A short and efficient synthesis of renealtins A and B

Article abstract of DOI:10.1016/j.tetlet.2007.09.025

The total syntheses of the first examples of diarylheptanoid natural products, renealtins A (1) and B (2), isolated from Renealmia exaltata are described, utilizing a δ-lactone intermediate 9. The key reactions involved are asymmetric dihydroxylation and oxy-Michael addition.

Full text of DOI:10.1016/j.tetlet.2007.09.025

Tetrahedron Letters 48 (2007) 8065–8068
A short and efficient synthesis of renealtins A and B
Gowravaram Sabitha,* K. Yadagiri and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 June 2007; revised 31 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—The total syntheses of the first examples of diarylheptanoid natural products, renealtins A (1) and B (2), isolated from
Renealmia exaltata are described, utilizing a d-lactone intermediate 9. The key reactions involved are asymmetric dihydroxylation
and oxy-Michael addition.
Ó 2007 Elsevier Ltd. All rights reserved.
Natural products with a tetrahydrofuran core unit1 ex-
hibit a diverse range of biological activities including
antitumor, anthelmintic, antimalarial, antimicrobial,
and antiprotozoal. Due to the importance of such mol-
ecules, considerable effort has been devoted to the devel-
opment of methods for the stereoselective construction
of substituted tetrahydrofurans.2 Despite the myriad of
transformations that have been employed in the con-
struction of the tetrahydrofuran moiety,3 many possibil-
ities remain for the development of new or improved
reactions.
As a part of our research program aimed at the synthesis
of biologically active natural products,9 we decided to
undertake the total syntheses of renealtin A and B.
The synthesis was initiated from readily available 4-
hydroxy-3-methoxycinnamaldehyde 3. The double bond
in a,b-unsaturated aldehyde 3 was selectively reduced
using NaBH4/NiCl2Æ6H2O10 in MeOH/H2O at room
temperature to afford the corresponding saturated alde-
hyde 4 in 70% yield. Under microwave irradiation con-
ditions,11 the reaction of aldehyde 4 with malonic acid 5
resulted in the selective formation of the b,c-unsaturated
acid 6 in 60% yield within 6 min. Treatment of acid 6
with BF3ÆOEt2 in ethanol under standard conditions
resulted in ester 7 in 72% yield. The 4-hydroxy group
in compound 7 was protected as a TBDMS ether 8 using
TBDMSCl and imidazole in DCM in 90% yield. Asym-
metric dihydroxylation of 8 using ADmix-b, with con-
comitant lactonization gave hydroxy lactone 9 in 80%
yield (92% ee). Careful reduction of lactone 9 with
DIBAL-H12 readily allowed the formation of the lactol
which, without isolation, was immediately treated with
Horner’s phosphonate 1013 under basic conditions to
afford the tri-substituted furan as a 4:6 diastereomeric
mixture of 2,5-cis/trans isomers, 11a/11b in an overall
yield of 60%, achieving Wittig–Horner and intramole-
cular oxy-Michael14 reactions in one-pot. Diastereomers
11a and 11b were separated by column chromatography
and their structures were confirmed by spectral data.
Deprotection of compounds 11a and 11b using TBAF
provided the target molecules renealtin A, 1 and renelal-
tin B, 2. The physical data of the synthetic materials
were fully consistent with those reported for the natural
products.5
Brazilian medicinal plants have proved to be a rich
source of compounds that might be useful for the devel-
opment of new pharmaceutical agents.4 Renealmia exal-
tata, a Brazilian medicinal plant, is known in Brazil as
‘pacova-catinga’ and used as a stomachic and a vermi-
fuge. Two new diarylheptanoids, renealtins A (1) and
B (2),5 were isolated in 2002 from the seeds of the R.
exaltata (Zingiberaceae), and their structures were eluci-
dated using spectroscopic data. Renealtins A (1) and B
(2) are the first examples of naturally occurring diaryl-
heptanoids containing a tetrahydrofuran ring, although
some diarylheptanoids possessing a tetrahydropyran
ring have been reported from Alpinia blepharocalyx6
and Zingiber officinale.7 A single report8 has appeared
on the synthesis of these molecules. As shown in Figure
1, renealtins (1 and 2) possess a five-membered cyclic
ether core with two aromatic side-chains.
Keywords: Natural products; Diarylheptanoids; Tetrahydrofuran ring;
Oxy-Michael; Dihydroxylation.
*
In conclusion, we have achieved the total synthesis of
renealtin A and B utilizing asymmetric dihydroxylation
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
gowravaramsr@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.025

8066
G. Sabitha et al. / Tetrahedron Letters 48 (2007) 8065–8068
HO
HO
HO
HO
O
O
OMe
OMe
OH
MeO
MeO
O
O
H
H
H
H
OH
renealtin A, 1
renealtin B, 2
Figure 1.
CHO
HO2C
CO2H
COOH
MeO
HO
MeO
HO
CHO
MeO
HO
a
5
b
4
3
6
MeO
HO
COOEt
COOEt
MeO
e
c
d
TBDMSO
7
8
O
O
EtO
EtO
P
OMe
HO
HO
4
TBDMSO
MeO
TBDMSO
MeO
O
2
10
OTBDMS
5
OMe
O
O
O
H
H
f
OTBDMS
9 (92% ee)
11a, 2R
11b, 2
S
h
1, 2
2, 2
R
S
Scheme 1. Reagents and conditions: (a) NaBH4/NiCl2Æ6H2O/MeOH/H2O, rt, 50 min, 70%; (b) SiO2, 5, MW (600 W), 6 min, 60%; (c) EtOH,
BF3etherate, 0 °C–rt, 2 h, 72%; (d) TBDMSCl, imidazole, dry DCM, 0 °C–rt, 2 h, 90%; (e) AD-mixb, CH3SO2NH2, 0 °C, 14 h, 80%; (f) (i) DIBAL-
H, dry DCM, ꢀ78 °C, 30 min; (ii) 10, n-BuLi, dry THF, ꢀ78 °C, 12 h, overall yield 60%; (h) TBAF, dry DCM, 0 °C, 1 h, 65%.
John Wiley & Sons: New York, 1988; pp 1–7; (h)Polyether
Antibiotics; Westly, J. W., Ed.; Marcel Dekker: New York,
1982; Vols. 1–2, (i) Donnelly, D. M. X.; Meegan, M. J. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol.
4, pp 705–709; (j) Danheiser, R. L.; Stoner, E. J.; Koyama,
H.; Yamashita, D. S.; Klade, C. A. J. Am. Chem. Soc.
1989, 111, 4407–4413; (k) Evans, D. A.; Ratz, A. M.; Huff,
B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995, 117, 3448–
3467; (l) Dutton, C. J.; Banks, B. J.; Cooper, C. B. Nat.
Prod. Rep. 1995, 12, 165–182; (m) Figadere, B. Acc. Chem.
Res. 1995, 28, 359–365; (n) Nicolaou, K. C. Tetrahedron
1977, 683–710; (o) Back, T. G. Tetrahedron 1977, 3041–
3059; (p) Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org.
Chem. 1995, 60, 5550–5555; (q) Molander, G. A.; Swal-
low, S. J. Org. Chem. 1994, 59, 7148–7551; (r) Marshall, J.
A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180–7184; (s)
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and oxy-Michael reactions as key steps from readily
available substituted cinnamaldehyde in seven steps.
Further studies are underway for the synthesis of pyran
derivatives and the results will be published in due
course (see Scheme 1).
Acknowledgment
K.Y. Thanks UGC, New Delhi, for the award of a
Fellowship.
References and notes
1. (a) Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barra-
china, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005,
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Nat. Prod. Rep. 2005, 696–716; (c) Faul, M. M.; Huff, B.
E. Chem. Rev. 2000, 100, 2407–2474; (d) Kang, E. J.; Lee,
E. Chem. Rev. 2005, 105, 4348–4378; (e) Wierenga, M. In
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Paterson, A.; Mansuri, M. M. Tetrahedron 1985, 41, 3569–
3624, p 3059; (g) Boeckman, R. H.; Goldstein, M. In The
Total Synthesis of Natural Products; Apsimon, J., Ed.;
2. For previous reviews on tetrahydrofuran synthesis, see: (a)
Boivin, T. L. B. Tetrahedron 1987, 43, 3309–3362; (b)
Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321–3408;
(c) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry
1993, 4, 1711–1754; (d) Koert, U. Synthesis 1995, 115–132;
(e) Miura, K.; Hosomi, A. Synlett 2003, 143–155.
3. (a) Nasveschuk, C. G.; Jui, N. T.; Rovis, T. Chem.
Commun. 2006, 3119–3121; (b) Tabler, D. F.; Song, Y.
Tetrahedron Lett. 1995, 36(15), 2587–2590; (c) Chandra
Roy, S.; Guin, C.; Kumar Rana, K.; Maiti, G. Tetra-

G. Sabitha et al. / Tetrahedron Letters 48 (2007) 8065–8068
8067
hedron 2002, 55, 2435–2439; (d) Taber, D. F.; Song, Y. J.
Org. Chem. 1996, 61, 6706–6712; (e) Chavre, S. N.; Choo,
H.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Cho, Y. S. Org.
Lett. 2006, 8, 3617–3619.
(2R,3R)-2-(4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-3-meth-
oxybenzyl)-5-methylenetetrahydro-3-furanol
25
(9):
½aꢁD
+28.2 (c 1, MeOH). IR (neat): 3442, 2931, 2857, 1768,
1
1515 cmꢀ1. H NMR (CDCl3, 300 MHz): d 6.76 (d, 1H,
4. Ohsaki, A.; Takashima, J.; Chiba, N.; Kawamura, M.
Bioorg. Med. Chem. Lett. 1999, 9, 1109–1112.
5. Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Koayashi, J. J.
Nat. Prod. 2002, 65, 375–376.
6. Shawkat, M.; Tezuka, Y.; Banskota, A.; Kadota, S. J.
Nat. Prod. 2001, 64, 491–496.
7. Kikuzaki, H.; Nakatani, N. Phytochemistry 1996, 43, 273–
277.
8. Katoh, T.; Matsuura, D.; Mase, N.; Takabe, K.; Yoda, H.
Synlett 2006, 2031–2034.
9. (a) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar,
M.; Yadav, J. S. Tetrahedron Lett. 2005, 46, 6567–6570;
(b) Sabitha, G.; Narjis, F.; Swapna, R.; Yadav, J. S.
Synthesis 2006, 17, 2879–2884; (c) Sabitha, G.; Reddy, E.
V.; Yadagiri, K.; Yadav, J. S. Synthesis 2006, 19, 3270–
3274; (d) Sabitha, G.; Sudhakar, K.; Yadav, J. S.
Tetrahedron Lett. 2006, 47, 8599–8602; (e) Sabitha, G.;
Bhaskar, V.; Yadav, J. S. Tetrahedron Lett. 2006, 47,
8179–8181; (f) Sabitha, G.; Swapna, R.; Reddy, E. V.;
Yadav, J. S. Synthesis 2006, 24, 4242–4246; (g) Sabitha,
G.; Bhikshapathi, M.; Yadav, J. S. Synth. Commun. 2007,
37(4), 561–569; (h) Sabitha, G.; Gopal, P.; Yadav, J. S.
Synth. Commun. 2007, 37(9), 1495–1502; (i) Sabitha, G.;
Yadagiri, K.; Yadav, J. S. Tetrahedron Lett. 2007, 48,
1651–1652.
10. Khurana, J. M.; Sharma, P. Bull. Chem. Soc. Jpn. 2004,
77, 549–552.
11. Sampath Kumar, H. M.; Reddy, B. V. S.; Reddy, E. J.;
Yadav, J. S. Tetrahedron Lett. 1999, 40, 2401–2404.
12. Vidari, G.; Ferrino, S.; Grieco, P. A. J. Am. Chem. Soc.
1984, 106, 3539–3548.
13. Solladie, G.; Wilb, N.; Bauder, C. J. Org. Chem. 1999, 64,
5447–5452. The required Horner phosphonate 10 was
synthesized in two steps from commercially available
methyl 4-hydroxy-3-methoxybenzoate by protection of the
phenol as TBDMS ether and treatment with methyl
diethylphosphonate and n-BuLi.
J = 8.3 Hz), 6.72 (s, 1H), 6.68 (dd, 1H, J = 1.5, 8.3 Hz),
4.51 (m, 1H), 4.35 (m, 1H), 3.79 (s, 3H), 3.06 (m, 2H), 2.71
(dd, 1H, J = 5.2, 17.3 Hz), 2.48 (dd, 1H, J = 5.2, 17.3 Hz),
0.98 (s, 9H), 0.13 (s, 6H). 13C NMR (CDCl3, 75 MHz): d
175.7, 150.9, 143.8, 129.4, 121.3, 120.9, 113.4, 85.3, 68.5,
55.5, 43.2, 39.4, 34.1, 25.6, 18.3, 14.1, ꢀ4.67. LCMS: m/z:
375.4 (M++Na).
2-[(2R,4R,5R)-5-(4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-
3-methoxybenzyl)-4-hydroxytetrahydro-2-furanyl]-1-(4-
[1-(tert-butyl)-1,1-dimethylsilyl]oxy-3-methoxyphenyl)-1-
25
ethanone (11a): ½aꢁD ꢀ6.2 (c 1, MeOH). IR (neat): 3442,
2929, 2856, 1671, 1590, 1512, 1465, 1286, 1160, 1036, 908,
1
839, 781 cmꢀ1. H NMR (CDCl3, 300 MHz): d = 7.49 (d,
1H J = 1.4 Hz), 7.45 (d, 1H, J = 2.2 Hz), 6.84 (d, 1H,
J = 8 Hz), 6.77 (br d, 1H), 6.68 (br d, 2H), 4.31 (m, 1H),
4.09, (m, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 3.72 (m, 1H), 3.34
(dd, 2H, J = 2.9, 5.8 Hz), 2.91 (m, 2H), 2.44 (m, 1H), 1.81
(dd, 1H, J = 5.8, 14.6 Hz), 1.01 (s, 9H), 0.98 (s, 9H), 0.17
(s, 6H), 0.12 (s, 6H). 13C NMR (CDCl3, 75 MHz): d 197.2,
151.1, 150.7, 150.2, 143, 131.8, 131.2, 122.7, 121.2, 120.7,
120.2, 113.3, 111.1, 84.5, 73.7, 72.4, 55.6, 43.4,40.6, 34.6,
31.9, 29.7, 26.1, 25.7,25.6, 22.7, 18.8, ꢀ4.6, ꢀ4.5. ESIMS:
639 (M++Na).
2-[(2S,4R,5R)-5-(4-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-
3-methoxybenzyl)-4-hydroxytetrahydro-2-furanyl]-1-(4-
[1-(tert-butyl)-1,1-dimethylsilyl]oxy-3-methoxyphenyl)-1-
25
ethanone (11b): ½aꢁD +9.4 (c 0.5, MeOH). IR (neat): 3443,
2931, 2857, 1671, 1590, 1512, 1464, 1287, 1159, 1036, 912,
839, 782 cmꢀ1. 1H NMR (CDCl3, 300 MHz): d 7.46 (d, 1H
J = 2.5 Hz), 7.41 (d, 1H, J = 6.5 Hz), 6.8 (d, 1H,
J = 8 Hz), 6.76 (br d, 1H), 6.67 (br d, 2H), 4.79 (m, 1H),
4.14, (m, 1H), 3.98 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.36
(dd, 1H, J = 5.8, 16 Hz), 2.92 (m, 3H), 2.29 (dd, 1H,
J = 5.8, 13 Hz), 1.81 (m, 1H), 0.99 (s, 9H), 0.98 (s, 9H),
0.16 (s, 6H), 0.12 (s, 6H). 13C NMR (CDCl3, 75 MHz):
d 196.8, 151.1, 150.7, 131.7, 131.1, 122.6, 121.2, 120.7,
120.2, 113.3, 111.1, 83.2, 73.9, 72.6, 55.4, 44.7, 41.8, 34.8,
O
O
O
P
P
OEt
OEt
TBDMSCl,
imidazole
OEt
OEt
CO2Me
MeO
MeO
MeO
HO
CO2Me
n
-BuLi,,
0 ºC- rt, 2 h, 90%
TBDMSO
TBDMSO
-78 ºC, 2 h, 75%
10
Diethyl [2-(4-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-3-meth-
oxyphenyl)-2-oxoethyl]phosphonate (10): 1H NMR
29.6, 26.1, 25.7, 25.6, 18.4, ꢀ4.5, ꢀ4.6. ESIMS: 639
(M++Na).
(CDCl3, 300 MHz):
d
7.53 (s, 1H), 7.50 (d, 1H,
2-[(2R,4R,5R)-4-Hydroxy-5-(4-hydroxy-3-methoxybenzyl)-
tetrahydro-2-furanyl]-1-(4-hydroxy-3-methoxyphenyl)-1-
J = 1.8 Hz), 6.85 (d, 1H, J = 7.9 Hz), 4.12 (q, 4H,
J = 7.1, 14.5 Hz), 3.88 (s, 3H), 3.55 (s, 1H), 3.48 (s, 1H),
1.3 (t, 6H, J= 7.1 Hz), 0.99 (s, 9H), 0.17 (s, 6H). ESIMS:
417 (M++1).
25
ethanone (renealtin A) (1): ½aꢁD +23.6 (c 0.5, MeOH), lit5
23
½aꢁD +22.4 (c 0.4, MeOH). IR (neat): 3432, 2927, 1631,
1280, 1150, 1030 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
.
14. For recent examples of the oxy-Michael reaction, see: (a)
Honda T.; Ishikawa, F. J. Org. Chem. 1999, 64, 5542–
5546. (b) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett.
2001, 3, 1363–1366. (c) Kigoshi, H.; Kita, M.; Ogawa, S.;
Itoh M.; Uemura, D. Org. Lett. 2003, 5, 957–960.
Spectroscopic data:
7.61 (dd, 1H, J = 1.4, 8.1 Hz), 7.50 (d, 1H, J = 2.2 Hz),
6.84 (d, 1H, J = 8.1 Hz), 6.78 (br d, 1H), 6.68 (br d, 2H),
4.31 (m, 1H), 4.09 (m, 1H), 3.91 (s, 3H), 3.76 (m, 1H), 3.74
(s, 3H), 3.54 (dd, 1H, J = 5.8, 13.9 Hz), 3.09 (dd, 1H,
J = 6.6, 12.4 Hz), 2.85 (dd, 1H, J = 7.3, 13.2 Hz), 2.80 (dd,
1H, J = 9.5, 11.7 Hz), 2.54 (m, 1H), 1.77 (m, 1H). 13C
NMR (CDCl3, 75 MHz): d 198.2, 151.8, 147.7 147.1,
144.3, 131.8, 131.2, 123.2, 122.2, 114.4, 114.1, 113.3, 110.1,
87.5, 75.7, 73.4, 55.6, 55.5, 47.4, 41.6, 34.6. ESIMS: 411
(M++Na).
Ethyl (E)-5-(4-hydroxy-3-methoxyphenyl)-3-pentenoate (7):
IR (neat): 3444, 2934, 1728, 1601, 1513, 1269, 1152,
1
1030 cmꢀ1. H NMR (CDCl3, 300 MHz): d 6.77 (d, 1H,
J = 9.1 Hz), 6.63 (s, 1H), 6.61 (d, 1H, J = 2.2 Hz), 5.62 (m,
2H), 4.12 (q, 2H, J = 6.7, 14.3 Hz), 3.87 (s, 3H), 3.28 (d,
2H, J = 6.0Hz), 3.02 (d, 2H, J = 6.04 Hz), 1.27 (t, 3H,
J = 6.8 Hz). ESIMS: 273 (M++Na).
2-[(2S,4R,5R)-4-Hydroxy-5-(4-hydroxy-3-methoxybenzyl)-
tetrahydro-2-furanyl]-1-(4-hydroxy-3-methoxyphenyl)-1-
25
ethanone (renealtin B) (2): ½aꢁD +72.7 (c 1, MeOH), lit5

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G. Sabitha et al. / Tetrahedron Letters 48 (2007) 8065–8068
23
½aꢁD +73.5 (c 0.15, MeOH). IR (neat): 3432, 2927, 1631,
J = 7.2, 16.1 Hz), 2.81 (dd, 1H, J = 7.2, 16.1 Hz), 2.77 (dd,
1H, J = 5.8, 13.7 Hz), 2.2 (m, 1H), 1.81 (m, 1H). 13C
NMR (CDCl3, 75 MHz): d 199.2, 154.1, 148.6, 148.2,
145.4, 132.6, 131.3, 125.1, 123.5, 116.6, 115.2, 113.2, 111.2,
84.8, 75.2, 72.6, 56.6, 46.2, 38.6, 36.5. ESIMS:
411(M++Na).
1280, 1150, 1030 cmꢀ1 1H NMR (CDCl3, 300 MHz):
.
d = 7.50 (dd, 1H, J = 1.4, 8.1 Hz), 7.41 (d, 1H, J =
2.1 Hz), 6.83 (d, 1H, J = 8.1 Hz), 6.79 (d, 1H, J = 1.4 Hz),
6.67 (br d, 2H), 4.8 (m, 1H), 4.14 (m, 1H), 3.98 (m, 1H),
3.85 (s, 3H),3.76 (s, 3H), 3.31 (m, 1H), 3.01 (dd, 1H,