Synthesis of Phosphonomethyl Tetrahydrofurans via the Mori-Tamaru Reaction of Phosphonodienes

Article abstract of DOI:10.1021/acs.orglett.0c01080

Nickel-catalyzed reductive addition of phosphonodienes to aldehydes (the Mori-Tamaru reaction) gives hydroxy vinyl phosphonates in good yields with excellent control of the relative stereochemistry. Base-induced cyclization of the vinyl phosphonates yields phosphonomethyl-substituted tetrahydrofurans. Inversion of the hydroxyl stereochemistry by Mitsunobu reaction and then cyclization yields a different set of phosphonomethyl-substituted tetrahydrofuran diastereoisomers.

Full text of DOI:10.1021/acs.orglett.0c01080

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Letter
Synthesis of Phosphonomethyl Tetrahydrofurans via the Mori−
Tamaru Reaction of Phosphonodienes
Rishi R. Paudel, Jeremy N. Ridenour, Nigam P. Rath, and Christopher D. Spilling*
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ABSTRACT: Nickel-catalyzed reductive addition of phosphono-
dienes to aldehydes (the Mori−Tamaru reaction) gives hydroxy
vinyl phosphonates in good yields with excellent control of the
relative stereochemistry. Base-induced cyclization of the vinyl
phosphonates yields phosphonomethyl-substituted tetrahydrofurans.
Inversion of the hydroxyl stereochemistry by Mitsunobu reaction
and then cyclization yields a different set of phosphonomethyl-substituted tetrahydrofuran diastereoisomers.
Scheme 1. Retrosynthetic Analysis for Phosphonomethyl
Tetrahydrofurans
-Nucleosides are hydrolytically stable analogues of N-
nucleosides, examples of which appear in nature.1 This
C
modification of the basic nucleoside structure leads to several
compounds that show interesting antiviral and anticancer
activity.1,2 For example, the C-nucleotide remdesivir (GS-
5734)3 has recently seen renewed interest because of its
activity against single-stranded RNA viruses, including various
corona viruses.4 Furthermore, in several synthetic C-nucleoside
analogues, the typical nucleoside nitrogen heterocycle can be
replaced other heterocycles or substituted benzene rings with
retention of the biological activity.2
Similarly, phosphonates are often prepared as more
metabolically stable analogues of biological phosphates.5
Several non-isosteric phosphonate analogues of nucleoside
phosphates have been synthesized,6 although in general they
possess limited biological activity. Furthermore, this approach
has been applied for analogues of ribose-1-phosphate and other
important anomeric phosphates.7
We saw the need for a synthetic approach that could address
the installation of both the C-nucleoside and the phosphonate
while also introducing the correct relative stereochemistry of
the substituents. A retrosynthetic analysis (Scheme 1) revealed
that the heterocyclic ring (A or B) could be formed via an oxa-
Michael reaction, wherein a hydroxyl nucleophile adds across a
vinyl phosphonate (C or D). On the basis of recent
experience,8 it was recognized that the 1,3-subsitution pattern
next to an alkene (D) could result from the Mori−Tamaru
reaction9,10 between a diene (E) and an aldehyde (F).
However, the stereochemistry of the carbinol carbon would
need to be corrected by a Mitsunobu reaction (D to C) in
order to give a tetrahydrofuran with the appropriate
disposition of the substituents found in C-nucleosides. Once
the relative stereochemistry is set in the Mori−Tamaru and
Mitsunobu reactions, the cyclization is expected to follow the
precedent established with related unsaturated esters.11
In the Mori−Tamaru reaction,9,10 a variety of 1- and 2-
substituted 1,3-dienes in combination with catalytic Ni(acac)2
and either Et3B or Et2Zn react (homoallylation) with
aldehydes to give bis-homoallylic alcohols with very high 1,3-
anti or 1,2-anti diastereoselectivity. We applied this reaction to
the construction of the tetrahydrofuran-containing C1−C9
fragment 1 of amphidinolides C and F.8 The key steps in this
synthesis (Scheme 2) were the Mori−Tamaru reaction to set
the stereochemistry (2), cross-metathesis (3), and base-
induced cyclization to form the tetrahydrofuran 4. We
subsequently showed that the metathesis step can be avoided
by using ester-functionalized diene 5 in the Mori−Tamaru
reaction.12
Received: March 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01080
© XXXX American Chemical Society
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Letter
Scheme 2. Application of the Mori−Tamaru Reaction to
Tetrahydrofuran Synthesis
Table 1. Mori−Tamaru Reaction of Diene 7a Using BEt3 or
AlEt3
yield of 9 (%)
a
b
entry
aldehyde (R)
Ph
ethyl
with BEt3
with AlEt3
a
b
c
d
e
f
45
41
26
48
47
36
17
72
65
63
59
61
60
0
2-furyl
2-thiophenyl
2-naphthyl
4-fluorophenyl
4-hydroxyphenyl
g
a
BEt3 (1 M in THF, 2.6 equiv), Ni(acac)2 (0.1 equiv), RCHO (2
b
equiv), THF, rt, 36 h. AlEt3 (1 M in hexane, 3.5 equiv), Ni(acac)2
(0.36 equiv), RCHO (3.5 equiv), THF, −50 to 0 °C, 5 h.
However, the isolated yields were lower than desired. The
reaction was complicated by the formation of byproducts,
typically in a ratio of 3:1:2 (9:10:11). The byproducts were
isolated and identified as alkenes 10 and 11.17 We speculated
that these compounds were the products of diene reduction,
presumably by nickel hydrides formed by decomposition of the
catalyst later in the reaction.
We postulated that a faster reaction between the diene and
aldehyde would lead to a reduction in byproduct formation.
We examined additional alkylmetal reagents that might lead to
a more rapid transfer of the alkyl group or improved activation
of the aldehyde, ultimately leading to a faster homoallylation
reaction. We were pleased to observe that replacing BEt3 with
AlEt3 resulted in faster reaction. The ratio of products (9, 10,
and 11) had improved to 10−40:2:1, resulting in improved
isolated yields of the desired vinyl phosphonates 9 (Table 1).
In all cases (BEt3 or AlEt3), nitrogen-containing heterocyclic
aldehydes (N-methylindole-3-carboxaldehyde, N-methylpyr-
role carboxaldehyde, and pyridine carboxaldehyde) and
unsaturated aldehydes (crotonaldehyde and ethyl trans-2-oxo-
2-butanoate) failed to react.
The Mori−Tamaru reaction of phosphonodienes is unex-
plored, and the regiochemical directing effects of the
phosphonate moiety are uncertain. In addition, only limited
examples of intramolecular oxa-Michael reactions of vinyl
phosphonates have been reported in the literature.7a,13
Dienes 7a−c were prepared via an olefination (Horner−
Wadsworth−Emmons) reaction between the appropriate
aldehyde and tetraethyl methylene diphosphonate (Scheme
3).14 Diene 7d was prepared following literature precedent by
silylation of unsaturated ketone 8.15,16
Scheme 3. Synthesis of the Dienes
Treatment of vinyl phosphonates 9a−g with sodium
methoxide in methanol resulted in cyclization, yielding
tetrahydrofurans 12a−g (Table 2). In all cases, the
Table 2. Cyclization of Vinyl Phosphonates 9
The reaction of 3-methyl diene 7a with benzaldehyde under
the standard Mori−Tamaru conditions (Ni(acac)2, BEt3, THF,
room temperature, 36 h) resulted in the formation of the
expected vinyl phosphonate 9a in 45% isolated yield (Scheme
4 and Table 1, entry a). Reactions with other aromatic and
aliphatic aldehydes (entries b−g) were also successful.
entry
substituent (R)
yield (%)
a
b
c
d
e
f
Ph
ethyl
2-furyl
2-thiophenyl
2-naphthyl
4-fluorophenyl
4-hydroxyphenyl
85
55
62
89
85
75
36
Scheme 4. Mori−Tamaru Reaction of Diene 7a
g
diastereoselectivity in the cyclization was >95%. X-ray crystal
structure determination of 12g allowed the assignment of the
relative stereochemistry of the ring substituents (see the
Supporting Information). Treatment of 9a with sodium
hydride in THF also resulted in cyclization to give 12a in
similar yield and diastereoisomeric ratio. Other bases were
B
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either ineffective (Et3N or iPr2NEt in CH2Cl2) or resulted in
complex mixtures (tBuOK in THF, DBU in CH2Cl2).
The reaction of diene 7b with benzaldehyde was much
slower than that with 7a and was complicated by significant
byproduct formation (Scheme 5). Vinyl phosphonate 13 was
experiment provides confirmation of the assigned relative
stereochemistry.
The Mitsunobu reaction18,19 of 9a using p-nitrobenzoic acid
as the nucleophile proceeded smoothly to give p-nitrobenzoate
ester 19 in high yield with clean inversion of the stereo-
chemistry (Scheme 7). Treatment of ester 19 with sodium
Scheme 5. Mori−Tamaru Reaction of Diene 7b with
Benzaldehyde
Scheme 7. Mitsunobu Reaction and Cyclization with
(Methyl) Vinyl Phosphonate 9a
difficult to isolate by column chromatography. Treatment of
the impure vinyl phosphonate 13 with sodium methoxide in
methanol resulted in cyclization to yield tetrahydrofuran 14 in
16% isolated yield over two steps. Unfortunately, the reaction
of diene 7c with benzaldehyde failed to yield any vinyl
phosphonate.
Although the 4-methyl- and 4-OBn-substituted dienes 7b
and 7c showed a lack of reactivity, we were pleased to observe
that reaction of the 3-OTBS-substituted diene 7d with
benzaldehyde successfully produced vinyl phosphonate 15 in
72% isolated yield (Scheme 6). Treatment of vinyl
methoxide in methanol resulted in both ester methanolysis and
in situ cyclization to give an inseparable mixture of
tetrahydrofuran diastereoisomers 20a and 20b in a 4:1 ratio.
In contrast, the Mitsunobu reaction with OTBS-substituted
vinyl phosphonate 15 required some modifications to the
reaction conditions (Scheme 8).19 Using tributylphosphine in
Scheme 6. Mori−Tamaru Reaction of Diene 7d with
Benzaldehyde
Scheme 8. Mitsunobu Reaction and Cyclization with
(OTBS) Vinyl Phosphonate 15
place of triphenylphosphine resulted in the formation of p-
nitrobenzoate 21 in excellent yield with clean inversion of the
stereochemistry. Treatment with sodium methoxide in
methanol again led to methanolysis and in situ cyclization to
give a 1:1.5 mixture of diastereoisomeric tetrahydrofurans 22a
and 22b in 77% yield.
Deprotection of the TBS group with TBAF allowed
assignment of the relative stereochemistry of the ring
substituents in compounds 22a and 22b (Scheme 9). Reaction
of the trans isomer 22a with TBAF in THF resulted in the
formation of alcohol 23a. In contrast, deprotection of the cis
isomer 22b led to in situ cyclization, giving a 1:1 mixture of
diastereoisomeric phostones 24 along with a small amount of
alcohol 23b, confirming the assigned relative stereochemistry.
In conclusion, we have shown that the Mori−Tamaru
reaction of phosphono-substituted dienes is an efficient route
to methylene phosphonate-substituted tetrahydrofurans. Nick-
phosphonate 15 with sodium methoxide in methanol resulted
in cyclization to yield tetrahydrofurans 16a, 16b, and 17a in
75% combined isolated yield. Since alcohol 17 arises by in situ
deprotection of 16a, the overall diastereoselectivity for the
cyclization is 3:1. Alcohol 17a is also formed when
tetrahydrofuran 16a is treated with TBAF in THF. In contrast,
treatment of the isomeric tetrahydrofuran 16b with TBAF in
THF led to the formation of a 1:1 mixture of alcohol 17b and
phostone 18. Since cyclization is more easily achieved when
the hydroxyl and phosphonate are in a cis relationship, this
C
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Scheme 9. Deprotection of OTBS-Protected
Tetrahydrofurans 22a and 22b
ACKNOWLEDGMENTS
■
The project described was supported by a grant from the
National Science Foundation (CHE-1465196). We are also
grateful to the National Science Foundation for grants to
purchase the NMR spectrometers (CHE-9974801 and CHE-
0959360), the X-ray diffractometer (CHE-0420497), and the
mass spectrometer (CHE-9708640) used in this project.
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aldehydes (the Mori−Tamaru reaction) gives hydroxy vinyl
phosphonates in good yields with excellent control of the
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phosphonates yields phosphonomethyl-substituted tetrahydro-
furans. Inversion of the hydroxyl stereochemistry by
Mitsunobu reaction followed by cyclization yields a different
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01080.
Experimental procedures; 1H, 13C, and 31P NMR spectra
for all compounds; and X-ray crystallographic data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Christopher D. Spilling − Department of Chemistry and
Biochemistry, University of Missouri-St. Louis, St. Louis,
Missouri 63121, United States; orcid.org/0000-0002-1765-
5746; Email: cspill@umsl.edu
Authors
Rishi R. Paudel − Department of Chemistry and Biochemistry,
University of Missouri-St. Louis, St. Louis, Missouri 63121,
United States
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Jeremy N. Ridenour − Department of Chemistry and
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Missouri 63121, United States
Nigam P. Rath − Department of Chemistry and Biochemistry,
University of Missouri-St. Louis, St. Louis, Missouri 63121,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01080
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