Asymmetric synthesis of (-)-9-epi-metazocine

Article abstract of DOI:10.1055/s-0031-1291047

(-)-9-epi-Metazocine was synthesized through an Evans syn aldol reaction, ring-closing metathesis reaction and intramolecular radical cyclization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291047

LETTER
▌1349
lAettserymmetric Synthesis of (–)-9-epi-Metazocine
Asymmetric Synthesis of (–)-9-epi-Metazocine
Qiang Chen,a Xing Huo,a Huaiji Zheng,a Xuegong She*a,b
a
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: shexg@lzu.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
Received: 08.03.2012; Accepted after revision: 28.03.2012
tion of 5 could be achieved from aldehyde 6 and N-propi-
onylthiazolidinethione (7) by an Evans aldol reaction.
Abstract: (–)-9-epi-Metazocine was synthesized through an Evans
syn aldol reaction, ring-closing metathesis reaction and intramolec-
ular radical cyclization.
RCM
Key word: asymmetric, drug development, aldol, ring-closing
metathesis, radical cyclization
H
O
Me
Me
OMe
N
NMe
HO
The natural alkaloid (–)-morphine is an important narcotic
analgesic but it exhibits undesired addictive side effects.1
Structural modification can reduce this problem to a con-
siderable extent, such as the clinically used (–)-pentazo-
cine (1) and (–)-9-epi-metazocine (2b) (Figure 1).2 Most
analogues of (–)-morphine feature a benzylic quaternary
carbon center, and the construction of such a center in an
enantioselective manner is an ongoing challenge for or-
ganic chemists. Methods for the enantioselective con-
struction of this center include Grewe-type cyclization,3
radical reaction,4 palladium-catalyzed asymmetric allylic
alkylation (AAA),5 Heck reaction,6 and Claisen rear-
rangement.7 Recently, our group reported that the synthe-
sis of a rigid benzobicyclo[3.3.1] lactone proceeds
through an intramolecular Friedel–Crafts type Michael
addition of the corresponding α,β-unsaturated lactone.8
However, application of the strategy to the synthesis of
(–)-9-epi-metazocine was not efficient. Herein, we report
an asymmetric synthesis of (–)-9-epi-metazocine through
the application of intramolecular radical cyclization.
Br
2b
3
radical cyclization
Evans aldol
O
OMe
OMe
O
OH
S
NH
N
S
Br
Br
Bn
5
4
Br
S
O
H
S
N
O
MeO
Bn
6
7
Scheme 1 Retrosynthetic analysis
The synthesis of intermediate 5 is shown in Scheme 2.
Starting from the commercially available 3-bromoanisole
(8), 2-bromo-4-methoxyacetophenone (9) was obtained in
70% yield through a Friedel–Crafts reaction.9 Upon treat-
ment of 9 with bromine, the substituted phenacyl bromide
10 was obtained in nearly quantitative yield. Reduction of
10 with NaBH4 followed by intramolecular SN2 reaction
generated the epoxy compound, which was transformed
into aldehyde 6 upon treatment with a catalytic amount of
BF3·OEt210 in 81% overall yield for the three steps. Gen-
eration of 5 through an Evans syn aldol reaction11 between
aldehyde 6 and N-propionylthiazolidinethione (7) in 76%
yield with excellent diastereoselectivity (>20:1 dr) com-
pleted the synthesis.12
H
H
Me
N
N
9
R
HO
HO
1 (–)-pentazocine
2a (–)-metazocine (R = α-Me)
2b (–)-9-epi-metazocine (R = β-Me)
Figure 1
Our retrosynthetic analysis is outlined in Scheme 1. The
framework of 2b may be accessed stereoselectively
through intramolecular radical cyclization of the α,β-un-
saturated lactam 3. The formation of 3 could be accom-
plished by using ring-closing metathesis (RCM) from
amide 4, which, in turn, was derived from 5. The prepara-
SYNLETT 2012, 23, 1349–1352
Advanced online publication: 08.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291047; Art ID: ST-2012-W0211-L
© Georg Thieme Verlag Stuttgart · New York

1350
Q. Chen et al.
LETTER
was generated by ring-closing metathesis (RCM)17 utiliz-
ing Hoveyda second-generation Grubbs catalyst, in 25%
yield (60% recovery of material, 40% brsm).18 In this pro-
cess, other Grubbs catalysts were also examined, but the
yields were low. Methylation (NaH, MeI) of 17, followed
by radical cyclization with Bu3SnH in the presence of
AIBN in benzene at reflux, led to aryl radical cyclization19
and the exclusive formation of 6-exo cyclization product
18 in 87% yield.20 Upon reduction and subsequent de-
methylation, (–)-9-epi-metazocine (2b)21 was obtained in
90% yield over two steps.
Br
Br
Br
O
O
Br
a
b
MeO
MeO
MeO
8
9
10
c, d
Br
OMe
O
OH
S
O
e
N
S
H
MeO
Br
In conclusion, we have finished the total synthesis of (–)-
9-epi-metazocine (2b) using an Evans syn aldol reaction,
ring-closing metathesis, and radical cyclization as key
Bn
5
6
Scheme 2 Reagents and conditions: (a) AlCl3·AcCl, CH2Cl2, 0 °C,
70%; (b) Br2, Et2O, r.t., 96%; (c) NaBH4, MeOH, then K2CO3, r.t., steps. The benzylic quaternary carbon center was estab-
93%; (d) BF3·Et2O, THF, r.t., 91%; (e) TiCl4, (–)-sparteine, 0 °C,
NMP, 7, CH2Cl2, –78 °C, 76%.
lished through intramolecular radical cyclization with
high stereoselectivity.
With the key intermediate 5 in hand, it was smoothly con-
Acknowledgment
verted into the corresponding Weinreb amide 11,13 and its
We are grateful for the generous financial support by the MOST
(2010CB833200), the NSFC (21072086, 21125207) and Program
111.
free hydroxy group was protected as the TBS ether to af-
ford 12 (Scheme 3). Treatment of 12 with excess methyl
magnesium iodide gave the corresponding ketone 13 in
92% yield. Subsequent Wittig reaction led to olefin 14 in
85% yield. Deprotection of 14 afforded 15, which was
Supporting Information for this article is available online at
converted into the corresponding azide 16 by the use of http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimnitgrSatnoIuifpog
r
t
iornat
(PhO)2P(O)N3.14,15
Under
Staudinger
reaction
conditions16 (PPh3, THF–H2O), azide 16 was reduced to
the primary amine, which was directly acylated with acry-
loyl chloride in the present of Et3N to give 4 in 50% yield
over two steps. The substituted α,β-unsaturated lactam 17
References
(1) (a) Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.;
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OMe
OMe
OMe
O
OTBS
O
OH
O
OR
S
a
c
d
O
N
Me
N
S
Br
Me
Br
Br
Bn
5
11 R = H
13
b
12 R = TBS
O
OMe
OMe
OMe
NH
OR
N3
g, h
f
i
Br
Br
Br
14 R = TBS
16
4
e
15 R = H
O
H
N
H
OMe
Me
Me
NR
N
k
l, m
Me
Me
MeO
HO
O
Me
18
Me
2b
Br
17 R = H
j
3 R = Me
Scheme 3 Reagents and conditions: (a) MeO(H)NMe·HCl, Imidazole, CH2Cl2, r.t., 90%; (b) TBSCl, Imidazole, DMF, r.t., 95%; (c) MeMgI,
THF, 0 °C, 92%; (d) MePPh3I, n-BuLi, THF, 0 °C, 85%; (e) TBAF·3H2O, THF, r.t., 84%; (f) PPh3, DIAD, DPPA, THF, 0 °C, 80%; (g) PPh3,
H2O, THF, 45 °C; (h) acryloyl chloride, Et3N, CH2Cl2, 0 °C, 50% for two steps; (i) Hoveyda–Grubbs II (8 mol%), CH2Cl2, reflux, 40% (brsm);
(j) NaH, MeI, r.t., 90%; (k) Bu3SnH, AIBN, benzene, reflux, 87%; (l) LiAlH4, THF, reflux; (m) BBr3, CH2Cl2, 90% for two steps.
Synlett 2012, 23, 1349–1352
© Georg Thieme Verlag Stuttgart · New York

LETTER
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Asymmetric Synthesis of (–)-epi-Metazocine
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[α]D18 +74.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ
= 7.21 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 6.84
(dd, J = 2.8, 8.4 Hz, 1 H), 4.91 (s, 1 H), 4.90 (s, 1 H), 3.80
(s, 3 H), 3.62–3.57 (m, 1 H), 3.12 (dd, J = 2.8, 14.0 Hz, 1 H),
2.58 (dd, J = 10.8, 14.4 Hz, 1 H), 2.52–2.45 (m, 1 H), 1.81
(s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100
MHz): δ = 159.0, 146.3, 132.3, 129.5, 124.5, 118.0, 113.6,
112.7, 65.5, 55.5, 45.7, 37.6, 20.0, 16.1; IR: 3366, 2961,
2925, 2853, 2102, 1604, 1492, 1243, 1034 cm–1; HRMS
(ESI): m/z [M + H]+ calcd for C14H19BrN3O: 324.0706;
found: 324.0718.
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(12) Compound 5: To a solution of thiazolidinethione
propionate 7 (4.27 g, 16.1 mmol) in CH2Cl2 (100 mL) at
0 °C, was added TiCl4 (1.86 mL, 16.9 mmol); a
atmosphere. The mixture was heated at reflux for 24 h, then
the solvent was removed in vacuum and the residue was
purified by chromatography (EtOAc) to afford 17 (46 mg,
25%) as a colorless solid; [α]D16 +172 (c 1.0, CHCl3); 1H
NMR (CDCl3, 400 MHz): δ = 7.11 (d, J = 2.4 Hz, 1 H), 7.03
(d, J = 8.8 Hz, 1 H), 6.81 (dd, J = 2.4, 8.8 Hz, 1 H), 5.71 (s,
1 H), 5.49 (s, 1 H), 3.78 (s, 3 H), 3.50–3.45 (m, 1 H), 2.96–
2.84 (m, 2 H), 2.18 (q, J = 6.8 Hz, 1 H), 1.96 (s, 3 H), 1.19
(d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 165.2,
159.0, 156.0, 132.0, 128.8, 124.8, 118.8, 118.4, 113.7, 55.6,
55.5, 40.6, 37.6, 22.0, 17.7; IR: 3242, 2965, 2929, 2866,
1675, 1606, 1492, 1241, 1031 cm–1; HRMS (ESI): m/z [M +
H]+ calcd for C15H19BrNO2: 324.0594; found: 324.0596.
(20) (a) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O.
J. Org. Chem. 2000, 65, 9022. (b) Tamura, O.;
characteristic orange slurry formed. After 10 min, (–)-
sparteine (3.78 g, 16.1 mmol) was added, and the color
changed to a deep red. After stirring for 30 min, the mixture
was cooled to –78 °C, N-methylpyrrolidinone (NMP; 1.6
mL, 16.1 mmol) was added and the mixture was stirred for
an additional 10 min. Aldehyde 6 (4.06 g, 17.7 mmol) in
CH2Cl2 (20 mL) was added and the mixture was stirred at –
78 °C for 1 h. After a further 2.5 hours stirring at 0 °C, the
reaction was quenched with sat. NH4Cl. After separation of
layers, the aqueous layer was further extracted with CH2Cl2
(2 × 30 mL) and the combined organic extract was dried
over anhydrous Na2SO4 and evaporated in vacuo. The
residue was purified by chromatography (petroleum ether–
Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org. Lett.
2001, 3, 2427.
(21) Preparation of compound 18 (Scheme 4):
To a solution of 3 (43 mg, 0.12 mmol) in benzene (10 mL)
at reflux, was added dropwise a solution of Bu3SnH (51 mg,
0.18 mmol) and AIBN (30 mg, 0.18 mmol) in benzene (10
mL) over 1 h by using a syringe. The mixture was then
heated at reflux for 3 h. After evaporation of the solvent, the
residue was purified by chromatography on silica gel
(hexane–EtOAc, 2:1) to give 18 (27 mg, 87%); [α]D22 –77 (c
1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 6.96 (d, J =
8.0 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.72 (dd, J = 2.4, 8.0
Hz, 1 H), 3.78 (s, 3 H), 3.53 (s, 1 H), 2.96 (s, 2 H), 2.93 (s,
3 H), 2.48 (d, J = 17.6 Hz, 1 H), 2.30 (d, J = 19.2 Hz, 1 H),
2.04 (q, J = 6.8 Hz, 1 H), 1.38 (s, 3 H), 1.19 (d, J = 7.2 Hz,
3 H); 13C NMR (CDCl3, 100 MHz): δ = 169.0, 158.6, 145.3,
130.6, 123.7, 112.4, 111.5, 61.0, 55.3, 43.4, 36.9, 36.9, 34.2,
18
EtOAc, 10:1) to afford 5 (6.0 g, 76%) as yellow liquid; [α]D
–79.3 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 7.37–
7.33 (m, 2 H), 7.29–7.27 (m, 3 H), 7.19 (d, J = 8.4 Hz, 1 H),
7.11 (d, J = 2.8 Hz, 1 H), 6.82 (dd, J = 2.4, 8.4 Hz, 1 H),
5.37–5.31 (m, 1 H), 4.62–4.56 (m, 1 H), 4.24 (br s, 1 H),
3.77 (s, 3 H), 3.37 (dd, J = 6.8, 11.2 Hz, 1 H), 3.21 (dd, J =
3.6, 13.2 Hz, 1 H), 3.07–3.00 (m, 1 H), 2.90–2.86 (m, 3 H),
1.38 (d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ =
201.0, 177.6, 158.8, 136.3, 131.9, 129.3, 129.2, 128.8,
127.1, 124.9, 118.0, 113.5, 71.9, 68.6, 55.4, 42.7, 39.6, 36.7,
31.9, 10.8; HRMS (ESI): m/z [M + H]+ calcd for
C22H25BrNO3S2: 494.0454; found: 494.0463.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1349–1352

1352
Q. Chen et al.
LETTER
33.8, 24.1, 14.4; HRMS (ESI): m/z [M + H]+ calcd for
C16H22NO2: 260.1645; found: 260.1657.
(22) (–)-9-epi-metazocine (2b): [α]D17 +22.0 (c 0.5, CHCl3); 1H
NMR (CDCl3, 400 MHz): δ = 6.95 (d, J = 8.0 Hz, 1 H), 6.80
(d, J = 2.4 Hz, 1 H), 6.61 (dd, J = 2.4, 8.0 Hz, 1 H), 3.13 (d,
J = 17.6 Hz, 1 H), 2.92 (d, J = 5.6 Hz, 1 H), 2.67 (dd, J = 5.6,
17.6 Hz, 1 H), 2.44 (d, J = 6.8 Hz, 1 H), 2.36 (s, 3 H), 2.03
(d, J = 8.4 Hz, 2 H), 1.88 (q, J = 6.8 Hz, 1 H), 1.29 (s, 3 H),
1.26 (d, J = 7.2 Hz, 3 H), 1.10 (d, J = 9.6 Hz, 1 H); 13C NMR
(CDCl3, 100 MHz): δ = 154.1, 146.4, 129.1, 128.6, 113.0,
111.5, 60.1, 47.6, 43.0, 38.2, 34.9, 34.8, 27.3, 24.0, 15.0; IR:
3254, 2932, 2865, 1610, 1496, 1485, 1360, 769 cm–1;
HRMS (ESI): m/z [M + H]+ calcd for C15H22NO: 232.1696;
found: 232.1692.
O
O
O
NMe
NMe
NMe
H
AIBN,
Bu3SnH
Br
•
benzene,
reflux
MeO
MeO
MeO
18
3
Scheme 4
g
Synlett 2012, 23, 1349–1352
© Georg Thieme Verlag Stuttgart · New York

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