Selective opening of ring C in the morphine skeleton by an unexpected cleavage of the C5-C6 bond in cycloadducts of thebaine and acyl nitroso compounds

Article abstract of DOI:10.1021/jo052016j

Acyl nitroso cycloadducts of the alkaloid thebaine undergo an unexpected cleavage of the C5-C6 bond when treated with 2 equiv of samarium(II) iodide in THF to give novel hexahydrobenzazocine products. A proposed mechanism for the transformation involves r

Full text of DOI:10.1021/jo052016j

Selective Opening of Ring C in the Morphine
Skeleton by an Unexpected Cleavage of the
C5-C6 Bond in Cycloadducts of Thebaine and
Acyl Nitroso Compounds
Gary N. Sheldrake* and Nicolas Soissons
School of Chemistry and Chemical Engineering, DaVid Keir
Building, Queen’s UniVersity of Belfast, Belfast BT9 5AG, U.K.
FIGURE 1. Morphine with conventional ring labeling.
g.sheldrake@qub.ac.uk
the 5O-,14N-oxazine products 3 shown in Scheme 2. As
expected, adducts of this type gave 14â-hydroxyamino substi-
tuted codeinones 4 under acid or base hydrolysis3 or 14â-amino
codeinones 5 with catalytic hydrogenation4 (Scheme 2).
In this Note, we report that reduction of adducts such as 3
with 2 equiv of the single-electron reducing agent samarium-
(II) iodide follows a different and unexpected pathway resulting
in cleavage of the C5-C6 bond.
ReceiVed September 26, 2005
A series of acyl nitroso dienophiles 7a-f were generated in
situ by the oxidation of the corresponding hydroxamic acids5
6a-f with benzyltrimethylammonium periodate6 in the presence
of thebaine 1 as diene to give the adducts 8a-f in good to
excellent yields (Table 1). In each case, the only observed
TABLE 1. Yields of Thebaine Acyl Nitroso Diels-Alder Adducts 8
and Corresponding SmI2 Reduction Products 9
entry
adduct
yield (%)
product
yield (%)
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
71
61
31
38
90
95
9a
9b
9c
9d
9e
9f
77
69
55
41
65
0a
Acyl nitroso cycloadducts of the alkaloid thebaine undergo
an unexpected cleavage of the C5-C6 bond when treated
with 2 equiv of samarium(II) iodide in THF to give novel
hexahydrobenzazocine products. A proposed mechanism for
the transformation involves rearrangement of the initial
radical anion.
a Complex mixture of products obtained, none of which could be
identified as 9f.
diastereoisomer was the 6âO-,14âN-adduct shown. Treatment
of these adducts with two molar equivalents of samarium(II)
iodide in THF7 at 0 °C did not give the expected codeinones,
but instead the major product in each case (except for 8f) was
Few areas of alkaloid chemistry have been studied as widely
as the morphine skeleton in the search for more effective
analgesics with fewer adverse side effects. In the huge body of
reported work on the structural features of the morphine skeleton
required for activity, hundreds of compounds have been prepared
with one or more of the five rings (see Figure 1) systematically
removed or modified, but very few examples have been reported
in which only ring C is missing.
One successful route into the generation of novel morphine-
like compounds has been via Diels-Alder cycloadditions of
dienophiles with the alkaloid thebaine 1. It has been shown that
â-functionalization of the C14 position of thebaine can lead to
compounds with greatly enhanced analgesic properties, for
example, the oripavines 2 derived from the Diels-Alder reaction
of thebaine with methyl vinyl ketone1 (Scheme 1).
(2) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun. 1973,
704-705.
(3) (a) Kirby, G. W.; McLean, D. J. Chem. Soc., Perkin Trans. 1 1985,
1443-1446. (b) Kirby, G. W.; Sweeney, J. G. J. Chem. Soc., Perkin Trans.
1 1981, 3250-3254. (c) Kirby, G. W.; McGuigan, H.; Mackinnon, J. W.
M.; McLean, D. J.; Sharma, R. P. J. Chem. Soc., Perkin Trans. 1 1985,
1437-1452. (d) Kirby, G. W.; Bladon, C. J. Chem Soc., Chem Commun.
1982, 1402-1404. (e) Kirby, G. W.; Gourlay, R. I. J. Chem. Res., Miniprint
1997, 1001-1020. (f) Schwab, L. S. J. Med. Chem. 1980, 698-702.
(4) (a) Horsewood, P.; Kirby, G. W. J. Chem. Soc., Perkin Trans. 1 1980,
1587-1591. (b) Sebastian, A.; Bidack, J. M.; Jiang, Q.; Deecher, D.; Teitler,
M. J. Med. Chem. 1993, 3154-3160.
(5) Benzohydroxamic acid 6a was purchased from Aldrich; the other
hydroxamic acids were prepared by standard methods from the correspond-
ing carboxylic acids (Defoin, A.; Pires, J.; Streith, J. HelV. Chim. Acta 1991,
74, 1653-1670) or from carboxylate esters (Liguori, A.; Sindona, G.;
Uccella, N. Gazz. Chim. Ital. 1986, 116, 377-380.
(6) Dang, H.-S.; Davies, A. G. J. Chem. Soc., Perkin Trans. 2 1991,
721-734.
(7) We found freshly prepared SmI2 in THF to be superior in performance
to any of the commercially available solutions. SmI2-THF was prepared
according to the method of Kagan et al. (Girard, P.; Namy, J. L.; Kagan,
H. B. J. Am. Chem. Soc. 1980, 102, 2693-2698).
The cycloadditions of heterodienophiles with thebaine have
also been studied, and the first examples of transient acyl nitroso
compounds as dienophiles were reported by Kirby et al.2 These
hetero-Diels-Alder reactions are usually regioselective to give
(1) Bentley, K. W.; Hardy, G. G.; Meek, B. J. Am. Chem. Soc. 1967,
89, 3273-3280.
10.1021/jo052016j CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/13/2005
J. Org. Chem. 2006, 71, 789-791
789

SCHEME 1. Synthesis of Oripavine Analgesics from Thebaine
SCHEME 2
that 10 undergoes a reductive rearrangement with SmI2 to give
a mixture of the cyclopentane 15 and the cyclobutane 16. If
the same initial steps apply to both cycloadducts, then it might
be expected that the radical anions 11 and 12 produced by
electron transfer from SmI2 could fragment to give the inter-
mediates 13 and 14, respectively. The polycyclic skeleton of
13 lacks the conformational flexibility of the open chain
intermediate 14, and it is our proposal that the radical anion 13
is unable to undergo either of the ring closures observed for 14
but instead is reduced by a second equivalent of SmI2, leading
to the observed product 9a after protonation. It appears that the
conversion of 8 to 9 requires conjugation of the amide carbonyl
group of the adduct to an aromatic ring either directly (Table
1, entries 1-3) or vinylagously (entries 4 and 5). When this
conjugation is absent (entry 6), then the ring cleavage product
is not observed. It is possible that this conjugation is necessary
to stabilize the initial radical anion allowing the C-C bond
cleavage to take place.
the hexahydrobenzazocine product 9 in which C6 of the Diels-
Alder adducts 8 has become the methyl ester carbonyl carbon
and the C5-C6 bond has been cleaved (Scheme 3).
The assignment of the proposed structures for 9a-e is clear
1
1
from the H and 13C NMR spectra. In the H NMR spectra, in
each case the singlet for 5-H in the adducts 8 has been replaced
by two coupled doublets corresponding to 5-HR and 5-Hâ of
the newly formed methylene group in the reduced hexahy-
drobenzazocine product 9. Furthermore, in the 13C NMR spectra,
the signal for the acetal carbon (6-C) in the adducts has been
replaced by an ester carbonyl signal in the product. Full
spectroscopic data for 8a-f and 9b-e may be found in the
Supporting Information.
Experimental Section
General Procedure for the Reduction of Thebaine Acyl
Nitroso Adducts with SmI2. Freshly prepared 0.1 M samarium-
(II) iodide in dry THF7 was added dropwise to the adduct (0.12
mmol) in dry THF (0.5 mL) under argon at 0 °C until a blue color
just persisted (2.6 mL, 0.26 mmol). After 3 h, a 10% aqueous
solution of 1:1 K2CO3/Rochelle salt9 (1 mL) was added to the
mixture, which was then extracted with EtOAc (3 × 2 mL). The
organic phases were combined, washed with saturated brine (2 ×
1 mL), dried (MgSO4), and concentrated under reduced pressure
We believe this to be an unprecedented transformation and
are unaware of any other published examples of the selectiVe
opening of ring C of the morphine structure. A possible
mechanism for this reaction becomes apparent when comparing
the structural similarities between the thebaine adduct 8a and
the oxazine cycloadduct 10 (Scheme 4). We reported previously8
SCHEME 3
790 J. Org. Chem., Vol. 71, No. 2, 2006

SCHEME 4
to give a crude product that was purified by preparative TLC using
Et2O/hexane (60:40) as eluant.
47.9 (C), 50.3 (CH3), 55.4 (CH3), 57.8 (C), 62.1 (CH), 81.9 (CH2),
112.8 (CH), 117.3 (CH), 120.6 (CH), 125.6 (C), 126.2 (CH), 127.5
(CH), 128.7 (C), 130.3 (CH), 133.6 (C), 140.9 (CH), 141.7 (C),
145.3 (C), 164.5 (C), 165.8 (C); MS (EI) m/z (relative intensity)
448 (M+, 32), 230 (60), 105 (40), 97 (18), 86 (70), 84 (100), 77
(23), 69 (25), 57 (40), 47 (30), 43 (40). HRMS (EI): calcd for
C26H28N2O5 448.199822, found 448.200058.
11â-Benzoylamino-11r-[cis-2-(methoxycarbonyl)ethenyl]-8-
methoxy-3-methyl-1,2,3,4,5,6-hexahydro-6r,7-(methyleneoxy)-
2,6-methano-3-benzazocine (9a). The pure product was obtained
as an off-white solid in 77% yield (41.2 mg, 0.09 mmol); mp 138-
140 °C; [R]D +23.6 (c 1.3, CH2Cl2); IR (KBr): ν ) 1203, 1478,
1507 (s), 1653, 1722, 2927, 3429 (br) cm-1; 1H NMR (500 MHz,
CDCl3): δ 1.56 (m, 1H), 2.01 (dt, J ) 5.0, 12.7 Hz, 1H), 2.14 (dt,
J ) 3.7, 12.1 Hz, 1H), 2.35 (d, J ) 5.0 Hz, 1H), 2.48 (s, 3H), 2.51
(dd, J ) 18.3, 5.7 Hz, 1H), 3.06 (d, J ) 18.6 Hz, 1H), 3.33 (s,
3H), 3.82 (s, 3H), 3.89 (d, J ) 5.5 Hz, 1H), 4.29 (d, J ) 10.1 Hz,
1H), 5.03 (d, J ) 10.1 Hz, 1H), 5.75 (d, J ) 12.6 Hz, 1H), 6.21
(d, J ) 12.6 Hz, 1H), 6.57 (d, J ) 8.0 Hz, 1H), 6.70 (d, J ) 8.0
Hz, 1H), 7.41 (m, 3H), 7.77 (m, 2H), 7.83 (s, 1H); 13C NMR (125
MHz, CDCl3): δ 20.0 (CH2), 30.2 (CH2), 42.0 (CH3), 45.0 (CH2),
Acknowledgment. We thank The Department of Education
for Northern Ireland (DENI) and Galen-CSS Ltd for a CAST
award (to N.S.) and Dr. Paul Stevenson for helpful discussions.
Supporting Information Available: General experimental
details, complete experimental details and spectroscopic data for
the thebaine acyl nitroso adducts 8a-f and the hexahydrobenza-
zocine products 9b-e, and NMR spectra for compounds 8a and
9a. This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) McAuley, B. J.; Nieuwenhuyzen, M.; Sheldrake, G. N. Org. Lett.
2000, 2, 1457-1459.
(9) Rochelle salt is potassium sodium tartrate tetrahydrate.
JO052016J
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