Asymmetric synthesis of (1R,5S)-2-methyl-6,7-benzomorphan via Aza-Prins reaction

Article abstract of DOI:10.1002/chir.23338

(1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy)(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)₃ promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S,4S)-2-benzyl-1- methylpiperidin-4-ol via a high-yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular Friedel?Crafts cyclisation of the piperidinol afforded (1R,5S)-2-methyl-6,7-benzomorphan in five steps with a yield of 25%.

Full text of DOI:10.1002/chir.23338

Received: 26 May 2021
DOI: 10.1002/chir.23338
Accepted: 6 July 2021
R E S E A R C H A R T I C L E
Asymmetric synthesis of (1R,5S)-2-methyl-6,7-benzomorphan
via Aza-Prins reaction
1
1
José A. Galvez | Ramon Badorrey | Alejandro Mahía2,3
|
ꢀ
ꢀ
María D. Díaz-de-Villegas1
1
ꢀ
Departamento de Química Organica,
Abstract
ꢀ
Instituto de Síntesis Química y Catalisis
Homogénea (ISQCH), CSIC - Universidad
de Zaragoza, Zaragoza, Spain
2Departamento de Bioquímica y
Biología Molecular y Celular, Facultad de
Ciencias, Universidad de Zaragoza,
Zaragoza, Spain
3Biocomputation and Complex Systems
Physics Institute (BIFI). Joint Unit IQFR-
CSIC-BIFI, Joint Unit EEAD-CSIC-BIFI,
Zaragoza, Spain
(1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy)
(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)3 promoted Aza-Prins
reaction with N-tosylhomoallylamine afforded an 88/12 mixture of
6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to
enantiomerically pure (2S,4S)-2-benzyl-1- methylpiperidin-4-ol via a high-
yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed
intramolecular FriedelꢀCrafts cyclisation of the piperidinol afforded (1R,5S)-
2-methyl-6,7-benzomorphan in five steps with a yield of 25%.
Correspondence
K E Y W O R D S
ꢀ
J. A. Galvez and M. D. Díaz-de-Villegas,
asymmetric synthesis, Aza-Prins reaction, benzomorphan, morphine analogues
ꢀ
Departamento de Química Organica,
ꢀ
Instituto de Síntesis Química y Catalisis
Homogénea (ISQCH), CSIC - Universidad
de Zaragoza, Pedro Cerbuna 12, E-50009
Zaragoza, Spain
Email: jagl@unizar.es; loladiaz@unizar.es
Funding information
Government of Aragꢀon, Grant/Award
Number: E45_20R
1 | INTRODUCTION
A number of synthetic routes have been developed
for the synthesis of benzomorphans.5 Among them, those
Isolated from opium in the beginning of the 19th
century,1 morphine has been widely used to provide
relief to patients that suffer from severe pain. Due to the
unwanted side effects that accompany the analgesic effect
of morphine, the search of strong analgesics derived from
morphine skeleton simplification with attenuated or no
harmful side-effects has been continuous.2 Truncated
systems containing a benzomorphan scaffold (Figure 1)
have proven to be particularly useful in this regard.3,4
using the acid-catalysed intramolecular FriedelꢀCrafts
cyclisation—of benzyl functionalised piperidines with
hydroxyl or C=C double moieties—to form ring B of the
benzomorphan skeleton have been applied successfully
to the synthesis of several active compounds (Figure 2).6–13
Because the stereochemistry of benzomorphan-based
compounds plays a pivotal role in their pharmacological
activity,14–19 a convenient, straightforward and practical
route to the synthesis of chiral benzomorphan analogues
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
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© 2021 The Authors. Chirality published by Wiley Periodicals LLC.
Chirality. 2021;1–6.
wileyonlinelibrary.com/journal/chir
1

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GALVEZ ET AL.
2
1
g/100 ml. H NMR and 13C NMR spectra were acquired
in deuterated solvent on a Bruker AV-400 spectrometer
1
operating at 400 MHz for H NMR and 100 MHz for 13C
NMR. Spectra were acquired at room temperature
unless otherwise stated using a 5-mm probe. All
chemical shifts (δ) are reported in parts per million
(ppm) from tetramethylsilane with the solvent reso-
nance as the internal standard (residual solvent signals
were set according to Fulmer et al20). Coupling con-
stants (J) are quoted in Hertz. Splitting patterns are
described as singlet (s), doublet (d), multiplet (m),
broad doublet (bd), doublet of doublet (dd), doublet of
doublet of doublet (ddd), and doublet of doublet of
doublet of doublet (dddd). High-resolution mass spectra
were recorded from methanolic solutions on a Bruker
Dalton MICROTOF-Q (quadrupole time-of-flight) micro
instrument using the positive electrospray ionisation
mode (ESI+).
FIGURE 1 Structures of morphine and 6,7-benzomorphan
FIGURE 2 Construction of the benzomorphan scaffold by
intramolecular Friedel–Crafts cyclisation
in enantiomerically pure form is highly desirable. Herein,
we report the asymmetric synthesis of (1R,5S)-2-methyl-
6,7-benzomorphan starting from (R)-(benzyloxy)(phenyl)
acetaldehyde.
2.2 | Experimental procedure
2.2.1 | (1R,5S,7R)-7-Phenyl-2-tosyl-6-oxa-
2-azabicyclo[3.2.1] octane (2A)
2 | MATERIALS AND METHODS
2.1 | General information
To a solution of N-(but-3-en-1-yl)-4-methylbenzene-
sulfonamide (225.3 mg, 1.0 mmol) and (R)-
2-(benzyloxy)-2-phenylacetaldehyde 121 (294.2 mg,
1.3 mmol) in acetonitrile (10 ml) at room temperature
was added Bi (OTf)3 (721.8 mg, 1.1 mmol). The
resulting solution was stirred for 24 h at 30ꢁC. The
crude product was concentrated under reduced pressure,
then diluted in CH2Cl2 (50 ml), and washed with a satu-
rated aqueous solution of NaHCO3 (30 ml). The aqueous
layer was extracted with CH2Cl2 (2 ꢃ 20 ml). The com-
bined organic layers were dried over anhydrous MgSO4,
filtered and evaporated under reduced pressure. The
crude product was purified by column chromatography
(eluent CH2Cl2) and recrystallised from MeOH to give
199.2 mg (58% yield) of compound 2A. White solid; mp
158 ꢁC; [α]D25 = ꢀ5.23 (c = 1.02 in CHCl3); 1H NMR
(400 MHz, CDCl3, δ): 7.49–7.54 (m, 2H), 7.43–7.47
(m, 2H), 7.26–7.40 (m, 3H), 7.18–7.23 (m, 2H), 5.17
(bd, J = 3.8 Hz, 1H), 4.92–4.96 (m, 1H), 4.65–4.71
(m, 1H), 3.41 (dd, J = 14.0, 7.2 Hz, 1H), 2.99
(ddd, J = 14.0, 11.4, 5.4 Hz, 1H), 2.41 (s, 3H), 2.13
(dddd, J = 11.7, 6.4, 3.4, 1.7 Hz, 1H), 1.64–1.77 (m, 2H),
1.46 (dddd, J = 13.3, 11.4, 7.2, 1.1 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3, δ): 142.9, 137.6, 137.4, 129.5,
128.0, 126.9, 126.8, 125.6, 82.0, 74.7, 57.0, 39.7, 37.2,
30.2, 21.4; IR (KBr): ν = 3079, 3062, 3041, 1658,
1594 cmꢀ1; HRMS (ESI, m/z): [M + Na]+ calcd. for
C19H21NNaO3S, 366.1134; found, 366.1152.
Unless otherwise specified, all reagents were obtained
from commercial suppliers and used without purifica-
tion. For anhydrous conditions, reactions were carried
out under Ar in solvents dried using a solvent purifica-
tion system (SPS). Heating was performed using an oil
bath mounted on a hot plate magnetic stirrer. Whenever
possible, the reactions were monitored by TLC. TLC
analysis was performed on precoated silica gel polyester
plates with an F254 indicator, and products were
visualised using UV light (254 nm) and ninhydrin,
anisaldehyde, potassium permanganate, or ethanolic
phosphomolybdic acid solutions followed by heating.
Column chromatography was performed on silica gel
(Kiesegel 60, 230–400 Mesh) with air pressure. Melting
points were determined in open capillaries using a
Gallenkamp capillary melting point apparatus and are
not corrected. The FT-IR spectra of oils were recorded
as thin films on NaCl plates, the FT-IR spectra of solids
were recorded on pressed KBr pellets using a Thermo
Nicolet Avatar 360 FT-IR spectrophotometer, νmax
values expressed in cmꢀ1 are given for the main absorp-
tion bands. Optical rotations were measured on a Jasco
1020 digital polarimeter at λ 589 nm and 25ꢁC in
cells with 1- or 10-cm path length, [α]D values are given
in 10ꢀ1 degꢂcm2ꢂgꢀ1 and concentrations are given in

ꢀ
GALVEZ ET AL.
3
2.2.2 | (2S,4S)-2-Benzyl-1-tosylpiperidin-
4-ol (3)
After stirring for 10 min at room temperature, NaBH3CN
(84.8 mg, 1.35 mmol) was added and the resulting
mixture was stirred for 1 h at room temperature. Solvent
was removed in vacuo, and the residue was dissolved in
water (5 ml) and was extracted with CH2Cl2 (3 ꢃ 20 ml).
The combined organic layers were dried over anhydrous
MgSO4, filtered and evaporated under reduced pressure.
The crude product was purified by column chromatogra-
phy (AcOEt/MeOH/Et3N 8.5:1:0.5) to give 65.6 mg
(71% yield) of compound 4. White solid; mp 143ꢁC
[lit.13 mp 118–120ꢁC]; [α]D25 = 93.20 (c = 1.08 in CHCl3)
[lit.13 [α]D23 = 55.2 (c = 1.28 in CHCl3)]; 1H NMR
(400 MHz, CDCl3, δ): 7.18–7.24 (m, 2H), 7.06–7.16
(m, 3H), 3.43 (dddd, J = 10.9, 10.9, 4.5, 4.5 Hz, 1H), 3.15
(dd, J = 13.1, 4.0 Hz, 1H), 2.92 (ddd, J = 12.2, 4.0, 3.3 Hz,
1H), 2.41 (dd, J = 13.1, 9.9 Hz, 1H), 2.39 (s, 3H),
2.16–2.26 (m, 2H), 1.85 (dddd, J = 4.5, 2.7, 2.7, 2.7 Hz,
1H), 1.69 (dddd, J = 12.7, 4.8, 2.5, 2.5 Hz, 1H), 1.58 (dddd,
J = 12.6, 12.6, 11.0, 4.2 Hz, 1H), 1.18 (ddd, J = 12.4, 11.1,
11.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, δ): 138.4,
129.4, 128.4, 126.3, 68.5, 63.6, 55.0, 41.8, 39.8, 39.0, 34.1;
IR (nujol): ν = 3137, 3023 cmꢀ1; HRMS (ESI, m/z):
[M + H]+ calcd. for C13H20NO, 206.1539; found, 206.1529.
To a solution of compound 2A (171.7 mg, 0.5 mmol) in
CH2Cl2 (5 ml), methanol (10 ml), trifluoroacetic acid
(15 drops) and 20% Pd (OH)2/C (115 mg) were succes-
sively added, and the mixture was stirred at room
temperature under an atmosphere of H2 at atmospheric
pressure for 24 h. After this period, the mixture was
filtered through Celite® 545 and concentrated under
reduced pressure. The crude product was purified by
column chromatography (first eluent: Et2O/hexanes 3:1,
second eluent: Et2O) to give 162.3 mg (94% yield) of
compound 3. Colourless oil; [α]D25 = ꢀ28.25 (c = 1.12 in
CHCl3); 1H NMR (400 MHz, CDCl3, δ): 7.56–7.61 (m,
2H), 7.18–7.30 (m, 7H), 4.23–4.32 (m, 1H), 4.12–4.17
(m, 1H), 3.68 (ddd, J = 14.0, 5.3, 2.2 Hz, 1H), 3.53 (ddd,
J = 14.0, 12.7, 2.8 Hz, 1H), 3.22 (dd, J = 13.2, 9.7 Hz,
1H), 2.97 (dd, J = 13.2, 6.4 Hz, 1H), 2.41 (s, 3H),
1.53–1.84 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3, δ):
142.9, 139.2, 138.1, 129.5, 129.5, 128.4, 127.0, 126.2,
64.4, 53.4, 38.7, 35.6, 32.1, 31.9, 21.4; IR (neat): ν = 3522,
3062, 3027, 1598 cmꢀ1; (ESI, m/z): [M + Na]+ calcd. for
C19H23NNaO3S, 368.1291; found, 368.1302.
2.2.4 | (1R,5S)-2-methyl-6,7-
benzomorphan (5)
2.2.3 | (2S,4S)-2-Benzyl-1-methylpiperidin-
4-ol (4)
Compound 4 (61.6 mg, 0.3 mmol) was heated in poly-
phosphoric acid (1.20 g) with stirring at 140ꢁC for
72 hours. Cooling to room temperature and water addi-
tion (5 ml) gave a brown solution which was made basic
with 5-M aqueous NaOH and extracted with CH2Cl2
(3 ꢃ 20 ml). The combined organic layers were dried over
anhydrous MgSO4, filtered and evaporated under reduced
pressure. The residue was dissolved in CH2Cl2, the solu-
tion was brought to pH 1 using 2 M ethereal HCl and the
organic solvents were evaporated under reduced pres-
sure. A suspension of crude hydrochloride in a mixture of
diethyl ether (8 ml) and acetone (1 ml) was stirred at
room temperature for 24 h and filtered. The solid was dis-
solved in 5-M aqueous NaOH (5 ml) and was extracted
with CH2Cl2 (2 ꢃ 20 ml). The combined organic layers
were dried over anhydrous MgSO4, filtered and evapo-
rated under reduced pressure to give 36.0 mg (64% yield)
of compound 5. Brownish oil; [α]D25 = 64.21 (c = 1.19,
CHCl3) [lit. [13] [α]D23 = 116 (c = 0.1 in CHCl3); 1H
NMR (400 MHz, CDCl3, δ): 7.08–7.15 (m, 3H), 7.02–7.07
(m, 1H), 3.20–3.26(m, 1H), 3.13 (d, J = 18.5 Hz, 1H),
3.00–3.05 (m, 1H), 2.72 (dd, J = 18.5, 5.9 Hz, 1H),
2.47–2.56 (m, 1H), 2.44 (s, 3H), 2.08–2.23 (m, 3H), 1.91
(ddd, J = 12.5, 5.7, 2.8 Hz, 1H), 1.52 (ddd, J = 9.2, 4.6,
2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, δ): 140.3,
Sodium naphthalenide (1 M in THF) was prepared by
stirring naphthalene (512.7 mg, 4.0 mmol) and small
pieces of sodium (101.2 mg, 4.4 mmol) in dry THF (4 ml)
at room temperature for 1 h under an argon atmosphere.
To a solution of compound 3 (155.5 mg, 0.45 mmol) in
dry THF (4 ml) at ꢀ78ꢁC under an argon atmosphere,
the above freshly prepared solution of sodium
naphthalenide (1 ml) was added dropwise until the green
colour persisted. The reaction was stirred for 10 min at
ꢀ78ꢁC and then quenched with MeOH (0.5 ml). The
solution was neutralised with 3-M aqueous HCl, and
the organic solvents were evaporated under reduced
pressure. The residue was dissolved in water (10 ml), and
the aqueous solution was brought to pH 1 by addition of
3-M aqueous HCl and washed with diethyl ether
(3 ꢃ 10 ml). The aqueous solution was basified until
pH 13 with 5-M aqueous NaOH solution and extracted
with CH2Cl2 (3 ꢃ 20 ml). Drying over anhydrous MgSO4,
filtration and evaporation of the solvent under reduced
pressure yielded 75 mg of crude (2S,4S)-2-benzyl-1-meth-
ylpiperidin-4-ol that was used without further
purification. To a solution of crude (2S,4S)-2-benzyl-
1-methylpiperidin-4-ol dissolved in methanol (5 ml),
formalin (37% CH2O, 365.2 mg, 4.5 mmol) was added.

ꢀ
4
GALVEZ ET AL.
136.9, 128.1, 127.7, 125.9, 125.7, 53.4, 45.9, 43.0, 32.9,
31.9, 31.4, 26.3; HRMS (ESI, m/z): [M + Na]+ calcd. for
C13H17NNa, 210.1253; found, 210.1243.
3 | RESULTS AND DISCUSSION
We have reported22 a diastereoselective approach the
construction of the 6-oxa-2-azabicyclo[3.2.1]octane scaf-
fold from chiral α-hydroxyaldehyde derivatives through
Aza-Prins reaction. Hydrogenolysis of chiral adduct
obtained by reaction of (R)-(benzyloxy)(phenyl)acetalde-
hyde with N-tosylhomoallylamine would offer
a
straightforward approach to chiral (2S,4S)-2-benzyl-
1-methylpiperidin-4-ol required for intramolecular
FriedelꢀCrafts cyclisation as outlined in our retro-
synthetic analysis (Scheme 1).
The synthesis of the tricyclic core of (1R,5S)-
2-methyl-6,7-benzomorphan was started from (R)-
(benzyloxy)(phenyl)acetaldehyde 1 (Scheme 2). Reaction
of 1 with N-tosylhomoallylamine according to Mahía
et al22 afforded the 6-oxa-2-azabicyclo[3.2.1]octane 2 as
an 87/13 mixture of diastereoisomers in 69% yield from
which major diastereoisomer could be isolated in 40%
yield. In order to improve these results, we investigated
the key Aza-Prins cyclisation under different reaction
conditions (Table 1).
SCHEME 2 Synthesis of (1R,5S)-2-methyl-6,7-benzomorphan 5
TABLE 1 Aza-Prins cyclisationa
Reaction of 1 with N-tosylhomoallylamine promoted
by BF3ꢂOEt2, In (OTf)3 or TsOHꢂH2O at 30ꢁC* and using
toluene, dichloromethane or acetonitrile as solvent was
first investigated (entries 1–9). The induced dia-
stereoselectivity was clearly better when acetonitrile was
used as reaction medium and the yield depended on the
catalyst (entries 7–9). Indium triflate provided the higher
yield of major compound (entry 8). With acetonitrile as
solvent, we also tested bismuth triflate, scandium triflate
or trifuoromethane sulphonic acid as catalysts. With bis-
muth triflate or scandium triflate, the reaction efficiency
was maintained or even improved and can be used as
alternative Lewis acids (entries 10 and 11), whereas when
Entry
1d
2
Solvent
Catalyst
BF3ꢂOEt2
In (OTf)3
TsOHꢂH2O
BF3ꢂOEt2
In (OTf)3
TsOHꢂH2O
BF3ꢂOEt2
In (OTf)3
TsOHꢂH2O
Bi (OTf)3
Sc (OTf)3
CF3SO3H
In (OTf)3
Bi (OTf)3
Yield 2A (%)b
d.r.c
Toluene
59
53
68/32
60/40
—
Toluene
3
4d
Toluene
0
DCM
27
63/37
66/34
78/22
88/12
88/12
90/10
89/11
87/13
—
5
DCM
63
6
7d
DCM
53
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
59
8
80
9
52
10
11
12
13e
14e
82
88
0
48 (37)
78 (58)
88/12
89/11
aReaction conditions: aldehyde (0.26 mmol), tosylamine (0.2 mmol), catalyst
(0.22 mmol), solvent (2 ml), 30ꢁC, 24 h.
bDetermined from the crude reaction mixture by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as internal standard.
cDetermined from the crude reaction mixture by 13C NMR.
dAnhydrous solvent.
eReaction conditions: Aldehyde (2.6 mmol), tosylamine (2 mmol), catalyst
(2.2 mmol), solvent (20 ml), 30ꢁC, 24 h. The yield of the major isolated
compound is in brackets.
SCHEME 1 Retrosynthetic analysis of 6,7-benzomorphans

ꢀ
GALVEZ ET AL.
5
trifuoromethane sulphonic acid was used as an alterna-
tive Brønsted acid, the formation adducts was not
detected (entry 12). When the reaction was performed
increasing the amount of reagents (entries 13 and 14),
isolated yields were optimal with the use of bismuth
triflate as catalyst.
ENDNOTE
* With some Lewis acids, we have observed variations in the
reaction yield depending on which is the room temperature.
These variations are minimised with optimal reaction yields if
temperature is fixed at 30ꢁC.
The complete synthetic route to (1R,5S)-2-methyl-
6,7-benzomorphan is represented in Scheme 2. Reaction
of (R)-(benzyloxy)(phenyl)acetaldehyde 1 (2.6 mmol)
with N-tosylhomoallylamine (2 mmol) in acetonitrile at
30ꢁC using Bi (OTf)3 (2.2 mmol) as the Lewis acid
afforded the 6-oxa-2-azabicyclo [3.2.1]octane 2 as an
89/11 mixture of diastereoisomers. Diastereomerically
pure 2A was isolated in 58% yield after column chroma-
tography on silica gel and recrystallisation. Catalytic
hydrogenolysis of benzyl ether in intermediate 2A over
palladium hydroxide gave tosylpiperidinol 3 in 94%
yield. Removal of the tosyl group of 3 with sodium
naphthalenide generated in situ prepared from
sodium and naphthalene in dry THF under argon and
subsequent reductive methylation with formaldehyde
and sodium cyanoborohydride in methanol at room tem-
perature afforded (2S,4S)-2-benzyl-1-methylpiperidin-4-ol
4 in 71% yield over two steps. Friedel–Crafts cyclisation
of piperidinol 4 in hot polyphosphoric acid13,23,24 led to
the desired benzomorphan 5 in 64% yield.
REFERENCES
1. Huxtable RJ, Schwarz S. The isolation of morphine. Mol Interv.
2001;1(4):189-191.
2. Fürst S, Hosztafi S. The chemical and pharmacological
importance of morphine analogues. Acta Physiol Hung. 2008;
95(1):3-44.
3. Turnaturi R, Marrazzo A, Parenti C, Pasquinucci L.
Benzomorphan scaffold for opioid analgesics and
pharmacological tools development: a comprehensive review.
Eur J Med Chem. 2018;148:410-422.
4. Turnaturi R, Montenegro L, Marrazzo A, Parenti R,
Pasquinucci L, Parenti C. Benzomorphan skeleton, a versatile
scaffold for different targets: a comprehensive review. Eur J
Med Chem. 2018;155:492-502.
5. Palmer DC, Strauss MJ. Benzomorphans: synthesis, stereo-
chemistry reactions, and spectroscopic characterizations. Chem
Rev. 1977;77(1):1-36.
6. Hu L, Zhang L, Zhai H. Enantioselective synthesis of
(–)-pentazocine and (–)-metazocine. Synlett. 2016;27(6):
876-879.
7. Chen Q, Huo X, Yang Z, She X. Asymmetric syntheses of
(–)-pentazocine and (–)-eptazocine through an Aza-Prins cycli-
zation. Chem Asian J. 2012;7(11):2543-2546.
8. Singh KN, Singh P, Sharma AK, Singh P, Kessar SV. A
short synthesis of benzomorphane analgesics ( )-metazocine
and ( )-phenazocine. Synthetic Commun. 2010;40(24):
3716-3720.
4 | CONCLUSION
In summary, we have shown that diastereoselective Aza-
Prins reaction of (R)-(benzyloxy)(phenyl)acetaldehyde
1 with N-tosylhomoallylamine can be an efficient key
step to the synthesis of enantiomerically pure (1R,5S)-
2-methyl-6,7-benzomorphan 5. Hydrogenolysis of
Aza-Prins adduct 2A and subsequent detosylation/meth-
ylation provides enantiopure (2S,4S)-2-benzyl-1-meth-
ylpiperidin-4-ol 4 from which benzomorphan 5 is
obtained by a known intramolecular Friedel–Crafts
cyclisation.
9. Matsuo JI, Okado R, Ishibashi H. A new synthesis of 2,3-di- or
2,3,3-trisubstituted 2,3-dihydro-4-pyridones by reaction of
3-ethoxycyclobutanones and N-p-toluenesulfonyl imines using
titanium (IV) chloride: synthesis of ( )-bremazocine. Org Lett.
2010;12(14):3266-3268.
10. Yang X, Zhai H, Li Z. Enantiocontrolled synthesis of
(–)-9-epi-pentazocine and (–)-aphanorphine. Org Lett. 2008;10
(12):2457-2460.
11. Anada M, Tanaka M, Washio T, Yamawaki M, Abe T,
Hashimoto S. Catalytic enantioselective amination of silyl enol
ethers using chiral dirhodium (II) carboxylates: asymmetric
formal synthesis of (–)-metazocine. Org Lett. 2007;9(22):
4559-4562.
ACKNOWLEDGEMENTS
ꢀ
Financial support from the Government of Aragon
(E45_20R) is acknowledged.
12. Thomas JB, Brieaddy LE, Boldt KG, Perretta C, Carroll FI.
Synthesis and resolution of the benzomorphan-based
kappa opioid agonist bremazocine. Synthesis. 2007;10:
1481-1484.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available from the corresponding author upon reasonable
request.
13. Comins DL, Zhang YM, Joseph SP. Enantiopure N-
acyldihydropyridones as synthetic intermediates: asymmetric
synthesis of benzomorphans. Org Lett. 1999;1(4):657-659.
14. Turnaturi R, Pasquinucci L, Chiechio S, et al. Exploiting the
power of stereochemistry in drug action: 3-[(2S,6S,11S)-
8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-
benzazocin-3(2H)-yl]-N-phenylpropanamide as potent sigma-1
receptor antagonist. ACS Chem Nerosci. 2020;11(7):999-1005.
ORCID
María D. Díaz-de-Villegas https://orcid.org/0000-0001-
9033-8459

ꢀ
GALVEZ ET AL.
6
ꢀ
15. Pasquinucci L, Turnaturi R, Calò G, et al. (2S)-N-2-Methoxy-
22. Mahía A, Badorrey R, Galvez JA, Díaz-de-Villegas MD.
Diastereoselective construction of the 6-oxa-2-azabicyclo
[3.2.1]octane scaffold from chiral α-hydroxyaldehyde deriva-
tives by the Aza-Prins reaction. J Org Chem. 2017;82(15):
8048-8057.
2-phenylethyl-6,7-benzomorphan
compound
(2S-LP2):
discovery of a biased mu/delta opioid receptor agonist. Eur J
Med Chem. 2019;168:189-198.
16. Halberstadt AL, Hyuna J, Ruderman MA, Powell SB. Effects of
the psychotomimetic benzomorphan N-allylnormetazocine
(SKF 10,047) on prepulse inhibition of startle in mice.
Pharmacol Biochem Behav. 2016;148:69-75.
17. Wang QY, Kondreddi RR, Xie X, et al. A translation inhibitor
that suppresses dengue virus in vitro and in vivo. Antimicrob
Agents Chemother. 2011;55(9):4072-4080.
23. Takeda M, Jacobson AE, Kanematsu K, May EL. 4-Methoxy-
1-methylpyridinium
iodide.
Grignard
products
and
transformations thereof. J Org Chem. 1969;34(12):4154-4157.
24. Kanematsu K, Takeda M, Jacobson AE, May EL. Synthesis
of 6,7-benzomorphan and related nonquaternary carbon
structures with marked analgetic activity. J Med Chem. 1969;
34:405-408.
18. Aceto MD, May EL, Harris LS, Bowman ER, Cook CD.
Pharmacological studies with
a nonpeptidic, delta-opioid
(ꢀ)-(1R,5R,9R)-5,9-dimethyl-20-hydroxy-2-(6-hydroxyhexyl)-
6,7-benzomorphan hydrochloride ((ꢀ)-NIH 11082). Eur
Pharmacol. 2007;566(1–3):88-93.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
J
19. Carroll FI, Bai X, Dehghani A, Mascarella SW,
Williams W, Bowen WD. Asymmetric synthesis of
9-alkyl-2-benzyl-6,7-benzomorphans: characterization as novel
σ receptor ligands. J Med Chem. 1999;42(22):4621-4629.
20. Fulmer GR, Miller AJM, Sherden NH, et al. NMR chemical
shifts of trace impurities: common laboratory solvents,
organics, and gases in deuterated solvents relevant to the
organometallic chemist. Organometallics. 2010;29(9):2176-2179.
21. Effenberger F, Hopf M, Ziegler T, Hudelmayer J. Synthesis of
O-protected (R)-2-hydroxy aldehydes and their hydrocyanation.
Chem Ber. 1991;124(7):1651-1659.
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How to cite this article: Galvez JA, Badorrey R,
Mahía A, Díaz-de-Villegas MD. Asymmetric
synthesis of (1R,5S)-2-methyl-6,7-benzomorphan
via Aza-Prins reaction. Chirality. 2021;1-6. https://
doi.org/10.1002/chir.23338