Total synthesis of (+)-chloriolide

Article abstract of DOI:10.1021/jo500527g

(+)-Chloriolide, a metabolite of the ascomycete Chloridium virescens var. chlamydosporum, was synthesized in 16 linear steps from cellulose as a source of a levoglucosenone that contributed the (Z)-alkene and the R stereocenter. The attachment of a spacer derived from l-lactate gave an ω-hydroxyacetal which was added to the phosphorus ylide Ph₃PCCO. The resulting ester ylide was treated with hydrochloric acid to liberate the hemiacetal shown. Addition of sodium hydroxide regenerated the corresponding ylide, which underwent a spontaneous intramolecular Wittig olefination to afford (+)-chloriolide in 65% yield without the necessity of high-dilution conditions. This is the third synthesis of (+)-chloriolide and the first one ever of a macrolide by a ring-closing Wittig olefination of a stabilized phosphorus ylide bearing an ω-hemiacetal. Our synthetic sample exhibited moderate cytotoxicity against cancer cells but no antimicrobial activity against Staphylococcus aureus.

Full text of DOI:10.1021/jo500527g

Article
pubs.acs.org/joc
Total Synthesis of (+)-Chloriolide
Michael Ostermeier and Rainer Schobert*
Organic Chemistry Laboratory, University of Bayreuth, 95440 Bayreuth, Germany
S
* Supporting Information
ABSTRACT: (+)-Chloriolide, a metabolite of the ascomycete
Chloridium virescens var. chlamydosporum, was synthesized in 16
linear steps from cellulose as a source of a levoglucosenone that
contributed the (Z)-alkene and the R stereocenter. The attachment
of a spacer derived from L-lactate gave an ω-hydroxyacetal which
was added to the phosphorus ylide Ph3PCCO. The resulting ester
ylide was treated with hydrochloric acid to liberate the hemiacetal
shown. Addition of sodium hydroxide regenerated the correspond-
ing ylide, which underwent a spontaneous intramolecular Wittig olefination to afford (+)-chloriolide in 65% yield without the
necessity of high-dilution conditions. This is the third synthesis of (+)-chloriolide and the first one ever of a macrolide by a ring-
closing Wittig olefination of a stabilized phosphorus ylide bearing an ω-hemiacetal. Our synthetic sample exhibited moderate
cytotoxicity against cancer cells but no antimicrobial activity against Staphylococcus aureus.
Scheme 1. Retrosynthetic Approach to (+)-Chloriolide 1
INTRODUCTION
■
(+)-Chloriolide 1, a 12-membered macrolide, was obtained in
2006 by Gloer et al. from an isolate of Chloridium virescens var.
chlamydosporum dwelling on decaying hardwood. It was
structurally characterized by single-crystal X-ray diffraction,
NMR spectroscopy, and the Mosher ester method.1 Tests for
the antibiotic activity of 1 against S. aureus, B. subtilis, and E. coli
were negative. Hitherto, two total syntheses of chloriolide were
reported by Kirsch et al.2 and Nanda et al.3 The first synthesis
of 1 by Kirsch et al. in 20 steps and 7% yield was based upon a
Yamaguchi lactonization of an ω-hydroxycarboxylic acid which
was obtained by connecting two silyl ether bridged allyl alcohol
precursors via alkene metathesis. Interestingly, attempts by this
group to close the macrocycle by formation of the (E)-alkene
via a Horner−Wadsworth−Emmons reaction or of the (Z)-
alkene via a ring-closing metathesis reaction failed. Nanda et al.
also employed a Yamuguchi lactonization for closing the
macrocycle. The required seco acid was built up by starting from
1,3-butanediol and installing the other two stereocenters via
asymmetric alkyne−aldehyde coupling reactions. This approach
afforded 1 in 20 steps and 2% overall yield. Herein we report a
third total synthesis of (+)-chloriolide 1 that starts from two
cheap enantiopure compounds, lactic acid and cellulose, and
uses an E-selective intramolecular Wittig olefination for the ring
closure.
compatible with the ylide form on the other end of 2. We
intended to liberate the hemiacetal−ylide 2 by acidic cleavage
of a corresponding acetonide−ylide and subsequent adjustment
of the pH with aqueous base. This required acetonide−ylide
should be accessible by addition of the secondary alcohol 4
across the CC bond of the cumulated ylide Ph3PCC
O (3).7,8 Alcohol 4, which already contains all crucial functional
3
groups and stereocenters, was to be built up by a Csp −
2
RESULTS AND DISCUSSION
Csp coupling between the silyl-protected lactic aldehyde 5 and
■
an organometallic component derived from iodide 6. This
iodide was reckoned to be accessible from the known pyrolysis
product 7 of cellulose by a sequence of reactions, including
ketone reduction to the corresponding alcohol, acetonide
formation, and elongation of the side chain via the cyanide.
Our retrosynthetic approach is outlined in Scheme 1. A Wittig-
type macrocyclization was to take place spontaneously upon
generation of the stabilized phosphorus ester ylide 2 bearing a
terminal hemiacetal. Although we had used similar Wittig
cyclizations of ω-formyl ester ylides in the past for the synthesis
of various macrolides with ring sizes ranging from 12 to 18,4−6
it was unclear at the outset whether enough aldehyde would be
present in equilibrium with the hemiacetal at pH values
Received: March 5, 2014
Published: April 7, 2014
© 2014 American Chemical Society
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Levoglucosenone 7 was prepared by pyrolysis of cellulose in
overall yield. Its quantitative desilylation with TBAF in THF
afforded the pivotal ω-hydroxyacetal 4. This strategy for the
coupling of the cellulose-derived building block and the side
chain containing the S-configured secondary alcohol was
2% yield as reported (Scheme 2).9,10 The reaction is easy to
a
Scheme 2. Synthesis of Building Block 6
3
3
chosen after initial attempts at Grignard-based Csp −Csp
coupling reactions had all failed. The reason for this might lie
in the presence of the three oxygen atoms in the acetonido−
acetals, which are ideally positioned to coordinate to
magnesium and so interfere with the Grignard process.
The key alcohol 4 was heated with the ylide Ph3PCCO (3) in
toluene, affording the air- and moisture-stable ester ylide 19 in
quantitative yield (Scheme 4). Ring closure via intramolecular
Scheme 4. Synthesis of Precursor Ylide 19 and Wittig
Cyclization to (+)-Chloriolide 1
a
Reagents and conditions: (i) H3PO4, ca. 500 °C, 2%; (ii) NaBH4,
H2O, room temperature, 5 min, 84%; (iii) HCl, H2O/dioxane, reflux,
1.5 h; (iv) pTosOH, 2,2-dimethoxypropane, acetone, room temper-
ature, 3 h, 60% (two steps); (v) pTosCl, pyridine, CH2Cl2, room
temperature, 24 h, 90%; (vi) NaCN, DMF, 60 °C, 22 h, 87%; (vii)
DIBAL-H, CH2Cl2, −65 → −40 °C, 1.5 h, 86%; (viii) NaBH4, EtOH,
0 °C, 1 h, 98%; (ix) CBr4, PPh3, THF, 0 °C → room temperature, 24
h, 83%; (x) NaI, acetone, 60 °C, 2 h, 98%.
carry out on a large scale, and thus the low yield is no object.
However, an improved synthesis of 7 was reported in 2013.11
Reduction of 7 with NaBH4 and hydrolytic workup gave the
hydroxyacetal 812,13 in 84% yield; addition of hydrochloric acid
liberated the triol 9. Its treatment with 2,2-dimethoxypropane
and pTosOH afforded the acetonido−acetal 10 (60%, two
steps). This was tosylated to give 11, which was substituted by
cyanide, leaving nitrile 12. The latter was reduced to aldehyde
13 with DIBAL-H in dichloromethane in 86% yield.
Quantitative reduction of 13 with sodium borohydride in
ethanol furnished alcohol 14, which was brominated with
CBr4/PPh3 to leave bromide 15. This was converted to the
corresponding iodide 6 in 98% yield.
Iodide 6 was metalated to the corresponding organolithium
derivative with t-BuLi and coupled with aldehyde 5, obtained
from ethyl lactate by a known route,14 to give the product
alcohol 16 in 75% yield (Scheme 3). This alcohol was
deoxygenated in two steps: tosylation afforded compound 17,
which was reduced with LiAlH4 to give the silyl ether 18 in 65%
Wittig olefination requires the presence of a hemiacetal in
equilibrium with the free hydroxyaldehyde form on the remote
end of the ylide. Thus, acetonido−acetal 19 was dissolved in
THF and treated with aqueous HCl to adjust to a pH value of
ca. 2.5, allowing cleavage of the acetonide. The resulting
solution of hemiacetal−phosphonium salt 20 was layered with
CH2Cl2 and neutralized with NaOH to generate the ylide 2,
which underwent spontaneous Wittig cyclization to (+)-chlor-
iolide 1 in 65% yield.
Our synthetic (+)-chloriolide showed spectroscopic proper-
ties in keeping with those reported in the literature and was
void of other diastereomers, as determined by NMR and GC.
However, it had a markedly greater specific optical rotation of
24
[α]D = 138° (c 0.2, CHCl3), possibly since it was
painstakingly freed from adherent solvents prior to measure-
ment.
a
Scheme 3. Synthesis of ω-Hydroxyacetal 4
We also tested our sample of 1 for biological activity (cf.
Supporting Information). In growth inhibition assays it showed
a moderate efficacy against three cancer cell lines, 518A2
melanoma, HCT-116 colon carcinoma, and multidrug-resistant
KB-V1/Vbl cervix carcinoma, with IC50(72 h) concentrations
ranging from 50 to 90 μM. This cytotoxic effect is presumably
not a feature of the macrocyclic lactone but is due to the
electrophilic enone and hydroxypentadienyl moieties. In agar
diffusion assays synthetic 1 did not inhibit the growth of
erythromycin-sensitive S. aureus and E. coli TolC bacteria at
concentrations as high as 20 μg/mL. However, this came as no
surprise, since most macrolide aglycones lack antimicrobial
activity. We are currently investigating chimeric glycosides of
chloriolide with desosamine, the amino sugar causative for the
high antibiotic activity of erythromycin.
a
Reagents and conditions: (i) t-BuLi (2.2 equiv), Et2O, −78 °C; (ii) +
5, −78 °C → room temperature, 20 h, 75%; (iii) pTosCl (5 equiv),
CH2Cl2, pyridine, DMAP, 60 °C, 2 d, 77%; (iv) LiAlH4 (8 equiv),
THF, 75 °C, 3.5 h, 85%; (v) TBAF (6.5 equiv), THF, room
temperature, 20 h, 100%.
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extracted three times with methyl tert-butyl ether. The combined
organic layers were dried and concentrated, and the residue was
purified by column chromatography (ethyl acetate/hexane 1/3; Rf =
0.21) to afford 250 mg of 12 (1.28 mmol, 87%) as a white waxy solid;
CONCLUSIONS
■
The mold metabolite (+)-chloriolide 1 was synthezised in 15
linear steps and 9% overall yield starting from a pyrolysis
product of cellulose and ethyl L-lactate. This synthesis is shorter
than the previously published methods by the groups of Kirsch
and Nanda, and it is also the first synthesis ever of a macrolide
by a ring-closing intramolecular Wittig olefination of a
stabilized phosphorus ylide bearing an ω-hemiacetal. Since
the protection of hydroxy groups is not necessary for this
reaction to work, it should be applicable to other carbohydrates
as well. This would allow the full exploitation of the abundance
of stereocenters and alcohols in sugars for the construction of
macrolides which are frequently rich in these features.
24
[α]D = 43° (c 1.0, CHCl3); IR (ATR) νmax 2987, 1382, 1370, 1227,
1
1178, 1164, 1130, 1069, 1004, 983, 885, 864, 775 cm−1; H NMR
(CDCl3, 300 MHz) δ 1.38 (s, 3 H), 1.53 (s, 3 H), 2.61 (dd, J = 16.6,
6.4 Hz, 1 H), 2.68 (dd, J = 16.6, 6.0 Hz, 1 H), 4.20−4.25 (m, 1 H),
4.37 (mc, 1 H), 5.25 (d, J = 3.0 Hz, 1 H), 6.01 (ddd, J = 10.2, 1.5, 0.7
Hz, 1 H), 6.13 (ddd, J = 10.2, 4.2, 2.2 Hz, 1 H); 13C NMR (CDCl3, 75
MHz) δ 23.6, 26.3, 28.2, 67.7, 69.8, 96.8, 112.2, 116.2, 124.8, 131.3;
MS (EI) m/z 180 [M+ − CH3], 155, 139, 137, 122, 107, 97, 79;
+
HRMS (ESI) m/z: [M + Na]+ calcd for C10H13NNaO3 218.0788,
found 218.0786.
2-{(3aS,5R,7aS)-2,2-Dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo-
[4,5-b]pyran-5-yl}acetaldehyde (13). DIBAL-H (2.52 mL of a 1 M
solution in hexanes, 2.52 mmol) was slowly added to a solution of 12
(0.41 mg, 2.10 mmol) in CH2Cl2 (32 mL) at −65 °C. The mixture
was stirred while being warmed from −65 to −40 °C over a period of
90 min. Saturated aqueous potassium sodium tartrate (40 mL) was
added, and stirring was continued for another 1 h at room
temperature. The phases were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic extracts were
dried over Na2SO4, concentrated, and purified by column chromatog-
raphy (hexane/ethyl acetate 2/1; Rf = 0.34) to leave 358 mg of 13
EXPERIMENTAL SECTION
■
General Remarks. IR spectra were recorded with an FT-IR
spectrophotometer equipped with an ATR unit. Chemical shifts of
NMR signals are given in parts per million (δ) downfield from
tetramethylsilane for 1H and 13C. Mass spectra were obtained under EI
(70 eV) conditions. High-resolution mass spectra were obtained with a
UPLC/Q-TOF MS system in ESI mode. For chromatography silica
gel 60 (230−400 mesh) was used.
Alcohol 10. A solution of 812,13 (13.1 g, 102.3 mmol) in dioxane
(125 mL) and 0.35 M HCl (250 mL) was heated at reflux for 1.5 h.
The reaction mixture was cooled to room temperature and neutralized
with NEt3. The volatiles were evaporated, acetone was added, and the
precipitate of the ammonium salt was filtered off. The filtrate was
concentrated, and the residue of crude 9 was dried under vacuum to
leave a yellow oil (14.95 g, 102.3 mmol). This was dissolved in acetone
(120 mL) and treated with 2,2-dimethoxypropane (57.5 mL, 463.4
mmol) and pTosOH (1.96 g, 10.3 mmol), and the resulting mixture
was stirred at room temperature for 3 h. The volatiles were removed
under reduced pressure, and the remainder was purified by column
chromatography (ethyl acetate/hexane 1/1; Rf = 0.37) to afford 10
(11.4 g, 61.4 mmol, 60% over two steps) as a yellow oil: [α]D24 = 39°
(c 2.0, CHCl3); IR (ATR) νmax 3457, 2986, 2889, 1678, 1458, 1371,
24
(1.81 mmol, 86%) as a colorless oil: [α]D = 58° (c 1.0, CHCl3); IR
(ATR) νmax 2986, 2933, 1724, 1458, 1381, 1225, 1178, 1068, 1050,
1
984, 883, 865, 670 cm−1; H NMR (CDCl3, 300 MHz) δ 1.39 (s, 3
H), 1.51 (s, 3 H), 2.64 (ddd, J = 17.0, 5.6, 1.8 Hz, 1 H), 2.74 (ddd, J =
17.0, 6.6, 2.0 Hz, 1 H), 4.17−4.22 (m, 1 H), 4.56−4.65 (m, 1 H), 5.22
(d, J = 3.0 Hz, 1 H), 5.97 (ddd, J = 10.2, 1.2, 0.7 Hz, 1 H), 6.04 (ddd, J
= 10.2, 4.1, 2.1 Hz, 1 H), 9.78 (t, J = 1.9 Hz, 1 H); 13C NMR (CDCl3,
75 MHz) δ 26.4, 28.4, 47.7, 67.7, 70.2, 97.0, 112.0, 123.3, 133.9, 200.2;
MS (EI) m/z 183 [M+ − CH3], 153, 139, 123, 112, 97, 83, 67, 59;
+
HRMS (ESI): m/z [M + Na]+ calcd for C10H14NaO4 221.0784,
found 221.0768.
(3aS,5R,7aS)-5-(2-Hydroxyethyl)-2,2-dimethyl-5,7a-dihydro-
3aH-[1,3]dioxolo[4,5-b]pyran (14). A solution of aldehyde 13 (991
mg, 4.99 mmol) in ethanol (45 mL) was treated with NaBH4 (125 mg,
3.30 mmol) and stirred at 0 °C for 1 h. Aqueous NaHCO3 was added,
and the resulting mixture was extracted three times with CH2Cl2. The
combined organic layers were dried with Na2SO4 and concentrated.
The crude product thus obtained was purified by column
chromatography (ethyl acetate/hexane 1/2) to afford 979 mg of 14
(4.89 mmol, 98%) as colorless crystals with mp 91−92 °C: Rf = 0.23
1316, 1223, 1186, 1163, 1129, 1066, 1043, 981, 882 cm−1; H NMR
1
(CDCl3, 300 MHz) δ 1.37 (s, 3 H), 1.51 (s, 3 H), 2.75 (s, 1 H; OH),
3.57−3.73 (m, 2 H), 4.14−4.24 (m, 2 H), 5.24 (d, J = 3.0 Hz, 1 H),
5.94 (d, J = 10.3 Hz, 1 H), 5.99−6.10 (m, 1 H); 13C NMR (CDCl3, 75
MHz) δ 26.4, 28.4, 64.6, 70.3, 73.2, 96.9, 111.5, 123.9, 131.8; MS (EI)
m/z 171 [M+ − CH3], 155, 111, 98, 83, 69, 59; HRMS (ESI) m/z [M
+
+ Na]+ calcd for C9H14NaO4 209.0784, found 209.0783.
{(3aS,5S,7aS)-2,2-Dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo-
[4,5-b]pyran-5-yl}methyl 4-Methylbenzenesulfonate (11). A
solution of 10 (3.45 g, 18.5 mmol) in CH2Cl2 (30 mL) was treated
with pyridine (30 mL) and p-toluenesulfonyl chloride (5.30 g, 27.8
mmol). The mixture was stirred at room temperature for 24 h, and
then the reaction was quenched with water (4.5 mL). The volatiles
were removed in vacuo, and the residue was purified by column
chromatography (methyl tert-butyl ether/hexane 1/8) to afford 11
(5.66 g, 90%) as a yellow oil: Rf = 0.27 (hexane/methyl tert-butyl ether
24
(ethyl acetate/hexane 1:1); [α]D = 90° (c 1.0, CHCl3); IR (ATR)
νmax 3432, 2985, 1370, 1311, 1224, 1049, 881, 864, 800, 754, 707
1
cm−1; H NMR (CDCl3, 300 MHz) δ 1.31 (s, 3 H), 1.44 (s, 3 H),
1.69−1.89 (m, 2 H), 2.70 (s, 1 H), 3.63−3.77 (m, 2 H), 4.08−4.13
(m, 1 H), 4.20−4.27 (m, 1 H), 5.10 (d, J = 3.0 Hz, 1 H), 5.87−5.96
(m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 26.3, 28.3, 36.7, 59.3, 70.3,
70.8, 96.8, 111.7, 122.0, 135.4; MS (EI) m/z 185 [M+ − CH3], 155,
142, 126, 125, 114, 97, 83, 67, 59; HRMS (ESI) m/z [M + Na]+ calcd
+
24
for C10H16NaO4 223.0941, found 223.0963.
3/2); [α]D = 22° (c 1.0, CHCl3); IR (ATR) νmax 2986, 1598, 1358,
1326, 1174, 1072, 977, 913, 884, 813, 762, 721, 705, 678 cm−1; H
1
(3aS,5R,7aS)-5-(2-Bromoethyl)-2,2-dimethyl-5,7a-dihydro-
3aH-[1,3]dioxolo[4,5-b]pyran (15). A solution of alcohol 14 (286
mg, 1.43 mmol) in THF (4.1 mL) was treated with PPh3 (450 mg,
1.71 mmol) and CBr4 (568 mg, 1.71 mmol). The resulting mixture
was stirred initially at 0 °C for 24 h and then warmed to room
temperature. The solvent was removed under vacuum, and the residue
was purified by column chromatography (hexane/diethyl ether 10/1;
Rf = 0.23) to afford 312 mg of 15 (1.19 mmol, 83%) as a colorless
waxy solid: [α]D24 = 144° (c 1.0, CHCl3); IR (ATR) νmax 2985, 1435,
NMR (CDCl3, 300 MHz) δ 1.32 (s, 3 H), 1.40 (s, 3 H), 2.38 (s, 3 H),
4.00 (dd, J = 10.0, 6.0 Hz, 1 H), 4.09 (dd, J = 10.0, 6.0 Hz, 1 H), 4.15−
4.19 (m, 1 H), 4.30 (mc, 1 H), 5.15 (d, J = 3.0 Hz, 1 H), 5.91 (ddd, J =
10.2, 1.5, 0.7 Hz, 1 H), 6.03 (ddd, J = 10.2, 4.2, 2.2 Hz, 1 H), 7.28 (mc,
2 H), 7.73 (mc, 2 H); 13C NMR (CDCl3, 75 MHz) δ 21.5, 26.4, 28.2,
69.8, 70.0, 70.2, 96.7, 111.8, 124.4, 127.9, 129.9, 130.1, 132.4, 144.9;
MS (EI) m/z 340 [M+], 325, 281, 207, 169, 155, 123, 97, 91; HRMS
(ESI) m/z [M + Na]+ calcd for C16H20NaO6S+ 363.0873, found
363.0885.
1
1381, 1225, 1186, 1124, 1054, 1007, 973, 883, 865, 777 cm−1; H
NMR (CDCl3, 300 MHz) δ 1.35 (s, 3 H), 1.48 (s, 3 H), 2.08−2.17
(m, 2 H), 3.32−3.60 (m, 2 H), 4.13−4.17 (m, 1 H), 4.19−4.26 (m, 1
H), 5.16 (d, J = 3.0 Hz, 1 H), 5.89 (ddd, J = 10.2, 1.3, 0.7 Hz, 1 H),
5.98 (ddd, J = 10.2, 4.2, 2.2 Hz, 1 H); 13C NMR (CDCl3, 75 MHz) δ
26.4, 28.5, 29.1, 37.8, 70.0, 70.5, 97.0, 111.8, 123.0, 134.6; MS (EI) m/
2-{(3aS,5R,7aS)-2,2-Dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo-
[4,5-b]pyran-5-yl}acetonitrile (12). A solution of tosylate 11 (0.50
g, 1.47 mmol) in DMF (5 mL) was treated with dried NaCN (288 mg,
5.88 mmol), and the resulting suspension was stirred under argon at
60 °C for 22 h. Water was added, and the resulting mixture was
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z 249 (68%) [M(81Br)+ − CH3], 247 (72%) [M(79Br)+ − CH3], 219,
207, 187, 176, 155, 135, 123, 109, 97, 81, 59.
122.5, 127.7, 129.6, 134.5, 135.3, 144.4. Minor diastereoisomer: 1H
NMR (CDCl3, 300 MHz) δ −0.04 (s, 3 H), −0.03 (s, 3 H), 0.80 (s, 9
H), 1.03 (d, J = 6.3 Hz, 3 H), 1.36 (s, 3 H), 1.47 (s, 3 H), 1.49−1.59
(m, 2 H), 1.69−1.77 (m, 2 H), 2.40 (s, 3 H), 3.88−4.00 (m, 2 H),
4.09−4.17 (m, 1 H), 4.24−4.32 (m, 1 H), 5.09 (d, J = 3.0 Hz, 1 H),
5.74 (mc, 1 H), 5.92 (ddd, J = 10.0, 4.3, 2.2 Hz, 1 H), 7.23−7.32 (m, 2
H), 7.71−7.78 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ −5.0, −4.9,
17.0, 17.8, 21.5, 23.1, 25.6, 26.5, 28.5, 30.6, 68.0, 70.9, 71.4, 85.4, 97.0,
111.7, 122.4, 127.7, 129.7, 134.2, 135.3, 144.6. Mixture: IR (ATR) νmax
2930, 2857, 1599, 1496, 1366, 1188, 1176, 1096, 1073, 1054, 915, 836,
812, 776, 665, 553 cm−1; MS (EI) m/z: 511 [M+ − CH3], 411, 341,
279, 229, 211, 165, 159, 113, 91, 73; HRMS (ESI) m/z [M + Na]+
calcd for C26H42NaO7SSi+ 549.2313, found 549.2304.
(3aS,5R,7aS)-5-(2-Iodoethyl)-2,2-dimethyl-5,7a-dihydro-
3aH-[1,3]dioxolo[4,5-b]pyran (6). A solution of bromide 15 (145
mg, 0.55 mmol) in dry acetone (4 mL) was treated with dry sodium
iodide (248 mg, 1.65 mmol), and the resulting mixture was stirred at
60 °C for 2 h. The solvent was removed, and the residue was divided
between CH2Cl2 and water. The organic layer was dried over Na2SO4
and under vacuum to yield 166 mg of pure 6 (0.54 mmol, 98%) as
colorless crystals with mp 49−50 °C: Rf = 0.22 (hexane/diethyl ether
10/1); [α]D24 = 110° (c 1.0, CHCl3); IR (ATR) νmax 2983, 1438, 1380,
1
1224, 1164, 1071, 1048, 1002, 882, 863, 802, 773 cm−1; H NMR
(CDCl3, 300 MHz) δ 1.30 (s, 3 H), 1.43 (s, 3 H), 1.98−2.08 (m, 2 H),
3.14−3.29 (m, 2 H), 4.05−4.13 (m, 2 H), 5.12 (d, J = 3.0 Hz, 1 H),
5.84 (ddd, J = 10.0, 1.3, 0.7 Hz, 1 H), 5.93 (ddd, J = 10.0, 4.1, 2.0 Hz,
1 H); 13C NMR (CDCl3, 75 MHz) δ 1.4, 26.3, 28.3, 38.3, 70.2, 71.5,
97.8, 111.5, 122.9, 134.1; MS (EI) m/z 310 [M+], 295, 265, 252, 235,
224, 183, 155, 137, 97, 79, 59; HRMS (ESI) m/z: [M + Na]+ calcd for
(3aS,5R,7aS)-5-[(4S)-4-tert-butyldimethylsilyloxypentyl]-2,2-
dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo[4,5-b]pyran (18). A
mixture of tosylate 17 (332 mg, 0.63 mmol), THF (14 mL), and
LiAlH4 (191 mg, 5.04 mmol) was placed in a sealed bomb tube and
heated to 75 °C for 3.5 h. After the mixture was cooled, a saturated
aqueous potassium sodium tartrate solution (30 mL) was added, and
stirring was continued for 1 h. The mixture was extracted twice with
ethyl acetate and twice with CH2Cl2. The combined organic phases
were dried with Na2SO4 and concentrated under vacuum, and the
remainder was purified by column chromatography (hexane/methyl
tert-butyl ether 5/1; Rf = 0.53) to afford 192 mg of 18 (0.54 mmol,
+
C10H15INaO3 332.9958, found 332.9947.
(3aS,5R,7aS)-5-[(4S)-3-hydroxy-4-tert-butyldimethylsilyloxy-
pentyl]-2,2-dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo[4,5-
b]pyran (16). A solution of iodide 6 (692 mg, 2.23 mmol) in diethyl
ether (7 mL) was slowly added to a stirred solution of t-BuLi (1.6 M in
hexanes, 3.07 mL, 4.91 mmol) in diethyl ether (46 mL) kept at −78
°C. After 5 min aldehyde 514 (504 mg, 2.69 mmol) was slowly added
and stirring was continued for 25 min at −78 °C. The cooling bath was
removed, and the mixture was stirred for a further 20 h. Aqueous
NH4Cl was added, the layers were separated, and the aqueous layer
was extracted twice with ethyl acetate. The combined organic phases
were dried with Na2SO4, and the solvent was removed under vacuum.
The residue was purified by column chromatography (diethyl ether/
hexane 1/3; Rf = 0.08) to afford 623 mg of 16 (1.67 mmol, 75%) as a
24
85%) as a colorless oil: [α]D = 54° (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ −0.01 (s, 6 H), 0.83 (s, 9 H), 1.06 (d, J = 6.1
Hz, 3 H), 1.29−1.48 (m, 4 H), 1.36 (s, 3 H), 1.51 (s, 3 H), 1.52−1.68
(m, 2 H), 3.67−3.79 (m, 1 H), 3.99−4.05 (m, 1 H), 4.12−4.15 (m, 1
H), 5.15 (d, J = 3.0 Hz, 1 H), 5.92−5.95 (m, 2 H); 13C NMR (CDCl3,
75 MHz) δ −4.7, −4.5, 18.0, 20.8, 23.7, 25.8, 26.5, 28.5, 34.6, 39.6,
68.4, 70.7, 71.9, 97.2, 111.6, 122.1, 135.8; IR (ATR) νmax 2930, 2858,
1473, 1370, 1321, 1237, 1183, 1075, 1052, 1006, 833, 772 cm−1; MS
(EI) m/z 341 [M+ − CH3], 281, 253, 241, 223, 213, 183, 171, 159,
149, 129, 107, 79, 75; HRMS (ESI) m/z [M + Na]+ calcd for
C19H36NaO4Si+ 379.2275, found 379.2275.
24
colorless oil: [α]D = 51° (c 1.0; CHCl3); 2.6/1 mixture of two
diastereoisomers. Major diastereoisomer: 1H NMR (CDCl3, 300 MHz)
δ 0.02 (s, 3 H), 0.03 (s, 3 H), 0.84 (s, 9 H), 1.03 (d, J = 6.3 Hz, 3 H),
1.38 (s, 3 H), 1.52 (s, 3 H), 1.39−1.94 (m, 4 H), 2.34 (s, 1 H), 3.43−
3.54 (m, 1 H), 3.71 (mc, 1 H), 4.00−4.19 (m, 2 H), 5.17 (d, J = 3.0
Hz, 1 H), 5.93−6.00 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ −4.9,
−4.5, 17.0, 18.0, 25.8, 26.5, 28.5, 30.9, 31.1, 70.7, 71.2, 71.5, 74.9, 97.2,
111.7, 122.4, 135.6. Minor diastereoisomer: 1H NMR (CDCl3, 300
MHz) δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.86 (s, 9 H), 1.11 (d, J = 6.3 Hz,
3 H), 1.38 (s, 3 H), 1.52 (s, 3 H), 1.39−1.94 (m, 4 H), 2.41 (s, 1 H),
3.20−3.34 (m, 1 H), 3.60 (mc, 1 H), 4.00−4.19 (m, 2 H), 5.16 (d, J =
3.0 Hz, 1 H), 5.93−6.00 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ
−4.9, −4.2, 18.0, 20.2, 25.7, 26.5, 28.8, 30.9, 31.1, 70.7, 71.2, 71.7, 75.8,
97.2, 111.7, 122.2, 135.9. Mixture: IR (ATR) νmax 3459, 2954, 2358,
2008, 1462, 1370, 1311, 1249, 1185, 1130, 1068, 939, 883, 832, 774
cm−1; MS (EI) m/z 357 [M+ − CH3], 297, 281, 257, 239, 221, 211,
187, 159, 145, 119, 115, 85, 75; HRMS (ESI) m/z [M + Na]+ calcd for
C19H36NaO5Si+ 395.2224, found 395.2221.
(3aS,5R,7aS)-5-[(4S)-4-Hydroxypentyl]-2,2-dimethyl-5,7a-di-
hydro-3aH-[1,3]dioxolo[4,5-b]pyran (4). A mixture of silyl ether
18 (20.8 mg, 0.06 mmol), THF (3 mL), and TBAF (123 mg, 0.39
mmol) was stirred at room temperature for 20 h. The volatiles were
removed in vacuo, and the residue thus obtained was divided between
CH2Cl2 and brine. The organic layer was dried with Na2SO4 and
concentrated, and the remainder was purified by column chromatog-
raphy (hexane/methyl tert-butyl ether 10/1) to afford 14 mg of 4 (0.06
mmol, 100%) as a colorless oil: Rf = 0.21 (hexane/ethyl acetate 1/1);
24
[α]D = 74° (c 1.0, CHCl3); IR (ATR) νmax 3397, 2937, 1459, 1371,
1
1227, 1189, 1073, 1052, 882 cm−1; H NMR (CDCl3, 300 MHz) δ
1.09 (d, J = 6.2 Hz, 3 H), 1.32 (s, 3 H), 1.35−1.50 (m, 4 H), 1.47 (s, 3
H), 1.51−1.63 (m, 2 H), 2.02 (s, 1 H), 3.65−3.77 (m, 1 H), 3.97−4.06
(m, 1 H), 4.08−4.12 (m, 1 H), 5.11 (d, J = 3.0 Hz, 1 H), 5.88−5.91
(m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 20.8, 23.3, 26.4, 28.4, 34.3,
38.9, 67.5, 70.5, 71.7, 97.0, 111.5, 122.0, 135.7; MS (EI) m/z 227 [M+
− CH3], 167, 155, 138, 109, 97, 81, 68, 59; HRMS (ESI) m/z [M +
(3aS,5R,7aS)-5-[(4S)-3-Tosyloxy-4-tert-butyldimethylsilylox-
ypentyl]-2,2-dimethyl-5,7a-dihydro-3aH-[1,3]dioxolo[4,5-
b]pyran (17). A solution of alcohol 16 (193 mg, 0.52 mmol) in
CH2Cl2 (3 mL) and pyridine (0.6 mL) was treated with p-
toluenesulfonyl chloride (493 mg, 2.59 mmol) and DMAP (63.3
mg, 0.52 mmol). The mixture was heated in a sealed bomb tube at 60
°C for 2 days. Aqueous NH4Cl was added, the resulting mixture was
extracted four times with CH2Cl2, and the combined organic extracts
were dried over Na2SO4, concentrated, and purified by column
chromatography (gradient 25−50% methyl tert-butyl ether in hexane)
to give 211 mg of 17 (0.40 mmol, 77%) as a colorless oil: Rf = 0.43
+
Na]+ calcd for C13H22NaO4 265.1410, found 265.1390.
(3aS,5R,7aS)-2,2-Dimethyl-5-[(4S)-4-(triphenylphos-
phoranylidenacetoxy)pentyl]-5,7a-dihydro-3aH-[1,3]dioxolo-
[4,5-b]pyran (19). A solution of alcohol 4 (36.0 mg, 0.15 mmol) and
Ph3PCCO (3; 44.9 mg, 0.15 mmol) in toluene (3 mL) was heated to
reflux for 1 h. The solvent was removed, and the remainder was
repeatedly extracted with diethyl ether to remove residual starting
materials. Upon drying of the residue under reduced pressure 80.9 mg
of ylide 26 (0.15 mmol, 100%) was obtained as a foamy, sticky solid:
Rf = 0.13 (rp-18-phase; MeOH/H2O 3/2, + 1% TFA); [α]D24 = 32° (c
1.0, CHCl3); IR (ATR) νmax 2933, 1611, 1574, 1484, 1368, 1262,
24
(hexane/methyl tert-butyl ether 3/1); [α]D = 31° (c 1.0; CHCl3);
2.6/1 mixture of two diastereoisomers. Major diastereoisomer: 1H NMR
(CDCl3, 300 MHz) δ −0.04 (s, 3 H), −0.03 (s, 3 H), 0.80 (s, 9 H),
1.01 (d, J = 6.4 Hz, 3 H), 1.36 (s, 3 H), 1.48 (s, 3 H), 1.49−1.59 (m, 2
H), 1.69−1.77 (m, 2 H), 2.39 (s, 3 H), 3.88−4.00 (m, 2 H), 4.09−4.17
(m, 1 H), 4.35−4.43 (m, 1 H), 5.10 (d, J = 3.0 Hz, 1 H), 5.77 (mc, 1
H), 5.92 (ddd, J = 10.0, 4.3, 2.2 Hz, 1 H), 7.23−7.32 (m, 2 H), 7.71−
7.78 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ −4.9, −4.7, 17.9, 19.9,
21.5, 23.3, 25.7, 26.5, 28.5, 29.7, 69.6, 70.6, 70.9, 86.8, 97.1, 111.7,
1
1102, 1071, 1049, 883, 715, 692 cm−1; H NMR (C6D6, 300 MHz) δ
0.77−0.88 (m, 3 H), 0.78−1.83 (m, 6 H), 1.33 (s, 3 H), 1.61 (s, 3 H),
3.19−3.33 (m, 1 H), 3.63−3.80 (m, 1 H), 3.86−3.98 (m, 1 H), 5.01
(d, J = 3.0 Hz, 1 H), 5.16−5.32 (m, 1 H), 5.54−5.66 (m, 1 H), 5.71−
5.85 (m, 1 H), 6.91−7.13 (m, 9 H) 7.51−7.79 (m, 6 H); 13C NMR
(C6D6, 75 MHz) δ 21.7, 22.0, 27.3, 29.4, 35.4, 37.7, 66.7, 67.4, 71.7,
72.4, 98.2, 112.0, 123.1, 129.0, 129.2, 131.1, 131.2, 132.0, 132.7, 132.8,
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dx.doi.org/10.1021/jo500527g | J. Org. Chem. 2014, 79, 4038−4042

The Journal of Organic Chemistry
Article
133.6, 133.8, 136.2, 172.3; 31P NMR (C6D6, 121.5 MHz) δ 13.1, 15.2
(rotamers); MS (EI) m/z 544 [M+], 529, 486, 457, 389, 333, 321, 277,
262, 201, 183, 152, 113, 97, 77; HRMS (ESI) m/z: [M + H]+ calcd for
C33H38O5P+ 545.2451, found 545.2472.
(11) Kudo, S.; Zhou, Z.; Yamasaki, K.; Norinaga, K.; Hayashi, J.
Catalysts 2013, 3, 757−773.
(12) Brimacombe, J. S.; Hunedy, F.; Mather, A. M.; Tucker, L. C. N.
Carbohydr. Res. 1979, 68, 231−238.
(+)-Chloriolide 1. A solution of phosphorus ylide 19 (95.0 mg,
0.17 mmol) in THF (1.8 mL) was treated with aqueous HCl (0.15 M,
4 mL), and the resulting mixture was stirred at room temperature for
ca. 20 h. The progress and completeness of the cleavage of the
acetonide was monitored by TLC on reversed-phase plates. The clear
solution finally obtained was poured into an ice-cold, vigorously stirred
emulsion of aqueous NaOH (0.25 M, 30 mL) and CH2Cl2 (30 mL).
The layers were separated immediately, the aqueous layer was
extracted three times with CH2Cl2, and the combined organic layers
were dried with MgSO4. After it was stirred for another 60 min, the
solution was concentrated under vacuum. The crude product thus
obtained was purified by column chromatography (hexane/methyl
tert-butyl ether 1/5; Rf = 0.2) to afford 25 mg of 1 (0.11 mmol, 65%)
as a white solid with mp 133−133.5 °C: [α]D24 = 138° (c 0.2, CHCl3)
(13) Zanardi, M. M.; Suar
1002.
́
ez, A. G. Tetrahedron Lett. 2009, 50, 999−
(14) Song, L.; Yao, H.; Zhu, L.; Tong, R. Org. Lett. 2013, 15, 6−9.
(lit.1 [α]D = 107° (c 0.2, CHCl3), lit.2 [α]D = 101° (c 0.21,
25
20
CH2Cl2), lit.3 [α]D = 105.9° (c 0.2, CHCl3)); IR (ATR) νmax 3283,
25
2924, 2853, 2383, 2342, 2309, 2178, 2151, 2029, 1713, 1456, 1377,
1259, 1173, 1064, 1021, 921, 800, 696, 664, 603, 567 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.26 (d, J = 6.4 Hz, 3 H), 1.35−1.83 (m, 6 H),
4.54 (t, J = 8.8 Hz, 1 H), 4.81−4.86 (m, 1 H), 5.04−5.11 (m, 1 H),
5.52 (dd, J = 11.8, 8.2 Hz, 1 H), 5.67 (ddd, J = 11.8, 7.3, 1.2 Hz, 1 H),
6.10 (dd, J = 16.0, 2.4 Hz, 1 H), 7.24 (dd, J = 16.0, 2.8 Hz, 1 H); 13C
NMR (CDCl3, 126 MHz) δ 19.7, 21.4, 34.2, 36.2, 68.0, 69.7, 73.9,
+
119.6, 126.6, 140.4, 152.6, 166.5; MS (EI) m/z 154 [C8H10O3 ], 125,
+
97, 84, 55; HRMS (ESI) m/z [M + Na]+ calcd for C12H18NaO4
249.1097, found 249.1077.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures and a table giving 1H and 13C NMR spectra of 1, 4−8,
and 10−19, cytotoxicity of (+)-1, and the sensitivity of E. coli to
(+)-1. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for R.S.: Rainer.Schobert@uni-bayreuth.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Ursula Bilitewski (HZI, Braunschweig, Germany)
for antimicrobial tests and Katharina Mahal, MSc, in our group
for cytotoxicity tests.
REFERENCES
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