Stereoselective total synthesis of passifloricin A

Article abstract of DOI:10.1002/hlca.201200356

The stereoselective total synthesis of passifloricin A (1), a naturally occurring dihydropyranone with leishmanicidal and antiprotozoal activities, has been accomplished starting from protected glyceraldehyde using Maruoka asymmetric allylation, diastereoselective iodo-carbonate cyclization, and Grubbs' olefin metathesis reactions as the key steps. Copyright

Full text of DOI:10.1002/hlca.201200356

Helvetica Chimica Acta – Vol. 96 (2013)
505
Stereoselective Total Synthesis of Passifloricin A1)
by Cheruku Ravindra Reddy, Boyapati Veeranjaneyulu, Siddavatam Nagendra, and Biswanath Das*
Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007,
India (phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
The stereoselective total synthesis of passifloricin A (1), a naturally occurring dihydropyranone with
leishmanicidal and antiprotozoal activities, has been accomplished starting from protected glyceralde-
hyde using Maruoka asymmetric allylation, diastereoselective iodo-carbonate cyclization, and Grubbsꢀ
olefin metathesis reactions as the key steps.
Introduction. – Dihydropyranones are an important group of bioactive natural
products [1]. They act as Michael acceptors to display their biological properties.
Passifloricin A, a member of this group, was isolated from Passiflora foetida var. hispida
(Passifloraceae) [2]. The compound was found to possess interesting leishmanicidal
and antiprotozoal activities [3].
The structure of passifloricin A was initially assigned as 1a on the basis of its
spectroscopic data [2]. Several syntheses of the compound with this proposed structure,
1a, were also reported [4]. Murga et al. synthesized different isomers of the compound,
and after inspection of their NMR spectra, they revised the structure of passifloricin A
as 1 [4a][5].
Due to the interesting structure and important biological properties, the synthesis of
passifloricin A (1) has been an attractive target for the organic chemists [4a][5][6]. In
continuation of our work [7] on bioactive natural products, here we report an attractive
and efficient new synthesis of compound 1 in a stereoselective manner.
Results and Discussion. – The retrosynthetic analysis (Scheme 1) indicates that
passifloricin A (1) can be synthesized from the homoallylic alcohol 2 [6c], which can be
prepared from the iodo-carbonate 3. The latter can be obtained from another
homoallylic alcohol 4, generated from the protected glyceraldehyde 5.
1
)
Part 63 in the series, ꢃSynthetic Studies on Natural Productsꢀ.
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 1. Retrosynthetic Pathway for Passifloricin A (1)
The present synthesis of passifloricin A (1) started from (R)-2,3-O-isopropylide-
neglyceraldehyde (5; Scheme 2), which was reacted with 1-bromotetradecane in the
presence of Mg to afford a mixture of diastereoisomeric alcohols 6a and 6b. The
reaction was carried out under different conditions to increase the yield of the desired
alcohol 6a (Table). When the reaction was conducted in THF at 708 for 8 h, the total
yield was 94%, favoring the anti-isomer (anti/syn 89 :11), was separated chromato-
graphically for the next step.
Scheme 2
Table. Reaction Conditions for the Synthesis of 6a/6b (anti/syn)
Solvent
Temp. [8]
Time [h]
Yield [%]
syn/anti
THF
THF
Et2O
70
r.t.
r.t.
8
24
24
94
74
78
11 : 89
32 : 68
37: 63
The alcohol 6a was reacted with MOMCl in the presence of EtNiPr2 to give the
corresponding MOM-protected alcohol 7 (Scheme 3). Acetonide deprotection of 7
with PPTS in MeOH yielded the diol 8, which was then treated with NaIO4, and the
resulting aldehyde underwent Wittig homologation with Ph3PCHCOOEt to furnish the
a,b-unsaturated ester 9. Reduction of 9 with NiCl2/NaBH4 in MeOH afforded the
saturated ester 10. Further reduction of the latter with DIBAL-H in dry CH2Cl2 gave
the corresponding aldehyde, which directly underwent the Maruoka asymmetric

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Scheme 3
a) Methoxymethyl chloride (MOMCl), EtNiPr2, CH2Cl2, 08 – r.t., 6 h; 92%. b) Pyridinium p-
toluenesulfonate (PPTS), MeOH, 08 – r.t., 8 h; 89%. c) 1. NaIO4, NaHCO3, CH2Cl2, 08, 10 h; 91%; 2.
Ph3PCHCOOEt, CH2Cl2, r.t., 5 h; 87%. d) NiCl2 · 6 H2O, NaBH4, MeOH, 08 – r.t., 30 min; 96%. e) 1.
Diisobutylaluminium hydride (DIBAL-H), CH2Cl2, ꢀ 788, 2 h; 79%. 2. A (10 mol-%), allyl(tributyl)-
stannane, 4-ꢄ molecular sieves (MS), CH2Cl2, 08, 25 h; 81%. f) Di(tert-butyl) dicarbonate ((Boc)2O),
Et3N, 4-(dimethylamino)pyridine (DMAP), CH2Cl2, 08 – r.t., 4 h; 93%. g) N-Iodosuccinimide (NIS),
MeCN, ꢀ 208, 2 h; 81%. h) K2CO3, MeOH, 08 – r.t., 5 h; 91%. i) CH2¼CHMgBr, CuI, THF, ꢀ 208 – r.t.,
3 h; 79%. j) 2,2-Dimethoxypropane (2,2-DMP), PPTS, CH2Cl2, 08 – r.t., 8 h; 96%. k) 1. OsO4, N-
methylmorpholine N-oxide (NMO), NaIO4, acetone/H2O, 08 – r.t., 6 h; 92%; 2. A (10 mol-%),
allyl(tributyl)stannane, 4-ꢄ MS, CH2Cl2, 08, 21 h; 69%. l) CH2¼CHC(O)Cl, EtNiPr2, CH2Cl2, 08 – r.t.,
6 h; 94%. m) Grubbsꢀ 1st generation catalyst B (10 mol-%), CH2Cl2, reflux, 10 h; 71%. n) 4n HCl, THF,
r.t., 10 h; 88%.

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allylation [4] with allyl(tributyl)stannane in the presence of the Ti complex of (R,R)-
BINOL (¼(R,R)-1,1’-binaphthalene-2,2’-diol), A, to yield the chiral allylic alcohol 4
(ee 97% determined by chiral HPLC). The OH group of 4 was protected by using
Boc2O, and the resulting product 11 was subjected to the iodo-carbonate cyclization [8]
by treatment with NIS in MeCN. The diastereoselectivity of the reaction was greater
than 95% favoring the syn-isomer 3; the other isomer was separated by column
chromatography. The iodo-carbonate 3 was then treated with K2CO3 in MeOH to give
the 1,3-syn-epoxy alcohol 12 in high yield [8]. The epoxy moiety was opened with vinyl
Grignard reagent in the presence of a catalytic amount of CuI in THF to furnish the
allylic 1,3-diol 13. The two OH groups of 13 were protected by using 2,2-
dimethoxypropane (2,2-DMP) and PPTS to afford the acetonide 14. The compound
14 was treated with OsO4 and NMO in acetone/H2O and then with NaIO4 to form an
aldehyde, which was immediately reacted with allyl(tributyl)stannane and the titanium
complex of (R,R)-BINOL (A) to yield the homoallylic alcohol 2. In analogy to [6c], the
alcohol 2 was acrylated with CH2¼CHC(O)Cl and EtNiPr2 to afford the unsaturated
ester 15, required for ring-closing metathesis (RCM) [6c][9]. The ring-closing
metathesis of 15 was successfully achieved by treatment with Grubbsꢀ 1st generation
catalyst, B, to furnish the lactone 16. Here, we used another catalyst, B, compared with
[6c]. The lactone 16 was subsequently treated with 4n HCl in THF, resulting in the
cleavage of the MOM-ether and simultaneous deprotection of the acetonide group to
afford the trihydroxy lactone 1, whose physical and spectroscopic properties were
identical to those reported for the natural passifloricin A [2].
In conclusion, we have developed an asymmetric total synthesis of the bioactive
natural product passifloricin A (1) starting from the protected (R)-glyceraldehydes 5
by applying Maruoka asymmetric allylation, iodo-carbonate cyclization , and Grubbsꢀ
olefin metathesis reaction as the key steps. The preparation of iodo-carbonate and its
conversion to an epoxy alcohol have been employed here for the first time to synthesize
this compound. The method can conveniently be applied to the preparation of different
analogs of passifloricin A.
The authors thank CSIR and UGC, New Delhi, for financial support.

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Experimental Part
General. All commercially available reagents were used directly without further purification unless
otherwise stated. The solvents used were all of anal. grade and were distilled under dry N2 where
necessary. All reactions were performed in pre-dried apparatus unless otherwise stated. The progress of
the reactions was monitored by anal. TLC performed on Merck silica gel 60 F254 plates. Yields were of
purified compounds unless otherwise stated. Column chromatography (CC): silica gel 60 – 120 mesh
(Qingdao Marine Chemical, China). Optical rotations: JASCO DIP 300 digital polarimeter. NMR
Spectra: Gemini 200 MHz spectrometer in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz.
ESI-MS: VG-Autospec-micromass instrument; in m/z. HR-MS: QSTAR-XL-Hybrid MS system (Applied
Biosystems); in m/z.
(aS,4R)-2,2-Dimethyl-a-tetradecyl-1,3-dioxolane-4-methanol (6a). To a stirred soln. of Me(CH2)13Br
(10 g, 36.10 mmol) in THF was added Mg (1.3 g, 54.15 mmol), and the temp. was slowly raised to 708. The
mixture was stirred for 8 h. After quenching the reaction with sat. NH4Cl soln. (15 ml), the mixture was
extracted with AcOEt (3 ꢁ 30 ml). After evaporation of the solvent, the residue was purified by CC to
afford pure 6a (8.9 g, 75%). Clear yellow liquid. [a]2D0 ¼ þ35.3 (c ¼ 0.2, CHCl3). IR: 3368, 1464, 1375,
1215. 1H-NMR (200 MHz, CDCl3): 3.96 – 3.80 (m, 3 H); 3.66 – 3.72 (m, 1 H); 3.91 (br. s, 1 H); 1.38 – 1.19
(m, 32 H); 0.87 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 108.9; 79.0; 70.8; 64.6; 32.9; 32.0; 29.8; 29.5;
27.9; 26.6; 25.8; 25.2; 22.8; 14.2. ESI-MS: 351 ([M þ Na]þ).
(4R)-4-[(1S)-1-(Methoxymethoxy)pentadecyl]-2,2-dimethyl-1,3-dioxolane (7). To a soln. of 6a
(9.5 g, 28.96 mmol) in anh. CH2Cl2 (10 ml) at 08 under N2 was added EtNiPr2 (4.17 g, 31.85 mmol)
dropwise, and after 5 min MOMCl (2.63 ml, 34.75 mmol) was added dropwise. The mixture was stirred at
r.t. for 6 h. After quenching the reaction with sat. NH4Cl soln. and brine, the mixture was extracted with
CH2Cl2 (3 ꢁ 30 ml). After evaporation of the solvent, the residue was purified by CC to afford pure 7
(9.9 g, 92%). Clear liquid. [a]2D0 ¼ þ9.5 (c ¼ 0.2, CHCl3). IR: 1462, 1374, 1264, 1215, 1155, 1036. 1H-NMR
(200 MHz, CDCl3): 4.69 (d, J ¼ 12.0, 1 H); 4.61 (d, J ¼ 12.0, 1 H); 4.02 – 3.94 (m, 2 H); 3.79 – 3.84 (m,
1 H); 3.57 – 3.63 (m, 1 H); 3.34 (s, 3 H); 1.53 – 1.45 (m, 2 H); 1.38 – 1.21 (m, 30 H,); 0.87 (t, J ¼ 7.0, 3 H).
13C-NMR (50 MHz, CDCl3): 109.0; 96.2; 78.9; 77.7; 66.2; 55.8; 32.1; 31.8; 29.9; 29.7; 26.9; 25.5; 25.0; 23.8;
14.2. ESI-MS: 395 ([M þ Na]þ).
(2R,3S)-3-(Methoxymethoxy)heptadecane-1,2-diol (8). To a stirred soln. of 7 (7.0 g, 18.8 mmol) in
MeOH (30 ml) at 08 was added a cat. amount of PPTS. The mixture was stirred at r.t. for 8 h. After
quenching the reaction with solid NaHCO3 under ice cooling and evaporation of the solvent, the residue
was purified by CC to afford pure 8 (5.55 g, 89%). Liquid. [a]2D0 ¼ þ8.7 (c ¼ 0.4, CHCl3). IR: 3421, 1463,
1213, 1100, 1033. 1H-NMR (200 MHz, CDCl3): 4.72 (d, J ¼ 12.0, 1 H); 4.64 (d, J ¼ 12.0, 1 H); 3.71 – 3.65
(m, 2 H); 3.62 – 3.57 (m, 2 H); 3.44 (s, 3 H); 3.32 (br. s, 1 H); 2.71 (br. s, 1 H); 1.61 – 1.43 (m, 2 H); 1.30
(br. s, 24 H); 0.90 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 98.0; 83.2; 73.1; 63.0; 56.0; 32.2; 31.8; 29.9;
29.2; 25.9; 22.9; 14.2. ESI-MS: 355 ([M þ Na]þ).
Ethyl (2E,4S)-4-(Methoxymethoxy)octadec-2-enoate (9). To a stirred soln. of 8 (5.4 g, 16.26 mmol)
in dry CH2Cl2 (20 ml) at 08, aq. NaHCO3 soln. (2.5 ml) was added, followed by careful addition of NaIO4
(8.74 g, 40.66 mmol). The mixture was allowed to reach slowly r.t., and stirred for 10 h. After quenching
the reaction with Na2SO4 (2.0 g), the mixture was stirred vigorously for 30 min and then filtered through
sintered funnel with CH2Cl2 (2 ꢁ 50 ml). The combined org. extracts were washed with brine (30 ml),
dried (Na2SO4), and concentrated under reduced pressure, the residue was purified by CC (AcOEt/
hexane 1:9) to afford pure aldehyde (4.43 g, 91%). Liquid.
To a stirred soln. of the aldehyde (4.43 g, 14.76 mmol) in CH2Cl2 was added Ph3PCHCOOEt (6.16 g,
17.72 mmol). The mixture was stirred at r.t. for 5 h. After quenching the reaction with ice, the mixture
was extracted with CH2Cl2 (3 ꢁ 20 ml). After evaporation of the solvent, the residue was purified by CC
to afford pure 9 (4.75 g, 87%) as a clear liquid. [a]2D0 ¼ ꢀ90.6 (c ¼ 0.4, CHCl3). IR: 1724, 1657, 1463, 1161.
1H-NMR (200 MHz, CDCl3): 6.75 (dd, J ¼ 16, 8.0,1 H); 5.92 (d, J ¼ 16.0, 1 H); 4.61 (d, J ¼ 12.0, 1 H); 4.52
(d, J ¼ 12.0, 1 H); 4.22 – 4.11 (m, 3 H); 3.34 (s, 3 H); 1.62 – 1.50 (m, 2 H); 1.34 – 1.18 (m, 27 H); 0.89 (t, J ¼
7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 173.5; 148.2; 122.0; 96.4; 75.1; 60.2; 55.9; 35.2; 32.0; 29.9; 29.8;
25.3; 22.8; 14.2. ESI-MS: 393 ([M þ Na]þ).

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Ethyl (4S)-4-(Methoxymethoxy)octadecanoate (10). To a stirred soln. of 9 (4.5 g, 12.16 mmol) in dry
MeOH (30 ml) under N2 at 08, NiCl2 · 6 H2O (0.575 g, 2.43 mmol) was added. After stirring for 5 min,
NaBH4 (0.899 g, 24.32 mmol) was added slowly (intermittently), and the mixture was stirred for 30 min.
After quenching the reaction with sat. NH4Cl soln. (5 ml), the mixture was extracted with AcOEt (3 ꢁ
10 ml). The combined org. extracts were dried (Na2SO4). After evaporation of the solvent, the residue
was purified by CC using AcOEt/hexane to afford pure 10 (4.33 g, 96%). Liquid. [a]2D0 ¼ þ19.2 (c ¼ 0.4,
1
CHCl3). IR: 1738, 1463, 1250, 1152. H-NMR (200 MHz, CDCl3): 4.59 (s, 2 H); 4.11 (q, J ¼ 7.0, 2 H);
3.46 – 3.59 ( m, 1 H); 3.34 (s, 3 H); 2.35 (t, J ¼ 7.0, 2 H); 1.91 – 1.79 (m, 1 H); 1.79 – 1.69 (m, 1 H); 1.53 –
1.40 (m, 2 H); 1.34 – 1.16 (m, 27 H); 0.89 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 173.3; 96.5; 76.0;
60.3; 55.7; 34.1; 31.9; 30.2; 29.8; 29.2; 25.3; 22.2; 14.2; 14.0. ESI-MS: 395 ([M þ Na]þ).
(4S,7S)-7-(Methoxymethoxy)henicos-1-en-4-ol (4). To a stirred soln. of 10 (4.3 g, 11.55 mmol) in dry
CH2Cl2 (20 ml) at ꢀ 788, DIBAL-H (1.0m, 13.87 ml, 13.87 mmol) was added dropwise, and the mixture
was stirred at r.t. for 2 h. After quenching the reaction by slow addition of dry MeOH (10 ml), the
mixture was allowed to reach r.t. Sat. sodium potassium tartrate (10 ml) was added and stirred for 1 h.
Then, the mixture was diluted with H2O (10 ml) and extracted with Et2O (2 ꢁ 50 ml). The org. layer was
separated and dried (Na2SO4), and concentrated in vacuo. The crude aldehyde (2.99 g, 79%) thus
obtained was used further without purification.
To a stirred soln. of TiCl4 (0.097 ml, 0.91 mmol) in CH2Cl2 (6 ml) was added dried Ti(OiPr)4 (774 mg,
2.73 mmol) at 08 under N2, and the mixture was allowed to warm to r.t. After 1 h, Ag2O (506 mg,
2.18 mmol) was added at the same temp., and the mixture was stirred for 5 h under exclusion of direct
light. The mixture was diluted with CH2Cl2 (10 ml) and treated with (R,R)-BINOL (1.24 g, 4.37 mmol) at
r.t. for 2 h to furnish chiral bis-TiIV oxide A. The in situ generated A was cooled to ꢀ 158, and treated
sequentially with the aldehyde (2.99 g, 9.11 mmol) and allyl(tributyl)stannane (3.35 ml, 10.93 mmol) at
the same temp. The mixture was allowed to warm to 08 and stirred for 25 h. After quenching the reaction
with sat. aq. NaHCO3 (25 ml), the mixture was extracted with Et2O (3 ꢁ 30 ml). The org. extracts were
dried (Na2SO4). After evaporation of solvent, the residue was purified by CC (petroleum ether/AcOEt
7:3) to afford pure 4 (2.73 g, 81% yield). Liquid. [a]2D0 ¼ þ7.5 (c ¼ 0.2, CHCl3). IR: 3447, 1640, 1459, 1147.
1H-NMR (200 MHz, CDCl3): 5.71 – 5.84 (m, 1 H); 5.18 – 5.07 (m, 2 H); 4.61 (s, 2 H); 3.68 – 3.50 (m, 2 H);
3.35 (m, 2 H); 2.30 – 2.10 (m, 2 H); 1.65 – 1.42 (m, 4 H); 1.29 (br. s, 28 H), 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR
(50 MHz, CDCl3): 134.9; 118.0; 95.5; 77.4; 71.1; 55.9; 42.1; 34.5; 32.2; 30.0; 29.9; 29.8; 28.0; 25.4; 22.8;
14.2. ESI-MS: 393 ([M þ Na]þ).
1,1-Dimethylethyl (4S,7S)-7-(Methoxymethoxy)henicos-1-en-4-yl Carbonate (11). Compound 4
(2.6 g, 7.02 mmol) was dissolved in 15 ml of dry CH2Cl2, and the mixture was stirred at 08. (Boc)2O
(2.41 ml, 10.54 mmol) was added, followed by addition of 1.27 ml (9.12 mmol) of Et3N and 85 mg
(0.70 mmol) of DMAP. The mixture was stirred from 08 to r.t. for 4 h and then extracted with CH2Cl2
(2 ꢁ 15 ml). The combined org. layers were dried (Na2SO4) and concentrated in vacuo. After evaporation
of the solvent, the residue was purified by CC to afford pure 11 (3.07 g, 93%). Liquid. [a]2D0 ¼ þ5.5 (c ¼
1
0.2, CHCl3). IR: 1738, 1461, 1367, 1279, 1166, 1040. H-NMR (200 MHz, CDCl3): 5.69 – 5.84 (m, 1 H);
5.12 – 5.03 (m, 2 H); 4.65 (s, 1 H); 4.57 (s, 2 H); 3.42 – 3.55 (m, 1 H); 3.32 (s, 3 H); 2.33 (t, J ¼ 7.0, 2 H);
1.68 – 1.42 (m, 15 H); 1.29 (br. s, 24 H); 0.89 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 153.1; 134.0;
118.1; 95.2; 81.6; 77.4; 55.7; 39.1; 34.5; 31.9; 30.0; 29.9; 29.7; 27.8; 25.2; 23.0; 14.2. ESI-MS: 493 ([M þ
Na]þ).
(4S,6S)-4-(Iodomethyl)-6-[(3S)-3-(methoxymethoxy)heptadecyl]-1,3-dioxan-2-one (3). To a stirred
soln. of 11 (2.9 g, 6.17 mmol) in dry MeCN (15 ml) under N2 at ꢀ 208 was added NIS (5.55 g,
24.68 mmol), and the temp. was raised to 08. The mixture was stirred for 2 h. After quenching the
reaction with Na2S2O3 (15 ml), the mixture was extracted with AcOEt (3 ꢁ 20 ml) and H2O (15 ml). The
org. layer were dried (Na2SO4) and concentrated in vacuo. After evaporation of the solvent, the residue
purified by CC to afford pure 3 (2.69 g, 81%). Light-yellow liquid. [a]2D0 ¼ þ64.5 (c ¼ 0.4, CHCl3). IR:
1712, 1463, 1382, 1125, 1027. 1H-NMR (200 MHz, CDCl3): 4.61 (d, J ¼ 12.0, 1 H); 4.58 (d, J ¼ 12.0, 1 H);
4.52 – 4.40 (m, 2 H); 3.46 – 3.58 (m, 1 H); 3.36 – 3.45 (m, 1 H); 3.34 (s, 3 H); 3.24 – 3.33 (m, 1 H); 1.82 –
1.60 (m, 3 H); 1.46 – 1.59 (m, 1 H); 1.25 (br. s, 28 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3):
150.8; 96.2; 76.9; 76.0; 72.1; 55.2; 37.9; 33.1; 32.5; 30.0; 29.9; 28.6; 25.9; 23.0; 14.2; 7.8. ESI-MS: 551 ([M þ
Na]þ).

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(aS,2S)-a-[(3S)-3-(Methoxymethoxy)heptadecyl]oxirane-2-ethanol (12). K2CO3 (1.91 g,
13.86 mmol) was added to a soln. of 3 (2.5 g, 4.62 mmol) in anh. MeOH (15 ml) at r.t., and the resulting
mixture was stirred for 5 h. Then, the mixture was diluted with Et2O (15 ml), and the reaction was
quenched with a mixture of Na2S2O3/sat. aq. NaHCO3 1:1. The aq. phase was extracted with Et2O (3 ꢁ
30 ml), and the org. extracts were washed with brine, dried (Na2SO4), and then concentrated. After
evaporation of the solvent, the residue was purified by CC to afford pure 12 (1.61 g, 91%). Yellow liquid.
1
[a]2D0 ¼ þ9.4 (c ¼ 0.4, CHCl3). IR: 3374, 1465, 1374, 1245, 1033. H-NMR (200 MHz, CDCl3): 4.62 (s,
2 H); 3.83 (br. s, 1 H); 3.48 – 3.59 (m, 1 H); 3.37 (s, 3 H); 3.18 – 3.26 (m, 1 H); 3.0 – 3.80 (m, 1 H); 2.69 –
2.75 (m, 1 H); 2.47 (m, 1 H); 1.82 – 1.63 (m, 2 H); 1.62 – 1.41 (m, 6 H); 1.28 (br. s, 24 H); 0.90 (t, J ¼ 7.0,
3 H). 13C-NMR (50 MHz, CDCl3): 96.2; 75.5; 2.8; 55.8; 50.9; 47.8; 42.0; 34.5; 32.0; 30.2; 29.3; 25.2; 22.5;
14.2. ESI-MS: 409 ([M þ Na]þ).
(4R,6S,9S)-9-(Methoxymethoxy)tricos-1-ene-4,6-diol (13). To a soln. of 12 (1.55 g, 4.01 mmol) in dry
THF (10 ml) under N2, a cat. amount of CuI was added, and the resulting mixture was stirred at 258 for
30 min. It was cooled to ꢀ208, CH2¼CHMgBr (2.68 ml, 1.0m in THF) was slowly added, and stirring was
continued at the same temp. for 30 min. The mixture was slowly warmed to r.t. After 3 h (monitored by
TLC), the reaction was quenched with sat. NH4Cl soln. (15 ml), and the mixture was diluted with AcOEt
(20 ml). The org. layer was separated, and the aq. layer was extracted with AcOEt (3 ꢁ 15 ml). The
combined org. layer was washed with brine (2 ꢁ 15 ml), dried (Na2SO4), and concentrated under reduced
pressure to afford the crude product which, by CC (hexane/AcOEt 5 :5) furnished 13 (1.31 g, 79%).
1
Liquid. [a]2D0 ¼ þ11.6 (c ¼ 0.2, CHCl3). IR: 3362, 1546, 1472, 1275, 1063. H-NMR (200 MHz, CDCl3):
5.80 (m, 1 H); 5.18 – 5.07 (m, 2 H); 4.62 (s, 2 H); 3.91 – 3.77 (m, 2 H); 3.51 – 3.59 (m, 1 H); 3.37 (s, 3 H);
2.22 (t, J ¼ 7.0, 2 H); 1.68 – 1.40 (m, 8 H); 1.23 (br. s, 24 H); 0.89 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz,
CDCl3): 144.6; 135.0; 118.7; 95.4; 79.6; 76.4; 72.5; 55.4; 42.5; 42.0; 34.6; 31.9; 31.2; 29.6; 25.4; 22.6; 14.4.
ESI-MS: 437 ([M þ Na]þ).
(4S,6R)-4-[(3S)-3-(Methoxymethoxy)heptadecyl]-2,2-dimethyl-6-(prop-2-en-1-yl)-1,3-dioxane (14).
Compound 13 (1.25 g, 3.01 mmol) was dissolved in 10 ml of dry CH2Cl2 at 08, and cat. amount of PPTS
and 2,2-DMP (0.74 ml, 6.03 mmol) were added. The mixture was stirred from 08 to r.t. for 8 h. After
quenching the reaction with ice, the mixture was extracted with CH2Cl2 (2 ꢁ 15 ml). The combined org.
layers were dried (Na2SO4) and concentrated in vacuo. After evaporation of the solvent, the residue was
purified by CC (petroleum ether/AcOEt 9 :1) to afford pure 14 (1.31 g, 96%). Liquid. [a]2D0 ¼ þ8.4 (c ¼
0.2, CHCl3). IR: 1638, 1462, 1379, 1257, 1040. 1H-NMR (200 MHz, CDCl3): 5.72 – 5.81 (m, 1 H); 5.10 –
4.98 (m, 2 H); 4.59 (s, 2 H); 3.84 – 3.68 (m, 2 H); 3.46 – 3.54 (m, 1 H); 3.34 (s, 3 H); 2.28 (m, 1 H);
2.08 – 2.14 (m, 1 H); 1.54 – 1.20 (m, 38 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 134.0; 117.2;
98.8; 96.2; 77.3; 69.2; 69.0; 55.5; 41.1; 36.8; 34.5; 32.0; 30.2; 30.0; 29.7; 25.8; 23.0. ESI-MS: 477 ([M þ
Na]þ).
(aR,4R,6S)-6-[(3S)-3-(Methoxymethoxy)heptadecyl]-2,2-dimethyl-a-prop-2-en-1-yl-1,3-dioxane-4-
ethanol (2). To a stirred soln. of 14 (1.3 g, 2.86 mmol) in aq. acetone (10 ml) was added NMO (1.0 g,
i
8.59 mmol), followed by OsO4 (2.5 wt% in BuOH) and NaIO4 (1.22 g, 5.72 mmol). The mixture was
stirred for 6 h. After quenching the reaction with sat. NaHSO3 (5 ml), the mixture was stirred for 30 min
and then filtered through sintered funnel with CH2Cl2 (2 ꢁ 30 ml). The org. extracts were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure. After evaporation of the solvent, the
residue was purified by CC (AcOEt/hexane) to afford an aldehyde (1.2 g, 92%) as a liquid.
To a stirred soln. of TiCl4 (48 mg, 0.263 mmol) in CH2Cl2 (3 ml) was added dried Ti(OiPr)4 (224 mg,
0.789 mmol) at 08 under N2, and the mixture was allowed to warm to r.t. After 1 h, Ag2O (121 mg,
0.526 mmol) was added at r.t., and the mixture was stirred for 5 h under exclusion of direct light. The
mixture was diluted with CH2Cl2 (6 ml), and treated with (R,R)-BINOL (298 mg, 1.05 mmol) at r.t. for
2 h to furnish chiral bis-TiIV oxide A. The in situ generated Awas cooled to ꢀ 158 and treated sequentially
with the aldehyde (1.2 g, 2.63 mmol) and allyl(tributyl)stannane (0.96 ml, 3.15 mmol) at 158. The mixture
was allowed to warm to 08 and stirred for 21 h. The reaction was quenched with sat. aq. NaHCO3 (20 ml),
and the mixture was extracted with Et2O (3 ꢁ 20 ml). The org. extracts were dried (Na2SO4). After
evaporation of solvent, the residue was purified by CC (petroleum ether/AcOEt 8 :2) gave 2 (904 mg,
69% yield). Liquid. [a]2D0 ¼ þ8.6 (c ¼ 0.4, CHCl3). IR: 3447, 1640, 1459, 1147, 1039. 1H-NMR (200 MHz,
CDCl3): 5.76 – 5.85 (m, 1 H); 5.18 – 5.04 (m, 2 H); 4.11 (br. s, 1 H); 3.90 – 3.67 (m, 2 H); 3.58 – 3.47 (m,

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Helvetica Chimica Acta – Vol. 96 (2013)
2 H); 3.36 (s, 3 H); 2.35 – 2.12 (m, 2 H); 1.61 – 1.18 (m, 42 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz,
CDCl3): 135.1; 117.3; 98.8; 96.8; 77.2; 71.1; 70.3; 69.2; 42.2; 37.4; 34.4; 32.1; 30.0; 29.8; 29.6; 25.1; 22.5; 14.0.
ESI-MS: 521 ([M þ Na]þ).
(1R)-1-({(4S,6S)-6-[(3S)-3-(Methoxymethoxy)heptadecyl]-2,2-dimethyl-1,3-dioxan-4-yl}methyl)-
but-3-en-1-yl Prop-2-enoate (15). CH2¼CHC(O)Cl (188 mg 2.08 mmol) was added dropwise under N2 to
a soln. of 2 (0.80 g, 1.60 mmol), and EtNiPr2 (0.33 ml, 1.92 mmol) in dry CH2Cl2 (8 ml) at 08. The mixture
was stirred for 6 h at r.t. The reaction was quenched with sat. aq. NH4Cl (10 ml) and org. layer was
separated. The aq. layer was extracted with CH2Cl2 (3 ꢁ 15 ml), and the combined org. layer was washed
with brine (20 ml), dried (Na2SO4), and concentrated. After evaporation of the solvent, the residue was
purified by CC (petroleum hexane/AcOEt 8 :2) to afford 15 (0.83 g, 94% yield). [a]2D0 ¼ þ7.2 (c ¼ 0.4,
CHCl3). IR: 1725, 1640, 1459, 1147, 1039. 1H-NMR (200 MHz, CDCl3): 6.46 (dd, J ¼ 16.0, 2.0, 1 H);
6.15 – 6.02 (m, 2 H); 5.79 – 5.86 (m, 1 H); 5.16 – 5.03 (m, 3 H); 4.64 (s, 2 H); 3.90 – 3.72 (m, 2 H); 3.48 –
3.56 (m, 1 H); 3.34 (s, 3 H); 2.34 – 2.15 (m, 2 H); 1.62 – 1.11 (m, 40 H); 0.82 (t, J ¼ 7.0, 3 H). 13C-NMR
(50 MHz, CDCl3): 166.2; 134.4; 128.9; 128.0; 118.1; 99.7; 97.2; 77.2; 71.0; 70.2; 68.6; 55.8; 42.0; 39.1; 37.3;
34.1; 32.0; 30.1; 29.9; 29.2; 22.8; 20.2; 14.0. ESI-MS: 553 ([M þ Na]þ).
(6R)-5,6-Dihydro-6-[(2S,4S,7S)-2,4,7-trihydroxyhenicosyl]-2H-pyran-2-one (1). A flame-dried
round-bottomed flask was charged with 15 (0.60 g, 1.13 mmol) in CH2Cl2 (40 ml), and Grubbsꢀ catalyst
B (1st generation, 93 mg, 0.11 mmol) was added as a solid. The mixture was heated at reflux for 10 h at r.t.
After completion of the reaction (by TLC), the mixture was concentrated in vacuo to provide a residue,
which was purified by CC (petroleum hexane/AcOEt 7:3) to give 16 (0.40 g, 71% yield).
To a soln. of 16 (0.40 g, 0.79 mmol) in THF (10 ml) was added aq. HCl (4n, 10 ml). The resulting
mixture was stirred 10 h at r.t., and then solid NaHCO3 was added. The mixture was filtered through a
pad of Celite and washed with AcOEt (25 ml). The filtrate was dried (Na2SO4) and concentrated. The
product was purified by CC (CHCl3/MeOH 8 :2) to afford 1 (0.29 g, 88% yield). Liquid. [a]2D0 ¼ þ31.2
(c ¼ 0.4, CHCl3). IR: 3357, 1719, 1605, 1421, 1251. 1H-NMR (200 MHz, CDCl3): 6.89 – 6.97 (m, 1 H); 6.02
(d, J ¼ 10.0, 1 H); 4.68 – 4.75 (m, 1 H); 4.11 – 4.19 (m, 1 H); 3.96 – 4.04 (m, 1 H); 3.64 – 3.73 (m, 1 H);
2.49 – 2.41 (m, 2 H); 1.99 – 2.08 (m, 1 H); 1.76 – 1.85 (m, 1 H); 1.70 – 1.42 (m, 8 H); 1.28 (br. s, 24 H); 0.89
(t, J ¼ 7.0, 3 H). 13C-NMR (50 MHz, CDCl3): 164.8; 145.5; 121.4; 75.0; 72.6; 71.8; 63.4; 43.2; 37.4; 34.1;
32.8; 32.2; 30.0; 29.9; 29.6; 25.9; 22.8; 14.4. ESI-MS: 463 ([M þ Na]þ).
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Received July 11, 2012