Investigation of the configurational stabilities of chiral isocyanoacetates in multicomponent reactions

Article abstract of DOI:10.1021/jo201817k

Isocyanoacetates are uniquely reactive compounds characterized by an ambivalent isocyano functional group and an enolizable α-carbon. It is widely believed that chiral α-substituted isocyanoacetates are configurationally unstable in some synthetically use

Full text of DOI:10.1021/jo201817k

Note
pubs.acs.org/joc
Investigation of the Configurational Stabilities of Chiral
Isocyanoacetates in Multicomponent Reactions
Daniel W. Carney, Jonathan V. Truong, and Jason K. Sello*
Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
S
* Supporting Information
ABSTRACT: Isocyanoacetates are uniquely reactive com-
pounds characterized by an ambivalent isocyano functional
group and an enolizable α-carbon. It is widely believed that
chiral α-substituted isocyanoacetates are configurationally
unstable in some synthetically useful isocyanide-based multi-
component reactions. Herein, we demonstrate that chiral
isocyanoacetates can be used with minimal to negligible
epimerization in a variety of canonical Ugi four-component
́
condensations as well as Joullie−Ugi three-component
condensations, reactions that are particularly useful for
constructing complex peptide structures in a single synthetic
operation.
socyanoacetates are synthons of growing utility in synthetic
method was used to prepare the enantiomerically pure
1
Iorganic chemistry. In addition to the intriguing reactivity of isocyanoacetate substrates from chiral N-formylamino acid
esters, and the reactions were performed under mildly acidic
conditions.4,5
their isocyano functional group, the α-carbon of an
isocyanoacetate is acidic and as such can act as a nucleophile.
These peculiar compounds have been used as substrates in the
synthesis of functionalized heterocycles wherein the nucleo-
philicity of their α-carbon is essential (Scheme 1).1−3 More
Despite their utility as substrates in the reactions described in
Scheme 1, chiral isocyanoacetates6 are thought to be unsuitable
substrates in two reactions for which isocyanides are best
known, specifically, the Ugi four-component condensation (U-
́
4CR) and Joullie−Ugi three-component condensation (JU-
Scheme 1. Reactions of Isocyanoacetates
3CR).1,7 The inherent lack of stereoselectivity in these
multicomponent reactions is often tolerated because of their
high yield and simple execution;8 however, the inclusion of
epimerizable isocyanoacetate substrates has been avoided
because it could yield an unacceptably complex mixture of
diastereomers. In our survey of the literature, we found that
widely held notions about the configurational instability of
isocyanoacetates are based on two U-4CRs7a,9 and one JU-
3CR.10 It seemed that such a small number of examples did not
justify this broad generalization. Clarification of this issue is
warranted by the utility of these substrates and multi-
component reactions in the facile preparation of complex
peptide-like structures.
The reported epimerization of chiral isocyanoacetates in U-
4CR and JU-3CRs could be explained by two distinct
mechanisms (Scheme 2). In one mechanism, the reactants
and/or intermediates promote epimerization by abstraction of a
proton from the isocyanoacetate α-carbon, which has an
estimated pKa of 9−11.7b Alternatively, epimerization could
occur via the reversible formation of an oxazole intermedi-
ate.3,11 Either or both of these mechanisms is feasible, but the
recently, Danishefsky and co-workers used these compounds as
chiral substrates in the preparation of N-methyl peptides
containing α-amino acids of prescribed configurations (Scheme
1).4 Unlike the heterocycle-forming reactions, the α-acidity of
isocyanoacetates is a potential liability in peptide synthesis due
to the possibility of racemization. Even under mildly basic
conditions, reversible enolization of chiral α-substituted
isocyanoacetates can occur.1,5 Indeed, in the aforementioned
synthesis of N-methyl peptides, a racemization-free, dehydrative
Received: September 7, 2011
Published: November 1, 2011
© 2011 American Chemical Society
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We hypothesized that the ability of the amine to promote
epimerization should be compromised by the oxo-compound
and carboxylic acid substrates of the U-4CR. The oxo-
compound undergoes a reversible reaction with the amine
forming an imine and thus limits the availability of free amine
for epimerization. On this basis, the enantiomerically pure
isocyanoacetate was incubated with benzylamine that had been
allowed to react for 2 h with benzaldehyde, isobutyraldehyde,
or cyclohexanone. Consistent with our hypothesis, the rates of
epimerization were suppressed relative to those observed in
incubations with benzylamine alone. Additionally, there was a
correlation between the reactivity of the oxo-compound and the
relative rates of isocyanoacetate epimerization. Specifically, the
addition of the ketone had a smaller effect on the rate of
epimerization than did either aldehyde (Table 1). Indeed, the
condensation equilibria for aldimines generally lies further in
favor of products than do those for ketimines.12 We also
suspected that the carboxylic acid component should limit the
availability of the basic amine species via proton transfer.
Accordingly, when the enantiomerically pure isocyanoacetate
was added to a solution of Boc-proline and benzylamine, the
rates of epimerization were suppressed relative to those of the
incubations with benzylamine alone (Table 1).
Since the carbonyl compound and the carboxylic acid
reactants individually suppress isocyanoacetate epimerization
by the amine, one would expect these reactants to synergisti-
cally suppress epimerization in an U-4CR. We assessed
epimerization in U-4CRs using model reactions of Boc-proline,
benzylamine, and enantiomerically pure isocyanoacetate
derived from (S)-N-formylalanine methyl ester and five
different oxo-compounds, including three aldehydes and two
symmetric ketones. Moreover, Boc-proline, benzylamine, and
isobutyraldehyde were reacted with three additional isocyanoa-
cetates derived from N-formylamino acid esters (Table 2).
Epimerization could be inferred from either measurement of
the enantiomeric ratio of the isocyanoacetate-derived amino
acid in the U-4CR product or of the diastereomeric ratios of the
products. In reactions with aldehydes and cyclobutanone, the
enantiomeric ratios of the isocyanoacetate-derived amino acids
in the reaction products were determined by “advanced Marfey
analysis”.13,14 Isocyanoacetate epimerization in the reaction
with cyclohexanone was assessed by measuring the relative
ratios of the two possible diastereomeric products using LC−
MS.15 In reactions with cyclohexanone and all three aldehydes,
we deduced that epimerization of all four isocyanoacetates was
negligible. Unexpectedly, in the case of cyclobutanone, an
appreciable amount of epimerization was observed. In any case,
the apparent stability of the chiral isocyanides in these model
reactions raised the possibility that this approach could be used
in the preparation of N-methyl peptides, an important class of
biomolecules. Indeed, the U-4CR of Boc-proline, methylamine,
isobutyraldehyde, and the isocyanoacetate derived from (S)-N-
formylleucine methyl ester yielded the expected N-methyl
tripeptide in 68% yield with 4.2% epimerization of the
isocyanoacetate (as determined by Marfey analysis).
Scheme 2. Hypothetical Mechanisms for Isocyanoacetate
Epimerization
complexities of these multicomponent reactions preclude
unambiguous elucidation of the operative mechanism(s) for
epimerization. Nevertheless, we assessed the influence of
reagents and reaction conditions over the configurational
stability of chiral isocyanoacetates. To the best of our
knowledge, this is the first comprehensive study of the
configurational stability of chiral isocyanoacetates in U-4CR
and JU-3CRs.
We first conducted a series of epimerization experiments
wherein enantiomerically pure isocyanoacetate derived from
(S)-N-formylalanine methyl ester was incubated with substrates
of the U-4CR reaction. After incubation for the indicated time,
the enantiomeric purity of the isocyanoacetate was determined
by chiral GC−MS analysis (Table 1). While the isocyanoacetate
Table 1. Effect of U-4CR Reactants on the Stereochemical
a
Configuration of a Chiral Isocyanoacetate
enantiomeric ratio (S:R) in methanol/
dichloromethane
reactant(s)
0 h
2 h
20 h
none
99:1/98:2
99:1/98:2
51:49/93:7
99:1/99:1
99:1/97:3
99:1/97:3
99:1/97:3
99:1/98:2
Boc-proline
benzylamine
52:48/67:36
52:48/99:1
racemic/racemic
racemic/66:34
isobutyraldehyde +
benzylamine
benzaldehyde +
benzylamine
97:3/98:2
73:27/99:1
99:1/99:1
90:10/98:2
54:46/81:19
79:21/91:9
61:39/97:3
cyclohexanone +
benzylamine
racemic/racemic
racemic/racemic
Boc-proline +
benzylamine
a
Enantiomeric ratios were determined by chiral GC−MS. Incubations
were conducted at 0.5 M concentration. Samples were analyzed at the
indicated time points.
was configurationally stable alone and in the presence of Boc-
proline, it racemized quickly when incubated with benzylamine,
a typical U-4CR reaction substrate. We found that racemization
was nearly instantaneous in methanol but took a few hours in
dichloromethane. The relative rates of racemization are
consistent with differences in the polarities of the two solvents
commonly used in U-4CRs. Our data clearly indicate that a
typical amine substrate in an U-4CR reaction can promote
epimerization of the isocyanoacetate.
Since our preliminary results showed that reaction of the
amine and the oxo-compound significantly reduced isocyanoa-
cetate epimerization, we systematically analyzed the effect of
their precondensation time on the reaction outcome. With
isobutyraldehyde, isocyanoacetate epimerization was minimal
with a precondensation time of seconds and undetectable with
a precondensation time of 1 h or longer. In contrast,
epimerization was significant in reactions with cyclohexanone
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cetate.10 Our group recently reported that a JU-3CR utilizing
the isocyanoacetate derived from (S)-N-formylalanine methyl
ester was diastereoselective on the basis of the observation of
two peaks in the HPLC chromoatogram.17 Subsequent Marfey
analyses of the resolved peaks indicated that the major peak was
in fact a mixture of three diastereomers rather than a single
diastereomer. These observations were indicative of epimeriza-
tion of the isocyanoacetate in the JU-3CR.
Table 2. Ugi Four-Component Condensations with Chiral
Isocyanoacetates
a
In light of our studies of U-4CRs (vide supra ),
isocyanoacetate epimerization in the JU-3CR is especially
curious, as there is no basic amine substrate. In our
observations, we suspected that the apparent isocyanoacetate
epimerization was a consequence of the manner in which the
cyclic imine was prepared. The cyclic imine, Δ1-piperideine,
was prepared by base-promoted dehydrohalogenation of N-
chloropiperidine and used without purification because of its
instability. We proposed that residual base from the
dehydrohalogenation was effecting epimerization of the
isocyanoacetate. To circumvent the use of a crude reactant,
the Δ1-piperideine was induced to undergo a reversible
trimerization yielding crystalline and easily isolated tripiper-
ideine.18 JU-3CR reactions of four different chiral isocyanoa-
cetates with Boc-proline and a molar excess of tripiperideine
(containing 1.5 equiv of Δ1-piperideine) yielded the expected
peptides in moderate to good yields (Table 4).19 Advanced
a
Reported yields are the average of two trials. Isocyanide epimerization
was inferred from Marfey analysis of products in all cases except entry
8, for which epimerization was inferred from LC−MS analysis of the
reaction product. Reactions were carried out at 2 M concentration.
Aldehyde reactions ran for 24 h, and ketone reactions ran for 48 h after
a 2 h precondensation of benzylamine and the indicated oxo-
Table 4. Joullie−Ugi Three-Component Condensations with
́
a
Isocyanoacetates
b
compound. All components were combined in an equimolar ratio. In
reactions with the isocyanoacetate derived from (S)-N-formylalanine
methyl ester, epimerization in quantities less than 5% could not be
reliably quantified.
when the precondensation time was less than 2 h (Table 3).
These observations are consistent with the relative suppression
Table 3. Effect of Benzylamine−Cyclohexanone
a
Precondensation Time on Isocyanoacetate Epimerization
precondensation time
0 min 30 min 60 min 120 min
9.1 6.5 6.4 5.6
isocyanoacetate epimerization %
a
Isocyanoacetate epimerization inferred from LC−MS analysis of the
products. Reactions were carried out at 2 M concentration for 48 h
after the indicated precondensation time.
a
Reported yields are the average of two trials. Isocyanide epimerization
was inferred from Marfey analysis. Reactions were carried out at 1 M
concentration for 48 h with a 0.5 molar excess of Δ1-piperideine. The
yields and epimerizations of reactions with equimolar reactants are
shown in parentheses.
of amine-promoted isocyanoacetate epimerization by aldehydes
and ketones as described above (see Table 1). Collectively,
these observations indicate in most cases the isocyanoacetates
are configurationally stable in U-4CRs.
Marfey analyses of these products revealed 17−28% epimeriza-
tion of the isocyanoacetate substrates. In the JU-3CR with the
isocyanoacetate derived from (S)-N-formylleucine methyl ester,
we found that epimerization could be reduced to 3.4% by using
1 equiv of Δ1-piperideine, in the form of tripiperideine. The
reaction with this stoichiometry provided the product in only
31% yield, which compares unfavorably to the reaction with an
excess of tripiperideine (Table 4, entry 2).
Although chiral isocyanoacetates have previously been shown
to be configurationally stable in the Passerini three-component
condensation,20,21 they have seldom been used as substrates in
U-4CRs and JU-3CRs because of concerns about their potential
Chiral isocyanoacetates can also serve as useful substrates for
́
Joullie−Ugi three-component condensations, in which an
isocyanide and carboxylic acid react with a cyclic imine.16
The use of this reaction with isocyanoacetates and N-protected
amino acids is particularly useful for the preparation of
tripeptides containing cyclic amino acids such as proline and
pipecolic acid.16 There is controversy about the configurational
stability of chiral isocyanoacetates in JU-3CR. Whereas Joullie
and co-workers reported the use of an optically active
isocyanoacetate without racemization,16b Riva and co-workers
reported a reaction product with a mixture of configurations at
the stereogenic center originating from their chiral isocyanoa-
́
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hydrochloride (5 mmol, 0.908 g) and dimethylaminopyridine
(DMAP) (1.0 mmol, 123 mg) were added directly to the solution
of the O-formylisourea. Five microliters of DCM was used to rinse
residual reagent from the neck of the flask into the reaction. Finally, N-
methylmorpholine (NMM) (8 mmol, 0.88 mL) was added, and the
reaction was allowed to stir for 16 h. Upon completion, the reaction
was concentrated in vacuo to near dryness and then suspended with
cold ethyl acetate and filtered through a short silica gel column (0.5 in.
× 1 in.). The filtrate was concentrated in vacuo, and the residue was
applied directly to a silica gel column (5 in. × 2 in. column). The N-
formylamino acid methyl ester product was eluted using an ethyl
acetate/hexanes mobile phase. Often times, the product was
contaminated with dicyclohexylurea (DCU) after flash chromatog-
raphy. To remove this impurity, the concentrated residue was
dissolved in ethyl acetate (0.5−1 mL) and stored at −20 °C
overnight, during which time the contaminating DCU precipitated.
The precipitate was filtered and washed with −20 °C ethyl acetate.
The filtrate was concentrated yielding a colorless oil.
for racemization in the course of the reaction. Indeed, several
groups have used elaborate protecting groups and cumbersome
reaction conditions to avoid isocyanoacetate epimerization.7
Our observations suggest that these strategies may only be
necessary in select cases. Here, we show that isocyanoacetate
epimerization does not take place in canonical Ugi four-
component reactions with aldehydes and can be significantly
suppressed in those with ketone substrates by increasing the
precondensation time. Further, we report a procedure for
́
racemization-free Joullie−Ugi reactions with chiral isocyanoa-
cetates and tripiperideine. These findings should prompt
reconsideration of multicomponent reactions for the diversity-
and target-oriented synthesis of structurally complex peptides
as alternatives to the classical synthetic methods that are labor-
intensive and require expensive coupling reagents.
(S)-N-Formylalanine Methyl Ester. Yield 1.162 g (89%): 1H
NMR (400 MHz, CDCl3) δ 8.20 (1 H, s), 6.20 (1 H, broad s), 4.71 (1
H, dt, J = 7.2 Hz, 7.2 Hz), 3.78 (3 H, s), 1.46 (3 H, d, J = 7.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 173.1, 160.4, 52.6, 46.8, 18.5; HRMS
(FAB) calcd for [C5H9NO3 + Na]+ 154.0480, found 154.0483.
(S)-N-Formylleucine Methyl Ester. Yield 801 mg (82%): 1H
NMR (400 MHz, CDCl3) δ 8.22 (1 H, s), 6.01 (1 H, broad s), 4.76 (1
H, td, J = 8.8, 3.5 Hz), 3.76 (3 H, s), 1.68 (2 H, m), 1.59 (1 H, m),
0.97 (3 H, d, J = 6.1 Hz), 0.95 (3 H, d, J = 6.1 Hz); 13C NMR (100
MHz, CDCl3) δ 173.1, 180.6, 52.5, 49.3, 41.7, 24.8, 22.9, 21.9; HRMS
(FAB) [M + Na]+ calcd for [C8H15NO3 + Na]+ 196.0950, found
196.0955.
EXPERIMENTAL SECTION
■
All commercially available reagents were used without further
purification. NMR spectra were obtained at 400 MHz for 1H and
100 MHz for 13C. Chemical shifts were referenced on residual solvent
1
peaks: CDCl3 (δ = 7.27 ppm for H NMR and 77.00 ppm for 13C
NMR).
Direct Measurement of Chiral Isocyanoacetate Epimeriza-
tion. As described in Table 1, epimerization of a chiral
isocyanoacetate was assessed by GC−MS analysis. Aliquots (100
μL) of 1 M stock solutions of the enantiomerically pure
isocyanoacetate derived from (S)-N-formylalanine in either methanol
or dichloromethane were treated with substrates of the U-4CR.
Negative control experiments in which the isocyanoacetate solution
was not treated with any substrate were carried out in parallel. At the
indicated time points, 3 μL samples were removed from the
isocyanoacetate solutions and dissolved in 1 mL of dichloromethane.
From the resulting solution, splitless injections of 1 μL were made
onto a Varian CP Chirasil-DEX 25 m × 0.32 mm column with an inlet
temperature of 150 °C and a detector temperature of 220 °C. Initial
column temperature of 50 °C was held for 4 min, followed by a 12 °C/
min ramp to 150 °C, and then holding for 2 min. Enantiomeric ratios
were determined by integration of the total ion chromatogram.
Indirect Measurement of Chiral Isocyanoacetate Epimeriza-
tion. As described in Tables 2−4, epimerization was inferred from
either measurement of the enantiomeric ratio of the isocyanoacetate-
derived amino acid in the U-4CR product or of the diastereomeric
ratios of the products. In the former, a published procedure for
advanced Marfey analysis was used.14 The derivatized amino acids
were separated on a Higgins Analytical-Hasil C18 column (100 mm ×
1.8 mm) using a binary mobile phase: A = H2O/0.1% formic acid and
B = acetonitrile. Solvent gradient: 20−60% B over 20 min at 0.250
mL/min. UV Detection: 350 nm. Negative ion mode was used for
mass detection. Epimerization was quantified directly by integration of
the Marfey analysis UV chromatograms. As determined in limits of
detection experiments, the ratio of derivatized (R)- and (S)-alanine
could not be measured in quantities less than 5%.
(S)-N-Formylphenylalanine Methyl Ester. Yield 869 mg
1
(84%): H NMR (400 MHz, CDCl3) δ 8.19 (1 H, s), 7.28 (3 H,
m), 7.11 (2 H, dd, J = 7.9 1.0 Hz), 6.05 (1 H, broad s), 4.99 (1 H, dt, J
= 7.9, 6.10 Hz), 3.76 (3 H, s), 3.18 (1 H, d, J = 5.3 Hz), 3.16 (1H, d, J
= 5.3 Hz); 13C NMR (100 MHz, CDCl3) δ 171.5, 180.4, 129.3, 128.9,
127.3, 52.5, 51.8, 37.7; HRMS (FAB) calcd for [C11H13NO3 + Na]+
230.0793, found 230.0785.
(S)-N-Formylmethionine Methyl Ester. Yield 939 mg (98%):
1H NMR (400 MHz, CDCl3) δ 8.25 (1 H, s), 6.35 (1 H d, J = 5.3 Hz),
4.82 (1 H, td, J = 7.85.3 Hz), 3.79 (1 H, s), 2.53 (2 H, t, J = 7.10 Hz),
2.21 (1 H, m), 2.10 (1 H, s), 2.04 (1 H, m); 13C NMR (100 MHz,
CDCl3) δ 172.0, 160.7, 52.8, 50.2, 31.6, 29.8, 15.5; HRMS (FAB)
calcd for [C7H13NO3S + Na]+ 214.0514, found 214.0508.
General Procedure for N-Formylamino Acid Ester Dehy-
dration. The N-formylamino acid ester was dissolved in dry DCM
(20 mL) under nitrogen and cooled to −78 °C. Triphosgene (0.35
equiv) was dissolved separately in dry DCM (5 mL). The triphosgene
solution was added dropwise to the cold N-formylamino acid ester
solution. After the mixture was stirred for 5 min, neat NMM (2 equiv)
was added slowly over the course of 10 min. With all reagents added,
the reaction was stirred at −78 °C for 2 h and quenched by the
addition of water (10 mL). The heterogeneous mixture was allowed to
warm until all of the ice had melted and the two phases were
partitioned. The aqueous phase was extracted with an additional 20
mL DCM, which was pooled and dried over magnesium sulfate. The
dried solution was then filtered through a short silica gel column (1.5
in. × 1 in.) and concentrated in vacuo.
Alternatively, isocyanoacetate epimerization in reactions with
symmetric ketones (e.g., cyclohexanone) was assessed by measuring
the relative ratios of the two possible diastereomeric U-4CR products
using LC−MS. After flash chromatography, the MCR products were
dissolved in methanol to a concentration of 1 mg/mL. Samples (3 μL)
were separated on a Higgins Analytical-Hasil C18 column (100 mm ×
1.8 mm). The compounds were separated using a binary mobile phase:
A = H2O/0.1% formic acid and B = acetonitrile. Solvent gradient: 20−
60% B over 20 min at 0.250 mL/min. UV Detection: 214 nm. Positive
ion mode was used for mass detection.
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
1
Ester. Yield 723.9 mg (71.2%): H NMR (400 MHz, CDCl3) δ 4.35
(1 H, quart, J = 7.3 Hz), 3.84 (3 H, s), 1.67 (3 H, d, J = 7.3 Hz); 13
C
NMR (100 MHz, CDCl3) δ 167.6, 159.5, 53.4, 51.6, 19.4; LRMS (EI)
[M]+ 113, [M − 45]+ 68, [M − 54]+ 59, [M − 59]+ 54.
Isocyanoacetate Derived from (S)-N-Formylleucine Methyl
1
Ester. Yield 506 mg (80%): H NMR (400 MHz, CDCl3) δ 4.29 (1
General Amino Acid Ester Formylation Procedure. Dicyclo-
hexylcarbodiimide (DCC) (6.5 mmol, 1.34 g) was dissolved in
dichloromethane (DCM) (20 mL), and the mixture was cooled to 0
°C. To this solution, 98% formic acid (6.5 mmol, 0.25 mL) was added,
and the mixture was allowed to stir for 10 min, over the course of
which a white precipitate formed. The amino acid methyl ester
H, dd, J = 10.1, 4.8 Hz), 3.83 (3 H, s), 1.87 (2 H, m), 1.70 (1 H, m),
0.99 (6 H, t, J = 6.6 Hz);13C NMR (100 MHz, CDCl3) δ 167.7, 160.1,
55.1, 53.3, 41.3, 24.8, 22.6, 20.9; LRMS (EI) [M − 15]+ 140, [M −
43]+ 112, [M − 59]+ 96, [M − 87]+ 68, [M − 100]+ 55.
Isocyanoacetate Derived from (S)-N-Formylphenylalanine
1
Methyl Ester. Yield 596 mg (80%): H NMR (400 MHz, CDCl3) δ
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Note
7.34 (3 H, m), 7.27 (2H, m), 4.48 (2 H, dd, J = 8.28, 4.88 Hz), 3.82 (3
H, s), 3.28 (1 H, dd, J = 14.03, 4.82 Hz), 3.15 (1 H, dd, J = 13.81, 8.33
Hz); 13C NMR (100 MHz, CDCl3) δ 166.6, 160.9, 134.3, 129.3,
128.89, 127.9, 58.0, 53.4, 38.9; LRMS (EI) [M − 32]+ 157, [M − 59]+
130, [M − 98]+ 91.
48.6, 48.4, 47.4, 47.2, 30.6, 29.8, 28.6, 28.5, 28.4, 28.4, 25.1, 24.8, 17.3;
HRMS (FAB) calcd for [C29H37N3O6 + Na]+ 546.2580, found
546.2588.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
Ester, and Hydrocinnamaldehyde (Table 2, Entry 2). Mixture
Isocyanoacetate Derived from (S)-N-Formylmethionine
1
1
of diastereomers and rotamers. Yield 167 mg (58%): H NMR (400
Methyl Ester. Yield 563 mg (81%): H NMR(400 MHz, CDCl3)
MHz, CDCl3) δ 8.27, 6.70 (1 H, 2 doublets, J = 6.1 Hz), 7.77, 6.80 (1
H 2 doublets, J = 7.3 Hz, 1 H), 7.07−7.40 (20 H, m), 7.03 (2 H, d, J =
7.0 Hz), 5.45 (0.5 H, dd, J = 7.9, 5.0 Hz), 5.20, 5.15 (1 H, 2 singlets),
4.74−4.83 (0.5 H, m), 4.47−4.73 (3 H, m), 4.46, 4.42, 4.38 (1.5 H, 3
singlets), 4.28 (1 H, t, J = 7.1 Hz), 3.95 (0.5 H, dd, J = 7.3, 6.3 Hz),
3.67 (3 H, s), 3.70 (3 H, s) 3.56−3.64 (1 H, m), 3.34−3.55 (3 H, m),
2.66−2.95 (2 H, m), 2.39−2.64, (3 H, m), 2.11−2.29 (1 H, m), 1.71−
2.03, (6 H, m) 1.52−1.71 (2 H, m), 1.49 (2 H, d, J = 7.4 Hz), 1.29−
1.47 (20 H, m), 1.27 (2 H, s), 1.14 (2H, d, J = 7.4 Hz), 1.34, 1.14 (6
H, 3 doublets, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 175.8,
174.3, 173.5, 173.4, 170.5, 168.9, 154.6, 154.5, 145.7, 141.6, 140.7,
138.3, 138.2, 130.6, 128.7, 128.5, 128.4, 128.4, 128.3, 128.3, 128.0,
127.5, 126.9, 126.5, 126.1, 125.8, 83.6, 80.2, 79.9, 77.2, 62.2, 59.3, 58.0,
56.4, 55.0, 52.1, 50.3, 48.5, 48.5, 47.4, 47.0, 46.1, 33.3, 32.4, 30.6, 30.4,
30.3, 30.2, 28.6, 28.4, 28.3, 25.0, 24.8, 17.2, 16.5; HRMS (FAB) calcd
for [C31H41N3O6 + Na]+ 574.2893, found 574.2876.
δ 4.57 (1 H, dd, J = 7.89, 6.14 Hz), 3.85 (3 H, s), 2.60−2.81 (2 H, m),
2.21 (2 H, dd, J = 14.03, 7.00 Hz), 2.12 (3 H, s); 13C NMR (100
MHz, CDCl3) δ 167.0, 160.7, 54.8, 53.5, 31.8, 26.6, 15.4; LRMS (EI)
[M]+ 173, [M − 59]+ 114, [M − 86]+ 87, [M − 99]+ 74, [M − 112]+
61.
N-Chloropiperidine. Piperidine (5.8 mmol, 1.39 mL) and tert-
butanol (5.8, 0.55 mL) were added to methyl tert-butyl ether (MTBE)
(30 mL), and the mixture was cooled to 0 °C. Acetic acid (11.8 mmol,
0.68 mL) and commercial grade cleaning bleach (11.8 mmol, 23.5 mL)
were added simultaneously with stirring. The reaction was stirred for
30 min, after which water (15 mL) was added. The phases were
partitioned, and the organic phase washed with brine (15 mL). The
organic material was dried over magnesium sulfate and then
1
concentrated. Yield 1.17 g (84.0%): H NMR (400 MHz, CDCl3) δ
3.14 (4 H, s broad), 1.72 (4 H, quint, J = 5.7 Hz), 1.46 (2 H, s broad);
13C NMR (100 MHz, CDCl3) δ 63.9, 27.6, 22.9; LRMS (EI) [M]+
119.3.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
Ester, and Isobutyraldehyde (Table 2, Entry 3). Mixture of
Tripiperideine. N-Chloropiperidine (0.915 g, 7.65 mmol) was
dissolved in diethylether (5 mL) and treated with 25% sodium
methoxide in methanol (2.28 mL, 9.95 mmol). After refluxing for 45
min, a white precipitate formed. The reaction was allowed to cool to
room temperature, after which water (7 mL) added, resulting in
solvation of the white precipitate. The phases were partitioned, and the
aqueous phase was washed with diethylether (4 × 10 mL). All of the
organic phases were pooled and dried over MgSO4. The ether layer
was then filtered and concentrated, yielding a pale, yellow oil. The oil
was dissolved in a minimum volume of acetone from which crystals
began to form at 0 °C. Either a seed crystal or scratching the inside of
the flask with a glass stirring rod was required to induce crystallization.
Once crystals were visible at 0 °C, the solution was stored at −20 °C
for 2−3 days, after which the large white tripiperideine crystals were
1
diastereomers and rotamers. Yield 246 mg (96%): H NMR (CDCl3,
400 MHz) δ 8.19 (1 H, d, J = 5.3 Hz), 7.80 (1 H, d, J = 5.3 Hz), 7.09−
7.42 (10 H, m), 4.79−5.03 (2 H, m), 4.25−4.60 (4 H, m), 4.13, 4.08
(1 H, 2 singlets), 3.74, 3.72, 3.65 (6 H, singlets), 3.58−3.75 (1 H, m),
3.43−3.57 (2 H, m), 3.30−3.43 (1 H, m), 2.43−2.67 (1 H, m), 2.24−
2.43 (1 H, m), 2.02−2.21 (2 H. m), 1.79−1.99 (2 H, m), 1.54−1.78 (2
H, m), 1.22−1.53 (21 H, m), 0.69−1.08 (17 H, m); 13C NMR (100
MHz, CDCl3) δ 176.1, 174.8, 173.4, 173.1, 170.3, 168.0, 154.6, 154.5,
137.9, 137.3, 128.6, 128.2, 127.7, 127.5, 127.4, 126.6, 80.3, 79.7, 77.5,
77.2, 77.0, 76.6, 65.8, 57.0, 54.5, 52.1, 52.0, 48.3, 48.1, 47.3, 47.3, 46.0,
30.7, 30.2, 28.6, 28.4, 28.3, 28.1, 26.4, 25.1, 24.5, 20.2, 19.9, 19.5, 19.1,
17.6, 16.7; HRMS (FAB) calcd for [C26H39N3O6 + Na]+ 512.2737,
found 512.2752.
1
filtered and washed with −20 °C acetone. Yield 0.4086 g (64%): H
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylleucine Methyl
Ester, and Isobutyraldehyde (Table 2, Entry 4). Mixture of
NMR (400 MHz, CDCl3) δ 3.13 (3 H dt, J = 10.64, 5.04 Hz), 2.80 (3
H, dd, J = 6.8, 1.9 Hz), 2.02 (3 H dt, J = 11.2, 5.9 Hz), 1.72 (9 H, m),
1.57 (6 H, m), 1.31 (3 H, m); 13C NMR (100 MHz, CDCl3) δ 81.9,
46.4, 29.2, 25.8, 22.3.
1
diastereomers and rotamers. Yield 263 mg (95%): H NMR (CDCl3,
400 MHz) δ 8.15 (1H, 2 doublets, J = 5.6 Hz), 7.86 (1 H, br s), 7.15−
7.43 (10 H, m), 4.58−5.12 (1 H, m), 4.60−4.73 (1 H, m), 4.45−4.60
(3 H, m), 4.41, 4.38, 4.37, 4.33 (2 H, 4 singlets), 3.79−3.89 (1 H, m),
3.73, 3.72, 3.71, 4.67 (6 H, 4 singlets), 3.69−3.74 (0.5 H, m), 3.58−
3.69 (0.5 H, m) 3.45−3.60 (2 H, m), 3.35−3.45 (1 H, m), 2.66−2.92
(1 H, m), 2.27−2.55 (1 H, m), 2.04−2.19 (2 H, m), 1.82−2.04 (2 H,
m), 1.82−2.04 (2 H, m), 1.52−1.81 (7 H, m), 1.51, 1.49, 1.46, 1.44
(18 H, 4 singlets), 1.12−1.35 (3 H, m), 0.88−1.03, (16 H, m), 0.73−
0.87 (8 H, m); 13C NMR (100 MHz, CDCl3) δ 176.0, 174.8, 173.3,
173.0, 172.7, 170.8, 168.2, 154.6, 154.3, 138.0, 137.0, 128.6, 128.3,
127.8, 127.6, 127.5, 126.7, 108.4, 80.2, 79.6, 77.4, 76.6, 66.1, 63.8, 57.2,
54.5, 52.0, 51.8, 51.4, 50.6, 47.3, 47.1, 46.1, 40.6, 40.4, 31.3, 30.8, 29.9,
28.6, 28.4, 28.3, 27.9, 27.6, 26.7, 25.0, 24.8, 24.6, 24.3, 22.9, 22.8, 21.9,
21.4, 20.2, 19.8, 19.4, 19.1; HRMS (FAB) calcd for [C29H45N3O6 +
Na]+ 554.3206, found 554.3220.
Ugi Product Derived from Boc-Proline, Methylamine,
Isocyanoacetate Derived from (S)-N-Formylleucine Methyl
Ester, and Isobutyraldehyde. Mixture of diastereomers and
rotamers. Yield 155 mg (68%): 1H NMR (CDCl3, 400 MHz) δ
8.38, 6.97, 6.57, 6.31 (2 H, 4 doublets, J = 7.9 Hz), 4.75−4.81 (1 H,
m), 4.42−4.76 (4 H, m), 4.29 (1 H, d, J = 10.7 Hz), 3.71, 3.70 (6 H, 2
singlets), 4.42−4.76 (4 H, m), 3.04, 3.00, 2.98, 2.74 (6 H, 4 singlets),
2.10−2.46 (4 H, m), 2.00−2.10 (2 H, m), 1.79−1.99 (4 H, m), 1.54−
1.74 (6 H, m), 1.44, 1.43, 1.40, 1.37 (18 H, 4 singlets), 1.00−1.09 (4
H, m), 0.86−0.97 (15 H, m), 0.77−0.84 (5 H, m); 13C NMR (100
MHz, CDCl3) δ 173.9, 173.4, 173.3, 170.5, 169.7, 168.8, 154.6, 154.5,
80.2, 79.6, 79.5, 77.2, 66.1, 56.2, 54.2, 52.0, 51.9, 51.0, 50.9, 50.3, 47.3,
47.0, 40.3, 40.2, 30.9, 29.4, 29.0, 28.4, 28.2, 26.1, 26.0, 24.9, 24.7, 24.6,
Ugi Reaction General Procedure. To a 1 dram glass vial
containing the prescribed volume of methanol, oxo-compound (0.5
mmol) and benzylamine (0.5 mmol, 54.6 μL) were added. After a
precondensation time of 0−2 h, Boc-proline (0.5 mmol, 107.6 mg)
and the isocyanoacetate (0.52 mmol) were added. With all reactants
added, the solution was allowed to stir for either 24 h in reactions with
aldehydes or 48 h in reactions with ketones. The reactions were
concentrated in vacuo and subsequently dissolved in 1:1 hexanes/ethyl
acetate. The solution was then applied to a silica gel column (4 in. ×
0.75 in.). Unreacted isocyanide was eluted with 3:1 hexanes/ethyl
acetate, and the product was eluted with 1:1 to 1:2 hexane/ethyl
acetate.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
Ester, and Benzaldehyde (Table 2, Entry 1). Mixture of
diastereomers and rotamers. Yield 234 mg (86%): 1H NMR (400
MHz, CDCl3) δ 8.11, 7.69, 6.36, 6.10 (2 H, 4 doublets, J = 7.0 Hz),
6.95−7.56 (20 H, m), 6.68 (1H, m), 6.57 (1 H, s), 6.27, 6.16, 5.96, (1
H, 3 singlets), 1.29, 5.24, 5.21, 5.14 (1H, 4 singlets), 4.35−4.78 (4.5 H,
m), 4.18−4.30 (1 H, m), 3.96−4.10 (0.5 H m), 3.80, 3.74, 3.73, 3.69
(6 H, 4 singlets), 3.56−3.67 (1 H, m), 3.21−3.56 (3 H, m), 1.99−2.40
(2 H, m), 1.59−1.99 (4 H, m), 1.33−1.58 (23 H, m), 1.25 (1.5 H, d),
0.95, (1.5 H, d, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 175.1,
174.9, 174.7, 173.6, 173.2, 173.0, 169.2, 167.7, 154.7, 138.0, 137.8,
135.5, 135.3, 130.6, 130.4, 129.8, 129.6, 129.4, 129.0, 128.8, 128.7,
128.6, 128.3, 128.2, 127.9, 127.8, 127.1, 126.9, 126.7, 126.7, 126.6,
126.3, 80.3, 79.9, 77.2, 63.3, 62.3, 56.5, 54.8, 52.4, 52.2, 52.1, 50.1,
10283
dx.doi.org/10.1021/jo201817k|J. Org. Chem. 2011, 76, 10279−10285

The Journal of Organic Chemistry
Note
24.6, 22.8, 22.8, 22.6, 21.8, 21.4, 20.7, 20.4, 19.0, 18.5; HRMS (FAB)
calcd for [C23H41N3O6 + Na]+ 478.2893, found 478.2878.
reaction solvent was removed in vacuo. The oily residue was applied to
a silica gel column, and the product was eluted with hexanes:ethyl
acetate.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylphenylalanine
Methyl Ester, and Isobutyraldehyde (Table 2, Entry 5). Mixture
of diastereomers and rotamers. Yield 238 mg (98%): 1H NMR
(CDCl3, 400 MHz) δ 8.44 (1 H, d, J = 6.5 Hz), 7.78 (1 H, br s), 6.92−
7.40 (20 H, m), 7.85 (0.5 H, dd, J = 7.2, 5.1 Hz), 4.76, 4.72, (0.5 H, 2
singlets), 4.49−4.69 (2 H, m), 4.31−4.48 (2 H, m), 4.23, (1 H, s),
4.09−4.21 (1 H, m), 3.61−3.75, (4 H, m), 3.43−3.60, (4 H, m), 3.27−
3.43 (1 H, m), 3.05−3.28 (1 H, m), 2.91−3.04 (1 H, m), 2.87 (1 H,
dd, J = 13.4, 8.6 Hz), 2.53−2.72 (1.5 H, m), 2.22−2.44 (1.5 H, m),
1.97−2.15 (2 H, m), 1.83−1.95 (1 H, m), 1.56−1.80 (2H, m), 1.49,
1.45, 1.44, 1.41 (18 H, 4 singlets), 0.95 (2 H, d, J = 6.3 Hz), 0.79−0.91
(8 H, m), 0.68, (2 H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
175.6, 174.7, 174.1, 172.3, 171.7, 168.1, 154.6, 154.3, 153.8, 145.2,
138.2, 136.6, 136.4, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 127.8,
127.4, 127.2, 126.9, 126.7, 126.6, 126.3, 80.3, 80.1, 79.4, 66.3, 57.7,
57.1, 54.5, 54.2, 53.2, 52.9, 52.1, 52.0, 51.6, 47.3, 47.0, 45.9, 37.6, 37.6,
31.1, 30.8, 29.8, 28.5, 28.3, 27.6, 26.5, 25.0, 24.4, 22.6, 20.2, 19.7, 19.6,
19.2, 19.1; HRMS (FAB) calcd for [C32H43N3O6 + Na]+ 485.2264,
found 485.2288.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylmethionine Methyl
Ester, and Isobutyraldehyde (Table 2, Entry 6). Mixture of
diastereomers and rotamers. Yield 274 mg (96%): 1H NMR (CDCl3,
400 MHz) δ 8.21 (1 H, d, J = 6.1 Hz), 7.92 (1 H, br s), 7.09−7.45 (10
H, m), 4.81−5.10 (2 H, m), 4.66−4.78 (1 H, m), 4.46−4.66 (3 H, m),
4.37−4.45 (1 H, m), 4.32, 4.29 (1 H, 2 singlets), 3.89 (1 H, q, J = 7.0
Hz), 3.74, 3.73, 3.67 (6 H, 3 singlets), 3.59−3.65 (1 H, m), 3.44−3.57
(2 H, m), 3.31−3.44 (1 H, m), 2.40−2.53 (3 H, m), 2.20−2.38 (3 H,
m), 2.06 (3 H, s), 2.01 (3 H, s), 1.61−1.17 (12 H, m), 1.49, 1.48, 1.45,
1.42 (18 H, 4 singlets), 4.84−1.06 (9 H, m), 0.75 (3 H, d, J = 6.8 Hz);
13C NMR (100 MHz, CDCl3) δ 175.8, 174.8, 174.4, 172.3, 172.0,
171.7, 170.5, 168.4, 154.7, 154.4, 137.9, 136.8, 128.6, 128.5, 128.4,
127.8, 127.5, 127.3, 127.1, 126.7, 126.5, 83.6, 80.3, 79.6, 79.4, 77.2,
66.1, 57.8, 57.2, 56.5, 54.5, 52.3, 52.2, 52.2, 52.0, 51.3, 51.2, 51.2, 47.4,
47.1, 46.1, 31.3, 31.0, 30.8, 30.1, 30.1, 29.8, 29.6, 28.5, 28.4, 27.7, 27.6,
27.5, 26.6, 25.0, 24.5, 24.4, 22.7, 20.2, 19.8, 19.7, 19.4, 19.2, 19.1, 18.8,
15.3; HRMS (FAB) [C28H43N3O6S + Na]+calcd 572.2770, found
572.2780.
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
Ester, and Cyclobutanone (Table 2, Entry 7). Mixture of
rotamers. Yield 207 mg (81%): 1H NMR (CDCl3, 400 MHz) δ
7.81, 7.75 (1 H, 2 doublets, J = 7.0 Hz), 7.29−7.49 (5 H, m), 5.20,
5.14, (1 H, 2 singlets), 4.43−4.63 (1 H, m), 4.41, 4.35 (1 H, 2
singlets), 4.10−4.31 (1H, m), 3.75, 3.73, 3.71, 3.65, (3 H, 4 singlets),
3.29−3.56, (2 H, m), 2.55−2.94 (1 H, m), 2.00−2.54 (4 H, m), 1.59−
1.99 (5 H, m), 1.49−1.57 (1 H, m), 1.32−1.45 (11 H, m); 13C NMR
(100 MHz, CDCl3) δ 174.8, 173.7, 173.3, 154.7, 138.6, 128.9, 128.8,
127.3, 126.1, 125.9, 79.7, 77.2, 66.1, 56.8, 52.1, 49.5, 48.5, 47.4, 30.7,
28.7, 28.5, 28.4, 24.6, 17.5, 15.1; HRMS (FAB) calcd for [C26H37N3O6
+ Na]+ 510.2580, found 510.2595.
Boc-(S)-Pro-Pip-(S)-Ala-Ome (Table 4, Entry 1). Mixture of
1
diastereomers and rotamers. Yield 158 mg (73%): H NMR (CDCl3,
400 MHz) δ 8.45, 7.37, 6.62, 6.59 (2 H, 4 doublets, J = 7.0 Hz), 5.14−
5.55 (1 H, m), 4.37−4.90 (5 H, m), 3.89, 3.86 (2 H, 2 singlets), 3.71,
3.68 (6H, 2 singlets), 3.52−3.61 (2H, m), 3.39−3.51 (2H, m), 2.43−
2.65 (2 H, m), 2.03−2.30 (5 H, m), 1.80−2.03 (6 H, m), 1.55−1.79 (7
H, m), 1.22−1.55 (26 H, m); 13C NMR (100 MHz, CDCl3) δ 173.7,
172.0, 171.5, 170.1, 169.8, 154.6, 79.9, 79.7, 56.3, 55.7, 55.6, 52.1, 52.1,
48.8, 48.3, 47.0, 46.8, 43.7, 39.7, 29.6, 29.5, 28.4, 26.1, 26.0, 24.8, 24.7,
20.6, 16.9, 16.5; HRMS (FAB) calcd for [C20H33N3O6 + Na]+
434.2267, found 434.2262.
Boc-(S)-Pro-Pip-(S)-Leu-Ome (Table 4, Entry 2). Mixture of
1
diastereomers and rotamers. Yield 129 mg (54%): H NMR (CDCl3,
400 MHz) δ 8.33 (1 H, d, J = 7.9 Hz), 7.13 (1 H, d, J = 7.5 Hz), 5.08−
5.47 (1 H, m), 4.29−4.75 (4 H, m), 3.84 (0.5 H, d, J = 12.4 Hz), 3.67,
3.65 (6 H, 2 singlets), 3.47−3.60 (2.5 H, m), 3.29−3.47 (3H, m),
2.31−2.60 (2 H, m), 1.97−2.23 (3 H, m), 1.76−1.95 (4 H, m), 1.54−
1.76 (10 H, m), 1.17−1.54 (29 H, m), 0.75−0.99 (12 H, m); 13C
NMR (100 MHz, CDCl3) δ173.5, 173.3, 171.8, 170.2, 170.0, 154.5,
79.8, 79.5, 56.2, 55.7, 55.5, 51.9, 51.8, 51.6, 50.9, 46.9, 46.7, 43.5, 40.1,
39.6, 38.7, 29.5, 28.3, 28.2, 26.1, 25.9, 24.8, 24.7, 24.6, 22.9, 22.7, 22.5,
21.8, 20.9, 20.6; HRMS (FAB) calcd for [C23H39N3O6 + Na]+
476.2737, found 476.2720.
Boc-(S)-Pro-Pip-(S)-Phe-Ome (Table 4, Entry 3). Mixture of
1
diastereomers and rotamers. Yield 148 mg (58%): H NMR (CDCl3,
400 MHz) δ 8.50 (1 H, d, J = 8.3 Hz), 7.46 (1 H, J = 7.7 Hz), 7.05−
7.38 (10 H, m), 5.04−5.41 (1 H, m), 4.78−4.04 (0.5 H, m), 4.54−4.78
(3 H, m), 4.36−4.54 (1 H, m), 4.33, 4.30 (0.5 H, 2 singlets), 3.86, 1.83
(1 H, 2 singlets), 3.63−3.78 (6 H, m), 3.52−3.63 (2 H, m), 3.53 −5.52
(2 H, m), 3.15−3.43 (3 H, m), 2.98−3.15 (2 H, m), 2.34−2.57 (1 H,
m), 1.99−2.28 (5 H, m), 1.80−1.99 (4 H, m), 1.58−1.80, (4 H, m),
1.00−1.58 (26 H, m); 13C NMR (100 MHz, CDCl3) δ 172.4, 172.1,
171.9, 171.3, 169.9, 169.7, 154.7, 137.5, 137.1, 129.2, 129.2, 128.4,
128.3, 127.0, 126.5, 126.5, 80.0, 79.7, 57.0, 56.2, 55.9, 55.6, 54.4, 54.2,
53.3, 52.1, 51.9, 47.0, 46.9, 43.5, 39.3, 37.4, 36.2, 29.6, 29.5, 28.4, 25.9,
25.9, 25.7, 24.8, 24.8, 24.7, 24.4, 20.5, 20.4; HRMS (FAB) calcd for
[C26H37N3O6 + Na]+ 510.2580, found 510.2566.
Boc-(S)-Pro-Pip-(S)-Met-Ome (Table 4, Entry 4). Mixture of
1
diastereomers and rotamers. Yield 135 mg (54%): H NMR (CDCl3,
400 MHz) δ 8.46 (1 H, d, J = 7.7 Hz), 7.30 (1 H, d, 8.2 Hz), 5.14−
5.44 (1 H, m), 4.74 (1 H, td, J = 8.6, 5.4 Hz), 4.52−4.67 (4 H, m),
3.89, 3.86 (1 H, 2 singlets), 3.72, 3.69, 3.65, (6 H, 3 singlets), 3.51−
3.63 (2 H, m), 3.33−3.51 (3 H, m), 2.42−2.63 (6 H, m), 2.08, 2.06 (6
H, 2 singlets), 2.02−2.29 (8 H, m), 1.79−2.02 (6 H, m), 1.52−1.79 (4
H, m), 1.30−1.52 (24 H, m); 13C NMR (100 MHz, CDCl3) δ172.7,
171.9, 171.4, 170.4, 170.3, 154.7, 83.6, 80.0, 79.7, 56.3, 55.8, 55.6, 52.1,
51.5, 47.0, 46.9, 43.6, 39.7, 30.7, 30.0, 29.7, 29.6, 28.5, 28.4, 26.1, 26.0,
24.8, 20.6, 15.5, 15.3; HRMS (FAB) calcd for [C22H37N3O6S + Na]+
494.2301, found 494.2311.
ASSOCIATED CONTENT
Ugi Product Derived from Boc-Proline, Benzylamine,
Isocyanoacetate Derived from (S)-N-Formylalanine Methyl
Ester, and Cyclohexanone (Table 2, Entry 8). Mixture of
rotamers. Yield 242 mg (90%): 1H NMR (CDCl3, 400 MHz) δ
7.18−7.61 (5 H, m), 7.65, 7.56 (1 H, 2 doublets, 7.0 Hz), 5.05, 4.99,
4.84, 4.78 (1 H, 4 singlets), 4.33−4.72, (3 H, m), 3.75, 3.73, 3.71, (3
H, 3 singlets), 3.47−3.65 (1 H, m), 3.28−3.47 (1 H, m), 2.13−2.56, (2
H, m), 1.54−1.99 (10 H, m), 1.37−1.54 (14 H, s); 13C NMR (100
MHz, CDCl3) δ 175.1, 173.8, 173.4, 154.5, 139.3, 138.9, 129.0, 128.9,
127.3, 126.3, 126.2, 80.1, 79.4, 72.5, 66.3, 57.8, 52.1, 48.4, 48.3, 47.9,
47.3, 32.8, 30.5, 28.7, 28.5, 25.4, 24.3, 23.1, 22.7, 22.5, 17.8; HRMS
(FAB) calcd for [C28H41N3O6 + Na]+ 538.2893, found 538.2876.
■
S
* Supporting Information
Passerini three-component reaction results, H and 13C NMR
1
spectra, epimerization measurement chromatograms, advanced
Marfey analysis chromatograms, and LC chromatograms. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Jason_Sello@Brown.edu.
■
́
Joullie−Ugi Reaction General Procedure. Tripiperideine
(either 0.17 or 0.25 mmol) and Boc-proline (0.5 mmol, 108 mg)
were dissolved in methanol and stirred until the solution was
homogeneous. Subsequently, the isocyanoacetate (0.52 mmol) was
added to the reaction. After stirring for 48 h at room temperature, the
ACKNOWLEDGMENTS
Brown University is gratefully acknowledged for financial
support of this work. J.V.T. was supported by the Royce
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dx.doi.org/10.1021/jo201817k|J. Org. Chem. 2011, 76, 10279−10285

The Journal of Organic Chemistry
Note
Fellows Program at Brown. We thank Dr. Aaron Socha for
helpful discussions.
REFERENCES
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(19) We also tried suppressing epimerization in a Joullie−Ugi
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dx.doi.org/10.1021/jo201817k|J. Org. Chem. 2011, 76, 10279−10285