Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of β3-oligopeptides by chemoselective amide ligation

Article abstract of DOI:10.1016/j.tet.2010.04.016

The design and general synthesis of enantiopure isoxazolidinone monomers as precursors for the preparation of enantiopure N-terminal hydroxylamine- β³-oligopeptides, which may be used as reaction partners with α-ketoacids in the decarboxylative

Full text of DOI:10.1016/j.tet.2010.04.016

Tetrahedron 66 (2010) 4841e4853
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of enantiopure isoxazolidinone monomers for the
synthesis of
b
3-oligopeptides by chemoselective amide ligation
*
M. Elisa Juarez-Garcia, Shouyun Yu, Jeffrey W. Bode
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6354, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and general synthesis of enantiopure isoxazolidinone monomers as precursors for the
preparation of enantiopure N-terminal hydroxylaminee
partners with -ketoacids in the decarboxylative amide ligation reaction, is described.
Ó 2010 Elsevier Ltd. All rights reserved.
b
3-oligopeptides, which may be used as reaction
Received 21 January 2010
Received in revised form 1 April 2010
Accepted 2 April 2010
a
Available online 14 April 2010
Dedicated to Professor Brian Stoltz in honor
of his 2009 Tetrahedron Young Investigator
Award
Keywords:
Enantiopure isoxazolidinone monomers
b
3-oligopeptides
Amide ligation
1. Introduction
metabolic stability, and ease of incorporating unnatural functional
groups for engineering novel reactivity.
b
3-Oligopeptides have emerged as one of the most powerful and
One of the greatest obstacles to the continued development of
versatile classes of foldamers1 for the design of molecules with
this exciting field is the synthetic access to higher order
peptides. For example, the Zwit-1F protein designed by Schepartz10
consists of 28
3-amino acid residues and must be synthesized
b
3-oligo-
defined higher order structures and properties. Pioneering studies
by Seebach2 and Gellman3 established the
b
3-oligopeptide motif as
b
a promising venue in which to design molecules that possess pre-
using harsh and often inefficient peptide coupling and Fmoc-
dictable secondary and tertiary structure4 that arise from a discrete
deprotection conditions as the peptide increases in length.1b Frag-
sequence of
b
3-amino acid residues. These principles have been
ment couplings of medium size (5e10 b-amino acid residues) are
widely exploited in the design, synthesis, and study of
b
3-oligo-
an attractive alternative to the direct synthesis of longer peptides,
but poor solubility of the protected peptide fragments and con-
comitant inefficiency in the key amide-forming reaction detracts
from this approach. The logical alternative, native chemical liga-
peptides, or structures incorporating b
3-amino acids, with a wide
range of biological properties including antimicrobial activity,5 the
disruption of proteineprotein interactions,6 and inhibition of
g
b
-secretase.7 Recently, Schepartz has demonstrated that a designed
3-oligopeptide possesses not only secondary and tertiary structure
tion11 of unprotected
b
-oligopeptide fragments, has been explored
by Seebach12 and has utility in certain cases. It is not applicable,
however, to the synthesis of -oligopeptides that lack a thiol-con-
taining side chain. Furthermore, the synthesis of the necessary
enantiopure
3-cysteine amino acid is lengthy and complicated.13
As part of our efforts to improve synthetic access to
3-oligo-
but quaternary structure as well, and forms helical bundles.8 Gell-
b
man and Hilvert have prepared a
an artificial enzyme.9 Taken together, these studies establish syn-
thetic
3-oligopeptides as the most promising platform for the
design of artificial macromolecules that can offer the properties
and activities of natural -oligopeptides with advantages including
b
3-oligopeptide that functions as
b
b
b
peptides, we have previously reported an alternative and orthog-
onal route to their preparation by the chemoselective amide-
a
stable secondary structure with short peptide sequences, improved
forming ligation of a
-ketoacids and cyclic hydroxylamines (Fig. 1).14
This reaction does not require any coupling reagents or side chain
protection during peptide bond formation, operates under aqueous
conditions, and produces CO2 as the only reaction byproduct. It
proceeds in the inverse, N/C synthetic direction.15 Furthermore,
* Corresponding author. Laboratorium fuer Organische Chemie, ETH-Zürich,
Santa Barbara, CA 93106-9510, USA. Tel.: þ41 44 633 2103; e-mail address: bode@
org.chem.ethz.ch (J.W. Bode).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.016

4842
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
In order to design a practical
required a suitable method for the synthesis, protection, in-
corporation, and deprotection of enantiomerically pure
3-peptide
hydroxylamines onto the N-terminus of a synthetic
3-oligopep-
tide. As part of ongoing work on the synthesis of enantiopure N-
hydroxy- -amino acids we have employed several approaches that
involve the hydrolysis of nitrone intermediates.17 In considering an
extension of this strategy to the synthesis of the corresponding b3
oligopeptides, we were concerned about the potential for nitrone
elimination via retro-Michael reaction with the
3-amino acids and
deterred by the need for a multi-step transformation of the pre-
cious, enantiomerically pure
3-amino acid derivatives. We there-
fore sought a de novo synthesis of enantiomerically pure N-
hydroxy-
3-amino acid monomers as well as new methods to in-
corporate them onto the N-terminus of a
3-oligopeptide chain.
b
3-peptide ligation strategy, we
O
R1
O
HN
R2
O
OMe
OMe
OH
N
H
b
O
O
b
1) H2O, no reagents
2) LiOH
a
O
R1
O
R2
O
HN
R3
O
OMe
OMe
OH
R2
-
N
N
H
H
O
O
b
1) H2O, no reagents
2) LiOH
b
O
R1
O
O
R3
O
b
OH
N
N
N
H
b
H
H
O
This article documents our successful strategy for the asym-
metric synthesis of enantiopure isoxazolidinone monomers that
Figure 1. Iterative, aqueous synthesis of b a-ketoacideisoxazolidine
3-oligopeptides via
couplings.
correspond to common
coupling with amine and peptide nucleophiles, and their depro-
tection to give the desired -N-hydroxyamino peptides (Scheme 2).
b-amino acids, a method for their direct
the necessary monomers are synthetically accessible by a conve-
nient diastereoselective nitrone cycloaddition. In our published
b
These procedures allow access to the requisite fragments for our
ongoing work on developing a general strategy for the synthesis of
work,15 we demonstrated the solution phase synthesis of short b3
-
b
3-oligopeptides by the combination of Fmoc-based peptide syn-
oligopeptides using this method, and our ongoing work has ex-
tended this to the solid-supported preparation of longer, fully un-
protected peptide fragments. We have also greatly improved and
optimized the synthesis of the requisite isoxazolidine monomers.
thesis, iterative
a-ketoacideisoxazolidine peptide-formation, and
a-ketoacidehydroxylamine ligations for fragment condensations.
β3−oligopeptide
N β3−oligopeptide
OH
amide coupling
H2N
C
R1
2. Results and discussion
O
HO
β3−oligopeptide
N
H
N
H
In the course of our studies we recognized that the unique N/C
b
3-oligo-
original
idea
Pg
synthetic direction of this amide-ligation approach to
peptide synthesis offers an exciting opportunity to interface with
the traditional Fmoc-based peptide coupling approach to
3-amino
acid synthesis. The products of our ketoacideisoxazolidine-based
synthesis are side-chain unprotected C-terminal
3-peptide
ketoacids I that would be ideally suited to react with
3-oligopep-
tide containing an N-terminal hydroxylamine II in a fragment li-
gation strategy by -ketoacidehydroxylamine ligation (Scheme 1).
Importantly, we have demonstrated, in the context of -peptide
N
O
5
C
N with a
terminal N−hydroxylamine
OH
*
b
R1
6
b
a-
OH
Pg
Pg
N
b
O
N O
O
OH
a
R1
R1
7
6
a
synthesis,16 that this ligation reaction meets all the criteria for
a truly chemoselective peptide-forming reaction and can operate at
low reactant concentrations (10 mM) and with equimolar reactant
stochiometries, which are usually encountered during attempted
fragment couplings.
Scheme 2. Retrosynthesis of the terminal N-hydroxylamine b
3-oligopeptide.
At the outset of our studies, we recognized that three distinct
but interconnected successes would be necessary for achieving our
goal of a general, convenient method for the synthesis of N-ter-
minal b
3-peptide hydroxylamines: (1) a suitable protecting group
Me
Me
Me
strategy for masking the sensitive hydroxylamine, (2) a method for
the introduction of a suitable monomer onto the peptide chain via
amide-bond formation and (3) a reliable method for the prepara-
tion of such monomers with >99% ee.
With these goals in mind, we were initially attracted to a 2007
report by Cordova on the enantioselective addition of carbamate-
CO2
β3-oligopeptide
O
NH3
Me
O
HO
N
H
OH
OH
β3-oligopeptide
H2N
O
HN
NH2
NH2
CO2
I
II
protected hydroxylamines to a,b-unsaturated aldehydes (Scheme 3),
C
N with a
N
C with a
terminal N−hydroxylamine
terminal α−ketoacid
Ph
Ph
OTMS
DMF
40-60 °C
H2O
CO2
N
H
Me
10
O
i) 20 mol% cat. 10, CHCl3
BocNHOH or CbzNHOH
3 h, 0 °C
Me
Me
NH3
Me
CO2
O
O
O
BnO
Ph
N O
β3-oligopeptide
Ph
H
N
H
β3-oligopeptide
OH
H2N
O
ii) 10 mol% TPAP,
1.2 equiv NMO, CH2Cl2
89% yield
CO2
9
11
HN
NH2
NH2
III
Scheme 3. Organocatalytic formation of enantioenriched isoxazolidinones from a,b-
Scheme 1. Decarboxylative amide formation reaction between a terminal
and a hydroxylamine.
a
-ketoacid
unsaturated aldehydes (TPAP¼tetrapropylammonium perruthenate, NMO N-methyl-
morpholine N-oxide).

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4843
catalyzed by (S)-O-TMS-diphenylprolinol 10.18 The resulting cyclic
acetal was oxidized to the isoxazolidinone carbamate, which
appeared to be ideal precursors to
3-peptide hydroxylamines.
availability of both
D
- and
L
-gulose-derived lactones as starting
materials. As we were already using and producing this auxiliary on
scale, seeking its application to the preparation of these enantio-
pure monomers seemed ideal.
b
We were pleased to find that Cbz-protected isoxazolidinone 11
could be readily coupled to an amine by stirring the two reactants
in CH2Cl2 or DMF (Scheme 4). Despite this promising result, two
obstacles remained. First, the benzyl carbamate was an unsuitable
protecting group for our eventual goal as it required hydrogenolysis
for its deprotection, which we feared could cleave the NeO bond.
Second, despite numerous attempts to improve the enantiose-
lectivity or enrich the enantiopurity of the isoxazolidines, we were
unable to prepare these monomers in >95% ee. This was particu-
larly true of the aliphatic substituted variants that were essential to
Me
O
Me
O
Me
O
Me
O
OH
OH
N
H
N
H
O
O
O
O
H
H
H
H
O
O
Me
Me
Me
D-Gulose
Me
D-Mannose
1
14
our eventual
b
3-peptide ligation strategy.
X
Y
O
O
RCHO
CH2Cl2
or DMF
OH
BnO
BnO
Ph
N
O
N O
Ph
Ph
H2N
1 h, rt
82% yield
N
H
Me
Me
Me
O
Ph
Me
O
O
11
12
13
O
O
O
O
Me
Me
Me
Me
Scheme 4. Coupling of N-Boc isoxazolidinone with an N-terminal amine.
O
O
H
H
O
O
N
O
N
O
H
H
X
Y
X
Our studies did establish the use of carbamate protected iso-
xazolidinones for the protection and introduction of the
3-N-
b
R
R
Y
hydroxyamino acid-residues into peptides, and our goals sub-
sequently shifted to a reliable preparation of such monomers in
enantiomerically pure form (Fig. 2).
NH2
O
NH2
O
O
R
OH
R
OH
Goal: general method
for 99% ee monomers
natural β3-derivate 15
unnatural β3-derivate 16
t
BuO
N
O
R1 = Bu, Pr, Me, Bn
Figure 3. Absolute configurations of b
3-amino acids prepared from D-mannose and D-
gulose-derived chiral auxiliaries.
i
i
R1
O
14
Figure 2. Boc protected isoxazolidinone monomers.
Several cycloaddition strategies were explored. The most at-
tractive, from a synthetic point of view, was the use of commercially
available substituted acrylonitriles 19 or 20.22,23 Indeed, the com-
In our parallel work on the synthesis and use of isoxazolines for
-peptide synthesis, we had outstanding results with several vari-
b
bination of -gulose derived hydroxylamine 1, an aldehyde, and
D
ations of Vasella’s D
-mannose derived hydroxylamine19 as a chiral
either of these acrylates afforded cycloadducts 21 or 22 in re-
spectable yield. In both cases, treatment of these products with
NEt3 and H2O afforded isoxazolidinones 23 or 24 in good yield.
Following recrystallization, these products were obtained as single
diastereomers in enantiomerically pure form (Scheme 5).
auxiliary for diastereoselective nitrone cycloadditions.20 Most im-
portantly, most of the cycloadducts were crystalline solids that
could be enriched to diastereo- and enantiopurity by re-
crystallization. The
the absolute stereochemistry opposite of that found in the ‘pseudo-
natural’ -mannose is
3-amino acids (Fig. 3). The corresponding
prohibitively expensive for use as a chiral auxiliary. Kibayashi21 has
reported the use of -gulose as a convenient surrogate for -man-
D-mannose derived auxiliary, however, afforded
The only problem with this approach was the limited availability
of both a-acetoxyacrylonitrile (19) and a-chloroacrylonitrile (20).
b
L
These restricted substances are not available to research laborato-
ries on scale and commercial supplies of even small quantities were
unreliable. The hazardous nature of their synthesis, while con-
ducted at times in our lab, effectively prohibited their preparation
in the quantities we desired. Therefore, despite these encouraging
results we were forced to consider alternatives.
D
L
nose and we had already adopted this auxiliary in our ongoing
studies. The use of gulose derived auxiliaries brings the additional
benefits of higher diastereoselectivities in the nitrone cycloaddi-
tions, increased crystallinity of the cycloadducts, and the ready
Me
Me
Me
Me
Me
O
Me
O
O
O
O
O
O
Me
Me
O
O
Me
Me
neat or toluene
85 -115 °C, 16 h
2 equiv Et3N
4:1 THF/H2O
X
O
O
H
H
O
H
O
OH
N
H
O
CN
N
H
O
O
N
O
H
H
H
R
X
O
Me
O
CN
Me
R
R
i
i
i
1
17 R = Pr
18 R = Ph
19 X = Cl
20 X = OAc
max. 68% on 500 mg scale
max. 45% on >1 g scale
68% 21 X= Cl, R = Pr
73% 23 R = Pr
84% 24 R = Ph
D-Gulose-NHOH
54% 22 X =OAc, R = Ph
single diastereomer
after recrystallization
Scheme 5. Preparation of isoxazolidinone monomers starting from a cyanoacrylate.

4844
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
An alternative was inexpensive, widely available vinyl acetate
form. Furthermore, although the vinyl acetate itself was an in-
expensive reagent, this approach required additional acetate hydro-
lysis and lactol oxidation steps that detracted from its overall appeal.
We therefore explored an alternative cycloaddition strategy
(26).24 Its low cost allowed us to use an excess of this olefin (10 equiv)
as the reaction solvent (Scheme 6). Following nitrone cycloaddition,
acetate hydrolysis and lactol oxidation afforded identical iso-
xazolidinones as were prepared from the substituted acrylates.
based on our prior experience with
a-ketoacids and their de-
rivatives. We believed that monomers of the type 34 or 35, which
O
were structurally very similar to those we had prepared for our
D GuloseN
R1
O
sealed tube
92 °C, 16 h
dr 9:6:2
iterative b
3-peptide synthesis,15 could be converted by oxidative
D Gulose NHOH
R1
H
OAc
OAc
decarboxylation to the desired isoxazolidinones (Scheme 7).
Following the preparation of cycloadducts derived from either
acrylate 32 or 33, we explored conditions for hydrolysis and oxi-
dative decarboxylation under basic conditions (Table 1). With 34,
derived from acrylate 32, only trace amounts of the desired product
were obtained upon treatment with basic peroxide. Increasing the
1 equiv
10 equiv
26
3 equiv
R1=Bn 18
R1= Bn 27 68%
1
i
i
Pr 25
Pr 28 61%
i
i
Bu 17
Bu 29 74%
Me
Me
O
O
a) 1.0 equiv K2CO3
10:1 MeOH/H2O, 1 h
O
Me
Me
O
Table 1
H
O
b) TPAP 10 mol%
1.2 equiv NMO, CH2Cl2
Screening of conditions for the decarboxylative oxidation
N
O
H
D GuloseN
O
D GuloseN
O
OX
OY
O
O
Me
Me
Me
O
Me
24 57%
Me
Me
Me
Y
X = Ac
41
37
23
Me
O
O
O
Y = Me
X
O
O
O
Me
Me
Me
Me
O
O
Yielda
H
H
Entry
Acetal
Solvent
T/ꢀC
Time/h
O
O
N
O
N
O
H
H
1
2
41
41
NaOH/H2O2
K2CO3/H2O2
equiv 5:5
NaOH/H2O2
NaOH/H2O2
K2CO3/H2O2
equiv 5:5
rt
1 h
16 h
Trace
No reac
rt/50 ꢀ
C
Me
O
O
Me
Me
Me
3
4
5
41
37
37
rt
rt
rt
16 h
16 h
16 h
decomp.
decomp.
82%
23 83%
30 75%
b
Scheme 6. Preparation of isoxazolidinone monomers from vinyl acetate.
Unfortunately, this cycloaddition afforded a much poorer ratio of
diastereomers and it was difficult to separate and isolate the desired
cycloadduct in pure form. In some cases, this made it difficult or im-
possible to prepare the isoxazolidinone in enantiomerically pure
6
37
NaOH/H2O2
rt
3 h
53%
a
Isolated yield.
b
After 1 h an additional 5 equiv K2CO3/5 equiv H2O2 are added and then stirred
overnight.
Me
Me
O
O
Me
O
O
Me
H
O
OAc
N
O
H
OAc
OMe
Table 1
CO2Me
32
R
Me
O
Me
O
O
34
O
D GuloseN
R
O
OH
R
H
N
H
O
O
O
H
H
O
Me
Me
Me
36
31
1
Me
O
O
O
Table 1
O
O
Me
Me
O
O
H
O
O
33
N
O
H
O
R
O
O
35
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
Me
Me
O
Me
Me
O
O
Me
Me
Me
Me
O
H
O
O
O
O
H
H
H
O
O
O
N
O
H
O
N
O
H
N
O
N
O
H
H
O
O
O
Me
O
Me
O
O
O
O
Me
Me
O
O
O
Me
37
38
39
73%
40
81%
65%
Scheme 7. Decarboxylative oxidation to the isoxazolidinone monomers.
65%

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4845
reaction time or changing the base did not improve the results. In
contrast, cycloadducts 35 derived from acrylate 33 could be oxi-
datively decarboxylated in good yield upon stirring overnight with
potassium carbonate and hydrogen peroxide (Scheme 8). This
general procedure was applied to the monomers corresponding to
The key advantage of this approach overall of the others con-
sidered is the ease of securing the cycloadducts in enantiomerically
pure form.25 Cycloadditions of nitrones generated in situ from an
aldehyde and the D-gulose-derived chiral auxiliary are generally
cleaner, higher yielding, and more diastereoselective with cyclic
acrylate 33. In almost all cases, the cycloadducts are obtained as
single enantiomers following a facile recrystallization.
b
3-leucine, valine, phenylalanine, and alanine in good to excellent
yields.
These cycloadditions with many different aldehydes and the
utility of the resulting enantiomerically pure products for
acid synthesis are the subject of a separate publication.25 For the
purpose of our studies on the incorporation of
3-N-hydroxyamino
acids into peptides, we selected the aliphatic substituted mono-
mers (leucine, valine, phenylalanine, and alanine) for further
investigations.
Removal of the carbohydrate auxiliary from the isoxazolidinone
proved to be initially more difficult than expected. These lactones
are hydrolytically unstable, and the standard conditions for auxil-
iary removal, perchloric acid in MeOH,15 both cleaved the auxiliary
and opened the lactone to give the corresponding methyl esters
(Table 2, entries 1e3). Decreased reaction times and lower reaction
temperatures allowed us to isolate some of the desired product
(entries 7e8).
The use of other alcohols, however, required higher tempera-
tures and did not favor the auxiliary removal (entries 4e6). Even-
tually, we found that conducting the auxiliary cleavage in CH3CN at
room temperature afforded clean removal without lactone open-
ing. This convenient procedure has proven to be generally useful for
removal of the D-gulose-derived auxiliary from a number of cyclic
hydroxylamine derivatives. It was applied to our targeted mono-
mers to give the desired products in good yield (Fig. 4).
Although our NMR evidence clearly showed only a single di-
astereomer, we carefully checked the enantiopurity of the iso-
xazolidinones prepared by this cycloaddition route. Direct assay of the
enantiopurity of the sensitive unprotected isoxazolidines by HPLC or
SFC analysis on chiral columns was complicated by decomposition.
We therefore elected to convert them to their corresponding N-phe-
nylethylamide esters by ligation with phenylpyruvic acid followed
b
3-amino
a) 5 equiv
1:1 K2CO3/H2O2
D GuloseN
O
O
b
THF/H2O
D GuloseN
O
R
O
O
or
R
O
35
b) 5 equiv
36
1:1 1M NaOH /H2O2
THF/H2O
Me
Me
Me
O
O
Me
O
O
O
Me
Me
Me
O
O
H
O
O
Me
H
O
H
N
O
H
N
O
O
Me
O
24 a) 45%
30 b) 90%
Me
b) 62%
Me
Me
Me
Me
O
O
O
O
O
Me
Me
O
Me
Me
O
H
O
H
O
H
O
H
N
O
N
O
O
O
Me
Me
Me
23 a) 82%
42 a) 52%
b) 53%
b) trace
Scheme 8. Decarboxylative oxidation to the isoxazolidinone monomers.
Table 2
Cleavage of the sugar auxiliary
Me
Me
O
O
O
Me
Me
HO
O
HN
O
NH
O
cleavage
H
O
N
O
O
H
OR
conditions
O
43
T/ꢀC
44
23
Entry
equiv HClO4
Solvent
Time/h
Conversion (43/44)a
1
2
3
4
5
6
7
8
2
0.5
2
2
2
2
2
2
2
MeOH
MeOH
MeOH
iPrOH
iPrOH
EtOH
MeOH
MeOH
THF/H2O 4:1
60 ꢀ
rt
rt
60 ꢀ
60 ꢀ
60 ꢀ
rt
C
3 h
3 h
3 h
3 h
30 min
30 min
1 h
35e50 min
3 h
99% (0/100)
99% (0/100)
99% (0/100)
99% (0/100)
23
C
C
C
Trace
56% (60/40)
53% (70/30)
Trace
rt
rt
9
10
11
12
13
2
2
3
3
Dioxane/H2O 4:1
DME/H2O 4:1
MeCN/H2O 3:1
MeCN
rt
rt
rt
rt
3 h
3 h
3 h
3 h
Trace
Trace
99%b [100/0]
99%c [100/0]
a
Conversion determined by 1H NMR spectroscopy. Ratio of products 43/44 is given in brackets.
The isolated yield after column chromatography was 62%.
The isolated yield after column chromatography was 84%.
b
c

4846
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
HN
O
HN
O
HN
O
O
HN
O
Me
Me
O
O
Me
O
Me
Me
Phe 43 84% yield
Val 45 67% yield
Leu 46 73% yield
Ala 47 42% yield
Figure 4. Free isoxazolidinones prepared by auxiliary removal.
hydroxylamine and also activated the isoxazolidinone toward am-
ide-formation with an amine or peptide. In all cases examined, this
was accomplished with Boc anhydride and DMAP in moderate to
good yield (Scheme 10). These products were purified by column
chromatography and were stable for weeks when stored at 4 ꢀC.
As a model study for our intended application of these mono-
43
O
O
Ph
Ph
NH
O
t
a) 48, BuOH/H2O 1:1
overnight, rt
OMe
OMe
O
(S/R)
Ph
OH
-H2O, -CO2
b) TMSCHN2, MeOH
52%
O
mers to the preparation of N-terminal
and their ligation with -ketoacids, we sought to introduce the
hydroxyamino acid onto a
3-dipeptide (Scheme 11). This study
b
3-peptide hydroxylamines
-N-
48
a
b
b
NH
O
Ph
O
was aimed to both identify conditions for the coupling of the
monomer and to establish that the Boc-deprotection could be
effected without damage to the hydroxylamine.
O
(S)
Ph
N
H
OCH3
*
With simple amines, mixing the Boc-protected monomer in
CH2Cl2 afforded the desired amide. With the more sterically de-
49
manding
b
3-peptides, however, this protocol was not effective.
Scheme 9. Amide ligation of the isoxazolidinone monomers with a-ketoacids.
Fortunately, a brief course of optimization identified the combi-
nation of DMF and 0.5 equiv of DMAP at 50 ꢀC as suitable for direct
introduction of the N-hydroxylamino acid. Removal of the Boc-
group with TFA proceeded smoothly and ligation with phenyl-
pyruvic acid afforded the expected triamide 56.
O
MeCN,1.5 equiv Boc2O
1.0 equiv DMAP, 1 h, rt
t
HN
O
BuO
N
O
O
O
R
R
3. Conclusion
50
14
enantiopure
isoxazolidinone
monomers
In summary, we have designed and implemented a scalable
route to enantiopure protected isoxazolidinone monomers, which
serve as precursors to the N-terminal hydroxylamineꢁ
tides that can be used in amide ligation reaction with
ketoacidse
3-oligopetides. Our four-step route to the monomers
b
3-oligope-
O
O
a
-
t
t
BuO
N
O
O
BuO
N
O
b
O
takes advantage of a general 1,3-cycloaddition procedure to access
enantiopure cycloadducts that may be readily oxidized to the
crystalline isoxazolidinones. This robust methodology for the
preparation of N-isoxazolidinone amino acid derivatives makes
Me
Me
3 63% yield
51 58% yield
O
O
possible our ongoing efforts to access b
3-oligopeptides by chemo-
t
t
BuO
N
O
O
BuO
Me
selective ligation of two independently prepared
units.
b
3-oligopeptide
N
O
O
Me
Me
52 48% yield
53 60% yield
4. Experimental
Scheme 10. Boc protection of the isoxazolidinone monomers.
4.1. General methods
by methyl ester formation. Analysis by SFC on chiral columns and
comparison to a racemic sample established the enantiopurity
(Scheme 9). The absolute configuration was confirmed by single
crystal X-ray analysis of the cycloadduct ent-37.25
The final step of the monomer synthesis was the introduction of
the Boc-group. This group served both as a protecting group for the
All reactions utilizing air- or moisture-sensitive reagents were
performed in oven-dried glassware under an atmosphere of dry N2.
CH2Cl2 was distilled from CaH2. THF and Et2O were distilled from
Na/benzophenone. Thin-layer chromatography (TLC) was per-
formed on EMD precoated plates (silica gel 60 F254, Art 5715,
Ph
Ph
O
O
O
O
O
a) 1:1 CH2Cl2/TFA
1 h
b) DMF, 45 °C
16 h
BocN O
Ph
HN
N
H
OEt
HN
N
H
OEt
O
O
O
0.5 equiv DMAP
DMF, 45 °C, 16 h
O
O
H2N
N
H
OEt
Me
OH
Boc
Me
O
Ph
56
Me
N
N
H
Me
Ph
OH
48
3
54
55
Me
Me
O
32% over 3 steps
Scheme 11. Preparation of an N-hydroxylamine terminal dipeptide and ligation with an a-ketoacid.

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4847
0.25 mm) and were visualized by fluorescence quenching under UV
light and by staining with phosphomolybdic acid or potassium
permanganate. Preparative thin-layer chromatography (PTLC) was
performed using plates prepared from silica gel EMD 60 PF254 (Art
7749). Column chromatography was performed on EMD Silica Gel
60 (230e400 mesh) using a forced flow of 0.5e1.0 bar. 1H NMR
(500 MHz) and 13C NMR (125 MHz) were measured on a Bruker
Avance AVII-500 spectrometer. Chemical shifts are expressed in
parts per million (ppm) and coupling constants are reported as
Hertz (Hz). Splitting patterns are indicated as follows: br, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Infrared (IR)
spectra were recorded on a JASCO FT/IR-4100 spectrophotometer
and are reported as wavenumber (cmꢁ1). Enantiomeric purity was
determined by preparation of both enantiomers of the peptide
followed by analysis on chiral SFC.
recrystallized from heptane (50 mL/g) to give the cycloadduct as
a single diastereomer.
4.4. General procedure C. Nitrone cycloadditions with the
gulose derived chiral auxiliary
A 0.3 M solution of -gulose oxime 1 (3.63 mmol, 1.00 equiv),
D
aldehyde (4.00 mmol, 1.10 equiv), and acetoxy 2-methoxy acrylate
32 (7.26 mmol, 2.00 equiv) in toluene was heated to reflux with
a DeaneStark trap fitted with a reflux condenser. The reaction was
monitored by TLC for the disappearance of the UV active nitrone
spot. After cooling to room temperature the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography and two of the four possible diastereomers, were
isolated as a 6:1 mixture. The resulting solid (or sometimes viscous
oil) was recrystallized from heptane (50 mL/g) to give the cyclo-
adduct as a single diastereomer.
4.1.1. SFC (supercritical fluid chromatography) conditions. Column:
Daicel Chiralpak OJ-H (4.6ꢂ250 mm). Eluents: gradient 5e80%
iPrOH (0.1% TFA v/v) in CO2, rate 3%/min or 5%/min, Flow rate
2.0 ml/min; isocratic iPrOH (0.1% TFA v/v) in CO2, Flow rate 2.0 ml/
min. Detection: 220 nm.
4.5. General procedure D. Nitrone cycloadditions with the
gulose derived chiral auxiliary
A 1 M solution of
D
-gulose oxime 1 (0.73 mmol, 1.00 equiv),
4.1.2. 2,3,5,6-O-Diisopropylidene-
D
-gulose hydroxylamine (1). The
aldehyde (1.46 mmol, 2.00 equiv), and 2-chloroacrylonitrile 19
(2.18 mmol, 3.00 equiv) was dissolved in toluene and heated at
100 ꢀC in a sealed tube overnight. After cooling to room tempera-
ture the resulting crude residue was purified by flash chromatog-
raphy to obtain a 4:1 mixture of two of the four possible
diastereomers. The resulting solid (or sometimes viscous oil) was
recrystallized from heptanes (50 mL/g) to give the cycloadduct as
a pure single diastereomer.
D
-gulose hydroxylamine 1 was prepared following a previously
published literature procedure and scaled up to 1 mol.21,26e29
Spectroscopic data was consistent with literature results.
4.1.3. Synthesis
of
3-methylene-1,4-dioxaspiro[4.5]decan-2-one
(33). The acrylate was prepared following a previously published
literature procedure and scaled up to 1 mol. Spectroscopic data was
consistent with literature results.
4.6. General procedure E. Nitrone cycloadditions with the
gulose derived chiral auxiliary
4.1.4. Synthesis of methyl 2-acetoxyacrylate (32). The acrylate was
prepared following a previously published literature procedure30
and scaled up to 1 mol. Spectroscopic data was consistent with
literature results.
A 1 M solution of
D
-gulose oxime 1 (0.73 mmol, 1.00 equiv),
-acetoxyacrylonitrile 20
aldehyde (1.46 mmol, 3.00 equiv), and
a
(2.18 mmol, 3.00 equiv) was dissolved in toluene and heated at
115 ꢀC in a sealed tube overnight. After cooling to room temperature
the resulting crude residue was purified by flash chromatography to
give a 1:1 mixture of two of the four possible diastereomers.
4.2. General procedure A. Nitrone cycloadditions with the
gulose derived chiral auxiliary
A mixture of -gulose oxime 1 (14.5 mmol, 1.00 equiv), aldehyde
D
4.7. General procedure F. Auxiliary cleavage with HClO4
(43.5 mmol, 3.00 equiv), and vinyl acetate 26 (0.14 mol,
10.00 equiv) was heated at 110 ꢀC in a sealed tube for 16 h. With
stirring, in some cases a minimal amount of toluene (1.0e2.0 mL)
was added to form a solution. After cooling to room temperature,
the resulting crude product was purified by flash chromatography
to obtain a mixture of three diastereomers in a ratio of 9:6:2, de-
termined by 1H NMR. In some cases the crude solid (or viscous oil)
was recrystallized from heptane (50 mL/g) to give a single di-
astereomer of the pure cycloadduct.
To a 0.1 M solution of the gulose-isoxazolidinone (0.32 mmol,
1.00 equiv) in MeCN was slowly added HClO4 (0.97 mmol, 70% w/w
in H2O, 3.00 equiv), and the solution was stirred at room temper-
ature for 3 h. The resulting mixture was quenched by the slow
addition of saturated NaHCO3 solution and extracted with EtOAc
(3ꢂ). The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by column chromatography to
afford the free isoxazolidinone.
4.3. General procedure B. Nitrone cycloadditions with the
gulose derived chiral auxiliary
4.8. General procedure G1. Oxidation of the
spirocyclohexanone acetal to the isoxazolidinone
A 0.3 M solution of -gulose oxime 1 (7.26 mmol, 1.00 equiv),
D
aldehyde (14.5 mmol, 2.00 equiv), and spiroacrylate 33 (8.71 mmol,
1.20 equiv) in toluene was heated to reflux with a DeaneStark trap
fitted with a reflux condenser overnight. The reaction was moni-
tored by TLC for the disappearance of the UV active nitrone spot.
After cooling to room temperature the mixture was concentrated
under reduced pressure. The crude product was purified by flash
chromatography and all the observed diastereomers were sepa-
rated (three of the four possible diastereomers, except in the case of
the alanine derivative, in which all of the diastereomers were ob-
served). The resulting solid (or sometimes viscous oil) was
A solution of D-gulose-isoxazolidine cyclohexanone acetal 35
(1.55 mmol, 1.00 equiv) in THF/H2O (6:1 v/v, 0.1 M) was cooled to
0 ꢀC. Then K2CO3 (7.77 mmol, 5.00 equiv) and H2O2 (30% w/w,
5.00 equiv) were slowly added. After stirring the reaction for 1 h at
room temperature, another 5.00 equiv (7.77 mmol) of both K2CO3
and H2O2 were added. The reaction was monitored by TLC, and in
some cases it was stirred overnight. The resulting mixture was
quenched by the addition of saturated Na2S2O7 (2ꢂ) and extracted
with EtOAc (3ꢂ). The combined organic layers were washed with
NaHCO3 (3ꢂ) and NH4Cl (3ꢂ), dried over Na2SO4, filtered, and

4848
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
concentrated under reduced pressure. The resulting residue was
purified by column chromatography to afford the isoxazolidinone
as a white solid.
important not to add an excess to avoid decomposition) were added
and stirred at room temperature. The reaction was stirred for 1e3 h.
After completion by TLC, the mixture was concentrated under re-
duced pressure and the resulting residue was purified by column
chromatography to afford the N-Boc protected isoxazolidinone.
4.9. General procedure G2. Oxidation of the
spirocyclohexanone acetal to the isoxazolidinone
4.14. General procedure L. Cbz-protected isoxazolidinone
from the a,b
unsaturated aldehyde11
A 0.1 M solution of D-gulose-isoxazolidine cyclohexanone acetal
35 (1.55 mmol, 1.00 equiv) in THF was cooled down to 0 ꢀC and 2 M
NaOH (7.77 mmol, 5.00 equiv) and H2O2 (30% w/w, 5.00 equiv)
were slowly added. After the reaction was stirred for 1 h at room
temperature, another 5.00 equiv of both NaOH and H2O2 were
added. The reaction was monitored by TLC, but was never stirred
longer than 3 h because it started to decompose. After completion
the resulting mixture was quenched by the addition of saturated
Na2S2O7 (2ꢂ) and extracted with EtOAc (3ꢂ). The combined organic
layers were washed with NaHCO3 (3ꢂ) and NH4Cl (3ꢂ), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by column chromatography to afford
the isoxazolidinone as a white solid.
To a 0.1 M solution of cat 10 (0.11 mmol, 20 mol %) in CH2Cl2
were added -unsaturated cynnamaldehyde (0.57 mmol,
a
,b
9
1.00 equiv) and CbzNHOH (0.68 mmol, 1.00 equiv) at 0 ꢀC. After
stirring the reaction for 3 h, it was concentrated down under re-
duced pressure and purified by column chromatography to afford
the isoxazolidinone in 94% yield as a yellow oil. The compound was
oxidized to the corresponding isoxazolidinone according general
procedure I.
4.15. General procedure M. Isoxazolidinone opening to the
amide bond and Cbz protected hydroxylamine
4.10. General procedure H. Deprotection of the acetate to the
isoxazolidine acetal
To
a 0.1 M solution of Cbz-protected isoxazolidinone 11
(40.0 mg, 0.135 mmol) in dry CH2Cl2 was added 1,2-phenylethyl
amine 12 (0.019 mL, 0.148 mmol). After 2 h stirring at room tem-
perature, the reaction mixture was concentrated under reduced
pressure. The resulting residue was purified by column chroma-
tography to afford coupled N-Cbz hydroxylamine 13 as a white
solid.
To a solution of
D-gulose-isoxazolidine acetate (3.22 mmol,
1.00 equiv) in MeOH/H2O (10:1 v/v, 0.1 M) was added K2CO3
(1.00 equiv), and the solution was stirred for 1e2 h at room tem-
perature. The resulting reaction mixture was quenched by the ad-
dition of saturated NH4Cl (3ꢂ) and extracted with a 9:1 mixture of
CHCl3/iPrOH (3ꢂ), the combined organic layers were washed with
brine (3ꢂ), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography to afford the isoxazolidine acetal.
4.16. General procedure N. Isoxazolidinone opening to the
amide bond and Cbz protected hydroxylamine
To
a 0.01 M solution of the amino-b-Phe-b-Ala-OEt 54
(0.034 mmol, 1.00 equiv) in DMF, Boc-Leu isoxazolidinone
3
4.11. General procedure I. Oxidation of the acetate to the
isoxazolidinone
(0.068 mmol, 2.00 equiv) was added and stirred at 60 ꢀC. After
16 h, the reaction mixture was concentrated under reduced pres-
sure and the resulting residue was purified by column chroma-
tography to afford the N-Boc-terminal-hydroxylamine tripeptide
55 as a yellow oil.
NMO (2.12 mmol, 1.20 equiv) and TPAP (0.17 mmol, 10 mol %)
was added to a 0.1 M solution of
D-gulose-isoxazolidine acetal
ꢀ
(1.76 mmol, 1.00 equiv) and preactivated molecular sieves (4 A) in
dry CH2Cl2. After stirring for 1 h at room temperature, hexanes (ꢂ1/
2 V of CH2Cl2) was then added to the reaction and stirred for an-
other 15 min. The resulting mixture was filtered through silica gel,
washed with EtOAc and the combined organic solvents were con-
centrated under reduced pressure. The resulting residue was pu-
rified by column chromatography to afford the isoxazolidinone.
4.17. General procedure O. Deprotection and coupling with
phenylpyruvic acid to the tripeptide
HO-Boc-N-b-Leu-b-Phe-b-Ala-OEt 55 (0.066 mmol, 1.00 equiv)
was stirred in a 0.01 M solution of 1:1 CH2Cl2/TFA for 1 h at room
temperature. The reaction mixture was then concentrated under
reduced pressure. The TFA salt of the hydroxylamine 4 (0.066 mmol,
1.00 equiv) was then dissolved in a 0.1 M solution of 1:1 tBuOH/H2O,
and phenylpyruvic acid 48 (0.066 mmol, 1.00 equiv) was added.
The reaction was stirred overnight at 50 ꢀC and the resulting residue
was concentrated down and purified by column chromatography to
afford the N-benzyl tripeptide 56.
4.12. General procedure J. Deprotection of the cyanoacetate to
the isoxazolidinone
To a solution of D-gulose-isoxazolidine cyanoacetate (1.00 equiv)
in THF/H2O (4:1 v/v, 0.5 M) was added Et3N (2.00 equiv), and the
mixture was stirred overnight at room temperature. The resulting
reaction mixture was quenched by the addition of saturated NH4Cl
(3ꢂ) and extracted with EtOAc (3ꢂ). The combined organic layers
were washed with brine (3ꢂ), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography to afford the isoxazolidinone
(62e75% yield).
4.18. General procedure P. Coupling of deprotected
isoxazolidines with phenylpyruvic acid
To a 0.15 M solution of isoxazolidinone (0.068 mmol, 1.00 equiv)
in tBuOH/H2O (1:1) was added phenylpyruvic acid 48 (0.074 mmol,
1.10 equiv) and heated at 45 ꢀC for 16 h. The reaction mixture was
directly concentrated under reduced pressure. The resulting resi-
due was dissolved in MeOH 0.1 M. After cooling to 0 ꢀC, TMSCHN2
2.0 M in Et2O (0.14 mmol, 2.00 equiv) was slowly added and stirred
for another 10 min. The reaction mixture was then concentrated
and purified by column chromatography to afford the amide
product. These reactions were not optimized and were performed
4.13. General procedure K. Boc protection of the free
isoxazolidinone
A
0.1 M solution of the free isoxazolidinone (0.34 mmol,
1.00 equiv) in dry MeCN was cooled to 0 ꢀC. Then Boc2O (0.51 mmol,
1.50 equiv) and DMAP (0.25e0.62 mmol, 0.50e1.20 equiv; it is

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4849
20
only to obtain material suitable for determining the enantiopurity
by SFC analysis.
(hexanes/EtOAc 4:1);
(500 MHz, CDCl3)
[
a
]
þ93.4 (c 1.00, CHCl3); 1H NMR
D
d
0.95 (dd, J¼16.1, 6.4 Hz, 6H),1.28 (m,1H),1.50 (s,
9H), 1.74 (m, 1H), 2.38 (dd, J¼17.6, 2.1 Hz, 1H), 2.96 (dd, J¼17.6,
8.7 Hz, 1H), 4.60 (m, 1H); 13C NMR (125 MHz, CDCl3)
173.7, 156.3,
84.0, 58.9, 43.2, 34.6, 28.1, 24.9, 22.7, 21.9; IR (thin film) 2959,
4.18.1.
D-Gulose-(S)-3-isobutylisoxazolidin-5-yl acetate (29). Pre-
d
pared according to general procedure A. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the diastereomeric mixture as a colorless solid in 74%
yield. Rf¼0.25 (hexanes/EtOAc 4:1); recrystallization from heptane
provided a single diastereomer. mp149e150 ꢀC; 1H NMR (500 MHz,
n
1807, 1745, 1469, 1370, 1302, 1134; HRMS (ESI): m/z: calcd for
C12H21NO4: 243.1471; found: 244.1538 [MþH]þ.
4.18.6. (S)-Methyl-5-methyl-3-(2-phenylacetamido)-hexanoate
(58). Prepared according to general procedure P. Purification by
column chromatography using hexanes/EtOAc (2:1 v/v) as the
CDCl3)
d
0.91 (dd, J¼6.3, 13.6 Hz, 6H), 1.11 (m, 1H), 1.26 (s, 3H), 1.37
(s, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 1.58 (m, 1H), 1.68 (m, 1H), 2.07 (s,
3H), 2.17 (m, 1H) 2.50 (dd, J¼7.5, 13.2 Hz, 1H), 3.72 (m, 2H), 4.07 (m,
1H), 4.37 (q, J¼4.2 Hz, 1H), 4.65 (m, 1H), 4.80 (m, 1H), 4.91 (d,
J¼5.6 Hz, 1H), 6.39 (d, J¼5.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
eluent afforded the carbamate as a yellow oil in 46% yield. Rf¼0.23
24
(hexanes/EtOAc 2:1);
[
a
]
ꢁ42.7 (c 0.94, CHCl3); 1H NMR
D
(500 MHz, CDCl3)
d
0.85 (d, J¼6.6 Hz, 3H), 0.87 (d, J¼6.5 Hz, 3H)1.22
d
170.4, 112.8, 109.8, 99.0, 98.3, 84.2, 84.1, 80.6, 75.6, 66.2, 59.4, 44.3,
(m, 1H), 1.36 (m, 1H), 1.48 (m, 1H), 2.46 (m, 2H), 3.55 (s, 2H), 3.60 (s,
40.9, 26.8, 26.2, 25.6, 25.4, 25.1, 23.2, 22.1, 21.4; IR (thin film)
n
3420,
3H), 4.29 (m, 1H), 5.80 (d, J¼8.46 Hz, 1H), 7.30 (m, 3H), 7.35 (m, 2H);
2955,1745,1653,1372,1236,1111, 1088,1066, 938, 850; HRMS (ESI):
13C NMR (125 MHz, CDCl3)
d 172.2, 170.4, 135.0, 129.5, 129.1, 127.4,
m/z: calcd for C21H35NO8: 429.2363; found: 452.2254 [MþNa]þ.
51.7, 44.4, 44.1, 43.1, 38.8, 25.2, 22.9, 22.3; IR (thin film) n 3434,
2956, 2362, 2099, 1646, 1559,1437, 1263; HRMS (ESI): m/z: calcd for
4.18.2.
D
-Gulose-(S)-3-isobutylisoxazolidin-5-ol (7). Prepared acc-
C16H23NO3: 277.1678; found: 278.1747 [MþH]þ.
ording to general procedure H. Purification by column chroma-
tography using hexanes/EtOAc (2:1 v/v) as the eluent afforded the
diastereomeric mixture as a colorless solid in 82% yield (5:1 dr).
Rf¼0.23 (hexanes/EtOAc 2:1); mp135e136 ꢀC; 1H NMR (500 MHz,
4.18.7.
D-Gulose-(S)-5-chloro-3-isobutylisoxazolidine-5-carbonitrile
(21). Prepared according to general procedure D. Purification by
column chromatography using hexanes/EtOAc (8:1 v/v) as the el-
uent afforded the diastereomeric mixture as a colorless solid in 68%
yield (6:1 dr). Rf¼0.40 (hexanes/EtOAc 4:1); recrystallization from
CDCl3)
d
0.88 (qd, J¼10.1, 6.4 Hz, 6H), 1.07 (m, 1H), 1.26 (s, 3H), 1.35
(s, 3H), 1.39 (s, 3H), 1.42 (s, 3H), 1.52 (m, 1H), 1.62 (m, 1H), 2.02 (m,
1H), 2.39 (m, 1H), 3.70 (m, 2H), 3.90 (m, 1H), 4.05 (m, 1H), 4.17 (m,
1H), 4.37 (m, 1H), 4.66 (m, 1H), 4.92 (m, 1H), 5.60 (m, 1H); 13C NMR
heptane provided a single diastereomer. Mp 129 ꢀC; [
a
]
22 ꢁ115.2 (c
D
0.95, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d
0.94 (dd, J¼6.6, 1.6 Hz,
(125 MHz, CDCl3)
66.2, 59.6, 44.6, 42.3, 26.8, 26.2, 25.7, 25.3, 25.1, 23.1, 22.4; IR (thin
film) 3436, 2986, 2955, 2872, 1456, 1371, 1211, 1163, 1086, 849;
d
112.9, 109.8, 99.6, 99.4, 84.4, 84.0, 80.7, 75.6,
6H), 1.32 (m, 4H), 1.38 (s, 3H), 1.42 (s, 3H), 1.47 (s, 3H), 1.63 (m, 1H),
1.75 (m, 1H), 2.94 (dd, J¼13.8, 6.8 Hz, 1H), 3.23 (dd, J¼13.8, 6.5 Hz,
1H), 3.73 (dd, J¼8.5, 6.8 Hz, 1H), 3.98 (m, 1H), 4.04 (dd, J¼8.5,
3.9 Hz, 1H), 4.21 (dd, J¼8.5, 6.9 Hz, 1H), 4.37 (q, J¼8.4 Hz, 1H), 4.70
(dd, J¼6.0, 4.0 Hz, 1H), 4.92 (d, J¼6.1 Hz, 1H), 5.03 (s, 1H); 13C NMR
n
HRMS (ESI): m/z: calcd for C19H33NO7: 387.2257; found: 388.2216
[MþNa]þ.
(125 MHz, CDCl3)
d 114.7, 113.3, 110.0, 98.5, 38.8, 88.8, 84.7, 84.1,
4.18.3.
D
-Gulose-(S)-3-isobutylisoxazolidin-5-one (23). Prepared acc-
80.2, 75.5, 66.1, 61.3, 53.5, 42.3, 26.8, 26.1, 25.9, 25.3, 24.9, 22.7, 22.6;
IR (thin film) 3425, 2985, 2959, 2936, 2872,1785, 1643, 1455,1373,
ording to general procedures I, G1, G2, J. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent affor-
ded the diastereomeric mixture as a colorless solid in 82% yield. It
n
1211, 1092, 1034, 876, 848; HRMS (ESI): m/z: calcd for C21H35NO8:
430.1871; found: 431.1938 [MþH]þ.
was recrystallized if necessary from heptane to afford a single
20
diastereomer. Rf¼0.25 (hexanes/EtOAc 4:1); mp142e143 ꢀC; [
a
]
4.18.8. D-Gulose-(S)-methyl-5-acetoxy-3-isobutylisoxazolidine-5-
D
þ21.1 (c 1.06, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d
0.94 (dd, J¼12.3,
carboxylate (41). Prepared according to general procedure C. Puri-
fication by column chromatography using hexanes/EtOAc (5:1 v/v)
as the eluent afforded the diastereomeric mixture as a colorless
solid in 60% yield (4:1 dr). Rf¼0.28 (hexanes/EtOAc 4:1); re-
crystallization from heptane provided a single diastereomer. Mp
6.3 Hz, 6H), 1.29 (s, 3H), 1.37 (s, 3H), 1.41 (s, 3H), 1.45 (s, 3H), 1.71 (m,
2H), 2.39 (dd, J¼17.6, 4.9 Hz, 1H), 2.87 (dd, J¼17.6, 7.9 Hz, 1H), 3.72
(dd, J¼8.6, 6.7 Hz,1H), 3.94 (m,1H), 4.02 (dd, J¼8.5, 4.0 Hz,1H), 4.20
(dd, J¼8.6, 6.8 Hz, 1H), 4.36 (q, J¼8.4 Hz, 1H), 4.72 (m, 2H), 4.90
(d, J¼6.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
176.2, 113.2, 110.0,
131e132 ꢀC; 1H NMR (500 MHz, CDCl3)
d
0.91 (d, J¼6.6 Hz, 3H), 0.93
98.0, 85.4, 84.2, 80.3, 75.7, 66.1, 58.9, 42.8, 33.8, 26.8, 26.1, 25.4, 25.2,
(d, J¼6.6 Hz, 3H), 1.17 (m, 1H), 1.28 (m, 3H), 1.36 (s, 3H), 1.40 (s, 3H),
1.44 (s, 3H), 1.67 (m, 1H), 1.78 (m, 1H), 2.10 (s, 3H), 2.34 (dd, J¼14.0,
2.5 Hz, 1H), 2.86 (dd, J¼14.0, 7.8 Hz, 1H), 3.70 (m, 1H), 3.79 (s, 3H),
4.03 (dd, J¼8.5, 4.0 Hz, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.63 (s, 1H),
4.66 (dd, J¼5.9, 4.2 Hz, 1H), 5.05 (d, J¼6.1 Hz, 1H); 13C NMR
24.8, 22.9, 22.3; IR (thin film)
n 2987, 2956, 1792, 1381, 1211, 1165,
1077, 1044, 892, 846; HRMS (ESI): m/z: calcd for C19H31NO7:
385.2101; found: 408.2004 [MþNa]þ.
4.18.4. (S)-3-Isobutylisoxazolidin-5-one (46). Prepared according to
general procedure F. Purification by column chromatography using
hexanes/EtOAc (3:1 v/v) as the eluent afforded the isoxazolidinone
(125 MHz, CDCl3) d 169.5, 168.1, 112.8, 109.8, 104.8, 97.5, 84.6, 84.0,
80.2, 75.7, 66.1, 59.4, 53.5, 43.5, 42.6, 26.7, 26.2, 25.7, 25.3, 25.0, 23.3,
22.0, 21.0; IR (thin film) 3402, 2954, 2361, 1757, 1648, 1456, 1371,
n
22
46 as a yellow oil in 73% yield. Rf¼0.33 (hexanes/EtOAc 2:1);.[
a
]
1208, 1088; HRMS (ESI): m/z: calcd for C21H37NO10: 487.2417;
D
ꢁ13.9 (c 0.775, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.92 (m, 6H),
found: 510.2299 [MþNa]þ.
1.40 (m, 1H), 1.53 (m, 1H), 1.69 (m, 1H), 2.39 (dd, J¼17.1, 8.9 Hz, 1H),
2.77 (m, 1H), 3.90 (m, 1H); 13C NMR (125 MHz, CDCl3)
41.1, 36.5, 25.4, 22.5, 22.4; IR (thin film) 3428, 2961, 2091, 1773,
d
178.4, 58.0,
4.18.9.
D-Gulose-(S)-5-cyano-3-benzylisoxazolidin-5-yl
acetate
n
(22). Prepared according to general procedure E. Purification by
column chromatography using hexanes/EtOAc (5:1 v/v) as the el-
uent afforded the diastereomeric mixture as a colorless solid in 54%
yield (w1:1 dr). Rf¼0.42 (hexanes/EtOAc 4:1); 1H NMR (500 MHz,
1647, 1200; HRMS (ESI): m/z: calcd for C7H13NO2: 143.0946; found:
143.0925 [MþH]þ.
4.18.5. (S)-tert-Butoxycarbonyl-3-isobutylisoxazolidin-5-one
(3).
CDCl3) d 1.26 (s, 3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.36 (s, 3H), 1.38
Prepared according to general procedure K. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the carbamate as a yellow oil in 63% yield. Rf¼0.35
(m, 6H), 1.41 (s, 3H), 1.44 (s, 3H), 2.14 (s, 3H), 2.19 (s, 3H), 1.32 (m,
4H), 2.67 (dd, J¼14.3, 3.7 Hz, 1H), 2.74 (m, 2H), 2.85 (d, J¼5.6 Hz,
2H), 2.96 (dd, J¼14.3, 7.8 Hz, 1H), 3.08 (m, 2H), 3.58 (q, J¼7.1 Hz,

4850
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
1H), 3.63 (dd, J¼8.4, 4.1 Hz, 1H), 3.74 (m, 1H), 3.99 (m, 1H), 4.04 (m,
1H), 4.13 (m, 2H), 4.28 (q, J¼7.6 Hz, 2H), 4.60 (m, 2H), 4.67 (s, 1H),
4.70 (s, 1H), 4.84 (d, J¼6.0 Hz, 1H), 4.93 (d, J¼6.0 Hz, 1H), 7.26e7.32
7.7 Hz, 1H), 2.75 (dd, J¼17.1, 6.8 Hz, 1H), 2.87 (m, 1H), 3.00 (dd,
J¼13.9, 6.9 Hz, 1H), 4.08 (m, 1H), 7.19 (m, 2H), 7.28 (m, 1H), 7.33 (m,
2H); 13C NMR (125 MHz, CDCl3)
d 177.1, 129.2, 129.0, 127.3, 60.4,
(m, 10H); 13C NMR (125 MHz, CDCl3)
d
168.2, 167.9, 137.7, 129.4,
35.5; IR (thin film) n 3235, 3062, 3028, 2922, 1780, 1603, 1497, 1454,
128.8, 127.0, 126.9, 113.2, 113.1, 109.9, 109.8, 98.3, 97.5, 96.7, 95.3,
84.5, 84.3, 83.9, 80.3, 80.1, 75.6, 75.5, 66.0, 63.2, 62.6, 47.0, 45.8,
39.9, 39.3, 26.9, 26.1, 26.0, 25.5, 25.4, 24.9, 24.8, 21.1, 21.0; IR (thin
1414, 1174, 1031, 997, 898, 746, 700; HRMS (ESI): m/z: calcd for
C10H11NO2: 177.0790; found: 178.0876 [MþH]þ.
film)
n
3422, 2987, 2936, 1769, 1654, 1455, 1372, 1211, 1162, 1087,
4.18.14. (S)-tert-Butoxycarbonyl-3-benzylisoxazolidin-5-one (51).
Prepared according to general procedure K. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
847, 701; HRMS (ESI): m/z: calcd for C25H32N2O8: 488.2159; found:
511.2042 [MþNa]þ.
afforded the carbamate as a yellow oil in 58% yield. Rf¼0.29 (hex-
20
4.18.10.
D-Gulose-(S)-3-benzylisoxazolidin-5-yl acetate (27). Pre-
anes/EtOAc 4:1); [
a
]
þ44.4 (c 1.04, CHCl3); 1H NMR (500 MHz,
D
pared according to general procedure A. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the diastereomeric mixture as a colorless solid in 68% yield
(3:1.2:1 dr). Rf¼0.39 (hexanes/EtOAc 2:1); major diastereomer 1H
CDCl3)
d
1.49 (s, 9H), 2.56 (dd, J¼17.8, 3.0 Hz,1H), 2.81e2.91 (m, 2H),
3.20 (dd, J¼13.8, 5.9 Hz, 1H), 4.75 (m, 1H), 7.21 (m, 2H), 7.26 (m, 1H),
7.31 (m, 2H); 13C NMR (125 MHz, CDCl3)
172.6, 155.6, 135.9, 129.5,
128.9, 127.3, 84.2, 61.1, 40.0, 33.6, 28.2; IR (thin film) 2980, 2930,
d
n
NMR (500 MHz, CDCl3)
d
1.27 (s, 3H),1.36 (s, 3H),1.40 (s, 3H),1.43 (s,
1806, 1741,1455,1370,1320,1254,1142, 1082, 846, 701; HRMS (ESI):
3H), 2.50 (s, 3H), 2.32 (m, 1H), 2.46 (m, 1H), 2.81 (dd, J¼13.4, 8.7 Hz,
1H), 3.12 (dd, J¼13.5, 6.8 Hz, 1H), 3.61 (m, 1H), 3.84 (m, 2H), 4.14 (m,
2H), 4.30 (m, 1H), 4.63 (m, 1H), 4.93 (d, J¼6.2 Hz, 1H), 6.43 (d,
J¼5.9 Hz, 1H), 7.17e7.22 (m, 3H), 7.23e7.33 (m, 2H); 13C NMR
m/z: calcd for C15H19NO4: 277.1314; found: 300.1204 [MþNa]þ.
4.18.15. (S)-Methyl-4-phenyl-3-(2-phenylacetamido)-butanoate
(60). Prepared according to general procedure P. Purification by
column chromatography using hexanes/EtOAc (2:1 v/v) as the el-
uent afforded the carbamate as a yellow oil in 52% yield. Rf¼0.15
(125 MHz, CDCl3)
d 170.1, 138.8, 129.5, 129.1, 128.6, 126.6, 112.8,
109.7, 99.2, 98.0, 96.7, 87.1, 84.2, 84.1, 80.4, 75.7, 66.1, 61.6, 40.0, 37.9,
27.0, 26.0, 25.4, 24.8, 21.5; IR (thin film) 2986, 2934, 1746, 1454,
n
(hexanes/EtOAc 2:1); mp 79 ꢀC; [
(500 MHz, CDCl3) d 2.45 (m, 2H), 2.75 (m, 1H), 2.82 (m, 1H), 3.50 (s,
a
]
21 ꢁ28.7 (c 0.5, CHCl3); 1H NMR
D
1372, 1212, 1163, 1088, 1039, 979, 934, 848, 701; HRMS (ESI): m/z:
calcd for C24H33NO8: 463.2206; found: 486.2104 [MþNa]þ.
1H), 3.61 (s, 1H), 4.45 (m, 1H), 5.90 (d, J¼8.8 Hz, 1H), 7.03 (m, 2H),
7.16 (m, 2H), 7.23 (m, 3H), 7.23 (m, 3H); 13C NMR (125 MHz, CDCl3)
4.18.11.
D-Gulose-(S)-3-benzylisoxazolidin-5-ol
(59). Prepared
d
172.1, 170.4, 137.4, 134.8, 129.5, 129.4, 129.1, 128.7, 127.4, 126.8,
according to general procedure H. Purification by column chro-
matography using hexanes/EtOAc (2:1 v/v) as the eluent afforded
the diastereomeric mixture as a colorless solid in 54% yield
(3:1.2:1 dr). Rf¼0.38 (hexanes/EtOAc 1:1); major diastereomer 1H
51.8, 47.5, 44.1, 39.8, 37.2; IR (thin film) 3285, 3063, 3029, 2924,
n
2337, 1736, 1647, 1547, 1496, 1437, 1206, 1152, 729, 700; HRMS (ESI):
m/z: calcd for C16H23NO3: 311.1521; found: 334.1421 [MþNa]þ.
NMR (500 MHz, CDCl3)
d
1.28 (s, 3H),1.37 (s, 3H),1.39 (s, 3H),1.45 (s,
4.18.16.
D
-Gulose-(S)-3-isopropylisoxazolidin-5-yl acetate (28). Pre-
3H), 2.18 (m, 1H), 2.21 (m,1H), 2.60 (dd, J¼13.3, 8.3 Hz,1H), 3.03 (m,
1H), 3.81 (m, 1H), 3.84 (m, 2H), 4.21 (m, 2H), 4.65 (m, 1H), 4.93 (m,
1H), 5.06 (m, 1H), 5.64 (m, 1H), 7.17e7.22 (m, 3H), 7.23e7.33 (m,
pared according to general procedure A. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the diastereomeric mixture as a colorless solid in 61%
yield. Rf¼0.20 (hexanes/EtOAc 4:1); recrystallization from heptane
2H); 13C NMR (125 MHz, CDCl3)
d
138.9, 129.6, 128.6, 126.7, 112.9,
109.8, 99.9, 99.2, 84.4, 83.8, 80.6, 75.7, 66.1, 62.7, 41.3, 40.0, 27.0,
26.4, 25.4, 25.0, 24.9, 21.5; IR (thin film) 3432, 2986, 2936, 1642,
provided
(500 MHz, CDCl3)
a
single diastereomer. Mp 154e155 ꢀC; 1H NMR
n
d
0.90 (dd, J¼6.7, 11.0 Hz, 6H), 1.13 (s, 3H), 1.26 (s,
1454, 1372, 1264, 1211, 1163, 1088, 1035, 979, 894, 848, 736, 702;
HRMS (ESI): m/z: calcd for C22H31NO7: 421.2101; found: 422.2162
[MþH]þ.
3H), 1.37 (s, 3H), 1.42 (s, 3H), 1.67 (m, 1H), 2.06 (s, 3H), 2.36 (m, 2H),
3.42 (m, 1H), 3.74 (m, 1H), 4.09 (dd, J¼3.5, 8.5 Hz, 1H), 4.19 (m, 1H),
4.36 (m, 1H), 4.65 (m, 1H), 4.80 (s, 1H), 4.91 (d, J¼6.0 Hz, 1H), 6.36
(d, 1H); 13C NMR (125 MHz, CDCl3)
d 170.4, 112.7, 109.8, 99.5, 98.7,
4.18.12.
D
-Gulose-(S)-3-benzylisoxazolidin-5-one
(24). Prepared
84.0, 83.9, 80.6, 75.7, 67.2, 66.2, 37.4, 31.9, 26.7, 26.2, 25.6, 25.4, 25.1,
21.4, 19.7, 18.8; IR (thin film) 3439, 2983, 2872, 1752, 1654, 1374,
1237, 1211, 1164, 1237, 1211, 1066, 851; HRMS (ESI): m/z: calcd for
C20H33NO8: 415.2206; found: 438.2104 [MþNa]þ.
according to general procedure I, G1, G2, J. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the diastereomeric mixture as a colorless solid in 84%
n
yield. It was recrystallized if necessary from heptane to give a single
20
diastereomer. Rf¼0.20 (hexanes/EtOAc 4:1); mp 124e125 ꢀC; [
a
]
4.18.17.
D
-Gulose-(S)-3-isopropylisoxazolidin-5-ol
(61). Prepared
D
þ11.9 (c 0.75, CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.27 (s, 3H), 1.36
according to general procedure H. Purification by column chro-
matography using hexanes/EtOAc (2:1 v/v) as the eluent afforded
the diastereomeric mixture as a colorless solid in 72% yield (5:1 dr).
Rf¼0.25 (hexanes/EtOAc 2:1); mp 145e146 ꢀC; 1H NMR (500 MHz,
(s, 3H), 1.40 (s, 3H), 1.44 (s, 3H), 2.52 (dd, J¼17.8, 5.3 Hz, 1H), 2.77
(m, 2H), 3.07 (dd, J¼13.7, 7.3 Hz, 1H), 3.57 (dd, J¼8.3, 7.0 Hz, 1H),
3.63 (dd, J¼8.4, 4.1 Hz, 1H), 4.11 (m, 2H), 4.28 (q, J¼8.3 Hz, 1H), 4.63
(dd, J¼5.93, 4.28 Hz, 1H), 4.72 (s, 1H), 4.87 (d, J¼6.0 Hz, 1H),
7.17e7.27 (m, 3H), 7.28e7.33 (m, 2H); 13C NMR (125 MHz, CDCl3)
CDCl3)
d
0.89 (d, J¼6.7 Hz, 3H), 0.91 (d, J¼6.7 Hz, 3H), 1.30 (s, 3H),
1.38 (s, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 1.69 (m, 1H), 2.27 (m, 2H), 3.16
(d, J¼3.1 Hz, 1H), 3.42 (m, 1H), 3.75 (dd, J¼8.6, 6.5 Hz, 1H), 4.11 (dd,
J¼8.6, 3.8 Hz, 1H), 4.21 (dd, J¼8.5, 7.0 Hz, 1H), 4.38 (q, J¼8.5 Hz, 1H),
d
175.5, 136.9, 129.4, 128.7, 126.9, 113.1, 109.8, 97.8, 84.8, 84.1, 80.0,
75.6, 65.9, 61.4, 39.8, 33.1, 26.9, 26.0, 25.3, 24.6; IR (thin film)
n
34,535, 2988, 1793, 1643, 1372, 1264, 1210, 1163, 1087, 1039, 891,
847, 702; HRMS (ESI): m/z: calcd for C22H29NO7: 419.1944; found:
442.1857 [MþNa]þ.
5.02 (m, 2H), 5.61 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 112.9, 109.8,
99.8, 84.2, 83.7, 80.7, 75.6, 67.2, 66.1, 39.1, 31.8, 26.7, 26.2, 25.4, 25.2,
19.9, 18.6; IR (thin film) 3434, 2987, 1642, 1372, 1210, 1082, 848;
n
HRMS (ESI): m/z: calcd for C18H31NO7: 374.2101; found: 374.2166
[MþH]þ.
4.18.13. (S)-3-Benzylisoxazolidin-5-one (43). Prepared according to
general procedure F. Purification by column chromatography using
hexanes/EtOAc (3:1 v/v) as the eluent afforded the isoxazolidinone
4.18.18.
D
-Gulose-(S)-3-isopropylisoxazolidin-5-one (30). Prepared
21
43 as a yellow oil in 84% yield. Rf¼0.30 (hexanes/EtOAc 2:1);.[
a]
according to general procedures I, G1, G2, J. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
D
ꢁ24.1 (c 0.96, CH2Cl2); 1H NMR (500 MHz, CDCl3)
d
2.53 (dd, J¼17.1,

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4851
afforded the diastereomeric mixture as a colorless solid in 90%
yield. It was recrystallized if necessary from heptane to give a single
4.18.23. (S)-3-Methylisoxazolidin-5-one (47). Prepared according to
general procedure F. Purification by column chromatography using
diastereomer. Rf¼0.28 (hexanes/EtOAc 4:1); mp 118 ꢀC; [
a
]
22 þ35.0
hexanes/EtOAc (1:1 v/v) as the eluent afforded the isoxazolidinone
D
24
(c 1.14, CHCl3); 1H NMR (500 MHz, CDCl3)
d
0.94 (m, 6H), 1.28 (s,
47 as a yellow oil in 42% yield. Rf¼0.09 (hexanes/EtOAc 2:1); [
a]
D
3H), 1.37 (s, 3H), 1.40 (s, 3H), 1.44 (s, 3H), 1.83 (m, 1H), 2.49 (dd,
J¼18.0, 3.7 Hz, 1H), 2.82 (dd, J¼18.0, 8.9 Hz, 1H), 3.63 (m, 1H), 3.74
(dd, J¼8.6, 6.5 Hz,1H), 4.05 (dd, J¼8.5, 3.9 Hz,1H), 4.20 (m,1H), 4.35
(q, J¼8.3 Hz, 1H), 4.65 (s, 1H), 4.72 (m, 1H), 4.90 (d, J¼6.0 Hz, 1H);
ꢁ6.2 (c 0.26, CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.32 (d, J¼6.4 Hz,
3H), 2.40 (dd, J¼17.1, 8.7 Hz, 1H), 2.81 (dd, J¼16.8, 5.8 Hz, 1H), 3.98
(m, 1H); 13C NMR (125 MHz, CDCl3)
film) 3537, 3227, 2977, 2934, 1779, 1654, 1459, 1415, 1385, 1326,
d 177.7, 55.4, 37.7, 29.8; IR (thin
n
13C NMR (125 MHz, CDCl3)
d
176.4,113.2, 110.0, 98.1, 85.2, 84.0, 80.3,
1200, 1146, 1081, 1033, 942, 900, 829; HRMS (ESI): m/z: calcd for
C4H7NO2: 101.0477; found: 102.0560 [MþH]þ.
75.7, 66.1, 65.2, 31.4, 30.2, 26.8, 26.1, 25.4, 24.8, 18.8, 18.7; IR (thin
film) 3434, 2987, 1791, 1645, 1372, 1210, 1162, 1078, 847; HRMS
n
(ESI): m/z: calcd for C18H29NO7: 371.1944; found: 394.1851
4.18.24. D-Gulose-(S)-3-isobutylisoxazolidin-5-carboxycyclohexan-
[MþNa]þ.
1,1-acetal (37). Prepared according to general procedure B. Purifi-
cation by column chromatography using hexanes/EtOAc (7:1 v/v) as
the eluent afforded the diastereomeric mixture as a colorless solid
in 81% yield. After recrystallization from heptane, it was obtained
4.18.19. (S)-3-Isopropylisoxazolidin-5-one (45). Prepared according
to general procedure F. Purification by column chromatography
using hexanes/EtOAc (3:1 v/v) as the eluent afforded the iso-
a
single diastereomer. Rf¼0.43 (hexanes/EtOAc 4:1); mp
xazolidinone 45 as a yellow oil in 67% yield. Rf¼0.13 (hexanes/EtOAc
193e194 ꢀC; [
a
]
D
19 ꢁ25.9 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3)
23
4:1);.[
a
]
D
þ9.1 (c 1.28, CHCl3); 1H NMR (500 MHz, CDCl3)
d
0.97
d
0.90 (d, J¼6.6 Hz, 3H), 0.90 (d, J¼6.6 Hz, 3H), 1.11 (m, 1H), 1.25 (s,
(dd, J¼10.9, 6.7 Hz, 6H), 1.77 (m, 1H), 2.49 (dd, J¼17.2, 8.8 Hz, 1H),
3H), 1.34 (s, 3H), 1.37 (m, 4H), 1.41 (s, 3H), 1.44 (m, 1H), 1.58e1.89
(m, 10H), 2.04 (d, J¼13.8 Hz, 1H), 2.91 (dd, J¼13.7, 7.7 Hz, 1H), 3.91
(m, 1H), 3.97 (dd, J¼8.4, 3.8 Hz, 1H), 4.17 (m, 1H), 4.33 (q, J¼7.8 Hz,
1H), 4.63 (m, 1H), 4.66 (s, 1H), 4.84 (d, J¼6.0 Hz, 1H); 13C NMR
2.73 (dd, J¼17.2, 6.9 Hz, 1H), 3.55 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 177.6, 65.2, 34.3, 31.6, 19.3, 19.0; IR (thin film) n 3223, 2964,
2935, 2877, 1782, 1782, 1469, 1416, 1299, 1190, 1145, 1079, 1014, 904,
850; HRMS (ESI): m/z: calcd for C6H11NO2: 129.0790; found:
130.0862 [MþH]þ.
(125 MHz, CDCl3)
d 169.5, 112.9, 111.7, 109.8, 105.9, 96.7, 84.5, 84.3,
80.3, 75.6, 66.0, 58.5, 42.6, 41.1, 37.6, 36.4, 26.6, 26.1, 25.3, 25.2, 25.0,
24.3, 23.5, 23.0, 22.9, 21.7; IR (thin film) 3430, 2988, 2943, 2870,
n
4.18.20. (S)-tert-Butoxycarbonyl-3-isopropylisoxazolidin-5-one
(53). Prepared according to general procedure K. Purification by
column chromatography using hexanes/EtOAc (8:1 v/v) as the el-
1802, 1454, 1376, 1259, 1237, 1166, 1087, 1034, 992, 923, 875, 848,
733; HRMS (ESI): m/z: calcd for C26H41NO9: 445.2625; found:
534.2679 [MþNa]þ.
uent afforded the carbamate as a yellow oil in 60% yield. Rf¼0.38
20
(hexanes/EtOAc 4:1);
[
a]
þ183.9 (c 0.44, CHCl3); 1H NMR
4.18.25. D-Gulose-(S)-3-benzylisoxazolidin-5-carboxycyclohexan-
D
(500 MHz, CDCl3)
d
0.98 (m, 6H), 1.50 (s, 9H), 1.91 (m, 1H), 2.54 (dd,
1,1-acetal (40). Prepared according to general procedure B. Purifi-
cation by column chromatography using hexanes/EtOAc (6:1 v/v)
as the eluent afforded the diastereomeric mixture as a colorless
solid in 65% yield. After recrystallization from heptane, it was
obtained a single diastereomer. Rf¼0.32 (hexanes/EtOAc 4:1); mp
J¼18.0, 2.1 Hz, 1H), 2.92 (dd, J¼18.0, 9.6 Hz, 1H), 4.35 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 173.7, 156.5, 83.9, 65.1, 32.1, 31.5, 28.2, 18.1,
17.9; IR (thin film)
n 2975, 2935, 2878, 1807, 1744, 1717, 1471, 1371,
1338, 1254, 1144, 1053, 958, 877, 849, 772; HRMS (ESI): m/z: calcd
for C12H21NO4: 229.1314; found: 252.1213 [MþNa]þ.
164e165 ꢀC; [
a]
21 ꢁ36.6 (c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3)
D
d
1.27 (s, 3H), 1.36 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.48 (m, 2H),
4.18.21. (S)-Methyl-4-methyl-3-(2-phenylacetamido)-pentanoate
(62). Prepared according to general procedure P. Purification by
column chromatography using hexanes/EtOAc (2:1 v/v) as the el-
1.65e1.84 (m, 6H), 1.91 (m, 2H), 2.20 (d, J¼13.9 Hz, 1H), 2.81 (dd,
J¼13.9, 8.6 Hz, 2H), 3.06 (dd, J¼13.6, 7.9 Hz, 1H), 3.53 (m, 1H), 3.57
(dd, J¼8.4, 4.0 Hz, 1H), 4.12 (m, 2H), 4.27 (q, J¼8.2 Hz, 1H), 4.55 (dd,
J¼5.8, 4.3 Hz, 1H), 4.69 (s, 1H), 4.84 (d, J¼6.0 Hz, 1H); 13C NMR
uent afforded the carbamate as a yellow oil in 52% yield. Rf¼0.29
24
(hexanes/EtOAc 1:1);
[
a
]
D
ꢁ57.5 (c 0.55, CHCl3); 1H NMR
(125 MHz, CDCl3) d 169.4, 138.6, 129.6, 128.6, 126.5, 112.9, 111.9,
(500 MHz, CDCl3)
d
0.78 (d, J¼6.7 Hz, 3H), 0.83 (d, J¼6.7 Hz, 3H),
109.7, 105.9, 96.4, 84.5, 84.0, 80.2, 75.7, 66.1, 61.5, 39.9, 33.4, 37.7,
36.5, 27.0, 26.1, 25.4, 24.9, 24.4, 23.2, 23.0; IR (thin film) 3432,
1.72 (m, 1H), 2.44 (m, 1H), 3.56 (s, 2H), 3.59 (s, 3H), 4.03 (m, 1H),
n
5.84 (d, J¼8.4 Hz, 1H), 7.29 (m, 3H), 7.34 (m, 2H); 13C NMR
2986, 2938, 2866, 1803, 1638, 1453, 1372, 1233, 1179, 1158, 1116,
1088, 1036, 936, 882, 849, 735, 701; HRMS (ESI): m/z: calcd for
C29H39NO9: 545.2625; found: 564.2517 [MþNa]þ.
(125 MHz, CDCl3)
d 172.2, 170.5, 135.1, 129.5, 129.1, 127.4, 51.8, 51.6,
44.1, 36.5, 31.4, 19.4, 18.7; IR (thin film)
n 3293, 3064, 3030, 2962,
2875,1739,1645,1549,1437,1371,1280,1195, 728, 696; HRMS (ESI):
m/z: calcd for C15H21NO3: 263.1521; found: 264.1591 [MþH]þ.
4.18.26. D-Gulose-(S)-3-methylisoxazolidin-5-carboxycyclohexan-
1,1-acetal (39). Prepared according to general procedure B. Purifi-
cation by column chromatography using hexanes/EtOAc (7:1 v/v) as
the eluent afforded the diastereomeric mixture as a colorless solid
in 73% yield (6:3:1:1 dr). After recrystallization from heptane, it
was obtained a single diastereomer. Rf¼0.30 (hexanes/EtOAc 4:1);
4.18.22.
D-Gulose-(S)-3-methylisoxazolidin-5-one
(42). Prepared
according to general procedures G1, G2. Purification by column
chromatography using hexanes/EtOAc (6:1 v/v) as the eluent
afforded the diastereomeric mixture as a colorless solid in 52% yield
(8:1 dr). Rf¼0.37 (hexanes/EtOAc 4:1); mp 113e114 ꢀC; [
a
]
19 þ40.6
[
a
]
24 þ14.2 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3)
d 1.28 (s, 3H),
D
D
(c 1.09, CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.26 (s, 3H), 1.35 (m,
1.31 (d, J¼6.6 Hz, 3H), 1.37 (s, 3H), 1.41 (m, 4H), 1.44 (m, 4H),
1.58e1.91 (m, 8H), 2.13 (dd, J¼13.7, 3.6 Hz, 1H), 2.88 (dd, J¼13.7,
3.6 Hz, 1H), 3.69 (dd, J¼8.5, 6.6 Hz, 1H), 3.87(m, 1H), 4.04(dd, J¼8.5,
3.8 Hz, 1H), 4.18 (dd, J¼8.5, 6.7 Hz, 1H), 4.34(q, J¼6.7 Hz, 1H), 4.66
6H), 1.39 (s, 3H), 1.43 (s, 3H), 2.51 (dd, J¼17.2, 9.1 Hz, 1H), 2.77 (dd,
J¼17.3, 7.5 Hz, 1H), 3.70 (dd, J¼8.6, 6.5 Hz, 1H), 3.83 (m, 1H), 4.02
(dd, J¼8.4, 4.0 Hz, 1H), 4.16 (dd, J¼8.6, 6.8 Hz, 1H), 4.31 (q, J¼8.3 Hz,
1H), 4.70 (m, 1H), 4.71 (s, 1H), 4.88 (d, J¼6.1 Hz, 1H); 13C NMR
(m, 2H), 4.86 (d, J¼9.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 169.2,
(125 MHz, CDCl3)
d
174.7, 113.1, 109.8, 98.7, 85.2, 84.0, 80.2, 77.4,
113.0, 111.8, 109.8, 105.1, 97.5, 84.4, 84.2, 80.4, 75.8, 66.2, 57.0, 42.9,
77.2, 76.9, 75.8, 66.0, 58.9, 36.3, 26.8, 26.0, 25.4, 24.7, 18.8; IR (thin
film) 3434, 2987, 2938, 1793, 1641, 1382, 1262, 1211, 1163, 1087,
894, 847, 620; HRMS (ESI): m/z: calcd for C16H25NO7: 343.1631;
found: 366.1515 [MþNa]þ.
37.6, 36.5, 26.9, 26.2, 25.5, 25.0, 24.4, 23.0, 22.9, 19.3; IR (thin film) n
n
3433, 2986, 2942, 2096, 1804, 1642, 1456, 1372, 1186, 1087, 936,
848; HRMS (ESI): m/z: calcd for C23H35NO9: 469.2312; found:
490.2376 [MþH]þ.

4852
M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4.18.27.
D
-Gulose-(S)-3-isopropylisoxazolidin-5-carboxy-cyclohexan-
J¼13.6, 8.6 Hz, 1H), 2.92 (dd, J¼13.5, 6.3 Hz, 1H), 3.50 (m, 3H), 4.16
(q, J¼7.1 Hz, 2H), 4.20 (m, 1H), 4.36 (m, 1H), 6.28 (m, 1H), 6.32 (d,
J¼8.8 Hz, 1H), 7.16 (d, J¼7.5 Hz, 2H), 7.20e7.34 (m, 8H); 13C NMR
1,1-acetal (38). Prepared according to general procedure B. Purifi-
cation by column chromatography using hexanes/EtOAc (7:1 v/v) as
the eluent afforded the diastereomeric mixture as a colorless solid
in 65% yield. Rf¼0.16 (hexanes/EtOAc 7:1). After recrystallization
(125 MHz, CDCl3)
d 172.6, 171.2, 170.8, 170.7, 138.1, 135.2, 129.4,
129.3, 128.9, 128.7,127.2, 126.8, 61.0, 48.2, 45.2, 44.0, 43.2,40.9, 40.0,
38.6, 35.0, 34.1, 25.2, 22.9, 22.3, 14.3; IR (thin film) 3283, 2926,
from heptane, it was obtained
a
single diastereomer. Mp
n
23
173e174 ꢀC; [
a]
ꢁ21.1 (c 1.07, CHCl3); 1H NMR (500 MHz, CDCl3)
1735, 1644, 1546, 1454, 1367, 1185, 698 HRMS (ESI): m/z: calcd for
C30H41N3O5: 523.3046; found: 546.2944 [MþNa]þ.
D
d
0.94 (d, J¼6.7 Hz, 3H), 1.00 (d, J¼6.5 Hz, 3H), 1.28 (s, 3H), 1.37 (s,
3H), 1.41 (s, 3H), 1.44 (m, 4H), 1.62e1.71 (m, 4H), 1.61e1.72 (m, 5H),
2.33 (d, J¼14.0 Hz, 1H), 2.79 (dd, J¼14.0, 7.9 Hz, 1H), 3.43 (m, 1H),
3.72 (dd, J¼8.6, 6.6 Hz,1H), 4.05 (dd, J¼8.5, 3.9 Hz,1H), 4.20 (m,1H),
4.35 (q, J¼8.4 Hz, 1H), 4.66 (m, 2H), 4.87 (d, J¼6.0 Hz, 1H); 13C NMR
Acknowledgements
This work was supported by the Arnold and Mabel Beckman
Foundation, the David and Lucille Packard Foundation, and Research
Corporation (Cottrell Scholar Award to J.W.B). We appreciate pro-
tocols from Nancy Carrillo and Justin Russak as well as the helpful
synthetic advice and discussions from Dr. Justin Struble and Dr.
Hiroshi Ishida. We are grateful to BioBlocks, Inc. for a generous gift 1.
(125 MHz, CDCl3)
d 169.7, 113.0, 111.7, 109.9, 106.1, 96.8, 84.5, 84.3,
80.3, 75.7, 67.1, 66.2, 37.7, 36.5, 29.8, 26.8, 26.2, 25.4, 25.0, 24.4, 23.1,
23.0, 20.9, 19.8; IR (thin film) 3419, 2939, 2869, 2361, 1803, 1452,
n
1372, 1229, 1196, 1114, 1089, 982, 936, 849, 734; HRMS (ESI): m/z:
calcd for C25H39NO9: 497.2625; found: 520.2518 [MþNa]þ.
4.18.28. (S)-Benzyloxycarbonyl-phenyl-3-isoxazolidin-5-one (11).
Prepared according to general procedure L. Purification by column
chromatography using hexanes/EtOAc (5:1 v/v) as the eluent
afforded the carbamate as a white solid in 89% yield. Rf¼0.22
(hexanes/EtOAc 4:1); mp 83e84 ꢀC; 1H NMR (500 MHz, CDCl3)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.016. This data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
d
2.85 (dd, J¼17.8, 3.7 Hz, 1H), 3.34 (dd, J¼17.8, 9.5 Hz, 1H), 5.24 (m,
2H), 5.64 (dd, J¼9.4, 3.7 Hz, 1H), 7.29e7.43 (m, 10H); 13C NMR
(125 MHz, CDCl3)
d 171.6, 156.3, 138.4, 134.8, 129.2, 128.7, 128.4,
References and notes
125.8, 69.0, 63.0, 37.2; IR (thin film)
n 2952, 1807, 1723, 1497, 1455,
1411, 1322, 1163, 1131, 750, 697; HRMS (ESI): m/z: calcd for
1. (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiv. 2004, 1, 1111e1239; (b)
Cheng, P. R.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219e3232; (c)
Goodman, C. M.; Choi, S.; Shandler, S.; Degrado, W. F. Nat. Chem. Biol. 2007, 3,
252e262.
2. Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B. Helv. Chim. Acta 1996,
79, 913e941.
3. Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 1996, 118, 13071e13072.
4. (a) Cheng, R. P.; DeGrado, W. F. J. Am. Chem. Soc. 2001, 123, 5162e5163; (b)
Arvidsson, P. I.; Rueping, M.; Seebach, D. Chem. Commun. 2001, 649e650.
5. Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404,
565.
C17H15NO4: 297.1001; found: 320.0897 [MþNa]þ.
4.18.29. Benzylhydroxy(3-oxo-3-(phenethylamino)-1-phenylpropyl)
carbamate (13). Prepared according to general procedure M. Puri-
fication by column chromatography using hexanes/EtOAc (2:1 v/v)
as the eluent afforded the carbamate as a colorless solid in 82% yield.
Rf¼0.31 (hexanes/EtOAc 1:1); 1H NMR (500 MHz, CDCl3)
d 2.56 (dd,
J¼14.1, 4.8 Hz, 1H), 2.70 (m, 2H), 3.02 (dd, J¼13.9, 11.2 Hz, 1H), 3.40
(m, 2H), 5.12 (m, 2H), 5.51 (dd, J¼11.1, 4.7 Hz, 1H), 6.14 (m, 1H), 7.10
(m, 2H), 7.22 (m,1H), 7.28 (m,10H), 7.26 (m, 2H); 13C NMR (125 MHz,
6. Sadowsky, J. D.; Schmitt, M. A.; Lee, H.-S.; Umezawa, N.; Wang, S.; Tomita, Y.;
Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11966e11968.
7. Imamura, Y.; Watanabe, N.; Umezawa, N.; Iwatsubo, T.; Kato, N.; Tomita, T.;
Higuchi, T. J. Am. Chem. Soc. 2009, 131, 7353e7359.
CDCl3)
d
171.0, 157.1, 139.3, 138.7, 136.0, 128.8, 128.7, 128.6, 128.2,
3305,
128.0, 127.0, 126.6, 68.0, 60.0, 41.0, 39.8, 35.4; IR (thin film)
n
8. (a) Qiu, X. J.; Petersson, E. J.; Matthews, E. E.; Schepartz, A. J. Am. Chem. Soc.
2006, 128, 11338e11339; (b) Daniels, D. S.; Petersson, E. J.; Qiu, X. J.; Schepartz,
A. J. Am. Chem. Soc. 2007, 129, 1532e1533; (c) Petersson, E. J.; Craig, C. J.;
Daniels, D. S.; Qiu, X. J.; Schepartz, A. J. Am. Chem. Soc. 2007, 129, 5344e5345.
9. Mueller, M. M.; Windsor, M. A.; Pomerantz, W. C.; Gellman, S. H.; Hilvert, D.
Angew. Chem., Int. Ed. 2009, 48, 922e925.
10. Petersson, E. J.; Schepartz, A. J. Am. Chem. Soc. 2008, 130, 821e823.
11. For recent reviews of peptide ligations, see: (a) Dawson, P. E.; Kent, S. B. H. Annu.
Rev. Biochem. 2000, 69, 923e960; (b) Macmillan, D. Angew. Chem., Int. Ed. 2006,
45, 7668e7672; (c) Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem., Int. Ed.
2008, 47, 10030e10074.
12. Kimmerlin, T.; Seebach, D.; Hilvert, D. Helv. Chim. Acta 2002, 85, 1812e1826.
13. Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo, M. A.; Beck, A. K. Tetrahedron
2004, 60, 7455e7506.
14. Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int. Ed. 2006, 45,
1248e1252.
2927, 2106,1697,1642, 1554,1497, 1454, 1303,1105, 748, 698; HRMS
(ESI): m/z: calcd for C25H26N2O4: 418.1893; found: 417.1816 [MꢁH].
4.18.30. Ethoxy-b-Ala-b-Phe-N-Boc-b-Leu-hydroxylamine (55). Pre-
pared according to general procedure N. Purification by column
chromatography using EtOAc as the eluent afforded a colorless oil.
21
Rf¼0.26 (EtOAc); [
a
]
D
ꢁ12.7 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
0.88 (d, J¼6.5 Hz, 3H), 0.91 (d, J¼6.5 Hz, 3H), 1.10 (m, 1H),
1.26 (m, 3H), 1.44 (s, 9H), 1.59 (m, 1H), 1.67 (m, 1H), 2.16 (dd, J¼14.5,
6.2 Hz,1H), 2.22 (dd, J¼13.6, 3.6 Hz,1H), 2.34 (dd, J¼14.6, 3.9 Hz,1H),
2.47e2.58 (m, 3H), 2.74 (dd, J¼13.6, 8.9 Hz,1H), 2.91 (m,1H), 3.51 (m,
2H), 4.15 (q, J¼7.1 Hz, 2H), 4.45 (m, 1H), 6.43 (m, 1H), 6.79 (d,
J¼8.8 Hz,1H), 7.16(m, 2H), 7.19e7.30 (m, 3H), 7.82 (brs,1H); 13C NMR
15. Carrillo, N.; Davalos, E. A.; Russak, J. A.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
1452e1453.
(125 MHz, CDCl3) d 173.0,172.0,171.0,157.1,137.9,129.3,128.7,126.8,
16. (a) Ju, L.; Lippert, A. R.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 4253e4255; (b)
Ju, L.; Bode, J. W. Org. Biomol. Chem. 2009, 7, 2259e2264.
17. (a) Tokuyama, H.; Kuboyama, T.; Amano, A.; Yamashita, T.; Fukuyama, T. Syn-
thesis 2000, 1299e1304; (b) Tokuyama, H.; Kuboyama, T.; Fukuyama, T. Org.
Synth. 2003, 80, 207e208.
81.6, 61.2, 48.1, 41.4, 39.9, 39.8, 38.5, 35.1, 34.0, 29.8, 28.4, 24.7, 23.3,
22.0, 14.3; IR (thin film) 3414, 3297, 2956, 2925, 2870, 2366, 1654,
n
1540, 1456, 1368, 1253, 1166, 1095, 1030, 846, 701; HRMS (ESI): m/z:
calcd for C27H43N3O7: 521.3103; found: 544.2994 [MþNa]þ.
18. Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Córdova, A. Chem. Commun. 2007,
849e851.
19. (a) Vasella, A. Helv. Chim. Acta 1977, 60, 426e446; (b) Mzengeza, S.; Whitney, R.
A. J. Org. Chem. 1988, 53, 4074e4081.
20. For elegant work on the use of diastereoselective nitrile oxide cycloadditions
4.18.31. Ethoxy-
b
-Ala-
b
-Phe-
b
-Leu-benzylamide
(56). Prepared
according to general procedure O. Purification by column chro-
matography using CHCl3/MeOH 20:1 as the eluent afforded a col-
for the synthesis of b-amino acids, see: (a) Minter, A. R.; Fuller, A. A.; Mapp, A.
K. J. Am. Chem. Soc. 2003, 125, 6846e6847; (b) Fuller, A. A.; Chen, B.; Minter, A.
R.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127, 5376e5383.
21. Iida, H.; Kasahara, K.; Kibayashi, C. J. Am. Chem. Soc. 1986, 108, 4647e4648; (b)
Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54, 2225e2233.
22. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. Synthesis 1977, 289e296.
orless oil in 32% yield over three steps. Rf¼0.17 (CHCl3/MeOH 20:1);
23
[
a]
ꢁ21.1 (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.83
D
(m, 6H), 0.89 (m, 1H), 1.17e1.29 (m, 3H), 1.36 (m, 1H), 1.44 (m, 1H),
2.19 (m, 1H), 2.22 (m, 1H), 2.34 (m, 2H), 2.53 (m, 2H), 2,70 (dd,

M.E. Juarez-Garcia et al. / Tetrahedron 66 (2010) 4841e4853
4853
23. Keirs, D.; Moffat, D.; Overton, K.; Tomanek, R. J. Chem. Soc., Perkins Trans. 1 1991,
26. Purchased from Aldrich or Acros Organics.
1041e1051.
27. Shing, T. K. M.; Gillhouley, J. G. Tetrahedron 1994, 50, 8685e8698.
24. Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.; Iannazzo, D.; Piperno, A.;
Romeo, G.; Romeo, R. J. Org. Chem. 1999, 64, 9321e9327.
25. Yu, S.; Ishida, H.; Juarez-Garcia, M.E.; Bode, J.W. submission in progress, see
Supplementary data.
28. Buchanan, J. G.; Lumbard, K. W.; Sturgeon, R. J.; Thompson, D. K.; Wightman, R.
H. J. Chem. Soc., Perkin Trans. 1 1990, 3, 699e706.
29. Mita, N.; Tamura, O.; Ishibashi, H.; Sakamoto, M. Org. Lett. 2002, 4, 1111e1114.
30. Wolinsky, J.; Novak, R.; Vasileff, R. J. Org. Chem. 1964, 29, 3596e3598.