A chiron approach for the total synthesis of crassalactone A

Article abstract of DOI:10.1002/hlca.201300231

The total synthesis of crassalactone A (1) has been achieved in twelve steps starting from commercially available 1,5-D-gluconolactone. Still-Gennari olefination, one-pot deprotection, and lactonization are the key reactions involved in the synthesis. Copyright

Full text of DOI:10.1002/hlca.201300231

Helvetica Chimica Acta – Vol. 96 (2013)
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A Chiron Approach for the Total Synthesis of Crassalactone A
by Jhillu Singh Yadav*, Gokada Maheswara Rao, and Bodakuntala Thirupathaiah
Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607,
India (fax: þ 91-40-27160512; e-mail: yadavpub@iict.res.in)
The total synthesis of crassalactone A (1) has been achieved in twelve steps starting from
commercially available 1,5-d-gluconolactone. StillꢀGennari olefination, one-pot deprotection, and
lactonization are the key reactions involved in the synthesis.
Introduction. – Styryl lactones isolated from Polyallthia species have been used as a
traditional medicine. The compounds from this species possess antimalarial [1], anti-
inflammatory [2], antimicrobial [3], anti-HIV [4], and cytotoxic activities [5]. Among
the styryl lactones crassalactone A (1), howiinol A (2), and tricinnamate (3) share the
same core skeleton (Fig.). Recently, 1 was isolated from a cytotoxic AcOEt extract of
the leaves and twigs of Polyalthia crassa by Tuchinda et al. [6]. Crassalactone A (1)
exhibited excellent cytotoxic activities against murine lymphocytic leukemia (P-388;
ED50 0.18 mg/ml), human nasopharyngeal carcinoma (KB; 1.7 mg/ml), human colon
cancer (Col-2; 1.9 mg/ml), human breast cancer (BCA-1; 0.92 mg/ml), human lung
cancer (Lu-1; 1.9 mg/ml), and rat glioma (ASK; 1.6 mg/ml). These excellent biological
activities have encouraged us to attempt at the total synthesis of crassalactone A (1)
and its analogs, and to investigate for further pharmacological properties. So far, there
is only one total synthesis reported for crassalactone A [7].
Fig. 1. Structures of some styryl-containing lactones
As part of our ongoing research program on synthesis of biologically active lactone-
containing natural products [8], herein, we report the total synthesis of crassalactone A
(1) starting from commercially available 1,5-d-gluconolactone in which all four
contiguous stereogenic centers are present as required for 1.
Results and Discussion. – Retrosynthetically, we envisioned crassalactone A (1) to
be synthesized from intermediate 4 through one-pot acetonide deprotection and
lactonization, 4, in turn, could be obtained from 5 via MOM protection, desilylation,
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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cinnamoylation, debenzylation, oxidation, and StillꢀGennari olefination reaction. The
key precursor 5 could be obtained from commercially available 1,5-d-gluconolactone in
five steps (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Crassalactone A (1)
The synthesis started from the commercially available, inexpensive 1,5-d-glucono-
lactone, which was converted to diol 6, in 65% overall yield, as described in [9]. The
primary OH group was selectively protected as the corresponding benzyl ether 7 by
using dibutyltinoxide (Bu2SnO), benzyl bromide (BnBr), and Bu4NI. The free
secondary OH group was masked as the silyl ether 8 by treatment of 7 with tBu(Ph)2-
SiCl chloride in the presence of NaH (Scheme 2).
Compound 8 was subjected to ꢂdehomologationꢃ by one-pot primary acetonide
deprotection and degradation of the resulting diol with H5IO6 in AcOEt [10] to furnish
the aldehyde, which was further subjected to Grignard reaction with PhMgBr (in situ
prepared from PhBr and Mg) to afford an easily separable (column chromotography)
diastereoisomer mixture 5/5a (in a ratio of 8 :2). The desired major product 5 was
treated with methoxymethyl chloride (MOMCl) in the presence of Hꢀnigꢃs base to
obtain the corresponding methoxymethyl ether 9 in 85% yield. With all the stereogenic
centers fixed, the stage was set to proceed further for cinnamoylation and lactone-ring
formation. For this purpose, we proceeded with silyl deprotection of 9 to yield the
alcohol 10, which was coupled to cinnamic acid according to standard protocol to yield
ester 11 in 85% yield (Scheme 3). Debenzylation with DDQ afforded primary alcohol
as the precursor for C2 homologation reaction and lactonization. Thus, the alcohol 12
was oxidized with 2-iodoxybenzoic acid (IBX) in DMSO to afford the corresponding
aldehyde, which was subjected to cis-selective StillꢀGennari olefination reaction with
bis(2,2,2-trifluoroethyl) [(methoxycarbonyl)methyl]phosphonate in the presence of
NaH to yield the (Z)-a,b-unsaturated ester 4 exclusively in 85% yield [11]. To obtain

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Scheme 2
a) Bu2SnO, BnBr, Bu4NI (TBAI), reflux, toluene, 12 h; 80%. b) NaH, tBu(Ph)2SiCl (TBDPSCl), THF,
08 to r.t., 6 h; 90%. c) i. H5IO6, AcOEt, 08 to r.t., 8 h; 87%; ii. PhBr, Mg, THF, 08 to r.t., 3 h; 76%. d)
Methoxymethyl (MOM) chloride, EtNiPr2, CH2Cl2, r.t., 12 h; 85%.
Scheme 3
a) Bu4NF (TBAF), THF, 08 to r.t., 5 h; 95%. b) Cinnamic acid (¼(E)-3-phenylprop-2-enoic acid), N,N’-
dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine, CH2Cl2, r.t., 4 h; 91%. c) 2,3-Dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O, 08 to r.t., 12 h; 72%. d) i. 2-Iodoxybenzoic acid
(IBX), CH2Cl2/DMSO, 08 to r.t, 4 h; ii. (CF3CH2)2P(O)CH2COOMe, NaH, THF, ꢀ 788, 1 h; overall
yield for two steps 85%. e) CF3COOH (TFA), CH2Cl2, H2O, r.t., 12 h; 65%.

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the lactone, we performed an acid-catalyzed one-pot deprotection and cyclization
reaction. Thus, compound 4 was treated with CF3COOH (TFA) in CH2Cl2/H2O to give
the desired product crassalactone A (1) in 65% yield (Scheme 3). The spectroscopic
and physical properties of our synthetic compound 1 were in good agreement with the
those in the literature [6][7].
Conclusions. – In summary, we have demonstrated an efficient synthetic route for
the total synthesis of crassalactone A. The key steps involved in this synthesis are
StillꢀGennari olefination, one-pot deprotection, and lactonization. The total synthesis
has been achieved in twelve steps with 8.09% overall yield.
G. M. R. and B. T. thank CSIR, New Delhi, India, for the award of fellowships. J. S. Y. thanks CSIR
for Bhatnagar Fellowship and DST for J. C. Bose Fellowship.
Experimental Part
General. All reagents were reagent grade and used without further purification, unless specified
otherwise. Solvents were distilled prior to use: THF, toluene and Et2O were distilled from Na and
benzophenone ketyl; MeOH from Mg and I2, and CH2Cl2 from CaH2. All air- or moisture-sensitive
reactions were conducted under N2 or Ar in flame-dried or oven-dried glassware with magnetic stirring.
Column chromatography (CC): silica gel (SiO2; 60 – 120 mesh or 100 – 200 mesh) packed in glass
columns; technical-grade AcOEt and petroleum ether (PE), distilled prior to use. Optical rotations:
digital polarimeter Jasco DIP-360, using a 1-ml cell with a 1-dm path length. FT-IR Spectra: on a
1
PerkinElmer 683 spectrometer in KBr pellets CHCl3/neat (as mentioned); ˜n in cmꢀ1. H- and 13C-NMR
spectra: in CDCl3 or C6D6, with 200 or 300-MHz, or 500-MHz spectrometer Bruker 300 or Varian Unity
500, resp., at r.t.; coupling constant J in Hz; the chemical shifts in ppm with TMS as internal standard.
ESI-MS and HR-ESI-MS: Finnigan MAT instrument.
(1S)-2-(Benzyloxy)-1-[(4R,4’R,5R)-2,2,2’,2’-tetramethyl-4,4’-bi-1,3-dioxol-5-yl]ethanol (7) [12]. A
soln. of 6 [9] (10 g, 38.1 mmol) and Bu2SnO (9.9 g, 40.0 mmol) was mixed azeotropically with toluene/
benzene three times on a rotavapor and was then taken in toluene (100 ml) and refluxed for 12 h. After
cooling to r.t., BnBr (6.3 ml, 53.0 mmol) and Bu4NI (21.1 g, 5.7 mmol) were added to the mixture, which
was heated at reflux for 1.5 h. The mixture was poured into H2O (100 ml) and extracted with AcOEt (3 ꢁ
40 ml). The combined org. layers were washed with sat. NaCl and dried (Na2SO4). The solvent was
removed under reduced pressure, and the residue was purified by CC (PE/AcOEt 6 :4) to give 7 (10.75 g,
80%). Colorless oil. [a]2D5 ¼ þ4.60 (c ¼ 1.55, CHCl3). IR (neat): 3479, 2988, 2928, 1627, 1375, 1247, 1214,
1151, 1070, 846. 1H-NMR (300 MHz, CDCl3): 7.34 – 7.20 (m, 5 H); 4.58 (dd, J ¼ 12.0, 8.3, 2 H); 4.17 – 4.10
(m, 1 H); 4.02 – 3.92 (m, 5 H); 3.59 (d, J ¼ 7.5, 2 H); 2.42 (d, J ¼ 7.7, 1 H); 1.40 (s, 3 H); 1.38 (s, 3 H); 1.37
(s, 3 H); 1.33 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 137.9; 128.2; 127.6; 127.5; 109.5; 109.3; 80.0; 77.0; 76.9;
73.1; 71.9; 68.8; 67.6; 27.0; 26.7; 26.4; 25.1. ESI-MS: 375 ([M þ Na]þ). HR-ESI-MS: 375.1797 ([M þ Na]þ,
C19H28NaOþ6 ; calc. 375.1784).
{(1S)-2-(Benzyloxy)-1-[(4R,4’R,5S)-2,2,2’,2’-tetramethyl-4,4’-bi-1,3-dioxol-5-yl]ethoxy}(tert-butyl)-
(diphenyl)silane (8). Alcohol 7 (1.0 g, 2.84 mmol) in THF (7 ml) was added to NaH (0.227 g, 5.68 mmol)
in THF (3ml) at 08. The mixture was warmed to r.t. for 1 h and TBDPSCl (0.72 ml, 2.84 mmol) was added
at 08. After warming to r.t. for 7 h, sat. NH4Cl (3 ml) was slowly added to the mixture at 08. The mixture
was poured into H2O (5 ml) and extracted with AcOEt (3 ꢁ 10 ml). The combined org. layers were
washed with H2O (3 ꢁ 5 ml) and dried (Na2SO4), and the solvent was removed under reduced pressure.
The residue was purified by CC (PE/AcOEt 8 :2) to give 8 (1.47 g, 90%). Colorless oil. [a]2D5 ¼ þ33.70
(c ¼ 1.9, CHCl3). IR (neat): 2927, 2857, 1460, 1374, 1216, 1073, 770. 1H-NMR (300 MHz, CDCl3): 7.75 –
7.65 (m, 4 H); 7.46 – 7.27 (m, 6 H); 7.24 – 7.17 (m, 3 H); 6.98 – 6.91 (m, 2 H); 4.24 (t, J ¼ 7.1, 1 H); 4.14 –
3.96 (m, 6 H); 3.83 (t, J ¼ 7.1, 1 H); 3.55 (dd, J ¼ 9.4, 5.4, 1 H); 3.41 (dd, J ¼ 9.2, 5.4, 1 H); 1.48 (s, 3 H);
1.38 (s, 3 H); 1.31 (s, 6 H); 1.03 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 137.7; 135.7; 135.5; 134.5; 134.5;

Helvetica Chimica Acta – Vol. 96 (2013)
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133.0; 129.4; 129.2; 127.7; 127.4; 127.1; 109.3; 109.2; 80.7; 76.8; 76.5; 72.5; 71.4; 71.3; 67.4; 27.2; 26.9; 26.7;
26.2; 25.1; 19.3. ESI-MS: 613 ([M þ Na]þ). HR-ESI-MS: 613.2934 ([M þ Na]þ, C35H46NaO6Siþ; calc.
613.2961).
(R)-{(4R,5S)-5-[(1S)-2-(Benzyloxy)-1-{[(tert-butyl)(diphenyl)silyl]oxy}ethyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}(phenyl)methanol (5). To a soln. of 8 (1 g, 1.73 mmol) in AcOEt (10 ml) cooled to 08. H5IO6
(0.79 g, 3.47 mmol) was added, and the soln. was allowed to warm to r.t. for 12 h. The reaction was
quenched by the addition H2O (5 ml), the mixture was extracted with AcOEt (10 ml), and the combined
org. layers were washed with brine (3 ml) and dried (Na2SO4). The solvent was removed under reduced
pressure, resulting in the formation of an aldehyde (0.761 g, 87%), which was immediately used for the
next step without further purification.
To a soln. of Grignard reagent (prepared in situ from Mg (0.07 g, 2.92 mmol) and PhBr (0.23 ml,
2.2 mmol) in THF (5 ml)) at ꢀ 58 was added a soln. of the crude aldehyde (0.76 g, 1.46 mmol) in THF.
Progress of the reaction was monitored by TLC, and after completion the reaction was cautiously
quenched by addition of sat. NH4Cl (5 ml). The mixture was then poured into H2O (10 ml) and extracted
with Et2O (3 ꢁ 7 ml). Combined Et2O extracts were washed with brine (4 ml) and dried (Na2SO4). After
evaporation of the solvent on rotavapor, the residue was purified by CC (SiO2; PE/AcOEt 9 :1) to yield 5
(0.529 g, 60.8%) as a pale-yellow liquid, and a minor isomer 5a (0.132 g, 15.2%). [a]2D5 ¼ þ24.2 (c ¼ 1.6,
1
CHCl3). IR (neat): 3451, 2930, 2858, 1374, 1107, 701. H-NMR (300 MHz, CDCl3): 7.60 – 7.56 (m, 2 H);
7.55 – 7.45 (m, 2 H); 7.40 – 7.21 (m, 11 H); 7.20 – 7.15 (m, 3 H); 6.91 – 6.86 (m, 2 H); 4.58 (d, J ¼ 6.0, 1 H);
4.39 (dd, J ¼ 8.3, 6.0, 1 H); 4.10 (dd, J ¼ 7.5, 2.2, 1 H); 3.87 (q, J ¼ 11.3, 9.0, 2 H); 3.42 – 3.32 (m, 2 H); 1.45
(s, 6 H); 1.00 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 140.1; 138.0; 135.8; 135.6; 133.0; 129.6; 129.4; 128.5;
128.0; 127.5; 127.3; 127.2; 126.9; 109.7; 80.3; 78.5; 75.0; 72.5; 70.8; 70.7; 27.6; 27.3; 26.9; 19.5. ESI-MS: 619
([M þ Na]þ). HR-ESI-MS: 619.2934 ([M þ Na]þ, C37H44NaO5Siþ; calc. 619.2956).
[(1S)-2-(Benzyloxy)-1-{(4S,5R)-5-[(R)-(methoxymethoxy)(phenyl)methyl]-2,2-dimethyl-1,3-dioxo-
lan-4-yl}ethoxy](tert-butyl)(diphenyl)silane (9). EtNiPr2 (2.60 ml, 15.1 mmol) and MOM-Cl (0.56 ml,
7.5 mmol) were added to a stirred soln. of 5 (1.5 g, 2.51 mmol) in dry CH2Cl2 (15 ml) at 08. After stirring
for 15 min at 08, the mixture was warmed to r.t. for 12 h. The reaction was quenched with H2O, and the
mixture was extracted with CH2Cl2 (3 ꢁ 10 ml). Combined org. layers were washed with brine (5 ml) and
dried (Na2SO4). Evaporation of the solvent, the residue was purified by CC (SiO2; PE/AcOEt 9.5 :0.5) to
yield 9 (1.36 g, 85%). Pale-yellow liquid. [a]2D5 ¼ þ58.0 (c ¼ 0.3, CHCl3). IR (neat): 2932, 2858, 1455,
1
1213, 1107, 702. H-NMR (300 MHz, CDCl3): 7.67 – 7.61 (m, 2 H); 7.56 – 7.51 (m, 2 H); 7.44 – 7.23 (m,
12 H); 7.18 – 7.12 (m, 3 H); 6.88 – 6.82 (m, 1 H); 4.69 – 4.50 (m, 5 H); 4.03 (d, J ¼ 7.5, 1 H); 3.75 (q, J ¼
12.0, 11.3, 2 H); 3.37 (s, 3 H); 3.15 – 3.00 (m, 2 H); 1.46 (s, 3 H); 1.30 (s, 3 H); 1.05 (s, 9 H). 13C-NMR
(75 MHz, CDCl3): 138.1; 137.2; 135.7; 135.5; 134.5; 133.2; 129.5; 129.3; 128.4; 128.2; 127.9; 127.4; 127.3;
127.0; 109.7; 93.5; 79.4; 78.7; 78.4; 71.9; 70.6; 70.0; 55.3; 27.5; 27.4; 26.8; 19.5. ESI-MS: 663 ([M þ Na]þ).
HR-ESI-MS: 663.3101 ([M þ Na]þ, C39H48NaO6Siþ; calc. 663.3118).
(1S)-2-(Benzyloxy)-1-{(4R,5R)-5-[(R)-(methoxymethoxy)(phenyl)methyl]-2,2-dimethyl-1,3-dioxo-
lan-4-yl}ethanol (10). Bu4NF (37.5 ml, 37.5 mmol) was added to stirred soln. of 9 (12 g, 18.7 mmol) in
THF (120 ml) at 08. The mixture was stirred for 5 h for r.t., and the reaction was quenched with H2O
(15 ml). The resulting mixture was diluted with AcOEt (3 ꢁ 50 ml). The org. phase was successively
washed with H2O (20 ml) and brine (20 ml), dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by CC (PE/AcOEt 8 :2) to afforded 10 (7.13 g, 95%). Colorless oil. [a]D25
¼
ꢀ25.0 (c ¼ 0.3, CHCl3). IR (neat): 3451, 2930, 1452, 1374, 1101, 1031, 701. 1H-NMR (300 MHz, CDCl3):
7.33 – 7.18 (m, 10 H); 4.64 (d, J ¼ 6.8, 1 H); 4.55 (dd, J ¼ 18.1, 6.6, 1 H); 4.51 (d, J ¼ 6.8, 1 H); 4.39 – 4.36
(m, 2 H); 4.31 (t, J ¼7.7, 1 H); 3.85 (t, J ¼ 7.9, 1 H); 3.33 (s, 3 H); 3.32 – 3.21 (m, 3 H); 2.89 (br. s, 1 H);
1.42 (s, 3 H); 1.35 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 137.9; 136.8; 128.4; 128.4; 128.2; 128.0; 127.5;
127.4; 109.7; 93.7; 79.2; 78.7; 77.3; 72.8; 71.5; 68.0; 55.3; 27.1. ESI-MS: 425 ([M þ Na]þ). HR-ESI-MS:
425.1941 ([M þ Na]þ, C23H30NaOþ6 ; calc. 425.1940).
(1S)-2-(Benzyloxy)-1-{(4R,5R)-5-[(R)-(methoxymethoxy)(phenyl)methyl]-2,2-dimethyl-1,3-dioxo-
lan-4-yl}ethyl (2E)-3-Phenylprop-2-enoate (11). Cinnamic acid (4.04 g, 27.3 mmol), DCC (4.20 g,
20.4 mmol), and DMAP (30 mg) were added to a soln. of 11 (5.5 g, 13.6 mmol) in CH2Cl2 (70 ml) at
r.t., and stirred for 4 h. After completion of the reaction, the mixture was filtered through a short pad of
Celite. The filtrate was washed with AcOEt (3 ꢁ 15 ml), and combined org. extracts were washed with

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Helvetica Chimica Acta – Vol. 96 (2013)
brine (20 ml) and dried (Na2SO4). After evaporation of the solvent, the residue was purified by CC (PE/
AcOEt 9 :1) to yield 11 (6.58 g, 91%). White solid. [a]2D5 ¼ þ4.60 (c ¼ 1.55, CHCl3). M.p. 139 – 1408 IR
(neat): 3440, 3252, 2929, 1711, 1642, 1163, 701. 1H-NMR (300 MHz, CDCl3): 7.67 (d, J ¼ 15.8, 1 H); 7.53 –
7.46 (m, 2 H); 7.41 – 7.18 (m, 13 H); 6.39 (d, J ¼ 15.8, 1 H); 4.69 – 4.65 (m, 1 H); 4.59 – 4.49 (m, 3 H); 4.38
(s, 2 H); 4.12 (d, J ¼ 3.7, 2 H); 3.54 – 3.43 (m, 2 H); 3.32 (s, 3 H); 1.44 (s, 3 H); 1.37 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 165.9; 145.4; 137.9; 136.7; 134.2; 130.3; 128.8; 128.6; 128.5; 128.2; 128.1; 128.0; 127.5;
127.4; 117.5; 110.1; 93.8; 79.3; 78.5; 76.3; 72.6; 69.5; 68.4; 55.4; 27.3; 27.1. ESI-MS: 555 ([M þ Na]þ). HR-
ESI-MS: 555.2360 ([M þ Na]þ, C32H36NaO7þ ; calc. 555.2359).
(1S)-2-Hydroxy-1-{(4R,5R)-5-[(R)-(methoxymethoxy)(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-
4-yl}ethyl (2E)-3-Phenylprop-2-enoate (12). DDQ (7.4 g, 33.0 mmol) was added to a stirred soln. of 11
(8.8 g, 16.5 mmol) in CH2Cl2 (90 ml) and H2O (10 ml) at 08. The mixture was stirred for 12 h at r.t., and
the reaction was quenched by the addition of 10 ml of sat. NaHCO3. The layers were separated, and the
aq. layer was extracted twice with CH2Cl2 (3 ꢁ 30 ml). The combined org. extracts were dried (Na2SO4)
and concentrated in vacuo. The crude product was purified by CC (SiO2; PE/AcOEt 8 :2) to give 12
(5.25 g, 72%). Yellow oil. [a]2D5 ¼ þ8.7 (c ¼ 0.4, CHCl3). IR (neat): 3462, 2933, 1712, 1635, 1165, 1031,
765. 1H-NMR (300 MHz, CDCl3): 7.70 (d, J ¼ 15.8, 1 H); 7.55 – 7.50 (m, 2 H); 7.41 – 7.29 (m, 8 H); 6.43 (d,
J ¼ 15.8, 1 H); 4.71 (d, J ¼ 6.0, 1 H); 4.57 (q, J ¼ 15.8, 6.8, 2 H); 4.23 (t, J ¼ 6.0, 2 H); 4.07 (dd, J ¼ 7.5, 2.2,
1 H); 3.70 – 3.65 (m, 2 H); 3.35 (s, 3 H); 1.49 (s, 3 H); 1.38 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 166.5;
145.8; 136.5; 134.1; 130.5; 128.9; 128.7; 128.2; 128.0; 127.8; 117.3; 110.4; 93.9; 79.2; 78.5; 77.7; 72.1; 63.0;
55.5; 27.2; 27.0. ESI-MS: 465 ([M þ Na]þ). HR-ESI-MS: 465.1907 ([M þ Na]þ, C25H30NaOþ7 ; calc.
465.1889).
Methyl (2E)-4-{(4R,5R)-5-[(R)-(Methoxymethoxy)(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}-4-{[(2E)-3-phenylprop-2-enoyl]oxy}but-2-enoate (4). IBX (0.70 g, 2.26 mmol) and DMSO (2 ml)
were added to a stirred soln. of 12 (0.5 g, 1.13 mmol) in anh. CH2Cl2 (7 ml) under N2 at r.t., and stirred for
4 h. After completion of the reaction, the mixture was diluted with Et2O (15 ml) and filtered through a
pad of Celite, and the filtrate was washed with sat. NaHCO3 (20 ml). The combined org. layers were dried
(Na2SO4) and concentrated under vacuum. The crude aldehyde formed was immediately used for the
further reaction without purification.
In a 50-ml round-bottom flask, NaH (0.068 g, 1.70 mmol) was taken in 4 ml of dry THF under N2.
After 5 min, bis(2,2,2-trifluoroethyl) [(methoxycarbonyl)methyl)]phosphonate (0.54 ml, 1.70 mmol)
was added at 08, and the mixture was stirred for 30 min. The mixture was cooled to ꢀ 788, and the
aldehyde (0.50 g, 1.13 mmol) in dry THF (5 ml) was added during 10 min, and the resulting mixture was
stirred for 1 h at ꢀ 788. The reaction was quenched with sat. NH4Cl (5 ml), and the mixture was extracted
with AcOEt (10 ml). The combined org. layers were concentrated under reduced pressure to give a
residue, which was purified by CC (SiO2; PE/AcOEt 9 :1) to furnish 4 (0.476 g, 85%). Yellow liquid.
1
[a]2D5 ¼ ꢀ15.0 (c ¼ 1.0, CHCl3). IR (neat): 2931, 1720, 1636, 1202, 1159, 1029, 767. H-NMR (300 MHz,
CDCl3): 7.66 (d, J ¼ 15.8, 1 H); 7.54 – 7.47 (m, 2 H); 7.40 – 7.26 (m, 8 H); 6.38 (d, J ¼ 15.8, 1 H); 6.08 (dd,
J ¼ 8.3, 3.7, 1 H); 5.92 – 5.78 (m, 2 H); 4.72 (d, J ¼ 6.0, 1 H); 4.60 (d, J ¼ 6.8, 1 H); 4.54 (d, J ¼ 6.8, 1 H);
4.28 – 4.19 (m, 2 H); 3.74 (s, 3 H); 3.33 (s, 3 H); 1.49 (s, 3 H); 1.33 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
165.7; 165.4; 143.2; 137.0; 134.1; 130.4; 128.8; 128.3; 128.1; 121.5; 117.4; 110.3; 94.0; 79.4; 78.8; 77.9; 70.0;
55.6; 51.5; 27.3; 27.1. ESI-MS: 519 ([M þ Na]þ). HR-ESI-MS: 519.1988 ([M þ Na]þ, C28H32NaOþ8 ; calc.
519.1995).
Crassalactone A (¼(2S,3S)-2-[(1R,2R)-1,2-Dihydroxy-2-phenylethyl]-6-oxo-3,6-dihydro-2H-pyran-
3-yl (2E)-3-Phenylprop-2-enoate; 1). TFA (0.1 ml) was added to a stirred soln. of 4 (0.03 g, 0.060 mmol)
in CH2Cl2 (3 ml)/H2O (0.02 ml) at 08, and the mixture was allowed to warm to r.t. for 12 h. The reaction
was quenched with sat. NaHCO3 (1 ml), and the mixture was extracted with CH2Cl2 (3 ꢁ 2 ml), and the
extract was washed with brine, dried (Na2SO4), and evaporated under reduced pressure to provide a
residue, which was purified by CC (SiO2; PE/AcOEt 6 :4) to furnish 1 (0.015 g, 65%). White solid.
[a]2D5 ¼ þ317.0 (c ¼ 0.4, CHCl3). M.p. 132 – 1348. IR (neat): 3424, 2924, 2854, 1750, 1711, 1168, 763.
1H-NMR (300 MHz, CDCl3): 7.62 (d, J ¼ 16.0, 1 H); 7.51 – 7.30 (m, 10 H); 7.01 (dd, J ¼ 9.5, 5.6, 1 H); 6.35
(d, J ¼ 16.0, 1 H); 6.20 (d, J ¼ 9.6, 1 H); 5.29 (dd, J ¼ 5.6, 2.6, 1 H); 4.90 (d, J ¼5.8, 1 H); 4.77 (dd, J ¼ 5.8,
2.6, 1 H); 4.27 (m, 1 H), 2.05 (br. s, 2 H). 13C-NMR (75 MHz, CDCl3): 165.6; 162.4; 146.6; 140.6; 139.8;

Helvetica Chimica Acta – Vol. 96 (2013)
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133.8; 130.8; 128.9; 128.7; 128.4; 128.2; 126.5; 123.5; 116.4; 77.5; 73.6; 73.4; 62.6. ESI-MS: 403 ([M þ
Na]þ). HR-ESI-MS: 403.1151 ([M þ Na]þ, C22H20NaOþ6 ; calc. 403.1158).
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Received June 6, 2013