Influence of steric parameters on the synthesis of tetramates from α-amino-β-alkoxy-esters and Ph3PCCO

Article abstract of DOI:10.1016/j.tet.2011.10.099

α-Aminoesters react with Ph₃PCCO in a domino addition-Wittig cyclization sequence affording enantiomerically pure tetramates. In the case of β-oxo functionalized α-aminoesters, e.g., esters of serine, threonine or β-hydroxyornithine the yields of this reaction depend heavily on the bulkiness of the β-OR group and on the configuration of β-carbon atom C-3. Smaller residues and 2R/3R-configured aminoesters give better yields. The alkoxycarbonyl group of the ester moiety and the residue on the N-atom are less important. These findings can be accounted for by assuming an early puckered transition state for the intramolecular ring-closing Wittig reaction. The addition of sub-stoichiometric amounts of benzoic acid or N-hydroxysuccinimide (for acid-sensitive compounds) is advantageous in some cases as it accelerates the formation of the intermediate amide ylides.

Full text of DOI:10.1016/j.tet.2011.10.099

Tetrahedron 68 (2012) 697e704
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Influence of steric parameters on the synthesis of tetramates from a-amino-
b-alkoxy-esters and Ph3PCCO
,
a,
*
Inga Loke a, Natja Park a, Karl Kempf b, Carsten Jagusch b, Rainer Schobert b , Sabine Laschat
*
a
€
€
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
b
€
€
€
Lehrstuhl fur Organische Chemie, Universitat Bayreuth, Universitatsstr. 30, D-95440 Bayreuth, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Aminoesters react with Ph3PCCO in a domino additioneWittig cyclization sequence affording enan-
tiomerically pure tetramates. In the case of -oxo functionalized -aminoesters, e.g., esters of serine,
threonine or -hydroxyornithine the yields of this reaction depend heavily on the bulkiness of the -OR
group and on the configuration of -carbon atom C-3. Smaller residues and 2R/3R-configured amino-
Received 9 September 2011
Received in revised form 25 October 2011
Accepted 27 October 2011
b
a
b
b
b
Available online 4 November 2011
esters give better yields. The alkoxycarbonyl group of the ester moiety and the residue on the N-atom are
less important. These findings can be accounted for by assuming an early puckered transition state for
the intramolecular ring-closing Wittig reaction. The addition of sub-stoichiometric amounts of benzoic
acid or N-hydroxysuccinimide (for acid-sensitive compounds) is advantageous in some cases as it ac-
celerates the formation of the intermediate amide ylides.
Keywords:
Amino acids
Tetramic acids
Phosphorus ylides
Wittig olefination
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Tetramic acids, i.e., pyrrolidine-2,4-diones 1 are frequently
found in natural products of both terrestrial and marine origin and
are often associated with antibiotic, anthelminthic, cytotoxic or
other sorts of biological activities. This and their challenging
structures and chemistry have spawned a steadily increasing
number of synthetic and biological studies over the last decade.1
Fig. 1 depicts a few naturally occurring bioactive 3-acyltetramic
acids: the marine sponge-bacteria metabolite melophlin A (2),2
reutericyclin (3) produced by Lactobacillus reuteri,3 the fungal
herbicides macrocidin A (4a) and B (4b)4 and the sponge-derived
cylindramide 5.5 Recently, the pivotal role of tetramic acids de-
rived from 3-oxo-N-acylhomoserines such as 6 for bacterial quo-
rum sensing was uncovered and might be exploited for the
development of conceptually novel antibiotics.6
Several routes are known for the synthesis of tetramic acids. Early
protocols were developed by Lacey7a who cyclized under basic Die-
ckmann conditions N-(
a
b-ketoacetyl)-a-aminoesters asobtainedfrom
-amino acids and diketene, and by Jouin et al.7b who gained tetramic
acids or directly 3-acyltetramic acids from reaction of amino acids
with Meldrum’s acid. More recent approaches to enantiopure tetra-
mic acids include the UgieDieckmann reaction of isocyanides,8 the
Fig. 1. Tetramic acid natural products.
Dieckmann cyclization of N-acyloxazolidines,9 the domino amide
* Corresponding authors. Tel.: þ49 921 552680; fax: þ49 921 552671 (R.S.); tel.:
þ49 711 685 64565; fax: þ49 711 685 64285 (S.L.); e-mail addresses: rain-
formation/Dieckmann condensation,10 the palladium-catalyzed
a-
arylation of pre-formed tetramic acids,11 the transannular rear-
rangement of diketopiperazines,12 the condensation of amino acid
er.schobert@uni-bayreuth.de(R.
(S. Laschat).
Schobert),
sabine.laschat@oc.uni-stuttgart.de
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.099

698
I. Loke et al. / Tetrahedron 68 (2012) 697e704
derivatives with malonates13 or diketene14 followed by Dieckmann
condensation and the ring expansion of 2-azetidinone-tethered
allenols.15 More pertinent to the target compounds of the current
paper are studies towards Dysidin, which also encompass an access to
5-(1-alkoxy)alkyltetramic acids.16 Also, Hunter and Thomson re-
protecting group on the b-oxygen atom on the readiness of the
cyclising olefination step and thus on the likelihood of competing
processes such as elimination of the corresponding silanol to give
5-exo-alkylidenetetramates, or even hydrolysis of the intermediate
amide ylides 11. Therefore, we investigated the b-substituent effect
ported the preparation of 5-(a-hydroxyalkyl)tetramic acids using
in cyclizations of various amino esters with ylide 10 in more detail.
a trimethylsilyl mediated aldol reaction of pyrrolinone with an alde-
hyde.17 Finally, Yodaetal.18 disclosedasyntheticroutetosuchsystems
by condensation of threonine derivatives with Meldrum’s acid.
Based on our previous experience with the efficient synthesis of
tetramates from
a-aminoesters and the cumulated phosphorus
ylide triphenylphosphoranylideneketene, Ph3PCCO 10,3e,19e21 we
planned to extend this methodology to tetramic acids derived from
b
-hydroxyornithine, which are subunits of naturally occurring
macrocyclic lactams such as cylindramide 5 or aburatubolactam.22
So far, 3-acyl-5-(1-alkoxy)alkyltetramic acids have been built up
mostly by the LaceyeDieckmann condensation utilizing
esters and Meldrum’s acid as exemplified for compound 9 (Scheme
1). We expected the reaction of -oxo functionalized -aminoesters
a-amino-
b
a
7 with ylide 10 to give the corresponding tetramates 12 by the usual
domino sequence of amine addition to the C]C bond of 10 fol-
lowed by an intramolecular Wittig olefination of the intermediate
amide ylide 11. The tetramates can be converted to the tetramic
acids, which, in turn, are amenable to acylation at C-3 by any of the
established methods.
Scheme 2.
2. Results and discussion
a
-Aminoesters 15 with residues of varying bulkiness on the
carboxylate (R2), the N-atom (R3) and the -C-atom (R4), were
reacted with ylide 10 under different conditions. Variations in R4
comprised -alkoxy- and -silyloxy substituted ones (Scheme 3,
a
b
b
Table 1). For comparison entries 1e5 and 8,9 were taken from lit-
erature and included.3e,20 The glycine and alanine esters 15aed
afforded the respective tetramates 16aed in good to excellent
yields (entries 1e4), regardless of reaction conditions and of the
bulkiness of the residues R2 (Me, t-Bu or Bn) and R3 (H or Me). In
contrast, a-aminoesters 15eei with sterically encumbered b-car-
bon atoms prepared from leucine, isoleucine, valine, phenylalanine
or tyrosine esters when reacted with 10 gave the corresponding
tetramates 16eei in merely moderate to fair yields (entries 5e9).
The analogous reactions of benzyl
b-t-BuO- and b-O-silyl-
substituted serinates furnished the product tetramates 16jem in
yields ranging from 15% to ca. 50% with the O-t-Bu-protected
benzyl ester 15j giving the best result (entries 10e13). In the case of
the benzyl serinate 15m O-protected with an acid labile TES group,
the reaction with ylide 10 in THF in the presence of 0.2 equiv
benzoic acid (method A) afforded only 15% of product 16m along-
side 22% of the corresponding elimination product 16x, benzyl 5-
methylidenetetramate and 2% of the starting amino ester, while
28% of 16m alongside 41% of elimination product 16x and 7% of the
amino ester were obtained in toluene in the absence of benzoic acid
(entry 14, method C). However, for less sensitive O-protecting
groups the addition of benzoic acid is advisable since accelerating
the amide ylide formation and thus the overall reaction. Alongside
the desired tetramates and the corresponding elimination products
no other products could be isolated.
Scheme 1.
In
preliminary
experiments
O-TBS
protected
3-
hydroxyornithine benzyl ester 7a was treated with 10 in the pres-
ence of 0.05 equiv of benzoic acid in THF (Scheme 2). The addition
of benzoic acid had been previously found to accelerate the first
step of the domino process, the addition of the amino group onto
the C]C bond of ylide 10.3e However, in the case of 7a no product
tetramate 12a was formed. Instead, the N-acetylated hydrox-
yornithine ester 14a could be isolated in 29% after column chro-
matography, presumably arising from hydrolysis of the
intermediate amide ylide 11. When the O-TIPS- and O-TES protected
hydroxyornithinates 7b and 7c were reacted under similar condi-
tions, the amount of N-acetamide 14b and 14c dropped to 6% and
7%, respectively, and 25% or 24% of the dehydration product 13 were
obtained. These findings demonstrate a distinct influence of the
Scheme 3.

I. Loke et al. / Tetrahedron 68 (2012) 697e704
699
Table 1
consumption of starting ester 17d was achieved when 0.1 equiv of
N-hydroxysuccinimide (NHS) was added and the reaction was
carried out in refluxing toluene. In contrast, the same reaction
with 0.3 equiv of NHS and 0.1 equiv of N,N-dimethylaminopyr-
idine added afforded 50% of 18d aside 33% of residual 17d. For
residues R1 other than TIPS the addition of NHS failed to produce
higher yields of the corresponding tetramates. Interestingly, the
addition of up to 0.3 equiv of HOBt, also customarily used to
generate ‘active esters’, gave mainly elimination product 18x and
very little tetramate 18d when reacted in toluene, presumably
due to the reluctance of the ‘active ester ylide’ formed by reaction
of ylide 10 with HOBt to react with the aminoester 17d. When set
in THF and with 0.3 equiv of HOBt added, the reaction afforded
44% of the desired product 18d as well as 46% of residual 17d. The
presence of a methyl group at the N-atom as in 17e (entry 5)
makes little difference in terms of yields and reactivity, nor does
exchanging the TIPS for a TES group as in 17f (entry 6). While the
Conversion of a
-aminoesters 15 to tetramates 16a
Entry
15
R2
R3
R4
Method
16
Yield (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Bn
H
Me
H
Me
H
H
H
H
Me
Me
i-Bu
i-Pr
A
B
B
B
C
A
A
A
A
A
A
A
A
C
a
b
c
d
e
f
g
h
i
j
k
l
m
m
83b
92b
84b
96b
45b
45
t-Bu
Me
t-Bu
Bn
Bn
g
h
i
j
k
l
Me
Bn
allyl
Bn
Bn
Bn
Me
H
H
H
H
H
H
H
s-Bu
Bn
60
52b
40b
47
9
4-HO-C6H4CH2
CH2Ot-Bu
CH2OTIPS
CH2OTBS
CH2OTES
CH2OTES
10
11
12
13
14
38
20
m
m
Bn
Bn
15c
28c
a
Reaction conditions: method A: 1.1 equiv 10, 0.2 equiv PhCO2H, THF, reflux,
18 h; method B: 1.0 equiv 10, 0.2 equiv PhCO2H, toluene, reflux, 18 h; method C:
1.1 equiv 10, toluene, reflux, 18 h.
threoninate 17g bearing a small b-methoxy group, which is also
b
Data are taken from Ref. 3e,20.
Alongside elimination product 16x
a poor leaving group gave rise to 82% of product tetramate 18g,
the corresponding 3S-diastereoisomer (‘allo-threoninate’) 17h
gave a miserable 8% of tetramate 18h. Interestingly, a similar
discrepancy was found for the yields of the 3R- and 3S-configured
benzyl tetramates bearing bigger TIPS- or TES-residues R1, i.e., for
the couples 18d/i and 18f/j. As a rule, the 3S-configured isomers
having the substituents at C-2/C-3 in anti-configuration gave
distinctly lower yields.
Finally, ornithine derivative 19 and ylide 10 were reacted under
standard conditions (methods B or C) to leave the tetramate 20 in
77% and 63% yield, respectively. This shows that the length of the
side chain at C-3 is not crucial (Scheme 5, Table 3, entries 1 and 2).
c
.
Next, a series of threonine derivatives 17 was submitted to the
domino additioneWittig cyclization reaction with ylide 10 under
the optimised conditions of method C to give the O-protected tet-
ramates 18 (Scheme 4, Table 2). Whereas benzyl
nate 17a afforded 59% of 18a, the yield decreased to 34% for the
b
-t-BuO threoni-
-O-
b
benzyl threoninates 17b. The similarity of the yields of 18b and 18c
Based on these results, b-hydroxy ornithinates 7 were once more
shows that the size of the residue R2 is less important. For the
reacted with 10 (Scheme 5, Table 3, entries 3e5). As expected, in the
absence of benzoic acid (method C) the tetramates 12bed were
obtained in yields ranging from 13% to 27% and no elimination
benzyl b-OTIPS threoninate 17d employing a slight excess of 10,
tetramate 18d was obtained in 46% yield.
product was formed. This confirms that a bulky b-group in the a-
aminoester is detrimental to the yield of the corresponding product
tetramate especially for an anti-configuration of C-2/C-3 and large
groups R1 such as benzyl, e.g., in 7d.
Scheme 4.
Table 2
Conversion of threonine esters 17 to O-protected tetramates 18a
Entry
17
Configuration
R1
R2
R3
Method
18
Yield (%)
at C-3
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
t-Bu
Bn
Bn
TIPS
TIPS
TES
Me
Me
TIPS
TES
Bn
Bn
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
Me
H
Me
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
a
b
c
d
e
f
g
h
i
59
34
38
46b
55
39
82
8
Scheme 5.
17
13
10
j
j
Table 3
a
Reaction conditions: method C: 1.1 equiv 10, toluene, reflux, 18 h.
Alongside elimination product 18x
Tetramates 20 and 12 from ornithine esters 19 and 7a
b
Entry
Ester
R1
Method
Tetramate
Yield (%)
1
2
3
4
5
19
19
7bb
7c
d
C
B
C
C
C
20
20
63
77
27
19
13c
.
d
TIPS
TES
Bn
12bb
12c
12d
7d
Further experiments showed that the addition of benzoic acid
led to elimination only upon heating in toluene but not in THF, yet
did not increase the yields. In case of -OTIPS threoninate an
increase in yield of 18d to 63% with virtually complete
a
Reaction conditions: method B: 1.0 equiv 10, 0.2 equiv PhCO2H, toluene, reflux,
18 h; method C: 1.1 equiv 10, toluene, reflux, 18 h.
b
b
A diastereomeric mixture of 2:1.
In addition 17% of the N-acetamide 14d was isolated.
c

700
I. Loke et al. / Tetrahedron 68 (2012) 697e704
The above results suggest that the intramolecular Wittig olefi-
4. Experimental
4.1. General
nation of the intermediate amide ylide 11 proceeds via an early,
puckered, reactant-like transition state in which the repulsion be-
tween the PPh3 group and the largest residue on the carbonyl
carbon atom, i.e., C-2, is decisive for the geometry.23 In this case, the
residues OR1 and OR2 get close to each other and the rotatability
around the C2eC3 bond is restricted. Such a sterically congested
transition state should occur whenever C-3 bears a bulky group OR1
and is S-configured (Scheme 6). It should thus lead to low yields of
product tetramates 12. This mechanistic rationale also rules out the
involvement of stabilising hydrogen bridges C2eNeHeOR1 be-
tween the alkoxy residue OR1 and the amide nitrogen. This is in line
with the finding that otherwise identical tetramates differing only
in NeMe versus NeH substitution such as 18b/c or 18d/e (Table 2)
were obtained in similar yields.
€
Melting points (uncorrected) were determined on a Buchi 510
melting point apparatus. Optical rotations were determined with
a PerkineElmer 241 LC polarimeter. IR spectra: Bruker Vektor 22
FT-IR spectrometer/PerkinElmer Spectrum 100 ATR. Mass spectra:
Finnigan MAT 95, Varian MAT 711 and Bruker Daltonics micrO-
TOF_Q spectrometers. NMR spectra: Bruker ARX 300 and Bruker
ARX 500 spectrometers. The spectra were recorded with TMS as an
internal standard. 13C NMR multiplicities were determined by
DEPT135 experiments. Signals with
*
denote the minor di-
astereomer. Assignments were done by using 1He1H-COSY,
1He13C-correlation and NOESY experiments. Column chromatog-
raphy: Fluka silica gel 60 (40e63 mm). All syntheses were per-
formed under nitrogen or argon using standard Schlenk technique.
4.2. Synthesis and characterization
4.2.1. General procedure. The
a-aminoester was dissolved in the
indicated solvent and the additives (Ph3PCCO 10, PhCO2H) were
added. The solution was stirred under the given conditions. After
cooling to rt the solvent was evaporated and the crude product was
purified.
4.2.2. tert-Butyl
pyrrol-2-yl)-3-((triisopropylsilyl)oxy)propyl)carbamate (12b). From
7b [18.0 mg, 36.8 mol, diastereomeric mixture of 2:1 (see
((S)-3-((S)-3-(benzyloxy)-5-oxo-2,5-dihydro-1H-
m
Supplementary data)]; solvent: toluene (3 mL), additives: Ph3PCCO
10 (1.1 equiv); conditions: reflux for 18 h; purification: flash
chromatography (EtOAc). Product: 12b (5.00 mg, 9.91
m
mol, 27%)
20
with a diastereomeric ratio of 2:1. Rf¼0.70 (EtOAc). [
1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3):
CH(CH3)2, CH(CH3)2], 1.42 [s, 18H, C(CH3)3, C(CH3)3
4H, 20-H, 20-H ), 3.06e3.26 (m, 4H, 30-H, 30-H
), 4.15e4.20 (m, 1H,
10-H), 4.24e4.28 (m, 1H, 10-H
), 4.30 (d, J¼3.2 Hz, 1H, 5-H), 4.36 (d,
J¼3.2 Hz, 1H, 5-H ), 4.52 (br, NH, NH ), 4.93e5.03 (m, 4H, CH2Ph,
CH2Ph ), 5.106 (s, 1H, 3-H), 5.114 (s, 1H, 3-H ), 5.55 (s, 1H, 1-H), 5.56
(s, 1H, 1-H ), 7.32e7.44 (m, 10H, Ar, Ar
) ppm. 13C NMR (125 MHz,
CDCl3): ], 17.71, 17.74, 18.1
¼12.6, 12.8 [CH(CH3)2, CH(CH3)2
[CH(CH3)2, CH(CH3)2], 28.4 [C(CH3)3, C(CH3)3 ),
], 30.6 (C-20, C-20
37.7 (C-30, C-30 ), 70.5 (C-10, C-10
), 62.8 (C-5), 62.9 (C-5 ), 73.4
(CH2Ph, CH2Ph ), 79.1 [C(CH3)3, C(CH3)3], 96.31 (C-3), 96.33 (C-3 ),
127.92, 127.94, 128.8, 128.9 (o-C, m-C, p-C, o-C , m-C , p-C ), 134.5
), 173.4 (C-4, C-4 ), 174.0 (C-2, C-
a
]
D
¼ꢀ34.7 (c
d
¼0.95e1.11 [m, 42H,
*
*
], 1.52e1.61 (m,
Scheme 6.
*
*
*
The mechanism also explains the conservation of the stereo-
genic centres at C-2/C-3 as ascertained by NMR spectroscopy. Since
no more than one stereoisomer were observed and a simultaneous
inversion of both centres C-2 and C-3 can be excluded the reaction
is assumed to proceed stereoselectively.
*
*
*
*
*
*
d
*
*
*
*
*
*
*
3. Conclusion
*
*
*
*
*
*
We have studied the domino additioneWittig cyclization re-
action between the cumulated phosphorus ylide Ph3PCCO (10) and
(i-C, i-C
*
), 155.7 (NHCOO, NHCOO
*
*
2
*
) ppm. FTIR (ATR): nmax/cmꢀ1¼3270, 2927, 2866, 1690, 1620,
a series of
a
-aminoesters with different substituents in the
b
-po-
1500, 1456, 1365, 1337, 1250, 1173, 1104, 1012, 882, 806, 738, 697.
MS (ESI): m/z¼541.3 [MþNa]þ, 519.3 [MþH]þ, 463.3
[MþHꢀC4H9]þ, 419.3 [MþHꢀC5H9O2]þ, 395.7, 360.9, 285.2, 245.1,
176.3, 154.4. HRMS (ESI): calcd for C28H47N2O5Siþ 519.3249, found
519.3260 [MþH]þ.
sition. Sterically bulky or large alkoxy or silyloxy residues at the
b
-
carbon atom C-3 give rise to relatively low chemical yields, espe-
cially if C-3 is S-configured. Smaller residues give fair to good yields.
The ester alkoxycarbonyl group and the residue on the N-atom are
of little influence. We assume an early, puckered, reactant-like
transition state for the intramolecular ring-closing Wittig reaction
step. In this case the repulsion between the large groups PPh3 and
C-2 is decisive for the transition state geometry. Although the
customary addition of benzoic acid to the reaction of ylide 10 with
aminoesters accelerates the initial addition step leading to the re-
spective intermediate amide ylides, it can be replaced in some cases
by N-hydroxysuccinimide. This allows the use of ‘small’ acid-
4.2.3. tert-Butyl
pyrrol-2-yl)-3-((triethylsilyl)oxy)propyl)carbamate (12c). From 7c
(46.0 mg, 102 mol); solvent: toluene (8 mL); additives: Ph3PCCO
10 (1.1 equiv); conditions: reflux for 18 h; purification: flash
((S)-3-((S)-3-(benzyloxy)-5-oxo-2,5-dihydro-1H-
m
chromatography (EtOAc). Product: 12c (10.1 mg, 19.0 mmol, 19%).
20
Rf¼0.47 (EtOAc). [
a
]
¼ꢀ13.7 (c 1.00, CH2Cl2). 1H NMR (500 MHz,
D
CDCl3):
d
¼0.66 (q, J¼7.9 Hz, 6H, CH2CH3), 0.96 (t, J¼7.9 Hz, 9H,
sensitive protecting groups such as OTIPS at C-3 of the starting
a
-
CH2CH3), 1.33e1.41 (m, 1H, 20-Ha), 1.43 [s, 9H, C(CH3)3], 1.52e1.63
(m, 1H, 20-Hb), 3.05e3.14 (m, 1H, 30-Ha), 3.15e3.25 (m, 1H, 30-Hb),
4.07e4.11 (m, 1H, 10-H), 4.24 (d, J¼3.2 Hz, 1H, 5-H), 4.58 (br, 1H,
NH), 4.93e5.02 (m, 2H, CH2Ph), 5.10 (s, 1H, 3-H), 5.66 (s, 1H, 1-H),
aminoesters. Their reaction with ylide 10 gives rise to good yields of
the respective enantiomerically pure tetramates. These empirical
rules should now enable us to employ this tetramate synthesis for
the construction of more complex macrocyclic derivatives of the
cylindramide type.
7.33e7.43 (m, 5H, Ar) ppm. 13C NMR (125 MHz, CDCl3):
d
¼4.8
(CH2CH3), 6.8 (CH2CH3), 28.4 [C(CH3)3], 30.1 (C-20), 37.7 (C-30),

I. Loke et al. / Tetrahedron 68 (2012) 697e704
701
62.7 (C-5), 70.4 (C-10), 73.4 (CH2Ph), 79.1 [C(CH3)3], 96.3 (C-3),
128.5, 128.6 (o-C, m-C), 128.8 (p-C), 134.5 (i-C), 155.8 (NHCOO),
173.4 (C-4), 174.1 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3264, 2956,
2876, 1687, 1620, 1526, 1437, 1365, 1335, 1249, 1179, 1118, 1000,
807, 720, 694. MS (ESI): m/z¼477.3 [MþH]þ, 453.3, 421.2, 279.1,
245.1. HRMS (ESI): calcd for C25H41N2O5Siþ 477.2779, found
477.2792 [MþH]þ.
128.4, 128.5, 128.7 (o-C, m-C, p-C), 135.1 (i-C), 155.9 (NHCOO), 169.5
(C-1), 169.7 (COCH3) ppm. FTIR (ATR): nmax/cmꢀ1¼3327, 2997, 2938,
2928, 2361, 1757, 1715, 1667, 1514, 1388, 1366, 1251, 1214, 1172, 1082,
1003, 837, 748, 698, 668, 533. MS (ESI): m/z¼517.3 [MþNa]þ, 495.3
[MþH]þ, 403.2, 381.2, 325.1, 307.3, 281.1. HRMS (ESI, [MH]þ) calcd
for C25H42N2O6Siþ 495.2885, found 495.2879.
4.2.7. (2S,3S)-Benzyl 2-acetamido-5-(tert-butoxycarbonylamino)-3-
4.2.4. tert-Butyl ((S)-3-(benzyloxy)-3-((S)-3-(benzyloxy)-5-oxo-2,5-
dihydro-1H-pyrrol-2-yl)propyl)carbamate (12d). From 7d (71.0 mg,
[triisopropylsilyloxy]pentanoate (14b). Rf¼0.79 (hexane/EtOAc 1:1,
20
UV). [
a
]
¼ꢀ5.8 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
D
166
(1.1 equiv); conditions: reflux for 18 h; purification: flash chroma-
tography (EtOAc). Product: 12d (10.0 mg, 22.0 mol, 13%) and the
m
mol); solvent: toluene (10 mL); additives: Ph3PCCO 10
d
¼0.98e1.06 {m, 21H, Si[CH(CH3)2]3}, 1.43 [s, 9H, C(CH3)3],
1.72e1.83 (m,1H, 4-Ha),1.85e1.97 (m,1H, 4-Hb), 2.05 (s, 3H, COCH3),
3.05e3.15 (m, 1H, 5-Ha), 3.34e3.46 (m, 1H, 5-Hb), 4.16e4.22 (m, 1H,
3-H), 4.64 (d, J¼7.6 Hz, 1H, 2-H), 5.16 (d, J¼11.9 Hz, 1H, CH2Ph), 5.18
(d, J¼11.9 Hz, 1H, CH2Ph), 5.29 (br, 1H, NH), 6.64 (br, 1H, NH),
m
byproduct 14d (13.0 mg, 28.0
m
mol, 17%). Rf¼0.39 (EtOAc).
20
[
d
a
]
¼ꢀ51.2 (c 1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3):
D
¼1.34e1.40 (m, 1H, 20-Ha), 1.41 [s, 9H, C(CH3)3], 1.60e1.69 (m, 1H,
7.33e7.38 (m, 5H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
d¼12.2 {Si
20-Hb), 3.09e3.26 (m, 2H, 30-H), 3.82 (ddd, J¼9.9, 2.9, 2.9 Hz, 10-H),
4.49 (d, J¼2.9 Hz, 1H, 5-H), 4.52e4.66 (m, 2H, OCH2Ph), 4.93e5.01
(m, 2H, COOCH2Ph), 5.12 (s,1H, 3-H), 5.72 (s,1H,1-H), 7.29e7.43 (m,
[CH(CH3)2]3},17.7 {Si[CH(CH3)2]3}, 23.1 (COCH3), 28.4 [C(CH3)3], 31.9
{Si[CH(CH3)2]3}, 34.7 (C-4), 37.2 (C-5), 65.4 (C-2), 67.4 (CH2Ph), 73.0
(C-3), 79.0 [C(CH3)3], 128.4, 128.5, 128.7 (o-C, m-C, p-C), 135.1 (i-C),
10H, Ar) ppm. 13C NMR (125 MHz, CDCl3):
d
¼28.3 (C-20), 28.4
156.0 (NHCOO), 169.4 (C-1), 169.9 (COCH3) ppm. FT-IR (ATR): nmax/
[C(CH3)3], 37.5 (C-30), 58.9 (C-5), 72.2 (OCH2Ph), 73.5 (COOCH2Ph),
76.7 (C-10), 79.1 [C(CH3)3], 96.3 (C-3),128.0,128.1,128.2 (o-C, m-C, p-
C COOCH2Ph),128.7,128.85,128.93 (o-C, m-C, p-C OCH2Ph),134.4 (i-C
COOCH2Ph),137.5 (i-C OCH2Ph),155.9 (NHCOO),173.3 (C-4),174.0 (C-
2) ppm. FTIR (ATR): nmax/cmꢀ1¼3280, 2929, 1965, 1682, 1617, 1499,
1455, 1365, 1335, 1251, 1168, 1097, 976, 911, 807, 733, 697. MS (ESI):
m/z¼453.0 [MþH]þ, 245.1, 228.1, 216.1, 129.4, 91.1 [C7H7]þ. HRMS
(ESI): calcd for C26H32N2O5Naþ 475.2203, found 475.2218 [MþNa]þ.
cmꢀ1¼3327, 2997, 2938, 2927, 2362, 1678, 1596, 1509, 1455, 1366,
1250, 1214, 1166, 983, 750, 698, 667. MS (ESI): m/z¼559.3 [MþNa]þ,
503.3, 459.3, 351.2, 285.1. HRMS (ESI, [MNa]þ): calcd for
C28H48N2O6SiNaþ 559.3174, found 559.3171.
4.2.8. (2S,3S)-Benzyl 2-acetamido-5-(tert-butoxycarbonylamino)-3-
[triethylsilyloxy]pentanoate (14c). Rf¼0.76 (hexane/EtOAc 1:1, UV).
20
[a
]
¼ꢀ5.2 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
¼0.52e0.67
d
D
[m, 6H, Si(CH2CH3)3], 0.83e0.99 [m, 9H, Si(CH2CH3)3], 1.41 [s, 9H,
C(CH3)3], 1.69e1.85 (m, 2H, 4-H), 2.00 (s, 3H, COCH3), 3.03e3.19 (m,
1H, 5-Ha), 3.21e3.32 (m,1H, 5-Hb), 4.00e4.13 (m,1H, 3-H), 4.62 (dd,
J¼7.1, 2.3 Hz, 1H, 2-H), 4.93 (br, 1H, NH), 5.16 (d, J¼11.9 Hz, 1H,
CH2Ph), 5.18 (d, J¼11.9 Hz, 1H, CH2Ph), 7.31e7.39 (m, 5H, Ar) ppm.
4.2.5. (Z)-tert-Butyl 2-(3-(benzyloxy)-5-oxo-1H-pyrrol-2(5H)ylidene)
ethylcarbamate (13). From 7b (90.0 mg, 0.18 mmol); solvent: THF
(1.5 mL), additives: Ph3PCCO 10 (1.0 equiv), PhCO2H (0.02 equiv),
conditions: 60 ꢁC for 18 h; purification: flash chromatography
(hexane/EtOAc 1:4). Products: 13 (15.6 mg, 45.0
(6.00 mg, 10.9 mol, 6%).
mmol, 25%) and 14b
13C NMR (75 MHz, CDCl3):
d¼4.1 (SiCH2CH3), 5.2 (SiCH2CH3), 23.2
m
(COCH3), 28.4 [C(CH3)3], 34.4 (C-4), 37.4 (C-5), 65.3 (C-2), 67.4
(CH2Ph), 72.9 (C-3), 79.1 [C(CH3)3], 128.4, 128.5, 128.7 (o-C, m-C, p-
C), 135.1 (i-C), 155.9 (NHCOO), 169.5 (C-1), 169.7 (COCH3) ppm. FTIR
(ATR): nmax/cmꢀ1¼3347, 2923, 2853, 2362, 1694, 1513, 1455, 1366,
1251, 1214, 1170, 745, 696. MS (ESI): m/z¼517.3 [MþNa]þ, 495.3
[MþH]þ, 411.2, 279.1, 204.1. HRMS (ESI, [MNa]þ): calcd for
C25H42N2O6SiNaþ 517.2704, found 517.2708.
From 7c (90.0 mg, 0.20 mmol); solvent: THF (1.5 mL), additives:
Ph3PCCO 10 (1.0 equiv), PhCO2H (0.02 equiv), conditions: 60 ꢁC for
18 h, purification: flash chromatography (hexane/EtOAc 1:3).
Products: crude 13 (16.6 mg, 48.0 mmol, 24%) and 14c (7.00 mg,
14.0
CDCl3):
m
mol, 7%). Rf¼0.62 (hexane/EtOAc 4:1, UV). 1H NMR (500 MHz,
d
¼1.43 [s, 9H, C(CH3)3], 2.35e2.46 (m, 2H, 20-H), 3.22e3.29
(m, 2H, 30-H), 4.89 (br, 1H, NH), 5.01 (s, 2H, CH2Ph), 5.18 (s, 1H, 3-H),
5.47 (t, J¼8.3 Hz, 1H, 10-H), 7.24 (br, 1H, NH), 7.34e7.42 (m, 5H, Ar)
4.2.9. (2S,3S)-Benzyl
ycarbonyl)amino)pentanoate (14d). Rf¼0.72 (EtOAc). [
(c 1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3):
2-acetamido-3-(benzyloxy)-5-((tert-butox-
20
ppm. 13C NMR (125 MHz, CDCl3):
d
¼28.4 [C(CH3)3], 28.7 (C-20), 39.7
a
]
¼ꢀ2.00
D
(C-30), 73.4 (CH2Ph), 79.2 [C(CH3)3], 94.6 (C-3), 106.6 (C-10), 128.4,
128.6, 128.7 (o-C, m-C, p-C), 134.8 (i-C), 156.1 (C-4), 164.7 (C-5),
168.7 (NHCOO), 171.9 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3353,
2939, 2927, 2361, 1678, 1596, 1509, 1455, 1366, 1250, 1214, 1166,
983, 750, 697, 667. MS (ESI): m/z¼711.3 [2MþNa]þ, 689.4 [2MþH]þ,
367.2 [MþNa]þ, 345.2 [MþH]þ, 307.1, 263.2.
d
¼1.43 [s, 9H, C(CH3)3],
1.52e1.68 (m, 1H, 4-Ha), 1.68e1.82 (m, 1H, 4-Hb), 1.97 (s, 3H, CH3),
3.05e3.30 (m, 2H, 5-H), 3.76e3.84 (m, 1H, 3-H), 4.47e4.63 (m, 2H,
OCH2Ph), 4.67 (br, 1H, NHCOO), 4.93e5.04 (m, 1H, 2-H), 5.09e5.28
(m, 2H, COOCH2Ph), 6.17 (d, J¼7.1 Hz, CONH), 7.28e7.41 (m, 10H,
Ar) ppm. 13C NMR (125 MHz, CDCl3):
d¼23.2 (CH3), 28.4 [C(CH3)3],
30.9 (C-4), 37.5 (C-5), 54.2 (C-3), 67.5 (COOCH2Ph), 72.1 (OCH2Ph),
77.5 (C-2), 79.2 [C(CH3)3],128.1, 128.5, 128.57, 128.6, 128.7 (o-C, m-C,
p-C), 135.1 (i-C COOCH2Ph), 137.6 (i-C OCH2Ph), 159.2 (NHCOO),
169.99 (C-1), 170.02 (NHCO) ppm. FTIR (ATR): nmax/cmꢀ1¼3312,
2976, 1966, 1667, 1506, 1455, 1366, 1250, 1168, 1101, 1056, 909, 804,
728, 696. MS (ESI): m/z¼471.0 [MþH]þ, 415.2, 371.2, 353.2, 307.1,
263.1, 245.1, 204.1, 186.1, 155.1, 113.1, 91.1 [C7H7]þ. HRMS (ESI): calcd
for C26H34N2O6Naþ 493.2309, found 493.2315 [MþNa]þ.
4.2.6. (2S,3S)-Benzyl 2-acetamido-5-(tert-butoxycarbonylamino)-3-
[tert-butyl(dimethyl)silyloxy]pentanoate (14a). From 7a (45.0 mg,
0.10 mmol); solvent: THF (0.35 mL), additives: Ph3PCCO 10
(1.0 equiv), PhCO2H (0.02 equiv), conditions: 60 ꢁC for 14 h, purifi-
cation: flash chromatography (hexane/EtOAc 1:1). Product: 14a
(13.0 mg, 30.0
m
mol, 29%). Rf¼0.65 (hexane/EtOAc 1:1, UV).
20
[
a]
¼ꢀ4.7 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
¼0.10 [s, 3H,
d
D
Si(CH3)2], 0.11 [s, 3H, Si(CH3)2], 0.81 [s, 9H, SiC(CH3)3], 1.41 [s, 9H,
C(CH3)3], 1.72e1.83 (m, 2H, 4-H), 2.10 (s, 3H, COCH3), 3.06e3.14 (m,
1H, 5-Ha), 3.21e3.30 (m, 1H, 5-Hb), 3.95e4.02 (m, 1H, 3-H), 4.61
(dd, J¼7.6, 2.3 Hz, 1H, 2-H), 4.87 (br, 1H, NH), 5.16 (d, J¼11.9 Hz, 1H,
CH2Ph), 5.18 (d, J¼11.9 Hz, 1H, CH2Ph), 7.33e7.38 (m, 5H, Ar) ppm.
4.2.10. (5S)-4-(Benzyloxy)-5-isopropyl-1H-pyrrol-2(5H)-one
(16f). From 15f (190 mg, 0.50 mmol); solvent: THF (1.5 mL), addi-
tives: Ph3PCCO 10 (1.1 equiv), PhCO2H (0.2 equiv), conditions:
reflux for 18 h, purification: flash chromatography (hexane/EtOAc
13C NMR (125 MHz, CDCl3):
d
¼ꢀ4.7 [Si(CH3)2], ꢀ4.6 [Si(CH3)2], 17.9
1:1). Product: 16f (52.0 mg, 0.23 mmol, 45%). Rf¼0.26 (EtOAc).
25
[SiC(CH3)3], 23.2 (COCH3), 25.7 [SiC(CH3)3], 28.4 [C(CH3)3], 34.4 (C-
4), 37.4 (C-5), 56.8 (C-2), 67.4 (CH2Ph), 72.4 (C-3), 79.1 [C(CH3)3],
[a
]
¼ꢀ7.15 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
¼0.73 (d,
d
D
J¼6.9 Hz, 3H, CHCH3), 0.96 (d, J¼6.9 Hz, 3H, CHCH3), 2.04e2.09 [m,

702
I. Loke et al. / Tetrahedron 68 (2012) 697e704
1H, CH(CH3)2], 3.98 (d, J¼3.3 Hz, 1H, 5-H), 4.86 (d, J¼11.2 Hz, 1H,
CH2Ph), 4.91 (d, J¼11.2 Hz,1H, CH2Ph), 5.03 (s,1H, 3-H), 6.67 (br,1H,
conditions: reflux for 18 h, purification: HPLC (hexane/EtOAc
2:1/0:1). Product: 16l (49.0 mg, 147
mol, 20%). Rf¼14.32 min
(GCeMS).1H NMR (500 MHz, CDCl3):
m
NH), 7.2e7.34 (m, 5H, Ar) ppm. 13C NMR (75.5 MHz, CDCl3):
d¼15.2
d
¼0.05 [s, 6H, Si(CH3)2], 0.88 [s,
(CHCH3), 19.5 (CHCH3), 29.4 [CH(CH3)2], 62.9 (C-5), 73.1 (CH2Ph),
95.4 (C-3), 127.8, 128.2, 128.8 (o-C, m-C, p-C), 134.9 (i-C), 171.6 (C-2),
176.3 (C-4) ppm. IR (ATR): nmax/cmꢀ1¼3186, 3068, 2963, 2933,
2875, 1666, 1616, 1499, 1464, 1455, 1401, 1385, 1370, 1333, 1306,
1223, 1207, 1135, 1103, 1081, 1039, 1004, 970, 952, 913, 846, 805,
760, 742, 695, 665. MS (EI, 70 eV): m/z (%)¼231 [Mþ] (10), 189 (26),
140 (7), 132 (8), 91 (100). HRMS: calcd for C14H17NOþ2 231.12593,
found 231.12597 [M]þ.
9H, SiC(CH3)3], 3.55 (dd, J¼10.1, 8.2 Hz, 1H, 10-Ha), 3.98 (dd, J¼10.1,
3.5 Hz, 1H, 10-Hb), 4.19 (ddd, J¼8.2, 3.5, 0.9 Hz, 1H, 5-H), 4.93e5.00
(m, 2H, CH2Ph), 5.12 (d, J¼0.9 Hz, 1H, 3-H), 5.69 (br, 1H, NH),
7.33e7.43 (m, 5H, Ar) ppm.13C NMR (125 MHz, CDCl3):
d¼ꢀ5.5, ꢀ5.4
[Si(CH3)2], 18.2 [SiC(CH3)3], 25.8 [SiC(CH3)3], 59.9 (C-5), 64.1 (C-10),
73.3 (CH2Ph), 95.8 (C-3),127.9 (o-C),128.77 (m-C),128.81 (p-C),134.6
(i-C), 173.9 (C-4), 174.0 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3219,
2952, 2928, 2884, 2856, 2364, 1689, 1624, 1499, 1463, 1388, 1336,
1256, 1220, 1201, 1125, 1030, 973, 900, 837, 808, 778, 738, 697. MS
(ESI): m/z¼334.2 [MþH]þ, 301.1, 297.1, 240.1, 202.1, 91.1 [C7H7]þ.
HRMS (ESI): calcd for C18H27NO3SiNaþ 356.1652, found 356.1652
[MþNa]þ.
4.2.11. (5S,6S)-5-s-Butyl-4-methoxy-1-methyl-1H-pyrrol-2(5H)-one
(16g). From 15g (196 mg, 1.00 mmol); solvent: THF (1.5 mL), addi-
tives: Ph3PCCO 10 (1.1 equiv), PhCO2H (0.2 equiv), conditions: reflux
for 18 h, purification: flash chromatography (hexane/EtOAc 1:1).
Product: 16g (99.0 mg, 0.60 mmol, 60%). Rf¼0.18 (EtOAc). 1H NMR
4.2.15. 4-(Benzyloxy)-5-((S)-(triethylsilyloxy)methyl)-1H-pyrrol-
2(5H)-one (16m). From 15m (0.77 g, 0.25 mmol); solvent: toluene
(5 mL), additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux for
18 h, purification: HPLC (EtOAc). Product: 16m (23.0 mg,
0.07 mmol, 28%) and 16x (0.10 mmol, 20.6 mg, 41%). Rf¼0.44
(300 MHz, CDCl3):
d
¼0.67 (d, J¼6.9 Hz, 3H, CHCH3), 0.89 (t, J¼7.4 Hz,
3H, CH2CH3), 1.27e1.52 (m, 2H, CH2), 1.76e1.85 (m, 1H, CHCH3), 2.79
(s, 3H, NCH3), 3.67 (s, 3H, OCH3), 3.76 (d, J¼2.7 Hz,1H, 5-H), 4.98 (s,1H,
3-H) ppm. 13C NMR (75.5 MHz, CDCl3):
d¼12.3 (CH2CH3), 12.9
(CHCH3), 25.2 (CH2CH3), 26.7 (NCH3), 35.0 (CHCH3), 57.7 (OCH3), 65.7
(EtOAc). 1H NMR (300 MHz, CDCl3):
d
¼0.57 (q, J¼8.2 Hz, 6H, SiCH2),
(C-5), 94.8 (C-3), 171.9 (C-2), 175.3 (C-4) ppm. IR (ATR): nmax
/
0.92 (t, J¼8.2 Hz, 9H, SiCH2CH3), 3.50 (dd, J¼10.4, 8.3 Hz, 1H, 10-Ha),
3.96 (dd, J¼10.4, 3.6 Hz, 1H, 10-Hb), 4.17 (dd, J¼8.3, 3.6 Hz, 1H, 5-H),
4.92 (d, J¼11.7 Hz, 1H, CH2Pha), 4.96 (d, J¼11.7 Hz, 1H, CH2Phb), 5.08
(d, J¼1.2 Hz, 1H, 3-H), 5.68 (br, 1H, NH), 7.30e7.39 (m, 5H, Ar) ppm.
cmꢀ1¼2964, 2936, 2875,1683,1621,1457,1423,1380,1362,1336,1231,
1174,1136,1066,1016, 990, 939, 905, 802, 713, 688. MS (EI, 70 eV): m/z
(%)¼183 [Mþ] (20), 152 (5), 126 (100), 112 (10), 98 (5), 85 (5), 42 (5).
HRMS: calcd for C10H17NO2þ 183.12593, found 183.12588 [M]þ.
13C NMR (75 MHz, CDCl3):
d
¼4.2 (SiCH2), 6.6 (SiCH2CH3), 59.9 (C-5),
64.0 (C-10), 73.2 (CH2Ph), 95.8 (C-3), 127.8 (o-C), 128.5 (m-C), 128.7
4.2.12. 4-(Benzyloxy)-5-((S)-(tert-butoxy)methyl)-1H-pyrrol-2(5H)-
one (16j). From 15j (251 mg, 1.00 mmol); solvent: toluene (8 mL),
additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux for 18 h, puri-
fication: flash chromatography (EtOAc). Product: 16j (130 mg,
(p-C), 134.6 (i-C), 173.77 (C-4), 173.84 (C-2) ppm. FTIR (ATR): nmax/
cmꢀ1¼3211, 2953, 2911, 2875, 1687, 1622, 1498, 1456, 1437, 1377,
1334, 1294, 1221, 1198, 1117, 1003, 970, 895, 845, 798, 721, 694. MS
(ESI): m/z¼304 [MꢀEt]þ, 261, 212, 201, 117, 115, 103, 91, 75, 65.
0.47 mmol, 47%). Rf¼0.25 (EtOAc).1H NMR (300 MHz, CDCl3):
¼1.13
d
[s, 9H, C(CH3)3], 3.20 (t, J¼9.1 Hz,1H, 5-H), 3.72 (dd, J¼9.1, 3.6 Hz,1H,
10-Ha), 4.17 (dd, J¼9.1, 3.6 Hz, 1H, 10-Hb), 4.89 (d, J¼11.8 Hz, 1H,
CH2Pha), 4.92 (d, J¼11.8 Hz, 1H, CH2Phb), 5.07 (d, J¼1.1 Hz, 1H, 3-H),
6.20 (br, 1H, NH), 7.29e7.35 (m, 5H, Ar) ppm. 13C NMR (75 MHz,
4.2.16. 4-(Benzyloxy)-5-methylene-1H-pyrrol-2(5H)-one (16x). 1H
NMR (300 MHz, CDCl3):
d
¼4.82 (t, J¼1.5 Hz, 1H, 3-H), 5.03 (s, 2H,
CH2Ph), 5.06 (d, J¼1.5 Hz, 1H, ]CH2a), 5.20 (t, J¼1.4 Hz, 1H, ]CH2b),
7.33e7.42 (m, 5H, Ar), 8.06 (br, 1H, NH) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼27.2 [C(CH3)3], 58.3 (C-5), 63.0 (C-10), 72.9 (CH2Ph), 73.4
CDCl3):
d
¼72.9 (CH2Ph), 92.5 (]CH2), 94.6 (C-3), 127.7, 128.66,
[C(CH3)3], 95.5 (C-3),127.6 (o-C),128.2 (m-C),128.5 (p-C),134.5 (i-C),
173.7 (C-4), 173.9 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3215, 2974,
1687, 1619, 1498, 1455, 1437, 1363, 1331, 1190, 1118, 1102, 1079, 1025,
996, 972, 913, 866, 807, 746, 719, 694. MS (EI): m/z¼260 [MꢀCH3]þ,
219 [MHꢀC4H9]þ, 201 [MꢀC4H10O]þ,189 [MHꢀC4H9]þ. HRMS: calcd
for C16H22NOþ3 276.1594, found 276.1605 [MþH]þ.
128.70, (o-C, m-C, p-C), 134.7 (i-C), 139.4 (C-5), 164.7 (C-4), 171.8 (C-
2) ppm. FTIR (ATR): nmax/cmꢀ1¼3089, 3036, 3013, 1731, 1661, 1604,
1497, 1453, 1402, 1355, 1304, 1227, 1196, 1012, 982, 946, 915, 876,
842, 822, 738, 710, 694, 655. MS (EI, 70 eV): m/z¼201 [M]þ,173,158,
91 [Bn]þ, 65.
4.2.17. (S)-4-(Benzyloxy)-5-((R)-1-(tert-butyloxy)ethyl)-1H-pyrrol-
2(5H)-one (18a). From 17a (0.77 g, 0.25 mmol); solvent: toluene
(5 mL), additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux for 18 h,
4.2.13. 4-(Benzyloxy)-5-((triisopropylsilyloxy)methyl)-1H-pyrrol-
2(5H)-one (16k). From 15k (112 mg, 0.32 mmol); solvent: THF
(2 mL), additives: Ph3PCCO 10 (1.1 equiv), PhCO2H (0.2 equiv), con-
ditions: reflux for 18 h, purification: HPLC (hexane/EtOAc 2:1/0:1).
purification: HPLC (EtOAc). Product: 18a (43.0 mg, 0.15 mmol, 59%).
20
Rf¼0.16 (EtOAc). [
a
]
¼þ7.9 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
D
Product: 16k (46.0 mg, 122
m
mol, 38%). Rf¼51.56 min (HPLC).
CDCl3):
d
¼1.15 [s, 9H, C(CH3)3], 1.26 (d, J¼6.0 Hz, 3H, 20-H), 3.71 (q,
20
[
a]
¼ꢀ51.2 (c 1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3):
J¼6.3 Hz,1H,10-H), 3.89 (d, J¼6.0 Hz,1H, 5-H), 4.92(s, 2H, CH2Ph), 5.10
(d, J¼1.9 Hz,1H, 3-H), 6.06 (br,1H, NH), 7.27e7.49 (m, 5H, Ar) ppm.13C
D
d
¼1.00e1.08 {m, 21H, Si[CH(CH3)2]3, Si[CH(CH3)2]3}, 3.66 (dd, J¼9.8,
8.1 Hz,1H,10-Ha), 4.06 (dd, J¼9.8, 3.4 Hz,1H,10-Hb), 4.21 (ddd, J¼8.1,
3.4, 0.8 Hz,1H, 5-H), 4.91e5.01 (m, 2H, CH2Ph), 5.12 (d, J¼0.8 Hz,1H,
3-H), 5.72 (br, 1H, NH), 7.32e7.44 (m, 5H, Ar) ppm. 13C NMR
NMR (75 MHz, CDCl3):
d
¼21.0 (C-20), 28.5 [C(CH3)3], 63.2 (C-10), 68.0
(C-5), 73.1 (CH2Ph), 95.7 (C-3),127.7,128.6,128.7 (o-C, m-C, p-C),134.7
(i-C),173.8 (C-4),174.6 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3239, 2974,
1683, 1619, 1499, 1455, 1437, 1366, 1331, 1257, 1221, 1189, 1118, 1082,
1027, 978, 913, 849, 806, 746, 720, 693. MS (EI): m/z¼276, 259, 216
[MꢀC4H9O]þ, 199 [MHꢀC7H7]þ, 189, 122, 101.91 [C7H7]þ, 57. HRMS:
calcd for C17H24NOþ3 290.1751, found 290.1760 [MþH]þ.
(125 MHz, CDCl3):
d
¼11.9 {Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 60.1
(C-5), 64.5 (C-10), 73.3 (CH2Ph), 95.8 (C-3), 127.9 (o-C), 128.76 (m-C),
128.79 (p-C), 134.6 (i-C), 173.9 (C-4), 174.0 (C-2) ppm. FTIR (ATR):
nmax/cmꢀ1¼3359, 3057, 2921, 2852, 2360, 2341, 1634, 1437, 1193,
1119, 1070, 997, 754, 720, 694, 669. MS (ESI): m/z¼376.2 [MþH]þ,
322.2, 254.1, 202.1, 163.1, 145.1, 91.1 [C7H7]þ. HRMS (ESI): calcd for
C21H33NO3SiNaþ 398.2122, found 398.2123 [MþNa]þ.
4.2.18. (S)-4-(Benzyloxy)-5-((R)-1-(benzyloxy)ethyl)-1H-pyrrol-
2(5H)-one (18b). From 17b (80.8 mg, 0.25 mmol), solvent: toluene
(5 mL), additives: Ph3PCCO10 (1.3 equiv), conditions: reflux for 18 h,
4.2.14. (S)-4-(Benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-
1H-pyrrol-2(5H)-one (16l). From 15l (227 mg, 0.73 mmol); solvent:
THF (3 mL), additives: Ph3PCCO 10 (1.1 equiv), PhCO2H (0.2 equiv),
purification: HPLC (EtOAc). Product: 18b (27.0 mg, 0.08 mmol, 34%).
20
Rf¼0.17 (EtOAc). [
a
]
D
¼ꢀ17.1 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
CDCl3):
d
¼1.34 (d, J¼6.2 Hz, 3H, 20-H), 3.67 (dq, J¼6.2, 6.2 Hz, 1H, 10-

I. Loke et al. / Tetrahedron 68 (2012) 697e704
703
H), 4.05 (d, J¼6.2 Hz,1H, 5-H), 4.43 (d, J¼11.5 Hz,1H, OCH2Pha), 4.61
(d, J¼11.5 Hz,1H, OCH2Phb), 4.95 (d, J¼11.8 Hz,1H, COOCH2Pha), 4.95
(d, J¼11.8 Hz, 1H, COOCH2Phb), 5.15 (d, J¼1.1 Hz, 1H, 3-H), 6.24 (br,
1H, NH), 7.21e7.40 (m, 10H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
toluene (5 mL); additives: Ph3PCCO 10 (1.1 equiv); conditions: reflux
for 18 h; purification: flash chromatography (EtOAc). Product: 18f
(35.0 mg, 0.10 mmol, 39%). Rf¼0.30 (EtOAc). 1H NMR (300 MHz,
CDCl3):
d¼0.56 (q, J¼7.7 Hz, 6H, SiCH2), 0.92 (t, J¼7.7 Hz, 9H,
d
¼16.7 (C-20), 62.4 (C-10), 71.0 (OCH2Ph), 73.2 (COOCH2Ph), 75.1 (C-
SiCH2CH3), 1.28 (d, J¼5.8 Hz, 3H, 20-H), 3.81e4.01 (m, 2H,10-H, 5-H),
5), 96.0 (C-3), 127.6, 127.7, 128.4, 128.5, 128.6, 128.7 (o-C, m-C, p-C),
4.94 (s, 2H, CH2Ph), 5.11 (d, J¼1.6 Hz, 1H, 3-H), 5.79 (br, 1H, NH),
134.7, 137.9 (i-C), 173.9 (C-4), 174.2 (C-2) ppm. FTIR (ATR): nmax
/
7.27e7.41 (m, 5H, Ar) ppm.13C NMR (75 MHz, CDCl3):
d
¼4.9 (SiCH2),
cmꢀ1¼3209, 3061, 2871, 1681, 1616, 1497, 1454, 1437, 1377, 1336,
1269, 1220, 1202, 1118, 1092, 1026, 997, 956, 914, 805, 737, 720, 694.
MS (EI): m/z¼324 [MHþ], 279, 251, 217,188,160,135,120, 91 [C7H7]þ.
6.8 (SiCH2CH3), 21.3 (C-20), 59.9 (C-5), 64.0 (C-10), 73.2 (CH2Ph), 95.8
(C-3), 127.8, 128.5, 128.7 (o-C, m-C, p-C), 134.6 (i-C), 173.77 (C-4),
173.84 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3216, 3062, 2953, 2875,
1685, 1619, 1499, 1456,1437, 1376,1335,1308,1220,1198, 1142, 1118,
1095,1003, 975, 950, 913, 881, 844, 805, 784, 719, 694. MS: m/z¼318
[MꢀEt]þ, 303, 215, 189, 159, 131, 115, 103 [Et2SiOH]þ, 91[C7H7]þ.
4.2.19. (S)-5-((R)-1-(Benzyloxy)ethyl)-4-methoxy-1-methyl-1H-pyr-
rol-2(5H)-one (18c). From 17c (0.65 g, 2.70 mmol); solvent: toluene
(8 mL), additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux for
18 h; purification: flash chromatography (EtOAc). Product: 18c
(0.27 g, 1.00 mmol, 38%). Rf¼0.25 (EtOAc). 1H NMR (300 MHz,
4.2.23. (S)-4-(Benzyloxy)-5-((R)-1-(methoxy)ethyl)-1H-pyrrol-
2(5H)-one (18g). From 17g (448 mg, 1.82 mmol); solvent: toluene
(8 mL); additives: Ph3PCCO 10 (1.1 equiv); conditions: reflux for
CDCl3):
d
¼0.96 (d, J¼6.3 Hz, 3H, CHCH3, 7-H), 2.92 (s, 3H, NCH3, 9-
H), 3.66 (s, 3H, OCH3, 8-H), 3.88 (dq, J¼6.3 Hz, J¼2.2 Hz, 1H, CHCH3,
6-H), 4.09 (d, J¼2.2 Hz, 1H, CHNH, 5-H), 4.48 (d, J¼12.0 Hz, 1H,
CH2Ph,10-H), 4.55 (d, J¼12.0 Hz,1H, CH2Ph,10-H), 4.99 (d, J¼0.7 Hz,
1H, CH, 3-H), 7.17e7.29 (m, 5H, Ar) ppm. 13C NMR (75.5 MHz,
18 h; purification: flash chromatography (EtOAc). Product: 18g
20
(365 mg, 1.48 mmol, 82%). Rf¼0.14 (EtOAc). [
a]
¼ꢀ2.4 (c 1.00,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
¼1.17 (d, J¼6.3 Hz, 3H, 20-H),
3.22 (s, 3H, OMe), 3.38 (qd, J¼6.3, 5.6 Hz, 1H, 10-H), 3.92 (d,
J¼5.6 Hz, 1H, 5-H), 4.87 (s, 2H, CH2Ph), 5.04 (d, J¼1.1 Hz, 1H, 3-H),
7.05 (s, 1H, NH), 7.20e7.29 (m, 5H, Ar) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼12.7 (C-7), 28.2 (C-9), 58.0 (C-8), 64.8 (C-5), 70.8 (C-10),
74.5 (C-6), 94.7 (C-3), 127.1, 127.4, 128.2 (o-C, m-C, p-C), 137.9 (i-C),
172.2 (C-4), 174.2 (C-2) ppm. FTIR (ATR): nmax (cmꢀ1)¼2936, 2341,
1679, 1623, 1496, 1483, 1453, 1436, 1380, 1349, 1231, 1196, 1100,
1027, 997, 950, 887, 802, 745, 719, 693. MS (EI, 70 eV); m/z (%): 164
(12), 126 (20) [Mþꢀ(CH3(CH)OBn)], 120 (19), 91 (100) [Bnþ].
CDCl3):
d
¼15.6 (C-20), 56.5 (C-10), 62.2 (C-5), 72.9 (CH2Ph), 76.4
(OCH3), 95.7 (C-3), 127.4, 128.3, 128.4 (o-C, m-C, p-C), 134.6 (i-C),
174.2 (C-4), 174.3 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3204, 3067,
2983, 2936, 2883, 2827, 1677, 1610, 1498, 1454, 1397, 1334, 1222,
1204, 1159, 1142, 1091, 1044, 1013, 996, 963, 913, 884, 848, 803, 755,
740, 699, 670. HRMS: calcd for C14H18NOþ3 248.1281, found
248.1269 [MþH]þ.
4.2.20. (S)-4-(Benzyloxy)-5-((R)-1-((triisopropylsilyl)oxy)ethyl)-1H-
pyrrol-2(5H)-one (18d). From 17d (97.2 mg, 0.25 mmol); solvent:
toluene (5 mL), additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux
for 18 h; purification: flash chromatography (EtOAc). Product: 18d
4.2.24. (S)-4-(Benzyloxy)-5-((S)-1-(methoxy)ethyl)-1H-pyrrol-
2(5H)-one (18h). From 17h (62.0 mg, 0.25 mmol); solvent: toluene
(8 mL); additives: Ph3PCCO 10 (1.1 equiv); conditions: reflux for
18 h; purification: flash chromatography (MeOH in EtOAc 0e10%).
Product: 18h (5.00 mg, 0.02 mmol, 8%). Rf¼0.15 (EtOAc). 1H NMR
20
(45.0 mg, 0.12 mmol, 46%). Rf¼0.45 (EtOAc). [
a
]
¼þ12.7 (c 1.00,
D
CH2Cl2).1H NMR (300 MHz, CDCl3):
d
¼0.98e1.03[m, 21H, CH(CH3)2],
1.29 (d, J¼6.0 Hz, 3H, 20-H), 3.95 (d, J¼4.6 Hz,1H, 5-H), 4.18 (dq, J¼6.0,
4.6 Hz,1H,10-H), 4.92 (s, 2H, CH2Ph), 5.11 (dd, J¼1.6, 0.5 Hz,1H, 3-H),
6.26 (br, 1H, NH), 7.30e7.36 (m, 5H, Ar) ppm. 13C NMR (75 MHz,
(300 MHz, CDCl3):
d
¼0.99 (d, J¼6.0 Hz, 3H, 20-H), 3.38 (s, 3H, OMe),
CDCl3):
d
¼12.5 [CH(CH3)2], 17.9 [CH(CH3)2], 20.9 (C-20), 64.0 (C-10),
3.72 (qd, J¼6.0, 3.2 Hz, 1H, 10-H), 4.45 (d, J¼3.2 Hz, 1H, 5-H), 4.94 (d,
J¼11.6 Hz, 1H, CH2Pha), 5.01 (d, J¼11.4 Hz, 1H, CH2Phb), 5.14 (d,
J¼1.7 Hz, 1H, 3-H), 5.66 (br, 1H, NH), 7.33e7.42 (m, 5H, Ar) ppm. 13C
68.4 (C-5), 73.0 (CH2Ph), 98.8 (C-3),127.8,128.4,128.5 (o-C, m-C, p-C),
134.6 (i-C),174.3 (C-4),174.5 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3213,
2942, 2866,1967,1686,1620,1463,1338,1261,1202,1099,1008, 952,
882, 803, 735, 696, 678. MS (ESI): m/z¼390.2 [MþH]þ, 346.2
[MꢀC3H7]þ, 201.2, 177.1, 159.1, 131.1, 91.0 [C7H7]þ. HRMS (ESI): calcd
for C22H36NO3Siþ 390.2459, found 390.2453 [MþH]þ.
NMR (75 MHz, CDCl3):
(CH2Ph), 75.9 (OCH3), 96.1 (C-3), 127.7, 128.4, 128.8 (o-C, m-C, p-C),
d
¼11.9 (C-20), 56.7 (C-10), 59.9 (C-5), 73.3
134.5 (i-C), 173.9 (C-4), 174.2 (C-2) ppm. FTIR (ATR): nmax
/
cmꢀ1¼3211, 2974, 2933, 2222, 1684, 1616, 1499, 1455, 1437, 1389,
1331, 1220, 1193, 1119, 1076, 975, 954, 913, 888, 848, 806, 782, 721,
695. HRMS: calcd for C14H18NOþ3 248.1281, found 248.1297 [MþH]þ.
4.2.21. (S)-4-(Benzyloxy)-1-methyl-5-((R)-1-((triisopropylsilyl)oxy)
ethyl)-1H-pyrrol-2(5H)-one (18e). From 17e (565 mg, 1.50 mmol);
solvent: toluene (10 mL); additives: Ph3PCCO 10 (1.1 equiv), con-
ditions: reflux for 18 h; purification: flash chromatography (cyclo-
4.2.25. (S)-4-(Benzyloxy)-5-((S)-1-((triisopropylsilyl)oxy)ethyl)-1H-
pyrrol-2(5H)-one (18i). From 17i (97.2 mg, 0.25 mmol); solvent: tol-
uene (5 mL); additives: Ph3PCCO 10 (1.1 equiv), conditions: reflux for
hexane /EtOAc 1:1). Product: 18e (330 mg, 0.82 mmol, 55%).
20
Rf¼0.27 (cyclohexane/ EtOAc 1:1). [
a
]
¼þ45.5 (c 1.1, CH2Cl2). 1H
18 h; purification: flash chromatography (EtOAc). Product: 18i
D
20
NMR (300 MHz, CDCl3):
d
¼0.93e1.02 {m, 21H, Si[CH(CH3)2]3}, 1.09
(25.0 mg, 0.06 mmol, 26%). Rf¼0.46 (EtOAc). [
a
]
¼ꢀ35.6 (c 1.00,
D
(d, J¼6.3 Hz, 3H, 20-H), 2.87 (s, 3H, NMe), 3.86 (d, J¼3.0 Hz,1H, 5-H),
4.32 (qd, J¼6.3, 3.0 Hz, 1H, 10-H), 4.87 (d, J¼11.8 Hz, 1H, CH2Pha)
4.87 (d, J¼11.8 Hz, 1H, CH2Phb), 5.09 (s, 1H, 3-H) 7.25e7.33 (m, 5H,
CH2Cl2). 1H NMR (300 MHz, CDCl3):
d
¼0.97 (d, J¼6.5 Hz, 3H, 20-H),
1.01e1.05 [m, 21H, SiCH(CH3)2], 4.25e4.34 (m, 2H, 5-H, 10-H), 4.90 (d,
J¼11.9 Hz, 1H, CH2Pha), 4.97 (d, J¼11.9 Hz, 1H, CH2Phb), 5.07 (d,
J¼1.3 Hz, 1H, 3-H), 5.53 (br, 1H, NH), 7.30e7.39 (m, 5H, Ar) ppm. 13C
Ar) ppm. 13C NMR (75 MHz, CDCl3):
d
¼12.1 [SiCH(CH3)2], 17.8
[SiCH(CH3)2], 18.3 (C-20), 27.5 (NMe), 66.4 (C-10), 67.4 (C-5), 72.5
(CH2Ph), 95.6 (C-3), 127.6, 128.2, 128.4 (o-C, m-C, p-C), 134.8 (i-C),
171.9 (C-4), 173.3 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼2942, 2865,
1689,1620,1499,1462,1422,1377,1351,1308,1225,1200,1141,1114,
1071, 989, 916, 881, 846, 802, 755, 737, 716, 676. MS (EI): m/z¼403
[M]þ, 359 [MꢀC3H7]þ, 268, 226, 203, 201, 157, 115, 91 [C7H7]þ.
HRMS: calcd for C23H37NO3Siþ 404.2615, found 404.2626 [MþH]þ.
NMR (125 MHz, CDCl3):
d
¼12.2 [SiCH(CH3)2], 16.0 (C-20), 18.0
[SiCH(CH3)2], 63.2 (C-5), 67.9 (C-10), 73.2 (CH2Ph), 96.1 (C-3), 127.7,
128.7 (o-C, m-C, p-C), 134.6 (i-C), 173.7 (C-4), 174.2 (C-2) ppm. FTIR
(ATR): nmax/cmꢀ1¼3216, 2942, 2865,1689,1620,1498,1462,1383,1353,
1332,1199,1143,1103,1068,1030, 984, 942, 915, 881, 857, 807, 744, 678.
MS (EI): m/z¼346 [MꢀC3H7]þ, 302, 255, 201, 157, 115, 91 [C7H7]þ.
HRMS: calcd for C22H36NO3Siþ 390.2459, found 390.2470 [MþH]þ.
4.2.22. (S)-4-(Benzyloxy)-5-((R)-1-((triethylsilyl)oxy)ethyl)-1H-pyr-
4.2.26. (S)-4-(Benzyloxy)-5-((S)-1-((triethylsilyl)oxy)ethyl)-1H-pyr-
rol-2(5H)-one (18f). From 17f (86.9 mg, 0.25 mmol); solvent:
rol-2(5H)-one (18j). From 17j (86.9 mg, 0.25 mmol); solvent:

704
I. Loke et al. / Tetrahedron 68 (2012) 697e704
toluene (5 mL); additives: Ph3PCCO 10 (1.1 equiv); conditions:
reflux for 18 h; purification: flash chromatography (EtOAc). Prod-
uct: 18j (11.0 mg, 0.03 mmol, 13%). Rf¼0.34 (EtOAc). 1H NMR
References and notes
1. Reviews: (a) Athanasellis, O. I.-M. G.; Markopoulos, J. Bioinorg. Chem. Appl. 2010,
1e11; (b) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203e4221; (c)
Edwards, P. Drug Discovery Today 2007, 12, 345e346; (d) Royles, B. J. L. Chem.
Rev. 1995, 95, 1981e2001; (e) Henning, H.-G.; Gelbin, A. Adv. Heterocycl. Chem.
1993, 57, 139e185.
(300 MHz, CDCl3):
d¼0.59 (q, J¼8.2 Hz, 6H, SiCH2), 0.97 (d, J¼6.0 Hz,
3H, 20-H), 0.94 (t, J¼8.2 Hz, 9H, SiCH2CH3), 4.08e4.32 (m, 2H, 10-H,
5-H), 4.92 (d, J¼11.7 Hz, 1H, CH2Pha), 4.99 (d, J¼11.7 Hz, 1H,
CH2Phb), 5.09 (dd, J¼1.9, 0.5 Hz, 1H, 3-H), 5.55 (br, 1H, NH),
2. (a) Biersack, B.; Diestel, R.; Jagusch, C.; Sasse, F.; Schobert, R. J. Inorg. Biochem.
2009, 103, 72e76; (b) Knoth, T.; Warburg, K.; Katzka, C.; Rai, A.; Wolf, A.;
Brockmeyer, A.; Janning, O.; Reubold, T. F.; Eschenburg, S.; Manstein, D. J.;
7.29e7.51 (m, 5H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
d¼4.7
(SiCH2), 6.7 (SiCH2CH3), 16.1 (C-20), 63.1 (C-5), 67.6 (C-10), 73.2
(CH2Ph), 96.1 (C-3), 127.8, 128.5, 128.8 (o-C, m-C, p-C), 134.7 (i-C),
173.8 (C-4), 174.1 (C-2) ppm. FTIR (ATR): nmax/cmꢀ1¼3212, 2954,
2876, 1687, 1618, 1498, 1456, 1381, 1333, 1220, 1199, 1142, 1099,
1063, 986, 942, 912, 857, 806, 783, 726, 695. MS (EI): m/z¼318
[MꢀEt]þ, 303, 215, 189, 159, 131, 115, 103 [Et2SiOH]þ, 91[C7H7]þ.
€
Hubel, K.; Kaiser, M.; Waldmann, H. Angew. Chem. 2009, 121, 7376e7381; An-
gew. Chem. Int. Ed. 2009, 48, 7240e7245; (c) Biersack, B.; Diestel, R.; Jagusch, C.;
Rapp, G.; Sasse, G.; Schobert, R. Chem. Biodiv. 2008, 5, 2423e2430; (d) Schobert,
R.; Jagusch, C. Tetrahedron 2005, 61, 2301e2307; (e) Aoki, S.; Higuchi, K.; Ye, Y.;
Satari, R.; Kobayashi, M. Tetrahedron 2000, 56, 1833e1836.
3. (a) Boehme, R.; Jung, G.; Bretmaier, E. Helv. Chim. Acta 2005, 88, 2837e2841; (b)
Marquardt, U.; Schmid, D.; Jung, G. Synlett 2000, 1131e1132; (c) Holtzel, A.;
€
Ganzle, M. G.; Nicholson, G. J.; Hamer, W. P.; Jung, G. Angew. Chem. 2000, 39,
€
2766e2768; Angew. Chem. Int. Ed. 2000, 39, 2766e2768; (d) Ganzle, M. G.;
€
Holtzel, A.; Walter, J.; Jung, G.; Hammer, W. P. Appl. Environ. Microbiol. 2000, 66,
4.2.27. (5Z)-4-(Benzyloxy)-5-ethylidene-1H-pyrrol-2(5H)-one
4325e4333; (e) Schobert, R.; Dietrich, M.; Mullen, G.; Urbina-Gonzalez, J.-M.
Synthesis 2006, 22, 3902e3914.
(18x). 1H NMR (300 MHz, CDCl3):
d
¼1.86 (d, J¼7.3 Hz, 3H, CH3),
4. (a) Yoshinari, T.; Ohmori, K.; Schrenz, M. G.; Pfaltz, A.; Suzuki, K. Angew. Chem.
2010, 122, 893e897; Angew. Chem., Int. Ed. 2010, 49, 881e885; (b) Barnickel, B.;
Schobert, R. J. Org. Chem. 2010, 75, 6716e6719; (c) Ramane, C. V.; Mondal, M. A.;
Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47, 4061e4064; (d)
Graupner, P. R.; Carr, A.; Clancy, E.; Gilbert, J.; Bailey, K. L.; Derby, J. A.; Gerwick,
B. C. J. Nat. Prod. 2003, 66, 1558e1561.
5.01 (s, 2H, CH2Ph), 5.16 (d, J¼1.6 Hz, 1H, 3-H), 5.55 (q, J¼7.3 Hz, 1H,
CHCH3), 7.30e7.44 (m, 5H, Ar), 8.54 (br, 1H, NH) ppm. 13C NMR
(75 MHz, CDCl3):
d¼12.1 (CHCH3), 72.6 (CH2Ph), 93.6 (C-3), 106.0
(CHCH3), 127.6, 128.5, 128.6, (o-C, m-C, p-C), 134.2 (C-5), 134.9 (i-C),
164.6 (C-2), 172.5 (C-4) ppm. FTIR (ATR): nmax/cmꢀ1¼3166, 3099,
3038, 2921, 1663, 1590, 1582, 1498, 1452, 1409, 1336, 1319, 1271,
1232, 1216, 1207, 1152, 1085, 1015, 976, 955, 915, 860, 802, 741, 699,
676. MS (EI, 70 eV): m/z¼215 [M]þ, 200 [MꢀCH3]þ, 172, 132, 124
[MꢀBn]þ, 91 [Bn]þ, 65, 54.
5. (a) Cramer, N.; Helbig, S.; Baro, A.; Laschat, S.; Diestel, R.; Sasse, F.; Mathieu, D.;
€
Richter, C.; Kummerlowe, G.; Luy, B.; Schwalbe, H. ChemBioChem 2008, 9,
2474e2486; (b) Cramer, N.; Buchweiz, M.; Laschat, S.; Frey, W.; Baro, A.; Ma-
thieu, D.; Richter, C.; Schwalbe, H. Chem.dEur. J. 2006, 12, 2488e2503; (c) Hart,
A. C.; Philipps, A. J. J. Am. Chem. Soc. 2006, 128, 1094e1095; (d) Cramer, N.;
Laschat, S.; Baro, A.; Schwalbe, H.; Richter, C. Angew. Chem. 2005, 117, 831e833;
Angew. Chem., Int. Ed. 2005, 44, 820e822; (e) Kanazawa, S.; Fusetani, N.; Mat-
sunaga, S. Tetrahedron Lett. 1993, 34, 1065e1068.
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Meijler, M. M.; Mueller, R. S.; Boskoff, H. I.; Ulrich, R. L.; Barry, C. E.; Bartlett, D.
E.; Kravchenko, V. V.; Kaufmann, G. F.; Janda, K. D. J. Am. Chem. Soc. 2009, 131,
14473e14479; (c) Gerke, G. D.; O’Neill, J. C.; Miller, D. M.; Wezeman, R. J.;
Mattmann, M. E.; Lin, Q.; Blackwell, H. E. ChemBioChem 2008, 9, 389e400; (d)
Hodgkinson, J. T.; Welch, M.; Spring, D. R. ACS Chem. Biol. 2007, 2, 715e717; (e)
Kaufmann, G. F.; Sartorio, R.; Lee, S.-H.; Rogers, C. J.; Meijler, M. M.; Moss, J. A.;
Clapham, B.; Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 309e314.
7. (a) Lacey, R. N. J. Chem. Soc. 1954, 850e854; (b) Jouin, P.; Castro, B.; Nisato, D. J.
Chem. Soc., Perkin Trans. 1 1987, 1177e1182.
8. Spatz, J. H.; Welsch, S. J.; Duhaut, D.-E.; Jager, N.; Bournier, T.; Fredrick, M.;
Allmendinger, L.; Ross, G.; Kolb, J.; Burdack, C.; Umkehrer, M. Tetrahedron Lett.
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11. Storgaard, M.; Zaragoza Dorwald, F.; Peschke, B.; Tanner, D. J. Org. Chem. 2009,
4.2.28. (S)-tert-Butyl-(3-(3-(benzyloxy)-5-oxo-2,5-dihydro-1H-pyr-
rol-2-yl)propyl)carbamate (20). Method B: from 19 (65.0 mg,
0.18 mmol); solvent: toluene (3 mL); additives: Ph3PCCO 10
(1.0 equiv), PhCO2H (0.2 equiv); conditions: reflux for 18 h; purifi-
cation: flash chromatography (EtOAc). Product: 20 (34.0 mg,
98.0 mmol, 77%). Method C: starting material: 19 (50.0 mg,
0.16 mmol); solvent: toluene (5 mL); additives: Ph3PCCO 10
(1.1 equiv); conditions: reflux for 18 h; purification: flash chroma-
tography (EtOAc). Product: 20 (34.0 mg, 98.0
m
mol, 63%). Rf¼0.3
20
(EtOAc). [
a]
¼ꢀ11.1 (c 1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3):
D
€
d
¼1.43 [s, 9H, C(CH3)3], 1.47e1.62 (m, 3H, 20-H, 10-Ha), 1.82e1.91 (m,
1H, 10-Hb), 3.06e3.19 (m, 2H, 30-H), 4.09e4.15 (m, 1H, 5-H), 4.67 (br,
1H, NH), 4.93e5.01 (m, 2H, CH2Ph), 5.08 (s, 1H, 3-H), 6.76 (br, 1H, 1-
H), 7.33e7.42 (m, 5H, Ar) ppm. 13C NMR (125 MHz, CDCl3):
d¼25.6
€
(C-20), 28.4 [C(CH3)3], 29.0 (C-10), 40.1 (C-30), 57.4 (C-5), 73.2
(CH2Ph), 79.2 [C(CH3)3], 94.8 (C-3), 127.8, 128.5, 128.6 (o-C, m-C, p-
C), 134.7 (i-C), 156.0 (NHCOO), 174.6 (C-2), 176.7 (C-4) ppm. FTIR
(ATR): nmax/cmꢀ1¼3280, 2932, 1966, 1674, 1615, 1515, 1454, 1335,
1250, 1166, 977, 913, 807, 730. HRMS (ESI): calcd for C19H26N2O4Naþ
369.1785, found 369.1790 [MþNa]þ. MS (ESI): m/z¼347.2 [MþH]þ,
291.1, 247.1, 230.1, 140.1, 91.1 [C7H7]þ.
74, 5032e5040.
12. Farran, D.; Parrot, I.; Martinez, J.; Dewynter, G. Angew. Chem. 2007, 119,
7632e7634; Angew. Chem., Int. Ed. 2007, 46, 7488e7489.
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Prousis, K. C.; Markopoulos, J.; McKee, V.; Igglessi-Markopoulou, O. Tetrahedron
2010, 66, 3944e3950.
14. Riache, N.; Bailly, C.; Deville, A.; Dubost, L.; Nay, B. Eur. J. Org. Chem. 2010,
5402e5408.
15. Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. R. Adv. Synth. Catal. 2010, 352,
621e626.
16. (a) Hofheinz, W.; Oberhansli, W. E. Helv. Chim. Acta 1977, 60, 660e669; (b)
€
€
Williard, P. G.; De Laszlo, S. E. J. Org. Chem. 1984, 49, 3489e3493; (c) Kohler, H.;
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Tetrahedron Lett. 1986, 27, 5285e5288.
Acknowledgements
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Financial support by the Deutsche Forschungsgemeinschaft
€
(grants Scho 402/9-2 and La 907/8-2), the Ministerium fur Wis-
€
senschaft, Forschung und Kunst des Landes Baden-Wurttemberg
(Landesgraduierten fellowship for N.P.), F. Hoffmann-La Roche AG,
Basel (internship for I.L.) and the Fonds der Chemischen Industrie is
gratefully acknowledged.
20. (a) Schobert, R.; Jagusch, C. Tetrahedron 2005, 61, 2301e2307; (b) Schobert, R.;
Jagusch, C.; Melanophy, C.; Mullen, G. Org. Biomol. Chem. 2004, 2, 3524e3529.
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T.; Yazawa, K.; Tomono, Y.; Uemura, D. Heterocycl. Commun. 1996, 2, 315e318.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.10.099.