Synthesis of enantiomerically enriched β,γ-unsaturated-α-amino acids

Article abstract of DOI:10.1016/S0040-4020(00)01146-7

A variety of enantiomerically enriched β,γ-unsaturated-α-amino acids are synthesized by olefination of a Cbz-protected serine aldehyde equivalent, readily prepared from serine. A cyclic ortho ester protecting group is employed to minimize racemization. The deprotected amino acids are obtained in good yield, ranging from 70-95% ee, with double-bond geometry determined by the type of Wittig reagent used. Isotopically labeled side chains are readily introduced by this procedure, and free γ-¹³C-vinylglycine was prepared in 44% yield from the protected serine aldehyde synthon.

Full text of DOI:10.1016/S0040-4020(00)01146-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1497±1507
Synthesis of enantiomerically enriched
b,g-unsaturated-a-amino acids
Nicholas G. W. Rose, Mark A. Blaskovich, Alex Wong and Gilles A. Lajoiep
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received 25 September 2000; accepted 6 December 2000
AbstractÐA variety of enantiomerically enriched b,g-unsaturated-a-amino acids are synthesized by ole®nation of a Cbz-protected serine
aldehyde equivalent, readily prepared from serine. A cyclic ortho ester protecting group is employed to minimize racemization. The
deprotected amino acids are obtained in good yield, ranging from 70±95% ee, with double-bond geometry determined by the type of Wittig
reagent used. Isotopically labeled side chains are readily introduced by this procedure, and free g-13C-vinylglycine was prepared in 44% yield
from the protected serine aldehyde synthon. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
alcohol.9a An oxidation step is then required to generate
the amino acid, limiting the type of side chain functional
groups which can be present. 9b±d A variation of this strategy
employs a cysteine derived N-acylthiazolidinone as the
cyclic aldehyde; much milder oxidation conditions are
required to regenerate the acid moiety.10
b,g-Unsaturated-a-amino acids 1, otherwise known as the
vinylglycines, have been isolated from a variety of natural
sources.1 There is considerable interest in their biological
activity, in particular their ability to act as suicide substrates
or mechanistic probes of pyridoxal phosphate (PLP)
dependent enzymes.2 These enzymes are a vital link in
many biosynthetic pathways as they are involved in catalyz-
ing chemical changes at the a-, b-, or g-carbons of amino
acids. In addition, b,g-unsaturated-a-amino acids some-
times possess antimicrobial activity,3 can be useful
synthetic intermediates,4 and can serve as conformationally
restricted analogs of common amino acids for structure-
activity relationship studies.
We have recently described the development of a new
strategy for the synthesis of a variety of classes of amino
acids, based upon the elaboration of an optically active
serine-derived aldehyde in which the optical integrity is
maintained by a cyclic ortho ester carboxyl protecting
group.11±14 These syntheses have previously utilized the
9-¯uorenylmethoxycarbonyl (Fmoc) group for amine
protection. While this base sensitive moiety is stable to
the reaction of the serine aldehyde with stabilized ylides,11
it is quickly cleaved during attempts at reaction with
unstabilized reagents. We now report the ole®nation of the
corresponding benzyloxycarbonyl (Cbz) protected serine
derived aldehyde with a number of Wittig-type reagents
and under both Nozaki15 and Peterson16 conditions.
The b,g-unsaturated-a-amino acids pose a synthetic chal-
lenge, primarily due to the tendency of these compounds to
isomerize to the conjugated a,b-unsaturated derivatives. A
number of routes to racemic b,g-unsaturated-a-amino acids
have been reported.2j,5 Racemic vinylglycine itself was ®rst
synthesized in 1974 by a Strecker synthesis,6 while a
number of ef®cient syntheses of optically active vinyl-
glycine have been published since 1980.7 However, most
procedures rely upon the degradation of an amino acid, so
isotopic labeling is dif®cult, and no 13C-labeled compounds
have been reported. More versatile procedures for preparing
a number of b,g-unsaturated-a-amino acids have also
appeared.8 Probably the most effective synthetic route
makes use of a Wittig ole®nation of the serine derived
Garner aldehyde 2 to generate a b,g-unsaturated amino
2. Results
Cbz-l-serine 4 was readily converted to the Cbz protected
4-methyl-2,6,7-trioxabicyclo[2.2.2] ortho (OBO) ester 6
and oxidized to the aldehyde 7 under conditions identical
Keywords: vinylglycines; ole®nation; a-amino acid.
Corresponding author. Tel.: 1519-888-4620; fax: 1519-746-0435;
e-mail: glajoie@uwaterloo.ca
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01146-7

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N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
Scheme 1.
to those employed for the analogous Fmoc-protected
compounds (Scheme 1).11,13 The Cbz-protected alcohol 6
and aldehyde 7 crystallize more easily than the correspond-
ing Fmoc compound and is obtained in high ee (.95%).11
The Boc-protected compounds were also prepared, but were
obtained in reduced yields and as oils.13
Attempts to react the aldehyde 7 with unstablized ylides
initially focussed on the simplest reagent, methylenetri-
phenylphosphorane, which leads to protected vinylglycine
9b. A variety of ylide generation conditions were explored
(NaNH2/DMSO, NaNH2/THF, NaH/DMSO, n-BuLi/
DMSO, n-BuLi/THF), with minimal success. However,
KOt-Bu/Et2O, recommended as the best base to methylenate
sterically hindered ketones with triphenylmethylphos-
phorane,18 gave good yields (71%) of the alkene adduct
9b. Both the Boc and Fmoc-protected aldehydes could be
ole®nated under these conditions, albeit with reduced yields
(54% and 6%, respectively).
Reaction of the Cbz aldehyde 7 with the stabilized ylide
Ph3PvCH±CO2CH3 gave the desired ole®n 9a in 77%
yield from 6, with a ratio better than 95:5 E:Z geometry.
Unfortunately, deprotection to give the highly unstable9a,17
free b,g-unsaturated glutamic acid was unsuccessful.
Table 1. Ole®nation reactions with protected aldehyde 7
Entry
Reagent
Product
E:Z
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
8a Ph3PvCHCO2CH3
8b Ph3P1±CH3Br2
9a±CHvCHCO2CH3
9b±CHvCH2
9c±CHvCH2
.95:,5
±
±
77b
71b
76b
71b
64b
71b
55b
35b
53c
.95
77
86
72
72
±
±
±
.95
8c AlMe3/CH2I2/Zn
8d Ph3P1±13CH3Br2
8e Ph3P1±CH2EtBr2
8f (EtO)2P(O)±CH2CN
8g Ph3P1±CH2CHvCH2Br2
8h Ph3P1±CH2OCH3
8i TMSCH2MgCl
9d±CHv13CH2
±
9e±CHvCH±Et
9f±CHvCH±CN
9g±CHvCH±CHvCH2
9h±CHvCH2±OCH3
11i±CHvCH2
17:83
78:22
92:8
63:37
±
a
%ee determined after deprotection.
Yields after two steps.
Yields after three steps.
b
c

Figure 1. Assessment of enantiomeric purity of l-vinylglycine obtained after deprotection of (A) Cbz-l-Ser(CH2TMS)±OBO ester 10 after ion exchange puri®cation (B) Cbz-l-Gly(±CHvCH2)±OBO ester 9b after
ion exchange puri®cation. Amino acid samples were prepared as described in Section 5.

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N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
The KOtBu/Et2O conditions were employed to generate a
number of other unstabilized and semistabilized ylides,
including 13C-labeled methylenetriphenylphosphorane
(Table 1). Reaction with the Cbz-protected aldehyde
produced the alkenes 9e±h in 35±71% yield from 6, with
the double bond geometry corresponding to that expected
for the nature of the reagent: unstabilized ylides adding with
cis stereoselectivity (entry 5) while semistabilized reagents
produced predominantly trans isomers (entries 6±8). In
most cases the two isomers were readily separable by
¯ash chromatography with cis possessing a lower Rf than
the trans isomer.
76% yield with 86% ee via Nozaki ole®nation. Unfortu-
nately, recrystallization of the protected intermediate 9b
does not result in enrichment of optical purity, in contrast
to the resolution achieved by recrystallizing partially race-
mic Cbz-vinylglycine benzyl ester.7h A similar optical
purity was observed with the deprotected substituted g-
ethylvinylglycine.
Since Cbz cleavage is quantitative, puri®cation on an anion
exchange column instead of a cation exchange column
allows for the easy separation of any non-hydrolyzed
ester. The anion exchange column also has the advantage
that the only exposure of the deprotected vinylglycine to
base is during the very brief neutralization while the sample
is loaded onto the column.
Methylenation of the Cbz protected serine aldehyde 7 under
Nozaki conditions (AlMe3/CH2I2/Zn)15 gave protected
vinylglycine 9b in both good yield (76%) and ee (86%) as
determined by derivatization and subsequent HPLC analysis
described previously.11
3. Discussion
Formation of the terminal alkene 9b under Peterson ole®n-
ation conditions was also investigated. The b-hydroxyalkyl-
silane 10 was generated by Grignard reaction of
trimethylsilylmethylene magnesium chloride with serine
aldehyde 7 and proceeded in quantitative yield with threo
stereochemistry as previously reported.11,13a Base mediated
elimination failed to afford the desired ole®n 9b giving
instead oxazolidinone 12 as a single diastereomer in high
yield regardless of base used, temperature or length of reac-
tion. On the other hand, acid promoted elimination and
simultaneous deprotection of b-hydroxyalkylsilane 10
gave vinylglycine 11i (R0vR00vH) in good yield (74%)
with little epimerization (.95% ee) providing a route to
isotopically labeled vinylglycine by incorporating the
label in trimethylsilylmethylene magnesium chloride.
The partial racemization observed with unstabilized ylides
occurs during carbonyl addition, as the aldehyde is known to
be enantiomerically pure and the deprotection and deri-
vatization reactions have been shown to cause minimal
racemization.11
Nevertheless, this procedure has certain advantages over use
of the Garner aldehyde, in that no oxidation step is required
following alkene formation. The side chain must only be
resistant to acid hydrolysis. It should be noted that the
Garner aldehyde does not always lead to enantiomerically
pure products; in fact with methylenetriphenylphosphorane
generated by n-BuLi/THF, the alkene is obtained in 27%
yield and 69% ee;9a with KH/benzene, racemic material
is obtained.22 It is unclear why the propyltriphenylphos-
phorane derived ylide gives a product with 70% ee when
reacted with the Cbz/OBO ester protected aldehyde, while
giving a product with a reported .95% ee when reacted
with the Garner aldehyde. Nozaki conditions give the
protected vinylglycine in good yield but partial racemiza-
tion is observed.
2.1. Deprotection
Removal of the protecting groups from 9b with TMSI,
under conditions successfully used to deprotect Fmoc/
OBO ester protected serine11 (neat TMSI, 808C, 20 h,
aqueous NaOH workup, cation exchange column), led to
nearly quantitative conversion to a-aminobutyric acid.
This was identi®ed by comparison to authentic material
by TLC, HPLC and 1H and 13C NMR. The a-aminobutyric
acid was racemic as determined by both chiral HPLC analy-
sis of the derivatized amino acid and by optical rotation. A
variety of modi®ed conditions were explored, including
fewer equivalents of TMSI, dilution with CH2Cl2, reduced
reaction temperature, and in situ generated TMSI. The opti-
mum conditions (7 equiv. of TMSI diluted in CH2Cl2 at
room temperature) produced the desired vinylglycine 11
(R0vR00vH), but still resulted in 10% a-aminobutyric
acid contamination. Derivatization with o-phthalaldehyde
and N-i-Bu-l-cysteine followed by HPLC analysis20
showed that the a-aminobutyric acid was racemic, but the
vinylglycine possessed approximately 70% ee (Fig. 1).21
Attempts at base mediated Peterson ole®nation consistently
resulted in formation oxazolidinone 12 in high yield regard-
less of base used. This may be explained by the requirement
of the b-hydroxysilane to adopt the syn con®rmation which
is not easily achieved due to steric considerations
whereas oxazolidinone formation does not suffer from this
constraint. This is in contrast to the recently reported
synthesis of (S)-2-amino-(Z)-3,5-hexadecanoic acid in
which conjugation is installed through base-mediated
elimination of the Peterson ole®nation addition product.19
In this case the diene system does not suffer from this
limitation.
The production of a-aminobutyric acid during attempts at
deprotection of Cbz-vinylglycine-OBO ester with TMSI
appears to be due to the presence of trace amounts of HI,
which may add to the isomerized a,b-unsaturated alkene
bond following OBO ester ring-opening. However, the use
of 6N HCl to remove both the OBO and Cbz protecting
groups proved to be very successful in giving excellent
yield of vinylglycines.
Acid hydrolysis with re¯uxing 6N HCl has previously been
used to deprotect Cbz protected methyl7a or isopropyl
esters7e of vinylglycine in good yield. When the same con-
ditions were applied to Cbz-vinylglycine-OBO ester 9b the
free amino acid 11 (R0vR00vH) was obtained in 72% yield
with 71% ee when derived through Wittig ole®nation and

N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
1501
4. Conclusions
EtOAc/hex; B, 3:1 EtOAc/hex; C, 1:1:1:1 H2O/EtOAc/n-
BuOH/MeOH.
We have demonstrated the ability of the serine derived alde-
hyde OBO ester synthon to provide entry to another class of
amino acids, the vinylglycines, through ole®nation with a
variety of reagents. Partial racemization (10±15%) with
Wittig-type reagents occurs during the alkene formation,
but this disadvantage is balanced by the possibilities of
being able to readily synthesize a variety of unusual highly
functionalized molecules, including isotopically labeled
compounds that are of immense interest in mechanistic
enzymology. With the Peterson ole®nation conditions,
vinylglycine can be obtained in excellent yield and optical
purity.
5.1.1. 3-Methyl-3-(toluenesulfonyloxymethyl)oxetane,
oxetane tosylate, 3. A dry, 1 L round-bottomed ¯ask was
charged with toluene-4-sulfonyl chloride (57.20 g, 0.3 mol)
to which pyridine (250 mL) was added whilst stirring under
nitrogen. The reaction ¯ask was placed inside a container to
which an ice/water mixture could be added in the event that
the reaction became too exothermic. 3-Methyl-3-oxetane-
methanol (20.4 g, 0.2 mol) was then added slowly and the
mixture stirred for 1.5 h. The mixture was then slowly added
to a vigorously stirring mixture of de-ionized water
(700 mL) and crushed ice (700 g) in a 2 L Erlenmeyer
¯ask and allowed to stir for an additional 0.5 h. The white
precipitate was then collected on Whatman ®lter paper #1
and washed with cold H2O. The product was dried under
high vacuum and/or P2O5 to obtain the white powder of
oxetane tosylate 3 (49.11 g, 92%). Mp 49.5±518C. TLC
5. Experimental
5.1. General methods
1
(3:2, Hex/EtOAc) Rfˆ0.42; H NMR (CDCl3, 250 MHz)
d 7.81 (d, Jˆ8.2 Hz, 2H), 7.37 (d, Jˆ8.2 Hz, 2H), 4.37
(m, 4H), 4.11 (s, 2H), 2.46 (s, 3H), 1.31 (s, 3H); 13C NMR
(CDCl3, 63 MHz) d 145.1, 132.8, 129.9, 127.9, 78.9, 74.2,
39.3, 21.6, 20.6. HRMS (FAB) calcd for (M1H1) C12H16O4S
256.0769, found 256.0774. Anal. Calcd for C12H16O4S: C,
56.23; H, 6.29. Found: C, 56.33; H, 6.44.
Cbz-l-Serine was purchased from Advanced Chemtech and
most other reagents from Aldrich Chemical Company and
were used without further puri®cation with the following
exceptions. Zn dust was washed several times with 5%
hydrochloric acid, washed with copious amounts of water,
followed by methanol, then ether and dried under high
vacuum. CH2Cl2, DMSO, and DIPEA were distilled from
CaH2; THF and Et2O from Na/benzophenone. Reactions
were carried out under Ar in glassware dried overnight at
1208C or ¯ame dried before use.
5.1.2. N-(Benzyloxycarbonyl)-l-serine-3-methyl-3-
hydroxymethyl-oxetane ester, Cbz-l-Ser-oxetane ester,
5. Cbz-l-Ser 4 (11.36 g, 0.047 mol) and Cs2CO3 (9.19 g,
0.028 mol) were combined and dissolved in H2O
(100 mL). The water was then removed in vacuo and the
resulting oil was lyophilized for 12 h to give a white foam.
To this foam was added oxetane tosylate (12.65 g,
0.049 mol) and NaI (1.41 g, 9.8 mmol) which was then
taken up in DMF (400 mL) and allowed to stir under Ar
for 48 h. The DMF was then removed in vacuo and the
resulting solid dissolved in EtOAc (600 mL) and H2O
(200 mL) and extracted with 10% NaHCO3 (2£100 mL),
saturated NaCl (100 mL) and dried over MgSO4. The
solvent was removed under reduced pressure to yield a
yellow oil which was recrystallized from ethyl acetate and
hexanes to yield colourless rod-like crystals in 78% yield
NMR spectra were recorded in CDCl3 (referenced to TMS
at 0.00 ppm for 1H, to CDCl3 at 77.00 ppm for 13C) or D2O
(referenced to 2,2,3,3-d4-3-(trimethylsilyl)propionic acid at
1
0.00 ppm for both H and 13C) on a Bruker AC-200, AM-
250 or AM-300 spectrometer. CDCl3 used for NMR
samples containing an ortho ester was pre®ltered through
basic alumina to remove traces of acid. IR spectra were
recorded on a Bomem MB-100 FT±IR spectrophotometer.
Optical rotations were measured on a Jasco DIP-360 digital
polarimeter. Melting points were determined on a Mel-
Temp apparatus in an open capillary tube and are uncor-
rected. Low and high-resolution mass spectral analyses
(11.85 g). Mp 70±70.58C; [a]20 ˆ176.1 (cˆ0.5, H2O);
Â
were carried out by Gaston Boulay at the Universite de
D
1
TLC (Solvent A), Rfˆ0.34; H NMR (CDCl3, 250 MHz)
Sherbrooke. For deprotected amino acids, a low resolution
mass was obtained on a Kratos MALDI 3 matrix assisted
laser desorption time of ¯ight mass spectrometer. Samples
were prepared using 1 mL of a 1 nmol/mL solution, mixed
on the sample slide with sinapinic acid. The sodium
(M1ˆ23), potassium (M1ˆ39), and sinapinic acid
(MH1ˆ225, MH1218ˆ207) peaks were used as internal
mass calibrants. Standard positive ion mode was used for
most samples for maximum sensitivity; for those
compounds with molecular weights close to matrix peaks
re¯ectron mode was used to increase resolution. Elemental
analyses were determined by M-H-W Laboratories in
Phoenix, Arizona. HPLC analyses were performed using a
Waters 600E System Controller with Waters 600 Multi-
solvent Delivery System, Model 481 or 486 Variable Wave-
length UV/Vis Detector, and Waters 745 Data Module. TLC
was carried out on Merck aluminum backed silica gel 60
F254, with visualization by UV, ninhydrin solution (2% in
EtOH), or I2. TLC solvent systems commonly used: A, 1:1
d 7.35 (s, 5H), 5.89 (d, Jˆ7.4 Hz, 1H), 5.12 (s, 2H),
4.55±4.39 (m, 6H), 4.14±4.06 (m, 1H), 4.11 (d,
Jˆ11.2 Hz, 1H), 3.92±3.78 (m, 1H), 3.12 (t, Jˆ6.0 Hz,
1H), 1.28 (s, 3H); 13C NMR (CDCl3, 62.9 MHz) d 170.6,
156.2, 136.1, 128.5, 128.2, 128.1, 79.4, 69.0, 67.1, 63.3,
56.4, 39.6, 20.7; IR (cast from CH2Cl2) 3371 (br m), 3064
(vw), 3034 (vw), 2956 (m), 2879 (m), 1723 (s), 1525 (m),
1457 (w), 1339 (m), 1214 (m), 1195 (m), 1061 (m), 978 (w),
834 (w), 744 (w), 699 (w) cm21; MS (CI, CH4) m/z 324
(MH1, 100), 306 (MH1218, 76), 293 (MH1231, 65),
280 (MH1244, 29); HRMS (CI, CH4) Calcd for
C16H22O6N: 324.1447. Found: 324.1454 (MH1); Anal.
Calcd for C16H21O6N: C, 59.43; H, 6.55; N, 4.33. Found:
C, 59.51; H, 6.57; N, 4.36.
5.1.3. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-2-ethanol]-
4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octane, Cbz-l-Ser-
OBO ester, 6. Cbz-Ser oxetane ester
5 (15.0 g,

1502
N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
46.2 mmol) was dissolved in dry CH2Cl2 (450 mL) and
cooled to 08C under Ar. BF3´Et2O (0.11 mL, 0.93 mmol)
was diluted in CH2Cl2 (5.0 mL) and added to the reaction
¯ask after which the reaction was allowed to warm up to
room temperature. After 6 h, Et3N (1.29 mL, 9.25 mmol)
was added and the reaction was stirred for an additional
30 min before being concentrated to a thick oil. The crude
product was redissolved in EtOAc (400 mL) and washed
with 3% NH4Cl (2£250 mL), 10% NaHCO3 (100 mL), satu-
rated NaCl (250 mL), dried (MgSO4), and evaporated to
dryness. The reaction yielded a colourless thick oil in
95% (14.2 g) yield was crystallized from EtOAc to give
rod-like shiny crystals in 93% (13.6 g) yield. Mpˆ103.5±
1046 (s), 1012 (m), 990 (w), 946 (w), 895 (w), 747 (w), 699
(w) cm21 HRMS (FAB) calculated for (M1H1)
C16H20O6N: 322.12906; observed: 322.12854. Anal. Calcd
for C16H20O6N: C, 59.81; H, 5.96; N, 4.36. Found: C, 59.72;
H, 6.12; N, 4.33.
;
5.2. General procedure for Wittig addition to the
protected aldehyde
The ylide was prepared by suspending potassium tert-
butoxide (2.1 equiv.) in freshly distilled Et2O (2±4 mL)
under N2. The phosphine salt or phosphine oxide
(2.3 equiv.) was then added, and the resulting brightly
colored suspension was re¯uxed for 15 min. The Et2O was
then evaporated with a stream of N2 until a thick slurry was
obtained, at which point a solution of crude Cbz-Ser(ald)-
OBO ester 7 (1 equiv., 0.8±1.6 mmol assuming 100% yield
of the aldehyde from the oxidation) in freshly distilled THF
(2±3 mL) was added. After 5±10 min at 508C, the reaction
was poured into H2O (20 mL) and CH2Cl2 (20 mL). The
layers were separated, the H2O washed with CH2Cl2
(50 mL), and the organic fractions were then combined,
washed with H2O (1£100 mL), dried (MgSO4), and evapo-
rated to dryness. The residue was puri®ed by ¯ash column
chromatography (1:1 EtOAc/hexane, loaded in CH2Cl2).
105.08C; [a]20 ˆ224.8 (cˆ1.00, EtOAc); TLC (3:1
D
1
EtOAc/hexane), Rfˆ0.37; H NMR (CDCl3, 250 MHz) d
7.36±7.31 (m, 5H), 5.34 (br d, Jˆ8.8 Hz, 1H), 5.17±5.11
(m, 2H), 3.94±3.83 (m, 2H), 3.91 (s, 6H), 3.71±3.67 (m,
1H), 2.60 (br s, 1H), 0.81 (s, 3H); 13C NMR (CDCl3,
62.9 MHz) d 156.3, 136.4, 128.4, 128.0, 127.9, 108.0, 72.7,
66.9, 61.9, 55.3, 30.5, 14.2; IR (cast from CH2Cl2) 3407 (br
m), 3063 (vw), 3033 (vw), 2948 (m), 2883 (m), 1716 (s), 1607
(vw), 1586 (vw), 1527 (m), 1399 (m), 1352 (m), 1237 (m),
1048 (s), 1010 (s), 990 (m), 885 (w), 773 (w), 743 (w), 699 (w)
cm21; MS (CI, CH4) m/z 324 (MH1, 100), 316 (MH128, 73);
HRMS (CI, CH4) Calcd for C16H22O6N: 324.1447. Found:
324.1435 (MH1); Anal. Calcd for C16H21O6N: C, 59.43; H,
6.55; N, 4.33. Found: C, 59.43; H, 6.64; N, 4.34.
5.2.1. Wittig addition of Ph3PvCH±CO2CH3 to Cbz-l-
Ser(ald)-OBO ester 7: 1-[methyl-N-(benzyloxycarbonyl)-
(1S)-1-amino-(E)-2-butenoate]-4-methyl-2,6,7-trioxabicyclo-
[2.2.2]-octane, Cbz-l-trans-b,g-dehydro-Glu (OCH3)±OBO
ester, 9a. Cbz-l-Ser(ald)-OBO ester 7 (0.099 g, 0.31 mmol
assuming 100% yield in the oxidation), Ph3PvCH±
CO2CH3 (0.120 g, 0.359 mmol, 1.2 equiv.), and dry
CH2Cl2 (6 mL) were added to a ¯ask and stirred at room
temperature for 20 min. The reaction was washed with 3%
NH4Cl (3£10 mL), dried (MgSO4), and evaporated to
dryness. Puri®cation by ¯ash column chromatography (1:1
EtOAc/hexane), yielded 0.089 g of white solid (77% from
6), with a .95:,5 E/Z ratio (as determined by NMR inte-
gration of the alkene protons). The oil crystallized upon
5.1.4. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-2-oxoethyl]-
4-methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-l-Ser(ald)-
OBO ester, 7. Cbz-Ser OBO ester 6 (9.04 g, 27.86 mmol)
was dissolved in freshly distilled CH2Cl2 (80 mL) under Ar
and cooled to 2788C in ¯ask 1. Oxalyl chloride (3.89 mL,
44.58 mmol, 1.60 equiv.) was added to CH2Cl2 (120 mL) in
a separate round bottom ¯ask (¯ask 2) under Ar, and cooled
to 2788C. Dry DMSO (7.03 mL, 91.94 mmol, 3.30 equiv.)
was added quickly to the oxalyl chloride solution (¯ask 2)
and the mixture was stirred at 2788C for 15 min. The alco-
hol solution was transferred slowly by cannula to ¯ask 2
over a period of 45 min and then rinsed with CH2Cl2
(50 mL). The resulting cloudy, white mixture was stirred
for 1.5 h at 2788C. DIPEA (24.27 mL, 0.14 mol) was
added and the solution stirred for 30 min at 2788C and
10 min at 08C. Ice-cold CH2Cl2 (250 mL) was added and
the solution was washed with ice-cold 3% NH4Cl
(3£250 mL), 10% NaHCO3 (100 mL), saturated NaCl
(250 mL), dried (MgSO4), and evaporated to dryness. The
reaction yielded a slightly yellowish solid in 96% (8.68 g)
yield. The enantiomeric purity of Cbz-Ser(ald) OBO ester
was determined by chiral shift 1H NMR studies. Cbz-
Ser(ald) OBO ester 6 (10 mg) was dissolved in benzene-
d6. Eu(hfc)3 (100 mL, 50 mg/mL in benzene-d6) was added
to obtain the 1H NMR spectrum at 250 MHz. The purity was
observed to be 97±99% ee. Recrystallization was possible
standing. Mp 106±1088C; [a]20 ˆ233.2 (cˆ1.16,
D
1
EtOAc); TLC (Solvent B) Rf 0.37 (E); H NMR (CDCl3,
200 MHz) d 7.35 (s, 5H), 6.99 (dd, Jˆ15.8, 5.0 Hz, 1H),
6.01 (dd, Jˆ15.8, 1.6 Hz, 1H), 5.20 (d, Jˆ9.3 Hz, 1H), 5.12
(s, 2H), 4.57 (ddd, Jˆ8.4, 4.3, 1.4 Hz, 1H), 3.89 (s, 6H),
3.72 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3, 50.3 MHz) d
166.4, 155.8, 143.2, 136.2, 128.4, 128.1, 122.4, 107.6, 72.8,
67.0, 56.0, 51.5, 30.7, 14.1; IR (Nujol mull) 3347 (br w),
3063 (vw), 3033 (vw), 2949 (w), 2883 (w), 1720 (s), 1663
(w), 1606 (vw), 1587 (vw), 1518 (m), 1456 (w), 1436 (w),
1309 (m), 1275 (m), 1247 (m), 1196 (m), 1172 (w), 1049 (s),
1013 (m), 887 (w), 862 (w), 750 (w), 699 (w) cm21; MS (EI,
70 eV) m/z 377 (M1, 81), 335 (M1242, 6), 302 (M1275,
18), 270 (M12107, 43), 242 (M12135, 1008); HRMS (EI,
70 eV) Calcd for C19H23O7N: 377.1474. Found:
377.1474^0.0011 (M1); Anal. Calcd for C19H23O7N: C,
60.47; H, 6.16; N, 3.71. Found: C, 60.43; H, 5.91; N, 3.73.
from EtOAc/hexane. Mp 139.5±141.58C; [a]20 ˆ299.3
D
(cˆ1.03, EtOAc); TLC (3:1 EtOAc/hex), Rfˆ0.60; 1H
NMR (CDCl3, 250 MHz) d 9.69 (s, 1H), 7.38±7.30 (m,
5H), 5.34 (d, Jˆ9.2 Hz, 1H), 5.15±5.10 (m, 2H), 4.61 (d,
Jˆ8.9 Hz, 1H), 3.94 (s, 6H), 0.83 (s, 3H); 13C NMR (CDCl3,
63 MHz); d 195.6, 156.1, 136.1, 128.4, 128.1, 107.1, 72.8,
67.1, 63.2, 30.8, 14.2; IR (cast from CH2Cl2) 3353 (br m),
3063 (vw), 3033 (vw), 2947 (w), 2884 (w), 1723 (s br), 1599
(vw), 1521 (m), 1355 (m), 1234 (m), 1192 (w), 1071 (m),
5.2.2. Wittig addition of Ph3PvCH2 to Cbz-l-Ser(ald)-
OBO ester 4: 1-[N-(benzyl-oxycarbonyl)-(1S)-1-amino-
2-propene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-
l-Gly(-CHvCH2)±OBO ester, 9b. Crude Cbz-Ser(ald)-
OBO ester 7 (0.524 g, 1.63 mmol assuming 100% yield of

N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
1503
the aldehyde from the oxidation) was reacted with the
yellow ylide generated from MeP1Ph3Br- according to the
general procedure. Puri®cation gave 0.368 g (71% from 6)
1H), 3.89 (s, 6H), 3.68 (d, Jˆ10.3 Hz, 1H), 0.85 (dd,
Jˆ9.6, 14.7 Hz, 1H), 0.78 (s, 3H), 0.60 (dd, Jˆ4.7,
14.7 Hz, 1H), 0.02 (s, 9H); 13C NMR (CDCl3, 75 MHz) d
157.2, 136.7, 128.6, 128.5, 128.2, 108.9, 72.8, 67.1, 60.5,
59.1, 30.7, 21.5, 14.3, 20.8; IR (cast from CH2Cl2) 3389 (br
w), 3064 (vw), 3033 (vw), 2944 (w), 2881 (m), 1719 (s br),
1510 (m), 1387 (w), 1336 (m), 1223 (m), 1053 (s), 995 (s),
cm21; Anal. Calcd for C20H31NO6Si: C, 58.65; H, 7.63; N,
3.42. Found: C, 58.56; H, 7.85; N, 3.21.
of a thick oil ([a]20 ˆ261.9 (cˆ1.00, EtOAc)); 75% ee by
D
HPLC analysis). The oil could be crystallized from Et2O/
hexane to give colourless crystals: mp 73±748C;
[a]20 ˆ268.5 (cˆ1.12, EtOAc); TLC (Solvent A) Rf
D
1
0.48; H NMR (CDCl3, 250 MHz) d 7.34±7.25 (m, 5H),
5.92 (ddd, Jˆ17.2, 10.5, 5.5 Hz, 1H), 5.31±5.06 (m, 3H),
5.12 (s, 2H), 4.43 (br t, Jˆ6.9 Hz, 1H), 3.89 (s, 6H), 0.78 (s,
3H); 13C NMR (CDCl3, 50.3 MHz) d 156.0, 136.5, 133.2,
128.4, 128.0, 116.7, 108.0, 72.8, 67.8, 57.1, 30.7, 14.3; IR
(cast from CH2Cl2) 3371 (br w), 3064 (vw), 3033 (vw), 2944
(w), 2881 (m), 1722 (s br), 1646 (vw), 1515 (m), 1397 (w),
1336 (m), 1223 (m), 1053 (s), 995 (s), 932 (w), 748 (w), 699
(w) cm21; MS (EI, 70 eV) m/z 319 (M1, 13), 246 (M1273,
100), 236 (M1283, 13), 228 (M1291, 22), 218 (M12101,
23); HRMS (EI, 70 eV) Calcd for C17H21O5N: 319.1420.
Found: 319.1427 (MH1); Anal. Calcd for C17H21O5N: C,
63.94; H, 6.64; N, 4.39. Found: C, 64.09; H, 6.73; N, 4.36.
5.2.5. Deprotection of Cbz-l-Gly(-CHvCH2)±OBO
ester 9b: l-vinylglycine, 11b.
(a) TMSI. Cbz-l-Gly(±CHvCH2)±OBO ester 9b (0.230 g,
0.720 mmol) was treated with TMSI (1.5 mL, 10.5 mmol,
15 equiv.) at 808C for 20 h. After cooling, Et2O (3 mL) was
carefully added, followed by the dropwise addition of 0.5N
NaOH (5 mL). The organic layer was removed and washed
with 0.5N NaOH (2£4 mL). The aqueous fractions were
combined, washed (2£5 mL Et2O), acidi®ed to pH,3
with 2N HCl and puri®ed on a cation exchange column
(loaded on a Bio-Rad AG 50W-X8 100±200 mesh, hydro-
gen form, 1£12 cm, washed with 0.01N HCl and H2O, then
eluted with 5% Et3N in H2O, or, alternately, a 1 M NH4OH
solution). The eluate was evaporated to dryness under
vacuum gave 0.0681 g (92%) of a colorless solid, which
NMR and ES±MS analysis revealed to be predominantly
5.2.3. Nozaki ole®nation of Cbz-l-Ser(ald)-OBO ester 7:
1-[N-(benzyl-oxycarbonyl)-(1S)-1-amino-2-propene]-4-
methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-l-Gly(-CHv
CH2)±OBO ester, 9b. Crude Cbz-Ser(ald)-OBO ester 7
(0.50 g, 1.56 mmol assuming 100% yield of the aldehyde
from the oxidation) was dissolved in dry THF (10 mL) then
added via cannula to a stirring mixture of zinc dust (0.918 g,
14.04 mmol), freshly distilled diiodomethane (0.376 g,
4.67 mmol) and trimethylaluminum (0.47 mL, 0.94 mmol,
2.0 M in hexanes) in dry THF (10 mL) under Ar. The
mixture was stirred at room temperature for 4 h before
cold 3% NH4Cl (10 mL) was added. The resulting alumi-
num salt was ®ltered off and the ®ltrate extracted with
EtOAc (3£40 mL). The organic layers were pooled and
extracted with 3% NH4Cl (2£25 mL), 10% NaHCO3
(25 mL), saturated NaCl (25 mL) and dried over MgSO4.
The solvent was removed under reduced pressure and the
resulting slightly yellow oil puri®ed by ¯ash chroma-
tography (EtOAc/hex 1:1) to give a clear oil which was
crystallized from Et2O/hexanes to give 0.35 g of 9c (76%
a-aminobutyric acid: [a]25 ˆ0.2 (cˆ0.47, AcOH); 1H
D
NMR (D2O, 250 MHz) d 4.27 (d, Jˆ7.6 Hz, 1H), 1.90
(quintet, Jˆ7.1 Hz, 2H), 0.98 (t, Jˆ7.5 Hz, 3H); 13C NMR
(D2O, 62.7 MHz) d 177.7, 58.7, 26.5, 11.3; MS (ES) m/z
104 (MH1). Derivatisation with o-phthaladehyde and N-iso-
butyryl-l-cysteine, and analysis by HPLC, with comparison
to commercial a-aminobutyric acid and vinylglycine stand-
ards, indicated a 50:50 ratio of l- and d-isomers (Waters
125, 8£100 mm m-Bondapak C18 Radial-Pake cartridge
column, 1 mL/min; 100% 30 mM sodium acetate buffer,
pH 6.5; linear gradient over 35 min to 50:50 buffer/
MeOH; detection at 338 nm; diastereomers formed by l-
a-aminobutyric acid at 28.9 min, by d-a-aminobutyric
acid at 31.1 min, by l-vinylglycine at 26.6 min, and by d-
vinylglycine at 28.5 min). The reaction time, temperature,
source of TMSI and equivalents of TMSI were all varied in
attempts to produce the desired vinylglycine. Ratios of a-
aminobutyric acid and vinylglycine were determined by
both 1H NMR and HPLC, as outlined above. For monitoring
the reactions over time, an aliquot (5±50 mL) was removed,
added to 0.5N NaOH (100±300 mL), and extracted with
Et2O (1 mL). A portion of the aqueous fraction (10±
40 mL) was then derivatized and analyzed as outlined
above. For the in situ generation of TMSI, NaI (10 equiv.)
and the alkene were dissolved in CH3CN, and TMSCl
(10 equiv.) was added.
yield). Mp 73±748C; [a]20 ˆ266.5 (cˆ0.9, EtOAc) 86%
D
ee by HPLC analysis.
5.2.4. Grignard addition of trimethylsilylmethylmag-
nesium chloride to Cbz-l-Ser(ald)-OBO ester 7: 1-[N-
(benzyloxycarbonyl)-(1S)-1-amino-2-hydroxy-3-(1,1,1-
trimethylsilyl)propyl]-4-methyl-2,6,7-trioxabicyclo[2.2.2]-
octane, Cbz-l-Ser(CH2TMS)±OBO ester, 10. Crude Cbz-
Ser(ald)-OBO ester 7 (0.40 g, 1.25 mmol assuming 100%
yield of the aldehyde from the oxidation) was dissolved in
dry THF (40 mL) to which trimethylsilylmethylmagnesium
chloride (5.0 mL, 5.0 mmol, 1.0 M in Et2O) was added by
syringe. The mixture was re¯uxed under Ar for 6 h before
3% NH4Cl (20 mL) was added and then extracted with
EtOAc (3£50 mL). The organic fractions were pooled and
then extracted with 3% NH4Cl (2£25 mL), 10% NaHCO3
(25 mL), saturated NaCl (25 mL) and dried over MgSO4.
The solvent was removed in vacuo and the resulting oil
puri®ed by ¯ash chromatography to give 1.42 g (72%
(b) Acid hydrolysis of 9b with 6N HCl. Cbz-l-Gly(±CHv
CH2)±OBO ester 9b (0.230 g, 0.720 mmol) was mixed with
6N HCl (2.0 mL) and re¯uxed for 1 h. The solution was
cooled, neutralized with a saturated solution of NaHCO3
(approx. 50 mL), then loaded on an anion exchange column
(Bio-Rad AG 1-X4 100±200 mesh, chloride form,
converted to hydroxide form by prewashing with 4N
NaOH). The column was washed with H2O, and eluted
with 1N AcOH, then lyopholized to give 0.0109 g (79%)
of a colorless powder. Recrystallization (H2O/acetone) gave
1
yield) of a colorless oil. TLC (Solvent A) Rf 0.58; H
NMR (CDCl3, 250 MHz) d 7.40±7.26 (m, 5H), 5.32 (d,
Jˆ10.3 Hz, 1H), 5.12 (s, 2H), 4.31 (dd, Jˆ4.8, 9.7 Hz,

1504
N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
0.0100 g (72%) of solid. Derivatisation with o-phthalalde-
hyde and N-isobutyryl-l-cysteine, and analysis by HPLC
indicated 77% ee (conditions as outlined above): mp 178±
with o-phthaladehyde and N-isobutyryl-l-cysteine, and
analysis by HPLC indicated 72.2% ee (conditions as
outlined above): mp 178±1818C (dec); TLC (Solvent C)
1
1
1808C (dec); TLC (Solvent C) Rf 0.46; H NMR (D2O,
Rf 0.46; H NMR (D2O, 250 MHz) d 5.92±5.72 (m, 1H),
200 MHz) d 5.85 (ddd, Jˆ17.4, 10.1, 7.4 Hz, 1H), 5.38
(d, Jˆ17.2 Hz, 1H), 5.38 (d, Jˆ10.4 Hz, 1H), 4.27 (d,
Jˆ7.3 Hz, 1H); 13C NMR (D2O, 50.3 MHz): d 174.7,
132.0, 124.8, 59.1; MS (LD, sinapinic acid) m/z 102 (MH1).
5.36 (ddd, Jˆ154.9, 17.0, 0.6 Hz, 1H), 5.36 (ddd, Jˆ161.1,
10.2, 0.7 Hz, 1H), 4.13 (td, Jˆ6.5, 0.7 Hz, 1H); 13C NMR
(D2O, 62.7 MHz): d 174.7, 132.9 (d, Jˆ70.1 Hz, CHv
13CH2), 124.0 (s, superimposed on d, Jˆ69.8 Hz, relative
intensity 180:1, CHv13CH2), 59.8; MS (LD, sinapinic acid)
m/z 103 (MH1); Anal. Calcd for C313CH7O2N: H, 6.91; N,
13.72. Found: H, 7.06; N, 13.55.
(c) Acid hydrolysis of 10 with 6N HCl. Cbz-l-Ser-
(CH2TMS)±OBO ester 10 (0.140 g, 0.34 mmol) was
mixed with 6N HCl (10.0 mL) and re¯uxed for 3 h. The
solution was cooled extracted twice with ether (2£5 mL),
neutralized with a saturated solution of NaHCO3 (approx.
50 mL), then loaded on an anion exchange column (Bio-Rad
AG 1-X4 100±200 mesh, chloride form, converted to
hydroxide form by prewashing with 4N NaOH). The
column was washed with H2O, and eluted with 1N AcOH,
then lyopholized to give 0.028 g (81%) of a colorless
powder. Recrystallization (H2O/acetone) gave 0.025 g
(74%) of solid. Derivatisation with o-phthaladehyde and
N-isobutyryl-l-cysteine, and analysis by HPLC indicated
95% ee (conditions as outlined above): mp 177±1808C
(dec); TLC (Solvent C) Rf 0.46.
5.2.8.
1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-(Z)-2-
pentene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-
l-cis-Gly(±CHvCH±Et)±OBO ester, 9e. Crude Cbz-
Ser(ald)-OBO ester 7 (0.241 g, 0.739 mmol assuming
100% yield of the aldehyde from the oxidation) was reacted
with the orange±yellow ylide generated from
Ph3P1CH2CH2CH3Br2 according to the general procedure.
Puri®cation gave 0.164 g (64% from 6) of an 83:17 Z/E
mixture as an oil. Crystallization from Et2O/hexane gave a
colorless solid with the same Z:E ratio: mp 98±99.58C;
[a]25 ˆ20.3 (cˆ1.26, EtOAc); TLC (Solvent A) Rf 0.72;
D
1H NMR (CDCl3, 250 MHz) Z/E 83:17: d 7.35±7.28 (m,
5H), 5.62 (br dt, Jˆ10.0, 7.6 Hz, 1H, cis1trans CHvCH±
CH2), 5.46 (dd, Jˆ15.6, 6.1 Hz, 0.17H, trans CHvCH±
CH2), 5.31 (br t, Jˆ10.0 Hz, 0.83H, cis CHvCH±CH2),
5.10 (br s, 3H), 4.67 (br t, Jˆ9.1 Hz, 1H), 3.90 (s, 6H),
2.20±2.00 (br m, 2H), 0.97 (br t, Jˆ7.3 Hz, 3H), 0.79 (s,
3H); 13C NMR (CDCl3, 62.9 MHz) d 155.6, 136.6 (cis
CHvCH±Et), 136.4, 135.1 (w, trans CHvCH±Et),
128.4, 128.0, 127.9, 124.0 (cis CHvCH±Et), 123.9 (w,
trans CHvCH±Et), 108.4, 72.8, 66.7, 52.1, 30.7, 25.3 (w,
trans vCH±CH2±CH3), 21.1 (cis vCH±CH2±CH3), 14.2,
14.0 (cis vCH±CH2±CH3), 13.2 (w, trans vCH±CH2±
CH3); IR (cast from CH2Cl2) 3451 (br w), 3360 (br w),
3063 (vw), 3029 (vw), 2962 (m), 2934 (w), 2879 (m),
1722 (s), 1608 (vw), 1587 (vw), 1511 (m), 1456 (w), 1397
(w), 1334 (m), 1219 (m), 1049 (s), 1008 (s), 995 (s), 890
(w), 811 (w), 754 (w), 699 (w) cm21; MS (EI, 70 eV) m/z
347 (M1, 100), 256 (M1291, 20), 218 (M12129, 41);
HRMS (EI, 70 eV) Calcd for C19H25O5N: 347.1733.
Found: 347.1729 (M1); Anal. Calcd for C19H25O5N: C,
65.69; H, 7.27; N, 4.03. Found: C, 65.72; H, 7.00; N, 4.04.
5.2.6. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-3-13C-2-
propene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-
l-Gly(±CHv13CH2)±OBO ester, 9d. Crude Cbz-Ser(ald)-
OBO ester 7 (0.395 g, 1.19 mmol assuming 100% yield of the
aldehyde from the oxidation) was reacted with the ylide
generated from (13CH3)3P1Ph3I2 according to the general
procedure. Puri®cation gave 0.237 g (62% from 6) of a
thick oil. The oil could be crystallized from Et2O/hexane to
give 0.082 g (21%) of a ®rst crop of colourless plate crystals.
The ®ltrate ([a]25 ˆ233.2, (cˆ0.62, EtOAc) was depro-
D
tected without further puri®cation. The deprotected amino
acid was determined to have 72% ee, the same as the
unlabeled analog prepared by the same procedure, despite
the unlabeled protected vinylglycine having substantially
better optical rotation. [a]25 ˆ24.7 (cˆ1.16, EtOAc); TLC
D
(Solvent A) Rf 0.46; 1H NMR (CDCl3, 250 MHz) d 7.34±7.25
(m, 5H), 5.92 (ddd, Jˆ16.7, 10.6, 5.8 Hz, 1H), 5.27 (dd,
Jˆ17.9, 15.8 Hz, 1H), 5.21 (dd, Jˆ15.9, 10.4 Hz, 1H),
5.15±5.06 (m, 1H), 5.12 (s, 2H), 4.49±4.35 (br m, 1H), 3.90
(s, 6H), 0.79 (s, 3H); 13C NMR (CDCl3, 62.9 MHz) d 155.9,
136.5, 133.2, 128.3, 127.9, 116.6 (s, superimposed on d,
Jˆ71.6 Hz, relative intensity s:d 172:1: CHv13CH2), 107.9,
72.8, 67.7, 57.1, 30.6, 14.2; IR (cast from CH2Cl2) 3369 (br
w), 3066 (vw), 3031 (vw), 2943 (w), 2880 (m), 1722 (s br),
1622 (vw), 1587 (vw), 1514 (m), 1456 (w), 1397 (w), 1335
(m), 1222 (m), 1052 (s), 994 (s), 922 (w), 882 (w), 773 (w),
748 (w), 698 (w) cm21; MS (EI, 70 eV) m/z 320 (M1, 100),
245 (M1275, 8), 229 (M1291, 14), 220 (M12100, 12), 213
(M12107, 25); HRMS (EI, 70 eV) Calcd for C1613CH21O5N:
320.1453. Found: 320.1445 (M1).
5.2.9. Deprotection of Cbz-l-Gly(±CHvCH2±Et)±OBO
ester 9e: Z-ethylvinylglycine, 11d. Cbz-l-Gly(±CHv
CH2±Et)±OBO ester 9d (0.071 g, 0.210 mmol) was depro-
tected with 6N HCl (2.0 mL) and puri®ed by anion
exchange column as described above to give 0.022 g
1
(83%) of a colorless powder, with 83:17 Z/E ratio by H
NMR. Derivatization with o-phthaladehyde and N-isobutyryl-
l-cysteine, and analysis by HPLC indicated 72% ee (Waters
125 m 8£100 mm m-Bondapak C18 Radial-Pake cartridge
column, 2 mL/min; 100% 30 mM sodium acetate buffer, pH
6.5; linear gradient over 60 min to 20:80 buffer/MeOH;
detection at 338 nm; diastereomers formed by l-ethylvinyl-
glycine at 38.0 min, and by d-ethylvinylglycine at 39.9 min.
The E and Z isomers were not resolved): TLC (Solvent C) Rf
5.2.7. Deprotection of Cbz-l-Gly(±CHv13CH2)±OBO
ester 9d: g-13C-vinylglycine 11d. Cbz-l-Gly(±CHv
13CH2)±OBO ester 9d (0.121 g, 0.376 mmol) was depro-
tected with 6N HCl (3.0 mL) and puri®ed by anion
exchange chromatography as outlined above to give
0.028 g (71%) of a colorless powder. Recrystallization
(H2O/acetone) gave 0.023 g (60%) of solid. Derivatization
1
0.58; H NMR (D2O, 250 MHz) cis isomer: d 5.82 (dt,
Jˆ10.2, 8.3 Hz, 0.85H), 5.29 (dd, Jˆ10.2, 0.5 Hz, 0.85H),
4.45 (dd, Jˆ10.2, 0.5 Hz, 0.85H), 2.10 (m, 1.7H), 0.90 (t,
Jˆ7.5 Hz, 2.55H) trans isomer: d 5.93 (dt, Jˆ15.3, 6.0 Hz,

N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
1505
0.15H), 5.43 (dd, Jˆ15.3, 8.3 Hz, 0.15H), 4.10 (d,
Jˆ8.3 Hz, 0.15H), 2.00 (m, 0.3H), 0.89 (m, 0.45H); 13C
NMR (D2O, 62.7 MHz): cis isomer: d 176.5, 143.9, 122.9,
54.6, 23.4, 15.8, trans isomer: 176.5, 144.1, 123.3, 59.5,
27.6, 14.9.
[a]25 ˆ233.0 (cˆ1.56, EtOAc); TLC (Solvent A) Rf 0.62;
D
1H NMR (CDCl3, 250 MHz) E/Z 90:10: d 7.34±7.26 (m,
5H), 6.34 (ddd, Jˆ16.4, 10.1, 10.1 Hz, 1H, trans1cis ±
CHBvCHC±CHDvCHEHF), 6.33±6.18 (br m, cis1trans
1H, ±CHBvCHC±CHDvCHEHF), 5.73 (dd, Jˆ14.6,
6.1 Hz, 0.9H, trans ±CHBvCHC±CHDvCHEHF), 5.39 (br
t, Jˆ9.9 Hz, 0.1H, cis ±CHBvCHC±CHDvCHEHF), 5.17
(br d, Jˆ17.1 Hz, 1H, trans1cis ±CHBvCHC±
CHDvCHEHF), 5.20±5.05 (m, 3H, NH, Cbz CH2O), 5.07
(br d, Jˆ10.0 Hz, 1H, trans1cis ±CHBvCHC±
CHDvCHEHF), 4.46 (br t, Jˆ7.2 Hz, 1H, a-CH), 3.89 (s,
6H, 3 OBO ester CH2±O), 0.78 (s, 3H, OBO ester CH3):
from decoupling experiments for trans isomer JAGˆ8.0,
JABˆ6.1 Hz, JBCˆ14.6, JCDˆ10.3, JDEˆ16.4, JDFˆ10.1;
13C NMR (CDCl3, 62.9 MHz) d 155.8, 136.5, 136.2 (trans
±CHvCH±CHvCH2), 132.7, 128.8 (trans ±CHvCH±
CHvCH2), 128.4, 128.0, 127.9, 117.5, 108.0, 72.8, 66.8,
56.5, 30.6, 14.2: observe weak peaks from cis isomer at d
132.1, 126.1, 119.6; IR (cast from CH2Cl2) 3373 (br w),
3086 (vw), 3063 (vw), 3034 (w), 2946 (m), 2880 (m),
1721 (s), 1655 (vw), 1604 (vw), 1515 (s), 1456 (w), 1396
(w), 1332 (m), 1224 (m), 1049 (s), 1009 (s), 910 (w), 887
(w), 850 (w), 773 (w), 742(w), 699 (w) cm21; MS (EI,
70 eV) m/z 345 (M1, 100), 254 (M1291, 21); HRMS (EI,
70 eV) Calcd for C19H31O5N: 345.1576. Found: 345.1570
(M1).
5.2.10. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-3-cyano-
(E)-2-propene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane,
Cbz-l-trans-Gly(±CHvCH±CN)±OBO ester, 9f. Crude
Cbz-Ser(ald)-OBO ester 7 (0.507 g, 1.54 mmol assuming
100% yield of the aldehyde from the oxidation) was reacted
with the yellow ylide generated from (EtO)2PO(CH2±CN)
according to the general procedure. Puri®cation gave
0.294 g (55% from 6) of the trans isomer and 0.084 g
(16%) of the cis isomer as well separated compounds
(71%, 78:22 E/Z overall). The trans isomer could be recrys-
tallized from Et2O/hexane; the cis from CH2Cl2/Et2O.
trans Isomer. Mp 106±107.58C; [a]25 ˆ20.7 (cˆ1.37,
EtOAc); TLC (Solvent A) Rf 0.44; 1DH NMR (CDCl3,
250 MHz) d 7.36 (s, 5H), 6.77 (dd, Jˆ16.4, 4.8 Hz, 1H),
5.53 (dd, Jˆ16.3, 1.1 Hz, 1H), 5.18±5.11 (m, 3H), 4.56±
4.51 (m, 1H), 3.90 (s, 6H), 0.82 (s, 3H); 13C NMR (CDCl3,
62.9 MHz) d 155.8, 149.7, 136.0, 128.5, 128.3, 128.1,
116.9, 107.4, 101.5, 72.9, 67.3, 56.6, 30.8, 14.1; IR (cast
from CH2Cl2) 3339 (br w), 3064 (vw), 3035 (vw), 2948 (w),
2884 (w), 2226 (w), 1720 (s), 1640 (vw), 1587 (vw), 1517
(m), 1332 (w), 1253 (m), 1226 (m), 1049 (s), 1018 (s), 966
(m), 736 (w), 699 (w) cm21; MS (EI, 70 eV) m/z 344 (M1,
100), 253 (M1291, 20), 237 (M12107, 53); HRMS (EI,
70 eV) Calcd for C18H20O5N2: 344.1372. Found: 344.1370
(M1); Anal. Calcd for C18H20O5N2: C, 62.78; H, 5.87; N,
8.14. Found: C, 62.64; H, 6.00; N, 8.03.
5.2.12. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-3-methoxy-
(E)-2-propene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane,
Cbz-l-trans-Gly(±CHvCH±OMe)±OBO ester, 9h.
Crude Cbz-Ser(ald)-OBO ester 7 (0.262 g, 0.802 mmol
assuming 100% yield of the aldehyde from the oxidation)
was reacted with the orange ylide generated from
Ph3P1CH2OCH3Cl2 according to the general procedure.
Puri®cation gave 0.063 g (22% from 6) of the trans isomer
and 0.038 g (13%) of the cis isomer as well-separated
compounds (35%, 63:37 E/Z overall). Both the trans and
cis isomers could be recrystallized from Et2O/hexane.
cis Isomer. Mp 161.5±162.58C; [a]25 ˆ10.9 (cˆ0.80,
EtOAc); TLC (Solvent A) Rf 0.35; 1DH NMR (CDCl3,
200 MHz) d 7.38±7.32 (m, 5H), 6.35 (br dd, Jˆ10.7,
8.1 Hz, 1H), 5.49 (br d, Jˆ11.2 Hz, 1H), 5.35 (br d,
Jˆ7.3 Hz, 1H), 5.13 (s, 2H), 4.74 (br t, Jˆ7.9 Hz, 1H),
3.91 (s, 6H), 0.81 (s, 3H); 13C NMR (CDCl3, 50.3 MHz) d
155.5, 147.8, 136.1, 128.4, 128.2, 128.1, 115.2, 107.4,
102.1, 72.9, 67.2, 56.0, 30.7, 14.1; IR (cast from CH2Cl2)
3355 (br w), 3062 (vw), 2949 (w), 2884 (w), 2223 (w), 1722
(s), 1652 (vw), 1634 (vw), 1512 (m), 1397 (w), 1327 (m),
1256 (m), 1223 (m), 1049 (s), 1016 (s), 1003 (s), 912 (w),
883 (w), 811 (w), 759 (w), 738 (w), 699 (w) cm21; MS (EI,
70 eV) m/z 344 (M1, 67), 300 (M1244, 8), 253 (M1291,
18), 237 (M12107, 42), 224 (M12120, 100); HRMS (EI,
70 eV) Calcd for C18H20O5N2: 344.1372. Found: 344.1370
(M1); Anal. Calcd for C18H20O5N2: C, 62.78; H, 5.87; N,
8.14. Found: C, 62.74; H, 6.00; N, 8.01.
trans Isomer. Mp 117±118.58C; [a]25 ˆ23.9 (cˆ0.90,
EtOAc); TLC (Solvent A) Rf 0.36; 1DH NMR (CDCl3,
250 MHz) d 7.36±7.29 (m, 5H), 6.52 (d, Jˆ12.4 Hz, 1H),
5.10 (br s, 3H), 4.73 (dd, Jˆ12.7, 8.3 Hz, 1H), 4.29 (t,
Jˆ8.6 Hz, 1H), 3.90 (s, 6H), 3.53 (s, 3H), 0.80 (s, 3H);
13C NMR (CDCl3, 62.9 MHz) d 155.7, 150.8, 136.6,
128.4, 128.1, 128.0, 108.2, 99.1, 72.8, 66.7, 56.2, 54.6,
30.7, 14.3; IR (cast from CH2Cl2) 3359 (br w), 3064 (vw),
3032 (vw), 2943 (m), 2880 (m), 2835 (vw), 1721 (s), 1659
(m), 1586 (vw), 1514 (s), 1456 (w), 1397 (w), 1333 (m),
1278 (m), 1217 (s), 1164 (m), 1049 (s), 1009 (s), 937 (w),
888 (w), 822 (w), 773 (w), 742 (w), 700 (w) cm21; MS (EI,
70 eV) m/z 349 (M1, 100), 274 (M1275, 4), 258 (M1291,
5), 220 (M12129, 54), 214 (M12135, 38); HRMS (EI,
70 eV) Calcd for C18H23O6N: 349.1525. Found: 349.1519
(M1); Anal. Calcd for C18H23O6N: C, 61.88; H, 6.65; N,
4.01. Found: C, 61.83; H, 6.60; N, 4.03.
5.2.11. 1-[N-(Benzyloxycarbonyl)-(1S)-1-amino-(Z)-2-
pentene]-4-methyl-2,6,7-trioxabicyclo[2.2.2]-octane, Cbz-
l-cis-Gly(±CHvCH±CHvCH2)-OBO ester, 9g. Crude
Cbz-Ser(ald)-OBO ester 7 (0.257 g, 0.778 mmol assuming
100% yield of the aldehyde from the oxidation) was
reacted with the orange±red ylide generated from
Ph3P1CH2CHvCH2Br2 according to the general pro-
cedure. Puri®cation gave 0.152 g (55% from 6) of predomi-
nantly trans isomer (approximately 92:8 E/Z as estimated
from 13C NMR) as an oil. Recrystallization attempts
resulted in a clear gel which was insoluble in most solvents:
cis Isomer. Mp 112±1148C; [a]25 ˆ11.3 (cˆ0.96,
D
EtOAc); TLC (Solvent A) Rf 0.25; 1H NMR (CDCl3,
200 MHz) d 7.37±7.28 (m, 5H), 6.06 (d, Jˆ6.1 Hz, 1H),
5.12 (br s, 3H), 4.87 (t, Jˆ9.2 Hz, 1H), 4.41 (dd, Jˆ9.1,
6.2 Hz, 1H), 3.91 (s, 6H), 3.61 (very br s, 3H), 0.79 (s, 3H);
13C NMR (CDCl3, 50.3 MHz) d 155.7, 149.1, 136.7, 128.3,

1506
N. G. W. Rose et al. / Tetrahedron 57 (2001) 1497±1507
4921±4927. (i) Walsh, C. Tetrahedron 1982, 38, 871±909.
(j) Angst, C. Pure Appl. Chem. 1987, 59, 373±380. (k)
Zabriskie, T. M.; Cheng, H.; Vederas, J. C. J. Am. Chem.
Soc. 1992, 114, 2270±2272.
128.1, 127.8, 108.4, 101.8, 72.8, 66.6, 60.1, 50.3, 30.7, 14.3;
IR (cast from CH2Cl2) 3373 (br w), 2939 (w), 2879 (m),
1722 (s), 1669 (w), 1514 (m), 1456 (w), 1396 (w), 1332 (w),
1238 (m), 1090 (m), 1049 (s), 1008 (s), 942 (w), 885 (w),
803 (w), 751 (w), 738 (w), 698 (w) cm21; MS (EI, 70 eV) m/
z 349 (M1, 100), 274 (M1275, 5), 258 (M1291, 6), 220
(M12129, 71), 214 (M12135, 65); HRMS (EI, 70 eV)
Calcd for C18H23O6N: 349.1525. Found: 349.1519 (M1);
Anal. Calcd for C18H23O6N: C, 61.88; H, 6.65; N, 4.01.
Found: C, 61.65; H, 6.63; N, 3.96.
3. (a) Sahm, U.; Knobloch, G.; Wagner, F. J. Antibiot. 1973, 26,
389±390. (b) Pruess, D. L.; Scannell, J. P.; Kellett, M.; Ax,
H. A.; Janecek, J.; Williams, T. H.; Stempel, A.; Berger, J.
J. Antibiot. 1974, 229±233.
4. (a) Baldwin, J. E.; Hoskins, C.; Kruse, L. J. Chem. Soc., Chem.
Commun. 1976, 795±796. (b) Hagedorn, A. A.; Miller, B. J.;
Nagy, J. O. Tetrahedron Lett. 1980, 21, 229±230. (c) Wade,
P. A.; Pillay, M. K.; Singh, S. M. Tetrahedron Lett. 1982, 23,
4563±4566. (d) Vyas, D. M.; Chiang, Y.; Doyle, T. W.
Tetrahedron Lett. 1984, 25, 487±490. (e) Mzengeza, S.;
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5.2.13. Attempted base-mediated Peterson ole®nation of
Cbz-l-Ser(CH2TMS)±OBO ester, 10. (5S)-4-(4-methyl-
2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-5-[(1,1,1-trimethylsilyl)-
methyl]-1,3-oxazolan-2-one, 12. Cbz-l-Ser(CH2TMS)±
OBO ester 10 (0.210 g, 0.52 mmol) was dissolved in dry
THF (20 mL) and rapidly transferred to a ¯ask containing
KH (0.063 g, 0.55 mmol, washed with Et2O) suspended in
THF (10 mL) at 2108C under Ar. One hour later a TLC
indicated total conversion to 12. TLC (1:2 EtOAc/hexane),
1
Rfˆ0.41; H NMR (CDCl3, 250 MHz) d 5.38 (s, 1H), 4.66
(ddd, Jˆ7.8, 6.8, 3.4 Hz, 1H), 3.85 (s, 6H), 3.30 (d,
Jˆ3.4 Hz, 1H), 1.06 (dd, Jˆ14.5, 7.8 Hz, 1H), 0.95 (dd,
Jˆ14.5, 6.8 1H), 0.76 (s, 3H), 0.02 (s, 9H); 13C NMR
(CDCl3, 62.9 MHz) d 158.9, 107.4, 76.3, 72.7, 62.8, 30.8,
24.7, 14.1, 21.1; Anal. Calcd for C16H21O6N: C, 51.80; H,
7.69; N, 4.65. Found: C, 52.09; H, 7.96; N, 4.34.
5. (a) Baldwin, J. E.; Haber, S. B.; Hoskins, C.; Kruse, L. I.
J. Org. Chem. 1977, 42, 1239±1241. (b) Suzuki, M.; Nunami,
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Acknowledgements
We thank the Natural Sciences and Engineering Research
Council of Canada for ®nancial support and for a Post-
graduate Scholarship to N. R. and M. B. We also thank
Â
Gaston Boulay at the Universite de Sherbrooke for mass
spectral determinations, and Kratos for the MALDI-TOF
results.
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