Enantiopure synthesis of side chain-modified α-amino acids and 5-cis-alkylprolines

Article abstract of DOI:10.1021/jo300653u

A short, concise synthesis of enantiopure, side chain-modified α-amino acids such as 4-oxo-l-norvaline, 6-oxo-l-homonorleucine, and 5-cis-alkyl prolines is described. Knoevenagel condensation of l-aminocarboxylate-derived β-ketoesters with aldehydes followed by reductive decarboxylation results in unnatural α-amino acids in good yield. A fluorescent amino acid is synthesized using a similar protocol. These studies show that aminocarboxylate-derived β-ketoesters are very useful intermediates and the method employed is both general and practical for the preparation of γ(δ)-oxo α-amino acids and alkylprolines.

Full text of DOI:10.1021/jo300653u

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Note
Enantiopure Synthesis of Side Chain Modified
alpha-Amino Acids and 5-cis-Alkyl Prolines
Amar Mohite, and Ramakrishna G. Bhat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300653u • Publication Date (Web): 22 May 2012
Downloaded from http://pubs.acs.org on May 23, 2012
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Graphical Abstract
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Enantiopure Synthesis of Side Chain-Modified -Amino Acids and 5-cis-Alkylprolines
Amar Mohite and Ramakrishna G. Bhat*
Department of Chemistry, Mendeleev Block, Indian Institute of Science Education and Research (IISER), Pune
Maharashtra, India, 411008,
rgb@iiserpune.ac.in
O
BocHN
O
OBn
n
O
O
O
O
BocHN
O
BocHN
O
n = 1,2
O
O
O
R
N
Boc
O
A short, concise synthesis of enantiopure, side chain-modified -amino acids such as 4-oxo-L-
norvaline, 6-oxo-L-homonorleucine, 5-cis-alkyl prolines is described. Knoevenagel
condensation of L-aminocarboxylate-derived -ketoesters with aldehydes followed by reductive
decarboxylation results in unnatural -amino acids in good yield. A fluorescent amino acid is
synthesized using a similar protocol. These studies show that aminocarboxylate-derived -
ketoesters are very useful intermediates and the method employed is both general and practical
for the preparation of ()-oxo -amino acids and alkylprolines.
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Naturally occurring and chemically synthesized non-natural amino acids are gaining significance
as useful and important tools for modern drug discovery research. Unnatural amino acids are
used as chiral building blocks and molecular scaffolds for constructing molecular libraries due to
their structural diversity and functional versatility. Some of these unnatural amino acids play a
vital role in pharmaceuticals and lead development in drug discovery. Non-genetically coded
amino acids, particularly non-natural α-amino acids, have contributed strongly in the area of
peptide research. These amino acids play a significant role in peptide analogs to limit
conformational flexibility, to enhance enzymatic stability, and to improve pharmacodynamics
and bioavailability.1-5 Side chain conformational restrictions deliver a practical approach in
peptidomimetics to understand the interactions of peptides with proteins, nucleic acids,
lipids, and sugars in biological systems.6
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Since reactions utilizing these modified α-amino acids as organocatalysts7,8 and/or scaffolds for
building of peptidomimetics9 are gaining importance, there is a need to synthesize such scaffolds
in a novel way. For this reason, syntheses and use of some unnatural α-amino acids have been
reported using different protocols.10
Herein, we wish to report a general, convenient and concise synthesis of enantiopure side
chain-modified amino acids and cis-5-alkylproline derivatives in good yields.
Coupling of N-Boc-L-aspartic acid 1-methyl ester11 4 with Meldrum’s acid in the
presence of DCC and DMAP gave the corresponding acyl Meldrum’s acid as an intermediate.
Subsequent treatment with benzyl alcohol afforded -keto ester 7 in 61% yield using a procedure
reported for similar compounds.12 We then considered its use in syntheses of very useful keto-
amino acids such as protected 4-oxo-L-norvaline 1. Hydrogenolysis of 7 using Pd/C and
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triethylsilane smoothly gave the corresponding protected 4-oxo-L-norvaline 1 in 89% yield
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(Scheme 1).
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OBn
O
OH
O
( )
O
n
O
( )
n
( )
n
OMe
OMe
OMe
BocHN
BocHN
BocHN
a
b
O
O
O
4: n = 1
5: n = 2
: n = 3
7:n = 1
:n = 2
:n = 3
1:n = 1
2:n = 2 (Not formed)
8
9
6
3
:n = 3
Scheme 1. Reagents and conditions: (a) Meldrum's acid, DMAP, DCC, CH2Cl2 then BnOH, benzene,
80 oC, 53-63% (b) Pd/C, triethylsilane, MeOH, r.t. 83-89%.
Similarly, N-Boc-6-oxo-L-homonorleucine methyl ester 3 was prepared from, N-Boc-L-
homoglutamic acid 1-methyl ester 6 in one pot in 83% yield (Scheme 1).13 An earlier synthesis
of a protected L-homonorleucine (6-oxo -amino acid) involved the reaction of the acid chloride
with a zinc reagent from iodoalanine, itself was derived from serine in four steps.14 A different
route to protected L-homonorleucine involved olefin metathesis of protected allyl glycine.15 The
method we have employed for the preparation of 1 and 3 promises to be general and high
yielding for the preparation of oxo -amino acids.
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O
O
OMe
N
.
N
BocHN
a
H
b
OMe
OMe
Boc
TFA
8
10
11
Scheme 2. Reagents and conditions: (a) Pd/C, triethylsilane, MeOH, r.t., 79%; b) TFA, CH2Cl2, 1.5 h
98%.
While the L-glutamic acid derived -keto ester 8 did not give the anticipated protected 5-oxo-L-
norleucine 2 on treatment with Pd/C and triethylsilane, instead we obtained 5-methyl-N-Boc-L-
proline methyl ester 10 exclusively in 79% yield, which on treatment with trifluoroacetic acid
gave 5-methylproline methyl ester 11 (Scheme 2).
Spectroscopic data for compound 1 were in a close agreement with reported values.16 In
order to ascertain the enantiopurity of the N-Boc 4-oxo-L-norvaline methyl ester 1, its
enantiomer N-Boc 4-oxo-D-norvaline methyl ester 1a and the racemic mixture N-Boc 4-oxo-DL-
norvaline methyl ester 1b were synthesized.17 HPLC18 showed that compound 1 was indeed
optically pure and, importantly, no trace of racemization could be detected in the preparation of 1
from N-Boc-L-aspartic acid 1-methyl ester 4. Earlier, protected 4-oxo-L-norvaline has been
prepared via reduction of 5-diazo-4-oxo-L-norvaline,19 by ozonolysis of 4,5-dehydroleucine
10b,c,20
from serine,
by insertion of diazoalkyl into aldehyde derived from homoserine using
diazomethane,10d and by alkylation using strong base such as LiHMDS.21
The optical and spectroscopic data of compound 10 were in a close agreement with
reported data.22 The cis-stereochemistry of 11 was unambiguously assigned by nOe studies.23
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It is important to note that we synthesized cis-N-Boc-5-methylproline methyl ester 10 in one pot
from N-Boc-L-glutamic acid -ketoester 8 under relatively mild conditions in contrast to the
harsh conditions and longer route used earlier.22 It is also interesting that the Boc-protected
amine reacts with a -ketoester which is expected to exist largely in the enol form. A plausible
mechanism involves -keto decarboxylation24 of compound 8 under hydrogenolytic conditions
(Pd/C, TES)25 giving rise to keto intermediate 2, which then cyclises to 10 via enamine
intermediate III (Scheme 3).
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O
O
O
O
Pd/C,
TES
O
N
O
MeOH
O
O
O
O
O
N
H
Pd/C,
TES
10
8
Pd/C,
TES
O
O
OH
H
O
O
O
H2O
CO2
N
O
O
O
O
O
O
O
O
N
H
O
O
O
N
O
N
H
O
H
O
O
I
2
III
II
Scheme 3: Plausible mechanism for the formation of 10
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Brimble26a and Sutherland26b have reported the formation of a similar six-membered enamine
intermediate in their syntheses of pipecolic acid derivatives by intramolecular condensation of
homoglutamic acid -semialdehyde with a protected amine.
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The synthetic strategy that we employed for the synthesis of 1, 3 and 11 is short and practical
and also avoids the use of explosive hazards, such as diazomethane and ozonolysis, and the use
of expensive starting materials.
Encouraged by this initial success, we next employed a related strategy to synthesize
additional keto amino acids based on aspartic and glutamic acids (Scheme 4).
Ar
Ar
( )
OBn
O
OBn
O
O
( )
n
O
O
( )
n
OMe
n
OMe
BocHN
OMe
BocHN
a
BocHN
b
O
O
O
12
13
7: n= 1
: n= 1; Ar = Ph
: n= 1; Ar = p-tBu-C6H5
16
: n= 1; Ar = Ph
17: n= 1; Ar = p-tBu-C6H5
8
: n= 2
14: n= 2; Ar = Ph
15
18: n= 2; Ar = Ph
19
: n= 1; Ar = Pyrene
: n= 1; Ar = Pyrene
Scheme 4. Reagents and conditions: (a) ArCHO, condensation 69‐77% (b) Pd/C, triethylsilane,
MeOH,
r.t., 54‐77%.
We earlier reported the use of aminocarboxylate-derived -ketoesters in the synthesis of
piperidine derivatives.27 We now planned to use aminodicarboxylate-derived -ketoesters 7 and
8 for Knoevenagel condensation with aldehydes to synthesize various keto-amino acids. -
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ketoesters 7 and 8 condense with aldehydes to give the corresponding unsaturated -ketoesters
12-14. These on treatment with Pd/C and triethylsilane gave the novel keto -amino acids 16-18
(Scheme 4).
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Interestingly, although compound 18 on subjection to hydrogenolytic conditions did not give the
corresponding proline derivative, treatment with B(C6F5)3 and triphenylsilane did give compound
20 in 82% yield (Scheme 5).
O
Ph
Ph
Ph
O
O
x
a
N
N
b
OMe
OMe
OMe
BocHN
Boc
Boc
O
20
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18
Scheme 5: (a) Pd/C, triethylsilane, MeOH, r.t.; (b) B(C6F5)3, triphenylsilane, -78 oC to r.t., 82%.
Fluorescent amino acids are widely applied as labels in biology and medicine and are also
valuable in combinatorial chemistry and chemical biology. Thus, attention has been directed to
the design and development of non-natural -amino acids that have a fluorophore in their side
chain.28 We therefore embarked on the synthesis of the pyrene-derived fluorescent amino acid
19. Hydrogenolysis of 15 led to the formation of the desired compound 19 (Scheme 4). The
absorption and fluorescence properties of compound 19 in dichloromethane resemble those of
pyrene (Fig. 1).
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Fig.1 Normalized absorption (blue) and fluorescence (red) spectrum of 19
Using this protocol any fluorescent aldehyde may easily be condensed with aminodicarboxylate-
derived -ketoesters and series of different fluorescent non-natural amino acids can be
synthesized according to need. This result is encouraging because compound 19 and similar
fluorescent amino acids can be inserted into peptides to be excited at long wavelength without
excitation of tryptophan, tyrosine, or phenylalanine.
In summary, we have developed a general and efficient approach for the preparation of protected
)-keto -amino acids. In addition, a concise synthesis of a cis-5-methylproline derivative is
described. The protocol thus developed should be applicable to a wide variety of keto peptides
since the approach is general, useful, and simple. It has been especially exemplified by the
synthesis of new fluorescent -amino acid. The penultimate step affords protected unsaturated
-keto ester that has high potential for incorporation into peptides and proteins. Further work
investigating the synthesis of various solvatochromic fluorescent amino acids and their
application is underway.
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Experimental Section
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General: Unless otherwise noted, all reactions have been carried out with distilled and dried solvents
under an atmosphere of dry N2 and oven-dried glassware. All reagents were purchased from commercial
sources and used as received, unless otherwise indicated. Thin-layer chromatography (TLC) was
performed using silica gel 60 GF254 pre-coated aluminum backed plates (2.5 mm). 1H NMR and 13C NMR
1
were recorded in CDCl3 and MeOH-d4. Chemical shifts in H NMR spectra are reported as δ in units of
parts per million (ppm) downfield from tetramethylsilane with the solvent resonance as the internal
13
standard, J values are given in Hz. C NMR are reported as δ in ppm downfield from tetramethylsilane
13
and relative to the signal of chloroform-d and MeOH-d4. C-NMR spectra were recorded with complete
proton decoupling. Mass samples were analyzed by High-resolution mass spectrometry using ESI TOF
and MALDI TOF/TOF. FT-IR spectra were obtained using a FT-IR spectrophotometer as thin films on
sodium chloride or KBr discs and reported in cm-1. Optical rotations were measured on a polarimeter.
Enantioselectivities were determined by HPLC analysis and enantiomeric excess was determined using
Chiralpak IA column with n-hexane and 2-propanol as eluents.
(S)-3-(tert-butoxycarbonylamino)-4-methoxy-4-oxobutanoic acid (4):11
White solid (12.2g, 45% yield): mp = 88-90 °C; Rf = 0.2 DCM:MeOH (90:10); IR (KBr) cm-1: 3310,
1711, 1735; δH (400 MHz, CDCl3) 9.12 (bs, 1H), 5.55 (d, J = 8Hz, 1H), 4.59 (t, J = 4Hz, 1H), 3.75 (s,
3H), 3.08-3.03 (m, 1H), 2.89-2.84 (m, 1H), 1.44 (s, 9H); δC (100 MHz, CDCl3) 176.3, 171.6, 155.6, 80.6,
52.9, 49.8, 36.7, 28.4; []22 -19.2 (c 1, MeOH); HRMS (ESI TOF) m/z calcd for C10H17NO6Na [M +
D
Na]+ 270.0954 , found 270.0957
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(R)-3-(tert-butoxycarbonylamino)-4-methoxy-4-oxobutanoic acid (4a):11
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White solid (8.2g, 43% yield); mp = 88-99 °C; Rf = 0.2 DCM:MeOH (90:10); IR (Neat) cm-1 : 3300,
1705, 1740; δH (400 MHz, CDCl3) 9.1 (bs, 1H), 5.55 (d, J = 8Hz, 1H), 4.60 (quintet, J = 4Hz, 1H), 3.75
(s, 3H), 3.08-3.02 (m, 1H), 2.89-2.83 (m, 1H), 1.44 (s, 9H); δC (100 MHz, CDCl3) 176.3, 171.6, 155.6,
80.6, 52.9, 49.8, 36.7, 28.4; []23 + 18.3 (c 1, MeOH); HRMS (ESI TOF) m/z: calcd for C10H17NO6Na
D
[M + Na]+ 270.0954, found 270.0955
(RS)-3-(tert-butoxycarbonylamino)-4-methoxy-4-oxobutanoic acid (4b):11
White solid (4.3g, 44% yield): mp = 88 °C; Rf = 0.2 DCM:MeOH (90:10); IR (KBr) cm-1: 3318, 1713,
1739, 685; δH (400 MHz, CDCl3) 9.11 (bs, 1H), 5.55 (d, J = 8Hz, 1H), 4.59 (t, J = 4Hz, 1H), 3.75 (s,
3H), 3.08-3.03 (m, 1H), 2.89-2.83 (m, 1H), 1.42 (s, 9H); δC (100 MHz, CDCl3) 176.3, 171.6, 155.6, 80.6,
52.9, 49.7, 36.7, 28.4; HRMS (ESI TOF) m/z: calcd for C10H17NO6Na [M + Na]+ 270.0954 , found
270.0962.
(S)-6-Benzyl 1-methyl 2-((tert-butoxycarbonyl)amino)-4-oxohexanedioate (7):
To a well stirred mixture of (S)-3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanoic acid 4 (2.5g,
10 mmol), Meldrum’s acid (1.5g, 10 mmol), DMAP (1.6g, 13 mmol) in anhydrous dichloromethane (40
mL) at 0 °C was added portion-wise dicyclohexyl carbodiimide (DCC) (2.7g, 13 mmol) over 10 min at 0
°C. Then reaction mixture was allowed to warm to rt and stirred 5 h. The precipitate formed was removed
by filtration through sintered glass funnel. Filtrate was washed with aq 1M KHSO4 solution (2 x 70 mL)
then brine (2 x 75 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced
pressure. The yellowish residue was dissolved in dry benzene (30 mL), benzyl alcohol (1.5 mL, 13 mmol)
added, then refluxed 4 h and solvent was removed under reduced pressure to give crude product, purified
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by column chromatography over silica gel eluting with Pet.Ether:EtOAc (97:5 to 90:30) to give 7 as a
light yellow oil (2.3g, 63% yield). Rf = 0.4 Pet. Ether:EtOAc (50:50); IR (Neat) cm-1: 1739, 1711, 1156;
δH (400 MHz, CDCl3) 7.38-7.34 (m, 5H), 5.45 (d, J = 8 Hz, 1H), 5.17 (s, 2H), 4.52 (quintet, J = 4 Hz,
1H), 3.71 (s, 3H), 3.51 (s, 2H), 3.29-3.23 (m, 1H), 3.11-3.05 (m, 1H), 1.44 (s, 9H); δC (100 MHz, CDCl3)
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200.8, 171.6, 166.5, 155.6, 135.2, 128.8, 128.7, 128.6, 80.3, 67.5, 52.9, 49.5, 49.2, 45, 28.4; []25 -12.3
D
(c 0.33, MeOH); HRMS (ESI TOF) m/z: calcd for C19H25NO7Na [M + Na]+ 402.1529, found 402.1537.
(R)-6-Benzyl 1-methyl 2-((tert-butoxycarbonyl) amino)-4-oxohexanedioate (7a):
Compound 7a was prepared from (R)-3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanoic acid (D-
aspartic acid derivative) 4a, following the experimental procedure described for 7 above. Light yellow
oil (1.3g, 53 % yield). Rf = 0.4 Pet. Ether:EtOAc (50:50); IR (Neat) cm-1: 1742, 1721, 1150, 962; δH (400
MHz, CDCl3) 7.37-7.30 (m, 5H), 5.44 (d, J = 8 Hz, 1H), 5.15(s, 2H), 4.52 (quintet, J = 4 Hz, 1H), 3.68
(s, 3H), 3.49(s, 2H), 3.26-3.20 (m, 1H), 3.09-3.03 (m, 1H), 1.42 (s, 9H); δC (100 MHz, CDCl3) 200.8,
171.6, 166.5, 155.5, 135.2, 128.7, 128.6, 128.5, 80.3, 67.4, 52.8, 49.4, 49.1, 44.9, 28.4; []25 + 12.9 (c,
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MeOH); HRMS (ESI TOF) m/z: calcd for C19H25NO7Na [M +Na]+ 402.1529 , found 402.1525.
(RS)-6-Benzyl 1-methyl 2-((tert-butoxycarbonyl) amino)-4-oxohexanedioate (7b):
Compound 7b was prepared from racemic-(RS)-3-((tert-butoxycarbonyl)amino)-4-methoxy-4-
oxobutanoic acid (DL-aspartic acid derivative) 4b using a similar experimental procedure to that
described for 7.
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Light yellow oil (1.45g, 59% yield). Rf = 0.4 Pet. Ether:EtOAc (50:50); IR (Neat) cm-1: 1738, 1712, 1149;
δH (400 MHz, CDCl3) 7.38-7.33 (m, 5H), 5.46 (d, J = 8 Hz, 1H), 5.16 (s, 2H), 4.54 (quintet, J = 4 Hz,
1H), 3.69 (s, 3H), 3.50 (s, 2H), 3.27-3.22 (m, 1H), 3.10-3.04 (m, 1H), 1.43 (s, 9H); δC (100 MHz, CDCl3)
200.8, 171.6, 166.5, 155.6, 135.2, 128.8, 128.7, 128.5, 80.3, 67.4, 52.8, 49.4, 49.1, 45, 28.4; HRMS (ESI
TOF) m/z :calcd for C19H25NO7Na [M +Na]+ 402.1529 , found 402.1532
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(S)-7-Benzyl 1-methyl 2-((tert-butoxycarbonyl)amino)-5-oxoheptanedioate (8):
Experimental procedure similar as described for (7). Light yellow oil (1.7 g, 53% yield). Rf = 0.5 Pet.
Ether: EtOAc (50:50); IR (Neat) cm-1: 2960, 2874, 1723, 1456, 1285; δH (400 MHz, CDCl3): 7.37-7.34
(m, 5H), 5.17 (s, 2H), 5.08 (d, J = 8 Hz, 1H), 4.26 (d, J = 4 Hz, 1H), 3.72 (s, 3H), 3.50 (s, 2H), 2.72-2.56
(m, 2H), 2.18-2.13 (m, 1H), 1.92-1.83 (m, 1H), 1.43 (s, 9H); δC (100 MHz, CDCl3): 201.5, 172.8, 166.9,
155.6, 135.4, 128.8, 128.6, 128.5, 80.2, 67.3, 52.7, 52.6, 49.4, 38.9, 28.4, 26.2; []25 -7.1 (c 1, MeOH);
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HRMS (ESI TOF) m/z: calcd for C20H27NO7Na [M + Na]+ 416.1685, found 416.1681.
(S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate (1):
To the stirred mixture of 7 (1g, 2.64 mmol) and 10% Pd/C (10% w/w, 0.100g) in dry MeOH (35 mL) at rt
was added triethylsilane (TES) (4.2 mL, 26 mmol). The progress of the reaction was monitored by TLC.
After completion of reaction (4-5 h), the solution was filtered through a Celite bed, the filtrate evaporated
under reduced pressure, and the residue purified over silica gel eluting with Pet.Ether/EtOAc (98:1 to
93:7) affording 1 as a colorless oil. (0.575g, 89%yield). Rf = 0.2 Pet. Ether: EtOAc (80:20); [α]22 = +
D
32.2 (c 1, CHCl3); IR (Neat) cm-1: 1708, 1499, 1157; δH (400 MHz, CDCl3): 5.50 (d, J = 4 Hz, 1H), 4.51
(quintet, J = 4 Hz, 1H), 3.73 (s, 3H), 3.20-3.16 (m, 1H), 2.98-2.94 (m, 1H), 2.17 (s, 3H), 1.44 (s, 9H); δC
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(100 MHz, CDCl3): 206.6, 171.8, 155.5, 79.9, 52.6, 49.4, 45.3, 29.8, 28.2; HRMS (ESI TOF) m/z:calcd
for C11H19NO5Na [M + Na]+ 268.1161, found 268.1161.
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(R)-Methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate (1a):
Compound 1a was prepared starting from (R)-6-benzyl 1-methyl 2-((tert-butoxycarbonyl) amino)-4-
oxohexanedioate 7a, following similar experimental procedure described for 1 above (0.153 g, 93%
yield). [α]22D = -31.6 (c 1, CHCl3). Colorless oil (0.153g, 93% yield); Rf = 0.2 Pet. Ether: EtOAc (80:20);
[α]22 = - 31.6 (c 1, CHCl3); IR (Neat) cm-1: 1712, 1485, 1151, 679; δH (400 MHz, CDCl3): 5.48 (d, J = 4
D
Hz, 1H), 4.47 (t, J = 4 Hz, 1H), 3.70 (s, 3H), 3.18-3.14 (m, 1H), 2.96-2.90 (m, 1H), 2.14 (s, 3H), 1.42 (s,
9H); δC (100 MHz, CDCl3): 206.7, 171.9, 155.62, 80.2, 52.7, 49.5, 45.5, 30, 28.4; HRMS (ESI TOF) m/z:
calcd for C11H19NO5Na [M + Na]+ 268.1161, found 268.1169.
(RS)-Methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate (1b):
Compound 1b was prepared starting from racemic (RS)-6-benzyl 1-methyl 2-((tert-butoxycarbonyl)
amino)-4-oxohexanedioate 7b, following similar experimental procedure described for 1 above (0.15 g,
90% yield). colorless oil (0.150g, 90% yield); Rf = 0.2 Pet. Ether: EtOAc (80:20); IR (Neat) cm-1: 1709,
1478, 1148, 684; δH (400 MHz, CDCl3): 5.48 (d, J = 4 Hz, 1H), 4.47 (t, J = 4 Hz, 1H), 3.69 (s, 3H), 3.18-
3.13 (m, 1H), 2.96-2.90 (m, 1H), 2.13 (s, 3H), 1.41 (s, 9H); δC (100 MHz, CDCl3): 206.7, 171.9, 155.6,
80.1, 52.7, 49.5, 45.5, 30, 28.4; HRMS (ESI TOF) m/z: calcd for C11H19NO5Na [M + Na]+ 268.1161,
found 268.1165.
(S)-Methyl 2-((tert-butoxycarbonyl)amino)-6-oxoheptanoate (3):
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Experimental procedure similar as described for (7). Colorless oil (0.062 g, 83% yield). Rf = 0.3 Pet.
Ether:EtOAc (65:35); IR (Neat) cm-1: 2954, 2360, 1746, 1715, 1517, 1163; δH (400 MHz, CDCl3): 5.11(d,
J = 8 Hz, 1H), 4.30 (q, J = 8 and 4 Hz, 1H), 3.74 (s, 3H), 2.61-2.45 (m, 2H), 2.14(s, 3H), 1.81-1.78 (m,
1H), 1.68-1.60 (m, 3H), 1.44 (s, 9H); δC (100 MHz, CDCl3): 208.4, 173.3, 155.5, 80.1, 53.2, 52.5, 42.9,
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32.1, 30.1, 28.4, 19.4; []23 + 8.2 (c 1, MeOH); HRMS (ESI TOF) m/z: calcd for C13H23NO5K [M + K]+
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312.1213 found 312.1219.
(2S,5S)-1-tert-Butyl 2-methyl 5-methylpyrrolidine-1,2-dicarboxylate (10):
To a stirred mixture of 8 (0.650g, 1.65 mmol) and Pd/C (10% w/w, 0.065 g) in dry MeOH (20 mL) at rt
was added triethylsilane (TES) (2.64 mL, 16.52 mmol) and after 1 h an additional amount of TES (1.32
mL) was added. After completion of reaction (4 h) methanol was evaporated under vacuum and the
residue purified over silica gel eluting with Pet. Ether/EtOAc (100:0 to 90:10) affording 10 as a colorless
oil (0.280 g, 79% yield); Rf = 0.4 Pet. Ether:EtOAc (80:20); [α]25D = -28.4 (c 1, MeOH); IR (Neat) cm-1:
1750, 1693, 1387, 1364, 1164; (rotamers) δH (400 MHz, CDCl3): 4.35-4.33 (m, 1H), 4.22-4.19 (m, 1H),
4.01 (bs, 1H), 3.91 (bs, 1H), 3.73 (s, 6H), 2.19-2.16 (m, 2H), 2.05-2 (m, 4H), 1.63 (m, 2H), 1.47 (s, 9H),
1.41 (s, 9H), 1.27 (d, J = 6 Hz, 6H); (showed a mixture of carbamate isomers) δC (100 MHz, CDCl3):
174.2, 173.9, 155.5, 154.4, 79.9, 60.3, 59.9, 54.2, 52.1, 32.6, 31.8, 28.9, 28.4, 20.7, 19.9; []25 -28.4 (c
D
1, MeOH); HRMS (MALDI TOF/TOF) m/z: calcd for C12H21NO4Na [M + Na]+ 266.1368 found
266.1369.
(2S,5S)-Methyl 5-methylpyrrolidine-2-carboxylate (11):
To a stirred solution of 10 (0.2g, 0.82 mmol) in dry DCM (3 mL) at 0 °C was added acetic acid (TFA)
(1.3 mL, 16 mmol) and gradually the reaction mixture was warmed to rt. After completion of reaction
(1.5 h) DCM was evaporated under vacuum and the residue precipitated with diethyl ether to give 11 as a
white solid (0.115 g, 98% yield); mp = 114-116 °C ; IR (KBr) cm-1: 1742, 1676, 1438, 1205, 1143; δH
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(400 MHz, MeOH-d4): 4.47 (t, J = 8 Hz, 1H), 3.85 (s, 3H), 3.77-3.72 (m, 1H), 2.45-2.37 (m, 2H), 1.75-
1.68 (m, 1H), 1.45 (d, J = 4 Hz, 3H); δC (100 MHz, MeOH-d4): 170.5, 60.7, 58.4, 53.9, 31.6, 28.2, 17.5;
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[]25 -4.3 (c 0.3, MeOH); HRMS (ESI TOF) m/z: calcd for C7H14NO2 [M + H]+ 144.1025, found
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144.1027.
(S)-(E,Z)-1-Benzyl 7-methyl 2-benzylidene-6-((tert-butoxycarbonyl)amino)-3-oxoheptanedioate (14):
To a stirred mixture of 8 (0.5g, 1.27 mmol) and benzaldehyde (0.1 mL, 1.27 mmol) in benzene (65 mL),
was added piperidine (0.013 mL, 0.127 mmol) and acetic acid (0.015 mL, 0.24 mmol). The reaction
mixture was refluxed using Dean-Stark apparatus to remove the water. After completion of reaction (2.5-
3 h) benzene was evaporated under vacuum and the residue purified by flash chromatography over silica
gel eluting with Pet. Ether/EtOAc (98:2 to 70:30) giving 14 as a light yellow oil (0.480g, 77% yield). (E:Z
= 0.96:1); Rf = 0.6 Pet. Ether: EtOAc (50:50); IR (Neat) cm-1: 1700, 1497, 1158; (mixture of E and Z
isomers) δH (400 MHz, CDCl3): 7.74 (s, 1H), 7.60 (s, 1H), 7.39-7.25 (m, 20H), 5.30-5.29 (m, 4H), 5.1 (bs,
1H), 4.94 (bs, 1H), 4.34 (bs, 1H), 4.21 (bs, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.84-2.82 (m, 2H), 2.66-2.62
(m, 2H), 2.05-1.96 (m, 2H), 1.94-1.91 (m, 2H), 1.44 (s, 9H), 1.40 (s, 9H); (mixture of E and Z isomers) δC
(100 MHz, CDCl3): 204.3, 95.8, 172.8, 167.6, 164.3, 155.5, 141.8, 141.5, 135.5, 133.3, 132.9, 130.8,
129.8, 129.7, 129.1, 128.9, 128.8, 128.7, 128.6, 128.3, 80.2, 79.9, 67.8, 67.4, 53.6, 52.6, 52.5, 39.7, 34.9,
28.4, 26.9, 26.6; []25 -4.2 (c 1, MeOH); HRMS (MALDI TOF/TOF) m/z:calcd for C27H31NO7Na [M +
D
Na]+ 504.1998 found 504.2009.
(S, Z)-1-Benzyl 6-methyl 2-benzylidene-5-((tert-butoxycarbonyl)amino)-3-oxohexanedioate (12):
Experimental procedure similar as described for (14). 12 was obtained as a pale yellow oil; (0.210 g,
74% yield) (E:Z = 0.71:1); IR (Neat) cm-1:1714, 1477, 1165; (mixture of E and Z isomers) δH (400 MHz,
CDCl3) 7.77 (s, 1H, E), 7.61 (s, 1H, Z), 7.41-7.23 (m, 20H), 5.55-5.48 (m, 2H), 5.29-5.26 (m, 4H), 4.62
(quintet, J = 4 Hz, 1H), 4.51 (quintet, J = 4 Hz, 1H), 3.74 (s, 3H), 3.64 (s, 3H), 3.51 (m, 1H), 3.35-3.25
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(m, 2H), 3.16 (m, 1H), 1.45 (d, J = 8 Hz, 18H); (mixture of E and Z isomers) δC (100 MHz, CDCl3) 202.9,
194.6, 171.8, 171.7, 167.1, 164.1, 155.6, 142.7, 135.4, 134.6, 133.3, 132.6, 132.1, 131.1, 130.9, 130.1,
129.8, 129.2, 129, 128.9, 128.8, 128.7, 128.6, 128.4, 80.2, 80.1, 67.9, 67.4, 52.8, 52.6, 49.5, 49.1, 45.6,
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41.2, 28.5, 28.4; []25 -3.8 (c 0.8, MeOH); HRMS (MALDI TOF/TOF) m/z: calcd for C26H29NO7Na [M
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+ Na]+ 490.1841 found 490.1844.
(S, E, Z)-1-Benzyl 6-methyl5-((tert-butoxycarbonyl)amino)-2-(4-(tert-butyl)benzylidene)-3-
oxohexanedioate (13):
The experimental procedure is similar as described for 14. Product 13 was obtained as a light yellow oil
(0.335 g, 73% yield). (E:Z = 0.64:1); IR (Neat) cm-1: 2977, 1718, 1498, 1167; (mixture of E and Z
isomers) δH (400 MHz, CDCl3): 7.71 (s, 1H, E), 7.58 (s, 1H, Z), 7.38-7.31 (m, 14H), 7.26-7.25 (m, 4H),
5.55-5.50 (m, 2H), 5.30-5.26 (m, 4H), 4.62-4.56 (m, 2H), 3.73 (s, 3H), 3.66 (s, 3H), 3.50-3.19 (m, 4H),
1.43 (d, J = 4 Hz, 18H), 1.30 (d, J = 8 Hz, 18H); (mixture of E and Z isomers) δC (100 MHz, CDCl3): 203,
194.6, 171.9, 167.4, 155, 148.3, 142.7, 135.6, 134.8, 130.9, 130.3, 129.9, 129.7, 129.3, 128.8, 128.74,
128.7, 128.6, 128.55, 128.4, 126.1, 126, 125.7, 80.2, 67.8, 67.4, 52.8, 52.6, 45.6, 41.1, 35.1, 31.5, 31.22,
31.19, 28.53, 28.47; []25 -4.4 (c 0.9, MeOH);HRMS (MALDI TOF/TOF) m/z: calcd for C30H37NO7Na
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[M + Na]+ 546.2468 found 546.2479.
(S, Z)-1-Benzyl 6-methyl-5-((tert-butoxycarbonyl)amino)-3-oxo-2-(pyren-1-
ylmethylene)hexanedioate (15):
The experimental procedure was similar to that described for 14 and gave product 15 as a light yellow oil
(0.180 g, 69% yield). (E:Z = 1:0.86); IR (Neat) cm-1: 1715, 2927, 1593, 1498, 1366, 1209, 1165, 848;
(mixture of E and Z isomers) δH (400 MHz, CDCl3): 8.83 (s, 1H, E), 8.73 (s, 1H, Z), 8.28-7.99 (m, 16H),
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(m, 3H), 5.13 (s, 2H), 4.71 (quintet, J = 4 Hz, 1H), 4.39 (quintet, J = 4 Hz, 1H), 3.80 (s, 3H), 3.69-3.63
(m, 1H), 3.48-3.41 (m, 4H), 3.20-3.14 (m, 1H), 3.01-2.95 (m, 1H), 1.48 (s, 9H), 1.37 (s, 9H); (mixture of
E and Z isomers) δC (100 MHz, CDCl3) 202.5, 194.4, 171.9, 171.6, 164.2, 155.7, 155.5, 142.2, 141.6,
135.5, 135.1, 134.5, 134.2, 133.1, 131.3, 130.8, 130, 129.9, 129.13, 129.1, 129.05, 128.9, 128.7, 128.6,
128.4, 128.35, 127.4, 127.3, 127, 126.6, 126.56, 126.5, 126.43, 126.4, 126.36, 125.9, 124.8, 124.7, 124.5,
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123.1, 123, 80.3, 80, 67.6, 67.5, 52.9, 52.5, 45.9, 41.9, 28.5, 28.4; []25 -5.9 (c 1, MeOH); HRMS
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(MALDI TOF/TOF) m/z: calcd for C36H33NO7Na [M + Na]+ 614.2155 found 614.2157.
(S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-oxo-6-phenylhexanoate (16):
Experimental procedure as for (1); product 16 obtained as a white solid (0.116 g, 77% yield). mp = 62-63
°C; IR (KBr) cm-1: 2962, 1715, 1492, 1391, 1161; δH (400 MHz, CDCl3) 7.29-7.26 (m, 2H), 7.21-7.15
(M, 3H), 5.49 (d, J = 8 Hz, 1H), 4.49 (quintet, J = 4 Hz, 1H), 3.71 (s, 1H), 3.12 (m, 1H), 2.94-2.86 (m,
3H), 2.77-2.72 (m, 2H), 1.44 (s, 9H); δC (100 MHz, CDCl3) 208.1, 171.9, 155.6, 140.6, 128.6, 128.4,
126.3, 80.2, 52.8, 49.5, 44.8, 44.3, 29.6, 28.4; []25 -12.8 (c 1, MeOH); HRMS (MALDI TOF/TOF) m/z:
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calcd for C18H25NO5Na [M + Na]+ 358.1630 found 358.1614.
(S)-Methyl 2-((tert-butoxycarbonyl)amino)-6-(4-(tert-butyl)phenyl)-4-oxohexanoate (17):
Experimental procedure as for (1); product 17 obtaibed as a colorless oil (0.192 g, 72% yield). Rf = 0.5
Pet. Ether:EtOAc (50:50); IR (Neat) cm-1: 2963, 1716, 1499, 1392, 1165; δH (400 MHz, CDCl3): 7.31 (d,
J = 8 Hz, 2H), 7.1 (d, J = 12 Hz, 2H), 5.51 (d, J = 12 Hz, 1H), 4.50 (quintet, J = 4 Hz, 1H), 3.71 (s, 3H),
3.18-3.12 (m, 1H), 2.96-2.71 (m, 5H), 1.44 (s, 9H), 1.30 (s, 9H); δC (100 MHz, CDCl3): 208.8, 172.6,
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(S)-Methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-7-phenylheptanoate (18)
Experimental procedure as described for (1); product 18 obtained as a colorless oil (0.268 g, 77% yield).
Rf = 0.5 Pet. Ether:EtOAc (50:50); IR (Neat) cm-1: 1742, 1705, 1158; δH (400 MHz, CDCl3): 7.30-7.26
(m, 2H), 7.21-7.16 (m, 3H), 5.10 (d, J = 8 Hz, 1H), 4.29 (q, J = 8 and 4 Hz, 1H), 3.73 (s, 3H), 3.90 (t, J =
8 Hz, 2H), 2.73 (t, J = 8 Hz, 2H), 2.55-2.42 (m, 2H), 2.15-2.10 (m, 1H), 1.19-1.84 (m, 1H), 1.44 (s, 9H);
δC (100 MHz, CDCl3): 208.8, 172.9, 155.6, 141, 128.6, 128.4, 126.3, 80.1, 52.9, 52.5, 44.5, 38.8, 29.8,
28.4, 26.6; []25 -12.6 (c 1, MeOH); HRMS (ESI TOF) m/z: calcd for C19H27NO5Na [M + Na]+
D
372.1787, found 372.1787.
(S)-Methyl 2-((tert-butoxycarbonyl)amino)-4-oxo-6-(pyren-1-yl)hexanoate (19):
Experimental procedure as described for (1); product 19 obtained as a pale yellow oil (0.075 g, 54%
yield). Rf = 0.2 Pet. Ether: EtOAc (80:20); IR (Neat) cm-1: 1732, 1708; δH (500 MHz, CDCl3): 8.22-8.10
(m, 5H), 8.03-8.00 (m, 3H), 7.86 (d, J = 8 Hz, 1H), 5.53 (d, J = 8 Hz, 1H), 4.52 (t, J = 4 Hz, 1H), 3.72 (s,
3H), 3.62 (t, J = 8 Hz, 2H), 3.19-3.13 (m, 1H), 3.00-2.93 (m, 3H), 1.44 (s, 9H); δC (100 MHz, CDCl3):
208.1, 172.1, 155.7, 134.7, 131.5, 130.3, 128.6, 127.8, 127.6, 127.2, 127, 126.1, 125, 125.1, 122.9, 80.3,
52.8, 49.6, 44.9, 44.4, 28.4, 27.2; []25 -4.1 (c 1, MeOH); HRMS (MALDI TOF/TOF) m/z: calcd for
D
C28H29NO5Na [M + Na]+ 482.1943 found 482.1937.
(2S, 5S)-1-tert-Butyl 2-methyl 5-phenethylpyrrolidine-1, 2-dicarboxylate (20):
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To a stirred mixture of 18 (0.558 g, 1.46 mmol) and B(C6F5)3 (0.075g) in dry DCM (10 mL) was added
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triphenylsilane (1.14 g) in dry DCM (3 mL) at -78 C and the reaction mixture allowed to warm to rt.
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After completion of reaction (2 h) DCM was evaporated and the residue purified by flash chromatography
over silica gel eluting with Pet. Ether/EtOAc (100:0 to 90:10) to give 20 as a colorless oil (0.339 g, 82%
yield). Rf = 0.5 Pet. Ether:EtOAc (80:20); IR (Neat) cm-1: 2973, 1751, 1697, 1392, 1169; (showed a
mixture of carbamate isomers) δH (400 MHz, CDCl3): 7.26-7.15 (m, 10H), 4.36 (t, J = 8 Hz, 1H), 4.22 (t,
J = 8 Hz, 1H), 3.98 (bs, 1H), 3.83 (bs, 1H), 3.71 (s, 6H), 2.67-2.65 (m, 4H), 2.20-2.16 (m, 4H), 2.0-1.92
(m, 4H), 1.76-1.72 (m, 4H), 1.43 (s, 9H), 1.40 (s, 9H); (rotational isomers) δC (100 MHz, CDCl3): 174.1,
153.8, 142.4, 142.1, 128.5, 128.4, 125.9, 125.8, 80.11, 80.02, 60.2, 59.8, 58.5, 58.2, 52.3, 52.11, 36.6,
36.2, 33.2, 33.1, 30.3, 29.6, 29.1, 28.6, 28.4, 28.3; []25 -4.4 (c 0.29, MeOH); HRMS (ESI) m/z: calcd
D
for C19H27NO4Na [M + Na]+ 356.1838, found 356.1831.
Acknowledgements: A. R. M. thanks IISER-Pune for the fellowship. Financial support from IISER-
Pune is gratefully acknowledged by authors to carry out this research work.
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Supporting Information: Copies of H-NMR, C-NMR spectra are provided for compounds 1, 1a,
1b, 3, 4, 4a, 4b, 7, 7a, 7b, 8, 10-20. HPLC choromatograms of 1, 1a, 1b are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(13) N-Boc 6-oxo-L-homoglutamic acid 1-methylester 6 prepared from L-homoglutamic acid following the
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