A Flexible Approach to (S)-5-Alkyl Tetramic Acid Derivatives: Application to the Asymmetric Synthesis of (+)-Preussin and Protected (3S,4S)-AHPPA

Article abstract of DOI:10.1021/ol035617a

(Equation presented) A flexible asymmetric approach to 5-alkyl tetramic acid derivatives is described, which is based on the use of 9 as the first synthetic equivalent to chiral nonracemic tetramic acid 5-carbanionic synthon 9b. The existence of the carbanion intermediate 9b was proven by trapping with trimethylchlorosilane. Application of the present method to the synthesis of antifungal alkaloid (+)-preussin, as well as protected (3S,4S)-AHPPA 6, is also described.

Full text of DOI:10.1021/ol035617a

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4341-4344
A Flexible Approach to (S)-5-Alkyl
Tetramic Acid Derivatives: Application
to the Asymmetric Synthesis of
(+)-Preussin and Protected
(3S,4S)-AHPPA
Pei-Qiang Huang,* Tian-Jun Wu, and Yuan-Ping Ruan
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian
ProVince, Xiamen UniVersity, Xiamen, Fujian 361005, P. R. China
pqhuang@xmu.edu.cn
Received August 26, 2003
ABSTRACT
A flexible asymmetric approach to 5-alkyl tetramic acid derivatives is described, which is based on the use of 9 as the first synthetic equivalent
to chiral nonracemic tetramic acid 5-carbanionic synthon 9b. The existence of the carbanion intermediate 9b was proven by trapping with
trimethylchlorosilane. Application of the present method to the synthesis of antifungal alkaloid (+)-preussin, as well as protected (3S,4S)-
AHPPA 6, is also described.
5-Alkyl tetramic acids 1 are the key structural features found
in a number of natural products that display a range of
biological properties.1 For example, melophlin B 2 is a
compound reversing the phenotype of ras-transformed cells
and was isolated from the Indonesian marine sponge
Melophlus sarassinorum.2 Moreover, 5-alkyltetramic acids
are ready precursors of 2-pyrrolidinones3 3, which are
valuable building blocks for another two classes of bioactive
natural products, namely, pyrrolidine alkaloids such as
preussin4 4 and â-hydroxy-γ-amino acids such as (3S,4S)-
statine 5 and (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic
acid (AHPPA) 6, which are important peptide mimetics.5
Consequently, the synthesis of tetramic acids has attracted
a great deal of interest.1
(1) For a review, see: Royles, B. J. L. Chem. ReV. 1995, 95, 1981.
(2) Aoki, S.; Higuchi, K.; Ye, Y.; Satari, R.; Kobayashi, M. Tetrahedron
2000, 56,
(3) (a) Jouin, P.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1987, 1177.
(b) Klutchko, S.; O’Brien, P.; Hodges, J. C. Synth. Commun. 1989, 19,
2573.
(4) (a) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
42, 1184. (b) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt,
S.; Garrity, G.; Fromtling, R. A. J. Antibiot. 1988, 41, 1774.
However, most of the known methods for the synthesis
of tetramic acids use R-amino acids as the starting materials
(5) Gante, J. Angew Chem., Int. Ed. Engl. 1994, 33, 1699.
10.1021/ol035617a CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/24/2003

Scheme 1
Scheme 2
(Scheme 1, path a),6 which although reliable has a lack of
flexibility because the alkyl group presents in the C-5
position of tetramic acids comes from the side chain of the
starting R-amino acid. A flexible approach to 5-substituted
tetramic acids would be one that allows the introduction of
the C-5 substituents in a flexible manner (Scheme 1, path
b).
Although chiral tetronic acid derivative 77-9 and nonchiral
tetramate 810,11 were reported 15 years ago as, respectively,
the synthetic equivalents to the corresponding tetronic acid
carbanionic synthon and tetramic acid synthon A and the
latter is currently being applied to the synthesis of other
natural products,12 the chiral nonracemic tetramic acid
synthon (R or S)-A remains unexploited. Inspired by the
pioneering work of Schlessinger on the chemistry of tetronic
acid 7,7 we now wish to report herein the development of
compound (S)-9 as the first synthetic equivalent to the chiral
nonracemic tetramic acid 5-carbanionic synthon (R or S)-A
and its use in the asymmetric synthesis of (+)-preussin 4
and protected (3S,4S)-AHPPA 6.
Acidic hydrolysis of 11 afforded N-protected tetramic acid
12 in 75% yield. Heating a mixture of 12 and (S)-prolinol
derivative 1314 in the presence of a catalytic amount of
pyridinium p-toluenesulfonate (PPTS) provided the desired
chiral tetramic acid synthon equivalent 9 in 50% yield.
With access to quantities of synthon equivalent 9 secured,
we then proceeded to study its deprotonation and subsequent
reaction with electrophiles (Scheme 3). As a first test,
Scheme 3
compound 9 was deprotonated with 1.2 molar equiv of tert-
butyllithium in THF (cosolvent HMPA, -78 °C, 1 h), and
the anion formed was quenched with deuteriomethanol
(MeOD, -78 °C, 20 min.), which yielded the C-5 deuterio
product 14a in 78% yield (Table 1, entry 1). Encouraged by
this result, the anion generated from 9 (1.2 equiv t-BuLi,
THF-HMPA 20:1, -78 °C, 1 h) was allowed to react with
methyl iodide (-78 °C, 7 h), which afforded 14b as the sole
regioisomer and in 99% de (combined yield, 87%) (Table
1, entry 2).
The reaction of the lithiated 9 with other carbon electro-
philes proceeded similarly (Table 1, entries 3-7) with
excellent regio- and diastereoselectivities, which were as-
certained by combining HPLC and 1H NMR spectral
analysis. In addition, on the basis of the comparison of the
allylation product 14e with an epimerized sample (in 55:45
ratio) by mean of HPLC analysis, the minor isomer appearing
in the HPLC analysis was attributed to the diastereomer
The synthesis of the requisite chiral nonracemic synthon
equivalent (S)-9 is depicted in Scheme 2. Treatment of
p-methoxybenzylamine with known methyl (E)-4-chloro-3-
methoxy-2-butenoate 1013 gave tetramate 11 in 75% yield.
(6) For other approaches to tetramic acids, see: (a) Banziger, M.;
McGarrity, J. F.; Meul, T. J. Org. Chem. 1993, 58, 4010. (b) Fustero, S.;
Garcia de la Torre, M.; Sanz-Cervera, J. F.; Ramirez de Arellano, C.; Piera,
J.; Simon, A. Org. Lett. 2002, 4, 3651.
(7) (a) Schlessinger, R. H.; Iwanowicz, E. J. Tetrahedron Lett. 1988,
29, 1489. (b) Schlessinger, R. H.; Mjalli, M. M.; Adams, A. D. J. Org.
Chem. 1992, 57, 2992. (c) Schlessinger, R. H.; Pettus, T. R. R. J. Org.
Chem. 1994, 59, 3246. (d) Schlessinger, R. H.; Li, Y. J. J. Am. Chem. Soc.
1996, 118, 3301. (e) Dankwardt, S. M.; Dankwardt, J. W.; Schlessinger,
R. H. Tetrahedron Lett. 1998, 39, 4971. (f) Dankwardt, S. M.; Dankwardt,
J. W.; Schlessinger, R. H. Tetrahedron Lett. 1998, 39, 4975. (g) Dankwardt,
J. W.; Dankwardt, S. M.; Schlessinger, R. H. Tetrahedron Lett. 1998, 39,
4979. (h) Dankwardt, J. W.; Dankwardt, S. M.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4983.
(8) Jatzke, H.; Evertz, U.; Schmidt, R. R. Synlett 1990, 191.
(9) Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.; Node, M.
Tetrahedron 1994, 50, 8337.
(10) (a) Jones, R. C. F.; Bates, A. D. Tetrahedron Lett. 1986, 27, 5285.
(b) Jones, R. C. F.; Patience, J. M. J. Chem. Soc., Perkin Trans. 1 1990,
2350.
(13) (a) Duc, L.; McGarrity, J. F.; Meul, T.; Warm, A. Synthesis 1992,
391. (b) Laffan, D. D. P.; Panziger, M.; Duc, L.; Evans, A. R.; McGarrity,
J. F.; Meul, T. HelV. Chim. Acta 1992, 75, 892.
(14) Enders, D.; Kipphardt, H.; Gerdes, P.; Brenak-Valle, L. J.; Bhushan,
V. Bull. Soc. Chim. Belg. 1988, 97, 691.
(11) James, G. D.; Mills, S. D.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1993, 2567.
(12) (a) Hunter, R.; Richards, P. Synlett 2003, 271. (b) Paintner, F. F.;
Metz, M.; Bauschke, G. Synlett 2003, 627.
4342
Org. Lett., Vol. 5, No. 23, 2003

Scheme 4
Table 1. Results for the Reaction between Lithiated 9 and
Electrophiles
entry
electrophiles
products (yields, %)a
% de
1
2
3
4
5
6
7
8
MeOD
MeI
n-C4H9I
14a (78)
14b (87)
14c (71)
14d (69)
14e (77)
14f (84)
14g (85)
14h (45)
4b
99c
100c
100c
97c
98c
100c
100c
n-C6H13
I
CH2dCHCH2I
BrCH2CO2Et
BnBr
TMSCl
a Isolated yields. b de determined by 1H NMR. c de determined by HPLC
analysis.
instead of regioisomer. It is noteworthy that, as indicated
1
by H and 13C NMR spectra, alkylation products 14b-14d
anions generated either from 716 or 810a have also been
reported. It is admitted that the isolated yield of 14h (45%)
could not reflect the real composition of the lithiated
intermediates 9a-9b in the reaction media, since more rapid
O-silylation of the minor intermediate 9a (comparing with
C-silylation) will favor its formation from 9b. On the basis
of this consideration, the carbanionic intermediate 9b should
be predominant over 9a in the reaction mixture.
Although the stereochemistry of the alkylation products
14 is unknown at this stage, on the basis of both the chelating
intermediate 9b and vinylogous enolate 9a, it is reasonable
to assume that the newly formed stereogenic center has
S-configuration that resulted either from an inversion of
configuration at C-5 of 9b or from the approach of electro-
philes from the si face of the vinylogous enolate 9a avoiding
the A1,3-interaction.
exist, in each case, in only one rotamer in CDCl3, whereas
compounds 14e-h exist as a rotameric mixture. The nature
of the rotameric mixture was proven by the ultimate
transformation of 14g into (+)-preussin 4 (Vide infra).
Compared with related systems (7 and 8), the high regio-,
chemo-, and diastereoselectivities observed during the alky-
lation of (S)-9 deserve comments. For the alkylation of the
vinylogous enolates derived from 4-(2,5-substituted pyrro-
lidino)-2(5H)-furanones 7, although excellent diastereo-
selectivities were obtained with the chiral auxiliary possess-
ing a C2 symmetry (7, R1 ) R2 ) Me or CH2OMe),7a,e-h,8
when using more cheap and easily available L-prolinol
derivatives as the chiral auxiliaries,7b,c,d,9 good diastereose-
lectivities could be obtained only in the cases where an alkyl
group is presented at the C-2 position of 7 (R * H).9 As
regarding the chemo- and regioselectivities during the
alkylation of the dienolates derived from tetramate 8, when
allyl halide or benzyl bromide was used as the alkylating
agent, significant quantities of C-3 allylation product12a and
5,5-dibenzylation product10b were observed, respectively.
To gain solid proof of the stereochemistry of the alkylated
products 14 and to demonstrate the versatility of the present
method, the asymmetric synthesis of (+)-preussin 4,17
a
potent antifungal agent isolated from fermentation broths of
both Aspergillus ochraceus and Preussia sp., was undertaken
(Schemes 5 and 6).
Thus treatment of 14g with a 10% HCl solution in THF
for 26 h gave the corresponding crude tetramic acid 15,
which without further purification was treated at 0 °C with
sodium borohydride in methanol,3 to provide cis-16. The
yield over two steps was 82%, and the cis/trans ratio was
about 20:1, which was deduced from the following step.
The different behavior of the anions derived from com-
pounds 7, 8, and 9 might implicate that, in our case, among
two possible lithiated intermediates 9a and 9b, the latter was
the predominant structure. To test this hypothesis, trapping
of the lithiated intermediates by trimethylchlorosilane was
envisioned. Thus when the lithiated intermediates derived
from 9 were treated with 2.5 molar equiv of trimethylchloro-
silane, C-5 silylated product 14h was isolated in 45% yield
together with a 45% yield of the starting material (Table 1,
entry 8). The recovery of 9 may due to the competing
O-silylation of 9a, which regenerated, during aqueous
workup, the starting 9 (Scheme 4).
(16) (a) Schlessinger, R. H.; Wu, X. H.; Pettus, T. R. R. Synlett 1995,
536. (b) Schlessinger, R. H.; Bergstrom, C. P. Tetrahedron Lett. 1996, 37,
2133.
(17) For the asymmetric syntheses of preussin, see: (a) Pak, C. W.; Lee,
G. H. J. Org. Chem. 1991, 56, 1128. (b) McGrane, P. L.; Livinghouse, T.
J. Am. Chem. Soc. 1993, 115, 11485. (c) Deng, W.; Overman, L. E. J. Am.
Chem. Soc. 1994, 116, 11241. (d) Overhand, M.; Hecht, S. M. J. Org. Chem.
1994, 59, 4721. (e) Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron:
Asymmetry 1996, 7, 373. (f) Verma, R.; Ghosh, S. K. Chem. Commun.
1997, 1601. (g) Beier, C.; Schaumann, E. Synthesis 1997, 1296. (h) Kadota,
I.; Saya, S.; Yamamoto, Y. Heterocycles 1997, 46, 335. (i) Armas, P. D.;
Tellado-Garcia, F.; Tellado-Marrero, J. J.; Robles, J. Tetrahedron Lett. 1998,
39, 131. (j) Dong, H. Q.; Lin, G. Q. Chin. J. Chem. 1998, 16, 458. (k)
Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org. Chem. 1998, 63,
4660. (l) Veeresa; G.; Datta, A. Tetrahedron 1998, 54, 15673. (m) Lee, K.
Y.; Kim, Y. H.; Oh, C. Y.; Ham, W. H. Org. Lett. 2000, 2, 4041. (n) Okue,
M.; Watanabe, H.; Kitahara, T. Tetrahedron 2001, 57, 4107.
This result is significant in carbanionic chemistry,15 since
the selective O-silylation of enolates is a very general and
routine chemoselective reaction, as the result of the formation
of a strong O-Si bond. The exclusive O-silylation of the
(15) (a) Giblin, G. M. P.; Kirk, D. T.; Mitchell, L.; Simpkins, N. S. Org.
Lett. 2003, 5, 1673. (b) Baussanne, I.; Royer, J. Tetrahedron Lett. 1998,
39, 845. (c) Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1978, 43, 881
and references therein.
Org. Lett., Vol. 5, No. 23, 2003
4343

NMR spectral data of synthetic material were identical with
those of natural 4.4
Scheme 5
Since 19 is a ready precursor to protected (3S,4S)-4-amino-
3-hydroxy-5-phenylpentanoic acid (AHPPA, 6), the synthesis
of the latter was considered. Thus, stirring a mixture of 19
and a catalytic amount of potassium cyanide19 in a mixed
EtOH/THF (1:1, v/v, rt) solvent system led smoothly to the
formation of N-Boc-(3S,4S)-4-amino-3-hydroxypentanoic
acid ethyl ester 21 {colorless oil, [R]20 -23.4 (c 0.7,
D
MeOH)}, a fully protected form of AHPPA, in 91% yield.
AHPPA20 is a key component found in naturally occurring
aphatinins,21 a protease inhibitor.
Scheme 7
O-Protection (TBDMSCl, imidazole, DMAP) of 16 fol-
lowed by N-deprotection (CAN, MeCN/H2O ) 3:1) afforded
2-pyrrolidinone 18. Treatment of 18 with di(tert-butyl)
In summary, the anion derived from 9 undergoes highly
C-5 regioselective and diastereoselective reaction with alkyl
halides to afford 5-alkyltetramic acid derivatives in good
yields. The successful trapping of the carbanionic intermedi-
ate by TMSCl served to demonstrate its structure. The
application of the present method to the asymmetric synthesis
of (+)-preussin and a fully protected form of (3S,4S)-AHPPA
both confirms the stereochemistry of the reaction and
illustrates the versatility of the method.
dicarbonate (NEt3, CH2Cl2) then furnished known 19 {[R]20
D
+34.3 (c 1.0, CHCl3) [lit.17e [R]23 +37.9 (c 1.20, CHCl3)]
D
in 97% yield. The dextrorotary property of thus synthesized
19 clearly indicated its (4S,5S) absolute configuration17e and
thus confirmed the above-mentioned stereochemical assign-
ment of the reaction of lithiated 9 with alkyl halides.
The diastereoselective installation of the nonyl group was
achieved by a known one-pot procedure (n-C9H19MgBr; Et3-
SiH, BF3-OEt2, -78 °C),17e,k which provided 20 {[R]20
D
Acknowledgment. The authors are grateful to the NNSF
of China (29832020; 20072031; 20272048; 203900505) for
financial support.
-48.6 (c 1.1, CHCl3) [lit.17e [R]25D -46.4 (c 1.50, CHCl3)]}
as the sole diastereomer. Heating a suspension of 20 and an
excess of lithium aluminum hydride in THF for 28 h18 gave
(+)-preussin 4 {[R]20 +21.9 (c 1.3, CHCl3) [natural 4,4
D
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
[R]25D +22.0 (c 1.0, CHCl3)]} in 91% yield. The 1H and 13
C
Scheme 6
OL035617A
(18) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663.
(19) Ho¨gberg, T.; Stro¨m, P.; Ebner, M.; Ra¨msby, S. J. Org. Chem. 1987,
52, 2033.
(20) For other non-amino-acid-based synthetic approaches to AHPPA
and derivatives, see: (a) Yanagisawa, H.; Kanazaki, T.; Nishi, T. Chem.
Lett. 1989, 687. (b) Enders, D.; Reinhold: U. Angew. Chem. 1995, 107,
1322; Enders, D.; Reinhold: U. Angew. Chem., Int. Ed. Engl. 1995, 34,
1219. (c) Doi, T.; Kokubo, M.; Yamamoto, K.; Takahashi, T. J. Org. Chem.
1998, 63, 428. (d) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419
and references therein.
(21) Omura, S.; Imamura, N.; Kawakita, K.; Mori, Y.; Yamazaki, Y.;
Masuma, R.; Takahashi, Y.; Tanaka, H.; Huang, L.-Y.; Woodruff, H. J.
Antibiot. 1986, 39, 1079.
4344
Org. Lett., Vol. 5, No. 23, 2003