Angewandte
Chemie
Notably, three new stereogenic centers are created in the
second step. The desymmetrization of cyclohexadienones
remains a topic of intense interest due to the generation of
significant levels of molecular complexity from the planar
aromatic starting material.[5a,10] With respect to morphine
syntheses, Magnus and co-workers deployed a related dis-
connection that accessed a cyclohexadienone intermediate
through an alkylative dearomatization tactic,[3ac] intercepting
with a nitro-Michael addition at a later stage in the synthesis.
However, they did not disclose an enantioselective protocol
to perform this desymmetrization and the synthesis resulted
in a racemate. In our case, the remote stereogenic center,
installed through Noyori reduction of a ketone, controls the
Michael addition of the aldehyde to the cyclohexadienone
with remarkably selectivity; no diastereomeric compounds
were observed. We propose that the origin of this selectivity
derives from the bulky OTIPS group controlling the con-
formation of the tetrahydrobenzopyran ring such that the
enolate of the aldehyde prefers to attack one side of the
pseudosymmetric cyclohexadienone leading to a single prod-
uct. Furthermore, 4 is produced as a single epimer at the
carbon adjacent to the formyl group, most likely reflecting the
thermodynamically favored product. Importantly, the struc-
ture of 4 displays all of the carbon atoms as well as a significant
proportion of the architectural complexity required for the
skeleton of morphine directly and can be readily derived from
an acyclic precursor on multigram scale. Confirmation of the
relative and absolute stereochemistry was obtained through
conversion of 4 into an amide derivative 12 whose structure
could be defined by X-ray diffraction of a single crystal
(Scheme 3).
With a plentiful supply of aldehyde 4 now available to us,
we advanced this intermediate through Pinnick oxidation to
the corresponding acid followed by Curtius rearrangement,
which we found worked best using diphenylphosphoryl
azide[11] delivering the N-Boc protected amine 13 in 53%
yield on a 9 g scale (Scheme 4). Apart from providing
a handle to control the stereochemistry of the “desymmetriz-
ing” Michael addition, the hydroxy function was also designed
to serve as a means to cleave the arylether linkage and
liberate the carbon chain required to form the piperidine ring
of the morphinan architecture. A simple three-step sequence
involving TBAF-mediated cleavage of the silyl ether, mesy-
lation of the resulting hydroxy group, and E2 elimination with
DBU gave the desired enol ether in 72% over the three steps
(on a 6 g scale), requiring only one chromatographic purifi-
cation. In preparation for the structurally rearranging cascade
reaction, we found that Luche reduction of the enone (14) to
the corresponding allylic alcohol was first necessary. Under
acidic conditions, and assisted by microwave irradiation,[12]
a cascade reaction was initiated and involved hydrolysis of the
enol ether, addition of the resulting phenol to a putative
allylic cation that resulted in the formation of tetrahydro-
benzofuran ring, cleavage of the Boc group to release the
amine, and subsequent intramolecular condensation with the
pendant aldehyde (liberated on enol ether hydrolysis) possi-
bly through a sequence involving intermediates 15a–c.
Immediate reduction with NaBH(OAc)3 delivered the sec-
ondary amine, which was protected to form ethyl carbamate
Scheme 4. Completion of the formal total synthesis: acid-mediated
rearrangement and conversion to the known intermediate 2. Reagents
and conditions: l) NaClO2 (4 equiv), NaH2PO4 (3 equiv) tBuOH/H2O,
2-methyl-2-butene, 08C to rt, 1 h, 95%; m) DPPA (1.1 equiv), NEt3
(1.1 equiv), tBuOH, 658C to 858C, 48 h, 53% over 2 steps; n) TBAF
(1.1 equiv), THF, rt, 0.5 h; o) MsCl (1.2 equiv), Et3N (1.3 equiv),
DMAP (0.12 equiv), CH2Cl2, 08C, 2 h; p) DBU (10 equiv), MeCN, 858C,
18 h, 72% over 3 steps; q) NaBH4 (1.6 equiv), CeCl3.7H2O (1.4 equiv),
MeOH, À788C, 1 h; r) HCl (aqueous, 3m), dioxane, 808C, mW, 2 h ;
s) NaBH(OAc)3 (2.3 equiv), AcOH/DCE, rt, 1 h, then ClCO2Et
(2.5 equiv), Et3N (5 equiv), rt, 1 h, 35% over 4 steps; DCE=dichloro-
ethene, DPPA=diphenylphosphoryl azide, MsCl=methanesulfonyl
chloride, TBAF=tetra-n-butylammonium fluoride.
2. This four-step sequence to intermediate 2 represents
a synthesis of an advanced compound, which is common to
several other approaches to morphine, as well as being
a potential precursor to derivatives of the morphinan class of
alkaloids.
In summary, we have completed an operationally simple
enantioselective synthesis of a key morphinan alkaloid
derivative. The overall yield is 4.3% over 18 steps. We have
demonstrated that our synthesis is scalable and capable of
producing multigram quantities of these important molecules.
The key feature of our synthesis is an ortho–para oxidative
phenolic coupling that can be linked with an asymmetric
Michael addition controlled from a remote stereocenter
(installed using enantioselective catalysis). Our current
efforts are geared toward a strategy that exploits a catalytic
enantioselective dearomatization approach as a means to
achieve a practical and scalable synthesis of this important
class of molecules.[13]
Received: August 21, 2014
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!
Tissot, Matthieu
