Stereoselective synthesis of enamides by a Peterson reaction manifold

Article abstract of DOI:10.1021/ol016848p

equation presented Vinylsilanes are converted into enamides by a sequence comprising epoxidation, nucleophilic ring opening of the resulting epoxysilanes with NaN₃, and reduction of the azide, followed by a "one-pot" N-acylation/Peterson elimin

Full text of DOI:10.1021/ol016848p

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3955-3957
Stereoselective Synthesis of Enamides
by a Peterson Reaction Manifold
Alois Fu1rstner,* Christof Brehm, and Yolanda Cancho-Grande
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received October 3, 2001
ABSTRACT
Vinylsilanes are converted into enamides by a sequence comprising epoxidation, nucleophilic ring opening of the resulting epoxysilanes with
NaN , and reduction of the azide, followed by a “one-pot” N-acylation/Peterson elimination process. This method is distinguished by its wide
3
applicability and stereoselective course.
The enamide linkage represents a fragile structural element
that is prominently featured in a wide range of natural
products with promising biological activities. This includes
compounds as diverse as lansiumamide A (1),1 the chon-
driamides (e.g., 2),2 the storniamides (e.g., 3),3 salicylihal-
amide (4a,b) and congeners,4,5 and a host of acyclic and
cyclic peptides such as 5,6 to mention just a few prototype
examples.
Recent investigations dealing with the synthesis and
biological evaluation of the potent cytotoxic agent 4 have
shown that the C(17)-C(18) enamide moiety is an essential
part of the pharmacophore of this lead compound.7,8 How-
ever, they have also revealed that the formation of this entity
is far from trivial.9 Therefore, we were prompted to devise
a novel and widely applicable method which provides
rigorous control over the stereochemistry of the enamide
(1) (a) Isolation: Lin, J.-H. Phytochemistry 1989, 28, 621 and references
therein. (b) Synthesis: Stefanuti, I.; Smith, S. A.; Taylor, R. J. K.
Tetrahedron Lett. 2000, 41, 3735.
(2) (a) Palermo, J. A.; Flower, P. B.; Seldes, A. M. Tetrahedron Lett.
1992, 33, 3097. (b) Davyt, D.; Entz, W.; Fernandez, R., Mariezcurrena,
R.; Mombru´, A. W.; Saldan˜a, J.; Dom´ınguez, L.; Coll, J.; Manta, E. J. Nat.
Prod. 1998, 61, 1560.
(3) (a) Isolation: Palermo, J. A.; Brasco, M. F. R.; Seldes, A. M.
Tetrahedron 1996, 52, 2727. (b) Preparative studies: Ebel, H.; Terpin, A.;
Steglich, W. Tetrahedron Lett. 1998, 39, 9165. (c) Boger, D. L.; Boyce, C.
W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
(4) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H.; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188. Correction: Erickson, K. L.; Beutler, J. A.;
Cardellina, J. H.; Boyd, M. R. J. Org. Chem. 2001, 66, 1532.
(5) For closely related compounds, see the following: (a) Lobatamides:
McKee, T. C.; Galinis, D. L., Pannell, L. K.; Cardellina, J. H.; Laakso, J.;
Ireland, C. M.; Murray, L.; Capon, R. J.; Boyd, M. R. J. Org. Chem. 1998,
63, 7805. (b) Oximidines: Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa,
Y.; Seto, H. J. Org. Chem. 1999, 64, 153. (c) CJ-12,950 and CJ-13,357:
Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara, T.; Suzuki,
Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J. Antibiot. 1998, 51, 14.
(d) Apicularens: Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur.
J. Org. Chem. 2000, 913.
(6) Morel, A. F.; Gehrke, I. T. S.; Mostardeiro, M. A.; Ethur, E. M.;
Zanatta, N.; Machado, E. C. S. Phytochemistry 1999, 51, 473.
10.1021/ol016848p CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/08/2001

double bond. Outlined below is the concept of our synthesis
route together with a series of model studies.
In view of the inherent lability of enamides toward acid-
catalyzed hydrolysis, we pursued a strategy which allows
for the stereoselective formation of the double bond under
mild, aprotic, and basic conditions (Schemes 1 and 2). The
Table 1. Stereoselective Synthesis of (E)- or (Z)-Configured
Enamides. The Yield Refers to Analytically Pure Material
Obtained over Two Steps (N-Acylation/Peterson Elimination),
cf. Text
Scheme 1. Stereoselective Conversion of (E)-Alkenylsilanes
into (E)-Enamidesa
a [a] m-CPBA, Na2HPO4, CH2Cl2, 60% (R1 ) n-pentyl); [b]
dimethyldioxirane, acetone/CH2Cl2, 89% (R1 ) Ph); [c] NaN3,
NH4Cl, MeOH/H2O, 75% (R1 ) n-pentyl); 68% (R1 ) Ph); [d]
LiAlH4, Et2O, 93% (R1 ) n-pentyl); 97% (R1 ) Ph); [e] (i) R2COCl,
THF, NEt3; (ii) KOtBu, -35 °C f rt, see Table 1.
famous Peterson elimination10-12 seems to meet these
stringent criteria. Thus, we envisaged the use of epoxysilanes
as starting materials which can be prepared by a variety of
efficient methods.11,13 Specifically, compounds trans-7 and
cis-7 used as model substrates are conveniently obtained by
reaction of vinylsilanes (E)-6 or (Z)-6, respectively,14 with
m-chloroperbenzoic acid or dimethyldioxirane.15 Silicon-
directed epoxide ring opening with NaN3 in a buffered
medium16 furnishes products 8, which can be selectively
reduced to the corresponding amino alcohols 9 in many
different ways.17 For the sake of convenience, we took
recourse to LiAlH4 or hydrogenolysis during this investiga-
tion.
Scheme 2. Stereoselective Conversion of (Z)-Alkenylsilanes
into (Z)-Enamidesa
a [a] m-CPBA, Na2HPO4, CH2Cl2, 90% (R1 ) n-pentyl); 81%
(R1 ) Ph); [b] NaN3, NH4Cl, MeOH/H2O, 88% (R1 ) n-pentyl);
89% (R1 ) Ph); [c] LiAlH4, Et2O, quantitative (R1 ) n-pentyl);
73% (R1 ) Ph); [d] (i) R2COCl, THF, NEt3; (ii) KOtBu, -35 °C
f rt, see Table 1.
3956
Org. Lett., Vol. 3, No. 24, 2001

The key steps of our new enamide synthesis can either be
carried out in a consecutive manner or, preferentially, in “one
pot” (for experimental details, see the Supporting Informa-
tion). Thus, N-acylation of amine syn-9 under standard
conditions followed by addition of KOtBu to the solution
of the resulting amide at low temperature affords the desired
enamides (E)-10 in virtually quantitative yield; the crude
material is usually pure enough for further use (>95% by
1H NMR). Analogously, anti-9 is converted into the diaster-
eomeric products (Z)-10. This includes a synthesis of
lansiumamide A (1, Table 1, entry 11) which compares
favorably with a previous approach to this natural product
reported in the literature.1b Analytically pure samples are
obtained by flash chromatography; although care was taken
to minimize the amount of adsorbent used as well as the
time of exposure, some loss of material can hardly be avoided
due to the lability of some of the products. This explains
why the isolated yields shown in Table 1 are only in the
range of 56-89%. It was noticed that the hydrolysis is
particularly facile for (Z)-configured enamides. Most im-
portant, however, is the fact that all products are obtained
as single diastereomers. Thus, the configuration of the
starting material is transferred in a predictable manner and
with high integrity into the final product. This rigorously
stereoselective and controlable course distinguishes the
protocol outlined above from many of the alternative methods
previously described in the literature. Further work aimed
at the implementation of this new strategy into the total
synthesis of bioactive target molecules18 is currently under-
way and will be reported soon.
(7) Total syntheses: (a) Wu, Y.; Esser, L.; De Brabander, J. K. Angew.
Chem. 2000, 112, 4478; Angew. Chem., Int. Ed. 2000, 39, 4308. (b)
Labrecque, D.; Charron, S.; Rej, R.; Blais, C.; Lamothe, S. Tetrahedron
Lett. 2001, 42, 2645. (c) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817.
(d) Smith, A. B.; Zheng, J. Synlett 2001, 1019. (e) Wu, Y.; Seguil, O. R.;
De Brabander, J. K. Org. Lett. 2000, 2, 4241. (f) Fu¨rstner, A.; Dierkes, T.;
Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001, 7, 5284.
(8) Partial syntheses: (a) Fu¨rstner, A.; Thiel, O. R.; Blanda, G. Org.
Lett. 2000, 2, 3731. (b) Georg, G. I.; Ahn, Y. M.; Blackman, B.; Farokhi,
F.; Flaherty, P. T.; Mossman, C. J.; Roy, S.; Yang, K. L. Chem. Commun.
2001, 255. (c) Feutrill, J. T.; Holloway, G. A.; Hilli, F.; Hugel, H. M.;
Rizzacasa, M. A. Tetrahedron Lett. 2000, 41, 8569.
(9) Various methods allowing the formation of enamides have been
described in the literature. For leading references see the following and
literature cited therein: (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2,
1333. (b) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407. (c) Hudrlick, P.
F.; Hudrlick, A. M.; Rona, R. J.; Misra, R. N.; Withers, G. P. J. Am. Chem.
Soc. 1977, 99, 1993. (d) Alonso, D. A.; Alonso, E.; Na´jera, C.; Yus, M.
Synlett 1997, 491. (e) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem.
Lett. 1991, 1443. (f) Trost, B. M.; Surivet, J.-P. Angew. Chem. 2001, 113,
1516; Angew. Chem., Int. Ed. 2001, 40, 1468. (g) Boar, R. B.; McGhie, J.
F.; Robinson, M.; Barton, D. H. R.; Horwell, D. C.; Stick, R. V. J. Chem.
Soc., Perkin Trans. 1 1975, 1237. (h) Brettle, R.; Mosedale, A. J. J. Chem.
Soc., Perkin Trans. 1 1988, 2185. (i) Kondo, T.; Tanaka, A.; Kotachi, S.;
Watanabe, Y. J. Chem. Soc., Chem. Commun. 1995, 413. (j) Ogawa, T.;
Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991, 1443. (k) Ramamurthy,
B.; Sugumaran, M. Synthesis 1987, 523. (l) For enecarbamates see:
Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem.
1978, 43, 2164.
(10) For pertinent reviews see: (a) Ager, D. J. Org. React. 1990, 38, 1.
(b) Ager, D. J. Synthesis 1984, 384.
(11) Brook, M. A. Silicon in Organic, Organometallic and Polymer
Chemistry; Wiley: New York, 2000.
(12) It is well established that a syn-elimination of the -OH and -SiMe3
group takes place in base-induced Peterson reactions, cf. (a) Hudrlick, P.
F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464. (b) Hudrlick, P. F.;
Peterson, D.; Rona, R. J. J. Org. Chem. 1975, 40, 2263.
(13) The use of epoxysilanes as substrates for the synthesis of enamides
has precedence in the two examples reported in ref 9c. In these cases the
epoxide ring is opened by acetonitrile used as solvent which clearly limits
the scope of the method.
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (Leibniz award to A.F.)
and the Fonds der Chemischen Industrie is gratefully
acknowledged.
Supporting Information Available: Representative pro-
cedures as well as analytical and spectroscopic data of all
new compounds. This material is available free of charge
via the Internet at http:pubs.acs.org.
OL016848P
(14) The vinylsilanes used have been prepared according to the following
references. (a) (E)-6a (R1 ) n-pentyl): Koumaglo, K.; Chan, T. H.
Tetrahedron Lett. 1984, 25, 717. (b) (Z)-6a (R1 ) n-pentyl): Page, P. C.
B.; Rosenthal, S. Tetrahedron 1990, 46, 2573. (c) (Z)-6b (R1 ) Ph): Barton,
T.; Lin, J.; Ijadi-Maghsoodi, S.; Power, M. D.; Zhang, X.; Ma, Z.; Shimizu,
H.; Gordon, M. S. J. Am. Chem. Soc. 1995, 117, 11695. (d) (E)-6b (R1 )
Ph): Jeffery, T. Tetrahedron Lett. 1999, 40, 1673.
(15) (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1989, 30, 5693.
(b) Alexakis, A.; Jachiet, D. Tetrahedron 1989, 45, 381.
(16) Chakraborty, T. K.; Reddy, G. V. Tetrahedron Lett. 1990, 31, 1335.
(17) For a compilation see: Larock, R. C. Synthetic Organic Methodol-
ogy: ComprehensiVe Organic Transformations. A Guide to Functional
Group Preparations; VCH: Weinheim, 1989.
(18) Fu¨rstner, A. Synlett 1999, 1523.
Org. Lett., Vol. 3, No. 24, 2001
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