Enantiocontrolled synthesis of (-)-9-epi-pentazocine and (-)-aphanorphine

Article abstract of DOI:10.1021/ol800737d

(Chemical Equation Presented) We have developed novel asymmetric routes to (-)-9-epi-pentazocine and (-)-aphanorphine from a D-tyrosine derivative. The tricyclic frameworks of (-)-9-epi-pentazocine and (-)-aphanorphine were assembled stereoselectively via intramolecular Friedel-Crafts reaction of the corresponding bicyclic precursors, generated with titanium-promoted enyne cyclization and indium-initiated atom-transfer radical cyclization, respectively.

Full text of DOI:10.1021/ol800737d

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2457-2460
Enantiocontrolled Synthesis of
(-)-9-epi-Pentazocine and
(-)-Aphanorphine
Xiaobao Yang,†,‡ Hongbin Zhai,*,† and Zhong Li*,‡
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China 200032, and School of
Pharmacy, East China UniVersity of Science and Technology, Shanghai, China 200237
zhaih@mail.sioc.ac.cn
Received April 2, 2008
ABSTRACT
We have developed novel asymmetric routes to (-)-9-epi-pentazocine and (-)-aphanorphine from a D-tyrosine derivative. The tricyclic frameworks
of (-)-9-epi-pentazocine and (-)-aphanorphine were assembled stereoselectively via intramolecular Friedel-Crafts reaction of the corresponding
bicyclic precursors, generated with titanium-promoted enyne cyclization and indium-initiated atom-transfer radical cyclization, respectively.
(-)-Pentazocine (1a), featuring a quaternary carbon and three
consecutive stereocenters, was first synthesized by Archer
and co-workers as a strong nonnarcotic analgesic without
significant addiction liability.1 Remarkedly, for subcutane-
ously injected 2,5-dimethyl-2′-hydroxy-9-propyl-6,7-benzo-
morphans, the 9ꢀ-propyl levo isomer was considerably more
analgesically potent than the 9R- counterpart; the latter has
the same configuration at C-9 as in 1a and was analgesically
equipotent with morphine.1d A similar trend was observed
with (-)-9-epi-pentazocine (1b, the diastereomer of 1a) when
compared to 1a itself.1e (-)-Aphanorphine (2), a 3-benza-
zepine alkaloid with a quaternary benzylic stereocenter
isolated from the freshwater blue-green alga Aphanizomenon
flos-aquae,2 bears close structural similarity to both (-)-
pentazocine and some natural analgesics such as morphine
and eptazocine. Both pentazocine and aphanorphine have
emerged as attractive target molecules for synthetic chemists
due to their prominent or potential pharmacological
activities.1e,3,4 Herein we wish to report an efficient enan-
tiocontrolled approach to constructing (-)-9-epi-pentazocine
(1b) and (-)-aphanorphine (2) from commercially available
chiral starting materials.
The retrosynthetic analysis is outlined in Scheme 1. The
frameworks of 1b and 2 may be accessed stereoselectively
† Shanghai Institute of Organic Chemistry.
(3) For synthesis of pentazocine, see: (a) Kametani, T.; Kigasawa, K.;
Hiiragi, M.; Hayasaka, T.; Wagatsuma, N.; Wakisaka, K. J. Heterocyclic
Chem. 1969, 6, 43. (b) Albertson, N. F.; Wetterau, W. F. J. Med. Chem.
1970, 13, 302. (c) Kametani, T.; Kigasawa, K.; Hayasaka, M.; Wakisaka,
K.; Satoh, F.; Aoyama, T.; Ishimaru, H. J. Heterocyclic Chem. 1971, 8,
769. (d) Kametani, T.; Huang, S. P.; Ihara, M.; Fukumoto, K. J. Org. Chem.
1976, 41, 2545. (e) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am.
Chem. Soc. 1985, 107, 7974. (f) Genisson, Y.; Marazano, C.; Das, B. C. J.
Org. Chem. 1993, 58, 2052. (g) Trost, B. M.; Tang, W. J. Am. Chem. Soc.
‡ East China University of Science and Technology.
(1) (a) Clarke, E. G. C. Nature 1959, 184, 451. (b) Archer, S.; Albertson,
N. F.; Harris, L. S.; Pierson, A. K.; Bird, J. G. J. Med. Chem. 1964, 7, 123.
(c) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wagatsuma, N. Heterocycles
1974, 2, 79. (d) Rice, K. C.; Jacobson, A. E. J. Med. Chem. 1976, 19, 430.
(e) Tullar, B. F.; Harris, L. S.; Perry, R. L.; Pierson, A. K.; Soria, A. E.;
Wetterau, W. F.; Albertson, N. F. J. Med. Chem. 1967, 10, 383.
(2) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J. Tetrahe-
dron Lett. 1988, 29, 4381.
2003, 125, 8744
.
10.1021/ol800737d CCC: $40.75
Published on Web 05/21/2008
2008 American Chemical Society

cine (1b) commenced from O-Me-D-tyrosine methyl ester
hydrochloride salt5 (7), converted from D-tyrosine in excellent
overall yield (92%) in four simple operations. Nosylation
of 7 (NsCl, TEA), Mitsunobu alkylation (3-butyn-1-ol, PPh3,
DIAD) and denosylation (PhSH, K2CO3) followed by treat-
ment with HCl gas in ether afforded 10 (in 88% overall yield
from 7) as the HCl salt. Selective monobenzylation (BnBr
(1.05 equiv), Bu4NI, K2CO3) and reduction of the ester
functionality with LiAlH4 led to benzylamino alcohol 12,
which was further converted to enyne 4 after a reaction
sequence including Swern oxidation, Wittig olefination
(MePPh3I, KHMDS), and trimethylsilylation of the terminal
alkyne (BuLi, TMSCl).
Scheme 1
.
Retrosynthetic Analyses of (-)-9-epi-Pentazocine
(1b) and (-)-Aphanorphine (2)
With the key intermediate 4 in hand, the organozirconium
and organotitanium-mediated reductive enyne cyclizations
were extensively investigated.6 Upon treatment6b with 2
equiv of Cp2Zr(nBu)2, enyne 4 remained essentially unre-
acted. When the amount of Cp2Zr(nBu)2 was increased to 5
equiv, only a small amount of the desired product was
isolated at the expense of complete consumption of the
starting material. However, the reaction presented a striking
contrast when an organotitanium species, iPr2Ti(OiPr)2,6e was
employed as a promoter. Approximately half of the substrate
underwent the expected cyclization in the presence of 2 equiv
i
of Pr2Ti(OiPr)2. The conversion rate was greatly improved
when 3 equiv or more of the titanium species was included
in the reaction mixture. To our delight, alkene 3 was
stereoselectively obtained as a reductive cyclization product
in 93% yield by subjecting enyne 4 to 4.4 equiv of
iPr2Ti(OiPr)2 in ether at -78 °C for 10 min and then at
-50 °C for 3 h. In addition, our experiments also confirmed
that protecting the terminal alkyne with a silyl group was
necessary6c because the relatively acidic sp-CH would
otherwise interfere with the cyclization. It is worthy of note
that the presence of sulfonamide functionalities in the
substrates was incompatible with the reductive cyclization.
An analogue of enyne 4, in which the benzyl on the nitrogen
was replaced with a tosyl, failed the cyclization. Essentially
no cyclization took place when the Ts-substituted enyne was
exposed to Cp2ZrCl2/BuLi6a,b or Cp2ZrCl2/HgCl2/Mg,6d
although alkynyl desilylation was observed in some cases.
Even though in one case this tosyl analogue cyclized when
treated with Ti(OiPr)4/iPrMgCl,6e the diastereoselectivity was
too low to be useful. Intramolecular Friedel-Crafts reactions
have been applied successfully to the construction of
alkaloids such as aphanorphine.4n,q,v,w Reaction of silylalkene
3 with AlCl3 (2.5-10 equiv) in CH2Cl2 at rt for a period
from 10 min to 12 h resulted in a desilylated terminal alkene
and the unreacted starting material; reaction with MeSO3H
in CH2Cl2 at rt for 12 h only led to complete desilylation.
via intramolecular Friedel-Crafts reaction of bicyclic pre-
cursors 3 and 5, respectively. The formation of 3 and 5 may,
in turn, be accomplished using titanium-promoted enyne
cyclization of 4 and indium-initiated atom-transfer radical
cyclization of 6, respectively. The precursors 4 and 6 may
both be generated efficiently from D-tyrosine as a chiral pool.
As shown in Scheme 2, the assembly of (-)-9-epi-pentazo-
(4) For synthesis of (-)-aphanorphine, see: (a) Takano, S.; Inomata,
K.; Sato, T.; Takahashi, M.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
1990, 290. (b) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem.
1995, 60, 1265. (c) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211.
(d) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6, 893. (e)
Meyers, A. I.; Schmidt, W.; Santiago, B. Heterocycles 1995, 40, 525. (f)
Node, M.; Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide, K.;
Fuji, K. Heterocycles 1996, 42, 811. (g) Shiotani, S.; Okada, H.; Nakamata,
K.; Yamamoto, T.; Sekino, F. Heterocycles 1996, 43, 1031. (h) Shimizu,
M.; Kamikubo, T.; Ogasawara, K. Heterocycles 1997, 46, 21. (i) Fadel,
A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371. (j) Tamura, O.;
Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427.
(k) Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42,
1049. (l) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Heterocycles 2002,
56, 39. (m) Tamura, O.; Yanagimachi, T.; Ishibashi, H. Tetrahedron:
Asymmetry 2003, 14, 3033. (n) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org.
Chem. 2003, 68, 8268. (o) Taylor, S. K.; Ivanovic, M.; Simons, L. J.; Davis,
M. M. Tetrahedron: Asymmetry 2003, 14, 743. (p) Kita, Y.; Futamura, J.;
Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. J. Org. Chem. 2003, 68,
5917. (q) Hu, H.; Zhai, H. Synlett 2003, 2129. (r) Bower, J. F.; Szeto, P.;
Gallagher, T. Chem. Commun. 2005, 5793. (s) Katoh, M.; Inoue, H.; Suzuki,
A.; Honda, T. Synlett 2005, 2820. (t) Li, M.; Zhou, P.; Roth, H. F. Synthesis
2007, 55. (u) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem.
2007, 5, 143. (v) Ma, Z.; Zhai, H. Synlett 2007, 161. (w) Ma, Z.; Hu, H.;
Xiong, W.; Zhai, H. Tetrahedron 2007, 63, 7523. (x) Grainger, R. S.; Welsh,
E. J. Angew. Chem., Int. Ed. 2007, 46, 5377. For synthesis of (()-
apanorphine, see: (y) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M.
J. Chem. Soc., Perkin Trans. 1 1992, 531. (z) Fuchs, J. R.; Funk, R. L.
Org. Lett. 2001, 3, 3923. For synthesis of (+)-apanorphine, see: (aa) Takano,
S.; Inomata, K.; Sato, T.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
1989, 1591.
(5) For synthesis of O-Me-D-tyrosine methyl ester hydrochloride salt
(7), see: Hulme, A. N.; Rosser, E. M. Org. Lett. 2002, 4, 265.
(6) (a) Kemp, M. I.; Whitby, R. J.; Coote, S. J. Synthesis 1998, 557. (b)
Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421.
(c) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J. Am.
Chem. Soc. 1988, 110, 7128. (d) Negishi, E.; Holmes, S. J.; Tour, J. M.;
Miller, J. A. J. Am. Chem. Soc. 1985, 107, 2568. (e) Urabe, H.;
Sato, F. Tetrahedron Lett. 1998, 39, 7329. (f) Urabe, H.; Suzuki, K.; Sato,
F. J. Am. Chem. Soc. 1997, 119, 10014. (g) Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH Verlag: Weinheim, Germany,
2002.
2458
Org. Lett., Vol. 10, No. 12, 2008

Scheme 2. Asymmetric Total Synthesis of (-)-9-epi-Pentazocine (1b)
Nevertheless, heating 3 in hydrobromic acid (48%) at reflux
for 10 h provided 14 in excellent yield (98%). This
transformation involved a series of reactions including
alkenyl desilylation, Friedel-Crafts alkylative cyclization
onto the phenyl ring with excellent stereocontrol, and
cleavage of the ether linkage. Finally, catalytic hydrogenoly-
sis of 14 under 1 atm of H2 in HCl (2.5 M)-EtOAc-EtOH
(1:5:5) in the presence of 10% Pd/C followed by prenylation
afforded (-)-9-epi-pentazocine7 (1b) in 77% overall
yield.
The formal synthesis of (-)-aphanorphine is described in
Scheme 3. Tosylation and propargylation of 7 provided
tertiary sulfonamide 16 in 93% yield over the two steps.
Reduction of the ester group with LiAlH4 led to the formation
of primary alcohol 17, which, after treatment with I2, PPh3,
and imidazole, was converted to 6, a compound suitable for
indium-initiated 5-exo atom-transfer radical cyclization.8
Indeed, reaction of 6 with In (2 equiv) and I2 (1 equiv) in
DMF for 3 days resulted exclusively in product 5 in 83%
yield. Both deiodinated alkene 5 and the corresponding
iodoalkenes (Z- and E-)8 were isolated if the reaction time
was shorter or if methanol was used as the solvent.
Analogous to the case of (-)-9-epi-pentazocine, the forma-
tion of ring B was achieved by a Friedel-Crafts alkylative
cyclization onto the phenyl ring. Under the reaction
conditions such as RuCl3/AgOTf/ClCH2CH2Cl/rt, MeSO3H/
CH2Cl2/rt, MeSO3H/ClCH2CH2Cl/80 °C, and polyphos-
phoric acid (PPA)/80-90 °C, alkene 5 cyclized to provide
tricycle 184n in 0-41% yields. Finally, exposure of 5 to
AlCl3 in CH2Cl2 at rt effected the anticipated intramo-
lecular Friedel-Crafts reaction and led to tricycle 189 in
1
60% yield. The H and 13C NMR spectroscopic data of
18 were in agreement with those reported in the
literature.4n Because it has been known that 18 can be
converted into 2 in three steps,4n this work constitutes a
new formal asymmetric synthesis of (-)-aphanorphine (2).
(7) 1b: mp 59-60 °C; [R]24 -120.3 (c 0.85, CHCl3); ee ) 98.5%
D
[Chiralpak OD column (250 × 4.6 mm), UV detector 220 nm,
eluent hexanes/2-propanol/diethylamine (95:5:0.2), flow rate 0.7 mL/
min].
(9) 18: mp 136-138 °C; lit.4n mp 137-138 °C; [R]25 -16.9 (c 0.89,
CHCl3); lit.4n [R]20 -13.4 (c 0.97, CHCl3); lit.4q [R]D D -14.3 (c 0.93,
20
(8) Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.;
Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417.
D
CHCl3).
Org. Lett., Vol. 10, No. 12, 2008
2459

Scheme 3. Asymmetric Formal Synthesis of (-)-Aphanorphine (2)
In summary, we have developed efficient asymmetric
routes to the synthesis of (-)-9-epi-pentazocine and (-)-
aphanorphine starting from O-Me-D-tyrosine methyl ester
hydrochloride salt, a known derivative of D-tyrosine. The
tricyclic frameworks of (-)-9-epi-pentazocine and (-)-
aphanorphine were assembled stereoselectively via intramo-
lecular Friedel-Crafts reaction of the corresponding bicyclic
precursors, generated with titanium-promoted enyne cycliza-
tion and indium-initiated atom-transfer radical cyclization,
respectively.
Acknowledgment. Financial support was provided by the
grants from NSFC (90713007; 20772141; 20625204;
20632030) and MOST_863 (2006AA09Z405).
Supporting Information Available: Experimental pro-
1
cedures, analytical data, and copies of H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800737D
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Org. Lett., Vol. 10, No. 12, 2008