The effect of Lewis acids on the stereochemistry in the Ugi three-component reaction with D-lyxo-pyrroline

Article abstract of DOI:10.1002/ejoc.200800340

A library of polyhydroxylated pyrrolidines was obtained by performing a tandem Staudinger/aza-Wittig/Ugi three-component reaction on a L-ribose-derived 4-azido aldehyde. In this paper we describe the effect of Lewis acids on the diastereoselectivity of th

Full text of DOI:10.1002/ejoc.200800340

FULL PAPER
DOI: 10.1002/ejoc.200800340
The Effect of Lewis Acids on the Stereochemistry in the Ugi Three-Component
Reaction with -lyxo-Pyrroline
D
Kimberly M. Bonger,[a][‡] Tom Wennekes,[a][‡] Dmitri V. Filippov,[a] Gerrit Lodder,[a]
Gijsbert A. van der Marel,[a] and Herman S. Overkleeft*[a]
Dedicated to Professor Jan Reedijk on the occasion of his 65th birthday and retirement
Keywords: Multicomponent reactions / Diastereoselectivity / Indium(III) chloride / Imines / Nitrogen heterocycles
A library of polyhydroxylated pyrrolidines was obtained by
performing a tandem Staudinger/aza-Wittig/Ugi three-com-
were formed. However, a significant amount of 2,3-trans
product was formed upon addition of Lewis acids to the Ugi
reaction mixture. The scope of this effect is explored by
evaluating a diverse set of Lewis acids in combination with
variation of other reaction parameters and the carboxylic
acid/isocyanide component.
ponent reaction on a
L-ribose-derived 4-azido aldehyde. In
this paper we describe the effect of Lewis acids on the dia-
stereoselectivity of the final Ugi three-component reaction
step that the intermediate (D-lyxo-pyrroline) cyclic imine un-
dergoes. When the Ugi reaction was performed in methanol
almost exclusively pyrrolidines with a 2,3-cis relationship
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Multicomponent reactions (MCRs) are frequently used In our studies on the scope of the SAWU-3CR, we observed
as a powerful method to generate large families of structur- that the 4-azidoaldehyde 1 produces pyrrolidines with
ally related molecules. Among MCRs, the Ugi reaction is counter-intuitive 2,3-cis stereochemistry at the new
one of the most explored to date.[1] We recently reported a stereogenic centre (Scheme 2).[3] This stereochemistry is es-
variation on the Ugi reaction that we named the tandem tablished in the final Ugi-3CR step with the cyclic imine[4]
Staudinger/aza-Wittig/Ugi
three-component
reaction (-lyxo-pyrroline 2). The Ugi-3CR mechanism consists of
(SAWU-3CR).[2] In this one-pot procedure, a carbohydrate- a series of successive equilibria where the C-2 stereogenic
derived 4-azido aldehyde (Scheme 1) is subjected to Stau- center is created upon attack of the isocyanide and fixed in
dinger reduction with trimethylphosphane. The inter- the irreversible Mumm-rearrangement (Scheme 2).
mediate phosphazene thereupon undergoes an intramolecu-
lar aza-Wittig reaction with the aldehyde to form an imine.
This cyclic imine is subsequently used as a component to-
gether with a carboxylic acid and an isocyanide in the Ugi
three-component reaction (Ugi-3CR).
Scheme 1. Overview of the SAWU-3CR reaction sequence.
[a] Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden
University,
PO Box 9502, 2300 RA Leiden, The Netherlands
Fax: +31-71-527-4307
E-mail: h.s.overkleeft@chem.leidenuniv.nl
[‡] K. M. Bonger and T. Wennekes contributed equally to this
work.
Scheme 2. Synthesis of pyrrolidines from the 4-azidoaldehyde 1
with the tandem SAWU-3CR.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ugi Three-Component Reaction with -lyxo-Pyrroline
The preferred formation of 2,3-cis pyrrolidines in the
In order to better understand what factors were causing
Ugi-3CR with 2 is not influenced by the carboxylic acid or the altered stereochemical outcome we further investigated
isocyanide component used.[3] Variation of the stoichiome- the InCl3-mediated Ugi-3CR. Table 2 presents the results
try of the carboxylic acid and isocyanide component or of of varying the amount of InCl3, the temperature and the
the reaction solvent and temperature also did not alter this concentration at which the reaction is performed. These ex-
preference for 2,3-cis products (unpublished results). In the periments show that formation of the 2,3-trans product is
study reported here we investigated what factors do influ- directly related to the amount of InCl3. In the presence of
ence the stereochemical outcome of the Ugi-3C reaction a catalytic amount of InCl3 the formation of 2,3-cis (3) was
with -lyxo-pyrroline 2.
still dominant. However, upon increasing the amount of
InCl3 the formation of 2,3-trans (4) also increased. Varia-
tion of the reaction temperature had a slight effect on the
stereochemical outcome and affected the overall yield. A
Results and Discussion
In related MCRs such as the Passerini-3CR, control of clear trend of increased yields at lower reaction tempera-
stereochemistry has been achieved by using Lewis acids tures was observed. Variation of the concentration of the
combined with chiral ligands.[5] For the Ugi reaction, cata- reaction had an effect on the stereochemical outcome of the
lytic properties of Lewis acids on the yield and reaction rate Ugi-3CR, but the effect does not appear to be associated
have been reported.[6] In addition, ZnCl2 has been shown with the presence of a Lewis acid. Performing the reaction
to induce diastereoselectivity in the Ugi reaction when com- in very dilute solutions increased the formation of the 2,3-
bined with chiral imines of glycosylamine derivatives.[7]
Consequently, we evaluated the effect of a diverse set of
Lewis acids on the Ugi-3C reaction of 2 with pentenoic acid
and 2,2,4,4-tetramethylbutyl isocyanide (tMB–NC). The re-
actions were performed by sequentially adding one equiv. of
Lewis acid, carboxylic acid and isocyanide to a methanolic
solution of 2 at 0 °C and stirring the reaction mixture for
2 h. The results are listed in Table 1 and it is apparent that
Lewis acids have a considerable effect on the stereochemical
outcome. In the presence of most Lewis acids, increased
formation of 2,3-trans isomer 4 occurred. Among all Lewis
trans product 4, both in the presence and absence of InCl3.
Table 2. The effect of Lewis acid amount and the temperature and
concentration of the Ugi-3C reaction.
Entry
InCl3
[equiv.]
T
[°C]
Conc.
[]
2,3-cis/2,3-trans
Yield (%)[a]
[8]
acids tested, InCl3 and HgBr2 (Entries 11 and 15) gave
Varying the amount of Lewis acid
the highest amount of the 2,3-trans product 4 with good
overall yields. For the other Lewis acids that showed high
amounts of the 2,3-trans product 4 [that is, AlCl3, SnCl4
and Yb(OTf)3], a significantly lower yield was observed.
1
2
3
4
0
0.2
1
0
0
0
0
0.1
0.1
0.1
0.1
Ͼ 90 : 10
75 : 25
42 : 58
72
70
75
81
5
28 : 72
Varying the reaction temperature
Table 1. The effect of Lewis acids on the Ugi-3C reaction of 2.
5
6
7
8
1
1
1
1
–40
0
20
40
0.1
0.1
0.1
0.1
48 : 52
42 : 58
33 : 67
60 : 40
85
75
63
44
Varying the reaction concentration (with InCl3)
9
10
11
1
1
1
0
0
0
2
0.2
0.02
45 : 55
42 : 58
30 : 70
74
62
52
Entry
Lewis acid
2,3-cis
2,3-trans
Yield (%)[a]
Varying the reaction concentration (no InCl3)
1
2
3
4
5
6
7
8
none
Ti(OiPr)4
CsF
LiOCl4
LiBr
MgBr2
TiCl4
Zr(OiPr)4
BF3·Et2O
ZnCl2
InCl3
AlCl3
Ͼ 90
Ͼ 90
81
76
74
63
60
57
55
50
42
40
34
33
29
10
10
19
24
26
37
40
43
45
50
58
60
66
67
71
72
50
53
87
58
91
42
61
63
85
75
47
42
58
84
12
13
14
0
0
0
0
0
0
2
0.2
0.02
Ͼ 90 : 10
Ͼ 90 : 10
78 : 22
58
66
80
[a] Ratio and yield based on products purified by column
chromatography.
The influence of the solvent on the Lewis acid mediated
Ugi reaction proved to be significant. Table 3 shows the ob-
tained ratios and yields for the Ugi-3CR with 2 as per-
formed in various solvents in the presence of one equiv. of
InCl3 at 0 °C. Only in DMF, methanol and acetonitrile a
significant amount of the 2,3-trans product 4 was formed.
The highest amount of the 2,3-trans product 4 was observed
for acetonitrile (Entry 10). When InCl3 was excluded from
9
10
11
12
13
14
15
SnCl4
Yb(OTf)3
HgBr2
[a] Ratio and yield based on products purified by column
chromatography.
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H. S. Overkleeft et al.
FULL PAPER
the Ugi reaction in acetonitrile the 2,3-cis product was Figure 1, respectively). In the presence of an excess isocya-
again the main product (Entry 11). This confirms that the nide and no InCl3, formation of the 2,3-cis product re-
solvent itself has no distinct effect on the stereochemical mained dominant and a significant increase in the reaction
outcome. The other efficient 2,3-trans promoting Lewis acid rate was observed (Figure 1, B). When 25-fold isocyanide
in methanol from Table 1, HgBr2, was also tested in aceto- was used in the presence of InCl3 the same increase in reac-
nitrile (Entry 12). Interestingly, no improved 2,3-trans prod- tion rate was observed but now accompanied with an in-
uct formation was observed, but instead the formation of crease in 2,3-trans (4) product formation. When an excess
2,3-trans decreased compared to the ratio obtained in meth- carboxylic acid was subjected to the reaction without InCl3,
anol.
similar increased reaction rates were observed as with excess
isocyanide (Figure 1, C). Upon addition of InCl3, the reac-
tion rate decreased significantly and the 2,3-cis isomer (3)
was again the main product. The same set of experiments
was also performed in acetonitrile with one equiv. of InCl3.
In this system, immediate formation of the Ugi-products
was observed in all cases (data not shown). As in the experi-
ments in methanol, a 25-fold excess of carboxylic acid in
acetonitrile with InCl3 altered the major product from 2,3-
trans (4) to 2,3-cis (3).
Table 3. The effect of the solvent of the Ugi-3C reaction.
Entry
Solvent
2,3-cis/2,3-trans Yield (%)[a]
1
2
3
4
5
6
7
8
THF
dioxane
CH2Cl2
2-propanol
hexane
toluene
EtOAc
DMF
MeOH
Ͼ 90 : 10
Ͼ 90 : 10
83 : 17
81 : 19
77 : 23
77 : 23
70 : 30
57 : 43
42 : 58
16 : 84
75 : 25
43 : 57
16
trace
41
27
66
56
39
32
75
Finally, the scope of the InCl3-mediated Ugi-3C reaction
with 2 in acetonitrile was evaluated with a diverse set of
carboxylic acids and isocyanides. Table 4 gives an overview
Table 4. The effect of the carboxylic acid and isocyanide compo-
nent on the InCl3-mediated Ugi-3CR of 2 in CH3CN.
9
10
11
12
CH3CN
CH3CN without InCl3
CH3CN with HgBr2
63
33
92
[a] Ratio and yield based on products purified by column
chromatography.
There is literature evidence that addition of (catalytic
amounts of) Lewis acid increases the reaction rate of Ugi-
MCRs.[6] We therefore investigated whether this also holds
true for our system with 2 and InCl3 in methanol. Part A
of Figure 1 depicts the formation of the 2,3-cis (3) and 2,3-
trans (4) products over time as monitored by LC/MS in the
presence and absence of InCl3. As previously observed the
addition of Lewis acid significantly increases the formation
of 2,3-trans (4). However, no effect on the overall reaction
rate was observed.
We next evaluated the effect of a 25-fold excess of the
isocyanide or carboxylic acid reaction partner on the Ugi-
3CR reaction rate and the product ratio in methanol in the
[a] Ratio and yield based on products purified by column
presence and absence of InCl3 (shown in parts B and C of chromatography.
Figure 1. Formation of Ugi-3CR products over time as monitored by LC/MS. A: 1 equiv. 2,2,4,4-tetramethylbutyl isocyanide (tMB–NC)
and 1 equiv. pentenoic acid, MeOH, 0.1 , 0 °C; B: 25 equiv. tMB–NC and 1 equiv. pentenoic acid, MeOH, 0.1 , 0 °C. C: 1 equiv. tMB–
NC and 25 equiv. pentenoic acid, MeOH, 0.1 , 0 °C. Filled gray circles: 2,3-cis (3) formed without InCl3; filled gray squares: 2,3-cis (3)
formed with 1 equiv. InCl3; open black squares: 2,3-trans (4) formed with 1 equiv. InCl3.
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Ugi Three-Component Reaction with -lyxo-Pyrroline
of the obtained products, 2,3-cis/trans ratios and overall
Attempts to substantiate the acyloxy model by investiga-
yields. For comparison, when these reactions are performed ting the intermediates of the Ugi-3CR with 13C-APT NMR
in methanol without Lewis acid the 2,3-cis substituted pyr- measurements in CD3OH were not conclusive. We did how-
rolidines are almost exclusively formed, as reported pre- ever observe an equilibrium of the imine 2 in CD3OH with
viously.[3] In all cases for the Lewis acid mediated Ugi-3C a second species that appears to be the CD3O adduct 8.
reaction with 2 formation of the 2,3-trans product equaled Upon addition of one equiv. of InCl3 to this solution the
or exceeded the formation of the 2,3-cis product. However, imine signals disappeared and the equilibrium fully shifted
the 2,3-cis/trans ratio is highly dependent on the carboxylic towards 8 (Figure 2). In the presence of InCl3, 8 proved
acid and isocyanide used. In the case of isocyanide V, a ca. stable to the addition of a carboxylic acid. When in a final
1:1 mixture of products was observed that is independent step isocyanide was added the species slowly disappeared
of the used carboxylic acid. In contrast, the isocyanide I (about 2 h) and the formation of 2,3-trans product 4 was
prefers formation of the 2,3-trans product in all cases. The observed.
overall yields are slightly lower than the reactions per-
formed in methanol without a Lewis acid.[9] The lower
yields could be caused by a known side reaction in which a
second isocyanide adds to intermediate 7 (see Scheme 3)
[10,5c]
or by the possible promotion of other side reactions,
such as the Ritter reaction,[11] by the Lewis acid in acetoni-
Figure 2. 13C-APT NMR showed addition of the solvent, CD3OH
to the imine 2. This equilibrium between 2 and 8 shifted towards
trile.
8 when InCl3 was added.
A second 13C-APT NMR experiment with 2 in CD3OH
in the absence of Lewis acid showed, upon addition of a
carboxylic acid, an equilibrium between 2 and two other
species that differed in their spectrum from putative 8.
These might be acyloxy intermediates, but could not be
conclusively assigned as such. The earlier mentioned obser-
vation that in the presence of InCl3, a 25-fold excess of car-
boxylic acid favours the formation of the 2,3-cis product
(Figure 2, C) while 2,3-trans product formation dominated
at a stoichiometric amount, might also indicate the involve-
ment of an acyloxy intermediate. However, the excess car-
Scheme 3. Isocyanide addition via acyloxy/contact ion-pair inter-
boxylic acid could also coordinate with InCl3, thereby make
it less available for interaction in the Ugi-3C reaction and
thus result in 2,3-cis pyrrolidine formation.
mediate 6.
A possible explanation for the diastereoselective forma-
Another plausible explanation for the 2,3-cis pyrrolidine
formation in the absence of Lewis acids involves the influ-
ence of electronic effects on the conformation of the acti-
vated cyclic imine 5 (X = H, Figure 3, A). Woerpel and co-
workers proposed a model for nucleophilic additions to
five-membered ring oxocarbenium ion electrophiles.[13] In
tion of 2,3-cis pyrrolidines in the Ugi-3C reaction with the
-lyxo-pyrroline 2 in the absence of Lewis acids may be
found in the existence of an acyloxy intermediate in the
course of the reaction (6; X = H, Scheme 3). This inter-
mediate was first postulated by Ugi and its involvement in
the Ugi reaction has subsequently been proposed by
others.[1b,4d,12]
The intermediate 6 (X = H) would be formed after pro-
tonation of the imine by the attack of the nearby carboxyl-
ate anion from the least hindered side of 5 (X = H). After
SN2 displacement by the isocyanide yielding 7-cis and sub-
sequent Mumm-rearrangement this pathway would lead to
the 2,3-cis pyrrolidine. Alternatively, the carboxylate anion
might form a contact ion pair with the protonated cyclic
imine and thereby shield the trans-face from isocyanide at-
tack.
A Lewis acid can coordinate to the endocyclic nitrogen
of the imine 2 and activate it. An explanation in the acyloxy
model for the increased formation of the 2,3-trans products
in the presence of Lewis acids may be that the Lewis acid
activated imine 5 (X = LA) might favour direct attack of
the isocyanide from the less hindered side to give 7-trans,
which leads to 2,3-trans-pyrrolidines (Scheme 3).
Figure 3. A: Formation of the 2,3-cis product from 5 by isocyanide
attack from the concave face of the favoured conformer. B: Forma-
tion of ca. 1:1 mixture from 10 due to absence of a favoured con-
former.
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H. S. Overkleeft et al.
FULL PAPER
this model, a pseudoaxial position of alkoxy substituents at acids could have an effect in the complex interplay of equi-
C-3 of the oxocarbenium ion produces the lowest energy libria between intermediates in the Ugi-3CR with 2
conformer by maximizing favourable intramolecular elec- (Scheme 2).
trostatic interactions. The nucleophile then attacks from the
In case of -lyxo-pyrroline 2, the imine at the basis of
concave site of the envelope conformation giving a 1,3-cis the here presented study, we now do have considerable con-
product. The -lyxo-pyrroline 2 also resides in an envelope trol over the stereochemical outcome when subjecting it to
conformation. The C-2/C-3 benzyloxy substituents in 2 also the Ugi-3CR. Increasing the amount of Lewis acid, per-
possess the required stereochemistry for the favoured pseu- forming the reaction at elevated temperature and in dilute
doaxial orientation after protonation to 5 (X = H). The solutions are factors that promote 2,3-trans pyrrolidine for-
favoured conformer of 5 (X = H) undergoes 1,3-cis attack mation. Omitting the Lewis acid or performing the reaction
of the isocyanide yielding 2,3-cis Ugi-3CR products (Fig- in an apolar solvent with Lewis acid leads to the formation
ure 3, A).
of the corresponding 2,3-cis pyrrolidines. The reaction con-
Woerpel and co-workers further demonstrated the “criti- ditions tolerate different carboxylic acids and isocyanides.
cal” electronic effect of the pseudoaxial C-3 alkyloxy sub- However, the extent of diastereoselectivity for 2,3-trans
stituents by testing a C-3 inverted -arabinose analogue.[13b] products in the InCl3 mediated Ugi-3CR in acetonitrile is
Adopting a C-3 pseudoaxial conformer for this oxocarb- dependent on the used pyrroline, carboxylic acid and isocy-
enium ion is disfavoured and a nucleophilic addition reac- anide. The fact that Lewis acids influence the stereochemi-
tion with it produced a 1:1 mixture of 1,3-cis and 1,3-trans cal outcome of the Ugi-3CR with -lyxo-pyrroline 2 might
attack products. Analogously, we performed the Ugi-3CR provide some insight into the mechanism of the Ugi-3C re-
on the -arabino-pyrroline 9, which is protonated to 10 (X action on prochiral imines.
= H; Figure 3, B). This reaction produced a 54:46 ratio of
We are currently investigating the (Lewis acid mediated)
2,3-cis (11) and 2,3-trans (12) products in 68% yield as op- SAWU-3C reaction with a set of 4-azido aldehydes and 5-
posed to the Ͼ 90:10 mixture obtained for -lyxo-pyrroline azido aldehydes derived from various furanose and pyra-
2. The loss of selectivity observed for 9 is in agreement with nose carbohydrates. The pyrrolidine and piperidine bis-
the results obtained by Woerpel and co-workers for five- amides obtained in these studies will be evaluated as imi-
membered ring oxocarbenium ions. This result can also be nosugar derivatives, with the potential to inhibit glycosyl
explained by the acyloxy model, because the inverted C- processing enzymes,[14] or as polyhydroxylated proline or pi-
3 position might lead to less stereoselective attack of the pecolic acid derivatives, which may be incorporated into
carboxylate on 10 (X = H).
peptides to improve their biophysical properties.[15]
Coordination and activation of the cyclic imine 2 by a
Lewis acid at the nitrogen might disturb the above (Fig-
ure 3, A) discussed electronic effects of the C-3 position. Experimental Section
Additionally, coordination of the Lewis acid with the ben-
General Methods: All solvents and reagents were obtained commer-
zyloxy ether substituents might stabilize the disfavoured
conformer or shield the cis-face of the activated imine 5 (X
= LA; Figure 3, A) and thereby lead to 2,3-trans products.
The increased formation of 2,3-trans pyrrolidines in the
cially and used as received unless stated otherwise. Methanol used
for Ugi reactions was distilled from magnesium turnings and io-
dine, and stored over activated 3-Å molecular sieves under argon.
Reactions were executed at ambient temperatures unless stated
presence of Lewis acid does not appear to be a general ef- otherwise. All moisture sensitive reactions were performed under
argon. Residual water was removed from starting compounds by
repeated coevaporation with toluene. All solvents were removed by
evaporation under reduced pressure. Column chromatography was
performed on silica gel (40–63 µm). 1H and 13C-APT NMR spectra
were recorded on a Bruker DMX 600 (600/150 MHz), Bruker
DMX 500 (500/125 MHz), or Bruker AV 400 (400/100 MHz) spec-
trometer in CDCl3. Chemical shifts are given in ppm (δ) relative to
tetramethylsilane as internal standard (1H NMR) or CDCl3 (13C
NMR). Coupling constants (J) are given in Hz. All presented 13C-
APT spectra are proton decoupled. High-resolution mass spectra
were recorded by direct injection (2 µL of a 2 µ solution in water/
acetonitrile; 50:50; v/v and 0.1% formic acid) with a mass spec-
trometer (Thermo Finnigan LTQ Orbitrap) equipped with an elec-
trospray ion source in positive mode (source voltage 3.5 kV, sheath
gas flow 10, capillary temperature 250 °C) with resolution R =
60000 at m/z 400 (mass range m/z = 150–2000) and dioctylphthalate
(m/z = 391.28428) as a “lock mass”.[16] The high-resolution mass
spectrometer was calibrated prior to measurements with a cali-
bration mixture (Thermo Finnigan). Optical rotations were mea-
sured with a Propol automatic polarimeter (sodium -line, λ =
589 nm). ATR-IR spectra were recorded with a Shimadzu FTIR-
fect for pyrroline cyclic imines in the Ugi-3CR. The -arab-
ino-pyrroline 9, pentenoic acid and 2,2,4,4-tetramethylbutyl
isocyanide were reacted in acetonitrile in the presence of
InCl3. In this Lewis acid mediated Ugi-3CR, a ca. 1:1
(44:56) 2,3-cis/trans product mixture was obtained (30%
yield). This ratio is almost the same as the ratio (54:46)
obtained for -arabino-pyrroline 9 in methanol in the ab-
sence of Lewis acid.
Conclusions
At present there is no conclusive evidence to discount or
confirm either of the above discussed models. However, if
the acyloxy intermediate is incorporated in the C-3/elec-
tronic model, in the absence of Lewis acid, it would predict
1,3-cis attack of the carboxylate resulting in 2,3-trans pyr-
rolidines. This fact makes the two models mutually exclus-
ive. It is challenging to further investigate the role of Lewis
acids because of the multitude of instances where Lewis 8300 fitted with a single bounce Durasample IR diamond crystal
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Ugi Three-Component Reaction with -lyxo-Pyrroline
ATR-element and are reported in cm–1. Rf values were determined
from TLC analysis using DC “fertigfolien” (Schleicher & Schuell,
F1500, LS254), detection was performed by spraying with a solu-
tion of (NH4)6Mo7O24·4H2O (25 g/L) and (NH4)4Ce(SO4)4·2H2O
(10 g/L) in 10% sulfuric acid or a solution of phosphomolybdic
acid hydrate (7.5 wt.-% in ethanol) followed by charring at ca.
150 °C.
CONH), 4.63 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.61 (d,
JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.58 (d, JHb-Ha = 12.0 Hz, 1 H,
CHH Bn), 4.52 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.51–4.46
(m, 2 H, CH2 Bn), 4.45 (s, 1 H, 2-H), 4.38–4.34 (m, 2 H, 4-H, 3-
H), 4.21–4.17 (m, 1 H, 5-H), 3.91–3.84 (m, 2 H, 6a-H, 6b-H), 1.68
(dd, J = 14.4, 55.8 Hz, 2 H, CH2 tBu), 1.34 (s, 6 H, 2ϫCH3), 0.95
(s, 9 H, 3ϫCH3 tBu) ppm. 13C NMR (100 MHz, CDCl3, HSQC),
major rotamer: δ = 167.3 (C), 163.8 (CHO), 137.8, 137.7, 137.4
(3ϫC Ar), 128.7, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6 (15ϫCH
Ar), 78.4 (C-4), 77.4 (C-3), 73.4, 72.6 (3ϫCH2 Bn), 70.7 (C-6), 63.4
(C-2), 58.4 (C-5), 55.3 (C tBu), 51.3 (CH2 tBu), 29.7, 29.2, 28.9
General Procedure for the SAWU-3CR Towards Substituted Pyrroli-
dines IA-D, IIA-D, IIIA-D, IVA-D, VA-D and 12-trans: The 4-azido-
pentanal 1 was coevaporated with toluene, dissolved in MeOH
(0.05 ) and cooled (0 °C). After dropwise addition of a solution
of trimethylphosphane (1  in toluene, 2 equiv.), stirring was con-
tinued for 3 h at 0 °C when TLC analysis indicated complete con-
sumption of the 4-azidopentanal and the appearance of the inter-
mediate phosphazene (Rf = 0 in 1:1; EtOAc/toluene). The reaction
mixture was concentrated and coevaporated with toluene, concomi-
tant TLC analysis showed complete disappearance of the baseline
phosphazene intermediate and emergence of the cyclic imine. For-
mation of the pyrroline 2 was confirmed by NMR analysis of the
crude product. (3R,4S,5R)-3,4-di-O-benzyl-5-(benzyloxymethyl)-1-
(5ϫCH ) ppm. IR (thin film): νmax = 3339, 2956, 1726, 1652, 1455,
˜
3
1365, 1284, 1125, 735, 698. [α]2D0 = –13.0 (c = 0.14, CHCl3). HRMS:
found 587.3476 [M + H]+, calculated for [C36H46O5N2 + H]+
587.3480.
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-formamido-N-(1,1,3,3-tet-
ramethylbutyl)-D-galacto-hexonamide (IA-2,3-cis): Yield 20%
(22.1 mg, 37 µmol), Ͼ10:1 mixture of rotamers. Rf = 0.26 (1:1; tolu-
1
ene/EtOAc). H NMR (500 MHz, CDCl3, COSY), major rotamer:
δ = 8.33 (s, 1 H, NCHO), 7.36–7.23 (m, 15 H, HAr), 6.05 (s, 1 H,
CONH), 4.78 (d, JHa-Hb = 11.6 Hz, 1 H, CHH Bn), 4.68 (d,
JHb-Ha = 11.5 Hz, 1 H, CHH Bn), 4.60 (d, JHa-Hb = 11.9 Hz, 1 H,
1
pyrroline (2). Rf = 0.34 (1:4; EtOAc/toluene). H NMR (200 MHz,
CDCl3): δ = 7.67 (s, 1 H, 2-H), 7.32–7.26 (m, 15 H, CHAr Bn),
4.72–4.50 (m, 7 H, 3ϫCH2 Bn, 3-H), 4.35 (d, J = 4.7 Hz, 1 H, 4- CHH Bn), 4.56 (d, JHa-Hb = 11.9 Hz, 1 H, CHH Bn), 5.52 (d,
H), 4.25–4.19 (m, 1 H, 5-H), 3.99–3.85 (m, 2 H, 6a-H, 6b-H) ppm.
13C NMR (50.1 MHz, CDCl3): δ = 166.9 (C-2), 138.0, 137.9, 137.2
(3ϫC Ar), 128.2, 127.9, 127.6, 127.4, 127.3 (9ϫCH Ar), 85.6, 77.7,
73.2 (C-3, C-4, C-5), 73.4, 73.1, 72.7 (3ϫCH2 Bn), 68.5 (C-6) ppm.
The crude pyrroline 2 is dissolved in MeOH or CH3CN (0.1 ),
divided in portions (0.2 mmol) and cooled (0 °C). The appropriate
JHb-Ha = 11.8 Hz, 1 H, CHH Bn), 4.46–4.39 (m, 3 H, 2-H, 3-H,
CHH Bn), 4.18–4.15 (m, 1 H, 5-H), 4.06 (app. t, J = 10.3 Hz, 1 H,
6a-H), 3.93 (dd, J = 4.1, 14.2 Hz, 1 H, 4-H), 3.77 (dd, J = 3.3,
10.4 Hz, 1 H, 6b-H), 1.64 (d, J = 15.0 Hz, 1 H, CHH tBu), 1.45
(d, J = 15.0 Hz, 1 H, CHH tBu), 1.29 (app. d, J = 35.8 Hz, 6 H,
2ϫCH3), 0.87 (s, 9 H, 3ϫCH3 tBu) . 13C NMR (125 MHz, CDCl3,
Lewis acid (1 equiv.) was added and subsequently the carboxylic HSQC), major rotamer: δ = 165.6 (C), 164.0 (CHO), 138.0, 137.7,
acid (1 equiv.) and isocyanide (1 equiv.) were added. The reaction
mixture was stirred for 2 h at 0 °C after which it was warmed to
137.0 (3ϫC Ar), 128.5, 128.4, 128.1, 127.9, 127.6, 127.5 (15ϫCH
Ar), 78.0 (C-4), 77.5 (C-3), 74.6, 73.2, 72.6 (3ϫCH2 Bn), 69.0 (C-
room temperature. Ethyl acetate was added to the mixture and the 6), 63.2 (C-2), 59.0 (C-5), 55.3 [C, NHC(CH3)2CH2tBu], 51.8 (CH2
organic phase was washed with aq. satd. NaHCO3. The organic
phase was dried (Na2SO4), concentrated and the product was iso-
lated by silica gel column chromatography (5Ǟ50% EtOAc in tol-
uene) to afford the SAWU-3CR product as a light yellow oil.
tBu), 31.5 (C tBu), 31.3, 28.4, 27.7 (5ϫCH3) ppm. IR (thin film):
ν
= 3290, 2955, 2871, 1725, 1682, 1455, 1366, 1286, 1128, 737,
˜
max
698 cm–1. [α]2D0 = +29.6 (c = 0.83, CHCl3). HRMS: found 587.3476
[M + H]+, calculated for [C36H46O5N2 + H]+ 587.3480.
Procedure for Monitoring the Formation of the 2,3-cis and 2,3-trans 2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(p-nitrobenzamido)-N-
Pyrrolidines (3 and 4) by LC/MS Analysis: The crude pyrroline 2
was dissolved in MeOH or CH3CN (0.1 ), and divided in portions
containing 0.1 mmol of 2. The solutions were cooled (0 °C) and
(when needed) InCl3 (0.1 mmol, 22.1 mg) was added. Subsequently,
pentenoic acid (0.1 mmol, 10.2 µL or 2.5 mmol, 255 µL) and
2,2,4,4-tetramethylbutyl isocyanide (0.1 mmol, 17.6 µL or
2.5 mmol, 440 µL) were added. The reaction was stirred for 2 h at
0 °C. During the reaction, samples (50 µL) were taken at t = 0.1,
0.5, 1, 2, 5, 10, 15, 30, 60 and 120 min and quenched in 500 µL of
a methanolic NaBH4 solution (1 ). After standing for 1 h the sam-
ples were further diluted with 500 µL of an acetone/methanol (1:5)
solution. For LC/MS analysis, 200 µL of the prepared samples was
further diluted with 800 µL methanol-containing Fmoc-phenylala-
(1,1,3,3-tetramethylbutyl)-D-talo-hexonamide (IB-2,3-trans): Yield
31% (43.9 mg, 62 µmol), 5:1 mixture of rotamers. Rf = 0.86 (1:1;
1
toluene/EtOAc). H NMR (400 MHz, CDCl3, COSY), major rot-
amer: δ = 7.98 (d, J = 8.4 Hz, 1 H, HAr), 7.43 (d, J = 8.4 Hz, 1 H,
HAr), 7.37–7.22 (m, 16 H, HAr), 6.93 (d, J = 8.4 Hz, 1 H, HAr),
5.87 (s, 1 H, CONH), 4.74 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn),
4.69 (s, 1 H, CHH Bn), 4.61 (d, J = 1.2 Hz, 1 H, CHH Bn), 4.57
(d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.52–4.50 (m, 1 H, 4-H), 4.46
(s, 1 H, 2-H), 4.38–4.35 (m, 1 H, 5-H), 4.16 (d, J = 4.2 Hz, 1 H, 3-
H), 4.11 (d, JHa-Hb = 10.8 Hz, 1 H, CHH Bn), 4.05 (d, J = 11.4 Hz,
1 H, CHH Bn), 3.74 (dd, J = 3.6, 10.2 Hz, 1 H, 6a-H), 3.67 (app. t,
J = 9.6 Hz, 1 H, 6b-H), 1.68 (dd, J = 14.4, 34.2 Hz, 2 H, CH2 tBu),
1.33 (app. d, J = 3.0 Hz, 6 H, 2ϫCH3), 0.97 (s, 9 H, 3ϫCH3 tBu)
nine (0.08 m) as an internal standard. The LC/MS UV-trace was ppm. 13C NMR (100 MHz, CDCl3, HSQC), major rotamer: δ =
measured at 214 nm and the peak surface areas of the 2,3-cis and 170.2, 167.6 (2ϫC), 148.0, 142.8, 137.6, 137.4 (5ϫC Ar), 128.6,
2,3-trans product were corrected to the internal standard. The total 128.5, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 123.3 (19ϫCH Ar),
Ugi product formation was normalized to 100% and the curves
were best-fitted by using Boltzmann sigmoidal equation
(GraphPad Prism V4.00, GraphPad Software, San Diego, CA).
79.0 (C-4), 78.2 (C-3), 73.1, 73.0, 72.9 (3ϫCH2 Bn), 70.4 (C-6),
66.6 (C-2), 60.1 (C-5), 55.7 [C, NHC(CH3)2CH2tBu], 51.7 (CH2
tBu), 31.6 (C tBu), 31.4, 28.9, 28.8 (5ϫCH3) ppm. IR (thin film):
a
ν
max = 3342, 2952, 1682, 1635, 1522, 1345, 1097, 911, 863, 734, 698
˜
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-formamido-N-(1,1,3,3-tet-
cm–1. [α]2D0 = –6.0 (c = 0.43, CHCl3). HRMS: found 708.3643 [M
ramethylbutyl)-D-talo-hexonamide (IA-2,3-trans): Yield 48%
+ H]+, calculated for [C42H49O7N3 + H]+ 708.3643.
(54.1 mg, 92 µmol), Ͼ10:1 mixture of rotamers. Rf = 0.71 (1:1; tolu-
1
ene/EtOAc). H NMR (400 MHz, CDCl3, COSY), major rotamer: 2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(p-nitrobenzamido)-N-
δ = 8.61 (s, 1 H, NCHO), 7.32–7.26 (m, 15 H, HAr), 6.72 (s, 1 H, (1,1,3,3-tetramethylbutyl)- -galacto-hexonamide (IB-2,3-cis): Yield
D
Eur. J. Org. Chem. 2008, 3678–3688
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3683

H. S. Overkleeft et al.
FULL PAPER
7% (9.9 mg, 14 µmol), complex mixture of rotamers. Rf = 0.40 (1:1;
toluene/EtOAc). 1H N M R (500 M H z, CD Cl3, COSY) broad
peaks: δ = 8.13 (br.s ppm. 2 H, HAr), 7.76 (br. s, 2 H, HAr), 6.56
(br. s, 1 H, CONH), 6.27 (br. s, 1 H, CONH), 7.31–7.26 (m, 15 H,
HRMS: found 641.3949 [M + H]+, calculated for [C40H52O5N2
H]+ 641.3949.
+
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-{N-[(9H-fluoren-9-yl-
methoxy)carbonyl]-2-aminoacetamido}-N-(1,1,3,3-tetramethyl-
butyl)-D-talo-hexonamide (ID-2,3-trans): Yield 19 % (31.8 mg,
H
Ar), 4.90–4.30 (m, 7 H), 4.30–3.70 (m, 5 H), 1.80–1.53 (m, 2 H,
CH2 tBu), 1.26 (s, 6 H, 2ϫCH3), 0.88 (s, 9 H, 3ϫCH3 tBu) ppm.
13C NMR (125 MHz, CDCl3, HSQC) broad peaks: δ = 128.4,
127.9, 127.8, 123.3 (CH Ar), 73.5 (CH2 Bn), 55.4 [C, NHC(CH3)2-
CH2tBu], 55.4 (CH2 tBu), 31.5 (C tBu), 31.4, 27.9 (5ϫCH3) ppm.
38 µmol), Ͼ10:1 mixture of rotamers. Rf = 0.77 (1:1; toluene/
1
EtOAc). H NMR (600 MHz, CDCl3, COSY), major rotamer: δ =
7.76 (d, J = 7.2 Hz, 2 H, HAr), 7.60 (d, J = 7.4 Hz, 2 H, HAr),
7.40–7.26 (m, 19 H, HAr), 5.76 (br. s, 1 H, CONH), 5.55 (br. s, 1
H, CONH), 4.68 (d, JHa-Hb = 12.2 Hz, 1 H, CHH Bn), 4.58–4.49
(m, 5 H, CH2 Bn, CHH Bn, CHH Bn, CHH Fmoc), 4.38–4.32 (m,
3 H, 5-H, 4-H, CHH Fmoc), 4.25–4.20 (m, 2 H, CH Fmoc, 3-H),
4.07–3.99 (m, 3 H, 2-H, 6a-H, CHH Bn), 3.81–3.77 (m, 1 H, 6b-
H), 1.75 (d, J = 15.0 Hz, 1 H, CHH tBu), 1.59 (d, J = 15.0 Hz, 1
H, CHH tBu), 1.32 (s, 6 H, 2ϫCH3), 0.95 (s, 9 H, 3ϫCH3 tBu)
ppm. 13C NMR (150 MHz, CDCl3, HSQC), major rotamer: δ =
170.1, 167.6, 156.2 (3ϫC), 143.9, 141.2, 137.8, 137.6, 137.3 (7ϫC
Ar), 128.5, 128.3, 127.8, 127.7, 127.4, 127.0, 125.2, 119.9 (23ϫCH
Ar), 78.5 (C-4), 78.0 (C-3), 73.3, 72.7, 72.6 (3ϫCH2 Bn), 70.8 (C-
6), 67.0 (CH2 Fmoc), 66.7 (C-2), 58.6 (C-5), 55.6 [C, NHC(CH3)2-
CH2tBu], 51.7 (CH2 tBu), 47.1 (CH Fmoc), 31.5 (C tBu), 31.4,
IR (thin film): ν
= 3032, 2950, 2868, 1679, 1523, 1346, 1098,
˜
max
910, 850, 735, 698 cm–1. [α]2D0 = –10.2 (c = 1.05, CHCl3). HRMS:
found 708.3642 [M + H]+ , calculated for [C42H 49O7N3 + H ]+
708.3643.
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(pent-4-enoylamido)-N-
(1,1,3,3-tetramethylbutyl)-D-talo-hexonamide (4, IC-2,3-trans):
Yield 53% (67.9 mg, 106 µmol), 6:1 mixture of rotamers. Rf = 0.72
1
(3:2; toluene/EtOAc). H NMR (400 MHz, CDCl3, COSY), major
rotamer: δ = 7.33–7.22 (m, 15 H, HAr), 6.28 (s, 1 H, CONH), 5.81–
5.74 (m, 1 H, =CH), 4.97 (ddd, J = 1.2, 16.8, 37.2 Hz, 2 H, =CH2),
4.65 (d, J H a-H b = 12.0 H z, 1 H , CH H Bn), 4.63 (d, J H a-H b
12.0 Hz, 1 H, CHH Bn), 5.58 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn),
4.55 (d, J H b-H a = 12.0 H z, 1 H , CH H Bn), 4.47 (d, J H a-H b
=
=
28.8, 28.7 (5ϫCH ) ppm. IR (thin film): ν
= 3335, 2951, 1718,
˜
3
max
1667, 1453, 1098, 737, 698 cm–1. [α]2D0 = +5.2 (c = 0.12, CHCl3).
12.0 Hz, 1 H, CHH Bn), 4.44 (dd, J = 4.2, 7.8 Hz, 1 H, 3-H), 4.41
(d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.34–4.32 (m, 2 H, 4-H, 5-
H), 4.16 (dd, J = 3.6, 10.8 Hz, 1 H, 6a-H), 4.08 (d, J = 4.2 Hz, 1
H, 2-H), 3.69 (dd, J = 5.4 Hz, 6b-H, 1 H, 10.8), 2.76–2.71 (m, 1
H, CHH pentenyl), 2.56–2.51 (m, 1 H, CHH pentenyl), 2.41–2.31
(m, 2 H, CH2 pentenyl), 1.71 (d, J = 15.0 Hz, 1 H, CHH tBu), 1.60
(d, J = 15.0 H z, 1 H , CH H tBu), 1.32 (d, J = 14.4 H z, 6 H ,
2ϫCH3), 0.95 (s, 9 H, 3ϫCH3 tBu) ppm. 13C NMR (100 MHz,
CDCl3, HSQC), major rotamer: δ = 174.1, 168.1 (2ϫC), 137.8,
137.7, 137.6 (3ϫC Ar), 137.3 (=CH), 128.4, 128.3, 128.2, 128.0,
127.6, 127.5, 127.4 (15ϫCH Ar), 114.9 (=CH2), 78.7 (C-3), 77.9
(C-2), 73.2, 72.4 (3ϫCH2 Bn), 71.5 (C-6), 65.8 (C-4), 59.1 (C-5),
55.2 [C, NHC(CH3)2CH2tBu], 51.4 (CH2 tBu), 33.6 (CH2 pen-
tenyl), 31.4 (C tBu), 31.3 (3ϫCH3 tBu), 29.0 (CH2 pentenyl), 28.8,
HRMS: found 838.4428 [M + H]+, calculated for [C49H61O10N3
H]+ 838.4399.
+
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-{N-[(9H-fluoren-9-yl-
methoxy)carbonyl]-2-aminoacetamido}-N-(1,1,3,3-tetramethyl-
butyl)-D-galacto-hexonamide (ID-2,3-cis): Yield 1 % (1.7 mg,
2 µmol), Ͼ10:1 mixture of rotamers. Rf = 0.24 (1:1; toluene/
1
EtOAc). H NMR (500 MHz, CDCl3, COSY), major rotamer: δ =
7.75 (d, J = 7.6 Hz, 2 H, HAr), 7.60 (d, J = 7.4 Hz, 2 H, HAr), 7.39
(t, J = 7.4 Hz, 2 H, HAr), 7.31–7.13 (m, 13 H, HAr), 5.98 (br. s, 1
H, CONH), 5.64 (br. s, 1 H, CONH), 4.74 (d, JHa-Hb = 11.5 Hz, 1
H, CHH Bn), 4.69 (d, JHb-Ha = 11.3 Hz, 1 H, CHH Bn), 4.64 (d,
JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.55–4.45 (m, 3 H, 2-H, CHH
Bn, CHH Bn), 4.43–4.38 (m, 4 H, 4-H, CHH Bn, CH2 Fmoc),
4.30–4.25 (m, 1 H, 5-H), 4.22 (t, J = 7.3 Hz, 1 H, CH Fmoc), 4.14–
4.07 (m, 1 H, 6a-H), 3.87–3.78 (m, 2 H, 3-H, 6b-H), 1.62 (d, J =
15.0 Hz, 1 H, CHH tBu), 1.45 (d, J = 15.0 Hz, 1 H, CHH tBu),
1.36 (s, 3 H, CH3), 1.20 (s, 3 H, 2ϫCH3), 0.87 (s, 9 H, 3ϫCH3 tBu)
ppm. 13C NMR (125 MHz, CDCl3, HSQC), major rotamer: δ =
170.3, 165.9, 156.2 (3ϫC), 143.9, 141.2, 138.0, 137.5, 136.9 (7ϫC
Ar), 128.5, 128.4, 128.1, 127.9, 127.6, 127.0, 125.1, 119.9 (23ϫCH
Ar), 78.5 (C-4), 76.3 (C-3), 74.9, 73.6, 72.4 (3ϫCH2 Bn), 69.1 (C-
6), 67.1 (CH2 Fmoc), 65.3 (C-2), 58.8 (C-5), 55.3 (C tBu), 53.7
(CH2 tBu), 47.1 (CH Fmoc), 31.3, 28.9, 27.3 (5ϫCH3) ppm. IR
28.6 (2ϫCH ) ppm. IR (thin film): ν
= 3329, 2950, 1679, 1624,
˜
3
max
1544, 1422, 1096, 733, 696 cm–1. [α]2D0 = +22.3 (c = 6.06, CHCl3).
HRMS: found 641.3949 [M + H]+, calculated for [C40H52O5N2
H]+ 641.3949.
+
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(pent-4-enoylamido)-N-
(1,1,3,3-tetramethylbutyl)- -galacto-hexonamide (3, IC-2,3-cis):
D
Yield 10% (12.8 mg, 20 µmol), 2:1 mixture of rotamers. Rf = 0.24
1
(3:2; toluene/EtOAc). H NMR (400 MHz, CDCl3, COSY), major
rotamer: δ = 7.32–7.25 (m, 15 H, HAr), 6.02 (s, 1 H, CONH), 5.85–
5.73 (m, 1 H, =CH), 5.06–4.91 (m, 2 H, =CH2), 4.75 (d, JHa-Hb
=
11.5 Hz, 1 H, CHH Bn), 4.69 (d, JHb-Ha = 11.6 Hz, 1 H, CHH Bn),
4.58 (d, JHa-Hb = 11.6 Hz, 1 H, CHH Bn), 4.53–4.47 (m, 3 H, 2-H,
CHH Bn, CHH Bn), 4.44–4.36 (m, 2 H, 4-H, CHH Bn), 4.34–4.27
(m, 1 H, 5-H), 4.11 (app. t, J = 10.2 Hz, 1 H, 6a-H), 3.87 (app. d,
(thin film): ν
= 3303, 2951, 1718, 1667, 1453, 1097, 736, 698
˜
max
cm–1. [α]2D0 = +10.2 (c = 1.64, CHCl3). HRMS: found 838.4428 [M
+ H]+, calculated for [C49H61O10N3 + H]+ 838.4399.
J = 9.9 Hz, 1 H, 6b-H), 3.83 (app. t, J = 4.8 Hz, 1 H, 3-H), 2.89– 2,5-Anhydro-3,4,6-tri-O-benzyl-N-(tert-butyl)-2-deoxy-2-form-
2.84 (m, 1 H, CHH pentenyl), 2.46–2.31 (m, 3 H, CHH pentenyl,
CH2 pentenyl), 1.61 (d, J = 14.8 Hz, 1 H, CHH tBu), 1.46 (d, J =
amido-
D-talo-hexonamide (IIA-2,3-trans): Yield 39% (41.4 mg,
78 µmol), Ͼ10:1 mixture of rotamers. Rf = 0.51 (1:1; toluene/
1
15.2 Hz, 1 H, CHH tBu), 1.00 (d, J = 5.6 Hz, 6 H, 2ϫCH3), 0.87 EtOAc). H NMR (600 MHz, CDCl3, COSY), major rotamer: δ =
(s, 9 H, 3ϫCH3 tBu) ppm. 13C NMR (100 MHz, CDCl3, HSQC),
major rotamer: δ = 173.8, 166.3 (2ϫC), 138.0, 137.5 (2ϫC Ar),
137.1 (=CH), 137.0 (C Ar), 128.3, 128.1, 128.0, 127.8, 127.7, 127.4,
8.57 (s, 1 H, NCHO), 7.34–7.27 (m, 15 H, HAr), 6.54 (br. s, 1 H,
CON H ), 4.65 (d, J H a-H b = 12.0 H z, 1 H , CH H Bn), 4.62 (d,
JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.56 (d, JHb-Ha = 12.0 Hz, 1 H,
127.3, 127.2, 127.1 (15ϫCH Ar), 114.9 (=CH2), 78.7 (C-4), 76.6 CHH Bn), 4.53 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.49 (s, 2 H,
(C-3), 74.6, 73.3, 72.0 (3ϫCH2 Bn), 69.8 (C-6), 64.7 (C-2), 59.0 CH2 Bn), 4.41–4.39 (m, 1 H, 4-H), 4.37 (s, 1 H, 2-H), 4.30 (d, J =
(C-5), 55.6 [C, NHC(CH3)2CH2tBu], 53.3 (CH2 tBu), 33.3 (CH2 3.7 Hz, 1 H, 3-H), 4.23 (dt, J = 2.8, 8.6 Hz, 1 H, 5-H), 3.89–3.83
pentenyl), 31.4 (C tBu), 31.3, 31.2 (2ϫCH3), 31.1 (3ϫCH3 tBu),
28.6 (CH2 pentenyl) ppm. IR (thin film): ν = 3323, 2951, 1666,
(m, 2 H , 6a-H , H 6b), 1.29 (s, 9 H , CH3 tBu) ppm. 13C N MR
(150 MHz, CDCl3, HSQC) mixture of rotamers: δ = 167.9 (C),
163.6 (CHO), 137.9, 137.6, 137.5 (3ϫC Ar), 128.5, 128.4, 127.9,
˜
max
1521, 1400, 1098, 734, 697 cm–1. [α]2D0 = +11.4 (c = 9.00, CHCl3).
3684
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3678–3688

Ugi Three-Component Reaction with -lyxo-Pyrroline
127.8, 127.7, 127.6 (15 CH Ar), 78.5 (C-4), 77.8 (C-3), 73.3, 72.8,
72.7 (3ϫCH2 Bn), 70.5 (C-6), 63.5 (C-2), 58.5 (C-5), 51.4 (C tBu),
127.7, 127.6, 127.0 125.2, 119.9 (23ϫCH Ar), 78.5 (C-4), 78.3 (C-
3), 73.3, 72.8, 72.6 (3ϫCH2 Bn), 70.7 (C-6), 67.0 (CH2 Fmoc), 66.8
(C-2), 58.5 (C-5), 51.5 (C tBu), 47.1 (CH Fmoc), 28.0 (3ϫCH3 tBu)
28.5 (CH tBu) ppm. IR (thin film): νmax = 3334, 2929, 1652, 1455,
˜
3
1363, 1096, 735, 698 cm–1. [α]2D0 = –4.9 (c = 0.41, CHCl3). HRMS:
found 531.2849 [M + H]+ , calculated for [C32H 38O5N2 + H ]+
531.2854.
ppm. IR (thin film): ν
= 3317, 2927, 2868, 1717, 1653, 1453,
˜
max
1346, 1098, 1049, 909, 734, 698 cm–1. [α]2D0 = +8.4 (c = 0.36,
CH Cl3). H R M S: found 782.3802 [M + H ]+ , calculated for
[C48H52O7N3 + H]+ 782.3800.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-(tert-butyl)-2-deoxy-2-(p-nitro-
benzamido)-
D
-talo-hexonamide (IIB-2,3-trans): Yield 19% (24.7 mg,
2,5-Anhydro-3,4,6-tri-O-benzyl-N-cyclohexyl-2-deoxy-2-formamido-
38 µmol), 5:1 mixture of rotamers. Rf = 0.73 (1:1; toluene/EtOAc).
1H NMR (400 MHz, CDCl3, COSY), major rotamer: δ = 7.97 (d,
D
-talo-hexonamide (IIIA-2,3-trans): Yield 48% (53.5 mg, 96 µmol),
Ͼ10:1 mixture of rotamers. Rf = 0.43 (1:1; toluene/EtOAc). 1H
J = 8.4 Hz, 1 H, HAr), 7.42 (d, J = 8.4 Hz, 1 H, HAr), 7.34–7.14 NMR (400 MHz, CDCl3, COSY), major rotamer: δ = 8.58 (s, 1 H,
(m, 16 H , HAr), 6.96 (d, J = 8.4 H z, 1 H , H Ar), 5.70 (s, 1 H ,
CON H ), 4.78 (d, J H a-H b = 12.0 H z, 1 H , CH H Bn), 4.62 (d,
JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.59 (d, JHb-Ha = 12.0 Hz, 1 H,
NCHO), 7.30–7.26 (m, 15 H, HAr), 6.66 (br. s, 1 H, CONH), 4.64
(d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.62 (d, JHa-Hb = 12.0 Hz, 1
H, CHH Bn), 4.57 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.52 (d,
CHH Bn), 4.55 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.51–4.49 JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.50 (s, 2 H, CH2 Bn), 4.45 (s,
(m, 1 H, 4-H), 4.39–4.35 (m, 2 H, 2-H, 5-H), 4.14–4.07 (m, 3 H, 1 H, 2-H), 4.39–4.37 (m, 1 H, 4-H), 4.34 (d, J = 3.8 Hz, 1 H, 3-
CH2 Bn, 3-H), 3.71–3.64 (m, 2 H, 6a-H, 6b-H), 1.28 (s, 9 H, CH3 H), 4.22 (d, J = 8.2 Hz, 1 H, 5-H), 3.90–3.83 (m, 2 H, 6a-H, 6b-
tBu) ppm. 13C NMR (100 MHz, CDCl3, HSQC), major rotamer: H), 3.67–3.60 (m, 1 H, CH cHex), 1.69–1.56 (m, 5 H, 5 ϫCH2
δ = 170.0, 168.1 (2ϫC), 148.0, 142.8, 137.6, 137.4 (3ϫC Ar), 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 127.8, 123.3, 123.2 (19ϫCH Ar),
78.9 (C-4), 78.6 (C-3), 73.3, 73.0 (3ϫCH2 Bn), 70.2 (C-6), 66.6 (C-
cH ex), 1.33–1.05 (m, 5 H , 5ϫCH 2 cH ex) pp m. 13C N M R
(100 MHz, CDCl3, HSQC), major rotamer: δ = 167.7 (C), 163.7
(CHO), 137.9, 137.6, 137.4 (3ϫC Ar), 128.5, 128.4, 128.0, 127.9,
2), 60.0 (C-5), 51.6 (C tBu), 28.5 (3ϫCH3 tBu) ppm. IR (thin film): 127.8, 127.7, 127.6 (15ϫCH Ar), 78.3 (C-4), 77.6 (C-3), 73.3, 72.8,
ν
= 3326, 2969, 1682, 1633, 1522, 1346, 1220, 1098, 1054, 909,
72.7 (3ϫCH2 Bn), 70.6 (C-6), 62.7 (C-2), 58.4 (C-5), 48.4 (CH
cHex), 32.7, 32.5 (2ϫCH2 cHex), 25.5, 24.6 (3ϫCH2 cHex) ppm.
˜
max
864, 735, 699 cm–1. [α]2D0 = –9.5 (c = 0.32, CHCl3). HRMS: found
652.3016 [M + H]+, calculated for [C38H41O7N3 + H]+ 652.3017.
IR (thin film): ν
= 3318, 2929, 2857, 1725, 1652, 1455, 1276,
˜
max
1124, 1074, 737, 698 cm–1. [α]2D0 = –6.5 (c = 0.22, CHCl3). HRMS:
found 557.3007 [M + H]+ , calculated for [C34H 40O5N2 + H ]+
557.3010.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-(tert-butyl)-2-deoxy-2-(pent-4-en-
oylamido)-D-talo-hexonamide (IIC-2,3-trans): Yield 48% (56.1 mg,
96 µmol), 4:1 mixture of rotamers. Rf = 0.66 (1:1; toluene/EtOAc).
1H NMR (600 MHz, CDCl3, COSY), major rotamer: δ = 7.35–
7.16 (m, 15 H, HAr), 6.15 (s, 1 H, CONH), 5.78–5.74 (m, 1 H,
=CH), 4.97 (ddd, J = 1.2, 17.4, 34.8 Hz, 2 H, =CH2), 4.69 (d,
JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.62 (d, JHa-Hb = 12.0 Hz, 1 H,
CHH Bn), 5.58 (d, JH b-H a = 12.0 Hz, 1 H, CHH Bn), 4.53 (d,
JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.48–4.46 (m, 2 H, CHH Bn, 4-
H), 4.42 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.36 (ddd, J = 3.5,
6.4, 7.6 Hz, 1 H, 5-H), 4.24 (s, 1 H, 2-H), 4.11 (dd, J = 3.6, 10.8 Hz,
1 H, 6a-H), 3.99 (d, JH3-H4 = 4.2 Hz, 1 H, 3-H), 3.69 (dd, J = 6.6,
2,5-Anhydro-3,4,6-tri-O-benzyl-N-cyclohexyl-2-deoxy-2-(p-nitro-
benzamido)-D-talo-hexonamide (IIIB-2,3-trans): Yield 17 %
(23.0 mg, 34 µmol), 3:1 mixture of rotamers. Rf = 0.71 (1:1; toluene/
1
EtOAc). H NMR (600 MHz, CDCl3, COSY), major rotamer: δ =
7.97 (d, J = 8.4 Hz, 1 H, HAr), 7.42 (d, J = 8.4 Hz, 1 H, HAr),
7.37–7.23 (m, 16 H, HAr), 6.96 (d, J = 8.4 Hz, 1 H, HAr), 5.78 (br.
s, 1 H, CONH), 4.77 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.64–
4.55 (m, 3 H, CHH Bn, CH2 Bn), 4.52–4.50 (m, 1 H, 4-H), 4.46 (s,
1 H, 2-H), 4.36–4.33 (m, 1 H, 5-H), 4.14–4.12 (m, 2 H, 3-H, CHH
10.8 Hz, 1 H, 6b-H), 2.76–2.71 (m, 1 H, CHH pentenyl), 2.56–2.50 Bn), 4.08 (d, J = 11.4 Hz, 1 H, CHH Bn), 3.72 (dd, J = 7.2 Hz,
(m, 1 H, CHH pentenyl), 2.40–2.27 (m, 2 H, CH2 pentenyl), 1.27
(s, 9 H, 3ϫCH3 tBu) ppm. 13C NMR (150 MHz, CDCl3, HSQC),
major rotamer: δ = 174.0, 168.8 (2ϫC), 137.9, 137.7 (3ϫC Ar),
137.6 (=CH), 128.3, 128.2, 127.8, 127.7, 127.6, 127.5 (15ϫCH Ar),
114.9 (=CH2), 78.8 (C-4), 78.2 (C-3), 73.2, 72.6, 72.5 (3ϫCH2 Bn),
71.4 (C-6), 65.9 (C-2), 58.9 (C-5), 51.2 (Cq tBu), 33.5, 29.1 (2ϫCH2
10.2, 1 H, 6a-H), 3.68–3.64 (m, 2 H, 6b-H, CH cHex), 1.82–1.56
(m, 5 H, 5ϫCH2 cHex), 1.33–1.05 (m, 5 H, 5ϫCH2 cHex) ppm.
13C NMR (150 MHz, CDCl3, HSQC), major rotamer: δ = 170.1,
167.9 (2ϫC), 148.0, 142.8, 137.5, 137.4 (5ϫC Ar), 128.6, 128.5,
128.2, 128.1, 128.0, 127.8, 127.7, 123.2 (19ϫCH Ar), 78.8 (C-4),
78.5 (C-3), 73.3, 73.0, 72.9 (3ϫCH2 Bn), 70.2 (C-6), 66.0 (C-2),
60.0 (C-5), 48.7 (CH cHex), 32.7, 32.6 (2ϫCH2 cHex), 25.4, 24.7,
pentenyl), 28.4 (3ϫCH3 tBu) ppm. IR (thin film): ν
= 3324,
˜
max
2970, 1668, 1624, 1454, 1433, 1362, 1096, 913, 734, 697 cm–1
.
24.6 (3ϫCH2 cHex) ppm. IR (thin film): ν
= 3297, 2930, 2856,
˜
max
[α]2D0 = +28.1 (c = 2.06, CHCl3). HRMS: found 585.3324 [M +
H]+, calculated for [C36H44O5N2 + H]+ 585.3323.
1651, 1522, 1346, 1097, 1055, 910, 864, 734, 698 cm–1. [α]2D0 = –6.9
(c = 0.23, CHCl3). HRMS: found 678.3172 [M + H]+, calculated
for [C40H43O7N3 + H]+ 678.3174.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-(tert-butyl)-2-deoxy-2-{N-[(9H-
fluoren-9-ylmethoxy)carbonyl]-2-aminoacetamido}-
D
-talo-hexon- 2,5-Anhydro-3,4,6-tri-O-benzyl-N-cyclohexyl-2-deoxy-2-(pent-4-
enoylamido)- -talo-hexonamide (IIIC-2,3-trans): Yield 30 %
amide (IID-2,3-trans): Yield 24% (37.5 mg, 48 µmol); Ͼ10:1 mix-
ture of rotamers. Rf = 0.57 (1:1; toluene/EtOAc). 1H N M R
(400 MHz, CDCl3, COSY), major rotamer: δ = 7.76 (d, J = 7.5 Hz,
2 H, HAr), 7.60 (d, J = 7.4 Hz, 2 H, HAr), 7.40–7.25 (m, 19 H,
HAr), 5.59 (br. s, 1 H, CONH), 5.54 (br. s, 1 H, CONH), 4.73 (d,
JHa-Hb = 12.2 Hz, 1 H, CHH Bn), 4.57–4.49 (m, 4 H, CH2 Bn,
CHH Bn, CHH Bn), 4.37–4.33 (m, 4 H, 5-H, 4-H, CH2 Fmoc),
D
(36.6 mg, 60 µmol), 1:3 mixture of rotamers. Rf = 0.62 (1:1; toluene/
1
EtOAc). H NMR (600 MHz, CDCl3, COSY), major rotamer: δ =
7.35–7.25 (m, 15 H, HAr), 6.22 (d, J = 8.4 Hz, 1 H, CONH), 5.79–
5.74 (m, 1 H , = CH ), 4.99–4.92 (m, = CH 2), 4.69 (d, J H a-H b
12.0 Hz, 1 H, CHH Bn), 4.61 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn),
4.57 (d, J H b-H a = 12.0 H z, 1 H , CH H Bn), 4.54 (d, J H b-H a
=
=
4.22 (t, J = 7.1 Hz, 1 H, CH Fmoc), 4.13 (m, 2 H, 2-H), 4.07–3.99 12.0 Hz, 1 H, CHH Bn), 4.48 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn),
(m, 2 H, 6a-H, CHH Bn), 3.93 (s, 1 H, 3-H), 3.84–3.77 (m, 1 H,
6b-H), 1.26 (s, 9 H, CH3 tBu) ppm. 13C NMR (100 MHz, CDCl3,
HSQC), major rotamer: δ = 170.1, 168.2, 156.3 (3ϫC), 143.9,
141.2, 137.8, 137.6, 137.3 (7ϫC Ar), 128.5, 128.4, 128.0, 127.8,
4.46–4.42 (m, 2 H, CHH Bn, 4-H), 4.37–4.34 (m, 1 H, 5-H), 4.32
(s, 1 H, 2-H), 4.13 (dd, J = 3.0, 10.2 Hz, 1 H, 6a-H), 3.04 (d, J =
4.2 Hz, 1 H, 3-H), 3.70 (dd, J = 3.6, 10.2 Hz, 1 H, 6b-H), 3.63–
3.58 (m, 1 H, CH cHex), 2.76–2.71 (m, 1 H, CHH pentenyl), 2.57–
Eur. J. Org. Chem. 2008, 3678–3688
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3685

H. S. Overkleeft et al.
FULL PAPER
2.50 (m, 1 H, CHH pentenyl), 2.46–2.28 (m, 2 H, CH2 pentenyl),
3 H, CHH Bn, CH2 Bn), 4.53–4.52 (m, 2 H, 2-H, 4-H), 4.39–4.35
1.69–1.56 (m, 5 H, 5ϫCH2 cH ex), 1.33–1.05 (m, 5 H , 5ϫCH2 (m, 1 H, 5-H), 4.16 (d, J = 4.2 Hz, 1 H, 3-H), 4.12 (d, JHa-Hb
=
cHex) ppm. 13C NMR (150 MHz, CDCl3, HSQC), major rotamer: 11.4 Hz, 1 H, CHH Bn), 4.07 (d, J = 11.4 Hz, 1 H, CHH Bn), 3.72
δ = 174.2, 168.5 (2ϫC), 138.0, 137.7 (3ϫC Ar), 137.6 (=CH), 128.4,
128.3, 127.9, 127.8, 127.7, 127.5 (15ϫCH Ar), 115.0 (=CH2), 78.7
(dd, J = 3.6, 10.2 Hz, 1 H, 6a-H), 3.67 (app. t, J = 7.2, 10.2 Hz, 1
H, 6b-H), 3.16 (q, J = 6.6 Hz, 2 H, CH2 butyl), 1.45–1.38 (m, 2 H,
(C-4), 78.2 (C-3), 73.3, 72.6, 72.5 (3ϫCH2 Bn), 71.5 (C-6), 65.3 (C- CH2 butyl), 1.30–1.25 (m, 2 H, CH2 butyl), 0.88 (t, J = 10.8 Hz, 3
2), 59.0 (C-5), 48.4 (CH cHex), 33.6 (CH2 pentenyl), 32.7, 32.5
H, CH3 butyl) ppm. 13C NMR (100 MHz, CDCl3, HSQC), major
(2ϫCH2 cHex), 29.1 (CH2 pentenyl), 25.4, 24.7 (2ϫCH2 cHex) rotamer: δ = 170.1, 167.7 (2ϫC), 148.0, 142.7, 137.5, 137.4 (5ϫC
ppm. IR (thin film): ν
= 3301, 2930, 2856, 1650, 1637, 1623,
Ar), 128.8, 128.6, 128.5, 127.8, 127.7, 127.5, 123.2 (19ϫCH Ar),
78.8 (C-4), 78.4 (C-3), 73.2, 73.0, 72.9 (3ϫCH2 Bn), 70.2 (C-6),
65.8 (C-2), 60.1 (C-5), 39.3, 31.3, 20.0 (3ϫCH2 butyl), 13.7 (CH3
˜
max
1420, 1096, 911, 733, 697 cm–1. [α]2D0 = +25.2 (c = 1.34, CHCl3).
HRMS: found 611.3478 [M + H]+, calculated for [C38H47O5N2
H]+ 611.3479.
+
butyl) ppm. IR (thin film): ν
= 3341, 2957, 2929, 2871, 1724,
˜
max
1274, 1124, 1074, 909, 864, 737, 699 cm–1. [α]2D0 = –6.9 (c = 0.29,
CH Cl3). H R M S: found 652.3016 [M + H ]+ , calculated for
[C38H41O7N3 + H]+ 652.3017.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-cyclohexyl-2-deoxy-2-{N-[(9H-flu-
oren-9-ylmethoxy)carbonyl]-2-aminoacetamido}- -talo-hexonamide
D
(IIID-2,3-trans): Yield 18% (29.1 mg, 36 µmol), Ͼ10:1 mixture of
rotamers. Rf = 0.54 (1:1; toluene/EtOAc). 1H NMR (400 MHz,
CDCl3, COSY), major rotamer: δ = 7.76 (d, J = 7.5 Hz, 2 H, HAr),
7.60 (d, J = 7.4 Hz, 2 H, HAr), 7.41–7.25 (m, 19 H, HAr), 5.79 (d,
J = 8.2 Hz, 1 H, CONH), 5.54 (br.t, 1 H, CONH), 4.71 (d, JHa-Hb
= 12.2 Hz, 1 H, CHH Bn), 4.56 (d, JHb-Ha = 12.2 Hz, 1 H, CHH
Bn), 4.53 (s, 2 H, CH2 Bn), 4.50 (dd, J = 5.2, 10.4 Hz, 2 H, CH2
Bn), 4.47–4.38 (m, 1 H, 5-H), 4.37–4.29 (m, 4 H, 2-H, 4-H, CH2
Fmoc), 4.21 (t, J = 7.3 Hz, 1 H, CH Fmoc), 4.11–4.00 (m, 2 H,
6a-H, 3-H), 3.84–3.80 (m, 1 H, 6b-H), 3.65–3.56 (m, 1 H, CH
cH ex), 1.82–1.56 (m, 5 H , 5ϫCH 2 cH ex), 1.33–1.05 (m, 5 H ,
5ϫCH2 cHex) ppm. 13C NMR (100 MHz, CDCl3, HSQC), major
rotamer: δ = 170.3, 167.8, 156.5 (3ϫC), 143.9, 143.8, 141.2, 137.8,
137.5, 137.2 (7ϫC Ar), 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.8, 127.7, 127.0 125.1, 119.9 (23ϫCH Ar), 78.3 (C-4), 78.2 (C-
3), 73.4, 72.6, 72.5 (3ϫCH2 Bn), 70.4 (C-6), 67.1 (CH2 Fmoc), 66.1
(C-2), 58.7 (C-5), 47.1 (CH Fmoc), 48.5 (CH cHex), 32.7, 32.6
(2ϫCH2 cHex), 25.4, 24.8, 24.7 (3ϫCH2 cHex) ppm. IR (thin film):
2,5-Anhydro-3,4,6-tri-O-benzyl-N-butyl-2-deoxy-2-(pent-4-enoyl-
amido)-D-talo-hexonamide (IVC-2,3-trans): Yield 29 % (33.9 mg,
58 µmol), 3:1 mixture of rotamers. 1H NMR (600 MHz, CDCl3,
COSY), major rotamer: δ = 7.35–7.24 (m, 15 H, HAr), 6.65–6.59
(br. s, 1 H, CONH), 5.80–5.73 (m, 1 H, =CH), 4.96 (ddd, J = 1.2,
17.4, 31.8 Hz, 2 H, =CH2), 4.67 (d, JHa-Hb = 12.0 Hz, 1 H, CHH
Bn), 4.61–4.53 (m, 3 H, CHH Bn, 2ϫCHH Bn), 4.49–4.42 (m, 2
H, CHH Bn, CHH Bn, 4-H), 4.40 (s, 1 H, 2-H), 4.39–4.36 (m, 1
H, 5-H), 4.13 (dd, J = 3.6, 10.8 Hz, 1 H, 6a-H), 3.04 (d, J = 4.2 Hz,
1 H, 3-H), 3.70 (dd, J = 6.0, 10.8 Hz, 1 H, 6b-H), 3.22–3.17 (m, 1
H, CHH butyl), 3.08–3.05 (m, 1 H, CHH butyl), 2.78–2.72 (m, 1
H, CHH pentenyl), 2.56–2.51 (m, 1 H, CHH pentenyl), 2.40–2.28
(m, 2 H, CH2 pentenyl), 1.42–1.38 (m, 2 H, CH2 butyl), 1.32–1.26
(m, 2 H, CH2 butyl), 0.97–0.85 (m, 3 H, CH3 butyl) ppm. 13C
NMR (150 MHz, CDCl3, HSQC), major rotamer: δ = 174.1, 168.4
(2ϫC), 138.0, 137.7 (3ϫC Ar), 137.4 (=CH), 128.4, 128.3, 127.9,
127.8, 127.7, 127.5 (15ϫCH Ar), 115.0 (=CH2), 78.7 (C-4), 78.2
(C-3), 73.3, 72.4 (3ϫCH2 Bn), 71.5 (C-6), 65.2 (C-2), 59.0 (C-5),
39.2 (CH2 butyl), 33.6 (CH2 pentenyl), 31.1 (CH2 butyl), 29.1 (CH2
pentenyl), 20.0 (CH2 butyl), 13.7 (CH3 butyl) ppm. Rf = 0.51 (1:1;
ν
= 3305, 2929, 2855, 1717, 1652, 1452, 1097, 911, 734, 698
˜
max
cm–1. [α]2D0 = +2.4 (c = 0.33, CHCl3). HRMS: found 808.3959 [M
+ H]+, calculated for [C50H53O7N3 + H]+ 808.3956.
toluene/EtOAc). IR (thin film): ν
= 3311, 2931, 1726, 1652,
˜
max
1623, 1453, 1421, 1096, 734, 697 cm–1. [α]2D0 = +26.5 (c = 1.24,
CH Cl3). H R M S: found 585.3324 [M + H ]+ , calculated for
[C36H44O5N2 + H]+ 585.3323.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-butyl-2-deoxy-2-formamido-D-
talo-hexonamide (IVA-2,3-trans): Yield 29% (30.8 mg, 58 µmol), 4:1
mixture of rotamers. Rf = 0.34 (1:1; toluene/EtOAc). 1H NMR
(400 M H z, CD Cl3, COSY), major rotamer: δ = 8.57 (s, 1 H ,
NCHO), 7.31–7.24 (m, 15 H, HAr), 6.78 (br. s, 1 H, CONH), 4.62
(d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.60 (d, JHa-Hb = 12.0 Hz, 1
H, CHH Bn), 4.56 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.51–4.47
(m, 4 H, CHH Bn, CH2 Bn, 2-H), 4.39–4.34 (m, 2 H, 4-H, 3-H),
4.21 (t, J = 7.4 Hz, 1 H, 5-H), 3.93–3.84 (m, 2 H, 6a-H, 6b-H),
3.17–3.13 (m, 1 H, CH2 butyl), 1.42–1.38 (m, 2 H, CH2 butyl),
1.32–1.26 (m, 2 H, CH2 butyl), 0.97–0.85 (m, 3 H, CH3 butyl) ppm.
13C NMR (100 MHz, CDCl3, HSQC), major rotamer: δ = 167.7
(C), 163.7 (CHO), 137.8, 137.6, 137.4 (3ϫC Ar), 128.5, 128.4,
128.2, 127.9, 127.8, 127.7, 127.6 (15ϫCH Ar), 78.3 (C-4), 77.6 (C-
3), 73.4, 72.7 (3ϫCH2 Bn), 70.6 (C-6), 62.6 (C-2), 58.4 (C-5), 39.3,
31.3, 20.0 (3ϫCH2 butyl), 13.7 (CH3 butyl) ppm. IR (thin film):
2,5-Anhydro-3,4,6-tri-O-benzyl-N-butyl-2-deoxy-2-{N-[(9H-fluoren-
9-ylmethoxy)carbonyl]-2-amino-acetamido}-D-talo-hexonamide
(IVD-2,3-trans): Yield 13% (20.3 mg, 26 µmol), Ͼ10:1 mixture of
rotamers. Rf = 0.46 (1:1; toluene/EtOAc). 1H NMR (400 MHz,
CDCl3, COSY), major rotamer: δ = 7.76 (d, J = 7.2 Hz, 2 H, HAr),
7.58 (d, J = 7.4 Hz, 2 H, HAr), 7.41–7.25 (m, 19 H, HAr), 6.11 (br.t,
1 H, CONH), 5.56 (br.t, 1 H, CONH), 4.69 (d, JHa-Hb = 12.0 Hz,
1 H, CHH Bn), 4.59 (d, JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.52 (s,
2 H, CH2 Bn), 4.50–4.44 (m, 3 H, CH2 Bn, 5-H), 4.37–4.27 (m, 4
H, 2-H, 4-H, CH2 Fmoc), 4.20 (t, J = 7.3 Hz, 1 H, CH Fmoc),
4.05–4.00 (m, 2 H, 6a-H, 3-H), 3.85–3.80 (m, 1 H, 6b-H), 3.11 (q,
J = 7.4 Hz, 2 H, CH2 butyl), 1.42–1.35 (m, 2 H, CH2 butyl), 1.28–
1.25 (m, 2 H, CH2 butyl), 0.86 (t, J = 7.3 Hz, 3 H, CH3 butyl)
ppm. 13C NMR (100 MHz, CDCl3, HSQC), major rotamer: δ =
170.5, 168.6, 156.5 (3ϫC), 143.8, 141.2, 137.8, 137.5, 137.2 (7ϫC
Ar), 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6,
127.1, 127.0, 125.1, 119.9 (23ϫCH Ar), 78.3 (C-4), 78.2 (C-3), 73.4,
72.5, 72.4 (3ϫCH2 Bn), 70.8 (C-6), 67.1 (CH2 Fmoc), 66.1 (C-2),
58.7 (C-5), 47.1 (CH Fmoc), 39.4, 31.3, 20.0 (3ϫCH2 butyl), 13.7
ν
max = 3318, 2957, 2930, 2871, 1724, 1652, 1455, 1381, 1275, 1123,
˜
1074, 736, 698 cm–1. [α]2D0 = –4.5 (c = 0.22, CHCl3). HRMS: found
531.2849 [M + H]+, calculated for [C32H38O5N2 + H]+ 531.2854.
2,5-Anhydro-3,4,6-tri-O-benzyl-N-butyl-2-deoxy-2-p-nitrobenz-
amido-D-talo-hexonamide (IVB-2,3-trans): Yield 47 % (61.2 mg,
94 µmol), 8:1 mixture of rotamers. Rf = 0.64 (1:1; toluene/EtOAc).
1H NMR (400 MHz, CDCl3, COSY), major rotamer: δ = 7.98 (d,
J = 8.4 Hz, 1 H, HAr), 7.43 (d, J = 8.4 Hz, 1 H, HAr), 7.36–7.24 1652, 1453, 1097, 910, 735, 698 cm–1. [α]2D0 = +3.2 (c = 0.25,
(CH3 butyl) ppm. IR (thin film): ν
= 3318, 2929, 2870, 1718,
˜
max
(m, 16 H, HAr), 6.95 (d, J = 8.4 Hz, 1 H, HAr), 6.00 (br. s, 1 H,
CONH), 4.77 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.62–4.57 (m,
CH Cl3). H R M S: found 782.3802 [M + H ]+ , calculated for
[C48H51O7N3 + H]+ 782.3800.
3686
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3678–3688

Ugi Three-Component Reaction with -lyxo-Pyrroline
2,5-Anhydro-3,4,6-tri-O-benzyl-N-[(tert-butyloxycarbonyl)methyl]-
2-deoxy-2-formamido-D-talo-hexonamide (VA-2,3-trans): Yield 33%
2,5-Anhydro-3,4,6-tri-O-benzyl-N-[(tert-butyloxycarbonyl)methyl]-
2-deox y-2-{N -[(9H -fluor en-9-ylmet hox y)ca r bonyl]-2-
(38.8 mg, 66 µmol), 1:1 mixture of rotamers. Rf = 0.59 (1:1; toluene/
aminoacetamido}-D-talo-hexonamide (VD-2,3-trans): Yield 23 %
EtOAc). 1H NMR (600 MHz, CDCl3, COSY) mixture of rotamers: (38.6 mg, 46 µmol), 4:1 mixture of rotamers. Rf = 0.38 (1:1; toluene/
1
δ = 8.60 (s, 1 H, NCHO), 8.21 (s, 1 H, NCHO), 7.33–7.14 (m,
2ϫ15 H, HAr), 6.28 (br. s, 2 H, CONH), 4.63–4.57 (m, 2ϫ3 H,
EtOAc). H NMR (600 MHz, CDCl3, COSY), major rotamer: δ =
7.75 (d, J = 7.2 Hz, 2 H, HAr), 7.46 (d, J = 7.2 Hz, 2 H, HAr),
CH2 Bn, 2-H), 4.51–4.46 (m, 2ϫ2 H, CH2 Bn), 4.36–4.35 (m, 2ϫ2 7.40–7.25 (m, 19 H, HAr), 6.57 (br. s, 1 H, CONH), 5.61 (br. s, 1
H, 4-H, 3-H), 4.28–4.25 (m, 2ϫ1 H, 5-H), 3.97 (d, J = 5.4 Hz, 2ϫ2 H, CONH), 4.68 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn), 4.61 (d,
H, NHCH2CO2tBu), 3.91–3.81 (m, 2ϫ2 H, 6a-H, 6b-H), 1.46 (s, 9
H, CH3 tBu), 1.44 (s, 9 H, CH3 tBu) ppm. 13C NMR (150 MHz,
CDCl3, HSQC) mixture of rotamers: δ = 168.8, 168.7, 168.3 (3ϫC),
163.6, 160.9 (2ϫCHO), 137.8, 137.4, 137.3 (2ϫ3C Ar), 128.8,
128.4, 128.3, 128.1, 127.9, 127.8, 127.6 (2ϫ15 CH Ar), 82.5, 82.1
JHb-Ha = 12.0 Hz, 1 H, CHH Bn), 4.55–4.45 (m, 6 H, 2ϫCH2 Bn,
5-H, 2-H), 4.41–4.38 (m, 2 H, 4-H, FmocNHCHHCO), 4.35–4.29
(m, 2 H, CH2 Fmoc), 4.19 (t, J = 7.2 Hz, 1 H, CH Fmoc), 4.16
(m, 2 H, 3-H, FmocNHCHHCO), 4.01–3.99 (m, 1 H, 6a-H), 3.85–
3.74 (m, 2 H, 6b-H, NHCH2CO2tBu), 1.40 (s, 9 H, CH3 tBu) ppm.
(2ϫC tBu), 78.0 (2ϫC-4), 77.7 (2ϫC-3), 73.3, 72.5, 70.5 (2ϫ3 CH2 13C NMR (150 MHz, CDCl3, HSQC), major rotamer: δ = 170.4,
Bn, 2ϫC-6), 62.3 (2ϫC-2), 58.3 (2ϫC-5), 42.1 (CH2), 40.5 (CH2),
168.8, 168.5, 156.5 (3ϫC), 143.8, 142.2, 137.8, 137.4, 137.3 (7ϫC
Ar), 128.4, 128.0, 127.8, 127.7, 127.6, 127.0 125.1, 119.9 (23ϫCH
Ar), 82.1 (C tBu), 78.3 (C-4), 78.2 (C-3), 73.4, 72.6, 72.5 (3ϫCH2
Bn), 70.7 (C-6), 67.0 (CH2 Fmoc), 65.7 (C-2), 58.7 (2ϫC-5), 47.0
(CH Fmoc), 43.8, 42.0 (2ϫCH2), 28.0 (3ϫCH3 tBu) ppm. IR (thin
30.0, 29.9 (2ϫ3 CH3 tBu) ppm. IR (thin film): ν
= 3316, 2979,
˜
max
1739, 1667, 1653, 1366, 1223, 1151, 735, 698 cm–1. [α]2D0 = –1.8 (c
= 1.44, CHCl3). HRMS: found 589.2908 [M + H]+, calculated for
[C34H40O7N2 + H]+ 589.2908.
film): ν
= 3313, 2934, 1726, 1653, 1528, 1226, 1153, 738, 699
˜
max
cm–1. [α]2D0 = +8.0 (c = 0.82, CHCl3). HRMS: found 840.3862 [M
2,5-Anhydro-3,4,6-tri-O-benzyl-N-[(tert-butyloxycarbonyl)methyl]-
2-deoxy-2-(p-nitrobenzamido)-D-talo-hexonamide (VB-2,3-trans):
+ H]+, calculated for [C50H54O9N3 + H]+ 840.3855.
Yield 14% (19.9 mg, 28 µmol), 4:1 mixture of rotamers. Rf = 0.64
(1:1; toluene/EtOAc). H NMR (600 MHz, CDCl3, COSY), major
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(pent-4-enoylamido)-N-
(1,1,3,3-tetramethylbutyl)-D-gluco-hexonamide (11-cis): Yield 13 %
1
rotamer: δ = 7.97 (d, J = 8.4 Hz, 1 H, HAr), 7.46 (d, J = 8.4 Hz, 1
H, HAr), 7.34–7.14 (m, 16 H, HAr), 6.96 (d, J = 8.4 Hz, 1 H, HAr),
6.57 (br. s, 1 H, CONH), 4.75 (d, JHa-Hb = 12.0 Hz, 1 H, CHH
Bn), 4.69 (s, 1 H, 2-H), 4.63 (d, JHa-Hb = 12.0 Hz, 1 H, CHH Bn),
4.57 (dd, J = 11.4, 23.4 Hz, 1 H, CH2 Bn), 4.49–4.47 (m, 1 H, 4-
H), 4.42–4.39 (m, 1 H, 5-H), 4.26 (d, JH3-H4 = 4.8 Hz, 1 H, 3-H),
4.10 (dd, J = 11.4, 33.6 Hz, 2 H, CH2 Bn), 3.87 (ddd, J = 6.0, 18.0,
93.6 Hz, 2 H, NHCH2CO2tBu), 3.71 (ddd, J = 3.6, 10.2, 48.6 Hz,
2 H, 6-H), 1.46 (s, 9 H, CH3 tBu) ppm. 13C NMR (150 MHz,
CDCl3, HSQC), major rotamer: δ = 170.2, 169.0, 168.3 (3ϫC),
148.0, 142.6, 137.3 (3ϫC Ar), 128.5, 128.3, 128.2, 128.1, 127.9,
127.6, 123.2 (19ϫCH Ar), 82.4 (C tBu), 78.6 (C-4), 78.2 (C-3), 73.0,
72.7, 70.2 (3ϫCH2 Bn, C-6), 65.5 (C-2), 60.1 (C-5), 42.1 (CH2),
(15.7 mg, 26 µmol), 4:1 mixture of rotamers. Rf = 0.32 (3:1; toluene/
EtOAc). H NMR (400 MHz, CDCl3, COSY), major rotamer: δ =
1
7.42–7.13 (m, 15 H, HAr), 6.98 (s, 1 H, CONH), 5.83 (ddd, J = 6.3,
11.3, 16.8 Hz, 1 H, =CH), 5.09–4.87 (m, 2 H, =CH2), 4.73–4.33
(m, 7 H, 3ϫCH2 Bn, 4-H/3-H/2-H), 4.22–4.19 (m, 2 H, 4-H/3-H/
2-H), 4.17 (dd, J = 4.3, 9.7 Hz, 1 H, CHH-6), 3.94–3.91 (m, 1 H,
5-H), 3.49 (dd, J = 2.3, 9.7 Hz, 1 H, CHH-6), 2.40–2.36 (m, 4 H,
2ϫCH2 pentenyl), 1.92 (d, J = 14.7 Hz, 1 H, CHH tBu), 1.59 (d,
J = 14.7 Hz, 1 H, CHH tBu), 1.32 (d, J = 9.4 Hz, 6 H, 2ϫCH3),
0.92 (s, 9 H , 3ϫCH3 tBu) ppm. 13C N MR (100 MH z, CD Cl3,
HSQC), major rotamer: δ = 173.9, 167.9 (2ϫC=O), 138.0, 137.8,
137.6 (3ϫCq Bn), 137.2 (=CH), 128.7, 128.6, 128.5, 128.3, 128.2,
128.0, 127.9 (15ϫCH Ar), 115.8 (=CH2), 82.7 (C-2/C-3/C-4), 79.4
(C-2/C-3/C-4), 73.4, 73.0, 72.8 (3ϫCH2 Bn), 66.2 (C-6), 64.5 (C-2/
C-3/C-4), 64.0, 60.7 (C-5), 55.7 [Cq, NHC(CH3)2CH2tBu], 51.5
(CH2-tBu), 33.7 (CH2 pentenyl), 31.7 (3ϫCH3 tBu), 31.6 (Cq tBu),
29.4 (CH3 tBu), 28.9 (CH3 tBu), 28.8 (CH2 pentenyl) ppm. IR (thin
28.0 (3ϫCH3 tBu) ppm. IR (thin film): ν
= 3311, 2980, 1738,
˜
max
1635, 1523, 1347, 1156, 912, 857, 735, 699 cm–1. [α]2D0 = –5.8 (c =
0.76, CHCl3). HRMS: found 710.3074 [M + H]+, calculated for
[C40H43O9N3 + H]+ 710.3072.
film): νmax = 3328, 2949, 1668, 1537, 1453, 1365, 1205, 1117, 1026,
˜
2,5-Anhydro-3,4,6-tri-O-benzyl-N-[(tert-butyloxycarbonyl)methyl]-
735, 698 cm–1. [α]2D0 = –23.3 (c = 0.30, CHCl3). HRMS: found
2-deoxy-2-(pent-4-enoylamido)-D-talo-hexonamide (VC-2,3-trans):
641.3949 [M + H]+, calculated for [C40H52O5N2 + H]+ 641.3949.
1
Yield 24% (30.8 mg, 48 µmol), 10:1 mixture of rotamers. H NMR
(600 MHz, CDCl3, COSY), major rotamer: δ = 7.36–7.25 (m, 15
H, HAr), 6.68 (br. s, 1 H, CONH), 5.79–5.74 (m, 1 H, =CH), 4.95
(ddd, J = 1.8, 17.4, 35.4 Hz, 2 H, =CH2), 4.69 (d, JHa-Hb = 12.0 Hz,
2,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(pent-4-enoylamido)-N-
(1,1,3,3-tetramethylbutyl)-D-manno-hexonamide (12-trans): 3:1 mix-
ture of rotamers, yield 17% (21.5 mg, 34 µmol), Rf = 0.47 (3:1;
1
1 H, CHH Bn), 4.61–4.56 (m, 3 H, CHH Bn, 2ϫCHH Bn), 4.49 toluene/EtOAc). H NMR (400 MHz, CDCl3, COSY), major rot-
(d, 1 H, CHH Bn), 4.47–4.38 (m, 5 H, CHH Bn, CHH Bn, 2-H,
4-H , 5-H ), 4.14–4.10 (m, 2 H , 6a-H , 3-H ), 3.94 (dd, J = 6.0,
1 8 . 6 H z , 1 H , N H C H H C O 2 t B u ) , 3 . 7 6 – 3 . 7 1 ( m , 2 H ,
amer: δ = 7.36–7.20 (m, 15 H, HAr), 6.13 (s, 1 H, CONH), 5.87–
5.74 (m, 1 H, =CH), 5.09–4.91 (m, 2 H, =CH2), 4.70–4.37 (m, 7
H, 3ϫCH2 Bn, 5-H), 4.27–4.09 (m, 3 H, 2-H, 3-H, 4-H), 3.99 (dd,
NHCHHCO2tBu, 6b-H), 2.82–2.75 (m, 1 H, CHH pentenyl), 2.56– J = 4.3, 8.8 Hz, 1 H, CHH-6), 3.44 (dd, J = 8.9, 10.5 Hz, 1 H,
2.51 (m, 1 H, CHH pentenyl), 2.40–2.28 (m, 2 H, CH2 pentenyl),
1.48 (s, 9 H, CH3 tBu) ppm. 13C NMR (150 MHz, CDCl3, HSQC),
major rotamer: δ = 174.0, 169.5, 168.5 (3ϫC), 137.9, 137.6 (3ϫC
Ar), 137.5 (=CH), 128.4, 128.3, 127.8, 127.7, 127.6, 127.5 (15ϫCH
Ar), 114.9 (=CH2), 82.1 (C tBu), 78.6 (C-4), 78.3 (C-3), 73.3, 72.6,
72.4 (3ϫCH2 Bn), 71.5 (C-6), 65.1 (C-2), 59.0 (C-5), 42.0 (CH2),
33.5 (CH2 pentenyl), 29.0 (CH2 pentenyl), 28.0 (3ϫCH3 tBu) ppm.
CH H -6), 2.48–2.23 (m, 4 H , 2ϫCH 2 pentenyl), 1.44 (d, J =
14.7 Hz, 1 H, CHH tBu), 1.35 (d, J = 14.7 Hz, 1 H, CHH tBu),
1.22 (d, J = 14.4 Hz, 6 H, 2ϫCH3), 0.86 (s, 9 H, 3ϫCH3 tBu) ppm.
13C NMR (100 MHz, CDCl3, HSQC), major rotamer: δ = 172.9,
168.7 (2ϫC=O), 138.6 (Cq Bn), 137.2 (Cq Bn), 137.1 (=CH), 137.0
(Cq Bn), 128.8, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7 (15ϫCH Ar), 115.8 (=CH2), 86.0
(C-5), 81.3 (C-2/C-3/C-4), 73.3 (CH2 Bn), 71.8 (2ϫCH2 Bn), 69.4
(C-2/C-3/C-4), 66.8 (C-6), 64.1 (C-2/C-3/C-4), 55.8 [Cq, NHC(CH3)2-
CH2tBu], 53.5 (CH2-tBu), 34.3 (CH2 pentenyl), 31.7 (3ϫCH3 tBu),
31.6 (Cq tBu), 31.7 (3ϫCH3 tBu), 28.9 (CH2 pentenyl), 28.3 (CH3
R = 0.54 (1:1; toluene/EtOAc). IR (thin film): ν
= 3306, 2933,
˜
f
max
1739, 1636, 1416, 1366, 1223, 1151, 735, 698 cm–1. [α]2D0 = +17.9 (c
= 1.14, CHCl3). HRMS: found 643.3379 [M + H]+, calculated for
[C38H46O7N2 + H]+ 643.3378.
Eur. J. Org. Chem. 2008, 3678–3688
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3687

H. S. Overkleeft et al.
FULL PAPER
hedron Lett. 2004, 45, 733–737; c) P. Cristau, J.-P. Vors, J. Zhu,
Org. Lett. 2001, 3, 4079–4082.
tBu), 27.4 (CH tBu) ppm. IR (thin film): νmax = 2950, 1663, 1535,
˜
3
1452, 1399, 1366, 1204, 1097, 736, 699 cm–1. [α]2D0 = –33.3 (c = 0.24,
CH Cl3). H R M S: found 641.3949 [M + H ]+ , calculated for
[C40H52O5N2 + H]+ 641.3949.
[7]
For other examples of Ugi MCRs involving chiral starting ma-
terials in order to obtain chiral induction see the following;
ferrocenylalkylamines: a) F. Siglmüller, R. Herrmann, I. Ugi,
Tetrahedron 1986, 42, 5931–5940; (thio)glycosylamines: b) G. F.
Ross, E. Herdtweck, I. Ugi, Tetrahedron 2002, 58, 6127–6133;
c) K. Oertel, G. Zech, H. Kunz, Angew. Chem. Int. Ed. 2000,
39, 1431–1433; d) S. Lehnhoff, M. Goebel, R. M. Karl, R.
Klösel, I. Ugi, Angew. Chem. Int. Ed. Engl. 1995, 34, 1104–
1107; e) H. Kunz, W. Pfrengle, J. Am. Chem. Soc. 1988, 110,
651–652. Bicyclic β-amino acid scaffolds: f) A. Basso, L. Banfi,
R. Riva, G. Guanti, J. Org. Chem. 2004, 70, 575–579.
We did not observe the formation of HCl and insoluble In(-
OMe)3.
Supporting Information (see also the footnote on the first page of
this article): Copies of 1H and 13C-APT NMR spectra for all re-
ported Ugi-3CR products. 13C-APT NMR spectra of discussed in-
termediates in CD3OH. Assignment of C-2 stereochemistry of the
2,3-cis (3) and 2,3-trans (4) diastereoisomers after depent-4-enoyl-
ation with 1H-NOESY NMR spectra.
[8]
[9]
Acknowledgments
This work was financially supported by the Council for Chemical
Sciences of the Netherlands Organization for Scientific Research
(CW-NWO) and Macrozyme B.V.
The yields for 2,3-cis pyrrolidines IIA-D, IIIA-D, IVA-D and
VA-D of the SAWU-3CR in methanol in the absence of Lewis
acid are listed in ref.[3]. Yields for 2,3-cis pyrrolidines IA: 72%,
IB: 63%, IC: 72%, ID: 83%. All (2,3-cis)/(2,3-trans) ratios were
Ͼ 90:10.
[1] For selected reviews about the Ugi reaction and other multi
component reactions see: a) A. Dömling, Chem. Rev. 2006, 106,
17–89; b) Multicomponent reactions (Eds: J. Zhu, H. Bien-
aymé), Wiley-VCH, Weinheim, 2005; c) J. P. Zhu, Eur. J. Org.
Chem. 2003, 7, 1133–1144; d) R. V. A. Orru, M. de Greef, Syn-
thesis 2003, 10, 1471–1499; e) A. Dömling, Curr. Opin. Chem.
Biol. 2002, 6, 306–313.
[2] M. S. M. Timmer, M. D. P. Risseeuw, M. Verdoes, D. V. Filip-
pov, J. R. Plaisier, G. A. van der Marel, H. S. Overkleeft, J. H.
van Boom, Tetrahedron: Asymmetry 2005, 16, 177–185.
[3] K. M. Bonger, T. Wennekes, S. V. P. de Lavoir, D. Esposito,
R. J. B. H. N. van den Berg, R. E. J. N. Litjens, G. A.
van der Marel, H. S. Overkleeft, QSAR Comb. Sci. 2006, 25,
491–503.
[4] Examples of Ugi-3CRs employing pyrroline-type cyclic imines:
a) L. Banfi, A. Basso, G. Guanti, S. Merlo, C. Repetto, R.
Riva, Tetrahedron 2008, 64, 1114–1134; b) T. M. Chapman,
I. G. Davies, B. Gu, T. M. Block, D. I. C. Scopes, P. A. Hay,
S. M. Courtney, L. A. McNeill, C. J. Schofield, B. G. Davis, J.
Am. Chem. Soc. 2005, 127, 506–507; c) L. Banfi, A. Basso, G.
Guanti, R. Riva, Tetrahedron Lett. 2004, 45, 6637–6640; d)
D. M. Flanagan, M. M. Joullié, Synth. Commun. 1989, 19, 1–
12; e) M. M. Bowers, P. Carroll, M. M. Joullié, J. Chem. Soc.
Perkin Trans. 1 1989, 857–865.
[5] a) S. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Eur. J. Org.
Chem. 2007, 24, 4076–4080; b) U. Kusebauch, B. Beck, K.
Messer, E. Herdtweck, A. Dömling, Org. Lett. 2003, 5, 4021–
4024; c) S. E. Denmark, Y. Fan, J. Org. Chem. 2005, 70, 9667–
9676; d) P. R. Andreana, C. C. Liu, S. L. Schreiber, Org. Lett.
2004, 6, 4231–4233.
[10]
[11]
[12]
T. Saegusa, N. Taka-Ishi, H. Fujii, Tetrahedron 1968, 24, 3795–
3798.
F. R. Benson, J. J. Ritter, J. Am. Chem. Soc. 1949, 71, 4128–
4129.
The acyliminium intermediate has been previously proposed in
the mechanism of Ugi MCR a) I. Ugi, K. Offerman, Angew.
Chem. Int. Ed. Engl. 1963, 2, 624; b) I. Ugi, K. Offerman, H.
Herlinge, D. Marquard, Justus Liebigs Ann. Chem. 1967, 709,
1–10; c) I. Ugi, G. Kaufhold, Justus Liebigs Ann. Chem. 1967,
709, 11–28; d) A. V. Gulevich, E. S. Balenkova, V. G.
Nenajdenko, J. Org. Chem. 2007, 72, 7878–7885.
a) C. H. Larsen, B. H. Ridgway, J. T. Shaw, K. A. Woerpel, J.
Am. Chem. Soc. 1999, 121, 12208–12209; b) C. H. Larsen,
B. H. Ridgway, J. T. Shaw, D. M. Smith, K. A. Woerpel, J. Am.
Chem. Soc. 2005, 127, 10879–10884.
a) Iminosugars (Eds.: P. Compain, O. R. Martin), John Wiley &
Sons Ltd., Chichester, 2007; b) T. Wennekes, R. J. B. H. N.
van den Berg, W. Donker, A. Strijland, J. F. M. G. Aerts, H. S.
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Published Online: June 3, 2008
3688
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Eur. J. Org. Chem. 2008, 3678–3688