Kirmse–Doyle- and Stevens-Type Rearrangements of Glutarate-Derived Oxonium Ylides

Article abstract of DOI:10.1002/chem.201704624

A novel chemoenzymatic synthetic cascade enables the preparation of densely decorated tetrahydrofuran building blocks. Here, the lipase-catalyzed desymmetrization of 3-alkoxyglutarates renders highly enantioenriched carboxylic acid intermediates, whose subsequent activation and oxonium ylide rearrangement by means of rhodium or copper complexes furnishes functionalized O-heterocycles with excellent diastereoselectivity. The two-step protocol offers a streamlined and flexible synthesis of tetrahydrofuranones bearing different benzylic, allylic or allenylic side chains with full control over multiple stereogenic centers.

Full text of DOI:10.1002/chem.201704624

A Journal of
Accepted Article
Title: Kirmse-Doyle- and Stevens-type Rearrangements of Glutarate-
derived Oxonium Ylides
Authors: Benedikt Skrobo, Nils E Schlörer, Jörg-M. Neudörfl, and Jan
Deska
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201704624
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Supported by

10.1002/chem.201704624
Chemistry - A European Journal
FULL PAPER
Kirmse-Doyle- and Stevens-type Rearrangements of Glutarate-
derived Oxonium Ylides
Benedikt Skrobo,[a] Nils E. Schlörer,[a] Jörg-M. Neudörfl,[a] and Jan Deska*[a,b]
Abstract: A novel chemoenzymatic synthetic cascade enables the preparation of densely decorated tetrahydrofuran building blocks.
Here, the lipase-catalyzed desymmetrization of 3-alkoxyglutarates renders highly enantioenriched carboxylic acid intermediates,
whose subsequent activation and oxonium ylide rearrangement by means of rhodium or copper complexes furnishes functionalized
O-heterocycles with excellent diastereoselectivity. The two-step protocol offers
a streamlined and flexible synthesis of
tetrahydrofuranones bearing different benzylic, allylic or allenylic side chains with full control over multiple stereogenic centers.
catalyzed decomposition of diazomethane or substituted diazo
Introduction
compounds in presence of ethers as nucleophilic counterpart
(Scheme 1, bottom).[7,8]
Among the various enzymatic approaches towards optically
active building blocks,[1] the conversion of symmetrical homo-
Stevens, 1928
[1,2]-benzyl
shift
bifunctional molecules by lipase-catalyzed selective trans-
R
R
R
–
NaOH
Ph
formations of ester, alcohol or amine groups represents a
particularly powerful tool.[2] Biocatalytic desymmetrizations
render synthetically attractive, enantioenriched, and orthogonally
prefunctionalized structural entities as valuable starting materials
for the preparation of intriguing target architectures.[3] At the
same time, the enzymatic manipulation of enantiotopic groups
allows for a theoretical yield of 100% as opposed to the more
commonly employed kinetic resolution approach. An intrinsic
drawback in this design, however, is that the required enzyme
substrates most often lack pronounced complexity and that the
early-stage character of enantioselective desymmetrizations ties
up with the necessity for a lengthy follow-up chemistry in order
to arrive at the desired complex target structures.
As part of our recent activities towards streamlined
implementations of desymmetrizative biocatalysis in a synthetic-
organic setting exploiting skeletal rearrangements as means for
the direct creation of molecular complexity,[4] we became
interested in onium ylides as potential intermediates in such a
chemoenzymatic scenario. Sigmatropic skeletal rearrangements
represent a very powerful tool when it comes to C-C-coupling
reactions with a high degree of stereochemical control in the
construction of multiple chirogenic centers and particularly
onium ylide rearrangements have found many applications in
complex organic synthesis in recent years.[5] Depending on the
nature of the onium ylides, the generation of these zwitterionic
reactive species can sometimes be achieved simply by
deprotonation of preformed ammonium or sulfonium salts
(Scheme 1, top).[6] In this work, however, we focussed on
oxonium ylides as reactive intermediates which are generally
inaccessible via deprotonation pathways. Based on the early
work by Kirmse, the most frequently employed approach
towards these oxygen-centred betaines relies on the metal-
Br–
N+ Ph
N+ Ph
N
fragmentation-
recombination
pathway
ammonium ylide
Kirmse, 1968
RO
[2,3]-allyl
transposition
CH2N2
cat. CuI
OR
R
+ O
R'
H2C–
sigmatropic
rearrangement
R'
R'
oxonium ylide
Scheme 1. Formation and rearrangement of onium ylides via deprotonation or
diazomethane decomposition.
With an impressive history of applications of oxonium ylide
shift reactions in total synthesis,[9] and the development of
powerful catalyst families and asymmetric ligand-controlled
protocols,[10]
we
envisioned
that
the
Kirmse-Doyle
rearrangement could act as an exquisite module in the context
of chemoenzymatic synthesis strategies. Particularly, with
regard to the direct structural relationship of Kirmse-Doyle-
relevant diazoketones and carboxylic acids, as exemplified in
countless instances as part of the Arndt-Eistert homologation,
our design aimed to link an enzymatic synthesis of carboxylic
acids by ester hydrolases with a metal-mediated rearrangement
reaction (Scheme 2). More specifically, our strategy relied on an
R
O
CO2Et
CO2Et
creation of chirality
enzymatic desymmetrization
R
O
CO2H
CO2Et
carboxylate activation
[a]
[b]
Dr. Benedikt Skrobo, Dr. Nils E. Schlörer, Dr. Jörg-Martin Neudörfl,
Prof. Dr. Jan Deska
Department of Chemistry, Universität zu Köln
Greinstrasse 4, 50939 Cologne (Germany)
creation of
molecular complexity
oxonium ylide rearrangement
&
O
Prof. Dr. Jan Deska
CO2Et
O
Department of Chemistry, Aalto-yliopisto
Kemistintie 1, 02150 Espoo (Finland)
jan.deska@aalto.fi
R
H
H
Scheme 2. Chemoenzymatic strategy for the stereocontrolled assembly of
complex, orthogonally functionalized tetrahydrofuranes.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201704624
Chemistry - A European Journal
FULL PAPER
enantioselective desymmetrization of ether-functionalized
glutarate diesters as substrates for lipase biocatalysts that would
be followed by conversion of the liberated carboxylic acids into
the corresponding diazoketones and their immediate copper- or
rhodium-catalyzed intramolecular oxonium ylide rearrangement.
As illustrated in scheme 2, this combination of a chirality-
creating and a complexity-creating reaction step offers a rapid
access to densely decorated and orthogonally functionalized O-
heterocycles with high control over multiple stereogenic
elements. Taking advantage of the unrivalled selectivities of
enzymatic catalysts, this method is thereby complementing the
modern synthetic toolbox for the stereoselective cyclization to
R'
O
CO2Et
CO2Et
O
CO2Et
R'
CO2Et
for 2a and 2b:
allylic carbonates
[allylPdCl]2/dppb
toluene, 110 °C
(from 1)
for 2e - 2j:
Et3SiH, benzaldehydes
TMSOTf, (TMS)2O
THF, –25 °C
RO
(from 1 or 1')
CO2Et
CO2Et
for 2c, 2d and 2k:
allylic or propargylic
trichloroacetimidates
Sc(OTf)3 or TMSOTf
toluene or DCM, r.t.
(from 1)
for 2l and 2m:
alkyl chloromethylethers
iPr2NEt
R = H, 1'
TMS, 1'
tetrahydrofuranones
relying
on
e.g.
oxidative
furan
rearrangements,[11] radical hydroacylations,[12] or propargyl
benzoate cycloisomerizations.[13]
DCM, r.t.
(from 1)
R'
Herein, we provide a detailed account on of our efforts to
develop this chemoenzymatic approach utilizing various
functionalized symmetric glutarates. On the basis of our
preliminary results focusing on benzyl shift rearrangements,[14]
this report puts emphasis on the synthetically even more
appealing [2,3]-sigmatropic oxonium ylide chemistry for the
synthesis of alkene and allene-substituted tetrahydrofurans and
its application in streamlined strategies towards complex
heterocyclic building blocks with full control over multiple
stereogenic centers.
O
R'O
O
CO2Et
CO2Et
CO2Et
CO2Et
Scheme 3. Synthesis of 3-alkoxy-substituted diethyl glutarates.
With a diverse set of symmetric glutarate ethers in hand,
the enzyme-catalyzed desymmetrization was surveyed. From a
number of lipases and proteases tested for the enantioselective
hydrolysis of allyl ether 2a, lipase B from Candida antarctica
stood out as a highly selective biocatalyst. Best results were
obtained using an aqueous solution of CALB (3a, 99%, 96% ee)
rather than the commonly employed immobilized form (3a, 90%,
81% ee). Moreover, we were delighted to see that under these
conditions, nearly all of the tested glutarates were smoothly
desymmetrized with high yields and generally excellent optical
purities (≥96% ee) (Scheme 4). As an exception, the reversely
prenylated diester 2d reacted sluggishly and in addition to a low
yield of 52% after an extended reaction period of seven days,
(S)-3d was isolated with a mediocre enantiomeric excess of
26%. A switch in enantioselectivity was observed replacing the
lipase catalyst by the protease α-chymotrypsin that allowed also
the preparation of (R)-configured 3a in high yield and good
enantiopurity, providing the flexibility required from a generally
applicable synthetic methodology.
Results and Discussion
In order to conduct an extensive study on various glutarates
bearing a series of different migrating groups for the oxonium
ylide rearrangement, our initial focus was placed on the
development of robust methods for the preparation of the
symmetric starting materials. While the most obvious approach
via Williamson etherification between 3-hydroxyglutarate and the
suitable alkyl halides proved to be ineffective in most cases, a
number of alternative methods based on previously described
etherification protocols have been applied (Scheme 3). For the
synthesis of O-allylated derivatives two protocols were
successfully adapted. On one side,
a palladium-catalyzed
allylation using allylic carbonates under virtually base-free
conditions yielded the allylated (2a, 95%) and cinnamylated
glutarates (2b, 75%).[15] Since prenylation of 1 by the Tsuji-Trost
protocol failed, an alternative Schmidt etherification by prenyl
trichloroacetimidate was employed, and scandium triflate-
catalyzed C-O bond formation resulted in a mixture of prenylated
and reversely prenylated glutarates (66%, 2c:2d = 64:36).[16]
The challenging separation of both regioisomers was achieved
by the dry column vacuum chromatography introduced by
Harwood and Petersen.[17] Under similar conditions (butynyl
trichloroacetimidate, TMSOTf, DCM, r.t.), propargylation yielded
2k in 60%.[18] As already disclosed in our previous
communication,[14] benzylic ethers were accessible via a Lewis
acid-mediated, reductive etherification to give rise to 2e - 2j in
moderate to good yields (46-82%). Finally, two alkoxymethyl
ethers were synthesized by treatment of alcohol 1 with the
respective alkoxymethyl chlorides and Hünig's base (2l, 60%;
2m, 64%).
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10.1002/chem.201704624
Chemistry - A European Journal
FULL PAPER
appropriate metal catalysts. A broad screening of Cu(II) and
Cu(I) complexes revealed that the very commonly employed
acetylacetonate catalyzed the [2,3]-sigmatropic rearrangement
to 4a in good yield and high trans diastereoselectivity while the
same complex failed to provide any conversion in the related
[1,2]-benzyl shift (Table 1, entries 1-3). Contrarily,
[Cu(MeCN)4BF4] catalysis gave the Stevens product 4e in 54%
yield but proved to be unproductive in the Kirmse-type reaction
(Table 1, entry 5). Most stunningly, variation of the counterion
lipase B from
C. antarctica
RO
RO
CO2Et
CO2Et
CO2H
CO2Et
phosphate buffer
DMSO, pH 7.5
r.t., 24 h
2a - 2m
3a - 3m
O
Ph
O
CO2H
CO2Et
CO2H
CO2Et
(BF4 to TfO– or PF6 ) not only rendered a Kirmse-active system
(Table 1, entry 6 & 7), but after slight optimization of the solvent
system and minor temperature adjustments, a highly efficient
and perfectly trans-selective catalytic rearrangement protocol
was obtained, yielding the desired allylated tetrahydrofuranone
4a in 96%yield and 99% diastereomeric excess (Table 1, entry
9).
–
–
(S)-3a
(S)-3b
99%, 96% ee
88%, 99% ee
O
O
CO2H
CO2Et
CO2H
CO2Et
(S)-3c
(S)-3d
52%,a 26% ee
48%, 99% ee
Br
Table 1. Screening of copper complexes for the [1,2]-Stevens shift and
[2,3]-sigmatropic rearrangement of glutarate-derived diazoketones.[a]
O
O
CO2H
CO2Et
CO2H
CO2Et
N2
copper complex
(1 mol%)
O
O
(S)-3e
(S)-3f
93%, 96% ee
86%, 96% ee
CO2Et
O
solvent, temp
O
H
H
O2N
CO2Et
5a or 5e
4a or 4e
O
O
CO2H
CO2Et
CO2H
CO2Et
temp
[°C]
"Kirmse"
5a to 4a
"Stevens"
Entry copper source
solvent
(S)-3g
(S)-3h
5e to 4e [b]
80%, 98% ee
70%, 99% ee
1
Cu(acac)2
Cu(hfacac)2
Cu(tfacac)2
CuOAc
DCM
DCM
DCM
DCM
23
90%
92% trans
no
MeO
O
O
conversion
O
O
CO2H
CO2Et
CO2H
CO2Et
2
23
23
23
23
23
23
0
16%
62% trans
complex
mixture
(S)-3i
(S)-3j
79%, 99% ee
86%, 99% ee
3
28%
82% trans
complex
mixture
4
48%
86% trans
n.d.
O
O
O
CO2H
CO2Et
CO2H
CO2Et
(S)-3k
(S)-3l
5
[Cu(MeCN)4]BF4 DCM
[Cu(MeCN)4]OTf DCM
[Cu(MeCN)4]PF6 DCM
[Cu(MeCN)4]PF6 DCM
[Cu(MeCN)4]PF6 DCE
[Cu(MeCN)4]PF6 DCE
[Cu(MeCN)4]PF6 CHCl3
[Cu(MeCN)4]PF6 benzene
[Cu(MeCN)4]PF6 THF
5%
97% trans
54%
72% trans
67%, 99% ee
61%, 97% ee
using α-chymotrypsin
6
55%
91% trans
n.d.
O
O
O
CO2H
CO2Et
CO2H
CO2Et
7
90%
99% trans
50%
72% trans
(R)-3a
(S)-3m
90%, 83% ee
74%, 96% ee
8
95%
99% trans
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Scheme 4. Enantioselective desymmetrization of glutarates. a after 7 days.
9
0
96%
99% trans
From the collection of optically pure glutaric monoesters,
allyl ether 3a and benzyl ether 3e were chosen for the
investigation and optimization of the planned activation-
rearrangement sequences as model substrates for the [2,3]-
sigmatropic allyl migration and the [1,2]-Stevens shift,
respectively. Therefore, the corresponding diazoketones 5a and
5e were synthesized and isolated using the previously identified
10
11
12
13
–78
0
63%
99% trans
38%
91% trans
0
38%
99% trans
0
30%
98% trans
optimized protocol via
chloride) and diazomethylation (diazomethane
a
sequence of chlorination (oxalyl
CaO).[19]
+
Numerous complexes of various transition metals have been
tested for the selective decomposition of either diazoketone, but
solely complexes based on copper and rhodium gave a positive
outcome. Interestingly, there was a very distinct difference
between the two reaction pathways and their respective, most
[a] Reaction conditions: 5a or 5e (0.2 mmol) and copper complex (2 µmol).
in 20 mL of solvent. Yields and selectivities were determined by 1H-NMR
using anisol as a standard. Abbreviations: acac = acetylacetonate; hfacac =
1,1,1,5,5,5-hexafluoroacetylacetonate; tfacac
nate. [b] 5 mol% catalyst were used.
= 1,1,1-trifluoroacetylaceto-
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10.1002/chem.201704624
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FULL PAPER
As none of the tested copper complexes met our
requirements for a selective [1,2]-benzyl shift, another catalyst
test was conducted, now investigating different dimeric rhodium
carboxylates. Firstly, although good to excellent yields were
obtained for the rearrangement of 4a, the induced
diastereoselectivities using rhodium complexes fell short in
comparison to the [Cu(MeCN)4PF6]-catalyzed procedure.
Regarding the unsolved Stevens rearrangement challenge, both
rhodium triphenylacetate and the Rh2esp2 complex gave rise to
4e in high yields, however, almost statistic mixtures of both
diastereomers were observed (Table 2, entry 1 & 2). The
corresponding trifluoroacetate on the other hand failed to yield
any of the C-benzylated product (Table 2, entry 3). Improved
inductions were observed using electronically and sterically
unbiased rhodium acetate and octanoate (Table 2, entry 5 & 6)
giving rise to the desired Stevens-product in acceptable yield
and selectivity. Efforts to further enhance the trans-preference
by temperature and solvent adjustments failed (Table 2, entries
6-9). Also, the attempt to reverse the selectivity in favor of the
cis-product, by exploiting a ligand-controlled approach, was not
pursued in much detail after literally no matched/mismatched
situation was observed employing enantiomeric proline-based
rhodium complexes (Table 2, entry 10 & 11). The lack of a clear
correlation between steric or electronic catalyst properties and
the induced diastereoselectivity remains puzzling and underlines
the necessity for a more systematic mechanistic study to shed
light on factors such as the involvement of metal-associated
ylides vs. 'metal-free' betaines, or the nature of the [1,2]-
transposition itself.[5a,10b] All tested benzylic substrates followed a
similar trend and the tetrahydrofuranones 4e - 4j were obtained
in trans-selectivities up to 88% (see Supporting Information).[11]
The major issue with the moderate induction under the
optimized conditions for the Stevens-type rearrangement
(Rh2(oct)4, DCM, 0 °C) was the fact that the two diastereomers
could not be separated chromatographically on a preparative
scale. However, after treatment of the obtained cis/trans-mixture
of tetrahydrofuranone 4e with L-Selectride at low temperature,
two epimeric alcohols could be separated and isolated in
stereochemically pure form (Scheme 5). The major isomer 6
was crystallized and X-ray crystal structure analysis
unambiguously confirmed the anticipated connectivity and
relative stereochemistry resulting from the previous oxonium
ylide rearrangement step (see Supporting Information for
ORTEP and crystallographic data). The thus obtained alcohols
can on one side be used as functional building blocks towards
more complex heterocyclic targets,[14] but could also act as
precursors for 2,5-disubstituted tetrahydrofurans through Barton-
McCombie deoxygenation.[20,21]
Table 2. Screening of rhodium complexes for the [1,2]-Stevens shift and [2,3]-
sigmatropic rearrangement of glutarate-derived diazoketones.
N2
rhodium complex
(1 mol%)
O
O
CO2Et
O
solvent, temp
O
H
H
O
CO2Et
5a or 5e
4a or 4e
Ph
CO2Et
O
H
H
temp
"Kirmse"
"Stevens"
Entry rhodium source
solvent
[°C]
5a to 4a
5e to 4e
4e (82% trans)
1
Rh2(tpa)4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
benzene
THF
0
97%
53% cis
81%
55% trans
L-Selectride
CO2Et
THF, –78 °C
2
Rh2(esp)2
Rh2(tfa)4
0
92%
73% trans
92%
69% trans
HO
HO
Ph
Ph
CO2Et
+
3
0
81%
59% trans
no
O
O
conversion
H
H
H
H
4
Rh2(OAc)4
Rh2(oct)4
Rh2(oct)4
0
94%
79% dr
80%
80% trans
6, 64%, 99% ee, 99% ds
7, 16%, 99% ee, 99% ds
5
0
70%
82% dr
79%
82% trans
6
–78
40
0
n.d.
n.d.
n.d.
n.d.
36%
81% trans
7
Rh2(oct)4
42%
82% trans
8
Rh2(oct)4
68%
70% trans
6
Scheme 5. Diastereoselective reduction of C-benzylated tetrahydrofuranone
4e, and X-ray crystal structure of the major isomer 6.
9
Rh2(oct)4
0
28%
83% trans
10
11
Rh2((R)-dosp)4
Rh2((S)-dosp)4
DCM
DCM
0
63%
74% trans
80%
80% trans
In contrast to the moderate diastereocontrol in the
rearrangement of simple diazoketones (such as 5e) derived from
diazomethane, a related stabilized α-diazo-β-ketoester exhibited
much higher selectivity. Here, the three-step cascade consisting
of (i) of activation of the previously desymmetrized acid 3e, (ii)
acid chloride trapping by ethyl diazoacetate, and (iii)
decomposition of the diazoketoester gave rise to the stereo-
chemically pure tetrahydrofuranone 8 (Scheme 6). Unfortunately,
0
84%
63% trans
83%
79% trans
[a] Reaction conditions: 5a or 5e (0.2 mmol) and rhodium complex (2 µmol). in
20 mL of solvent. Yields and selectivities were determined by 1H-NMR using
anisol as a standard. Abbreviations: tpa = triphenylacetate; esp = α,α,α',α'-
tetramethyl-1,3-benzenedipropionate; tfa = trifluoroacetate, oct = octanoate;
dosp = N-(4-dodecylphenylsulfonyl)prolinate.
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10.1002/chem.201704624
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FULL PAPER
the very high diastereomeric excess of the product was
accompanied by a rather low overall yield of 17% which seemed
surprising since no particularly low rates or significant side
product formation could be observed in the decomposition of the
diazoketoester.
for the desired stereoisomers. Crotyl ether 3n was obtained in
99% ee and 97% E-configuration after enzymatic
desymmetrization
followed
by
Fürstner's
E-selective
hydrogenation protocol using Cp*Ru(cod)Cl as catalyst.[23] In
contrast to the high E-preference in the reduction of monoester
3k, the very same procedure applied on diester 2k yielded a
mixture of isomers (E/Z = 87/13). For the preparation of the Z-
crotyl substituted monoester 3o, best results were obtained
when the reduction (Lindlar hydrogenation, Pd/CaCO3,
Pb(OAc)4) was performed prior to the actual desymmetrization.
Here, also monoester 3o was isolated in 99% ee and 97% Z-
selectivity over two steps. Attempts to perform the alternative
Lindlar hydrogenation of the propargylic monoester 3k remained
fruitless. With both E- and Z-olefins in hand, the activation-
rearrangement sequence was tested. To our delight, the
formation of the 3n-derived diazoketone and its copper-
catalyzed decomposition proceeded smoothly and the desired
tetrahydrofuranone 4n was isolated with a high degree of
diastereoselectivity. Comparative NMR- and GC-studies of the
product with mixtures obtained from less selective catalysts (e.g.
Rh2tfa4) revealed that out of the four possible stereoisomers only
one pair was formed which was assigned to the two epimers
differing from each other at the exogenic center (4n:4o = 98:2).
Moreover, also the rearrangement of the Z-derivative 3o showed
an optimal induced trans-selectivity and, as anticipated, the
opposite preference regarding the configuration at the exocyclic
center was observed (4o:4n = 88:12).
(i) (COCl)2, DMF
CH2Cl2, 0°C
(ii) ethyl diazoacetate
80 °C
O
BnO
CO2H
CO2Et
Bn
EtO2C
CO2Et
O
(iii) [Rh2(oct)4]
DCM, 0 °C
H
3e, 99% ee
8, 17%, 99% ee, 99% ds
Scheme 6. Formation and rearrangement of a glutarate-derived α-diazo-β-
ketoester.
Due to the apparent benefit of excellent selectivities in the
[2,3]-sigmatropic oxonium ylide rearrangement, and the flexibility
of allylic groups to act as versatile functional handle for
numerous subsequent synthetic transformations, our particular
focus was put on the in-depth study of the copper-mediated
Kirmse-Doyle-type reaction. Initial experiments focused on the
[2,3]-sigmatropic rearrangement of oxonium ylides bearing
symmetrically terminated olefins that would allow the
investigation of the induced diastereoselectivity of the Cu-
catalyzed system. While already the formation of a diazoketone
from the reversely prenylated glutarate 3d failed, both the plain
allyl ether 3a and the prenyl derivative 3c were cleanly activated
in
a
two-step fashion using oxalyl chloride and etheral
mol% of
O
diazomethane, whereupon treatment with
5
lipase from
CO2Et
C. antarctica
H2 (1 bar)
Pd/CaCO3
[Cu(MeCN)4PF6] resulted in the production of the allylated
tetrahydrofuranones 4a and 4c in 72% and 45%, respectively
(Scheme 7). In addition to a perfect induced selectivity in favor
of the trans-isomer, the specific formation of the reversely C-
prenylated 4c underlines the truly sigmatropic character of the
transformation in preference over alternative feasible
fragmentation-recombination pathways.[22]
CO2Et
phosphate buffer
DMSO
Pb(OAc)4
MeOH, r.t.
2k
pH 7.5, r.t.
O
O
CO2H
CO2Et
3k, 67%, 99% ee
CO2Et
CO2Et
2o, 60%, 97% Z
(i) (COCl)2, DMF
CH2Cl2, 0°C
(ii) CH2N2, CaO
lipase from
H2 (10 bar)
Cp*Ru(cod)Cl
DCM, r.t.
C. antarctica
phosphate buffer
DMSO
O
R
O
Et2O, 0 °C
CO2H
CO2Et
CO2Et
R
O
(iii) [Cu(MeCN)4]PF6
CH2Cl2, r.t.
pH 7.5, r.t.
R
H
H
R
O
O
R = H: 3a, 96% ee
Me: 3c, 99% ee
R = H: 4a, 72%, 96% ee, 99% ds
Me: 4c, 45%, 99% ee, 99% ds
CO2H
CO2Et
CO2H
CO2Et
Scheme 7. Induced diastereoselectivity in the Kirmse-Doyle-type
rearrangement of symmetrically terminated allylic ethers.
3o, 84%, 99% ee, 97% Z
3n, 60%, 99% ee, 97% E
(i) (COCl)2, DMF
DCM, 0°C
With the incorporation of unsymmetric allylic fragments in
the rearrangement scenario (E- or Z-configured 3-substituted
allyl ethers) a further increase of molecular complexity can be
attained as a selective C-C-bond forming process would result in
the controlled introduction of a third stereogenic, exocyclic
center. Starting from the symmetric propargylic ether 2k, a
(ii) CH2N2, CaO
Et2O, 0 °C
(iii) [Cu(MeCN)4]PF6
DCE, 0 °C
O
O
CO2Et
CO2Et
sequence consisting of
a metal-catalyzed selective alkyne
O
O
H
H
H
H
reduction and the previously disclosed lipase-mediated
desymmetrization should give access to either E- or Z-crotyl
ethers 3n or 3o in optically pure form. Interestingly, here the
order of events proved to be pivotal to achieve high selectivities
4o, 61%, 99% ee, 88% ds
4n, 48%, 99% ee, 98% ds
Scheme 8. Highly enantio- and diastereocontrolled synthesis of tetrahydro-
furanones bearing three stereogenic centers.
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10.1002/chem.201704624
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The perfect induced diastereoselectivity can easily be
explained by the preferred formation of a trans-configured
oxonium ylide due to the steric bias caused by ethoxyacetyl
substituent at the existing stereogenic center. Under the
assumption of a prevailing trans-arrangement, the migration of
crotyl-derived onium ylides can occur via two distinct
orientations of the allylic fragment relative to the newly formed
O-heterocyclic system. The preference for either exo- or endo-
alignment dictating the simple diastereoselectivity can serve to
explain the stereochemical outcome regarding the exocyclic
chirogenic element (Scheme 9). As illustrated for the
rearrangement of an E-configured O-crotyl oxonium ylide, the
[Cu(MeCN)4PF6]-induced transformation obviously proceeded
via the endo-alignment in >99% selectivity, considering the
imperfect E-selectivity in the preceding alkyne reduction, from
where the observed major isomer 4n is formed. Likewise, the
rearrangement of the Z-configured crotyl species occurred with
endo-preference too, although the apparent selectivity for the
tetrahydrofuran 4o remained slightly lower. While we are unable
to provide a clear rational for this stereochemical feature at the
moment, we are aiming to address this open mechanistic
question in a focussed study combining experimental and
computational techniques.
Furthermore, this reaction cascade also highlights the synthetic
potential of the presented chemoenzymatic approach as tool in
heterocyclic chemistry providing excellent control over multiple
stereocenters and rapid amplification of molecular complexity.
(i) (COCl)2, DMF
DCM, 0°C
(ii) CH2N2, CaO
Et2O, 0 °C
O
Ph
O
CO2H
CO2Et
CO2Et
O
(iii) [Cu(MeCN)4]PF6
DCE, 0 °C
H
H
Ph
3b, 99% ee, 99% E
4b, 72%, 99% ee, 95% ds
L-selectride
THF, –78 °C
O
O
acroyl chloride
NEt3, DMAP
HO
CO2Et
O
CO2Et
DCM, r.t.
O
H
H
H
H
Ph
Ph
10, 60%, 99% ee, >95% de
9, 49%, 99% ee, >95% de
Hoveyda-
Grubbs II
toluene
110 °C
O
H
O
O
H
O
CO2Et
CO2Et
O
H
H
H
Ph
selected NOE
signals
exo
alignment
4o
11, 73%, 99% ee, >95% de
vs.
endo
alignment
11
Scheme 10. Rearrangement of
a glutarate-derived cinnamyl ether and
subsequent synthesis of the bicyclic 11 via ring-closing metathesis.
O
CO2Et
O
The use of propargylic ethers in the desymmetrization/
rearrangement strategy represents a highly interesting extension
of the concept, as the [2,3]-sigmatropic shift would render
heterocyclic products with allenic side chains as additional
functional moiety that provide an additional set of allene-specific
H
H
4n
Scheme 9. Illustration of potential alignments in the diastereoselective
formation of exocyclic stereogenic centers in the rearrangement of crotyl
ethers.
follow-up
reactions.[25]
Gratifyingly,
not
only
the
desymmetrization by CALB yielded 3k in high enantiomeric
excess, but also the activation-rearrangement protocol
proceeded smoothly giving rise to the allenic tetrahydrofuranone
4k in enantio- and diastereomerically pure form (Scheme 11).
The same trend was also observed in the rearrangement
of cinnamyl ether 3b. Activation and [2,3]-sigmatropic allyl shift
of the enantio- and diastereomerically pure glutaric monoester
occurred with high yield and gave rise to the tetrahydrofuranone
4b in 90% diastereomeric excess. The stereopurity could be
further enhanced after chromatographic purification of the
corresponding alcohol 9 that was obtained by selective reduction
using L-Selectride. Subsequent esterification by acryloyl chloride
and ruthenium-catalyzed ring closing olefin metathesis yielded
the bicyclic derivative 11. Both spectroscopic and
crystallographic methods were used to thoroughly analyse the
final product of the sequence that helped to unequivocally
confirm the anticipated induced and simple diastereoselectivity
in the involved [2,3]-sigmatropic rearrangement (see Supporting
Information for ORTEP and crystallographic data).[24]
(i) (COCl)2, DMF
CH2Cl2, 0°C
(ii) CH2N2, CaO
O
O
Et2O, 0 °C
CO2H
CO2Et
CO2Et
(iii) [Cu(MeCN)4]PF6
DCE, 0 °C
O
H
H
3k, 99% ee
4k, 47%, 99% ee, 99% ds
Scheme 11. Allene synthesis based on the [2,3]-sigmatropic oxonium ylide
rearrangement.
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10.1002/chem.201704624
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dried glassware, unless otherwise stated. pH-stat titrations were run on a
Titroline alpha plus (SI Analytics). All products were purified by column
chromatography over silica gel (Macherey-Nagel MN-Kieselgel 60 (40-60
µm, 240−400 mesh)). Dry vaccum chromatography was performed with
Macherey-Nagel MN-Kieselgel 60 (15-40 µm, 400−800 mesh). Reactions
were monitored by thin layer chromatography (TLC) carried out on
The broad success of the presented chemoenzymatic
strategy prompted us to try to expand our studies to other
onium-generating substrates. Unfortunately, all efforts to engage
alkoxyalkyl ethers like 3l and 3m in the desired rearrangement
chemistry failed and produced complex mixtures of non-cyclized
side products. A more selective, even if not anticipated, pathway
was observed when a structurally related sulfur-derivative was
subjected to the reaction cascade. Here, the benzyl thioether 13
was synthesized in good yield via thia-Michael addition to diethyl
glutaconate (12) and subsequent enantioselective enzymatic
hydrolysis gave access to monoester 14 in 95% ee. Applying the
identical activation protocol as for the etheral substrates,
decomposition of the intermediate diazoketone resulted in the
formation of two distinct olefinic products (15 and 16) in high
overall yield and with good to excellent selectivity in favor of the
E-configured C-C double bonds (Scheme 12). Apparently, after
formation of the sulfonium ylide, a Hofmann-type elimination
pathway prevails over the expected benzyl shift, where the
differences in flexibility for the elimination of exo- and endocyclic
protons likely account for the superior stereoselectivity observed
in the formation of enone 15 in comparison to enoate 16.
Macherey-Nagel pre-coated silica gel plates (TLC Silica gel 60 F254
)
using UV light as the visualizing agent and Hanessian stain as
developing agent. 1H- and 13C-NMR-spectra were recorded on Bruker
AV-600, AV-500 and AV-300 instruments at room temperature. Chemical
shifts are reported in parts per million (ppm) calibrated using residual
non-deuterated solvent as internal reference (CHCl3 at 7.26 ppm (1H-
NMR) & 77.16 ppm (13C-NMR)). Infrared-spectra were recorded on a
Shimadzu IRAffinity-1 FT-IR-spectrometer, absorption bands are
reported in wave numbers [cm-1]. High resolution mass spectrometry was
performed on a Finnigan MAT 900 S by electrospray ionization. For
standard resolution either Agilent LC/MSD VL with electron spray
ionization or an Agilent GC-System 8940A with a mass detector 5975
employing helium as carrier gas was used. Chiral gas chromatography
was coducted on a Hewlett Packard HP 6890 system with an Agilent
6890 series injector on a Lipodex E column (25 m x 0.25 mm, 0.25 µm)
using flame ionisation dectection. Hydrogen (from a Domnick Hunter 20H
H2-generator) was used as carrier. High performance liquid chromato-
graphy was performed on a Merck Hitachi L-7250 with a Merck L-7455
detector and Merck column oven L-7360 (18 °C) using analytical Daicel
BnS
BnSH, NEt3
AD-H/OD-H columns (250 mm x 4.6 mm). Optical rotations were
CO2Et
measured on a Perkin-Elmer 343plus. X-Ray crystal structure analysis
was conducted using a Bruker D8 Venture equipped with a copper micro
focus source and Photon 100 detector. The analysis program used was
Apex 3. The structures were solved with Shelxt and refined using the
program Shelxl. Commercially available reagents were used without
further purification. Dry dichloromethane was freshly distilled from
calcium hydride. Anhydrous tetrahydrofuran and toluene was freshly
distilled from sodium/benzophenone, Anhydrous dichloroethane was
obtained from Sigma-Aldrich. The copper and rhodium complexes were
purchased from Sigma-Aldrich and Strem. Lipase B from C. antarctica
was obtained as aqueous solution from Sigma-Aldrich (L3170). Etheral
diazomethane was synthesized from N-methyl-N-nitrosourea.[26] Caution:
Diazomethane is toxic and potentially explosive. All operation involving
this reagent must be carried out in a well-ventilated hood wearing heavy
gloves and googles. The work must be conducted behind an adequate
safety screen, ground joints and sharp surfaces should be avoided.
EtO2C
CO2Et
THF, r.t.
CO2Et
12
13, 73%
lipase from
C. antarctica
phosphate buffer
DMSO, pH 7.5, r.t.
O
(i) (COCl)2, DMF
CH2Cl2, 0°C
BnS
CO2Et
(ii) CH2N2, CaO
Et2O, 0 °C
15, 60%, >95% E
BnS
CO2H
CO2Et
+
(iii) [Cu(MeCN)4]PF6
DCE, 0 °C
O
BnS
CO2Et
14, 80%, 95% ee
16, 31%, 88% E
Scheme 12. Unexpected Hofmann-type elimination of a 3-mercaptoglutarate-
derived sulfonium ylide.
Representative procedure for the enantioselective enzymatic
desymmetrization: Diethyl 3-allyloxyglutarate (2a, 5.0 g, 20.5 mmol)
was dissolved in phosphate buffer (250 mL, 0.1 M, pH 7.5, 20% DMSO)
connected to a pH-stat titrator (SI Analytics, Titroline alpha plus). After
initiation of the reaction by addition of a solution of lipase B from Candida
antarctica (250 µL, Sigma L3170), the mixture was stirred at room
temperature and the pH was kept constant by automatic addition of
aqueous NaOH (1 M). After 24 h, aqueous HCl (1 M, 25 mL) was added,
the solution was extracted with diethyl ether (3x 50 mL) and the
combined organic layers were dried over MgSO4. The solvent was
removed in vacuo and the crude carboxylic acid was purified by column
chromatography (SiO2, mixtures of cyclohexane and diethyl ether + 1%
AcOH). 3a (4.39 g, 20.3 mmol, 99%, 96% ee) was obtained as colorless
Conclusions
In summary, we were able to successfully construct a novel
chemoenzymatic approach yielding functionalized tetrahydro-
furans
with
excellent
control
over
enantio-
and
diastereoselectivity. Here, the combination of
a
broadly
applicable biocatalytic desymmetrization of ether-functionalized
glutarates with the copper-mediated [2,3]-sigmatropic
20
rearrangement provides a concise access to the O-heterocyclic
building blocks bearing allylic and allenylic moieties. The
resulting pattern of functional groups that can be modified in a
highly orthogonal manner allows for a rich follow-up chemistry
with great perspectives to implement the strategy in more
complex synthetic scenarios.
liquid. Rf (cyclohexane/ethyl acetate/acetic acid 70/29/1) = 0.40. [α]D (c
1.07, CHCl3) = +1.32. 1H-NMR (400 MHz, CDCl3): δ = 5.87 (ddt, 3J = 17.2
Hz, 3J = 10.4 Hz, 3J = 5.7 Hz, 1H), 5.26 (ddt, 3J = 17.2 Hz, 2J = 1.1 Hz, 4J
= 1.6 Hz, 1H), 5.16 (ddt, 3J = 10.4 Hz, 2J = 1.1 Hz, 4J = 1.6 Hz, 1H), 4.22
(dddd, 3J = 6.7 Hz, 3J = 6.5 Hz, 3J = 6.0 Hz, 3J = 5.8 Hz, 1H), 4.14 (q, 3
J
= 7.1 Hz, 2H), 4.07 (dd, 3J = 5.7 Hz, 4J = 1.6 Hz, 2H), 2.68 (dd, 2J = 15.9
Hz, 3J = 6.5 Hz, 1H), 2.65 (dd, 2J = 15.6 Hz, 3J = 6.7 Hz, 1H) 2.64 (dd, 2J
= 15.9 Hz, 3J = 5.8 Hz, 1H), 2.62 (dd, 2J = 15.6 Hz, 3J = 6.0 Hz, 1H), 1.26
(t, 3J = 7.1 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 176.7 (s), 171.0 (s),
134.5 (d), 117.5 (t), 72.2 (d), 71.2 (d), 60.9 (t), 39.6 (t), 39.5 (t), 14.3 (q).
IR (ATR): ν [cm–1] = 3669 (w), 3174 (br, w), 2986 (m), 2901 (m), 1732 (s),
1709 (s), 1375 (m), 1194 (m), 1074 (s). Elemental analysis calcd (%) for
C10H16O5: C 55.55, H 7.46; found: C 55.18, H 7.43.
Experimental Section
General remarks: All reactions carried out under argon atmosphere
were performed with dry solvents using anhydrous conditions in flame-
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10.1002/chem.201704624
Chemistry - A European Journal
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Representative procedure for the synthesis of diazoketones: Under
argon, monoester 3a (649 mg, 3.0 mmol) was dissolved in dry
dichloromethane (15 mL) and cooled to 0 °C. Dry DMF (15 mL) and
oxalyl chloride (1.14 g, 9.0 mmol) were added, and the reaction progress
was monitored by IR spectrometry. After 2 h, all volatiles were removed
in vacuo and the residue was redissolved in dry dichloromethane (3 mL).
The solution of the acid chloride was added dropwise at 0 °C to a mixture
of CaO (1.68 g, 30.0 mmol) and diazomethane (0.4 M in Et2O, 75 mL, 30
mmol). After 15 min, argon was purged through the resulting suspension
(10 min) to remove excess CH2N2. Afterwards, the mixture was filtered
over Celite, the filtrate was washed with aqueous bicarbonate (saturated,
50 mL) and the aqueous layer was extracted with diethyl ether (2 x 50
mL). The combined organic layers were dried over MgSO4 and the
solvent was removed in vacuo. After purification by column
chromatography (SiO2, cyclohexane/ethyl acetate/triethylamine 90/9/1),
diazoketone 5a (505 mg, 2.10 mmol, 70%) was obtained as yellow liquid.
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20
Rf (cyclohexane/ethyl acetate 6/4) = 0.45. [α]D (c 1.09, CHCl3) = 18.3.
1H-NMR (400 MHz, CDCl3): δ = 5.90-5.80 (m, 1H), 5.34 (s, 1H), 5.24
(dddd, 3J = 17.2 Hz, 4J = 3.2 Hz, 3J = 1.6 Hz, 4J = 1.1 Hz, 1H), 5.14 (dddd,
3J = 10.4 Hz, 4J = 2.6 Hz, 2J = 1.6 Hz, 4J = 1.1 Hz, 1H), 4.23 (m, 1H, H-5),
4.13 (q, 3J = 7.1 Hz, 2H), 4.05-4.01 (m, 2H), 2.65-2.50 (m, 4H), 1.24 (t, 3J
= 7.1 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 192.3 (s), 171.0 (s), 134.6
(d), 117.3 (t), 72.8 (d), 71.1 (t), 60.7 (t), 55.8 (d), 45.8 (t), 39.7 (t), 14.3 (q).
IR (ATR): ν [cm–1] = 3090 (w), 2936 (w), 2100 (s), 1730 (s), 1634 (s),
1368 (s), 1350 (s), 1072 (s). ESI-HRMS calcd for C11H16N2O4Na
[M+Na]+: 263.1008; found: 263.1007.
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Representative procedure for the [2,3]-sigmatropic oxonium ylide
rearrangement: Diazoketone 5a (48 mg, 200 µmol) was dissolved in 1,2-
dichloroethane (19 mL). At 0 °C, [Cu(MeCN)4]PF6 (1 mg, 2 µmol) in 1,2-
dichloroethane (1 mL) was added and the reaction mixture was stirred at
0 °C for 60 min. The solution was washed with aqueous Na2EDTA (0.4 M,
50 mL) and the aqueous layer was extracted with dichloromethane (3 x
50 mL). The combined organic layers were dried over MgSO4,
concentrated in vacuo and the crude product was purified by column
chromatography (SiO2, cyclohexane/diethyl ether 95/5 to 8/2) and 4a
(39 mg, 0.19 mmol, 93 %, 99.5 % trans) was obtained as colorless liquid.
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4198-4202; Angew. Chem. 2013, 125, 4292-4296 (from alkynes).
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20
Rf (cyclohexane/ethyl acetate 7/3) = 0.48. [α]D (c 0.74, CHCl3) = +64.4.
Major diastereomer: 1H-NMR (500 MHz, CDCl3): δ = 5.80 (ddt, 3J = 17.2
Hz, 3J = 10.1 Hz, 3J = 7.1 Hz, 1H), 5.14 (dd, 3J = 17.2 Hz, 2J = 1.5 Hz,
1H), 5.11 (dd, 3J = 10.1 Hz, 2J = 1.5 Hz, 1H), 4.76 (dddd, 3J = 7.2 Hz, 3
J
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= 6.8 Hz, 3J = 6.5 Hz, 3J = 6.0 Hz, 1H, H-5), 4.15 (q, 3J2,1 = 7.1 Hz, 2H, H-
2), 4.04 (dd, 3J = 7.3 Hz, 3J = 4.8 Hz, 1H), 2.75 (dd, 2J = 16.0 Hz, 3J = 6.0
Hz, 1H), 2.66 (dd, 2J = 18.4 Hz, 3J = 7.2 Hz, 1H), 2.61 (dd, 2J = 16.0 Hz,
3J = 6.8 Hz, 1H), 2.55-2.30 (m, 3H), 1.25 (t, 3J = 7.1 Hz, 3H). 13C-NMR
(125 MHz, CDCl3): δ = 201.6 (s), 171.0 (s), 134.7 (d), 117.4 (t), 71.1 (d),
68.9 (d), 60.8 (t), 39.8 (t), 39.4 (t), 39.2 (t), 14.3 (q). Minor diastereomer
(selected signals): 1H-NMR (500 MHz, CDCl3): δ = 4.57-4.47 (m, 1H, H-5),
3.86 (dd, 3J = 10.3 Hz, 3J = 6.7 Hz, 1H), 2.83 (dd, 2J = 15.9 Hz, 3J = 6.1
Hz, 1H), 2.21 (dd, 2J = 18.2 Hz, 3J = 10.3 Hz, 1H). 13C-NMR (125 MHz,
CDCl3): δ = 170.9 (s), 134.5 (d), 117.2 (t), 43.9 (t). IR (ATR): ν [cm–1] =
2984 (w), 1798 (s), 1730 (s), 1167 (s), 1076 (m), 1026 (m). ESI-HRMS
calcd for C11H16O4Na [M+Na]+: 235.0941; found: 235.0942.
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Acknowledgements
This work was generously supported by the Fonds der
Chemischen Industrie, the Deutsche Forschungsgemeinschaft
(DE 1599/4-1), and the Dr.-Otto-Röhm-Gedächtnisstiftung.
Special thanks to Dr. Martin Breugst for the illustration of
potential exo/endo-alignments (Scheme 9).
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Keywords: heterocycles • chemoenzymatic • lipase •
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10.1002/chem.201704624
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Benedikt Skrobo, Nils E. Schlörer, Jörg-
M. Neudörfl, Jan Deska*
Page No. – Page No.
Kirmse-Doyle- and Stevens-type
Rearrangements of Glutarate-derived
Oxonium Ylides
A novel chemoenzymatic cascade enables the preparation of densely decorated
tetrahydrofuran building blocks. The direct combination of a lipase-catalyzed de-
symmetrization of 3-alkoxy-glutarates rendering highly enantioenriched carboxylic
acid intermediates and the subsequent activation and copper-mediated oxonium
ylide rearrangement furnishes stereodefined functionalized O-heterocycles. The
two-step protocol offers a streamlined and flexible access to tetrahydrofuranones
bearing unsaturated side chains with full control over multiple stereogenic centers.
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