Efficient and scalable one-Pot Synthesis of 2,4-Dienols from cycloalkenones: Optimized total synthesis of valerenic acid

Article abstract of DOI:10.1021/ol202170c

A mild and selective one-pot procedure to provide 2,4-dienols from simple cycloalkenones in high yields is described. This transformation is based on the in situ formation of acid-labile allylic alcohols, which on treatment with trifluoroacetic acid under

Full text of DOI:10.1021/ol202170c

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5310–5313
Efficient and Scalable One-Pot
Synthesis of 2,4-Dienols from
Cycloalkenones: Optimized Total
Synthesis of Valerenic Acid
Juergen Ramharter and Johann Mulzer*
Institute of Organic Chemistry, University of Vienna, Waehringer Strasse 38, 1090
Wien, Austria
johann.mulzer@univie.ac.at
Received August 10, 2011
ABSTRACT
A mild and selective one-pot procedure to provide 2,4-dienols from simple cycloalkenones in high yields is described. This transformation is based on
the in situ formation of acid-labile allylic alcohols, which on treatment with trifluoroacetic acid undergo a formal [1,3]-hydroxy migration to form diastereo-
and enantiomerically enriched 2,4-dienols. The usefulness of this protocol is demonstrated in a short synthesis of valerenic acid.
2,4-Dienols are very important building blocks in nat-
ural product synthesis.1 However, as even simple 2,4-
dienols require several steps for their synthesis, a general
and efficient access to these compounds would be
welcome.
A straightforward access to 2,4-dienols is the [1,3]-
hydroxy isomerization of tertiary allylic alcohols. This
thermodynamically driven reaction has been known for
several decades and has often been based on the use of
metalꢀoxo catalysts,2 although the pioneering investiga-
tions were carried out with sulfuric acid.3 However, one of
the disadvantages of this reaction type is the moderate
stability of the required precursors. Therefore, we devised
an effective and mild one-pot procedure that combines the
preparation of the precursors with the [1,3]-hydroxy
isomerization.4,5
As a proof of concept, 2-cyclopentenone (1) was
chosen as a simple test substrate (see Table 1). After
treatment with vinylmagnesium bromide, the in situ
formed tertiary alkoxide 2 was treated with different
aqueous Brønsted acids to trigger the transformation
into 3-vinylcyclopent-2-enol (3a). The difference be-
tween sulfuric acid and hydrochloric acid was margin-
al, and at best, the isolated yields were only slightly
higher than 40% (entries 1ꢀ3). After applying inor-
ganic Brønsted acids, we switched to organic Brønsted
acids instead (entries 4ꢀ6). Gratifyingly, when acetic
acid or trifluoroacetic acid was used, decomposition
and side reactions seemed to be much less competitive,
in both cases, and much better results were obtained.
(1) For examples, see: (a) Corey, E. J.; Da Silva Jardine, P.; Rohloff,
J. C. J. Am. Chem. Soc. 1988, 110, 3672. (b) He, F.; Bo, Y.; Altom, J. D.;
Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771. (c) Ramharter, J.;
Mulzer, J. Org. Lett. 2009, 11, 1151.
(2) For a review, see: Bellemin-Laponnaz, S.; Le Ny, J.-P. Compt.
Rend. Chim. 2002, 5, 217.
(3) For a review, see: Braude, E. A. Q. Rev. Chem. Soc. 1950, 4, 404.
(4) For reviews about one-pot reactions, see: (a) Posner, G. H. Chem.
Rev. 1986, 86, 831. (b) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2011, 50, in press. (c) Vaxelaire, C.; Winter, P.; Christmann,
M. Angew. Chem., Int. Ed. 2011, 50, 3605.
(5) For a recent application of one-pot reactions in natural product
synthesis from our group, see: Ramharter, J.; Weinstabl, H.; Mulzer, J.
J. Am. Chem. Soc. 2010, 132, 14338.
r
10.1021/ol202170c
Published on Web 09/06/2011
2011 American Chemical Society

Table 1. Screening of Different Brønsted Acids
Table 2. Conversion of Simple Substratesa
entry
acid (equiv)
temp (°C) time (h) product, yield (%)
1
2
3
4
5
6
H2SO4 (2.5)
25
0
1
1
3a, traces
3a, 45
H2SO4 (2.5)
HCl (2.5)
0
1
3a, 42
CH3COOH (2.5)
CF3COOH (2.5)
CF3COOH (2.5)
25
0
24
1
3a, 68 þ 3b, 27
3a, 78
0
1.5
3a, 73 (gram scale)
Unfortunately, in the case of acetic acid, it took much
longer to reach full conversion, and 1-acetoxy-2,4-dienol
3b was isolated as side product (entry 4). Finally com-
plete and selective isomerization to the desired 2,4-
dienol 3a was observed when trifluoroacetic acid was
used (entry 5). The reaction was scalable, and nearly the
same yield was obtained on a larger scale (entry 6).
After these initial results, the isomerization of other
substrates was studied (see Table 2). The conversion of
cycloalkenones with larger ring size was also highly selec-
tive (entries 1 and 2). Whereas treatment of 2-cyclopent-
enone (1) with 2-propenylmagnesium bromide led to the
formation of considerable amounts of the 1,4-addition
product, use of the corresponding organolithium com-
pound and subsequent treatment with trifluoroacetic acid
resulted in clean formation of the desired 2,4-dienol 8.
Scale up to gram scale did not reduce the yield (entry 4).
Interestingly, whilethesubstituent in2-methylcyclopent-2-
enone did not affect the transposition of the hydroxy
group, the conversion of 3-methylcyclopent-2-enone
was much more acid sensitive than most other sub-
strates. As a consequence, better results were obtained
when acetic acid was used instead of trifluoroacetic
acid (entries 6 and 7). Remarkably, no other products
were obtained in this case. Finally, also an aryl
Grignard was used instead of an alkenyl Grignard
(entry 8). Although the subsequent isomerization
was much slower than before, a very selective forma-
tion of the expected 3-phenylhex-2-enol was observed
in nearly quantitative yield.
a Key: (i) 0.1 M in Et2O at 0 °C or ꢀ78 °C, 2.0 equiv of nucleophile;
(ii) 0 °C or rt, H2O, 2.5 equiv of acid.
formed, high diastereomeric ratios were obtained for
the resulting products (entries 2 and 3).7 However, when
the 1,2-addition was not selective, roughly the same
diastereomeric ratio was observed for the rearranged
dienols (entry 1).
Interestingly, cis intermediates led to the formation of
trans products, indicating that a different mechanism is
operating than for metalꢀoxo catalyst mediated reactions.8
To account for the observed stereoselectivity, we propose
that trifluoroacetic acid does not only protonate the
tertiary alcohol but also blocks the site of the molecule
syn to the alcohol (see Figure 1). The interaction of acid
and hydroxyl group may result either in the formation of
an instable trifluoroacetate followed by SN2 hydrolysis or
Because metalꢀoxo-catalyzed 1,3-isomerizations of
allylic alcohols often proceed stereoselectively,6 the con-
version of chiral substrates was investigated as well (see
Table 3). According to our results, the limiting factor in
the selectivity of the overall transformation appears to
be the 1,2-addition. When a single intermediate was
(7) Diastereomers were separated by means of HPLC. cis- and trans-
configurations were assigned by NOE experiments.
(8) Bellemin-Laponnaz, S.; Le Ny, J.-P.; Dedieu, A. Chem.;Eur. J.
1999, 5, 57.
(6) (a) Matsubara, S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1985, 58, 844. (b) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 2000, 122, 11262. (c) Morrill, C.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 2842.
Org. Lett., Vol. 13, No. 19, 2011
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Table 3. Selective Conversion of Chiral Substratesa
Scheme 1. Limitationsa
a Key: (i) 0.1 M in Et2O at 0 °C, 2.0 equiv of 2-methyl-1-propenyl-
magnesium bromide; (ii) 0 °C, H2O, 2.5 equiv of CF3COOH.
bromide and subsequent addition of aqueous trifluoro-
acetic acid led to compounds 25 and 26 as a 1:1 mixture.
This can be rationalized by assuming a significant car-
benium character in the isomerization. Normally, a
stereoelectronic preference for the endocyclic position
is observed. If, however, the exocyclic position can
stabilize a positive charge, nucleophilic attack can occur
there too. A pronounced carbenium character also sup-
ports the proposed formation of a contact ion pair as
intermediate (see discussion above).
a Key: (i) 0.1 M in Et2O at 0 °C, 2.0 equiv of vinylmagnesium
bromide; (ii) rt, H2O, 2.5 equiv of CF3COOH. b Only the major isomer
is depicted. c Combined yield of cis and trans products. d A 5-fold excess
of CF3COOH is used to speed up the reaction.
Finally, we highlight the usefulness of the described one-
pot procedure by improving our previous synthesis of
valerenic acid (see Scheme 2).1c,9 We began with the one-
pot synthesis of racemic dienol 8(see Table 2, entries 3 and 4).
Chiral resolution provided the optically enriched alcohol
28 and ester 27.10 The ester could easily be recycled to
racemic dienol 8 by treatment with silica gel. Interestingly,
during this reaction, the optical activity was completely
lost,11 indicating an SN1 displacement of the acetate was
occurring by water. With enantioenriched alcohol 28
in hand, a hydroxy-directed DielsꢀAlder reaction
(HDDA), according to a modified protocol by the
group of Barriault and co-workers, was conducted to
provide tricyclic lactone 29.12 This compound is a
Scheme 2. Optimized Synthesis of Valerenic Acida
Figure 1. Proposed reaction mechanism for the diastereoselec-
tive [1,3]-hydroxy isomerization.
in the formation of a contact ion pair, whichimmediately is
attacked by water from the opposite ring face.
Although, so far, all isomerizations have proven
regioselective, some limitations must be taken into
account. As outlined in Scheme 1, treatment of 2-
cyclohexenone (4) with 2-methyl-1-propenylmagnesium
(9) For a different total synthesis of valerenic acid, see: Kopp, S.;
Schweizer, W. B.; Altmann, K.-H. Synlett 2009, 11, 1769.
(10) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetra-
hedron 2003, 59, 8571.
a Abbreviations: TFA, trifluoroacetic acid; MTBE, methyl tert-butyl
ether; DIPEA, diisopropylethylamine.
(11) Proven by optical rotation: [R]20D = 0.000.
(12) Barriault, L.; Thomas, J. D. O.; Clement, R. J. Org. Chem. 2003,
68, 2317.
5312
Org. Lett., Vol. 13, No. 19, 2011

key intermediate in our recently published synthesis of
valerenic acid and only seven steps away from
the target. The simplified access to dienol 8 shortens
the route by five steps and increases the overall yield
from 8% to 13% (25% if compound 27 is fully
recycled).
In conclusion, we have developed a selective, flex-
ible, and scalable one-pot synthesis of optically en-
riched 2,4-dienols from simple cycloalkenones. The
underlying [1,3]-hydroxy isomerization is simple and
stereoselective. Stereochemically, it complements the
well-known oxo-metal-catalyzed [1,3]-hydroxy iso-
merization. An application in the synthesis of valerenic
acid has led to a significant reduction in the overall
number of steps.
€
Acknowledgment. We thank H. P. Kahlig and S.
€
Felsinger for NMR analysis as well as A. Korner and F.
Nasufi for HPLC analysis, all at the University of Vienna,
and the Austrian Science Fund (FWF) for financial sup-
port (projects P21241-N19 and TRP 107-B11).
Supporting Information Available. Experimental pro-
cedures and analytical characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5313