Diastereoselective total synthesis of (±)-codeine

Article abstract of DOI:10.1002/chem.200800744

A study was conducted to demonstrate a total diastereoselective synthesis of (?)-codeine, involving the construction of the morphinan skeleton. The study provided an efficient method for the elaboration of the quaternary carbon at C-13 and for the highly diastereoselective introduction of the C-14 stereogenic center of the morphinan system. It was demonstrated that codeine can be obtained from amine intermediate by using an intramolecular hydroamination reaction to form the D ring. It was found the C-14 substituent can be diastereoselectively introduced in the reaction under Eschenmoser's condition.

Full text of DOI:10.1002/chem.200800744

DOI: 10.1002/chem.200800744
Diastereoselective Total Synthesis of (Æ)-Codeine
Marie Varin, Elvina BarrØ, Bogdan Iorga,* and Catherine Guillou*[a]
Codeine 1 and morphine 2, the principal constituents of
opium, continue to attract the attention of organic chemists
thanks to both their biological activities and their unique
structure.[1] Their complex pentacyclic skeleton, which in-
cludes a quaternary carbon center, has stimulated extensive
efforts. To date there have been more than 20 total synthe-
ses of codeine (1), morphine (2), and thebaine (3).[2] We
were interested in the synthesis of codeine for two reasons:
first, codeine was found to be an allosteric potentiating
ligand of nicotinic receptors,[3] and second we have a general
program underway in the laboratory in which we have
shown that tricyclic spirocyclohexadienones are valuable in-
termediates for the synthesis of natural products in the
Amaryllidacea galanthamine-type, maritidine-type, and As-
pidosperma alkaloids.[4]
C-13 and for the highly diastereoselective introduction of
the C-14 stereogenic center of the morphinan system.
Our retrosynthetic analysis of (Æ)-codeine (1) is shown in
Scheme 1. Codeine could be obtained from amine inter-
In an effort to develop new allosteric potentiating ligands
of nicotinic receptors with a codeine-type scaffold, we initi-
ated our own studies of a total synthesis of codeine. Herein
we disclose a total diastereoselective synthesis of (Æ)-co-
deine (1), which involves a new construction of the mor-
phinan skeleton. The present study provides an efficient
method for the elaboration of the quaternary carbon at
Scheme 1. Retrosynthesis of (Æ)-codeine 1.
mediate 4 by using an intramolecular hydroamination reac-
tion to form the D ring. Compound 4 could in turn be pre-
pared from aldehyde 5. In our synthetic pathway, we plan-
ned to use for the first time a Claisen-type rearrangement to
introduce the C-14 substituent. This type of rearrangement
applied to compound 6 would provide a precursor of the al-
dehyde 5 and control the stereochemistry of the substituent
at C-14 of 5. The tricyclic amine 6 would be obtained from
the spirocyclohexadienone 7 by a lactone ring opening with
an amine followed by a spontaneous intramolecular Michael
[a] M. Varin, E. BarrØ, Dr. B. Iorga, Dr. C. Guillou
Institut de Chimie des Substances Naturelles
CNRS
Avenue de la Terrasse, 91190 Gif-sur-Yvette (France)
Fax : (+33)(0)69077247
E-mail: guillou@icsn.cnrs-gif.fr
iorga@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800744.
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COMMUNICATION
addition of the resulting phenol to cyclohexadienone. Com-
pound 7 could be prepared in two steps from the ester 8 by
an intramolecular Heck reaction followed by an oxidation.
Our synthesis started with esterification of 2-iodo-6-me-
thoxyphenol (9)[5] with acid 10[6] according to a known pro-
cedure.[4a] Heck cyclization of 8 was accomplished in 67%
yield under new conditions. Indeed, in the absence of phos-
phine ligands, the reaction time for the cyclization of 8 to 11
was greatly reduced from three days[4a] to 5 h.[7] After hy-
drolysis of the dioxolane group of 11 with triphenylcarbeni-
um tetrafluoroborate,[4a] oxidation of the a,b-unsaturated
ketone function of the resulting product to the correspond-
ing dienone 7[4a] was realized in the presence of (PhSeO)2O
and NaHCO3 (Scheme 2).
Scheme 3. Synthesis of amide 13.
However, we found that, under Eschenmoserꢁs[15] condi-
tions, the C-14 substituent could be diastereoselectively in-
troduced. Heating 12 in the presence of dimethylacetamide
dimethylacetal in decalin at 2158C afforded the expected
amide 13 (49%) and diene 14 (32%) as a by-product
(Scheme 3). In spite of numerous attemps,[16] it was not pos-
sible to reduce the amount of 14 produced.
Reduction of the amide 13 with PhSiH3 in the presence of
[17]
TiACHTER(UGN OiPr)4 yielded the aldehyde 15, which upon treatment
with p-TSA in toluene furnished the amine 16 (Scheme 4).
The next step was the introduction of the allylic alcohol
function. To prevent oxidation of the nitrogen atom, the N-
benzyl group was first removed in the presence of 1-chloro-
Scheme 2. Synthesis of tricyclic spirocyclohexadienone 7. EDCI= 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMAP=4-dimethylami-
nopyridine, dba=dibenzylideneacetone.
AHCTREeUNG thyl chloroformate to give the corresponding secondary
amine, which was then protected with TsCl to give the sulfo-
namide 17. Oxidation of 17 with SeO2 in presence of
tBuOOH in dioxane furnished the allylic alcohol 18 with in-
correct stereochemistry. The latter was thus oxidized into
the corresponding ketone 19 by reaction with Dess–Martin
periodinane. Reduction of ketone 19 proceeded stereoselec-
tively using NaBH4 in methanol to give the required alcohol
20 now having the correct stereochemistry. The final step re-
quired to construct the D ring of codeine involves a hydro-
The reaction of lactone 7 with N-methylbenzylamine with
concurrent amide formation and lactone ring opening af-
forded the corresponding enone, which was then reduced
with LiAlH4 to give the allylic alcohol 12 in 77% yield
(Scheme 3). With a ready access to the key tricyclic allylic
alcohol 12, we then turned our attention to the introduction
of the crucial substituent at C-14.
Several approaches have been developed to introduce this
substituent based on the intramolecular Heck reaction,[2a,e,8]
the tandem radical cyclization,[9] 1,4-addition of vinyl mag-
nesium bromide (in the presence of copper(I) bromide) to
a,b-enone,[10] CpCO-mediated [2+2+2] cyclization of func-
tionalized 4-(3-butynyl)benzofurans,[11] or by aldol condensa-
tion.[2c]
AHCTREaUNG mination reaction. This type of cyclization was recently ap-
plied to a precursor of codeine (using HgCATHRE(UGN OAc)2 and then
LiAlH4) to give (+)-codeine in 17.6% yield.[2d] In our case,
we found that exposure of the sulfonamide 20 to lithium in
liquid ammonia[18] resulted in reductive cyclization to furnish
codeine (1) in satisfactory yield (51%).
In conclusion, we have achieved a diastereocontrolled
synthesis of (Æ)-codeine (1) from the tricyclic spirocyclo-
hexadienone 7 in 10 steps. An intramolecular Heck reaction
followed by a Claisen–Eschenmoser rearrangement, a reduc-
tive deprotection, and an intramolecular hydroamination re-
action constitute the key steps of this new total synthesis of
codeine.
In our study, introduction of the C-14 substituent starting
from allylic alcohol 12 proved difficult. Attempts to achieve
a Claisen rearrangement on 12 under Kazmaierꢁs,[12] Ire-
landꢁs,[13] or Johnsonꢁs[14] conditions failed.
Chem. Eur. J. 2008, 14, 6606 – 6608
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B. Iorga, C. Guillou et al.
[1] For pertinent reviews on the synthesis of morphine, see: a) T. Hud-
licky, G. Butora, S. P. Fearnley, A. G. Gum, M. R. Stabile, Studies in
Natural Products Chemistry (Ed.: Atta-ur-Rahman), Elsevier, Am-
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Commun. 2002, 1159–1168; c) J. Zezula, T. Hudlicky, Synlett 2005,
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[2] For the syntheses of morphine and codeine after ref. [1c] see
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Rice, T. Hudlicky, Synlett 2007, 2863–2867.
[3] a) A. Maelicke, A. Schrattenholz, M. Samochocki, M. Radina, E. X.
Albuquerque, Behav. Brain Res. 2000, 113, 199–206; b) A. Maelicke,
M. Samochocki, R. Jostock, A. Fehrenbacher, J. Ludwig, E. X. Al-
buquerque, M. Zelin, Biol. Psychiatry 2001, 49, 279–288; c) J. T.
Coyle, H. Geerts, K. Sorra, J. Amatniek, J. Alzheimer’s Dis. 2007,
11, 491–507.
[4] a) C. Guillou, J. L. Beunard, E. Gras, C. Thal, Angew. Chem. 2001,
113, 4881–4882; Angew. Chem. Int. Ed. 2001, 40, 4745–4746; b) C.
Bru, C. Thal, C. Guillou, Org. Lett. 2003, 5, 1845–1846; c) C. Bru,
C. Guillou, Tetrahedron 2006, 62, 9043–9048; d) J. Pereira, M. Barli-
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[5] C. Y. Chen, J. P. Liou, M. J. Lee, Tetrahedron Lett. 1997, 38, 4571–
4574.
[6] Acid 10 was obtained by Birch reduction of p-methoxyphenyl acetic
acid followed by protection with ethylene glycol (See Supporting In-
formation).
[7] For an example of reduction of the reaction time (19.5 h to 5 h) of a
Heck arylation reaction under ligand-free conditions see: M. Qadir,
T. Mçchel, K. K. Hii, Tetrahedron 2000, 56, 7975–7979.
[8] B. M. Trost, W. Tang, J. Am. Chem. Soc. 2002, 124, 14542–14543.
[9] K. A. Parker, D. Fokas, J. Org. Chem. 2006, 71, 449–455.
[10] H. Nagata, N. Miyazawa, K. Ogasawara, Chem. Commun. 2001,
1094–1095.
[11] D. PØrez, B. A. Siesel, M. J. Malaskaa, E. David, K. P. C. Vollhardt,
Synlett 2000, 306–311.
[12] U. Kazmaier, Angew. Chem. 1994, 106, 1046–1047; Angew. Chem.
Int. Ed. Engl. 1994, 33, 998–999.
[13] R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897–
5898.
Scheme 4. Synthesis of (Æ)-codeine 1. p-TSA=p-toluenesulfonic acid.
[14] W. S. Johnson, L. Werthermann, W. R. Barlett, T. J. Brocksom, T. T.
Li, D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc. 1970, 92, 741–
743.
[15] A. E. Wick, K. Steen, A. Eschenmoser, Helv. Chim. Acta 1964, 47,
2425.
Acknowledgements
[16] Variations of reaction time, temperature, or use of microwaves did
not modify the amount of diene produced.
The authors thank the CNRS for financial support, Prof. J. Y. Lallemand
for his interest in this work, and Dr. R. H. Dodd, ICSN-CNRS, Gif-sur-
Yvette, France for carefully reading the manuscript and for helpful com-
ments.
[17] S. Bower, K. A. Kreutzer, S. L. Buchwald, Angew. Chem. 1996, 108,
1662–1664; Angew. Chem. Int. Ed. Engl. 1996, 35, 1515–1516.
[18] These conditions were used for the synthesis of (À)-O-methylpallidi-
nine (K. Hanada, N. Miyazawa, K. Ogasawara, Org. Lett. 2002, 4,
4515–4517) and for the synthesis of (À)-dihydrocodeinone.[2b]
Keywords: alkaloids · diastereoselectivity · Heck reaction ·
hydroamination · rearrangement · total synthesis
Received: April 18, 2008
Published online: June 18, 2008
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