Biomimetic synthesis of resorcylate natural products utilizing late stage aromatization: Concise total syntheses of the marine antifungal agents 15G256ι and 15G256β

Article abstract of DOI:10.1021/ja803445u

Diketo-1,3-dioxin-2-ones underwent retro-Diels-Alder reaction on heating in toluene at 110°C to generate α,γ,ε-triketo-ketenes. These were trapped with alcohols to provide 2,4,6-triketocarboxylates, which were smoothly aromatized by sequential reaction wi

Full text of DOI:10.1021/ja803445u

Published on Web 07/09/2008
Biomimetic Synthesis of Resorcylate Natural Products
Utilizing Late Stage Aromatization: Concise Total Syntheses
of the Marine Antifungal Agents 15G256ι and 15G256ꢀ
Ismael Navarro, Jean-Franc¸ois Basset, Se´verine Hebbe, Sarah M. Major,
Thomas Werner, Catherine Howsham, Jan Bra¨ckow, and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, London SW7 2AZ, England
Received May 8, 2008; E-mail: agm.barrett@imperial.ac.uk
Abstract: Diketo-1,3-dioxin-2-ones underwent retro-Diels-Alder reaction on heating in toluene at 110 °C
to generate R,γ,ꢀ-triketo-ketenes. These were trapped with alcohols to provide 2,4,6-triketocarboxylates,
which were smoothly aromatized by sequential reaction with potassium carbonate and methanolic hydrogen
chloride to give resorcylate esters. The reaction was applied in the total synthesis of the marine antifungal
agents 15G256ꢀ (1), 15G256ι (2), and 15G256π (3) and the mycotoxin S-(-)-zearalenone (4).
Introduction
The 6-alkyl-2,4-dihydroxybenzoic acid unit occurs widely in
numerous macrocyclic bioactive natural products1 isolated from
the marine fungus Hypoxylon oceanicum LL-15G256,2 including
the antifungal agent 15G256ꢀ (1) and the related resorcylates
15G256ι (2) and 15G256π (3), the mycotoxin S-(-)-zearalenone
(4),3 and the protein tyrosine kinase inhibitor radicicol (5)4
(Figure 1). This class of natural products has been the subject
of considerable synthetic studies. Most reported total syntheses
employ 6-alkyl-2,4-hydroxybenzoic acids as intermediates and
proceed via stepwise derivatization of these key building
blocks.1 Such strategies are often limited by moderate yields in
the macrolactonization step and/or the need for multiple
protecting group manipulations. A noteworthy strategic excep-
tion is shown in the total synthesis of radicicol (5) reported by
Danishefsky, which uses a Diels-Alder reaction for the
construction of the aromatic ring.5
Inspired by the polyketide biosynthesis of resorcylate natural
products6 and the biomimetic syntheses of simple resorcylates
by Harris and others,7 we sought to establish a strategy for the
synthesis of lactones 6 containing these units utilizing tandem
late stage aromatization, from 2,4,6-triketo-ester precursors 7,
and macrocyclization. In addition, we sought mild, highly
selective C-acylation conditions to prepare the requisite triketo-
esters 7 that avoid the strongly Brønsted basic or Lewis acidic
reaction conditions that have hitherto significantly limited the
scope of resorcylate biomimetic synthesis. Herein we report the
Figure 1. Bioactive resorcylate lactones.
synthesis of dioxinones 9 under mild conditions, their ther-
molysis and efficient trapping of the resultant novel triketo-
ketenes 8 with alcohols8 X1-OH to afford the triketo-esters 7
and macrocyclization as key steps in the total synthesis of the
marine antifungal agents 15G256ꢀ (1), 15G256ι (2), and
15G256π (3), and the mycotoxin S-(-)-zearalenone (4).9 Most
noteworthy is the fact that delicate functionality such as esters
including derivatives of 3-hydroxy-butanoic acid survive the
(1) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
(2) Schlingmann, G.; Milne, L.; Carter, G. T Tetrahedron 2002, 58, 6825,
and references therein.
(3) (a) Taub, D.; Girotra, N. N.; Hoffsommer, R. D.; Kuo, C. H.; Slates,
H. L.; Weber, S.; Wendler, N. L. Tetrahedron 1968, 24, 2443. (b)
Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G.
Nature 1962, 196, 1318.
(8) For other studies on the generation of acyl-ketenes from dioxinone
derivatives see (a) Rodr´ıguez, H.; Reyes, O.; Suarez, M.; Garay, H. E.;
´
P; erez, R.; Cruz, L. J.; Verdecia, Y.; Mart´ın, N.; Seoane, C.
(4) (a) Delmotte, P.; Delmotte-Plaquee, J. Nature 1953, 171, 344. (b)
Nozawa, K.; Nakajima, S. J. Nat. Prod. 1979, 42, 374.
(5) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J.
J. Am. Chem. Soc. 2001, 123, 10903, and references therein.
(6) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380.
(7) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159.
Tetrahedron Lett. 2002, 43, 439. (b) Hyatt, J. A.; Feldman, P. L.;
Clemens, R. J. J. Org. Chem. 1984, 49, 5105. (c) Clemens, R. J.;
Witzeman, J. S. J. Am. Chem. Soc. 1989, 111, 2186.
(9) For the total synthesis of zearalenone using RCM and earlier references
see (a) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org.
Chem. 2000, 65, 7990.
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A R T I C L E S
Navarro et al.
Thermolysis of the dioxinone 12 and in situ trapping of the
triketo-ketene with alcohol 11 gave triketo-ester 13. This was
smoothly aromatized and ketal deprotected to provide the
resorcylate 14. The application of reaction conditions previously
described for the aromatization of simple triketo-esters7 proved
unsuccessful, in that the use of a pH ) 9.2 buffer15 or treatment
under strongly basic conditions with potassium methoxide only
gave a small amount of the desired aromatic product 14.
However, using base-catalyzed aldol condensation with subse-
quent addition of a strong acid to promote dehydration and
aromatization provided resorcylate 14 (87%). Subsequent ring-
closing metathesis using the second generation Hoveyda-Grubbs
catalyst 15 gave the corresponding macrocyclic lactones (E:Z
86:14) from which S-(-)-zearalenone (4) (71%) was isolated.
Attempted macrocyclization using catalyst 16 or by the ring
closing metathesis of the side chain ketal of ketone 14 or of 13
gave intractable mixtures containing S-(-)-zearalenone (4). By
simple modification of the reaction conditions, we found that
the four-step reaction sequence from alcohol 11 and dioxinone
12 to S-(-)-zearalenone (4) could be carried out without
isolation of any intermediates in a single vessel.16
Figure 2. Late stage aromatization-macrocyclization strategy.
Scheme 1. Synthesis of S-(-)-Zearalenone (4)
Having established the biomimetic aromatization on this
model system, we turned our attention to the more complex
15G256 marine antifungal agents, and to facilitate this synthesis,
we developed a mild new method for the synthesis of the
dioxinones 9. Sequential double C-acylation of dioxine 17
(Scheme 2) with acyl chloride 1817,18 and chloride 20 gave
diketo-ester 21.19 Subsequent palladium-catalyzed deallylation-
decarboxylation provided the key triketo-ester 22. Thermal
decomposition of dioxinone 22 in the presence of alcohol 23
gave triketo-ester 24, which was aromatized by sequential
reaction with potassium carbonate and methanolic hydrogen
chloride to provide the 15G256 monomer unit 25 (75%). We
have found this mild catalyzed double Claisen condensation
strategy and the use of allyl ester 19 to be especially valuable
for the synthesis of polyfunctional resorcylates.
The synthesis of the 15G256 diester 25 was extended to the
corresponding triester 27 (Scheme 3). Thus thermolysis of
dioxinone 2620 in the presence of alcohol 23 and aromatization
gave the resorcylate triester 27. It is noteworthy that ester
hydrolysis also did not occur in this example at a significant
rate during aromatization.
C-acylation, thermolysis, alcohol trapping, and aromatization
reaction (Figure 2).
Results and Discussion
We subsequently applied the resorcylate methods to the total
syntheses of the macrocyclic natural products 15G256ι (2) and
15G256π (3). Thermal decomposition of dioxinone 22 in the
presence of alcohol 28 (Scheme 4) afforded the intermediate
triketo-ester 29, which was aromatized as in Scheme 3 to provide
resorcylate 30 (70%). Protection of the phenols in 30 by
benzylation gave 31 (92%), which was selectively desilylated
As an initial approach to this chemistry, we investigated the
late stage aromatization with the model substrate S-(-)-
zearalenone (4) as a target (Scheme 1). The key S-(+)-alcohol
1110 (99% > ee) was prepared in four steps from (()-5-
hexanolide using lipase-mediated kinetic resolution.11 The
second building block 12 was prepared12 from dioxinone 10
using a Mukaiyama aldol reaction13,14 as the key step.
(15) Barrett, A. G. M.; Morris, T. M.; Barton, D. H. R. J. Chem. Soc.,
Perkin Trans. 1 1980, 10, 2272.
(10) (()-5-Hexanolide was allowed to react sequentially with 4-penten-
1-ylmagnesium bromide, Ac2O, HOCH2CH2OH-PPTS, and KOH-
MeOH (60% over three steps) and the resultant (()-11 resolved with
CAL-B lipase and CH2dCHOAc (48%). See Supporting Information.
(11) (a) Cordova, A.; Janda, K. D. J. Org. Chem. 2001, 66, 1906. (b) Nanda,
S.; Scott, A. I. J. Mol. Catal. B: Enzym. 2004, 30, 1.
(16) The yield of S-(-)-zearalenone (4) using a one-vessel reaction without
isolation of any intermediates was 43%. This yield was increased to
63% when the Dowex resin was filtered off before the addition of
catalyst 15.
(17) (a) Lida, A.; Osada, J.; Nagase, R.; Misaki, T.; Tanabe, Y. Org. Lett.
2007, 9, 1859. (b) Ollevier, T.; Desyroy, V.; Catrinescu, C.; Wischert,
R. Tetrahedron Lett. 2006, 47, 9089.
(12) Sequential BF3 ·OEt2-catalyzed Mukaiyama aldol reaction of the silyl
enol
ether
derived
from
dioxinone
10
with
(E)-
MeCHdCHCH(OTBS)CH2CHO. (See Collins, I.; Nadin, A.; Holmes,
A. B.; Long, M. E.; Man, J.; Baker, R. J. Chem. Soc., Perkin Trans.
1994, 1, 2205. ) (61%); Dess Martin oxidation; desilylation using HF
in H2O and further Dess Martin oxidation gave 12 (45%, three steps).
See Supporting Information.
(18) (a) Alternatively to ref 17, compound 19 can be synthesized Via
alkylationoftheenolateofdioxinone10with1-(CH2dCHCH2OCOCH2CO)-
benzotriazole. See Supporting Information. (b) Katritzky, A. R.; Wang,
Z.; Wang, M.; Hall, C. D.; Suzuki, K. J. Org. Chem. 2005, 70, 4854.
(19) All the di- and tri-keto-esters exist as mixtures of keto and enol
tautomers. However, for convenience, they are drawn as single entities.
(20) The synthesis of the dioxinone 26 closely follows the methods in
Scheme 2; see the Supporting Information.
(13) Giovanni, C.; Zanadi, F.; Appendino, G.; Rassu, G. Chem. ReV 2000,
100, 1929.
(14) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800.
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Biomimetic Synthesis of Resorcylate Natural Products
A R T I C L E S
Scheme 2. Synthesis of 15G256 Monomer Unit 25
Scheme 4. Synthesis of Tetraester 34
Scheme 3. Synthesis of the Resorcylate Triester 27
(65% from 37). Finally, debenzylation by hydrogenolysis gave
the antifungal resorcylate 15G256ꢀ (1) (85%).
Conclusion
In summary, we report a new strategy for the synthesis of
resorcylate natural products using a biomimetic highly selective
late-stage aromatization reaction and its application to concise
total syntheses of the antifungal natural products 15G256ꢀ (1),
15G256ι (2), and 15G256π (3), and the mycotoxin S-(-)-
zearalenone (4). The stability of delicate functionality to the
generation of the resorcylate units by cyclization and aromati-
zation is especially noteworthy. Further applications of this
strategy toward more complex biologically active targets are
currently under investigation.
or deallylated giving alcohol 32 (85%) and carboxylic acid 33
(93%), respectively. Yamaguchi esterification21 of both units
32 and 33 gave the corresponding tetraester 34 (86%). Finally
selective deallylation of ester 34 (Scheme 5) gave acid 35 (87%),
which was subsequently debenzylated by hydrogenolysis and
desilylated to give the hydroxy acid natural product 15G256π
(3) (86%). Alternatively, desilylation of 35 and Yamaguchi
macrolactonization gave lactone 36 (76%). Debenzylation gave
the resorcylate natural product 15G256ι (2) (75%), the structure
of which was confirmed by X-ray crystallography and by
comparison with authentic material (see Supporting Informa-
tion).2
Experimental Section
(S,E)-6-Oxoundec-10-en-2-yl 2,4-Dihydroxy-6-(prop-1-enyl)-
benzoate (14). Alcohol 11 (33.8 mg, 0.15 mmol), dioxinone 12
(37.3 mg, 0.15 mmol), and PhMe (0.4 mL) were heated to reflux
for 1.5 h. After rotary evaporation, the residue containing triketo-
ester 1322 was dissolved in MeOH (2.0 mL), KOH (39.8 mg, 0.71
mmol) was added, and the mixture was vigorously stirred at room
temperature for 12 h. Subsequently, the pH was reduced to 1 with
HCl in MeOH (1.25 M; 2.5 mL, 3.1 mmol) and the mixture stirred
for 20 min. The mixture was poured into H2O (2.0 mL) and
extracted with EtOAc (3 × 2 mL), and the combined organic layers
were washed with brine and dried (MgSO4). Rotary evaporation
and chromatography (hexanes:EtOAc 1:3) gave resorcylate 14 (43.5
This synthetic methodology was extended to the unsym-
metrical macrolactone 15G256ꢀ (1). Acid 35 and alcohol 28
were esterified under Yamaguchi conditions to give the pen-
taester 37 (71%) (Scheme 6). Subsequent deallylation, desily-
lation, and intramolecular macrolactonization gave lactone 38
(22) The triketo-esters 13 or 29 were used directly as a crude material as
indicated in the experimental procedure. All attempts to purify the
product by chromatography were unsuccessful. The consumption of
the starting material was monitored by TLC and 1H NMR.
(21) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
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A R T I C L E S
Navarro et al.
Scheme 5. Synthesis of 15G256π (3) and 15G256ι (2)
Scheme 6. Synthesis of 15G256ꢀ (1)
J ) 2.6 Hz, 1H), 6.21 (d, J ) 2.6 Hz, 1H), 5.68 (br s, 1H),
5.67-5.51 (m, 1H), 5.18-5.07 (m, 1H), 4.30-4.18 (m, 1H), 3.69
(s, 3H), 3.26 (dd, J ) 13.5, 4.2 Hz, 1H), 2.91 (dd, J ) 13.5, 9.1
Hz, 1H), 2.81 (dd, J ) 15.5, 7.1 Hz, 1H), 2.68 (dd, J ) 15.5, 5.7
Hz, 1H), 2.48 (dd, J ) 14.6, 5.0 Hz, 1H), 2.30 (dd, J ) 14.6, 7.9
Hz, 1H), 1.47 (d, J ) 6.1 Hz, 3H), 1.27 (d, J ) 6.1 Hz, 3H), 1.13
(d, J ) 6.1 Hz, 3H), 1.02 (m, 21H);13C NMR (100 MHz, CDCl3)
δ 170.9, 170.5, 170.1, 165.5, 160.3, 142.8, 112.4, 105.2, 102.3,
71.1, 68.9, 65.6, 51.9, 45.2, 42.3, 40.4, 23.6, 20.2, 19.8, 18.0 (6
C), 12.2 (3C); MS (ESI) m/z 555 [M + H]+; HRMS (ESI) calcd
C28H47O9Si: [M + H]+, 555.2989; found: [M + H]+, 555.2991.
Anal. Calcd for C28H46O9Si: C, 60.62; H, 8.36. Found: C, 60.58;
H, 8.41.
(R)-4-(Allyloxy)-4-oxobutan-2-yl 2,4-Dihydroxy-6-((R)-2-(tri-
isopropylsilyloxy)propyl)benzoate (30). Dione 22 (1000 mg, 2.34
mmol) and alcohol 28 (360 mg, 2.5 mmol) in PhMe (15 mL) were
heated at reflux for 1.5 h. After rotary evaporation, the residue was
dissolved in CH2Cl2 and iso-PrOH (1.5:1; 400 mL).22 K2CO3 (5 g,
36 mmol) was added, and the mixture was stirred at room
temperature for 3 h. The solution was acidified to pH 2 with HCl
in MeOH (1.25 M; 100 mL, 125 mmol) and stirred for an additional
1 h. The reaction mixture was filtered, diluted with CH2Cl2 (250
mL), and washed with H2O and brine, and the organic layer was
dried (MgSO4). Rotary evaporation and chromatography (hexanes:
EtOAc 4:1) gave resorcylate 30 (811 mg, 70%):23 Rf 0.83 (hexanes:
EtOAc 7:3); [R]D -84.1 (c 0.6 CHCl3); IR (KBr) 3403, 1741, 1648,
25
mg, 82%) as a colorless oil: Rf 0.43 (EtOAc:hexanes 1:3); [R]D
+16.1 (c 15.3 CH2Cl2); IR (film) 3371 (br), 1644, 1260 cm-1; 1H
NMR (400 MHz, CDCl3) δ 11.71 (s, 1H), 6.93 (dd, J ) 1.6, 15.4
Hz, 1H), 6.31 (d, J ) 2.6 Hz, 1H), 6.33 (d, J ) 2.6 Hz, 1H),
5.91-5.70 (m, 3H), 5.19-5.12 (m, 1H), 5.00 (d, J ) 17.2 Hz,
1H), 4.81 (d, J ) 10.3 Hz, 1H), 2.47-2.41 (m, 4H), 2.04 (q, J )
7.2 Hz, 2H), 1.83 (dd, J ) 6.6, 1.6 Hz, 3H), 1.71-1.65 (m, 6H),
1.38 (d, J ) 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.9,
170.8, 164.7, 160.5, 144.4, 137.8, 132.4, 127.0, 115.3, 108.4, 104.2,
102.1, 72.2, 42.3, 41.9, 35.3, 33.0, 22.8, 19.9, 19.3, 18.4; MS (CI)
m/z 361 [M + H]+; HRMS (CI) calcd for C21H29O5: [M + H]+,
361.1937; found: [M + H]+, 361.1956. Anal. Calcd for C21H28O5:
C, 69.98; H, 7.83. Found: C, 69.96; H, 7.92.
(R)-4-Methoxy-4-oxobutan-2-yl 2,4-Dihydroxy-6-((R)-2-methyl-
4-oxo-4-((R)-1-(triisopropylsilyloxy)ethoxy)butyl)benzoate (27). Di-
oxinone 26 (20 mg, 0.040 mmol) and alcohol 23 (5.6 mg, 0.048
mmol) in PhMe (2.4 mL) were heated at reflux for 1.5 h. After
rotary evaporation, the residue was dissolved in CH2Cl2 and iso-
PrOH (1.5:1; 6.4 mL). K2CO3 (120 mg, 0.87 mmol) was added,
and the mixture was vigorously stirred at room temperature for
1 h. The solution was acidified to pH 2 with HCl in MeOH (1.25
M; 2.5 mL, 3.1 mmol) and stirred for an additional 45 min. The
reaction mixture was poured into H2O (10 mL) and extracted with
CH2Cl2 (2 × 15 mL). The combined organic layers were washed
with brine and dried (MgSO4). Rotary evaporation and chroma-
tography (hexanes:EtOAc 4:1) gave resorcylate 27 (15.0 mg, 70%)
as a yellow oil: Rf 0.83 (hexanes:EtOAc 7:3); [R]D -31.1 (c 1.33
CHCl3); IR (KBr) 3385, 1736, 1469, 1620, 1450, 1312, 1257, 1194,
1100 cm-1; 1H NMR (CDCl3, 400 MHz) δ 11.65 (s, 1H), 6.28 (d,
(23) In some experiments, traces of the transesterification product with
methanol were detected. To circumvent this problem, trifluoroacetic
acid was used instead of methanolic HCl. Alternatively, filtration and
evaporation of the solvent after the K2CO3 treatment of 29 gave a
crude aldol product, which was aromatized using TFA (1 equiv) in
chloroform.
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1619, 1450, 1311, 1257, 1189 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 11.62 (s, 1H), 6.29 (d, J ) 2.6 Hz, 1H), 6.27 (d, J ) 2.6 Hz,
1H), 5.95-5.80 (m, 1H), 5.65-5.55 (m, 1H), 5.29 (d, J ) 15.9
Hz, 1H), 5.21 (d, J ) 9.8 Hz, 1H), 5.11 (s, 1H), 4.58 (d, J ) 6.0
Hz, 2H), 4.24-4.14 (m, 1H), 3.34 (dd, J ) 13.2, 3.2 Hz, 1H),
2.80 (dd, J ) 15.6, 7.3 Hz, 1H), 2.68 (dd, J ) 15.6, 5.6 Hz, 1H),
2.57 (dd, J ) 13.2, 9.0 Hz, 1H), 1.44 (d, J ) 6.1 Hz, 3H), 1.25 (d,
J ) 6.1 Hz, 3H), 0.92 (m, 21H);13C NMR (75 MHz, CDCl3) δ
170.4, 169.7, 165.4, 159.9, 145.0, 131.5, 118.9, 113.5, 105.2, 101.7,
69.5, 68.5, 65.6, 46.5, 40.8, 24.6, 19.9, 18.0 (3C), 17.9 (3C), 12.5
(3C). MS (ESI) m/z 495 [M + H]+; HRMS (ESI) calcd C26H43O7Si:
[M + H]+, 495.2778; found: [M + H]+, 495.2776. Anal. Calcd
for C26H42O7Si: C, 61.13; H, 8.56. Found: C, 61.23; H, 8.66.
(R)-4-(Allyloxy)-4-oxobutan-2-yl 2,4-Bis(benzyloxy)-6-((R)-2-
(triisopropylsilyloxy)propyl)benzoate (31). Cs2CO3 (140 mg, 0.43
mmol) and BnBr (86 µL, 0.69 mmol) were added to diphenol 30
(85 mg, 0.172 mmol in DMF (1.5 mL) at 0 °C, the mixture was
allowed to warm up to room temperature, and, after 1 h, saturated
aqueous NH4Cl (4 mL) was added. The mixture was diluted with
Et2O (25 mL), subsequently washed with aqueous HCl (1 M; 2 ×
10 mL), saturated aqueous NaHCO3 (2 × 10 mL), and brine, and
dried (MgSO4). Rotary evaporation and chromatography (hexanes:
EtOAc 9:1) gave diether 31 (106 mg, 92%) as a pale yellow oil:
[R]D -21.0 (c 0.53 CHCl3); IR (KBr) 1739, 1602, 1454, 1380, 1268,
1160, 1093, 1056 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.42-7.26
(m, 10H), 6.50 (s, 1H), 6.44 (s, 1H), 5.92-5.80 (m, 1H), 5.52-5.41
(m, 1H), 5.28 (d, J ) 15.9 Hz, 1H), 5.21 (d, J ) 9.8 Hz, 1H), 5.01
(bs, 4H), 4.56 (d, J ) 6.0 Hz, 2H), 4.22-4.12 (m, 1H), 2.81 (dd,
J ) 13.5, 6.1 Hz, 1H), 2.73 (dd, J ) 15.8, 6.2 Hz, 1H), 2.66 (dd,
J ) 13.5, 6.7 Hz, 1H), 2.44 (dd, J ) 15.8, 7.2 Hz, 1H), 1.27 (d, J
) 6.1 Hz, 3H), 1.09 (d, J ) 6.1 Hz, 3H), 1.03 (m, 21H); 13C NMR
(75 MHz, CDCl3) δ 169.7, 167.3, 159.9, 156.9, 139.1, 136.5, 136.4,
131.9, [128.6, 128.4, 128.0, 127.9, 127.4] (10C), 118.3, 117.8,
108.4, 98.6, 70.4, 70.0, 69.2, 68.0, 65.2, 43.5, 40.5, 23.4, 19.6, 18.1
(3C), 18.0 (3C), 12.4 (3C). MS (ESI) m/z 675 [M + H]+; HRMS
(ESI) calcd C40H55O7Si: [M + H]+, 675.3708; found: [M + H]+,
675.3717. Anal. Calcd for C40H54O7Si: C, 71.18; H, 8.06. Found:
C, 71.24; H, 7.97.
(R)-4-(Allyloxy)-4-oxobutan-2-yl 2,4-Bis(benzyloxy)-6-((R)-2-
hydroxypropyl)benzoate (32). HF·pyridine (0.2 mL) was added
with stirring to ether 31 (20 mg, 0.03 mmol) in THF and pyridine
(4:1; 2 mL) at 0 °C. The mixture was allowed to warm up to room
temperature and, after 12 h stirring, poured into H2O and EtOAc
(1:1; 30 mL), and the solution was basified to pH 6 with K2CO3.
The organic layer was washed with H2O and brine and dried
(MgSO4). Rotary evaporation gave alcohol 32 (13 mg, 85%) as an
oil, which was used in the next step without further purification.24
Chromatography (hexanes:AcOEt 9:1) gave a sample of 32: 1H
NMR (CDCl3, 300 MHz) δ 7.43-7.29 (m, 10H), 6.47 (s, 1H), 6.45
(s, 1H), 5.94-5.82 (m, 1H), 5.55-5.45 (m, 1H), 5.29 (d, J ) 15.9
Hz, 1H), 5.22 (d, J ) 9.8 Hz, 1H), 5.02 (d, J ) 11.7 Hz, 4H), 4.56
(d, J ) 5.8 Hz, 2H), 3.92-4.02 (m, 1H), 2.76-2.62 (m, 6H), 2.50
(dd, J ) 15.8, 7.2 Hz, 1H), 1.24 (d, J ) 6.1 Hz, 3H), 1.22 (d, J )
6.1 Hz, 3H).
7:3); [R]D -17.5 (c 1.0 CHCl3); IR (KBr) 1716, 1602, 1456, 1270,
1160, 1093, 1058 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.42-7.28
(m, 10H), 6.49 (s, 1H), 6.44 (s, 1H), 5.48-5.36 (m, 1H), 5.01 (d,
J ) 4.3 Hz, 4H), 4.22-4.12 (m, 1H), 2.81 (dd, J ) 13.5, 6.1 Hz,
1H), 2.69 (dd, J ) 15.8, 6.2 Hz, 1H), 2.66 (dd, J ) 13.5, 6.7 Hz,
1H), 2.44 (dd, J ) 15.8, 7.2 Hz, 1H), 1.28 (d, J ) 6.1 Hz, 3H),
1.10 (d, J ) 6.1 Hz, 3H), 1.02 (m, 21H); 13C NMR (75 MHz,
CDCl3) δ 174.4, 167.3, 159.9, 156.9, 139.2, 136.5, 136.3, 128.6
(2C), 128.4 (2C), 128.0 (2C), 127.9 (2C), 127.4 (2C), 117.6, 108.5,
98.6, 70.4, 70.0, 69.2, 67.7, 43.5, 40.1, 23.4, 19.5, 18.1(3C), 18.0
(3C), 12.4 (3C); MS (ESI) m/z 635 [M + H]+; HRMS (ESI) calcd
C37H51O7Si: [M + H]+, 635.3419; found: [M + H]+, 635.3404.
Anal. Calcd for C37H50O7Si: C, 70.00; H, 7.94. Found: C, 69.98;
H, 8.03.
(R)-4-(Allyloxy)-4-oxobutan-2-yl 2,4-Bis(benzyloxy)-6-((R)-2-
((R)-3-(2,4-bis(benzyloxy)-6-((R)-2-(triisopropylsilyloxy)propyl)-
benzoyloxy)butanoyloxy)propyl)benzoate (34). 2,4,6-Trichlo-
robenzoyl chloride (8 µL, 0.054 mmol) was added with stirring to
acid 33 (15 mg, 0.024 mmol) and iso-Pr2NEt (24 µL, 0.14 mmol)
in PhMe (0.9 mL) at 0 °C. After 30 min, alcohol 32 (15 mg, 0.029
mmol) and DMAP (6 mg, 0.054 mmol) in PhMe (0.5 mL) were
added, giving a white precipitate. The mixture was allowed to warm
up to room temperature, after 30 min stirring, poured into EtOAc
(15 mL), washed with 1 M HCl and brine, and dried (MgSO4).
Rotary evaporation and chromatography (CH2Cl2:MeOH 19:1) gave
tetraester 34 (24 mg, 86%) as a yellow oil: Rf 0.75 (hexanes:EtOAc
7:3); [R]D -21.4 (c 4.80 CHCl3); IR (KBr) 1731, 1602, 1456, 1378,
1270, 1160, 1093, 1054, 736 cm-1;1H NMR (CDCl3, 300 MHz) δ
7.42-7.26 (m, 20H), 6.50 (s, 1H), 6.44 (m, 2H), 6.41 (s, 1H),
5.92-5.80 (m, 1H), 5.52-5.42 (m, 1H), 5.44-5.34 (m, 1H), 5.28
(d, J ) 15.9 Hz, 1H), 5.20 (d, J ) 9.8 Hz, 1H), 5.13-5.03 (m,
1H), 5.01 (bs, 8H), 4.55 (d, J ) 6.0 Hz, 2H), 4.22-4.12 (m, 1H),
2.90 (dd, J ) 13.8, 6.7 Hz, 1H), 2.86-2.52 (m, 5H), 2.45 (dd, J )
15.9, 6.7 Hz, 1H), 2.35 (dd, J ) 15.3, 8.3 Hz, 1H), 1.27 (d, J )
6.1 Hz, 3H), 1.21 (d, J ) 6.1 Hz, 3H), 1.17 (d, J ) 6.1 Hz, 3H),
1.09 (d, J ) 6.1 Hz, 3H), 1.03 (m, 21H); 13C NMR (75 MHz,
CDCl3) δ 169.8, 169.3, 167.2, 167.0, 160.2, 159.8, 157.1, 156.9,
139.1, 137.6, 136.5, 136.4 (2C), 136.3, 131.9, [128.5, 128.4, 128.0,
127.9, 127.9, 127.5, 127.4, 127.3] (20C), 118.3, 117.8, 117.6, 108.5,
107.7, 99.1, 98.6, 71.4, 70.4, 70.3, 70.1, 69.9, 69.2, 68.2, 68.1, 65.2,
43.6, 40.9, 40.4, 39.2, 23.4, 19.6, 19.4 (2C), 18.1 (3C), 18.0 (3C),
12.4 (3C). MS (ESI) m/z 1135 [M + H]+; HRMS (ESI) calcd
C68H83O13Si: [M + H]+, 1135.5613; found: [M + H]+, 1135.5603.
Anal. Calcd for C68H82O13Si: C, 71.93; H, 7.28. Found: C, 71.87;
H, 7.27.
(R)-3-(2,4-Bis(benzyloxy)-6-((R)-2-((R)-3-(2,4-bis(benzyloxy)-6-
((R)-2-(triisopropylsilyloxy)propyl)benzoyloxy)butanoyloxy)pro-
pyl)benzoyloxy)butanoic Acid (35). Morpholine (4 µL, 0.044
mmol) and Pd(PPh3)4 (3 mg, 0.002 mmol) in THF (0.1 mL) were
added with stirring to tetraester 34 (25 mg, 0.022 mmol) in THF
(0.8 mL) at 0 °C. The mixture was allowed to warm up to room
temperature, and, after 30 min stirring, the reaction was quenched
with saturated aqueous NH4Cl (0.8 mL). The mixture was poured
into H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine and dried
(MgSO4). Rotary evaporation and chromatography (CH2Cl2:MeOH
9:1) gave acid 35 (21 mg, 87%) as an amorphous solid: Rf 0.30
(hexanes:EtOAc 7:3); [R]D -19.8 (c 7.5 CHCl3); IR (KBr) 3100,
1725, 1602, 1545, 1434, 1378, 1272, 1162, 1093, 1054 cm-1;1H
NMR (CDCl3, 300 MHz) δ 7.42-7.26 (m, 20H), 6.50 (d, J ) 1
Hz, 1H), 6.45 (d, J ) 1 Hz, 1H), 6.42 (d, J ) 1 Hz, 1H), 6.41 (d,
J ) 1 Hz, 1H), 5.54-5.40 (m, 2H), 5.12-5.05 (m, 1H), 5.05-4.94
(bs, 8H), 4.24-4.14 (m, 1H), 2.92 (dd, J ) 13.8, 7.2 Hz, 1H),
2.84-2.74 (m, 2H), 2.73-2.62 (m, 3H), 2.48 (dd, J ) 16.1, 5.3
Hz, 1H), 2.36 (dd, J ) 15.2, 8.0 Hz, 1H), 1.26 (d, J ) 6.1 Hz,
3H), 1.20 (d, J ) 6.1 Hz, 3H), 1.17 (d, J ) 6.1 Hz, 3H), 1.10 (d,
J ) 6.1 Hz, 3H), 1.03 (m, 21H); 13C NMR (75 MHz, CDCl3) δ
173.4, 169.6, 167.5, 167.0, 160.2, 159.9, 157.2, 157.0, 139.2, 137.6,
136.5, 136.4 (2C), 136.2, [128.5, 128.4, 128.0, 128.0, 127.9, 127.4,
(R)-3-(2,4-Bis(benzyloxy)-6-(()-2-(triisopropylsilyloxy)propyl)-
benzoyloxy)butanoic Acid (33). Morpholine (7 µL, 0.08 mmol)
and Pd(PPh3)4 (4.5 mg, 0.004 mmol) in THF (0.1 mL) were added
with stirring to diester 31 (26 mg, 0.04 mmol) in THF (0.8 mL) at
0 °C. The mixture was allowed to warm up to room temperature,
and, after 30 min stirring, the reaction mixture was quenched with
saturated aqueous NH4Cl (0.8 mL). The mixture was poured into
H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine and dried (MgSO4). Rotary
evaporation and chromatography (CH2Cl2:MeOH 19:1) gave acid
33 (23 mg, 93%) as an amorphous solid: Rf 0.30 (hexanes:EtOAc
(24) All attempts to purify the product by chromatography were unsuc-
cessful, giving a less pure material as a result of lactonization to
provide the corresponding isocumarin.
9
J. AM. CHEM. SOC. VOL. 130, NO. 31, 2008 10297

A R T I C L E S
Navarro et al.
127.3] (20C), 117.5 (2C), 108.5, 107.8, 99.1, 98.7, 71.7, 70.4, 70.3,
70.0, 69.9, 69.2, 68.3, 68.1, 43.6, 41.1, 40.1, 39.1, 23.4, 19.6, 19.5,
19.4, 18.1 (3C), 18.0 (3C), 12.4 (3C). MS (ESI) m/z 1095 [M +
H]+; HRMS (ESI) calcd C65H79O13Si: [M + H]+, 1095.5290;
found: [M + H]+, 1095.5305. Anal. Calcd for C65H78O13Si: C,
71.27; H, 7.18. Found: C, 71.31; H, 7.10.
EtOAc (15 mL) and washed with 1 M HCl and brine and dried
(MgSO4). Rotary evaporation and chromatography (hexanes:EtOAc
4:1) gave macrolactone 38 (32.5 mg, 65% from 37) as a yellow
oil: Rf 0.75 (hexanes:EtOAc 7:3); [R]D -28 (c 0.4, CHCl3); IR
(KBr) 1733, 1604, 1454, 1380, 1270, 1162, 1095, 1052, 738
cm-1;1H NMR (CDCl3, 300 MHz) δ 7.40-7.28 (m, 20H), 6.43
(d, J ) 1 Hz, 1H), 6.42 (d, J ) 1 Hz, 1H), 6.35 (d, J ) 1 Hz, 1H),
6.32 (d, J ) 1 Hz, 1H), 5.57-5.48 (m, 2H), 5.30-5.21 (m, 1H),
5.05-4.85 (m, 10H), 2.88 (d, J ) 7.2 Hz, 2H), 2.72-2.38 (m,
8H), 1.33-1.24 (m, 12 H), 1.22 (d, J ) 6.2 Hz, 3H).13C NMR (75
MHz, CDCl3) δ 169.5, 169.4, 169.3, 167.3, 166.9, 160.0, 159.8,
156.9, 156.8, 137.5, 137.1, 136.5, 136.3, 136.3(2C), [128.6, 128.5,
128.3, 128.1, 128.0, 127.9, 127.8, 127.4, 127.4, 127.2] (20C), 118.2,
118.0, 108.2 (2C), 99.0, 98.5, 71.9, 71.2, 70.4, 70.3, 70.1, 70.0,
68.4, 67.9, 67.7, 41.0, 40.9, 40.3, 38.9, 38.8, 19.7, 19.4, 18.8 (3C);
MS (ESI) m/z 1007 [M + H]+; HRMS (ESI) calcd C60H63O14: [M
+ H]+, 1007.4218; found: [M + H]+, 1007.4247. Anal. Calcd for
C60H62O14: C, 71.55; H, 6.21. Found: C, 71.48; H, 6.15.
(R)-4-((R)-4-(Allyloxy)-4-oxobutan-2-yloxy)-4-oxobutan-2-yl 2,4-
Bis(benzyloxy)-6-((R)-2-((R)-3-(2,4-bis(benzyloxy)-6-((R)-2-(triiso-
propylsilyloxy)propyl)benzoyloxy)butanoyloxy)propyl)benzoate
(37). 2,4,6-Trichlorobenzoyl chloride (16 µL, 0.108 mmol) was
added with stirring to acid 35 (60 mg, 0.055 mmol) and iso-Pr2NEt
(56 µL, 0.33 mmol) in PhMe (1.9 mL) at 0 °C. After 30 min,
alcohol 28 (13 mg, 0.090 mmol) and DMAP (12 mg, 0.108 mmol)
in PhMe (0.9 mL) was added, giving a white precipitate. The
mixture was allowed to warm up to room temperature, after 30
min stirring, poured into EtOAc (20 mL), washed with HCl 1 M
and brine, and dried (MgSO4). Rotary evaporation and chroma-
tography (hexanes:AcOEt 4:1) gave pentaester 37 (48 mg, 71%)
as a yellow oil: Rf 0.70 (hexanes:EtOAc 7:3); [R]D -20.0 (c 3.25,
CHCl3); IR (KBr) 1737, 1602, 1454, 1380, 1272, 1162, 1093, 1054,
738 cm-1;1H NMR (CDCl3, 300 MHz) δ 7.50-7.26 (m, 20H),
6.49 (d, J ) 1.0 Hz 1H), 6.44 (s, 2H), 6.41 (s, 1H), 5.92-5.81 (m,
1H), 5.49-5.34 (m, 2H), 5.32-5.18 (m, 3H), 5.13-5.05 (m, 1H),
5.00 (d, J ) 3.0 Hz, 4H), 4.97 (d, J ) 3.0 Hz, 4H), 4.54 (d, J )
6.0 Hz, 2H), 4.23-4.14 (m, 1H), 2.90 (dd, J ) 13.9, 6.9 Hz, 1H),
2.83-2.60 (m, 6H), 2.48 (dd, J ) 15.6, 6.0 Hz, 1H), 2.38 (dd, J )
11.9, 7.9 Hz, 1H), 2.34 (dd, J ) 11.9, 7.9 Hz, 1H), 1.27 (d, J )
6.1 Hz, 3H), 1.26 (d, J ) 6.1 Hz, 3H), 1.20 (d, J ) 6.1 Hz, 3H),
1.17 (d, J ) 6.1 Hz, 3H), 1.09 (d, J ) 6.1 Hz, 3H), 1.03 (m, 21H);
13C NMR (75 MHz, CDCl3) δ 169.7, 169.3, 169.2, 167.2, 166.9,
160.2, 159.8, 157.1, 156.9, 139.1, 137.6, 136.5, 136.3(2C), 136.2,
131.8, [128.5, 128.4, 128.0, 127.9, 127.8, 127.5, 127.4, 127.3]
(20C), 118.5, 117.7, 117.5, 108.5, 107.6, 99.0, 98.6, 71.4, 70.4,
70.3, 70.0, 69.9, 69.2, 68.1 (2C), 67.5, 65.2, 43.6, 40.9, 40.7, 40.5,
39.2, 23.4, 19.7, 19.4 (3C), 18.1 (3C), 18.0 (3C), 12.4 (3C); MS
(ESI) m/z 1221 [M + H]+; HRMS (ESI) calcd C72H89O15Si: [M +
H]+, 1221.5971; found: [M + H]+, 1221.5968. Anal. Calcd for
C72H88O15Si: C, 70.79; H, 7.26. Found: C, 70.90; H, 7.16.
(7R,11R,15R,23R,27R)-2,4,18,20-Tetrakis(benzyloxy)-
7,11,15,23,27-pentamethyl-7,8,11,12,15,16,23,24,27,28-decahydro-
5H-dibenzo[k,u][1,5,9,15,19]pentaoxacyclotetracosine-5,9,13,21,25-
pentaone (38). Morpholine (10 µL, 0.051 mmol) and Pd(PPh3)4
(8 mg, 0.007 mmol) in THF (0.15 mL) were added with stirring to
pentaester 37 (60 mg, 0.049 mmol) in THF (1.0 mL) at 0 °C. The
mixture was allowed to warm up to room temperature, and, after
30 min stirring, the reaction was quenched with saturated aqueous
NH4Cl (0.9 mL). The mixture was poured into H2O (5 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with brine and dried (MgSO4). Rotary evaporation
gave the crude carboxylic acid, which was used in the next step
without further purification. HF ·pyridine (0.3 mL) was added with
stirring to the crude carboxylic acid in THF and pyridine (4:1; 3
mL) at 0 °C. The mixture was allowed to warm up to room
temperature and, after 12 h stirring, poured into H2O and EtOAc
(1:1; 30 mL), and the solution was basified to pH 6 with K2CO3.
The organic layer was washed with H2O and brine and dried
(MgSO4). Rotary evaporation gave crude hydroxy acid as a yellow
oil, which was used in the next step without further purification.
2,4,6-Trichlorobenzoyl chloride (9 µL, 0.060 mmol) was added with
stirring to crude hydroxy acid and iso-Pr2NEt (47 µL, 0.22 mmol)
in PhMe (1.5 mL) at 0 °C. After 30 min, the mixture was diluted
with PhMe (2.0 mL) and added dropwise over 1 h to a solution of
DMAP (11 mg, 0.092 mmol) in PhMe (1.0 mL), giving a white
precipitate. After 30 min stirring, the mixture was poured into
(7R,11R,15R,23R,27R)-2,4,18,20-Tetrahydroxy-7,11,15,23,27-
pentamethyl-7,8,11,12,15,16,23,24,27,28-decahydro-5H-
dibenzo[k,u][1,5,9,15,19]pentaoxacyclotetracosine-5,9,13,21,25-
pentaone (15G256ꢀ) (1). Pd/C (10%, 25 mg) was added to
macrolactone 38 (20 mg, 0.020 mmol) in EtOAc (4 mL). After
12 h stirring under H2, the mixture was filtered through celite, rotary
evaporated, and chromatographed (hexanes:EtOAc 4:1) to give
15G256ꢀ (1) (11 mg, 85%) as a white amorphous solid whose
analytical properties were identical to those described for the natural
product: Rf 0.40 (hexanes:EtOAc 7:3); [R]D -21.0 (c 0.23 MeOH);
IR (KBr) 3384, 1733, 1648, 1619, 1450, 1384, 1313, 1094, 1189,
1054 cm-1; 1H NMR (CD3OD, 300 MHz) δ 6.23 (d, J ) 5.3 Hz,
2H), 6.20 (s, J ) 5.3 Hz, 2H), 5.55-5.45 (m, 2H), 5.30-5.20 (m,
1H), 5.05-4.95 (m, 2H), 3.45 (dd, J ) 13.2, 6.2 Hz, 1H), 3.34
(dd, J ) 13.3, 6.5 Hz, 1H), 2.89 (d, J ) 13.5, 7.7 Hz, 1H), 2.84
(dd, J ) 11.2, 7.9 Hz, 1H), 2.80 (dd, J ) 11.5, 7.4 Hz, 1H), 2.75
(dd, J ) 13.5, 8.3 Hz, 1H), 2.71-2.55 (m, 4H), 1.40 (d, J ) 6.2
Hz, 3H), 1.39 (d, J ) 6.2 Hz, 3H), 1.23 (d, J ) 6.3 Hz, 3H), 1.16
(d, J ) 6.1 Hz, 3H), 1.12 (d, J ) 6.3 Hz, 3H).13C NMR (75 MHz,
CD3OD) δ 171.4, 171.2, 171.2 (2C), 171.0, 165.5, 165.0, 163.5,
163.3, 143.2, 142.9, 113.2, 112.7, 107.3, 106.5, 102.8, 102.7, 73.8,
73.3, 70.2, 70.1, 69.1, 42.5, 41.9, 41.5, 41.4, 41.1, 20.2, 20.1, 19.9,
19.7, 19.6. MS (ESI) m/z 647 [M + H]+; HRMS (ESI): calcd
C32H39O14: [M + H]+, 647.2340, found: [M + H]+, 647.2341.
Acknowledgment. We thank GlaxoSmithKline for the generous
endowment (to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society Wolfson Research Merit Award
(to A.G.M.B.), the Novartis Institutes for BioMedical Research for
a Novartis Graduate Fellowship in Organic Chemistry (S.M.), the
EPSRC, the EU for Marie-Curie Human Mobility Intra-European
Fellowships (I.N. and H.S.), the DFG for a Research Fellowship
(T.W.), and Steven R. Lenger and Simon R. Linke (Astra Zeneca)
for determining ee values. We especially thank Dr. Gerhard
Schlingmann (Wyeth Research) for authenticating our synthetic
samples of 15G256ι (2) and 15G256ꢀ (1) by comparison with
samples of the natural products.
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of 1H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA803445U
9
10298 J. AM. CHEM. SOC. VOL. 130, NO. 31, 2008