Siloxycyclopropanes in Ugi four-component reaction: A new method for the synthesis of highly substituted pyrrolidinone derivatives

Article abstract of DOI:10.1055/s-2001-16762

Reaction of methyl trimethylsiloxycyclopropanecarboxylates 3 with amino acids, tert-butylisonitrile and methanol furnished amino diacid derivatives 2 as the result of an Ugi 5-center 4-component reaction. This one-pot reaction involves β-formyl esters such as 1 as intermediate, which are liberated in situ. Adducts 2 could be thermally cyclized to provide γ-lactams 4 in good yields. The multi component reaction was combined with this cyclization process to a fairly efficient one-pot procedure. Thus, cyclopropane derivative 3a was converted into γ-lactam 4a in good yield. Two of the γ-lactams 4 were reduced with lithium aluminum hydride to give pyrrolidine derivatives 5. Based on an X-ray analysis of the major diastereomer of compound 5d, the diastereoselectivity of the 4-component reaction is discussed.

Full text of DOI:10.1055/s-2001-16762

PAPER
1649
Siloxycyclopropanes in Ugi Four-Component Reaction: A New Method for the
Synthesis of Highly Substituted Pyrrolidinone Derivatives
S
iloxycyclopropa
e
nes in
U
gi
i
Four-C
n
omponent
R
h
eaction old Zimmer,a Antje Ziemer,b Margit Gruner,c Irene Brüdgam,d,1 Hans Hartl,d,1 Hans-Ulrich Reissig*a
a
Institut für Chemie – Organische Chemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
Fax +49 (30)83855367; E-mail: Hans.Reissig@chemie.fu-berlin.de
b
c
d
Institut für Polymerforschung Dresden e.V., Hohe Strasse 6, 01069 Dresden, Germany
Institut für Organische Chemie, Technische Universität Dresden, 01062 Dresden, Germany
Institut für Chemie - Anorganische und Analytische Chemie, Freie Universität Berlin, Fabeckstrasse 34–36, 14195 Berlin, Germany
Received 26 April 2001
Abstract: Reaction of methyl trimethylsiloxycyclopropanecarbox-
ylates 3 with amino acids, tert-butylisonitrile and methanol
furnished amino diacid derivatives 2 as the result of an Ugi 5-cen-
ter 4-component reaction. This one-pot reaction involves -formyl
esters such as 1 as intermediate, which are liberated in situ. Adducts
2 could be thermally cyclized to provide -lactams 4 in good yields.
The multi component reaction was combined with this cyclization
process to a fairly efficient one-pot procedure. Thus, cyclopropane
derivative 3a was converted into -lactam 4a in good yield. Two of
the -lactams 4 were reduced with lithium aluminum hydride to
give pyrrolidine derivatives 5. Based on an X-ray analysis of the
major diastereomer of compound 5d, the diastereoselectivity of the
4-component reaction is discussed.
Key words: amino acids, cyclopropanes, pyrrolidines, lactams,
Ugi reaction
Scheme 1
Introduction
In numerous applications we could establish that methyl
2-siloxycyclopropanecarboxylates
A (Figure 1) may
The use of multi-component transformations is a very ef-
ficient strategy for the production of compound ensem-
bles (libraries) of high diversity required in modern search
for lead structures. Among these processes the Ugi four-
component reaction (U-4CR) is one of the oldest, but most
frequently employed schemes.2,3 The combination of al-
dehyde, carboxylic acid, isonitrile and amine in a multi-
step process furnishes compounds with amino acid-like
backbones in an intriguingly simple and flexible fashion.
In 1996 Ugi and co-workers reported that -amino acids
may also be employed as amine component and that by
use of methanol as solvent the U-4CR could be extended
to an Ugi 5-center 4-component reaction (U5C-4CR) pro-
serve as equivalents of -ketocarboxylates B which are
smoothly liberated under certain conditions of ring cleav-
age.11 This concept could be exploited in many one-pot re-
actions which are based on ring-opening of A and
subsequent reactions without isolation of intermediate di-
carbonyl components B. Of particular synthetic value are
cyclopropane derivatives A which contain a hidden enone
functionality (R1 = alkenyl)12 or aldehyde group (R1 =
H)13 because the corresponding dicarbonyl compounds
are often hardly accessible and occasionally very sensi-
tive. Fascinated by the possibilities of the Ugi 5-center
4-component reaction we investigated the use of 2-silox-
ycyclopropanecarboxylates A as precursor in this process.
We envisaged that A may directly be introduced as pre-
cursor of B since under protic conditions as employed for
the U-5C-4CR, trimethylsiloxycyclopropanes A undergo
smooth cleavage to furnish B. As particularly interesting
aspect of this approach we considered the cyclization of
the primary Ugi reaction products to highly functionalized
pyrrolidinones which are interesting peptido mimetics.14
viding functionalized
-amino diacid derivatives
(Scheme 1).4 The configuration of the new stereogenic
center generated at the former carbonyl carbon of the al-
dehyde component is controlled by the configuration of
the amino acid used. The Ugi reaction has also been ex-
tended to functionalized -amino acids,5–7 anthranilic
acid8 as well as to - and -ketocarboxylic acids.9,10 The
latter compounds allow preparation of -lactams and -
lactams in an efficient fashion.
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1649,1658,ftx,en;T02901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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R. Zimmer et al.
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Having demonstrated that -formyl esters such as 1
smoothly react in this type of Ugi reaction we proceeded
to our actual goal and used siloxycyclopropanes as direct
precursor. Thus, reaction of methyl 3-methyl-2-trimethyl-
siloxycyclopropanecarboxylate (3a) with tert-butylisoni-
trile and alanine in methanol under similar conditions as
above afforded the expected adduct 2c in moderate yield
(Scheme 3). Again, all four diastereomers were obtained.
When siloxycyclopropane 3b was employed as starting
material the corresponding reactions with amino acids
phenylalanine, alanine and isoleucine furnished the cou-
pling products 2d, 2e and 2f in good or moderate yields.
In these examples only two diastereomers are observed
since the in situ generated -formyl ester is achiral. The
diastereoselectivity induced by the stereogenic center of
the amino acid is only moderate (ca 2:1 to 5:1, again only
the major diastereomers are depicted in Scheme 3).
Figure 1 Methyl 2-siloxycyclopropanecarboxylates A as equiva-
lents of -ketocarboxylates B
Results
In first orientating experiments we used the -formyl ester
1, which is easily available by ring-cleavage of siloxycy-
clopropane 3a,15 and combined this aldehyde with tert-bu-
tylisonitrile and phenylalanine or tryptophane in methanol
as solvent (Scheme 2). The reaction temperature was al-
lowed to rise from –30 °C to room temperature. After
evaporation of the solvent the residue was purified by col-
umn chromatography providing the expected coupling
products 2a and 2b in 82% and 71% yield, respectively,
as mixture of the expected four diastereomers. Only the
two major diastereomers are depicted in Scheme 2; the
configurational assignment is based on an X-ray analysis
of a subsequent product discussed below. Since chiral al-
dehyde 1 was used as a racemic mixture, pairs of diastere-
omers in a ratio of approximately 1:1 were obtained. As to
be expected no kinetic resolution occurs under the condi-
tions employed.16
Primary adducts 2a–f could efficiently be cyclized by
heating in toluene for 3 hours providing the desired pyrro-
lidinone derivatives 4a–f in good to excellent yields
(Scheme 4). For compounds 4a–c, derived from a chiral
-formyl ester, again four diastereomers were identified at
this stage, with some deviations from the initially record-
ed ratios of isomers. Thus, under the rather harsh cycliza-
tion conditions isomerization at the stereogenic center to
the carbonyl group may to some extend have occurred.
Likewise, the precursors 2d–f were converted into the two
diastereomers of 4d–f with ratios similar to those of the
starting materials.
Scheme 2
Scheme 3
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

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Siloxycyclopropanes in Ugi Four-Component Reaction
1651
Scheme 4
Scheme 5
Scheme 6
With siloxycyclopropane 3a and phenylalanine we at- corresponding adduct 2g containing a quarternary center
tempted a one-pot protocol and successfully obtained the were isolated. Thus, participation of -keto esters seems
pyrrolidinone 4a in 67% overall yield and almost identical to be much less efficient compared to the related alde-
ratio of diastereomers as observed in the two-step se- hydes.17
quence (Scheme 5). The overall transformation 3a to 4a
may be classified as 6-center 4-component reaction (6-C
4CR). Similarly, we introduced methyl 3,3-dimethyl-2-
Structural Elucidation
trimethylsiloxycyclopropanecarboxylate (3c) as precursor
for an in situ generated -dimethyl-substituted -formyl The relative stereochemistry at the centers C-2 and C-3 in
ester. However, for this example the steric hinderance ex- cis-4a and trans-4a as model compounds for 2,3-disubsti-
hibited by the two methyl groups seems to hamper the Ugi tuted pyrrolidinones 4 could be determined by means of
reaction considerably. The expected pyrrolidinone deriv- 2D-NMR measurements (COSY, HSQC, HMBC, NOE-
ative 4g was isolated in only 16% yield and negligible di- SY). The most significant signal in the 1H NMR is the pro-
astereoselectivity.
ton at position 2 in the pyrrolidinone ring. The 2-H signal
in cis-4a appears at 3 as a doublet with J = 8.5 Hz
For further exploration of scope and limitations of this
modification of the Ugi reaction we introduced methyl
2-methyl-2-trimethylsiloxycyclopropanecarboxylate
(3d). This cyclopropane derivative is equivalent to methyl
levinulate, but its reaction with phenylalanine and tert-bu-
tylisonitrile in methanol was very inefficient under stan-
dard conditions (Scheme 6). Only 16% of the
whereas the corresponding signal for this proton in trans-
4a is shifted slightly upfield and shows a coupling con-
stant of 4 Hz. Further characteristics in the 1H NMR spec-
tra of phenylalanine or tryptophane derived
pyrrolidinones 4 are the signals of the -proton of the ami-
no acid moiety (1’-H) as a doublet of doublet which gen-
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

1652
R. Zimmer et al.
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Scheme 7
erally couple with 5 Hz to 6 Hz and 10 Hz to 11 Hz at
=
lectivity at the newly formed stereogenic center (ca 65:35)
3.9 to 4.4. In the 13C NMR spectra, the chemical shifts for whereas isoleucine and phenylalanine provide higher ra-
C-2 in cis-4 are 3 to 5 ppm higher than the corresponding tios of diastereomers (ca 75:25 and 85:15). For series a
signals of the trans-4 diastereomers whereas the chemical (precursor 3a) the stereogenic center in the -formyl ester
shifts for C-3 in cis compounds ( 31–32) are very sim- makes the analysis more complex, however, the diastere-
ilar to those in trans-isomers (
33).
oselectivity of the process may be simplified by adding
the percentage values of the two major and those of the
two minor diastereomers. We assume that both enanti-
omers of the intermediate aldehyde 1 react with approxi-
mately the same rate and that no kinetic resolution took
place.16 Alanine again shows only low selectivity in the
range as observed in series b, but phenylalanine and tryp-
tophane gave rather high ratios in favour of one diastere-
omer (with respect to the new stereogenic center).
Reduction of pyrrolidinones 4c and 4d with lithium alu-
minum hydride furnished proline related amino alcohols
5c and 5d in good yields (Scheme 7). We were able to
grow suitable crystals from the major diastereomer of 5d,
which could be analysed by an X-ray analysis (Figure 2).
This unequivocally established the R-configuration of the
major diastereomer at the pyrrolidine ring which is in ac-
cordance with the configuration of a product in a related
example described by Kim et al.6,18
The X-ray analysis obtained from a product derived from
the major diastereomer of 4d revealed R-configuration at
C-2 in the pyrrolidine ring (Figure 2). On this basis we
suggest that the preferred attack of the isonitrile to the in-
termediate iminium ion C formed from the aldehyde and
the amino acid proceeds from the front side giving a nitri-
lium ion D as depicted in Scheme 8. Cyclization provides
intermediate E, which is ring-opened by methanol to fur-
nish the isolated product F. The front side attack is more
favoured and hence the diastereoselectivity higher if sub-
stituent R1 is larger. If R2 also contains a stereogenic cen-
ter in -position, as in intermediates derived from
Figure 2 Structure of compound 5d as determined by X-ray crystal-
lography
Discussion of the Stereochemistry
The examples presented here demonstrate that the Ugi
5-center 4-component reaction of in situ liberated
-
formyl esters proceeds with moderate to good diastereose-
lectivity. In series b (precursor 3b) – where the interpreta-
tion is not complicated by an additional stereogenic center
of the aldehyde component – alanine induces moderate se-
Scheme 8
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Siloxycyclopropanes in Ugi Four-Component Reaction
1653
Table 1 Synthesis of Iminodicarboxylic Derivatives 2a–g (General Procedure 1)
Substrate Amount
g (mmol)
Amino Acid Amount
g (mmol)
Time
(h)
Producta
Yield
(Ratio) g (%)
Appearance IRb
(cm–1)
1
0.650 (5.00) Phe
0.825 (5.00) 30
2a
(42:39:10.9) resin
1.62 (82)
3390 (N H), 3100–2860
(=CH, C H), 1735 (C=O,
ester), 1670 (C=O, amide)
1
0.285 (2.20) Trp
0.405 (2.00) Ala
0.449 (2.20) 30
0.178 (2.00) 48
2b
2c
(35:35:15:15) foam
0.673 (71)
3425 (N H), 3070–2850
(=CH, C H), 1735 (C=O,
ester), 1655 (C=O, amide)
3a
(37:32:17:14) oil
0.31 (49)
3325–3310 (N–H), 2970–
2835 (=CH, C–H), 1745
(C=O, ester), 1685 (C=O,
amide)
3b
3b
0.413 (2.00) Phe
0.345 (2.00) Ala
0.330 (2.00) 48
0.178 (2.00) 48
2d
2e
(83:17)
0.636 (81)
oil
3450, 3340 (N–H), 3100–
2880 (=CH, C–H) 1740
(C=O, ester), 1675 (C=O,
amide)
(67:33)
0.279 (46)
resin
3320–3315 (N–H), 2965–
2840 (=CH, C–H)), 1735
(C=O, ester), 1675 (C=O,
amide)
3b
3d
0.345 (2.00) Ile
0.292 (1.45) Phe
0.262 (2.00) 72
0.239 (1.45) 72
2f
(74:26)
0.557 (81)
oil
3330 (N–H) 2965–2875
(=CH, C–H), 1740 (C=O,
ester), 1670 (C=O, amide)
2g
(73:27)
0.072 (16)
resin
3450, 3355 (N–H), 3090–
2815 (=CH, C–H), 1745,
1740 (C=O, ester), 1760
(C=O, amide)
a Satisfactory microanalyses obtained: C 0.37, H 0.25, N 0.31; exception: 2a (C –0.53) and 2c (N –0.65).
b Oils and resins as film or in CCl4, foams as KBR pellets.
Table 2 Synthesis of Lactams 4a–f (General Procedure 2)
Substrate 2 Amount
Yield of Product 4a
(Ratio) g(%)
Appear- IRb
ance
g (mmol)
(cm–1)
2a
2b
2c
2d
2e
2f
0.453 (1.15)
0.402 (0.93)
0.175 (0.55)
0.520 (1.37)
0.170 (0.56)
0.550 (1.60)
4a (50:42:4:4)c 0.337 (81)
4b (52:42:3:3)d 0.258 (69)
4c (34:22:22:22) 0.111 (71)
foam
3400, 3335 (N–H), 3100–2920 (=CH, C–H), 1735 (C=O, ester),
1705 (C=O, lactam), 1675 (C=O, amide)
foam
resin
3390, 3360, 3330 (N–H), 3050–2960 (=CH, C–H), 1730 (C=O,
ester), 1680 (C=O, br, lactam, amide)
3325 (N–H), 2970–2935 (C-H), 1745 (C=O, ester), 1710 (C=O,
lactam), 1675 (C=O, amide)
4d (90:10)
4e (64:36)
4f (85:15)
0.461 (96)e resin
3305 (N–H), 3100–2820 (=CH, C–H), 1735 (C=O, ester), 1715
(C=O, lactam), 1690 (C=O, amide)
0.130 (86)
0.406 (82)
oil
3365–3025 (N–H), 2970–2930 (C–H), 1740 (C=O, ester), 1710
(C=O, lactam), 1675 (C=O, amide)
resin
3330 (N–H), 1735 (C=O, ester), 1710 (C=O, lactam), 1680 (C=O,
amide)
a Satisfactory microanalyses obtained: C 0.34, H 0.27, N 0.26; exception: 4c (N –0.46).
b Oils and resins as film or in CCl4, foams as KBR pellets.
c cis-4a/trans-4a = 54:46.
d cis-4b/trans-4b = 55:45.
e After chromatography 182 mg of major diastereomer of 4d was isolated in isomerically pure form;
[ ]D23 –65.5 (c = 1.0, CHCl3).
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Table 3 1H NMR Data of Compounds 2
Product 1H NMR (300 MHz, CDCl3/TMS); , J (Hz)
2aa
2ba
2c
7.35–7.21 (m, 5 H, C6H5), 7.05–6.85, 6.45 (m, br s, 0.81 H, 0.19 H, NH), 3.79–1.82 (m, 12 H with 8 s at = 3.73, 3.71, 3.69, 3.67,
3.65, 3.64, 3.60, 3.57, OCH3, NH, aliphat CH), 1.35–0.74 (m, 14 H, t-C4H9, CH3, aliphat CH)
8.70–8.35 (m, 1 H, NH), 7.70–6.75 (m, 6 H, arom CH, NH), 4.18–3.40, 3.30–1.65 (2 m, 7 H, 6 H, OCH3, NH, aliphat CH, CH2),
1.50–0.80 (m, 11.9 H with 3 s at = 1.33, 1.31, 1.28, t-C4H9, CH3, aliphat CH), 0.68 (d, J = 7, 1.1 H, CH3)
6.90–6.73 (m, 1 H, NH), 4.32–4.03, 4.01–3.90, 3.87–1.81 (3 m, 12 H, CH, CH2, CHN, NH, OCH3), 1.45–0.82 (m, 15 H with 3 s at
= 1.25, 1.24, 1.23, CH3, t-C4H9)
2d
7.38–7.16 (m, 5 H, C6H5), 6.97 (br s, 1 H, NH), 3.68, 3.64 (2 s, 6 H, 2 OCH3), 3.45 (dd, J = 6.2, 7.6, 1 H, CH), 3.06 (dd, J = 6, 13.6,
(major) 1 H, CH), 2.97–2.81, 2.19, 1.93–1.69 (m, mc, m, 2 H, 2 H, 3 H, CH2, CH, NH), 1.31 (s, 9 H, t-C4H9)
2db
6.52 (s, 1 H, NH), 3.67, 3.63 (2 s, 6 H, 2 OCH3), 3.33–3.28, 2.70–2.58 (2 m, 1 H, 1 H, aliphat CH), 2.45 (t, J = 7.5, 2 H, CH2), 1.30
(minor) (s, 9 H, t-C4H9)
2e
7.03 (s, 1 H, NH), 3.72, 3.68 (2 s, 6 H, OCH3), 3.33 (q, J = 6.9, 1 H, CH), 3.06 (dd, J = 5.8, 6.7, 1 H, CH), 2.50–2.38 (m, 2 H, CH2),
(major) 2.03–1.85 (m, 3 H, CH2, NH), 1.34 (s, 9 H, t-C4H9), 1.30 (d, J = 7.1, 3 H, CH3)
2eb
(minor) (d, J = 6.9, 3 H, CH3)
7.09 (s, 1 H, NH), 3.71, 3.68 (2 s, 6 H, OCH3), 3.20 (q, J = 7.1, 1 H, CH), 2.87 (dd, J = 5.4, 7.2, 1 H, CH), 1.35 (s, 9 H, t-C4H9), 1.28
2f
6.77 (br s, 1 H, NH), 3.70, 3.68 (2 s, 6 H, OCH3), 3.09 (d, J = 5.6, 1 H, CH), 3.01 (t, J = 6.0, 1 H, CH), 2.45, 2.44 (2 t, J = 7.2, 7.5,
(major) 2 H, CH2), 1.94 (mc, 2 H, CH, CH2), 1.83–1.69 (m, 3 H, CH2, NH), 1.54–1.40, 1.25–1.11 (2 m, 1 H each, CH2), 1.33 (s, 9 H, t-C4H9),
0.90 (t, J = 7.4, 3 H, CH3), 0.89 (d, J = 6.8, 3 H, CH3)
2f
7.30 (br s, 1 H, NH), 3.71, 3.69 (2 s, 6 H, OCH3), 3.00 (d, J = 5.3, 1 H, CH), 2.80 (dd, J = 6.9, 7.0, 1 H, CH), 2.47 (br t, J = 7.4, 2
(minor) H, CH2), 2.10–1.87, 1.71–1.63, 1.52–1.43 (3 m, 4 H, 1 H, 1 H, CH, CH2, NH), 1.35 (s, 9 H, t-C4H9), 1.30–1.12 (m, 1 H, CH2), 0.96
(d, J = 6.8, 3 H, CH3), 0.91 (t, J = 7.2, 3 H, CH3)
2g
7.33–7.11 (m, 5 H, C6H5), 6.91 (br s, 1 H, NH), 3.67, 3.63 (2 s, 6 H, 2 OCH3), 3.41 (dd, J = 6.3, 7.5, 1 H, CH), 2.89–2.75 (m, 2 H,
(major) CH2), 2.41–1.73 (m, 5 H, CH2, NH), 1.29 (s, 3 H, CH3), 1.18 (s, 9 H, t-C4H9)
2gb
3.68, 3.62 (2 s, 6 H, 2 OCH3), 3.53 (dd, J = 5.7, 8, 1 H, CH), 2.97 (dd, J = 5.6, 13.4, 1 H, CH2), 1.11 (s, 3 H, CH3)
(minor)
a Recorded on a 200 MHz spectrometer.
b Missing signals are hidden by the signals of the major isomer.
aldehyde 1, no clear effect of this additional chiral unit is the reactions is moderate to good depending on the amino
recorded. The diastereoselectivities of series a and b are acid employed and deserves further investigations.
rather similar and mainly dependent on the size of the
amino acid substituent R1.19
All reactions were performed under argon in flame-dried flasks, and
the components were added by means of syringes. All solvents were
dried by standard methods. IR spectra were measured with a Perkin
Elmer spectrometer IR-325 or Nicolet 205. 1H and 13C NMR spectra
were recorded on Bruker instruments (AC 200, AC 300 or DXR
Conclusion
500) in CDCl3 solution. The chemical shifts are given in relative to
We could demonstrate in this study that methyl 2-siloxy-
the TMS or to the CDCl3 signal ( H = 7.27, C = 77.0). Missing sig-
cyclopropanecarboxylates A may serve as equivalent of
nals of minor isomers are hidden by signals of major isomers, or
-formyl esters B in the Ugi 5-center 4-component reac-
they could not be unambiguously identified due to low intensity.
tion. The primary products 2 are interesting in themselves,
since compounds of this type or derivatives thereof may
have biological activity. The four functional groups in 2
provide many possibilities for further transformations – as
an example the cyclization to pyrrolidine derivatives 4 has
been performed. If executed in a one-pot sequence the
overall process may be classified as a 6-center 4-compo-
nent reaction. Since precursor cyclopropanes A are easily
available in many structural variations, this new modifica-
tion of the Ugi reaction as presented here should allow
preparation of highly diverse libraries of compounds 2 or
4 as well as of other products. The diastereoselectivity of
Neutral alumina (activity III, Fa. Merck) was used for column chro-
matography. Melting points (uncorrected) were measured with an
apparatus from Büchi (SMP-20). Optical rotations were determined
in a 1 mL cell with a pathlength of 10 cm using a Perkin-Elmer 241
polarimeter (Na D-line). The [ ]D values are given in 10–1 deg cm2
g–1 and the concentrations are given in g/100 mL. Amino acids were
commercially available and were used as received.
Siloxycyclopropanes 3a–d,20 and the formyl ester 115 were prepared
by literature known methods.
Iminodicarboxylic Derivatives 2, General Procedure 1
To a solution of -keto ester 1 or cyclopropanecarboxylate 3 (1.0
equiv) in MeOH (10 mL/mmol), the appropriate amino acid (1.0
equiv) and tert-butylisonitrile (1.0 equiv) were added at –30 °C. The
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

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Siloxycyclopropanes in Ugi Four-Component Reaction
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Table 4 13C NMR Data of Primary Products 2
Product
13C NMR (CDCl3, 75.5 MHz),
2aa
174.2, 174.0, 173.2, 173.0, 172.2, 171.7, 171.3, 171.0, 170.6 (9 s, CO2Me, CONHt-Bu), 137.5, 136.9, 136.8, 136.7, 129.4, 129.3,
129.2, 129.0, 128.9, 128.8, 128.7, 128.6, 127.2, 127.0, 126.9 (4 s, 11 d, C6H5), 66.0, 65.8, 65.7, 65.6, 62.8, 62.3, 62.1, 59.3 (8 d,
CHN), 52.0, 51.9, 51.8, 51.5, 51.4, 51.3, 50.8 (7 q, OCH3), 50.8, 50.7, 50.2, 50.1 [4 s, C(CH3)3], 40.3, 39.1, 38.9, 38.0, 37.8, 37.7,
37.6, 37.5 (8 t, CH2), 33.8, 33.7, 33.6, 33.1 (4 d, CH), 28.7, 28.6, 28.55, 28.5 [4 q, C(CH3)3], 16.0, 15.6, 15.2, 15.1 (4 q, CH3)
2ba
2c
175.5, 174.7, 173.3, 172.9, 171.9, 171.5, 171.2, 171.1 (8 s, CO2Me, CONHt-Bu), 136.5–110.6 (several s and d, indolyl-C), 66.1,
62.1, 61.5, 61.45, 61.4, 58.6, 52.9, 52.8 (8 d, CHN), 51.9-51.4 (several q, OCH3), 50.7, 28.6, 28.56, 28.4 [s, 3 q, C(CH3)3], 37.8–
37.5, 32.0–30.5 (several t, CH2), 33.7, 33.65, 33.4, 28.4 (4 d, CH), 15.9, 15.6, 15.0 (3 q, CH3)
175.3, 175.0, 174.8, 173.8, 173.3, 173.1, 171.9, 171.7, 171.6, 171.5, 170.9, 170.7 (12 s, CO2Me, CONHt-Bu), 69.3, 68.2, 65.9,
65.8, 65.2, 64.8, 64.6, 64.5 (8 d, CHN), 52.6, 52.5, 51.9, 51.7, 51.6, 51.6, 51.5, 51.4 (8 q, OCH3), 51.3, 51.0, 50.8, 50.6, 28.7, 28.6,
28.5, 28.4 [4 s, 4 q, C(CH3)3], 37.8, 37.7, 37.6, 37.3 (4 t, CH2), 34.0, 33.7, 33.6, 33.3, (4 d, CH), 21.1, 20.0, 19.7, 17.9, 16.0, 15.5,
15.4, 15.3, 14.5, 14.1, 13.8, 13.4 (12 q, CH3)
2d
173.9, 173.6, 172.2 (3 s, CO2Me, CONHt-Bu), 136.8, 129.3, 129.1, 128.6 (s, 3 d, C6H5), 61.8, 61.6 (2 d, 2 CH), 51.8, 51.5 (2 q, 2
(major)
OCH3), 50.5, 28.6 [s, q, C(CH3)3], 39.0, 30.0, 28.5 (3 t, 3 CH2)
2d
174.8, 173.7, 171.9 (3 s, CO2Me, CONHBu-t), 137.5, 129.1, 128.6, 126.9 (s, 3 d, C6H5), 62.1, 61.9 (2 d, 2 CH), 51.9, 51.55 (2 q,
(minor)
2 OCH3), 50.0, 28.3 [s, q, C(CH3)3], 40.1, 30.5, 28.9 (3 t, 3 CH2)
2e
174.7, 173.7, 172.3 (3 s, CO2Me, CONHt-Bu), 60.6, 55.1 (2 d, CHN), 51.8, 51.5 (2 q, OCH3), 50.5, 28.5 [s, q, C(CH3)3], 30.3, 28.5
(major)
(2 t, CH2), 17.8 (q, CH3)
2e
175.5, 173.6, 172.2 (3 s, CO2Me, CONHt-Bu), 61.9, 55.4 (2 d, CHN), 51.7, 51.3 (2 q, OCH3), 50.3, 28.4 [s, q, C(CH3)3], 30.4, 28.6
(minor)
(2 t, CH2), 19.6 (q, CH3)
2f
(major)
174.6, 173.9, 172.5 (3 s, CO2Me, CONHt-Bu), 64.9, 62.2 (2 d, CHN), 51.7, 51.6 (2 q, OCH3), 50.7, 28.6 [s, q, C(CH3)3], 38.1 (d,
CH), 30.3b (t, CH2), 25.4 (t, CH2), 15.3 (q, CH3), 11.5 (q, CH3)
2f
174.9, 173.8, 172.3 (3 s, CO2Me, CONHt-Bu), 65.0, 62.4 (2 d, CHN), 51.6, 51.5 (2 q, OCH3), 50.4, 28.7 [s, q, C(CH3)3], 38.4 (d,
(minor)
CH), 30.6, 28.9, 24.8 (3 t, 3 CH2), 16.4, 11.6 (2 q, CH3)
2g
176.4, 173.7, 173.6 (3 s, CO2Me, CONHt-Bu), 137.0, 129.4, 128.6, 127.0 (s, 3 d, C6H5), 61.8 (s, CNH), 58.1 (d, CH), 52.0, 51.6
(major)
(2 q, OCH3), 50.3, 28.5 [s, q, C(CH3)3], 41.8, 35.6, 29.7 (3 t, 3 CH2), 21.4 (q, CH3)
2g
175.8, 174.0 (2 s, CO2Me, CONHt-Bu), 136.9, 129.3 (s, d, C6H5), 61.5 (s, CNH), 57.2 (d, CH), 51.5 (q, OCH3), 50.5, 28.6 [s, q,
(minor)
C(CH3)3], 41.2, 33.3, 28.7 (3 t, 3 CH2), 22.9 (q, CH3)
a Recorded on a 50.3 MHz spectrometer.
b Two C atoms.
resulting suspension was allowed to warm up to r.t. and stirred for
the time indicated in Table 1. After removal of MeOH the residue
was purified by column chromatography. The spectroscopic data
are compiled in Tables 3 and 4.
Methyl 2-(2-tert-Butylcarbamoyl-3,3-dimethyl-5-
oxopyrrolidin-1-yl)-3-phenylpropanoate (4g); One-pot
Procedure
According to the general procedure 1, cyclopropanecarboxylate 3c
(0.648 g, 3.0 mmol), phenylalanine (0.495 g, 3.0 mmol), and tert-
butylisonitrile (0.249 g, 3.0 mmol) in MeOH (30 mL) were stirred
for 72 h at r.t. and subsequently 24 h under reflux. Column chroma-
tography (hexane–EtOAc, 1:1 2:1) of the resulting crude product
yielded 4g (0.157 g, 16%, mixture of 2 diastereomers = 53:47) as a
colourless resin.
Lactams 4, General Procedure 2
A solution of primary product 2 in toluene (3 mL/mmol) was stirred
for 3 h (exception 2f: 96 h) under reflux (Table 2). After evapora-
tion of the solvent the residue was purified by column chromatog-
raphy. The spectroscopic data are compiled in Tables 4 and 5.
1H NMR (300 MHz, CDCl3): (major diastereomer) = 7.32–7.20
(m, 5 H, C6H5), 6.55 (br s, 1 H, NH), 5.02 (dd, J = 7, 10 Hz, 1 H, 1’-
H), 3.68 (s, 3 H, OCH3), 3.50 (s, 1 H, 2-H), 3.30 (dd, J = 7, 14.5 Hz,
1 H, 2’-H), 2.98 (dd, J = 10, 14.5 Hz, 1 H, 2’-H), 2.45 (d, J = 16.5
Hz, 1 H, 4-H), 1.98 (d, J = 16.5 Hz, 1 H, 4-H), 1.34 (s, 9 H, t-C4H9),
1.08, 0.80 (2 s, 3 H each, 3-CH3);
Methyl 2-(2-tert-Butylcarbamoyl-3-methyl-5-oxopyrrolidin-1-
yl)-3-phenylpropanoate (4a); One-pot Procedure
According to the general procedure 1, cyclopropanecarboxylate 3a
(0.404 g, 2.0 mmol), phenylalanine (0.330 g, 2.0 mmol), and tert-
butylisonitrile (0.166 g, 2.0 mmol) in MeOH (20 mL) were stirred
for 50 h at r.t. After removal of the solvent, the residue was dis-
solved in toluene (10 mL) and the solution was heated for 3 h. Col-
umn chromatography (hexane–EtOAc, 1:1) of the crude product
yielded 4a (0.483 g, 67%) as a mixture of 4 diastereomers
(51:41:4:4). An amount of 56 mg of the major cis diastereomer
(minor diastereomer) = 7.32–7.20 (m, 5 H, C6H5), 7.05 (br s, 1 H,
NH), 4.12 (dd, J = 6.5, 10 Hz, 1 H, 1’-H), 3.82 (s, 3 H, OCH3), 3.43
(dd, J = 10, 14 Hz, 1 H, 2’-H), 3.34 (dd, J = 6.5, 14 Hz, 1 H, 2’-H),
2.97 (s, 1 H, 2-H), 2.33 (d, J = 16.5 Hz, 1 H, 4-H), 2.03 (d, J = 16.5
Hz, 1 H, 4-H), 1.33 (s, 9 H, t-C4H9), 1.02, 0.75 (2 s, 3 H each, 3-
CH3).
23
could be separated; [ ]D –88.3 (c = 0.49, CHCl3). The spectro-
scopic data are compiled in Tables 4 and 5.
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

1656
R. Zimmer et al.
PAPER
Table 5 1H NMR Data of Lactams 4
Product
1H NMR (300 MHz, CDCl3/TMS); , J (Hz)
4aa
(cis)
7.42–7.08 (m, 6 H, C6H5, NH), 3.93 (dd, J = 6, 10, 1 H, 1’-H), 3.84 (s, 3 H, OCH3), 3.41 (dd, J = 10, 14, 1 H, 2’-H), 3.30 (dd, J =
6, 14, 1 H, 2’-H), 2.98 (d, J = 8.5, 1 H, 2-H), 2.39 (dd, J = 7, 13.5, 1 H, 4-H), 2.32–2.19 (m, 2 H, 3-H, 4-H), 1.32 (s, 9 H, t-C4H9),
0.95 (d, J = 6.5, 3 H, 3-CH3)
4aa
(trans)
7.35 (s, 1 H, NH), 7.32–7.15 (m, 5 H, C6H5), 3.97 (dd, J = 5.5, 11, 1 H, 1’-H), 3.86 (s, 3 H, OCH3), 3.47 (dd, J = 11, 14, 1 H, 2’-
H), 3.36 (dd, J = 5.5, 14, 1 H, 2’-H), 2.73 (d, J = 4, 1 H, 2-H), 2.60 (dd, J = 9, 17, 1 H, 4-H), 2.25–2.18 (m, 1 H, 3-H), 1.86 (dd, J
= 5, 17, 1 H, 4-H), 1.32 (s, 9 H, t-C4H9), 0.76 (d, J = 7, 3 H, 3-CH3)
4ab,c
7.09, 6.55 (2 br s, 0.5 H each, NH), 3.71, 3.67 (2 s, 1.5 H each, OCH3), 3.53 (d, J = 3, 0.5 H, 2-H), 2.68 (dd, J = 8.5, 17, 0.5 H, 2’-
H), 2.38 (d, J = 7.5, 0.5 H, 2-H), 1.37, 1.36 (2 s, 4.5 H each, t-C4H9), 1.06, 0.86 (2 d, J = 6.5, 7, 1.5 H each, 3-CH3)
4ba
(cis)
8.16 (br s, 1 H, NH), 7.55–6.98 (m, 6 H, arom CH, NH), 4.11 (dd, J = 5, 11, 1 H, 1’-H), 3.86 (s, 3 H, OCH3), 3.59 (dd, J = 11, 15,
1 H, 2’-H), 3.43 (dd, J = 5, 15, 1 H, 2’-H), 3.08 (d, J = 9, 1 H, 2-H), 2.33 (dd, J = 8.5, 16.5, 1 H, 4-H), 2.08 (dd, J = 11.5, 16.5, 1
H, 4-H), 2.03–1.92 (m, 1 H, 3-H), 1.26 (s, 9 H, t-C4H9), 0.88 (d, J = 7, 3 H, 3-CH3)
4ba
(trans)
8.55 (br s, 1 H, NH), 7.55–6.98 (m, 6 H, arom CH, NH), 4.09 (dd, J = 5, 11, 1 H, 1’-H), 3.87 (s, 3 H, OCH3), 3.67 (dd, J = 11, 15,
1 H, 2’-H), 3.45 (dd, J = 5, 15, 1 H, 2’-H), 2.67 (d, J = 4, 1 H, 2-H), 2.55 (dd, J = 9, 17, 1 H, 4-H), 2.18–2.13 (m, 1 H, 3-H), 1.78
(dd, J = 5, 17, 1 H, 4-H), 1.28 (s, 9 H, t-C4H9), 0.50 (d, J = 7, 3 H, 3-CH3)
4bb,d
8.60 (br s, 1 H, NH), 7.54, 7.51 (br s, 1 H, NHindol), 3.80, 3.85 (2 s, 3 H, OCH3), 0.89, 0.55 (2 d, J = 7 each, 3 H, 3-CH3)
4ca
7.25 (s, 1 H, NH), 4.41 (q, J = 7.6, 1 H, 1’-H), 4.02 (d, J = 9, 1 H, 2-H), 3.77 (s, 3 H, OCH3), 2.74–2.67 (m, 1 H, 3-H), 2.45 (dd, J
(cis)
= 8.5, 16.6, 1 H, 4-H), 2.23 (dd, J = 11.3, 16.6, 1 H, 4-H), 1.43 (d, J = 7.7, 3 H, 2’-H), 1.35 (s, 9 H, t-C4H9), 1.13 (d, J = 7, 3 H, 3-
CH3)
4c
(trans)
6.80 (s, 1 H, NH), 4.07 (q, J = 7.2, 1 H, 1’-H), 3.77 (s, 3 H, OCH3), 3.57 (d, J = 3.1, 1 H, 2-H), 2.67 (dd, J = 8.3, 16.8, 1 H, 4-H),
2.48–2.43 (m, 1 H, 3-H), 1.93 (dd, J = 3.7, 16.8, 1 H, 4-H), 1.42 (d, J = 7.2, 3 H, 2’-H), 1.34 (s, 9 H, t-C4H9), 1.22 (d, J = 7, 3 H,
3-CH3)
4da
(major)
7.58 (s, 1 H, NH), 7.31–7.25, 7.14–7.12 (2 m, 3 H, 2 H, C6H5), 3.88–3.86 (m, 1 H, 1’-H), 3.86 (s, 3 H, OCH3), 3.40 (dd, J = 11.4,
13.8, 1 H, 2’-H), 3.31 (dd, J = 5, 13.8, 1 H, 2’-H), 2.92 (q, J = 3.8, 1 H, 2-H), 2.41–2.34, 2.25–2.19, 2.03–1.88 (3 m, 1 H, 1 H, 2
H, 3-H, 4-H), 1.30 (s, 9 H, t-C4H9)
4db
3.85 (s, 3 H, OCH3), 1.29 (s, 9 H, t-C4H9)
(minor)
4e
7.63, 6.87 (2 br s, 0.36 H, 0.64 H, NH), 4.18–4.03, 3.73–3.60 (2 m, 1 H each, CH), 3.79, 3.80 (2 s, 3 H each, OCH3), 2.59–2.05 (m,
4 H, CH2), 1.90–0.85 (m, 12 H, CH3, with s at = 1.36, t-C4H9)
4f
6.81, 6.45 (2 br s, 0.85 H, 0.15 H, NH), 4.48 (dd, J = 3, 9, 0.15 H, 2-H), 4.11 (dd, J = 3, 9.5, 0.85 H, 2-H), 4.06 (d, J = 7.5, 1 H, 1’-
H), 3.77, 3.72 (2 s, 2.55 H, 0.45 H, OCH3), 2.69–2.51, 2.41–2.25, 2.21–1.95 (3 m, 1 H, 2 H, 2 H, 3-H, 4-H, 2’-H), 1.62–1.51 (m,
1 H, 3’-H), 1.37, 1.35 (2 s, 7.65 H, 1.35 H, t-C4H9), 1.19–1.02 (m, 1 H, 3’-H), 0.96 (d, J = 7, 1 H, 2’-CH3), 0.88 (t, J = 7.5, 1 H, 4’-H)
a Recorded on a 500 MHz spectrometer.
b Missing signals are hidden by the signals of the major isomer.
c Overlapped with signals of both 4% diastereomers of 4a.
d Overlapped with signals of both 3% diastereomers of 4b.
13C NMR (75.5 MHz, CDCl3): (major diastereomer) = 175.6,
171.7, 168.6 (3 s, CO2Me, CON), 135.9, 128.8, 128.6, 127.1 (s, 3 d,
C6H5), 70.5 (d, C-2), 55.4 (d, C-1’), 52.5 (q, OCH3), 51.7, 28.6 [s,
q, C(CH3)3], 44.4 (t, C-4), 37.3 (s, C-3), 34.5 (t, C-2’), 29.7, 23.9 (2
q, 3-CH3); (minor diastereomer) = 174.7, 171.0, 168.5 (3 s,
CO2Me, CON), 136.7, 129.2, 128.8, 127.1 (s, 3 d, C6H5), 74.5 (d, C-
2), 58.6 (d, C-1’), 52.8 (q, OCH3), 51.1, 28.6 [s, q, C(CH3)3], 45.1
(t, C-4), 36.4 (s, C-3), 34.7 (t, C-2’), 29.7, 24.4 (2 q, 3-CH3).
2-(2-tert-Butylcarbamoylpyrrolidin-1-yl)-3-phenylpropan-1-ol
(5d)
To a solution of the isomerically pure lactam 4d (0.030 g, 0.086
mmol) in anhyd THF (2 mL) was added LiAlH4 (0.026 g, 0.688
mmol) and the suspension was stirred for 16 h at r.t. Then the reac-
tion mixture was carefully treated with H2O (0.03 mL), aq 2 N
NaOH solution (0.06 mL) and again with H2O (0.03 mL). After ex-
traction with EtOAc (3 5 mL) the combined organic phases were
dried (Na2SO4) and concentrated to provide the crude product
(0.030 g). Purification by colum chromatography (silica gel,
EtOAc–MeOH, 95:5) afforded 0.021 g (81%) of 5d as colorless
crystals, mp 125–127 °C; [ ]D22 +37.6 (c = 0.34, CHCl3).
1H NMR (300 MHz, CDCl3): = 7.41 (s, 1 H, NH), 7.31–7.14 (m,
5 H, C6H5), 3.63–3.49 (m, 2 H, 1’-H), 3.33 (dd, J = 4, 9.7 Hz, 1 H,
2-H), 3.12–3.06, 3.01–2.93, 2.85–2.73 (3 m, 4 H, 5-H, 2’H, 3’-H),
2.55 (dd, J = 9.8, 13.4 Hz, 1 H, 3’-H), 2.14–1.67 (m, 5 H, 3-H, 4-H,
OH), 1.31 (s, 9 H, t-C4H9).
IR (neat): = 3330 (N–H), 3100–2940 (=C–H, C–H), 1730 (C=O,
ester), 1700 (C=O, lactam), 1675 cm–1 (C=O, amide).
MS (EI, 70 eV): m/z (%) = 734 (M+, 1), 276 (15), 274 (70), 214 (15),
91 (12), 57 (15), 41 (13), 32 (100), 26 (13).
Anal. Calcd for C21H30N2O4 (374.5): C, 67.36; H, 8.07; N, 7.48.
Found C, 67.70; H, 8.56; N, 7.95.
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Siloxycyclopropanes in Ugi Four-Component Reaction
1657
Table 6 13C NMR Data of Lactams 4a
Product
C-2 (d)
68.4
C-3 (d) C-4 (t)
C-5 (s)
168.0
Other Signals
4ab
30.9
37.5
175.2 (s, CONHt-Bu), 170.7 (s, CO2Me), 136.9, 129.0, 128.8, 127.2 (s, 3 d, C6H5), 59.3
(cis)
(d, C-1’), 52.9 (q, OCH3), 51.6, 28.6 [s, q, C(CH3)3], 34.5 (t, C-2’), 15.6 (q, 3-CH3)
4ab
71.8
33.1
37.8
170.6
175.1 (s, CONHt-Bu), 171.0 (s, CO2Me), 136.6, 129.3, 128.9, 127.2 (s, 3 d, C6H5), 58.8
(trans)
(d, C-1’), 53.0 (q, OCH3), 51.2, 28.5 [s, q, C(CH3)3], 34.2 (t, C-2’), 20.9 (q, 3-CH3)
4ac
67.9
64.2
33.9
31.9
37.4
37.2
170.7
168.3
176.5, 176.1 (2 s, CONHt-Bu), 172.5, 170.6 (2 s, CO2Me), 135.9, 135.8, 129.3, 129.2,
128.7, 128.4, 127.1, 126.9 (2 s, 6 d, C6H5), 56.1, 55.6 (2 d, C-1’), 52.7, 52.5 (2 q, OCH3),
51.7, 51.6, 28.5 [2 s, q, C(CH3)3], 34.6, 34.4 (2 t, C-2’), 20.6, 15.4 (2 q, 3-CH3)
4b
(cis)
68.2
71.6
30.7
32.9
37.6
37.7
168.3
170.9
175.4, 171.0 (2 s, CO2Me, CONHt-Bu), 136.2, 127.2, 122.4, 122.3, 119.5, 118.2, 111.4,
111.1 (2 s, 5 d, s, indolyl-C), 58.9 (d, C-1’), 52.9 (q, OCH3), 51.6, 28.4 [s, q, C(CH3)3],
24.1 (t, C-2’), 15.5 (q, 3-CH3)
4b
(trans)
175.4, 171.2, (3 s, CO2Me, CONHt-Bu), 136.3, 127.2, 122.8, 122.3, 119.7, 118.3,
111.4, 110.7 (2 s, 5 d, s, indol-C), 58.5 (d, C-1’), 53.0 (q, OCH3), 51.2, 28.6 [s, q,
C(CH3)3], 23.8 (t, C-2’), 20.4 (q, 3-CH3)
4cb
(cis)
64.6
69.4
64.5
60.3
61.9
60.7
61.2
59.4
31.5
37.7
37.7
29.3
25.7
25.7
25.0
168.6
170.6
170.7
170.9
171.2
171.5
170.8
171.5
175.9 (s, CONHt-Bu), 173.5 (s, CO2Me), 52.8 (q, OCH3), 51.7 (d, C-1’), 51.6, 28.6 [s,
q, C(CH3)3], 15.8 (q, 3-CH3), 14.2 (q, C-2’)
4cb
(trans)
33.3
175.0 (s, CONHt-Bu), 171.6 (s, CO2Me), 52.7 (q, OCH3), 52.0 (d, C-1’), 51.4, 28.6 [s,
q, C(CH3)3], 21.1 (q, 3-CH3), 13.8 (q, C-2’)
4db
(major)
25.2, t
34.4, t
29.4, t
29.3, t
175.9, 171.0 (2 s, CO2Me, CONHt-Bu), 136.9, 129.0, 128.9, 127.3 (s, 3 d, C6H5), 59.5
(d, C-1’), 53.1 (q, OCH3), 51.4, 28.6 [s, q, C(CH3)3], 34.2 (t, C-2’)
4db
(minor)
176.9, 172.2 (2 s, CO2Me, CONHt-Bu), 136.7 (s, C6H5), 56.3 (d, C-1’), 52.4 (q, OCH3),
51.2, 28.3 [s, q, C(CH3)3]
4e
(major)
175.8, 174.0 (2 s, CO2Me, CONHt-Bu), 52.7 (d, C-1’), 52.0 (q, OCH3), 51.4, 28.7 [s, q,
C(CH3)3], 14.1 (q, CH3)
4e
(minor)
176.9, 171.7 (2 s, CO2Me, CONHt-Bu), 51.9 (q, OCH3), 51.7 (d, C-1’), 51.3, 28.8 [s, q,
C(CH3)3], 14.15 (q, CH3)
4f
(major)
29.35, t 25.5
29.25, t 26.4
176.1, 171.2 (2 s, CO2Me, CONHt-Bu), 62.6 (d, C-1’), 52.2 (q, OCH3), 51.4, 28.5 [s, q,
C(CH3)3], 35.4 (d, C-2’), 24.8 (t, C-3’), 16.3, 11.2 (2 q, 2 CH3)
4f
176.1, 171.3 (2 s, CO2Me, CONHt-Bu), 59.7 (d, C-1’), 52.1 (q, OCH3), 51.4, 28.5 [s, q,
(minor)
C(CH3)3], 33.8 (d, C-2’), 26.0 (t, C-3’), 15.4, 10.9 (2 q, 2 CH3)
a 75.5 MHz, CDCl3, .
b Recorded on a 126 MHz spectrometer.
c Overlapped with signals of both 4% diastereomers of 4a.
13C NMR (75.5 MHz, CDCl3): = 174.4 (s, CONHt-Bu), 139.0,
129.1, 128.6, 126.3 (s, 3 d, C6H5), 65.0 (d, C-2), 63.5 (d, C-2’), 62.0
(t, C-1’), 50.3, 28.6 [s, 3 q, C(CH3)3], 46.0 (t, C-3’), 32.7, 31.0 (2 t,
C-3, C-4).
The isolated pure diastereomer of 5c
[ ]D23 +67.0 (c = 0.42, CHCl3).
1H NMR (270 MHz, CDCl3): = 7.35 (s, 1 H, NH), 3.39 (d, J = 8
Hz, 2 H, 1’-H), 3.25–3.00, 2.85–2.76 (2 m, 2 H, 3 H, 3-H, 5-H, 2’-
H, OH), 2.63 (d, J = 9 Hz, 1 H, 2-H), 2.20–2.03, 1.95–1.78 (2 m, 1
H each, 4-H), 1.35 (s, 9 H, t-C4H9), 1.05, 0.87 (2 d, J = 7 Hz, 3 H
each, 3-CH3, 3’-H).
13C NMR (62.9 MHz, CDCl3): = 173.9 (s, CONHt-Bu), 72.7 (d,
C-2), 65.1 (t, C-1’), 56.4 (d, C-2’), 50.3, 28.7 [s, 3 q, C(CH3)3]), 43.2
(t, C-5), 38.9 (d, C-3), 32.4 (t, C-4), 20.1, 10.0 (2 q, 3-CH3, C-3’).
IR (KBr): = 3300 (br, O H, N H), 2990–2930 (C H), 1695
cm–1 (C=O).
Anal. Calcd for C18H28N2O2 (304.4): C, 70.99; H, 9.27; N, 9.24.
Found C, 70.51; H, 9.08; N, 8.96.
2-(2-tert-Butylcarbamoyl-3-methylpyrrolidin-1-yl)-1-propanol
(5c)
NMR signals of the other 3 diastereomers (* Signal has double in-
tensity).
1H NMR (270 MHz, CDCl3): = 7.30, 7.25 (2 br s, 0.7 H, 0.3 H,
NH), 3.43, 3.41, 3.40 (3 d, J = 8 Hz each, 2 H, 1’-H), 3.20–2.20 (m,
7 H, 2-H, 3-H, 4-H, 5-H, 2’-H, OH), 1.98–1.83 (m, 1 H, 4-H), 1.35
According to the procedure described above, a mixture of lactam 4c
(0.200 g, 0.704 mmol) and LiAlH4 (0.191 g, 6.20 mmol) in anhyd
THF (15 mL) was stirred for 18 h. Workup and purification of the
crude product (0.252 g) by chromatography (silica gel, EtOAc–
MeOH, 95:5) yielded 0.028 g (16%) of isomerically pure compound
5c and 0.077 g (45%) of 5c as a mixture of four diastereomers
(30:30:30:10).
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York

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R. Zimmer et al.
PAPER
(s, 9 H, t-C4H9), 1.08, 0.95, 0.93, 0.89, 0.88, 0.875 (6 d, J = 7 Hz
each, 6 H, 3-CH3, 3’-H).
(4) (a) Ugi, I.; Dömling, A.; Hörl, W.; Herdtweck, E. Angew.
Chem. 1996, 108, 185. (b) Ugi, I.; Dömling, A.; Hörl, W.;
Herdtweck, E. Angew. Chem. Int. Ed. Engl. 1996, 35, 173.
(5) Ugi, I.; Demharter, A.; Hörl, W.; Schmid, T. Tetrahedron
1996, 52, 11657.
(6) Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.; Lee,
D. H. Tetrahedron Lett. 1998, 39, 7109.
(7) Ugi, I.; Hörl, W.; Hanusch-Kompa, C.; Schmid, T.;
Herdtweck, E. Heterocycles 1998, 47, 965.
(8) Ebert, B. M.; Ugi, I.; Grosche, M.; Herdtweck, E.;
Herrmann, W. A. Tetrahedron 1998, 54, 11887.
(9) Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591.
(10) Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39,
2725.
(11) Review: Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73.
(12) Typical examples: (a) Schnaubelt, J.; Zschiesche, R.;
Reissig, H.-U.; Lindner, H. J.; Richter, J. Liebigs Ann. Chem.
1993, 61. (b) Ullmann, A.; Gruner, M.; Reissig, H.-U.
Chem.–Eur. J. 1999, 5, 187. (c) Schnaubelt, J.; Frey, B.;
Reissig, H.-U. Helv. Chim. Acta 1999, 82, 666. (d) Patra, P.
K.; Reissig, H.-U. Synlett 2001, 33.
(13) (a) Angert, H.; Czerwonka, R.; Reissig, H.-U. Liebigs Ann.
Chem. 1996, 259. (b) Khan, F. A.; Czerwonka, R.; Zimmer,
R.; Reissig, H.-U. Synlett 1997, 995. (c) Khan, F. A.;
Czerwonka, R.; Reissig, H.-U. Eur. J. Org. Chem. 2000,
3607.
(14) (a) Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1305.
(b) Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl.
1993, 32, 1244.
13C NMR (62.9 MHz, CDCl3): = 172.5*, 172.1 (2 s, CONHt-Bu),
71.2, 68.4* (2 d, C-1’), 65.0, 62.6, 61.6 (3 t, C-2), 58.9, 56.9, 56.4
(3 d, C-2’), 50.5, 50.2, 50.0, 28.7*, 28.6 [3 s, 2 q, C(CH3)3], 44.5,
43.2, 39.5 (3 t, C-5), 36.0, 33.3* (2 d, C-3), 32.1*, 29.9 (2 t, C-4),
20.5, 15.7*, 14.4, 10.4*, 10.0, 9.95 (6 q, 3-CH3, C-3’).
IR (KBr): = 3350 (br, O–H, N–H), 2990–2900 (C–H), 1690 cm–1
(C=O).
Anal. Calcd for C13H26N2O2 (242.4): C, 64.43; H, 10.81; N, 11.61.
Found C, 63.98; H, 10.68; N, 11.96.
X-Ray Crystal Structure Analysis of the Pyrrolidine 5d
Crystals of 5d suitable for X-ray analysis were obtained by recrys-
tallization from hexane–EtOAc.
C18H28N2O2, Mr = 304.4; T = 153(2) K; crystal size: 0.92 0.62
0.5 mm; orthorhombic, space group P212121, a = 6.3389(6), b =
9.4044(9), c = 30.300(3) Å; V = 1806.3(3) Å3; Z = 4; Dc = 1.119
Mg/m3; F(000) = 664; (Mo-K) = 0.073 mm–1. range for data
collection: 2.27–30.03°; index ranges: –8
h 8, –13 k 13, –42
l
42; reflections collected/unique: 21156/5258 (Rint = 0.0204);
final R [I>2 (I)]: R1 = 0.0547, wR2 = 0.1451; R (all data): R1 =
0.0633, wR2 = 0.1518. For structure solution and refinement, the
programs SHELXS97 and SHELXL97 were used.21 Atomic coordi-
nates and further crystallographic details have been deposited at the
Cambridge Crystallographic Data Centre, deposition number
CCDC 162256, and copies of this data can be obtained in applica-
tion to CCDC, University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, UK (fax: +44 1223-336033; E-mail: depos-
it@ccdc.cam.ac.uk).
(15) (a) Kunkel, E.; Reichelt, I.; Reissig, H.-U. Liebigs Ann.
Chem. 1984, 802. (b) Reissig, H.-U.; Reichelt, I.; Kunz, T.
Org. Synth. 1992, 71, 189.
(16) Use of enantiomerically pure 1 would not be very helpful to
reduce the number of stereoisomers, since it has been
reported that rather similar aldehydes undergoe partial
racemization during the Ugi reaction: Kelly, C. L.; Lawrie,
K. W. M.; Morgan, P.; Willis, C. L. Tetrahedron Lett. 2000,
41, 8001.
(17) This type of Ugi reactions with ketones has been reported
mainly with sterically less hindered isonitriles.9,10
(18) The configuration of the new stereogenic center of an (S)-
proline derived adduct was S-configured according to an X-
ray analysis, whereas the corresponding formula of this
compound was drawn as R-configured at this carbon.4
(19) The methyl group and the methoxycarbonylmethyl in R2
thus seem to have similar size in this reaction; for other
reactions of this type of -formyl esters, see: Angert, H.;
Kunz, T.; Reissig, H.-U. Tetrahedron 1992, 48, 5681.
(20) Kunkel, E.; Reichelt, I.; Reissig, H.-U. Liebigs Ann. Chem.
1984, 512.
Acknowledgement
We are most grateful for generous support of this work by the Fonds
der Chemischen Industrie. We thank Regina Czerwonka, Ute Hain
(TU Dresden) and Julia Richter (FU Berlin) for their experimental
help.
References
(1) X-ray analysis.
(2) For excellent up to date reviews, see: (a) Dömling, A.; Ugi,
I. Angew. Chem. 2000, 118, 3300. (b) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168. (c) Bienayme, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem.–Eur. J. 2000, 6,
3321. (d) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991, Chap. 4.6. (e) Ugi, I. J.
Prakt. Chem. 1997, 339, 499.
(3) For asymmetric variations of the Ugi reaction, see: Review:
(a) Kunz, H. In Houben-Weyl, 4th ed., Vol. E 21b;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 1945. (b) Lehnhoff, S.;
Goebel, M.; Karl, R. M.; Klösel, R.; Ugi, I. Angew. Chem.
1995, 107, 1208. (c) Lehnhoff, S.; Goebel, M.; Karl, R. M.;
Klösel, R.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1995, 34,
1104. (d) Ziegler, T.; Schlömer, R.; Koch, C. Tetrahedron
Lett. 1998, 39, 5960.
(21) Sheldrick, G. M. SHELX97 (Includes SHELXS97,
SHELXL97, CIFTAB) Programs for Crystal Structure
Analysis (Release 97-2); Universität Göttingen: Germany,
1998.
Synthesis 2001, No. 11, 1649–1658 ISSN 0039-7881 © Thieme Stuttgart · New York