Preparation of syn-δ-Hydroxy-β-amino Esters via an Intramolecular Hydrogen Bond Directed Diastereoselective Hydrogenation. Total Synthesis of (3S,4aS,6R,8S)-Hyperaspine

Article abstract of DOI:10.1021/ol036097m

(Equation presented) Hydrogenation of δ-hydroxy-β-ketoester- derived enamines 8 produces syn-δ-hydroxy-β-amino esters 9 diastereoselectively, which may be directed by the formation of an intramolecular hydrogen bond between the δ-hydroxyl and β-amino groups. By using this method and a Dieckmann reaction as the key steps, (3S,4aS,6R,8S)-hyperaspine, a new type of ladybird alkaloid, is synthesized.

Full text of DOI:10.1021/ol036097m

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5063-5066
Preparation of syn-δ-Hydroxy-â-amino
Esters via an Intramolecular Hydrogen
Bond Directed Diastereoselective
Hydrogenation. Total Synthesis of
(3S,4aS,6R,8S)-Hyperaspine
Wei Zhu and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received October 28, 2003
ABSTRACT
Hydrogenation of δ-hydroxy-â-ketoester-derived enamines 8 produces syn-δ-hydroxy-â-amino esters 9 diastereoselectively, which may be
directed by the formation of an intramolecular hydrogen bond between the δ-hydroxyl and â-amino groups. By using this method and a
Dieckmann reaction as the key steps, (3S,4aS,6R,8S)-hyperaspine, a new type of ladybird alkaloid, is synthesized.
The δ-hydroxy-â-amino ester moiety exists in many biologi-
cally important molecules such as scytonemin A,1 the potent
gastroprotective agent AI-77B1;3 and the antibacterial natural
products negamycin4 and sperabillin A-D.5 To synthesize
these molecules, several concise protocols for preparing the
δ-hydroxy-â-aminoester units have been developed.2,6 How-
ever, most of them are long or use not so readily available
starting materials.
method for preparing syn-δ-hydroxy-â-amino esters because
our proposed strategy would make use of such a compound
as a starting material.
Hyperaspine is a new type of ladybird alkaloid that was
isolated by Braekman and co-workers from Hyperaspis
campestris.7 We envisioned accessing the natural product
from the bicyclic ketone 1, which would be prepared from
(6) (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem.
Soc. 1982, 104, 6465. (b) Hashiguchi, S.; Kawada, A.; Natsugari, H. J.
Chem. Soc., Perkin Trans. 1 1991, 2435. (c) Chakraborty, T. K.; Hussain,
A. K.; Joshi, S. P. Chem. Lett. 1992, 2385. (d) Broady, S. D.; Rexhausen,
J. E.; Thomas, E. J. J. Chem. Soc., Chem. Commun. 1991, 708. (e) Ward,
R. A.; Procter, G. Tetrahedron Lett. 1992, 33, 3359. (f) Masters, J. J.;
Hegedus, L. S. J. Org. Chem. 1993, 58, 4547. (g) Jain, R. P.; Williams, R.
M. J. Org. Chem. 2002, 67, 6361. (h) Shimizu, M.; Morita, A.; Fujisawa,
T. Chem. Lett. 1998, 467. (i) Schmidt, U.; Sta¨bler, F.; Lieberknecht, A.
Synthesis 1992, 482. (j) Maycock, C. D.; Barros, M. T.; Santos, A.; Godinho,
L. S. Tetrahedron Lett. 1992, 33, 4633. (k) Socha, D.; Jurczak, M.;
Chemielewski, M. Tetrahedron Lett. 1995, 36, 135. (m) Davies, S. G.;
Ichihara, O. Tetrahrdeon: Asymmetry 1996, 7, 1919. (n) Davies, S. G.;
Ichihara, O. Tetrahedron Lett. 1999, 40, 9313.
In the course of our investigations into the total synthesis
of hyperaspine, we became interested in developing a good
(1) Helms, G. L.; Moore, R. E.; Niemczura, W. P.; Patterson, G. M. L.;
Tomer, K. B.; Gross, M. L. J. Org. Chem. 1988, 53, 1298.
(2) Ensch, C.; Hesse, M. HelV. Chim. Acta 2003, 86, 233 and references
therein.
(3) Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M. Agric. Biol.
Chem. 1982, 46, 1823.
(4) Hamada, M.; Takeuchi, T.; Kondo, S.; Ikeda, Y.; Naganawa, H.;
Maeda, K.; Okami, Y.; Umezawa, H. J. Antibiot. 1970, 23, 170.
(5) Katayama, N.; Nozaki, Y.; Tsubotani, S.; Kondo, M.; Harada, S.;
Ono, H. J. Antibiot. 1992, 45, 10.
10.1021/ol036097m CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003

Scheme 1
Figure 1. Retrosynthetic analysis of hyperaspine.
the δ-hydroxy-â-amino ester 2 via a Dieckmann reaction and
subsequent transformations (Figure 1).8
In 1986, Prasad and co-workers reported that the hydro-
genation of δ-hydroxyl-â-ketoesters 3 preferentially gave
syn-1,3-diols 4 with high diastereoselectivity (Figure 2).9
reaction of aldehydes with ethyl acetoacetate.10 Hydrogena-
tion of 8d was initially attempted by exposing it to Pd/C
and H2 in ethanol. It was found that hydrogenation and
debenzylation occurred under these conditions to give the
free δ-hydroxy-â-amino ester as a diastereomeric mixture.
Because of the difficulty in separating these two diastereo-
mers, we decided to protect them in situ. Accordingly, the
hydrogenation of 8 was carried out in the presence of di-
tert-butyl dicarbonate, which provided the syn-hydroxylamine
9d and the anti-hydroxylamine 10d in a ratio of 5.3:1 and
61% combined yield. The stereochemistry of the major
diastereomer 9d was established by analyzing the NOE
correlations of lactone 11, which was obtained from 9d by
treatment with PPTS. Of the other enamines that were tested,
the δ-methyl-substituted compound 8a gave poorer syn-
selectivity (entry 1, Table 1). The best selectivity was
Table 1. Hydrogenation of 8 to 9 and 10
Figure 2. Possible stereochemical courses in the hydrogenation
of ketoester 3 and enamine 5.
entry
substrate
yield (%)a
9/10 ratio
1
2
3
4
5
8a
8b
8c
8d
8e
79
78
65
61
71
3.4
5.2
5.7
5.3
7.4
Formation of an intramolecular hydrogen bond as indicated
in conformer A was proposed to explain this stereochemical
outcome. Stimulated by this result, we envisaged that if the
enamine 5 was hydrogenated, then the syn-hydroxylamine
6 would be obtained selectively as a result of similar
intramolecular hydrogen bonding between the δ-hydroxyl
group and the nitrogen atom as illustrated in conformer B.
To explore this possibility, we prepared a series of
enamines 8, as inseparable mixtures of cis and trans isomers,
by the condensation of benzylamine with the δ-hydroxy-â-
ketoesters 7, which were readily available from the aldol
a Isolated yield.
observed when the δ-tert-butyl-substituted enamine 8e was
used as a substrate (entry 5). For 8b and 8c, two substrates
possessing similar bulky groups at the δ-position, almost the
same ratio of syn and anti products was obtained (compare
entries 2-4). This selectivity pattern gave strong support to
the hydrogenation mechanism proposed in Figure 2, where
H2 is delivered to the less hindered face of the alkene in this
internally hydrogen-bonded arrangement.
(7) Lebrun, B.; Braekman, J.-C.; Daloze, D.; Kalushkov, P.; Pasteels, J.
M. Tetrahedron Lett. 2001, 42, 4621.
(8) For our recent results on the synthesis of enantiopure piperidines
using this strategy, see: (a) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503. (b)
Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009.
As the N-benzyl group of 8 could have been undergoing
hydrogenolytic cleavage before the olefin moiety was being
(9) Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.;
Stabler, R. S.; Widler, L. HelV. Chim. Acta 1986, 69, 803.
(10) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 2157.
Org. Lett., Vol. 5, No. 26, 2003
5064

Scheme 2
Scheme 3
reduced, this prompted us to examine the hydrogenation of
enamine 12. Enamine 12 gave syn-product 13 and its
3-epimer in a ratio of 6.7:1. This result indicated that there
was about a 2-fold increase in syn-selectivity compared with
the hydrogenation reaction of 8a, which provided further
evidence for our mechanistic hypothesis. Interestingly, when
12 was hydrogenated in the absence of di-tert-butyl dicar-
bonate, 3-oxopiperidine 14 was isolated as a single isomer,
after the hydrogenated product was treated with 37%
formaldehyde. This result implied that only the syn-δ-
hydroxy-â-amino ester was being formed during the hydro-
genation and that the presence of di-tert-butyl dicarbonate
was altering the diastereoselectivity. On the basis of the
above investigations, a protocol for the first total synthesis
of (3S,4aS,6R,8S)-hyperaspine was developed.11 As illustrated
in Scheme 3, the synthesis started with the preparation of
the two intermediates 15 and 16.
First, treatment of ethyl propiolate with n-BuLi followed
by trapping of the anion with commercially available (S)-
propylene oxide in the presence of boron trifluoride diethyl
etherate afforded alkynoic ester 15.12 In a parallel procedure,
the enantiopure â-amino ester 16 was obtained in 89% yield
by the diastereoselective Michael addition of lithium (S)-N-
benzyl-R-methylbenzylamide13 to (E)-2-nonenoic acid ethyl
ester and subsequent hydrogenolysis. Next, Michael addition
of the â-amino ester 16 to the alkynoic ester 15 was carried
out in DMF at 60-70 °C to provide the enamine 17 in 83%
yield.14 According to 1H NMR analysis and Back’s report15
it was found that this enamine was a mixture of trans and
cis isomers in a ratio of 1:1.6; both isomers were inseparable
by column chromatography.
ature under the action of a catalytic amount of ethanol and
1 equiv of sodium to provide the corresponding â-keto esters,
which were subjected to decarboxylation with sodium
chloride in DMSO.16 A separable mixture of 1 (60% yield)
and 20 (9% yield) was obtained. NOESY studies confirmed
the stereochemistry of 1 by the marked NOE correlation
between H-3 and H-4a that was observed. The difference in
hydrogenation selectivity between 12 and 17 might result
from the influence of the additional ester group in 17.
Reduction of the bicyclic ketone 1 with LS-selectride17 in
THF at -78 °C produced alcohol 21 in 83% yield as a single
isomer. Finally, esterification of 21 with pyrrole 2-carboxylic
acid mediated with triphenylphosphine and diethyl azodi-
Hydrogenation of 17 followed by treatment with 37%
formaldehyde provided the cyclic products 18 and 19 in 77%
combined yield. These two isomers were inseparable by
column chromatography and existed in a ratio of 6.3:1 as
1
determined by H NMR spectroscopy. Dieckmann reaction
of this mixture was carried out in benzene at room temper-
(11) For synthesis of (-)-8-epi-hyperaspine, see: Ma, D.; Zhu, W.
Tetrahedron Lett. 2003, 44, 8609.
(12) Merrer, T. L.; Gravier-Pelletier, C.; Micas-Languin, D.; Mestre, F.;
Dureault, A.; Depezay, J.-C. J. Org. Chem. 1989, 54, 2409.
(13) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
(14) (a) Pu, X.; Ma, D. J. Org. Chem. 2003, 68, 4400. (b) Ma, D.; Pu,
X.; Wang, J. Tetrahedron: Asymmetry 2002, 13, 2257.
(16) Oehlschlager, A. C.; Dodd, D. S. J. Org. Chem. 1992, 57, 2794.
(17) Bardot, V.; Gardette, D.; Gelas-Mialhe, Y.; Gramain, J.; Remuson,
R. Heterocycles 1998, 48, 507.
(15) Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566.
Org. Lett., Vol. 5, No. 26, 2003
5065

carboxylate provided (3S,4aS,6R,8S)-hyperaspine18 in 65%
yield. Its analytical data were identical with those reported.7
In conclusion, we have described a simple and useful
method for preparing syn-δ-hydroxy-â-amino esters. The key
element was an intramolecular hydrogen bond directed
diastereoselective hydrogenation of the δ-hydroxyl-â-ke-
toester-derived enamines. Using this method we have
achieved the first total synthesis of (3S,4aS,6R,8S)-hy-
peraspine in 18% overall yield over nine linear steps. Because
the absolute stereochemistry of natural hyperaspine, as well
as its biological activities, has not yet been determined owing
to the very limited amount from the natural source, our
synthetic protocol should be helpful in addressing these
issues. Further application for the present strategy to the
synthesis of AI-77-B, negamycin, and sperabillin A-D is
in progress and will be reported in due course.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant 20242003), and Science and Technology
Commission of Shanghai Municipality (grant 02JC14032)
for their financial support.
1
(18) Selected data: [R]20 +85.0 (c 0.30, CH3OH); H NMR (CD2Cl2,
D
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 1, 9a-e, 13-
15, and 17-21. This material is available free of charge via
the Internet at http://pubs.acs.org.
300 MHz) δ 9.64 (br s, 1H), 6.96 (m, 1H), 6.87 (m, 1H), 6.25 (m, 1H),
5.10 (m, 1H), 4.77 (d, J ) 10.8 Hz, 1H), 4.22 (d, J ) 10.8 Hz, 1H), 3.61
(m, 1H), 3.38 (m, 1H), 3.16 (m, 1H), 1.86 (m, 1H), 1.67-1.15 (m, 16H),
0.86 (m, 3H); 13C NMR (CD2Cl2, 75 MHz) δ 161.1, 124.0, 123.5, 115.6,
111.0, 81.4, 74.6, 69.5, 56.2, 49.9, 37.3, 37.0, 33.9, 33.1, 33.0, 24.9, 23.4,
22.5, 14.6; IR (KBr) 3313, 1699 cm-1; MS m/z 334 (M+); HRMS calcd
for C19H30N2O3 334.22564 (M+), found 334.22207.
OL036097M
5066
Org. Lett., Vol. 5, No. 26, 2003