Stereoselective synthesis of dienyl phosphonates via extended tethered ring-closing metathesis

Article abstract of DOI:10.1021/ol4020078

Allylphosphonates of allylic alcohols were converted to conjugated dienyl phosphonates in a one-flask reaction, comprising a ring-closing metathesis (RCM), a base-induced ring-opening, and an alkylation. The ring-opening proceeds with very high diastereoselectivity, giving exclusively the (1Z,3E)-configured dienes. Single diastereomers and mixtures of diastereomers can be used as starting materials without noticeable effect on the diastereoselectivity of the sequence.

Full text of DOI:10.1021/ol4020078

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4470–4473
Stereoselective Synthesis of Dienyl
Phosphonates via Extended Tethered
Ring-Closing Metathesis
Bernd Schmidt* and Oliver Kunz
Institut fuer Chemie (Organische Synthesechemie), Universitaet Potsdam,
Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany
bernd.schmidt@uni-potsdam.de
Received July 17, 2013
ABSTRACT
Allylphosphonates of allylic alcohols were converted to conjugated dienyl phosphonates in a one-flask reaction, comprising a ring-closing
metathesis (RCM), a base-induced ring-opening, and an alkylation. The ring-opening proceeds with very high diastereoselectivity, giving
exclusively the (1Z,3E)-configured dienes. Single diastereomers and mixtures of diastereomers can be used as starting materials without
noticeable effect on the diastereoselectivity of the sequence.
Due totheir highand specific binding affinities toseveral
biological receptors, phosphonic acids are very common
structural elements in drugs and drug candidates.1,2 They
are often administered as a prodrug to improve bioavail-
ability, e.g., as the corresponding phosphonate or phos-
phonic acid diamide. An example of a phosphonate-
containing prodrug is tenofovir disoproxil fumarate (1),
which is a reverse transcriptase inhibitor used as an AIDS
therapeutic. In contrast, the antibiotic fosfomycin (2) is
administered as its disodium salt.3 The furan-2-phospho-
nic acid 3 has been designed as a 50-adenosinemonopho-
sphate mimic and was evaluated for its potency as a
fructose-1,6-bisphosphatase inhibitor, with a view toward
the treatment of type-2 diabetes.4 The cyclic enol phos-
phonate 4 and its three diastereomers were synthesized
as hydrolytically more stable analogues of the recently
isolated natural product cyclophostin. They act as inhibi-
tors of microbial lipases, inter alia of Mycobacterium
tuberculosis, and may assist in understanding the mecha-
nism of bacterial growth.5 The 1,3-dienyl pyrophosphonate
5 has been synthesized as a mimic of natural phospho
antigens with increased metabolic stability. This and sev-
eral related compounds were tested for their ability to
activate human lymphocytes and show immunoregulatory
activity, with a perspective to treat infections and cancer
(Figure 1).6
Several methods for the synthesis of phosphonates exist
and have been covered in recent reviews.1,2 Nevertheless,
the development of alternative routes remains a subject of
interest, because hitherto unexplored and more conve-
niently available starting materials may be used, and pre-
viously unaccessible substitution patterns and configura-
tions can be addressed. From a synthetic point of view, vinyl
phosphonates should be particularly valuable, because the
double bond in conjugation with the phosphonate moiety
may undergo numerous useful transformations, such as
epoxidation or conjugate addition. Herein, we report a
convenient and highly stereoselective approach to Z,E-
configured dienyl phosphonates, which relies on a one-flask
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F.; Reddy, K. R.; Scarlato, G. R.; Gibson, T.; van Poelje, P. D.; Potter,
S. C.; Erion, M. D. J. Med. Chem. 2010, 53, 441–451.
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r
10.1021/ol4020078
Published on Web 08/14/2013
2013 American Chemical Society

one-flask metathesis sequence has recently been reported
by us,13 and a related ring-opening of benzooxepines14 and
benzoazepines15 obtained through RCM was reported by
Ramachary et al.
We started our investigation into a stereoselective synthe-
sis of dienyl phosphonates with the preparation of RCM
precursor 12a by adapting a sequence previously reported
by Virieux et al.16 To this end, allyl alcohol 10a was treated
with allyl chloro phosphonate 11 under slightly modified
conditions to give the required precursor 12a in 79% yield
as a 1:1 mixture of diastereomers. We chose the second-
generation catalyst A17 to accomplish the cyclization of
12a, because we suspected from previous experience with
the RCM of substituted allyl butenoates that this reaction
would most likely proceed slowly and in poor yield with
first-generation catalysts, even if comparatively high cata-
lyst loadings were used.18 However, it should be noted that
good yields had previously been reported for the RCM of
similar allyl phosphonates16,19,20 with sterically less de-
manding allylic substituents, using the first-generation
Grubbs catalyst.21 We found that 12a underwent RCM
Figure 1. Drugs and medicinal chemistry test substances con-
taining phosphonate units.
1
to 13a quantitatively as judged from the H NMR spec-
tethered ring-closing metathesis (RCM)ꢀring-opening re-
trum of the crude mixture within one hour by using a
comparatively low catalyst loading of 1 mol % of A and a
conveniently manageable initial substrate concentration
of 0.1 M in toluene at slightly elevated temperature. The
cyclic phosphonate 13a was isolated in 74% yield as a 1:1
mixture of diastereomers, indicating that RCM of both
diastereomers of 12a proceeds at a similar rate under these
metathesis conditions. In the next step, the projected one-
flask RCMꢀring-opening sequence was applied to pre-
cursor 12a by adding the base NaH to the reaction mixture
upon completion of the metathesis step. Monitoring the
reaction by TLC revealed that under these conditions the
intermediate RCM product 13a was completely consumed
after 2 h, and upon aqueous acidic workup the hemi-
phosphonate 14a was isolated as a single (1Z,3E)-diaster-
eomer in good yield. Similarly, the alkyl-substituted phos-
phonates 14b,c could be isolated as single diastereomers in
comparable yields (Scheme 2).
action following the general sequence outlined in Scheme 1.
Scheme 1. General Principle of Tethered RCMꢀRing-Opening
Sequences
In these reactions, RCM substrates of the general struc-
ture 6 comprising an electron-withdrawing functional
group Y and an acidic R-H atom are first subjected to
RCM, followed by in situ deprotonation of 7 and a base-
induced ring-opening of intermediate 8. After aqueous
workup, diene 9 results. In contrast to other tethered
RCM reactions,7,8 the XꢀY bond remains intact, but
the double bond formed during RCM is shifted and an
additional functionality, i.e., a second double bond, is
created. Precedence for the base-induced stereospecific
ring-opening of endocyclic alkenes of the general structure
7 exists for the conversion of R,β-unsaturated-δ-lactones
into (2Z,4E)-dienoic acids.9ꢀ12 The implementation of
this particular base-induced ring-opening reaction in a
At this stage we realized that the chromatographic
purification of the ring-opening products 14 was very
laborious, due to their high polarity. In addition, complex
(13) Schmidt, B.; Kunz, O. Eur. J. Org. Chem. 2012, 1008–1018.
(14) Ramachary, D. B.; Narayana, V. V.; Ramakumar, K. Eur. J.
Org. Chem. 2008, 3907–3911.
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3514–3522.
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Virieux, D. Tetrahedron 2010, 66, 758–764.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
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(8) Venukadasula, P. K. M.; Chegondi, R.; Suryn, G. M.; Hanson,
P. R. Org. Lett. 2012, 14, 2634–2637.
(18) Schmidt, B.; Kunz, O. Synlett 2012, 23, 851–854.
(19) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem.
Rev. 2004, 104, 2239–2258.
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(10) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 2317–2320.
(11) Roush, W. R.; Spada, A. P. Tetrahedron Lett. 1982, 23, 3773–
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(12) Ciabatti, R.;Maffioli, S. I.;Panzone, G.;Canavesi, A.;Michelucci,
E.; Tiseni, P. S.; Marzorati, E.; Checchia, A.; Giannone, M.; Jabes, D.;
(20) (a) Hanson, P. R.; Stoinova, D. S. Tetrahedron Lett. 1998, 39,
3939–3942. (b) Stoianova, D. S.; Whitehead, A.; Hanson, P. R. J. Org.
Chem. 2005, 70, 5880–5889. (c) Zhang, H.; Tsukuhara, R.; Tigyi, G.;
Prestwich, G. D. J. Org. Chem. 2006, 71, 6061–6066. (d) Bravo-Altamirano,
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Romano, G.; Brunati, C.; Candiani, G.; Castiglione, F. J. Med. Chem.
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Org. Lett., Vol. 15, No. 17, 2013
4471

This prompted us to investigate the RCMꢀring-openingꢀ
alkylation sequence for 12d in THF, using 1.1 or 1.5 equiv of
NaH and 1.0 or 0.5 mol % of catalyst (Table 1, entries 4ꢀ6).
Scheme 2. Synthesis and RCMꢀRing-Opening of Allyl Phos-
phonates 12
Table 1. Optimization of RCMꢀRing-OpeningꢀAlkylation
Sequence of Allyl Phosphonate 12d
cat. loading
(mol %)
NaH
additive
(equiv)
product
(yield)
entry
solvent (equiv)
1
2
3
4
5
6
1.0
1.0
0.5
1.0
1.0
0.5
toluene
toluene
THF
1.5
1.1
C2H5I (4.0)
14d (ꢀ)
Et3OBF4 (1.3) 15d (44%)
13d (92%)
NMR spectra had to be expected for derivatives with an
additional stereocenter in the side chain, because in the
hemi-esters 14 the phosphorus atom is still a stereocenter,
leading to the formation of two diastereomers. For these
reasons we decided to extend the RCMꢀring-opening
sequence by an O-alkylation of the sodium phosphonate
obtained prior to aqueous acidic workup. In a first experi-
ment (Table 1, entry 1), ethyl iodide was added to the
reaction mixture after completed ring-opening. Under
these conditions no phosphonate 15d was formed, but
only the hemi-ester 14d was present in the crude reaction
mixture obtained after aqueous workup. We reasoned that
ethyl iodide is not sufficiently electrophilic to alkylate a
THF
1.1
1.5
1.5
Et3OBF4 (1.3) 15d (62%)
Et3OBF4 (1.3) 15d (85%)
Et3OBF4 (1.3) 15d (88%)
THF
THF
Having identified the optimized conditions listed in
Table 1, entry 6, we investigated the scope of the one-flask
synthesis of dienyl phosphonates 15 from allyl phospho-
nates 12 (Table 2).
With the exception of 12n, all precursors were converted
to defined products in synthetically useful yields. In this
particular case, a complex mixture was obtained, which
can most likely be explained by the presence of an addi-
tional CH-acidic position R to the ester group. An in-
creased catalyst loading of 1.0 mol % was required for the
successful conversion of precursors with a geminally
disubstituted double bond (Table 2, entries 16ꢀ19). Although
conversion to the intermediate RCM products proceeds
quantitatively (TLC), the isolated yields of the final pro-
ducts 15pꢀs are, for unclear reasons, significantly lower.
Confirmation of the assumed 3E-configuration was ac-
complished for the example 15p, using 2D-NOE spectro-
scopy. A positive NOE between the methyl group at C3
and the methylene group at C4 of the diene was indicative
for the assigned double-bond configuration.
The only case in which a product other than the (1Z,3E)-
configured dienyl phosphonate 15 was obtained is the
benzyl-substituted precursor 12e, which reacts with the
allyl phosphonate 16 under the optimized conditions. We
assume that the expected phosphonate 15e is originally
formed, but undergoes a base-catalyzed isomerization to
the E,E-configured allyl phosphonate 16, which is presum-
ably thermodynamically preferred due to its extended
conjugated π-system. With a view to the synthesis of
rather weak nucleophile such as 14d Naþ and therefore
3
tested triethyl oxonium tetrafluoroborate (Meerwein’s
reagent).22,23 This led to the isolation of the desired diethyl
phosphonate 15d in 44% yield (Table 1, entry 2). The
reason for this moderate yield might be the comparatively
low reactivity of Meerwein’s reagent in an unpolar solvent
such as toluene. However, more polar solvents that are
commonly used for alkylation reactions, such as DMSO,
DMF, or THF, have previously been reported either to be
incompatible with olefin metathesis reactions due to cata-
lystdecompositionorinhibitionor tolead toasignificantly
decreased turnover frequency. Although the latter obser-
vation has been reported for cross metathesis reactions in
THF,24 we tested this solvent for the RCM of 12d (Table 1,
entry 3). Surprisingly, the RCM product 13d could be
isolated in very high yield with just 0.5 mol % of catalyst A.
(22) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E.
J. Prakt. Chem. 1937, 147, 257–285.
(23) Meerwein, H. Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, pp 1080ꢀ1083.
(24) Stark, A.; Ajam, M.; Green, M.; Raubenheimer, H. G.; Ranwell,
A.; Ondruschka, B. Adv. Synth. Catal. 2006, 348, 1934–1941.
4472
Org. Lett., Vol. 15, No. 17, 2013

Table 2. Scope and Limitations of One-Flask
RCMꢀRing-OpeningꢀAlkylation
Scheme 3. RCMꢀRing-OpeningꢀAlkylation of Benzyl
Derivative 12e
and thedevelopment of alternative syntheticroutes and the
synthesis of novel derivatives is therefore a field of con-
tinuous interest.25
In summary, we developed a one-flask synthesis of Z,E-
configured dienyl phosphonates starting from conve-
niently accessible RCM precursors. The use of these reagents
for stereoselective CꢀC bond formation and for the
synthesis of novel phosphonates or phosphonic acids with
interesting biological properties is currently under investi-
gation in our laboratory.
a Complex mixture of products. b 1.0 mol % of catalyst A was used.
Acknowledgment. This work was generously supported
by the Deutsche Forschungsgemeinschaft (DFG grant
Schm 1095/6-3).
products with even further extended π-systems we investi-
gated the use of 16 in olefination reactions. Upon depro-
tonation using KHMDS and reaction with aldehydes
17a,b, the conjugated all-E-trienes 18a,b were obtained in
high yields (Scheme 3).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Diarylhexatrienes, e.g., 18a, have attracted attention as
fluorescent probes for application in biological studies,
(25) Mesganaw, T.; Im, G. Y. J.; Garg, N. K. J. Org. Chem. 2013, 78,
3391–3393.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4473