Remote asymmetric induction in an intramolecular ionic Diels-Alder reaction: Application to the total synthesis of (+)-dihydrocompactin

Article abstract of DOI:10.1021/ja043506g

The total synthesis of (+)-dihydrocompactin via an intramolecular ionic Diels-Alder reaction that proceeds with remote stereocontrol is described. This reaction proceeds by an intermediate vinyl-oxocarbenium ion (6), the conformational constraints of whic

Full text of DOI:10.1021/ja043506g

Published on Web 04/14/2005
Remote Asymmetric Induction in an Intramolecular Ionic Diels-Alder
Reaction: Application to the Total Synthesis of (+)-Dihydrocompactin
Tarek Sammakia,* Deidre M. Johns, Ganghyeok Kim, and Martin A. Berliner
Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
Received October 27, 2004; E-mail: Sammakia@colorado.edu
Scheme 1
The mevinic acids are a medicinally important class of com-
pounds that have been the subject of numerous synthetic studies.1
One of these compounds, (+)-dihydrocompactin (Scheme 1), was
originally isolated as a minor constituent of the fermentation broth
of Penicillium breVicompactum2,3 and contains an octahydronaph-
thalene (octalin) unit and a δ-lactone joined by an ethylene bridge.
One of the challenges in synthesizing this molecule is controlling
the stereochemistry between these two remote units, and most
syntheses of mevinic acids have avoided this issue by coupling
enantiomerically enriched fragments, or racemic fragments, and
separating the resulting diastereomers.4 In this communication, we
report a synthesis of (+)-dihydrocompactin that proceeds with
remote stereocontrol via an intramolecular ionic Diels-Alder
cycloaddition as shown in the retrosynthesis depicted in Scheme
1. While this is arguably the most direct approach to this molecule,
it has not been described in the literature because it requires that
the cycloaddition proceed with remote stereocontrol. The Diels-
Scheme 2
Alder reaction is not intrinsically capable of this; however, we have
previously described asymmetric ionic Diels-Alder reactions,5,6 and
we wished to apply this method to the synthesis of (+)-dihydro-
compactin. We reasoned that intramolecular cycloaddition of
oxocarbenium ion 2 could proceed to provide 3, which upon
hydrolysis would provide the (+)-dihydrocompactin core (4) with
stereocontrol due to the conformational constraints of the cyclic
dieneophile. This species, in turn, could be prepared in situ from
the acyclic TMS ether 1, thereby enabling the synthesis of 4 by
this direct strategy. The broader significance of this study is that
this method allows for the control of stereochemistry between
remote sites in an intramolecular Diels-Alder reaction in a
amounts of acid in the reaction mixture were responsible for this
systematic way, thereby enhancing this already powerful reaction.
behavior. After careful experimentation, we found the combination
of Al(OTf)3 (3 equiv) and triflic acid (0.1 equiv) reproducibly
provided a 70% yield of cycloadducts 8 and 9 in a 1:1 ratio along
with 14% of 10 on gram scale. As such, treatment of 5 with this
acid combination followed by acid-catalyzed hydrolysis of the
resulting cycloadducts provided a mixture of cis- and trans-
octalones, which upon treatment with K2CO3 in methanol underwent
base-catalyzed epimerization to provide the trans-octalone (11) as
Our synthesis of the key intramolecular Diels-Alder substrate
5 is described in the Supporting Information, and with this
compound in hand, we turned our attention to studying the
cycloaddition. Our plan was to induce formation of the desired
oxocarbenium ion by subjecting compound 5 to the Noyori
ketalization reaction conditions.7 This reaction involves treatment
of a TMS ether and a ketone or aldehyde with TMSOTf and likely
proceeds via the corresponding oxocarbenium ion. In the event,
a 9:1 mixture of diastereomers in 49% yield for the three-step
sequence (eq 1). The structure of this material was confirmed by
single-crystal X-ray analysis.
we were pleased to find that treatment of 5 with 5% TMSOTf in
CH2Cl2 at -20 °C provided a mixture of two Diels-Alder adducts
(8 and 9) as well as compound 10 in which the enone has undergone
isomerization from cis to trans (Scheme 2). Cycloadducts 8 and 9
are formed with remote stereocontrol as a 9:1 mixture of diaster-
eomers, presumably from intermediate 7 either by loss of a proton
or by trapping of the oxocarbenium ion by the pendant TMS ether,
respectively. The trans-enone (10) cannot form a cyclic oxocar-
benium ion and as such does not provide any cycloadducts under
these conditions, thereby simplifying the analysis of the products.
While this reaction worked well on small scale, we found that it
provided erratic yields on gram scale. Triflic acid is produced as a
byproduct in the formation of 8, and we suspected that variable
The stereochemical outcome of this reaction is such that the
product is derived from attack of the diene from the same face as
the pendant side chain in the cyclic oxocarbenium ion structure
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10.1021/ja043506g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Figure 1. AM1 conformation of 6 and cycloaddition transition states.
(Figure 1). This seemingly contrasteric result can be understood
by considering the preferred conformation of the cyclic oxocarbe-
nium ion. The lowest energy conformation of this intermediate was
determined via a Monte Carlo conformational search using the AM1
method.8 The four sp2 centers within the seven-membered ring are
nearly coplanar, while the remaining three sp3 atoms adopt a more
staggered conformation. The alkyl substituent on the ring splays
outward from the periphery of the molecule and does not interfere
with the incoming diene. However, the three sp3 hybridized atoms
contain three pseudoaxial hydrogens (Ha, Hb, and Hc in Figure 1)
that could potentially interfere with the approach of the diene. Of
these, Ha and Hb point toward the top face of the structure as
depicted, and Hc points toward the bottom. We hypothesize that
Ha and Hb more effectively block the top face of the molecule
and thereby dictate that the diene approach from the bottom face.9
To probe for the intermediacy of an oxocarbenium ion, we
studied the corresponding bis-TIPS ether (12), which cannot form
an oxocarbenium ion under our optimized reaction conditions
(Al(OTf)3/TfOH, CH2Cl2, -20 °C, eq 2). Under these conditions,
this compound provides an 85:15 mixture of the trans-alkene 14
with both TIPS ethers intact and the Diels-Alder adducts 13 as a
mixture of diastereomers. At 0 °C, a 10:90 mixture of 14 and 13,
again as a mixture of diastereomers, is observed. The decreased
reactivity and selectivity of 12 as compared to that of 5 suggests
that these compounds react via different mechanisms and that 5
reacts via the corresponding oxocarbenium ion.
Acknowledgment. We thank the NIH (GM48498) for financial
support of this work, Dr. Bruce Noll for obtaining the X-ray crystal
structure of compound 11, and Professor Andrew Phillips for
assistance with the AM1 calculations. NMR instrumentation used
in this work was supported in part by the National Science
Foundation CRIF program (CHE-0131003).
Supporting Information Available: Experimental procedures for
the synthesis and characterization of all new compounds as well as 1H
and 13C spectra for selected compounds, and X-ray crystallography data
for compound 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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(4) Danishefsky and Uskokov´ıc have described syntheses of compactin and
mevinolin, respectively, which proceed with remote stereocontrol in which
the key step is a diastereoselective hetero-Diels-Alder reaction used to
construct the lactone. See: (a) Danishefsky, S. J.; Simoneau, B. Pure
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(8) For details of the molecular modeling, including the structures of other
low-energy conformers, see the Supporting Information.
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Lam, K.-P.; Wu, K.-Y.; Williams, I. D.; Yeung, L.-L. Tetrahedron 1999,
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Completion of the synthesis was accomplished as described in
Scheme 3. The primary alcohol of compound 11 was selectively
protected as the trityl ether (73%) and the ketone at C-1 reduced
with L-selectride to the hindered axial alcohol (93%).1 The less
hindered hydroxyl group at C-5′ was then acylated with bromoacetyl
bromide (87%) to provide compound 15, and the hindered alcohol
at C-1 was acylated with (S)-2-methylbutyric anhydride using
Vedejs’ conditions (96%).10 Deprotection of the trityl ether with
excess zinc bromide11 provided the primary alcohol at C-3 (80%),
which was oxidized with the Dess-Martin periodinane12 to
aldehyde 16 (79%). Compound 16 then underwent a SmI2 promoted
intramolecular Reformatsky reaction as described by Molander13
to provide (+)-dihydrocompactin in 75% yield as a 7:1 mixture of
isomers at C-3′, which was crystallized to homogeneity.14
(10) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
(11) Kohli, V.; Blo¨cker, H.; Ko¨ster, H. Tetrahedron Lett. 1980, 21, 2683.
(12) (a) Dess, D. B.; Matrin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer,
S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(13) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am. Chem.
Soc. 1991, 113, 8036.
(14) This material was fully characterized and displays identical spectral
properties to that described in the literature (see Supporting Information).
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