Concise total syntheses of (±)-mesembrane and (±)-crinane

Article abstract of DOI:10.1039/c5ob00183h

A straightforward and unified strategy to access Amaryllidaceae alkaloids comprising a cis-3a-aryloctahydroindole scaffold has been developed. The strategy features Eschenmoser-Claisen rearrangement of allylalcohol as a key step for the installation of al

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Concise Total Syntheses of (±)-Mesembrane and (±)-
Crinane
Cite this: DOI: 10.1039/x0xx00000x
Mrinal Kanti Das,† Subhadip De,† Shubhashish, and Alakesh Bisai*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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natural products, lycoraneꢀ and galanthamineꢀtype alkaloids as they
all are derived from the same precursor norbelladine.7 These cisꢀ3aꢀ
aryloctahydroindole alkaloids8 display vicinal quaternary and tertiary
A straightforward and unified strategy to access Amarylidaceae
alkaloids comprising cis-3a-aryloctahydroindole scaffold has
been developed. The strategy features Eschenmoser-Claisen
rearrangement of allylalcohol as key step for the installation of
all-carbon quaternary stereocenters present in these alkaloids.
Consequent iodolactonization-reduction-oxidation sequence
beautifully assembles the advanced intermediate keto-aldehyde
10a-b in synthetically viable yields. The methodology has been
successfully applied in the efficient syntheses of (±)-mesembrane
(1a) and (±)-crinane (2a).
carbon stereocenters with
a fused pyrrolidine ring whose
stereochemical incorporation is indeed a challenge.9 We envisaged a
unified strategy to access all of these alkaloids having the cisꢀ3aꢀ
aryloctahydroindole skeleton (Figure 1) with a sterically congested
quaternary carbon center located at the hydroindolone bridgehead
(Cꢀ3a) position as a common structural feature. Herein, we report
the development of a powerful strategy involving Eschenmoserꢀ
Claisen rearrangement followed by iodolactonization which would
permit the late stage, divergent introduction of
a range of
functionality to address total synthesis of several congeners of this
family.
The cisꢀ3aꢀaryloctahydroindole alkaloids possessing an allꢀcarbon
quaternary stereocenter1 constitute the core structure of many
alkaloids with impressive diversity of biological activity.2 Their
biological potential is significantly manifested by their antiꢀviral,
antiꢀtumor, antiꢀcholinergic and antiꢀHIV properties.3 These
activities together with their intriguing structures, have brought a
major impetus for synthetic exploration in this direction from
organic chemists across the globe.
Scheme 1. Retrosynthetic analysis of (±)ꢀ1a and (±)ꢀ2a.
Retrosynthetically, we envisioned that the advanced intermediate
ketoaldehyde 10a-b would lead to a unified pathway to access both
mesembrane (1a) and crinane (2a). The dimethylamides 4a-b
(Scheme 1) would afford 3a-b,10 via iodolactonization, which in turn
can be synthesized from allylalcohols 5a-b following Eschenmoserꢀ
Claisen rearrangement.11 Allylalcohols 5a-b can be accessed from 3ꢀ
arylꢀ2ꢀcyclohexenones 7a-b (Scheme 2), and the latter could easily
Figure 1. The Amarylidaceae alkaloids.
Especially, the cisꢀ3aꢀaryloctahydroindole alkaloids 1 and 2
(Figure 1) are found in plants of Amaryllidaceae family4 and elicit
continuing interest in the synthetic community due to their intriguing
physiological acitivities.5ꢀ6 Biogenetically, crinane (2a) and related
alkaloids are closely related with other major Amarylidaceae family
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be obtained directly from vinylogous ester 6 via a wellꢀknown Storkꢀ
Danheiser sequence.12
Scheme 2. Synthesis of 3ꢀArylꢀcyclohexenol (±)ꢀ5a-b.
Moving forward with our proposed strategy, we carried out the
StorkꢀDanheiser sequence on compound 6 using arylmagnesium
bromides to afford 3ꢀarylꢀ2ꢀcyclohexenones 7a-b in 73ꢀ85% yields
(Scheme 2). The latter were then reduced under Luche reduction13 to
access allylalcohols 5a-b in 92ꢀ96% yields. With allyl alcohols 5a-b
in hand, we sought after conditions to effect EschenmoserꢀClaisen
rearrangement for the synthesis of 1ꢀalkylꢀ1ꢀarylꢀ2ꢀcyclohexenes 4a-
b (Scheme 3) having allꢀcarbon quaternary stereocenter.
Scheme 4. Synthesis of ketoaldehydes (±)ꢀ10a-b.
Optimization studies were further conducted to carry out
reductive amination of compound 10a in order to complete total
synthesis of mesembrane (1a) (Table 1). Initially, we carried out
reductive amination of 10a in presence of 2 equiv. of ammonium
acetate and 4 equiv. of sodium cyano borohydride in different
solvent such as MeOH, EtOH, and THF in presence of 1 equiv. of
trifluoroacetic acid and acetic acid. To our delight, we found that cisꢀ
3aꢀaryloctahydroindole 11a could be obtained in 32ꢀ89% isolated
yields (entries 1ꢀ6, Table 1).
Scheme 3. EschenmoserꢀClaisen rearrangement of (±)ꢀ5a-b.
Table 1. Optimization of reductive amination of (±)ꢀ10a.a,b
Preliminary studies indicate that 2ꢀ6 equiv. of dimethylacetal of
N,Nꢀdimethylacetamide (DMAꢀDMA) in different solvents furnished
product 4a only in 26ꢀ53% yields. After exhaustive optimization, it
was found that 7 equiv. of DMAꢀDMA under heating at 160 ˚C led
to the formation of desired product in 82% yield (Scheme 3). Under
optimized condition, 5b afforded product 4b in 87% isolated yield
(Scheme 3). We then turned our attention to functionalize 2ꢀposition
of cyclohexene ring. Iodolactonization of 1ꢀalkylꢀ1ꢀaryl substituted
cyclohexenes 4a-b in presence of iodine in THF and water mixture
provided iodolactone intermediates 3a-b without event in 85ꢀ86%
yield (Scheme 4). The iodolactones 3a-b upon treatment with DBU
furnished alkenes 9a-b in excellent yields, which can in turn be
utilized as advanced intermediates for the synthesis of various
Amarylidaceae alkaloids. However, for total synthesis of
mesembrane (1a) and crinane (2a) we required γꢀketo aldehydes
10a-b to be further charged under reductive amination conditions to
afford cisꢀ3aꢀaryloctahydroindole. To synthesize γꢀketo aldehyde
10a-b, we reduced 3a-b in presence of lithium aluminum hydride to
afford 1,4ꢀdiols 8a-b in quantitative yield (Scheme 4). Among
various oxidation procedures tried to synthesize γꢀketo aldehydes
10a-b, we found that the Swern oxidation14 afforded 10a-b in 89ꢀ
92% yields (Scheme 4).
a2.0 equiv. of NH4OAc and 4.0 equiv. NaBH3CN were used in each case and
all the reactions were performed on a 0.20 mmol of (±)ꢀ10a in 2 mL of
solvent under inert atmosphere. bisolated yields after column
chromatography.
Following further optimization, we were pleased to find that
secondary amine 11a could be obtained in 83ꢀ85% yields when
reduction amination were carried out in presence of only 10 mol% of
trifluoroacetic acid and acetic acid, respectively (entries 7 and 8,
Table 1). Further, we synthesized carbamates 12a-b in 82ꢀ85%
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yields from 11a by treatment with chloromethylformate and benzyl
chloroformate in presence of NaHCO3 (Scheme 5). In fact, we
strongly feel that 12a-b could serve as potential precursors for the
synthesis of tricyclic core with additional amide functionality (see
red arrows) related to many amarylidaceae alkaloids (see, 2a-c,
Figure 1) via a BischlerꢀNapieralski type process.15
Conclusions
In conclusion, total synthesis of Amarylidaceae alkaloids
mesembrane (1a) and crinane (2a) has been demonstrated. The
strategy features the EschemoserꢀClaisen rearrangement as the
key step to install all carbon quaternary stereocenter. As allylic
alcohols of the type 5a-b could easily be accessed in
entioenriched form either using resolution or employing CBS
reduction,16 our strategy could be nicely adopted to an
enantioselective version as well.
Acknowledgements
Scheme 5. Synthesis of cisꢀ3aꢀaryloctahydroindole derivatives (12a-
b).
A.B. thanks the DST, SERB, India, for a research grant through
FASTꢀTRACK scheme (SB/FT/CSꢀ54/2011). M.K.D. and S.D.
thank the Council of Scientific and Industrial Research (CSIR), New
Delhi, for predoctoral fellowships. We thank the Department of
Chemistry, IISER Bhopal for infrastructure.
For total synthesis of (±)ꢀmesembrane 1a, we then carried out
reductive amination using methylamine under optimized condition,
which in turn provided 1a in 86ꢀ88% yields (Scheme 6). Along
similar line, we have also synthesized 13 in 87ꢀ91% isolated yields
(Scheme 6).
Notes and references
Department of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal, MP-462066, India.
Corresponding author: alakesh@iiserb.ac.in
†Both authors contributed equally.
Electronic Supplementary Information (ESI) available:
Experimental procedures, characterization data, NMR spectra,
See DOI: 10.1039/b000000x/
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Scheme 6. Total synthesis of (±)ꢀmesembrane (1a).
Next, we shifted our attention for a concise synthesis of crinane
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