Conformationally unbiased macrocyclization reactions by ring closing metathesis

Full text of DOI:10.1021/jo960733v

3942
J . Org. Chem. 1996, 61, 3942-3943
Sch em e 1
Con for m a tion a lly Un bia sed
Ma cr ocycliza tion Rea ction s by Rin g
Closin g Meta th esis
Alois Fu¨rstner* and Klaus Langemann
Max-Planck-Institut fu¨r Kohlenforschung,
Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim/ Ruhr, Germany
Sch em e 2a
Received April 23, 1996
The discovery of well-defined single component me-
tathesis catalysts has had a great impact on organic
synthesis and on polymer chemistry.1 Among them, the
ruthenium carbene 1 is particularly noteworthy.2,3 The
well-balanced electronic and coordinative unsaturation
of its Ru2+ center accounts for its high performance as
well as for the remarkable tolerance toward an array of
functional groups. Both features are evident from many
applications of this catalyst to the formation of fairly
complex 5-, 6, and 7-membered carbo- and heterocycles
by ring-closing metathesis (RCM) of suitable diolefin
precursors (Scheme 1).4 The formation of medium or
large ring systems, however, is yet largely unexplored
and impaired by the assumption that only conformation-
ally predisposed dienes are suitable starting materials.5,6
The syntheses of natural odoriferous macrolides reported
below prove that this is not the case since substrates
devoid of any conformational contraints can be efficiently
cyclized by RCM to macrocyclic products. Even more
surprisingly, they highlight the notion that RCM is
amongst the most straightforward entries into large ring
systems and favorably compares to all current alterna-
tives.7
a
Key: (a) 1 (4 mol %), CH2Cl2; (b) H2 (1 atm), Pd/C.
On principle, olefin metathesis is a reversible process
and therefore under thermodynamic control.1 As RCM
generates two molecules from one with evaporative loss
of, e.g., ethene as the byproduct (Scheme 1), the gain in
entropy should provide sufficient driving force whenever
∆H is small. This is expected to be the case for the
formation of a highly flexible macrocycle from an equally
flexible acyclic diene precursor. Exaltolide (2), a valuable
musk-odored olfactory ingredient of Archangelica offici-
nalis,8 was chosen as target in order to test this hypoth-
esis (Scheme 2).
Acylation of 1-hex-5-enol with 10-undecenoyl chloride
or of 10-undecen-1-ol with 5-hexenoic acid gave dienes 3
and 5, respectively. Slow addition of a CH2Cl2 solution
of these compounds to a solution of the Grubbs carbene
1 (4 mol %) in the same solvent at ambient temperature
led to the corresponding 16-membered lactones 4 (Z:E )
54:46) and 6 (Z:E ) 23:77) in excellent yields. Hydro-
genation of these compounds afforded 2 almost quanti-
tatively. Our synthesis of this valuable perfumery
ingredient requires only three steps from commercially
available starting materials and is therefore significantly
more efficient than previous approaches.8
(1) Reviews: (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446-452. (b) Schmalz, H.-G. Angew. Chem. 1995, 107,
1981-1984. (c) Koert, U. Nachr. Chem. Techn. Lab. 1995, 43, 809-
814. Applications to polymer chemistry: (c) Grubbs, R. H.; Tumas, W.
Science 1989, 243, 907-915. (d) Schrock, R. R. in Ring Opening
Polymerization; Brunelle, D. J ., Ed.; Hanser: Munich, 1993; p 129-
156. (e) Ivin, K. J . Olefin Metathesis; Academic: New York, 1983.
(2) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1993, 115, 9858-9859. (b) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R.
H.; Ziller, J . W. J . Am. Chem. Soc. 1992, 114, 3974-3975. See also:
(c) Binger, P.; Mu¨ller, P.; Benn, R.; Mynott, R. Angew. Chem. 1989,
101, 647-648.
(3) For leading references on other RCM catalysts see, i.a.: (a)
Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .; DiMare, M.;
O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886. (b) Schwab,
P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew. Chem. 1995,
107, 2179-2181. (c) Nugent, W. A.; Feldman, J .; Calabrese, J . C. J .
Am. Chem. Soc. 1995, 117, 8992-8998. (d) Herrmann, W. A.; Wagner,
W.; Flessner, U. N.; Volkhardt, U.; Komber, H. Angew. Chem. 1991,
103, 1704-1706. (e) Quignard, F.; Leconte, M.; Basset, J . M. J . Mol.
Catal. 1986, 36, 13-29.
Even much larger rings can be readily accessed by
RCM. This is evident from the synthesis of 20-eicosano-
lide 7, a major component in the secretion of the
abdominal Dufour gland of solitary bees of the genera
Colletes and Halictus.9 This product is easily prepared
by acylation of 10-undecen-1-ol with 10-undecenoyl chlo-
(4) See the following for leading references: (a) Fu, G. C.; Nguyen,
S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115, 9856-9857. (b)
Huwe, C. M., Blechert, S. Tetrahedron Lett. 1995, 1621-1624. (c)
Schneider, M. F.; J unga, H.; Blechert, S. Tetrahedron 1995, 51, 13003-
13014. (d) Morken, J . P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H.
J . Am. Chem. Soc. 1994, 116, 3123-3124. (e) Kinoshita, A.; Mori, M.
Synlett 1994, 1020-1022. (f) Maier, M. F.; Langenbacher, D.; Rebien,
F. Liebigs Ann. Chem. 1995, 1843-1848. (g) Overkleeft, H. S.; Pandit,
U. K. Tetrahedron Lett. 1996, 547-550. (h) Garro-Helion, F.; Guibe´,
F. J . Chem. Soc., Chem. Commun. 1996, 641-642.
(5) For macrocyclizations of conformationally constrained dienes
using 1 as catalyst see: (a) Borer, B. C.; Deerenberg, S.; Biera¨ugel,
H.; Pandit, U. K. Tetrahedron Lett. 1994, 3191-3194. (b) Miller, S. J .;
Grubbs, R. H. J . Am. Chem. Soc. 1995, 117, 5855-5856.
(6) For macrocyclizations using other RCM catalysts see: (a) Houri,
A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1995,
117, 2943-2944. (b) Forbes, M. D. E.; Patton, J . T.; Myers, T. L.;
Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener, K. B. J . Am.
Chem. Soc. 1992, 114, 10978-10980. (c) Martin, S. F.; Liao, Y.; Chen,
H. J .; Pa¨tzel, M.; Ramser, M. N. Tetrahedron Lett. 1994, 6005-6008.
(d) Tsuji, J .; Hashiguchi, S. Tetrahedron Lett. 1980, 2955-2958. (e)
Villemin, D. Tetrahedron Lett. 1980, 1715-1718.
(7) Review on macrocycle syntheses: Roxburgh, C. J . Tetrahedron
1995, 51, 9767-9822.
(8) Exaltolide is a trademark of Firmenich SA, CH-1211 Geneva,
Switzerland. For leading references see: (a) Ruzicka, L.; Stoll, M. Helv.
Chim. Acta 1928, 11, 1159-1173. (b) Trost, B. M.; Verhoeven, T. R. J .
Am. Chem. Soc. 1977, 99, 3867-3868. (c) Becker, J .; Ohloff, G. Helv.
Chim. Acta 1971, 54, 2889-2895. (d) Mukaiyama, T.; Narasaka, K.;
Kikuchi, K. Chem. Lett. 1977, 441-444.
(9) (a) Hefetz, A.; Fales, H. M.; Batra, S. W. T. Science 1979, 204,
415-417. (b) Bergstro¨m, G. Chem. Scripta 1974, 5, 39-46. (c) Duffield,
R. M.; Fernandes, A.; Lamb, C.; Wheeler, J . W.; Eickwort, G. C. J .
Chem. Ecol. 1981, 7, 319-331. (d) Bergstro¨m, G.; Tengo¨, J . Acta Chem.
Scand. 1979, B33, 390.
S0022-3263(96)00733-5 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 12, 1996 3943
Sch em e 3
Sch em e 5a
Sch em e 4
ride (95%), followed by efficient RCM of the resulting 1,ω
-diene 8 as described above and final hydrogenation of
the resulting unsaturated macrocycle 9 (Z:E ) 55:45)
(Scheme 3). Thus, a sequence of only three steps converts
well accessible substrates into the 21-membered lactone
7 in 66% overall yield. This approach is distinguished
by its unparallelled straightness, efficiency and “atom
economy”10 from conceivable alternatives.
The 14-membered macrolide 10, the (5Z,13S)-enanti-
omer of which is a synergist of the aggregation phero-
mone of the flat grain beetle Cryptoletes pusillus,11 is also
readily assembled. DCC-mediated esterification of 9-de-
cen-2-ol with 5-hexenoic acid (88%) followed by RCM of
the resulting diene 11 with 4 mol % of the Ru-carbene 1
afforded the desired product as a mixture of the geo-
metrical isomers (Z:E ) 69:31) (Scheme 4).
A final application of RCM to the synthesis of enan-
tiomerically pure (12R)-(+)-12-methyl-13-tridecanolide
(12), a minor musk-odored component of Angelica root
oil,12 may help to define the essential parameters for
productive metathetic ring closure and to assess the scope
of RCM in a more realistic way (Scheme 5).
Acylation of commercially available 2-methyl-3-buten-
1-ol with 10-undecenoyl chloride gave diene (()-13 in 68%
yield. Treatment of this substrate with catalytic amounts
of 1 under standard conditions, however, led to the
desired macrocycle 14 in disappointingly low yield (10%,
GC yield 24%, (E)-isomer only). In contrast, RCM of
derivative (()-15 proceeded smoothly, affording the 14-
membered lactone (()-16 in 72% isolated yield (E:Z )
96:4), which was hydrogenated to racemic 12. This latter
approach is easily adapted to the synthesis of enantio-
merically pure (+)-12. Alkylation of N-propionylbornane-
10,2-sultam (17) with 1-iodo-4-pentene according to
a
Key: (a) 1 (4 mol %), CH2Cl2; (b) H2 (1 atm), Pd/C; (c)
NaN(SiMe3)2, 5-iodo-1-pentene, -78 °C f rt, THF/HMPA, over-
night; (d) LiAlH4, THF, 57% over steps c and d; (e) 7-octenoyl
chloride, DMAP, CH2Cl2.
Oppolzer’s protocol,13 followed by reduction of the result-
ing amide with LiAlH4, gave alcohol (+)-19 (ee > 99%,
[R]23D ) +10.4 (c 14.0, CH2Cl2)). Subjecting this material
to the sequence described above cleanly led to the
optically active olfactory product (+)-12 (ee > 99%; [R]25
D
) +14.54 (c 4.25, CH2Cl2) (lit.12d [R]25 ) +14.7 (c 1.4))).
D
This synthesis clearly surpasses previous ones in terms
of accessibility of the substrates, number of steps, flex-
ibility, atom economy, optical purity, and overall yield.
Since the approaches to lactone 12 displayed in Scheme
5 differ only in the site of ring closure it is evident that
this parameter rather than the ring size formed is pivotal
for productive RCM. The poor reactivity of 13 may arise
from the steric effect of the adjacent methyl substituent
and/or from sequestering the catalyst in form of unpro-
ductive chelate complexes due to the coordination of the
ester group onto the proximate Ru carbene intermedi-
ate.14 We are presently probing this aspect in more
detail.
Ack n ow led gm en t. K.L. thanks the Fonds der Che-
mischen Industrie for a Kekule´-Stipendium.
(10) Trost, B. M. Angew. Chem. 1995, 107, 285-307.
(11) (a) Millar, J . G.; Oehlschlager, A. C.; Wong, J . W. J . Org. Chem.
1983, 48, 4404-4407. (b) Naoshima, Y.; Nakamura, A.; Munakata, Y.;
Kamezawa, M.; Tachibana, H. Bull. Chem. Soc. J pn. 1990, 63, 1263-
1265. (c) Keinan, E.; Sinha, S. C.; Singh, S. P. Tetrahedron 1991, 47,
4631-4638. (d) Hamada, T.; Daikai, K.; Irie, R.; Katsuki, T. Tetrahe-
dron: Asymmetry 1995, 6, 2441-2451. (e) Boden, C. D. J .; Chambers,
J .; Stevens, I. D. R. Synthesis 1993, 411-420.
(12) Isolation: (a) Taskinen, J .; Nyka¨nen, L. Acta Chem. Scand.
1975, B29, 757-764. Syntheses: (b) Voss, G.; Gerlach, H. Helv. Chim.
Acta 1983, 66, 2294-2307. (c) Stanchev, S.; Hesse, M. Helv. Chim.
Acta 1987, 70, 1389-1392. (d) Kraft, P.; Tochtermann, W. Liebigs Ann.
Chem. 1994, 1161-1164.
Su p p or tin g In for m a tion Ava ila ble: Representative pro-
cedures and the analytical data of all products (7 pages).
J O960733V
(13) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
5603-5606.
(14) For related considerations see: (a) Feldman, J .; Murdzek, J .
S.; Davis, W. M.; Schrock, R. R. Organometallics 1989, 8, 2260-2265.
(b) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 7324-7325.