Chiral sulfur ylides for the synthesis of bengamide e and analogues

Article abstract of DOI:10.1021/jo100696w

A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and allowed access to the generation of a wide array of new bengamide analogues.

Full text of DOI:10.1021/jo100696w

pubs.acs.org/joc
Chiral Sulfur Ylides for the Synthesis of Bengamide E and Analogues
ꢀ
Francisco Sarabia,* Francisca Martın-Galvez, Samy Chammaa, Laura Martın-Ortiz, and
ꢀ
Antonio Sanchez-Ruiz
Department of Organic Chemistry, Faculty of Sciences, University of Malaga,
Campus de Teatinos s/n 29071, Malaga, Spain
frsarabia@uma.es
Received April 10, 2010
A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been
employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic
position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and
reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the
bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using
an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position
of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This
latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and
allowed access to the generation of a wide array of new bengamide analogues.
Introduction
antihelmintic properties.7 More recently, the biological mode
of action of the bengamides has been disclosed,8 revealing an
intriguing mechanism characterized by their binding to either
methionine aminopeptidase type 1 (MetAp1) or type 2 (Met-
Ap2),9 enzymes involved in the cell cycle of endothelial cells and
angiogenesis.10 Interestingly, this is a mode of action similar to
The bengamides A-F were discovered and isolated between
19861 and 19892 by the research group of Professor Crews from
an undescribed member of an orange sponge belonging to the
Jaspidae family. Following these discoveries, the isolation of
new members, such as the bengamides G-J,3 L,4 and M-R5
(Figure 1), together with bengamides Z and Y,6 K3 and
isobengamide E,2 were described. Rapidly, these natural pro-
ducts were recognized as interesting bioactive compounds
possessing potent cytotoxic activity against larynx epithelial
carcinoma (1.0 μg/mL) as well as prominent antibiotic and
~ ꢀ
(7) (a) Crews, P.; Matthews, T. R.; Quınoa, E.; Adamczeski, M. U.S. Patent,
4,831,135, 1989. (b) 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. (c) 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.
(8) (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. (c) Hu, X.; Dang, Y.; Tenney, K.; Crews, P.; Tsai,
C. W.; Sixt, K. M.; Cole, P. A.; Liu, J. O. Chem. Biol. 2007, 14, 764–774.
(9) (a) Lowther, W. T.; Orville, A. M.; Madden, D. T.; Lim, S.; Rich,
D. H.; Matthews, B. W. Biochemistry 1999, 38, 7678–7688. (b) Sashidhara,
K. V.; White, K. N.; Crews, P. J. Nat. Prod. 2009, 72, 588–603.
~ ꢀ
(1) Quınoa, E.; Adamczeski, M.; Crews, P.; Bakus, G. J. J. Org. Chem.
1986, 51, 4494–4497.
~ ꢀ
(2) (a) Adamczeski, M.; Quınoa, E.; Crews, P. J. Am. Chem. Soc. 1989,
~ ꢀ
111, 647–654. (b) Adamczeski, M.; Quınoa, E.; Crews, P. J. Org. Chem. 1990,
55, 240–242.
(3) D’Auria, M. V.; Giannini, C.; Minale, L.; Zampella, A.; Debitus, C.;
Frostin, M. J. Nat. Prod. 1997, 60, 814–816.
ꢀ
(4) Fernandez, R.; Dherbomez, M.; Letourneux, Y.; Nabil, M.; Verbist,
J. F.; Biard, J. F. J. Nat. Prod. 1999, 62, 678–680.
(5) 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.
(6) Groweiss, A.; Newcomer, J. J.; O’Keefe, B. R.; Blackman, A.; Boyd,
M. R. J. Nat. Prod. 1999, 62, 1691–1693.
(10) (a) Folkman, J.; Klagsburn, M. Science 1987, 235, 442–447.
(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) Hu, X.;
Addlagatta, A.;Lu, J.;Matthews,B.W.; Liu,J.O.Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 18148–18153.
5526 J. Org. Chem. 2010, 75, 5526–5532
Published on Web 07/22/2010
DOI: 10.1021/jo100696w
r
2010 American Chemical Society

Sarabia et al.
JOCArticle
FIGURE 2. Potent bioactive analogues of bengamides.
design and syntheses of analogues13 for biological evalua-
tions.13,14 A particularly important structural feature is the
terminal olefinic group as it has been demonstrated with the
synthetic tert-butyl analogue LAF-389 (18),12f which displays
greater antitumor activity versus the natural members.15 Simi-
larly, modifications of the caprolactam moiety have led to
potent antitumor analogues with promising pharmacokinetic
properties, such as compounds 19 and 2013d (Figure 2).
Early on our research group became interested by the biolo-
gical potential of these natural products, and thus initiated a
research program directed toward the total syntheses of this class
of natural products, recently culminating with the total synthesis
of bengamide E (16) and a series of analogues.16 Our synthetic
strategy for the bengamides consisted of three key steps: (1) an
epoxide opening for the introduction of the methoxyl group at
the C-2 position, (2) an olefin cross metathesis, as a means for the
introduction of the isopropyl substituent of the olefin, and (3) an
amide coupling for the incorporation of the ε-caprolactam resi-
due. Interestingly, this strategy was envisioned as a diversity-
oriented synthetic approach,17 capable of delivering a wide array
of analogues, allowing the incorporation of structural modifica-
tions at positions essential in the interaction of the molecule with
the active site of methionine aminopeptidases.18
FIGURE 1. Molecular structures of bengamides.
that of fumagillin and ovalicin despite their structural
differences.11 These biological features render the bengamides
as promising new anticancer compounds and subsequently
have elicited intense research activity in biology and chemistry,
including the total syntheses of natural bengamides12 and the
(11) (a) 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. (b) Sin, N.; Meng,
L.; Wang, M. Q.; Wen, J. J.; Bornmann, W. G.; Crews, C. M. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 6099–6103. (c) Zhang, Y.; Yeh, J. R.; Mara, A.;
Ju, R.; Hines, J. F.; Cirone, P.; Griesbach, H. L.; Schneider, I.; Slusarski,
D. C.; Holley, S. A.; Crews, C. M. Chem. Biol. 2006, 13, 1001–1009.
(12) Synthetic approaches to bengamides: (a) Gurjar, M. K.; Srinivas, N. R.
Tetrahedron Lett. 1991, 32, 3409–3412. (b) Marshall, J. A.; Luke, G. P. Synlett
1992, 1007–1008. (c) Fonseca, G.; Seoane, G. A. Tetrahedron: Asymmetry 2005,
16, 1393–1402. Synthesis of bengamide A: Chida, N.; Tobe, T.; Okada, S.;
Ogawa, S. J. Chem. Soc., Chem. Commun. 1992, 1064–1066. Syntheses of
bengamides B and E: (a) Broka, C. A.; Ehrler, J. Tetrahedron Lett. 1991, 32,
5907–5910. (b) Chida, N.; Tobe, T.; Murai, K.; Yamazaki, K.; Ogawa, S.
Heterocycles 1994, 38, 2383–2388. (c) 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. (d) Boeckman, R. K., Jr.; Clark,
T. J.; Shook, B. C. Helv. Chim. Acta 2002, 85, 4532–4560. (e) Boeckman, R. K.,
Jr.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4, 2109–2112. (f) Kinder, F. R., Jr.
Org. Prep. Proc. Int. 2002, 34, 561–583. Syntheses of bengamide E: (a) Chida, T.;
Tobe, T.; Ogawa, S. Tetrahedron Lett. 1991, 32, 1063–1066. (b) Kishimoto, H.;
Ohrui, H.; Meguro, H. J. Org. Chem. 1992, 57, 5042–5544. (c) Marshall, J. A.;
Luke, G. P. J. Org. Chem. 1993, 58, 6229–6234. (d) Mukai, C.; Kataoka, O.;
Hanaoka, M. Tetrahedron Lett. 1994, 35, 6899–6902. (e) Mukai, C.; Kataoka, O.;
Hanaoka, M. J. Org. Chem. 1995, 60, 5910–5918. (f) Mukai, C.; Moharram,
S. M.; Kataoka, O.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1995, 2849–2854.
(g) Mukai, C.; Hanaoka, M. Synlett 1996, 11–17. (h) Liu, W.; Szewczyk, J. M.;
Waykole, L.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2002, 43, 1373–1375.
(13) (a) 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. (b) Banwell, M. G.; McRae, K. J. J. Org. Chem. 2001, 66,
6768–6774. (c) 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, 856–865. (d) Liu, G.; Ma, Y.-M.; Tai, W.-T.; Xie,
C.-M.; Li, Y.-L.; Li, J.; Nan, F.-J. ChemMedChem 2008, 3, 74–78.
The development of this strategy provided ready access to
a set of analogues by modifications at C-2 and olefinic posi-
tions, as well as modification of the lactam residue. Initially,
we achieved the construction of the oxirane ring by reaction
of aldehyde 2119 with the sulfur ylide derived from sulfonium
(14) Hoffmann, H.; Haag-Richter, S.; Kurz, M.; Tietgen, H. Patent WO
2005/044803, 2005.
(15) Dumez, H.; Gall, H.; Capdeville, R.; Dutreix, C.; van Oosterom,
A. T.; Giaccone, G. Anti-Cancer Drugs 2007, 18, 219–225.
ꢀ
(16) Sarabia, F.; Sanchez-Ruiz, A. J. Org. Chem. 2005, 70, 9514–9520.
ꢀ
(17) Sarabia, F.; Sanchez-Ruiz, A. Tetrahedron Lett. 2005, 46, 1131–
1135.
(18) (a) Cunningham, D. F.; O0Connor, B. Biochim. Biophys. Acta 1997,
1343, 160–186. (b) Giaccia, A. J.; Kastan, M. B. Genes Dev. 1998, 12, 2973–2983.
(19) (a) Chen, J.; Marx, J. N. Tetrahedron Lett. 1997, 38, 1889–1892. (b)
Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337–3342.
J. Org. Chem. Vol. 75, No. 16, 2010 5527

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SCHEME 1. Divergent Strategy to Bengamides via Sulfur
Ylides
SCHEME 2. Chiral Sulfonium Salt 30 and Its Reactions with
Aldehydes
As an alternative to the Sharpless methodology, and as a
continuation of our efforts in the chemistry of sulfur ylides,24
we recently designed a new class of chiral ylides25 that provides
the epoxide in excellent chemical and stereochemical yields.26 In
particular, this class of new chiral ylides, represented by the
sulfonium salt precursor 30, readily prepared from L-methio-
nine, smoothly reacted with aldehydes under basic conditions
to yield epoxy amides of type A (Scheme 2).
In the present article, we wish to report the use of this new
methodology of asymmetric epoxidation for the stereoselective
preparation of bengamide E and analogues at the terminal
olefinic position using an olefin cross metathesis reaction as
described in our first total synthesis of bengamide E.
Results and Discussion
This new synthetic strategy to the bengamides was based on
the use of the cyclic sulfonium salt 30 as precursor of its
corresponding ylide and source of asymmetric induction for
the stereoselective generation of an oxirane ring with a desired
stereochemistry. To this aim, aldehyde 21 was reacted with the
sulfur ylide, generated from its corresponding sulfonium salt 30,
to provide epoxy amide 31 in a 72% yield and excellent dia-
stereoselectivity estimated to be greater than 98% according to
NMR and GC-MS analyses. Treatment of this epoxy amide
with Super-H27 afforded the corresponding epoxy alcohol 29,
from which one could prepared the natural bengamide E (16)
via the synthetic route previously described by us.16 Never-
theless, we wished to improve upon the oxirane-ring-opening
reaction, which was previously achieved by treatment of 29 with
neutral alumina in refluxing methanol,28 providing the ring-
opened product 32 in a moderate 57% yield and complete
regioselectivity. Our efforts toward improving the reaction with
respect to chemical yield and development of a more efficient
procedure led us to the methodology described by Miyashita
et al.29 In their work, they employed trimethyl borate for the
activation of epoxy alcohols in their regioselective opening with
nitrogen or sulfur nucleophiles. Taking into account the reduced
nucleophilic character of alcohols, we decided to modify the
original Miyashita procedure by the addition of DBU to
enhance the nucleophilicity of the alcohol. Thus, epoxy alcohol
29 was treated with methanol in the presence of trimethyl borate
and DBU to obtain the corresponding 2-methoxyl opening
product 32 in an improved 70% yield. Compound 32 was
salt 23.20 However, this reaction delivered a 4:1 mixture of
epoxy amides 24:25 in favor of the epoxide with the unde-
sired stereochemistry, as the Felkin-Ahn model predicts.21
The use of the benzylated aldehyde 2222 provided a 1:1
mixture of epoxy amides 26 and 27. Consequently, we
employed a Sharpless asymmetric epoxidation23 to prepare
stereoselectively the epoxy alcohol 29 from the allylic alcohol
28, a common precursor for the preparation of the natural
bengamides and analogues thereof (Scheme 1).
ꢀ
(20) (a) Sarabia, F.; Martın-Ortiz, L.; Lopez-Herrera, F. J. Org. Lett.
2003, 5, 3927–3930. (b) Sarabia, F.; Sanchez-Ruiz, A.; Chammaa, S. Bioorg.
ꢀ
Med. Chem. 2005, 13, 1691–1705. (c) Sarabia, F.; Martın-Ortiz, L. Tetra-
hedron 2005, 61, 11850–11865.
ꢀ
(21) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 38,
2199–2204. (b) Anh, G. T.; Eisenstein, O. Tetrahedron Lett. 1976, 38, 155–158.
(22) Heo, J. N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693–
1696.
(23) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; pp 103-158.
ꢀ
ꢀ
ꢀ
(24) (a) Lopez Herrera, F. J.; Heras Lopez, A.; Pino Gonzalez, M. S.;
ꢀ
Sarabia Garcıa, F. J. Org. Chem. 1996, 61, 8839–8848. (b) Lopez Herrera,
F. J.; Sarabia Garcıa, F.; Heras Lopez, A.; Pino Gonzalez, M. S. J. Org.
ꢀ
ꢀ
ꢀ
Chem. 1997, 62, 6056–6059. (c) Heras-Lopez, A.; Pino-Gonzalez, M. S.;
Sarabia-Garcıa, F.; Lopez-Herrera, F. J J. Org. Chem. 1998, 63, 9630–9634.
ꢀ
ꢀ
ꢀ
ꢀ
(d) Lopez-Herrera, F. J.; Sarabia, F.; Pedraza-Cebrian, G. M.; Pino-
Gonzalez, M. S. Tetrahedron Lett. 1999, 40, 1379–1380. (e) Martın-Ortiz,
ꢀ
ꢀ
L.; Chammaa, S.; Pino-Gonzalez, M. S.; Sanchez-Ruiz, A.; Garcıa-Castro,
M.; Assiego, C.; Sarabia, F. Tetrahedron Lett. 2004, 45, 9069–9072. (f )
ꢀ
ꢀ
Sarabia, F.; Sanchez-Ruiz, A.; Martın-Ortiz, L.; Garcıa-Castro, M.;
Chammaa, S. Org. Lett. 2007, 9, 5091–5094. (g) Sarabia, F.; Martın-Galvez,
ꢀ
ꢀ
(26) Sarabia, F.; Chammaa, S.; Garcıa-Castro, M.; Martın-Galvez, F.
ꢀ
ꢀ
F.; Garcıa-Castro, M.; Chammaa, S.; Sanchez-Ruiz, A.; Tejon-Blanco, J. F.
J. Org. Chem. 2008, 73, 8979–8986.
Chem. Commun. 2009, 5763–5765.
(27) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980, 45,
1–12.
(28) (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.
(25) Reviews on chiral sulfur ylides: (a) Aggarwal, V. K.; Badine, D M.;
Moorthie, V. A. In Aziridines and Epoxides in Organic Synthesis; Yudin,
A. K., Ed.; Wiley-VCH: Weinheim, Germany, 2006; Chapter 1, pp 1-35. (b)
Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341–2372. (c)
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611–620. (d) Fulton,
J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479–1492.
(29) Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5,
1789–1791.
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SCHEME 3. Synthesis of Bengamides E and Analogues via a
New Asymmetric Methodology of Epoxidation
bengamide analogues. In pursuit of an alternative route that
would allow the introduction of different substituents at the
terminal olefinic position in a stereoselective manner, we devised
vinyl iodide 4231 as an intermediate for the construction of the
ketide chain of bengamides and allowing the opportunity to
incorporate various alkyl groups at the terminal olefinic posi-
tion via a palladium-mediated reaction.
To determine the viability of this new route, we initially
targeted the natural compound bengamide E. The vinyl iodide
42 was transformed into the aldehyde 44 by oxidation of alcohol
43, prepared by treatment of 42 with TBAF. This aldehyde 44
was reacted with the chiral sulfonium salt 30 under biphasic
conditions32 to afford surprisingly a 4:1 mixture of epoxy amides
in a 62% combined yield which, after separation by flash column
chromatography and spectroscopic analyses, were identifed as
trans epoxy amides 45 and its cis isomer, respectively. The
unexpected formation of this cis epoxy amide, not previously ob-
served in reactions involving sulfonium salt 30 with aldehydes,26
likely is due to steric factors present in the starting aldehyde that
could block the thermodynamic equilibrium that leads to the
predominant formation of the trans isomer.33 With epoxy amide
45 in hand, the synthesis toward lactam 49 was conducted in a
more straightforward manner versus our previous route.16 Thus,
epoxy amide 45 was subjected to reduction by treatment with
Super-H to obtain epoxy alcohol 46, which was converted into
diol 47 by treatment with MeOH in the presence of trimethyl-
borate. From 47, we then decided to attempt selective oxidation
of the primary alcohol to the acid by treatment with TEMPO/
BAIB,34 followed by coupling with the amino lactam 48, which
was already attempted with diol 32. In that case, we found 25%
epimerization at C-2 of the resulting coupling product, which
could be avoided by protection of the secondary alcohol. To our
delight, in contrast to that diol case, lactam 49 was obtained in
63% overall yield with no detectable epimerization at C-2.
Finally, the introduction of the isopropyl group was achieved
by a Negishi reaction,35 using diisopropyl zinc and Pd(dpephos)-
Cl2 in a DMF:THF mixture to give 50 in 67% yield, which after
acidic hydrolysis provided natural bengamide E (16) in 85%
yield (Scheme 4).
transformed into the olefin cross metathesis precursor 33 with-
out major difficulties via the chemistry already described. To
complete the synthesis of the terminal alkyl olefinic analogues,
we used the olefin cross metathesis reaction as described for
compounds 35-3716 to prepare other analogues via reaction of
33 with various commercially available alkenes in the presence
of the second generation Hoveyda-Grubbs catalyst (34).30
Thus, the homologue series of bengamides E and its tert-butyl
analogue (compounds 38 and 39), branched aliphatic analogue
40, and the cyclohexyl derivative 41 were prepared (Scheme 3).
The results of all these metathesis reactions were reasonable in
terms of chemical yields, with the exception of compound 40.
Furthermore, the preparation of trisubstituted derivatives via
this cross metathesis reaction was attempted. However, this
strategy failed to give the desired bengamide analogue with an
additional methyl group when 33 reacted with 2,3-dimethyl-1-
butene in the presence of 34, instead giving compound 35, with
no detection of the expected trisubstituted derivative.
Even though the olefin cross metathesis reaction is efficient
for installation of the terminal olefinic substituent, the moderate
to poor conversion observed for some cases and failure for other
bengamide precursors, in particular the 2-C-alkyl analogues, as
we reported in our previous article,16 or for the synthesis of
trisubstituted olefinic derivatives, as described above, led to
uncertainty. This observed unpredictability made the reaction
unsuitable as a general method for the generation of libraries of
On the other hand, hydroxy amide 49 is a useful interme-
diate for the incorporation of various alkyl, alkenyl, or alky-
nyl groups via Negishi, Suzuki, or Sonogashira couplings,
respectively.36 Given the range of possibilities, we decided to
initially carry out Suzuki couplings37 with alkenyl pinacol
esters 51 and 52, which gave in modest yields coupling
products 53 and 54 in 42% and 41% yields, respectively.
The extension of the Negishi reaction by using alkylzinc
bromides38 with 49 was unsuccessful, thus the alcohol was
protected as its silyl ether 55. Subsequently, the ether was
(31) (a) Haustedt, L. O.; Panicker, S. B.; Kleinert, M.; Hartung, I. V.;
Eggert, U.; Niess, B.; Hoffmann, H. M. R. Tetrahedron 2003, 59, 6967–6977.
(b) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.; Jung, S. K.; Lee,
E. Angew. Chem., Int. Ed. 2006, 45, 8019–8021.
ꢀ
ꢀ
(32) Lopez-Herrera, F. J.; Sarabia Garcıa, F.; Heras Lopez, A.; Ortega
Alcantara, J. J.; Pedraza Cebrian, G. M.; Pino-Gonzalez, M. S. Tetrahedron:
ꢀ
ꢀ
ꢀ
Asymmetry 1996, 7, 2065–2071.
(33) See the Supporting Information for theoretical calculations.
(34) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
(35) Yin, N.; Wang, G.; Qian, M.; Negishi, E. Angew. Chem., Int. Ed.
2006, 45, 2916–2920.
(36) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442–4489.
(37) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531–13540.
(38) Graf, K. M.; Tabor, M. G.; Brown, M. L.; Paige, M. Org. Lett. 2009,
11, 5382–5385.
(30) Harrity, J. P. A.; La, D.; Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H.
J. Am. Chem. Soc. 1998, 120, 2343–2351.
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SCHEME 4. Synthesis of Bengamide E through Vinyl Iodide 42
SCHEME 6. Removal of Protecting Groups of Bengamide De-
rivatives: Synthesis of New Bengamide E Analogues
SCHEME 5. Synthesis of Bengamide E Analogues at the
Terminal Olefinic Position via Suzuki and Negishi Couplings
the generation of a wide array of bengamide analogues at the
terminal olefinic position.
Finally, removal of the protective groups by acidic hydro-
lysis of 53 and 54, or by sequential desilylation with TBAF
followed by acidic hydrolysis for 38-41 and 56, provided
bengamide analogues 62-68 (Scheme 6). Thus, together
with the previously synthesized tert-butyl and phenyl deri-
vatives obtained from 36 and 37, the current set of com-
pounds represent an interesting group of bengamide E ana-
logues to evaluate the role of the terminal alkyl group toward
antitumoral activity for this class of compounds.
Conclusions
In conclusion, we have described a new synthesis of
bengamide E and analogues at the terminal olefinic position.
This route utilizes our synthetic methodology of epoxide
formation with chiral sulfur ylides for the preparation of key
intermediates. As an alternative to the strategy described by
us in a previous synthesis of the bengamides, we have
developed a modified synthesis of the bengamide analogues,
from vinyl iodide 42. The route improves upon the previous
syntheses in terms of chemical efficiency and gives access to a
larger variety of analogues by modifications at the terminal
olefinic position by using palladium chemistry. The genera-
tion of a broad library of bengamides as well as their
biological evaluations39 represent our focus in current and
future investigations.
reacted with different alkylzinc bromides, such as commer-
cially available cyclopropyl- or tert-butylzinc bromides, in the
presence of tetrakistriphenylphosphine palladium(0) to pro-
vide in good yields alkyl analogues 56 and 36, respectively
(Scheme 5). These examples are representative and reflect the
potential of vinyl iodides 49 and its silyl ether derivative 55 for
(39) Biological evaluations are being conducted by Dr. Frederick Valer-
iote from Henry Ford Health System (Detroit, MI).
5530 J. Org. Chem. Vol. 75, No. 16, 2010

Sarabia et al.
JOCArticle
Experimental Section40
Epoxy Alcohol 46. A solution of epoxy amide 45 (899 mg, 1.86
mmol) in THF (10.0 mL) was treated with Super-H (4.7 mL 1.0
M in THF, 2.5 equiv) at 0 °C. After 1.0 h at this temperature, the
reaction mixture was treated with MeOH at 0 °C and quenched
by the addition of saturated aqueous NH4Cl solution. The
aqueous phase was washed with Et2O and the combined organic
extracts were washed with water and brine then dried over
anhydrous MgSO4 and the solvent was evaporated. The result-
ing crude product was purified by flash column chromatogra-
phy (silica gel, 10% AcOEt in hexanes) to provide epoxy alcohol
46 (386 mg, 67%) as a yellow oil: Rf 0.23 (silica gel, 30% AcOEt
in hexanes); [R]25D þ52.4 (c 0.4, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 1.37 (s, 3 H), 1.39 (s, 3 H), 3.11 (dd, J = 4.2, 2.3 Hz, 1
H), 3.15-3.18 (m, 1 H), 3.65-3.72 (m, 1 H), 3.93 (dd, J = 12.9,
2.3 Hz, 1 H), 4.05 (dd, J = 12.4, 3.4 Hz, 1 H), 4.32 (ddd, J = 8.2,
6.5, 1.5 Hz, 1 H), 6.54 (dd, J = 14.6, 6.6 Hz, 1 H), 6.61 (d, J =
14.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 26.5, 26.9, 53.0,
55.3, 60.4, 78.7, 80.1, 81.4, 110.3, 141.7; FAB HRMS (NBA) m/e
327.0105, M þ Hþ calcd for C10H15IO4 327.0093.
Alcohol 43. To a solution of silyl ether 4231 (1.72 g, 4.32 mmol)
in THF (22 mL) was added TBAF (5.2 mL, 5.18 mmol, 1.2
equiv) at 25 °C. After 30 min, the reaction mixture was diluted
with Et2O and washed with saturated aqueous NH4Cl solution.
The aqueous phase was washed with Et2O and the combined
organic phases were washed with brine and dried over anhy-
drous MgSO4 and the solvent was evaporated. The crude
product was then purified by flash column chromatography
(silica gel, 25% AcOEt in hexanes) to obtain alcohol 43 (1.15 g,
94%) as a yellow oil: Rf 0.43 (silica gel, 30% AcOEt in hexanes);
1
[R]25 þ14.5 (c 0.2, CH2Cl2); H NMR (400 MHz, CDCl3) δ
D
1.39 (s, 6 H), 2.10 (br s, 1 H), 3.54 (dd, J = 12.9, 4.4 Hz, 1 H),
3.78-3.83 (m, 2 H), 4.29 (ddd, J = 8.3, 3.1, 3.0 Hz, 1 H), 6.56 (d,
J = 3.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 26.8, 26.9,
60.5, 79.0, 80.1, 80.9, 109.6, 142.4.
Aldehyde 44. A solution of oxalyl chloride (0.69 mL, 7.96
mmol, 2.0 equiv) in CH2Cl2 (10.0 mL) was cooled to -78 °C,
and DMSO (1.13 mL, 15.91 mmol, 4.0 equiv) was added
dropwise. After 5 min, a solution of alcohol 43 (1.13 g, 3.98
mmol) in CH2Cl2 (15 mL) was added. The reaction mixture was
stirred at -78 °C for 40 min, and then TEA (3.32 mL, 23.87
mmol, 6.0 equiv) was added at this temperature. After 10 min at
-78 °C, the reaction was allowed to reach room temperature
and was then diluted with Et2O and washed with saturated
aqueous NH4Cl solution. The aqueous phase was washed with
Et2O and the combined organic phases were washed with water
and brine, dried over anhydrous MgSO4, and filtered and the
solvent was evaporated. The crude aldehyde obtained was used
in the next step without purification.
Diol 47. Epoxy alcohol 46 (345 mg, 1.06 mmol) was dissolved
in a 1:1 mixture of MeOH/B(OMe)3 (10 mL) and the resulting
solution was treated with DBU (0.16 mL, 1.06 mmol, 1.0 equiv)
and heated at 70 °C for 1 day. After this time, the reaction mixture
was allowed to reach room temperature, cooled to 0 °C, and then
treated with a saturated aqueous NaHCO3 solution. After the
mixture was stirred for 30 min at 0 °C, AcOEt was added and both
phases were separated. The aqueous phase was extracted with
AcOEt and the combined organic extracts were washed with water
and brine then dried over anhydrous MgSO4 and the solvent was
evaporated under reduced pressure. The resulting crude product
was purified by flash column chromatography (silica gel, 40%
AcOEt in hexanes) to afford diol 47 (281 mg, 74%) as a yellow oil:
Rf 0.25 (silica gel, 60% AcOEt in hexanes); [R]25D þ46.2 (c 0.03,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 6 H), 2.20 (br s, 2
H), 3.16 (ddd, J = 8.2, 3.9, 3.3 Hz, 1 H), 3.41 (s, 3 H), 3.58 (dd, J =
8.2, 1.5 Hz, 1 H), 3.79 (dd, J = 11.9, 3.3 Hz, 1 H), 3.88 (dd, J =
11.9, 3.9 Hz, 1 H), 3.93 (dd, J = 8.5, 1.6 Hz, 1 H), 4.42 (ddd, J =
8.4, 4.7, 1.6 Hz, 1 H), 6.54 (d, J = 4.7 Hz, 1 H), 6.55 (d, J = 1.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3) δ 26.8, 27.0, 58.0, 60.6, 67.6,
78.8, 79.3, 81.40, 81.43, 109.7, 142.2; FAB HRMS (NBA) m/e
359.0363, M þ Hþ calcd for C11H19IO5 359.0355.
Epoxy Amide 45. To a solution of sulfonium salt 30 (1.60 g,
5.17 mmol, 1.3 equiv) in H2O (8.0 mL) was added a solution of
NaOH 3.0 M in H2O (1.32 mL, 4.77 mmol, 1.2 equiv). After 1 h at
25 °C, a solution of crude aldehyde 44 (∼3.98 mmol) in CH2Cl2
(8.0 mL) was added and the reaction mixture was vigorously
stirred overnight at 25 °C. After this time, both phases were
separated and the aqueous layer was extracted with CH2Cl2 twice.
Combined organic extracts were then washed with water and brine,
filtered, and concentrated. Purification by flash column chroma-
tography (silica gel, 30% AcOEt in hexanes) provided epoxy
amides 45 (958 mg, 49.5%) together with its cis epoxy amide
(242 mg, 12.5%) (62% combined yield, 4:1 proportion) as colorless
oils. 45: yellow oil; Rf 0.53 (silica gel, 40% AcOEt in hexanes);
[R]25D þ50.0 (c 0.9, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.34
(s, 3H), 1.37(s, 3H),1.51(s, 3H), 1.61(s, 3H),1.75-1.81 (m, 1 H),
2.00-2.08 (m, 1 H), 2.10 (s, 3 H), 2.45 (ddd, J = 13.3, 8.5, 7.2 Hz, 1
H), 2.59 (ddd, J = 12.8, 7.6, 5.0 Hz, 1 H), 3.31 (dd, J = 2.6, 2.1 Hz,
1 H), 3.66 (d, J = 2.0 Hz, 1 H), 3.88 (dd, J = 8.4, 2.6 Hz, 1 H), 3.90
(d, J = 9.2 Hz, 1 H), 3.99 (ddd, J = 9.2, 5.2, 1.3 Hz, 1 H), 4.32
(ddd, J = 10.2, 4.8, 3.3 Hz, 1 H), 4.41 (dd, J = 8.2, 7.2 Hz, 1 H),
Amide 49. Diol 47 (43 mg, 0.12 mmol) was dissolved in a
mixture of CH3CN/H2O (2.0 mL, 1/1) and the resulting solution
was treated with BAIB (237 mg, 0.72 mmol, 6.0 equiv) followed by
TEMPO (9.8 mg, 0.06 mmol, 0.5 equiv) at 25 °C. After 5 h, the
crude mixture was diluted with AcOEt, quenched by the addition of
a saturated aqueous Na2S2O3 solution and, after separation of both
layers, the aqueous phase was then extracted with AcOEt. The
combined organic solution was washed with saturated aqueous
Na2S2O3 solution again then dried over anhydrous MgSO4 and the
solvent was evaporated under reduced pressure. The crude acid
(∼0.12 mmol) was dissolved in DMF (1.5 mL) and treated with
DIPEA (41 μL, 0.24 mmol, 2.0 equiv), L-Lys-Lactam 48 (30 mg,
0.18 mmol, 1.5 equiv), and BOP (65 mg, 0.14 mmol, 1.20 equiv) at
25 °C. After being stirred at this temperature overnight, the crude
mixture was diluted with Et2O and washed with a saturated
aqueous NH4Cl solution. The aqueous phase was washed with
Et2O and the combined organic phases were washed with brine
then dried over anhydrous MgSO4 and the solvent was evaporated
under vacuum. Purification of the obtained crude product by flash
column chromatography (silica gel, 90% AcOEt in hexanes) pro-
vided amide 49 (30 mg, 63% over 2 steps) as a white solid: Rf 0.29
(silica gel, 70% AcOEt in hexanes); mp 90-95 °C; [R]25D þ61.4 (c
0.1, CH2Cl2);1H NMR (400 MHz, CDCl3) δ1.40(s, 3H), 1.42(s, 3
H), 1.47-1.61 (m, 2 H), 1.76-1.88 (m, 2 H), 1.97-2.12 (m, 2 H),
3.23-3.33(m, 2H), 3.48(s, 3H), 3.61(dd, J=8.3, 1.8 Hz, 1 H), 3.70
(d, J = 8.3 Hz, 1 H), 3.90 (dd, J = 8.4, 1.7 Hz, 1 H), 4.48-4.55
(m, 2 H), 6.11 (t, J=6.0 Hz, 1 H), 6.52 (d, J=2.7 Hz, 1 H), 6.53
6.57 (dd, J = 14.6, 7.1 Hz, 1 H), 6.66 (d, J = 14.6 Hz, 1 H); 13
C
NMR (100 MHz, CDCl3) δ 15.8, 22.8, 26.1, 26.2, 27.0, 30.8, 34.3,
51.3, 55.4, 55.9, 66.9, 76.7, 80.3, 82.1, 95.9, 110.3, 141.3, 163.0; FAB
HRMS (NBA) m/e 498.0802, M þ Hþ calcd for C18H28INO5S
498.0811. cis-Epoxy amide: yellow oil; Rf 0.43 (silica gel, 40%
AcOEt in hexanes); [R]25D -12.5 (c 0.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 1.31 (s, 3 H), 1.39 (s, 3 H), 1.52 (s, 3 H), 1.60 (s,
3 H), 1.89-2.05 (m, 2 H), 2.10 (s, 3 H), 2.37-2.46 (m, 1 H), 2.55-
2.60 (m, 1 H), 3.23 (dd, J=7.9, 4.3 Hz, 1 H), 3.67 (dd, J = 7.8 Hz,
1 H), 3.74 (d, J=4.3 Hz, 1 H), 3.87 (d, J=9.1 Hz, 1 H), 3.99 (dd, J=
9.1, 5.1 Hz, 1 H), 4.24-4.28(m, 1 H), 4.41 (dd, J=7.7, 3.9 Hz, 1H),
6.60 (d, J=3.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ15.7, 22.9,
26.0, 26.6, 26.8, 30.8, 33.2, 52.5, 55.9, 56.3, 67.3, 75.9, 80.6, 82.1,
96.1, 110.4, 141.6, 161.7; FAB HRMS (NBA) m/e 498.0815, M þ
Hþ calcd for C18H28INO5S 498.0811.
(40) See the Supporting Information for General Techniques.
J. Org. Chem. Vol. 75, No. 16, 2010 5531

Sarabia et al.
JOCArticle
(d, J=3.7 Hz, 1 H), 7.90 (d, J = 6.1 Hz, 1H);13C NMR (100 MHz,
CDCl3) δ 26.7, 27.1, 27.9, 28.8, 31.2, 42.1, 51.9, 59.8, 69.1, 78.5,
78.6, 81.1, 81.2, 109.6, 142.4, 171.3, 174.8; FAB HRMS (NBA) m/e
483.0985, M þ Hþ calcd for C17H27IN2O6 483.0992.
0.088 mmol, 2.0 equiv). After 0.5 h at 0 °C, the reaction mixture
was quenched by addition of MeOH (0.1 mL), followed by
addition of aqueous saturated NH4Cl solution and dilution with
Et2O (2 mL). After separation of both phases, the aqueous phase
was extracted with Et2O (2 ꢀ 10 mL), then the combined organic
layers were washed with brine and dried with MgSO4. After
filtration, the solvents were removed by reduced pressure to obtain
a crude product that was purified by flash column chromatography
(silica gel, 50% EtOAc in hexanes) to afford silyl ether 55 (25 mg,
95%) as a yellow foam: Rf 0.49 (silica gel, 60% AcOEt in hexanes);
[R]25D þ20.0 (c 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.06
(s, 3 H), 0.08 (s, 3H), 0.84 (s, 9 H), 1.34 (s, 3 H), 1.33 (s, 3 H),
1.37-1.52 (m, 1 H), 1.71 (br s, 1 H), 1.77-1.88 (m, 2 H), 1.96-2.04
(m, 2 H), 3.21-3.26 (m, 2 H), 3.47 (s, 3 H), 3.73 (d, J = 2.0 Hz, 1
H), 3.91 (dd, J = 8.1, 6.3 Hz, 1 H), 4.27 (dd, J = 6.3, 2.0 Hz, 1 H),
4.41 (ddd, J = 11.1, 5.6, 1.5 Hz, 1 H), 4.55 (ddd, J = 8.0, 6.1, 1.0
Hz, 1 H), 6.15 (t, J = 5.9 Hz, 1 H), 6.46 (dd, J = 14.5, 1.1 Hz, 1 H),
Amide 50. To a solution of vinyl iodide 49 (20.0 mg, 0.04
mmol) in a 1:1 mixture of DMF:THF (1.0 mL) was added
Pd(dpephos)Cl2 (3.0 mg, 0.004 mmol, 0.1 equiv), followed by
diisopropylzinc (27 μL, 1 M solution in THF, 0.027 mmol, 0.65
equiv) at 25 °C. After being stirred for 2.5 h at 25 °C, the crude
mixture was treated with water, diluted with Et2O and, after
separation of both layers, the aqueous phase extracted with
Et2O twice. The resulting organic solution was then washed with
brine, dried (MgSO4), filtered, and concentrated. Purification
by flash column chromatography (silica gel, AcOEt) provided
compound 50 (11.0 mg, 67%) whose physical and spectroscopic
properties were identical with those reported elsewhere.16
Amide 53. A solution of vinyl iodide 49 (22.0 mg, 0.046 mmol)
and pinacol boronic ester 51 (12 μL, 0.050 mmol, 1.1 equiv) in a 3:1
mixture of THF:H2O (2.0 mL) was treated with Pd(dpephos)Cl2
(3.2 mg, 0.0046 mmol, 0.1 equiv) and Tl2CO3 (43 mg, 0.09 mmol,
2.0 equiv). After being stirred overnight at 25 °C, the crude mixture
was diluted with Et2O and washed with a saturated aqueous
KHSO4 solution. The aqueous phase was washed with Et2O and
the combined organic phases were washed with brine then dried
over anhydrous MgSO4 and the solvent was evaporated under
vacuum. The crude product was purified by flash column chroma-
tography (silica gel, AcOEt) to afford compound 53 (8.0 mg, 42%)
as a pale yellow solid: Rf 0.22 (silica gel, AcOEt); mp 110-113 °C;
[R]25D þ70.0 (c 2.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.44
(s, 6 H), 1.47-1.50 (m, 2 H), 1.73 (s, 3 H), 1.75 (s, 3 H), 1.78 (s, 3 H),
1.75-1.88 (m, 2 H), 1.97-2.10 (m, 2 H), 3.22-3.32 (m, 2 H), 3.47
(s, 3 H), 3.60 (dd, J = 8.3, 1.6 Hz, 1 H), 3.69 (d, J = 8.3 Hz, 1 H),
3.88 (dd, J = 8.6, 1.6 Hz, 1 H), 4.50-4.54 (m, 1 H), 4.57 (dd, J =
8.5 Hz, 1 H), 5.45 (dd, J = 15.4, 8.3 Hz, 1 H), 5.98-6.01 (m, 1 H),
6.79 (d, J= 15.4 Hz, 1 H), 7.82 (d, J= 6.1 Hz, 1 H); 13CNMR(100
MHz, CDCl3) δ 14.3, 20.4, 21.9, 26.8, 27.4, 27.9, 28.9, 31.3, 42.1,
51.9, 59.6, 69.0, 78.8, 79.4, 81.5, 81.2, 108.9, 122.2, 125.6, 134.7,
171.2, 174.9; FAB HRMS (NBA) m/e 425.2647, M þ Hþ calcd for
C22H36N2O6 425.2652.
6.64 (dd, J = 14.5, 6.1 Hz, 1 H), 7.87 (d, J = 5.5 Hz, 1 H); 13
C
NMR (100 MHz, CDCl3) δ -4.9, -4.6, 18.1, 25.8, 26.7, 26.8, 27.9,
28.9, 31.4, 42.1, 52.0, 59.5, 73.9, 79.5, 79.6, 80.7, 83.9, 108.9, 143.9,
168.7, 174.9; FAB HRMS (NBA) m/e 597.1843, M þ Hþ calcd for
C23H41IN2O6Si 597.1857.
Amide 56. To a solution of silyl ether 55 (18.0 mg, 0.032 mmol)
in THF (1.0 mL) was added cyclopropylzinc bromide (318 μL,
0.5 M solution in THF, 0.16 mmol, 5.0 equiv) followed by
Pd[PPh3]4 (4.0 mg, 0.0032 mmol, 0.1 equiv) at 25 °C. After 1 h
at 25 °C, the crude mixture was diluted with Et2O then washed
with a saturated aqueous NH4Cl solution and the aqueous phase
was extracted with Et2O twice. The combined organicphases were
washed with brine then dried over anhydrous MgSO4 and the
solvent was evaporated under reduced pressure. Purification by
flash column chromatography (silica gel, 50% AcOEt in hexanes)
of the resulting crude product provided amide 56 (12.0 mg, 80%)
as a colorless oil: Rf 0.34 (silica gel, 50% AcOEt in hexanes); [R]25
D
þ30.0 (c 0.2, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 3
H), 0.07 (s, 3 H), 0.30-0.39 (m, 2 H), 0.67-0.69 (m, 2 H), 0.82 (s, 9
H), 1.34 (s, 6 H), 1.45-1.51 (m, 2 H), 1.69-1.89 (m, 2 H),
1.98-2.14 (m, 2 H), 3.19-3.28 (m, 2 H), 3.41 (s, 3 H), 3.72 (d,
J = 1.9 Hz, 1 H), 3.98 (dd, J = 8.2, 6.8 Hz, 1 H), 4.08 (dd, J = 6.8,
1.9 Hz, 1 H), 4.27 (dd, J = 8.0 Hz, 1 H), 4.43 (dd, J = 10.1, 6.0 Hz,
1 H), 5.25 (dd, J = 15.2, 9.0 Hz, 1 H), 5.60 (dd, J = 15.2, 8.1 Hz, 1
H), 6.03-6.11 (m, 1 H), 7.85 (d, J = 5.6 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ -4.7, -4.6, 6.8, 6.9, 13.6, 18.2, 25.8, 26.9, 27.0,
27.9, 29.0, 31.4, 42.1, 51.9, 58.7, 74.3, 79.2, 80.7, 83.5, 108.1, 125.3,
140.5, 169.3, 174.9; FAB HRMS (NBA) m/e 511.3195, M þ Hþ
calcd for C26H46N2O6Si 511.3203.
Amide 54. A solution of vinyl iodide 49 (32.0 mg, 0.066 mmol)
and pinacol boronic ester 52 (15 mg, 0.073 mmol, 1.1 equiv) in a 3:1
mixture of THF:H2O (2.0 mL) was treated with Pd(dpephos)Cl2
(5.0 mg, 0.0066 mmol, 0.1 equiv) and Tl2CO3 (62 mg, 0.13 mmol,
2.0 equiv). The reaction mixture was then heated at 60 °C for 4 h,
after which it was left to reach room temperature, diluted with
Et2O, and washed with a saturated aqueous KHSO4 solution. The
aqueous phase was washed with Et2O and the combined organic
phases were washed with brine then dried over anhydrous MgSO4
and the solvent was evaporated under vacuum. The crude product
was purified by flash column chromatography (silica gel, 10%
MeOH and 45% AcOEt in hexanes) to afford compound 54
Amide 36. Amide 55 (20.0 mg, 0.035 mmol) was converted
into amide 36 (12.4 mg, 67%) according to the procedure des-
cribed above for 56 with Pd(dpephos)Cl2 (3.0 mg, 0.004 mmol,
0.1 equiv) as catalyst and tert-butylzinc bromide (360 μL, 0.5 M
solution in THF, 0.18 mmol, 5.0 equiv). Amide 36 displayed
identical physical and spectroscopic properties to those reported
elsewhere.16
(12.0 mg, 41%) as a pale yellow solid: Rf 0.23 (silica gel, AcOEt);
1
mp 122-125 °C; [R]25 þ58.8 (c 1.6, CH2Cl2); H NMR (400
D
MHz, CDCl3) δ 0.99 (s, 9 H), 1.41 (s, 3 H), 1.42 (s, 3 H), 1.49-1.52
(m, 2 H), 1.72-1.90 (m, 2 H), 1.98-2.10 (m, 2 H), 3.22-3.32 (m, 2
H), 3.46(s, 3H), 3.59(dd,J=8.3, 1.6Hz, 1H), 3.68(d, J=8.3Hz,
1 H), 3.85 (dd, J = 8.6, 1.5 Hz, 1 H), 4.49-4.55 (m, 1 H), 4.50 (dd,
J = 8.5 Hz, 1 H), 5.50 (dd, J = 15.2, 8.1 Hz, 1 H), 5.70 (d, J = 15.5
Hz, 1 H), 5.93 (dd, J= 15.5, 10.3 Hz, 1 H), 6.07-6.10(m, 1H), 6.27
(dd, J = 15.2, 10.3 Hz, 1 H), 7.83 (d, J = 6.3 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ 26.8, 27.3, 27.9, 28.9, 29.4, 31.3, 33.2, 42.1,
51.9, 59.6, 69.0, 78.8, 79.3, 81.5, 109.0, 124.1, 126.4, 135.9, 147.5,
171.3, 174.9; FAB HRMS (NBA) m/e 439.2787, M þ Hþ calcd for
C23H38N2O6 439.2808.
Acknowledgment. This work was financially supported by
ꢀ
Ministerio de Educacion y Ciencia (ref CTQ2007-66518),
Junta de Andalucıa (FQM-03329), and a fellowship from
Junta de Andalucıa (F.M.-G.). We thank Dr. J. I. Trujillo
from Pfizer (St. Louis, MO) for assistance in the preparation
of this paper. We thank Unidad de Espectroscopıa de Masas
de la Universidad de Granada for exact mass spectroscopic
assistance.
Silyl Ether 55. A solution of hydroxy amide 49 (21 mg, 0.044
mmol, 1.0 equiv) in CH2Cl2 (2 mL) was treated with tert-butyldi-
methylsilyl trifluoromethanesulfonate (TBSOTf) (15 μL, 0.065
mmol, 1.5 equiv) at 0 °C in the presence of 2,6-lutidine (10 μL,
Supporting Information Available:
Experimental proce-
dures 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.
5532 J. Org. Chem. Vol. 75, No. 16, 2010