General synthesis for chiral 4-alkyl-4-hydroxycyclohexenones

Article abstract of DOI:10.1021/ol061000s

Some selective transformations of resorcinol-derived cyclohexadienone are reported. Efforts led to a structure reported to display anticancer properties. On the basis of the results, the structures for natural products reported to contain a 4,6-dihydroxy-4-alkyl-cyclohexenone nucleus are corrected.

Full text of DOI:10.1021/ol061000s

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2843-2846
General Synthesis for Chiral
4-Alkyl-4-hydroxycyclohexenones
Christophe Hoarau and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
pettus@chem.ucsb.edu
Received April 26, 2006
ABSTRACT
Some selective transformations of resorcinol-derived cyclohexadienone are reported. Efforts led to a structure reported to display anticancer
properties. On the basis of the results, the structures for natural products reported to contain a 4,6-dihydroxy-4-alkyl-cyclohexenone nucleus
are corrected.
Active ingredients from extracts of the tree, Tapirira
guianensis Aublet, were assigned as structures 1 and 2
(Figure 1).1 Because of their lipophilic tails and polar head-
groups, these oily compounds undoubtedly proved difficult
to crystallize. Therefore, the structures were inferred from
1H NMR, 13C NMR, and MS data as well as from Cotton
effects in the CD spectrum to account for the absolute stereo-
chemistry in 1.1 In the NCI-60 panel of human cancer cell
lines, these compounds were reported to display selective
cytotoxicity toward prostate cancer (0.2 and 0.3 µg/mL for
LCAP, respectively).
The geometry and location of the olefinic side chains of
compounds 1 and 2 were rigorously determined using a
technique developed by Francis and Veland:2 transformation
into the corresponding R,â-bis(methylthio) derivative and
analysis of the resulting 1H NMR and MS spectra. Boyd used
the method to secure the olefin position in the related ω-9
hydroquinone called lanneaquinol.3
Our route to the reported structures 1 and 2 begins with
palmitoleic acid (3), an ω-7 fatty acid found in the fruit of
the sea buckhorn, in macadamia nuts, and in the 2005 Aldrich
catalog. Reduction of carboxylic acid 3 (0.5 M in Et2O) with
lithium aluminum hydride (1 equiv) affords the desired
alcohol. Subsequent treatment of this intermediate alcohol
(0.23 M in benzene) with triphenylphosphinedibromide (1.2
equiv) provides the bromide 4 in 94% overall yield (Scheme
1). After distillation, the bromide 4 is converted into a 2 M
THF solution of the Grignard reagent 5 by the addition of a
slight excess of magnesium powder.
The aldehyde 66 (0.1 M in THF/H2O) undergoes reduction
with sodium borohydride (3 equiv, 10 s) to afford the
corresponding benzyl alcohol. Subsequent treatment (0.05
M in Et2O) with sodium hydride (1 equiv) and the Grignard
reagent 5 provides the differentiated 1,4-hydroquinone
nucleus, whereupon addition of aqueous 3 M HCl cleaves
the remaining O-Boc residue and affords the hydroquinone
2 in 45% overall yield. All of the spectral data for synthetic
2 prove identical to those previously reported for natural 2.
The architecture proposed for the cyclohexenone 1 is sur-
prisingly unique. A literature search revealed only one other
natural product displaying its 4,6-dihydroxy-4-alkyl cyclo-
hexenone core.4 The obvious simplicity and unusual proposed
biosynthesis of natural 1 among more complex anticancer
agents5 provided a compelling case for total synthesis.
(1) David, J. M.; Cha´vez, J. P.; Chai, H. B.; Cordell, G. A. J. Nat. Prod.
1998, 61, 287-289.
(2) Francis, G. W.; Veland, K. J. Chromatogr. 1981, 219, 379-384.
(3) Groweiss, A.; Cardellina, J. H.; Pannell, L. K.; Uyakul, D.; Kashman,
Y.; Boyd, M. R. J. Nat. Prod. 1997, 60, 116-121.
Figure 1. Original assignments for agents found in T. guianensis
Aublet.
10.1021/ol061000s CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/01/2006

Scheme 1. Preparation of the 16-Carbon Grignard Reagent
Moreover, because of a problematic demethylation in the
previous synthesis of its relative lanneaquinol,3 our four-
step route to this general class of hydroquinones is surpris-
ingly efficient when compared to the alternative strategy of
lithiation, alkylation, and demethylation of 1,4-dimethoxy-
benzene.3
Figure 2. o-Quinone methide cascade leading from 6 and 7 to 2
and 8.
Next, we began the synthesis of the cyclohexenone 1,
which is the supposed biosynthetic precursor of 2. Our
strategy required that the aldehyde 77 (0.1 M in THF/H2O)
undergo reduction with NaBH4 (2 equiv) to afford the
corresponding benzyl alcohol, whereupon successive treat-
ment (0.2 M in THF) with NaH (2 equiv) and a solution of
5 (2 equiv, 0.5 M in THF) affords the differentially protected
resorcinol derivative 8 in 73% yield (Scheme 2).
trimethylsilyltriflate (2 equiv) provides the cyclohexadienone
11 in 55% isolated yield (Scheme 3). We presume this
Scheme 3. Dearomatization and Diastereoselective Synthesis
of 11
Scheme 2. Elaboration of the o-Quinone Methide Intermediate
transformation involves in situ formation of PhI(OTf)OTMS
leading to the generation of a phenoxonium cation and cycli-
zation with the carbonyl of the amide. The resulting iminium
species then undergoes hydrolysis to afford the δ-lactone
(-)-11. In this example, the other diastereomer is not evident
in the 1H NMR spectrum of the crude product mixture. These
modified conditions have significantly improved the versatil-
ity of this dearomatization process; other derivatives display
gains in yields when compared to our previous conditions
that employed PhI(O2CCF3)2 as the oxidant.7
Four transition states explain the two possible diastereo-
meric products. These include the Meax-boat, the Meax-chair
shown in Figure 3, and their corresponding ring flips, the
Meeq-boat and the Meeq-chair. However, the severe allylic
1,3-steric interaction between the methoxy amide residue and
the methyl moiety in the Meeq-boat and the Meeq-chair
precludes a substantial effect on the product distribution, and
these less important transition states are not shown. The
absolute stereochemistry of the major product, which has
been confirmed in other examples through X-ray analysis,
relay of relative stereochemistry to a known natural product,
and extensive analysis of nOe’s, proves that the Meax-boat
transition state is favored. Because of the number of
contributing sp2 carbon atoms, the boat does not experience
These two coupling processes follow the sequence shown
in Figure 2.6 Reduction of the aldehyde and workup provide
a benzyl alcohol. Addition of sodium hydride reinitiates the
cascade by causing Boc migration. In the presence of the
magnesium ion, â-elimination proceeds to an o-quinone
methide, which is immediately intercepted by the Grignard
reagent to form a C-C bond. Workup affords the differenti-
ated phenol. The phenol 8 (1.7 M in DMF) is then coupled
with the chiral tosylate (-)-9 (1.1 equiv) by the action of
potassium carbonate (1.3 equiv). Cleavage of the remaining
O-Boc residue with zinc bromide (5 equiv in CH3NO2)
affords the phenol 10 in 86% overall yield displaying an
S-configuration about the inverted chiral center.
Our usual dearomatization conditions (0.05 M CH3NO2,
2 equiv of PhI(O2CCF3)2) afforded a 48% yield of the desired
cyclohexadienone (-)-11 from 10.7 However, after consider-
able experimentation, we find that successive treatment of
10 (0.1 M in CH2Cl2) with iodosyl benzene (2 equiv) and
(4) Aziz-ur-Rehman; Malik, A.; Riaz, N.; Nawaz, H. R.; Ahmad, H.;
Nawaz, S. A.; Choudhary, M. I. J. Nat. Prod. 2004, 67, 1450-1454.
(5) Kim, J. Curr. Med. Chem. 2002, 2, 485-537.
(6) Hoarau, C.; Pettus, T. R. R. Synlett 2003, 127-137.
(7) Mejorado, L.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535-
1538.
2844
Org. Lett., Vol. 8, No. 13, 2006

Therefore, the carbonyl moieties in 14 (0.05 M in THF)
are reduced with diisobutylaluminum hydride (6 equiv) to
provide a lactol intermediate that undergoes ring opening
upon consecutive treatment with Me2NNH2 (2.0 equiv) to
afford the hydrazone 15 in 40% overall yield (Scheme 5).
Scheme 5. Completion of Synthetic 1
Figure 3. Probable transition states leading to (-)-11 and the
unseen diastereomer.
any destabilizing steric effects. Its dipole (µ), derived from
the iminium and the phenoxonium functionality, is smaller
than the corresponding (µ) for the Meax-chair transition state.
Sevin has used a similar dipole stabilization argument to
explain the diastereoselective addition of enamines to
unsaturated aldehydes.8
Using Morrow’s protocol (Scheme 4),9 the vinylogous
ester portion of compound 11 succumbs to a diastereose-
Scheme 4. Diastereoselective Synthesis of 14
An oxidation of 15 (0.1 M in CH2Cl2, 1.5 equiv of NMO,
0.2 equiv of TPAP) is followed by a noteworthy cleavage
(Figure 4) of the chiral tether under mild acidic conditions
Figure 4. Unusual transformation that enables ether cleavage.
lective 1,4-reduction and after treatment (0.2 M in CH3CN)
with iodotrimethysilane10 (2 equiv) affords the des-bromo
compound 12 in an overall yield of 50%. After significant
experimentation with newer procedures, we find Ojima’s 1,4-
hydrosilylation method [10 equiv of triethylsilane and
catalytic chloro(triphenylphosphine)rhodium in benzene] to
be superior in providing the desired silyl enol ether inter-
mediate.11 Subsequent treatment of the crude enol ether (0.4
M in CH2Cl2) with dimethyldioxirane (1.01 equiv) affords
the epoxide 13 as a single diastereomer in 84% yield as
established through several nOe’s. Successive treatment of
the unstable epoxide (0.45 M in H2O/THF) with camphor
sulfonic acid followed by protection of the resulting crude
alcohol (0.1 M in DMF) affords the silyl ether 14 in 63%
overall yield. â-Elimination and subsequent deprotection
would seem to complete the synthesis of 1. However, this
proves impossible because of the trans-fused ring system,
which positions the leaving group in an equatorial orientation.
(2 equiv of TMSCl, 0.1 M CH2Cl2). These conditions afford
the corresponding â-hydroxy ketone. Conversion of the
â-alcohol into an acetate with acetic anhydride (1.5 equiv)
and base (0.4 equiv of DBU) facilitates acetylation and
â-elimination thereby providing the R-siloxy enone 16 in
39% overall yield. The silyl ether of 16 succumbs to
deprotection (1 equiv of TBAF, 0.02 M in THF) and affords
the syn-diol (-)-1 in 90% isolated yield.
High-resolution mass spectroscopy [ESI+/TOF: m/z calcd
for C23H40O3 ) 364.5619, found (M + Na)+ ) 387.2853]
confirms the elemental composition of the synthetic 1 to be
the same as that for the natural diol 1. However, the structure
proposed for natural 1 had stipulated that the diol functional-
ity adopts a 1,3-diaxial arrangement. In the case of synthetic
1, however, a sizable nOe between the methylene of the
lipophilic side chain and the axial proton adjacent to the
secondary alcohol proves the hydroxy residues to be disposed
in 1,3-diequatorial fashion. Upon further inspection and
comparison of the 1H NMR and 13C NMR data, it becomes
evident that synthetic 1 and natural 1 are different com-
pounds. After careful consideration of our intervening
transformations and the integrity of our intermediates and
(8) Sevin, A.; Maddaluno, J. J. Org. Chem. 1987, 52, 5611-5615.
(9) Doty, B. J.; Morrow, G. W. Tetrahedron Lett. 1990, 31, 6125-6128.
(10) Jung, M. E.; Ornstein, P. L. Tetrahedron Lett. 1977, 31, 2659-
2662.
(11) Ojima, I.; Kogure, T.; Nihonyanagi, M.; Nagai, Y. Bull. Chem. Soc.
Jpn. 1972, 45, 3506.
Org. Lett., Vol. 8, No. 13, 2006
2845

further analysis of the data that led to the structural
assignment for natural 1,1 particularly the unusually large
2.7 Hz W-coupling proposed for C3H-C5H (on a type A),
it is painfully apparent that the ring architecture for natural
1 was improperly assigned.12
natural product previously assigned as 11 does not have the
C architecture, it should be noted that some related natural
products possess a C architecture and are presumably related
by biosynthesis to supposed natural 1.3
After careful reexamination of the reported data for natural
1, it became evident that architecture B was mistaken for
architecture A. The supposed 2.7 Hz W-coupling is actually
a vicinal coupling (C3-H-C6-H). In addition to our syn-
thesis of 1, additional evidence was found in the structural
assignment for compound 18, a related natural product iso-
lated from Tapirira obtusa.13 Although this analogue displays
a slightly longer side chain with an ω-5 site of unsaturation,
Three regioisomers (A-C, Table 1) accommodate the
functionality that comprises the six-membered ring and
Table 1
1
the H NMR data for 18 are strikingly similar to those
previously recorded for natural 1, particularly the (4.70 ppm)
shift of the C6 methine. Furthermore, the 13C NMR data
prove to be practically identical to those of homologue 18
in regards to the six-membered ring. We therefore propose
that the natural product reported to be structure 11 is in
fact its regioisomer 17. The confusion between type A and
B regioisomers has led others to improper structural assign-
ments as well. For example, the compound assigned as
structure 19 was reported in extracts of Periploca aphylla.4
We propose that the natural product assigned as 194 is
actually acremine A (20),14 a structure proVen by X-ray.
Furthermore, from a chemist’s perspective, the B and C
architectures can readily lead to a hydroquinone nucleus, such
as 2, by enolization, elimination, and tautomerization. How-
ever, architecture A requires a 1,2-alkyl shift, which is un-
precedented among biosynthetic transformations, to produce
the corresponding 1,4-hydroquinone. Given our synthesis of
1, the considerable stability of synthetic 1 to acidic and basic
conditions, as compared to natural 11 (17), and our reassign-
ments of natural 11 as its regioisomer 17 and of natural 194
as its regioisomer 20, no evidence for a biocatalyzed dione
rearrangement exists as of yet. We hope this letter helps to
clarify future cyclohexenone assignments and prevents future
confusion between these regiomeric cyclohexenones. At the
very least, we have described several new diastereoselective
transformations, introduced an innovative method for the
cleavage of the chiral directing group (Figure 4), and
increased the utility of chiral cyclohexadienones as building
bocks15 for future enantioselective syntheses.
Acknowledgment. A Research Grant from the National
Institutes of Health (GM-64831) is greatly appreciated.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 3-16 and 1 are
available. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL061000S
includes an enone, a secondary alcohol, a tertiary alcohol,
and a methylene functionality. In the case of regioisomer
C, however, the C5 methylene affords an AB-quartet in the
1H NMR,3 whereas the methylene in regioisomers A and B
would show some additional proton coupling. Although the
(13) de Jesus, S.; David, J. M.; David, J. P.; Chai, H.-B.; Pezzuto, J.
M.; Cordell, G. A. Phytochemistry 2001, 56, 781-784.
(14) Assanta, Z. G.; Dallavalle, S.; Malpezzi, L.; Nasini, G.; Burrano,
S.; Torta, L. Tetrahedron 2005, 61, 7686-7692. At our behest, these authors
1
confirm that the compound previously assigned as 194 gives the same H
NMR spectra as 20 when analyzed in the same deuterated solvent.
(15) (a) Magdziak, D.; Meek, S.; Pettus, T. R. R. Chem. ReV. 2004, 104,
1383-1429. (b) Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R.
Tetrahedron Lett. 2003, 44, 5109-5113. (c) Pettus, L. H.; Van De Water,
R. W.; Pettus, T. R. R. Org. Lett. 2001, 3, 905-908.
(12) Nicolaou, K. C.; Snyder, A. A. Angew Chem., Int. Ed. 2005, 44,
1012-1044.
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