Total synthesis of diospongin A via an enzymatic kinetic resolution of (±)-tetrahydropyranol derived from prins cyclization

Article abstract of DOI:10.1055/s-2007-984886

A concise and efficient total synthesis of diospongin A is described; it utilizes Prins cyclization and enzymatic kinetic resolution as key steps. This is the first report on the synthesis of diospongin A by means of lipase-mediated transesterification of

Full text of DOI:10.1055/s-2007-984886

LETTER
2045
Total Synthesis of Diospongin A via an Enzymatic Kinetic Resolution of
( )-Tetrahydropyranol Derived from Prins Cyclization
Total
S
ynt
.
hesis of
D
ios
S
pongin
A
. Yadav,* B. Padmavani, B. V. Subba Reddy, Ch. Venugopal, A. Bhaskar Rao
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 19 April 2007
reports on the total synthesis of diospongins using Prins
cyclization. In recent years, the application of enzymes as
biocatalysts has received great importance in organic
synthesis. In particular, lipases are the most widely used
enzymes for the regio- and enantioselective biotrans-
formations as they are inexpensive, stable at different pH
values and temperatures, and easy to recycle on immobi-
lization of enzyme. Lipase-catalyzed reactions have been
applied to solve a number of synthetic problems, one of
which is the kinetic resolution of diastereomeric and enan-
tiomeric mixtures of primary and secondary alcohols
either by selective hydrolysis of the racemic esters or by
transesterification of racemic alcohols.3a Lipases (tri-
glycerol acylhydrolases, EC 3.1.1.3) are particularly
suited for the resolution of secondary alcohols, since these
enzymes exhibit enhanced stability and enantioselectivity
in organic solvents while accepting a broad range of sub-
strates. For these reasons Porcine pancreatic lipase
(PPL), which is available as an inexpensive crude prepa-
ration, has found many practical applications.3b Porcine
pancreatic lipase (PPL) is one of the most versatile and
widely used enzymes in the resolution of esters and alco-
hols in both aqueous and organic media. This enhanced
our interest in employing the Porcine pancreatic lipase for
the kinetic resolution of ( )-tetrahydropyranol 3 derived
by means of Prins cyclization.
Abstract: A concise and efficient total synthesis of diospongin A is
described; it utilizes Prins cyclization and enzymatic kinetic re-
solution as key steps. This is the first report on the synthesis of
diospongin A by means of lipase-mediated transesterification of
( )-tetrahydropyranol derived from Prins cyclization.
Key words: Prins cyclization, kinetic resolution, Mitsunobu inver-
sion, Wacker oxidation
Diospongins A and B possess a six-membered cyclic ether
core with two aromatic side chains (Figure 1). Diospon-
gins A and B were first isolated recently from the
rhizomes of Dioscorea spongiosa.1 They are known to ex-
hibit potent anti-osteoporotic activity. Due to the promis-
ing biological activities of diospongins, we have been
interested in the total synthesis of bioactive natural prod-
ucts, which contain substituted tetrahydropyran rings.
Prins cyclization2 is one of the most simple and straight-
forward approaches for the construction of tetrahydro-
pyran ring system. Surprisingly, there have been no
OH
OH
O
O
O
O
In this report, we wish to describe an enzymatic approach
for the synthesis of diospongin A starting from cinnamal-
dehyde in six steps. Retrosynthetic analysis of (–)-dio-
spongin A is depicted in Scheme 1.
diospongin A (1)
diospongin B
Figure 1
OH
O
OAc
O
OH
O
O
1
4
3
OH
CHO
+
2
Scheme 1
SYNLETT 2007, No. 13, pp 2045–2048
1
3
.0
8
.2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984886; Art ID: D12307ST
© Georg Thieme Verlag Stuttgart · New York

2046
J. S. Yadav et al.
LETTER
..
HOCOCF3
Ph
O
H
Ph
TFA
O
+
Ph
+
HO Ph
H
Ph
..
O
+
Ph
O
H
H
H
OCOCF3
OH
K2CO3
Ph
Ph
O
Ph
Ph
O
Scheme 2
Retrosynthetic analysis of 1 illustrates that optically state, which has an increased stability relative to the open
active tetrahydropyranol 4 could be achieved by means of oxocarbenium ion due to delocalization. The optimal
an enzymatic kinetic resolution of 3, which could easily geometry for this delocalization places the hydrogen atom
be prepared from the Prins cyclization (Scheme 1). The at C4 in a pseudo-axial position, which favors equatorial
synthesis of diaspongin A began with cinnamaldehyde attack of the nucleophile (Scheme 2).5
and 1-phenylbut-3-en-1-ol (2), which could be easily ob-
Subsequent resolution of product 3 by using Porcine pan-
tained by means of Barbier allylation of benzaldehyde.
creatic lipase and vinyl acetate in the presence of cyclo-
Accordingly, homoallylic alcohol 2 was subjected to Prins
hexane afforded pure acetate
4 and alcohol 5
cyclization with cinnamaldehyde to produce product 3 in
78% yield as a single diastereomer, the stereochemistry of
which was determined by NOE studies as reported previ-
ously.4 A rationale for the all-cis selectivity involves for-
mation of an E-oxocarbenium ion via a chairlike transition
approximately in a 1:1 ratio. The pure acetate 4 was then
deprotected by using K2CO3 in MeOH to furnish alcohol
6 in 92% yield. The enantiomeric excess of compound 6
was 94%, which was determined by chiral HPLC.6 Inver-
sion of the alcohol 6 was achieved by the Mitsunobu
OH
OH
CHO
O
a
+
2
3
OAc
OH
b
O
3
O
+
4
5
O
OH
O
NO2
O
c
O
d
4
6
7
O
O
OH
NO2
O
e
O
f
O
O
1
8
Scheme 3 Reagents and conditions: (a) cinnamaldehyde, TFA, CH2Cl2 then K2CO3, MeOH, r.t., 4 h, 78%; (b) porcine pancreatic lipase (PPL,
20%w/w), vinyl acetate, cyclohexane, r.t., 5 d, (1:1); (c) K2CO3 (1 equiv), MeOH, r.t., 15 min, (92%) (d) PPh3 (1.1 equiv), DIAD (1.1 equiv),
p-nitrobenzoic acid (1.5 equiv), dry toluene, 0 °C to r.t., 3–4 h, (90%); (e) PdCl2 (0.5 equiv), CuCl (3 equiv), DMF–H2O (1:7), 50–55 °C, O2,
3 d, (89%); (f) K2CO3 (1 equiv), MeOH, r.t., 15 min (90%).
Synlett 2007, No. 13, 2045–2048 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Diospongin A
2047
reaction7 using diisopropylazodicaboxylate (DIAD),
triphenylphosphine, and p-nitrobenzoic acid in toluene to
afford the product 7 in 90% yield. Subsequent Wacker
oxidation8 of compound 7 using PdCl2 and CuCl in DMF–
H2O afforded product 8 in 89% yield. Compound 8 was
then subjected to hydrolysis using K2CO3 in MeOH to fur-
nish the target molecule, diospongin A (1) in 90% yield
(Scheme 3). The structure of the diospongin A was con-
firmed by comparing its spectral and physical data with
the natural product isolated by Jun Yin et al.,1 and also
with previous synthetic reports.9
(6) The enantiomeric excess of the product 6 was determined by
using the Shimadzu high-performance liquid-chromatog-
raphy (HPLC) system equipped with a chiral HPLC column
(Eurocel 01, 5 mm OD) and a UV detector (225 nm). A
solvent system of n-hexane–i-PrOH (8:2) and a flow rate of
1.0 mL/min were used.
(7) Mitsunobu, O. Synthesis 1981, 1.
(8) For a review on Wacker oxidation: Tsuji, J. Synthesis 1984,
369.
(9) (a) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71,
7911. (b) Bressy, C.; Allais, F.; Cossy, J. Synlett 2006,
3455. (c) Chandrasekhar, S.; Shyamsunder, T.; Jayaprakash,
S.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47,
47.
(10) (E)-2-Phenyl-6-styryl-tetrahydro-2H-pyran-4-ol (3)
Trifluoroacetic acid (16.3 mL) was added slowly to a
solution of 2 (1.2 g, 8.0 mmol) and cinnamaldehyde (3.16 g,
24.0 mmol) in CH2Cl2 (50 mL) at r.t. under a nitrogen
atmosphere. The reaction mixture was stirred for 3.0 h and
then treated with sat. aq NaHCO3 solution (40 mL) followed
by Et3N to adjust pH > 7. The organic layer was separated
and then the aqueous layer was extracted with CH2Cl2
(3 × 40 mL). The solvent was removed in vacuo and the
resulting crude product was treated with K2CO3 (2 g) in
MeOH (30 mL) over 0.5 h. Then, MeOH was removed under
reduced pressure and diluted with H2O (15 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed
under reduced pressure. The crude product was purified by
column chromatography to afford product 3 as yellow liquid
(1.77 g, 78%). Rf = 0.4 (SiO2, 30% EtOAc in hexane). IR
(KBr): n = 3420, 3029, 2922, 1717, 1602, 1494, 1450, 1063,
755, 699 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.44–7.13
(m, 10 H), 6.62 (d, J = 15.8 Hz, 1 H), 6.24 (dd, J = 15.8, 5.2
Hz, 1 H), 4.53 (d, J = 11.3 Hz, 0.5 H), 4.44 (d, J = 11.3 Hz,
0.5 H), 4.17 (dd, J = 10.5, 4.5 Hz, 1 H), 4.11–3.92 (m, 1 H)
2.33–2.10 (m, 2 H), 1.63–1.35 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 141.8, 136.7, 130.4, 129.5, 128.4, 128.3, 128.3,
127.5, 127.4, 126.4, 126.0, 125.8, 77.7, 76.3, 68.4, 42.8,
41.1. MS (EI): m/z = 281 [M + 1].
In summary, we have described a short and efficient
enzymatic synthetic route for the synthesis of diospongin
A. The synthesis involves direct and straightforward
reactions such as the Prins cyclization, enzymatic kinetic
resolution, Mitsunobu inversion, and Wacker oxidation
that make it quite simple and more convenient for scaling
up the products.10
Acknowledgment
B.P.V. and Ch.V. thank CSIR New Delhi for the award of
fellowships.
References and Notes
(1) Yin, J.; Kouda, K.; Tezuka, Y.; Le Tran, Q.; Miyahara, T.;
Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54.
(2) For the Prins cyclization, see for example: (a) Barry, C. S.
J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001,
66, 739. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew.
Chem. Int. Ed. 2005, 44, 3485. (d) Barry, C. S.; Bushby, N.;
Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683.
(e) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407. (g)Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919. (h) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(i) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679. (j) Kopecky, D. J.; Rychnovsky, S. D. J.
Am. Chem. Soc. 2001, 123, 8420. (k) Rychnovsky, S. D.;
Thomas, C. R. Org. Lett. 2000, 2, 1217. (l) Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
3022. (m) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425. (n) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.;
Gunasekar, D. Synthesis 2001, 885. (o) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. S.; Niranjan, N. J. Mol. Catal. A: Chem.
2004, 210, 99. (p) Yadav, J. S.; Reddy, B. V. S.; Reddy, M.
S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779. (q) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.;
Prasad, A. R. Tetrahedron Lett. 2007, 48, 1469.
(2S,4R,6R)-2-Phenyl-6-[(E)-styryl]tetrahydro-2H-
pyran-4-yl Acetate (4)
A mixture of ( )-3 (1.5 g, 5.3 mmol) and vinyl acetate (5
mL) in cyclohexane (10 mL) was stirred with the enzyme
Porcine pancreatic lipase (EC 3.1.1.3) type II (ca. 300 mg,
20% w/w) supplied by Sigma Aldrich at r.t. for 5 d. The
reaction mixture was filtered through a pad of Celite. The
combined filtrate and washings (EtOAc) were evaporated
under reduced pressure. The residue obtained was purified
by column chromatography on silica gel to furnish the
required enantiomerically pure acetate 4 (759 mg, 44%) and
alcohol 5 (690 mg, 46%).
Compound 4: liquid; [a]D25 –8.5 (c 1.15, CHCl3). IR (KBr):
n = 3445, 3029, 2926, 2852, 1737, 1632, 1450, 1366, 1240,
1164, 1061, 1033, 968, 912, 754, 697 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.42–7.15 (m, 10 H), 6.63 (d, J = 16.6 Hz,
1 H), 6.23 (dd, J = 6.0, 16.6 Hz, 1 H), 5.26–5.03 (m, 1 H),
4.53 (dd, J = 1.5, 11.3 Hz, 1 H), 4.26 (dd, J = 6.0, 11.3 Hz, 1
(3) (a) Chojnacka, A.; Robert, O.; Wawrzeńczyka, C.
Tetrahedron: Asymmetry 2007, 18, 101. (b) Morgan, B.;
Oehlschlager, C. A.; Stokes, M. T. J. Org. Chem. 1992, 57,
3231.
(4) Yadav, J. S.; Reddy, B. V. S.; Mahesh Kumar, G.; Murthy
Ch., V. S. R. Tetrahedron Lett. 2001, 42, 89.
(5) (a) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem.
Soc. 2002, 124, 4960. (b) Ramesh, J.; Rychnovsky, S. D.
Org. Lett. 2006, 8, 2175. (c) Biermann, U.; Lutzen, A.;
Metzger, J. O. Eur. J. Org. Chem. 2006, 2631.
H), 2.35–2.14 (m, 2 H), 2.04 (s, 3 H), 1.73–1.50 (m, 2 H). 13
C
NMR (75 MHz, CDCl3): d = 170.7, 142.0, 141.8, 137.0,
130.9, 129.5, 128.8, 128.6, 127.9, 126.8, 126.2, 126.1, 78.0,
77.8, 70.9, 70.7, 39.6, 39.3, 37.6, 21.5. MS (EI): m/z = 345
[M + 23].
Compound 5: liquid; [a]D25 +4.5 (c 0.35, CHCl3).
(2S,4R,6R,E)-2-Phenyl-6-styryltetrahydro-2H-pyran-4-
ol (6)
Compound 4 (500 mg, 1.5 mmol) was dissolved in MeOH
(10 mL) and stirred with K2CO3 (214 mg, 1.5 mmol) for 15
Synlett 2007, No. 13, 2045–2048 © Thieme Stuttgart · New York

2048
J. S. Yadav et al.
LETTER
min at r.t. Then, MeOH was removed under reduced
pressure and H2O (15 ml) was added. The mixture was
extracted with CH2Cl2 (3 × 15 mL) and the combined
organic layers were dried with Na2SO4 and concentrated
under vacuum. The crude was purified by column
chromatography on silica gel to furnish desired product 6 as
yellow liquid (399 mg, 92%). Rf = 0.4 (SiO2, 30% EtOAc in
hexane); [a]D25 –5.2 (c 0.35, CHCl3, 94% ee). IR (KBr): n =
3420, 3029, 2922, 1717, 1602, 1494, 1450, 1063, 755, 699
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.41–7.15 (m, 10 H),
6.62 (d, J = 15.8 Hz, 1 H), 6.24 (dd, J = 5.2, 15.8 Hz, 1 H),
4.44 (dd, J = 2.2, 12.0 Hz, 1 H), 4.17 (dd, J = 4.5, 10.5 Hz, 1
H), 4.11–3.92 (m, 1 H), 2.31–2.11 (m, 2 H), 1.62–1.39 (m, 2
H). 13C NMR (75 MHz, CDCl3): d = 141.8, 136.7, 130.4,
129.5, 128.4, 128.3, 128.3, 127.5, 127.4, 126.4, 126.0,
125.8, 77.7, 76.3, 68.4, 42.8, 41.1. MS (EI): m/z = 281 [M +
1].
was raised to 50–55 °C. The mixture was kept stirring for
3 d while maintaining the heating conditions under the
atmosphere of oxygen. Then, H2O (5 mL) was added to
quench the reaction, and the resulting mixture was extracted
with Et2O (4 × 15 mL). The combined organic phases were
washed with H2O (10 mL) and brine, dried over Na2SO4, and
concentrated in vacuo. Chromatography of the residue on
silica gel (PE–EtOAc, 20:1) afforded 8 (323 mg, 89%) as
yellow solid. Rf = 0.5 (SiO2, 20% EtOAc in hexane); mp
167–169 °C(unknown); [a]D25 +31.4 (c 0.85, CHCl3). IR
(KBr): n = 2923, 2854, 1722, 1684, 1602, 1526, 1449, 1346,
1275, 1108, 1061, 1008, 870, 784, 753 cm–1. 1H NMR (200
MHz, CDCl3): d = 8.37–8.28 (m, 4 H), 7.97 (dd, J = 1.5, 6.7
Hz, 2 H), 7.61–7.35 (m, 3 H), 7.30–7.17 (m, 5 H), 5.63–5.54
(m, 1 H), 4.88 (dd, J = 2.2, 11.7 Hz, 1 H), 4.75–4.57 (m, 1
H), 3.46 (dd, J = 5.8, 16.1 Hz, 1 H), 3.04 (dd, J = 5.8, 16.1
Hz, 1 H), 2.23 (d, J = 13.9 Hz, 2 H), 2.07–1.61 (m, 2 H). 13
NMR (75 MHz, CDCl3): d = 197.8, 163.8, 150.7, 141.6,
137.2, 135.7, 133.2, 130.8, 128.5, 128.3, 128.2, 127.6,
125.7, 123.6, 74.5, 69.9, 69.6, 44.7, 36.9, 35.3, 29.6. MS
(EI): m/z 468 [M + 23].
C
(2S,4S,6R)-2-Phenyl-6-[(E)-styryl]tetrahydro-2H-pyran-
4-yl-4-nitrobenzoate (7)
To a solution of compound 6 (300 mg, 1.0 mmol) in dry
toluene, cooled to 0–5 °C, PPh3 (308 mg, 1.1 mmol), p-
nitrobenzoic acid (268 mg, 1.5 mmol), and DIAD (238, 1.1
mmol) were added under inert conditions and kept stirring
for 3 h at r.t. After the completion of reaction toluene was
removed under vacuum and the resulting crude was
subjected to column chromatography that afforded the
product 7 as white solid (416 mg, 90%). Rf = 0.8 (SiO2, 20%
EtOAc in hexane); mp149–151 °C(unknown); [a]D25 –21.5
(c 1.0, CHCl3). IR (KBr): n = 3029, 2956, 2922, 2856, 1722,
1604, 1526, 1494, 1450, 1344, 1273, 1107, 1056, 1017, 965,
872, 750, 695 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.39–
8.27 (m, 4 H), 7.43–7.16 (m, 10 H), 6.67 (d, J = 15.8 Hz, 1
H), 6.25 (dd, J = 5.2, 15.8 Hz, 1 H), 5.66–5.59 (m, 1 H), 4.93
(d, J = 9.8 Hz, 1 H), 4.65 (dd, J = 5.2, 11.3 Hz, 1 H), 2.33–
2.13 (m, 2 H), 2.07–1.88 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 163.7, 150.6, 141.6, 136.5, 135.7, 130.7, 129.3,
128.4, 128.4, 127.7, 127.6, 126.4, 125.9, 125.7, 123.6, 74.5,
73.3, 69.7, 37.1, 35.5. MS (EI): m/z = 452 [M + 23].
(2R,4S,6S)-2-(2-Oxo-2-phenylethyl)-6-phenyltetra-
hydro-2H-pyran-4-yl-4-nitrobenzoate (8)
2-[(2R,4S,6S)-4-Hydroxy-6-phenyltetrahydro-2H-
pyran-2-yl]-1-phenylethanone (1)
Compound 8 (250 mg) was dissolved in MeOH (10 mL)
and stirred with K2CO3 (77 mg, 1 equiv) for 15 min. Then
MeOH was removed under reduced pressure and H2O (15
mL) was added. The mixture was extracted with CH2Cl2
(3 × 15 mL), the combined organic layers dried with
Na2SO4, and concentrated under vacuum. The crude was
purified by column chromatography on silica gel to furnish
desired product, diospongin A(1) as colorless amorphous
solid in 90% (149 mg) yield. Rf = 0.21 (SiO2, 40% EtOAc in
hexane); mp 68–70 °C(unknown); [a]D25 –19.8 (c 0.35,
CHCl3); lit.9 [a]D25 –19.6, (c 0.0084, CHCl3). IR (KBr): n =
3377, 2922, 1683, 1596, 1450, 1369, 1209, 1060, 998, 914,
750, 694 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.98 (dd,
J = 1.0, 7.5 Hz, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5
Hz, 2 H), 7.33–7.17 (m, 5 H), 4.93 (dd, J = 2.2, 12.0 Hz, 1
H), 4.64 (dddd, J = 1.5, 5.2, 6.0, 11.3 Hz, 1 H), 4.39–4.34
(m, 1 H), 3.41 (dd, J = 5.2, 15.8 Hz, 1 H), 3.06 (dd, J = 7.5,
15.8 Hz, 1 H), 1.96 (d, J = 14.3 Hz, 2 H), 1.80–1.57 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 198.3, 142.6, 137.2, 133.0,
128.5, 128.3, 128.2, 127.2, 125.8, 73.7, 69.0, 64.6, 45.1,
40.0, 38.4. MS (EI): m/z = 297 [M + 1].
Oxygen was bubbled into a mixture of PdCl2 (72 mg, 0.4
mmol), CuCl (416 mg, 2.4 mmol), DMF (7 mL), and H2O (1
mL) at r.t. The reaction mixture was stirred at r.t. for 30 min
to give a deep green mixture, and then compound 7 (350 mg,
0.8 mmol) was added. The temperature of reaction mixture
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