A diversity-oriented synthetic approach to bengamides

Article abstract of DOI:10.1016/j.tetlet.2004.12.096

A new approach to the bengamides, a new class of antitumor natural products of marine origin, is reported from epoxyamides, prepared by reaction of aldehydes with sulfur ylides. The synthetic strategy has been designed for the delivery of a wide array of

Full text of DOI:10.1016/j.tetlet.2004.12.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1131–1135
A diversity-oriented synthetic approach to bengamides
*
Francisco Sarabia and Antonio Sanchez-Ruiz
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´ ´ ´
Departamento de Bioquımica, Biologıa Molecular y Quımica Organica, Facultad de Ciencias, Universidad de Malaga,
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29071 Malaga, Spain
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Received 30 October 2004; revised 18 November 2004; accepted 17 December 2004
Available online 11 January 2005
Abstract—A new approach to the bengamides, a new class of antitumor natural products of marine origin, is reported from epoxy-
amides, prepared by reaction of aldehydes with sulfur ylides. The synthetic strategy has been designed for the delivery of a wide array
of analogues. Thus, the terminal alkyl substituent is introduced by a cross olefin metathesis from the corresponding terminal olefin.
The combination of cross olefin metathesis, introduction of different nucleophiles by the oxirane ring opening and the introduction
of different amines via amide bond formation, can produce a wide array of bengamides analogues.
Ó 2004 Elsevier Ltd. All rights reserved.
The bengamides (1–6) (Fig. 1) comprise a family of
natural products isolated from marine sponges of the
Jaspidae family (order Choristida = Astrophorida)1 that
display a wide and interesting range of biological activ-
ities, including antitumor, antibiotic, and antihelmintic
properties.2 Particularly striking and attractive are their
antitumor properties,3 which have stimulated intense re-
search activity, covering synthetic4 and biological as-
pects.2,3 Recent proteomic investigations have cast
some light on the mode of action of the bengamides,5
revealing that they may be involved in the inhibition
of methionine aminopeptidases (types 1 and 2, MetAp1
and MetAp2).6 These enzymes are proposed to play
important roles in endothelial cell proliferation and
other sensitive cell types prior to cdk activation, thereby
mediating the cell cycle progression of such cells, and
may serve as a target for the identification of novel
inhibitors of angiogenesis. In contrast to the other
known MetAp2 inhibitors such as fumagillin or ovali-
cin,7 in which the mode of inhibition is due to a covalent
bond formed from the amine group of a histidine
aminoacid residue, located at the active site, with the
oxirane ring of these compounds; the bengamides exert
their inhibition as a result of multiple highly specific
interactions. In particular, these molecules are embed-
ded at the active site of the enzyme due to a hydrophobic
interaction between the terminal alkyl group of the ole-
fin in the P1 pocket, a polar interaction of the caprolac-
tam moiety in the solvent exposed P2 region and
coordination of the cobalt ion via the hydroxyls at
C-3, C-4, and C-5. These biological observations have
been performed with a more soluble analogue of the nat-
ural bengamides, the compound LAF-389 (7),8 which
possesses improved bioavaliability over the natural
products. Nevertheless, all these valuable biological dis-
closures do not permit the establishment of a direct
effect of the inhibition of MetAp on the protein regula-
tion, and, consequently, with the antiproliferative prop-
erties of the bengamides. All these outstanding
biological properties, in conjuction with the attractive
molecular structures of the bengamides, encouraged us
to design a synthesis that would allow access to a wide
family of analogues, including the natural congeners.
To this aim, and after careful chemical inspection of
their molecular structures, we devised a synthetic strat-
egy involving three key steps into a synthetic scheme
capable of reaching either the natural bengamides or
analogues by modification of the building blocks em-
ployed in each one of these key steps. In particular, these
three steps are: (a) a cross olefin metathesis for the ste-
reoselective introduction of the terminal alkyl group; (b)
an epoxide ring opening reaction, that would allow the
introduction of various nucleophiles; and, (c) an amide
bond formation by displacement of a suitable leaving
group by different nitrogen nucleophiles, including the
lactams found in the natural compounds. The introduc-
tion of structural modifications along the proposed syn-
thesis would provide a diverse set of bengamide
Keywords: Bengamides; LAF-389; Methionine aminopeptidase inhib-
itors; Sulfur ylides; Epoxyamides; Cross metathesis; Stereoselective
synthesis.
*
Corresponding author. Tel.: +34 952134258; fax: +34 952131941;
e-mail: frsarabia@uma.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.096

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F. Sarabia, A. Sanchez-Ruiz / Tetrahedron Letters 46 (2005) 1131–1135
1132
of an additional step of hydrolysis to the acid13 and sub-
sequent coupling with 13 mediated by the action of (ben-
zotriazol-1-yloxy) tris-(dimethylamino)phosphonium
hexafluorophosphate (BOP) to afford compound 14 in
a 65% yield. At this stage, we decided to tackle the
cross-olefin metathesis in order to test the synthetic
strategy devised for the bengamides. Thus, exposure of
a solution of olefinic epoxyamide 14 in DCM and 3-
methyl-1-butene as cosolvent to the second generation
Grubbs catalyst 1514 at 40 °C for 38 h, yielded the alk-
ene 16 in a 76% yield (9:1 mixture of E:Z isomers).
In a similar way, the reaction of 14 with 3,3-dimethyl-
1-butene provided the corresponding tert-butyl substi-
tuted alkene 17 in similar diastereomeric proportion
but in much lower yield (28%, 9:1 E:Z mixture). The
hydrolysis of 16 by the action of Amberlyst-15 afforded
the dihydroxy epoxy-bengamide analogue 18 in a quan-
titative yield (Scheme 1).
Figure 1. Molecular structures of bengamides and retrosynthetic
analysis.
analogues, modified in key regions where interaction
with the enzyme seems to be essential. According to this
synthetic strategy, the epoxyamide 8, which can be pre-
pared via reaction of aldehydes with a sulfur ylide,9
would represent the suitable precursor to initiate this re-
search. In fact, analogues containing the oxirane ring
functionality promise to be especially interesting as they
could interact in a fumagillin mode of action by cova-
lently interacting with the enzyme through an oxirane
ring opening reaction.
The synthesis of the synthetic subtarget 8 commenced
with the reaction of aldehyde 910 with the in situ gener-
ated sulfur ylide from sulfonium salt 10, providing a dia-
stereomic mixture of epoxyamides 8 and 11 in a 59%
combined yield (4:1 proportion in favor of the undesired
epoxyamide 11). After separation by flash column chro-
matography, the minor isomer, compound 8, was trans-
formed into the more reactive indole derivative 12,
which is potentially susceptible to direct displacement11
by the aminolactam 13.12 However, after obtaining 12 in
a very good yield (83%), the reaction with the aminolac-
tam 13 failed to provide the desired result, under a wide
variety of reaction conditions. The lack of reactivity of
12 toward 13 prompted us to modify the straightfor-
ward preparation of 14, resulting in the introduction
Scheme 1. Synthesis of the bengamide precursors 16 and 17 and
bengamide analogue 18. Reagents and conditions: (a) 1.5 equiv 10,
1.5 equiv NaOH, CH2Cl2/H2O, 0 °C, 12 h, 59% (4:1 mixture of 11:8).
(b) 4.0 equiv DDQ, C6H6, reflux, 8 h, 83%. (c) 2.0 equiv LiOH (0.1 M),
THF/H2O, 0 °C, 0.5 h, 67%. (d) 1.5 equiv 13, 1.2 equiv BOP, 2.2 equiv
DIEA, DMF, 25 °C, 8 h, 65%. (e) 0.1 equiv 15, CH2Cl2/Alkene (4/1),
40 °C, 38 h, 76% for 16 (E/Z ꢀ 9/1); 28% for 17 (E/Z ꢀ 9/1). (f)
Amberlyst-15, MeOH, 8 h, 25 °C, 99%.

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F. Sarabia, A. Sanchez-Ruiz / Tetrahedron Letters 46 (2005) 1131–1135
1133
Since the reaction of aldehyde 9 with the sulfur ylide did
not supply sufficient amounts of the correct epoxide, we
decided to stereoselectively prepare the epoxide via
Sharpless asymmetric epoxidation. Accordingly, the
a,b-unsaturated ester 19, prepared in a 80% yield from
aldehyde 9 by reaction with the corresponding phospho-
rous ylide, was transformed into the allylic alcohol 20 by
treatment with DIBAL-H, and subjected to the Sharp-
less asymmetric epoxidation, using (À)-DET, to provide
epoxyalcohol 21 in 87% yield and excellent diastereose-
lectivity. The oxidation to the epoxyacid 23 was under-
taken in two steps, through aldehyde 22, obtained via
Swern oxidation of alcohol 21, followed by treatment
with OxoneÒ.15 The preparation of epoxyamide 16 was
then carried out as described before in Scheme 1. With
the construction of the main backbone of the beng-
amides complete, the oxirane ring contained in these
products represented a suitable functionalization point
amenable to the final introduction of the requisite meth-
oxyl group. Thus, we attempted this final key step by
exploring an extensive set of reaction conditions that in-
cluded either basic or acidic conditions, resulting in no
formation of the coveted product 24. Despite being an
important synthetic hurdle for the total synthesis of
the bengamides, this epoxide offers the opportunity of
preparing a series of 2-C-modified analogues of the
bengamides via oxirane ring opening with various nucleo-
philes.16 In fact, the 2-amino derivatives 25–27 were
efficiently prepared, providing interesting biological
probes for the aminopeptidase enzymes with a poten-
tially strong coordination with the cobalt ions present
at the active site. With the objective of broadening the
structural diversity of the bengamide analogues, we
undertook the opening reaction with other nucleophiles
including alkyl organometallics and sulfur nucleo-
philes.17 However, in both cases, the elimination prod-
ucts, for example, 28 were obtained as the main
products. On the other hand, proceeding in the manner
described above for 16, the 2,3-epimeric compound 29
was easily prepared from epoxyamide 11 and reacted
with nitrogen nucleophiles to obtain the 2-amino deriv-
atives 30–32 in excellent yields (Scheme 2).
Scheme 2. Synthesis of the 2-amino analogues of bengamides.
Reagents and conditions: (a) 2.0 equiv DIBAL-H, CH2Cl2, À78 °C,
0.5 h, 85%. (b) 0.1 equiv (À)-DET, 0.1 equiv Ti(Oi-Pr)4, 2.0 equiv
˚
TBHP, 4 A MS, CH2Cl2, À20 °C, 20 h, 87%. (c) 2.0 equiv (COCl)2,
2.0 equiv DMSO, CH2Cl2, À78 °C, 0.5 h, then 5.0 equiv Et3N, 78%.
(d) 1.0 equiv OxoneÒ, DMF, 25 °C, 1.5 h, 75%. (e) and (f). As
described in Scheme 1. (g) See text for information. (h) RNH2 (excess),
MeOH/H2O, 25 °C, 12 h, 95–99% for 25–27. (i) 3.0 equiv NaSMe,
3.0 equiv AcOH, THF, 25 °C, 6 h, 80%. (j) RNH2 (excess), MeOH/
H2O, 25 °C, 12 h, 95–99% for 30–32.
Owing to the problems that arose in the oxirane ring
opening with alcohols, we opted to work with the more
robust O-benzyl protected aldehyde 3318 in order to ex-
pand the reaction conditions for the epoxide opening
process. Then, 33 was reacted with the sulfur ylide under
similar conditions as for 9, to obtain a 1:1 mixture of
epoxyamides 34 and 35. This lower stereoselectivity
compared with aldehyde 9 was considered satisfactory
since it was secured adequate supplies of both diastereo-
isomers. After separation of both isomers by flash
column chromatography, the desired isomer 35 was
subjected to a wide variety of catalysts (TiCl4, Ti(Oi-
Pr)4, ZrCl4, Zn(OTf)2, Sc(OTf)3, Yb(OTf)3, Cu(BF4)2,
BF3, CSA, H2SO4, etc.)19 and reaction conditions (sol-
vents and temperatures) with the objective of introduc-
ing the alkoxyl group. Unfortunately, this extensive
exploration was not successful in providing the com-
pound 36, recovering starting material or obtaining the
chlorhydrine 37 when ZrCl4 was employed as catalyst,
probably through the intermediate A.20 The cross-olefin
metathesis of epoxyamide 35 was similarly disappoint-
ing, because of the poor yields obtained for 38 (50%)
and 39 (29%), ascribed to steric reasons, which devalu-
ated the synthetic interest of this olefin metathesis
approach (see Scheme 3).
In conclusion, a new synthetic approach to the beng-
amides has been described based on the chemistry of sul-
fur ylides, according to a synthetic scheme capable of
generating a variety of bengamide analogues.21 The
extension of this synthetic strategy to the natural beng-
amides will require some modifications in order to intro-
duce the methoxyl group. These synthetic efforts as well
as biological evaluations of the described bengamide
analogues are currently in progress and will be presented
in the due course.

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1134
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experimental details. (c) 1.2 equiv ZrCl4, CH2Cl2/MeOH, 25 °C, 6 h,
85%. (d) 0.1 equiv 15, CH2Cl2/Alkene (4/1), 40 °C, 38 h, 50% for 38
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Acknowledgments
´
This work was financially supported by Fundacion
Ramon Areces and the Direccion General de Investi-
´
´
´
gacion (ref. BQU2001-1576), and fellowships from
Ministerio de Educacion y Ciencia (A.S.R.). We thank
´
Dr. J. I. Trujillo from Pfizer (St. Louis, MO) for assis-
tance in the preparation of this manuscript. We thank
´
Unidad de Espectroscopıa de Masas de la Universidad
de Sevilla for exact mass spectroscopic assistance.
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