A Protecting-Group-Free Synthesis of (?)-Salvinorin A

Article abstract of DOI:10.1002/chem.202100560

A concise enantioselective total synthesis of the neoclerodane diterpene (?)-salvinorin A is reported. The stereogenic center at C-12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels-Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2-diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (?)-salvinorin A was synthesized in only 16 steps starting from 3-furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels-Alder strategy employing a 2-bromo-1,3-diene moiety was investigated.

Full text of DOI:10.1002/chem.202100560

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A Protecting-Group-Free Synthesis of (À )-Salvinorin A
Patrick Zimdars,[a] Yuzhou Wang,[a] and Peter Metz*[a]
In memory of Professor Siegfried Hünig (1921–2021)
Abstract: A concise enantioselective total synthesis of the
neoclerodane diterpene (À )-salvinorin A is reported. The
stereogenic center at C-12 was installed by catalytic asym-
metric propargylation with excellent enantioselectivity, and
the remaining six stereogenic centers were set up highly
diastereoselectively under substrate control. As for our
previous synthesis of racemic salvinorin A, two intramolecular
Diels-Alder reactions were applied to generate the tricyclic
core. A chemoselective Mitsunobu inversion of a syn 1,2-diol
allowed for further streamlining of the original reaction
sequence by two steps. Overall, (À )-salvinorin A was synthe-
sized in only 16 steps starting from 3-furaldehyde with 1.4%
total yield. Furthermore, an alternative intramolecular Diels-
Alder strategy employing a 2-bromo-1,3-diene moiety was
investigated.
Introduction
(À )-Salvinorin A (1), a neoclerodane diterpene isolated from the
leaves of the Mexican medicinal plant Salvia divinorum,[1] is a
potent and highly selective k opioid receptor (KOR) agonist.[2]
Smoking of microgram amounts of 1 leads to hallucinogenic
perceptions, and the leaves of Salvia divinorum have been used
over centuries for spiritual practices by indigenous people in
Mexico.[3] Today, the diterpene 1 is considered to be a
promising lead for the development of drugs against disorders
of the central nervous system, such as depression, pain, and
drug addiction.[3,4] Thus, 1 represents an attractive synthetic
target. To this date, four asymmetric total syntheses[5] of (À )-
salvinorin A (1) have been developed by the groups of Evans[6a]
(2007), Hagiwara[6b,c] (2008 and 2009), and Forsyth[6d] (2016).
Moreover, further synthetic studies towards 1[7] and extensive
investigations on hundreds of analogues prepared by chemical
modification of the natural product 1 have been reported.[3] An
exciting novel research direction focusses on the rapid gener-
ation of designed KOR agonistic analogues of 1 by total
synthesis.[5,8]
Scheme 1. Retrosynthetic analysis of our previous synthesis[9] of racemic
salvinorin A (rac-1).
eocontrol and set up the relative configuration of the stereo-
genic centers at C-4, C-5, C-10 (transformation of rac-3 to rac-2)
as well as C-8 (with subsequent epimerization) and C-9 (rac-5 to
rac-4). As part of the final five steps from rac-2 to rac-1, the
stereogenic center at C-2 was installed via cis dihydroxylation
from the β face of rac-2 and subsequent Mitsunobu inversion.
In conclusion, except for C-12, each stereogenic center was
formed diastereoselectively under substrate control. Therefore,
transition from our route in the racemic series to an asymmetric
synthesis would be easily achieved by enantioselective con-
struction of the stereogenic center at C-12 (see structure 5).
Moreover, we strived for a streamlining of the final synthetic
sequence (Scheme 2). While we used a selective triethylsily-
lether monoprotection to differentiate the two secondary
alcohols formed upon dihydroxylation of rac-2, we now wanted
to realize a completely protecting-group-free synthesis. We
envisioned to install a suitable substituent X at C-1 to combine
In 2018, we established an 18-step synthesis of racemic
salvinorin
A (rac-1) starting from 3-furaldehyde (6) that
employed two intramolecular Diels-Alder reactions (IMDA) as
the key steps for construction of the tricyclic framework
(Scheme 1).[9] Both Diels-Alder reactions featured good diaster-
[a] P. Zimdars, Dr. Y. Wang, Prof. Dr. P. Metz
Fakultät Chemie und Lebensmittelchemie
Organische Chemie I, Technische Universität Dresden
Bergstraße 66, 01069 Dresden (Germany)
E-mail: peter.metz@chemie.tu-dresden.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100560
© 2021 The Authors. Chemistry - A European Journal published by Wiley-
VCH GmbH. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and re-
production in any medium, provided the original work is properly cited.
the dihydroxylation step with
a subsequent collapse of
intermediate 12 to form α-hydroxy ketone 13 in a single step.[10]
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Scheme 3. Synthesis of the racemic IMDA substrate rac-5 and various
strategies for asymmetric construction of the stereogenic center at C-12. a)
°
°
Mg, cat. HgCl2, propargyl bromide, Et2O, À 78 C to 0 C, 40 min, 97%; b)
°
Cp2ZrCl2, AlMe3, CH2Cl2, RT, overnight, then I2, THF, À 50 C, 2 h, 77%; c) CuTC,
°
(2-propenyl)SnBu3, NMP, 0 C, 24 h, 95%; d) acryloyl chloride, cat. DMAP,
Scheme 2. Possible pathways for streamlining of the final synthetic
sequence.
°
NEt3, CH2Cl2, À 78 C to RT, 5 h, 91%; e) (À )-DIPT, Ti(Oi-Pr)4, 0.65 equiv. TBHP,
°
CH2Cl2, À 21 C, 24 h, 44%, 99% ee; f) cat. (À )-DIPT, cat. Ti(Oi-Pr)4, 0.65 equiv.
°
°
TBHP, CH2Cl2, À 21 C, 48 h, 43%, 94% ee; g) DMP, NaHCO3, CH2Cl2, 0 C to RT,
35 min, 96%; h) cat. [Ru(p-cymene)Cl2]2, cat. (S,S)-TsDPEN, KOH, i-PrOH, RT,
°
38 h, 66%, 99% ee; i) cat. 19, 22, PhMe, 4 Å molecular sieves, 0 C, 6 d, 64%
°
16, 81% ee; j) cat. 20, SiCl4, 23, CH2Cl2, À 30 C, 18 h, 96% 16, 77% ee; k) cat.
The known Mitsunobu inversion of 13[6b,9] would complete the
synthesis of (À )-salvinorin A (1). An alternative strategy was
inspired by the work of O’Doherty et al.[11] who reported a
chemoselective Mitsunobu inversion of a cyclohexane syn 1,2-
diol with conversion of the axial hydroxy group only. According
to our NMR analysis of racemic diol 14,[9] the hydroxy group at
C-2 indeed occupies an axial position, which provides the
opportunity for a selective transformation of 14 to give 15.
Oxidation of 15 to afford (À )-1 was already reported by Forsyth
et al.[6d]
°
°
21, 23, CH2Cl2, À 35 C to 0 C, 19 h, then RT, 3 d, 80% 16, 97% ee.
Cp=cyclopentadienyl, TC=thiophene-2-carboxylate, NMP=N-methyl-2-pyr-
rolidone, DMAP=4-dimethylaminopyridine, DIPT=diisopropyl tartrate,
TBHP=tert-butylhydroperoxide, DMP=Dess–Martin periodinane, Ts=Tosyl,
DPEN=1,2-diphenyl-1,2-ethylenediamine.
converted 3-furaldehyde (6) to homopropargylic alcohol 16.
However, four or five steps were needed, respectively. Our aim
was to apply
a methodology using a
chiral catalyst.[15]
Specifically, we focused on catalysts bearing chiral binaphthyl
moieties that already performed well for asymmetric propargy-
lation (Figure 1). Independently of each other, Houk and Antilla
et al. as well as Reddy developed a protocol using (S)-TRIP (19)
as the chiral catalyst and allenyl pinacol borane (22) as the
propargylation agent.[16a,b] Adaption to 3-furaldehyde (6) gave
the desired homopropargylic alcohol 16 in 64% yield with 81%
ee (Scheme 3). Furthermore, we applied Denmark’s chiral
phosphoramide 20 in combination with SiCl4 as a Lewis acid,
Results and Discussion
We started our investigations with the asymmetric synthesis of
Diels-Alder substrate 5, the racemic form of which is readily
available in four steps starting from 3-furaldehyde (6;
Scheme 3).[7d,9] For enantioselective construction of the stereo-
genic center at C-12 we pursued several strategies.
Kinetic resolution of the racemic homopropargylic alcohol
rac-16[7d] using the Sharpless asymmetric epoxidation[12] deliv-
ered the desired (S)-enantiomer 16 in 44% yield with 99% ee
(stoichiometric method) or 43% yield with 94% ee (catalytic
method), respectively. However, yields are limited to 50% using
this methodology. Alternatively, alkyne rac-16 was first con-
verted to dienol rac-17.[7d,9] After oxidation with DMP, the
resulting dienone 18 was subjected to an asymmetric Noyori
reduction[13] to give the (S)-configured dienol 17 in fair yield
(66%) with excellent enantioselectivity (99% ee).
A third and most direct strategy replaced the Grignard
propargylation of 6 by an asymmetric method (Scheme 3). In
2006, Singaram et al. achieved this transformation under
indium-mediated Barbier-like conditions using stoichiometric
amounts of (1S,2R)-(+)-2-amino-1,2-diphenylethanol as a chiral
auxiliary.[14a] The groups of Evans[6a] and Prisinzano[14b] also
Figure 1. Examples of known catalytic systems for enantioselective prop-
argylation of aldehydes – chiral catalysts (top line) and corresponding
nucleophiles (bottom line).[16]
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which can be used for both allylation and propargylation of
aldehydes.[16c] Using allenyltributylstannane (23) as the nucleo-
phile, 16 was obtained in high yield (96%) with 77% ee. Finally,
we also tested Maruoka’s chiral bis-titanium(IV)-oxide catalyst
21 with 23 as the nucleophile.[16d] To our delight, 16 was
isolated in 80% yield with an excellent 97% ee. Noteworthy,
upscaling of this reaction up to 1.5 g 3-furaldehyde (6) affected
neither the yield nor the enantioselectivity. Due to the high ee
of the desired homopropargylic alcohol 16, the option of
running the reaction on a gram scale, and the facile in situ
generation of catalyst 21, we selected Maruoka’s system for our
synthetic purpose.
With almost enantiopure 16 (97% ee) in hand, preparation
of lactone 4 was achieved as for our synthesis in the racemic
series[7d,9] through carboalumination/iodolysis of alkyne 16 to
vinyl iodide 24, Liebeskind coupling to give diene 17, acylation
of the alcohol, IMDA of the resulting acrylate 5, and subsequent
de-/reprotonation to increase the diastereomeric purity of 4.
Some parts of this known sequence were studied in more depth
(Scheme 4): (1) Stoichiometric carboalumination of alkyne 16[7d]
was replaced by Wipf’s catalytic version[17] without significant
loss of yield. (2) Installation of the diene moiety of 17 was
alternatively accomplished in a one-pot process by Pd-catalyzed
cross-coupling of the intermediate vinylalane with 2-bromopro-
pene. After intensive optimization of the reaction conditions
performed with the racemic starting material rac-16, a mixture
of diene rac-17 and olefin rac-25 was obtained in 54% and
13% yield (NMR), respectively. Formation of olefin rac-25 could
not be prevented, but after double flash chromatography the
desired diene rac-17 was isolated nearly without loss in 51%
yield as a pure compound. Regarding the efficiency of this
transformation, the two-step procedure (74%[7d] for carboalumi-
nation/iodolysis+95%[9] for Liebeskind coupling=70% over
two steps) is still superior to the one-pot reaction. (3) Use of
stoichiometric amounts of the radical inhibitor BHT increased
the yield of the IMDA of 5 to 94%.
the target diterpene 1, lactone 4 was employed as the racemic
mixture (Scheme 5). Thus, rac-4 was converted to keto aldehyde
rac-28 as previously reported.[9] We first focused on the
preparation of the brominated tricycle rac-7, which should be
available by IMDA using a 2-bromo-1,3-diene moiety.[18] For
substrate synthesis, keto aldehyde rac-28 was subjected to a
Ramirez dibromoolefination.[19] Installation of the diene moiety
could then be achieved either by a three-step protocol
consisting of (E)-selective Sonogashira cross-coupling[20] of rac-
29 with TIPS-acetylene, desilylation, and alkyne semi-
reduction[21] or preferably by a direct (E)-selective Stille cross-
coupling[22] of dibromoolefin rac-29. The resulting ketone rac-32
was subjected to Horner-Wadsworth-Emmons (HWE) olefina-
tion. In analogy to our previous work,[9] partial C-8 epimerization
occurred, leading to four diastereomers rac-33, rac-34, and two
(Z)-enoate isomers. Enoate rac-33, which was isolated as a pure
compound by simple flash chromatography, could in principle
be a suitable IMDA substrate given the option of post-
cycloaddition epimerization at C-8. On the other hand, rac-34
could only be separated from rac-33 by semi-preparative HPLC.
Moreover, compounds rac-33 and rac-34 were rather unstable
and should be used for the next reaction step quickly. Due to
this lability and the laborious isolation of pure rac-34, we did
not favor C-8 epimerization of rac-33 at this stage.
In an alternative attempt for the preparation of IMDA
substrate rac-34, we simply changed the order of events and
For a first evaluation of the idea to use functionalized
cyclohexenes 7–11 (see Scheme 2) as intermediates en route to
Scheme 5. Preparation of IMDA substrates rac-33 and rac-34. a) cat. OsO4,
°
Scheme 4. Synthesis of enantiopure lactone 4. a) cat. Cp2ZrCl2, AlMe3, H2O,
NMO, acetone, H2O, 0 C to RT, 24 h, 69%; b) PIDA, CH2Cl2, RT, 1.5 h, 88%; c)
°
°
°
CH2Cl2, À 25 C to RT, 5 h, then I2, THF, À 50 C to RT, 17 h, 74% 24; b) CuTC,
CBr4, PPh3, CH2Cl2, 0 C, 45 min, 95%; d) cat. Pd(DPEphos)Cl2, cat. CuI, NEt3,
°
°
°
°
(2-propenyl)SnBu3, NMP, 0 C, 24 h, 95%; c) performed with rac-16: cat.
TIPS-acetylene, PhH, 3 C to 5 C, 35 min, 87%; e) TBAF, HOAc, THF, À 70 C to
°
°
Cp2ZrCl2, AlMe3, H2O, CH2Cl2, À 30 C to RT, 4 h, then cat. Pd2dba3, 2-
0 C, 50 min, 100%; f) cat. (IPr)Cu(Ot-Bu), PMHS, i-BuOH, PhMe, RT, 24 h, 99%;
bromopropene, THF, reflux, 18 h, crude mixture: 54% rac-17+13% rac-25,
purely isolated: 51% rac-17, 3% rac-25; d) acryloyl chloride, cat. DMAP, NEt3,
g) cat. Pd2dba3, cat. P(o-furyl)3, Bu3Sn(vinyl), PhMe, RT, 24 h, 90%; h) NaH,
methyl diethylphosphonoacetate, THF, RT, 24 h, 41% rac-33, 11% rac-34.
NMO=N-methylmorpholine N-oxide, PIDA=phenyliodine(III) diacetate, DPE-
phos=bis(2-diphenylphosphino)phenyl ether, TBAF=tetrabutylammonium
fluoride, IPr=1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene,
PMHS=polymethylhydrosiloxane.
°
°
CH2Cl2, À 78 C to RT, 16 h, 92% 5; e) BHT, PhCl, sealed tube, 183 C, 2.8 d,
°
°
then RT, 19 h, 94% 4, 91% ds; f) LiHMDS, THF, À 78 C to 0 C, 2 h, then
°
°
MeOH, À 95 C to À 86 C, 1 h, 87%, ds�97%. BHT=2,6-di-tert-butyl-4-
methylphenol.
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built the dienophile moiety first through HWE reaction of
ketone rac-29 still bearing the dibromoolefin substructure
(Scheme 6).
for this unexpected process.[23] To the best of our knowledge,
such a halogen exchange during Diels-Alder reactions has not
been reported yet. Thus, one run gave a mixture of cyclo-
adducts rac-37 and rac-38, presumably formed via two different
endo-chair transition states,[9] in a combined yield of 85% with a
diastereomeric ratio of 3:1.
Again, C-8 epimerization occurred during HWE olefination,
but all four isomers could be separated from each other by
simple flash chromatography. Unfortunately, additional forma-
tion of products with a bromo alkyne moiety was observed that
contaminated the product fractions of rac-36 and rac-35. The
latter compound was subjected to C-8 epimerization with DBU
delivering rac-36 in 22% (81% brsm) yield along with reisolated
starting material. After running this reaction a few times, the
majority of rac-35 was transformed to rac-36, which was then
submitted to Stille coupling. To our delight, double flash
chromatography afforded rac-34 as a pure compound free from
bromoalkyne or eneyne impurities.
Both trienes rac-33 and rac-34 were subjected to the crucial
second IMDA reaction (Scheme 7). For rac-33, featuring a cis
relationship between diene and dienophile, several runs of the
IMDA were accompanied by either partial or complete Br/Cl-
exchange at C-1. Since we used the radical inhibitor BHT in
large excess, it is unlikely that this exchange occurs via a radical
mechanism with the solvent PhCl acting as the chlorine source.
Alternatively, traces of transition metals could be responsible
In anticipation of an improved diastereoselectivity,[9] we
examined the IMDA of rac-34 with a trans relationship between
diene and dienophile. Unfortunately, this reaction lacked
reproducibility over the six runs made. Scheme 7 illustrates this
issue exemplified by the results of two different runs under
similar reaction conditions. Whereas in one case Br/Cl-exchange
only occurred in negligible amounts and provided the desired
cycloadduct rac-7 in good yield (72%, 84% brsm) with excellent
diastereoselectivity (98%), complete Br/Cl-exchange took place
to deliver rac-8 contaminated by 10% of an unknown isomer
and rac-39 as the only products in another experiment. From a
mechanistic point of view, formation of rac-7/rac-8 is assumed
via an endo-chair transition state,[9] whereas rac-39 is formed by
epimerization at C-12.[24] The use of bromobenzene as the
solvent to prevent formation of chlorine-containing cyclo-
adducts only led to decomposition of the substrate rac-34.
Nevertheless, we had obtained enough material of rac-7
and rac-8 to investigate our initial strategy for the direct
synthesis of rac-13 (Scheme 8). We tested a wide range of
conditions for dihydroxylation, such as (1) stoichiometric use of
OsO4, (2) OsO4/H2O2 according to Vogel et al.,[10c] (3) various
reagents for reoxidation of Os(VI) such as trimethylamine N-
oxide[25] and potassium perchlorate,[26] (4) additives like citric
acid[27] or 3,5-lutidine for ligand acceleration, (5) Narasaka’s
modification,[28] (6) Sharpless asymmetric dihydroxylation,[29] and
(7) Ru-catalysis.[30] In general, vinyl chloride rac-8 exhibited
higher reactivity than vinyl bromide rac-7, but in all cases yields
remained in a very poor range. The best results were achieved
applying Vogel’s conditions[10c] to furnish rac-13 in 5% yield
(from vinyl bromide rac-7) or 20% yield (from vinyl chloride rac-
8), respectively. Furthermore, synthesis of rac-13 through
epoxidation of rac-7 or rac-8 with m-CPBA[29] or meth-
yltrioxorhenium[31] failed as well. We tried to overcome this
issue by converting vinyl halides rac-7 or rac-8 into the vinyl
acetate[32] rac-9, or aryl[33] and silyl ethers[34] rac-10 or rac-11.
Unfortunately, no conversion to any of the desired compounds
could be achieved.
Scheme 6. Alternative preparation of IMDA substrate rac-34. a) NaH, methyl
diethylphosphonoacetate, THF, RT, 25 h, 32% rac-35, 15% rac-36; b) DBU,
°
CH2Cl2, 0 C to RT, 2 h, 22% (81% brsm); c) cat. Pd2dba3, cat. P(o-furyl)3,
Bu3Sn(vinyl), PhMe, RT, 26 h, 76%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
Scheme 7. IMDA of substrates rac-33 and rac-34. a) BHT, PhCl, sealed tube,
°
°
200 C, 4.5 d, 85%, dr=76:24; b) BHT, PhCl, sealed tube, 200 C, 4.6 d, 72%
Scheme 8. Attempts for utilization of IMDA products rac-7 and rac-8. a)
°
°
rac-7 (84% brsm), 98% ds; c) BHT, PhCl, sealed tube, 200 C, 3.7 d, 44% rac-8,
OsO4, H2O2, NaHCO3, THF/PhMe/H2O, for rac-7: 0 C to RT, 20 h, 5% (29%
°
°
90% purity, 14% rac-39, >99% ds.
brsm), for rac-8: 0 C to 60 C, 72 h, 20% (38% brsm).
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As a consequence, the IMDA strategy using a 2-bromo-1,3-
diene moiety was abandoned, and no further efforts were made
to optimize the production of rac-7 or rac-8 by cycloaddition.
Instead, we then focused on shortening our access to (À )-
salvinorin A (1) by a chemoselective Mitsunobu inversion of diol
14 (Scheme 9). Thus, keto aldehyde 28 prepared in two steps
from lactone 4 (97% ee) was converted to diol 14 in six steps
according to the route developed in the racemic series.[9] After
optimization of reaction time, temperature, and amounts of
reagents, we were indeed able to convert 14 to monoacetate
15 in 50% (61% brsm) yield along with reisolated starting
material. Although a large excess of reagents was required,
virtually enantiopure homopropargyl alcohol 16 in hand, our
synthesis in the racemic series was reproduced with some
improvements up to the stage of diol 14. Finally, the route to
(À )-salvinorin A (1) was shortened by two steps through
application of a chemoselective Mitsunobu esterification. Over-
all, (À )-salvinorin A (1) was synthesized from the commercially
available 3-furaldehyde (6) in only 16 steps with 1.4% total yield
without the use of any protecting group. Thus, this second-
generation synthesis represents the shortest enantioselective
route to 1 with the highest overall yield.
isolation of the pure product 15 was achieved without Experimental Section
problems by simple flash chromatography. Finally, oxidation[6d]
Experimental Details see Supporting Information.
of alcohol 15 furnished (À )-salvinorin A (1), the spectroscopic
data of which were in full agreement with the literature.[1]
Acknowledgements
Conclusion
We thank Dr. Tilo Lübken (TU Dresden) and Dr. Ingmar Bauer
(TU Dresden) for analytical support. Open access funding
enabled and organized by Projekt DEAL.
We succeeded in the transition from our previous total
synthesis of racemic salvinorin A (rac-1) into a streamlined
enantioselective version. Several systems for catalytic asymmet-
ric propargylation of aldehydes were applied to 3-furaldehyde
(6), and the methodology of Maruoka et al. was found to be Conflict of Interest
superior, especially due to its high enantioselectivity. With
The authors declare no conflict of interest.
Keywords: Asymmetric catalysis · Cycloaddition · Mitsunobu
reaction · Terpenoids · Total synthesis
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Scheme 9. Final synthetic steps to (À )-salvinorin A (1). a) CrCl2, CHI3, THF,
°
°
8 C to 10 C, 5 h, 58%; b) NaH, methyl diethylphosphonoacetate, DME, RT,
48 h, 40% 41, 21% 42; c) DBU, CH2Cl2, RT, 3 h, 34% (100% brsm); d) cat.
°
Pd(MeCN)2Cl2, Bu3Sn(vinyl), NMP, 24 h, 0 C, 93%; e) BHT, PhCl, sealed tube,
°
200 C, 87.5 h, 66% (88% brsm), 94% ds; f) OsO4, 3,5-lutidine, THF, toluene,
°
°
0 C to RT, 24 h, 95%; g) Ph3P, DBAD, HOAc, THF, 60 C, 47 h, 50% (61%
brsm); h) cat. TPAP, NMO, CH2Cl2, 4 Å molecular sieves, RT, 2 h, 92%.
DME=dimethoxyethane, DBAD=di-tert-butyl azodicarboxylate, TPAP=te-
trapropylammonium perruthenate.
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Chemistry—A European Journal
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Manuscript received: February 12, 2021
Accepted manuscript online: March 30, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–7
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© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
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These are not the final page numbers!

FULL PAPER
A divine sage: The potent KOR
P. Zimdars, Dr. Y. Wang, Prof. Dr. P.
Metz*
agonist (À )-salvinorin A was synthe-
sized in only sixteen steps by modifi-
cation of our previous route to the
racemic title compound. Transition to
asymmetric synthesis succeeded by a
highly enantioselective propargylation
to install the stereogenic center at C-
12. Shortening of the original reaction
sequence by two steps was finally
achieved using a chemoselective
Mitsunobu esterification of a cyclic
syn 1,2-diol. Furthermore, an alterna-
tive intramolecular Diels-Alder
1 – 7
A Protecting-Group-Free Synthesis
of (À )-Salvinorin A
strategy employing a 2-bromo-1,3-
diene moiety was investigated.