Biomimetic total syntheses of flinderoles B and C

Article abstract of DOI:10.1021/ja1116974

A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.

Full text of DOI:10.1021/ja1116974

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Biomimetic Total Syntheses of Flinderoles B and C
Dattatraya H. Dethe,* Rohan D. Erande, and Alok Ranjan
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, Maharashtra, India
S Supporting Information
b
Scheme 1. Structures of Flinderoles A-C and the Proposed
Biosynthetic Pathway
ABSTRACT: A simple and efficient biomimetic synthesis
of pyrrolo[1,2-a]indoles using a highly stereo- and regiose-
lective [3 þ 2] reaction cascade was developed and then
further applied in the first total synthesis of flinderoles B and
C, which proceeded in 17.2% yield over the longest linear
sequence of 11 steps.
alaria chemotherapy is under continuous threat from the
M
evolution and rise of multidrug resistance of Plasmodium
falciparum.1 To counter the threat of resistance, structurally and
functionally novel antimalarial compounds with new mechan-
isms of action are needed. In 2009, flinderoles A-C (1-3,
respectively; Scheme 1) were isolated through an initial anti-
malarial natural product extract screening program.2 All of the
flinderoles have shown impressive selective antimalarial activity
against the P. falciparum parasite,2 with flinderole C being most
active (IC50 = 150 nM), and flinderoles thus present new
molecular scaffolds for antimalarial drug discovery. Flinderoles
have a new skeleton that is rearranged relative to the known
borreverine class of tryptamine isoprene-derived compounds
borreverine, isoborreverine, and dimethylisoborreverine.3 The
dimeric structure of the flinderoles lends itself to a symmetrical
retrosynthetic dissection through the center of the molecule.
This dissection reveals monomeric tryptamine diene as a possible
precursor—a scenario that might not be so dissimilar to their
biosynthetic pathway (Scheme 1).
Scheme 2. Exploration of the Biosynthetic Pathwaya
Our explorations to test this overall hypothesis began with the
preparation of diene 4 from the known indole aldehyde 54
(Scheme 2) on a multigram scale. Treatment of indole aldehyde
5 with Ph3PdCHCO2Et followed by reaction of the resultant
ester with MeMgBr generated the tertiary alcohol 6. Mesylation
of alcohol 6 and subsequent elimination yielded diene 7, which
gave the required diene 4 upon desulfonylation using methanolic
NaOH. To our surprise, diene 4 was found to polymerize with
different Lewis acids under various reaction conditions em-
ployed, resulting in intractable mixtures. This could be explained
by reasoning that the actual site of protonation in 4 is at C3 of the
indole nucleus to produce a conjugated enamine, which could
undergo cationic polymerization. At this juncture, it was rea-
soned that if diene 4 were generated in situ in sufficiently low
concentration, it might undergo dimerization by a formal inter-
molecular [3 þ 2] cycloaddition,5,6 leading to the flinderole
framework. On the basis of this hypothesis, the available alcohol
6 was desulfonylated to obtain alcohol 8. Various Lewis acids
were screened for the proposed dimerization of 8, and results are
summarized in Table 1.
a Conditions: (a) Ph3PdCHCO2Et (1.5 equiv), CH2Cl2, RT, 6 h, 95%;
(b) MeI (7.0 equiv), Mg turnings (6.0 equiv), I2 (cat.), Et2O, 0 °C to RT,
2 h, 81%; (c) MsCl (3.0 equiv), Et3N (6.0 equiv), THF, 0 °C to reflux, 2
h, 82%; (d) NaOH (5.0 equiv), MeOH, 70 °C, 3 h, 75%; (e) Na/Hg (4.0
equiv), Na2HPO4 (4.0 equiv), MeOH, RT, 1 h, 91%.
The reaction of alcohol 8 with TMSOTf furnished a complex
mixture of products, and the dimers 9a and 9b were obtained in
Received: December 29, 2010
Published: February 11, 2011
r
2011 American Chemical Society
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COMMUNICATION
Table 1. Invention and Optimization of the Dimerization
Reaction of Alcohol 8a
Scheme 3. Intermolecular Cascade Reactiona
entry
Lewis acid
yield (%)b
dr (9a:9b)c
1
2
3
4
5
6
7
TMSOTf
Yb(OTf)3
Sc(OTf)3
10
25
25
38
46
35
0
1:1
1:1
1:1
3:2
2:1
3:2
N.A.
BF3 OEt2
3
Cu(OTf)2
TFA
Tf2O
a All reactions were carried out on a 0.25 mmol scale in CH2Cl2 as the
solvent (0 °C to RT). b Isolated yield. c Determined by 1H NMR analysis
of the crude reaction mixture.
poor yield as 1:1 mixture of diastereomers (Table 1, entry 1).
Similarly, Yb(OTf)3 and Sc(OTf)3 gave the desired adducts 9a
and 9b in low yield (entries 2 and 3). BF3 OEt2 was found to be a
3
useful catalyst for effecting this transformation in a much cleaner
manner, generating the products 9a and 9b in moderate yield and
diastereoselectivity (entry 4). Even though Tf2O did not give any
desired product, trifluoroacetic acid (TFA) did furnish the
required products 9a and 9b in comparable yield (Table 1,
entries 6 and 7). More interestingly Cu(OTf)2 generated the
flinderole frameworks 9a and 9b in much improved yield and
diastereoselectivity (Table 1, entry 5). It is worth mentioning
that no [4 þ 2] cycloaddition product was observed even in trace
amounts under these conditions. The dimers 9a and 9b could be
separated by careful column chromatography, and their struc-
tures were established by spectroscopic analysis (1H and 13C
NMR, IR, HRMS) through comparison with flinderole spectral
data.2 Their relative stereochemistry was determined by rota-
tional Overhauser effect spectroscopy (ROESY). Weak ROESY
correlations between H30 and H14 and between 3H15 and H120
indicated that the C17 methyl group and the isobutene group
must be on the same side of the five-membered ring in the major
isomer 9a.7
a Conditions: (a) Cu(OTf)2 (0.2 equiv), CH2Cl2, RT, 30 min, 95%; (b)
BF3 OEt2 (0.2 equiv), CH2Cl2, RT, 20 min, 92%; (c) Na/Hg (4.0
3
equiv), Na2HPO4 (4.0 equiv), MeOH, RT, 1 h, 94%.
Scheme 3 describes the scope of this dimerization reaction. It
was envisaged that the dimerization reaction would be more
facile if the intermediate generated in situ from alcohol 8 were
reacted with an olefin such as 7 bearing a sulfonyl group. It was
anticipated that since the olefin would be preformed and the
intermediate trapped immediately, the formation of polymeriza-
tion products would be significantly reduced. Gratifyingly, when
tertiary alcohol 8 and diene 7 were mixed together and treated
with Cu(OTf)2, the dimers 10a and 10b were indeed obtained in
Figure 1. Proposed stereochemical model for the [3 þ 2] cycloaddition.
protection could be readily accomplished using sodium amal-
gam, furnishing the dimers 9a and 9b, whose 1H and 13C NMR
data were identical to those of the samples generated earlier. In
order to expand the scope of the reaction, several diverse
examples were carried out, as illustrated in Scheme 3. The
reaction was found to work with equal efficiency when the
tertiary alcohol had ethyl rather than methyl substitution (cf.
adduct 11). Similarly, having an ethoxymethyl substituent at C3
of the indole did not affect the yield or selecivity (cf. adducts 12
and 13). It is noteworthy that not only indole derivatives but also
even simple 1-phenyl-3-methylbutadiene derivatives reacted to
give the corresponding highly substituted pyrrolo[1,2-a]indole
derivatives in good yield, albeit with only modest selectivity.9
These results encouraged us to proceed further to a biomimetic
total synthesis of flinderoles.10
excellent yield and diastereosectivity (g19:1). When BF3 OEt2
3
was used as the catalyst, the diastereomeric ratio decreased to 2:1.
The relative stereochemistry of 10a and 10b was determined by
ROESY and nuclear Overhauser effect spectroscopy (NOESY)
experiments. Although the reason for the excellent diastereos-
electivity is not very clear at this moment, it was observed that
excellent diastereoselectivity was obtained only when the -
SO2Ph group was present and Cu(OTf)2 was used as catalyst;
thus, the diastereoselectivity could be rationalized in terms of a
transition-state structure in which copper is coordinated to the -
SO2Ph group of one indole unit and the nitrogen of the other
unit. The approach of the olefin is endo, similar to the Diels-
Alder reaction (Figure 1).8 This transition-state structure
reduces the unfavorable steric interaction present when the
olefin approaches in exo mode. Removal of the benzenesulfonyl
To access flinderoles B and C, indole tertiary alcohol 18 and
indole diene 19 were identified as appropriate precursors for the
key [3 þ 2] cycloaddition reaction. The synthesis began with
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COMMUNICATION
Scheme 4. Total Synthesis of Flinderoles B (2) and C (3)a
with excellent diastereoselectivity. Surprisingly, treatment of a
mixture of 18 and 19 with excess BF3 OEt2 not only gave the
3
expected dimerization product but also deprotected both
TBDMS groups, directly generating diols 26a and 26b in
excellent overall yield, albeit with moderate diastereoselectivity
(4:1). In line with the earlier observation, the major compound
was found to be isomer 26a, in which the methyl and isobutylene
groups are cis to each other. The mixture of diols 26a and 26b
was not separated at this stage, given the fact that both isomers
would finally lead to the natural products, which could be
separated in the last step. All of our attempts to convert 26a
and 26b to the corresponding diamines via their mesylates or
triflates failed to give the desired products. Finally, oxidation of
the mixture of 26a and 26b using IBX followed by reductive
amination of the resultant bisaldehydes 27a and 27b gave a
mixture of amines 28a and 28b in 91% yield. Deprotection of the
indole nitrogens of 28a and 28b followed by purification by
preparative TLC delivered flinderoles B (2) and C (3), which
were then treated individually with 0.005 M TFA in acetonitrile
to get the corresponding TFA salts. The TFA salts of synthetic
flinderoles B and C thus obtained possessed physical properties
(IR, mass, 1H and 13C NMR data) identical to those reported in
the literature.2
In summary, a highly stereo- and regioselective formal [3 þ 2]
cycloaddition reaction between a tertiary alcohol and an olefin
has been developed for use in the synthesis of pyrrolo[1,2-a]
indoles. The potential of this methodology has been amply
demonstrated in the first total synthesis of the isomeric flinder-
oles B and C, which involves 11 steps in the longest linear
sequence and gave an overall yield of 17.2%. The strategy is fairly
general and is amenable to the synthesis of other natural products
of this class as well as their analogues.
a Conditions: (a) Ac2O (5.0 equiv), DMAP (0.2 equiv), pyridine (5.0
equiv), CH2Cl2, RT, 6 h, 91%; (b) dichloromethyl methyl ether (5.0
equiv), stannic chloride (5.0 equiv), CH2Cl2, -78 to -10 °C, 1 h, 80%;
(c) (i) LiOH (5.0 equiv), H2O, THF, RT, 3 h; (ii) TBSCl (1.3 equiv),
imidazole (1.5 equiv), CH2Cl2, 0 °C to RT, 6 h, 81% (over two steps);
(d) (i) Ph3PdCHCO2Et (1.5 equiv), CH2Cl2, RT, 6 h, 91%; (ii) MeI
(10 equiv), Mg turnings (9 equiv), I2 (cat.), Et2O, 0 °C to RT, 2 h, 89%;
(e) Na/Hg (4.0 equiv), Na2HPO4 (4.0 equiv), MeOH, RT, 1 h, 97%; (f)
MsCl (3.0 equiv), Et3N (6.0 equiv), THF, 0 °C to reflux, 2 h, 81%. (g)
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
Cu(OTf)2 (0.2 equiv), CH2Cl2, RT, 30 min, 62%; (h) BF3 OEt2 (4.0
3
spectral data for all of the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
equiv), CH2Cl2, RT, 30 min, 78%; (i) IBX (6.0 equiv), EtOAc, reflux, 1
h, 84%; (j) NHMe2 (4.0 equiv), NaCNBH3 (4.0 equiv), AcOH (cat.),
MeOH, RT, 12 h, 91%; (k) Na/Hg (4.0 equiv), Na2HPO4 (4.0 equiv),
MeOH, RT, 1 h, 2 (62%), 3 (15%).
’ AUTHOR INFORMATION
Corresponding Author
dh.dethe@ncl.res.in
known protected tryptophol 20.11 The primary hydroxyl group
of 20 was acylated using acetic anhydride to furnish acetate 21.
Formylation of 21 using dichloromethyl methyl ether and
stannic chloride gave acetate 22. The acetyl protection in indole
derivative 22 was changed to TBS protection following hydro-
lysis of acetate and reaction of the resultant alcohol with TBSCl
to obtain TBS ether 23. Wittig olefination of aldehyde 23 with
Ph3PdCHCO2Et generated the unsaturated ester in 91% yield,
which upon treatment with methylmagnesium iodide gave
tertiary alcohol 24 in excellent yield. Dehydration of the hydroxyl
group of 24 was achieved via its mesylate followed by elimination
to furnish the requisite olefin 19. On the other hand, deprotec-
tion of the phenylsulfonyl group in 24 using sodium amalgam
gave the other coupling partner, alcohol 18 (Scheme 4). With
gram quantities of tertiary alcohol 18 and diene 19 in hand, the
stage was set for the key dimerization reaction for the synthesis of
the flinderole skeleton.
’ ACKNOWLEDGMENT
This paper is dedicated to Prof. A. Srikrishna. We thank Dr.
C. V. Ramana and Dr. S. J. Gharpure for their valuable suggestions.
We thank Dr. P. R. Rajmohanan and team for recording NMR
spectra. R.D.E. and A.R. thank CSIR, New Delhi, for the award of
research fellowship. Financial support from NCL, Pune (Project
MLP017726) and DST, New Delhi (Project GAP291026) is
gratefully acknowledged.
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COMMUNICATION
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