Synthesis of (-)-morphine: Application of sequential claisen/claisen rearrangement of an allylic vicinal diol

Article abstract of DOI:10.1002/chem.201203284

A detailed exploration of the synthesis of (-)-morphine based on sequential [3,3]-sigmatropic rearrangements is described. The sequential Claisen/Claisen rearrangements of an allylic vicinal diol resulted in the stereoselective formation of the two contiguous carbon centers, including a sterically encumbered quaternary carbon, in a single operation. The two ethyl esters generated in this reaction were successfully differentiated during a subsequent Friedel-Crafts-type cyclization. The (-)-morphine double bond was introduced at a late stage in our first-generation synthesis, but was formed at an earlier stage in the second-generation synthesis, resulting in a more efficient route to the end product.

Full text of DOI:10.1002/chem.201203284

FULL PAPER
DOI: 10.1002/chem.201203284
Synthesis of (ꢀ)-Morphine: Application of Sequential Claisen/Claisen
Rearrangement of an Allylic Vicinal Diol
Masato Ichiki, Hiroki Tanimoto, Shohei Miwa, Ryosuke Saito, Takaaki Sato, and
Noritaka Chida*[a]
Abstract: A detailed exploration of the
synthesis of (ꢀ)-morphine based on se-
quential [3,3]-sigmatropic rearrange-
ments is described. The sequential
Claisen/Claisen rearrangements of an
allylic vicinal diol resulted in the
carbon, in a single operation. The two
ethyl esters generated in this reaction
were successfully differentiated during
a subsequent Friedel–Crafts-type cycli-
zation. The (ꢀ)-morphine double bond
was introduced at a late stage in our
first-generation synthesis, but was
formed at an earlier stage in the
second-generation synthesis, resulting
in a more efficient route to the end
product.
Keywords: allylic compounds · chi-
AHCTUNGTRENNUNG
stereo
contiguous carbon centers, including a
sterically encumbered quaternary
ACHTUNGTRENNUNGselective formation of the two
AHCTUNGTRENNUNG
Introduction
Our laboratory is engaged in a program devoted to the de-
velopment of sequential [3,3]-sigmatropic rearrangements of
allylic vicinal diols 1 with applications in the total synthesis
of complex natural products (Scheme 1).[1] Whereas the
[3,3]-sigmatropic rearrangement of simple allylic alcohols
has been recognized as a well-defined method in organic
synthesis, the reactions derived from allylic vicinal diols
such as 1 are still undeveloped in spite of their potential util-
ity. Allylic vicinal diols can undergo two sigmatropic rear-
rangements in a sequential manner. In this process, the first
rearrangement results in new carbon–carbon or carbon–het-
eroatom bond, accompanied by regeneration of a new allylic
alcohol, which undergoes the second rearrangement. Based
on this concept, we have succeeded in developing a method
consisting of two sequential sigmatropic rearrangements uti-
lizing the Claisen rearrangement.[2–4] The Claisen/Claisen re-
arrangement of 1 forms two functional groups in a one-pot
reaction (1!2!3), whereas the Claisen/Overman rear-
rangement introduces two different functional groups from
the same initial allylic diol (1!4!5). This Claisen/Overman
rearrangement technique was successfully applied to the
total synthesis of (ꢀ)-kainic acid (7).[2]
Scheme 1. Sequential Claisen/Claisen rearrangement and Claisen/Over-
man rearrangement applied to the total synthesis of natural products.
the well-known principal alkaloid (ꢀ)-morphine (6), isolated
from the opium poppy, Papaver Somniferum.[5] This opiate
has been used as an efficient analgesic and anaesthetic for a
long time, despite its potentially serious addictive side ef-
fects. Structurally, (ꢀ)-morphine includes a strained pentacy-
clic core with five contiguous chiral centers, one of which is
a benzylic quaternary carbon. The important biological ac-
tivity of this compound, as well as its challenging structure,
have resulted in continuous interest within the synthetic or-
ganic community.[6,7] In this paper, we report the full details
of a formal synthesis of (ꢀ)-morphine using the sequential
Claisen/Claisen rearrangement of an allylic vicinal diol.
To demonstrate the practical utility of the sequential
Claisen/Claisen rearrangement, we chose the synthesis of
[a] M. Ichiki, Dr. H. Tanimoto, S. Miwa, R. Saito, Dr. T. Sato,
Prof. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology, Keio University
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
Fax : (+81)45-566-1551
E-mail: chida@applc.keio.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203284.
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Results and Discussion
Our central strategy for the total synthesis of (ꢀ)-morphine
was based on the sequential Claisen/Claisen rearrangement
of an allylic vicinal diol 8 (Scheme 2). The first Claisen rear-
Scheme 2. Synthetic plan for the total synthesis of (ꢀ)-morphine (6).
rangement of 8 would give 9, which would spontaneously
undergo the second Claisen rearrangement. This reaction se-
quence would establish two contiguous stereocenters, includ-
ing the highly congested C13-quaternary center. The stereo-
chemical outcomes of 10 are completely dependent on the
stereochemistry of diol 8, which is derived from the two sec-
ondary alcohols of d-glucal (Scheme 2). To succeed in this
synthetic strategy, differentiation between the two identical
functional groups resulting from the sequential rearrange-
ment was critical. We therefore considered the use of a
new Friedel–Crafts-type reaction of bis-aldehyde 11
(Scheme 2).[8] In this reaction, only the spatially proximal al-
dehyde group to the aromatic ring would undergo cycliza-
tion to give the tetracyclic system 12, which would be an ap-
propriate intermediate for the total synthesis of (ꢀ)-mor-
phine (6).
As shown in Scheme 3, the allylic vicinal diol 8 was pre-
pared by taking advantage of the d-glucal scaffold through
Ferrierꢁs carbocyclization.[9] Deacetylation of tri-O-acetyl-d-
glucal (13) with sodium methoxide provided the d-glucal,
which was converted to the p-anisylidene derivative. The re-
maining secondary alcohol was protected as a TBS ether to
give the known compound 14.[10] The regioselective cleavage
of anisylidene acetal 14 with diisobutylaluminium hydride
(DIBAL) at ꢀ208C afforded primary alcohol 15. The glucal
was then converted to the methyl glycoside by treatment of
15 with PPh3·HBr and MeOH in DME,[11] followed by iodi-
nation of the primary alcohol to give 16 in 84% yield (2
Scheme 3. Synthesis of allylic vicinal diol 8. PMP=p-methoxyphenyl,
PPTS=pyridinium p-toluenesulfonate, Ms=methane sulfonyl, DMAP=
4-dimethylaminopyridine, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none.
steps). Elimination of 16 with tBuOK then gave 5-enopy
side 17. Exposure of 17 to a catalytic amount of Hg-
AHCTUNGRTEGN(NNU OCOCF3)2 in acetone/acetate buffer efficiently initiated the
ACHTUNGTRENNUNGran-
ACTHUNGTRENNUGoAHCTUNGTRENNNUG
Ferrierꢁs carbocyclization, followed by b elimination through
the mesylate to give cyclohexenone derivative 19 in 83%
yield (3 steps). The 1,4-reduction of 19 with L-Selectride,
followed by subsequent in situ-trapping with PhNTf2 provid-
ed enol triflate 20.[12] Suzuki–Miyaura coupling of 20 with
2,3-dimethoxyphenylboronic acid (21) proceeded smoothly
at 99% yield despite the steric congestion.[13] The removal
of the 4-methoxybenzyl (MPM) and tert-butyl dimethylsilyl
(TBS) groups afforded the key intermediate 8.
Although our goal was the development of the sequential
Claisen/Claisen rearrangement as a one-pot process, we first
investigated a stepwise double Claisen rearrangement.[14]
The Johnson-type Claisen rearrangement of allylic alcohol
23 with propionic acid in the presence of molecular sieves
(MS, 4 ꢂ) gave 24 in 87% yield (Table 1, entry 1). After the
removal of the TBS group with tetrabutylammonium fluo-
ride (TBAF), the resulting allylic alcohol 25 was subjected
to the second Johnson-type Claisen rearrangement with pro-
pionic acid, giving 10a with a quaternary carbon center in
44% yield. The yield of the first rearrangement was low
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Synthesis of (ꢀ)-Morphine
FULL PAPER
Table 1. Results of stepwise double Claisen rearrangements.[a]
ment of allylic vicinal diol 8 with MeCACTHNURGTNEUNG(OEt)3 in
the presence of 2-nitrophenol at 140 to 1708C in a
sealed tube initiated the sequential Claisen/Claisen
rearrangement in 36% yield.[16] Although the yield
was moderate, likely because the most optimal
acid may not have been used as suggested by
Table 1, it is noteworthy that the vicinal tertiary
and quaternary carbons required for the subse-
quent synthesis of (ꢀ)-morphine were stereoselec-
tively created in a single operation.
Having successfully developed the sequential
Claisen/Claisen rearrangement, we next attempted
the construction of the dihydrobenzofuran moiety
(Scheme 5). Treatment of 10a with meta-chloroper-
benzoic acid (m-CPBA) induced demethylating
etherification through the epoxide to give 26 in
79% yield.[7t] The resulting alcohol was protected
as a TBS ether. The stage was now set for the cru-
cial Friedel–Crafts-type reaction (Table 2). After
the partial reduction of bis-ester 27 with DIBAL,
the crude bis-aldehyde was immediately subjected
to the next Friedel–Crafts type reaction without
further purification, since the bis-aldehyde is prone
to hydrate formation. Whereas treatment with
aqueous toluene sulfonic acid (p-TsOH·H2O) in
benzene at 808C resulted in decomposition of the
reacting species (Table 2, entry 1), the reaction
with camphorsulfonic acid (CSA) gave phenan-
Entry
Claisen I
Claisen II
Yield [%][b]
24
10
1
2
3
4
MeC
EtCO2H, MS (4 ꢂ)
MeC(OEt)3,
2-nitrophenol
MeC(OEt)3,
EtCO2H, MS (4 ꢂ)
MeC(OEt)3,
EtCO2H, MS (4 ꢂ)
A
MeC
MeC
MeC
MeC
A
87
10a: 44
N
E
53
87
87
10a: 44
10a: 57
10b: 90
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
[a] Claisen I: Compound 23, acid (0.4 equiv), MS (4 ꢂ), MeC
sealed tube; Claisen II: Compound 25, acid (5 mol%), MeC(OEt)3, 1408C in a sealed
tube. [b] Yield of the isolated product after purification by column chromatography
on silica gel.
ACHTUNGRTEN(NUNG OEt)3, 1408C in a
AHCTUNGTRENNUNG
when the less acidic 2-nitrophenol was employed (Table 1,
entry 2). On the other hand, the second Claisen rearrange-
ment was more efficient when 2-nitrophenol was used, pro-
viding 10a in 57% yield (Table 1, entry 3).[15] The moderate
yields of the second rearrangement were mainly due to de-
composition of the substrates, probably through the forma-
tion of stabilized conjugated carbocations. The use of an
ACHTUNGTRENNUNGEschenmoser-type reaction for the second rearrangement
proved to be the best conditions giving 10b in 90% yield
(Table 1, entry 4). Although the combination of Johnson
and Eschenmoser-type rearrangements created optimal con-
ditions in terms of the yield of the stepwise double Claisen
rearrangement itself, the further transformation of dimethyl
amide 10b turned out to be troublesome due to its inertness.
Thus, we concluded the most appropriate intermediate for
the total synthesis was bis-ethylester 10a as synthesized by
the Johnson-type reaction.
With the two contiguous carbon centers thus established
in a stepwise fashion, we turned our attention to the cascade
version of this portion of the synthesis (Scheme 4). Treat-
Scheme 4. Sequential Claisen/Claisen rearrangement of allylic vicinal
diol 8.
Scheme 5. First-generation synthesis of (ꢀ)-morphine (6).
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N. Chida et al.
Table 2. Differentiation of the two ethyl esters through a Friedel–Crafts-
type cyclization.
Entry
Conditions
Yield [%][a]
12
31
Scheme 6. New synthetic plan toward the total synthesis of (ꢀ)-morphine
(6).
1
2
3
4
5
6
p-TsOH·H2O, PhH, 808C
CSA, PhH, 808C
CSA, 1,2-dichlorobenzene, 808C
CSA, (CH2Cl)2, 808C
CSA, (CH2Cl)2, RT
montmorillonite K-10, (CH2Cl)2, RT
0
24
0
0
0
0
32
37
38
0
0
43
[a] Yield of the isolated product after purification by column chromatog-
raphy on silica gel.
throfuran 12 in 24% yield (Table 2, entry 2). As we antici-
pated, the proximal aldehyde to the aromatic ring selectively
underwent cyclization. The nature of the solvent employed
also had effects on the yield. The best results were obtained
with dichloroethane, resulting in 32% yield (Table 2, en-
tries 2–4). Because prolonged reaction times at 808C led to
the decomposition of 12, we subsequently lowered the reac-
tion temperature, resulting in a slight improvement (Table 2,
entry 5). We ultimately found that the utilization of mont-
morillonite K-10 at room temperature significantly im-
proved the reaction efficiency, giving 12 in 38% yield, along
with the free alcohol 31 in 43% yield, which was readily
converted to 12 (Table 2, entry 6).[17] Thus, we successfully
developed the new Friedel–Crafts-type cyclization.
The one remaining challenge for the total synthesis of
(ꢀ)-morphine (6) was the formation of the piperidine ring
(Scheme 5). The reductive amination of 12 with methyl
amine, followed by N-tosylation and TBS-deprotection gave
29 (a known intermediate reported by Parker) in 86% yield
(3 steps).[7af] Finally, synthesis of (ꢀ)-dihydroisocodeine (30)
was achieved under Birch conditions by using Li/NH3 in the
presence of tBuOH, resulting in the first-generation formal
synthesis of (ꢀ)-morphine.[7af]
Although we succeeded in developing the first-generation
synthesis of (ꢀ)-morphine (6), (ꢀ)-dihydroisocodeine (30)
still required several reaction steps to complete the total
synthesis of (ꢀ)-morphine, primarily due to the requirement
for olefination. We reasoned that, if the double bond in the
cyclohexene ring could be introduced at an earlier stage, the
synthetic route would become more efficient (Scheme 6,
26!32). Our major concern in this respect was that the
Friedel–Crafts-type reaction under acidic conditions (32!
33) might lead to decomposition due to the labile allylic
TBS ether in 32.
Scheme 7. Second-generation synthesis of (ꢀ)-morphine (6).
tion of ketone 34 was not trivial. Treatment with PhSeCl
under basic conditions by using NaNACTHNUTRGENUN(G TMS)2, followed by
oxidative elimination with NaIO4 provided the enone 35 in
34% yield over two steps (Table 3, entry 1). Under acidic
conditions this reaction produced a similar result (Table 3,
entry 2).[19] Employing the more reactive PhSeOTf resulted
The second-generation synthesis commenced with the 2-
iodoxybenzoic acid (IBX)-oxidation of 26 at 608C
(Scheme 7).[18] As shown in Table 3, the subsequent olefina-
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Synthesis of (ꢀ)-Morphine
FULL PAPER
Table 3. Results for insertion of a double bond through selenylation.
ment of an allylic vicinal diol resulted in the formation of
two contiguous stereocenters, including a benzylic quaterna-
ry carbon, in a single step. The two ester groups generated
in the rearrangment were successfully differentiated during
the subsequent Friedel–Crafts type cyclization to give the
phenanthrofuran structure. Whereas our first-generation
synthesis required the troublesome introduction of the key
double bond at a late stage in the process, the second-gener-
ation synthesis introduced the double bond much sooner, re-
sulting in a more efficient synthesis. In addition, the Frie-
del–Crafts type cyclization used in the second-generation
synthesis showed this reaction to be highly effective even in
the presence of an acidic labile functional group.
Entry Selenylation
Elimination
ACHTUNGTRENNUNG(TMS)2, NaIO4, THF/H2O, RT
Yield [%][a]
34
1
2
3
4
5
PhSeCl, NaN
THF, RT
PhSeCl, conc. HCl,
EtOAc, RT
PhSeCl, AgOTf,
EtOAc, RT
PhSeCl, AgOTf,
BF3·Et2O, EtOAc, RT
PhSeCl, AgOTf,
BF3·Et2O, EtOAc, RT
NaIO4, THF/H2O, RT
NaIO4, THF/H2O, RT
NaIO4, THF/H2O, RT
36
27
47
Davis Reagent, CHCl3, RT 60
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in decreased yield (Table 3, entry 3). After the extensive in-
vestigation, we eventually determined that the addition of
BF3·Et2O[20] to PhSeOTf optimized the conditions of the se-
lenylation step (Table 3, entries 3 and 4). The oxidative
elimination step was improved with the use of Davis re-
agent,[21] giving enone 35 in 60% yield over 2 steps (Table 3,
entry 5).
With enone 35 in hand, we turned our attention to the
Friedel–Crafts-type cyclization (Scheme 7). A stereoselec-
tive 1,2-reduction of 35 under Lucheꢁs conditions[22] gave the
b-alcohol, which was protected as a TBS ether to give 36 in
94% (2 steps). Bis-aldehyde 32 was then prepared through a
two-step sequence including LiAlH4-reduction and Swern
oxidation.[23] The crude aldehyde 32 was immediately sub-
jected to the next Friedel–Crafts reaction. As we had
feared, the reaction of bis-aldehyde 32 containing the acidic
labile allylic TBS-ether led to significant decomposition with
montmorillonite K-10. Extensive screening, however, re-
vealed that the utilization of p-TsOH·H2O at room tempera-
ture induced both cyclization and the removal of the TBS
group simultaneously, giving phenanthrofuran 33 in 53%
yield, along with undeprotected product 37 in 24% yield,
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which was converted to 33 with HF·Py in MeCN. The reduc-
ae]
tive amination of 33[7ad,
and subsequent N-tosylation af-
forded Guillouꢁs intermediate 39.[7ai] Our synthetic sample
was indistinguishable from their spectral data based on H
1
and 13C NMR spectroscopy, HRMS, and IR. It is known that
39 can be converted into (ꢀ)-morphine through two further
reaction steps, therefore we have accomplished the second-
generation synthesis of (ꢀ)-morphine (6).
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Conclusion
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We have demonstrated the formal synthesis of (ꢀ)-mor-
phine based on a new strategy by using a [3,3]-sigmatropic
rearrangement. The sequential Claisen/Claisen rearrange-
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Received: September 14, 2012
Published online: && &&, 2012
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of (ꢀ)-Morphine
FULL PAPER
Total Synthesis
M. Ichiki, H. Tanimoto, S. Miwa,
R. Saito, T. Sato, N. Chida* &&&& — &&&&
Synthesis of (ꢀ)-Morphine: Applica-
tion of Sequential Claisen/Claisen
Rearrangement of an Allylic Vicinal
Diol
Pain-free synthesis! The sequential sig-
matropic rearrangements of allylic vici-
nal diols offer a practical process for
the synthesis of structurally complex
chiral compounds. The synthesis of
(ꢀ)-morphine was achieved by
rearrangement as a key step (see
scheme). The reaction of an allylic
vicinal diol was employed to introduce
a vicinal tertiary and quaternary
carbon centers, and the resulting bis-
ester was differentiated in a subse-
quent Friedel–Crafts-type cyclization.
employing a sequential Claisen/Claisen
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!