The preparation and alkylation of a butanedione-derived chiral glycine equivalent and its use for the synthesis of α-amino acids and α,α-disubstituted amino acids

Article abstract of DOI:10.1016/j.tet.2004.06.063

A benzyloxycarbonyl protected glycine equivalent 2 has been prepared in enantiopure form and has been used in the synthesis of both α-substituted amino acids and α,α-disubstituted amino acids. The process involved deprotonation to form the corresponding enolates which underwent stereoselective alkylation with various electrophiles and upon hydrolysis gave the corresponding amino acid derivatives as enantiomerically pure products.

Full text of DOI:10.1016/j.tet.2004.06.063

Tetrahedron 60 (2004) 7679–7692
The preparation and alkylation of a butanedione-derived chiral
glycine equivalent and its use for the synthesis of a-amino acids
and a,a-disubstituted amino acids
*
Christopher I. Harding, Darren J. Dixon and Steven V. Ley
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 21 May 2004; revised 9 June 2004; accepted 10 June 2004
Available online 17 July 2004
Dedicated to Dieter Seebach with congratulations on receipt of the 2003 Tetrahedron Prize
Abstract—A benzyloxycarbonyl protected glycine equivalent 2 has been prepared in enantiopure form and has been used in the synthesis of
both a-substituted amino acids and a,a-disubstituted amino acids. The process involved deprotonation to form the corresponding enolates
which underwent stereoselective alkylation with various electrophiles and upon hydrolysis gave the corresponding amino acid derivatives as
enantiomerically pure products.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Owing to the importance of a-amino acids in organic
synthesis, innumerable methods for their preparation have
been developed over the years.1 However, based on
extensive knowledge of metal enolate formation as well as
the diversity of electrophiles available to quench the anions,
chiral glycine anion equivalents form the basis of one of
the more commonly used synthetic procedures to a-amino
acids.2 Whilst many chiral glycine equivalents are reported,
in terms of practicality, molecular weight, atom economy,
solubility and reactivity, issues remain that still need to be
addressed for their general use in synthesis programmes. In
addition, the ability of a chiral glycine equivalent to deliver
amino acids with useful N-protection as well as allowing
access to a,a-diaminoacids in enantiopure form still
remains a challenge.
Figure 1.
for the synthesis of the natural product Herbarumin II
(Fig. 1).3e,5
In a logical extension of this glycolate chemistry and in the
hope of addressing some of the important issues related to
amino acid synthesis, we have recently reported benzyl-
oxycarbonyl (Z)-protected glycine equivalent 2 and its use
in the synthesis of a-amino acid derivates.6 Here we report
in detail on the preparation of 2 in enantiopure form,
and discuss its use in the synthesis of a range of mono- and
a,a-di-substituted amino acids.
Our group has been interested in the synthesis of various
chiral building blocks, and recently we developed a butane
diacetal protected (BDA) glycolic acid derivative 1 that was
used in the preparation of a-hydroxy acids.3 This auxiliary
was utilised in a range of reactions, including alkylation,3a
aldol3b,c and Michael reactions4 which generally proceeded
in excellent yields and with high diastereoselectivity.
Compound 1 has also been used as the starting point
2. Results and discussion
Our favoured route to compound 2 begins from (S)-glycidol
3, this is commercially available in enantiomerically pure
form and was readily converted to the (S)-amino alcohol 4
in 54% yield over three straightforward steps. A Mitsunobu
reaction with phthalimide mediated by di-tert-butyl azido-
dicarboxylate (DTBAD) and triphenylphosphine7 installed
the required nitrogen atom. Subsequent treatment of 5 with
aqueous hydrobromic acid facilitated N-deprotection and
epoxide ring opening and gave salt 6.8 This was then
Keywords: Chiral glycine equivalent; Amino acid synthesis.
*
Corresponding author. Tel.: þ44-1223-336402; fax: þ44-1223-336442;
e-mail address: svl1000@cam.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.063

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C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
positions and the favoured formation of axial methoxyl
groups in the acetal owing to maximum anomeric (exo
anomeric) stabilisation.
Treatment of 7 with potassium bis(trimethylsilyl)amide
(KHMDS) in tetrahydrofuran afforded the exo-enol ether 9
in a 64% yield preferentially over the endo-enol ether 10
(.20:1). The exo-enol ether 9 was subsequently oxidatively
cleaved to give the desired chiral glycine equivalent 2
(Scheme 3). Initially ozone was employed as the oxidant;
however with a view to ease of synthesis and possible scale-
up, oxidative cleavage using ruthenium trichloride with
sodium periodate to generate ruthenium tetroxide in situ was
employed. This was buffered with sodium hydrogen
carbonate (1.5 equiv.) to prevent the build-up of significant
acidic side products. The best yield was achieved using the
Sharpless conditions (carbon tetrachloride, water and
acetonitrile)11 and the crystalline product 2 was isolated
in an 85% yield, representing a 24% overall yield from
(S)-glycidol. The conditions of Yoshifuji et al.12 using ethyl
acetate in place of carbon tetrachloride were also investi-
gated which gave a 69% yield in the presence of benzyl
triethyl ammonium chloride (as a phase transfer catalyst).
On larger scales the last two steps could be performed
without any intermediate purification, to provide 2 in 52%
yield over the two steps.
Scheme 1. (a) 1.1 equiv. Phthalimide, 1.1 equiv. PPh3, 1.1 equiv. DTBAD,
THF, reflux, 16 h; (b) 48% aq. HBr, reflux, 16 h, 73%; (c) 1.1 equiv. benzyl
chloroformate, MeOH, then 2 equiv. DIPEA, 0 8C to rt, 2h, 74%; 54% from
3.
protected as the benzyloxy carbamate to give 4. The
benzyloxy carbamate was chosen due to its perceived acid
stability in the subsequent Lewis acid mediated butane
diacetal protection step (Scheme 1).
Treatment of 4 with 2,2,3,3-tetramethoxybutane and
catalytic boron trifluoride tetrahydrofuran complex in
dichloromethane at 30 8C gave the desired cyclic precursor
as a mixture of diastereoisomers, 7 and 8, in an approximate
10:1 ratio in favour of the desired diastereoisomer 7
(Scheme 2). After column chromatography and recrystalli-
zation from petroleum ether it was possible to isolate 7 in
69% yield as a white crystalline solid.
The enantiomeric auxiliary 11 was also synthesised in an
analogous manner from (R)-glycidol 12 (Scheme 4). This
material aided in the determination of the enantiopurity of
the new building blocks using chiral HPLC.13 For both
enantiomers the enantiomeric excess was shown to be
greater than 99%. Eventually we hope these building blocks
will be available from commercial compound supply
sources.
Scheme 4. Synthesis of enantiomer 11 from (R)-glycidol 12.
With the new glycine equivalent (2) in hand we next
investigated its conversion to an enolate by deprotonation
and its subsequent reaction with various electrophiles. In
initial experiments with allyl bromide as the electrophile,
the best results were observed with lithium diisopropyl-
amide (LDA), which give an 14:1 diastereoisomeric ratio
in favour of the pseudo-equatorial diastereoisomer: dia-
stereoselection was not affected by the quantity of base
included in the reaction. The reactivity of the lithium
enolate was however low, presumably due to the formation
of lithium enolate aggregates, but the use of 1.1 equiv. of
Scheme 2. (a) 5 equiv. 2,2,3,3-tetramethoxybutane, 0.1 equiv. BF3·OEt2,
CH2Cl2, 30 8C, 2 h; 69% of 7.
The approach to compound 7 makes use of a chiral memory
protocol9 where the chirality of the suitably protected amino
alcohol 4 was used to control the configurations of the
newly formed acetal stereocentres10 during protection with
2,2,3,3-tetramethoxybutane. The reaction makes use of the
known preference of alkyl substituents for equatorial
Scheme 3. (a) 2 equiv. KHMDS (1 M in PhMe), THF, 278 8C to rt, 64% (.20:1 9:10); (b) 4 equiv. NaIO4, 0.02 equiv. RuCl3, 1.5 equiv. NaHCO3, H2O/
MeCN/CCl4 (1:1:2), rt, 85%.

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7681
hexamethylphosphoramide (HMPA) in the mixture
increased reactivity and the reactions were complete in
around 22 h at temperatures between 255 and 250 8C. The
results of the alkylations with a range of alkyl halides,
following the optimal conditions, to give monosubstituted
products 13 are summarised below (Scheme 5, Table 1). A
particularly attractive aspect of these auxiliaries is the
methyl and methoxy signals in the NMR spectra which
greatly facilitate structural assignments. Moreover, these
units often impart crystallinity to the products again aid
product purification and characterisation.
Figure 2. Proposed approach model leading to the major diastereomeric
product.
Table 2. Comparison of additives on the alkylation reaction with allyl
bromide
In general the reactions proceeded with good to excellent
yields and usually exhibited high diastereoselectivities.
The lower diastereoselectivities observed with propargyl
bromide 13f and tert-butyl bromoacetate 13d are difficult
to rationalise, but may arise through secondary chelation
effects in the transition state. In the majority of cases, a
simple recrystallization or trituration with petrol, facilitated
the isolation of the major equatorial diastereoisomer. In a
number of cases these were additionally characterised via
single crystal X-ray analysis. In all the cases the major
product arises from attack of the alkyl halide from the
opposite face to the hindering axial methoxy group (Fig. 2).
Additive
Conversiona (%)
Additive
Conversiona (%)
None
HMPA
DMPU
55
74
68
TMEDA
PMDETA
12-Crown-4
75
64
63
a
1
Conversion by H NMR after 22 h at 250 to 255 8C.
enediamine (TMEDA) showed a similar kinetic enhance-
ment to HMPA and has since been used in the subsequent
alkylations. In all the cases the diastereoselectivity of the
reaction was not significantly affected by the different
additives.
The requirement for HMPA to improve reactivity in these
reactions was not ideal so we briefly investigated alternative
additives for the alkylation reaction with allyl bromide
(Table 2). The conversion with the addition of DMPU was
poorer than HMPA, however N,N,N,N-tetramethylethyl-
In the next experiments we investigated the feasibility of
performing a second diastereoselective alkylation on the
mono-alkylated products 13. In the initial reaction, 13b was
alkylated with benzyl bromide in an 85% yield giving 14a
Scheme 5. (a) 1.1 equiv. LDA, 1.1 equiv. HMPA, THF, 278 8C, 1 h, then
RX, 255 8C, 22 h, then 1.1 equiv. AcOH, Et2O, to rt.
Scheme 6. (a) 1.1 equiv. LDA, 1.1 equiv. HMPA, THF, 278 8C, 1 h, then
R2X, 255 8C, 22 h, then 1.1 equiv. AcOH, Et2O, to rt.
Table 1. Results of the monoalkylation reactions of 2
RX
Product
d.r.a
Yield (%)b
RX
Product
d.r.a
Yield (%)b
13a
13b
14:1
22:1
73
82
13gc
13h
13:1
10:1
81
89
13c
13d
19:1
3:1
72
68
13id
13j
11:1
11:1
37
70
13e
13f
14:1
2:1
74
92
13ke
13l
12:1
8:1
49
25
a
Ratio of diastereoisomers in crude 1H NMR.
Yield of reaction after purification by column chromatography.
Bromide synthesised from corresponding alcohol using PPh3Br2.14
Iodide synthesised via Finklestein reaction from corresponding bromide.15
b
c
d
e
4-(Bromomethyl)-2-[(2,2-dimethylpropanoyl)oxy]phenyl pivalate synthesised from 3,4-dihydroxybenzaldehyde in 3 steps: (i) pyridine, 215 8C, 16 h, 51%;
(ii) sodium borohydride, IPA, 0 8C, 2 h, 48%; (iii) PPh3, CBr4, MeCN, 0 8C, 1.5 h, 64%.

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C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
Table 3. Results of second alkylation reactions to give disubstituted products 14
Product
Yield (%)a,b
Product
Yield (%)a,b
14c
14d
41
14i
14j
15
36
30
31
44
72
38
79
14e
14f
14k
14l
14g
14h
62
25
14m
a
1
Only single diastereoisomers were observed in the crude reaction mixtures by H NMR spectroscopy.
Yield of reaction after purification by column chromatography.
b
as the only observable product by 1H NMR spectroscopy of
the crude reaction mixture (Scheme 6). In the complemen-
tary alkylation of 13e with methyl iodide, 14b was produced
in a 73% yield again as the only observable product.
In both cases single crystal X-ray diffraction studies
unambiguously established the stereochemistry of the
products. The pseudo-equatorial placement of the new
group suggests again that the electrophile was approaching
from the least hindered face. Additionally, the outstanding
diastereoselection was independent of the diastereomeric
excess of the starting material.
Scheme 7. (a) Grubbs-II catalyst, THF, reflux.
A number of other a,a-disubstituted products (14a-m) were
obtained in an analogous manner (Scheme 6, Table 3) and in
all cases only a single diastereomeric product was observed
In a few examples we studied the conversion of the mono-
alkylated products 13a, b and e to the corresponding
a-amino acids 16 using aqueous TFA (1:9) at room
temperature (rt) (Scheme 8 and Table 4). In all the cases
the yields of the amino acids were good to excellent and the
products could be purified by either column chroma-
tography or preparative HPLC. The cleavage of a single
diastereoisomer was shown to lead to a single enantiomer of
the a-amino acid (confirmed by chiral HPLC) showing that
there was no racemisation of the a-centre in the cleavage
step.
1
in the reaction mixture by H NMR spectroscopy.
The possible synthesis of cyclic a-amino acid precursors
was investigated using a ring closing metathesis strategy
with disubstituted products 14k-m in a similar method to
Undheim.16 In all three cases the cyclic products 15k-m
were obtained in good yields after treatment with the
Grubbs second generation catalyst (Scheme 7).17

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7683
Table 5. Results of the cleavages of the disubstituted products 14 to give
a,a-amino acids 17
Starting material
Amino acid
Yielda (%)
14b
14d
14e
14g
15l
17b
17d
17e
17g
17l
76
52
97
81
84
Scheme 8. (a) 9:1 TFA–H2O, rt, 30 min.
Table 4. Results of the cleavage reactions of the mono-substituted products
to give a-amino acids
a
As the starting materials had .99:1 d.r. and racemisation is not possible,
the amino acids are assumed to have .98% ee.
R
Amino acid
Yield (%)
ee (%)
Allyl
Me
Bn
16a
16b
16c
77
71
85
.99a
.99a
.99b
a
Determined on Chiralcel OD column, 9:1 hexane–IPA, 1 mL/min.
Determined on Chiralcel OD column, 95:5 hexane–IPA, 1 mL/min.
b
Similarly, the corresponding a,a-disubstituted amino acids
17 were produced by treating the disubstituted products 14
with aqueous TFA (2:1 TFA–water) followed by neutrali-
sation with 1 N sodium hydroxide in methanol. The
neutralisation was required to release the desired free
acids from the cyclic intermediates 18 (Scheme 9).18 As
before, the a,a-amino acids 17 could be purified by either
column chromatography or preparative HPLC and the
results are shown in Table 4.
Figure 3. Structure of FTY-720 20 and the biologically active (R) chiral
analogue 19.
This b-hydroxy amine 19 had been identified by Kiuchi
et al.19 and was recently synthesised by Hinterding et al.20
3. Conclusion
In summary, we have described in full the preparation of a
new chiral glycine equivalent 2. It undergoes lithium
enolate mediated monoalkylation reactions in good to
excellent yields and good diastereoselectivities and the
corresponding dialkylation reactions in good yields and
outstanding diastereoselectivities. These products can be
readily deprotected under mild conditions to yield N–Z
a-amino acids 5 and disubstituted N–Z a,a-amino acids 17
in generally excellent yields, with no evidence of racemisa-
tion of the a-centre. We hope that this glycine equivalent
will become more generally useful in amino acid synthesis
when the more traditionally used equivalents are
unsatisfactory.
Scheme 9. (a) 9:1 TFA–H2O, rt, 30 min. (b) 1 N NaOH–MeOH (1:1), rt,
30 min.
In order to extend the use of the chiral auxiliary 2 towards
the preparation of a biologically relevant a-branched amine
19, designed as an analogue of the powerful amino alcohol
immuno-suppressant FTY-720 (20), we have prepared the
amino acid 21 from the dialkylated precursor 14e (Table 3)
by hydrolytic cleavage in 97% yield (Scheme 10, Table 5,
Fig. 3).
4. Experimental
4.1. General
2,2,3,3-Tetramethoxybutane was synthesised and
purified according to the method of Frost et al.21
Scheme 10. (a) 9:1 TFA/H2O, rt, 30 min; (b) 1 N NaOH–MeOH, rt, 30 min. 97% from 14e.

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3-(Bromomethyl)furan was prepared with phosphorous
dibromide according to the method of Sandri et al.14b
Phenethyl iodide was prepared according to the method of
Mendenhall et al.15 1-Heptyloxy-4-(2-iodo-ethyl)-benzene
was prepared according to the method of Kiuchi et al.19 All
other reagents were used as obtained from commercial
sources. Column chromatography was carried out using
Merck Kieselgel (230–400 mesh) and analytical tlc was
performed on pre-coated glass-backed plates (Merck
Kieselgel 60 F254). Filtration of crude reaction mixtures
through silica was carried out in fritted plastic tubes (1 or
2 cm diameter, 2–3 cm silica depth) washing through with
the indicated solvents. Chiral HPLC was performed on an
Agilent 1100 series HPLC or a Gilson HPLC. Melting
points were performed on a Reichert hot stage apparatus and
are uncorrected. Boiling points were measured during
distillation. Optical rotations were measured using a
Perkin–Elmer Model 343 polarimeter and values are
given in 1021 deg cm2 g21, concentration (c) in g per
100 mL. Infra-red spectra were recorded on a Perkin–Elmer
Spectrum-One spectrometer. Microanalyses were deter-
mined using a CE-440 Elemental Analyser. Mass spectra
were obtained on Kratos Concept 1H, Micromass Q-TOF or
Bruker BIOAPEX 4.7E T FTICR spectrometers, using
solution was stirred at rt for 2 h. The solvent was removed
under reduced pressure and the residue purified by column
chromatography (petrol/ether, 3:1–1:1) to give amino
alcohol 4 (9.03 g, 74%) as white needles. Mp 33–34 8C
(petrol/ether). IR (neat) 3329 (OH), 1691 (NCvO) cm21
;
1H NMR (600 MHz, CDCl3) d 7.33–7.37 (m, 5H, Ph), 5.17
(br s, 1H, NH), 5.11 (s, 2H, PhCH2), 3.94 (br s, 1H), 3.50 (m,
1H), 3.46 (dd, J¼10.4, 5.1 Hz, 1H), 3.40 (dd, J¼10.4,
6.3 Hz, 1H), 3.33 (m, 1H), 3.07 (d, J¼3.4 Hz, 1H, OH); 13C
NMR (150 MHz, CDCl3) d 157.8 (CvO), 138.1, 128.6,
128.3, 128.1, 70.7, 67.2 (PhCH2), 44.9, 35.8. 212.1 (c 5.0,
CHCl3). Anal Calcd for C11H14O3N C, 45.9; H, 4.9; N,
4.9%; found C, 46.0; H, 4.9; N, 4.8%. HRMS (þESI) Calcd
for C11H14O3NBr [MþNa]þ 310.0063, found 310.0055.
4.1.3. Benzyl-(2S,3R,6S)-6-(bromomethyl)-2,3-dimeth-
oxy-2,3-dimethylmorpholine-4-carboxylate (7). Amino
alcohol 4 (4.0 g, 13.9 mmol) was dissolved in CH2Cl2
(40 mL)
and
2,2,3,3-tetramethoxybutane
(12.36 g,
69.5 mmol) was added to the stirred solution. The solution
was warmed to 30 8C and BF3.THF (0.152 mL, 1.39 mmol)
added dropwise. After 2 h, the reaction was cooled to rt,
triethylamine (1 mL) was added to quench the reaction
and the resulting solution was stirred for 1 h. The solution
was then diluted with CH2Cl2 (50 mL), washed with
NaHCO3 (50 mL), brine (50 mL) and dried (MgSO4). The
solvent was removed under reduced pressure and the residue
was purified by column chromatography (petrol/ether, 5:1 to
neat ether) to leave a mixture of bromides 7 and 8 (10:1 d.r.).
The mixture was recrystallized (petrol/ether) to give the
bromide 7 (3.84 g, 69%) as white needles. Mp 67–69 8C
(ether). IR (neat) 1718 (NCvO) cm21. 1H NMR (600 MHz,
CHCl3) d 7.36–7.31 (m, 5H, Ph), 5.17–5.12 (m, 2H,
OCH2Ph), 4.11 (dd, J¼13.2, 2.6 Hz, 1H), 4.00 (m, 1H),
3.31–3.25 (m, 2H), 3.24 (s, 3H, CH3O), 3.18 (s, 3H, CH3O),
3.02 (dd, J¼13.2, 11.4 Hz, 1H), 1.55 (s, 3H, CH3C), 1.35 (s,
3H, CH3). 13C NMR (150 MHz, CHCl3) d 156.2 (NCvO),
136.6, 128.5, 127.9, 127.7, 101.3, 90.2, 67.9 (OCH2Ph),
67.1, 48.5 (CH3OC), 48.2 (CH3OC), 44.1, 31.5 (CH2Br),
18.9 (CH3C), 17.8 (CH3C). [a]2D5¼þ62.6 (c 2.1, CHCl3).
Anal Calcd for C17H24NO5Br C, 50.8; H, 6.0; N, 3.5; Br,
19.9%; found C, 50.8; H, 6.1; N, 3.4; Br, 19.8%. HRMS
(þESI) Calcd for C17H24NO5BrNa [MþNa]þ 424.0748,
found 424.0736. Structure and absolute stereochemistry
were confirmed by single crystal X-ray diffraction studies.
1
electron impact (EI) or electrospray techniques (ESI). H
NMR and 13C NMR spectra were recorded on Bruker
Avance 600, 500 or 400 spectrometers in CDCl3 at 300 K
unless otherwise stated.
4.1.1. (2S)-3-Bromo-2-hydroxypropan-1-ammonium
bromide (6).8 Triphenyl phosphine (68.8 g, 0.47 mol) was
added to a stirred solution of phthalimide (38.6 g, 0.47 mol)
in THF (400 mL) at 0 8C, followed by (S)-(2)-glycidol
(22.4 g, 0.53 mol). Di-tert-butyl azodicarboxylate (60.4 g,
0.47 mol) was added dropwise and the solution stirred for
5 h at rt. The solvent was removed under reduced pressure,
dissolved in methanol (200 mL) and cooled to 0 8C.
Hydrobromic acid (48% aq.) was added slowly to the
rapidly stirred solution until no further effervescence was
observed and a white precipitate formed. The solution was
diluted with water (200 mL) and filtered. The aqueous layer
extracted with CH2Cl2 (3£300 mL) and the solvent was
removed under reduced pressure. The residue was dissolved
in hydrobromic acid (48% aq., 500 mL) and heated at reflux
overnight. The solvent was removed under reduced pressure
and the residue dissolved in toluene (100 mL). The solvent
was removed under reduced pressure and the residue
washed with ether (3£100 mL), chloroform (3£100 mL),
ether (50 mL) and isopropanol (50 mL) before drying over
KOH and P2O5 to give hydrobromide salt 6 (45.1 g, 73%) as
white needles. Mp 134–140 8C (iPrOH, lit. 115–117 8C,
4.1.4. (2S,3R)-2,3-Dimethoxy-2,3-dimethyl-6-methylene-
4-(3-phenylpropanoyl)morpholine (9). Potassium bis(tri-
methylsilyl)amide (1 M in toluene, 96.4 mL, 48.2 mmol)
was added dropwise to a solution of bromide 7 (9.69 g,
24.1 mmol) in THF (96.4 mL) at 278 8C. The solution was
allowed to warm to rt overnight and stir at rt for 4 h. The
reaction was quenched by addition of water (100 mL) and
the aqueous layer was extracted with ether (3£100 mL) and
the combined organics washed with brine (20 mL) and dried
(MgSO4). The solvent was removed under reduced pressure
and the residue purified by column chromatography (ether/
petrolþ1% Et3N, 5:1–1:1) to give enol ether 9 (4.97 g,
64%) as a colourless oil. IR (neat) 1718 cm21 (NCvO). 1H
NMR (600 MHz, CHCl3) d 7.37–7.29 (m, 5H, Ph), 5.16 (s,
2H, OCH2Ph), 4.35 (s, 1H, CvCHAHB), 4.26–4.17 (2H, br
m, NCH2), 4.09 (s, 1H, CvCHAHB), 3.27 (s, 3H, CH3OC),
3.25 (s, 3H, CH3OC), 1.74 (s, 3H, CH3C), 1.47 (s, 3H,
1
ethanol);8 IR (neat) 3327 (OH), 2999 (br NþH3) cm21. H
NMR (400 MHz, CD3OD) d 3.85 (m, 1H), 3.48 (dd,
J¼10.6, 4.7 Hz, 1H) 3.42 (dd, J¼10.6, 5.9 Hz, 1H), 3.29
(dd, J¼13.8, 5.0 Hz, 1H), 3.16 (dd, J¼13.8, 6.5 Hz, 1H);
13C NMR (100 MHz, CD3OD) d 71.3, 36.5, 28.7. 212.7
(c 2.0, H2O). HRMS (þEI) Calcd for C3H9NOBr [M2Br]þ
153.9868, found 153.9869.
4.1.2. Benzyl (2S)-3-bromo-2-hydroxypropylcarbamate
(4). Benzyl chloroformate (7.98 g, 46.8 mmol) was added to
a solution of 6 (10.0 g, 42.6 mmol) in methanol (100 mL) at
0 8C, followed by DIPEA (11.0 g, 85.2 mmol) and the

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7685
CH3C). 13C NMR (150 MHz, CHCl3) d 155.2 (NCvO),
152.5 (CvCH2), 136.4, 128.4, 127.9, 127.7, 103.7, 89.7,
89.2 (CvCH2), 67.2 (OCH2Ph), 50.3 (CH3OC), 48.8
(CH3OC), 43.4, 17.8. [a]2D5¼þ60.0 (c 4.24, CHCl3).
HRMS (þESI) Calcd for C17H23NO5Na [MþNa]þ
344.1479, found 344.1474.
(1.6 or 2.5 M in hexanes, 1.1 equiv.) was added and the
solution was warmed up to rt. Upon reaching rt, the solution
was cooled back down to 278 8C, a solution of the lactone
(1 equiv.) in THF (1 mL) added via cannula followed by
TMEDA (1.1 equiv.) and the solution stirred at 278 8C for
1 h. The alkyl halide (3 equiv.) was added, the reaction
stirred at 255 8C for 21 h. The reaction was quenched by
the addition of glacial acetic acid (1.1 equiv.) at 255 8C
followed by the addition of ether (5 mL per 200 mg of
substrate) and the solution stirred at rt for 2 h. The turbid
mixture was filtered through silica (ether), concentrated
under reduced pressure and the residue purified by column
chromatography (petrol/ether, 3:1).
4.1.5. Benzyl (2S,3R)-2,3-Dimethoxy-2,3-dimethyl-6-
oxomorpholine-4-carboxylate (2). Enol ether 9 (0.41 g,
1.27 mmol) was dissolved in water (4 mL), carbon tetra-
chloride (2.6 mL) and acetonitrile (2.6 mL). Ruthenium
trichloride (5.8 mg, 0.28 mmol) was added followed by
sodium periodate (1.11 g, 5.22 mmol) and the reaction was
stirred for 2 h. The reaction was diluted with water (20 mL)
and dichloromethane (20 mL) and the aqueous layer
extracted with dichloromethane (2£20 mL). The combined
organic extracts were dried (MgSO4) and the solvent was
removed under reduced pressure. The residue was dissolved
in ether and filtered through a silica plug (eluting with
ether). The solvent was removed under reduced pressure and
the residue purified by column chromatography (petrol/
ether, 3:1) to give lactone 2 (351 mg, 85%) as white needles.
Mp 41–43 8C (ether/petrol). IR 1755 (OCvO), 1725
4.4. General method C for the deprotonation of the
glycinate
Lithium diisopropylamide (0.125 M in THF/hexanes,
1.1 equiv.) was added to a solution of the lactone
(1 equiv.) in THF (1 mL) at 278 8C, followed by HMPA
(1.1 equiv.) and the solution was stirred at 278 8C for 1 h.
The alkyl halide (3 equiv.) was added and the reaction
stirred at 255 8C for 21 h. The reaction was quenched by
the addition of glacial acetic acid (1.1 equiv.) at 255 8C
followed by the addition of ether (5 mL per 200 mg of
substrate) and the solution stirred at rt for 2 h. The turbid
mixture was filtered through silica (ether) and concentrated
under reduced pressure and the residue purified by column
chromatography (petrol/ether, 3:1).
1
(NCvO) cm21. H NMR (500 MHz, CHCl3) d 7.36–7.32
(m, 5H, Ph), 5.14 (d, J¼12.4 Hz, 1H, OCHAHBPh), 5.13 (d,
J¼12.4 Hz, 1H, OCHAHBPh), 4.45 (d, J¼18.2 Hz, 1H),
3.97 (d, J¼18.2 Hz, 1H), 3.40 (s, 3H, CH3OC), 3.23 (s, 3H,
CH3OC), 1.81 (s, 3H, CH3C), 1.54 (s, 3H, CH3C). 13C NMR
(125 MHz, CHCl3) d 166.4 (OCvO), 154.8 (NCvO),
135.9, 128.6, 128.3, 127.9, 106.6, 88.9, 67.5 (OCH2Ph),
50.5 (CH3OC), 49.9 (CH3OC), 45.6, 17.9; [a]2D5¼þ86.4 (c
2.9, CHCl3). Anal Calcd for C16H21NO6 C, 59.4; H, 6.6; N,
4.3%, found C, 59.6; H, 6.7; N, 4.5%. HRMS (þESI) Calcd
for C16H21NO6Na [MþNa]þ 346.1267, found 346.1253.
Enantiomeric excess determined by chiral HPLC analysis
(Chiralcel AD column, 95:5 hexane/IPA, 1 mL min21) to be
greater than 99%. Structure and relative stereochemistry
were confirmed by single crystal X-ray diffraction studies.
4.5. General method D for the deprotonation of the
glycinate
Lithium diisopropylamide (0.125 M in THF/hexanes,
1.1 equiv.) was added to a solution of the lactone
(1 equiv.) in THF (1 mL) at 278 8C, followed by TMEDA
(1.1 equiv.) and the solution was stirred at 278 8C for 1 h.
The alkyl halide (3 equiv.) was added and the reaction was
stirred at 255 8C for 21 h. The reaction was quenched by
the addition of glacial acetic acid (1.1 equiv.) at 255 8C
followed by the addition of ether (5 mL per 200 mg of
lactone) and the solution stirred at rt for 2 h. The turbid
mixture was filtered through silica (ether), concentrated
under reduced pressure and the residue purified by column
chromatography (petrol/ether, 3:1).
4.2. General method A for the deprotonation of the
glycinate
Diisopropyl amine (1.15 equiv.) was dissolved in THF
(5 mL per 200 mg of substrate) at 278 8C and butyl lithium
(1.6 or 2.5 M in hexanes, 1.1 equiv.) was added and the
solution was allowed to warm to rt. Upon reaching rt, the
solution was cooled back down to 278 8C, a solution of
the lactone (1 equiv.) in THF (1 mL) added via cannula
followed by HMPA (1.1 equiv.) and stirred at 278 8C for
1 h. The alkyl halide (3 equiv.) was added, the reaction was
stirred at 255 8C for 21 h. The reaction was quenched by
the addition of glacial acetic acid (1.1 equiv.) at 255 8C
followed by the addition of ether (5 mL per 200 mg of
substrate) and the solution stirred at rt for 2 h. The turbid
mixture was filtered through silica (ether), concentrated
under reduced pressure and the residue purified by column
chromatography (petrol/ether, 3:1).
4.5.1. Benzyl (2S,3R,5R)-5-allyl-2,3-dimethoxy-2,3-
dimethyl-6-oxomorpholine-4-carboxylate (13a). Lactone
2 (196 mg, 0.61 mmol) was alkylated with allyl bromide
(220 mg, 1.82 mmol) according to method A to give lactone
13a (161 mg, 73%, 14:1 crude d.r.) as a white solid.
Recrystallization (petrol/ether) gave only the major dia-
stereoisomer as white needles. Mp 53–54 8C (petrol/ether).
IR (neat) 1754 (OCvO), 1718 (NCvO), 1694 and 1642
(CvC) cm21. 1H NMR (600 MHz, CDCl3) d 7.37–7.31 (m,
5H, Ph), 5.82–5.75 (m, 1H, CH2CHvCH2), 5.18 (s, 2H,
OCH2Ph), 5.02 (d, J¼10.1 Hz, 1H, CHvCHcisHtrans), 4.98
(d, J¼17.0 Hz, 1H, CHvCHcisHtrans), 4.49 (dd, J¼9.4,
4.7 Hz, 1H), 3.41 (s, 3H, CH3OC), 3.15 (s, 3H, CH3OC),
2.79–2.74 (m, 1H), 2.59–2.55 (m, 1H), 1.85 (s, 3H, CH3C),
1.59 (s, 3H, CH3C). 13C NMR (150 MHz, CDCl3) d 168.2
(OCvO), 155.1 (NCvO), 135.6, 133.5, 128.6, 128.4,
128.3, 117.6, 107.1, 89.2, 67.8 (OCH2Ph), 57.5, 50.6
4.3. General method B for the deprotonation of the
glycinate
Diisopropyl amine (1.15 equiv.) was dissolved in THF
(5 mL per 200 mg of lactone) at 278 8C and butyl lithium

7686
C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
(CH3OC), 49.6 (CH3OC), 38.9, 19.6 (CH3C), 18.7 (CH3C).
[a]2D5¼þ14.3 (c 0.7, CHCl3). Anal Calcd for C19H25NO6
requires C, 62.8; H, 6.9; N, 3.9%; found C, 62.5; H, 6.8; N,
3.8%. HRMS (þESI) Calcd for C19H25NO6Na [MþNa]þ
386.1580, found 386.1577. Structure and relative stereo-
chemistry were confirmed by single crystal X-ray diffrac-
tion studies.
81.1 (OC(CH3)3), 67.7 (OCH2Ph), 54.3, 50.8 (CH3OC),
49.7 (CH3OC), 41.4, 27.9 (C(CH3)3), 19.7, 17.9. [a]2D5¼
21.1 (c 0.75, CHCl3, 6:1 d.r.). HRMS (þESI) Calcd for
C22H31O8NNa [MþNa]þ 460.1947, found 460.1959.
4.5.5. Benzyl (2S,3R,5R)-5-benzyl-2,3-dimethoxy-2,3-
dimethyl-6-oxomorpholine-4-carboxylate (13e). Lactone
2 (182 mg, 0.56 mmol) was alkylated with benzyl bromide
(287 mg, 1.68 mmol) according to method A to give lactone
13e (174 mg, 74%, 14:1 crude d.r.) as a white solid.
Recrystallization (petrol/ether) gave only the major dia-
stereoisomer as white needles. Mp 141–142 8C (ether). IR
4.5.2. Benzyl (2S,3R,5R)-2,3-dimethoxy-2,3,5-trimethyl-
6-oxomorpholine-4-carboxylate (13b). Lactone
2
(188 mg, 0.58 mmol) was alkylated with methyl iodide
(273 mg, 1.75 mmol) according to method A to give lactone
13b (160 mg, 82%, 22:1 crude d.r.) as a yellow oil which
crystallized on standing. Recrystallization (petrol/ether)
gave only the major diastereoisomer as white needles.
Mp 78–79 8C (ether). IR (neat) 1754 (OCvO), 1718
(neat) 1756 (OCvO), 1718 (NCvO) cm21 1H NMR
.
(600 MHz, CDCl3) d 7.37–7.35 (m, 5H, Ph(carbamate)),
7.21–7.19 (m, 3H), 7.08 (d, J¼6.4 Hz, 2H), 5.19 (d, J¼
11.9 Hz, 1H, OCHAHBPh), 5.03 (d, J¼11.9 Hz, 1H,
OCHAHBPh), 4.65 (dd, J¼9.3, 4.4 Hz, 1H), 3.50 (s, 3H,
CH3OC), 3.32 (dd, J¼13.7, 4.4 Hz, 1H), 3.16 (s, 3H,
CH3OC), 3.05 (dd, J¼13.7, 9.3 Hz, 1H), 1.91 (s, 3H,
CH3C), 1.62 (s, 3H, CH3C). 13C NMR (150 MHz, CDCl3) d
167.8 (OCvO), 155.1 (NCvO), 137.1, 135.5, 129.3, 128.6,
128.5, 128.4, 128.3, 126.7, 107.2, 89.3, 67.9, 59.5, 50.7,
49.6, 40.6, 19.6, 18.3. [a]2D5¼þ63.0 (c 0.3, CHCl3). Anal
Calcd for C23H27NO6 C, 66.8; H, 6.6; N, 3.4%, found C,
66.1; H, 6.6; N, 3.3%. HRMS (þEI) Calcd for C23H27NO6
[M]þ 413.183, found 413.1831. Structure and relative
stereochemistry were confirmed by single crystal X-ray
diffraction studies.
1
(NCvO) cm21. H NMR (600 MHz, CDCl3) d 7.37–7.33
(m, 5H, Ph), 5.18 (s, 2H, OCH2Ph), 4.55 (q, J¼6.8 Hz, 1H),
3.41 (s, 3H,CH3OC), 3.16 (s, 3H, CH3OC), 1.85 (s, 3H,
CH3C), 1.58 (d, J¼6.8 Hz, 3H, CH3C), 1.54 (s, 3H, CH3C).
13C NMR (150 MHz, CDCl3) d 170.7 (OCvO), 155.1
(NCvO), 135.8, 128.6, 128.3, 128.1, 106.9, 89.1, 67.6
(OCH2Ph), 53.2, 50.6 (CH3OC), 49.6 (CH3OC), 20.3
(CH3C-3), 19.5 (CH3C), 18.1 (CH3C). [a]2D5¼þ37.2 (c
2.24, CHCl3). Anal Calcd for C17H23NO6 C, 60.5; H, 6.9; N,
4.2%; found C, 60.5; H, 6.8; N, 4.1%. HRMS (þESI) Calcd
for C17H23NO6Na [MþNa]þ 360.1423, found 360.1418.
Structure and relative stereochemistry were confirmed by
single crystal X-ray diffraction studies.
4.5.6. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3-dimethyl-6-
oxo-5-prop-2-ynyl-morpholine-4-carboxylate
4.5.3. Benzyl (2S,3R,5R)-5-ethyl-2,3-dimethoxy-2,3-
dimethyl-6-oxomorpholine-4-carboxylate (13c). Lactone
2 (181 mg, 0.56 mmol) was alkylated with ethyl iodide
(262 mg, 1.68 mmol) according to method A to give lactone
13e (142 mg, 72%, 19:1 crude d.r.) as a white solid. Mp
61–62 8C (petrol/ether). IR (neat) 1751 (OCvO), 1718
(13f).
Lactone 2 (180 mg, 0.58 mmol) was alkylated with
propargyl bromide (80% in toluene, 259 mg, 1.75 mmol)
according to method A to give lactone 13f (194 mg, 92%,
2:1 d.r.) as a yellow oil. IR (neat) 1751 (OCvO), 1722
1
(NCvO) cm21. H NMR (600 MHz, CDCl3) d 7.40–7.31
1
(NCvO) cm21. H NMR (600 MHz, CDCl3) d 7.37–7.33
(m, 5H, Ph), 5.20 (d, J¼12.3 Hz, 1H, OCHAHBPh), 5.11 (d,
J¼12.3 Hz, 1H, OCHAHBPh), 4.97 (ap t, J¼6.8 Hz, 1H),
3.37 (s, 3H, CH3OC), 3.34 (s, 3H, CH3OC), 2.97 (ddd,
J¼17.1, 6.1, 2.6 Hz, 1H), 2.66 (ddd, J¼17.1, 7.7, 2.7 Hz,
1H), 1.97 (ap t, J¼2.7 Hz, 1H), 1.80 (s, 3H, CH3C), 1.51 (s,
3H, CH3C). 13C NMR (150 MHz, CDCl3) d 167.7 (OCvO),
160.3 (NCvO), 135.8, 128.5, 128.2, 128.1, 106.9, 89.8,
80.4, 70.5, 67.9 (OCH2Ph), 54.2, 50.6 (CH3OC), 50.5, 24.2,
18.6, 18.0. [a]2D5¼þ79.5 (c 0.42, CHCl3). HRMS (þEI)
Calcd for C19H23NO6 [M]þ 361.1525, found 361.1525.
(m, 5H, m), 5.17 (ap q, 2H, OCH2Ph), 4.27 (dd, J¼9.8,
3.7 Hz, 1H), 3.38 (s, 3H, CH3OC), 3.15 (s, 3H, CH3OC),
1.99 (m, 1H), 1.88–1.84 (m, 4H), 1.58 (s, 3H, CH3C), 0.98
(t, J¼7.6 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 168.8
(OCvO), 155.2 (NCvO), 135.8, 128.6, 128.3, 128.2,
107.0, 89.2, 67.7 (OCH2Ph), 59.2, 50.6 (CH3OC), 49.6
(CH3OC), 28.1 (CH2CH3), 19.4, 18.3, 10.9. [a]2D5¼þ41.0
(c 0.21, CHCl3). HRMS (þESI) Calcd for C18H25NO6Na
[MþNa]þ 374.1580, found 374.1575. Structure and relative
stereochemistry were confirmed by single crystal X-ray
diffraction studies.
4.5.7. Benzyl (2S,3R,5R)-5-furan-3-ylmethyl-2,3-
dimethoxy-2,3-dimethyl-6-oxomorpholine-4-carboxyl-
ate (13g). Lactone 2 (180 mg, 0.56 mmol) was alkylated
with 3-(bromomethyl)furan (268 mg, 1.67 mmol) according
to method A to give lactone 13g (182 mg, 81%, 13:1 crude
d.r.) as a white solid. Mp 38–40 8C (CHCl3). IR (neat) 1758
(OCvO), 1720 (CvO) cm21. 1H NMR (600 MHz, CDCl3)
d 7.37–7.35 (m, 5H, Ph), 7.29 (s, 1H), 7.11 (s, 1H), 6.17 (s,
1H), 5.18 (d, J¼12.0 Hz, 1H, OCHAHBPh), 5.14 (d, J¼
12.0 Hz, 1H, OCHAHBPh), 4.54 (dd, J¼9.4, 3.8 Hz, 1H),
3.45 (s, 3H, CH3OC), 3.17 (s, 3H, CH3OC), 3.05 (dd, J¼
14.7, 3.8 Hz, 1H), 2.94 (dd, J¼14.7, 9.4 Hz, 1H), 1.89 (s,
3H, CH3C), 1.61 (s, 3H, CH3C). 13C NMR (150 MHz,
CDCl3) d 168.0 (OCvO), 142.7, 140.3, 135.5, 128.7, 128.5,
128.5, 111.2, 107.1, 89.2, 67.9 (OCH2Ph), 58.6, 50.7, 49.6,
30.3, 19.4, 18.3. [a]D25¼215.4 (c 0.45, CHCl3). HRMS
4.5.4. Benzyl-(2S,3R,5R)-5-tert-butoxycarbonylmethyl-
2,3-dimethoxy-2,3-dimethyl-6-oxomorpholine-4-carb-
oxylate (13d). Lactone 2 (195 mg, 0.60 mmol) was
alkylated with tert-butyl bromoacetate (351 mg,
1.80 mmol) according to method A to give lactone 13d
(177 mg, 68%, 3:1 crude d.r.) as a white solid. Mp 52–56 8C
(ether). IR (neat) 1753 (OCvO lactone), 1722 (NCvO,
1
OCvO ester) cm21. H NMR (600 MHz, CDCl3) d 7.40–
7.31 (m, 5H, Ph), 5.19 (s, 2H, OCH2Ph), 5.02 (dd, J¼9.1,
4.1 Hz, 1H), 3.42 (s, 3H, CH3OC), 3.16 (s, 3H, CH3OC),
2.87 (dd, J¼15.1, 4.1 Hz, 1H), 2.68 (dd, J¼15.1, 4.1 Hz,
1H), 1.82 (s, 3H, CH3C), 1.58 (s, 3H, CH3C), 1.44 (s, 9H,
C(CH3)3). 13C NMR (150 MHz, CDCl3) d 168.7, 168.1,
154.8 (NCvO), 135.7, 128.6, 128.3, 128.1, 107.1, 89.0,

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7687
(þESI) Calcd for C21H25NO7Na [MþNa]þ 426.1529, found
426.1516. Structure and relative stereochemistry were
confirmed by single crystal X-ray diffraction.
CHCl3). Anal Calcd for C20H27NO6 C, 63.6; H, 7.2; N,
3.7%, found C, 63.3; H, 7.2; N, 3.7%. Structure and relative
stereochemistry were confirmed by single crystal X-ray
diffraction studies.
4.5.8. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3-dimethyl-5-
naphthalen-2-ylmethyl-6-oxomorpholine-4-carboxylate
(13h). Lactone 2 (184 mg, 0.57 mmol) was alkylated with
2-(bromomethyl)napthalene (378 mg, 1.71 mmol) accord-
ing to method A to give lactone 13h (236 mg, 89%, 10:1
crude d.r.) as a white solid. Mp 87–89 8C (ether). IR (neat)
4.5.11. Benzyl-(2S,3R,5R)-5-[3,4-bis-(2,2-dimethyl-pro-
pionyloxy)-benzyl]-2,3-dimethoxy-2,3-dimethyl-6-oxo-
morpholine-4-carboxylate (13k). Lactone 2 (135 mg,
0.42 mmol) was alkylated with 4-(bromomethyl)-2-[(2,2-
dimethylpropanoyl)oxy]phenyl
1.25 mmol) according to method D to give lactone 13k
pivalate
(465 mg,
1
1756 (OCvO), 1719 (CvO) cm21. H NMR (600 MHz,
CDCl3) d 7.78–7.76 (m, 1H), 7.68 (d, J¼8.2 Hz, 1H), 7.66
(d, J¼5.9 Hz, 1H), 7.50 (br s, 1H), 7.43–7.40 (m, 2H),
7.36–7.32 (m, 5H, Ph), 7.22 (d, J¼8.2 Hz, 1H), 5.18 (d,
J¼11.9 Hz, 1H, OCHAHBPh), 5.01 (d, J¼11.9 Hz, 1H,
OCHAHBPh), 4.76 (dd, J¼9.3, 4.4 Hz, 1H), 3.54 (s, 3H,
CH3OC), 3.50–3.46 (m, 1H), 3.22 (dd, J¼18.6, 9.3 Hz,
1H), 3.18 (s, 3H, CH3OC), 1.94 (s, 3H, CH3C), 1.65 (s, 3H,
CH3C). 13C NMR (150 MHz, CDCl3) d 167.8 (OCvO),
155.1 (NCvO), 135.5, 134.6, 133.4, 132.4, 128.7, 128.6,
128.5, 127.9, 127.8, 127.7, 127.6, 127.5, 125.8, 125.4,
107.2, 89.3, 68.0 (OCH2Ph), 59.4, 50.7, 49.7, 40.8, 18.3,
15.2. [a]2D5¼22.2 (c 0.32, CHCl3). HRMS (þEI) Calcd for
C27H29NO6 [M]þ 463.1995, found 463.1993.
(125 mg, 49%, 12:1 crude d.r.) as a colourless foam. IR
(neat) 1756 (OCvO), 1722 (NCvO) cm21 1H NMR
.
(500 MHz, CDCl3) d 7.37–7.29 (m, 5H, OCH2Ph), 6.96–
6.90 (m, 3H), 5.16 (d, J¼12.0 Hz, 1H, OCHAHBPh), 5.01
(d, J¼12.0 Hz, 1H, OCHAHBPh), 4.65 (dd, J¼8.5, 4.7 Hz,
1H), 3.45 (s, 3H, CH3OC), 3.26 (dd, J¼14.1, 4.7 Hz, 1H),
3.13 (s, 3H, CH3OC), 3.03 (dd, J¼14.1, 8.5 Hz, 1H), 1.88 (s,
1H, CH3C), 1.60 (s, 3H, CH3C), 1.32 (s, 9H, C(CH3)3), 1.31
(s, 9H, C(CH3)3). 13C NMR (150 MHz, CDCl3) d 175.7,
175.7, 168.0 (OCvO), 155.0 (NCvO), 142.1, 141.1, 135.7,
135.6, 128.6, 128.6, 128.4, 127.1, 124.2, 123.0, 107.2, 89.3,
67.8 (OCH2Ph), 59.0, 50.7 (CH3OC), 49.7 (CH3OC), 40.1,
39.1, 39.0, 27.2, 27.2, 19.5, 18.2. [a]2D5¼þ21.6 (c 0.57,
CHCl3). HRMS (þESI) Calcd for C33H43NO10Na
[MþNa]þ 636.2784, found 636.2781.
4.5.9. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3-dimethyl-6-
oxo-5-phenethyl-morpholine-4-carboxylate (13i). Lac-
tone 2 (98 mg, 0.30 mmol) was alkylated with phenethyl
iodide (209 mg, 0.90 mmol) according to method A for 3.5
days to give lactone 13i (48 mg, 37%, 11:1 crude d.r.) as a
white solid. Mp 75–78 8C (CHCl3). IR (neat) 1752
4.5.12. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3-dimethyl-
6-oxo-5-phenylselanyl-morpholine-4-carboxylate (13l).
Lactone 2 (84 mg, 0.260 mmol) was alkylated with
phenylselenium chloride (149 mg, 0.780 mmol) according
to method D to give lactone 13l (31 mg, 25%, 8:1 crude d.r.)
as yellow needles. Mp 39–42 8C (CHCl3). IR (neat) 1745
(OCvO), 1720 (NCvO) cm21
.
1H NMR (400 MHz,
CDCl3) d 7.40–7.30 (m, 5H, OCH2Ph), 7.26–7.22 (m,
2H), 7.18–7.14 (m, 1H), 7.09–7.04 (m, 2H), 5.13 (d, J¼
12.0 Hz, 1H, OCHAHBPh), 5.11 (d, J¼12.0 Hz, 1H,
OCHAHBPh), 4.42 (dd, J¼9.8, 3.5 Hz, 1H), 3.39 (s, 3H,
CH3OC), 3.16 (s, 3H, CH3OC), 2.75 (td, J¼12.6, 5.1 Hz,
1H), 2.65 (td, J¼12.6, 6.3 Hz, 1H), 2.27–2.04 (m, 2H), 1.85
(s, 3H, CH3C), 1.60 (s, 3H, CH3C). 13C NMR (125 MHz,
CDCl3) d 168.9 (OCvO), 155.1 (NCvO), 141.1, 135.7,
128.7, 128.4, 128.3, 107.1, 89.2, 67.7 (OCH2Ph), 57.4, 50.7,
49.7, 36.6, 32.6, 19.2, 18.3. [a]2D5¼22.0 (c 0.57, CHCl3).
HRMS (þESI) Calcd for C24H29NO6Na [MþNa]þ requires
450.1893, found 450.1899.
(OCvO), 1724 (NCvO) cm21
.
1H NMR (600 MHz,
CDCl3) d 7.66–7.60 (m, 3H, SePh), 7.39–7.19 (m, 7H,
OCH2Ph, SePh), 5.61 (1s, 1H), 5.21 (d, J¼12.1 Hz, 1H,
OCHAHBPh), 5.08 (d, J¼12.1 Hz, OCHAHBPh), 3.55 (s,
3H, CH3OC), 3.17 (s, 3H, CH3OC), 1.87 (s, 3H, CH3C),
1.65 (s, 3H, CH3C). 13C NMR (150 MHz, CDCl3) d 167.0
(OCvO), 154.0 (NCvO), 135.4, 134.7, 131.5, 129.0,
128.6, 128.4, 107.2, 89.4, 68.2, 57.2, 51.2, 50.7, 17.8.
[a]2D5¼þ32.3 (c 1.4, CHCl3). HRMS (þESI) Calcd for
C22H25O6NSe [MþNa]þ 502.0745, found 502.0721.
4.5.13. Benzyl (2S,3R,5R)-5-benzyl-2,3-dimethoxy-2,3,5-
trimethyl-6-oxo-morpholine-4-carboxylate (14a). Lac-
tone 13b (160 mg, 0.47 mmol) was alkylated with benzyl
bromide (239 mg, 1.41 mmol) according to method A to
give lactone 14a (171 mg, 85%) as white needles. Mp 72–
74 8C (petrol/ether). IR (neat) 1751 (OCvO), 1718
4.5.10. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3-dimethyl-
5-(2-methylprop-2-enyl)-6-oxomorpholine-4-carboxyl-
ate (13j). Lactone 2 (79 mg, 0.24 mmol) was alkylated with
3-bromo-2-methylpropene (99 mg, 0.73 mmol) according
to method B (for 35 h) to give lactone 13j (160 mg, 70%,
11:1 crude d.r.) as a yellow oil. Recrystallization (petrol/
ether) gave only the major diastereoisomer as white prisms.
Mp 51–53 8C (ether/petrol). IR (neat) 1758 (OCvO),
1720 (NCvO) cm21. 1H NMR (500 MHz, CDCl3) d 7.36–
7.32 (m, 5H, Ph), 5.16 (s, 2H, OCH2Ph), 4.78 (s, 1H,
CvCHAHB), 4.66 (s, 1H, CvCHAHB), 4.63 (dd, J¼10.0,
4.7 Hz, 1H), 3.41 (s, 3H, CH3OC), 3.15 (s, 3H, CH3OC),
2.72 (dd, J¼13.4, 4.7 Hz, 1H), 2.55 (dd, J¼13.4, 10.0 Hz,
1H), 1.84 (s, 3H, CH3C), 1.58 (s, 3H, CH3C), 1.56 (s, 3H,
CH3C). 13C NMR (125 MHz, CDCl3) d 167.5 (OCvO),
155.1 (NCvO), 141.1 (CvCH2), 135.6, 128.6, 128.5,
128.5, 114.3 (CvCH2), 107.1, 89.3, 67.9 (OCH2Ph), 56.3,
50.7, 49.5, 42.7, 21.4, 19.8, 18.3. [a]2D5¼þ16.2 (c 1.0,
1
(NCvO) cm21. H (600 MHz, CDCl3) d 7.46–7.36 (m,
5H), 7.19, (m, 3H), 6.98 (m, 2H), 5.57 (d, J¼12.1 Hz, 1H,
OCHAHBPh), 5.24 (d, J¼12.1 Hz, 1H, OCHAHBPh), 3.67
(d, J¼13.7 Hz, 1H), 3.37 (d, J¼13.7 Hz, 1H), 3.26 (s, 3H,
CH3OC), 3.25 (s, 3H, CH3OC), 1.79 (s, 3H, CH3C), 1.59 (s,
3H, CH3C), 1.54 (s, 3H, CH3C). 13C NMR (150 MHz,
CDCl3) d 170.2 (OCvO), 155.5 (NCvO), 136.2, 135.6,
130.7, 128.7, 128.6, 128.5, 127.9, 126.7, 106.5, 90.5,
67.7 (OCH2Ph), 66.0, 50.3, 49.7, 43.6, 22.2, 19.4, 18.9.
[a]2D5¼þ66.7 (c 3.6, CHCl3). HRMS Calcd for C24H29NO6
[M]þ 427.1995, found 427.1996. Structure and relative
stereochemistry confirmed by single crystal X-ray diffrac-
tion studies.

7688
C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
4.5.14. Benzyl (2S,3R,5S)-5-benzyl-2,3-dimethoxy-2,3,5-
trimethyl-6-oxo-morpholine-4-carboxylate (14b). Lac-
tone 13e (30 mg, 0.073 mmol) was alkylated with methyl
iodide (31 mg, 0.22 mmol) according to method A to give
lactone 14b (23 mg, 73%) as white plates. Mp 116–118 8C
with
0.54 mmol) according to method C for 36 h to give lactone
1-heptyloxy-4-(iodo-ethyl)-benzene
(173 mg,
14e (30 mg, 30%) as a colourless oil. IR (neat) 1749
.
1H NMR (500 MHz,
(OCvO), 1713 (NCvO) cm21
CDCl3) d 7.36–7.33 (m, 5H), 6.83 (d, J¼2.0 Hz, 2H),
6.73 (d, J¼2.0 Hz, 2H), 5.13 (ap q, 2H, OCH2Ph), 3.90 (t,
J¼6.6 Hz, 2H), 3.41 (s, 3H, CH3OC), 3.26 (s, 3H, CH3OC),
2.47–2.33 (m, 4H), 1.80 (s, 3H, CH3), 1.79–1.73 (m, 2H),
1.65 (s, 3H, CH3C), 1.56 (s, 3H, CH3OC), 1.44–1.41 (m,
2H), 1.35–1.24 (m, 6H), 0.88 (t, J¼6.8 Hz, 3H, CH2CH3).
13C NMR (125 MHz, CDCl3) d 171.8 (OCvO), 157.3,
155.4 (NCvO), 135.6, 133.5, 129.1, 128.6, 128.5, 128.3,
114.4, 106.5, 90.4, 68.0 (OCH2Ph), 67.5, 64.8, 50.4, 49.9,
41.7, 31.7, 30.6, 29.3, 29.1, 26.0, 23.1, 22.6, 19.3, 18.9,
14.1. [a]2D5¼þ2.0 (c 0.9 CHCl3). HRMS (þESI) Calcd for
C32H45NO7Na [MþNa]þ 578.3094, found 578.3094.
(petrol/ether). IR (neat) 1749 (OCvO), 1711 (CvO) cm21
.
1H MR (600 MHz, CDCl3) d 7.46–7.40 (m, 5H), 7.20–7.13
(m, 5H), 5.28 (d, J¼11.9 Hz, 1H, OCHAHBPh), 5.19 (d, J¼
11.9 Hz, 1H, OCHAHBPh), 3.62 (d, J¼14.0 Hz, 1H), 3.49
(d, J¼14.0 Hz, 1H), 3.42 (s, 3H, CH3OC), 2.31 (s, 3H,
CH3OC), 1.80 (s, 3H, CH3C), 1.68 (s, 3H, CH3C), 1.50 (s,
3H, CH3C). 13C NMR (150 MHz, CDCl3) d 172.3 (OCvO),
155.3 (NCvO), 137.8, 135.6, 131.4, 128.9, 128.7, 128.5,
128.0, 126.5, 106.0, 89.4, 67.6 (OCH2Ph), 65.4, 49.6, 49.2,
42.1, 27.7, 19.5, 18.6. [a]2D5¼þ102.1 (c 1.23, CHCl3).
HRMS Calcd for C24H29NO6 [MþNa]þ 450.1893, found
450.1905. Structure and relative stereochemistry confirmed
by single crystal X-ray diffraction studies.
4.5.18. Benzyl-(2S,3R,5S)-5-benzyl-2,3-dimethoxy-2,3-
dimethyl-5-(5-methyl-isoxazol-3-ylmethyl)-6-oxo-mor-
4.5.15. Benzyl-(2S,3R,5S)-5-allyl-2,3-dimethoxy-2,3,5-
trimethyl-6-oxo-morpholine-4-carboxylate (14c). Lac-
tone 13a (150 mg, 0.41 mmol) was alkylated with methyl
iodide (176 mg, 1.24 mmol) according to method A to give
lactone 14c (61 mg, 41%) as white needles. Mp 52–54 8C
(CHCl3). IR (neat) 1748 (OCvO), 1712 (NCvO) cm21. 1H
NMR (500 MHz, CHCl3) d 7.39–7.33 (m, 5H), 5.78 (m, 1H,
CHvCH2), 5.14 (s, 2H, OCH2Ph), 4.92 (d, J¼9.8 Hz, 1H,
CHvCHAHB), 4.84 (d, J¼16.6 Hz, 1H, CHvCHAHB),
3.41 (s, 3H, CH3OC), 3.27 (s, 3H, CH3OC), 2.90 (dd, J¼
14.3, 6.1 Hz, 1H), 2.87 (dd, J¼14.3, 8.7 Hz, 1H), 1.79
pholine-4-carboxylate (14f). Lactone
2
(119 mg,
0.37 mmol) was alkylated with 3-bromomethyl-5-isoxazole
(176 mg, 1 mmol) according to method D to give an
intermediate lactone as a colourless oil, a portion of which
(33 mg, 0.079 mmol) which was alkylated with benzyl
bromide (41 mg, 0.237 mmol) according to method A to
give lactone 14f (47 mg, 31%) as a white solid. Mp 156–
160 8C (ether). IR (neat) 1752 (OCvO), 1712
1
(CvO) cm21. H NMR (600 MHz, CHCl3) d 7.57–7.56
(m, 2H), 7.47–7.41 (m, 3H), 7.18–7.14 (m, 4H), 6.89–6.87
(m, 1H), 5.87 (s, 1H), 5.33 (d, J¼11.5 Hz, 1H, OCHAHBPh),
5.32 (d, J¼11.5 Hz, 1H, OCHAHBPh), 3.89 (d, J¼13.8, 1H),
3.68 (d, J¼14.3, 1H), 3.51 (s, 3H, CH3OC), 3.45 (d,
J¼13.8 Hz, 1H), 3.02 (d, J¼14.3 Hz, 1H), 2.92 (s, 3H,
CH3OC), 2.60 (s, 3H, CH3OC), 1.80 (s, 3H, CH3C), 1.58 (s,
3H, CH3C). 13C NMR (150 MHz, CHCl3) d 171.4 (OCvO),
168.3 (CvN), 160.3 (CvC–O), 155.4 (NCvO), 140.1,
135.7, 135.5, 130.8, 129.3, 128.7, 128.6, 128.5, 128.2,
128.1, 107.1, 103.9, 89.6, 68.6 (OCH2Ph), 67.9, 49.9, 49.7,
44.0, 33.3, 28.5, 20.0, 18.2. [a]2D5¼þ104.8 (c 0.5, CHCl3).
(s, 3H, CH3C), 1.70 (s, 3H, CH3C), 1.56 (s, 3H, CH3C). 13
C
NMR (150 MHz, CHCl3)
d 172.4 (OCvO), 155.4
(NCvO), 136.6, 135.0 (CHvCH2), 128.7, 128.6, 128.4,
117.7 (CHvCH2), 106.1, 89.7, 67.5 (OCH2Ph), 62.7, 51.5,
49.7, 42.2, 26.8, 19.5, 18.3. [a]2D5¼þ82.2 (c 0.48, CHCl3).
HRMS (þESI) Calcd for C20H27NO6Na [MþNa]þ
400.1736, found 400.1740.
4.5.16. Benzyl-(2S,3R,5R)-5-benzyl-2,3-dimethoxy-2,3-
dimethyl-5-(5-methyl-isoxazol-3-ylmethyl)-6-oxo-mor-
pholine-4-carboxylate (14d). Lactone 13e (82 mg,
0.199 mmol) was alkylated with in 3-bromomethyl-5-
isoxazole (105 mg, 0.517 mmol) according to method D to
give lactone 14d (35 mg, 36%) as a yellow oil. IR (neat)
1752 (OCvO), 1712 (CvO), 1693 (CvN) cm21. 1H NMR
(600 MHz, CHCl3) d 7.46 (m, 2H), 7.43–7.37 (m, 3H),
7.14–7.08 (m, 5H), 5.83 (d, J¼0.7 Hz, 1H), 5.32 (d, J¼
11.9 Hz, 1H, OCHAHBPh), 5.23 (d, J¼11.9 Hz, 1H,
OCHAHBPh), 4.09 (d, J¼14.2 Hz, 1H), 3.65 (d, J¼
13.9 Hz, 1H), 3.59 (d, J¼13.9 Hz, 1H), 3.58 (d, J¼
14.2 Hz, 1H), 3.50 (s, 3H, CH3OC), 2.36 (d, J¼0.7 Hz,
3H, CH3C), 2.12 (s, 3H, CH3OC), 1.64 (s, 3H, CH3C), 1.50
(s, 3H, CH3C). 13C NMR (150 MHz, CHCl3) d 169.0
(OCvO), 168.5 (CvN), 159.6, 155.4 (NCvO), 137.1,
135.4, 131.5, 129.0, 128.7, 128.6, 128.2, 126.7, 106.5,
102.9, 89.6, 68.7, 67.9 (OCH2Ph), 50.0, 49.1, 39.5, 35.7,
19.9, 18.6, 12.3. [a]D25¼þ34.2 (c 3.49, CHCl3). HRMS
(þESI) Calcd for C28H32N2O7Na [MþNa]þ 531.2107,
found 531.2097.
4.5.19. Benzyl-(2S,3R,5R)-2,3-dimethoxy-2,3,5-tri-
methyl-5-(5-methyl-isoxazol-3-ylmethyl)-6-oxo-morpho-
line-4-carboxylate (14g). Lactone 13b (62 mg, 0.19 mmol)
was alkylated with 3-bromomethyl-5-isoxazole (99 mg,
0.56 mmol) according to method C to give lactone 14g
(50 mg, 62%) as a colourless oil. IR (neat) 1754 (OCvO),
1713 (CvO), 1608 (CvN) cm21 1H NMR (500 MHz,
.
CDCl3) d 7.42–7.33 (m, 5H), 5.72 (d, J¼0.6 Hz, 1H), 5.23
(d, J¼12.1 Hz, 1H, CHAHBPh), 5.20 (d, J¼12.1 Hz, 1H,
CHAHBPh), 3.80 (d, J¼14.2 Hz, 1H, CHAHBCvN), 3.40 (s,
3H, CH3OC), 3.35 (d, J¼14.2 Hz, 1H, CHAHBCvN), 3.24
(s, 3H, CH3OC), 2.33 (d, J¼0.6 Hz, 3H), 1.77 (s, 3H,
CH3C), 1.68 (s, 3H, CH3C), 1.54 (s, 3H, CH3C). 13C NMR
(125 MHz, CDCl3) d 169.9 (OCvO), 168.8 (CvN), 159.4,
155.3 (NCvO), 135.6, 128.7, 128.5, 128.4, 106.5, 102.8,
90.6, 67.7 (OCH2Ph), 64.3, 50.4, 50.0, 34.9, 22.4, 19.4,
18.8, 12.5 (CvCO–CH3). [a]2D5¼þ33.6 (c 1.0, CHCl3).
HRMS (þESI) Calcd for C22H28N2O7Na [MþNa]þ
455.1794, found 455.1787.
4.5.17. Benzyl-(2S,3R,5R)-5-(4-Heptyloxy-benzyl)-2,3-
dimethoxy-2,3,5-trimethyl-6-oxomorpholine-4-carboxyl-
ate (14e). Lactone 13b (60 mg, 0.18 mmol) was alkylated
4.5.20. Benzyl-(2S,3R,5R)-5-benzothiazol-2-ylmethyl-
2,3-dimethoxy-2,3,5-trimethyl-6-oxo-morpholine-4-
carboxylate (14h). Lactone 13b (49 mg, 0.151 mmol) was

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7689
alkylated with 2-bromomethyl-1,3-benzathiazole (103 mg,
0.453 mmol) according to method C to give lactone 14h
(18 mg, 25%) as a brown solid. Mp 82–84 8C (petrol/ether).
IR (neat) 1754 (OCvO), 1716 (NCvO), 1693
tone 13a (30 mg, 0.083 mmol) was alkylated with allyl
bromide (30 mg, 0.249 mmol) according to method A to
give lactone 14k (24 mg, 72%) as white needles. Mp 88–
1
90 8C. IR (neat) 1751 (OCvO), 1710 (NCvO) cm21. H
(CvN) cm21
;
1H NMR (600 MHz, CDCl3) d 7.98 (d,
NMR (500 MHz, CDCl3) d 7.41–7.35 (m, 5H), 5.82–5.73
(m, 1H, CHvCH2), 5.70–5.62 (m, 1H, CHvCH2) 5.17
(d, J¼12.0 Hz, 1H, OCHAHBPh), 5.12 (d, J¼12.0 Hz, 1H,
OCHAHBPh), 5.05–4.88 (m, 4H, 2£CHvCH2), 3.42 (s, 3H,
CH3OC), 3.31 (s, 3H, CH3OC), 3.17 (ddt, J¼14.2, 8.1 Hz,
1H, CAHAHBCHvCH2), 3.02 (ddt, J¼14.5, 5.1, 1.7 Hz,
1H, CBHAHBCHvCH2), 2.93 (ddt, J¼14.2, 7.1, 1.2 Hz,
1H, CAHAHBCHvCH2), 2.84 (dd, J¼14.5, 9.5 Hz, 1H,
CBHAHBCHvCH2), 1.81 (s, 3H, CH3C), 1.58 (s, 3H,
CH3C). 13C NMR (125 MHz, CDCl3) d 169.4 (OCvO),
155.5 (NCvO), 135.5, 134.9, 133.4, 128.7, 128.7, 128.5,
118.2, 117.9, 106.6, 89.9, 67.8, 67.3, 51.9, 49.7, 43.1, 40.0,
19.8, 18.3. [a]2D5¼þ28.5 (c 2.0, CHCl3). HRMS (þESI)
Calcd for C22H29NO6Na [MþNa]þ 426.1893, found
426.1912. Structure and relative stereochemistry confirmed
by single crystal X-ray diffraction studies.
J¼8.1 Hz, 1H) 7.79 (d, J¼7.9 Hz, 1H), 7.46–7.31 (m, 7H),
5.33 (d, J¼12.1 Hz, 1H, OCHAHBPh), 5.29 (d, J¼12.1 Hz,
1H, OCHAHBPh), 4.13 (d, J¼14.1 Hz, 1H), 3.99 (d, J¼
14.1 Hz, 1H), 3.26 (s, 3H, CH3OC), 3.09 (s, 3H, CH3OC),
1.84 (s, 3H, CH3C), 1.76 (s, 3H, CH3C), 1.50 (s, 3H, CH3C).
13C NMR (125 MHz, CDCl3) d 170.0 (OCvO), 165.1
(CvN–C), 155.4 (NCvO), 153.7 (CvN–C), 135.9,
135.7, 128.7, 128.5, 128.4, 125.7, 124.8, 123.2, 121.3,
106.5, 90.6, 67.8 (OCH2Ph), 65.1, 50.4, 50.3, 43.1, 23.6,
19.2, 18.9. [a]2D5¼þ2.0 (c 0.9, CHCl3). HRMS (þESI)
Calcd for C25H28N2O6SNa [MþNa]þ 507.1567, found
507.1566.
4.5.21. Benzyl-(2S,3R,5R)-5-[3,4-bis-(2,2-dimethyl-pro-
pionyloxy)-benzyl]-2,3-dimethoxy-2,3,5-trimethyl-6-
oxo-morpholine-4-carboxylate (14i). Lactone 13b (98 mg,
0.29 mmol) was alkylated with 4-(bromomethyl)-2-[(2,2-
4.5.24. Benzyl-(2S,3R,5S)-5-allyl-2,3-dimethoxy-2,3-
dimethyl-5-(2-methyl-allyl)-6-oxo-morpholine-4-carb-
oxylate (14l). Lactone 13j (198 mg, 0.53 mmol) was
alkylated with allyl bromide (193 mg, 1.59 mmol) accord-
ing to method D to give lactone 14l (85 mg, 38%) as white
needles. Mp 62–64 8C (petrol/ether). IR (neat) 1749
dimethylpropanoyl)oxy]phenyl
0.87 mmol) according to method D to give lactone 14i
pivalate
(323 mg,
(27 mg, 15%) as a colourless oil. IR (neat) 1760, 1715
1
(NCvO) cm21. H NMR (500 MHz, CDCl3) d 7.42–7.32
(m, 5H), 6.90 (d J¼8.9 Hz, 1H), 6.70–6.77 (m, 2H), 5.22 (d,
J¼12.0 Hz, 1H, OCHAHBPh), 5.21 (d, J¼12.0 Hz, 1H,
OCHAHBPh), 3.39 (d, J¼10 Hz, 1H, CHACHBAr), 3.24 (d,
J¼10 Hz, 1H, CHACHBAr), 3.23 (s, 3H, CH3OC), 3.17 (s,
3H, CH3OC), 1.73 (s, 3H, CH3C), 1.59 (s, 3H, CH3C),
1.48 (s, 3H, CH3OC), 1.30 (s, 18H, C(CH3)3). 13C NMR
(OCvO), 1710 (NCvO) cm21
.
1H NMR (500 MHz,
CDCl3) d 7.41–7.35 (m, 5H), 5.65 (dddd, J¼16.9, 10.1,
8.1, 7.0 Hz, 1H), 5.19 (d, J¼12.0 Hz, 1H, OCHAHBPh),
5.11 (d, J¼12.0 Hz, 1H, OCHAHBPh), 5.01 (d, J¼10.1 Hz,
1H), 4.93 (d, J¼16.9 Hz, 1H), 4.76 (s, 1H), 4.65 (s, 1H),
3.41 (s, 3H, CH3OC), 3.33 (dd, J¼14.2, 8.1 Hz, 1H,
CH3OC), 3.10 (s, 3H, CH3OC), 2.98 (d, J¼13.9 Hz, 1H),
2.96 (d, J¼13.9 Hz, 1H), 2.87 (dd, J¼14.2, 7.0 Hz, 1H),
1.80 (s, 3H, CH3C), 1.72 (s, 3H, CH3C), 1.58 (s, 3H, CH3C).
13C NMR (125 MHz, CDCl3) d 168.8 (OCvO), 155.5
(NCvO), 142.5, 135.4, 133.5, 128.8, 128.7, 128.6, 118.1,
116.6, 106.3, 89.5, 67.8 (OCH2Ph), 66.7, 51.1, 49.6, 43.6,
42.3, 23.9, 19.7, 18.5. [a]2D5¼þ39.0 (c 1.0, CHCl3). HRMS
(þESI) Calcd for C23H31NO6Na [MþNa]þ 440.2049, found
440.2051. Structure and relative stereochemistry confirmed
by single crystal X-ray diffraction studies.
(125 MHz, CDCl3)
d
175.9 (OCvOtBu), 175.7
(OCvOtBu), 170.8 (OCvO), 155.5 (NCvO), 141.9,
141.5, 135.5, 134.8, 128.7, 128.65, 128.62, 128.5, 127.8,
125.4, 106.4, 90.5, 67.7 (OCH2Ph), 65.8, 50.4, 49.9, 43.2,
39.1, 39.0, 27.24, 27.20, 22.9, 19.2, 19.0. [a]2D5¼þ15.0
(c 0.4, CHCl3). HRMS (þESI) Calcd for C34H45NO9Na
[MþNa]þ 650.2941, found 650.2940.
4.5.22. Benzyl-(2S,3R,5S)-5-[3,4-bis-(2,2-dimethyl-pro-
pionyloxy)-benzyl]-2,3-dimethoxy-2,3,5-trimethyl-6-
oxo-morpholine-4-carboxylate (14j). Lactone 13k (80 mg,
0.13 mmol) was alkylated with methyl iodide (55 mg,
0.39 mmol) according to method A to give lactone 14j
(36 mg, 44%) as a colourless oil. IR (neat) 1758 (OCvO),
1714 (NCvO) cm21. 1H NMR (500 MHz, CHCl3) d 7.42–
7.21 (m, 5H), 7.08 (d, J¼2.0 Hz, 1H), 7.00 (dd, J¼8.3,
2.0 Hz, 1H), 6.83 (d, J¼8.3 Hz, 1H), 5.32 (d, J¼7.3 Hz, 1H,
OCHAHBPh), 5.18 (d, J¼7.3 Hz, 1H, OCHAHBPh), 3.59 (d,
J¼14.0 Hz, 1H), 3.51 (d, J¼14.0 Hz, 1H), 3.40 (s, 3H,
CH3OC), 2.47 (s, 3H, CH3OC), 1.79 (s, 3H, CH3C), 1.63
(s, 3H, CH3C), 1.47 (s, 3H, CH3C), 1.30 (6£CH3). 13C NMR
4.5.25. Benzyl-(2S,3R,5R)-5-allyl-2,3-dimethoxy-5-(2-
methoxycarbonyl-allyl)-2,3-dimethyl-6-oxo-morpholine-
4-carboxylate (14m). Lactone 13a (91 mg, 0.25 mmol) was
alkylated with methyl (2-bromomethyl)-acrylate (149 mg,
0.83 mmol) according to method D to give lactone 14m
(92 mg, 79%) as white needles. Mp 124–126 8C (CHCl3).
1
IR (neat) 1746 (OCvO), 1714 (NCvO) cm21. H NMR
(500 MHz, CDCl3) d 7.44–7.34 (m, 5H), 6.16 (d, J¼1.5 Hz,
1H), 5.67–5.5.61 (m, 1H), 5.38 (s, 1H), 5.18 (d, J¼11.8 Hz,
1H, OCHAHBPh), 5.13 (d, J¼11.8 Hz, 1H, OCHAHBPh),
4.91 (dd, J¼10.1, 1.5 Hz, 1H), 4.84 (dd, J¼17.1, 1.5 Hz,
1H), 3.69 (s, 3H, CH3OC), 3.55 (d, J¼13.6 Hz, 1H), 3.52 (s,
3H, CH3OC), 3.30 (s, 3H, CH3OC), 3.29 (d, J¼13.6 Hz,
1H), 2.90–2.83 (m, 2H), 1.81 (s, 3H, CH3C) 1.58 (s, 3H,
CH3C). 13C NMR (125 MHz, CDCl3) d 168.8 (OCvO),
167.3 (OCvO), 155.6 (NCvO), 136.4, 135.4 (CvCH2),
134.8 (CHvCH2), 129.7, 128.9, 128.7, 128.6, 117.7
(CHvCH2), 106.5, 89.6, 67.9 (OCH2Ph), 66.8, 52.2, 51.8,
50.1, 39.4, 38.5, 19.8, 18.3. [a]2D5¼þ70.2 (c 1.2, CHCl3).
(125 MHz, CHCl3)
d
176.1 (OCvOtBu), 175.9
(OCvOtBu), 172.3 (OCvO), 155.2 (NCvO), 142.2,
141.1, 136.5, 135.6, 129.3, 128.8, 128.7, 128.6, 128.4,
126.2, 106.2, 86.7, 67.7 (OCH2Ph), 65.4, 49.7 (CH3OC),
49.6 (CH3OC), 41.1, 39.1, 39.0, 27.3, 27.2, 19.6, 18.7, 15.3.
[a]2D5¼þ43.0 (c 1.5, CHCl3). HRMS (þESI)
C34H45NO10Na [MþNa]þ 650.2941, found 650.2961.
4.5.23. Benzyl-(2S,3R)-5,5-diallyl-2,3-dimethoxy-2,3-
dimethyl-6-oxo-morpholine-4-carboxylate (14k). Lac-

7690
C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
HRMS (þESI) Calcd for C24H31NO8Na [MþNa]þ
484.1947, found 484.1948. Structure and relative stereo-
chemistry confirmed by single crystal X-ray diffraction
studies.
hexylphosphine)ruthenium (11 mg, 13 mmol) was added to
a solution of lactone 14m (59 mg, 0.13 mmol) in dichloro-
methane (10 mL) and the solution heated at reflux for 2
days. The solution was allowed to cool and the solvent
removed under reduced pressure and the residue was
purified by column chromatography (petrol/ether, 3:1) to
give cyclopentene 15m (44 mg, 79%) as a yellow oil. IR
4.5.26. Benzyl-(7R,8S)-7,8-dimethoxy-7,8-dimethyl-10-
oxo-9-oxa-6-aza-spiro[4.5]dec-2-ene-6-carboxylate
(15k). 1,3-Bis-(2,4,6-trimethylphenyl)-2-(imidazolidinyl-
idene)dichloro(phenylmethylene)-(tricyclohexylphosphine)-
ruthenium (5.9 mg, 6.9 mmol) was added to a solution of
lactone 14k (28 mg, 6.9 mmol) was dissolved in dichloro-
methane (5 mL) and the solution heated at reflux for 2 h.
The solution was allowed to cool to rt and the solvent
removed under reduced pressure. The residue was purified
by column chromatography (petrol/ether, 3:1) to give
cyclopentene 15k (23 mg, 89%) as white needles. IR
1
(neat) 1749 (OCvO) and 1713 (NCvO) cm21. H NMR
(500 MHz, CHCl3) d 7.32–7.30 (m, 3H), 7.26–7.24 (m,
2H), 6.50 (qn, J¼2.1 Hz, 1H), 5.06 (d, J¼11.7 Hz, 1H,
OCHAHBPh), 5.05 (d, J¼11.7 Hz, 1H, OCHAHBPh), 3.62
(s, 3H, CH3OC), 3.45–3.41 (m, 4H), 3.24 (ddt, J¼17.8, 3.2,
1.6 Hz, 1H), 3.20 (s, 3H, CH3OC), 2.84 (dt, J¼17.8, 2.4 Hz,
1H), 2.69 (dq, J¼18.9, 2.5 Hz, 1H), 1.80 (s, 3H, CH3C),
1.57 (s, 3H, CH3C). 13C NMR (125 MHz, CHCl3) d 171.7
(CvOOCH3), 164.3 (OCvO), 154.7 (NCvO), 141.2,
134.9, 132.0 (C-8), 128.9, 128.5, 128.4, 106.2, 90.2, 67.9
(OCH2Ph), 66.0, 51.3, 50.2, 49.7, 46.2, 45.9, 18.8,
17.8. [a]2D5¼246.8 (c 0.98, CHCl3). HRMS (þESI)
C22H27NO8Na [MþNa]þ 456.1634 found 456.1648.
(neat) 1752 (OCvO), 1714 (NCvO) cm21 1H NMR
.
(500 MHz, CHCl3) d 7.33–7.31 (m, 5H), 5.61 (m, 1H,
CHAvCHB), 5.43 (m, 1H, CHAvCHB), 5.10 (d, J¼
12.0 Hz, 1H, OCHAHBPh), 5.09 (d, J¼12.0 Hz, 1H,
OCHAHBPh), 3.41 (s, 3H, CH3OC), 3.26 (dq, J¼16.3,
2.5 Hz, 1H), 3.20 (s, 3H, CH3OC), 3.07 (dm, J¼17.7 Hz,
1H, CBHAHBC), 2.64 (dq, J¼17.7, 2.5 Hz, 1H, CBHAHBC),
2.57 (dqn, J¼16.3, 2.2 Hz, 1H, CAHAHB), 1.79 (s, 3H,
CH3C), 1.55 (s, 3H, CH3C). 13C NMR (125 MHz, CHCl3) d
172.3 (OCvO), 154.9 (NCvO), 135.5, 129.3 (CAvCB),
128.7, 128.4, 128.3, 126.3 (CAvCB), 106.0, 90.1, 67.4
(OCH2Ph), 66.3, 50.0, 49.6, 47.6, 45.1, 18.9, 17.9. [a]2D5¼
þ4.0 (c 0.25, CHCl3). HRMS (þESI) C20H25NO6Na
[MþNa]þ 398.1580, found 398.1579. Structure and
relative stereochemistry confirmed by single crystal X-ray
diffractions studies.
4.6. Cleavage method A for the preparation of mono
substituted a-amino acids
The lactone was treated with aqueous trifluoroacetic acid
(9:1 TFA–H2O, 1 mL per 10 mg) and the solution stirred
for 30 min. The solvent was removed under reduced
pressure and the residue purified by column chromatog-
raphy (petrol/ether, 2:1–2:1þ5% acetic acid) or preparative
HPLC to give the amino acid.
4.7. Cleavage method B for the preparation of
disubstituted a,a-amino acids
4.5.27. Benzyl-(5R,7R,8S)-7,8-dimethoxy-2,7,8-tri-
methyl-10-oxo-9-oxa-6-aza-spiro[4.5]dec-2-ene-6-carb-
oxylate (15l). 1,3-Bis-(2,4,6-trimethylphenyl)-2-(imidazol-
idinylidene)dichloro(phenylmethylene)-(tricyclohexylphos-
phine)ruthenium (12 mg, 0.014 mmol) was added to a
solution of lactone 14l (60 mg, 0.14 mmol) in tetrahydro-
furan (5 mL) and the solution heated at reflux for 2 h. The
solution was allowed to cool and the solvent removed under
reduced pressure. The residue was purified by column
chromatography (petrol/ether, 3:1) to give cyclopentene 15l
(49 mg, 87%) as white needles. Mp 129–132 8C (ether).
The lactone (1 equiv.) was treated with aqueous trifluoro-
acetic acid (2:1 TFA–H2O, 1 mL per 10 mg) and the
solution stirred for 30 min. The solvent was removed under
reduced pressure and the residue treated with 1 N NaOH–
MeOH (1 mL per 10 mg) for 30 min. The solvent was
removed under reduced pressure and the residue purified by
column chromatography (petrol/ether, 1:1–1:1þ5% acetic
acid) or prep-HPLC to give the amino acid.
4.7.1. (2R)-2-Benzyloxycarbonylamino pent-4-enoic acid
(16a). Lactone 13a (20.6 mg, 0.044 mmol) was treated
according to method A to yield amino acid 16a (12 mg,
77%) as a colourless oil. IR (neat) 3400 (OH), 1671 (br
2£CvO) cm21. 1H NMR (500 MHz, CD3OD) d 7.36–7.26
(m, 5H, Ph), 5.83–5.74 (m, 1H), 5.13–5.04 (m, 4H), 4.19
(dd, J¼8.2, 4.9 Hz, 1H, NHCH), 2.60–2.52 (m, 1H), 2.46–
2.40 (m, 1H). 13C NMR (125 MHz, CD3OD) d 175.6
(CvOOH), 158.4 (NCvO), 138.3, 134.8, 129.4, 129.0,
128.8, 118.5, 67.6 (OCH2Ph), 55.5, 37.4. [a]2D5¼29.3 (c
0.8, CHCl3). HRMS (þESI) Calcd for C13H15NO4Na
[MþNa]þ 272.0899, found 272.0903.
1
IR (neat) 1747 (OCvO), 1710 (NCvO) cm21. H NMR
(500 MHz, CHCl3) d 7.33–7.30 (m, 5H), 5.12 (d, J¼
11.9 Hz, 1H, OCHAHBPh), 5.03 (d, J¼11.9 Hz, 1H,
OCHAHBPh), 4.98 (d, J¼1.7, 1H), 3.41 (s, 3H, CH3OC),
3.20 (s, 3H, CH3OC), 3.06 (d, J¼16.0 Hz, 1H), 3.00 (dqn,
J¼17.4, 2.0 Hz, 1H), 2.61 (dq, J¼17.4, 2.2 Hz, 1H), 2.46
(d, J¼16.0 Hz, 1H), 1.79 (s, 3H, CH3C), 1.54 (br s, 3H,
CH3CvC), 1.53 (s, 3H, CH3C). 13C NMR (125 MHz,
CHCl3) d 172.3 (OCvO), 154.9 (NCvO), 138.7, 135.5,
128.7, 128.4, 128.3, 120.1, 105.9, 90.1, 67.4 (OCH2Ph),
66.8, 49.9 (CH3OC), 49.6 (CH3OC), 48.7, 47.9, 18.9, 18.0,
16.2 (CHvCCH3). [a]D25¼þ12.2 (c 0.58, CHCl3). HRMS
(þESI) Calcd for C21H27NO6 [MþNa]þ 412.1736, found
412.1729.
4.7.2. (2R)-2-Benzyloxycarbonylamino propanoic acid
(16b). Lactone 13b (25.7 mg, 0.076 mmol) was treated
according to cleavage method A to yield amino acid 16b
(12 mg, 71%) as white plates. Mp 71–73 8C (H2O). IR
4.5.28. 6-Benzyl-2-methyl-(5R,7R,8S)-7,8-dimethoxy-
7,8-dimethyl-10-oxo-9-oxa-6-aza-spiro[4.5]dec-2-ene-
2,6-dicarboxylate (15m). 1,3-Bis-(2,4,6-trimethylphenyl)-
2-(imidazolidinylidene)dichloro(phenylmethylene)-(tricyclo-
(neat) 1701 (br, 2£CvO) cm21
.
1H NMR (500 MHz,
CD3OD) d 7.36–7.26 (m, 5H, Ph), 5.08 (s, 2H, OCH2Ph),
4.17 (q, J¼7.3 Hz, 1H, NHCH), 1.37 (d, J¼7.3 Hz, 3H,

C. I. Harding et al. / Tetrahedron 60 (2004) 7679–7692
7691
CH3). 13C NMR (125 MHz, CD3OD) d 176.5 (CvOOH),
158.4 (NCvO), 138.2, 129.4, 129.0, 128.8, 67.5 (OCH2Ph),
51.1 (NHCH), 17.9 (CH3). [a]2D5¼þ12.1 (c 0.9, CHCl3).
HRMS (þESI) Calcd for C11H13NO4Na [MþNa]þ
246.0742, found 246.0732.
5.09 (s, 2H, OCH2Ph), 3.89 (t, J¼6.6 Hz, 2H), 2.55 (dd,
J¼11.2, 8.8 Hz, 1H), 2.43 (m, 2H), 2.13 (m, 1H), 1.74 (ap
qn, J¼7.0 Hz, 2H), 1.64 (s, 3H, CH3), 1.43–1.21 (m, 8H),
0.87 (t, J¼6.2 Hz, 3H). [a]2D5¼24.0 (c 0.5, CHCl3). HRMS
(þESI) Calcd for C26H35NO5Na [MþNa]þ 464.2413, found
464.2393.
4.7.3. (2R)-2-Benzyloxycarbonylamino-3-phenylpropa-
noic acid (16e). Lactone 13e (21 mg, 0.051 mmol) was
treated according to method A to yield amino acid 16e
(13 mg, 85%) as a white solid. Mp 85–88 8C (H2O). IR
4.7.7. (2R)-2-Benzyloxycarbonylamino-2-methyl-3-(5-
methylisoxazol-3-yl)propanoic acid (17g). Lactone 14g
(26 mg, 61.4 mmol) was treated according to cleavage
method B to obtain amino acid 17g (16 mg, 81%) as a
colourless oil. IR (neat) 1717 br (2£CvO) cm21. 1H NMR
(600 MHz, CHCl3) d 7.38–7.26 (m, 5H), 5.79 (s, 1H, NH),
5.62 (s, 1H), 5.18 (d, J¼12.2 Hz, 1H, OCHAHBPh), 5.07 (d,
J¼12.2 Hz, 1H, OCHAHBPh), 3.46 (d, J¼14.2 Hz, 1H),
(neat) 1691 (br, 2£CvO) cm21
.
1H NMR (500 MHz,
CD3OD) d 7.32–7.19 (m, 10H), 5.03 (d, J¼12.5 Hz, 1H,
OCHAHBPh), 5.01 (d, J¼12.5 Hz, 1H, OCHAHBPh),
4.39 (dd, J¼9.0, 4.9 Hz, 2H, CHCH2), 3.18 (dd, J¼13.8,
4.9 Hz, 1H, CHCHAHBPh), 2.92 (dd, J¼13.8, 9.0 Hz, 1H,
CHCHAHB). 13C NMR (125 MHz, CD3OD) d 158.3
(NCvO), 138.7, 138.3, 130.3, 129.4, 129.37, 128.9,
128.7, 127.7, 67.4 (OCH2Ph), 57.1, 38.7 (COOH not
observed). [a]2D5¼þ4.1 (c 1.0. MeOH). HRMS (þESI)
Calcd for C17H17NO4Na [MþNa]þ 322.1055, found
322.1042.
3.34 (d, J¼14.2 Hz, 1H), 2.65 (s, 3H, CH3), 1.70 (s, 3H). 13
C
NMR (125 MHz, CHCl3) d 174.1 (OCvO), 169.6 (CvN),
159.4, 155.2 (NCvO), 136.2, 128.5, 128.3, 128.2, 103.1,
66.8 (OCH2Ph), 59.1, 32.4, 23.7, 12.2. [a]2D5¼24.1 (c 0.8,
CHCl3). HRMS (þESI) Calcd for C16H18N2O5Na
[MþNa]þ 341.1113, found 341.1115.
4.7.4. (2S)-2-Benzyloxycarbonylamino-2-methyl-3-phenyl-
propanoic acid (17b). Lactone 14b (15 mg, 0.035 mmol)
was treated according to cleavage method B to obtain amino
acid 17b (10 mg, 76%) as a colourless oil. IR (neat) 3333
4.7.8. (1S)-1-Benzyloxycarbonylamino-3-methylcyclo-
pent-3-ene-1-carboxylic acid (17l). Lactone 15l (22 mg,
56 mmol) was treated according to cleavage method B to
obtain amino acid 17l (13 mg, 84%) as a colourless oil. IR
(OH), 1714 (br, 2£CvO) cm21
.
1H NMR (500 MHz,
(neat) 1709 (br, 2£CvO) cm21
.
1H NMR (500 MHz,
CHCl3) d 7.38–7.32 (m, 5H), 7.22–7.19 (m, 3H), 7.03–
7.02 (m, 2H), 5.33 (s, 1H, NH), 5.15 (d, J¼12.3 Hz, 1H,
OCHAHBPh), 5.11 (d, J¼12.3 Hz, 1H, OCHAHBPh), 3.34
(d, J¼13.6 Hz, 1H), 3.27 (d, J¼13.6 Hz, 1H), 1.63 (s, 3H,
CH3C). 13C NMR (150 MHz, CHCl3) d 176.9 (CvOOH),
155.0 (NCvO), 136.3, 135.6, 130.0, 128.5, 128.3, 128.2,
127.0, 66.7 (OCH2Ph), 60.3, 41.3, 23.5 (CH3C).
[a]2D5¼225.8 (c 1.5, CHCl3). HRMS (þESI) Calcd for
C18H19NO4Na [MþNa]þ 336.1206, found 336.1214.
CHCl3) d 7.37–7.30 (m, 5H, Ph), 5.36 (s, 1H, CHvC),
5.23 (s, 1H, NH), 5.10 (s, 2H, OCH2Ph), 3.07 (br d, J¼
16.2 Hz, 2H, CAHAHBC, CBHAHBC), 2.58 (ap t, J¼
17.0 Hz, 2H, CAHAHBC, CBHAHBC), 1.72 (s, 3H, CH3).
13C NMR (125 MHz, CHCl3) d 155.9 (NCvO), 137.6
(CHvCCH3), 135.9, 128.5, 128.2, 128.1, 120.7
(CHvCCH3), 67.1 (OCH2Ph), 64.9, 48.3, 44.8, 16.1.
[a]2D5¼23.2 (c 0.5, CHCl3). HRMS (þESI) Calcd for
C15H17NO4Na [MþNa]þ 298.1055, found 298.1042.
4.7.5. (2R)-2-Benzyloxycarbonylamino-2-(5-methyl-
isoxazol-3-ylmethyl)-3-phenyl-propionic acid (17d).
Lactone 14d (10 mg, 19.7 mmol) was treated according to
cleavage method B to obtain amino acid 17d (4 mg, 52%)
as a colourless oil. IR (neat) 3367 (OH), 1711 (br
Acknowledgements
We gratefully acknowledge financial support from the
EPSRC (C.I.H. and D.J.D.), the BP endowment and a
Novartis Research Fellowship (to S.V.L.) and a Syngenta
postgraduate scholarship (to C.I.H.).
1
2£CvO) cm21. H NMR (500 MHz, CHCl3) d 7.39–7.34
(m, 5H, OCH2Ph), 7.21–7.17 (m, 3H, Ph), 7.08–7.07 (m,
2H, Ph), 5.69 (s, 1H, NH), 5.57 (s, 1H, CHvCCH3), 5.17 (d,
J¼12.3 Hz, 1H, OCHAHBPh), 5.15 (d, J¼12.3 Hz, 1H,
OCHAHBPh), 3.82 (d, J¼13.9 Hz, 1H, CAHAHBC), 3.66 (d,
J¼13.4 Hz, 1H, CBHAHBC), 3.41 (d, J¼13.9 Hz, 1H,
CAHAHBC), 3.31 (d, J¼13.4 Hz, 1H, CBHAHBC), 2.26
(s, 3H, CH3). 13C NMR (125 MHz, CHCl3) d 172.3
(CvOOH), 169.6 (CvN), 154.7 (NCvO), 136.6, 135.3,
129.8, 128.5, 128.4, 128.3, 128.2, 127.1, 125.5, 103.2
(CHvCCH3), 66.4 (OCH2Ph), 40.8, 34.3, 12.2. [a]2D5¼þ3.0
(c 0.4, CHCl3). HRMS (þESI) Calcd for C22H22N2O5Na
[MþNa]þ 417.1426, found 417.1425.
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