A new methodology for the synthesis of β-amino acids

Article abstract of DOI:10.1039/a908747h

A differentially functionalized succinic acid unit 6 undergoes alkylation with excellent regio- and high stereocontrol at the carbon α to the imide to furnish the alkylated product 7 in 60-83% yield. Selective removal of the imide provides 8 in 80-90% yie

Full text of DOI:10.1039/a908747h

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A new methodology for the synthesis of ꢀ-amino acids
Mukund P. Sibi* and Prasad K. Deshpande
Department of Chemistry, North Dakota State University, Fargo, ND 58105
Received (in Cambridge, UK) 3rd November 1999, Accepted 4th February 2000
1
A differentially functionalized succinic acid unit 6 undergoes alkylation with excellent regio- and high stereocontrol
at the carbon α to the imide to furnish the alkylated product 7 in 60–83% yield. Selective removal of the imide
provides 8 in 80–90% yields. Curtius rearrangement of 8 with retention of stereochemistry provides N-protected
β-amino acids (9) in 70–83% yields. Alternatively, selective deprotection of the ester group followed by Curtius
rearrangement provides isomeric β-amino acids 14a, 14b, and 14e in good yields. The methodology has been
successfully applied to the synthesis of N-Boc-iturinic acid and 2-methyl-3-aminopropanoic acid, components
of the antifungal peptide iturin and the cytotoxic depsipeptide cryptophycin respectively.
Naturally occurring β-amino acids are compounds with an
interesting pharmacological profile.1 They are also found as
components in a wide variety of biologically active com-
pounds2 including peptides such as bestatin3 and pepstatin.4
The β-amino acids are useful precursors in the synthesis of
β-lactams.5 Recently, α-substituted β-amino acids have received
greater scrutiny since they serve as important segments of bio-
active molecules. For example, one of the promising anti-
tumor agents in cancer chemotherapy, Paclitaxel, contains an
α-hydroxy β-amino acid side chain as its key pharmacophore.6
Given the importance of the β-amino acids, development of a
general methodology for their synthesis is important.
regio- and stereoselective manner. The succinate unit is an ideal
fragment23 for the synthesis of β-amino acids if substituents
can be introduced regio- and stereoselectively on the carbon
framework and further selective conversion of one of the
carboxy groups to an amino functionality can occur. Scheme 1
A variety of diastereoselective methods have been reported
for the synthesis of β-amino acids.7 These include the elegant
chemistry from the Davies group8 on the addition of chiral
nitrogen nucleophiles to enoates and addition of achiral amines
to chiral enoates by d’Angelo and co-workers.9 Other diastereo-
selective methodologies for β-amino acids, which do not involve
conjugate amine additions, have also been reported. Most not-
able of these are the Davis’s chemistry10 of chiral sulfinimines,
Seebach’s11 hydropyrimidines, Juaristi’s pyrimidinones,12 and
Konopelski’s13 dihydropyrimidinones. Wyatt and co-workers14
have reported a new method for the synthesis of β-amino acids,
which involves chiral enolate alkylation with ‘NH2CH2’ equiv-
alents (ZNHCH2OAc or BrCH2COOR). Recently, Evans and
co-workers reported a protocol for β-amino acids, which also
involves chiral enolate alkylation with BrCH2COOR followed
by selective hydrolysis and Curtius rearrangement.15
Only a few reports of chiral Lewis acid catalyzed conjugate
additions of amines to enoates have appeared. The first report
was the work of Jørgensen16 in which a chiral titanium Lewis
acid was employed. Ishikawa has reported that N-benzyl-
hydroxylamine adds to enoates with moderate selectivity using
a chiral aluminium TADDOLate.17 We have recently shown
that 3,5-dimethylpyrazole derived enoates undergo conjugate
amine addition with high enantioselectivity using substoichio-
metric amounts of chiral Lewis acids.18 One of the most
successful methodologies for the synthesis of functionalized
β-amino acids with high selectivity is Sharpless’s amino-
hydroxylation.19 Other selected nonconjugate addition method-
ologies for the synthesis of β-amino acids (or derivatives)
which utilize chiral Lewis acids are Corey’s addition to imines,20
and Yamamoto’s21 Diels–Alder reaction.
Scheme 1
illustrates our approach wherein the starting material is a
readily available succinate unit 1. This method is comple-
mentary to the recently published work from Evans’ group.15
The two carboxy groups are differentiated by forming an ester
at one end and by attachment of a chiral auxiliary (oxazol-
idinone) to the other carboxy group. With the two ends
differentiated, the first step is a regio- and stereoselective func-
tionalization at the carbon α to the imide to furnish 2. The
second step involves the selective removal of either the imide or
the ester functionality followed by a Curtius rearrangement of
the free carboxy group with retention of stereochemistry (if
applicable). Thus, intermediate 2 serves as a common precursor
for two different β-amino acids 3 and 4. The realization of the
above strategy and its application in the synthesis of β-amino
acid components of biologically active peptides iturin and
cryptophycin are illustrated.
Our methodology begins with the attachment of the mono
tert-butyl succinate24 to an oxazolidinone 5 derived from
-diphenylalaninol by an anhydride method to provide 6
(Scheme 2).25 The preparation26 of 5 has been accomplished
in our laboratory.27 Treatment of 6 with one equivalent of
NaHMDS in THF at Ϫ78 ЊC for 20 minutes followed by
quenching with a reactive alkyl bromide furnished the mono
alkylated compounds in good chemical yields and diastereo-
We have addressed in this paper the synthesis of β-amino
acids in the context of a general methodology involving
functionalization of linear dicarboxylic acid derivatives22 in a
DOI: 10.1039/a908747h
J. Chem. Soc., Perkin Trans. 1, 2000, 1461–1466
This journal is © The Royal Society of Chemistry 2000
1461

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Table 1 Synthesis of N-protected β-amino acids
Yield 7
Yield 8
(%)
Yield 9
(%)
Entry RBr
[%a (de)b]
a
b
c
d
e
C6H5CH2Br
Allyl bromide
(E)-1-Bromoundec-3-ene 60 (>97)
Cinnamyl bromide
Methyl iodide
83 (92)
72 (92)
90
88
87
80
83
80
70
78
73 (84)
83 (81)
a Yields are for column purified material. b de’s were determined by 1H
NMR analysis of the crude alkylation products.
Scheme 3 Reagents and conditions: (a) Pd/C, EtOH, H2, 100%; (b) (i)
TFA, CH2Cl2, rt, (ii) Boc2O, Et3N, rt, 73% (two steps).
Scheme 2 Reagents and conditions: (a) DCC, CH2Cl2, HO2CH2-
CCH2CO2t-Bu, LiCl, Et3N, THF, rt, 86%; (b) (i) NaHMDS, THF,
Ϫ78 ЊC, (ii) RBr, Ϫ78 ЊC, 1 h, warm to Ϫ48 ЊC, 3 h; (c) LiOH–H2O2,
THF–H2O, Ϫ5 to 0 ЊC; (d) (i) Et3N, ClCO2Et, acetone, 0 ЊC, 1 h, (ii)
NaN3, H2O, acetone, 0 ЊC, 1 h, (iii) toluene, heat, 1 h, (iv) t-BuOH, heat,
24 h.
selectivity (Scheme 2, Table 1). Temperature and counterion
play an important role in the generation of the enolate. When
reactions were warmed to above Ϫ48 ЊC after sodium enolate
generation, cleavage of the chiral auxiliary was observed.
Similarly, lithium enolates were found to be unstable at Ϫ78 ЊC.
The regioselectivity observed in enolate generation from 6 may
be attributed to the increased acidity of these α-hydrogens
adjacent to imide over the ester.28 The next step involved the
selective hydrolysis of the imide functionality. This could be
accomplished by the treatment of 7 with LiOH–H2O2 in THF–
H2O at low temperatures to furnish 8. The key step in our
methodology was the one-pot conversion of the carboxy group
to the protected amino group with retention of stereochemistry
(8→9). This was carried out using a Curtius rearrangement29
in moderate to good yields (Table 1).30 The stereochemical
outcome in this rearrangement is well precedented in the liter-
ature.31 Thus, the synthesis of β-amino acids could be accom-
plished in four steps in good overall yields and high optical
purity. The absolute stereochemistry of the newly formed chiral
center was established by conversion to compounds of known
configuration (vide infra).32
Scheme 4 Reagents and conditions: (a) TFA, CH2Cl2, rt, 2 h; (b) (i)
Et3N, ClCO2Et, acetone, 0 ЊC, 15 min, (ii) NaN3, H2O, acetone, 0 ЊC,
15 min, (iii) toluene, heat, 1 h, (iv) t-BuOH, heat 12 h; (c) LiO2H,
THF–H2O, Ϫ5 to 0 ЊC.
toxins associated with the terrestrial blue–green algae Nostoc
sp.36,37
In conclusion we have developed a new methodology for the
preparation of a variety of β-amino acids in excellent optical
purity. The application of the new protocol in the synthesis of
β-amino acid segments of biologically active peptides was also
illustrated. Extension of the new methodology in the synthesis
of more complex targets is underway.
The utility of the new methodology is illustrated in the
synthesis of N-Boc-iturinic acid (n-C14),33 the β-amino acid
component of naturally occurring antifungal peptide iturin
(Scheme 3). Catalytic hydrogenation of the β-amino acid 9c
furnished the saturated compound 10 in quantitative yield.
Cleavage of the tert-butyl as well as the N-Boc functionalities
using TFA followed by reprotection of the amino group pro-
vided (ϩ)-N-Boc-iturinic acid.34 This synthesis also establishes
the absolute stereochemistry of the Curtius rearrangement
products.
The intermediate 7 also serves as a useful precursor for the
synthesis of isomeric β-amino acids (Scheme 4). Selective
deprotection of the tert-butyl ester functionality was achieved
in high yields using trifluoroacetic acid.35 Curtius rearrange-
ment followed by cleavage of the imide provided the isomeric
β-amino acids in good yields (12→14). The amino acid 14e
is a component of cryptophycins, potent tumor-selective cyto-
Experimental
General
NaHMDS (1 M solution in THF), allyl bromide, benzyl brom-
ide were purchased from Aldrich. All bromides were purified
over neutral alumina prior to use. Tetrahydrofuran was distilled
from benzophenone–ketyl prior to use. Thin layer chromato-
graphic analyses were performed on silica gel Whatmann-60 F
glass plates and components were visualized by illumination
with UV light or by staining with phosphomolybdic acid. Flash
chromatography was performed using E. Merck silica gel
60 (230–400 mesh). Melting points were determined using a
Thomas Hoover capillary melting point apparatus, and are
uncorrected. All glassware was oven and/or flame dried,
assembled hot, and cooled under a stream of dry nitrogen or
argon before use. Reactions with air sensitive materials were
carried out by standard syringe techniques.
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1H NMR were recorded on JEOL GSX-400 (400 MHz) and
JEOL GSX-270 (270 MHz) spectrometers. Chemical shifts are
reported in parts per million (ppm) downfield from TMS, using
TMS (0.00 ppm) as an internal standard. Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet
of doublet of doublet, m = multiplet, br = broad), coupling
constant(s), integration and peak assignment. 13C NMR were
recorded on JEOL-GSX-400 (100 MHz) and JEOL GSX-270
(65 MHz) spectrometers using broad band proton decoupling.
Chemical shifts are reported in parts per million (ppm) down-
field from TMS, using the middle resonance of CDCl3 (77.0
ppm) as an internal standard. Optical rotations were recorded
on a JASCO-DIP-370 instrument and are given in 10Ϫ1 deg
cm2 gϪ1. Elemental analyses were performed on an in house
Perkin-Elmer Series 2, CHNS/O, Analyzer 2400 or by MHW
laboratories, Phoenix, AZ. A few of the elemental analyses are
slightly outside the defined limits of the journal. This is most
likely a result of inconsistent calibration of the in house
instrument.
gel using 5% EtOAc in hexanes as eluant to afford the alkylated
products 7a–e.
Alkylation with benzyl bromide to give 7a. Yield, 83%; mp
123–124 ЊC; 1H NMR (270 MHz, CDCl3) δ 1.36 (s, 9H,
C(CH3)3), 2.13 (m, 2H, PhCH2), 2.66 (dd, J = 16.8, 10.9 Hz, 1H,
COCH), 2.89 (dd, J = 13.2, 3.7 Hz, 1H, COCH), 4.18 (m, 1H,
NCOCH), 4.43 (m, 2H, OCH2), 4.72 (d, J = 6.6 Hz, 1H,
Ph2CH), 5.38 (ddd, J = 8.8, 5.9, 1.5 Hz, 1H, NCH), 7.10–7.35
(m, 15H, Ar); 13C NMR (65 MHz, CDCl3) δ 174.7, 171.3, 153.3,
138.5, 138.4, 138.3, 129.4, 129.3, 128.9, 128.6, 128.6, 128.5,
127.8, 127.0, 80.5, 65.2, 56.6, 51.4, 41.4, 37.5, 35.6, 28.0; [α]D25
Ϫ79.5 (c 1.5, CH2Cl2); Anal. Calcd for C31H33NO5: C, 74.53;
H, 6.66; N, 2.80. Found: C, 74.73; H, 6.95; N, 3.05%.
Alkylation with allyl bromide to give 7b. Yield, 72%; mp 79–
1
80 ЊC; H NMR (270 MHz, CDCl3) δ 1.39 (s, 9H, C(CH3)3),
1.83 (m, 1H, allyl CH), 2.21 (m, 1H, allyl CH), 2.34 (dd,
J = 17.6, 3.7 Hz, 1H, COCH), 2.66 (dd, J = 17.2, 11.7 Hz, 1H,
COCH), 3.97 (m, 1H, NCOCH), 4.40 (m, 2H, OCH2), 4.69 (d,
J = 5.7 Hz, 1H, Ph2CH), 5.01 (m, 2H, allyl), 5.34 (ddd, J = 8.8,
5.9, 2.9 Hz, 1H, NCH), 5.55 (m, 1H, allyl), 7.13–7.35 (m, 10H,
Ar); 13C NMR (65 MHz, CDCl3) δ 174.6, 171.3, 153.2, 139.5,
138.1, 134.5, 129.1, 128.8, 128.6, 128.4, 127.7, 126.9, 117.7,
80.5, 65.2, 56.5, 51.5, 38.6, 35.8, 35.7, 28.0; [α]D25 Ϫ118.7 (c 1.0,
CH2Cl2); Anal. Calcd for C27H31NO5: C, 72.14; H, 6.95; N, 3.12.
Found: C, 72.33; H, 7.19; N, 3.62%.
Preparation of succinate 6
Dicyclohexylcarbodiimide (8.28 g, 40.22 mmol) was added in
portions to a solution of mono tert-butyl succinate (10.00 g,
57.71 mmol) in CH2Cl2 (250 mL) at room temperature. The
reaction mixture was stirred for an additional 15 minutes. The
precipitated solid was filtered and the filtrate was concentrated.
The residue was diluted with hexane and passed through a short
silica gel column. The eluent, after concentration under reduced
pressure, afforded an anhydride (8.65 g) in 92% yield. To the
anhydride (8.65 g, 26.21 mmol) in THF (60 mL) were added
Et3N (4.00 mL, 28.83 mmol), LiCl (1.13 g, 26.21 mmol)
and 4-diphenylmethyloxazolidin-2-one 5 (5.96 g, 23.59 mmol)
successively at Ϫ20 ЊC. The reaction mixture was then allowed
to warm up gradually to room temperature. The progress of the
reaction was monitored by TLC (~4 h). The volume of the
reaction was reduced by evaporation of THF. The residue
was diluted with CH2Cl2 (150 mL) and was washed with 3 M
aqueous HCl followed by aqueous NaHCO3 solution. The
organic layer was washed with water followed by brine and
dried over MgSO4. Concentration in vacuum and chromato-
graphic purification on silica gel using 5% EtOAc in hexane
gave compound 6 (8.3 g, 86%).
Alkylation with (E)-undec-2-enyl bromide to give 7c. Yield,
60%; oil; 1H NMR (270 MHz, CDCl3) δ 0.89 (t, J = 6.6 Hz, 3H,
CH2CH3), 1.26–1.43 (m, 12H, CH2), 1.39 (s, 9H, C(CH3)3), 1.79
(m, 1H, allylic CH), 2.00 (m, 2H, allylic CH2), 2.17 (m, 1H,
allylic CH), 2.33 (dd, J = 16.9, 3.7 Hz, 1H, COCH), 3.63 (dd,
J = 17.2, 11.7 Hz, 1H, COCH), 3.90 (m, 1H, NCOCH), 4.39 (m,
1H), 4.68 (d, J = 6.6 Hz, 1H, Ph2CH), 5.19 (m, 1H, NCH), 5.36
(m, 2H, vinyl), 7.13–7.39 (m, 10H, Ar); 13C NMR (65 MHz,
CDCl3) δ 174.7, 171.4, 153.1, 139.5, 138.2, 134.0, 129.1, 128.8,
128.5, 128.4, 127.7, 126.9, 125.7, 80.3, 65.1, 56.4, 51.4, 39.0,
35.6, 34.5, 32.4, 31.8, 29.4, 29.3, 29.2, 27.9, 22.6, 14.0; [α]D25
Ϫ82.8 (c 1.3, CH2Cl2); Anal. Calcd for C35H47NO5: C, 74.83; H,
8.43; N, 2.49. Found: C, 74.85; H, 8.38; N, 2.16%.
Alkylation with cinnamyl bromide to give 7d. Yield, 73%; mp
65–66 ЊC; 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H, C(CH3)3),
1.98 (m, 1H, allylic CH), 2.43 (m, 2H, allyl CH, COCH), 2.73
(dd, J = 17.7, 11.3 Hz, 1H, COCH), 4.06 (m, 1H, NCOCH),
4.43 (m, 2H, OCH2), 4.73 (d, J = 6.5 Hz, 1H, Ph2CH), 5.39
(ddd, J = 8.3, 6.5, 2.7 Hz, 1H, NCH), 6.06 (ddd, J = 15.6, 8.6,
6.9 Hz, 1H, vinyl CH), 6.40 (d, J = 16.1 Hz, 1H, vinyl CH),
7.17–7.39 (m, 15H, Ar); 13C NMR (100 MHz, CDCl3) δ 174.6,
171.4, 153.4, 139.6, 138.2, 137.0, 132.8, 129.2, 128.9, 128.6,
128.5, 127.8, 127.4, 127.0, 126.3, 126.2, 80.6, 65.4, 56.6, 51.6,
39.1, 35.9, 35.1, 28.1; [α]D25 Ϫ84.1 (c 1.0, CH2Cl2); Anal. Calcd
for C33H35NO5: C, 75.41; H, 6.71; N, 2.66. Found: C, 75.64; H,
7.01; N, 2.30%.
1
Mp 109–111 ЊC; H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H,
C(CH3)3), 2.48 (m, 2H, CH2), 2.93 (m, 1H, COCH), 3.13 (m,
1H, COCH), 4.37 (m, 2H, OCH2), 4.66 (d, J = 5.4 Hz, 1H,
Ph2CH), 5.24 (ddd, J = 8.0, 5.1, 2.7 Hz, 1H, NCH), 7.01–7.30
(m, 10H, Ar); 13C NMR (270 MHz, CDCl3) δ 171.8, 171.6,
153.9, 139.6, 137.9, 129.4, 128.9, 128.7, 128.3, 127.8, 127.0,
80.5, 64.9, 56.2, 50.4, 30.9, 29.4, 28.0; [α]D25 Ϫ148.9 (c 1.5,
CH2Cl2); Anal. Calcd for C24H27NO5: C, 70.40; H, 6.65; N, 3.42.
Found: C, 70.75; H, 6.84; N, 3.82%.
Typical procedure for NaHMDS alkylation
To a three-necked round-bottomed flask fitted with a therm-
ometer and N2 inlet, was added 6 (4.21 mmol) and dry THF (42
mL). The reaction was cooled to Ϫ78 ЊC and NaHMDS (1 M
in THF, 4.63 mL, 4.63 mmol,) was added via syringe over 10
minutes. The reaction mixture was allowed to stir for an addi-
tional 20 minutes to ensure complete enolization and the alkyl
bromide (6.32 mmol) in THF (3 mL) was added via syringe at
Ϫ78 ЊC. The reaction was stirred at Ϫ78 ЊC for 1 h and then
warmed to Ϫ48 ЊC and stirred at that temperature for an addi-
tional 3 h. After completion (TLC), the reaction was quenched
with aqueous NH4Cl solution. The reaction mixture was
concentrated by evaporating THF under reduced pressure. The
residue was diluted with CH2Cl2 (200 mL), washed successively
with water, brine, dried over MgSO4 and concentrated to give
crude product. The product was chromatographed on silica
Alkylation with methyl iodide to give 7e. Yield, 83%; 1H NMR
(400 MHz, CDCl3) δ 0.94 (d, J = 7.0 Hz, 3H, CH3), 1.40 (s, 9H,
C(CH3)3), 2.24 (dd, J = 17.2, 4.3 Hz, 1H, COCH), 2.75 (dd,
J = 17.2, 10.8 Hz, 1H, COCH), 3.39 (m, 1H, NCOCH), 4.38
(dd, J = 8.7, 2.7 Hz, 1H, OCH), 4.44 (dd, J = 9.1, 8.1 Hz, 1H,
OCH), 4.70 (d, J = 6.5 Hz, 1H, Ph2CH), 5.35 (ddd, J = 9.1, 5.9,
2.7 Hz, 1H, NCH), 7.13–7.34 (m, 10H, Ar); 13C NMR (100
MHz, CDCl3) δ 175.7, 171.2, 153.0, 139.4, 138.0, 129.2, 128.8,
128.5, 128.4, 127.7, 126.9, 80.5, 65.1, 56.3, 51.3, 38.3, 34.2, 28.0,
17.2; [α]D26 Ϫ101.1 (c 1.9, CH2Cl2); Anal. Calcd for C25H29NO5:
C, 70.90; H, 6.90. Found: C, 70.42; H, 6.81%.
Typical procedure for cleaving the chiral auxiliary
To a solution of 7a (1.0 g, 2.00 mmol) in THF and H2O (4:1,
J. Chem. Soc., Perkin Trans. 1, 2000, 1461–1466
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20 mL) at 0 ЊC was added H2O2 (30% aqueous, 0.90 mL, 8.00
mmol) followed by aqueous LiOH solution (0.1 g 5 mLϪ1, 3.84
mL, 3.20 mmol). The reaction mixture was stirred at 0 ЊC for
1 h and then an aqueous solution of Na2SO3 (1.0 g 6 mLϪ1, 6.0
mL, 8.00 mmol) was added. After stirring for an additional
20 minutes, THF was evaporated under reduced pressure and
the residue was diluted with CH2Cl2 (100 mL) and water.
The organic layer was separated which contained the chiral
auxiliary. The aqueous layer was acidified with 3 M aqueous
HCl solution and was extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were washed with water, brine and
dried over MgSO4. Concentration in vacuum yielded chemically
pure acids 8a–d. The chiral auxiliary 5 could be recovered in
>95% yield and showed no loss of optical purity.
trated. The oily material was chromatographed on silica gel
using 2% EtOAc in hexane to yield N-Boc-amino acid esters
9a–d.
1
Amino ester 9a. Yield, 83%; mp 84–85 ЊC; H NMR (270
MHz, CDCl3) δ 1.40 (s, 9H, C(CH3)3), 1.46 (s, 9H, C(CH3)3),
2.30 (dd, J = 15.4, 5.9 Hz, 1H, COCH), 2.41 (dd, J = 15.4, 5.9
Hz, 1H, COCH), 2.82 (m, 2H, PhCH2), 4.11 (m, 1H, NCH),
5.06 (m, 1H, NH), 7.17–7.32 (m, 5H, Ar); 13C NMR (65 MHz,
CDCl3) δ 170.9, 154.9, 137.8, 129.4, 128.3, 126.4, 80.8, 79.0,
48.9, 40.4, 38.8, 28.2, 27.9; [α]D25 ϩ10.0 (c 1.1, CH2Cl2); Anal.
Calcd for C19H29NO4: C, 68.03; H, 8.71. Found: C, 68.24; H,
8.71%.
Amino ester 9b. Yield, 80%; oil; 1H NMR (270 MHz, CDCl3)
δ 1.43 (s, 9H, C(CH3)3), 1.45 (s, 9H, C(CH3)3), 2.29 (t, J = 6.6
Hz, 2H, allyl CH2), 2.41 (d, J = 5.9 Hz, 2H, COCH), 3.95 (m,
1H, NCH), 4.9 (s, 1H, NH), 5.10 (m, 2H, vinyl CH), 5.78 (m,
1H, vinyl CH); 13C NMR (65 MHz, CDCl3) δ 170.7, 155.0,
134.0, 117.8, 80.6, 78.8, 47.2, 39.5, 38.8, 28.2, 27.8; [α]D25 Ϫ10.09
(c 1.1, MeOH); Anal. Calcd for C15H27NO4: C, 63.13; H, 9.54.
Found: C, 62.71; H, 9.20%.
Acid 8a. Yield, 90%; mp 60–61 ЊC; 1H NMR (270 MHz,
CDCl3) δ 1.41 (s, 9H, C(CH3)3), 2.35 (dd, J = 16.7, 4.4 Hz, 1H,
COCH), 2.55 (dd, J = 16.7, 8.8 Hz, 1H, COCH), 2.76 (dd,
J = 15.4, 11.0 Hz, 1H, PhCH), 3.10 (m, 2H, PhCH and COCH),
7.17–7.33 (m, 5H, Ar); 13C NMR (65 MHz, CDCl3) δ 180.7,
170.8, 138.0, 129.0, 128.5, 127.7, 81.0, 43.1, 37.3, 35.9, 27.9;
[α]D25 ϩ8.4 (c 1.6, CH2Cl2); Anal. Calcd for C15H20O4: C, 68.16;
H, 7.63. Found: C, 67.65; H, 7.67%.
Amino ester 9c. Yield, 70%; oil; 1H NMR (270 MHz, CDCl3)
δ 0.90 (t, J = 7.1 Hz, 3H, CH3), 1.28–1.43 (m, 12H, CH2), 1.45
(s, 9H, C(CH3)3), 1.47 (s, 9H, C(CH3)3), 2.00 (m, 2H, allyl CH2),
2.22 (m, 2H, allyl CH2), 2.42 (d, J = 5.9 Hz, 2H, COCH), 3.93
(m, 1H, NCH), 4.98 (s, 1H, NH), 5.37 (m, 1H, vinyl CH), 5.51
(m, 1H, vinyl CH); 13C NMR (65 MHz, CDCl3) δ 170.9, 155.1,
134.4, 125.1, 80.6, 78.9, 47.6, 39.5, 37.7, 32.5, 31.8, 29.4, 29.3,
29.2, 29.1, 28.3, 27.9, 22.6, 14.0; [α]D25 Ϫ5.57 (c 0.7, MeOH);
Anal. Calcd for C23H43NO4: C, 69.48; H, 10.91. Found: C,
69.08; H, 10.59%.
Acid 8b. Yield, 88%; oil; 1H NMR (270 MHz, CDCl3) δ 1.44
(s, 9H, C(CH3)3), 2.41 (m, 3H, allyl CH2, COCH), 2.61 (dd,
J = 16.9, 9.5 Hz, 1H, COCH), 2.90 (m, 1H, COCH), 5.12 (m,
2H, allyl CH), 5.73 (m, 1H, allyl CH); 13C NMR (65 MHz,
CDCl3) δ 180.5, 170.9, 134.2, 117.9, 80.9, 40.9, 36.1, 35.5, 27.9;
[α]D25 ϩ3.4 (c 1.4, CH2Cl2); Anal. Calcd for C11H18O4: C, 61.66;
H, 8.47. Found: C, 60.91; H, 8.25%.
Acid 8c. Yield, 87%; oil; 1H NMR (270 MHz, CDCl3) δ 0.83
(t, J = 6.6 Hz, 3H, CH3), 1.21–1.35 (m, 12H, CH2), 1.39 (s, 9H,
C(CH3)3), 1.93 (m, 2H, allyl CH2), 2.19 (m, 1H, CH2CH), 2.33
(m, 2H, allyl CH2), 2.53 (dd, J = 16.8, 8.7 Hz, 1H, COCH), 2.80
(m, 1H, COCH), 5.28 (m, 1H, vinyl CH), 5.40 (m, 1H, vinyl
CH); 13C NMR (65 MHz, CDCl3) δ 180.8, 170.9, 134.3, 125.2,
80.7, 41.3, 35.9, 34.4, 32.4, 31.8, 29.3, 29.2, 29.1, 29.0, 27.8,
22.5, 13.9; [α]D25 ϩ1.8 (c 1.6, CH2Cl2); Anal. Calcd for C19H34O4:
C, 69.90; H, 10.50. Found: C, 70.08; H, 10.38%.
1
Amino ester 9d. Yield, 78%; mp 87–89 ЊC; H NMR (400
MHz, CDCl3) δ 1.41 (s, 9H, C(CH3)3), 1.46 (s, 9H, C(CH3)3),
2.47 (m, 4H, allyl CH2, COCH2), 4.06 (m, 1H, NCH), 5.07 (d,
J = 8.3 Hz, 1H, NH), 6.16 (dt, J = 15.6, 7.2, 1H, vinyl CH), 6.43
(d, J = 15.6 Hz, 1H, vinyl CH), 7.20–7.36 (m, 5H, Ar); 13C
NMR (270 MHz, CDCl3) δ 170.9, 155.1, 137.2, 133.0, 128.4,
127.2, 126.1, 125.7, 80.9, 79.2, 47.6, 39.6, 38.2, 28.3, 28.0; [α]D25
ϩ8.4 (c 1.0, MeOH); Anal. Calcd for C21H31NO4: C, 69.78; H,
8.64; N, 3.87. Found: C, 69.37; H, 8.60; N, 3.22%.
Acid 8d. Yield, 80%; mp 71–72 ЊC; 1H NMR (270 MHz,
CDCl3) δ 1.42 (s, 9H, C(CH3)3), 2.44 (m, 2H, allyl CH2), 2.62
(m, 2H, COCH2), 2.98 (m, 1H, COCH), 6.13 (dt, J = 15.4, 7.3
Hz, 1H, vinyl CH), 6.43 (d, J = 16.1 Hz, 1H, vinyl CH), 7.13–
7.36 (m, 5H, Ar); 13C NMR (65 MHz, CDCl3) δ 180.6, 170.9,
136.9, 133.0, 128.5, 127.3, 126.1, 125.8, 81.0, 41.2, 36.1, 34.7,
27.9; [α]D25 ϩ7.9 (c 1.0, CH2Cl2); Anal. Calcd for C17H22O4: C,
70.32; H, 7.64. Found: C, 69.87; H, 7.47%.
(R)-tert-Butyl 3-[N-(tert-butyloxycarbonyl)amino]tetra-
decanoate 10
The (R)-tert-butyl 3-[N-(tert-butyloxycarbonyl)amino]tetradec-
5-enoate 9c (0.132 g, 0.33 mmol) in EtOH (5 mL) was hydro-
genated using hydrogen (1 atm) and 10% Pd on activated
carbon (0.015 g) as the catalyst. The reaction mixture was
filtered through a small pad of Celite by diluting with CHCl3
(20 mL). Concentration in vacuum and chromatography on
silica gel gave 10 (0.127 g) in quantitative yield.
Typical procedure for Curtius rearrangement
To a two-necked round-bottomed flask fitted with N2 inlet was
added acid 8a (0.176 g, 0.67 mmol) in dry acetone (5 mL). The
solution was cooled to 0 ЊC and Et3N (0.111 mL, 0.80 mmol)
and ClCO2Et (0.070 mL, 0.73 mmol) were added. The reaction
mixture was stirred for 1 h. To this mixture was added NaN3
(0.108 g, 1.67 mmol) in H2O (3 mL) and stirred at 0 ЊC for
another 1 h. The solvent was evaporated below room temper-
ature either by air flow or by rotoevaporator. The residue was
then extracted with toluene (3 × 20 mL). The organic layer was
dried over MgSO4 and heated carefully by using a distillation
condenser. The volume was reduced to ~10 mL over a 1 h
period. Addition of t-BuOH (5 mL) was carried out via
syringe and the distillation condenser was replaced by a reflux
condenser. The reaction was gently allowed to reflux for an
additional 12 h. The solvent was evaporated and the residue
was diluted with CH2Cl2 (50 mL) and was washed with 3 M
aqueous HCl, water, brine, dried over MgSO4, and concen-
1
Oil; H NMR (270 MHz, CDCl3) δ 0.87 (t, J = 6.6 Hz, 3H,
CH3), 1.43 (s, 9H, C(CH3)3), 1.44 (s, 9H, C(CH3)3), 2.84 (m, 2H,
COCH2), 3.87 (m, 1H, NCH), 4.89 (m, 1H, NH); 13C NMR (65
MHz, CDCl3) δ 170.9, 155.2, 80.5, 78.7, 47.7, 40.4, 34.7, 31.7,
29.4, 29.3, 29.2, 29.1, 28.2, 27.9, 25.9, 22.5, 13.9; [α]D25 ϩ13.09
(c 1.1, CH2Cl2); Anal. Calcd for C23H45NO4: C, 69.11; H, 11.36.
Found: C, 68.68; H, 10.97%.
(R)-N-(tert-Butyloxycarbonyl)iturinic acid 11†
Compound 10 (0.051 g, 0.127 mmol) was treated with
CF3COOH (0.10 mL, 1.28 mmol) in CH2Cl2 (5 mL) at room
temperature and the reaction stirred for 12 h. The solvent was
† The IUPAC name for 11 is (3R)-3-[N-(tert-butyloxycarbonyl)amino]-
tetradecanoate.
1464
J. Chem. Soc., Perkin Trans. 1, 2000, 1461–1466

View Article Online
evaporated under reduced pressure. To the residue was added
Et3N (3 mL) followed by Boc2O (0.030 g, 0.137 mmol) at room
temperature and stirred for an additional 12 h. The excess Et3N
was removed by a steady air flow and the residue was treated
with 3 M aqueous HCl and then diluted with CH2Cl2 (20 mL).
The organic layer was washed with water, dried over MgSO4,
and concentrated. Column chromatography on silica gel using
2% EtOAc in hexane gave 11 (0.054 g) in 70% yield.
CDCl3) δ 173.8, 155.7, 153.2, 139.5, 137.9, 129.6, 129.2, 129.1,
128.7, 128.6, 128.5, 128.3, 127.6, 126.9, 79.2, 64.8, 56.4, 50.8,
45.8, 41.1, 35.5, 28.2; [α]D25 Ϫ102.72 (c 1.15, CH2Cl2); Anal.
Calcd for C31H34N2O5: C, 72.35; H, 6.66. Found: C, 71.85; H,
6.69%.
1
Amino oxazolidinone 13b. Yield, 69%; mp 45 ЊC; H NMR
(270 MHz, CDCl3) δ 1.42 (s, 9H, C(CH3)3), 1.98 (m, 1H, allyl
CH), 2.29 (m, 1H, allyl CH), 3.19 (m, 1H, NCH), 3.44 (m, 1H,
NCH), 3.74 (m, 1H, NCOCH), 4.43 (m, 2H, OCH2), 4.64 (d,
J = 6.7 Hz, 1H, Ph2CH), 4.75 (m, 1H, NH), 5.08 (m, 2H, vinyl
CH), 5.31 (m, 1H, NCH), 5.65 (m, 1H, vinyl CH), 7.12–7.34 (m,
10H, Ar); 13C NMR (65 MHz, CDCl3) δ 173.9, 155.7, 153.2,
139.5, 138.1, 134.6, 129.1, 129.0, 128.9, 128.6, 128.5, 128.4,
127.8, 127.1, 79.2, 65.3, 56.6, 51.5, 43.6, 40.5, 33.7, 28.3; [α]D25
Ϫ107.17 (c 1.1, CH2Cl2); Anal. Calcd for C27H32N2O5: C, 69.81;
H, 6.94. Found: C, 69.42; H, 6.68%.
Mp 61 ЊC (lit.33 63–65 ЊC); 1H NMR (400 MHz, CDCl3)
δ 0.88 (t, J = 7.2 Hz, 3H, CH3), 1.25 (s, 18H, CH2), 1.44 (s, 9H,
C(CH3)3), 1.51 (m, 2H, NCHCH2), 2.55 (s, 2H, COCH2), 3.89
(s, 1H, NCH), 4.89 (s, 1H, NH); 13C NMR (100 MHz, CDCl3)
δ 176.7, 155.6, 79.5, 47.5, 39.3, 34.6, 31.9, 29.6, 29.5, 29.3, 28.3,
26.1, 22.7, 14.1; [α]D25 ϩ5.3 (c 0.9, MeOH) (lit.33 ϩ5.3 (c 1.0,
MeOH)).
Typical procedure for deprotection of the tert-butyl ester
To 7a (0.725 g, 1.45 mmol) in CH2Cl2 (20 mL) was added
CF3COOH (1.12 mL, 14.50 mmol) at room temperature and
the reaction mixture was stirred for 12 h. The solvent was evap-
orated under reduced pressure and the residue was chromato-
graphed directly on silica gel using 10% EtOAc in hexane to
afford oxazolidinone acid 10a.
1
Amino oxazolidinone 13e. Yield, 66%; mp 135 ЊC; H NMR
(400 MHz, CDCl3) δ 0.98 (d, J = 7.0 Hz, 3H, CH3), 1.42 (s, 9H,
C(CH3)3), 3.20 (m, 1H, NCH), 3.32 (m, 1H, NCH), 3.67 (m,
1H, NCOCH), 4.37 (dd, J = 9.1, 2.7 Hz, 1H, OCH), 4.43 (m,
1H, OCH), 4.63 (d, J = 6.4 Hz, 1H, Ph2CH), 5.33 (m, 1H,
NCH), 7.13–7.34 (m, 10H, Ar); 13C NMR (100 MHz, CDCl3)
δ 175.1, 155.6, 152.8, 139.2, 137.9, 128.9, 128.7, 128.4, 128.2,
127.6, 126.9, 79.0, 65.2, 56.1, 51.3, 42.2, 39.0, 28.1, 14.9; [α]D26
Ϫ100.8 (c 1.2, CH2Cl2); Anal. Calcd for C25H30N2O5: C, 68.47;
H, 6.90. Found: C, 68.01; H, 6.81%.
1
Acid 12a. Yield, 93%; mp 157–159 ЊC; H NMR (400 MHz,
Acetone-d6) δ 2.21 (dd, J = 17.4, 3.7 Hz, 1H, COCH), 2.34 (dd,
J = 12.9, 10.2 Hz, 1H, COCH), 2.72 (dd, J = 16.9, 10.3 Hz, 1H,
PhCH), 3.00 (dd, J = 13.4, 4.8 Hz, 1H, PhCH), 4.26 (m, 1H,
NCH), 4.47 (br d, J = 8.3 Hz, 1H, Ph2CH), 4.68 (m, 2H,
OCH2), 5.45 (m, 1H, NCH), 7.15–7.37 (m, 10H, Ar); 13C NMR
(65 MHz, CDCl3 MeOH-d4) δ 174.8, 153.5, 139.5, 138.1, 137.9,
129.0, 128.6, 128.4, 128.3, 128.2, 127.5, 126.8, 126.5, 65.2, 56.4,
51.2, 41.2, 37.2, 34.5; [α]D25 Ϫ73.0 (c = 1.1, CH2Cl2); Anal. Calcd
for C27H25NO5: C, 73.12; H, 5.68; N, 3.16. Found: C, 73.01; H,
5.94; N, 2.66%.
Cleavage of the chiral auxiliary
For procedures see preparation of 8a.
N-Boc-amino acid 14a. Yield, 87%; mp 81–82 ЊC; 1H
NMR (400 MHz, Acetone-d6) δ 1.39 (s, 9H, C(CH3)3), 2.81–
2.94 (m, 5H, PhCH2, NH, COCH, NCH), 3.30 (apparent t,
J = 5.4, 4.8 Hz, 1H, NCH), 7.19–7.30 (m, 5H, Ar); 13C NMR
(100 MHz, Acetone-d6) δ 175.1, 156.7, 140.0, 129.6, 128.9,
126.9, 78.6, 48.0, 42.5, 36.1, 28.4; [α]D25 ϩ40.10 (c 1.0, CH2Cl2);
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58. Found: C, 64.07;
H, 7.45%.
1
Acid 12b. Yield, 97%; mp 144–146 ЊC; H NMR (400 MHz,
CDCl3) δ 1.82 (dt, J = 13.4, 8.6 Hz, 1H, allyl CH2), 2.25 (m, 1H,
allyl CH2), 2.46 (dd, J = 17.7, 3.8 Hz, 1H, COCH), 2.76 (dd,
J = 17.7, 11.3 Hz, 1H, COCH), 3.98 (m, 1H, NCOCH), 4.40 (m,
2H, OCH2), 4.65 (d, J = 6.5 Hz, 1H, Ph2CH), 5.07 (m, 2H, vinyl
CH2), 5.37 (ddd, J = 9.7, 6.2, 2.7 Hz, 1H, NCH), 5.60 (m,
1H, vinyl CH), 7.15–7.37 (m, 10H, Ar); 13C NMR (100 MHz,
CDCl3) δ 178.3, 174.3, 153.3, 139.4, 138.1, 134.1, 129.1, 128.9,
128.5, 128.4, 127.8, 127.0, 118.1, 65.5, 56.5, 51.6, 38.5, 35.6,
34.2; [α]D25 Ϫ83.09 (c 1.1, CH2Cl2); Anal. Calcd for C23H23NO5:
C, 70.21; H, 5.89. Found: C, 70.00; H, 5.47%.
N-Boc-amino acid 14b. Yield, 97%; oil; 1H NMR (400 MHz,
Acetone-d6) δ 1.39 (s, 9H, C(CH3)3), 2.34 (m, 2H, allyl CH2),
2.67 (m, 1H, COCH), 3.27 (apparent t, J = 5.9, 5.4 Hz, 2H,
NCH2), 5.01 (br d, J = 10.2 Hz, 1H, vinyl CH), 5.10 (dq,
J = 16.9, 1.5 Hz, 1H, vinyl CH), 5.85 (m, 1H, vinyl CH); 13C
NMR (100 MHz, Acetone-d6) δ 175.3, 156.5, 136.1, 117.0, 78.6,
45.8, 42.1, 34.3, 28.4; [α]D25 ϩ17.0 (c 1.0, CH2Cl2); Anal. Calcd for
C11H19NO4: C, 57.63; H, 8.35. Found: C, 57.67; H, 8.59%.
Acid 12e. Yield, 55% after crystallization; mp 185–188 ЊC
(from hot EtOAc with very slow cooling); 1H NMR (400 MHz,
CDCl3) δ 0.98 (d, J = 7.0 Hz, 3H, CH3), 2.34 (dd, J = 17.5, 4.3
Hz, 1H, COCH), 2.84 (dd, J = 17.5, 10.7 Hz, 1H, COCH), 3.92
(m, 1H, NCOCH), 4.42 (m, 2H, OCH2), 4.65 (d, J = 6.7 Hz,
1H, Ph2CH), 5.37 (m, 1H, NCH), 7.13–7.37 (m, 10H, Ar); 13C
NMR (100 MHz, Acetone-d6) δ 176.0, 173.4, 153.8, 141.0,
139.9, 130.2, 129.6, 129.4, 129.2, 128.2, 127.5, 65.8, 56.8, 52.1,
37.1, 35.0, 17.6; [α]D26 Ϫ92.2 (c 1.0, CH2Cl2); Anal. Calcd for
C21H21NO5ؒH2O: C, 65.61; H, 5.84; N, 3.55. Found: C, 65.44;
H, 6.01; N, 3.63%.
N-Boc-amino acid 14e. Yield, 83%; mp 72–73 ЊC (lit.36 69.5–
70.5 ЊC); 1H NMR (400 MHz, Acetone-d6) δ 1.13 (d, J = 7.0 Hz,
3H, CH3), 1.40 (s, 9H, C(CH3)3), 2.65 (dd, J = 14.0, 7.0 Hz, 1H,
NCH), 2.87 (br d, J = 12.9 Hz, 1H, NCH), 3.17 (m, 1H,
COCH), 3.31 (m, 1H, NH); 13C NMR (100 MHz, Acetone-d6)
δ 176.5, 156.6, 78.6, 43.8, 40.3, 28.5, 14.9; [α]D26 Ϫ18.0 (c 1.9,
CH3OH), [α]D26 Ϫ7.7 (c 1.0, CH2Cl2) (lit.36 [α]D26 Ϫ18.4 (c 2.0,
CH3OH)).
Phenyl methyl succinic acid
Curtius rearrangement of 12a, 12b and 12e
CF3COOH (0.46 mL, 5.98 mmol) was added to the solution
of tert-butyl hydrogen (2-phenyl methyl)succinate 8a (0.158 g,
0.59 mmol) in CH2Cl2 (5 mL) and allowed to stir for 12 h. The
solvent was evaporated and the residue was chromatographed
on silica gel to afford the title compound (0.120 g) in quantit-
ative yield.
See procedure for 9a.
Amino oxazolidinone 13a. Yield, 68%; mp 65–67 ЊC; 1H
NMR (270 MHz, CDCl3) δ 1.41 (s, 9H, C(CH3)3), 2.49 (m, 1H,
benzyl CH), 2.98 (m, 1H, benzyl CH), 3.21 (m, 1H, NCH), 3.58
(m, 1H, NCH), 4.12 (m, 1H, NCOCH), 4.41 (m, 2H, OCH2),
4.60 (d, J = 5.1 Hz, 1H, Ph2CH), 4.76 (m, 1H, NH), 5.32 (m,
1H, NCH), 6.85–7.35 (m, 15H, Ar); 13C NMR (65 MHz,
1H NMR (270 MHz, CDCl3) δ 2.41 (dd, J = 17.2, 4.0 Hz, 1H,
COCH), 2.65 (dd, J = 17.6, 8.06 Hz, 1H, COCH), 2.79 (m, 1H,
PhCH), 3.14 (m, 2H, PhCH, COCH), 7.16–7.32 (m, 5H, Ar);
J. Chem. Soc., Perkin Trans. 1, 2000, 1461–1466
1465

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13C NMR (65 MHz, CDCl3 Acetone-d6) δ 175.1, 172.8, 138.5,
128.8, 128.2, 126.2, 42.4, 36.9, 34.1; [α]D25 ϩ26.64 (c 1.7, EtOAc)
(lit.38 for the (S)-enantiomer [α]D26 Ϫ27.0 (c 2, EtOAc)).
see: T. Hintermann and D. Seebach, Helv. Chim. Acta, 1998, 81,
2093.
15 D. A. Evans, L. D. Wu, J. J. M. Wiener, J. S. Johnson, D. H. B. Ripin
and J. S. Tedrow, J. Org. Chem., 1999, 64, 6411.
16 L. Falborg and K. A. Jørgensen, J. Chem. Soc., Perkin Trans. 1,
1996, 2823.
17 (a) T. Ishikawa, K. Nagai, M. Senzaki, A. Tatsukawa and S. Saito,
Tetrahedron, 1998, 54, 2433; (b) T. Ishikawa, K. Nagai, T. Kudoh
and S. Saito, Synlett, 1998, 1292.
18 M. P. Sibi, J. J. Shay, M. Liu and C. P. Jasperse, J. Am. Chem. Soc.,
1998, 120, 6615.
19 (a) P. O’Brien, Angew. Chem., Int. Ed. Engl., 1998, 38, 326; (b) L. J.
Goossen, H. Liu, K. R. Dress and K. B. Sharpless, Angew. Chem.,
Int. Ed., 1999, 39, 1080 and references therein.
Acknowledgements
We thank NSF (OSR-9108770) and FMC Lithium for provid-
ing financial support for our research programs. Partial support
for this work was provided by the NSF’s Instrumentation
and Laboratory Improvement Program through grant #USE-
9152532.
20 E. J. Corey, C. P. Decicco and R. C. Newbold, Tetrahedron Lett.,
1991, 32, 5287.
Notes and references
21 K. Ishihara, M. Miyata, K. Hattori and H. Yamamoto, J. Am.
Chem. Soc., 1994, 116, 10520.
22 For uses of differentially functionalized succinates in synthesis see:
(a) M. P. Sibi, P. K. Deshpande and A. J. La Loggia, Synlett, 1996,
343; (b) M. P. Sibi, J. Lu and C. L. Talbacka, J. Org. Chem., 1996, 61,
7848; (c) M. P. Sibi, J. Lu and J. Edwards, J. Org. Chem., 1997, 62,
5864.
23 For other selected methods for the synthesis of substituted
succinates see: (a) C.-B. Xue, X. He, J. Roderick, W. F. DeGrado,
R. J. Cherney, K. D. Hardman, D. J. Nelson, R. A. Copeland, B. D.
Jaffee and C. P. Decicco, J. Med. Chem., 1998, 41, 1745; (b) R. P.
Becket, M. J. Crimmins, M. H. Davis and Z. A. Spavold, Synlett,
1993, 137.
24 G. Buchi and E. C. Robert, J. Org. Chem., 1968, 33, 460.
25 G.-J. Ho and D. J. Mathre, J. Org. Chem., 1995, 60, 2271.
26 M. P. Sibi, P. K. Deshpande, A. J. La Loggia and J. W. Christensen,
Tetrahedron Lett., 1995, 36, 8961.
27 For the use of this auxiliary see: (a) M. P. Sibi, C. P. Jasperse and
J. Ji, J. Am. Chem. Soc., 1995, 117, 10779; (b) M. P. Sibi and J. Ji,
Angew. Chem., Int. Ed. Engl., 1996, 35, 190; (c) M. P. Sibi, P. K.
Deshpande and J. Ji, Tetrahedron Lett., 1995, 36, 8965.
28 For selective aldol or alkylation of similar structural units see:
(a) D. A. Evans and J. M. Takacs, Tetrahedron Lett., 1980, 21, 4233;
(b) D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc.,
1982, 104, 1737; (c) D. A. Evans, J. Bartroli and T. L. Shih, J. Am
Chem. Soc., 1981, 103, 2127; (d) D. A. Evans, F. Urpi, T. C. Somer,
J. S. Clark and M. T. Bilodeau, J. Am. Chem. Soc., 1990, 112, 8215;
(e) D. A. Evans, M. T. Bilodeau, T. C. Somer, J. Clardy, D. Cherry
and Y. Kato, J. Org. Chem., 1991, 56, 5750; ( f ) W. Oppolzer,
P. Cintas-Moreno, O. Tamura and F. Cardinaux, Helv. Chim. Acta,
1993, 76, 187.
29 (a) J. Weinstock, J. Org. Chem., 1961, 26, 3511; (b) C. Kaiser and
J. Weinstock, Org. Synth. 1988, coll. vol. 6, 910; The use of
diphenylphosphoryl azide for the Curtius rearrangement gave lower
yields and product purification was also difficult.
30 The diastereomers were purified by silica gel column chromato-
graphy. The two diastereomers from compound 7e were inseparable
on column chromatography.
1 For a discussion of the synthesis and biology of β-amino acids
see: Enantioselective Synthesis of β-Amino Acids, ed. E. Juaristi,
Wiley-VCH, New York, 1997; For comprehensive reviews on
β-amino acids see: D. C. Cole, Tetrahedron 1994, 50, 9517;
E. Juaristi, D. Quintana and J. Escalante, Aldrichimica Acta, 1994,
27, 3.
2 For a recent review on β-peptides see: S. H. Gellman, Acc. Chem.
Res., 1998, 31, 173; (a) S. Shinagawa, T. Kanamaru, S. Harada,
M. Asai and H. Okazaki, J. Med. Chem., 1987, 30, 1458; (b) A.
Bongini, G. Cardillo, M. Orena, G. Porzi and S. Sandri,
Tetrahedron, 1987, 43, 4377; (c) N. Kabawata, T. Inamoto and
S. Hashimoto, J. Antibiot., 1992, 45, 513; (d) H. Oki, M. Hirano,
K. Tomatsu, K. I. Numata and H. Kamei, J. Antibiot., 1989, 42,
1756; (e) G. Casiraghi, L. Colombo, G. Rassu and P. Spanu, J. Org.
Chem., 1991, 56, 6523; ( f ) F. Matsuura, Y. Hamada and T. Shioiri,
Tetrahedron, 1994, 50, 11303; (g) M. F. Beatty, C. J. White and
M. A. Avery, J. Chem. Soc., Perkin Trans. 1, 1992, 1637.
3 (a) F. Gueritte-Voegelein, V. Senilh, B. David, D. Guenard and
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32 The absolute stereochemistry of the alkylation product 7a was
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33 J. M. Bland, Synth. Commun., 1995, 25, 467 and references cited
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34 11: mp 61 ЊC, [α]D26 ϩ5.3 (c 0.9, MeOH); lit.33 [α]D26 ϩ5.33 (c 1.0,
MeOH).
35 The acid 12e was purified to a single diastereomer by crystallization.
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1466
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