Enantiospecific synthesis of α-amino acid semialdehydes: A key step for the synthesis of unnatural unsaturated and saturated α-amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00354-1

The enantiospecific synthesis of unnatural unsaturated and saturated α- amino acids based on a Wittig type reaction is described. The versatile synthetic intermediates, L-glutamic and L-aspartic acid semialdehydes, are obtained from the corresponding N,N-di-Boc-diesters, by the selective reduction of the ω-ester with DIBAL under controlled conditions. The semialdehydes are chemically stable for a prolonged time and react with various phosphorous ylides, under controlled conditions, to produce the enantiomerically pure unsaturated α-amino acids in high yields. The method is equally applicable to homologated diesters obtained by the presented methodology providing unsaturated amino acids with variable unsaturated- positions and geometries. The corresponding saturated products can be obtained by simple hydrogenation.

Full text of DOI:10.1016/S0957-4166(98)00354-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3381–3394
Enantiospecific synthesis of α-amino acid semialdehydes: a key
step for the synthesis of unnatural unsaturated and saturated
α-amino acids
José M. Padrón,a George Kokotos,b Tomás Martín,a Theodoros Markidis,b
William A. Gibbons c and Víctor S. Martín a,∗
aInstituto Universitario de Bio-Orgánica ‘Antonio González’, Unidad Asociada al CSIC, Universidad de La Laguna,
C/Astrofísico Francisco Sánchez, 2, 38206 La Laguna, Tenerife, Spain
bDepartment of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, 15771 Athens, Greece
cDepartment of Pharmaceutical Chemistry, The School of Pharmacy, University of London, 29–39 Brunswick Square, London,
WC1N 1AX, UK
Received 2 July 1998; accepted 2 September 1998
Abstract
The enantiospecific synthesis of unnatural unsaturated and saturated α-amino acids based on a Wittig type
reaction is described. The versatile synthetic intermediates, L-glutamic and L-aspartic acid semialdehydes, are
obtained from the corresponding N,N-di-Boc-diesters, by the selective reduction of the ω-ester with DIBAL®
under controlled conditions. The semialdehydes are chemically stable for a prolonged time and react with various
phosphorous ylides, under controlled conditions, to produce the enantiomerically pure unsaturated α-amino acids
in high yields. The method is equally applicable to homologated diesters obtained by the presented methodology
providing unsaturated amino acids with variable unsaturated positions and geometries. The corresponding saturated
products can be obtained by simple hydrogenation. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Optically active natural and unnatural α-amino acids are constituents of many biologically and
pharmacologically important compounds, e.g. inhibitors of renin, angiotensin converting enzymes,
immunomodulators, cytostatic drugs, peptide antibiotics, as well as important precursors for the synthesis
of pharmaceuticals, agrochemical, and food ingredients. Modified amino acids have been widely used in
medicinal chemistry and biochemistry to change the conformation, restrict the flexibility and enhance
the potency of molecules. Moreover, the synthesis of new non-proteinogenic amino acids and their
∗
Corresponding author. E-mail: vmartin@ull.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00354-1

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incorporation into natural biologically active peptides might become a powerful method for the design
of peptide and peptidomimetics therapeutics.
Of particular interest for us is a special class of non-natural α-amino acids, the lipidic α-amino acids
(LAAs), which combine structural features of amino acids with those of lipids.1 The LAAs and their
derivatives are molecules with long aliphatic side chains exhibiting interesting biological properties. In
particular, lipidic 2-amino alcohols and 1,2- and 1,3-diamines, derived from racemic LAAs, have been
shown to exhibit in vivo anti-inflammatory activity2 and in vitro cytotoxic activity,3 while lipidic 2-amino
alcohols have been proved to be potent immunosuppressants.4
Many ingenious techniques have been devised for the efficient asymmetric synthesis of α-amino acids
and have been extensively reviewed.5 We have previously described the synthesis of saturated LAAs
and their derivatives, based on the oxidative cleavage of 3-amino-1,2-diols obtained by the regioselective
opening of enantiomerically enriched long chain 2,3-epoxy alcohols.6 Unfortunately, this approach was
not suitable for the preparation of the desired unsaturated LAAs.
In principle, the selective chemical modification of the side chains of inexpensive proteinogenic amino
acids offers attractive access to rare or unnatural α-amino acids, provided the original chirality can be
preserved. Based on this approach we synthesized enantiomerically pure α-amino arachidonic acid from
glutamic acid semialdehyde using Wittig type reactions.7
In the present paper8 we wish to report in full the results concerning the synthesis of enantiomerically
pure unsaturated α-amino acids, which eventually can be transformed into the saturated products by
simple hydrogenation. The key steps in our methodology are the selective reduction with DIBAL® of
N,N-di-Boc-glutamic or aspartic dialkyl esters and further Wittig reaction, both steps being performed
under controlled conditions. Furthermore, it is possible to control the stereochemistry of the double bond
in the final products. This method provides almost unlimited possibilities, with the only restriction being
the synthesis of the suitable ylide and the corresponding Wittig reaction.
2. Results and discussion
The retrosynthetic pathway we have followed is outlined in Scheme 1. We based our strategy on
the possibility of building the chain using Wittig type reactions from aldehydes such as 2 that could
be obtained from glutamic or aspartic acid. These amino acids are inexpensive and available in both
enantiomeric forms. In addition, this approach permits both convergence in the synthetic procedure and
stereoselectivity in the formation of the double bond.
Scheme 1.
Glutamic and aspartic acid semialdehydes are configurationally stable compounds and were selected as
chiral building blocks. Although these intermediates are known and their syntheses have been reported
previously,9 the strategies found in the literature afford only low chemical yield due to the number of
steps and/or the use of expensive, impractical starting material or reagents. Our approach describes a new
synthesis of protected derivatives of enantiomerically pure glutamic and aspartic acid semialdehydes in

J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
3383
a limited number of steps using readily available reagents. This procedure permitted us to easily increase
the scale of the reaction.
2.1. Glutamic acid semialdehyde and derivatives
In a first attempt, commercial L-glutamic acid was submitted to perbenzylation under known con-
ditions to afford the diester 4 in 70% yield.10 Then, this compound was reduced with DIBAL® under
controlled conditions (1.1 equivalents, −78°C, 15 min) to yield 5 as the only compound in 87% yield.
Further homologation under usual Wittig conditions (n-BuLi, THF, −78°C) permitted us to obtain the
protected LAA 6 with total stereoselection in the double bond formed and in a good yield (78%)
(Scheme 2).11 This method was, however, discarded because of the impossibility of cleavage of the
benzyl protecting groups under non-hydrogenating conditions.12
Scheme 2.
We thus decided to employ other, more easily removed protecting groups. As an alternative approach
for the protection of free L-glutamic acid we designed a one-pot procedure for the esterification of both
carboxyl groups and further N-Boc protection. Thus, L-glutamic acid was treated for 12 h with Me3SiCl
in dry MeOH13 followed by the addition of Et3N and di-tert-butyl dicarbonate,14 to obtain 7 in high
yields (95%). Disappointingly, we were unable to obtain the desired aldehyde when 7 was submitted to
reduction with DIBAL® under our conditions, presumably because of some participation of the nitrogen.
This result induced us to minimize the nucleophilic power of the nitrogen by the introduction of a second
N-Boc group. The dimethyl N-Boc-glutamate 7 was treated with di-tert-butyl dicarbonate under known
conditions to afford 8 in almost quantitative yield.15 In this case, fortunately, when 8 was submitted to
reduction with DIBAL® under our conditions the aldehyde 9 was obtained in 85% yield (Scheme 3).
Scheme 3.
Unsuccessful results were obtained when the aldehyde 9 was submitted to usual Wittig conditions
(n-BuLi, THF, −78°C). We therefore changed the reaction conditions. In fact, when NaN(TMS)2 was
used as base, in THF, the unsaturated LAA derivative 10 was obtained in 10% yield. In addition, when
the generation of the ylide was performed with KN(TMS)2, in toluene, at 0°C and the Wittig reaction
performed at −78°C, the Z-ester 10 was obtained in 92% isolated yield (Scheme 4).16
The saponification of the methyl esters must be carried out under controlled conditions in order
to avoid any epimerization.17 Although a procedure based on di-N-Boc cleavage, N-Boc protection
and saponification18 is plausible, we found that depending on the reaction conditions such as rate of

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Scheme 4.
stirring, concentration and reaction time, on occasion, racemization may occur. Therefore, we strongly
recommend the alternative sequence based on Scheme 5 to obtain the free acid without racemization.
Firstly, we removed the two N-Boc groups under acid conditions. Then, we hydrolyzed the methyl ester
under alkaline conditions during a relatively short period of time. In order to obtain the N-Boc derivative,
the free amino compound was N-Boc-protected to 12. These steps proceeded with a very good overall
yield. In contrast, if the methyl N-Boc-ester 13 is the desired product, the best method is the one based
on the cleavage of the two N-Boc groups in 10, under acid conditions, and consecutive N-Boc protection
to afford 13.
Scheme 5.
Interestingly, the simple reduction of 13 with DIBAL® can then be considered to be a general method
to obtain unsaturated lipidic 2-amino-1-alcohols 14 or 15 which can be further converted to 1,2- and
1,3-diamines 16.6,19 In addition, the catalytic hydrogenation of compound 10 led us to the saturated
derivative 17 in high yields (Scheme 6). Thus, this approach offers an alternative, and perhaps more
convenient, method for the preparation of saturated LAAs.
Scheme 6.
Once the methodology was set up, we were able to achieve the synthesis of different LAAs analogues
and, importantly, the analysis of structure–activity relationships. Thus, by performing the Wittig reaction
over (Scheme 7) with different phosphorous ylides20 we prepared in high yields a series of derivatives,
which presented various Z-unsaturations in the aliphatic chain, such as 18, 19, 20 and 21.
In order to explore the scope and limitations of the aldehyde 9 we extended the Wittig reaction to
the use of stabilized phosphoranes and phosphonates. We attempted the synthesis of compounds that
presented either E or Z geometry in the double bond formed. Thus, the use of methyl (triphenylphospho-
ranylidene)acetate provided the E-olefin 22 as the sole stereoisomer. Complementarily, the treatment of
9 with the anion of methyl diphenoxyphosphorylacetate provided cleanly the Z-isomer 23.21 However,

J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
3385
Scheme 7.
the use of ylide derived from benzyl triphenylphosphonium bromide provided a 4:1 E:Z mixture of the
unsaturated compounds 24 (Scheme 8).
Scheme 8.
2.2. Aspartic acid semialdehyde and derivatives.
All the above compounds can be obtained from glutamic acid and therefore present the formed double
bond at C-5. Because of our aforementioned interest in structure–activity relationships and search for a
general methodology to place a double bond at any position of the chain, we thought about the possibility
of using aspartic acid in the same manner in order to obtain LAA derivatives with the unsaturation at C-4.
Thus, when commercially available L-aspartic acid was submitted to the sequence described earlier we
could obtain, in similar yields, not only the aspartic acid semialdehyde 27, but also the corresponding
unsaturated LAA derivative 28, in a similar manner to that using glutamic acid (Scheme 9).
Scheme 9.

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2.3. α-Amino diacid ω-semialdehydes
The similarity in the methodology to obtain semialdehydes such as 9 and 27 derived from glutamic
and aspartic acids, respectively, induced us to envisage that the reduction of any ester located in a
longer chain should lead to the suitable aldehyde in a similar manner. In order to explore such an idea,
we decided to prepare new α-amino diacids with a longer carbon chain. Thus, semialdehydes 9 and
27, respectively, were submitted to Wittig reaction using methyl (triphenylphosphoranylidene)acetate to
obtain the corresponding E-unsaturated esters. The simple hydrogenation of the double bond led us again
to the saturated N,N-di-Boc dialkyl esters, 30 and 31. Gratifyingly, the reduction of these compounds
using the earlier described reduction procedure led to the desired aldehydes 32 and 33 in a straightforward
manner. Thus, the use of these compounds and/or the iteration of the procedure permit tailoring the
location of a new double bond at any position of the chain (Scheme 10).
Scheme 10.
2.4. Conclusions
In summary, we have reported on a simple, efficient and general method to prepare unsaturated α-
amino acids and derivatives in their enantiomeric forms, which can eventually be transformed into the
saturated products by simple hydrogenation. The use of this methodology opens the way to the synthesis
of almost unlimited types of non-proteinic α-amino acids. Although the presented methodology has been
described only for one enantiomer series, the choice of the proper enantiomer of glutamic or aspartic acid
permits the control of the absolute configuration in the final products.
3. Experimental
1H and 13C NMR spectra were recorded on a Bruker AMX 400 and/or Bruker AC 200 spectrometer in
CDCl3 as solvent, and chemical shifts are reported relative to Me4Si. Low-resolution mass spectra were
taken using a Hewlett–Packard model 257. Elemental analyses were performed on a Carlo–Erba model
1106. Optical rotations were determined for solutions in chloroform with a Perkin–Elmer model 241
polarimeter. Infrared spectra were recorded on a Bruker model IFS55. Melting points were determined on
a Büchi model 535 melting point apparatus and are uncorrected. HPLC chromatography was performed
using a Waters pump model 515 with a Waters 2487 dual λ absorbance detector using a µ-Porasil silica 10
µm Waters column. Column chromatography was performed on silica gel, 0.015–0.04 and 0.04–0.063
mm, and TLC and PLC were performed on silica gel, all Merck products. Visualization of spots was
effected with UV light and/or phosphomolybdic acid and/or ninhydrin both in ethanol stain. All solvents
were purified by standard techniques. Reactions requiring anhydrous conditions were performed under
argon. Anhydrous magnesium sulfate was used for drying solutions.

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3.1. General procedure for the one-pot protection of free α-amino acids: dimethyl (S)-2-tert-
butoxycarbonylamino-pentanodioate 7
To a stirred suspension of commercially available L-glutamic acid (1.47 g, 10 mmol) in dry MeOH (33
ml, 0.3 M) was added slowly Me3SiCl (5.6 ml, 44 mmol, 4.4 equiv.) in an ice-cold bath. After the addition
was completed the ice-cold bath was removed and the reaction was stirred overnight until TLC showed
complete conversion. Then, Et3N (9 ml, 65 mmol, 6.5 equiv.) and (Boc)2O (2.4 g, 11 mmol, 1.1 equiv.)
were sequentially added. The reaction mixture was stirred until TLC showed complete protection. The
solvent was removed under reduced pressure and the residue triturated and washed with Et2O (3×150
ml, 15 ml/mmol) using a pad of Celite. The combined organic layers were evaporated and the resulting
crude was purified by silica gel column chromatography to afford 7 (2.60 g, 95% yield) as an oil: [α]25
D
+12.9 (c 2.0, CHCl3); 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.91 (m, 1H), 2.14 (m, 1H), 2.37 (m, 2H), 3.64
(s, 3H), 3.70 (s, 3H), 4.29 (br s, 1H), 5.14 (br s, 1H); 13C NMR (CDCl3) δ 27.7 (t), 28.2 (q), 30.0 (t),
51.7 (q), 52.3 (q), 52.8 (d), 79.9 (s), 155.3 (s), 172.6 (s), 173.1 (s); IR (CHCl3) (cm−1) 3436, 3025, 2981,
1737, 1714, 1503, 1369, 1167; MS m/z (relative intensity) 276 (M+1)+ (1), 219 (22), 216 (48), 187 (25),
174 (31), 160 (63), 142 (41), 116 (99), 84 (86), 57 (100). Anal. calcd for C12H21NO6: C, 52.35; H, 7.69;
N, 5.09. Found: C, 52.26; H, 7.81; N, 5.05.
3.2. General procedure for the N,N-di-Boc-protection of the N-Boc-methyl ester of α-amino acids:
dimethyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxy- carbonyl]carbonylamino}-pentanedioate 8
To a stirred solution of the N-Boc amino ester 7 (2.5 g, 9 mmol) and DMAP (220 mg, 1.8 mmol, 0.2
equiv.) in dry CH3CN (30 ml, 0.3 M) was added (Boc)2O (2.2 g, 9.9 mmol, 1.1 equiv.) at rt. The reaction
became slightly red with gas evolution. The mixture was stirred for 2 h, after which time TLC showed
that some starting material still remained. More (Boc)2O (1.1 g, 4.9 mmol, 0.5 equiv.) was added and the
mixture was additionally stirred overnight. The solvent was evaporated, and the crude purified by silica
gel column chromatography, to afford 8 (3.32 g, 98% yield) as an oil: [α]25 −37.2 (c 2.15, CHCl3); 1H
D
NMR (CDCl3) δ 1.49 (s, 18H), 2.17 (m, 1H), 2.40 (m, 2H), 2.46 (m, 1H), 3.67 (s, 3H), 3.71 (s, 3H), 4.93
(dd, J=9.2, 4.4 Hz, 1H); 13C NMR (CDCl3) δ 25.2 (t), 27.9 (q), 30.6 (t), 51.6 (q), 52.2 (q), 57.3 (d), 83.3
(s), 151.9 (s), 170.8 (s), 173.1 (s); IR (CHCl3) (cm−1) 3024, 2984, 1789, 1742, 1699, 1370, 1141; MS
m/z (relative intensity) 376 (M+1)+ (3), 320 (58), 264 (42), 220 (100), 176 (100), 116 (66), 84 (16). Anal.
calcd for C17H29NO8: C, 54.37; H, 7.79; N, 3.73. Found: C, 54.64; H, 7.92; N, 3.73.
3.3. General procedure for the selective reduction of the ω-ester group of dimethyl N,N-di-
Boc-α-amino-diesters to semialdehydes: methyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]-
carbonylamino}-5-oxopentanoate 9
To a stirred solution of the dimethyl ester 8 (1 g, 2.7 mmol) in dry Et2O (27 ml, 0.1 M) was added
dropwise DIBAL® (3 ml, 1.0 M in hexane, 3 mmol, 1.1 equiv.) at −78°C. The reaction was stirred for
5 min and then quenched with H2O (0.4 ml, ≈7 equiv.). The mixture was stirred for 30 min, dried over
MgSO4, and filtered through a pad of Celite. The solvent was evaporated and the crude purified by silica
gel column chromatography to afford 9 (2.5 g, 85% yield) as an oil: [α]25 −35.3 (c 2.3, CHCl3); H
1
D
NMR (CDCl3) δ 1.50 (s, 18H), 2.17 (m, 1H), 2.50 (m, 2H), 2.59 (m, 1H), 3.71 (s, 3H), 4.87 (dd, J=9.6,
5.2 Hz, 1H), 9.76 (s, 1H); 13C NMR (CDCl3) δ 22.5 (t), 27.9 (q), 40.5 (t), 52.2 (q), 57.3 (d), 83.4 (s),
151.9 (s), 170.7 (s), 200.9 (d); IR (CHCl3) (cm−1) 3028, 2984, 1789, 1743, 1699, 1370, 1144; MS m/z

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J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
(relative intensity) 234 (M−111)+ (1), 206 (15), 189 (10), 174 (37), 162 (35), 144 (31), 128 (100), 102
(26), 86 (35). Anal. calcd for C16H27NO7: C, 55.64; H, 7.88; N, 4.06. Found: C, 55.45; H, 8.10; N, 4.09.
3.4. General procedure for the synthesis of lipidic (Z)-unsaturated N,N-di-Boc-α-amino esters: methyl
(2S)(5Z)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}icos-5-enoate 10
To a stirred suspension of n-pentadecyl-triphenylphosphonium bromide (3.85 g, 7 mmol, 1.2 equiv.)
in dry toluene (0.15 M) under argon was added dropwise KN(TMS)2 (12.8 ml, 0.5 M, 6.4 mmol, 1.1
equiv.) at 0°C. After 15 min the flask was cooled to −78°C and 9 (2 g, 5.8 mmol, 1 equiv.) dissolved
in toluene (5 ml) was added dropwise. The reaction mixture was stirred for 2 h after which time TLC
showed complete conversion. Then the reaction mixture was quenched with a saturated aqueous solution
of NH4Cl (50 ml) and extracted with ether (3×10 ml). The combined organic phases were washed with
brine, dried over MgSO4, filtered and the solvent evaporated. The crude was purified by silica gel column
chromatography to afford 10 (2.7 g, 87% yield) as an oil: [α]25 −26.2 (c 2.2, CHCl3); 1H NMR (CDCl3)
D
δ 0.88 (t, J=6.8 Hz, 3H), 1.25 (br s, 24H), 1.49 (s, 18H), 1.90 (m, 1H), 2.00 (dd, J=13.6, 6.8 Hz, 2H),
2.08 (dd, J=14.0, 7.2 Hz, 2H), 2.15 (m, 1H), 3.71 (s, 3H), 4.86 (dd, J=8.8, 4.8 Hz, 1H), 5.38 (m, 2H); 13
C
NMR (CDCl3) δ 14.1 (q), 22.7 (t), 24.0 (t), 27.3 (t), 28.0 (q), 29.3 (t), 29.4 (t), 29.5 (t), 29.6 (t), 29.7 (t),
30.1 (t), 31.9 (t), 52.1 (q), 57.7 (d), 83.0 (s), 128.1 (d), 131.3 (d), 152.1 (s), 171.4 (s); IR (CHCl3) (cm−1
)
2928, 2855, 1787, 1742, 1698, 1458, 1370, 1144; MS m/z (relative intensity) 382 (M−157)+ (4), 366 (9),
339 (30), 280 (83), 156 (10), 143 (25), 133 (100), 106 (24). Anal. calcd for C31H57NO6: C, 68.96; H,
10.65; N, 2.60. Found: C, 68.67; H, 10.88; N, 2.65.
3.5. General procedure for the synthesis of lipidic N-Boc-α-amino acids: (2S)(5Z)-2-[(tert-butoxy)-
carbonylamino]icos-5-enoic acid 12
A solution of 10 (540 mg, 1 mmol) in HCl/THF (4 M, 25 ml, 100 mmol) was stirred for 30 min at rt.
The excess acid and the solvent were evaporated and the residue was treated twice with dry THF (2×5 ml)
and evaporated. The solid mixture was dissolved in MeOH (2 ml) and treated with an aqueous solution
of NaOH (1 M aqueous solution, 2.80 ml, 2.8 mmol) with vigorous stirring for 2 h at rt. The organic
solvent was removed and the aqueous residue carefully neutralized with aqueous HCl (1 M) affording 11
as a white solid that was filtered and washed with H2O.
To a stirred suspension of the crude free amino acid in MeOH (10 ml), was added Et3N (1 ml, 7.14
mmol) and Boc2O (327 mg, 1.5 mmol) at rt. The mixture was vigorously stirred for 15 min at 50–60°C
and for 30 min at rt. The solvent was evaporated and the residue cooled, acidified with 0.5 M aqueous
HCl and extracted immediately with AcOEt (3×10 ml). The combined organic phases were dried over
Na2SO4 and the solvent was evaporated. The crude was purified by silica gel column chromatography
using CHCl3:MeOH (9:1) as eluent, to yield 12 (383 mg, 90%): [α]25 +13.6 (c 0.5, CHCl3); 1H NMR
D
(CDCl3) δ 0.88 (t, J=7.0 Hz, 3H), 1.25 (br s, 24H), 1.45 (s, 9H), 1.72 (m, 1H), 1.92 (m, 1H), 2.01 (m,
2H), 2.14 (m, 2H), 4.30 (br s, 1H), 5.00 (br s, 1H), 5.32 (m, 1H), 5.43 (m, 1H); 13C NMR (CDCl3) δ
14.0 (q), 22.6 (t), 23.2 (t), 27.2 (t), 28.0 (q), 29.2 (t), 29.3 (t), 29.4 (t), 29.5 (t), 29.6 (t), 29.7 (t), 31.9
(t), 32.2 (t), 53.1 (d), 80.2 (s), 127.4 (d), 131.8 (d), 155.6 (s), 177.6 (s); IR (CHCl3) (cm−1) 3441, 2928,
2855, 1712, 1504, 1369, 1165; MS (FAB) m/z (relative intensity) 464 (M+K) (10), 448 (M+Na) (85), 404
(7), 392 (28), 380 (4), 370 (28), 364 (56), 348 (15), 326 (100). Anal. calcd for C25H47NO4: C, 70.53; H,
11.14; N, 3.29. Found: C, 70.52; H, 10.61; N, 3.39.

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3.6. General procedure for the synthesis of saturated lipidic N,N-di-Boc-α-amino esters: methyl (2S)-2-
{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}icosanoate 17
To a stirred solution of 10 (202 mg, 0.37 mmol) in dry EtOAc (0.1 M) was added Pd/C (20 mg). The
reaction was stirred under hydrogen atmosphere until TLC showed complete conversion. The mixture
was filtered through a pad of Celite, the solvent was evaporated and the crude purified by silica gel
column chromatography to afford 15 (196 mg, 98% yield) as an oil: [α]25 −26.0 (c 2.07, CHCl3); H
1
D
NMR (CDCl3) δ 0.87 (t, J=6.5 Hz, 3H), 1.25 (br s, 32H), 1.49 (s, 18H), 1.88 (m, 1H), 2.06 (m, 1H),
3.70 (s, 3H), 4.83 (dd, J=9.6, 4.8 Hz, 1H); 13C NMR (CDCl3) δ 14.1 (q), 22.6 (t), 26.1 (t), 28.0 (q), 29.2
(t), 29.3 (t), 29.4 (t), 29.5 (t), 29.6 (t), 29.7 (t), 29.8 (t), 31.9 (t), 52.0 (q), 58.1 (d), 82.9 (s), 152.1 (s),
171.5 (s); IR (CHCl3) (cm−1) 3044, 2925, 2856, 1725, 1700, 1540, 1369, 1238, 1125; MS m/z (relative
intensity) 385 (M−157)+ (2), 326 (48), 282 (26), 133 (5), 57 (100). Anal. calcd for C31H59NO6: C, 68.72;
H, 10.98; N, 2.59. Found: C, 68.66; H, 10.92; N, 2.74.
3.7. Methyl (2S)(5Z,8Z)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}icosa-5,8-
dienoate 18
The general procedure for the synthesis of (Z)-unsaturated lipidic α-amino esters was applied to 9 on
a 1 g (2.9 mmol) scale using the ylide of (3Z)-3-pentadecenyl-triphenylphosphonium iodide, yielding 16
(1.32 g, 85% yield) as an oil: [α]25 −29.2 (c 3.37, CHCl3); 1H NMR (CDCl3) δ 0.87 (t, J=7.0 Hz, 3H),
D
1.26 (br s, 18H), 1.49 (s, 18H), 1.93 (m, 1H), 2.02 (m, 2H), 2.15 (m, 3H), 2.76 (dd, J=5.7, 5.7 Hz, 2H),
3.71 (s, 3H), 4.87 (dd, J=8.8, 4.5 Hz, 1H), 5.35 (m, 4H); 13C NMR (CDCl3) δ 14.1 (q), 22.7 (t), 24.0 (t),
25.6 (t), 27.2 (t), 28.0 (q), 29.3 (t), 29.5 (t), 29.6 (t), 29.7 (t), 30.0 (t), 31.9 (t), 52.1 (q), 57.7 (d), 83.0
(s), 127.6 (d), 128.4 (d), 129.4 (d), 130.5 (d), 152.1 (s), 171.3 (s); IR (CHCl3) (cm−1) 3021, 2928, 2855,
1790, 1742, 1698, 1457, 1369, 1143; MS m/z (relative intensity) 362 (M−175)+ (12), 337 (28), 278 (90),
222 (37), 194 (38), 157 (46), 142 (67), 128 (100), 114 (30). Anal. calcd for C31H55NO6: C, 69.22; H,
10.31; N, 2.61. Found: C, 69.14; H, 10.55; N, 2.57.
3.8. Methyl (2S)(5Z,11Z)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}icosa-5,11-
dienoate 19
The general procedure for the synthesis of (Z)-unsaturated lipidic α-amino esters was applied to 9 on a
1.42 g (4.11 mmol) scale using the ylide of (6Z)-6-pentadecenyl-triphenylphosphonium iodide, yielding
17 (1.8 g, 84% yield) as an oil: [α]25 −29.9 (c 2.76, CHCl3); H NMR (CDCl3) δ 0.88 (t, J=7.2 Hz,
1
D
3H), 1.30 (br s, 16H), 1.49 (s, 18H), 1.92 (m, 1H), 2.02 (m, 6H), 2.15 (m, 3H), 3.71 (s, 3H), 4.87 (dd,
J=8.8, 4.4 Hz, 1H), 5.36 (m, 4H); 13C NMR (CDCl3) δ 14.1 (q), 22.7 (t), 24.0 (t), 27.1 (t), 27.2 (t), 28.0
(q), 29.3 (t), 29.4 (t), 29.5 (t), 29.8 (t), 30.1 (t), 31.9 (t), 52.1 (q), 57.7 (d), 83.0 (s), 128.2 (d), 129.6 (d),
130.0 (d), 131.1 (d), 152.1 (s), 171.4 (s); IR (CHCl3) (cm−1) 3021, 2928, 2856, 1790, 1742, 1698, 1457,
1370, 1142; MS m/z (relative intensity) 364 (M−173)+ (11), 337 (21), 278 (68), 196 (10), 143 (24), 133
(100), 115 (22). Anal. calcd for C31H55NO6: C, 69.22; H, 10.31; N, 2.61. Found: C, 69.15; H, 10.47; N,
2.60.

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3.9. Methyl (2S)(5Z,14Z)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}icosa-5,14-
dienoate 20
The general procedure for the synthesis of (Z)-unsaturated lipidic α-amino esters was applied to 9 on a
536 mg (1.55 mmol) scale using the ylide of (9Z)-9-pentadecenyl-triphenylphosphonium iodide, yielding
19 (716 mg, 86% yield) as an oil: [α]25 −27.5 (c 2.20, CHCl3); 1H NMR (CDCl3) δ 0.87 (t, J=6.9 Hz,
D
3H), 1.30 (br s, 16H), 1.48 (s, 18H), 1.90 (m, 1H), 1.99 (m, 6H), 2.07 (m, 3H), 3.69 (s, 3H), 4.85 (dd,
J=8.8, 4.4 Hz, 1H), 5.33 (m, 4H); 13C NMR (CDCl3) δ 14.0 (q), 22.5 (t), 24.0 (t), 27.1 (t), 27.2 (t), 28.0
(q), 29.2 (t), 29.4 (t), 29.6 (t), 29.7 (t), 30.1 (t), 31.4 (t), 52.0 (q), 57.7 (d), 82.9 (s), 128.0 (d), 129.8 (d),
129.8 (d), 131.2 (d), 152.0 (s), 171.3 (s); IR (CHCl3) (cm−1) 3030, 2929, 2856, 1787, 1742, 1698, 1457,
1370, 1143; MS m/z (relative intensity) 381 (M−156)+ (5), 337 (15), 278 (32), 142 (10), 133 (83), 101
(17), 57 (100). Anal. calcd for C31H55NO6: C, 69.22; H, 10.31; N, 2.61. Found: C, 69.14; H, 10.74; N,
2.64.
3.10. Methyl (5Z,8Z,11Z,14Z)-(2S)-2-di-tert-butoxycarbonylamino-5,8,11,14-eicosa-tetraenoate 21
The general procedure for the synthesis of (Z)-unsaturated lipidic α-amino esters was applied to 9 on
a 993 mg (2.87 mmol) scale using the ylide of (3Z,6Z,9Z)-3,6,9-pentadecatrienyl-triphenylphosphonium
iodide, yielding 20 (1.34 g, 88% yield) as an oil: [α]25 −27.7 (c 2.00, CHCl3); 1H NMR (CDCl3) δ 0.88
D
(t, J=6.2 Hz, 3H), 1.30 (m, 6H), 1.49 (s, 18H), 1.93 (m, 1H), 2.03 (m, 2H), 2.15 (m, 3H), 2.81 (m, 6H),
3.70 (s, 3H), 4.87 (dd, J=8.5, 4.4 Hz, 1H), 5.36 (m, 8H); 13C NMR (CDCl3) δ 14.1 (q), 22.5 (t), 24.0 (t),
25.6 (t), 27.2 (t), 28.0 (q), 29.3 (t), 30.0 (t), 31.5 (t), 52.1 (q), 57.6 (d), 83.0 (s), 127.5 (d), 127.8 (d), 128.1
(d), 128.2 (d), 128.6 (d), 128.7 (d), 129.0 (d), 130.4 (d), 152.1 (s), 171.3 (s); IR (CHCl3) (cm−1) 3525,
3010, 2932, 2860, 1787, 1742, 1698, 1457, 1370, 1143; MS m/z (relative intensity) 377 (M−157)+ (1),
274 (4), 174 (11), 142 (55), 133 (33), 128 (100), 95 (28), 81 (55), 57 (100). Anal. calcd for C31H51NO6:
C, 69.76; H, 9.63; N, 2.62. Found: C, 69.70; H, 9.90; N, 2.76.
3.11. General procedure for the synthesis of unsaturated (E)-N,N-di-Boc-α-amino diesters: dimethyl
(2E)(6S)-6-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}hept-2-ene-dioate 22
To a stirred solution of 9 (345 mg, 1 mmol) in benzene (10 ml) was added commercially available
methyl (triphenylphosphoranylidene)acetate (400 mg, 1.2 mmol) at 0°C. The mixture was stirred until
TLC showed the end of the reaction. The reaction mixture was evaporated and the crude purified by silica
gel chromatography to yield 21 (356 mg, 89% yield) as an oil: [α]25 −33.0 (c 2.54, CHCl3); 1H NMR
D
(CDCl3) δ 1.44 (s, 18H), 2.00 (m, 1H), 2.23 (m, 3H), 3.67 (s, 6H), 4.92 (dd, J=9.5, 4.6 Hz, 1H), 5.80 (d,
J=15.6 Hz, 1H), 6.90 (m, 1H); 13C NMR (CDCl3) δ 27.9 (q), 28.3 (t), 28.8 (t), 51.3 (q), 52.1 (q), 57.4
(d), 83.2 (s), 121.6 (d), 147.8 (d), 151.9 (s), 166.7 (s), 170.8 (s); IR (CHCl3) (cm−1) 2987, 1781, 1735,
1645, 1361, 1142; MS m/z (relative intensity) 402 (M+1)+ (1), 346 (4), 245 (15), 201 (60), 142 (100),
128 (27), 110 (49), 57 (100). Anal. calcd for C19H31NO8: C, 56.83; H, 7.79; N, 3.49. Found: C, 56.54;
H, 7.87; N, 3.49.
3.12. Dimethyl (2Z)(6S)-6-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}hept-2-ene-dioate
23
The general procedure for the synthesis of lipidic (Z)-unsaturated N,N-di-Boc-α-amino esters was
applied to 9 on a 536 mg (1.55 mmol) scale, using methyl (diphenoxyphosphoryl)acetate (1.11 g, 1.86

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3391
mmol), yielding 23 (716 mg, 86% yield) as an oil: [α]25 −52.0 (c 1.56, CHCl3); H NMR (CDCl3) δ
1
D
1.41 (s, 18H), 1.96 (m, 1H), 2.19 (m, 1H), 2.26 (m, 2H), 3.60 (s, 3H), 3.62 (s, 3H), 4.81 (dd, J=9.6, 5.2
Hz, 1H), 5.70 (d, J=11.6 Hz, 1H), 6.90 (m, 1H); 13C NMR (CDCl3) δ 25.7 (t), 27.9 (q), 29.2 (t), 50.8 (q),
52.0 (q), 57.5 (d), 83.0 (s), 120.1 (d), 148.6 (d), 151.9 (s), 166.3 (s), 170.9 (s); IR (CHCl3) (cm−1) 2984,
1788, 1742, 1646, 1439, 1370, 1143; MS m/z (relative intensity) 346 (M−69)+ (20), 290 (16), 202 (50),
142 (36), 124 (10), 57 (100). Anal. calcd for C19H31NO8: C, 56.83; H, 7.79; N, 3.49. Found: C, 56.52;
H, 7.99; N, 3.47.
3.13. Dimethyl (S)-2-tert-butoxycarbonylamino-butanodioate 25
The general one-pot protection of free α-amino acids was applied to commercially available L-aspartic
acid on a 1.33 g (10 mmol) scale yielding 25 (2.43 g, 93% yield) as a white solid: mp=60°C; [α]25 +30.8
D
1
(c 2.1, CHCl3); H NMR (CDCl3) δ 1.42 (s, 9H), 2.79 (dd, J=16.9, 4.7 Hz, 1H), 2.97 (d, J=16.9 Hz,
1H), 3.67 (s, 3H), 3.73 (s, 3H), 4.55 (br s, 1H), 5.48 (br s, 1H); 13C NMR (CDCl3) δ 28.2 (q), 36.6 (t),
49.9 (d), 51.9 (q), 52.6 (q), 80.1 (s), 155.3 (s), 171.3 (s), 171.5 (s); IR (CHCl3) (cm−1) 3440, 3029, 2982,
1733, 1711, 1501, 1369, 1227, 1166; MS m/z (relative intensity) 262 (M+1)+ (20), 205 (79), 162 (58),
145 (73), 127 (20), 102 (100), 59 (85), 57 (100). Anal. calcd for C11H19NO6: C, 50.55; H, 7.33; N, 5.36.
Found: C, 50.66; H, 7.32; N, 5.28.
3.14. Dimethyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}butane-1,4-dioate 26
The general procedure for the di-N-Boc-protection was applied to 25 on a 2.1 g (8 mmol) scale,
yielding 26 (2.83 g, 98% yield) as a white solid: mp=57°C; [α]25 −61.0 (c 2.0, CHCl3); H NMR
1
D
(CDCl3) δ 1.49 (s, 18H), 2.72 (dd, J=16.4, 6.6 Hz, 1H), 3.23 (dd, J=16.4, 7.0 Hz, 1H), 3.69 (s, 3H), 3.72
(s, 3H), 5.43 (dd, J=6.8, 6.8 Hz, 1H); 13C NMR (CDCl3) δ 7.9 (q), 35.7 (t), 51.9 (q), 52.5 (q), 54.9 (d),
83.5 (s), 151.5 (s), 170.2 (s), 171.0 (s); IR (CHCl3) (cm−1) 3031, 2984, 1791, 1743, 1698, 1370, 1271,
1142; MS m/z (relative intensity) 362 (M+1)+ (1), 302 (16), 217 (36), 205 (47), 188 (25), 162 (100), 146
(100), 128 (34), 102 (100), 86 (50), 57 (100). Anal. calcd for C16H27NO8: C, 53.18; H, 7.53; N, 3.88.
Found: C, 53.13; H, 7.51; N, 3.84.
3.15. Methyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}-4-oxobutanoate 27
The general reduction of the ω-ester to the corresponding aldehyde was applied to 26 on a 2.89 g (8.0
mmol) scale yielding 27 (2.33 g, 88% yield) as an oil: [α]25 −54.9 (c 2.0, CHCl3); 1H NMR (CDCl3) δ
D
1.48 (s, 18H), 2.82 (dd, J=17.0, 6.6 Hz, 1H), 3.38 (dd, J=17.0, 7.0 Hz, 1H), 3.71 (s, 3H), 5.50 (dd, J=6.6,
6.6 Hz, 1H), 9.76 (s, 1H); 13C NMR (CDCl3) δ 27.9 (q), 44.9 (t), 52.5 (q), 52.9 (d), 83.6 (s), 151.6 (s),
170.2 (s), 198.3 (d); IR (CHCl3) (cm−1) 3026, 2984, 1792, 1744, 1698, 1370, 1146; MS m/z (relative
intensity) 288 (M−43)+ (4), 247 (12), 191 (51), 147 (70), 132 (100), 116 (100), 103 (59), 88 (100), 72
(83), 57 (100). Anal. calcd for C15H25NO7: C, 54.35; H, 7.61; N, 4.23. Found: C, 54.29; H, 7.75; N, 4.19.
3.16. Methyl (2S)(4Z)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}nonadec-4-enoate
28
The general procedure for the synthesis of (Z)-unsaturated lipidic α-amino esters was applied to 27 on
a 2 g (6 mmol) scale using n-pentadecyl-triphenylphosphonium bromide (3.85 g, 7 mmol), yielding 28
(2.8 g, 89% yield) as an oil: [α]25 −54.9 (c 2.02, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, J=6.4 Hz, 3H),
D

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J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
1.25 (br s, 22H), 1.49 (s, 18H), 2.02 (m, 2H), 2.74 (m, 1H), 2.81 (m, 1H), 3.71 (s, 3H), 4.92 (dd, J=10.0,
4.9 Hz, 1H), 5.33 (m, 1H), 5.48 (m, 1H); 13C NMR (CDCl3) δ 14.0 (q), 22.6 (t), 27.3 (t), 28.0 (q), 29.3
(t), 29.5 (t), 29.6 (t), 31.9 (t), 52.1 (q), 58.1 (d), 82.8 (s), 124.4 (d), 133.4 (d), 152.0 (s), 171.0 (s); IR
(CHCl3) (cm−1) 3029, 2927, 2854, 1787, 1738, 1696, 1370, 1278, 1145; MS m/z (relative intensity) 526
(M+1)+ (1), 414 (8), 308 (32), 133 (15), 111 (16), 88 (20), 57 (100). Anal. calcd for C30H55NO6: C,
68.52; H, 10.55; N, 2.71. Found: C, 67.99; H, 10.94; N, 2.71.
3.17. Dimethyl (2E)(5S)-5-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}hex-2-ene-1,6-
dioate 29
The general procedure for the synthesis of unsaturated (E)-N,N-di-Boc-α-amino diesters was applied
to 27 on a 2 g (6 mmol) scale, yielding 28 (2.1 g, 90% yield): [α]25 −55.5 (c 2.17, CHCl3); 1H NMR
D
(CDCl3) δ 1.46 (s, 18H), 2.81 (m, 1H), 2.96 (m, 1H), 3.67 (s, 3H), 3.70 (s, 3H), 4.99 (dd, J=9.6, 5.1 Hz,
1H), 5.84 (d, J=15.6 Hz, 1H), 6.87 (m, 1H); 13C NMR (CDCl3) δ 27.8 (q), 33.0 (t), 51.3 (q), 52.3 (q),
56.9 (d), 83.4 (s), 123.7 (d), 144.2 (d), 151.7 (s), 166.3 (s), 170.1 (s); IR (CHCl3) (cm−1) 2987, 1780,
1735, 1645, 1360, 1142; MS m/z (relative intensity) 316 (M−71)+ (1), 302 (1), 228 (1), 100 (6), 57 (100).
Anal. calcd for C18H29NO8: C, 55.80; H, 7.54; N, 3.62. Found: C, 55.81; H, 7.74; N, 3.69.
3.18. Dimethyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}heptanedioate 30
The general procedure for the synthesis of saturated lipidic N,N-di-Boc-α-amino esters was applied
to 22 on a 1.2 g (4 mmol) scale, yielding 30 (1.14 g, 93% yield) as an oil: [α]25 −31.0 (c 2.22, CHCl3);
D
1H NMR (CDCl3) δ 1.38 (m, 2H), 1.49 (s, 18H), 1.65 (m, 2H), 1.87 (m, 1H), 2.10 (m, 1H), 2.31 (dd,
J=7.5, 7.5 Hz, 2H), 3.66 (s, 3H), 3.70 (s, 3H), 4.84 (dd, J=9.4, 5.2 Hz, 1H); 13C NMR (CDCl3) δ 24.6
(t), 25.8 (t), 27.9 (q), 29.6 (t), 33.9 (t), 51.4 (q), 52.1 (q), 57.9 (d), 83.0 (s), 152.1 (s), 171.3 (s), 173.8 (s);
IR (CHCl3) (cm−1) 3024, 2984, 1789, 1742, 1699, 1370, 1140; MS m/z (relative intensity) 344 (M−59)+
(1), 288 (2), 244 (2), 188 (6), 57 (100). Anal. calcd for C19H33NO8: C, 56.56; H, 8.24; N, 3.47. Found:
C, 56.54; H, 8.29; N, 3.54.
3.19. Dimethyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}hexanedioate 31
The general procedure for the synthesis of saturated lipidic N,N-di-Boc-α-amino esters was applied to
29 on a 0.6 g (2.1 mmol) scale, yielding 31 (570 g, 93% yield) as an oil: [α]25 −35.9 (c 2.25, CHCl3);
D
1H NMR (CDCl3) δ 1.48 (s, 18H), 1.67 (m, 2H), 1.91 (m, 1H), 2.09 (m, 1H), 2.33 (m, 2H), 3.64 (s,
3H), 3.71 (s, 3H), 4.85 (dd, J=9.6, 5.1 Hz, 1H); 13C NMR (CDCl3) δ 21.7 (t), 28.0 (q), 29.4 (t), 33.6
(t), 51.5 (q), 52.1 (q), 57.8 (d), 83.2 (s), 152.1 (s), 171.1 (s), 173.6 (s); IR (CHCl3) (cm−1) 3020, 2982,
1786, 1740, 1699, 1370, 1140; MS m/z (relative intensity) 330 (M−59)+ (1), 274 (1), 230 (4), 174 (17),
57 (100). Anal. calcd for C18H31NO8: C, 55.51; H, 8.02; N, 3.60. Found: C, 55.51; H, 8.07; N, 3.69.
3.20. Methyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}-7-oxoheptanoate 32
The general reduction of the ω-ester to the corresponding aldehyde was applied to 29 on a 2 g (5.1
mmol) scale, yielding 31 (1.6 g, 87% yield) as an oil: [α]25 −32.4 (c 4.3, CHCl3); 1H NMR (CDCl3) δ
D
1.38 (m, 2H), 1.49 (s, 18H), 1.65 (m, 2H), 1.87 (m, 1H), 2.10 (m, 1H), 2.43 (dd, J=9.7, 1.93 Hz, 2H),
3.71 (s, 3H), 4.84 (dd, J=12.5, 7.0 Hz, 1H), 9.75 (s, 1H); 13C NMR (CDCl3) δ 25.8 (t), 27.1 (t), 28.0
(q), 29.6 (t), 43.6 (t), 52.1 (q), 57.8 (d), 83.1 (s), 152.1 (s), 171.2 (s), 202.2 (s); IR (CHCl3) (cm−1) 3028,

J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
3393
2984, 1789, 1742, 1370, 1144; MS m/z (relative intensity) 330 (M−43)+ (2), 300 (1), 230 (6), 57 (100).
Anal. calcd for C18H31NO7: C, 57.89; H, 8.37; N, 3.75. Found: C, 57.86; H, 8.48; N, 3.59.
3.21. Methyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino}-7-oxohexanoate 33
The general reduction of the ω-ester to the corresponding aldehyde was applied to 30 on a 1.2 g (3.2
mmol) scale, yielding 31 (905 mg, 82% yield) as an oil: [α]25 −30.2 (c 3.3, CHCl3); 1H NMR (CDCl3)
D
δ 1.48 (s, 18H), 1.67 (m, 2H), 1.92 (m, 1H), 2.12 (m, 1H), 2.41 (m, 1H), 2.48 (m, 1H), 3.70 (s, 3H),
4.85 (dd, J=9.4, 5.1 Hz, 1H), 9.75 (s, 1H); 13C NMR (CDCl3) δ 18.7 (t), 21.3 (t), 28.0 (q), 29.3 (t), 52.2
(q), 57.6 (d), 83.3 (s), 152.0 (s), 171.1 (s), 201.9 (s); IR (CHCl3) (cm−1) 3024, 2980, 1789, 1742, 1699,
1370, 1142; MS m/z (relative intensity) 330 (M−29)+ (1), 258 (1), 230 (1), 57 (100). Anal. calcd for
C17H29NO7: C, 56.81; H, 8.13; N, 3.90. Found: C, 56.88; H, 8.38; N, 3.50.
Acknowledgements
This research was supported by the DGICYT (PB95-0751) of Spain, the Human Capital and Mobility
Program (ERBCHRXCT93-0288) of the European Community and the Consejería de Educación, Cultura
y Deportes del Gobierno de Canarias. J.M.P. and T.M. thank the Gobierno Autónomo de Canarias for a
fellowship.
References
1. Kokotos, G.; Martín, V. S.; Constantinou-Kokotou, V.; Gibbons, W. A. Amino Acids 1996, 11, 329.
2. Kokotos, G.; Hadjipavlou-Litina, D.; Constantinou-Kokotou, V.; Noula, C.; Gibbons, W. A. 5th International Congress on
Amino Acids, Chalkidiki, Greece, 25–29 August 1997; abstract in Amino Acids 1997, 13, 36.
3. Kokotos, G.; Theodorou, V.; Constantinou-Kokotou, V.; Gibbons, W. A.; Roussakis, C. Bioorg. Med. Chem. Lett. 1998, in
press.
4. Hirose, R.; Hamamichi, N.; Kitao, Y.; Matsuzaki, T.; Chiba, K.; Fujita, T. Bioorg. Med. Chem. Lett. 1996, 6, 2647.
5. (a) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids; Chapman and Hall: London, 1985. (b) Williams, R. M.
In Organic Chemistry Series: Synthesis of Optically Active α-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds; Pergamon:
Oxford, 1989. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
6. Kokotos, G.; Padrón, J. M.; Noula, C.; Gibbons, W. A.; Martín, V. S. Tetrahedron: Asymmetry 1996, 7, 857.
7. Kokotos, G.; Padrón, J. M.; Martín, T.; Gibbons, W. A.; Martín, V. S. J. Org. Chem. 1998, 63, 3741.
8. Presented in part at the 5th International Congress on Amino Acids, Chalkidiki, Greece, 25–29 August 1997; abstract in
Amino Acids 1997, 13, 77.
9. (a) Meffre, P.; Durand, P.; Le Goffic, F. Synthesis 1995, 1111. (b) Omstein, P. L.; Melikian, A.; Martinelli, M. J. Tetrahedron
Lett. 1994, 35, 5759. (c) Robl, J. A. Tetrahedron Lett. 1994, 35, 393. (d) Dehmlow, E. V.; Westerheide, R. Synthesis 1993,
1225. (e) Bold, G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405. (f) Baldwin, J. E.; Flinn, A.
Tetrahedron Lett. 1987, 28, 3605. (g) Benz, G. Liebigs Ann. Chem. 1984, 1424.
10. Gmeiner, P.; Kärtner, A.; Junge, D. Tetrahedron Lett. 1993, 34, 4325–4326.
11. The phosphonium salts were prepared by refluxing Ph3P and the corresponding alkyl halide in CH3CN at 80°C for 5–10
h, and were used in the Wittig reactions without purification.
12. Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis, 2nd Edition; John Wiley & Sons: New York,
1991.
13. Brook, M. A.; Chan, T. H. Synthesis 1983, 201.
14. Ponnusamy, E.; Fotadar, U.; Spisni, A.; Fiat, D. Synthesis 1986, 48.
15. Almeida, M. L. S.; Grehn, L.; Ragnarsson, U. J. Chem. Soc., Perkin Trans. 1 1988, 1905.
16. Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org. Chem. 1980, 45, 4260.
17. Bodanszky, M.; Bodanszky, A. In The Practice of Peptide Synthesis; Springer-Verlag: Berlin, 1984, p. 177.

3394
J. M. Padrón et al. / Tetrahedron: Asymmetry 9 (1998) 3381–3394
18. (a) Buehler, C. A.; Pearson, D. A. In Survey of Organic Synthesis; Wiley-Interscience: New York, 1970, Vol. I, p. 801 and
II, p. 711. (b) Callahan, J. F.; Newlander, K. A.; Bryan, H. G.; Huffman, W. F.; Moore, M. L.; Yim, N. C. F. J. Org. Chem.
1988, 53, 1727.
19. Kokotos, G.; Constantinou-Kokotou, V.; Del Olmo, E.; Toth, I.; Gibbons, W. A. Liebigs Ann. Chem. 1992, 961.
20. The unsaturated alkyl halides were prepared from the suitable alcohol (Ph3P, imidazole, I2), that was obtained by
hydrogenation of the corresponding acetylene. For the synthesis of similar acetylenes, see: (a) Añorbe, B.; Martín, V.
S.; Palazón, J. M.; Trujillo, J. M. Tetrahedron Lett. 1986, 27, 4991. (b) Palazón, J. M.; Martín, V. S. ibid. 1988, 29, 681.
21. Ando, K. Tetrahedron Lett. 1995, 36, 4105.