Diastereoselective synthesis of α-methyl and α-hydroxy-β- amino acids via 4-substituted-1,3-oxazinan-6-ones

Article abstract of DOI:10.1021/jo0700326

(Chemical Equation Presented) 1,3-Oxazinan-6-ones have been utilized in a series of enolate reactions to produce 5-hydroxy and 5-alkyl-4-substituted-1,3- oxazinan-6-ones with excellent trans diastereoselectivity. Highlighting the versatility of the oxazin

Full text of DOI:10.1021/jo0700326

Diastereoselective Synthesis of r-Methyl and r-Hydroxy-â-Amino
Acids via 4-Substituted-1,3-Oxazinan-6-ones
Brad E. Sleebs‡ and Andrew B. Hughes*
Department of Chemistry, La Trobe UniVersity, Bundoora, Victoria 3086, Australia
a.hughes@latrobe.edu.au
ReceiVed January 6, 2007
1,3-Oxazinan-6-ones have been utilized in a series of enolate reactions to produce 5-hydroxy and 5-alkyl-
4-substituted-1,3-oxazinan-6-ones with excellent trans diastereoselectivity. Highlighting the versatility
of the oxazinanone, a number of transformations were performed to produce a variety of protected N-H
and N-methyl R-hydroxy- and R-methyl-â-amino acids.
Introduction
â-amino acids in the past 10 years, and these methods have
been reviewed.3,6-16
â-Amino acids are found uncommonly in natural products;1,2
however of these, the R,â-disubstituted-â-amino acids are the
most abundant. When incorporated in secondary metabolites,
R-alkyl-â-amino acids have an important structural and con-
formational role and syn and anti stereoisomers of R-hydroxy-
â-amino acids are known to be part of the active moiety of
secondary metabolites.1,2 The example most often quoted is the
R-hydroxy-â-amino acid residue of Taxol.3 Such is the utility
and importance of these residues as demonstrated in pharma-
ceutical natural products, they also find application in peptido-
mimetics4,5 and as precursors to other synthetic targets.3 It is
for these reasons there has been a plethora of syntheses of
A majority of the synthetic methods for â-amino acids are
concerned with asymmetric synthesis using non-â-amino acid
substrates, and they use expensive chiral catalysts. Furthermore,
some methods have been developed to produce a certain type
of residue.14,16 Most importantly, a majority of the syntheses
do not produce diastereomerically pure products. Only a handful
of methods are capable of producing a range of stereopure
â-amino acids.12
Manipulating the R-center of a â-amino acid is another
attractive method, although stereospecific reactions are scarce.
(6) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117-128.
(7) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med.
Chem. 1999, 6, 955-970.
(8) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517-3599.
‡ Current address: The Walter and Eliza Hall Institute of Medical Research,
Structural Biology Division, Medicinal Chemistry Group, 4 Research Avenue,
La Trobe University Research and Development Park, Victoria 3086, Australia.
(1) Von Nussbaum, F.; Spiteller, P. In Highlights in Bioorganic
Chemistry; Schmuck, C., Wennemers, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; pp 63-89.
(2) Spiteller, P.; Von Nussbaum, F. In EnantioselectiVe Synthesis Of
â-Amino Acids, 2nd ed.; Juaristi, E., Ed.; John Wiley & Sons: New York,
2005; pp 19-91.
(3) Juaristi, E. EnantioselectiVe Synthesis Of â-Amino Acids; Wiley: New
York, 1997.
(9) Cole, D. C. Tetrahedron 1994, 50, 9517-9582.
(10) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983-1004.
(11) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27,
3-11.
(12) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
(13) Ma, Z.-H.; Zhao, Y.-H.; Wang, J.-B. Chin. J. Org. Chem. 2002,
22, 807-816.
(14) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927-954.
(15) Romanova, N. N.; Gravis, A. G.; Bundel, Y. G. Russ. Chem. ReV.
1996, 65, 1083-1092.
(4) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, I. A.; Aguilar, M.-I.
Curr. Med. Chem. 2002, 9, 811-822.
(5) Wiley, R. A.; Rich, D. H. Med. Res. ReV. 1993, 13, 327-384.
(16) Sewald, N. Amino Acids 1996, 11, 397-408.
10.1021/jo0700326 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007
3340
J. Org. Chem. 2007, 72, 3340-3352

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
SCHEME 1. Synthesis of N-Methyl-â-Amino Acids 2 via
1,3-Oxazolidin-5-ones 117,18 (R refers to amino acid side
chain)a
SCHEME 3. 5-Alkylation of the 1,3-Oxazinan-6-one 3a
a Reagents and conditions: (a) 1. base, THF, -78 °C, 40 min; 2. MeI,
3 h at -78 °C, then warmed to -15 °C, sat. NH4Cl quench.
(Scheme 2). However, the use of 1,3-oxazolidin-5-ones 1
allowed for smooth conversion of the 20 common R-amino acids
to their N-methyl homologues 2 using various protective group
strategies for specific side chains (Scheme 1).
1,3-Oxazinan-6-ones are attractive templates for elaboration
of â-amino acids in a variety of ways. However, to better utilize
1,3-oxazinan-6-ones in the efficient production of R,â-disub-
stituted-â-amino acids, the yields of the oxazinanones 3-9 (30-
45%) (Scheme 2) we reported17 using the procedure of Ben-
Ishai needed to be improved.19 Several other methods were
attempted without any improvement in yield until the conditions
of Burtin et al.20,21 were applied. It was found that stirring the
N-protected â-amino acids in toluene, with a catalytic amount
of acid and activated 4 Å molecular sieves at 90 °C for 3-4 h,
resulted in a marked improvement in yields of the oxazinanones
3-9 (65-78%).
a Reagents and conditions: (a) (CH2O)n, cat. CSA, C6H6, reflux; (b)
CF3CO2H, Et3SiH, CH2Cl2; (c) 1. EtOCOCl, NMM; 2. CH2N2; (d)
AgO2CCF3, H2O, sonicate.
SCHEME 2. Synthesis of N-Methyl-â-Amino Acids 2 via
1,3-Oxazinan-6-ones 3-917,18 (R refers to alkyl and aryl
groups)a
Recently, Govender et al.22 reported further improvement to
the yields of 1,3-oxazinan-6-ones up to 82-96% using micro-
wave technology. This pleasing development further strength-
ened our attraction to the oxazinanones as intermediates for the
efficient synthesis of â-amino acid derivatives.
1,3-Oxazinan-6-one 5-Alkylation. Burtin et al.20,21 is the only
group to have prepared 5-alkyl-1,3-oxazinan-6-ones. The ox-
azinanones were derived from an N-Boc-protected aspartic acid
derived residue; thus two acidic protons were present, requiring
2 equiv of base to form enolates. The enolates were then
alkylated employing methyl iodide and benzyl bromide. The
stereochemistry of the products was predominantly trans;
however, the diastereoselectivity was poor. These results did
not hold great promise for the series of alkylations we intended
to perform.
Our initial enolate chemistry involved using the least sterically
demanding chiral oxazinanone 3. This oxazinanone 3 was treated
with a variety of common amide bases (LDA, LiHMDS,
NaHMDS, and KHMDS), and the resulting enolate was then
treated with methyl iodide (Scheme 3).
All alkylations performed provided the trans-10 and cis-11
products (Scheme 3, Table 1). Alkylation using LDA (entry 1)
or LiHMDS (entry 2) as base provided selectivity similar to
the results observed by Burtin et al.20,21 However, NaHMDS
(entry 3) and KHMDS (entry 4) both afforded significantly
better selectivity. This trend in the results suggests the anion is
less important than the metal counterion. It appears use of
sodium or potassium bases that are less likely to coordinate both
the enolate oxygen and carbamate carbonyl, as a lithium
counterion could, leads to higher diastereoselectivity (Table 1,
entries 3 and 4) than the lithium bases (Table 1, entries 1 and
2).
a Reagents and conditions: (a) 1. EtOCOCl, NMM; 2. CH2N2, (CH2O)n,
cat. CSA, C6H6, reflux; (b) AgO2CCF3, H2O, sonicate; (c) (CH2O)n, cat.
CSA, C6H6, reflux; (d) CF3CO2H, Et3SiH, CH2Cl2.
The only method exhibiting versatility and excellent selectivity
uses perhydropyrimidinones.3 However, these intermediates have
the disadvantage of a lengthy preparation reaction sequence,
and once the manipulation of the R-center has occurred, a harsh
acid hydrolysis is performed to reveal the target â-amino acid.
This hydrolysis leaves the â-amino acid with no protection
usually required for subsequent reactions, and it also raises the
question as to whether the hydrolysis will be as effective with
more highly functionalized side chains. As Liu and Sibi stated
in regard to this problem, “The deVelopment of an efficient
process suitable for large-scale synthesis, which is easy to
operate, practical and inexpensiVe, remains a significant
challenge”.12 The application of 1,3-oxazinan-6-ones to produce
R-substituted-â-amino acids, detailed herein, is a significant step
toward solving these difficulties and providing access to a
diverse range of these compounds.
Results and Discussion
Previously, we have described the use of both 1,3-oxazolidin-
5-ones 1 and 1,3-oxazinan-6-ones for the production of N-meth-
yl-â-amino acid derivatives 2 (Schemes 1 and 2).17,18 It was
found that synthesis of the N-methyl-â-residues 2 utilizing 1,3-
oxazinan-6-ones 3-9 proceeded in lower than expected yields
(19) Ben-Ishai, D. J. Am. Chem. Soc. 1957, 79, 5736-5738.
(20) Burtin, G.; Corringer, P.-J.; Young, D. W. J. Chem. Soc., Perkin
Trans. 1 2000, 3451-3459.
(21) Burtin, G.; Corringer, P.-J.; Hitchcock, P. B.; Young, D. W.
Tetrahedron Lett. 1999, 40, 4275-4278.
(17) Sleebs, B. E.; Hughes, A. B. HelV. Chim. Acta 2006, 89, 2611-
2637.
(18) Sleebs, B. E.; Hughes, A. B. Aust. J. Chem. 2005, 58, 778-784.
(22) Govender, T.; Arvidsson, P. I. Tetrahedron Lett. 2006, 47, 1691-
1694.
J. Org. Chem, Vol. 72, No. 9, 2007 3341

Sleebs and Hughes
TABLE 1. 5-Alkylation of the 1,3-Oxazinan-6-one 3 Using
Different Bases
recovered
product
yield
product
yield
3
ratio
entry
base
LDA
LiHMDS
NaHMDS
KHMDS
(%)
10 + 11 (%)
10:11
12 (%)
1
2
3
4
15
18
24
18
33
38
44
38
5:1
5.5:1
9:1
11
18
8
11:1
14
TABLE 2. 5-Alkylation of the Oxazinanone 3 Using Different
Bases with Cosolvent HMPA or DMPUa
product
yield
product
yield
recovered
ratio
entry
base
LDA
LiHMDS HMPA
NaHMDS HMPA
KHMDS HMPA
KHMDS DMPU
cosolvent
HMPA
3 (%)
10 + 11 (%) 10:11 12 (%)
FIGURE 1. Newman and Haworth projections of oxazinanones 10
and 11 showing the H-5 coupling constants.
1
2
3
4
5
25
10
17
25
26
55
71
55
38
42
4:1
4:1
14:1
19:1
19:1
3
8
6
20
18
SCHEME 4. 5-Alkylation of Oxazinanones 4-7a
a Reagents and conditions: 1. base, THF, HMPA, -78 °C, 40 min; 2.
MeI, 3 h at -78 °C, then warmed to -15 °C and sat. NH4Cl quench.
TABLE 3. 5-Alkylation of the Oxazinanones 4-7 and 8
recovered
oxazinanone
(%)
product
(%)
ratio
trans:cis
product
(%)
entry oxazinanone
a Reagents and conditions: (a) 1. KHMDS, THF, HMPA, 40 min; 2.
1
2
3
4
5
6
7
8
8
21
28
17
35
13 (49)
14 (30)
15 (55)
16 (35)
20/Eb
>19:1
>19:1
>19:1
>19:1
14:1
17 (17)
18 (20)
19 (10)
MeI, 3 h at -78 °C, then warmed to -15 °C and quenched.
was apparent, but there was a significant increase in yield of
the desired singly substituted products 10 and 11 (Table 2,
entries 1 and 2). Furthermore, pleasing results were found when
employing either NaHMDS or KHMDS in association with
HMPA (Table 2, entries 3 and 4). The stereoselectivities were
increased, and this was attributed to chelation by the HMPA.
Although the yield was only increased in the case of NaHMDS,
this result was a significant step toward producing diastereoi-
somerically pure products.
DMPU is less toxic than HMPA and is known as “the safe
alternatiVe to HMPA.”23 DMPU is reported as a cosolvent to
produce similar reaction results as HMPA.23 Use of DMPU as
a cosolvent (DMPU/THF 1:2) was trialed (Table 2, entry 5) to
ascertain its effect on the R-alkylation. This reaction confirmed
that DMPU was a suitable replacement for HMPA. The reaction
yield and selectivity were not compromised. However, due to
the availability of DMPU at the time in our laboratory, HMPA
was used to complete the remainder of the study.
4
5a
6c
13
20 (20)
>19:1
a Note the reaction was quenched at -15 °C with sat. NH4Cl. b E )
C-5 epimer of compound 20. c Note the reaction was quenched at -40 °C.
The product mixtures from these reactions were purified by
column chromatography. Both starting material 3 and dialkylated
product 12 were obtained, along with reasonable yields of the
desired monoalkylated products 10 and 11. However, the two
diastereoisomers 10 and 11 were inseparable by column
chromatography. HPLC separation was attempted on a semi-
preparative scale, using a normal phase and both C-8 and C-18
reversed phase columns. The attempted separations all
failed.
Fortunately, the trans diastereoisomer 10 is crystalline, and
pure trans isomer 10 was obtained by multiple crystallizations
of the mixture using ether and hexane. However, the cis isomer
11, being an oil, could not be purified as some compound 10
The conditions determined in Table 2 were then applied to
more highly substituted oxazinanones. Alkylation of the residues
4-7 employing KHMDS as base in a HMPA/THF solvent
system (Scheme 4) proceeded well and with complete diaste-
1
persisted. H NMR spectroscopy was used to determine the
selectivity observed in the R-alkylation reactions by inspection
of the integration ratios and J couplings. Figure 1 shows the J
values of H-5 in compounds 10 and 11.
1
reoselectivity (as determined by H NMR). The yields of the
alkylations, however, were slightly lower than desired, ranging
between 35 and 55% (Table 3).
The addition of hexamethylphosphoramide (HMPA) to eno-
late reactions had varying effects on reaction yields and
stereoselectivity. Burtin et al.20,21 observed that the addition of
HMPA to the R-alkylation of oxazinanones did not affect the
stereochemical outcome of the reaction. In their hands, the
addition of HMPA resulted only in lower yields of the desired
products. The reactions shown in Table 1 were repeated using
the solvent THF/HMPA 4:1 (Table 2).
It transpired that the temperature at which the alkylation
reactions were quenched was of importance for stereoselectivity.
When the oxazinanone 8 was alkylated with NaHMDS as base
and then quenched at -15 °C, the compound 20 was isolated
in 14:1 ratio with its C-5 epimer. When the same reaction was
quenched with ammonium chloride solution at -40 °C, the trans
isomer 20 was obtained exclusively (as determined by 1H NMR)
The results of the R-alkylation with lithium amide bases
(Table 2) were as expected; a slight decrease in stereoselectivity
(23) Seebach, D.; Beck, A. K.; Studer, A. Mod. Synth. Methods 1995,
7, 1-178.
3342 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
SCHEME 5. 5-Alkylation of the Oxazinanone 8 Quenched
at -40 °Ca
FIGURE 3. Reagents for hydroxylation of oxazinanone enolates.
a Reagents and conditions: (a) 1. NaHMDS, 4:1 THF/HMPA, 40 min;
2. MeI, 3 h at -78 °C, then warmed to -40 °C and sat. NH4Cl quench.
SCHEME 6. 5-Hydroxylation and Acetylation of the
Oxazinanone 3a
a Reagents and conditions: (a) 1. KHMDs, THF, -78 to -50 °C, 40
min; 2. 21, -50 to -40 °C, 4 h, then warmed to -20 °C and sat. NH4Cl
quench. (b) acetic anhydride, pyridine, CH2Cl2, 0 °C to rt, 20 h.
FIGURE 2. Illustration of the angle of approach of the electrophile
to the oxazinanone enolate.
albeit in only 20% yield. The yield of the trans product 20 was
compromised as a result of the lower reaction temperature
(Scheme 5 and Table 3, entry 6).
oxaziridine 23,26 and molybdenum oxide pyridinium hexam-
ethylphosphoramide complex (MoOPH) 2427 (Figure 3).
The camphorsulfonyloxaziridine was the first electrophile
used in conjunction with the oxazinanone 3 (Scheme 6). The
first reaction was conducted with KHMDS as a base without
HMPA as a cosolvent. The electrophile (+)-(2R,8aS)-camphor-
sulfonyloxaziridine 21 was added 40 min after enolate formation.
The solution was left to stir for 4 h at -78 °C, and it was then
quenched with an ammonium chloride solution. A majority of
the imine product 26 was crystallized from the product mixture
using ether. Although this measure was taken to remove the
imine 26, separation of the imine and the product was still very
difficult using column chromatography. The crude product 25
from the column was obtained in a poor yield (ca.10%). The
assumption was that the (+)-(2R,8aS)-oxaziridine 21 could be
the mismatched isomer and so a poor yield resulted.
The reaction was performed again using the protocol above,
this time employing the (-)-(2S,8aR)-oxaziridine 22. No
improvement in yield resulted nor was the product 25 clean
after column chromatography. HMPA was then trialed as a
cosolvent in a reaction using KHMDS, but again, a poor yield
of impure product 25 resulted. Another possibility was that
KHMDS was an inappropriate base, and so LDA was tried, but
the poor yield persisted.
Although poor yields were obtained throughout this series
of reactions, it seemed that the product was one diastereoisomer
25. Proof of this was obtained when one alcohol was purified
by acetylating the hydroxyl group using acetic anhydride and
pyridine, enabling the acetate 27 to be easily separated from
residual imine 26 (Scheme 6).
The configuration of compound 27 was determined from the
coupling constants of the H-4 and H-5 spin system (Figure 4).
The observed J4,5 ) 9.1 Hz is consistent with a trans config-
uration.
The following rationale may explain the selectivity observed
(Figure 2). The Houk trajectory24 suggests the electrophile
approaches the molecule at an angle of 106°, near perpendicular
to the enolate plane. This is due to the interaction of the highest
occupied molecular orbital (HOMO) of the enolate with the
lowest unoccupied molecular orbital (LUMO) of the electro-
phile. Furthermore, the electrophile is tilted at a right angle to
the enolate plane, due to the repulsive interaction between the
electrophile LUMO and the oxygen atom of the enolate. This
also signifies the electrophile starts its approach from the
opposite side of the oxazinanone ring to the carbonyl group.
Essentially, the electrophile sweeps across the face of the
oxazinanone ring. As one face of the ring is hindered by the
substituent at C-4, preferential approach occurs from the
opposite face giving excellent trans selection as observed (Figure
2). Since the R groups in compounds 4-7 are larger than the
methyl group of oxazinanones 3 and 8, this facial selectivity is
greater and no C-5 epimers of compounds 13-16 were isolated.
The series of reactions above shows that the enolates of the
1,3-oxazinan-6-ones can be alkylated at C-5 with exclusive trans
selectivity if the C-4 substituent is larger than a methyl group.
In the case of the R group being methyl, exclusive trans
selection can be achieved by quenching the reaction at -40 °C
albeit at the cost of a low product yield. In the next phase, we
aimed to intercept the enolates with hydroxylating reagents that
would allow development of 2-hydroxy-â-amino acids.
5-Hydroxylation of 1,3-Oxazinan-6-ones. Many methods
offer a means of R-hydroxylation of a â-amino acid, but the
majority do not offer complete selectivity.3,6-16 Thus, it was
postulated that suitably adapted oxazinanone methodology might
offer a new avenue to these residues.
In order to 5-hydroxylate oxazinanones via their enolates,
an electrophilic source of oxygen was required. Three hydroxy-
lation agents that are commonly used in enolate chemistry were
used in the study to determine which reagent would produce
the highest yield and diastereoselectivity. The reagents were
the camphorsulfonyloxaziridines 21 and 22,25 the Davis-type
Since the oxaziridines 21 and 22 did not effect hydroxylation
in the desired manner, another electrophilic source of oxygen
was required. It was assumed that the oxaziridines 21 and 22
were too hindered, and so the less hindered Davis-type oxaziri-
dine 23 (Figure 3) might enable hydroxylation of the enolate.
(24) Houk, K. N.; Paddon-Row, M. N. J. Am. Chem. Soc. 1986, 108,
2659-2662.
(25) Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P.
J. J. Am. Chem. Soc. 1988, 110, 8477-8482.
(26) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Organic Syntheses;
John Wiley & Sons: New York, 1988; Vol. 66, pp 203-210.
(27) Vedejs, E.; Larsen, S. Organic Syntheses; John Wiley & Sons: New
York, 1984; Vol. 64, pp 127-137.
J. Org. Chem, Vol. 72, No. 9, 2007 3343

Sleebs and Hughes
SCHEME 8. 5-Hydroxylation of the Oxazinanones 3-7 and
9 Employing MoOPH 24a
FIGURE 4. Newman and Haworth projections of the acetate 27.
SCHEME 7. 5-Hydroxylation of the Oxazinanone 4
Employing the Davis-Type Oxaziridine 23 (a 5:3 dr of
trans:cis isomers was obtained)a
a Reagents and conditions: (a) 1. NaHMDS, THF, -78 to -50 °C, 40
min; 2. MoOPH 24, -50 to -40 °C, 4 h, then warmed to -20 °C and sat.
NH4Cl quench.
a Reagents and conditions: (a) 1. NaHMDS, THF, -78 to -50 °C, 40
min; 2. 23, -50 °C, 4 h, then warmed to -20 °C and sat. NH4Cl quench.
TABLE 4. 5-Hydroxylation of the Oxazinanones 3-7 and 9 Using
The oxaziridine 23 was exposed to the enolate of compound
4 in similar reaction conditions as the oxaziridines 21 and 22.
Numerous bases were employed to generate the enolate, but
no combination of base and oxaziridine 23 gave improved yields
in comparison to those obtained with the oxaziridines 21 and
22. In fact, use of the oxaziridine 23 resulted in lower yields
(<10%) (Scheme 7).
After the workup of the reaction, crystallization of the imine
aided its removal from the crude product mixture prior to
column chromatography. However, purification of the products
28 or 29 by column chromatography was ineffectual; the product
and the remaining imine coeluted. A moderately clean sample
of 28 was collected, but a clean sample of 29 was never
obtained.
The failure of oxaziridines 21, 22, and 23 to hydroxylate
effectively was unexpected and disappointing. The findings
prompted the use of an inorganic source of electrophilic oxygen.
MoOPH 24 (Figure 3) is another reagent commonly used for
installing an R-hydroxyl in enolate chemistry.27-30 MoOPH 24
has been used in the preparation of R-hydroxy-â-amino
acids.31-34
A range of conditions was used in the development of
methodology for the application of MoOPH 24 with oxazi-
nanone enolate chemistry. Initial attempts at hydroxylation
applying MoOPH 24 as an electrophile failed. The electrophile
at -78 °C was allowed 4 h to react, but very little product was
observed. Variation in the type of base did not alter the amount
of product produced either.
MoOPH 24
recovered
oxazinanone
(%)
product
(%)
ratio
trans:cis
oxazinanone
alanine 3
valine 4
leucine 5
phenylglycine 6
phenylalanine 7
isoleucine 9
5
7
5
20
6
7
25 (40)
28 (44)
30 (46)
32 (23)
31 (19)
33 (39)
>6:1
>19:1
>19:1
>19:1
>19:1
>19:1
24, and so the reaction was proceeding. The solution was
maintained at this temperature for 3 h and was then quenched
at -30 °C with a saturated solution of sodium sulfite. The
sodium sulfite destroys excess MoOPH and aids in its removal
in the aqueous workup (Scheme 8).
NaHMDS was used predominantly as the base in these
reactions as it complemented the hydroxylation with MoOPH
24 well, allowing good yields and selectivity. The only residue
for which this did not occur was the oxazinanone 3, which was
hydroxylated to form compound 25 as a mixture with the C-2
epimer (Scheme 8). Presumably, the lack of steric hindrance
conferred by the methyl group meant it was not able to
completely control the approach of the electrophile from one
face. However, while the larger groups controlled the facial
selection very well giving compounds 28 and 30-33, it was
observed that the larger the C-4 substituent, the lower were the
yields of the desired product (Table 4). Even though complete
selectivity in the hydroxylation was pleasing, the lower yields
of the larger substituents, such as phenyl or benzyl, were
disappointing, as these residues are most sought after (for
example, in Taxol3,35).
Mitsunobu Inversion of the 5-Hydroxyl Substituent. The
5-hydroxylation of the oxazinanone produced trans configured
residues. To produce the cis isomer, a Mitsunobu inversion of
the alcohol might be used. The ester produced from the
Mitsunobu reaction would then be hydrolyzed to produce the
free inverted alcohol. Numerous syntheses employing a Mit-
sunobu reaction for inversion of the R-hydroxyl on â-amino
acids are known.3,36,37
However, when the temperature of the reaction was increased,
significantly greater yields of the desired product were obtained.
Following formation of the oxazinanone enolate at -78 °C, the
reaction temperature was allowed to rise to -50 °C and the
MoOPH 24 was then added. The reaction was allowed to warm
further to around -40((5) °C. At this stage, the solution took
on a dark green coloration, indicating the reduction of MoOPH
(28) Marin, J.; Didierjean, C.; Aubry, A.; Briand, J.-P.; Guichard, G. J.
Org. Chem. 2002, 67, 8440-8449.
(29) Hara, O.; Takizawa, J.; Yamatake, T.; Makino, K.; Hamada, Y.
Tetrahedron Lett. 1999, 40, 7787-7790.
(30) Gamboni, R.; Tamm, C. HelV. Chim. Acta 1986, 69, 615-620.
(31) Hanessian, S.; Vanasse, B. Can. J. Chem. 1993, 71, 1401-1406.
(32) Hanessian, S.; Sanceau, J.-Y. Can. J. Chem. 1996, 74, 621-624.
(33) May, B. C. H.; Abell, A. D. Synth. Commun. 1999, 29, 2515-
2525.
(34) Sardina, F. J.; Paz, M. M.; Fernandez-Megia, E.; De Boer, R. F.;
Alvarez, M. P. Tetrahedron Lett. 1992, 33, 4637-4640.
(35) Nicolaou, K. C.; Dai, W.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15-44.
(36) Hennings, D. D.; Williams, R. M. Synthesis 2000, 1310-1314.
(37) Cardillo, G.; Tolomelli, A.; Tomasini, C. Tetrahedron 1995, 51,
11831-11840.
3344 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
SCHEME 9. Mitsunobu Reaction of the
SCHEME 10. Mitsunobu Reaction of the Oxazinanone 30
and Resulting Hydrolysesa
5-Hydroxyoxazinanone 30 and Resulting Degradationa
a Reagents and conditions: (a) PPh3, DEAD, THF, p-nitrobenzoic acid,
0 °C to rt, 20 h; (b) silica column chromatography.
The initial attempts at the Mitsunobu inversion of the
5-hydroxyl in the oxazinanones were performed using p-
nitrobenzoic acid as the nucleophile (Scheme 9). The application
of p-nitrobenzoic acid affords high reaction yields in comparison
to other nucleophiles.38 Due to the electron-withdrawing nature
of p-nitrobenzoic acid, saponification of the resulting benzoate
is facile.
a Reagents and conditions: (a) PPh3, DEAD, THF, p-nitrobenzoic acid,
0 °C to rt, 20 h; (b) 4 M LiOH, MeOH, 0 °C, 10 min; (c) AcOH/H2O, 4:1,
0.01 equiv of HCl, 45 °C, 20 h.
The Mitsunobu reaction was conducted in the usual manner
in THF, and the reaction was complete, as indicated by TLC,
in 20 h. An aqueous workup allowed removal of any remaining
benzoic acid. The resulting crude could be further purified by
crystallization of the triphenylphosphine oxide byproduct, using
a mixture of 75% ether/hexane. The crude residue was then
purified by column chromatography. The resulting ester 34 was
unexpectedly obtained in a low yield (39%). This result was at
first puzzling as numerous repetitions of the reaction resulted
in yields lower than 39%. On every occasion, the TLC indicated
the complete absence of the starting oxazinanone 30 and the
crude yield of the product was high. It was assumed that
degradation of the product 34 was occurring. When a 2D TLC
was performed, it was apparent that the product 34 was
degrading on silica (Scheme 9). The use of neutral and basic
alumina for chromatography also resulted in no isolation of the
desired product.
FIGURE 5. Oxazinanone ring openings.
SCHEME 11. Reductive Cleavage of Oxazinanones 10 and
13-16a
Due to the electron-withdrawing nature of the p-nitrobenzoate,
it was postulated that the use of benzoic acid might quell the
degradation of the product. However, no improvement was
observed using benzoic acid. It was decided not to perform
chromatography at this point, but rather attempt purification after
the hydrolysis of the benzoate was performed. Chromatography
after saponification resulted in incomplete inversion of the
hydroxyl stereocenter. This is attributed to incomplete Mit-
sunobu reaction and remnants of the starting oxazinanone 30.
The hydrolysis of the acetate 33 was not very successful,
and although saponification of the benzoate 34 occurred using
4 M LiOH at 0 °C in 10 min, hydrolysis of the oxazinanone
ring also occurred, resulting in benzoic acid and the lactone 35
(Scheme 10).
When an acidic hydrolysis was performed, employing acetic
acid/water 4:1, a mixture of benzoic acid, the product 36, and
an unknown byproduct was obtained. This mixture was diaboli-
cal to separate by crystallization and column chromatography.
Furthermore, the crude residue was obtained in low yield
(Scheme 10).
a Reagents and conditions: (a) TFA/CH2Cl2, 50:50, Et3SiH, rt, 3 days.
versatility of oxazinanones (Figure 5), in comparison to other
synthetic approaches reviewed elsewhere.3,6-16
Reductive Cleavage of 5-Methylated 1,3-Oxazinan-6-ones.
N-Methyl amino acids are of great interest to us for reasons
discussed elsewhere,17,18,39-41 and so reductive cleavage of the
5-methyl-4-substituted oxazinanones was performed. The reduc-
tive cleavage of these oxazinanones occurs in a fashion
analogous to the reductive cleavage of 1,3-oxazolidin-5-ones.40,41
Reductive cleavage of the 5-methyl oxazinanones 10 and 13-
16 proceeded smoothly. The yields of the products 37-41
ranged from 54 to 70% (Scheme 11).
The smooth conversion of the 5-methyl oxazinanones to the
N-methyl â-amino acids 37-41 prompted examination of the
reductive cleavage of the corresponding 5-hydroxy oxazi-
nanones. It was not known whether any hydroxyl protection
Further Elaboration of Oxazinanones. 1,3-Oxazinan-6-
ones, like many lactones, can undergo useful manipulations
contributing to their overall appeal as synthetic intermediates.
The following reactions are examples of how the oxazinanone
can be manipulated and exploited to deliver various â-amino
acid derivatives. The manipulations performed highlight the
(39) Sleebs, B. E. Ph.D. Thesis, La Trobe University, 2006.
(40) Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs,
M. M. J. Org. Chem. 2003, 68, 2652-2667.
(41) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, B. E. Aust.
J. Chem. 2000, 53, 425-433.
(38) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
J. Org. Chem, Vol. 72, No. 9, 2007 3345

Sleebs and Hughes
SCHEME 12. Reductive Cleavage of the Oxazinanone 28a
SCHEME 14a
a Reagents and conditions: (a) H2, Pd/C, MeOH (R refers to amino acid
side chain).
SCHEME 15. Base Hydrolysis of Oxazinanones 3 and 6a
a Reagents and conditions: (a) Et3SiH, 50:50 TFA/CH2Cl2, rt, 3 days.
SCHEME 13. Opening of the Oxazinanone 3 with Benzyl
Aminea
a Reagents and conditions: (a) 2 equiv of BnNH2, CH2Cl2, rt, 24 h.
a Reagents and conditions: (a) 4 M LiOH, H2O/MeOH, 0 °C, 10 min;
(b) NaHCO3, dry EtOH, reflux, 20 h.
was required for the reductive cleavage of the oxazinanones to
the N-methyl-R-hydroxy-â-amino acid (Scheme 12). In studies
conducted by Aurelio et al.,41 reductive cleavage of an
unprotected threonine-derived 1,3-oxazolidin-5-one produced a
mixture of products with some resulting from participation of
the side chain hydroxyl. This prompted use of side chain
protection to give the desired N-methyl threonine.40 In the first
instance, the 5-hydroxy oxazinanone 28 was subjected to
reductive cleavage using triethylsilane and trifluoroacetic acid
over a period of 3 days. Only the N-methyl residue 42 was
obtained (50% yield) (Scheme 12).
The 5-methyl and 5-hydroxy oxazinanones can thus be
converted into the corresponding N-methyl 2-methyl and
2-hydroxy-â-amino acids. Recently, Govender et al.22 showed
that using microwaves in the presence of a Lewis acid greatly
improved the yields in the reductive cleavage of 1,3-oxazinan-
6-ones. This is a further enhancement of the effectiveness of
oxazinanones as substrates for the synthesis of â-amino acid
derivatives.
N-methyl; that is, the Cbz protection is cleaved to produce an
oxazolidinone N-H. These findings are in accord with the
hydrogenolysis of N-tert-butyloxycarbonyl-1,3-oxazolidin-5-
ones, which produces no N-methyl product, and N-benzyloxy-
carbonyl-1,3-oxazolidin-5-one 1 reduction, which produces a
mixture of N-H 45 and N-methyl 46 amino acids.
Hydrogenolysis of the oxazinanone 3 produced the deformy-
lated product 47 (85%) (Scheme 14). Only small amounts
(<5%) of the N-methyl derivative were observed in the crude
1H NMR spectrum. This result should be compared with that
of Burtin et al.,20 who reported no ring opening when a
hydrogenation on a tert-butoxycarbonyl-N-protected oxazi-
nanone was performed. These results suggest that the oxazi-
nanone is only opened by hydrogenolysis when an N-H is
present, that is, after the Cbz protection has been hydrogenolyti-
cally cleaved, and this is in accord with the results of
hydrogenolysis of oxazolidinones described by Itoh44 and
Aurelio et al.41
Oxazinanone Basic Hydrolysis. Saponification of the 1,3-
oxazolidin-5-one ring affords the N-protected R-amino acid. An
aqueous methanolic solution of 1 M sodium hydroxide solution
at room temperature effects the hydrolysis in 4 h.44 The same
conditions did not cause efficient hydrolysis of the oxazinanone
ring. The solution was heated to 50 °C, and only a mixture of
the oxazinanone and product was obtained. The difference
between the hydrolysis rates of the two lactones is attributable
to the oxazinanone ring being more stable than the five-
membered analogue. A more concentrated reaction solution was
trialed while being cognizant of the possibility of racemization
of the residue. To a solution of the oxazinanone 6 in cold
methanol was added a 4 M lithium hydroxide solution. The
oxazinanone ring 6 hydrolyzed in 10 min at 0 °C, as monitored
by TLC. The reaction mixture was acidified to obtain the
N-benzyloxycarbonyl-â-amino acid 48 in 89% yield (Scheme
15).
Oxazinanone Aminolysis. Micheel et al.42 and Ben-Ishai19
are responsible for initial developments in this area. They used
primary amines as nucleophiles to open 1,3-oxazolidin-5-ones,
producing amides. In a similar vein, the oxazinanone 3 was
exposed to an excess of amine in a minimal volume of
methylene chloride. The oxazinanone 3 was consumed in a
period of 24 h at room temperature. The transformation most
likely proceeded via the N-hydroxymethylbenzylamide 43,
affording the benzylamide 44 in excellent yield (87%) (Scheme
13).
Oxazinanone Hydrogenolysis. Hydrogenolysis of N-benzy-
loxycarbonyl-1,3-oxazolidin-5-ones results in a mixture of
N-methyl and N-H amino acids.41 Others have described
contradictory results for the hydrogenolysis of oxazolidinones,43
but these results were clarified by Aurelio et al.41 Aurelio et
al.41 describe the need for an N-H to be present for the
hydrogenolytic reduction of an oxazolidinone to obtain an
A more facile solvolysis is cleavage of the oxazolidinone by
sodium hydrogen carbonate, as used effectively by Allevi et
(42) Micheel, F.; Meckstroth, W. Chem. Ber. 1959, 92, 1675-1679.
(43) Reddy, G. V.; Rao, G. V.; Iyengar, D. S. Tetrahedron Lett. 1998,
39, 1985-1986.
(44) Itoh, M. Chem. Pharm. Bull. 1969, 17, 1679-1686.
3346 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
Similar conditions were used for hydroxylating the 5-position
of the 1,3-oxazinan-6-one. A number of electrophilic hydroxy-
lating reagents were tried. It was found that MoOPH was the
most successful hydroxylating reagent, also providing the desired
residues with excellent trans selectivity.
The 5-substituted 1,3-oxazinan-6-ones were then subjected
to reductive cleavage conditions to give the N-methyl-R-
substituted-â-amino acids in good yields. A Mitsunobu reaction
was attempted on the 5-hydroxy-1,3-oxazinan-6-ones to invert
C-5. However, complications occurred, and degradation of the
product on silica gel was observed. Subsequent hydrolysis also
resulted in poor yields and purification problems. More devel-
opment is required in this area for the method to find a wider
range of applicability.
The 1,3-oxazinan-6-ones are versatile substrates, allowing
excellent trans selectivity. Subsequent reactions give access to
a variety of R-substituted-â-amino acids. These residues, many
of which are found in nature, are highly biologically active and
will find a wide variety of applications in therapeutics or
pharmaceutics.
FIGURE 6. Attempted base hydrolysis of 5-hydroxy oxazinanone 28.
(a) Reagents and conditions: 4 M LiOH, MeOH, 0 °C, 10 min.
SCHEME 16. Acidic Hydrolysis of Oxazinanone 3a
a Reagents and conditions: (a) 6 M HCl, dioxane, reflux, 4 h.
Experimental Section
al.45 This reaction involves refluxing the 1,3-oxazolidin-5-one
in dry alcoholic solvent with an excess of dry sodium hydrogen
carbonate. Complete reaction occurs in 10 min, and the
N-benzyloxycarbonyl-R-amino acid ester is obtained in high
yields. The same solvolysis performed on oxazinanones was
not complete in 10 min as observed by TLC. Complete reaction
required 20 h, and again, this was attributed to the stability of
the 1,3-oxazinan-6-one over the 1,3-oxazolidin-5-one. The
N-benzyloxycarbonyl-â-amino acid ethyl ester 49 was obtained
in 67% yield (Scheme 15).
The LiOH hydrolysis conditions were then applied to the
5-hydroxy-1,3-oxazinan-6-ones. To oxazinanone 28 in methanol
was added 4 M lithium hydroxide solution at 0 °C. The
hydrolysis of the oxazinanone was complete in 10 min; however,
the expected product 50 was not obtained. Although hydrolysis
of the oxazinanone did occur, the initial product was able to
undergo an intramolecular cyclization. Evidently, the 5-hydroxyl
in basic solution was converted to the alkoxide, and the
nucleophilic alkoxide attacked the carbamate carbonyl, produc-
ing benzyl alcohol and forming a new lactone 51 (Figure 6).
There is evidence of this phenomenon occurring elsewhere.46
Oxazinanone Acidic Hydrolysis. Acid hydrolysis of any
amino acid lactone gives the salt of the amino acid. Acid
hydrolysis of the oxazinanone opens the ring, and N-carbamoyl
protection is also cleaved under these conditions. Refluxing the
oxazinanone 3 in 6 M hydrochloric acid/aqueous dioxane
solution resulted in a 65% yield of the hydrochloride salt 52
(Scheme 16).
General experimental details and spectra of key intermediates
can be found in the Supporting Information.
General Procedure A. 1,3-Oxazinan-6-ones. To the N-benzy-
loxycarbonyl â-amino acid (1 mmol) in dry toluene (30 mL) were
added camphorsulfonic acid (0.1 mmol), paraformaldehyde (6
mmol), and activated 4 Å molecular sieves (150 mg) under an inert
atmosphere. The reaction mixture was stirred at 90 °C for 4 h. The
mixture was allowed to cool and filtered through Celite. The filtrate
was diluted with ethyl acetate (30 mL), and the organic layer was
washed with saturated sodium bicarbonate (20 mL) and water (20
mL). The organic layer was dried (MgSO4), and the solvent was
removed in vacuo. The residue was purified using column chro-
matography, eluting with 20-45% ethyl acetate/hexane.
(4S)-N-Benzyloxycarbonyl-4-methyl-1,3-oxazinan-6-one 3. The
N-Cbz-â-amino acid (1 mmol) was transformed according to
General Procedure A and afforded the oxazinanone 3 as an oil (65%
yield), with spectra identical to those of an authentic sample.17
(4S)-N-Benzyloxycarbonyl-4-(1-methylethyl)-1,3-oxazinan-6-
one 4. The N-Cbz-â-amino acid (1 mmol) was transformed
according to General Procedure A and afforded the oxazinanone 4
as an oil (65% yield), with spectra identical to those of an authentic
sample.17
(4S)-N-Benzyloxycarbonyl-4-(2-methylpropyl)-1,3-oxazinan-
6-one 5. The N-Cbz-â-amino acid (1 mmol) was transformed
according to General Procedure A and afforded the oxazinanone 5
as an oil (68% yield), with spectra identical to those of an authentic
sample.17
N-Benzyloxycarbonyl-4-phenyl-1,3-oxazinan-6-one 6. The
N-Cbz-â-amino acid (1 mmol) was transformed according to
General Procedure A and afforded the oxazinanone 6 as an oil (55%
yield), with spectra identical to those of an authentic sample.17
(4S)-N-Benzyloxycarbonyl-4-phenylmethyl-1,3-oxazinan-6-
one 7. The N-Cbz-â-amino acid (1 mmol) was transformed
according to General Procedure A and afforded the oxazinanone 7
as an oil (78% yield), with spectra identical to those of an authentic
sample.17
Conclusion
1,3-Oxazinan-6-ones have been utilized in a variety of enolate
reactions to produce important R-substituted-â-amino acids. The
R-position was methylated using methyl iodide. The best
conditions for the reaction employed KHMDS with HMPA
cosolvent in THF to give the residues with excellent trans
selectivity.
(4R)-N-Benzyloxycarbonyl-4-methyl-1,3-oxazinan-6-one 8. The
â-amino acid (1 mmol) was transformed according to General
Procedure A, which afforded the oxazinanone 8 as a clear colorless
oil (65% yield). Found: M + H, 250.1079; C13H15NO4 requires M
+ H, 250.1079. [R]20 -105.3 (c 3.3, CH2Cl2). νmax(NaCl)/cm-1
D
(45) Allevi, P.; Cighetti, G.; Anastasia, M. Tetrahedron Lett. 2001, 42,
5319-5321.
(46) Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garcia-Lopez, M. T. J.
Org. Chem. 1990, 55, 2232-2234.
2973, 2932, 1767, 1714, 1455, 1266, 1159, 999, 771, 750, 699. 1H
NMR (300 MHz, CDCl3) (rotamers): δ 7.25 (5H, s), 5.67 (1H, d,
J ) 10.0 Hz), 5.11 (2H, s), 4.95 (1H, d, J ) 10.8 Hz), 4.18 (1H,
J. Org. Chem, Vol. 72, No. 9, 2007 3347

Sleebs and Hughes
br s), 2.65 (1H, dd, J ) 6.6 and 16.0 Hz), 2.40 (1H, dd, J ) 10.3
and 6.3 Hz), 1.18 (3H, d, J ) 6.2 Hz); 13C NMR (75 MHz, CDCl3)
(rotamers): δ 169.7, 153.7, 135.2, 128.0, 127.9, 127.8, 127.5, 71.2,
67.3, 45.8, 36.3, 20.9.
(2R)-N-Benzyloxycarbonyl-4-((1S)-1-methylpropyl)-1,3-oxazi-
nan-6-one 9. The N-Cbz-â-amino acid (1 mmol) was transformed
according to General Procedure A and afforded the oxazinanone 9
as an oil (76% yield), with spectra identical to those of an authentic
sample.17
Synthesis of R,â-Disubstituted-â-Amino Acid Derivatives.
5-Alkylated 1,3-Oxazinan-6-ones. General Procedure B. Alky-
lation of Oxazinanones. The oxazinanone (0.5 mmol) was dis-
solved in dry THF (4 mL), and the solution was cooled to -78 °C
under an argon atmosphere. The amide base (0.52 mmol) was added
dropwise and the solution was left to stir at -78 °C for 40 min.
Methyl iodide (5 mmol) was added, and stirring was continued for
4 h at -78 °C. The solution was then allowed to warm to -15 °C,
and the reaction was then quenched with saturated ammonium
chloride solution (5 mL). The solution was diluted with ethyl acetate
(20 mL) and washed with water (20 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to give
an oily residue. The oil was subjected to column chromatography,
eluting with 5-20% ethyl acetate/hexane, to afford starting material,
5,5-disubstituted, and 5-substituted products.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using LiHMDS (1.0 M solution in hexanes)
as the base and THF as the solvent to afford the starting material
3 (18% recovery), a mixture of the diastereoisomers 10 and 11 in
a 5.5:1 (trans:cis) ratio (38% yield), and the oxazinanone 12 (18%
yield). The spectra were identical to those of the samples prepared
above.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using NaHMDS (1.0 M solution in hexanes)
as the base and THF as the solvent to afford starting material 3
(24% recovery), a mixture of the diastereoisomers 10 and 11 in a
9:1 (trans:cis) ratio (44% yield), and the oxazinanone 12 (8% yield).
The spectra were identical to those of the samples prepared above.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using KHMDS (0.5 M solution in toluene)
as the base and THF as the solvent to afford the starting material
3 (18% recovery), a mixture of the diastereoisomers 10 and 11 in
a 11:1 (trans:cis) ratio (38% yield), and the oxazinanone 12 (14%
yield). The spectra were identical to those of the samples prepared
above.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using a pre-prepared solution of LDA as the
base [prepared by adding n-butyl lithium (1.53 M solution in
hexanes, 0.52 mmol) to a stirred solution of diisopropylamine (0.52
mmol) in dry THF (2 mL)] in a 4:1 mixture of THF/HMPA as the
solvent to afford the starting material 3 (25% recovery), a mixture
of the diastereoisomers 10 and 11 in a 4:1 (trans:cis) ratio (55%
yield), and the oxazinanone 12 (3% yield). The spectra were
identical to those of the samples prepared above.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using LiHMDS (1.0 M solution in hexanes)
as the base in a 4:1 mixture of THF/HMPA as the solvent to afford
the starting material 3 (10% recovery), a mixture of the diastere-
oisomers 10 and 11 in a 4:1 (trans:cis) ratio (71% yield), and the
oxazinanone 12 (8% yield). The spectra were identical to those of
the samples prepared above.
(4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-1,3-oxazinan-6-
one 10, (4S,5R)-N-Benzyloxycarbonyl-4,5-dimethyl-1,3-oxazi-
nan-6-one 11, and (4S)-N-Benzyloxycarbonyl-4,5,5-trimethyl-
1,3-oxazinan-6-one 12. The oxazinanone 3 (0.5 mmol) was
transformed according to General Procedure B using KHMDS (0.5
M in toluene) as the base and a THF/HMPA 4:1 mixture as the
solvent to afford starting material 3 (25% recovery) and a mixture
of diastereoisomers 10 and 11 in a 18:1 (trans:cis) ratio. The
5-substituted oxazinanone 10 was crystallized from the mixture
using ether and hexane, affording 10 as a white solid (38% yield).
Found: C, 63.91; H, 6.62; N, 5.24; C14H17NO4 requires C, 63.97;
H, 6.51; N, 5.32. Mp 81-83 °C. [R]20 +148.1 (c 0.77, CH2Cl2).
D
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using NaHMDS (10 M solution in hexanes)
as the base and a 4:1 mixture of THF/HMPA as the solvent to
afford the starting material 3 (17% recovery), a mixture of the
diastereoisomers 10 and 11 in a 14:1 (trans:cis) ratio (55% yield),
and the oxazinanone 12 (6% yield). The spectra were identical to
those of the samples prepared above.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using KHMDS (0.5 M solution in toluene)
as the base and a 2:1 mixture of THF/DMPU as the solvent to
afford the starting material 3 (26% recovery), a mixture of the
diastereoisomers 10 and 11 in a 19:1 (trans:cis) ratio (42% yield),
and the oxazinanone 12 (18% yield). The spectra were identical to
those of the samples prepared above.
ν
max(KBr)/cm-1 2981, 1766, 1711, 1413, 1247, 1138, 1010, 752,
1
698. H NMR (300 MHz, CDCl3) (325 K): δ 7.34 (5H, s), 5.84
(1H, d, J ) 10.7 Hz), 5.17 (2H, s), 5.02 (1H, d, J )10.6 Hz), 3.80-
3.74 (1H, m), 2.47 (1H, dq, J ) 10.4 and 6.6 Hz), 1.36 (3H, d, J
) 6.2 Hz), 1.28 (3H, d, J ) 6.6 Hz). 13C NMR (75 MHz, CDCl3)
(300 K): δ 172.5, 153.9, 135.5, 128.5, 128.3, 128.1, 70.7, 68.0,
52.8, 41.3, 19.2, 13.2.
The cis isomer 11 was isolated as a chromatographically
inseparable mixture of cis and trans diastereoisomers (differentiated
from the trans NMR data). 1H NMR (300 MHz, CDCl3) (325 K):
δ 7.32 (5H, s), 5.59 (1H, d, J ) 9.5 Hz), 5.41 (1H, d, J ) 9.8 Hz),
5.22 (2H, s), 4.28-4.20 (1H, m), 2.98 (1H, dq, J ) 6.9 and 6.5
Hz), 1.20 (3H, d, J ) 6.6 Hz), 1.19 (3H, d, J ) 6.9 Hz). 13C NMR
(75 MHz, CDCl3) (325 K): δ 171.9, 154.0, 135.9, 128.6, 128.4,
128.2, 73.2, 68.1, 50.9, 39.1, 15.9, 11.6.
(4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-methyl-1,3-oxazi-
nan-6-one 13 and (4S)-N-Benzyloxycarbonyl-4-isopropyl-5,5-
dimethyl-1,3-oxazinan-6-one 17. The oxazinanone 4 (0.5 mmol)
was transformed according General Procedure B using KHMDS
(0.5 M in toluene) as the base and a 4:1 mixture of THF/HMPA as
the solvent to afford the starting material 4 (21% yield), and the
oxazinanone 13 was isolated as a clear colorless oil (49% yield).
Found: M + H, 292.1548; C16H21NO4 requires M + H, 292.1549.
[R]20D +119.3 (c 0.56, CH2Cl2). νmax(NaCl)/cm-1 2968, 1754, 1712,
1408, 1258, 1133, 1000, 698. 1H NMR (300 MHz, CDCl3): δ 7.34
(5H, s), 5.89 (1H, br s), 5.16 (2H, s), 4.93 (1H, d, J ) 10.7 Hz),
3.80 (1H, br s), 2.71 (1H, dq, J ) 6.7 and 8.6 Hz), 2.02-1.94 (1H,
m), 1.31 (3H, d, J ) 6.7 Hz), 1.01 (3H, d, J ) 5.7 Hz), 0.94 (3H,
d, J ) 6.8 Hz). 13C NMR (75 MHz, CDCl3): δ 172.8, 155.4, 135.4,
128.6, 128.4, 128.2, 73.0, 68.3, 61.0, 38.1, 31.4, 20.4, 17.0, 15.2.
The oxazinanone 17 was isolated as an oil (17% yield). Found:
The 5,5-disubstituted oxazinanone 12 was isolated as a clear
colorless oil (20% yield). Found: M + H, 278.1392; C15H19NO4
requires M + H, 278.1392. [R]20 +44.8 (c 0.77, CH2Cl2). νmax
-
D
(NaCl)/cm-1 2980, 2945, 1746, 1712, 1421, 1248, 1109, 1010, 746,
1
698. H NMR (300 MHz, CDCl3) (323 K): δ 7.24 (5H, s), 5.87
(1H, d, J ) 9.9 Hz), 5.23-5.18 (3H, m), 4.21-4.15 (1H, m), 1.29-
1.22 (9H, m). 13C NMR (75 MHz, CDCl3) (323 K): δ 174.5, 153.7,
135.6, 128.6, 128.5, 128.2, 72.4, 68.1, 54.3, 44.2, 26.8, 19.3, 15.2.
The oxazinanone 3 (0.5 mmol) was transformed according to
General Procedure B using a solution of LDA as the base [prepared
by adding n-butyl lithium (1.53 M solution in hexanes, 0.52 mmol)
to a stirred solution of diisopropylamine (0.52 mmol) in dry THF
(2 mL)]. The LDA solution was added dropwise at 0 °C under an
inert atmosphere to afford starting material 3 (15% recovery), a
mixture of the diastereoisomers 10 and 11 in a 5:1 (trans:cis) ratio
(33% yield), and the oxazinanone 12 (11% yield). The spectra were
identical to those of the samples prepared above.
M + H, 306.1700; C17H23NO4 requires M + H, 306.1705. [R]20
D
+17.0 (c 0.28, CH2Cl2). νmax(KBr)/cm-1 3033, 2967, 1747, 1713,
1
1392, 1246, 1101, 1011, 747, 698. H NMR (300 MHz, CDCl3)
3348 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
(323 K): δ 7.33 (5H, s), 5.92 (1H, br s), 5.26-5.07 (3H, m), 4.00
(1H, br s), 2.12-2.05 (1H, m), 1.31-1.29 (6H, m), 1.04-0.88 (6H,
m). 13C NMR (75 MHz, CDCl3) (323 K): δ 174.3, 154.8, 135.9,
128.6, 128.4, 128.2, 128.1, 128.0, 75.1, 68.2, 63.7, 43.1, 29.6, 27.8,
22.0, 21.4, 18.5.
Hz). 13C NMR (75 MHz, CDCl3) (323 K): δ 172.4, 154.1, 135.6,
135.3, 130.0, 128.6, 128.4, 128.1, 127.2, 72.0, 68.2, 56.7, 37.3,
13.2.
(4R,5R)-N-Benzyloxycarbonyl-4,5-dimethyl-1,3-oxazinan-6-
one 20. The oxazinanone 8 (0.5 mmol) was dissolved in dry THF
(4 mL) and HMPA (1 mL), and the solution was cooled to -78 °C
under an argon atmosphere. NaHMDS (0.58 M in hexanes, 0.52
mmol) was added dropwise, and the solution was left to stir at -78
°C for 40 min. Methyl iodide (5 mmol) was added, and stirring
was continued for 4 h at -78 °C. The solution was then allowed
to warm to -40 °C, and it was then quenched with saturated
ammonium chloride solution (5 mL). The solution was diluted with
ethyl acetate (20 mL) and washed with water (20 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pressure
to give an oily residue. The oil was subjected to column chroma-
tography, eluting with 5-20% ethyl acetate/hexane, to afford the
starting material 8 (13% recovery), and trace amounts of the 5,5-
disubstituted product and the oxazinanone product 20 were isolated
as a white solid (20% yield). Mp 97-98 °C. [R]20D -126.2 (c 0.9,
CH2Cl2). νmax(KBr)/cm-1 2981, 1759, 1713, 1415, 1245, 1136,
(4S,5S)-N-Benzyloxycarbonyl-4-isobutyl-5-methyl-1,3-oxazi-
nan-6-one 14 and (4S)-N-Benzyloxycarbonyl-4-isobutyl-5,5-
dimethyl-1,3-oxazinan-6-one 18. The oxazinanone 5 (0.5 mmol)
was transformed according to General Procedure B using KHMDS
(0.5 M in toluene) as the base and a 4:1 mixture of THF/HMPA as
the solvent to afford the starting material 5 (28% recovery), and
the oxazinanone 14 was isolated as a clear colorless oil (30% yield).
Found: M + H, 306.1705; C17H23NO4 requires M + H, 306.1705.
[R]20D +88.2 (c 0.45, CH2Cl2). νmax(NaCl)/cm-1 2958, 1757, 1714,
1414, 1251, 1134, 963, 698. 1H NMR (300 MHz, CDCl3) (323 K):
δ 7.32 (5H, s), 5.84 (1H, d, J ) 10.5 Hz), 5.16 (2H, s), 4.96 (1H,
d, J ) 10.6 Hz), 3.94 (1H, br s), 2.40 (1H, dq, J ) 6.8 and 7.3
Hz), 1.66-1.39 (2H, m), 1.28 (3H, d, J ) 6.7 Hz), 0.89 (6H, d, J
) 6.4 Hz). 13C NMR (75 MHz, CDCl3): δ 172.22, 155.0, 135.6,
128.6, 128.4, 128.3, 71.5, 68.3, 55.0, 44.2, 41.5, 24.4, 23.7, 21.8,
14.5.
1
1009, 754, 698. H NMR (300 MHz, CDCl3) (rotamers) (323 K):
The oxazinanone 18 was isolated as a clear colorless oil (20%
yield). Found: M + H, 320.1861; C18H25NO4 requires M + H,
δ 7.33 (5H, s), 5.82 (1H, d, J ) 10.5 Hz), 5.16 (2H, s), 5.02 (1H,
d, J ) 10.6 Hz), 3.80-3.72 (1H, m), 2.47 (1H, dq, J ) 10.3 and
6.6 Hz), 1.35 (3H, d, J ) 6.1 Hz), 1.26 (3H, d, J ) 6.6 Hz). 13C
NMR (75 MHz, CDCl3) (323 K): δ 172.3, 154.0, 135.7, 128.6,
128.4, 128.1, 70.8, 68.0, 53.0, 41.4, 19.4, 13.2.
320.1862. [R]20 +24.7 (c 0.36, CH2Cl2). νmax(NaCl)/cm-1 2958,
D
1
2872, 1746, 1712, 1420, 1249, 1106, 1006, 747, 699. H NMR
(300 MHz, CDCl3) (rotamers) (323 K): δ 7.33 (5H, s), 5.98 (1H,
br s), 5.19 (2H, s), 5.02 (1H, d, J ) 10.1 Hz), 4.17 (1H, br s),
1.63-1.40 (3H, m), 1.27 (3H, s), 1.19 (3H, s), 0.93-0.88 (6H,
m). 13C NMR (75 MHz, CDCl3) (323 K): δ 174.4, 154.5, 135.7,
128.6, 128.5, 128.3, 128.0, 72.7, 68.3, 57.0, 44.9, 36.8, 27.6, 24.5,
23.7, 21.8, 21.0.
5-Hydroxylated 1,3-Oxazinan-6-ones. (4S,5S)-N-Benzyloxy-
carbonyl-5-acetoxy-4-methyl-1,3-oxazinan-6-one 27. The oxazi-
nanone 3 (0.5 mmol) was dissolved in dry THF (4 mL), and the
solution was cooled to -78 °C under an argon atmosphere.
KHMDS (0.5 M in toluene, 0.525 mmol) was added dropwise with
stirring, and then the solution was allowed to warm to -50 °C
over 40 min. The (+)-(2R,8aS)-oxaziridine 21 (0.625 mmol) was
added in one portion, and the solution was allowed to warm to
-40 °C. The reaction was maintained at this temperature for 4 h
or until disappearance of starting material had occurred, as indicated
by TLC. The solution was then allowed to warm to -20 °C, and
it was then quenched with saturated ammonium chloride solution
(5 mL). The solution was diluted with ethyl acetate (20 mL), and
the organic phase was washed with water (20 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pressure
to give in an oily residue. Some of the byproduct imine 26 was
removed by crystallization using ether and subsequent filtration.
The filtrate was concentrated under reduced pressure, and the
residue was dissolved in dichloromethane (3 mL). Acetic anhydride
(1.5 mmol) and pyridine (1.5 mmol) were added to the dichlo-
romethane solution at 0 °C. The reaction was allowed to stir for
20 h at room temperature or until the disappearance of starting
material had occurred, as indicated by TLC. The mixture was diluted
with dichloromethane (5 mL), and the organic phase was washed
with water (10 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo. The oily residue was subjected to column
chromatography, eluting with 5-15% ethyl acetate/hexane, to afford
starting material 3 (7%) and the acetate 27 as a clear colorless oil
(12% yield). [R]20D +72.0 (c 0.15, CH2Cl2). νmax(NaCl)/cm-1 2977,
2933, 1784, 1750, 1716, 1416, 1225, 992, 752, 699. 1H NMR (300
MHz, CDCl3) (323 K): δ 7.33 (5H, s), 5.89 (1H, d, J ) 11.0 Hz),
5.28 (1H, d, J ) 9.8 Hz), 5.18 (2H, s), 5.07 (1H, d, J ) 11.0 Hz),
4.18 (1H, dq, J ) 6.0 and 9.1 Hz), 2.17 (3H, s), 1.35 (3H, d, J )
6.2 Hz). 13C NMR (75 MHz, CDCl3) (323 K): δ 169.4, 166.5,
153.8, 135.4, 128.7, 128.6, 128.2, 71.2, 70.5, 68.6, 51.1, 20.3,
18.4.
(4R,5S)-N-Benzyloxycarbonyl-4-phenyl-5-methyl-1,3-oxazinan-
6-one 15 and (4S)-N-Benzyloxycarbonyl-4-phenyl-5,5-dimethyl-
1,3-oxazinan-6-one 19. The oxazinanone 6 (0.5 mmol) was
transformed according to General Procedure B using KHMDS (0.5
M in toluene) as the base and a 4:1 mixture of THF/HMPA as the
solvent to afford the starting material 6 (17% recovery), and the
oxazinanone 15 was isolated as a white solid (55% yield). Found:
M + H, 326.1390; C19H19NO4 requires M + H, 326.1392. Mp 127-
131 °C. [R]20D +75.1 (c 3.0, CH2Cl2). νmax(KBr)/cm-1 3034, 2933,
1
1761, 1714, 1409, 1256, 1007, 699. H NMR (300 MHz, CDCl3)
(323 K): δ 7.33-7.07 (10H, m), 6.10 (1H, d, J ) 9.0 Hz), 5.43
(1H, d, J ) 10.7 Hz), 5.08 and 5.01 (each 1H, d, JAB ) 12.2 Hz),
4.56 (1H, d, J ) 9.7 Hz), 2.96 (1H, dq, J ) 11.3 and 6.1 Hz), 1.14
(3H, d, J ) 6.3 Hz). 13C NMR (75 MHz, CDCl3): δ 171.9, 154.3,
140.4, 135.5, 128.9, 128.5, 128.4, 128.3, 128.0, 126.8, 72.9, 68.3,
61.1, 41.2, 10.8.
The oxazinanone 19 was isolated as a colorless solid (10% yield).
Found: M + H, 340.1552; C20H21NO4 requires M + H, 340.1549.
Mp 87-90 °C. [R]20 0.0 (c 0.1, CH2Cl2). νmax(KBr)/cm-1 3033,
D
1
2981, 1752, 1713, 1409, 1248, 1102, 1023, 749, 701. H NMR
(300 MHz, CDCl3) (323 K): δ 7.31-7.21 (10H, m), 5.93 (1H, d,
J ) 9.6 Hz), 5.43 (1H, d, J ) 9.7 Hz), 5.16-5.04 (3H, m), 1.46
(3H, s), 1.07 (3H, s). 13C NMR (75 MHz, CDCl3) (323 K): δ 173.9,
153.7, 136.9, 135.6, 128.8, 128.5, 128.4, 128.0, 73.2, 68.2, 63.9,
42.4, 27.0, 22.8.
(4S,5S)-N-Benzyloxycarbonyl-4-benzyl-5-methyl-1,3-oxazinan-
6-one 16. The oxazinanone 7 (0.5 mmol) was transformed according
to General Procedure B using KHMDS (0.5 M in toluene) as the
base and a 4:1 mixture of THF/HPMA as the solvent to afford the
starting material 7 (35% recovery), and trace amounts of the 5,5-
disubstituted oxazinanone and the oxazinanone 16 were isolated
as a clear colorless oil (35% yield). Found: M + H, 340.1546;
C20H21NO4 requires M + H 340.1540. [R]20D +138.4 (c 0.96, CH2-
Cl2). νmax(NaCl)/cm-1 3030, 2942, 1760, 1713, 1413, 1249, 1137,
General Procedure C. The oxazinanone (0.5 mmol) was
dissolved in dry THF (4 mL), and the solution was cooled to -78
°C under an argon atmosphere. NaHMDS (0.4 M in hexanes, 0.52
mmol) was added dropwise with stirring, and then the solution was
allowed to warm to -50 °C over 40 min. MoOPH (0.65 mmol)
was added in six portions over 30 min, while the solution was
allowed to warm to -40 °C. The reaction was maintained at this
1
1009, 700. H NMR (300 MHz, CDCl3) (323 K): δ 7.39-7.06
(5H, m), 5.66 (1H, br s), 5.17 (2H, s), 4.27 (1H, d, J ) 10.7 Hz),
4.04 (1H, br s), 3.24-3.20 (1H, m), 2.84 (1H, dd, J ) 3.2 and
14.0 Hz), 2.60 (1H, dq, J ) 6.5 and 10.3 Hz), 1.33 (3H, d, J ) 6.6
J. Org. Chem, Vol. 72, No. 9, 2007 3349

Sleebs and Hughes
temperature for 2 h. The solution was then allowed to warm to
-30 °C and was quenched with saturated sodium sulfite solution
(5 mL). The solution was diluted with ethyl acetate (20 mL), and
it was then washed with water (20 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure give in
an oily residue. The residue was subjected to column chromatog-
raphy, eluting with 10-25% ethyl acetate/hexane, to afford starting
material and product.
oil (19% yield). Found: M + H, 296.1497; C15H21NO5 requires M
+ H, 296.1498. [R]20 +77.2 (c 0.18, CH2Cl2). νmax(NaCl)/cm-1
D
3440, 3030, 2943, 1768, 1713, 1454, 1250, 1106, 990, 742, 699.
1H NMR (300 MHz, CDCl3) (323 K): δ 7.36-7.10 (10H, m), 5.71
(1H, d, J ) 9.9 Hz), 5.21 (2H, s), 4.25 (1H, d, J ) 9.9 Hz), 4.14-
4.10 (2H, m), 3.30 (1H, dd, J ) 12.5 and 2.3 Hz), 3.02 (1H, dd, J
) 14.0 and 3.2 Hz). 13C NMR (75 MHz, CDCl3) (323 K): δ 172.3,
153.8, 135.0, 134.5, 130.0, 128.3, 128.2, 127.9, 126.8, 72.0, 68.6,
65.8, 56.7, 35.7.
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-4-methyl-1,3-oxazi-
nan-6-one 25. The oxazinanone 3 (0.5 mmol) was transformed
according to General Procedure C and gave starting material 3 (5%
recovery) and the oxazinanone 25 in a 6:1 (trans:cis) diastereoi-
someric ratio as a clear colorless oil (40% yield). The trans isomer
25 was isolated as a chromatographically inseparable mixture of
cis and trans diastereoisomers (differentiated from the cis NMR
data). Found: M + H, 266.1027; C13H15NO5 requires M + H,
266.1028. νmax(NaCl)/cm-1 3425, 3034, 2977, 1764, 1713, 1415,
1244, 1100, 993, 752, 698. 1H NMR (300 MHz, CDCl3) (325 K):
δ 7.34 (5H, s), 5.91 (1H, d, J ) 10.8 Hz), 5.17 (2H, s), 5.98 (1H,
d, J ) 10.8 Hz), 4.13 (1H, d, J ) 9.4 Hz), 3.89 (1H, dq, J ) 6.1
and 9.3 Hz), 3.30 (1H, br s), 1.46 (3H, d, J ) 6.2 Hz). 13C NMR
(75 MHz, CDCl3) (323 K): δ 172.9, 154.0, 135.4, 128.7, 128.6,
128.2, 71.1, 70.8, 68.4, 53.9, 18.8. An insufficient amount of the
cis isomer was obtained for analysis.
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-4-isopropyl-1,3-ox-
azinan-6-one 28. The oxazinanone 4 (0.5 mmol) was transformed
according to General Procedure C and afforded starting material 4
(7% recovery) and the hydroxy product 28 as a clear colorless oil
(44% yield). Found: M + H, 294.1341; C15H19NO5 requires M +
H, 294.1341. [R]20D +71.5 (c 1.1, CH2Cl2). νmax(NaCl)/cm-1 3446,
2965, 1768, 1714, 1410, 1254, 1105, 984, 746, 698. 1H NMR (300
MHz, CDCl3) (323 K): δ 7.34 (5H, s), 5.94 (1H, d, J ) 10.8 Hz),
5.17 (2H, s), 4.88 (1H, d, J ) 10.8 Hz), 4.33 (1H, d, J ) 8.5 Hz),
3.87 (1H, dd, J ) 5.6 and 8.0 Hz), 3.42 (1H, br s), 2.16-2.07 (1H,
m), 1.05 (1H, d, J ) 6.9 Hz), 0.99 (1H, d, J ) 6.9 Hz). 13C NMR
(75 MHz, CDCl3) (323 K): δ 173.5, 154.9, 135.3, 128.5, 128.4,
128.1, 72.8, 68.6, 68.0, 62.0, 32.1, 18.6, 18.1.
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-(4R)-sec-butyl-1,3-
oxazinan-6-one 33. The oxazinanone 9 (0.5 mmol) was transformed
according to General Procedure C and yielded starting material 9
(7% recovery) and the 5-hydroxy product 33 as a clear colorless
oil (39% yield). Found: M + H, 308.1498; C16H21NO5 requires M
+ H, 308.1489. [R]20 +95.9 (c 1.7, CH2Cl2). νmax(NaCl)/cm-1
D
1
3450, 2965, 2879, 1769, 1713, 1415, 1246, 1111, 991, 698. H
NMR (300 MHz, CDCl3) (323 K): δ 7.32 (5H, s), 5.91 (1H, d, J
) 10.7 Hz), 5.17 and 5.14 (each 1H, d, JAB ) 12.2 Hz), 4.89 (1H,
d, J ) 10.8 Hz), 4.40 (1H, d, J ) 8.6 Hz), 3.93 (1H, dd, J ) 5.1
and 7.8 Hz), 2.00-1.17 (3H, m), 1.02 (3H, d, J ) 6.9 Hz), 0.88
(3H, t, J ) 7.3 Hz). 13C NMR (75 MHz, CDCl3) (323 K): δ 173.7,
154.7, 135.3, 128.5, 128.3, 128.0, 72.8, 68.5, 67.4, 60.8, 39.0, 25.4,
14.5, 11.7.
(4S,5R)-N-Benzyloxycarbonyl-5-(4-nitrobenzoyloxy)-4-(2-me-
thylpropyl)-1,3-oxazinan-6-one 34. The 5-hydroxy oxazinanone
30 (0.3 mmol), triphenylphosphine (0.6 mmol) and p-nitrobenzoic
acid (0.6 mmol) were dissolved in dry THF (4 mL) under an argon
atmosphere. At 0 °C, diethyl azodicarboxylate (0.57 mmol) was
added dropwise while stirring. The solution was allowed to warm
to room temperature, and it was stirred at this temperature for 20
h. The mixture was diluted with ethyl acetate (10 mL) and washed
with saturated sodium hydrogen bicarbonate solution. The organic
layer was dried (MgSO4) and concentrated in vacuo. A majority
of the triphenylphosphine oxide byproduct was removed by
crystallization, using 75% ether/hexane as the crystallizing solvent,
and filtering off the solid. The filtrate was concentrated under
vacuum. The residual mixture was applied to a silica column,
resulting in degradation of the product. A short chromatography
column was performed eluting with 30% ethyl acetate/hexane and
afforded the benzoate 34 as a clear colorless oil (39% yield).
Found: M + H, 457.1608; C23H24N2O8 requires M + H, 457.1611.
[R]20D +50.8 (c 0.39, CH2Cl2). νmax(NaCl)/cm-1 2960, 2870, 1765,
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-4-isobutyl-1,3-oxazi-
nan-6-one 30. The oxazinanone 5 (0.5 mmol) was transformed
according to General Procedure C and gave starting material 5 (5%
recovery) and the oxazinanone product 30 as a clear colorless oil
(46% yield). Found: M + H, 308.1492; C16H21NO5 requires M +
H, 308.1498. [R]20D +44.2 (c 0.94, CH2Cl2). νmax(NaCl)/cm-1 3437,
2957, 2871, 1765, 1714, 1414, 1249, 1103, 985, 753, 698. 1H NMR
(300 MHz, CDCl3) (323 K): δ 7.33 (5H, s), 5.88 (1H, d, J ) 10.8
Hz), 5.18 and 5.15 (2H, q, JAB ) 12.1 Hz), 4.92 (1H, d, J ) 10.8
Hz), 4.12 (1H, d, J ) 8.0 Hz), 4.04 (1H, dt, J ) 6.4 and 6.9 Hz),
1
1725, 1529, 1410, 1350, 1244, 1119, 738. H NMR (300 MHz,
CDCl3) (323 K): δ 8.32-8.20 (4H, m), 7.37 (5H, s), 6.00 (1H, d,
J ) 9.8 Hz), 5.72 (1H, d, J ) 6.3 Hz), 5.26 and 5.23 (each 1H, d,
JAB ) 12.3 Hz), 5.16 (1H, d, J ) 10.4 Hz), 4.87 (1H, br s), 1.72-
1.60 (3H, m), 0.96 (3H, d, J ) 3.0 Hz), 0.89 (3H, d, J ) 2.8 Hz).
13C NMR (75 MHz, CDCl3) (323 K): δ 165.4, 163.1, 154.0, 151.2,
135.2, 134.2, 131.1, 128.8, 128.3, 123.7, 72.0, 69.2, 69.0, 51.0,
35.3, 24.3, 23.2, 21.4.
3.53 (1H, br s), 1.82-1.52 (3H, m), 0.90 (6H, d, J ) 6.4 Hz). 13
C
NMR (75 MHz, CDCl3) (323 K): δ 173.0, 154.5, 135.3, 128.6,
128.5, 128.3, 71.6, 71.2, 68.6, 56.0, 44.1, 24.2, 22.9, 22.6.
General Procedure D. Reductive Cleavage of the Oxazi-
nanones. To the oxazinanone (1 mmol) and triethylsilane (3 mmol)
in dichloromethane (min. vol.) was added trifluoroacetic acid (50:
50, v/v), and the solution was stirred for 72 h (monitored by TLC).
Toluene (15 mL) was added to the solution, and it was then
evaporated in vacuo. This process was repeated three times to
remove any trace of trifluoroacetic acid. The residue was taken up
in ether (30 mL) and extracted with saturated sodium bicarbonate
solution (20 mL × 3). The aqueous layer was adjusted to pH 2
with dilute hydrochloric acid solution and extracted with ethyl
acetate (25 mL × 3). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. The resulting
residue was subjected to silica chromatography, eluting with a
mixture of ethyl acetate and methanol, to afford the N-methyl
residue.
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-4-phenyl-1,3-oxazi-
nan-6-one 31. The oxazinanone 6 (0.5 mmol) was transformed
according to General Procedure C and furnished starting material
6 (20% recovery) and the oxazinanone product 31 as a clear
colorless oil (23% yield). Found: M + H, 328.1181; C18H17NO5
requires M + H, 328.1185. [R]20D 0.0 (c 1.0, CH2Cl2). νmax(NaCl)/
cm-1 2430, 3066, 3034, 1767, 1712, 1413, 1252, 1107, 971, 733,
1
698. H NMR (300 MHz, CDCl3) (323 K): δ 7.35-7.06 (10H,
m), 6.16 (1H, d, J ) 10.4 Hz), 5.26 (1H, d, J ) 10.8 Hz), 5.12 and
5.06 (each 1H, d, JAB ) 12.3 Hz), 4.84 (1H, d, J ) 9.1 Hz), 4.48
(1H, d, J ) 9.5 Hz), 3.44 (1H, br s). 13C NMR (75 MHz, CDCl3)
(323 K): δ 172.3, 154.1, 139.1, 135.2, 128.9, 128.5, 128.4, 127.8,
126.1, 72.6, 70.7, 68.5, 60.8.
(4S,5S)-N-Benzyloxycarbonyl-5-hydroxy-4-benzyl-1,3-oxazi-
nan-6-one 32. The oxazinanone 7 (0.5 mmol) was transformed
according to General Procedure C and yielded starting material 7
(6% recovery) and the oxazinanone product 32 as a clear colorless
N-Methyl-R,â-disubstituted-â-amino acids. (2R,3S)-N-Ben-
zyloxycarbonyl-3-methylamino-2-methylbutanoic Acid 37. The
oxazinanone 10 (1 mmol) was transformed according to General
3350 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of R-Methyl and R-Hydroxy-â-Amino Acids
Procedure D, affording the acid 37 as a white solid (56% yield).
Found: M + H, 266.1393; C14H19NO4 requires M + H, 366.1392.
(3S)-N-Benzyloxycarbonyl-3-aminobutan-1-benzylamide 44.
The oxazinanone 3 (0.5 mmol) was dissolved in dichloromethane
(4 mL), and benzyl amine (1.05 mmol) was added. The solution
was allowed to stir at room temperature for 20 h. The reaction
mixture was washed successively with 1 M hydrochloric acid (4
mL) and then water (4 mL). The organic layer was dried (MgSO4)
and concentrated in vacuo. Column chromatography was performed
on the resulting oil, eluting with 70% ethyl acetate/hexane, to afford
the amide 44 as a clear colorless oil (87% yield). Found: M + H,
Mp 86-88 °C. [R]20 +9.6 (c 0.21, CH2Cl2). νmax(NaCl)/cm-1
D
1
3033, 2980, 1732, 1698, 1682, 1455, 1329, 1139, 698. H NMR
(300 MHz, CDCl3) (323 K): δ 7.31 (5H, s), 5.11 (2H, s), 4.27
(1H, dq, J ) 6.8 and 9.3 Hz), 2.82 (3H, s), 2.75 (1H, br s), 1.19
(3H, d, J ) 5.9 Hz), 1.16 (3H, d, J ) 6.1 Hz). 13C NMR (75 MHz,
CDCl3) (rotamers): δ 179.6, 156.2, 136.8, 128.4, 127.8, 127.7, 67.3,
67.0, 54.5, 54.2, 43.6, 43.3, 29.6, 15.6, 15.2, 14.7.
(2R,3S)-N-Benzyloxycarbonyl-3-methylamino-2,4-dimethyl-
pentanoic Acid 38. The oxazinanone 13 (1 mmol) was transformed
according to General Procedure D, furnishing the acid 38 as a clear
colorless oil (65% yield). Found: M + H, 294.1705; C16H23NO4
327.1710; C19H22N2O3 requires M + H, 327.1709. [R]20 +16.7
D
(c 1.5, CH2Cl2). νmax(NaCl)/cm-1 3314, 3031, 2973, 2934, 1698,
1
1650, 1549, 1424, 1341, 1258, 1028, 698. H NMR (300 MHz,
CDCl3) (325 K): δ 7.29-7.16 (10H, m), 6.55 (1H, br s), 5.09 and
5.04 (each 1H, d, JAB ) 12.8 Hz), 4.87-4.33 (2H, m), 4.28 (2H,
br s), 2.85-2.32 (2H, m), 1.22-1.11 (3H, m). 13C NMR (75 MHz,
CDCl3) (rotamers) (325 K): δ 171.2, 155.6, 138.4, 138.1, 136.3,
136.1, 128.45, 128.41, 128.0, 127.9, 127.8, 127.6, 127.5, 127.2,
127.1, 74.8, 70.0, 67.4, 67.1, 50.3, 43.4, 42.3, 19.1.
requires M + H, 294.1705. [R]20 -29.0 (c 0.15, CH2Cl2). νmax
-
D
(NaCl)/cm-1 3032, 2966, 1733, 1698, 1761, 1456, 1340, 1162, 697.
1H NMR (300 MHz, CDCl3) (323 K): δ 7.31 (5H, s), 5.12 (2H,
s), 4.04 (1H, br s), 2.96-2.85 (1H, m), 2.81 (3H, s), 2.17-2.10
(1H, m), 1.21-1.15 (3H, m), 1.05-0.96 (3H, m), 0.88-0.84 (3H,
m). 13C NMR (75 MHz, CDCl3) (rotamers): δ 179.3, 157.5, 157.1,
137.1, 136.9, 128.4, 128.0, 127.9, 127.6, 67.4, 67.2, 64.5, 40.4,
31.1, 28.6, 28.4, 20.3, 19.5, 19.2, 14.8, 14.6.
(3S)-3-Aminobutanoic Acid 47. The oxazinanone 3 (0.5 mmol)
was dissolved in methanol (5 mL), and 10% palladium-on-carbon
catalyst (0.05 mmol) was added. The mixture was stirred at room
temperature for 20 h under an atmosphere of hydrogen. The mixture
was filtered through Celite, and the filtrate was concentrated in
vacuo. The resulting residue was triturated with ethanol to furnish
the amino acid 47 as a white solid (85% yield). The data were
identical to that previously described.47
(2R,3S)-N-Benzyloxycarbonyl-3-methylamino-2,5-dimethyl-
hexanoic Acid 39. The oxazinanone 14 (1 mmol) was transformed
according to General Procedure D, affording the N-methyl amino
acid 39 as a clear colorless oil (70% yield). Found: M + H,
308.1862; C17H25NO4 requires M + H, 308.1862. [R]20D -22.0 (c
0.14, CH2Cl2). νmax(NaCl)/cm-1 2956, 1706, 1664, 1447, 1326,
1161, 696. 1H NMR (300 MHz, CDCl3): δ 7.30 (5H, s), 5.11 (2H,
s), 4.29 (1H, br s), 2.77 (3H, s), 2.67 (1H, br s), 1.51-0.91 (6H,
m), 0.91-0.77 (6H, m). 13C NMR (75 MHz, CDCl3) (rotamers):
δ 178.6, 178.4, 156.7, 137.2, 136.8, 128.4, 128.1, 127.8, 127.6,
67.4, 67.1, 57.5, 43.2, 38.6, 38.4, 30.1, 24.9, 24.6, 23.7, 21.6, 21.4,
14.8.
(3R)-N-Benzyloxycarbonyl-3-aminophenylpropanoic Acid 48.
The oxazinanone 6 (0.3 mmol) was dissolved in methanol (3.5 mL)
at 0 °C, and a 4 M lithium hydroxide solution (2.5 mL) was added.
The mixture was stirred for 10 min while warming to room
temperature, and the methanol was removed under vacuum. The
aqueous solution was washed with ether (5 mL), the aqueous layer
was acidified with 1 M hydrochloric acid solution, and then it was
extracted with ethyl acetate (3 × 5 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to afford
the acid 48 as a white solid (89% yield). This compound had data
identical to that previously described.48
(2R,3R)-N-Benzyloxycarbonyl-3-methylamino-2-methyl-3-
phenylpropanoic Acid 40. The oxazinanone 15 (1 mmol) was
transformed according to General Procedure D, yielding the acid
40 as a clear colorless oil (71% yield). Found: M + H, 328.1554;
C19H21NO4 requires M + H, 328.1549. [R]20D +57.9 (c 1.7, CH2-
Cl2). νmax(NaCl)/cm-1 3033, 2982, 1713, 1681, 1455, 1329, 1160,
1
703. H NMR (300 MHz, CDCl3) (325 K): δ 10.64 (1H, br s),
(3S)-Ethyl-N-benzyloxycarbonyl-3-aminobutanoate 49. The
oxazinanone 3 (1 mmol) was dissolved in dry ethanol (10 mL),
and dry sodium hydrogen carbonate (2.5 mmol) was added under
an inert atmosphere. The solution was refluxed for 20 h. The solvent
was removed in vacuo, the residue was taken up in ethyl acetate
(20 mL), and it was then washed with water (20 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pressure.
The resulting residue was purified by column chromatography,
eluting with 35% ethyl acetate/hexane. The ester 49 was isolated
as a clear colorless oil (67% yield). Found: M + H, 266.1392;
C14H19NO4 requires M + H, 266.1392. νmax(NaCl)/cm-1 3344,
2980, 2937, 1731, 1530, 1245, 1058, 738, 697. 1H NMR (300 MHz,
CDCl3): δ 7.31 (5H, s), 5.26 (1H, br s), 5.06 (2H, s), 4.14-4.07
(3H, m), 2.48 (2H, d, J ) 5.38 Hz), 1.24-1.20 (6H, m). 13C NMR
(75 MHz, CDCl3): δ 171.2, 155.4, 136.5, 128.4, 127.9, 66.4, 60.4,
44.0, 40.5, 20.3, 14.0.
7.32 (10H, s), 5.40 (1H, d, J ) 11.4 Hz), 5.15 (2H, s), 3.43 (1H,
br s), 2.84 (3H, s), 1.12 (3H, d, J ) 6.7 Hz). 13C NMR (75 MHz,
CDCl3) (323 K): δ 179.2, 156.3, 136.8, 136.7, 128.6, 128.3, 128.0,
127.7, 67.4, 62.3, 40.6, 29.8, 15.5.
(2R,3R)-N-Benzyloxycarbonyl-3-methylamino-2-methyl-4-
phenylbutanoic Acid 41. The oxazinanone 16 (1 mmol) was
transformed according to General Procedure D, affording the acid
41 as a clear colorless oil (54% yield). Found: M + H, 342.1712;
C20H23NO4 requires M + H, 342.1705. [R]20D -58.0 (c 0.2, CH2-
Cl2). νmax(NaCl)/cm-1 3029, 2977, 1725, 1703, 1677, 1452, 1343,
1
1146, 737, 698. H NMR (300 MHz, CDCl3) (323 K): δ 7.34-
7.07 (10H, m), 5.26-4.88 (2H, m), 4.40-4.13 (1H, m), 3.14-
2.58 (6H, m), 1.29 (3H, d, J ) 6.8 Hz). 13C NMR (75 MHz, CDCl3)
(rotamers) (323 K): δ 179.1, 178.9, 156.4, 156.1, 138.2, 138.0,
137.1, 136.7, 129.0, 128.4, 128.4, 127.9, 127.8, 127.6, 126.8, 126.7,
126.5, 67.3, 66.8, 63.1, 61.5, 43.1, 42.6, 35.7, 35.2, 33.6, 15.2.
(2R,3S)-N-Benzyloxycarbonyl-3-methylamino-2-hydroxy-4-
methylpentanoic Acid 42. The oxazinanone 28 (1 mmol) was
transformed according to General Procedure D and afforded the
N-methyl amino acid 42 as a clear colorless oil (63% yield).
Found: M + H, 296.1497; C15H21NO5 requires M + H, 296.1498.
[R]20D -1.3 (c 0.39, CH2Cl2). νmax(NaCl)/cm-1 3432, 2965, 2876,
1729, 1673, 1456, 1312, 1138, 975, 736, 697. 1H NMR (300 MHz,
CDCl3) (323 K): δ 7.33 (5H, s), 5.15 (2H, s), 4.44-4.36 (1H, m),
3.75 (1H, br s), 2.97-2.90 (3H, m), 2.43-4.30 (1H, m), 0.95 (3H,
d, J ) 6.5 Hz), 0.90 (3H, d, J ) 6.5 Hz). 13C NMR (75 MHz,
CDCl3) (323 K): δ 174.0, 158.3, 136.3, 128.6, 128.2, 127.7, 73.5,
72.5, 68.6, 67.9, 34.9, 26.4, 20.2, 19.5.
(3S)-3-Aminobutanoic Acid Hydrochloride 52. To the oxazi-
nanone 3 (1 mmol) dissolved in dioxane (10 mL) was added 6 M
hydrochloric acid solution (10 mL). The solution was refluxed for
4 h, and the solution was cooled to room temperature. The solvent
was evaporated to dryness in vacuo, and the resulting residue was
dissolved in a minimal volume of isopropanol. Diethyl ether
(47) Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach, D. J. Org. Chem.
1992, 57, 2396-2398.
(48) Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32,
651-657.
J. Org. Chem, Vol. 72, No. 9, 2007 3351

Sleebs and Hughes
was added to the alcoholic solution, and a precipitate formed. The
precipitate was filtered off and washed with diethyl ether to give
the salt 52 as a white solid (65%). This compound had data identical
to that previously described.49
Acknowledgment. The authors thank La Trobe University
for scholarship funding of B.E.S.
Supporting Information Available: General experimental
procedures, including spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(49) Estermann, H.; Seebach, D. HelV. Chim. Acta 1988, 71, 1824-
1839.
JO0700326
3352 J. Org. Chem., Vol. 72, No. 9, 2007