Formal Synthesis of (-)-Codeine by Application of Temporary Thio Derivatization

Article abstract of DOI:10.1021/acs.orglett.7b03972

Desymmetrization of a p-quinone monoacetal by organocatalytic sulfa-Michael addition provided rapid access to a C-ring building block for a formal synthesis of (-)-codeine. By means of a diastereoselective 1,2-addition for A/C-ring union, an intramolecula

Full text of DOI:10.1021/acs.orglett.7b03972

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Formal Synthesis of (−)-Codeine by Application of Temporary Thio
Derivatization
Julia Rautschek, Anne Jager, and Peter Metz*
̈
Fakultat Chemie und Lebensmittelchemie, Organische Chemie I, Technische Universitat Dresden, Bergstrasse 66, 01069 Dresden,
̈
̈
Germany
S
* Supporting Information
ABSTRACT: Desymmetrization of a p-quinone monoacetal
by organocatalytic sulfa-Michael addition provided rapid access
to a C-ring building block for a formal synthesis of
(−)-codeine. By means of a diastereoselective 1,2-addition
for A/C-ring union, an intramolecular nitrone cycloaddition
for construction of the phenanthrene core, and a sulfoxide
elimination, an enantiopure key intermediate of the authors’
previous synthesis of racemic codeine was available in 12 steps from isovanillin.
community. These endeavors contribute to the development of
flexible routes toward morphine and ensure a certain
independence from poppy cultivation.3b
espite groundbreaking changes in medicine during the past
Dcenturies, (−)-morphine (1) and (−)-codeine (2) have
remained indispensable drugs for the treatment of pain (Scheme
1).1 Produced from the opium poppy (Papaver somniferum) until
the present time, these alkaloids have been a challenging
synthetic target ever since the structure proposal for morphine by
Robinson in 1925.2 More than 30 total and formal syntheses3,4
give evidence of the enormous interest of the scientific
In 2011 we disclosed a total synthesis of ( )-codeine (2)
featuring an intramolecular nitrone cycloaddition to construct
the ABC-ring system with simultaneous generation of four
contiguous stereogenic centers.5 We recently turned to the
enantioselective preparation of the key isoxazolidine 3. We
planned to carry out the crucial cycloaddition step from a chiral
precursor in which an olefin was temporarily masked with a
phenylthio group instead of the prochiral p-quinol ether used
before. This concept of desymmetrization by reversible thiol
addition has been applied previously in enantioselective synthesis
by the Figueredo, Evans, and Roberts groups.6−8
Scheme 1. Retrosynthetic Analysis
As depicted in Scheme 1, we reasoned that enantiopure 3
could be synthesized from β-sulfenyl ketone 4 (path A) or α-
sulfenyl ketone 5 (path B). Depending on the position of the
phenylthio group, reinstallation of the double bond might be
achieved by base-promoted elimination (path A) or thermal
elimination of the corresponding sulfoxide (path B). Con-
struction of aldehyde 4 could involve 1,2-addition to known
chiral enone 6.9,10 For path B, an analogous disconnection leads
to dimethyl acetal 7 as the C-ring unit, the racemic mixture of
which is known.11 Both enones could be synthesized by
enzymatic kinetic resolution of allylic alcohol ( )-8, an approach
based on the previous preparation of 6, where the analogous
ethylene acetal was used.12 Alternatively, asymmetric sulfa-
Michael addition13 of thiophenol to the corresponding p-
quinone monoacetal might enable more rapid access to the
desired enones.
The absolute configuration at the benzylic carbon in 4 and 5
depends on both the choice of the starting enantiomers and the
stereochemical outcome of the A/C-ring union. In order to
Received: December 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
correctly install the S stereogenic center required for the
synthesis of (−)-codeine (2), preliminary examinations were
undertaken. They revealed that nucleophilic 1,2-addition of the
respective A-ring fragments to ketones 6 and 7 took place
exclusively anti to the sulfenyl group, leading to (4S,6R)-6 and
(S)-7 as the required C-ring units.
For the enzymatic route, allylic alcohol ( )-8 was readily
prepared by base-mediated addition of thiophenol11 to dienone 9
and subsequent diastereoselective 1,2-reduction (Scheme 2).14
subsequent acetal cleavage17 in (+)-11 gave enone (4S,6R)-6.
The latter sequence offers an alternative to the previous route
toward 69 with improved yield and ee.
We continued with the direct organocatalytic preparation of
(+)-7 from p-quinone monoacetal 9. Our studies of the sulfa-
Michael addition to 9 delivered very satisfying results comparable
to those reported for enones by Singh and co-workers.18 Best ee
values of 90% were obtained with only a 0.5 mol % loading of
quinidine-based catalyst 1219 in toluene at room temperature.
Interestingly, both higher and lower catalyst loadings and lower
reaction temperature led to decreased enantioselectivity.
Recrystallization of the product raised the ee to >99% and
provided crystals suitable for X-ray diffraction analysis, which
confirmed the absolute configuration of (+)-7 as S. This efficient
route to (+)-7 can additionally be utilized for a rapid synthesis of
6 using the pseudoenantiomeric quinine-based catalyst.20
Having gained access to the C-ring building blocks,
investigation of the A/C-ring union for path A was undertaken
(Scheme 3). The required aromatic A-ring fragment 13 was
synthesized from isovanillin (14) under optimization of our
previous route:21 Wittig reaction of aldehyde 1522,23 to give 1624
followed by hydroboration/oxidation and silyl protection
furnished 13. Halogen−lithium exchange with 13 and
subsequent reaction with 6 in the presence of the LaCl3·2LiCl
complex25 resulted in the formation of the tertiary alcohol as a
single diastereomer, which was methylated to give 17. The
configuration at the benzylic stereogenic center was assigned on
the basis of NOE experiments. Desilylation and oxidation then
provided cycloaddition precursor 4 in very good yield. It was
subjected to nitrone generation/cycloaddition using our
previously established conditions5 with additional dilution
(0.01 M). We isolated a highly unstable product matching the
Scheme 2. Enantioselective Synthesis of Enones 6 and (+)-7
1
expected H NMR and MS data. It was quickly reduced with
NaBH4 in order to confirm the structure. Unfortunately, the
resulting alcohol 18 exhibited the undesired H8,H9 cis relation-
ship.26 No other isoxazolidine was isolable after variation of the
solvent (dichloromethane) and reaction temperature (−40 °C).
The cycloaddition product thus results from a different transition
state geometry (exo) than that operating in the racemic route
(endo).27 These findings could be attributed to the higher steric
constraints due to the additional sulfenyl group. The exo/endo
selectivity of nitrone cycloadditions is in fact not clearly
predictable,28 and different outcomes have been described for
cycloadditions similar to the one reported herein.26,29
Pleasingly, enantioselective acetylation catalyzed by Candida
antarctica lipase B yielded alcohol (+)-8 and acetate (−)-10 with
excellent enantiomeric excesses.15,16 Oxidation of (+)-8 using
Dess−Martin periodinane (DMP) led to enone (S)-(+)-7, while
methanolysis of (−)-10, silylation of the resulting alcohol, and
Scheme 3. Synthesis of Cycloaddition Precursor 4 (Path A) and Its Conversion into cis-Isoxazolidine 18
B
DOI: 10.1021/acs.orglett.7b03972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As the nitrone derived from aldehyde 4 failed to undergo
cycloaddition with the desired diastereoselectivity, we focused on
the synthesis of aldehyde 5 (path B). A/C-ring union was
conducted analogously to path A with the known aryl bromide
195 and enone (+)-7 to give tertiary alcohol 20 in good yield as a
single diastereomer (Scheme 4). Its relative configuration was
was shown by reduction of the crude mixture to give alcohols 24a
and 24b in 42% and 22% yield, respectively.31 Furthermore, 22a
could be isolated by crystallization. It epimerized to 22c upon
standing without formation of 23. We therefore concluded that
23 originated exclusively from cis-isoxazolidine 22b.
In principle, the required reinstallation of the alkene by
sulfoxide elimination might be realized at the stage of the alcohol
or ketone. From the relevant H8,H9 trans products, alcohol 24a
exhibited the undesired β-OH configuration at C11, so we
focused on the synthesis of 22c. Eventually we found that the
cycloaddition/epimerization sequence was best carried out as a
one-pot process with spontaneous epimerization at 0 °C, giving
22c in 52% yield from 5.
Scheme 4. Rapid Access to Cycloaddition Precursor 5 (Path
B)
We then examined the reduction of 22c, which proceeded with
complete diastereoselectivity in high yield (Scheme 6). After
Scheme 6. Completion of the Formal Synthesis of
(−)-Codeine (2) by Preparation of 3
confirmed by X-ray diffraction analysis. Methylation of the
alcohol afforded ether 21, which smoothly underwent double
acetal cleavage with a catalytic amount of ceric ammonium
nitrate30 to afford aldehyde 5 in excellent yield.
Gratifyingly, subsequent nitrone cycloaddition using aldehyde
5 proceeded with formation of the desired H8,H9 trans product,
but sulfenyl ketone 22c epimerized at C12 was isolated along
with phenanthrene 23 after column chromatography (Scheme
5). Initially, however, isoxazolidines 22a and 22b were formed, as
protection of the alcohol, silyl ether 25 was oxidized with H2O2 in
hexafluoroisopropanol (HFIP)32 to give a separable mixture of
diastereomeric sulfoxides 26a and 26b. Unfortunately, neither
sulfoxide underwent elimination to afford olefin 3 at temper-
atures up to 160 °C. Presumably, the required conformation for
syn elimination could not be adopted because of restricted
rotation around the C−S bond. An alternative elimination of a
phenyl sulfilimine generated in situ by reaction of 25 with O-
mesitylenesulfonylhydroxylamine33 proved unsuccessful, too.
Subsequently, we investigated an oxidation/elimination/reduc-
tion sequence starting from 22c. Although the derived sulfoxides
turned out to be prone to phenanthrene formation analogous to
the generation of 23, we were able to gain access to allylic alcohol
27 in a good overall yield of 38% over three steps. Silylation of 27
finally led to the target compound 3.
Scheme 5. Assembly of the Phenanthrene Core from 5 by
Intramolecular Nitrone Cycloaddition
In conclusion, we have accomplished a formal synthesis of
(−)-codeine (2) by straightforward construction of the
enantiopure key intermediate 3 in 12 steps from isovanillin.
Central to our approach was the temporary installation of a
phenylthio group for desymmetrization. We examined two
pathways differing in the position of the sulfenyl group and found
that only the α-sulfenyl ketone could be used to generate the
desired diastereomer in the key intramolecular nitrone cyclo-
addition step. The latter thio derivative 5 was readily available
through a highly enantioselective sulfa-Michael addition to p-
quinone monoacetal 9, a reaction that should prove useful
beyond the application reported herein.
C
DOI: 10.1021/acs.orglett.7b03972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) In this work, application of the ethylene acetal was not feasible, as
preliminary investigations of path B showed that ethylene acetal cleavage
to give 5 was unsuccessful because of competing side reactions.
(13) For recent reviews, see: (a) Chauhan, P.; Mahajan, S.; Enders, D.
Chem. Rev. 2014, 114, 8807. (b) Heravi, M. M.; Hajiabbasi, P. Mol.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03972.
■
S
Diversity 2014, 18, 411. (c) Enders, D.; Luttgen, K.; Narine, A. A.
Experimental procedures, spectroscopic data, 1H and 13
NMR spectra, and HPLC traces (PDF)
C
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Synthesis 2007, 959.
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E.; Rodríguez, S. Tetrahedron: Asymmetry 2000, 11, 4473.
(15) Absolute configurations were assigned after oxidation of (+)-8
and comparison of specific rotation and chiral HPLC data with those for
(+)-7 from organocatalytic sulfa-Michael addition.
(16) For kinetic resolution of the analogous ethylene acetal,10 ee values
of 81% for the alcohol and 95% for the acetate were obtained.
(17) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org. Chem.
2004, 69, 8932.
Accession Codes
CCDC 1578109 and 1578110 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-
mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: peter.metz@chemie.tu-dresden.de.
ORCID
Sladojevich, F.; Dixon, D. J. Synthesis 2011, 1880.
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1967.
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(21) Rautschek, J.; Metz, P. Heterocycles 2017, 95, 1106.
Peter Metz: 0000-0002-0592-9850
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (ME 776/22-1) and the Graduate Academy of TU
Dresden funded by the Excellence Initiative of the German
Federal and State Governments (scholarship to J.R.).
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DOI: 10.1021/acs.orglett.7b03972
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