LETTER
Synthesis of (S)-3-Aminopyran
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ing the internal temperature ≤ 15 °C, a solution of 9 (1.0 kg, 3.63
mol, dissolved in 2.0 L of anhyd THF) was added dropwise. After
the addition was complete, the mixture was slowly warmed to 20 °C
and stirred overnight. The reaction mixture was then cooled to 0 °C
and MeOH (10.0 L) was added slowly to quench any excess reduc-
ing reagent. After concentration in vacuo, the residue was diluted
with H2O (5.0 L) and extracted with EtOAc. The combined organic
phase was dried over Na2SO4, filtered, and the solvent was removed
in vacuo to give crude product (0.68 kg, 85% yield) as a pale yellow
oil. IR (neat): 3343, 2987, 2957, 2941, 2916, 2865, 1679 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 5.08 (s, 1 H), 3.74–3.51 (m, 5 H), 3.44
(s, 2 H), 1.74–1.47 (m, 4 H), 1.44 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 156.5, 79.6, 65.0, 62.2, 52.3, 28.7, 28.4, 27.9. ESI-
HRMS: m/z [M + Na]+ calcd for C10H21NO4Na: 242.1368; found:
242.1355.
Various Mitsunobu-type conditions were evaluated to fur-
ther optimize the cyclization to afford N-Boc-aminopyran
11. Ultimately, we identified dichloromethane as the best
solvent with either DIAD or diethyl azodicarboxylate
(DEAD) working equally well in promoting the reaction
and providing 11 in 50–60% yield. The reaction sequence
shown in Scheme 3 was scaled up successfully to produce
multikilogram quantities. Although initially the removal
of triphenylphosphine oxide from N-Boc-aminopyran 11
necessitated the use of silica gel chromatography, we
identified crystallization conditions using petroleum ether
and ethyl acetate to purge this impurity. This modification
reduced the yield of the cyclization reaction to 37%, how-
ever, it resulted in faster processing and improved opera-
tional simplicity and thus made it the preferred
purification method. Determination of chiral purity of the
product was achieved via chiral HPLC using the cinnama-
mide derivative of the product as illustrated in Scheme 3.7
Preparation of (S)-tert-Butyl (Tetrahydro-2H-pyran-3-yl)car-
bamate
To a 20 L reactor equipped with a mechanical stirrer was charged
diol 10 (0.95 kg, 4.33 mol), Ph3P (2.27 kg, 8.66 mol) and CH2Cl2
(10 L). Diisopropylazodicarboxylate (1.75 kg, 8.66 mol) was then
added dropwise to the reaction mixture. The solution was stirred for
48 h at 20 °C, and the reaction was monitored for completion by
TLC. The reaction mixture was concentrated and triturated with
PE–EtOAc (12:1 v/v, 20 L). The solid was filtered off and washed
with 4-5 additional portions of PE–EtOAc (12:1 v/v, 20 L). The
combined filtrates were concentrated to ca. 10% of the original vol-
ume, and the pure product was isolated by filtration to give com-
pound 11 (320 g, 37%) as a white solid after drying; mp 94–96 °C.
IR (neat): 3357, 2948, 2847, 1678, 1518 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 4.89 (s, 1 H), 3.79 (dd, J = 11.2, 2.5 Hz, 1 H), 3.71–3.49
(m, 3 H), 3.37 (dd, J = 10.0, 5.6 Hz, 1 H), 1.94–1.82 (m, 1 H), 1.80–
1.67 (m, 1 H), 1.66–1.50 (m, 2 H), 1.45 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 155.2, 79.2, 71.6, 68.0, 46.0, 29.0, 28.4, 23.3. ESI-
HRMS: m/z [M + Na]+ calcd for C10H19NNaO3: 224.1263; found:
224.1258.
In summary, this route represents an inexpensive and rap-
id entry to kilogram quantities of this useful chiral build-
ing block, though further optimization is needed to
improve the process for larger-scale manufacture. Previ-
ously reported racemic preparations of 3-aminopyran
would have required chiral separation. However, our ap-
proach can provide easy access to both enantiomers of
compound 1 depending on the stereoisomer of glutamic
acid used. Mitsunobu cyclization of N-Boc-protected 3-
amino diol 10 was used as the key step in this preparation
of (S)-3-aminopyran (1). The short and efficient route re-
lied upon a chiral-pool approach employing inexpensive
and readily available starting materials. To our knowl-
edge, this is the first reported stereospecific route to ac-
cess both enantiomers of 3-aminopyran.
Preparation of (S)-Tetrahydro-2H-pyran-3-amine Hydrochlo-
ride
To a 20 L reactor equipped with a mechanical stirrer was charged
aminopyran 11 (2.0 kg, 4.97 mol) and 6 N HCl in MeOH (12 L, 72.0
mol) at 20 °C. The reaction was stirred until complete conversion of
starting material (monitored by TLC). The solution was concentrat-
ed and then triturated with EtOAc (12 L). The resulting slurry was
filtered and washed with PE (3 L). The solids were dried in vacuo
to give the target compound 1 (1.36 kg, >99%) as a white solid; mp
Preparation of (S)-Dimethyl 2-[(tert-Butoxycarbonyl)ami-
no]pentanedioate
To a 20 L reactor equipped with a mechanical stirrer was charged
MeOH (7.0 L). This was cooled to 0–5 °C, followed by slow addi-
tion of TMSCl (2.59 kg, 23.8 mol). The solution was stirred for 30
min, then L-glutamic acid (700 g, 4.76 mol) was added at 0–5 °C.
The reaction was warmed to 20 °C and stirred for 2–4 h. After the
reaction completion was checked by TLC, the solution was again
cooled to 0 °C. Et3N (3.130 kg, 31 mol) and Boc2O (1.142 kg, 5.23
mol) were slowly added to the reactor while keeping the internal
temperature below 25 °C. The resultant slurry was stirred over-
night. After concentration in vacuo, the residue was diluted with de-
ionized H2O (5.0 L) and extracted with EtOAc (10.0 L). The organic
phase was washed with 20% aq citric acid (4.0 L) and brine, then
dried over Na2SO4. After filtration and concentration in vacuo, the
crude product (1.243 kg, 95% yield) was obtained as pale yellow
1
112–114 °C. IR (neat): 2864, 2677, 2588, 2051, 1613 cm–1. H
NMR (300 MHz, DMSO-d6): δ = 8.48 (s, 3 H), 3.84 (dd, J = 11.4,
3.2 Hz, 1 H), 3.71–3.58 (m, 1 H), 3.54–3.35 (m, 2 H), 3.12 (s, 1 H),
2.06–1.89 (m, 1 H), 1.83–1.60 (m, 2 H), 1.58–1.41 (m, 1 H). 13C
NMR (75 MHz, CDCl3): δ = 67.8, 67.0, 45.9, 26.3, 22.4. ESI-
HRMS: m/z [M + H]+ calcd for C5H12NO: 102.0919; found:
102.0913.
Preparation of (S)-N-(Tetrahydro-2H-pyran-3-yl)cinnam-
amide
A solution of aminopyran 1 (0.65 g, 4.7 mmol) in CH2Cl2 (30 mL)
was cooled to 0 °C. Cinnamoyl chloride (1.2 g, 7.2 mmol) and Et3N
(1.43 g, 14.4 mmol) were added, and the mixture was stirred for 2 h
at 20 °C. The reaction mixture was washed with brine (10 mL), and
the organic phase was dried with Na2SO4, filtered, and concentrat-
ed. The residue was purified by SiO2 chromatography (CH2Cl2–
MeOH, 97:3) giving the desired product 13 (1.0 g, 90% yield) as a
white solid; mp 148–149 °C. IR (neat): 3279, 3056, 2969, 2843,
1654, 1618 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 15.7
Hz, 1 H), 7.54–7.46 (m, 2 H), 7.42–7.32 (m, 3 H), 6.42 (d, J = 15.6
Hz, 1 H), 6.02 (d, J = 7.1 Hz, 1 H), 4.20–4.10 (m, 1 H), 3.84–3.71
(m, 2 H), 3.67–3.53 (m, 2 H), 1.96–1.73 (m, 3 H), 1.67–1.54 (m, 1
H). 13C NMR (75 MHz, CDCl3): δ = 165.2, 141.2, 134.8, 129.7,
1
oil. IR (neat): 3370, 3179, 2977, 2955, 1694 cm–1. H NMR (300
MHz, CDCl3): δ = 5.17 (d, J = 7.0 Hz, 1 H), 4.34 (dd, J = 7.6, 5.4
Hz, 1 H), 3.75 (s, 3 H), 3.68 (s, 3 H), 2.42 (dt, J = 7.9, 5.5 Hz, 2 H),
2.26–2.11 (m, 1 H), 2.03–1.88 (m, 1 H), 1.44 (s, 9 H). 13C NMR (75
MHz, CDCl3): δ = 173.1, 172.6, 155.3, 80.0, 52.8, 52.4, 51.7, 30.0,
28.2, 27.7. ESI-HRMS: m/z [M + Na]+ calcd for C12H21NO6Na:
298.1267; found: 298.1255.
Preparation of (S)-tert-Butyl (1,5-Dihydroxypentan-2-yl)carba-
mate
To a 20 L reactor equipped with a mechanical stirrer was charged
anhyd THF (10.0 L) and LiBH4 (0.4 kg, 18.4 mol). While maintain-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 987–990