Stereoselective total synthesis of multiplolide A and of a diastereoisomer

Article abstract of DOI:10.1002/hlca.201200164

A stereoselective total synthesis of multiplolide A (1) and of its diastereoisomer 2 was described from easily accessible starting materials (Schemes 2-4). The synthetic strategy involves a Jacobsen resolution, Sharpless epoxidation, Swern oxidation, Yamaguchi reaction, and ring-closing metathesis (RCM). Copyright

Full text of DOI:10.1002/hlca.201200164

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Helvetica Chimica Acta – Vol. 96 (2013)
Stereoselective Total Synthesis of Multiplolide A and of a Diastereoisomer
by Bandi Chennakesava Reddy, Vikas Madhukar Bangade, Palakuri Ramesh, and
Harshadas Mitaram Meshram*
Discovery Laboratory, Organic Chemistry Division – I, Indian Institute of Chemical Technology,
Hyderabad – 500007, India (fax: þ 91-40-27160512; e-mail: hmmeshram@yahoo.com)
A stereoselective total synthesis of multiplolide A (1) and of its diastereoisomer 2 was described
from easily accessible starting materials (Schemes 2 – 4). The synthetic strategy involves a Jacobsen
resolution, Sharpless epoxidation, Swern oxidation, Yamaguchi reaction, and ring-closing metathesis
(RCM).
Introduction. – Natural products are a versatile source for therapeutic agents.
Among them, lactone containing molecules are often shown to possess a wide spectrum
of biological activity [1]. Particularly, ten-membered lactones, formerly called
decanolides, are abundant in nature and display a wide range of biological properties
such as, antifungal and antibacterial achivity and the inhibition of cholesterol
biosynthesis [2].
Multiplolides A (1) and B are ten-membered lactones, which have been isolated
from the culture broth of Xylaria multiplex in 2001 [3]. They exhibit antifungal activity
against Candida albicans with an IC50 value of 7 and 2 mg/ml, respectively. Ramana and
co-workers reported the first total synthesis [4] and absolute configuration of
multiplolide A. Their synthetic strategy was based on the use of chiral starting
material and ring-closing methathesis (RCM). Recently, we have initiated a research
programme for the total synthesis of bioactive natural products from achiral sources
[5]. Our approach to the total synthesis of multiplolide A (1) and its diastereoisomer 2
involves the use of commercially available 2-methyloxirane and (2Z)-but-2-ene-1,4-
diol as starting materials.
Results and Discussions. – The retrosynthetic analysis of lactones 1 and 2 is shown
in Scheme 1. The cleavage of the lactone leads to the oxiranecarboxylic acids 3 and 4
and (protected) olefinic alcohol 5, which in turn could be obtained from (2Z)-but-2-
ene-1,4-diol (6) and (2R)-2-methyloxirane (8) via 7, respectively (Scheme 1).
The synthesis of fragment 5 began with the kinetic resolution of 2-methyloxirane
with (R,R)-Jacobsen catalyst (A) [6]. The chiral oxirane 8 was then opened with ethyl
prop-2-ynoate (9) in the presence of BuLi at ꢀ 788 to give hydroxyalkynoate 10 in 81%
yield [7] (Scheme 2). The selective reduction of the alkyne and ester moiety of 10 with
LiAlH4 furnished allylic alcohol 11 in 78% yield [8]. The primary-alcohol moiety of 11
was protected by treatment with pivaloyl chloride (81% yield), then the secondary-
t
alcohol moiety was protected as BuPh2Si ether (91% yield), and finally the pivaloyl
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Retrosynthetic Analysis of Multiplolide A (1) and of Its Diastereoisomer 2
group was deprotected with K2CO3 in MeOH leading to the tBuPh2Si-protected allylic
alcohol 12 in 88% yield. The latter was transformed into oxirane alcohol 7 via Sharpless
epoxidation [9]. Conversion of oxirane alcohol 7 into 13 was accomplished in good
yield by Swern oxidation [10] followed by a one-C-atom homologation [11] with
Ph3(Me)PI (60% overall yield after 2 steps). Treatment of the ethenyloxirane alcohol
13 with Sc(OTf)3 in THF/H2O 10 :1 (0.25m) cleanly afforded olefinic diol 14 in 70%
yield [12]. Protection of 14 with 2,2-dimethoxypropane and camphorsulfonic acid (CSA)
in CH2Cl2 at 08 gave ethenyl-1,3-dioxol 15 in 90% yield. Removal of the tBuPh2Si group
with Bu4NF in THF led to the required olefinic alcohol 5 in 88% yield [4] (Scheme 2).
Scheme 2
a) BuLi, BF3 · Et2O,THF, ꢀ 788, 2 h; 81%. b) LiAlH4, THF, 08 to 808, 2 h; 78%. c) 1. Pivalolyl chloride,
N,N-dimethylpyridin-4-amine (DMAP),CH2Cl2, 08, 2 h; 81%; 2. tBuPh2SiCl, 1H-imidazole, CH2Cl2, r.t.;
t
91%; 3. K2CO3, MeOH, r.t., 10 h; 88%. d) (ꢀ)-Diisopropyl tartrate ((ꢀ)-DIPT), Ti(iPrO)4, BuOOH,
CH2Cl2, 4-ꢂ molecular sieves, ꢀ 208; 90%. e) 1. (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ 788, 1 h; 2.
Ph3(Me)PI, sodium hexamethyldisilazanide (NaHMDS), 08, 1 h; 80%. f) Sc(OTf)3, THF/H2O 10 :1, r.t.,
2.5 h; 70%. g) 2,2-dimethoxypropane, CSA, CH2Cl2, 08, 30 min; 90%. h) Bu4NF, THF, r.t., 2 h; 88%.

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Helvetica Chimica Acta – Vol. 96 (2013)
The synthesis of oxiranecarboxylic acids 3 and 4 started from the known (2Z)-but-2-
ene-1,4-diol (6) (Scheme 3). Thus, selective monoprotection of the OH group with
tBuPh2SiCl in CH2Cl2 at room temperature gave the mono tBuPh2Si ether in 86% yield,
which on further Sharpless epoxidation [14] with (þ)- and (ꢀ)-diisopropyl tartrate
((þ)- and (ꢀ)-DIPT) gave enantiomeric oxirane alcohols 16 and 17 in 90% yield,
respectively. Swern oxidation of primary alcohols 16 and 17 gave the corresponding
aldehydes, which on further one-C-atom homologation furnished ethenyloxiranes 18
t
and 19 in good yield (60% overall yield after 2 steps). Deprotection of the BuPh2Si
ether was achieved by treatment with Bu4NF in THF to give 20 and 21 [15], which on
further oxidation [16] with 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO) and [bis-
(acetoxy)iodo]benzene (BAIB) gave the required 3-ethenyloxirane-2-carboxyclic
acids 3 and 4, respectively, in 84% yield (overall yield for 2 steps).
Scheme 3
a) 1. (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ 788, 1 h; 2. Ph3(Me)PI, NaHMDS, 08, 1 h; 80%. b) Bu4NF, THF,
r.t., 2 h; 88%. c) TEMPO, BAIB, MeCN/H2O 1:1; 78%.
The esterification of 3 and 4 with olefinic alcohol 5 under Yamaguchi reaction
conditions [17] (2,4,6-trichlorobenzoyl chloride) gave compounds 22 and 23 in 80%
yield (Scheme 4). The RCM reaction [18] of bis-olefins 22 and 23 with Grubbs second-
generation catalyst (B; 10 mol-%) afforded the penultimate compounds 24 and 25 [4],
respectively, in 65% yield, which after deprotection of the acetonide with CF3COOH
gave target molecules 1 and 2 in good yield (70%). The prepared synthetic multiplolide
A (1) and its diastereoisomer 2 were identical (IR, 1H- and 13C-NMR, and MS) with the
natural product and its diastereoisomer and also had optical rotations ([a]2D5 ¼ þ25.8
(c ¼ 0.4, CHCl3) for 1 and [a]2D5 ¼ ꢀ12.1 (c ¼ 0.59, CHCl3) for 2) in good agreement
with the literature values ([a]D25 ¼ þ22.6 (c ¼ 0.3, CHCl3) for 1 and [a]2D5 ¼ ꢀ11.8 (c ¼
0.5, CHCl3) for 2 [4]).

Helvetica Chimica Acta – Vol. 96 (2013)
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Scheme 4
a) 2,4,6-Trichlorobenzoyl chloride, THF, Et3N, r.t.,6 h, DMAP, toulene, r.t., 14 h; 80%. b) 2nd-
Generation Grubbs catalyst (B), benzene, reflux 2 h; 65%. c) CF3COOH, CH2Cl2, r.t., 10 h; 70%.
In summary, a new stereoselective total synthesis of multiplolide A (1) and its
diastereoisomer 2 was achieved from inexpensive and commercially available starting
materials. The synthesis is highlighted by Jacobsen resolution, Sharpless epoxidation,
Swern oxidation, Yamaguchi reaction, and RCM reactions as key steps.
B. C. K. R., V. M. B. , and P. R. thank CSIR-UGC for the award of a fellowship, and Dr. J. S. Yadav,
Director IICT, for his support and encouragement.
Experimental Part
General. All reactions were carried out without any special precautions in an atmosphere of air.
Chemicals were purchased from Fluka and S. D. Fine Chemicals. TLC: precoated silica gel plates 60 F254
(SiO2, 0.2 mm layer; Merck). Column chromatography (CC): SiO2 60 – 120 mesh (Merck) 1H-NMR
Spectra: Varian-200 or Bruker-300 spectrometer; in CDCl3; d in ppm rel. to Me4Si as internal standard, J
in Hz. MS: VG Autospec; in m/z.
Ethyl (5R)-5-Hydroxyhex-2-ynoate (10) [7]. A soln. of 9 (6.3 g, 64.2 mmol) in dry THF (100 ml) was
stirred at ꢀ 788, then 1.6m BuLi in hexane (40.0 ml, 64.2 mmol) was added, and the mixture was stirred
for 30 min at ꢀ 788. BF3 · Et2O (8.2 ml, 64.2 mmol) was added followed by a soln. of 8 (2.5 g,
43.0 mmol) in dry THF (20 ml) and stirred at ꢀ 788 for 2 h. The reaction was quenched by sat. aq. NH4Cl
soln. and extracted with Et2O. The org. layer was washed with brine, dried (Na2SO4), and concentrated
and the residue purified by CC (SiO2, 10% AcOEt/hexane): 10 (8.11 g, 81%). [a]2D5 ¼ ꢀ9.85 (c ¼ 3.05,
1
CHCl3). IR(KBr): 3457, 2954, 2858, 1738, 1254, 1118. H-NMR (300 MHz): 1.06 – 1.22 (m, 6 H); 2.30 –
2.41 (m, 2 H); 3.82 – 3.96 (m, 1 H); 3.99 – 4.14 (m, 2 H). 13C-NMR (75 MHz): 13.4; 21.9; 28.3; 61.5;
65.0; 74.1; 86.2; 153.4. ESI-MS: 156 (Mþ). ESI-HR-MS: 156.1818 (C8H12Oþ3 ; calc. 156.1814).
(2E,5R)-Hex-2-ene-1,5-diol (11) [8]. To a stirred soln. of LiAlH4 (5.4 g, 143 mmol) in dry THF
(130 ml) at 08, 10 (10.14 gm, 65 mmol) was added dropwise in THF (130 ml) for 10 min. Then, the temp.
was increased to r.t. and then to reflux for 2 h. The reaction was quenched by ice and sat. aq. Na2SO4 soln.
the mixture and stirred for 1 h at r.t. The mixture was filtered through Celite, the Celite washed with
MeOH, the combined org. layer concentrated, and the residue purified by CC (SiO2, 70% AcOEt/
hexane): 11 (5.88 g, 78%). [a]2D5 ¼ ꢀ11.8 (c ¼ 1.6, CHCl3). IR (KBr): 3417, 2925, 1646, 1545, 1235.
1H-NMR (300 MHz): 1.19 (d, J ¼ 6.04, 3 H); 2.00 – 2.30 (m, 2 H); 3.80 – 3.84 (m, 1 H); 4.10 (d, J ¼ 3.77,

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Helvetica Chimica Acta – Vol. 96 (2013)
2 H); 5.68 – 5.70 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 25.2; 44.2; 66.2; 70.3; 128.7; 129.3. ESI-MS: 139
([M þ Na]þ). ESI-HR-MS: 139.1492 (C6H12O2Naþ; calc. 139.1498).
(2E,5R)-5-{[(1,1-Dimethylethyl)diphenylsilyl]oxy}hex-2-en-1-ol (12) [8]. To a stirred soln. of 11
(5.3 g, 45.68 mmol) in CH2Cl2 (182 ml), Et3N (13.88 ml, 100.5 mmol), DMAP (cat.), and pivaloyl
chloride (5.3 ml, 45.68 mmol) were sequentially added at 08 and stirred at r.t. for 1 h. The mixture was
diluted with H2O (30 ml) and extracted with AcOEt (4 ꢁ 25 ml). The combined org. layer was washed
with brine (20 ml), dried (Na2SO4), and concentrated and the residue purified by CC (SiO2 20% AcOEt/
hexane): primary-alcohol-protected pivaloyl compound (7.4 g, 81%). IR (KBr): 3404, 3067, 2957, 2929,
1
2858, 1692, 1604, 1258. H-NMR (300 MHz): 1.18 (d, J ¼ 6.04, 3 H); 1.17 (s, 9 H); 2.01 – 2.25 (m, 2 H);
3.78 (sext., J ¼ 6.04, 1 H); 4.50 (d, J ¼ 6.04, 2 H); 5.53 – 5.80 (m, 2 H). 13C-NMR (75 MHz): 22.9; 27.3;
38.7; 42.2; 64.6; 66.9; 127.6; 131.3; 177.8. ESI-MS: 223 ([M þ Na]þ).ESI-HR-MS: 223.2678 (C11H20O3-
Naþ; calc. 223.2677).
To a stirred soln. of this pivaloyl compound (5.6 g, 28 mmol) in CH2Cl2 (112 ml), 1H-imidazole
(4.0 gm, 61.6 mmol) and tBuPh2SiCl (8.46 g, 30.8 mmol) were subsequently added at 08 and stirred at r.t.
for 30 min. The mixture was diluted with H2O and extracted with AcOEt (4 ꢁ 20 ml). The combined org.
layer was washed with brine, dried (Na2SO4), and concentrated and the residue purified by CC (SiO2,
AcOEt/hexane): secondary-alcohol-protected tBuPh2Si compound (11.16 g, 91%). Liquid. [a]2D5 ¼ þ20.1
(c ¼ 2.0, CHCl3). IR (KBr): 3069, 2928, 2857, 1679, 1222, 1102. 1H-NMR (300 MHz): 1.04 (s, 9 H); 1.18 (s,
9 H); 1.27 (d, J ¼ 9.82, 3 H); 2.15 – 2.22 (m, 2 H); 3.80 – 3.97 (m, 1 H); 4.42 (d, J ¼ 5.85, 2 H); 5.40 – 5.53
(m, 1 H); 5.59 – 5.72 (m, 1 H); 7.28 – 7.42 (m, 6 H); 7.60 – 7.67 (m, 4 H). 13C-NMR (75 MHz): 19.2; 22.9;
27.0; 27.1; 38.8; 42.3; 64.8; 69.0; 126.4; 127.4; 127.5; 129.5; 131.5; 135.8; 175.4. ESI-MS: 438 (Mþ). ESI-
HR-MS: 438.6822 (C27H38O3Siþ; calc. 438.6824).
To a soln. of the above tBuPh2Si compound (8.7 g, 20 mmol) in MeOH (100 ml) was added K2CO3
(3.6 g, 26 mmol) and stirred at r.t. for 10 h. The mixture was then passed through Celite and the MeOH
evaporated. The residue was extracted with AcOEt (3 ꢁ 10 ml), the extract washed with brine (20 ml),
dried (Na2SO4), and concentrated, and the residue purified by CC (SiO2, 5% AcOEt/hexane): 12 (6.2 g,
88%). Colorless liquid. [a]2D5 ¼ þ42.7 (c ¼ 1.4, CHCl3). IR (KBr): 3463, 3047, 1589, 1470, 1427, 1107.
1H-NMR (300 MHz):1.08 (d, J ¼ 6.04, 3 H); 1.10 (s, 9 H); 2.11 – 2.23 (m, 2 H); 3.82 – 3.92 (m, 1 H); 3.98
(d, J ¼ 3.58, 2 H); 5.52 – 5.57 (m, 2 H); 7.31 – 7.45 (m, 6 H); 7.62 – 7.70 (m, 4 H). 13C-NMR (75 MHz):
19.2; 23.1; 27.0; 42.2; 63.6; 69.2; 127.4; 129.2; 129.5; 131.3; 134.4; 135.9. ESI-MS: 377 ([M þ Na]þ). ESI-
HR-MS: 377.5547 (C22H30O2NaþSi; calc. 377.5542).
(2R,3R)-3-{(2R)-2-{[(1,1-Dimethylethyl)diphenylsilyl]oxy}propyl}oxirane-2-methanol (¼2,3-Anhy-
dro-4,6-dideoxy-5-O-[(1,1-dimethylethyl)diphenylsilyl]-d-arabino-hexitol; 7). To a stirred suspension of
activated 4-ꢂ molecular sieves (1.0 g) in CH2Cl2 (80 ml) was added (ꢀ)-d-DIPT (0.338 ml, 1.3 mmol)
and Ti(iPrO)4 (0.316 ml, 0.356 mmol) with stirring, and the resulting mixture was stirred for 30 min at ꢀ
208. Then 12 (4.0 g, 11.29 mmol) in dry CH2Cl2 (42 ml) was added dropwise, and the resulting mixture was
stirred for another 30 min at ꢀ 208. tBuOOH (6.8 ml, 3.0m in toluene, 22.58 mmol) was then added and
the resulting mixture stirred at ꢀ 208 for 8 h. After warming to 08, the mixture was quenched with H2O
(1 ml) and stirred for 2 h at r.t. Aq. NaOH soln. (30%, sat. with NaCl) was then added and the mixture
stirred vigorously for another 30 min at r.t. The mixture was filtered through Celite, the filtrate extracted
with CH2Cl2 (3 ꢁ 10 ml), washed with brine, dried (Na2SO4), and concentrated, and the residue purified
by CC (SiO2, AcOEt/hexane 0.5 :9.5); 7 (3.75 g, 90%). Colorless viscous liquid. [a]2D5 ¼ þ23 (c ¼ 0.8,
CH2Cl2). IR (KBr): 3068, 2926, 2854, 1690, 1602, 1299, 1178. 1H-NMR (300 MHz): 1.05 (s, 9 H); 1.14 (d,
J ¼ 6.23, 3 H); 1.58 – 1.68 (m, 1 H); 1.72 – 1.81 (m, 1 H); 2.80 – 2.85 (m, 1 H); 3.05 – 3.09 (td, J ¼ 2.33, J ¼
3.11, 1 H); 3.84 (m, 1 H); 4.48 (d, J ¼ 6.23, 2 H); 7.34 – 7.46 (m, 6 H); 7.64 – 7.70 (m, 4 H). 13C-NMR
(75 MHz): 21.7; 26.9; 40.9; 52.9; 58.1; 67.3; 70.4; 127.5; 129.5; 129.6; 135.7. EI-MS: 393 ([M þ Na]þ). ESI-
HR-MS: 393.5539 (C22H30O3NaþSi; calc. 393.553).
(2R,3R)-2-{[2R)-2-{[1,1-Dimethylethyl)diphenylsilyl]oxy}propyl}-3-ethenyloxirane (13). To a soln.
of oxalyl chloride (0.82 ml, 7.5 mmol) in CH2Cl2 (10 ml) at ꢀ 788 was added DMSO (1.13 ml, 16.0 mmol)
within 20 min. The resulting mixture was stirred for an additional 15 min. Then 7 (1.85 g, 5 mmol) in
CH2Cl2 (10 ml) was added dropwise. The mixture was stirred for 30 min, Et3N (3.47 ml, 25 mmol) was
added dropwise, and the mixture was warmed to r.t. for 30 min. After completion of
the reaction, the mixture was quenched with H2O (30 ml) and the aq. phase extracted with CH2Cl2

Helvetica Chimica Acta – Vol. 96 (2013)
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(2 ꢁ 20 ml). The combined org. layer was washed with brine, dried (Na2SO4), and concentrated:
aldehyde (1.472 g, 80%) as a colorless liquid.
To a soln. of Ph3(Me)PI (4.84 g, 12.0 mmol) in dry THF (35 ml) was added 1.6m NaHMDS in hexane
(7.5 ml) at 08 and stirred for 2 h at 08. A soln. of the aldehyde (0.560 g, 4.0 mmol) in THF (15 ml) was
added via cannula to the mixture at 08 and stirred for 30 min. The reaction was quenched with sat. aq.
NH4Cl soln., and the mixture extracted with AcOEt (3 ꢁ 40 ml). The combined org. extract was washed
with brine (30 ml), dried (Na2SO4), and concentrated, and the residue purified by CC (SiO2, 5% AcOEt/
hexane): 13 (1.17 g, 80%). Yellow syrup. [a]2D5 ¼ þ15 (c ¼ 0.67, CH2Cl2). IR (KBr): 3029, 2985, 2851,
1555, 1229, 1056. 1H-NMR (300 MHz): 1.06 (s, 9 H); 1.15 (d, J ¼ 6.00, 3 H); 1.61 – 1.83 (m, 2 H); 2.94 –
3.01 (m, 1 H); 3.02 (d, J ¼ 8.00, 1 H); 4.04 – 4.11 (sext., J ¼ 6.00, 1 H); 5.22 – 5.28 (m, 1 H); 5.41 – 5.47 (d,
J ¼ 16.01, 1 H); 5.49 – 5.59 (m, 1 H); 7.34 – 7.47 (m, 6 H); 7.64 – 7.73 (m, 4 H). 13C-NMR (75 MHz,
CDCl3): 22.3; 26.9; 41.4; 57.3; 58.4; 67.4; 119.2; 127.4; 127.5; 129.5; 129.6; 135.8. ESI-MS: 366 (Mþ). ESI-
HR-MS: 366.5754 (C23H30O2Siþ; calc. 366.5755).
(3S,4R,6R)-6-{[(1,1-Dimethylethyl)diphenylsilyl]oxy}hept-1-ene-3,4-diol (14). To a stirred soln. of
13 (1.3 g, 3.36 mmol) in THF/H2O 10 :1 (8 ml) was added Sc(OTf)3 (0.20 equiv., 310 mg, 0.68 mmol), and
the mixture was stirred at r.t. for 2.5 h. The resulting diol was extracted with AcOEt (20 ml), the extract
washed sequentially with sat. aq. NH4Cl soln. and brine, dried (Na2SO4), and concentrated, and the
residue purified by flash chromatography (AcOEt/hexane 2 :8): 14 (0.903 g, 70%). Pale yellow syrup.
[a]2D5 ¼ ꢀ9.0 (c ¼ 0.5, CHCl3). IR (KBr): 3348, 3070, 2961, 2858, 1589, 1467, 1108, 999. 1H-NMR
(300 MHz): 1.04 (s, 9 H); 1.12 (d, J ¼ 6.0, 3 H); 1.56 – 1.78 (m, 2 H); 3.84 – 3.93 (m, 1 H); 4.07 – 4.20 (m,
2 H); 5.20 – 5.35 (dd, J ¼ 10.5, 17.3, 2 H); 5.77 – 5.90 (m, 1 H); 7.35 – 7.47 (m, 6 H); 7.66 – 7.77 (m, 4 H).
13C-NMR (75 MHz): 19.1; 24.0; 26.8; 40.2; 65.8; 70.4; 75.5; 116.9; 127.5; 127.7; 129.7; 135.9; 136.2. ESI-
MS: 407 ([M þ Na]þ). ESI-HR-MS: 407.5812 (C23H32O3NaþSi; calc. 407.5805).
(4R,5S)-4-{(2R)-2-{[(1,1-Dimethylethyl)diphenylsilyl]oxy}propyl}-5-ethenyl-2,2-dimethyl-1,3-dioxo-
lane (15). To a soln. of 14 (768 mg, 2 mmol) in CH2Cl2 (10 ml) was added CSA (cat.) and 2,2-
dimethoxypropane (0.96 ml, 6 mmol) at 08, and the mixture was stirred for 15 – 20 min. The reaction was
quenched with Et3N (1 or 2 drops), the mixture concentrated, and the residue purified by CC (SiO2,
AcOEt/hexane 0.5 :9.5): 15 (0.804 g, 90%). Pale yellow syrup. [a]2D5 ¼ ꢀ9.8 (c ¼ 0.9, CHCl3). IR (KBr):
1
3434, 3081, 2981, 2930, 1642, 1457, 1375, 1217, 1042. H-NMR (300 MHz): 1.05 (s, 9 H); 1.13 (d, J ¼ 6.0,
3 H); 1.25 (s, 3 H); 1.28 (s, 3 H); 1.68 – 1.90 (m, 2 H); 3.93 – 3.99 (m, 1 H); 4.06 – 4.32 (m, 2 H); 5.03 – 5.34
(m, 2 H); 5.56 – 5.91 (m, 1 H); 7.32 – 7.44 (m, 6 H); 7.64 – 7.75 (m, 4 H). 13C-NMR (75 MHz): 19.1; 24.0;
26.9; 29.7; 40.1; 70.5; 75.5; 85.3; 107.3; 117.0; 127.5; 127.7; 129.6; 129.8; 135.8; 136.1. ESI-MS: 447 ([M þ
Na]þ). ESI-HR-MS: 424.2435 (C26H36O3NaþSi; calc. 424.2433).
(2R,3S)-2-{{[(1,1-Dimethylethyl)diphenylsilyl]oxy}methyl}-3-ethenyloxirane (18). To a soln. of
oxalyl chloride (1.3 ml, 15 mmol) in CH2Cl2 (70 ml) at ꢀ 788 was added DMSO (1.4 ml, 20 mmol)
within 20 min. The mixture was stirred for an additional 15 min. Then 16 (3.42 g, 10 mmol) in CH2Cl2
(30 ml) was added dropwise. After 30 min stirring, Et3N (7 ml, 50 mmol) was added dropwise. The
mixture was allowed to warm to r.t. and stirred for 30 min. After completion of the reaction, the mixture
was quenched with H2O (30 ml) and the aq. phase extracted with CH2Cl2 (2 ꢁ 30 ml). The combined org.
layer was washed with brine, dried (Na2SO4), and concentrated: aldehyde (3.06 g, 90%). Colorless
liquid.
To a soln. of Ph3(Me)PI (14.9 g, 54.0 mmol) in dry THF (65 ml) was added a 1.6m NaHMDS in
hexane (36 ml) at 08 and stirred for 2 h at 08. A soln. of the aldehyde (3.06 g, 9.0 mmol) in THF (35 ml)
was added via cannula at 08 and stirred for 30 min. The reaction was quenched with sat. aq. NH4Cl soln.
and the mixture extracted with AcOEt (3 ꢁ 40 ml). The combined org. layer was washed with brine
(30 ml), dried (Na2SO4), and concentrated and the residue purified by CC (SiO2, 10% AcOEt/hexane):
18 (2.43 g, 80%). Yellow syrup. [a]2D5 ¼ þ5.9 (c ¼ 1.2, CHCl3). IR (KBr): 3064, 2962, 2931, 1469, 1259,
1103. 1H-NMR (300 MHz): 1.06 (s, 9 H); 3.32 (q, J ¼ 5.0, 1 H); 3.42 – 3.45 (m, 1 H); 3.76 (d, J ¼ 5.0, 2 H);
5.20 (d, J ¼ 10.0, 1 H); 5.40 (d, J ¼ 18.0, 1 H); 5.55 – 5.61 (m, 1 H); 7.45 – 7.60 (m, 6 H); 7.75 – 7.80 (m,
4 H). 13C-NMR (75 MHz): 19.0; 26.7; 56.4; 59.2; 65.9; 119.4; 129.4; 130.9; 134.6; 134.9. ESI-MS: 338
(Mþ). ESI-HR-MS: 338.1700 (C21H26O2Siþ; calc. 338.1702).
(2S,3R)-2-{{[(tert-Butyl)diphenylsilyl]oxy}methyl-3-ethenyloxirane (19). As described for 18: 19.
Liquid. [a]2D5 ¼ ꢀ2.3 (c ¼ 2.5, CHCl3). IR (KBr): 3064, 2992, 2931, 1457, 1259, 1105. 1H-NMR (200 MHz):

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Helvetica Chimica Acta – Vol. 96 (2013)
1.07 (s, 9 H); 3.28 (dd, J ¼ 4.5, 5.2, 1 H); 3.38 – 3.43 (m, 1 H); 3.75 (d, J ¼ 5.2, 2 H); 5.23 (dd, J ¼ 1.5, 8.3,
1 H); 5.37 (dd, J ¼ 1.5, 15.8, 1 H); 5.47 – 5.60 (m, 1 H); 7.32 – 7.46 (m, 6 H); 7.63 – 7.71 (m, 4 H). 13C-NMR
(75 MHz): 19.1; 26.8; 56.4; 59.0; 65.9; 119.4; 129.4; 130.9; 134.5; 134.9. ESI-MS: 338 (Mþ). ESI-HR-MS:
338.1696 (C21H26O2Siþ; calc. 338.1702).
(2R,3S)-3-Ethenyloxirane-2-methanol (20). To 18 (2.028 g, 6 mmol) in dry THF (20 ml) was added
1m Bu4NF in THF (3.48 ml, 12 mmol), dropwise at 08, and the mixture was stirred at r.t. for 30 min. H2O
(2 ml) was added and the mixture extracted with AcOEt (2 ꢁ 20 ml). The org. layer was washed with
brine, dried (Na2SO4) , and concentrated and the residue purified by CC (SiO2, AcOEt/hexane 0.5 :9.5):
20 (528 mg, 88%). Liquid. [a]2D5 ¼ þ8.0 (c ¼ 1.0, CHCl3). IR (KBr): 3433, 3076, 2986, 2871, 1639, 1453,
1379, 1216, 1056, 925, 758. 1H-NMR (200 MHz): 1.27 (s, 6 H); 2.20 – 2.23 (m, 2 H); 3.73 – 3.78 (m, 1 H);
3.95 – 3.99 (m, 2 H); 5.05 – 5.08 (m, 2 H); 5.82 – 5.86 (m, 1 H). 13C-NMR (75 MHz): 57.1; 58.1; 60.7; 121.1;
134.5. ESI-MS: 100 (Mþ). ESI-HR-MS: 100.1170 (C5H8Oþ2 ; calc. 100.1173).
(2S,3R)-3-Ethenyloxirane-2-methanol (21). As described for 20: 21. Liquid. [a]2D5 ¼ ꢀ10.0 (c ¼ 0.9,
CHCl3). IR (KBr): 3427, 3011, 1619, 1276, 1041. 1H-NMR (200 MHz): 1.27 (s, 6 H); 2.20 – 2.22 (m, 2 H);
3.73 – 3.77 (m, 1 H); 3.95 – 3.97 (m, 2 H); 5.05 – 5.07 (m, 2 H); 5.82 – 5.88 (m, 1H). 13C-NMR (75 MHz):
55.4; 56.8; 59.4; 122.6; 133.4. ESI-MS: 100 (Mþ). ESI-HR-MS: 100.1171 (C5H8Oþ2 ; calc. 100.1173).
(2S,3S)-3-Ethenyloxirane-2-carboxylic Acid (3). To a vigorously stirred soln. of 20 (400 mg, 4 mmol)
in MeCN (4 ml) and H2O (4 ml) was added TEMPO (0.150 g, 0.8 mmol) and BAIB (3.41 g, 8.8 mmol).
Stirring was continued until complete conversion of 20 to 3 (TLC monitoring). The reaction was
quenched by sat. aq. Na2S2O3 soln. (5 ml), the mixture then extracted with AcOEt (2 ꢁ 10 ml), the
combined org. layer dried (Na2SO4) and concentrated, and the residue purified by CC (SiO2, AcOEt/
hexane 3 :7): pure 3 (0.358 g, 78%). Colorless liquid. [a]2D5 ¼ þ15.0 (c ¼ 1.0, CHCl3). IR (KBr): 3422,
3006, 1724, 1618, 1570, 1256, 1099. 1H-NMR (300 MHz): 3.65 (dd, J ¼ 4.0, 5.0, 1 H); 3.72 (d, J ¼ 5.0, 1 H);
5.47 (d, J ¼ 10.0, 1 H); 5.67 (d, J ¼ 18.0, 1 H); 5.80 – 5.89 (m, 1 H). 13C-NMR (75 MHz): 56.5; 58.2; 116.3;
136.1; 174.4. EI-MS: 115 ([M þ 1]þ). ESI-HR-MS: 114.0318 (C5H6Oþ3 ; calc. 114.0316).
(2R,3R)-3-Ethenyloxirane-2-carboxylic Acid (4). As described for 3: 4. Liquid. [a]2D5 ¼ ꢀ12.1 (c ¼
1
0.8, CHCl3). IR (KBr): 3429, 3016, 1745, 1620, 1496, 1255, 1079. H-NMR (300 MHz): 3.52 (dd, J ¼
2.2, 4.5, 1 H); 3.72 – 3.75 (m, 1 H); 5.37 (d, J ¼ 10.5, 1 H); 5.52 (d, J ¼ 17.3, 1 H); 5.75 – 5.78 (m, 1 H).
13C-NMR (75 MHz): 56.6; 58.6; 116.4; 135.6; 173.4. EI-MS: 115 ([M þ 1]þ). ESI-HR-MS: 114.0321
(C5H6Oþ3 ; calc. 114.0316).
(2R)-2-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethyl (2S,3S)-3-Ethenyloxirane-
2-carboxylate (22). To a stirred soln. of 3 (0.114 g, 1 mmol) in dry CH2Cl2 (10 ml) were added Et3N
(0.40 g, 2 mmol) and a soln. of 2,4,6-trichlorobenzoyl chloride (0.55 g, 1.5 mmol) in dry CH2Cl2 (10 ml)
and stirred at 08 for 20 min. A soln. of 5 (0.204 g, 1.1 mmol) in dry CH2Cl2 (5 ml) and DMAP (cat.) were
added and stirred for 6 h at r.t. After completion of the reaction (TLC monitoring), the solvent was
evaporated and the residue purified by CC (SiO2 (60 – 120 mesh) 10% AcOEt/hexane): 22 (0.226 g,
80%). Colorless liquid. [a]2D5 ¼ þ8.9 (c ¼ 0.6, CHCl3). IR (KBr): 3030, 1714, 1616. 1H-NMR (300 MHz):
1.24 (d, J ¼ 5.9, 3 H); 1.34 (s, 6 H); 1.83 – 1.87 (m, 2 H); 3.67 – 3.69 (m, 1 H); 4.10 – 4.14 (m, 1 H); 4.20 –
4.22 (m, 1 H); 4.50 (t, J ¼ 6.9, 1 H); 5.05 – 5.09 (m, 1 H); 5.20 – 5.36 (m, 4 H); 5.72 – 5.83 (m, 2 H).
13C-NMR (75 MHz): 21.9; 27.0; 35.6; 56.7; 66.1; 69.9; 85.4; 113.4; 117.0; 118.1; 135.6; 139.2; 172.7. EI-MS:
283 ([M þ 1]þ). ESI-HR-MS: 282.3364 (C15H22Oþ5 ; calc. 282.3366).
(1R)-2-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethyl 3-(2R,3R)-3-Ethenyloxir-
ane-2-carboxylate (23). As described for 22: 23. Liquid. [a]2D5 ¼ ꢀ2.1 (c ¼ 0.49, CHCl3). IR (KBr): 3016,
1
1724, 1612, 1489, 1058. H-NMR (300 MHz): 1.27 (d, J ¼ 6.1, 3 H); 1.33 (s, 6 H); 1.75 – 1.89 (m, 2 H);
3.45 – 3.47 (m, 1 H); 4.10 – 4.12 (m, 1 H); 4.19 – 4.22 (m, 1 H); 4.53 (t, J ¼ 5.2, 1 H); 5.01 – 5.02 (m, 1 H);
5.23 – 5.36 (m, 4 H); 5.68 – 5.80 (m, 2 H). 13C-NMR (75 MHz): 21.7; 26.9; 35.3; 56.8; 66.6; 69.8; 85.2;
113.1; 116.8; 118.0; 135.5; 139.1; 172.4. EI-MS: 283 ([M þ 1]þ). ESI-HR-MS: 282.3360 (C15H22O5þ ; calc.
282.3366).
(1aS,4R,5aR,8aS,9E,10aS)-1a,4,5,5a,8a,10a-Hexahydro-4,7,7-trimethyl-2H-[1,3]dioxolo[4,5-g]oxire-
no[c]oxecin-2-one (¼(4E)-2,3-Anhydro-4,5,8,10-tetradeoxy-6,7-O-(1-methylethylidene)-d-glycero-d-
manno-dec-4-enonic Acid 9-Lactone; 24). To a soln. of 22 (0.056 g, 0.2 mmol) in freshly distilled
degassed anh. benzene (0.5 ml) was added Grubbs second generation catalyst (B; 0.017 mg, 0.02 mmol)
and stirred at 25o for 2 h under Ar until complete consumption of the starting material (TLC

Helvetica Chimica Acta – Vol. 96 (2013)
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monitoring). The solvent was evaporated and the brown residue purified by CC (SiO2, 10% AcOEt/
hexane): 24 (33 mg, 65%). Colorless oil. [a]D25 ¼ þ14.6 (c ¼ 0.6, CHCl3). IR (KBr): 3025, 2992, 1757,
1
1605, 1222, 1128. H-NMR (300 MHz): 1.34 (d, J ¼ 6.0, 3 H); 1.47 – 1.49 (m, 6 H); 1.51 – 1.68 (m, 2 H);
3.33 (d, J ¼ 5.2, 1 H); 3.81 – 3.97 (m, 2 H); 4.19 – 4.21 (m, 1 H); 4.61 – 4.67 (m, 1 H); 5.77 (dd, J ¼ 9.8, 15.8,
1 H); 5.82 (dd, J ¼ 6.7, 15.8, 1 H). 13C-NMR (75 MHz): 21.6; 26.6; 34.1; 56.9; 57.1; 67.8; 67.9; 85.9; 112.6;
126.6; 129.5; 171.4. ESI-MS: 254 (Mþ). ESI-HR-MS: 254.2825 (C13H18Oþ5 ; calc. 254.2829).
(1aR,4R,5aR,8aS,9E,10aR)-1a,4,5,5a,8a,10a-Hexahydro-4,7,7-trimethyl-2H-[1,3]dioxolo[4,5-g]oxir-
eno[c]oxecin-2-one (¼(4E)-2,3-Anhydro-4,5,8,10-tetradeoxy-6,7-O-(1-methylethylidene)-d-glycero-d-al-
lo-dec-4-enonic Acid 9-Lactone; 25). As described for 24: 25. Oil. IR (KBr): 3070, 2999, 1734, 1615, 1479,
1
1254, 1110, 1025. [a]2D5 ¼ ꢀ9.3 (c ¼ 0.4, CHCl3). H-NMR (300 MHz): 1.32 (d, J ¼ 6.9, 3 H); 1.40 – 1.43
(m, 6 H); 1.58 – 1.61 (m, 2 H); 3.41 (d, J ¼ 5.7, 1 H); 3.67 – 3.89 (m, 2 H); 4.21 – 4.24 (m, 1 H); 4.47 – 4.49
(m, 1 H); 5.72 (dd, J ¼ 8.9; 16.1, 1 H); 5.82 (dd, J ¼ 6.6, 16.1, 1 H). 13C-NMR (75 MHz): 21.0; 26.2; 33.8;
56.8; 57.0; 67.9; 67.6; 85.4; 112.1; 126.0; 129.25; 170.9. ESI-MS: 254 (Mþ). ESI-HR-MS: 254.2822
(C13H18Oþ5 ; calc. 254.2829).
Multiplolide A (¼(4E)-2,3-Anhydro-4,5,8,10-tetradeoxy-d-glycero-d-manno-dec-4-enonic Acid 9-
Lactone; 1). To a stirred soln. of 24 (0.025 g, 0.1 mmol) in dry CH2Cl2 (2 ml), CF3COOH (0.10 ml) was
added and the mixture stirred for 6 h at 08 (TLC monitoring). The solvent was evaporated and the
residue purified by CC (SiO2, 10% AcOEt/hexane): 1 (0.014 g, 70%). Colorless liquid. [a]2D5 ¼ þ25.8
(c ¼ 0.4, CHCl3). IR (KBr): 3425, 3070, 2932, 2858, 1740, 1590, 1467, 1262, 1108, 1045. 1H-NMR
(300 MHz): 1.34 (d, J ¼ 6.9, 3 H); 1.62 – 1.91 (m, 2 H); 3.40 (d, J ¼ 4.6, 1 H); 3.88 – 3.90 (m, 1 H); 3.99 –
4.01 (m, 1 H); 4.67 – 4.69 (m, 1 H); 5.07 – 5.10 (m, 1 H); 5.66 (dd, J ¼ 1.1, 15.8, 1 H); 5.90 (dd, J ¼ 2.2, 15.8,
1 H). 13C-NMR (75 MHz): 20.5; 35.1; 53.7; 55.1; 67.7; 68.2; 72.1; 117.9; 135.1; 169.1. ESI-MS: 214 (Mþ).
ESI-HR-MS: 214.0837 (C10H14Oþ5 ; calc. 214.0841).
(4E)-2,3-Anhydro-4,5,8,10-tetradeoxy-d-glycero-d-alloo-dec-4-enonic Acid 9-Lactone (2). As de-
scribed for 1: 2. Liquid. [a]2D5 ¼ ꢀ12.1 (c ¼ 0.59, CHCl3). IR (KBr): 3425, 3070, 2932, 2858, 1740, 1590,
1
1467, 1262, 1108, 1045. H-NMR (300 MHz): 1.37 (d, J ¼ 6.7, 3 H); 1.81 – 1.83 (m, 2 H); 3.30 – 3.33 (m,
1 H); 3.88 – 3.89 (m, 1 H); 3.99 (dd, J ¼ 2.1, 6.7, 1 H); 4.51 – 4.54 (m, 1 H); 5.05 – 5.08 (m, 1 H); 5.72 (dd,
J ¼ 2.1, 16.0, 1 H); 5.89 (dd, J ¼ 1.7, 16.0, 1 H). 13C-NMR (75 MHz): 21.2; 35.0; 53.3; 54.7; 67.4; 68.1; 72.0;
117.7; 135.3; 170.0. ESI-MS: 214 (Mþ). ESI-HR-MS: 214.0834 (C10H14Oþ5 ; calc. 214.0841).
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Received March 29, 2012