Expeditious access to unprotected racemic pyroglutamic acids

Article abstract of DOI:10.1021/jo0700225

(Chemical Equation Presented) A series of biologically intriguing pyroglutamic acids were synthesized in racemic form by employing indole-isonitrile and ammonium acetate in the Ugi 4-center-3-component reaction of γ-ketoacids.

Full text of DOI:10.1021/jo0700225

the amine component in the Ugi 4C-3CR. We now report an
expansion of the scope of this discovery by demonstrating the
expeditious synthesis of a series of unprotected pyroglutamic
acids.
Expeditious Access to Unprotected Racemic
Pyroglutamic Acids
Jerry Isaacson, Cynthia B. Gilley, and Yoshihisa Kobayashi*
Levulinic acid (2) is known to participate in the U4C-3CR
to give an anilide of type 3, so this γ-ketoacid was used in our
initial screen of amines (Table 1). Although p-methoxybenzyl-
amine gives the Ugi product in good yield,8 we preferred to
find an alternative nitrogen source because the use of this amine
generally requires subsequent deprotection, using harsh condi-
tions such as ceric ammonium nitrate.9 Ammonia in MeOH and
ammonium carboxylate salts6,10 (trifluoroacetate, formate, and
acetate) were initially screened with 1.1 equiv of isonitrile 1,
and only ammonium acetate (1.1 equiv) was found to participate
in the U4C-3CR with reasonable yield (entry 1). Ammonium
halide salts did not afford the Ugi product. It was necessary to
use 2 equiv of ammonium acetate to achieve a good conversion
(entry 2), but further excess (>3 equiv) did not increase the
yield (not shown). Pleasantly, the acetate counterion was not
incorporated into the condensation products, presumably due
to the intramolecular relationship between the imine and
carboxylic acid. This also explains the suppression of six-
component couplings and other byproducts sometimes observed
when using ammonia equivalents in the Ugi reaction.11 Using
2 equiv of isonitrile 1 afforded only a moderate increase in yield
(entry 3). Consequently, we chose the condition listed in entry
2 as the standard procedure. Recent results have shown that
the addition of 4 Å molecular sieves (20 mg/mmol) effects a
significant increase in yield, and we recommend their use (entry
4). A commercially available, cheap, and stable solid, am-
monium acetate is a user-friendly source of ammonia. We found
that hexamethyldisilazane (2 equiv), a known ammonia equiva-
lent, also participates in the Ugi reaction in acceptable yield
(72%, entry 5).
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 January 4, 2007
A series of biologically intriguing pyroglutamic acids were
synthesized in racemic form by employing indole-isonitrile
and ammonium acetate in the Ugi 4-center-3-component
reaction of γ-ketoacids.
The pyroglutamic acid moiety is found in such natural
products as lactacystin,1 salinosporamide A,2 dysibetaine,3 and
oxazolomycin4 and is a common building block in asymmetric
synthesis.5 Despite their abundance in nature, there is no
straightforward general synthesis available for this simple
framework. The Ugi 4-center-3-component reaction (U4C-3CR)6
of γ-ketoacids, [RCO(CH2)2CO2H], provides ready access to
the carbon framework of many pyroglutamic acid analogues.7
However, until recently it has not been possible to hydrolyze
the hindered C-terminal amides of pyroglutamic acid amides
that result from the Ugi reaction of γ-ketoacids to the corre-
sponding carboxylic acids, severely limiting the usefulness of
this method. We reported the development of a convertible
isonitrile, 1-isocyano-2-(2,2-dimethoxyethyl)benzene, also known
as indole-isonitrile (1), for use in the Ugi reaction and
demonstrated the ready selective cleavage of the resulting
C-terminal amide bond with the total synthesis of omuralide.8
The synthetic utility of the pyroglutamic acid moiety would be
increased further if ammonia or equivalents could be used as
Scheme 1 shows the conversion of levulinic acid (2) into
2-methylpyroglutamic acid.12 Ammonium acetate (2 equiv) and
2 (1 equiv) were premixed in trifluoroethanol with gentle heating
(60 °C) to promote imine formation. After addition of the
isonitrile (1.1 equiv) to the mixture the U4C-3CR was complete
within 2 h. A small amount (<5%) of Passerini product (3a)13
is formed in the reaction, indicating incomplete imine formation,
and is easily removed by chromatography. No acetal exchange
was observed between trifluoroethanol and the dimethoxy acetal.
All Ugi and Passerini products described (3, 3a in Scheme 1
(1) (a) Omura, S.; Fujimoto, T.; Otoguro, 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.
(2) 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.
(3) Sakai, R.; Oiwa, C.; Takaishi, K.; Kamiya, H.; Tagawa, M.
Tetrahedron Lett. 1999, 40, 6941-6944.
(4) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.; Katayama,
C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.; Matsuzaki, A.
Tetrahedron Lett. 1985, 26, 1073-1076.
(5) Na´jera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-2303.
(6) For a comprehensive review of the Ugi reaction: Ugi, I.; Do¨mling,
A. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(7) (a) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359-
362. (b) Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591-5594. (c)
Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725-2728. (d)
Tye, H.; Whittaker, M. Org. Biomol. Chem. 2004, 2, 813-815.
(8) Indole-isonitrile (1) was named after the facilitation of hydrolysis
of the resulting 2-(2,2-dimethoxyethyl)anilide 3 by Ugi/(Passerini) multi-
component condensation reaction, via N-acylindole 4. The first demonstra-
tion of the utility as a convertible isonitrile in the Ugi reaction and its
application to natural product synthesis were reported from our laboratory:
Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Angew. Chem., Int. Ed. Submitted
for publication.
(9) Corey, E. J.; Li, W.; Nagamitsu, T. Angew. Chem., Int. Ed. 1998,
37, 1676-1679.
(10) Polyakov, A. J.; Aseeva, V. G.; Bezrukova, V. G. IzV. Akad. Nauk
SSSR Ser. Khim. 1974, 7, 1597.
(11) (a) Kazmaier, U.; Hebach, C. Synlett 2003, 11, 1591-1594. (b) Pick,
R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 5, 757-760.
(12) (a) Takenishi, T.; Simamura, O. Bull. Chem. Soc. Jpn. 1954, 27,
207-209. (b) Pfister, K., III; Leanza, W. J.; Conbere, J. P.; Becker, H. J.;
Matzuk, A. R.; Rogers, E. F. J. Am. Chem. Soc. 1955, 77, 697-700.
(13) Application of indole-isonitrile (1) to Passerini reaction, see:
Vamos, M.; Ozboya, K.; Kobayashi, Y. Synlett. Submitted for publication.
10.1021/jo0700225 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/07/2007
J. Org. Chem. 2007, 72, 3913-3916
3913

TABLE 1. Screening of Amine and the Reaction Condition of the
Ugi Reaction
TABLE 2. Ugi 4-Center-3-Component Condensation Reaction of
γ-Ketoacids with Indole-Isonitrile (1)
X
(equiv)
isonitrile 1
(equiv)
yield
(%)a
entry
amine
1
2
NH4‚OAc
NH4‚OAc
NH4‚OAc
NH4‚OAc
HMDSc
1.1
2
2
2
2
1.1
1.1
1.1
1.1
1.1
61
77
82
84
72
3
4b
5
a Isolated yield (1 mmol scale). b MS4Å was added (20 mg/mmol).
c HMDS ) hexamethyldisilazane.
SCHEME 1. Synthesis of 2-Methylpyroglutamic Acid (5) by
Ugi Reaction with Indole-Isonitrile (1)
a Isolated yield (1 mmol scale). b Homopyroglutamic acid.
We explored the utility of this methodology for the synthesis
of a series of pyroglutamic acids. The mild conditions of the
U4C-3CR should make it amenable to a wide variety of
functional groups (Table 2). To test the hypothesis we conducted
the reaction with levulinic acid derivatives (6-9) containing
nitrogen, oxygen, and bromine and all successfully gave the
corresponding anilide (6a-9a). The decreased yield for the
reaction of 9 may be due to nucleophilic displacement of
bromine; however, we did not detect any significant side product
(entry 4). Commercially available 4-acetylbutyric acid (10, entry
5) successfully participates in the U4C-3CR to afford the
expected homopyroglutamic acid anilide (10a) in surprisingly
high yield considering the intermediacy of a seven-membered
cyclic acylimidate.7a
and 6a-10a in Table 2) were obtained as racemic mixtures.
The Ugi product 3 was successfully converted to the N-acyl-
indole 4 upon treatment with a catalytic amount of camphor-
sulfonic acid (0.2 equiv) in benzene and gentle heating for 1 h.
Despite the steric congestion at the neighboring fully sub-
stituted carbon, the N-acylindole 4 is readily cleaved to the free
pyroglutamic acid 514 by treatment with sodium hydroxide (1
equiv) via the intermediate methyl ester. The methyl ester 5a15
(not shown) can be isolated in high yield (90%) by stirring for
1 h in methanol, using only a catalytic amount (0.03 equiv) of
the base. Isolation of the final products was initially difficult
due to their strong hydrophilicity. However, the free acid is
readily obtained by recrystallization of the resulting sodium salt
from methanol/diethyl ether, removing the indole byproduct,
followed by treatment with acid resin. The methyl ester, on the
other hand, is readily separated from the less polar indole by
column chromatography.
Compounds 6,16 8,17 and 918 were prepared according to
literature precedents. Compound 7 was synthesized in four steps
from the commercially available benzyl succinate (Scheme 2).
Benzyl succinate was converted into the corresponding acid
(14) For previous preparations of 5, see ref 12.
(16) Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69, 2773-2784.
(17) Battah, S. H.; Chee, C-E.; Nakanishi, H.; Gerscher, S.; MacRobert,
A. J.; Edwards, C. Bioconj. Chem. 2001, 12, 980-988.
(15) For previous preparations of 5a: (a) Gillan, T.; Mor, G.; Pepper,
F. W.; Cohen, S. G. Bioorg. Chem. 1977, 6, 329-342. (b) Mkhairi, A.;
Hamelin, J. Tetrahedron Lett. 1986, 27, 4435-4436.
(18) MacDonald, S. F. Can. J. Chem. 1974, 52, 3257-3258.
3914 J. Org. Chem., Vol. 72, No. 10, 2007

SCHEME 2. Preparation of Compound 7
by radical reaction or nucleophilic substitution. Homopyro-
glutamic acid analogue 10a was also readily cleaved to the
corresponding methyl ester (10c),15b,21 suggesting the potential
of this method for the preparation of various homopyroglutamic
acids.
The synthesis of this series of pyroglutamic acid derivatives
shows the utility of the indole-isonitrile (1) for cleaving the
C-terminal amides products of the U4C-3CR to the more useful
carboxylic acids. Furthermore, we demonstrated the mild and
high yielding cleavage of such amides adjacent to a highly
hindered carbon center. The use of an ammonia equivalent as
the amine component in these reactions allows for the quick
construction of complex heterocycles with no protecting groups.
By varying the substitution pattern of the γ-ketoacid starting
material more substituted pyroglutamic acids and homopyro-
glutamic acids can be accessed. Current studies are underway
in our laboratory toward the application of this methodology to
the synthesis of the pyroglutamic acid natural product dysibe-
taine.
TABLE 3. Facile Conversion of Anilide to Ester via N-Acylindole
Experimental Section
General Procedure for the Ugi Reaction: Preparation of 3.
Ammonium acetate (2.0 mmol) was added to levulinic acid (2) (1.0
mmol) in 2,2,2-trifluoroethanol (2 mL) and the reaction was heated
to 60 °C. After 30 min, 1-isocyano-2-(2,2-dimethoxyethyl)benzene
(1) (1.1 mmol) was added and the reaction continued to stir at 60 °C
until the isonitrile was consumed according to TLC (about 2 h).
The reaction was removed from heat and the 2,2,2-trifluoroethanol
was evaporated. The residue was diluted with water (10 mL) then
extracted with ethyl acetate (2 × 15 mL). The combined organic
portions were washed with brine (10 mL), dried over Na2SO4, then
concentrated. Ugi product 3 (0.236 g, 77%) as colorless solid and
Passerini product 3a (<5%) as a colorless oil were recovered after
purification by silica gel column chromatography (100% EtOAc).
1
3: Mp 142-143 °C. H NMR (400 MHz, CDCl3) δ 9.41 (s,
1H), 7.78 (d, J ) 8.0 Hz, 1H), 7.27 (t, J ) 8.0 Hz, 1H), 7.18 (d,
J ) 7.3 Hz, 1H), 7.11 (t, J ) 7.3 Hz, 1H), 6.87 (s, 1H), 4.45 (t, J
) 5.3 Hz, 1H), 3.44 (s, 3H), 3.43 (s, 3H), 2.88 (dd, J ) 3.8, 5.3
Hz, 2H), 2.58-2.44 (m, 3H), 2.19-2.14 (m, 1H), 1.62 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 178.0, 172.8, 136.3, 131.3, 128.5,
127.8, 125.5, 124.3, 106.8, 63.8, 54.8, 54.6, 37.3, 34.4, 30.5, 26.0.
HR-EI-MS C16H22N2O4 calcd 306.1574, obsd 306.1579.
a Isolated yield of Xc (2 steps from Xa, 0.2-0.5 mmol scale).
b Homopyroglutamic acid.
chloride by using oxalyl chloride in benzene. The crude acid
chloride was dissolved in acetonitrile and was treated with 2
equiv of (trimethylsilyl)diazomethane to create the unstable
diazoketone intermediate that was captured in situ by ethanol
after the addition of boron trifluoride etherate to give benzyl
5-ethoxy-4-oxopentanoate in 56% yield over 3 steps.19 Finally
the benzyl ester was removed by hydrogenolysis to give the
desired ketoacid 7.
3a (oil): 1H NMR (400 MHz, CDCl3) δ 9.73 (br s, 1H), 7.81
(dd, J ) 8.2, 0.8 Hz, 1H), 7.28 (td, J ) 7.7, 1.4 Hz, 1H), 7.91 (dd,
J ) 7.7, 1.4 Hz, 1H), 7.12 (td, J ) 7.7, 1.4 Hz, 1H), 4.52 (t, J )
4.8 Hz, 1H), 3.45 (s, 3H), 3.42 (s, 3H), 2.95-2.84 (m, 2H), 2.81-
2.75 (m, 1H), 2.67-2.61 (m, 2H), 2.26-2.18 (m, 1H), 1.73 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 175.5, 171.0, 136.1, 131.7,
128.9, 127.8, 125.7, 124.2, 105.8, 86.1, 54.1, 37.1, 32.6, 28.7, 25.3.
HR-EI-MS C16H21NO5 calcd 307.1414, obsd 307.1410.
The Ugi products (6a-10a) were successfully converted to
the N-acylindoles (Xb), which were all easily cleaved to their
corresponding methyl esters (Xc) in excellent yields (Table 3).
The methyl esters were prepared due to the ease of isolation,
and the corresponding acids could be made by employing
additional base, as above. Compound 6c20 contains the full
carbon backbone of the biologically interesting lactacystin.1 The
bromine in compound 9c is a particularly useful synthetic handle
because of the potential for further elaboration of the backbone
N-Acylindole (4). Camphorsulfonic acid (0.4 mmol) was added
to the Ugi product 3 (2.0 mmol) in benzene (10 mL) and the reaction
was heated to 60 °C for 1 h. The reaction was washed with saturated
NaHCO3 (aq) and brine, dried over Na2SO4, then filtered and
1
concentrated. 4 (0.485 g, 2.0 mmol) was recovered as an oil. H
NMR (500 MHz, CDCl3) δ 8.49 (d, J ) 8.3 Hz, 1H), 7.57 (d, J )
7.6 Hz, 1H), 7.47 (d, J ) 3.6 Hz, 1H), 7.39 (t, J ) 7.6 Hz, 1H),
7.31 (t, J ) 7.6 Hz, 1H), 6.79 (br s, 1H), 6.70 (d, J ) 3.6 Hz, 1H),
2.83-2.77 (m, 1H), 2.66-2.59 (m, 1H), 2.52-2.41 (m, 2H), 1.80
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 175.4, 172.1, 129.7, 128.5,
126.0, 124.6, 124.1, 121.1, 117.4, 110.6, 64.8, 33.3, 30.2, 28.2.
HR-EI-MS C14H14N2O2 calcd 242.1050, obsd 242.1053.
(19) (a) Newman, M. S.; Beal, P. F., III J. Am. Chem. Soc. 1950, 72,
5161-5163. (b) Maruga´n, J.; Anaclerio, B.; Lafrance, L.; Lu, T.; Markotan,
T.; Leonard, K. A.; Crysler, C.; Eisennagel, S.; Dasgupta, M.; Tomczuk,
B. J. Med. Chem. 2005, 48, 926-934.
(20) The corresponding ethyl ester of 6c was prepared previously:
Guillena, G.; Mico, I.; Najera, C.; Ezquerra, J.; Pedregal, C. An. Quim. Int.
Ed. 1996, 92, 362-369.
2-Methylpyroglutamic Acid (5). 4 (0.242 g, 1.0 mmol) was
dissolved in methanol (3 mL). Solid sodium hydroxide (1.0 mmol)
(21) For previous preparations of 10c: Overberger, C. G.; Shalati, M.
D. Eur. Polym. J. 1983, 19, 1055-1065.
J. Org. Chem, Vol. 72, No. 10, 2007 3915

1
was added and the reaction was stirred until no starting material
remained by TLC (about 1 h). The reaction was concentrated and
the sodium salt of the product was recrystallized from methanol/
diethyl ether to yield 0.162 g (0.98 mmol) of white solid. The
sodium salt was treated with Amberlyst 15 in methanol and upon
concentration 0.124 g (90% from 3) of the free carboxylic acid 5
was recovered as a white solid. Mp 144-145 °C (lit.13 mp 144-
145 °C). 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 2.48-2.37
(m, 3H), 2.07-1.99 (m, 1H), 1.49 (s, 3H). 13C NMR (100 MHz,
CD3OD) δ 179.0, 176.4, 62.7, 32.6, 32.5, 24.1. HR-EI-MS C6H9-
NO3 calcd 143.0577, obsd 143.0575.
7a: Mp 101-102 °C. H NMR (400 MHz, CDCl3) δ 9.53 (s,
1H), 7.73 (d, J ) 8.0 Hz, 1H), 7.26 (t, J ) 7.6 Hz, 1H), 7.18 (d,
J ) 7.6 Hz, 1H), 7.11 (t, J ) 7.4 Hz, 1H), 6.37 (s, 1H), 4.48 (dd,
J ) 4.4, 6.4 Hz, 1H), 4.02 (d, J ) 8.8 Hz, 1H), 3.53-3.47 (m,
2H), 3.42 (s, 6H), 3.39 (d, J ) 8.8 Hz, 1H), 2.97 (dd, J ) 6.4, 14
Hz, 1H), 2.82 (dd, J ) 4.4, 14 Hz, 1H), 2.52-2.36 (m, 3H), 2.11-
2.06 (m, 1H), 1.14 (t, J ) 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 177.4, 171.4, 136.1, 131.1, 128.6, 127.5, 125.4, 124.3, 106.1,
75.2, 67.0, 66.6, 54.4, 53.5, 36.8, 29.3, 28.7, 14.9. HR-EI-MS
C18H26N2O5 calcd 350.1836, obsd 350.1843.
7c (oil): 1H NMR (400 MHz, CD3OD) δ 3.76 (s, 3H), 3.55-
3.49 (m, 4H), 2.38-2.26 (m, 3H), 2.15-2.13 (m, 1H), 1.16 (t, J )
7.0 Hz, 3H). 13C NMR (100 MHz, CD3OD) δ 178.9, 173.2, 74.8,
67.1, 66.8, 52.2, 29.6, 27.6, 14.3. HR-EI-MS C9H15NO4 calcd
201.0996, obsd 201.0995.
2-Methylpyroglutamic Acid Methyl Ester (5a). Aqueous
sodium hydroxide (1 N, 6 µmol) was added to crude N-acylindole
4 (1.0 mmol) dissolved in methanol (3 mL) and the reaction was
stirred for 1 h then concentrated and purified by column chroma-
tography (100% CH2Cl2 to 9:1 CH2Cl2:methanol). The combined
fractions were dried over Na2SO4 and treated with activated charcoal
(if necessary) then filtered and concentrated. White crystalline solid
methyl ester 5a (0.282 g, 90%) was recovered. Mp 87-89 °C (lit.15a
mp 58-59 °C). 1H NMR (400 MHz, CD3OD) δ 3.74 (s, 3H), 2.47-
2.32 (m, 3H), 2.07-1.99 (m, 1H), 1.49 (s, 3H). 13C NMR (100
MHz, CD3OD) δ 178.9, 174.9, 62.8, 52.0, 32.5, 29.9, 24.1. HR-
EI-MS C7H11NO3 calcd 157.0733, obsd 157.0736.
8a: Mp 83-86 °C. 1H NMR (500 MHz, CDCl3) δ 9.72 (s, 1H),
7.77 (d, J ) 8.1 Hz, 1H), 7.29 (t, J ) 7.4 Hz, 1H), 7.20 (d, J ) 7.6
Hz, 1H), 7.14 (t, J ) 7.4 Hz, 1H), 7.08 (s, 1H), 5.16 (s, 1H), 4.49
(t, J ) 5.1 Hz, 1H), 3.58-3.48 (m, 1H), 3.39 (s, 3H), 3.37 (s, 3H),
2.86 (d, J ) 5.1 Hz, 2H), 2.50-2.39 (m, 3H), 2.14-2.12 (m, 1H),
1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 178.3, 172.2, 157.5,
136.1, 131.5, 129.0, 127.7, 125.8, 124.4, 106.1, 80.4, 68.3, 54.3,
54.2, 48.0, 37.0, 30.7, 29.9, 28.5. HR-EI-MS C21H31N3O6 calcd
421.2207, obsd 421.2213.
1
6a: Mp 129-131 °C. H NMR (500 MHz, CDCl3) δ 9.44 (s,
1H), 7.78 (d, J ) 7.9 Hz, 1H), 7.28 (t, J ) 7.9 Hz, 1H), 7.19 (d,
J ) 7.6 Hz, 1H), 7.12 (t, J ) 7.5 Hz, 1H), 6.33 (s, 1H), 4.48 (t, J
) 5.3 Hz, 1H), 3.44 (s, 3H), 3.43 (s, 3H), 2.88 (d, J ) 5.3 Hz,
2H), 2.59-2.53 (m, 1H), 2.46-2.39 (m, 2H), 2.22-2.13 (m, 2H),
1.80-1.74 (m, 1H), 1.61 (dd, J ) 6.2, 14.1 Hz, 1H), 1.00 (d, J )
6.7 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 178.1, 172.8, 136.5, 131.5, 128.6, 127.9, 125.6, 124.4, 106.6,
66.7, 54.5, 54.4, 47.8, 37.2, 34.9, 29.7, 25.4, 24.4, 23.2. HR-EI-
MS C19H28N2O4 calcd 348.2044, obsd 348.2039.
8c (oil): 1H NMR (400 MHz, CD3OD) δ 3.75 (s, 3H), 3.48 (d,
J ) 14.1 Hz, 1H), 3.38 (d, J ) 14.1 Hz, 1H), 2.40-2.14 (m, 4H),
1.42 (s, 9H). 13C NMR (100 MHz, CD3OD) δ 179.0, 173.2, 157.4,
79.4, 66.9, 52.2, 46.4, 29.5, 27.8, 27.5. HR-EI-MS C12H20N2O5
calcd 272.1367, obsd 272.1367.
1
9a: Mp 130 °C dec. H NMR (300 MHz, CDCl3) δ 9.67 (s,
1H), 7.74 (s, 1H), 7.33-7.15 (m, 3H), 6.23 (s, 1H), 4.51 (t, J )
5.5 Hz, 1H), 4.19 (d, J ) 7.5 Hz, 1H), 3.50 (d, J ) 7.5 Hz, 1H),
3.45 (s, 3H), 3.44 (s, 3H), 3.01 (dd, J ) 5.5, 13.8 Hz, 1H), 2.85
(dd, J ) 5.5, 13.8 Hz, 1H), 2.66-2.52 (m, 3H), 2.30-2.25 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 176.8, 170.2, 136.1, 131.6,
129.0, 127.9, 126.1, 124.7, 106.5, 66.8, 54.7, 54.1, 39.2, 37.3, 32.0,
30.3. HR-EI-MS C16H21BrN2O4 calcd 384.0679, obsd 384.0678.
9c: Mp 92-94 °C. 1H NMR (400 MHz, CD3OD) δ 3.85-3.71
(m, 2H), 3.80 (s, 3H), 2.51-2.21 (m, 4H). 13C NMR (100 MHz,
CD3OD) δ 178.8, 172.0, 66.6, 52.4, 37.4, 29.8, 29.6. HR-EI-MS
C7H10BrNO3 calcd 234.9839, obsd 234.9835.
1
6c: Mp 81-84 °C. H NMR (400 MHz, CD3OD) δ 3.74 (s,
3H), 2.45-2.31 (m, 3H), 2.12-2.05 (m, 1H), 1.85-1.69 (m, 3H),
0.93 (d, J ) 6.5 Hz, 3H), 0.87 (d, J ) 6.5 Hz, 3H). 13C NMR (100
MHz, CD3OD) δ 178.6, 174.7, 66.1, 52.0, 47.4, 32.0, 29.7,
24.7, 23.7, 22.1. HR-EI-MS C10H17NO3 calcd 199.1203, obsd
199.1199.
5-Ethoxy-4-oxopentanoic Acid (7). Benzyl succinate (6.3 mmol)
was treated with oxalyl chloride (8.1 mmol, 1.3 equiv) in benzene
(20 mL) and the reaction was heated to 60 °C for 1 h after which
time all volatile components were removed by vacuum. The crude
acid chloride was dissolved in acetonitrile (15 mL) then (trimeth-
ylsilyl)diazomethane (2.0 M solution in Et2O, 6.3 mL, 2.0 equiv)
was slowly added. After 30 min the reaction was cooled to 0 °C
then ethanol (5 mL) was added followed by the careful addition of
BF3‚OEt2 (1.16 mL, 1.5 equiv). After 1 h the reaction was diluted
with water (50 mL) then extracted with ethyl acetate (2 × 20 mL).
The combined organic portions were washed with brine (20 mL)
then dried over Na2SO4 and concentrated. The crude product was
purified by column chromatography, using 4:1 hexanes:ethyl
acetate, to yield benzyl 5-ethoxy-4-oxopentanoate (11) (3.5 mmol,
56%) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.30 (m,
5H), 5.11 (s, 2H), 4.06 (s, 2H), 3.53 (q, J ) 7.0 Hz, 2H), 2.79 (t,
J ) 6.5 Hz, 2H), 2.68 (t, J ) 6.5 Hz, 2H), 1.24 (t, J ) 7 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 207.8, 172.7, 136.0, 128.8, 128.5,
128.4, 76.0, 67.4, 66.8, 33.7, 27.8, 15.3. HR-EI-MS C14H18O4 calcd
250.1200, obsd 250.1201. 11 (0.46 mmol) was dissolved in
methanol (3 mL) and catalytic palladium on carbon (10% w/w, 5
mg) was added. The reaction was stirred under 1 atm of H2 for 3
h then filtered through Celite and concentrated to yield 7 (0.38
1
10a: Mp 157-159 °C. H NMR (400 MHz, CDCl3) δ 9.44 (s,
1H), 7.72 (d, J ) 8.0 Hz, 1H), 7.26 (t, J ) 7.4 Hz, 1H), 7.18 (d,
J ) 7.4 Hz, 1H), 7.12 (t, J ) 7.4 Hz, 1H), 6.51 (s, 1H), 4.45 (t, J
) 5.3 Hz, 1H), 3.43 (s, 3H), 3.41 (s, 3H), 2.86 (d, J ) 5.3 Hz,
2H), 2.49-2.37 (m, 3H), 1.87-1.80 (m, 2H), 1.65-1.59 (m, 1H),
1.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.8, 172.1, 136.4,
131.3, 128.8, 127.7, 125.7, 124.7, 106.6, 61.8, 54.9, 54.3, 37.3,
33.8, 31.3, 27.9, 18.6. HR-EI-MS C17H24N2O4 calcd 320.1731, obsd
320.1728.
10c: Mp 98-100 °C (lit.20a mp 98.5-99.5 °C). H NMR (400
1
MHz, CD3OD) δ 3.74 (s, 3H), 2.31-2.19 (m, 3H), 1.86-1.82 (m,
1H), 1.74-1.61 (m, 2H), 1.47 (s, 3H). 13C NMR (100 MHz, CD3-
OD) δ 174.9, 173.6, 59.9, 52.1, 32.4, 30.1, 25.3, 17.8. HR-EI-MS
C8H13NO3 calcd 171.0890, obsd 171.0892.
Acknowledgment. In memory of Dr. Ivar Ugi. The authors
acknowledge the University of California and a GAANN
fellowship (CBG) for financial support of this research. The
authors also thank Dr. Yongxuan Su for mass spectroscopy.
1
Supporting Information Available: Copies of H NMR and
1
13C NMR spectra for compounds 3-5, 3a, 5a, 7, 6a-10a, 6c-
10c, and 11. This material is available free of charge via the Internet
at http://pubs.acs.org.
mmol, 82%) as a clear oil. H NMR (400 MHz, CD3OD) δ 4.16
(s, 1H), 3.55 (q, J ) 7.0 Hz, 2H), 2.71 (t, J ) 6.4 Hz, 2H), 2.57
(t, J ) 2.6 Hz, 2H), 1.21 (t, J ) 7.0 Hz, 3H). 13C NMR (100 MHz,
CD3OD) δ 208.4, 175.1, 75.2, 66.9, 33.0, 27.1, 14.1. HR-EI-MS
C7H12O4 calcd 160.0730, obsd 160.0728.
JO0700225
3916 J. Org. Chem., Vol. 72, No. 10, 2007