Total synthesis of bengamide E and analogues by modification at C-2 and at terminal olefinic positions

Article abstract of DOI:10.1021/jo0516032

The total synthesis of the natural product Bengamide E, one of the members of a new class of antitumor natural products of marine origin, is reported based on a convergent and flexible synthetic route featuring an oxirane ring-opening reaction and an olefin cross metathesis. In a similar way, analogues structurally modified at C-2 and at the terminal vinyl positions were prepared by introduction of various nucleophiles and alkyl substituents during the epoxide opening and the olefin cross metathesis steps, respectively. These studies demonstrate the validity of our synthetic strategy, although they reveal some problems associated with the olefin cross metathesis, whose efficiency depends on the substituent at the C-2 position as well as the steric environment of the alkene.

Full text of DOI:10.1021/jo0516032

Total Synthesis of Bengamide E and Analogues by Modification at
C-2 and at Terminal Olefinic Positions
Francisco Sarabia* and Antonio Sa´nchez-Ruiz
Department of Biochemistry, Molecular Biology and Organic Chemistry, Faculty of Sciences, University of
Malaga, 29071 Malaga, Spain
frsarabia@uma.es
Received July 31, 2005
The total synthesis of the natural product Bengamide E, one of the members of a new class of
antitumor natural products of marine origin, is reported based on a convergent and flexible synthetic
route featuring an oxirane ring-opening reaction and an olefin cross metathesis. In a similar way,
analogues structurally modified at C-2 and at the terminal vinyl positions were prepared by
introduction of various nucleophiles and alkyl substituents during the epoxide opening and the
olefin cross metathesis steps, respectively. These studies demonstrate the validity of our synthetic
strategy, although they reveal some problems associated with the olefin cross metathesis, whose
efficiency depends on the substituent at the C-2 position as well as the steric environment of the
alkene.
Introduction
bengamides possess an intriguing mode of action char-
acterized by their binding to methionine aminopeptidases
type 2 (MetAp2),4 enzymes that are involved in the cell
cycle of endothelial cells and angiogenesis.5 This mode
is similar to those of fumagillin and ovalicin, despite their
structural differences.6 All these biological features in
conjuction with their molecular architectures have elic-
ited great interest among chemists7 and biologists.8 Our
group engaged recently in a research program directed
toward the total syntheses of these naturally occurring
cytotoxic molecules, of which six representative members
are depicted in Figure 1.
The bengamides represent an interesting and promis-
ing family of marine natural products, isolated from
sponges of the Jaspidae family,1 with unique molecular
structures and a broad array of biological activities that
include antitumor, antibiotic, and antihelmintic proper-
ties.2 According to recent biological investigations,3 the
(1) (a) Qu´ın˜oa´, E.; Adamczeski, M.; Crews, P.; Bakus, G. J. J. Org.
Chem. 1986, 51, 4494-4497. (b) D’Auria, M. V.; Giannini, C.; Minale,
L.; Zampella, A.; Debitus, C.; Frostin, M. J. Nat. Prod. 1997, 60, 814-
816. (c) Ferna´ndez, R.; Dherbomez, M.; Letourneux, Y.; Nabil, M.;
Verbist, J. F.; Biard, J. F. J. Nat. Prod. 1999, 62, 678-680.
(2) (a) Kinder, F. R.; Bair, K. W.; Bontempo, J.; Crews, P.; Czuchta,
A. M.; Nemzek, R.; Thale, Z.; Vattay, A.; Versace, R. W.; Weltchek, S.;
Wood, A.; Zabludoff, S. D.; Phillips, P. E. Proc. Am. Assoc. Cancer Res.
2000, 41, 600. (b) Phillips, P. E.; Bair, K. W.; Bontempo, J.; Crews, P.;
Czuchta, A. M.; Kinder, F. R.; Vattay, A.; Versace, R. W.; Wang, B.;
Wang, J.; Wood, A.; Zabludoff, S. Proc. Am. Assoc. Cancer Res. 2000,
41, 59. (c) Groweiss, A.; Newcomer, J. J.; O’Keefe, B. R.; Blackman,
A.; Boyd, M. R. J. Nat. Prod. 1999, 62, 1691-1693.
(3) (a) Towbin, H.; Bair, K. W.; DeCaprio, J. A.; Eck, M. J.; Kim, S.;
Kinder, F. R.; 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, 52964-52971. (b) Kim, S.;
LaMontagne, K.; Sabio, M.; Sharma, S.; Versace, R. W.; Yusuff, N.;
Phillips, P. E. Cancer Res. 2004, 64, 2984-2987.
Our early synthetic studies were conducted according
to a synthetic strategy utilizing sulfur ylides to construct
an oxirane ring as a means for the introduction of the
(4) Lowther, W. T.; Orville, A. M.; Madden, D. T.; Lim, S.; Rich, D.
H.; Matthews, B. W. Biochemistry 1999, 38, 7678-7688.
(5) (a) Folkman, J.; Klagsburn, M. Science 1987, 235, 442-446. (b)
Brooks, P. C.; Montgomery, A. M. P.; Rosenfeld, M.; Reisfled, R. A.;
Hu, T.; Klier, G.; Cherest, D. A. Cell 1994, 79, 1157-1164. (c) Quesada,
A. R.; Medina Torres, M. A.; Mun˜oz-Cha´puli, R. In Angiogenesis;
University of Malaga: Malaga, Spain, 2004.
(6) Griffith, E. C.; Su, Z.; Turk, B. E.; Chen, S.; Chang, Y.-H.; Wu,
Z.; Biemann, K.; Liu, J. O. Chem. Biol. 1997, 4, 461-471.
10.1021/jo0516032 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/08/2005
9514
J. Org. Chem. 2005, 70, 9514-9520

Synthesis of Bengamide E and Analogues
SCHEME 1. Interaction of Bengamides with
Methionine Aminopeptidases and Synthetic
Strategy
FIGURE 1. Molecular structures of bengamides.
methoxide group at the C-2 position via a regioselective
oxirane ring-opening reaction,9 and an olefin cross meta-
thesis reaction for the introduction of the terminal alkyl
group.10 Our synthetic course offered the possibility of
introducing structural modifications at key positions
involved in the interaction of the molecule with the
methionine aminopeptidases, leading us to epoxy amide
8, prepared by reacting the corresponding aldehyde with
the stabilized sulfur ylide derived from the indoline
amide, as the key suitable precursor. As depicted in
Scheme 1, the highly specific affinity of the bengamides
toward methionine aminopeptidases is the result of
multiple interactions that include hydrophobic and polar
interactions of the terminal alkyl group of the olefin and
the caprolactam moiety with the P1 pocket and the
solvent-exposed P2 region, respectively, together with a
coordination of the cobalt ions, present at the active site,
with the hydroxyls at the C-3, C-4, and C-5 positions.
An example of the biological importance of the terminal
alkyl group is the synthetic tert-butyl analogue LAF-389
(7), which displays greater antitumor activity compared
with its natural counterpart.11 On the basis of these
precedents, we demonstrated the efficiency of this strat-
egy for the preparation of 2-amino analogues of beng-
amides. Unfortunately, we were unable to introduce the
requisite methoxyl group at C-2 to give the 2-methoxy
derivative 9 when 8 was treated with methanol under a
wide array of reaction conditions. In light of this unsuc-
cessful result, we decided to modify the original synthetic
strategy, figuring that epoxy alcohol 10 could represent
an alternative for the preparation of 11. This slight
modification in our synthesis would allow us to surmount
the synthetic hurdle imposed by the lack of reactivity of
epoxy amides toward alcohols, and would allow us to
maintain a synthetic strategy capable of rendering a
variety of analogues, modified at key regions, that are
involved in the biological interactions with the active site
of enzymes, as illustrated in Scheme 1.
(7) (a) Kinder, F. R., Jr. Org. Prep. Proced. Int. 2002, 34, 561-583.
(b) Chida, T.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1991, 32, 1063-
1066. (c) Gurjar, M. K.; Srinivas, N. R. Tetrahedron Lett. 1991, 32,
3409-3412. (d) Broka, C. A.; Ehrler, J. Tetrahedron Lett. 1991, 32,
5907-5910. (e) Kishimoto, H.; Ohrui, H.; Meguro, H. J. Org. Chem.
1992, 57, 5042-5544. (f) Marshall, J. A.; Luke, G. P. Synlett 1992,
1007-1008. (g) Chida, N.; Tobe, T.; Okada, S.; Ogawa, S. J. Chem.
Soc., Chem. Commun. 1992, 1064-1066. (h) Marshall, J. A.; Luke, G.
P. J. Org. Chem. 1993, 58, 6229-6234. (i) Chida, N.; Tobe, T.; Murai,
K.; Yamazaki, K.; Ogawa, S. Heterocycles 1994, 38, 2383-2388. (j)
Mukai, C.; Kataoka, O.; Hanaoka, M. Tetrahedron Lett. 1994, 35,
6899-6902. (k) Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka,
M. J. Chem. Soc., Perkin Trans. 1 1995, 2849-2854. (l) Mukai, C.;
Kataoka, O.; Hanaoka, M. J. Org. Chem. 1995, 60, 5910-5918. (m)
Mukai, C.; Hanaoka, M. Synlett 1996, 11-16. (n) Kinder, F. R.;
Wattanasin, S.; Versace, R. W.; Bair, K. W.; Bontempo, J.; Green, M.
A.; Lu, Y. J.; Marepalli, H. R.; Phillips, P. E.; Roche, D.; Tran, L. D.;
Wang, R. M.; Waykole, L.; Xu, D. D.; Zabludoff, S. J. Org. Chem. 2001,
66, 2118-2122. (o) Banwell, M. G.; McRae, K. J. J. Org. Chem. 2001,
66, 6768-6774. (p) Liu, W.; Szewczyk, J. M.; Waykole, L.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2002, 43, 1373-1375. (q) Boeckman,
R. K., Jr.; Clark, T. J.; Shook, B. C. Helv. Chim. Acta 2002, 85, 4532-
4560. (r) Boeckman, R. K., Jr.; Clark, T. J.; Shook, B. C. Org. Lett.
2002, 4, 2109-2112. (s) Fonseca, G.; Seoane, G. A. Tetrahedron:
Asymmetry 2005, 16, 1393-1402.
Results and Discussion
(8) (a) Thale, Z.; Kinder, F. R.; Bair, K. W.; Bontempo, J.; Czuchta,
A. M.; Versace, R. W.; Phillips, P. E.; Sanders, M. L.; Wattanasin, S.;
Crews, P. J. Org. Chem. 2001, 66, 1733-1741. (b) Kinder, F. R.;
Versace, R. W.; Bair, K. W.; Bontempo, J.; 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, 3692-3699.
The synthesis of epoxy alcohol 10 was efficiently
accomplished from aldehyde 12, as previously described
by our laboratory.10 The regioselective opening of the
epoxy alcohol with methanol represented a key reaction
for the construction of the complete framework contained
in the bengamides, which previously had failed in the
epoxy amide case. An extensive search of the literature
(9) (a) Valpuesta-Ferna´ndez, M.; Durante-Lanes, P.; Lo´pez-Herrera,
F. J. Tetrahedron Lett. 1995, 36, 4681-4684. (b) Lo´pez-Herrera, F. J.;
Sarabia, F.; Pedraza Cebria´n, G. M.; Pino-Gonza´lez, M. S. Tetrahedron
Lett. 1999, 40, 1379-1380. (c) Mart´ın-Ortiz, L.; Chammaa, S.; Pino-
Gonza´lez, M. S.; Sa´nchez-Ruiz, A.; Garc´ıa-Castro, M.; Assiego, C.;
Sarabia, F. Tetrahedron Lett. 2004, 45, 9069-9072.
(11) 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. Org. Process Res. Dev. 2003, 7, 856-865.
(10) Sarabia, F.; Sa´nchez-Ruiz, A. Tetrahedron Lett. 2005, 46, 1131-
1135.
J. Org. Chem, Vol. 70, No. 23, 2005 9515

Sarabia and Sa´nchez-Ruiz
SCHEME 2. Synthesis of Bengamide E Precursor
19 and Analogue 21a
revealed the difficulty of such a task given the scarcity
of described methods.12 Among them, the neutral condi-
tions employed by Hudlicky13 seemed to be the most
adequate procedure, taking into account the acidic labil-
ity of the acetal present in 10. Thus, treatment of 10 with
neutral alumina in refluxing methanol proceeded
smoothly, to provide the opening product 11 in 57% yield
and complete regioselectivity.14 The oxidation of the
resulting diol 11 was attempted in a straightforward
manner, via TEMPO oxidation15 followed by NaClO2/
NaH2PO4 treatment16 in the presence of an excess of
2-methylbutene.17 Disappointingly, the second oxidation
afforded a complex mixture of products, prompting us to
investigate other methods. This resulted in the identifi-
cation of a TEMPO/BAIB18 system in the presence of
water, which provided the acid in quantitative yield. The
crude acid 13 was then coupled with the commercially
available aminolactam 1819 mediated by the action of
(benzotriazol-1-yloxy) tris(dimethylamino)phosphonium
hexafluorophosphate (BOP) to furnish the corresponding
amide 20, together with its 2-epimer, in 25% yield. The
epimerization was circumvented by protection of the
secondary hydroxyl group of 11 as the tert-butyldimeth-
ylsilyl ether. This was achieved by selective protection
of the primary hydroxyl group of 11 as its pivaloate 14,
followed by silylation of the secondary hydroxyl to give
the silyl ether 15, which was treated with DIBAL to give
the alcohol 16. Thus, oxidation of 16 with TEMPO/BAIB,
in a way similar to that for 11, afforded acid 17, which
was reacted with aminolactam 18 under the influence of
BOP to give compound 19 in 50% overall yield from
alcohol 16 and no detectable epimerization according to
1H NMR. Removal of the protecting groups of 19 was
achieved in two steps (TBAF treatment, followed by
reaction with acetic acid in H2O) to provide the methylene
analogue of Bengamide E, compound 21 (Scheme 2).
In our pursuit of the natural product, Bengamide E
(5), we initiated studies on the olefin cross metathesis20
in order to introduce the terminal isopropyl group. Our
preliminary results obtained in this reaction with epoxy
amide derivatives represented promising precedent for
surmising that this reaction would proceed in a similar
fashion for compound 19. However, when a solution of
olefinic compound 19 in DCM with 3-methyl-1-butene as
cosolvent was exposed to the action of the second-
a Reagents and conditions: (a) Al2O3 (large excess), MeOH,
reflux, 3 days, 57%; (b) 0.3 equiv of TEMPO, 3.0 equiv of BAIB,
1:1 CH3CN:H2O, 25 °C, 2.0 h; (c) 1.3 equiv of PivCl, 2:1 pyr:CH2Cl2,
-20 °C, 0.5 h, 96%; (d) 1.2 equiv of TBSOTf, 1.5 equiv of
2,6-lutidine, CH2Cl2, 0 °C, 15 min, 93%; (e) 2.2 equiv of DIBAL-
H, CH2Cl2, -78 °C, 20 min, 90%; (f) 1.5 equiv of 18, 1.2 equiv of
BOP, 2.0 equiv of DIPEA, DMF, 25 °C, 3.0 h, 50% for 20 together
with its 2-epimer (ca. 25% epimerization) from 11, 50% for 19 from
16; (g) 1.5 equiv of TBAF, THF, 25 °C, 0.5 h; (h) 70% AcOH in
H2O, 50 °C, 8 h, 45% over two steps from 19.
generation Grubbs catalyst 2221 at 40 °C, the reaction
did not proceed as expected. This resulted in no detection
of the coveted alkene 24, even after a long reaction time
with the recovery of the starting olefin. The lack of
reactivity found for this substrate toward the catalytic
action of 22 was overcome by use of the more reactive
second-generation Hoveyda-Grubbs catalyst (23),22 which
promoted olefin cross metathesis of 19 in the presence
of 3-methyl-1-butene, to furnish compound 24 in 89%
yield and with excellent selectivity (9:1 mixture of E:Z
(12) (a) Chittari, P.; Hamada, Y.; Shiori, T. Heterocycles 2003, 59,
465-472. (b) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3, 333-336. (c)
Honda, T.; Mizutani, H. Heterocycles 1998, 48, 1753-1757. (d) Jarosz,
S. Carbohydr. Res. 1988, 183, 217-225.
(13) (a) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. U.S. Patent
5306846, 1994. (b) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J.
Am. Chem. Soc. 1990, 112, 9439-9440.
1
isomers, as determined by H NMR spectroscopy). For
the unprotected olefin 20, the result was discouraging;
utilization of either catalyst 22 or 23 resulted in no
formation of the expected cross olefin product 25. In light
of these results, the introduction of different terminal
alkyl substituents was undertaken from the precursor
19, using 23 as the catalyst. Thus, in a way similar to
that for 24, the reaction of 19 with 3,3-dimethyl-1-butene
provided the corresponding tert-butyl-substituted alkene
26, albeit in poor conversion (90% for a 33% conversion,
9:1 E:Z mixture). On the other hand, treatment of 19 with
styrene under the influence of 23 provided in a reason-
(14) The complete regioselectivity found with this reaction was
ascribed to a mixed aluminate formation between Al2O3 with methanol
and epoxy alcohol 10 that led to a regioselective attack of a methoxyl
group at the C-2 position of 10 in an intramolecular opening process.
(15) Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett.
1992, 33, 5029.
(16) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888-890. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091-2096.
(17) Komatsu, K.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed.
2004, 43, 4341-4345.
(18) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.
(19) L-(-)-R-Amino-ꢀ-caprolactam hydrochloride 18 was purchased
from Fluka.
(21) Scholl, M.; Truka, T.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 40, 2247-2250.
(22) Harrity, J. P. A.; La, D.; Cefalo, D. R.; Visser, M. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1998, 120, 2343-2351.
(20) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900-1923. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751-1753.
9516 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of Bengamide E and Analogues
SCHEME 3. Synthesis of Bengamide E (5) and
Analogues 28 and 29a
SCHEME 4. Synthesis of 2-C-Modified Bengamide
Analogues from Epoxy Alcohol 10a
a Reagents and conditions: (a) all the metathesis reactions were
performed in 2:1 alkene:CH2Cl2, 40 °C for 6-72 h (for yields see
table); (b) 1.5 equiv of TBAF , THF, 25 °C, 0.5 h; (c) 70% AcOH,
50 °C, 0.5 h, 62% over 2 steps for Bengamide E (5), 43% for 28,
60% for 29.
a Reagents and conditions: (a) (i) Al2O3 (large excess), EtOH,
reflux, 3 days, 20% for 30; (ii) 10.0 equiv of Me2CuLi, THF, 25 °C,
3 h, 60% for 31; (iii) 6.0 equiv of EtMgBr, 2.0 equiv of CuI, THF,
25 °C, 3 h, 65% for 32; (b) 1.3 equiv of PivCl, 2:1 pyr:CH2Cl2, -20
°C, 0.5 h, 90% for 33, 72% for 34; (c) 1.7 equiv of TBSOTf, 2.0
equiv of 2,6-lutidine, CH2Cl2, 0 °C, 15 min, 86% for 35, 85% for
36; (d) 2.2 equiv of DIBAL-H, CH2Cl2, -78 °C, 0.5 h, 96% for 37,
97% for 38; (e) 0.3 equiv of TEMPO, 8.0 equiv of BAIB, CH3CN/
H2O (1:1), 25 °C, 3.0 h; (f) 1.5 equiv of 18, 1.2 equiv of BOP, 2.0
equiv of DIPEA, DMF, 25 °C, 1.5 h, 58% for 39 overall yield from
37, 63% for 40 overall yield from 38; (g) 0.3 equiv of 23, 1:2 CH2Cl2:
2-methyl-2-butene, 40 °C, 6-48 h, 22% for 41 (E:Z ≈ 9:1); 12%
for 42 (E:Z ≈ 9:1); (h) 0.3 equiv of 22, 1:2 CH2Cl2:2-methyl-2-
butene, 40 °C, 38 h, 94%.
able conversion the phenyl analogue 27 (94% for a 66%
conversion, 9:1 E:Z mixture). Finally, the cleavage of
protecting groups of the olefin cross metathesis products
24, 26, and 27 was performed as described previously
for 19 to obtain Bengamide E (5) and its tert-butyl and
phenyl analogues 28 and 29 (Scheme 3).
Another structural point amenable to modification is
the C-2 position, which takes advantage of the reactivity
of the oxirane ring. Thus, epoxy alcohol 10 was subjected
to the action of various nucleophiles to obtain the
corresponding opened products in a wide range of yields
depending on the nature of the nucleophile. In particular,
the introduction of different alcohols such as ethanol was
achieved as previously described for methanol, providing
a poor yield of the corresponding 2-ethoxy derivative 30.
In contrast, the treatment of 10 with organocuprate
reagents yielded the 2-alkyl opening compounds in good
yields, 60% and 65% for 2-methyl 31 and 2-ethyl 32,
respectively.23 Other nucleophiles such as sulfides were
more problematic, yielding a mixture of compounds,
probably through Payne rearrangement processes.24 For
compounds 31 and 32, we proceeded in a similar syn-
thetic sequence as described before for Bengamide E (5),
to obtain the 2-C-alkyl analogues of bengamides 39 and
40, through compounds 33, 35, and 37, and 34, 36, and
38, respectively. With the key products for the final olefin
cross metathesis in hand, we proceeded with the reaction
under similar conditions as before; however, unlike with
the 2-methoxy derivative 24, on this occasion the reac-
tions were not so efficient, providing the targeted prod-
(23) (a) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952,
17, 1630-1634. (b) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P.
Tetrahedron 2001, 57, 9461-9467. (c) Nicolaou, K. C.; Oshima, T.;
Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. Chem. Commun.
1999, 809-810.
(24) (a) Payne, G. B. J. Org. Chem. 1962, 27, 3819-3822. (b)
Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15, 47-64. (c)
Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.;
Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982,
47, 1373-1378.
J. Org. Chem, Vol. 70, No. 23, 2005 9517

Sarabia and Sa´nchez-Ruiz
SCHEME 5. Synthesis of 2-C-Modified Bengamide
Analogues from Epoxy Amide 49a
chloride, obtaining 2-chlorohydrine 53 in a 60% yield by
treatment with lithium chloride in the presence of acetic
acid.9c This is in contrast to other halogens, such as
fluoride, in which, after different reagents and reaction
conditions were used, the starting material was recov-
ered, or to sulfides, in which elimination products were
obtained10 (Scheme 5).
Conclusions
In conclusion, a new synthetic route has been estab-
lished for the bengamides capable of generating a variety
of bengamide analogues, providing significant advantages
over previous reported syntheses. Particularly, this new
strategy proved to be efficient for the synthesis of
Bengamide E (5), as well as terminal alkyl-modified
analogues such as 21, 28, and 29. On the other hand,
the modifications at the C-2 position were also possible
by opening of the oxirane ring with different nucleophiles
(alcohols and organometallics for epoxy alcohol 10, and
nitrogen- or halide-type nucleophiles for epoxy amide 49).
However, the results obtained during the cross meta-
thesis reactions revealed that the substituent at C-2
might play an important role in this reaction, probably
because of steric reasons, which requires a more thorough
mechanistic investigation. The biological evaluation of
these compounds will allow for the establishment of a
pharmacophore model for the molecule and, conse-
quently, a refined design of new analogues, which will
allow for the discovery of biologically active compounds
with potential therapeutic applications. All these items
represent our priorities in current and future investiga-
tions.
a Reagents and conditions: (a) 1.8 equiv of (COCl)2, 1.8 equiv
of DMSO, CH2Cl2, -78 °C, 0.5 h, then 5.4 equiv of Et3N, 10 min;
(b) 1.0 equiv of Oxone, DMF, 25 °C, 1 h; (c) 1.5 equiv of 18, 1.2
equiv of PyBOP, 2.0 equiv of DIPEA, DMF, 25 °C, 8 h, 38% overall
yield from 10; (d) 0.3 equiv of 23, 1:1 CH2Cl2:2-methyl-2-butene,
40 °C, 38 h, 78% (E:Z ≈ 9:1); (e) (i) RNH2 (excess), MeOH, 25 °C,
12 h, 95% for 50, 97% for 51, 95% for 52, (ii) 1.5 equiv of LiCl, 1.5
equiv of AcOH, THF, reflux, 12 h, 60%.
ucts 41 and 42 in low yields and overall conversions.
These unexpected results seem to demonstrate the influ-
ence of the substituent at the C-2 position in the course
of the metathesis process. To overcome this inconven-
ience, we decided to introduce the terminal isopropyl
group earlier in the synthetic sequence, prior to the
incorporation of the alkyl groups. Thus, olefin cross
metathesis of the earlier precursor 43 delivered the
corresponding E-alkene 44 in excellent yield (94%, after
a 100% conversion) by the action of the second-generation
Grubbs catalyst 22. From compound 44, we prepared the
targeted 2-alkyl analogues 41 and 42 through intermedi-
ates 45 and 46 following the same synthetic pathway as
described for 31 and 32, encountering no significant
difficulties along the synthetic course, and obtaining
yields similar to those of the corresponding methylene
derivatives (Scheme 4).
On the other hand, 2-amino derivatives of bengamides
represent very interesting 2-C-modified analogues be-
cause of a potential strong coordination with the cobalt
ions present at the active site of aminopeptidases. To this
end, epoxy amide 48 was prepared from epoxy alcohol
10, involving a two-step oxidation to the epoxy acid 49,
and coupling with L-Lys-ꢀ-caprolactam 18, by the action
of PyBOP, in a 38% overall yield. The epoxy amide was
treated with 3-methyl-1-butene under the influence of
Grubbs catalyst 23 to obtain in a very gratifying yield
(78%) the corresponding E-olefin 49. The treatment of
the resulting epoxy amide 49 with different amines,
including ammonia, N-methylamine, and N,N-dimethyl-
amine, provided the corresponding 2-amino derivatives
50-52 in very high yields (95-97%) and with complete
regio- and stereoselectivities. The introduction of different
heteroatoms, such as halogens, proved to be efficient for
Experimental Section
Epoxy Alcohol 10. A suspension of 4 Å molecular sieves
(1.15 g) in CH2Cl2 (39 mL) was cooled to -20 °C, followed by
the addition of Ti(OiPr)4 (0.15 mL, 0.5 mmol, 0.1 equiv) and
D-(-)-DET (0.084 mL, 0.5 mmol, 0.1 equiv). The reaction
mixture was stirred for 30 min at -20 °C, and after that time
a solution of the corresponding allylic alcohol (see Supporting
Information) (0.91 g, 5 mmol, 1.0 equiv) in CH2Cl2 and TBHP
(1.8 mL of a 5.5 M solution in decane, 2.0 equiv) was
sequentially added. The reaction mixture was stirred at -20
°C for 48 h, after which the crude mixture was filtered through
Celite, concentrated under reduced pressure, and purified by
flash column chromatography (silica gel, 30% AcOEt in hex-
anes) to obtain epoxy alcohol 10 (666 mg, 86% based on the
reacted material) together with unreacted allylic alcohol (197
mg) as a colorless oil: Rf ) 0.16 (silica gel, 30% AcOEt in
hexanes); [R]25D ) +2.39 (c 0.23, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.39 (s, 3H), 1.40 (s, 3H), 1.76 (bs, 1H), 3.09-3.19
(m, 2H), 3.61 (dd, J ) 4.3, 8.6 Hz, 1H), 3.65 (dd, J ) 3.7, 12.9
Hz, 1H), 3.93 (dd, J ) 2.2, 12.9 Hz, 1H), 4.33 (t, J ) 8.1 Hz,
1H), 5.28 (d, J ) 10.2 Hz, 1H), 5.40 (d, J ) 17.2 Hz, 1H), 5.78-
5.87 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 26.5, 26.9, 53.4,
55.3, 60.6, 79.5, 79.9, 109.9, 119.6, 134.6.
Diol 11. To a solution of epoxy alcohol 10 (50 mg, 0.25 mmol,
1.0 equiv) in MeOH (50 mL) was added neutral Al2O3 (2.5 g),
and the resulting suspension was refluxed for 3 days. After
that time, the Al2O3 was filtered off and washed with hot
MeOH (3 × 10 mL). The filtrate was evaporated, and the crude
was purified by flash column chromatography (silica gel, 60%
AcOEt in hexanes) to afford diol 11 (24.4 mg, 57% based on
recovered starting material) as a clear oil: Rf ) 0.18 (silica
gel, 60% AcOEt in hexanes); [R]25 ) +11.3 (c 0.16, CH2Cl2);
D
1H NMR (400 MHz, CDCl3) δ 1.42 (s, 6H), 3.14-3.18 (m, 1H),
9518 J. Org. Chem., Vol. 70, No. 23, 2005

Synthesis of Bengamide E and Analogues
3.41 (s, 3H), 3.57 (dd, J ) 1.6, 8.1 Hz, 1H), 3.77 (dd, J ) 3.7,
11.8 Hz, 1H), 3.86 (dd, J ) 4.8, 11.8 Hz, 1H), 3.88 (dd, J )
1.6, 8.1 Hz, 1H), 4.42 (t, J ) 8.1 Hz, 1H), 5.26 (d, J ) 9.6 Hz,
1H), 5.38 (d, J ) 17.2 Hz, 1H), 5.76-5.86 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 26.8, 27.1, 57.9, 60.7, 67.5, 78.6, 79.3, 81.5,
109.4, 119.7, 134.7; FAB HRMS (NBA) m/e 255.1210, [M +
Na]+ calcd for C11H20O5 255.1208.
Acid 13. Diol 11 (20 mg, 0.073 mmol, 1.0 equiv) was
dissolved in a 1:1 CH3CN/H2O mixture (0.12 mL). BAIB (70.8
mg, 0.22 mmol, 3 equiv) and TEMPO (3.42 mg, 0.022 mmol,
0.3 equiv) were added at rt, and the reaction was monitored
by TLC (60% AcOEt in hexanes) to detect depletion of the
starting material and formation of the intermediate aldehyde
(step 1, Rf ) 0.6, 1 h approximately), followed by the disap-
pearance of this aldehyde and formation of the desired acid
13 (step 2, Rf ) 0.17) after an additional 1 h. The reaction
was then quenched by the addition of saturated aqueous
Na2S2O3 solution (2 mL); the aqueous phase was then ex-
tracted with AcOEt (3 × 5 mL), and the combined organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. The crude was employed in the next step without
purification.
) 8.1 Hz, 1H), 4.50 (dd, J ) 2.7, 12.4 Hz, 1H), 5.25 (d, J )
10.7 Hz, 1H), 5.37 (d, J ) 17.2 Hz, 1H), 5.77-5.87 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 18.4, 25.9, 26.9, 26.96, 27.2, 38.7,
58.1, 64.1, 71.6, 78.2, 81.2, 81.7, 108.8, 119.0, 135.7, 178.3; FAB
HRMS (NBA) m/e 453.2654, [M + Na]+ calcd for C22H42O6Si
453.2648.
Alcohol 16. A solution of 15 (135 mg, 0.32 mmol, 1.0 equiv)
in CH2Cl2 (2 mL) was cooled at -78 °C, and then treated with
DIBAL (0.74 mL of a 1 M solution in CH2Cl2, 2.3 equiv). After
20 min, the reaction was quenched by adding AcOEt (10 mL)
at -78 °C, and the mixture was allowed to reach room
temperature and was then treated with saturated aqueous
Na+/K+-tartrate solution (5 mL). The resulting mixture was
vigorously stirred until a clear separation of both organic and
aqueous phases. The aqueous phase was then separated; the
organic extracts were washed with saturated aqueous Na/K-
tartrate solution (5 mL) and dried (MgSO4), and the solvents
were evaporated. The crude was purified by flash column
chromatography (silica gel, 20% AcOEt in hexanes) to yield
16 (110 mg, 90%) as a clear oil: Rf ) 0.12 (silica gel, 20%
AcOEt in hexanes); [R]25D ) -1 (c 0.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 0.07 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 1.39 (s,
3H), 1.41 (s, 3H), 3.18-3.22 (m, 1H), 3.37 (s, 3H), 3.63 (dd, J
) 4.8, 11.8 Hz, 1H), 3.72 (dd, J ) 3.2, 8.6 Hz, 1H), 3.82 (dd, J
) 5.4, 11.8 Hz, 1H), 3.90 (t, J ) 3.2 Hz, 1H), 4.36 (t, J ) 8.1
Hz, 1H), 5.28 (d, J ) 10.7 Hz, 1H), 5.38 (d, J ) 17.2 Hz, 1H),
5.76-5.85 (m, 1H); 13C NMR (100 MHz, CDCl3) δ -4.8, -4.3,
18.4, 25.9, 26.9, 27.0, 57.2, 59.9, 70.8, 78.4, 81.2, 83.4, 109.1,
119.6, 135.3; FAB HRMS (NBA) m/e 369.2085, [M + Na]+ calcd
for C17H34O5Si 369.2073.
Acid 17. A solution of alcohol 16 (23.5 mg, 0.07 mmol, 1.0
equiv) in a 1:1 CH3CN/H2O mixture (0.12 mL) was treated with
BAIB (84.0 mg, 0.28 mmol, 4.0 equiv) and TEMPO (3.8 mg,
0.021 mmol, 0.3 equiv) under conditions similar to those
described for 11, to obtain crude acid 17: 1H NMR (400 MHz,
CDCl3) δ 0.08 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 1.41 (s, 3H),
1.43 (s, 3H), 3.45 (s, 3H), 3.84 (d, J ) 2.2 Hz, 1H), 3.90 (dd, J
) 4.8, 8.1 Hz, 1H), 4.06 (dd, J ) 2.2, 4.8 Hz, 1H), 4.42 (t, J )
8.1 Hz, 1H), 5.30 (d, J ) 10.2 Hz, 1H), 5.40 (d, J ) 17.2 Hz,
1H), 5.81-5.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ -4.7,
-4.6, 18.2, 25.7, 26.6, 26.9, 58.7, 72.9, 78.3, 81.8, 82.7, 109.5,
119.7, 135.0, 170.1.
Amide 19. The coupling of crude acid 17 (24.6 mg, 0.07
mmol, 1.0 equiv) with L-Lys-caprolactam 18 (17 mg, 0.11
mmol, 1.5 equiv) was carried out under exactly the same
conditions as before for 20 to obtain amide 19, which was
subjected to flash column chromatography (silica gel, 50%
AcOEt in hexanes) to afford pure 19 (16 mg, 50% over 3 steps)
as a white solid: Rf ) 0.33 (silica gel, 50% AcOEt in hexanes);
[R]25D ) +50.3 (c 0.06, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
0.06 (s, 3H), 0.09 (s, 3H), 0.82 (s, 9H), 1.34 (s, 3H), 1.37 (s,
3H), 1.40-1.67 (m, 2H), 1.75-2.16 (m, 4H), 3.22 (m, 2H), 3.43
(s, 3H), 3.70 (d, J ) 1.6 Hz, 1H), 4.29 (t, J ) 7.5 Hz, 1H), 4.42
(dd, J ) 5.4, 10.2 Hz, 1H), 5.24 (d, J ) 10.2 Hz, 1H), 5.34 (d,
J ) 17.2 Hz, 1H), 5.92-6.00 (m, 1H), 6.00 (bs, 1H), 7.87 (bd,
J ) 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -4.7, -4.6,
18.2, 25.7, 26.8, 27.0, 27.9, 28.9, 31.4, 42.1, 51.9, 58.8, 74.4,
79.3, 80.8, 83.8, 108.6, 118.6, 136.6, 168.8, 174.8; FAB HRMS
(NBA) m/e 493.2715, [M + Na]+]calcd for C23H42N2O6Si
493.2710.
Amide 20. Coupling of Acid 13 with L-Lys-Lactam. To
a solution of crude acid 13 (21 mg, 0.073 mmol, 1.0 equiv) in
DMF (2 mL) were added Hu¨nig’s base (0.025 mL, 0.16 mmol,
2.2 equiv) and L-Lys-caprolactam 18 (17.7 mg, 0.11 mmol, 1.5
equiv). When the solution was homogeneous, BOP (44.3 mg,
0.087 mmol, 1.2 equiv) was added in one portion, and the
reaction mixture was stirred for 3 h at rt. After this time, Et2O
(10 mL) was added, and the organic phase was washed with
saturated aqueous NH4Cl solution (2 × 5 mL); the organic
extracts were dried with MgSO4, and the solvent was evapo-
rated. The crude product was subjected to flash column
chromatography (silica gel, 100% AcOEt) to yield coupling
product 20 (13.3 mg, 50% over 3 steps) as a white solid, which
was accompanied with its 2-epimer in a 25% yield according
1
to its H NMR spectra.
Pivaloyl Ester 14. Diol 11 (100 mg, 0.37 mmol, 1.0 equiv)
was dissolved in a 2:1 pyridine/CH2Cl2 mixture (0.78 mL), and
cooled to -20 °C. Pivaloyl chloride (0.06 mL, 0.48 mmol, 1.3
equiv) was added, and the reaction mixture was stirred at this
temperature until the starting material was depleted (ca. 20
min). The mixture was then diluted with CH2Cl2 (10 mL), and
the organic phase was washed with saturated aqueous NaH-
CO3 solution (2 × 5 mL), dried (MgSO4), and concentrated.
After flash column chromatography (silica gel, 20% AcOEt in
hexanes), pure pivaloate ester 14 (125 mg, 96%) was obtained
as a colorless oil: Rf ) 0.25 (silica gel, 20% AcOEt in hexanes);
[R]25D ) +7.69 (c 0.20, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
1.19 (s, 9H), 1.43 (s, 6H), 3.30-3.60 (m, 1H), 3.40-3.42 (m,
1H), 3.42 (s, 3H), 3.94 (bd, J ) 8.6 Hz, 1H), 4.10-4.16 (m,
1H), 4.42 (t, J ) 8.6 Hz, 1H), 4.55 (dt, J ) 2.2, 12.4 Hz, 1H),
5.26 (d, J ) 10.2 Hz, 1H), 5.38 (d, J ) 17.2 Hz, 1H), 5.77-
5.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.9, 27.2, 38.7,
58.6, 63.3, 67.0, 78.6, 78.8, 80.1, 109.4, 119.6, 134.8, 178.5; FAB
HRMS (NBA) m/e 339.1783, [M + Na]+ calcd for C16H28O6
339.1784.
Silyl Ether 15. To a solution of 14 (125 mg, 0.035 mmol,
1.0 equiv) in CH2Cl2 (2 mL) and 2,6-lutidine (0.06 mL, 0.053
mmol, 1.5 equiv) was added at 0 °C TBSOTf (0.096 mL, 0.042
mmol, 1.2 equiv). Monitoring of the reaction by TLC showed
that it was complete in 15 min. The mixture was then diluted
with Et2O (10 mL), and washed with saturated aqueous NH4-
Cl solution (2 × 4 mL). After drying (MgSO4) and solvent
evaporation, the crude product was subjected to purification
by flash column chromatography (silica gel, 5% AcOEt in
hexanes) to yield pure 15 (135 mg, 93%) as a colorless oil: Rf
) 0.23 (silica gel, 5% AcOEt in hexanes); [R]25D ) -7.63 (c 0.20,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 3H), 0.09 (s,
3H), 0.88 (s, 9H), 1.18 (s, 9H), 1.38 (s, 3H), 1.41 (s, 3H), 3.37
(s, 3H), 3.37-3.40 (m, 1H), 3.78 (dd, J ) 4.3, 8.6 Hz, 1H), 3.83
(t, J ) 4.3 Hz, 1H), 4.01 (dd, J ) 6.9, 11.8 Hz, 1H), 4.33 (t, J
Hydroxy Amide 20. To a solution of 19 (8 mg, 0.0017
mmol, 1.0 equiv) in THF (1 mL) was added TBAF (0.026 mL
of a 1 M solution in THF, 1.5 equiv) at rt. After being stirred
for 30 min, the reaction mixture was diluted with Et2O (5 mL)
and washed with saturated aqueous NH4Cl solution (2 mL).
The organic phase was dried (MgSO4), and the solvent
evaporated. The crude product 20 (6 mg, clear oil) was used
without further purification in the next step: Rf ) 0.07 (silica
1
gel, 100% AcOEt); H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H),
1.43 (s, 3H), 1.42-1.59 (m, 2H), 1.78-1.88 (m, 2H), 1.97-2.11
(m, 2H), 3.22-3.30 (m, 2H), 3.47 (s, 3H), 3.62 (dd, J ) 1.6, 8.1
Hz, 1H), 3.70 (d, J ) 8.1 Hz, 1H), 3.86 (dd, J ) 1.6, 8.6 Hz,
J. Org. Chem, Vol. 70, No. 23, 2005 9519

Sarabia and Sa´nchez-Ruiz
1H), 4.48 (t, J ) 7.5 Hz, 1H), 4.53 (dd, J ) 6.4, 11.3 Hz, 1H),
5.23 (d, J ) 10.2 Hz, 1H), 5.36 (d, J ) 17.2 Hz, 1H), 5.76-
5.84 (m, 1H), 6.11 (bt, J ) 5.9 Hz, 1H), 7.83 (bd, J ) 5.9 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 174.8, 171.1, 134.9, 119.5,
109.3, 81.5, 79.1, 78.1, 69.1, 59.6, 51.8, 42.1, 31.3, 28.8, 27.9,
27.2, 26.7.
sponding to the alcohol (7 mg) was used without further
purification in the next step: Rf ) 0.09 (silica gel, 100%
AcOEt); 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J ) 3.2 Hz, 3H),
0.97 (d, J ) 3.2 Hz, 3H), 1.41 (s, 6H), 1.44 (m, 1H), 1.72-1.89
(m, 3H), 1.97-2.12 (m, 2H), 2.23-2.32 (m, 1H), 3.21-3.31 (m,
2H), 3.47 (s, 3H), 3.57 (dd, J ) 1.6, 8.6 Hz, 1H), 3.69 (d, J )
8.6 Hz, 1H), 3.82 (dd, J ) 1.6, 8.6 Hz, 1H), 4.45 (t, J ) 8.6 Hz,
1H), 4.53 (dd, J ) 5.4, 11.3 Hz, 1H), 5.34 (ddd, J ) 1.6, 8.1,
15.6 Hz, 1H), 5.79 (dd, J ) 6.5, 15.6 Hz, 1H), 6.05 (bs, 1H),
7.84 (bd, J ) 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 26.7,
27.3, 27.9, 28.9, 29.7, 30.8, 31.3, 42.1, 51.8, 52.1, 59.6, 68.9,
78.0, 79.1, 81.4, 108.5, 123.2, 144.5, 171.3, 174.9.
Methylene Analogue of Bengamide E 21. A solution of
alcohol 20 (6 mg, 0.00175 mmol, 1.0 equiv) in AcOH (0.5 mL
of a 70% aqueous solution) was heated at 50 °C. When the
reaction was complete, the solvent was evaporated, and the
crude residue was purified by flash column chromatography
(silica gel, 10% MeOH in AcOEt) to yield the methylene
analogue of Bengamide E 21 (2.3 mg, 45% over 2 steps) as a
The resulting alcohol (7 mg, 0.00175 mmol, 1.0 equiv) was
treated with AcOH (0.5 mL of a 70% aqueous solution) at 50
°C for 30 min. After this time, the solvent was removed by
evaporation under high vacuum, and the crude product was
purified by flash column chromatography (silica gel, 10%
MeOH in AcOEt) to yield Bengamide E (5) (4.3 mg, 62% over
2 steps) as a white solid whose physical and spectroscopic
properties were identical to those reported in the literature:1
white solid: Rf ) 0.27 (silica gel, 10% MeOH in AcOEt); [R]25
D
) +23.7 (c 0.11, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.33-
1.47 (m, 1H), 1.50-1.62 (m, 1H), 1.73-1.90 (m, 3H), 1.98-
2.08 (m, 1H), 2.91-3.17 (bm, 3H), 3.24-3.31 (m, 2H), 3.52 (s,
3H), 3.63 (dd, J ) 1.1, 4.8 Hz, 1H), 3.78 (d, J ) 6.9 Hz, 1H),
3.83 (dd, J ) 1.1, 6.9 Hz, 1H), 4.28 (t, J ) 4.8 Hz, 1H), 4.52
(dd, J ) 6.4, 10.7 Hz, 1H), 5.23 (d, J ) 10.2 Hz, 1H), 5.38 (d,
J ) 17.2 Hz, 1H), 5.83-5.91 (m, 1H), 6.21 (bs, 1H), 7.96 (bd,
J ) 5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 27.9, 28.7, 30.9,
42.1, 51.9, 60.1, 71.8, 73.1, 74.3, 80.6, 117.5, 136.7, 172.1, 174.7.
Amide 24. Cross Metathesis of 19. Amide 19 (10.3 mg,
0.022 mmol, 1.0 equiv) was dissolved in a 1:2 CH2Cl2/3-methyl-
1-butene mixture (3 mL), and Hoveyda-Grubbs catalyst 23
(4.1 mg, 0.0066 mmol, 0.3 equiv) was added. The flask was
then capped and heated at 40 °C overnight, after which the
crude mixture was concentrated and purified by flash column
chromatography (silica gel, 40% AcOEt in hexanes) to yield
24 (10 mg, 89%) as a brown foamy solid: Rf ) 0.43 (silica gel,
50% AcOEt in hexanes); 1H NMR (400 MHz, CDCl3) δ 0.05 (s,
3H), 0.07 (s, 3H), 0.82 (s, 9H), 0.96 (d, J ) 3.2 Hz, 3H), 0.98
(d, J ) 3.2 Hz, 3H), 1.34 (s, 3H), 1.35 (s, 3H), 1.35-1.52 (m,
2H), 1.76-1.89 (m, 2H), 1.91-2.03 (m, 1H), 2.05-2.15 (m, 1H),
2.26-2.37 (m, 1H), 3.17-3.27 (m, 2H), 3.40 (s, 3H), 3.72 (d, J
) 1.6 Hz, 1H), 4.00 (t, J ) 6.9 Hz, 1H), 4.04 (dd, J ) 1.6, 6.9
Hz, 1H), 4.24 (t, J ) 8.1 Hz, 1H), 4.43 (dd, J ) 5.4, 10.7 Hz,
1H), 5.50 (dd, J ) 8.1, 15.0 Hz, 1H), 5.71 (dd, J ) 6.5, 15.0
Hz, 1H), 5.94 (bs, 1H), 7.83 (bd, J ) 5.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ -4.8, -4.7, 21.9, 22.0, 25.6, 25.65, 26.8,
26.9, 27.7, 28.8, 28.9, 30.2, 30.8, 31.3, 42.0, 51.8, 58.5, 68.0,
79.4, 80.7, 83.1, 108.0, 125.2, 143.3, 168.6, 174.8; FAB HRMS
(NBA) m/e 535.3186, [M + Na]+ calcd for C26H48N2O6Si
535.3179.
Rf ) 0.28 (silica gel, 10% MeOH in AcOEt); [R]25 ) +35 (c
D
1
0.22, CHCl3) ([R]lit. ) +32 (c 0.2, CHCl3); H NMR (400 MHz,
CDCl3) δ 0.97 (d, J ) 2.2 Hz, 3H, (CH3)2CH), 0.98 (d, J ) 2.2
Hz, 3H, (CH3)2CH), 1.33-1.47 (m, 2H, -CH2-), 1.50-1.62 (m,
1H, -CH2-), 1.71-1.90 (m, 3H, -CH2-), 2.24-2.34 (m, 1H,
CH(CH3)2), 3.21-3.32 (m, 2H, -CH2-NH), 3.52 (s, 3H, OMe),
3.59 (m, 1H, CH-OH), 3.76 (d, J ) 7.5 Hz, 1H, CH-OMe), 3.81
(bd, J ) 7.5 Hz, 1H, CH-OH), 4.21 (bt, J ) 5.9 Hz, 1H, CH-
OH), 4.52 (dd, J ) 6.5, 10.2 Hz, 1H, CH-CON), 5.43 (dd, J )
6.91, 15.6 Hz, 1H, dCH-), 5.76 (dd, J ) 6.5, 15.6 Hz, 1H,
-CH)), 6.12 (bs, 1H, NH), 7.97 (bd, J ) 6.5 Hz, 1H, NH); 13
C
NMR (100 MHz, CDCl3) δ 22.1, 22.2, 27.9, 28.8, 30.8, 31.0,
42.1, 51.9, 59.9, 72.3, 72.8, 74.3, 80.8, 125.3, 141.9, 172.4, 174.7;
FAB HRMS (NBA) m/e 381.2008, [M + Na]+ calcd for
C17H30N2O6 381.2002.
Acknowledgment. This work was financially sup-
ported by Fundacio´n Ramo´n Areces and the Direccio´n
General de Investigacio´n (ref. CTQ2004-08141), and a
fellowship from Ministerio de Educacio´n y Ciencia (A.S.-
R.). We thank Dr. J. I. Trujillo from Pfizer (St. Louis,
MO) for assistance in the preparation of the manuscript.
We thank Unidad de Espectroscop´ıa de Masas de la
Universidad de Granada for exact mass spectroscopic
assistance.
Bengamide E (5). Alkene 24 (10 mg, 0.002 mmol, 1.0 equiv)
was dissolved in THF (1 mL), and treated with TBAF (0.03
mL of a 1 M solution in THF, 1.5 equiv) at 25 °C for 30 min.
After this time, the reaction mixture was diluted with Et2O
(5 mL), and washed with saturated aqueous NH4Cl solution
(2 mL). The organic phase was separated and dried (MgSO4),
and the solvent was evaporated. The crude product corre-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new compounds, as well
as 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0516032
9520 J. Org. Chem., Vol. 70, No. 23, 2005