X. Xie, M. Liebhold, S. Schütz, T. Stehle, S.-M. Li, Chem.
Biol. 2013, 20, 1492–1501.
[9] a) Y. Zeng, Q. Li, R. P. Hanzlik, J. Aubé, Bioorg. Med. Chem. Lett. 2005, 15,
3034–3038; b) T. Furukawa, T. Akutagawa, H. Funatani, T. Uchida, Y. Hotta,
M. Niwa, Y. Takaya, Bioorg. Med. Chem. 2012, 20, 2002–2009.
[10] N. S. Lamango, R. Duverna, W. Zhang, S. Y. Ablordeppey, Open Enzym.
Inhib. J. 2009, 1, 12–27.
[11] A. Lin, J. Yang, M. Hashim, Org. Lett. 2013, 15, 1950–1953.
[12] a) N. Kagawa, J. P. Malerich, V. H. Rawal, Org. Lett. 2008, 10, 2381–2384;
b) Y. Zhu, V. H. Rawal, J. Am. Chem. Soc. 2011, 134, 111–114; c) Y. Liu, H.
Du, Org. Lett. 2013, 15, 740–743; d) M. Kimura, M. Futamata, R. Mukai, Y.
Tamuru, J. Am. Chem. Soc. 2005, 127, 4592–4593.
[13] a) Z. Meng, H. Yu, L. Li, W. Tao, H. Chen, M. Wan, P. Yang, D. J. Edmonds,
J. Zhong, A. Lia, Nat. Commun. 2015, 6, 6069; b) A. H. Trotta, Org. Lett.
2015, 17, 3358–3361.
[14] Stereochemistry was determined based on the NOE correlation pattern
between H-1′ (for 6/9) or H-11′ (for 14/15) allylic protons and protons
on the pyrroloindoline–diketopiperazine scaffold.
[15] a) A. F. Barrero, J. Altarejos, E. J. Alvarez-Manzaneda, J. M. Ramos, S. Sal-
ido, J. Org. Chem. 1996, 61, 2215–2218; b) Q. Xiong, X. Zhu, W. K. Wilson,
A. Ganesan, S. P. T. Matsuda, J. Am. Chem. Soc. 2003, 125, 9002–9003; c)
K. Ishihara, H. Ishibashi, H. Yamamoto, J. Am. Chem. Soc. 2002, 124, 3647–
3655; d) S. A. Snyder, D. S. Treitler, Angew. Chem. Int. Ed. 2009, 48, 7899–
7903; Angew. Chem. 2009, 121, 8039; e) S. A. Snyder, D. S. Treitler, Org.
Synth. 2012, 54–69; f) A. Snyder, D. S. Treitler, A. P. Bucks, J. Am. Chem.
Soc. 2010, 132, 14303–14314.
[16] Among others: sulfuric acid in nitromethane led to a non-exploitable
mixture of partially cyclized compounds, Snyder's bromination reagent
(Et2SBr·SbCl5Br) only provided a mixture of brominated compounds,
both on the farnesyl side chain with unclear regioselectivity and on C-9
position of the aromatic ring.
23.4, 21.9, 21.3, 21.3, 20.8, 19.16, 19.13 ppm. IR (neat): ν = 3340,
˜
2945, 2923, 2830, 1677–1664, 1606, 1442, 1173 cm–1. HRMS (ESI):
calcd. for C33H47N2O2 [M + H]+ 504.3590; found 504.3584. [α]D
–161.4 (c = 0.22 CH2Cl2).
=
+
(2S,3S)-cyclo-Leucinyl-{3-[8ꢀ-9ꢀ-15(10→9)-abeodriman-5(10)-
en-11-yl]-N,2-cyclo-2,3-dihydrotryptophyl} (16): 1H NMR
(400 MHz, [D]chloroform): δ = 7.06 (m, 2 H), 6.76 (t, J = 7.4 Hz, 1 H),
6.63 (d, J = 3.9 Hz, 1 H), 6.57 (d, J = 7.8 Hz, 1 H), 5.51 (s, 1 H), 3.91
(m, 2 H), 2.72 (dd, J = 12.3, 6.0 Hz, 1 H), 2.62 (s, 2 H), 2.34 (t, J =
12.3 Hz, 1 H), 2.08–2.00 (m, 2 H), 1.77–1.36 (m, 4 H), 1.60–1.38 (m,
5 H), 1.36 (s, 3 H), 1.33 (m, 1 H), 1.10–0.98 (m, 2 H), 0.95–0.92 (m,
12 H), 0.85 (s, 3 H), 0.81 (s, 3 H) ppm. 13C NMR (101 MHz, [D]chloro-
form): δ = 169.5, 166.8, 149.2, 137.4, 132.7, 131.9, 128.8, 124.1, 119.5,
109.3, 81.37, 6.42, 56.0, 55.7, 51.3, 43.1, 41.7, 40.9, 38.0, 34.1, 33.7 (3
C), 33.6, 24.4, 23.2, 21.8, 21.4, 21.2, 21.1, 19.2, 19.1 ppm. IR (neat):
ν = 3345, 2950, 2925, 1680–1669, 1610, 1466, 1163 cm–1. HRMS
˜
(ESI): calcd. for C33H47N2O2 [M + H]+ 504.3590; found 504.3585.
+
[α]D = +145.8 (c = 0.22 CH2Cl2).
Supporting Information (see footnote on the first page of this
article): General procedures, complete experimental section, charac-
terization of all compounds, NMR charts and copies of the spectra.
[17] D. D. Dixon, J. W. Lockner, Q. Zhou, P. S. Baran, J. Am. Chem. Soc. 2012,
134, 8432–8435.
[18] a) K. I. Kuchkova, Y. M. Chumakov, Y. A. Simonov, G. Bocelli, A. A. Panas-
enko, P. F. Vlad, Synthesis 1997, 9, 1045–1048; b) S. Poigny, T. Huor, M.
Guyot, M. Samadi, J. Org. Chem. 1999, 64, 9318–9320.
Acknowledgments
[19] All of the attempted bromination conditions on the homoallylic alcohol
resulted in the formation of the corresponding diene after elimination
of HBr.
[20] a) A. Jermstad, Parfum. Mod. 1927, 19, 151; b) Y. Volmar, A. Jermstad,
Compt. Rend. 1928, 186, 783–785; c) A. Jermstad, Pharm. Acta Helv. 1927,
Karine Leblanc is gratefully acknowledged for HPLC analysis and
Jean-Christophe Julian for NMR assistance. LabEx LERMIT (ANR-
10-LABX-0033-LERMIT) is acknowledged for financial support
(grant to A. S.).
Eur. J. Org. Chem. 2016, 2954–2958
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2, 182–190; A. Jermstad, Pharm. Acta Helv. 1927, 2, 191–196; d) A. F.
Barrero, E. J. Alvarez-Manzaneda, R. Chahboun, A. F. Arteaga, Synth. Com-
mun. 2004, 34, 3631–3643.
[22] K. W. L. Yong, A. Jankam, J. N. A. Hooper, A. Suksamrarn, M. J. Garson,
Tetrahedron 2008, 64, 6341–6348.
[21] J. H. George, J. E. Baldwin, R. M. Adlington, Org. Lett. 2010, 12, 2394–
2397.
Received: April 8, 2016
Published Online: June 8, 2016
Eur. J. Org. Chem. 2016, 2954–2958
www.eurjoc.org
2958
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim