Stereocontrolled synthesis of quaternary β,γ-unsaturated amino acids: Chain extension of D- and L-α-(2-tributylstannyl)vinyl amino acids

Article abstract of DOI:10.1016/S0040-4020(01)00499-9

A pair of diastereomeric (4S,5S)- and (4S,5R)-4-methoxycarbonyl-5-phenylselenomethyl-2-phenyl oxazolines, derived from L-vinylglycine, serve as precursors to protected, quaternary, L- and D-α-(2-tributylstannyl)vinyl amino acids, respectively, in three st

Full text of DOI:10.1016/S0040-4020(01)00499-9

TETRAHEDRON
Pergamon
Tetrahedron 57&2001) 6329±6343
Stereocontrolled synthesis of quaternary b,g-unsaturated amino
acids: chain extension of d- and l-a-ꢀ2-tributylstannyl)vinyl
amino acids
David B. Berkowitz,p Esmort Chisowa and Jill M. McFadden
Department of Chemistry, University of Nebraska, Lincoln, NE 68588-0304, USA
Received 2 March 2001; revised 27March 2001; accepted 28 March 2001
AbstractÐA pair of diastereomeric &4S,5S)- and &4S,5R)-4-methoxycarbonyl-5-phenylselenomethyl-2-phenyl oxazolines, derived from
l-vinylglycine, serve as precursors to protected, quaternary, l- and d-a-&2-tributylstannyl)vinyl amino acids, respectively, in three steps {&i)
alkylative side chain installation, &ii) eliminative ring-opening and &iii) vinyl selenide to vinyl stannane interconversion}. The title
compounds may be protodestannylated to the corresponding free, quaternary l- and d-vinyl amino acids. Alternatively, the 2-stannylvinyl
a-branch &or the derivative 2-iodovinyl branch) may be exploited to access novel quaternary, l- and d-b,g-unsaturated amino acids via a
range of transition metal-mediated cross-coupling reactions. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Nature produces a number of b,g-unsaturated amino acids,
generally bearing an a-hydrogen.1 The simplest member of
this family, a-vinylglycine &1), has been isolated from
mushroom sources.2 Such amino acids are potential
mechanism-based inactivators &MBIs) for enzymes that
process amino acids by ®rst removing the a-proton, includ-
ing racemases, transaminases, and b- and g-elimination and
replacement enzymes. Indeed, vinylglycine is known to
inactivate transaminases for l-aspartate, l-alanine, l-serine
and d-alanine,3a±e as well as cysteine sul®nate decarboxy-
Scheme 1. The vinyl trigger for mechanism-based inactivation of PLP
enzymes.
lase.4 Incorporation of d-vinylglycine into an appropriate
peptide leads to inhibition of peptidylglycine a-hydroxylat-
ing monooxygenase &Scheme 1).5
potential alternative to &methadone) replacement therapy
in the treatment of substance addiction.10
Another member of this family, APPA &2-amino-5-phos-
phono-3-pentenoic acid &2); the b,g-unsaturated phos-
If one wishes to apply a similar vinyl-triggering strategy
to the mechanism-based inactivation of amino acid
decarboxylase &AADC) enzymes, quaternary b,g-unsatu-
rated amino acids become attractive targets. That is, the
usual AA side chain functional group is retained, to direct
the inhibitor to the active site of interest, and an a-decar-
boxylation event, rather than an a-deprotonation event, is
expected to conjugate the otherwise unreactive C±C double
bond with the quinonoid intermediate along the PLP-
enzyme reaction coordinate.11 Adding to the value of this
family of higher12 a-vinyl AA0s, we have found that they
conveniently serve as precursors to previously unexplored
classes of potential AADC MBIs, including a-oxiranyl,13
a-&2E-chloro)vinyl,14 a-&1-chloro)vinyl14 and a-&2Z-¯uoro)-
vinyl15 amino acids &Scheme 2).
phonate analogue of homoserine phosphate), inactivates
the b-elimination enzyme, threonine synthase.6 E-APPA
inhibits the g-replacement enzyme, cystathionine
g-synthase.7 But perhaps the most well-studied example
of an amino acid bearing unsaturation b- and g- to the
amino group that acts as a mechanism-based inhibitor is
vigabatrin &3, g-vinyl GABA). Vigabatrin inactivates
GABA transaminase,8 thereby raising brain GABA levels.
This drug has seen extensive clinical use as an anti-
epileptic9 and, quite recently, has shown promise as a
Keywords: self regeneration of stereocenters; b,g-unsaturated amino acids;
vinyl selenides; vinyl stannanes; chain extension.
p
Corresponding author. Tel.: 1402-472-2738; fax: 1402-472-9402;
e-mail: dbb@unlserve.unl.edu
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&01)00499-9

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D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
Scheme 2. Novel quaternary AA0s from a-vinyl AA0s.
The divergency of this approach is attractive from a tactical
point of view, both in terms of overall synthetic ef®ciency
and in terms of stereochemical control. That is, given the
stability of these quaternary AA0s to racemization, control
of absolute stereochemistry in the construction of the parent
higher a-vinyl amino acids should translate into stereo-
chemical control for all such derivative classes, as well.
The ability to generate a variety of a-branched AA0s from
parent a-vinyl or a-stannylvinyl AA0s also has implications
for unnatural amino acid mutagenesis16 and for combi-
natorial chemistry. In the latter case, libraries of a-amino
acids are often used and library diversity is a variable of
great import.17 Indeed, it may be advantageous to broaden
the number and type of quaternary AA0s included in such
AA libraries, as a-branched AA0s, including those bearing
unsaturation,18 tend to promote peptidyl secondary struc-
ture, particularly a-helical, and 310-helical motifs.19 At the
same time, these unnatural AA0s often confer resistance to
proteolysis upon their derivative peptides.20 In fact, of late,
great success has been achieved with a-branched AA0s for
the design of short peptides &i) that fold into helical struc-
tures in aqueous solution,19 &ii) that bind to receptors,20a,21 or
&iii) that catalyze chemical reactions.22
for the stereocontrolled construction of quaternary b,g-
unsaturated AA0s. Among these the title a-&2-tributyl-
stannyl)vinyl AA0s are especially attractive, as these are
available in either d- or l-form, and lead either to
unsubstituted a-vinyl AA0s &protodestannylation) or to
more complex, chain-extended congeners, as desired.
2.1. Substituted alkenylglycines
As noted before, the simplest b,g-unsaturated vinyl AA is
vinylglycine itself, for which a good number of asymmetric
syntheses have been developed.24 Derivatives of vinyl-
glycine in which the double bond bears one or more sub-
stituents, but in which the a-proton is retained, will be
termed alkenylglycines here.
Williams and coworkers described a nice route to such
compounds that passes through an interesting class of b,g-
alkynylglycines.25 The same 4,5-diphenyl-1,4-oxazin-2-one
template that serves as the basis of Williams' chiral glycine
enolate equivalent, provides for a chiral electrophilic
glycine equivalent here. Condensation of 4 with trialkyl-
stannylalkynes leads to the protected a-alkynyl AA0s 5,
presumably via the intermediacy of the corresponding
a-iminium ion &Scheme 3).25a The alkyne is then reduced
under dissolving metal conditions, with Na0-NH3&l) giving
the higher chemical yields, but with Li0-NH3&l) giving better
optical yields.
2. Enantioselective synthesis of b,g-unsaturated AA0s
For most of the applications enumerated in Section 1,
enantiomerically enriched a-branched amino acids of
known handedness are preferable.23 This article will focus
on the asymmetric synthesis of AA0s bearing a b,g-
unsaturation. At the outset, we wish to highlight several
particularly elegant enantiocontrolled syntheses of b,g-
unsaturated AA0s for systems in which an a-proton is
present &substituted alkenylglycines). From there, the
discussion will move into a summary of available methods
O'Donnell has developed the related electrophilic glycine
equivalent, 7. This system is cleverly out®tted with the
benzophenone imine protecting group on nitrogen, allowing
for Pd-mediated allylic substitution at the a-carbon. Trans-
metallation can be effected with in situ-generated vinyl-
aluminum reagents, thereby providing alkenylglycines
Scheme 3.

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6331
Scheme 4.
directly.26a This cross-coupling chemistry was carried out in
racemic fashion initially, but more recent developments
suggest that enantioselective variants may be achievable.
Thus, the O'Donnell group has successfully performed
allylic substitution upon imine-protected glycine a-acetates,
using a BINAP ligand as the source of chirality and potas-
sium malonate as the nucleophile &Scheme 4).26b
peptidic ligands for titanium, they identi®ed the catalyst
derived from tripeptide 16 as particularly effective
&Scheme 6).28,29
2.2. Quaternary b,g-unsaturated AA0s
There are fewer methods available for the stereocontrolled
synthesis of quaternary b,g-unsaturated AA0s. These are
more densely functionalized targets with the a-carbon
directly bearing amino, carboxyl and alkenyl functional
groups, in addition to the usual &and often functionalized)
side chain R group itself. Among the earliest entries into this
Petasis has disclosed a nicely convergent, three component
Mannich reaction which produces an allylic amine from the
reaction of an alkenyl boronate with an amine and an
aldehyde or electrophilic ketone. When glyoxylic acid is
condensed with boronate 13 through the agency of
l-phenylglycinol, protected d-a-cinnamylglycine is
obtained in excellent ee &Scheme 5).27
È
AA class is the work of Schollkopf in which bis-lactim
ether, 18, serves as a chiral alanine enolate equivalent.30
Here the chiral element is essentially an l-valine auxiliary
built into 18. Condensation with acetone or acetophenone
proceeds with high 1,4-stereoinduction. Subsequent
dehydration and methanolysis produces methyl esters of
substituted l-vinylalanine derivatives &20) &Scheme 7).
All of the approaches discussed heretofore involve discon-
nections at the Ca±R bond, wherein the unsaturated side
chain is coupled with an electrophilic glycine equivalent.
By contrast, Snapper and Hoveyda target alkenylglycines
by disconnecting at the Ca±CO2H bond. They have
optimized the Ti&IV)-mediated 1,2-addition of cyanide to
a,b-unsaturated iminium ions. Screening a library of chiral
Seebach's classic synthesis of higher vinyl AA0s served as
part and parcel of a programmatic thrust to establish the
principle of `self-regeneration of stereocenters' [SRS;
Scheme 5.
Scheme 6.

6332
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
Scheme 7.
Scheme 8. `Self-regeneration of stereocenters'.
previously referred to as SRC or self-regeneration &or repro-
duction) of chirality] in asymmetric synthesis. In this case,
the a-stereocenter originally present in methionine is used
to induce a second stereocenter at the N,X-acetal carbon in a
cyclic oxazolidinone or imidazolidinone derivative
&Scheme 8). Upon subsequent generation of the enolate,
the a-stereocenter is temporarily removed, and then
reinstalled via alkylative introduction of the side chain.
The &methyl)thioethyl methionine side chain is used to
install the requisite unsaturation, via oxidation and
pyrolysis, either before or after the alkylation event. This
chemistry has been used to access enantiomerically
enriched a-vinyl AA0s bearing the alanine,31a butyrine,31a
phenylalanine,31b and &p-hydroxy)phenylglycine31c side
chains.
Very recently, Avenoza and Cativiela and their associates
have reported an approach to a-vinylalanine that shares an
`end game' methylenation with the Hegedus route.33
However, in this case, the requisite a-formylalanine equiva-
lent is generated by entirely different chemistry. Namely,
absolute stereochemistry is set via a Sharpless±Katsuki
asymmetric epoxidation &SAE)34 of allylic alcohol 31.
Imidate formation and 5-exo cyclization is then performed
under Et2AlCl-promotion according to the procedure of
Hatakeyama.35 The a-amino group is thereby installed
with inversion of con®guration. Protecting group inter-
change and Swern oxidation set the stage for Wittig methyl-
enation, leading to the targeted quaternary b,g-unsaturated
amino acid &Scheme 10).36
As part of a program directed at developing new AADC
inhibitors, we have been engaged in a multi-pronged
approach toward quaternary, a-vinyl amino acids, with
three principal synthetic aims: &i) control of absolute stereo-
chemistry; &ii) introduction of biologically relevant AA side
chains; and &iii) transformation of the parent a-vinyl AA0s
into potential second generation inhibitor families &Scheme
2). Our initial approach was to formally a-vinylate an AA-
derived dianion. These dianions are generated with two
equivalents of base from N-benzoyl amino acid methyl
esters. Ethylene oxide serves as an economical `vinyl cation
More recently, Hegedus and coworkers have combined their
chromium carbene complex-mediated b-lactam synthesis
with Ojima's diastereoselective lactam enolate alkylation
methodology, resulting in a novel entry into a-vinylalanine
&Scheme 9).32 Chiral b-lactam, 28, may be regarded as a
masked a-formylglycine equivalent. Alkylation of the
potassium enolate thereof with methyl iodide proceeds
with high diastereofacial selectivity. Unravelling of the
formyl group, followed by methylenation and hydrolytic
deprotection yields l-a-vinylalanine.
Scheme 9. Chiral b-lactam approach.

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6333
Scheme 10.
Scheme 11. Formal vinylation of amino acidsÐkinetic enzymatic resolution.
equivalent' &Scheme 11).37 a-Alkylation predominates and
yields are improved in the presence of TMEDA. Interest-
ingly, Michelle Pedersen &Morris) found that, in addition to
simple alkyl side chains &i.e. Ala, Phe, Val), with appro-
priate protection, heteroatom-functionalized side chains
&DOPA, Lys, His, Orn, HomoSer) may be carried into
these dianions, without deleterious effects. Given that
these alkylations proceed smoothly with a modest electro-
phile such as ethylene oxide, we expect this dianion
chemistry to be of utility for the generation of other
quaternary AA analogues.
lithium. It would then remain only to control the facial
selectivity of the alkylation reaction to achieve a high
level of stereoselection. We envisioned doing so in an
acyclic fashion, whereby the aryl p-system of an aryl-
menthyl type ester auxiliary would shield one face of the
enolate. In fact, these goals were reduced to practice in the
alkylation of the vinylglycine-derived dianionic dienolate
41, which is out®tted with d'Angelo's 8-&b-naphthyl)-
menthyl auxiliary.39 Our working model for the reactive
conformation of this dienolate is provided in Scheme 12.
Through the diligent work of Jill McFadden, it was
established that the alkylation of 41 with appropriate
electrophiles provides a convergent route to a range of
important l-a-vinyl AA0s, including the AADC inhibitors
a-vinylornithine, a-vinyl-m-tyrosine and a-vinyllysine.40 If
desired, the chiral auxiliary may be recovered and recycled
via a modi®cation of Gassman's `anhydrous hydroxide'
protocol for the cleavage of hindered esters.41
The resulting a-substituted homoserine lactones 37 undergo
selective ring opening at the alkyl carbon±oxygen bond
with a new, non-reducing phenylselenolate equivalent
developed in the work.37b Oxidation and selenoxide pyroly-
sis then serves to install the a-vinyl group. At this stage,
global deprotection &6N HCl re¯ux) provides the racemic
free, a-vinyl amino acids. Alternatively, James Pumphrey,
an undergraduate co-worker, noted that if one ®rst reduces
the esters to the corresponding N-benzoyl a-vinyl amino
alcohols, one can partially resolve these by enzymatic acyl-
ation. Chemical deacylation of the enzymatic product then
permits a second round of resolution. In this way, enantio-
merically enriched l-a-vinylalanine and l-a-vinylphenyl-
alanine may be obtained.38
Parallel to this study, we had begun to explore a comple-
mentary approach to the targeted higher vinyl AA0s, also
emanating from vinylglycine &Scheme 13).42 Here, rather
than recruit chiral information from an external auxiliary,
the chiral information inherent at Ca in l-vinylglycine
would be parlayed divergently into enantiomeric directing
centers at Cb. An episelenonium ion-mediated 5-exo trig
cyclization serves to mask the double bond and, in so
doing, install the b-phenylselenomethyl directing group.
Because the diastereomeric oxazolines 44t and 44c are
separable by standard silica gel chromatography, yet yield
mirror image enolates upon a-deprotonation, this may be
regarded as a sort of divergent SRS approach. Oxazoline 44t
In light of the favorable reactivity of the aforementioned
AA-derived dianions, it became attractive to investigate
asymmetric versions of that chemistry. After all, it seemed
likely that enolate geometry in these systems could be
controlled via benzamidate nitrogen chelation to the enolate

6334
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
Scheme 12. Acyclic stereocontrol: alkylation of chiral vinylglycine-based dienolates.
serves as a synthon for higher l-a-vinyl AA0s, while 44c
conveniently provides an entry into the d-series.
AA0s. Alternatively, one can exploit the g-stannyl group
to position-speci®cally introduce a deuterium label by
employing aqueous DCl &Scheme 14). In the case of l-a-
&2E-tributylstannyl)vinylphenylalanine, this transformation
proceeds cleanly and stereospeci®cally, with retention of
con®guration, as expected. Presumably, the same approach
would provide a valuable means to introduce a tritium label
into members of this AADC suicide substrate family for
enzyme labelling studies.
Treatment of the alkylation products 45 with KO-t-Bu
effectively unmasks the b,g-unsaturation via eliminative
oxazoline ring opening with release of an amidate leaving
group. The resulting a-&2E-phenylseleno)vinyl AA0s &46)
are of interest in their own right, both from a chemical
and spectroscopic &77Se provides a potential NMR reporter
group) point of view. However, they served here as the
platform for the discovery of a new entry into vinyl
stannanes. Namely, exposure of these vinyl selenides to
trialkyltin radical leads to an ef®cient substitution reaction.
A set of heretofore unexplored,43 a-&2E-trialkylstannyl)-
vinyl AA0s &47) results, and these may be obtained in high
ee, and in either enantiomeric form, as desired. This simple
substitution reaction had not been seen before and certainly
merits further investigation. However, it is our purpose here
to explore the chain extension chemistry of this novel class
of quaternary, g-stannyl-b,g-unsaturated AA0s.44
The same stannylvinyl AA, l-47a, was used to explore the
possibility for extending the a-branch via Pd0-mediated
couplings of the Stille variety.45 As is illustrated in Scheme
15, no signi®cant complications were encountered with
these quaternary AA scaffolds. Successful chain extensions
were achieved with a range of electrophiles, from an aryl
halide, to an acid chloride, to allylic and benzylic halides. In
the latter case, the &Ph3P)2ClPdBn complex, originally
reported by Stille for couplings with benzylic substrates,46
also proved successful here.
If desired, protodestannylation may be carried out upon
vinylstannanes 47, concommitant with global acidolytic
deprotection &Scheme 13), to provide the parent a-vinyl
We were also pleased to ®nd that the a-&2E-stannyl)vinyl
branch in these densely functionalized AA0s may be con-
veniently transformed into an a-&2E-iodo)vinyl branch,47 in

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6335
Scheme 13. A new SRS approach: access to d- or l-stannylvinyl AA0s.
nearly quantitative yield, upon treatment with I2 &Scheme
16). This permitted us to explore transition metal catalyzed
chain extension reactions of the opposite sense of polarity.
That is, rather than enter the catalytic cycle `late' at the
stage of the transmetallation, these new b,g-unsaturated
amino acids presumably enter the cycle `early' via oxidative
addition to a PdL2 or [PdL2X]- species.48
variety of organozinc reagents available, and the functional
group tolerance of such reagents, this opens up an important
new manifold for chain extension. Finally, using the iodo-
vinyl AA derived from d-serine &d-53c), good results were
also obtained for an sp±sp2 coupling of the Sonagashira
variety.51
In a demonstration of proof of principle, the dienyl-AA 54
successfully participated in a Diels±Alder reaction with
dimethyl acetylenedicarboxylate &DMAD) as dienophile
&Scheme 18). There is particular signi®cance to this result
as this cycloaddition is expected to proceed via a sterically
demanding transition state. Namely, two C±C bonds are
formed along the a-branch, and one of these forms directly
adjacent to the quaternary a-center. A bromine addition/
HBr elimination sequence then allows one to aromatize
the newly formed 6-membered ring. Overall, this chemistry
provides a route into an interesting family of quaternary,
arylglycine derivatives bearing the natural AA side chains.
Pleasingly, protected a-&2E-iodo)vinyl amino acids, 53,
derived from l- and d-phenylalanine and d-serine could
be successfully deployed in such Pd0-mediated C±C bond-
forming reactions &Scheme 17). Employing vinyltributyl-
stannane with l-53a, and Pd2dba3 as Pd0 source, one obtains
54, in which a 1,3-butadienyl branch now formally replaces
the a-proton. Such quaternary amino acids hold potential as
substrates for [4p12p]-cycloadditions &vide infra). Alter-
natively, subjecting the antipode d-53a to a Negishi-type
reaction49 with a 1-styrenylzinc reagent derived from
Rieke Znp50 leads to ef®cient cross coupling. Given the
Lastly, as a streamlined alternative to the Sonagashira route
for the construction of g,d-sp2±sp bond, we have been able
to apply Shen's recently reported variant52 of the Stille
reaction to this system. In this reaction, 1,1-dibromoalkenes
couple with alkenylstannanes, to give enynes, particularly in
polar solvents and in the presence of electron rich ligands.
Under these conditions, the quaternary, a-&2E-stannyl)vinyl
Scheme 14. Facile stereo speci®c introduction of a deuterium label.

6336
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
Scheme 15. Stille couplings of the quaternary, stannylvinyl AA0s.
AA, d-47a, couples with geminal dibromomethylene
partner 59 to yield directly the functional equivalent of a
Sonagashira product &60), without the need to synthesize the
iodovinyl AA &Scheme 19).
&iv) oxazoline opening/alkene unmasking under classical
E2-type conditions to produce a family of a-&2E-phenyl-
seleno)vinyl AA0s and
&v) direct transformation of the a-&2E-phenylseleno)vinyl
a-branch to an a-&2E-tributylstannyl)vinyl branch via
treatment with tributyltin radical.
3. Conclusions
The a-&2E-stannyl)vinyl AA0s &or their iodovinyl
derivatives), in turn, are shown to effectively participate
in transition metal-mediated cross couplings of the
Stille, Negishi, Sonagashira and Shen varieties. The
AA products of these chain extension reactions bear a
b,g-unsaturated a-branch, in addition to the usual
a-amino, a-carboxyl and side chain functional groups.
Thus, the title stannylvinyl AA0s serve as convenient
building blocks for a wide range of enantiomerically
enriched, sterically congested amino acids, of either d-
or l-handedness, that would otherwise be dif®cult to
obtain.
A divergent SRS-type approach to protected, d- or l-
quaternary, a-&2-stannyl)vinyl AA0s has been developed.
The enantiomeric purity of the starting l-vinylglycine is
preserved through a sequence that involves:
&i) installation of a directing b-stereocenter via an
episelenonium ion-mediated alkene-masking step,
&ii) chromatographic separation of the diastereomeric d-
and l-vinyl AA synthons, 44c and 44t,
&iii) enolate generation with KHMDS and alkylative side
chain introduction with nearly absolute 1,2-stereo-
induction,
Scheme 16. Ready access to a complementary set of cross-coupling partners: quaternary a-&2-iodo)vinyl AA0s.

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6337
Scheme 17. Reversed polarity Pd-catalyzed couplings.
Scheme 18. Diels±Alder chemistry along the a-branch.
Scheme 19. Coupling under the conditions of Shen.
4. Experimental
4.1. General
acquired at the Nebraska Center for Mass Spectrometry
&University of Nebraska).
4.1.1. ꢀ4S,5S)-4-Methoxycarbonyl-5-ꢀphenylseleno)methyl-
2-phenyloxazoline ꢀ44t)/ꢀ4S,5R)-4-methoxycarbonyl-5-
ꢀphenylseleno)methyl-2-phenyloxazoline ꢀ44c). To a solu-
tion of phenylselenenyl chloride &1.92 g, 10.0 mmol) in
THF &40 mL) at 2788C was added silver tri¯ate &2.82 g,
10.9 mmol) in THF &30 mL). The resulting orange mixture
was stirred at 2788C for 20 min and then cooled to 21008C
[EtOH±N2&l) slush bath]. A solution of l-4324c &2.00 g,
9.12 mmol) in THF &20 mL) at 21008C was then added
via cannula and the reaction stirred for 2 h. EtOAc
&60 mL) was added and the mixture was extracted with
All reactions were conducted under an argon atmosphere
using ¯ame-dried glassware unless otherwise noted.
Toluene, THF, and Et2O were distilled from sodium benzo-
phenone ketyl. HMPA and DMF were distilled from Na, in
vacuo. Methylene chloride was distilled from CaH2. NMR
spectra were recorded on a Bruker-DRX-Avance-500 or a
GE Omega-300 instrument. Chemical shifts are reported
relative to residual CHCl3 &7.25 ppm, 1H; 77.0 ppm, 13C).
Infrared spectra were obtained using an Nicolet Avatar 360
FTIR spectrometer. High resolution mass spectra were

6338
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
H2O &3£80 mL). The organic layer was dried &MgSO4),
®ltered, evaporated. Chromatography [PhCH3 or PhH/
CH2Cl2/EtOAc &4:4:1)] provided trans-oxazoline &44t)
&1.42 g, 42%) in a ®rst fraction, and then cis-oxazoline
&44c) &1.28 g, 37%).
2H), 7.55 &t, Jˆ7.5 Hz, 1H), 7.62±7.64 &m, 2H), 7.88 &d,
Jˆ7.3 Hz, 2H); 13C NMR &125 MHz, CDCl3) d 28.4, 44.3,
52.6, 81.1, 84.8, 126.9, 127.5, 128.0, 128.2, 128.6, 129.2,
129.4, 130.9, 131.7, 133.4, 134.9, 142.0, 164.3, 171.7; IR
&ATR) 3012, 1747, 1659 cm21
.
For 44t: [a]D ˆ150.3 &c 0.5, CHCl3); 1H NMR &500 MHz,
24
4.2.3. ꢀ4S,5R)-4-ꢀBenzyloxy)methyl-4-methoxycarbonyl-
5-ꢀphenylseleno)methyl-2-phenyloxazoline ꢀd-45c). From
44c &.99% ee, Chiralcel OD) &1.00 g, 2.67mmol) and
benzyloxymethyl bromide &0.64 g, 3.20 mmol), following
general procedure A, was obtained d-45c &1.20 g, 90%,
.99% ee, Chiralcel OD) as an oil, after ¯ash chromato-
CDCl3) d 3.17&dd, Jˆ7, 13 Hz, 1H), 3.29 &dd, Jˆ7, 13 Hz,
1H), 3.79 &s, 3H), 4.71 &d, Jˆ7Hz, 1H), 5.12 &app dt, Jˆ5,
7 Hz, 1H), 7.24 &m, 3H), 7.36 &m, 2H), 7.47 &m, 1H), 7.56
&m, 2H), 7.86 &d, Jˆ8 Hz, 2H); 13C NMR &125 MHz,
CDCl3) d 31.6, 52.6, 73.7, 81.3, 126.9, 127.6, 128.2,
128.6, 128.7, 129.2, 131.8, 133.7, 165.3, 171.1; IR &ATR)
1743, 1643 cm21. Anal. Calcd for C18H17NO3Se: C, 57.76,
H, 4.58; N, 3.74. Found: C, 57.57; H, 4.22; N, 3.93.
24
graphy &25% EtOAc/hexanes): [a]D ˆ236.5 &c 1.0,
1
CHCl3); H NMR &300 MHz, CDCl3) d 3.17&dd, Jˆ4.5,
8.5 Hz, 1H), 3.26 &dd, Jˆ4, 8.5 Hz, 1H), 3.77 &s, 3H), 3.85
&d, Jˆ9.9 Hz, 1H), 3.89 &d, Jˆ9.9 Hz, 1H), 4.58 &s, 2H), 5.00
&dd, Jˆ4.5, 8.8 Hz, 1H), 7.23±7.28 &m, 7H), 7.37±7.40 &m,
3H), 7.48 &t, Jˆ7.3, 1H), 7.56±7.57 &m, 2H), 7.89 &d,
Jˆ7.4 Hz, 2H); 13C NMR &75 MHz, CDCl3) d 28.2, 52.6,
73.2, 73.7, 80.9, 83.5, 126.9, 127.3, 127.6, 127.7, 128.2,
128.3, 128.6, 128.7, 129.1, 129.2, 129.5, 131.7, 133.1,
137.8, 165.2, 170.3; IR &ATR) 1734, 1652, 1450 cm21; MS
&FAB, 3-NBA), 518 &100, M1Na); HRMS &FAB, 3-NBA)
m/z calcd for C26H25NO4Se &M1Na) 518.0846, obsd
518.0839 &Dˆ11.4).
For 44c: [a]D ˆ116.2 &c 0.6, CHCl3); 1H NMR
24
&500 MHz, CDCl3) d 3.16 &dd, Jˆ5.5, 13 Hz, 1H), 3.24
&dd, Jˆ8, 13 Hz, 1H), 3.77 &s, 3H), 5.02 &d, Jˆ10 Hz,
1H), 5.09 &ddd, Jˆ5.5, 8, 10 Hz, 1H), 7.24 &m, 3H), 7.36
&m, 2H), 7.47 &m, 1H), 7.56 &m, 2H), 7.88 &d, Jˆ8 Hz, 2H);
13C NMR &125 MHz, CDCl3) d 27.4, 52.4, 71.2 &CH), 81.0,
126.7, 127.6, 128.3, 128.6, 129.0, 129.2, 132.0, 133.5,
165.9, 170.1; IR &ATR) 1740, 1643 cm21. Anal. Calcd for
C18H17NO3Se: C, 57.76; H, 4.58; N, 3.74. Found: C, 57.88;
H, 4.42; N, 3.98.
4.3. General procedure B
4.2. General procedure A
4.3.1. Methyl N-benzoyl-l-a-ꢀ2E-phenylseleno)vinyl-
phenylalaninate ꢀl-46a). To a solution of l-45a &79 mg,
0.17mmol) at 0 8C in DMF &2.3 mL) was added KO-t-Bu
&38 mg, 0.34 mmol). After warming to rt and stirring for 2 h,
the resulting solution was poured into EtOAc &15 mL) and
1N HCl &15 mL). Following a second extraction with
EtOAc &10 mL), the combined organics were dried
&MgSO4), ®ltered, and evaporated. The crude product was
taken up in ether &10 mL) and treated with diazomethane.
Evaporation of the solvent and ¯ash chromatography &25%
4.2.1. ꢀ4R,5S)-4-Benzyl-4-methoxycarbonyl-5-ꢀphenyl-
seleno)methyl-2-phenyloxazoline ꢀl-45a). To a solution
of KHMDS &7.0 mL, 0.5 M in toluene) and HMPA
&3.0 mL) in THF &3.0 mL) at 2788C was added 44t &98%
ee, Chiralcel OD) &1.20 g, 3.20 mmol) in THF &10 mL) at
2788C via cannula. The resulting deep orange/red solution
was stirred for 20 min at 2788C followed by addition of
benzyl bromide &0.45 mL, dˆ1.44, 3.80 mmol). After stir-
ring for 3 h, the reaction mixture was poured into ether
&15 mL) and NH4Cl &aqueous, 15 mL). Following further
extraction with EtOAc &3£15 mL), the combined organics
were dried &MgSO4), ®ltered, evaporated, and chromato-
graphed &10% EtOAc/hexanes) to give l-45a &1.34 g,
90%, 98% ee, Chiralcel OD) as a white solid: mp 79±
818C; [a]D ˆ148.5 &c 1.0, CHCl3); H NMR &500 MHz,
CDCl3) d 3.21±3.24 &m, 3H), 3.49 &d, Jˆ13.7Hz, 1H), 3.84
&s, 3H), 4.89 &t, Jˆ6.6 Hz, 1H), 7.23±7.34 &m, 5H), 7.36±
7.38 &m, 3H), 7.44 &t, Jˆ7.7 Hz, 2H), 7.55 &t, Jˆ7.5 Hz,
1H), 7.62±7.64 &m, 2H), 7.88 &d, Jˆ7.3 Hz, 2H); 13C
NMR &125 MHz, CDCl3) d 28.3, 44.3, 52.6, 81.1, 84.8,
126.8, 127.0, 127.4, 128.0, 128.2, 128.5, 129.2, 129.3,
130.9, 131.7, 133.6, 134.9, 164.2, 171.7. Anal. Calcd For
C25H23NO3Se: C, 64.66; H, 4.99; N, 3.02. Found: C, 64.98;
H, 4.58; N, 3.03.
EtOAc/hexanes)
yielded
l-46a
&60 mg,
76%):
[a]D ˆ121.4 &c 0.1, CDCl3); 1H NMR &500 MHz,
CDCl3) d 3.40 &d, Jˆ13 Hz, 1H), 3.82 &s, 3H), 3.91 &d,
Jˆ13 Hz, 1H), 6.29 &d, Jˆ16 Hz, 1H), 6.70 &d, Jˆ16 Hz,
1H), 6.97 &s, 1H), 7.05 &m, 2H), 7.22 &m, 3H), 7.27 &m, 3H),
7.39 &t, Jˆ7.5 Hz, 2H), 7.47 &m, 3H), 7.68 &d, Jˆ7.5 Hz,
2H); 13C NMR &125 MHz, CDCl3) d 40.3, 53.1, 66.5, 121.5,
126.9, 127.1, 127.3, 128.3, 128.4, 128.6, 129.3, 129.9,
131.6, 132.3, 133.3, 134.7, 135.4, 166.3, 171.7; IR &ATR)
1736, 1650 cm21. Anal. Calcd for C25H23NO3Se: C, 64.66;
H, 4.99; N, 3.02. Found: C, 64.86; H, 5.30; N, 2.92.
24
24
1
4.3.2. Methyl N-benzoyl-d-a-ꢀ2E-phenylseleno)vinyl-
phenylalaninate ꢀd-46a). From d-45a &0.51 g, 1.1 mmol)
in DMF &6 mL), following general procedure B, was
obtained d-46a &357mg, 70%) as an oil after diazomethane
esteri®cation and ¯ash chromatography &30% EtOAc/
4.2.2. ꢀ4S,5R)-4-Benzyl-4-methoxycarbonyl-5-ꢀphenyl-
seleno)methyl-2-phenyloxazoline ꢀd-45a). From 44c
&.99% ee, Chiralcel OD) &1.00 g, 2.67mmol) and benzyl
bromide &0.40 mL, dˆ1.44, 3.20 mmol) following general
procedure A, was obtained d-45a &0.99 g, 80%, .99% ee,
hexanes): [a]D ˆ220.4 &c 0.3, CHCl3); 1H NMR
24
&500 MHz, CDCl3) d 3.40 &d, Jˆ13 Hz, 1H), 3.82 &s, 3H),
3.91 &d, Jˆ13 Hz, 1H), 6.29 &d, Jˆ16 Hz, 1H), 6.70 &d,
Jˆ16 Hz, 1H), 6.97 &s, 1H), 7.05 &m, 2H), 7.22 &m, 3H),
7.27 &m, 3H), 7.39 &t, Jˆ7.5 Hz, 2H), 7.47 &m, 3H), 7.68 &d,
Jˆ7.5 Hz, 2H); 13C NMR &125 MHz,CDCl3) d 40.3, 53.1,
66.5, 121.5, 126.9, 127.1, 127.3, 128.3, 128.4, 128.6, 129.3,
129.9, 131.6, 132.3, 133.3, 134.7, 135.4, 166.3, 171.7; IR
24
1
Chiralcel OD): [a]D ˆ251.1 &c 1.0, CHCl3); H NMR
&500 MHz, CDCl3) d 3.21±3.25 &m, 3H), 3.49 &d,
Jˆ13.7Hz, 1H), 3.84 &s, 3H), 4.89 &t, Jˆ6.6 Hz, 1H),
7.23±7.34 &m, 5H), 7.36±7.38 &m, 3H), 7.44 &t, Jˆ7.7 Hz,

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6339
&ATR) 1736, 1677 cm21; MS &FAB, 3-NBA) 466 &M1H,
100); HRMS &FAB, 3-NBA) m/z calcd for C25H23NO3Se
&M1H) 466.0921, obsd 466.0907& Dˆ13.1 ppm).
4.4.3. Methyl N-benzoyl-O-benzyl-d-a-ꢀ2E-tri-n-butyl-
stannyl)vinylserinate ꢀd-47c). From d-46c &800 mg,
1.6 mmol), following general procedure C, was obtained
d-47c &748 mg, 74%) after ¯ash chromatography &20%
24
1
4.3.3. Methyl N-benzoyl-O-benzyl-d-a-ꢀ2E-phenyl-
seleno)vinylserinate ꢀd-46c). From d-45c &1.2 g, 2.42
mmol) in THF &30 mL), following general procedure B,
was obtained d-46c &900 mg, 75%) after diazomethane
esteri®cation and ¯ash chromatography &25% EtOAc/
EtOAc/hexanes): [a]D ˆ124.4 &c 0.8, CHCl3); H NMR
&300 MHz, CDCl3) d 0.84±0.93 &m, 15H), 1.24±1.32 &m,
6H), 1.45±1.50 &m, 6H), 3.78 &s, 3H), 4.06 &d, Jˆ9.3 Hz,
1H), 4.33 &d, Jˆ9.3 Hz, 1H), 4.49 &d, Jˆ12 Hz, 1H), 4.56 &d,
Jˆ12 Hz, 1H), 6.09 &d, Jˆ19.3 Hz, 1H), 6.36 &d,
Jˆ19.3 Hz, 1H), 7.18 &s, 1H), 7.24±7.32 &m, 5H), 7.47 &t,
Jˆ7.5 Hz, 2H), 7.52 &t, Jˆ7.5 Hz, 1H), 7.48 &d, Jˆ7.5 Hz,
2H); 13C NMR &75 MHz, CDCl3) d 9.6, 13.6, 27.1, 28.9,
52.9, 67.2, 70.9, 73.3, 17.1, 127.5, 127.6, 128.3, 128.5,
131.4, 131.6, 134.8, 138.0, 141.0, 166.1, 171.4; IR &ATR)
1735, 1443 cm21; MS &FAB, 3-NBA), 636 &100, M1Li);
HRMS &FAB, 3-NBA) m/z calcd for C32H47NO4Sn &M1Li)
636.2687, obsd 636.2698 &Dˆ21.8 ppm).
hexanes): [a]D ˆ120.4 &c 2.0, CHCl3); 1H NMR
24
&300 MHz, CDCl3) d 3.82 &s, 3H), 3.99 &d, Jˆ9.3 Hz,
1H), 4.30 &d, Jˆ9.3 Hz, 1H), 4.48 &d, Jˆ12.3 Hz, 1H),
4.55 &d, Jˆ12.3 Hz, 1H), 6.23 &d, Jˆ15.6 Hz, 1H), 6.79
&d, Jˆ15.6 Hz, 1H), 7.23±7.32 &m, 9H), 7.46±7.48 &m,
4H), 4.52 &m, 1H), 7.84 &d, Jˆ7.5 Hz; 2H); 13C NMR
&75 MHz, CDCl3) d 53.2, 65.9, 70.7, 73.4, 122.6, 127.0,
127.2, 127.6, 127.8, 128.3, 128.5, 129.3, 129.8, 130.0,
131.7, 132.2, 134.2, 137.6, 166.3, 170.7; IR &ATR) 3018,
1747, 1665 cm21; MS &FAB, 3-NBA) 502 &100, M1Li);
HRMS &FAB, 3-NBA) m/z calcd for C26H25NO4Se
&M1Li) 502.1109, obsd 502.1100 &Dˆ11.7ppm).
4.4.4. ꢀ20E-Deuterio)-l-a-vinylphenylalanine ꢀl-48a). A
solution of l-47a &46 mg, 0.08 mmol) in 6N DCl &1.0 mL)
was stirred at light re¯ux for 4.5 h. Then the solution was
cooled, taken up in H2O &5 mL) and extracted with CH2Cl2
&2£5.5 mL). The residue was applied to a Dowex 50£8 ion-
exchange column. After washing the column with deionized
H2O, elution was carried out with 1.3 M NH4OH to afford
4.4. General procedure C
4.4.1. Methyl N-benzoyl-d-a-ꢀ2E-tri-n-butylstannyl)-
vinylphenylalanine ꢀd-47a). To a deoxygenated solution
of d-46a &0.52 g, 1.12 mmol) in toluene &15 mL) was
added AIBN &42 mg, 0.26 mmol) and tributyltin hydride
&0.58 mL, 2.24 mmol). The solution was then stirred at
858C for 1.5 h. After cooling to rt, the reaction mixture
was partitioned between EtOAc &3£50 mL) and H2O
&50 mL). The combined organics were dried &MgSO4),
®ltered, evaporated, and chromatographed &0±10%
EtOAc/hexanes) to give d-47a &0.53 g, 80%):
l-48a &11.3 mg, 75%): [a]D ˆ26.6 &c 0.3, D2O); 1H NMR
24
&300 MHz, D2O) d 3.10 &d, Jˆ14.3 Hz, 1H), 3.43 &d,
Jˆ14.3 Hz, 1H), 5.30 &d, Jˆ17.9 Hz, 1H), 6.19 &d,
Jˆ17.7 Hz, 1H), 7.28 &m, 2H), 7.38 &m, 3H); 13C NMR
&75 MHz, D2O) d 42.1, 66.9, 117.4, 128.8, 129.7, 130.9,
134.4, 135.8, 174.4; MS &FAB, 3-NBA) 193 &69, M11),
219 &100); HRMS &FAB, 3-NBA) m/z calcd for
C11H12NO2D &M11) 193.1087, obsd 193.1085
&Dˆ11.1 ppm).
24
[a]D ˆ216.6 &c 2.3, CHCl3); 1H NMR &300 MHz,
4.4.5. Methyl N-benzoyl-a-1-[ꢀ40-nitro)-E-styrenyl]-l-
phenylalaninate ꢀ49). A solution of Pd2&dba)3 &14 mg,
0.02 mmol) and 1-iodo-4-nitrobenzene &21.0 mg,
0.09 mmol) in THF &1.0 mL) was stirred for 10 min at rt.
Then l-47a &50.0 mg, 0.09 mmol) in THF &1.0 mL) was
added via cannula. The reaction was stirred at 508C for
2 h, then cooled to rt. Ethyl acetate &4 mL) was added,
followed by ®ltration through Celite and evaporation. Chro-
matography &10±30% EtOAc/hexanes) gave 49 &30.6 mg,
CDCl3) d 0 84±0.95 &m, 15H), 1.25±1.34 &m, 6H), 1.45±
1.56 &m, 6H), 3.55 &d, Jˆ13 Hz, 1H), 3.80 &s, 3H), 3.82 &d,
Jˆ13 Hz, 1H), 6.16 &d, Jˆ19.2 Hz, 1H), 6.23 &d,
Jˆ19.2 Hz, 1H), 6.82 &s, 1H), 7.07±7.11 &m, 2H), 7.18±
7.20 &m, 3H), 7.42 &t, Jˆ7.3 Hz, 2H), 7.48 &t, Jˆ7.3 Hz,
1H), 7.71 &d, Jˆ7.3 Hz, 2H); 13C NMR &75 MHz, CDCl3)
d 9.6, 13.7, 27.2, 28.9, 33.7, 52.8, 67.4, 126.8, 126.9, 128.1,
128.5, 130.1, 130.3, 131.4, 135.0, 136.3, 143.9, 166.3,
172.3; IR &ATR) 1737, 1483 cm21; HREI, calcd for
C31H45NO3Sn &M2t-butyl) 542.1717, obsd 542.1709
&Dˆ11.5).
24
1
85%): [a]D ˆ171.8 &c 0.6, CHCl3); H NMR &500 MHz,
CDCl3) d 3.49 &d, Jˆ13 Hz, 1H), 3.88 &s, 3H), 4.02 &d,
Jˆ13 Hz, 1H), 6.64 &d, Jˆ16 Hz, 1H), 6.78 &d, Jˆ16 Hz,
1H), 7.09 &m, 2H), 7.17 &s, 1H), 7.24 &m, 3H), 7.45 &app t,
Jˆ7.6 Hz, 2H), 7.54 &m, 3H), 7.76 &d, Jˆ7.2 Hz, 2H), 8.18
&d, Jˆ8.8 Hz, 2H); 13C NMR &125 MHz, CDCl3) d 40.8,
53.3, 65.6, 123.9, 126.9, 127.3, 127.4, 128.5, 128.7, 128.9,
129.9, 131.9, 132.9, 135.1, 142.7, 143.3, 147.2, 166.3,
171.8; IR &ATR) 3020, 1740, 1653, 1515, 1483,
1342 cm21; MS &FAB, 3-NBA) 431 &100, M11); HRMS
&FAB, 3-NBA) m/z calcd for C25H22N2O5 &M11)
431.1607, obsd 431.1613 &Dˆ21.4 ppm).
4.4.2. Methyl N-benzoyl-l-a-ꢀ2E-tri-n-butylstannyl)-
vinylphenylalanine ꢀl-47a). From l-46a &45 mg,
0.10 mmol) in toluene &1.3 mL), following general pro-
cedure C, was obtained l-47a &48 mg, 84%), after ¯ash
24
chromatography &20% EtOAc/hexanes): [a]D ˆ117.7 &c
1
0.7, CHCl3); H NMR &300 MHz, CDCl3) d 0 84±0.98
&m, 15H), 1.25±1.33 &m, 6H), 1.45±1.56 &m, 6H), 3.55 &d,
Jˆ13 Hz, 1H), 3.79 &s, 3H), 3.80 &d, Jˆ13 Hz, 1H), 6.16 &d,
Jˆ19.2 Hz, 1H), 6.23 &d, Jˆ19.2 Hz, 1H), 6.80 &s, 1H),
7.07±7.17 &m, 2H), 7.18±7.20 &m, 3H), 7.42 &t, Jˆ7.3 Hz,
2H), 7.48 &t, Jˆ7.3 Hz, 1H), 7.71 &d, Jˆ7.3 Hz, 2H); 13C
NMR &75 MHz, CDCl3) d 9.6, 13.7, 27.2, 28.9, 33.7, 52.8,
67.4, 126.8, 126.9, 128.1, 128.5, 130.1, 130.3, 131.4, 135.0,
4.4.6. Methyl N-benzoyl-a-ꢀ2E-benzoyl)vinyl-d-phenyl-
alaninate ꢀ50). To
a solution of d-47a &20 mg,
0.05 mmol) and Pd&PPh3)2Cl2 &7mg, 0.01 mmol) in THF
&0.5 mL) was added benzoyl chloride &6 mL, 0.05 mmol).
The reaction mixture was re¯uxed for 3 h, cooled to rt,
poured into EtOAc &0.5 mL) and extracted with H2O
136.3, 143.9, 166.3, 172.3; IR &ATR) 1738, 1482 cm21
.
Anal. Calcd for C31H45NO3Sn: C, 62.22; H, 7.58; N, 2.34.
Found: C, 62.40; H, 7.32; N, 2.28.

6340
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
&2£0.5 mL). The organic layer was dried &MgSO4), ®ltered,
24
0.26 mmol) in CCl4 &4.4 mL) at 48C was added iodine
&167mg, 0.66 mmol). The mixture was stirred at 4 8C for
30 min. Sodium bisul®te &10% aqueous) was added and
the solution was extracted with ether &2£5 mL). The
organics were combined, dried &MgSO4), ®ltered, evapo-
rated and chromatographed &10% EtOAc/hexanes) to give
l-53a &100 mg, 92%): [a]D ˆ152.7& c 0.7, CHCl3); H
NMR &300 MHz, CDCl3). d 3.35 &d, Jˆ13.6 Hz, 1H), 3.86
&s, 3H), 3.92 &d, Jˆ13.6 Hz, 1H), 6.46 &d, Jˆ14.8 Hz, 1H),
6.92 &d, Jˆ14.8 Hz, 1H), 7.02 &s, 1H), 7.07 &m, 2H), 7.24
&m, 3H), 7.44 &app t, Jˆ7.4 Hz, 2H), 7.52 &app t, Jˆ7.3 Hz,
1H), 7.77 &d, Jˆ7.1 Hz, 2H); 13C NMR &75 MHz, CDCl3) d
41.2, 54.3, 68.9, 80.2, 127.9, 128.4, 129.5, 129.7, 130.9,
132.8, 135.3, 135.8, 143.5, 167.3, 172.0; IR &ATR) 2949,
1735, 1653 cm21; MS &FAB, 3-NBA) 436 &100, M11);
HRMS &FAB, 3-NBA) m/z calcd for C19H18NO3I &M11)
436.0410, obsd 436.0413 &Dˆ20.8 ppm).
evaporated and chromatographed &30% EtOAc/hexanes) to
give 50 &8 mg, 60%) as an oil: [a]D ˆ226.3 &c 0.4,
CHCl3); 1H NMR &300 MHz, CDCl3)
d
3.48 &d,
Jˆ13.4 Hz, 1H), 3.84 &s, 3H), 3.94 &d, Jˆ13.4 Hz, 1H),
7.00 &d, Jˆ16.0 Hz, 1H), 7.10±7.13 &m, 3H), 7.22 &d,
Jˆ16.0 Hz, 1H), 7.25±7.28 &m, 3H), 7.44±7.50 &m, 4H),
7.56 &app t, Jˆ7.6 Hz, 2H), 7.75 &d, Jˆ7.2 Hz, 2H), 7.90
&d, Jˆ7.2 Hz, 2H); 13C NMR &75 MHz, CDCl3) d 40.4,
53.5, 65.6, 126.5, 127.0, 127.5, 128.5, 128.6, 128.7, 128.8,
129.8, 131.9, 133.0, 134.8, 144.7, 166.4, 171.2; IR &ATR)
2993, 1734, 1659, 1634, 1508 cm21; MS &FAB, 3-NBA)
414 &100, M11); HRMS &FAB, 3-NBA) m/z calcd for
C26H23NO4 &M11) 414.1705, obsd 414. 1718
&Dˆ23.0 ppm).
24
1
4.4.7. Methyl N-benzoyl-a-1-ꢀE-1,4-pentadienyl)-d-phenyl-
alaninate ꢀ51). To a solution of &PPh3)2Pd&PhCH2)Cl &1.1 mg,
1.5 mmol) in THF &0.4 mL) was added allyl bromide &4 mL,
0.05 mmol) and d-47a &30 mg, 0.05 mmol). The reaction
mixture was stirred at re¯ux for 3 h. After cooling to rt,
EtOAc &5 mL) was added and the mixture was ®ltered through
Celite, evaporated and chromatographed &10% EtOAc/
4.5.2. Methyl N-benzyl-a-ꢀ2E-iodo)vinyl-d-phenylalani-
nate ꢀd-53a). From d-47c &240 mg, 0.41 mmol), following
general procedure D, was obtained d-53a &160 mg, 90%)
after ¯ash chromatography &10% EtOAc/hexanes):
[a]D ˆ250.0 &c 0.5, CHCl3); 1H NMR &300 MHz,
24
24
hexanes) to give 51 &15 mg, 84%)as an oil: [a]D ˆ233.2
CDCl3). d 3.35 &d, Jˆ13.6 Hz, 1H), 3.86 &s, 3H), 3.92 &d,
Jˆ13.6 Hz, 1H), 6.46 &d, Jˆ14.8 Hz, 1H), 6.92 &d,
Jˆ14.8 Hz, 1H), 7.02 &s, 1H), 7.07 &m, 2H), 7.24 &m, 3H),
7.44 &app t, Jˆ7.4 Hz, 2H), 7.52 &app t, Jˆ7.3 Hz, 1H), 7.77
&d, Jˆ7.1 Hz, 2H); 13C NMR &75 MHz, CDCl3) d 40.1,
53.3, 67.9, 79.3, 126.9, 127.4, 128.5, 128.7, 129.9, 131.8,
134.3, 134.8, 142.4, 167.3, 171.0; IR &ATR) 3031, 1753,
1671 cm21; MS &FAB, 3-NBA) 436 &100, M11); HRMS
&FAB, 3-NBA) m/z calcd for C19H18NO3I &M11)
436.0410, obsd 436.0396 &Dˆ13.2 ppm).
&c 1.1, CHCl3); 1H NMR &300 MHz, CDCl3) d 2.86 &t,
Jˆ6.4 Hz, 2H), 3.44 &d, Jˆ13.5 Hz, 1H), 3.84 &s, 3H), 3.89
&d, Jˆ13.5 Hz, 1H), 5.04 &br d, Jˆ10.5 Hz, 1H), 5.06 &br d,
Jˆ17Hz, 1H), 5.72 &dt, Jˆ6, 16 Hz, 1H), 5.85 &d, Jˆ16 Hz,
1H), 5.80±5.90 &m, 1H), 6.96 &s, 1H), 7.08±7.11 &m, 2H),
7 .19±7 .27 &m, 3H), 7 .43 &appJˆt,7.4 Hz, 2H), 7.51 &app t,
Jˆ7.4 Hz, 1H), 7.72 &d, Jˆ7.0 Hz, 2H); 13C NMR &7 5 MHz,
CDCl3) d 36.1, 40.2, 52.9, 65.3, 115.9, 126.9, 127.0, 128.2,
128.6, 129.4, 129.9, 130.0, 134.9, 135.8, 135.9, 166.3, 172.6;
IR &ATR) 3031, 1747, 1671, 1514, 1483 cm21; MS &FAB, 3-
NBA) 350 &100, M11); HRMS &FAB, 3-NBA) m/z calcd for
C22H23NO3 &M11) 350.1756, obsd 350.1759 &Dˆ10.8 ppm).
4.5.3. Methyl N-benzoyl-O-benzyl-a-ꢀ2E-iodo)vinyl-d-
serinate ꢀd-53c). From d-47a &738 mg, 1.17 mmol), follow-
ing general procedure D, was obtained d-53c &540 mg, 98%)
after ¯ash chromatography &10% EtOAc/hexanes):
4.4.8. Methyl N-benzoyl-a-1-[E-ꢀ3-phenyl)propenyl]-d-
phenylalaninate ꢀ52). To a solution of &PPh3)2Pd&PhCH2)Cl
&6 mg, 8 mmol) and benzyl bromide &10.5 mg, 0.06 mmol)
in THF &1 mL) was added d-47a &30 mg, 0.05 mmol). The
solution was re¯uxed for 3 h. After cooling to rt, the reaction
mixture was partitioned between H2O &5 mL) and EtOAc
&2£5 mL). The organics were combined, dried &MgSO4),
®ltered, evaporated and chromatographed &0±10% EtOAc/
[a]D ˆ124.7& c 0.6, CDCl3); 1H NMR &300 MHz,
24
CDCl3) d 3.82 &s, 3H), 3.91 &d, Jˆ9.3 Hz, 1H), 4.22 &d,
Jˆ9.3 Hz, 1H), 4.50 &d, Jˆ12.2 Hz, 1H), 4.58 &d, Jˆ
12.2 Hz, 1H), 6.52 &d, Jˆ14.8, 1H), 6.81 &d, Jˆ14.8 Hz,
1H), 7.24±7.33 &m, 6H), 7.46 &app t, Jˆ7.3 Hz, 2H), 7.55
&app t, Jˆ7.3 Hz, 1H), 7.82 &d, Jˆ7.4 Hz, 2H); 13C NMR
&75 MHz, CDCl3) d 53.4, 67.3, 70.4, 73.4, 80.3, 127.1,
127.7, 127.9, 127.5, 128.6, 131.9, 133.9, 137.3, 139.8,
166.3, 170.0; IR &ATR) 3018, 1747, 1671, 1514 cm21; MS
&FAB, 3-NBA) 472 &100, M1Li); HRMS &FAB, 3-NBA)
m/z calcd for C20H20NO4I &M1Li) 472.0597, obsd 472.0602
&Dˆ20.9 ppm).
24
hexanes) to give 52 &13 mg, 63%) as an oil: [a]D ˆ247.8
1
&c 0.7, CHCl3); H NMR &300 MHz, CDCl3) d 3.46 &d,
Jˆ13.4 Hz, 1H), 3.47&d, Jˆ6.2 Hz, 2H), 3.84 &s, 3H),
3.96 &d, Jˆ13.4 Hz, 1H), 5.85 &dt, Jˆ6, 16 Hz, 1H), 5.94
&d, Jˆ16 Hz, 1H), 6.96 &s, 1H), 7.07±7.10 &m, 2H), 7.17±
7.24 &m, 6H), 7.27±7.33 &m, 2H), 7.42 &app t, Jˆ7.2 Hz,
2H), 7.51 &app t, Jˆ7.2 Hz, 1H), 7.72 &d, Jˆ7.0 Hz, 2H); 13C
NMR &75 MHz, CDCl3) d 38.4, 40.3, 65.1, 126.2, 126.8,
126.9, 128.2, 128.4, 128.6, 130.0, 130.1, 130.7, 131.5,
134.8, 135.9, 139.6, 166.3, 172.6; IR &ATR) 3018, 1741,
1671, 1527, 1482 cm21; MS &FAB, 3-NBA) 400 &100,
M11); HRMS &FAB, 3-NBA) m/z calcd for C26H25NO3
&M11) 400.1894, obsd 400.1895 &Dˆ20.1 ppm).
4.5.4. Methyl N-benzoyl-a-1-ꢀE-1,3-butadienyl)-l-phenyl-
alaninate ꢀ54). To a solution of Pd2&dba)3 &1.9 mg,
2.00 mmol) and tris-&2-furyl)phosphine &4.3 mg, 20 mmol)
in THF &2 mL) was added l-53a &50 mg, 0.12 mmol). The
mixture was stirred for 10 min at rt. Then tributyl&vinyl)tin
&38.1 mg, 0.12 mmol) was added. The resulting reaction
mixture was stirred at 508C for 2 h, ®ltered through Celite
and evaporated. Chromatography &10% EtOAc/hexanes)
24
gave 54 &24.9 mg, 65%): [a]D ˆ152.3 &c 0.5, CHCl3);
4.5. General procedure D
1H NMR &500 MHz, CDCl3) d 3.42 &d, Jˆ13 Hz, 1H),
3.82 &s, 3H), 3.92 &d, Jˆ13 Hz, 1H), 5.15 &d, Jˆ10 Hz,
1H), 5.21 &d, Jˆ16.6 Hz, 1H), 6.04 &d, Jˆ15.5 Hz, 1H),
4.5.1. Methyl N-benzoyl-a-ꢀ2E-iodo)vinyl-l-phenyl-
alaninate ꢀl-53a). To a solution of l-47a &150 mg,

D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
6341
6.24 &dd, Jˆ15.4 Hz, 1H), 6.38 &dt, Jˆ15.7, 10 Hz, 1H),
7.00 &s, 1H), 7.07 &m, 2H), 7.20 &m, 3H), 7.40 &app t,
Jˆ7.6 Hz, 2H), 7.50 &app t, Jˆ7.4 Hz, 1H), 7.71 &d,
Jˆ7.3 Hz, 2H); 13C NMR &125 MHz, CDCl3) d 40.3,
53.1, 65.3, 118.8, 126.9, 127.1, 128.3, 128.6, 129.9, 131.6,
131.8, 134.7, 135.7, 137.8, 142.0, 166.3, 172.3; IR &ATR)
3029, 1735, 1653 cm21; MS &FAB, 3-NBA) 336 &100,
M11); HRMS &FAB, 3-NBA) m/z calcd for C21H21NO3
&M11) 336.1600, obsd 336.1598 &Dˆ10.4 ppm).
0.90 mmol). The reaction mixture was stirred at re¯ux for
12 h, followed by evaporation of the toluene. Puri®cation by
chromatography &30% EtOAc/hexanes) gave 57 &71 mg,
50%): MS &FAB, 3-NBA) 478 &M11, 45), 105 &100);
HRMS &FAB, 3-NBA) m/z calcd for C27H27NO7 &M11)
478.1848, obsd 478.1847 &Dˆ10.3).
4.6.1. Methyl N-benzoyl-a-benzyl-l-20,30bisꢀcarbo-
methoxy)phenylglycinate ꢀ58). To a solution of 57
&27mg, 0.06 mmol) in carbon tetrachloride &0.6 mL) was
added bromine &47.9 mg, 0.3 mmol). The reaction mixture
was stirred for 1 h at rt. Sodium thiosulfate &1 N) was added
and the solution was extracted with EtOAc &3 mL), dried
&MgSO4), ®ltered, evaporated and chromatographed &30%
EtOAc/hexanes) to give the intermediate dibromide&s)
&17.3 mg, 55%). To this product in DMF &0.3 mL) was
added KO-t-Bu &3.5 mg, 0.03 mmol). The reaction mixture
was stirred at rt for 2 h. Then, 0.5N HCl &0.5 mL) was added
and the solution was extracted with EtOAc &2£1 mL). The
organics were combined, dried &MgSO4), ®ltered, evapo-
rated and chromatographed &30% EtOAc/hexanes) to give
4.5.5. Methyl N-benzoyl-a-1-[ꢀ3-phenyl)-E-1,3-butadi-
enyl]-d-phenylalaninate ꢀ55). To a solution of d-53a
&30 mg, 70 mmol) and Pd2&dba)3 &11 mg, 14 mmol) in THF
&0.6 mL) was added 1-phenylvinylzinc bromide [0.6 mL of
a 0.5 M solution in THF &Rieke Metals, Inc.; Lincoln,
Nebraska); 0.3 mmol]. The solution was then stirred at
408C for 8 h. The reaction mixture was cooled and poured
into NH4Cl &aq. 5 mL) and extracted with EtOAc &2£5 mL).
The combined organic layers were dried &MgSO4), ®ltered,
evaporated and chromatographed &10% EtOAc/hexanes) to
24
give 55 &22 mg, 79%) as an oil: [a]D ˆ212.4 &c 1.1,
CHCl3); 1H NMR &300 MHz, CDCl3)
d
3.46 &d,
58 &12.7mg, 86%): [ a]D ˆ124.4 &c 0.4, CHCl3); 1H NMR
24
Jˆ13.6 Hz, 1H), 3.84 &s, 3H), 3.90 &d, Jˆ13.6 Hz, 1H),
5.28 &d, Jˆ16.9 Hz, 2H), 6.00 &d, Jˆ16 Hz, 1H), 6.52 &d,
Jˆ16 Hz, 1H), 6.98 &s, 1H), 7.07±7.09 &m, 2H), 7.21±7.24
&m, 4H), 7.33±7.39 &m, 4H), 7.45 &app t, Jˆ7.3 Hz, 2H),
7.53 &app t, Jˆ7.3 Hz, 1H), 7.75 &d, Jˆ7.3 Hz, 2H); 13C
NMR &75 MHz, CDCl3) d 40.3, 53.0, 65.3, 117.9,126.9,
127.0, 127.6, 128.2, 128.3, 128.6, 130.0, 131.3, 131.6,
132.4, 134.8, 135.8, 139.7, 146.7, 166.3, 172.3; IR &ATR)
3043, 1741, 1671, 1508 cm21; MS &FAB,3-NBA) 434
&M1Na, 74); HRMS &FAB, 3-NBA) m/z calcd for
C27H25NO3 &M1Na) 434.1711, obsd 434.1711 &Dˆ10.7).
&300 MHz, CD2Cl2) d 3.35 &s, 3H), 3.73 &d, Jˆ12.6 Hz, 1H),
3.76 &s, 3H), 3.81 &s, 3H), 4.33 &d, Jˆ12.6 Hz, 1H), 6.99±
7.02 &m, 2H), 7.19±7.28 &m, 4H), 7.41, &app t, Jˆ7.4 Hz,
2H), 7.51 &app t, Jˆ7.4 Hz, 1H), 7.59 &app d, Jˆ7Hz, 2H),
7.66 &t, Jˆ8.0 Hz, 1H), 7.96 &d, Jˆ8.0 Hz, 1H), 8.14 &d,
Jˆ8.0 Hz, 1H); 13C NMR &75 MHz, CDCl3) d 40.0, 52.2,
53.3, 64.8, 126.9, 127.4, 128.2, 128.4, 129.3, 129.6, 131.6,
131.8, 132.9, 134.2, 134.8, 138.0, 166.9, 167.2, 169.1,
171.2; IR &ATR) 3018, 1747, 1665, 1514, 1482 cm21; MS
&FAB, 3-NBA) 476 &M11, 24), 154 &100); HRMS &FAB,
3-NBA) m/z calcd for C27H25NO7 &M11) 476.1709, obsd
476.1708 &Dˆ10.2).
4.5.6. Methyl N-benzoyl-O-benzyl-a-1-ꢀE-oct-1-en-3-
ynyl)-d-serinate ꢀ56). To a solution of d-53a &20 mg,
40 mmol), CuI &400 mg, 2 mmol) and &PPh3)2PdCl2
&300 mg, 0.43 mmol) in diethylamine &0.5 mL) was added
1-hexyne &5 mL, dˆ0.715, 40 mmol). The reaction mixture
was stirred at rt for 2 h. The diethylamine was evaporated
and the residue partitioned between H2O &5 mL) and EtOAc
&2£5 mL). The combined organics were ®ltered through
Celite, dried &MgSO4), evaporated and chromatographed
&10% EtOAc/hexanes) to yield 56 &15.7mg, 87%) as an
4.6.2. Methyl N-benzoyl-a-1-[[ꢀ40-acetoxy)-4-phenyl]-E-
but-1-en-3-ynyl]-d-phenylalaninate ꢀ60). A solution of
d-47a &30 mg, 0.05 mmol), 1,1-dibromo-2[4-acetoxyphenyl]-
ethylene &15.5 mg, 0.05 mmol), diisopropylethylamine
&9.4 mg, 0.07mmol), Pd 2&dba)3 &1.1 mg, 1.3 mmol) and
&p-MeO-C6H4)3P &3.0 mg, 7.3 mmol) in DMF &0.5 mL)
was stirred at 808C for 4 h. Then the reaction mixture was
diluted with EtOAc &5 mL) and washed with H2O &10 mL).
The organic layer was dried &MgSO4), ®ltered, evaporated
and chromatographed &30% EtOAc/hexanes) to give 60
24
1
oil: [a]D ˆ123.8 &c 0.8, CHCl3); H NMR &300 MHz,
CDCl3) d 0.90 &t, Jˆ7.2 Hz, 3H), 1.36±1.51 &m, 4H), 2.28
&t, Jˆ7.0 Hz, 2H), 3.80 &s, 3H), 3.93 &d, Jˆ9.3 Hz, 1H), 4.27
&d, Jˆ9.3 Hz, 1H), 4.48 &d, Jˆ12.2 Hz, 1H), 4.58 &d,
Jˆ12.2 Hz, 1H), 5.76 &d, Jˆ16.2 Hz, 1H), 6.24 &d, Jˆ
16.2 Hz, 1H), 7.22±7.31 &m, 6H), 7.45 &app t, Jˆ7.2 Hz,
2H), 7.51 &app t, Jˆ7.2 Hz, 1H), 7.82 &d, Jˆ7.2 Hz, 2H);
13C NMR &75 MHz, CDCl3) d 13.5, 19.1, 21.9, 30.6, 53.3,
65.0, 70.8, 73.4, 93.3, 113.1, 127.1, 127.6, 127.8, 128.4,
128.6, 131.7, 134.2, 135.8, 137.6, 166.2, 170.9; IR &ATR)
3043, 1741, 1678, 1508, 1489 cm21; MS &FAB, 3-NBA)
420 &100, M11); HRMS &FAB, 3-NBA) m/z calcd for
C26H29NO4 &M11) 420.2157, obsd 420. 2156 &Dˆ
10.1 ppm).
24
1
&13 mg. 55%): [a]D ˆ267.7 &c 0.2, CHCl3); H NMR
&300 MHz, CDCl3) d 2.28 &s, 3H), 2.39 &d, Jˆ13.4 Hz,
1H), 3.84 &s, 3H), 3.91 &d, Jˆ13.4 Hz, 1H), 5.95 &d,
Jˆ16.1 Hz, 1H), 6.57&d, Jˆ16.1 Hz, 1H), 7.05±7.11 &m,
5H), 7.24±7.27 &m, 3H), 7.45 &d, Jˆ1.4 Hz, 2H), 7.47 &d,
Jˆ1.7Hz, 2H), 7.55 &app t, Jˆ7.0 Hz, 1H), 7.72 &d,
Jˆ7.0 Hz, 2H); 13C NMR &75 MHz, CDCl3) d 21.1, 40.3,
65.7, 111.6, 121.7, 127.0, 127.3, 128.5, 128.7, 129.9, 130.0,
131.8, 132.3, 132.7, 135.1, 140.4, 150.5, 166.4, 171.6,
172.5; IR &ATR) 3031, 1747, 1665, 1595 cm21; MS
&FAB, 3-NBA) 468 &M1H, 100); HRMS &FAB, 3-NBA)
m/z calcd for C25H25NO5 &M1H) 468.1811, obsd
468.1791 &Dˆ14.1 ppm).
4.6. Diels±Alder adductꢀs) 57
Acknowledgements
To a solution of 54 &100 mg, 0.30 mmol) in toluene &7mL)
was added dimethyl acetylenedicarboxylate &0.10 mL,
Financial support from the National Institutes of Health &CA

6342
D. B. Berkowitz et al. / Tetrahedron 57 12001) 6329±6343
Kamphuis, J.; Formaggio, F.; Crisma, M.; Toniolo, C.
Tetrahedron 2000, 56, 3589±3601.
62034) is gratefully acknowledged. D. B. B. is an Alfred P.
Sloan Research Fellow &1997±2001). We thank R. K.
Shoemaker for assistance with 2D NMR experiments and
R. Cerny &Nebraska Center for Mass Spectrometry) for mass
spectral support.
19. Theoretical study: &a) Aleman, C. J. Phys. Chem. B 1997, 101,
5046±5050. Helical peptide development: &b) Formaggio, F.;
Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman,
Q. B.; Kamphuis, J.; Toniolo, C. Chem. Eur. J. 2000, 6, 4498±
4504. &c) Schafmiester, C. E.; Po, J.; Verdine, G. L. J. Am.
Chem. Soc. 2000, 122, 5891±5892. &d) Mammi, S.; Rainaldi,
M.; Bellanda, M.; Schievano, E.; Peggion, E.; Broxterman,
Q. B.; Formaggio Fernando, C.; Marco Toniolo, C. J. Am.
Chem. Soc. 2000, 122, 11735±11736. &e) Yokum, T. S.;
Gauthier, T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am.
Chem. Soc. 1997, 119, 1167±1168. &f) Jaun, B.; Tanaka, M.;
Seiler, P.; KuÈhnle, F. N. M.; Braun, C.; Seebach, D. Liebigs
Ann. Recueil 1997, 1697±1710.
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