Synthesis of potent CERT inhibitor HPA-12 featuring a tandem corey-link and intramolecular nucleophilic acyl substitution reaction

Article abstract of DOI:10.1055/s-0033-1338495

A novel preparation of the potent CERT protein inhibitor (1R,3S)-HPA-12 is described. The synthesis is accomplished in five steps from (S)-Wynberg lactone and features a diastereoselective tandem Corey-Link and intramolecular nucleophilic acyl substitution reaction in a key step. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338495

PAPER
▌1899
paper
Synthesis of Potent CERT Inhibitor HPA-12 Featuring a Tandem Corey–Link
and Intramolecular Nucleophilic Acyl Substitution Reaction
Synthesis of Potent CERT Inhibitor HPA-12
Jason R. Snider, Jordan T. Entrekin, Timothy S. Snowden,* Debra Dolliver1
The University of Alabama, Department of Chemistry, Box 870336, Tuscaloosa, AL 35487-0336, USA
Fax +1(205)3489104; E-mail: snowden@bama.ua.edu
Received: 22.04.2013; Accepted after revision: 28.05.2013
Dedicated to Prof. Scott E. Denmark on the occasion of his 60th birthday
O
O
Abstract: A novel preparation of the potent CERT protein inhibitor
(1R,3S)-HPA-12 is described. The synthesis is accomplished in five
steps from (S)-Wynberg lactone and features a diastereoselective
tandem Corey–Link and intramolecular nucleophilic acyl substitu-
tion reaction in a key step.
R represents alkyl chain
of various fatty acids
OH HN
R
OH HN
10
OH
12
OH
ceramide (1)
(1R,3S)-HPA-12 (2)
Key words: HPA-12, CERT protein, gem-dichloroepoxide,
Corey–Link reaction, Wynberg lactone
Figure 1
We intended to employ our recently published tandem
Corey–Link13 and intramolecular nucleophilic acyl sub-
stitution reaction (i.e., conversion of 6 into 9 via gem-di-
chloroepoxide 7 and substituted acid chloride 8) as a
featured step in the synthesis of 2 (Scheme 1).14 One-pot
reduction of the resulting lactone and the attached azide
present in 9 using lithium aluminum hydride was expected
to afford aminodiol 10. N-Acylation of the amine in 10
would then furnish the target. This approach was designed
to provide a concise path to (1R,3S)-HPA-12 (2) without
the need for any protection/deprotection steps.
Friedel–Crafts acylation of (S)-Wynberg lactone 4,15 pre-
pared in one step from chloral, acetyl chloride, N,N-diiso-
propylethylamine, and catalytic quinine, provided
crystalline (S)-β-hydroxy ketone 5 in 89% yield (Scheme
1). It was important to conduct the Friedel–Crafts reaction
at a 0.05 M substrate concentration to limit formation of
the O-acylation byproduct 3 (Figure 2).16 The use of gran-
ular aluminum trichloride, rather than finely powdered
Lewis acid also resulted in significantly lower yields of 5.
Sonication of the powdered aluminum trichloride in ben-
zene prior to addition of 4 created a fine suspension of the
Lewis acid and furnished a modest increase in the yield of
5. However, conducting the actual acylation reaction with
ultrasound offered no noticeable increase in reaction rate
or product yield.
CERT is an ATP-dependent trafficking protein that trans-
ports ceramides 1 (Figure 1) from the endoplasmic reticu-
lum to the Golgi apparatus.2 There, ceramides are
converted enzymatically into sphingomyelin, which plays
vital roles in cell signaling, apoptosis, and the formation
of lipid rafts in biomembranes.3 The amidodiol N-
[(1R,3S)-3-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]do-
decamide (HPA-12, 2) is a potent CERT inhibitor
(IC50 = 50 nm) that was discovered and extensively stud-
ied by Kobayashi and Hanada.4 Compound 2 has become
an established tool for investigating sphingolipid meta-
bolic pathways in cultured cells and animals. For exam-
ple, it has recently been used to inhibit hepatitis C
secretion from infected cells,5 to study the function of
CERT in UVB-irradiated keratinocytes,6 and to help de-
termine the mechanism of action of limonoid compounds
in the inhibition of sphingomyelin biosynthesis.7 In addi-
tion, modulation of sphingolipid metabolic pathways, in-
cluding trafficking protein inhibition, is an emerging
strategy for certain cancer and antiviral therapies.8
Several syntheses of HPA-12 have been published, in-
cluding preparations by Kobayashi, involving transition-
metal-mediated asymmetric Mannich-type reactions,4b,9
Raghavan, featuring elaboration of a β-sulfonamido sulf-
oxide,10 and Berkeš, highlighting a crystallization-
induced asymmetric transformation approach.11 Notably,
the authors of this last report proposed a revised absolute
configuration of the most potent HPA-12 stereoisomer
from (R,R)-anti, as originally reported by Kobayashi,4a,9a
to (R,S)-syn based upon a combination of synthesis, X-ray
analysis, and comparative 1H NMR data. A synthesis of a
less potent isomer, (S,R)-HPA-12, was also reported in
2012.12
O
OH
O
O
CCl3
CCl3
3
Figure 2
SYNTHESIS 2013, 45, 1899–1903
Advanced online publication: 06.06.2013
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0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338495; Art ID: SS-2013-C0306-OP
© Georg Thieme Verlag Stuttgart · New York

1900
J. R. Snider et al.
PAPER
NaN3 (2 equiv)
NaOH (4 equiv)
DME–H2O, r.t.
ONa
O
Me4N(AcO)3BH
O
O
OH
OH OH
MeCN–AcOH, –45 °C
O
PhH, AlCl3
(89%)
Ph
Cl
(80%)
(77%)
Ph
CCl3
Ph
CCl3
Cl
CCl3
(dr = 96:4)
–
(dr = 90:10)
N3
4
5
6
7
OH NH2
LiAlH4
C11H23CO2Su (ref. 11)
O
O
OH
Ph
Cl
NaO
N3
10
O
Ph
N3
O
H
N
C
11H23CO2Su
Ph
Ph3P, THF–H2O
NaBH4, EtOH
(93%)
O
2
10
8
9
(75%)
O
Ph
11
Scheme 1
Directed 1,3-reduction of 5 using tetramethylammonium separation of the diastereomers by chromatography fur-
triacetoxyborohydride in acetonitrile–acetic acid17 pro- nished pure trans-disubstituted lactone 9 in 70% yield.
ceeded in 80% yield with a diastereomeric ratio (anti/syn)
Despite the satisfactory outcome of the tandem Corey–
Link and intramolecular acyl substitution reaction con-
of 96:418 when the reaction temperature was held below
–40 °C. Higher temperatures led to comparable yields of
ducted under our previously reported conditions (Table 1,
combined anti- and syn-1,3-diols; however, under such
entry 1),14 we screened other solvent systems and bases to
conditions, the anti/syn product ratios were severely erod-
ensure that the formation of 9 was fully optimized. Changes
ed.
in the 1,2-dimethoxyethane–water solvent ratio (entry 2)
Diol 619 was then treated with four equivalents of sodium did not improve the reaction, and employment of less so-
hydroxide and two equivalents of sodium azide in 1,2-di- dium hydroxide severely limited conversion of 6 (entry
methoxyethane–water (1:4) to promote formation of a 2- 3). Substitution of sodium hydroxide with tetrabutylam-
azidocarboxylic acid chloride intermediate 8 by a Corey– monium hydroxide (entry 4)21 or DBU and 18-crown-6
Link reaction.13 This intermediate underwent intramolec- (entry 5),22 conditions that have been employed success-
ular O-acylation to generate substituted butyrolactone 9.20 fully in other Jocic–Reeve or Corey–Link reactions,23 also
As established previously, it was important to conduct the offered no benefit.
reaction at a 0.05 M substrate concentration to mitigate
With trans-azidolactone 9 in hand, we attempted reduc-
tion of both the azide and lactone carbonyl in one pot us-
ing lithium aluminum hydride at temperatures ranging
epimerization of 9.14 A portion of the lactone was hydro-
lyzed under the basic reaction conditions; however, mix-
ing the crude reaction mixture in dilute aqueous
from 0–65 °C and with concentrations of the reductant
hydrochloric acid for 2–3 hours prior to isolation provided
ranging from 6–15 equivalents. In all cases, a complex
a 90:10 mixture of trans/cis lactone epimers.18 A simple
Table 1 Optimization Studies for the Conversion of 6 into 9
O
NaN3 (2 equiv)
OH OH
base, solvent, r.t.
N3
O
Ph
Ph
CCl3
6
9
Entry
Base (equiv)
Solvent
[6] (M)
Yielda (%)
1
2
3
4
5
NaOH (4)
NaOH (4)
NaOH (2.5)
TBAH (6.7)
DME–H2O (1:4)
DME–H2O (2:3)
DME–H2O (1:4)
CH2Cl2–TBAH (2:1)
MeOH
0.05
0.05
0.05
0.05
0.05
70
45
b
–
c
–
DBU (5), 18-crown-6 (cat.)
40
a Isolated yield of pure trans-butyrolactone 9.
b Reaction showed <5% conversion after 24 h.
c A complex mixture of products was formed.
Synthesis 2013, 45, 1899–1903
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Potent CERT Inhibitor HPA-12
1901
(MgSO4), and concentrated by rotary evaporation yielding a light
tan solid. The solid was placed under vacuum to remove excess vol-
atile components then purified by bulb-to-bulb distillation (82
°C/0.27 mbar) to give 4 as a white solid (mixture of enantiomers).
The solid was recrystallized (methylcyclohexane)15 yielding pure
(S)-4 (23.4 g, 49%) as white, fluffy crystals; mp 52–53 °C.
[α]D22 +15.6 (c 1.0, CH2Cl2) (corresponds to >98% ee15).
IR (KBr): 2972, 1644, 1101, 788 cm–1.
1H NMR (360 Hz, CDCl3): δ = 5.01 (dd, J = 3.8, 5.7 Hz, 1 H), 3.74
(dd, J = 5.7, 17 Hz, 1 H), 3.60 (dd, J = 3.8, 17 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 163.9, 96.6, 76.1, 42.5.
mixture of products was formed, and the desired aminodi-
ol 10 could not be obtained in satisfactory yield.
As a result, we slightly altered our approach to the prepa-
ration of 2 by attempting a tandem Staudinger reduction
and N-acylation reaction adapted from the method report-
ed by Bittmann and co-workers.24 Treatment of 9 with tri-
phenylphosphine and lauric acid N-hydroxysuccinimide
ester in tetrahydrofuran–water (9:1) provided amidolac-
tone 11 in 75% yield. The expected trans stereochemistry
was supported by NOE difference and NOESY experi-
ments. Subsequent reduction of 11 with sodium borohy-
dride in ethanol furnished the target (1R,3S)-HPA-12 (2)
in 93% yield and >98% ee19 after column chromatogra-
phy. All characterization data of 2 are consistent with
those reported for the most potent HPA-12 stereoisomer,4a
and the synthetic route and characterization data substan-
tiate the revised absolute configuration proposed by
Berkeš.11,25
MS (EI): m/z = 71.0 [M – CCl3].
HRMS (EI): m/z [M – CCl3] calcd for C3H3O2: 71.0133; found:
71.0130.
(S)-4,4,4-Trichloro-3-hydroxy-1-phenylbutan-1-one (5)
Powdered AlCl3 (6.3 g, 47 mmol) in anhyd benzene (250 mL) was
placed in a 1-L round-bottom flask. The system was sonicated for
1.5 h to create a fine suspension of the Lewis acid. The mixture was
then cooled to 0 °C, and a soln of (S)-Wynberg lactone 4 (2.00 g,
12.5 mmol) in anhyd benzene (125 mL) was added dropwise. The
reaction was warmed to r.t. and stirred until judged complete by
TLC analysis (~12 h). The reaction was quenched by slow addition
of aq sat. NH4Cl (250 mL) and the aqueous layer was extracted with
benzene (4 × 60 mL). The combined organic layers were washed
with brine (30 mL), dried (MgSO4), and concentrated. The residue
was purified by column chromatography (hexanes–EtOAc, 9:1) to
give 5 (2.99 g, 89%) as white crystals; mp 62–63 °C.
In summary, a synthesis of potent CERT protein inhibitor
(1R,3S)-HPA-12 (2) was accomplished in five steps and
33% overall yield from (S)-Wynberg lactone 4. The out-
lined approach, which features a tandem Corey–Link and
intramolecular nucleophilic acyl substitution step, rivals
the most efficient preparations of the CERT trafficking
protein inhibitor yet reported.
[α]D22 –35.6 (c 1.0, CH2Cl2).
1H and 13C NMR spectra were recorded on Bruker instruments at
360, 500, or 600 MHz and 90 or 125 MHz, respectively. 19F NMR
spectra were recorded at 338 MHz. Chemical shifts were referenced
to acetone-d6 (δ = 2.05 and 30.83) or CDCl3 (δ = 7.26 and 77.0).
Mass spectra were recorded on an AutoSpec-Ultima_NT mass
spectrometer using electron ionization (EI) at 70 eV and an EBE
sector mass analyzer. Melting points were determined with a Mel-
Temp 1001D capillary melting point apparatus and are uncorrected.
Ultrasonication was conducted with a Bransonic 2510R-DTH ultra-
sonic cleaner. IR spectra were recorded on a Jasco FT/IR-4100 in-
strument. Optical rotations were measured with a Rudolph
AUTOPOL IV/6W polarimeter. TLC visualization was achieved by
UV light (254 nm) or KMnO4 staining. MeCN and benzene were
dried over 4-Å molecular sieves prior to use. THF and Et2O were
distilled from Na/benzophenone ketyl radical. Chloral was pur-
chased from Riedel-de Haën and distilled neat onto 4-Å molecular
sieves. AcCl was distilled from PhNMe2 (one-tenth volume). An-
hyd AcOH was prepared by stirring AcOH–Ac2O (1:1) for 1 h, and
then AcOH was distilled onto 4-Å molecular sieves. All other re-
agents and solvents were used as received from commercial sourc-
es.
IR (KBr): 3448, 3061, 2924, 1683, 1449 cm–1.
1H NMR (360 Hz, CDCl3): δ = 8.0 (d, J = 7.8 Hz, 2 H), 7.62 (t,
J = 7.3 Hz, 1 H), 7.50 (t, J = 7.9 Hz, 2 H), 4.88 (ddd, J = 1.7, 4.5,
9.1 Hz, 1 H), 3.79 (d, J = 4.3 Hz, 1 H), 3.65 (dd, J = 0.7, 17.3 Hz, 1
H), 3.50 (dd, J = 9.1, 17.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 197.1, 136.4, 133.9, 128.8, 128.3,
102.6, 79.1, 40.8.
MS (EI): m/z = 249.0 [M – OH].
HRMS (EI): m/z [M – OH] calcd for C10H8OCl3: 248.9641; found:
248.9638.
(1S,3S)-4,4,4-Trichloro-1-phenylbutane-1,3-diol (6)
A soln of tetramethylammonium triacetoxyborohydride (1.57 g,
5.98 mmol) in anhyd MeCN (3.4 mL) and anhyd AcOH (3.4 mL)
under argon was stirred at r.t. for 1 h. The soln was then cooled to
–50 °C. Hydroxy ketone 5 (200 mg, 0.75 mmol) in anhyd MeCN
(1.1 mL) was added to the soln by syringe. The mixture stirred for
30 h at a bath temperature between –45 °C and –50 °C. The reaction
was quenched with 0.5 M aq sodium potassium tartrate (8 mL) and
warmed to r.t. The mixture was diluted with CH2Cl2 (6 mL) and the
layers were separated. The organic phase was washed with aq sat.
NaHCO3 (10 mL). The aqueous phase was back extracted with
CH2Cl2 (4 × 5 mL), and the combined organic layers were washed
with aq sat. NaHCO3 until the aqueous layer reached pH 7. The or-
ganic layers were then dried (MgSO4) and concentrated. The crude
(S)-4-(Trichloromethyl)oxetan-2-one (4)
A dry 1-L, 3-neck round-bottom flask was fitted with two addition
funnels and an argon supply. Quinine (406 mg, 1.25 mmol) and an-
hyd Et2O (165 mL) were added to the round-bottom flask, then an-
hyd DIPEA (47.5 mL, 0.273 mol) was transferred to the flask by
cannula. Chloral (24.5 mL, 0.251 mol) in anhyd Et2O (115 mL) was
added to one addition funnel. AcCl (17.8 mL, 0.250 mol) in anhyd
Et2O (115 mL ) was added to the other addition funnel. While cool-
ing to –15 °C, the chloral and AcCl were added dropwise to the mix-
ture under argon at approximately equal rates over 1.5 h. After the
addition was complete, the mixture was stirred at –15 °C for 2 h. Aq
1 M HCl (150 mL) was added and the mixture was warmed to r.t.
and then filtered through Celite. The layers were separated, and the
aqueous layer was extracted with Et2O (5 × 30 mL). The combined
organic layers were washed with 1 M HCl (3 × 25 mL), dried
1
product was evaluated by H NMR spectroscopy to establish dr
(anti/syn) = 96:4 and then purified by column chromatography
(hexanes–EtOAc, 8:2) to obtain 6 (155 mg, 77%) as white crystals;
mp 104–105 °C.
[α]D22 –65.7 (c 2.0, CH2Cl2).
IR (KBr): 3419, 2906, 1641, 1427 cm–1.
1H NMR (360 Hz, CDCl3): δ = 7.43–7.29 (m, 5 H), 5.12 (dt, J = 3.2,
9.5 Hz, 1 H), 4.44 (ddd, J = 1.9, 4.4, 10.0 Hz, 1 H), 3.25 (dd, J = 1.2,
4.7 Hz, 1 H), 2.45 (ddt, J = 1.4, 9.5, 14.3 Hz, 1 H), 2.27 (d, J = 3.9
Hz, 1 H), 2.07 (ddd, J = 2.6, 9.7, 14.2 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1899–1903

1902
J. R. Snider et al.
PAPER
13C NMR (125 MHz, CDCl3): δ = 143.7, 128.7, 127.9, 125.6, 103.8,
79.8, 70.8, 40.1.
MS (EI): m/z = 268.0 [M]+.
mL), and the resultant organic layers were combined, dried
(Na2SO4), and concentrated. The product was purified by column
chromatography (EtOAc–hexanes, 4:1) to obtain 2 (37.6 mg, 93%)
as a white crystalline solid; mp 90–91 °C.
[α]D22 –34.8 (c 1.0, CHCl3).
IR (KBr): 3417, 3294, 1643 cm–1.
1H NMR (360 Hz, CDCl3): δ = 7.36–7.24 (m, 5 H), 6.43 (d, J = 6.6
Hz, 1 H), 4.80 (dd, J = 3.3, 8.9 Hz, 1 H), 4.08–4.01 (m, 1 H), 3.93
(s, 1 H), 3.70–3.62 (m, 2 H), 3.31 (s, 1 H), 2.15 (dd, J = 7.3, 8.0 Hz,
2 H), 2.04 (ddd, J = 3.5, 5.5, 14.6 Hz, 1 H), 1.92 (ddd, J = 7.0, 9.0,
15.8 Hz, 1 H), 1.64–1.55 (m, 2 H), 1.33–1.23 (m, 16 H), 0.88 (dd,
J = 6.6, 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 174.3, 144.3, 128.6, 127.7, 125.5,
71.9, 65.6, 50.5, 40.7, 36.8, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 29.3,
25.7, 22.7, 14.1.
HRMS (EI): m/z [M] calcd for C10H11O2Cl3: 267.9825; found:
267.9827.
(3R,5S)-3-Azido-5-phenyldihydrofuran-2(3H)-one (9)
Trichloromethyl carbinol 6 (100 mg, 0.37 mmol) in DME–H2O (1.5
mL:6.0 mL) was placed in a sample vial with a magnetic stir bar.
NaN3 (48.2 mg, 0.74 mmol) (CAUTION: may explode if ground or
contacted by metal surfaces) and freshly powdered NaOH (59.4 mg,
1.49 mmol) were added at once. The reaction was stirred rapidly at
r.t. until judged complete by TLC analysis (12–24 h). The mixture
was cooled to 0 °C, and the pH was adjusted to pH 2 with 0.5 M
HCl. This mixture was stirred for 3 h to promote lactonization of
any hydrolyzed product. The aqueous phase was extracted with
EtOAc (5 × 15 mL), dried (MgSO4), and concentrated. The crude
MS (EI): m/z = 363.3 [M]+.
1
product was evaluated by H NMR spectroscopy to establish dr
HRMS (EI): m/z [M] calcd for C22H37NO3: 363.2773; found:
363.2766.
(trans/cis) = 90:10 and then purified by column chromatography
(hexanes–EtOAc, 2:1) to obtain 9 (74.0 mg, 70%) as a clear, color-
less oil.
[α]D22 +175.4 (c 1.0, CH2Cl2).
IR (KBr): 2923, 2852, 1780, 1458 cm–1.
Acknowledgment
We are grateful to the National Science Foundation CAREER pro-
gram (CHE-0847686) for financial support. We also thank Saige
Miller for her contributions.
1H NMR (360 Hz, CDCl3): δ = 7.45–7.34 (m, 3 H), 7.30–7.28 (m, 2
H), 5.65 (t, J = 6.6 Hz, 1 H), 4.36 (dd, J = 6.1, 7.9 Hz, 1 H), 2.60–
2.44 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 172.7, 138.0, 129.0, 128.8, 125.0,
79.2, 57.1, 36.8.
MS (EI): m/z = 203.1 [M]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (EI): m/z [M] calcd for C10H9N3O2: 203.0695; found:
203.0691.
References
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Southeastern Louisiana University, SLU 10878 Hammond,
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N-[(3R,5S)-2-Oxo-5-phenyltetrahydrofuran-3-yl]dodecan-
amide (11)
To a soln of 9 (50 mg, 0.25 mmol) in THF–H2O (6.6 mL:0.73 mL)
were added lauric acid N-hydroxysuccinimide ester (183 mg, 0.62
mmol) and Ph3P (78 mg, 0.30 mmol). The mixture was stirred at r.t.
under argon for 48 h. The solvents were then removed by evapora-
tion [t-BuOH (3–4 mL) was added to azeotropically remove resid-
ual H2O], and the residue was dissolved in EtOAc (25 mL) and
washed with ice cold 1% K2CO3 (4 × 5 mL). The organic phase was
dried (Na2SO4) and concentrated. The crude material was purified
by column chromatography (hexanes–EtOAc, 8:2) to afford 11
(66.2 mg, 75%) as a white solid; mp 96–97 °C.
[α]D22 +38.2 (c 1.0, CH2Cl2).
IR (KBr): 3303, 2918, 1648, 1164 cm–1.
1H NMR (360 Hz, CDCl3): δ = 7.41–7.27 (m, 5 H), 6.52 (d, J = 6.7
Hz, 1 H), 5.73 (dd, J = 2.5, 8.5 Hz, 1 H), 4.61–4.54 (m, 1 H), 2.79
(ddd, J = 2.8, 9.3, 12.7 Hz, 1 H), 2.67–2.59 (m, 1 H), 2.23 (t, J = 7.8
Hz, 2 H), 1.66–1.58 (m, 2 H), 1.35–1.20 (m, 16 H), 0.88 (t, J = 6.7
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 175.4, 173.7, 138.9, 128.9, 128.5,
125.0, 78.6, 48.3, 36.9, 36.1, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 29.2,
25.4, 22.7, 14.1.
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MS (EI): m/z = 359.2 [M]+.
HRMS (EI): m/z [M] calcd for C22H33NO3: 359.2460; found:
359.2468.
N-[(1R,3S)-3-Hydroxy-1-(hydroxymethyl)-3-phenylpropyl]do-
decamide (2)
To a suspension of 11 (40.0 mg, 0.11 mmol) in abs EtOH (1.5 mL)
was added NaBH4 (21 mg, 0.55 mmol), and the mixture was stirred
at r.t. for 20 h. The reaction was then quenched by the addition of
5% K2CO3 soln (2.4 mL), and the EtOH was removed by rotary
evaporation. The aqueous phase was extracted with EtOAc (5 × 3
(9) (a) Ueno, M.; Kitagawa, H.; Ishitani, H.; Yasuda, S.;
Hanada, K.; Kobayashi, S. Tetrahedron Lett. 2001, 42, 7863.
Synthesis 2013, 45, 1899–1903
© Georg Thieme Verlag Stuttgart · New York

PAPER
(b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett.
Synthesis of Potent CERT Inhibitor HPA-12
1903
(18) The dr was determined from the 1H NMR spectrum of the
crude reaction mixture.
(19) At the request of a reviewer, the ee (%) was determined by
preparing the Mosher diester derivative of this compound.
The analysis showed the material to have >98% ee. See
Supporting Information for details.
(20) For related lactonization reactions, see ref. 16 and:
Tennyson, R. L.; Cortez, G. S.; Galicia, H. J.; Kreiman, C.
R.; Thompson, C. M.; Romo, D. Org. Lett. 2002, 4, 533.
(21) Oliver, J. E.; Schmidt, W. F. Tetrahedron: Asymmetry 1998,
9, 1723.
(22) Dominguez, C.; Ezquerra, J.; Baker, S. R.; Borrelly, S.;
Prieto, L.; Espada, C. M.; Pedregal, C. Tetrahedron Lett.
1998, 39, 9305.
2002, 4, 143. (c) Kobayashi, S.; Matsubara, R.; Nakamura,
Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
2507.
(10) Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059.
(11) Ďuriš, A.; Wiesenganger, T.; Moravčíková, D.; Baran, P.;
Kožíšek, J.; Daïch, A.; Berkeš, D. Org. Lett. 2011, 13, 1642.
(12) Karyakarte, S. D.; Smith, T. P.; Chemler, S. R. J. Org. Chem.
2012, 77, 7755.
(13) (a) Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett.
1992, 33, 3431. (b) Corey, E. J.; Link, J. O. Tetrahedron
Lett. 1992, 33, 3435. (c) Corey, E. J.; Link, J. O. J. Am.
Chem. Soc. 1992, 114, 1906.
(14) Ganta, A.; Shamshina, J. L.; Cafiero, L. R.; Snowden, T. S.
Tetrahedron 2012, 68, 5396.
(15) (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982,
104, 166. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem.
1985, 50, 1977.
(23) For a recent review of Corey–Link, Jocic–Reeve, and related
reactions, see: Snowden, T. S. ARKIVOC 2012, (ii), 24.
(24) He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65,
7627.
(16) This is a modification of the procedure originally reported
by: Fujisawa, T.; Ito, T.; Fujimoto, K.; Shimizu, M.;
Wynberg, H.; Staring, E. G. J. Tetrahedron Lett. 1997, 38,
1593.
(25) Kobayashi and co-workers recently published a revised
absolute configuration of HPA-12 that is consistent with that
reported in reference 11 and herein. See: Ueno, M.; Huang,
Y.-Y.; Yamano, A.; Kobayashi, S. Org. Lett. 2013, 15, 2869.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1899–1903