Deconstructive Asymmetric Total Synthesis of Morphine-Family Alkaloid (?)-Thebainone A

Article abstract of DOI:10.1002/anie.202103553

Herein, we describe the development of a deconstructive strategy for the first asymmetric synthesis of (?)-thebainone A, capitalizing on an enantioselective C?C bond activation and a C?O bond cleavage reaction. The rhodium-catalyzed asymmetric “cut-and-sew” transformation between sterically hindered trisubstituted alkenes and benzocyclobutenones allowed efficient construction of the fused A/B/C rings and the quaternary center of the natural product. The newly optimized conditions show broad substrate scope and excellent enantioselectivity (up to 99.5:0.5 er). Taking advantage of boron-mediated ether bond cleavage, we completed the synthesis of the morphine alkaloid (?)-thebainone A by two complementary routes.

Full text of DOI:10.1002/anie.202103553

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International Edition: doi.org/10.1002/anie.202103553
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À
C C Activation
Hot Paper
Deconstructive Asymmetric Total Synthesis of Morphine-Family
Alkaloid (À)-Thebainone A
Si-Hua Hou, Adriana Y. Prichina, and Guangbin Dong*
Abstract: Herein, we describe the development of a decon-
structive strategy for the first asymmetric synthesis of (À)-
a unique poly-bridged/fused ring system, a quaternary center,
a basic tertiary amine moiety, and a 1,2,3,4-tetrasubstituted
arene, which have posted significant challenges for their
preparation. Consequently, morphine alkaloids have contin-
uously attracted significant attentions from the synthetic
community for more than 70 years. Since the first synthesis of
morphine by Gates in 1952,[3] over 40 synthesis routes of
morphine alkaloids have been reported and more than 30
prominent synthetic research groups have been involved.[4–6]
Beyond just a target of synthesis, the morphine scaffold has
more or less become a touchstone for examining efficiency of
new synthetic strategies or robustness of new synthetic
methods.
À
thebainone A, capitalizing on an enantioselective C C bond
À
activation and a C O bond cleavage reaction. The rhodium-
catalyzed asymmetric “cut-and-sew” transformation between
sterically hindered trisubstituted alkenes and benzocyclobute-
nones allowed efficient construction of the fused A/B/C rings
and the quaternary center of the natural product. The newly
optimized conditions show broad substrate scope and excellent
enantioselectivity (up to 99.5:0.5 er). Taking advantage of
boron-mediated ether bond cleavage, we completed the syn-
thesis of the morphine alkaloid (À)-thebainone A by two
complementary routes.
Among various morphine alkaloids, thebainone A (4)
with a unique enone-containing C ring has served as a pre-
cursor to access morphine (1) and codeine (2) in the seminal
work of Gates.[3] The Tius group in 1992 developed the second
total synthesis of racemic thebainone A in 24 steps taking
advantage of a chemo- and regiospecific Diels–Alder reac-
tion.[7] Very recently, another elegant racemic synthesis of this
natural product was reported by Metz and co-workers in
22 steps, which features an intramolecular nitrone cycloaddi-
tion and a Heck cyclization as the key steps.[6a] To the best of
our knowledge, enantioselective synthesis of thebainone A is
not known yet. Herein, we describe the development of
a deconstructive strategy for the rapid and asymmetric
Introduction
Isolated from the opium poppy latex, morphine (1) and its
congeners are among the oldest and most extensively studied
alkaloid natural products known to date (Figure 1).[1] Given
their potent neurological and immunological activity, mor-
phine alkaloids and the unnatural semisynthetic opioids, such
as ketorfanol,[2a] oxycodone,[2b] and naltrexone,[2c] have found
various important therapeutic applications, including acting
as pain killers or treating opioid abuse and alcohol depend-
ence. Besides the biological importance, these compounds
also exhibit very intriguing chemical structures, such as
preparation of (À)-thebainone A, capitalizing on a catalytic
[8]
À
À
enantioselective C C bond activation and a C O bond
cleavage[9] reaction.
Deconstructive synthesis, namely building new (and often
more challenging) structures through bond cleavage of easily
accessible moieties, has emerged as a useful design principle
in synthesizing bioactive natural products and other target
molecules (Scheme 1a).[10] For example, from readily avail-
able cyclic ketones and ethers, more complex fused and
bridged rings could be prepared rapidly through cleavage and
À
À
subsequent functionalization of a C C or C O bond. Such
deconstructive strategies could enhance the overall efficiency
and provide a concise synthetic route. As one of ongoing
research efforts, our laboratory has been engaged in devel-
oping catalytic “cut-and-sew” transformations for preparing
bridged and fused rings through activation of relatively inert
Figure 1. Morphine and related alkaloids.
C C bonds in cyclic ketones.[11] Here, we anticipated that such
À
a deconstructive strategy could be applied to the first
enantioselective total synthesis of (À)-thebainone A and
formal syntheses of codeine and morphine (Scheme 1b).
From the retrosynthetic viewpoint (Scheme 2), the enone
in the C ring of thebainone A could be introduced by late-
stage dehydrogenation of the saturated intermediate (5). The
amine and the phenol functional groups (FGs) in 5 is expected
[*] Dr. S.-H. Hou, A. Y. Prichina, Prof. Dr. G. Dong
Department of Chemistry, University of Chicago
Chicago, Illinois, 60637 (USA)s
E-mail: gbdong@uchicago.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202103553.
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Scheme 3. The key enantioselective “cut-and-sew” step.
Scheme 1. Deconstructive synthesis of (À)-thebainone A.
a new challenge (Scheme 3). Unlike mono- and disubstituted
alkenes, trisubstituted alkenes have not been used in the
asymmetric “cut-and-sew” reaction as they typically exhibit
much lower reactivity due to the steric hindrance. In addition,
almost all the previous intramolecular carboacylations with
benzocyclobutenones use
a five-membered-ring-forming
tether,[11] which is kinetically favorable; the extended linkage
in substrate 7 is expected to increase the kinetic barrier for the
2p-insertion. Moreover, the more flexible linker could also
add difficulty for the enantioselective control. Therefore, the
primary difficulty arises from the challenging enantiodeter-
mining migratory insertion step.
To explore the feasibility of the key enantioselective “cut-
and-sew” step, a simplified model substrate (7a) was pre-
pared from commercially available aryl bromide 11 through
a sequence of benzocyclobutenone synthesis using our
previously developed protocol,[13a] followed by the Mitsunobu
coupling with a known alcohol (8a)[13b] (Scheme 4). Notably,
phenol 9 can be prepared on decagram scales in 70% overall
yield with only one column chromatography purification
needed.
With model substrate 7a in hand, the previously reported
conditions were found to be ineffective for the desired “cut-
and-sew” reaction (entries 1 and 2, Table 1).[11e] Interestingly,
when using the neutral Rh/dppb/ZnCl2 system, changing the
solvent from THF to 1,4-dioxane afforded the desired
tetracyclic product (6a) in 37% yield (entry 3), though the
Scheme 2. Retrosynthetic analysis.
À
to be installed through the deconstructive C O bond cleavage
strategy from intermediate 6 that contains a dihydropyran
moiety. A rhodium-catalyzed enantioselective “cut-and-sew”
transformation with benzocyclobutenones appears to be well-
suited to access tetracycle 6 that contains the fused A/B/C
rings along with the quaternary center.[12] This step not only
sets the important stereochemistry at the C13 and C14
À
positions, but also provides all the C C bonds present in the
natural product. The benzocyclobutenone precursor (7) could
be readily prepared in a convergent manner from alcohol 8
and phenol 9 by the Mitsunobu reaction. Finally, fragments 8
and 9 could be straightforwardly produced from commercially
available compounds 10 and 11, respectively.
Results and Discussion
À
The Key C C Activation Reaction
To explore the proposed synthetic strategy, the key “cut-
and-sew” reaction was investigated first. While a number of
alkene-tethered benzocyclobutenones have previously
proved to be viable substrates for the rhodium-catalyzed
asymmetric carboacylation,[11d–f] compound 7, which contains
an acid-sensitive ketal, a sterically hindered trisubstituted
olefin and a relatively long linker, nevertheless represents
Scheme 4. Preparation of substrate 7a. Bn: benzyl; DIAD: diisopropyl
azodicarboxylate; PCC: pyridinium chlorochromate.
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[a]
À
Table 1: Selected optimization of the C C activation reaction with substrate 7a.
formation
from
anisole
10
(Scheme 5). Surprisingly, subject-
ing substrate 7 to the above opti-
mized racemic conditions (en-
tries 1 and 2, Table 2) gave only
trace desired product with most of
7 decomposed, suggesting the sen-
sitivity of the ketal moiety. To our
delight, under the asymmetric con-
ditions, the desired tetracycle 6 was
obtained in 59% yield with 91.5:8.5
er (entry 3). It is likely that the
enhanced reaction efficiency with
the chiral ligand outcompeted the
decomposition pathway.[11a] Reduc-
ing the reaction temperature to
1308C further enhanced the yield
and enantioselectivity (83% yield,
93:7 er) (entry 4). After examining
various chiral bidentate phosphine
ligands, solvents, and counterions
(entries 5–13), product 6 was ulti-
mately isolated in 80% yield with
97:3 er by switching [Rh-
(COD)2]BF4 to [Rh(COD)2]NTf2
as the catalyst and changing 1,4-
dioxane to 1,2-difluorobenzene
(DFB) as the solvent (entry 13).
Notably, the asymmetric “cut-and-
sew” reaction can be run on a 2 g
scale with a reduced catalyst load-
ing without loss of enantioselectiv-
ity (entry 14). The structure and
relative configuration of com-
pound 6 were confirmed by X-ray
crystallography;[14] its absolute ste-
reochemistry was later confirmed
by X-ray crystallography of its
Entry
1
Catalytic conditions
7a
Conv. [%]
6a
Yield [%][b]
[Rh(CO)2Cl]2 (5 mol%), P(C6F5)3 (40 mol%)
THF (0.04 M), 1408C, 5 days
50
10
n.d.
2[c]
3[c]
4
[Rh(COD)Cl]2 (5 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), THF (0.04 M), 1308C, 12 h
5
[Rh(COD)Cl]2 (5 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), 1,4-dioxane (0.04 M), 1308C, 12 h
57
37
7
[Rh(COD)Cl]2 (5 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), 1,4-dioxane (0.1 M), 1408C, 24 h
10
5[d]
[Rh(C2H4)2Cl]2 (5 mol%), dppb (12 mol%), ZnCl2 (20 mol%),
1,4-dioxane (0.1 M), 1408C, 24 h
30
10
72
5
6
[Rh(COD)2]BF4 (10 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), 1,4-dioxane (0.1 M), 1408C, 24 h
93
7
[Rh(NBD)2]BF4 (10 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), 1,4-dioxane (0.1 M), 1408C, 24 h
10
8
[Rh(COD)MeCN]BF4 (10 mol%), dppb (12 mol%),
ZnCl2 (20 mol%), 1,4-dioxane (0.1 M), 1408C, 24 h
55
45
73
89
9
[Rh(COD)2]BF4 (10 mol%), dppb (12 mol%),
1,4-dioxane (0.1 M), 1408C, 24 h
100
10
[Rh(COD)dppb]BF4 (10 mol%), 1,4-dioxane (0.1 M), 1408C, 24 h
100
11
[Rh(COD)2]BF4 (10 mol%), L1 (12 mol%),
1,4-dioxane (0.1 M), 1408C, 24 h
100
60
(er 89:11)
12
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
1,4-dioxane (0.1 M), 1408C, 24 h
100
83
(er 88.5:11.5)
derivative
16
(see
below,
Scheme 6).[14]
[a] All reactions were run on a 0.1 mmol scale. [b] Yields are isolated yields; numbers in parentheses are
enantiomeric ratio (er) values determined by HPLC on a chiral stationary phase. [c] A second portion of
the same catalysts was added after 12 h. Conv.: conversion; n.d.: not detected; COD: 1,5-cyclo-
octadiene; NBD: norbornadiene; dppb: 1,4-bis(diphenylphosphino)butane; L1: (R)-(À)-DTBM-seg-
phos.
Scope of the Enantioselective “Cut-
and-Sew” Reaction
exact reason is still unclear. After surveying different rhodium
The high efficiency and selec-
precatalysts (entries 4–8), [Rh(COD)2]BF4 proved to be
optimal, giving 72% isolated yield (entry 6). With the cationic
catalyst, the addition of ZnCl2 was found unnecessary
(entry 9). In addition, up to 89% yield was obtained using
a precoordinated [Rh(COD)dppb]BF4 catalyst (entry 10).
Finally, promising enantioselectivity was obtained when
switching the ligand from dppb to chiral ligand (R)-(À)-
DTBM-segphos (L1; entry 11), giving 6a in 83% yield and
88.5:11.5 er with only 5 mol% Rh loading (entry 12).
tivity enabled by the new catalytic conditions motivated us to
examine the scope of the enantioselective “cut-and-sew”
transformation with different cyclic trisubstiuted alkenes
Encouraged by the model study, the ketal-containing
substrate (7) was first prepared in 93% yield through
a Mitsunobu coupling between phenol 9 and alcohol 8 that
was easily accessed through Birch reduction and ketal
Scheme 5. Preparation of substrate 7. DEAD: diethyl azodicarboxylate;
glycol: ethylene glycol; PPTS: pyridinium p-toluenesulfonate.
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[a]
À
Table 2: Optimization of the C C activation of substrate 7.
(Table 3). First, as expected, the
model susbtrate (7a) afforded even
higher yield and higher enantiose-
lectivity under the optimal condi-
tions (entry 1). Cyclic olefins with
different ring sizes all provided the
desired tetracyclic products in
good to excellent yields. The five-
and six-membered-ring substrates
(7a–c) generally offered excellent
enantioselectivity, while the seven-
and eight-membered ring sub-
strates (7e,f) exhibited reduced
enantioselectivity. In addition, the
benzofused olefins (7b and 7d)
gave somewhat lower yields and
er than their nonconjugated coun-
terpartners. Gratifyingly, excellent
enantioselectivity was observed
with these containing heterocyclic
alkenes (7g,h). The more sterically
demanding b-dihydronaphthyl sub-
strate (7i) still proved to be com-
petent, albeit in lower yield and er
under the current conditions. In the
absence of the OMe substituent on
the arene, the six- and five-mem-
bered-ring substrates (7j,k) gave
slightly lower yield but still excel-
lent enantioselectivity. Besides us-
ing an oxygen linker, the nitrogen-
tethered substrates (7l,m) worked
even better, which afforded good
yield and excellent enantioselectiv-
ity (up to 99.5: 0.5 e.r.) likely
benefited from the rigidity of the
linkers. Finally, the new catalytic
conditions are also suitable for the
Entry
1
Catalytic conditions
7a
Conv. [%]
6
er[b]
–
Yield [%][b]
[Rh(COD)dppb]BF4 (10 mol%),
1,4-dioxane (0.1 M), 1408C
95
95
n.d.
5
2
3
[Rh(COD)2]BF4 (10 mol%), dppb (12 mol%),
1,4-dioxane (0.1 M), 1408C
–
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
1,4-dioxane (0.1 M), 1408C
100
100
90
59
83
60
41
n.d.
28
6
91.5:8.5
93:7
4
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
1,4-dioxane (0.1 M), 1308C
5
[Rh(COD)2]BF4 (5 mol%), L2 (6 mol%),
1,4-dioxane (0.1 M), 1308C
37.5:62.5
64:36
–
6
[Rh(COD)2]BF4 (5 mol%), L3 (6 mol%),
1,4-dioxane (0.1 M), 1308C
97
7
[Rh(COD)2]BF4 (5 mol%), L4 (6 mol%),
1,4-dioxane (0.1 M), 1308C
30
8
[Rh(COD)2]BF4 (5 mol%), L5 (6 mol%),
1,4-dioxane (0.1 M), 1308C
95
72:28
–
9
[Rh(COD)2]PF6 (5 mol%), L1 (6 mol%),
1,4-dioxane (0.1 M), 1308C
53
10
11
12
13[c,d]
14[c,d]
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
1,3-DFB (0.1 M), 1308C
100
100
100
100
100
60
52
55
80
76
94.5:5.5
85.5:14.5
96.5:3.5
97:3
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
toluene (0.1 M), 1308C
one-methylene-short
substrate
[Rh(COD)2]BF4 (5 mol%), L1 (6 mol%),
1,2-DFB (0.1 M), 1308C
(7n), giving good yield but poor
er. The exact reason for the signifi-
cantly better enantioselectivity
with the six-membered-ring-form-
ing substrates remains unclear for
this specific catalytic system.
[Rh(COD)2]NTf2 (5 mol%), L1 (6 mol%),
1,2-DFB (0.1 M), 1308C
[Rh(COD)2]NTf2 (4 mol%), L1 (4.8 mol%),
1,2-DFB (0.4 M), 1308C (2 g scale)
97:3
[a] All reactions were run on a 0.1 mmol scale for 24 h. [b] Yields are isolated yields; the enantiomeric
ratio (er) was determined by HPLC on a chiral stationary phase. [c] The reaction was run for 48 h. [d] The
reaction was run on a 2 g scale. DFB: difluorobenzene; Tf: trifluoromethanesulfonyl; n.d.: not detected.
Total Synthesis of (À)-Thebainone A
With
a scalable asymmetric
route to access key intermediate
6, the stage was set for the next
deconstructive
transformation
À
through cleavage of the C O bond
and installation of the nitrogen
moiety (Scheme 6). First, reduc-
tion of the ketone in compound 6
proceeded stereoselectivity with
LiAlH4; the subsequent acetate
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Scheme 6. The first-generation route to (À)-thebainone A (4). DCM: dichloromethane; DMSO: dimethyl sulfoxide; TMS: trimethylsilyl; TFA:
trifluoroacetic acid.
protection followed by in situ ketal removal afforded ketone
radical was further reduced to a carbanion that be protonated
during the acidic workup. This step completes the construc-
tion of the piperidine ring and reveals the ketone moiety in
the C ring.
12[14] in 94% yield over two steps on gram scales. There are
À
substantial challenges to cleave the C O bond of the
dihydropyran moiety in intermediate 12: 1) the ether bond
lacks sufficient ring strain for opening; 2) the presence of
other oxygen functional groups, including ketones and esters,
in the substrate can inhibit Lewis acid coordination; and
In the end game, the more sterically hindered methyl
ether can be selectively cleaved under the nucleophilic
condition, that is, using NaSEt, in 87% yield on a 120 mg
scale.[16] Such a high selectivity is likely due to a more
available s* orbital of the middle ether moiety, as the
bulkiness of the structure disfavors a “flat” conformation
(Figure 2). Notably, the mono-deprotected product 5 is
a known precursor for the total syntheses of codeine (2) and
morphine (1).[17] Finally, (À)-thebainone A (4) was prepared
through the a,b-desaturation of ketone 5 using the Pd(TFA)2/
DMSO system described by Stahl and co-workers (see
Table S2 for details).[5c,18] The spectroscopic data of synthetic
(À)-thebainone A (4) match those reported previously.[6a]
Thus, using this route, the asymmetric total synthesis of (À)-
thebainone A was accomplished from compound 6 in 9 steps
and 13% overall yield.
À
3) due to the rigid molecular scaffold, the C O bond
reformation was found to be facile, which became a significant
difficulty for handling the ring-opened product. Ultimately,
we found that treatment of 12 with BBr3 (5 equiv) in DCM at
À308C for 72 h delivered the diphenol intermediate (13) in
good yield. For comparison, running the reaction at a higher
temperature led to notable decomposition. Protection of the
free phenol moieties proved to be necessary; otherwise, any
basic conditions (tested so far) resulted in reforming the
À
dihydropyran C O bond. After systematic evaluation of
various reaction conditions, the use of CH2N2 in methanol and
ether provided an extremely mild methylation protocol,
giving the desired dimethoxy product in 50% yield on
a 79 mg scale (see Table S1 for details). On a gram scale,
the yield of 14 dropped to 28% plus 32% of the partially
protected product (13a) and 28% of the prior substrate
(12).[14] However, 13a can be further transformed to 14 in
68% yield, along with forming 18% of 12 that can be cycled,
combined, and reused. With a sufficient amount of 14 in hand,
the subsequent ketone protection and amination through an
SN2 reaction, followed by removal of the Ac protecting group,
occurred smoothly in one pot to provide 15 with 76% yield.
Upon elimination of the alcohol moiety with the Martin
sulfurane, a formal hydroamination process took place using
To avoid the acetate protection of the secondary C9
alcohol, an alternative approach to construct intermediate 16
has been developed (Scheme 7). From the “cut-and-sew”
product 6, ketone reduction followed by dehydration provid-
À
ed alkene 18. The subsequent cleavage of the C O bond with
BBr3 still delivered the desired diphenol intermediate, which
was then subjected to the doubly methylation conditions with
CH2N2 to deliver 19 in moderate yield. Finally, a one-pot
sequence of ketal installation and SN2 amination smoothly
delivered sulfonamide 16 (the same one present in the first-
generation route) in good yield. Overall, the second-gener-
ation route saves one step in the longest linear sequence of the
synthesis.
sodium naphthalenide.[15] Under this condition, the Ts N
À
bond was first cleaved to generate a nitrogen-centered radical
that then adds to the olefin; the resulting carbon-centered
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Table 3: Substrate scope of the enantioselective carboacylation with cyclic trisubstituted olefins.[a]
[a] The reaction was carried out with 0.1 mmol of substrate, [Rh(COD)2]NTf2 (5 mol%), and (R)-DTBM-segphos (6 mol%) in 1,2-DFB (1 mL) at 1308C
for 48 h. [b] All yields are isolated yields; the enantiomeric ratio (er) value was determined by HPLC on a chiral stationary phase. [c] The reaction was
carried out with 1 mmol of substrate, [Rh(COD)2]NTf2 (4 mol%), and (R)-DTBM-segphos (4.8 mol%) in 1,2-DFB (0.5 mL) at 1308C for 48 h. Ts: p-
toluenesulfonyl.
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Conflict of interest
The authors declare no conflict of interest.
À
Keywords: alkaloids · asymmetric synthesis · C C activation ·
fused rings · total synthesis
Figure 2. Selective demethylation of vicinal ethers.
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Scheme 7. The second-generation route: Avoiding the Ac protection.
[5] For selected recent studies on the asymmetric total synthesis of
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Arias, H. E. Dela Paz, R. Simionescu, T. Hudlicky, J. Am. Chem.
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Conclusion
In summary, the first enantioselective total synthesis of
(À)-thebainone A (4) has been achieved in 13 (and 14) steps
with 4.7% (and 7.2%) overall yield from commercially
available starting material 11. The efficiency of this synthetic
strategy is primarily highlighted by an asymmetric rhodium-
catalyzed “cut-and-sew” transformation to access the all-
carbon fused-ring structure and the quaternary stereocenter.
Notably, an improved catalytic system has been identified for
the asymmetric “cut-and-sew” transformation with sterically
hindered olefins, which allows for a broad substrate scope
with high enantioselectivity (up to 99.5:0.5 er). The decon-
structive approach illustrated in this synthesis, that is, through
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À
À
cleaving C C and C O bonds in readily available substrates
to build more complex structures, could have broader
implications beyond this work.
Acknowledgements
À
[8] For selected books and reviews on catalytic C C bond activa-
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NIGMS (2R01GM109054) and University of Chicago are
acknowledged for research support. S.-H.H. acknowledges
the International Postdoctoral Exchange Fellowship Program
2017 from the Office of China Postdoctoral Council. We
thank Shusuke Ochi and Dr. Ki-Young Yoon for X-ray
crystallography. Umicore AG & Co. KG and Chiral Technol-
ogy are acknowledged for their generous donation of Rh salts
and chiral HPLC columns, respectively.
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Accepted manuscript online: April 6, 2021
Version of record online: && &&
,
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These are not the final page numbers!

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Research Articles
À
C C Activation
S.-H. Hou, A. Y. Prichina,
G. Dong*
&&&& — &&&&
Deconstructive Asymmetric Total
Synthesis of Morphine-Family Alkaloid
(À)-Thebainone A
A deconstructive strategy involving the
ing materials (see scheme). The rhodium-
catalyzed asymmetric carboacylation
reaction was applied successfully to the
construction of various polycyclic skel-
etons.
À
À
cleavage of relatively inert C C and C O
bonds to build more complex scaffolds
enabled the total synthesis of morphine
alkaloid (À)-thebainone A in 13 (and 14)
steps from commercially available start-
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 10
These are not the final page numbers!