The stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy- 6-phenylhexyl]-2H-pyran-2-one via Prins cyclization

Article abstract of DOI:10.1002/hlca.200900414

The stereoselective total synthesis of an antiproliferative and antifungal a-pyrone natural product (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H- pyran-2-one is described. The key steps involved are the Prins cyclization, Mitsunobu reaction, and r

Full text of DOI:10.1002/hlca.200900414

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The Stereoselective Total Synthesis of (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-
phenylhexyl]-2H-pyran-2-one via Prins Cyclization
by Jhillu Singh Yadav*, Dandekar Chandrakanth, Yerragorla Gopala Rao, Kontham Ravindar, and
Basi V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
(fax: þ 91-40-27160512; e-mail: yadavpub@iict.res.in)
The stereoselective total synthesis of an antiproliferative and antifungal a-pyrone natural product
(6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is described. The key steps in-
volved are the Prins cyclization, Mitsunobu reaction, and ring-closing metathesis reaction.
Introduction. – Antiproliferative and antifungal a-pyrone natural product (6S)-5,6-
dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (1) was isolated by Hos-
tettmann and co-workers in 2001 from Ravensara crassifolia [1]. The a-pyrone moiety is
one of the most commonly encountered structural motif among the various natural-
product skeletons. Many of these natural products exhibit varied pharmacological
properties such as antimicrobial, antifungal, and cytotoxicity against human tumor cells
[2]. Some of these compounds such as fostriecin [3] and goniothalamin [3] are known
to display anticancer properties, and (ꢀ)-pyronetin [4] is known to exhibit immuno-
suppressive activity. Passifloricin-A [5] and strictifolione [6] are found to exhibit
antifungal activity. (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-
one (1) is also one such natural product which is known to exhibit antifungal activity
against phytopathogenic fungus Cladosporium cucumarinum (Fig.) [1]. In a recent
investigation, this compound was found to display antiproliferative activity against
three human cancer cell lines: leukemia (THP-1 and U-937) and melanoma (A-375)
[7].
Figure. Structure of (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenyl-
hexyl]-2H-pyran-2-one (1)
The Prins cyclization is a powerful synthetic tool for the construction of
tetrahydropyran scaffolds and has been utilized in the synthesis of several natural
products [8]. Our group has made a significant effort to explore the utility of Prins
cyclization in the synthesis of various polyketide intermediates and applied it to the
total synthesis of some natural products [9]. The structural uniqueness of compound 1,
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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coupled with interesting biological activity and our interest on the 6-substituted a,b-
unsaturated-d-lactones [10], prompted us to explore the total synthesis via the Prins
cyclization. In our retrosynthetic analysis, we envisaged that the target molecule 1 could
be achieved from the diene ester 2 by a ring-closing metathesis approach. The ester 2
can be easily prepared from 2,4,6-trisubstituted tetrahydropyran 3, which could in turn
be obtained via the Prins cyclization of homoallylic alcohol 4 with aldehyde 5
(Scheme 1).
Scheme 1. Retrosynthetic Analysis of Compound (1)
Results and Discussion. – The synthesis of the natural product 1 started with chiral
homoallyl alcohol 4 (Scheme 2). The precursor 4 was prepared in two steps by CuI-
mediated regioselective opening [11] of (ꢀ)-(R)-2-[(benzyloxy)methyl]oxirane (6)
with vinyl magnesium bromide, followed by subsequent reductive cleavage of
benzyloxy alcohol 7 with Li in liquid NH3. The Prins cyclization of 4 with 5-
phenylpentanal (5) in the presence of TFA (10 equiv.), followed by hydrolysis of the
resulting trifluoroacetate, gave the trisubstituted pyran 8 in 50% yield [12]. The
Scheme 2
a) CH2¼CHMgBr, CuCN, ꢀ 788 to ꢀ 408, 4 h; 92%. b) Li, liquid NH3, THF, 20 min; 75%. c) 5-
Phenylpentanal (5), CF3COOH (TFA), CH2Cl2, then K2CO3, MeOH, r.t., 3 h; 50%. d) Et3N, TsCl,
CH2Cl2, 08 to r.t., 3 h; 96%. e) (t-Bu)Me2SiCl (TBSCl), 4-(dimethylamino)pyridine (DMAP), 1H-
imidazole, CH2Cl2, 08 to r.t., 3 h; 95%. f) NaI, acetone, reflux, 24 h; 95%. g) Zn, EtOH, reflux, 1 h; 98%.

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stereochemistry of step c leading to 8 was assumed to be in accordance with previous
results [9]. However, it was later established after elaborating compound 8 to the target
molecule 1, which in all respects was identical with that described in literature [1].
The chemoselective tosylation of primary alcohol 8 with 1.1 equiv. of TsCl in the
presence of Et3N in CH2Cl2 gave the corresponding tosyl derivative 9 in 96% yield [13].
TBS Protection of the secondary alcohol 9 with TBSCl, DMAP, and 1H-imidazole
afforded the TBS ether 10 in 95% yield. Treatment of 10 with NaI in refluxing acetone
gave the corresponding iodo compound 3 in 95% yield, which, on exposure to activated
Zn in refluxing EtOH, furnished key intermediate 11.
Secondary alcohol 11 was protected as its methoxymethyl (MOM) ether 12 using
MOM-Cl and EtN(i-Pr)2 in CH2Cl2 (Scheme 3). Deprotection of TBS ether 12 with
Bu4NF in THF gave the alcohol 13 in 90% yield, which was subjected to standard
Mitsunobu reaction conditions [14] using diethyl azodicarboxylate (DEAD), PPh3,
and 4-nitrobenzoic acid, followed by hydrolysis of the resulting ester with K2CO3 in
MeOH, to give the homoallylic alcohol 14 with inversion of configuration. Homoallyl
alcohol 14 was then subjected to esterification with acryloyl chloride to obtain the diene
ester 2. The obtained ester 2 was used for the ring-closing metathesis (RCM) with
Grubbsꢂ first-generation catalyst (5 mol-%) to provide the desired lactone 15 [15].
Finally, deprotection of MOM ether 15 was achieved with 6n HCl/THF/H2O 1:2 :1 to
afford the target natural product 1. The spectral and physical data of all the compounds
were in good agreement with literature values [1].
Scheme 3
a) Methoxymethyl chloride (MOM-Cl), DIPEA, CH2Cl2, 4 h, 08; 93%. b) Bu4NF, THF, 08 to r.t., 2 h;
90%. c) 4-Nitrobenzoic acid, diethyl azodicarboxylate (DEAD), PPh3 then K2CO3, MeOH, r.t., 0.5 h;
86%. d) Acryloyl chloride, EtN(i-Pr)2, CH2Cl2, 08 to r.t.; 83%. e) Grubbsꢀ I generation catalyst
[(PCy3)2Cl2Ru¼CHPh] (5 mol-%), dry CH2Cl2, 558, 12 h; 90%. f) 6n HCl/THF/H2O 1:2 :1, r.t., 24 h;
92%.
In conclusion, we have established the versatility of the Prins cyclization and a
subsequent reductive cleavage in natural-product synthesis by achieving the stereo-

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selective synthesis of the antiproliferative and antifungal natural product (6S)-5,6-
dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (1). To the best of our
knowledge, this is the first report on the total synthesis of 1 by means of the Prins
cyclization.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from the Aldrich and Acros, and were used without further purification unless
otherwise stated. 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; 60 –
120 mesh, Acme). Optical rotations: Horiba high-sensitive polarimeter SEPA-300 at 258. IR Spectra:
Perkin-Elmer IR-683 spectrophotometer with NaCl optics. 1H- (300 MHz) and 13C-NMR (75 MHz)
spectra: Bruker Avance 300 instrument with TMS as internal standard in CDCl3; J values in Hz. MS:
Agilent Technologies 1100 Series (Agilent Chemistation Software).
(1R)-1,5-Anhydro-2,4-dideoxy-1-(4-phenylbutyl)-l-threo-hexitol (8). Trifluoroacetic acid (TFA;
23.4 ml, 306 mmol) was added to a soln. of homoallylic alcohol 4 (1.04 g, 10.18 mmol) and 5-
phenylpentanal (5 g, 30.6 mmol) in dry CH2Cl2 (30 ml) under N2. The progress of the reaction was
followed by TLC. Upon completion, the reaction was quenched with aq. NaHCO3 soln., and the pH was
adjusted to > 7 by addition of Et3N. The aq. phase was extracted with CH2Cl2 (3 ꢁ 20 ml), and the
combined org. layers were dried (MgSO4) and concentrated under reduced pressure. The resulting crude
trifluoroacetate was then dissolved in MeOH (20 ml) and treated with K2CO3 (770 mg, 7.2 mmol)
overnight. After complete conversion, MeOH was removed under reduced pressure, and then the
reaction was quenched with H2O (20 ml), and the mixture was extracted with CH2Cl2 (3 ꢁ 25 ml). The
combined org. layers were dried (MgSO4) and concentrated in vacuo. The product was then purified by
flash CC to afford 8 (310 mg, 50% yield over two steps). White solid. [a]2D0 ¼ ꢀ1.1 (c ¼ 1.4, CHCl3). IR
(KBr): 3310, 3083, 3025, 2929, 2855, 1941, 1702, 1605, 1472, 1369, 1260, 1159, 1077, 1018, 934, 828, 694,
635. 1H-NMR: 7.29 – 7.05 (m, 5 H); 3.85 – 3.65 (m, 1 H); 3.61 – 3.21 (m, 4 H); 2.60 (t, J ¼ 7.5, 2 H); 2.09 –
1.72 (m, 4 H); 1.71 – 1.31 (m, 5 H); 1.29 – 1.00 (m, 2 H). 13C-NMR: 142.4; 128.3; 128.2; 125.6; 75.8; 75.5;
67.8; 65.8; 40.9; 36.7; 35.8; 35.7; 31.3; 25.0. LC/MS: 287 ([M þ Na]þ).
(1R)-1,5-Anhydro-2,4-dideoxy-6-O-[(4-methylphenyl)sulfonyl]-1-(4-phenylbutyl)-l-threo-hexitol
(9). To a soln. of 8 (300 mg, 1.16 mmol) in dry CH2Cl2 (10.0 ml), Et3N (0.32 ml, 2.32 mmol) was added at
08. Then, TsCl (265 mg, 1.39 mmol) was added over 2 h. The resulting mixture was allowed to stir at r.t.
for 3 h. Then, the mixture was treated with 1m aq. HCl (4 ml) and extracted with CH2Cl2 (3 ꢁ 5 ml). The
org. layer was washed with sat. NaHCO3 (5 ml) and H2O (5 ml). The combined org. phases were dried
(Na2SO4) and concentrated under reduced pressure. Flash chromatography (FC) of the crude product
afforded 9. [a]2D0 ¼ þ13.2 (c ¼ 0.55, CHCl3). H-NMR: 7.76 (d, J ¼ 8.0, 2 H); 7.34 – 7.07 (m, 7 H); 4.01 –
1
3.90 (m, 1 H); 3.80 – 3.63 (m, 1 H); 3.58 – 3.42 (m, 1 H); 3.30 – 3.13 (m, 1 H); 2.63 – 2.53 (m, 2 H); 2.45
(s, 3 H); 1.96 – 1.69 (m, 3 H); 1.67 – 1.48 (m, 2 H); 1.47 – 1.20 (m, 4 H); 1.19 – 0.86 (m, 2 H). 13C-NMR:
144.7; 142.4; 132.8; 129.7; 128.3; 128.2; 127.8; 125.5; 75.6; 72.7; 71.9; 67.5; 40.6; 36.8; 35.7; 35.5; 31.3; 25.0;
21.5. LC/MS: 441 ([M þ Na]þ).
(1R)-1,5-Anhydro-3-O-[(tert-butyl)(dimethyl)silyl]-2,4-dideoxy-6-O-[(4-methylphenyl)sulfonyl]-1-
(4-phenylbutyl)-l-threo-hexitol (10). To a soln. of 9 (300 mg, 0.71 mmol) in dry CH2Cl2 (5 ml) and 1H-
imidazole (98 mg, 1.43 mmol) at 08 under N2 was added (t-Bu)Me2SiCl (TBSCl; 215 mg, 1.43 mmol), and
the resulting mixture was allowed to stir for 3 h at r.t. Then, the mixture was diluted with H2O (3 ml) and
extracted with CH2Cl2 (2 ꢁ 5 ml). The combined org. layers were washed with brine (1 ꢁ 5 ml), dried
(Na2SO4), and concentrated under vacuum to afford the crude product. CC of the crude product gave 10.
Colorless liquid. [a]2D0 ¼ þ2.3 (c ¼ 1.15, CHCl3). 1H-NMR: 7.97 – 7.94 (d, J ¼ 8.3, 2 H); 7.50 – 7.36 ( m,
5 H); 7.33 – 7.26 (m, 2 H); 4.15 – 4.08 (m, 2 H); 3.91 – 3.80 (m, 1 H); 3.72 – 3.62 (m, 1 H); 3.41 – 3.31 (m,
1 H); 2.76 (t, J ¼ 7.5, 2 H); 2.62 (s, 3 H); 1.95 – 1.83 (m, 2 H); 1.82 – 1.70 (m, 2 H); 1.69 – 1.39 (m, 4 H);
1.37 – 1.22 (m, 2 H); 1.03 (s, 9 H); 0.20 (s, 6 H). 13C-NMR: 144.6; 142.5; 129.7; 128.3; 128.2; 127.9; 125.5;
75.6; 72.7; 72.1; 68.1; 41.2; 37.4; 35.8; 35.6; 31.4; 25.7; 25.0; 21.6; 17.9; ꢀ 4.5. LC/MS: 555 ([M þ Na]þ).

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(tert-Butyl){[(2R,4S,6R)-2-(iodomethyl)-6-(4-phenylbutyl)tetrahydro-2H-pyran-4-yl]oxy}dimethyl-
silane (3). NaI (493 mg, 3.28 mmol) was added to a soln. of 10 (350 mg, 0.657 mmol) in 10 ml of acetone
and heated to reflux for 24 h. Acetone was removed under reduced pressure, the residue was diluted with
H2O and AcOEt, and the org. layer was separated, dried (Na2SO4), and concentrated in vacuo. The
resulting crude product was purified by CC to afford 3. Colorless liquid. [a]2D0 ¼ ꢀ11.4 (c ¼ 1.1, CHCl3).
IR (KBr): 3449, 3025, 2930, 2855, 1636, 1495, 1461, 1254, 1130, 1073, 838, 774, 746, 697. 1H-NMR: 7.45 –
7.23 (m, 5 H); 3.95 – 3.82 (m, 1 H); 3.51 – 3.36 (m, 1 H); 3.35 – 3.24 (m, 2 H); 2.80 – 2.73 (m, 2 H); 2.21 –
2.11 (m, 2 H); 1.89 – 1.48 (m, 6 H); 1.46 – 1.23 (m, 2 H); 1.03 (s, 9 H); 0.20 (s, 6 H). 13C-NMR: 142.7;
128.3; 128.3; 125.5; 75.8; 75.2; 68.4; 41.3; 41.2; 35.9; 35.7; 31.4; 25.8; 25.3; 18.0; 9.0; ꢀ 4.5. LC/MS: 489
([M þ H]þ).
(5R,7R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-1-phenyldec-9-en-5-ol (11). To 3 (300 mg, 0.613 mmol)
in EtOH (10 ml), commercial Zn dust (66.3 mg, 9.20 mmol) was added, and the resulting mixture was
refluxed for 1 h and then cooled to 258. Addition of solid NH4Cl and Et2O (15 ml), followed by stirring
for 5 min, gave a gray suspension which was filtered through Celite, and the filtrate was concentrated in
vacuo. The resulting crude product was purified by FC to give 11. Colorless liquid. [a]2D0 ¼ ꢀ10.6 (c ¼ 0.35,
CHCl3). IR (KBr): 3456, 3073, 2931, 2856, 1640, 1462, 1365, 1253, 1072, 1000, 912, 834, 775, 742, 697.
1H-NMR: 7.28 – 7.07 (m, 5 H); 5.78 – 5.62 (m, 1 H); 5.09 – 4.99 (m, 2 H); 4.05 – 3.96 (m, 1 H); 3.93 – 3.82
(m, 1 H); 2.89 (br. s, 1 H); 2.60 (t, J ¼ 7.5, 2 H); 2.36 – 2.28 (m, 2 H); 1.68 – 1.23 (m, 8 H); 0.90 (s, 9 H);
0.09 (s, 3 H); 0.08 (s, 3 H). 13C-NMR: 142.6; 134.6; 128.3; 128.1; 125.8; 117.3; 71.2; 68.0; 41.1; 40.9; 37.7;
35.9; 31.5; 25.7; 25.2; 17.8; ꢀ 4.5; ꢀ 4.8. LC/MS: 363 ([M þ H]þ).
(4S,6R)-6-(Methoxymethoxy)-10-phenyldec-1-en-4-ol (14). To a stirred mixture of 13 (200 mg,
0.492 mmol), Ph3P (387 g, 1.47 mmol), and 4-nitrobenzoic acid (1.3 g, 0.639 mmol) in dry THF (5 ml) at
08 was added diethyl azodicarboxylate (DEAD; 0.18 ml, 1.47 mmol) via a syringe. The mixture was then
stirred for another 0.5 h at r.t., then diluted with H2O (5 ml), and extracted with AcOEt (2 ꢁ 15 ml).
After removal of the solvent, the crude residue was dissolved in MeOH (5 ml) and treated with K2CO3
(66 mg, 0.96 mmol). After stirring the mixture for 4 h at r.t., it was diluted with H2O (5 ml) and extracted
with CH2Cl2 (3 ꢁ 5 ml). Removal of solvent under reduced pressure, followed by FC, afforded 14.
1
Colourless liquid. [a]2D0 ¼ ꢀ25.4 (c ¼ 1.15, CHCl3). H-NMR: 7.27 – 7.07 (m, 5 H); 5.86 – 5.74 (m, 1 H);
5.11 – 5.03 (m, 2 H); 4.59 (s, 2 H); 3.87 – 3.80 (m, 1 H); 3.78 – 3.72 (m, 1 H); 3.34 (s, 3 H); 2.61 – 2.57 (m,
2 H); 2.21 – 2.15 (m, 2 H); 1.69 – 1.45 (m, 7 H); 1.42 – 1.29 (m, 2 H). 13C-NMR: 142.1; 134.8; 128.7; 125.8;
117.5; 95.3; 71.1; 67.17; 55.5; 41.9; 40.8; 36.6; 34.1; 31.4; 30.6; 24.3. LC/MS: 292 (Mþ).
(1S,3R)-3-(Methoxymethoxy)-7-phenyl-1-(prop-2-en-1-yl)hept-1-yl Prop-2-enoate (2). To a stirred
soln. of 14 (200 mg, 0.69 mmol) in dry CH2Cl2 (5 ml) were added acryloyl chloride (0.1 ml, 1.37 mmol)
and EtN(i-Pr)2 (0.4 ml, 2.748 mmol) at 08. The resulting mixture was allowed to stir at r.t. for 3 h. The
mixture was then diluted with H2O (5 ml) and extracted with CH2Cl2 (3 ꢁ 5 ml). The combined org.
layers were dried (Na2SO4), and the solvent was removed under vacuum to give the crude residue, which
was purified by SiO2 CC to afford pure 2. [a]D20 ¼ þ25.1 (c ¼ 1.0, CHCl3). IR (KBr): 3506, 3432, 1926,
1733, 1450, 1098, 985, 746. 1H-NMR (200 MHz, Varian gemini FT-200): 7.21 (t, J ¼ 7.5, 2 H); 7.11 (t, J ¼
5.2, 3 H); 6.36 (d, J ¼ 7.3, 1 H); 6.12 – 6.0 (m, 1 H); 5.82 – 5.65 (m, 2 H); 5.15 – 5.01 (m, 3 H); 4.63 – 4.50
(m, 2 H); 3.63 – 3.49 (m, 1 H); 3.39 – 3.28 (m, 3 H); 2.59 (t, J ¼ 7.5, 2 H); 2.45 – 2.26 (m, 2 H); 2.0 – 1.23
(m, 8 H). FAB-MS: 285 ([M þ OCH2 ꢀ OMe]þ).
(6S)-5,6-dihydro-6-[(2R)-2-(methoxymethoxy)-6-phenylhexyl]-2H-pyran-2-one (15). To a stirred
soln. of bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride (Grubbsꢂ catalyst; 22 mg,
5 mol-%) in CH2Cl2 (50 ml) at 558 was added a soln. of 14 (190 mg, 0.54 mmol) in CH2Cl2 (10 ml). The
resulting mixture was heated for 12 h. After completion of the reaction, the contents were cooled, and the
solvent was removed under reduced pressure to yield a crude product, which was purified by SiO2 CC to
afford pure 15. [a]2D0 ¼ ꢀ38.6 (c ¼ 0.65, CHCl3). IR (KBr): 2933, 1724, 1386, 1299, 1034, 750. 1H-NMR:
7.22 (t, J ¼ 8.3, 2 H); 7.11 (t, J ¼7.1, 3 H); 6.87 – 6.79 (m, 1 H); 5.99 (d, J ¼ 9.4, 1 H); 4.63 – 4.49 (m, 3 H);
3.75 – 3.66 (m, 1 H); 3.30 (s, 3 H); 2.60 (t, J ¼ 7.5, 2 H); 2.41 – 2.25 (m, 2 H); 2.15 – 2.02 (m, 1 H); 1.70 (m,
5 H). LC/MS: 318 (Mþ).
(6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one (1). Compound 15 (150 mg,
0.414 mmol) was stirred in 4 ml of 6n HCl/THF/H2O 1:2 :1 for 24 h. The reaction was quenched with sat.
NaHCO3 (5 ml) and H2O (5 ml), and the mixture was extracted with AcOEt. The combined org. layers

Helvetica Chimica Acta – Vol. 93 (2010)
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were washed with brine (1 ꢁ 5 ml), dried (Na2SO4), and concentrated in vacuo. The resulting crude
product was purified by CC to afford 1. Pale-yellow solid. M.p. 33 – 358. [a]2D0 ¼ ꢀ64.9 (c ¼ 0.65, CHCl3).
1
IR (KBr): 3457, 2938, 2848, 1695, 1487, 1392, 1254. H-NMR: 7.33 – 7.12 (m, 5 H); 6.94 – 6.84 (m, 1 H);
6.02 (dd, J ¼ 1.4, 9.4, 1 H); 4.82 – 4.65 (m, 1 H); 4.07 – 3.93 (m, 1 H); 2.62 (t, J ¼ 7.2, 2 H); 2.40 – 2.30 (m,
2 H); 1.97 – 1.81 (m, 1 H); 1.70 – 1.58 (m, 3 H); 1.52 – 1.38 (m, 4 H). 13C-NMR: 164.4; 145.4; 142.3; 128.2;
128.1; 125.5; 121.2; 74.9; 66.8; 42.2; 37.7; 35.8; 31.3; 29.8; 25.1. LC/MS: 275 ([M þ H]þ).
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Received November 23, 2009