Novel and efficient synthesis of spirocyclic morpholinones as precursors of ψ[CH2O] dipeptide isosteres

Article abstract of DOI:10.1055/s-1999-6050

A series of novel dipeptide mimetics 4, featuring replacement of peptide bond by ψ[CH₂O], was synthesized in high yields from their precursors, novel spirocyclic morpholinones 2. Efficient and reliable chemistry leading to 2 was accomplished by alkylating morpholinone 1 with 1-chloro-ω- iodoalkanes, followed by Finkelstein iodide exchange and LDA-mediated intramolecular spirocyclization.

Full text of DOI:10.1055/s-1999-6050

112
PAPER
Novel and Efficient Synthesis of Spirocyclic Morpholinones as Precursors of
ψ[CH2O] Dipeptide Isosteres
Paul C. Fritch, Wieslaw M. Kazmierski*¦
Glaxo Wellcome Inc., Division of Medicinal Chemistry, Research Triangle Park, NC 27709, USA
Fax: +1(919)-315-0430; E-mail: wmk35860@glaxowellcome.com
Received 14 July1998
Norman et al. reported syntheses of benzyl, allyl, and alkyl
Abstract: A series of novel dipeptide mimetics 4, featuring replace-
derivatives of several morpholinones, including 1.15,16, 23
ment of peptide bond by ψ[CH2O], was synthesized in high yields
from their precursors, novel spirocyclic morpholinones 2. Efficient
and reliable chemistry leading to 2 was accomplished by alkylating
morpholinone 1 with 1-chloro-ω-iodoalkanes, followed by Finkel-
stein iodide exchange and LDA-mediated intramolecular spirocy-
clization.
While 4 could conceivably be obtained by hydrolysis of
2,15,16,23 extensive database searches yielded no prior
chemistry applicable towards the spirocyclic morpholino-
nes 2.24 Initially, we attempted to utilize the Ten Brink
protocol,14 but soon discovered that the spirocyclic mor-
pholinones 2 did not form, owing to a competing decom-
position of the intermediate bromide.13Ð14 We then tried to
dialkylate either 1 or 3 with 1,5-dibromopentane/potassi-
um tert-butoxide, as exemplified in the literature,17Ð20 but
observed no desired product 2. We also carried out
dialkylations under reportedly superior conditions of ul-
trasonic irradiation,25 again detecting no 2. Encouraging-
ly, we were able to confirm that 3 could be easily
monoalkylated with highly reactive electrophiles such as
allyl iodide, yielding (3S,6R)-6-allyl-3-benzyl-5-oxo-1,4-
oxazinane-4-tert-butyl carboxylate (2f, 46%) as an exclu-
sive diastereomer. We also observed that the tert-butylox-
ycarbonyl protecting group was unstable to the conditions
of alkylation, thus negatively affecting the final yields.
We therefore reverted to the para-methoxybenzyl (PMB)
group, successfully used by Norman et al.,16, 23 and were
pleased to find that it was compatible with the chemistry
that we have subsequently developed and wish to report
herein.
Key words: dipeptide isosteres, spirocyclic morpholinone,
ψ[CH2O] ether
Although peptides and proteins-based molecules have
found many pharmaceutical applications, their develop-
ment into drugs is nonetheless complicated by poor oral
bioavailability,1 absorbance,2 and metabolic stability often
associated with peptide bonds.3Ð5 Substantial effort has
been devoted to mimetics of amide bonds, including cis-
constrained hydroxyethylamine peptide bond isostere,6 (E)-
olefin dipeptide isosteres,7Ð9 flouroolefin isosteres,10 and
others.11,12 Successful replacements of peptide bonds in re-
nin inhibitors,13 of the type NH2CH(R1)-ψ[CH2O]-
CH(R2)CO2H, with both R1 and R2 side chains correspond-
ing to those of natural amino acids, have been also report-
ed.13Ð16 One of our synthetic programs required significant
quantities of both 2 and 4. Alkylated morpholinones, direct
precursors to ψ[CH2O] isosteres, can be assembled from al-
cohols (corresponding to R1) and alkyl bromides (corre-
sponding to R2),14 however, this methodology is limited in
scope, as neither Phe-ψ[CH2O]-Phe nor Phe-ψ[CH2O]-D-
Phe could be prepared in this fashion.14 Bis-alkylations of
malonates and/or phenyl acetates have been extensively
used in syntheses of cycloalkanes, although robustness and
yields of these approaches vary quite substantially.17Ð20
Thus, bisalkylation of ethyl malonate with a-bromoace-
tophenone azines provided 77% of 5,6-dihydrodiaz-
epines,17 and 74% of 4,4-disubstituted piperidine when 2-
bromo-N-(2-bromoethyl)-N-ethoxycarbonylethanamine was
used as a substrate.18 On the other hand, alkylation of enol
ethers of cyclic 1,3-diketones with di-bromopentane yield-
ed 44% of the desired product,19 while similar alkylation of
benzylacetyl group in fluoroquinolones resulted in only
26% of cyclo-hexylfluoroquinolone.20 Furthermore, aziri-
dine (abundantly available from corresponding â-amino al-
cohols) opening by primary alkoxides suffers variable
regioselectivity and low to moderate yields, even with large
excess of alkoxides.21, 22 More recently, Anthony et al. and
The first step in our chemistry involves alkylations of
(5S)-5-benzyl-4-(4-methoxybenzyl)-1,4-oxazinan-3-one
(1) with a 5-fold excess of ω-chloro-1-iodoalkanes and re-
sults in 2:1 to 3:1 (trans/cis) diasteromeric mixtures of
(5S)-5-benzyl-2-(ω-chloroalkyl)-4-(4-methoxybenzyl)-
1,4-oxazinan-3-ones (Scheme). Since the final intramo-
lecular spirocyclization removes R2 chirality in 2, we de-
cided to carry the intermediates through as diastereomeric
mixtures. Nonetheless, a very high diastereoselectivity
(>99:1) in these reactions is possible, as demonstrated by
allylation of N-Boc- (rather than MOB-protected) mor-
pholinone 3, leading to 2f. A subsequent Finkelstein con-
version of (5S)-5-benzyl-2-(ω-chloroalkyl)-4-(4-methoxy-
benzyl)-1,4-oxazinan-3-ones to (5S)-5-benzyl-2-(ω-io-
doalkyl)-4-(4-methoxybenzyl)-1,4-oxazinan-3-ones pro-
ceeded smoothly, with yields of 88Ð91%. Final formation
of spiromorpholinones 2aÐd was carried out at 0.01 M
concentration in THF at Ð10¡C for 4 hours (44Ð70% after
purification, Table 1). No cross-linked dimers were de-
tected, even at higher concentrations.
Synthesis 1999, No. 1, 112Ð116 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
Novel and Efficient Synthesis of Spirocyclic Morpholinones
113
Reagents and conditions: a) LDA/THF/w-chloro-1-iodoalkane, Ð78¡C; b) NaI/acetone, reflux; c) (c = 0.01, see text)/LDA/THF, Ð78 to Ð
10¡C; d) LDA/THF, allyl iodide, Ð78¡C; NaIO4/OsO4 (cat), THF/H2O; f) NaBH4/THF/EtOH, g) TFA, reflux, 2.5 h for 2aÐe; h) 4 N HCl/
dioxane, 1 h, r.t. for 2f; i) 6 N aq HCl, sealed tube, 95¡C, 20 h
Scheme
Table 1 Compounds 2a–e Prepared
Prod-
ucta
Yield
(%)b
[a]D20
(CHCl3)
mp°C
IR (neat)
MS (ES+)
m/z (rel.
intensity)
1H NMR (CDCl3/TMS)
d, J (Hz)
2a
2b
2c
45
50
70
44.6 (c, 1.0)
–38.5 (c, 1.0)
–32.3 (c, 1.0)
101.5–102.5
2938, 1647, 390 (M+K 12), 1.92–2.23 (m, 4 Hcyclobutyl), 2.59–2.66 (m, 1
1513, 1248, 374 (M+Na, cyclobutyl), 2.74–2.84 (m, 1 Hcyclobutyl), 2.91 (dd, 1 H,
1034, 701
H
100), 352 (M+H, J = 3.9, 13.4 Hz, CH2Ph), 3.06 (dd, 1 H, J = 10.1,
45), 244 (45), 13.4 Hz, CH2Ph), 3.22 (m, 1 H, H–5), 3.40–3.54
121 (36)
(m, 2 H, OCH2), 3.78 (s, 3 H, OCH3), 3.83 (NCHA,
1 H), 5.42 (NCHx, 1 H, JAX = 14.7 Hz), 6.87 (d, 2
H, J = 8.7 Hz, CHarom), 7.10–7.31 (m, 7 H, CHarom
)
114–114.5
2950, 1646, 388 (M+Na,
1513, 1457, 100), 366 (M+H,
1247, 1175, 87), 258 (50),
1117, 1034, 121 (23)
701
1.75–2.00 (m, 6 Hcyclopentyl), 2.08–2.16 (m, 1
cyclopentyl), 2.33–2.38 (m, 1 Hcyclopentyl), 2.91 (dd, 1
H, J = 10.1, 13.4 Hz, CH2Ph), 3.07 (dd, 1 H, J = 3.9,
13.4 Hz, CH2Ph), 3.23–3.28 (m, 1 H, H–5), 3.52
(m, 2 H, OCH2), 3.79 (s, 3 H, OCH3), 3.82 (NCHA,
1 H), 5.41 (NCHx, 1 H) (JAX = 14.7 Hz), 6.88 (d, 2
H
H, J = 8.4 Hz, CHarom), 7.32–7.13 (m, 7 H, CHarom
)
94–94.5
2929, 1646, 418 (M+K, 20), 1.28–1.35 (m, 1 Hcyclohexyl), 1.50–1.70 (m, 5
1513, 1455, 402 (M+Na, 75), cyclohexyl), 1.78–1.95 (m, 2 Hcyclohexyl), 1.95–2.10
1249, 1108, 380 (M+H, 100), (m, 2 Hcyclohexyl), 2.93–3.05 (m, 2 H, CH2Ph), 3.24–
701 272 (42), 121 3.19 (m, 1 H, H–5), 3.54 (m, 2 H, OCH2), 3.72–
H
(27)
3.78 (m, 4 H, NCH+OCH3), 5.36 (d, 1 H, J = 14.7
Hz, NCH), 6.86 (d, 2 H, J = 8.4 Hz, CHarom), 7.14–
7.31 (m, 7 H, CHarom
)
2d
2e
44
74
–36.9 (c, 1.1)
–50.9 (c, 1.1)
oil
2925, 1644, 432 (M+K, 20), 1.43–1.89 (m, 9Hcycloheptyl), 2.02–2.12 (m,
1513, 1455, 416 (M+K, 44), cycloheptyl), 2.18–2.28 (m, 1 Hcycloheptyl), 2.94–3.07
1247, 1175, 394 (M+H, 100), (m, 2 H, CH2Ph), 3.20 (m, 1 H, H–5), 3.58 (m, 2 H,
2
H
1118, 1034, 286 (35)
701
OCH2), 3.79 (s, 3 H, OCH3), 3.72 (NCHA, 1 H),
5.36 (NCHx, 1 H, JAX = 14.7 Hz), 6.87 (d, 2 H, J =
8.4 Hz, CHarom), 7.14–7.32 (m, 7 H, CHarom
)
79–80
1649, 1512, 376 (M+K, 10), 0.90 (m, 1 Hcyclopropyl), 1.19 (m, 1 Hcyclopropyl), 1.32
1247, 1035, 360 (M+Na, (m, 1 Hcyclopropyl), 1.58 (m, 1 Hcyclopropyl), 3.04 (dd, 1
700
100), 338 (M+H, H, J = 10.1, 13.3 Hz, CH2Ph), 3.15 (dd, 1 H, J = 4.2,
32), 230 (36), 13.3 Hz, CH2Ph), 3.39 (m, 1 H, H–5), 3.65 (m, 2 H,
121 (25)
OCH2), 3.80 (s, 3 H, OCH3), 3.91 (NCHA, 1 H),
5.43 (NCHx, 1 H, JAX = 14.7 Hz), 6.90 (d, 2 H, J =
8.7 Hz, CHarom), 7.14–7.36 (m, 7 H, CHarom
)
a Satisfactory microanalyses were obtained: C ± 0.24, H ± 0.14, N ± 0.19
b Yields based on 1.
Synthesis 1999, No. 1, 112–116 ISSN 0039-7881 © Thieme Stuttgart · New York

114
P. C. Fritch, W. M. Kazmierski
PAPER
Cyclopropane 2e, could not be synthesized by the above oxybenzyl)-3-oxo-1,4-oxazinan-2-yl]ethyl
methane-
route, owing to unsatisfactory alkylation with 1-chloro-2- sulfonate, which was then subjected to LDA-mediated
iodoethane. Instead, the anion of 1 was reacted with allyl spirocyclization, yielding 2e (74%). The hydrolyses of
iodide, the product (2R,5S)-2-allyl-5-benzyl-4-(4-meth- Boc- or PMB-protected morpholinones 2aÐf to 4aÐf were
oxybenzyl)-1,4-oxazinan-3-one, oxidatively cleaved to performed in two steps: (i) trifluoroacetic acid-mediated
the corresponding 2-[(2R,5S)-5-benzyl-4-(4-methoxy- removal of the protecting group (reflux, 2.5 h) for 2 aÐe
benzyl)-3-oxo-1,4-oxazinan-2-yl]acetaldehyde by osmi- and 1 hour in 4 N HCl in dioxane for 2f, (ii) 6 N aqueous
um tetroxide/sodium periodate, and then reduced to the HCl (reflux, 20 h, sealed tube), with cumulative yields of
corresponding alcohol with NaBH4. The latter compound 84Ð89% over both steps (Table 2).
was then mesylated to 2-[(2R,5S)-5-benzyl-4-(4-meth-
Table 2 Compounds 4a–e Prepared
Prod-
uct
Yield
(%)
mp (°C)
[a]D20
(1.0 M
HCl)
IR (KBr)
HRMS (FAB)
m/z
1H NMR (DMSO-d6/TMS)
d, J (Hz)
13C NMR (DMSO-d6/
TMS)
d
n (cm–1)
4a
94
155–157
+ 4.1
(c, 0.4)
3427 (H2O), calcd for
2958, 1718, C14H20NO3
1493, 1202, (M–Cl)+:
1.72–1.80 (m,
2.10–2.36 (m, 4 Hcyclobutyl), 2.83 cyclobutyl),
(dd, 1 H, J = 9.4, 13.3 Hz, (CH2PH), 51.8 (CHN),
(Cquart), 78.9
2
H
cyclobutyl), 12.7, 30.3, 30.4 (CH2,
30.4
1159, 734, 250.1443,found: CH2Ph), 3.00 (dd, 1 H, J = 4.8, 62.4
696
250.1438
13.4, CH2Ph), 3.22–3.56 (m, 3 (CH2O), 126.8, 128.5,
H, OCH2 + H–5), 7.24–7.36 (m, 129.2, 136.3 (arom),
5 Harom), 8.08–8.38 (br, 3 H, 174.1 (C=O)
+
NH3 ), 12.85–12.96 (bs, 1 H,
CO2H)
4b
96
178–181
+ 3.7
(c, 0.5)
3423 (H2O), calcd for
2955, 1718, C15H22NO3
1496, 1178, (M–Cl)+:
1.60–1.78 (m, 4 Hcyclopentyl), 23.8 (2×CH2, cyclopen-
1.81–1.92 (m, 4 Hcyclopentyl), 2.82 tyl), 34.9 (CH2Ph), 35.1,
(dd, 1 H, J = 8.9, 13.6 Hz, 35.6 (CH2, cyclopentyl),
1077, 745, 264.1600,found: CH2Ph), 2.94 (dd, 1 H, J = 5.3, 52.0
(CHN),
62.9
701
264.1611
13.7, CH2Ph), 3.22–3.52 (m, 3 (Cquart), 87.5 (CH2O),
H, OCH2 + H–5), 7.22–7.35 (m, 128.6, 128.5, 129.2,
5 Harom), 7.96–8.16 (br, 3 H, 136.4 (arom), 175.2
+
NH3 ), 12.60–12.00 (bs, 1 H, (C=O)
CO2H)
4c
91
98
104–106
147–149
+3.0
(c, 0.5)
3423 (H2O), calcd for
2955, 1718, C16H24NO3
1496, 1178, (M–Cl)+:
1.07–1.30 (m,
1.37–1.58 (m,
1.59–1.80 (m, 4 H), 2.82–3.01 35.0 (CH2Ph), 52.1
1
5
H
H
cyclohexyl), 20.9, 21.0, 24.7, 31.2,
cyclohexyl), 31.7 (CH2, cyclohexyl),
1077, 745, 278.1756,found: (m, 2 H, CH2Ph), 3.22–3.58 (m, (CHN), 61.8 (Cquart),
701
278.1759
3 H, OCH2+H–5), 7.22–7.36 78.7 (CH2O), 126.8,
(m, 5 Harom), 7.84–8.16 (br, 3 H, 128.5, 129.2, 136.5
+
NH3 ), 12.70–12.90 (bs, 1 H, (arom), 175.3 (C=O)
CO2H)
4d
+ 3.4
3414 (H2O), calcd for
3028, 2926, C17H26NO3 (M–
2859, 1718, Cl)+: 292.1913,
1496, 1457, found: 292.1918
1170, 1094,
1.28–1.58 (m, 8 Hcycloheptyl), 21.7, 21.8 (CH2, cyclo-
1.64–1.84 (m, 4 Hcycloheptyl), 2.79 heptyl), 29.1 (2×CH2,
(dd, 1 H, J = 9.5, 13.4 Hz, cycloheptyl), 34.9 (CH2,
CH2Ph), 2.99 (dd, 1 H, J = 4.2, cycloheptyl,
13.2 Hz, CH2Ph), 3.22–3.42 (m, 35.4 (CH2, cycloheptyl),
3 H, OCH2) + H–5), 7.16–7.29 52.2 (CHN), 62.0
CH2Ph),
743, 700
(m, 5 Harom), 7.95–8.40 (br, 3 H, (Cquart), 82.2 (CH2O),
+
NH3 ), 12.30–12.90 (bs, 1 H, 126.8, 128.5, 129.2,
CO2H)
136.5 (arom), 175.8
(C=O)
4e
90
215–216
+ 3.2
(c, 0.5)
3244, 3163, calcd for
2846, 1708, C13H18NO3 (M–
1582, 1510, Cl)+: 236.1287,
1181, 1157, found: 236.1294
1073, 747,
1.13–1.19 (m,
1.22–1.29 (m,
2.79 (dd, 1 H, J = 9.7, 13.7 Hz, 51.6
CH2Ph), 2.98 (dd, 1 H, J = 5.0, (Cquart), 67.4 (CH2O),
13.6 Hz, CH2Ph), 3.14–3.43 (br, 126.8, 128.5, 129.2,
1 H, H–5 + H2O), 3.51–3.60 (m, 136.2 (arom), 175.8
1 H, OCH2), 3.63–3.68 (m, 1 H, (C=O)
3
1
H
H
cyclopropyl), 15.5, 15.7 (CH2, cyclo-
cyclopropyl), propyl), 34.9 (CH2Ph),
(CHN),
59.8
702
OCH2), 7.22–7.36 (m, 5 Harom),
+
8.06–8.25 (br, 3 H, NH3 ),
12.40–12.80 (bs, 1 H, CO2H)
Synthesis 1999, No. 1, 112–116 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Novel and Efficient Synthesis of Spirocyclic Morpholinones
115
To a solution of the above chloride (0.972 mmol) in acetone
(10 mL) was added NaI (1.46 g, 9.72 mmol), refluxed for 5 h,
cooled and concentrated in vacuo. Next, the residue was partitioned
between EtOAc (30 mL) and H2O (20 mL), the organic phase
washed with brine (15 mL), dried (Na2SO4), concentrated and chro-
matographed through a short plug of silica gel (30% EtOAc/hex-
anes) affording (5S)-5-benzyl-2-(w-iodoalkane)-4-(4-methoxy-
benzyl)-1,4-oxazinan-3-ones (88Ð91%).
In summary, utilizing earlier observations of Anthony et al.
and Norman et al.,15, 16, 23 we have developed efficient and
reliable syntheses of novel spirocyclic morpholinones 2aÐ
e, and related dipeptide mimetics Phe-ψ[CH2O]-(Cn)-
CO2H, 4aÐe. To our knowledge, both spirocyclic morpholi-
nones 2, the dipeptide mimetics 4, and overall process lead-
ing to them are novel and unprecedented in the literature.24
A solution of this iodide (0.850 mmol) in THF (85 mL) was treated
with LDA (0.49 mL, 0.98 mmol, 2 M in heptane/THF/ ethylben-
zene) at Ð78¡C. The reaction mixture was then warmed up to Ð10¡C
over 4 h and quenched with aq NH4Cl solution, organic solvents
evaporated in vacuo and the solid residue partitioned between
CHCl3 and H2O. The organic phase was dried (Na2SO4), concentrat-
ed and chromatographed on silica gel (EtOAc/hexanes, 1:4), afford-
ing the desired 2aÐd as white solids (Table 1).
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus and are uncorrected. Optical rotations were
measured at 25¡C. H NMR spectra were recorded in CDCl3 on
1
Bruker (200 MHz) spectrometer. 13C NMR spectra were recorded
in CDCl3 on Varian Unity spectrometer at 75.42 MHz. Chemical
shifts are reported downfield from TMS in ppm. Peak multiplicities
are abbreviated: singlet, s; broad singlet; bs; doublet, d; triplet, t;
quartet, q; multiplet, m. Coupling constants (J values) are reported
in Hertz. Analytical TLC was performed on 2.5 × 10 cm plates pre-
coated with silica gel (GHLF of 0.25 mm thickness), supplied by
Analtech. Microanalyses were performed by Atlantic Microlab,
Inc., Norcross, GA.
(6S)-6-Benzyl-7-(4-methoxybenzyl)-4-oxa-7-azaspiro[2.5]oc-
tan-8-one (2e)
A solution of 1 (375.5 mg, 1.20 mmol) in THF (1.0 mL) was added
dropwise to LDA (0.66 mL, 1.33 mmol, 2.0 M in heptane/THF/eth-
ylbenzene) at Ð78¡C. After stirring for 30 min, freshly distilled allyl
iodide (120 mL, 1.33 mmol) was added dropwise and the reaction
allowed to warm up to Ð10¡C over 2 h, then quenched with aq
NH4Cl solution and the organic solvents removed. To the aqueous
solution was then added solid NH4Cl and partitioned with Et2O
(20 mL). The organic layer was separated and washed with aq
Na2S2O5 solution (10 mL), brine (10 mL), dried (MgSO4) and con-
centrated. Column chromatography on silica gel (22% EtOAc/hex-
anes) afforded 340.3 mg (81%) of the diastereomeric (5S)-5-
benzyl-2-allyl-4-(4-methoxybenzyl)-1,4-oxazinan-3-one. A solu-
tion of the latter (340.3 mg, 0.970 mmol) in THF/H2O (40 mL, 4:1)
was added at r.t. to OsO4 (0.61 mL, 2.5% wt solution in 2-methyl-
propan-2-ol) and NaIO4 (436 mg, 2.04 mmol). After 1 h, the crude
mixture was filtered, THF removed and the aqueous layer parti-
tioned with CHCl3 (40 mL). The organic phase was then washed
with brine (15 mL), dried (Na2SO4), concentrated and purified on a
short plug of silica gel (EtOAc/hexanes, 1:1). The resulting crude
aldehyde was dissolved in THF/EtOH (6 mL, 1:2), NaBH4 (36.7
mg, 0.970 mmol) was added, stirred for 15 min and quenched with
acetone (1 mL). The mixture was then concentrated and chromato-
graphed on silica gel (EtOAc/hexanes, 4:1), affording 262.0 mg
(76%) of the diastereomeric (5S)-5-benzyl-2-(2-hydroxyethyl)-4-
(4-methoxybenzyl)-1,4-oxazinan-3-one. To the CH2Cl2 solution (4
mL) of the latter alcohol (262.0 mg, 0.738 mmol) cooled to 0¡C was
added MeSO2Cl (103 mL, 1.33 mmol) in CH2Cl2 (0.5 mL), fol-
lowed by ethyldiisopropylamine (232 mL, 1.33 mmol) in CH2Cl2
(1.0 mL). After stirring for 30 min, the crude mixture was poured
into ice water (5 mL), extracted with CHCl3 (15 mL), the organic
phase washed with brine (5 mL), dried (Na2SO4) and concentrated,
affording the desired diastereomeric 2-[(5S)-5-benzyl-4-(4-meth-
oxybenzyl)-3-oxo-1,4-oxazinan-2-yl]ethyl methanesulfonate (230
mg, 72% after column chromatography on silica gel with 36 to 66%
EtOAc/hexanes). THF solution (53 mL) of mesylate (230 mg,
0.529 mmol) was treated with 2.0 M LDA in heptane/THF/ ethyl-
benzene (304 mL, 0.608 mmol) at Ð70¡C. The reaction was then
continued at 0¡C over 3 h and quenched with aqueous NH4Cl. The
organics were then removed in vacuo and partitioned between
CHCl3 and brine, the CHCl3 fraction dried (Na2SO4), concentrated
and chromatographed on silica gel (EtOAc/hexanes, 1:3), affording
124.8 mg (74%) of 2e as a white solid (Table 1).
(5S)-5-Benzyl-4-(4-methoxybenzyl)-1,4-oxazinan-3-one (1)23
To a solution of (S)-2-amino-3-phenylpropan-1-ol (22.3 g,
147 mmol) in THF (30 mL) was added ethyldiisopropylamine
(19.6 g, 147 mmol) at 0¡C, followed by dropwise addition of chlo-
roacetyl chloride (16.60 g, 147 mmol) at the same temperature. The
reaction was continued overnight at r.t., the solvents were removed
and the residue was partitioned between EtOAc and H2O. The solid
residue obtained from the organic phase was dissolved in THF
(30 mL), the solution cooled to 0¡C and treated with KOBu-t
(18.0g, 160 mmol) After stirring for 30 min at r.t., the solvents were
removed and the residue partitioned between EtOAc and brine. Sil-
ica gel chromatographic purification of the organic fraction using
EtOAc/hexane/MeOH (1:2:0.1) as eluent provided 23.8 g (85%) of
(5S)-5-benzyl-1,4-oxazinan-3-one. Next, 5.73 g (30 mM) of this
product was dissolved in anhyd DMF (5 mL), cooled down to 0¡C
and NaH (95%, 0.82g, 32 mmol) was added. After 15 min at r.t., the
solution was cooled again to 0¡C, p-methoxybenzyl chloride
(4.70 g, 32 mmol ) was added and the reaction continued at r.t. for
2 h. Chromatographic purification on silica gel (EtOAc/hexane.
1:1) provided 4.72 g (15.2 mmol) of 1 (oil, cumulative yield over all
steps 43%); [a]D25 Ð56.4 (c = 1.0, MeOH) [Lit.23 [a]D25 Ð54.8 (c = 1.0,
MeOH).
MS (AP+) = 312.1 (M+1)+.
1H NMR (200 MHz, CDCl3): d = 2.95 (m, 2 H, benzyl-CH2), 3.26
(m, 1 H, H-5), 3.42 (dd, 1 H, J = 11.6, 1.5 Hz, OCH), 3.68 (d, 1 H,
J = 11.6 Hz, OCH), 3.79 (s, 3 H, OCH3), 3.85 (NCHA-phenyl, 1 H),
5.42 (NCHX-phenyl, 1 H, AX system, JAX = 14.5 Hz), 4.20 (OCHA-
CO, 1 H), 4.34 (OCHX-CO, 1 H, AX system, JAX = 16.5 Hz), 6.87Ð
7.26 (m, 9 Harom).
2-Spiroalkane-(5S)-5-benzyl-4-(4-methoxybenzyl)-
1,4-oxazinan-3-ones 2aÐd; General Procedure
(5S)-5-Benzyl-4-(4-methoxybenzyl)-1,4-oxazinan-3-one (1; 332.7
mg, 1.07 mmol) in THF (1.0 mL) was added dropwise to 2.0 M
LDA in heptane/THF/ethylbenzene (0.615 mL, 1.23 mmol) at
Ð78¡C. After stirring for 30 min, 1-iodo-w-chloroalkane (n = 2Ð5,
5.35 mmol) was added. The reaction mixture was then warmed up
to Ð10¡C over 1 h, quenched with aq NH4Cl solution, organic sol-
vents were evaporated and the residue was partitioned between
CHCl3 (40 mL) and aq NH4Cl solution (15 mL). The organic phase
was then washed with aq Na2S2O5 solution (15 mL), brine (15 mL),
dried (Na2SO4), concentrated and chromatographed on silica gel
(30% EtOAc/hexanes); yield: 76Ð91%.
(2R,5S)-2-Allyl-5-benzyl-4-(tert-butyloxycarbonyl)-
1,4-oxazinan-3-one (2f)
(5S)-5-Benzyl-1,4-oxazinan-3-one (see the synthesis of 1) (4.1 g,
21.5 mmol) was dissolved in MeCN (30 mL), cooled to 0¡C and
Synthesis 1999, No. 1, 112–116 ISSN 0039-7881 © Thieme Stuttgart · New York

116
P. C. Fritch, W. M. Kazmierski
PAPER
added di-tert-butyl dicarbonate (6.95g, 32 mmol), followed by
DMAP (0.262 g, 2.15 mmol) and ethyldiisopropylamine (4.16 g,
32 mmol). After stirring overnight at r.t., solvents were removed
and the solid residue purified on silica gel using 1:3 (v/v) EtOAc/
hexanes, yielding 5.5 g (91%) of the tert-butyl-(3S)-3-benzyl-5-
oxo-1,4-oxazinane-4-carboxylate (3); Rf 0.46 (EtOAc/hexanes,
1:3). To a solution of 3 (4.53 g, 15.6 mmol) in THF (40 mL) was
added a 1 M solution of lithium hexamethyldisiazide in THF
(17.1 mL, 17.1 mmol). After 45 min at Ð78¡C, freshly distilled allyl
iodide (2.87g, 17.1 mmol) was added over 10 min. After an addi-
tional 90 min at Ð78¡C, the reaction was quenched with 1 M aq cit-
ric acid (10 mL), and the product purified on silica gel (EtOAc/
hexane, 1:4), yielding a single diastereomer 2f (2.4 g, 47%); Rf 0.7
(EtOAc/hexanes, 1:3). (Daicel OF, 10% IPA/hexane).
References
¦
Address until December 1998: Glaxo Wellcome S.p.A., Lead
Discovery, Via A. Fleming 4, I-37135 Verona, Italy. Fax
+39(45)9218196; E-mail: wmk35860@glaxowellcome.co.uk
(1) Pauletti, G.; Gangwar, S.; Siahaan, T.J.; Jeffrey, A.T.; Bor-
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13C NMR (75.42 MHz, CDCl3): d = 28.0 [C(CH3)3], 36.0 (benzyl
CH2), 38.1 (allyl CH2), 57.2 (CHN), 61.4 (OCH2), 77.5 (CHO), 83.5
(CMe3), 118.0 (CH2=), 126.9 (CH=), 128.69 (ar), 129.65 (ar),
133.81 (ar), 137.1 (Cq-ar), 151.1 (CO), 169.6 (CO).
1H NMR (200 MHz, CDCl3): d = 1.57 (s, 9 H, t-C4H9), 2.67 (m, 2
H, =CHCH2), 3.00 (m, 2 H, benzyl CH2), 3.60 (dd, 1 H, J = 2.6, 12.3
Hz, OCH2), 3.77 (dd, 1 H, J = 2.4, 12.4 Hz, OCH2), 4.22 (m, 1 H,
CH-N), 4.36 (1 H, dd, J = 4.5, 8.5 Hz, OCH), 5.15 (m, 2 H, CH2=),
5.83 (m, 1 H, CH=), 7.23 (m, 5 H, ar).
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Phe-ψ[CH2O](Cn)CO2H 4aÐf; General Procedure
A solution of 2aÐe (0.286 mmol) in 0.5 mL of TFA was refluxed for
2.5 h, cooled, concentrated and chromatographed on silica gel (45Ð
55% EtOAc/hexanes) affording the deprotected morpholinone (86Ð
99%). Compound 2f was deprotected with 4 N HCl in dioxane
(5 mL) for 1 h at r.t. To the above deprotected products
(0.351 mmol) was added 6 N aq HCl (2 mL) and placed in an am-
poule. The sealed ampoule was heated at 95¡C for 20 h, cooled to
r.t., and the contents were evaporated to dryness. The residue was
dissolved in warm water (10 mL), washed with CHCl3 (5 mL) and
lyophillized, affording the isostere 4 as white hygroscopic solid in
90Ð98% yield (Table 2).
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Acknowledgement
We thank D. Minick, L. St. John, A. Seßer and B. Hall for their
superb analytical support. Drs F. Salituro, M. Hale (Vertex Phar-
maceuticals) and A. Spaltenstein, E. FunÞne (GW) are thanked for
fruitful discussions (Salituro, et al. Bioorg. Med. Chem., submit-
ted). PCF is a Glaxo Wellcome postdoctoral fellow.
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Synthesis 1999, No. 1, 112–116 ISSN 0039-7881 © Thieme Stuttgart · New York