Wittig Reaction: Domino Olefination and Stereoselectivity DFT Study. Synthesis of the Miharamycins' Bicyclic Sugar Moiety

Article abstract of DOI:10.1021/acs.orglett.5b02849

2-O-Acyl protected-d-ribo-3-uloses reacted with [(ethoxycarbonyl)methylene]triphenylphosphorane in acetonitrile to afford regio- and stereoselectively 2-(Z)-alkenes in 10-60 min under microwave irradiation. This domino reaction is proposed to proceed via tautomerization of 3-ulose to enol, acyl migration, tautomerization to the 3-O-acyl-2-ulose, and Wittig reaction. Alternatively, in chloroform, regioselective 3-olefination of 2-O-pivaloyl-3-uloses gave (E)-alkenes, key precursors for the miharamycins' bicyclic sugar moiety.

Full text of DOI:10.1021/acs.orglett.5b02849

Letter
pubs.acs.org/OrgLett
Wittig Reaction: Domino Olefination and Stereoselectivity DFT Study.
Synthesis of the Miharamycins’ Bicyclic Sugar Moiety
Vasco Cachatra, Andreia Almeida, Joao Sardinha, Susana D. Lucas, Ana Gomes, Pedro D. Vaz,
̃
M. Helena Florencio, Rafael Nunes, Diogo Vila-Vico
̧
sa, Maria Jose Calhorda,* and Amelia P. Rauter*
̂
́
́
Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Cien
Piso 5, Campo Grande, 1749-016 Lisboa, Portugal
̂
cias, Universidade de Lisboa, Ed. C8,
S
* Supporting Information
ABSTRACT: 2-O-Acyl protected-D-ribo-3-uloses reacted with
[(ethoxycarbonyl)methylene]triphenylphosphorane in aceto-
nitrile to afford regio- and stereoselectively 2-(Z)-alkenes in
10−60 min under microwave irradiation. This domino
reaction is proposed to proceed via tautomerization of 3-
ulose to enol, acyl migration, tautomerization to the 3-O-acyl-
2-ulose, and Wittig reaction. Alternatively, in chloroform,
regioselective 3-olefination of 2-O-pivaloyl-3-uloses gave (E)-
alkenes, key precursors for the miharamycins’ bicyclic sugar
moiety.
α,β-Unsaturated esters are often easily accessed by the reaction
of the resonance-stabilized [(alkoxycarbonyl)methylene]-
triphenylphosphoranes with carbonyl compounds, and the
reagent is frequently used in sugar elongation and the synthesis
of branched-chain sugars.1 One of the major challenges
encountered in keto sugar olefination is reaction stereocontrol.
The direct and regioselective oxidation of position 2 may also
be quite challenging, although the synthesis of a 2-ulose from a
3,4,6-tri-O-acetyl-protected sugar was successful with Ac2O/
DMSO2 but with concomitant elimination of acetic acid to give
an α,β-unsaturated carbonyl compound. In this work, we
present a facile, regio- and stereoselective method for the Wittig
reaction of 2-O-acyl-D-ribo-hexopyran-3-uloses with Ph3P
CHCO2Et (1) that allows olefination either at position 2 or 3,
depending on the solvent used, with the alkene (E)- or (Z)-
configuration being controlled by the bulky acyl group vicinal
to the carbonyl functionality.
alcohol at the newly formed tetrahydrofuran ring. This
antibiotic displays a potent activity against Pyricularia oryzae,
a fungus which causes the rice blast disease, which is now
considered a bioterrorism agent. Miharamycins were isolated 40
years ago from Streptomyces miharaensis SF-489.4 Their bicyclic
sugar residue has been synthesized by samarium iodide
cyclization of a 2-O-propargyl-3-ulose, followed by ozonolysis
and stereoselective reduction.5 Focusing our attention on these
antibiotics, our group has developed the first synthesis of the
miharamycins’ sugar epimer at the sugar-fused tetrahydrofuran
ring6 and that of the structurally related antibiotic amipur-
imycin sugar residue, embodying a branched chain at C-3 of a
4-deoxypyranose.7 The first total synthesis of the miharamycins’
core was also reported by us in 2008.8 The miharamycins’
bicyclic sugar moiety is also a structural feature of nucleosides
(Figure 1, C) that have shown a potent and selective inhibition
of butyrylcholinesterase (BChE), an enzyme whose concen-
tration increases considerably in later Alzheimer’s disease
stages.9 BChE has been found in senile plaques, and the
recently reported association of the BChE locus with Aβ
deposition merits further investigation and may have significant
implications for therapeutic treatment.10
Carbohydrates that embody (ethoxycarbonyl)methylene
have been successfully used by us as scaffolds for the generation
of bicyclic, sugar-fused, five-membered α,β-unsaturated lac-
tones.3 However, attempts to convert such compounds into the
bicyclic miharamycin sugar moiety (Figure 1, A and B) have
failed, affording instead the epimer of the chiral secondary
Hence, we were motivated to explore the utility of Wittig
olefination for the efficient synthesis of this type of compound.
We disclose now the first stereoselective and facile synthesis of
such bicyclic sugars starting from a 2-O-pivaloyl-3-ulose.
The Wittig reaction of 3-uloses differing in their 2,4,6-O-
protection was carried out with 1 in chloroform or acetonitrile
under conventional or microwave-assisted heating, and the
results are summarized in Table 1.
Figure 1. Miharamycins (A, B) and related BChE-selective inhibitor
nucleoside (C).
Received: October 1, 2015
© XXXX American Chemical Society
A
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Letter
pivaloyl-3-ulose in chloroform afforded exclusively the (E)-
alkene in high yield.7 We have found that when the equatorial
H-4 is replaced by a hydroxy group (ulose 2), intramolecular
cyclization is favored to give 3 in 90% yield. The latter
compound embodies a five-membered lactone fused to
positions 3 and 4, suggesting that the Wittig reaction
stereoselectivity proceeded toward the (E)-alkene, which
underwent cyclization both in chloroform and acetonitrile.
However, the reaction time was considerably reduced when the
solvent was acetonitrile, resulting from the increased solvent
polarity and higher reaction temperature. Reaction of ribo-3-
uloses 4, 7, 10, and 13 (differing in the 2,4,6-protecting group
pattern) with 1 in acetonitrile resulted in C2-olefination. The
major alkenes formed had a configuration in which the
ethoxycarbonyl group occupied the less sterically congested
side of the double bond, defined as the (Z)-configuration by the
Cahn, Prelog, and Ingold rules,11 in the presence of either the
benzoyl or the pivaloyl protecting groups. Solvation of the ylide
in acetonitrile favored keto−enol tautomerization of 3-uloses,
followed by intramolecular acyl migration and tautomerization
that gave the 2-ulose, which reacted in situ with the ylide. The
resulting Wittig products had the substituent at position 3 in
the equatorial position. This gives rise to coupling constants
3J3,4 with values between 9.2 and 10.3 Hz, characteristic of a
trans diaxial coupling. The insertion of the double bond at
position 2 was confirmed by the presence of H-1 at chemical
shifts δ 6.28−6.48 as a singlet; the signal of H-3 appeared either
Table 1. Wittig Reaction of 3-/2-Uloses with Phosphorane 1
by Conventional and Microwave-Assisted Heating
a
4
as a broad d or a dd when coupling constant J2′,3 with the
olefinic proton was detected. The proposed double-bond
configuration was assigned by NOESY, mainly based on the
correlation detected between H-2′ and protons of the
substituent at position 3, and that of H-1 with the methylene
of the ethoxycarbonyl group. Interestingly, the reaction time of
this domino reaction is much lower than that of the direct
olefination at position 3 in chloroform, in particular for the
reaction of uloses 10 and 13, whose reaction time decreased
from 3 days for 3-olefination to 6 h.
The stereochemical input of position 4 was investigated by
conducting the Wittig reaction with the D-xylo-3-ulose 16. Only
3-olefination took place both in chloroform and acetonitrile
with the same reaction time and similar yield, possibly due to
hindrance caused by the 4,6-benzylidene group. However,
domino olefination of D-lyxo-ulose 18, which embodies the
carbonyl group at position 2, took place in acetonitrile to afford,
in 68% yield, the 3-alkene 17E, where the substituent at
position 2 was in equatorial orientation. As expected,
olefination in chloroform led to the 2-alkene 19Z as the
major reaction product.
When reactions were carried out under microwave
irradiation, reaction stereo- and regioselectivity did not change
as shown by comparable product yields, but reaction times
decreased considerably, with the exception of direct 3-
olefination of uloses 4 and 10 in chloroform, for which
reaction time was maintained when compared to conventional
heating. In chloroform, Wittig reaction of 3-uloses always
afforded 3-alkenes as major products, their configuration
depending on the acyl protecting group at position 2. The
bulky pivaloyl group forces the formation predominantly of
(E)-alkenes (compounds 5E, 11E, 17E), as expected for
reactions with stabilized ylides,12 while in the presence of 2-O-
benzoyl protection, the major alkene has the (Z)-configuration
(compounds 8Z and 14Z). DFT calculations [Gaussian09,
PBE0/6-31G**(CHCl3)] were performed in order to gain
a
All reactions were performed under reflux conditions. Key: conv,
conventional heating; MW, microwave-assisted heating. E/Z ratio is
given when both isomers are detected in the 1H NMR spectrum of the
reaction mixture.
The contribution of the protecting group functionality,
vicinal to the carbonyl group, on the reaction outcome was
investigated. 3-Uloses bearing a bulky O-pivaloyl or a O-
benzoyl group at position 2 and exhibiting a free hydroxy or a
free benzyloxy group at position 4, or a 4,6-O-benzylidene
group were evaluated (for their synthesis, in good yields, see
the Supporting Information). Previously, it has been observed
that Wittig reaction of phosphorane 1 with 4-deoxy-2-O-
B
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insight into the factors governing this stereoselectivity. We
addressed the reaction of the benzylidene-protected 3-uloses 4
and 7 with phosphorane 1 to afford alkenes 5E and 8Z,
respectively. In the accepted mechanism,12 salt-free Wittig
reactions usually proceed through [2 + 2 + 0]-cycloaddition to
form an oxaphosphetane intermediate followed by pseudor-
otation around phosphorus and stereospecific [2 + 2 + 0]-
cycloreversion to yield the alkene and phosphine oxide.
Extensive computational evidence supports this mechanism
for aldehyde reactions.12−14 The reaction that leads to the
formation of alkene 8Z (Figure 2 and Figure S1) starts with 7
and 1 approaching (7*) to form the oxaphosphetane
intermediate OP1. The reagents can approach with different
orientations, the stereochemistry of the product alkene being
determined by the relative stability of the cycloaddition
transition states, in agreement with the model first proposed
by Vedejs and co-workers.12 The lower transition-state energy
for TS1 (29.5 kcal mol−1) corresponds to the concerted
addition of the ylide to the ulose when it proceeds from the less
hindered upper face of the sugar ring15 and also leads to the
lowest energy intermediate OP1. C−C bond formation (1.920
Å) is well advanced, while the P−O distance (2.996 Å)
characterizes a weak interaction, conferring an asynchronous
nature to TS1. A weak C−H···O hydrogen bond (2.008 Å,
144.2°) between the carbonyl oxygen and one carbon atom of a
phenyl group stabilizes the slightly puckered four-atom cycle
(PCCO = −13.9°). OP1 converts into OP2 by exchanging an
apical oxygen with an apical carbon with a barrier of 3.4 kcal
mol−1 (TSOP), preceded by small rotation of substituents
(OP1*). This low energy conversion is not clear in the
literature,12−14,16 and TSOP (only calculated for this reaction
pathway) is the first reported transition state that is effectively
connected to the two intermediates OP1 and OP2. The latter
undergoes cycloreversion (8*), decomposing into alkene 8Z
and triphenylphosphine oxide via another transition state
(TS2), with a low barrier of ∼5.3 kcal mol−1. The formation of
alkene 8E follows an analogous pathway (Figure S3), but both
transition states have higher energies (32.1 and 31.3 kcal mol−1
for TS1 and TS2, respectively), in agreement with the observed
stereoselectivity. Interestingly, alkene 8Z is not the thermody-
namically favored product, as its energy is higher by 0.9 kcal
mol−1. On the other hand, the energy profiles for the
conversion of 2-O-pivaloyl-3-ulose 4, into alkenes 5Z and 5E
(Figures S4 and S5), reveal that the observed product 5E is
formed with a barrier of 32.5 kcal mol−1 (TS1), while the other
(5Z) requires 35.0 kcal mol−1. 5E is also the thermodynami-
cally favored product. These calculations pinpoint a key role for
steric effects in controlling the stereoselectivity of Wittig
reactions involving stabilized ylides and uloses bearing acyl
protection vicinal to the carbonyl functionality.
Figure 2. Energy profiles for the conversion of 2-O-benzoyl-3-ulose 7
into alkenes 8Z (in red) and 8E (in gray) (ΔG in kcal mol−1 and
distances in Å). Selected optimized geometries (truncated for clarity)
are shown for the lower energy path.
Pursuing our studies to achieve an alternative strategy for the
synthesis of the miharamycin bicyclic sugar moiety, we outline
here an efficient and easy to run methodology involving
osmylation of the (E)-alkenes type 5 or 11 for generating key
Scheme 1. Miharamycins’ Bicyclic Sugar Moiety Synthesis
C
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Letter
precursors with the stereochemistry appropriate for the
miharamycin tetrahydrofuran secondary alcohol.
DEDICATION
Dedicated to the memory of Prof. Dr. Derek Horton.
■
As shown for compound 11E, double-bond osmylation was
followed by cyclization to lactone 21 by reaction with LiOH
and acetylation of the crude product (Scheme 1A). Reductive
deoxygenation of lactone 21 with trichlorosilane, BH3−DMS/
NaBH4, and Et3SiH/TiCl4−TMSOTf was attempted. However,
only Et3SiH in the presence of catalytic InBr3 succeeded to give
the target compound. This method, developed by Sakai and co-
workers17 and herein applied to carbohydrate templates for the
first time, seems to be promising for reducing this type sugar-
fused lactone. Preliminary studies on the readily available
bicyclic lactone 3 afforded, after 45 min, the reduced
unsaturated lactone 24 in 71% yield and compound 25,
bearing the fully reduced tetrahydrofuran ring, in 16% yield,
both keeping the pivaloyl group in the structure (Scheme 1B).
However, when the system was applied to lactone 21, a
complex reaction mixture was obtained. The target molecule 23
was synthesized by replacing the acetyl by benzyl groups. This
transformation was carried out by treatment of 21 with a
methanolic solution of K2CO3 for deprotection, followed by
benzylation with benzyl trichloroacetimidate. Reductive deox-
ygenation of 22 assisted by Et3SiH and InBr3 afforded the fully
protected miharamycins’ sugar moiety 23 in 51% yield over
three steps (Scheme 1A).
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Spectroscopic and analytical data are in full agreement with
those predicted for structure 23, which can be used, after
deprotection/orthogonal protection, as starting material for the
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ASSOCIATED CONTENT
* Supporting Information
■
S
́
(14) Stępien, M. J. Org. Chem. 2013, 78, 9512.
(15) Addition of the ylide from the opposite face of the pyranose ring
requires a significantly higher (∼8.5 kcal mol−1) activation barrier (see
Figure S2, Supporting Information).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02849.
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Detailed experimental procedures, compound character-
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1
copies of H and 13C NMR spectra of new compounds
(PDF)
Computational details, full results for the energy profiles,
and geometrical parameters (PDF)
Coordinates for the optimized intermediates and
transition states (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: aprauter@fc.ul.pt.
*E-mail: mjc@ciencias.ulisboa.pt.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Gerry Moss (Queen Mary University of London)
for advice regarding the compounds’ IUPAC systematic names.
Fundaca̧ o para a Ciencia e a Tecnologia is gratefully
̂
̃
acknowledged for financial support of the project UID/
MULTI/00612/2013 and for Ph.D. grants for V.C. (SFRH/
BD/90359/2012) and D.V.-V. (SFRH/BD/81017/2011).
D
DOI: 10.1021/acs.orglett.5b02849
Org. Lett. XXXX, XXX, XXX−XXX