Synthesis of conjugated polyenes via sequential condensation of sulfonylphosphonates and aldehydes

Article abstract of DOI:10.1021/ol203431e

Selective metalation of sulfonylphosphonates results in sufficiently stable carbanions that undergo chemoselective Julia-Kocienski condensation with various aldehydes to provide (E)-allylic phosphonates in good yields and selectivities. The subsequent Horner-Wadsworth-Emmons condensation with aldehydes is used to synthesize various unsymmetrical trans-dienes, trienes, and tetraenes. This methodology is utilized for the concise synthesis of a naturally occurring fluorescent probe for membrane properties, β-parinaric acid.

Full text of DOI:10.1021/ol203431e

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1058–1061
Synthesis of Conjugated Polyenes via
Sequential Condensation of
Sulfonylphosphonates and Aldehydes
Nathan R. Cichowicz and Pavel Nagorny*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109,
United States
nagorny@umich.edu
Received December 22, 2011
ABSTRACT
Selective metalation of sulfonylphosphonates results in sufficiently stable carbanions that undergo chemoselective JuliaÀKocienski
condensation with various aldehydes to provide (E)-allylic phosphonates in good yields and selectivities. The subsequent
HornerÀWadsworthÀEmmons condensation with aldehydes is used to synthesize various unsymmetrical trans-dienes, trienes, and
tetraenes. This methodology is utilized for the concise synthesis of a naturally occurring fluorescent probe for membrane properties,
β-parinaric acid.
Conjugated polyenes represent a diverse class of natural
and unnatural products. The problems associated with the
stereoselective syntheses of these motifs have been of great
interest due to the importance of polyenes in biology,
material science, and organic synthesis.1 Although a num-
ber of different methods are available for the synthesis of
conjugated polyenes, the majority of these methods are
based on the use of transition-metal-catalyzed cross-
couplings1,2 or stereoselective condensations such as Wittig
and HornerÀWadsworthÀEmmons (HWE) olefination.3
Traditional approaches rely on a stepwise carbonÀcarbon
bond or carbonÀcarbon double bond formation and often
(4) Selected examples of double cross-couplings in the synthesis of
symmetrical and unsymmetrical polyenes: (a) Babudri, F.; Flandanese,
V.; Mazzone, L.; Naso, F. Tetrahedron Lett. 1994, 35 (47), 8847–8850.
(b) Babudri, F.; Farinola, G. M.; Flandanese, V.; Mazzone, L.; Naso, F.
Tetrahedron 1998, 54, 1085–1094. (c) Pihko, P. M.; Koskinen, A. M. P.
Synlett 1999, 1966–1968. (d) Waterson, A. G.; Kruger, A. W.; Meyers,
A. I. Tetrahedron Lett. 2001, 42, 4305–4308. (e) Anderson, O. P.; Barrett,
A. G. M.; Edmunds, J. J.; Hachiya, S.; Hendrix, J. A.; Horita, K.;
Malecha, J. W.; Parkinson, C. J.; VanSickle, A. Can. J. Chem. 2001, 79,
1562–1592. (f) Vaz, B.; Alvarez, R.; de Lera, A. R. J. Org. Chem. 2002,
67, 5040–5043. (g) Sorg, A.; Bruckner, R. Angew. Chem., Int. Ed. 2004,
43, 4523–4526. (h) Murakami, M.; Matsuda, T.; Itami, K.; Ashida, S.;
Terayama, M. Synthesis 2004, 9, 1522–1526. (i) Coleman, R. S.; Walczak,
M. C. Org. Lett. 2005, 7 (11), 2289–2291. (j) Denmark, S. E.; Tymonko,
S. A. J. Am. Chem. Soc. 2005, 127, 8004–8005. (k) Denmark, S. E.;
Fujimori, S. J. Am. Chem. Soc. 2005, 127 (25), 8971–8973. (l) Lee,
S. J.; Anderson, T. M.; Burke, M. D. Angew. Chem., Int. Ed. 2010, 49,
8860–8863. (m) Fujii, S.; Chang, S. Y.; Burke, M. D. Angew. Chem.,
Int. Ed. 2011, 50, 7862–7864.
(1) For recent reviews of polyene synthesis refer to: (a) Thirsk, C.;
Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 999–1023. (b) Krasnaya,
Zh. A.; Tatikolov, A. S. Russ. Chem. Bull., Int. Ed. 2003, 52 (8), 1641–
1666. (c) Babudri, F.; Farinola, G. M.; Naso, F. J. Mater. Chem. 2004, 14,
11–34.
(2) Representative examples: (a) Zeng, F.; Negishi, E. Org. Lett.
2002, 4, 703–706. (b) Dominguez, B.; Iglesias, B.; de Lera, A. R.
Tetrahedron 1999, 55, 15071–15098. (c) Lipshutz, B. H.; Ullman, B.;
Lindsley, C.; Pecchi, S.; Buzard, D. J.; Dickson, D. J. Org. Chem. 1998,
63, 6092–6093. (d) Torrado, A.; Iglesias, B.; Lopez, S.; de Lera, A. R.
Tetrahedron 1995, 51, 2435–2454.
(3) For selected reviews of Wittig and HWE reactions in the synthesis
of natural products refer to: (a) Bestmann, H. J.; Vostrowsky, O. Top.
Curr. Chem. 1983, 109, 85–163. (b) Nicolaou, K. C.; Harter, M. W.;
Gunzner, J. L.; Nadin, A. Liebigs Ann./Recueil 1997, 1283–1301.
r
10.1021/ol203431e
Published on Web 01/31/2012
2012 American Chemical Society

require multiple postcoupling manipulations in order to
carry on the installation of the olefin functionality. Recently,
the development of transition-metal-catalyzed double cou-
plings and iterative cross-couplings has enabled convergent
syntheses of symmetrical and unsymmetrical polyenes.4
Scheme 1. Synthesis of the Bifunctional Precursors for Sequen-
tial Condensation
Figure 1. Cross-coupling and condensation-based convergent
approaches to polyenes.
In contrast, very few sequential coupling protocols
involving condensation of bifunctional reagents with alde-
hydes are available (Figure 1). The double condensation of
vinylogous R,β-bisphosphonates with aldehydes has been
known for many decades.5 However, to the best of our
knowledge, no condensation-based methods for the con-
vergent two-stepassembly of unsymmetrical polyeneshave
been reported.6 Such a strategy might be especially valu-
able for the rapid generation of unsymmetrical trans-
polyene libraries since it would avoid the additional steps
required for the synthesis of various vinyl halides, boronic
acids, stannanes, and silanes. Herein we now describe new,
highly chemoselective, sequential condensations of sulfo-
nylphosphonates and aldehydes that can be used for the
rapid construction of conjugated unsymmetrical polyenes.
Being interested in developing new strategies for the
convergent assembly of natural and unnatural polyenes,
we sought to exploit various bifunctional substrates for the
condensation-based synthesis of unsymmetrical polyenes
(Scheme 1).
We envisioned that monodeprotonation of symmetrical
bis-sulfone 2a7 or bisphosphonate 2b, followed by con-
densation with 1 equiv of aldehyde, might lead to an allylic
sulfone or phosphonate. These products could then under-
go a second olefination upon exposure to an additional
equivalent of base and aldehyde.
Unfortunately, the attempts to utilize substrates 2a and
2b for selective mono-olefination were met with limited
success (Scheme 2). The deprotonation of bis-sulfone 2a
Scheme 2. Monocondensation of 3-Phenylpropanal and 2aÀ2f
with KHMDS resulted in rapid elimination leading to the
butadienylarylsulfone 4a.8 The condensation of mono-
metalated bisphosphonate 2b with 3-phenylpropanal
(1.1 equiv) provided 5a (20À45% yield). This reaction was
sluggish and suffered from a competitive condensation
leading to symmetrical triene 4b. We surmised that the
problems encountered with 2b could be avoided if one of
the phosphonates of 2b was replaced with triphenylphos-
phonium or arylsulfone functionalities. The protons next
to the triphenylphosphonium or arylsulfone moieties of 2c,
2e, or 2f would be more acidic than the protons adjacent
to diethylphosphonate. Thus, substrate 2c may undergo
chemoselective Wittig reaction, while 2e and 2f could
undergo chemoselective JuliaÀKocienski condensation7
to provide 5a. To test this hypothesis, the unsymmetrical
bifunctional substrates 2c, 2e (3 steps, 57%), and 2f
(59% yield, three steps) were synthesized on a multigram
scale from the commercially available (E)-1,4-dibromo-2-
butene 1a.
(5) Stilz, W.; Pommer, H. Germ. Pat. 1,092,472, 1958 (to BASF AG).
(6) Minami and coworkers utilized sequential Wittig/HWE conden-
sations in the synthesis of symmetrical 1,2-bis(ylidene)cyclobutanes.
However, applying this strategy to the synthesis of unsymmetrical
substrates proved to be challenging: Minami, T.; Harui, N.; Taniguchi,
Y. J. Org. Chem. 1986, 51, 3572–3576.
(7) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1
2002, 2563–2585.
(8) Hughes, S.; Griffiths, G.; Stirling, C. J. M. J. Chem. Soc., Perkin
Trans. 2 1987, 1253–1264.
Org. Lett., Vol. 14, No. 4, 2012
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of 2e and 3-phenylpropenal was carried out on a gram scale
without any erosion in yield or selectivity.
Table 1. Reactions of Monodeprotonated 2e and 2f with
Aldehydes
Table 2. Reactions of Monodeprotonated 3 with Aldehydes
a Conditions: (i) THF, KHMDS (1.2 equiv), À78 °C, 5 min; (ii) aldehyde
(1.5 equiv), À78 °C, 20 min; (iii) 0 °C, 1 h. PT = 1-phenyl-1H-tetrazole;
BT = 2-benzo[d]thiazole. b Average of two runs. c Determined by 1H NMR.
a Conditions: (i) 3, THF, KHMDS (1.2 equiv), À78 °C, 5 min; (ii)
aldehyde (1.5 equiv), À78 °C, 20 min; (iii) 0 °C, 1 h. PT = 1-phenyl-1H-
tetrazole. b Average of two runs. c Determined by 1H NMR.
While sulfonylphosphonates 2e and 2f could be even-
tually converted to conjugated trienes, tetraenes, or pen-
taenes, they cannot be used for the synthesis of dienes. In
order to demonstrate that our methodology is applicable
to the synthesis of dienes, sulfonylphosphonate 3 was
prepared from triethylphosphite and 1b (64%, three steps)
(Scheme 1). Similar to 2e and 2f, 3 could be monodepro-
tonated with KHMDS and reacted with various aldehydes
to provide allylic phosphonates 6aÀh (Table 2). Impor-
tantly, these reactions were completely chemoselective and
no HWE or double condensation products were detected.
In general, the yields and selectivities for the condensations
with 3 were superior to the corresponding yields and
selectivities of olefinations with 2e and 2f. Both the un-
branched (entries 1À3) and β-substituted (entries 4À7)
aliphatic aldehydes reacted with 3 to provide allylic phos-
phonates 6aÀg in 40À84% yields and excellent selec-
tivities. Importantly, 3 could be condensed with R,β-
unsaturated aldehydes such as 3-phenyl-2-propenal
(entry 8). The corresponding allylic phosphonate 6h was
isolated in 75% yield with an 86:14 E/Z ratio. In addition,
the condensations with 3 could be carried out on a gram
scale without any erosion of yield or selectivity (entry 1).
In order to demonstrate that sulfonylphosphonates
could be used for the convergent synthesis of polyenes
(cf. Figure 1), the HWE condensation of phosphonates 5a
and 6a with aldehydes was investigated (Table 3). It is
known that allylic phosphonates can be utilized in the
The attempted Wittig condensation of 2c with 3-phenyl-
propanal provided only trace amounts of the desired
allylic phosphonate 5a. However, the treatment of sulfonyl-
phosphonates2eand2fwith KHMDS(1.1 equiv) followed
by the addition of 3-phenylpropanal (1.2 equiv) resulted
in the clean formation of 5a (Scheme 2). Both reactions
proceeded with remarkable levels of chemoselectivity,
and no competing HWE condensation was detected by
1H NMR analysis of the crude mixture. Neither the
formation of the symmetrical triene side product nor
the elimination of the arylsulfone was observed in these
experiments.
Based on these encouraging results, the effect of the
aldehyde structure on the yields and selectivities of this
reaction was explored next (Table 1). Our general compar-
ison of the reactions of metalated 2e and 2f with aldehydes
illustrates that both substrates react with comparable
efficiencies to provide allylic phosphonates 5. However,
olefinations with metalated 1-phenyl-1H-tetrazole-sulfone
2e proceed with higher selectivities. The JuliaÀKocienski
condensations with metalated 2e proceed with good yields
and selectivities with both the unbranched (entries 1, 3,
and 5) and β-substituted aliphatic aldehydes(entries6À10).
However, condensations with R,β-unsaturated aldehydes
such as 3-phenyl-2-propenal proceed with moderate yields
and selectivities (entries 11 and 12). To demonstrate that
these reactions are not sensitive to scale up, a condensation
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Org. Lett., Vol. 14, No. 4, 2012

resultant product, the hydrolysis of the β-parinaric acid
methyl ester was conducted in situ without isolation of
this intermediate. The resultant acid was obtained in 49%
yield and 7:1 ratio of the desired all-(E)-isomer to the sum
of (Z)-olefin containing isomers.12 Our synthesis included
5 linear steps (6 steps total) and is among the shortest
approaches to β-parinaric acid.13
Table 3. HWE Reactions of 5a and 6a with Aldehydes
In summary, this report describes a new protocol for the
synthesis of trans-dienes, trienes, and tetraenes that is
based on chemoselective condensation of monometalated
sulfonylphosphonates and aldehydes followed by HornerÀ
WadsworthÀEmmons olefination of the resultant allylic
phosphonates. We envision that this strategy will find its
application for the rapid generation of trans-polyene li-
braries as well as for the convergent synthesis of polyene-
containing natural products.
a Conditions: (i) 5 or 6, THF, base (1.1 equiv), À78 °C, 20 min to 1 h;
(ii) aldehyde (1.5 equiv), À78 °C, 15 min; (iii) rt, 10À15 h. b Average of
two runs. c Determined by 1H NMR.
Scheme 3. Synthesis of β-Parinaric Acid
(E)-selective HWE condensation to provide (E)-polyenes in
good yields and selectivities, and our results reinforce these
findings.9 Our evaluation of the optimal base (entries 1À5)
demonstrated that the deprotonation of dienyl phospho-
nates with n-BuLi provides superior yields and selectivities.
However, NaHMDS was found to be the base of choice for
the reactions of allylic phosphonate 6a (entries 6À7).
The described method was applied to the synthesis
of β-parinaric acid. β-Parinaric acid is a naturally occur-
ring tetraene fatty acid that is a widely used fluores-
cent membrane probe.10 Our synthesis commenced from
known aldehyde 8 obtained in one step from the commer-
cially available methyl oleate (Scheme 3).11 Condensation
of 8 with sulfonylphosphonate 2e led to phosphonate 9
(70% yield, 91:9 9E,11E:9Z,11E). Phosphonate 9 could be
used for the HWE condensation with commercially available
(E)-2-pentenal. Due to the light and air sensitivity of the
Acknowledgment. P.N. acknowledges the University of
Michigan and Robert A. Gregg for financial support.
We thank Prof. J. Montgomery, Prof. E. Vedejs, and
Prof. A. McNeil for helpful discussions.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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