New stereoselective synthesis of paeonilactone B

Article abstract of DOI:10.1055/s-0028-1088039

A new stereoselective synthesis of paeonilactone B has been achieved in ten steps and in 11.5% overall yield starting from the enantiomerically enriched terpenol 2. Key synthetic steps are based on a regioselective metalation and on a regio- and diastereo

Full text of DOI:10.1055/s-0028-1088039

PAPER
1287
New Stereoselective Synthesis of Paeonilactone B
S
tereoselectiv
r
S
ynthe
a
sis of Paeon
n
ilactone
B
cesco G. Gatti,*a Stefano Serrab
a
Dipartimento di Chimica dei Materiali, Ingegneria Chimica ‘G. Natta’ del Politecnico, Via Mancinelli 7, 20131 Milan, Italy
Fax +39(02)23993080; E-mail: francesco.gatti@polimi.it
CNR- Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milan, Italy
b
Received 21 August 2008; revised 5 January 2009
mediate 2 on which our strategy is based. Indeed, from
such an intermediate we planned to proceed similarly to
other reported syntheses.4a,b
Abstract: A new stereoselective synthesis of paeonilactone B has
been achieved in ten steps and in 11.5% overall yield starting from
the enantiomerically enriched terpenol 2. Key synthetic steps are
based on a regioselective metalation and on a regio- and diastereo-
selective epoxidation.
Recently we have described a new and efficient prepara-
tion of the enantiomerically enriched trans-terpenol 3
(81% ee) by enzymatic resolution.8
Key words: natural product, terpene, metalation, homoallylic ep-
oxidation, lactone
HO
O
HO
HO
O
H
O
H
Paeony roots (Paeonia albiflora Pallas) are largely used in
traditional Chinese medicine for the treatment of abdomi-
nal pain.1 In the 1985, the terpenes 1a–c, called respec-
tively paeonilactone A, B, and C, were identified as the
main biological active constituents of this plant
(Figure 1).2
H
O
OH
H
H
H
O
I
2
1b
O
OH
7
HO
HO
1
O
6
5
2
O
H
H
ref. 6, 8
H
O
3
4
O
OH
H
H
H
8
10
9
O
O
R
3
1b, paeonilactone B
1a, paeonilactone A, R = H
1c, paeonilactone C, R = OBz
Scheme 1 Retrosynthesis of paeonilactone B
Figure 1
The synthesis of 1b is shown in Scheme 2. First, we regio-
selectively introduced the hydroxy functionality at C10 by
quenching the metalated form of 3, obtained by treatment
with butyllithium and potassium tert-butoxide in hexane
at room temperature, with fluorodimethoxyborane at –78
°C, and successively with hydrogen peroxide at –50 °C to
give diol 4, as a white solid, in 41% yield after crystalliza-
tion in hexane–diethyl ether.9 The crystallization allowed
a substantial improvement in the initial enantiomeric ex-
cess up to 98% (vide infra). The observed complete regi-
oselectivity is likely due to the presence of the hydroxy
group, indeed, the metalation of limonene under similar
experimental conditions gives a mixture of the two possi-
ble regioisomers.10 Then, we proceeded with the inversion
of the C3 stereocenter by a standard oxidation–reduction
protocol. However, first we selectively protected the pri-
mary hydroxy group with tert-butyldiphenylsilyl chloride
in N,N-dimethylformamide and in the presence of imida-
zole to give 5 in 94% yield. Thus, the alcohol 5 was oxi-
dized with Dess–Martin periodinane in dichloromethane
to give the corresponding ketone,11 which was then re-
duced with L-Selectride at –78 °C in tetrahydrofuran to
give the cis-alcohol 6 in 74% yield over two steps. Epoxi-
The important biological activity and unique structural
complexity of these terpenes have attracted the attention
of several organic chemists, who have been challenged by
its preparation, either in racemic3 or in enantiomerically
pure form.4,5 Herein, we present a new stereoselective
synthesis of paeonilactone B (1b).
Inspection of 1b reveals three main structural features: (1)
a tertiary alcohol a to a ketone, (2) a butanolide lactone
cis-fused to a six-membered ring, and (3) an exocyclic
double bond. Our retrosynthetic analysis led us to envis-
age 3 as the optimal starting material (Scheme 1).6 Indeed,
3 bears an isopropenyl and a hydroxy group in favorable
positions. Moreover, the latter might assist the formation
of the required quaternary stereocenter exploiting the
Sharpless epoxidation of chiral homoallylic alcohols.7
Thus, it is matter of how to introduce functionality at C10
and manipulate it in such a way to prepare the key inter-
SYNTHESIS 2009, No. 8, pp 1287–1290
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088039; Art ID: T14208SS
x
x
.
x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1288
F. G. Gatti, S. Serra
PAPER
dation of the latter with one stoichiometric equivalent of {[a]D25 +22.7 (c 0.5, MeOH) [Lit.2 [a]D +23.2 (MeOH)]}
tert-butyl hydroperoxide in the presence of a catalytic in 91% yield.
amount of vanadyl acetylacetonate, in benzene at room
In conclusion we have reported a new and concise stereo-
temperature, gave exclusively 7 in 93% yield.7,12,13 We
selective synthesis of 1b in ten steps starting from 2, and
were quite surprised by the high regioselectivity, because
in 11.5% overall yield.
the epoxidation of the exocyclic double bond of (+)-
neoisopulegol12,13 proceeds in high yield under identical
1H NMR and 13C NMR: Bruker AMX 400 (400 MHz); CDCl3 solns
experimental conditions.
at r.t. unless otherwise stated, chemical shifts relative to internal
TMS. TLC analyses: Merck Kieselgel 60 F254 plates. All the gravi-
metric chromatographic columns were carried out using silica gel.
All solvents and reagents were purchased from Fluka and were used
H
H
H
a
c
without any further purification.
OH
OH
OH
H
H
H
(1S,6R)-6-[1-(Hydroxymethyl)vinyl]-3-methylcyclohex-3-en-1-
ol (4)
3
OR
OTBDPS
4, R = H
6
To a well-stirred soln of BuLi (14. mL, 35.5 mmol) in hexane (20
mL) was added dropwise a soln of 3 (2.7 g, 17.8 mmol) in hexane
(5 mL) and t-BuOK (2.2 g, 19.6 mmol) at 0 °C to r.t. under an N2
atmosphere. After 4 h, (MeO)2BF (8.3 g, 53.3 mmol) was added
dropwise at –78 °C, and, after 1 h H2O2 (6 mL, 30%) was added at
–50 °C over 10 min. After 1 h of vigorous stirring at r.t., the mixture
was poured into 1 M NaOH (100 mL) and extracted with Et2O
(2 × 50 mL). The combined organic phases were washed with brine
(40 mL), dried (Na2SO4), and concentrated under reduced pressure.
Column chromatography purification (hexane–EtOAc, 7:3) gave, in
order of elution, 3 (0.9 g) and 4 (1.9 g, 63%). Upon crystallization
(hexane–Et2O, 9:1), diol 4 (1.3 g, 41%) was obtained as white crys-
tals; mp 110 °C.
b
5, R = TBDPS
d
HO
H
O
HO
H
AcO
RO
g
e
H
OH
H
O
H
OH
H
O
OTBDPS
OR
7
10, R = Ac
8, R = TBDPS
9, R = H
[a]D25 +96.1 (c 1.0, CHCl3).
h
f
2, R = H
1H NMR (400 MHz, CDCl3): d = 5.33(m, 1 H), 5.24 (dd, J = 1.2,
0.9 Hz, 1 H), 5.08 (br s, 1 H), 4.21–4.07 (mAB, 2 H), 3.81 (ddd,
J = 10.6, 9.6, 5.6 Hz, 1 H), 2.35 (br s, 1 H), 2.36–2.25 (m, 2 H),
2.20–2.0 (m, 3 H), 1.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 149.7, 132.0, 120.0, 113.9, 70.2,
64.8, 46.6, 39.1, 31.9, 23.0.
i
1b
Scheme 2 Synthesis of the key intermediate 2. Reagents and condi-
tions: (a) 1. BuLi, t-BuOK, hexane, 0°C to r.t., 4 h; 2. (MeO)2BF, –78
°C, H2O2, –50 °C, 63%; 41% after crystallization; (b) TBDPSCl, imi-
dazole, DMF, r.t., 94%; (c) 1. DMP, CH2Cl2; 2. L-Selectride, THF,
–78 °C; 78% (2 steps); (d) cat. VO(acac)2, TBHP, benzene, r.t., 93%;
(e) NaOAc, AcOH, 50 °C, 78%; (f) TBAF, THF, 95%; (g) PhI(OAc)2,
cat. TEMPO, CH2Cl2, r.t.; 1 h, 88%; (h) K2CO3, MeOH, 68%; (i) IBX,
DMSO, 91%.
(1S,6R)-6-{1-[(tert-Butyldiphenylsiloxy)methyl]vinyl}-3-meth-
ylcyclohex-3-en-1-ol (5)
To a r.t. soln of 4 (0.98 g, 5.8 mmol) and imidazole (0.8 g, 11.6
mmol) in DMF (10 mL) was added TBDPSCl (1.75 g, 1.6 mmol).
After complete conversion [TLC (hexane–EtOAc, 8:2)], the mix-
ture was quenched with brine (20 mL) and washed with Et2O (2 ×
50 mL). The combined organic phases were washed with 0.1 M HCl
(30 mL) and brine (50 mL). Then, the organic phase was dried
(Na2SO4) and the solvent was removed under reduced pressure to
give crude material, which was purified by column chromatography
(hexane–EtOAc, 9:1) to give 5 (2.2 g, 94%) as yellow oil.
Next, the epoxide ring was opened by treatment with
sodium acetate in acetic acid at 50 °C to give the hydroxy
acetate 8 in 78% yield.
At this stage the synthetic sequence was completed by
cleavage of the protective silyl group with tetrabutylam-
monium fluoride in tetrahydrofuran to give 9 in 95%
yield, which was then transformed to the lactone 10 by ox-
idation of the primary alcohol with a catalytic amount of
2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and (di-
acetoxyiodo)benzene as co-oxidant in dichloromethane at
room temperature in 88% yield.14 Then, hydrolysis of 10
with potassium carbonate in methanol gave 2 in 68% yield
{[a]D25 +30.8 (c 1.0, CHCl3) [Lit.4a [a]D +31.6 (CHCl3)]}.
Finally, 2 was converted into paeonilactone B (1b) by
Swern oxidation of the secondary hydroxy group follow-
ing the previously reported procedure in a modest 37%
yield, moreover, the resulting purification was trouble-
some.3a,4a,b Alternatively, oxidation of 2 with 2-iodoxy-
benzoic acid (IBX)15 in dimethyl sulfoxide gave 1b
[a]D25 +34.1 (c 1.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.75–7.71 (m, 4 H), 7.48–7.39 (m,
6 H), 5.37 (d, J = 1.6 Hz, 1 H), 5.31 (m, 1 H), 5.12 (br s, 1 H), 4.24–
4.11 (mAB, 2 H), 3.90 (ddd, J = 10.6, 9.6, 5.6 Hz, 1 H), 2.58 (br s, 1
H), 2.36 (m, 1 H), 2.25 (dt, J = 10.4, 5.4 Hz, 1 H), 2.12–2.01 (m, 3
H), 1.69 (s, 3 H), 1.12 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 149.9, 135.6, 133.1, 132.2, 129.8,
127.7, 119.9, 113.0, 69.6, 66.0, 46.7, 38.7, 31.8, 26.8, 23.0, 19.1.
(1R,6R)-6-{1-[(tert-Butyldiphenylsiloxy)methyl]vinyl}-3-meth-
ylcyclohex-3-en-1-ol (6)
To a soln of 5 (1.9 g, 4.7 mmol) in CH2Cl2 (10 mL) was added DMP
(2.2 g, 5.2 mmol). After complete conversion [TLC (hexane–
EtOAc, 8:2)], the mixture was quenched with sat. Na2SO3 soln (20
mL) and sat. NaHCO3 soln (20 mL) and washed with Et2O (2 × 50
mL). The combined organic phases were washed with 0.1 M HCl
Synthesis 2009, No. 8, 1287–1290 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Paeonilactone B
1289
(30 mL) and brine (50 mL). Then, the organic phase was dried
(Na2SO4) and the solvent was removed under reduced pressure to
give crude material, which was of sufficient purity for the next step.
Thus, to a soln of the ketone in THF (20 mL) was added dropwise
1 M L-Selectride in THF (6 mL) at –78 °C over 10 min under an N2
atmosphere. After complete conversion (TLC), the mixture was
quenched with sat. NH4Cl soln (30 mL) and washed with Et2O (2 ×
50 mL). The combined organic phases were washed with brine (50
mL). Then, the organic phase was dried (Na2SO4) and the solvent
was removed under reduced pressure to give crude material. Col-
umn chromatography purification (hexane–Et2O, 9:1) gave 6 (1.4 g,
74%).
duced pressure to give crude material. Column chromatography pu-
rification (silica gel, EtOAc) afforded 9 (0.60 g, 95%) as an oil.
[a]D25 +30.4 (c 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.21 (s, 1 H), 5.05 (s, 1 H), 4.87
(m, 1 H), 4.81 (br s, 1 H), 4.15–4.07 (m, 4 H), 2.57 (br d, J = 13.5
Hz, 1 H), 2.38 (dt, J = 14.5, 2.6 Hz, 1 H), 2.08 (s, 3 H), 1.95 (br d,
J = 14.5 Hz, 1 H), 1.84 (dd, J = 14.8, 2.6 Hz, 1 H), 1.65 (dt, J = 14.1,
2.9 Hz, 1 H), 1.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.1, 148.6, 115.6, 75.3, 70.6,
70.0, 64.5, 40.5, 38.1, 26.1, 24.2, 21.3.
[a]D25 –4.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.76–7.73 (m, 4 H), 7.47–7.41 (m,
6 H), 5.48 (m, 1 H), 5.27 (m, 1 H), 5.09 (br s, 1 H), 4.28–4.17 (mAB
2 H), 4.05 (m, 1 H), 2.40–2.25 (m, 3 H), 2.17–1.95 (m, 2 H), 1.69
(m, 4 H), 1.10 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 149.9, 135.5, 133.2, 130.3 129.7,
127.7, 120.0, 111.9, 66.9, 66.4, 41.6, 40.0, 26.8, 24.9, 23.3, 19.1.
(3aR,5S,6S,7aR)-5-Acetoxy-6-hydroxy-6-methyl-3-methylene-
hexahydrobenzofuran-2(3H)-one (10)
A soln of 9 (0.50 g, 2.0 mmol) in CH2Cl2 (10 mL) was treated with
PhI(OAc)2 (2.1 g, 6.5 mmol) and TEMPO (0.1 g) and stirred at r.t.
until no 9 was detected by TLC (1 h). The mixture was poured into
ice (50 g) and washed with 0.5 M Na2SO3 (50 mL) and extracted
with Et2O (2 × 50 mL). The organic phase was dried (Na2SO4) and
the solvent was removed under reduced pressure. Column chroma-
tography purification (silica gel, EtOAc) afforded 10 (0.43 g, 88%)
as an oil.
,
(1R,2R,4R,5S)-2-{1-[(tert-Butyldiphenylsiloxy)methyl]vinyl}-
4,5-epoxy-5-methylcyclohexan-1-ol (7)
[a]D25 +69.1 (c 0.8, CHCl3).
To a well stirred soln of 6 (1.30 g, 3.2 mmol) in benzene (20 mL)
was added a soln of TBHP in toluene (6.6 mL, 3.23 mmol) and a
catalytic amount of VO(acac)2. After 10 h, the mixture was diluted
with Et2O and washed with brine (30 mL).The organic phase was
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. Column chromatography purification (silica gel, hexane–
EtOAc, 7:3) afforded 7 (1.26 g, 93%) as an oil.
1H NMR (400 MHz, CDCl3): d = 6.25 (d, J = 1.9 Hz, 1 H), 5.64 (d,
J = 1.9 Hz, 1 H), 4.78 (dd, J = 3.6, 6.6 Hz, 1 H), 4.63 (dd, J = 5.6,
11.3 Hz, 1 H), 3.14 (br dd, J = 6.6, 13.1 Hz, 1 H), 2.21–2.00 (m, 5
H), 1.92–1.84 (m, 2 H), 1.22 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 170.3, 169.6, 138.6, 121.2, 75.6,
73.7, 69.2, 37.9, 36.6, 27.0, 23.7, 21.0.
[a]D25 +3.0 (c 1.0, CHCl3).
(3aR,5S,6S,7aR)-5,6-Dihydroxy-6-methyl-3-methylenehexahy-
drobenzofuran-2(3H)-one (2)
1H NMR (400 MHz, CDCl3): d = 7.75–7.65 (m, 4 H), 7.32–7.50 (m,
6 H), 5.26 (br s, 1 H), 5.07 (br s, 1 H), 4.21–4.07 (mAB, 2 H), 3.82
(ddd, J = 10.6, 9.6, 5.6 Hz, 1 H), 3.13 (m, 2 H), 2.28 (dd, J = 2.6,
15.4 Hz, 1 H), 2.16–2.00 (m, 3 H), 1.88 (dd, J = 3.9, 15.4 Hz, 1 H),
1.33 (s, 3 H), 1.08 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 148.6, 135.5, 133.5, 129.9, 127.9,
111.1, 68.0, 66.6, 60.2, 59.8, 39.8, 37.4, 27.1, 25.2, 23.2, 19.5.
An ice-cold mixture of 10 (0.35 g, 1.44 mmol) and K2CO3 (0.40 g,
2.9 mmol) in MeOH (10 mL) was left to reach r.t., and, after com-
plete conversion (TLC), the mixture was concentrated under re-
duced pressure without heating. The moisture was then diluted in
CH2Cl2 (50 mL) and washed with brine (20 mL). The organic phase
was dried (Na2SO4) and the solvent was removed under reduced
pressure. Column chromatography purification (silica gel, EtOAc)
afforded 2 (0.19 g, 68%) as a white solid.
(1S,3R,4R,6S)-6-Acetoxy-4-{1-[(tert-butyldiphenylsiloxy)meth-
yl]vinyl}-1-methylcyclohexane-1,3-diol (8)
[a]D25 +30.8 (c 1.0, CHCl3) {Lit.4a [a]D +31.6 (CHCl3)}.
A soln of 7 (1.2 g, 2.8 mmol) and NaOAc (1.0 g, 12.2 mmol) in
AcOH (10 mL) was heated at 50 °C for 3 h. Then, the mixture was
poured in brine (20 mL) and washed with Et2O (4 × 20 mL). The
combined organic phases were washed with brine (20 mL) and
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. Column chromatography purification (silica gel, hexane–
EtOAc, 2:8) afforded 8 (1.07 g, 78%) as an oil.
1H NMR spectral data are consistent with those previously report-
ed.4a
13C NMR (100 MHz, CDCl3): d = 169.5, 138.3, 121.1, 74.2, 73.8,
68.6, 37.1, 36.6, 23.8, 21.2.
Paeonilactone B (1b)
[a]D2 +18.3 (c 0.7, CHCl3).
A soln of 2 (0.10 g, 0.50 mmol) and IBX (0.28 g, 1.0 mmol) in
DMSO (5 mL) was stirred at r.t. for 3 h. Then the mixture was
quenched with ice (10 g) and brine (10 mL), and washed with
CH2Cl2 (5 × 10 mL). The combined organic phases were dried
(Na2SO4) and the solvent was removed under reduced pressure.
Column chromatography purification (silica gel, EtOAc–hexane,
7:3) afforded 1b (0.09 g, 91%) as a white solid.
1H NMR (400 MHz, CDCl3): d = 7.75–7.65 (m, 4 H), 7.32–7.50 (m,
6 H), 5.26 (br s, 1 H), 5.02 (br s, 1 H), 4.89 (br s, 1 H), 4.66 (br s, 1
H), 4.21–4.07 (mAB, 2 H), 4.01 (br s, 1 H), 3.03 (br s, 1 H), 2.57 (br
d, J = 13.5 Hz, 1 H), 2.38 (dt, J = 14.5, 2.6 Hz, 1 H), 2.03 (s, 3 H),
1.98 (br d, J = 14.5 Hz, 1 H), 1.79 (dd, J = 14.8, 2.6 Hz, 1 H), 1.64
(dt, J = 14.1, 2.9 Hz, 1 H), 1.12 (s, 3 H), 1.06 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 169.9, 148.6, 135.5, 132.8, 129.9,
127.9, 127.8, 114.2, 75.6, 70.1, 68.9, 66.1, 39.1, 37.8, 26.7, 26.0,
24.0, 21.2, 19.1.
[a]D25 +22.7 (c 0.6, MeOH) {Lit.2 [a]D +23.2 (MeOH)}.
1H and 13C NMR spectral data are consistent with those previously
reported.2
(1S,3R,4R,6S)-6-Acetoxy-4-[1-(hydroxymethyl)vinyl]-1-meth-
ylcyclohexane-1,3-diol (9)
Acknowledgment
To a soln of 8 (1.20 g, 2.6 mmol) in THF (10 mL) was added TBAF
(1.0 g, 3.2 mmol). After 1 h the mixture was concentrated under re-
We thank COFIN-MIUR for financial support.
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1290
F. G. Gatti, S. Serra
PAPER
(5) For a review on the synthesis of biological active a-
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(8) Brenna, E.; Fuganti, C.; Gatti, F. G.; Perego, M.; Serra, S.
Tetrahedron: Asymmetry 2006, 17, 792.
(9) Schlosser, M.; Kotthaus, M. Eur. J. Org. Chem. 1999, 459.
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Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 1992, 33,
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Synthesis 2009, No. 8, 1287–1290 © Thieme Stuttgart · New York