Development of the Ireland-Claisen rearrangement of alkoxy- and aryloxy-substituted allyl glycinates

Article abstract of DOI:10.1021/jo1017124

The Ireland-Claisen rearrangement of 3-alkoxy- and 3-aryloxy-substituted allyl glycinates is presented. This [3,3]-sigmatropic rearrangement route offers direct access to syn β-alkoxy and β-aryloxy α-amino acid systems. In particular, N,N-diboc glycine esters rearrange with excellent diastereoselectivities (dr > 25:1). The synthesis of substrates, rearrangement optimization, and a discussion of stereoselection are presented.

Full text of DOI:10.1021/jo1017124

pubs.acs.org/joc
Development of the Ireland-Claisen Rearrangement of Alkoxy- and
Aryloxy-Substituted Allyl Glycinates
James P. Tellam and David R. Carbery*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom
d.carbery@bath.ac.uk
Received August 31, 2010
The Ireland-Claisen rearrangement of 3-alkoxy- and 3-aryloxy-substituted allyl glycinates is presented.
This [3,3]-sigmatropic rearrangement route offers direct access to syn β-alkoxy and β-aryloxy
R-amino acid systems. In particular, N,N-diboc glycine esters rearrange with excellent diastereo-
selectivities (dr>25:1). The synthesis of substrates, rearrangement optimization, and a discussion of
stereoselection are presented.
Introduction
number of important natural products.2 Kaitocephalin,3
sphingofungins E and F,4 altemicidin5 and the acyl deriva-
tives, lactacystin,6 salinosporamide,7 oxazolomycin,8 and
With serine and threonine constituting 10% of nature’s
proteinogenic repertoire, β-hydroxy R-amino acids can be
viewed as an important set of amino acids. In particular,
serine logically contributes to the serine protease family of
enzymes, providing the key nucleophilic residue that enables
peptide cleavage in many instances. Serine proteases, which
include chymotrypsins, trypsins, and elastases, are crucial to
the human digestive process.1
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DOI: 10.1021/jo1017124
r
Published on Web 10/19/2010
J. Org. Chem. 2010, 75, 7809–7821 7809
2010 American Chemical Society

Tellam and Carbery
JOCArticle
The demonstrable importance of β-hydroxy R-amino acids
and their O-alkyl and O-aryl congeners has led to an impressive
wealth of synthetic methodologies for the synthesis of β-hydroxy
R-amino acids for proteomic and synthetic examination. These
include aldol reactions,20 enzymatic aldol reactions,21 enantio-
selective Mannich reactions,22 biochemical hydroxylation,23
reduction of amino β-keto esters,24 enantioselective dihydro-
xylations,25 enantioselective aminohydroxylations,26 asym-
metric B-allylation,27 asymmetric Strecker reactions,28 nucleo-
philic epoxide opening,29 intramo lecular Pd(0)-catalyzed allylic
alkylation,30 photocycloadditions,31 azomethine ylide cycloaddi-
tions,32 dynamic kinetic resolutions,33 enantioselective hydro-
genations,34 and oxy-Michael reaction.35 However, few sigma-
tropic approaches have been reported, an exception being
Sutherland’s Pd-catalyzed [3,3]-sigmatropic Overman rear-
rangement route36 and the Ireland-Claisen route discussed
in this article.37
FIGURE 1. Representative natural products containing complex
β-alkoxy R-amino acids residues (renieramycin D, 1, and polyoxin
B, 2) and β-aryloxy R-amino acid (adouetine Y, 3). Molecular
fragment of relevance to this report are highlighted in red.
Frequently, O-alkylation and O-arylation steps are at-
tempted when β-alkoxy and β-aryloxy R-amino acids are
required. In some instances such O-functionalizations have
been reported to be problematic with elimination and retro-
aldol reactions occurring.38,39 We envisaged that a novel
and synthetically versatile access to functionalized β-alkoxy
neooxazolomycin9 have all resulted in considerable synthetic
work in recent years. In contrast, β-alkoxy and β-aryloxy
R-amino acid residues do not feature as extensively in natural
peptide chemistry. However, there is a significant mapping
of such β-alkoxy and β-aryloxy R-amino acid residues into
a number of biologically interesting natural products. For
example, β-alkoxy R-amino acid residues are observed
in renieramycin 110 (Figure 1) brasilicardin A,11 cyclomarin,12
papuamide,13 and callipeltin A.14 Related to these examples
are β-alkoxy R-amino acid incorporates where the ether is
cyclic, for example, polyoxin B, 2 (Figure 1).15 Further
examples of this class include amipurimycin16 and mihara-
mycin B.17 In addition, β-aryloxy R-amino acid residues are
observed in greater frequency within cyclopeptide
alkaloids.18 For example, the cyclopeptide adouetine Y, 319
(Figure 1), features a β-aryl ether unit as a key fragment of
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and β-aryloxy amino acids could be achieved through an
application of the Ireland-Claisen [3,3]-sigmatropic rear-
rangement of suitable enol ether substrates. To accomplish
this proposal, a combination of Kazmaier’s highly diaster-
eoselective Zn-enolate Claisen rearrangement40 with allylic
enol ether ester systems examined by Ireland41 would be
required. On rearrangement, the Csp2-O bond is trans-
posed to a stereogenic Csp3-O bond (Figure 2). If success-
ful, β-alkoxy and β-aryloxy R-amino acids I would be
formed from enol ether amino esters II (Figure 2).
SCHEME 1. Initial Substrate Synthesis and Rearrangement
Attempts
particularly sensitive with facile degradation seen on at-
tempted purification by flash chromatography. However,
substrate 6 was obtained cleanly if 5 was submitted to this
coupling protocol with sufficient purity. Initial examination
of this rearrangement strategy was unpromising, with complex
mixtures formed on application of methods developed by
Kazmaier. However, it became apparent when using hexa-
methyldisilazide bases that the parent N-Boc glycine was
being recovered as the major component of these attempted
rearrangements. The incompatible combination of the two
previously fruitful Claisen rearrangement structural moi-
eties, i.e., enol ether and glycinate, was confirmed by
quickly reproducing a Kazmaier report of the rearrangement
of crotyl glycinate in comparable yield and diastereocontrol
to that reported.40 Furthermore, attempts to promote re-
arrangement reaction using Ireland conditions, similar to
those used by Bartlett,43 were unsuccessful with intractable
mixtures seen to form.
The inability of Boc-glycinate 6 to perform adequately in
this rearrangement reaction led to the consideration that the
dianionic nature of the intermediate Li-enolate was of high
energy and displayed significant instability. On enolization
of the glycinate ester the central C-O σ-bonding orbital and
the C-O σ-antibonding orbital is overlapped by two highly
electron-rich π-systems (Figure 3).
FIGURE 2. Retrosynthetic proposal for a [3,3]-sigmatropic rear-
rangement entry to β-alkoxy and β-aryloxy R-amino acids.
The Ireland-Claisen rearrangement has found wide-
spread application in organic synthesis and target-orientated
synthesis.42 This popularity is due to a key number of
advantageous synthetic properties. The Ireland-Claisen
rearrangement benefits from ease of substrate synthesis
and mild reaction conditions, especially when contrasted
with the traditional Claisen [3,3]-sigmatropic rearrange-
ment. It is widely accepted that, for acyclic substrates, the
rearrangement of allylic silylketene acetals proceeds through
a chair geometry. Subsequently, this rearrangement offers
predictable and divergent syn/anti relative stereochemistry
through the judicious choice of either silylketene acetal or
allyl alkene geometry. The chair geometry also offers control
of absolute stereochemistry through the application of en-
antiopure substrates derived from chiral secondary alcohols.
The chair transition state geometry leads to a highly ordered
arrangement that benefits the formation of congested qua-
ternary stereocenters. When considering these properties
together, the synthetic utility of the Ireland-Claisen [3,3]-
sigmatropic rearrangement reaction is manifest.
Results and Discussion
Preliminary synthetic work concerned the synthesis of a
suitable enol ether substrate. We chose to marry the sub-
strate classes studied by Ireland and Kazmaier. Accordingly,
we wished to incorporate the enol ether moiety studied by
Ireland with the glycinate fragment utilized by Kazmaier
in the highly effective chelated Zn-enolate rearrangement
chemistry. We believed this would offer a novel set of enol
ether amino ester substrates and ultimately on [3,3]-rear-
rangement a stereocontrolled entry to β-alkoxy R-amino
acids (Scheme 1).
FIGURE 3. Possible explanation for enolate instability.
Dibal-H reduction of vinylogous carbonate 4 formed the
sensitive allylic alcohol 5 in a reproducible yield of 77%.
Subsequent carbodiimide coupling with Boc-glycine formed
enol ether 6. This ester was once again observed to be
The possibility exists that this level of donation into this
C-Oσ* leads to the decomposition of this enol ether system.
Ireland has discussed how the presence of a methoxy group
on the allyl group of 9 (Figure 3) leads to a lowering of
rearrangement diastereoselectivity. This was explained
through a lengthening of the C-O bond, resulting in a
transition state possessing higher levels of charge-separated,
ionic character. We believe the lack of rearrangement seen
with 6 is an electronic extrapolation with strong electron
(40) Kazmaier, U. Angew. Chem., Int. Ed. 1994, 33, 998–999.
(41) Ireland, R. E.; Wipf, P.; Xiang, J.-N. J. Org. Chem. 1991, 56, 3572–
3582.
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see: (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939. (b) Chai, Y. H.; Hong,
S. P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58,
2905–2928. (c) McFarland, C. M.; McIntosh, M. C. The Claisen Rearrange-
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(43) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 3933–3941.
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TABLE 1. Optimization of Ireland-Claisen Rearrangement of Phtha-
limide 7a
base +counterion is also crucial: Na or KHMDS at -95 °C
leads to a significant drop in reaction quality, both in terms
of yield and diastereoselectivity compared to LiHMDS
(entries 4, 7, and 8). Other Li-amide bases such as LDA
(entry 9) are not suitable for this Ireland-Claisen protocol,
nor are silyl triflate additives (entry 10).
With an optimized protocol developed, a range of sub-
strates were examined for competency in this Ireland-
Claisen rearrangement reaction. We sought to examine a
range of O-alkyl and O-aryl systems including substituents
that would offer later synthetic flexibility (Table 2).
entry
base
solvent
temp (°C)
yield (%)
dra
1
2
3
4
5
6
7
8
9
10
LiHMDS
NaHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
LDA
THF
THF
THF
THF
Et2O
PhMe
THF
THF
THF
THF
-78
-78
-78
-95
-95
-95
-95
-95
-95
-95
0b
0b
0b
It can be seen that O-alkyl substrates rearrange smoothly
with a similar level of reaction efficiency and diastereoselection
(entries 1-8). This set includes functional handles (entries
5, 7) and oxygen protecting groups (entries 5, 6, and 8).
Interestingly, aryl-substituted enol ethers are unpredictable
substrates. Rearrangement is observed with the phenoxy-
and o-iodophenoxy enol ethers (entries 9, 13); however, no
β-aryloxy R-amino ester is isolated with substrates 10k-l.
Aryl systems bearing electron-withdrawing groups (entries
11-12) fail to react with complete recovery of starting
material. In contrast, electron-rich substitution (entry 10)
leads to a complex reaction profile. Analysis of crude
74c
65
0b
11:1
9:1
45
34
0b
7:1
6:1
LiHMDS
0c,d
aDiastereomeric ratio (syn/anti) determined by 1H NMR analysis of
crude reaction mixture. bIntractable mixture formed. cLiHMDS added
via syringe pump over 15 min. dMe3SiOTf used as silylation additive.
donation from both π-termini of substrate 6 feeding into this
connecting C-Oσ* and ultimately cleavage to form the
parent amino acid 7.44
1
reaction mixtures by H NMR but is consistent with the
presence of products derived from anticipated [3,3]-rear-
rangement and subsequent elimination of p-methoxyphenol,
forming diene products (entry 10).
With the unsuccessful attempts to rearrange 6 and the
mechanistic postulate discussed, we reconsidered the general
structure of our substrates. Accordingly, N-phthaloyl sub-
strates were considered for two reasons. First, the presence of
two carbonyl groups upon the nitrogen atom would not only
remove the N-based anion but would also lower the level of
N-lone pair donation into the enolate and subsequent silyl-
ketene acetal. Second, the symmetrical nature of the phthali-
mide group would lead to simplification in our under-
standing of the rearrangement with respect to the geometry of
substitution around the nitrogen of the amino ester substrate
compared to two inequivalent N-protecting groups.
Therefore, N-phthaloyl ester 10a was prepared by cou-
pling of allylic alcohol 4 with N-phthaloyl glycine in good
yield (see Supporting Information for details). This methyl
enol ether was subsequently exposed to a traditional Ireland-
Claisen protocol using amide bases and silyl chlorides. This
process of optimization is detailed in Table 1.
It became apparent that this attempted rearrangement was
particularly sensitive to the conditions adopted. After con-
siderable investigation, ester 10a was observed to rearrange
efficiently when LiHMDS is added via syringe pump over 15
min to a solution of 10a and Me3SiCl at -95 °C before
warming to 0 °C and stirring for 90 min (entry 4). The
rearranged acid was derivatized as the methyl ester to aid
isolation and purification. When the reaction is initiated at
higher temperatures (-78 °C, entries 1-3) or when none-
thereal solvents (PhMe, entry 6) are used, the reaction
While proof of principle had been achieved with N-phthaloyl
substrates, a number of key issues required subsequent examina-
tion. The key issue faced was developing a set of substrates that
offered a synthetically practical and versatile N-protecting
group other than phthaloyl. Second, it may be envisaged
that incorporation of suitable functionality upon the nitro-
gen may allow for subsequent synthetic elaboration. In
addition, the diastereoselectivity observed with the phtha-
loyl substrates, while good in some instances, generally
offered significant scope for improvement.
Therefore, a study was initiated to examine the influence
of nitrogen substitution upon rearrangement efficiency and
diastereoselectivity (Table 3). Initial rearrangement sub-
strates in this study were accessed from the union of (E)-
3-methoxyprop-2-en-1-ol and suitably protected sarcosines
(entries 1-5). These substrates allowed for a probing of
electronic and steric influences, and in all instances a successful
rearrangement was observed on applying the conditions devel-
oped from the previous phthaloyl optimization study (Table 3).
In each instance, negligible diastereoselectivity was ob-
served in the isolated β-methoxy sarcosine methyl esters (syn/
anti 1:1 f 2:1; entries 1-5) with the N-Boc and N-Ts
protection strategies offering the best levels of rearrange-
ment efficiency. Subsequent substrate alterations examined
the substitution of an N-methyl group for N-benzyl and
N-allyl groups (entries 6, 7). Disappointingly, poor diastereo-
control was once again observed in the isolated methyl
esters. However, the introduction of a second N-Boc pro-
tecting group leads to an impressive level of diastereoselec-
tion with only the syn-diastereomer observable and isolated
in good yield (entry 8).
1
provides an intractable reaction product mixture with H
NMR analysis of crude reaction mixtures suggesting the
formation of small amounts of desired rearranged pro-
duct along with elimination, silylation products together
with unconverted starting material. The choice of amide
During the N-phthaloyl study, it had become apparent that
the nature of the oxygen substituent was crucial to accessing
these enol ether substrates. For example, we were unable to
prepare enol ethers substrates prepared from simple secondary
(44) In contrast to oxygen substitution at C-3 of ester 6 in the allyl unit,
silicon substitution at C-3 and rearrangement is a fruitful method for forming
allyl silane amino acids; see: Mohamed, M.; Brook, M. A. Tetrahedron Lett.
2001, 42, 191–193.
7812 J. Org. Chem. Vol. 75, No. 22, 2010

Tellam and Carbery
JOCArticle
TABLE 2. Scope of Enol Ether Moietya
TABLE 3. Influence of N-Substitution on Rearrangement Diastereo-
selectivitya
entry
R1
R2
R3
Boc
Cbz
CO2Me
Ts
yield (%)
drb
2:1
2:1
1:1
1:1
2:1
3:1
2:1
1 (12a)
2 (12b)
3 (12c)
4 (12d)
5 (12e)
6 (14a)
7 (14b)
8 (16a)
9 (16b)
Me
Me
Me
Me
Me
Me
Me
Me
iPr
Me
Me
Me
Me
Me
Bn
Allyl
Boc
Boc
73 (13a)
41 (13b)
42 (13c)
70 (13d)
61 (13e)
57 (15a)
62 (15b)
74 (17a)
50 (17b)
Ac
Boc
Boc
Boc
Boc
>25:1
>25:1
aLiHMDS added via syringe pump over 15 min. bDiastereomeric
ratio (syn/anti) determined by 1H NMR analysis of crude reaction
mixture.
With the rearrangement of di-N-Boc protected glycine
esters 16a and 16b furnishing optimal diastereoselectivity
thus far, we felt this N-protection system necessitated sub-
sequent evaluation of substrate scope. Therefore, a series of
di-N-Boc protected substrates were prepared and assessed
(Table 4).
Again, excellent levels of diastereoselectivity are encoun-
tered throughout this study and confirm the utility of the di-
N-Boc unit within this Ireland-Claisen rearrangement con-
text. O-Alkyl enol ethers rearrange, generally in good yield
(entries 1-12), in contrast to O-aryl substrates. Of particular
note is the rearrangement of neopentyl enol ether 16e (entry 5)
where the product methyl ester is isolated in 80% yield and
as a single diastereomer. It is conceivable that synthesizing
this β-alkoxy R-amino ester via O-alkylation of the corre-
sponding β-hydroxy R-amino ester would be synthetically
very difficult. Enol ether substrates derived from secondary
alcohols rearrange successfully (entries 2, 4). In these in-
stances, a significant quantity of methyl di-N-Boc glycinate
is isolated. The rearrangement of enol ethers possessing
synthetic handles is also possible. Accordingly, O-allyl and
O-propargyl ethers rearrange smoothly (entries 6, 7), although
an extra equivalent of base and silyl chloride is required for
16g as a consequence of product C-silylation. Aryl-substi-
tuted enol ethers are once again observed to be unproductive
substrates, and therefore this reaction, we feel, does not
represent a feasible entry to β-aryloxy R-amino ester systems.
Generally speaking, the rearrangement of the di-N-Boc
substrates is slower than the analogous phthalimide systems,
requiring 24 h at ambient temperatures and initiation at higher
temperatures relative to the N-phthalimide substrates.
A chiral benzyl enol ether 16k was prepared during this
study with a view to controlling absolute stereochemistry.
Rearrangement was observed to proceed under standard
conditions (entry 12) and provided a 70:30 mixture of dia-
stereomers with respect to the 2-phenethyl fragment relative
to the syn-β-alkoxy R-amino ester fragment. This sense of
diastereoselectivity was confirmed after hydrogenation of
the terminal alkene and hydrogenolysis of the phenylethyl
moiety (Scheme 2).
aLiHMDS added via syringe pump over 15 min. bDiastereomeric
ratio (syn/anti) determined by 1H NMR analysis of crude reaction
mixture. cStarting material recovered (>95%).
alcohols such as isopropyl alcohol. In contrast, the use of di-N-
Boc glycine now allowed for the formation of such isopropyl
enol ether substrates. Pleasngly, 16b rearranged under standard
conditions to afford the desired β-isopropoxy R-amino ester
17b, after methylation, in 50% yield and with the excellent level
of diastereoselectivity previously observed with methyl enol
ether substrate 16a (entry 9).
J. Org. Chem. Vol. 75, No. 22, 2010 7813

Tellam and Carbery
SCHEME 2. Removal of Stereocontrol Element
JOCArticle
TABLE 4. Scope of Enol Ether in Ireland-Claisen Rearrangement Reaction
TABLE 5. Silylketene Acetal Formation Using Model Amino Esters
entry
20
P1
P2
% mass return
21/20
Z/Ea
2:1
11:1
>25:1
>25:1
1
2
20a
20b
20c
20c
Me
Boc
Phth
Boc
Boc
100
99
72
89
4:1
7:1
1:3.5
1.4:1
Phth
Boc
Boc
3
4b
aMeasured by 1H NMR spectroscopy. bSilylketene acetal formation
initiated at -78 °C.
the mixture of diastereomers displaying a positive optical
rotation (see Supporting Information for details), consistent
with the formation of the enantiomer displayed, as the major
enantiomer.45 The magnitude of π-facial selectivity is com-
parabletothatreportedbyGreenefora[2þ 2]-cycloaddition of
a chiral phenethyl enol ether and dichloroketenes.46 Facial
selectivity was rationalized by considering the conformational
model used by Greene to understand selectivity of phenethyl
enol ethers. Therefore, we believe the selectivity is predicted by
the transition state geometry in Figure 4.
FIGURE 4. Proposed model for understanding the stereoselectiv-
ity of chiral enol ether rearrangement.
With the di-N-Boc protection strategy superseding the
N-phthaloyl protection as a result of the superior levels of dia-
stereoselection, the question was asked as to why this improved
stereoselection was arising. Indeed, both of these protecting
systems feature two carbonyl groups sited upon the nitrogen
and point to an electronic influence relative to the sarcosine
substrates 12a-12e. To probe the reasoning behind the sensi-
tivity of diastereoselection to structure, a number of model
silylketene acetals were prepared to examine E/Z selectivity on
formation. Accordingly, methyl esters 20a-20c were exposed
to our rearrangement conditions, and the isolated silylketene
acetals were analyzed by 1H NMR (Table 5).
This study was particularly informative with E/Z ratios ob-
served in the isolated silylketene acetals closely mirroring the
magnitude of rearrangement diastereoselection. Furthermore,
the major geometrical isomer (Z) seen in the model systems is
consistent with the same geometrical isomer forming in the re-
arrangement with subsequent [3,3]-sigmatropic rearrangement
aDetermined by 1H NMR analysis of crude reaction mixture. b20%
methyl di-N-Boc glycinate isolated. c10% methyl di-N-Boc glycinate
e
isolated. d3.0 equiv of both LiHMDS and Me3SiCl used. Isolated as
trimethylsilyl alkyne. f40% methyl di-N-Boc glycinate isolated. g2:1
mixture of diastereomers with respect to phenethyl and allyl ether
moieties observed; structure of major isomer shown.
(45) Delle Monache, G.; Di Giovanni, M. C.; Misiti, D.; Zappia, G.
Tetrahedron: Asymmetry 1997, 8, 231–243.
(46) Nebois, P.; Greene, A. E. J. Org. Chem. 1996, 61, 5210–5211.
The absolute configuration was confirmed by converting
to the known β-hydroxy N-Boc R-amino ester, syn-19, with
7814 J. Org. Chem. Vol. 75, No. 22, 2010

Tellam and Carbery
JOCArticle
SCHEME 3. Preparation and Rearrangement of Z-Enol Ether
Substrate, Z-10a
SCHEME 4. Deprotection Strategies
through a chair geometry. The di-N-Boc substrates are seen to
convert to β-alkoxy R-amino acids considerably more slowly
than either the N-phthaloyl or N-allyl Boc systems, requiring
24 h at room temperature. Therefore, it would appear reason-
able to assume that an equilibrium geometry of silylketene
acetals is rearranging in the di-N-Boc-glycinate systems.
Having assessed the scope and influence of both O- and
N-substitution, a number of key structural influences were
explored. The adoption of a cyclic transition state possessing a
chair geometry offers the ability to control diastereoselection
through controlling the E/Z geometry of either the vinyl or allyl
fragment. As the ability to access the E-enolate is out of reach
because of the decomposition in HMPA, only utilization of a
Z-enol ether will offer access to the anti-diastereomer and there-
fore expand the synthetic utility of this chemistry. To examine
this idea, Z-6a was prepared according to Scheme 3. A Z-selective
silver-catalyzed addition of methyl propiolate was utilized to
form Z-4 in good yield.47 Subsequent reduction and coupling
afforded the requisite enol ether Z-10a
A disappointingly low level of anti-diastereoselectivity was
observed on rearrangement of enol ether Z-10a (Scheme 3).
Examination of chair transition state geometries for E- and
Z-10a is informative (Figure 5) and clearly predicts a sub-
stantial steric clash between the methoxy and silyloxy moi-
eties in a 1,3-transannular manner (II, Figure 5). Therefore,
the possibility exists that a boat geometry (III) is energeti-
cally competitive with II. Alternatively, enol ether geometry
may undergo interconversion from Z to E and subsequent
rearrangement via I or a nonconcerted C-C bond formation
event may occur. These possibilities are currently being exam-
ined through computational methods.
alcohol (Scheme 4). However, we have been unable to per-
form a hydrolytic cleavage of the methyl ester, which highlights
the sensitivity of these products, by virtue of being allylic ethers,
to methanol elimination.
Conclusions
In conclusion, a novel route to syn-β-alkoxy-R-amino acids
that utilizes an Ireland-Claisen [3,3]-sigmatropic rearrangement
of enol ethereal amino esters has been developed. When NBoc2-
glycinate substrates are used in this rearrangement, excellent
diastereoselectivity is observed with a single syn-isomer isolable
in good yields. Control of absolute stereochemistry, through the
application of a chiral enol, is present for the first time in an
Ireland-Claisen [3,3]-sigmatropic rearrangement.
Experimental Section
General Procedure for the Synthesis of Vinylogous Esters. To a
stirred solution of 1,4-diazabicyclo[2.2.2]octane (0.1 equiv) and
alcohol (1.1 equiv) in THF (150 mL) at room temperature was
added methyl propiolate (1 equiv) via syringe pump over 10 min,
with stirring at room temperature for a further 30 min. Sodium
hydroxide (10% solution, 200 mL) was added, and the aqueous
phase was extracted with CH2Cl2 (4 ꢀ 100 mL), combined,
washed with brine (3 ꢀ 150 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. Product ester was isolated after
subsequent purification on silica gel by flash chromatography.
General Procedure for the Synthesis of Allylic Alcohols. To a
stirred solution of the ester (1 equiv) in toluene (100 mL) at -78 °C
was added diisobutylaluminium hydride solution (1 M in toluene,
2.5 equiv) at a rate of 1 mL min-1. After addition the reaction was
stirred at -78 °C for 6 h, before being poured onto Rochelle salt
solution (satd, 100 mL) followed by the addition of EtOAc
(100 mL). The biphasic mixture was vigorously stirred for 2 h
before separation and extraction with EtOAc (3 ꢀ 100 mL). The
organics were combined, dried over Na2SO4, filtered, and
concentrated in vacuo to afford the primary allylic alcohol product
without further purification, unless stated otherwise.
General Procedure for the Synthesis of Allylic Amino Ester
Substrates. To a stirred solution of EDCi HCl (2 equiv) in
3
FIGURE 5. Possible transition state geometries (I-III) for enol
ether substrate geometries.
CH2Cl2 (50 mL) were added triethylamine (2 equiv), amino acid
(2 equiv), catalytic DMAP (5 mol %), and allylic alcohol
(1 equiv). The reaction was stirred at room temperature for 4 h
or until consumption of allylic alcohol was complete by TLC. The
mixture was diluted with CH2Cl2 to 100 mL, followed by washing
with saturated sodium bicarbonate solution (3 ꢀ 100 mL), citric
acid (10% solution, 3 ꢀ 100 mL), and brine (3 ꢀ 100 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to afford amino
esters without any further purification, unless stated otherwise.
General Procedure for the Synthesis of β-Alkoxy r-Amino
Acids via Ireland-Claisen Rearrangement. To a stirred solution
of the allylic amino ester (1 equiv) in THF (1 mL) at -78 °C was
With a highly stereoselective sigmatropic route tosyn-β-
alkoxy-R-amino esters developed, we have sought to demon-
strate some synthetic value through a short demonstration of
chemoselective deprotection. Accordingly, mono-Boc deprotec-
tion48 is possible as is the full reduction of the ester to primary
(47) Kataoka, Y.; Matsumoto, O.; Tani, K. Chem. Lett. 1996, 25,
727–728.
(48) Cisar, J. S.; Ferreras, J. A.; Soni, R. K.; Quadri, L. E. N.; Tan, D. S.
J. Am. Chem. Soc. 2007, 129, 7752–7753.
J. Org. Chem. Vol. 75, No. 22, 2010 7815

Tellam and Carbery
JOCArticle
added TMSCl (2 equiv), and the mixture was stirred for 10 min.
LiHMDS (1 M in THF, 2 equiv) was added via syringe pump at
a rate of 3 mL h-1, and the mixture was stirred at -78 °C for a
further 10 min before being warmed to room temperature and
stirred for 24 h. The reaction was quenched by the addition of
methanol (10 mL). Treatment of the crude acid with diazo-
methane in ether afforded the methyl ester. Purification was
achieved by flash chromatography to afford the title compound
as a single diastereomer.
13C NMR (125 MHz, CDCl3) δ 23.4, 51.0, 80.5, 98.1, 125.7, 128.2,
128.8, 141.2, 161.5, 168.2; HRMS (ESI, þve) m/z calcd for
C12H14O3Na 229.0841, found 229.0832. (M þ Na)þ.
(E)-3-(Isopropyloxy)prop-2-enol (5b). (E)-Methyl 3-(isopro-
poxy)acrylate (2.00 g, 13.8 mmol) was reduced according to
general procedure to afford the title compound as a yellow oil
(1.19 g, 74%). FTIR (film/cm-1) υmax 3371.8, 2976.5, 2931.2,
2874.6, 1670.6, 1650.9; 1H NMR (500 MHz, d6-acetone) δ 1.15
(d, 6H, J = 6.2 Hz), 3.81 (app. t, 2H, J = 6.5 Hz), 4.00 (quin, 1H,
J = 6.2 Hz), 4.36 (t, 1H, J = 6.5 Hz), 4.88 (dt, 1H, J = 12.5,
6.5 Hz), 6.33 (d, 1H, J = 12.5 Hz); 13C NMR (125 MHz,
d6-acetone) δ 22.4, 59.0, 72.3, 105.7, 147.6.
(E)-Methyl 3-Isopropoxyacrylate (4b). DABCO (0.26 g, 2.38
mmol) in THF (40 mL), 2-propanol (1.43 g, 2.62 mmol), and
methyl propiolate (2.00 g, 23.8 mmol) were combined according
to general procedure. Purification was achieved by flash chro-
matography (10:1 pet./EtOAc) to afford the title compound as a
colorless oil (2.4 g, 70%). 1H NMR (500 MHz, CDCl3) δ 1.22 (d,
6H, J = 6.4 Hz), 3.63 (s, 3H), 4.17 (sept, 1H, J = 6.4 Hz), 5.17
(d, 1H, J = 12.9 Hz), 7.47 (d, 1H, J = 12.9 Hz); 13C NMR
(125 MHz, CDCl3) δ 21.9, 50.9, 75.6, 96.8, 161.6, 168.4. All
analytical data are in accordance with reported literature values.49
(E)-Methyl 3-(Pentan-3-yloxy)acrylate (4c). DABCO (0.26 g,
2.38 mmol) in THF (40 mL), 3-pentanol (2.09 g, 2.62 mmol), and
methyl propiolate (2.00 g, 23.8 mmol) were combined according
to general procedure. Purification was achieved by flash chro-
matography (12:1 pet./EtOAc) to afford the title compound as a
colorless oil (3.05 g, 75%). FTIR (film/cm-1) υmax 2971.6,
2944.9, 2881.6 2846.7, 1713.4, 1641.7; 1H NMR (500 MHz,
CDCl3) δ 0.90 (t, 6H, J = 7.6 Hz), 1.61 (quin, 4H, J = 7.6 Hz),
3.68 (s, 3H), 3.75 (quin, 1H, J = 7.6 Hz), 5.23 (d, 1H, J =
12.8 Hz), 7.53 (d, 1H, J = 12.8 Hz); 13C NMR (125 MHz,
CDCl3) δ 9.5, 26.7, 50.9, 86.9, 96.4, 163.1, 168.7; HRMS (ESI, þve)
m/z calcd for C9H16O3Na 195.0992, found 195.0997 (M þ Na)þ.
(E)-Methyl 3-(Prop-2-ynyloxy)acrylate (4d). DABCO (0.40 g,
3.57 mmol) in THF (300 mL), propagyl alcohol (2.3 mL, 3.93 mmol),
and methyl propiolate (3.2 mL, 35.7 mmol) were combined
according to general procedure. Purification was achieved by
flash chromatography (10:1 pet./EtOAc) to afford the title
(E)-3-(Pentan-3-yloxy)prop-2-enol (5c). (E)-Methyl 3-(pen-
tan-3-yloxy)acrylate 4b (1.32 g, 10.4 mmol) was reduced according
to general procedure to afford the title compound as a colorless
oil (1.05 g, 68%). FTIR (film/cm-1) υmax 3347.2, 2966.1, 2937.3,
1
2878.9, 1699.1, 1650.3; H NMR (500 MHz, d6-acetone) δ 0.89
(t, 6H, J=7.4 Hz), 1.55 (m, 4H), 3.31 (t, 1H, J=5.8 Hz), 3.54 (quin,
1H, J=5.9 Hz), 4.00 (dd, 2H, J=7.6, 1.0 Hz), 5.08 (dt, 1H, J=12.3,
7.6 Hz), 6.37 (d, 1H, J=12.3 Hz); 13C NMR (125 MHz, d6-acetone)
δ 8.9, 26.2, 59.4, 82.8, 104.7, 148.8.
(E)-3-(Prop-2-ynyloxy)prop-2-en-1-ol (5d). (E)-Methyl 3-(prop-
2-ynyloxy)acrylate 4c (1.03 g, 7.35 mmol) was reduced according to
general procedure to afford the title compound as a colorless oil
(0.63 g, 75%). FTIR (film/cm-1) υmax 3380.5, 3289.2, 2926.0,
2869.7, 2120.7, 1671.8, 1653.0; 1H NMR (500 MHz, d6-acetone) δ
2.60 (dt, 1H, J = 2.4, 0.8 Hz), 4.06 (d, 2H, J = 7.2 Hz), 4.43 (d, 2H,
J = 2.4 Hz), 5.17 (dt, 1H, J = 12.7, 7.2 Hz), 6.52 (d, 1H, J =
12.7 Hz); 13C NMR (125 MHz, d6-acetone) δ 57.0, 60.1, 75.3, 78.5,
105.4, 148.1.
(E)-3-(2,6-Dichlorobenzyloxy)prop-2-en-1-ol (5e). (E)-Methyl
3-(2,6-dichlorobenzyloxy)acrylate 4d (1.25 g, 4.79 mmol) was
reduced according to the general procedure to afford the title
compound as a white solid (0.74 g, 67%). Mp 80-83 °C; FTIR
(film/cm-1) υmax 3300.2, 3078.3, 2945.4, 2863.0, 1672.2, 1583.1,
1
1563.1; H NMR (500 MHz, d6-acetone) δ 3.46 (t, 1H, J =
compound as a colorless oil (5.10 g, 98%). FTIR (film/cm-1
)
5.6 Hz), 4.02 (m, 2H), 5.03 (s, 2H), 5.18 (dt, 1H, J = 12.6,
7.2 Hz), 6.63 (d, 1H, J = 12.6 Hz), 7.41-7.45 (m, 1H), 7.49-
7.51 (m, 2H); 13C NMR (125 MHz, d6-acetone) δ 59.2, 65.5,
104.8, 128.6, 131.0, 132.4, 136.5, 148.2.
υmax 3293.2, 3096.0, 2998.8, 2953.6, 2124.5, 1704.9, 1646.0,
1624.3; 1H NMR (500 MHz, CDCl3) δ 2.60 (t, 1H, J = 2.6 Hz),
3.71 (s, 3H), 4.53 (d, 2H, J = 2.6 Hz), 5.35 (d, 1H, J = 12.7 Hz),
7.58 (d, 1H, J = 12.7 Hz); 13C NMR (125 MHz, CDCl3) δ 51.2,
58.1, 76.6, 77.0, 98.3, 160.6, 167.6; HRMS (ESI, þve) m/z calcd
for C7H8O3Na 163.0371, found 163.0364 (M þ Na)þ.
(S,E)-3-(1-phenylethoxy)prop-2-enol (5f). (S,E)-Methyl 3-(1-
phenylethoxy)acrylate 4e (2.65 g, 12.9 mmol) was reduced
according to general procedure to afford the title compound
as a colorless oil (1.72 g, 75%). [R]20D -68 (c 1, CH2Cl2); FTIR
(film/cm-1) υmax 3347.2, 3086.6, 3062.8, 3031.0, 2977.6, 2930.0,
2872.4, 1670.1, 1671.2, 1651.2; 1H NMR (500 MHz, d6-DMSO)
δ 1.42 (d, 3H, J = 6.5 Hz), 3.75 (app. t, 2H, J = 6.6 Hz), 4.38
(t, 1H, J = 5.4 Hz), 4.88-4.95 (m, 2H), 6.33 (d, 1H, J = 12.4 Hz),
7.30-7.38 (m, 5H); 13C NMR (125 MHz, d6-DMSO) δ 23.8, 58.8,
77.7, 106.6, 125.7, 126.3, 127.9, 128.4, 128.9, 143.4, 147.4.
(E)-Methyl 3-(2,6-Dichlorobenzyloxy)acrylate (4e). DABCO
(0.27 g, 23.8 mmol) in THF (300 mL), 2,6-dichlorobenzyl
alcohol (4.63 g, 26.2 mmol), and methyl propiolate (2.00 g,
23.8 mmol) were combined according to general procedure.
Purification was achieved by flash chromatography (10:1 pet./
EtOAc) to afford title compound as a colorless oil (3.82 g, 62%).
FTIR (film/cm-1) υmax 3090.0, 2951.1, 2892.8, 1706.6, 1644.1,
1620.7, 1583.0, 1565.4; 1H NMR (500 MHz, CDCl3) δ 3.73 (s,
3H), 5.16 (s, 2H), 5.39 (d, 1H, J = 12.6 Hz), 7.25-7.28 (m, 1H)
7.35 (s, 1H), 7.37 (s, 1H), 7.71 (d, 1H, J = 12.6 Hz); 13C NMR
(125 MHz, CDCl3) δ 51.2, 67.5, 128.5, 130.7, 131.0, 137.0, 162.1,
167.9; HRMS (ESI, þve) m/z calcd for C11H10Cl2O3Na
282.9905, found 282.9887 (M þ Na)þ.
(E)-3-Methoxyallyl 2-((tert-Butoxycarbonyl)amino)acetate (6).
EDCi HCl (2.50 g, 17.0 mmol), triethylamine (1.6 mL, 17.0 mmol),
3
N-Boc-Gly-OH (2.24 g, 17.0 mmol), and (E)-3-(methoxy)prop-2-
enol (0.75 g, 8.51 mmol) were combined according to general
procedure to afford the title compound as a colorless oil (1.45 g
mass recovery; because of product instability, this ester was used
without further purification; see Supporting Information for NMR
spectra relating to purity). FTIR (film/cm-1) υmax 2880.3, 1736.1,
1717.6, 1673.9; 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 3.51
(s, 3H), 3.83 (app. q, 2H, J = 5.6 Hz), 4.51 (d, 2H, J = 7.8 Hz), 4.89
(dt, 1H, J = 12.7, 7.8 Hz), 4.99 (br, 1H), 6.59 (d, 1H, J = 12.7 Hz);
13C NMR (125 MHz, CDCl3) δ 28.4, 42.7, 55.1, 66.3, 80.2, 125.9,
136.7, 156.0, 171.4; HRMS (ESI, þve) m/z calcd for C11H19NO5Na
268.1161, found 268.1175 (M þ Na)þ.
(S,E)-Methyl 3-(1-Phenylethoxy)acrylate (4f). DABCO (0.26 g,
2.38 mmol) in THF (200 mL), (S)-1-phenylethanol (2.90 g,
26.2 mmol), and methyl propiolate (2.00 g, 23.8 mmol) were
combined according to general procedure. Purification was
achieved by flash chromatography (30:1 pet./EtOAc) to afford
the title compound as a white solid (4.0 g, 81%). [R]20D = -113
(c 1, CH2Cl2); mp 38-39 °C; FTIR (film/cm-1) υmax 2993.6,
1
2950.2, 1713.4, 1643.4; H NMR (500 MHz, CDCl3) δ 1.60 (d,
3H, J = 7.2 Hz), 3.65 (s, 3H), 5.04 (q, 1H, J = 6.7 Hz), 5.25 (d,
1H, J = 12.5 Hz), 7.39-7.29 (m, 5H), 7.52 (d, 2H, J = 12.5 Hz);
(E)-3-Methoxyallyl 2-(Bis(tert-butoxycarbonyl)amino)acetate
(16a). EDCi HCl (1.01 g, 5.27 mmol), triethylamine (0.74 mL,
3
5.27 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic acid (1.15 g,
5.27 mmol), and (E)-3-methoxyprop-2-enol (0.31 g, 2.63 mmol)
(49) Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450.
7816 J. Org. Chem. Vol. 75, No. 22, 2010

Tellam and Carbery
JOCArticle
were combined according to general procedure to afford the title
compound as a yellow oil (0.85 g mass recovery; because of product
instability, this ester was used without further purification; see
Supporting Information for NMR spectra relating to purity). FTIR
(s, 2H), 4.55 (d, 2H, J = 7.8 Hz), 4.89 (dt, 1H, J = 12.6, 7.8 Hz),
6.61 (d, 1H, J = 12.6 Hz); 13C NMR (125 MHz, CDCl3) δ 26.4,
28.0, 43.0, 47.4, 63.6, 79.3, 82.9, 96.6, 151.8, 153.6, 169.2; HRMS
(ESI, þve) m/z calcd for C20H35NO7Na 424.2311, found
424.2299 (M þ Na)þ.
1
(film/cm-1) υmax 2980.8, 2936.5, 1732.0, 1697.3; H NMR (500
MHz, CDCl3) δ1.49 (s, 18H), 3.55 (s, 3H), 4.30 (s, 2H), 4.56 (d, 2H,
J = 7.9 Hz), 4.91 (dt, 1H, J = 12.7, 7.9 Hz), 6.63 (d, 1H, J =
12.7 Hz); 13C NMR (125 MHz, CDCl3) δ 28.0, 47.4, 56.1, 63.3,
83.0, 96.6, 151.9, 153.6, 169.2; HRMS (ESI, þve) m/z calcd for
C16H27NO7Na 368.1685, found 368.1673 (M þ Na)þ.
(E)-3-(Allyloxy)allyl 2-(Bis(tert-butoxycarbonyl)amino)acetate
(16f). EDCi HCl (0.53 g, 2.76 mmol), triethylamine (0.40 mL,
3
2.76 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic acid (0.76 g,
2.76 mmol), and (E)-3-(allyloxy)prop-2-enol (0.16 g, 1.38 mmol)
were combined according to general procedure to afford the title
compound as a yellow oil (0.40 g mass recovery; because of
product instability, this ester was used without further purifica-
tion; see Supporting Information for NMR spectra relating to
purity). FTIR (film/cm-1) υmax 2981.3, 2936.0, 1755.8, 1735.8,
(E)-3-Isopropyloxyallyl 2-(Bis(tert-butoxycarbonyl)amino)-
acetate (16b). EDCi HCl (0.79 g, 4.12 mmol), triethylamine
3
(0.60 mL, 4.12 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (1.13 g, 4.12 mmol), and (E)-3-(isopropoxy)prop-2-enol
(0.24 g, 2.06 mmol) were combined according to general proce-
dure, omitting the citric acid wash, to afford the title compound
as a brown oil (0.72 g mass recovery; because of product
instability, this ester was used without further purification; see
Supporting Information for NMR spectra relating to purity).
FTIR (film/cm-1) υmax 2978.5, 2936.4, 1757.1, 1736.3, 1697.0,
1671.0; 1H NMR (500 MHz, CD2Cl2) δ 1.21 (d, 6H, J = 6.3 Hz),
1.49 (s, 18H), 4.12 (sept, 1H, J = 6.3 Hz), 4.27 (s, 2H), 4.55 (d,
2H, J = 7.8 Hz), 4.97 (dt, 1H, J = 12.8, 7.8 Hz), 6.62 (d, 1H, J =
12.8 Hz); 13C NMR (125 MHz, CD2Cl2) δ 21.4, 27.3, 47.1, 63.1,
72.9, 82.1, 98.6, 152.0, 168.8; HRMS (ESI, þve) m/z calcd for
C18H31NO7Na 396.1998, found 396.2005 (M þ Na)þ.
1
1698.0, 1673.1, 1654.7; H NMR (500 MHz, CDCl3) δ 1.51 (s,
18H), 4.26 (dt, 2H, J = 5.6, 1.5 Hz) 4.32 (s, 2H), 4.58 (d, 2H, J =
7.8 Hz), 4.99 (dt, 1H, J = 12.7, 7.8 Hz), 5.26 (dq, 1H, J = 10.5,
1.5 Hz), 5.34 (dq, 1H, J = 17.2, 1.5 Hz), 5.90-5.98 (m, 1H), 6.60
(d, 1H, J = 12.7 Hz); 13C NMR (125 MHz, CDCl3) δ 28.0, 47.4,
63.4, 70.3, 83.0, 98.1, 118.0, 132.7, 151.9, 152.3, 169.2; HRMS
(ESI, þve) m/z calcd for C18H29NO7Na 394.1842, found
394.1831 (M þ Na)þ.
(E)-3-(prop-2-yn-1-yloxy)allyl 2-(Bis(tert-butoxycarbonyl)amino)-
acetate (16g). EDCi HCl (1.09 g, 5.69 mmol), triethylamine
3
(0.80 mL, 5.69 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (1.57 g, 5.69 mmol), and (E)-3-(prop-2-yn-1-yloxy)prop-
2-en-1-ol (0.32 g, 2.84 mmol) were combined according to
general procedure to afford the title compound as a yellow oil
(0.90 g mass recovery; because of product instability, this ester
was used without further purification; see Supporting Information
for NMR spectra relating to purity). FTIR (film/cm-1) υmax
2980.4, 2940.0, 2146.1, 1796.1, 1753.6, 1734.5, 1696.5, 1654.5; 1H
NMR (500 MHz, CDCl3) δ 1.47 (s, 18H), 2.52 (t, 1H, J = 2.5 Hz),
4.28 (s, 2H), 4.36 (d, 2H, J = 2.5 Hz), 4.55 (dd, 2H, J = 7.9,
0.6 Hz), 5.05 (dt, 1H, J = 12.7, 7.9 Hz), 6.55 (d, 1H, J = 12.7 Hz);
13C NMR (125 MHz, CDCl3) δ 27.9, 47.3, 57.0, 62.9, 75.9, 77.7,
83.0, 99.5, 150.9, 151.8, 169.1; HRMS (ESI, þve) m/z calcd for
C18H27NO7Na 392.1685, found 392.1705 (M þ Na)þ.
(E)-3-Ethyloxyallyl 2-(Bis(tert-butoxycarbonyl)amino)acetate
(16c). EDCi HCl (0.75 g, 3.91 mmol), triethylamine (0.54 mL,
3
3.91 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic acid (1.07 g,
3.91 mmol), and (E)-3-ethoxyprop-2-enol (0.20 g, 1.96 mmol) were
combined according to general procedure to afford the title
compound as a yellow oil (0.64 g mass recovery; because of product
instability, this ester was used without further purification; see
Supporting Information for NMR spectra relating to purity).
FTIR (film/cm-1) υmax 2980.6, 2935.6, 1755.7, 1743.7, 1697.4,
1652.9; 1H NMR (500 MHz, CDCl3) δ 1.20 (t, 3H, J = 6.8 Hz),
1.43 (s, 18H), 3.69 (q, 2H, J = 6.8 Hz), 4.23 (s, 2H), 4.48 (d, 2H,
J = 7.9 Hz), 4.85 (dt, 1H, J = 12.7, 7.9 Hz), 6.51 (d, 1H, J =
12.7 Hz); 13C NMR (125 MHz, CDCl3) δ 14.5, 27.9, 47.3, 63.4,
64.9, 82.8, 97.2, 151.7, 152.7, 169.1; HRMS (ESI, þve) m/z calcd
for C17H29NO7Na 382.1842, found 382.1853 (M þ Na)þ.
(E)-3-(Benzyloxy)allyl 2-(Bis(tert-butoxycarbonyl)amino)-
acetate (16h). EDCi HCl (0.94 g, 4.90 mmol), triethylamine
3
(0.70 mL, 4.90 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (1.35 g, 4.90 mmol), and (E)-3-bezyloxyprop-2-enol (0.20 g,
2.45 mmol) were combined according to general procedure. Puri-
fcation was achieved by flash chromatography (Al2O, 10:1 petrol/
EtOAc) to afford the title compound as a colorless oil (0.32 g mass
recovery; because of product instability, this ester was used without
further purification; see Supporting Information for NMR spectra
relating to purity). FTIR (film/cm-1) υmax 2980.4, 2938.6, 1757.7,
1736.4, 1698.3; 1H NMR (500 MHz, CDCl3) δ 1.51 (s, 18H), 4.33
(s, 2H), 4.60 (d, 2H, J = 7.8 Hz), 4.78 (s, 2H), 5.08 (dt, 1H, J =
(E)-3-(Pentan-3-yloxy)allyl 2-(Bis(tert-butoxycarbonyl)amino)-
acetate (16d). EDCi HCl (0.62 g, 3.23 mmol), triethylamine
3
(0.45 mL, 3.23 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.89 g, 3.23 mmol), and (E)-3-(pentan-3-yloxy)prop-2-enol
(0.24 g, 1.62 mmol) were combined according to general procedure,
omitting the citric acid wash, to afford the title compound as a
brown oil (0.49 g mass recovery; because of product instability, this
ester was used without further purification; see Supporting Informa-
tion for NMR spectra relating to purity). FTIR (film/cm-1) υmax
2978.7, 2937.9, 2881.5, 1798.9, 1755.9, 1736.3, 1697.7, 1669.7; H
12.4, 7.8 Hz), 6.71 (d, 1H, J = 12.4 Hz), 7.33-7.41 (m, 5H); 13
C
1
NMR (500 MHz, d6-acetone) δ 0.90 (t, 6H, J = 7.5 Hz), 1.49
(s, 22H), 3.70 (quin, 1H, J = 5.8 Hz), 4.28 (s, 2H), 4.55 (d, 2H, J =
7.9 Hz), 4.99 (dt, 1H, J = 12.2, 7.9 Hz), 6.66 (d, 1H, J = 12.2 Hz);
13C NMR (125 MHz, d6-acetone) δ 8.9, 26.3, 27.3, 47.1, 63.2, 82.1,
3.6, 98.2, 151.8, 153.2, 168.9; HRMS (ESI, þve) m/z calcd for
C20H35NO7Na 424.2311, found 424.2349 (M þ Na)þ.
NMR (125 MHz, CDCl3) δ 28.0, 47.4, 63.4, 71.4, 83.1, 98.2, 127.7,
128.2, 128.6, 136.2, 151.9, 152.5, 169.2; HRMS (ESI, þve) m/z
calcd for C22H31NO7Na 444.1998, found 444.1996 (M þ Na)þ.
(E)-3-(4-Methoxybenzyloxy)allyl 2-(Bis(tert-butoxycarbonyl)-
amino)acetate (16i). EDCi HCl (0.44 g 2.31 mmol), triethylamine
3
(0.32 mL, 2.31 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.64 g, 2.31 mmol), and (E)-3-((4-methoxybenzyl)oxy)-
prop-2-en-1-ol (0.22 g, 1.15 mmol) were combined according
to general procedure to afford the title compound as a yellow oil
(0.73 g mass recovery; because of product instability, this ester was
used without further purification; see Supporting Information for
NMR spectra relating to purity). FTIR (film/cm-1) υmax 3054.2,
3026.5, 2998.7, 2968.1, 1759.6, 1731.9, 1698.3; 1H NMR (500 MHz,
CDCl3) δ 1.49 (s, 18H), 3.80 (s, 3H), 4.31 (s, 2H), 4.57 (d, 2H, J =
7.6 Hz), 4.68 (s, 2H), 5.04 (dt, 1H, J = 12.6, 7.6 Hz), 6.66 (d, 1H,
J = 12.6 Hz), 6.86-6.90 (m, 2H), 7.24-7.29 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 28.0, 47.4, 55.3, 63.4, 71.2, 83.0, 98.1, 114.0,
(E)-3-(Neopentyloxy)allyl 2-(Bis(tert-butoxycarbonyl)amino)-
acetate (16e). EDCi HCl (0.45 g, 2.33 mmol), triethylamine
3
(0.32 mL, 2.33 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.64 g, 2.33 mmol), and (E)-3-(neopentyloxy)prop-2-en-1-
ol (0.17 g, 1.16 mmol) were combined according to general
procedure to afford the title compound as a yellow oil (0.33 g
mass recovery; because of product instability, this ester was used
without further purification; see Supporting Information for
NMR spectra relating to purity). FTIR (film/cm-1) υmax 2979.9,
1
2868.7, 1796.5, 1756.3, 1736.1, 1698.4, 1651.9; H NMR (500
MHz, CDCl3) δ 0.92 (s, 9H), 1.48 (s, 18H), 3.32 (s, 2H), 4.28
J. Org. Chem. Vol. 75, No. 22, 2010 7817

Tellam and Carbery
JOCArticle
128.3, 129.4, 151.9, 152.5, 159.6, 169.2; HRMS (ESI, þve) m/z
calcd for C23H33NO8Na 474.2104, found 474.2123 (M þ Na)þ.
(E)-3-((2,6-dichlorobenzyl)oxy)allyl 2-(Bis(tert-butoxycarbonyl)-
(0.30 mL, 2.14 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.59 g, 2.14 mmol), and (E)-3-(4-methoxyphenyloxy)prop-2-
enol (0.20 g, 1.07 mmol) were combined according to general
procedure to afford the title compound as a yellow oil (0.41 g mass
recovery; because of product instability, this ester was used without
further purification; see Supporting Information for NMR spectra
relating to purity). FTIR (film/cm-1) υmax 2979.9, 2940.1, 1796.2,
1755.6, 1735.3, 1697.3, 1673.1; 1H NMR (500 MHz, CDCl3) δ 1.47
(s, 18H), 3.75 (s, 3H), 4.30(s, 2H), 4.60 (d, 2H, J =7.7Hz), 5.29 (dt,
1H, J = 12.2, 7.7 Hz), 6.72 (d, 1H, J = 12.2 Hz), 6.82 (app. dt, 2H,
J = 8.9, 2.9 Hz), 6.90 (app. dt, 2H, J = 8.9, 2.9 Hz); 13C NMR
(125 MHz, CDCl3) δ 27.9, 47.4, 55.6, 62.4, 83.1, 103.7, 114.7, 118.6,
150.0, 150.3, 151.8, 155.9, 169.1; HRMS (ESI, þve) m/z calcd for
C22H31NO8Na 460.1947, found 460.1916 (M þ Na)þ.
amino)acetate (16j). EDCi HCl (0.55 g, 2.87 mmol), triethylamine
3
(0.40 mL, 2.87 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.79 g, 2.87 mmol), and (E)-3-(2,6-dichlorobenzyloxy)-
prop-2-enol (0.34 g, 1.43 mmol) were combined according to
general procedure to afford the title compound as a yellow oil
(0.74 g mass recovery; because of product instability, this ester was
used without further purification; see Supporting Information for
NMR spectra relating to purity). FTIR (film/cm-1) υmax 2980.9,
2939.7, 2887.4, 1754.9, 1735.3, 1696.7, 1651.4; 1H NMR (500
MHz, CDCl3) δ 1.52 (s, 18H), 4.34 (s, 2H), 4.62 (d, 2H, J = 8.8
Hz), 5.03 (s, 2H), 5.13 (dt, 1H, J = 12.7, 7.8 Hz), 6.73 (d, 1H, J =
12.7 Hz), 7.23-7.36 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 28.0,
47.4, 63.2, 66.1, 83.0, 98.4, 128.4, 130.6, 131.7, 136.9, 151.9, 152.3,
169.2; HRMS (ESI, þve) m/z calcd for C22H29NO7Cl2Na 512.1190,
found 512.1194 (M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
methoxypent-4-enoate (17a). (E)-3-Methoxyallyl 2-(bis(tert-
butoxycarbonyl)amino)acetate 16a (0.10 g, 0.28 mmol), TMSCl
(0.07 mL, 0.55 mmol), and LiHMDS (0.55 mL, 0.55 mmol) were
combined according to the general procedure. Treatment with
diazomethane and purification by flash chromatography (15:1
pet./EtOAc þ 1% NEt3) afforded the title compound as a colorless
oil (0.07 g, 72%). FTIR (film/cm-1) υmax 2986.3, 2938.0, 1752.4,
1698.1, 1649.9; 1H NMR (500 MHz, CDCl3) δ 1.51 (s, 18H), 3.27
(s, 3H), 3.70 (s, 3H), 4.18 (app. t, 1H, J = 7.8 Hz), 4.87 (d, 1H, J =
8.5 Hz), 5.33 (dq, 1H, J = 10.4, 1.2 Hz), 5.42 (dq, 1H, J = 17.1, 1.2
Hz), 5.88 (ddd, 1H, J = 17.1, 10.4, 6.9 Hz); 13C NMR (125 MHz,
CDCl3) δ 30.0, 52.0, 56.8, 61.4, 79.1, 82.9, 118.6, 136.4, 152.2, 169.4;
HRMS (ESI, þve) m/z calcd for C17H29NO7Na 382.1842, found
382.1830 (M þ Na)þ.
(S,E)-3-(1-Phenylethoxy)allyl 2-(Bis(tert-butoxycarbonyl)-
amino)acetate (16k). EDCi HCl (0.56 g, 2.90 mmol), triethylamine
3
(0.40 mL, 2.90 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic
acid (0.80 g, 2.90 mmol), and (S,E)-3-(1-phenylethoxy)prop-2-enol
(0.26 g, 1.45 mmol) were combined according to general procedure
to afford the title compound as a yellow oil (0.31 g mass recovery;
because of product instability, this ester was used without further
purification; see Supporting Information for NMR spectra relating
to purity). [R]20 = -60 (c 1, CH2Cl2); FTIR (film/cm-1) υmax
D
3002.5, 2999.3, 2985.2, 1754.6, 1734.2, 1698.21651.7; 1H NMR (500
MHz, d6-acetone) δ 1.02-1.13 (m, 3H), 1.37 (s, 18H), 4.14 (s, 2H),
4.38 (d, 2H, J = 7.9 Hz), 4.85-4.97 (m, 2H), 6.53 (d, 1H, J = 12.7
Hz), 7.08-7.34 (m, 5H); 13C NMR (125 MHz, d6-acetone) δ 23.9,
28.4, 46.4, 58.8, 77.7, 82.6, 106.6, 125.7, 126.3, 127.9, 128.4, 128.9,
143.4, 147.4, 152.7, 169.5; HRMS (ESI, þve) m/z calcd for
C23H33NO7Na 458.2155, found 458.2140 (M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
neopentyloxypent-4-enoate (17b). (E)-3-Isopropoxyallyl 2-(bis(tert-
butoxycarbonyl)amino)acetate 16b (0.10 g, 0.31 mmol), TMSCl
(0.08 mL, 0.61 mmol), and LiHMDS (0.61 mL, 0.61 mmol) were
combined according to the general procedure. Treatment with
diazomethane and purification by flash chromatography (15:1
pet./EtOAc þ 1% NEt3) afforded the title compound as a colorless
oil (0.05 g, 50%). FTIR (film/cm-1) υmax 2979.2, 2937.1, 1798.7,
1750.2, 1698.2; 1H NMR (500 MHz, CDCl3) δ 1.09 (dd, 6H, J =
11.0, 6.1 Hz), 1.51 (s, 18H), 3.63 (sept, 1H, J =6.1 Hz), 3.70 (s, 3H),
4.41-4.44 (m, 1H), 4.80 (d, 1H, J=9.4Hz), 5.24(dq, 1H, J=10.5,
0.8 Hz), 5.44 (dq, 1H, J = 15.4, 0.8 Hz), 6.03 (ddd, 1H, J = 15.4,
10.5, 6.3 Hz); 13C NMR (125 MHz, CDCl3) δ:21.4, 23.3, 28.0, 47.2,
52.1, 62.1, 69.9, 74.9, 83.1, 117.1, 138.1, 152.2, 169.7; HRMS
(ESI, þve) m/z calcd for C19H33NO7Na 410.2154, found 410.2144
(M þ Na)þ.
(E)-3-Phenoxyallyl 2-(Bis(tert-butoxycarbonyl)amino)acetate
(16l). EDCi HCl (0.58 g, 3.03 mmol), triethylamine (0.42 mL,
3
3.03 mmol), 2-(bis(tert-butoxycarbonyl)amido)acetic acid (0.84 g,
3.03 mmol), and (E)-3-phenoxyprop-2-enol (0.23 g, 1.51 mmol)
were combined according to general procedure to afford the title
compound as a yellow oil (0.62 g mass recovery; because of product
instability, this ester was used without further purification; see
Supporting Information for NMR spectra relating to purity). FTIR
(film/cm-1) υmax 2980.1, 2936.0, 1755.7, 1735.9, 1697.0; 1H NMR
(500 MHz, CDCl3) δ 1.51 (s, 18H), 4.35 (s, 2H), 4.67 (d, 2H, J =
7.9 Hz), 5.45 (dt, 1H, J = 12.4, 7.9 Hz), 6.82 (d, 1H, J = 12.4 Hz),
7.01 (d, 2H, J = 8.3 Hz), 7.11 (t, 1H, J = 7.7 Hz), 7.34 (t, 2H,
J = 8.3 Hz); 13C NMR (125 MHz, CDCl3) δ 28.4, 47.6, 62.6, 83.0,
105.1, 117.2, 123.6, 130.0, 148.5, 152.0, 156.8, 169.3; HRMS
(ESI, þve) m/z calcd for C21H29NO7Na 430.1842, found 430.1827
(M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
ethoxypent-4-enoate (17c). (E)-3-Ethoxyallyl 2-(bis(tert-butoxy-
carbonyl)amino)acetate 16c (0.10 g, 0.27 mmol), TMSCl
(0.07 mL, 0.53 mmol), and LiHMDS (0.53 mL, 0.53 mmol)
were combined according to the general procedure. Treatment
with diazomethane and purification by flash chromatography
(10:1 pet./EtOAc þ 1% NEt3) afforded the title compound as a
colorless oil (0.07 g, 56%). FTIR (film/cm-1) υmax 2980.4,
(E)-3-(4-Trifluoromethylphenoxyallyl 2-(Bis(tert-butoxycar-
bonyl)amino)acetate (16m). EDCi HCl (0.33 g, 1.72 mmol),
3
triethylamine (0.22 mL, 1.72 mmol), 2-(bis(tert-butoxycarbonyl)-
amido)acetic acid (0.47 g, 1.72 mmol), and (E)-3-bezyloxyprop-2-
enol (0.19 g, 0.86 mmol) were combined according to general
procedure to afford the title compound as a colorless oil (0.40 g mass
recovery; because of product instability, this ester was used without
further purification; see Supporting Information for NMR spectra
relating to purity). FTIR (film/cm-1) υmax 3013.2, 2937.1, 1795.5,
1756.0, 1735.2, 1698.6, 1612.7; 1H NMR (500 MHz, CDCl3) δ 1.51
(s,18H),4.36(s,2H),4.69(dd,2H,J= 7.6, 1.0 Hz), 5.55 (dt, 1H, J=
12.2, 7.6 Hz), 6.82 (dt, 1H, J = 12.2, 1.0 Hz), 7.09 (app. d, 2H, J =
8.6Hz), 7.60(app. d, 2H,J=8.6Hz);13C NMR (125 MHz, CDCl3)
δ 28.0, 47.3, 61.7, 83.2, 107.3, 116.9, 125.4, 125.7, 127.2 (q, J =
3.8 Hz), 146.9, 152.0, 158.9, 169.1; HRMS (ESI, þve) m/z calcd for
C22H28F3NO7Na 498.1716, found 498.1719 (M þ Na)þ.
1
2937.3, 1794.1, 1748.2, 1698.2; H NMR (500 MHz, CDCl3) δ
1.14 (t, 3H, J=7.0Hz),1.52(s,18H),3.30(dq,1H,J= 9.2, 7.0 Hz),
3.59 (dq, 1H, J = 9.2, 7.0 Hz), 3.71 (s, 3H), 4.32 (dd, 1H, J =
9.0 Hz), 4.86 (d, 1H, J = 9.0 Hz), 5.28 (dq, 1H, J = 10.4, 1.0 Hz),
5.42 (dq, 1H, J = 17.2, 1.0 Hz), 5.96 (ddd, 1H, J = 17.2, 10.4,
6.7 Hz); 13C NMR (125 MHz, CDCl3) δ 15.2, 28.0, 47.2, 51.9, 61.6,
64.6, 82.7, 117.7, 137.2, 152.24, 169.5; HRMS (ESI, þve) m/z calcd
for C18H31NO7Na 396.1998, found 396.2001 (M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
(pentan-3-yloxy)pent-4-enoate (17d). (E)-3-(Pentan-3-yloxy)allyl
2-(bis(tert-butoxycarbonyl)amino)acetate 16d (0.22 g, 0.55 mmol),
TMSCl (0.14 mL, 1.10 mmol), and LiHMDS (1.10 mL, 1.10 mmol)
were combined according to the general procedure. Treatment with
diazomethane and purification by flash chromatography (15:1 pet./
EtOAc þ 1% NEt3) afforded the title compound as a colorless oil
(E)-3-(4-Methoxyphenyloxy)allyl 2-Bis(tert-butoxycarbonyl)-
amino)acetate (16n). EDCi HCl (0.41 g, 2.14 mmol), triethylamine
3
7818 J. Org. Chem. Vol. 75, No. 22, 2010

Tellam and Carbery
JOCArticle
(0.10 g, 45%)FTIR (film/cm-1) υmax 2980.0, 2937.7, 2879.8, 1797.7,
1751.0, 1698.6; 1H NMR (500 MHz, d6-acetone) δ 0.84 (t, 6H, J =
7.6 Hz), 1.48-1.51 (m, 22H), 3.31 (quin, 1H, J = 5.9 Hz), 3.66 (s,
3H), 4.45 (dd, 1H, J = 9.2, 2.3 Hz), 4.84 (d, 1H, J = 9.2 Hz), 5.25
(dd, 1H, J= 10.5, 1.7 Hz), 5.39 (d, 1H, J= 17.1Hz), 5.94(ddd, 1H,
J = 17.1, 10.5, 6.8 Hz); 13C NMR (125 MHz, d6-acetone) δ 8.0, 9.2,
24.2, 25.7, 27.3, 51.2, 61.8, 75.0, 78.2, 82.0, 117.3, 138.5, 152.2, 168;
HRMS (ESI, þve) m/z calcd for C21H38NO7 416.2648, found
416.2625 (M þ H)þ.
(d,1H,J=11.6Hz),4.47(dd,1H,J= 9.1, 2.1 Hz), 4.61 (d, 1H, J=
11.6 Hz), 4.99 (d, 1H, J = 9.1 Hz), 5.38 (dd, 1H, J = 10.4, 1.4 Hz),
5.49 (dd, 1H, J = 17.3, 1.4 Hz), 5.89 (ddd, 1H, J = 17.3, 10.4,
7.0 Hz), 7.23-7.39 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 27.9,
52.0, 61.6, 70.5, 77.2, 82.9, 118.9, 127.3, 127.7, 128.1, 136.6, 138.3,
152.3, 169.3; HRMS (ESI, þve) m/z calcd for C23H33NO7Na
458.2155, found 458.2161 (M þ Na)þ.
(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-(4-methoxy-
benzyloxy)pent-4-enoate (17i). (E)-3-(4-Methoxybenzyloxy)allyl
2-(bis(tert-butoxycarbonyl)amino)acetate 16i (0.14 g, 0.31 mmol),
TMSCl (0.08 mL, 0.62 mmol), and LiHMDS (0.62 mL, 0.62 mmol)
were combined according to the general procedure. Treatment with
diazomethane and purification by flash chromatography (15:1 pet./
EtOAc þ 1% NEt3) afforded the title compound as a colorless oil
(0.06 g, 40%). FTIR (film/cm-1) υmax 3010.5, 2955.0, 1794.7,
1751.3, 1697.4; 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 18H), 3.70
(s, 3H), (s, 3H), 4.26 (d, 1H, J = 9.7 Hz), 4.44 (dd, 1H, J = 8.5,
6.9 Hz), 4.53 (d, 1H, J = 9.7 Hz), 4.95 (d, 1H, J = 8.5 Hz), 5.37 (dd,
1H, J = 10.4, 1.1 Hz), 5.47 (dd, 1H, J = 17.7, 1.1 Hz), 5.98 (ddd,
1H, J = 17.7, 10.4, 6.9 Hz), 6.84 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H,
J = 8.4 Hz); 13C NMR (125 MHz, CDCl3) δ 27.9, 51.9, 55.2, 61.7,
65.8, 70.2, 82.9, 113.6, 118.7, 129.3, 130.2, 130.5, 136.7, 152.2, 159.0,
169.3; HRMS (ESI, þve) m/z calcd for C24H35NO8Na 488.2260,
found 488.2243 (M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
neopentyloxypent-4-enoate (17e). (E)-3-(Neopentyloxy)allyl
2-(bis(tert-butoxycarbonyl)amino)acetate 16e (0.10 g, 0.25 mmol),
TMSCl (0.06 mL, 0.49 mmol), and LiHMDS (0.49 mL, 0.49 mmol)
were combined according to the general procedure. Treat-
ment with diazomethane and purification by flash chroma-
tography (15:1 pet./EtOAc þ 1% NEt3) afforded the title
compound as a colorless oil (0.08 g, 80%). FTIR (film/cm-1
υ
)
max 2979.6, 2955.0, 1796.3, 1749.2, 1698.4; 1H NMR (500 MHz,
CDCl3) δ 0.88 (s, 9H), 1.51 (s, 18H), 2.80 (d, 1H, J = 8.4 Hz),
3.23 (d, 1H, J = 8.4 Hz), 3.70 (s, 3H), 4.28 (dd, 1H,
J = 9.0, 2.4 Hz) 4.94 (d, 1H, J = 9.0 Hz), 5.30 (dd, 1H,
J = 10.3, 1.9 Hz), 5.43 (dt, 1H, J = 17.4, 1.9 Hz), 5.90 (ddd,
1H, J = 17.4, 10.3, 8.4 Hz); 13C NMR (125 MHz, CDCl3) δ
26.8, 28.1, 32.0, 51.9, 61.7, 77.3, 79.4, 82.8, 118.1, 137.6,
152.0, 169; HRMS (ESI, þve) m/z calcd for C21H38NO7
416.2648, found 416.2620 (M þ H)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-(2,6-
dichlorobenzyloxy)pent-4-enoate (17j). (E)-2,6-Dichlorobenzylox-
yallyl 2-(bis(tert-butoxycarbonyl)amino)acetate 16j (0.07 g,
0.15 mmol), TMSCl (0.04 mL, 0.30 mmol), and LiHMDS
(0.30 mL, 0.30 mmol) were combined according to the general
procedure. Treatment with diazomethane and purification by flash
chromatography (15:1 pet./EtOAc þ 1% NEt3) afforded the title
compound as a colorless oil (0.06 g, 78%). FTIR (film/cm-1) υmax
2979.9, 2933.7, 1796.6, 1749.3, 1697.7; 1H NMR (500 MHz, CDCl3)
δ 1.38 (s, 18H), 3.70 (s, 3H), 4.51-4.54 (m, 2H), 4.89 (dd, 2H, J =
36.6,9.6Hz),5.42(dd,1H,J= 10.7, 0.6 Hz), 5.61 (dq, 1H, J=17.4,
0.6Hz),6.05(ddd,1H,J= 17.4, 10.7, 6.9 Hz), 7.15 (dd, 1H, J=8.7,
0.9 Hz), 7.28 (d, 2H, J = 8.7 Hz); 13C NMR (125 MHz, CDCl3) δ
27.8, 51.9, 62.0, 65.3, 77.7, 82.6, 118.9, 128.1, 129.7, 133.7, 136.5,
137.1, 152.0, 169.1; HRMS (ESI, þve) m/z calcd for C23H32Cl2NO7
504.1556, found 504.1562 (M þ H)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-allyloxy-
pent-4-enoate(17f). (E)-3-Allyloxyallyl 2-(bis(tert-butoxycarbonyl)-
amino)acetate16f(0.12 g, 0.21 mmol), TMSCl (0.05 mL, 0.41 mmol),
and LiHMDS (0.41 mL, 0.41 mmol) were combined according to the
general procedure. Treatment with diazomethane and purification by
flash chromatography (10:1 pet./EtOAc þ 1% NEt3) afforded the
title compound as a colorless oil (0.08 g, 65%). FTIR (film/cm-1
)
υ
max 2981.7, 2935.6, 1747.9, 1698.3; 1H NMR (500 MHz, CDCl3) δ
1.51 (s, 18H), 3.70 (s, 3H), 3.81 (ddt, 1H J = 12.9, 5.7, 1.6 Hz), 4.07
(ddt, 1H, J= 12.9, 5.1, 1.6 Hz), 4.36-4.40 (m, 1H), 4.91 (d, 1H, J =
8.9 Hz), 5.12 (dq, 1H, J = 10.4, 1.6 Hz), 5.24 (dq, 1H, J = 17.1, 1.6
Hz), 5.32 (dq, 1H, J = 10.5, 1.0 Hz), 5.43 (dq, 1H, J = 17.2, 1.0 Hz),
5.80-5.88 (m, 1H), 5.94 (ddd, 1H, J= 17.2, 10.5, 6.8 Hz); 13CNMR
(125 MHz, CDCl3) δ:28.0, 51.9, 61.5, 69.6, 74.9, 82.9, 116.4, 118.4,
134.7, 136.7, 152.2, 169.4; HRMS (ESI, þve) m/z calcd for
C19H31NO7Na 408.1998, found 408.1976 (M þ Na)þ.
(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-((S)-1-
phenylethoxy)pent-4-enoate (17k). (S,E)-3-(1-Phenylethoxy)-
allyl 2-(bis(tert-butoxycarbonyl)amino)acetate 16k (0.24 g,
0.54 mmol), TMSCl (0.14 mL, 1.08 mmol), and LiHMDS
(1.08 mL, 1.08 mmol) were combined according to the general
procedure. Treatment with diazomethane and purification by
flash chromatography (15:1 pet./EtOAc þ 1% NEt3) afforded
the title compound as a colorless oil (0.10 g, 42%). [R]20D = -55
(c 1, CH2Cl2); FTIR (film/cm-1) υmax 2982.7, 1789.2, 1745.6,
+(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
(3-(trimethylsilyl)prop-2-ynyloxy)pent-4-enoate (17g). (E)-3-(Prop-
2-yn-1-yloxy)allyl 2-(bis(tert-butoxycarbonyl)amino)acetate 16g
(0.10 g, 0.30 mmol, 1 equiv), TMSCl (0.10 mL, 0.89 mmol, 3 equiv),
and LiHMDS (0.89 mL, 0.89 mmol, 3 equiv) were combined
according to the general procedure. Treatment with diazomethane
and purification by flash chromatography (10:1 pet./EtOAc þ 1%
NEt3) afforded the title compound as a colorless oil (0.10 g, 71%).
FTIR (film/cm-1) υmax 2979.7, 2867.7, 2182.2, 1794.0, 1749.6,
1700.7; 1H NMR (500 MHz, CDCl3) δ 0.16 (s, 9H), 1.52
(s, 18H), 3.70 (s, 3H), 4.05 (d, 1H, J = 15.6 Hz), 4.17 (d, 1H, J =
15.6 Hz), 4.51 (t, 1H, J = 8.0 Hz), 4.93 (d, 1H, J = 8.0 Hz), 5.36 (d,
1H, J = 10.6 Hz), 5.48 (d, 1H, J = 17.2 Hz), 5.86 (ddd, 1H, J =
17.2, 10.6, 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ -0.2, 28.0, 51.9,
56.6, 61.2, 76.5, 82.9, 90.9, 101.6, 119.8, 135.7, 152.1, 169.2; HRMS
(ESI, þve) m/z calcd for C22H37NO7SiNa 478.2237, found 478.2222
(M þ Na)þ.
1
1696.4; H NMR (500 MHz, CDCl3) major δ 1.38 (d, 3H, J =
6.3 Hz), 1.52 (s, 18H), 3.71 (s, 3H), 4.35 (d, 1H, J = 6.2 Hz), 4.56
(q, 1H, J = 6.3 Hz), 4.92-4.95 (m, 1H), 5.16-5.34 (m, 2H), 5.90
(ddd, 1H, J = 17.1, 10.8, 6.7 Hz), 7.21 -7.36 (m, 5H); minor δ
1.35 (d, 1H, J = 6.3 Hz), 1.52 (s, 18H), 3.64 (s, 3H),4.34 (d, 1H,
J = 6.2 Hz), 4.56 (q, 1H, J = 6.3 Hz), 4.92-4.95 (m, 1H),
5.37-5.42 (m, 2H), 5.97 (ddd, 1H, J = 13.8, 10.0, 6.7 Hz),
7.21-7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) δ Major δ
22.3, 28.0, 51.9, 61.8, 73.2, 75.2, 83.0, 118.0, 126.2, 126.7, 128.0,
128.5, 137.4, 152.3, 169.4; Minor δ 22.1, 27.9, 51.7, 62.2,73.3, 75.6,
82.8, 118.0, 126.1, 126.8, 128.1, 128.4, 137.5, 151.8, 168.4; HRMS
(ESI, þve) m/z calcd for C24H 35NO7Na, 472.2311 found 472.2293
(M þ Na)þ.
(()-(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-(ben-
zyloxy)pent-4-enoate (17h). (E)-3-Benzyloxyallyl 2-(bis(tert-butoxy-
carbonyl)amino)acetate 16h (0.09 g, 0.22 mmol), TMSCl (0.05 mL,
0.43 mmol), and LiHMDS (0.43 mL, 0.43 mmol) were combined
according to the general procedure. Treatment with diazomethane
and purification by flash chromatography (10:1 pet./EtOAc þ 1%
NEt3) afforded the title compound as a colorless oil (0.05 g,
55%). FTIR (film/cm-1) υmax 2980.7, 2890.6, 1750.9, 1700.6;
1H NMR (500 MHz, CDCl3) δ 1.45 (s, 18H), 3.71 (s, 3H), 4.33
(2R,3S)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-hydroxy-
pent-4-enoate (syn-18). To a stirred solution of 17k (0.08 g,
0.17 mmol) in methanol (20 mL) was added catalytic palladium
on carbon (0.02 g), and the mixture was stirred under 1 atm of
hydrogen for 16 h. The solution was filtered through Celite and
washed with another 20 mL of methanol, dried over Na2SO4,
J. Org. Chem. Vol. 75, No. 22, 2010 7819

Tellam and Carbery
JOCArticle
filtered, and concentrated in vacuo to afford the title compound
as a colorless oil (0.04 g, 73%). FTIR (film/cm-1) υmax 3428.0,
2980.0, 1737.2, 1693.7; 1H NMR (500 MHz, CDCl3) δ 1.00 (t,
3H, J = 7.6 Hz), 1.49-1.52 (m, 2H), 1.53 (s, 18H), 3.78 (s, 3H),
3.96 (d, 1H, J = 9.0 Hz), 4.11-4.17 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 10.2, 27.5, 27.9, 52.4, 62.4, 83.6, 1534.0, 169.7;
HRMS (ESI, þve) m/z calcd for C16H30NO7 348.2022, found
348.1986 (M þ H)þ.
(Z)-Methyl 3-Methoxyacrylate (Z-4a). To a stirred solution
of silver(I) trifluoromethanesulfonate (0.29 g, 1.12 mmol, 0.1
equiv) in methanol (15 mL) was added methyl propiolate (0.95 g,
11.2 mmol, 1 equiv). The solution was stirred at room tempera-
ture for 20 h and concentrated in vacuo. The solution was taken
up in chloroform, filtered through Celite, and concentrated to
afford the title compound as a pale brown oil (1.10 g, 71%)
FTIR (film/cm-1) υmax 2990.0, 2950.5, 2877.1, 2833.7, 1709.4,
1646.2, 1626.2; 1H NMR (500 MHz, CDCl3) δ 3.65 (s, 3H), 3.84
(2R,3S)-Methyl 2-(tert-Butoxycarbonyl)amino)-3-hydroxy-
pentanoate (syn-19).45. To a stirred solution of syn-18 (0.07 g,
0.19 mmol, 1 equiv) in CH2Cl2 (5 mL) was added TFA (0.03 mL,
0.38 mmol, 2 equiv) at 0 °C. The mixture was stirred for 30 min
before being concentrated in vacuo. The residue was taken up in
saturated sodium bicarbonate solution (10 mL) and extracted with
EtOAc (4 ꢀ 20 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. Purification was achieved by flash chromatography (2:1
(s, 3H), 4.82 (d, 1H, J = 7.1 Hz), 6.43 (d, 1H, J = 7.1 Hz); 13
C
NMR (125 MHz, CDCl3) δ 50.8, 62.5, 95.9, 160.1, 165.6;
HRMS (ESI, þve) m/z calcd for C5H8O3Na 139.0371, found
139.0378 (M þ Na)þ.
(Z)-3-(Methoxy)prop-2-enol (Z-5a). (Z)-Methyl 3-(methoxy)-
acrylate Z-4a (0.51 g, 4.39 mmol) was reduced according to
general procedure to afford the title compound as a colorless oil
(0.13 g, 33%). FTIR (film/cm-1) υmax 3337.8, 3046.0, 2936.2,
2859.6, 1662.9; 1H NMR (300 MHz, d6-acetone) δ 1.85 (br, 1H),
3.63 (s, 3H), 4.16 (dd, 2H, J = 6.9, 1.1 Hz), 4.64 (q, 1H, J =
6.9 Hz), 6.02 (dt, 1H, J = 6.3, 1.2 Hz); 13C NMR (75 MHz, d6-
acetone) δ 56.9, 60.6, 106.3, 149.2.
pet./EtOAc) to afford the title compound as a colorless oil (0.04 g,
1
78%). [R]20 = þ3.2 (c 0.85, EtOH abs); H NMR (500 MHz,
D
CDCl3) δ 0.94 (t, 3H, J = 7.0 Hz), 1.42 (s, 9H), 1.51-1.55 (m, 2H),
3.71 (s, 3H), 3.97-3.99 (m, 1H), 4.19 (br, 1H), 4.23 (d, 1H, J =
9.0 Hz), 5.72 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 10.0, 27.8,
28.3, 52.2, 58.3, 73.7, 80.1, 155.5, 173.7.
(Z)-3-Methoxyallyl2-(Bis(tert-butoxycarbonyl)amino)acetate
(Z-10a). EDCi HCl (1.06 g, 5.45 mmol), triethylamine
(Z)-tert-Butyl (2-Methoxy-2-((trimethylsilyl)oxy)vinyl)(methyl)-
carbamate (21a). To a stirred solution of methyl 2-((tert-
butoxycarbonyl)(methyl)amino)acetate (0.06 g, 0.26 mmol, 1 equiv)
in THF (0.5 mL) at -95 °C was added TMSCl (0.06 mL, 0.52
mmol, 2 equiv), and the mixture was stirred for 10 min.
LiHMDS (1 M in THF, 0.52 mL, 0.52 mmol, 2 equiv) was
added via syringe pump, and then the solution was allowed to
warm to room temperature. Rapid concentration in vacuo
afforded the title compound as a yellow oil (0.05 g, 81%, Z/E
2:1, 2:1 rotamers). FTIR (film/cm-1) υmax 2955.1, 1756.9, 1698.7;
1H NMR (400 MHz, CDCl3) Z δ 0.22 and 0.26 (2s, 9H), 1.49 and
1.51 (2s, 9H), 2.99 and 3.00 (2s, 3H), 3.58 and 3.60 (2s, 3H), 4.88
and 4.93 (2br, 1H); E δ 0.22 and 0.26 (2s, 9H) 1.49 and 1.51 (2s,
9H), 2.99 and 3.00 (2s, 3H), 3.58 and 3.60 (2s, 3H), 4.99 and 5.08
(2br, 1H); 13C NMR (100 MHz, CDCl3) Z δ 5.5, 28.5, 55.2, 87.7,
164.1, 179.3; HRMS (ESI, þve) m/z calcd for C12H 26NO4Si
276.1631, found 276.1627 (M þ H)þ.
3
(0.76 mL, 5.45 mmol), 2-(bis(tert-butoxycarbonyl)amido)-
acetic acid (1.52 g, 5.45 mmol), catalytic DMAP, and (Z)-
3-methoxyprop-2-enol Z-5a (0.24 g, 2.72 mmol) were com-
bined according to general procedure to afford a yellow oil.
Purification by flash chromatography (Al2O, 15:1 pet./
EtOAc) afforded the title compound as colorless oil (0.28 g,
30%). FTIR (film/cm-1) υmax 2979.6, 2937.6, 1799.3, 1756.9,
1736.0, 1697.7, 1666.7; 1H NMR (500 MHz, d6-acetone) δ
1.48 (s, 18H), 3.65 (s, 3H), 4.28 (s, 2H), 4.54-4.58 (m, 1H),
4.67 (dd, 2H, J = 7.8, 0.9 Hz), 6.21 (dt, 1H, J = 6.3, 1.1 Hz);
13C NMR (125 MHz, d6-acetone) δ 32.4, 52.2, 63.3, 64.6,
87.3, 104.6, 156.0, 157.0, 174.1; HRMS (ESI, þve) m/z calcd
for C16H27NO7Na 368.1685, found 368.1684 (M þ Na)þ.
(()-(2R,3R)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)-3-
methoxypent-4-enoate (anti-17a). (Z)-3-Methoxyallyl 2-(bis-
(tert-butoxycarbonyl)amino)acetate Z-10a (0.10 g, 0.29 mmol),
TMSCl (0.07 mL, 0.58 mmol), and LiHMDS (0.58 mL, 0.58 mmol)
were combined according to general procedure. Treatment
with diazomethane and purification by flash chromatography
(15:1 pet./EtOAc þ 1% NEt3) afforded the title compound as a
colorless oil (0.06 g, 55%, dr 1.5:1). A small fraction of the major
anti product was isolated for identification. FTIR (film/cm-1) υmax
2983.1, 2932.2, 1788.9, 1745.9, 1695.6; 1H NMR (500 MHz,
CDCl3) δ 1.49 (s, 18H), 3.37 (s, 3H), 3.76 (s, 3H), 4.28 (t, 1H,
J = 8.2 Hz), 4.86 (d, 1H, J = 8.2 Hz), 5.25-5.32 (m, 2H), 5.61
(ddd, 1H, J = 17.9, 9.5, 1.6 Hz); 13C NMR (125 MHz, CDCl3)
δ 28.0, 52.2, 56.5, 60.5, 82.1, 83.3, 120.1, 133.8, 151.6, 170.0;
HRMS (ESI, þve) m/z calcd for C17H30NO7 360.2022, found
360.2032 (M þ H)þ.
(Z)-2-(2-Methoxy-2-((trimethylsilyl)oxy)vinyl)isoindoline-1,3-
dione (21b). To a stirred solution of methyl 2-(1,3-dioxoisoindo-
lin-2-yl)acetate (0.05 g, 0.24 mmol, 1 equiv) in THF (0.5 mL) at
-95 °C was added TMSCl (0.06 mL, 0.48 mmol, 2 equiv), and
the mixture was stirred for 10 min. LiHMDS (1 M in THF, 0.48
mL, 0.48 mmol, 2 equiv) was added via syringe pump, and then
the solution was allowed to warm to room temperature. Rapid
concentration in vacuo afforded the title compound as a yellow
solid (0.06 g, 87%, Z/E 12:1). FTIR (film/cm-1) υmax 3119.3,
1
3024.9, 2977.4, 1780.6, 1719.1, 1669.9, 1659.7; H NMR (400
MHz, CDCl3) Z δ 0.22 (s, 9H), 3.80 (s, 3H), 4.69 (s, 1H),
7.73-7.75 (m, 2H), 7.88-7.90 (m, 2H); E δ 0.22 (s, 9H), 3.81
(s, 3H), 4.74 (s, 1H), 7.73-7.75 (m, 2H), 7.88-7.90 (m, 2H); 13C
NMR (100 MHz, CDCl3) Z δ 5.5, 55.5, 71.8, 123.1, 132.4, 133.8,
159.6, 168.1; HRMS (ESI, þve) m/z calcd for C14H17NO4SiNa
314.0825, found 314.0837 (M þ Na)þ.
(()-(2R,3S)-Methyl 2-((tert-Butoxycarbonyl)amino)-3-methoxy-
pent-4-enoate (syn-22). To a stirred solution of (()-(2R,3S)-
methyl 2-(bis(tertbutoxycarbonyl)amino)-3-methoxypent-4-
enoate (0.07 g, 0.19 mmol, 1 equiv) in CH2Cl2 (5 mL) was added
TFA (0.03 mL, 0.38 mmol, 2 equiv) at 0 °C. The mixture was
stirred for 30 min before concentratinmg in vacuo. The residue
was taken up in saturated sodium bicarbonate solution (10 mL)
and extracted with EtOAc (4 ꢀ 20 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. Purification was achieved
by flash chromatography (6:1 pet./EtOAc) to afford the title
(Z)-Bis(tert-butyl (2-methoxy-2-((trimethylsilyl)oxy)vinyl))car-
bamate (21c). To a stirred solution of methyl 2-(bis(tert-butoxycar-
bonyl) amino)acetate (0.06 g, 0.22 mmol, 1 equiv) in THF (0.5 mL)
at -78 °C was added TMSCl (0.06 mL, 0.44 mmol, 2 equiv), and the
mixture was stirred for 10 min. LiHMDS (1 M in THF, 0.44 mL,
0.44 mmol, 2 equiv) was added via syringe pump, and then the
solution was allowed to warm to room temperature. Rapid con-
centration in vacuo afforded the title compound as a yellow oil (0.05 g,
51%, Z/E> 25:1). FTIR (film/cm-1) υmax 2980.5, 2900.9, 1736.9,
1739.8, 1700.0; 1H NMR (400 MHz, CDCl3) δ 0.19 (s, 9H), 1.47 (s,
18H), 3.72 (s, 3H), 4.33 (s, 1H);13C NMR (100 MHz, CDCl3) δ 5.6,
28.1, 55.2, 81.7, 156.9, 168.1, 178.4; HRMS (ESI, þve) m/z calcd for
C16H31NO6SiNa 384.1818, found 384.1822 (M þ Na)þ.
compound as a colorless oil (0.04 g, 78%). FTIR (film/cm-1
)
1
υmax 3372.0, 2980.6, 2940.1, 1756.0, 1718.8, 1502.9; H NMR
(500 MHz, CDCl3) δ 1.45 (s, 9H), 3.26 (s, 3H), 3.78 (s, 3H), 4.12
(d, 1H, J = 6.8 Hz), 4.38 (dd, 1H, J = 9.9, 2.8 Hz), 5.24 (d, 1H,
J = 9.9 Hz), 5.34-5.39 (m, 2H), 5.75 (ddd, 1H, J = 17.6, 9.9,
7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 28.3, 52.4, 56.9, 57.5,
7820 J. Org. Chem. Vol. 75, No. 22, 2010

Tellam and Carbery
JOCArticle
79.9, 82.0, 119.6, 133.8, 155.9, 171.1; HRMS (ESI, þve) m/z
calcd for C12H21NO5Na 282.1317, found 282.1304 (M þ Na)þ.
(()-(2S,3S)-2-Bis(tert-butoxycarbonyl)amino-3-methoxypent-
4-en-1-ol (syn-23). To a stirred solution of lithium aluminum hy-
dride (0.01 g, 0.26 mmol, 2 equiv) in ether (7 mL) at -78 °C was
added a solution of (()-(2R,3S)-methyl 2-(bis(tert-butoxycarbonyl)-
amino)-3-methoxypent-4-enoate (0.05 g, 0.13 mmol) in ether (3 mL).
The mixture was stirred at -78 °C for 5 h before being quenched by
the addition of EtOAc and then poured onto ice-cold saturated
Rochelle salt solution (100 mL) followed by the addition of further
EtOAc (100 mL). The biphasic mixture was vigorously stirred at
0 °C for 2 h before being separated and extracted with EtOAc (3 ꢀ
10 mL). The organics were dried over Na2SO4, filtered, and concen-
trated in vacuo. Purification was achieved by flash chromatography
(pet./EtOAc 10:1) to afford the title compound as a colorless oil
(0.03 g, 60%, 2:1 rotamers). FTIR (film/cm-1) υmax 3338.7, 2967.3,
2928.0, 2882.8, 1705.4, 1596.4; 1H NMR (500 MHz, CDCl3) δ 1.49
and 1.56 (2s, 18H), 3.29-3.32 (m, 1H), 3.34 (s, 3H), 3.72 (t, 1H, J =
3.2 Hz), 3.94 (t, 1H, J = 7.9 Hz), 4.14 (dd, 1H, J = 7.9, 3.2 Hz), 4.67
(br, 1H), 5.27-5.34 (m, 2H), 5.76 (ddd, 1H, J = 17.5, 9.9, 7.2 Hz);
13C NMR (125 MHz, CDCl3) δ 26.8, 28.4 ( ꢀ 2), 57.0, 57.3, 79.4,
80.5, 119.5, 127.5, 127.6, 133.9, 135.8, 135.9, 152.8; HRMS (ESI, þve)
m/z calcd for C16H30NO6Na 332.2073, found 332.2064 (M þ H)þ.
(Z)-Methyl 2-(Bis(tert-butoxycarbonyl)amino)penta-2,4-di-
enoate (24). FTIR (film/cm-1) υmax 2914.3, 2851.5, 1796.6, 1727.8,
1644.8; 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 18H), 3.81 (s, 3H),
5.58 (d, 1H, J = 10.8 Hz), 5.71 (d, 1H, J = 17.3 Hz), 6.50 (dt, 1H,
J = 17.3, 10.8 Hz), 7.17 (d, 1H, J = 10.8 Hz); 13C NMR (125 MHz,
CDCl3) δ 27.8, 52.3, 83.0, 126.9, 128.0, 130.2, 136.8, 150.4, 165.0;
HRMS (ESI, þve) m/z calcd for C16H25NO6Na 350.1580, found
350.1578 (M þ Na)þ.
Acknowledgment. We thank the EPSRC and University
of Bath for studentship funding (J.P.T.).
Supporting Information Available: Full experimental details
and NMR spectra of novel compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 22, 2010 7821