Synthesis of (+)-centrolobine and its analogues by using acyl anion chemistry

Article abstract of DOI:10.1002/ejoc.201300097

A new route based on the use of acyl anion chemistry was developed for the synthesis of (+)-centrolobine and its analogues. Acid-catalyzed benzylic cation initiated cyclization was the key step in the stereoselective formation of the cis-2,6-disubstituted tetrahydropyran ring. The developed methodology was applied to the synthesis of (+)-centrolobine analogues containing electron-donating substituents in the aryl rings.

Full text of DOI:10.1002/ejoc.201300097

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300097
Synthesis of (+)-Centrolobine and Its Analogues by Using Acyl Anion
Chemistry
Kasireddy Sudarshan[a] and Indrapal Singh Aidhen*[a]
Keywords: Natural products / Anions / Oxygen heterocycles / Decarbonylation / Cyclization
A new route based on the use of acyl anion chemistry was
developed for the synthesis of (+)-centrolobine and its ana-
logues. Acid-catalyzed benzylic cation initiated cyclization
was the key step in the stereoselective formation of the cis-
2,6-disubstituted tetrahydropyran ring. The developed meth-
odology was applied to the synthesis of (+)-centrolobine ana-
logues containing electron-donating substituents in the aryl
rings.
There are several syntheses reported for 1;[4] however, in
sharp contrast to 1, there are limited approaches for the
synthesis of 2.[5] Disconnection envisaging use of an aryl
acyl anion for the synthesis of 2 has never been attempted.
In light of this fact and the attractive diversity factor associ-
ated with varying the aryl residue, we were prompted to
explore a new synthetic route based on this disconnection
(Figure 1). Presented herein are the results of these efforts,
which delivered a successful route to 2 and its analogues.
Introduction
Diarylheptanoids, a group of natural products charac-
terized by the presence of two aromatic rings across the
termini of a seven carbon atom chain, have attracted in-
tense interest from medicinal and synthetic chemists be-
cause of their wide-ranging biological activities.[1–3] Among
diarylheptanoids containing a tetrahydropyran (THP) ring,
(–)-centrolobine (1) and its enantiomer (+)-centrolobine (2),
in particular, have continued to remain in prominence.
Results and Discussion
Among the several synthetic equivalents available for the
acyl anion,[6] we were attracted by the less frequently used
α-aminonitriles for the aryl acyl anion synthon A/AЈ, be-
cause of the simplicity and the convenience involved in their
preparation on a multigram scale.[7] Following a literature-
known procedure and starting from commercially and
abundantly available d-mannitol, bromide 4[8] was obtained
as the requisite synthetic equivalent for five carbon atom
electrophilic synthon B. α-Aminonitrile 3[9] underwent clean
alkylation with bromide 4 to afford alkylated intermediate
5 as a diastereoisomeric mixture. Without any purification,
alkylated intermediate 5 was directly subjected to hydrolysis
by using hydrated CuSO4 in aqueous methanol at 60 °C.[10]
Clean hydrolysis ensued, which furnished desired aryl
ketone 6 in 75% yield (Scheme 1).
To effect benzylic cation initiated cyclization, aryl ketone
6 was reduced to a diastereoisomeric mixture of benzylic
alcohol 7 with NaBH4 in methanol. To our satisfaction,
upon treatment with p-toluenesulfonic acid (pTsOH) in
methanol, 7 underwent stereoselective cyclization to afford
desired cis-2,6-disubstituted THP product 8 through depro-
tection of the ketal followed by intramolecular cyclization
initiated by the formation of a benzylic cation under the
acidic conditions[4s] (Scheme 2). The cyclization and the for-
mation of 8 was confirmed from a signal at δ = 4.35 ppm
Figure 1. New disconnection for the synthesis of (+)-centrolobine
(2).
[a] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai 600036, India
Fax: +91-44-22574202
E-mail: isingh@iitm.ac.in
Homepage: http://chem.iitm.ac.in/professordetails/profsingh/
index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300097.
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Synthesis of (+)-Centrolobine and Its Analogues
spectroscopic data (1H NMR, 13C NMR, IR) of compound
2 including the optical rotation value of [α]2D5 = +96.6 (c =
0.1, MeOH) {ref.[2c] [α]2D5 = +97.5 (c = 0.1, MeOH)} are in
agreement with the reported natural product values.
Scheme 1. Synthesis of aryl ketone 6.
(dd, J = 11.2, 1.6 Hz) in the 1H NMR spectrum, which
corresponds to the C-2 benzylic methine proton in the ob-
tained product. Upon irradiation of this peak, an NOE en-
hancement (3.8%) of the peak at δ = 3.65 ppm correspond-
ing to the methine proton at C-6 in the THP ring was ob-
served, and this demonstrates the close proximity of the C-
2 and C-6 protons and hence the cis stereochemistry.
Scheme 3. Synthesis of (+)-centrolobine (2). TFA = trifluoroacetic
acid.
The successful synthesis of 2 through a novel disconnec-
tion on the basis of the use of aryl acyl anion chemistry
prompted us to explore the generality of the developed syn-
thetic route. Towards this end, α-aminonitriles 3a–c with
varying substituents were prepared to serve as a source for
both the aryl residue present in 2 and possibly to provide a
diverse array of analogues through various combinations.
Although aryl ketones 6a–c were easily prepared in good
yields (by using the conditions in Scheme 1), the diastereo-
isomeric mixture of benzylic alcohols 7a–c obtained after
reduction failed to cyclize under the acidic conditions de-
scribed earlier for the conversion of 7Ǟ8 in the successful
synthesis of 2. The only reaction that took place under
these conditions, even after prolonged stirring, was deketal-
ization, which resulted in triols 13a–c. This was substanti-
ated by the absence of signals for the ketal functionality in
1
the H NMR and 13C NMR spectra of the obtained prod-
ucts. The failure of substrates 7a–c to undergo cyclization
is probably a result of their inability to form the benzylic
Scheme 2. Stereoselective formation of the THP ring.
To complete the synthesis of 2, THP alcohol 8 was con- cation. The ease of formation of the benzylic cation and the
verted into corresponding bromide 9 with tetrabromometh- subsequent cyclization in the case of benzylic alcohol 7 are
ane and then treated with the carbanion derived from para- due to stabilization by the para-methoxy substituent. To
O-benzyl-protected α-aminonitrile 10 for the incorporation validate this argument, para-methoxy-substituted interme-
of the second aryl residue. The need for final deprotection diate 7d was prepared by using 3d as the starting α-amino-
in addition to the ease with which it could be performed nitrile. To our satisfaction, a clean reaction occurred under
dictated the choice of benzyl ether protected α-aminonitrile the acidic conditions described earlier for the conversion of
10. The desired alkylation reaction ensued and subsequent 7Ǟ8, and desired cis-2,6-disubstituted THP alcohol 14 was
hydrolysis furnished corresponding aryl ketone 11 in 83% furnished in good yield (Scheme 4). The formation of the
yield. With the synthesis of 11, wherein the carbon frame- THP ring in 14 was confirmed by the signal at δ = 4.34 ppm
1
work and aryl residues A and B of 2 were assembled, the in the H NMR spectrum. The exclusive obtainment of the
promise of the new strategy based on aryl acyl anion chem- cis stereoisomer of 14 was once again confirmed by NOE
istry was fully demonstrated. Simple debenzylation followed studies (3.4% enhancement). A simple two-step, high-yield-
by decarbonylation by using a known procedure[5f] afforded ing conversion to iodide 15 set the stage for the incorpora-
target (+)-centrolobine (2) in good yield (Scheme 3). All the tion of the second aryl residue as an acyl anion.
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K. Sudarshan, I. S. Aidhen
SHORT COMMUNICATION
17a–d was confirmed by NOE studies (3.7, 3.8, 3.8, 4.4%
enhancement for 17a–d, respectively). In the case of 17c,
we were fortunate to obtain good-quality crystals for X-ray
crystallographic studies, and the single-crystal X-ray dif-
fraction data of 17c[11] further confirmed the cis geometry
(Figure 2). The successful synthesis of analogues 17a–d has
clearly demonstrated the versatility of the new disconnec-
tion and the generality of the developed synthetic route for
(+)-centrolobine.
Figure 2. ORTEP diagram of 17c.
Conclusions
To conclude, the successful synthesis of (+)-centrolobine
was achieved through a new disconnection involving the use
of acyl anion chemistry. Because the incorporation of the
Scheme 4. Cyclization to the THP ring with electron-donating sub- aryl residues in the architecture of (+)-centrolobine oc-
stituents.
curred at different stages in the developed synthetic scheme,
the new strategy disclosed herein is robust and capable of
providing ready access to analogues of choice and design.
Upon reaction of 15 with the carbanions generated from
α-aminonitriles 3d and 3 and subsequent hydrolysis of the
alkylated products, aryl ketones 16a and 16b were obtained,
respectively, in good yields. Successful decarbonylation fur-
nished 17a and 17b, which are hitherto unknown analogues
of (+)-centrolobine (Scheme 5). Similar reactions of brom-
ide 9, used earlier in the synthesis of 2 (Scheme 3), with the
carbanions derived from α-aminonitriles 3d and 3 provided
ready access to analogues 17c and 17d, respectively
Experimental Section
General Procedure for the Preparation of Aryl Ketones 6, 6a–d, and
16a–d (Procedure A): To a suspension of NaH (1.2 equiv.) in DMF
(8 mL) was added a solution of α-aryl aminonitrile 3, 3a–d
(1.1 equiv.) in DMF (9 mL) at 0 °C under an inert atmosphere. Af-
ter 20 min, a solution of the bromide (5.7 mmol, 1 equiv.) in DMF
(Scheme 5). The cis stereochemistry in final compounds (17 mL) was added, and the reaction mixture was stirred for 2 h at
Scheme 5. Synthesis of various analogues of (+)-centrolobine.
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Synthesis of (+)-Centrolobine and Its Analogues
room temperature. A saturated solution of NH4Cl (15 mL) was
added, and the mixture was extracted with ethyl acetate (3ϫ
20 mL). The ethyl acetate layer was washed with water (3ϫ 20 mL),
dried with Na2SO4, and concentrated to obtain alkylated com-
pound 5. Without further purification, a solution of CuSO4·5H2O
(5 equiv.) in CH3OH/H2O (7:3, 15 mL/g of alkylated compound)
was added, and the mixture was heated at reflux at 60 °C for
90 min. The solvents were evaporated under reduced pressure, and
water (10 mL) was added to the obtained residue. The aqueous
layer was extracted with ethyl acetate (3ϫ 20 mL), and the com-
bined organic layer was washed with a saturated solution of
NaHSO3 (3ϫ 15 mL), brine (10 mL), and dried with Na2SO4. The
solvent was evaporated, and the obtained residue was purified by
silica gel column chromatography (ethyl acetate/ hexanes, 2:8) to
afford the aryl ketones.
Infrastructure (FIST) program. The Board of Research in Nuclear
Sciences (BRNS) is acknowledged for funding the project. The au-
thors also thank Mr. V. Ramkumar of the Department of Chemis-
try, IIT Madras, for X-ray crystallographic studies. K. S. acknowl-
edges the University Grants Commission, New Delhi, for a Junior
Research Fellowship.
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General Procedure for the Decarbonylation Reaction: To a solution
of aryl ketone 16a–d (1 equiv.) in methanol (5 mL) was added so-
dium borohydride (1 equiv.), and the mixture was stirred for 1 h.
The solvent was evaporated, and the residue was dissolved in water
(10 mL). The aqueous layer was extracted with ethyl acetate (3ϫ
15 mL). The combined organic layer was washed with brine
(20 mL), dried with Na2SO4, and concentrated. The obtained resi-
due was dissolved in CH2Cl2 (8 mL) and Et3SiH (5 equiv.) and
CF3COOH (1 equiv.) were then added at 0 °C under an inert atmo-
sphere. After 15 min, the reaction mixture was warmed to room
temperature and then stirred for 45 min. A saturated solution of
NaHCO3 (6 mL) was added, and the mixture was extracted with
ethyl acetate (3ϫ 10 mL). The ethyl acetate layer was washed with
water (3ϫ 20 mL), dried with Na2SO4, and concentrated. The
crude product was purified by silica gel column chromatography
(ethyl acetate/hexanes, 2:8) to afford the various analogues of (+)-
centrolobine in good yields.
Supporting Information (see footnote on the first page of this arti-
1
cle): General information, characterization data, copies of the H
NMR and 13C NMR spectra of all new compounds, and NOE
spectra of compounds 2, 8, 14, and 17a–d.
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Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi, for funding towards the 400 MHz NMR spec-
trometer to the Department of Chemistry, Indian Institute of Tech-
nology Madras (IIT Madras), under the Intensification of Research
in High Priority Areas (IRHPA) Scheme, and towards the ESI-MS
facility under the Fund for Improvement of Science & Technology
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Eur. J. Org. Chem. 2013, 2298–2302
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K. Sudarshan, I. S. Aidhen
SHORT COMMUNICATION
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17.5760(13) Å, β = 92.693(3)°; space group P21; CCDC-906158
contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Received: January 18, 2013
Published Online: March 5, 2013
2763.
[11] Crystal data for compound 17c: Formula: C22H28O4; unit
cell parameters: a = 8.3095(6) Å, b = 6.6828(6) Å, c =
2302
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