Total synthesis of phenalamide A2

Article abstract of DOI:10.1021/ol990944x

(formula presented) Phenalamide A₂ (1b) has been synthesized for the first time. The synthesis features the homologation of aldehyde 5 to trienal 3 with the new conjunctive reagent 6 and the formation of amide 14 with the functionalized Horner-

Full text of DOI:10.1021/ol990944x

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1713-1715
Total Synthesis of Phenalamide A2
Reinhard W. Hoffmann,* Thorsten Rohde, Eckart Haeberlin, and Frank Scha1fer
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, Hans-Meerwein-Strasse,
D-35032 Marburg, Germany
rwho@ps1515.chemie.uni-marburg.de
Received August 13, 1999
ABSTRACT
Phenalamide A2 (1b) has been synthesized for the first time. The synthesis features the homologation of aldehyde 5 to trienal 3 with the new
conjunctive reagent 6 and the formation of amide 14 with the functionalized Horner−Emmons reagent 4.
The myxalamides1 2 and the phenalamides2 (stipiamides3)
(1) belong to a class of natural products isolated from gliding
bacteria (Figure 1). These compounds attract attention
1999.5 The Andrus group has expanded their route to access
a series of analogues of the phenalamides.6 In addition, the
group of D. A. Whiting has come up with a concise synthon
approach to the main chain of the myxalamides.7
The nature of approaches depends on whether a C-6/C-7
Z- or C-6/C-7 E-double bond is targeted. We envisaged and
realized a convergent route to phenalamide A2, with the C-6/
C-7 E-configuration.
Key to our approach was the novel conjunctive reagent 6,
by which C-9-C-18 enal 5 can be homologated to tetraenal
3 and subsequently joined to C-1/C-2 amide building block
4 (Scheme 1). The homologation process is effected by an
Scheme 1
Figure 1. Myxalamides and phenalamides.
because of antibiotic, antifungal, and antiviral activity, as
well as being agents to reverse multidrug resistance phe-
nomena. A first synthesis of phenalamide A1 () stipiamide)
(1a) has been reported by M. B. Andrus in 19974 followed
by a synthesis of myxalamide A by C. H. Heathcock in
10.1021/ol990944x CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/02/1999

allylboration reaction of the aldehyde 5 followed by a
cycloreversion of the dioxene ring.
ring.10 Addition of a catalytic amount of iodine equilibrated
the mixture toward the E-isomer (E/Z-ratio > 20:1, deter-
mined by NMR). This reaction sequence can be conveniently
carried out in toluene as solvent as a one-pot procedure
giving, e.g., 11 in 90-93% yield.
Conversion of 11 to trienal 12 requires the elimination of
water. To this end, brief treatment of 11 with methanesulfonic
anhydride and ethyldiisopropylamine in dichloromethane
furnished 90% of tetraenal 12. This reaction sequence was
then applied to aldehyde 5 in order to effect the synthesis of
phenalamide A2 (1b) (Scheme 4).
The requisite enantiomerically pure enal 5 was prepared
by a route8 which is equivalent to the one used by Andrus.4
The other component, the C-1/C-2 amide 4, was generated
in a simple manner from monoprotected alaninol 7 (Scheme
2).
Scheme 2
Reaction of enal 5 with conjunctive reagent 6 including a
treatment with iodine furnished 69% of alcohol 13 as a 9:1
mixture of E/Z-isomers, from which the labile polyenal 3
(6,7-E/6,7-Z ) 9:1) could be obtained in 85% yield. This
(8) Synthesis of aldehyde 5 started from oxazolidinone 15, which was
alkylated to give 16, followed by transformation into aldehyde 17. Standard
homologation led to aldehyde 18. We used the enantiomerically pure
R-chlorocrotylboronate 1912 to create the two new stereogenic centers in
20 with reagent control of diastereoselectivity.13 Alcohol 20 was obtained
diastereomerically pure. Even if the asymmetric induction was not complete,
the few percent of the diastereomeric byproduct could be easily identified
and separated on account of the E-chlorovinyl unit as opposed to the
Z-chlorovinyl unit of desired product 20. The use of chloroboronate 19
entailed an additional step to remove the chlorine atom. This was effected
after silylation of the alcohol by reduction with lithium in liquid ammonia.14
Selective oxidative cleavage of the terminal double bond followed the
precedent set by Andrus.15 Aldehyde 21 obtained was again homologated
in a standard fashion to give the key aldehyde 5.
The novel conjunctive reagent 6 was obtained from 1,3-
dioxene 89 by lithiation10 followed by alkylation with
R-chloroallyl boronate 911 (Scheme 3).
Scheme 3
Racemic reagent 6 is a mixture of diastereomers, which
need not be separated in the present context. Reaction of 6
with aldehydes, e.g., isobutyraldehyde at room temperature,
furnished adducts 10 as a 2:1 mixture of E/Z-isomers
(determined by NMR). Subsequent heating of 10 to 110 °C
generated hydroxydienal 11 by cycloreversion of the dioxene
(1) (a) Jansen, R.; Reifenstahl, G.; Gerth, K.; Reichenbach, H.; Ho¨fle,
G. Liebigs Ann. Chem. 1983, 1081-1095. (b) Jansen, R.; Sheldrick, W.
S.; Ho¨fle, G. Liebigs Ann. Chem. 1984, 78-84.
(2) Trowitzsch-Kienast, W.; Forche, E.; Wray, V.; Reichenbach, H.;
Jurkiewicz, E.; Hunsmann, G.; Ho¨fle, G. Liebigs Ann. Chem. 1992, 659-
664.
(9) Durrant, G.; Edwards, P. D.; Owen, L. N. J. Chem. Soc., Perkin Trans.
1 1973, 1271-1274.
(3) Kim, Y. J.; Furihata, K.; Yamanaka, S.; Fudo, R.; Seto, H. J. Antibiot.
1991, 44, 553-556.
(10) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1988, 110, 1290-
1292.
(4) (a) Andrus, M. B.; Lepore, S. D. J. Am. Chem. Soc. 1997, 119, 2327-
2328. (b) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc.
1997, 119, 12159-12169.
(11) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 1039-
1053.
(12) Hoffmann, R. W.; Dresely, S. Synthesis 1988, 103-106.
(13) (a) Hoffmann, R. W.; Dresely, S.; Lanz, J. W. Chem. Ber. 1988,
121, 1501-1507. (b) Hoffmann, R. W.; Dresely, S.; Hildebrandt, B. Chem.
Ber. 1988, 121, 2225-2230.
(14) Cf.: Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1994, 629-638.
(15) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett. 1997,
38, 4043-4046.
(5) Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23-27.
(6) Andrus, M. B.; Turner, T. M.; Asgari, D.; Li, W. J. Org. Chem.
1999, 64, 2978-2979.
(7) (a) Cox, C. M.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1991,
660-662. (b) Cox, C. M.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1
1991, 1901-1905. (c) Cox, C. M.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1991, 1907-1911.
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Org. Lett., Vol. 1, No. 11, 1999

from 5 were carried out with essentially complete exclusion
of light, to avoid E/Z-isomerization of the polyene system.
Thus, at the stage of 14 the material was g 90% all-E.
Phenalamide A2 (1b) was ultimately liberated in 86% yield
by treatment with HF in acetonitrile at 0 °C.
Scheme 4
When the 500 MHz NMR spectrum of the product
obtained was compared with data published by Ho¨fle,2 we
noted that due to a brief thermal exposure on measuring the
NMR spectrum the obtained phenalamide was admixed with
ca. 40% of other double bond isomers, among which was
phenalamide A1 to ca. 20%. To substantiate this assignment,
the iodine treatment after adding allylboronate 6 to aldehyde
5 was omitted in a complementary reaction sequence. This
allowed hydroxydienal 13 (6,7-E/6,7-Z ) 2:1) to be carried
through as an E/Z-isomeric mixture. This reaction sequence
resulted eventually in a 4:1 mixture of phenalamide A2 and
the C-6/C-7-Z isomeric phenalamide A1.
Acknowledgment. This study has been supported by the
Deutsche Forschungsgemeinschaft (SFB 260, Graduierten-
Kolleg Metallorganische Chemie) and the Fonds der che-
mischen Industrie.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1b, 3, 4, 7,
13, and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
was immediately condensed with phosphonate 4 to give bis-
protected phenalamide 14 (76%). All the operations onward
OL990944X
Org. Lett., Vol. 1, No. 11, 1999
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