Synthesis of a diarylheptanoid, (+)-centrolobine

Article abstract of DOI:10.1016/j.tetasy.2010.01.002

A chiron approach for the total synthesis of (+)-centrolobine has been described from the commercially available aldehyde 3 employing an acid-catalyzed stereoselective formation of tetrahydropyran ring as the key step. The desired molecule was accomplished in eight steps with 62% overall yield.

Full text of DOI:10.1016/j.tetasy.2010.01.002

Tetrahedron: Asymmetry 21 (2010) 103–105
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of a diarylheptanoid, (+)-centrolobine
*
Ch. Raji Reddy , P. Phani Madhavi, S. Chandrasekhar
Organic division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiron approach for the total synthesis of (+)-centrolobine has been described from the commercially
available aldehyde 3 employing an acid-catalyzed stereoselective formation of tetrahydropyran ring as
the key step. The desired molecule was accomplished in eight steps with 62% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 November 2009
Accepted 11 January 2010
Available online 1 February 2010
1. Introduction
2. Results and discussion
Diarylheptanoid natural products containing a tetrahydropyran
(THP) ring have received considerable attention due to their wide
range of biological activities.1–3 The centrolobine family is one of
the diarylheptanoids with a 2,6-disubstituted tetrahydropyran
ring isolated from centrolobium species (Leguminasae). The heart
wood of Centrolobium robustum was found to contain (ꢀ)-centrol-
obine 1 while the other species Centrolobium tomentosum was
found to contain (+)-centrolobine 2 (Fig. 1).2 Furthermore, cen-
trolobine and related natural products have been found to exhibit
anti-inflammatory and anti-bacterial as well as anti-leishmanial
activities.2c,3 Among the centrolobine family members, (ꢀ)-cen-
trolobine has received significant attention from synthetic organic
chemists after the determination of its absolute configuration by
Solladie et al. via the first asymmetric total synthesis.4a Since
then, a variety of approaches have been reported towards the syn-
thesis of 1 in both racemic and optically active forms.4b–t How-
ever, to date there is only one report in the literature describing
the formal synthesis of (+)-centrolobine5a and recently one total
synthesis has been reported5b while the present work was in pro-
gress. In continuation of our interest on the synthesis of diaryl-
heptanoids,4k,6 in particular the synthesis of centrolobine
analogues, we herein report the stereoselective synthesis of (+)-
centrolobine.
Our synthesis of (+)-centrolobine (Scheme 1) started from the
commercially available (R)-1,4-dioxaspiro[4,5]-decane-2-carboxal-
dehyde 3. Wittig-olefination of aldehyde 3 with known 3-(benzyl-
oxy)-propyl) triphenylphosphonium bromide 47 in the presence of
nBuLi in THF provided compound 5 in 89% yield (E/Z ratio 5:95).
Hydrogenation of compound 5 in methanol under 10% Pd/C catal-
ysis at room temperature gave alcohol 6 in 98% yield. Next, oxida-
tion of alcohol 6 to aldehyde (IBX, DMSO, THF, 1 h) followed by
Grignard reaction with 4-methoxyphenyl magnesium bromide,
derived from 7, afforded benzylic alcohol 8 in 89% yield over two
steps. Now the stage was set for the key stereoselective cyclization
to obtain 2,6-disubstituted tetrahydropyran. The treatment of
compound 8 with camphorsulfonic acid in methanol at room tem-
perature gave the desired tetrahydropyran 9 within 30 min (92%),
through the deprotection of the ketal followed by intramolecular
cyclization of the 1,5-diol.8 The exclusive formation of cis-2,6-
disubstituted tetrahydropyran 9 was confirmed by NOE studies.9
Alcohol 9 was oxidized using Dess–Martin periodinane into the
aldehyde, which was then subjected to a Wittig-olefination with
4-benzyloxybenzyl triphenylphosphonium bromide 10, (prepared
using a literature procedure)4c in the presence of nBuLi in THF.
The above-mentioned reaction gave compound 11 in 90% yield
(over two steps) as a mixture of E/Z isomers (3:1). Finally, the
reduction of the olefin functionality and deprotection of the benzyl
ether in compound 11 were accomplished in a one-pot reaction
using hydrogenation in the presence of PtO2 in EtOAc/MeOH
(3:1), which completed the total synthesis of (+)-centrolobine (2).
The spectroscopic data (IR, 1H and 13C NMR) of the obtained (+)-
centrolobine (2) were identical and the specific rotation observed
HO
OMe HO
OMe
R
S
S
R
O
O
(-)-Centrolobine (1)
(+)-Centrolobine (2)
for 2, ½a 2D7
¼ þ94:7 (c 0.1, MeOH), was comparable to that reported
ꢁ
for the natural product {lit: ½a D25
ꢁ
¼ þ97:5 (c 0.1, MeOH)}.2c
Figure 1. Structures of (ꢀ)-centrolobine and (+)-centrolobine.
3. Conclusions
In conclusion, an efficient total synthesis of (+)-centrolobine 2
has been demonstrated via a chiron approach. The target molecule
* Corresponding author. Tel.: +91 40 27191885; fax: +91 40 27160512.
E-mail address: rajireddy@iict.res.in (C.R. Reddy).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.002

104
C. R. Reddy et al. / Tetrahedron: Asymmetry 21 (2010) 103–105
CHO
OBn
OH
BnO
PPh3+Br-
i) IBX , DMSO
THF, rt, 1 h
10% Pd/C-H2
MeOH
4
n-BuLi, THF
O
O
O
O
O
O
º
rt, 8 h, 98%
-78 C-rt, 1 h
89%
ii) 4-MeO-PhBr 7
Mg, THF
3
6
5
-78 oC-rt, 2 h
89% (two steps)
OMe
OMe
i) Dess-Martin periodinane BnO
OMe
º
CSA, MeOH
30 min, rt, 92%
CH2Cl2, 0 C-rt, 2 h
O
O
O
O
OH
HO
ii)
BnO
+
PPh3 Br-
9
8
10
(E/Z mixture, 3:1)
n-BuLi, THF
-78 oC-rt, 1 h
11
90% (two steps)
5% PtO2-H2
HO
OMe
EtOAc/MeOH (3:1)
O
8 h, rt, 97%
(+)-Centrolobine 2
Scheme 1. Synthesis of (+)-centrolobine.
was accomplished in eight steps with 62% overall yield, which is
significant. The synthetic route is new and unique which would
also lead to the synthesis of (ꢀ)-centrolobine (starting from the
other isomer of aldehyde 3) as well as other analogues.
4.1.2. (S)-4-(1,4-Dioxaspiro[4.5]decan-2-yl)butan-1-ol 6
To asolution of compound 5(0.2 g, 0.66 mmol)inmethanol(2 mL)
was added a catalytic amount of 10% Pd/C and the mixture was kept
under a H2 atmosphere (balloon) for 8 h at room temperature. After
the reaction was complete (monitored by TLC), the reaction mixture
was filtered through a pad of Celite and concentrated to dryness. Puri-
fication of the residue by silica gel column chromatography (25% of
EtOAc in hexanes) afforded the product 6 (0.139 g) in 98% yield.
4. Experimental section
4.1. General
½
a 2D6
ꢁ
¼ þ2:6 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d = 4.14–3.99
(m, 2H), 3.69–3.62 (m, 2H), 3.55–3.47 (m, 1H), 1.71–1.33 (m, 16H);
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra are recorded on a Perkin–Elmer 683
spectrometer. Optical rotations were obtained on a Perkin–Elmer
digital polarimeter. 1H and 13C NMR spectra were recorded in
CDCl3 solution on a Brucker Avance 300. Chemical shifts were re-
ported in parts per million (ppm) with respect to internal TMS.
Coupling constants (J) are quoted in Hz. Mass spectra were ob-
tained on an Agilent Technologies LC/MSD Trap SL.
13C NMR (75 MHz, CDCl3): d = 109.2, 75.5, 69.0, 62.6, 36.5, 35.2,
33.3, 32.5, 25.1, 23.9, 23.8, 22.0; IR (neat):
m 3420, 2935, 2860, 1631,
1384, 1105, 1037, 931, 758 cmꢀ1; HRMS (ESI): m/z [M+Na]+ calcd
for C12H22O3Na: 237.1466; found: 237.1473.
4.1.3. (S)-1-(4-Methoxyphenyl)-4-(1,4-dioxaspiro[4.5]decan-2-
yl)butan-1-ol 8
To a solution of iodoxybenzoic acid (0.39 g, 1.4 mmol) in DMSO
(1 mL), was added a solution of alcohol 6 (0.2 g, 0.93 mmol) drop-
wise in THF (15 mL). The reaction mixture was stirred at room
temperature for 1 h. After the completion of reaction (monitored
by TLC), ether (5 mL) was added to the reaction mixture and the
resulting solid materials were filtered through a sintered funnel.
The resulting filtrate was washed with saturated NaHCO3 solution
(10 mL) and the organic layer was separated. The aqueous layer
was extracted with diethyl ether (3 ꢂ 10 mL). The combined
organic layers were washed with brine (10 mL), dried over Na2SO4
and concentrated in vacuo to afford the aldehyde, which was used
as such without purification.
To a solution of Mg turnings (0.056 g, 2.35 mmol) in anhydrous
THF (5 mL) was slowly added dropwise the bromo compound 7
(0.23 mL, 1.88 mmol) at room temperature. After the formation
of the Grignard reagent, the reaction mixture was cooled to
ꢀ78 °C. The above-mentioned crude aldehyde (0.2 g, 0.94 mmol)
in THF (15 mL) was added and stirred for 2 h. After completion of
the reaction (monitored by TLC), it was quenched with saturated
NH4Cl (15 mL) and the organic layer was separated. The aqueous
layer was extracted with EtOAc (3 ꢂ 10 mL) and the combined or-
ganic layers were washed with brine (15 mL), dried over Na2SO4
and concentrated to dryness. Purification of the residue by silica
gel column chromatography (18% of EtOAc in hexanes) gave the
benzylic alcohol 8 (0.269 g) in 89% yield (for two steps). 1H NMR
(300 MHz, CDCl3): d = 7.21 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 9.1 Hz,
4.1.1. 4.1.1.(S)-2-(4-(Benzyloxy)but-1-enyl)-1,4-dioxaspiro[4.5]-
decane 5
To a solution of (3-benzyloxy)-propyl) triphenylphosphonium
bromide 4 (0.40 g, 0.82 mmol) in THF (10 mL) at ꢀ78 °C was added
nBuLi (0.28 mL of a 2.5 M solution in hexanes, 0.71 mmol). The
reaction mixture was allowed to warm up to 0 °C for 30 min, where
the solution turned orange-red. Next, it was cooled to ꢀ78 °C and
to this, a solution of aldehyde 3 (0.1 g, 0.59 mmol) in THF (5 mL)
was added. It was stirred for 30 min at room temperature. After
completion of the reaction (monitored by TLC), it was quenched
with aqueous saturated NH4Cl (10 mL) and the organic layer was
separated. The aqueous layer was extracted with EtOAc
(3 ꢂ 10 mL), the combined organic layers were washed with brine
(15 mL), dried over Na2SO4 and concentrated to dryness. The resi-
due was purified by silica gel column chromatography (4% of EtOAc
in hexanes) to give compound 5 (0.158 g) in 89% yield. 1H NMR
(300 MHz, CDCl3): d = 7.35–7.20 (m, 5H), 5.69–5.58 (m, 1H),
5.53–5.43 (m, 1H), 4.84–4.74 (m, 1H), 4.48 (s, 2H), 4.02–3.95 (m,
1H), 3.53–3.38 (m, 3H), 2.42 (q, J = 6.8, 13.9 Hz, 2H), 1.65–1.55
(m, 8H), 1.44–1.35 (m, 2H); 13C NMR (75 MHz, CDCl3): d = 138.2,
130.5, 129.4, 128.3, 127.5, 109.6, 72.9, 71.5, 69.4, 69.0, 36.3, 35.4,
28.4, 25.1, 23.9, 23.8; IR (neat):
m 3402, 2935, 2859, 1726, 1162,
1101, 1042, 929, 739 cmꢀ1; HRMS (ESI): m/z [M+Na]+ calcd for
C19H26O3Na: 325.1779; found: 325.1794.

C. R. Reddy et al. / Tetrahedron: Asymmetry 21 (2010) 103–105
105
2H), 4.62–4.55 (m, 1H), 4.05–3.92 (m, 2H), 3.79 (s, 3H), 3.47–3.39
(m, 1H), 1.87–1.31 (m, 16H); 13C NMR (75 MHz, CDCl3): d = 158.9,
136.8, 127.0, 113.7, 109.1, 75.5, 73.9, 69.0, 55.2, 38.8, 36.5, 35.2,
plete (monitored by TLC), the reaction mixture was filtered
through a pad of Celite and concentrated to dryness. Purification
of the residue by silica gel column chromatography (14% EtOAc
in hexanes) afforded the desired product 2 (0.038 g) in 97% yield.
33.5, 25.1, 23.9, 23.8, 22.2; IR (neat):
m 3425, 2930, 2857, 1611,
1511, 1245, 1102, 1034, 930, 830 cmꢀ1; HRMS (ESI): m/z [M+Na]+
½
a 2D7
ꢁ
¼ þ94:7 (c 0.1, MeOH), 1H NMR (300 MHz, CDCl3): d = 7.27
calcd for C19H28O4Na: 343.1885; found: 343.1886.
(d, J = 7.0 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H),
6.69 (d, J = 8.5 Hz, 2H), 4.65–4.52 (br s, 1H), 4.31–4.22 (m, 1H),
3.79 (s, 3H), 3.49–3.34 (m, 1H), 2.79–2.57 (m, 2H), 2.0–1.41 (m,
8H); 13C NMR (75 MHz, CDCl3): d = 158.6, 153.4, 135.8, 134.6,
129.5, 127.0, 115.0, 113.5, 79.0, 77.1, 55.2, 38.2, 33.2, 31.2, 30.7,
4.1.4. ((2R,6S)-2-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-
yl)methanol 9
To a solution of benzylic alcohol 8 (0.05 g, 0.15 mmol) in meth-
anol (8 mL) was added a catalytic amount of camphorsulfonic acid
at room temperature. The reaction mixture was stirred at the same
temperature for 30 min. After the disappearance of the starting
material (monitored by TLC), solid NaHCO3 (catalytic amount)
was added to the reaction mixture, then it was filtered and concen-
trated to dryness. Purification of the residue by silica gel column
24.0; IR (neat):
m 3444, 2936, 1737, 1642, 1434, 1373, 1239,
1045, 756, 666, 487 cmꢀ1; HRMS (ESI): m/z [M+Na]+ calcd for
C20H24O3Na: 335.1623; found: 335.1640.
Acknowledgements
The authors thank DST, New Delhi for financial assistance and
CSIR, New Delhi for research fellowship to P.P.M.
chromatography (21% of EtOAc in hexanes) gave alcohol
9
(0.032 g) in 92% yield. ½a D26
ꢁ
¼ þ53:8 (c 1.8, CHCl3); 1H NMR
(300 MHz, CDCl3): d = 7.23 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1 Hz,
2H), 4.36–4.29 (m, 1H), 3.79 (s, 3H), 3.67–3.45 (m, 3H), 2.20–2.09
(br s, 1H), 2.02–1.92 (m, 1H), 1.84–1.23 (m, 5H); 13C NMR
(75 MHz, CDCl3): d = 158.8, 135.1, 127.2, 113.6, 79.3, 78.6, 66.2,
References
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55.2, 33.4, 26.8, 23.4; IR (neat):
m 3442, 2933, 2855, 1612, 1514,
1246, 1080, 1036, 829, 765, 546 cmꢀ1. HRMS (ESI): m/z [M+Na]+
calcd for C13H18O3Na: 245.1153; found: 245.1151.
4.1.5. (2R,6S)-2-(4-(Benzyloxy)styryl)-2-(4-methoxyphenyl)-
tetrahydro-2H-pyran 11
To a solution of alcohol 9 (0.2 g, 0.9 mmol) in anhydrous CH2Cl2
(10 mL) under a nitrogen atmosphere was added Dess–Martin
periodinane (0.57 g, 1.35 mmol) at 0 °C and the reaction mixture
was stirred at ambient temperature for 2 h. Then, the reaction
was quenched with aqueous saturated Na2S2O3 (10 mL), the organ-
ic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 ꢂ 10 mL). The combined organic layers were washed
with brine (15 mL), dried over Na2SO4 and evaporated in vacuo
to obtain the aldehyde, which was used as such for the next step
without purification.
To a solution of 4-benzylyoxybenzyl triphenylphosphonium bro-
mide 10 (1.22 g, 2.27 mmol) in THF (20 mL) at 0 °C was slowly added
dropwise nBuLi (0.72 mL of a 2.5 M solution in hexanes, 1.8 mmol).
After 30 min (orange-red solution formed), the above-mentioned
aldehyde (0.2 g, 0.91 mmol) in THF (10 mL) was added dropwise at
0 °C and thestirringcontinuedfor 30 min. Thereactionwasquenched
with aqueous saturated NH4Cl (15 mL), the organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (3 ꢂ 10 mL).
The combined organic layers were washed with brine (15 mL), dried
over Na2SO4 and concentrated to dryness. Purification of the residue
by silica gel column chromatography (4% of EtOAc in hexanes) gave
11 (0.33 g) as a E/Z mixture (3:1) in 90% yield over two steps. 1H
NMR (300 MHz, CDCl3): d = 7.54–7.23 (m, 8H), 7.20 (d, J = 9.1 Hz,
1H), 6.89 (d, J = 9.1 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 6.55–6.40 (m,
1H), 6.15–6.04 and 5.66–5.56 (m, 1H), 5.04 (d, J = 5.3 Hz, 2H), 4.42–
4.28 (m, 2H), 3.78 (s, 3H), 2.04–1.90 (m, 1H), 1.86–1.45 (m, 5H); 13C
NMR (75 MHz, CDCl3): d = 158.8, 157.9, 136.8, 135.4, 132.2, 132.1,
131.4, 130.7, 130.1, 129.8, 129.1, 128.9, 128.5, 128.3, 127.9, 127.5,
127.4, 114.7, 113.6, 79.5, 78.9, 78.8, 74.8, 69.9, 55.2, 33.3, 31.7, 31.5,
6. (a) Chandrasekhar, S.; Shyamsunder, T.; Prakash, S. J.; Prabhakar, A.; Jagadesh, B.
Tetrahedron Lett. 2006, 47, 47–49; (b) Reddy, Ch. R.; Madhavi, P. P.;
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8. The selective formation of 9 may be explained by the addition of a chiral
hydroxy group on to benzylic cation, which is in conjugation with 4-
methoxyphenyl ring.
A similar cyclization was used for the synthesis of
centrolobine.2b,4s
9. NOE experiments have been carried out on compound 9 and the enhancement is
24.0, 23.8; IR (KBr):
m 3418, 2929, 2855, 1608, 1511, 1251, 1176,
1032, 832, 740, 710 cmꢀ1; HRMS (ESI): m/z [M+Na]+ calcd for
shown below.
nOe enhancement
C27H28O3Na: 423.1936; found: 423.1954.
H
H
4.1.6. (+)-Centrolobine 2
O
To a solution of compound 11 (0.05 g, 0.12 mmol) in a mixture
of ethyl acetate/methanol (3:1, 3 mL) was added a catalytic
amount of PtO2 and the mixture was kept under a H2 atmosphere
(balloon) for 8 h at room temperature. After the reaction was com-
OH
MeO