Diastereoselective synthesis of cyclic β2,3-amino acids utilizing 4-substituted-1,3-oxazinan-6-ones

Article abstract of DOI:10.1016/j.tet.2013.05.016

The 4-substituted-1,3-oxazinan-6-one scaffold is a versatile synthon enabling access to a diverse array of β-amino acid derivatives. In this study, the synthetic utility of the 1,3-oxazinan-6-one is expanded to include the diastereoselective synthesis of

Full text of DOI:10.1016/j.tet.2013.05.016

Tetrahedron 69 (2013) 6275e6284
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Diastereoselective synthesis of cyclic
b
2,3-amino acids utilizing
4-substituted-1,3-oxazinan-6-ones
,
,
Brad E. Sleebs a b, Nghi H. Nguyen c, Andrew B. Hughes c
*
a The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
b Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
c Department of Chemistry, La Trobe University, Victoria 3086, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2012
Received in revised form 25 April 2013
Accepted 9 May 2013
Available online 18 May 2013
The 4-substituted-1,3-oxazinan-6-one scaffold is a versatile synthon enabling access to a diverse array of
b
-amino acid derivatives. In this study, the synthetic utility of the 1,3-oxazinan-6-one is expanded to
include the diastereoselective synthesis of cyclic
b
2,3-amino acids. Enolate chemistry is used to first al-
kylate the 4-vinyl, 4-allyl, and 4-butenyl oxazinan-6-ones with various alkenyl electrophiles, in high dr.
The resulting 4,5-bis-alkene adducts are then transformed into 4,5-cyclic-1,3-oxazinan-6-ones utilizing
the ring closing metathesis reaction. The metathesis products are subsequently converted into a variety
Keywords:
of five-, six-, and seven-membered cyclic
oxazinan-6-one as a versatile synthon for producing
b
2,3-amino acids. The research further highlights the 1,3-
-amino acid derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
b
-Amino acid
b
1,3-Oxazinan-6-one
Ring closing metathesis
Enolate chemistry
N-Methyl amino acids
1. Introduction
The recent rise in applications of
b-amino acids has seen
a plethora literature reviews summarizing synthetic approaches
devised to access these important compounds.1e31 However, many
of these synthetic procedures have limitations, in that they are not
stereoselective and they do not produce a large variety of analogues
from a common precursor. Recently, we have demonstrated the
synthetic utility of the 1,3-oxazinan-6-one to gain access to a vari-
ety of known and novel stereopure
Originally, it was demonstrated 1,3-oxazinan-6-ones can allow
b
-amino acids (Fig. 1).32e37
the production of all 20 homologous proteinogenic N-methyl b-
amino acids.32,33 In another study it was shown the enolate
chemistry allowed 1,3-oxazinan-6-ones to be 5-alkylated and 5-
hydroxylated with high diastereoselectivity.34 The resulting ad-
ducts could then be subjected to a range of transformations to give
rise to a variety of stereopure 2-alkyl and 2-hydroxy b
2,3-amino acid
Fig. 1. 1,3-Oxazinan-6-one transformations to produce stereopure
derivatives.
b-amino acid
derivatives.34 More recently, it was further established the 1,3-
oxazinan-6-ones could be utilized to produce an assortment of
highly substituted
the synthetic utility of the 1,3-oxazinan-6-one to enable access to
an array of cyclic
2,3-amino acids.
b
2,2,3-analogues (Fig. 1).37 Herein, we investigate
Cyclic
due to the findings of a number of studies investigating the sec-
ondary structures -Peptides predominately
-peptides form.38,39
form helical secondary structures. The nature of the -peptide helix
is dependent on the type and make-up of the -residue used to
construct the peptide. It has been demonstrated that cyclic -amino
acids can play an important role in inducing the formation of the
b-amino acids have risen to prominence in recent times,
b
b
b
b
b
b
* Corresponding author. E-mail address: andrew.hughes2@optusnet.com.au (A.B.
Hughes).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.016

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B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
secondary structure, particularly in
b-peptides that possess a small
2. Results and discussion
number of residues. It has also been found the type of the cyclic b-
residue can dramatically influence the nature of secondary helix
formeddthat is, a helix that consists of only five-membered cyclic
The starting scaffolds required to perform the metathesis re-
actions were three 4-alkenyl substituted 1,3-oxazinan-6-ones 1e3.
These residues would then be enolized and alkylated with the
appropriate alkenyl electrophile. The bis-olefin products 4e8
would then be cyclized using a metathesis reaction to afford the
cyclic adducts. It was proposed to prepare five-, six-, and seven-
membered cyclic adducts 9e13. In order to produce all three
sizes of carbocycle, the synthesis of the appropriate starting 1,3-
oxazinan-6-ones was required. The 4-vinyl, 4-allyl, and 4-butenyl
oxazinan-6-ones 1e3 would allow access to the respective five-,
six-, and seven-membered cyclic adducts 9e13 (Fig. 2).
b
-residues will be markedly different to a helix that is fabricated
from six-membered cyclic
-residues.39e41
-Peptide helices have found use in multiple applications, but
most importantly in the design of tool compounds in drug dis-
covery. In particular, -peptide helices are considered good mi-
metics for therapeutically important helical
-peptides.42e46
Several of these -peptide mimetics, possess a number of cyclic
2,3-amino residues, to aid in adopting the secondary helical
structure desired. These studies have highlighted the importance of
cyclic -residues in this emerging field.
However, given the emerging importance of cyclic
b
b
b
a
b
b
b
Previously, 1,3-oxazinan-6-ones have been synthesized in good
b
-residues,
yields from the corresponding N-protected
this study, it was proposed to synthesize the vinyl, allyl, and butenyl
3-amino acids, from the N-Cbz protected
-amino acids, to enable
a
-amino acid.32e36 In
there are only a limited number of synthetic procedures in the
literature.2,4e6,47 Further, many of these procedures are not ster-
eoselective and do not produce a variety of analogues from a com-
mon starting material. Herein, we demonstrate that the 1,3-
oxazinan-6-one synthon excels where other synthetic strategies
b
a
the subsequent cyclization to the corresponding 4-alkenyl
substituted oxazinan-6-ones 1e3.
The only commercially available alkenyl
-allyl glycine 14 ( -allyl glycine was Cbz protected). Cbz-
alanine 15 was synthesized from Cbz- -aspartic acid (tert-butyl
a
-amino acid was Cbz-
are lacking in the production of cyclic
b
2,3-amino acids.
L
L
L
-vinyl b3
-
The synthetic strategy proposed to be employed is similar to the
L
research of Abell et al.48 (Fig. 2). Abell et al. used 4-vinyl, 4-allyl, and
ester) 16 using a modified procedure by Zappia et al.49 (Scheme 1).
Briefly, the orthogonally protected aspartic acid 16, was trans-
formed into the alcohol 17, by firstly activating the acid as a mixed
anhydride. Subsequent addition of sodium borohydride gave the
alcohol 17 in high yield (83%). A two-step process utilizing a Swern
oxidation followed by a Wittig reaction converted the alcohol 17
into the olefin 18 in good yield (61%). Removal of the tert-butyl ester
4-butenyl protected
study by Abell et al. the
b
-amino esters as a starting material. In the
-amino esters were enolized, typically
b
using LDA, and trapped with an alkenyl electrophile. The bis-alkene
products were obtained in good diastereoselectivity and in poor to
good yields. The bis-alkene products were then subjected to ring
closing metathesis to obtain the cyclic b-amino ester products. In
the study herein, it was proposed to utilize 1,3-oxazinan-6-ones
under a similar synthetic strategy to Abell et al., and demonstrate
the versatility of this synthon in producing a number of stereopure
gave the Cbz-vinyl
transformation to the 1,3-oxazinan-6-one 1.
b
2-alanine 15 (86% ee) in readiness for the
cyclic b
2,3-amino residues.
Scheme 1. Synthesis of the Cbz-vinyl b
3-alanine 15 and the 4-vinyl-1,3-oxazinan-6-
one 1.49 Reagents and conditions: (a) 1. EtOCOCl, N-methylmorpholine, THF, ꢀ15 ꢁC;
2. NaBH4/H2O; (b) 1. DMSO, (COCl)2, Et3N, DCM; 2. THF, KHMDS, CH3PPh3Br,
ꢀ78 ꢁCe25 ꢁC; (c) DCM, TFA; (d) cat. CSA, (CH2O)n, toluene, 90 ꢁC.
Cbz-
Cbz-
-glutamate 20 using a modified procedure by Zappia et al.49
L-buten-3-yl b
3-alanine 19 was synthesized from methyl
L
(Scheme 2). The unprotected side chain acid of 20 was available
to transform into the but-3-enyl group. The acid 20 was reduced via
the mixed anhydride using sodium borohydride to afford the al-
cohol 21 in high yield (81%). Swern and Wittig reactions followed to
produce the but-3-enyl methyl ester 22 in a mediocre yield (32%).
The low yield was attributed to nucleophilic attack of the methyl
ester during the Wittig reaction. Although not undertaken, it was
hypothesized a tert-butyl ester could be used in future to negate
any undesired nucleophilic side reactions. Finally, hydrolysis of the
methyl ester 22 under acidic conditions afforded the N-Cbz but-3-
enyl glycine 19.
The residues N-Cbz-allyl glycine 14 and N-Cbz but-3-enyl glycine
19 were then converted intothe b
3-amino acids via a procedure used
previously, the well-known ArndteEistert homologation
(Scheme 3).32e35,50 Both the intermediate diazoketones 23 and 24
Fig. 2. Comparison of the research by Abell et al.48 and the proposed strategy for this
research.
and b
3-amino acid products 25 (100% ee) and 26 were obtained in

B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
6277
Table 1
5-Allylation of the 1,3-oxazinan-6-ones 1e3. Reagents and conditions: (a) 1. KHMDS,
ꢀ78 ꢁC, 45 min; 2. allyl iodide or bromide or 2-methyl allyl iodide, ꢀ78 ꢁC to ꢀ40 ꢁC;
3. aq NH4Cl quench
Scheme 2. Synthesis of N-Cbz but-3-enyl glycine 19. Reagents and conditions: (a) 1.
EtOCOCl, NMM, THF, ꢀ15 ꢁC; 2. NaBH4/H2O; (b) 1. DMSO, (COCl)2, Et3N, DCM; 2. THF,
KHMDS, CH3PPh3Br, ꢀ78 ꢁCe25 ꢁC; (c) AcOH: 1 N aq HCl (1:1), 100 ꢁC.
Entry
N
R
Recovered
substrate (%)
trans-mono
adduct (%)
5,5-Disubstituted
adduct (%)
1
2
3
4
5
0
1
1
2
2
H
H
Me
H
Me
15
16
17
13
16
4
5
7
6
8
48
38
42
42
44
27
28
30
29
31
17
20
9
20
8
excellent yields. However, it was noted that the 4-but-3-enyl
b
-amino acid 26 racemized during the synthetic sequence, as de-
termined bychiral HPLC. Although not determined, it was suspected
that racemization occurred during the Wittig transformation
(Scheme 2). The racemic 4-but-3-enyl analogue was advanced
through the ensuing synthetic sequence as a racemate.
A 5,5-disubstituted oxazinanone 32 was also synthesized.
Firstly, the 4-allyl oxazinanone 2 was enolized and the addition of
the electrophile methyl triflate exclusively gave the anti di-
astereoisomer 33 in 46% yield. The oxazinanone 33 was again
subjected to enolization, and in this instance allyl bromide was
used as the electrophile. The trans-5,5-disubstituted oxazinanone
32 was exclusively obtained in a yield of 38% (Scheme 4).
Scheme 4. 5-Allylation of the 5-methyl-1,3-oxazinan-6-one 33. Reagents and condi-
tions: (a) 1. KHMDS, ꢀ78 ꢁC, 45 min; 2. MeOTf, ꢀ78 ꢁC to ꢀ40 ꢁC; 3. NH4Cl quench; (b)
1. KHMDS, ꢀ78 ꢁC, 45 min; 2. allyl bromide, ꢀ78 ꢁC to ꢀ40 ꢁC; 3. aq NH4Cl quench.
Scheme 3. Synthesis of 1,3-oxazinan-6-ones 2 and 3. Reagents and conditions: (a) 1.
EtOCOCl, N-methylmorpholine; 2. CH2N2; (b) AgO2CCF3, dioxane, H2O, sonication; (c)
cat. CSA, (CH2O)n, toluene, 90 ꢁC.
The first analogues to undergo ring-closing metathesis (RCM)
were the 4,5-diallyl-oxazinanones 5, 7, and 32. To effect RCM, the
Grubbs II catalyst was used in toluene at 25 ꢁC for 20 h (Table 2). The
six-membered bicyclic adducts 10, 12, and 34 were afforded in
excellent yields (80e86%) (Table 2). The same RCM conditions were
then applied to the 4-but-3-enyl oxazinanones 6 and 8. Compared
to the six-membered RCM products 10, 12, and 34, the seven-
membered RCM products 6 and 8 were obtained in slightly re-
duced yields of 60% and 69%, respectively. The 4-vinyl oxazinanone
4 was also subjected to the same RCM conditions at 25 ꢁC. However,
in this instance only 5% yield of the desired product 9 resulted.
When the solution was heated to reflux for 2 days, a mixture of the
isomerized five-membered RCM products 9 and 35 were obtained
in a 17% yield. No starting material was recovered from the complex
reaction mixture, and the side products from the reaction could not
be identified. The low yield of the desired product 9 was attributed
to the ring strain of the five, six-membered bicyclic ring system.
During the RCM transformations all compounds retained their
stereochemical integrity as determined by 1H NMR spectroscopy.
Finally, to highlight the versatility of the 1,3-oxazinanone, the
RCM products 10, 11, and 13 were subjected to a number of trans-
The b-residues 15, 25, and 26 were then cyclized to the corre-
sponding 1,3-oxazinan-6-ones 1, 2, and 3 using a previously de-
scribed procedure,32e36 employing paraformaldehyde, a catalytic
amount of camphorsulfonic acid (CSA) in toluene at 90 ꢁC for 4e6 h.
The 1,3-oxazinan-6-ones 1, 2, and 3 were obtained in good yields
(56e76%) (Schemes 1 and 3).
Previously, 5-alkylation and 5-allylation of various 4-substituted
oxazinanones were performed in a diastereoselective manner.37 It
was proposed that using the 4-vinyl, 4-allyl, and 4-but-3-enyl
oxazinanones 1, 2, and 3, the same high diastereoselectivity
would be achieved with allylation reactions. Each oxazinanone 1, 2,
and 3 was deprotonated with KHMDS at ꢀ78 ꢁC. After the enolate
had formed the allyl iodide or bromide electrophile was added. The
solution was then allowed to slowly warm to ꢀ40 ꢁC before the
reaction was quenched (Table 1). The yields of the 5-allylation re-
actions are shown in Table 1. The 5-allylation of the oxazinanones 1,
2, and 3 occurred in good yields. In each entry the yields of the
desired mono 5-allyl products 4e8 were compromised by the for-
mation of diallylated products 27e31. Unreacted starting material
was also recovered from the reaction mixture. However, in each
transformation the desired mono 5-allyl product 4e8 was obtained
exclusively in the anti configuration. 2-Methyl allyl iodide was also
used as an electrophile to produce the substituted allyl products 7
and 8, also exclusively in the anti configuration (Table 1).
formations to produce the cyclic b
2,3-amino acids. A particular in-
terest of the authors lies in the production of N-methylated amino
acid residues.32e34,50e52 Accordingly, the bicyclic adducts 10 and 13
were subjected to reductive cleavage conditions used previously to
produce the novel N-methyl cyclic b
2,3-amino acid residues 36 and

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B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
Table 2
Hydrogenation of the alkenyl bicyclic adducts 10 and 11, reduced
the alkene, while leaving both the oxazinanone ring and benzyl
carbamate intact (Scheme 6). The reduced product was then hy-
Synthesis of bicyclic adducts 9e13 and 34 by RCM. Reagents and conditions: (a) cat.
Grubbs’ II, toluene, 25 ꢁC to reflux
drolyzed with lithium hydroxide to give the NeH cyclic
acid 39 in high yield (78%). The hydrogenated product of 11 was
then converted into the N-methyl cyclic
2,3-amino acid 40 using
b
2,3-amino
b
reductive cleavage conditions in good yield (65%)(Scheme 6).
3. Conclusions
In summary, a route to access stereopure five-, six-, and seven-
membered cyclic b
2,3-amino acids utilizing 1,3-oxazinan-6-ones has
been described. The precursors required to access such residues were
the 4-vinyl-, 4-allyl-, and 4-but-3-enyl-oxazinanones 1, 2, and 3.
Modifications of existing procedures were used to smoothly syn-
thesize the oxazinanones 1, 2, and 3 from the respective aspartic acid
16, allylglycine 14, and glutamic acid 20 starting materials. The 4-
alkenyl oxazinanones 1, 2, and 3 were then allylated using enolate
chemistry. The 4,5-bis-olefinated products 4e8 and 32 were ob-
tained in good yields and all exclusively in the anti configuration.
These precursors 4e8 and 32 were then smoothly converted into the
4,5-cyclic oxazinanones 10e13 and34 using RCMin goodto excellent
yields. The exception was the five-membered RCM product 9, which
was obtained in a 5% yield. Finally, a number of lactone opening
transformations were conducted to produce both the N-methylated
Entry
n
R1
R2
Cyclic adduct (%)
1
2
3
4
5
6
0
1
1
1
2
2
H
H
Me
H
H
H
H
H
Me
H
9
10
12
34
11
13
5
86
80
81
60
69
and NH cyclic
again highlights the versatilityof the oxazinanone as a useful scaffold
b
2,3-amino acids 36e40. The methodology herein
Me
H
to produce a variety of stereopure
4. Experimental section
4.1. General methods
b-amino acid derivatives.
37 in 94 and 66%, respectively (Scheme 5). The N-methyl product 36
was then subjected to hydrogenation conditions to produce the
saturated N-methyl cyclic b
2,3-amino acid 38. Under these condi-
Unless otherwise stated, all reactions were carried out under an
argon atmosphere in oven-dried glassware. KHMDS was purchased
commercially and titrated before use.53 TLC was performed on
kieselgel 60 F254 plates and visualized with a UV lamp or staining.
Optical rotations were measured at the stated temperatures in the
stated solvent using a polarimeter at the sodium d-line (589 nm);
tions the benzyl carbamate remained intact (Scheme 6).
[a]
D values are given in 10ꢀ1 deg cm2 gꢀ1. Elemental analyses were
performed by Chemical and Microanalytical Services, Melbourne
using a Carlo Erba NA1106 Elemental Analyser. Flash column
chromatography was carried out using silica gel 60 particle size
0.040e0.063 mm (230e400 mesh ASTM). NMR spectra were de-
Scheme 5. Reductive cleavage performed on the bicyclic adducts 10 and 13. Reagents
and conditions: (a) BF3$Et2O, DCM, Et3SiH, 25 ꢁC.
termined in chloroform-d at 300 K unless otherwise stated on
a 300 MHz spectrometer. Data for 1H NMR spectroscopy are re-
ported as follows: chemical shift (d in parts per million), multi-
plicity (s, singlet; br s, broad singlet; d, doublet; dd, doublet of
doublets; t, triplet; q, quartet; m, multiplet). Coupling constant (J)
are reported in Hertz (Hz). Infrared spectra were recorded on
a Fourier transform IR spectrometer using a thin film between NaCl
plates. Low-resolution mass spectra were recorded on a mass
spectrometer at 300 ꢁC and a scan rate of 5500 m/z/second using
either acetonitrile/formic acid (99:1) or methanol/formic acid
(99:1) mixtures as the mobile phase. High-resolution electrospray
ionization mass spectra were recorded on a mass spectrometer
with an ionization energy of 70 eV using methanol/acetic acid
(99:1) mixtures as the mobile phase. High resolution electron
ionization mass spectra were recorded on a Kratos Concept ISQ
mass spectrometer using an ionization energy of 70 eV and 5.3 kV
accelerating voltage with the sample being introduced by direct
insertion probe into the ion source and spectra were scanned over
the range m/z 35 to 800, with the ion source held at 200 ꢁC and
probe tip heated to 300 ꢁC. Accurate masses were obtained at
a resolution of 8000 by ‘peak matching’ using perfluorokerosene.
Parent ion peaks are reported as m/z values. High performance
Scheme 6. Hydrogenation of the N-methyl cyclic
b-amino acid 36 and the bicyclic
adducts 10 and 11. Reagents and conditions: (a) H2, 10% Pd/C, EtOH, 20 h, 25 ꢁC; (b)
LiOH, THF/H2O; (c) BF3$Et2O, Et3SiH, DCM.

B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
6279
liquid chromatography (HPLC) was conducted using a Waters in-
strument fitted with a Chiralpak AD-H 5
eluting with an isocratic solvent gradient of 90% petroleum and 10%
isopropyl alcohol (IPA) and 0.1% trifluoroacetic acid (TFA) with UV
detection of output at 254 nm.
dissolved in CH2Cl2 (30 mL), the mixture was cooled to ꢀ78 ꢁC and
m
m, 4.6ꢂ250 mm column
a solution of dry DMSO (3.60 mL, 50.7 mmol) in CH2Cl2 (10 mL) was
added dropwise during 15 min. The N-(benzyloxycarbonyl)-L-glu-
tamic amino alcohol (methyl ester) 21 (3.57 g, 12.7 mmol) in CH2Cl2
(15 mL) was added dropwise during 10 min, the resulting solution
was stirred for 10 min at ꢀ78 ꢁC. A solution of triethylamine
(10.60 mL, 76.2 mmol) in CH2Cl2 (30 mL) was added dropwise
during 15 min. After 20 min water (5 mL) was added to the vigor-
ously stirred solution at ꢀ78 ꢁC. The resulting slurry was poured
into Et2O (200 mL) and washed with 20% aq KHSO4 (2ꢂ70 mL), the
layers were separated and the aqueous layer was back-extracted
with Et2O (2ꢂ70 mL). The combined organic layers were washed
with brine solution (2ꢂ50 mL), dried over MgSO4, and the solvent
was removed under reduced pressure (20 ꢁC) to afford the crude
aldehyde, which was immediately used in the next reaction with-
out any further purification.
4.2. Synthesis
4.2.1. Synthesis of the alkenyl
4.2.1.1. N-Carbonylbenzyloxy-
lution of NaOH (700 mg, 17.4 mmol) in water (40 mL) was added
a
-amino acids
L
-allyl glycine 14. To a stirred so-
L-
allyl (glycine)eOH (2.00 g, 17.4 mmol). N-(Benzyloxycarbonyloxy)-
succinimide (4.30 g, 17.4 mmol) in acetone (25 mL) was added in
one portion with vigorous stirring. After the addition was complete,
NaHCO3 (1.50 g, 17.4 mmol) was added and stirring was continued
for 20 h. The reaction mixture was extracted once with Et2O
(50 mL) to remove any excess neutral organic compounds and the
aqueous layer was acidified to pH 2 with 5 M aq HCl. The aqueous
layer was extracted with EtOAc (3ꢂ25 mL) and dried (MgSO4) and
evaporated in vacuo to give 14 as a brown oil (4.10 g, 95% yield),
with spectra identical to those of an authentic sample.52
Methyl triphenylphosphonium bromide (9.08 g, 25.4 mmol) was
suspended in dry THF (250 mL) at 25 ꢁC and KHMDS (0.5 M in
toluene, 53.20 mL, 26.6 mmol) was added. The resultant yellow
solution was stirred at 25 ꢁC for 2.5 h, then cooled to ꢀ78 ꢁC and
a solution of the crude aldehyde in dry THF (20 mL) was added
dropwise. The reaction mixture was slowly warmed to 25 ꢁC over
1 h and then stirred for a further 2 h. The reaction was quenched
with MeOH (25 mL) and the resulting mixture was poured into
a mixture of satd aq potassium sodium tartrate and H2O (1:1,
300 mL). Extraction with Et2O (3ꢂ200 mL), drying over MgSO4, and
evaporation under reduced pressure gave the crude residue. The
residue was purified by silica gel chromatography eluting with
10e20% EtOAc/hexane to give olefin 22 as an oil (1.12 g, 32% yield);
Rf (20% EtOAc/hexane) 0.42; m/z HRMS (ESI, MeOH/AcOH):
4.2.1.2. tert-Butyl-(3S)-3-([(benzyloxy)carbonyl]amino)-4-
hydroxy-butanoate 17. To
a stirred solution of N-(benzylox-
ycarbonyl- -aspartic acid) (tert-butyl ester) 16 (4.54 g,14.0 mmol) in
L
THF (70 mL) at ꢀ15 ꢁC, N-methylmorpholine (1.85 mL, 16.8 mmol)
was added followed by ethyl chloroformate (1.61 mL, 16.8 mmol).
The reaction mixture was stirred at the same temperature for
15 min, and NaBH4 (1.59 g, 42.4 mmol) in H2O (20 mL) was added,
followed by addition of H2O (300 mL) at ꢀ15 ꢁC immediately af-
terward. The solution was stirred for 15 min and neutralized with
1 N aq HCl. The reaction mixture was extracted with EtOAc
(3ꢂ100 mL). The combined organic phases were washed with 1 N aq
HCl (70 mL), H2O (2ꢂ70 mL), 5% aq NaHCO3 (2ꢂ70 mL), dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by silica gel chromatography eluting with 30e50% EtOAc/
hexane to give the amino alcohol 17 (3.67 g, 83% yield), with spectra
identical to those of an authentic sample.54
[MþH]þ, found 278.1377. C15H20NO4 requires 278.1387;
½ ꢃ
a 2D4
þ6.5 (c 1.23, MeOH); nmax (NaCl)/cmꢀ1 3340, 3067, 3032, 2951,1713,
1694, 1504, 1435, 1346, 1215, 1049, 914, 737; dH (300 MHz, CDCl3)
(320 K):
d 7.32 (5H, br s), 5.79e5.71 (1H, m), 5.36 (1H, d, J 6.9 Hz),
5.09 (2H, s), 5.04 (1H, d, J 16.2 Hz), 4.99 (1H, d, J 9.3 Hz), 4.39 (1H, d, J
4.8 Hz), 3.71 (3H, s), 2.11e2.05 (2H, m),1.93e1.89 (1H, m), 1.76e1.69
(1H, m); dC (75 MHz, CDCl3) (320 K) 172.3, 155.4, 136.4, 136.0, 128.1,
127.7, 127.6, 115.3, 66.6, 53.2, 51.8, 31.6, 28.9.
4.2.1.5. (2S)-2-([(Benzyloxy)carbonyl]amino)-5-hexenoic acid
19. A solution of methyl ester 22 (1.80 g, 6.53 mmol) was dissolved
in a mixture of AcOH and 1 N aq HCl (1:1, 26.0 mL) and the solution
was heated to 100 ꢁC for 3 h. The mixture was concentrated under
reduced pressure, and the residue was taken up in Et2O (50 mL) and
washed with H2O (3ꢂ40 mL) and brine. The organic layer was
extracted with satd aq NaHCO3 solution (3ꢂ30 mL). The combined
aq layers were acidified to pH 2 with 5 N aq HCl, and then re-
extracted with EtOAc (3ꢂ20 mL). The combined organic extracts
were dried (MgSO4) and evaporated in vacuo. The residue was
purified by silica gel chromatography eluting with 10e40% EtOAc/
hexane to give the acid 19 (1.60 g, 91% yield) as a white solid, with
spectra identical to those of authentic sample.55
4.2.1.3. Methyl-(3S)-3-([(benzyloxy)carbonyl]amino)-5-hydroxy-
pentanoate 21. To a stirred solution of N-(benzyloxycarbonyl-L-
glutamic acid (methyl ester)) 20 (4.16 g, 14.0 mmol) in THF (70 mL)
at ꢀ15 ꢁC, N-methylmorpholine (1.85 mL, 16.8 mmol) was added
followed by ethyl chloroformate (1.61 mL, 16.8 mmol). The reaction
mixture was stirred at the same temperature for 15 min, and NaBH4
(1.60 g, 42.4 mmol) in H2O (20 mL) was added, followed by addition
of H2O (300 mL) at ꢀ15 ꢁC immediately afterward. The solution was
stirred for 15 min and neutralized with 1 N aq HCl. The reaction
mixture was extracted with EtOAc (3ꢂ100 mL). The combined or-
ganic phase was washed with 1 N aq HCl (70 mL), H2O (2ꢂ70 mL),
5% aq NaHCO3 (2ꢂ70 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by silica gel chroma-
tography eluting with 30e50% EtOAc/hexane to afford the amino
alcohol 21 as a colorless oil (3.19 g, 81% yield); Rf (50% EtOAc/hex-
ane) 0.31; m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 282.1340.
4.2.2. Synthesis of the alkenyl diazoketones
4.2.2.1. General procedure A. Preparation of the diazoketones. The
Cbz-L-a-amino acid (1 mmol) was dissolved in anhydrous THF
C14H20NO5 requires 282.1336; ½a D24
ꢃ
ꢀ18.8 (c 5.56, MeOH); nmax
(25 mL) and cooled to ꢀ15 ꢁC. To this solution, ethyl chloroformate
(NaCl)/cmꢀ1 3341, 3062, 3036, 2951, 2878, 1748, 1705, 1504, 1498,
1450,1335, 1215, 1049, 914, 741; dH (300 MHz, CDCl3) 7.31 (5H, br s),
5.71 (1H, d, J 7.8 Hz), 5.06 (2H, s), 4.38e4.31 (1H, m), 3.68 (3H, s),
3.58 (2H, t, J 6.0 Hz), 2.49 (1H, br s), 1.94e1.82 (1H, m), 1.75e1.66
(1H, m), 1.61e1.51 (2H, m); dC (75 MHz, CDCl3) 172.7, 155.8, 135.9,
128.1, 127.8, 127.7, 66.6, 61.4, 53.3, 51.9, 28.7, 27.8.
(100 mL, 1.05 mmol) and N-methylmorpholine (115 mL, 1.05 mmol)
were added and the mixture was stirred for 15 min. Then, a solution
of CH2N2 (5 mmol; CAUTION!) in CH2Cl2 was added slowly, and the
yellow solution was allowed to warm to 25 ꢁC. Stirring was con-
tinued until there was no starting material remaining (TLC). Excess
CH2N2 was destroyed by the addition of AcOH. The mixture was
concentrated under reduced pressure, and the residue was taken
up in EtOAc (40 mL). The organic phase was washed successively
with satd aq NaHCO3 (30 mL), 10% aq citric acid (30 mL), and then
4.2.1.4. 1-Methyl ester-(2S)-2-([(benzyloxy)carbonyl]amino)-5-
hexenoate 22. Oxalyl chloride (2.20 mL, 25.4 mmol) was

6280
B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
brine (30 mL). The organic layer was dried over MgSO4, filtered, and
evaporated to dryness in vacuo. The product was of sufficient purity
to be used directly in the next reaction. The residue was subjected
to flash column chromatography for characterization.
4.2.2.1.1. Phenylmethyl [(1S)-3-diazo-1-allyl-2-oxopropyl] carba-
mate 23. N-(Benzyloxycarbonyl-a-allylglycine) 14 (249 mg,
bath until no diazoketone remained (TLC). The mixture was then
concentrated in vacuo. The residue was dissolved in Et2O (50 mL)
and washed with 10% aq citric acid solution. The organic layer was
extracted with satd aq NaHCO3 solution (3ꢂ20 mL). The combined
aq layers were acidified to pH 2 with 5 N aq HCl, and then re-
extracted with EtOAc (3ꢂ30 mL). The combined organic extracts
were dried (MgSO4) and evaporated in vacuo. The residue was
subjected to flash column chromatography for characterization.
4.2.3.2.1. (3S)-3-(([(Phenylmethyl)oxy]carbonyl)amino)hexenoic
acid 25. Treatment a solution of allylglycine diazoketone 23
(273 mg, 1 mmol) according to General procedure B, furnished the
1 mmol) was transformed according to General procedure A to
afford the diazoketone 23 as a yellow oil (210 mg, 77% yield); Rf
(30% EtOAc/hexane) 0.46; m/z HRMS (ESI, MeOH/AcOH): [MþNa]þ,
found 296.1009. C14H16N3NaO3 requires 296.1006; ½a D24
ꢀ37.9 (c
ꢃ
3.95, MeOH); nmax (NaCl)/cmꢀ1 3318, 3086, 3034, 2106, 1712, 1643,
1504,1366,1250,1041, 918, 733; dH (300 MHz, CDCl3) 7.30 (5H, br s),
5.72e5.63 (1H, m), 5.57 (1H, d, J 6.9 Hz), 5.43 (1H, s), 5.12e5.10 (4H,
m), 4.28 (1H, br s), 2.54e2.47 (1H, m), 2.39e2.35 (1H, m); dC
(75 MHz, CDCl3) 192.6, 155.5, 135.8, 131.9, 128.2, 127.8, 127.7, 118.9,
67.7, 56.9, 53.7, 36.2.
b
-amino acid 25 as a white solid (212 mg, 80% yield); m/z HRMS
(ESI, MeOH/AcOH): [MþH]þ, found 264.1232. C14H18NO4 requires
264.1230; mp 82e84 ꢁC; ½a D24
þ23.8 (c 2.93, MeOH); nmax (NaCl)/
ꢃ
cmꢀ1 3325, 3071, 2963, 2916, 1697, 1535, 1265, 1130, 918, 733; dH
(300 MHz, CDCl3) 7.34e7.31 (5H, m), 5.78e5.69 (1H, m), 5.17 (1H, br
s), 5.12 (2H, d, J 3.3 Hz), 5.08 (2H, s), 4.09e4.05 (1H, m), 2.61 (2H, d, J
4.8 Hz), 2.35 (2H, t, J 6.9 Hz); dC (75 MHz, CDCl3) 176.3, 155.5, 135.9,
133.2, 128.2, 127.8, 127.7, 118.3, 66.5, 47.0, 38.2, 37.6. HPLC (Chir-
alpak AD-H, 90:10 Pet/IPA, 25 ꢁC 254 nm): tR (major)¼8.7 min,
100% ee.
4.2.2.1.2. Phenylmethyl
carbamate 24. N-Benzyloxycarbonyl-
[(1S)-3-diazo-1-butenyl-2-oxopropyl]
-butenylglycine 19 (263 mg,
a
1 mmol) was transformed according to General procedure A to
afford the diazoketone 24 as a yellow oil (266 mg, 93% yield); Rf
(20% EtOAc/hexane) 0.26; m/z HRMS (ESI, MeOH/AcOH): [MþNa]þ,
a 24
found 310.1172. C15H17N3NaO3 requires 310.1162; ½ ꢃD þ23.4 (c
4.2.3.2.2. (3S)-3-(([(Phenylmethyl)oxy]carbonyl)amino)heptenoic
acid 26. Treatment of a solution of the but-3-enyl glycine diazo-
ketone 24 (287 mg, 1 mmol) according to General procedure B,
0.68, MeOH); nmax (NaCl)/cmꢀ1 3318, 3078, 2947, 2928, 2110, 1713,
1643, 1504, 1369, 1246, 1206, 914, 736; dH (300 MHz, CDCl3) (320 K)
7.30 (5H, br s), 5.80e5.69 (1H, m), 5.37 (2H, br s), 5.09e4.97 (4H, m),
4.24 (1H, br s), 2.11 (2H, d, J 6.9 Hz), 1.93e1.87 (1H, m), 1.69e1.61
(1H, m); dC (75 MHz, CDCl3) 192.9, 155.6, 136.5, 135.8, 128.2, 127.9,
127.7, 115.5, 66.7, 56.8, 53.8, 31.4, 28.9.
furnished the b-amino acid 26 as a white solid (204 mg, 73% yield);
m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 278.1388. C15H20NO4
requires 278.1387; mp 81e83 ꢁC; ½a D24
þ10.2 (c 0.98, MeOH); nmax
ꢃ
(NaCl)/cmꢀ1 3323, 3067, 2976, 2916, 1713, 1694, 1520, 1452, 1246,
1056, 910, 733; dH (300 MHz, CDCl3) (325 K) 8.88 (1H, br s), 7.32
(5H, br s), 5.81e5.70 (1H, m), 5.19 (1H, br s), 5.09 (2H, s), 5.04 (1H, d,
J 17.4 Hz), 4.94 (1H, d, J 10.2 Hz), 3.99 (1H, br s), 2.58 (2H, s), 2.11
(2H, d, J 6.9 Hz), 1.66 (2H, t, J 6.9 Hz); dC (75 MHz, CDCl3) 176.4,
155.6, 136.9, 136.0, 128.2, 128.1, 127.8, 115.1, 66.5, 47.2, 38.3, 33.1,
29.9. HPLC (Chiralpak AD-H, 90:10 Pet/IPA, 25 ꢁC 254 nm): tR
(major)¼8.35 min (52%), tR (minor)¼8.65 min (48%).
4.2.3. Synthesis of the alkenyl b-amino acids
4.2.3.1. tert-Butyl-(3S)-3-[(benzyloxy)carbonyl]amino-4-
pentenoate 18. Oxalyl chloride (2.20 mL, 25.4 mmol) was dissolved
in CH2Cl2 (30 mL), the mixture was cooled to ꢀ78 ꢁC and a solution
of dry DMSO (3.60 mL, 50.7 mmol) in CH2Cl2 (10 mL) was added
dropwise during 15 min. The amino alcohol 17 (3.93 g, 12.7 mmol)
in CH2Cl2 (15 mL) was added dropwise during 10 min, the resulting
solution was stirred for 10 min at ꢀ78 ꢁC, and a solution of trie-
thylamine (10.63 mL, 76.2 mmol) in CH2Cl2 (30 mL) was added
dropwise during 15 min. After 20 min, water (5.0 mL) was added to
the vigorously stirred solution at ꢀ78 ꢁC. The resulting slurry was
poured in Et2O (200 mL) and washed with 20% aq KHSO4
(2ꢂ70 mL), the layers were separated and the aqueous layer was
back-extracted with Et2O (2ꢂ70 mL). The combined organic layers
were washed with brine solution (2ꢂ50 mL), dried over MgSO4, and
the solvent was removed under reduced pressure (20 ꢁC) to afford
the crude aldehyde, which was immediately used in the next re-
action without any further purification.
Methyl triphenylphosphonium bromide (9.08 g, 25.4 mmol) was
suspended in dry THF (250 mL) at 25 ꢁC and KHMDS (0.5 M in
toluene, 53.20 mL, 26.6 mmol) was added. The resultant yellow
solution was stirred at 25 ꢁC for 2.5 h, then cooled to ꢀ78 ꢁC and
a solution of the crude aldehyde in dry THF (20 mL) was added
dropwise. The reaction mixtures was slowly warmed to 25 ꢁC over
1 h and then stirred for a further 2 h. The reaction was quenched
with MeOH (25 mL) and the resulting mixture was poured into
a mixture of satd aq potassium sodium tartrate and H2O (1:1,
300 mL). Extraction with Et2O (3ꢂ200 mL), drying over MgSO4, and
evaporation under reduced pressure gave a crude residue. The
residue was purified by silica gel chromatography eluting with
10e20% EtOAc/hexane to give olefin 18 as an oil (2.38 g, 61% yield),
with spectra identical to those of an authentic sample.49
4.2.4. Synthesis of the alkenyl 1,3-oxazinan-6-ones
4.2.4.1. General procedure C. Preparation of 1,3-oxazinan-6-
ones. To the N-benzyloxycarbonyl b-amino acid (1 mmol) in dry
toluene (30 mL) were added camphorsulfonic acid (23.2 mg,
ꢀ
0.1 mmol), paraformaldehyde (1.66 g, 6 mmol), and activated 4 A
molecular sieves (150 mg) under an argon atmosphere. The re-
action mixture was stirred at 90 ꢁC for 4e6 h. The mixture was
allowed to cool and filtered through Celite pad. The filtrate was
diluted with EtOAc (30 mL), and the organic layer was washed with
satd aq NaHCO3 solution (20 mL) and water (20 mL). The organic
layer was dried (MgSO4), and the solvent was removed in vacuo.
The residue was subjected to flash column chromatography, eluting
with 10e30% EtOAc/hexane.
4.2.4.1.1. (4S)-N-Benzyloxycarbonyl-4-vinyl-1,3-oxazinan-6-one
1. The N-Cbz-b-amino acid 15 (249 mg, 1 mmol) was transformed
according to General procedure C and afforded the oxazinanone 1
as an oil (149 mg, 76% yield); Rf (30% EtOAc/hexane) 0.29; m/z
HRMS (ESI, MeOH/AcOH): [MþH]þ, found 261.1075. C14H16NO4
requires 262.1074; ½a D24
ꢃ
ꢀ93.1 (c 4.4, MeOH); nmax (NaCl)/cmꢀ1
3088, 3034, 2916, 1757, 1713, 1699, 1414, 1260, 1155, 1001; dH
(300 MHz, CDCl3) 7.33 (5H, br s), 5.88e5.76 (2H, m), 5.25e5.17 (4H,
m), 5.03 (1H, d, J 10.5 Hz), 4.71 (1H, br s), 2.93 (1H, dd, J 8.4,16.2 Hz),
2.67 (1H, dd, J 8.4, 16.2 Hz); dC (75 MHz, CDCl3) (320 K) 168.4, 153.9,
135.1, 131.0, 128.2, 128.1, 127.7, 116.3, 72.1, 67.9, 51.2, 34.5.
4.2.4.1.2. (4S)-N-Benzyloxycarbonyl-4-allyl-1,3-oxazinan-6-one
2. The N-Cbz-b-amino acid 25 (263 mg, 1 mmol) was transformed
4.2.3.2. General procedure B. Preparation of the N-(benzylox-
ycarbonyl)-b-amino acids. The diazoketone (1 mmol) was dissolved
in 1,4-dioxane/H2O 9:1 (v/v, 50 mL). On addition of CF3CO2Ag
(2.21 mg, 0.01 mmol), the mixture was sonicated in an ultrasound
according to General procedure C and afforded the oxazinanone 2
as an oil (155 mg, 56% yield); Rf (30% EtOAc/hexane) 0.43; m/z
HRMS (ESI, MeOH/AcOH): [MþH]þ, found 276.1234. C15H18NO4
requires 276.1230; ½a D24
ꢃ
þ162.0 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1

B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
6281
3067, 2929, 1759, 1713, 1697, 1418, 1261, 1153, 999; dH (300 MHz,
CDCl3) 7.36e7.28 (5H, m), 5.82 (1H, d, J 10.5 Hz), 5.76e5.62 (1H, m),
5.20e5.10 (4H, m), 4.99 (1H, d, J 10.5 Hz), 4.27e4.18 (1H, m), 2.75
(1H, dd, J 8.6, 16.2 Hz), 2.60 (1H, dd, J 8.6, 16.2 Hz), 2.42 (2H, t, J
6.6 Hz); dC (75 MHz, CDCl3) 169.5, 153.9, 135.1, 131.3, 128.3, 128.2,
127.8, 119.6, 72.2, 67.9, 49.0, 38.4, 33.9.
1749, 1713, 1697, 1418, 1254, 1001, 918; dH (300 MHz, CDCl3)
7.40e7.31 (5H, m), 5.94e5.80 (3H, m) 5.19e5.09 (6H, m), 4.94 (1H,
d, J 10.2 Hz), 4.09 (1H, br s), 2.74e2.68 (2H, m), 2.48e2.36 (2H, m),
2.34e2.30 (1H, m); dC (75 MHz, CDCl3) 171.2, 153.7, 135.1, 133.8,
131.4, 128.3, 128.1, 127.8, 119.9, 117.9, 71.7, 67.9, 52.5, 42.4, 35.7, 31.5.
The oxazinanone 28 was isolated as a colorless oil (57.3 mg, 20%
yield); Rf (20% EtOAc/hexane) 0.41; m/z HRMS (ESI, MeOH/AcOH):
4.2.4.1.3. N-Benzyloxycarbonyl-4-butenyl-1,3-oxazinan-6-one
3. The N-Cbz-
b-amino acid 26 (277 mg, 1 mmol) was transformed
[MþH]þ, found 356.1861. C21H26NO4 requires 356.1856;
½ ꢃ
a 2D4
according to General procedure C and afforded the oxazinanone 3
as an oil (204 mg, 71% yield); Rf (20% EtOAc/hexane) 0.23; m/z
HRMS (EI): [M]þ, found 289.1314. C16H19NO4 requires 289.1314;
nmax (NaCl)/cmꢀ1 3067, 2920,1755,1713,1694,1416,1261,1155, 999;
dH (300 MHz, CDCl3) 7.39e7.30 (5H, m), 5.85e5.73 (2H, m), 5.17 (2H,
s), 5.04e4.95 (3H, m), 4.23 (1H, br s), 2.89 (1H, dd, J 8.4, 16.2 Hz),
2.52 (1H, dd, J 8.4, 16.2 Hz), 2.12e2.02 (2H, m), 1.91e1.79 (1H, m),
1.71e1.63 (1H, m); dC (75 MHz, CDCl3) (323 K) 168.8, 154.1, 136.3,
135.2, 128.3, 128.1, 127.9, 115.2, 71.9, 67.9, 49.2, 35.3, 34.2, 29.1.
þ94.0 (c 1.1, MeOH); nmax (NaCl)/cmꢀ1 3076, 2978, 2916, 1748, 1713,
1639,1418,1246,1107, 921; dH (300 MHz, CDCl3) (325 K) 7.34 (5H, br
s), 5.89 (1H, br s), 5.84e5.58 (3H, m) 5.21e4.99 (9H, m), 4.37 (1H, br
s), 2.75 (1H, dd, J 6.9, 15.3 Hz), 2.63 (1H, br s), 2.39 (2H, br s),
2.28e2.17 (2H, m); dC (75 MHz, CDCl3) (325 K) 170.9, 153.6, 135.4,
132.5, 131.5, 130.9, 128.3, 128.1, 127.7, 119.6, 118.9, 117.9, 72.6, 67.7,
54.9, 50.2, 39.2, 34.7, 32.2.
4.2.5.1.3. (4S,5S)-N-Benzyloxycarbonyl-4-allyl-5-(2-methylallyl)-
1,3-oxazinan-6-one 7, and (4S,5S)-N-benzyloxycarbonyl-4-allyl-5,5-
di(2-methylallyl)-1,3-oxazinan-6-one 30. The General procedure D
was followed for the alkylation of oxazinanone 2 (103 mg,
4.2.5. Alkylation of the 1,3-oxazinan-6-ones
4.2.5.1. General procedure D. 5-Alkylation of oxazinanones. A
solution of the oxazinanone (0.125 M in dry freshly distilled THF)
was cooled to ꢀ78 ꢁC under an argon atmosphere. Then KHMDS
(1.1 equiv of 0.50 M solution in toluene) was added dropwise and
the solution was left to stir at ꢀ78 ꢁC for 40 min. The alkylating
agent (5.00 equiv) was then added dropwise and stirring was
continued for 3 h at ꢀ78 ꢁC. The solution was then allowed to warm
to ꢀ40 ꢁC, and the reaction was then quenched with satd aq NH4Cl
solution (5.00 mL). The solution was diluted with EtOAc (20 mL)
and washed with water (20 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo to give a residue. The residue was
subjected to flash column chromatography, eluting with 5e20%
EtOAc/hexane.
0.37 mmol) with 2-methyl allyl iodide (202 mL, 1.87 mmol) as the
electrophile to afford starting material 2 (17% recovery). The oxa-
zinanone 7 was isolated as a colorless oil (50.8 mg, 42% yield); Rf
(30% EtOAc/hexane) 0.67; m/z HRMS (ESI, MeOH/AcOH): [MþH]þ,
found 330.1705. C19H24NO4 requires 330.1700; ½a D24
þ156.0 (c 0.40,
ꢃ
MeOH); nmax (NaCl)/cmꢀ1 3076, 2916, 2849, 1749, 1713, 1699, 1418,
1250, 1128, 1003; dH (300 MHz, CDCl3) (320 K) 7.38e7.31 (5H, m),
5.87 (1H, d, J 10.3 Hz), 5.81e5.67 (1H, m), 5.21e5.08 (4H, m), 5.02
(1H, d, J 10.3 Hz), 4.84 (1H, s), 4.76 (1H, s), 4.08 (1H, br s) 2.77 (1H,
dd, J 6.8, 13.9 Hz), 2.64 (2H, dd, J 6.8, 13.9 Hz), 2.39 (1H, dd, J 6.4,
14.1 Hz), 2.28 (1H, dd, J 6.4, 14.1 Hz), 1.74 (3H, s); dC (75 MHz, CDCl3)
(323 K) 170.9, 153.8, 141.5, 135.2, 131.7, 128.2, 128.0, 127.7, 119.4,
112.7, 71.7, 67.8, 53.3, 42.0, 36.4 (2), 22.1.
4.2.5.1.1. (4S,5S)-N-Benzyloxycarbonyl-4-vinyl-5-allyl-1,3-
oxazinan-6-one 4, and (4S,5S)-N-benzyloxycarbonyl-4-vinyl-5,5-
diallyl-1,3-oxazinan-6-one 27. The General procedure D was fol-
lowed for the alkylation of oxazinanone 3 (119 mg, 0.46 mmol) with
The oxazinanone 30 was isolated as a colorless oil (13.3 mg, 9%
yield); Rf (30% EtOAc/hexane) 0.78; m/z HRMS (EI): [M]þ, found
383.2097. C23H29NO4 requires 383.2097; ½a D24
þ69.2 (c 0.43,
ꢃ
MeOH); nmax (NaCl)/cmꢀ1 3073, 2949, 1749, 1713, 1699, 1418, 1244,
1132, 901; dH (300 MHz, CDCl3) (325 K) 7.37e7.33 (5H, m), 5.90 (1H,
d, J 9.3 Hz), 5.68e5.61 (1H, m), 5.18 (2H, s), 5.14 (1H, d, J 16.8 Hz),
5.02e4.97 (3H, m), 4.86 (2H, m), 4.71 (1H, s), 4.65 (1H, d, J 11.7 Hz),
2.76 (2H, dd, J 4.8,11.4 Hz), 2.58 (1H, d, J 14.7 Hz), 2.33e2.21 (3H, m),
1.78 (3H, s), 1.45 (3H, s); dC (75 MHz, CDCl3) (325 K) 171.6, 153.7,
140.5, 140.2, 135.4, 132.9, 128.2, 128.0, 127.7, 117.6, 115.8, 114.3, 72.6,
67.7, 55.1, 52.3, 42.8, 38.3, 32.6, 24.9, 23.1.
allyl iodide (208 mL, 2.3 mmol) as the electrophile to afford starting
material 3 (17% recovery). The oxazinanone 4 was isolated as
a colorless oil (65.9 mg, 48% yield); Rf (30% EtOAc/hexane) 0.47; m/z
HRMS (ESI, MeOH/AcOH): [MþH]þ, found 302.1385. C17H20NO4
requires 302.1387; ½a D24
ꢃ
ꢀ119.5 (c 2.9, MeOH); nmax (NaCl)/cmꢀ1
3076, 2980, 2916, 1759, 1713, 1641, 1414, 1252, 1139, 995, 924; dH
(300 MHz, CDCl3) (325 K) 7.32 (5H, br s), 5.90e5.76 (3H, m),
5.29e5.01 (7H, m), 4.39 (1H, br s), 2.65e2.59 (1H, m), 2.48 (2H, br
s); dC (75 MHz, CDCl3) (325 K) 170.2, 153.6, 135.2, 133.9, 133.8, 128.2,
128.1, 127.7, 117.9, 117.7, 71.2, 67.8, 55.6, 44.0, 31.3.
4.2.5.1.4. (4S,5S)-N-Benzyloxycarbonyl-4-butenyl-5-allyl-1,3-
oxazinan-6-one 6, and (4S,5S)-N-benzyloxycarbonyl-4-butenyl-5,5-
diallyl-1,3-oxazinan-6-one 29. The General procedure D was fol-
lowed for the alkylation of oxazinanone 3 (153 mg, 0.53 mmol)
The oxazinanone 27 was isolated as a colorless oil (22.8 mg, 15%
yield); Rf (30% EtOAc/hexane) 0.62; m/z HRMS (EI): [M]þ, found
with allyl iodide (430 mL, 2.65 mmol) as the electrophile to afford
341.1617. C20H23NO4 requires 341.1627. ½a D24
ꢃ
ꢀ39.0 (c 1.89, MeOH);
starting material 3 (13% recovery). The oxazinanone 6 was isolated
as a colorless oil (73.5 mg, 42% yield); Rf (20% EtOAc/hexane) 0.46;
m/z HRMS (EI): [M]þ, found 329.1618. C19H23NO4 requires
nmax (NaCl)/cmꢀ1 3078, 2980,1746,1713,1699,1398,1246,1111, 921;
dH (300 MHz, CDCl3) (310 K) 7.35e7.33 (5H, m), 5.88e5.77 (2H, m)
5.74e5.64 (2H, m), 5.36 (2H, d, J 10.2 Hz), 5.30 (1H, d, J 10.2 Hz),
5.23e5.04 (6H, m), 4.27 (1H, br s), 2.66 (1H, dd, J 7.3, 14.7 Hz), 2.57
(1H, dd, J 7.3, 14.4 Hz), 2.33 (1H, dd, J 7.3, 14.4 Hz) 2.26 (1H, dd, J 7.3,
14.7 Hz); dC (75 MHz, CDCl3) (325 K) 170.6, 153.1, 135.3, 131.7, 131.1,
130.9, 128.2, 128.0, 127.7, 119.7 (2), 119.3, 72.7, 67.7, 58.2, 49.1, 38.7,
35.9.
329.1627; ½a 2D4
ꢃ
þ53.7 (c 0.48, MeOH); nmax (NaCl)/cmꢀ1 3074, 2976,
2922, 1755, 1713, 1682, 1414, 1250, 1126, 989, 916; dH (300 MHz,
CDCl3) (323 K) 7.36 (5H, br s), 5.89e5.75 (3H, m), 5.17 (2H, s),
5.13e4.94 (5H, m), 4.15e4.09 (1H, m), 2.54e2.43 (3H, m), 2.13 (2H,
dd, J 7.8, 14.7 Hz), 1.90e1.79 (1H, m), 1.74e1.59 (1H, m); dC (75 MHz,
CDCl3) 170.8, 154.3, 136.2, 135.1, 133.9, 128.3, 128.1, 127.9, 118.0,
115.1, 71.3, 67.9, 52.7, 44.8, 33.1, 32.6, 28.8.
4.2.5.1.2. (4S,5S)-N-Benzyloxycarbonyl-4,5-diallyl-1,3-oxazinan-
6-one 5, and (4S,5S)-N-benzyloxycarbonyl-4,5,5-triallyl-1,3-
oxazinan-6-one 28. The General procedure D was followed for the
alkylation of oxazinanone 2 (224 mg, 0.81 mmol) with allyl bro-
The oxazinanone 29 was isolated as a colorless oil (38.2 mg, 20%
yield); Rf (20% EtOAc/hexane) 0.63; m/z HRMS (EI): [M]þ, found
369.1940. C22H27NO4 requires 369.1940. ½a D24
þ19.8 (c 1.41, MeOH);
ꢃ
mide (350
m
L, 4.05 mmol) as the electrophile to afford starting
nmax (NaCl)/cmꢀ1 3076, 2978, 2922, 1748, 1713, 1639, 1418, 1248,
1107, 991, 918; dH (300 MHz, CDCl3) (325 K) 7.34 (5H, br s), 5.94 (1H,
br s) 5.77e5.57 (3H, m), 5.19e4.94 (9H, m), 4.27 (1H, br s), 2.73 (1H,
dd, J 7.1, 15.3 Hz), 2.37 (2H, br s), 2.29 (1H, dd, J 7.1, 15.3 Hz),
1.99e1.81 (3H, m) 1.66e1.53 (1H, m); dC (75 MHz, CDCl3) (325 K)
material 2 (16% recovery). The oxazinanone 5 was isolated as
a colorless oil (98.4 mg, 38% yield); Rf (20% EtOAc/hexane) 0.22; m/z
HRMS (EI): [M]þ, found 315.1456. C18H21NO4 requires 315.1471;
½
a 2D4
ꢃ
þ132.8 (c 0.47, MeOH); nmax (NaCl)/cmꢀ1 3075, 2916, 2849,

6282
B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
171.1, 153.8, 135.3, 136.2, 131.6, 130.9, 128.2, 128.1, 127.8, 119.5, 118.8,
115.4, 72.3, 67.8, 55.4, 50.4, 39.2, 34.6, 29.1, 26.5.
reduced pressure, and the residue was purified by flash column
chromatography, eluting with 5e20% EtOAc/hexane.
4.2.5.1.5. (4S,5S)-N-Benzyloxycarbonyl-4-butenyl-5-(2-
methylallyl)-1,3-oxazinan-6-one 8, and (4S,5S)-N-benzyloxycarbonyl-
4-butenyl-5,5-di(2-methylallyl)-1,3-oxazinan-6-one 31. The General
procedure D was followed for the alkylation of oxazinanone 3
4.2.6.1.1. (4S,7S)-N-Benzyloxycarbonyl-4,4a,5,7a-tetrahydro-2H-
cyclopenta[d][1,3]-oxazinan-4-one 9. The diene oxazinanone
4
(54.0 mg, 0.18 mmol) in toluene (1.70 mL) was transformed at 25 ꢁC for
20 h according to General procedure E, and afforded the oxazinanone
9 as an oil (2.50 mg, 5% yield); Rf (30% EtOAc/hexane) 0.40; m/z HRMS
(ESI, MeOH/AcOH): [MþH]þ, found 274.1075. C15H16NO4 requires
274.1074; nmax (NaCl)/cmꢀ1 3036, 2955, 2916, 2847, 1744, 1713, 1699,
1419, 1250, 1134, 1010, 910; dH (300 MHz,CDCl3)(300K)7.39e7.33 (5H,
m), 6.11e6.08 (1H, m) 5.78 (1H, d, J 10.2 Hz), 5.68e5.64 (1H, m), 5.44
(1H, br s), 5.19 (2H, s), 4.85 (1H, d, J 10.2 Hz), 3.49e3.41 (1H, m), 3.01
(1H, dd, J 10.5, 17.4 Hz), 2.76e2.67 (1H, m); dC (75 MHz, CDCl3) 170.7,
153.1, 135.1, 134.5, 128.3, 128.2, 128.0, 127.9, 70.6, 67.9, 59.5, 40.1, 36.7.
4.2.6.1.2. An isomerized mixture of (4S,7S)-N-benzyloxycarbonyl-
(115 mg, 0.41 mmol) with 2-methyl allyl iodide (215 mL, 1.99 mmol)
as the electrophile to afford starting material 3 (16% recovery). The
oxazinanone 8 was isolated as a colorless oil (62.4 mg, 44% yield); Rf
(20% EtOAc/hexane) 0.41; m/z HRMS (EI): [M]þ, found 343.1789.
C20H25NO4 requires 343.1784; ½a D24
þ45.0 (c 0.49, MeOH); nmax
ꢃ
(NaCl)/cmꢀ1 3076, 2916, 2849, 1749, 1713, 1694, 1418, 1250, 1126,
989; dH (300 MHz, CDCl3) (323 K) 7.34 (5H, br s), 5.89 (1H, d, J
10.5 Hz), 5.82e5.68 (1H, m), 5.18 (2H, s), 5.04e4.74 (5H, m), 4.12
(1H, br s), 2.62e2.55 (2H, m), 2.28 (1H, dd, J 8.1, 16.5 Hz), 2.11 (2H,
dd, J 7.2, 14.4 Hz), 1.85e1.63 (5H, m); dC (75 MHz, CDCl3) (323 K)
170.6, 154.2, 141.4, 135.2, 136.7, 128.2, 128.1, 127.8, 115.0, 112.9, 71.3,
67.9, 53.3, 43.9, 37.3, 32.4, 29.2, 22.3.
4,4a,5,7a-tetrahydro-2H-cyclopenta[d][1,3]-oxazinan-4-one
(7aS)-benzyl 4-oxo-4,4a,7,7a-tetrahydrocyclopenta[d][1,3]oxazine-
1(2H)-carboxylate 35. The diene oxazinanone (34.3 mg,
9 and
4
The oxazinanone 31 was isolated as a colorless oil (13.4 mg, 8%
0.11 mmol) in toluene (1.00 mL) was transformed at reflux for 2 h
according to General procedure E, and afforded the bicyclic-
oxazinanone 9 and 35 as an oil (17% yield), in a ratio of 1.8:1. Se-
lected data for 35 (from mixture): dH (300 MHz, CDCl3) (325 K) 5.13
(1H, d, J 10.2 Hz), 5.09 (1H, br s), 2.47 (1H, br d, J 18.0 Hz).
yield); Rf (20% EtOAc/hexane) 0.51; m/z HRMS (EI): [M]þ, found
397.2246. C24H31NO4 requires 397.2253;
½
a 2D4
ꢃ
þ24.8 (c 0.56,
MeOH); nmax (NaCl)/cmꢀ1 3074, 2970, 2918, 1746, 1713, 1641, 1418,
1246, 1003, 903; dH (300 MHz, CDCl3) (325 K) 7.35 (5H, br s), 5.94
(1H, d, J 9.6 Hz) 5.78e5.66 (1H, m), 5.24e5.13 (3H, m), 4.99e4.92
(3H, m), 4.86 (2H, d, J 13.5 Hz), 4.69 (1H, s), 4.57 (1H, d, J 10.8 Hz),
2.79 (2H, dd, J 9.9, 13.5 Hz), 2.31 (1H, d, J 4.2 Hz), 2.25 (1H, s),
2.08e1.94 (2H, m), 1.85e1.17 (5H, m), 1.64 (3H, s); dC (75 MHz,
CDCl3) (325 K) 171.8, 154.0, 140.5, 140.2, 136.5, 135.3, 128.2, 128.1,
127.9, 115.8, 115.1, 114.2, 72.4, 67.8, 55.5, 51.0, 42.7, 38.1, 29.4, 27.0,
24.9, 23.1.
4.2.6.1.3. (4S,8S)-N-Benzyloxycarbonyl-2,4,4a,5,8,8a-hexahydro-
1H-benzo[d][1,3]-oxazinan-4-one 10. The diene oxazinanone
5
(52.8 mg, 0.17 mmol) in toluene (2.80 mL) was transformed at
reflux for 2 h according to General procedure E, and afforded the
cyclic-oxazinanone 10 as an oil (42.2 mg, 86% yield); Rf (20% EtOAc/
hexane) 0.24; m/z HRMS (ESI, MeOH/AcOH): [MþNa]þ, found
310.1050. C16H17NNaO4 requires 310.1050; ½a D24
þ174.0 (c 2.23,
ꢃ
4.2.5.1.6. (4S,5S)-N-Benzyloxycarbonyl-4-allyl-5-methyl-1,3-
oxazinan-6-one 33. The General procedure D was followed for the
alkylation of oxazinanone 2 (103 mg, 0.37 mmol) with MeOTf
MeOH); nmax (NaCl)/cmꢀ1 3067, 2920, 1755, 1713, 1694, 1416, 1261,
1155, 999; dH (300 MHz, CDCl3) (325 K) 7.38e7.32 (5H, m), 5.92 (1H,
d, J 10.7 Hz), 5.72e5.61 (2H, m), 5.18 (2H, s), 5.10 (1H, d, J 10.7 Hz),
3.88e3.83 (1H, m), 2.80e2.71 (2H, m), 2.47e2.38 (2H, m), 2.18e2.12
(1H, m); dC (75 MHz, CDCl3) (325 K) 171.1, 154.3, 135.3, 128.2, 128.0,
127.7, 124.9, 124.3, 71.4, 67.8, 52.3, 39.8, 32.1, 26.6.
(61.5
2 (26% recovery) and trace amount of the 5,5-disubstituted com-
pound. The oxazinanone 33 was isolated as colorless oil
mL, 0.56 mmol) as the electrophile to afford starting material
a
(50.2 mg, 46% yield); Rf (20% EtOAc/hexane) 0.30; m/z HRMS (ESI,
4.2.6.1.4. (4S,8S)-N-Benzyloxycarbonyl-6-methyl-2,4,4a,5,8,8a-
hexahydro-1H-benzo[d][1,3]-oxazinan-4-one 12. The diene oxazi-
nanone 7 (35.3 mg, 0.11 mmol), in toluene (1.80 mL) was trans-
formed at reflux for 2 h according to General procedure E, and
afforded the oxazinanone 12 as white solid (25.7 mg, 80% yield); Rf
(20% EtOAc/hexane) 0.24; m/z HRMS (EI): [M]þ, found 301.1303.
MeOH/AcOH): [MþH]þ, found 290.1393. C16H20NO4 requires
290.1387; ½a 2D4
ꢃ
þ171.0 (c 1.4, MeOH); nmax (NaCl)/cmꢀ1 2978, 2931,
1744, 1713, 1643, 1420, 1250, 1111, 910; dH (300 MHz, CDCl3)
7.38e7.29 (5H, m), 5.87e5.71 (2H, m), 5.22e5.09 (4H, m), 4.95
(1H, d, J 10.8 Hz), 3.86 (1H, br s), 2.73e2.65 (2H, m), 2.35e2.26
(1H, m), 1.28 (3H, d, J 6.6 Hz); dC (75 MHz, CDCl3) 172.1, 153.9,
135.2, 131.4, 128.0, 128.2, 127.7, 119.5, 71.8, 67.8, 55.6, 37.5, 36.1,
12.8.
C17H19NO4 requires 301.1314; mp 113e115 ꢁC; ½a D24
þ183.1 (c 0.83,
ꢃ
MeOH); nmax (NaCl)/cmꢀ1 3032, 2916, 1767, 1713, 1674, 1412, 1265,
1242, 1142, 1011, 972; dH (300 MHz, CDCl3) (325 K) 7.38e7.32 (5H,
m), 5.93 (1H, d, J 10.5 Hz), 5.34 (1H, br s), 5.23 (1H, d, JAB 12.3 Hz),
5.17 (1H, d, JAB 12.3 Hz), 5.10 (1H, d, J 10.5 Hz), 3.87e3.78 (1H, m),
2.83e2.66 (2H, m), 2.37 (2H, d, J 6.9 Hz), 2.13e2.04 (1H, m), 1.71
(3H, s); dC (75 MHz, CDCl3) (325 K) 171.3, 154.3, 135.3, 132.6, 128.2,
128.0, 127.7, 118.4, 71.4, 67.7, 52.3, 39.9, 31.9, 31.1, 22.4.
4.2.5.1.7. (4S,5S)-N-Benzyloxycarbonyl-4-allyl-5-methyl-5-allyl-
1,3-oxazinan-6-one 32. The General procedure D was followed for
the alkylation of 5-methyl-oxazinanone 33 (80.0 mg, 0.28 mmol)
with toluene as a solvent and allyl bromide (120 mL, 1.38 mmol) as
the electrophile to afford starting material 33 (21% recovery) and
5,5-disubstituted oxazinanone 32 (35.3 mg, 38% yield); Rf (20%
EtOAc/hexane) 0.51; m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found
4.2.6.1.5. (4S,8S)-N-Benzyloxycarbonyl-4a-methyl-2,4,4a,5,8,8a-
hexahydro-1H-benzo[d][1,3]-oxazinan-4-one 34. The diene oxazina-
none 32 (19.4 mg, 0.06 mmol) in toluene (1 mL) was transformed at
reflux for 2 h according to General procedure E, and afforded the
oxazinanone 34 as an oil (14.6 mg, 81% yield); Rf (20% EtOAc/hexane)
0.38; m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 302.1387.
330.1703. C19H24NO4 requires 330.1700.
½
a 2D4
ꢃ
þ127.1 (c 0.39,
MeOH); nmax (NaCl)/cmꢀ1 3078, 2982, 2916, 1746, 1713, 1697, 1423,
1248, 1111, 1011, 918, 733; dH (300 MHz, CDCl3) (320 K) 7.33 (5H, br
s), 5.91 (1H, br s), 5.66 (2H, br s), 5.22e5.01 (7H, m), 4.32 (1H, br s),
2.53 (1H, d, J 14.4 Hz), 2.39e2.18 (3H, m), 1.18 (3H, s); dC (75 MHz,
CDCl3) (325 K) 172.6, 153.6, 135.3, 132.6, 131.4, 128.2, 128.1, 127.8,
119.4, 117.9, 72.5, 67.7, 55.2, 47.5, 42.8, 32.6, 18.8.
C17H20NO4 requires 302.1387; ½a D24
þ30.9 (c 0.52, MeOH); nmax (NaCl)/
ꢃ
cmꢀ1 3032, 2974, 2916, 1753, 1713, 1645, 1519, 1454, 1346, 1246, 1045,
1002; dH (300 MHz, CDCl3) (325 K) 7.39e7.32 (5H, m), 5.92 (1H, d, J
10.7 Hz), 5.68e5.56 (2H, m), 5.36 (1H, d, J 10.7 Hz), 5.22 (1H, d, JAB
12.0 Hz), 5.17 (1H, d, JAB 12.0Hz), 3.89(1H, dd, J4.8,11.1 Hz), 2.87(1H, d,
J 17.4 Hz), 2.55 (1H, d, J 16.2 Hz), 2.32 (1H, dd, J 4.8,16.2 Hz), 2.22e2.18
(1H, m), 1.41 (3H, s); dC (75 MHz, CDCl3) (325 K) 171.8, 154.9, 135.3,
128.2, 128.0, 127.8, 125.1, 123.8, 72.4, 67.8, 54.7, 39.3, 37.1, 27.7, 16.5.
4.2.6.1.6. (4S,9S)-N-Benzyloxocarbonyl-4,4a,5,6,9,9a-hexahydro-
2H-cyclohepta[d][1,3]-oxazinan-4-one 11. The diene oxazinanone 6
4.2.6. Bicyclic adduct formation by way of RCM
4.2.6.1. General procedure E. Ring-closing metathesis. A solution
of the diene (0.04e0.11 M solution) in dry degassed toluene was
added to a solution of catalyst (Grubb’s II) (5 mol %) in dry degassed
toluene (0.017 M solution) under argon. The solution was then ei-
ther stirred at 25 ꢁC or at reflux. The solvent was evaporated under

B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
6283
(80.1 mg, 0.24 mmol) in toluene (5.80 mL) was transformed at 25 ꢁC
for 3 h according to General procedure E, and afforded the oxazi-
nanone 11 as an oil (43.6 mg, 60% yield); Rf (20% EtOAc/hexane)
0.33; m/z HRMS (EI): [M]þ, found 301.1309. C17H19NO4 requires
with hydrogen (3ꢂ), then it was left to stir at 25 ꢁC for 3 h. The
mixture was then filtered through a small bed of Celite and washed
with ethanol and the solvent was removed under reduced pressure
to give an oily residue. The residue was subjected to flash column
chromatography, eluting with 10e40% EtOAc/hexane, to afford the
301.1314; ½a 2D4
ꢃ
þ58.2 (c 0.45, MeOH); nmax (NaCl)/cmꢀ1 3028, 2918,
2849, 1755, 1713, 1414, 1248, 1128, 1010, 970; dH (300 MHz, CDCl3)
(325 K) 7.39e7.30 (5H, m), 5.94e5.79 (3H, m), 5.16 (2H, br s), 5.07
(1H, d, J 10.2 Hz), 3.83 (1H, br s), 2.96 (1H, dd, J 8.4, 16.2 Hz), 2.44
(1H, t, J 10.8 Hz), 2.33e2.03 (4H, m), 1.43e1.39 (1H, m); dC (75 MHz,
CDCl3) (325 K) 171.3, 153.6, 135.3, 132.2, 128.4, 128.2, 128.0, 127.6,
71.0, 67.7, 59.5, 44.4, 32.8, 26.7, 24.3.
desired cyclic N-methyl-b-amino acid 38 as an oil (19.5 mg, 61%
yield); m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 292.1543.
C16H22NOþ4 requires 292.1548; mp 138e140 ꢁC; ½a 2D4
þ10.5 (c 0.57,
ꢃ
MeOH); nmax (NaCl)/cmꢀ1 3272e2854, 2939, 1697, 1450, 1412, 1319,
1150, 912, 733; dH (300 MHz, CDCl3) (300 K) 7.33e7.27 (5H, m), 5.11
(2H, s), 4.11 (1H, br s), 2.84 (3H, s), 2.66e.58 (1H, m), 2.05 (1H, br d, J
12.3 Hz),1.81e1.71 (3H, m),1.60e1.52 (2H, m),1.41e1.33 (1H, m),1.16
(1H, br s); dC (75 MHz, CDCl3) (300 K) 178.8,156.0,136.5,128.0,127.4,
127.3, 66.8, 56.8, 46.4, 46.0, 28.9, 28.5, 24.7, 24.2.
4.2.6.1.7. (4S,9S)-N-Benzyloxycarbonyl-7-methyl-4,4a,5,6,9,9a-
hexahydro-2H-cyclohepta[d][1,3]-oxazinan-4-one 13. The diene
oxazinanone 8 (49.5 mg, 0.14 mmol) in toluene (3.30 mL) was
transformed at 25 ꢁC for 3 h according to General procedure E, and
afforded the oxazinanone 13 as an oil (31.3 mg, 69% yield); Rf (20%
EtOAc/hexane) 0.35; m/z HRMS (EI): [M]þ, found 315.1466.
4.2.8.2. (1S,2S)-N-Benzyloxycarbonyl-3-methylamino-cyclohex-
3-anecarboxylic acid 39. To a solution of oxazinanone 10 (29 mg,
0.10 mmol) in dry ethanol (7 mL) was added 10% palladium-on-
charcoal catalyst (20% w/w). The mixture was evacuated and
purged with hydrogen (3ꢂ), then it was left to stir at 25 ꢁC for 3 h. The
mixture was then filtered through a small bed of Celite and washed
with ethanol and the solvent was removed under reduced pressure
to give an oily residue. The residue was dissolved in THF (5 mL) and
4 M aq LiOH (0.8 mL) was added at 0 ꢁC. The reaction mixture was left
to stir at 25 ꢁC for 2 h and THF was removed under reduced pressure.
The aqueous solutionwas washed with ether (5 mL) and the aqueous
layer was acidified to pH 2 with 1 M aq HCl and then it was extracted
with EtOAc (3ꢂ5 mL). The combined organic layers were dried with
MgSO4 and evaporated under reduced pressure to give the acid 39 as
an oil (27.9 mg, 78% yield) and it was then converted into a tert-
butylammonium salt for analysis; m/z HRMS (ESI, MeOH/AcOH):
[MþH]þ, found 351.2278. C19H31N2Oþ4 requires 351.2278. Mp
C18H21NO4 requires 315.1471; ½a D24
þ60.6 (c 0.67, MeOH); nmax
ꢃ
(NaCl)/cmꢀ1 3034, 2960, 2916, 2849, 1759, 1713, 1699, 1409, 1248,
1128, 1014, 962, 912; dH (300 MHz, CDCl3) (325 K) 7.37 (5H, br s),
5.87 (1H, d, J 10.7 Hz) 5.63 (1H, br s), 5.17 (2H, s), 5.05 (1H, d, J
10.7 Hz), 3.84 (1H, t, J 10.7 Hz), 2.77 (1H, d, J 15.9 Hz), 2.47 (1H, t, J
10.7 Hz), 2.27e2.14 (3H, m), 2.08e2.04 (1H, m), 1.77 (3H, s),
1.43e1.33 (1H, m); dC (75 MHz, CDCl3) (325 K) 171.6, 153.7, 135.3,
137.2, 128.2, 128.1, 127.6, 125.7, 721.1, 67.7, 59.7, 43.5, 32.9, 31.8, 25.5,
23.9.
4.2.7. Reductive cleavage of the bicyclic adducts
4.2.7.1. General procedure F. Reductive cleavage of the bicyclic
oxazinanone. To the bicyclic oxazinanone in dry CH2Cl2 (0.06 M
solution) were added boron trifluoride etherate (2.00 equiv) and
triethylsilane (3.00 equiv). Then, the reaction mixture was stirred
for 6e20 h (monitored by TLC). The solvent was evaporated under
reduced pressure. The resulting residue was subjected to silica
chromatography, eluting with 10e30% EtOAc/hexane.
123e125 ꢁC; ½a 2D4
ꢃ
ꢀ13.3 (c 0.3, H2O); nmax (KBr)/cmꢀ1 3341, 2932,
2862, 2739, 2623, 2538, 2199,1713,1628,1543,1497,1404,1219,1126,
1034, 702; dH (300 MHz, D2O) (323 K) 7.49 (5H, br s), 5.16 (2H, br s),
3.62 (1H, br s), 2.20 (1H, br s),1.96 (2H, br s),1.76 (2H, br s),1.61e1.25
(13H, m); dC (75 MHz, D2O) (320 K) 182.9, 157.2, 136.3, 128.4, 127.9,
127.2, 66.3, 65.2, 52.4, 51.9, 51.6, 31.9, 29.3, 26.2, 24.2.
4.2.7.1.1. (1S,6S)-N-Benzyloxycarbonyl-3-methylamino-cyclohex-
3-enecarboxylic acid 36. The oxazinanone 10 (40.0 mg, 0.14 mmol)
was transformed according to General procedure F, affording N-
methyl acid 36 as a white solid (38.3 mg, 94% yield); m/z HRMS (ESI,
MeOH/AcOH): [MþNa]þ, found 312.1208. C16H19NNaO4 requires
4.2.8.3. (1S,2S)-N-Benzyloxycarbonyl-3-methylamino-cyclohept-
3-anecarboxylic acid 40. To a solution of oxazinanone 11 (34.7 mg,
0.12 mmol) in dry ethanol (7.00 mL) was added 10% palladium-on-
charcoal catalyst (20% w/w). The mixture was evacuated and
purged with hydrogen (3ꢂ), then it was left to stir at rt for 3 h. The
mixture was then filtered through a small bed of Celite and washed
with ethanol and the solvent was removed under reduced pressure
to give an oily residue. The residue was dissolved in dry CH2Cl2
312.1206; mp 162e164 ꢁC; ½a D24
þ7.4 (c 0.61, MeOH); nmax (NaCl)/
ꢃ
cmꢀ1 3287e2861, 2916, 1703, 1645, 1454, 1408, 1346, 1307, 1147,
912, 733; dH (300 MHz, CDCl3) (300 K) 8.15 (1H, br s), 7.33e7.25 (5H,
m), 5.63 (2H, s), 5.12 (2H, s), 4.44e4.34 (1H, m), 2.99e2.81 (4H, m),
2.79 (2H, s), 2.43e2.28 (2H, m); dC (75 MHz, CDCl3) (320 K) 177.6,
156.1, 136.5, 128.1, 127.4, 127.3, 124.7, 124.1, 66.9, 54.1, 42.7, 29.8,
28.9, 27.5.
(5 mL) and boron trifluoride etherate (29.2
mL, 0.23 mmol) and
4.2.7.1.2. (1S,2S)-N-Benzyloxycarbonyl-3-methylamino-5-
methylcyclohept-4-enecarboxylic acid 37. The oxazinanone 13
(30.2 mg, 0.096 mmol) was transformed according to General
procedure F, affording N-methyl acid 37 as an oil (19.9 mg, 66%
yield); m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 318.1704.
C18H24NOþ4 requires 318.1705; nmax (NaCl)/cmꢀ1 3268e2862, 2932,
2855, 1728, 1697, 1450, 1312, 1211, 1142, 910, 731; dH (300 MHz,
CDCl3) (300 K) 7.33e7.26 (5H, m), 5.61 (1H, br s), 5.12 (2H, s), 4.29
(1H, d, J 11.1 Hz), 2.83 (3H, s), 2.66e2.45 (2H, m), 2.16e1.98 (3H, m),
1.74 (3H, s), 1.59e1.46 (2H, m); dC (75 MHz, CDCl3) 177.1, 155.6,
136.9, 136.6, 128.1, 127.5, 127.3, 126.0, 66.7, 61.5, 45.8, 40.9, 30.5,
30.1, 24.8, 24.4.
triethylsilane (55.1 mL, 0.35 mmol) were added sequentially. The
reaction mixture was left to stir at 25 ꢁC for 3 h. The residue was
subjected to flash column chromatography, eluting with 10e40%
EtOAc/hexane, to furnish the desired cyclic N-methyl-b-amino acid
40 as an oil (18.9 mg, 65% yield); m/z HRMS (ESI, MeOH/AcOH):
[MþH]þ, found 306.1713. C17H24NO4þ requires 306.1700; ½a D24
ꢃ
þ9.5 (c 0.6, MeOH); nmax (NaCl)/cmꢀ1 3287e2860, 3032, 2932,
2862, 1697, 1450, 1412, 1319, 1188, 1142, 964, 733; dH (300 MHz,
CDCl3) (300 K) 7.33e7.28 (5H, m), 5.10 (2H, s), 4.23e4.16 (1H, m),
2.92e2.79 (4H, m), 1.84e1.47 (10H, m); dC (75 MHz, CDCl3) 179.8,
155.7, 136.5, 128.0, 127.4, 127.3, 66.9, 60.1, 48.2, 31.9, 30.7, 28.2, 27.5,
24.7 (2).
4.2.8. Hydrogenation to afford
4.2.8.1. (1S,2S)-N-Benzyloxycarbonyl-3-methylamino-cyclohex-
3-ane carboxylic acid 38. To a solution of cyclic- -amino acid 36
(31.9 mg, 0.11 mmol) in ethanol (7 mL) was added 10% palladium-on-
charcoal catalyst (20% w/w). The mixture was evacuated and purged
b-amino analogues
Acknowledgements
b
We thank La Trobe University for the provision of a postgraduate
scholarship awarded to N.H.N.; and the NHMRC (App. 1010326) for
funding B.E.S.

6284
B.E. Sleebs et al. / Tetrahedron 69 (2013) 6275e6284
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