Total synthesis of aculeatins A and B from L-malic acid

Article abstract of DOI:10.1002/hlca.201000084

An efficient total synthesis of the cytotoxic spiroketal natural products aculeatin A and B is described. The synthesis of the 1,3,5-triol moiety with appropriate configuration was accomplished from the commercially available L-malic acid. The key steps in this synthesis are the Barbier allylation, LiAlH₄/LiI-mediated syn-stereoselective 1,3-asymmetric reduction, and phenyliodine bis(trifluoroacetate) (=[bis(trifluoroacetoxy)iodo]benzene; PIFA) mediated oxidative spirocyclization.

Full text of DOI:10.1002/hlca.201000084

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Helvetica Chimica Acta – Vol. 93 (2010)
Total Synthesis of Aculeatins A and B from l-Malic Acid
by Jhillu S. Yadav*, Yerragorla Gopala Rao, Dandekar Chandrakanth, Kontham Ravindar, and
Basi V. Subba Reddy
Discovery Laboratory, Organic Chemistry Division – I, Indian Institute of Chemical Technology,
Hyderabad – 500007, India
(phone: þ 91-40-27193535; fax: þ 91-40-27160512; e-mail: yadavpub@iict.res.in)
An efficient total synthesis of the cytotoxic spiroketal natural products aculeatin A and B is
described. The synthesis of the 1,3,5-triol moiety with appropriate configuration was accomplished from
the commercially available l-malic acid. The key steps in this synthesis are the Barbier allylation,
LiAlH4/LiI-mediated syn-stereoselective 1,3-asymmetric reduction, and phenyliodine bis(trifluoroace-
tate) (¼ [bis(trifluoroacetoxy)iodo]benzene; PIFA) mediated oxidative spirocyclization.
Introduction. – In 2000, Heilmann et al. reported the isolation of the three
biologically active spiroketals aculeatins A – C (1 – 3, resp.) from the extract of
Amomum aculeatum (Zingiberaceae) [1]. Amomum aculatum is a herbaceous plant
distributed in Malaysia, Indonesia, and Papua New Guinea. It is used as a folk medicine
to treat fever and malaria [2], etc. The aculeatins A – C (1 – 3, resp.) were identified as
potent inhibitors of the human tumor KB cell line, and they also displayed promising
activity against the Plasmodium falciparum strains K1 and NF 54. The same group
discovered aculeatin D (4) from the same family, and reported its remarkably high
cytotoxic, antibacterial, and antiprotozoal activities [2]. The observed biological
activities of the aculeatins may be related to the presence of the Michael-acceptor
moiety1). Aculeatins A – D (1 – 4, resp.) represent a novel kind of natural compounds,
which display the unprecedented spirocyclic 1,7-dioxadispiro[5.1.5.2]pentadecane
system. The first total synthesis of racemic aculeatins A and B has been reported by
Wong [4] in 2002. Subsequently, the enantioselective synthesis of aculeatins A and B
has been accomplished by Marco and co-workers in 2005 [5]. Recently, Baldwin et al.
have reported for the first time the total synthesis of aculeatin D [6]. Later, a number of
other syntheses have also been appeared in literature. Many of these approaches utilize
phenol oxidation as a final step to construct the spirocyclic system [7].
The potent cytotoxicity together with the novel structural features of aculeatins A
and B make them attractive synthetic targets. In this article, we wish to disclose the total
synthesis of aculeatin A (1) and its spiro-epimer aculeatin B (2) from the commercially
available and inexpensive starting material l-malic acid. This strategy mainly relies on
the Barbier allylation, syn-stereoselective 1,3-asymmetric reduction, and phenyliodi-
ne(III) bis(trifluoroacetate) (PIFA)-mediated oxidative phenol spirocyclization.
1
)
For the importance of Michael acceptor moieties for cytotoxicity, see, e.g., [3].
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
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The retrosynthetic analysis for 1 and 2 is depicted in Scheme 1. The spiroketal
system could be generated via phenol oxidation of the appropriate intermediate ketone
5, which can be prepared from the terminal epoxide 7 via alkene 6. From epoxide 7, one
can access their functionalized analogs very easily by the late-stage introduction of the
alkyl chain and aromatic segments. The epoxide 7 could be easily prepared from l-
malic acid.
Scheme 1. Retrosynthetic Analysis of Aculeatin A (1) and Aculeatin B (2)
Results and Discussion. – The synthesis of aculeatins started from epoxide 7, which
was easily prepared from l-malic acid according to known procedures [8].
The regioselective opening of epoxide 7 with C12H25MgBr (prepared from C12H25Br
and Mg in Et2O) in the presence of CuI in THF gave the secondary alcohol 9 in good
yield (Scheme 2). Deprotection of 9 using Li-naphthalene in THF gave the diol 10,
which was further converted into its TBSO derivative 6 in 90% yield using TBSOTf and
2,6-lutidine. The terminal alkene 6 was subjected to ozonolytic cleavage, followed by
oxidation with NaClO2/NaH2PO4 to afford the acid 11, which was further converted

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into the amide 12 by treatment with morpholine and diisopropylcarbodiimide (DIC).
Treatment of 12 with lithiated [4-(benzyloxy)phenyl]acetylene in THF [9] afforded the
alkynone 13. Debenzylation and a subsequent alkyne reduction of 13 were achieved in
a single step using Pd/C under H2 atmosphere to provide compound 5 in 90% yield [10]
(Scheme 2). In a synthesis reported in [7f], 1,3-diol was protected as acetonide, and
then the terminal olefin was subjected to hydroboration, a reaction which was well
studied by Gurjar and co-workers [11]. The resulting alcohol was converted into an
aldehyde, and then treated with lithiated [4-(benzyloxy)phenyl]acetylene to yield the
corresponding alkynol, which was subsequently converted into the corresponding
ketone. In the present protocol, the key intermediate was synthesized via the
substitution of morpholinamide with lithiated [4-(benzyloxy)phenyl]acetylene to
accomplish alkynone 13 directly as described in Scheme 2.
Scheme 2
a) C12H25MgBr, CuI, THF, 08 ! r.t., 2 h; 80%. b) Li, naphthalene, THF, –788, 1 h; 90%. c) TBSOTf
(TBS ¼ (t-Bu)Me2Si, Tf ¼ CF3SO2), 2,6-lutidine, CH2Cl2, 08 ! r.t., 4 h; 90%. d) 1. O3, Ph3P, CH2Cl2,
ꢀ 788; 2. NaClO4, NaH2PO4. e) Morpholine, diisopropylcarbodiimide (DIC), 4-(dimethylamino)pyr-
idine (DMAP), CH2Cl2, 08 ! r.t., 3 h; 85%. f) [4-(Benzyloxy)phenyl]acetylene, BuLi, THF, ꢀ 788, 1 h;
92%. g) H2 (1 atm), 10% Pd/C, AcOEt, r.t., 5 h; 90%.
The deprotection of the TBS ethers in 5 with TBAF in THF afforded the
corresponding diol, which was used as such (without further purification) for the
oxidative spirocyclization using PIFA (phenyliodine(III) bis(trifluoroacetate)) in
acetone/H2O 10 :1 (v/v) to furnish a mixture of aculeatin A (1), which is thermody-
namically more stable (stabilized by a favorable anomeric effect) [12] and its
spiroepimer aculeatin B (2) in 64% overall yield in a ratio of 5 :2. These stereoisomers
were smoothly separated by column chromatography. Aculeatin A (1) was obtained in
46% and aculeatin B (2) in 18% yield. The physical and spectroscopic data of
compounds 1 and 2 were in good agreement with the data reported in [7] (Scheme 3).

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 3
a) Bu4NF (TBAF), THF, 08, 30 min, then PhI(OC(O)CF3)2, acetone/H2O 10 :1, r.t., 4 h; 64% (aculeatin
A (1; 46%) and aculeatin B (2; 18%)).
In conclusion, we have accomplished an efficient total synthesis of the naturally
occurring cytotoxic spiroketals aculeatin A (1) and its spiroepimer aculeatin B (2). The
synthesis of the 1,3,5-triol core has been achieved starting from the commercially
available and inexpensive l-malic acid. The synthesis involves Barbier allylation,
LiAlH4/LiI-mediated syn-stereoselective 1,3-asymmetric reduction [8a], and PIFA-
mediated oxidative spirocyclization as key steps. This approach employs the late-stage
introduction of the alkyl chain and aromatic segments which provides sufficient
flexibility for the synthesis of various analogs of aculeatins.
Experimental Part
General. The solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros, and were used without further purification unless
otherwise stated. The preparation of epoxide 7 was described in [8a]. All moisture-sensitive reactions
were carried out under N2. Org. solns. were dried over anh. Na2SO4 and concentrated in vacuo below 408.
Column chromatography (CC): silica gel (SiO2; Acmeꢂs 60 – 120 mesh). Optical rotations: Horiba high-
sensitive polarimeter SEPA-300 at 258. IR Spectra: Perkin-Elmer IR-683 spectrophotometer with NaCl
optics. 1H- (200 and 300 MHz) and 13C-NMR (50 and 75 MHz) spectra: Varian Gemini FT-200 and
Bruker Avance 300 instruments with TMS as internal standard in CDCl3; J values are given in Hz. MS:
Agilent Technologies 1100 Series (Agilent ChemStation software).
Synthesis. (4S,6R)-4-(Benzyloxy)nonadec-1-en-6-ol (9). A 50-ml three-necked flask containing Mg
turnings (484 mg, 20.18 mmol) and a stirring bar were dried in an oven at 1008 for 2 h and cooled to r.t.
under a stream of dry N2. A portion of 1-bromododecane (4.56 g, 18.34 mmol) in anh. THF (20 ml) was
introduced, the reaction was initiated with a small crystal of I2, and the remaining soln. was added within
10 min at 08. The stirring was continued for another 2 h at r.t., and the mixture was cooled to ꢀ 408. Then,
CuI (173.3 mg, 0.917 mmol) was added, the mixture was allowed to stir for 30 min, and then a soln. of
epoxide 7 [8a] (2.0 g, 9.17 mmol) in dry THF was added dropwise within 10 min. The resulting mixture
was stirred at ꢀ 408 for 1 h and at r.t. for 2 h. After completion, the reaction was quenched by addition of
sat. NH4Cl soln., and the mixture was extracted with Et2O, washed with H2O and brine, and dried
(Na2SO4). Removal of the solvent, followed by purification on SiO2, gave pure 9 (2.85 g, 80%). Pale
yellow liquid. [a]D20 ¼ þ49.8 (c ¼ 1.5, CHCl3). IR (KBr): 3429, 3070, 2926, 2859, 1715, 1640, 1495, 1450,
1
1351, 1275, 1069, 916, 742, 698, 665. H-NMR (300 MHz, CDCl3): 7.36 – 7.24 (m, 5 H); 5.86 – 5.71 (m,
1 H); 5.15 – 5.05 (m, 2 H); 4.56 (dd, J ¼ 11.3, 5.3, 2 H); 3.84 – 3.71 (m, 1 H); 3.63 – 3.57 (m, 2 H); 3.43 –
3.29 (m, 1 H); 3.26 – 3.14 (m, 1 H); 2.48 – 2.27 (m, 2 H); 1.77 – 1.66 (m, 2 H); 1.59 – 1.49 (m, 2 H); 1.39 –
1.20 (m, 20 H); 0.89 (t, J ¼ 6.0, 3 H). 13C-NMR (75 MHz, CDCl3): 137.9; 133.8; 128.4; 127.8; 117.7; 79.5;

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71.3; 68.9; 40.9; 38.5; 37.9; 31.8; 29.5 (br., several overlapped signals); 29.3; 25.6; 22.6; 14.9. LC/MS: 389
([M þ H]þ).
(4S,6R)-Nonadec-1-ene-4,6-diol (10). To a soln. of naphthalene (4.61 g, 36 mmol) in dry THF
(30 ml) was added Li (253 mg, 36 mmol) at r.t. The resulting mixture was stirred for 1 h at the same temp.
and then cooled to ꢀ 788. Later, a soln. of 9 (2.8 g, 7.21 mmol) in dry THF was added slowly, and the
stirring was continued at the same temp. for 1 h. Then, the reaction was quenched with solid NH4Cl, and
the mixture was extracted with AcOEt (2 ꢁ 20 ml), washed with H2O (2 ꢁ 10 ml) and brine (1 ꢁ 20 ml),
and dried (Na2SO4). Evaporation of the solvent, followed by purification on CC, afforded 10. Semi-solid.
[a]2D5 ¼ þ16.9 (c ¼ 1.3, CHCl3); IR (neat): 3507, 3360, 2918, 2860, 1647, 1467, 1356, 1070. 1H-NMR
(400 MHz, CDCl3): 5.88 – 5.73 (m, 1 H); 5.18 – 5.07 (m, 2 H); 4.01 – 3.85 (m, 2 H); 2.32 – 2.21 (m, 2 H);
1.62 – 1.54 (m, 2 H); 1.53 – 1.37 (m, 2 H); 1.36 – 1.23 (m, 24 H); 0.88 (t, J ¼ 6.4, 3 H). 13C-NMR (75 MHz,
CDCl3): 134.6; 118.1; 69.2; 68.0; 42.1; 41.9; 37.4; 31.9; 29.7 – 29.5 (br., several overlapped signals); 29.3;
25.9; 22.6; 14.0. ESI-MS: 321 ([M þ Na]þ).
(5S,7R)-2,2,3,3,9,9,10,10-Octamethyl-5-(prop-2-en-1-yl)-7-tridecyl-4,8-dioxa-3,9-disilaundecane (6).
To a stirred soln. of 10 (2.0 g, 6.71 mmol) in anh. CH2Cl2 (20 ml) at 08 were added TBSOTf (3.90 ml,
14.76 mmol) and 2,6-lutidine (2.16 ml, 20.13 mmol) successively, and the mixture was stirred for 4 h at
258. Then, the reaction was quenched with H2O (10 ml), and the mixture was extracted with CH2Cl2 (3 ꢁ
20 ml). The org. extracts were washed with brine (10 ml), dried (Na2SO4), and concentrated in vacuo.
The crude product was further purified by CC to afford pure 6 (3.15 g, 90%). Colorless liquid. [a]D20
¼
1
ꢀ3.9 (c ¼ 0.8, CHCl3). IR (KBr): 3483, 2967, 2885, 1640, 1030. H-NMR (300 MHz, CDCl3): 5.92 –
5.62 (m, 1 H); 5.10 – 4.90 (m, 2 H); 3.86 – 3.63 (m, 2 H); 2.30 – 2.14 (m, 2 H); 1.67 – 1.45 (m, 2 H);
1.44 – 1.05 (m, 27 H); 0.85 (s, 18 H); 0.06 (s, 6 H); 0.04 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 135.0; 116.2;
70.1; 69.8; 44.9; 42.2; 37.8; 31.9; 29.5 (br., several overlapped signals); 25.9; 25.6; 25.86; 22.6; 18.0; 14.1;
ꢀ 4.0; ꢀ 4.1. LC-MS: 550 ([M þ Na]þ).
(3R,5R)-3,5-Bis{[(tert-butyl)(dimethyl)silyl]oxy}octadecanoic Acid (11). A stirred soln. of 6 (2.0 g,
3.78 mmol) in CH2Cl2 (5 ml) at ꢀ 788 was subjected to ozonolysis by passing O3 gas until no starting
material was observed on TLC. The soln. was purged with N2 to remove the excess of O3 and cooled to 08;
then, Ph3P (1.95 g, 7.57 mmol) was added, and the resulting mixture was stirred for 2.5 h at 08 and then
concentrated in vacuo. The resulting crude product was diluted with hexane (10 ml) and filtered through
a Celite pad, and the residue was further washed with hexane (50 ml), and the filtrate was dried
(Na2SO4). The solvent was removed under reduced pressure, and the resulting aldehyde was subjected to
oxidation without further purification. To a stirred soln. of the crude aldehyde in t-BuOH (4 ml) was
added 2-methylbut-2-ene (1 ml) in t-BuOH (1 ml). The soln. was cooled to 08 and then treated with a
soln. of NaClO2 (0.11 g, 1.25 mmol) and NaH2PO4 (0.455 g, 3.8 mmol) in H2O (2 ml). After 2 h, the
mixture was partitioned between brine (5 ml) and Et2O (5 ml). The org. phase was separated, and the aq.
phase was extracted with Et2O (3 ꢁ 10 ml). The combined org. phases were washed with brine (10 ml),
dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography (Et2O) to afford pure 11
(1.82 g, 90%). Rf (SiO2; 30% AcOEt in hexane) 0.25. [a]2D0 ¼ ꢀ22.9 (c ¼ 1.5, CHCl3). IR (KBr): 3460,
2989, 2855, 1710, 1055. 1H-NMR (300 MHz, CDCl3): 4.26 – 4.10 (m, 1 H); 3.81 – 3.66 (m, 1 H); 2.66 – 2.39
(m, 2 H); 1.76 – 1.58 (m, 2 H); 1.41 – 1.17 (m, 29 H); 0.89 (s, 18 H); 0.08 (d, J ¼ 3.6, 6 H); 0.06 (d, J ¼ 1.4,
6 H). 13C-NMR (75 MHz, CDCl3): 176.3; 70.1; 67.5; 45.2; 43.0; 37.2; 32.0; 29.4 (br., several overlapped
signals); 22.6; 24.8; 25.8; 25.7; 18.0; 17.8; 14.1; ꢀ 4.0; ꢀ 4.5; ꢀ 4.2; ꢀ 4.3. LC/MS: 545 ([M þ H]þ).
(3R,5R)-3,5-Bis{[(tert-butyl)(dimethyl)silyl]oxy}-1-(morpholin-4-yl)octadecan-1-one (12). To a
stirred soln. of morpholine (0.30 g, 1.6 mmol) in CH2Cl2 (10 ml) were added 11 (1.5 g, 1.74 mmol) and
diisopropylcarbodiimide (0.36 g, 1.74 mmol) at r.t. After stirring the mixture for 10 min, DMAP (0.1 g,
0.8 mmol) was added, and the mixture was stirred for 4 h. After completion, the reaction was quenched
with H2O (8 ml) and extracted with CH2Cl2 (2 ꢁ 10 ml). The org. layer was dried (Na2SO4), concentrated
in vacuo, and purified by CC to afford 12 (1.32 g, 85%). Colorless oil. [a]2D0 ¼ ꢀ79.9 (c ¼ 0.9, CHCl3). IR
(KBr): 3170, 2928, 1630, 1385, 1250, 1160. 1H-NMR (200 MHz, CDCl3): 4.36 – 4.14 (m, 1 H); 3.84 – 3.42
(m, 9 H); 2.59 – 2.24 (m, 2 H); 1.70 – 1.55 (m, 2 H); 1.50 – 1.12 (m, 27 H); 0.87 (s, 9 H); 0.85 (s, 9 H); 0.07
(d, J ¼ 3.6, 6 H); 0.03 (d, J ¼ 5.0, 6 H). 13C-NMR (75 MHz, CDCl3): 169.3; 154.0; 70.0; 69.4; 46.5; 43.9;
37.0; 31.9; 29.6 (br., several overlapped signals); 25.8; 25.0; 22.8; 21.7; 18.0; 14.0; ꢀ 4.3; ꢀ 4.2. ESI-MS:
568 ([M þ H]þ).

Helvetica Chimica Acta – Vol. 93 (2010)
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(5R,7R)-1-[4-(Benzyloxy)phenyl]-5,7-bis{[(tert-butyl)(dimethyl)silyl]oxy}icos-1-yn-3-one (13). To
a stirred soln. of 1-(benzyloxy)-4-ethynylbenzene (0.37 g, 8.8 mmol) in THF (30 ml) was added BuLi
(5.5 ml; 1.6m soln. in hexane, 8.8 mmol) at ꢀ 788, and the mixture was stirred for 20 min. Then, BF3 ·
Et2O was added, stirring was continued for 30 min, and then a soln. of 12 (2.0 g, 4.4 mmol) in THF
(10 ml) was added at ꢀ 788. The resulting mixture was warmed to 08 and allowed to stir for 1 h, then the
reaction was quenched with aq. NH4Cl (40 ml), and the mixture was extracted with Et2O (3 ꢁ 50 ml).
The combined org. extracts were washed with brine (60 ml), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by CC to afford 13 (0.36 g, 77%). [a]2D0 ¼ ꢀ11.8 (c ¼ 1.1,
CHCl3). IR (KBr): 3059, 2926, 2855, 2201, 1731, 1678, 1125. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.22 (m,
7 H); 6.89 – 6.80 (d, J ¼ 8.3, 2 H); 5.04 (s, 2 H); 4.21 – 4.10 (m, 1 H); 3.75 – 3.61 (m, 1 H); 2.54 – 2.90 (m,
3 H); 1.60 – 1.45 (m, 3 H); 1.40 – 1.16 (m, 23 H); 0.85 (s, 18 H); 0.08 (d, J ¼ 5.6, 6 H); 0.07 (d, J ¼ 1.4,
6 H). 13C-NMR (75 MHz, CDCl3): 209.6; 127.5; 127.8; 128.5; 128.7; 128.6; 114.7; 70.0; 67.3; 51.0; 45.7;
44.1; 37.6; 31.8; 29.6 (br., several overlapped signals); 27.8; 25.7; 25.8; 25.5; 24.9; 22.7; 22.25; 14.0; 13.8;
ꢀ 4.13; ꢀ 4.5. LC/MS: 736 ([M þ H[þ).
(5R,7R)-5,7-Bis{[(tert-butyl)(dimethyl)silyl]oxy}-1-(4-hydroxyphenyl)icosan-3-one (5). To a stirred
soln. of 13 (350 mg, 0.62 mmol) in AcOEt (10 ml) was added 10% Pd/C (40 mg). The mixture was stirred
under H2 atmosphere for 8 h. After completion, the mixture was filtered through Celite, and the solvent
was removed under reduced pressure to give the crude product, which was purified by CC on SiO2
(hexane/AcOEt 4 :1) to afford pure 5 (260 mg, 88%). Colorless solid. [a]2D0 ¼ ꢀ4.8 (c ¼ 1.5, CHCl3). IR
1
(KBr): 3388 (OH), 2929, 1720, 1258, 1075. H-NMR (300 MHz, CDCl3): 7.05 (d, J ¼ 8.4, 2 H); 6.74 (d,
J ¼ 8.6, 2 H); 4.24 – 4.13 (m, 1 H); 3.74 – 3.59 (m, 1 H); 2.86 – 2.64 (m, 4 H); 2.60 – 2.42 (m, 2 H); 1.70 –
1.50 (m, 7 H); 1.34 – 1.20 (m, 27 H); 0.86 (s, 9 H); 0.85 (s, 9 H); 0.07 (s, 6 H); 0.04 (s, 6 H). 13C-NMR
(75 MHz, CDCl3): 208.6; 154.0; 133.7; 129.3; 115.2; 71.0; 70.5; 42.9; 39.6; 37.4; 36.3; 31.9; 30.7; 30.2; 29.6
(br., several overlapped signals); 29.3; 24.9; 22.6; ꢀ 4.16; ꢀ 4.28. ESI-MS: 649 ([M þ H]þ).
Aculeatin A (¼(2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-9,12-dien-11-
one; 1) and Aculeatin B (¼(2R,4R,6S)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-9,12-
dien-11-one; 2). To a stirred soln. of 5 (75 mg, 0.16 mmol) in anh. THF (2 ml) was added TBAF (0.2 ml,
0.2 mmol), and the mixture was stirred for 3 h at 08. Then, the reaction was quenched with H2O (3 ml),
and the mixture was extracted with AcOEt (2 ꢁ 2 ml). The combined org. extracts were dried (Na2SO4)
and concentrated in vacuo. To a soln. of crude product in acetone/H2O mixture (9 :1, 10 ml) was added
PhI(OCOCF3)2 (206 mg, 0.48 mmol) in one portion. The resulting mixture was stirred for 5 h at 258 in the
dark. After completion, the reaction was quenched with H2O (2 ml), and the mixture was extracted with
AcOEt (3 ꢁ 4 ml). The combined org. layers were dried (Na2SO4) and concentrated in vacuo to give a
mixture 1/2, which was separated by CC to afford pure 1 (24 mg, 46%) and 2 (13 mg, 18%).
Data of 1. See [7]. Oil. [a]2D0 ¼ ꢀ52.3 (c ¼ 1.0, CHCl3). IR (KBr): 3416 (OH), 2926, 1671, 1630, 1512,
1459, 1102. 1H-NMR (300 MHz, CDCl3): 6.85 (dd, J ¼ 9.8, 3.0, 1 H); 6.78 (dd, J ¼ 9.8, 3.0, 1 H); 6.14 (dd,
J ¼ 9.8, 1.5, 1 H); 6.09 (dd, J ¼ 10.5, 2.2, 1 H); 4.05 – 4.15 (m, 2 H); 3.31 (br. s, 1 H); 2.38 (m, 1 H); 2.23
(m, 1 H); 1.94 – 2.03 (m, 3 H); 1.95 (br. d, J ¼ 14.2, 1 H); 1.75 (br. d, J ¼ 13.5, 1 H); 1.60 – 1.39 (m, 4 H);
1.21 – 1.36 (m, 21 H); 0.87 (t, J ¼ 6.7, 3 H). 13C-NMR (75 M, CDCl3): 185.3; 150.9; 148.9; 127.4; 127.1;
109.1; 79.6; 65.4; 64.8; 39.1; 38.0; 35.9; 34.2; 32.1; 29.7 (br., several overlapped signals); 29.6; 29.4; 25.7;
22.8; 14.1. EI-MS: 441.29 ([M þ Na]þ).
Data of 2. See [7]. Oil. [a]2D0 ¼ 54.5 (c ¼ 0.7, CHCl3). IR (KBr): 3416 (OH), 2926, 2854, 1671, 1630,
1
1510, 1459, 1102. H-NMR (300 MHz, CDCl3): 6.99 (dd, J ¼ 9.8, 3.0, 1 H); 6.78 (dd, J ¼ 9.8, 3.0, 1 H);
6.14 (dd, J ¼ 9.8, 1.6, 1 H); 6.09 (dd, J ¼ 9.8, 1.6, 1 H); 4.36 (quint., J ¼ 3.1, 1 H); 3.87 (m, 1 H); 2.68 (dd,
J ¼ 12.8, 7.2, 1 H); 2.30 (td, J ¼ 12.3, 7.2, 1 H); 2.10 – 2.01 (m, 2 H); 1.95 – 1.83 (m, 2 H); 1.60 – 1.39 (m,
8 H); 1.40 – 1.19 (m, 19 H); 0.88 (t, J ¼ 6.9, 3 H). 13C-NMR (75 MHz, CDCl3): 185.5; 151.0; 148.6; 127.5;
127.3; 109.3; 79.8; 65.5; 65.0; 39.3; 38.3; 36.1; 34.4; 32.0; 29.9 (br., several overlapped signals); 29.8; 29.5;
25.8; 22.9; 14.3. EI-MS: 441.29 ([M þ Na]þ).

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Received March 2, 2010