Chiral resolution and absolute configuration of the enantiomers of the psychoactive designer drug 3,4-methylenedioxypyrovalerone

Article abstract of DOI:10.1002/chir.22423

Illicit rac-MDPV (3,4-methylenedioxypyrovalerone), manufactured in clandestine labs, has become widely abused for its cocaine-like stimulant properties. It has recently been found as one of the toxic materials in the so-called bath salts, producing, among other effects, psychosis and tachycardia in humans when introduced by any of the several routes of administration (e.g., intravenous, oral, etc.). The considerable toxicity of this designer drug probably resides in one of the enantiomers of the racemate. In order to obtain a sufficient amount of the enantiomers of rac-MDPV to determine their activity, we improved the known synthesis of rac-MDPV and found chemical resolving agents, (+)- and (-)-2'-bromotetranilic acid, that gave the MDPV enantiomers in >96% enantiomeric excess as determined by ¹H nuclear magnetic resonance and chiral high-performance liquid chromatography. The absolute stereochemistry of these enantiomers was determined by single-crystal X-ray diffraction studies. Chirality 27:287-293, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Full text of DOI:10.1002/chir.22423

CHIRALITY 27:287–293 (2015)
Chiral Resolution and Absolute Configuration of the Enantiomers of
the Psychoactive “Designer Drug” 3,4-Methylenedioxypyrovalerone
1
MASAKI SUZUKI,1,† JEFFREY R. DESCHAMPS,2 ARTHUR E. JACOBSON,1 AND KENNER C. RICE
*
1Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of
Health, Department of Health and Human Services, Bethesda, Maryland
2Center for Biomolecular Science and Engineering, Naval Research Laboratory, Washington, D.C.
ABSTRACT
Illicit rac-MDPV (3,4-methylenedioxypyrovalerone), manufactured in clandes-
tine labs, has become widely abused for its cocaine-like stimulant properties. It has recently
been found as one of the toxic materials in the so-called “bath salts,” producing, among other
effects, psychosis and tachycardia in humans when introduced by any of the several routes of
administration (e.g., intravenous, oral, etc.). The considerable toxicity of this “designer drug”
probably resides in one of the enantiomers of the racemate. In order to obtain a sufficient
amount of the enantiomers of rac-MDPV to determine their activity, we improved the known
synthesis of rac-MDPV and found chemical resolving agents, (+)- and (–)-2’-bromotetranilic
1
acid, that gave the MDPV enantiomers in >96% enantiomeric excess as determined by H nu-
clear magnetic resonance and chiral high-performance liquid chromatography. The absolute
stereochemistry of these enantiomers was determined by single-crystal X-ray diffraction studies.
Chirality 27:287-293, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
KEY WORDS: 3,4-methylenedioxypyrovalerone (MDPV); designer drug; bath salts; euphoric
stimulant; synthesis; non-chromatographic chiral resolution
1-(Benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one
(3,4-methylenedioxypyrovalerone, MDPV, “Bath Salts”) was
originally synthesized as a stimulant at Boehringer Ingelheim
in 1969,1 and has been widely abused because of its potent eu-
phoric effect.2 It has recently been classified as a Schedule 1
controlled substance, like heroin and LSD. The compound
remained obscure until recently when its illicit production
and distribution caused a rise in hospitalizations. Human
abuse of MDPV and its dependence-producing properties
was observed since it became available as a “designer drug”
for “recreational” use.3–5 It was found to have considerable
toxicity associated with its use as one of the components in
bath salts (agitation, psychosis, tachycardia).6 MDPV itself
was examined and found to have reinforcing effects and was
self–administered in rats.7 MDPV has no approved medical
use in the U.S. It is a synthetic derivative of the natural prod-
uct cathinone, which has itself been misused by individuals
presumably seeking its stimulant effects. It has been found
that on the molecular level MDPV is more potent than co-
caine as a catecholamine-transporter blocker: it was able to
block all three transporters, DAT, NET, and SERT.2 All of
the pharmacological data on MDPV have been obtained with
its racemic mixture, since the compound has not hitherto
been resolved. Chiral resolution of racemates has been
known, on occasion, to provide enantiomers with quite differ-
ent pharmacological effects, and the toxicity of a racemate is
sometimes confined to a specific enantiomer. Furthermore,
the less toxic enantiomer could eventually prove to be a use-
ful medication, and even a more toxic enantiomer has been
eventually found, in some cases, to be medically useful. For
these reasons, we sought a method for chiral resolution of
MDPV that would provide a sufficient amount of its enantio-
mers for pharmacological evaluation, and we determined
the stereochemical stability of this relatively simple molecule.
In order to find a method for the chiral resolution, we needed
to resynthesize the racemic compound. We improved the
synthesis of MDPV and we designed a simple and efficient
nonchromatographic chiral resolution that provides enantio-
mers in >96% enantiomeric excess (ee). We also determined
that the HCl salt of the enantiomers did not racemize on stand-
ing in water for at least 24h at room temperature, removing any
concern that this might occur during pharmacological testing.
EXPERIMENTAL
General
Melting points were determined on a Thomas-Hoover melting point
apparatus and are uncorrected. Thin-layer chromatography (TLC)
analyses were carried out on Analtech (Newark, DE) silica gel GHLF
0.25 mm plates using various concentrations of CHCl3/MeOH contain-
ing 10% NH4OH (10% of 28% NH4OH in MeOH solution) or of
EtOAc/n-hexane. Visualization was accomplished under UV light or
by staining in an iodine chamber. Proton and carbon nuclear mag-
netic resonance (1H and 13C nuclear magnetic resonance [NMR])
spectra were recorded in CDCl3 with CHCl3 (δ 7.26), CD3OD with
CH3OH (δ 3.31), and DMSO-d6 with DMSO (δ 2.50) as an internal
standard, on a Bruker (Billerica, MA) DMX500 wide-bore spectrome-
ter (proton frequency 500.13 MHz, running XWINNMR v3.1) and on a
Varian (Palo Alto, CA) 400 (proton frequency 400 MHz, running
VnmrJ v. 4.0), with the values given in ppm and J (Hz) assignments
of 1H resonance coupling. Mass spectra (HRMS) were recorded on
a VG 7070E spectrometer or a JEOL SX102a mass spectrometer.
Micro-Analysis (Wilmington, DE), performed elemental analyses,
and the results were within 0.4% of the theoretical values. The opti-
cal rotation data were obtained on a Perkin-Elmer (Boston, MA)
*Correspondence to: Kenner C. Rice, Drug Design and Synthesis Section,
Molecular Targets and Medications Discovery Branch, National Institute on
Drug Abuse, National Institutes of Health, Department of Health and Human
Services, 9800 Medical Center Dr., Rm. 228A, Bethesda, MD 20892-3373.
E-mail: kr21f@nih.gov
†On leave from: The Medicinal Chemistry Group, Qs’ Research Institute,
Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Received for publication 23 October 2014; Accepted 9 December 2014
DOI: 10.1002/chir.22423
Published online 26 February 2015 in Wiley Online Library
(wileyonlinelibrary.com).
Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

288
SUZUKI ET AL.
polarimeter model 341. The enantiomeric purity was assessed using
an Agilent (Palo Alto, CA) 1100 series high-performance liquid chro-
matography (HPLC).
Calculated for C16H22ClNO3: C, 61.63, H, 7.11, N, 4.49.
Found: C, 61.57; H, 7.11, N, 4.52. The hydrochloride salt
was converted to its free base by adding aqueous 20%
Na2CO3 to a suspension of the salt in Et2O at room tem-
perature. The aqueous layer was extracted with Et2O.
The combined organic layer was dried over MgSO4 or
Na2SO4. This was filtered, concentrated, and dried in
vacuo to give the free base as a yellow syrup. The base
from this salt was homogenous on silica gel TLC (Et2O:
hexane: concd NH4OH; 3 mL: 2 mL: 1 drop). 1H NMR
(CDCl3, 500 MHz): δ7.80 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H),
6.984 (d, J = 8.0 Hz, 1H), 6.04 (s, 2H), 3.77-3.75 (m, 1H),
2.66-2.64 (m, 2H), 2.54-2.53 (m, 2H), 1.90-1.85 (m, 1H),
1.75-1.72 (m, 5H), 1.26-1.18 (m, 2H), 0.86 (t, J = 7.3 Hz,
3H). HRMS (ES+): Calcd for C16H22NO3 (M + H)+
276.1600; found: 276.1606.
1-(Benzo[d][1,3]dioxol-5-yl)pentan-1-one (2). Piperonal (benzo
[d][1,3]dioxole-5-carbaldehyde, 45.0 g, 0.36 mol) in 60 mL of
dry tetrahydrofuran (THF) was added dropwise to a mechan-
ically stirred solution of 2 M butylmagnesium chloride in THF
(180 mL, 0.36 M) under argon in a 2 L 3-neck flask, keeping
the internal temperature between 5–20 °C with cooling in
dry ice-acetone. The mixture was stirred 0.5 h and treated
cautiously with 625 mL of saturated NH4Cl in portions. Ether
(375 mL) was added and the aqueous layer was separated and
reextracted with ether (200 mL). The combined ethereal solu-
tion was washed with 50 mL H2O and evaporated to give
70.8 g of the alcohol intermediate 1 (1-(benzo[d][1,3]dioxol-
5-yl)pentan-1-ol) that still contained some solvent. It showed
one spot on TLC in ether-hexane 1:1. The alcohol 1 was added
to a well-stirred suspension of 248 g of MnO2 in 700 mL of
CHCl3 in a 2 L 3-neck flask. The mixture was stirred mechan-
ically and refluxed with a water separator for liquids heavier
than water. After 1 h no additional water was produced and
TLC showed clean conversion to one spot that appeared at
higher Rf than the intermediate alcohol 1. The MnO2 mixture
was filtered and washed well with CHCl3. The filtrate and
washings were evaporated and the residue was distilled
in vacuo to give 1-(benzo[d][1,3]dioxol-5-yl)pentan-1-one
(2, 55.9 g, 90.4% based on 1), bp 125–129 °C/0.2–0.15 mm.
Optical Resolution of rac-MDPV•HCl. The hydrochloride salt
4, 6.2 g, 0.02 mol) was partitioned between ether and aque-
ous Na2CO3 and the ether was evaporated to give the free-
base rac-MDPV as a yellow oil. The free-base was dis-
solved in 54 mL of acetone containing 6.8 g (0.021 mol) of
(+)-2’-bromotartranilic acid ((+)-BTA) and slowly diluted
with 40 mL of ether. It was seeded with a sample of
S-(–)-MDPV•(+)-BTA (5) from a prior run that crystallized
from acetone-ether (4:3). The resulting crystals were fil-
tered, washed with 40 mL acetone-ether (4:3) to give the
S-(–)-MDPV•(+)-BTA salt 5 (4.6 g , 79%). This was dis-
solved in a mixture of CH2Cl2 and methanol (200:3) and
evaporated to a foam. Addition of acetone rapidly gave
white crystals of pure S-(–)-MDPV•(+)-BTA (5). Mp
130–132 °C, [α]2D3 = +57.5 (c 0.89, MeOH). Anal: Calculated
for C26H31BrN2O8: C, 53.89; H, 5.39; N, 4.83. Found: C,
53.89; H, 5.14, N, 4.90. X-ray crystallographic analysis of
this material showed that the absolute configuration of
(–)-MDPV was S (Fig. 1). A sample of this salt from a sim-
ilar experiment was converted to the free base, [α]2D3 = -6.5
(c 0.89, CHCl3). The filtrate and washings from the prepa-
ration of 5 were combined, evaporated, and treated with
aqueous Na2CO3. Extraction with ether and evaporation
gave 2.3 g (8.42 mmol) of free-base rac-MDPV (4)
enriched with (+)-MDPV (6). These mixed bases were
rac-1-(Benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-
one•HCl (rac-3,4-methylenedioxypyrovalerone•HCl, rac-MDPV•HCl)
(4). The ketone 2 (20.6 g, 0.1 mol) was dissolved in CHCl3
(200 mL) and treated dropwise at room temperature with a
solution of Br2 (16.0 g, 0.1 mol) in 50 mL of CHCl3 to give a
very rapid reaction to form 3 (1-(benzo[d][1,3]dioxol-5-yl)-
2-bromopentan-1-one). When the solution showed a nega-
tive reaction with moist starch-iodide paper, excess satu-
rated NaHCO3 solution was cautiously added to the
stirred solution to give a final aqueous pH of ~8. The
CHCl3 was separated and evaporated. The residue was dis-
solved in 200 mL of ether and treated with pyrrolidine
(14.2 g, 0.2 mol) and stirred overnight. The basic fraction
was extracted into excess 10% citric acid. The citric acid
solution was washed with ether (discarded) and made ba-
sic to pH 13–14 with 25% NaOH. The basic material was
extracted with ether twice and the combined ether ex-
tracts were washed with brine and evaporated to a light
yellowish-red oil (23.4 g). The oil was dissolved in
isopropanol (50 mL) and treated with 20 mL of isopropanol
containing about 2.7 g of HCl gas. The resulting crystalline
material (24.7 g) was heated to solution in 100 mL of 100%
EtOH, cooled, and diluted with 50 mL of ether. The salt
was filtered, washed with 50 mL of 2:1 ethanol-ether, and
dried in a vacuum oven to give 1-(benzo[d][1,3]dioxol-
5-yl)-2-(pyrrolidin-1-yl)pentan-1-one•HCl (4, 22.2g (80%)
of white crystalline material, mp 247–249 °C (dec, brown be-
1
fore mp; lit.1 mp 229–231 °C). H NMR (CDCl3, 400 MHz):
δ12.3 (brs, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 6.91
(d, J = 8.0 Hz, 1H), 6.09 (s, 2H), 5.16-5.15 (m, 1H), 3.82-
3.74 (m, 2H), 3.67-3.59 (m, 1H), 2.94-2.89 (m, 1H), 2.23-
2.08 (m, 4H), 2.04-1.98 (m, 2H), 1.481.36 (m, 1H), 1.35-1.26
(m, 1H), 0.89 (t, J=7.2Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ194.4, 153.6, 148.9, 130.6, 125.9, 108.4, 107.7,
102.4, 62.4, 52.7, 49.4, 33.0, 23.9, 23.6, 19.5, 13.9. Anal:
Chirality DOI 10.1002/chir
Fig. 1. X-ray crystal structure of (S)-(–)-1-(benzo[d][1,3]dioxol-5-yl)-2-
(pyrrolidin-1-yl)pentan-1-one from the salt with (+)-2’-bromotartranilic acid
(5, S-(–)-MDPV•((+)-BTA).

ENANTIOMERS OF PSYCHOACTIVE “DESIGNER DRUG” MDPV
289
treated with 2.9 g (9.0 mmol) of (–)-BTA in 25 mL of ace-
tone to give 2.8 g of crystalline R-(+)-MDPV•(–)-BTA (6).
The material was filtered, washed with acetone then hex-
ane, and dried to give 2.8 g of 6 as a pure solid. Mp
131–133 °C, [α]2D3 = –57.6 (c 0.98, MeOH). Anal: Calculated
for C26H31BrN2O8: C, 53.89; H, 5.39; N, 4.83. Found: C,
53.97; H, 5.08, N, 4.92.
obtained, free of charge, on application to CCDC, e-mail:
deposit@ccdc.cam.ac.uk.
RESULTS AND DISCUSSION
The synthesis of rac-MDPV (4, Scheme 1) followed the
general method of Heffe8 as employed by Meltzer et al.9
The first few steps in the known synthesis of rac-MDPV were
modified (Scheme 1). In our hands, this procedure for the
preparation of 1-(benzo[d][1,3]dioxol-5-yl)pentan-1-ol (1,
Scheme 1) proved superior to the literature reaction of
butylmagnesium chloride with piperonylnitrile followed by
hydrolysis. The NMR spectrum of the ketone 2, obtained
by oxidation of 1, matched that described by Echavarren
and Stille.10
Thus, Grignard reaction of piperonal (benzo[d][1,3]
dioxole-5-carbaldehyde) with n-butylmagnesium chloride
gave the alcohol 1 (1-(benzo[d][1,3]dioxol-5-yl)pentan-1-ol,
Scheme 1). Manganese dioxide oxidation gave ketone 2
(1-(benzo[d][1,3]dioxol-5-yl)pentan-1-one) in 90% yield for
the 2-step procedure. Bromination alpha to the keto moiety
in 2 gave 1-(benzo[d][1,3]dioxol-5-yl)-2-bromopentan-1-one
(3), and 3 reacted with pyrrolidine to give the desired
rac-MDPV (1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-yl)
pentan-1-one, 4) in 80% yield for the last two steps in the
synthesis.
Chiral resolution was achieved through salt formation of
rac-MDPV with (–)- and (+)-2’-bromotartranilic acid (BTA)
to give S-(–)-MDPV•(+)-BTA (5) and R-(+)-MDPV•(–)-BTA
(6, Fig. 1). The (+)- and (–)-BTA were prepared using the pro-
cedure of Montzka et al.11 via tartaric acids with known abso-
lute configuration. An X-ray crystallographic structure
determination of the (–)-MDPV•(+)-BTA salt 5 provided the
necessary proof that the configuration at C8 in (–)-MDPV
was S (Fig. 1).
X-ray crystal data for S-(–)-MDPV•(+)-BTA (5). Single-crystal
X-ray diffraction data on compound S-(–)-MDPV•(+)-BTA
(5) was collected using CuKα radiation and a Bruker
Platinum-135 CCD area detector. A 0.109 × 0.064 × 0.016
mm3 crystal was prepared for data collection by coating
with high viscosity microscope oil, mounted on a micro-
mesh mount (MiTeGen, Ithaca, NY), and a dataset col-
lected at 150°K. The crystal was orthorhombic in space
group P 212121, with unit cell dimensions a = 9.3654(2),
b = 9.8370(3), and c = 28.0706(7). Data were 95.9% com-
plete to 68.19° θ (~0.83 Å) with an average redundancy
of 5.49. The structure was solved by direct methods and
refined by full-matrix least squares on F2 values using
the programs found in the SHELXTL suite (Bruker,
SHELXTL v. 6.10, 2000, Bruker AXS, Madison, WI). Cor-
rections were applied for Lorentz, polarization, and ab-
sorption effects. Parameters refined included atomic
coordinates and anisotropic thermal parameters for all
nonhydrogen atoms. Hydrogen atoms on carbons were in-
cluded using a riding model [coordinate shifts of C ap-
plied to H atoms] with C-H distance set at 0.96 Å.
Complete information on data collection and refinement
is available in the Supplemental Material. The final aniso-
tropic full matrix least-squares refinement on F2 with 334
variables converged at R1 = 2.90%, for the observed data
and wR2 = 8.80% for all data. The absolute configuration
was determined from the diffraction data. The absolute
configuration as reported by PLATON is C2’ = R, C3’ = R
(both from the reference molecule), and C8 = S. Atomic
coordinates for S-(–)-MDPV have been deposited with
the Cambridge Crystallographic Data Centre (deposition
number CCDC 1026174). Copies of the data can be
Determination of Enantiopurity Through HPLC and 1H NMR
1) 1H NMR. The HCl salts, made for pharmacological
evaluation, were found to be stable in aqueous solution (vide
infra). They were prepared from the free-bases obtained from
Scheme 1. Synthesis of S-(–)-MDPV•(+)-BTA (5) and R-(+)-MDPV•(–)-BTA (6).
Chirality DOI 10.1002/chir

290
SUZUKI ET AL.
5 and 6 (Scheme 1). The HCl salts of the S-(–)- and R-(+)-
MDPV were converted back to their free-bases needed for this
study using the usual procedures. The enantiomeric purity of
the free bases was assessed by 1H NMR (Figs. 2 and 3) using
25 uL of R-(–)-1-phenyl-2,2,2-trifluoroethanol as a chiral shift
reagent in CDCl3 (0.6 mL, concentration: 0.055 mol/L). The
free bases showed > 98% ee as seen in Figures 2 and 3. The
presence of the other enantiomer was not detected.
2) HPLC. Several chiral columns were examined to deter-
mine their suitability for this analysis. None were found
Fig. 2. 1H NMR of R-(+)-MDPV base.
Fig. 3. 1H NMR of S-(–)-MDPV base.
Fig. 4. HPLC separation of the enantiomers of the rac-MDPV free-base.
Chirality DOI 10.1002/chir

ENANTIOMERS OF PSYCHOACTIVE “DESIGNER DRUG” MDPV
291
Limits of Detection for 1H NMR and Chiral HPLC Methods
that gave satisfactory results; baseline separation could not
be obtained on any column. The best chiral column was a
Daicel CHIRACEL OJ chiral HPLC column (flow rate;
0.2 mL/ min, eluent: hexane / IPA / n-butylamine (99 /
1 / 0.1)). The retention times of the enantiomers from the
free base of rac-MDPV were determined. Enantiomer reten-
tion times of A, 37.88 min (R-(+)-MDPV), B, 39.50 min (S-
(–)-MDPV) (area: A / B = 48 / 51.6 (1 / 1.08) were observed.
Baseline separation was not achieved (Fig. 4), but the peaks
could be easily distinguished.
1H NMR method. In order to measure the experimental
1
limits of accuracy of the H NMR (using a chiral shift re-
agent) and the chiral HPLC methods for determining en-
antiomeric purity, various amounts of the opposite
enantiomer were deliberately added to the examined enan-
tiomer in each method. Thus, 0.5% of R-(+)-MDPV•(–)-
BTA (11.9 uL of 7.55 mg/mL of 6 in EtOH) was added
to a suspension of S-(–)-MDPV•(+)-BTA (5) in water,
and 20% Na2CO3 aq. was added to the mixture. The aque-
ous layer was extracted with Et2O and the combined or-
ganic layer was dried over MgSO4 or Na2SO4. This was
filtered, concentrated, and dried in vacuo to give the
free-bases as a yellow syrup. The NMR samples were pre-
pared using CDCl3 (ca. 0.5–0.6 mL, concentration of enantio-
meric free-bases: ca. 0.05~0.06mol/ L) and 25 uL of R-(–)-1-
phenyl-2,2,2-trifluoroethanol was added as a chiral shift
Each of the separated free-base enantiomers obtained from
their 2’-bromotartranilic acid salt was examined separately
(Figs. 5 and 6) and it was determined that the purity of A
(R-(+)-MDPV in Fig. 4) and B (S-(–)-MDPV in Fig. 4) was
>98% ee. The other enantiomer was not seen in Figures 5
or 6.
Fig. 5. HPLC data for R-(+)-MDPV (6) as free base.
Fig. 6. HPLC data for S-(–)-MDPV (5) as free base.
Chirality DOI 10.1002/chir

292
SUZUKI ET AL.
reagent. Each of the samples were prepared with 0.5%,
1.0%, or 2.0% of the other enantiomer.
When 0.5% and 1% of the minor isomer was added, they
could be observed only at very high magnification of the
spectral area (see Supporting Information). The minor iso-
mer could easily be observed (see circled area in Fig. 7)
when 2% of the R-(+)-isomer was added to S-(–)-MDPV.
However, when 2% of the S-(–)-MDPV was added to
R-(+)-MDPV, the minor isomer was observed as a broad
area (Fig. 8) and was not as apparent as seen in the re-
verse experiment (Fig. 7). Again, addition of 0.5% and 1%
was observable, but only when greatly magnified (see
Supporting Information). From these data, the purity of
the isomers was estimated to be >96% ee.
Chiral HPLC method. An analogous procedure to that used in
1
the H NMR method was used to examine R-(+)-MDPV•(–)-
BTA (6) with 0.5% of S-(–)-MDPV•(+)-BTA (5). For HPLC,
the free-base syrup was dissolved in EtOH (ca. 1–2 mL). Both
enantiomers were examined using samples prepared with
1.0% and 2.0% of the other enantiomer. In Figure 9 the addi-
tion of 2.0 wt% of R-(+)-MDPV to S-(–)-MDPV was clearly dis-
cernable. That same amount of S-(–)-MDPV added to R-(+)-
MDPV could not be seen (Fig. 10). Thus, the HPLC analysis
was clearly not as sensitive as the NMR method that could de-
tect 0.5% of the other enantiomer (when the spectra was en-
larged greatly), and where a 2% addition was much more
easily observed.
Fig. 7. 1H NMR discernment of 2% of R-(+)-MDPV added to S-(–)-MDPV.
Stereochemical Stability of the HCl Salt of the Enantiomers
The HCl salt of each enantiomer was dissolved in H2O/
EtOH and the solution was allowed to stand for 24 h at
room temperature. The HCl salt of each enantiomer in
these solutions was converted into the free-base and the
enantiomeric purity of the S-(–)-MDPV free-base was
assessed by chiral HPLC and NMR; the enantiomeric pu-
rity of the R-(+)-base was assessed by NMR alone. Since
the presence of the other enantiomer was not detected in
either of the enantiomers, the free base could be said to
have remained > 96% ee. Therefore, the HCl salt appeared
to be stereochemically stable under these time and tem-
perature conditions.
Fig. 8. 1H NMR discernment of 2% of S-(–)-MDPV added to R-(+)-MDPV.
Fig. 9. Chiral HPLC discernment of 2% of (+)-MDPV (A) added to (–)-MDPV (B).
Chirality DOI 10.1002/chir

ENANTIOMERS OF PSYCHOACTIVE “DESIGNER DRUG” MDPV
293
Fig. 10. Chiral HPLC discernment of 2% of (–)-MDPV (B) added to (+)-MDPV (A).
CONCLUSION
SUPPORTING INFORMATION
The synthesis of rac-MDPV was improved and its enan-
tiomers were separated through salt formation with (–)-
and (+)-2’-bromotartranilic acid (BTA). The purified
S-(–)-MDPV•(+)-BTA (5) and R-(+)-MDPV•(–)-BTA (6)
salts, with their absolute configuration determined
through the X-ray crystallographic analysis of S-(–)-
MDPV•(+)-BTA (5), were free-based and the S-(–)-MDPV
and R-(+)-MDPV were converted to their pharmacologi-
cally useful HCl salts. The HCl salt was found to be stable
on standing in water for 24 h. These enantiomers will be
pharmacologically evaluated in the future to determine
which retains the biological activity found in the racemate
and whether the less toxic enantiomer might prove useful
for other purposes.
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV),
a
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The work of the Drug Design and Synthesis Section,
NIDA, & NIAAA, was supported by the NIH Intramural
Research Programs of the National Institute on Drug
Abuse (NIDA) and the National Institute of Alcohol Abuse
and Alcoholism. The X-ray crystallographic work was sup-
ported by NIDA through an Interagency Agreement
#Y1-DA1101 with the Naval Research Laboratory. We
thank Dr. Klaus Gawrisch and Dr. Walter Teague (Labora-
tory of Membrane Biochemistry and Biophysics, NIAAA),
for NMR spectral data. The authors also thank Noel
Whittaker, Mass Spectrometry Facility, NIDDK, for mass
spectral data.
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Chirality DOI 10.1002/chir