Stereoselective Synthesis of a Ceramide Transporter Protein (CERT)-Dependent Ceramide-Trafficking Inhibitor, (1R,3S)-HPA-12, via Gold(I)-Catalyzed Cyclization of a Propargylic N-Hydroxylamine

Article abstract of DOI:10.1055/s-0036-1588369

A ceramide transporter protein (CERT)-dependent ceramide-trafficking inhibitor, HPA-12, is efficiently synthesized using gold(I)-catalyzed cyclization of a propargylic N-hydroxylamine, which is prepared via a stereoselective nitrone-alkyne addition reaction. The resulting 4-isoxazoline is converted into a syn-1,3-amino alcohol through stereoselective reduction and reductive ring opening.

Full text of DOI:10.1055/s-0036-1588369

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
B. Chandrasekhar et al.
Paper
Synthesis
Stereoselective Synthesis of a Ceramide Transporter Protein
(CERT)-Dependent Ceramide-Trafficking Inhibitor, (1R,3S)-HPA-
12, via Gold(I)-Catalyzed Cyclization of a Propargylic N-Hydroxyl-
amine
Bandari Chandrasekhar
Sewon Ahn
Jae-Sang Ryu*
College of Pharmacy & Graduate School of Pharmaceutical
Sciences, Ewha Womans University, 52 Ewhayeodae-gil,
Seodaemun-Gu, Seoul 03760, Republic of Korea
ryuj@ewha.ac.kr
Received: 06.10.2016
Accepted after revision: 11.11.2016
Published online: 13.12.2016
tion of ER stress. On the other hand, increased expression of
CERT is observed in drug-resistant cell lines and in residual
tumors following paclitaxel treatment of ovarian cancer.5
These observations support that CERT could be a potential
drug target for chemotherapy-resistant cancers.
DOI: 10.1055/s-0036-1588369; Art ID: ss-2016-f0702-op
Abstract A ceramide transporter protein (CERT)-dependent ceramide-
trafficking inhibitor, HPA-12, is efficiently synthesized using gold(I)-cat-
alyzed cyclization of a propargylic N-hydroxylamine, which is prepared
via a stereoselective nitrone–alkyne addition reaction. The resulting 4-
isoxazoline is converted into a syn-1,3-amino alcohol through stereose-
lective reduction and reductive ring opening.
The function of CERT is impeded by a novel ceramide-
trafficking inhibitor, (1R,3S)-N-(3-hydroxy-1-hydroxymethyl-
3-phenylpropyl)dodecanamide (HPA-12) (1),6 which acts as
a direct antagonist of CERT, whereas it does not inhibit SM
synthase or the ER-to-Golgi transport pathway of glycopro-
teins.7 HPA-12 (1) was discovered from an amino alcohol li-
brary by Kobayashi and co-workers in 2001.8 As a ceramide
analogue, HPA-12 (1) contains a 1,3-amino alcohol scaffold
and its absolute stereochemistry was initially assigned as
(1R,3R). However, it was revised to (1R,3S) by Berkeš et al. in
2011,9 and it was unambiguously confirmed as (1R,3S) by
X-ray crystallographic analysis10 by the Kobayashi group in
2013 (Figure 1).
Key words HPA-12, gold, nitrone, 4-isoxazoline, stereoselective syn-
thesis
Sphingolipids (SLs) are a class of lipids containing an
amino alcohol sphingosine backbone. They are omnipres-
ent components of plasma membrane lipids in eukaryotic
cells that play key roles in cell proliferation, differentiation,
and apoptosis.1 Although the biosynthesis and transport of
sphingolipids between the endoplasmic reticulum (ER) and
Golgi apparatus have long been understood, the detailed
mechanism of sphingolipid trafficking has only been eluci-
dated very recently: ceramide, one of the sphingosine phos-
pholipids, is produced in the ER, transported to the Golgi
apparatus either by vesicular trafficking or by a specific cer-
amide transporter protein (CERT),2 and converted into gly-
cosphingolipids (GSLs) or sphingomyelin (SM) in the Golgi
apparatus.3
O
NH OH
HO
(1R,3S)-HPA-12 (1)
Figure 1 The structure of the ceramide-trafficking inhibitor (1R,3S)-
HPA-12 (1)
CERT mediates ATP-dependent interorganelle traffick-
ing of ceramide from the ER to the Golgi site.4 Interestingly,
downregulation of this protein leads to an increased sensi-
tivity of cancer cells toward anticancer agents and potentia-
As seen in the structure of HPA-12, enantioenriched
1,3-amino alcohols are important structures frequently
found in bioactive compounds and natural products. We
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
B. Chandrasekhar et al.
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Synthesis
have recently developed the gold(I)-catalyzed cyclization of
propargylic N-hydroxylamine leading to 4-isoxazolines,11
which are versatile synthetic intermediates that can be eas-
ily converted into useful building blocks such as β-amino
ketones,12 1,3-amino alcohols,12 β-lactams,13 2-acylaziri-
dine,14 and 4-oxazoline15 owing to the instability of the N–
O bond associated with the π-system (Figure 2). We found
that 5 mol% of (PPh3)AuNTf2 or 5 mol% of (PPh3)AuCl/AgOTf
mediates cyclization of propargylic N-hydroxylamine very
efficiently at room temperature in one hour. In particular,
the reaction was mild enough to allow the synthesis of 4-
isoxazolines from enantioenriched propargylic N-hydroxyl-
amines with retention of configuration and without any
loss of enantiopurity. Therefore, we believe that the method
is applicable to the stereoselective synthesis of bioactive
compounds containing 1,3-amino alcohols when it is cou-
pled to diastereoselective synthesis of the propargylic N-
hydroxylamine. This result prompted us to apply this meth-
od to the stereoselective synthesis of HPA-12. Herein, we
report a straightforward approach for the synthesis of en-
antiomerically pure HPA-12 using gold(I)-catalyzed 4-isox-
azoline synthesis following a reductive ring-opening reac-
tion resulting in either a syn-1,3-amino alcohol or an anti-
1,3-amino alcohol.
O
O
Ph
N
NH OH
H23C11
HO
Ph
BnO
1
3
Ph
HPA-12 (1)
2
O
N
Ph
OH
Ph
N
BnO
H
BnO
4
Ph
3
Ph
5
Scheme 1 Retrosynthetic analysis of (1R,3S)-HPA-12 (1)
trones had previously been successful using catalytic
amounts of zinc bromide and stoichiometric amounts of
TMSOTf,11,16 the addition of phenylacetylene (5) to chiral
nitrone 4 under the same conditions was not fruitful. After
searching for an effective method to prepare propargylic N-
hydroxylamine 3 with high diastereoselectivity, we found
Ph
(5)
Zn(OTf)2, Et3N
CH2Cl2
HO
O
N
Ph
O
H
N
Ph
R1
BnO
β−lactams
NH OH
H
BnO
CH2Cl2, MgSO4
r.t., 75%
H
r.t., 99%
2-acylaziridine
R2
R4
6
4
(dr 78:22)
R3
ref. 13
ref. 14
β-amino alcohols
ref. 12
ref. 12
(PPh3)AuCl (5 mol%)
AgOTf (5 mol%)
OH
Ph
N
R1
N
O
O
Ph
N
ref. 15
BnO
R4
Ph
β-amino ketones
4-oxazoline
BnO
toluene, r.t., 96%
R2
Ph
R3
2
3
Figure 2 4-Isoxazoline as a versatile synthetic intermediate
Zn powder
NaBH4
AcOH, r.t.
Ph
NH OH
AcOH, r.t.
O
A retrosynthetic analysis of (1R,3S)-HPA-12 (1) is de-
picted in Scheme 1. We envisioned that the enantioen-
riched syn-1,3-amino alcohol moiety of HPA-12 (1) could
be installed by a diastereoselective reductive ring opening
of 4-isoxazoline 2. The chiral N-(1-phenethyl) moiety and
the O-benzyl group in compound 2 could easily be cleaved,
and subsequently the resultant –NH2 group would be acy-
lated. 4-Isoxazoline 2 could be synthesized by gold(I)-cata-
lyzed cyclization of propargylic N-hydroxylamine 3, which
would be assembled from chiral nitrone 4 and phenylacety-
lene (5) by a diastereoselective alkyne addition reaction
(Scheme 1).
Ph
N
Ph
BnO
BnO
Ph
75%
76% (dr 91:9)
8
7
O
Na
a. H2/Pd, r.t.
i
naphthalene
b. Pr2NEt, CH2Cl2, r.t.
NH OH
H23C11
BnO
O
THF, 0 °C
72%
Ph
Cl
9
H23C11
(52% for 2 steps)
O
Our synthetic formation of (1R,3S)-HPA-12 (1) began
with commercially available benzyloxyacetaldehyde (6),
which was readily condensed with (S)-N-(1-phenyleth-
yl)hydroxylamine to provide chiral nitrone 4 with a 75%
yield (Scheme 2). Although the addition of alkynes to ni-
NH OH
H23C11
HO
Ph
(1R,3S)-HPA-12 (1)
Scheme 2 Synthesis of (1R,3S)-HPA-12 (1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
B. Chandrasekhar et al.
Paper
Synthesis
that the reaction conditions using Zn(OTf)2 developed by
Carreira and co-workers17 were effective, and afforded two
diastereomers in a ratio of 78:22 in a 99% combined yield.
Both diastereomers of 3 were separated by silica gel column
chromatography. At this stage, the absolute configuration of
the newly generated stereogenic center in the major isomer
3 was not determined. If the synthesis was completed suc-
cessfully as planned, the chiral centers of the final product
could be created with the desired absolute stereochemistry
by choosing the correct enantiomer of N-(1-phenyleth-
yl)hydroxylamine. Therefore, the absolute stereochemistry
at the newly established chiral center of 3 was tentatively
assigned as R.
Next, we carried out gold(I)-catalyzed cyclization of
propargylic N-hydroxylamine 3 in the presence of 5 mol% of
(PPh3)AuCl and 5 mol% of AgOTf, which provided the de-
sired 4-isoxazoline 2 in a 96% yield in five minutes at room
temperature. The reaction was very rapid and proceeded
with preservation of stereochemical integrity. NaBH4 re-
duction of 4-isoxazoline 2 in AcOH12 afforded cis-isoxazoli-
dine 7 and trans-isoxazolidine 7 in a ratio of 91:9. The rela-
tive stereochemistry of the major isomer was unambigu-
ously determined as cis, and the minor diastereomer was
assigned as trans by serial NOE experiments (see the Sup-
porting Information). The selected NOEs are shown in Fig-
ure 3.
In conclusion, we have developed a stereoselective syn-
thetic means of producing (1R,3S)-HPA-12 (1) using a high-
ly efficient gold(I)-catalyzed cyclization of a propargylic N-
hydroxylamine and a subsequent reductive ring-opening
reaction. By this method, a synthetically useful chiral 4-
isoxazoline was afforded with a high yield and a high selec-
tivity, and the 4-isoxazoline was further converted into an
enantiomerically pure chiral 1,3-amino alcohol. This meth-
od is general and versatile, and can be applied to the stereo-
selective synthesis of complex molecules containing chiral
1,3-amino alcohol moieties. We are certain that the versa-
tility and ease of this method will allow the synthesis of
many new derivatives for a detailed SAR study of HPA-12
and will spur further research on CERT-mediated ceramide
transport.
All reactions were performed in oven-dried glassware fitted with
glass stoppers under positive Ar gas pressure with magnetic stirring,
unless otherwise noted. Air- and moisture-sensitive liquids and solu-
tions were transferred via syringe or stainless-steel cannula. TLC was
performed on 0.25 mm E. Merck silica gel 60 F254 plates and visual-
ized under UV light (254 nm) or by staining with cerium ammonium
molybdenate (CAM), potassium permanganate (KMnO4), or p-anisal-
dehyde. Flash chromatography was performed on E. Merck 230–400
mesh silica gel 60. Reagents were purchased from commercial suppli-
ers, and used without further purification unless otherwise noted.
Solvents were distilled from appropriate drying agents (CaH2 or Na
wire) under an Ar atmosphere at 760 mmHg. All moisture- and/or ox-
ygen-sensitive solids were handled and stored in a glovebox under N2.
Melting points were obtained using an Electrothermal 1A-8101 melt-
ing point apparatus. Optical rotations were recorded using a JASCO P-
1010 polarimeter. Infrared spectra were recorded as a thin film on a
KBr disk using a Thermo Fisher model Nicolet iS10 spectrometer with
peaks reported in cm–1. NMR spectra were recorded on Varian Unity
400 instruments at 24 °C. Chemical shifts are expressed in ppm rela-
tive to TMS (1H, 0 ppm), CDCl3 (1H, 7.26 ppm; 13C, 77.2 ppm), acetone-
d6 (1H, 2.05 ppm; 13C, 206.2, 29.9 ppm), and C6D6 (1H, 7.15 ppm; 13C,
128.62 ppm); coupling constants are expressed in Hz. High-resolu-
tion mass spectra (HRMS) were obtained with an Agilent Technolo-
gies 6220 TOF LC/MS spectrometer (electrospray ionization: ESI). Ele-
mental analyses were obtained using a Thermo Scientific FLASH 2000
instrument.
7.62
3.87
H
Ph
H
Ph
H
O
H
O
N
N
H
Ph
2.37
H
Ph
Ph
O
Ph
O
H
H
2.63
26.09
H
5.43
H
29.52
6.90
cis-7 (major)
trans-7 (minor)
Figure 3 Selected NOEs of cis-7 and trans-7
Subsequent N–O bond cleavage of the major isomer cis-
7 using Zn powder12 gave the ring-opened 1,3-amino alco-
hol 8 in 75% yield. Next, we attempted to deprotect the chi-
ral N-(S)-α-phenylethyl group and the O-benzyl group in a
stepwise process. First, hydrogenolysis using H2/Pd selec-
tively removed only the chiral N-(S)-α-phenylethyl group,
while the O-benzyl group remained intact. The deprotec-
tion reaction proceeded cleanly and afforded the primary
amine, which was directly acylated with dodecanoyl chlo-
ride to yield 9. Finally, the deprotection of the O-benzyl
group was achieved by treating 9 with Na/naphthalene to
furnish the final product 1 in 72% yield. The spectral data
and optical rotation of the synthesized product 1 were in
good agreement with those reported in the literature.
Therefore, we concluded that the absolute configuration of
the chiral center of 3 tentatively assigned as R was correct.
(S,Z)-N-[2-(Benzyloxy)ethylidene]-1-phenylethanamine Oxide (4)
2-(Benzyloxy)acetaldehyde (6) (1.30 g, 8.66 mmol) in anhydrous
CH2Cl2 (20 mL) was added to a mixture of (S)-N-(1-phenylethyl)hy-
droxylamine (750 mg, 5.47 mmol) and anhydrous MgSO4 (1.97 g, 16.4
mmol). The reaction mixture was stirred at r.t. for 16 h. After comple-
tion of the reaction, the resulting suspension was filtered and washed
with CH2Cl2 (20 mL). The filtrate was concentrated by rotary evapora-
tion. Purification by column chromatography (hexanes/EtOAc, 7:3) af-
forded nitrone 4 (1.10 g, 75%) as a white solid.
26.4
Mp 115–117 °C; Rf = 0.5 (hexanes/EtOAc, 1:1); [α]D
–30.0 (c 1.0,
CHCl3).
IR (film): 3063, 1616, 1453, 1162, 759, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.26 (m, 10 H), 6.89 (t, J = 4.4 Hz,
1 H), 4.98 (q, J = 6.8 Hz, 1 H), 4.52 (s, 2 H), 4.48 (dd, J = 17.2, 4.4 Hz, 1
H), 4.42 (dd, J = 17.2, 4.4 Hz, 1 H), 1.79 (d, J = 6.8 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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B. Chandrasekhar et al.
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13C NMR (100 MHz, CDCl3): δ = 137.9, 137.4, 135.8, 129.0, 128.9,
128.6, 128.2, 128.1, 127.5, 73.9, 73.4, 66.3, 19.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO2: 270.1489; found:
270.1493.
Celite, and rinsed with Et2O (20 mL). The filtrate was concentrated by
rotary evaporation. Purification by flash column chromatography
(hexanes/EtOAc, 19:1) afforded 2 (168 mg, 96%) as a colorless oil.
Rf = 0.63 (hexanes/EtOAc, 4:1); [α]D26.4 +117.8 (c 1.0, CHCl3).
IR (film): 3061, 3028, 2360, 1493, 1101, 734, 698 cm–1
.
N-[1-(Benzyloxy)-4-phenylbut-3-yn-2-yl]-N-[(S)-1-phenyleth-
yl]hydroxylamine (3)
1H NMR (400 MHz, CDCl3): δ = 7.59–7.57 (m, 2 H), 7.39–7.20 (m, 13
H), 5.28 (d, J = 2.8 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.37 (d, J = 12.0
Hz, 1 H), 4.14 (td, J = 6.8, 2.8 Hz, 1 H), 4.08 (q, J = 6.4 Hz, 1 H), 3.41 (dd,
J = 10.0, 6.8 Hz, 1 H), 3.37 (dd, J = 9.2, 6.8 Hz, 1 H), 1.60 (d, J = 6.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 153.8, 142.3, 138.5, 129.1, 129.0,
128.7, 128.6, 128.4, 128.3, 127.8, 127.6, 127.5, 125.8, 93.8, 73.7, 73.3,
68.4, 66.3, 21.7.
Zn(OTf)2 (90.0 mg, 0.25 mmol) was placed in an oven-dried, 25 mL
one-arm round-bottomed flask. Anhydrous CH2Cl2 (1 mL), phenyl-
acetylene (5) (0.16 mL, 1.5 mmol) and Et3N (0.1 mL, 0.75 mmol) were
added sequentially. The resulting mixture was stirred at r.t. for 20
min. (S,Z)-N-[2-(benzyloxy)ethylidene]-1-phenylethanamine oxide
(4) (140 mg, 520 μmol) in anhydrous CH2Cl2 (1 mL) was then added
dropwise. After stirring at r.t. for 1 h, the heterogeneous mixture was
quenched with saturated aqueous NH4Cl solution (1 mL). The organic
layer was separated and the aqueous layer was extracted with CH2Cl2
(4 × 5 mL). The combined organic extracts were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated by rotary
evaporation. Purification by column chromatography (hexanes/EtOAc,
9:1) afforded two diastereomers as colorless oils: major diastereomer
3a (150 mg, 78%), minor diastereomer 3b (42 mg, 21%).
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO2: 372.1958; found:
372.1965.
(3R)-3-(Benzyloxymethyl)-5-phenyl-2-[(S)-1-phenylethyl]isoxazo-
lidine (7)
To a solution of (R)-3-(benzyloxymethyl)-5-phenyl-2-[(S)-1-phenyl-
ethyl]-2,3-dihydroisoxazole (2) (150 mg, 404 μmol) in AcOH (2 mL)
was added NaBH4 (47.0 mg, 1.23 mmol). The reaction mixture was
stirred at r.t. for 15 min. Additional NaBH4 (47.0 mg, 1.23 mmol) was
added and the mixture stirred for an additional 15 min. Upon com-
pletion, the reaction was quenched with saturated aqueous NaHCO3
(20 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL).
The combined organic extracts were washed with saturated aqueous
NaHCO3 (20 mL), dried over anhydrous MgSO4, filtered, and concen-
trated by rotary evaporation. Purification by column chromatography
on silica gel (hexanes/EtOAc, 19:1) afforded the major isomer 7a (104
mg, 69%) as a colorless oil and the minor isomer 7b (10.0 mg, 7%) as a
colorless oil in the ratio 7a/7b = 91:9.
Major Diastereomer 3a
Rf = 0.42 (hexanes/EtOAc, 9:1); [α]D26.4 –182.0 (c 1.0, CHCl3).
IR (film): 3385, 2866, 2360, 1489, 756, 698 cm–1
.
1H NMR (400 MHz, C6D6): δ = 7.47–7.43 (m, 4 H), 7.26–7.23 (m, 2 H),
7.17–7.04 (m, 6 H), 6.97–6.94 (m, 3 H), 4.46 (s, 1 H), 4.35–4.30 (m, 2
H), 4.27 (d, J = 12.0 Hz, 1 H), 4.06 (dd, J = 7.6, 5.6 Hz, 1 H), 3.94 (dd, J =
10.0, 7.6 Hz, 1 H), 3.67 (dd, J = 10.0, 5.6 Hz, 1 H), 1.55 (d, J = 6.4 Hz, 3
H).
13C NMR (100 MHz, C6D6): δ = 143.9, 139.3, 132.7, 129.4, 129.1, 129.0,
128.8, 128.6, 128.4, 128.3, 128.2, 124.2, 88.1, 85.8, 73.3, 71.9, 66.6,
57.6, 22.8.
Major Isomer 7a
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO2: 372.1958; found:
Rf = 0.37 (hexanes/EtOAc, 9:1); [α]D26.4 –9.8 (c 1.0, CHCl3).
372.1963.
IR (film): 2850, 2360, 1492, 1103 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 13 H), 7.19–7.16 (m, 2
H), 5.25 (t, J = 8.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.31 (d, J = 12.0
Hz, 1 H), 4.05 (q, J = 6.8 Hz, 1 H), 3.48–3.43 (m, 2 H), 3.35–3.30 (m, 1
H), 2.81 (m, 1 H), 2.07 (ddd, J = 12.0, 8.0, 3.2 Hz, 1 H), 1.50 (d, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, acetone-d6): δ = 144.7, 141.7, 139.7, 129.4, 129.3,
129.0, 128.8, 128.5, 128.4, 128.3, 128.2, 127.7, 79.1, 73.9, 73.3, 64.3,
64.2, 40.6, 22.3.
Minor Diastereomer 3b
Rf = 0.45 (hexanes/EtOAc, 9:1); [α]D26.4 –100.7 (c 1.0, CHCl3).
IR (KBr film): 3530, 3420, 2974, 2360, 1490, 1097, 756, 697 cm–1
1H NMR (400 MHz, C6D6): δ = 7.48–7.46 (m, 2 H), 7.37–7.33 (m, 4 H),
7.19–7.06 (m, 6 H), 6.98–6.94 (m, 3 H), 4.48 (d, J = 12.4 Hz, 1 H), 4.44
(d, J = 12.4 Hz, 1 H), 4.39 (t, J = 6.8 Hz, 1 H), 4.33 (q, J = 6.8 Hz, 1 H),
4.12 (s, 1 H), 3.98 (dd, J = 7.6, 6.8 Hz, 1 H), 3.84 (dd, J = 9.2, 6.8 Hz, 1
H), 1.26 (d, J = 6.8 Hz, 3 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO2: 374.2115; found:
13C NMR (100 MHz, acetone-d6): δ = 146.2, 140.0, 132.6, 129.4, 129.1,
129.0, 128.9, 128.5, 128.4, 128.3, 127.5, 124.4, 87.1, 86.3, 73.7, 72.8,
68.8, 57.3, 21.1.
374.2121.
Minor Isomer 7b
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO2: 372.1958; found:
Rf = 0.35 (hexanes/EtOAc, 9:1); [α]D26.4 –38.8 (c 1.0, CHCl3).
372.1964.
IR (film): 2928, 2360, 1452, 749, 698 cm–1
.
1H NMR (400 MHz, C6D6): δ = 7.34–7.30 (m, 4 H), 7.19–7.03 (m, 11 H),
5.05 (dd, J = 10.0, 6.8 Hz, 1 H), 4.18 (s, 2 H), 3.94 (q, J = 6.4 Hz, 1 H),
3.41 (m, 1 H), 3.27 (dd, J = 9.2, 8.0 Hz, 1 H), 3.17 (dd, J = 9.2, 5.6 Hz, 1
H), 2.42 (ddd, J = 12.4, 6.8, 2.8 Hz, 1 H), 2.13 (m, 1 H), 1.65 (d, J = 6.4
Hz, 3 H).
13C NMR (100 MHz, acetone-d6): δ = 144.8, 142.1, 139.7, 129.3, 129.2,
129.1, 128.7 (2 C), 128.4, 128.3, 128.2, 127.4, 80.4, 73.4, 72.6, 67.4,
64.1, 40.3, 21.3.
(R)-3-(Benzyloxymethyl)-5-phenyl-2-[(S)-1-phenylethyl]-2,3-di-
hydroisoxazole (2)
In a 25 mL one-arm round-bottomed flask, N-[(R)-1-(benzyloxy)-4-
phenylbut-3-yn-2-yl]-N-[(S)-1-phenylethyl]hydroxylamine (3a) (175
mg, 471 μmol), (PPh3)AuCl (11.0 mg, 22.2 μmol, 5 mol%) and AgOTf
(5.7 mg, 22.2 μmol, 5 mol%) were dissolved in anhydrous toluene (9
mL). The resulting suspension was stirred at r.t. for 5 min. Upon com-
pletion of the reaction, the suspension was filtered through a plug of
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B. Chandrasekhar et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO2: 374.2115; found:
374.2119.
13C NMR (100 MHz, CDCl3): δ = 173.5, 144.8, 137.9, 128.7, 128.6,
128.2, 128.0, 127.5, 125.9, 73.6, 72.1, 72.0, 47.4, 42.1, 37.0, 32.1, 29.9,
29.8, 29.7, 29.6, 29.5, 29.4, 25.8, 22.9, 14.3.
Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.55;
H, 7.24; N, 3.88.
HRMS (ESI): m/z [M + H]+ calcd for C29H44NO3: 454.3316; found:
454.3321.
(1S,3R)-4-(Benzyloxy)-1-phenyl-3-{[(S)-1-phenylethyl]amino}bu-
tan-1-ol (8)
(1R,3S)-N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecan-
amide [(–)-HPA-12] (1)
To (3R,5S)-3-[(benzyloxy)methyl]-5-phenyl-2-[(S)-1-phenylethyl]isox-
azolidine (7a) (100 mg, 268 μmol) in AcOH (2 mL) was added activat-
ed Zn dust (168 mg, 2.55 mmol). The reaction mixture was stirred at
r.t. for 30 min. Additional Zn dust (168 mg, 2.57 mmol) was added and
the mixture stirred at r.t. for 16 h. The reaction was quenched with
saturated aqueous NaHCO3 (50 mL), and extracted with CH2Cl2 (2 × 20
mL). The combined organic extracts were washed with saturated
aqueous NaHCO3 (20 mL), dried over anhydrous MgSO4, filtered, and
concentrated by rotary evaporation. Purification by column chroma-
tography (hexanes/EtOAc, 2:1) afforded 8 (75.0 mg, 75%) as a colorless
oil.
Small pieces of Na metal (20.3 mg, 882 μmol) were added to a stirred
solution of naphthalene (113 mg, 882 μmol) in anhydrous THF (20
mL) and the reaction mixture was stirred at 40 °C for 1 h until the Na
metal had completely dissolved. After the resulting dark green solu-
tion of Na-naphthalenide had been cooled to 0 °C, compound 9 (40
mg, 88.2 μmol) in anhydrous THF (1 mL) was added and the mixture
stirred at 0 °C for 5 min. The reaction mixture was quenched with
MeOH (1 mL) and concentrated by rotary evaporation. The crude resi-
due was partitioned between CH2Cl2 (20 mL) and H2O (20 mL). The
organic layer was separated, dried over anhydrous MgSO4, filtered
and concentrated by rotary evaporation. Purification by column chro-
matography (EtOAc/iPrOH, 97:3) afforded 1 (23.0 mg, 72%) as white
solid.
Rf = 0.5 (hexanes/EtOAc, 1:1); [α]D26.4 –17.5 (c 1.0, CHCl3).
IR (film): 2923, 2360, 1452, 754, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.24 (m, 15 H), 5.00 (dd, J = 9.2,
2.8 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.38 (d, J =12.0 Hz, 1 H), 3.96 (q,
J = 6.8 Hz, 1 H), 3.43 (dd, J = 9.2, 4.4 Hz, 1 H), 3.28 (dd, J = 9.2, 2.8 Hz, 1
H), 3.25 (m, 1 H), 1.88 (dd, J = 14.4, 10.4 Hz, 1 H), 1.81 (dt, J = 14.4, 3.2
Hz, 1 H), 1.48 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, acetone-d6): δ = 147.5, 147.4, 139.7, 129.4, 129.1,
128.9, 128.4, 128.3, 127.9, 127.5, 127.4, 126.5, 74.8, 73.6, 72.7, 56.5,
56.3, 43.2, 23.7.
Mp 91–92 (Lit.6e 90–91 °C, Lit.8 75.5–77.0 °C, Lit.9 81–82 °C, Lit.10 80–
26.4
81 °C, Lit.18 76–78 °C); Rf = 0.3 (EtOAc); [α]D
–29.4 (c 1.0, CHCl3)
[Lit.6e [α]D15 –36.3 (c 0.505, CHCl3), Lit.8 [α]D25 –35.1 (c 0.8, CHCl3), Lit.9
[α]D25 –34.4 (c 0.36, CHCl3), Lit.10 [α]D25 –30.5 (c 0.36, CHCl3)].
IR (film): 3292, 2919, 2360, 1641, 1550 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.24 (m, 5 H), 6.43 (br d, J = 6.8
Hz, 1 H), 4.79 (dd, J = 8.8, 2.8 Hz, 1 H), 4.04 (m, 1 H), 3.93 (br s, 1 H),
3.68 (d, J = 11.2 Hz, 1 H), 3.64 (d, J = 11.2 Hz, 1 H), 3.39 (br s, 1 H), 2.16
(t, J = 7.6 Hz, 2 H), 2.04–2.01 (m, 1 H), 2.00–1.88 (m, 1 H), 1.59 (m, 2
H), 1.32–1.26 (m, 16 H), 0.88 (t, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C25H30NO2: 376.2271; found:
376.2276.
13C NMR (100 MHz, CDCl3): δ = 174.5, 144.5, 128.8, 127.9, 125.8, 72.1,
65.9, 50.7, 40.9, 37.0, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 25.9, 22.9,
14.3.
HRMS (ESI): m/z [M + H]+ calcd for C22H38NO3: 364.2846; found:
364.2849.
N-[(2R,4S)-1-(Benzyloxy)-4-hydroxy-4-phenylbutan-2-yl]dodec-
anamide (9)
5% Pd/C (120 mg) was placed in a 25 mL one-arm round-bottomed
flask. A solution of (1S,3R)-4-(benzyloxy)-1-phenyl-3-{[(S)-1-phenyl-
ethyl]amino}butan-1-ol (8) (120 mg, 320 μmol) in MeOH (4 mL) was
added and the resulting mixture stirred under an atmosphere of H2 at
r.t. for 12 h. Upon completion of the reaction, the black suspension
was filtered through a plug of Celite, and washed with MeOH (20 mL).
The filtrate was concentrated by rotary evaporation and the crude
residue (60.0 mg, 221 μmol) was used in the next reaction without
Acknowledgment
This research was supported by the Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by
the Ministry of Science, ICT and Future Planning (NRF-
2015R1A2A2A01004511 and NRF-2014R1A2A1A11050112).
i
further purification. Pr2NEt (114 μL, 655 μmol) was added to a solu-
tion of the crude residue (60.0 mg, 221 μmol) in CH2Cl2 (2 mL) and
stirred at 0 °C for 20 min. Dodecanoyl chloride (58.0 μL, 244 μmol) in
CH2Cl2 (2 mL) was added and the mixture stirred at 0 °C for 20 min.
After stirring at r.t. for an additional 30 min, the mixture was diluted
with CH2Cl2 (20 mL), and washed with H2O (20 mL). The organic layer
was separated, dried over anhydrous MgSO4, filtered, and concentrat-
ed by rotary evaporation. Purification by column chromatography
(hexanes/EtOAc, 2:1) afforded 9 (75.0 mg, 52%) as a colorless oil.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588369.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Rf = 0.5 (hexanes/EtOAc, 1:1); [α]D26.4 –22.6 (c 1.0, CHCl3).
References
IR (film): 3295, 1643, 1541, 734, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.22 (m, 10 H), 5.95 (d, J = 8.4 Hz,
1 H), 4.75 (t, J = 6.4 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0
Hz, 1 H), 4.24 (m, 1 H), 3.57 (dd, J = 9.6, 3.6 Hz, 1 H), 3.51 (dd, J = 9.6,
3.6 Hz, 1 H), 2.10–2.02 (m, 4 H), 1.56 (m, 2 H), 1.30–1.26 (m, 16 H),
0.88 (t, J = 6.8 Hz, 3 H).
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