De novo asymmetric syntheses of muricatacin and its analogues via dihydroxylation of dienoates

Article abstract of DOI:10.1021/jo061057s

A short and highly efficient route to both enantiomers of muricatacin as well as the C-5-epimer has been developed. The key to the overall transformation is the highly regio- and enantioselective Sharpless asymmetric dihydroxylation of an (E,Z)-dienoate. The highly efficient stereoselective synthesis prepares (-)-muricatacin in seven steps and 66% overall yield.

Full text of DOI:10.1021/jo061057s

SCHEME 1. An Iterative Dihydroxylation Approach to
Various Talose Sugars
De Novo Asymmetric Syntheses of Muricatacin
and Its Analogues via Dihydroxylation of
Dienoates
Md. Moinuddin Ahmed, Hu Cui, and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506
envisioned would be amenable to a palladium-catalyzed dimer-
ization of these stereoisomers, toward acetogenin analogues.
Previously, we have had significant success at the synthesis
of various carbohydrates by means of the iterative dihydroxy-
lation of dienoates.5 Thus establishing the C-2 to C-5 tetrol
stereochemistry of the hexoses from dienoates (e.g., 3 from 1).6
As part of our efforts to apply this methodology to talo-sugars
(3) (Scheme 1), we discovered a simple approach to enantioen-
riched 5-hydroxy-γ-butylrolactones (2). Thus we decided to
explore the potential to use this approach toward muricatacin
and eventually dimeric acetogenin analogues.7 Herein, we would
like to report a very short and highly efficient approach for the
synthesis of either enantiomer of muricatacin (4) and its 5-epi-
muricatacin (12) via a regioselective asymmetric Sharpless
dihydroxylation (Scheme 2).
George.ODoherty@mail.wVu.edu
ReceiVed May 23, 2006
A short and highly efficient route to both enantiomers of
muricatacin as well as the C-5-epimer has been developed.
The key to the overall transformation is the highly regio-
and enantioselective Sharpless asymmetric dihydroxylation
of an (E,Z)-dienoate. The highly efficient stereoselective
synthesis prepares (-)-muricatacin in seven steps and 66%
overall yield.
SCHEME 2. Retrosynthetic Analysis of Muricatacin
The muricatacins are a class of naturally occurring 5-hydroxy-
γ-butyrolactones with potent cytotoxicity (∼1 to 10 µg/mL)
against several human tumor cell lines. Various SAR studies
of the muricatacin showed that its activity is influenced
significantly by the nature of the side chain.1 In 1991, muri-
catacin was isolated by McLaughlin et al. from the seeds of
the tropical fruit, Annona muricata as a quasi-racemic compo-
nent (ca. 25% ee), with the (-)-enantiopode being the predomi-
nate form.2 In addition to their potent biological activity,
muricatacin and related γ-butyrolactones have served as precur-
sors in syntheses of complex bioactive natural products.3
Although, numerous synthetic approaches to this class of
molecule have been reported,4 the development of a flexible
and efficient route for the preparation of 5-hydroxy-γ-butyro-
lactone natural products still remains exigent.
Retrosynthetically, we targeted the Z,E-dienoate 6, which we
envisioned preparing by means of a Still-Gennari olefination8
of enal 10. Similarly, the enal 10 could be prepared from
(4) For recent synthesis of muricatacin, see the following: (a) Dhotare,
B.; Chattopadhyay, A. Tetrahedron Lett. 2005, 46, 3103-3105. (b) Quinn,
K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143-4145. (c)
Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2003, 68, 7548-
7550. (d) Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Org. Lett.
2003, 5, 2923-2926. (e) Popsavin, V.; Krstic, I.; Popsavin, M. Tetrahedron
Lett. 2003, 44, 8897-8900. (f) Raghavan, S.; Joseph, S. C. Tetrahedron:
Asymmetry 2003, 14, 101-105. (g) Carda, M.; Rodriguez, S.; Gonzalez,
F.; Castillo, E.; Villanueva, A.; Marco, J. A. Eur. J. Org. Chem. 2002, 15,
2649-2655. (h) Chandrasekhar, M.; Chandra, K. L.; Singh, V. K.
Tetrahedron Lett. 2002, 43, 2773-2775. (i) Konno, H.; Hiura, N.; Yanura,
M. Heterocycles 2002, 57, 1793-1797. (j) Baylon, C.; Prestat, G.; Heck,
M. P.; Mioskowski, C. Tetrahedron Lett. 2000, 41, 3833-3835. (k) Trost,
B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680-11683. (l) Solladie,
G.; Hanquet, G.; Izzo, I.; Crumbie, R. Tetrahedron Lett. 1999, 40, 3071-
3074. (m) Couladouros, E. A.; Mihou, A. P. Tetrahedron Lett. 1999, 40,
4861-4862. (n) Marshall, J. A.; Welmaker, G. S. J. Org. Chem. 1994, 59,
4122-4125. (o) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron
Lett. 1992, 33, 6407-6410. (p) Wright, A. E.; Schafer, M.; Midland, S.;
Munnecke, D. E.; Slims, J. J. Tetrahedron Lett. 1989, 30, 5699. (q) Kotsuki,
H.; Miyazaki, A.; Ochi, M.; Slims, J. J. Bull. Chem. Soc. Jpn. 1991, 64,
721.
As part of a program aimed at the synthesis of a library of
anticancer compounds, we were interested in the access to large
amounts of muricatacin and its stereoisomers. In particular,
we desired access to the R,â-unsaturated variants, which we
(1) Cave, A.; Chaboche, C.; Figadere, B.; Harmange, J. C.; Laurens,
A.; Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-Laffite, J.; Quero, A. M.
Eur. J. Med. Chem. 1997, 32, 617-623.
(2) Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.
Tetrahedron Lett. 1991, 32, 1137-1140.
(3) (a) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843-
2846. (b) Hu, Y.; Brown, R. C. D. Chem. Commun. 2005, 69, 5636-5637.
(c) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2005, 69, 1993-
1998. (d) Avedissain, H.; Sinha, S. C.; Yazhak, A.; Neogi, P.; Sinha, S. C.;
Keinan, E. J. Org. Chem. 2000, 65, 6035-6051. (e) Ha, J. D.; Cha, J. K.
J. Am. Chem. Soc. 1999, 121, 10012-6028. (f) Towne, T. B.; McDonald,
F. E. J. Am. Chem. Soc. 1997, 119, 6022-6028.
(5) (a) Ahmed, Md. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46,
3015-3019. (b) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D.
J.; O’Doherty, G. A. Org. Lett. 2005, 7, 745-748.
10.1021/jo061057s CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/28/2006
6686
J. Org. Chem. 2006, 71, 6686-6689

SCHEME 3. Synthesis of Z,E-Dienoate 6
By a nearly identical protocol the (+)-muricatacin ent-4
could also be synthesized from dienoate 6 (Scheme 5). All
SCHEME 5. Enantioselective Synthesis of (+)-Muricatacin
that was required was simply switch to the pseudoenantio-
meric AD-mix catalyst system (2% OsO4/2.1% (DHQ)2PHAL,
3 equiv K3Fe(CN)6/K2CO3, 1 equiv MeSO2NH2). Thus exposing
(2Z,4E)-dienoate 6 to the pseudoenantiomeric AD-mix catalyst
(AD-R*) yielded the enantiomeric lactone ent-5 in a similarly
good yield (83%) and enantiopurity (>92% ee). As with it
enantiomer, ent-5 could be converted to (+)-muricatacin ent-4
via hydrogenation of a methanol solution of lactone ent-5 with
Pd/C in an excellent yield of 97%.
commercially available aldehyde 7 (Scheme 3). In practice, we
found it was significantly cheaper and procedurally easy to
prepare aldehyde 7 from 13-carbon alcohol 8 via a TEMPO
oxidation (95% yield).9 The aldehyde 7 was homologated to
the allylic alcohol 9 by a stablized Wittig olefination/DIBALH
reduction sequence (90%). Allylic oxidation of 9 with MnO2
afforded the enal 10 in excellent yield (98%), which coupled
smoothly under the typical Still-Gennari conditions to give
the desired Z,E-dienoate 6 in good yield and stereoselectivity
(>20:1, Z,E to E,E). This five-step procedure allowed for the
preparation of multigram quantities of dienoate 6 in excellent
overall yield from alcohol 8 (78%).
We could also easily access the C-5 epimer of muricatacin
by means of the Mitsunobu reaction (Scheme 6). Thus, exposing
SCHEME 6. Enantioselective Synthesis of
5-Epi-Muricatacin
We next investigated the dihydroxylation/lactonization of
the dienoate 6 (Scheme 4). Simply exposing the (2Z,4E)-
SCHEME 4. Enantioselective Synthesis of (-)-Muricatacin
(+)-muricatacin ent-4 to the typical Mitsunobu reaction condi-
tion afforded the p-nitro-benzoic ester 11 in excellent yield
(92%). Hydrolysis of the ester 11 with K2CO3 in MeOH yielded
the C-5-epi-muricatacin 12 in good yield (85%).
In conclusion, short, flexible, and highly efficient syntheses
of either enantiomer of muricatacin and its C-5 epimer have
been developed. This highly enantio- and diastereocontrolled
route illustrates the utility of the Sharpless dihydroxylation and
Mitsunobu reaction. This approach provides both enantiomers
of muricatacin (4 and ent-4) in 66% and 63% overall yields
from commercially available 13-carbon alcohol 8, respectively.
This route was also amenable to C-5 epimer of muricatacin 12
in 49% overall yields from alcohol 8. Further application of
this approach toward the synthesis of acetogenin analogues is
ongoing.
dienoate 6 to the typical Sharpless AD-mix procedure (2% OsO4/
2.1% (DHQD)2PHAL, 3 equiv K3Fe(CN)6/K2CO3, 1 equiv
MeSO2NH2), afforded lactone 5 in good yield (86%) and
excellent enantiomeric excess (>95% ee).10 Finally the natural
product (-)-muricatacin 4 was prepared by hydrogenation (1
atm H2, 5% Pd/C in MeOH) of the butenolide double bond,
which gave synthetic material (98%) with identical physical and
spectral data to that of the isolated natural product2 (1H NMR,
13C NMR, optical rotation,11 and melting point).
Experimental Section12
(E)-Pentadec-2-en-1-ol (9). A solution of (E)-ethyl pentadec-
2-enoate (1.8 g, 6.72 mmol) in THF (80 mL) was cooled to -78
°C, and then Dibal-H (1M, 16.8 mL, 16.8 mmol) was added
dropwise. After the mixture was stirred for 30 min, the reaction
mixture was quenched with 2 mL acetone. Bulk THF was removed
under reduced pressure, and the residue was treated with 30 mL 1
N HCl solution and then extracted with ether (3 × 30 mL). The
organic extracts were washed with brine, dried (Na2SO4), filtered,
and concentrated. The crude product was purified by flash chro-
(6) To control the double selectivity in the oxidation, we chose to take
advantage of both the differing double bond reactivity in dienoates and the
Sharpless reagent systems preference of trans-double bonds. See ref 5 as
well as (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483-2547. (b) Zhang, Y.; O’Doherty, G. A. Tetrahedron
2005, 61, 6337-6351.
(7) Previously, Sharpless has shown that muricatacin can be prepared
by the asymmetric dihydroxylation of a partially saturated 6 ((4E)-ethyl
heptadeca-4-enoate), see ref 4o. Because we were also interested in access
to an unsaturated form of muricatacin (5), we decided to pursue this dienoate
oxidation approach.
(8) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(9) Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041-
3043.
(10) All enantiomeric excesses were determined by chiral HPLC (for
details see Supporting Information).
(11) Because natural muricatacin was isolated in low enantiopurity, we
compared our optical rotation data ([R]25D -22.3 (c 1.8, CHCl3)) with that
of synthetic material ([R]25 -22.9 (c 1.84, CHCl3)), see ref 4b and 4n.
D
(12) Presented in this text are the experimental procedures for the
preparation of compounds 9-12. Complete experimental procedures and
spectral data for all compounds are presented in the Supporting Information.
J. Org. Chem, Vol. 71, No. 17, 2006 6687

matography on silica gel (20:1 (v/v) hexane/EtOAc) to yield
(E)-pentadec-2-en-1-ol 9 (1.5 g, 96% yield) as a white solid: mp:
31-33 °C; Rf (20% EtOAc/ hexanes) ) 0.52. IR (thin film, cm-1):
3288, 2955, 2917, 2848, 1472, 1462, 1081, 1001, 961, 719, 666.
1H NMR (CDCl3, 600 MHz): δ 5.69 (m, 1H), 5.63 (m, 1H), 4.0
(d, J ) 6 Hz, 2H), 2.0 (tdd, J ) 7, 7, 1.2 Hz, 2H), 1.25 (m, 20H),
0.88 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 150 MHz): δ 133.6,
128.8, 63.8, 32.2, 31.9, 29.66, 29.65, 29.63, 29.60, 29.4, 29.3, 29.2,
29.1, 22.6, 14.0; HRMS(ESI): calcd for [C15H30ONa]+, 249.2194;
found, 249.2189.
hexanes/EtOAc) afforded 379 mg (86% yield) of (R)-5-((R)-1′-
hydroxytridecyl)furan-2(5H)-one 5 as a white solid: mp 89-91
°C; Rf (50% EtOAc/hexanes) ) 0.55; [R]25 69 (c 1.8, CH2Cl2).
D
IR (thin film, cm-1): 3370, 2952, 2913, 2849, 1715, 1603, 1471,
1
1179, 1108, 1020, 919, 866, 836, 827, 801, 718, 658 cm-1. H
NMR (CDCl3, 600 MHz): δ 7.45 (dd, J ) 6, 1.8 Hz, 1H), 6.18
(dd, J ) 6, 1.8 Hz, 1H), 4.98 (ddd, J ) 5.6, 1.8, 1.8 Hz, 1H), 3.75
(ddd, J ) 12, 6, 6 Hz, 1H), 2.1 (m, 1H), 1.59 (m, 2H), 1.52 (m,
2H), 1.32-1.25 (m, 20H), 0.87 (t, J ) 7.2 Hz, 3H). 13C NMR
(CDCl3, 150 MHz): δ 172.7, 153.5, 122.7, 86.0, 71.9, 33.2, 31.9,
29.63, 29.60 (2C), 29.5, 29.46, 29.40, 29.3, 25.4, 22.6, 14.0. HRMS-
(ESI): calcd for [C17H30O3Na]+, 305.2093; found, 305.2086.
(R)-Dihydro-5-((R)-1′-hydroxytridecyl)furan-2(3H)-one (4).
Into a 10 mL round-bottom flask was added (R)-5-((R)-1′-
hydroxytridecyl)furan-2(5H)-one 5 (52 mg, 0.18 mmol), 4 mL of
MeOH and 10 mg 10 wt % Pd on activated carbon. The reaction
was stirred under 1 atm of H2 for 24 h. Filtration and evacuation
under reduced pressure afforded 51 mg (98% yield) (-)Muricatacin
as white solid: mp 68-70 °C; Rf (50% EtOAc/hexane) ) 0.55;
[R]25D -19 (c 1.8, CH2Cl2). IR (thin film, cm-1): 3394, 2953, 2916,
2849, 1743, 1471, 1364, 1319, 1189, 1099, 975, 810, 720. 1H NMR
(CDCl3, 600 MHz): δ 4.41 (ddd, J ) 7.2, 7.2, 4.2 Hz, 1H), 3.55
(ddd, J ) 8.4, 4.8, 4.8 Hz, 1H), 2.60 (dd, J ) 18, 9.6, 1H), 2.52
(dd, J ) 18, 9.6 Hz, 1H), 2.22 (m, 1H), 2.12 (m, 1H), 1.52 (m,
2H), 1.28-1.24 (m, 20H), 0.86 (t, J ) 7.2 Hz, 1H). 13C NMR
(CDCl3, 150 MHz): δ 177.1, 82.9, 73.6, 32.9, 31.8, 29.63, 29.61-
(2C), 29.5, 29.49, 29.48, 29.3, 28.6, 25.4, 24.0, 22.6, 14.0. HRMS-
(ESI): calcd for [C17H32O3Na]+, 307.2249; found, 307.2243.
(E)-Pentadecthyl-2-enal (10). To a solution of (E)-pentadec-2-
en-1-ol 9 (1.0 g, 4.58 mmol) in 30 mL hexane was added
manganese(IV) oxide (4.8 g, 55 mmol). The mixture was stirred
for 24 h at room temperature and then filtrated. The solvent was
removed under reduced pressure, and the residue was purified by
flash chromatography on silica gel (hexane) to yield (E)-penta-
decthyl-2-enal 10 (0.97 g, 98% yield) as a colorless oil: Rf (10%
EtOAc/ hexanes) ) 0.7. IR (thin film, cm-1): 2923, 2853, 2732,
1
1694, 1638, 1466, 1378, 1138, 974, 722. H NMR (CDCl3, 600
MHz): δ 9.48 (dd, J ) 7.8, 1.2 Hz, 1H), 6.82 (dtd, J ) 15.6, 6.6,
1.2 Hz, 1H), 6.1 (ddt, J ) 15.6, 7.8, 1.2 Hz, 1H), 2.3 (dtd, J ) 7.8,
6, 1.2 Hz, 2H), 1.48 (tt, J ) 7.2, 7.2 Hz, 2H), 1.26-1.24 (m, 20H),
0.85 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 150 MHz): δ 193.4,
158.8, 132.9, 32.6, 31.8, 29.58, 29.56, 29.54, 29.4, 29.29, 29.28,
29.1, 27.8, 22.6, 14.0. HRMS(ESI): calcd for [C15H28ONa]+,
247.2038; found, 247.2032.
(2Z,4E)-Methyl Heptadeca-2,4-dienoate (6). A solution of
(CF3CH2O)2P(O)CH2CO2CH3 (1.03 g, 4.58 mmol) and 18-crown-6
(5.13 g, 19.4 mmol) in THF (100 mL) was cooled to -78 °C and
treated with t-BuOK (0.62 g, 5.5 mmol). After the mixture was
stirred for 15 min, a solution of the (E)-pentadecthyl-2-enal 10 (1.03
g, 4.58 mmol) in THF (10 mL, plus 5 mL of rinse) was added by
cannula. The resulting mixture was stirred at -78 °C for 2.5 h,
and the reaction mixture was quenched by the addition of saturated
aqueous NH4Cl. The bulk of THF was removed under reduced
pressure. The residue was extracted with ether (3 × 30 mL), and
the organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated. The crude product was purified by flash
chromatography on silica gel (hexane) to yield (2Z,4E)-methyl
heptadeca-2,4-dienoate 6 (1.2 g, >20:1 Z, E/E, E ratio, 93% yield)
as a viscous oil. Major isomer (6): Rf (10% EtOAc/hexanes) )
0.85. IR (thin film, cm-1): 2922, 2853, 1719, 1639, 1437, 1192,
(S)-5-((S)-1′-hydroxytridecyl)furan-2(5H)-one (ent-5). Into a
25 mL round-bottom flask was added 2 mL of t-BuOH, 2 mL of
water, K3Fe(CN)6 (2.4 g, 7.26 mmol), K2CO3 (1.0 g, 7.26 mmol),
MeSO2NH2 (0.23 g, 1.57 mmol), (DHQ)2PHAL (39 mg, 50 µmol,
2.1 mol %), and OsO4 (6 mg, 24 µmol, 1 mol %). The mixture
was stirred at room temperature for about 15 min and then cooled
to 0 °C. To this solution was added (2Z,4E)-methyl heptadeca-2,4-
dienoate 6 (0.68 g, 2.42 mmol), and the reaction was stirred
vigorously at 0 °C overnight. The reaction was quenched with solid
sodium sulfite (15 mg) at room temperature. Ethyl acetate (10 mL)
was added to the reaction mixture, and after separation of the layers,
the aqueous phase was further extracted with the organic solvent
(2 × 10 mL). The combined organic layers were washed with brine
and dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (5:1 (v/v)
hexanes/EtOAc) afforded 557 mg (83% yield) of (S)-5-((S)-1′-
hydroxytridecyl)furan-2(5H)-one ent-5 as a white solid: mp 89-
91 °C; Rf (50% EtOAc/hexanes) ) 0.55; [R]25D -68 (c 1.2, CH2Cl2).
IR (thin film, cm-1): 3393, 3358, 3080, 2914, 2849, 1714, 1702,
1604, 1471, 1360, 1225, 1180, 1073, 1021, 919, 867, 838, 830,
1
1074, 999, 962, 895, 816, 721. H NMR (CDCl3, 600 MHz): δ
7.34 (ddt, J ) 15.0, 11.4, 1.2 Hz, 1H), 6.54 (dd, J ) 11.4, 11.4
Hz, 1H), 6.07 (dt, J ) 15.0, 7.2 Hz, 1H), 5.56 (d, J ) 11.4, 1H),
3.71 (s, 3H), 2.2 (m, 2H), 1.25 (m, 20H), 0.87 (t, J ) 7.2 Hz, 3H).
13C NMR (CDCl3, 150 MHz): δ 166.9, 146.0, 145.6, 126.8, 114.9,
51.0, 33.0, 31.9, 29.65, 29.62 (2C), 29.5, 29.4, 29.3, 29.2, 28.8,
22.6, 14.0. MS(EI): calcd for [C18H32O2]+, 280; found, 280.13
(R)-5-((R)-1′-hydroxytridecyl)furan-2(5H)-one (5). Into a 10
mL round-bottom flask was added 1 mL of t-BuOH, 1 mL of
water, K3Fe(CN)6 (1.6 g, 4.7 mmol), K2CO3 (0.6 g, 4.7 mmol),
MeSO2NH2 (0.2 g, 1.57 mmol), (DHQD)2PHAL (26 mg, 34 µmol,
2.1 mol %), and OsO4 (4 mg, 16 µmol, 1 mol %). The mixture
was stirred at room temperature for about 15 min and then cooled
to 0 °C. To this solution was added (2Z,4E)-methyl heptadeca-2,4-
dienoate 6 (0.4 g, 1.57 mmol), and the reaction was stirred
vigorously at 0 °C overnight. The reaction was quenched with solid
sodium sulfite (10 mg) at room temperature. Ethyl acetate (5 mL)
was added to the reaction mixture, and after separation of the layers,
the aqueous phase was further extracted with the ethyl acetate (2
× 5 mL). The combined organic layers were washed with brine
and dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (5:1 (v/v)
1
803, 718, 656 cm-1. H NMR (CDCl3, 600 MHz): δ 7.45 (dd, J
) 6, 1.8 Hz, 1H), 6.18 (dd, J ) 6, 1.8 Hz, 1H), 4.98 (ddd, J ) 5.6,
1.8, 1.8 Hz, 1H), 3.75 (ddd, J ) 12, 6, 6 Hz, 1H), 2.1 (m, 1H),
1.59 (m, 2H), 1.52 (m, 2H), 1.32-1.25 (m, 20H), 0.87 (t, J ) 7.2
Hz, 3H). 13C NMR (CDCl3, 150 MHz): δ 172.7, 153.6, 122.7,
86.0, 71.8, 33.2, 31.8, 29.63, 29.60, 29.59, 29.52, 29.45, 29.40,
29.3, 25.4, 22.6, 14.0.14
(S)-Dihydro-5-((S)-1′-hydroxytridecyl)furan-2(3H)-one (ent-
4). Into a 50 mL round-bottom flask was added (S)-5-((S)-1′-
hydroxytridecyl)furan-2(5H)-one ent-5 (200 mg, 0.69 mmol), 20
mL of CH3OH, and 20 mg 10 wt % Pd on activated carbon. The
reaction was stirred under 1 atm of H2 for 24 h. Filtration and
evacuation under reduced pressure afforded 195 mg (97% yield)
ent-4 (+)-muricatacin as a white solid: mp 68-70 °C; Rf (50%
EtOAc/hexane) ) 0.55; [R]25D 19.7 (c 1.5, CH2Cl2). IR (thin film,
cm-1): 3394, 2952, 2915, 2848, 1742, 1471, 1362, 1268, 1186,
1101, 1019, 998, 977, 902, 832, 721. 1H NMR (CDCl3, 600 MHz):
(13) While we were able to generate a molecular ion for dienoate 6 using
electron impact ionization, we were unable to generate a molecular ion
using electrospray ionization techniques, thus we were unable to obtain
any high-resolution mass data.
(14) High-resolution MS data was not obtained for the enantiomers of
compounds 4 and 5.
6688 J. Org. Chem., Vol. 71, No. 17, 2006

δ 4.41 (ddd, J ) 7.2, 7.2, 4.2 Hz, 1H), 3.55 (ddd, J ) 8.4, 4.8, 4.8
Hz, 1H), 2.60 (dd, J ) 18, 9.6, 1H), 2.52 (dd, J ) 18, 9.6 Hz, 1H),
2.22 (m, 1H), 2.12 (m, 1H), 1.52 (m, 2H), 1.28-1.24 (m, 20H),
0.86 (t, J ) 7.2 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ 177.2,
82.9, 73.5, 32.9, 31.8, 29.6, 29.57 (2C), 29.51, 29.4 (2C), 29.2,
28.6, 25.4, 24.0, 22.6, 14.0.14
potassium carbonate (289 mg, 2.1 mmol) and (S)-1′-((R)-tetrahydro-
5′′-oxofuran-2′′-yl)tridecyl 4-nitrobenzoate 11 (180 mg, 0.42 mmol).
The mixture was stirred for 10 min at room temperature and then
filtered through a pad of Celite. The solvent was removed under
reduced pressure, and the residue was purified by chromatography
on silica gel (4:1 (v/v) hexanes/EtOAc) to afford 100 mg (85%
yield) of (S)-dihydro-5-((R)-1′-hydroxytridecyl)furan-2(3H)-one 10
(S)-1′-((R)-Tetrahydro-5′′xofuran-2′′-yl)tridecyl 4-Nitroben-
zoate (11). Into a 50 mL round-bottom flask was added 20 mL
THF. The mixture was cooled to 0 °C, and then triphenylphosphine
(440 mg, 1.89 mmol) and DEAD(330 mg, 1.89 mmol) were added,
followed by (S)-dihydro-5-((S)-1′-hydroxytridecyl)furan-2(3H)-one
(ent-4) (180 mg, 0.63 mmol) and p-nitro-benzoic acid (127 mg,
0.76 mmol). The mixture was stirred at room temperature for 2 h.
The solvent was removed under reduced pressure and the residue
was purified by chromatography on silica gel (20:1 (v/v) hexanes/
EtOAc) to afford 255 mg (92% yield) of (S)-1′-((R)-tetrahydro-
5′′-oxofuran-2′′-yl)tridecyl 4-nitrobenzoate 11 as a light yellow
as solid: mp 70-72 °C; Rf (50% EtOAc/hexane) ) 0.50; [R]25
D
14 (c 1.2, CH2Cl2). IR (thin film, cm-1): 3415, 2956, 2917, 2849,
1783, 1471, 1462, 1268, 1206, 1191, 1082, 1071, 1011, 729, 720.
1H NMR (CDCl3, 600 MHz): δ 4.40 (ddd, J ) 7.2, 7.2, 3 Hz,
1H), 3.92 (m, 1H), 2.58 (dd, J ) 18, 9.6, 1H), 2.50 (m, 1H), 2.25
(m, 1H), 2.13 (m, 1H), 1.51 (m, 2H), 1.41(m, 2H), 1.31-1.25 (m,
18H), 0.87 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 150 MHz): δ
177.4, 82.8, 71.3, 31.90, 31.88, 29.62, 29.60, 29.59, 29.53, 29.50,
29.47, 29.3, 28.6, 25.6, 22.6, 21.0, 14.0; HRMS(ESI): calcd for
[C17H32O3Na]+, 307.2249; found, 307.2243.
solid: mp 42-44 °C; Rf (30% EtOAc/hexane) ) 0.75; [R]25 8.1
D
(c 1.0, CH2Cl2). IR (thin film, cm-1): 2924, 2854, 1781, 1726,
Acknowledgment. We are grateful to NIH (Grant GM63150)
and NSF (Grant CHE-0415469) for the support of our research
program and NSF-EPSCoR (Grant 0314742) for a 600 MHz
NMR and an LTQ-FT mass spectrometer at WVU.
1608, 1528, 1465, 1348, 1268, 1179, 1115, 1102, 1014, 921, 873,
1
783, 719. H NMR (CDCl3, 600 MHz): δ 8.29 (m, 2H), 8.18 (m,
2H), 5.38 (ddd, J ) 9, 4.8, 4.8 Hz, 1H), 4.68 (ddd, J ) 7.8, 7.8,
4.2 Hz, 1H), 2.58 (m, 2H), 2.36 (dddd, J ) 13.2, 9.6, 7.8, 6.0 Hz,
1H), 2.21 (dddd, J ) 12.6, 9.6, 8.4, 7.2 Hz, 1H), 1.80 (m, 1H),
1.73 (m, 2H), 1.28-1.22 (m, 20H), 0.86 (t, J ) 7.2 Hz, 3H). 13C
NMR (CDCl3, 150 MHz): δ 176.0, 164.0, 150.7, 135.0, 130.7,
128.8, 123.6, 123.5, 79.8, 75.2, 31.8, 29.8, 29.57, 29.56, 29.52,
29.4, 29.3, 29.29, 29.28, 27.9, 25.1, 23.1, 22.6, 14.0. HRMS(ESI):
calcd for [C24H35NO6Na]+, 456.2362; found, 456.2357.
Supporting Information Available: Complete experimental
procedures and spectral data for all new compounds can be found
in the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
(S)-Dihydro-5-((R)-1′-hydroxytridecyl)furan-2(3H)-one (12).
Into a 5 mL round-bottom flask was added 3 mL CH3OH, then
JO061057S
J. Org. Chem, Vol. 71, No. 17, 2006 6689