2-Nitrophenyl isocyanide as a versatile convertible isocyanide: Rapid access to a fused γ-lactam β-lactone bicycle

Article abstract of DOI:10.1021/jo800486k

(Chemical Equation Presented) 2-Nitrophenyl isocyanide is introduced as a convertible isocyanide with demonstration of its feasibility and applicability in an efficient synthesis of the fused γ-lactam β-lactone bicycle of proteasome inhibitor omuralide. Starting from a linear keto acid precursor, the fused γ-lactam β-lactone bicycle was prepared in four steps by a sequential biscyclization strategy; a stereocontrolled Ugi reaction and the concomitant direct β-lactonization following the formation of an N-acylbenzotriazole intermediate. The N-acylbenzotriazole is amenable to intra- or intermolecular attack from a variety of nucleophiles with a catalytic amount of base to form the pyroglutamic acid derivatives.

Full text of DOI:10.1021/jo800486k

2-Nitrophenyl Isocyanide as a Versatile Convertible Isocyanide:
Rapid Access to a Fused γ-Lactam ꢀ-Lactone Bicycle
Cynthia B. Gilley and Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe Mail Code 0343, La Jolla, California 92093-0343
ykoba@chem.ucsd.edu
ReceiVed February 29, 2008
2-Nitrophenyl isocyanide is introduced as a convertible isocyanide with demonstration of its feasibility
and applicability in an efficient synthesis of the fused γ-lactam ꢀ-lactone bicycle of proteasome inhibitor
omuralide. Starting from a linear keto acid precursor, the fused γ-lactam ꢀ-lactone bicycle was prepared
in four steps by a sequential biscyclization strategy; a stereocontrolled Ugi reaction and the concomitant
direct ꢀ-lactonization following the formation of an N-acylbenzotriazole intermediate. The N-acylben-
zotriazole is amenable to intra- or intermolecular attack from a variety of nucleophiles with a catalytic
amount of base to form the pyroglutamic acid derivatives.
Introduction
A fused γ-lactam ꢀ-lactone bicyclic ring system is the
common core structure found in a growing number of potent
proteasome inhibitors including omuralide (clasto-lactacystin-
ꢀ-lactone, 1),1 salinosporamides A and B (2 and 3),2 and
cinnabaramides A-C (4-6, Figure 1).3 Due to the recent
validation of proteasome inhibition as a novel therapeutic target
for cancer,4 these natural products are emerging as an important
class of drugs that offer potential new therapies. Salinosporamide
A (2), a marine natural product produced by the recently
described obligate marine bacterium Salinispora tropica, is a
FIGURE 1. Proteasome inhibitors containing fused γ-lactam ꢀ-lactone
bicyclic ring.
(1) (a) Omura, S.; Fujimoto, T.; Otoguru, K.; Matsuzaki, K.; Moriguchi, R.;
Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113–116. (b) Omura, S.; Matsuzaki,
K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A. J. Antibiot.
1991, 44, 117–118.
potent anticancer agent that recently entered phase I human
clinical trials for the treatment of multiple myeloma.5 X-ray
crystallographic studies have demonstrated that the ꢀ-oxygen
atom of the N-terminal threonine of the 20S proteasome is
(2) Isolation of salinosporamide A: (a) Feling, R. H.; Buchanan, G. O.;
Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Angew. Chem., Int.
Ed. 2003, 42, 355–357. For congeners of salinosporamide A, see: (b) Williams,
P. G.; Buchanan, G. O.; Feling, R. H.; Kauffman, C. A.; Jensen, P. R. J. Org.
Chem. 2005, 70, 6196–6203. (c) Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.;
Mueller, H.; Benet-Buchholz, J.; Gantner, F.; Tichy, H. V.; Reinemer, P.; Bacon,
K. B. J. Nat. Prod. 2007, 70, 246–252. (d) Reed, K. A.; Manam, R. R.; Mitchell,
S. S.; Xu, J.; Teisan, S.; Chao, T. H.; Deyanat-Yazdi, G.; Neuteboom, S. T. C.;
Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2007, 70, 269–276.
(5) (a) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.; Velonkar,
M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C.;
Nicholson, B.; Chao, T. H.; Neuteboom, S. T.; Richardson, P.; Palladino, M. A.;
Anderson, K. C. Cancer Cell 2005, 8, 407–419. (b) Macherla, V. R.; Michell,
S. S.; Manam, R. R.; Reed, K. A.; Chao, T. H.; Nicholson, B.; Deyanat-Yazdi,
G.; Mai, B.; Jensen, P. R.; Fenical, W.; Neuteboom, S. T. C.; Lam, K. S.;
Palladino, M. A.; Potts, B. C. M. J. Med. Chem. 2005, 48, 3684–3687.
(3) Cinnabaramides, A.-G.; Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.;
Muller, H.; Benet-Buchholz, J.; Gantner, F.; Tichy, H. V.; Reinemer, P.; Bacon,
K. B. J. Nat. Prod. 2007, 70, 246–52.
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4198 J. Org. Chem. 2008, 73, 4198–4204
10.1021/jo800486k CCC: $40.75 2008 American Chemical Society
Published on Web 05/07/2008

2-Nitrophenyl Isocyanide as a ConVertible Isocyanide
selectively acylated by the ꢀ-lactone moieties of both omuralide6
and salinosporamide A.7
To date, a series of total syntheses of omuralide (1)8 and
salinosporamide A (2)9 have been reported, with a number of
routes showing the isopropyl or cyclohex-2-enylcarbinol side
chains of the heterobicyclic core structure introduced in the late
stage via an aldehyde intermediate. Romo recently reported a
diastereocontrolled 1,2-addition of a cyclohexenyl zinc reagent
even in the presence of the preformed ꢀ-lactone.10 With
methodology already established to introduce those side chains
in the late stage, we sought the rapid construction of the common
core fused γ-lactam ꢀ-lactone bicyclic ring system starting from
a linear precursor through two consecutive ring formation steps.
For the initial γ-lactam formation, we chose to utilize the
Ugi 4-center 3-component (4C-3C) condensation reaction
because it affords pyroglutamic acid amide derivatives from
readily accessible γ-keto acids.11 We recently described a formal
total synthesis of omuralide (1) employing a stereocontrolled
Ugi reaction as the key step.12a We reported the development
FIGURE 2. Structures of convertible isocyanides 1-isocyano-2-(2,2-
dimethoxyethyl)benzene (7) and 2-nitrophenyl isocyanide (8).
of a convertible isocyanide, 1-isocyano-2-(2,2-dimethoxyethyl)-
benzene (7) (Figure 2), for its utility in the Ugi reaction and
demonstrated the selective cleavage of the resultant C-terminal
amide bond of 7a derived from the isocyanide 7.11a,12b,c The
sterically hindered exo-anilide was successfully converted to a
methyl ester via methanolysis of an N-acylindole 7b. However,
the direct intramolecular conversion of the activated N-acylin-
dole intermediate to the ꢀ-lactone (and concurrent expulsion
of indole) was never realized. In addition, the acidic conditions
required to form the N-acylindole intermediate were not
compatible with the adjacent unprotected alcohols causing
unwanted side products.13
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Results and Discussion
Design of Convertible Isocyanide. We then sought an
alternative convertible isocyanide 8 which would allow for the
conversion of the Ugi product amide 8a to the corresponding
ꢀ-lactone via its appropriate activation (i.e., 8b, Figure 2). It
should satisfy the following requirements: (a) quick and easy
preparation from an inexpensive commercially available mate-
rial, (b) mild activation conditions that are compatible with
unprotected functional groups, (c) enhanced activation of the
carbonyl group, and (d) spontaneous formation of the ꢀ-lactone
when generated.
Our strategy was to access the fused γ-lactam ꢀ-lactone
bicyclic ring system (compound 9) of omuralide (1) via an
N-acylbenzotriazole (N-acylBt) 10, instead of N-acylindole
(Scheme 1). The presence of two additional electronegative
nitrogen atoms in benzotriazole, compared with the carbon
atoms in indole, should make it a better leaving group. Indeed,
the proton on the nitrogen atom of benzotriazole (pKa 11.9 in
DMSO) is more acidic then that of indole (pKa 20.95).14 Also,
N-acylbenzotriazoles are known as stable non-moisture-sensitive
acid chloride equivalents. They have been used as acylating
agents for the preparation of esters, amides, Weinreb amides,
C-acylated heterocycles, N-acylsulfonamides, acyl azides, ke-
tones, ꢀ-keto esters, and ꢀ-diketones, as well as acyl ketones,
cyanides, and sulfones.15 Therefore, we speculated the enhanced
activation of the carbonyl group would allow for direct ꢀ-lactone
(10) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143–2146.
(11) (a) Isaacson, J.; Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2007, 72,
3913–3916. (b) Tye, H.; Wittaker, M. Org. Biomol. Chem. 2004, 2, 813–815.
(c) Hulme, C.; Ma, L.; Cherrier, M. P.; Romano, J. J.; Morton, G.; Duquenne,
C.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1883–1887. (d)
Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725–2728. (e) Short,
K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359–362. (f) Harriman,
G. C. B. Tetrahedron Lett. 1997, 38, 5591–5594.
(13) The acidic conditions required to activate the (2,2-dimethoxyethyl)anilide
to the N-acylindole intermediate with the convertible isocyanide, 1-isocyano-
2-(2,2-dimethoxyethyl)benzene, in our previous synthesis caused unwanted N,O-
acetal formation as the major product by reaction with the unprotected alcohols
(see ref 12a).
(14) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(15) For recent reviews on the application of N-acylbenzotriazoles in organic
synthesis, see: (a) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 11, 1656–
1665. (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. ReV.
1998, 98, 409–548.
(12) (a) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631–
3634. (b) Vamos, M.; Ozboya, K.; Kobayashi, Y. Synlett 2007, 1595–1599. (c)
Kreye, O.; Westermann, B.; Wessjohann, L. A. Synlett 2007, 3188–3192.
J. Org. Chem. Vol. 73, No. 11, 2008 4199

Gilley and Kobayashi
SCHEME 2. Synthesis of N-Acylbenzotriazole 16
SCHEME 1. Retrosynthetic Analysis of Fused γ-Lactam
ꢀ-Lactone Bicyclic Ring 9
with p-methoxybenzylamine and isocyanide 8, is readily
converted to the corresponding N-acylBt 16 through hydro-
genolysis of the nitro group to the aniline 15 and subsequent
diazotization of the amino group followed by 5-endo-dig
cyclization of the anilide toward the diazonium salt. The
N-acylBt 16 is an isolable solid, which is purified by SiO2
column chromatography. Interestingly, the resulting isoamyl
alcohol did not react with the N-acylBt to afford the corre-
sponding isoamyl ester during the reaction, probably due to the
steric hindrance of 16 and also the so-called Newman’s rule of
six (regarding isoamyl alcohol).20 Methanolysis of N-acylBt 16
occurred with a catalytic amount of Et3N in DCM/MeOH (2:1)
at room temperature in 10 min. The corresponding pure methyl
ester (21a in Table 1) was obtained in 94% yield after basic
aqueous extraction (1 N NaOH) of benzotriazole without the
need for further purification.
formation, when the N-acylBt is generated in the presence of a
hydroxyl group at the ꢀ position. Synthetically, benzotriazole
is a convenient byproduct after the coupling reaction, because
the relatively low pKa allows for simple removal by extraction
with aqueous alkaline solution (1 N NaOH).
N-acylBt 10 could be generated in situ from the diazotization
of o-aminoanilide 11 by 5-endo-dig cyclization of the amide
nitrogen.16 The o-aminoanilide 11 could have derived from the
diastereoselective Ugi reaction of γ-keto acid 12 with 2-nitro-
phenyl isocyanide (8) and p-methoxybenzylamine.17 Upon
investigation, it was found that isocyanide 8 is a readily available
solid which can be prepared in two steps (87%) from 2-nitroa-
niline and has been reported as a ligand of a metal complex
previously.18
Synthesis of the Fused γ-Lactam ꢀ-Lactone Bicycle.
Having established 2-nitrophenyl isocyanide (8) as a convertible
isocyanide, we undertook our original goal of the stereocon-
trolled synthesis of the common γ-lactam ꢀ-lactone bicyclic core
among known proteasome inhibitors. The remaining challenges
were the stereoselective formation of the fully substituted carbon
(C4 of omuralide) during the Ugi reaction, the compatibility of
unprotected functional groups during the conversion of the
nitroanilide to an N-acylBt, and the intramolecular ꢀ-lactone
formation with the activated N-acylBt. We chose omuralide core
bicycle 20 as a probe to evaluate the feasibility and applicability
of isocyanide 8 in natural product synthesis (Scheme 3). The
enantioselective preparation of 12 was previously reported in
our synthesis of omuralide (1).12a
The Ugi 4C-3C reaction of functionalized chiral γ-keto acid
12 with isocyanide 8 furnished γ-lactam 17 in 67% yield as a
single diastereomer. The relative stereochemistry of the resulting
stereocenter of Ugi product 17 was unambiguously assigned
by X-ray crystallography (Figure 3).21 As expected, axial attack
of the isocyanide toward the iminium intermediate exclusively
furnished the desired isomer 17. Attempted hydrolysis of the
o-nitroanilide under basic conditions did not provide the
corresponding carboxylic acid presumably due to steric hin-
drance.19
Ugi Reaction with 2-Nitrophenyl Isocyanide. We report
here 2-nitrophenyl isocyanide (8) as a convertible isocyanide.
The rapid construction of the fused γ-lactam ꢀ-lactone bicyclic
ring system of omuralide (1) is introduced via a diastereo-
selective Ugi reaction of cyclic ꢀ,δ-dihydroxy-γ-keto acids
with isocyanide 8. In addition, it readily affords ester,
thioester, primary amide, and ketone derivatives of pyro-
glutamic acid via the Ugi reaction of levulinic acid. A similar
isocyanide, 4-methoxy-2-nitrophenyl isocyanide,19 was intro-
duced previously as a hydrolyzable isocyanide in the Ugi
4-component condensation reaction. Due to the activation of
the amide bond of the resulting Ugi product anilide, via the
electron-withdrawing o-nitro group, direct hydrolysis was
achieved without additional activation. However, rather harsh
basic conditions (6 equiv of LiOH in refluxing MeOH, 3 h) are
required for the hydrolysis of the anilide.
In order to quickly ascertain whether 2-nitrophenyl isocyanide
(8) would be an effective convertible isocyanide, allowing for
the synthesis of a series of pyroglutamic acid derivatives, we
sought to prepare N-acylBt 16 starting from commercially
available levulinic acid (13) (Scheme 2). The initial o-nitroa-
nilide 14, derived from the Ugi reaction of levulinic acid (13)
(16) (a) Katritzky, A. R.; Ji, F. B.; Fan, W. Q.; Beretta, P.; Bertoldi, M.
J. Heterocycl. Chem. 1992, 29, 1519–1523. (b) Plummer, B. F.; Russell, S. R.;
Reese, W. G.; Watson, W. H.; Krawiec, M. J. Org. Chem. 1991, 56, 3219–23.
(c) Hart, H.; Ok, D. J. Org. Chem. 1986, 51, 979–986.
Methanolysis of 17 with a catalytic amount of CSA smoothly
deprotected the acetonide moiety to give the free 1,3-diol 18 in
90% yield. Fortunately, the transfer of the nitrobenzene func-
tionality onto the resulting alcohols via a Meisenheimer
(17) We expected a single diastereomer in the Ugi reaction of ketacid 11
based on our previous studies (see ref 12a).
(18) Hahn, F. E.; Plumed, C. G.; Muender, M.; Luegger, T. Chem. Eur. J.
2004, 10, 6285–6293.
(19) (a) Maison, W.; Schlemminger, I.; Westerhoff, O.; Martens, J. Bioorg.
Med. Chem. Lett. 2000, 8, 1343–1360. (b) Maison, W.; Schlemminger, I.;
Westerhoff, O.; Martens, J. Bioorg. Med. Chem. Lett. 1999, 9, 581–584.
(20) Newman, M. S. J. Am. Chem. Soc. 1950, 72, 4783–4786.
(21) The CIF file of the X-ray analysis of compound 17 is available in the
Supporting Information.
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2-Nitrophenyl Isocyanide as a ConVertible Isocyanide
TABLE 1. Nucleophile Addition to N-Acylbenzotriazole 16
FIGURE 3. ORTEP figure of Ugi product 17.
an N-acylbenzoimidazole24 (pKa 16.4, between an indole and a
benzotriazole).
Diazotization of the aniline 19 and subsequent benzotriazole
formation 19a by 5-endo-dig cyclization of amide at the ortho
position occurred smoothly under the neutral conditions medi-
ated by isoamyl nitrite in chloroform at room temperature. The
mild nature of the reaction allowed efficient conversion even
in the presence of the unprotected diols without any side
reactions.13 The formation of the N-acylBt 19a was indicated
by TLC without ꢀ-lactone formation at that moment. Again,
the isoamyl alcohol formed during nitrosonation of the aniline
19 did not react with the resulting N-acylBt 19a in situ to afford
the corresponding isoamyl ester.
As designed, fused γ-lactam ꢀ-lactone formation occurred
in situ with the addition of a catalytic amount of triethylamine
(0.1 equiv). Spiro-γ-lactam ꢀ-lactone formation was not de-
tected. The remaining primary alcohol of the γ-lactam ꢀ-lactone
bicycle 19b8j and the resulting isoamyl alcohol were protected
as a TBS ether, and then the core fused γ-lactam ꢀ-lactone
bicycle 20 was isolated in 71% yield in one pot (three steps
from 19). In summary, the synthesis of the fused γ-lactam
ꢀ-lactone bicycle of omuralide (1) was achieved via a stereo-
controlled Ugi 4C-3C condensation reaction with isocyanide
8. The subsequent N-acylBt formation was compatible with the
unprotected alcohols, and direct ꢀ-lactonization occurred. These
results show the superior activation of the carbonyl group
provided by the N-acylBt, compared to the N-acylindole.
Utility of N-Acylbenzotriazole. Table 1 shows the synthetic
utility of the N-acylbenzotriazole 16. Conversion of 16 into
2-methylpyroglutamic acid esters 21a-c (entry 1-3), thioester
21d (entry 4), amide 21e (entry 5), and ketone 21f (entry 6)
a 0.1 equiv Et3N; rt. b 1.1 equiv nucleophile; 0.1 equiv Et3N; DCM, rt.
c 1.1 equiv EtNH2; DCM, rt. d 3.0 equiv nucleophile; THF. e 0 °C to rt.
f DCM/MeOH (2:1).
SCHEME 3. Stereocontrolled Ugi Reaction with Keto Acid
12 and Convertible Isocyanide 8
(22) For use of the smiles rearrangement in Ugi reactions, see: (a) El Ka¨ım,
L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7691. (b) El Ka¨ım,
L.; Gizolme, M.; Grimaud, L. Org. Lett. 2006, 8, 2051–2053. (c) El Ka¨ım, L.;
Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169–4180.
(23) Alternative conditions for the reduction of the nitro group are as follows:
SnCl2 HCl, EtOH, heat. These conditions are compatible with the presence of
unsaturated bonds as well as other functionality not compatible with hydrogenolysis.
(24) Tanaka, K.; Shimazak, M.; Murakami, Y. Chem. Pharm. Bull. 1982,
30, 2714–2722.
complex, known as the Smiles rearrangement,22 did not occur
(although it could readily happen under basic conditions).
Hydrogenolysis of the nitro group provided o-aminoanilide 19
as a precursor of the N-acylBt in quantitative yield.23 In addition,
we are aware that aminoanilide 19 could be a precursor to form
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Gilley and Kobayashi
SCHEME 4. Synthesis of Fused γ-Lactam ꢀ-Lactone
Bicycle 20
derivatives as well as the reduction to its hydroxymethyl
derivative 21g (entry 7) are described. In general, primary oxo-,
thio-, and amine-containing nucleophiles (1.1 equiv) displace
benzotriazole with a catalytic amount of triethylamine (0.1
equiv) in dichloromethane at room temperature. The reactions
were complete within 10 min, and excellent yields of the
corresponding adducts were obtained (84-99%). In addition,
when employing volatile nucleophiles (entries 1, 4-6) the
products were obtained in pure form without SiO2 column
chromatography because the resulting benzotriazole could be
extracted by washing with aqueous alkaline solution.
The nucleophilic addition of secondary and tertiary alcohols
and amines failed presumably due to the steric hindrance of
the substrate. On the other hand, trimethylsilylmethylmagnesium
chloride was efficiently added to N-acylBt 16 yielding the
corresponding R-silyloxy ketone in 97% yield. However, the
addition of other Grignard and alkyllithium species to 16 resulted
predominantly in formation of the corresponding tertiary alcohol
by addition of 2 equiv of the reagent, which is in contrast to
previously reported results using similar, but less hindered,
substrates.25 Allylmagnesium bromide, lithium phenylacetylide,
and 2-lithiothiophene gave the corresponding tertiary alcohol
in 78%, 65%, and 78% yield, respectively. It may be that the
steric congestion at the neighboring fully substituted carbon
causes the collapse of the proposed tetrahedral intermediate
(similar to the case with Weinreb amides), which normally
allows for preferential formation of ketones over tertiary
alcohols. This table indicates the reactivity and versatility of
N-acylbenzotriazoles, which are effective even with the hindered
pyroglutamic amides.
SCHEME 5. Synthesis of N-Acylbenzotriazole 23 Derived
from Linear Ugi Product 22
Conclusions
Synthesis of Amino Acid. We further explored the utility
of this methodology to extend to linear Ugi products. The
conformational flexibility of the linear system provided the
possibility of azlactone/ mu¨chnone formation, similar to that
reported by Armstrong with the “universal isocyanide”.26
Anilide 22, derived from the Ugi reaction of hydrocinnamal-
dehyde with 2-nitrophenyl isocyanide 8, p-methoxybenzylamine,
and trifluoroacetic acid (65% yield), was converted to N-acylBt
23 by hydrogenolysis and subsequent benzotriazole formation
(Scheme 5). Interestingly, the formation of an azalactone
intermediate and subsequent hydrolysis was not observed.
Instead, the N-acylBt 23 was isolable and stable to flash column
chromatography. Most likely, the suppression of the azalactone
formation was possible due to the neutral conditions employed
to generate the N-acylbenzotriazole and the poor nucleophilicity
of the carbonyl group of the trifluoroacetamide. The synthetic
utility of N-acylbenzotriazole species of this type, including
direct peptide coupling, has been shown previously.25,27 Typi-
cally, N-acylbenzotriazoles are prepared via the direct acylation
of benzotriazole itself, instead of derivatization from o-amino
anilides.16
In this paper, we introduced 2-nitrophenyl isocyanide (8) as
a convertible isocyanide and demonstrated its feasibility and
applicability in efficient synthesis of the fused γ-lactam ꢀ-lac-
tone bicycle of omuralide (1). To our knowledge, this is the
first demonstration of the isocyanide as a convertible isocyanide
in the Ugi reaction. The resulting sterically hindered anilide can
be converted under mild neutral conditions to an N-acylbenzo-
triazole, which is known as a stable acid chloride equivalent.
Staring from the linear γ-keto acid precursor, the fused γ-lactam
ꢀ-lactone bicycle was prepared only in four steps by a sequential
biscyclization strategy: a stereocontrolled Ugi reaction and the
concomitant direct ꢀ-lactonization following the formation of
N-acylbenzotriazole intermediate. The N-acylbenzotriazole is
amenable to intra- or intermolecular attack from a variety of
nucleophiles with a catalytic amount of base to form the
coupling products of the pyroglutamic acid derivatives. Con-
veniently, after the coupling reaction, the resulting benzotriazole
can be readily removed from the reaction mixture by extraction
with 1 N NaOH. Owing to the mild nature of the reaction
conditions, as well as the high compatibility with other
functional groups, the applicability of this methodology will
be extended to the synthesis of other natural products, which
contain a fused γ-lactam ꢀ-lactone bicycle as the core structure.
Application to total synthesis of salinosporamide A (2) will be
reported in due course.
(25) Katritzky, A. R.; Le, K. N. B.; Khelashvili, L.; Mohapatra, P. P. J. Org.
Chem. 2006, 71, 9861–9864.
(26) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574–
2583.
(27) (a) Katritzky, A. R.; Angrish, P. Synthesis 2006, 24, 4135–4142. (b)
Katritzky, A. R.; Meher, G.; Angrish, P. Chem. Biol. Drug Des. 2006, 68, 326–
333. (c) Katritzky, A. R.; Todadze, E.; Shestopalov, A. A.; Cusido, J.; Angrish,
P. Chem. Biol. Drug Des. 2006, 68, 42–47. (d) atritzky, A. R.; Todadze, E.;
Cusido, J.; Angrish, P.; Shestopalov, A. A. Chem. Biol. Drug Des. 2006, 68,
37–41. (e) Katritzky, A. R.; Angrish, P.; Suzuki, K. Synthesis 2006, 3, 411–
424. (f) Katritzky, A. R.; Jiang, R.; Suzuki, K. J. Org. Chem. 2005, 70, 4993–
5000. (g) Katritzky, A. R.; Angrish, P.; Huer, D.; Suzuki, K. Synthesis 2005, 3,
397–402. (h) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 16, 2645–
2652. (i) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004, 11,
1806–1813.
Experimental Section
1-(4-Methoxybenzyl)-2-methyl-N-(2-nitrophenyl)-5-oxopyrroli-
dine-2-carboxamide (14). To a solution of levulinic acid (13) (152
mg, 1.31 mmol, 1.0 equiv) in TFE (5 mL) were added p-
methoxybenzylamine (216 mg, 1.58 mmol, 1.2 equiv) and isocya-
nide 8 (243 mg, 1.64 mmol, 1.2 equiv) at room temperature. The
4202 J. Org. Chem. Vol. 73, No. 11, 2008

2-Nitrophenyl Isocyanide as a ConVertible Isocyanide
reaction mixture was stirred overnight and then concentrated in
vacuo. The crude mixture was applied directly to flash chroma-
tography (30-75% EtOAc/hexanes) to yield 445 mg (89%) of 14
as a viscous orange oil: Rf (75% EtOAc/hexanes) ) 0.53; HRMS
(EI) m/z calcd for C20H21N4O5 (M+) 383.1476, found 383.1474;
1H NMR (400 MHz, CDCl3, ppm) δ 10.47 (s, 1H), 8.50 (d, J )
8.4 Hz, 1H), 8.10 (d, J ) 8.4 Hz, 1H), 7.55 (t, J ) 8.8 Hz, 1H),
7.11-7.15 (m, 3H), 6.56 (d, J ) 8.4 Hz, 2H), 4.53 (d, J ) 14.8
Hz, 1H), 4.37 (d, J ) 15.2, Hz 1H), 3.55 (s, 3H), 2.64-2.73 (m,
1H), 2.48-2.56 (m, 1H), 2.32-2.39 (m, 1H), 1.96-2.07 (m, 1H),
1.56 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 175.6, 172.9,
159.0, 136.5, 136.0, 134.3, 130.1, 129.1, 125.9, 123.8, 121.8, 113.9,
67.8, 55.2, 44.1, 33.0, 29.5, 22.8; IR (film, cm-1) 2937, 1693, 1608,
1581, 1499, 1398, 1250, 1173, 1037, 742.
129.4, 125.9, 124.5, 124.3, 114.3, 103.7, 76.1, 69.3, 65.3, 55.5,
45.3, 38.8, 29.3, 19.5, 9.8; IR (film, cm-1) 2998, 2942, 2917, 2886,
1711, 1608, 1583, 1513, 1434, 1345, 1274, 1250, 1180, 738.
(2R,3S,4R)-1-(4-Methoxybenzyl)-3-hydroxy-2-(hydroxymethyl)-
4-methyl-N-(2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide (18).
To a solution of 17 (130.5 mg, 0.278 mmol, 1.0 equiv) in MeOH
(3 mL) was added camphorsulfonic acid (7 mg, 0.03 mmol, 0.1
equiv). The reaction mixture was heated to 70 °C with stirring for
1 h. After being cooled to room temperature, the mixture concen-
trated and purified directly by flash chromatography (50-75%
EtOAc/hexanes) to yield 107 mg (90%) of diol 18 as a yellow solid:
Rf (75% EtOAc/hexanes) ) 0.15; mp ) 72-75 °C; [R]25D ) +28
(c ) 0.014, CHCl3); HRMS (EI) m/z calcd for C21H23N3O7 (M+)
1
429.1531, found 429.1526; H NMR (400 MHz, CDCl3) δ 10.88
1-(4-Methoxybenzyl)-N-(2-aminophenyl)-2-methyl-5-oxopyrro-
lidine-2-carboxamide (15). To a solution of 14 (445 mg, 1.16 mmol,
1.0 equiv) in MeOH (30 mL) was added ∼10% by weight Pd/C at
room temperature. A balloon of H2 was applied, and the reaction
mixture was stirred for 2 h. The mixture was then filtered through
Celite and washed with methanol. Concentration in vacuo yielded
394 mg (96%) of 15 as a white solid which was used without further
purification: Rf (75% EtOAc/hexanes) ) 0.18; mp ) 47-52 °C;
HRMS (EI) m/z calcd for C20H23N3O3 (M+) 353.1734, found
(s, 1H), 8.63 (d, J ) 8.8 Hz, 1H), 8.17 (d, J ) 8.4 Hz, 1H), 7.65
(t, J ) 7.2 Hz, 1H), 7.24 (m, 2H), 6.72 (d, J ) 8.4 Hz, 2H), 5.01
(d, J ) 15.2 Hz, 1H), 4.71 (dd, J ) 5.6, 8.0 Hz, 1H), 4.18 (d, J )
15.2 Hz, 1H), 3.71 (s, 3H), 3.58 (dd, J ) 6.8, 12.0 Hz, 1H), 2.86
(quint, J ) 7.6 Hz, 1H), 2.50 (d, J ) 5.2 Hz, 1H), 2.25 (t, J ) 6.0
Hz, 1H), 1.29 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 178.3, 170.1, 159.3, 137.5, 135.8, 133.6, 130.0, 129.7,
125.9, 129.7, 125.9, 124.2, 122.8, 114.3, 75.3, 71.4, 64.0, 55.4,
45.2, 40.6, 9.6; IR (film, cm-1) 3340, 2942, 1670, 1607, 1583, 1505,
1437, 1340, 1272, 1233, 1175, 1029, 738.
1
353.1730; H NMR (400 MHz, CDCl3, ppm) δ 7.97 (s, 1H), 7.24
(d, J ) 9.4 Hz, 2H), 7.00 (t, J ) 7.6 Hz, 1H), 6.78-6.81 (m, 3H),
6.67-6.72 (m, 2H), 4.62 (d, J ) 15.2, 1H), 4.36 (d, J ) 15.2, 1H),
3.74 (s, 3H), 3.64 (s, 2H), 2.54-2.63 (m, 1H), 2.41-2.50 (m, 2H),
1.96-2.03 (m, 1H), 1.50 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 176.5, 172.3, 159.4, 140.9, 129.9, 129.9, 127.4, 125.3,
124.1, 119.6, 118.7, 114.5, 68.3, 55.5, 44.5, 34.1, 29.8, 23.4; IR
(film, cm-1) 2969, 2060, 1667, 1501, 1449, 1404, 1248, 1186, 1029,
750.
(2R,3S,4R)-1-(4-Methoxybenzyl)-N-(2-aminophenyl)-3-hydroxy-
2-(hydroxymethyl)-4-methyl-5-oxopyrrolidine-2-carboxamide (19).
To a solution of diol 18 (95.1 mg, 0.221 mmol, 1.0 equiv) in MeOH
(6 mL) was added ∼10% by weight activated palladium on carbon.
The flask was fitted with a rubber septum, and a balloon of H2 gas
was introduced at room temperature with stirring. After 30 min,
N2 gas was flushed through the reaction mixture, and the palladium
was removed by filtration through Celite. The clear solution was
concentrated to yield 88.4 mg of o-aminoanilide 19 (100%) as a
clear oil which was used without further purification: Rf (100%
1-(4-Methoxybenzyl)-2-methyl-2-(N-acylbenzotriazol)-5-oxopyr-
rolidine (16). To a solution of anilide 15 (363 mg, 1.03 mmol, 1.0
equiv) in CHCl3 (10 mL) was added isoamyl nitrite (0.4 mL, 2.99
mmol, 3.0 equiv) at room temperature. The reaction mixture was
stirred overnight and then concentrated in vacuo. The crude mixture
was applied directly to flash chromatography (50-75% EtOAc/
hexanes) to yield 365 mg (98%) of N-acylbenzotriazole 16 as a
yellow solid: Rf (75% EtOAc/hexanes) ) 0.50; mp ) 136-139
°C; HRMS (EI) m/z calcd for C20H20N4O3 (M+) 364.1530, found
EtOAc) ) 0.18; [R]25 ) +8.3 (c ) 0.021, CHCl3); HRMS (EI)
D
m/z calcd for C21H25N3O5 (M+) 399.1789, found 399.1792; 1H NMR
(400 MHz, CDCl3, ppm) δ 8.15 (s, 1H), 7.22 (d, J ) 6.8 Hz, 2H),
7.03 (t, J ) 5.6 Hz, 1H), 6.79 (d, J ) 7.4 Hz, 2H), 6.72 (t, J ) 6.0
Hz, 1H), 6.66 (d, J ) 6.0 Hz, 1H), 4.83 (d, J ) 15.2 Hz, 1H), 4.49
(d, J ) 7.2 Hz, 1H), 4.17 (d, J ) 14.8 Hz, 1H), 3.80-3.67 (m,
6H), 3.44 (d, J ) 12.0 Hz, 1H), 2.72 (quint., J ) 8.0 Hz, 1H), 1.17
(d, J ) 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 178.7,
170.2, 159.3, 140.8, 129.9, 129.7, 128.4, 127.3, 122.9, 119.8, 117.9,
114.4, 74.9, 71.1, 64.0, 55.5, 45.4, 40.5, 9.6; IR (film, cm-1) 3369,
3010, 2932, 2825, 1670, 1612, 1510, 1456, 1408, 1296, 1238, 1175,
1029, 748.
1
364.1535; H NMR (400 MHz, CDCl3, ppm) δ 8.02 (d, J ) 8.4
Hz, 1H), 7.90 (d, J ) 8.4 Hz, 1H), 7.53 (t, J ) 8.0 Hz, 1H), 7.44
(t, J ) 8.4 Hz, 1H), 6.90 (d, J ) 8.4 Hz, 2H), 6.27 (d, J ) 8.8 Hz,
2H), 4.80 (d, J ) 14.8 Hz, 1H), 4.15 (d, J ) 14.8 Hz, 1H), 3.41 (s,
3H), 2.85-2.98 (m, 2H), 2.59-2.68 (m, 1H), 2.17-2.26 (m, 1H),
1.83 (s, 3H)); 13C NMR (100 MHz, CDCl3, ppm) δ 175.9, 172.5,
158.6, 130.4, 129.9, 127.8, 126.3, 120.0, 114.8, 113.4, 68.1, 55.0,
43.7, 31.3, 29.7, 25.0; IR (film, cm-1) 2995, 2943, 1724, 1689,
1522, 1398, 1363, 1239, 1033, 959, 757.
(1S,2R,5R)-4-(4-Methoxybenzyl)-5-(tert-butylsilyloxymethyl)-2-
methyl-7-oxa-4-azabicyclo[3.2.0]heptane-3,6-dione (20). To a solu-
tion of o-aminoanilide 19 (9.1 mg, 0.023 mmol, 1.0 equiv) in CHCl3
(1 mL) was added isoamyl nitrite (0.03 mL, 0.22 mmol, 10 equiv)
at room temperature. The reaction mixture was stirred for 5 min,
and after detection of N-acylbenzotriazole 19a by TLC analysis,
triethylamine (0.01 mL) was added to form ꢀ-lactone 19b. The
reaction mixture was stirred an additional 5 min, and tert-
butyldimethylsilyl trifluoromethanesulfonate (0.02 mL, 0.087 mmol,
3.8 equiv) and additional triethylamine (0.02 mL, 0.22 mmol, 10
equiv total) were added. The reaction mixture was stirred for 1 h
and then diluted with ethyl acetate (5 mL) and washed with brine
(2 × 5 mL). After drying with sodium sulfate, the solution was
concentrated and purified by preparative thin-layer chromatography
(30% EtOAc/hexanes) to yield 6.5 mg (71%) of ꢀ-lactone 20 as a
(4aR,7R,7aS)-5-(4-Methoxybenzyl)hexahydro-2,2,7-trimethyl-
N-(2-nitrophenyl)-6-oxo[1,3]dioxino[5,4-b]pyrrole-4a-carboxamide
(17). To a solution of γ-keto acid 12 (98.0 mg, 0.485 mmol, 1.0
equiv) in TFE (2 mL) were added p-methoxybenzylamine (66.5
mg, 0.485 mmol, 1.0 equiv) and isocyanide 8 (86.0 mg, 0.581
mmol, 1.2 equiv) at room temperature. The reaction mixture was
stirred overnight and then concentrated to yield a red-brown oil.
The mixture was purified by flash chromatography (30-50%
EtOAc/hexanes) to yield 153 mg (67%) of anilide 17 as a yellow
solid which was a single diastereomer: Rf (50% EtOAc/hexanes)
) 0.40; mp ) 68-71 °C; [R]25D ) +15 (c ) 0.020, CHCl3); HRMS
(EI) m/z calcd for C24H27N3O7 (M+) 469.1844, found 469.1836;
1H NMR (500 MHz, CDCl3, ppm) δ 11.46 (s, 1H), 8.63 (d, J )
9.0 Hz, 1H), 8.17 (d, J ) 8.0 Hz, 1H), 7.67 (t, J ) 7.5 Hz, 1H),
7.26 (m, 1H), 7.16 (d, J ) 8.0 Hz, 2H), 6.82 (d, J ) 8.0, Hz 2H),
5.11 (d, J ) 14.5 Hz, 1H), 4.45 (d, J ) 8.5 Hz, 1H), 3.84 (m, 2H),
3.80 (s, 3H), 3.64 (d, J ) 11.5 Hz, 1H), 2.86 (quint., J ) 8.5 Hz,
1H), 1.55 (s, 3H), 1.54 (s, 3H), 1.26 (d, J ) 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 177.0, 171.0, 159.6, 135.4, 133.4, 130.3,
clear oil: Rf (30% EtOAc/hexanes) ) 0.39; [R]25 ) -31 (c )
D
0.016, CHCl3); HRMS (EI) m/z calcd for C21H31N1O5Si1 (M+)
1
405.1966, found 405.1973; H NMR (400 MHz, CDCl3, ppm) δ
7.19 (d, J ) 8.4 Hz, 2H), 6.83 (d, J ) 8.4 Hz, 2H), 5.03 (d, J )
6.0 Hz, 1H), 4.85 (d, J ) 15.2 Hz, 1H), 4.22 (d, J ) 15.2 Hz, 1H),
3.90 (d, J ) 10.8 Hz, 1H), 3.79 (s. 3H), 3.43 (d, J ) 10.8 Hz, 1H),
2.77 (quint., J ) 7.2 Hz, 1H), 1.37 (d, J ) 7.6 Hz, 3H), 0.82 (s,
9H), -0.01 (s, 3H), -0.04 (s, 3H); 13C NMR (100 MHz, CDCl3,
J. Org. Chem. Vol. 73, No. 11, 2008 4203

Gilley and Kobayashi
ppm) δ 175.2, 167.8, 159.6, 129.5, 129.1, 114.3, 81.0, 74.4, 58.5,
55.5, 44.8, 38.6, 25.8, 18.3, 8.6, -5.5, -5.5; IR (film, cm-1) 2932,
2854, 1835, 1709, 1510, 1461, 1393, 1248, 1117, 835, 767.
Methyl 1-(4-Methoxybenzyl)-2-methyl-5-oxopyrrolidine-2-car-
boxylate (21a). To a solution of N-acylbenzotriazole 16 (182 mg,
0.499 mmol, 1.0 equiv) in DCM/MeOH (2/1, 3 mL) was added
triethylamine (0.01 mL, 0.07 mmol, 0.1 equiv) at room temperature.
The reaction mixture was stirred for 10 min and then concentrated
in vacuo. The crude oil was diluted with EtOAc and washed with
1 N NaOH and brine. The solution was dried over Na2SO4 and
concentrated in vacuo to yield 130 mg (94%) of methyl ester 21a
as a clear oil. No further purification was necessary: Rf (50% EtOAc/
hexanes) ) 0.29; HRMS (EI) m/z calcd for C15H19N1O4 (M+)
the reaction mixture, and the palladium was removed by filtration
through Celite. The light yellow solution was concentrated to yield
509 mg of 22a (90%) as a light yellow foamy solid which was
used without further purification: Rf (20% EtOAc/hexanes) ) 0.24;
mp ) 45-49 °C; HRMS (EI) m/z calcd for C26H26N3O3F3 (M+)
1
485.1921, found 485.1925; H NMR (500 MHz, CDCl3, ppm) δ
7.40 (br s, 1H), 7.23-7.33 (m, 3H), 7.14 (d, J ) 7.5 Hz, 2H),
7.00-7.05 (m, 3H), 6.84-6.89 (m, 3H), 6.68-6.78 (m, 2H), 4.76
(d, J ) 15.5 Hz, 1H), 4.36 (d, J ) 15.5 Hz, 1H), 4.14 (d, J ) 7.5
Hz, 1H), 3.80 (s, 3H), 3.73 (br s, 2H), 2.62-2.68 (m, 3H),
2.13-2.15 (m, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.2,
160.2, 141.1, 140.4, 130.3, 129.9, 129.0, 128.7, 128.6, 127.6, 126.7,
126.1, 125.5, 123.1, 119.0, 117.5, 114.9, 61.1, 55.6, 51.9, 32.6,
29.7; IR (film, cm-1) 3369, 3039, 2981, 1684, 1617, 1515, 1447,
1248, 1199, 1146, 1034, 820, 743.
1
277.1309, found 277.1312; H NMR (400 MHz, CDCl3, ppm) δ
7.18 (d, J ) 8.4 Hz, 2H), 6.79 (d, J ) 8.8 Hz, 2H), 4.42 (d, J )
15.6 Hz, 1H), 4.35 (d, J ) 14.8 Hz, 1H), 3.76 (s, 3H), 3.44 (s,
3H), 2.52-2.60 (m, 1H), 2.40-2.47 (m, 1H), 2.25-2.31(m, 1H),
1.82-1.90 (m, 1H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 175.9, 174.2, 159.1, 129.9, 129.6, 113.9, 66.0, 55.5, 52.6,
43.9, 32.4, 29.9, 23.4; IR (film, cm-1) 2995, 2943, 1740, 1693,
1608, 1503, 1398, 1247, 1169, 1115, 1021, 812.
N-(1-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-oxo-4-phenylbutan-2-yl)-
N-(4-methoxybenzyl)-2,2,2-trifluoroacetamide (23). To a solution
of 22a (21.0 mg, 0.0443 mmol, 1.0 equiv) in CHCl3 (1 mL) was
added isoamyl nitrite (0.02 mL, 0.150 mmol, 3.5 equiv). The
reaction mixture was stirred for 10 min at room temperature and
then concentrated to yield a yellow oil. The mixture was purified
by preparative thin-layer chromatography (20% EtOAc/hexanes)
to yield 19.0 mg (88%) of 23 as a clear oil: Rf (20% EtOAc/hexanes)
) 0.53; HRMS (EI) m/z calcd for ] C26H23N4O3F3 (M+) 496.1717,
found 496.1714. The title compound exists at room temperature as
a 3.7/1 mixture of rotamers. When peaks corresponding to the same
proton(s) from each rotamer can be identified, they are listed
separately as major and minor: 1H NMR (400 MHz, CDCl3, ppm)
major δ 8.13 (d, J ) 8.0 Hz, 1H), 8.10 (d, J ) 8.0 Hz, 1H), 7.63
(t, J ) 7.0 Hz, 1H), 7.51 (t, J ) 7.5 Hz, 1H), 7.08-7.25 (m, 5H),
7.00 (d, J ) 7.0 Hz, 2H), 6.72 (d, J ) 9.0 Hz, 2H), 5.24 (dd, J )
5.0,8.0 Hz, 1H), 3.70 (s, 3H), 2.66-2.75 (m, 2H), 2.47-2.55 (m,
1H), 1.87-1.94 (m, 1H); minor δ 8.04 (d, J ) 8.0 Hz, 1H), 8.03
(d, J ) 8.0 Hz, 1H), 6.92 (d, J ) 7.0 Hz, 2H), 6.57 (d, J ) 9.0 Hz,
2H), 6.10 (t, J ) 6.5 Hz, 1H), 4.89 (d, J ) 4.5 Hz, 1H), 3.60 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.8, 160.0, 146.1,
140.5, 131.3, 130.9, 130.8, 130.5, 129.3, 128.8, 128.6, 128.5, 126.9,
126.7, 126.5, 125.5, 120.5, 120.3, 114.6, 114.4, 114.0, 60.6, 55.4,
55.3, 52.0, 48.8, 33.0, 32.8, 32.7, 31.0; IR (film, cm-1) 2942, 1738,
1684, 1612, 1505, 1447, 1379, 1257, 1209, 1180, 1150, 1029, 961,
835, 743.
2-(N-(4-Methoxybenzyl)-2,2,2-trifluoroacetamido)-N-(2-nitro-
phenyl)-4-phenylbutanamide (22). To a solution of hydrocinna-
maldehyde, 90% (300 mg, 2.01 mmol, 1.0 equiv) in TFE (10 mL)
were added p-methoxybenzylamine (338 mg, 2.46 mmol, 1.2 equiv)
and trifluoroacetic acid (0.19 mL, 2.47 mmol, 1.2 equiv). The
mixture was stirred with 4 Å molecular sieves at room temperature
for 20 min, and then isocyanide 10 (365 mg, 2.46 mmol, 1.2 equiv)
was added. The reaction mixture was stirred overnight and then
concentrated to yield a brown oil. The mixture was purified by
flash chromatography (10-30% EtOAc/hexanes) to yield 750 mg
(65%) of 22 as a yellow solid: Rf (20% EtOAc/hexanes) ) 0.50;
mp ) 95-97 °C; HRMS (EI) m/z calcd for C26H24N3O5F3 (M+)
515.1663, found 515.1672. The title compound exists at room
temperature as a 2.2/1 mixture of rotamers. When peaks corre-
sponding to the same proton(s) from each rotamer can be identified,
they are listed separately as major and minor: 1H NMR (400 MHz,
CDCl3, ppm) major δ 10.4 (br s, 1H), 8.45 (d, J ) 8.4 Hz, 1H),
8.16 (d, J ) 8.4 Hz, 1H), 7.56 (t, J ) 8.8 Hz, 1H), 7.14-7.31 (m,
7H), 7.04 (d, J ) 8.4 Hz, 2H), 6.73 (d, J ) 8.4 Hz, 2H), 4.65 (d,
J ) 16.0 Hz, 1H), 4.50 (d, J ) 15.6 Hz, 1H), 4.34 (d, J ) 6.8 Hz,
1H), 3.71 (s, 3H), 2.64-2.74 (m, 3H), 2.10-2.15 (m, 1H); minor
δ 10.6 (br s, 1H), 8.51 (d, J ) 8.4 Hz, 1H), 8.13 (d, J ) 8.4 Hz,
1H), 7.58 (t, J ) 8.8 Hz, 1H), 7.09 (d, J ) 8.4 Hz, 2H), 6.54 (d,
J ) 8.4 Hz, 2H), 4.90 (d, J ) 16.0 Hz, 1H), 4.64 (d, J ) 15.6 Hz,
1H), 4.37 (d, J ) 8.0 Hz, 1H), 3.60 (s, 3H), 2.48-2.59 (m, 3H),
1.94-2.05 (m, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 168.0,
167.0, 160.1, 157.9, 140.4, 140.1, 136.9, 135.8, 134.3, 130.5, 130.3,
129.0, 128.9, 128.8, 128.6, 126.7, 125.8, 125.4, 124.0, 123.8, 122.8,
122.1, 118.1, 115.2, 114.5, 113.8, 61.4, 60.4, 55.4, 55.2, 50.8, 47.4,
32.9, 32.5, 31.5, 29.9; IR (film, cm-1) 3350, 2942, 1694, 1607,
1587, 1500, 1456, 1432, 1335, 1272, 1199, 1150, 1029, 748.
2-(N-(4-Methoxybenzyl)-2,2,2-trifluoroacetamido)-N-(2-ami-
nophenyl)-4-phenylbutanamide (22a). To a solution of 22 (600 mg,
1.16 mmol, 1.0 equiv) in MeOH (20 mL) was added ∼10% by
weight activated palladium on carbon. The flask was fitted with a
rubber septum, and a balloon of H2 gas was introduced at room
temperature with stirring. After 30 min, N2 gas was flushed through
Acknowledgment. We thank the University of California and
a GAANN fellowship (CBG) for financial support of this
research. We also thank Professor Leo A. Paquette at The Ohio
State University for a valuable suggestion. We acknowledge
Dr. Yongxuan Su of the UCSD Mass Spectrometry Facility as
well as Dr. Antonio DiPasquale and Professor Arnold Rheingold
of the UCSD Small Molecule X-Ray Facility.
Supporting Information Available: Experimental procedure
1
for compounds 21b-g, copies of H and 13C NMR spectra of
14-20, 21a-g, 22, 22a, and 23, and a CIF file for compound
17. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800486K
4204 J. Org. Chem. Vol. 73, No. 11, 2008