that contain bis(THF) cores with cis/threo/cis, trans/erythro/
cis, and trans/threo/trans relative stereochemistry about the
adjacent THF rings.
acetate) 3 in excellent yield. However, RO/CM of C2-
symmetric 2 and ent-2 under the same conditions gave the
corresponding diol bis(allylic acetates) in low yield.11
Substituting 1,4-dibenzoyloxy-cis-2-butene and using 5 (5
mol %) yielded diol bis(allylic benzoates) 4 and ent-4 in
good yield. In all reactions, the major product is that with
all E double bonds, with a small amount of E/Z double bond
isomers also detectable.12 Our experience with asymmetric
double cycloetherification13 has shown the presence of E/Z
isomers to be inconsequential. This independence of the
cycloetherification reaction on double bond geometry was
verified for five-membered ring formation (vide infra).
With the meso-symmetric bis(allylic acetate) and the
enantiomeric C2-symmetric bis(allylic benzoate) substrates
in hand, we systematically evaluated the Pd(0)-mediated
asymmetric double cycloetherification. A general representa-
tion of this reaction using (R,R)-N-[2,(2′-diphenylphosphino)-
benzamidocyclohexyl] (2′-diphenylphosphino) benzamide
ligand [(R,R)-DPPBA] and 3 is shown in Scheme 3.
We initially demonstrated the utility of asymmetric double
cycloetherification to construct 2,5-disubstituted bis(THF)
ring systems in a formal synthesis of uvaricin.6 In this letter,
we present short, efficient syntheses of several diol bis(allylic
acetate) and diol bis(allylic benzoate) cycloetherification
substrates as well as a general approach to six stereoisomeric
bis(THF) cores of annonaceous acetogenins and analogues
thereof.
Our synthetic strategy is illustrated in Scheme 1. We
envisioned using reagent control through asymmetric double
Scheme 1. Synthetic Strategy
Scheme 3. Double Cycloetherification of 3
cycloetherification of diol bis(allylic acetates) to set the
outermost stereocenters of the bis(THF) cores to maintain
C2-symmetry or to break meso-symmetry. The requisite diol
bis(allylic esters) could be accessed via ring opening/cross
metathesis (RO/CM) of meso- or C2-symmetric dihydroxy-
cyclooctenes, which are available7,8 from inexpensive cy-
clooctadiene (COD).
The syntheses of meso-diol bis(allylic acetate) 3 and C2-
symmetric diol bis(allylic benzoates) 4 and ent-4 are shown
in Scheme 2. Known 1,2-dihydroxycyclooctenes 1,7 2,8 and
Although early attempts resulted in complete conversion to
an adjacent bis(THF) core, we obtained a mixture of the
desired desymmetrized product 6 and two undesired meso-
symmetric diastereomers 7 and 8 in which stereochemical
errors had occurred in one of the THF ring-forming reactions.
The configuration of the newly formed stereocenters in
this Pd(0)-mediated, chiral ligand-controlled cycloetherifi-
cation can be predicted using Trost’s transition-state model
shown in Figure 2.14 The phenyl groups from the C2-
Scheme 2. Preparation of meso-Bis(allylic acetate) 3 and
C2-Symmetric Bis(allylic benzoates) 4 and ent-49
(5) For select recent examples, see: (a) Das, S.; Li, L.-S.; Abraham, S.;
Chen, Z.; Sinha, S. C. J. Org. Chem. 2005, 70, 5922. (b) Mertz, E.; Tinsley,
J. M.; Roush, W. R. J. Org. Chem. 2005, 70, 8035. (c) Crimmins, M. T.;
Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369. (d) Marshall, J. A.; Sabatini,
J. J. Org. Lett. 2006, 8, 3557. (e) Zhao, H.; Gorman, J. S .T.; Pagenkopf,
B. L. Org. Lett. 2006, 8, 4379.
(6) Burke, S. D.; Jiang, L. Org. Lett. 2001, 3, 1953.
(7) Kawazoe, K.; Furusho, Y.; Nakanishi, S.; Takata, T. Synth. Commun.
2001, 31, 2107.
(8) Horikawa, T.; Norimine, Y.; Tanaka, M.; Sakai, K.; Suemune, H.
Chem. Pharm. Bull. 1998, 46, 17.
(9) (S,S)-Diol ent-2 affords ent-4 in 73% yield.
(10) Morgan, J. P.; Morrill, C.; Grubbs, R. H. Org. Lett. 2002, 4, 67.
(11) Scherman, O. A.; Walker, R.; Grubbs, R. H. Polym. Prepr. (Am.
Chem. Soc., DiV. Polym. Chem.) 2003, 44, 952.
(12) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
ent-28 were subjected to RO/CM. Treatment of 1 with
Grubbs’ second-generation ruthenium catalyst 5 (10 mol %)
and 1,4-diacetoxy-cis-2-butene10 gave meso-diol bis(allylic
(13) (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915. (b) Lucas,
B. S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965. (c) Keller, V.
A.; Kim, I.; Burke, S. D. Org. Lett. 2005, 7, 737.
(4) Chavez, D.; Mata, R.; Iglesias-Prieto, R.; Lotina-Hennsen, B. Physiol.
Plant. 2001, 111, 262.
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Org. Lett., Vol. 8, No. 24, 2006