The passerini reaction with CF3-carbonyl compounds - Multkomponent approach to trifluoromethyl depslpeptides

Article abstract of DOI:10.1002/ejoc.200900330

The first detailed investigation of the Paserini reaction with CF ₃-carbonyl compounds is reported. The reaction provides a new approach to trifluorolactic acid derivatives and CF₃-substituted depsipeptides. The method is promising f

Full text of DOI:10.1002/ejoc.200900330

FULL PAPER
DOI: 10.1002/ejoc.200900330
The Passerini Reaction with CF3-Carbonyl Compounds – Multicomponent
Approach to Trifluoromethyl Depsipeptides
Anton V. Gulevich,[a] Inga V. Shpilevaya,[a] and Valentine G. Nenajdenko*[a]
Keywords: Multicomponent reactions / Peptidomimetics / Depsipeptide / Chiral resolution
The first detailed investigation of the Paserini reaction with
CF3-carbonyl compounds is reported. The reaction provides
a new approach to trifluorolactic acid derivatives and CF3-
substituted depsipeptides. The method is promising for the
synthesis of chiral trifluoromethyl depsipeptides, i.e. orthogo-
nally protected building blocks for incorporation into natu-
rally occurring depsipeptides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Depsides and depsipeptides are interesting classes of bio-
polymers that have recently received much attention.[1]
These polymeric compounds are analogues of peptides: de-
psides are composed of hydroxy acids linked by ester bonds,
and depsipeptides are formed by hydroxy and amino acids
linked together by ester and amide bonds. In general, depsi-
peptides are peptides bearing a COO group instead of a
CONH group (Scheme 1). Naturally occurring depsipep-
tides show promising biological activities, including anti-
bacterial, antiviral, antifungal and anti-inflammatory prop-
erties.[2] However, their greatest future therapeutic potential
is in cancer treatment.[3] Additionally, amide-to-ester substi-
tutions in the backbone of peptides were found to be a use-
ful tool for evaluating the role of protein hydrogen bond-
ing.[4] Furthermore, depsipeptides can serve as branching
units for building dendrimers[5] and can function as nonvi-
ral vectors for drug delivery.[6]
The Passerini, three-component condensation (P-3CC),
which is the reaction of an isocyanide, a carbonyl com-
pound and a carboxylic acid, is experiencing a growing
interest owing to its efficiency in the synthesis of diverse
products.[7] It is arguably the best method for producing α-
acyloxy amides in a highly convergent manner and the most
convergent approach to depsipeptides.[8]
The modification of peptides and proteins by the incor-
poration of α-trifluoromethyl- (α-Tfm-) substituted amino
acids has attracted considerable attention[9] due to the
unique stereoelectronic properties of the trifluoromethyl
group.[10] Consequently, α-Tfm depsipeptides could become
interesting candidates for medicinal chemistry. Recently, the
Scheme 1. Synthesis of CF3-depsipeptides.
synthesis of a CF3-depsides, based on OH insertion of CF3-
substituted metal carbenoid into the carboxylic group of N-
protected amino acids, was described.[11]
The enhanced carbonyl activity of polyfluoro carbonyl
compounds[12] allowed us to propose that their use in isocy-
anide-based, multicomponent reactions can result in a
straightforward approach to fluorinated amino acids build-
ing blocks. Recently, we have shown that imines of CF3-
[a] Department of Chemistry, Moscow State University,
199991 Leninskije Gory, Moscow University, Moscow, Russian
Federation
E-mail: nen@acylium.chem.msu.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900330.
Eur. J. Org. Chem. 2009, 3801–3808
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. V. Gulevich, I. V. Shpilevaya, V. G. Nenajdenko
FULL PAPER
carbonyl compounds are effective precursors for the Ugi Table 1. CF3-carbonyl compounds in the Passerini reaction.
reaction,[13] and we proposed that CF3-carbonyl com-
pounds can be very interesting partners for the P-3CC. To
the best of our knowledge, CF3-carbonyl compounds have
not been systematically investigated in the Passerini reac-
tion. Previously, only a few selected examples of the Pass-
erini reaction with hexafluoroacetone and trifluoromethyl
ketones were described.[14]
In this paper, we report the detailed investigation of the
Passerini reaction with CF3-carbonyl compounds that pro-
vides a new approach to trifluorolactic acid derivatives and
CF3-substituted depsipeptidesϪconvenient trifluoromethyl
building blocks for incorporation into naturally occurring
depsipeptides (Scheme 1). Valinomycin (A), a symmetric
cyclodepsipeptide isolated from Streptomyces fuivissimus, is
formed by three repeating units of depsipeptide -Val--
Lac--Val connected by -hydroxyisovaleric acid.[15] Valino-
mycin shows excellent K+/Na+ selectivity, acts as an ion-
conducting antibiotic and allows uncontrolled movement of
ions across the cell membrane.[16] Unfortunately, it shows
[a] CH2Cl2, –20 °C to room temp. [b] Gaseous 1c was condensed
into the mixture of carboxylic acid and isocyanide at –40 °C.
no selective toxicity for bacterial cells over mammalian cells
and is, therefore, useless as a therapeutic agent.[17] The in-
corporation of fluorinated fragments into valinomycin can
improve its medicinal properties. Our suggested protocol
can be an effective synthesis of fluorinated depsipeptide
building blocks for incorporation into naturally occurred
depsipeptides.
Table 2. Influence of the carboxylic component.
Results and Discussion
Trifluoroacetaldehyde (fluoral) methyl hemiacetal (1a) is
the most convenient and commercially available form of
gaseous trifluoroacetaldehyde (b.p. –18.8 to –17.5 °C). We
have found that 1a readily reacts in the Passerini reaction
with acetic acid and tert-butyl isocyanide (tBuNC) to give
the product 2a in 93% yield (Table 1, Entry 1). We tested
other CF3-carbonyl compounds in the model reaction. CF3-
ketones 1b–d reacted smoothly (Table 1, Entries 2–4). We
found trifluoroacetophenone
(1e) to be less reactive (Table 1, Entry 5), possibly due to
the lower electrophilicity of the carbonyl group and in-
creased steric hindrance. Commercially available aqueous
hexafluoroacetone (CF3COCF3ϫ1.5H2O) failed to react,
while anhydrous hexafluoroacetone gave the product in
high yield (Table 1, Entry 3).[14a]
We next investigated the influence of the acid component
on the model reaction of fluoral hemiacetal and tBuNC
(Table 2). Acetic and benzoic acid led to the corresponding
products in good yields. N-protected, chiral, amino acids
gave no stereoinduction and led to the corresponding de-
psides 2h,i in good yields as mixtures of diastereomers (dr
≈ 1:1).
[a] CH2Cl2, –20 °C to room temp., 24 h. [b] After column
chromatography. [c] dr ≈ 1:1.
Formic and trifluoroacetic acids gave directly trifluoro-
acetic amide 2g with a free hydroxy group after column the OH group, as in, for example, ester formation. More-
chromatograhy due to a facile deprotection of the trifluoro- over, amides of α-(trifluoromethyl)lactic acid were found to
acetyl- or formyl-lactic amides during the work-up.[7,18] be inhibitors of PDHKs (Pyruvate Dehydrogenase Kin-
This seems to be useful for subsequent fictionalization of ases).[19]
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Multicomponent Approach to Trifluoromethyl Depsipeptides
We have investigated the influence of the isocyanide on Table 4. Synthesis of CF3-depsipeptides.
the yield of Passerini reaction. Aliphatic, aromatic and ste-
rically hindered isocyanides reacted straightforwardly. In
general, the structure of the isocyanide did not affect the
reaction outcome significantly, except for the less reactive
trifluoroacetone (Table 3, Entry 10).
Table 3. Synthesis of trifluorolactic amides.
[a] CH2Cl2, room temp., 24 h. [b] dr ≈ 1:1. [c] THF was used as
solvent.
[a] CH2Cl2, –20 °C to room temp., 24 h. [b] dr ≈ 1:1.
Consequently, we have demonstrated that the Passerini
reaction with CF3-carbonyl compounds is a general ap-
proach to a broad variety of α-Tfm-substituted hydroxy
acid derivatives. It should be noted that compounds 3a–c
are amides of trifluorolactic acid (CF3-hydroxyacetic acid),
which were found to be effective precursors for the synthesis
of liquid crystals.[20]
The Passerini reaction with CF3-carbonyl compounds,
isocyanoacetic acid derivatives 4a,b and N-protected amino
acids opens a new multicomponent, one-step route to or-
thogonally protected depsipeptides containing natural
amino acid residues and α-Tfm-substituted hydroxy acid
fragments (Table 4). We have synthesized a number of vari-
ous CF3-depsipeptides in high yields. Unfortunately, we ob-
served no stereoinduction, and we isolated products 5b–d
as a mixture of diastereomeric pairs (dr ≈ 1:1). Protected
amino acids were ineffective chiral auxiliaries in the Pass-
erini reaction, which is in agreement with literature data.[21]
Previously, Ostaszewski et al. reported that chiral isocy-
anoacetates can undergo racemization in the Passerini reac-
Scheme 2. [a] CH2Cl2, room temp., 24 h. [b] Crystallisation: petro-
leum ether/CHCl3.
tion.[22] Recently, we have developed new nonracemizable zation. The absence of stereoinduction cannot be caused by
isocyanoacetates with an ortho-ester protective group OBO racemization of the product under the reaction condi-
for multicomponent reactions.[23] We decided to use the chi- tions.[24] We have found that depsipeptide 5g fully retains
ral isocyanide 4c, fluoral 1a and Boc--valine for the syn- its absolute configuration in presence of both piperidine
thesis of chiral depsipeptide unit -Val--trifluoroLac--Val (2 equiv., 24 h), and DBU (1.4 equiv., 30 min).[25]
(Scheme 2).
We confirmed the absolute configuration of 5g by X-ray
Unfortunately, we observed no stereoinduction under the analysis (unfortunately, due to the low quality of the crys-
influence of two chiral components and found the dia- tals formed, the necessary number of reflections have not
stereomeric ratio of 5g/5h to be ca. 1:1. However, the mix- been collected).[26] Nevertheless, the X-ray picture con-
ture of isomers 5g,h can be easily separated by crystalli- firmed the assigned configuration of diastereomer 5g. The
Eur. J. Org. Chem. 2009, 3801–3808
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A. V. Gulevich, I. V. Shpilevaya, V. G. Nenajdenko
FULL PAPER
53.2 [C(CH3)3], 28.1 [C(CH3)3], 20.5 (OCOCH3) ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –73.0 (s, 2 CF3) ppm. IR (nujol):
fact that both diastereomers can be separated easily is an
advantage for the further synthesis of CF3-substituted val-
inomycin. The suggested approach can be effective for the
preparation of other diastereopure depsipeptides.
ν
=
3380 (CONH), 1800 (CONH), 1770 (COMe) cm–1.
˜
C10H13F6NO3 (309.21): calcd. C 38.84, H 4.24; found C 39.04, H
4.12.
Methyl 2-(Acetyloxy)-2-[(tert-Butylamino)carbonyl]-3,3,3-trifluoro-
propanoate (2d): Yield 67% (200 mg, 0.67 mmol). White solid, m.p.
43–45 °C. Rf (hexanes/EtOAc, 2:1) = 0.55. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.7 (br. s, 1 H, NH), 3.84 (s, 3 H, COOCH3),
2.24 (s, 3 H, OCOCH3), 1.36 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 168.8 (COCH3), 165.4 (COCO2-
CH3), 156.9 (CONHtBu), 120.7 (q, J = 286.2 Hz, CF3); 79.2 [q, J
= 30.0 Hz, C(CF3)CO2CH3], 54.2 (COOCH3), 52.4[C(CH3)3], 28.1
[C(CH3)3], 20.2 (OCOCH3) ppm. 19F NMR (376.3 MHz, CDCl3,
Conclusions
In conclusion, the first example of the Passerini reaction
with fluoral methyl hemiacetal was described. A number
of CF3-carbonyl compounds were tested in the Passerini
condition. The scope and limitations of the reaction were
discussed. A novel approach to trifluorolactic acid deriva-
tives and trifluoromethyl-depsipeptides was described.
OBO-protected chiral isocyanoacetate was successfully em-
ployed in the synthesis of a diastereopure depsipeptide for
incorporation into valinomycin. The method is promising
for the synthesis of chiral α-Tfm depsipeptides.
25 °C): δ = –74.05 (s, CF ) ppm. IR (nujol): ν = 3385 (CONH),
˜
3
1740 (CONH), 1715 (COCH3) cm–1. C11H16F3NO5 (299.24): calcd.
C 44.35, H 5.38; found C 44.15, H 5.39.
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoro-1-phenylethyl Acetate
(2e): Yield 53% (170 mg, 0.53 mmol). White solid, m.p. 86–87 °C.
Rf (hexanes/EtOAc, 2:1) = 0.55. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.50–7.58 (m, 2 H, ArH); 7.36–7.47 (m, 3 H, ArH), 5.9
(br. s, 1 H, NH), 2.29 (s, 3 H, OCOCH3), 1.34 [s, 9 H, NHC-
(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 167.8 (OC-
OCH3), 162.7 (CONH), 131.2 (ArC), 129.6 (ArCH), 128.4 (ArCH),
127.2 (ArCH), 122.6 (q, J = 285.4 Hz, CF3), 83.5 [m, C(CF3)Ph],
52.2 [C(CH3)3], 28.2 [C(CH3)3], 21.3 (OCOCH3) ppm. 19F NMR
Experimental Section
General Procedure for the Passerini Reaction: Isocyanide (1 mmol)
was added to a mixture of carbonyl compound (1 mmol) and car-
boxylic acid (1 mmol) in CH2Cl2 (10 mL) at –20 °C. The mixture
was stirred for 12 or 24 h, concentrated, and the product was iso-
lated by column chromatography (if needed).
(376.3 MHz, CDCl , 25 °C): δ = –76.1 (s, CF ) ppm. IR (nujol): ν =
˜
3
3
3370 (CONH), 1760 (CONH), 1710 (COCH3) cm–1. C15H18F3NO3
(317.30): calcd. C 56.78, H 5.72; found C 56.70, H 5.88.
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoroethyl Acetate (2a):
Yield 93% (220 mg, 0.93 mmol). White solid m.p. 120–122 °C. Rf
(hexanes/EtOAc, 2:1) = 0.7. H NMR (400 MHz, CDCl3, 25 °C):
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoroethyl Benzoate (2f):
Yield 60% (180 mg, 0.6 mmol). White solid, m.p. 159–160 °C. Rf
1
1
δ = 1.37 (s, 9 H, tBu), 2.24 (s, 3 H, COCH3), 5.43 (q, JH,F
=
(hexanes/EtOAc, 2:1) = 0.8. H NMR (400 MHz, CDCl3, 25 °C):
7.32 Hz, 1 H, CHCF3), 5.8 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 167.9 (OCOCH3), 160.3 (CONH),
121.4 (q, J = 281.7 Hz, CF3), 70.0 (q, J = 32.0 Hz, CHCF3), 52.2
[C(CH3)3], 28.4 [C(CH3)3], 20.4 (OCOCH3) ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –70.6 (d, J = 7.1 Hz, CF3) ppm.
δ = 8.10 (d, J = 7.20 Hz, 2 H, ArH), 7.66 (t, J = 7.47 Hz, 1 H,
ArH), 7.51 (t, J = 7.76 Hz, 2 H, ArH), 6.0 (br. s, 1 H, NH), 5.67
(q, J = 7.08 Hz, 1 H, CHCF3); 1.37 [s, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 163.8 (OCOPh), 160.4 (CONH),
134.4, 130.1, 128.8, 127.7 (ArCH), 122.1 (q, J = 281.7 Hz, CF3),
70.4 (q, J = 31.5 Hz, CHCF3), 52.2 [C(CH3)3], 28.4 [C(CH3)3] ppm.
19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –76.8 (d, J = 6.9 Hz)
IR (nujol): ν = 3310 (CONH), 1760 (CONH), 1680 (COCH ) cm–1.
˜
3
C9H14F3NO3 (241.21): calcd. C 44.81, H 5.85; found C 44.70, H
5.88.
ppm. IR (nujol): ν = 3320 (CONH), 1740 (CONH), 1680 (COPh)
˜
cm–1. C14H16F3NO3 (303.28): calcd. C 55.44, H 5.32; found C
55.63, H 5.37.
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoro-1-methylethyl Acetate
(2b): Gaseous hexafluoroacetone (15 mmol) was bubbled[27]
through the solution of acetic acid (10 mmol) and tBuNC
(10 mmol) in CH2Cl2 (50 mL) at –40 °C. The reaction stood over-
night at room temp., after which it was concentrated, and the solid
residue was washed with hexanes; yield 87% (220 mg, 0.87 mmol).
White solid, m.p. 93–94 °C. Rf (hexanes/EtOAc, 2:1) = 0.7. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 5.60 (s, 1 H, NH), 2.15 (s, 3
H, OCOCH3), 1.78 (s, 3 H, CF3CCH3), 1.33 [s, 9 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 167.8 (OCOCH3), 162.7
(CONH), 123.1 (q, J = 283.2 Hz, CF3), 73.6 [m, C(CF3)CH3], 52.0
[C(CH3)3], 28.1 [C(CH3)3], 21.2 (OCOCH3), 15.6 (CH3CF3) ppm.
19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –82.6 (s, CF3) ppm. IR
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoroethyl Formate (2g):
Yield 82% (162 mg, 0.82 mmol). White solid, m.p. 105–107 °C. Rf
1
(hexanes/EtOAc, 2:1) = 0.8. H NMR (400 MHz, CDCl3, 25 °C):
δ = 8.17 (s, 1 H, OH), 5.9 (br. s, 1 H, NH), 5.55 (q, J = 6.8 Hz, 1
H, CHCF3), 1.37 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 159.6 (CONH), 157.4 (HCO), 121.5 (q, J =
281.8 Hz, CF3), 69.3 (q, J = 32.2 Hz, CHCF3), 52.4 [C(CH3)3], 28.3
[C(CH3)3] ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –74.7
(d, J = 6.9 Hz, 3 F, CF ) ppm. IR (Nujol): ν = 3400 (OH), 3320
˜
3
(CONH), 1750 (CONH) cm–1. C7H12F3NO3 (215.17): calcd. C
42.21, H 6.07; found C 42.33, H 6.30.
(nujol): ν = 3380 (CONH), 1690 (CONH), 1675 (COCH ) cm–1.
˜
3
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoroethyl N-Formyl-L-valin-
C10H16F3NO3 (255.23): calcd. C 47.06, H 6.32; found C 47.10, H
6.28.
ate (2h, ≈ 1:1 mixture of diastereomers): Yield 54% (176 mg,
0.54 mmol). White solid, m.p. 152–154 °C. Rf (hexanes/EtOAc, 1:1)
1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoro-1-(trifluoromethyl)ethyl = 0.45. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.32, 8.16 (s, 1
Acetate (2c): Yield 68% (210 mg, 0.68 mmol). White solid, m.p. 79–
80 °C. Rf (hexanes/EtOAc, 2:1) = 0.85. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 5.5 (br. s, 1 H, NH), 2.23 (s, 3 H, CH3), 1.35
[s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
H, NHCHO), 7.07–7.09 (m, 1 H, NHCHO), 6.71, 6.55 [s, 1 H,
NHC(CH3)3], 5.45, 5.39 (q, J = 7.1 Hz, 1 H, CHCF3), 4.45–4.53,
4.25–4.33 (m, 1 H, NHCHiPr), 2.23–2.33, 2.05–2.17 [m, 1 H,
CH(CH3)2], 1.33, 1.31 [s, 9 H, C(CH3)3], 0.90–1.05 [m, 6 H,
166.0 (OCOCH3); 155.9 (CONH); 120.5 (q, J = 288.5 Hz, CF3), CH(CH3)2] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.6,
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Multicomponent Approach to Trifluoromethyl Depsipeptides
168.4 (OCOCHiPr), 162.4, 161.9 (CONHtBu), 160.5, 160.3
134.0 (ArC), 128.4 (ArCH), 123.1 (q, J = 284.0 Hz, CF3), 120.9
(NHCHO), 121.6, 121.7 (q, J = 281.4 Hz, CF3), 70.1 (m, CHCF3), (ArCH), 81.0 (q, J = 30.0 Hz, CH3CCF3), 28.3 (PhCH2CH3), 21.1
57.4, 56.6 (CHNHCHO), 52.4 [C(CH3)3]; 29.9, 30.2 [CH(CH3)2];
28.1 [C(CH3)3]; 18.8, 18.5, 18.2, 17.3 [CH(CH3)2] ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –73.9 (d, J = 7.2 Hz, 0.74 CF3),
(OCOCH3), 15.8 (PhCH2CH3), 15.6 (CH3CCF3) ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –76.75 (d, J = 1.0 Hz, CF3) ppm.
IR (nujol): ν = 3345 (CONH), 1730 (CONH), 1695 (COOCH )
˜
3
–74.32 (d, J = 6.9 Hz, 0.37 CF3), –74.35 (d, J = 7.2 Hz, 0.52 CF3), cm–1. C14H16F3NO3 (303.28): calcd. C 55.44, H 5.32; found C
–74.43 (d, J = 6.9 Hz, 0.36 CF ) ppm. IR (nujol): ν = 3340
55.22, H 5.06.
˜
3
(CONH), 1755 (CONH), 1710 (NHCHO) cm–1. C13H21F3N2O4
2,2,2-Trifluoro-1-{[(4-methoxybenzyl)amino]carbonyl}-1-phenylethyl
Acetate (3e): Yield 61% (232 mg, 0.61 mmol). Colorless oil. Rf
(326.31): calcd. C 47.85, H 6.49; found C 47.99, H 6.73.
1
1-tert-Butyltyl 2-{1-[(tert-Butylamino)carbonyl]-2,2,2-trifluoroethyl} (hexanes/EtOAc, 2:1) = 0.6. H NMR (400 MHz, CDCl3, 25 °C):
(2S)-Pyrrolidine-1,2-dicarboxylate (2i, ca. 1:1 mixture of dia-
δ = 7.55 (d, J = 4.52 Hz, 2 H, ArH), 7.40 (s, 3 H, ArH), 7.16 (d, J
= 8.2 Hz, 2 H, ArH), 6.85 (d, J = 8.2 Hz, 2 H, ArH), 6.4 (br. s, 1
H, NH), 4.33–4.43 (m, 2 H, NHCH2Ph), 3.78 (s, 3 H, PhOCH3),
3.77 (s, 3 H, OCH3), 2.25 (s, 3 H, COCH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 167.9 (OCOCH3), 163.8 (CONH),
stereomers): Yield 84% (330 mg, 0.84 mmol). Colorless oil. Rf (hex-
1
anes/EtOAc, 1:1) = 0.75. H NMR (400 MHz, CDCl3, 25 °C): δ =
7.2, 6.8 (br. s, 1 H, NHtBu), 5.50, 5.25 (q, J = 7.3 Hz, CHCF3),
4.43–4.46, 4.27–4.31 (m, 1 H, CHCOO), 3.39–3.52 (m, 2 H,
CH2NBoc), 1.84–2.30 (m, 4 H, CH2CH2), 1.47, 1.43 (s, 9 H, 159.1 (ArC), 130.9 (ArC), 129.6 (ArCH), 129.2 (ArC), 129.1
tBuOOC), 1.36–1.39 (m, 9 H, tBuNH) ppm. 13C NMR (100 MHz,
(ArCH), 128.4 (ArCH), 127.2 (ArCH), 114.1 (ArCH), 122.6 (q, J
CDCl3, 25 °C): δ = 171.3, 169.8 (COO), 160.5, 160.4 (CONHtBu), = 285.4 Hz, CF3), 83.2 (m, CCF3), 55.2 (PhOCH3), 43.4 (CH2),
155.1, 154.3 (COOtBu), 121.8, 121.7 (q, J = 281.0 Hz, CF3), 80.4, 21.2 (OCOCH ) ppm. IR (film): ν = 3380 (CONH), 1760 (CONH),
˜
3
80.2 [COOC(CH3)2], 71.5, 69.5 (q, J = 30.7 Hz), 58.6, 58.6
(CHCOO), 52.1, 52.0 [CONHC(CH3)3], 46.6, 46.5 –76.3 (s, CF3) ppm. C19H18F3NO4 (381.35): calcd. C 59.84, H 4.76;
1730 (COCH3) cm–1. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ =
(CH2CH2CH2N), 30.1, 29.6 (CH2CH2CH2N), 28.14, 28.09 found C 59.74, H 4.74.
[NHC(CH3)3], 28.05, 28.03 [COOC(CH3)3] ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –76.5 (d, J = 7.3 Hz, 0.45 CF3),
–77.1 (d, J = 7.3 Hz, 0.55 CF3) ppm. C17H27F3N2O5 (396.40):
calcd. C 51.51, H 6.87; found C 51.80, H 6.88.
Methyl 2-(Acetyloxy)-3,3,3-trifluoro-2-{[(4-methoxybenzyl)amino]-
carbonyl}propanoate (3f): Yield 96% (350 mg, 0.96 mmol). White
solid, m.p. 82–84 °C. Rf (hexanes/EtOAc, 2:1) = 0.55. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.2 (s, 1 H, NH), 7.17 (d, J = 8.4 Hz,
2 H, ArH), 6.85 (d, J = 8.4 Hz, 2 H, ArH), 4.46 (d, J = 5.6 Hz, 2
H, NHCH2), 3.82 (s, 3 H, COOCH3), 3.76 (s, 3 H, PhOCH3), 2.26
(s, 3 H, OCOCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
169.0 (COCH3), 165.0 (COOCH3), 159.1 (ArC), 158.7 (CONH),
128.9 (ArC), 128.7 (ArCH), 121.6 (q, J = 286.1 Hz, CF3), 114.1
(ArCH), 79.2 (m, CCF3), 55.2 (ArOCH3), 54.3 (COOCH3), 43.8
2,2,2-Trifluoro-1-{[(4-methoxybenzyl)amino]carbonyl}ethyl Acetate
(3b): Yield 84% (162 mg, 0.53 mmol). White solid, m.p. 84–85 °C.
Rf (hexanes/EtOAc, 2:1) = 0.7. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.15 (d, J = 8.7 Hz, 2 H, ArH), 6.84 (d, J = 8.7 Hz, 2
H, ArH), 6.6 (br. s, 1 H, NH), 5.56 (q, J = 7.1, Hz, 1 H, CHCF3),
4.30–4.46 (m, 2 H, NHCH2Ph), 3.78 (s, 3 H, PhOCH3), 2.19 (s, 3
H, OCOCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 168.1
(OCOCH3), 161.4 (CONH), 159.2 (ArC), 137.4 (ArC), 128.9
(CH Ar), 20.1 (OCOCH ) ppm. IR (nujol): ν = 3400 (CONH),
˜
2
3
1760 (CONH), 1685 (COOCH3) cm–1. 19F NMR (376.3 MHz,
(ArCH), 121.7 (q, J = 281.0 Hz, CF3), 114.1 (ArCH), 69.9 (q, J = CDCl3, 25 °C): δ = –77.2 (s, CF3) ppm. C15H16F3NO6 (363.29):
32.2 Hz, CHCF3), 55.1 (OCH3), 43.0 (NHCH2), 20.1 (OCOCH3) calcd. C 49.59, H 4.44; found C 49.71, H 4.50.
ppm. IR (nujol): ν = 3300 (CONH), 1760 (CONH), 1680 (COCH )
˜
3
Methyl 2-(Acetyloxy)-2-{[(4-ethylphenyl)amino]carbonyl}-3,3,3-tri-
fluoropropanoate (3g): Yield 40% (140 mg, 0.4 mmol). Green oil. Rf
(hexanes/EtOAc, 2:1) = 0.6. 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 9.8 (br. s, 1 H, NH), 7.48 (d, J = 8.0 Hz, 2 H, ArH), 7.18 (d, J
cm–1. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –76.95 (d, J =
7.2 Hz, CF3) ppm. C13H14F3NO4 (305.25): calcd. C 51.15, H 4.62;
found C 51.05, H 6.66.
1-{[(4-Ethylphenyl)amino]carbonyl}-2,2,2-trifluoroethyl acetate (3c): = 8.0 Hz, 2 H, ArH), 3.9 (s, 3 H, COOCH3), 2.62 (q, J = 7.6 Hz,
Yield 83% (240 mg, 0.83 mmol). Green solid, m.p. 113–114 °C. Rf 2 H, CH2CH3), 2.29 (s, 3 H, OCOCH3), 1.21 (t, J = 7.6, Hz, 3 H,
1
(hexanes/EtOAc, 2:1) = 0.7. H NMR (400 MHz, CDCl3, 25 °C):
CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 168.8
δ = 7.9 (br. s, 1 H, NH), 7.40 (d, J = 8.3 Hz, 2 H, ArH), 7.15 (d, (COCH3), 165.6 (COOCH3), 156.2 (CONH), 141.5 (ArC), 134.2
J = 8.3 Hz, 2 H, ArH), 5.69 (q, J = 6.90 Hz, 1 H, CHCF3), 2.62
(q, J = 7.6 Hz, 2 H, PhCH2CH3), 2.28 (s, 3 H, OCOCH3), 1.21 (t,
(ArC), 128.3 (ArCH), 121.2 (q, J = 286.2 Hz, CF3), 120.4 (ArCH),
78.6 (m, CCF3), 54.5 (COOCH3), 28.2 (CH2CH3), 19.9 (OCOCH3),
J = 7.6 Hz, 3 H, PhCH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 15.5 (CH CH ) ppm. IR (film): ν = 3400 (CONH), 1780 (CONH),
˜
2
3
25 °C): δ = 168.1 (OCOCH3), 159.5 (CONH), 141.8 (ArC), 133.7
1680 (COOCH3) cm–1. C15H16F3NO5 (347.28): calcd. C 51.88, H
(ArC), 128.4 (ArCH), 121.7 (q, J = 281.8 Hz, CF3), 120.7 (ArCH), 4.64; found C 52.04, H 4.80.
70.5 (q, J = 32.9 Hz, CHCF3), 28.3 (PhCH2CH3), 20.2 (OCOCH3),
Ethyl N-[2-(Acetyloxy)-3,3,3-trifluoropropanoyl]alaninate (3h, ca.
15.5 (PhCH2CH3) ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ
1:1 mixture of diastereomers): Yield 66% (188 mg, 0.66 mmol).
White solid, m.p. 78–80 °C. Rf (hexanes/EtoAc, 1:1) = 0.8. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 6.9 (br. s, 1 H, NH), 5.58 (m,
1 H, CHCF3), 4.55 (m, 1 H, NHCHCH3), 4.21 (q, J = 7.1 Hz, 2
= –73.40 (d, J = 7.0 Hz) ppm. IR (nujol): ν = 3385 (CONH), 1770
˜
(CONH), 1680 (COCH3) cm–1. C13H14F3NO3 (289.25): calcd. C
53.98, H 4.88; found C 53.78, H 4.92.
1-{[(4-Ethylphenyl)amino]carbonyl}-2,2,2-trifluoro-1-methylethyl H, OCH2CH3), 2.24 (s, 3 H, OCOCH3), 1.39–1.46 (m, 3 H,
Acetate (3d): Yield 48% (145 mg, 0.48 mmol). Green solid, m.p.
110–112 °C. Rf (hexanes/EtOAc, 2:1) = 0.8. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.5 (br. s, 1 H, NH), 7.37 (d, J = 8.4 Hz, 2 H,
ArH), 7.15 (d, J = 8.4 Hz, 2 H, ArH), 2.61 (q, J = 7.6 Hz, 2 H,
NHCHCH3), 1.27 (s, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 172.1 (OCOCH3), 168.0 (COOEt),
160.9 (CONH), 123.1 (q, J = 281.7 Hz, CF3), 69.9 (m, CHCF3),
61.9 (OCH2CH3), 48.3 (NHCHCH3), 20.2, 20.1 (OCOCH3), 18.1,
PhCH2CH3), 2.18 (s, 3 H, OCOCH3), 1.91 (3 H, CH3CCF3), 1.20 18.0 (NHCHCH3), 14.0, 13.9 (OCH2CH3) ppm. 19F NMR
(t, J = 7.6 Hz, 3 H, PhCH2CH3) ppm. 13C NMR (100 MHz, (376.3 MHz, CDCl3, 25 °C): δ = –76.9, –77.11 (d, J = 6.9 Hz, CF3)
CDCl3, 25 °C): δ = 168.1 (OCOCH3), 162.0 (CONH), 141.5 (ArC), ppm. IR (nujol): ν = 3390 (CONH), 1750 (CONH), 1670 (CO-
˜
Eur. J. Org. Chem. 2009, 3801–3808
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3805

A. V. Gulevich, I. V. Shpilevaya, V. G. Nenajdenko
FULL PAPER
OCH3) cm–1. C10H14F3NO5 (285.22): calcd. C 42.11, H 4.95; found
C 42.34, H 5.01.
Ethyl 2,2,12-Trimethyl-4,7,10-trioxo-9-(trifluoromethyl)-3,8-dioxa-
5,11-diazatridecan-13-oate (5b, ca. 1:1 mixture of diastereomers):
Yield 55% (220 mg, 0.55 mmol). White solid, m.p. 50–51 °C. Rf
Ethyl N-[2-(Acetyloxy)-3,3,3-trifluoro-2-methylpropanoyl]alaninate
(3i, ca. 1:1 mixture of diastereomers): Yield 33% (100 mg,
0.33 mmol). White solid, m.p. 79–81 °C. Rf (hexanes/EtOAc, 1:1)
= 0.8. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.6 (br. s, 1 H,
NH), 4.48–4.56 (m, 1 H, NHCHCH3), 4.23–4.14 (m, 2 H,
OCH2CH3), 2.15, 2.13 (s, 3 H, OCOCH3), 1.80 (s, 3 H, CH3CCF3),
1.38 (m, 3 H, NHCHCH3), 1.25 (t, J = 7.13 Hz, 3 H, OCH2CH3)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 172.2 (OCOCH3),
167.9 (COOEt), 163.3 (CONH), 122.9 (q, J = 284.0 Hz, CF3), 80.5
[m, C(CF3)CH3], 61.7 (OCH2CH3), 48.6 (NHCHCH3), 21.0, 20.9
(OCOCH3), 18.1, 17.7 (NHCHCH3), 15.7, 15.5 (CH3CCF3), 13.9,
1
(hexanes/EtOAc, 1:1) = 0.7. H NMR (400 MHz, CDCl3, 25 °C):
δ = 7.61–7.68 (m, 1 H, CONH), 5.50–5.56 (m, 1 H, CHCF3), 4.44–
4.51 (m, 1 H, CHCH3), 3.90–4.20 (m, 4 H, CH2NHBoc, CO-
OCH2CH3), 1.39, 1.40 [s, 9 H, C(CH3)3], 1.20–1.29 (m, 6 H,
CHCH3 and OCOCH2CH3) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 171.9, 171.8 (COOEt), 167.8, 167.7 (OCOCH2NH),
161.3 (CF3CONH), 156.6, 156.5 (OCOtBu), 121.3 (q, J = 281 Hz,
CF3), 80.8, 80.7 [C(CH3)3], 70.5 (m, CHCF3), 61.7, 61.6
(OCH2CH3), 48.5, 48.4 (NHCHCH3), 42.4, 42.3 (CH2NHBoc),
28.1 [C(CH3)3], 17.8, 17.7 (NHCHCH3); 13.9 13.8 (OCH2CH3)
ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –76.7 (d, J =
6.9 Hz, 0.34 CF3), –76.8 (d, J = 7.2 Hz, 0.31 CF3), –79.7 (d, J =
7.2 Hz, 0.19 CF3), –79.7 (d, J = 7.2 Hz, 0.16 CF3) ppm. IR (nujol):
13.8 (OCH CH ) ppm. IR (nujol): ν = 3420 (CONH), 1770
˜
2
3
(CONH), 1690 (COCH3) cm–1. C11H16F3NO5 (299.24): calcd. C
44.15, H 5.39; found C 44.36, H 5.44.
ν = 3375 (CONH), 1720 (CONH), 1680 (COOtBu), 1680 (COOEt)
˜
cm–1. C15H23F3N2O7 (400.35): calcd. C 45.00, H 5.79; found C
45.25, H 5.55.
Ethyl N-[2-(Acetyloxy)-3,3,3-trifluoro-2-phenylpropanoyl]alaninate
(3j, ca. 1:1 mixture of diastereomers): Yield 14% (51 mg,
0.14 mmol). Yellow oil. Rf (hexanes/EtoAc, 1:1) = 0.8. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.60 m (2 H, ArH), 7.50–7.39 (m,
3 H, ArH), 6.8 (br. s, 1 H, NH), 4.54–4.70 (m, 1 H, NHCH), 4.13–
4.25 (m, 2 H, OCH2CH3), 2.31, 2.29 (s, 3 H, COCH3), 1.35–1.45
(m, 3 H, NHCHCH3), 1.19–1.30 (m, 3 H, CH2CH3) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 172.3 (COCH3), 167.7
(CONH), 163.9 (COOEt), 130.9 (ArC), 129.6 (ArCH), 128.4
(ArCH), 127.2 (ArCH), 122.4 (q, J = 285.8 Hz, CF3), 81.4 (m,
CCF3Ph), 61.8 (COOCH2CH3), 48.6 (NHCHCH3), 21.2 (OC-
Ethyl (6S)-6-Isopropyl-2,2-dimethyl-4,7,10-trioxo-9-(trifluorometh-
yl)-3,8-dioxa-5,11-diazatridecan-13-oate (5c, ca. 1:1 mixture of dia-
stereomers): Yield 58% (249 mg, 0.58 mmol). Colorless oil. Rf (hex-
1
anes/EtOAc, 1:1) = 0.7. H NMR (400 MHz, CDCl3, 25 °C): δ =
7.6, 7.5 (m, 1 H, CONHiPr), 5.62–5.72, 5.42–5.55 (m, 1 H,
CHCF3), 4.90–5.08 (m, 1 H, COCHiPr), 4.00–4.52 (m, 4 H, CH2,
CH2), 1.95–2.40 [m, 1 H, CH(CH3)2], 1.43, 1.39 [s, 9 H, C(CH3)3],
1.18–1.28 (m, 3 H, OCOCH2CH3), 0.84–1.07 [m, 6 H, CH(CH3)2]
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 174.9, 174.7
(CONH), 171.7, 171.6 (OCOCHiPr), 161.5, 161.1 (COOEt), 156.0,
155.9 (OCOtBu), 121.5 (q, J = 281 Hz CF3), 81.0, 80.8 [C(CH3)3],
69.3 (q, J = 32.0 Hz, CHCF3), 61.5, 61.4 (OCH2CH3), 60.0, 59.9
(CHiPr), 48.5, 48.4 (NHCH2CO2Et), 30.1 (CH3CHCH3), 28.2, 28.1
[C(CH3)3], 19.1, 19.0, 18.6, 18.5, 17.4, 17.3, 17.2, 17.0
(CH3CHCH3); 14.0, 13.9 (OCH2CH3) ppm. 19F NMR
(376.3 MHz, CDCl3, 25 °C): δ = –76.7 (d, J = 7.2 Hz, 0.25 CF3),
–76.1 (d, J = 7.2 Hz, 0.25 CF3), –76.7 (d, J = 7.2 Hz, 0.27 CF3),
OCH ), 17.9 (NHCHCH ), 14.0 (COOCH CH ) ppm. IR (film): ν
˜
3
3
2
3
= 3400 (CONH), 1780 (CONH), 1750 (COOEt), 1700 (COCH3)
cm–1. C16H18F3NO5 (361.31): calcd. C 53.19, H 5.02; found C
53.50, H 5.41.
Ethyl N-[2-(Acetyloxy)-3,3,3-trifluoro-2-(methoxycarbonyl)propa-
noyl]alaninate (3k, ca. 1:1 mixture of diastereomers): Yield 78%
(267 mg, 0.78 mmol). Yellow oil. Rf (hexanes/EtoAc, 1:1) = 0.8. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 8.6, 8.3 (br. s, 1 H, NH), 4.53
(sept, J = 7.1 Hz, 1 H, NHCH), 4.12–4.30 (m, 2 H, OCOCH2CH3),
3.86 (3 H, COOCH3), 2.24 (s, 3 H, OCOCH3), 1.40–1.50 (m, 3 H,
NHCHCH3), 1.23–1.31 (m, 3 H, OCOCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 171.7, 171.6 (COOEt), 168.8, 168.6
(COCH3), 164.7, 164.4 (COOCH3), 158.1, 158.0 (CONH), 122.5,
122.3 (q, J = 281.2 Hz, CF3), 78.4 (CCF3), 61.7, 61.2 (OCH2CH3),
54.4 (COOCH3), 49.3 (NHCH), 20.1, 20.0 (OCOCH3), 17.7, 17.6
(NHCHCH3), 14.0, 13.9 (OCH2CH3) ppm. 19F NMR (376.3 MHz,
–76.8 (d, J = 7.2 Hz, 0.23 CF ) ppm. IR (nujol): ν = 3340 (CONH),
˜
3
1780 (CONH), 1700 (COCH3), 1680 (COOEt) cm–1.
C17H27F3N2O7 (428.40): calcd. C 47.66, H 6.35; found C 47.80, H
5.49.
Ethyl (6S)-6-Isopropyl-12-methyl-2,2-dimethyl-4,7,10-trioxo-9-(tri-
fluoromethyl)-3,8-dioxa-5,11-diazatridecan-13-oate (5d, ca. 1:1 mix-
ture of diastereomers): The reaction was performed in THF; yield
58% (277 mg, 0.58 mmol). Colorless oil. Rf (hexanes/EtOAc, 1:1)
= 0.7. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.6, 7.4 (br. s, 1
H, CONH), 7.25–7.39 (m, 5 H, ArH), 5.5–5.75 (m, 2 H, NHCBz,
CHCF3), 5.00–5.20 (m, 2 H, CH2Ph), 4.31–4.40, 4.15–4.25 (m, 1
H, CHiPr), 4.10–4.18 (m, 2 H, OCH2CH3), 3.84–4.06 (m, CHCH3),
2.10–2.40 [m, 1 H, CH(CH3)2], 1.15–1.35 (m, 6 H, NHCHCH3,
OCH2CH3), 0.95–1.08 [m, 6 H, CH(CH3)2] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 170.3 (CONH), 169.1, 168.7 (OCO-
CHiPr), 161.6, 161.5 (COOEt), 157.2, 156.6 (OCOtBu), 135.8,
135.7, (ArC), 128.6, 128.3, 128.0, 127.9 (ArCH), 121.5 (q, J =
281 Hz, CF3), 70.1 (m, CHCF3), 67.4, (OCH2Ph), 61.5 (CO-
OCH2CH3), 60.0, 59.4 (CHiPr), 30.3, 30.1 (CH3CHCH3), 19.0,
18.6 (CHCH3), 18.1, 17.2 (CHCH3), 13.9 (OCH2CH3) ppm. 19F
NMR (376.3 MHz, CDCl3, 25 °C): δ = –76.3 (d, J = 7.2 Hz, 0.5
CDCl , 25 °C): δ = –77.2, –77.4 (s, CF ) ppm. IR (film): ν = 3380
˜
3
3
(CONH), 1750 (CONH), 1660 (COOCH3) cm–1. C12H16F3NO7
(343.25): calcd. C 41.99, H 4.70; found C 42.20, H 4.87.
Ethyl 2,2-Dimethyl-4,7,10-trioxo-9-(trifluoromethyl)-3,8-dioxa-5,11-
diazatridecan-13-oate (5a): Yield 62% (240 mg, 0.62 mmol). White
solid, m.p. 129–130. Rf (hexanes/EtOAc, 1:1) = 0.8. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.4 (m, 1 H, CONH), 5.18 (q, J =
6.8 Hz, 1 H, CHCF3), 5.2 (br. s, 1 H, NHBoc), 4.20 (q, J = 7.1 Hz,
2 H, OCOCH2CH3), 3.95–4.15 (m, 4 H, CH2, CH2); 1.44 s [9 H,
C(CH3)3], 1.27 (t, J = 7.1 Hz, 3 H, OCOCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 168.7 (COCH2NH), 167.9 (COOEt),
162.1 (CF3CONH), 156.7 (OCOtBu), 121.5 (q, J = 281.0 Hz, CF3),
80.8 [C(CH3)3], 70.2 (q, J = 32.2 Hz, CHCF3), 61.5 (OCH2CH3),
42.3 (CH2NHBoc), 41.2 (NHCHCO2Et), 28.1 [C(CH3)3], 13.8
(OCH2CH3) ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ =
CF ), –76.6 (d, J = 6.5 Hz, 0.5 CF ) ppm. IR (film): ν = 3360
˜
3
3
(CONH), 1750 (CONH), 1700 (COOCH2Ph), 1680 (COOEt) cm–1.
C21H27F3N2O7 (476.44): calcd. C 52.94, H 5.71; found C 53.20, H
5.99.
–74.3, –77.4 (s, CF ) ppm. IR (nujol): ν = 3370 (CONH), 1760
˜
3
(CONH), 1710 (COCH3), 1690 (COOEt) cm–1. C14H21F3N2O7 Ethyl 2,2,9-Trimethyl-4,7,10-trioxo-9-(trifluoromethyl)-3,8-dioxa-
(386.32): calcd. C 43.53, H 5.48; found C 43.86, H 5.82. 5,11-diazatridecan-13-oate (5e): Yield 35% (155 mg, 0.35 mmol).
3806
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3801–3808

Multicomponent Approach to Trifluoromethyl Depsipeptides
Yellow oil. Rf (hexanes/EtOAc, 1:1) = 0.75. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.4 (1 H, CONH), 5.27 (br. s, 1 H, NHBoc),
(d, J = 10.1 Hz, 1 H, NHBoc), 5.53 (q, J = 6.8 Hz, 1 H, CHCF3),
4.94 (d, J = 8.8 Hz, 1 H, NH), 4.31–4.39 (m, 1 H, CHiPr), 4.10
3.80–4.23 (m, 6 H, CO2CH2CH3, CH2NHBoc, CH2CO2Et), 1.87 (dd, J = 3.8, 6.3 Hz, 1 H, CHiPr), 3.85 [s, 6 H, C(OCH2)3], 2.55–
(s, 3 H, CH3CF3), 1.45 [s, 9 H, C(CH3)3], 1.24 (t, J = 7.3 Hz, 3 H, 2.33 [m, 1 H, CH(CH3)2], 2.11–2.21 [m, 1 H, CH(CH3)2], 1.45 [s,
OCOCH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 9 H, C(CH3)3], 1.03 (d, J = 6.8 Hz, 3 H, CH3), 0.93 (d, J = 6.8 Hz,
168.9 (OCOCH2NH), 167.4 (COOEt), 164.1 (CF3CONH), 156.7
(OCOtBu), 122.9 (q, J = 284.0 Hz, CF3), 81.0 [C(CH3)3], 71.4 (m,
3 H, CH3), 0.80–0.90 (m, 6 H, 2 CH3), 0.78 [s, 3 H, (OCH2)3CCH3]
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.7 (COO), 161.1
CHCF3), 61.4 (OCH2CH3), 43.3 (CH2NHBoc), 41.7 (NHCH2- (CONH), 155.7 (CONHBoc), 121.6 (J = 281.0 Hz, CF3), 108.1
CO2Et), 28.2 [C(CH3)3], 15.9 (CF3CH3), 14.0 (OCH2CH3) ppm.
[C(OCH2)3], 80.2 [C(CH3)3], 72.3 [C(OCH2)3], 70.8 (q, J = 32.9 Hz,
CHCF3), 58.5 (CHiPr), 57.0 (CHiPr), 30.7 [CH(CH3)2], 30.42
19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –82.5 (s, CF3) ppm. IR
(film): ν = 3380 (CONH), 1775 (CONH), 1700 (COOtBu), 1680 [(OCH2)3CCH3], 28.0 [C(CH3)3], 27.5 [CH(CH3)2], 20.7 (CH3),
˜
(COOEt) cm–1. C18H29F3N2O7 (442.43): calcd. C 48.87, H 6.61;
20.0 (CH3), 17.1 (CH3), 16.9 (CH3), 14.1 [(OCH2)3CCH3] ppm. 19
NMR (376.3 MHz, CDCl3, 25 °C): δ = –74.2 (d, J = 6.9 Hz, CF3)
F
found C 48.90, H 6.80.
ppm. IR (nujol): ν = 3340 (CONH), 1710 (CONH), 1690 (CO-
˜
Ethyl 2,2-Dimethyl-4,7,10-trioxo-9,9-bis(trifluoromethyl)-3,8-dioxa-
5,11-diazatridecan-13-oate (5f): Compound 5f was obtained ac-
cording to the procedure for 2b; yield 64% (268 mg, 0.64 mmol).
White solid, m.p. 132–134 °C. Rf (hexanes/EtOAc, 1:1) = 0.8. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 6.3 (br. s, 1 H, CONH), 5.2
OtBu) cm–1. [α]2D0 = –5.63 (c = 0.025, MeOH). ESI-MS (m/z): calcd.
for C23H37F3N2NaO8 [M+] 549.2400, found 549.2398.
Supporting Information (see also the footnote on the first page of
this article): General information, X-ray analysis of 5g, racemiza-
tion experiment details and copies of NMR spectra of all com-
pounds.
(br. s,
1 H, NHBoc), 4.16–4.34 (m, 4 H, CO2CH2CH3,
CH2NHBoc), 3.53–4.70 (m, 2 H, CH2CO2Et), 1.39 [s, 9 H, C(CH3)
3], 1.29 (t, J = 7.2 Hz, 3 H, OCOCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 176.5 (OCOCH2NH), 169.3 (CO-
OEt), 159.8 (CF3CONH), 157.0 (OCOtBu), 121.2 (q, J = 280 Hz,
CF3, CF3), 81.0 [C(CH3)3], 79.1 [m, C(CF3)2], 62.8 (OCH2CH3),
44.9 (CH2NHBoc), 42.7 (NHCH2CO2Et), 28.0 [C(CH3)3], 13.9
(OCH2CH3) ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C): δ = –74.7
(q, J = 8.9 Hz, 1.5 F, 0.5 CF3), –75.2 (q, J = 8.9 Hz, 1.5 F, 0.5
Acknowledgments
The authors thank A. G. Zhdanko for OBO-isocyanide 4c, Dr.
B. V. Lokshin for the optical rotation measurements and Dr. V. E.
Zavodnik for the X-rays analysis.
CF ) ppm. IR (nujol): ν = 3370 (CONH), 1790 (CONH), 1720
˜
3
(COOtBu), 1680 (COOEt) cm–1. C18H26F6N2O7 (496.40): calcd. C
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Synthesis of Chiral Depsipeptides 5g,h: Isocyanide (992 mg,
4.7 mmol) was added to a mixture of 1a (611 mg, 4.7 mmol), and
Boc--Valine (1030 mg, 4.7 mmol) in CH2Cl2 (50 mL). The mixture
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due was crystallized from petroleum ether/chloroform (10:1). After
the material was cooled to –20 °C, compound 5g precipitated. The
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(hexanes/EtOAc, 3:1) to afford 5h (790, mg, 32%). The precipitate
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5g: Yield 30% (750 mg). White solid, m.p. 105–107 °C. Rf (hexanes/
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EtOAc, 2:1) = 0.5. H NMR (400 MHz, CDCl3, 25 °C): δ = 6.41
(d, J = 9.6 Hz, 1 H, NHBoc), 5.67 (q, J = 6.8 Hz, 1 H, CHCF3),
4.99 (d, J = 8.6 Hz, 1 H, NH), 4.32–4.41 (m, 1 H, CHiPr), 4.05
(dd, J = 3.3, 6.6 Hz, 1 H, CHiPr), 3.80–3.90 [m, 6 H, C(OCH2)3],
2.13–2.30 [m, 2 H, CH(CH3)2, CH(CH3)2], 1.43 [s, 9 H, C(CH3)3],
1.03 (d, J = 6.8 Hz, 3 H, CH3), 0.84–0.96 (m, 9 H, 3 CH3), 0.76 [s,
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= 169.6 (COO), 161.3 (CONH), 154.9 (CONHBoc), 121.6 (J =
281.2 Hz, CF3), 108.1 [C(OCH2)3], 80.1 [C(CH3)3], 72.4 [C-
(OCH2)3], 70.3 (q, J = 32.2 Hz, CHCF3), 58.5 (CHiPr), 57.1
(CHiPr), 30.8 [CH(CH3)2], 30.5 [(OCH2)3CCH3], 28.2 [C(CH3)3],
27.7 [CH(CH3)2], 20.8 (CH3), 19.0 (CH3), 17.1 (CH3), 16.9 (CH3),
14.1 [(OCH2)3CCH3] ppm. 19F NMR (376.3 MHz, CDCl3, 25 °C):
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˜
3
1710 (CONH), 1690 (COOtBu) cm–1. [α]2D0 = –23.55 (c = 0.025,
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Eur. J. Org. Chem. 2009, 3801–3808
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: March 26, 2009
Published Online: June 17, 2009
3808
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3801–3808