A concise formal synthesis of unnatural (+)-aphanorphine from (2S,4R)-4-hydroxyproline

Article abstract of DOI:10.1055/s-2006-956499

(-)-Aphanorphine methyl ether was synthesized in ten steps from commercially available (2S,4R)-4-hydroxyproline, featuring the C-2 configuration inversion of an intermediate amide and intramolecular Friedel-Crafts reaction. The present work constitutes a

Full text of DOI:10.1055/s-2006-956499

LETTER
161
A Concise Formal Synthesis of Unnatural (+)-Aphanorphine from (2S,4R)-4-
Hydroxyproline
C
oncise Formal
h
Synthesis of
i
U
nnat
q
ural (+)-Aph
i
anorph
a
ine ng Ma,a Hongbin Zhai*a,b
a
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, P. R. of China
b
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Road,
Beijing 100083, P. R. of China
Fax +86(21)64166128; E-mail: zhaih@mail.sioc.ac.cn
Received 19 September 2006
H
HO2C
N
Abstract: (–)-Aphanorphine methyl ether was synthesized in ten
steps from commercially available (2S,4R)-4-hydroxyproline,
featuring the C-2 configuration inversion of an intermediate amide
and intramolecular Friedel–Crafts reaction. The present work
constitutes a formal synthesis of unnatural (+)-aphanorphine.
OH
previous
current
work
work
2
Key words: aphanorphine, configuration inversion, intramolecular
Friedel–Crafts, marine alkaloid, synthesis
H
H
3
3
A
A
B
N
Me
12
B
8
N Me
8
12
HO
C
HO
C
1
1
Me
Me
(–)-Aphanorphine [(–)-1, Scheme 1], a novel marine
alkaloid isolated from the freshwater blue-green alga
Aphanizomenon flos-aquae 18 years ago,1 has received
tremendous attention from the scientific community2
owing to its unique structure containing tricyclic 3-benz-
azepine framework that resembles benzomorphane3,4
analgesics such as pentazocine. The majority of the
known syntheses of aphanorphine started from either
1,3-disubstituted or 1,2,4-trisubstituted benzenes, except
the two reports from this laboratory describing the use of
1,4-disubstituted benzenes such as 4-methoxyphenyl-
acetaldehyde2r and 4-bromoanisole.2s Note that our
previous syntheses2r,s featured the formation of ring B at
the final stage by Friedel–Crafts alkylative cyclization,
while ring B was constructed prior to ring C in most other
strategies. Moreover, chiral pools, such as amino acids,5a
carbohydrates,5b and terpenes,5c have found wide applica-
tions in the total synthesis of natural products. We
previously reported an efficacious asymmetric synthesis
of (–)-aphanorphine commencing from (2S,4R)-4-hy-
droxyproline (2), a chiron.2s Recently we were engaged in
constructing (+)-aphanorphine [(+)-1, the enantiomer of
the natural form] by taking advantage of the same chiron,
as a part of our long-term marine natural product program.
The current research should be of great significance in
terms of diversity-oriented synthesis.
(–)-1: (–)-aphanorphine
(+)-1: (+)-aphanorphine
Scheme 1
selective N-benzoylation (BzCl, NaOH, Et2O, 0 °C and
then r.t., 24 h, 76%) of (2S,4R)-4-hydroxyproline (2).6b
Treating7 a mixture of bicycle 4 and Me(MeO)NH·HCl
(120 mol%) in tetrahydrofuran with p-methoxyphenyl-
magnesium bromide (370 mol%) at –78 °C furnished g-
hydroxy-a-amido ketone 6 (41%) along with diamide in-
termediate 5 (55%). Since additional 6 could be formed
from the Weinreb amide 5 in moderate yield (64%) by re-
acting with excess p-methoxyphenylmagnesium bromide
(–35 °C and then r.t.), phenyl ketone 6 could be obtained
from lactone 4 in 76% overall yield. For comparison,
direct addition of p-methoxyphenylmagnesium bromide
(130 mol%) to lactone 4 at –78 °C [i.e., without the
involvement of Me(MeO)NH·HCl] gave 6 in only 44%
yield.
Neither Wolff–Kishner/Huang–Minlon nor Clemensen
reaction seemed likely to provide a feasible and clean av-
enue to deoxygenation product 8 from 6. Thus alcohol 88
was obtained by benzylic deoxygenation of ketone 6 im-
plemented in two steps consisting of: (i) 1,3-dithiolane
formation (HSCH2CH2SH, BF3·OEt2, CH2Cl2, reflux,
80%),9 and (ii) desulfurization via a free-radical reaction
(n-Bu3SnH, AIBN, MePh, 90 °C; 8: 73% + 7: 15%; the
yield of 8 was 86% based on the recovered starting
material).10 Under typical Swern conditions, secondary
alcohol 8 was oxidized to afford pyrrolidinone 9 in
excellent yield (98%). Nucleophilic addition11 of methyl-
lithium to ketone 9 (from the less hindered face) in tetra-
hydrofuran at –78 °C produced tertiary alcohol 10 in 39%
yield (or 80% yield based on the recovered starting
material) and in excellent stereoselectivity along with the
As delineated in Scheme 2, the synthesis of unnatural (+)-
aphanorphine [(+)-1] benefited from the successful C-2
configuration inversion of amide 3 to generate lactone 4
by heating 3 in acetic anhydride (90 °C, 5 h, 90%) accord-
ing to an efficient protocol developed recently by Rosa,6a
while amido acid 3 was easily accessible from chemo-
SYNLETT 2007, No. 1, pp 0161–0163
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-956499; Art ID: W19506ST
© Georg Thieme Verlag Stuttgart · New York

162
Z. Ma, H. Zhai
LETTER
Bz
Bz
Bz
H
O
O
Me(MeO)NH·HCl
H
BzCl
H
O
O
Bz
Me
HO2C
HO2C
PMPMgBr
NaOH
Ac2O
N
N
N
N
N
N
PMP
+
55% (5) + 41% (6)
76%
90%
ref. 6a
OMe
ref. 6b
OH
OH
OH
OH
6
3
4
5
2
PMPMgBr
64%
Bz
N
Bz
Bz
Bz
N
S
H
H
nBu3SnH
AIBN
H
S
(CH2SH)2
BF3·OEt2
N
N
Swern
98%
MeLi
80%
PMP
PMP
PMP
6
H
80%
86%
MeO
OH
OH
OH
O
Me
7
8
9
10
NaOH
CH2O
NaBH3CN
H
H
N
H
3
AlCl3
76%
ref. 2a
B
N
Bz
Me
N
Me
12
8
MeO
MeO
HO
71%
(2 steps)
1
Me
Me
12
Me
(+)-1: (+)-aphanorphine
11
Scheme 2 Synthesis of (+)-aphanorphine (Bz = benzoyl; PMP = p-methoxyphenyl)
1
recovered 9 (52%). The H NMR of 10 showed two sets
of peaks for some protons as a result of the presence of
two rotamers in a ratio of 5:1. Reduction of 10 with
lithium aluminum hydride in refluxing tetrahydrofuran
gave the corresponding benzylamine that displayed only
Acknowledgment
We thank NSFC, STCSM (‘Post-Venus’ Program, No.
05QMH1416), and GCCP of ECNU for financial support.
1
References and Notes
one set of resonance signals in the H NMR spectrum.
Aluminum chloride promoted intramolecular Friedel–
Crafts reaction2r,s of alcohols 10 took place in dichloro-
methane at room temperature to generate the desired
alkylative cyclization product 1112 as a colorless oil
(76%). Thus the tricyclic framework of aphanorphine was
constructed in only six steps from lactone 4. Hydrolysis of
11 with 50% aqueous sodium hydroxide solution in
refluxing ethanol,13 followed by N-methylation with
formalin and sodium cyanoborohydride2r in methanol at
room temperature, afforded (–)-aphanorphine methyl
ether 1214 in 71% overall yield for the two steps from 11.
The [a]D28 of 12 was found to be –10.38 (c = 1.36, CHCl3)
{lit.2a [a]D27 –7.40 (c = 0.35, CHCl3); lit.2v [a]D30 –9.72 (c
(1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381.
(2) (a) Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1989, 1591. (b) Takano, S.;
Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1990, 290. (c) Honda, T.;
Yamamoto, A.; Cui, Y. S.; Tsubuki, M. J. Chem. Soc.,
Perkin Trans. 1 1992, 531. (d) Hume, A. N.; Henry, S. S.;
Meyers, A. I. J. Org. Chem. 1995, 60, 1265. (e) Meyers, A.
I.; Schmidt, W.; Santiago, B. Heterocycles 1995, 40, 525.
(f) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6,
893. (g) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51,
12211. (h) Node, M.; Imazato, H.; Kurosaki, R.; Kawano,
Y.; Inoue, T.; Nishide, K. Heterocycles 1996, 42, 811.
(i) Shiotani, S.; Okada, H.; Nakamata, K.; Yamamoto, T.;
Sekino, F. Heterocycles 1996, 43, 1031. (j) Fadel, A.;
Arzel, P. Tetrahedron: Asymmetry 1997, 8, 283. (k) Fadel,
A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371.
(l) Shimizu, M.; Kamikubo, T.; Ogasawara, K. Heterocycles
1997, 46, 21. (m) Tamura, O.; Yangimachi, T.; Kobayashi,
T.; Ishibashi, H. Org. Lett. 2001, 3, 2427. (n) Fuchs, J. R.;
Funk, R. L. Org. Lett. 2001, 3, 3923. (o) Tanaka, K.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42,
1049. (p) El Azab, A. S.; Taniguchi, T.; Ogasawara, K.
Heterocycles 2002, 56, 39. (q) Kita, Y.; Futamura, J.; Ohba,
Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. J. Org. Chem.
2003, 68, 5917. (r) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org.
Chem. 2003, 68, 8268. (s) Hu, H.; Zhai, H. Synlett 2003,
2129. (t) Taylor, S. K.; Ivanovic, M.; Simons, L. J.; Davis,
M. M. Tetrahedron: Asymmetry 2003, 14, 743. (u) Tamura,
O.; Yanagimachi, T.; Ishibashi, H. Tetrahedron: Asymmetry
2003, 14, 3033. (v) Katoh, M.; Inoue, H.; Suzuki, A.;
Honda, T. Synlett 2005, 2820. (w) Bower, J. F.; Szeto, P.;
Gallagher, T. Chem. Commun. 2005, 5793.
21
= 0.67, CHCl3); lit.2i (ent-12) [a]D +10.4 (c = 1.24,
CHCl3)}. Other spectroscopic data of 12 were also in
agreement with those disclosed in the literature.2i
In summary, (–)-aphanorphine methyl ether 12 has been
synthesized in eight steps from the know lactone 4 or in
ten steps from (2S,4R)-4-hydroxyproline (2), featuring the
C-2 configuration inversion of amide 3 and intramolecu-
lar Friedel–Crafts reaction. The present work constitutes a
formal synthesis of unnatural (+)-aphanorphine [(+)-1],
which is obtainable from 12 in one step, i.e., by 8-O-de-
methylation.2a So far we have succeeded in synthesizing
both natural (–)-aphanorphine2s [(–)-1] and unnatural (+)-
aphanorphine [(+)-1] from the same commercially avail-
able amino acid, (2S,4R)-4-hydroxyproline (2).
Synlett 2007, No. 1, 161–163 © Thieme Stuttgart · New York

LETTER
Concise Formal Synthesis of Unnatural (+)-Aphanorphine
163
(3) Shiotani, S.; Kometani, T.; Mitsuhashi, K.; Nozawa, T.;
Kurobe, A.; Fitsukaichi, O. J. Med. Chem. 1976, 19, 803.
(4) Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1.
(5) (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis–
Construction of Chiral Molecules Using Amino Acids; John
Wiley & Sons: New York, 1987. (b) Hanessian, S. Total
Synthesis of Natural Products: The ‘Chiron’ Approach;
Pergamon: Oxford, 1983. (c) Ho, T.-L. Enantioselective
Synthesis: Natural Products from Chiral Terpenes; John
Wiley & Sons: New York, 1992.
(6) (a) Croce, P. D.; Rosa, C. L. Tetrahedron: Asymmetry 2002,
13, 197. (b) Portoghese, P. S.; Turcotte, J. G. Tetrahedron
1971, 27, 961.
(7) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995,
36, 5461.
(12) 11: colorless oil; [a]28D +76.2 (c = 1.53, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 1.48 (s, 2 H), 1.59 (s, 1 H), 1.90–2.10
(m, 2 H), 2.81 (s, 0.67 H), 2.98 (dd, J = 2.4, 17.1 Hz, 0.67
H), 3.30–3.54 (m, 2.66 H), 3.76 (s, 2 H), 3.80 (s, 1 H), 4.32–
4.37 (m, 0.33 H), 4.85–4.91 (m, 0.67 H), 6.70–6.80 (m, 1.65
H), 6.86 (d, J = 2.4 Hz, 0.35 H), 6.97 (d, J = 8.4 Hz, 0.35 H),
7.07 (d, J = 8.4 Hz, 0.65 H), 7.30–7.37 (m, 3.25 H), 7.41–
7.48 (m, 1.75 H). 13C NMR (75 MHz, CDCl3): d = 20.6, 20.8,
34.8, 37.3, 40.0, 41.0, 41.9, 42.2, 54.7, 54.9, 55.0, 56.4, 61.5,
64.1, 109.4, 109.5, 111.4, 111.5, 124.0, 125.3, 126.1, 126.5,
127.8, 128.1, 129.1, 129.2, 129.9, 130.2, 136.7, 137.2,
144.7, 145.6, 157.5, 157.9, 168.7, 169.8. MS (ESI): m/z =
308 (100) [M + H], 330 (6) [M + Na], 362 (19) [M + MeOH
+ Na]. HRMS (EI): m/z calcd for C20H21NO2: 307.1572;
found: 307.1570.
(13) Albaugh, P. A.; Marshall, L.; Gregory, J.; White, G.;
Hutchison, A.; Ross, P. C.; Gallagher, D. W.; Tallman, J. F.;
Crago, M.; Cassella, J. V. J. Med. Chem. 2002, 45, 5043.
(8) 8: colorless solid; mp 70–72 °C; [a]26D +95.7 (c = 0.91,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.70–2.20 (m, 2
H), 2.55–3.05 (m, 1.5 H), 3.08–3.24 (m, 1.5 H), 3.50–3.60
(m, 1 H), 3.78 (s, 3 H), 4.00–4.30 (m, 1 H), 4.40–4.60 (m, 1
H), 6.55–6.70 (m, 1 H), 6.87 (d, J = 8.1 Hz, 1.5 H), 7.20 (d,
J = 7.8 Hz, 1.5 H), 7.35–7.50 (m, 5 H). 13C NMR (75 MHz
CDCl3): d = 37.0, 37.8, 55.1, 57.0, 57.6, 69.2, 113.6, 126.2,
127.1, 128.1, 130.1, 130.6, 136.4, 158.0, 170.0. MS (ESI):
m/z = 312 (100) [M + H], 333 (73) [M + Na – H], 366 (15)
[M + MeOH + Na], 645 (21) [2 × M + Na]. HRMS (EI):
m/z calcd for C19H21NO3: 311.1521; found: 311.1518.
(9) Huffman, J. W.; Yu, S. Bioorg. Med. Chem. 1998, 6, 2281.
(10) Mäkelä, T.; Matikainen, J.; Wähälä, K.; Hase, T.
Tetrahedron 2000, 56, 1873.
(14) (–)-Aphanorphine methyl ether 12: colorless oil; [a]28
–
D
10.38 (c = 1.36, CHCl3). 1H NMR (300 MHz, CDCl3): d =
1.46 (s, 3 H, CH3), 1.83 (d, J = 11.1 Hz, 1 H, 0.5 × CH2), 2.01
(dd, J = 6.0, 11.1 Hz, 1 H, 0.5 × CH2), 2.46 (s, 3 H, NCH3),
2.74 (d, J = 6.0 Hz, 1 H, 0.5 × CH2), 2.81 (s, 1 H, 0.5 × CH2),
2.84 (s, 1 H, 0.5 × CH2), 3.02 (d, J = 16.8 Hz, 1 H, 0.5 ×
CH2), 3.37–3.40 (m, 1 H, NCH), 3.75 (s, 3 H, OCH3), 6.67
(dd, J = 2.1, 8.4 Hz, 1 H, CH), 6.77 (s, 1 H, CH), 7.00 (d,
J = 8.4 Hz, 1 H, CH). 13C NMR (75 MHz, CDCl3): d = 21.2,
35.3, 41.3, 41.4, 42.9, 54.9, 61.1, 71.0, 109.1, 110.8, 125.6,
129.9, 147.6, 157.5. MS (EI): m/z = 218 (18) [M + H], 217
(48) [M], 202 (100), 159 (64), 144 (28), 115 (38). HRMS
(EI): m/z calcd for C14H19NO: 217.1467; found: 217.1460.
(11) Barton, D. H. R.; Bielska, M. T.; Cardoso, J. M.; Cussans, N.
J.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1981, 1840.
Synlett 2007, No. 1, 161–163 © Thieme Stuttgart · New York

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