Step-economic synthesis of (±)-debromoflustramine A using indole C3 activation strategy

Article abstract of DOI:10.1016/j.tetlet.2011.01.020

A concise and practical strategy to obtain C3 reverse-prenylated pyrrolidinoindoline scaffold has been executed in 28.8% overall yield. The key conjugative step involved a Booker-Milburn-Feudoloff reaction involving an NCS-mediated activation of indole, followed by coupling to C₅ dimethylallylalcohol. This linchpin step proceeded in 74% yield. The overall sequence proceeded in five steps from commercially available N-methyltryptamine with a single protection-deprotection operation and a single redox manipulation. Mechanistic insights of NCS activation, and an ensuing rearrangement of the isoprene unit were gained by rationally varying the C3 substituent.

Full text of DOI:10.1016/j.tetlet.2011.01.020

Tetrahedron Letters 52 (2011) 1269–1272
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Step-economic synthesis of ( )-debromoflustramine A using indole C3
activation strategy
⇑
Vasily A. Ignatenko, Ping Zhang, Rajesh Viswanathan
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and practical strategy to obtain C3 reverse-prenylated pyrrolidinoindoline scaffold has been
executed in 28.8% overall yield. The key conjugative step involved a Booker-Milburn–Feudoloff reaction
involving an NCS-mediated activation of indole, followed by coupling to C5 dimethylallylalcohol. This
linchpin step proceeded in 74% yield. The overall sequence proceeded in five steps from commercially
available N-methyltryptamine with a single protection–deprotection operation and a single redox manip-
ulation. Mechanistic insights of NCS activation, and an ensuing rearrangement of the isoprene unit were
gained by rationally varying the C3 substituent.
Received 24 December 2010
Accepted 7 January 2011
Available online 13 January 2011
Keywords:
( )-Debromoflustramine A
Flustra foliacea
Ó 2011 Elsevier Ltd. All rights reserved.
Alkaloid
NCS-mediated activation
C3 reverse prenylation
The North Atlantic waters hosting the marine bryozoan Flustra
foliacea have been a prolific source of natural product small mole-
cules possessing awe-inspiring structural diversity and concomi-
tant biological potency.1 For example, an array of bromo-
tryptamine alkaloids called flustramines were isolated from this
species and investigations into their pharmacological potential
are an active subject of discovery.2 The structural similarity be-
tween flustramines and those of the terrestrially formed physostig-
mine alkaloids was noted in one of the many pioneering isolation
studies from the Christophersen laboratory.3 C5 isoprene units con-
jugated to tryptamine in myriad ways are noticed in several cong-
eners of the Flustra alkaloid family (Fig. 1A).4 By virtue of dense
structural features present on the tricyclic core, including a C3 re-
verse-prenyl moiety, of the Flustra alkaloid family, several syn-
thetic methods have been devised to target flustramines.5 Herein
we report a concise and practical entry into prenylated pyrrolidi-
noindoline skeleton employing conjugation of tryptamine deriva-
tives to C5 prenols that work under relatively mild conditions.
This strategy was projected to serve as an orthogonal entry to
the method recently reported by us, toward highly substituted
oxindoles.6 Key bond disconnections that were applied to form
( )-debromoflustramine A (1) are outlined in Figure 1B. In order
to test the utility of a C3 reverse-prenylation reaction, we chose
a conjugative union of protected-tryptamine (2) and a simple
allylic alcohol (3) under mild conditions, devoid of toxic metal-
mediated reagents as reported in the literature.7 An early-stage
protection of the tryptamine nitrogen with a Nosyl group was ex-
pected to render chemo and regio-selectivity in the ensuing pre-
nylation events.
A late-stage reductive cyclization was projected to yield the C
ring of the pyrrolidinoindoline skeleton. N-Prenylation using pre-
nyl bromide (4) was expected to be selective to the B-ring of the
target based on the fact that an N-methyl group would protect
the terminal nitrogen (C-ring) of an appropriate tryptamine scaf-
fold. Concomitantly we envisioned a short mechanistic interroga-
tion to gain insights into the electrophilic activation of indoles as
a key step toward installing the C3 quaternary center of ( )-deb-
romoflustramine A (1).
N-Methyltryptamine (5) served as a practical candidate to initi-
ate the synthetic sequence. Though commercially available, we
were able to access N-methyltryptamine (5) from tryptamine using
a two-step procedure involving carbamate formation followed by
reduction with lithium aluminum hydride (see Supplementary
data). Nosylation of secondary amine 5 proceeded smoothly under
nucleophilic catalysis8 in the presence of DMAP in excellent conver-
sion yielding 6 (Scheme 1). The linchpin event that sets C3 reverse-
prenyl motif of ( )-debromoflustramine A is an intermolecular
oxidative-reverse-prenylation reaction of intermediate 6.
Accordingly, nosylated-N-methyltryptamine 6 was activated at
the most nucleophilic position of the indole ring with N-chlorosuc-
cinimide. An ensuing Meerwein-Eschenmoser-Claisen rearrange-
ment was effected upon trapping the indolenine species, in situ,
with dimethylallylalcohol and trichloroacetic acid in DCM result-
ing in the reverse-prenylated oxindole 7 in 74% yield. The next step
involved the installation of an N-prenyl group, and was executed
under the treatment of oxindole 7 with sodium hydride and prenyl
⇑
Corresponding author.
E-mail address: rajesh.viswanathan@case.edu (R. Viswanathan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.020

1270
V. A. Ignatenko et al. / Tetrahedron Letters 52 (2011) 1269–1272
Nos
A
CH3
CH3
NHCH3
N
CH3
CH3
Nosyl chloride
CH3
Et3N, DMAP
DCM, 0 °C to rt
(97.5%)
3
N
Br
N
H
6
3
H
N
Br
N
N
N-methyl tryptamine
CH3
H
N
CH3
commercially
NCS
1,4-dimethylpiperazine
available
CAS # 61-49-4
(−) - flustramine C
(antibacterial agent)
H3C
(−) - flustramine A
then
CH3
CH3
5
(74%)
(3)
HO
CH3
(smooth muscle relaxant)
Cl3CCOOH
DCM
H
CH3
O
O
H
N
3
H
N
CH3
CH3
CH3
N
H
CH3
CH3
3
NaH
H C
3
H
N
H
CH3
N
Nos
CH3
prenyl bromide (4)
N
Nos
O
THF, 0 °C to rt
N
O
N
(−) - amauromine
(MDR reversing agent)
CH3
(85%)
H
7
Meerwein-Eschenmoser-Claisen
rearrangement
H3C
CH3
B
8
H3C
H3C
Cs2CO3
N
(87%)
CH3
thiophenol
N
H
R
A
C
N
H
3
DMF, rt
B
2
3
N
CH3
CH3
CH3
CH3
CH3
CH3
N-Prenylation
HO
CH3
CH3
reductive cyclization
AlH3-Me2NEt
CH3
H3C
NH
CH3
THF
(54%)
N
H
O
- debromoflustramine A (1)
N
N
Br
CH3
CH3
4
Figure 1. (A) Representative examples of bioactive C3 reverse-prenylated trypto-
phan-derived natural products. Tryptophan core is highlighted in red. (B) Bond
disconnections for the step-economic synthesis of ( )-debromoflustramine A via a
key tryptamine-prenol conjugation event.
H3C
H3C
CH3
CH3
9
( ) - debromoflustramine A (1)
Scheme 1. Concise entry to pyrrolidinoindoline skeleton. Synthesis of ( ) deb-
romoflustramine A (1).
bromide yielding 8 in 85% yield. The Nosyl group proved to be an
excellent choice of protection for the nucleophilic secondary amino
functionality, as the ensuing deprotection event occurred effi-
ciently in the presence of thiophenol and cesium carbonate yield-
dimethylallylalcohol caused the reverse prenylation event to take
over. From this attempt, a mixture of oxindoles 11 and 12 was de-
tected and isolated in approximately a 14.5:1 ratio. The major
product obtained was the C3 reverse-prenylated oxindole 11
(R = CH3), while the minor product was found to be a dimeric ad-
duct 12, presumably arising out of a C–N bond-forming event be-
tween an activated indole species and the major product
oxindole itself. Upon further increasing the magnitude of the steric
bulk on the C3 substituent, substrate possessing a phthalimide-
protected tryptamine (10, R = CH2CH2NPhth) underwent complete
conversion to give the C3 reverse-prenylated product 11 as the sole
component after the reaction in 85% isolated yield.
Consistent with this observation was the fact that along the
synthesis toward target 1, the N-nosyl-protected methyl trypt-
amine 6 also underwent the reverse prenylation to 7 with similar
efficiency (74% isolated yield). Inherently, due to higher coeffi-
cients of the corresponding HOMO, indoles are expected to be
more nucleophilic at C3 than at C2 by a factor of ꢀ2.7, and evi-
dently the frontier electron population corroborates to this obser-
vation (C3 has a density of +0.595, while C2 having a density of
+0.219).11 Therefore, consistent with the report of Booker-Milburn
and coworkers, we expected the chlorination event using NCS to
transiently result in C3-chloroindoleninium ion pair represented
by species 14 (Scheme 2). The fate of this ion pair 14 will then
be expected to stream into distinct paths (A or B, in Scheme 2)
depending on the specific nature of the nucleophile that adds to
the electrophilic carbon at C2. If the methyl or alkyl substitutions
ing the penultimate intermediate
9
in 87% yield.5c Alane-
dimethylethylamine complex-mediated reductive cyclization was
effected in THF to result in ( )-debromoflustramine A (1) in 54%
yield in this final step. The structure of ( )-debromoflustramine A
was confirmed unambiguously via 1H NMR and 13C NMR analyses.
The overall synthetic sequence involved five linear steps starting
from commercially available N-methyltryptamine 5.
The linchpin step that installed the structurally complex C3
substituent has been originally developed by Booker-Milburn and
coworkers,7 and later improved to impart enantioselection using
transition-metal-catalysis by Linton and Kozlowski.9 We noted
that a systematic variation of the indole C3 substituent and its ef-
fect on this prenylation reaction has not been investigated thus far.
The exact nature of substitution involved in this modular process
proved to be important to us toward building the C3 reverse-
prenylated oxindole skeleton of several families of alkaloids in
addition to the Flustra alkaloids (for e.g., welwistatin core lacks a
C3 substituent). Therefore, we attempted a deeper exploration by
rationally varying the C3 substituent. As illustrated in Table 1, in-
dole (10, R = H) was subjected to the reverse-prenylation event un-
der identical conditions that had earlier led to oxindole 7 to be
formed (Scheme 1). We observed that neither oxindole 11 nor 12
was detected by 1H NMR analysis. Instead, 3-chloroindole was
the only observed product in quantitative yield. However, upon
replacing H from the C3 position with a methyl substitution on in-
dole (10, R = CH3), treatment with NCS followed by the addition of

V. A. Ignatenko et al. / Tetrahedron Letters 52 (2011) 1269–1272
1271
Table 1
Systematic variation of C3 substituent in the linchpin conjugation event
H3C
H3C
R
Cl
CH3
CH3
NCS
R
1,4-dimethylpiperazine
R
O
then
CH3
N
N
H
N
N
H
11
N
H
R
H
HO
CH3
O
10
12
13
Cl3CCOOH
DCM
Entry
C3 substitution
% Yield of 11a
% Yield of 12a
% Yield of 13a
1
2
3
4
R = H only 3-chloroindole formed
R = CH3
ndb
37.7
85
nd
2.6
nd
nd
Quant.
nd
nd
R = CH2CH2NPhthc
R = CH2CH2N(CH3)Nosd
74
nd
a
b
c
Isolated yield.
Not detected (1H NMR).
Phth = phthalimide.
d
Nos = p-nitrobenzenesulfonyl.
O
CH3
1,4-dimethylpiperazine
Cl
N
N
H
NCS
O
10
nOe %
1.19
H3C
H3C
O
CH3
CH3
2.02
Cl
H
CH3
H
CH3
O
CH3
oxindole 11
N
+
N
N
H
Path B
N
CH3
N
H
H
O
O
11
12
ion pair 14
Meerwein-Eschenmoser-Claisen
rearrangement
then
CH3
CH3
NH
HO
Cl3CCOOH
DCM
CH3
H3C
O
H3C
H3C
Path A
CH3
CH3
O
HCl
N
H
15
Scheme 2. Mechanistic analysis for C3 activation of indoles by N-chlorosuccinimide leading to reverse prenylation of tryptamines.10
were replaced by a hydrogen, which can be lost as a proton to the
media, the corresponding ion pair will result in 3-chloroindole 13.
However, in the absence of a C3 proton, dimethylallyl alcohol re-
acted with this ion pair and caused an addition to occur, leading
to, a precursor for an ensuing Meerwein-Eschnmoser-Claisen rear-
rangement, after the loss of an equivalent of HCl (path A). In our
experience and of others, this allyloxyimidate 15 was transforming
immediately even at ambient temperature into its corresponding
rearranged oxindole product 11. The primary driving force for this
thermodynamically driven downhill process is accountable based
on the fact that an amide bond is generated in the event. In con-
trast, if the ion pair 14 is encountering the oxindole 11 itself as a
nucleophile, especially promoted in the presence of basic compo-
nents in the reaction mixture, the mechanistic cascade is projected
to lead to formation of a different oxindole 12.12 In the case of C3
methyl substitution, this dimeric adduct was indeed observed, al-
beit in low conversion, and was structurally characterized using
1H and 13C NMR and high resolution MS techniques. The atropiso-
meric nature of the C–N bond in 12 is noted and, therefore, its
corresponding barrier to rotation will be a subject of future
investigations.
In addition the spatial distribution of the two indolic rings was
identified through-space NOESY analysis involving C3 methyl pro-
tons as the signals to which C4 (indole numbering) proton re-
sponded in addition to C7 proton of the proximal oxindole ring
(see NOE values embedded in Scheme 2). This mechanistic explo-
ration also expedited our synthesis by giving us a direct answer
to the nature of C3 substituent appropriate for the rearrange-
ment-based reverse-prenylation reaction (from 6 to 7) to be ef-
fected. In conclusion, the overall synthetic sequence proceeded in
five steps from commercially available N-methyltryptamine with
a single protection–deprotection operation and with a single redox
maneuver. The overall strategy was executed in 28.8% overall yield.
A concise and practical strategy to obtain C3 reverse-prenyl pyrr-

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V. A. Ignatenko et al. / Tetrahedron Letters 52 (2011) 1269–1272
olidinoindoline scaffold has been devised with consideration to
biogenetic relation of these alkaloids to tryptophan.13 Therefore,
a deliberate emphasis was laid to preserve the indole scaffold
and to use C5 isoprenoid units as precursors. Also the fact that
References and notes
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a4b2 neuronal nicotinic receptors
rendering them an excellent progenitor for the development of
selective regulators of this receptor14 calls for reliable generation
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order to aid in full evaluation of pharmacological effects elicited
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efforts are underway to render access to these scaffolds in high
enantioselection and to obtain each antipode of this important nat-
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orbitals. Transisition state assembly of 15 to 11 does not represent any
enantioselection during the process, one conformation is represented for
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11. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley-Chichester:
New York, 1978.
12. Based on the pKa of oxindole NH, it is expected to be a competing nucleophile
to an OH group.
Acknowledgments
The authors thank Dr. Larry Sallans (Univ. Cincinnati) for MS
data collection of all new compounds reported here. RV thanks
Ms. Deepti Sharma for obtaining IR data of select compounds. RV
thanks Dr. Karthikeyan Thandavamurthy for efforts toward com-
pletion of the experimental section of the manuscript.
13. Li, S. M. Nat. Prod. Rep. 2010, 27, 57–78.
14. Sala, F.; Mulet, J.; Reddy, K. P.; Bernal, J. A.; Wikman, P.; Valor, L. M.; Peters, L.;
Konig, G. M.; Criado, M.; Sala, S. Neurosci. Lett. 2005, 373, 144–149.
15. (a) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N. J. Am.
Chem. Soc. 2003, 125, 163–168; (b) Chandra, A.; Viswanathan, R.; Johnston, J. N.
Org. Lett. 2007, 9, 5027–5029.
16. (a) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc. 2007, 129,
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Supplementary data
Supplementary data (general experimental methods, additional
experimental procedures, compound characterization data and
copies of spectra for all new compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/j.tetlet.
2011.01.020.