Stereoselective synthesis of the naturally occurring styryllactones (+)-goniofufurone and (+)-cardiobutanolide

Article abstract of DOI:10.1021/jo0483116

(Chemical Equation Presented) The naturally occurring γ-lactones (+)-goniofufurone 1 and (+)-cardiobutanolide 2, two pharmacologically active products from Goniothalamus species (Annonaceae), have been synthesized in enantiopure form using L-erythrulose a

Full text of DOI:10.1021/jo0483116

Stereoselective Synthesis of the Naturally
Occurring Styryllactones
(+)-Goniofufurone and
(+)-Cardiobutanolide
Purificacio´n Ruiz,† Juan Murga,*,† Miguel Carda,† and
J. Alberto Marco*,‡
FIGURE 1. Structures of (+)-goniofufurone 1 and (+)-
cardiobutanolide 2.
Departamento de Quı´mica Inorga´nica y Orga´nica,
Universidad Jaume I, E-12071 Castello´n, Spain, and
Departamento de Quı´mica Orga´nica, Universidad de
Valencia, E-46100 Burjassot, Valencia, Spain
not only toward the natural product but also toward
several stereoisomers thereof.5 Cardiobutanolide has very
recently been isolated from Goniothalamus cardiopeta-
lus.6 No synthesis has been reported so far for this
compound. Within our general interest in the application
of aldol reactions to the stereoselective synthesis of
bioactive natural compounds,7 we have now achieved a
synthesis of these two natural styryllactones in enan-
tiopure form.
alberto.marco@uv.es; jmurga@qio.uji.es
Received September 22, 2004
Lactones 1 and 2 contain five contiguous stereocenters
and display a clear structural similarity. In fact, 1 may
be formally derived from 2 through dehydration between
the hydroxyl groups at C-3 and C-6 with cyclic ether
formation and configurational retention at both ends. We
thus wanted to design a divergent synthesis for both
compounds from a common intermediate. Among other
methods,8 a tetrahydrofuran system can be formed
through internal 5-exo-tet nucleophilic displacement of
a suitable leaving group by a hydroxyl function with
subsequent configurational inversion. Accordingly, we
envisaged the retrosynthetic concept depicted in Scheme
The naturally occurring γ-lactones (+)-goniofufurone 1 and
(+)-cardiobutanolide 2, two pharmacologically active prod-
ucts from Goniothalamus species (Annonaceae), have been
synthesized in enantiopure form using L-erythrulose as the
chiral starting material. Key steps of these syntheses were
a stereoselective anti boron aldol reaction and an asymmetric
allylboration.
(4) The 8-acetate (Zhang, Y. J.; Zhou, G. X.; Chen, R. Y.; Yu, D. Q.
J. Asian Nat. Prod. Res. 1999, 1, 189-197) and the 7-epimer of
goniofufurone (Fang, X. P.; Anderson, J. E.; Chang, C. J.; McLaughlin,
J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54, 1034-1043) are the only
other reported natural representatives of the rare furanofurone class
within styryllactones. Due to differences in numbering system, the
latter compound is named as 7-epi-goniofufurone in some cases (see
above), as 8-epi-goniofufurone in others (see ref 2), and even with both
forms in others (see ref 5p).
Introduction
The plant family Annonaceae, with its about 128
genera and over 2000 species, has for a long time aroused
a considerable interest from a pharmacological point of
view, most particularly because of its polyketide con-
stituents.1 One of its most notorious representatives, the
Indomalayan genus Goniothalamus has given rise to the
isolation of a range of compounds endowed with cytotoxic,
pesticidal, teratogenic, and other various biological prop-
erties.2 Two of these compounds are (+)-goniofufurone 1
and (+)-cardiobutanolide 2 (Figure 1). The former was
isolated in 1990 from Goniothalamus giganteus and found
to display significant cytotoxic properties.3,4 Not surpris-
ingly, it has been the object of numerous synthetic efforts,
(5) (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. Tetrahedron 1999, 55, 2493-2514. (m) Bruns, R.; Wernicke, 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.; Vate`le, J.-M. Tetrahedron
1999, 55, 13011-13028. (p) Su, Y.-L.; Yang, C.-S.; Teng, S.-J.; Zhao,
G.; Ding, Y. Tetrahedron 2001, 57, 2147-2153.
* Corresponding Authors: (J.A.M.) Phone: 34-96-3544337. Fax:
34-96-3544328. (J.M.) Phone: 34-964-728174.
† Universidad Jaume I.
‡ Universidad de Valencia.
(1) (a) Cave´, A.; Figade`re, B.; Laurens, A.; Corte´s, D. Prog. Chem.
Org. Nat. Prod. 1997, 70, 81-288. (b) Zafra-Polo, M. C.; Figade`re, B.;
Gallardo, T.; Tormo, J. R.; Corte´s, D. Phytochemistry 1998, 48, 1087-
1117. (c) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504-540.
(6) Hisham, A.; Toubi, M.; Shuaily, W.; Bai, M. D. A.; Fujimoto, Y.
Phytochemistry 2003, 62, 597-600.
(7) (a) Carda, M.; Gonza´lez, F.; Sa´nchez, R.; Marco, J. A. Tetrahe-
dron: Asymmetry 2002, 13, 1005-1010. (b) Carda, M.; Rodr´ıguez, S.;
Segovia, B.; Marco, J. A. J. Org. Chem. 2002, 67, 6560-6563. (c) D´ıaz-
Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron
2004, 60, 2979-2985. (d) Murga, J.; Ruiz, P.; Falomir, E.; Carda, M.;
Peris, G.; Marco, J. A. J. Org. Chem. 2004, 69, 1987-1992.
(8) (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. (b)
Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711-
1754. (c) Koert, U. Synthesis 1995, 115-132. (d) Hoppe, R.; Scharf,
H.-D. Synthesis 1995, 1447-1464.
(2) Bla´zquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Corte´s, D.
Phytochem. Anal. 1999, 10, 161-170.
(3) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655-1661.
For some compounds, these cytotoxic properties have been related to
damage of topoisomerase I: Lo´pez-La´zaro, M.; Mart´ın-Cordero, C.;
Bermejo, A.; Corte´s, D.; Ayuso, M. J. Anticancer Res. 2001, 21, 3493-
3497.
10.1021/jo0483116 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/15/2004
J. Org. Chem. 2005, 70, 713-716
713

(-)-DIP-Cl and allymagnesium bromide11 reacted with
8 to yield homoallyl alcohol 9. The epimeric alcohol 13
(see below) was not present in the reaction mixture as
judged by means of NMR detection. The free hydroxyl
group of 9 was then mesylated, and mesylate 10 was
treated with TBAF (Scheme 2). This treatment not only
caused desilylation but also intramolecular nucleophilic
attack of the generated alkoxide anion to the mesylate-
bearing carbon, with configurational inversion at the lat-
ter and formation of the tetrahydrofuran ring. Compound
11 was then subjected to ozonolytic cleavage of the
olefinic double bond in alkaline medium12 to yield methyl
ester 12. Treatment of the latter with boron trifluoride
etherate and dimethyl sulfide13 caused complete elimina-
tion of the two acetal protecting groups and, in addition,
in situ lactonization to give (+)-goniofufurone 1.
SCHEME 1. Retrosynthetic Plan for Compounds 1
and 2
Aldehyde 8 was also a key intermediate in the syn-
thesis of cardiobutanolide. Thus, allylation of 8 with
(+)-DIP-Cl and allymagnesium bromide11 exclusively
provided homoallyl alcohol 13. Silylation of the hydroxyl
group and oxidative cleavage of the olefinic bond fur-
nished methyl ester 15. Finally, cleavage of all protecting
groups in 15 and subsequent lactonization yielded
(+)-cardiobutanolide 2, with spectral properties identical
to those reported in the literature.6
Conclusion
We have performed a divergent, stereoselective syn-
thesis of the natural γ-lactones (+)-goniofufurone 1 and
(+)-cardiobutanolide 2. The chiral starting material was
the protected L-erythrulose derivative 3,7d which has
again been shown to be a useful chiral d4 synthon that
maximizes atom economy.14 Furthermore, this is the first
synthesis of cardiobutanolide reported so far.
Experimental Section
1. For both compounds, lactone ring-opening and, in the
case of 1, intramolecular displacement would give rise
via, respectively, A and B, to the two epimeric homoallyl
alcohols C and D. These can be prepared from the same
precursor aldehyde E by means of asymmetric allylation.
Compound E in turn can be referred to â-hydroxy ketone
F via standard functional manipulations. The structural
features of F suggest that it can be obtained by means
of an anti-aldol addition with a suitably protected
L-erythrulose derivative7d as the chiral starting material.
(1S)-2-(tert-Butyldimethylsilyloxy)-1-[(4R,5R,6R)-5-(tert-
butyldimethylsilyloxy)-2,2-dimethyl-6-phenyl-[1,3]dioxan-
4-yl]ethanol (5). Oil; [R]D +4 (c 1.4, CHCl3). 1H NMR (500 MHz,
CDCl3) δ 7.40-7.30 (m, 5H), 4.54 (d, 1H, J ) 7.3 Hz), 4.27 (dd,
1H, J ) 4.5, 2 Hz), 4.23 (dd, 1H, J ) 7.3, 4.5 Hz), 3.95 (m, 1H),
3.75 (dd, 1H, J ) 9.4, 8.4 Hz), 3.66 (dd, 1H, J ) 9.4, 4.6 Hz),
3.40 (br s, 1H, OH), 1.52 (s, 3H), 1.40 (s, 3H), 0.93 (s, 9H), 0.83
(s, 9H), 0.10 (s, 6H), 0.00 (s, 3H), -0.62 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 139.3, 101.3, 18.2, 17.8 (C), 128.5 (x 2), 128.4 (x
3), 78.3, 77.0, 71.5, 69.1 (CH), 62.3 (CH2), 25.9 (x 3), 25.8 (x 4),
24.4, -4.7, -5.5 (x 2), -5.6 (CH3). IR νmax 3550 (br, OH) cm-1
.
HR FAB MS m/z 519.2942 (M + Na)+; calcd for C26H48NaO5Si2,
519.2938.
Results and Discussion
(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-[(1S)-2-(tert-
butyldimethylsilyloxy)-1-(methoxymethoxy)ethyl]-2,2-di-
methyl-6-phenyl-[1,3]dioxane (6). Solid, mp 51-52 °C (from
The synthesis of 1 and 2 is shown in Scheme 2. The
common starting material was acetonide 4, obtained
via an anti boron aldol reaction of L-erythrulose de-
rivative 3 with benzaldehyde,7d followed by functional
manipulation.9 Interchange of protecting groups in
compound 4 gave 6, which was then selectively desily-
lated with the HF-pyridine complex10 to primary alcohol
7. Swern oxidation of the latter gave aldehyde 8, which
was used in crude form in either of the two following
allylation steps. The chiral allylborane generated from
1
hexanes-Et2O); [R]D -12.2 (c 1.4, CHCl3). H NMR (500 MHz,
CDCl3) δ 7.40-7.30 (m, 5H), 4.84 (d, 1H, J ) 6.5 Hz), 4.78 (d,
1H, J ) 6.5 Hz), 4.60 (d, 1H, J ) 5.5 Hz), 4.20 (m, 2H), 3.89 (m,
(11) (a) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahe-
dron Lett. 1997, 2417-2420. (b) For a recent review on asymmetric
allylborations, see: Ramachandran, P. V. Aldrichimica Acta 2002, 35,
23-35.
(12) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675-
3680.
(13) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J.
Org. Chem. 1995, 60, 4419-4427. See also: Fuji, K.; Kawabata, T.;
Fujita, E. Chem. Pharm. Bull. 1980, 28, 3662-3664.
(14) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-
281. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705.
(9) Acetonide 4 corresponds to compound 9b in ref 7d.
(10) See, for example: Cuzzupe, A. N.; Hutton, C. A.; Lilly, M. J.;
Mann, R. K.; McRae, K. J.; Zammit, S. C.; Rizzacasa, M. A. J. Org.
Chem. 2001, 66, 2382-2393.
714 J. Org. Chem., Vol. 70, No. 2, 2005

SCHEME 2. Stereoselective Synthesis of Goniofufurone 1 and Cardiobutanolide 2a
a Reagents and conditions: (a) Excess K2CO3, MeOH, rt, 24 h. (b) MOMCl, EtNiPr2, CH2Cl2, ∆, 12 h. (c) HF-py, py/THF, rt, 12 h. (d)
Swern oxidation, the crude aldehyde 8 is used in the subsequent allylation step (overall yields are given for the two consecutive steps).
(e) AllylBIpc2 from (-)-DIP-Cl and allylmagnesium bromide, Et2O, -90 °C, 1 h. (f) MsCl, Et3N, DMAP, CH2Cl2, rt, 1 h. (g) TBAF, THF,
rt, 24 h (overall yield given for the two consecutive steps). (h) O3, CH2Cl2, 2.5 M NaOH/MeOH, -78 °C. (i) BF3‚Et2O, SMe2, -10 °C, 40
min. (j) AllylBIpc2 from (+)-DIP-Cl, Et2O, -90 °C, 1 h. (k) TBDMSOTf, 2,6-lutidine, rt, CH2Cl2, 4 h. (l) (1) BF3‚Et2O, SMe2, -10 °C, 5
min; (2) aq TFA, rt, 24 h; (3) CSA (cat.), toluene, 80 °C, 4 h. Abbreviations and acronyms: DIP-Cl ) diisopinocampheylboron chloride;
TBAF ) tetra-n-butylammonium fluoride hydrate; CSA ) camphorsulfonic acid.
1H), 3.83 (dd, 1H, J ) 10.8, 3 Hz), 3.78 (dd, 1H, J ) 10.8, 4.7
Hz), 3.43 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H), 0.91 (s, 9H), 0.84 (s,
9H), 0.08 (s, 3H), 0.07 (s, 3H), -0.14 (s, 3H), -0.32 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 140.0, 100.9, 18.3, 18.2 (C), 128.5 (x
2), 128.4 (x 2), 128.3, 77.8, 77.0, 74.5, 72.0 (CH), 97.3, 63.4 (CH2),
55.5, 26.0 (x 3), 25.9 (x 3), 25.8, 24.4, -4.0, -4.8, -5.4, -5.5
(CH3). HR EIMS m/z (% rel intensity) 525.3003 (M+ - Me, 1),
363 (100), 319 (45), 279 (90); calcd for C28H52O6Si2 - Me,
525.3067.
(4R,4aR,6R,7S,7aS)-6-Allyl-7-methoxymethoxy-2,2-dimeth-
yl-4-phenyl-tetrahydrofuro[3,2-d][1,3]dioxine (11). Oil; [R]D
+0.7 (c 0.75, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.43 (d, 2H,
J ) 8 Hz), 7.32 (t, 2H, J ) 8 Hz), 7.23 (t, 1H, J ) 8 Hz), 5.85 (m,
1H), 5.15 (dd, 1H, J ) 17.2, 1.8 Hz), 5.07 (dd, 1H, J ) 10.2, 1.8
Hz), 4.76 (d, 1H, J ) 6.8 Hz), 4.66 (d, 1H, J ) 6.8 Hz), 4.55 (d,
1H, J ) 8.5 Hz), 4.42 (d, 1H, J ) 5 Hz), 4.33 (dd, 1H, J ) 8.5,
5 Hz), 4.25 (dt, 1H, J ) 7, 3 Hz), 4.07 (d, 1H, J ) 3 Hz), 3.38 (s,
3H), 2.47 (m, 2H), 1.43 (s, 3H), 1.42 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 140.3, 100.8 (C), 134.8, 128.4 (x 2), 127.6, 126.4 (x 2),
82.5, 81.6, 80.1, 75.4, 71.0 (CH), 116.9, 96.3, 32.8 (CH2), 56.0,
24.8, 24.0 (CH3). HR EIMS m/z (% rel intensity) 319.1511 (M+
- Me, 1), 363 (100), 319 (45), 279 (90); calcd for C19H26O5 - Me,
319.1545.
(2S)-2-[(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-2,2-di-
methyl-6-phenyl-[1,3]dioxan-4-yl]-2-(methoxymethoxy)-
ethanol (7). Oil; [R]D -37.4 (c 1.5, CHCl3). 1H NMR (500 MHz,
CDCl3) δ 7.40-7.30 (m, 5H), 4.82 (d, 1H, J ) 6.5 Hz), 4.77 (d,
1H, J ) 6.5 Hz), 4.56 (d, 1H, J ) 6 Hz), 4.22 (dd, 1H, J ) 6, 3.5
Hz), 4.14 (dd, 1H, J ) 8.3, 3.5 Hz), 3.92 (ddd, 1H, J ) Hz), 3.79
(dd, 1H, J ) 11.7, 2.5 Hz), 3.65 (dd, 1H, J ) 11.7, 5.4 Hz), 3.44
(s, 3H), 2.90 (br s, 1H, OH), 1.52 (s, 3H), 1.38 (s, 3H), 0.84 (s,
9H), -0.15 (s, 3H), -0.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
139.5, 101.1, 18.2 (C), 128.6 (x 2), 128.5 (x 2), 128.4, 78.7, 77.8,
74.4, 72.2 (CH), 97.6, 62.6 (CH2), 55.8, 26.0 (x 3), 25.6, 24.1, -4.0,
-4.8 (CH3). IR νmax 3470 (br, OH) cm-1. HR EIMS m/z (% rel
intensity) 411.2231 (M+ - Me, 8), 231 (100), 177 (25); calcd for
Methyl (4R,4aR,6R,7S,7aS)-2-(7-Methoxymethoxy-2,2-di-
methyl-4-phenyltetrahydrofuro[3,2-d][1,3]dioxin-6-yl)-ac-
1
etate (12). Oil; [R]D -17.3 (c 1.5, CHCl3). H NMR (500 MHz,
CDCl3) δ 7.44 (d, 2H, J ) 8 Hz), 7.34 (t, 2H, J ) 8 Hz), 7.27 (t,
1H, J ) 8 Hz), 4.75 (d, 1H, J ) 6.8 Hz), 4.65 (dt, 1H, J ) 7, 3.3
Hz), 4.62 (d, 1H, J ) 6.8 Hz), 4.57 (d, 1H, J ) 8.5 Hz), 4.44 (d,
1H, J ) 5 Hz), 4.33 (dd, 1H, J ) 8.5, 5 Hz), 4.23 (d, 1H, J ) 3.3
Hz), 3.70 (s, 3H), 3.38 (s, 3H), 2.76 (d, 2H, J ) 7 Hz), 1.45 (s,
3H), 1.45 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 171.5, 140.1,
100.8 (C), 128.4 (x 2), 127.6, 126.4 (x 2), 82.7, 81.7, 76.7, 75.5,
71.0 (CH), 96.3, 33.6 (CH2), 55.9, 51.7, 24.8, 24.0 (CH3). IR νmax
1740 (CdO) cm-1. HR FAB MS m/z 367.1779 (M + H+); calcd
for C19H27O7, 367.1757.
C
22H38O6Si - Me, 411.2197.
(1S,2S)-1-[(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-2,2-
dimethyl-6-phenyl-[1,3]dioxan-4-yl]-1-(methoxymethoxy)-
pent-4-en-2-ol (9). Oil; [R]D -43.2 (c 0.7, CHCl3).1H NMR (500
MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.95 (m, 1H), 5.15 (dd, 1H, J
) 17.2, 1.8 Hz), 5.11 (dd, 1H, J ) 10.2, 1.8 Hz), 4.80 (d, 1H, J )
6.5 Hz), 4.78 (d, 1H, J ) 6.5 Hz), 4.60 (d, 1H, J ) 5.6 Hz), 4.17
(dd, 1H, J ) 5.6, 3.2 Hz), 4.10 (dd, 1H, J ) 7.5, 3.2 Hz), 3.93 (m,
2H), 3.44 (s, 3H), 3.10 (d, 1H, J ) 7 Hz, OH), 2.35 (t, 2H, J )
6.5 Hz), 1.53 (s, 3H), 1.38 (s, 3H), 0.85 (s, 9H), -0.10 (s, 3H),
-0.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 139.6, 101.2, 18.2
(C), 135.6, 128.6 (x 2), 128.5, 128.4 (x 2), 81.9, 78.1, 74.3, 72.7,
70.0 (CH), 117.1, 98.9, 37.4 (CH2), 56.1, 26.0 (x 3), 25.8, 24.1,
-4.0, -4.8 (CH3). IR νmax 3460 (br, OH) cm-1. HR FAB MS m/z
489.2724 (M + Na)+; calcd for C25H42NaO6Si, 489.2649.
(+)-Goniofufurone (1). Colorless crystals, mp 154-156 °C
(from hexanes-EtOAc), lit.3 mp 152-154 °C); [R]D +39.5 (c 1,
CHCl3), lit.5m [R]D +44.9 (c 1.12, CHCl3). 1H NMR (500 MHz,
CDCl3) δ 7.45-7.30 (m, 5H), 5.19 (d, 1H, J ) 4.8 Hz), 5.10 (dd,
1H, J ) 5.7, 4.2 Hz), 4.86 (d, 1H, J ) 4.2 Hz), 4.40 (d, 1H, J )
2.7 Hz), 4.10 (dd, 1H, J ) 4.8, 2.7 Hz), 2.74 (dd, 1H, J ) 18.8,
5.7 Hz), 2.68 (d, 1H, J ) 18.8 Hz). 13C NMR (125 MHz, CDCl3)
δ 175.3, 139.1 (C), 128.8 (x 2), 128.4, 126.0 (x 2), 87.5, 83.1, 77.4,
74.6, 73.5 (CH), 36.1 (CH2). IR νmax 3340 (br, OH), 1755 (CdO)
cm-1. EIMS m/z (% rel intensity) 251 (M + H+, 1), 233 (M + H+
J. Org. Chem, Vol. 70, No. 2, 2005 715

- H2O, 11), 126 (60), 107 (100), 79 (64). The spectral features of
synthetic 1 were identical to those of the natural compound.3,5m
(1S,2R)-1-[(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-2,2-
dimethyl-6-phenyl-[1,3]dioxan-4-yl]-1-(methoxymethoxy)-
pent-4-en-2-ol (13). Colorless solid, mp 71-72 °C (from hexanes-
Et2O); [R]D -46 (c 1.4, CHCl3). 1H NMR (500 MHz, CDCl3) δ
7.40-7.30 (m, 5H), 5.93 (m, 1H), 5.15 (dd, 1H, J ) 17.2, 1.5 Hz),
5.12 (dd, 1H, J ) 10.2, 1.5 Hz), 4.96 (d, 1H, J ) 6.6 Hz), 4.76 (d,
1H, J ) 6.6 Hz), 4.58 (d, 1H, J ) 5.5 Hz), 4.36-4.30 (m, 2H),
3.80-3.74 (m, 2H), 3.46 (s, 3H), 2.47 (m, 1H), 2.33 (m, 1H), 2.20
(d, 1H, J ) 8 Hz, OH), 1.52 (s, 3H), 1.38 (s, 3H), 0.84 (s, 9H),
-0.17 (s, 3H), -0.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 139.6,
101.0, 18.2 (C), 135.0, 128.6 (x 2), 128.5 (x 2), 128.4, 78.8, 78.0,
76.8, 73.2, 70.0 (CH), 117.7, 98.3, 39.5 (CH2), 56.4, 26.0 (x 3),
25.7, 24.2, -3.8, -4.7 (CH3). IR νmax 3460 (br, OH) cm-1. HR
EIMS m/z (rel intensity) 451.2430 (M+ - Me, 1), 231 (88), 177
(100), 105 (90); calcd for C25H42O6Si - Me, 451.2515.
3H), -0.50 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 172.8, 139.7,
101.1, 18.2 (x 2) (C), 128.6 (x 2), 128.5 (x 2), 128.4, 78.7, 77.6,
75.4, 71.0, 69.9 (CH), 98.4, 39.5 (CH2), 56.2, 51.4, 26.1 (x 3), 26.0
(x 3), 25.4, 24.6, -4.1, -4.2, -4.3, -4.5 (CH3). IR νmax 1742
(CdO) cm-1. HR EIMS m/z (rel intensity) 597.3313 (M+ - Me,
1), 555 (M+ - tBu, 2), 231 (100), 177 (26), 73 (60); calcd for
C
31H56O8Si2 - Me, 597.3279.
Cardiobutanolide (2). Colorless crystals, mp 196-198 °C
(from acetone), lit.6 mp 189-190 °C; [R]D +5.5 (c 0.3; MeOH),
lit.6 [R]D +6.4 (c 0.28; MeOH). 1H NMR (500 MHz, Me2CO-d6) δ
7.44 (br d, 1H, J ) 7.5 Hz), 7.30 (br t, 7.5 Hz, 1H), 7.23 (br t,
1H, J ) 7.5 Hz), 4.80 (dd, 1H, J ) 7.3, 5 Hz), 4.70 (d, 1H, J )
5 Hz, OH), 4.62 (br s, 2H), 4.55 (dd, 1H, J ) 7.5, 3 Hz), 4.39 (m,
1H), 4.30 (d, 1H, J ) 5 Hz, OH), 3.92 (td, 1H, J ) 8, 1.5 Hz),
3.80 (d, 1H, J ) 8 Hz, OH), 2.82 (m, overlapped by residual
water), 2.37 (d, 1H, J ) 17 Hz). 13C NMR (125 MHz, Me2CO-d6)
δ 176.1, 144.2 (C), 128.6, 128.0, 127.8, 86.6, 75.6, 74.2, 70.4, 68.7
(CH), 40.4 (CH2). IR νmax 3380 (br, OH), 1759 (CdO) cm-1. The
spectral features of synthetic 2 were identical to those of the
natural compound.6
(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-[(1R,2R)-2-
(tert-butyldimethylsilyloxy)-1-(methoxymethoxy)pent-4-
enyl]-2,2-dimethyl-6-phenyl-[1,3]dioxane (14). Oil; [R]D -44
(c 1.7; CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H),
5.92 (m, 1H), 5.11 (dd, 1H, J ) 17.2, 1.5 Hz), 5.05 (dd, 1H, J )
10.2, 1.5 Hz), 4.95 (d, 1H, J ) 6.6 Hz), 4.75 (d, 1H, J ) 6.6 Hz),
4.60 (d, 1H, J ) 6 Hz), 4.40 (dd, 1H, J ) 7, 3.5 Hz), 4.24 (dd,
1H, J ) 6, 3.5 Hz), 3.99 (dt, 1H, J ) 6.5, 2.9 Hz), 3.75 (dd, 1H,
J ) 7, 2.9 Hz), 3.46 (s, 3H), 2.56 (m, 1H), 2.43 (m, 1H), 1.52 (s,
3H), 1.40 (s, 3H), 0.95 (s, 9H), 0.84 (s, 9H), 0.16 (s, 3H), 0.13 (s,
3H), -0.12 (s, 3H), -0.42 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
139.9, 101.0, 18.3, 18.2 (C), 135.6, 128.5 (x 2), 128.4 (x 2), 128.3,
78.0, 77.8, 75.0, 72.9, 72.0 (CH), 117.2, 98.5, 38.8 (CH2), 56.2,
26.2 (x 6), 25.7, 24.3, -3.1, -3.8, -3.9, -4.0 (CH3). HR EIMS
m/z (rel intensity) 565.3446 (M+ - Me, 12), 403 (16), 231 (100);
calcd for C31H56O6Si2 - Me, 565.3380.
Acknowledgment. Financial support has been
granted by the Spanish Ministry of Science and Tech-
nology (Project BQU2002-00468), by the AVCyT (Project
Grupos03/180), and by the BANCAJA-UJI foundation
(Project PI-1B2002-06). J.M. thanks the Spanish Min-
istry of Education and Science for a Ramo´n y Cajal
fellowship. The authors further thank Prof. D. Corte´s,
from the Department of Pharmacology at the University
of Valencia, and Prof. A. Hisham, from the Sultan
Qaboos University, Oman, for providing spectra of
goniofufurone and cardiobutanolide, respectively.
Methyl
(3R,4R)-3-(tert-Butyldimethylsilyloxy)-4-
[(4R,5R,6R)-5-(tert-butyldimethylsilyloxy)-2,2-dimethyl-6-
phenyl-[1,3]dioxan-4-yl]-(4-methoxymethoxy)butyrate (15).
Oil; [R]D -26.8 (c 2; CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.40-
7.30 (m, 5H), 4.95 (d, 1H, J ) 6.6 Hz), 4.72 (d, 1H, J ) 6.6 Hz),
4.59 (d, 1H, J ) 6.5 Hz), 4.52 (m, 1H), 4.43 (dd, 1H, J ) 5.5, 4
Hz), 4.22 (dd, 1H, J ) 6.5, 4 Hz), 3.73 (dd, 1H, J ) 5.5, 3.3 Hz),
3.68 (s, 3H), 3.44 (s, 3H), 2.72 (m, 2H), 1.51 (s, 3H), 1.41 (s, 3H),
0.91 (s, 9H), 0.82 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H), -0.06 (s,
Supporting Information Available: General information
about spectral measurements and experimental procedures
and graphical NMR spectra of compounds 1, 2, 5-7, 9, and
11-15. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0483116
716 J. Org. Chem., Vol. 70, No. 2, 2005