Alkylation studies of N-protected-5-substituted morpholin-3-ones. A stereoselective approach to novel methylene ether dipeptide isosteres

Article abstract of DOI:10.1021/jo960496w

We have developed a versatile new synthesis of the Ψ[CH₂O] pseudopeptides from N-protected-5-substituted morpholin-3-ones. The morpholin-3-ones are prepared in two steps from the corresponding amino alcohols by treatment with ethyl chloroacetate, followed by protection of the amide. We found that direct alkylation of the protected morpholin-3-ones gives the expected alkylation product where the electrophile approaches from the face opposite to the existing side chain (derived from the amino alcohol). If an S amino alcohol is used, this procedure results in the formation of the (S,R) Ψ[CH₂O] dipeptide. Alternatively, the (S,S) Ψ[CH₂O] dipeptide can be obtained if the protected morpholin-3-one enolate is quenched with an aldehyde and the aldol product is dehydrated and reduced. We have explored an alkylation/deprotonation/kinetic protonation scheme which is also amenable to the preparation of (S,S) pseudodipetides. It is, of course, possible to obtain the corresponding (R,R) and (S,R) Ψ[CH₂C] dipeptides by simply selecting the appropriate amino alcohols and reaction conditions. Finally, we have established that this method is general and can be applied to the preparation of numerous Ψ[CH₂C] dipeptides which were previously unavailable by existing methods.

Full text of DOI:10.1021/jo960496w

4990
J . Org. Chem. 1996, 61, 4990-4998
Alk yla tion Stu d ies of N-P r otected -5-su bstitu ted Mor p h olin -3-on es.
A Ster eoselective Ap p r oa ch to Novel Meth ylen e Eth er Dip ep tid e
Isoster es
Bryan H. Norman* and J ulian S. Kroin
Eli Lilly and Co., Cancer Research, Lilly Corporate Center, Indianapolis, Indiana 46285
Received March 13, 1996X
We have developed a versatile new synthesis of the Ψ[CH2O] pseudopeptides from N-protected-
5-substituted morpholin-3-ones. The morpholin-3-ones are prepared in two steps from the
corresponding amino alcohols by treatment with ethyl chloroacetate, followed by protection of the
amide. We found that direct alkylation of the protected morpholin-3-ones gives the expected
alkylation product where the electrophile approaches from the face opposite to the existing side
chain (derived from the amino alcohol). If an S amino alcohol is used, this procedure results in the
formation of the (S,R) Ψ[CH2O] dipeptide. Alternatively, the (S,S) Ψ[CH2O] dipeptide can be
obtained if the protected morpholin-3-one enolate is quenched with an aldehyde and the aldol product
is dehydrated and reduced. We have explored an alkylation/deprotonation/kinetic protonation
scheme which is also amenable to the preparation of (S,S) pseudodipetides. It is, of course, possible
to obtain the corresponding (R,R) and (S,R) Ψ[CH2O] dipeptides by simply selecting the appropriate
amino alcohols and reaction conditions. Finally, we have established that this method is general
and can be applied to the preparation of numerous Ψ[CH2O] dipeptides which were previously
unavailable by existing methods.
In tr od u ction
opening reaction. An additional drawback to this ap-
proach is that even in the presence of a large excess of
alkoxide, only moderate yields were obtained. Another
approach which has been used to prepare Ψ[CH2O]
dipeptides is the displacement of R-halo esters 6 by
protected amino alcohols 5 (approach 2).5 Unfortunately,
this scheme was only successful for the simplest R-halo
esters or acids. In 1986, Nicolaides and co-workers
reported that the Williamson ether route illustrated
above could be carried out with greater success if the
critical carbon-oxygen bond was formed intramolecularly
from substrates such as 7 (approach 3).6 Then in 1987,
TenBrink further investigated this method and described
the approach in greater detail.7 It was shown that the
intermediate morpholin-3-one 8 could be readily opened
under acidic conditions to give the desired Ψ[CH2O]
The isosteric replacement of an amide bond in a small
peptide can lead to a peptidomimetic which retains the
ability to bind to its target receptor but has enhanced
metabolic stability. This approach has been used to
address numerous disease targets and offers the medici-
nal chemist attractive opportunities for converting pep-
tide-based leads into useful therapeutics.1 Although the
reduced amide isostere Ψ[CH2NH] (1) has been employed
frequently in approaches to peptide mimics,2 the meth-
ylene ether isostere Ψ[CH2O] (2)3 has not been fully
exploited. This could be due, in part, to the fact that
(1) The Annual Reports in Medicinal Chemistry has published
several recent reviews on disease targets which have been addressed
by peptidomimetics. Greenlee, W. J .; Siegl, P. K. S. In Annual Reports
in Medicinal Chemistry; Bristol, J . A., Ed.; Acedemic Press: San Diego,
1992; Vol. 27, p 59 (ACE and Renin Inhibitors). Blackburn, B. K.;
Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J .
A., Ed.; Acedemic Press: San Diego, 1993; Vol. 28, p 79 (Glycoprotein
IIb/IIIa Antagonists). Thaisrivongs, S. In Annual Reports in Medicinal
Chemistry; Bristol, J . A., Ed.; Acedemic Press: San Diego, 1994; Vol.
29, p 133 (HIV Protease Inhibitors). Bolton, G. L.; Sebolt-Leopold, J .
S.; Hodges, J . C. In Annual Reports in Medicinal Chemistry; Bristol,
J . A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 165 (Ras
Farnesyltransferase Inhibitors) and references cited therein.
(2) Grahm, S. L.; deSolms, S. J .; Giuliani, E. A.; Kohl, N. E.; Mosser,
S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J .; Deana,
A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J . B.; Smith, R. L. J . Med.
Chem. 1994, 37, 725.
(3) Breton, P.; Monsigny, M.; Mayer, R. Int. J . Pep. Protein Res.
1990, 35, 346.
(4) Ho, M.; Chung, J . K. K.; Tang, N. Tetrahedron Lett. 1993, 34,
6513. Ho, M.; Uhrin, A.; Huang, M. Bioorg. Med. Chem. Lett. 1994, 4,
553.
(5) Ondetti, M.; Pluscec, J .; Weaver, E.; Williams, N.; Sabo, E.; Kocy,
O. In Proceedings of the Third American Peptide Symposium; Meien-
hofer, J ., Ed.; Ann Arbor, 1972; p 525.
(6) Nicolaides, E. D.; Tinney, F. J .; Kaltenbronn, J . S.; Repine, J .
T.; DeJ ohn, D. A.; Lunney, E. A.; Roark, W. H.; Marriott, J . G.; Davis,
R. E.; Voigtman, R. E. J . Med. Chem. 1986, 29, 959.
there are no general methods for the preparation of these
pseudopeptides (Scheme 1). The most straightforward
approach would depend upon a reaction between an
amino alcohol derivative (3) and an R-hydroxy ester 4 to
form the desired dipeptide isostere 2 (approach 1). This
approach has been studied recently by Ho, who has
shown that structures such as 3 typically form aziri-
dines.4 Ho has investigated aziridine ring opening with
simple primary alkoxides to give mixtures of ethers,
derived from a lack of regioselectivity in the aziridine ring
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(7) TenBrink, R. E. J . Org. Chem. 1987, 52, 418.
S0022-3263(96)00496-3 CCC: $12.00 © 1996 American Chemical Society

Alkylation Studies of N-Protected Morpholin-3-ones
J . Org. Chem., Vol. 61, No. 15, 1996 4991
Sch em e 1
Sch em e 2
available amino alcohols and ethyl chloroacetate using
the method of Clarke.10 We initially explored the alky-
lation of 12a , for we felt that if a selective alkylation were
possible, this would be a preferred route to Ψ[CH2O]
dipeptides since 2, 5-disubstituted morpholin-3-ones are
suitable precursors to these dipeptides. Additionally, we
felt that this approach held promise given the successes
of Williams11 and others12 in the selective alkylations of
the related morpholin-2-ones. Our initial efforts to
alkylate 12a (2 equiv of LDA or LHMDS, PhCH2Br)
resulted in significant N-alkylation. We decided that we
would simply block that position as the benzylamide and
proceed. We subsequently discovered that the benzyl
group could not be removed using reasonable methods
and turned to p-methoxybenzyl (PMB), since it could be
easily removed using ceric ammonium nitrate (CAN).
Treatment of the 5-substituted morpholin-3-ones with
sodium hydride, followed by the addition of p-methoxy-
benzyl chloride (PMBCl), resulted in the preparation of
the N-protected morpholin-3-ones 13a -e (Scheme 2).
With these substrates in hand, it was our hope that
selective alkylations would occur, giving us easy access
to Ψ[CH2O]dipeptides.
dipeptide. However, this method provides a limited
number of Ψ[CH2O] dipeptides and relies on a synthetic
approach where the side chain functionality is deter-
mined at an early stage in the synthesis. Additionally,
this method cannot be used for most X-Ψ[CH2O]-Phe
dipeptides due to an undesired dehydrohalogenation
which occurs during the formation of the important ether
bond. Thus, substrates such as 9 give only products
corresponding to 10, and not the desired morpholin-3-
one 11. Since we required a more general route to these
The alkylation of 5-sec-butylmorpholin-3-one 13a (de-
rived from (S) isoleucinol) proceeded smoothly using LDA
as the base in THF. We initially chose to study benzyl
bromide as our electrophile since we were interested in
the preparation of pseudopeptides where the second
residue corresponded to phenylalanine. The alkylation
proceeded in 84% yield with good diastereospecificity (8:
1) to yield the 2-benzyl-5-sec-butyl-4-(4-methoxybenzyl)-
3-morpholinone (14a ) (Scheme 3, Table 1). The PMB
group could be easily removed by treatment of 14a with
ceric ammonium nitrate (CAN) to give the expected N-H
morpholin-3-one 15.
In an effort to firmly establish the stereochemistry of
the alkylation product, we decided to study the alkylation
of 13a with methyl iodide. We used the same alkylation
conditions to prepare the 2-methyl-substituted morpholi-
nones 23 and 24, as an inseparable 3:1 mixture. The
mixture was deprotected using CAN to give a 3:1 mixture
dipeptide isosteres and were specifically interested in
preparing the phenylalanine derivatives, we investigated
the possibility of introducing the side chain funtionality
into the morpholin-3-ones via selective alkylation reac-
tions.8,9 We felt that this approach would give us access
to previously unavailable Ψ[CH2O] dipeptides and could
be more amenable to preparing multiple pseudopeptide
analogs. Additionally, it was hoped that this approach
could provide all of the possible Ψ[CH2O] dipeptide
diasteromers.
Resu lts a n d Discu ssion
(10) Clarke, F. H. J . Org. Chem. 1962, 27, 3251.
(11) Williams, R. M.; Im, M. N. Tetrahedron Lett. 1988, 29, 6075.
Williams, R. M.; Im, M. N. J . Am. Chem Soc. 1991, 113, 9276.
(12) Dellaria, J . F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29,
6079. Dellaria, J . F. J . Org.Chem. 1989, 54, 3916. Ornstein, P. L. J .
Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S.
Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L.
Tetrahedron Lett. 1992, 33, 1577.
Our method begins with the preparation of the 5-sub-
stituted morpholin-3-ones 12a -e from commercially
(8) Norman, B. H.; Kroin, J . S. Tetrahedron Lett. 1995, 36, 4151.
(9) Anthony, N. J .; Gomez, R. P.; Holtz, W. J .; Murphy, J . S.; Ball,
R. G.; Lee, T. Tetrahedron Lett. 1995, 36, 3821.

4992 J . Org. Chem., Vol. 61, No. 15, 1996
Norman and Kroin
Sch em e 3
Ta ble 1. Ster eoselective Mor p h olin -3-on e Alk yla tion s
Sch em e 4
a n d P r ep a r a tion of Ψ[CH2O] Dip ep tid es
substrate
R1
R2
product yielda selectivityb
13a
13a
13a
13a
13a
13c
13d
13e
14a
15
s-Bu
s-Bu
s-Bu
s-Bu
s-Bu
CH3
PhCH2
ChxCH2
PhCH2CH2
CH2dCHCH2
CH3(CH2)5
PhCH2
14a
14b
14c
14d
14e
14f
14g
14h
15
84
65
66
85
75
85
73
88
76
100
100
62c
68c
97
98
81
100
100
8:1
7:1
3:1
6:1
6:1
3:1
5:1
CH2Ph PhCH2
t-Bu
s-Bu
s-Bu
s-Bu
s-Bu
i-Bu
s-Bu
i-Bu
s-Bu
s-Bu
s-Bu
PhCH2
PhCH2
PhCH2
PhCH2
PhCHd
PhCHd
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
>20:1
16
17
16
13a
13b
18a
18b
19a
20
18a
18b
19a
19b
20
8:1
10:1
21
22
21
a
b
Isolated yields are reported. Selectivities were determined
on crude reaction mixtures using NMR integration techniques and
are reported only for reactions where the new chiral center was
formed. Single diastereomers were purified, and subsequent
chemistry did not compromise stereochemical integrity. c Yields
are for three steps (from 13a or 13b).
of N-H morpholin-3-ones 25 and 26, which could be
separated by flash chromatography. An independent
synthesis of the expected minor isomer 26 was ac-
complished via the intramolecular Williamson ether
synthesis, as described by TenBrink (Scheme 4).7 These
two materials were identical by 1H NMR. This study
shows that the 5-substituent is responsible for directing
the alkylation to the opposite face.
To show the generality of this reaction, we decided to
study alkylations of various substituted protected mor-
pholin-3-ones with several alkyl halides. The first set of
experiments which we performed to address this issue
focused on alkylation of 13a with several electrophiles.
Scheme 3 and Table 1 show that 13a can be alkylated in
good to excellent yields, giving selectivity ratios for the
desired products (14a -e) of 3:1 to 8:1. It should be
pointed out that alkylation occurred in all of the cases
which we tried, which included activated (benzyl bromide
and allyl bromide) as well as unactivated (cyclohexyl-
methyl bromide and phenethyl bromide) alkyl halides.
We also sought to show that facial selectivity could be
achieved using substituted morphlin-3-ones derived from
alanol (13c), phenylalanol (13d ), and tert-leucinol (13e).
Along with isoleucinol (13a ), we felt that this represented
a diverse collection of branched and unbranched sub-
strates. Each of these substrates was subjected to
standard alkylation conditions (LDA, -78 °C), using
benzyl bromide as the electrophile (Scheme 3, Table 1).
The selectivity ratios for the preparation of the products
(14a ,f-h ) followed an expected trend. The poorest
selectivity was observed for the alkylation of 13c (3:1),
which has the smallest and least branched substituent
at the 5-position (methyl). Accordingly, the greatest
selectivity was observed for the alkylation of 13e (>20:
1), the largest and most branched (tert-butyl) of the
substrates which we studied. This result supports our
belief that this side chain directs the stereochemistry of
the alkylation.
Although we initially assumed that the electrophile
would approach the enolate from the face opposite to the
side chain functionality, it occurred to us that the large
p-methoxybenzyl protecting group may be lying signifi-
cantly under the morpholinone ring, due to A1,2 strain.
This effect could negatively impact our selectivity ratios.
We knew that the protecting group had an influence on
the conformation of the morpholin-3-ones by directing the
side chain to a pseudoaxial conformation with concom-

Alkylation Studies of N-Protected Morpholin-3-ones
J . Org. Chem., Vol. 61, No. 15, 1996 4993
Sch em e 5
F igu r e 1. Conformational analysis of 12a and 13a .
mitant relief of A1,2 strain. This was evident from NMR
data obtained on the unprotected morpholin-3-one 12a
and the protected analog 13a (Figure 1). For 12a , the
vicinal coupling constants J 1,2 and J 1,3 were 7.4 and 4.0
Hz, respectively. For 13a , however, the vicinal coupling
constants J 1,2 and J 1,3 were 2.5 and 3.6 Hz, respectiviely.
This is consistant with a chairlike conformation of 12a ,
where the side chain is in a pseudoequatorial conforma-
tion. Additionally, these coupling constants support a
conformation of 13a where the sec-butyl group occupies
a pseudoaxial position, thus relieving A1,2 strain and
blocking this face of the molecule. This is consistent with
the findings of Anthony and co-workers9 in a closely
related system.
acidic reaction mixture before concentration, the corre-
sponding methyl esters 17 and 22 could be isolated
(Scheme 3, Table 1).
Although this alkylation approach was applicable to
the stereospecific synthesis of (2R,5S)-substituted mor-
pholin-3-ones, we had hoped to be able to prepare the
(2S,5S) analogs as well, since these would be precursors
to (S,S) Ψ[CH2O] dipeptide isosteres. Our initial efforts
to invert the stereochemistry at the 2-position via depro-
tonation/kinetic protonation using LDA were unsuccess-
ful. We therefore turned to an aldol approach to the
(2S,5S)-morpholin-3-ones where the diasteroselectivity
could be derived from a catalytic hydrogenation of the
dehydrated aldol product. This approach is shown in
Scheme 3. The lithium enolates of 13a and 13b were
quenched with benzaldehyde to provide the aldol prod-
ucts, as diastereomeric mixtures. These materials could
be dehydrated by initial preparation of the mesylate,
followed by heating in DMF at 150 °C in the presence of
triethylamine. This sequence provided benzylidenemor-
pholinones 18a and 18b as single olefin isomers13 (Z) in
good yield. Finally, catalytic hydrogenation gave the
expected (2S,5S)-morpholin-3-ones 19a and 19b in near
quantitative yield with 8:1 and 10:1 selectivities, respec-
tively.
Although our observed diastereoselectivities with the
PMB group were good, we were concerned that this large
protecting group could be hindering an opportunity to
obtain even higher facial selectivities in the alkylation
reactions. Additionally, it occurred to us that it may be
beneficial to use an acid labile amide protecting group
which could be removed under the lactam hydrolysis
conditions (5 N HCl, reflux). We felt that the much
smaller methoxymethyl (MOM) protecting group could
be used to achieve both of these goals. The MOM-
protected sec-butyl morpholin-3-one 28 was prepared in
excellent yield by treatment of 12a with sodium hydride,
followed by quenching with methoxymethyl chloride
(MOMCl). Although 28 could be efficiently deprotonated
with LDA, we found it more convenient to use n-BuLi.
We should point out that the PMB-protected morpholi-
nones could also be deprotonated with n-BuLi. These
reactions were carried out at -78 °C, and products
derived from addition to the amide carbonyl were not
detected. The facial selectivity observed using the MOM
protection was only slightly improved (10:1 compared to
8:1 with PMB)15 for alkylation with benzyl bromide,
forming 29 in good yield (Scheme 5). An unexpected
benefit of MOM protection is that the kinetic protonation
approach to stereochemical inversion of 29 was much
more efficient than in the PMB-protected products such
as 14a . This precludes the need for the aldol approach
to the 2S isomer. The diastereoselectivity for this reac-
tion was diminished, relative to the direct alkylation,
producing 30 as a 5:1 mixture of isomers. As expected,
29 was converted to (S,R)-Ile-Ψ[CH2O]-Phe (16) in quan-
titative yield, with concommitant removal of the MOM
group and lactam hydrolysis. In a similar fashion, (S,S)-
Ile-Ψ[CH2O]-Phe (21) was prepared from 30, with no loss
of stereochemical purity.
Preparation of the Ψ[CH2O] dipeptide isosteres was
accomplished via deprotection of the (2R,5S) and the
(2S,5S) morpholin-3-ones 14a and 19a using CAN to give
the corresponding N-H morpholinones 15 and 20.14 Acid
hydrolysis (5 N HCl, 2 h) provided the Ψ[CH2O] dipep-
tides 16 and 21 cleanly, with no loss of stereochemical
integrity. We found that if methanol were added to the
(13) The heteronuclear coupling between the C-3 carbonyl and the
olefinic proton in 18a is dependent upon the stereochemistry with a
value of 7 Hz or greater signifying an E configuration (between the C
and H). Less than 7 Hz is indicative of a Z orientation. The coupling
was measured using a gated 13C spectrum in which the proton was
decoupled using low power. The observed coupling constant J CH ) ∼3
Hz, indicating a Z orientation between the C-3 carbonyl and the olefinic
proton. Therefore, we have assigned the olefin as Z.
(14) The stereochemistries of 15 and 20 have been established by
NOE studies.
(15) The selectivities in these reactions are not base dependent. 29
was formed with 10:1 selectivity using LDA or n-BuLi.

4994 J . Org. Chem., Vol. 61, No. 15, 1996
Norman and Kroin
Sch em e 6
the preparation of all four possible Ψ[CH2O] dipeptides
by the appropriate selection of amino alcohol enantiomer
and reaction conditions. Furthermore, this approach is
useful for the preparation of Ψ[CH2O] dipeptides which
were previously unavailable using existing methods,
namely, the X-Ψ[CH2O]-Phe dipeptides. Another impor-
tant advantage to this new method is the fact that the
side chain functionality is chosen at a later stage in the
synthesis, thus being more amenable to SAR studies of
potential Ψ[CH2O] dipeptide enzyme inhibitors.
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were per-
formed at the indicated field strengths in the indicated
solvents. Anhydrous solvents were purchased from Aldrich,
stored over 3A molecular sieves, and transferred via syringe
or canula. E. Merck silica gel 60 was used for flash chroma-
tography. All reaction were performed under a nitrogen
atmosphere. All yields are isolated yields of diastereomerically
pure products unless otherwise noted. Selectivities were
determined using NMR integration techniques.
Although we had shown that the facial selectivity in
the alkylation reactions was related to the size of the
5-substituent, we were interested in learning if substitu-
tion at the 6-position could have any effect on diastereo-
selectivity in these reactions. Morpholinone 31 was
prepared from (1S,2R)-(+)-norephedrine using the usual
conditions, and this material was protected as the MOM
amide 32. On the basis of our model of these N-
substituted morpholin-3-ones, which indicates that the
5-substituent occupies a pseudoaxial conformation, we
did not expect much enhancement of facial selectivity for
alkylation of these substrates. For 32, if the 5-substitu-
ent were pseudoaxial, then the 6-substituent would be
pseudoequatorial and subsequently have little effect on
the facial selectivity. The NMR coupling constants are
consistent with this conformation, and as expected, no
enhancement of stereoselectivity was observed (Scheme
6). In fact, the 3:1 selectivity favoring 33 is nearly
identical to the selectivity observed for the alkylation of
13c, indicating that the additional equatorial phenyl
group in 32 has absolutely no effect on selectivity. We
had hoped that the alkylation products such as 33 could
be converted to optically pure R-hydroxy acids 35 via
lactam hydrolysis/reductive hydrogenolysis. One draw-
back to this approach to R-hydroxy acids is that the
carbon-oxygen bond is cleaved during the hydrogenolysis
reaction. This necessarily precludes recycling of the
norephedrine group by destoying a chiral center, thus
preventing norephedrine from being a true chiral auxil-
iary. This approach, however, could be acceptable if the
alkylation selectivities can be improved, since optically
pure norephedrines are relatively inexpensive. We are
presently exploring this approach to optically pure R-hy-
droxy acids.
In conclusion, we have shown that N-protected-5-
substituted morpholin-3-ones can be alkylated with good
to excellent selectivity to give 2-substituted products. The
facial selectivity in these reactions is derived from the
5-substituent, where the electrophile prefers to approach
the enolate from the face opposite the side chain. We
have also shown that the epimeric 2-isomer can be
obtained via an aldol reaction, followed by dehydration
and catalytic hydrogenation. Alternatively, this isomer
can also be prepared utilizing a kinetic protonation of
the alkylation product enolate, under appropriate condi-
tions. These materials were shown to be suitable precur-
sors to novel methylene ether dipeptide isosteres. It
should be emphasized that this method is amenable to
(S)-5-sec-Bu tylm or p h olin -3-on e (12a ). A solution con-
taining 1.00 g (8.53 mmol) of (S)-isoleucinol in 100 mL of THF
was stirred at 25 °C under a nitrogen atmosphere. To this
solution was added 375 mg of sodium hydride (9.38 mmol, 60%
in mineral oil). The reaction mixture was stirred at 25 °C for
30 min, at which time hydrogen evolution had ceased. To this
solution was added 0.90 mL of ethyl chloroacetate (8.53 mmol),
dropwise, over 5 min. The reaction mixture was stirred for
30 min at 25 °C and then 3 h at reflux. The resulting light
brown solution was cooled to 25 °C and poured into 100 mL of
1 N HCl. The mixture was extracted with ethyl acetate (3 ×
100 mL). The resulting organic extracts were dried over
sodium sulfate and concentrated in vacuo to give a crude beige
solid. This material was recrystallized from 50% ethyl acetate-
isooctane to give 1.14 g (85%) of 12a as a white crystalline
solid (mp 112-114 °C): [R]25 ) +14.9 (c 1.0, CH3OH); 1H
D
NMR (CDCl3, 300 MHz) δ 0.92 (t, 3H, J ) 7.2 Hz), 0.93 (d,
3H, J ) 6.8 Hz), 1.21 (m, 1H), 1.42-1.65 (m, 2H), 3.43 (m,
1H), 3.58 (dd, 1H, J ) 11.7 and 7.4 Hz), 3.87 (dd, 1H, J ) 11.7
and 4.0 Hz), 4.07 (d, 1H, J ) 16.6 Hz), 4.17 (d, 1H, J ) 16.6
Hz), 6.70 (bs, 1H); 13C NMR (CDCl3, 75 MHz) δ 11.4, 14.4, 25.2,
37.2, 55.4, 65.4, 67.6, 169.9; IR (KBr) 3220, 2965, 1668 cm-1
;
MS (FD+) m/ z 157 (M)+.
12b-e were prepared according to the procedure for 12a .
(S)-5-Isobu tylm or p h olin -3-on e (12b) (82%) (mp 70-71
°C): [R]25D ) -3.2 (c 1.0, CH3OH); 1H NMR (CDCl3, 300 MHz)
δ 0.95 (d, 3H, J ) 9.9 Hz), 0.99 (d, 3H, J ) 5.8 Hz), 1.40 (m,
1H), 1.46 (m, 1H), 1.72 (m, 1H), 3.45 (dd, 1H, J ) 11.5 and 7.2
Hz), 3.66 (m, 1H), 3.94 (dd, 1H, J ) 11.5 and 3.5 Hz), 4.14 (d,
1H, J ) 16.7 Hz), 4.23 (d, 1H, J ) 16.7 Hz), 7.05 (bs, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 22.3, 22.7, 24.1, 41.8, 49.6, 67.6, 68.1,
169.4; IR (KBr) 3202, 2958, 2872, 1674, 1119 cm-1; MS (FD+)
m/ z 158 (M + 1)+. Anal. Calcd for C8H15NO2: C, 61.12; H,
9.62; N, 8.91. Found: C, 60.93; H, 9.90; N, 8.77.
(S)-5-Meth ylm or p h olin -3-on e (12c). Due to the aqueous
solubility of 12c, the conditions described above did not result
in the isolation of 12c. Instead of applying the aqueous
workup conditions, we simply concentrated the reaction mix-
ture, dissolved the crude material in DMF, and carried out
the introduction of the p-methoxybenzyl protecting group as
described below.
(S)-5-Ben zylm or p h olin -3-on e (12d ) (88%) (mp 86-87
°C): [R]25D ) +3.8 (c 1.0, CH3OH); 1H NMR (CDCl3, 300 MHz)
δ 2.78 (dd, 1H, J ) 13.3 and 8.4 Hz), 2.92 (dd, 1H, J ) 13.3
and 6.0 Hz), 3.60 (dd, 1H, J ) 11.7 and 6.4 Hz), 3.80 (m, 1H),
3.93 (dd, 1H, J ) 11.7 and 2.5 Hz), 4.15 (s, 2H), 6.41 (bs, 1H),
7.20-7.45 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 39.4, 52.8,
67.4, 67.8, 127.2, 129.0, 129.2, 136.0, 169.0; IR (KBr) 3189,
2970, 1677, 1121 cm-1; MS (FD+) m/ z 191 (M)+. Anal. Calcd
for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 68.90;
H, 6.75; N, 7.26.
(S)-5-ter t-Bu tylm or p h olin -3-on e (12e) (69%) (mp 114-
115 °C): [R]25 ) +14.7 (c 1.0, CH3OH); 1H NMR (CDCl3, 300
D

Alkylation Studies of N-Protected Morpholin-3-ones
J . Org. Chem., Vol. 61, No. 15, 1996 4995
MHz) δ 0.96 (s, 9H), 2.80 (m, 1H), 3.61 (dd, 1H, J ) 11.9 and
7.8 Hz), 3.92 (dd, 1H, J ) 11.9 and 4.2 Hz), 4.06 (d, 1H, J )
16.6 Hz), d, 1H, J ) 16.6 Hz), 6.38 (bs, 1H); 13C NMR (CDCl3,
75 MHz) δ 25.9, 33.2, 60.1, 64.8, 67.5, 170.0; IR (KBr) 3203,
2970, 1674, 1127 cm-1; MS (FD+) m/ z 157 (M)+. Anal. Calcd
for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.33;
H, 9.41; N, 8.85.
cm-1; MS (FD+) m/ z 277 (M)+. Anal. Calcd for C16H23NO3:
C, 69.29; H, 8.36; N, 5.05. Found: C, 69.00; H, 8.56; N, 4.81.
(2R,5S)-2-Ben zyl-5-sec-bu tyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (14a ). LDA was prepared at 0 °C from 0.697
mL (4.98 mmol) of diisopropylamine and 3.11 mL (4.98 mmol)
of n-butyllithium (1.6 M in hexane) in 10 mL of THF under a
nitrogen atmosphere. The solution of LDA was then cooled
to -78 °C, and 1.15 g (4.15 mmol) of the N-protected morpho-
lin-3-one 13a in tetrahydrofuran (5 mL) was added dropwise.
The bright yellow solution was stirred at -78 °C for 30 min,
after which 0.592 mL (4.98 mmol) of benzyl bromide was
added. The reaction mixture was allowed to warm to 25 °C
and stirred for an additional 2 h. The reaction mixture was
poured into 1 N HCl and extracted with ethyl acetate (3 × 50
mL). The combined extracts were dried over sodium sulfate
and concentrated in vacuo to give a crude oil, which was
purified by flash chromatography on a silica gel column using
3:1 hexane-ethyl acetate as the eluent. The major fractions
were combined and concentrated in vacuo to give 1.29 g (84%,
8:1 selectivity) of 14a as a clear oil: 1H NMR (CDCl3, 300 MHz)
δ 0.83 (t, 3H, J ) 7.4 Hz), 0.88 (d, 3H, J ) 7.0 Hz), 1.17 (m,
2H), 1.86 (m, 1H), 3.19 (m, 2H), 3.33 (dd, 1H, J ) 14.2 and 3.5
Hz), 3.60-3.85 (m, 3H), 3.79 (s, 3H), 4.41 (dd, 1H, J ) 7.7
and 3.5 Hz), 5.53 (d, 1H, J ) 14.8 Hz), 6.79 (d, 2H, J ) 8.5
Hz), 6.94 (d, 2H, J ) 8.5 Hz), 7.32 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 12.3, 13.5, 26.3, 34.4, 37.9, 44.8, 55.2, 56.4, 61.9,
77.7, 114.0, 126.5, 128.2, 128.4, 129.2, 130.0, 138.0, 158.9,
169.8; IR (CHCl3) 3031, 2967, 1640, 1513, 1248 cm-1; MS (FD+)
m/ z 367 (M)+. Anal. Calcd for C23H29NO3: C, 75.17; H, 7.95;
N, 3.81. Found: C, 75.46; H, 7.95; N, 3.91.
(S)-5-sec-Bu t yl-4-(4-m et h oxyb en zyl)m or p h olin -3-on e
(13a ). A solution containing 1.00 g of the morpholin-3-one 12a
(6.36 mmol) in 50 mL of DMF was stirred at 25 °C under a
nitrogen atmosphere as 305 mg (7.63 mmol, 60% in mineral
oil) of sodium hydride was added. The reaction was stirred
at 25 °C for 30 min, after which 1.03 mL (7.63 mmol) of
p-methoxybenzyl chloride was added dropwise over 5 min. The
resulting solution was stirred at 25 °C for 4 h and then poured
into 1 N HCl. The mixture was extracted with ethyl acetate
(3 × 100 mL), and the combined extracts were washed twice
with brine, dried over sodium sulfate, and concentrated in
vacuo to give a brown oil. This crude material was purified
by flash chromatography on a silica gel column using 50% ethyl
acetate-hexane as the eluent. The major fraction was col-
lected and concentrated in vacuo to give 1.61 g (91%) of 13a
as a clear oil: [R]25D ) -83.4 (c 1.0, CH3OH); 1H NMR (CDCl3,
300 MHz) δ 0.93 (t, 3H, J ) 7.4 Hz), 1.00 (d, 3H, J ) 7.0 Hz),
1.32 (m, 2H), 1.96 (m, 1H), 3.15 (m, 1H), 3.61 (dd, 1H, J )
12.1 and 3.6 Hz), 3.83 (s, 3H), 3.85 (d, 1H, J ) 14.7 Hz), 3.95
(dd, 1H, J ) 12.1 and 2.5 Hz), 4.20 (d, 1H, J ) 16.7 Hz), 4.28
(d, 1H, J ) 16.7 Hz), 5.50 (d, 1H, J ) 14.7 Hz), 6.89 (d, 2H, J
) 8.4 Hz), 7.21 (d 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.4, 14.4, 26.6, 35.2, 45.3, 55.3, 56.2, 64.5, 67.7, 114.1, 128.6,
159.1, 167.9; IR (CHCl3) 3010, 2967, 1640, 1513, 1247 cm-1
;
(2R,5S)-5-sec-Bu tyl-2-(cycloh exylm eth yl)-4-(4-m eth oxy-
ben zyl)-m or p h olin -3-on e (14b). 14b was prepared accord-
ing to the procedure for 14a , by quenching the enolate of 13a
with cyclohexylmethyl bromide. 14b (65%, 7:1 selectivity): 1H
NMR (CDCl3, 300 MHz) δ 0.80-1.10 (m, 8H), 1.10-1.38 (m,
5H), 1.40-1.60 (m, 1H), 1.60-1.77 (m, 5H), 1.78-2.10 (m, 3H)
3.25 (m, 1H), 3.43-4.18 (m, 3H), 3.80 (s, 3H), 4.21 (dd, 1H, J
) 9.2 and 3.0 Hz), 5.50 (d, 1H, J ) 14.7 Hz), 6.86 (d, 2H, J )
8.5 Hz), 7.15 (d, 2H, J ) 8.5 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.62, 14.16, 27.26, 27.43, 27.53, 27.65, 33.12, 35.18, 35.37,
35.99, 39.75, 46.26, 55.69, 58.25, 61.50, 75.52, 115.12, 129.83,
130.38, 160.69, 173.62; IR (CHCl3) 2926, 1632, 1513, 1248,
MS (FD+) m/ z 277 (M)+. Anal. Calcd for C16H23NO3: C, 69.29;
H, 8.36; N, 5.05. Found: C, 69.18; H, 8.35; N, 4.95.
13b-e were prepared according to the procedure for 13a .
(S)-5-Isob u t yl-4-(4-m et h oxyb en zyl)m or p h olin -3-on e
(13b) (85%): 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, 3H, J )
6.4 Hz), 1.00 (d, 3H, J ) 6.5 Hz), 1.45 (m, 1H), 1.62 (m, 1H),
1.90 (m, 1H), 3.15 (m, 1H), 3.61 (m, 1H), 3.78 (d, 1H, J ) 14.7
Hz), 3.85 (s, 3H), 3.88 (d, 1H, J ) 14.7 Hz), 4.23 (d, 1H, J )
16.7 Hz), 4.33 (d, 1H, J ) 16.7 Hz), 5.46 (d, 1H, J ) 14.7 Hz),
6.91 (d, 2H, J ) 8.6 Hz), 7.24 (d, 2H, J ) 8.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.5, 23.8, 25.1, 38.8, 45.9, 52.1, 55.3, 66.3,
67.9, 114.1, 128.8, 129.6, 159.2, 166.8; IR (CHCl3) 3010, 2962,
1641, 1513, 1247 cm-1; MS (FD+) m/ z 277 (M)+. Anal. Calcd
for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.23;
H, 8.45; N, 5.03.
1036 cm-1; MS (FD+) m/ z 373 (M)+. Anal. Calcd for C23H35
-
NO3: C, 73.96; H, 9.45; N, 3.75. Found: C, 74.24; H, 9.46; N,
3.96.
(2R,5S)-5-sec-Bu t yl-4-(4-m et h oxyb en zyl)-2-(2-p h en yl-
eth yl)m or p h olin -3-on e (14c). 14c was prepared according
to the procedure for 14a , by quenching the enolate of 13a with
2-phenylethyl bromide. 14c (66%, 3:1 selectivity): 1H NMR
(CDCl3, 300 MHz) δ 0.80-1.10 (m, 6H), 1.18-1.40 (m, 2H),
1.92 (m, 1H), 2.10 (m, 1H), 2.35 (m, 1H), 2.78 (m, 2H), 3.30
(m, 1H), 3.48-4.10 (m, 3H), 3.79 (s, 3H), 4.11 (dd, 1H, J ) 9.2
and 3.0 Hz), 5.52 (d, 1H, J ) 14.9 Hz), 6.85 (d, 2H, J ) 8.1
Hz), 7.14-7.45 (m, 7H); IR (CHCl3) 3033, 2968, 1639, 1513,
(S)-5-Meth yl-4-(4-m eth oxyben zyl)m or ph olin -3-on e (13c)
(62%, 2 steps): [R]25 ) -112.5 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 1.32 (d, 3H, J ) 6.5 Hz), 3.35 (m, 1H),
3.67 (dd, 1H, J ) 11.7 and 3.0 Hz), 3.75 (dd, 1H, J ) 11.7 and
3.2 Hz), 3.84 (s, 3H), 3.92 (d, 1H, J ) 14.8 Hz), 4.24 (d, 1H, J
) 16.6 Hz), 4.33 (d, 1H, J ) 16.6 Hz), 5.37 (d, 1H, J ) 14.8
Hz), 6.90 (d, 2H, J ) 8.5 Hz), 7.23 (d, 2H, J ) 8.5 Hz); 13C
NMR (CDCl3, 75 MHz) δ 16.7, 45.7, 49.6, 55.3, 68.1, 69.5,
114.1, 128.7, 129.5, 159.1, 166.9; IR (CHCl3) 3010, 2980, 1643,
1513 cm-1; MS (FD+) m/ z 235 (M)+.
1248 cm-1; MS (FD+) m/ z 381 (M)+. Anal. Calcd for C24H31
-
NO3: C, 75.55; H, 8.19; N, 3.67. Found: C, 75.31; H, 8.12; N,
3.74.
(S)-5-Ben zyl-4-(4-m eth oxyben zyl)m or ph olin -3-on e (23d)
1
(79%): [R]25 ) -54.8 (c 1.0, CH3OH); H NMR (CDCl3, 300
(2R,5S)-2-Allyl-5-sec-b u t yl-4-(4-m et h oxyb en zyl)m or -
p h olin -3-on e (14d ). 14d was prepared according to the
procedure for 14a , by quenching the enolate of 13a with allyl
bromide. 14d (85%, 6:1 selectivity): 1H NMR (CDCl3, 300
MHz) δ 0.80-1.10 (m, 6H), 1.16-1.38 (m, 2H), 1.90 (m, 1H),
2.63 (m, 1H), 2.7-2.9 (m, 1H), 3.29 (m, 1H), 3.63-4.05 (m,
3H), 3.80 (s, 3H), 4.20 (dd, 1H, J ) 8.3 and 3.6 Hz), 5.10-5.25
(m, 2H), 5.52 (d, 1H, J ) 14.8 Hz), 5.90 (m, 1H) 6.86 (d, 2H, J
) 8.6 Hz), 7.16 (d, 2H, J ) 8.6 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.60, 13.93, 27.33, 35.78, 37.26, 46.18, 55.69, 58.20, 62.37,
77.51, 115.10, 118.07, 129.62, 130.45, 135.47, 160.07, 172.33;
IR (CHCl3) 3011, 2969, 1640, 1513, 1464, 1247, 1176, 1036
cm-1; MS (FD+) m/ z 317 (M)+. Anal. Calcd for C19H27NO3:
C, 71.89; H, 8.58; N, 4.41. Found: C, 71.79; H, 8.68; N, 4.20.
(2R,5S)-5-sec-Bu tyl-2-n -h exyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (14e). 14e was prepared according to the
procedure for 14a , by quenching the enolate of 13a with
n-hexyl iodide. 14e (75%, 6:1 selectivity): 1H NMR (CDCl3,
300 MHz) δ 0.80-1.10 (m, 9H), 1.16-1.60 (m, 10H), 1.61-
D
MHz) δ 2.99 (dd, 1H, J ) 13.3 and 10.3 Hz), 3.12 (dd, 1H, J )
13.3 and 4.0 Hz), 3.32 (m, 1H), 3.47 (dd, 1H, J ) 11.7 and 1.6
Hz), 3.74 (d, 1H, J ) 11.7 Hz), 3.85 (s, 3H), 3.90 (d, 1H, J )
14.8 Hz), 4.26 (d, 1H, J ) 16.7 Hz), 4.40 (d, 1H, J ) 16.7 Hz),
5.48 (d, 1H, J ) 14.8 Hz), 6.92 (d, 2H, J ) 8.3 Hz), 7.17 (d,
2H, J ) 7.4 Hz), 7.29-7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 36.6, 46.6, 55.3, 55.6, 65.6, 68.0, 114.2, 126.8, 128.6, 128.8,
129.3, 129.7, 137.5, 159.3, 166.9; IR (CHCl3) 3013, 2935, 1644,
1513, 1248 cm-1; MS (FD+) m/ z 311 (M)+.
(S )-5-t er t -B u t yl-4-(4-m e t h o xy b e n zyl)m o r p h olin -3-
on e (13e) (82%): [R]25 ) -77.4 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 1.15 (s, 9H,), 2.89 (d, 1H, J ) 1.5 Hz),
3.42 (dd, 1H, J ) 12.0 and 2.7 Hz), 3.84 (s, 3H), 3.87 (d, 1H,
J ) 14.7 Hz), 4.14 (d, 1H, J ) 12.0 Hz), 4.26 (d, 1H, J ) 17.2
Hz), 4.33 (d, 1H, J ) 17.2 Hz), 5.77 (d, 1H, J ) 14.7 Hz), 6.90
(d, 2H, J ) 8.5 Hz), 7.21 (d, 2H, J ) 8.5 Hz); 13C NMR (CDCl3,
75 MHz) δ 28.9, 36.7, 49.8, 55.3, 61.6, 66.5, 67.0, 114.1, 128.8,
129.6, 159.1, 168.5; IR (CHCl3) 3010, 2967, 1639, 1513, 1249

4996 J . Org. Chem., Vol. 61, No. 15, 1996
Norman and Kroin
2.10 (m, 3H), 3.26 (m, 1H), 3.63-4.05 (m, 3H), 3.80 (s, 3H),
4.10 (dd, 1H, J ) 8.9 and 3.3 Hz), 5.52 (d, 1H, J ) 14.9 Hz),
6.86 (d, 2H, J ) 8.5 Hz),7.16 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3, 75 MHz) δ 12.62, 13.97, 14.42, 23.63, 26.56, 27.36,
30.12, 32.64, 32.94, 35.84, 46.12, 55.69, 58.24, 62.03, 77.73,
115.10, 129.80, 130.40, 160.69, 173.25; IR (CHCl3) 3009, 2964,
2931, 1635, 1513, 1464, 1248, 1176, 1036 cm-1; MS (FD+) m/ z
361 (M)+. Anal. Calcd for C22H35NO3: C, 73.08; H, 9.76; N,
3.88. Found: C, 72.87; H, 9.72; N, 3.80.
(2R,5S)-2-Ben zyl-4-(4-m et h oxyb en zyl)-5-m et h ylm or -
p h olin -3-on e (14f). 14f was prepared according to the
procedure for 14a , by quenching the enolate of 13c with benzyl
bromide. 14f (85%, 3:1 selectivity): 1H NMR (CDCl3, 300
MHz) δ 1.10 (d, 3H, J ) 6.1 Hz), 3.19 (m, 1H), 3.22-3.46 (m,
2H), 3.63 (s, 1H), 3.79 (s, 3H), 3.83 (m, 1H), 3.86 (d, 1H, J )
14.8 Hz), 4.45 (dd, 1H, J ) 7.7 and 3.5 Hz), 5.36 (d, 1H, J )
14.8 Hz), 6.79 (d, 2H, J ) 8.5 Hz), 6.90 (d, 2H, J ) 8.5 Hz),
7.20-7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 15.9, 37.9,
45.1, 49.8, 55.3, 67.7, 78.0, 114.0, 126.4, 128.0, 128.2, 129.0,
130.0, 137.9, 158.9, 168.8; IR (CHCl3) 3010, 2965, 1642, 1513,
1454, 1175 cm-1; MS (FD+) m/ z 325 (M)+.
(2R,5S)-2,5-Diben zyl-4-(4-m et h oxyb en zyl)m or p h olin -
3-on e (14g). 14g was prepared according to the procedure
for 14a , by quenching the enolate of 13d with benzyl bromide.
14g (73%, 5:1 selectivity): 1H NMR (CDCl3, 300 MHz) δ 2.81
(dd, 1H, J ) 13.2 and 10.3 Hz), 3.06 (dd, 1H, J ) 13.3 and 4.1
Hz), 3.26 (m, 3H), 3.47 (m, 2H), 3.82 (s, 3H), 3.83 (d, 1H, J )
14.8 Hz), 4.55 (dd, 1H, J ) 7.4 and 4.2 Hz), 5.48 (d, 1H, J )
14.8 Hz), 6.85 (d, 2H, J ) 8.5 Hz), 7.05 (m, 3H), 7.18-7.40 (m,
9H); IR (CHCl3) 3005, 1642, 1513, 1248 cm-1; MS (FD+) m/ z
401 (M)+.
(2R,5S)-2-Ben zyl-5-ter t-bu tyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (14h ). 14h was prepared according to the
procedure for 14a , by quenching the enolate of 13e with benzyl
bromide. 14h (88%, >20:1 selectivity): 1H NMR (CDCl3, 300
MHz) δ 1.07 (s, 9H), 2.76 (d, 1H, J ) 1.2 Hz), 3.25 (m, 3H),
3.79 (s, 3H), 3.85 (m, 2H), 4.51 (dd, 1H, J ) 6.3 and 4.4 Hz),
5.75 (d, 1H, J ) 14.7 Hz), 6.81 (d, 2H, J ) 8.5 Hz), 7.02 (d,
2H, J ) 8.5 Hz), 7.30 (m, 5H); IR (CHCl3) 2962, 1639, 1513,
1249, 1130 cm-1; MS (FD+) m/ z 367 (M)+.
and 4.7 Hz), 7.18-7.35 (m, 5H); IR (CHCl3) 3028, 2991, 1745,
1113 cm-1; MS (FD+) m/ z 280 (M + 1)+.
(2Z,5S)-2-Ben zylid en e-5-sec-b u t yl-4-(4-m et h oxyb en -
zyl)m or p h olin -3-on e (18a ). LDA was prepared at 0 °C from
1.36 mL (9.71 mmol) of diisopropylamine and 6.06 mL (9.71
mmol) of n-butyllithium (1.6 M in hexane) in 30 mL of THF
under a nitrogen atmosphere. The solution of LDA was then
cooled to -78 °C, and 2.00 g (8.09 mmol) of the N-protected
morpholin-3-one 13a in tetrahydrofuran (10 mL) was added
dropwise. The bright yellow solution was stirred at -78 °C
for 30 min, after which 0.99 mL (9.71 mmol) of benzaldehyde
was added. The reaction was allowed to warm to 25 °C and
stirred an additional 1 h. The reaction mixture was poured
into 1 N HCl and extracted with ethyl acetate (3 × 50 mL).
The combined extracts were dried over sodium sulfate and
concentrated in vacuo to give the crude aldol product, as a
mixture of four diastereomers, which was used without further
purification. This material was dissolved in 20 mL of meth-
ylene chloride and cooled to 0 °C. To the reaction mixture was
added 1.69 mL (12.1 mmol) of triethylamine, followed by 0.94
mL (12.1 mmol) of methanesulfonyl chloride, dropwise, with
stirring, at 0 °C. The cooling bath was removed, and the
reaction mixture was allowed to warm to 25 °C, after which
the reaction mixture was washed with 1 N HCl (2×), brine
(2×), and a saturated sodium bicarbonate solution (2×). The
organic phase was dried over sodium sulfate and concentrated
in vacuo to give the mesylate, which was dissolved in 50 mL
of DMF. To this solution was added 1.69 mL (12.1 mmol) of
triethylamine, and the reaction mixture was heated to 150 °C
for 20 min, cooled to 25 °C, and poured into 100 mL of water.
The mixture was diluted with 150 mL of ethyl acetate, and
the organic phase washed with 1 N HCl (2×), brine (2×), and
a saturated sodium bicarbonate solution (2×). The solution
was dried over sodium sulfate and concentrated in vacuo to
give the crude dehydrated aldol product. This material was
purified by flash chromatography on a silica gel column using
50% ethyl acetate-hexane as the eluent. The major fractions
were combined and concentrated in vacuo to give 1.85 g (62%
from 13a ) of 18a as a clear oil: 1H NMR (CDCl3, 300 MHz) δ
0.93 (t, 3H, J ) 7.4 Hz), 0.99 (d, 3H, J ) 7.0 Hz), 1.35 (m,
1H), 1.43 (m, 1H), 1.94 (m, 1H), 3.19 (m, 1H), 3.78 (s, 3H),
3.84 (d, 1H, J ) 14.8 Hz), 3.92 (dd, 1H, J ) 12.1 and 3.6 Hz),
4.30 (d, 1H, J ) 12.1 Hz), 5.59, 1H, J ) 14.8 Hz), 6.87 (d, 2H,
J ) 8.5 Hz), 6.90 (s, 1H), 7.20-7.26 (m, 1H), 7.24 (d, 2H, J )
(2R,5S)-2-Ben zyl-5-sec-bu tylm or p h olin -3-on e (15).
A
solution of 1.00 g (2.72 mmol) of 14a in 25 mL of 50%
acetonitrile-water was stirred at 25 °C as 2.98 g (5.44 mmol)
of ceric ammonium nitrate (CAN) was added. The reaction
mixture was stirred at 25 °C for 3 h and poured into 1 N HCl.
The mixture was extracted with ethyl acetate (3 × 50 mL).
The organic extracts were dried over sodium sulfate, concen-
trated in vacuo, and purified by flash chromatography on a
silica gel column using 50% ethyl acetate-hexane as the
eluent. The major fractions were combined and concentrated
in vacuo to give 510 mg (76%) of (2R,5S)-2-benzyl-5-sec-
butylmorpholin-3-one (15) as a clear oil: 1H NMR (CDCl3, 300
MHz) δ 0.88 (d, 3H, J ) 6.8 Hz), 0.91 (t, 3H, J ) 7.2 Hz), 1.21
(m, 1H), 1.45 (m, 2H), 3.01 (dd, 1H, J ) 14.4 and 8.6 Hz), 3.34
(dd, 1H, J ) 14.8 and 3.1 Hz), 3.43 (m, 2H), 3.95 (m, 1H), 4.26
(dd, 1H, J ) 8.6 and 3.1 Hz), 6.44 (bs, 1H), 7.18-7.35 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 11.2, 14.1, 25.0, 36.9, 37.7, 56.0,
65.5, 78.2, 126.5, 128.2, 129.6, 138.0, 171.0; IR (CHCl3) 3395,
3011, 2971, 1666, 1455, 1120 cm-1; MS (FD+) m/ z 247 (M)+.
(S,R)-Isoleu cin e-Ψ[CH2O]-p h en yla la n in e‚HCl (16). A
suspension of 500 mg (2.02 mmol) of morpholin-3-one 15 in
15 mL of 5 N HCl was heated to reflux for 2 h, cooled to 25
°C, and concentrated in vacuo to give 635 mg (99%) of 16 as a
white amorphous solid: 1H NMR (CD3OD, 300 MHz) δ 0.89
(m, 6H), 1.19 (m, 1H), 1.44 (m, 1H), 1.70 (m, 1H), 2.97 (dd,
1H, J ) 14.1 and 8.0 Hz), 3.13 (m, 1H), 3.16 (dd, 1H, J ) 14.1
and 4.3 Hz), 3.58 (m, 2H), 4.22 (dd, 1H, 8.0 and 4.3 Hz), 7.2-
7.35 (m, 5H). If the reaction is diluted with 150 mL of
methanol prior to concentration, the corresponding methyl
ester 17 is isolated instead in quantitative yield.
8.5 Hz), 7.35 (t, 2H, J ) 7.6 Hz), 7.73 (d, 2H, J ) 7.6 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 12.0, 15.2, 26.6, 36.0, 48.2, 55.3, 57.2,
64.9, 112.6, 114.2, 127.5, 128.3, 128.8, 129.7, 129.9, 134.7,
144.2, 159.2, 160.6; IR (CHCl3) 2964, 2934, 1662, 1616, 1512,
1246 cm-1; MS (FD+) m/ z 365 (M)+.
(2Z,5S)-2-Ben zylid en e-5-isobu tyl-4-(4-m eth oxyben zyl)-
m or p h olin -3-on e (18b). 18b was prepared according to the
procedure for 18a , by quenching the enolate of 13b with
benzaldehyde, and following the dehydration procedure as
described. 18b (68% from 13b): 1H NMR (CDCl3, 300 MHz)
δ 0.93 (d, 3H, J ) 6.4 Hz), 1.02 (d, 3H, J ) 6.5 Hz), 1.47 (m,
1H), 1.66 (m, 1H), 1.88 (m, 1H), 3.35 (m, 1H), 3.85 (s, 3H),
3.88 (d, 1H, J ) 14.6 Hz), 3.99 (d, 1H J ) 12.1 Hz), 4.19 (d,
1H, J ) 12.1 Hz), 5.51 (1H, J ) 14.6 Hz), 6.92 (d, 2H, J ) 8.5
Hz), 6.93 (s, 1H), 7.25-7.29 (m, 1H), 7.28 (d, 2H, J ) 8.5 Hz),
7.39 (t, 2H, J ) 7.6 Hz), 7.77 (d, 2H, J ) 7.6 Hz); IR (CHCl3)
3009, 2963, 1660, 1613, 1512, 1248 cm-1; MS (FD+) m/ z 366
(M + 1)+.
(2S,5S)-2-Ben zyl-5-sec-bu tyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (19a ). To a solution of 100 mg (0.274 mmol) of
the olefin 18a in 20 mL of methanol was added 20 mg of
palladium on carbon (10%) catalyst in a 500 mL Parr bottle.
The reaction was run at 20 psi of hydrogen on a Parr shaker
for 12 h, after which the catalyst was removed by filtration
over a pad of Celite. The solution was concentrated in vacuo
to give the reduced product. This material was purified by
flash chromatography on a silica gel column using 50% ethyl
acetate-hexane as the eluent. The major fractions were
combined and concentrated in vacuo to give 97 mg (97%, 8:1
selectivity) of 19a as a clear oil: 1H NMR (CDCl3, 300 MHz)
δ 0.90 (m, 6H), 1.28 (m, 2H), 1.81 (m, 1H), 3.03 (m, 1H), 3.08
(dd, 1H, J ) 14.0 and 8.5 Hz), 3.44 (dd, 1H, J ) 14.8 and 2.9
(S,R)-Isoleu cin e-Ψ[CH2O]-p h en yla la n in e m eth yl ester ‚
HCl (17). 1H NMR (CDCl3, 300 MHz) δ 0.90 (m, 6H), 1.19
(m, 1H), 1.45 (m, 1H), 1.72 (m, 1H), 2.99 (dd, 1H, J ) 14.1
and 7.8 Hz), 3.10 (dd, 1H, J ) 14.1 and 4.7 Hz), 3.14 (m, 1H),
3.57 (d, 2H, J ) 5.6 Hz), 3.70 (s, 3H), 4.27 (dd, 1H, J ) 7.8

Alkylation Studies of N-Protected Morpholin-3-ones
J . Org. Chem., Vol. 61, No. 15, 1996 4997
Hz), 3.50 (dd, 1H, J ) 14.8 and 3.2 Hz), 3.84 (s, 3H), 3.86 (d,
1H, J ) 12.3 Hz), 3.99 (d, 1H, J ) 12.3 Hz), 4.37 (dd, 1H, J )
8.5 and 2.9 Hz), 5.45 (d, 1H, J ) 14.6 Hz), 6.90 (d, 2H, J ) 8.5
Hz), 7.22 (d, 2H, J ) 8.5 Hz), 7.35 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 12.2, 14.9, 26.6, 35.4, 38.4, 46.6, 55.2, 57.3, 63.9,
78.7, 114.1, 126.4, 128.1, 129.0, 129.6, 129.8, 138.1, 159.1,
169.4; IR (neat) 2964, 1647, 1512, 1247 cm-1; MS (FD+) m/ z
367 (M)+. Anal. Calcd for C23H29NO3: C, 75.17; H, 7.95; N,
3.81. Found: C, 74.93; H, 8.02; N, 3.91.
(2S,5S)-2-Ben zyl-5-isob u t yl-4-(4-m et h oxyb en zyl)m or -
p h olin -3-on e (19b). 19b was prepared according to the
procedure for 19a . 19b (98%, 10:1 selectivity): 1H NMR
(CDCl3, 300 MHz) δ 0.76 (d, 3H, J ) 6.5 Hz), 0.82 (d, 3H, J )
6.6 Hz), 0.99 (m, 1H), 1.28 (m, 1H), 1.44 (m, 1H), 2.97 (d, 1H,
J ) 10.5 Hz), 3.17 (dd, 1H, J ) 14.0 and 6.4 Hz), 3.26 (dd, 1H,
J ) 14.0 and 3.9 Hz), 3.50 (d, 1H, J ) 12.0 Hz), 3.67 (d, 1H,
J ) 14.6 Hz), 3.75 (d, 1H, J ) 12.0 Hz), 3.79 (s, 3H), 4.35 (dd,
1H, J ) 6.4 and 3.9 Hz), 5.30 (d, 1H, J ) 14.6 Hz), 6.83 (d,
2H, J ) 8.5 Hz), 7.17 (d, 2H, J ) 8.5 Hz), 7.22-7.35 (m, 5H);
IR (CHCl3) 2960, 1641, 1512, 1247, 1176 cm-1; MS (FD+) m/ z
367 (M)+.
(2S,5S)-2-Ben zyl-5-sec-bu tylm or p h olin -3-on e (20). 20
was prepared from 19a using the procedure for the preparation
of 15. 20 (81%): 1H NMR (CDCl3, 300 MHz) δ 0.88 (m, 6H),
1.09 (m, 1H), 1.25-1.40 (m, 2H), 3.08 (m, 1H), 3.15 (dd, 1H, J
) 14.3 and 7.5 Hz), 3.26 (dd, 1H, J ) 14.3 and 3.6 Hz), 3.72
(dd, 1H, J ) 12.1 and 3.3 Hz), 3.91 (d, 1H, J ) 12.1 Hz), 4.39
(dd, 1H, J ) 7.5 and 3.6 Hz), 6.85 (bs, 1H), 7.30 (m, 5H); IR
(CHCl3) 3404, 3010, 2970, 1666 cm-1; MS (FD+) m/ z 247 (M)+.
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.56; H, 8.72; N, 5.51.
(S,S)-Isoleu cin e-Ψ[CH2O]-p h en yla la n in e‚HCl (21). 21
was prepared according to the procedure for 16. 21: 1H NMR
(CD3OD, 300 MHz) δ 0.76 (d, 3H, J ) 6.9 Hz), 0.89 (t, 3H, J )
7.3 Hz), 1.15 (m, 1H), 1.46 (m, 1H), 1.69 (m, 1H), 2.95 (dd,
1H, J ) 14.0 and 8.7 Hz), 3.14 (m, 2H), 3.53 (dd, 1H, J ) 10.6
and 5.8 Hz), 3.68 (dd, 1H, J ) 10.6 and 3.3 Hz), 4.18 (dd, 1H,
J ) 8.6 and 4.0 Hz), 7.21 (m, 5H).
3.1 Hz), 4.20 (q, 1H, J ) 6.9 Hz), 6.21 (bs, 1H); IR (CHCl3)
3395, 3015, 2967, 1669, 1450, 1120 cm-1; MS (FD+) m/ z 171
(M)+.
(R)-N-(2-Ch lor op r op ion yl)-(S)-isoleu cin ol, ter t-Bu tyl-
d im eth ylsilyl Eth er (27). To a solution of 500 mg (4.61
mmol) of (R)-(+)-2-chloropropionic acid in 40 mL of methylene
chloride at 0 °C was added 622 mg (4.61 mmol) of 1-hydroxy-
benzotriazole (HOBt), followed by 883 mg (4.61 mmol) of
1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC). The
reaction mixture was stirred at 0 °C for 1.5 h, after which 1.07
g (4.61 mmol) of (S)-isoleucinol, tert-butyldimethylsilyl ether
in 10 mL of methylene chlorice was added. The reaction
mixture was stirred for 2 h at 0 °C. The reaction mixture was
worked up by washing with saturated sodium bicarbonate
solution (2×), brine (2×) and 1 M citric acid (2×). The organic
solution was dried over sodium sulfate and concentrated in
vacuo to give 855 mg (58%) of 27 as a clear oil: 1H NMR
(CDCl3, 300 MHz) δ 0.05 (s, 6H), 0.88-1.02 (m, 6H), 0.95 (s,
9H), 1.18 (m, 1H), 1.55 (m, 1H), 1.73 (m 1H), 1.79 (d, 3H, J )
7.1 Hz), 3.63 (dd, 1H, J ) 12.3 and 3.0 Hz), 3.80 (m, 2H), 4.46
(q, 1H, J ) 7.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 11.3, 15.5,
18.2, 22.9, 25.5, 25.7, 25.8, 35.4, 54.8, 56.3, 62.3, 169.0; IR
(CHCl3) 3279, 2963, 1656, 1258, 1124 cm-1; MS (FD+) m/ z 322
(M+1)+. Anal. Calcd for C15H32NO2Cl: C, 55.96; H, 10.02;
N, 4.35. Found: C, 55.91; H, 9.88; N, 4.63.
P r ep a r a tion of (2S,5S)-5-sec-Bu tyl-2-m eth ylm or p h o-
lin -3-on e (26) fr om (R)-N-(2-Ch lor op r op ion yl)-(S)-isoleu -
cin ol, t-bu tyld im eth ylsilyl eth er (27). A solution contain-
ing 842 mg (2.61 mmol) of 27 in 20 mL of chloroform was cooled
to 0 °C under a nitrogen atmosphere. To this solution was
added 0.35 mL (2.87 mmol) of boron trifluoride etherate, and
the reaction mixture was allowed to slowly warm to 25 °C,
where it was stirred for an additional 1.5 h. An additional
0.35 mL of boron trifluoride etherate was added, and the
reaction mixture was stirred for an additional 1 h at 25 °C.
The reaction was quenched with water, and the organic
solution was washed with water (2×) and a saturated sodium
bicarbonate solution (2×), dried over sodium sulfate, and
concentrated in vacuo to give the (R)-N-(2-Chloroproprionyl)-
(S)-isoleucinol as a white amorphous solid (mp 89-90 °C),
which was characterized on the basis of its NMR spectrum:
1H NMR (CDCl3, 300 MHz) δ 0.85-0.95 (m, 6H), 1.21 (m, 1H),
1.57 (m, 1H), 1.77 (m, 1H), 1.80 (d, 3H, J ) 7.1 Hz), 3.70-
3.88 (m, 3H), 4.50 (q, 1H, J ) 7.1 Hz), 6.79 (bs, 1H). A solution
of 50 mg (0.24 mmol) of this material, which was used without
further purification, in 5 mL of THF was added to a suspension
of 154 mg (0.96 mmol) of potassium hydride (25% in oil) in 5
mL of THF and 1 mL of DMF at 0 °C. The reaction mixture
was stirred at 0 °C for 4 h, and the reaction was quenched by
pouring the reaction mixture into methanol. The mixture was
diluted with ethyl acetate and the organic phase washed with
1 N HCl, dried over sodium sulfate, and concentrated in vacuo
to give 29 mg (72%) of 26. This material was identical to the
minor isomer (26) from the alkylation sequence described
above.
(S,S)-Isoleu cin e-Ψ[CH2O]-p h en yla la n in e m eth yl ester ‚
HCl (22). 22 was prepared according to the procedure for
17. 22: [R]25 ) -33.3 (c 1.0, CH3OH); 1H NMR (CD3OD, 300
D
MHz) δ 0.82 (d, 3H, J ) 6.9 Hz), 0.95 (t, 3H, J ) 7.3 Hz), 1.20
(m, 1H), 1.52 (m, 1H), 1.74 (m, 1H), 3.00 (dd, 1H, J ) 14.0
and 8.6 Hz), 3.18 (m, 1H), 3.31 (m, 1H), 3.57 (dd, 1H, J ) 10.6
and 5.9 Hz), 3.73 (dd, 1H, J ) 10.6 and 3.1 Hz), 3.77 (s, 3H),
4.27 (dd, 1H, J ) 8.6 and 4.4 Hz) 7.28 (m, 5H); 13C NMR (CD3-
OD, 75 MHz) δ 9.1, 12.2, 24.5, 34.0, 37.5, 50.5, 54.8, 66.3, 79.5,
125.2, 127.0, 128.5, 135.5, 174.1; IR (CHCl3) 3032, 2972, 1743,
1116 cm-1; MS (FD+) m/ z 280 (M + 1)+.
(2R,5S)-5-sec-Bu tyl-4-(4-m eth oxyben zyl)-2-m eth ylm or -
p h olin -3-on e (23). 23 and 24 were prepared as an insepa-
rable 3:1 according to the procedure for 14a . 23 (77%): 1H
NMR (CDCl3, 300 MHz) (major diastereomer, 23) δ 0.90-0.95
(m, 6H), 1.29 (m, 2H), 1.53 (d, 3H, J ) 6.8 Hz), 1.92 (m, 1H),
3.30 (m, 1H), 3.71 (dd, 1H, J ) 12.2 and 6.2 Hz), 3.82 (s, 3H),
3.86 (m, 2H), 4.28 (q, 1H, J ) 6.8 Hz), 5.52 (d, 1H, J ) 15.1
Hz), 6.89 (d, 2H, J ) 8.4 Hz), 7.19 (d, 2H, 8.4 Hz); IR (CHCl3)
3009, 2968, 1637, 1513, 1247 cm-1; MS (FD+) m/ z 291 (M)+.
Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81.
Found: C, 70.27; H, 8.85; N, 4.61.
Dep r otection of 23 a n d 24 Usin g CAN. 23 and 24 (as a
3:1 mixture) were subjected to the conditions for the prepara-
tion of 15. This gave 25 and 26 as a 3:1 mixture, which was
separated by flash chromatography, as described.
(2R,5S)-5-sec-Bu tyl-2-m eth ylm or ph olin -3-on e (25) (55%):
1H NMR (CDCl3, 300 MHz) δ 0.89 (m, 6H), 1.22 (m, 1H), 1.40-
1.60 (m, 2H), 1.42 (d, 3H, J ) 6.9 Hz), 3.40-3.56 (m, 2H), 3.92
(dd, 1H, J ) 11.1 and 3.6 Hz), 4.07 (q, 1H, J ) 6.9 Hz), 6.65
(bs, 1H); 13C NMR (CDCl3, 75 MHz) δ 11.1, 14.2, 17.3, 25.0,
36.9, 56.4, 65.7, 73.7, 172.5; IR (CHCl3) 3398, 3010, 2971, 1664,
1451, 1118 cm-1; MS (FD+) m/ z 171 (M)+.
(S)-5-sec-Bu tyl-4-(m eth oxym eth yl)m or ph olin -3-on e (28).
28 was prepared according to the procedure for the preparation
of 13a , with the reaction being quenched with 1.2 molar equiv
of chloromethyl methyl ether (instead of p-methoxybenzyl
chloride). 28 (85%): [R]25 ) +16.4 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 0.94 (m, 6H), 1.31 (m, 2H), 1.90 (m, 1H),
3.31 (s, 3H), 3.42 (m, 1H), 3.73 (dd, 1H, J ) 12.3 and 3.9 Hz),
3.94 (dd, 1H, J ) 12.3 and 3.5 Hz), 4.16 (s, 2H), 4.52 (d, 1H,
J ) 10.3 Hz), 5.23 (d, 1H, J ) 10.3 Hz); 13C NMR (CDCl3, 75
MHz) δ 12.3, 14.2, 26.6, 35.6, 56.4, 56.5, 64.5, 67.5, 73.9, 169.2;
IR (CHCl3) 3020, 2968, 1658, 1461, 1112 cm-1; MS (FD+) m/ z
201 (M)+. Anal. Calcd for C10H19NO3: C, 59.68; H, 9.52; N,
6.96. Found: C, 59.42; H, 9.31; N, 7.10.
(2R,5S)-2-Ben zyl-5-sec-b u t yl-4-(m et h oxym et h yl)m or -
p h olin -3-on e (29). A solution containing 350 mg (1.74 mmol)
of 28 in 5 mL of THF was cooled to -78 °C under a nitrogen
atmosphere. To this solution was added 1.30 mL of n-
butyllithium (2.09 mmol, 1.6 M in hexane) via syringe. The
bright yellow reaction mixture was stirred at -78 °C for 20
min, after which 0.228 mL (1.91 mmol) of benzyl bromide was
added via syringe. The reaction mixture was stirred at -78
(2S,5S)-5-sec-Bu tyl-2-m eth ylm or ph olin -3-on e (26) (20%):
1H NMR (CDCl3, 300 MHz) δ 0.92 (m, 6H), 1.22 (m, 1H), 1.45
(d, 3H, J ) 6.9 Hz), 1.55 (m, 1H), 1.67 (m, 1H), 3.19 (m, 1H),
3.75 (dd, 1H, J ) 12.2 and 3.7 Hz), 3.91 (dd, 1H, J ) 12.2 and

4998 J . Org. Chem., Vol. 61, No. 15, 1996
Norman and Kroin
°C for 30 min, the cooling bath was removed, and the reaction
mixture was allowed to warm to 25 °C and stirred for an
additional 30 min. The reaction mixture was poured into
water and diluted with ethyl acetate. The organic phase was
separated, dried over sodium sulfate, and concentrated in
vacuo. This crude material was purified by flash chromatog-
raphy on a silica gel column using 50% ethyl acetate-hexane
as the eluent. The major fractions were combined and
concentrated to give 380 mg (75%, 10:1 selectivity) of 29 as a
clear oil: 1H NMR (CDCl3, 300 MHz) δ 0.86 (d, 3H, J ) 6.8
Hz), 0.93 (t, 3H, J ) 7.3 Hz), 1.21 (m, 1H), 1.28 (m, 1H), 1.88
(m, 1H), 3.09 (dd, 1H, J ) 14.3 and 8.2 Hz), 3.12 (s, 3H), 3.30
(dd, 1H, J ) 14.3 and 3.3 Hz), 3.52 (m, 1H), 3.65 (dd, 1H, J )
12.1 and 7.1 Hz), 3.88 (dd, 1H, J ) 12.1 and 4.4 Hz), 4.34 (dd,
1H, J ) 8.2 and 3.3 Hz), 4.50 (d, 1H, J ) 10.4 Hz), 5.28 (d,
1H, J ) 10.4 Hz), 7.15-7.35 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 12.3, 13.3, 26.4, 34.4, 37.8, 56.0, 56.7, 62.2, 73.6, 78.0,
126.5, 128.2, 129.8, 137.9, 171.1; IR (CHCl3) 3012, 2967, 1656,
1454, 1114 cm-1; MS (FD+) m/ z 291 (M)+. Anal. Calcd for
C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.99; H,
8.84; N, 5.04.
5H); IR (CHCl3) 3011, 2967, 1655, 1455, 1092 cm-1; MS (FD+)
m/ z 291 (M)+. Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65;
N, 4.81. Found: C, 69.99; H, 8.69; N, 4.86.
30 could be converted directly to (S,S)-isoleucine-Ψ[CH2O]-
phenylalanine‚HCl (21), by acid hydrolysis (5 N HCl, 2 h,
reflux) as described above. This single operation accomplishes
MOM removal and lactam hydrolysis.
(5R,6S)-5-Meth yl-6-ph en ylm or ph olin -3-on e (31). 31 was
prepared according to the procedure for 12a . 31 (78%) (mp
128-129 °C): [R]25D ) +205.2 (c 1.0, CH3OH); 1H NMR (CDCl3,
300 MHz) δ 0.97 (d, 3H, J ) 6.5 Hz), 3.72 (m, 1H), 4.33 (d,
1H, J ) 16.9 Hz), 4.46 (d, 1H, J ) 16.9 Hz), 4.93 (d, 1H, J )
2.6 Hz), 6.86 (bs, 1H), 7.25-7.39 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 15.3, 50.4, 67.0, 76.0, 124.5, 126.7, 127.4, 136.6,
168.4; IR (KBr) 3264, 2980, 1691, 1446, 1116 cm-1; MS (FD+)
m/ z 191 (M)+. Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85;
N, 7.32. Found: C, 68.79; H, 6.75; N, 7.61.
(5R,6S)-4-(Meth oxym eth yl)-5-m eth yl-6-p h en ylm or p h o-
lin -3-on e (32). 32 was prepared according to the procedure
for 28. 32 (82%): [R]25 ) +81.2 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 0.97 (d, 3H, J ) 6.5 Hz), 3.37 (s, 3H),
3.78 (dq, 1H, J ) 6.5 and 2.6 Hz), 4.37 (d, 1H, J ) 17.0 Hz),
4.47 (d, 1H, J ) 17.0 Hz), 4.53 (d, 1H, J ) 10.2 Hz), 4.92 (d,
1H, J ) 2.4 Hz), 5.21 (d, 1H, J ) 10.2 Hz), 7.28-7.40 (m 5H);
13C NMR (CDCl3, 75 MHz) δ 13.1, 54.2, 56.4, 67.8, 74.9, 78.0,
125.5, 127.8, 128.4, 137.6, 168.0; IR (CHCl3) 3012, 1658, 1452,
29 could be converted directly to (S,R)-isoleucine-Ψ[CH2O]-
phenylalanine‚HCl (16), by acid hydrolysis (5 N HCl, 2 h,
reflux) as described above. This single operation accomplishes
MOM removal and lactam hydrolysis.
(2S,5S)-2-Ben zyl-5-sec-b u t yl-4-(m et h oxym et h yl)m or -
p h olin -3-on e (30). A solution containing 350 mg (1.74 mmol)
of 28 in 5 mL of THF was cooled to -78 °C under a nitrogen
atmosphere. To this solution was added 1.30 mL of n-
butyllithium (2.09 mmol, 1.6 M in hexane) via syringe. The
bright yellow reaction mixture was stirred at -78 °C for 20
min, after which 0.228 mL (1.91 mmol) of benzyl bromide was
added via syringe. The reaction mixture was stirred at -78
°C for 30 min, the cooling bath was removed, and the reaction
mixture was allowed to warm to 25 °C and stirred for an
additional 30 min. The reaction mixture was recooled to -78
°C, and another 1.30 mL of n-butyllithium was added. The
reaction mixture was stirred at -78 °C for 30 min, after which
the enolate was quenched by the dropwise addiition of 200 µL
of glacial acetic acid in 1 mL of THF. The reaction mixture
was warmed to 25 °C, poured into water, and diluted with
ethyl acetate. The organic phase was washed with saturated
sodium bicarbonate solution, dried over sodium sulfate, and
concentrated in vacuo. This crude material was purified by
flash chromatography on a silica gel column using 50% ethyl
acetate-hexane as the eluent. The major fractions were
combined and concentrated to give 365 mg (72%, 5:1 selectiv-
1108 cm-1; MS (FD+) m/ z 235 (M)+. Anal. Calcd for C13H17
-
NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.34; H, 7.32; N,
5.82.
(2S,5R,6S)-2-Ben zyl-4-(m et h oxym et h yl)-5-m et h yl-6-
p h en ylm or p h olin -3-on e (33). 33 was prepared using the
n-butyllithium alkylation condition as described in the prepa-
ration of 29. 33 (76%, 3:1 selectivity): 1H NMR (CDCl3, 300
MHz) δ 0.95 (d, 3H, J ) 6.5 Hz), 3.22-3.31 (m, 2H), 3.33 (s,
3H), 3.72 (dq, 1H, J ) 6.5 and 2.0 Hz), 4.51 (d, 1H, J ) 10.2
Hz), 4.68 (dd, 1H, J ) 7.2 and 4.8 Hz), 4.88 (d, 1H, J ) 2.0
Hz), 5.28 (d, 1H, J ) 10.2 Hz), 7.18-7.45 (m, 10H); IR (CHCl3)
3010, 1657, 1453, 1103 cm-1; MS (FD+) m/ z 325 (M)+.
Ack n ow led gm en t. We thank the Physical Chem-
istry Department at Eli Lilly and Co. for their help in
the characterization of products. We specifically thank
J onathan Paschal for his NOE studies which allowed
us to make the necessary stereochemical assignments.
Su p p or tin g In for m a tion Ava ila ble: 300 MHz 1H and/
or 75 MHz 13C spectra for compounds lacking combustion data
(25 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
1
ity) of 30 as a clear oil: H NMR (CDCl3, 300 MHz) δ 0.83 (d,
3H, J ) 7.0 Hz), 0.88 (t, 3H, J ) 7.3 Hz), 1.25 (m, 2H), 1.68
(m, 1H), 3.03 (dd, 1H, J ) 14.1 and 8.4 Hz), 3.27-3.36 (m,
2H), 3.33 (s, 3H), 3.64 (dd, 1H, J ) 12.4 and 3.5 Hz), 4.04 (d,
1H, J ) 12.4 Hz), 4.32 (dd, 1H, J ) 8.4 and 3.5 Hz), 4.48 (d,
1H, J ) 10.2 Hz), 5.26 (d, 1H, J ) 10.2 Hz), 7.18-7.35 (m,
J O960496W