Total synthesis and stereochemical assignment of cis-uvariamicin I and cis-reticulatacin

Article abstract of DOI:10.1021/jo9012578

(Graph Presented) Diastereoisomeric mixtures of cis-uvariamicin I (15R,16R,19S,20S,36S and 15S,16S,19R,20R,36S) and cis-reticulatacin (17R,18R,21S,22S,36S and 17S,18S,21R,22R,36S) were synthesized to determine the stereochemistry of the natural products i

Full text of DOI:10.1021/jo9012578

pubs.acs.org/joc
Total Synthesis and Stereochemical Assignment of cis-Uvariamicin I and
cis-Reticulatacin
†
Sherif B. Abdel Ghani, James M. Chapman, Bruno Figadere, Julie M. Herniman,
‡
§
ꢀ
G. John Langley, Scott Niemann,^ and Richard C. D. Brown*,
†Plant Protection Department, Faculty of Agriculture, Ain Shams University, Hadayek Shoubra 11241, Cairo, Egypt,
‡Department of Chemistry, Rockhurst University, Richardson 320-C, 1100 Rockhurst Road, Kansas City, Missouri
§
ꢁ
ꢁ
ꢁ
64110, Laboratoire de Pharmacognosie, associe au CNRS (BioCIS), Universite Paris-Sud, Faculte de Pharmacie,
Rue J-B Cleꢁment, Chatenay-Malabry, France 92296, France, School of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, United Kingdom, and ^CSS Analytical Company, Shawnee, Kansas 66218
rcb1@soton.ac.uk
Received June 22, 2009
Diastereoisomeric mixtures of cis-uvariamicin I (15R,16R,19S,20S,36S and 15S,16S,19R,20R,36S)
and cis-reticulatacin (17R,18R,21S,22S,36S and 17S,18S,21R,22R,36S) were synthesized to determine
the stereochemistry of the natural products isolated from Annona muricata. It was not possible to
resolve a mixture of the four synthetic isomers using chiral HPLC, but the mixed isomers could be
distinguished using chiral HPLC EIMS with extracted fragment ion analysis. Comparison of synthetic
standards with the natural isolate revealed that cis-uvariamicin I and cis-reticulatacin are present in
nature as mixtures of threo-cis-threo diastereoisomers. It is suggested that the nomenclature for the
natural products is amended as follows: (15R,16R,19S,20S,36S)-cis-uvariamicin I (cis-uvariamicin
IA); (15S,16S,19R,20R,36S)-cis-uvariamicin I (cis-uvariamicin IB); (17R,18R,21S,22S,36S)-cis-reti-
culatacin (cis-reticulatacin A); (17S,18S,21R,22R,36S)-cis-reticulatacin (cis-reticulatacin B).
Introduction
C34 unbranched fatty acids and frequently share several fea-
tures including 2,5-disubstituted tetrahydrofuran rings, secondary
alcohol groups, and a butenolide or lactone ring. Despite these
structural similarities, stereochemical and positional diversity
means that in excess of 400 annonaceous acetogenins are known.1a
Due to their waxy physical nature, structural determina-
tion of annonaceous acetogenins by X-ray diffraction has
rarely been possible.2 As a consequence, stereochemical
Annonaceous acetogenins are a substantial group of bioactive
natural products isolated from plants belonging to the Annon-
aceae family.1 Structuraly, these acetogenins derive from C32 or
(1) Reviews of the chemistry and biology of Annonaceous acetogenins:
ꢀ
(a) Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell,
E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303. (b) Alali, F. Q.; Liu, X. X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540. (c) Zeng, L.; Ye, Q.;
Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Nat. Prod.
Rep. 1996, 13, 275–306. (d) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.;
Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087–1117. (e) Saez, J.;
Sahpaz, S.; Villaescusa, L.; Hocquemiller, R.; Cave, A.; Cortes, D. J. Nat.
Prod. 1993, 56, 351–356. (f) Rupprecht, J. K.; Hui, Y. H.; McLaughlin, J. L.
J. Nat. Prod. 1990, 53, 237–278.
(2) (a) Yu, J. G.; Hu, X. F. E.; Ho, D. K.; Bean, M. F.; Stephens, R. E.;
Cassady, J. M.; Brinen, L. S.; Clardy, J. J. Org. Chem. 1994, 59, 1598–1599.
(b) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.; Goswami, A.;
Smith, C. R.; Moretti, C.; Schmidt, J. M.; Weisleder, D. Can. J. Chem.-Rev.
Can. Chim. 1987, 65, 1433–1435.
ꢁ
6924 J. Org. Chem. 2009, 74, 6924–6928
Published on Web 08/12/2009
DOI: 10.1021/jo9012578
r
2009 American Chemical Society

Abdel Ghani et al.
JOCFeatured Article
SCHEME 1. Synthesis of cis-Uvariamicin I Diastereoisomers
3A/B
FIGURE 1. Structures of selected mono-THF acetogenins isolated
from Annona muricata L. Ψcis-uvariamicin I and cis-reticulatacin
isolated together as a mixture.
assignment within the THF-containing regions has relied
upon analysis of NMR data from the natural products and
their derivatives.3-5 The position of THF rings along the
carbon backbone can be readily deduced from EIMS frag-
mentation patterns. However, additional synthesis and frag-
mentation of unsymmetrical derivatives may be necessary to
determine which chain is connected to which side of a central
mono- or bis-THF unit.4a Comparison of spectroscopic data
from the natural products with data collected from samples
prepared by total synthesis might have been expected to
answer these stereochemical issues, but certain groups
of stereoisomeric acetogenins give “substantially identical”
1H and 13C NMR spectra.5,6 In the present work, we show
how the structures of a mixture of four isomeric acetogenins
can be deduced by comparison of synthetic standards with
the natural isolate using chiral HPLC linked to EIMS with
extracted fragment ion analysis.
Seven mono-THF acetogenins, including cis-solamin (1),
cis-uvariamicin I (3), and cis-reticulatacin (5), were isolated
from the roots of a tropical fruit tree Annona muricata L.
(Figure 1).7 On the basis of their NMR chemical shift data,
six of these acetogenins, including 1-5, were shown to
contain threo-cis-threo configured 2,5-bis(hydroxyalkyl)-
tetrahydrofuran (THF-diol) motifs. However, only the re-
lative stereochemistry of the THF-diol could be determined
due to local symmetry within these molecules. Through total
synthesis of both likely threo-cis-threo diastereoisomers of
cis-solamin and chiral HPLC analysis, we discovered that
natural cis-solamin had actually been isolated as a mixture
of the two possible threo-cis-threo diastereoisomers [cis-sol-
amin A (1A) and cis-solamin B (1B)].6
existence of two stereoisomers A/B for each but also to the
fact that these structural isomers 3 and 5 had not been
separated during isolation. To resolve this puzzle, we decided
to synthesize both natural products as predefined mixtures of
threo-cis-threo isomers 3A/B and 5A/B and then use the
synthetic mixtures to facilitate the analysis of the natural
isolate using chiral HPLC.
We were intrigued whether this observation extended to
other mono-THF acetogenins. The stereochemical assign-
ment of cis-uvariamicin I (3) and cis-reticulatacin (5) pre-
sented an exceptional challenge due not only the possible
Results and Discussion
The synthesis of cis-uvariamicin I (3) was tackled first using
the permanganate-mediated oxidative cyclization of (E,E)-
1,5-dienoyl system 8 to secure the threo-cis-threo-configured
THF-diol core (Scheme 1).6 The (2R)-camphor sultam auxili-
ary was used to impart diastereofacial bias in the oxidative
cyclization, thereby delivering a separable mixture of THF-
diols 9A and 9B (dr ∼ 1:6).8 This diastereoisomeric mixture
was used in the subsequent steps so that cis-uvariamicin I was
ultimately obtained as a mixture of two diastereoisomers
3A and 3B in an approximate ratio of 1:6. As anticipated,
the fact that a mixture of cis-uvariamicin I diastereoisomers
had been synthesized was not apparent from inspection of
1H or 13C NMR spectra, with only one set of signals observed.
Furthermore, physical and spectroscopic data recorded for
(3) Analysis of relative stereochemistry by NMR: (a) Hoye, T. R.;
Suhadolnik, J. C. J. Am. Chem. Soc. 1987, 109, 4403–4404. (b) Hoye,
T. R.; Zhuang, Z. P. J. Org. Chem. 1988, 53, 5578–5580. (c) Born, L.; Lieb,
F.; Lorentzen, J. P.; Moeschler, H.; Nonfon, M.; Sollner, R.; Wendisch, D.
Planta Med. 1990, 56, 312–316. (d) Fujimoto, Y.; Murasaki, C.; Shimada, H.;
Nishioka, S.; Kakinuma, K.; Singh, S.; Singh, M.; Gupta, Y. K.; Sahai, M.
Chem. Pharm. Bull. 1994, 42, 1175–1184.
(4) Application of Mosher’s ester derivatives of Annonaceous aceto-
genins: (a) Rieser, M. J.; Hui, Y. H.; Rupprecht, J. K.; Kozlowski, J. F.;
Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang, Z. P.; Hoye, T. R.
J. Am. Chem. Soc. 1992, 114, 10203–10213. (b) Hoye, T. R.; Jeffrey, C. S.;
Shao, F. Nature Protoc. 2007, 2, 2451–2458.
(5) Curran, D. P.; Zhang, Q. S.; Lu, H. J.; Gudipati, V. J. Am. Chem. Soc.
2006, 128, 9943–9956.
(6) (a) Cecil, A. R. L.; Hu, Y.; Vicent, M. J.; Duncan, R.; Brown, R. C. D.
J. Org. Chem. 2004, 69, 3368–3374. (b) Hu, Y. L.; Cecil, A. R. L.; Frank, X.;
Gleye, C.; Figadere, B.; Brown, R. C. D. Org. Biomol. Chem. 2006, 4, 1217–
1219.
ꢁ
(7) Gleye, C.; Duret, P.; Laurens, A.; Hocquemiller, R.; Cave, A. J. Nat.
Prod. 1998, 61, 576–579.
(8) The diastereoisomers were separated for characterization, then
recombined.
J. Org. Chem. Vol. 74, No. 18, 2009 6925

Abdel Ghani et al.
JOCFeatured Article
FIGURE 2. Ruthenium-catalyzed Alder-ene reaction products 14B
and 15B (major diastereoisomers shown).
FIGURE 3. Characteristic EIMS fragment ions for 3 and 5.
our mixture were in excellent agreement with data reported for
the mixture of cis-uvariamicin I and cis-reticulatacin isolated
from Annona muricata L.7
The synthesis of the butenolide ring system deserves some
comment because the regioisomeric addition byproduct 14
(R=Et) obtained from the Trost Alder-ene reaction, be-
tween 11A/11B and (S)-ethyl 4-hydroxypent-2-ynoate, pro-
ved very difficult to separate from the desired butenolide 15
(Figure 2). The commercially available catalyst Cp(CH3-
9
CN)3RuPF6 gave some advantage in terms of regioselec-
tivity over CpRu(cod)Cl (15:14 ∼ 10:1),10 but a significant
quantity of the regioisomer was still present. Changing the
alkyne ester group to 4-nitrobenzyl ultimately permitted
separation of the desired Alder-ene product from the
regioisomeric addition byproduct 14.
The total synthesis of a mixture of cis-reticulatacin stereo-
isomers 5A/5B (dr ∼ 1:8)8 was accomplished similarly in 11
steps and 17% overall yield from alkyne 6. 1H and 13C NMR
data for 5A/5B were consistent with those reported for the
natural isolate and very similar to those obtained for syn-
thetic cis-uvariamicin I.7,11
FIGURE 4. Reconstructed chromatograms for a mixture of syn-
thetic 3A/B and 5A/B (traces A and B), and the natural isolate
(traces C and D).
the effluent from the chiral column by EIMS, enabling
reconstruction of chromatograms using the total ion and
extracted ion currents (TIC and EIC) for the two fragment
ions (Figure 4). Four peaks could then be visualized for the
mixture of synthetic standards using the reconstructed chro-
matograms. Furthermore, the natural isolate clearly showed
two peaks corresponding to uvariamicin I isomers (3A and
3B) in approximately equal amounts (blue trace). Also
evident were two weak peaks (red trace), which corre-
sponded to the reticulatacin isomers (5A and 5B), thereby
showing that the natural isolate was in fact a mixture of
structural and stereoisomers.12,13
In summary, we have determined that natural cis-uvariami-
cin I and cis-reticulatacin, isolated from Annona muricata L.,
are each mixtures of both possible threo-cis-threo diastereoi-
somers. We believe that it is likely that other related mono-THF
acetogenins, which possess the same relative configuration in
their THF diol cores, are also mixtures of diastereoisomers. For
cis-solamin, cis-uvariamicin I, and cis-reticulatacin we have
found it to be convenient to refer to the diastereoisomers with
R,R,S,S- and S,S,R,R-configured THF cores as A and B,
respectively (i.e., (17R,18R,21S,22S,36S)-cis-reticulatacin is
Chiral HPLC analysis of the synthetic samples using a
CD-Ph column allowed us to achieve baseline separation of
the cis-uvariamicin I diastereoisomers (3A/3B, ∼1:6 mixture)
and near baseline separation of the cis-reticulatacin di-
astereoisomers (5A/5B, ∼1:8 mixture).12 However, it was
not possible to fully resolve the mixture obtained after the
four synthetic isomers (3A/3B and 5A/5B) were combined,
with only three peaks being evident in the HPLC chromato-
gram (UV detection at 214 nm). Furthermore, chiral HPLC
analysis of the natural isolate (cis-uvariamicin I þ cis-
reticulatacin) showed only two peaks. These two peaks
corresponded to 3A and 3B rather than 3A/B and 5A/B,
an observation that was consistent with the presence of
cis-reticulatacin as a minor component in the natural
isolate.
Fortunately, the structural isomers 3 and 5 are distin-
guished on the basis of their EIMS fragment ions m/z 295
and 323, respectively (Figure 3). It was possible to analyze
(9) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739–7743.
(10) Exclusive formation of the desired butenolide has been reported
for a very similar substrate: Goksel, H.; Stark, C. B. W. Org. Lett. 2006, 8,
3433–3436.
(11) 1H and 13C NMR data are compared in the Supporting Information.
(12) See the Supporting Information for copies of HPLC chromato-
grams.
(13) The results were further supported by collecting fractions from the
chiral HPLC and analyzing the individual fractions using APCI MS (see the
Supporting Information).
6926 J. Org. Chem. Vol. 74, No. 18, 2009

Abdel Ghani et al.
JOCFeatured Article
EtOAc/hexane 20:80 f 35:65) gave the monotosylate (210 mg,
cis-reticulatacin A). It is suggested that, where possible, a
similar nomenclature is applied to other mono-THF acetogen-
ins possessing threo-cis-threo-configured THF-diol core units
when the absolute stereochemistry of the core is in doubt.
However, some caution should be exercised due to the existing
use of letters in the names for certain acetogenins.1a
0.41 mmol, 100%, er ∼ 6:1) as a white solid: mp 70-72 ꢀC; [R]26
D
þ10.2 (CHCl3, c 0.30); IR (neat) 3425, 3309, 2915, 2848, 1593
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 (2H, d, J=8.2 Hz),
7.35 (2H, d, J=8.2 Hz), 4.09 (2H, d, J=6.0 Hz), 4.00 (1H, dt, J=
3.0, 6.8 Hz), 3.84 (1H, dt, J = 4.0, 6.9 Hz), 3.77-3.71 (1H, m),
3.45-3.39 (1H, m), 3.36 (1H, br). 2.54 (1H, br), 2.45 (3H, s),
2.02-1.7 (4H, m), 1.47-1.40 (2H, m), 1.34-1.20 (24H, m), 0.88
(3H, t, J=6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 145.0, 132.9,
130.0, 128.1, 82.7, 78.6, 74.2, 71.7, 71.6, 34.6, 32.0, 29.8, 29.7,
29.4, 28.2, 27.9, 25.9, 22.8, 21.7, 14.2; LRMS (ESþ) m/z 535
([M þ Na]þ).
Experimental Section
Oxidative Cyclization Products 9A and 9B. At -30 ꢀC,
powdered KMnO4 (221 mg, 1.40 mmol) was added in one batch
to a rapidly stirred solution of diene 8 (520 mg, 1.00 mmol) in
AcOH/acetone (25 mL, 2:3). The reaction mixture was allowed
to warm to -10 ꢀC over 1 h, whereupon ice-cold saturated
aqueous Na2S2O5 (20 mL) was added followed by EtOAc
(40 mL). The organic phase was separated,and the aqueous
layer was re-extracted with EtOAc (3 ꢀ 20 mL). The combined
organic extracts were dried (MgSO4), and solvents were
removed in vacuo to give a yellow oil. Purification by column
chromatography (silica gel, Et2O/hexane 1:4 f 3:2) gave the title
THF-diols a two separate diastereoisomers (9A and 9B com-
bined: 399 mg, 0.7 mmol, 70%) as gummy oil. The two diaster-
eoisomers were separated, and after all the required physical and
analytical data were collected, the two separated diastereoi-
somers were mixed to form an approximately 6:1 mixture of 9B
and 9A, respectively. Data for 9B (syrup): [R]26D -20.5 (CHCl3,
(R)-1-((2R,5S)-5-((S)-oxiran-2-yl)-tetrahydrofuran-2-yl)penta-
decan-1-ol (10B) (er ∼ 6:1). To a solution of the above tosylate
(750 mg, 1.46 mmol) in THF (2 mL) and MeOH (10 mL) at 0 ꢀC
was added dried powdered K2CO3 (253 mg, 1.83 mmol) in one
batch. The solution was allowed to stir at rt for 1 h before
concentration in vacuo to give an oily residue which was filtered
through a plug of silica gel, eluting with EtOAc/hexane (3:7).
Following removal of the solvents in vacuo, the residue was
purified by column chromatography (silica gel, EtOAc/hexane
3:7) to give the epoxides 10A/B (470 mg, 1.39 mmol, 95%,
er ∼ 1:6) as a white solid: mp 36-40 ꢀC; [R]26D þ16.6 (CHCl3,
c 0.25); IR νmax (neat) 3420, 2921, 2825, 1462 cm-1; 1H NMR
(400 MHz, CDCl3) δ 4.06 (1H, dt, J=3.2, 6.9 Hz), 3.88 (1H, dt,
J = 4.5, 7.4 Hz), 3.47-3.30 (1H, m), 3.03 (1H, td, J = 3.0,
4.0 Hz), 2.84-2.72 (2H, m), 2.80 (1H, br), 2.17-1.83 (4H, m),
1.57-1.12 (26 H, m), 0.88 (3H, t, J = 6.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 83.1, 77.2, 74.3, 54.6, 44.4, 34.8, 32.0,
29.9, 29.8, 29.5, 29.3, 28.2, 26.0, 22.8, 14.2; LRMS (ESþ) m/z 363
([M þ Na]þ); HRMS (ES) C21H40O3Naþ calcd 363.2870, found
363.2867.
c 0.39); IR (neat) 2922, 1690, 1332, 1272, 1218, 1136, 1111 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.60-4.54 (2H, m), 4.05 (1H, br,
m), 3.96 (1H, dd, J=5.1, 7.5 Hz), 3.87 (1H, dt, J = 4.6, 7.1 Hz),
3.51 (1H, d, J = 13.8 Hz), 3.48-3.43 (1H, m), 3.43 (1H, d,
J=13.8 Hz), 2.30-2.21 (1 H, m), 2.14-2.00 (3H, m), 1.98-1.70
(5H, m), 1.55-1.20 (28H, m), 1.15 (3H, s), 0.97 (3H, s), 0.88 (3H,
t, J=6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 171.8, 83.3, 78.7,
74.0, 73.6, 65.9, 53.1, 49.1, 47.9, 44.7, 38.3, 34.6, 33.0, 32.0, 29.4,
28.4, 28.2, 26.5, 25.9, 22.7, 20.9 19.9, 14.2; LRMS (ESþ) m/z
1161 592 ([M þ Na]þ), 570 ([M þ H]þ). Data for 9A are included
in the Supporting Information.
(S)-1-((2S,5R)-5-((R)-1-Hydroxypentadecyl)tetrahydrofuran-
2-yl)tridec-12-en-1-ol (11B) (er ∼ 6:1). At -60 ꢀC, undec-10-
enylmagnesium bromide in THF (2 mL of a 0.4 M solution,
0.8 mmol) was added dropwise to a suspension of CuBr (70 mg,
0.367 mmol) in THF (5 mL). The mixture was warmed to -30 ꢀC
(gray color) and after 20 min recooled to -60 ꢀC whereupon a
solution of epoxide 10A/B (50 mg, 0.147 mmol, er ∼ 1:6) in THF
(5 mL) was added dropwise. The mixture was allowed to warm
to -20 ꢀC over 1 h. Aqueous NH4Cl/NH3 (9:1, 12 mL) was
added to the reaction mixture, followed by EtOAc (20 mL). The
organic phase was separated, and the aqueous phase was re-
extracted with EtOAc (2 ꢀ 20 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to give
a yellow oil. Purification by column chromatography (silica
gel, EtOAc/hexane 7:93 f 1:4) gave the title olefin (73 mg,
(S)-1-((2S,5R)-5-((R)-1-Hydroxypentadecyl)tetrahydrofuran-
2-yl)ethane-1,2-diol (er ∼ 6:1). To a solution of 9A/9B (1.52 g,
2.72 mmol, dr ∼ 1:6) in THF (80 mL) and H2O (5 mL) at -10 ꢀC
was added NaBH4 (206 mg, 5.44 mmol). The mixture was
allowed to warm to 0 ꢀC over 2 h, and then aqueous HCl
(2 M, 10 mL), EtOAc (30 mL), and brine (20 mL) were added
and the organic layer was separated. The aqueous layer was re-
extracted with EtOAc (5 ꢀ 20 mL), the combined organic phases
were dried (MgSO4), and solvents were removed in vacuo to give
a colorless oil. Purification by column chromatography (silica
gel, MeOH/CH2Cl2 0:1 f 3:97) gave the title triols (781 mg,
2.17 mmol, 80%, er ∼ 6:1) as a white solid: mp 49-51 ꢀC;
0.16 mmol, 82%) as a white solid: mp 48-51 ꢀC; [R]27 þ0.5
D
(CHCl3, c 0.7); IR (neat) 3431, 2918, 2849 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 5.82 (1H, tdd, J = 7.0, 10.1, 17.0 Hz),
4.99 (1H, tdd, J=1.4, 2.3, 17.0 Hz), 4.93 (1H, tdd, J=1.2, 2.3,
10.1 Hz), 3.86-3.79 (2H, m), 3.42 (2H, td, J=5.3, 6.7 Hz), 2.37
(2H, br), 2.04 (2H, q, J = 7.0 Hz), 1.99-1.86 (2H, m), 1.81-1.69
(2H, m) 1.56-1.18 (42H, m), 0.88 (3H, t, J=6.7 Hz); 13C NMR
(100 MHz, CDCl3) δ 139.4, 114.2, 82.8, 74.5, 34.3, 33.9, 32.1,
29.8, 29.7, 29.6, 29.5, 29.3, 29.1, 28.3, 25.8, 22.8, 14.2; LRMS
(ESþ) m/z 517 ([M þ Na]þ); HRMS (ES) C32H62O3Naþ calcd
517.4591, found 517.4581.
[R]26D þ12.4 (CHCl3, c 0.45); IR (neat) 3375, 2922, 2852 cm-1
;
1H NMR (400 MHz, CD3OD) δ 4.00 (1H, dt, J=4.0, 6.3 Hz),
3.83 (1H, dt, J=4.8, 6.8 Hz), 3.64 (1H, dd, J = 6.0, 11.2 Hz),
3.6 (1H, dd, J = 6.3, 11.2 Hz), 3.56-3.51 (1H, m), 3.46-3.41
(1H, m), 2.04-1.80 (4H, m), 1.55-1.45 (2H, m), 1.42-1.26
(24H, m), 0.93 (3H, t, J = 6.5 Hz); 13C NMR (100 MHz,
CD3OD) δ 83.8, 80.8, 75.2, 74.9, 65.1, 35.2, 33.1, 30.8,
30.7, 30.5, 28.9, 28.6, 26.9, 23.7, 14.4; LRMS (ESþ) m/z 381
([M þ Na]þ).
(4E)-4,5-Didehydro-cis-uvariamicin I (15B) (dr ∼ 6:1). The
procedure was carried out by an adaptation of the method
described by Trost and Toste.9 Under an atmosphere of nitro-
(S)-2-Hydroxy-2-((2S,5R)-5-((R)-1-hydroxypentadecyl)tetra-
hydrofuran-2-yl)ethyl 4-methylbenzenesulfonate (er ∼ 6:1). To a
solution of the above triol (146 mg, 0.41 mmol, er ∼ 6:1) in
benzene (5 mL) was added Bu2SnO (121 mg, 0.49 mmol), and
the mixture was heated at reflux for 3 h. After the reaction
mixture was cooled to rt, TsCl (86 mg, 0.45 mmol) was added
followed after 10 min by TBAB (132.17 mg, 0.41 mmol). After
30 min, the reaction mixture was concentrated in vacuo. Pur-
ification of the residue by column chromatography (silica gel,
gen, [CpRu(CH3CN)3]þPF6 (17.4 mg, 0.04 mmol, 5 mol %)
-
was added to a stirred solution of the terminal olefin 11B
(200 mg, 0.4 mmol, er ∼ 6:1) and alkyne 13 (120 mg, 0.48 mmol)
in DMF (15 mL). The solution was allowed to stir at rt for
1 h before the reaction mixture was passed through a plug
of silica (4 cm, EtOAc/hexane, 2:3) and then concentrated
in vacuo. Purification by column chromatography (silica gel,
J. Org. Chem. Vol. 74, No. 18, 2009 6927

Abdel Ghani et al.
JOCFeatured Article
EtOAc/hexane 1:9 f 1:1) gave the title butenolide 15B (166 mg,
0.29 mmol, 70%) as a white solid and uncyclized nitrobenzyl
ester (21 mg, 0.028 mmol, 7%) as a white solid. Data for the title
compound 15B: mp 65-68 ꢀC; [R]27D þ10.6 (CHCl3, c 0.39); IR
(neat) 3428, 2917, 2848, 1739, 1470 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.99 (1H, q, J=1.5 Hz), 5.58 (1H, ttd, J=1.2, 6.8,
15.0 Hz), 5.47 (1H, ttd, J = 1.2, 6.5, 15.0 Hz), 5.03 (1H, qq,
J=1.7, 6.8 Hz), 3.865-3.79 (2H, m), 3.45-3.40 (2H, m), 2.98-
2.94 (2H, m), 2.36 (2H, br), 2.06-1.99 (2H, m), 1.98-1.89
(2H, m), 1.81-1.71 (2H, m), 1.54-1.20 (40H, m), 1.42 (3H, d,
J = 6.8 Hz), 0.89 (3H, t, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 173.6, 149.5, 134.3, 133.7, 124.3, 82.8, 77.7, 74.4 34.2,
32.6, 32.0, 29.8, 29.7, 29.7, 29.6, 29.5, 29.4, 29.2, 28.5, 28.2,
25.8, 22.8, 19.2, 14.2; LRMS (ESþ) m/z 613 ([M þ Na]þ), 591
([M þ H]þ); HRMS (ES) C37H66O5Naþ calcd 613.4802, found
613.4795.
cis-Uvariamicin I (3A/B, dr ∼ 1:6). To a solution of 4,
5-dihydro-cis-uvariamicin I B (15B, 160 mg, 0.27 mmol, dr ∼
6:1) and TsNHNH2 (503 mg, 2.7 mmol) in THF (5 mL) was
added a solution of NaOAc (81.4 mg, 2.7 mmol) in H2O (2 mL).
The mixture was heated at 80 ꢀC for 36 h. EtOAc (10 mL) and
brine (3 mL) were added. The organic phase was separated, and
the aqueous phase was extracted with EtOAc (2 ꢀ 10 mL). The
combined organic extracts were dried (MgSO4), and solvents
were removed in vacuo to give a white solid. The residue was
dissolved in Et2O, washed with 1 M HCl solution, brine, satu-
rated KHCO3, and then dried (MgSO4). Purification by column
chromatography (silica gel, EtOAc/hexane 15:85 f 25:75) gave
cis-uvariamicin I (3A/B) (144 mg, 0.24 mmol, 90%, dr ∼ 1:6) as a
white solid. Spectroscopic data are consistent with those reported
for a mixture of 3 and 5:7 mp 68-72 ꢀC; [R]27 þ12.5 (CHCl3,
D
c 0.87); IR (neat) 3513, 3437, 2915, 2847, 1743, 1469, 1373, 1169,
1120, 1078 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.98 (1H, q, J=
1.6 Hz), 4.99 (1H, qq, J=1.6, 6.8 Hz), 3.85-3.78 (2H, m), 3.42
(2H, td, J=5.3, 6.6 Hz), 2.55 (2H, br, s), 2.28-2.23 (2H, m),
1.98-1.88 (2H, m), 1.79-1.69 (2H, m), 1.62-1.10 (46H, m), 1.47
(3H, d, J=6.8 Hz,), 0.87 (3H, t, J=6.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 174.0, 148.9, 134.5, 82.8, 77.5, 74.5, 34.2, 32.0, 29.8,
29.7, 29.6, 29.4, 29.4, 29.3, 28.2, 27.5, 25.9, 25.3, 22.8, 19.3, 14.2;
LRMS (ESþ) m/z 615 ([M þ Na]þ), 593 ([M þ H]þ); HRMS
(ESþ) C37H68O5þ calcd 592.496, found 592.494.
Acknowledgment. We thank The Royal Society (R.C.D.B.,
University Research Fellowship), Dr. L. J. Brown for assis-
tance during the preparation of the manuscript, and The
Egyptian Education & Culture Bureau (S.B.A.G., Mission
Scholarship).
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data for cis-reticu-
latacin series 6-8 and 13. Spectroscopic characterization data
1
for 9A and 14. Copies of H and 13C NMR spectra for com-
pounds 3, 5, 7-11, and 13-15 and cis-reticulatacin series.
HPLC chromatograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
6928 J. Org. Chem. Vol. 74, No. 18, 2009