Total synthesis of citrafungin A

Article abstract of DOI:10.1021/jo801708q

(Chemical Equation Presented) The antifungal natural product citrafungin A was synthesized using, as key steps, an asymmetric aldol reaction of a chiral oxazolidinone, diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, semihydrogenation of an enyne, and selective methyl ester deprotection.

Full text of DOI:10.1021/jo801708q

Total Synthesis of Citrafungin A
Frederick Calo,† Jeffery Richardson,‡ and Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, England, and
Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, England
agm.barrett@imperial.ac.uk
ReceiVed August 12, 2008
The antifungal natural product citrafungin A was synthesized using, as key steps, an asymmetric aldol
reaction of a chiral oxazolidinone, diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, semihy-
drogenation of an enyne, and selective methyl ester deprotection.
SCHEME 1. Key Steps in the Hatakeyama Total Synthesis
of Citrafungin A (1)a
Introduction
In 2004, the Rahway Merck group reported the isolation and
structural determination of two novel alkyl citrate natural
products, citrafungin A (1) and citrafungin B (2) (Figure 1),
from the fermentation broth of an Alaskan coprophilous fungus.1
These compounds are potent inhibitors of fungal geranylgera-
nyltransferase I (GGTase I) enzymes, which catalyze the transfer
of a terpene side chain to a cysteine residue of the proteins
Rho1p and Cdc42p, thereby promoting their membrane localiza-
tion and biological activity. Rho1p is a regulatory subunit of
the crucial enzyme 1,3-ꢀ-D-glucan synthase, which is involved
in fungal cell wall biosynthesis. Since there are only low levels
of homology between fungal and human GGTase I, inhibition
of the fungal enzyme is likely to provide novel fungicidal agents
of low toxicity. Citrafungin A (1) inhibits a range of fungal
pathogens including strains of Candida albicans, Candida
neoformans and Aspergillus fumigatus with MIC values of
0.4-13 µM. It is clear from these results that the citrafungins
are intriguing hit structures for the development of new classes
of antifungal drugs.
a Reagents and conditions: (a) LDA, THF, HMPA, -78 °C; 6; (b) DDQ,
CH2Cl2, H2O.
strategy in their synthesis of citrafungin A (1) by using the aldol
reaction between R-ketoester 6 and the lithium enolate of lactone
3 as the key step (Scheme 1). This reaction led to a mixture of
four diastereoisomers (44:24:16:16), in favor of desired lactone,
which were only separable after deprotection of the p-meth-
oxybenzyl group. In the late stages of the synthesis, the Japanese
group used the Keck esterification4 to introduce the isocitrate
unit.
The Hatakeyama group recently reported the first total
synthesis of citrafungin A (1).2 Having successfully accom-
plished the total synthesis of (()-trachyspic acid3 and thereby
determining its relative stereochemistry, they applied the same
* To whom correspondence should be addressed. Phone: +44-207-594-5766.
Fax: +44-207-594-5805.
† Imperial College London.
‡ Eli Lilly and Company Limited.
(1) Singh, S. B.; Zink, D. L.; Doss, G. A.; Polishook, J. D.; Ruby, C.; Register,
E.; Kelly, T. M.; Bonfiglio, C.; Williamson, J. M.; Kelly, R. Org. Lett. 2004, 6,
337–340.
(2) Amer, M. F. A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Heterocycles
2007, 72, 181–185.
(3) Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2003, 5, 857–859.
(4) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
(5) Bryan, D. B.; Hall, R. F.; Holden, K. G.; Huffman, W. F.; Gleason, J. G.
J. Am. Chem. Soc. 1977, 99, 2353–2355.
9692 J. Org. Chem. 2008, 73, 9692–9697
10.1021/jo801708q CCC: $40.75 2008 American Chemical Society
Published on Web 10/04/2008

Total Synthesis of Citrafungin A
SCHEME 3. Synthesis of Dioxolanone 13a
FIGURE 1. Structures of citrafungins A and B.
SCHEME 2. Proposed Retrosynthesis
a Reagents and Conditions: (a) (i) EtOCOCl, Et3N, Et2O; (ii) n-BuLi
and (R)-4-benzyl-2-oxazolidinone; (b) n-Bu2BOTf, Et3N, CH2Cl2, -78 °C;
CH2dCHCHO, CH2Cl2, -78 to 0 °C; (c) Ac2O, Et3N, 4-DMAP, Et2O; (d)
O3, DMS, CH2Cl2, -78 °C; (e) NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH, THF, H2O (1:1:1); (f) LiOH, H2O2, THF, H2O (1:1); (g) tBuCHO,
p-TsOH, n-hexane, THF (10:1).
Results and Discussion
Commercially available 4-benzyloxybutyric acid 16 was
converted into the acyl-oxazolidinone 15 by formation of the
mixed anhydride with ethyl chloroformate followed by reaction
with (R)-4-benzyl-N-lithio-2-oxazolidinone at -78 °C (Scheme
3).9 Evans syn-selective aldol reaction using di-n-butylboron
triflate, triethylamine and propenal gave alcohol 14 in 91% yield
with excellent diastereoselectivity (d.r. > 99%). Sequential
acetylation, ozonolysis10 and Pinnick oxidation of hydroxy-
alkene 14 gave the carboxylic acid 18 in 80% yield over the 3
steps.11 Dual oxazolidinone and acetate hydrolysis using lithium
hydroxide and hydrogen peroxide gave diacid 19, which was
converted into dioxolanone 13 by condensation with excess
pivaldehyde catalyzed with p-toluenesulfonic acid in 80% yield
as a 94:6 mixture in favor of the desired cis-isomer, the structure
1
As part of our studies on alkylcitrate metabolites, we sought
to extend our stereoselective synthesis of the viridiofungins6 to
the related citrafungins. The proposed retrosynthesis is shown
in Scheme 2. Following the Hatakeyama precedent, citrafungin
A (1) should be available from the deprotection of tetraester 7
derived from acid 8 and alcohol 9. In our approach, acid 8
should be available using a late-stage aldehyde 11 and alk-
enylzinc 10 addition-lactonization reaction. In turn, aldehyde
11 should be available from ether 12, which should be prepared
from dioxolanone 13 using a stereoselective Seebach “Self
Reproduction of Stereocenter”7,8 (SRS) enolate alkylation
reaction. The precursor 14 of dioxolanone 13 should be available
using an Evans aldol reaction.9 Herein we report the application
of this approach in a stereoselective total synthesis of citrafungin
A (1).
of which was confirmed by H NOESY NMR.
The alkylation of dioxolanone 13 was carried out by double
deprotonation in dry DMF at -70 °C using lithium hexameth-
yldisilazide followed by alkylation using t-butyl bromoacetate
in DMF solution (Scheme 4).6 Whereas this reaction was
completely diastereoselective in the case of the viridiofungins,
the reaction proceeded with a d.r. > 9:1 with substrate 13.
Selective deprotection of the t-butyl ester in 12 was achieved
using trifluoroacetic acid in dichloromethane and gave diacid
20 (100%). This partial deprotection was essential to prevent
extensive decomposition during the opening of the dioxolanone
ring. Dioxolanone 20 was smoothly opened using benzyl alcohol
and lithium hexamethyldisilazide in toluene to afford, after
diazomethane methylation, ester 21 in 50% yield over the 4
steps. It was found to be crucial to open the dioxolanone at this
stage since it enabled differentiation between the carboxyl
groups in 21. Selective debenzylation of the benzyl ester in the
presence of the benzyl ether was achieved by hydrogenolysis
(6) Goldup, S. M.; Pilkington, C. J.; White, A. J. P.; Burton, A.; Barrett,
A. G. M. J. Org. Chem. 2006, 71, 6185–6191.
(7) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2708–2748.
(8) Sefkow, M. J. Org. Chem. 2001, 66, 2343–2349.
(9) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org.
Chem. 2003, 68, 4215–4234.
(10) VanOrnum, S. G.; Champeau, R. M.; Pariza, R. Chem. ReV. 2006, 106,
2990–3001.
(11) Wipf, P.; Methot, J. L. Org. Lett. 2000, 2, 4213–4216.
J. Org. Chem. Vol. 73, No. 24, 2008 9693

Calo et al.
SCHEME 4. Synthesis of Aldehyde 11a
SCHEME 5. Synthesis of Acid 8a
a
t
Reagents and Conditions: (a) LiN(SiMe3)2, BrCH2CO2 Bu, DMF; (b)
TFA, CH2Cl2; (c) BnOH, LiN(SiMe3)2, PhMe; (d) CH2N2, EtOAc; (e) H2,
Pd/C, THF; (f) 22, CH2Cl2; (g) Me3SiCl, imidazole, CH2Cl2; (h) Dess Martin
periodinane, CH2Cl2.
over palladium on carbon in THF.12 Reprotection of the free
carboxylic acid as the t-butyl ester 23 was carried out using
freshly prepared N,N′-di-isopropyl-O-t-butylisourea (22) in 72%
yield over the 2 steps.13 Sequential trimethylsilylation, benzyl
ether hydrogenolysis (which was slower than the ester 21
hydrogenolysis) and Dess-Martin oxidation14 of 23 gave alde-
hyde 11 which was directly used in the next step.
The citrafungin lipophilic side chain was synthesized using
the Wittig reaction15 of commercially available 1-nonyltriph-
enylphosphonium bromide 25 and 4-pentynal16 26 to afford
alkyne 27 as the cis isomer in 65% yield (Scheme 5). Alkyne
27 hydrozirconation17 using the Schwarz reagent followed by
transmetalation18,19 at low temperature with dimethylzinc gave
selectively the trans organozinc compound 10, which was
directly added at 0 °C to the crude aldehyde 11. Subsequent
acid catalyzed lactonization gave a mixture of the trans-28 and
the cis-29 lactones (1.8:1). During chromatography on silica,
partial cleavage of the trimethylsilyl group occurred but
fortunately the resultant four lactones were separable. Treatment
of either lactone 28 or 29 with acetic acid buffered tetrabuty-
lammonium fluoride20 cleanly gave lactones 30 or 31 respec-
tively in 98% yield. Overall the lactones 30 and 31 were
obtained in 70% yield from 24 in with the major isomer having
the correct trans-stereochemistry (2:1). The stereoselectivity of
a Reagents and Conditions: (a) LiN(SiMe3)2, 4-pentynal, THF; (b)
Cp2ZrHCl, CH2Cl2, 0-20 °C; Me2Zn, -65 °C; 11, 0-20 °C; (c) p-TsOH,
Et2O, reflux; (d) Bu4NF, AcOH, THF; (e) Me3SnOH, ClCH2CH2Cl, 85 °C.
this reaction could be possibly enhanced using Wipf methodol-
ogy18 although such a modification was not investigated. The
structures of lactones 30 and 31 were confirmed by 1H NOESY
1
and H-13C HMBC NMR experiments.
The final step to obtain acid 8 was the selective deprotection
of the methyl ester in presence of a t-butyl ester and a delicate
lactone susceptible to epimerization. All standard saponification
procedures21-24 were indiscriminate giving mixture of acids.
These results may be explained by a neighboring group effect
of the tertiary alcohol leading to partial hydrolysis of the adjacent
t-butyl ester via the R-lactone or Via the combined inductive
effect of the two adjacent carbonyls and hydroxyl groups
enhancing the electrophilicity of the t-butyl ester. Attempted
demethylation using lithium iodide25 or thiophenol and cesium
carbonate26 were too slow or resulted in partial lactone trans
to cis epimerization respectively. However, selective demethy-
lation was achieved using hydroxytrimethylstannane in 1,2-
dichloroethane27 giving acid 8 in 94% yield.
Following the Hatakeyama precedent, alcohol 9 was prepared2
from commercially available (R)-malic acid 32 via ester 33,
which was alkylated with allyl bromide by double deprotonation
(Scheme 6). Sequential acylation, ruthenium oxidation28 and
esterification of 34 gave ester 36 in 72% yield over the 3 steps.
(12) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–
1757.
(13) Burk, R. M.; Berger, G. D.; Bugianesi, R. L.; Girotra, N. N.; Parsons,
W. H.; Ponpipom, M. M. Tetrahedron Lett. 1993, 34, 975–978.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(15) Murakami, T.; Hirono, R.; Furusawa, K. Tetrahedron 2005, 61, 9233–
9241.
(16) Adams, T. C.; Dupont, A. C.; Carter, J. P.; Kachur, J. F.; Guzewska,
M. E.; Rzeszotarski, W. J.; Farmer, S. G.; Noronha-Blob, L.; Kaiser, C. J. Med.
Chem. 1991, 34, 1585–1593.
(17) White, J. D.; Kim, T. S.; Nambu, M. J. Am. Chem. Soc. 1997, 119,
103–111.
(21) Corey, E. J.; Sze´kely, I.; Shiner, C. S. Tetrahedron Lett. 1977, 18, 3529–
3532.
(22) Boger, D. L.; Yohannes, D.; Zhou, J.; Patane, M. A. J. Am. Chem. Soc.
1993, 115, 3420–3430.
(23) Inoue, K.; Sakai, K. Tetrahedron Lett. 1977, 18, 4063–4066.
(24) Honda, M.; Hirata, K.; Sueoka, H.; Katsuki, T.; Yamaguchi, M.
Tetrahedron Lett. 1981, 22, 2679–2682.
(25) Lepage, O.; Kattnig, E.; Furstner, A. J. Am. Chem. Soc. 2004, 126,
15970–15971.
(18) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–6455.
(19) Ichige, T.; Kamimura, S.; Mayumi, K.; Sakamoto, Y.; Terashita, S.;
Ohteki, E.; Kanoh, N.; Nakata, M. Tetrahedron Lett. 2005, 46, 1263–1267.
(20) Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095–13096.
(26) Eren, D.; Keinan, E. J. Am. Chem. Soc. 1988, 110, 4356–4362.
(27) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew.
Chem., Int. Ed. Engl. 2005, 44, 1378–1382.
9694 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Citrafungin A
SCHEME 6. Synthesis of Alcohol 9a
mL, 100 mmol) and Et3N (15 mL, 50.6 mmol) were added with
stirring to oxazolidinone 15 (31.5 g, 89.2 mmol) in CH2Cl2 (600
mL) at -78 °C. After 1 h at -78 °C and 1 h at 0 °C, the mixture
was cooled to -78 °C and freshly distilled CH2dCHCHO (7.8 mL,
116 mmol) was added with stirring. After 1 h at -78 °C and 1 h
at 0 °C, the mixture was poured onto aqueous HCl (1 M; 600 mL),
the phases were separated and the aqueous phase extracted with
CH2Cl2 (2 × 200 mL). The combined organic layers were washed
with brine (500 mL), dried (MgSO4) and rotary evaporated.
Chromatography (hexanes/EtOAc 4:1) gave alcohol 14 (33.2 g,
91%) as a viscous oil: Rf 0.30 (hexanes: Et2O 6: 1); [R]D25 -29 (c
1.0, CHCl3); IR (KBr) 3488, 1778, 1695, 1386, 1351, 1205, 1101,
1
1018, 738, 700 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-7.24
(m, 8H), 7.12-7.10 (m, 2H), 5.88 (m, 1H), 5.33 (dt, J ) 17.2, 1.4
Hz, 1H), 5.21 (dt, J ) 10.6, 1.3 Hz, 1H), 4.60-4.54 (m, 1H), 4.46
(d, J ) 2.6 Hz, 2H), 4.44-4.39 (m, 1H), 4.26 (m, 1H), 4.10 (t, J
) 8.4 Hz, 1H), 4.04 (dd, J ) 9.0, 2.7 Hz, 1H), 3.60 (dd, J ) 5.4,
1.5 Hz, 1H), 3.59 (d, J ) 5.3 Hz, 1H), 3.16 (dd, J ) 13.4, 3.2 Hz,
1H), 2.81 (d, J ) 3.1 Hz, 2H), 2.27-2.17 (m, 1H), 2.09 (dd, J )
13.4, 10.5 Hz, 1H), 2.00-1.93 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 175.0, 153.6, 138.1, 137.3, 135.7, 129.3, 128.8, 128.4,
128.2, 127.7, 127.1, 116.7, 73.6, 73.3, 68.9, 66.0, 55.7, 46.2, 37.2,
28.0; MS (CI) m/z 410 (M + H)+, 427 (M + NH4)+; HRMS (ESI)
calcd for C24H28NO5: (M + H)+, 410.1967, found: (M + H)+,
410.1973.
a Reagents and Conditions: (a) 22, CH2Cl2; (b) LiN(SiMe3)2, allyl
bromide, THF -78 to 0 °C; (c) Ac2O, Et3N, 4-DMAP, Et2O; (d) RuCl3,
NaIO4, CCl4, MeCN, H2O (5:5:8); (e) K2CO3, MeOH.
(R)-2-Acetoxy-(R)-3-((R)-4-benzyl-2-oxo-oxazolidine-3-carbo-
nyl)-5-benzyloxy-pentanoic acid (18). Acetate 17 (33 g, 73.2
mmol) in CH2Cl2 (20 mL) was cooled to -78 °C and a stream of
ozone was bubbled through the mixture until a deep-blue color
persisted. Oxygen was then bubbled through the solution for an
additional 20 min to remove excess of ozone. Me2S (25 mL, 366
mmol) was added at -78 °C, and the solution was allowed to warm
to room temperature. Rotary evaporation gave the crude aldehyde,
which was directly oxidized. Solid NaH2PO4 (44 g, 366 mmol)
and NaClO2 (26.5 g, 293 mmol) were added sequentially with
stirring to aldehyde and 2-methyl-2-butene (116 mL, 1.1 mol) in
t-BuOH, H2O, THF (1:1:1; 600 mL) at 0 °C. The mixture was
allowed to warm to room temperature overnight and quenched by
the addition of saturated aqueous Na2SO3 (600 mL) and saturated
aqueous NH4Cl (200 mL). The mixture was acidified to pH 1 using
aqueous HCl (concd), saturated with NaCl and extracted with
EtOAc (2 × 500 mL). The combined organic layers were washed
with brine (500 mL), dried (MgSO4) and rotary evaporated.
Chromatography (gradient hexanes/EtOAc 1:1; EtOAc/MeOH 4:1
to 7:3) gave carboxylic acid 18 (30 g, 63.8 mmol, 87%) as a
SCHEME 7. Synthesis of Citrafungin A (1)a
a Reagents and Conditions: (a) DCC, DMAP ·HCl, CH2Cl2; (b) TFA,
CH2Cl2.
Hydrolysis of the acetate group with potassium carbonate in
methanol cleanly provided alcohol 9 in 97% yield. The full
experimental procedures for these transformations are provided
in this paper, since they are not reported in the prior Hatakeyama
work.
Again following the Hatakeyama precedent, esterification of
carboxylic acid 8 with alcohol 9 using the Keck’s esterification
procedure4 (Scheme 7) gave pentaester 7 in 50% yield. Global
deprotection using trifluoroacetic acid quantitatively gave cit-
rafungin A (1), which was further purified by HPLC. The sample
showed 1H and 13C NMR data in excellent agreement with those
reported by the Rahway Merck group.1
25
colorless oil: Rf 0.32 (MeOH: CH2Cl2 1: 4); [R]D -59.5 (c 1.0,
MeOH); IR (KBr) 1778, 1751, 1700, 1388, 1213, 1105, 1074, 744,
1
700 cm-1; H NMR (400 MHz, CDCl3) δ 7.32-7.22 (m, 8H),
7.12-7.10 (m, 2H), 5.55 (d, J ) 5.4 Hz, 1H), 4.66-4.46 (m, 2H),
4.52 (d, J ) 11.8 Hz, 1H), 4.45 (d, J ) 11.8 Hz, 1H), 4.16 (t, J )
8.4 Hz, 1H), 4.04 (dd, J ) 9.1, 2.8 Hz, 1H), 3.65-3.54 (m, 2H),
3.14 (dd, J ) 13.4, 3.2 Hz, 1H), 2.38-2.28 (m, 1H), 2.22 (dd, J )
13.3, 10.4 Hz, 1H), 2.13 (s, 3H), 2.07-1.99 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 171.8, 171.5, 169.9, 153.3, 137.8, 135.3,
129.3, 128.8, 128.4, 128.0, 127.7, 127.1, 73.1, 71.2, 67.9, 66.3,
55.6, 42.3, 37.3, 28.0, 20.5; HRMS (ESI) calcd for C25H28NO8:
(M + H)+, 470.1815, found: (M + H)+, 470.1817; Anal. calcd for
C25H27NO8: C, 63.96; H, 5.80; N, 2.98. Found: C, 63.92; H, 5.70;
N, 2.91.
Conclusion
In summary, we report the total synthesis of citrafungin A
using an Evans aldol reaction, Seebach dioxolanone alkylation
and introduction of the lipophilic chain Via an alkyne hydrozir-
conation-aldehyde addition-lactonization sequence. The meth-
odology developed should be applicable to the synthesis of
related natural products such as (-)-trachyspic acid,29 (R,R)-
CJ-13,981, (R,R)-CJ-13,982,30 (R,R)-agaric acid and their
enantiomers.
4-Benzyloxy-(R)-2-((R)-2-tert-butyl-(R)-5-oxo-[1,3]dioxolan-4-
yl)-butyric acid (13). p-TsOH (3.9 g, 20.5 mmol) and t-BuCHO
(22.6 mL, 205.8 mmol) were added with stirring to carboxylic acid
19 (18.4 g, 68.6 mmol) in n-hexane and THF (10:1; 500 mL), and
the mixture was stirred under reflux for 5 h with azeotropic removal
of water (Dean-Stark). The mixture was cooled to room temper-
ature and poured onto aqueous HCl (1 M; 400 mL). The organic
layer was washed with brine (500 mL), dried (MgSO4) and rotary
evaporated. Chromatography (CH2Cl2/MeOH 40:1) gave dioxol-
anone 13 (18.4 g, 54.8 mmol, 80%) as a white solid: Rf 0.30
Experimental Section
(R)-4-Benzyl-3-[2-((R)-2-benzyloxyethyl)-(S)-3-hydroxy-4-pen-
tenoyl]-oxazolidin-2-one (14). n-Bu2BOTf in CH2Cl2 (1 M; 100
(28) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938.
(29) Zammit, S. C.; White, J. M.; Rizzacasa, M. A. Org. Biomol. Chem.
2005, 3, 2073–2074.
(30) Watanabe, S.; Hirai, H. J. Antibiot. 2001, 54, 1025–1030.
J. Org. Chem. Vol. 73, No. 24, 2008 9695

Calo et al.
25
(CH2Cl2/MeOH 20:1); mp 105-110 °C (hexanes/CH2Cl2); [R]D
+10.2 (c 1.0, CHCl3); IR (KBr) 1799, 1714, 1484, 1409, 1195,
1091, 971, 736, 698 cm-1 1H NMR (400 MHz, CDCl3) δ
acid (310 mg, 87 mmol, 100%) as a colorless oil. This crude acid
(310 mg, 0.87 mmol) in CH2Cl2 (15 mL) was allowed to react with
N,N′-di-isopropyl-O-t-butylisourea (22) (2 mL, excess) and the
mixture stirred under reflux for 12 h. Rotary evaporation and
chromatography (hexanes: Et2O 1: 1) gave t-butyl ester 23 (260
mg, 0.63 mmol, 72%) as a colorless oil: Rf 0.30 (Et2O/hexanes
1:1); [R]D25 -1.1 (c 1.0, CH2Cl2); IR (KBr) 1741, 1436, 1369, 1157,
;
7.37-7.30 (m, 5H), 5.14 (d, J ) 1.0 Hz, 1H), 4.69 (dd, J ) 3.9,
1.1 Hz, 1H), 4.57 (d, J ) 11.8 Hz, 1H), 4.53 (d, J ) 11.8 Hz, 1H),
3.69-3.64 (m, 1H), 3.16 (dt, J ) 8.8, 3.9 Hz, 1H), 2.24-2.15 (m,
1H), 1.95-1.88 (m, 1H), 0.98 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 176.5, 171.6, 137.7, 128.4, 127.74, 127.71, 109.4, 75.1, 73.0,
67.5, 43.3, 34.2, 27.1, 23.5; HRMS (ESI) calcd for C18H23O6: (M
- H)+, 335.1495, found: (M - H)+, 335.1506; Anal. calcd for
C18H24O6: C, 64.27; H, 7.19. Found: C, 64.37; H, 7.23.
1
1103, 669 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m,
5H), 4.45 (dd, J ) 15.6, 12.0 Hz, 2H), 3.87 (brs, 1H), 3.66 (s,
3H), 3.63 (s, 3H), 3.51-3.45 (m, 1H), 3.43-3.38 (m, 1H), 3.07
(d, J ) 16.2 Hz, 1H), 2.90 (dd, J ) 11.6, 2.6 Hz, 1H), 2.71 (d, J
) 16.2 Hz, 1H), 2.17-2.08 (m, 1H), 1.90-1.82 (m, 1H), 1.49 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 172.5, 172.4, 170.7, 138.2,
128.2, 127.6, 127.5, 83.6, 75.2, 72.8, 68.1, 51.8, 51.7, 51.1, 40.7,
27.7, 27.6; HRMS (ESI) calcd for C21H30NaO8: (M + Na)+,
433.1838, found: (M + Na)+, 433.1841.
4-Benzyloxy-(R)-2-(4-tert-butoxycarbonylmethyl-2-(R)-tert-
butyl-(R)-5-oxo-[1,3]dioxolan-4-yl)-butyric acid (12). LiN-
(SiMe3)2 in THF (1 M; 1 mL, 1 mmol) was added dropwise to
acid 13 (168 mg, 0.5 mmol) in dry DMF (1 mL) and the resulting
pale yellow solution stirred at -70 °C for 50 min, when t-butyl
bromoacetate (82 µL, 0.5 mmol) was added. The reaction temper-
ature was maintained at -70 °C for 15 min after which time the
solution was poured onto aqueous HCl (1 M; 10 mL) and Et2O
(30 mL) was added. The organic phase was washed with brine (3
× 20 mL), dried (MgSO4) and rotary evaporated. Chromatography
(CH2Cl2/MeOH 40:1)) gave carboxylic acid 12 (165 mg, 0.37 mmol,
73%), a yellow gum, as a mixture of diastereoisomers (9:1): Rf
0.32 (CH2Cl2/MeOH 20:1); IR (KBr) 1800, 1730, 1366, 1244, 1192,
tert-Butyl (R)-3-methoxycarbonyl-(R)-2-methoxycarbonyl-
methyl-5-oxo-(R)-2-trimethylsilanyloxy-pentanoate (11). Pow-
dered Pd/C (10%, 300 mg) was added to benzyl ether 24 (270 mg,
0.56 mmol) in dry THF (20 mL) under H2 pressure and the mixture
was stirred for 15 h, filtered through Celite while being rinsed with
Et2O, and rotary evaporated to give the crude alcohol (219 mg,
0.56 mmol, 100%) as a colorless oil. This alcohol (219 mg, 0.56
mmol) in CH2Cl2 (20 mL) was allowed to react with Dess-Martin-
periodinane (356 mg, 0.84 mmol) at 0 °C. After 2 h, the reaction
was quenched with saturated aqueous NaHCO3 (15 mL) and
saturated aqueous Na2SO3 (15 mL) and the mixture stirred for 30
min. The organic layer was dried (MgSO4) and rotary evaporated
to give the crude aldehyde 11 (204 mg, 0.52 mmol, 93%) as a
colorless oil: Rf 0.40 (Et2O/hexanes 1:2); 1H NMR (400 MHz,
CDCl3) δ 9.75 (s, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.30 (dd, J )
10.9, 2.9 Hz, 1H), 3.09 (dd, J ) 18.5, 11.3 Hz, 1H), 3.01 (d, J )
15.5 Hz, 1H), 2.79 (d, J ) 15.5 Hz, 1H), 2.65 (dd, J ) 18.5, 2.9
Hz, 1H), 1.47 (s, 9H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 199.4, 171.3, 170.5, 170.0, 82.9, 78.3, 52.0, 51.5, 47.6, 42.5,
42.2, 27.7, 2.3; HRMS (ESI) calcd for C17H30NaO8Si: (M + Na)+,
413.1608, found: (M + Na)+, 413.1590.
1-tert-Butyl 4-methyl (R)-2-((R)-2-oxo-5-tetradeca-1,5-dienyl-
tetrahydro-furan-(R)-3-yl)-(R)-2-trimethylsilanyloxy-succinate
(28). Alkyne 27 (160 mg, 0.83 mmol) in CH2Cl2 (2 mL) was added
dropwise with stirring to Cp2ZrHCl (180 mg, 0.76 mmol) in CH2Cl2
(2 mL) at 0 °C. The mixture was stirred at room temperature until
a homogeneous solution was formed and subsequently cooled to
-65 °C. Me2Zn in PhMe (1.2 M; 0.55 mL, 0.76 mmol) was added
over 5 min after which time the mixture was warmed to 0 °C and
aldehyde 11 (200 mg, 0.51 mmol) in CH2Cl2 (2 mL) was added
over 10 min. The reaction mixture was stirred at room temperature
for 12 h and poured onto aqueous HCl (1 M; 20 mL). Et2O (30
mL) was added and the layers were separated. The organic layer
was washed with brine (30 mL), dried (MgSO4) and p-TsOH (200
mg, excess) was added with stirring. After 3 h at reflux, rotary
evaporation and chromatography (gradient hexanes/Et2O 6:1 to 4:1
to 2:1) gave in order of increasing polarity (1) silyl protected trans-
lactone 28 (95 mg, 0.17 mmol, 34%) as a pale-yellow oil; (2) silyl
protected cis-lactone 29 (55 mg, 0.10 mmol, 19%) as a colorless
oil; (3) trans-lactone 30 (33 mg, 0.07 mmol, 14%) as a colorless
oil; (4) cis-lactone 31 (10 mg, 0.02 mmol, 4%) as a colorless oil.
28: Rf 0.40 (Et2O/hexanes 1:5); [R]D25 +9.8 (c 0.8, CH2Cl2); IR
(KBr) 1770, 1747, 1436, 1369, 1249, 1186, 1153, 1070, 1002, 844,
757, 686 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.76 (dt, J ) 15.0,
6.2 Hz, 1H), 5.48-5.29 (m, 3H), 4.87 (q, J ) 7.2 Hz, 1H), 3.67 (s,
3H), 3.27-3.18 (m, 3H), 2.40 (ddd, J ) 13.1, 7.6, 5.3 Hz, 1H),
2.11 (brm, 4H), 2.04-1.98 (m, 3H), 1.47 (s, 9H), 1.27 (brs, 12H),
0.88 (t, J ) 6.8 Hz, 3H), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 175.4, 170.5, 170.2, 134.7, 130.9, 128.4, 128.2, 82.6, 79.5, 79.3,
51.6, 47.4, 41.8, 32.2, 31.9, 31.2, 29.6, 29.5, 29.3, 27.8, 27.3, 26.5,
22.7, 14.1, 2.2; HRMS (ESI) calcd for C30H53O7Si: (M + H)+,
553.3561, found: (M + H)+, 553.3561; Anal. calcd for C30H52O7Si:
C, 65.18; H, 9.48. Found: C, 65.25; H, 9.39.
1155, 1097 cm-1; H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m,
1
5H), 5.28 (s, 1H), 4.50 (d, J ) 12.0 Hz, 1H), 4.46 (d, J ) 12.0 Hz,
1H), 3.58-3.45 (m, 2H), 3.16 (d, J ) 16.5 Hz, 1H), 3.10 (dd, J )
11.3, 2.6 Hz, 1H), 2.84 (d, J ) 16.5 Hz, 1H), 2.20-2.12 (m, 1H),
2.05-1.97 (m, 1H), 1.45 (s, 9H), 0.95 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 175.8, 172.5, 168.6, 138.0, 128.2, 127.5, 127.5, 109.7,
82.3, 79.6, 72.9, 67.5, 49.4, 38.8, 34.4, 27.9, 23.6; HRMS (ESI)
calcd for C24H34NaO8: (M + Na)+, 473.2151, found: (M + Na)+,
473.2157.
Benzyl 5-Benzyloxy-(R)-2-hydroxy-(R)-3-methoxycarbonyl-
(R)-2-methoxycarbonylmethyl-pentanoate (21). t-Butyl ester 12
(165 mg, 0.37 mmol) in CH2Cl2 (5 mL) was treated at 0 °C with
trifluoroacetic acid (1 mL). The mixture was stirred for 4 h at room
temperature and toluene was added (10 mL) and solvent rotary
evaporated to give crude diacid 20 (144 mg, 0.37 mmol, 100%) as
a yellow gum, which was dissolved in dry PhMe (15 mL) and
cooled at 0 °C. Benzyl alcohol (303 µL, 3 mmol) was added
followed by slow addition of LiN(SiMe3)2 in THF (1 M; 1.85 mL,
1.87 mmol), and the mixture was stirred at room temperature. After
12 h, the solution was poured onto saturated aqueous NaHCO3 (20
mL), the aqueous phase was extracted with EtOAc (3 × 20 mL)
and the combined organic layers were discarded. The aqueous layer
was slowly acidified with concentrated hydrochloric acid to pH 1
and extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine (2 × 50 mL), dried (MgSO4) and
freshly prepared diazomethane (solution in Et2O) was added until
the yellow coloration persisted. Rotary evaporation followed by
chromatography (hexanes/Et2O 3:2) gave benzyl ester 21 (111 mg,
0.26 mmol, 70%) as a pale yellow oil: Rf 0.25 (Et2O/hexanes 1:1);
25
[R]D -0.3 (c 1.0, CH2Cl2); IR (KBr) 1737, 1436, 1357, 1195,
1172, 1099, 738, 698 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.36-7.26 (m, 10H), 5.22 (q, J ) 12.1 Hz, 2H), 4.42 (dd, J )
15.2, 11.9 Hz, 2H), 3.96 (brs, 1H), 3.60 (s, 3H), 3.51 (s, 3H),
3.48-3.35 (m, 2H), 3.13 (d, J ) 16.5 Hz, 1H), 2.95 (dd, J ) 11.5,
2.7 Hz, 1H), 2.73 (d, J ) 16.5 Hz, 1H), 2.15-2.06 (m, 1H),
1.86-1.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.3, 172.3,
170.9, 138.1, 134.8, 128.6, 128.5, 128.2, 127.6, 127.5, 75.7, 72.8,
68.1, 67.9, 51.9, 51.8, 50.8, 40.6, 27.4; HRMS (ESI) calcd for
C24H29O8: (M + H)+, 445.1862, found: (M + H)+, 445.1862.
tert-Butyl 5-Benzyloxy-(R)-2-hydroxy-(R)-3-methoxycarbonyl-
(R)-2-methoxycarbonylmethyl-pentanoate (23). Powdered Pd/C
(10%, 300 mg) was added to benzyl ester 21 (390 mg, 0.88 mmol)
in dry THF (15 mL) under H2 pressure. The mixture was
magnetically stirred for 1 h, filtered through Celite while being
rinsed with Et2O and rotary evaporated to give crude carboxylic
9696 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Citrafungin A
25
29: Rf 0.30 (Et2O/hexanes 1:5); [R]D +36.7 (c 0.8, CH2Cl2);
Di-tert-butyl (S)-3-tert-Butoxycarbonyl-(R)-2-[(R)-3-tert-bu-
toxycarbonyl-(R)-3-hydroxy-(R)-3-((R)-2-oxo-5-tetradeca-1,5-di-
enyl-tetrahydro-furan-(R)-3-yl)-propanoyloxy]-pentanedioate
(7). DMAP·HCl (66 mg, 0.42 mmol)) and DCC (57 mg, 0.28
mmol) were sequentially added to carboxylic acid 8 (20 mg, 0.043
mmol) and alcohol 9 (31 mg, 0.086 mmol) in CH2Cl2 (5 mL) and
this mixture stirred for 4 h. Rotary evaporation and chromatography
(hexanes/Et2O 4:1) gave t-butyl ester 7 (17.2 mg, 0.021 mmol, 50%)
IR (KBr) 1774, 1745, 1436, 1369, 1249, 1176, 1157, 1072, 1006,
844, 755, 688 cm-1; H NMR (400 MHz, CDCl3) δ 5.81 (dt, J )
1
15.0, 6.2 Hz, 1H), 5.50-5.30 (m, 3H), 4.68 (dt, J ) 9.87, 6.99 Hz,
1H), 3.67 (s, 3H), 3.40 (d, J ) 15.4 Hz, 1H), 3.32 (dd, J ) 11.4,
8.9 Hz, 1H), 3.29 (d, J ) 15.4 Hz, 1H), 2.26 (ddd, J ) 12.8, 8.9,
6.5 Hz, 1H), 2.12 (brm, 5H), 2.01 (dd, J ) 6.9, 6.8 Hz, 2H), 1.47
(s, 9H), 1.26 (brs, 12H), 0.88 (t, J ) 6.8 Hz, 3H), 0.15 (s, 9H); 13
C
25
as a colorless oil: Rf 0.20 (Et2O/hexanes 1:4); [R]D +2.1 (c 1,
NMR (100 MHz, CDCl3) δ 174.5, 170.6, 170.3, 135.5, 130.8, 128.2,
127.9, 82.5, 78.2, 77.7, 51.5, 47.6, 41.2, 32.2, 31.8, 30.9, 29.6, 29.5,
29.3, 27.8, 27.2, 26.4, 22.6, 14.0, 2.1; HRMS (ESI) calcd for
C30H53O7Si: (M + H)+, 553.3561, found: (M + H)+, 553.3568;
Anal. calcd for C30H52O7Si: C, 65.18; H, 9.48. Found: C, 65.18;
H, 9.55.
1
CHCl3); IR (KBr) 3487, 1730, 1369, 1225, 1153, 844 cm-1; H
NMR (400 MHz, CDCl3) δ 5.82-5.75 (m, 1H), 5.47-5.30 (m,
3H), 5.18 (d, J ) 3.2 Hz, 1H), 4.99 (q, J ) 7.1 Hz, 1H), 4.05 (d,
J ) 0.9 Hz, 1H), 3.72 (d, J ) 17.4 Hz, 1H), 3.31 (ddd, J ) 10.1,
4.7, 3.4 Hz, 1H), 3.05 (d, J ) 17.4 Hz, 1H), 2.83 (dd, J ) 9.8, 5.3
Hz, 1H), 2.62 (dd, J ) 16.9, 10.0 Hz, 1H), 2.42 (dd, J ) 16.8, 4.7
Hz, 1H), 2.34 (ddd, J ) 12.9, 7.4, 5.3 Hz, 1H), 2.12-2.09 (brm,
4H), 2.03-1.91 (m, 3H), 1.48-1.44 (m, 36H), 1.27 (brs, 12H),
0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9,
171.9, 170.4, 169.6, 168.9, 166.4, 135.0, 130.9, 128.2, 128.0, 83.8,
83.0, 81.9, 80.9, 79.7, 77.2, 75.2, 72.2, 46.4, 43.5, 40.4, 33.0, 32.1,
31.8, 30.5, 29.6, 29.4, 29.3, 28.0, 27.6, 27.2, 26.4, 22.6, 14.1; HRMS
(ESI) calcd for C44H72O13Na: (M + Na)+, 831.4871, found: (M +
Na)+, 831.4853.
25
30: Rf 0.32 (Et2O/hexanes 1:2); [R]D -18.5 (c 0.6, CH2Cl2); IR
(KBr) 3482, 1768, 1743, 1438, 1269, 1282, 1253, 1189, 1155, 1122,
993, 971, 844 cm-1; H NMR (400 MHz, CDCl3) δ 5.79 (dt, J )
1
14.6, 6.1 Hz, 1H), 5.45-5.28 (m, 3H), 4.98 (q, J ) 7.1 Hz, 1H), 3.99
(brs, 1H), 3.68 (s, 3H), 3.57 (d, J ) 16.6 Hz, 1H), 2.93 (d, J ) 16.6
Hz, 1H), 2.86 (dd, J ) 9.8, 5.4, 1H), 2.33 (ddd, J ) 13.0, 7.4, 5.4 Hz,
1H), 2.11 (brm, 4H), 2.02-1.93 (m, 3H), 1.49 (s, 9H), 1.26 (brs, 12H),
0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 172.0,
171.1, 135.0, 130.9, 128.1, 127.9, 83.7, 79.6, 75.5, 51.8, 46.2, 40.5,
32.1, 31.8, 30.5, 29.6, 29.4, 29.2, 27.7, 27.2, 26.4, 22.6, 14.1; HRMS
(ESI) calcd for C27H44O7Na: (M + Na)+, 503.2985, found: (M + Na)+,
503.2991; Anal. calcd for C27H44O7: C, 67.47; H, 9.23. Found: C,
67.47; H, 9.19.
Citrafungin A (1). Pentaester 7 (15 mg, 6.3 µmol) in CH2Cl2
(5 mL) was treated at 20 °C with trifluoroacetic acid (2 mL). After
4 h, PhMe (10 mL) was added and solvent rotary evaporated to
give crude citrafungin A (1) (11 mg, 6.3 µmol, 100%). Purification
using reverse phase HPLC (column: Xbridge Prep C18 OBD 30
cm × 10 cm 5 µm (P/N186002982) and gradient elution H2O/
MeCN with 0.1% TFA 85:15 to 5.3:94.7 over 12 min) gave
25
31: Rf 0.30 (Et2O/hexanes 1:2); [R]D +11.6 (c 0.5, CH2Cl2);
IR (KBr) 3480, 1773, 1743, 1438, 1369, 1284, 1252, 1156, 995,
844 cm-1; H NMR (400 MHz, CDCl3) δ 5.82 (dt, J ) 15.2, 6.5
1
25
citrafungin A (1): [R]D + 3.2 (c 0.25, MeOH); IR (KBr) 3453,
Hz, 1H), 5.55-5.30 (m, 3H), 4.71 (dt, J ) 9.7, 7.0 Hz, 1H), 3.97
(brs, 1H), 3.77 (d, J ) 16.5 Hz, 1H), 3.68 (s, 3H), 2.95 (dd, J )
11.5, 8.7 Hz, 1H), 2.89 (d, J ) 16.5 Hz, 1H), 2.18 (ddd, J ) 12.7,
8.8, 6.2 Hz, 1H), 2.12-2.06 (m, 5H), 1.99 (q, J ) 6.9 Hz, 2H),
1.50 (s, 9H), 1.26 (brs, 12H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.2, 171.9, 171.0, 136.1, 130.9, 128.1,
127.4, 83.7, 78.7, 74.0, 51.7, 46.9, 40.1, 32.1, 31.8, 30.3, 29.6, 29.4,
29.2, 27.7, 27.2, 26.3, 22.6, 14.1; HRMS (ESI) calcd for
C27H44O7Na: (M + Na)+, 503.2985, found: (M + Na)+, 503.2981;
Anal. calcd for C27H44O7: C, 67.47; H, 9.23. Found: C, 67.51; H,
9.27.
1731, 1405, 1250, 1187, 967 cm-1; 1H NMR (600 MHz, d6-Me2CO)
δ 5.82 (dt, J ) 14.9, 6.3 Hz, 1H), 5.58 (dd, J ) 15.4, 7.4 Hz, 1H),
5.49 (d, J ) 3.4 Hz, 1H), 4.99 (q, J ) 7.1 Hz, 1H), 5.41-5.33 (m,
2H), 3.70 (d, J ) 16.3 Hz, 1H), 3.56 (ddd, J ) 8.8, 4.8, 3.7 Hz,
1H), 3.16 (d, J ) 16.3 Hz, 1H), 3.05 (dd, J ) 9.7, 5.8 Hz, 1H),
2.81 (dd, J ) 17.2, 9.4 Hz, 1H), 2.61 (dd, J ) 17.2, 4.9 Hz, 1H),
2.39 (ddd, J ) 13.2, 7.4, 6.0 Hz, 1H), 2.16-2.03 (m, 7H), 1.29
(brm, 12H), 0.87 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, d6-
Me2CO) δ 175.0, 173.8, 172.3, 171.1, 169.2, 169.0, 134.4, 130.6,
129.2, 128.8, 79.5, 75.6, 71.9, 46.2, 42.7, 40.8, 32.3, 32.0, 31.8,
30.9, 30.3, 27.2, 26.7, 22.7, 13.8; HRMS (ESI) calcd for
C28H40NaO13: (M + Na)+, 607.2367, found: (M + Na)+, 607.2363,
calcd for C28H41O13: (M + H)+, 585.2547, found: (M + H)+,
585.2550.
tert-Butyl (R)-2-hydroxy-(R)-2-((R)-2-oxo-5-tetradeca-1,5-di-
enyl-tetrahydro-furan-(R)-3-yl)-succinate (8). Solid Me3SnOH
(213 mg, 1.17 mmol) was added to methyl ester 30 (113 mg, 0.23
mmol) in ClCH2CH2Cl (5 mL) and heated at 85 °C in a sealed
tube for 12 h. After rotary evaporation, the crude product was
dissolved in EtOAc (20 mL) and washed with aqueous HCl (1 M;
2 × 20 mL) and brine (20 mL), dried (MgSO4) and rotary
evaporated. Chromatography (CH2Cl2/MeOH 15:1) gave carboxylic
acid 8 (103 mg, 0.22 mmol, 94%) as a pale-yellow gum: Rf 0.30
(CH2Cl2/MeOH 15:1); [R]D25 -9.9 (c 1.0, CH2Cl2); IR (KBr) 3452,
1728, 1435, 1399, 1370, 1275, 1251, 1191, 1155, 1119, 999, 969,
Acknowledgment. We thank GlaxoSmithKline for the gener-
ous endowment (to A.G.M.B.), Eli Lilly and Company and the
Engineering and Physical Sciences Research Council for grant
support, Peter R. Haycock and Richard N. Sheppard both at
Imperial College London for high-resolution NMR spectroscopy,
Marie Cribb, Colin Byrne and Paul Tan from Eli Lilly and
Company for NMR spectroscopy and HPLC purification of
citrafungin A (1), and Professor Susumi Hatakeyama for
providing copies of the 1H and 13C NMR spectra of compounds
7 and 8 and experimental conditions for the esterifications of 8
and 9.
1
840 cm-1; H NMR (400 MHz, CDCl3) δ 5.79 (dt, J ) 15.2, 6.1
Hz, 1H), 5.47-5.30 (m, 3H), 4.99 (dd, J ) 14.0, 7.00 Hz, 1H),
3.97 (brs, 1H), 3.58 (d, J ) 16.8 Hz, 1H), 2.99 (d, J ) 16.8 Hz,
1H), 2.88 (dd, J ) 9.8, 5.6 Hz, 1H), 2.33 (ddd, J ) 13.1, 7.4, 5.6
Hz, 1H), 2.11 (brm, 4H), 2.02-1.94 (m, 3H), 1.48 (s, 9H), 1.26
(brs, 12H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 175.1, 174.5, 171.7, 135.2, 130.9, 128.1, 127.8, 84.1, 79.8, 75.3,
46.2, 40.4, 32.1, 31.8, 30.4, 29.6, 29.4, 29.3, 27.7, 27.2, 26.4, 22.6,
14.1; HRMS (ESI) calcd for C26H42O7Na: (M + Na)+, 489.2828,
found: (M + Na)+, 489.2837; Anal. calcd for C26H42O7: C, 66.93;
H, 9.07. Found: C, 66.86; H, 8.98.
Supporting Information Available: Experimental proce-
dures, 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.
JO801708Q
J. Org. Chem. Vol. 73, No. 24, 2008 9697