A practical and stereoselective synthesis of (+/-)-trans-4- benzyloctahydropyrrolo[3,4-b][1,4]oxazine

Article abstract of DOI:10.1002/jhet.476

(Chemical Equation Presented) trans-Octahydropyrrolo[3,4-b][1,4]oxazine is an important heterocycle within the pharmaceutical industry for the preparation of biologically active analogs, including the phase III drug, finafloxacin. A practical synthesis of the title compound (2) is described in eight steps and ca. 10% overall yield. The key synthetic step is the formation of the pyrrolo[3,4-b][1,4]oxazine core 20 via a one pot double N-alkylation of the corresponding bis-tosylate 18 with 4-nitrobenzenesulfonamide. Subsequent removal of the nosyl group occurred under mild conditions.

Full text of DOI:10.1002/jhet.476

September 2010
A Practical and Stereoselective Synthesis of (þ/ꢀ)-trans-4-
Benzyloctahydropyrrolo[3,4-b][1,4]oxazine
1095
Daniel P. Walker,* Joseph W. Strohbach, Molly A. McGlynn,
and Hwang-Fun Lu
Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West,
Chesterfield, Missouri 63017
*E-mail: daniel.p.walker@pfizer.com
Received December 10, 2009 Revised 3 March 2010; accepted 27 March 2010
DOI 10.1002/jhet.476
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
trans-Octahydropyrrolo[3,4-b][1,4]oxazine is an important heterocycle within the pharmaceutical
industry for the preparation of biologically active analogs, including the phase III drug, finafloxacin. A
practical synthesis of the title compound (2) is described in eight steps and ca. 10% overall yield. The
key synthetic step is the formation of the pyrrolo[3,4-b][1,4]oxazine core 20 via a one pot double
N-alkylation of the corresponding bis-tosylate 18 with 4-nitrobenzenesulfonamide. Subsequent removal
of the nosyl group occurred under mild conditions.
J. Heterocyclic Chem., 47, 1095 (2010).
INTRODUCTION
The morpholine ring is utilized extensively in drug
discovery research. Due to its hydrophilic nature, medic-
inal chemists will often look for opportunities to incor-
porate morpholine into their analogs as a means to
increase solubility. Within a chemical series, morpho-
line, with its lower pKa compared to isosteric piperidine
(8.3 vs. 11.1), has been shown to reduce hERG activity
[1], which is an early indicator of cardiovascular risk.
Numerous drugs incorporating the morpholine ring have
been approved for the treatment of human diseases; a
snapshot of some recent examples is shown in Chart 1,
R
V
R
V
including linezolid (Zyvox ) [2], gifitinib (Iressa ) [3],
and reboxetine [4]. Finafloxacin, which is currently
undergoing clinical trials for the treatment of Helico-
bacter pylori (H. pylori) infections [5], possesses a mor-
pholine ring fused onto a pyrrolidine ring, giving rise to
the trans-pyrrolo[3,4-b][1,4]oxazine heterocycle. The
ring fusion restricts the spatial orientation of the mor-
pholine ring compared to the unfused analog; this
restriction is presumably important for optimal binding
to the biological receptor. In addition, the pyrrolidine
nitrogen provides a chemical handle for attaching the
heterocycle to the analog of interest.
Chart 1.
rolo [3,4-b][1,4]oxazine-4(4aH)-carboxylate [(4aS,7aS)-1],
wherein the morpholine nitrogen is differentially protected
with respect to the pyrrolidine nitrogen. In connection with
our own medicinal chemistry efforts, we were also inter-
ested in preparing this novel heterocycle wherein the mor-
pholine nitrogen was selectively protected. We detail below
a stereoselective synthesis of (þ/ꢀ)-trans-4-benzyloctahy-
dropyrrolo[3,4-b][1,4]oxazine (2).
Recently, Hong et al. [6] have disclosed a synthesis of
enantiomerically pure (4aS,7aS)-tert-butyl hexahydro pyr-
C
V
2010 HeteroCorporation

1096
D. P. Walker, J. W. Strohbach, M. A. McGlynn, and H.-F. Lu
Vol 47
Scheme 2. Reagents and conditions: (i) BnNH2 (excess), H2O, reflux,
3 h; (ii) AcCl, EtOH, 0ꢁC, 1h; add substrate, reflux, 72 h; (iii) chloroa-
cetyl chloride, CH2Cl2-aq. 1 N NaOH, 0ꢁC, 15 min; (iv) NaH (1.8
eq.), THF-CH3CN-DMF (90:5:5), 0ꢁC, 1 h.
RESULTS AND DISCUSSION
Hong prepared enantiomerically pure pyrrolo[3,4-b]
[1,4]oxazine (4aS,7aS)-1 by a ten step synthesis outlined
in Scheme 1 [6]. Thus, epoxypyrrolidine 4 was prepared
in three steps from commercial (Z)-but-2-ene-1,4-diol
(3). Opening epoxide 4 with (R)-a-methylbenzylamine
led to diastereomers 5 and 6, which were readily sepa-
rated by solvent extraction and crystallization techni-
ques. Treatment of diastereomer 5 with chloroacetyl
chloride, followed by exposure to base effected ring clo-
sure, and subsequent reduction of the lactam carbonyl
afforded the intact pyrrolo[3,4-b][1,4]oxazine hetero-
cycle 7. Exchanging the a-methylbenzyl protecting
group on N(4) for a tert-butoxycarbonyl (BOC) group
and deprotection of the pyrrolidine nitrogen led to pyr-
rolo[3,4-b][1,4]oxazine (4aS,7aS)-1.
Our approach toward synthesizing the trans-fused
pyrrolo[3,4-b][1,4]oxazine heterocycle focused on ster-
eoselectively preparing a 2,3-disubstituted morpholine
wherein the sustituents at C(2) and C(3) are trans with
respect to each other. Thus, the known dicarboxylic acid
9 [7], prepared in near quantitative yield from commer-
cial cis-epoxysuccinic acid (8), served as the logical
starting point (Scheme 2). Esterification of 9 with abso-
lute ethanol and hydrogen chloride, generated in situ
from ethanol and acetyl chloride, provided the corre-
sponding diester in good yield. Esterification with etha-
nol in the presence of thionyl chloride was also effec-
tive; however, the yield was significantly lower, and chro-
matography was necessary to remove the impurities
formed during the reaction. Treatment of the diester with
chloroacetyl chloride under Shotten-Baumann conditions
afforded a-chloroacetamide 10. Under these conditions, 5–
10% of the corresponding o-acylated product was formed
along with 1–2% of di-acylated product. However, the o-
acylated product could be easily removed by extracting the
crude reaction mixture with aqueous hydrochloric acid.
Subjection of chloroalcohol 10 to sodium hydride gave
rise, after purification, to a 9:1 mixture [8] of morpholi-
nones 11 and 12, respectively. Fortuitously, whereas the
desired trans-diester 11 was a solid (mp 117–118ꢁC), the
undesired cis-diester 12 was an oil. Thus, a simple tritura-
tion of the product mixture efficiently removed the unde-
sired 12, affording a 76% yield of pure 11.
Scheme 1
The structural assignments of 11 and 12 were based
on a combination of 1D and 2D NMR experiments. For
trans-diester 11, the vicinal coupling constant between
H2 and H3 was 1.7 Hz, which suggested that the ester
groups adopt a pseudo trans-diaxial orientation to avoid
A1,2 strain between the C(3) ester moiety and the ben-
zylic hydrogens (Fig. 1). This interpretation is consistent
Figure 1. 3D representation of diester 11. Arrow shows vicinal cou-
pling relationship.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
A Practical and Stereoselective Synthesis of
(þ/ꢀ)-trans-4-Benzyloctahydropyrrolo[3,4-b][1,4]oxazine
1097
Scheme 3. Reagents and conditions: (i) BnNH2 (excess), H2O, reflux,
3 h; (ii) AcCl, EtOH, 0ꢁC; add substrate, reflux, 72 h; (iii) chloroacetyl
chloride, CH2Cl2-aq. 1.0 N NaOH, 0ꢁC, 15 min; (iv) NaH (1.8 eq.),
THF-CH3CN-DMF (90:5:5), 0ꢁC, 1 h.
Scheme 4. Reagents and conditions: (i) LiAlH4 (5.0 eq.), THF, 0o
!
room temperature, 30 min, room temperature ! reflux, 30 min; (ii)
Ts2O (3.0 eq.), pyridine (3.0 eq.), CH2Cl2, 0ꢁC, 30 min; (iii) 4-nitro-
benzenesulfonamide (3.0 eq.), DBU (2.0 eq.), CH3CN, 70ꢁC, 2 h; (iv)
C
12H25SH (2.0 eq.), LiOHꢂH2O (2.0 eq.), DMF, room temperature, 2
h, 77%; (v) 4 M HCl-dioxane, MeOH, room temperature!40ꢁC, 60%.
with observations made by others on similar ring sys-
tems [9]. Also, once the pyrrolidine ring was fused onto
11 (vide infra), the H2–H3 vicinal coupling constant
changed to ca. 9 Hz, which is consistent with a trans-
diaxial orientation of the two vicinal hydrogens. The
H2–H3 vicinal coupling constant for cis-diester 12 was
2.7 Hz, which is consistent with an axial-equitorial ori-
entation of the two ester moieties.
Interestingly, prolonged exposure of either 11 or 12 to
sodium hydride in tetrahydrofuran at 0ꢁC resulted, in
addition to decomposition, in the formation of a new
product, which, based on spectral data, we have
assigned as ethyl 3-benzyl-2-(2-ethoxy-2-oxoethyl)-4-
oxooxazolidine-2-carboxylate (16, Chart 2) [10].
With the stereochemistry at C(2) and C(3) secure,
efforts were directed toward installing the remaining pyr-
rolidine ring. Toward this end, reduction of 11 with lith-
ium aluminum hydride afforded diol 17 (Scheme 4). Bis-
tosylate 18 was realized in 76% yield by treating diol 17
with tosic anhydride. The use of tosyl chloride in pyridine
led, in addition to bis-tosylate 18, a significant amount of
monotosylate-monochloride products 19 (Chart 2).
Unexpectedly, subjection of alcohol 15, prepared
according to Scheme 3, to identical cyclization condi-
tions [NaH (1.8 eq.), THF-CH3CN-DMF (90:5:5), 0ꢁC,
30 min] afforded a 2.5:1 mixture of 11 and 12, respec-
tively [8]. Clearly, equilibration of one of the esters is
taking place during the reaction. Furthermore, it is likely
that equilibration is occurring after ring closure based
on the following observations: (1) resubmitting pure
trans-diester 11 to the cyclization conditions for 30 min
led to a 10:1 mixture of 11 and 12, respectively. Like-
wise, resubmitting pure cis-diester 12 to the cyclization
conditions for 30 min led to a 6:1 ratio of 11 and 12,
respectively; (2) stopping the cyclization reaction of 10
prior to completion (Scheme 2) and analysis of the reac-
tion mixture found no evidence of diastereomer 15.
Fukuyama has popularized the use of 2-nitro- and 4-
nitrobenzenesulfonamide (2-Ns-NH2, Ns-NH2, respec-
tively) as useful starting materials for the efficient con-
struction of cyclic secondary amines [11]. The protocol
involves
a two-step alkylation-cyclization sequence
(Scheme 5). Since this two-step protocol was primarily
developed for the preparation of medium-sized rings, we
were curious as to whether a pyrrolidine ring could be
formed in a single pot via a double N-alkylation with
Ns-NH2. While we could find no examples of pyrroli-
dine ring formation via a double N-alkylation with Ns-
NH2, pyrrolidine ring formation via double N-alkylation
with para-toluenesulfonamide (Ts-NH2) is well prece-
dented [12], including one example by Hong et al. [6]
to prepare (4aS,7aS)-1. However, Ts-NH2 was a less
Scheme 5. Fukuyama’s nitrobenzenesulfonamide methodology for the
construction of secondary cyclic amines.
Chart 2.
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D. P. Walker, J. W. Strohbach, M. A. McGlynn, and H.-F. Lu
Vol 47
Scheme 6. Reagents and conditions: (i) (CF3CO)2O (2.0 eq.), Et3N
(4.0 eq.), CH2Cl2, 0ꢁC ! room temperature, 1.5 h; (ii) H2, 10% Pd/C,
MeOH, 42 psi, room temperature, 48 h; (iii) (BOC)2O, CH2Cl2, room
temperature, 24 h; (iv) K2CO3 (2.0 eq.), MeOH-water (5:1), room tem-
perature, 1 h.
attractive nucleophile to us in that subsequent removal
of the tosyl group typically requires either strongly
reducing conditions, such as sodium naphthalide, or
strongly acidic conditions. On the contrary, the nosyl
group is typically removed under mild conditions [11].
We were pleased to find that heating an acetonitrile so-
lution of bis-tosylate 18 with 4-nitrobenzenesulfonamide
in the presence of DBU gave rise (57%) to pyrrolo[3,4-
b][1,4]oxazine 20 (Scheme 4). While other bases, such
as sodium hydride, potassium carbonate, or diisopropy-
lethylamine, did effect ring closure, the reactions did
not go to completion, even when additional base was
added. No other organic-soluble product could be iso-
lated from this reaction. Given the presence of DBU
and the ease of bis-tosylate 18 forming an anti-peripla-
nar relationship between the carbon-oxygen bond of one
of the tosylates and the axial carbon-hydrogen bond at
C(2) or C(3), it is possible that the elimination pathway
was competing with substitution. However, no elimina-
tion byproducts could be isolated upon workup. That
pyrrolo[3,4-b][1,4]oxazine 20 possessed a trans-ring
fusion was readily confirmed based on the large cou-
pling constant (9.0 Hz) between the bridgehead protons,
Hong’s BOC-protected pyrrolo[3,4-b][1,4]oxazine 1 by
the sequence outlined in Scheme 6. Thus, trifluoroacety-
lation of 2 and subsequent hydrogenolysis of the benzyl
group led to amine 22, which should serve as a useful in-
termediate for the preparation of pyrrolo[3,4-b][1,4]oxa-
zine analogs connected through N(4). BOC protection of
N(4) and hydrolysis of the trifluoroacetamide group
afforded (þ/ꢀ)-1. The spectral properties of our racemic
(þ/ꢀ)-1 were consistent with those of (4aS,7aS)-1 [6,15].
1
H4a and H7a in the H-NMR spectrum (Fig. 2). Addi-
tional 2D NMR experiments on 20 were also in support
of the proposed structure (data not shown).
Cleavage of the nosyl group to afford pyrrolo[3,4-b]
[1,4]oxazine 2 was realized in 77% yield via treatment of
sulfonamide 20 with dodecanethiol in the presence of lith-
ium hydroxide [13] (Scheme 4). Under these conditions,
ca. 15% of aryl thioether 21 was formed (Chart 2). This
was not surprising given others have also observed this
byproduct during thiol-mediated deprotection of nosyl-
protected cyclic amines [14]. Wuts et al. [14a] has further
observed that 2-nitrobenzenesulfonamide (2-Ns-NH2) was
less likely to produce the corresponding byproduct.
Unfortunately, the use of 2-Ns-NH2 in the pyrrolidine cy-
clization reaction led to inferior yields (20% vs. 57%).
As a final proof of structure, we have converted
CONCLUSIONS
In summary, we have reported a practical and stereo-
selective eight-step synthesis of (þ/ꢀ)-trans-4-benzyloc-
tahydropyrrolo[3,4-b][1,4]oxazine (2) from inexpensive
starting materials and reagents. Only two intermediates
required chromatographic purification; otherwise, the
remaining compounds were purified by precipitation or
trituration. The conditions developed for the one pot
double N-alkylation-pyrrolidine ring formation using 4-
nitrobenzenesulfonamide and DBU will likely be of gen-
eral interest to the synthetic community.
benzyl-protected pyrrolo[3,4-b][1,4]oxazine
2
into
EXPERIMENTAL
Proton (1H), carbon (13C), and fluorine (19F) nuclear mag-
netic resonance (NMR) spectra were recorded on a Bruker 400
spectrometer. Chemical shifts are reported in parts per million
(d) relative to tetramethylsilane (d 0.0). Assignments of key
NMR signals were made by a combination of gHSQC,
gHMBC, and ROESY experiments. Stereochemical assign-
ments for compounds 11, 12, 20 and (þ/ꢀ)-1 were made
based on a combination of ROESY and non-overlapping J
coupling constants. Infrared (IR) spectra were recorded on a
Bruker Vector 33 FTIR. High resolution mass spectra (MS)
were acquired on an Agilent 1200 series LCMS TOF with UV
detection. Combustion analyses were performed by QTI Inter-
tek, Whitehouse, NJ. Melting points were recorded on an
Figure 2. 3D Representation of compound 20. Arrow shows vicinal
coupling relationship.
R
VElectrothermal Mel-Temp 3.0 device and are uncorrected.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
A Practical and Stereoselective Synthesis of
(þ/ꢀ)-trans-4-Benzyloctahydropyrrolo[3,4-b][1,4]oxazine
1099
Reactions were monitored by thin layer chromatography
(TLC) using Analtech silica gel GF 250 micron plates. The
plates were visualized either by UV inspection or by staining
with an ammonium molybdate/ ceric sulfate mixture. Flash
chromatography was performed as described by Still et al.
[16] using Aldrich column chromatography grade silica gel
(200–400 mesh). All reagents were purchased from either the
Aldrich Chemical Co. or TCI America Chemical Co. and used
without further purification. All solvents were HPLC grade
unless otherwise stated. Anhydrous solvents were purchased
from EMD Chemical Co. and used as supplied.
Anal. Calcd. for C15H21NO5: C, 61.00; H, 7.17; N, 4.74.
Found: C, 61.06; H, 7.13; N, 4.67.
Diethyl 2-(N-benzyl-2-chloroacetamido)-threo-3-hydroxy-
succinate (10). To a rapidly stirred solution of diethyl N-Ben-
zyl-threo-b-hydroxy-DL-aspartate (20.0 g, 67.7 mmol) in
dichloromethane (160 mL) at 0ꢁC, ice cold sodium hydroxide
(102 mL of a 1.0 M aqueous solution) was added, followed by
dropwise addition of a solution of chloroacetyl chloride (8.1
mL, 102 mmol) in dichloromethane (8.0 mL). After complete
addition, the mixture was stirred at 0ꢁC for 15 min. Sodium
hydroxide (20 mL of a 1.0 M aqueous solution) was added,
followed by separation of the layers. The aqueous layer was
extracted with dichloromethane. The combined organic layers
were washed with brine, dried over anhydrous magnesium sul-
fate, filtered and concentrated in vacuo. The remaining oil was
dissolved in ether and extracted three times with 3.0 M aque-
ous hydrochloric acid (to remove o-acylated byproduct). The
ethereal layer was washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to afford
an oil. Trituration of the oil in hexanes-ether (9:1) gave 20.2 g
(80%) of 10 as a white solid: mp 69–71ꢁC; Rf 0.20 (hexanes-
acetone, 85:15); IR (CH2Cl2) 3427, 2984, 1738, 1660, 1452,
1267, 1026, 737 cmꢀ1; 1H-NMR (400 MHz, CDCl3) d 7.35–
7.18 (m, 5H), 4.95–4.83 (m, 2H), 4.69 (ABq, 2H, JAB ¼ 17.2
Hz, DmAB ¼ 85.6 Hz), 4.25–4.10 (m, 4H), 4.00–3.85 (m, 2H),
1.51 (br s, 1H), 1.25 (t, 3H, J ¼ 7.0 Hz), 1.18 (t, 1H, J ¼ 7.0
Hz); 13C-NMR (100 MHz, CDCl3) d 171.5, 169.2, 167.4,
135.4, 128.9, 128.1, 126.9, 70.94, 62.26, 62.13, 62.03, 53.58,
41.43, 13.99, 13.91; high resolution MS (ESI) Calcd. for
C17H23ClNO6 [M þ H] m/e 372.1247. Found: 372.1208. Anal.
Calcd. for C17H22ClNO6: C, 54.92; H, 5.96; N, 3.77. Found:
C, 54.87; H, 5.73; N, 3.70.
Diethyl trans-4-benzyl-5-oxomorpholine-2,3-dicarboxylate
(11) and diethyl cis-4-benzyl-5-oxomorpholine-2,3-dicarbox-
ylate (12). To a stirred suspension of sodium hydride (60% oil
dispersion, 1.98 g, 49.4 mmol) in dry tetrahydrofuran (150
mL) at 0ꢁC under nitrogen atmosphere, a solution of alcohol
10 (10.2 g, 27.4 mmol) in tetrahydrofuran-acetonitrile (50 mL,
4:1) via canula was added. After complete addition, DMF (10
mL) was added, and the mixtue was stirred at 0ꢁC for 1 h.
Once the reaction was complete (TLC monitoring), it was
poured over a rapidly stirred solution of 10% aqueous acetic
acid (100 mL). Note: once the cyclization was complete, the
mixture becomes dark orange in color. If the reaction was not
quenced shortly after the orange color appeared, 4-oxooxazoli-
dine 16 began to form. In latter runs, we found that adding
solid alcohol 10 directly to a 0ꢁC suspension of 1.4 equiva-
lents of sodium hydride in tetrahydrofuran-acetonitrile-DMF
(9:0.5:0.5) for 1 h minimized the formation of 16. The mixture
was concentrated in vacuo to a volume of ca. 80 mL. The
remaining liquid was extracted with ethyl acetate. The organic
layer was extracted with saturated aqueous potassium carbon-
ate solution (to remove carboxylic acid byproducts). The or-
ganic layer was washed with brine and dried over anhydrous
magnesium sulfate. The organic layer was passed through a
short plug of silica gel to remove base-line impurities. The or-
ganic layer was concentrated in vacuo to a tan solid. Tritura-
tion of the remaining solid in hexanes-ether (9:1) gave 5.9 g
(64%) of 11 as a fluffy white solid. The mother liquor was
concentrated in vacuo and purified by flash chromatography on
silica gel. Elution with hexanes-ethyl acetate (70:30) afforded
N-Benzyl-threo-b-hydroxy-DL-aspartic acid (9). This
compound was prepared according to the procedure of Liws-
citz [7] with slight modification:
To a stirred solution of cis-epoxysuccinic acid (8, 30 g, 227
mmol) in water (50 mL), benzylamine (84 mL, 770 mmol)
was added. The mixture was heated to reflux for 3 h. The mix-
ture was cooled to room temperature, followed by the addition
of 15% aqueous sodium hydroxide until pH ¼ 13. The aque-
ous layer was extracted with ether (3ꢃ) to remove the benzyl-
amine. The ethereal layer was discarded. The aqueous layer
was acidified with concentrated hydrochloric acid to pH ¼ 4,
which caused a white precipitate to form. The precipitate was
filtered and washed with water. The pH of the mother liquor
was re-adjusted to 4 with concentrated hydrochloric acid and
additional precipitation occurred. The precipitate was filtered,
washed with water. The combined precipitates were dried in
vacuo to afford 52 g (96%) of 9 as a white solid: 1H-NMR
(400 MHz, DMSO-d6) d 11.0–10.0 (br s, 2H), 7.35–7.22 (m,
5H), 4.25 (d, 1H, J ¼ 5.5 Hz), 3.92 (ABq, 2H, JAB ¼ 12.9
Hz, DmAB ¼ 61.6 Hz), 3.58 (d, 1H, J ¼ 5.9 Hz); 13C-NMR
(100 MHz, DMSO-d6) d 173.5, 171.0, 137.1, 129.2, 128.9,
128.1, 69.79, 61.55, 50.75; high resolution MS (ESI) Calcd.
for C11H14NO5 [M þ H] m/e 240.0892. Found: 240.0866. An
analytical sample was prepared via recrystallization from
water: mp 224–225ꢁC (dec.) (Ref. [7] 225–226ꢁC).
Diethyl N-benzyl-threo-b-hydroxy-DL-aspartate. To
a
stirred solution of dry ethyl alcohol (550 mL) at 0ꢁC, acetyl
chloride (54 mL, 760 mmol) was added. After complete addi-
tion, the solution was stirred at 0ꢁC for 1 h. To this solution,
diacid 9 (45.0 g, 190 mmol) was added, and the whole mixture
was heated to reflux for 72 h. The mixture was cooled to room
temperature, and the ethanol was removed in vacuo to afford a
clear oil. The oil was partitioned between ether and saturated
aqueous potassium carbonate solution. The ethereal layer was
washed with aqueous potassium carbonate solution and brine.
The ethereal layer was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to afford 43 g (77%) of
diethyl N-Benzyl-threo-b-hydroxy-DL-aspartate as
a white
solid: Rf 0.31 (hexanes-ethyl acetate, 3:1), IR (CH2Cl2) 3490,
3347, 3028, 2982, 2906, 2872, 1741, 1465, 1454, 1258, 1190,
1
1107, 740, 700 cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.27 (m,
5H), 4.46 (d, 1H, J ¼ 2.7 Hz), 4.22 (q, 2H, J ¼ 7.0 Hz),
4.25–4.16 (m, 1H), 4.13–4.05 (m, 1H), 3.74 (ABq, 2H, JAB
¼
13.3 Hz, DmAB ¼ 124 Hz), 3.59 (d, 1H, J ¼ 2.8 Hz), 1.26 (t,
3H, J ¼ 6.8 Hz), 1.16 (t, 3H, J ¼ 7.2 Hz); 13C-NMR (100
MHz, CDCl3) d 172.4, 171.7, 139.5, 128.3, 128.2, 127.1,
72.10, 62.03, 61.93, 61.43, 52.15, 14.17, 14.00; high resolution
MS (ESI) Calcd. for C15H22NO5 [M þ H] m/e 296.1529.
Found: 296.1492. An analytical sample was prepared via
recrystallization from hexanes-ethyl acetate: mp 40–41ꢁC.
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1100
D. P. Walker, J. W. Strohbach, M. A. McGlynn, and H.-F. Lu
Vol 47
an additional 1.1 g of 11 as a fluffy white solid (76% com-
bined yield of 11). Further elution afforded 0.70 g (8%) of cis-
diester 12 as a clear oil.
3.71–3.65 (m, 2H), 3.64 (ABq, 2H, JAB ¼ 13.3 Hz, DmAB
¼
392 Hz), 3.58 (td, 1H, J ¼ 11.3, 1.9 Hz), 3.55 (m, 1H), 2.73,
(br s, 1H), 2.67 (dm, 1H, J ¼ 11.8 Hz), 2.45 (m, 1H), 2.33
(td, 1H, J ¼ 11.3, 3.5 Hz), 2.07 (br s, 1H); 13C-NMR (100
MHz, CDCl3) d 137.9, 128.1, 127.8, 126.7, 77.31, 64.99,
62.64, 62.19, 58.02, 50.54; high resolution MS (ESI) Calcd.
for C13H20NO3 [M þ H] m/e 238.1472. Found: 238.1437.
%Water (KF): 2.07. Anal. Calcd. for C13H19NO3ꢂ2.07% H2O:
C, 64.48; H, 8.13; N, 5.78. Found: C, 64.15; H, 8.17; N, 5.74.
trans-(4-Benzylmorpholine-2,3-diyl)bis(methylene) bis(4-
methylbenzenesulfonate) (18). To a stirred solution of diol 17
(1.00 g, 4.21 mmol) in dichloromethane (40 mL) at 0ꢁC, pyri-
dine (1.0 mL, 12.6 mmol), followed by p-toluenesulfonic an-
hydride (4.13 g, 12.6 mmol) was added. The mixture was
stirred at 0ꢁC for 30 min. The mixture was diluted with ether
and water. The organic layer was washed with water and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo to an amber oil. The
crude product was purified by flash chromatography on silica
gel. Elution with hexanes-ethyl acetate (80:20 ! 70:30), fol-
lowed by further elution with hexanes-ethyl acetate-triethyl-
amine (58:40:2) afforded 1.75 g (76%) of 18 as a clear oil: Rf
trans-Diester 11. Rf 0.32 (hexanes-acetone, 85:15); IR
(CH2Cl2) 2987, 2941, 1738, 1657, 1454, 1426, 1296, 1137,
1
737, 702 cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.30–7.10 (m,
5H), 4.68 (m, 1H), 4.57 (ABq, 2H, JAB ¼ 14.8 Hz, DmAB 676
Hz), 4.50 (ABq, 2H, JAB ¼ 13.2 Hz, DmAB ¼ 184 Hz), 4.23
(d, 1H, J ¼ 1.8 Hz), 4.20 (dq, 2H, J ¼ 7.4, 2.3 Hz), 4.05 (m,
1H), 3.75 (m, 1H), 1.23 (t, 3H, J ¼ 7.4 Hz), 1.00 (t, 3H, J ¼
7.4 Hz); 13C-NMR (100 MHz, CDCl3) d 168.5, 168.0, 166.3,
135.1, 128.9, 128.6, 128.0, 72.88, 64.80, 62.51, 61.93, 58.61,
48.79, 14.05, 13.73; high resolution MS (ESI) Calcd. for
C17H22NO6 [M þ H] m/e 336.1478. Found: 336.1441. An ana-
lytical sample was prepared via recrystallization from hexanes-
ethyl acetate: mp 117–118ꢁC. Anal. Calcd. for C17H21NO6: C,
60.89; H, 6.31; N, 4.18. Found: C, 60.95; H, 6.23; N, 4.12.
cis-Diester 12. Rf 0.15 (hexanes-acetone, 85:15); IR
(CDCl3) 2984, 1750, 1669, 1453, 1209, 1140, 1028, 704
1
cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.35–7.19 (m, 5H), 4.65
(ABq, 2H, JAB ¼ 14.9 Hz, DmAB ¼ 576 Hz), 4.47 (ABq, 2H,
JAB ¼ 17.2 Hz, DmAB ¼ 62.5 Hz), 4.42 (d, 1H, J ¼ 2.7 Hz),
4.23–4.03 (m, 5H), 1.24 (t, 3H, J ¼ 7.0 Hz), 1.18 (t, 3H, J ¼
7.4 Hz); 13C-NMR (100 MHz, CDCl3) d 167.2, 166.1, 166.1,
135.1, 128.9, 128.6, 128.1, 74.67, 67.75, 62.51, 62.05, 59.09,
49.35, 14.06, 14.01; high resolution MS (ESI) Calcd. for
C17H22NO6 [M þ H] m/e 336.1478. Found: 336.1441. Anal.
Calcd. for C17H21NO6: C, 60.89; H, 6.31; N, 4.18. Found: C,
60.64; H, 6.24; N, 4.12.
1
0.25 (hexanes-ethyl acetate, 3:1); H-NMR (400 MHz, CDCl3)
d 7.73 (d, 2H, J ¼ 8.2 Hz), 7.72 (d, 2H, J ¼ 8.6 Hz), 7.30 (d,
2H, J ¼ 8.2 Hz, 7.28 (d, 2H, J ¼ 8.4 hz), 7.25–7.10 (m, 5H),
4.26 (dd, 1H, J ¼ 10.9, 5.4 Hz), 4.23–4.18 (m, 2H), 4.15 (td,
1H, J ¼ 10.5, 3.9 Hz), 3.69–3.65 (m , 1H), 3.63–3.54 (m, 1H),
3.51 (ABq, 2H, JAB ¼ 13.3 Hz, DmAB ¼ 188 Hz), 3.47–3.38
(m, 1H), 2.66–2.60 (m, 1H), 2.56–2.48 (m, 1H), 2.39 (s, 6H),
2.21–2.13 (m, 1H); 13C-NMR (100 MHz, CDCl3) d 145.1,
144.9, 137.6, 132.7, 132.4, 130.0, 129.8, 128.6, 128.3, 128.0,
127.9, 127.2, 72.55, 68.32, 65.29, 63.13, 58.43, 57.81, 48.29,
21.61; low resolution MS (ESI) m/e 546 [M þ H]. Note: In
our hands, bis-tosylate 18 decomposed at room temperature
4-Oxooxazolidine 16. Rf 0.34 (hexanes-acetone, 85:15); IR
(CHCl3) 2983, 1735, 1717, 1404, 1266, 1182, 1057, 1028, 704
1
cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.30–7.20 (m, 5H), 4.54
(ABq, 2H, JAB ¼ 16 Hz, DmAB ¼ 45 Hz); 4.47 (ABq, 2H, JAB
¼ 14 Hz, DmAB ¼ 38 Hz); 4.06–3.87 (m, 4H), 2.90 (ABq, 2H,
JAB ¼ 15 Hz, DmAB ¼ 108 Hz); 1.15 (t, 6H, J ¼ 7 Hz); 13C-
NMR (100 MHz, CDCl3) d 170.4, 167.9, 167.6, 135.4, 128.5,
128.1, 127.7, 93.1, 67.3, 62.1, 60.9, 43.72, 39.3, 13.80, 13.65;
high resolution MS (ESI) Calcd. for C17H22NO6 [M þ H]
m/e 336.1478. Found: 336.1441. Anal. Calcd. for
C17H21NO6ꢂ0.25H2O: C, 60.07; H, 6.38; N, 4.12. Found: C,
59.94; H, 6.15; N, 4.02.
1
under nitrogen atmosphere by ca. 20% (based on the H-NMR
spectrum) over a two week period. In latter runs, bis-tosylate
18 was stored at 0ꢁC and used in the next reaction within a
24 h period, which minimized decomposition.
trans-4-Benzyl-6-(4-nitrophenylsulfonyl)octahydro- pyr-
rolo[3,4-b][1,4]oxazine (20). To a stirred solution of 4-nitro-
benzenesulfonamide (1.44 g, 7.15 mmol) and DBU (0.71 mL,
4.76 mmol) in dry acetonitrile (10 mL) at 70ꢁC, a solution of
bis-tosylate 18 (1.30 g, 2.38 mmol) in acetonitrile (5.0 mL)
via canula was added. After complete addition, the mixture
was stirred at 70ꢁC and monitored by TLC. Once the starting
material had been consumed (ca. 2 h), the mixture was diluted
with ether-ethyl acetate (1:1) and water. The organic layer was
washed five times with 1.0 M aqueous sodium hydroxide solu-
tion (to remove excess 4-nitrobenzenesulfonamide). The or-
ganic layer was washed with brine, dried over anhydrous mag-
nesium sulfate, filtered through a short pad of silica gel (to
remove baseline impurities), and concentrated in vacuo to an
orange solid. Trituration of the crude product in hexanes-ether
afforded 560 mg (58%) of 20 as a tan solid: Rf 0.23 (hexanes-
ethyl acetate, 3:1); IR (CH2Cl2) 3104, 3060, 2988, 2871, 2822,
trans-(4-Benzylmorpholine-2,3-diyl)dimethanol (17). To a
stirred suspension of lithium aluminum hydride (3.71 g, 97.7
mmol) in dry tetrahydrofuran (250 mL) at 0ꢁC, a solution of
diester 11 (6.55 g, 19.5 mmol) in tetrahydrofuran (50 mL) via
canula was added. After complete addition, the mixture was
warmed to room temperature for 30 min, followed by heating
to reflux for 30 min. The mixture was cooled to 0ꢁC, and 3.7
mL of water was added dropwise, followed by sodium hydrox-
ide (3.7 mL of a 3.0 M aqueous solution), followed by 11 mL
of water. The mixture was stirred at room temperature for 15
min, followed by the addition of ethyl acetate and anhydrous
potassium carbonate. After further stirring for 15 min, the mix-
ture was filtered, and the precipitate was washed with ethyl ac-
etate. The filtrate was concentrated in vacuo to afford an oil.
The crude product was purified by flash chromatography on
silica gel. Elution with ethyl acetate gave 3.1 g (67%) of 17 as
a clear oil: Rf 0.23 EtOAc; IR (CH2Cl2) 3650, 3550, 30390,
1532, 1351, 1266, 1172, 1140, 740 cmꢀ1 1H-NMR (500
;
MHz, CD3CN) d 8.45 (d, 2H, J ¼ 8.2 Hz), 8.06 (d, 2H, J ¼
8.2 Hz), 7.38–7.33 (m, 5H), 3.85 (dd, 1H, J ¼ 11.7, 3.7 Hz),
3.69 (dd, 1H, J ¼ 8.0, 8.0 Hz), 3.65 (dd, 1H, J ¼ 9.2, 6.8 Hz),
3.57 (td, 1H, J ¼ 11.8, 2.67), 3.43 (ABq, 2H, JAB ¼ 13.3 Hz,
DmAB ¼ 160 Hz), 3.11 (dd, 1H, J ¼ 10.4, 9.2 Hz), 2.95 (dd,
1
3005, 1450, 1400, 1275, 1130, 1075, 925 cmꢀ1; H-NMR (400
MHz, CDCl3) d 7.34–7.21 (m, 5H), 4.00 (dd, 1H, J ¼ 12.1,
3.5 Hz), 3.82, (m, 1H), 3.78 (ddd, 1H, J ¼ 11.7, 3.5, 1.9 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
A Practical and Stereoselective Synthesis of
(þ/ꢀ)-trans-4-Benzyloctahydropyrrolo[3,4-b][1,4]oxazine
1101
1H, J ¼ 10.8, 9.7 Hz), 2.63 (ddd, 1H, J ¼ 12.1, 2.67, 1.24
Hz), 2.12 (ddd, 1H, J ¼ 10.8, 9.0, 7.1 Hz); 13C-NMR (125
MHz, CD3CN) d 156.6, 142.5, 137.7, 129.1, 128.6, 128.3,
127.4, 124.7, 77.9, 67.7, 65.2, 60.6, 52.0, 49.4, 48.6; high reso-
lution MS (ESI) Calcd. for C19H22N3O5S [M þ H] m/e
404.1312. Found: 404.1274. An analytical sample was pre-
pared via recrystallization from hexanes-ethyl acetate: mp
155–157ꢁC. Anal. Calcd. for C19H21N3O5S: C, 56.56; H, 5.25;
N, 10.41. Found: C, 56.21; H, 4.89; N, 10.21.
with hexanes-ethyl acetate-triethylamine (75:24:1) afforded 85
mg (79%) of 2,2,2-trifluoro-1-(trans-hexahydropyrrolo[3,4-
b][1,4] oxazin-6(2H)-yl)ethanone as an oil: Rf 0.62 (hexanes-
ethyl acetate, 1:1); 1H-NMR [400 MHz, CDCl3, two rotomers
present (1:1)] d 7.30–7.18 (m, 5H), 3.98–3.58 (m, 4H), 3.41–
3.08 (m, 3H), 2.67 (t, 1H, J ¼ 12.5 Hz), 2.37 (m, 1H), 2.18 (m,
1H); 13C-NMR [100 MHz, CDCl3, two rotomers present (1:1)]
d 156.1 (q, J ¼ 37 Hz), 155.9 (q, J ¼ 37 Hz), 136.7, 136.5,
129. 1, 129.0, 128.4, 128.3, 127. 7, 127.6, 116.0 (q, J ¼ 286
Hz), 115.9 (q, J ¼ 285 Hz), 78.14, 77.01, 67.94, 67. 89, 65.69,
63.85, 61.32, 61.01, 52.34, 52.08, 48.24, 48.15, 47.76, 47.72;
19F-NMR [376 MHz, methanol-d4, 2 rotomers present (1:1)]
d ꢀ 73.68, ꢀ73.90; low resolution MS (ESI) m/e 315 [M þ H].
The product from above (85 mg, 0.27 mmol) was dissolved
in methanol (15 mL), and 80 mg of 10% palladium on acti-
vated carbon was added. The suspension was placed in a Parr
hydrogenation bottle and hydrogenated (42 PSI, room tempera-
ture) for 48 h. The reaction mixture was filtered through Celite
and washed with methanol. The solution was concentrated in
vacuo to afford 57 mg (95%) of 22 as an oil: Rf 0.40 (hex-
anes-ethyl acetate, 1:1); 1H-NMR [400 MHz, CDCl3, 2 roto-
mers present (1:1)] d 3.90–3.77 (m, 3H), 3.70–3.59 (m, 1H),
3.50–3.39 (m, 1H), 3.34 (t, 0.5H, J ¼ 10.1 Hz), 3.26–3.15 (m,
1H), 3.06 (t, 0.5H, J ¼ 11.3 Hz); 3.00–2.73 (m, 3H), 1.91 (br
s, 1H); 13C-NMR [100 MHz, CDCl3, 2 rotomers present (1:1)]
d 156.1 (q, J ¼ 37 Hz), 155.9 (q, J ¼ 37 Hz); 116.0 (q, J ¼
284 Hz); 78.90, 77.74, 68.05, 67.99, 59.31, 57.68, 48.54,
48.50, 47.80, 47.62, 45.83, 45.72; 19F-NMR [376 MHz,
CDCl3, 2 rotomers present (1:1)] d ꢀ72.51, ꢀ72.76; low reso-
lution MS (ESI) 225 [M þ H].
trans-4-Benzyloctahydropyrrolo[3,4-b][1,4]oxazine dihy-
drochloride (2). To a stirred solution of sulfonamide 20 (600
mg, 1.49 mmol) in DMF (2.0 mL), dodecanethiol (0.71 mL,
2.97 mmol) and lithium hydroxide hydrate (125 mg, 2.97
mmol) were added. The mixture was stirred at room tempera-
ture for 2 h. The mixture was diluted with hexanes-ethyl ace-
tate (1:1) and 1.0 M aqueous hydrochloric acid, and the layers
were separated. The organic layer was extracted with aqueous
hydrochloric acid, and the combined aqueous layers were back
extracted with 1:1 hexanes-ethyl acetate. The organic layers
were discarded, and the aqueous layer was basified with 50%
aqueous sodium hydroxide to pH ¼ 13. The aqueous layer was
extracted twice with dichloromethane-methanol (9:1). The or-
ganic layer was washed with brine, dried over anhydrous so-
dium sulfate, filtered and concentrated in vacuo to afford 250
mg (77%) of the free base of 2 as a brown semi-solid: Rf 0.40
1
(chloroform-methanol-ammonium hydroxide, 90:9:1); H-NMR
(400 MHz, CDCl3) d 7.27–7.18 (m, 5H), 3.85 (dd, 1H, J ¼
11.7, 3.5 Hz), 3.67 (m, 1H), 3.57 (ddd, 1H, J ¼ 10.1, 9.0, 7.0
Hz), 3.46 (ABq, 2H, JAB ¼ 12.9 Hz, DmAB ¼ 168 Hz), 3.43–
3.25 (br s, 1H), 3.22–3.11 (m, 2H), 2.85 (t, 1H, J ¼ 10.1 Hz),
2.71 (t, 1H, J ¼ 10.1 Hz), 2.63, dm, 1H, J ¼ 12.1 Hz), 2.27
(ddd, 1H, J ¼ 11.0, 9.0, 6.7 Hz), 2.09 (td, 1H, J ¼ 12.2, 3.6
Hz); 13C (100 MHz, CDCl3) d 137.5, 129.1, 128.2, 127.3,
80.34, 68.08, 66.97, 61.42, 52.60, 46.75, 46.29; low resolution
MS (ESI) m/e 219 [M þ H].
tert-Butyl (þ/ꢀ)-trans-hexahydropyrrolo[3,4-b][1,4] oxa-
zine-4(4aH)-carboxylate [(þ/ꢀ)-1]. To a stirred solution of
22 (55 mg, 0.25 mmol) in dichloromethane (1.0 mL), di-tert-
butyl dicarbonate (60 mg, 0.27 mmol) was added. The mixture
was stirred under nitrogen atmosphere for 4 h. The reaction
mixture was purified by chromatography on silica gel. Elution
with heptane-ethyl acetate (9:1 ! 1:1) afforded 55 mg (70%)
To a solution of the above semi-solid (250 mg) in methanol
(3 mL), a 4.0 M solution of hydrogen chloride in dioxane (1.0
mL) was added. The solution was warmed to 40ꢁC in a water
bath for 10 min, followed by concentration in vacuo. Tritura-
tion of the remaining residue in ethyl acetate afforded 200 mg
(60%) of 2 as a white solid: mp 253–255ꢁC; 1H-NMR (400
MHz, D2O) d 7.41–7.34 (m, 5H), 4.26 (ABq, 2H, JAB ¼ 12.9
Hz, DmAB ¼ 48.31 Hz), 4.11 (dd, 1H, J ¼ 13.3, 3.9 Hz), 4.00
(ddd, 1H, J ¼ 11.0, 10.2, 7.5 Hz), 3.76 (td, 1H, J ¼ 12.5, 2.4
Hz), 3.64–3.56 (m, 2H), 3.47 (ddd, 1H, J ¼11.4, 10.1, 7.4 Hz),
3.33 (dm, 1H, J ¼ 10.5 Hz), 3.14–3.05 (m, 3H); 13C-NMR (100
MHz, D2O) d 130.5, 130.0, 128.9, 127.7, 74.27, 64.87, 61.46,
59.82, 50.94, 43.05, 41.61; high resolution MS (ESI)
C13H19N2O [M þ H] m/e 219.1525. Found: 219.1491. %Water
(KF): 0.47. Anal. Calcd. for C13H18N2Oꢂ2HClꢂ0.47% H2O: C,
53.35; H, 6.94; N, 9.57. Found: C, 52.97; H, 6.81; N, 9.35.
2,2,2-Trifluoro-1-(trans-hexahydropyrrolo[3,4-b][1,4] oxa-
zin-6(2H)-yl)ethanone (22). To a stirred suspension of 2 (100
mg, 0.34 mmol) in dichloromethane (3 mL) at 0ꢁC were added
triethylamine (190 lL, 1.37 mmol) and trifluoroacetic anhy-
dride (95 lL, 0.69 mmol). The mixture was allowed to warm
to room temperature and stirred for 1.5 h. The reaction was
diluted with dichloromethane and washed with water and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo to an oil. The crude
product was purified by chromatography on silica gel. Elution
of
tert-butyl
trans-6-(2,2,2-trifluoroacetyl)hexahydropyr-
rolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate as an oil: Rf 0.58
(hexanes-ethyl acetate, 1:1); 1H-NMR [400 MHz, CDCl3, 2
rotomers present (1:1)] d 4.43 (m, 0.5H), 4.35 (m, 0.5H),
4.00–3.94 (m, 1H), 3.93–3.75 (m, 3H), 3.69–3.59 (m, 2H),
3.57–3.42 (m, 1H), 3.34 (t, 0.5H, J ¼ 10.6 Hz), 3.20 (t, 0.5H,
J ¼ 10.9 Hz), 3.11–2.87 (m, 2H), 1.40 (s, 9H); 13C-NMR [100
MHz, CDCl3, 2 rotomers present (1:1)] d 160.0 (q, J ¼ 37
Hz), 159.9 (q, J ¼ 37 Hz), 155.3, 155.2, 116.0 (q, J ¼ 288
Hz), 115.9 (q, J ¼ 288 Hz), 81.50, 78.51, 77.49, 67.40, 67.37,
57.96, 56.59, 49.06, 48.97, 46.67, 46.61, 28.15, 28.09; 19F-
NMR [376 MHz, CDCl3, 2 rotomers present (1:1)] d ꢀ72.22,
ꢀ72.63; high resolution MS (ESI) Calcd. for C13H19N2O4F3Na
[M þ Na] m/e 347.1222. Found: 347.1189.
To a stirred solution of trans-6-(2,2,2-trifluoroacetyl) hexa-
hydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (27 mg,
0.83 mmol) in methanol-water (600 lL, 5:1) at room tempera-
ture, potassium carbonate (23 mg, 0.17 mmol) was added. The
mixture was stirred at room temperature for 1 h. The mixture
was diluted with water and ethyl acetate, and the layers were
separated. The aqueous layer was extracted with ethyl acetate,
and the combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered and concen-
trated in vacuo to afford 18 mg (95%) of (þ/ꢀ)-1 as an oil:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1102
D. P. Walker, J. W. Strohbach, M. A. McGlynn, and H.-F. Lu
Vol 47
Rf 0.42 (dichloromethane-methanol-ammonium hydroxide,
Diethyl 2-(N-benzyl-2-chloroacetamido)-erythro-3-hydroxy-
succinate (15). To a stirred solution of diethyl N-benzyl-
erythro-b-hydroxy-DL-aspartate (5.0 g, 17 mmol) in dichloro-
methane (40 mL) in an ice-brine bath (ꢀ10ꢁC) under nitrogen
atmosphere, sodium hydroxide (25 mL of 1.0 N aqueous solu-
tion) was added. The mixture was vigorously stirred while a
solution of chloroacetyl chloride (2.0 mL, 25 mmol) in
dichloromethane (4.0 mL) was added dropwise via syringe
(addition time ꢄ10 min). Halfway through the addition, the
reaction mixture began to thicken. The ice-brine bath was
replaced with an ice bath. After complete addition, the reaction
mixture was stirred at 0ꢁC for an additional 15 min. Sodium
hydroxide (10 mL of a 1.0 N aqueous solution) was added,
and the layers were separated. The aqueous layer was
extracted with dichloromethane (2 ꢃ 50 mL). The combined
organic layers were washed with brine, dried over anhydrous so-
dium sulfate, filtered, and concentrated in vacuo. The remaining
residue was dissolved in ether (100 mL) and extracted with 3 N
hydrochloric acid (to remove o-acylated byproduct). The ethe-
real layer was washed with brine (2ꢃ), dried over anhydrous so-
dium sulfate, and concentrated in vacuo to afford 6.2 g (99%) of
15 as a viscous tan oil: Rf 0.17 (heptane-ethyl acetate, 75:25); IR
(CDCl3) 3462, 2983, 1738, 1163, 1203, 1127, 1203, 1025, 669
1
89:10:1); H-NMR (500 MHz, CD3CN) d 3.99 (ddd, 1H, J ¼
11.8, 3.9, 1.56 Hz), 3.81 (ddd, 1H, J ¼ 13.5, 3.06, 1.53 Hz),
3.64 (td, 1H, J ¼ 11.9, 3.1 Hz), 3.6–3.5 (br m, 1H), 3.48 (app.
q, 1H, J ¼ 9.6 Hz), 3.15–2.90 (br m, 2H), 2.99–2.94 (m, 1H),
2.91 (ddd, 1H, J ¼ 13.5, 12.0, 3.8 Hz), 2.85–2.68 (br m, 1H),
1.46 (s, 9H); 13C-NMR (125 MHz, CD3CN) d 155.9, 81.3,
79.8, 67.2, 59.9, 47.8, 45.0, 44.6, 27.9; high resolution MS
t
(ESI) Calcd. for C7H13N2O3 [M – Bu þ 2H] m/e 173.0945.
Found: 173.0920.
N-Benzyl-erythro-b-hydroxy-DL-aspartic acid (14). This
material was prepared according to the established procedure
with slight modification:
To a stirred solution of (þ/ꢀ)-trans-epoxysuccinic acid
(13, 20.0 g, 151 mmol) in deionized water (70 mL), benzyl-
amine (50 mL, 460 mmol) was added. The mixture was
heated to reflux under nitrogen atmosphere. A precipitant
began to form after ꢄ15 min at reflux. After 4 h of heating,
the reaction was cooled to room temperature and treated with
2.5 N aqueous sodium hydroxide (ꢄ140 mL) to adjust the
pH to ꢄ11. The aqueous layer was extracted with ether (4 ꢃ
100 mL) to remove the benzylamine. The aqueous layer was
acidified with concentrated hydrochloric acid to pH ꢄ4 (ca.
19 mL), which caused a white precipitate to form. The pre-
cipitate was collected by suction filtration, washed with water
(2 ꢃ 100 mL) and dried in vacuo (vacuum oven, 65ꢁC,
house vacuum) to afford 30.4 g (84%) of 14 as a white
solid: 1H-NMR (400 MHz, D2O) d 7.41 (s, 5H), 4.10–4.34
(m, 3H), 3.81 (d, 1H, J ¼ 4.1 Hz); 13C-NMR (100 MHz,
D2O) d 175.9, 170.1, 130.6, 129.9, 129.6, 129.2, 70.24,
64.06, 50.60; high resolution MS (ESI) Calcd. for
C11H14NO5 [M þ H] m/e 240.0892. Found: 240.0866. An
additional 3.0 g of 20 was obtained from the filtrates upon
standing overnight. Combined yield: 92%.
1
cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.43–7.23 (m, 5H), 5.56
(s, 1H), 4.96–4.81 (m, 2H), 4.44 (br s, 1H), 4.31 (q, 2H, J ¼ 7.2
Hz), 4.26–4.00 (m, 4H), 3.71 (d, 1H, J ¼ 2.4 Hz), 1.34 (t, 3H, J
¼ 7.2 Hz), 1.24 (t, 3H, J ¼ 7.1 Hz); 13C-NMR (100 MHz,
CDCl3) d 171.4, 168.8, 167.6, 136.6, 129.0, 127.8, 126.1, 70.85,
62.70, 62.02, 61.34, 51.17, 41.61, 14.11, 13.97; high resolution
MS (ESI) Calcd. for C17H23ClNO6 [M þ H] m/e 372.1247.
Found: 372.1208. %Water(KF): 0.46. Anal. Calcd. for
C17H22ClNO6ꢂ0.46% H2O: C, 54.66; H, 5.98; N, 3.75. Found:
C, 54.32; H, 5.98; N, 3.61.
Diethyl trans-4-benzyl-5-oxomorpholine-2,3-dicarboxylate
(11) and diethyl cis-4-benzyl-5-oxomorpholine-2,3-dicarboxy-
late (12). To a stirred suspension of sodium hydride (60% oil
dispersion, 0.22 g, 5.5 mmol) in dry tetrahydrofuran (25 mL) at
0ꢁC under nitrogen atmosphere, a solution of alcohol 15 (0.99 g,
2.7 mmol) in tetrahydrofuran-acetonitrile (5 mL, 4:1) was added
dropwise via syringe (addition took ꢄ10 min). During the addi-
tion, the reaction turned from a grey suspension to a yellow sus-
pension. After complete addition, the reaction mixture was
stirred at 0ꢁC for 30 min. The reaction mixture was poured into
a rapidly stirred solution of 10% aqueous acetic acid (20 mL).
The mixture was concentrated in vacuo to a volume of ca. 15
mL. The remaining residue extracted with ethyl acetate (3 ꢃ 50
mL). The combined organic layers were washed with 1.0 N
aqueous sodium hydroxide solution (to remove minor carboxylic
acid byproducts), brine, dried over anhydrous sodium sulfate,
Diethyl N-benzyl-erythro-b-hydroxy-DL-aspartate. To
a
stirred solution of dry ethyl alcohol (250 mL) at 0ꢁC under
nitrogen atmosphere, acetyl chloride (18 mL, 250 mmol) was
added dropwise. After complete addition, the reaction was
stirred at 0ꢁC for 30 min. Diacid 14 (12.0 g, 50 mmol) was
added in one portion, and the suspension was slowly heated to
reflux for 72 h. The reaction mixture was filtered, and the col-
lected precipitate (unreacted 14) was set aside. The filtrate was
concentrated under reduced pressure. The remaining residue
was partitioned between ether (100 mL) and half-saturated
aqueous potassium carbonate solution (50 mL). The ethereal
layer was extracted with potassium carbonate solution. The
combined aqueous layers were back-extracted with ether. The
combined ethereal layers were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo
to afford 6.1 g (41%) of diethyl N-Benzyl-erythro-b-hydroxy-
DL-aspartate as a tan oil: Rf 0.20 (heptane-ethyl acetate,
75:25); IR (CDCl3) 3475, 2983, 1734, 1189, 1116, 1026, 739,
and concentrated in vacuo to afford an orange solid (0.9 g). The
R
V
crude product was purified by Biotage on silica gel. Elution
with heptane-ethyl acetate (95:5) afforded 0.45 g (50%) of
trans-product 11 as a white solid and 0.18 g (20%) of cis-prod-
uct 12 as an oil. The spectral properties of compounds 11 and 12
from this experiment were identical in all respects to compounds
11 and 12 obtained above.
1
669 cmꢀ1; H-NMR (400 MHz, CDCl3) d 7.39–7.25 (m, 5H),
4.51 (d, 1H, J ¼ 3.4 Hz), 4.29–4.15 (m, 4H), 3.98 (d, 1H, J ¼
13.0 Hz), 3.77 (d, 1H, J ¼ 13.0 Hz), 3.71 (d, 1H, J ¼ 3.1 Hz),
3.43 (br s, 1H), 2.30 (br s, 1H), 1.29 (t, 6H, J ¼ 7.2 Hz); 13C-
NMR (100 MHz, CDCl3) d 171.9, 171.0, 139.3, 128.5, 128.3,
127.2, 71.83, 63.23, 61.81, 61.38, 52.60, 14.18, 14.13; high re-
solution MS (ESI) Calcd. for C15H22NO5 [M þ H] m/e
296.1529. Found: 296.1492. Anal. Calcd. for C15H21NO5: C,
61.00; H, 7.17; N, 4.74. Found: C, 60.87; H, 7.23; N, 4.73.
1
Acknowledgments. The authors thank Shen Yang for H-, 1D-,
and 2D-NMR studies and Professor William R. Roush for stimu-
lating discussions during the preparation of this manuscript. We
thank Donn Wishka and Geeta Yalamanchi for analytical support.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
A Practical and Stereoselective Synthesis of
(þ/ꢀ)-trans-4-Benzyloctahydropyrrolo[3,4-b][1,4]oxazine
1103
[10] The formation of 4-oxooxazolidine 16 could arise via base-
catalyzed-elimination of either 11 or 12 to afford ring-opened interme-
diate 23, followed by conjugate addition of the alkoxide at C(3),
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in the H NMR spectrum of (þ/ꢀ)-1 (CDCl3), exact comparison of our
spectra of (þ/ꢀ)-1 to Hong’s reported 1H NMR spectra of (4aS,7aS)-1
was difficult [6]. However, we believe our structure of (þ/ꢀ)-1 to be
correct based on extensive 1D and 2D NMR experiments performed in
CD3CN, where the line broadening was less severe.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet