Tandem oxidation processes for the preparation of functionalized cyclopropanes

Article abstract of DOI:10.1021/ol0483394

(Chemical Equation Presented) A novel manganese dioxide-mediated tandem oxidation process (TOP) has been developed which allows the direct conversion of allylic alcohols into cyclopropanes, the intermediate aldehydes being trapped in situ with a stabilized sulfur-ylide. This methodology has been applied successfully to a variety of allylic alcohols and to a formal synthesis of the simple, naturally occurring lignan, (±)-picropodophyllone.

Full text of DOI:10.1021/ol0483394

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3997-4000
Tandem Oxidation Processes for the
Preparation of Functionalized
Cyclopropanes
Magalie F. Oswald, Steven A. Raw, and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K.
rjkt1@york.ac.uk
Received August 20, 2004
ABSTRACT
A novel manganese dioxide-mediated tandem oxidation process (TOP) has been developed which allows the direct conversion of allylic
alcohols into cyclopropanes, the intermediate aldehydes being trapped in situ with a stabilized sulfur-ylide. This methodology has been
applied successfully to a variety of allylic alcohols and to a formal synthesis of the simple, naturally occurring lignan, (±)-picropodophyllone.
We have had a long-standing interest in the development of
manganese dioxide mediated tandem oxidation processes
(TOPs) for the elaboration of alcohols.1 These TOP meth-
odologies offer a number of advantages to the organic
chemist: they are operationally simple, the MnO2 and its
byproducts being removed by a simple filtration; they result
in a reduced number of operations, giving significant time-
cost benefits; they allow the use of “difficult” carbonyl inter-
mediates (i.e., volatile, toxic, or noxious) as they are synthe-
sized and elaborated in situ. All our previous research has
concentrated on trapping intermediate carbonyl compounds
via 1,2-addition, e.g., oxidation-Wittig trapping (Scheme
1A) or oxidation-imine formation,1 and we were interested
to see if the concept could be extended to 1,4-additions
of R,â-unsaturated compounds generated in situ (Scheme
1B).
The cyclopropane moiety is an important motif in organic
chemistry, found in many natural products and biologically
active compounds,2 and there are numerous methods for its
synthesis.3 One established procedure involves the 1,4-
addition of a stabilized sulfur-ylide to an R,â-unsaturated
carbonyl system,3 and we hoped that chemistry of this type
could be incorporated into an MnO2-mediated TOP sequence
(Scheme 1B). As shown, the allylic alcohol would be
oxidized to the intermediate aldehyde which would then be
trapped by a sulfur-ylide in situ, yielding the cyclopropane.
In pursuit of this strategy, we first examined the reaction
of 2-methyl-2-propen-1-ol 1a with activated MnO2 in the
presence of (carbethoxymethylene)dimethylsulfurane 2a3d
and powdered 4 Å molecular sieves in benzene at reflux
(Scheme 2). We were delighted to observe the formation of
the desired cyclopropanecarboxaldehyde 3a4a in 37% yield.
We rapidly established that the use of dichloromethane as
Scheme 1. MnO2-Mediated TOPs
Scheme 2. Synthesis of Cyclopropane 3a via TOP
Methodology
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Table 1. MnO2-Mediated TOP Methodology for the Preparation of Cyclopropanes5,6
a It is probable that the low yield for this example is due in part to the volatility of 3b. b Of a possible four isomers, this product was isolated as a ∼5.0:1
mixture of just two. We are not yet able to unambiguously assign the major isomer. c Based on 1H NMR analysis of the unpurified reaction mixture showed
only aldehyde 3m or 3n and ylide 2a.
solvent gave the optimal yield, 71% as a ∼5:1 trans/cis
mixture of isomers.5
With this result in hand, we then moved on to establish
the scope of the TOP-cyclopropanation methodology, with
respect to the alcohol and ylide; the results are shown in
Table 1.6 Allyl alcohol 1b also gave the desired cyclopropane
3b (entry i), but in a low yield of 36%, presumably due in
part to the volatility of the product. With (benzoylmethylene)-
dimethylsulfurane 2b,3e allylic alcohol 1b gave the adduct
3c in a much better yield of 77% (entry ii). 2-Methyl propen-
1-ol 1a also works well with ylide 2b (entry iv). In addition,
a further 2-substituted propen-1-ol 1c proved to be a viable
(1) For examples, see: (a) Raw, S. A.; Reid, M.; Roman, E.; Taylor, R.
J. K. Synlett 2004, 819. (b) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K.
Org. Biomol. Chem. 2004, 2, 788. (c) Blackburn, L.; Taylor, R. J. K. Org.
Lett. 2001, 3, 1637. (d) Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65,
616 and references therein.
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Org. Lett., Vol. 6, No. 22, 2004

substrate, giving the desired adducts 3e,f (entries v and vi).
Cyclopropane 3e (entry v) is an interesting example as it is
trisubstituted, with each substituent being in a different
oxidation state (i.e., alkoxy, aldehyde, and carboxylate),
offering the possibility of further functionalization in a
selective manner. Cyclopropane 3f (entry vi) is similarly
interesting (i.e., alkoxy, aldehyde, and ketone).
those with the benzoyl unit cis to the ketone, due to steric
interactions in the cyclopropanation “enolate” intermediate.
We also investigated the use of 3-substituted 2-propen-
1-ols (entries xiii-xiv). Unfortunately, under the current
conditions, no cyclopropanation was observed with 1h and
1i, despite complete oxidation occurring. We are investigat-
ing the use of more reactive sulfur-ylides to allow the use
of substrates such as 1h,i in TOP cyclopropanations.
Next, we went on to explore the use of polysubstituted
2-propen-1-ols which, on oxidation, give chalcones which
are known to be good substrates for cyclopropanation with
2a.7 The results are summarized in Table 2.8 The results for
these alcohols were more solvent-dependent, and each
example was carried out in CH2Cl2, THF, and 1,2-dichlo-
roethane (DCE), the optimum solvent being indicated in
Table 2. As can be seen, in all cases the yields are good to
excellent (51-100%), with electron-rich, electron-deficient,
and “electron-neutral” examples being investigated. Both
ylides 2a and 2b work well with alcohol 1j (entries i and
ii). The observed erosion of the original double bond
stereochemistry is explained by the equilibration of reaction
intermediates, as discussed earlier.
1-Substituted propen-1-ols (i.e., secondary alcohols) also
gave excellent results (entries vii-xi), with good yields and
complete trans-selectivity about the cyclopropane. Further-
more, with divinylmethanol 1f (entries x and xi), oxidation
and double-cyclopropanation occurs, giving 3j and 3k in 60%
and 69% yield respectively, each as a mixture of isomers
1
(∼1:1 as determined by H NMR spectroscopy).
The trends in stereochemistry seen with 1- and 2-substi-
tuted propen-1-ols are consistent with the reaction mechanism
proposed by Curley and DeLuca involving equilibration of
initial adducts.4c With 1-substituted propen-1-ols (entries vii-
xi), the increased size of the substituent in the intermediate
(ketone vs aldehyde) results in an equilibrium giving solely
the trans-cyclopropane products. A more detailed analysis
of the stereochemistry of these processes will be presented
in a full paper.
Finally, we examined the dihydrochalcone 1o (Scheme 3).
We were delighted to find that this was cleanly converted
into cyclopropane 3t. This result is noteworthy as 1o is
particularly electron rich, and in our experience, this slows
The more complex (-)-trans-pinocarveol 1g also worked
very well in this methodology, giving the spirocyclopropane
3l in 76% yield (entry xii). Of the four possible isomers,
this product was isolated as a ∼5.0:1 mixture of just two
(shown in Table 1). Models suggest these are most likely
Scheme 3. Picropodophyllone Precursor via TOP
Methodology
(2) (a) Ningsanont, N.; Black, D. S. C.; Chanpen, R.; Thebtaranonth, Y.
J. Med. Chem. 2003, 46, 2397. (b) Wipf, P.; Reeves, J. T.; Balachandran,
R.; Day, B. W. J. Med. Chem. 2002, 45, 1901. (c) Rugutt, J. K.; Henry, C.
W.; Franzblau, S. G.; Warner, I. M. J. Agric. Food Chem. 1999, 47, 3402.
(d) Han, S.-Y.; Cho, S.-H.; Kim, S.-Y.; Seo, J.-T.; Moon, S.-J.; Jhon, G.-
L. Bioorg. Med. Chem. Lett. 1999, 9, 59. (e) Barrett, A. G. M.; Doubleday,
W. W.; Hamprecht, D.; Kasdorf, K.; Tustin, G. J.; White, A. J. P.; Williams,
D. J. Chem. Commun. 1997, 1693. (f) Bucsh, R. A.; Domagala, J. M.;
Laborde, E.; Sesnie, J. C. J. Med. Chem. 1993, 36, 4139. (g) Martinez, G.
R.; Walker, K. A. M.; Hirschfeld, D. R.; Maloney, P. J.; Yang, D. S.;
Rosenkranz, R. P. J. Med. Chem. 1989, 32, 890.
(3) (a) For a comprehensive summary, see: Larock, R. C. ComprehensiVe
Organic Transformations; VCH: New York, 1989; Chapter 4, p 71. (b)
Helquist, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 1, Chapter 4.6, p 951. (c) Johnson,
C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973, 95, 7424.
(d) Payne, G. B. J. Org. Chem. 1967, 32, 3351. (e) Quintana, J.; Torres,
M.; Serratosa, F. Tetrahedron 1973, 29, 2065.
(4) General Procedure. To a solution of monosubstituted 2-propen-1-
ol in CH2Cl2 were added powdered 4 Å molecular sieves (1.0 g/mmol),
(carbethoxymethylene)dimethylsulfurane (1.2 equiv), and activated MnO2
(10.0 equiv). The mixture was heated to reflux and stirred until complete
reaction was observed by TLC. The mixture was then filtered through Celite
and the residue washed with CH2Cl2. Concentration of the combined
organics in vacuo followed by flash column chromatography on silica gave
the desired product. For more specific procedures, see the Supporting
Information.
(5) All known compounds gave satisfactory data (see ref 4); all novel
compounds were fully characterized by spectroscopic methods and HRMS.
(6) (a) Boland, W.; Niedermeyer, U. Synthesis 1987, 28. (b) Wu, P.-L.:
Wang, W.-S. J. Org. Chem. 1994, 59, 622. (c) Curley, R. W., Jr.; DeLuca,
H. F. J. Org. Chem. 1984, 49, 1944. (d) Hammerschmidt, F.; Zbiral, E.
Liebigs Ann. Chem. 1977, 1026. (e) Doyle, M. P.; Dorow, R. L.; Tamblyn,
W. H. J. Org. Chem. 1982, 47, 4059. (f) Duhamel, P.; Poirier, J.-M.;
Hennequin, L. Tetrahedron Lett. 1984, 25, 1471. (g) Aggarwal, V. K.; Smith,
H. W.; Hynd, G.; Jones, R. V. H.; Fieldhouse, R.; Spey, S. E. J. Chem.
Soc., Perkin Trans. 1 2000, 3267. For the methyl ester analogue: Adams,
J.; Hoffman, L., Jr.; Trost, B. M. J. Org. Chem. 1970, 35, 1600. (h) Matano,
Y. J. Chem. Soc., Perkin Trans. 1 1994, 2703 (i) Rai, K. M. L.;
Anjanamurthy, C.; Radhakrisan, P. M. Synth. Commun. 1990, 9, 1273.
(7) For examples, see; Hantawong, K.; Murphy, W. S. J. Chem. Res.,
Miniprint 1988, 2520 (b) Murphy, W. S.; Wattanasin, S. J. Chem. Soc.,
Perkin Trans. 1 1982, 1029.
(8) General Procedure. To a solution of polysubstituted 2-propen-1-ol
in the solvent of choice were added powdered 4 Å molecular sieves (1.0
g/mmol), (carbethoxymethylene)dimethylsulfurane (1.2-2.0 equiv), and
MnO2 (10.0 equiv). The mixture was heated to reflux and stirred until
complete reaction was observed by TLC. The mixture was then filtered
through Celite and the residue washed with solvent. Concentration in vacuo
followed by flash column chromatography on silica gave the desired product.
For more specific procedures, see the Supporting Information.
(9) Murphy, W. S.; Wattanasin, S. J. Chem. Soc., Perkin Trans. 1 1982,
271.
Org. Lett., Vol. 6, No. 22, 2004
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Table 2. Polysubstituted 2-Propen-1-ols in MnO2-Mediated TOP Cyclopropanation6,8
oxidation by MnO2. Moreover, cyclopropane 3t was utilized
by Murphy and Wattanasin as a late-stage intermediate in
their synthesis of (()-picropodophyllone9 which, along with
related lignan lactones, is of interest as a cancer chemo-
therapeutic agent. This sequence therefore represents a formal
synthesis of this simple natural product.
MnO2-mediated TOP cyclopropanations. We also plan to
apply these methodologies to target-led synthesis.
Acknowledgment. We thank the EÄ cole Normale Su-
pe´rieure de Lyon and Universite´ Claude Bernard Lyon 1
(M.F.O., ERASMUS) and the EPSRC (S.A.R., ROPA
fellowship) for financial support. We also thank Dr. T. A.
Dransfield and B. R. Glennie for mass spectroscopy service.
In conclusion, we have developed a manganese dioxide
mediated tandem-oxidation process which allows the forma-
tion of functionalized cyclopropanes 3 in one step from the
corresponding allylic alcohols 1. This represents the first
example of a MnO2-mediated TOP methodology exploiting
1,4-addition to trap the intermediate carbonyl species and
has been applied to a wide range of substrates. We are
currently investigating the use of alternative sulfur-ylides in
Supporting Information Available: Experimental pro-
cedures and data for compounds not previously described
in the literature (3d-f,j-l,q,s). This material is available
free of charge via the Internet at http://pubs.acs.org.
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