Chain extension of amino acid skeletons: Preparation of ketomethylene isosteres

Article abstract of DOI:10.1016/S0040-4020(03)00052-8

Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension reaction in which a variety of amino acid-derived β-keto esters are converted to γ-keto esters in a single step. The reaction tolerates a variety of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter.

Full text of DOI:10.1016/S0040-4020(03)00052-8

Tetrahedron 59 (2003) 1521–1527
Chain extension of amino acid skeletons: preparation of
ketomethylene isosteres
*
Cory R. Theberge and Charles K. Zercher
Department of Chemistry, University of New Hampshire, Parsons Hall, Durham, NH 03824, USA
Received 12 September 2002; revised 7 January 2003; accepted 7 January 2003
Abstract—Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension
reaction in which a variety of amino acid-derived b-keto esters are converted to g-keto esters in a single step. The reaction tolerates a variety
of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
From a synthetic chemistry viewpoint, the aim of the
proposed research was the adaptation of a synthetic method
discovered in our laboratories for the simple and efficient
conversion of b-keto esters (3) to g-keto esters (7) through a
one-pot, zinc-mediated chain extension reaction (Scheme
1).2 Treatment of b-keto esters, amides, and phosphonates
with the electrophilic Furukawa reagent, ethyl(iodomethyl)-
zinc, results in efficient generation of the chain extended
species. However, chain extension of substrates that
contained ancillary Lewis basic functionality had not yet
been studied. A report3 that implicated the Furukawa
reagent in the methylation of an amide’s nitrogen suggested
that the direct application of this chain extension method-
ology to amino acid-derived substrates may be challenging.
Furthermore, utilization of basic reagents with amino acid
substrates presents the potential for epimerization of the
critical stereocenter. With these concerns we undertook the
study of the zinc-mediated chain extension of amino acid
derived b-keto esters.
Utilization of isosteric replacements for peptide bonds has
been an attractive strategy for enzyme inhibition. Successful
inhibition of aspartic acid protease targets like HIV-protease
and renin has validated the use of ketomethylene (1) and
hydroxyethylene (2) isosteres in peptide systems.1 How-
ever, generation of these peptide mimics has often relied
upon lengthy and resource intensive synthetic sequences.
The availability of a simple, efficient reaction that facilitates
the preparation of heavily functionalized, amino acid-
derived g-keto esters would find utility in the preparation
of these isosteres, regardless of the inhibition target.
Furthermore, identification of a flexible and efficient
synthetic method or strategy amenable to the incorporation
of these isosteres into a peptide fragment immobilized on a
solid support would facilitate the general development and
study of peptide isosteres (Fig. 1).
2. Results and discussion
A variety of amino acids were selected as starting materials,
although the primary focus of the study were amino acids
with aliphatic and aromatic side chains. Racemic amino
acids were utilized to establish the chemical efficiency of the
reaction sequence, at which time a sampling of L-amino
acids were used to establish the stereochemical integrity of
the procedure. A diverse group of nitrogen protecting
groups was chosen, including carbamate groups Cbz,4 Boc,5
and Fmoc,6 as well as an amide group (Bz) designed to
mimic the presence of a peptide bond.
Figure 1. Peptide isosteric replacements.
Keywords: isostere; zinc; carbenoid; peptide mimic; chain extension.
*
The typical strategy by which the C-terminus is manipulated
is illustrated in Scheme 2. After N-protection of the amino
Corresponding author. Tel.: þ1-603-862-2697; fax: þ1-603-862-4278;
e-mail: ckz@christa.unh.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00052-8

1522
C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
Scheme 1. Zinc-mediated chain extension.
Scheme 2. g-Keto ester formation.
acids, the corresponding b-keto esters 9 were formed via the
neutral C-acylation reaction of acyl imidazoles as described
by Masamune and Brooks.7 Conversion of N-protected
amino acids to b-keto esters using a similar method8 at
elevated temperatures resulted in the formation of 12–16%
of the racemate. However, the simplicity of the Masamune
procedure made it the most attractive option for generation
of the chain extension substrates. The results of the b-keto
ester formation are summarized in Table 1. The reactions to
provide b-keto methyl esters 9 were relatively slow,
possibly due to the heterogeneous nature of the monomethyl
malonate complex in THF. Reaction times of one to two
days were required in order to get maximum yields of 50–
75%. When methylene chloride was used as the solvent,
improved solubility of malonate complex was observed.
Initial formation of b-keto ester in 40% yield was observed,
yet a reaction time of two days was required 00in order to
optimize the yield. Monobenzyl malonate (R ¼Bn) was
used in the sequence described in Scheme 3. This reaction
was homogenous in THF and commonly proceeded to 50–
75% yields after one day stirring at room temperature.
While Cbz, Boc, and Bz protected amino acids were easily
converted to the b-keto esters, Fmoc-protected amino acids
degraded slowly during the acylation procedure.
After formation of the b-keto esters, the chain extension
reaction was performed by exposure of the b-keto ester 9 to
the carbenoid. The typical chain extension reaction utilized
excess carbenoid generated from 5.0 equiv. of Et2Zn and
7.5 equiv. of methylene iodide in a solvent of methylene
chloride. The derivatized amino acid was added as a
solution in methylene chloride and the resulting solution
monitored for consumption of starting b-keto ester by TLC.
Every amino acid derivative underwent the chain extension
reaction, although differences in efficiency were observed.†
In a few instances, unreacted starting material was identified
in the crude reaction mixture. Similar retention factors,
which required careful chromatographic separation, were
observed for the starting material and chain-extended
products. This resulted in diminished isolated yields. The
fate of the remaining starting material is unclear, although
intermolecular aldol reactions have been observed in other
reactions of this type.9
Table 1. Two-step generation of amino acid-derived g-keto methyl esters
SMa
P
R
Yield of 9b
Yield of 10b
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
Boc
Boc
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Bz
Bz
Bz
Bz
Fmoc
Fmoc
Fmoc
Fmoc
H
91
70
41
63
65
66
45
71
65
47
28
74
65
76
85
67
25
48
57
49
60
60
48
68
58
58
43
58
55
57
63
68
Me
Ph
Bn
H
Me
Ph
Bn
H
Me
Ph
Bn
H
Me
Ph
Bn
A number of features of zinc-mediated chain extension
reaction are noteworthy. The protective groups were not
degraded by these reactions. Even the base sensitive Fmoc
group tolerated the reaction conditions. The presence of a
modestly acidic amide or carbamate proton (NH) does not
negatively affect the chain extension reaction. It is unclear
whether the NH is deprotonated in the reaction, although the
required use of 5 equiv. of carbenoid suggests that the amide
or carbamate protons may consume some of the reagent. It is
a
†
Starting material.
Isolated yield (%) of purified material.
The products, following purification by column chromatography, were
one spot by TLC analysis and possessed clean 13C NMR spectra.
b

C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
1523
starting materials revealed that this epimerization took place
during formation of the b-keto ester. No observation of
amino acid epimerization during the zinc-mediated chain
extension reaction was observed.
As a further demonstration of the utility of the zinc-
mediated reaction we have successfully prepared 14, a
g-keto amide functionality that is flanked by two amino
acids (Scheme 3). Treatment of b-keto ester 11 with the
zinc-carbenoid provided access to the targeted g-keto ester
12. Cleavage of the benzyl ester, followed by EDC coupling
with the methyl ester of phenylalanine 13 yielded the
tripeptide mimic 14. No epimerization of amino acid
stereocenters was observed during analysis of the product
by NMR or by chiral HPLC.
3. Conclusion
Scheme 3. Tripeptide mimic.
Amino acid derived b-keto esters have been successfully
chain extended to provide their g-keto ester analogues.
These products have the requisite structural features to find
use as ketomethylene isosteric replacements for peptide
bonds. No amino acids with polar side chains, heterocyclic
rings, or olefinic functionality have been included in this
study. However, the compatibility of the zinc-mediated
chain extension method with olefinic functionality2 and
with the Lewis basic functionality present in the peptide
substrates suggest that the chain extension reaction should
have broad applicability. Furthermore, the ease with which
the substrates can be prepared presents this method as an
attractive alternative to established approaches to these
functional groups. The extension of this methodology to
additional amino acid derivatives, including those with
polar side chains, is being studied and will be reported in the
future.
also possible that the amide or carbamate protons could
serve to quench the intermediate enolate (6) generated after
chain extension. Regardless of the role of the NH, it is clear
that the presence of modestly acidic functionality is
tolerated in the reaction.
Methylation of the amide or carbamate nitrogen was not
observed, although extended exposure of the amino acid
substrate to the carbenoid may result in partial methylation.
Control of reaction time and carbenoid equivalents was
sufficient to prevent N-methylation.
Modest variation in the efficiency of the reaction was
observed with respect to the different protecting groups.
While the Cbz and Bz protecting groups appeared to tolerate
the reaction conditions quite well, the Boc groups appeared
to be somewhat labile under these Lewis acidic conditions.
Although chain-extended products were formed from the
Boc-protected amino acids, the yields were usually lower
than reactions performed on analogous Cbz-protected
amino acids. The efficient conversion of amide-protected
(Bz) amino acids bodes well for polypeptide substrates.
4. General experimental
All reactions were run in oven-dried glassware under
nitrogen atmosphere and stirred with teflon-coated magnetic
stir-bars. The terms concentrated in vacuo or under reduced
pressure refer to the use of a rotary-evaporator. Methylene
chloride was distilled from phosphorous pentoxide. Ethyl
acetate and hexanes were distilled prior to use. Reagents
were purchased from commercial suppliers and used
without further purification. Diethyl zinc was used as a
1.0 M solution in hexanes as supplied by Aldrich.
Methylene iodide (CH2I2) was purchased from commercial
suppliers and non-oxidized copper wire was added as a
stabilizer. Column chromatography was performed on EM
Science flash silica gel (35–75 mm). Mobile phases were
used as noted. Thin layer chromatography (TLC) was
carried out on EM Science F254 glass plates and visualized
by UV and anisaldehyde or phosphomolybdic acid stains.
Low resolution mass spectroscopy was performed by the
University of New Hampshire Instrumentation Center on a
Perkin–Elmer 2400 Analyzer. High resolution mass
spectroscopy was performed at Merck Pharmaceutical
Research, West Point, PA.
Successful chain extension has been observed for all of the
amino acid substrates studied to this point, however the
Boc-glycine substrate reacts with the least efficiency. No
clear picture has arisen which can explain this diminished
reactivity, although the intermediate enolate reagent appears
to have limited stability and undergoes further reaction/
decomposition to provide unidentifiable products. The
reaction time was shortened (with a concomitant cost in
yield) in order to obtain clean product.
Epimerization of the amino acid stereocenter would
diminish dramatically the attractiveness of the proposed
approach to ketomethylene isosteres. In order to probe the
integrity of the stereocenters, a single enantiomer of
selected amino acids was selected and transformed to the
g-keto esters using the sequence of reactions described
above. The b-keto esters and g-keto esters were compared
on a Daicel Chiralpakw AD-RH reverse phase chiral
column. Approximately 5–7% racemization was observed
in the g-keto esters, although comparison to the b-keto ester

1524
C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
4.1. Representative procedures
5.22 (bs, 1H), 4.11 (d, 2H, J¼5.1 Hz), 3.72 (s, 3H), 3.49 (s,
2H), 1.43 (s, 9H); 13C NMR (90 MHz, CDCl3) d 198.6,
167.0, 155.6, 80.1, 52.5, 50.5, 46.2, 28.2. HRMS (MþNaþ)
calcd for C10H17NO5Na 254.1104, found 254.1108.
4.1.1. Formation of the b-keto ester: methyl 4-(carbo-
benzyloxy)amino-3-oxo-5-phenyl-pentanoate (9h). Into a
25 mL round-bottomed flask equipped with a stir bar were
placed 300 mg (1.00 mmol) Cbz-phenylalanine (8h) and
10 mL anhydrous THF. Carbonyl diimidazole (CDI)
178 mg (1.10 mmol) was added and the solution stirred
approximately 15 min. In a separate 100 mL round-bottom
flask which contained a solution of monomethyl malonate
(352 mg, 3.00 mmol) in 30 mL of anhydrous THF was
added 1.50 mL (1.50 mmol) of a 1 M hexane solution of
dibutylmagnesium at 08C. This solution, which appears as a
white slurry, was allowed to warm to room temperature. The
acyl imidazole solution was transferred to the flask which
contained the magnesium salt and the reaction was
monitored by TLC. The solution was allowed to stir for
48 h and quenched by the addition of 30 mL sat. aq. NH4Cl
solution. The solution was extracted three times with 20 mL
Et2O. The combined organics were dried with MgSO4,
filtered, and concentrated. The crude residue was chro-
matographed on silica with 15% EtOAc in hexanes to yield
252 mg (71%) of 9h as a colorless oil. 1H NMR (360 MHz,
CDCl3) d 7.39–7.23 (m, 8H), 7.15 (m, 2H), 5.35 (d, 1H,
J¼7.7 Hz), 5.12 (s, 2H), 4.67 (dd, 1H, J¼7.0, 13.8 Hz), 3.70
(s, 3H), 3.55–3.43 (AB, 2H, J¼16 Hz), 3.19–3.14 (AX, 1H,
J¼6.1, 6.1 Hz), 3.04–2.98 (BX, 1H, J¼7.1, 7.2 Hz); 13C
NMR (90 MHz, CDCl3) d 201.6, 167.3, 155.8, 136.2, 135.8,
129.2, 128.8, 128.5, 128.2, 128.1, 127.2, 67.1, 60.8, 52.4,
46.7, 36.9. HRMS (MþNaþ) calcd for C20H21NO5Na
378.1312, found 378.1305.
4.2.2. (6)-Methyl 4-(carboxy-t-butyl)-amino-3-oxo-pen-
1
tanoate (9b). 70%. White solid; mp 52–548C. H NMR
(360 MHz, CDCl3) d 5.15 (bs, 1H), 4.36 (dq, 1H, J¼7.0,
7.0 Hz), 3.73 (s, 3H), 3.57 (AB, 2H, J¼15.8 Hz), 1.43 (s,
9H), 1.36 (d, 3H, J¼7.0 Hz); 13C NMR (90 MHz, CDCl3) d
202.3, 167.5, 155.3, 80.0, 55.3, 52.4, 45.5, 28.2, 16.9.
HRMS (MþNaþ) calcd for C11H19NO5Na 268.1161, found
268.1157.
4.2.3. (6)-Methyl 4-(carboxy-t-butyl)-amino-3-oxo-4-
phenylbutanoate (9c). 41%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.54–7.29 (m, 5H), 5.82 (bs, 1H),
5.44 (m, 1H), 3.65 (s, 3H), 3.50–3.31 (AB, 2H, J¼16.0 Hz),
1.40 (s, 9H); 13C NMR (90 MHz, CDCl3) d 198.3, 166.6,
154.7, 135.7, 129.3, 128.8, 128.1, 80.1, 64.4, 52.4, 45.8,
28.2. HRMS (MþNaþ) calcd for C16H21NO5Na 330.1312,
found 330.1314.
4.2.4. (6)-Methyl 4-(carboxy-t-butyl)-amino-3-oxo-5-
phenylpentanoate (9d). 63%. White solid; mp 78–798C.
1H NMR (360 MHz, CDCl3) d 7.33–7.16 (m, 5H), 5.02 (m,
1H), 4.56 (dt, 1H, J¼7.2, 7.2 Hz), 3.71 (s, 3H), 3.49 (AB,
2H, J¼16.0 Hz), 3.06 (AB, 2H, J¼6.0, 14.0 Hz), 1.40 (s,
9H); 13C NMR (90 MHz, CDCl3) d 201.8, 167.3, 155.2,
136.0, 129.2, 128.7, 127.0, 80.2, 60.4, 52.4, 46.6, 36.9, 28.2.
HRMS (MþHþ) calcd for C17H24NO5 322.1649, found
322.1668.
4.1.2. Zinc-mediated chain extension: methyl 5-(carbo-
A
benzyloxy)amino-4-oxo-6-phenyl-hexanoate (10h).
4.2.5. Methyl 4-(carboxybenzyl)-amino-3-oxo-butanoate
1
(9e). 65%. Yellow oil. H NMR (360 MHz, CDCl3) d 736
50 mL round-bottomed flask was charged with 30 mL
anhydrous CH2Cl2 and 255 mL (3.16 mmol) of methylene
iodide was added. The solution was cooled to 08C and
2.11 mL (2.11 mmol) of a 1 M solution of diethylzinc in
hexanes was added slowly. The ice bath was removed
immediately and a white precipitate formed rapidly. After
stirring for 2 min, 150 mg (0.42 mmol) of 9h dissolved in
5 mL CH2Cl2 was added and the reaction monitored by TLC
(normal phase). The product spot appeared at a slightly
higher Rf than starting material and was best visualized by
staining the TLC plates with anisaldehyde. The reaction was
complete after 30 min and was quenched with 25 mL sat.
aq. NH4Cl solution. The organic solution was dried with
MgSO4, filtered, and evaporated under reduced pressure.
Flash chromatography on silica using 15% EtOAc in hexane
(m, 5H), 5.41 (bs, 1H), 5.13 (s, 2H), 4.22 (d, 2H, J¼5.0 Hz),
3.75 (s, 3H), 3.51 (s, 2H); 13C NMR (90 MHz, CDCl3) d
198.3, 166.7, 156.2, 136.2, 128.5, 128.2, 128.1, 67.1, 52.6,
50.8, 46.2. HRMS (MþNaþ) calcd for C13H15NO5Na
288.0848, found 288.0855.
4.2.6. (6)-Methyl 4-(carboxybenzyl)-amino-3-oxo-pen-
tanoate (9f). 66%. Yellow oil. 1H NMR (360 MHz, CDCl3)
d 7.39–7.26 (m, 5H), 5.72 (d, 1H, J¼7.1 Hz), 5.08 (s, 2H),
4.46–4.38 (s, 2H), 3.68 (s, 3H), 3.60–3.47 (m, 2H), 1.33 (d,
3H, J¼7.1 Hz); 13C NMR (90 MHz, CDCl3) d 202.0, 167.3,
155.8, 136.2, 128.5, 128.2, 128.0, 67.0, 55.8, 52.4, 45.5,
16.8. HRMS (MþNaþ) calcd for C14H17NO5Na 302.1004,
found 302.1008.
1
provided 106 mg (68%) of 10h as a colorless oil. H NMR
(360 MHz, CDCl3) d 7.38–7.14 (m, 10H), 5.38 (d, 1H,
J¼7.3 Hz), 5.08 (s, 2H), 4.64 (q, 1H, J¼6.6 Hz), 3.67 (s,
3H), 3.16 (dd (A of ABX), 1H, J¼6.4, 14.1 Hz), 2.99 (dd (B
of ABX), 1H, J¼6.9, 14.1 Hz), 2.81–2.74 (m, 2H), 2.60–
2.57 (m, 2H); 13C NMR (90 MHz, CDCl3) d 207.0, 173.0,
156.0, 136.2, 135.9, 129.2, 128.7, 128.5, 128.2, 128.1,
127.1, 66.9, 60.5, 51.8, 37.4, 35.1, 27.5. HRMS (MþNaþ)
calcd for C21H23NO5Na 392.1474, found 392.1477.
4.2.7. (6)-Methyl 4-(carboxybenzyl)-amino-3-oxo-4-
phenylbutanoate (9g). 45%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.38–7.26 (m, 10H), 6.14 (bs, 1H),
5.52 (m, 1H), 5.13–5.00 (AB, 2H), 3.66 (s, 3H), 3.51–3.32
(AB, 2H, J¼12.1 Hz); 13C NMR (90 MHz, CDCl3) d 197.7,
166.5, 155.2, 136.0, 135.3, 129.4, 129.4, 129.0, 128.5,
128.1, 128.1, 67.1, 64.6, 52.5, 45.7. HRMS (MþNaþ) calcd
for C19H19NO5Na 364.1155, found 364.1171.
4.2. Characterization data for Table 1
4.2.8. (6)-Methyl 4-(carboxybenzyl)-amino-3-oxo-5-
phenylpentanoate (9h). 71%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.39–7.23 (m, 8H), 7.15 (m, 2H),
5.35 (d, 1H, J¼7.7 Hz), 5.12 (s, 2H), 4.67 (dd, 1H, J¼7.0,
4.2.1. Methyl 4-(carboxy-t-butyl)-amino-3-oxo-butano-
1
ate (9a). 91%. Yellow oil. H NMR (360 MHz, CDCl3) d

C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
1525
13.8 Hz), 3.70 (s, 3H), 3.55–3.43 (AB, 2H, J¼16 Hz),
3.19–3.14 (AX, 1H, J¼6.1, 6.1 Hz), 3.04–2.98 (BX, 1H,
J¼7.1, 7.2 Hz); 13C NMR (90 MHz, CDCl3) d 201.6, 167.3,
155.8, 136.2, 135.8, 129.2, 128.8, 128.5, 128.2, 128.1,
127.2, 67.1, 60.8, 52.4, 46.7, 36.9. HRMS (MþNaþ) calcd
for C20H21NO5Na 378.1312, found 378.1305.
4.2.15. (6)-Methyl 4-(carboxy-9-fluorenylmethyl)-
amino-3-oxo-4-phenylbutanoate (9o). 85%. White solid;
mp 139–1428C. H NMR (360 MHz, CDCl3) d 7.77–7.75
(m, 2H), 7.58–7.56 (m, 2H), 7.42–7.26 (m, 9H), 6.16 (d,
1H, J¼5.7 Hz), 5.54 (d, 1H, J¼6.3 Hz), 4.42–4.30 (m, 2H),
4.21–4.18 (m, 1H), 3.68 (s, 3H), 3.44 (AB, 2H, J¼15.7 Hz);
13C NMR (90 MHz, CDCl3) d 197.8, 166.4, 155.2, 143.8,
141.2, 135.3, 129.4, 129.1, 128.1, 127.7, 127.0, 125.0,
119.9, 67.1, 64.6, 52.5, 47.1, 45.7. HRMS (MþNaþ) calcd
for C26H23NO5Na 452.1474, found 452.1479.
1
4.2.9. Methyl 4-(N-benzoyl)-amino-3-oxo-butanoate (9i).
65%. White solid; mp 83–868C. 1H NMR (360 MHz,
CDCl3) d 7.83 (m, 2H), 7.55–7.43 (m, 3H), 6.93 (bs, 1H),
4.47 (d, 2H, J¼4.7 Hz), 3.76 (s, 3H), 3.59 (2, 2H); 13C NMR
(90 MHz, CDCl3) d 198.1, 167.3, 166.9, 133.5, 131.9,
128.6, 127.1, 56.2, 49.9, 46.5. HRMS (MþHþ) calcd for
C12H14NO4 236.0923, found 236.0919.
4.2.16. (6)-Methyl 4-(carboxy-9-fluorenylmethyl)-
amino-3-oxo-5-phenylpentanoate (9p). 67%. White
1
solid; mp 75–788C. H NMR (360 MHz, CDCl3) d 7.78
(m, 2H), 7.55 (m, 2H), 7.42 (m, 2H), 7.31–7.24 (m, 5H),
7.16 (m, 2H), 5.48 (d, 1H, J¼7.81 Hz), 4.67 (dt, 1H, J¼7.6,
7.8 Hz), 4.46–4.38 (m, 2H), 4.20–4.15 (m, 1H), 3.71 (s,
3H), 3.49 (AB, 2H, J¼16 Hz), 3.19 (A of AB, 1H, J¼6.0,
14.0 Hz), 3.00 (B of AB, 1H, J¼7.5, 14.0 Hz); 13C NMR
(90 MHz, CDCl3) d 201.4, 167.2, 155.8, 143.7, 141.3,
135.9, 129.3, 128.8, 127.8, 127.2, 127.1, 125.0, 120.0, 66.9,
60.8, 52.5, 47.2, 46.6, 36.7. HRMS (MþNaþ) calcd for
C27H25NO5Na 466.1625, found 466.1617.
4.2.10. (6)-Methyl 4-(N-benzoyl)-amino-3-oxo-pentano-
ate (9j). 47%. Colorless oil. 1H NMR (360 MHz, CDCl3) d
7.80–7.76 (m, 2H), 7.52–7.38 (m, 3H), 7.11 (d, 1H,
J¼6.5 Hz), 4.85 (dt, 1H, J¼7.1, 14.2 Hz), 3.70 (s, 3H), 3.63
(AB, 2H, J¼15.9 Hz), 1.41 (d, 3H, J¼7.3 Hz); 13C NMR
(90 MHz, CDCl3) d 201.9, 167.3, 166.9, 133.5, 131.8,
128.6, 127.0, 54.7, 52.5, 45.7, 16.8. HRMS (MþHþ) calcd
for C13H16NO4 250.1079, found 250.1081.
4.2.11. (6)-Methyl 4-(N-benzoyl)-amino-3-oxo-4-phenyl-
1
butanoate (9k). 28%. Colorless oil. H NMR (360 MHz,
4.2.17. Methyl 5-(carboxy-t-butyl)-amino-4-oxo-pen-
tanoate (10a). Reaction time 5 min. 25%. Colorless oil.
1H NMR (360 MHz, CDCl3) d 4.06 (m, 1H), 3.67 (s, 3H),
2.74–2.62 (m, 4H), 1.43 (s, 9H); 13C NMR (90 MHz,
CDCl3) d 204.2, 172.8, 155.6, 79.8, 51.8, 50.2, 34.3, 28.2,
27.5. HRMS (MþNaþ) calcd for C11H19NO5Na 268.1161,
found 268.1165.
CDCl3) d 7.81 (m, 1H), 7.52–7.33 (m, 10H), 5.90 (d, 1H,
J¼6.1 Hz), 3.67 (s, 3H), 3.52 (AB, 2H, J¼15.4 Hz); 13C
NMR (90 MHz, CDCl3) d 198.3, 166.5, 166.3, 135.3, 133.5,
131.8, 129.4, 129.0, 128.5, 128.3, 127.1, 63.5, 52.5, 45.9.
HRMS (MþHþ) calcd for C18H18NO4 334.1046, found
334.1050.
4.2.18. (6)-Methyl 5-(carboxy-t-butyl)-amino-4-oxo-
1
hexanoate (10b). 48%. Colorless oil. H NMR (360 MHz,
4.2.12. (6)-Methyl 4-(N-benzoyl)-amino-3-oxo-5-phenyl-
1
pentanoate (9l). 74%. Colorless oil. H NMR (360 MHz,
CDCl3) d 5.21 (bs, 1H), 4.34 (dt, 1H, J¼6.2, 6.2 Hz), 3.68
(s, 3H), 2.91–2.56 (m, 4H), 1.44 (s, 9H), 1.36 (d, 3H,
J¼6.2 Hz); 13C NMR (90 MHz, CDCl3) d 207.8, 173.2,
155.1, 79.9, 55.0, 51.8. 33.6, 28.3, 27.5, 17.7. HRMS
(MþNaþ) calcd for C12H21NO5Na 282.1317, found
282.1312.
CDCl3) d 7.69 (m, 2H), 7.51 (m, 1H), 7.39 (m, 2H), 7.32–
7.19 (m, 5H), 6.87 (d, 1H, J¼7.2 Hz), 5.10 (dt, 1H, J¼6.9,
7.2 Hz), 3.69 (s, 3H), 3.56 (AB, 2H, J¼15.9 Hz), 3.21
(ABX, 2H, J¼6.4, 14.1 Hz); 13C NMR (90 MHz, CDCl3) d
201.2, 167.2, 167.1, 135.8, 133.4, 131.9, 129.2, 128.8,
128.6, 127.2, 127.0, 59.6, 52.4, 46.8, 36.6. HRMS
(MþNaþ) calcd for C19H19NO4Na 348.1206, found
348.1211.
4.2.19. (6)-Methyl 5-(carboxy-t-butyl)-amino-4-oxo-5-
phenylpentanoate (10c). 57%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.40–7.30 (m, 5H), 5.86 (bs, 1H), 5.33
(d, 1H, J¼5.4 Hz), 3.65 (s, 3H), 2.81–2.46 (m, 4H), 1.40 (s,
9H); 13C NMR (90 MHz, CDCl3) d 204.3, 172.6, 154.8,
136.8, 129.1, 128.5, 127.8, 79.9, 64.1, 51.8, 34.3, 28.2, 27.6.
HRMS (MþNaþ) calcd for C17H23NO5Na 322.1648, found
322.1655.
4.2.13. Methyl 4-(carboxy-9-fluorenylmethyl)-amino-3-
oxo-butanoate (9m). 65%. White solid; mp 115–1178C.
1H NMR (360 MHz, CDCl3) d 7.77 (m, 2H), 7.59 (m,
2H), 7.42–7.29 (m, 4H), 5.63 (m, 1H), 4.44 (m, 2H),
4.21 (m, 3H), 3.73 (s, 3H), 3.49 (s, 2H); 13C NMR
(90 MHz, CDCl3) d 198.3, 167.1, 156.2, 143.7, 141.3,
127.7, 127.1, 125.0, 120.0, 67.1, 52.6, 50.8, 47.1, 46.2.
HRMS (MþNaþ) calcd for C20H19NO5Na 376.1161, found
376.1153.
4.2.20. (6)-Methyl 5-(carboxy-t-butyl)-amino-4-oxo-6-
phenylhexanoate (10d). 49%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.33–7.25 (m, 4H), 7.19 (m, 1H), 5.05
(bs, 1H), 4.54 (m, 1H), 3.68 (s, 3H), 3.16–3.10 (AX, 1H,
J¼7.1, 14.0 Hz), 2.98–2.93 (BX, 1H, J¼7.0, 13.9 Hz),
2.78–2.69 (m, 2H), 2.60–2.56 (m, 2H), 1.40 (s, 9H); 13C
NMR (90 MHz, CDCl3) d 207.4, 172.9, 155.1, 136.2, 129.2,
128.6, 126.9, 80.0, 60.1, 51.8, 37.5, 35.1, 28.2, 27.5. HRMS
(MþNaþ) calcd for C18H25NO5Na 358.1625, found
358.1635.
4.2.14. (6)-Methyl 4-(carboxy-9-fluorenylmethyl)-
amino-3-oxo-pentanoate (9n). 76%. White solid; mp
1
105–1078C. H NMR (360 MHz, CDCl3) d 7.77 (m, 2H),
7.59 (m, 2H), 7.42–7.29 (m, 4H), 5.52 (bs, 1H), 4.48–4.38
(m, 3H), 4.23–4.19 (m, 1H), 3.73 (s, 3H), 3.55 (m, 2H), 1.39
(d, 3H, J¼7.0 Hz); 13C NMR (90 MHz, CDCl3) d 202.1,
167.0, 155.8, 143.7, 141.3, 127.7, 127.1, 125.0, 120.0, 66.9,
55.8, 52.5, 47.1, 45.5, 17.0. HRMS (MþNaþ) calcd for
C21H21NO5Na 390.1317, found 390.1314.
4.2.21. Methyl 5-(carboxybenzyl)-amino-4-oxo-pentano-
ate (10e). 60%. Colorless oil. 1H NMR (360 MHz, CDCl3) d

1526
C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
7.36–7.30 (m, 5H), 5.46 (bs, 1H), 5.12 (s, 2H), 4.16 (m,
2H), 3.68 (s, 3H), 2.75–2.68 (m, 4H); 13C NMR (90 MHz,
CDCl3) d 203.7, 172.8, 156.1, 136.2, 128.5, 128.1, 128.0,
67.0, 51.9, 50.6, 40.2, 34.3, 27.5. HRMS (MþHþ) calcd for
C14H18NO5 280.1185, found 280.1180.
CDCl3) d 7.72 (m, 2H), 7.51–7.20 (m, 8H), 6.77 (d, 1H,
J¼6.8 Hz), 5.07 (dt, 1H, J¼6.6, 6.6 Hz), 3.68 (s, 3H), 3.23
(ABX, 2H, J¼6.7, 14.1 Hz), 2.83 (m, 2H), 2.62 (m, 2H); 13C
NMR (90 MHz, CDCl3) d 206.8, 173.2, 166.8, 136.0, 133.9,
131.8, 129.3, 128.7, 128.6, 127.1, 126.9, 59.3, 51.9, 37.2,
35.2, 27.6. HRMS (MþNaþ) calcd for C20H21NO4Na
362.1363, found 362.1364.
4.2.22. (6)-Methyl 5-(carboxybenzyl)-amino-4-oxo-hex-
anoate (10f). 60%. Colorless oil. 1H NMR (360 MHz,
CDCl3) d 7.41–7.30 (m, 5H), 5.51 (bs, 1H), 5.11 (s, 2H),
4.43 (dq, 1H, J¼7.1 Hz), 3.68 (s, 3H), 2.94–2.59 (m, 4H),
1.41 (d, 3H, J¼7.1 Hz); 13C NMR (90 MHz, CDCl3) d
207.6, 172.9, 155.7, 136.1, 128.5, 128.1, 128.0, 66.9, 55.5,
51.8, 33.7, 28.7, 27.5, 17.6. HRMS (MþHþ) calcd for
C15H20NO5 294.1341, found 294.134147.
4.2.29. Methyl 5-(carboxy-9-fluorenylmethyl)-amino-4-
oxo-pentanoate (10m). 55%. White solid; mp 65–688C. 1H
NMR (360 MHz, CDCl3) d 7.75 (m, 2H), 7.60 (m, 2H),
7.42–7.29 (m, 4H), 5.56 (bs, 1H), 4.40 (m, 2H), 4.27 (m,
1H), 4.15 (m, 2H), 3.68 (s, 3H), 2.73–2.66 (m, 4H); 13C
NMR (90 MHz, CDCl3) d 204.0, 172.8, 156.2, 143.9, 141.3,
127.7, 127.0, 125.1, 119.9, 67.1, 52.2, 50.6, 47.1, 34.3, 27.5.
HRMS (MþHþ) calcd for C21H22NO5 368.1498, found
368.1497.
4.2.23. (6)-Methyl 5-(carboxybenzyl)-amino-4-oxo-5-
phenylpentanoate (10g). 48%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.40–7.33 (m, 10H), 6.16 (bs, 1H),
5.39 (d, 1H, J¼6.1 Hz), 5.05 (AB, 2H, J¼12.2 Hz), 3.67 (s,
3H), 2.73–2.51 (m, 4H); 13C NMR (90 MHz, CDCl3) d
204.0, 172.5, 155.5, 136.5, 136.2, 133.1, 129.2, 128.7,
128.5, 128.1, 127.9, 66.9, 64.5, 51.8, 34.3, 27.6. HRMS
(MþHþ) calcd for C20H21NO5 356.1492, found 356.1491.
4.2.30. (6)-Methyl 5-(carboxy-9-fluorenylmethyl)-
amino-4-oxo-hexanoate (10n). 57%. White solid; mp
1
95–978C. H NMR (360 MHz, CDCl3) d 7.77 (m, 2H),
7.60 (m, 2H), 7.42–7.30 (m, 4H), 5.56 (bs, 1H), 4.45–4.35
(m, 3H), 4.22 (m, 1H), 3.68 (s, 3H), 2.92–2.59 (m, 4H), 1.42
(d, 3H, J¼7.1 Hz); 13C NMR (90 MHz, CDCl3) d 207.7,
173.0, 155.8, 144.0, 141.3, 127.7, 127.0, 125.0, 120.0, 66.8,
55.5, 51.9, 47.1, 33.7, 27.5, 17.8. HRMS (MþHþ) calcd for
C22H24NO5 382.1654, found 382.1661.
4.2.24. (6)-Methyl 5-(carboxybenzyl)-amino-4-oxo-6-
phenylhexanoate (10h). 68%. Colorless oil. 1H NMR
(360 MHz, CDCl3) d 7.38–7.14 (m, 10H), 5.38 (d, 1H,
J¼7.3 Hz), 5.08 (s, 2H), 4.64 (q, 1H, J¼6.6 Hz), 3.67 (s,
3H), 3.16 (dd (A of AB), 1H, J¼6.4, 14.1 Hz), 2.99 (dd (B
of AB), 1H, J¼6.9, 14.1 Hz), 2.81–2.74 (m, 2H), 2.60–2.57
(m, 2H); 13C NMR (90 MHz, CDCl3) d 207.0, 173.0, 156.0,
136.2, 135.9, 129.2, 128.7, 128.5, 128.2, 128.1, 127.1, 66.9,
60.5, 51.8, 37.4, 35.1, 27.5. HRMS (MþNaþ) calcd for
C21H23NO5Na 392.1468, found 392.1472.
4.2.31. (6)-Methyl 5-(carboxy-9-fluorenylmethyl)-
amino-4-oxo-5-phenylpentanoate (10o). 63%. White
1
solid; mp 110–1158C. H NMR (360 MHz, CDCl3) d 7.76
(m, 2H), 7.56 (m, 2H), 7.41–7.21 (m, 9H), 6.21 (m, 1H),
5.41 (m, 1H), 4.40–4.29 (m, 2H), 4.21–4.17 (m, 1H), 3.64
(s, 3H), 2.81–2.48 (m, 4H); 13C NMR (90 MHz, CDCl3) d
204.0, 172.5, 155.8, 143.8, 141.2, 136.3, 129.3, 128.8,
127.9, 127.6, 127.0, 125.0, 119.9, 67.0, 64.5, 51.9, 47.1,
34.3, 27.2. HRMS (MþHþ) calcd for C27H26NO5 444.1811,
found 444.1815.
4.2.25. Methyl 5-(N-benzoyl)-amino-4-oxo-pentanoate
1
(10i). 58%. Colorless oil. H NMR (360 MHz, CDCl3) d
7.83–7.75 (m, 2H), 7.55–7.41 (m, 3H), 6.93 (bs, 1H), 4.42
(d, 2H, J¼4.5 Hz), 3.70 (s, 3H), 2.88–2.70 (m, 4H); 13C
NMR (90 MHz, CDCl3) d 203.9, 172.8, 167.2, 133.7, 131.7,
128.6, 127.0, 51.9, 49.6, 34.6, 27.6. HRMS (MþNaþ) calcd
for C13H15NO4Na 272.0899, found 272.0907.
4.2.32. (6)-Methyl 5-(carboxy-9-fluorenylmethyl)-
amino-4-oxo-6-phenylhexanoate (10p). 68%. White
1
solid; mp 108–1108C. H NMR (360 MHz, CDCl3) d 7.78
(m, 2H), 7.55 (m, 2H), 7.42 (m, 2H), 7.31–7.24 (m, 5H),
7.16 (m, 2H), 5.48 (d, 1H, J¼7.81 Hz), 4.67 (dt, 1H, J¼7.6,
7.8 Hz), 4.43–4.33 (m, 2H), 4.21–4.17 (m, 1H), 3.68 (s,
3H), 3.19 (A of AB, 1H, J¼6.0, 14.0 Hz), 3.00 (B of AB,
1H, J¼7.5, 14.0 Hz), 2.79–2.74 (m, 2H), 2.64–2.60 (M,
2H); 13C NMR (90 MHz, CDCl3) d 206.8, 173.0, 155.8,
143.7, 141.3, 136.0, 129.2, 128.7, 127.7, 127.1, 127.0,
125.0, 120.0, 66.9, 60.5, 51.9, 47.1, 37.3, 35.0, 27.5. HRMS
(MþHþ) calcd for C28H28NO5 458.1962, found 458.1938.
4.2.26. (6)-Methyl 5-(N-benzoyl)-amino-4-oxo-hexano-
ate (10j). 58%. Colorless oil. 1H NMR (360 MHz, CDCl3) d
7.82–7.79 (m, 2H), 7.53–7.42 (m, 3H), 7.02 (d, 1H,
J¼6.3 Hz), 4.85 (dq, 1H, J¼7.0, 7.0 Hz), 3.68 (s, 3H),
3.01–2.61 (m, 4H), 1.52 (d, 3H, J¼7.1 Hz); 13C NMR
(90 MHz, CDCl3) d 207.9, 173.0, 166.6, 134.0, 131.7,
128.5, 127.0, 54.4, 51.9, 33.8, 27.6, 17.6. HRMS (MþNaþ)
calcd for C14H17NO4Na 286.1055, found 286.1049.
4.2.27. (6)-Methyl 5-(N-benzoyl)-amino-4-oxo-5-phenyl-
pentanoate (10k). 43%. Colorless oil. 1H NMR (360 MHz,
CDCl3) d 7.81 (m, 1H), 7.55–7.33 (m, 9H), 5.79 (d, 1H,
J¼6.1 Hz), 3.65 (s, 3H), 2.90–2.50 (m, 4H); 13C NMR
(90 MHz, CDCl3) d 204.6, 172.8, 166.5, 136.5, 133.9,
131.7, 129.3, 128.7, 128.5, 128.1, 127.1, 63.3, 52.0, 34.5,
27.7. HRMS (MþNaþ) calcd for C19H19NO4Na 348.1206,
found 348.1199.
4.3. Scheme 3 experimentals
4.3.1. Phenylmethyl (4S)-4-(carboxy-t-butyl)-amino-3-
oxo-pentanoate (11). Boc-L-alanine 8b (176 mg,
0.93 mmol) was dissolved in 10 mL anhydrous THF in a
25 mL round-bottomed flask and 154 mg (0.95 mmol) CDI
added while stirring. After being allowed to stir for 15 min,
the acyl imidazole was transferred to a 100 mL flask
containing a solution of monobenzyl malonate (722 mg,
3.72 mmol) in 30 mL anhydrous THF to which 1.86 mL
(1.86 mmol) of a 1 M solution of dibutylmagnesium was
4.2.28. (6)-Methyl 5-(N-benzoyl)-amino-4-oxo-6-phenyl-
1
hexanoate (10l). 58%. Colorless oil. H NMR (360 MHz,

C. R. Theberge, C. K. Zercher / Tetrahedron 59 (2003) 1521–1527
1527
1
added at 08C and warmed to room temperature (solution is
colorless and clear). The reaction was monitored by TLC
and stirred for 24 h before quenching in 30 mL sat. aq.
NH4Cl solution and extracting three times with 20 mL
Et2O. The combined organics were dried with MgSO4 and
concentrated before chromatographing on silica with 15%
EtOAc in hexanes to yield 208 mg (70%) 11 as a colorless
oil. 1H NMR (360 MHz, CDCl3) d 7.38–7.31 (m, 5H), 5.18
(s, 2H), 5.08 (s, 1H), 4.36 (m, 1H), 3.66–3.56 (m, 2H), 1.44
(s, 9H), 1.33 (d, 3H, J¼7.1 Hz); 13C NMR (90 MHz,
CDCl3) d 202.4, 166.4, 155.5, 135.0, 128.6, 128.4, 128.3,
79.8, 67.2, 55.4, 45.7, 28.2, 16.8. HRMS (MþNaþ) calcd
for C17H23NO5 344.1468, found 344.1464.
89–908C. H NMR (360 MHz, CDCl3) d 7.31–7.21 (m,
3H), 7.11–7.09 (m, 2H), 6.12 (d, 1H, J¼6.4 Hz), 5.25 (m
1H), 4.83 (q, 1H, J¼5.8 Hz), 4.29 (m, 1H), 3.70 (s, 3H),
3.14–3.00 (m, 2H), 2.91–2.71 (m, 2H), 2.50–2.41 (m, 2H),
1.43 (s, 9H), 1.32 (d, 3H, J¼7.16 Hz); 13C NMR (90 MHz,
CDCl3) d 208.5, 171.9, 171.0, 155.0, 135.8, 129.2, 128.5,
127.1, 79.9, 55.0, 53.1, 52.2, 37.8, 33.8, 29.4, 28.3, 17.6.
HRMS (MþNaþ) calcd for C21H30N2O6Na 429.1996,
found 429.2010.
Acknowledgements
This research was funded by a grant from the National
Institutes of Health (GM60967-01). C. R. T. acknowledges
pre-doctoral support from Merck Pharmaceutical Research.
Charles W. Ross, III, with Merck Pharmaceutical Research,
provided HRMS data.
4.3.2. Phenylmethyl (5S)-5-(carboxy-t-butyl)-amino-4-
oxo-hexanoate (12). A 50 mL round-bottomed flask was
charged with 30 mL anhydrous CH2Cl2 and 375 mL
(4.67 mmol) methylene iodide. The solution was cooled to
08C and 3.11 mL (3.11 mmol) of a 1 M solution of
diethylzinc in hexanes was slowly added. The ice bath
was removed and a white precipitate formed rapidly. After
stirring 2 min, 200 mg (0.62 mmol) of 11 dissolved in 5 mL
CH2Cl2 was added and the reaction was monitored by TLC.
The product spot appeared at a slightly higher Rf than
starting material and was best visualized by staining the
TLC plates with anisaldehyde. The reaction was complete
after 30 min and was washed with 25 mL sat. aq. NH4Cl
solution before drying with MgSO4 and concentrating. Flash
chromatography on silica using 15% EtOAc in hexane
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1
yields 164 mg (79%) of 12 as a colorless oil. H NMR
(360 MHz, CDCl3) d 7.39–7.29 (m, 5H), 5.18 (m, 1H), 5.11
(s, 2H), 4.33 (m, 1H), 2.92–2.62 (m, 4H), 1.44 (s, 9H), 1.33
(d, 3H, J¼7.1 Hz); 13C NMR (90 MHz, CDCl3) d 207.9,
172.3, 155.5, 135.7, 128.5, 128.3, 128.2, 79.8, 66.5, 55.0,
33.6, 28.3, 27.8, 17.6. HRMS (MþNaþ) calcd for
C18H25NO5Na 358.1625, found 358.1599.
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(carboxy-t-butyl)-amino-4-oxo-hexanoamide (14). Into a
10 mL round-bottomed flask containing 90 mg (0.26 mmol)
12 dissolved in 4 mL abs. EtOH was added 30 mg 10%
Pd(C). The reaction vessel was stoppered and thoroughly
flushed with nitrogen. The vessel was charged with
hydrogen and the solution stirred for 10 min. After checking
by TLC to ensure starting material was consumed, then
reaction was filtered and concentrated to give 65 mg (99%)
of a white crystalline solid. The dry solid was dissolved in
4 mL anhydrous DMF and to this solution was added 53 mg
(0.27 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (EDC), 37 mg (0.27 mmol) 1-hydro-
xybenzotriazole hydrate (HOBt), 60 mg (0.27 mmol)
L-phenylalanine methyl ester hydrochloride, and 37 ml
(0.27 mmol) triethylamine. The reaction was stirred over-
night and then 10 mL sat. aq. NH4Cl solution was added and
the reaction was extracted with 2£20 mL EtOAc. The
organic portion was washed with 15 mL sat. NaHCO3 and
2£15 mL H2O before drying with MgSO4 and concentrat-
ing. Flash chromatography on silica using 40% EtOAc in
hexanes yielded 99 mg (89%) 14 as a white solid; mp
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