Stereoselective total synthesis of (+)-cardiobutanolide and (+)-3-epi-cardiobutanolide from diacetone d-glucose

Article abstract of DOI:10.1016/j.tetlet.2006.04.146

A chiron approach starting with 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-pentodialdo-1,4-furanose utilizing a Grignard reaction, Mitsunobu stereoinversion, ethyl diazoacetate addition, and selective reduction of the ketone is employed as a key step for th

Full text of DOI:10.1016/j.tetlet.2006.04.146

Tetrahedron Letters 47 (2006) 4627–4630
Stereoselective total synthesis of (+)-cardiobutanolide and
(+)-3-epi-cardiobutanolide from diacetone D-glucoseI
Palakodety Radha Krishna* and P. V. Narsimha Reddy
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 February 2006; revised 18 April 2006; accepted 27 April 2006
Abstract—A chiron approach starting with 3-O-benzyl-1,2-O-isopropylidene-a-D-xylo-pentodialdo-1,4-furanose utilizing a Grig-
nard reaction, Mitsunobu stereoinversion, ethyl diazoacetate addition, and selective reduction of the ketone is employed as a key
step for the total synthesis of (+)-cardiobutanolide described; a similar strategy is also reported for the first total synthesis of
(+)-3-epi-cardiobutanolide.
Ó 2006 Elsevier Ltd. All rights reserved.
The annonaceae plant family has been under extensive
investigation by natural product chemists due to the
diverse and potent polyketide constituents it offers.1
Amongst this family, the most interesting is the genus
Goniothalamus since a wide range of compounds with
varied properties were isolated from it. Of the many nat-
ural products isolated, (+)-goniofufurone and its stereo-
isomers2 have been extensively studied synthetic targets
not only because of their interesting biological proper-
ties3 but also due to their exquisite bicyclic core skele-
ton. (+)-Cardiobutanolide 1,4 a structurally dissimilar
natural product was isolated recently from Goniothala-
mus cardiopetalus along with various styryl-lactones.
using D-glucuronolactone as the starting material.6 The
reported strategy derives stereogenic centers at C(3),
C(4), and C(5) from D-glucuronolactone translating as
those of C(3), C(4), and C(5) of 1. As a part of our inter-
est in the synthesis of the butenolide and valerolactone
skeleton-containing bioactive natural products,7 herein
a chiron approach is reported for the synthesis of 1 from
an inexpensive starting material, diacetone D-glucose
(DAG). The first synthesis of 3-epi-cardiobutanolide 2,
a nonnatural product, is also reported wherein ethyl ace-
tate addition resulted in an exclusive isomer, later iden-
tified as the C(3)-epimer of 1, with the remainder of the
chiral centers derived from a common intermediate 5
employed for the synthesis of 1.
OH OH
OH
OH OH
OH
Thus, the synthesis (Scheme 1) was begun following the
literature procedure.8 For instance, the known9 3-O-
benzyl-1,2-O-isopropylidene-a-D-xylo-pentodialdo-1,4-
furanose, obtained from diacetone-D-glucose, on expo-
sure to PhMgBr in THF resulted in 3-O-benzyl-1,2-O-
isopropylidene-5-C-phenyl-a-L-ido-pentofuranose 6 as
the major product and the desired C(5) epimer 7 as
the minor product (78%, 85:15 ratio, respectively). The
diastereomers were separated by column chromatogra-
phy and the major product was subjected to Mitsunobu
reaction (p-NO2C6H4COOH/DEAD/TPP/THF) fol-
lowed by methanolysis (K2CO3/MeOH/rt) of the benzo-
ate formed to invert the chiral center, as a simple means
of enhancing the chemical yield of 7 (85% over two
steps). The gluco configuration at C(5) in 7 was con-
firmed by comparison with reported data.8 Next the
C(5) hydroxyl group in 7 was protected as its benzyl
Ph
3
1
Ph
3
1
OH
O
OH
O
O
O
1
2
(+)-cardiobutanolide
3-epi-cardiobutanolide
An earlier synthesis5 of 1 relied on the anti boron aldol
reaction and asymmetric allylboration of the chiral
starting material for generating the additional stereo-
genic centers. While this manuscript was in preparation,
a stereocontrolled asymmetric synthesis of 1 appeared
Keywords: Diacetone-D-glucose; Cardiobutanolide; 3-epi-Cardiobut-
anolide; Mitsunobu stereoinversion; LiEt3BH reduction.
q IICT communication No. 060101.
*
Corresponding author. Fax: +91 40 27160387; e-mail: prkgenius@
iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.146

4628
P. Radha Krishna, P. V. Narsimha Reddy / Tetrahedron Letters 47 (2006) 4627–4630
HO
Ph
HO
Ph
O
Ref. 8
O
O
D-glucose
O
+
O
BnO
O
BnO
6
7
BnO
Ph
OBn OBn
OBn OBn
O
a, b
O
e, f
c, d
7
Ph
OTBS
10
OBn OBn
Ph
OH
O
O
O
OH OH
BnO
8
9
OBn OBn
OH
O
OBn OBn OH
g
j
h, i
COOEt
Ph
OH
Ph
Ph
O
O
OH
O
O
O
11
5
4
OH OH
OH
O
k
Ph
OH
O
2
Scheme 1. Reagents and conditions: (a) (i) p-NO2–C6H4COOH, DEAD, TPP, THF, 0 °C–rt, 6 h; (ii) K2CO3, MeOH, rt, 1 h (85% over two steps);
(b) BnBr, NaG, THF, 0 °C–rt, 1 h (80%); (c) 30% aq AcOH, reflux, 6 h (70%); (d) LiAlH4, THF, 2 h 0 °C–rt (65%); (e) TBSCl, imidazole, CH2Cl2
(85%); (f) 2,20-DMP, PPTS, CH2Cl2, rt (85%); (g) TBAF, THF, rt (90%); (h, i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C; EtOAc, LiHMDS, THF,
ꢀ78 °C, 1 h (60% over two steps); (j) 80% aq AcOH, 6 h (70%); (k) 10% Pd–C/H2, MeOH (80%).
ether with BnBr in the presence of NaH in DMF to
afford 8 (80%). Cleavage of the 1,2-O-isopropylidene
group of 8 in refluxing 30% aq AcOH (70%) followed
by reduction with LiAlH4 in THF provided triol 9
(65%). The primary alcohol group of 9 was protected
as its TBS ether with TBSCl and imidazole (85%) and
the two secondary 1,3-hydroxy groups were protected
as the acetonide under conventional reaction conditions
using 2,20-DMP in CH2Cl2 catalyzed by PPTS affording
10 (85%). Subsequent desilylation with TBAF in THF
gave 5 in 90% yield.
hyde (EtOAc/LiHMDS/THF/ꢀ78 °C) to afford product
4 (60%) as a single isomer. To determine the configura-
tion of the newly formed stereogenic center unambigu-
ously, the remainder of the synthesis was continued as
planned. b-Hydroxy ester 4 was treated with 80% AcOH
to afford a five-membered lactone 11 in 70% yield, which
on debenzylation (H2/Pd–C/MeOH/rt) afforded the
1
final target compound (80%). However, the H NMR,
25
physical data and ½aꢁD values did not match with the re-
ported values of the natural product. The 1H NMR
spectrum revealed that two of the protons were more
shielded in comparison to those of the natural product
(d 3.82 instead of d 4.40 and d 4.53 instead of d 4.62).
Hence it may be assumed that the EtOAc addition gave
exclusively the anti product, since the other chiral cen-
ters remained untouched. Formation of 4 can be ex-
plained by presuming a metal chelated six-membered
With alcohol 5 in hand, our next task was the two-car-
bon chain elongation preferably with a terminal ester
functional group for later conversion into the lactone
functionality. Thus 5 was subjected to Swern oxidation
and an EtOAc addition reaction on the resulting alde-
OBn OBn
OH
O
OBn OBn OH
O
OBn OBn
e
d
a
COOEt
Ph
COOEt
4
Ph
Ph
OH
O
O
O
O
O
13
3
12
5
f
b, c
OH OH
OH
O
Ph
OH
O
1
˚
Scheme 2. Reagents and conditions: (a) PDC, CH2Cl2, 4 A MS, reflux, 8 h (30%); (b) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C; (c) ethyl
˚
diazoacetate, BF3ÆOEt2, 4 A MS, 0 °C–rt (70% for two steps); (d) LiEt3BH, THF, ꢀ78 °C (85%); (e) 80% aq AcOH, 8 h (80%); (f) H2/Pd–C, MeOH
(80%).

P. Radha Krishna, P. V. Narsimha Reddy / Tetrahedron Letters 47 (2006) 4627–4630
4629
transition state leading to anti addition.10 Consequently,
(+)-3-epi-cardiobutanolide 2 was synthesized instead of
1.
Tetrahedron 1999, 55, 2493–2514; (m) Bruns, R.; Wer-
nicke, A.; Ko¨ll, P. Tetrahedron 1999, 55, 9793–9800; (n)
Mereyala, H. B.; Gadikota, R. R.; Joe, M.; Arora, S. K.;
Datidar, S. G.; Agarwal, S. Bioorg. Med. Chem. 1999, 7,
´
2095–2103; (o) Surivet, J.-P.; Vatele, J.-M. Tetrahedron
Exposure of 4 to PDC in refluxing CH2Cl2 gave b-keto-
ester 12 albeit in a low 30% yield (Scheme 2). In order to
increase the chemical yield, 5 was subjected to Swern
oxidation and then treated with ethyl diazoacetate in
1999, 55, 13011–13028; (p) Su, Y.-L.; Yang, C.-S.; Teng,
S.-J.; Zhao, G.; Ding, Y. Tetrahedron 2001, 57, 2147–2153.
3. Blazquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes,
D. Phytochem. Anal. 1999, 10, 161–170.
4. Hisham, A.; Toubi, M.; Shuaily, W.; Bai, M. D. A.;
Fujimoto, Y. Phytochemistry 2003, 62, 597–600.
5. Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org.
Chem. 2005, 70, 713–716.
6. Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett.
2006, 47, 1371–1374.
7. (a) Radha Krishna, P.; Narsingam, M.; Kannan, V.
Tetrahedron Lett. 2004, 45, 4773–4775; (b) Radha
Krishna, P.; Ramana Reddy, V. V.; Sharma, G. V. M.
Synthesis 2004, 2107–2114; (c) Radha Krishna, P.;
Ramana Reddy, V. V. Tetrahedron Lett. 2005, 46, 3905–
3907.
8. Inch, T. D. Carbohydr. Res. 1967, 5, 45–52.
9. (a) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102,
6304–6311; (b) Anushnab, E.; Venishetti, P.; Leiby, R. W.;
Singh, H. K.; Mikkilineni, A. B.; Wu, D. C.-J.; Saibaba,
R.; Panzica, P. J. Org. Chem. 1988, 53, 2598–2602.
10. Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H.
N. C. J. Org. Chem. 1997, 62, 6359–6366; Mengel, A.;
Reiser, O. Chem. Rev. 1999, 99, 1191–1223.
`
´
˚
the presence of BF3ÆOEt2 and 4 A MS in CH2Cl2 at
0 °C to afford 12 in 70% yield. Stereoselective reduction
of 12 with LiEt3BH11 in THF at ꢀ78 °C gave an easily
separable mixture of 3 and 4 in a 95:5 ratio. The spectral
data of the minor isomer 4 matched with that of the ear-
lier sample (Scheme 1). Next, 3 was treated with 80%
AcOH to give lactone 13 (80%) and finally debenzyl-
ation (H2/Pd–C/MeOH/rt) afforded the natural product
25
25
1, ½aꢁD +8.5 (c 0.4, MeOH) {natural 1; ½aꢁD +6.4 (c
25
0.28, MeOH)4 and synthetic 1, ½aꢁD +5.5 (c 0.28,
25
MeOH),5 ½aꢁD +9.2 (c 1.00, MeOH)6} in 80% yield.
The physical and spectroscopic data of the synthetic
sample 1 were identical to those of the reported natural
and synthetic products.
In conclusion, stereoselective syntheses of (+)-cardio-
butanolide and (+)-3-epi-cardiobutanolide were accom-
plished by means of
a
versatile strategy.12
A
combination of a Mitsunobu stereoinversion reaction,
ethyl diazoacetate addition and selective 1,2-syn reduc-
tion was used as the key step to prepare 1. The synthesis
of 2 was accomplished from a common intermediate 5
wherein ethyl acetate addition resulted in an exclusive
anti product that was further elaborated to the target
compound by a comparable reaction sequence.
11. Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H.
N. C. J. Org. Chem. 1997, 62, 6359–6366.
12. Spectral data of selected compounds. Compound 11:
25
White solid, mp: 118–120 °C; ½aꢁD ꢀ84.14 (c 0.75, CHCl3);
1H NMR (300 MHz, CDCl3); d 7.41–7.21 (m, 15H), 4.75
(d, 1H, J = 11.3 Hz), 4.50 (d, 1H, J = 10.5 Hz), 4.45–4.33
(m, 4H), 4.12 (d, 1H, J = 11.3 Hz), 4.05 (dd, 1H, J = 2.2,
6.9 Hz), 3.81 (dd, 1H, J = 1.51, 8.3 Hz), 2.79 (dd, 1H,
J = 7.5, 18.1 Hz), 2.41 (dd, 1H, J = 6.0, 17.3 Hz); 13C
NMR (75 MHz, CDCl3); 174.41, 138.18, 137.46, 137.34,
128.53, 128.35, 128.29, 128.24, 128.00, 127.89, 127.74,
87.59, 80.53, 76.34, 74.21, 73.19, 70.31, 68.01, 37.15; IR
(KBr), 3443, 3064, 3030, 2924, 2863, 1753, 1497,
1079 cmꢀ1; ESIMS; 471 (M+Na)+, 466 (M+NH4)+, 449
(M+H)+. Anal. Calcd for C27H28O6: C, 72.30; H, 6.29.
Acknowledgment
One of the authors (P.V.N.R.) thanks the CSIR, New
Delhi, for financial support in the form of a fellowship.
25
Found: C, 72.28; H, 6.32. Compound 2: Thick syrup; ½aꢁD
+26.5 (c 0.7, MeOH); 1H NMR (200 MHz, acetone-d6):
7.44 (d, 2H, J = 8.2 Hz), 7.22–7.36 (m, 3H), 4.75 (d, 1H,
J = 8.2 Hz), 4.53 (d, 2H, J = 2.7 Hz), 3.96 (t, 1H,
J = 3.2 Hz), 3.82 (dd, 1H, J = 4.1, 6.8 Hz), 2.84 (m, 1H,
overlapped by residual water), 2.29 (dd, 1H, J = 2.7,
17.8 Hz); 13C NMR (50 MHz, acetone-d6): 177.3, 144.8,
129.6, 129.0, 128.9, 90.3, 76.6, 75.5, 72.6, 71.0, 39.5; IR
(thin film): 3381, 2925, 1766, 1494, 1194 cmꢀ1; HRMS:
calcd m/z 291.0844 (C13H16O6Na). Found m/z 291.0833,
ppm error ꢀ3.9788. Compound 13: White solid, mp: 138–
References and notes
´
´
´
1. (a) Cave, A.; Figadere, B.; Laurens, A.; Cortes, D. Prog.
Chem. Org. Nat. Prod. 1997, 70, 81–288; (b) Zafra-Polo,
´
´
M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes,
D. Phytochemistry 1998, 48, 1087–1117; (c) Alali, F. Q.;
Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–
540.
2. (a) Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H. Tetrahedron
1992, 48, 8659–8666; (b) Prakash, K. R. C.; Rao, S. P.
Tetrahedron 1993, 49, 1505–1510; (c) Murphy, P. J.;
Dennison, S. T. Tetrahedron 1993, 49, 6695–6700; (d) Ye,
J.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1993, 34,
8007–8010; (e) Gracza, T.; Ja¨ger, V. Synthesis 1994, 1359–
1367; (f) Yang, Z.-C.; Zhou, W.-S. Tetrahedron 1995, 51,
1429–1436; (g) Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H.
J. Org. Chem. 1996, 60, 3121–3130; (h) Mukai, C.; Hirai,
S.; Kim, I. J.; Kido, M.; Hanaoka, M. Tetrahedron 1996,
52, 6547–6560; (i) Cagnolini, C.; Ferri, M.; Jones, P. R.;
Murphy, P. J.; Ayres, B.; Cox, B. Tetrahedron 1997, 53,
4815–4820; (j) Yi, X.-H.; Meng, Y.; Hua, X.-G.; Li, C.-J.
J. Org. Chem. 1998, 63, 7472–7480; (k) Chen, W.-P.;
Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 103–
105; (l) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
25
1
140 °C; ½aꢁ ꢀ58.6 (c 1.0, CHCl3); H NMR (200 MHz,
CDCl3); d D7.35–7.17 (m, 15H), 4.85 (d, 1H, J = 11.3 Hz),
4.44 (d, 1H, J = 11.3 Hz), 4.20–4.36 (m, 4H), 4.10 (d, 1H,
J = 8.0 Hz), 3.97 (d, 1H, J = 11.3 Hz), 3.70 (d, 1H, J =
8.0 Hz), 2.55 (dd, 1H, J = 4.0, 16.9 Hz), 2.39 (d, 1H,
J = 17.7 Hz); 13C NMR (75 MHz, CDCl3); 175.45, 138.10,
137.75, 137.08, 128.58, 128.49, 128.44, 128.26, 128.06,
127.94, 85.44, 81.13, 75.46, 74.59, 72.38, 70.46, 68.96,
38.86; IR (KBr), 3412, 3061, 3030, 2925, 2862, 1777, 1453,
1093 cmꢀ1; ESIMS; 471 (M+Na)+, 466 (M+NH4)+, 449
(M+H)+. Anal. Calcd for C27H28O6: C, 72.30; H, 6.29.
Found: C, 72.38; H, 6.21. Compound 1: White crystalline
25
solid; mp: 191–192 °C; ½aꢁ +8.5 (c 0.4, MeOH); 1H NMR
(300 MHz, acetone-d6): dD7.44 (d, 1H, J = 6.7 Hz), 7.22–

4630
P. Radha Krishna, P. V. Narsimha Reddy / Tetrahedron Letters 47 (2006) 4627–4630
7.33 (m, 4H), 4.80 (d, 1H, J = 7.5 Hz), 4.62 (br s, 1H), 4.55
acetone-d6): 176.0, 144.0, 129.8, 128.0, 127.0, 88.5, 76.0,
75.3, 71.6, 70.7, 39.0; IR (KBr): 3512, 3476, 2930, 2853,
1760, 1447, 1207 cmꢀ1; HRMS: calcd m/z 291.0844
(C13H16O6Na). Found m/z 291.0834, ppm error ꢀ3.6353.
(dd, 1H, J = 3.0, 6.7 Hz), 4.40 (d, 1H, J = 7.5 Hz), 3.96 (d,
1H, J = 6.0 Hz), 2.84 (m, 1H, overlapped by residual
water), 2.38 (d, 1H, J = 16.6 Hz); 13C NMR (75 MHz,