Rhodium-Catalyzed Cyclization of Terminal and Internal Allenols: An Atom Economic and Highly Stereoselective Access Towards Tetrahydropyrans

Article abstract of DOI:10.1002/ange.202009166

A comprehensive study of a diastereoselective Rh-catalyzed cyclization of terminal and internal allenols is reported. The methodology allows the atom economic and highly syn-selective access to synthetically important 2,4-disubstituted and 2,4,6-trisubstituted tetrahydropyrans (THP). Furthermore, its utility and versatility are demonstrated by a great functional-group compatibility and the enantioselective total synthesis of (?)-centrolobine.

Full text of DOI:10.1002/ange.202009166

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Zitierweise:
Internationale Ausgabe: doi.org/10.1002/anie.202009166
Deutsche Ausgabe: doi.org/10.1002/ange.202009166
Cyclizations
Rhodium-Catalyzed Cyclization of Terminal and Internal Allenols: An
Atom Economic and Highly Stereoselective Access Towards
Tetrahydropyrans
Johannes P. Schmidt and Bernhard Breit*
the principle of atom economy[17] by generating stoichiomet-
Abstract: A comprehensive study of a diastereoselective Rh-
ric amounts of waste (Scheme 1). An atom economic alter-
native to this method, is the transition-metal-catalyzed
addition of nucleophiles to allenes and alkynes. This reaction
was studied by our group intensively and represents a power-
catalyzed cyclization of terminal and internal allenols is
reported. The methodology allows the atom economic and
highly syn-selective access to synthetically important 2,4-
disubstituted and 2,4,6-trisubstituted tetrahydropyrans
(THP). Furthermore, its utility and versatility are demon-
strated by a great functional-group compatibility and the
enantioselective total synthesis of (À)-centrolobine.
À
À
À
À
ful tool to construct C O, C S, C N and C C bonds in
a highly regio-, enantio-, and diastereoselctive fashion.[18–20] In
addition to the broad range of different nucleophiles, the
utility of this methodology has been demonstrated in various
natural and bioactive product syntheses.[19]
Introduction
Herein, we present our atom economic and stereoselec-
tive strategy to access the THP moiety by employing terminal
Oxygen containing heterocycles, in particular substituted
THP scaffolds, are important structural elements and building
blocks in natural and bioactive products like centrolobine,[1]
cryptoconcatone K,[2] clavosolide A[3] and neopeltolide
(Figure 1).[4]
Due to their high variety, biological properties and
potential use in pharmaceuticals, the synthesis of THP was
tackled repeatedly, resulting in various methods allowing
their stereoselective access.[5] Some of the more recent
approaches focused mainly on the cyclization onto oxocarbe-
nium ions,[6] oxa-Michael reactions,[7] hetero-Diels–Alder
cycloaddition,[8] reduction of cyclic hemi ketals,[9] gold cata-
lyzed [2+2+2] cycloadditions[10] and gold catalyzed cyclisa-
tion.[11] Besides these concepts, the transition metal catalyzed
substitution reaction of allylic alcohols and esters started to
emerge. Trost, displayed his approach in 2002.[13] He focused
on a combined Ru-catalyzed ene-yne reaction followed by
a Pd-catalyzed substitution reaction to access the THP
scaffold (Scheme 1).[13] Uenishi et al. described a methodology
based on a 1,3-chirality transfer starting from 2,8-diols.[13]
Krische demonstrated a catalyst-directed diastereoselective
formation of different tetrahydropyrans starting from 1,3-
diols using a chiral palladium- or an iridium-based catalyst
system.[15]
Figure 1. Natural products containing THP moieties as structural key
elements.
Despite their respective benefits and their high selectivity,
all these methods represent versions of transition-metal-
catalyzed substitution reactions[16] and therefore undermine
[*] Dr. J. P. Schmidt, Prof. Dr. B. Breit
Institute for Organic Chemistry, Albert-Ludwigs-Universitꢀt Freiburg
Albertstraße 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
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.202009166.
ꢁ 2020 The Authors. 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 reproduc-
tion in any medium, provided the original work is properly cited.
Scheme 1. Representative examples of transition-metal-mediated meth-
odologies for THP synthesis.[13,15] Cp=cyclopentadiene, dba=dibenzy-
lidenacetone, COD=1,5-cyclooctadiene.
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and internal allenols as key units in an intramolecular
rhodium catalyzed cyclization.
Figure 2. Unsymmetric internal allenols: Point and axial chirality.
Results and Discussion
Our study commenced by investigating terminal allenes,
drafting the phenyl substituted allenol 1 as model substrate
(Table 1). Primary reactivity examinations employing a com-
bination of [Rh(COD)Cl]2 and bis[(2-diphenylphosphino)-
phenyl] ether (DPEphos) were not successful (entry 1).
Switching from DPEphos to combination of Bis(diphenyl-
phosphino)ferrocene (dppf) and chloroacetic acid as additive,
delivered the syn-configurated adduct in excellent 92% and
a satisfactory diastereoselectivity of 83/17 (entry 3).[21]
Further optimizations resulted in the finalized conditions,
examined a variety of different additives and were delighted
to find that PTSA provided a promising result.[21] To increase
the selectivity, derivatives of dppf with different steric and
electronic properties were evaluated.[24] The derivative bear-
ing an electron donating methoxy group (L1) delivered an
excellent d.r. but poor E/Z selectivity. Employing the dppf
derivative L2, a ligand substituted with an electron with-
drawing CF3-group, increased the E/Z ratio to 84/16 while
maintaining a good yield and d.r. Final optimizations were
carried out by replacing the solvent to PhF and increasing the
amount of additive to 30 mol% (entry 7).[22] These adjust-
ments allowed access to compound 4 in 96% yield, an E/Z
ratio of 84/16 and a perfect d.r. of 95/5 (entry 7).
employing
a combination of [Rh(COD)Cl]2, dppf and
diphenyl phosphate in DCM. These modifications provided
2 in an excellent yield and d.r. (Table 1, entry 5).[23]
Table 1: Optimization of reaction conditions for terminal allenes.[22]
Furthermore, the highly diastereo convergent cyclization
of rac-3 (Table 2) indicates, that an epimerization of the
allene moiety must take place. At this point the determination
of relative configuration of compound 2 and 4 was accom-
plished by NOE experiments.[22]
With the optimized conditions in hand, the scope and
limitations of this reaction were explored (Table 3 and 4).
First, a variety of 3-substituted terminal allenols were
subjected to the catalysis conditions. Straight-chain and
cyclic alkyl functionalized alcohols behaved well and fur-
nished the corresponding syn-tetrahydropyrans 5 to 9 in
excellent yield and d.r. Next, substrates bearing phenyl,
naphthyl and biaryl groups were investigated and provided
the corresponding THP in yields up to 97% and a d.r. up to
96/4. Notably, even sterically high congested substrates
reacted well (7 and 16). Functional groups like CF3, halides,
ether and thioether attached to the aromatic ring were
Entry Ligand
Additive
Solvent Yield syn/anti[b]
[%][a]
1
2
3
4
5
DPEphos
DPEphos ClCH2CO2H
dppf
dppf
dppf
–
DCE
DCE
DCE
–
–
68
92
87
92
86/14
83/17
93/7
95/5
ClCH2CO2H
Diphenyl phosphate DCE
Diphenyl phosphate DCM
All reactions were performed on a 0.3 mmol scale. [a] Yield of isolated
diastereomeric mixture. [b] Selectivity determined by 1HNMR analysis of
the crude reaction mixture. dppf=1,1-bis(diphenylphosphino)ferrocene,
DCE=1,2-dichloroethane, DCM=dichloromethane.
After the successful optimization for terminal
Table 2: Optimization of reaction conditions for internal allenes.[22]
allenes, we focused on the ring closure of unsym-
metrical internal allenols (Table 2). These com-
pounds display point and axial chirality (Figure 2)
and are therefore employed as a diastereomeric
mixture (1/1) in the catalysis.[22]
In order to obtain a divergent reaction starting
from the diastereomeric mixture rac-3, an initial
isomerization of the allene axis is required prior to
nucleophilic addition. In earlier studies, our group
found that in the presence of a transition metal, the
racemization of enantiomerically enriched internal
allenes takes place. Based on this knowledge, we
propose that the epimerization of rac-3 (Table 2)
follows a similar mechanism.[18a,k,m]
Entry Ligand Additive (mol%)
Solvent Yield E/Z[b]
syn/anti[b]
[%][a]
1
2
3
4
5
6
7
dppf
dppf
L1
L2
L3
Diphenyl phosphate (20) DCE
98
98
89
96
65
94
96
79/21 70/30
70/30 92/8
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
DCE
DCE
DCE
DCE
PhF
65/35 94/6
84/16 91/9
80/20 92/8
83/17 90/10
84/16 95/5
L2
L2
PhF
An initial experiment was conducted using the
diastereomeric mixture of 3-(4-methoxyphenyl)tri-
deca-5,6-dien-1-ol (3) as screening substrate.
Employing the conditions previously developed for
terminal allenes (Table 2, entry 5) delivered the
corresponding THP compound 4 in excellent yield,
albeit low d.r. and E/Z ratio. In this respect, we
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Table 3: Scope of the catalytic diastereoselective cyclization of terminal allenols towards syn-tetrahydropyrans.
All reactions were performed on a 0.3 mmol scale. Yield of isolated diastereomeric mixture. Selectivity determined by 1HNMR analysis of the crude
reaction mixture. [a] Yield and d.r. of large-scale reaction (1.4 mmol). DCM=dichloromethane.
Table 4: Scope of the catalytic diastereoselective cyclization of internal allenols towards syn-tetrahydropyrans.
All reactions were performed on a 0.3 mmol scale. Yield of isolated diastereomeric mixture. Selectivity determined by 1HNMR analysis of the crude
reaction mixture. [a] Yield and d.r. of large-scale reaction (1.4 mmol).
compatible and afforded the desired adducts 18 to 21 in good
to excellent yields.
vided the corresponding adducts in comparable yield and
diastereoselectivities to terminal allenes. The E/Z ratio
showed to be consistent across the different functionalization
pattern (up to 89/11), albeit a slight deterioration was
observed for more bulky (25) and halide substituted (37)
compounds. The alteration of the allene moiety provided
excellent results as well (41 to 44). Compounds 4 and 20
Next, different functionalized internal allenols were
investigated (Table 4). Reactants substituted with linear and
branched aliphatic chains (23–25) as well as cycloaliphatic
(26, 27) and PhC3 residues (28) transformed smoothly in good
to excellent yields. Aromatic compounds, displaying higher
steric hinderance and different electronic properties, pro-
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(Tables 3 and 4) were synthesized by large-scale catalysis
without any decline in yield and d.r.
Tetrahydropyran as part of natural products are com-
monly substituted in 2,4,6-position (Figure 1). Therefore, we
attempted the access to these scaffolds, by employing the
more complex syn- and anti-1,3-disubstitued allenols
(Tables 5 and 6). First, the syn-1,3-disubstituted terminal
and internal hydroxy allenes 45–48 were subjected to the
catalysis conditions. The terminal as well as the internal
allenes provided the thermodynamically favoured all equato-
rial-THP compounds 45A–48A in superb yields and diaste-
reoselectivity (Table 5). Further the anti-1,3-substituted alle-
nols were examined. The terminal allenes 49 and 50 pro-
ceeded smoothly and provided the 4,6-syn configurated
compound 49A and 50A in up to 94% and a diastereoselec-
tivity up to 95/5. Similar results were obtained for the anti-4,6-
substitued internal allene 51 and 52 (Table 6, entries 3 and 4).
However, a deterioration in diastereoselectivity occurs when
the substituent in 1-position is changed from methyl (49, 51)
to phenyl (50, 52).
Scheme 2. Presumed transition state. Ar=4-methoxyphenyl, R=H or
C6H13).
This lower energetic difference can account for the decrease
in selectivity between 49,51 and 50,52 (Scheme 2).
To enable the synthesis of enantioenriched tetrahydro-
pyrans, the enantiomerically enriched starting materials 53
and 54 were subjected to the catalysis conditions.[26] We were
satisfied to observe that the enantiomeric purity was main-
tained for both, the terminal and internal allene (Scheme 3).
An alternative to the method shown in Table 4, can be the
application of the commercially available dppf ligand, in
combination with PTSA, followed by an in situ hydrogena-
tion. This procedure allows the straightforward selective
access of saturated THPs in high yields and diastereoselecti-
vites (Table 7).
To highlight the synthetic utility of this catalytic reaction,
the enantioselective total synthesis of (À)-centrolobine (64),
starting from cyclopentanone (60), was pursued (Scheme 4).
First a Grignard addition followed by elimination and
ozonolysis furnished the oxopentanal 61. Next, the addition of
ethenylmagnesium bromide in combination with an SN2’
reaction enabled the synthesis of allene 62 which was further
reduced to allenol 63, by CBS reduction. Employing the
conditions developed in Table 7, the enantiomerically
It is conceivable that, due to the Ph group, a decrease of
energetic difference between transition states C and D
(Scheme 2) compared to the more favored transition state
A, for the methyl-substituted compound 49 and 51 occurs.
Table 5: Scope of syn-1,3-substituted allenols.[25]
Entry
Substrate
R1
R2
Cond.
Yield [%][a]
A/B[b]
1
2
3
4
45
46
47
48
Me
Ph
Me
Ph
H
H
C6H13
C6H13
A
A
B
B
93
96
91
90
95/5
93/7
95/5
95/5
Conditions A: [Rh(COD)Cl]2 (2.5 mol%); dppf (5.0 mol%); diphenyl
phosphate (20 mol%); DCM (0.3 M), 808C, 14 h; Conditions B: [Rh-
(COD)Cl]2 (2.5 mol%); L2 (5.0 mol); PTSA (30 mol%); PhF (0.3 M),
808C, 14 h. [a] Combined yield. [b] A/B ratio determined by 1HNMR
analysis of the crude reaction mixture. Ar=4-methoxyphenyl.
Scheme 3. Enabling the stereoselective synthesis of 5ee and 55ee, by
employing enantiomerically enriched starting material 53 and 54.
Table 6: Scope of anti-1,3-substituted allenols.[25]
Table 7: Catalysis reaction followed by in situ hydrogenation.
Entry
Substrate
R1
R2
Cond.
Yield [%][a]
A/B[b]
1
2
3
4
49
50
51
52
Me
Ph
Me
Ph
H
H
C6H13
C6H13
A
A
B
B
92
94
92
88
95/5
85/15
80/20
73/27
Conditions A: [Rh(COD)Cl]2 (2.5 mol%); dppf (5.0 mol%); diphenyl
phosphate (20 mol%); DCM (0.3 M), 808C, 14 h; Conditions B: [Rh-
(COD)Cl]2 (2.5 mol%); L2 (5.0 mol%); PTSA (30 mol%); PhF (0.3 M),
808C, 14 h. [a] Combined yield. [b] A/B ratio determined by 1HNMR
analysis of the crude reaction mixture.
All reactions were performed on a 0.3 mmol scale. Yield of isolated
diastereomeric mixture. Selectivity determined by 1HNMR analysis of
the crude reaction mixture.
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reflux, 2 h, 95%; b] I) O3, MeOH, À788C; II) SMe2 (5.0 equiv), À788C
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rt., 2 h; II) AcCl (1.0 equiv), 08C to rt., 2 h, 85%; d) (4-(Benzyloxy)phe-
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Conclusion
In conclusion, we have established a general and efficient
highly diastereoselective intramolecular O-allylation of ter-
minal and internal allenols. The presented procedure enables
the construction of synthetically important syn-2,4-disubsti-
tuted and 2,4,6-trisubstituted tetrahydropyrans. The method-
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Acknowledgements
This work was supported by the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie.
We thank Dr. Manfred Keller for extensive NMR experi-
mentats. Open access funding enabled and organized by
Projekt DEAL.
Conflict of interest
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The authors declare no conflict of interest.
Keywords: allenes · cyclizations · diastereoselectivity ·
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heterocycles · rhodium
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[21] We propose that the acid additive promotes the generation of
a rhodium hydride species and therefore initiates the catalytic
cycle. Detailed mechanistic studies are currently investigated in
our group. A proposed mechanistic cycle can be found in the
Supporting Information.
[22] For further information see the Supporting Information.
[23] Other solvents were tested. However, these could not achieve
better results. For further screening information see the Sup-
porting Information.
[24] The synthesis of the dppf derivatives and a complete ligand
screening is described in the Supporting Information.
[25] Determination of E/Z ratio by 1HNMR spectroscopy of the
crude reaction mixture was not possible.
[26] Enantiomerically enriched starting material 53 and 54 were
obtained by an asymmetric 1,4-addition. Based on B. L. Feringa
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ester was determined. For further information see the Support-
ing Information.
[27] To obtain a high yield the reaction time of the hydrogenation had
to be extended to 72 hours. Due to solubility a 1/1 mixture of
MeOH/DCM had to be added.
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Manuscript received: July 2, 2020
Revised manuscript received: August 22, 2020
Accepted manuscript online: September 17, 2020
Version of record online: && &&, &&&&
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