Enantiospecific total syntheses and assignment of absolute configuration of cannabinol-skeletal carbazole alkaloids murrayamines-O and -P

Article abstract of DOI:10.1002/chem.201406434

First enantiospecific total syntheses of the cannabinol-skeletal carbazole alkaloids murrayamines-O and -P isolated from root barks of Murraya euchrestifoli, have been accomplished by highly diastereoselective, Lewis acid catalyzed coupling reactions of commercially available monoterpenes with carbazole derivative, which in addition to confirming the structure also established the absolute configuration of the natural products. Synthesis of both natural products and their enantiomers was achieved with high atom economy, in a protecting-group free manner and in six steps longest linear sequence from commercially available aniline derivative and verbenol.

Full text of DOI:10.1002/chem.201406434

DOI: 10.1002/chem.201406434
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Total Synthesis |Hot Paper|
Enantiospecific Total Syntheses and Assignment of Absolute
Configuration of Cannabinol-Skeletal Carbazole Alkaloids
Murrayamines-O and -P
Dattatraya H. Dethe,* Saikat Das, Balu D. Dherange, and Samarpita Mahapatra[a]
Dedicated to Dr. A. V. Rama Rao on the occasion of his 80th birthday
natural products either by chiral pool or asymmetric catalytic
Abstract: First enantiospecific total syntheses of the can-
synthesis.[9] With our ongoing interest in total synthesis[10–12] of
nabinol-skeletal carbazole alkaloids murrayamines-O and
biologically active natural products,[13,14] herein we report the
-P isolated from root barks of Murraya euchrestifoli, have
first enantiospecific total syntheses of murrayamine-O (1) and
been accomplished by highly diastereoselective, Lewis
murrayamine-P (2) as well as their antipodes ent-1 and ent-2,
acid catalyzed coupling reactions of commercially avail-
respectively, facilitated by Lewis acid catalyzed coupling of
able monoterpenes with carbazole derivative, which in ad-
cyclic allylic alcohol 6 with carbazole derivative 7 for one pot
dition to confirming the structure also established the ab-
CÀC and CÀO bond formation and a strategic effort to avoid
solute configuration of the natural products. Synthesis of
the use of protecting group and expensive reagents.
both natural products and their enantiomers was achieved
It was envisioned that murrayamine-O/P could be obtained
with high atom economy, in a protecting-group free
from compound 8 by regioselective epoxide ring opening. Ep-
manner and in six steps longest linear sequence from
oxide 8 could be easily accessed from compound 9 by diaste-
commercially available aniline derivative and verbenol.
reoselective epoxidation. The key intermediate 9 in turn could
be obtained by treatment of carbazole derivative 7 with verbe-
Murrayamines-O (1) and -P (2) are the two novel pentacyclic al-
kaloids isolated from the plant of genus Murraya.[1] Both 1 and
2 are the first representatives of cannabinol-skeletal carbazole
alkaloids. Murraya is a genus of flowering plants in the citrus
family Rutaceae, that has been used in traditional medicine for
the treatment of fever, pain, diabetics, dysentery, painful in-
flammatory conditions, to induce labor and for cancer treat-
ments.[2] Murrayamine and related carbazole alkaloids have
been reported to show a potent antiplatelet aggregation activ-
ity.[3] The structure of 1 and 2 were determined by extensive
1D and 2D NMR analysis. The relative stereochemistry was as-
signed based on splitting patterns; coupling constants and
NOESY experiments revealed a trans fused chair-like oxadecalin
Scheme 1. Retrosynthetic analysis of murrayamine-O (1).
core and the equatorial C-3 methyl.
So far more than fifty natural products belonging to this
family and having various potent biological activities have
been isolated.[4] Although there have been no synthesis report-
ed of murrayamine-O/P, recently racemic total synthesis of
some natural products of this class such as murrayazoline
(3),[5,6] cyclomahanimbine (4),[6] murrafoline-A (5),[7] and related
natural products[8] have been reported in the literature. Also,
there are few reports on enantioselective synthesis of these
[a] Dr. D. H. Dethe, S. Das,+ B. D. Dherange,+ S. Mahapatra
Department of Chemistry
Indian Institute of Technology Kanpur, Kanpur 208016 (India)
E-mail: ddethe@iitk.ac.in
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406434.
Scheme 2. Synthesis of carbazole derivative 7.
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terestingly when epoxidation of
compound 14 was carried out at
room temperature, a diastereo-
meric mixture of epoxides 15
and 16 were obtained in 12:1
ratio with 79% yield. Regioselec-
tive independent opening of the
epoxides 8 and 15 by lithium
aluminum hydride (LAH) fur-
nished 1 as a single diastereo-
mer in 90 and 89% yield
(Scheme 5), the NMR spectro-
scopic data for which (1H, 13C, IR,
HRMS) were identical to those
reported for the natural prod-
uct.[1]
The optical rotation data ob-
tained for 1 [a]D =À117 (c 0.07,
CHCl3) also confirmed that the
Scheme 3. Synthesis of pentacyclic core of murrayamine-O/P.
absolute
configuration
(1’R,3’R,6’R) depicted in Figure 1
nol 6 by simultaneous CÀC and CÀO bond formation by taking
advantage of the strained four-membered ring in verbenol 6
(Scheme 1).
Carbazole derivative 7 could be synthesized using metal-cat-
alyzed coupling reactions from aniline derivative 10 and
phenyl boronic acid 11. So to begin with, carbazole derivative
7 was prepared using three steps. A mixture of phenyl boronic
acid 11 and compound 10 on treatment with catalytic amount
of copper acetate in refluxing toluene under basic conditions
afforded compound 12 in 86% yield (Scheme 2).[15]
Compound 12, on treatment with catalytic amount of
Pd(OAc)2 furnished 13 in 81% yield.[6] Demethylation of 13 by
BBr3 at 08C afforded the required carbazole 7. Carbazole 7 and
(À)-(S)-cis-verbenol (6) were then merged together using
20 mol% BF3·OEt2 catalyzed coupling reaction to furnish the
pentacyclic core 9 of murrayamines-O (1) and -P (2) as a single
diastereomer in 79% isolated yield in just 15 min at room tem-
perature (Scheme 3).
Scheme 4. Plausible mechanism for formation of pentacyclic core 14 from
carabzole 7 and verbenol 6.
Formation of the single diastereomer might be due to the
favorable exo approach of incoming carbazole deriva-
tive on allylic carbocation, as endo attack is sterically
hindered, as shown in Scheme 4. When the reaction
was allowed to stir for 1 h, isomerization of the
double bond was observed to generate compound
14, presumably due to the thermodynamic stability
of the latter.
It was contemplated that individual epoxidation of
compound 9 and 14, followed by regioselective
opening of epoxides thus formed would generate
both natural products murrayamines-O (1) and -P (2).
To our delight independent epoxidation of com-
pound 9 and 14 with m-CPBA at 08C afforded epox-
ides 8 and 15 as single diastereomers in 77 and 81%
yield, respectively. Stereochemistry of epoxide 15
was established by single crystal X-ray analysis.[16] In- Scheme 5. Completion of total synthesis of murrayamines-O and -P.
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Scheme 7. Total syntheses of (+)-murrayamines-O (ent-1) and (+)-murraya-
mine-P (2).
Figure 1. Selected examples of natural products from plant genus Murraya.
corresponds to that of the natural product (À)-murrayamine-O
([a]D =À137.6 (c 0.07, CHCl3)).[1]
Surprisingly, minor epoxide 16, on treatment with LAH re-
sulted in formation of antipode of murrayamine-P (ent-2) along
with secondary alcohol 17 in 2:3 ratio with 88% yield. Al-
though spectral data of synthetic 2 (1H, 13C, IR, HRMS) were in
complete agreement with natural murrayamine-P, the optical
rotation sign of synthetic 2 ([a]D =À89.8 (c 0.1, CHCl3)) was ex-
actly opposite to that of natural murrayamine-P ([a]D = +92 (c
0.015, CHCl3)),[1] confirming that synthetic 2 is an antipode of
the natural murrayamine-P.[1] Poor regioselectivity observed in
opening of epoxide 16 might be due to preference for axial
hydride attack by LAH on cyclohexane epoxide (Scheme 6).
Figure 2. ORTEP diagram of ent-19. Thermal ellipsoids are drawn at the 50%
probability level.
BF3·OEt2, gave pentacyclic core 9 in 74% yield in 20 min. When
the reaction was quenched within 5 min, we were able to iso-
late compound 19 in 80% yield as a single diastereomer. The
structure and stereochemistry of 19 was established by single
crystal X-ray analysis (Figure 2).[16]
Scheme 6. Mechanism of epoxide 16 opening by LAH.
Natural (+)-murrayamine-P (2) and antipode of (À)-murray-
amine-O (1) were synthesized starting from (+)-(R)-cis-verbenol
(ent-6) in a similar fashion with 1.37 and 30.63% overall yield,
respectively (Scheme 7). Optical rotation [a]D = +91.2 (c 0.1,
CHCl3) for synthetic murrayamine-P (2) established its absolute
configuration as (1’S,3’S,6’S).
We also became interested in coupling of carbazole deriva-
tive 7 with cyclic alcohol 18 and its enantiomer (ent-18). Thus,
carbazole 7 and alcohol 18, on treatment with 10 mol%
Scheme 8. Synthesis of pentacyclic core of murrayamine from monoterpene
18.
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In conclusion, using a simple strategy we have achieved first
enantiospecific total syntheses of representatives of cannabi-
nol-skeletal carbazole alkaloids murrayamine-O and -P. Synthe-
sis of both natural products and their enantiomers were
achieved in highly atom economical, gram scale, protecting-
group free manner, in six steps longest linear sequence start-
ing from (À)-(S)- and (+)-(R)-cis-verbenol.
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Experimental Section
Full details of experimental procedures, characterization data, and
NMR spectra can be found in the Supporting Information.
Acknowledgements
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Sharma for crystal structures. S.D. and B.D.D. thank CSIR, New
Delhi and S.M. thanks UGC, New Delhi for the award of re-
search fellowships. Financial support from DST, New Delhi
(Project No. SB/S1/OC-01/2014) is gratefully acknowledged.
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mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Keywords: cannabinol carbazole alkaloids · murrayamines ·
natural products · total synthesis · verbenol
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Received: December 11, 2014
Revised: March 17, 2015
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COMMUNICATION
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Total Synthesis
D. H. Dethe,* S. Das, B. D. Dherange,
S. Mahapatra
&& – &&
Back to the roots: First enantiospecific
total syntheses of the cannabinol-skele-
tal carbazole alkaloids murrayamines-O
and -P isolated from root barks of Mur-
raya euchrestifoli, have been accom-
plished by highly diastereoselective,
Lewis acid catalyzed coupling reactions
of commercially available monoterpenes
with carbazole derivative (see scheme).
Enantiospecific Total Syntheses and
Assignment of Absolute Configuration
of Cannabinol-Skeletal Carbazole
Alkaloids Murrayamines-O and -P
Chem. Eur. J. 2015, 21, 1 – 5
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