Total synthesis of (±)-desoxycodeine-D: A novel route to the morphine skeleton

Article abstract of DOI:10.1016/S0040-4039(99)02188-7

A novel approach towards the construction of the morphine skeleton was demonstrated by a total synthesis of (±)-desoxycodeine-D (11) from 5,6,7,8- tetrahydroisoquinoline and isovanillin. The key steps are two consecutive Pd- catalyzed cyclizations and a Stevens rearrangement for the formation of ring B. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02188-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 915–918
Total synthesis of (±)-desoxycodeine-D: a novel route to the
morphine skeleton
Jing-Ping Liou and Chen-Yu Cheng ∗
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, 1, Sec 1, Jen-Ai Road, Taipei,
Taiwan 10018
Received 3 September 1999; revised 1 November 1999; accepted 19 November 1999
Abstract
A novel approach towards the construction of the morphine skeleton was demonstrated by a total synthesis of
(±)-desoxycodeine-D (11) from 5,6,7,8-tetrahydroisoquinoline and isovanillin. The key steps are two consecutive
Pd-catalyzed cyclizations and a Stevens rearrangement for the formation of ring B. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: analgesics; alkaloids; palladium; palladium compounds; rearrangements.
Morphine is a potent analgesic alkaloid with a rigid pentacyclic (ABCNO) structure. A number of
total syntheses of morphine have been published since the first one achieved by Gates and Tschudi in
1952.1 However, a more practical and stereoselective synthetic route for morphine alkaloids remains an
attractive research goal for synthetic organic chemists.2 In a previous publication,3 we have demonstrated
an efficient synthesis of morphine ANO and ACNO fragments, namely spiro[benzofuran-3(2H),40-
piperidine] and octahydro-1H-benzofuro[3,2-e]isoquinoline, by intramolecular Heck reaction. We have
now developed a novel approach for the construction of ring B in morphine, based on a Pd-catalyzed
intramolecular N-benzylation followed by a Stevens rearrangement. The current strategy coupled with
our previous method for the construction of the ACNO ring system has provided us an efficient access to
the complete pentacyclic skeleton of morphine. Described here is a total synthesis of (±)-desoxycodeine-
D (11),4 which serves to exemplify the applicability of the above methodology.
∗
Corresponding author. Fax: 886-2-23512086; e-mail: cyc@ha.mc.ntu.edu.tw (C.-Y. Cheng)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02188-7
tetl 16116

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Scheme 1. Reagents and conditions: i. CH3I, CH2Cl2, room temp.; ii. NaBH4, MeOH, 0°C; iii. EtOOCCl, KHCO3,
ClCH2CH2Cl, reflux; iv. NaOH, MeOH, 0°C; v. 2-bromoisovanillin, DEAD, (n-C4H9)3P, THF.; vi. NaBH4, MeOH, 0°C; vii.
Pd(OAc)2, PPh3, Et3N, CH3CN, 120–130°C; viii. TBDMSCl, imidazole, THF; ix. (n-C4H9)4N+F−, THF, room temp.; x. NCS,
PPh3, THF, room temp.; xi. Pd(PPh3)4, Et3N, CH3CN, 120–130°C; xii. CH3I, CH2Cl2, room temp.; xiii. PhLi, ether, 0°C
As outlined in Scheme 1, the synthesis of 11 starts from readily available 5,6,7,8-
tetrahydroisoquinoline and isovanillin. Thus, 5-acetoxy-5,6,7,8-tetrahydroisoquinoline (1)5,6 derived
from 5,6,7,8-tetrahydroisoquinoline was treated with iodomethane, followed by NaBH4 reduction,
to give the octahydroisoquinoline 2.7 Compound 2 was treated with ethyl chloroformate followed
by hydrolysis of the acetate group to give carbamate 3. The condensation of compound 3 with
2-bromoisovanillin8 under Mitsunobu conditions9 provided compound 4, which was reduced with
NaBH4 to give the benzyl alcohol intermediate 5. The formation of the O-ring was achieved when
compound 5 was subjected to Heck reaction conditions, and the tetracyclic (ACNO) compound 610 was
obtained in 42% yield. The yield of the above intramolecular cyclization was significantly increased
via prior protection of the alcohol function in 5 as a silyl ether. Compound 6 was then converted to
the benzyl chloride 8 via treatment with N-chlorosuccinimide and triphenylphosphine. Our original
plan for the construction of ring B was to utilize the documented Pd-catalyzed cyclization of benzyl

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halides containing alkenes.11 However, when compound 8 was subjected to Heck reaction conditions
(Pd(PPh3)4, Et3N, CH3CN, 120°C), instead of giving the anticipated compound 12, an intramolecular
N-benzylation occurred and provided the tertiary amine 9.10 A likely mechanism for the formation of
compound 9 from 8 is given in Scheme 2. Prompted by literature reports12 of Stevens rearrangement of
quaternary tetrahydroisoquinoline alkaloids, compound 9 was first converted into the corresponding N-
methylammonium iodide 10, which was then treated with PhLi in ether. To our gratification, compound
10 underwent the anticipated Stevens rearrangement, and provided (±)-desoxycodeine-D (11) in 83%
yield.13
Scheme 2.
In summary, we have demonstrated a novel synthetic route to the morphine skeleton, starting from
5,6,7,8-tetrahydroisoquinoline and isovanillin. Notable features of the synthesis include an unexpected
Pd-catalyzed intramolecular N-benzylation and the efficient formation of ring B via a Stevens rearrange-
ment. Further work towards a total synthesis of (−)-morphine is currently underway in our laboratory.

918
Acknowledgements
This research was supported by the National Science Council of the R.O.C. under grant no. NSC
87-2113-M002-027.
References
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Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp. 357–369. (c) Szántay, G.;
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1
7. All compounds synthesized were characterized by H, 13C, IR, and mass spectrometric analysis. Chemical yields refer to
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10. Selected spectral and analytical data: 6: 1H NMR (200 MHz, CDCl3) δ 1.22 (t, J=7.0 Hz, 3H), 1.58 (m, 1H), 1.75 (m, 1H),
1.98–2.15 (m, 3H), 2.27 (m, 1H), 2.44–2.56 (m, 1H), 3.00–3.20 (m, 1H), 3.70–3.90 (m, 1H), 4.05–4.15 (m, 4H), 4.45–4.62
(m, 3H), 5.95 (m, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H); 13C NMR (50 MHz) δ 15.1, 21.6, 27.7, 35.1, 40.0,
48.4, 49.4, 56.2, 61.7, 62.3, 88.8, 110.0, 111.6, 122.9, 129.9, 130.9, 132.2, 133.6, 144.7, 148.8, 156.2; HRMS m/e calcd
1
for C20H25NO5+: 359.1733, found: 359.1732. 9: H NMR (400 MHz, CDCl3) δ 1.65–1.75 (m, 1H), 1.80–1.92 (m, 1H),
1.93–1.98 (m, 1H), 2.09–2.21 (m, 1H), 2.23–2.31 (m, 2H), 3.17 (m, 2H), 3.53 (d, J=17 Hz, 1H), 3.74 (d, J=17.1 Hz, 1H),
3.81 (s, 3H), 4.16 (d, J=17.4 Hz, 1H), 4.28 (d, J=17.4 Hz, 1H), 4.63 (m, 1H), 5.42 (m, 1H), 6.49 (d, J=8.2 Hz, 1H), 6.66 (d,
J=8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.6, 24.5, 37.4, 44.9, 48.6, 53.6, 56.5, 60.2, 87.5, 112.4, 118.2, 118.6, 129.5,
134.7, 138.7, 142.9, 146.1; HRMS m/e calcd for C17H19NO2+: 269.1389, found: 269.1395. 11: mp (HCl salt) 238–239°C
(lit.7 mp 234–235°C); 1H NMR (400 MHz, CDCl3) δ 1.32–1.36 (m, 1H), 1.81–1.91 (m, 2H), 1.99–2.10 (m, 3H), 2.45 (s,
3H), 2.52–2.65 (m, 3H), 3.28 (d, J=18.1 Hz, 1H), 3.57 (d, J=6.4 Hz, 1H), 3.83 (s, 3H), 4.73 (m, 1H), 5.66 (dd, J=6.2, 2.0 Hz,
1H), 6.59 (d, J=8.1 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0, 26.5, 27.8, 34.8, 41.8, 43.3, 46.2,
53.3, 56.4, 61.7, 90.1, 113.2, 118.0, 119.1, 127.3, 132.4, 137.0, 143.3, 143.5; HRMS m/e calcd for C18H21NO2+: 283.1573,
found: 283.1579.
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1998, 63, 1706–1708.