A bidirectional approach to the synthesis of a complete library of adjacent-bis-THF annonaceous acetogenins

Article abstract of DOI:10.1021/jo050697c

Thirty-six stereoisomers of bifunctional adjacent bis-THF (tetrahydrofuran) lactones have been synthesized, which can afford a complete library of the adjacent bis-THF Annonaceous acetogenins. The bis-THF lactones were synthesized, starting from the enant

Full text of DOI:10.1021/jo050697c

A Bidirectional Approach to the Synthesis of a Complete Library
of Adjacent-Bis-THF Annonaceous Acetogenins
Sanjib Das, Lian-Sheng Li, Sunny Abraham, Zhiyong Chen, and Subhash C. Sinha*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
subhash@scripps.edu
Received April 7, 2005
Thirty-six stereoisomers of bifunctional adjacent bis-THF (tetrahydrofuran) lactones have been
synthesized, which can afford a complete library of the adjacent bis-THF Annonaceous acetogenins.
The bis-THF lactones were synthesized, starting from the enantioselectively pure 8,9:12,13-(E,E
and Z,E)-16-benzyloxy-5-hydroxy-hexadeca-1,4-olide, in a highly distereoselective manner using
oxidative reactions, including rhenium(VII) oxides-mediated oxidative cyclization, Shi’s asymmetric
epoxidation, and Sharpless asymmetric dihydroxylation reactions. Using the nonsymmetrical bis-
THF lactones, syntheses of two nonnatural acetogenins were achieved.
Introduction
Many Annonaceous acetogenins, especially the adja-
cent bis-THF (tetrahydrofuran) acetogenins are known
for their impressive antitumor activities.1 Few of these
compounds, including asimicin (Ia),2 bullatacin (Ib),3
trilobacin (1c),4 and rolliniastatin-1 (Id)5 (Figure 1), have
shown in vitro antitumor potency 108 times greater than
that of adriamycin. The antitumor properties of these
molecules originate from their ability to strongly inhibit
the complex I in the mitochondria,6 which also make
these compounds an interesting tool to investigate the
(1) Alali, Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504 and references therein.
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L. Heterocycles 1986, 24, 1197.
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D. L.; Chang, C.-J.; McLaughlin, J. L. J. Nat. Prod. 1989, 52, 463.
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K. V. J. Nat. Prod. 1992, 55, 347. (b) Zhao, G.-X.; Gu, Z.-M.; Zeng, L.;
Chao, J.-F.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L. Tetra-
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therein.
FIGURE 1. Structure of the representative adjacent bis-THF
acetogenins.
structure-function problems of complex I.7 These natural
products share very similar carbon skeletons, in that a
10.1021/jo050697c CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/22/2005
5922
J. Org. Chem. 2005, 70, 5922-5931

Synthesis of Adjacent-Bis-THF Acetogenins
SCHEME 1. Partial retro-Synthetic Analysis of
long alkyl chain tethers THF fragments to a butenolide
group, which represents the conserved part of most
acetogenins. Yet, they exhibit remarkable structural
diversity with the main variations being the relative and
absolute configuration of the various stereogenic oxygen
functions. An adjacent bis-THF acetogenin can exist in
as many as 64 diastereomeric forms due to six stereogenic
centers of the bis-THF fragment. The cytotoxicity and
selectivity of these molecules to the specific cell lines are
expected to be highly dependent upon the stereo- and
regiochemistry of all stereogenic centers, including the
bis-THF fragment. Hence, to properly address the rela-
tionship between the stereochemistry of this fragment
and the biological activity of these acetogenins, it is
imperative that all 64 diastereomeric acetogenins be
produced and evaluated.
Adjacent Bis-THF Librariesa
Production of a library of the adjacent bis-THF aceto-
genins has remained a challenging goal despite numerous
reports on the syntheses of natural and nonnatural
acetogenins.8 Only recently, synthesis of all 16 stereo-
isomers of a mono-THF acetogenin has been reported.9
Also, there has been some advancement toward the
library of the adjacent bis-THF acetogenins.10 Earlier, we
also designed the synthetic strategies that could give 32
of the 64 adjacent bis-THF acetogenins.11 Nevertheless,
there is no report yet on the synthesis of the complete
library of the adjacent bis-THF acetogenins. Here, we
report the synthesis of 36 stereoisomeric bifunctional
lactones that can afford all 64 stereoisomers of the
adjacent bis-THF acetogenins, I. We also describe the
total synthesis of two nonnatural diastereomeric aceto-
genins, Ie and If, starting from a common bis-THF
(7) (a) Zafra-Polo, M. C.; Gonzalez, M. C.; Estornell, E.; Sahpaz, S.;
Cortes, D. Phytochemistry 1996, 42, 253. (b) Miyoshi, H.; Ohshima,
M.; Shimada, H.; Akagi, T.; Iwamura, H.; McLaughlin, J. L. BBA -
Bioenergetics 1998, 1365, 443. (c) Tormo, J. R.; Gonzalez, M. C.; Cortes,
D.; Estornell, E. Arch. Biochem. Biophys. 1999, 369, 119.
a Compounds 39, 40, 43, and 44 are the enantiomers of 38, 37,
42, and 44, respectively, and they can be named as ent-38, ent-
37, and so on. However, for simplicity, hereon we used a new
number for each enantiomer.
(8) (a) Reference 15. (b) Hoye, T. R.; Hanson, P. R.; Kovelesky, A.
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Koert, U. Tetrahedron Lett. 1994, 35, 2517. (d) Hoye, T. R.; Ye, Z. J.
Am. Chem. Soc. 1996, 118, 1801. (e) Marshall, J. A.; Hinkle, K. W. J.
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G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632. (g) Marshall, J. A.;
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2004, 43, 2 and references therein.
lactone to show the viability of our approach for the
generation of the combinatorial library of the 64 stereo-
isomers of I and their analogues.
Results and Discussion
An examination of the adjacent bis-THF acetogenin
molecules reveals that a complete library of 64 stereo-
isomers of I can be synthesized by the coupling of 64 bis-
THF fragments (such as II) with a single butenolide
precursor (Scheme 1). The coupling reaction can be
achieved using a number of methodologies, including the
intramolecular and cross-metathesis reaction,12 palladium-
catalyzed coupling processes,13 and the Wittig reaction.14
Earlier, we had successfully utilized the palladium-
catalyzed coupling processes, and the Wittig reaction for
the synthesis of a number of Annonaceous acetogenins,
such as, solamin, reticulatacin, asimicin, bullatacin,
trilobacin, trilobin, uvaricin, rolidecin C and D, and
(9) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc.
2004, 126, 36.
(12) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(13) Sonogashira, K.; Thoda, Y.; Magihara, N. Tetrahedron Lett.
1975, 13, 4467.
(14) (a) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369. (b)
Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (c) Nicolaou,
K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann./Recl.
1997, 7, 1283.
(10) (a) Maezaki, N.; Kojima, N.; Tominaga, H.; Yanai, M.; Tanaka,
T. Organic Lett. 2003, 5, 1411. (b) Kojima, N.; Maezaki, N.; Tominaga,
H.; Yanai, M.; Urabe, D.; Tanaka, T. Chem.-Eur. J. 2004, 10, 672.
(11) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J. Org. Chem.
1996, 61, 7640.
J. Org. Chem, Vol. 70, No. 15, 2005 5923

Das et al.
mucocin.15 Here, we decided to test the utility of cross
metathesis reaction for the assembly of I.16 Thus, using
all possible stereoisomers of II and the butenolide alkene
III, one may produce the 64 stereoisomers of I in a
parallel combinatorial synthesis. Obviously, synthesis of
all stereoisomers of II remains the major determining
factor for the production of the bis-THF acetogenin
library considering that there exists a number of syn-
thetic methods8 for the synthesis of the butenolide
fragment, III.15b We anticipated that all 64 stereoisomeric
II could be obtained via the intermediates IV and/or V
in two ways. In one case, 64 stereoisomers of the
intermediates IV or V will be used, which will be obtained
from the identical number of their precursors. Alterna-
tively, all 64 stereoisomers of II can be prepared starting
from the 36 stereoisomeric bifunctional lactones (1-36,
Table 1) using a combination of intermediates IV and V.
The adjacent bis-THF acetogenins can be divided into
two sets, which differ from each other being the threo
(set I) or erytho (set II) configuration of C-19/C-20 joining
the bis-THF rings (Table 1). Each set is comprised of 32
compounds and can further be divided into three subsets
on the basis of the stereochemistry of bis-THF rings,
trans-trans, cis-cis, and trans-cis or cis-trans. As
shown in Table 1, four trans-trans and four cis-cis
acetogenins in set I are pseudo-symmetric at C-19/C-20
center, whereas the remaining 56 acetogenins are non-
symmetrical. Likewise, 8 bis-THF lactones (1-4 and
7-10) are pseudo-symmetric at C-8/C-9 center, and the
remaining 28 (5,6 and 11-36) are nonsymmetrical. The
nonsymmetrical bis-THF lactones (5,6 and 11-36) can
flip along the x-axis to afford the identical number of
stereoisomers. Thus, lactones 5,6 and 11-36 can be
functionalized at the two alternative ends to give each
28 stereoisomeric intermediates of IV and V, thereby
leading to a total of 56 stereoisomers of II. Functional-
ization of the remaining eight lactones 1-4 and 7-10,
at either end, will afford an additional eight stereo-
isomers of II via IV or V.
TABLE 1. Stereochemical Correlation of All 64
Adjacent Bis-THF Acetogenins of the General Structure I
with Bis-THF Lactones, 1-36a
a C ompounds 2, 4, 6, etc. are the enantiomers of 1, 3, 5, and
so on, and they can be named as ent-1, ent-3, ent-5, etc. However,
for simplicity, hereon we used a new number for each enantiomer.
um(VII) oxides-mediated oxidative cyclization (OC)19
reactions. These reactions were combined with William-
son’s type etherification20 and Mitsunobu inversion21 to
produce various bis-THF compounds. An analysis of
compounds 1-36 suggested that they could be syn-
thesized by stereospecific oxidative cyclizations of the
isomeric diene-lactones 37-40 using five key reac-
tions, which include Shi mono- or bis-asymmetric epoxi-
dation (AE),22 beside the rhenium(VII) oxides mediated
mono- or bis-OC, Sharpless AD, Williamson’s etheri-
fication, and the Mitsunobu inversion reactions. How-
ever, using the above-described key reactions, several bis-
THF compounds could be accessed better starting from
diene-lactones 41-44. Hence, we used diene-lactones
37-44 to synthesize 1-36. Table 2 shows the specific sets
of reactions used to convert 37-44 to 1-36. Here,
rhenium(VII) oxides-mediated OC reaction was con-
ducted on both cis and trans double bonds, whereas Shi
AE and Sharpless AD were executed with trans double
Earlier, we synthesized a number of Annonaceous
acetogenins starting from the “naked” carbon skeletons,
in that all of the oxygen functions were installed using
enantioselective and diastereoselective reactions, includ-
ing Sharpless asymmetric dihydroxylation (AD)17 and
asymmetric epoxidation (AE)18 reactions, and the rheni-
(15) (a) For solamin and reticulatacin, see: Sinha, S. C.; Keinan,
E. J. Am. Chem. Soc. 1993, 115, 4891. (b) Asimicin and bullatacin: (i)
Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahedron
Lett. 1995, 36, 9257. (ii) Avedissian, H.; Sinha, S. C.; Yazbak, A.; Sinha,
A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65, 6035.
(iii) Han, H.; Sinha, M. K.; D’Souza, L. J.; Keinan, E.; Sinha, S. C.
Chem.-Eur. J. 2004, 10, 2149. (c) Trilobacin: see ref 11. (d) Trilobin:
Sinha, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999,
64, 2381. (e) Uvaricin: Yazbak, A.; Sinha, S. C.; Keinan, E. J. Org.
Chem. 1998, 63, 5863. (f) Rolidecin C and D: D’Souza, L. J.; Sinha, S.
C.; Lu, S.-L.; Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57, 5255. (g)
Mucocin: Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha,
S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279. (h) Squamota-
cin: Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64,
7067. (i) Goniocin and epigoniocins: (i) Sinha, S. C.; Sinha, A.; Sinha,
S. C.; Keinan, E. J. Am. Chem. Soc. 1997, 119, 12014. (ii) Sinha, S. C.;
Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 4017.
(16) (a) See ref 8y. (b) For a related approach where acetogenin has
recently been synthesized by metathesis approach, see: Evans, P. A.;
Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem.
Soc. 2003, 125, 14702.
(18) (a) Pfenninger, A. Synthesis 1986, 2, 89. (b) Katsuki, T.; Martin,
V. S. Asymmetric epoxidation of allylic alcohols: The Katsuki-
Sharpless epoxidation reaction. Organic Reactions; John Wiley & Sons,
Inc.: New York, 1996; Vol. 48, pp 1-299.
(19) Keinan, E.; Sinha, S. C. Pure Appl. Chem. 2002, 74, 93.
(20) Koert, U. Synthesis 1995, 115.
(17) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Kolb, H. C.; Sharpless, K. B. Trans. Met. Org.
Synth. 1998, 2, 219.
(21) Dodge, J. A.; Jones, S. A. Rec. Res. Dev. Org. Chem. 1997, 1,
273.
(22) For a review, see: Shi, Y. Acc. Chem. Res. 2004, 37, 488.
5924 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Adjacent-Bis-THF Acetogenins
TABLE 2. Synthesis of Bis-THF Lactones 1-36a
SCHEME 2. Rhenium(VII) Oxides Mediated
Oxidative Cyclization (OC) of 37-44 To Produce
Mono- and Bis-THF Lactonesa
com-
starting
com-
starting
pounds materials methods pounds materials methods
1
41
44
38
39
37
40
12
11
40
37
38
39
37
40
37
40
39
38
38
39
D-2
D-1
C-1
C-2
C-1
C-2
E
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
41
43
43
42
27
38
37
40
37
40
37
40
38
39
39
38
A
C-1
A
A
E
B-2
B-2
B-1
D-2
D-1
B-1
B-2
D-2
D-1
B-2
B-1
2
3
4
5
6
7
8
E
9
F-1
F-2
F-2
F-1
C-2
C-1
A
10
11
12
13
14
15
16
17
18
19
20
A
A
A
a Key: (R ) -CH2CH2CH2OBn) (a) TFAOReO3, lutidine, CH2Cl2,
0 °C to rt, 6 h; (b) TFAOReO3, TFAA, CH2Cl2, 0 °C to rt, 6 h.
C-2
C-1
a Key: (A) bis-OC, (B-1) bis-R-AE, (B-2) bis-â-AE, (C-1) mono-
OC, then mono-R-AE, (C-2) mono-OC, then mono-â-AE, (D-1)
mono-OC, then R-AD, (D-2) mono-OC, then â-AD, (E) Mitsunobu
inversion, (F-1) mono-R-AE, then R-AD, (F-2) mono-â-AE, then
â-AD.
reagents used as well as the substrates. In general, OC
reaction of the bis-homoallylic and poly-bis-homoallylic
alcohols using TFAOReO3-lutidine or TFAOReO3-TFAA
has been found to be highly selective.26 TFAOReO3-
lutidine system is suitable for the production of mono-
THF compounds from the bis-homoallylic and poly-bis-
homoallylic alcohols, whereas TFAOReO3-TFAA affords
a poly-THF compound from the poly-bis-homoallylic
alcohol. Based on previous reports as well as our studies,25b
we have also derived the empirical rules for the mono-
and bis-oxidative cyclization of the isomeric diene alco-
hols. The rules state that the first THF ring is always
trans irrespective of the reagents and substrates, whereas
the second THF ring depends on the stereochemistry
of the first double bond and reagents used. Using
TFAOReO3-TFAA as a reagent, the second THF-ring is
cis with substrates possessing the first trans double bond
and trans THF-ring with the cis double bond. Thus, it
was anticipated that the mono- and bis-OC reactions of
dienes 37-44 using TFAOReO3-lutidine and TFAOReO3-
TFAA, respectively would also afford the corresponding
mono- and bis-THF compounds, the steroselectivity of
which could be predicted.
As required by our design (Table 2), we carried out
the mono-OC of dienes 37-41 and 43,44, and bis-OC of
37-43 (Scheme 2). The mono OC reaction of 37-41 and
43,44 was carried out with TFAOReO3-lutidine to afford
seven mono-THF compounds, 45-51. The latter products
became the precursors of several bis-THF compounds (see
latter). The bis-OC reaction of 37-43 was carried out
using TFAOReO3-TFAA to give seven bis-THF com-
pounds 15, 18, 17, 16, 21, 24, and 23, respectively
(Scheme 2). As expected, both mono-OC and bis-OC
reactions were found to be highly stereoselective, and the
bis-THF compounds obtained from 37-40 and 41-43
had trans,cis and trans,trans configurations, respec-
tively. The cis-stereochemistry of the second THF ring
in trans,cis-bis-THF compounds, such as 16 and 18, was
bonds only. Both one-step tandem and stepwise oxidation
of the two double bonds using rhenium(VII) oxides and
Shi AE were applied. Finally, Mitsunobu reaction was
carried out to invert the stereochemistry of C-13 in the
selected bis-THF compounds.
Using the one-step tandem reactions of 37-44, 14 bis-
THF lactones were synthesized, whereas the remaining
22 compounds required stepwise reactions, in that the
double bond nearer to the lactone ring was first oxidized
followed by the next double bond. Interestingly, many
of the bis-THF lactones 1-36 are potentially accessible
from 37-44 using more than one method. Hence, the
choice of method was based on the number of steps
required to accomplish the synthesis of the bis-THF
compounds from the starting diene lactones, 37-44.
Therefore, rhenium(VII) oxides-mediated bis-OC and Shi
bis-AE methods were applied as the first and second
choice, which afforded the bis-THF compounds from the
starting dienes in one and two steps, respectively. The
next set of bis-THF compounds was synthesized by
rhenium(VII) oxides-mediated mono-OC followed by Shi-
AE or the combination of Sharpless AD and Williamson’s
etherification. Finally, the remaining compounds were
prepared by using a combination of Shi-AE and Sharpless
AD, and by the Mitsunobu inversion of other bis-THF
compounds.
Rhenium(VII) Oxides-Mediated Oxidative Cy-
clization (OC) of 37-44.23 The rhenium(VII) oxides-
mediated oxidative cyclization24 of the bis-homoallylic and
poly-bis-homoallylic alcohols affords THF and poly-THF
compounds with very high selectivity.25 The selectivity
and the stereochemistry of the THF rings depend on the
(23) For the synthesis of starting materials, see the Supporting
Information.
(24) (a) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 3729.
(b) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299. (c) Tang,
S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303. (d) Boyce, R. S.;
Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133.
(25) (a) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Am. Chem.
Soc. 1995, 117, 1447. (b) Sinha, S. C.; Keinan, E.; Sinha, S. C. J. Am.
Chem. Soc. 1998, 120, 9076.
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(b) Towne, B. T.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022.
(c) Morimoto, Y.; Iwai, T. J. Am. Chem. Soc. 1998, 120, 1633.
J. Org. Chem, Vol. 70, No. 15, 2005 5925

Das et al.
SCHEME 3. Synthesis of Mono- and Bis-THF
verified by an NOE experiment on the corresponding
benzoate ester, which showed an NOE between the
signals for H-9 and H-12 (see Scheme 1 for the number-
ing). In contrast, the benzoate ester of compound 21,
which possesses both trans THF rings, did not display
any NOE between the signals for H-9 and H-12.
Lactones via the Enantioselective Shi Mono- and
Bis-Epoxidation Reactionsa
Synthesis of the Mono- and Bis-THF Lactones by
the Enantioselective Shi Bis-Epoxidation Followed
by Regioselective Epoxide Opening Reactions. Next,
we examined the application of Shi enantioselective
epoxidation for the synthesis of the mono- and bis-THF
lactones. Based on the reported literature,22 it was
expected that the Shi epoxidation of trans olefins would
afford the corresponding epoxides with high enantio-
selectivities, and accordingly we executed the Shi AE on
trans alkenes only. As shown in Table 2, seven bis-THF
lactones were designed using Shi bis-AE reactions on the
trans dienes 37-40. Thus, dienes 37-40 underwent
asymmetric epoxidation in the presence of D-fructose-
based (-)-Shi catalyst to give the corresponding desired
bisepoxides contaminated with the bis-THF compounds
(5-10%). Cycloetherification of the respective bisepoxides
using the catalytic amount of camphorsulfonic acid (CSA)
afforded the bis-THF compounds 27, 26, 35, and 32 as
the major products (Scheme 3). A minor amount of the
byproducts with high polarity was also detected in each
cycloetherification reaction, which was found to be devoid
of the benzyl protecting groups. The ratio of the major
and minor products after the completion of reactions
remained virtually identical even after a prolong reaction
time, confirming that the minor products were a result
of the competitive side reaction. Similarly, starting from
dienes, 37, 38, and 40, three more bis-epoxides were
prepared using the L-fructose-based (+)-Shi catalyst,27
which underwent cycloetherification to afford the bis-
THF compounds, 31, 36, and 28, respectively. In general,
the bis-THF compounds so obtained had very high
diastereomeric purity.
a Key: (R ) -CH2CH2CH2OBn) (a) (-)-Shi catalyst (60 mol %),
nBu4NHSO4, oxone, K2CO3, buffer, CH3CN-DMM; (b) CSA,
CH2Cl2-MeOH; (c) (+)-Shi catalyst (60 mol %), reagents same as
step A; (d) (-)-Shi catalyst (30 mol %), 1/2 equiv of the reagents
used in step a; (e) (+)-Shi catalyst (30 mol %), 1/2 equiv of the
reagents used in step c.
SCHEME 4. Synthesis of Bis-THF Lactones from
the Mono-THF Lactones via the Enantioselective
Shi Epoxidation Reactionsa
Our design for the synthesis of several other bis-THF
lactones required the regioselective Shi AE of compounds
37-40 (Table 2). Thus, two mono-THF compounds had
to be prepared using (-)-Shi on 37,38 and two from 39,40
using (+)-Shi catalysts at the C-8,C-9 double bond
(Scheme 3). We anticipated that this could be achieved
by using half equivalents of the reagents and catalysts
that were required for the bis-AE of 37-40. As expected,
epoxidation of 37,38 using (-)-Shi catalyst afforded the
mixture of desired epoxides together with their regio-
isomers (epoxides at C-12,C-13) and the bis-epoxides.
Interestingly, the desired mono-epoxides were the major
products, as the crude epoxides underwent acid-catalyzed
cyclization to afford the mono-THF lactones 52 and 53
in 54% and 48% yields (two steps), respectively. A minor
amount of unreacted dienes and bis-epoxides was also
isolated. Similarly, compounds 39,40 were epoxidized
using (+)-Shi catalyst, and the crude epoxides were
cyclized using CSA to afford the mono-THF lactones
54,55.
a Key: (R ) -CH2CH2CH2OBn) (a) (+)-Shi catalyst, nBu4NHSO4,
oxone, K2CO3, buffer, CH3CN-DMM; (b) CSA, CH2Cl2-MeOH;
(c) (-)-Shi catalyst, reagents same as step A.
synthesis of the major portion of the remaining bis-THF
lactones, we used the mono-THF compounds that were
prepared by the rhenium(VII) oxides mediated mono-OC
and Shi mono-AE reactions. The mono-THF compounds
underwent either Shi AE reaction or Sharpless AD and
Williamson’s type etherification as required (Table 2).
Thus, mono-THF lactones 45-48 and 50 were epoxidized
using (+)-Shi catalyst, and the resultant epoxides were
cyclized with CSA to afford the bis-THF compounds 5,
3, 20, 14, and 22 (Scheme 4). Similarly, compounds 45-
48 were epoxidized using (-)-Shi catalyst and the prod-
ucts were cyclized to afford bis-THF compounds 13, 19,
Synthesis of the Bis-THF Lactones from Mono-
THF Lactones and Other Bis-THF Lactones. For the
(27) (-)-Shi catalyst was purchased from Aldrich (cat. # 52016-0),
and (+)-Shi catalyst was synthesized as described in the literature,
see: Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
5926 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Adjacent-Bis-THF Acetogenins
the signals for the diagnostic protons (H-4, H-5, H-8, and
H-9) and the related oxy-carbons in their NMR spectra.
Because the C-4/C-5 relationship was not expected to
affect the outcome of relative stereochemistry of the THF
ring or the newly generated C-8/C-9 centers, the above-
made observations also supported the structure of the
diastereomeric trans mono-THF compounds. Similarly,
a comparison of 52 and 54 (or their enantiomers) with
the alternate feasible trans stereoisomers 49 and 50,
respectively, revealed that they were not identical,
confirming the cis stereochemistry in 52-55, as expected.
The foregoing data also supported the expected stereo-
chemistry of the first THF ring and C-8/C-9 centers in
the bis-THF lactones 1-36, as the latter were synthe-
sized via the mono-THF lactones, 45-55, or by the
processes similar to that used in their syntheses.
FIGURE 2. (R ) -CH2CH2CH2OBn) Bis-THF lactones pre-
pared (A) from the mono-THF lactones via the enantioselective
Sharpless AD and Williamson’s type etherification reactions,
and (B) by Mitsunobu inversion reaction of bis-THF lactones.
4, and 6, respectively. This way, a total of nine bis-THF
lactones were prepared.
The Sharpless AD and Williamson’s type etherification
were carried out on the mesylate derivatives of mono-
THF compounds 45-49 and 51-55. For this, the latter
compounds were mesylated using mesyl chloride and
triethylamine. The mesylates of compounds 45, 46, 49,
and 52, 53 underwent Sharpless AD using the dihydro-
quinidine-based PHAL-DHQD ligand, whereas the
mesylates of 47, 48, 51, and 54, 55 were dihydroxylated
using the dihydroquinine-based PHAL-DHQ ligand.
The resultant mesyloxy-diols were cyclized using the
Williamson-type etherification by heating them in pyri-
dine at elevated temperature, affording the bis-THF
lactones 29, 33, 1, 10, 11, 34, 30, 2, 12, and 9, respectively
(Figure 2). Interestingly, compounds 1 and 2 can also be
obtained by the second oxidative cyclization of the mono-
THF lactones 45 and 48, respectively, using TFAReO3.
This preliminary finding, if general, can open a new
approach to prepare the trans,trans bis-THF compounds
from the trans,trans dienes in a stepwise manner.
Finally, the remaining three bis-THF lactones 7, 8, and
25 were obtained by Mitsunobu inversion of 12, 11, and
27, respectively, followed by base-acid treatment.
Structure Analysis of the Bis-THF Lactones. All
of the bis-THF compounds, 1-36, were synthesized
starting from the stereochemically defined substrates,
37-44, in that the stereochemistry of the C-4/C-5 hy-
droxy functions was set by the Sharpless AE or AD
reactions. These reactions are known to produce epoxides
and diols with defined absolute stereochemistry depend-
ing upon the ligands used. Besides Sharpless AD, the
other methodologies used for the production of new
stereogenic centers, C-8/C-9 and/or C-12/C-13, in com-
pounds 1-36 from 37-44, included Shi AE and/or
rhenium(VII) oxides-mediated oxidative cyclization (OC).
The Shi AE and OC reactions have also been shown
earlier to follow certain rules and trends, which were
taken into account when Table 2 was drafted. The fact
that the bis-THF lactones, 1-36, possessed the expected
structures was confirmed by a comparative analysis of
the 1H and 13C NMR of the mono- and bis-THF lactones,
as well as the tetracetates derived from 1-36. In addi-
tion, NOE experiments were carried out on the repre-
sentative compounds (the benzoate esters of compounds
16, 18, and 21, vide supra).
Next, comparison of the 1H NMR and 13C NMR spectra
of the bis-THF lactones (altogether 20 spectra excluding
the corresponding enantiomers) allowed us to reaffirm
the relative stereochemistry of the C-4/C-5 and C-12/C-
13 centers. It should be noted that stereochemistry of the
C-4/C-5 centers was already established in the starting
materials, and that of the C-12/C-13 center depended
upon the olefin configuration. Thus, the following trends
are obvious in the NMR spectra: (i) All compounds, which
possess threo stereochemistry between C-4/C-5 centers,
display H-2/H-2′ of the butyrolactone ring separated by
about 0.3 ppm, and 0.1 ppm for those with erythro
stereochemistry; and (ii) compounds with the expected
threo stereochemistry between C-12/C-13 show H-13
signals at δ 3.32-3.42, and C-13 at >δ 73 in the 1H NMR
and 13C NMR spectra, respectively, and at δ 3.74-3.82
and <δ 73 in erythro compounds. Using this information,
we could compare the compounds possessing identical
C-4/C-5, C-8/C-9 centers, but the reverse C-12/C-13
absolute stereochemistry. Here, the comparison was
made between compounds 1/15, 5/13, 23/34, 22/35, and
20/4 (or the corresponding enantiomers; see Table 3).
There were no counterparts for the remaining compounds
in our list of bis-THF lactones. As shown in the table,
1
the compounds in each group display different H and/
or 13C NMR spectral properties, suggesting that the
second THF ring in these compounds possesses the
expected stereochemistry, or else those of both com-
pounds are incorrect. The latter is less likely.
1
Finally, the H NMR spectral properties of the tetra-
acetate derivatives28 of compounds 1-36 (designated by
letter “T” after the number of bis-THF lactones used for
the synthesis of the tetraacetates; only one enantiomer
was used in cases when both enantiomers of the lactones
were present) show trends that are similar to the
previously reported analogous bis-THF diacetates29 (Table
4). Moreover, the signals for the diagnostic protons of 12
(28) The tetraacetates were synthesized in a sequence of three steps,
including LAH reduction of lactones to the corresponding triols,
deprotection of the benzyl protecting group by hydrogenolysis in the
presence of H2/Pd-C, and esterification of the resultant tetra hydroxy
bis-THF compounds using Ac2O/pyridine.
(29) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Soc. 1987, 109,
4402.
First, we confirmed the trans stereochemistry of the
mono THF compounds 45 and 49 (or their enantiomers)
with the previously known trans-THF compounds VI15a
and VII,25a respectively, which showed a close match of
J. Org. Chem, Vol. 70, No. 15, 2005 5927

Das et al.
C-13
TABLE 3. A Comparative Study of the 1H NMR Data of Compounds 1-36
chemical shifts
stereochemistry
compounds
(4,5,8,9,12,1 3)
configuration
H-4
H-5
(H-8,9)a
H-12
H-13
H-2,2′
1 (or 2)
15 (or 16)
5 (or 6)
13 (or 14)
21
29 (or 30)
31 (or 32)
27 (or 28)
25
10 (or 9)
23 (or 24)
34 (or 33)
22
35 (or 36)
4 (or 3)
20 (or 19)
17 (or 18)
8 (or 7)
11 (or 12)
26
RRRRRR (or SSSSSS)
RRRRSS (or SSSSRR)
RRRRRS (or SSSSSR)
RRRRSR (or SSSSRS)
RRRSSS
RRRSRR (or SSSRSS)
RRRSRS (or SSSRSR)
RRSRSR (or SSRSRS)
RRSRSS
RRSSRR (or SSRRSS)
RSSRRR (or SRRSSS)
RSSRSS (or SRRSRR)
RSSRRS
RSSRSR (or SRRSRS)
RSSSSR (or SRRRRS)
RSSSRS (or SRRRSR)
RSSSRR (or SRRRSS)
SRSSRS (or RSRRSR)
SRSSRR (or RSRRSS)
SRSRSR
th-t-th-t-th
th-t-th-c-th
th-t-th-t-er
th-t-th-c-er
th-t-er-t-th
th-t-er-c-th
th-t-er-c-er
th-c-er-c-er
th-c-er-c-th
th-c-th-c-th
er-t-er-t-th
er-t-er-c-th
er-t-er-t-er
er-t-er-c-er
er-t-th-t-er
er-t-th-c-er
er-t-th-c-th
er-c-th-c-er
er-c-th-c-th
er-c-er-c-er
4.46
4.44
4.48
4.48
4.46
4.47
4.46
4.50
4.50
4.48
4.43
4.40
4.43
4.40
4.47
4.44
4.43
4.43
4.42
4.39
4.09
4.10
4.11
4.11
4.08
4.04
4.08
4.00
4.01
4.06
4.08
4.02
4.09
4.02
4.08
4.05
4.05
3.97
3.95
3.95
3.89, 3.86
3.91, 3.91
3.89, 3.88
3.95, 3.92
3.94, 3.89
4.06, 3.96
4.13, 3.96
3.94, 3.92
3.94, 3.91
3.85, 3.83
3.96, 3.92
4.08, 3.94
4.00, 3.98
4.17, 3.97
3.94, 3.91
3.98, 3.88
3.97, 3.90
3.90, 3.88
3.90, 3.88
4.06, 3.98
3.80
3.91
3.87
3.89
3.78
3.84
3.90
3.85
3.76
3.78
3.81
3.84
3.87
3.91
3.88
3.92
3.88
3.86
3.85
3.89
3.41
3.38
3.80
3.78
3.40
3.37
3.75
3.78
3.41
3.41
3.40
3.38
3.74
3.75
3.80
3.80
3.39
3.80
3.40
3.75
2.69, 2.44
2.67, 2.42
2.70, 2.45
2.67, 2.43
2.67, 2.44
2.67, 2.42
2.64, 2.43
2.71, 2.44
2.71, 2.41
2.70, 2.40
2.55, 2.48
2.55, 2.48
2.56, 2.49
2.54, 2.48
2.55, 2.49
2.54, 2.49
2.55, 2.50
2.56, 2.49
2.55, 2.49
2.54, 2.48
73.6
74.4
72.9
72.9
73.7
74.3
72.9
72.8
73.8
73.7
73.6
74.1
72.9
72.8
72.9
72.8
74.2
72.9
73.9
72.8
TABLE 4. A Comparative Study of the 1H NMR Data of
Tetraacetates (T)
ppm) in comparison to those with the threo stereochem-
istry. The only exception was observed with compound
22T, where the acetate methyl protons resonated at the
same δ value in comparison to the corresponding threo
isomer, 21T.
Synthesis of the Adjacent Bis-THF Acetogenin
Stereoisomers. To show that each of the 28 nonsym-
metrical lactones (5, 6 and 11-36) would afford two
adjacent bis-THF acetogenin analogues, we used lactone
17 to synthesize Ie and If as shown in Scheme 5. Thus,
lactone 17 was protected as TBS ether to afford 17a.
Alkyl group was introduced at the two alternative ends
of 17a affording 56 and 57, respectively. The latter
compounds were hydrogenated to give compounds 58 and
59. Methylenation of the aldehyde or lactol products of
58 and 59, respectively, afforded two diastereomeric
alkenes, 60 and 61. The alkenes were subjected to the
cross-metathesis reaction with butenolide alkene III (P
) TBS) in the presence of Grubbs’ second-generation
catalyst VIII,30 and the products 62 and 63 underwent
deprotection with dilute HF in CH3CN followed by
diimide reduction to afford Ie (19,23-bis-epi-trilobacin)
and If (16,19-bis-epi-trilobacin), respectively.
In conclusion, we have developed methods to synthe-
size a complete library of the Annonaceous bis-THF
acetogenins. Specifically, 36 stereoisomeric bis-THF lac-
tones, 1-36, have been synthesized, which can be
transformed to all 64 stereoisomers of the adjacent bis-
THF acetogenins. The key reactions used for the syn-
thesis of these lactones include: rhenium(VII) oxides
mediated mono- or bis-oxidative cyclization, Shi mono-
or bis-asymmetric epoxidation, Sharpless asymmetric
dihydroxylation, Williamson’s type etherification, and
Mitsunobu inversion. Using one isomeric bis-THF lac-
tone, 17, we accomplished the synthesis of 19,23-bis-epi-
trilobacin (Ie) and 16,19-bis-epi-trilobacin (If). Synthesis
of all 64 stereoisomeric library of trilobacin is in progress
and will be published together with their biological data
in due course.
1H NMR chemical shifts
com-
pounds configuration H-2/H-2′ H-5/H-5′ H-6/H-6′
Me/Me′
2.08
2.05
2.08, 2.05
2.04
1T
3T
6T
7T
th-t-th-t-th 3.91
er-t-th-t-er 3.87
th-t-th-t-er 3.91
er-c-th-c-er 3.79
th-c-th-c-th 3.86
er-c-th-c-th 3.85, 3.80 3.99, 3.93 4.92
th-t-th-c-er 3.88, 3.82 4.00, 3.91 4.90
th-t-th-c-th 3.96, 3.83 4.09, 3.90 4.91
er-t-th-c-th 3.89, 3.81 4.05, 3.96 4.92
er-t-th-c-er 3.88, 3.79 3.99, 3.92 4.91
4.00
3.97
3.98
3.93
3.94
4.90
4.90
4.90
4.89
5.00
10T
12T
14T
16T
18T
19T
21T
22T
24T
25T
26T
28T
30T
32T
33T
36T
2.07
2.08, 2.05
2.09, 2.06
2.08
2.08, 2.06
2.05
2.06
2.06
2.08, 2.06
2.07
2.05
th-t-er-t-th 3.83
3.96
3.96
3.98
3.94
3.90
4.87
4.91
4.90
4.88
4.94
er-t-er-t-er
er-t-er-t-th
3.86
3.85
th-c-er-c-th 3.76
er-c-er-c-er 3.74
th-c-er-c-er 3.78, 3.73 3.94, 3.90 4.95, 4.89 2.08, 2.05
th-t-er-c-th 3.82
th-t-er-c-er 3.82
er-t-er-c-th 3.82
3.98, 3.93 4.88
3.99, 3.90 4.95, 4.88 2.08, 2.06
3.97, 3.94 4.89 2.07, 2.06
3.98, 3.90 4.96, 4.90 2.07, 2.06
2.08, 2.07
er-t-er-c-er
3.82
tetraacetate derivatives (T) match closely with the 12
reported diastereochemically equivalent THF diacetates.
As shown in Table 4, the following trends were noticed:
signals for (i) H-2 and H-5 are downfield shifted (∆δ
0.03-0.09 ppm) in a trans/trans compound than the
corresponding cis/cis isomer; (ii) H-2 in a given cis/cis or
trans/trans bis-THF compound is downfield shifted (∆δ
0.02-0.10 ppm) when C-2/C-2′ relationship is threo
compared with that of erythro; (iii) H-2 and H-2′ in an
unsymmetrical cis/trans isomer are nearly superimposed
in the C-2/C-2′ erythro isomers and significantly sepa-
rated (∆δ 0.06-0.09 ppm) in the C-2/C-2′ threo com-
pounds; and (iv) methyl protons of the secondary acetate
groups in compounds possessing an erythro configuration
between C-5(5′)/C-6(6′) are upfield shifted (∆δ 0.02-0.03
(30) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
5928 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Adjacent-Bis-THF Acetogenins
NH4Cl and was slowly warmed to 0 °C. It was further stirred
for another 1 h with Celite (until the reaction mixture became
clear) and was then filtered through a sintered funnel using
dichloromethane as solvent. The filtrate and washings were
combined and evaporated under vacuum to obtain the crude
lactol, which was taken to next step without further purifica-
tion.
SCHEME 5. Synthesis of the Adjacent Bis-THF
Acetogenin Stereoisomers, Ie and Ifa
n-BuLi (1.6 M in hexane, 0.85 mL, 1.36 mmol) was added
to an ice-cooled suspension of the heptyltriphenylphosphonium
bromide31 (688 mg, 1.56 mmol) in anhydrous THF (3 mL) and
stirred for 20 min. A solution of the above-described lactol in
THF (2 mL) was added slowly to the mixture and stirred for
an additional 30 min. The reaction mixture was quenched with
aqueous NH4Cl and extracted with ether. The organic layer
was washed with brine, dried (MgSO4), filtered, and evapo-
rated to dryness to get the crude product, which was purified
by flash chromatography to obtain the olefin 56 as a colorless
1
oil (164 mg, 70%, two steps). H NMR: δ 7.42-7.32 (m, 5H),
5.49-5.38 (m, 2H), 4.57 (s, 2H), 4.05-3.93 (m, 4H), 3.83-3.81
(m, 2H), 3.58 (t, J ) 6.6 Hz, 2H), 2.20-1.34 (m, 29H), 0.96-
0.94 (m, 12H), 0.12 (s, 3H), 0.11 (s, 3H). 13C NMR: δ 138.5,
130.6, 128.8, 128.2, 127.5, 127.4, 82.6, 82.5, 82.2, 81.9, 73.6,
72.6, 70.7, 70.4, 32.3, 31.7, 29.6, 28.9, 28.8, 28.1, 27.9, 27.1,
26.1, 25.8, 24.6, 23.7, 22.6, 18.0, 14.0, -4.4, -4.7. MS (ESI):
603 (MH+), 625 (MNa+).
(4R,5R,8S,9S,12S,13R)-4,13-Di-tert-butyldimethylsilyl-
oxy-5:8,9:12-dioxido-tricosa-1-ol, 58. Compound 56 (120 mg,
0.2 mmol) was subjected to TBS-protection, as described earlier
for 17a. Purification by flash chromatography provided the
corresponding TBS derivative (136 mg, 95%) as an oil. 1H
NMR: δ 7.45-7.33 (m, 5H), 5.37-5.29 (m, 2H), 4.48 (s, 2H),
3.92-3.81 (m, 4H), 3.73-3.68 (m, 2H), 3.46-3.41 (m, 2H),
2.15-1.25 (m, 26H), 0.88-0.86 (m, 21H), 0.05-0.04 (m, 12H).
13C NMR: δ 138.7, 130.1, 129.3, 128.2, 127.5, 127.4, 82.3, 82.2,
82.0, 81.6, 74.0, 73.0, 72.7, 70.6, 34.9, 31.7, 29.6, 29.0, 28.6,
28.5, 27.9, 27.2, 26.3, 26.0, 26.0, 25.9, 25.9, 25.6, 23.5, 22.6,
18.1, 18.1, 14.1, -4.2, -4.3, -4.6, -4.7. MS (ESI): 718 (MH+),
740 (MNa+).
Pd/C (10% w/w, 15 mg) was added to a solution of the above-
described TBS-protected compound (80 mg, 0.11 mmol) in
EtOAc (2 mL), and the mixture was stirred under H2 atmo-
sphere for 1 h. It was filtered through a Celite pad using EtOAc
as solvent, the filtrate was evaporated to dryness, and the
crude product was purified by flash chromatography to afford
58 (62 mg, 90%) as a colorless oil. [R]D ) +4.9 (c ) 0.83, CHCl3).
1H NMR: δ 3.92-3.68 (m, 6H), 3.59 (t, J ) 6.25 Hz, 2H), 1.90-
2.22 (m, 31H), 0.85 (br s, 21H), 0.043, 0.035, 0.03 & 0.02 (4xs,
together 12H). 13C NMR: δ 82.4, 82.1, 81.9, 81.5, 74.0, 73.2,
63.1, 34.8, 31.9, 29.8, 29.6, 29.6, 29.3, 29.0, 28.7, 28.6, 27.9,
26.2, 26.0, 25.9, 25.5, 25.5, 22.7, 18.1, 18.1, 14.1, -4.2, -4.3,
-4.6, -4.7. MS (ESI): 629 (MH+), 651 (MNa+).
(5R,6R,9S,10S,13S,14R)-5,14-Di-tert-butyldimethylsilyl-
oxy-6:9,10:13-dioxi do-tetracosa-1-en, 60. Activated 4 Å
molecular sieves (20 mg) was added to a solution of alcohol
58 (50 mg, 0.08 mmol) in CH2Cl2 (3 mL). After the mixture
was stirred for 5 min at room temperature, NMO (14 mg, 0.12
mmol) and TPAP (3 mg, 0.008 mmol) were added sequentially
to the reaction mixture, and the stirring was continued for
additional 15 min. The crude mixture was filtered over a short
silica gel column (CH2Cl2-MeOH, 20:1) to yield the corre-
sponding aldehyde (45 mg, 90%) as a colorless oil.
nBuLi (1.6 M in hexane, 0.18 mL, 0.28 mmol) was added to
a suspension of MePPh3I (129 mg, 0.32 mmol) in dry ether at
0 °C. After 0.5 h, a solution of the above-described aldehyde
(45 mg) in dry ether (1 mL) was added to the reaction mixture,
cooling bath was removed, and the stirring was continued for
1 h at rt. The mixture was quenched with aq NH4Cl and
extracted with EtOAc. The combined organic layer was washed
with brine and dried (MgSO4). Inorganic material was filtered
a Key: (a) TBSOTf, lutidine, CH2Cl2; (b) DIBAL-H, THF; (c)
C7H15PPh3I, BuLi, THF; (d) Pd-C, H2, EtOAc; (e) TPAP, NMO,
CH2Cl2, MS 4 Å; (f) CH3PPh3I, BuLi, ether; (g) (i) III (P ) TBS),
RuCl2[imid-H2-Mes2][CHPh]PCy3 (VIII, Grubbs’ second generation
catalyst), CH2Cl2, rt, (ii) 5% HF in CH3CN, (iii) TsNHNH2, NaOAc,
CH3CN-DME-H2O.
Experimental Section
Total Synthesis of 19,23-Bis-epi-trilobacin, 1e. (4R,5S,8S,
9S,12R,13R)-5:8,9:12-Dioxido-13-tert-butyldimethylsilyl-
oxy-16-benzyloxy-hexadeca-1,4-olide, 17a. TBSOTf (0.34
mL, 1.47 mmol) was added slowly to an ice-cooled solution of
the alcohol 17 (495 mg, 1.23 mmol) and lutidine (0.214 mL,
1.84 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred
for 30 min and was quenched with aq NH4Cl, extracted with
ether, and washed successively with aq CuSO4 solution and
brine. The organic layer was dried (MgSO4), filtered, and
evaporated to dryness to get the crude product, which was
purified by flash chromatography to yield the pure TBS ether
17a (603 mg, 95%) as a viscous liquid. [R]D +5.83 (c ) 1,
CHCl3). 1H NMR (400 MHz): δ 7.29-7.22 (m, 5H), 4.45 (s,
2H), 4.36 (q, J ) 5.6 Hz, 1H), 4.00 (q, J ) 6.4 Hz, 1H), 3.91-
3.82 (m, 2H), 3.71 (m, 1H), 3.64 (ddd, J ) 8.4, 5.2, 3.2 Hz,
1H), 3.42 (t, J ) 6.4 Hz, 2H), 2.52-2.36 (m, 2H), 2.23 (m, 1H),
2.07-1.92 (m, 3H), 1.78-1.53 (m, 9H), 1.32 (m, 1H), 0.82 (s,
9H), 0.01 (s, 3H), 0.005 (s, 3H). 13C NMR (100 MHz): δ 177.1,
138.6, 128.2, 127.4, 127.3, 82.21, 82.2, 81.8, 81.7, 80.1, 73.9,
72.6, 70.5, 28.6, 28.2, 28.1, 28.0, 27.9, 26.2, 25.8, 25.7, 24.1,
18.1, -4.10, -4.8.
(4R,5R,8S,9S,12S,13R)-1-Benzyloxy-4-tert-butyldi-
methylsilyloxy-5:8,9:12-dioxido-tricosa-13-hydroxy-16-en,
56. DIBAL-H (1.5 M in toluene, 0.4 mL, 0.6 mmol) was added
dropwise to a solution of compound 17a (200 mg, 0.39 mmol)
in CH2Cl2 (2 mL) at -78 °C and stirred for 1 h at the same
temperature. The reaction mixture was quenched with aq
(31) Pempo, D.; Cintrat, J.-C.; Parrain, J.-L.; Santelli, M. Tetra-
hedron 2000, 56, 5493-5497.
J. Org. Chem, Vol. 70, No. 15, 2005 5929

Das et al.
out, and the filtrate was evaporated to dryness. The resultant
silyloxy-tricosa-16-en-1,4-olide, 57. Compound 17a (300 mg,
0.58 mmol) was hydrogenolyzed in EtOAc (5 mL) using 10%
Pd/C (60 mg) under H2 atmosphere in 1 h as described for the
synthesis of 58. Crude product was purified by flash chroma-
tography to afford the corresponding free primary alcohol (223
mg, 90%) as a thick liquid. [R]D +3.95 (c ) 2, CHCl3). 1H NMR
(400 MHz): δ 4.41 (ddd, J ) 7.6, 6.8, 5.6 Hz, 1H), 4.05 (dt, J
) 8.0, 3.6 Hz, 1H), 3.92-3.84 (m, 2H), 3.73 (m, 1H), 3.68 (ddd,
J ) 8.0, 5.6, 3.6 Hz, 1H), 3.62-3.54 (m, 2H), 2.57-2.40 (m,
2H), 2.27 (m, 1H), 2.10-1.92 (m, 3H), 1.85-1.49 (m, 9H), 1.34
(m, 1H), 0.84 (s, 9H), 0.031 (s, 3H), 0.023 (s, 3H). 13C NMR
(100 MHz): δ 177.3, 82.2, 81.8, 81.6, 80.2, 74.0, 62.8, 28.9, 28.6,
28.2, 28.1, 28.1, 28.1, 26.2, 25.8, 25.8, 23.8, 18.1, -4.4, -4.7.
The above-described alcohol (100 mg, 0.23 mmol) was
oxidized in CH2Cl2 (5 mL) using NMO (40 mg, 0.34 mmol) and
TPAP (8 mg, 0.023 mmol), by the method described for the
oxidation of 58. The resultant aldehyde (94 mg, 96%) was
obtained as a colorless oil after filtration over a short silica
gel column (CH2Cl2-MeOH, 20:1). 1H NMR: δ 9.76 (t, J ) 1.7
Hz, 1H), 4.11 (q, J ) 6.8 Hz, 1H), 4.04 (q, J ) 6.3 Hz, 1H),
3.94-3.85 (m, 2H), 3.75-3.68 (m, 2H), 2.59-2.41 (m, 4H), 2.28
(m, 1H), 2.11-2.06 (m, 2H), 1.98 (m, 1H), 1.9-1.66 (m, 6H),
1.62-1.52 (m, 2H), 0.84 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H).
Wittig reaction (method described earlier for the synthesis
of 56) of the above-described aldehyde (80 mg, 0.19 mmol) was
carried out using ylide, generated from the reaction of hep-
tyltriphenylphosphonium bromide (124 mg, 0.28 mmol) and
n-BuLi (1.6M in hexane, 0.18 mL, 0.28 mmol) in anhydrous
THF (3 mL). Olefin 57 (72 mg, 75%) was obtained as a mixture
of cis- and trans-isomer after purification by flash chromatog-
raphy. 1H NMR: δ 5.39-5.34 (m, 2H), 4.43 (q, J ) 6.6 Hz,
1H), 4.06 (q, J ) 6.2 Hz, 1H), 3.96 (q, J ) 6.6 Hz, 1H), 3.9 (q,
J ) 6.6 Hz, 1H), 3.78-3.67 (m, 2H), 2.59-2.45 (m, 2H), 2.35-
1.68 (m, 14H), 1.34-1.25 (m, 10H), 0.89 (s, 9H), 0.88 (t, J )
6.9 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H). MS (ESI): 509 (MH+),
531 (MNa+).
(4R,5S,8S,9S,12R,13R)-5:8,9:12-Dioxido-13-tert-butyldi-
methylsilyloxy-tricosan-1,4-olide, 59. Olefin 57 (50 mg, 0.1
mmol) was hydrogenated using Pd/C (10% w/w, 10 mg) in
EtOAc (2 mL) and under H2 atmosphere for 20 min to afford
lactone 59 (46 mg, 92%) as a viscous liquid after purification
by flash chromatography. [R]D +4.7 (c ) 0.48, CHCl3). 1H NMR
(500 MHz): δ 4.44 (q, J ) 6.6 Hz, 1H), 4.07 (q, J ) 6.6 Hz,
1H), 3.96 (q, J ) 6.2 Hz, 1H), 3.89 (q, J ) 6.6 Hz, 1H), 3.76
(m, 1H), 3.65 (m, 1H), 2.58-2.45 (m, 2H), 2.31 (m, 1H), 2.16-
2.08 (m, 2H), 2.00 (m, 1H), 1.83-1.68 (m, 6H), 1.32-1.2 (m,
18H), 0.88 (s, 9H), 0.87 (t, J ) 6.9 Hz, 3H), 0.06 (s, 3H), 0.05
(s, 3H). 13C NMR (100 MHz): δ 177.2, 82.4, 82.3, 81.9, 81.7,
80.2, 74.3, 32.1, 31.9, 29.9, 29.6, 29.6, 29.3, 28.2, 28.2, 28.1
(×2), 28.0, 26.3, 25.9, 25.7, 24.3, 22.6, 18.1, 14.1, -4.3, -4.7.
MS (ESI): 511 (MH+), 533 (MNa+).
residue was purified by flash chromatography to afford 60 (37
1
mg, 75% after two steps) as a colorless oil. H NMR: δ 5.79
(ddt, J ) 16.9, 10.2, 6.6 Hz, 1H), 4.99 (dq, J ) 16.9, 1.8 Hz,
1H), 4.89 (dd, J ) 10.3, 1.8 Hz, 1H), 3.91-3.68 (m, 6H), 2.17-
1.47 (m, 12H), 1.23 (br m, 18H), 0.87-0.84 (m, 21H), 0.042,
0.035, 0.03 & 0.025 (4xs, together 12H). 13C NMR: δ 139.1,
114.2, 82.4, 82.4, 81.9, 81.6, 73.5, 73.2, 34.8, 31.9, 31.1, 30.1,
29.8, 29.6, 29.6, 29.3, 28.8, 28.0, 26.1, 26.0, 25.9, 25.5, 25.4,
22.7, 18.2, 18.1, 14.1, -4.2, -4.3, -4.6, -4.7. MS (ESI): 625
(MH+).
11,12-Dehydro-19,23-bis-epi-trilobacin-4,15,24-(tri-tert-
butyldimethylsilyl) Ether, 62. Grubb’s catalyst VIII (7 mg,
0.008 mmol) was added to a solution of compound 60 (25 mg,
0.04 mmol) and III (P ) TBS, 59 mg, 0.16 mmol) in CH2Cl2
(1.5 mL), and the mixture was stirred for 12 h at room
temperature under Ar-atmosphere. DMSO (10.6 µL, 0.15
mmol) was added, and the mixture was stirred for an ad-
ditional 12 h. Solvents were removed under reduced pressure,
and the crude compound was purified by flash chromatography
to give the required olefin 62 (24 mg, 62%) as a viscous oil. 1H
NMR: δ 7.09 (d, J ) 1.1 Hz, 1H), 5.40-5.31 (m, 2H), 4.97 (m,
1H), 3.94-3.67 (m, 7H), 2.40-1.40 (m, 16H), 1.39 (d, J ) 6.95
Hz, 3H), 1.30-1.22 (m, 28H), 0.86-0.84 (m, 30H), 0.04-0.01
(m, 18H). 13C NMR: δ 175.0, 151.6, 151.4, 130.9, 130.3, 130.2,
82.4, 81.9, 81.7, 77.4, 73.7, 73.2, 70.2, 37.0, 34.8, 31.7, 32.6,
31.9, 31.8, 29.9, 29.6, 29.6, 29.3, 29.2, 28.9, 28.7, 28.0, 26.1,
26.0, 25.9, 25.9, 25.9, 25.8, 25.5, 25.4, 25.1, 22.7, 19.2, 19.0,
18.2, 18.1, 18.0, 14.1, -4.1, -4.3, -4.4, -4.5, -4.6, -4.6. MS
(ESI): 964 (MH+), 986 (MNa+).
19,23-Bis-epi-trilobacin, Ie. A solution of 5% HF32 (CH3CN:
H2O, 0.4 mL) was added to a solution of 62 (15 mg, 0.015
mmol) in CH2Cl2 (1.5 mL), and stirred for 2 h at room
temperature. The reaction was quenched by saturated aqueous
NaHCO3, extracted with EtOAc, washed with brine, dried over
Na2SO4, and purified by flash chromatography to provide the
corresponding desilylated triol (8 mg, 82%) as a viscous oil.
1H NMR (600 MHz): δ 7.16 (s, 1H), 5.45-5.33 (m, 2H), 5.03
(q, J ) 7.9 Hz, 1H), 3.93-3.81 (m, 6H), 3.37 (m, 1H), 2.51-
1.69 (m, 17H), 1.41 (d, J ) 7.9 Hz, 3H), 1.31-1.23 (m, 28H),
0.85 (t, J ) 7.5 Hz, 3H). 13C NMR: δ 174.6, 151.8, 131.2, 130.8,
130.7, 130.6, 130.3, 129.9, 129.8, 129.3, 82.9, 82.7, 82.2, 81.8,
78.0, 73.8, 71.5, 69.9, 69.9, 69.8, 37.4, 33.3, 32.5, 32.5, 31.9,
29.7, 29.6, 29.6, 29.4, 29.4, 29.3, 28.9, 28.7, 28.4, 28.2, 26.0,
25.6, 24.8, 22.7, 19.1, 19.1, 14.1. MS (ESI): 621 (MH+), 643
(MNa+).
A solution of NaOAc (60 mg, 0.74 mmol) in distilled water
(0.7 mL) was added to a refluxing solution of the above-
described desilylated triol (6 mg, 0.009 mmol) and p-TsNHNH2
(115 mg, 0.62 mmol) in 1,2-DME (1 mL), over a period of 4 h
(via syringe pump). The reaction was stirred under reflux for
an additional 1 h. Finally, it was cooled to room temperature
and partitioned between water and EtOAc. Organic layer was
again washed with water and brine, dried over Na2SO4,
filtered, and solvent was removed under reduced pressure. The
crude material was then subjected to flash chromatography
to afford the final compound Ie (5 mg, 95%) as a viscous oil.
[R]D ) +3.0 (c ) 0.33, CHCl3). 1H NMR (600 MHz): δ 7.18 (s,
1H), 5.06 (q, J ) 7.2 Hz, 1H), 3.92-3.84 (m, 6H), 3.37 (m, 1H),
2.89 (m, 1H), 2.53 (dd, J ) 13.8, 1.8 Hz, 1H), 2.39 (dd, J )
8.4, 15 Hz, 1H), 2.29 (bd, J ) 4.8 Hz, 1H), 2.11 (br s, 1H),
2.01-1.73 (m, 9H), 1.47-1.45 (m, 7H), 1.44 (d, J ) 7 Hz, 3H),
1.25 (br s, 30H), 0.87 (t, J ) 7 Hz, 3H). 13C NMR: δ 174.6,
151.8, 131.2, 82.9, 82.8, 82.2, 81.8, 77.9, 74.6, 71.5, 70.0, 37.4,
34.3, 33.3, 32.5, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3, 29.2, 28.4,
28.2, 26.0, 25.8, 25.6, 24.8, 22.7, 19.1, 14.1. HRMS (ESI-
TOF): calcd for C37H67O7 ) 623.4881 (MH+), found 623.487;
calcd for C37H66O7Na ) 645.4700 (MNa+), found 645.4692.
Total Synthesis of 16,19-Bis-epi-trilobacin, If. (4R,5S,
8S,9S,12R,13R)-5:8,9:12-Dioxido-13-tert-butyldimethyl-
(5R,6S,9S,10S,13R,14R)-5-Hydroxy-6:9,10:13-dioxido-
14-tert-butyldimethylsilyloxy-tetracos-1-en, 61. Com-
pound 59 (30 mg, 0.06 mmol) in CH2Cl2 (2 mL) at -78 °C was
reduced using DIBAL-H (1.5 M in toluene, 60 µL, 0.09 mmol)
as described for 17a to afford the corresponding lactol. The
latter in dry ether (2 mL) was added to the ylide generated
from MePPh3I (73 mg, 0.18 mmol) and n-BuLi (1.6M in hexane,
106 µL, 0.17 mmol) at 0 °C. Workup of the reaction and
purification of the crude product using flash chromatography
gave olefin 61 (23 mg, 75%, after two steps) as a thick liquid.
1
[R]D +7.98 (c ) 0.45, CHCl3). H NMR: δ 5.89 (m, 1H), 5.13
(dd, J ) 17.2, 1.9 Hz, 1H), 5.05 (dd, J ) 8.1, 1.9 Hz, 1H), 4.05-
3.89 (m, 4H), 3.76-3.69 (m, 2H), 2.26 (m, 1H), 2.16 (d, J ) 1.8
Hz, 1H), 2.09 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.81 (m,
3H), 1.62 (m, 1H), 1.5-1.42 (m, 4H), 1.29-1.22 (m, 18H), 0.88-
0.86 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (150 MHz):
δ 138.3, 114.8, 82.6, 82.5, 82.3, 82.1, 73.9, 70.7, 31.9, 31.6, 30.3,
29.9, 29.7, 29.6, 29.3, 28.9, 28.0, 26.0, 25.9, 24.6, 22.7, 18.1,
14.1, -4.3, -4.6. MS (ESI): 511 (MH+), 533 (MNa+).
11,12-Dehydro-16,19-bis-epi-trilobacin-4,24-(di-tert-
butyldimethylsilyl) ether, 63. Compound 61 (15 mg, 0.03
(32) HF solution was prepared by diluting 48% aqueous HF with
CH3CN to make 5%.
5930 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Adjacent-Bis-THF Acetogenins
mmol) and III (P ) TBS, 43 mg, 0.12 mmol) in CH2Cl2 (2 mL)
was metathesized using Grubb’s catalyst VIII (5 mg, 0.006
mmol) as described earlier for the synthesis of 62. Workup
using DMSO (10.6 µL, 0.15 mmol) and purification by flash
chromatography gave olefin 63 (15 mg, 60%). 1H NMR: δ 7.10
(d, J ) 1.5 Hz, 1H), 5.46-5.34 (m, 2H), 4.90 (qd, J ) 6.9, 1.6
Hz, 1H), 3.93-3.68 (m, 6H), 2.40-1.56 (m, 20H), 1.27-1.22
(m, 28H), 0.87-0.84 (m, 21H), 0.03-0.01 (m, 12H). MS (ESI):
850 (MH+), 872 (MNa+).
1.8 Hz, 1H), 2.32 (q, J ) 5.4 Hz, 1H), 2.18 (br m, 1H), 2.02-
1.71 (m, 8H), 1.48-1.45 (m, 5H), 1.43 (dd, J ) 6.6, 0.9 Hz,
2H), 1.35-1.25 (m, 34H), 0.88 (t, J ) 7.0 Hz, 3H). 13C NMR:
δ 174.6, 151.8, 131.2, 82.9, 82.8, 82.2, 81.8, 78.0, 74.6, 71.5,
70.0, 37.4, 34.3, 33.3, 32.4, 31.9, 29.7, 29.6, 29.5, 29.45, 29.3,
29.2, 28.4, 29.2, 25.9, 25.8, 25.6, 24.8, 22.7, 19.1, 14.1. HRMS
(ESI-TOF): calcd for C37H67O7 ) 622.4881 (MH+), found
623.4871, calcd for C37H66O7Na ) 645.4700 (MNa+), found
645.469.
16,19-Bis-epi-trilobacin, If. TBS protecting group in com-
pound 63 (10 mg, 0.012 mmol) was removed using 5% HF32
(CH3CN-H2O, 0.25 mL) in CH2Cl2 (1 mL) at room temperature
in 2 h. The reaction was worked-up and purified as described
earlier for the TBS deprotection in 62 and purified by flash
chromatography to provide the corresponding desilylated triol
(6.2 mg, 85%). 1H NMR: δ 7.19 (d, J ) 1.1 Hz, 1H), 5.52-5.36
(m, 2H), 5.05 (qd, J ) 6.95, 1.45 Hz, 1H), 4.04-3.85 (m, 6H),
3.36 (m, 1H), 3.08 (br m, 1H), 2.54-1.71 (m, 20H), 1.47 (d, J
) 6.6 Hz, 3H), 1.42-1.25 (m, 25H), 0.87 (d, J ) 6.95 Hz, 3H).
MS (ESI): 621 (MH+), 643 (MNa+).
Acknowledgment. We thank the Skaggs Institute
for Chemical Biology and the National Institutes of
Health (R01 GM063914) for financial support.
Note Added after ASAP Publication: The version
published June 22, 2005 contained errors in Table 3 and
in the Acknowledgment. The corrected version published
July 6, 2005.
The above-described triol (5 mg, 0.008 mmol) was hydro-
genated (method described earlier for the synthesis of Ie) using
and p-TsNHNH2 (103 mg, 0.55 mmol) and NaOAc (54 mg, 0.66
mmol, in 1 mL of distilled water) in 1,2-dimethoxyethane (1
mL). The crude material was purified by flash chromatography
to afford compound If (4.7 mg, 94%). [R]D ) +4.7 (c ) 0.34,
CHCl3 ). 1H NMR (600 MHz): δ 7.18 (s, 1H), 5.06 (qd, J ) 7.0,
1.3 Hz, 1H), 3.96-3.84 (m, 6H), 3.37 (br m, 1H), 2.95 (br m,
1H), 2.53 (dq, J ) 15.0, 1.8 Hz, 1H), 2.41 (ddd, J ) 14.6, 8.3,
Supporting Information Available: General methods,
synthetic schemes, and physical data for the bis-THF lactones
1-36, their starting materials 37-44, mono-THF lactone
intemediates 45-55, and tetraacetate derivatives 1T-36T,
and 1H and 13C NMR spectra of 1-44, 17a, 60, 61, and Ie, If.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050697C
J. Org. Chem, Vol. 70, No. 15, 2005 5931