Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine

Article abstract of DOI:10.1002/chem.201503641

(+)-Ryanodine (1) is the ester derivative of 1H-pyrrole-2-carboxylic acid and the complex terpenoid (+)-ryanodol (2), which possesses eleven contiguous stereogenic centers on the ABCDE-ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1, the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3-hydroxy group must be acylated in a site-selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE-ring 7. Stereoselective construction of the C3-secondary, C2- and C6-tertiary alcohols was achieved by three nucleophilic reactions. The C9- and C10-trisubstituted carbon centers were regio- and stereoselectively introduced by hydroboration/oxidation of the six-membered C-ring, which was formed by the ring-closing metathesis reaction. Direct esterification of the C3-alcohol with pyrrole-2-carboxylic acid proved unsuccessful; therefore, we developed a new, two-step protocol for attachment of the pyrrole moiety. The C3-hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3-bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1.

Full text of DOI:10.1002/chem.201503641

DOI: 10.1002/chem.201503641
Full Paper
&
Total Synthesis
Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine
Kengo Masuda, Masaki Koshimizu, Masanori Nagatomo, and Masayuki Inoue*[a]
Abstract: (+)-Ryanodine (1) is the ester derivative of 1H-pyr-
role-2-carboxylic acid and the complex terpenoid (+)-ryano-
dol (2), which possesses eleven contiguous stereogenic cen-
ters on the ABCDE-ring system. Compound 1 is known to be
a potent modulator of intracellular calcium release channels,
whereas the activity of 2 is significantly weaker. To chemical-
ly construct 1, the multiple oxygen functional groups must
be installed on the fused pentacycle in stereoselective fash-
ions and the extremely hindered C3-hydroxy group must be
acylated in a site-selective manner. First, the total synthesis
of 2 was accomplished by introducing the five stereocenters
from the previously prepared enantiopure ABDE-ring 7. Ste-
reoselective construction of the C3-secondary, C2- and C6-
tertiary alcohols was achieved by three nucleophilic reac-
tions. The C9- and C10-trisubstituted carbon centers were
regio- and stereoselectively introduced by hydroboration/ox-
idation of the six-membered C-ring, which was formed by
the ring-closing metathesis reaction. Direct esterification of
the C3-alcohol with pyrrole-2-carboxylic acid proved unsuc-
cessful; therefore, we developed a new, two-step protocol
for attachment of the pyrrole moiety. The C3-hydroxy group
was first converted into the less sterically cumbersome gly-
cine ester, which was then transformed into the pyrrole ring
through condensation with 1,3-bis(dimethylamino)allylium
tetrafluoroborate. This procedure resulted in the first total
synthesis of 1.
Introduction
(+)-Ryanodine (1) is a plant natural product that exhibits pow-
erful pharmacological and insecticidal actions.[1] Evidence indi-
cates that the site of action is an intracellular calcium channel,
which is generally termed the ryanodine receptor (RyR).[2] RyRs
form homotetrameric assemblies and constitute the largest ion
channels known to date, with molecular masses of 2.2 MDa
and each monomer consisting of 5000 amino acid residues.
They release Ca2+ ions from the endoplasmic (sarcoplasmic) re-
ticulum, and thus control many Ca2+-dependent processes
within the cell. Binding of 1 alters the channel conductance by
inducing a long-lived, particularly open conformation of RyR.[3]
At millimolar concentrations, ryanodine induces a closed state
of the channel. In addition, altered RyR gating has been impli-
cated in a range of skeletal and cardiac diseases. Therefore,
1 has been used as a biological probe for the investigation of
RyR function, and is regarded as a lead structure for develop-
ment of therapeutic agents for various diseases.[4]
Scheme 1. Preparation and biological activity of (+)-ryanodine (1) and its de-
rivatives.
To pinpoint biologically essential functionalities within the
molecule, various ryanoids were prepared from natural 1 and
employed for structure-activity relationship (SAR) studies
(Scheme 1).[5,6] Whereas 1 binds to RyRs of vertebrate skeletal
muscle with a dissociation constant (KD) of 7 nm, (+)-ryanodol
(2), which was generated by the basic hydrolysis of 1,[1a] exhib-
its 1,700 times weaker affinity.[7] Moreover, the C3-stereoisomer
(3) and regioisomer of 1 (4) show larger KD values.[7,8] These
data together demonstrate the significance of both the pres-
ence and orientation of the pyrrole moiety to exert strong
binding towards RyRs.[9]
The unique structure of (+)-ryanodine (1) comprises a fused
pentacyclic ABCDE-ring system, a pyrrole-2-carboxylate ester,
and eleven contiguous stereocenters including eight tetrasub-
stituted carbon atoms.[10] Given its biological activities and
wide array of intriguing structural features, many synthetic
chemists have faced formidable chemical challenges posed by
[a] K. Masuda, M. Koshimizu, Dr. M. Nagatomo, Prof. Dr. M. Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: inoue@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503641.
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1.[11] In 1979, Deslongchamps reported the successful total syn-
thesis of (+)-ryanodol (2) from (+)-carvone in 43 total steps.[12]
However, attempted conversion of 2 into 1 resulted in the for-
mation of the regioisomer of natural product 4.[8] Even now,
chemical construction of 1 has not yet been accomplished,
which clearly indicates the exceeding difficulty in assembly of
the complex architecture of 1 in combination with the regiose-
lective esterification at the C3-position of heptaol 2. In the pre-
ceding publication, we reported the preparation of the enan-
tiopure ABDE-ring system 7 from 2,5-dimethylbenzene-1,4-diol
(9) in 21 steps (Scheme 2).[13,14] Herein, the total synthesis of
reoselective C6-functionalization of 7 and C-ring formation
would give the entire ring skeleton 6, to which the four stereo-
centers (C2, 3, 9, 10) would be stereoselectively introduced to
construct the highly advanced intermediate 5. While hydroge-
nation of the C13-olefin and hydrogenolysis of the two benzyl
(Bn) groups would furnish 2, attachment of the pyrrole moiety,
followed by the hydrogenation/hydrogenolysis procedure,
would give rise to 1. Realization of the simple transformations
envisioned here turned out to be extremely challenging, be-
cause the requisite groups needed to be introduced to sterical-
ly congested positions surrounded by the fused rings and the
pre-existing tetrasubstituted carbon centers. In fact, the design
of three-dimensional shapes of the intermediates and selection
of powerful reactions were the most critical issues with respect
to the successful synthesis of 1 and 2.
Total synthesis of (+)-ryanodol
To separately address the stereoselective synthesis of the ter-
penoid portion and the regioselective introduction of the pyr-
role portion, the total synthesis of (+)-ryanodol (2) was pur-
sued first. As an opening phase of this endeavor, the C6-
ketone and C10-olefin were constructed from the ABDE-ring
system 7 prior to introduction of the C6-, C9-, and C10-stereo-
genic centers (Scheme 3). First, the C6-OMOM of bis-MOM-
ether 7 was selectively removed by the action of BF3·OEt2 and
Me2S at À408C,[16] affording C6-alcohol 10. The regioselectivity
observed in the deprotection is attributable to the electron-
withdrawing property of the C3-ketone that decreased the
Lewis-basicity of the C2-OMOM group toward BF3·OEt2 in com-
parison to that of the C6-OMOM group. The liberated C6-hy-
droxy group of 10 was oxidized with Dess–Martin reagent[17] to
produce C6-ketone 11. Next, the terminal olefin of 11 was then
isomerized to the C10-(E)-olefin of 12 using PdCl2(MeCN)2.[18]
The remaining MOM group of 12 was, in turn, detached by ap-
plying the same reagent system to 7 at À208C, leading to 13.
The top face of the C6-ketone and both faces of the C3-
ketone of 13 were sterically protected by the methyl groups at
the C5-position and the acetonide. As a result, addition of (3-
methylbut-3-en-1-yl)lithium[19] occurred regio- and stereoselec-
tively at the C6-ketone of diketone 13 from the bottom face
to produce 14.[20] The C9-olefin of the elongated chain, in turn,
underwent the ring-closing metathesis reaction with the iso-
merized C10-olefin upon use of second generation Hoveyda–
Grubbs’ catalyst (A),[21,22] resulting in formation of the six-mem-
bered C-ring 6.
Scheme 2. Synthetic plan for the synthesis of (+)-ryanodol (2) and (+)-rya-
nodine (1).
(+)-ryanodol (2) from 7 is first described.[15] We disclose
a novel synthetic method for installation of the pyrrole-2-car-
boxylate ester at C3-OH, and its application to the first total
synthesis of (+)-ryanodine (1). The new strategies and tactics
developed here will enable the generation of chemical deriva-
tives of this exceedingly complex structure, and will have fur-
ther applications to the total syntheses of numerous highly
oxygenated natural products beyond this achievement.
Results and Discussion
Synthetic plan
In our synthetic plan of (+)-ryanodine (1), recognition of the
embedded symmetric structure allowed application of a series
of pairwise functionalizations from the enantiopure C2-symmet-
ric bicyclo[2.2.2]octene (+)-8 (Scheme 2). Consequently, the
synthesis of the densely functionalized ABDE-ring 7 from 9
was efficiently realized in 21 steps, including the installations
of six contiguous tetrasubstituted carbon centers (C1, 4, 5, 11,
12, 15). Therefore, the most critical issue for the total synthesis
of 1 from 7 was to accommodate the five remaining stereo-
centers (C2, 3, 6, 9, 10) and conjugate 1H-pyrrole-2-carboxylic
acid at the C3-hydroxy group. In the synthetic direction, ste-
Combination of the Pd-mediated isomerization and Ru-cata-
lyzed metathesis reactions set the C9,10-double bond, which
was then utilized for introduction of the requisite C9,10-stereo-
genic centers. Application of the hydroboration/oxidation pro-
tocol to olefin 6, however, led to formation of the undesired
diastereomer 15. The borane reagent approached from the
convex face of the oxa-cis-decalin CD-ring to introduce the in-
correct C9,10-stereochemistries (JH9H10 =3.7 Hz). To override the
intrinsic steric bias, the C6-hydroxy group was capped with the
bulky TMS group. Thus, diol 6 was converted into bis-TMS-
ether 16 using TMSOTf and pyridine at 808C. Since the TMS
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protected the C10-OTMS to furnish bis-TMS-ether 19. Benzyl
protection of the C10-alcohol 19 was, in turn, realized by using
the reagent combination of BnO(C=NPh)CF3 and Sc(OTf)3,[23]
and subsequent basic work-up removed the TMS group at the
C2-oxygen atom, giving rise to alcohol 20. Thus, liberated C2-
alcohol 20 was oxidized to the corresponding C2-ketone 21 by
using Dess–Martin reagent.
At this stage, nucleophilic attack of the three-carbon unit on
the C2-ketone of 21 was necessitated. Although the target
structure 2 possesses an isopropyl group at C2, the isopropen-
yl anion was selected over the isopropyl counterpart due to
the higher nucleophilicity of the former.[24] However, even addi-
tion of the isopropenyl group was no easy task because of the
chemical instability of the 1,2-diketone structure of 21 and the
surrounding bulky substituents of the reacting C2-ketone. For
instance, treatment of 21 with isopropenyl lithium or isopro-
penyl magnesium bromide generated the adduct 22 in negligi-
ble yield with concomitant decomposition of 21. Whereas
LaCl3·2LiCl[25] did not enhance the reactivity of isopropenyl lithi-
[26]
um for this substrate, anhydrous CeCl3 in combination with
isopropenyl lithium effectively promoted the stereoselective re-
action from the opposite face of the acetonide-protected diol
to furnish 22.[27] Despite the modest yield, the procedure
proved to be reproducible, and allowed preparation of approx-
imately 100 milligrams of 22. Notably, this reaction installed
the correct C2-tetrasubstituted carbon of 22 without touching
the C3-ketone, which was kinetically protected by the aceto-
nide and C5-methyl groups.
The last remaining C3-stereogenic center was introduced by
reduction of the C3-ketone (Scheme 4). First, the TMS and ace-
tonide groups, which served as the stereocontrolling elements
for introductions of C9/C10 and C2/C6 centers, respectively,
were removed from 22. Namely, treatment of 22 with TAS-F[28]
produced 23, which was subjected to 0.5m HCl in EtOAc/
methanol to afford tetraol 24. Even though the C3-ketone was
resistant to potent nucleophiles (e.g., 13!14, 21!22), release
of the free alcohols permitted the intramolecular hydride deliv-
ery at the C3-ketone of 24 from the top face by means of NaB-
H(OAc)3,[29] realizing the requisite stereoselective reduction. In-
terestingly, the stable bis-borate ester 25 was obtained after
the work-up with methanol and silica gel.[30] The use of KHF2 in
methanol led to the successful conversion of 25 into pentaol
5.[31] Lastly, hydrogenation of the C13-olefin and hydrogenoly-
sis of the C10- and C15-Bn-ethers transformed 5 into fully syn-
thetic (+)-ryanodol (2). The structure of synthetic 2 was deter-
Scheme 3. Introduction of C6-, 9-, and 10-stereocenters. Reagents and con-
ditions: a) BF3·OEt2, Me2S, CH2Cl2, À408C; b) Dess–Martin reagent, NaHCO3,
CH2Cl2, rt, 67% (two steps); c) PdCl2(MeCN)2 (20 mol%), NaHCO3, toluene,
1008C; d) BF3·OEt2, Me2S, CH2Cl2, À208C; e) Me(C=CH2)CH2CH2Br, tBuLi, THF,
À788C; f) A (8 mol%), toluene, 808C, 58% (four steps); g) BH3·THF, AcOH,
THF, rt; NaBO3·4H2O, rt; 1m aqueous NaOH, rt, 48%; h) Me3SiOSO2CF3
(TMSOTf), pyridine, (CH2Cl)2, 808C, 87%; i) BH3·THF, THF, rt; NaBO3·4H2O, rt;
1m aqueous NaOH, rt, 80%.
group of 16 blocked the top face, BH3·THF was forced to ap-
proach from the concave face of the CD-ring, producing the
desired diastereomer 17 in regio- and stereoselective fashion.
The less hindered C2-OH was concomitantly deprotected
under oxidative work-up conditions to form the mono-TMS-
ether 17. The coupling constants between H9 and H10
(JH9H10 =10.0 Hz) corroborated the correct stereochemistry of
17.
The remaining key issues towards the total synthesis of 2
were stereoselective constructions of the C2-tertiary and C3-
secondary alcohols (Scheme 4). Before doing so, the appropri-
ately protected C2-ketone 21 was prepared from diol 17
through highly optimized three-step manipulations. The two
hydroxy groups of 17 were temporarily capped with TMS
groups using TMSOTf and pyridine at À788C to generate tris-
TMS-ether 18, the acidic work-up of which regioselectively de-
1
mined by H NMR, 13C NMR, MS, and [a]D analyses to be identi-
cal to that of an authentic sample of 2 obtained from the hy-
drolysis of (+)-ryanodine (1; Scheme 1). Therefore, the total
synthesis of 2 was completed from 7 in 16 steps by efficiently
constructing the C-ring and introducing the five stereocenters
(C2, 3, 6, 9, 10) within the congested environment.
Model study for the introduction of the pyrrole moiety
Having established the synthetic route to (+)-ryanodol (2) and
its precursor 5, regioselective esterification between the C3-al-
cohol and 1H-pyrrole-2-carboxylic acid was explored to finish
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Scheme 4. Total synthesis of (+)-ryanodol (2). Reagents and conditions: a) TMSOTf, pyridine, CH2Cl2, À788C; 10% HCl in MeOH, À408C, 83% (100% brsm);
b) BnO(C=NPh)CF3, Sc(OTf)3, 5 Š MS, 1,4-dioxane, rt; 1m aqueous NaOH, rt, 78%; c) Dess–Martin reagent, CH2Cl2, 08C; d) 2-bromopropene, tBuLi, CeCl3, THF,
À95 to À788C, 24% (two steps); e) tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F), DMF, rt; f) 0.5m HCl in EtOAc/MeOH (1:1), 358C; g) NaB-
H(OAc)3, MeCN, 708C; 3m aqueous KHF2, MeOH, 408C, 68% (three steps); h) H2, Pd/C, MeOH, rt, 100%.
the total synthesis of (+)-ryanodine (1). As shown in Scheme 1,
Deslongchamps and co-workers encountered inertness of the
secondary C3-alcohol, and higher reactivity of the other secon-
dary C10-alcohol upon treatment with the carboxylic acid, N,N-
dicyclohexylcarbodiimide (DCC) and 4-(N,N-dimethylamino)pyr-
idine (DMAP)[32] (2!4).[8] To effectively find a solution to the
unsolved C3-esterification, we first performed systematic
model experiments using an abbreviated version of 2. Namely,
we decided to exploit racemic 9-demethyl-10,15-dideoxyryano-
dol (26; Scheme 5) as the more synthetically accessible model.
While compound 26 has the entire pentacyclic skeleton and all
five hydroxy groups on the AB-ring of 2, its large-scale prepa-
ration was more easily realized in fewer total steps (29 steps
from 9).[14a,b]
Pentaol 26 possesses one secondary alcohol at C3, and four
tertiary alcohols at C2, 4, 6, and 12 (Scheme 5). Therefore, the
secondary C3-OH of 26 was expected to react selectively over
the other C2-, 4-, 6-, and 12-OHs to produce the desired com-
pound 35. To our dismay, when the Yamaguchi–Yonemitsu[33]
conditions (2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP)
were applied to 26 in the presence of N-Boc-pyrrole-2-carbox-
ylic acid (B),[34,35] the tertiary C12-OH was mainly acylated to
afford 27 in 18% yield.[36]
their boronate esters.[30] Accordingly, 26 was treated with
PhB(OH)2 in benzene,[38] and subsequently with SiO2 for remov-
al of the phenyl boronate at C3-OH, producing mono-alcohol
29 (Scheme 5).[39] However, application of the powerful esterifi-
cation conditions (e.g., NaH, C) failed to give the desired prod-
uct 30. The extremely low reactivity of the C3-secondary alco-
hol of 26 would be explained by its kinetically protected
nature. The X-ray crystallographic structure of 26 revealed that
its C3-OH was shielded by the proximal C14-hydrogen atom
and by the C19-, 20-methyl groups.
These negative results forced us to abandon the direct con-
densation of pyrrole-2-carboxylic acid, and undertake an alter-
native two-step approach, in which the esterification and pyr-
role formation[40] were performed separately. First, we selected
a glycine derivative as a less sterically cumbersome reactant to
facilitate the acylation of the congested C3-hydroxy group. In
fact, C3-esterification between bis-boronate ester 29 and N,N-
Boc2-glycine (D)[35,41] proceeded smoothly in the presence of
2,4,6-trichlorobenzoyl chloride, DMAP and Et3N, giving rise to
31 in 85% yield. Next, the amino methyl group was trans-
formed into the pyrrole ring by coupling with the three-carbon
unit.[42] After treatment of 31 with CF3CO2H to detach the two
Boc groups, amine 32 was subjected to 1,3-bis(dimeth-
ylamino)allylium tetrafluoroborate (vinamidinium salt) E[43] and
Et3N at 1508C in acetonitrile under microwave irradiation con-
ditions. In the reaction, the nucleophilic addition of the amino
group of 32 to bis-electrophile E was followed by deprotona-
tion, intramolecular Mannich-type reaction of 33 and ejection
of dimethylamine to furnish the requisite pyrrole-2-carboxylate
ester 34. Finally, aqueous KHF2 in methanol promoted libera-
tion[31] of the four tertiary alcohols to deliver 9-demethyl-10,15-
To enhance the nucleophilicity of the alcohols of 26, NaH
was utilized in combination with mixed anhydride C.[37] Howev-
er, the C4- and C12-tertiary hydroxy groups were functional-
ized with no reaction at the C3-secondary alcohol, affording 28
in 63% yield.[36] These data clarified that the C4- and C12-OHs
required protected before acylation at C3-OH.
Facile formation of borate ester 25 in Scheme 4 inspired us
to block all four tertiary hydroxy groups on the top face as
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Scheme 5. Model study for introduction of the pyrrole moiety. Reagents and conditions: a) B, 2,4,6-trichlorobenzoyl chloride, N,N-dimethyl-4-aminopyridine
(DMAP), Et3N, toluene, rt, 18% (25% brsm); b) NaH, C, DMAP, DMF, À308C, 63%; c) PhB(OH)2, benzene, 408C; SiO2, hexane/EtOAc, rt, 87%; d) D, 2,4,6-trichloro-
benzoyl chloride, DMAP, Et3N, toluene, rt, 85%; e) CF3CO2H, CH2Cl2, rt; f) E, Et3N, MeCN, 1508C (microwave); g) 3m aqueous KHF2, MeOH, 408C, 56% (three
steps).
dideoxyryanodine 35. Consequently, we devised a protective
group strategy and new two-step tactics for regioselective in-
stallation of the pyrrole moiety at the C3-hydroxy group.
including 1H NMR, 13C NMR, melting point, [a]D, and HRMS
data, matched in all respects those of naturally occurring
(+)-ryanodine. Hence, the chemical construction of 1 was at-
tained for the first time.
Total synthesis of (+)-ryanodine
Conclusion
Despite the increased structural complexity, the procedures de-
veloped through the model study were successfully imple-
mented in the total synthesis of (+)-ryanodine (1; Scheme 6).
The four tertiary alcohols of the key advanced intermediate 5
were regioselectively protected as the two boronate esters
simply by mixing with PhB(OH)2 in benzene at room tempera-
ture, yielding 36. The direct esterification of C3-alcohol 36 with
pyrrole-2-carboxylic acid again proved unsuccessful. In con-
trast, the glycine ester was smoothly appended at the C3-sec-
ondary hydroxy group of 36 by condensation with N,N-Boc2-
glycine (D) under Yamaguchi conditions to afford 37. After
CF3CO2H-promoted Boc-removal from 37, treatment of amine
38 with vinamidinium salt E and Et3N at 1508C induced forma-
tion of the requisite pyrrole, leading to 39. The two phenyl
boronate moieties of 39 were removed by means of aqueous
KHF2 in methanol to deliver 40. Finally, hydrogenation of the
C13-olefin of 40 and hydrogenolysis of the C10- and C15-
benzyl ethers were accomplished simultaneously by using Pd/
C in MeOH, resulting in formation of fully synthetic (+)-ryano-
dine (1). All the spectral and physical data of thus obtained 1,
We accomplished the asymmetric total synthesis of (+)-ryano-
dol (2) and (+)-ryanodine (1) from the core ABDE-ring system
7 in 16 and 21 steps, respectively (37 total steps from 9 to 2
and 42 total steps from 9 to 1). Introduction of the five periph-
eral stereocenters of the ABDE-ring was realized by judiciously
selecting powerful reaction conditions, controlling the three-di-
mensional structures of the polycyclic intermediates, and de-
veloping a sound protective group strategy. Salient methodol-
ogies employed in our synthesis include: 1) regio- and stereo-
selective introduction of the C6-carbon chain (13!14); 2) Pd-
mediated olefin isomerization (11!12) and Ru-catalyzed ring-
closing metathesis reaction to build the C-ring with the C9,10-
olefin (14!6); 3) regio- and stereoselective hydroboration/oxi-
dation of the C9,10-olefin (16!17); 4) regio- and stereoselec-
tive installation of the C2-carbon chain (21!22); 5) hydroxy-
directed reduction of the C3-ketone (24!5); and 6) regioselec-
tive construction of the pyrrole-2-carboxylate ester at the ex-
tremely hindered C3-secondary alcohol (5!1). Transforma-
tion (6) was developed through a systematic model study
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M.I., and by a Grant-in-Aid for Young Scientists (B) (JSPS) to
M.N. Fellowships from JSPS to M.N., K.M., and M.K. are grate-
fully acknowledged. We thank to Dr. Kenji Yoza (Bruker AXS)
for X-ray crystallographic analysis.
Keywords: acylation · natural products · regioselectivity ·
terpenoids · total synthesis
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Scheme 6. Total synthesis of (+)-ryanodine (1). Reagents and conditions:
a) PhB(OH)2, benzene, rt, 61% (four steps from 22); b) D, 2,4,6-trichloroben-
zoyl chloride, DMAP, Et3N, toluene, rt; c) CF3CO2H, CH2Cl2, rt; d) E, Et3N,
MeCN, 1508C (microwave); e) 3m aqueous KHF2, MeOH, 408C, 45% (four
steps); f) H2, Pd/C, MeOH, rt, 76%.
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using the simplified analogue 26: the C3-hydroxy group was
first converted into the less bulky glycine ester, which was
then transformed into the pyrrole ring through condensation
with bis-electrophile E. This new, two-step protocol enabled us
to construct the biologically significant pyrrole moiety and
complete the first total synthesis of 1. Because of their flexibili-
ty and robustness, the novel synthetic routes to 1 and 2 will
accelerate the synthesis and biological studies of ryanodine
and its artificial analogues for investigating RyR-mediated bio-
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Experimental Section
The experimental procedures and characterization of the com-
pounds studied herein can be found in the Supporting Informa-
tion.
CCDC 914023 (26) contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
Acknowledgements
[13] M. Nagatomo, K. Hagiwara, K. Masuda, M. Koshimizu, T. Kawamata, Y.
Matsui, D. Urabe, M. Inoue, Chem. Eur. J. 2015, DOI: 10.1002/
chem.201503640.
This research was financially supported by a Grant-in Aid for
Scientific Research (A) and Challenging Exploratory Research to
Chem. Eur. J. 2016, 22, 230 – 236
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Full Paper
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À
À
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Received: September 10, 2015
Published online on November 30, 2015
Chem. Eur. J. 2016, 22, 230 – 236
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236
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim