Stereoselective synthesis of tetrahydropyranyl diarylheptanoids (-)-centrolobine and (+)-centrolobine

Article abstract of DOI:10.1055/s-0030-1258341

A versatile chiron approach to the tetrahydropyranyl diarylheptanoid natural products (-)-centrolobine and (+)-centrolobine has been described. The use of an aldol reaction followed by reductive etherification for the formation of tetrahydropyran ring is of importance. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258341

PAPER
123
Stereoselective Synthesis of Tetrahydropyranyl Diarylheptanoids
(–)-Centrolobine and (+)-Centrolobine
Stereoselective
S
h
a
)
-Centrolo
d
bine
a
nd (+)-
a
Centrolobine Raji Reddy, Pasupulety Phani Madhavi, Srivari Chandrasekhar*
Organic Division – I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
Received 30 September 2010; revised 8 October 2010
report the stereoselective synthesis of both the enantio-
mers of centrolobine.
Abstract: A versatile chiron approach to the tetrahydropyranyl di-
arylheptanoid natural products (–)-centrolobine and (+)-cen-
trolobine has been described. The use of an aldol reaction followed
by reductive etherification for the formation of tetrahydropyran ring
is of importance.
The synthesis of (–)-centrolobine (1a) began from com-
mercially available dimethyl (R)-malate (2a), which was
taken forward to diol 3a using a known procedure
(Scheme 1).7 The diol 3a was protected using 2,2-
dimethoxypropane/4-toluenesulfonic acid in dichlo-
romethane to give ketal 4a (96%). Reduction of the ester
group in 4a using lithium aluminum hydride in tetrahy-
drofuran gave the alcohol 5a in 91% yield. Then, oxida-
tion of alcohol 5a to the aldehyde (IBX) followed by an
aldol reaction with 4-methoxyacetophenone using butyl-
lithium/N,N-diisopropylethylamine at –78 °C provided
the product 6a in 88% (over two steps) as a mixture of dia-
stereomers. The deoxygenation of the hydroxy group in
6a was accomplished in two steps. Thus, the compound
6a was treated with carbon tetrabromide/triphenylphos-
phine in dichloromethane to give the corresponding bro-
mide, which was further subjected to tributylstannane/
2,2¢-azobis(isobutyronitrile) in toluene at reflux tempera-
ture to yield the dehydroxylated product 7a in 77% yield
(over two steps). The stage was set for the deprotection of
acetonide followed by reductive etherification to prepare
the cis-2,6-disubstituted tetrahydropyran ring. According-
ly, the treatment of 7a with triethylsilane in the presence
of boron trifluoride–diethyl ether complex at 0 °C pro-
moted the one-pot deketalization/intramolecular cycliza-
tion to provide exclusively the desired cis-2,6-
disubstituted tetrahydropyran 8a in 75% yield. The syn-
stereochemistry of 8a was confirmed by NOE experi-
ments (Figure 2).
Key words: diarylheptanoid, tetrahydropyran, centrolobine, aldol
reaction, reductive etherification
Tetrahydropyranyl diarylheptanoids are a significant class
of compounds having a wide spectrum of biological activ-
ity; they have received considerable attention from medic-
inal as well as synthetic organic chemists.1–3 The
centrolobine family is one of the diarylheptanoids having
a 2,6-disubstituted tetrahydropyran ring, isolated from
centrolobium species (Leguminasae). (–)-Centrolobine
(1a) was first isolated from the heart wood of Centrolobi-
um robustum, later from the stem of Brosinium potabile
and (+)-centrolobine was isolated from Centrolobium to-
mentosum (1b, Figure 1).2 Furthermore, centrolobines
have found to exhibit anti-inflammatory and antibacterial
as well as anti-leishmanial activity.2c,3 After the basic
structure was elucidation in 1964,2a its absolute configura-
tion was established based on the configurational and con-
formational facts in the Newmann formulation in 1970.2c
However, this absolute configuration was revised by
Colobert and co-workers via the first enantioselective to-
tal synthesis of (–)-centrolobine.4a Since then, (–)-cen-
trolobine has significantly received the notice of synthetic
organic chemists, which has resulted a variety of ap-
proaches towards the synthesis of 1a in both racemic and
optically active forms.4 Whereas, to date one formal syn-
thesis of (+)-centrolobine and two total synthesis have
been reported.5 In continuation of our interest in the syn-
thesis of tetrahydropyranyl diarylheptanoids,5c,6 herein we
The alcohol 8a was oxidized to aldehyde using Dess–
Martin periodinane followed by a Wittig olefination with
[4-(benzyloxy)benzyl]triphenylphosphonium
bromide
via a known literature procedure.4c The above reaction
gave compound 9a in 90% yield (over two steps) as a mix-
HO
OMe
HO
OMe
R
S
S
R
O
O
6
2
6
2
(–)-centrolobine (1a)
(+)-centrolobine (1b)
Figure 1 Structure of (–)- and (+)-centrolobine
SYNTHESIS 2011, No. 1, pp 0123–0126
x
x
.
x
x
.2
0
1
0
Advanced online publication: 26.11.2010
DOI: 10.1055/s-0030-1258341; Art ID: Z24510SS
© Georg Thieme Verlag Stuttgart · New York

124
Ch. R. Reddy et al.
PAPER
BH3⋅DMS,
NaBH4, TsOH
2,2-DMP
TsOH ( 5 mol%)
OH
O
OH
O
LiAlH4
CO2Me
O
HO
CO2Me
O
CO2Me
MeO2C
OH
THF, 0 °C to r.t.
3 h, 91%
CH2Cl2, r.t.
1.5 h, 96%
THF, 0 °C to r.t.
2 h, 91%
5a
2a
3a
4a
i) CBr4, Ph3P
CH2Cl2, 0 °C, 4 h
i) IBX, DMSO–THF
r.t., 1 h
O
OH
O
O
O
Et3SiH, BF3⋅OEt2
O
O
ii) 4-methoxyacetophenone
n-BuLi, DIPEA, THF
–78 °C to –20 °C, 3 h
88% (2 steps)
ii) n-Bu3SnH, AIBN
toulene, reflux, 6 h
77% (2 steps)
CH2Cl2, 0 °C
20 min, 75%
6a
7a
OMe
OMe
OMe
BnO
OMe
5% PtO2, H2
EtOAc–MeOH (3:1)
i) Dess–Martin periodinane
CH2Cl2, r.t., 2 h
O
O
1a
HO
ii) (4-benzyloxybenzyl)triphenyl-
phosphonium bromide
n-BuLi, THF, 0 °C to r.t., 2 h
90% (2 steps)
r.t., 8 h, 97%
(–)-centrolobine
8a
9a
Scheme 1 Synthesis (–)-centrolobine
NOE enhancement
In conclusion, we have accomplished the total synthesis
of (–)-centrolobine and (+)-centrolobine using a chiron
approach. The target molecules were accomplished start-
ing from dimethyl malate in eight steps. The aldol reaction
and reductive etherification for the formation of the tet-
rahydropyran ring are the key steps.
H
H
O
OH
MeO
Figure 2 NOE enhancements for 8a
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 were recorded on Perkin–Elmer 683
spectrometer. Optical rotations were obtained on Jasco Dip 360 dig-
ital polarimeter. 1H and 13C NMR spectra were recorded in CDCl3
soln on a Varian Inova 500 and Bruker Avance 300, with respect to
internal TMS. Mass spectra were recorded on CEC-21-11013 or
Fannigan Mat 1210 double focusing mass spectrometers operating
at a direct inlet system or LC/MSD Trap SL (Agilent Technologies).
ture of E/Z isomers (3:2). Finally, the reduction of the ole-
fin functionality and deprotection of the benzyl ether in
compound 9a was accomplished in a one-pot reaction us-
ing hydrogenation in the presence of platinum(IV) oxide
in ethyl acetate–methanol (3:1), which completed the total
synthesis of (–)-centrolobine (1a).
The attractive feature of the new route shown above is that
the other enantiomer, (+)-centrolobine (1b), has also been
obtained starting from the enantiomer of 2a, (–)-dimethyl
(S)-malate (2b), by following the same sequence of reac-
Methyl (R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)acetate (4a)
To a soln of 3a (2 g, 14.9 mmol) in anhyd CH2Cl2 (20 mL) were
added 2,2-dimethoxypropane (2.74 mL, 22.3 mmol) dropwise and
catalytic amount of TsOH at r.t.; this mixture was stirred for 1.5 h.
When the reaction was complete (TLC monitoring), the mixture
was cooled to 0 °C and quenched with solid NaHCO3 (cat.). Then,
the soln was decanted and concentrated to dryness. Purification of
the residue by column chromatography (silica gel, 5% EtOAc–hex-
anes) gave 4a; yield: 2.48 g (96%).
[a]D28 –16.5 (c 1.0, CHCl3).8a,b
IR (neat): 3457, 2988, 1740, 1439, 1375, 1212, 1065, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.47 (quint, J = 6.4, 13.0 Hz, 1 H),
4.16 (dd, J = 6.0, 8.3 Hz, 1 H), 3.70 (s, 3 H), 3.65 (dd, J = 6.4, 8.3
Hz, 1 H), 2.72 (dd, J = 6.4, 15.8 Hz, 1 H), 2.53 (dd, J = 6.9, 15.8 Hz,
1 H), 1.41 (s, 3 H), 1.36 (s, 3 H).
1
tions used for 2a (Scheme 2). The spectral data (IR, H
and 13C NMR) of both the obtained compounds 1a and 1b
were identical with the reported data. The optical rotation
observed for 1a, [a]D27 –95.2 (c 0.1, MeOH), is compara-
25
ble with that reported for the natural product {Lit.2c [a]D
–97.6 (c 0.1, MeOH)}. The optical rotation observed for
27
1b, [a]D +94.6 (c 0.1, MeOH), is comparable with that
reported for the natural product {Lit.2c [a]D25 +97.0 (c 0.1,
MeOH)}.
same sequence
of reactions as
in Scheme 1
OH
13C NMR (75 MHz, CDCl3): d = 170.7, 108.9, 71.8, 68.8, 51.5, 38.5,
26.6, 25.2.
MS (ESI): m/z = 197 [M + Na]+.
CO2Me
MeO2C
1b
(via 3b to 9b)
2b
(+)-centrolobine
Scheme 2 Synthesis (+)-centrolobine
(R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (5a)
To a suspension of LiAlH4 (0.65 g, 17.2 mmol) in anhyd THF (20
mL) at 0 °C, 4a (2 g, 11.5 mmol) in anhyd THF (20 mL) was added
slowly and the mixture was stirred at r.t. for 2 h. When the reaction
Synthesis 2011, No. 1, 123–126 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (–)-Centrolobine and (+)-Centrolobine
125
was complete (TLC monitoring), the mixture was cooled to 0 °C
and was quenched with moistened Na2SO4 and stirring was contin-
ued for 3 h. The residue was filtered through Celite and filtrate was
washed with brine (20 mL), dried (Na2SO4), and concentrated to
dryness. The residue was purified by column chromatography (sili-
ca gel, 22% EtOAc–hexanes) to afford alcohol 5a; yield: 1.53 g
(91%).
trate was concentrated under reduced pressure. The residue was pu-
rified by column chromatography (silica gel, filter column) to
afford the bromo compound, which was used in the next step imme-
diately.
To a soln of the above bromo compound in anhyd toluene (15 mL)
at reflux temperature were added Bu3SnH (0.23 mL, 0.84 mmol)
and AIBN (0.009 g, 0.05 mmol) and the mixture was stirred at this
temperature for 6 h. When the reaction was complete (TLC moni-
toring), solvent was removed under reduced pressure and residue
was purified by column chromatography (silica gel, 11% EtOAc–
hexanes) to afford compound 7a; yield: 0.12 g (77%, 2 steps).
[a]D28 +2.3 (c 2.0, MeOH).8a,c
IR (neat): 3417, 2925, 2361, 1654, 1554, 1459, 1370, 1220, 1058,
771 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.32–4.20 (m, 1 H), 4.13–4.05 (m,
1 H), 3.80–3.71 (m, 2 H), 3.63–3.54 (m, 1 H), 3.12 (br s, 1 H), 1.90–
1.75 (m, 2 H), 1.42 (s, 3 H), 1.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 108.6, 74.2, 69.2, 59.5, 35.6, 26.6,
25.4.
[a]D28 –5.6 (c 0.5, CHCl3) {for 7b: [a]D28 +5.4 (c 0.5, CHCl3)}.
IR (neat): 2943, 2361, 1670, 1598, 1375, 1256, 1172, 1044, 820,
599 cm–1.
1 H NMR (300 MHz, CDCl3): d = 7.94 (d, J = 8.9 Hz, 2 H), 6.93 (d,
J = 8.9 Hz, 2 H), 4.18–4.02 (m, 2 H), 3.87 (s, 3 H), 3.54 (t, J = 7.2
Hz, 1 H), 2.98 (t, J = 7.2 Hz, 2 H), 1.91–1.58 (m, 4 H), 1.40 (s, 3 H),
1.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.4, 163.3, 130.2, 130.0, 113.6,
108.6, 75.8, 69.3, 55.4, 37.8, 33.0, 26.9, 25.6, 20.6.
MS (ESI): m/z = 279 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H23O4: 279.1596; found:
MS (APCI): m/z = 147 [M + H]+.
(R)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-1-(4-meth-
oxyphenyl)butan-1-one (6a)
To a soln of 2-iodoxybenzoic acid (1.44 g, 5.13 mmol) in DMSO
(10 mL), a soln of alcohol 5a (0.5 g, 3.42 mmol) in THF (15 mL)
was added dropwise at r.t. and stirred for 1 h. When the reaction was
complete (TLC monitoring), Et2O (15 mL) was added to the mix-
ture and the resulting solid materials were filtered. The resulting fil-
trate was washed with aq sat. NaHCO3 soln (15 mL) and the organic
layer was separated. The aqueous layer was extracted with Et2O
(3 × 10 mL). The combined organic layers were washed with brine
(20 mL), dried (Na2SO4), and evaporated in vacuo to obtain the
crude aldehyde, which was used for the next step without purifica-
tion.
279.1608.
[(2S,6R)-2-(4-Methoxyphenyl)tetrahydro-2H-pyran-6-yl]meth-
anol (8a)
To a soln of 7a (0.1 g, 0.35 mmol) in anhyd CH2Cl2 (10 mL) were
added Et3SiH (0.17 mL, 1.1 mmol) and BF3·OEt2 (0.1 equiv) at 0
°C. The mixture was stirred at this temperature for 20 min. Then, the
mixture was quenched with solid NaHCO3 (cat.). The residue was
decanted and concentrated under reduced pressure. Purification of
the residue by column chromatography (silica gel, 16% EtOAc–
hexanes) gave 8a as a viscous liquid; yield: 0.06 g (75%).
[a]D28 –51.6 (c 1, CHCl3).
IR (neat): 3430, 2931, 1612, 1514, 1247, 1037, 829 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.21 (d, J = 7.7 Hz, 2 H), 6.81 (d,
J = 7.7 Hz, 2 H), 4.31 (dd, J = 1.9, 11.5 Hz, 1 H), 3.78 (s, 3 H),
3.64–3.48 (m, 3 H), 2.20 (br s, 1 H), 1.98–1.93 (m, 1 H), 1.80–1.74
(m, 1 H), 1.73–1.62 (m, 1 H), 1.57–1.46 (m, 2 H), 1.40–1.30 (m, 1
H).
To a soln of DIPEA (1.07 mL, 7.63 mmol) in anhyd THF (15 mL)
under an N2 atmosphere at –78 °C, was added 1.6 M BuLi in hex-
anes (4.3 mL, 6.94 mmol) dropwise and the mixture was stirred for
30 min gradually warming up to –20 °C. Then, the mixture was
cooled to –78 °C and 4-methoxyacetophenone (0.52 g, 3.5 mmol) in
anhyd THF (20 mL) was added and the stirring was continued for
40 min. The above crude aldehyde in THF (15 mL) was added to the
mixture and it was stirred at this temperature until complete. The re-
action was quenched with aq sat. NH4Cl (30 mL), the organic layer
was separated, and the aqueous layer was extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine
(20 mL), dried (Na2SO4), and concentrated to dryness. Purification
of the residue by column chromatography (silica gel, 12% EtOAc–
hexanes) gave compound 6a; yield: 0.89g (88%, 2 steps); E/Z iso-
mers 1:1.
13C NMR (75 MHz, CDCl3): d = 158.8, 135.1, 127.2, 113.6, 79.3,
78.5, 66.2, 55.2, 33.3, 26.7, 23.4.
MS (ESI): m/z = 245 [M + Na]+.
IR (neat): 3457, 2924, 2361, 1669, 1601, 1460, 1372, 1259, 1030,
772 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94 (dd, J = 3.2, 8.9 Hz, 2 H),
6.94 (d, J = 8.9 Hz, 2 H), 4.46–4.31 (m, 2 H), 4.17–4.08 (m, 1 H),
3.88 (s, 3 H), 3.68–3.56 (m, 1 H), 3.24–3.0 (m, 2 H), 1.88–1.77 (m,
2 H), 1.67 (br s, 1 H), 1.42 (d, J = 4.5 Hz, 3 H), 1.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.4, 163.8, 130.4, 129.7, 113.8,
108.6, 74.3, 73.5, 69.7, 69.5, 66.6, 65.5, 55.4, 44.7, 39.7, 26.9, 25.7.
MS (ESI): m/z = 295 [M + H]+.
(2S,6R)-6-[4-(Benzyloxy)styryl]-2-(4-methoxyphenyl)tetrahy-
dro-2H-pyran (9a)
To a soln of primary alcohol 8a (0.5 g, 2.25 mmol) in anhyd CH2Cl2
(20 mL) under an N2 atmosphere, was added Dess–Martin periodi-
nane (1.43 g, 3.37 mmol) at r.t. and stirring was continued for 2 h.
Then the mixture was quenched with aq sat. Na2S2O3 soln. The or-
ganic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), and concentrated under re-
duced pressure to give the crude aldehyde, which was used in the
next step without purification.
(R)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(4-methoxyphe-
nyl)butan-1-one (7a)
To a soln of (4-benzyloxybenzyl)triphenylphosphonium bromide
(3.1 g, 5.68 mmol) in THF (35 mL) at 0 °C, 2.5 M BuLi in hexanes
(1.8 mL, 4.5 mmol) was added dropwise slowly over a period of 5
min. This mixture was stirred at this temperature for 30 min. When
the mixture had turned orange-red, a soln of the above crude alde-
hyde in THF (20 mL) was added dropwise at 0 °C and the mixture
was stirred for 1 h. When the reaction was complete (TLC monitor-
To a soln of 6a (0.2 g, 0.68 mmol) in anhyd CH2Cl2 (15 mL), CBr4
(0.27 g, 0.82 mmol) in CH2Cl2 (12 mL) was added and cooled to 0
°C. Ph3P (0.25 g, 0.95 mmol) was added in portions and the mixture
was stirred for 4 h. When the reaction was complete (TLC monitor-
ing), hexanes (15 mL) was added and the mixture was stirred for 10
min. The precipitate was filtered through a pad of Celite and the fil-
Synthesis 2011, No. 1, 123–126 © Thieme Stuttgart · New York

126
Ch. R. Reddy et al.
PAPER
(2) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.;
ing), the mixture was quenched with aq sat. NH4Cl (20 mL) and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The com-
bined organic layers were washed with brine (20mL), dried
(Na2SO4), and concentrated to dryness. Purification of the residue
by column chromatography (silica gel, 4% EtOAc–hexanes) afford-
ed 9a; yield: 0.82 g (90%, 2 steps).
Marini-Bettolo, G. B. Gazz. Chim. Ital. 1964, 94, 287.
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(b) Araujo, C. A. C.; Alefrio, L. V.; Leon, L. L.
IR (neat): 2932, 1608, 1511, 1250, 1176, 1032, 833, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.14 (m, 9 H), 6.91–6.74 (m,
4 H), 6.54–6.39 (m, 1 H), 6.12–6.01 and 5.64–5.54(m, 1 H), 5.03 (d,
J = 4.3 Hz, 2 H), 4.39–4.25 (m, 2 H), 3.77 (s, 3 H), 2.04–1.90 (m, 1
H), 1.86–1.66 (m, 3 H), (1.62–1.44 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 159.2, 158.8, 157.9, 137.0, 136.8,
136.0, 135.4, 132.2, 131.4, 130.7, 130.1, 129.6, 129.0, 128.9, 128.5,
128.3, 127.9, 127.4, 127.3, 115.3, 115.0, 114.2, 79.5, 79.3, 74.8,
69.9, 55.2, 33.8, 33.2, 32.7, 32.0, 24.3, 24.2.
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MS (ESI): m/z = 401 [M + H]+.
(–)-Centrolobine (1a)
To 9a (0.2 g, 0.5 mmol) in a mixture of EtOAc–MeOH (3:1, 10
mL), a catalytic amount of PtO2 was added at r.t. and the mixture
was stirred at r.t. for 8 h under a H2 atmosphere (balloon). When the
reaction was complete (TLC monitoring), the mixture was filtered
through a pad of Celite and evaporated under reduced pressure. The
residue was purified by column chromatography (silica gel, 12%
EtOAc–hexanes) to afford the desired product 1a; yield: 0.15 g
(97%).
IR (neat): 3383, 2929, 2853, 1612, 1513, 1447, 1246, 1035, 828,
763 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.23 (d, J = 8.9Hz, 2 H), 6.97 (d,
J = 8.5 Hz, 2 H), 6.81 (d, J = 8.9 Hz, 2 H), 6.64 (d, J = 8.5 Hz, 2 H),
4.66 (br s, 1 H), 4.24 (dd, J = 1.7, 10.7 Hz, 1 H), 3.78 (s, 3 H), 3.46–
3.32 (m, 1 H), 2.75–2.55 (m, 2 H), 1.99–1.38 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 158.8, 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, 30.6, 23.9.
MS (ESI): m/z = 313 [M + H]+.
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Acknowledgment
P.P.M. thanks CSIR, New Delhi for financial assistance.
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