A stereoselective aldol approach for the total syntheses of two 6-Alkylated 2H-pyran-2-ones

Article abstract of DOI:10.1002/hlca.201300139

A simple and highly efficient stereoselective total synthesis of the 6-alkylated pyranones (6R)-6-[(1E,4R,6R)-4,6-dihydroxy-10-phenyldec-1-en-1-yl]- 5,6-dihydro-2H-pyran-2-one (1) and (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6- phenylhexyl]-2H-pyran-2-one (2) w

Full text of DOI:10.1002/hlca.201300139

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Helvetica Chimica Acta – Vol. 97 (2014)
A Stereoselective Aldol Approach for the Total Syntheses of Two 6-Alkylated
2H-Pyran-2-ones
by Singanaboina Rajaram, Dasari Ramesh, Udugu Ramulu, Peddikotla Prabhakar, and Yenamandra
Venkateswarlu*†1)
Division of Natural Products Chemistry, Organic Chemistry Division – I, Indian Institute of Chemical
Technology, Hyderabad – 500 007, India
(phone: þ 91-40-27191881; fax: þ 91-40-27160512; e-mail: suresh@iict.res.in)
A simple and highly efficient stereoselective total synthesis of the 6-alkylated pyranones (6R)-6-
[(1E,4R,6R)-4,6-dihydroxy-10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (1) and (6S)-5,6-dihy-
dro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (2) was developed using Crimminsꢀ aldol
reaction, SmI2 reduction, Grubbs-II-catalyzed olefin cross-metathesis, and Stillꢀs modified Hor-
nerꢀWadsworthꢀEmmons reaction.
Introduction. – The a-pyrone (¼2H-pyran-2-one) ring system occurs in a number of
natural products and is also featured in many intermediates that are required for the
synthesis of biologically important compounds [1]. 5,6-Dihydro-a-pyrone-containing
natural products with a substituted arylalkyl side chain at C(6) have attracted much
attention over the last decade due to the Michael-acceptor nature of the a,b-
unsaturated a-pyrones for the amino acid residues of receptors [2]. In particular, a,b-
unsaturated a-pyrones have been shown to exhibit a wide range of biological activities
including inhibition of HIV protease, and antileukemic, anticancer, antifeedent,
antifungal, antibacterial, and antitumor activities [3]. Most of these compounds carry a
(poly)hydroxylated chain at C(6) of the a-pyrone moiety, e.g., (6R)-6-[(1E,4R,6R)-4,6-
dihydroxy-10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (1), (6S)-5,6-dihydro-
6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (2) and, (þ)-strictifolione (3)
(Fig.). Compounds 1 and 2 were isolated from Ravensara crassifolia by Hostetmann
and co-workers [4a], and a structurally similar compound 3 was isolated by Aimi and
co-workers [4b] from the stem bark of Cryptocarya strictifolia. The structures and
absolute configurations were established through NMR spectroscopic studies. Com-
pounds 1 and 2 exhibited antifungal activities against the phytopathogenic fungus
Cladosporium cucumarinum. Therefore, the syntheses of both compounds 1 [5] and 2
[6] have recently become attractive targets to organic chemist. Recently, we reported
the synthesis of compound 2 [6a] and evaluated its biological properties. Our
continuing interest towards the total synthesis of lactone-containing natural products
[7] and important biological properties of 1 and 2 (Fig.) prompted us to undertake the
1
)
Deceased, July 17, 2013; correspondance should be addressed to Dr. K. Suresh Babu (phone: þ 91-
4027191881; e-mail: suresh@iict.res.in)
ꢁ 2014 Verlag Helvetica Chimica Acta AG, Zꢂrich

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113
Figure. Structures of (6R)-6-[(1E,4R,6R)-4,6-dihydroxy-10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyr-
an-2-one (1), (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (2), and (þ)-stricti-
folione (3)
synthesis of these compounds starting from a common, commercially available starting
material.
Herein, we report the stereoselective synthesis of (6R)-6-[(1E,4R,6R)-4,6-dihy-
droxy-10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (1) by applying Crimminsꢀ
aldol reaction, SmI2 reduction of an alkoxy ketone, Grubbs-II-catalyzed olefin cross-
metathesis from commercially available 5-phenylpentan-1-ol (4) and l-aspartic acid.
The synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one
(2) was accomplished by Crimminꢀs aldol reaction and Stillꢀs modified Hor-
nerꢀWadsworthꢀEmmons olefination reaction as key steps starting from commercially
available 5-phenylpentan-1-ol (4). The retrosynthetic analyses of compounds 1 and 2
are depicted in Scheme 1.
Results and Discussion. – The synthesis of 1 and 2 started from 5-phenylpentan-1-ol
(4), which was subjected to oxidation using 2-iodoxybenzoic acid (IBX) in DMSO to
give the corresponding aldehyde in 94% yield. The latter was reacted with (R)-1-(4-
benzyl-2-thioxothiazolidin-3-yl)ethanone [8] in the presence of EtNiPr2 and TiCl4
according to the Crimminsꢀ protocol to give the easily separable diastereoisomers of
the b-hydroxy amide with the required syn-product 5 and anti-product 5a in 82% yield
(syn/anti 8.4 :1.6 [9]; Scheme 2). The diastereoselectivity of the Crimminsꢀ aldol
reaction was determined by HPLC (column, DISCOVERY C8 250 ꢁ 4.6 mm, 5 mm;
MeCN/H2O 60 :40; flow rate, 1.0 ml/min, l ¼ 210 nm: tR 17.01 min (minor; 16%),
17.98 min (major; 84%). The OH group in compound 5 was then protected as MOM
(methoxymethyl) ether 6, and subsequent reaction with DIBAL-H afforded aldehyde 7
[6e] (Scheme 2), which was subjected to the Zn-mediated allylation in aqueous
medium to afford diastereoisomers of secondary alcohol 8 (1:1), which, on further
oxidation with DessꢀMartin periodinane (DMP), furnished the ketone 9. The
stereoselective reduction of the oxo group in 9 with SmI2 [10a] (Scheme 2) in THF
and MeOH as proton source for 12 h afforded the required anti-1,3-diastereoisomer 10
as the major product (Yadav et al. prepared this intermediate via a different approach
using a Prins cyclization [6f]). The 1,3-anti-relationship of the two OH groups in 9 was
established by analysis of the 13C-NMR spectrum of the corresponding acetonide [10b].

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Scheme 1. Retrosynthetic Analysis
The lactone 16 is a key intermediate in the syntheses of various compounds and has
been prepared by several groups [11]; thus, there is still a need for a simple and efficient
procedure for its synthesis. We have prepared 16 according to a known procedure [11e]
from the chiral synthon 11, which was obtained from l-aspartic acid [12] (Scheme 3).
Opening of epoxide 11 with Me3SI and BuLi in dry THF provided the secondary allyl
alcohol 12 in 77% yield (Scheme 3), which was protected as its methoxymethyl
(MOM) ether 13. Deprotection of the Bn group in compound 13 was achieved with
lithium naphthalenide [13] to yield the primary alcohol 14 in 81% yield. The OH group
of 14 was oxidized using 2-iodoxybenzoic acid (IBX) in DMSO to give the
corresponding aldehyde in 85% yield, which was subjected to Stillꢀs modified
HornerꢀWadsworthꢀEmmons olefination reaction [14] to afford the unsaturated ester
15 in 76% yield. Compound 15 was treated with TsOH in benzene to afford 5,6-
dihydro-6-vinyl-a-pyrone 16 in 80% yield (Scheme 3).
Finally, compounds 10 and 16 (in a 1:3 ratio) were subjected to olefin cross-
metathesis using Grubbs-II catalyst (5 mol-%) [15] in CH2Cl2 under reflux conditions
to yield the desired compound 17 in 74% yield (Scheme 4). The MOM protecting group
in 17 was removed by treatment with CeCl3 · 7 H2O, MeCN/MeOH 1:1 to afford 1 in
1
78% yield (Scheme 4). The optical rotation, H- and 13C-NMR data of the synthetic
compound 1 are in good agreement with those of the natural product [4].
After having accomplished the synthesis of 1, we prepared compound 2, by reacting
aldehyde 7 with (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone in the presence of
TiCl4 using Crimminsꢀ protocol to give the easily separable diastereoisomers of b-
hydroxy amide, i.e., the required syn-product 18 and the anti-product 18a in 79% yield
(syn/anti 7.8 :2.8; Scheme 5). The OH group of 18 was protected as MOM ether 19,

Helvetica Chimica Acta – Vol. 97 (2014)
115
Scheme 2
a) 1. IBX (2-Iodoxybenzoic acid), dry DMSO, dry CH2Cl2, 08 to r.t., 2 h; 94%; 2. 1-[(4R)-4-benzyl-2-
thioxo-1,3-thiazolidin-3-yl]ethanone, TiCl4, EtNiPr2, dry CH2Cl2, ꢀ 788, 30 min, 82%. b) Methoxy-
methyl chloride (MOMCl), EtNiPr2, dry CH2Cl2, 08 to r.t., 4 h; 87%. c) Diisobutylaluminium hydride
(DIBAL-H), dry CH2Cl2, ꢀ 788, 3 h; 90%. d) Zn, allyl bromide (C3H5Br), NH4Cl, 08 to r.t., 4 h; 92%. e)
DessꢀMartin periodinane (DMP), NaHCO3, dry CH2Cl2, 08 to r.t., 3 h; 90%. f) SmI2, MeOH/THF, r.t.,
12 h, 76%.
Scheme 3
a) Me3SI (trimethylsulfonium iodide), BuLi, dry THF, ꢀ 108 to r.t., 12 h; 77%. b) MOMCl, EtNiPr2, dry
CH2Cl2, 08 to r.t., 3 h; 85%, c) Li in naphthalene, ꢀ 208, 3 h; 81%. d) 1. IBX, dry DMSO, dry CH2Cl2, 08
to r.t., 3 h; 85%; 2. MeO2CCH2P(O)(OCH2CF3)2, NaH, dry THF, ꢀ 788, 4 h; 76%. e) TsOH, dry
benzene, reflux, 12 h; 80%.

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Helvetica Chimica Acta – Vol. 97 (2014)
Scheme 4
a) Grubbs-II-catalyst (5 mol-%), dry CH2Cl2, 408, 12 h; 74%. b) CeCl3 · 7 H2O, MeCN/MeOH 1:1,
reflux, 6 h; 85%.
which was reduced with DIBAL-H to yield the corresponding aldehyde, which was
further subjected to Stillꢀs modified HornerꢀWadsworthꢀEmmons olefination reaction
[14] to afford the unsaturated ester 20 in a (Z)/(E) ratio of 95 :5 and 74% yield.
Lactonization of compound 20 was carried out by treatment with 3% HCl in THF to
afford a separable mixture of the natural product 2 and compound 2a (7:3) in 78%
yield. The formation of a significant amount of the bicyclic lactone 2a was presumably
due to the involvement of the OH group of 2 (Scheme 5) in the Michael addition
Scheme 5
a) 1-[(4R)-4-Benzyl-2-thioxo-1,3-thiazolidin-3-yl]ethanone, TiCl4, EtNiPr2, dry CH2Cl2, ꢀ 788, 30 min;
79%. b) MOMCl, EtNiPr2, dry CH2Cl2, 08 to r.t., 5 h; 83%. c) 1. DIBAL-H, dry CH2Cl2, ꢀ 788, 3 h; 82%;
2. MeO2CCH2P(O)(OCH2CF3)2, NaH, dry THF, ꢀ 788, 4 h; 74%. d) 3m HCl/THF 1:1, 08 to r.t., 3 h;
78%.

Helvetica Chimica Acta – Vol. 97 (2014)
117
reaction. The optical rotation, and 1H- and 13C-NMR data of the synthetic compound 2
are in good agreement with those of the natural product [4].
Conclusions. – In conclusion, total syntheses of (6R)-6-[(1E,4R,6R)-4,6-dihydroxy-
10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (1) and (6S)-5,6-dihydro-6-
[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (2) have been achieved by successful
application of Crimminsꢀ aldol reaction, SmI2 reduction of alkoxy ketone, and Grubbs-
II-catalyzed olefin cross-metathesis as key steps starting from commercially available 5-
phenylpentan-1-ol (4) and l-aspartic acid.
The authors are thankful to CSIR, New Delhi, India, for the financial support and the Director of the
Indian Institute of Chemical Technology (IICT), for his encouragement.
Experimental Part
General. 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. All moisture-sensitive reactions were carried out under N2. Org. soln. were dried over
anh. Na2SO4 and concentrated in vacuo below 408. Column chromatographic (CC) separations: silica gel
(Acmeꢀs, 60 – 120 mesh and 100 – 200 mesh; SiO2). Optical rotations: Horiba highly sensitive polarimeter
SEPA-300 at 258. IR Spectra: PerkinElmer IR-683 spectrophotometer with NaCl optics. 1H- and
13C-NMR (300 and 75 MHz, resp.) spectra: Bruker Avance 300 instrument with TMS as internal standard
in CDCl3; J values in Hz. MS: Agilent Technologies 1100 Series (Agilent Chemistation Software).
(3R)-1-[(4R)-4-Benzyl-2-thioxo-1,3-thiazolidin-3-yl]-3-hydroxy-7-phenylheptan-1-one (5). To a
cooled (08) stirred soln. of IBX (5.56 g, 19.87 mmol) in dry DMSO (15 ml) was added a soln. of 4
(2.2 g, 13.25 mmol) in dry CH2Cl2 (25 ml) at 08, and the mixture was stirred for 2 h at r.t. After
completion of the reaction, the mixture was filtered, diluted with H2O (15 ml), and extracted into CH2Cl2
(2 ꢁ 30 ml). The combined org. extract was washed with brine, dried (Na2SO4), and the solvent was
removed under reduced pressure. The crude residue was purified by CC (AcOEt/hexane 1:9) to give
pure aldehyde (2.04 g, 94%) as a colorless liquid. The aldehyde was directly used for the next reaction. To
a cooled (08) soln. of the chiral 1-[(4R)-4-benzyl-2-thioxo-1,3-thiazolidin-3-yl]ethanone [8] (3.06 g,
12.19 mmol ) in dry CH2Cl2 (25 ml) was added dropwise TiCl4 (1.60 ml, 14.63 mmol), and the soln. was
stirred for 5 min turning to a yellow color, followed by the addition of EtNiPr2 (3.05 ml, 17.56 mmol) [9].
The suspension now turned to dark red (enolate) and was stirred for 20 min at 08 and then cooled to
ꢀ788. The above aldehyde (2.0 g, 12.19 mmol) in dry CH2Cl2 (15 ml) was added dropwise, and the
mixture was stirred for 15 min at ꢀ788. After completion, the reaction was quenched with sat. NH4Cl
(15 ml) soln., and the mixture was extracted with CH2Cl2 (3 ꢁ 40 ml). The combined org. extract was
washed with brine, dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC
(AcOEt/hexane 3 :7): pure 5 (4.12 g, 82%). Yellow liquid. [a]2D5 ¼ ꢀ281 (c ¼ 1.65, CHCl3), determined by
chiral HPLC (DISCOVERY C8 250 ꢁ 4.6 mm, 5 mm; MeCN/H2O 60 :40; flow rate, 1.0 ml/min, l ¼
210 nm): tR 17.01 min (minor; 16%), 17.98 min (major; 84%). IR (neat): 3448, 3025, 2927, 2855, 1698,
1
1452, 1366, 1263, 1165, 1102, 1036, 916, 746, 701. H-NMR: 7.36 – 7.08 (m, 10 H); 5.41 – 5.32 (m, 1 H);
4.14 – 4.04 (m, 1 H); 3.63 (dd, J ¼ 2.2, 17.3, 1 H); 3.39 (dd, J ¼ 7.5, 11.3, 1 H); 3.22 (dd, J ¼ 3.0, 12.8, 1 H);
3.10 – 2.98 (m, 2 H); 2.89 (d, J ¼ 12.0, 1 H); 2.63 (t, J ¼ 7.5, 2 H); 1.73 – 1.23 (m, 6 H). 13C-NMR: 201.3;
173.1; 142.4; 136.3; 129.3; 128.8; 128.3; 128.2; 127.2; 125.6; 68.2; 67.6; 45.8; 36.7; 36.1; 35.9; 31.8; 31.3; 25.1.
ESI-MS: 436 ([M þ Na]þ).
(3R)-1-[(4R)-4-Benzyl-2-thioxo-1,3-thiazolidin-3-yl]-3-(methoxymethoxy)-7-phenylheptan-1-one
(6). To a cooled (08) soln. of 5 (3.2 g, 7.74 mmol) in dry CH2Cl2 (10 ml), EtNiPr2 (2.69 ml, 15.49 mmol)
and then dropwise MOMCl (0.87 ml, 11.62 mmol) were added, and the mixture was stirred for 4 h. After
completion of the reaction, the mixture was extracted with CH2Cl2, washed with brine, dried (anh.
Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8): pure 6 (3.08 g,

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Helvetica Chimica Acta – Vol. 97 (2014)
87%). Colorless liquid. [a]2D5 ¼ ꢀ232.72 (c ¼ 0.55, CHCl3). IR (neat): 3425, 3025, 2927, 2854, 1688, 1601,
1493, 1451, 1342, 1261, 1163, 1042, 745, 700. 1H-NMR: 7.37 – 7.24 (m, 8 H); 7.20 – 7.16 (m, 2 H); 5.36 – 5.27
(m, 1 H); 4.70 (d, J ¼ 6.7, 1 H); 4.64 (d, J ¼ 6.7, 1 H); 3.57 (dd, J ¼ 7.9, 17.3, 1 H); 3.42 – 3.29 (m, 5 H); 3.23
(dd, J ¼ 3.7, 12.4, 2 H); 3.09 – 2.98 (m, 1 H); 2.88 (d, J ¼ 11.5, 1 H); 2.63 (t, J ¼ 7.5, 2 H); 1.72 – 1.58 (m,
4 H); 1.49 – 1.37 (m, 2 H). 13C-NMR: 201.2; 171.9; 142.5; 136.5; 129.4; 128.9; 128.4; 128.2; 127.2; 125.6;
96.6; 74.9; 68.6; 55.6; 44.2; 36.6; 35.8; 35.0; 32.1; 31.4; 24.8. ESI-MS: 480 ([M þ Na]þ).
(3R)-3-(Methoxymethoxy)-7-phenylheptanal (7) [6e]. To a cooled (ꢀ 788) soln. of 6 (0.7 g,
1.53 mmol) in dry CH2Cl2 (10 ml) was added 1m DIBAL-H in toluene (1.83 ml, 1.83 mmol), and the
mixture was stirred for 10 min at ꢀ 788. After completion, the reaction was quenched with sat. sodium
potassium tartarate (10 ml), and the mixture was stirred for 0.5 h and then extracted with CH2Cl2 (3 ꢁ
15 ml). The combined org. extract was washed with brine, dried (anh. Na2SO4), and concentrated. The
crude residue was purified by CC (AcOEt/hexane 2 :8): 7 (0.344 g, 90%). Colorless liquid. IR (neat):
3432, 3061, 3026, 2934, 2858, 2728, 1724, 1602, 1494, 1454, 1373, 1210, 1147, 1102, 1035, 917, 747. 1H-NMR:
9.79 (t, J ¼ 2.2, 1 H); 7.32 – 7.14 (m, 5 H); 4.65 (s, 2 H); 4.12 – 4.02 (m, 1 H); 3.33 (s, 3 H); 2.70 – 2.48 (m,
4 H); 1.74 – 1.52 (m, 4 H); 1.47 – 1.34 (m, 2 H). 13C-NMR: 201.3; 142.2; 128.3; 128.2; 125.7; 95.8; 73.0;
55.5; 48.7; 35.7; 34.7; 31.2; 24.7. ESI-MS: 273 ([M þ Na]þ).
(6R)-6-(Methoxymethoxy)-10-phenyldec-1-en-4-ol (8). To a cooled (08) stirred soln. of 7 (0.3 g,
1.2 mmol), Zn dust (0.23 g, 3.6 mmol), and allyl bromide (C3H5Br) (0.16 ml, 2.4 mmol) in THF (15 ml), a
sat. NH4Cl soln. (0.4 ml) was added dropwise. The mixture was stirred for 4 h at r.t., until the aldehyde
was totally consumed (TLC). The mixture was filtered, and the precipitate was thoroughly washed with
AcOEt. The aq. layer was separated and treated with 5% HCl to dissolve the suspended turbid material.
The clear soln. was extracted with AcOEt. The combined org. extract was washed with 10% NaHCO3,
dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8): pure
8 (0.32 g, 92%). Colorless liquid. IR (neat): 3454, 3026, 2935, 2858, 1640, 1602, 1494, 1448, 1211, 1148,
1
1035, 915, 746, 700. H-NMR: 7.31 – 7.14 (m, 5 H); 5.92 – 5.76 (m, 1 H); 5.16 – 5.06 (m, 2 H); 4.72 – 4.60
(m, 2 H); 3.97 – 3.75 (m, 2 H); 3.38 (s, 3 H); 2.65 – 2.58 (t, J ¼ 7.5, 2 H); 2.27 – 2.19 (t, J ¼ 7.5, 2 H); 1.69 –
1.29 (m, 8 H). ESI-MS: 315 ([M þ Na]þ).
(6R)-6-(Methoxymethoxy)-10-phenyldec-1-en-4-one (9). To a cooled (08) soln. of 8 (0.2 g,
0.68 mmol) in dry CH2Cl2 (10 ml) was added DessꢀMartin periodinane (DMP; 0.58 g, 1.36 mmol),
and the mixture was stirred for 3 h at r.t. After completion, the reaction was quenched with sat. Na2S2O3
soln., and the mixture was washed with sat. NaHCO3, extracted with CH2Cl2 (2 ꢁ 5 ml), and washed with
brine, dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane
2 :8): pure 9 (0.18 g, 90%). Colorless liquid. IR (neat): 3024, 2934, 2858, 1714, 1639, 1453, 1370, 1147,
1098, 1037, 918, 745, 700. 1H-NMR: 7.31 – 7.31 (m, 5 H); 5.99 – 5.84 (m, 1 H); 5.21 – 5.09 (m, 2 H); 4.62 (q,
J ¼ 6.7, 2 H); 4.08 – 3.99 (m, 1 H); 3.31 (s, 3 H); 3.20 (dt, J ¼ 1.5, 6.7, 2 H); 2.74 (q, J ¼ 6.7, 1 H); 2.61 (t, J ¼
7.5, 2 H); 2.52 (d, J ¼ 4.5, 1 H); 1.69 – 1.49 (m, 6 H). 13C-NMR: 207.0; 142.3; 130.2; 128.3; 128.2; 125.6;
118.9; 95.9; 74.3; 55.5; 48.5; 47.4; 35.7; 34.5; 31.3; 24.7. ESI-MS: 313 ([M þ Na]þ).
(4R,6R)-6-(Methoxymethoxy)-10-phenyldec-1-en-4-ol (10) [6f]. To a stirred soln. of 9 (0.15 g,
0.51 mmol ) in THF (1 ml) at r.t. was added MeOH (0.6 ml, 15.3 mmol), followed by drtopwise addition
of 0.1m SmI2 in dry THF (17.83 ml, 1.78 mmol). The resulting mixture was stirred for 12 h before the
septum was removed and stirring was continued until the color of the soln. changed. The reaction was
then quenched with sat. Na2S2O3 soln. (5 ml), the mixture was extracted with AcOEt (3 ꢁ 5 ml), and the
combined org. extract was washed with H2O (2 ꢁ 5 ml), dried (anh. Na2SO4), and concentrated. The
crude residue was purified by CC (AcOEt/hexane 2 :8): pure 10 (0.11 g, 76%).
(6R)-5,6-Dihydro-6-[(1E,4R,6R)-4-hydroxy-6-(methoxymethoxy)-10-phenyldec-1-en-1-yl]-2H-pyr-
an-2-one (17). A soln. of 10 (0.03 g, 0.1 mmol) and 16 (0.038 g, 0.3 mmol) in dry CH2Cl2 (25 ml) in a 1:3
ratio was first bubbled with N2 flow, then Grubbs-II catalyst (0.017 g, 0.02 mmol) was added at once, and
the resulting mixture was heated under N2 at 408 for 12 h. After completion of the reaction, the solvent
was removed, and the residue was purified by CC (AcOEt/hexane 3 :7): pure 17 (0.029 g, 74%).
Colorless liquid. [a]2D5 ¼ ꢀ4.37 (c ¼ 0.8, CHCl3). IR (neat): 3455, 3024, 2926, 2855, 1718, 1456, 1382, 1248,
1147, 1033, 969, 816, 746. 1H-NMR: 7.31 – 7.14 (m, 5 H); 6.92 – 6.84 (m, 1 H); 6.05 (d, J ¼ 9.8, 1 H); 5.95 –
5.83 (m, 1 H); 5.68 (dd, J ¼ 6.7, 15.8, 1 H); 4.90 (q, J ¼ 7.5, 1 H); 4.64 (s, 2 H); 3.99 – 3.89 (m, 1 H); 3.85 –
3.74 (m, 1 H); 3.39 (s, 3 H); 2.62 (t, J ¼ 7.5, 2 H); 2.47 – 2.39 (m, 2 H); 2.29 – 2.20 (m, 2 H); 1.71 – 1.48 (m,

Helvetica Chimica Acta – Vol. 97 (2014)
119
6 H); 1.44 – 1.18 (m, 2 H). 13C-NMR: 164.0; 144.6; 142.3; 131.3; 129.3; 128.3; 128.2; 125.6; 121.5; 96.3;
77.9; 75.9; 67.0; 55.8; 40.7; 40.1; 35.8; 34.6; 31.4; 29.6; 25.0. ESI-MS: 406 ([M þ NH4]þ).
(6R)-6-[(1E,4R,6R)-4,6-Dihydroxy-10-phenyldec-1-en-1-yl]-5,6-dihydro-2H-pyran-2-one (1) [5]. To
a stirred soln. of 17 (0.02 g, 0.05 mmol) in a mixture of MeOH (3 ml) and MeCN (3 ml) was added
CeCl3 · 7 H2O (0.019 g, 0. 05 mmol) under N2, then the mixture was stirred at reflux for 6 h. After
completion, the reaction was quenched with solid NaHCO3, the mixture was filtered, and the filtrate was
concentrated, diluted with H2O and extracted in to AcOEt (3 ꢁ 5 ml). The combined org. extract was
washed with brine, dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC
(AcOEt/hexane 4 :6): 1 (0.015 g, 85%). White solid. M.p. 62 – 648.
(3R,5R)-1-[(4R)-4-Benzyl-2-thioxo-1,3-thiazolidin-3-yl]-3-hydroxy-5-(methoxymethoxy)-9-phenyl-
nonan-1-one (18). To a cooled (08) soln. of the chiral 1-[(4R)-4-benzyl-2-thioxo-1,3-thiazolidin-3-
yl]ethanone [8] (0.5 g, 2.0 mmol ) in dry CH2Cl2 (15 ml) was added dropwise TiCl4 (0.263 ml, 2.4 mmol),
and the soln. was stirred for 5 min, the color turning to a yellow, followed by the addition of EtNiPr2
(0.41 ml, 2.4 mmol). The suspension now turned to dark red (enolate) and was stirred for 20 min at 08. To
this entirely dark red enolate, 7 (0.5 g, 2.0 mmol) in dry CH2Cl2 (10 ml) was added dropwise, and the
mixture was stirred for 15 min at ꢀ 788. After completion, the reaction was quenched with sat. NH4Cl
(5 ml) soln., and the mixture was extracted with CH2Cl2 (2 ꢁ 20 ml). The combined org. extract was
washed with brine, dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC
(AcOEt/hexane 3 :7): pure 18 (0.79 g, 79%). Yellow liquid. [a]2D5 ¼ ꢀ128.1 (c ¼ 2.2, CHCl3). IR (neat):
3445, 3032, 2931, 1690, 1496, 1455, 1343, 1282, 1271, 1169, 1032, 755, 740. 1H-NMR: 7.39 – 7.24 (m, 8 H);
7.21 – 7.14 (m, 2 H); 5.43 – 5.34 (m, 1 H); 4.67 (q, J ¼ 6.7, 2 H); 4.41 – 4.30 (m, 1 H); 3.87 – 3.77 (m, 1 H);
3.53 (dd, J ¼ 3.0, 17.5, 1 H); 3.44 – 3.39 (m, 1 H); 3.38 (s, 3 H); 3.34 – 3.19 (m, 2 H); 3.05 (dd, J ¼ 10.5, 13.4,
1 H); 2.89 (d, J ¼ 11.5, 1 H); 2.63 (t, J ¼ 3.3, 2 H); 1.88 – 1.75 (m, 1 H); 1.72 – 1.50 (m, 5 H); 1.46 – 1.34 (m,
2 H). 13C-NMR: 201.2; 172.5; 142.4; 136.4; 129.4; 128.8; 128.3; 128.2; 127.2; 125.6; 95.2; 76.4; 68.4; 66.5;
55.7; 46.1; 40.6; 36.7; 35.8; 34.1; 32.0; 31.5; 24.5. ESI-MS: 524 ([M þ Na]þ).
(3R,5R)-1-[(4R)-4-Benzyl-2-thioxo-1,3-thiazolidin-3-yl]-3,5-bis(methoxymethoxy)-9-phenylnonan-
1-one (19). To a cooled (08) soln. of 18 (0.35 g, 0.69 mmol) in dry CH2Cl2 (10 ml), EtNiPr2 (0.24 ml,
1.39 mmol) and then MOMCl (0.08 ml, 1.0 mmol) was added dropwise, and the mixture was stirred for
5 h. After completion of the reaction, the mixture was extracted with CH2Cl2 (2 ꢁ 10 ml), washed with
brine, dried (anh. Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane
2 :8): pure 19 (0.31 g, 83%). Colorless liquid. [a]2D5 ¼ ꢀ155.8 (c ¼ 0.6, CHCl3). IR (neat): 3427, 3028, 2924,
1
1685, 1606, 1493, 1344, 1265, 1166, 1046, 754, 734. H-NMR: 7.39 – 7.12 (m, 10 H); 5.37 – 5.27 (m, 1 H);
4.73 – 4.62 (m, 4 H); 4.36 – 4.25 (m, 1 H); 3.72 – 3.55 (m, 2 H); 3.44 – 3.40 (m, 1 H); 3.37 (s, 3 H); 3.35 (s,
3 H); 3.24 (dd, J ¼ 3.0, 13.5, 1 H); 3.10 – 2.98 (m, 1 H); 2.89 (d, J ¼ 11.3, 1 H); 2.63 (t, J ¼ 7.5, 2 H); 1.78 –
1.55 (m, 5 H); 1.50 – 1.34 (m, 4 H). 13C-NMR: 201.1; 171.7; 142.5; 136.5; 129.4; 128.8; 128.3; 128.2; 127.1;
125.6; 96.7; 95.4; 74.5; 72.5; 68.6; 66.5; 55.7; 44.5; 39.8; 36.5; 35.9; 34.3; 32.1; 31.5; 24.8. ESI-MS: 568
([M þ Na]þ).
Methyl (2Z,5S,7R)-5,7-Bis(methoxymethoxy)-11-phenylundec-2-enoate (20). To a cooled (ꢀ 788)
soln. of 19 (0.25 g, 0.45 mmol) in dry CH2Cl2 (10 ml) was added 1m DIBAL-H in toluene (0.55 ml,
0.55 mmol), and the mixture was stirred at ꢀ 788 for 10 min. After completion, the reaction was
quenched with sat. sodium potassium tartarate (3 ml) soln., and the mixture was srirred for 0.5 h and then
extracted with CH2Cl2 (3 ꢁ 15 ml). The combined org. extract was washed with brine, dried (anh.
Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 2 :8): pure aldehyde
(0.12 g, 82%). Colorless liquid. The aldehyde was directly used for the next reaction. To a cooled (08)
suspension of NaH (0.017 g, 0.71 mmol) in dry THF (10 ml) under N2 was added methyl [bis(2,2,2-
trifluoroethoxy)phosphoryl]acetate (0.11 ml, 0.53 mmol), and the mixture was stirred for 30 min and
then cooled to ꢀ788. The soln. of aldehyde (0.12 g, 0.35 mmol) in dry THF (5 ml) was added dropwise
over a period of 5 min. The resulting mixture was stirred for 3 h at ꢀ788. After completion, the reaction
was quenched with sat. NH4Cl soln., and the mixture was extracted with Et2O (3 ꢁ 5 ml). The combined
org. extract washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by CC
(AcOEt/hexane 2 :8): pure 20 (0.1 g, 74%). Colorless liquid. [a]2D5 ¼ þ12.7 (c ¼ 0.9, CHCl3). IR (neat):
3433, 2931, 2856, 1722, 1645, 1442, 1406, 1175, 1099, 1036, 917. 1H-NMR: 7.31 – 7.12 (m, 5 H); 6.34 (dt, J ¼
7.1, 11.5, 1 H); 5.92 – 5.85 (m, 1 H); 4.67 – 4.59 (m, 4 H); 3.88 – 3.78 (m, 1 H); 3.70 (s, 3 H); 3.69 – 3.60 (m,

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Helvetica Chimica Acta – Vol. 97 (2014)
1 H); 3.36 (s, 3 H); 3.34 (s, 3 H); 3.07 – 2.84 (m, 2 H); 2.61 (t, J ¼ 7.5, 2 H); 1.90 – 1.77 (m, 1 H); 1.70 – 1.47
(m, 5 H); 1.45 – 1.30 (m, 2 H). 13C-NMR: 166.6; 146.0; 142.5; 128.3; 128.2; 125.6; 121.0; 95.4; 95.2; 74.6;
73.8; 55.6; 55.5; 51.0; 39.4; 35.8; 34.3; 33.5; 31.5; 24.7. ESI-MS: 417 ([M þ Na]þ).
(6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (2) [6]. To a cooled (08) soln.
of 20 (0.04 g, 0.1 mmol) in THF (2 ml) was added 3m HCl (2 ml), and the mixture was stirred for 3 h.
After completion of the reaction, the mixture was diluted with AcOEt, and the reaction was quenched
with solid NaHCO3, and the mixture was filtered. The filtrate was washed with brine, dried (anh.
Na2SO4), and concentrated. The crude residue was purified by CC (AcOEt/hexane 1:1): compounds 2
and 2a (70 :30; 78% yield). Compound 2 (0.014 g): pale-yellow solid. M.p. 34 – 368.
(1R,7R)-7-(4-Phenylbutyl)-2,6-dioxa-bicyclo[3.3.1]nonan-3-one (2a). White solid (0.006 g). M.p.
36 – 388. [a]2D5 ¼ ꢀ17.1 (c ¼ 0.3, CHCl3). IR (KBr): 2924, 2855, 2102, 1736, 1494, 1078. 1H-NMR: 7.31 – 7.16
(m, 5 H); 4.93 – 4.88 (m, 1 H); 4.38 – 4.33 (m, 1 H); 3.79 – 3.65 (m, 1 H); 2.87 – 2.78 (m, 2 H); 2.58 (t, J ¼
7.5, 2 H); 2.05 – 1.86 (m, 3 H); 1.77 – 1.27 (m, 7 H). 13C-NMR: 169.7; 142.4; 128.2 (2); 125.6; 73.0; 65.6;
65.4; 36.8; 36.2; 35.7; 35.4; 31.2; 29.7; 24.6. ESI-MS: 297 ([M þ Na]þ).
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Received March 25, 2013