Constrained tetramic acids, homostreptopyrrolidine, and their analogues based on unusual intramolecular wittig olefination with phosphorus ylides

Article abstract of DOI:10.1055/s-0030-1260793

The synthesis of bicyclic tetramic acids based on the nonclassical intramolecular Wittig reaction catalyzed by the corresponding phosphonium salt was developed. We have found that such applications proceed smoothly with high yield with N-substituted amino

Full text of DOI:10.1055/s-0030-1260793

LETTER
1631
Constrained Tetramic Acids, Homostreptopyrrolidine, and their Analogues
Based on Unusual Intramolecular Wittig Olefination with Phosphorus Ylides
C
onstrained Tetra
m
n
ic Acids Ba
d
sed on
U
nus
r
ual Intr
a
e
molecular
W
j
ittig Olefina
Ď
tion uriš,a Adam Daïch,*b Dušan Berkeš*a
a
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
Fax +421(2)52968560; E-mail: dusan.berkes@stuba.sk
b
Laboratoire de Chimie, URCOM, EA 3221, INC3M CNRS-FR 3038, UFR des Sciences et Techniques, Université du Havre,
BP: 540, 25 Rue Philipe Lebon, 76058 Le Havre Cedex, France
Fax +33(2)32744391; E-mail: adam.daich@univ-lehavre.fr
Received 21 March 2011
angiogenesis inhibitor.15 These facts attract considerable
interests for synthesis, and consequently new synthetic
methodologies have been reported recently in this line.16
Abstract: The synthesis of bicyclic tetramic acids based on the
‘nonclassical’ intramolecular Wittig reaction catalyzed by the cor-
responding phosphonium salt was developed. We have found that
such applications proceed smoothly with high yield with N-substi-
tuted aminobutanolides when catalyzed with hydrochloride salt of
the starting aminolactones. In addition, a convenient multigram
synthesis of optically pure 4-hydroxy-5-substituted pyrrolidinones,
including homostreptopyrrolidine as methylene homologues of nat-
urally occurring streptopyrrolidine, via two consecutive reduction is
also developed.
The pivotal synthetic intermediates for streptopyrrolidine
and derivatives are considered to be 5-benzyltetramic acid
and corresponding 5-alkyl derivatives. To date, a number
of synthetic approaches to these skeletons have been
developed. Among them, the Lacey–Dieckmann
condensation1 seems to be the useful one and the intramo-
lecular Wittig olefination the most frequently implement-
ed. Although the Dieckmann cyclization is convenient for
the preparation of tetramic acids, it is not completely suit-
able for the synthesis of such compounds with high enan-
tiomeric purity. In fact, the expected optically active
product was accompanied with its epimer in appreciable
amounts (up to 7:3 ratio) due to the epimerization during
the process at the C5-position of the pyrrolidinone nu-
clei.1f,g In addition to these drawbacks in chiral series, the
overall yields of the target compounds are moderate ex-
cept the case in which a ‘lactamic’ nitrogen atom is acy-
lated.14a More recently, Schobert and co-workers reported
Key words: intramolecular Wittig, streptopyrrolidine analogues,
tetramic acid, Wittig olefination, N-debenzylation
(S)-4-Hydroxypyrrolidin-2-one motif 1, which could be
considered as a reduced form of the well-known and im-
portant tetramic acid compound 2 (Figure 1),1 contains
several natural and synthetic products which are associat-
ed with a broad spectrum of pharmacological activity. The
latter could be exemplified with oxiracetam 3, a nootropic
drug for the Alzheimer’s disease2 and N-acylated pyrroli-
din-3-ol derivatives 4 (R = H, OH) with significant HIV
protease inhibition effects.3 This motif also constitutes
important key intermediate for the synthesis, for example,
of pyrrolam A and corresponding hydroxyindolizidines of
type 5,4 pseudo C2-symmetric 1,3-diamino-2-propanols,5
statines,6 dolastatin and its congeners,7 microcolins,8 g-
amino acids (GABAs), g-amino-b-hydroxybutyric acids
(GABOBs),9 and more complex alkaloids such as
lucilactaene10 and UCS1025-A11 with relevant biological
properties. In addition, Geissman–Waiss lactone12 and de-
rivatives as well as pyroglutaminols,13 related to the motif
1, were also used successfully as versatile chiral building
blocks for the synthesis of optically active compounds.
HO
HO
HO
4
3
O
N
5
2
1
O
O
N
H
N
1
H
CONH2
tetramic acid (2)
oxiracetam (3)
HO
HO
HO
*
N
H
O
N
H
N
t-Boc
O
O
N
Of particular interest, streptopyrrolidine (6, Figure 1) syn-
thesized first14 before its isolation as a natural product
from the fermentation of a Streptomyces sp.15 seems to be
displaying significant anti-angiogenesis activity without
accompanying cytotoxicity towards HUVEC cells. It
blocks the capillary tube formation of the cells at the same
potency level such as compound SU11248, a well-known
R
streptopyrrolidine (6)
(1S)-1-hydroxy
(4) R = H, OH
indolizidine (5)
HO
O
*
Ar/Al
O
N
Ar
*
*
H
O
R
N
R
R
7
this work
8
SYNLETT 2011, No. 11, pp 1631–1637
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260793; Art ID: B06411ST
x
x
.x
x
.2
0
1
1
Figure 1 Examples of natural and unnatural active compounds 2–6
containing a 4-hydroxypyrrolidin-2-one motif 1 and our targets 7 and 8.
© Georg Thieme Verlag Stuttgart · New York

1632
A. Ďuriš et al.
LETTER
a highly efficient route to 5-alkyl-tetramates by addition intramolecular Wittig olefination applied successfully to
of the a-amino-esters salts to the cumulated phosphorus the synthesis of several natural lactones.26
ylide (Ph3PC=C=O) either free17 or polystyrene-immobi-
Our strategy is based on the use of an expedient straight-
lized.18 Here, the reaction proceeds via the well-ordered
forward transformation of enantiomerically and diastereo-
domino addition, and the intramolecular Wittig reaction
merically pure 4-aryl-2-aminobutanolides. The latter are
occurs giving unsaturated heterocycles such as tetronates
easily accessible in both enantiomeric forms via crystalli-
zation-induced asymmetric transformation (CIAT) from
and tetramates.19
From these considerations, the commonly called a ‘non- available substrates produced earlier.25 In this context, the
classical’ Wittig olefination20 of stabilized phosphoranes aminobutanolides 9a–h represent the convenient starting
with substituted esters or lactones under neutral or basic chiral synthons for the following short-sequence synthesis
conditions is a very useful transformation mainly in the of the targeted compounds 7 and 8.
chemistry of exo-glycals,21 and especially when applied
intramolecularly. This straightforward transformation has
The first set of reactions was settled starting from known
aminobutanolides 9a–h and phosphorus ylide 10 in tolu-
found numerous applications in the synthesis of tetronic
ene at reflux according to the previously reported classical
acids.22 Tetramic acid derivatives have been targeted in an
conditions (method A).27 As shown in Table 1, prolonged
effective and valuable extention.23
reaction time (2–3 d) was required for the reaction
In the continuation of our programs directed toward the achievement, and the expected bicyclic tetramic acids 7a–
production of new g-lactams24 and g-lactones25 and their h were isolated. However, only low to good yields rang-
use in the synthesis of relevant compounds, we report here ing from 24% up to 77% were obtained (see Table 1, en-
the synthesis of constrained tetramic acids, homostrepto- tries 1–8). We were delighted to observe that side
pyrrolidine, and its analogues starting from chiral 4-sub- products potentially arising from the lactone opening
stituted-2-aminobutanolides based on their Wittig were never observed, but only the tandem amidation–
olefination with phosphorus ylides. A ‘nonclassical’ in- intramolecular Wittig olefination takes place in all cases
tramolecular Wittig reaction constitutes a key step of this to provide enantiopure tetramic acid derivatives 7a–h as
short sequence, which renders ultimately the bicyclic an- the sole reaction products.
alogues of tetramic acids in high yields and stereoselectiv-
ity. This approach complements the tandem O-acylation–
Table 1 Conditions for the Synthesis of Constrained Tetramic Acids 7a–h Using the Tandem Amidation–Intramolecular Wittig Olefination
O
O
Ar
Ar
O
Ph3P
O
Ph3P
O
*
*
*
toluene
*
O
or
+
N
reflux
A, B or C
R
R
NH
O
O
Ph
9a–h
Ph
7a–h
Br
10
11
Entry
g-Lactam product 7
Method Aa
Time, yield (%)
Method Bb
Time, yield (%)
Method Cc
Time, yield (%)
O
Ph
O
N
1
2 d, 36–77
1 h (5 h)d, 93 (93)d
2 h, 94
3 h, 94
3 h, 91
Ph
7a
O
4-MeC6H4
O
2
3
–
8 h, 95
N
Ph
O
7b
4-MeC6H4O
O
3 d, 24–61
1 h, 91
N
Ph
7c
Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York

LETTER
Constrained Tetramic Acids Based on Unusual Intramolecular Wittig Olefination
1633
Table 1 Conditions for the Synthesis of Constrained Tetramic Acids 7a–h Using the Tandem Amidation–Intramolecular Wittig Olefination
(continued)
O
O
Ar
Ar
O
Ph3P
O
Ph3P
O
*
*
*
toluene
*
O
or
+
N
reflux
A, B or C
R
R
NH
O
O
Ph
9a–h
Ph
7a–h
Br
10
11
Entry
g-Lactam product 7
Method Aa
Time, yield (%)
Method Bb
Time, yield (%)
Method Cc
Time, yield (%)
O
Ph
O
N
4
3 d, 24–33
9 h, 75
6 h, 86
4 d, 49
3 h, 95
Ph
7d
O
5
3 d, 57–58
O
N
Ph
7e
O
Ph
O
N
6
7
3 d, 32–59
4 h, 92
4 h, 81
3 h, 93
2 h, 95
Ph
7f
O
O
–
N
Ph
7g
O
8
–
2 h, 93
2 h, 92
O
N
Ph
7h
a Conditions: method A: 2 equiv of ylide 10.
b Conditions: method B: 1.7 equiv of ylide 10, 5 mol% of hydrochloride 9·HCl.
c Conditions: Method C: 1 equiv of 11, 1 equiv of Et3N.
d Conditions: 5 mol% of 11.
It is worth mentioning that during the optimization of the These results led us to test another conditions of method
Wittig olefination reaction, we observed the positive ef- C (Table 1, column 5) using phosphonium salt 11 with the
fect of acid traces on the yield and the rate of the tandem association of triethylamine as a base. Interestingly, under
process. Thus, by using the conditions of method B these conditions the high yields and short reaction times
(Table 1), the catalytic amount of acid being provided in were observed in all examples presented. The lower yield
the form of hydrochloride salt of the starting aminobutan- of the derivative 7d can be explained by the steric crowd-
olides (9a–h·HCl) which was found to be sufficient for the ing. The possible epimerization on the C2-position of
high-yield transformation within several hours (Table 1, butanolides plays a marginal role in all cases using condi-
entries 1–8). Moreover, the same yield (93%) was ob- tions B or C (only traces <1%, HPLC).
tained during the reaction of aminobutanolide 9a with
From these results, the role of salt 11 seems to be crucial
for the high yield of the intramolecular Wittig olefination.
We suppose that the more reactive ester function is prone
phosphorus ylide 10 by adding 5 mol% of the phosphoni-
um salt 11 (Ph3P+CH2CO2Et, Br–).
to react more rapidly in the amidation phase of the reac-
Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York

1634
A. Ďuriš et al.
LETTER
O
tion, and the ylide is used to abstract the proton to form the
ylide intermediate IIa which cyclized directly into the bi-
cyclic product.
Ph
EtOH
O
NH
9a
O
On the basis of our experiments highlighted in Table 2,
which outline the effectiveness of the tandem amidation–
intramolecular Wittig olefination, the catalytic effect of
the hydrochloric salt (9·HCl, entries 6–10) as well as the
effect of the phosphonium salt additive 11 (entries 3 and
4) is very effective. Elsewhere, the results arising from the
neutral and alkaline conditions outlined in the literature
for intramolecular Wittig olefination conducted for relat-
ed compounds18,26 supported our observations also by
their similar high yields. In contrary to our report herein,
acid catalysis in this type of reaction is, in our knowledge,
not mentioned yet. Finally, from our results, we assume
that the mechanistic paradigm of such cyclizations could
start with the formation of the phosphonium salt Ia as the
key intermediate accompanied with ethanol (Scheme 1).
The latter salt, in an acid–base exchange with the ylide
form of phosphorane 10 could lead to amide IIa, which
undergoes an intramolecular Wittig olefination into inter-
mediate IIIa. Ultimately, the departure of the stable tri-
phenylphosphine oxide provides the expected enantiopure
tetramic acid derivative 7a.28
Ph
Ph
O
+
PPh3
amidation
key step
+
Ph3P
N
O
O
Br–
O
11
Ph
O
Br–
Ia
acid–base
exchange
O
–
Ph
Ph3+P
O
O
PPh3
O
O
N
IIa
intramolecular
Wittig olefination
Ph3P
O
Ph
10
O
PPh3
O
O
O
Ph
Ph
O
N
N
– Ph3P
O
IIIa
7a
Ph
Ph
Scheme 1 Plausible catalytic cycle of the tandem reaction amidati-
on–intramolecular Wittig olefination to provide enantiopure tetramic
acid derivatives 7a–h
Having in hand the expected bicyclic tetramic acid deriv-
atives 7a–h with different substitutions in high diastereo-
meric and enantiomeric purities, the multigram synthesis
Table 2 Screening of the Catalytic Action of the Hydrochloric Salt 9b·HCl and the Phosphonium Salt Additive 11 (Ph3P+CH2CO2Et, Br–)
During the Tandem Amidation–Intramolecular Wittig Olefination
Entry
1
Reagent 9b (equiv) 9b·HCl (equiv) Ylide 10 (equiv) Additive 11 (equiv) Solvent
Temp
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
Time (h) Yield (%)
–
1.0
1.0
–
1.0
2.0
–
–
THF
24
35
57
40
80a
81
89
89
80
81
73b
71c
2
–
–
THF
24
3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.7
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
3
4
–
–
3
5
–
0.3
2.0
1.7
1.5
1.2
1.0
2.0
2.0
–
2
6
0.05
0.05
0.05
0.05
0.05
–
1
7
–
1
8
–
2
9
–
3
10
11
12
13
14
–
3
–
12 + 1
d
–
–
24 + 1
–
–
1.0e
1.2e
toluene
toluene
4
3
73
94
–
–
a After 8 h of the reaction, other nonidentified byproducts were appeared.
b The reagent 9b was not consumed totally during the reaction.
c After 12 h of the reaction, only 20% conversion was observed. When 5 mol% of 9b·HCl was added and refluxed for an additional 1 h, the
chemical conversion of the starting 9a was complete, and the expected product was isolated in good yield.
d A conversion of 5% of the starting material was observed after 24 h of the reaction. When 5 mol% of 9b·HCl was added and refluxed for
additional 1 h, other non-dentified byproducts were appeared.
e 1 Equiv of Et3N was added to the reaction mixture.
Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York

LETTER
Constrained Tetramic Acids Based on Unusual Intramolecular Wittig Olefination
1635
of the targeted homostreptopyrrolidine (8a) and its ana- work in this direction is now under investigations in our
logues 8b–e was investigated by using two simple reduc- laboratory, and the results will be published soon in a full
tion steps (Scheme 2). The first one was the catalytic account.
double bond reduction of 7a–h into the constrained re-
duced tetramic acids 12a–h, which proceeds with high
Acknowledgment
yields ranging from 60% up to 93% using ethyl acetate as
a solvent.29,30 Interestingly, the chemoselectivity of the re-
Financial support of this work by the Slovak Grant Agency No. 1/
0629/08 and NMR measurements provided by the Slovak State Pro-
duction reaction was entirely changed when protic solvent
gram Project numbered No.2003SP200280203 are gratefully ac-
knowledged.
instead of aprotic ethyl acetate was used. For this purpose,
using methanol in the otherwise unchanged conditions,
the reduction of tetramic acids 7a–e resulted in the isola-
tion of corresponding 5-arylakyltetramic acids 13a–e in References and Notes
50% up to 65% yield as a main products31 presumably
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O
O
Ar
Ar
(Alk)
*
(Alk)
*
H2, Pd/C, EtOAc
*
*
O
O
N
N
R
2–4 h
R
60–93%
Ph
7a–h
Ph
12a–h
IV
HO
H2, Pd/C
MeOH
4–5 h
Na, NH3(aq)
excess
–78 °C, 1 h
73–93%
50–65%
O
N
14g,h
O
HO
Ar
O
Ar
Alk
*
O
*
O
N
O
N
R
N
H
R
H
Ph
13a–e
Alk = t-Bu, Cy
73%, 83%
8a–e
(3) Courcambeck, J.; Bihel, F.; De Michelis, C.; Quéléver, G.;
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Tetrahedron 1993, 49, 1547.
Scheme 2 Synthesis of tetramic acid derivatives 12a–h, 13a–e, and
14g,h and homostreptopyrrolidine reduced analogues 8a–e
(6) (a) Gennari, C.; Moresca, D.; Vulpetti, A.; Pain, G.
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To achieve our synthesis, the conditions of straightfor-
ward scalable debenzylation process were developed. In
the case of aryl-substituted derivatives 12a–e, an excess
of sodium in a mixture of liquid ammonia and THF seems
to be the best formulation to both N- and O-debenzylation
in a single operation (Scheme 2). Under these conditions,
the homostreptopyrrolidine analogues 8a–e were isolated
in good to high yield (73% up to 93%) and excellent dia-
stereomeric and enantiomeric purities.33 By using the
same protocol, the alkyl derivatives 12g,h yielded the cor-
responding bicyclic enantiopure furo[3,2-b]pyrrol-5-one
derivatives 14g,h, which resulted from the sole N-deben-
zylation process.34
(10) Coleman, R. S.; Walczak, M. C.; Campbell, E. L. J. Am.
Chem. Soc. 2005, 127, 16038.
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In summary, we have developed a simple, efficient, and
multigram protocol for the synthesis of optically pure con-
strained tetramic acids, homostreptopyrrolidine, and their
analogues based on unusual intramolecular Wittig olefi-
nation with phosphorus ylides. The short-step syntheses
were performed using easily available chiral starting ma-
terials and inexpensive reagents. Finally, since both enan-
tiomers of phenylethylamine are readily available, both
antipodes of the final compounds could be obtained. The
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Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York

1636
A. Ďuriš et al.
LETTER
(16) (a) Xiang, S.-H.; Yuan, H.-Q.; Huang, P.-Q. Tetrahedron:
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127.6, 127.1, 126.2 (ArC), 91.4 (C-6), 90.8 (C-2), 59.6 (C-
1¢), 48.7 (C-3a), 41.3 (C-3), 18.7 (C-2¢). Anal. Calcd for
C20H19NO2 (305.14): C, 78.66; H, 6.27; N, 4.59. Found: C,
80.00; H, 6.51; N, 4.66.
Method C
To a mixture of lactone 9a (0.391 g, 1.39 mmol) in dry
toluene (15 mL) were added subsequently the additive 11
(0.718 g, 1.67 mmol) and Et3N (0.141 g, 1.39 mmol). The
reaction mixture was refluxed under argon atmosphere for 2
h. The white precipitate deposited was filtered off and
washed with toluene. Filtrates were then evaporated under
reduced pressure, and the residue was purified by chroma-
tography on silica gel column (hexane–EtOAc = 3:1) to
provide the constrained tetramic acid 7a (0.401 g, 1.31
mmol, 94%) as a white solid.
(19) Schobert, R. Naturwissenschaften 2007, 94, 1.
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(22) (a) Murphy, P. J.; Dennison, S. T. Tetrahedron 1993, 49,
6695. (b) Cagnolini, C.; Ferri, M.; Jones, P. R.; Murphy,
P. J.; Ayres, B.; Cox, B. Tetrahedron 1997, 53, 4815.
(c) Bittner, C.; Burgo, A.; Murphy, P. J.; Sung, C. H.;
Thornhill, A. J. Tetrahedron Lett. 1999, 40, 3455. (d)Heys,
L.; Murphy, P. J.; Coles, S. J.; Gelbrich, T.; Hursthouse,
M. B. Tetrahedron Lett. 1999, 40, 7151. (e) Evans, L. A.;
Griffiths, K. E.; Guthmann, H.; Murphy, P. J. Tetrahedron
Lett. 2002, 43, 299.
(23) (a) Brennan, J.; Murphy, P. J. Tetrahedron Lett. 1988, 29,
2063. (b) Reddy, G. V.; Rao, G. V.; Iyengar, D. S.
Tetrahedron Lett. 1999, 40, 775.
(24) (a) Comesse, S.; Sanselme, M.; Daïch, A. J. Org. Chem.
2008, 73, 5566. (b) Oukli, N.; Comesse, S.; Chafi, N.;
Oulyadi, H.; Daïch, A. Tetrahedron Lett. 2009, 50, 1459.
(c) Allous, I.; Comesse, S.; Berkeš, D.; Alkyat, A.; Daïch, A.
Tetrahedron Lett. 2009, 50, 4411. (d) Saber, M.; Comesse,
S.; Dalla, V.; Daïch, A.; Sanselme, M.; Netchitaïlo, P.
Synlett 2010, 2197.
(25) (a) Kolarovič, A.; Berkeš, D.; Baran, P.; Považanec, F.
Tetrahedron Lett. 2005, 46, 975. (b) Berkeš, D.; Kolarovič,
A.; Manduch, R.; Baran, P.; Považanec, F. Tetrahedron:
Asymmetry 2005, 16, 1927. (c) Berkeš, D.; Jakubec, P.;
Winklerová, D.; Považanec, F.; Daïch, A. Org. Biomol.
Chem. 2007, 5, 121.
(26) (a) Ohtsuki, K.; Matsuo, K.; Yoshikawa, T.; Moriya, C.;
Yokotani-Tomita, K.; Shishido, K.; Shindo, M. Org. Lett.
2008, 10, 1247. (b) Matsuo, K.; Ohtsuki, K.; Yoshikawa, T.;
Yokotani-Tomita, K.; Shindo, M. Tetrahedron 2010, 66,
8407. (c) Matsuo, K.; Shindo, M. Org. Lett. 2010, 12, 5346.
(27) For an example, see: Schobert, R.; Siegfried, S.; Gordon,
G. J. J. Chem. Soc., Perkin Trans. 1 2001, 2393.
(29) General Procedure for the Reduction of Tetramic Acids
7a–h into Corresponding Compounds 12a–h
To the bicyclic tetramate 7a (2.33 g, 7.63 mmol) dissolved
in EtOAc (190 mL) was added catalyst (0.47 g, 10 mol% Pd/
C), and the resultant suspension was then vigorously stirred
under an hydrogen atmosphere for 2 h. After the reaction
was complete, the catalyst was filtered off and the product
purified by flash chromatography on silica gel column
(hexane–EtOAc = 4:1) to provide the sat. bicyclic lactam
20
12a (1.82 g, 77%); mp 52–54 °C (Et2O–heptane); [a]D
–69.3 (c 0.23, CHCl3). IR (KBr): nmax = 3064, 2929 (CH),
1661 (C=O), 1056 (COC) cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.15–7.32 (m, 10 H, ArH), 5.53 (q, 1 H, J = 7.3
Hz, H-1¢), 4.74 (dd, 1 H, J = 5.2, 10.5 Hz, H-2), 4.50 (td, 1
H, J = 5.5, 7.5 Hz, H-7), 3.86 (dd, 1 H, J = 7.4, 14.2 Hz, H-
3a), 2.78 (d, 2 H, J = 5.4 Hz, H-6), 2.51 (ddd, 1 H, J = 5.3,
7.5, 12.6 Hz, H-3A), 1.84 (ddd, 1 H, J = 6.6, 10.6, 12.4 Hz,
H-3B), 1.53 (d, 3 H, J = 7.3 Hz, H-2¢). 13C NMR (75 MHz,
CDCl3): d = 172.6 (C-5), 140.0, 139.4, 128.7, 128.6, 128.0,
127.9, 127.5, 125.8 (ArC), 81.7 (C-2), 74.9 (C-7), 61.2 (C-
1¢), 50.4 (C-3a), 43.8 (C-6), 38.3 (C-3), 17.7 (C-2¢). Anal.
Calcd for C20H21NO2 (307.16): C, 78.15; H, 6.89; N, 4.56.
Found: C, 78.23; H, 7.04; N, 4.54.
(30) Niwa, H.; Okamoto, O.; Miyachi, Y.; Uosaki, Y.; Yamada,
K. J. Org. Chem. 1987, 52, 2941.
(31) General Procedure for the Reduction of Bicycles 7a–h
into Corresponding Tetramic Acids 13a–h
To the bicyclic tetramate 7a (1.013 g, 3.3 mmol) dissolved
in MeOH (50 mL) was added catalyst (0.203 g, 10 mol% Pd/
C), and the resultant suspension was then vigorously stirred
under an hydrogen atmosphere for 4 h. After the reaction
was complete, the catalyst was filtered off and the product
purified by flash chromatography on silica gel column
(hexane–EtOAc = 4:1) to provide the 5-arylalkyltetramic
acid 13a (0.648 g, 64%) as colorless oil; [a]D20 11 (c 0.42,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.01–7.35 (m, 10
H, ArH), 5.70 (q, 1 H, J = 7.3 Hz, H-1¢¢), 3.58 (dd, 1 H,
J = 2.9, 6.7 Hz, H-5), 3.05 (s, 1 H, H-3), 2.68 (ddd, 2 H,
J = 4.1, 11.4, 13.7 Hz, H-2¢A), 2.38 (ddd, 1 H, J = 6.6, 11.3,
13.4 Hz, H-2¢B), 2.13 (dddd, 2 H, J = 3.1, 6.6, 11.2, 14.3 Hz,
H-1¢A), 1.80–1.92 (m, 1 H, H-1¢B), 1.73 (d, 3 H, J = 7.3 Hz,
H-2¢¢). 13C NMR (75 MHz, CDCl3): d = 207.0 (C-4), 169.2
(C-2), 140.0, 138.0, 128.9, 128.6, 128.3, 128.2, 127.6, 126.4
(ArC); 65.6 (C-5), 50.9 (C-1¢¢), 41.8 (C-3), 33.3 (C-2¢), 29.5
(C-1¢), 18.4 (C-2¢¢).
(28) General Procedure for ‘Nonclassical’ Wittig Reaction –
Method B
To a mixture of lactone 9a (2.19 g, 7.78 mmol) in dry toluene
(120 mL) were added subsequently the catalyst 9a·HCl
(0.124 g, 0.39 mmol) and the ylide 10 (4.608 g, 13.23
mmol). The reaction mixture was refluxed under argon
atmosphere for 1 h. The solvent was then evaporated under
reduced pressure, and the residue was purified by chroma-
tography on silica gel column (hexane–EtOAc = 3:1) to
provide the constrained tetramic acid 7a (2.33 g, 7.63 mmol,
93%) as a white solid; mp 111–113 °C (Et2O–heptane),
[a]D20 205.7 (c 0.32, CHCl3). IR (KBr): nmax = 3105, 2983
(CH), 1668 (C=O), 1644 (C=C), 1185 (COC) cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.26–7.41 (m, 10 H, ArH), 5.55–
5.65 (m, 1 H, H-1¢, 1 H, H-2), 5.06 (s, 1 H, H-6), 4.02 (ddd,
1 H, J = 1.0, 6.6, 11.7 Hz, H-3a), 2.66 (ddd, 1 H, J = 4.4, 6.5,
10.9 Hz, H-3A), 1.93 (q, 1 H, J = 22.9 Hz, H-3B), 1.56 (d, 3
H, J = 7.3 Hz, H-2¢). 13C NMR (75 MHz, CDCl3): d = 178.7
(C-6a), 175.6 (C-5), 140.9, 137.7, 129.2, 128.9, 128.8,
(32) For a recent paper stating on this equilibrium, see: Storgaard,
M.; Dörwald, F. Z.; Peschke, B.; Tanner, D. J. Org. Chem.
2009, 74, 5032; and the references cited therein.
(33) General Procedure for the Debenzylation Process
A solution of 12a (1.591 g, 5.16 mmol) in dry THF (30 mL)
was added to liquid NH3 (40 mL) at –78 °C. Small pieces of
Na (15–20 equiv) were added until the reaction mixture
Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York

LETTER
Constrained Tetramic Acids Based on Unusual Intramolecular Wittig Olefination
1637
remained blue, and the mixture was stirred at –78 °C. After
MHz, CDCl3): d = 176.8 (C-2), 141.1, 128.5, 128.3, 126.1
(ArC), 68.6 (C-4), 59.2 (C-5), 41.0 (C-3), 32.3 (C-2¢), 30.4
(C-1¢).
30 min of the reaction, the solution was then quenched with
aq NH4Cl. The residual ammonia was evaporated, and the
mixture was extracted three times with Et2O. The combined
organic layers were dried over Na2SO4, filtered, and
(34) Synthesis of Products 14
By using same procedure such as from the substrate 12g as
starting material, the expected (2R,3aS,7S)-2-tert-butyl-
hexahydrofuro[3,2b]-pyrrol-5-one (14g) was isolated in
73% yield; mp 145–147 °C (Et2O); [a]D20 13.5 (c 0.1,
MeOH). 1H NMR (300 MHz, CDCl3): d = 4.74 (t, 1 H,
J = 5.6 Hz, H-7), 4.31 (t, 1 H, J = 5.5 Hz, H-3a), 3.78 (dd, 1
H, J = 4.8, 10.9 Hz, H-2), 2.40–2.68 (m, 2 H, H-6), 1.86 (dd,
1 H, J = 4.8, 13.2 Hz, H-3A), 1.40–1.49 (m, 1 H, H-3B), 0.88
(s, 9 H, H-2¢¢). 13C NMR (75 MHz, CDCl3): d = 177.7 (C-5),
85.5 (C-2), 59.6 (C-7), 51.1 (C-3a), 38.9 (C-6), 34.1 (C-3),
32.9 (C-1¢¢), 25.9 (C-2¢¢).
evaporated in vacuo. The residue was purified by column
chromatography on silica gel column (MeOH–EtOAc =
1:10) to provide ultimately (4S,5S)-4-hydroxy-5-phenyl-
ethylpyrrolidin-2-one (8a) in yield 80% (0.85 g); mp 104–
106 °C (Et2O); [a]D20 –18.4 (c 0.114, MeOH). 1H NMR (300
MHz, CDCl3): d = 7.14–7.30 (m, 5 H, H-Ar), 4.25 (t,
1 H, J = 4.3 Hz, H-4), 3.52 (dd, 1 H, J = 7.0, 11.7 Hz, H-5),
2.67 (t, 2 H, J = 7.2 Hz, H-2¢), 2.53 (dd, 1 H, J = 5.8, 17.2
Hz, H-3A), 2.28 (dd, 1 H, J = 1.4, 17.2 Hz, H-3B), 1.91–2.05
(m, 1 H, H-1¢A), 1.80–1.90 (m, 1 H, H-1¢B). 13C NMR (75
Synlett 2011, No. 11, 1631–1637 © Thieme Stuttgart · New York