A stereoselective total synthesis of decarestrictine I

Article abstract of DOI:10.1002/hlca.201300256

A convergent and stereoselective total synthesis of decarestrictine I, a polyketide natural product, is described. Both acid and alcohol fragments were prepared from the readily available L-malic acid via Still-Gennari olefination and Sharpless asymmetric epoxidation. The Steglich esterification and ring-closing metathesis (RCM) are employed to combine both acid and alcohol fragments. Copyright

Full text of DOI:10.1002/hlca.201300256

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Helvetica Chimica Acta – Vol. 97 (2014)
A Stereoselective Total Synthesis of Decarestrictine I
by Jhillu Singh Yadav*, Miriyal Venkatesh, Alleni Suman Kumar, Poli Adi Narayana Reddy,
Basi V. Subba Reddy, and Attaluri R. Prasad
Pheromone Group, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500607, India
(fax: 91-40-27160387; e-mail: yadavpub@iict.res.in)
A convergent and stereoselective total synthesis of decarestrictine I, a polyketide natural product, is
described. Both acid and alcohol fragments were prepared from the readily available l-malic acid via
StillꢀGennari olefination and Sharpless asymmetric epoxidation. The Steglich esterification and ring-
closing metathesis (RCM) are employed to combine both acid and alcohol fragments.
Introduction. – Decanolides are a very important class of compounds in the
decarestrictine family. The decarestrictines were isolated from various Penicillium
strains [1] and identified as bioactive compounds by virtual screening. Several members
of the decarestrictine family of natural products were found to inhibit the biosynthesis
of cholesterol in HEP-G2 liver cells [2][3]. Among them, decarestrictine I (1)
possesses unique structural features such as a ten-membered lactone fused with a
dihydrofuran ring comprising a (Z)-configured C¼C bond. Recent reports illustrated
its total synthesis [4][5]. Due to its fascinating structural features and biological
importance, we were interested to take up its total synthesis too. Our strategy relies on
StillꢀGennari olefination, Sharpless asymmetric epoxidation, Steglich esterification,
ring-closing metathesis, and an intramolecular epoxide ring-opening sequence as key
steps to accomplish the total synthesis of 1.
Results and Discussion. – The retrosynthetic analysis (Scheme 1) reveals that the
target molecule 1 could be obtained by ring-closing metathesis of the diene 2 followed
by epoxide ring opening. The diene ester 2 in turn could be prepared by esterification of
acid 4 with alcohol 3. Though our retrosynthetic analysis is analogous to the earlier
approach [5], the key fragments 3 and 4 were prepared from a common precursor, l-
malic acid, whereas, in the previous synthesis, both 3 and 4 were synthesized via the
kinetic resolution of an epoxide, wherein half of the epoxide could not be used for the
synthesis.
We initiated the synthesis of alcohol fragment 3 (Scheme 2) from commercially
available l-malic acid (5). Accordingly, the esterification of 5, followed by reduction of
the diester 6 [6] with NaBH4, BH3 · SMe2 afforded the dihydroxy ester 7 in 74% yield
over two steps. Chemoselective mono-tosylation of 7, followed by reduction of the p-
toluenesulfonate with LiAlH4 afforded the 1,3-diol 8 [7] in 82% yield. (tert-
Butyl)(dimethyl)silyl (TBS) protection of 8 with TBSCl and 1H-imidazole furnished
the disilyl ether in 90% yield, which, upon selective removal of the primary silyl ether
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Retrosynthetic Analysis of Decarestrictine I (1)
Scheme 2
a) EtOH, cat. H2SO4, reflux, 18 h; 80%. b) BH3 · SMe2, NaBH4, THF, r.t., 90 min; 92%. c) 1. TsCl, Et3N,
t
CH2Cl2, 08 to r.t., 8 h; 2. LiAlH4, THF, 08 to r.t., 8 h; 82%. d) 1. BuMe2SiCl (TBSCl), 1H-imidazole,
CH2Cl2, 08 to r.t., 8 h; 90%; 2. cat. camphorsulfonic acid (CSA), CH2Cl2/MeOH 4 :1, ꢀ 108, 30 min;
80%. e) 1. 2-Iodoxybenzoic acid (IBX), DMSO, CH2Cl2, 08 to r.t., 2 h; 2. (CF3CH2O)2POCH2CO2Et,
NaH, THF, ꢀ 788, 1 h; 75%. f) Diisobutylaluminium hydride (DIBAL-H), CH2Cl2, ꢀ 788 to r.t., 2 h;
90%. g) (ꢀ)-Diethyl tartrate ((ꢀ)-DET), Ti(OiPr)4, t-BuOOH (TBHP), CH2Cl2, ꢀ 208, 16 h; 85%. h) 1.
IBX, DMSO, CH2Cl2, 08 to r.t., 2 h; 2. Ph3PCH3I, BuLi, THF, ꢀ 108 to r.t., 2 h, 68%. i) Bu4NF, THF, r.t.,
4 h, 88%.
with camphorsulfonic acid (CSA) in CH2Cl2/MeOH, gave the alcohol 9, which was
subjected to oxidation with 2-iodoxybenzoic acid (IBX) in DMSO, followed by chain
elongation with the StillꢀGennari reagent [8], (F3CCH2O)2P(O)CH2CO2Et, to furnish
the corresponding (Z)-a,b-unsaturated ester 10 in 75% yield, along with a trace
amount of the (E)-isomer, which was separated by column chromatography. Reduction
of 10 with DIBAL-H afforded the corresponding allylic alcohol 11 in 90% yield. The
Sharpless asymmetric epoxidation [9] of 11 with (ꢀ)-diethyl tartrate (DET)/Ti(OiPr)4/
t-BuOOH (TBHP) in CH2Cl2 gave the epoxide 12 in 85% yield with the required
configuration. In analogy to [5], oxidation of 12 with IBX [10] in DMSO/CH2Cl2,
followed by C1 homologation [11] with Ph3P¼CH2, gave the corresponding vinyl
epoxide 13 in 68% yield over two steps. Deprotection of the silyl ether by treatment
with TBAF in THF afforded the required alcohol 3 in 88% yield.

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Next, we attempted the synthesis of acid fragment 4 from commercially available l-
malic acid (5; Scheme 3). Accordingly, 5 was converted to the triol 14 in 90% yield
using BH3 · SMe2 and B(OMe)3 [12]. Conversion of 14 to the acetal 15 was achieved by
treatment with anisaldehyde dimethyl acetal using a catalytic amount of CSA [12].
Oxidation of 15 using IBX in DMSO/CH2Cl2 afforded the aldehyde, which was then
subjected to Wittig olefination with (methylidene)(triphenyl)phosphorane to furnish
the vinyl derivative 16 in 69% yield [13]. Regioselective reductive ring opening of the
4-methoxybenzylidene acetal using DIBAL-H at ꢀ 158 in CH2Cl2 gave the alcohol 17
in 88% yield [13][14]. Oxidation of the latter with IBX in dry DMSO/CH2Cl2 gave the
aldehyde, which was further oxidized with NaClO2 and NaH2PO4 in the presence of 2-
methylbut-2-ene [15] in t-BuOH/H2O to afford the desired acid 4 in 89% yield. Though
the conversion of 17 to 4 was analogous to an earlier approach [5], a different oxidation
protocol [10] was used to improve the yield.
Scheme 3
a) BH3 · SMe2, B(OMe)3, THF, 08 to r.t., 24 h; 90%. b) 4-MeOꢀC6H4CH(OMe)2 (PMP ¼ 4-
MeOꢀC6H4), 08 to r.t., CSA, CH2Cl2, 20 h; 82%. c) 1. IBX, DMSO, CH2Cl2, 08 to r.t., 2 h; 2. Ph3PCH3I,
BuLi, THF, ꢀ 108 to r.t., 2 h; 69%. d) DIBAL-H, CH2Cl2, ꢀ 158, 2 h; 88%. e) 1. IBX, DMSO, CH2Cl2, 08
to r.t., 2 h; 2. NaClO2, NaH2PO4, 2-methylbut-2-ene, t-BuOH, 6 h, 89%.
In the present strategy, the key fragments 3 and 4 were synthesized in 14.9 and
39.8% yield, respectively, whereas in the earlier approach they were prepared in 8 and
21.4% yield, respectively [5]. Finally, in contrast to the esterification described in [5],
we attempted the coupling of the fragments 3 and 4 (Scheme 4) under Steglich
conditions [16] using DCC/DMAP in CH2Cl2 to afford the diene 2 ester in 80% yield.
Ring-closing metathesis of 2 according to [5] in the presence of Grubbsꢂ second-
generation catalyst [17] afforded the desired lactone (Z)-18 in 65% yield as the major
product. The (Z)-configuration in 18 was established by its spectroscopic data, wherein
the signal of one of the olefinic H-atoms appeared at 5.64 ppm as ddd (J ¼ 1.8, 8.3,
11.7). Deprotection of the PMB (4-MeOꢀC6H4CH2) ether 18, followed by an
intramolecular ring opening of the epoxide in the presence of DDQ [18] in CH2Cl2,
gave the target molecule, decarestrictine I (1), in 70% yield. The physical data of the
synthetic decarestrictine I (1) were in agreement with those reported in [5].

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833
Scheme 4
a) N,N’-Dicyclohexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), CH2Cl2, 08 to r.t.,
10 h; 80%. b) Grubbsꢂ II catalyst, CH2Cl2, reflux, 12 h; 65%. c) 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), CH2Cl2/H2O, 08 to r.t., 1 h; 70%.
Conclusions. – In summary, a modified efficient strategy has been described for the
total synthesis of decarestrictine I (1) in a convergent manner starting from the
precursor l-malic acid (5). The target molecule was synthesized with an overall yield of
5.4%, whereas in earlier approach, the yield reported was 2.8%. The present synthesis
involves cis-selective Wittig olefination, Sharpless asymmetric epoxidation, and ring-
closing metathesis (RCM) as key steps.
M. V., P. A. N. R., and A. S. K. thank CSIR-New Delhi for the award of research fellowships.
Experimental Part
General. All reactions were conducted under N2 in anh. solvents such as CH2Cl2, THF, AcOEt, and
Et2O. Progress of the reaction was monitored by TLC using silica gel plates with fluorescent indicator
(254 nm) and visualized with a UV lamp, anisaldehyde or b-naphthol soln., or alkaline KMnO4 soln. All
commercially available reagents were purchased and used as supplied. Optical rotations: at ambient
temp. (258) in CHCl3 with a polarimeter using 2-ml capacity cell with 100-mm path length. IR Spectra:
PerkinElmer IR-683 spectrophotometer with NaCl optics; ˜n in cmꢀ1. 1H- and 13C-NMR spectra: Fourier
transform mode at the field strength specified either on a Bruker UXNMR FT-300 MHz (Avance) or a
Varian VXR-unity-500 MHz spectrometer; spectra were recorded in CDCl3 in 5-mm diameter tubes; d in
ppm rel. to the residual signals of CHCl3 (7.25 ppm or 77.0 ppm); coupling constants, J in Hz. MS: Agilent
Technologies 1100 Series (Agilent ChemStation software); in m/z.
Diethyl (2S)-2-Hydroxybutanedioate (6) [18]. To a stirred soln. of l-malic acid (5.0 g, 37.31 mmol) in
EtOH (60 ml) was added a cat. amount of H2SO4 (0.5 ml). The resulting mixture was then stirred under
reflux for 18 h, and the solvent was removed in vacuo. After completion, the reaction was quenched with
sat. NaHCO3 soln. (50 ml), and the mixture was extracted with AcOEt (2 ꢁ 40 ml). The combined org.
extracts were washed with brine (50 ml), dried (Na2SO4), and concentrated under reduced pressure. The
crude residue was purified by column chromatography (CC) to afford pure 6 (5.6 g, 80%). Liquid.
1
[a]2D5 ¼ ꢀ5.2 (c ¼ 0.9, CHCl3). IR (neat): 3492, 2985, 2933, 1735, 1468, 1393, 1269, 1105, 859. H-NMR
(500 MHz, CDCl3): 4.50 – 4.46 (m, 1 H); 4.31 – 4.24 (m, 2 H); 4.18 (q, J ¼ 7.1, 2 H); 2.88 – 2.76 (m, 2 H);
1.63 (br. s, 1 H); 1.31 (t, J ¼ 7.1, 3 H); 1.27 (t, J ¼ 7.0, 3 H). 13C-NMR (75 MHz, CDCl3): 173.2; 170.4; 67.2;
61.8; 60.8; 38.6; 14.0. ESI-MS: 213 ([M þ Na]þ).

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Ethyl (3S)-3,4-Dihydroxybutanoate (7) [6]. To a stirred soln. of 6 (4.0 g, 21.05 mmol) in THF (50 ml)
was added BH3 · SMe2 (10.8 ml, 21.68 mmol, 2m in THF) dropwise at r.t. The resulting soln. was stirred at
r.t., until evolution of H2 ceased (30 min). The flask was then cooled in an ice bath (108), and stirring was
continued for another 10 min. To this mixture was added NaBH4 (39 mg, 5 mol-%) under vigorous
stirring at the same temp. The mixture was stirred at r.t. until the disappearance of 6 (1 h; by TLC). To
this mixture, EtOH (10 ml) and TsOH (200 mg, 5 mol-%) were added, and the resulting cloudy soln. was
stirred for 30 min at r.t. Removal of the solvent resulted in the formation of a colorless gum, which was
treated with benzene/EtOH 1:l (50 ml), and the solvent was removed again in vacuo. This process was
repeated thrice, and the resulting residue was purified by CC to afford 7 (2.9 g, 92%). Colorless viscous
liquid. [a]2D5 ¼ þ6.22 (c ¼ 1.22, CHCl3). IR (neat): 3419, 2966, 2926, 1771, 1467, 1372, 1177, 968. 1H-NMR
(300 MHz, CDCl3): 4.28 – 4.14 (m, 1 H); 4.14 (q, J ¼ 7.1, 2 H); 3.79 (br. s, 1 H); 3.68 – 3.42 (m, 2 H); 3.24
(br. s, 1 H); 2.60 – 2.38 (m, 2 H); 1.24 (t, J ¼ 7.2, 3 H). 13C-NMR (75 MHz, CDCl3): 172.4; 68.5; 65.6; 60.7;
37.7; 14.0. ESI-MS: 171 ([M þ Na]þ).
(3R)-Butane-1,3-diol (8) [7]. To a stirred soln. of 7 (1.0 g, 6.76 mmol) in CH2Cl2 (20 ml) was added
Et3N (2.82 ml, 20.27 mmol) at 08. After 15 min, TsCl (1.29 g, 6.76 mmol) was added at r.t., and the
mixture was stirred for 10 h. After completion, the mixture was treated with H2O (20 ml) and extracted
with CH2Cl2 (40 ml). The combined extracts were washed with brine (20 ml) and dried (Na2SO4). The
solvent was evaporated under reduced pressure, and the resulting p-toluenesulfonate was directly used in
the next step without further purification. To a stirred suspension of LiAlH4 (0.51 g, 13.51 mmol) in THF
(10 ml) at 08 was added a soln. of the p-toluenesulfonate in THF (10 ml) under N2. The mixture was
stirred at r.t. for 8 h, then cooled to 08, treated with sat. aq. Na2SO4 soln. (10 ml), and filtered through
Celite. The residue was washed with AcOEt (30 ml), and the filtrate was dried (Na2SO4). Removal of the
solvent, followed by purification by CC (SiO2; 50% AcOEt in hexane), gave 8 (0.50 g, 82%). Colorless
oil. [a]2D5 ¼ ꢀ10.2 (c ¼ 1.04, EtOH). IR (neat): 3350, 2969, 2935, 1377, 1053. 1H-NMR (300 MHz, CDCl3):
4.12 – 4.00 (m, 1 H); 3.92 – 3.75 (m, 2 H); 2.53 (br. s, 2 H); 1.73 – 1.64 (m, 2 H); 1.22 (d, J ¼ 6.2, 3 H).
13C-NMR (75 MHz, CDCl3): 67.7; 61.1; 40.0; 23.5. EI-MS: 91 ([M þ H]þ).
(5R)-2,2,3,3,5,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecane. To an ice-cold soln. of 8 (0.5 g,
5.55 mmol) and 1H-imidazole (2.26 g, 33.30 mmol) in anh. CH2Cl2 (10 ml) was added a soln. of TBSCl
(2.5 g, 16.65 mmol) in CH2Cl2 (5 ml). The mixture was stirred at r.t. for 24 h, then diluted with H2O
(10 ml), and extracted with Et2O (3 ꢁ 10 ml). The combined org. phases were washed with brine (10 ml)
and dried (Na2SO4). Removal of the solvent, followed by purification by CC, gave the bis-TBS ether
(1.59 g, 90%). Colorless oil. [a]2D5 ¼ ꢀ10.2 (c ¼ 0.7, CHCl3). IR (neat): 2958, 2931, 1472, 1256, 1095, 836.
1H-NMR (300 MHz, CDCl3): 4.01 – 3.89 (m, 1 H); 3.66 (t, J ¼ 6.6, 2 H); 1.71 – 1.52 (m, 2 H); 1.13 (d, J ¼
6.2, 3 H); 0.89 (s, 9 H); 0.88 (s, 9 H); 0.05 (s, 6 H); 0.04 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 65.5; 60.0;
42.7; 25.9; 25.8; 25.6; 23.8; ꢀ 4.4; ꢀ 4.8. ESI-MS: 341 ([M þ Na]þ).
(3R)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}butan-1-ol (9). To an ice-bath cooled soln. of the bis-TBS
ether (1.5 g, 4.71 mmol) in CH2Cl2/MeOH 4 :1 (10 ml) was added a cat. amount of CSA. The resulting
mixture was stirred at ꢀ 108 for 30 min, and then the reaction was quenched with solid NaHCO3 (1 g),
followed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the crude
product was purified by CC to afford 9 (0.76 g, 80%). Colorless oil. [a]2D5 ¼ þ2.3 (c ¼ 0.5, CHCl3). IR
1
(neat): 3390, 2952, 1462, 1252, 1082, 834. H-NMR (300 MHz, CDCl3): 4.17 – 4.05 (m, 1 H); 3.91 – 3.78
(m, 1 H); 3.77 – 3.65 (m, 1 H); 1.85 – 1.72 (m, 1 H); 1.70 – 1.56 (m, 1 H); 1.19 (d, J ¼ 6.0, 3 H); 0.89
(s, 9 H); 0.09 (s, 3 H); 0.08 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 68.3; 60.4; 40.3; 25.7; 25.6; 23.3; ꢀ 4.3;
ꢀ 4.9. ESI-MS: 227 ([M þ Na]þ).
Ethyl (2Z,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}hex-2-enoate (10). To a stirred soln. of IBX
(2.05 g, 7.35 mmol) in DMSO (6 ml) at 258 was added a soln. of 9 (1.0 g, 4.90 mmol) in CH2Cl2 (12 ml).
The mixture was stirred at 258 for 2 h, and the resulting solid was filtered and then washed with Et2O
(10 ml). The filtrate was extracted with Et2O, washed with H2O, followed by brine, and dried (Na2SO4),
and then concentrated under reduced pressure to afford the crude aldehyde, which was immediately used
for the next reaction without further purification. To a stirred soln. of bis(trifluoroethyl)(ethoxycarbon-
yl)methylphosphonate (2.11 g, 6.37 mmol) in dry THF (20 ml) at 08 was added NaH (0.235 g, 9.8 mmol),
and the mixture was stirred for 30 min at 08. To this mixture was added a soln. of aldehyde in dry THF
(5 ml) and stirred for 30 min at ꢀ 788. The reaction was quenched with sat. aq. NH4Cl soln. (5 ml), and

Helvetica Chimica Acta – Vol. 97 (2014)
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the mixture was stirred at r.t. for another 10 min. The layers were separated, and the aq. layer was
extracted with AcOEt (2 ꢁ 10 ml). The combined org. layers were washed with brine (2 ꢁ 15 ml), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was purified by CC to afford 10 (0.95 g,
75%). Viscous oil. [a]2D5 ¼ ꢀ10.2 (c ¼ 1.8, CHCl3). IR (neat): 2931, 2851, 1721, 1219, 772. 1H-NMR
(300 MHz, CDCl3): 6.41 – 6.30 (m, 1 H); 5.87 – 5.81 (m, 1 H); 4.17 (q, J ¼ 6.7, 2 H); 4.01 – 3.91 (m, 1 H);
2.89 – 2.70 (m, 2 H); 1.29 (t, J ¼ 6.7, 3 H); 1.16 (d, J ¼ 6.0, 3 H); 0.88 (s, 9 H); 0.06 (s, 3 H); 0.05 (s, 3 H).
13C-NMR (75 MHz, CDCl3): 166.3; 146.7; 120.7; 67.9; 59.7; 38.6; 25.8; 23.6; 18.0; 14.2; ꢀ 4.4; ꢀ 4.7. ESI-
MS: 295 ([M þ Na]þ).
(2Z,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}hex-2-en-1-ol (11) [19]. To a stirred soln. of 10 (1.8 g,
6.61 mmol) in dry CH2Cl2 was added DIBAL-H (13.1 ml, 13.22 mmol,1.0m in toluene) dropwise at 08.
The resulting mixture was stirred for 1 h at r.t. After completion, the reaction was quenched with sat.
sodium potassium tartarate soln., and the mixture was filtered through Celite and washed with CH2Cl2.
The org. layer was separated, and the aq. layer was extracted with CH2Cl2. The combined org. layers were
dried (Na2SO4), and concentrated in vacuo. The residue was purified by CC (SiO2; 25% AcOEt/hexane)
to afford pure 11 (1.36 g, 90%). Colorless liquid. [a]2D5 ¼ þ0.5 (c ¼ 1.6, CHCl3). IR (neat): 3346, 2956,
2930, 1219, 1004, 772. 1H-NMR (300 MHz, CDCl3): 5.84 – 5.52 (m, 2 H); 4.25 – 4.08 (m, 2 H); 3.94 – 3.77
(m, 1 H); 2.38 – 2.12 (m, 2 H); 1.62 (br. s, 1 H); 1.15 (d, J ¼ 6.0, 3 H); 0.89 (s, 9 H); 0.06 (s, 3 H); 0.05 (s,
3 H). 13C-NMR (75 MHz, CDCl3): 130.3; 129.4; 68.1;58.3; 37.4; 32.7; 25.8; 23.5; ꢀ 4.6. ESI-MS: 253
([M þ Na]þ).
4,5-Anhydro-2-O-[(tert-butyl)(dimethyl)silyl]-1,3-dideoxy-d-arabino-hexitol (12). To a stirred mix-
ture of molecular sieves (4 ꢃ, 3.0 g) and Ti(OiPr)4 (0.46 ml, 1.56 mmol) in CH2Cl2 (10 ml) at ꢀ 208 was
added (ꢀ)-diethyl tartrate (DET) in CH2Cl2 (0.26 ml, 1.56 mmol), and the mixture was stirred at ꢀ 208
for 10 min. To this mixture, a soln. of 11 (1.2 g, 5.21 mmol) in CH2Cl2 (10 ml) and 3.3m soln. of t-BuOOH
(TBHP; 3.1 ml, 10.42 mmol) were added successively. The resulting mixture was stirred at ꢀ 208 for 16 h,
and the reaction was quenched with H2O (0.46 ml) and 30% NaOH (0.26 ml). After 30 min, the mixture
was filtered through Celite, and the aq. layer was extracted with CH2Cl2 (2 ꢁ 10 ml). The combined org.
extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residual oil was
purified by CC (SiO2; 15% AcOEt in hexane) to give 12 (1.09 g, 85%). Colorless oil. [a]2D5 ¼ ꢀ18.3 (c ¼
1.8, CHCl3). IR (neat): 3419, 2957, 2931, 1465, 1255, 1039. 1H-NMR (300 MHz, CDCl3): 4.13 – 4.00 (m,
1 H); 3.88 – 3.64 (m, 2 H); 3.25 – 3.16 (m, 1 H); 3.14 – 3.05 (m, 1 H); 1.85 – 1.74 (m, 1 H); 1.70 – 1.58 (m,
1 H); 1.22 (d, J ¼ 6.0, 3 H); 0.90 (s, 9 H); 0.10 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 66.8; 60.8; 56.2; 54.7;
37.4; 25.8; 24.4; ꢀ 4.6. ESI-MS: 269 ([M þ Na]þ).
(1R)-1,2-Anhydro-4-O-[(tert-butyl)(dimethyl)silyl]-3,5-dideoxy-1-ethenyl-d-threo-pentitol (13). To
a stirred soln. of IBX (1.4 g, 4.87 mmol) in DMSO (4.2 ml) under N2 was added 12 (1.0 g, 4.06 mmol) in
anh. CH2Cl2 (10 ml) at r.t., and the mixture was stirred for 2 h. The mixture was then diluted with Et2O
(10 ml) and filtered through Celite. The filtrate was washed with sat. aq. NaHCO3 (15 ml), dried
(Na2SO4), and concentrated in vacuo. The crude aldehyde was immediately used for the next reaction
without further purification.
To a soln. of (methyl)(triphenyl)phosphonium iodide (4.93 g, 12.27 mmol) in anh. THF (50 ml) at
ꢀ 108 was added BuLi (4.8 ml, 12.22 mmol, 2.5m in hexane) dropwise. The resulting mixture was stirred at
258 for 1 h and then cooled to ꢀ 108. To this mixture, a soln. of aldehyde in anh. THF (10 ml) was added.
After 2 h, the reaction was quenched with sat. aq. NH4Cl (20 ml), and the mixture was extracted with
Et2O (50 ml) and then washed sequentially with H2O (30 ml), followed by brine (30 ml) soln. The org.
layers were dried (Na2SO4) and concentrated in vacuo. Purification of the resulting residue by flash CC
(SiO2; 5% AcOEt in hexane) gave 13 (670 mg, 68%). Colorless oil. [a]2D5 ¼ þ13.2 (c ¼ 0.85, CHCl3). IR
1
(neat): 2926, 2950, 1463, 1219, 773. H-NMR (300 MHz, CDCl3): 5.79 – 5.65 (m, 1 H); 5.52 – 5.32 (m,
2 H); 4.08 – 3.97 (m, 1 H); 3.47 – 3.41 (m, 1 H); 3.27 – 3.19 (m, 1 H); 1.74 – 1.63 (m, 1 H); 1.62 – 1.52 (m,
1 H); 1.19 (d, J ¼ 6.0, 3 H); 0.89 (s, 9 H); 0.08 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 132.7; 120.2; 66.5;
57.2; 56.2; 37.5; 25.8; 24.2; ꢀ 4.5; ꢀ 4.8. ESI-MS:265 ([M þ Na]þ).
(1R)-1,2-Anhydro-3,5-dideoxy-1-ethenyl-d-threo-pentitol (3) [5]. To a stirred soln. of 13 (0.6 g,
2.47 mmol) in anh. THF (5 ml) was added TBAF (4.9 ml, 4.94 mmol, 1.0m soln. in THF) at 08. The
resulting soln. was stirred at r.t. for 4 h. After completion, the reaction was quenched with Et2O/H2O 1:1
(10 ml). The org. layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue

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Helvetica Chimica Acta – Vol. 97 (2014)
was purified by flash CC (SiO2; 20% AcOEt in hexane) to yield pure 3 (280 mg, 88%). Colorless oil.
[a]2D5 ¼ ꢀ25.3 (c ¼ 1.6, CHCl3). IR (neat): 3404, 2923, 2853, 1459, 1375, 1219, 772. H-NMR (300 MHz,
1
CDCl3): 5.80 – 5.67 (m, 1 H); 5.54 – 5.35 (m, 2 H); 4.15 – 4.01 (m, 1 H); 3.52 – 3.44 (m, 1 H); 3.34 – 3.26
(m, 1 H); 1.80 – 1.55 (m, 2 H); 1.29 (d, J ¼ 6.7, 3 H). 13C-NMR (75 MHz, CDCl3): 132.3; 120.5; 66.0; 56.9;
55.9; 36.6; 23.7. LC/MS: 151 ([M þ Na]þ).
(ꢀ)-(2S)-Butane-1,2,4-triol (14) [12]. To a soln. of BH3 · SMe2 (11.4 ml, 120 mmol) at 08 was added
B(OMe)3 (12.5 ml, 110 mmol) in 25 ml of dry THF. The mixture was stirred at the same temp. for 15 min,
and then 5 (5.00 g, 37.3 mmol) was added. After stirring for 23 h at r.t., the reaction was quenched with
MeOH at 08. The solvent was removed under reduced pressure, and the residue was filtered through a
short pad of SiO2 eluting with MeOH/CH2Cl2 1:4. Evaporation of the solvent gave 14 (3.84 g, 97%).
Colorless oil. The crude product was instantly used in the next reaction without further purification.
[(4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methanol (15) [12]. To a soln. of 14 (3.64 g, 34.3 mmol)
and 1-(dimethoxymethyl)-4-methoxybenzene (11.6 ml, 68.1 mmol) in CH2Cl2 (36.4 ml) at r.t. was added
a cat. amount of CSA (799 mg, 3.44 mmol). After stirring for 19 h at r.t., the reaction was quenched with
Et3N, and the mixture was concentrated under reduced pressure. The crude product was purified by CC
(AcOEt/hexane 1:1) to afford 15 (6.25 g, 81%). Colorless oil. [a]2D5 ¼ þ5.8 (c ¼ 1.5, CHCl3). IR (neat):
3387, 2923, 2852, 1459, 1516, 1246, 772. 1H-NMR (300 MHz, CDCl3): 7.46 – 7.39 (m, 2 H); 6.93 – 6.87 (m,
2 H); 5.51 (s, 1 H); 4.33 – 4.25 (m, 1 H); 4.06 – 3.92 (m, 2 H); 3.81 (s, 3 H); 3.75 – 3.61 (m, 2 H); 2.09 – 1.84
(m, 2 H). 13C-NMR (75 MHz, CDCl3): 160.0; 130.9; 127.3; 113.5; 101.1; 66.5; 65.6; 55.2; 26.7. ESI-MS:
247 ([M þ Na]þ).
(4S)-4-Ethenyl-2-(4-methoxyphenyl)-1,3-dioxane (16) [13]. Compound 15 (1.5 g, 6.69 mmol) was
subjected to IBX oxidation as described for the synthesis of 13. The crude aldehyde thus formed was
immediately converted to 16 as described for the synthesis of 13. Purification by CC (SiO2; 10% AcOEt
in hexane) afforded 16 (1.01 g, 69%). Colorless oil. [a]2D5 ¼ ꢀ22.7 (c ¼ 1.5, CHCl3). IR (neat): 2958, 2837,
1610, 1515, 1247. 1H-NMR (500 MHz, CDCl3): 7.43 (d, J ¼ 8.8, 2 H); 6.88 (d, J ¼ 7.7, 2 H); 5.99 – 5.90 (m,
1 H); 5.53 (s, 1 H); 5.33 (d, J ¼ 17.6, 1 H); 5.17 (d, J ¼ 11.0, 1 H); 4.38 – 4.32 (m, 1 H); 4.27 (dd, J ¼ 11.0,
5.5, 1 H); 3.98 (td, J ¼ 12.1, 2.2, 1 H); 3.79 (s, 3 H); 1.92 (qt, J ¼ 12.1, 4.4, 1 H); 1.62 – 1.57 (m, 1 H).
13C-NMR (75 MHz, CDCl3): 159.8; 137.8; 131.1; 127.3; 115.5; 113.5; 101.0; 77.5; 66.8; 55.2; 31.0. ESI-MS:
243 ([M þ Na]þ).
(3S)-3-[(4-Methoxybenzyl)oxy]pent-4-en-1-ol (17) [13]. To a stirred soln. of 16 (0.5 g, 2.27 mmol) in
dry CH2Cl2 (10 ml) was added DIBAL-H (6.8 ml, 6.81 mmol, 1.0m in toluene) dropwise at ꢀ 158. The
resulting mixture was stirred for 1 h at ꢀ 158 After completion, the reaction was quenched with sat.
sodium potassium tartarate soln., and the mixture was filtered through Celite. The residue was washed
with CH2Cl2, and the aq. layer was extracted with CH2Cl2 (2 ꢁ 10 ml). The combined org. layers were
dried (Na2SO4), and concentrated in vacuo. Purification of the resulting residue by CC (SiO2; 25%
AcOEt in hexane) gave 17 (443 mg, 88%). Colorless liquid. [a]2D5 ¼ ꢀ38.5 (c ¼ 1.1, CHCl3). IR (neat):
3374, 2923, 2853, 1512, 1245, 1033. 1H-NMR (300 MHz, CDCl3): 7.30 – 7.22 (m, 2 H); 6.93 – 6.85 (m, 2 H);
5.86 – 5.73 (m, 1 H); 5.31 – 5.22 (m, 2 H); 4.60 – 4.53 (m, 1 H); 4.33 – 4.26 (m, 1 H); 4.05 – 3.96 (m, 1 H);
3.80 (s, 3 H); 3.79 – 3.66 (m, 2 H); 1.93 – 1.71 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 159.1; 138.1; 129.4;
117.4; 113.8; 79.6; 69.8; 60.6; 55.2; 37.6. ESI-MS: 245 ([M þ Na]þ).
(3S)-3-[(4-Methoxybenzyl)oxy]pent-4-enoic Acid (4) [5][10]. Compound 17 (400 mg, 1.80 mmol)
was subjected to IBX oxidation as described for the synthesis of 13. To a stirred soln. of the crude
aldehyde and 2-methylbut-2-ene (2.5 ml) in t-BuOH (5 ml) at r.t. were added a soln. of NaClO2 (0.330 g,
3.62 mmol) and NaH2PO4 (0.435 g, 3.62 mmol) in H2O (4 ml) in two portions. The resulting mixture was
stirred at r.t. for 6 h, before dilution with sat. aq. NH4Cl soln. (10 ml). The resulting carboxylic acid was
extracted with AcOEt (3 ꢁ 5 ml), dried (Na2SO4), and concentrated in vacuo. The residue was purified
by flash CC (SiO2, 25% AcOEt in hexane) to yield pure 4 (378 mg, 89%). Pale-yellow oil. [a]2D5 ¼ ꢀ11.3
(c ¼ 0.85, CHCl3). IR (neat): 3404, 2924, 2853, 1712, 1513, 1248, 1035. 1H-NMR (500 MHz, CDCl3): 7.24
(d, J ¼ 7.9, 2 H); 6.87 (d, J ¼ 7.9, 2 H); 5.84 – 5.74 (m, 1 H); 5.38 – 5.23 (m, 2 H); 4.59 – 4.54 (m, 1 H);
4.38 – 4.33 (m, 1 H); 4.27 – 4.21 (m, 1 H); 3.79 (s, 3 H); 2.73 – 2.66 (m, 1 H); 2.60 – 2.54 (m, 1 H).
13C-NMR (75 MHz, CDCl3): 175.6; 159.2; 136.7; 129.8; 129.4; 118.4; 113.8; 76.2; 70.2; 55.2; 40.7. ESI-MS:
259 ([M þ Na]þ).

Helvetica Chimica Acta – Vol. 97 (2014)
837
(1R)-1,2-Anhydro-3,5-dideoxy-1-ethenyl-4-O-{(3S)-3-[(4-methoxybenzyl)oxy]pent-4-enoyl}-d-
threo-pentitol (2) [5][16a]. To a stirred soln. of 3 (100 mg, 0.78 mmol) in CH2Cl2 (10 ml) were added
DCC (402 mg, 1.95 mmol) and DMAP (190 mg, 1.56 mmol) at 08. The mixture was stirred for 30 min, and
then 4 (221 mg, 0.93 mmol) was added. The mixture was stirred for 10 h, and then the volatiles were
evaporated under reduced pressure.The resulting crude product was adsorbed on silica gel and purified
by flash CC (SiO2, 6% AcOEt in hexane) to give 2 (216 mg, 80%). Colorless oil. [a]2D5 ¼ ꢀ15.0 (c ¼ 0.5,
CHCl3). IR (neat): 2923, 2853, 1733, 1462, 1219, 772. 1H-NMR (300 MHz, CDCl3): 7.22 (d, J ¼ 8.6, 2 H);
6.85 (d, J ¼ 8.6, 2 H); 5.84 – 5.61 (m, 2 H); 5.52 – 5.21 (m, 4 H); 5.17 – 5.03 (m, 1 H); 4.50 (d, J ¼ 11.1,
1 H); 4.31 (d, J ¼ 11.3, 1 H); 4.27 – 4.19 (m, 1 H); 3.79 (s, 3 H); 3.45 – 3.38 (m, 1 H); 3.20 – 3.08 (m, 1 H);
2.68 – 2.56 (m, 1 H); 2.51 – 2.41 (m, 1 H); 1.85 – 1.66 (m, 2 H); 1.30 (d, J ¼ 6.4, 3 H).13C-NMR (75 MHz,
CDCl3): 170.2; 159.1; 137.3; 132.2; 129.3; 120.4; 117.9; 113.7; 76.8; 70.2; 68.9; 56.7; 55.4; 55.2; 41.3; 34.2;
20.2. ESI-MS: 369 ([M þ Na]þ).
(1S,3R,7S,8Z,10R)-7-[(4-Methoxybenzyl)oxy]-3-methyl-4,11-dioxabicyclo[8.1.0]undec-8-en-5-one
(18) [5]. To a stirred soln. of 2 (0.12 g, 0.35 mmol) in CH2Cl2 (100 ml) was added 10 mol-% Grubbs II
catalyst. The resulting mixture was stirred at reflux for 12 h under N2. The solvent was then distilled off,
and the residual soln. was stirred at r.t. for 2 h under air bubbling in order to decompose the catalyst. The
remaining solvent was evaporated to dryness to give the brown-colored residue which was purified by CC
(SiO2; 5% AcOEt in hexane) to give 18 (71 mg, 65%). [a]2D5 ¼ ꢀ63.0 (c ¼ 0.3, CHCl3). IR (neat): 3450,
1
2925, 2854, 1731, 1513, 1248. H-NMR (300 MHz, CDCl3): 7.14 (d, J ¼ 8.4, 2 H); 6.77 (d, J ¼ 8.7, 2 H);
5.64 (ddd, J ¼ 1.8, 8.3, 11.7, 1 H); 5.49 – 5.42 (m, 1 H); 5.19 (ddq, J ¼ 1.8, 8.3, 11.7, 1 H); 4.49 (d, J ¼ 11.3,
1 H); 4.40 – 4.31 (m, 2 H); 3.75 – 3.69 (m, 4 H); 3.24 (m, 1 H); 2.83 (dt, J ¼ 3.3, 10.5, 1 H); 2.60 (dd, J ¼
3.3, 10.3, 1 H); 2.28 (t, J ¼ 10.5, 1 H); 2.11 – 2.05 (m, 1 H); 1.23 (d, J ¼ 6.7, 3 H). 13C-NMR (75 MHz,
CDCl3): 169.2; 159.2; 133.6; 130.0; 129.7; 114.2; 76.9; 71.9; 70.0; 66.8; 55.4; 54.4; 53.9; 41.2; 32.9. LC/MS:
341 ([M þ Na]þ).
Decarestrictine I (¼(1S,5R,7S,8S)-7-Hydroxy-5-methyl-4,11-dioxabicyclo[6.2.1]undec-9-en-3-one; 1)
[5]. To a stirred soln. of 2 (0.07 g, 0.2 mmol) in CH2Cl2/H2O (2 ml, 19 :1) was added DDQ (0.042 g,
0.33 mmol). The mixture was stirred at r.t. for 1 h. After completion, the reaction was quenched with sat.
aq. NaHCO3 soln. (2 ml), and the mixture was filtered through Celite and then washed with CH2Cl2
(20 ml). The filtrate was washed again with H2O (15 ml), followed by brine (5 ml), and dried (Na2SO4).
Removal of the solvent under reduced pressure followed by purification by CC (SiO2; 15% AcOEt and
hexane), gave 1 (0.030 g, 70%). [a]2D5 ¼ ꢀ129.1 (c ¼ 0.3, MeOH). IR (neat): 3405.5, 2956.3, 2854, 1710,
1431.2, 1385, 1070. 1H-NMR (300 MHz, CDCl3): 5.95 – 5.82 (m, 2 H); 5.10 – 4.95 (m, 2 H); 4.92 – 4.85 (m,
1 H); 3.90 (dt, J ¼ 4.6, 10.9, 1 H); 2.76 – 2.54 (m, 1 H); 2.01 (dd, J ¼ 2.3, 3.1, 2 H); 1.68 – 1.60 (m, 1 H);
1.40 – 1.37 (m, 1 H); 1.25 (d, J ¼ 6.2, 3 H). 13C-NMR (75 MHz, CDCl3): 171.5; 132.2; 127.5; 92.6; 81.6;
73.7; 71.2; 42.5; 39.9; 21.9. LC/MS: 221 ([M þ Na]þ).
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Received June 25, 2013