Synthesis of chiral five-, six-, and seven-membered heterocycles from (S)-3-hydroxy-γ-butyrolactone

Article abstract of DOI:10.1055/s-0031-1289677

Chiral small molecules such as amino alcohols and their heterocyclic derivatives are useful building blocks for asymmetric synthesis and the preparation of biologically active compounds. Using a common starting material derived from carbohydrate, the (S)-3-hydroxy - butyrolactone, we have synthesized several five-, six-, and seven-membered nitrogen-containing chiral heterocycles. These include (S)-3-benzyloxypyrrolidine, a protected 6-substituted morpholin-3-one and its homologous 1,4-oxazepan-3-one, and 6-trityloxymethyl tetrahydro-1,3-oxazine-2-thiones. These chiral small heterocycles were synthesized from the lactone via efficient cyclization reactions. Their syntheses and characterization are reported here. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1289677

PAPER
561
Synthesis of Chiral Five-, Six-, and Seven-Membered Heterocycles from
(S)-3-Hydroxy-g-butyrolactone
C
hira
l
Small Heter
a
ocycles
f
ro
o
m
(
S
)-3-Hydroxy-
g
Y
-butyrolactone ang, Navneet Goyal, Jean Rene Ella-Menye, Kristopher Williams, Guijun Wang*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: gwang2@uno.edu
Received 26 October 2011; revised 26 November 2011
tant class of nitrogen containing heterocycles is the cyclic
carbamates. These functional groups are also found in
several drug molecules, for instance, 5-aminomethyl ox-
azolidinone is the core structure of the orally available
Abstract: Chiral small molecules such as amino alcohols and their
heterocyclic derivatives are useful building blocks for asymmetric
synthesis and the preparation of biologically active compounds. Us-
ing a common starting material derived from carbohydrate, the (S)-
3-hydroxy-g-butyrolactone, we have synthesized several five-, six- factor Xa inhibitor rivaroxaban (5)11 and antibacterial
agent linezolid (6).12 We have previously demonstrated
, and seven-membered nitrogen-containing chiral heterocycles.
These include (S)-3-benzyloxypyrrolidine, a protected 6-substituted
that the 6-aminomethyloxazinan-2-one derivatives also
morpholin-3-one and its homologous 1,4-oxazepan-3-one, and 6-
have important antibacterial activities.1,13 Other oxazinan-
trityloxymethyl tetrahydro-1,3-oxazine-2-thiones. These chiral
2-one compounds have been explored as inhibitors of the
small heterocycles were synthesized from the lactone via efficient
11-b-hydroxysteroid dehydrogenase type 1 (11b-HSD1),
which may have implications in the treatment of obesity
and insulin resistance. Compound 7 is an example of this
class of compounds.14 The analogous thiocarbamate func-
tional group also has shown interesting biological rele-
vance. Compound 8 is a nonsteroidal progesterone
receptor agonist; its fluorinated analogues have been ap-
plied in breast tumor imaging.15,16
cyclization reactions. Their syntheses and characterization are re-
ported here.
Key words: amino alcohols, heterocycles, cyclization, lactones,
chiral pool, asymmetric synthesis
Chiral nitrogen and oxygen-containing heterocycles are
important intermediates for the preparation of many bio-
logically active compounds including natural products
and medicinally relevant molecules. Among these, five-
and six-membered-ring heterocycles are especially useful
either as core structures for biologically active
molecules1or as ligands for asymmetric synthesis.2,3
Among five-membered-ring heterocycles, functionalized
3-hydroxypyrrolidines are very useful moieties found in
many biologically interesting compounds.4,5 Figure 1
shows several examples of medicinally active compounds
containing various heterocyclic structures. Compounds 1
and 2 contain the 3-hydroxypyrrolidine core structure.
The cyclohexylpyrrolidinol 1 and its analogues are ion
channel modulating compounds and are also useful for the
treatment of arrhythmia.4 Compound 2 is a human 5-HT1D
receptor antagonist, which has significance in neurologi-
cal disorder treatment.5 Several other disubstituted pyrro-
lidines also exhibit both serotonergic activity6 and
phosphodiesterase 10A inhibition.7 The six-membered-
ring morpholinones or morpholines contained in com-
pounds 3–6 are heterocyclic compounds that are of medic-
inal importance as well; they are present in many drug
classes either as core structures or as functional groups
that improve pharmacokinetic properties.8 Compound 3 is
a selective rat 5-hydroxytryptamine1B (5-HT1B) receptor
antagonist.9 The aminomethyl morpholine 4 has shown
activity against checkpoint kinase 1 (CHK1),10 and may
have applications in anticancer therapies. Another impor-
N
O
N
OMe
OMe
N
N
N
OH
N
OBn
H
1
2
O
N
H2N
O
O
O
N
H
O
EtO2C
Cl
N
N
N
N
3
H
O
N
4
O
S
H
N
N
O
O
O
O
5
O
N
N
O
O
F
NHAc
6
O
N
Ph
NC
N
N
O
S
N
O
CN
7
Me
H
N
H
8
Figure 1 Structures of biological active compounds containing
small chiral heterocycles derived from amino alcohols
SYNTHESIS 2012, 44, 561–568
Advanced online publication: 30.01.2012
x
x
.x
x
.2
0
1
1
DOI: 10.1055/s-0031-1289677; Art ID: M101111SS
© Georg Thieme Verlag Stuttgart · New York

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Because of their importance in the preparation of biologi-
cally active compounds, there have been many studies for
the synthesis of these heterocycles and their deriva-
tives.17–32 Chiral amino alcohols are often used for the
synthesis of heterocycles that are of biological relevance
or that are used as ligands for asymmetric synthesis. In re-
cent years, a versatile building block, (S)-3-hydroxy-g-bu-
tyrolactone, has found many applications in organic
synthesis. It is a commercially available compound that
can be synthesized readily in large scale from carbohy-
drate feed stock such as starch or lactose.33 The lactone
has been converted into 1,2- and 1,3-amino alcohols and
their derivatives via very efficient methods.34,35 Using the
(S)-3-hydroxy-g-butyrolactone (9) as the starting materi-
al, we report here new and efficient synthetic routes to
several protected small molecule heterocycles including
the protected five-membered-ring pyrrolidine 10, 6-hy-
droxymethylmorpholin-3-one 11, 7-hydroxymethyl-1,4-
oxazepan-3-one 12, and the six-membered-ring oxazinan-
2-thione 13 (Figure 2).
O
NH
PO
O
a)
NH4OH
98%
BnO
CCl3
HO
O
9
NH2
PO
or b) TrCl, pyridine
15a P = Bn, 98%
15b P = Tr, 99%
14a P = Bn, 85%
14b P = Tr, 97%
OBn
CF3
PO
NH2
MsCl
pyridine
LiAlH4
79%
CF3CO2Et
HO
N
O
THF, 0 °C
96%
H
85%
OH
17
16a P = Bn
O
OBn
CF3
NH
O
NH
NaH, THF
91%
MsO
N
O
H
BnO
18
10
BnO
19
Scheme 1 Synthesis of five-membered-ring pyrrolidine 10
amino alcohol.27 However, this cyclization reaction did
not work for the 1,4-amino alcohol 16. Other methods of
forming the cyclic carbamate were then tried in several at-
tempts, including the conversion of the amino group into
the corresponding open-chain carbamate using benzyl
chloroformate or Boc anhydride, followed by base treat-
ment to afford the cyclization product. However, none of
these conditions were able to produce the seven-mem-
bered-ring carbamate 19.
O
O
NH
O
BnO
NH
TrO
O
HO
10
11
9
S
O
O
O
NH
NH
TrO
TrO
The benzyl protecting group was optimal for the scheme.
The hydroxy group of the lactone could be protected using
trityl chloride to afford compound 14b, and the subse-
quent ammonia ring-opening gave compound 15b in ex-
cellent yield. However, reduction of amide 15b using
LiAlH4 did not afford the desired amino alcohol product
16b, instead, the amide decomposed rapidly under LiAlH4
treatment, mostly leading to eliminated intermediates and
intractable mixture of by-products. We speculate that the
trityl group is too bulky for the reaction to proceed as
planned; under even mild basic conditions, elimination is
favored over reduction. The benzyl group, on the other
hand, causes much less steric hindrance and the amide re-
duction could be carried out successfully.
From amino alcohol 20,26 which was synthesized from the
lactone 9, 3,6-disubstituted 3-morpholinones can be syn-
thesized (Scheme 2). Treating compound 20 with a slight
excess of bromoacetic anhydride afforded the O- and N-
acylated product, and the ester was selectively hydrolyzed
using sodium bicarbonate at room temperature to give b-
hydroxyamide 21 quantitatively. It was then cyclized us-
ing sodium hydroxide in dichloromethane under refluxing
condition to afford the trityl-protected morpholinone 11.
Other conditions were tried for the cyclization of 21 such
as using K2CO3, Na2CO3, and NaOH in THF, which all
failed to give the desired product in good yield. The trityl
group can be removed to afford the free 6-hydroxymeth-
ylmorpholin-3-one (22) in excellent yield, giving us a free
hydroxy group that can be further functionalized. The ni-
trogen in 11 can be functionalized as well by N-alkylation,
13
12
Figure 2 Structures of the heterocycles
The protected 3-hydroxypyrrolidine 10 can be synthe-
sized from the lactone in a few steps. As shown in
Scheme 1, the lactone was protected with a benzyl group
under slightly acidic conditions to give compound 14a,
ring-opening with ammonia in water afforded the amide
15a in nearly quantitative yield. Subsequent reduction of
the amide afforded the key intermediate 1,4-amino alco-
hol 16a. Protection of the primary amino group in 16a
gave trifluoroacetamide 17, which was then converted
into the mesylate 18. Treating 18 with sodium hydride in
THF directly produced the desired protected product (S)-
3-benzyloxypyrrolidine (10). The trifluoromethyl group
was released during the workup procedure. This proce-
dure of converting the lactone into the protected pyrroli-
dine is very efficient and nearly all steps gave good to
excellent yields. Therefore, this is a new and convenient
route for the synthesis of pyrrolidine derivatives from car-
bohydrate raw materials.
During the synthesis, we also attempted to prepare a seven-
membered-ring cyclic carbamate 19. We had hoped that
direct treatment of the 1,4-amino alcohol 16 with 1,1¢-car-
bonyldiimidazole (CDI) would afford compound 19, sim-
ilarly to our previous synthesis of the six-membered-ring
oxazinan-2-one by cyclization of the corresponding 1,3-
Synthesis 2012, 44, 561–568
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Chiral Small Heterocycles from (S)-3-Hydroxy-g-butyrolactone
563
1) (BrCH2CO)2O
K2CO3, THF, 0 °C to r.t.
no alcohol 24 was converted into the corresponding
bromoacetamide 25, followed by an intramolecular SN2
reaction to afford the 7-trityl-protected hydroxymethyl-
1,4-oxazepan-3-ones 12 (≡ 26a) and 26b. When R = H,
the cyclization reaction worked well, however, when
R = Bn, the cyclization from the bromo compound gave a
poorer yield of 26b, probably due to steric hindrance of
the benzylamide. However, this issue can be circumvent-
ed by alkylating the already cyclized oxazepan-3-one 12
(≡ 26a) to obtain substituted products such as 26c and 26d
in good yields. These novel seven-membered-ring hetero-
cycles are expected to be valuable building blocks in the
synthesis of biologically active compounds.
OH
OH
H
N
NH2
TrO
TrO
Br
2) NaHCO3
O
21
20
O
NaOH
O
O
LiAlH4, THF
TrO
NH
TrO
NH
CH2Cl2, reflux
80%
0 °C to r.t.
70%
23
11
TFA, CH2Cl2
0 °C to r.t.
98%
O
O
Besides the cyclic amides, several sulfur-containing cy-
clic carbamate derivatives were also synthesized using
amino alcohols derived from the lactone 9. As shown in
Scheme 4, treating amino alcohol 24a with thiocarbonyl-
diimidazole (TCDI) afforded the trityl-protected 6-trityl-
oxymethyltetrahydro-1,3-oxazine-2-thione 13 smoothly
in 88% yield. From this compound, we attempted alkyla-
tion on the nitrogen to obtain the N-ethyl-alkylated com-
pound 28, however, the reaction only led to the sulfur-
alkylated product 27 as the main product. An alternative
route was then used for the preparation of N-alkylated an-
alogues. Starting from the amino alcohol 24c, cyclization
with TCDI afforded the ethyl-substituted product 28.
HO
NH
22
Scheme 2 Preparation of 3-morpholinones
reductive amination, or N-arylation reactions to synthe-
size thrombin inhibitor analogous to compound 1. The
morpholinone can also be reduced to give the correspond-
ing 6-trityl-protected hydroxymethylmorpholine 23, an-
other useful moiety in the synthesis of biologically active
compounds.
Seven-membered homologues of 11 were also synthe-
sized using a similar method. As shown in Scheme 3, ami-
O
O
NR
(BrCH2CO)2O
OH NHR
K2CO3, THF, 0 °C to r.t.
NaOH
O
OH RN
TrO
CH2Cl2, reflux
TrO
TrO
Br
24a R = H
24b R = Bn
25a R = H, 75%
25b R = Bn, 70%
12 R = H, 83%
26b R = Bn, 50%
O
O
KOt-Bu, DMF
0 °C, RI
O
O
NR
NH
TrO
TrO
12 (26a)
26c R = Me, 82%
26d R = Et, 77%
Scheme 3 Preparation of trityl-protected oxazepan-3-one
S
S
TCDI
THF, reflux
I
OH NH2
, THF
O
NH
O
N
TrO
88%
TrO
TrO
NaH or KOt-Bu
24a
27
13
S
S
Et
OH NHEt
TCDI
O
N
TFA, CH2Cl2
THF, reflux
O
N
TrO
TrO
quant.
73%
HO
24c
28
29
Scheme 4 Synthesis of thiazinan-3-one and derivatives
© Thieme Stuttgart · New York
Synthesis 2012, 44, 561–568

564
H. Yang et al.
PAPER
centration of the solution on the rotavap, the crude residue was pu-
rified by silica gel flash column chromatography using a gradient of
hexane–EtOAc (16:1 to 6:1) to give the final compound as a white
solid; yield: 3.27 g (97%, 9.49 mmol); mp 92–93 °C; [a]D25 –10.1
(c = 10, EtOAc).
Deprotection of the trityl group led to compound 29,
which can be converted into the corresponding mesylate
and then alkylated with various halides to generate a small
molecule library for the screening of biological activities.
In conclusion, using amino alcohols derived from (S)-3-
hydroxy-g-butyrolactone, we have synthesized several ni-
trogen-containing heterocycles. These include the (S)-3-
benzyloxypyrrolidine, which was obtained from the cor-
responding 1,4-amino alcohol. Starting from 1,3-amino
alcohol derivatives obtained from the lactone, 6-hy-
droxymethylthiaoxazinanone, 6-hydroxymethylmorpho-
lin-3-one, and 7-hydroxymethyl[1,4]oxazepan-3-one
were synthesized efficiently. Since the lactone 9 can be
prepared from readily available starch or lactose in a one-
pot reaction, the methods reported here represent access to
important chiral molecules using affordable and renew-
able carbohydrates as starting materials. These com-
pounds are expected to be useful in the preparation of
medicinally important compounds.
1H NMR (400 MHz, CDCl3): d = 7.52–7.43 (m, 6 H), 7.40–7.28 (m,
9 H), 4.51 (m, 1 H), 3.86 (dd, J = 5.9, 9.9 Hz, 1 H), 3.80 (dd, J = 4.4,
9.9 Hz, 1 H), 2.34 (dd, J = 5.5, 17.9 Hz, 1 H), 2.29 (dd, J = 7.0, 17.9
Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 175.3, 143.6, 128.4, 128.1, 127.5,
87.8, 73.3, 69.4, 35.6.
HRMS: m/z calcd for C23H20O3 + Na [M + Na]+: 367.1310; found:
367.1310.
(S)-3-Benzyloxy-4-hydroxybutanamide (15a)
To a solution of 14a (600 mg, 3.12 mmol) in THF (5 mL) was added
NH4OH (218 mg, 6.24 mmol) and the reaction mixture was stirred
overnight. The mixture was diluted with CH2Cl2 (25 mL) and the
solvent phases were separated. The aqueous layer was extracted
with CH2Cl2 (2 × 25 mL). The combined organic phases were
washed with brine (20 mL) and dried (Na2SO4). After filtration, the
solution was concentrated on a rotovap. The obtained residue was
purified using silica gel flash chromatography (hexane–EtOAc, 3:1)
to afford the pure product as a semi-solid; yield: 1.06 g (98%, 5.06
mmol); [a]D25 –23.4 (c = 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.30–7.37 (m, 5 H), 4.61 (s, 2 H),
3.93–3.98 (m, 1 H), 3.78 (dd, J = 4.0, 11.7 Hz, 1 H), 3.62 (dd,
J = 4.3, 11.7 Hz, 1 H), 2.48–2.58 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 173.3, 137.7, 128.6, 128.0, 127.9,
76.6, 72.2, 63.5, 38.2.
General chemicals and reagents were purchased from Sigma-Ald-
rich or VWR International and used directly. The optically pure lac-
tone was provided by Afid Therapeutics. NMR spectra were
recorded using a 400 MHz Varian NMR spectrometer and a Bruker
250 MHz NMR spectrometer. High-resolution mass spectrometry
data were measured on the Q-Tof UE521 of the Mass Spectrometry
lab at the University of Illinois at Urbana Champaign after the low-
resolution masses were confirmed. The ionization technique used
was ESI (electrospray ionization) in ES+ mode. Melting points
were measured using a Fisher-Jones melting point apparatus. Opti-
cal rotations were measured using a Rudolph Autopol III 6768MFG
1991 polarimeter; the concentrations reported here are in g/100 mL.
HRMS: m/z calcd for C11H15NO3 + Na [M + Na]+: 232.0950; found:
232.0948.
(S)-4-Hydroxy-3-(trityloxy)butanamide (15b)
To a stirred solution of 14b (1.00 g, 2.80 mmol) in THF (10 mL)
was added NH4OH (0.969 mL, 27.7 mmol). The reaction mixture
was stirred at r.t. overnight, then diluted with CH2Cl2 (100 mL), and
the organic layer was washed with H2O (70 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 100 mL). The organic phases were
combined, washed with brine (50 mL), and dried (Na2SO4). After
filtration and concentration on the rotovap, the crude mixture was
purified by silica gel flash chromatography using a gradient of hex-
ane–CH2Cl2–acetone (8:1:1 to 2:1:1) to give the pure product as a
semi-solid; yield: 1.03 g (99%, 2.84 mmol); mp 135.0–136.0 °C;
[a]D25 +14.2 (c = 1.7, EtOAc).
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J = 7.3 Hz, 6 H), 7.30 (m,
9 H), 5.52 (s, 2 H, NH2), 4.00 (m, 1 H), 3.52 (m, 2 H), 2.91 (m, 1 H,
OH), 2.02 (dd, J = 3.7, 14.7 Hz, 1 H), 1.94 (dd, J = 7.0, 14.7 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = 173.7, 144.3, 128.7, 128.1, 127.4,
87.4, 70.8, 64.3, 38.4.
(S)-3-Benzyloxy-g-butyrolactone (14a)
(S)-3-Hydroxy-g-butyrolactone (9; 0.400 g, 4.90 mmol) was dis-
solved in 1,4-dioxane (5 mL) in a round-bottomed flask. Then, ben-
zyl 2,2,2-trichloroacetimidate (1.48 g, 5.88 mmol) and
trifluoroacetic acid (0.056 g, 0.49 mmol) were added to the flask.
The reaction mixture was stirred at r.t. for 16 h, and then partitioned
between EtOAc (150 mL) and H2O (100 mL). The organic layer
was separated and the aqueous phase was extracted with EtOAc (2
× 200 mL). The combined organic phases were washed with brine
(200 mL) and dried (Na2SO4). The solvent was removed on a ro-
tovap and the residue was purified by silica gel flash column chro-
matography (hexane–EtOAc, 4:1). The pure product was obtained
as a colorless oil; yield: 0.64 g (85%, 3.33 mmol); [a]D25 –27.6
(c = 1.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.30–7.38, (m, 5 H), 4.56 (d,
J = 11.7 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.34–4.40 (m, 3 H),
2.60–2.72 (m, 2 H).
HRMS: m/z calcd for C23H24NO3 [M + H]+: 362.1756; found:
362.1769.
13C NMR (100 MHz, CDCl3): d = 175.5, 136.9, 128.6, 128.2, 127.7,
73.8, 73.1, 71.2, 35.0.
The NMR data matched with the values reported in the literature.36
(S)-4-Amino-2-(benzyloxy)butan-1-ol (16a)
To a stirred suspension of LiAlH4 (0.0597 g, 11.9 mmol) in anhyd
THF (10 mL) at 0 °C was added slowly the amide 15a (0.500 g, 2.39
mmol). The solution was brought to r.t. and refluxed for 6 h under
anhydrous conditions. The reaction was quenched with cold MeOH
(10 mL) and diluted with CH2Cl2 (20 mL). The solution was filtered
through a pad of Celite and concentrated on the rotovap. The crude
product was purified by silica gel flash chromatography (2% MeOH
in CH2Cl2) to afford pure amino alcohol 16a as a semi-solid; yield:
0.370 g (79%, 1.88 mmol); [a]D25 –18.7 (c = 1.0, CHCl3).
(S)-3-Trityloxy-g-butyrolactone (14b)
To a stirred solution of 9 (1.00 g, 9.8 mmol) in THF (20 mL) were
added trityl chloride (3.00 g, 10.8 mmol) and pyridine (1.74 mL,
19.6 mmol). The reaction mixture was stirred at 50 °C for 48 h, after
which the reaction mixture was partitioned between EtOAc (200
mL) and H2O (150 mL). The aqueous phase was extracted with
EtOAc (2 × 200 mL). The organic phases were combined, washed
with brine (100 mL), and dried (Na2SO4). After filtration and con-
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Chiral Small Heterocycles from (S)-3-Hydroxy-g-butyrolactone
565
1H NMR (400 MHz, CDCl3): d = 7.27–7.34 (m, 5 H), 4.54–4.62 (m,
2 H), 3.65 (dd, J = 5.4, 11.7 Hz, 1 H), 3.62 (dd, J = 4.0, 11.7 Hz, 1
H), 3.56 (q, J = 5.1 Hz, 1 H), 2.89–2.96 (m, 1 H), 2.72–2.78 (m, 1
H), 1.68–1.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 138.5, 128.4, 127.7, 127.6, 78.0,
71.1, 63.6, 37.6, 35.3.
gel flash chromatography using a gradient of hexane–EtOAc (12:1
to 6:1). The pure product was obtained as a yellow liquid; yield:
0.023 g (91%, 0.13 mmol); [a]D25 +2.2 (c = 1.00, EtOH).
1H NMR (400 MHz, CDCl3): d = 7.28–7.38 (m, 5 H), 4.48 (br s, 2
H), 4.11 (m, 1 H), 3.05–3.18 (m, 1 H), 2.78–2.91 (m, 1 H), 1.84–
1.96 (m, 2 H), 1.75–2.07 (m, 3 H).
HRMS: m/z calcd for C11H18NO2 [M + H]+: 196.1338; found:
196.3333.
13C NMR (100 MHz, CDCl3): d = 138.3, 128.4, 127.6, 127.6, 80.0,
70.9, 53.2, 45.8, 32.8.
HRMS: m/z calcd for C11H16NO [M + H]+: 178.1232; found:
178.1230.
(S)-N-[3-(Benzyloxy)-4-hydroxybutyl]-2,2,2-trifluoroaceta-
mide (17)
Compound 16a (0.100 g, 0.510 mmol) was dissolved in THF (2.50
mL) and cooled to 0 °C in an ice-bath. Ethyl trifluoroacetate (0.060
mL, 1.0 mmol) was added to the solution and the mixture was
stirred at 0 °C for 10 min, by which time the reaction was complete.
The reaction was quenched by the addition of ice-cold H2O (5 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
phases were dried (Na2SO4). After filtration and concentration on
the rotovap, the crude residue was purified by silica gel flash chro-
matography using a gradient of hexane–EtOAc (12:1 to 6:1) to af-
ford the pure product as a colorless liquid; yield: 0.143 g (96%, 0.49
mmol); [a]D25 –22.5 (c = 1, EtOAc).
(S)-2-Bromo-N-[2-hydroxy-3-(trityloxy)propyl]acetamide (21)
(S)-1-Amino-3-(trityloxy)propan-2-ol (20; 0.990 g, 2.97 mmol)
was dissolved in anhyd THF (10.0 mL). The reaction mixture was
kept at 0 °C and bromoacetic anhydride (0.926 g, 3.56 mmol) and
K2CO3 (0.820 g, 5.94 mmol) were added to the solution. After stir-
ring at 0 °C for 30 min and at r.t. for 2 to 3 h, the K2CO3 was filtered
off and the THF evaporated on the rotovap. Ice-water (5–10 mL)
was then added and the diacetylated product was extracted with
EtOAc (3 × 25 mL). After evaporating the EtOAc, the product was
directly stirred with NaHCO3 in a mixture of EtOH, THF, and H2O
(1:1:1) at r.t. for 12 h. The EtOH and THF were removed by con-
centration on the rotovap and the monoacetylated product was ex-
tracted with CH2Cl2 (3 × 25 mL). After removing the CH2Cl2, the
product was obtained as an off-white semi-solid; yield: 1.34 g
(99%, 2.95 mmol), which was used without further purification.
1H NMR (400 MHz, CDCl3): d = 7.29–7.50 (m, 5 H), 4.68 (d,
J = 11.5 Hz, 1 H), 4.55 (d, J = 11.5 Hz, 1 H), 3.84 (dd, J = 7.3, 4.7
Hz, 1 H), 3.48–3.69 (m, 2 H), 3.29–3.45 (m, 1 H), 1.83–1.93 (m, 1
H), 1.65–1.82 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 157.6, 157.3, 156.9, 156.5, 137.5,
128.7, 128.2, 128.0, 120.1, 117.2, 114.3, 111.5, 77.8, 71.8, 63.3,
37.0, 30.0.
1H NMR (400 MHz, CDCl3): d = 7.54–7.15 (m, 15 H), 6.77 (br s, 1
H), 3.91 (m, 1 H), 3.78 (s, 2 H), 3.54 (m, 1 H), 3.27 (m, 1 H), 3.17
(m, 2 H).
HRMS: m/z calcd for C13H16F3NO3 + Na [M + Na]+: 314.0980;
found: 314.0986; m/z calcd for C13H17F3NO3 [M + H]+: 292.1161;
found: 292.1164.
13C NMR (100 MHz, CDCl3): d = 166.3, 143.5, 128.5, 127.9, 127.2,
86.9, 69.7, 64.9, 43.1, 28.9.
HRMS: m/z calcd for C24H24BrNO3 + Na [M + Na]+: 476.0837;
found: 476.0839.
(S)-2-Benzyloxy-4-(2,2,2-trifluoroacetamido)butyl Methane-
sulfonate (18)
(S)-6-[(Trityloxy)methyl]morpholin-3-one (11)
Compound 17 (0.150 g, 0.51 mmol) was mixed with pyridine (0.41
mL, 5.1 mmol) in anhyd THF (2.00 mL). The solution was cooled
to 0 °C and MsCl (0.120 mL, 1.53 mmol) was added and the mixture
was stirred at r.t. overnight. The mixture was diluted with CH2Cl2
(20 mL) and washed with H2O (3 × 5 mL). The combined organic
phases were dried (Na2SO4). After filtration and concentration on
the rotovap, the crude residue was purified by silica gel flash chro-
matography with a gradient of hexane–EtOAc (12:1 to 6:1). The
pure product was obtained as a colorless liquid; yield: 0.16 g (85%,
0.43 mmol); [a]D25 –20.2 (c = 1.3, EtOAc).
1H NMR (400 MHz, CDCl3): d = 7.45–7.30 (m, 5 H), 6.70 (s, 1 H),
4.75 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.35 (dd,
J = 4.4, 11.0 Hz, 1 H), 4.23 (dd, J = 4.7, 11.0 Hz, 1 H), 3.78 (td,
J = 8.4, 4.2 Hz, 1 H), 3.52 (ddd~dt, J = 6.6, 13.2 Hz, 1 H), 3.35
(ddd~dt, J = 5.4, 6.6, 13.2 Hz, 1 H), 3.03 (s, 3 H), 1.76–1.94 (m, 2
H).
The amide 21 (0.211 g, 0.464 mmol) was dissolved in anhyd
CH2Cl2 (8 mL). NaOH (0.093 g, 2.33 mmol) was added to the solu-
tion, which was refluxed for 1.5 h. The solid residue was filtered off
and washed with CH2Cl2 (~5 mL), and the organic phase was
washed with sat. aq NH4Cl (2 × 5 mL), H2O (2 × 5 mL), and brine
(5 mL). The aqueous phase was separated and the organic phase
dried (Na2SO4). After filtration, the solvent was evaporated and the
pure product was obtained as a white crystalline solid after drying
under high vacuum and used without further purification; yield:
0.139 g (80%, 0.372 mmol); mp 187–187.5 °C; [a]D25 –47.4
(c = 1.04, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 7.52–7.22 (m, 16 H), 4.29 (d,
J = 16.9 Hz, 1 H), 4.17 (d, J = 16.9 Hz, 1 H), 3.87 (m, 1 H), 3.37 (m,
3 H), 3.15 (dd, J = 9.6, 5.9 Hz, 1 H).
13C NMR (63 MHz, CDCl3): d = 169.4, 143.4, 128.5, 127.8, 127.1,
86.8, 72.0, 67.4, 63.8, 43.9.
13C NMR (101 MHz, CDCl3): d = 157.3, 156.9, 136.9, 128.7, 128.5,
128.3, 117.1, 114.0, 74.9, 72.5, 69.5, 37.6, 36.8, 30.2.
HRMS: m/z calcd for C14H19F3NO5S [M + H]+: 370.0936; found:
HRMS: m/z calcd for C24H24NO3 [M + H]+: 374.1756; found:
374.1773.
370.0936.
(S)-6-(Hydroxymethyl)morpholin-3-one (22)
Compound 11 (0.090 g, 0.242 mmol) was dissolved in anhyd
CH2Cl2 (4 mL). The solution was cooled to 0 °C for 5 min and trif-
luoroacetic acid (0.036 mL, 0.485 mmol) was added slowly. The
mixture was stirred at r.t. for 4 h. The solvent was then evaporated
and MeOH (4 × 1 mL) was successively added and evaporated. The
crude mixture was taken up in H2O (5 mL) and the precipitated trityl
salts were filtered off. The aqueous phase was extracted with hex-
ane (2 × 5 mL) and then dried under N2 and subsequently under high
vacuum. The pure product was obtained as a colorless semi-solid,
(S)-3-(Benzyloxy)pyrrolidine (10)37
The mesylate 18 (0.050 g, 0.14 mmol) was dissolved in anhyd THF
(1.5 mL). The mixture was cooled to 0 °C in an ice-bath, and then
NaH (0.0071 g, 0.30 mmol) was added. The reaction mixture was
stirred at r.t. for 6 h. The reaction was quenched with ice-cold H2O
(5 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organ-
ic phases were dried (Na2SO4). After filtration, the solvent was re-
moved on the rotovap and the crude residue was purified by silica
© Thieme Stuttgart · New York
Synthesis 2012, 44, 561–568

566
H. Yang et al.
PAPER
which was used without further purification; yield: 0.0311 g (98%;
stirred for 6 h. The solid residue was filtered off and the organic lay-
er was washed with sat. aq NH4Cl (2 × 5 mL), then with H2O (5 mL)
and brine (5 mL). After drying (Na2SO4) and filtration, the solvent
was evaporated and the residue dried under vacuum to afford a
fluffy white solid; yield: 107 mg (83%, 0.276 mmol); mp 88–90 °C;
[a]D25 –36.2 (c = 1.02, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 7.41–7.11 (m, 15 H), 6.42 (br s, 1
H), 4.32 (d, J = 15.9 Hz, 1 H), 4.05 (d, J = 15.9 Hz, 1 H), 3.70 (m,
1 H), 3.34 (m, 1 H), 3.20 (dd, J = 9.6, 5.9 Hz, 1 H), 2.94 (dd, J = 9.6,
5.0 Hz, 1 H), 1.92 (m, 1 H), 1.70 (m, 1 H).
13C NMR (63 MHz, CDCl3): d = 175.4, 143.8, 128.6, 127.8, 86.6,
79.9, 71.5, 65.8, 39.2, 32.5.
HRMS: m/z calcd for C25H25NO3 + Na [M + Na]+: 410.1732; found:
410.1734.
0.237 mmol); [a]D25 –42.9 (c = 1.04, EtOH).
1H NMR (250 MHz, CDCl3): d = 6.26 (br s, 1 H), 4.34 (d, J = 16.9
Hz, 1 H), 4.22 (d, J = 16.9 Hz, 1 H), 3.85 (m, 1 H), 3.78 (m, 1 H),
3.68 (dd, J = 11.7, 5.6 Hz, 1 H), 3.47 (m, 1 H), 3.30 (m, 1 H).
13C NMR (63 MHz, CDCl3): d = 171.3, 72.9, 66.7, 62.6, 42.5.
(S)-2-(Trityloxymethyl)morpholine (23)
Compound 11 (0.055 g, 0.15 mmol) was dissolved in anhyd THF (5
mL). The solution was cooled to 0 °C and stirred for 10 min. LiAlH4
(0.017 g, 0.45 mmol) was added to the solution under N2 and the re-
action mixture was stirred for 2 h. Ice-water (10 mL) was added to
quench the reaction, and the precipitated aluminum salts were fil-
tered off. The THF was evaporated and the product was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers was washed
with H2O (5 mL) and brine (5 mL), then evaporated and the product
was dried under N2 and under vacuum to afford a colorless semi-
solid, which was used without further purification; yield: 0.037 g
(70%, 0.103 mmol); [a]D25 +13.0 (EtOH, c = 1.00).
1H NMR (250 MHz, CDCl3): d = 7.49–7.19 (m, 16 H), 3.86 (m, 1
H), 3.69 (m, 1 H), 3.59 (dd, J = 11.2, 3.4 Hz, 1 H), 3.22 (dd, J = 9.3,
5.1 Hz, 1 H), 3.04 (m, 2 H), 2.81 (m, 2 H), 2.62 (m, 1 H).
13C NMR (63 MHz, CDCl3): d = 143.9, 128.6, 127.8, 127.0, 86.5,
75.9, 67.9, 65.1, 49.0, 45.9.
(S)-4-Benzyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26b)
Compound 25b (0.070 g, 0.13 mmol) was mixed with NaOH (0.025
g, 0.60 mmol) in THF (1.50 mL) and the mixture was heated to re-
flux for 24 h. The crude was diluted with CH2Cl2 (10 mL) and the
organic layer was washed with H2O (3 × 5 mL). The organic phase
was dried (Na2SO4) and after filtration, the solvent was removed in
vacuo. The crude residue was purified by silica gel flash chromatog-
raphy (hexane–EtOAc, 3:1). The pure product was obtained as a
white solid; yield: 0.031 g (50%, 0.065 mmol); mp 145.0–146.5 °C;
[a]D25 –29.7 (c = 1.00, EtOH).
(S)-2-Bromo-N-[3-hydroxy-4-(trityloxy)butyl]acetamide (25a)
(S)-4-Amino-1-(trityloxy)butan-2-ol (24a; 3.85 g, 11.1 mmol) was
dissolved in anhyd THF (60 mL). K2CO3 (3.06 g, 22.1 mmol), then
bromoacetic anhydride (3.80 g, 14.6 mmol) were added and the so-
lution was stirred at r.t. for 5–6 h. The K2CO3 was filtered off and
the THF was evaporated on the rotovap. The solid residue was pu-
rified by silica gel flash chromatography (hexane–CH2Cl2–THF
6:3:1) and the pure product was isolated as a white solid; yield: 6.21
g (75%, 8.33 mmol); mp 79.0–80.0 °C.
1H NMR (400 MHz, CDCl3): d = 7.46–7.23 (m, 15 H), 7.18 (s, 1 H),
3.87 (m, 1 H), 3.84 (s, 2 H), 3.58 (m, 1 H), 3.26 (m, 1 H), 3.14 (m,
2 H), 2.93 (br s, 1 H), 1.65 (m, 1 H), 1.56 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 165.7, 143.6, 128.5, 127.8, 127.1,
86.8, 69.8, 67.4, 37.8, 32.0, 29.2.
1H NMR (400 MHz, CDCl3): d = 7.40–7.45 (m, 6 H), 7.20–7.36 (m,
14 H), 4.60 (s, 2 H), 4.54 (d, J = 15.7 Hz, 1 H), 4.26 (d, J = 15.7 Hz,
1 H), 3.73 (m 1 H), 3.46 (ddd, J = 14.6, 8.4, 2.2 Hz, 1 H), 3.30 (ddd,
J = 14.6, 8.8, 2.2 Hz, 1 H), 3.24 (dd, J = 5.9, 9.5 Hz, 1 H), 2.98 (dd,
J = 9.5, 5.1 Hz, 1 H), 1.82–1.92 (m, 1 H), 1.62–1.74 (m, 1 H).
13C NMR (101 MHz, CDCl3): d = 172.3, 143.8, 137.1, 128.6, 128.1,
127.8, 127.5, 127.0, 86.6, 79.2, 71.8, 65.7, 51.6, 45.1, 31.6.
HRMS: m/z calcd for C32H31NO3 + Na [M + Na]+: 500.2202; found:
500.2206.
(S)-4-Methyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26c)
The oxazepanone 26a (≡ 12) (0.126 g, 0.325 mmol) was dissolved
in anhyd DMF (1.50 mL) and cooled to 0 °C. KOt-Bu (0.077 g, 0.65
mmol) was added to the solution. After stirring at 0 °C for 5 min,
the reaction mixture was allowed to warm to r.t. and stirred for an
additional 50 min, at which point MeI (0.060 mL, 0.94 mmol) was
added. The mixture was stirred under anhydrous atmosphere using
CaCl2 drying tube for about 2 h. The reaction mixture was quenched
by the addition of dil HCl (~0.1 M; 5 mL). The product was extract-
ed from the aqueous layer with CH2Cl2 (3 × 10 mL) and dried
(Na2SO4). After filtration, the solvent was removed in vacuo and the
crude residue was purified by silica gel flash chromatography (hex-
ane–acetone, 9:1). The pure product was obtained as a light yellow
liquid; yield: 0.106 g (82%, 0.265 mmol); [a]D25 –38.0 (c = 3.9,
EtOAc).
1H NMR (400 MHz, CDCl3): d = 7.51–7.40 (m, 6 H), 7.35–7.20 (m,
9 H), 4.44 (d, J = 15.7 Hz, 1 H), 4.18 (d, J = 15.7 Hz, 1 H), 3.77 (m,
1 H), 3.52 (ddd, J = 14.6, 8.6, 2.1 Hz, 1 H), 3.32–3.42 (m, 1 H), 3.27
(dd, J = 9.5, 5.9 Hz, 1 H), 3.01 (m, 1 H), 2.99 (s, 3 H), 1.98–2.07
(m, 1 H), 1.75–1.88 (m, 1 H).
13C NMR (101 MHz, CDCl3): d = 172.1, 143.8, 128.6, 127.8, 127.0,
86.6, 78.8, 71.5, 65.6, 47.5, 36.4, 31.3.
(S)-N-Benzyl-2-bromo-N-[3-hydroxy-4-(trityloxy)butyl]acet-
amide (25b)
(S)-4-(Benzylamino)-1-(trityloxy)butan-2-ol (24b; 0.230 g, 0.530
mmol) was mixed with K2CO3 (0.218 g, 1.58 mmol) in THF (3.00
mL) and the mixture was cooled to 0 °C. Bromoacetic anhydride
(0.205 g, 0.790 mmol) was added and the reaction mixture was
stirred at r.t. The mixture was then diluted with CH2Cl2 (15 mL), the
organic layer was washed with H2O (3 × 5 mL), and dried (Na2SO4).
After filtration, the solvent was removed in vacuo and the crude was
purified by silica gel flash chromatography (hexane–EtOAc, 3:1).
The pure product was obtained as a colorless liquid; yield: 0.207 g
(70%, 0.370 mmol).
1H NMR (400 MHz, CDCl3): d (major rotamer) = 7.17–7.51 (m, 20
H), 4.69 (d, J = 16.9 Hz, 1 H), 4.56 (d, J = 16.9 Hz, 1 H), 3.58–3.76
(m, 3 H), 3.31–3.54 (m, 2 H), 2.99–3.17 (m, 2 H), 2.41 (d, J = 3.3
Hz, 1 H, OH), 1.45–1.70 (m, 2 H).
13C NMR (100 MHz, CDCl3): d (major rotamer) = 168.1, 143.9,
136.8, 129.1, 128.7, 128.6, 128.0, 127.8, 127.5, 127.3, 127.0,
126.23, 86.6, 67.7, 67.4, 52.2, 48.1, 43.5, 31.3, 26.3.
HRMS: m/z calcd for C26H27NO3 + Na [M + Na]+: 424.1889; found:
424.1888.
(S)-7-(Trityloxy)methyl-1,4-oxazepan-3-one (12 ≡ 26a)
(S)-4-Ethyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26d)
Compound 26d was prepared from 26b using EtI by a similar meth-
od as for the synthesis of compound 26c and the pure product was
(S)-2-Bromo-N-[3-hydroxy-4-(trityloxy)butyl]acetamide (25a; 156
mg, 0.333 mmol) was dissolved in anhyd CH2Cl2 (10 mL). NaOH
(66.6 mg, 1.67 mmol) was added to the solution and the mixture was
Synthesis 2012, 44, 561–568
© Thieme Stuttgart · New York

PAPER
Chiral Small Heterocycles from (S)-3-Hydroxy-g-butyrolactone
567
obtained as a colorless liquid; yield: 0.109 g (77%, 0.262 mmol);
1H NMR (400 MHz, CDCl3): d = 7.39–7.46 (m, 6 H), 7.20–7.37 (m,
9 H), 4.37 (m, 1 H), 3.89 (m, 2 H), 3.50 (dd, J = 9.7, 4.4 Hz, 1 H),
3.41–3.29 (m, 2 H), 3.23 (dd, J = 9.6, 7.2 Hz, 1 H), 2.25–2.36 (m, 1
H), 1.95–2.08 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).
[a]D25 –48.5 (c = 2.4, EtOAc).
1H NMR (400 MHz, CDCl3): d = 7.41–7.50 (m, 6 H), 7.21–7.35 (m,
9 H), 4.44 (d, J = 15.6 Hz, 1 H), 4.18 (d, J = 15.6 Hz, 1 H), 3.75 (m,
1 H), 3.48–3.57 (m, 1 H), 3.43 (m, 2 H), 3.31–3.40 (m, 1 H), 3.27
(dd, J = 9.5, 5.9 Hz, 1 H), 3.02 (dd, J = 9.5, 5.3 Hz, 1 H), 1.96–2.03
(m, 1 H), 1.71–1.83 (m, 1 H), 1.12 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): d = 171.4, 143.7, 128.5, 127.7, 126.9,
86.4, 79.0, 71.8, 65.6, 45.0, 43.3, 31.9, 12.7.
NMR (101 MHz, CDCl3): d = 185.1, 143.4, 128.5, 127.9, 127.2,
87.0, 76.3, 64.2, 50.6, 44.6, 24.3, 10.9.
HRMS: m/z calcd for C26H27NO2S [M ]+: 417.1761; found:
417.1762.
(S)-3-Ethyl-6-(hydroxymethyl)-1,3-oxazinane-2-thione (29)
The thione 28 (0.100 g, 0.24 mmol) was dissolved in CH2Cl2 (3.00
mL) and the solution was cooled to 0 °C. Trifluoroacetic acid (0.070
mL, 2.4 mmol) was added and the mixture was stirred at r.t. over-
night. The reaction was quenched by the addition of MeOH (3 mL)
and the organic phase was washed with H2O (3 × 3 mL). After dry-
ing (Na2SO4) and filtration, the solvent was removed in vacuo on
the rotovap. The crude residue was purified by silica gel flash chro-
matography (hexane–CH2Cl2–acetone 6:1:1). The pure product was
obtained as a colorless liquid; yield: 0.042 g (~100%, 0.24 mmol).
HRMS: m/z calcd for C27H29NO3 + Na [M + Na]+: 438.2045; found:
438.2050.
(S)-6-[(Trityloxy)methyl]-1,3-oxazinane-2-thione (13)
(S)-4-Amino-1-(trityloxy)butan-2-ol (24a; 0.057g, 0.16 mmol) was
mixed with thiocarbonyldiimidazole (TCDI) (0.059 g, 0.32 mmol)
in 1,4-dioxane (6.0 mL) and the solution was heated to reflux at 120
°C for 24 h. The mixture was diluted with CH2Cl2 (10 mL), the or-
ganic layer washed with H2O (2 × 5 mL), and dried (Na2SO4). The
crude residue was purified by silica gel flash column chromatogra-
phy using a gradient of hexane–EtOAc (6:1 to 2.5:1). The pure
product was obtained as a light yellow solid; yield: 0.055 g (88%,
0.14 mmol); mp 155.0–156.0 °C; [a]D25 +23.3 (c = 2.90, EtOAc).
1H NMR (400 MHz, CDCl3): d = 4.33 (m, 1 H), 3.81–4.03 (m, 3 H),
3.73 (dd, J = 12.5, 4.8 Hz, 1 H), 3.38–3.52 (m, 2 H), 2.02–2.24 (m,
2 H), 1.30 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.07 (br s, 1 H), 7.38–7.48 (m, 6
H), 7.21–7.35 (m, 9 H), 4.40 (m, 1 H), 3.48 (dd, J = 9.9, 4.4 Hz, 1
H), 3.21–3.40 (m, 3 H), 2.12–2.24 (m, 1 H), 1.85–2.03 (m, 1 H).
13C NMR (101 MHz, CDCl3): d = 185.1, 78.7, 63.4, 50.5, 44.9, 22.9,
10.9.
13C NMR (101 MHz, CDCl3): d = 186.9, 143.3, 128.6, 128.0, 127.3,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra for compounds 10–18, 21–23, and 25–
29.
87.1, 77.5, 64.3, 39.8, 22.5.
HRMS: m/z calcd for C24H23NO2S [M]+: 389.1448; found:
389.1449.
(S)-2-(Ethylthio)-6-[(trityloxy)methyl]-5,6-dihydro-4H-1,3-ox-
azine (27)
Acknowledgment
The thione 13 (0.030 g, 0.077 mmol) was mixed with EtI (0.014
mL, 0.0800 mmol) in anhyd THF (1.00 mL). The reaction mixture
was cooled in an ice-bath and KOt-Bu (0.013 g, 0.11 mmol) was
added slowly. The mixture was stirred at r.t. for 80 min after which
the reaction was complete. Dil HCl (4 mL) was added to quench the
reaction and the mixture was extracted with CH2Cl2 (3 × 7 mL). The
combined organic layers were dried (Na2SO4) and after filtration
and concentration, the crude residue was purified by silica gel flash
chromatography using a gradient of hexane–EtOAc (10:1 to 5:1).
The pure product was obtained as a colorless liquid; yield: 0.026 g
(81%, 0.062 mmol); [a]D25 +42.1 (c = 1.70, EtOAc).
1H NMR (400 MHz, CDCl3): d = 7.50–7.41 (m, 6 H), 7.21–7.36 (m,
9 H), 4.34 (m, 1 H), 3.56–3.35 (m, 2 H), 3.29 (dd, J = 9.9, 5.4 Hz, 1
H), 3.17 (dd, J = 9.9, 4.9 Hz, 1 H), 2.94–2.78 (m, 2 H), 1.97–1.77
(m, 2 H), 1.30 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): d = 157.8, 143.7, 128.7, 127.9, 127.1,
86.6, 75.8, 65.5, 43.5, 25.0, 24.7, 14.7.
We thank Afid Therapeutics for their general gift of the lactone star-
ting material. We also thank the Mass Spectrometry lab at the Uni-
versity of Illinois at Urbana Champaign for their assistance with
measuring the HRMS. The research was supported in part by a sum-
mer research grant from UNO.
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(S)-3-Ethyl-6-[(trityloxy)methyl]-1,3-oxazinane-2-thione (28)
(S)-4-(Ethylamino)-1-(trityloxy)butan-2-ol (24c; 0.218 g, 0.58
mmol) was mixed with TCDI (0.205 g, 1.16 mmol) in 1,4-dioxane
(7.00 mL). The reaction mixture was heated to reflux for 24 h and
the mixture was cooled to r.t., diluted with CH2Cl2 (20 mL), and the
organic layer was washed with H2O (2 × 10 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. The crude
residue was purified by silica gel flash chromatography using a gra-
dient of hexane–EtOAc (4:1 to 1:1). The pure product was obtained
as a white solid; yield: 0.177 g (73%, 0.42 mmol); mp 170.0–
171.0 °C; [a]D25 +25.6 (c = 1.00, CH2Cl2).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 561–568

568
H. Yang et al.
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