A chemo- and stereoselective reduction of cycloalkynes to (E)-cycloalkenes

Article abstract of DOI:10.1039/b207169j

A stereoselective entry into (E)-cycloalkenes is described, comprising the ring closing alkyne metathesis (RCAM) of suitable diynes, a ruthenium-catalyzed trans-selective hydrosilylation of the cycloalkynes thus formed, followed by a desilylation of the r

Full text of DOI:10.1039/b207169j

A chemo- and stereoselective reduction of cycloalkynes to
(E)-cycloalkenes
Alois Fürstner* and Karin Radkowski
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany.
E-mail: fuerstner@mpi-muelheim.mpg.de; Fax: +49 208 306 2994; Tel: +49 208 306 2342
Received (in Cambridge, UK) 24th July 2002, Accepted 14th August 2002
First published as an Advance Article on the web 28th August 2002
A stereoselective entry into (E)-cycloalkenes is described,
comprising the ring closing alkyne metathesis (RCAM) of
suitable diynes, a ruthenium-catalyzed trans-selective hy-
drosilylation of the cycloalkynes thus formed, followed by a
desilylation of the resulting vinylsilanes mediated by AgF.
methodology into the total synthesis of targets as complex as the
epothilones,4 prostaglandins,5 glycolipids,6 alkaloids,7 perfume
ingredients,8 peptide isosteres9 and other bioactive com-
pounds.10
To increase the relevance of RCAM further, it is desirable to
use the cycloalkynes as relays for the corresponding (E)-alkenes
as well (Scheme 1). Although several methods for the reduction
of alkynes to (E)-alkenes are known in the literature,11–13 none
of them meets all the criteria of selectivity and functional group
tolerance required for applications to advanced organic synthe-
sis. Described below is a two-step protocol which intends to fill
this gap. Our disclosure is prompted by a very recent publication
of Trost et al. reporting a conceptually similar conversion of
acyclic alkynes into the corresponding (E)-alkenes.14
Key to success is the hydrosilylation of the cycloalkynes
formed by RCAM which proceeds in a highly chemo- and
stereoselective manner if catalyzed by the cationic ruthenium
complex [Cp*Ru(MeCN)3]PF6 (Scheme 2).15,16 This reaction
provides good to excellent yields even with catalyst loadings
@1 mol%, it proceeds with high selectivity in favor of the trans
One of the few shortcomings limiting the superb application
profile of ring closing olefin metathesis (RCM) is the lack of
stereocontrol over the emerging double bond during the
formation of macrocyclic rings.1 The cycloalkenes are usually
obtained as (E,Z)-mixtures, the ratio of which can, at present, be
neither controlled nor even accurately predicted. Although this
problem may eventually be solved by the development of more
selective catalysts and/or the implementation of improved
retrosynthetic logic,2 the use of ring closing alkyne metathesis
(RCAM) opens an alternative approach to macrocycles which is
devoid of this shortcoming.3 Thus, RCAM followed by Lindlar
reduction of the resulting cycloalkynes constitutes a widely
applicable, mild and stereoselective route to (Z)-alkenes
(Scheme 1) as evident from successful implementations of this
Scheme 1 Cycloalkynes as relays for the preparation of either (Z)- or (E)-
Scheme 2 Reagents and conditions: [a] (EtO)3SiH, [Cp*Ru(MeCN)3]PF6
cycloalkenes.
(1 mol%), CH2Cl2, r.t.; [b] AgF (2 eq.), THF/aq. MeOH, r.t.
Table 1 Reduction of cycloalkynes prepared by RCAM to (E)-cycloalkenes via the corresponding vinylsiloxanes
Substrate
Vinylsiloxane
Yield (%) (E+Z)
Cycloalkene
Yield (%) (E+Z)
84 (90+10)
90 (91+9)
86 ( > 98+2)
93 (95+5)
85 ( > 98+2)
92 (95+5)
92 ( > 98+2)a
93 ( > 98+2)
88 ( > 98+2)
70 ( > 98:2)
a This product is obtained as a 1+1 mixture of regioisomers.
CHEM. COMMUN., 2002, 2182–2183
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42.0, 36.9, 31.4, 29.5, 29.1, 28.7, 28.5, 28.4, 27.9, 27.4, 24.5, 23.6, 18.3; IR:
1712 cm21; MS (EI) m/z (rel. intensity): 412 ([M+], 1.5), 366 (100%).
A suspension of AgF (1 M in aq. MeOH, 0.47 mL, 0.47 mmol) was added
to a solution of this vinylsiloxane (95 mg, 0.23 mmol) in THF (1.2 mL) and
the resulting mixture was stirred in the dark for 3 h. The insoluble residues
were filtered off and carefully washed with Et2O and EtOAc (3 mL each),
the combined filtrates were evaporated and the residue purified by flash
chromatography (pentane–Et2O, 8+1) to give (E)-cycloheptadec-9-en-
addition, and is known to be compatible with a host of
functional groups. Although various silanes can be used,
(EtO)3SiH turned out to be best suited for the envisaged further
elaboration.
Next, the protodesilylation of the vinylsiloxanes thus formed
was investigated. Although several methods for this seemingly
trivial transformation are known in the literature, none of them
is particularly attractive from the application point of view.
Specifically, simple protonation with strong mineral acids such
as HI suffers from a narrow functional group tolerance and
possible problems with the configurational integrity of the
double bond.17 The use of TBAF in various media, on the other
hand,18 requires high temperatures (!80 °C) and was found to
be rather unselective even when applied to the otherwise
unfunctionalized cyclododecene derivative depicted in entry 1
(Table 1).
1
1-one as a colorless syrup (40 mg, 70%). H NMR (400 MHz, CDCl3): d
5.31 (m, 2H), 2.37 (t, J 7.1 Hz, 4H), 2.01 (m, 4H), 1.60 (m, 4H), 1.20–1.37
(m, 16H); 13C NMR (100 MHz, CDCl3): d 213.0, 131.0, 42.5, 32.0, 28.9,
28.8, 28.4, 27.4, 24.1; IR n/cm21: 1711 (CNO), 966 ((E)-alkene); MS (EI)
m/z (rel. intensity): 250 ([M+], 100%).
‡ Other fluoride sources tested include: HF–pyridine, NaF, KF, CsF, TBAF,
(Bu4N)(Ph2SiF3), ZnF2, FeF2.
1 (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; (b) A.
Fürstner, Angew. Chem., Int. Ed., 2000, 39, 3012.
As a consequence, we have carried out a screening of other
possible reagents that might effect the desired protodesilylation
under sufficiently mild conditions. We were pleased to find that
AgF is exquisitely suited for this purpose, meeting the stringent
criteria of general applicability and compatibility with sensitive
functional groups. Stirring of the vinylsiloxanes with AgF
(1.5–2.0 eq.) in THF–aq. MeOH in the dark at ambient
temperature effects the rapid, quantitative and selective proto-
desilylation without noticable isomerization of the alkene
interfering; the corresponding (E)-alkenes are obtained in good
to excellent yields (Table 1).† Although the mode of action of
AgF has not yet been elucidated in detail, the fact that it is far
more effective than other flouride sources‡ suggests a syner-
getic action which may result from the specific affinity of the
fluoride anion for silicon and that of the silver cation for p-
bonds. It is assumed that the fluoride initially leads to a
pentacoordinate silicate species,19 thus facilitating a trans-
metalation to a transient vinylsilver intermediate that is
immediately trapped to give the alkene product.
In summary, a two step protocol for the net conversion of
cycloalkynes to (E)-cycloalkenes has been developed which is
sufficiently mild and selective to serve advanced organic
synthesis. It helps to upgrade the now readily available
cycloalkynes into versatile relays for the stereoselective
formation of either geometrical isomer of the corresponding
macrocyclic cycloalkenes. Further studies on this and related
reactions are in progress and will be reported in due course.
2 For an example of (E/Z)-control by catalyst tuning see: A. Fürstner, K.
Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann and R. Mynott, J.
Am. Chem. Soc., 2002, 124, 7061.
3 (a) A. Fürstner and G. Seidel, Angew. Chem., Int. Ed., 1998, 37, 1734;
(b) A. Fürstner, C. Mathes and C. W. Lehmann, J. Am. Chem. Soc.,
1999, 121, 9453.
4 (a) A. Fürstner, C. Mathes and K. Grela, Chem. Commun., 2001, 1057;
(b) A. Fürstner, C. Mathes and C. W. Lehmann, Chem. Eur. J., 2001, 7,
5299.
5 (a) A. Fürstner and K. Grela, Angew. Chem., Int. Ed., 2000, 39, 1234; (b)
A. Fürstner, K. Grela, C. Mathes and C. W. Lehmann, J. Am. Chem.
Soc., 2000, 122, 11799; (c) A. Fürstner and C. Mathes, Org. Lett., 2001,
3, 221.
6 A. Fürstner, K. Radkowski, J. Grabowski, C. Wirtz and R. Mynott, J.
Org. Chem., 2000, 65, 8758.
7 (a) A. Fürstner, O. Guth, A. Rumbo and G. Seidel, J. Am. Chem. Soc.,
1999, 121, 11108; (b) A. Fürstner and A. Rumbo, J. Org. Chem., 2000,
65, 2608.
8 A. Fürstner and G. Seidel, J. Organomet. Chem., 2000, 606, 75.
9 B. Aguilera, L. B. Wolf, P. Nieczypor, F. P. J. T. Rutjes, H. S.
Overkleeft, J. C. M. van Hest, H. E. Schoemaker, B. Wang, J. C. Mol,
A. Fürstner, M. Overhand, G. A. van der Marel and J. H. van Boom, J.
Org. Chem., 2001, 66, 3584.
10 (a) A. Fürstner, F. Stelzer, A. Rumbo and H. Krause, Chem. Eur. J,
2002, 8, 1856; (b) A. Fürstner and T. Dierkes, Org. Lett., 2000, 2,
2463.
11 Metal hydride reductions of propargyl alcohols: T. K. Jones and S. E.
Denmark, Org. Synth., 1986, 64, 182.
12 Dissolving metal reductions: L. Brandsma, W. F. Nieuwenhuizen, J. W.
Zwikker and U. Mäeorg, Eur. J. Org. Chem., 1999, 775.
13 Reductions with Cr(II): (a) C. E. Castro and R. D. Stephens, J. Am.
Chem. Soc., 1964, 86, 4358; (b) A. B. Smith, P. A. Levenberg and J. Z.
Suits, Synthesis, 1986, 184; (c) E. M. Carreira and J. Du Bois, J. Am.
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Notes and references
†
Representative procedure: To a solution of cycloheptadec-9-yn-1-one
14 B. M. Trost, Z. T. Ball and T. Jöge, J. Am. Chem. Soc., 2002, 124,
7922.
(65 mg, 0.262 mmol)8 and (EtO)3SiH (51 mg, 0.31 mmol) in CH2Cl2 (0.5
mL) was added [Cp*Ru(MeCN)3]PF6 (1.3 mg, 1 mol%) and the resulting
mixture was stirred for 15 min at ambient temperature. Prior to work-up,
P(CH2OH)3 (5 mg) was added and stirring continued for 30 min. The
mixture was filtered through a short pad of silica which was carefully rinsed
with Et2O, and the combined filtrates were evaporated to give (Z)-
9-[(trisethoxy)silyl]cycloheptadec-9-en-1-one as a colorless syrup (100 mg,
93%). 1H NMR (400 MHz, CDCl3): d 6.04 (t, J 7.4 Hz, 1H), 3.80 (q, J 7.0
Hz, 6H), 2.36 (q, J 7.1 Hz, 4H), 2.28 (q, J 7.1 Hz, 2H), 2.12 (t, J 6.3 Hz, 2H),
1.57–1.63 (m, 4H), 1.38–1.43 (m, 4H), 1.26–1.30 (m, 12H), 1.22 (t, J 7.0
Hz, 9H); 13C NMR (100 MHz, CDCl3): d 213.0, 148.7, 132.2, 58.1, 43.1,
15 B. M. Trost and Z. T. Ball, J. Am. Chem. Soc., 2001, 123, 12726.
16 (a) T. P. Gill and K. R. Mann, Organometallics, 1982, 1, 485; (b) B.
Steinmetz and W. A. Schenk, Organometallics, 1999, 18, 943.
17 (a) I. Fleming, T. W. Newton and F. Roessler, J. Chem. Soc., Perkin
Trans. 1, 1981, 2527; (b) A. D. Kaye, G. Pattenden and S. M. Roberts,
Tetrahedron Lett., 1986, 27, 2033.
18 H. Oda, M. Sato, Y. Morizawa, K. Oshima and H. Nozaki, Tetrahedron,
1985, 41, 3257.
19 K. Tamao, K. Kobayashi and Y. Ito, Tetrahedron Lett., 1989, 30,
6051.
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