A concise synthesis of bengamide E and analogues via E-selective cross-metathesis olefination

Article abstract of DOI:10.1055/s-0030-1259015

A modular, eight-step synthesis of bengamide E and six analogues from a common chiral pool has been developed. The key step in this approach is a cross-metathesis coupling of various commercial terminal olefins and a common alkene bearing the required ste

Full text of DOI:10.1055/s-0030-1259015

LETTER
2923
A Concise Synthesis of Bengamide E and Analogues via E-Selective
Cross-Metathesis Olefination
C
oncise Synth
a
esis of Be
n
f
gamide
E
i
andA
u
nalogues l Alam, Hamid Dhimane*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS/Université Paris Descartes,
UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris cedex 06, France
Fax +33(1)42864050; E-mail: hamid.dhimane@parisdescartes.fr
Received 2 September 2010
ly inhibit one of the two human MetAP isoforms is still a
challenge.
Abstract: A modular, eight-step synthesis of bengamide E and six
analogues from a common chiral pool has been developed. The key
step in this approach is a cross-metathesis coupling of various com-
mercial terminal olefins and a common alkene bearing the required
stereogenic centers of bengamides lateral chain, which was easily
derived from a-D-glucoheptonic-g-lactone. Complete E-selectivity,
and up to 92% yield were achieved for this crucial cross-metathesis
step.
OR3 OMe
O
R5
H
R1
N
N
OR2 OR4
O
5'
R6
Key words: bengamide, analogues, cross-metathesis, stereoselec-
tive olefination, isomerization
bengamide A R1 = i-Pr; R2 = R3 = R4 = R5 = H; R6 = OCO(CH2)12Me
bengamide B R1 = i-Pr; R2 = R3 = R4 = H; R5 = Me; R6 =OCO(CH2)12Me..
bengamide E R1 = i-Pr; R2 = R3 = R4 = R5 = R6 = H
LAF 389 R1 = t-Bu; R2 = R3 = R4 = R5 = H; R6 = OCO-c-Hex (5'-R)
1 R1 = R5 = R6 = H; R2, R3 = CMe2; R4 = OTBS (Sarabia's synthon)
Bengamides are sponge-derived natural products of
mixed biosynthesis (polyketides and amino acids); the
first two members, isolated from Jaspidae sponges in cor-
al surrounding Fiji islands, were reported in 1986 by
Crews et al.1 To this date, 19 members of these natural
products have been identified; they share a common
syn,syn,anti-polyol-containing C10 side chain. The main
structural variation is located on the 3-aminocaprolactam
moiety (Figure 1). Beyond the synthetic challenge, some
of the known bengamides have a great intrinsic value as
they are endowed with nanomolar level of antiprolifera-
tive activity against various cancer cell lines, with striking
differential cytotoxicity.2 These interesting biological fea-
tures, together with their limited supply from natural
sources, have made these sponge secondary metabolites
popular targets for synthetic chemists.3
Figure 1 Natural bengamides and synthetic analogues
We recently developed a methodology for the synthesis of
substituted cyclic L-lysines towards bengamide analogues
having structural variations at the caprolactam unit.8 As
all previous strategies,3 our synthesis relies on the acyla-
tion of 3-aminocaprolactam moieties with the C10 polyol
side chain. In our initial synthetic plan, we intended to
prepare the required acylating polyol moiety according to
the most efficient procedure, recently described by Xu et
al.9 for the synthesis of LAF389. The key step of this route
relies on a Julia–Kocienski olefination of aldehyde 3 de-
rived in four steps from the commercially available a-D-
glucoheptonic-g-lactone9 (Scheme 1). In this procedure,
the olefination was reported with variable stereoselectivi-
ty (3:1 < E/Z < 10:1) and moderate yields (40–50%), de-
pending on the solvents and additives used. We examined
this procedure with 2-(isobutylsulfonyl)benzo[d]thiazole
(i-BuSO2BTS), as well as with 5-(isobutylsulfonyl)-1-
phenyl-1H-tetrazole (i-BuSO2PT). After extensive studies
we were able to achieve olefination of 3 with excellent
diastereoselectivity (E/Z up to 20:1) by using a polar sol-
vent system (DMF–HMPA = 4:1); but yields of 5a were
disappointingly poor (20–30%; Scheme 1). Following the
same procedure, methylenation compound 4 was obtained
with lower yields (6–10%) starting from aldehyde 3 and
5-(methylsulfonyl)-1-phenyl-1H-tetrazole.10 At this point
we decided to examine alternative methods for this E-ole-
fin installation, both in terms of yield and stereoselectivi-
ty. To this end, we directed our attention towards olefin
cross metathesis (CM) involving alkene 4 (Scheme 1).
The significant in vitro and in vivo antitumoral activities
observed for bengamides A and B led Kinder et al. to the
design and synthesis of a bengamide B analogue LAF389
(Figure 1), which exhibited promising antitumoral activi-
ty during preclinical trials.4
Recently, Towbin et al.5 have shown that bengamides tar-
get both isoforms of human methionine aminopeptidases
(MetAP), resulting in the inhibition of the N-terminal me-
thionine excision, an essential co- or post-translational
modification of most nascent proteins in all living organ-
isms.6 More recently, Hu et al. suggested that inhibition of
both MetAP isoforms could indirectly impair the func-
tioning of c-Src and probably that of other oncogenes es-
sential for tumor growth.7 Therefore, the design and
synthesis of new bengamide analogues that can selective-
SYNLETT 2010, No. 19, pp 2923–2927
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.11.2010
DOI: 10.1055/s-0030-1259015; Art ID: G24310ST
© Georg Thieme Verlag Stuttgart · New York

2924
S. Alam, H. Dhimane
LETTER
O
O
First, we tested the reactivity of 4 in CM reaction towards
a model terminal alkene; 3,3-dimethylbut-1-ene 7b
(Table 1), a type III olefin according to Grubbs’ olefin
categorization.14 No CM was observed between 4 and 7b
(5 equiv) in presence of first-generation Grubbs catalyst
[Ru]-I (up to 0.5 equiv), and only moderate conversion
was observed when olefin 4 was reacted with p-chlorosty-
rene, 7f (5 equiv) in the presence of the same catalyst
[Ru]-I. Using 10 mol% of catalyst [Ru]-II (Table 1, entry
1), olefin 7b and 4 led to the expected cross-metathesis
compound 5b, along with unreacted substrate 4 and its
isomerization compound 4′ (Figure 3).
OH
O
O
O
Me
a
O
O
Me
OH
O
O
O
O
2
3
b
c
O
MeO
O
O
O
O
O
d
R
O
O
Me
Me
(for 4 R = H)
O
O
O
O
Table 1 Cross-Metathesis of 4 and Olefins 7
6
4
R = H
5a R = i-Pr
O
O
O
O
Ru catalyst
additive
Scheme 1 Reagents and conditions: (a) NaIO4, H2O–MeOH, r.t.,
85%; (b) RCH2SO2PT, LiHMDS, DMF–HMPA (4:1), –35 °C to
35 °C, 12 h, 6% for 4, 22% for 5a (E/Z = 20:1); (c) HC(OMe)3, PPTS,
THF, r.t., 94%; (d) Ac2O, 150 °C, 93%.
R
O
O
+
CH2Cl2
(reflux), 16 h
R
Me
Me
O
O
O
O
7
4
5a–h
Recently, Sarabia et al.3e synthesized bengamide E and
two analogues via CM olefination starting from a protect-
ed methylene analogue of bengamide E; compound 1
(Figure 1) which was obtained in 17 steps from D-tartrate.
The authors reported variable conversions (33–100%) of
1 by using 30 mol% of Hoveyda–Grubbs catalysts; the E/
Z ratios were around 9:1. We hypothesized that this low
conversion (observed in the case of styrene and t-
BuCH=CH2) could be due to catalyst inhibition with the
substrate amide functionalities. A priori, such inhibition
was not expected with olefin 4, which we were planning
to use as a key substrate, and whose synthesis was expect-
ed to be significantly shorter than the construction of the
key olefin 1 (Figure 1) employed by Sarabia.3e
a R = i-Pr; b R = t-Bu; c R = c-Hex; d R = i-Bu; e R = Ph;
f R = p-ClC6H4; g R = p-FC6H4; h R = Me3SiCH2
Entry
1
7
Ru cat. (equiv) Additive (equiv) Yield of 5 (%)
7b
7b
7b
7b
7b
7b
7a
7c
7d
7e
7f
II (0.1)
none
5b (70)a,b
5b (70)a,c
5b (70)a
5b (71)
5b (100)a,d
5b (80)
5a (66)e
5c (86)
2
II (0.1)
TFQ (0.2)
DCQ (0.2)
DCQ (0.3)
none
3
II (0.1)
4
II (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
III (0.15)
5
6
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
DCQ (0.3)
7
Thus our synthesis commenced from the known vicinal
diol 2, which is routinely obtained in multigram scale
from a-D-glucoheptonic-g-lactone.4 Diol 2 was converted
to the desired key olefin 411 following Eastwood’s se-
quence (Scheme 1).12 First, 2 was converted to the corre-
sponding 2-methoxy-1,3-dioxolane 6 in 94% yield, as
diastereomeric mixture (2:3), by treatment with trimethyl
orthoformate in the presence of PPTS;13 then, pyrolysis of
6 in refluxing acetic anhydride led to the desired olefin 4
in good and reproducible yields (Scheme 1). Once the
synthesis of this key synthon was settled up, we selected
three of the most common catalysts (Figure 2) in order to
examine CM olefination of 4 with various commercially
available terminal olefins.
8
9
5d (78)
5e (87)
10
11
12
13
5f (92)
7g
7h
5g (91)
5h (72)
a Conversion.
b 5b:4′ = 1:0.6 as determined by 1H NMR.
c 5b:4′ = 1:0.2.
d 5b:4′ = 1:0.3.
e Performed with large excess of volatile olefin 7a, in a tight Teflon-
capped tube; 85% conversion after 48 h.
N
N
Mes
Cl
Mes
Similar results were obtained with other olefins 7a–g, al-
though with less isomerization (1:0.1 < 5:4′ < 1:0.3) in the
case of styrenes 7e–g (results not shown). These prelimi-
nary results were promising in terms of diastereoselectiv-
ity since only E-isomer was detected in all cases;
however, the substrate isomerization rendered the com-
pounds purification very tedious.15 Alkene isomerization
N
N
Ru
Mes
Cl
Cl
Mes
Ph
PCy3
Ru
Cl
Cl
Cl
O
Ru
PCy3
[Ru]-II
Ph
PCy3
[Ru]-I
[Ru]-III
Figure 2 Ru catalysts (Cy = c-Hex; Mes = mesityl)
Synlett 2010, No. 19, 2923–2927 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of Bengamide E and Analogues
2925
of both substrates and adducts is a well-known and impor- Less isomerization was observed when Hoveyda–Grubbs
tant side reaction in ruthenium-catalyzed metathesis reac- catalyst [Ru]-III (15 mol%) was used alone instead of
tions. It was first reported with the primary metathesis [Ru]-II (Table 1, entry 5). In the presence of DCQ (30
products in presence of catalyst [Ru]-I.16 Fürstner and co- mol%), [Ru]-III (15 mol%) provided good to excellent
workers reported the first example where the isomeriza- yields for CM of 4 with olefins 7a–h (Table 1, entries 6–
tion occurred with the ring-closing metathesis (RCM) 13); in all examples, only the trans-isomer was observed
substrate prior to its cyclization.17 It has since been also by NMR, and no isomerization compound 4′ was detect-
observed, with both generations of catalysts, on a broad ed.22 With the polyol side-chain precursors 5 in hand, we
variety of alkenes,18 particularly those including sub- proceeded to their coupling with (3S)-3-aminocaprolac-
strates containing allylic functionalities.19 Recent mecha- tam 8,23 and subsequent cleavage of acetonide, towards
nistic studies suggest the involvement of ruthenium the natural bengamide E and analogues (Table 2).
mono- or dihydride intermediates.20 Formation of com-
pound 4′, which was not observed with catalyst [Ru]-I, is
The coupling step was first carried out with 5b by aminol-
ysis under nearly neutral pH conditions, as described by
expected to be thermodynamically irreversible, since 4′ is
a conjugated olefin. Recently, Grubbs and coworkers dis-
closed the advantageous effect of electron-deficient 1,4-
benzoquinone additives: since it avoids the generation of
ruthenium hydride species, it prevents olefin isomeriza-
tion.21 Accordingly, we examined the effect of tetrafluo-
ro-1,4-benzoquinone (TFQ) and 2,6-dichloro-1,4-
benzoquinone (DCQ) on the irreversible formation of 4′
(Figure 3).
Liu et al.24 Lactone 5b and (3S)-3-aminocaprolactam hy-
drochloride 8 (1.5 equiv) were stirred in the presence of
sodium 2-ethylhexanoate (NaEH; 2 equiv) in THF at
room temperature for 20 hours to afford amide 9b as a sin-
gle diastereomer (75%). Coupling of 8 with other lactones
5, under the same mild conditions, proceeded smoothly to
afford the corresponding amides 9 with good yields
(Table 2). Subsequent treatment of acetonides 9a–g with
aqueous HCl (1 M) and THF (2:1) mixture, at room tem-
perature, led to the corresponding bengamide analogues
10a–g in satisfactory to good yields (Table 2).
O
X
Y
O
OMe
Table 2 Synthesis of Bengamide E and Analogues 10
O
O
CO2Na
O
O
O
OH OMe
5
H
(2 equiv)
X
Y
n-Pr
Et
R
N
NH
+
+NH3
4'
TFQ X = Y = F
DCQ X = Cl, Y = H
THF, r.t., 20 h
Cl–
OR1 OR2
O
O
Figure 3 Structure of isomer 4′ and benzoquinones TFQ and DCQ
9 R1, R2 = CMe2
10 R1 = R2 = H
aq 1 M HCl–THF
(2:1), r.t., 4 h
NH
In order to determine the optimal 1,4-benzoquinone for
prevention of olefin 4 isomerization, the latter was first re-
acted with 7b in presence of 0.1 equivalents of catalyst
[Ru]-II and 0.2 equivalents of TFQ in refluxing CH2Cl2.
Although limited isomerization was observed, this benzo-
quinone could not totally preclude substrate isomerization
(Table 1, entry 2). Using DCQ (0.2 equiv) instead of TFQ
completely suppressed the unwanted olefin isomerization
reaction; only substrate 4 and its olefin cross-metathesis
product 5b were observed in the crude mixture; no trace
of its isomerization compound 4′ was detected after 16
hours (Table 1, entry 3). However, in both cases, the con-
version was limited to 70% of substrate 4. Upon increas-
ing the catalyst loading to 15 mol% – and hence
dichloroquinone to 30 mol% – we observed complete con-
version providing 5b in 71% isolated yield (Table 1, entry
4) as a single detectable diastereomer based upon 500
MHz NMR analysis. The optimized procedure thus deter-
8
Entry 5 (R)
Yield of 9 (%)
9a 75
Yield of 10 (%)
10a 64
1
2
3
4
5
6
7
8
5a (i-Pr)
5b (t-Bu)
9b 75
10b 65
5c (c-Hex)
5d (i-Bu)
9c 85
10c 62
9d 84
10d 58
5e (Ph)
9e 89
10e 66
5f (4-ClC6H4)
5g (4-FC6H4)
5h (Me3SiCH2)
9f 79
10f 72
9g 90
10g 70
a
9h 75
–
a Diene 11 (Figure 4) was obtained in 80% yield.
mined was then applied to CM of substrate 4 with other al- In the case of 9h, the same acidic conditions led to the
iphatic olefins 7a,c,d and styrenes 7e–g, as well as
allyltrimethylsilane 7h. Conversion of olefin 4 was gener-
ally completed within 16 hours, except with 7a (R = i-Pr),
which gave limited conversion; the pure CM compounds
5a–h were isolated in satisfactory to good yields (62–
82%, results not shown); moreover, we were pleased to
obtain exclusively the E-isomer in each case.
conjugated diene 11 (Figure 4) via the acetonide removal
and subsequent acid-catalyzed vinylogous Peterson elim-
ination.
In conclusion, we have achieved the synthesis of beng-
amide E, a natural marine compound, and six analogues,
three of them structurally novel (10d,f,g). The synthetic
pathway reported here offers an easy access to the polyol
Synlett 2010, No. 19, 2923–2927 © Thieme Stuttgart · New York

2926
S. Alam, H. Dhimane
LETTER
Tai, W.-Y.; Xie, C.-M.; Li, Y.-L.; li, J.; Nan, F.-J.
O
OH OMe
H
ChemMedChem 2008, 3, 74.
N
NH
(4) Kinder, F. R.; Versace, R. W.; Bair, K. W.; Bontempo, J. M.;
Cesarz, D.; Chen, S.; Crews, P.; Czuchta, A. M.; Jagoe, C.
T.; Mou, Y.; Nemzek, R.; Phillips, P. E.; Tran, L. D.; Wang,
R.; Weltchek, S.; Zabludoff, S. J. Med. Chem. 2001, 44,
3692.
OH
11
O
Figure 4 Diene 11 obtained from silylated compound 9h
(5) Towbin, H.; Bair, K. W.; DeCaprio, J. A.; Eck, M. J.; Kim,
S.; Kinder, F. K.; Morollo, A.; Mueller, D. R.; Schindler, P.;
Song, H. K.; van Oostrum, J.; Versace, R. W.; Voshol, H.;
Wood, J.; Zabludoff, S.; Phillips, P. E. J. Biol. Chem. 2003,
278, 52964.
(6) For recent reviews, see: (a) Bernier, S. G.; Taghizadeh, N.;
Thompson, C. D.; Westlin, W. F.; Hannig, G. J. Cell.
Biochem. 2005, 95, 1191. (b) Selvakumar, P.;
Lakshmikuttyamma, A.; Dimmock, J.; Sharma, R. K.
Biochim. Biophys. 2006, 1765, 148. (c) Frottin, F.;
Martinez, A.; Peynot, P.; Mitra, S.; Holz, R. C.; Giglione, C.;
Meinel, T. Mol. Cell. Proteomics 2006, 5, 2336.
(d) Wiltschi, B.; Merkel, L.; Budisa, N. ChemBioChem
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(7) Hu, X.; Dang, Y.; Tenney, K.; Crews, P.; Tsai, C. W.; Sixt,
K. M.; Cole, P. A.; Liu, J. O. Chem. Biol. 2007, 14, 764.
(8) (a) Levraud, C.; Calvet-Vitale, S.; Bertho, G.; Dhimane, H.
Eur. J. Org. Chem. 2008, 1901. (b) David, M.; Dhimane, H.
Synlett 2004, 1029.
(9) Xu, D. D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee,
G. T.; Liu, W.; Szewczyk, J.; Vargas, K.; Prasad, K.; Repic,
O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 856.
(10) Aldehyde 3 is highly hygroscopic and sensitive to both acid
and base; it should be freshly prepared and dehydrated by
azeotropic evaporations with i-PrOAc prior to its use.
(11) Our initial attempt to carry out the Julia–Kocienski
methylenation of aldehyde 3 led to the required olefin 4 in
poor yields (<10%).
side chain with different E-olefinic moieties, thus intro-
ducing structural modification at a position involved in a
key noncovalent interaction of bengamides with the active
site of MetAP enzymes.5 We successfully developed syn-
thon 4 as good alternative starting material for olefination;
major improvement was made on this step by using cross-
metathesis conditions in the presence of 15 mol% of CM
catalysts [Ru]-II or [Ru]-III and 2,6-dichloro-1,4-benzo-
quinone (0.3 equiv). This procedure offers the key olefins
5 in good to excellent yields for both alkyl- and aryl-sub-
stituted alkenes, with complete E-selectivity. Unlike alde-
hyde 3 or Sarabia’s synthon 1, alkene 4 is easy to store and
handle and is easily prepared in an efficient five-step se-
quence from a reasonably priced chiral pool; a-D-gluco-
heptonic-g-lactone. The benefits of the present synthesis
are threefold: (1) tedious purifications of olefins 5 are
avoided due to complete E-selectivity in cross-metathesis
olefination, (2) good to excellent yields of cross-metathe-
sis olefination improve the overall yield, (3) this modular
route is amenable to the preparation of a variety of ana-
logues that could be helpful for bengamides SAR studies.
Supporting Information for this article (preparation of 4
and a typical procedure for its transformation into a bengamide
analogue) is available online at http://www.thieme-connect.com/
ejournals/toc/synlett.
(12) (a) Grank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17,
1392. (b) Ando, M.; Ohhara, H.; Takase, K. Chem. Lett.
1986, 879.
(13) Use of PTSA as catalyst in toluene at 80 °C gave similar
yields; however, in large-scale batches, we observed
transprotection of the acetonide, thus leading to the
corresponding bisorthoester. Orthoester 6 was found to be
stable at r.t. in the solid state; however, it undergoes gradual
hydrolysis (into methyl formiate and diol 2) on standing in
CDCl3.
Acknowledgment
This work was financially supported by Paris Descartes University
and the Centre National de Recherche Scientifique (CNRS), and a
post-doctoral fellowship (S.A.) from the Ministère de l’Enseigne-
ment Supérieur et de la Recherche (MESR).
(14) Chatterjee, A. K.; Choi, R.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
(15) The CM adducts 5 could not be quantitatively recovered
from the reaction mixtures; aromatic compounds 5e–g could
not be fully separated from substrate 4, while the aliphatic
ones 5a–d were always contaminated with the substrate
isomer 4′.
(16) (a) Maynard, H. D.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 4137. (b) Edwards, S. D.; Lewis, T.; Raylor, R. J. K.
Tetrahedron Lett. 1999, 40, 4267. (c) Bourgeois, D.;
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(18) For review, see: (a) Schmidt, B. Eur. J. Org. Chem. 2004,
1865. (b) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9,
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Synlett 2010, No. 19, 2923–2927 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of Bengamide E and Analogues
2927
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