An oxidative dearomatization-induced [5 + 2] cascade enabling the syntheses of α-cedrene, α-pipitzol, and sec -cedrenol

Article abstract of DOI:10.1021/ja109925g

Efficient syntheses of α-cedrene (1), α-pipitzol (2), and sec-cedrenol (3) were carried out using a new method, which was inspired by the proposed biosynthesis of the tricyclic skeleton of cedrol (12). The key transformation begins with the oxidative dearomatization of curcuphenol (5a) followed by an intramolecular [5 + 2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin. The benzylic stereocenter effectively guides the formation of the first two stereocenters during the [5 + 2] reaction. The cascade then terminates with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic [5 + 2] reactions. The phenolic precursors (5a-h) are constructed from readily available salicylaldehydes, either as the racemate (one pot) or as a specific enantiomer (four pots) by a modification to our method for the generation of ortho-quinone methides (o-QMs).

Full text of DOI:10.1021/ja109925g

ARTICLE
pubs.acs.org/JACS
An Oxidative Dearomatization-Induced [5 þ 2] Cascade Enabling
the Syntheses of R-Cedrene, R-Pipitzol, and sec-Cedrenol
Jason C. Green and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
ABSTRACT: Efficient syntheses of R-cedrene (1), R-pipitzol
(2), and sec-cedrenol (3) were carried out using a new method,
which was inspired by the proposed biosynthesis of the tricyclic
skeleton of cedrol (12). The key transformation begins with
the oxidative dearomatization of curcuphenol (5a) followed by
an intramolecular [5 þ 2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin. The benzylic
stereocenter effectively guides the formation of the first two stereocenters during the [5 þ 2] reaction. The cascade then terminates
with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic
[5 þ 2] reactions. The phenolic precursors (5a-h) are constructed from readily available salicylaldehydes, either as the racemate
(one pot) or as a specific enantiomer (four pots) by a modification to our method for the generation of ortho-quinone methides
(o-QMs).
’ INTRODUCTION
cipating in a [5 þ 2] cycloaddition, nor are there any examples
whereby the cascade terminates by the incorporation of a sepa-
rate nucleophile.
The cedranoids comprise a venerable family of unique natural
sesquiterpenes (Figure 1). R-Cedrene (1), an approved food
preservative,1 conveys antimicrobial,2 insecticidal, and termitici-
dal properties3 to the timber of the American red cedar Juniperus
virginiana from which it is isolated.4 Its characteristic tricyclo-
[5.3.1.01,5]-undecane skeleton was first proposed and then ver-
ified by Stork more than a century after its isolation.5 Many
creative strategies for building its congested skeleton have since
emerged,6 culminating in the arene-olefin meta-photocycloaddi-
tion strategy championed by Wender.7 Similarly, R-pipitzol (2),
which was isolated from the root extracts of Perezias cuernavacana,
remained unsolved for over a hundred years.8 The relatively few
approaches to R-pipitzol (2) include a semisynthesis from
perezone,9 a racemic synthesis featuring a [4 þ 2] tropone olefin
cyclization,10 and the lone enantioselective synthesis requiring
more than 30 steps from methyl R-D-mannopyranoside.11
sec-Cedrenol (3) is a relative newcomer to the cedranoid family.
It is produced by the Rhodococcus bacterium sp. KSM-7358 upon
exposure to feed stocks of R-cedrene (1).12 It has been shown to
be a potent stimulant of the histamine H3 receptor, and it might
prove useful for the prevention and treatment of bronchial
asthma, hyperlipidemia, and inflammation.13
A number of cationic intramolecular [5 þ 2] cycloadditions
have been described in the literature.14 All prior examples,
however, necessitate the use of highly oxygenated aromatic
precursors capable of forming a cationic species resembling a
para-quinone, either by the addition of a Lewis acid to a para-
quinone monoketal, or by the oxidation of a monoprotected
para-quinol, or by addition of a Lewis acid to a para-quinone
itself. To the best of our knowledge, there are no reports of
ortho-(pent-4-enyl)-phenols, such as curcuphenol (5a),15 parti-
Our inspiration for this cascade arose from the biosynthesis of
cedrol (12), which is proposed to commence from nerolidyl
pyrophosphate 8 as shown in Scheme 1.16 A sesquiterpene
cyclase triggers the ionization of the tertiary alcohol, whereupon
cyclization with the adjacent olefin and a 1,2-hydride shift affords
the bisabolyl cation 9, which upon further reaction leads to the
spirocyclic acorane intermediate 10. Subsequent cyclization to
the cedryl cation 11 and addition of water affords cedrol (12).
We therefore hypothesized that oxidative dearomatization of
curcuphenol (5a) would provide the intermediate phenoxonium
7 that might behave in an analogous manner, whereby the benzylic
stereocenter would govern the assembly of the tricyclic skeleton
with the cascade terminating by the addition of an oxygen nucleophile.
’ RESULTS AND DISCUSSION
Syntheses of Curcuphenol (5a) and Its Derivatives. To
test our hypothesis, we required efficient access to an assortment
of ortho-(pent-4-enyl)-phenols including curcuphenol (5a).
After some experimentation, we found that a slight modification
to our previously reported low temperature o-QM generation
procedure enables the direct use of unprotected salicylaldehydes
6 in a one-pot process (Scheme 2).17 For the racemic process, the
sequence commences with the addition of 2 equiv of MeLi to the
appropriate salicylaldehyde 6a (R1 = -Me, R2 = -H). This
results in both deprotonation of the phenol and addition to the
Received: November 16, 2010
Published: December 31, 2010
r
2010 American Chemical Society
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ARTICLE
Scheme 2. Racemic and Enantioselective Syntheses of Var-
ious ortho-(Pent-4-enyl)-phenolsa
Figure 1. Retrosyntheses of the cedranoid family.
Scheme 1. Biosynthetically Inspired [5 þ 2] Cycloaddition
a Reagents and conditions for curcuphenol (5a) synthesis: Racemic [one
pot: 6a to 5a] (a). MeLi (2.05 equiv), Et2O, 0 °C; then Boc2O (1.1
equiv), -40 °C; then 15 (1.1 equiv), 84%. Enantioselective [four pots:
6a to 17] (a) MeMgBr (2.05 equiv), 16 (3 equiv), Et2O, 0 °C; then
Boc2O (1.1 equiv), -40 °C, 73%, 16:1 dr; (b) CSA (0.1 equiv),
CH3CN, H2O, 92%; (c) ClPh3PCH2OCH3 (2.5 equiv), n-BuLi (2.3
equiv), THF; then aqueous HCl, 84% over two steps; (d) IPh3PCH-
(CH3)2 (2.5 equiv), n-BuLi (2.4 equiv), THF, 78%.
to the corresponding lactol and sequential elaboration with the
respective Wittig reagents produces (-)-curcuphenol 5a in four pots
(48% overall yield from 6a).
With an assortment of ortho-(pent-4-enyl)-phenols (5a-h) in
hand, we were poised to test the proposed dearomatization
reaction (Table 1). Unfortunately, various hypervalent iodine
oxidants failed to provide any of the desired tricyclic products.
However, we were gratified to find that addition of Pb(OAc)4
(1.1 equiv) to 5a (1.0 M in AcOH) provided a trace (6%) of the
tricyclic compound 4a, presumably from acetic acid addition to
the allyl cation 19, along with a 44% yield of the ortho-acet-
oxylation diastereomers 20. We suspect that the latter arises from
the stereoindiscriminate addition of acetic acid to the phenox-
onium 7.18 Nevertheless, the formation of the tricyclic adduct 4a
as a single diastereomer, the relative stereochemistry of which
was secured by single crystal X-ray analysis, indicated that the
single benzylic stereocenter had governed the creation of two
additional rings before a selective incorporation of acetic acid. In
view of the molecular complexity afforded from the simple
starting material in this transformation, we sought conditions to
favor the intramolecular cycloaddition reaction. The key optimi-
zation involved changing the solvent to chloroform, thus allow-
ing for a lower reaction temperature and limiting the equivalents
of acetic acid to those liberated from the Pb(OAc)4, which
increased the yield of the tricyclic compound 4a to 61%.
aldehyde, thereby yielding an intermediate dianion that undergoes
mono carbonylation with di-tert-butyl dicarbonate. Upon addi-
tion of the Grignard reagent 15, elimination occurs after for-
mation of the magnesium phenoxide 13a (M = -MgX, R1 =
R3 = -Me, R2 = -H), thereby producing the intermediate o-QM
14a (R1 = R3 = -Me, R2 = -H). This intermediate is intercepted
in a 1,4-addition and rearomatization reaction with the Grignard
reagent 15 to produce (()-5a (R1 = R3 = R4 = R5 = -Me,
R2 = -H) in 84% yield in a single pot. If, however, optically
enriched material is required, the procedure begins by addition of
2 equiv of MeMgBr to a flask containing the salicylaldehyde 6a
and the enol ether 16. The resulting dianion similarly undergoes
mono carbonylation leading to generation of the same o-QM 14a
intermediate. However, in this case without a nucleophile to induce
the 1,4-addition and rearomatization, a diastereoselective inverse-
demand Diels-Alder reaction proceeds to afford the chroman ketal
17a (R1 = R3 = -Me, R2 = -H) in 73% yield (16:1 dr). Hydrolysis
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Table 1. Dearomatization of ortho-(Pent-4-enyl)-phenols
Scheme 3. R-Pipitzol (2) Synthesis and Unexpected Frag-
mentationa
a Reagents and conditions: (a) CrO3, H2SO4, H2O, 96%; (b) OsO4,
THF, 79%; (c) p-TsOH, benzene, 80 °C, 85%; (d) DMDO, acetone,
78%; (e) H2SO4, AcOH, THF, silica gel, <15 mmHg, 70 °C, 72%.
and stereoselective outcome for the acetic acid incorporation, as
the addition reaction could be expected to produce a mixture of
regioisomers. Removal of the benzylic stereocenter (R3) proved
most detrimental as the oxidation ceded a meager 32% yield of
the compound 4c (entry 3). We therefore believe that the ben-
zylic substituent assists in positioning the tethered olefin
for the subsequent cyclization. Indeed, the dearomatization
of achiral bis-prenylated substrate 5d afforded the anticipated
adduct 4d in 65% yield along with 8% of the diastereomeric
acetate (entry 4). The ethylated derivative 5e afforded a similar
diastereomeric ratio upon oxidation, although the yield was not
as high (entry 5). Oxidation of the disubstituted olefin derivative
5f yielded 4f as the sole tricyclic product in a poor yield (entry 6).
This outcome likely suggests an olefin capable of stabilizing the
incipient charge during the course of the reaction as a critical
component for success. In the case of a para-methoxy residue 5g,
oxidation followed by acidic workup results mostly in the corre-
sponding curcuquinone by hydrolysis of the para-acetoxy mixed
ketal. However, a small amount of the desired adduct 4g could be
obtained (entry 7). This result implies that the predominate
cation character rests with the p-phenoxonium contributor,
which is intercepted by acetic acid, as opposed to the corre-
sponding o-phenoxonium species 7, which is intercepted by the
tethered olefin in all the preceding reactions. In a somewhat
similar manner, exchange of the aryl methyl residue for a
methoxy group provided a mixture of tricyclic allylic acetates
upon oxidation of 5h. These crude materials subsequently
converge to the β-diketone 4h upon acidic workup (entry 8).
a Conditions: (A) Pb(OAc)4 (1.05 equiv), CHCl3, -40 °C. (B) 1.05
equiv of Pb(OAc)4, CHCl3, -40 °C, remove 4g by column chromatog-
raphy, submit the remaining fractions to 5 M aqueous HCl. (C) Pb(OAc)4
(1.05 equiv), CHCl3, -40 °C; 5 M aqueous HCl. b Determined by crude
1H NMR. c Ratio of [5 þ 2] adduct to p-acetoxylation products. d Complex
mixture of regioisomers and diastereomers in the crude 1H NMR.
Stripping the aromatic core of its substitution resulted in a
slight decrease in the overall efficiency as the reaction afforded 4b
in 54% yield (entry 2). Remarkably, we observed the same regio-
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Scheme 4. Reactivity of the [5 þ 2] Adduct 4aa
Scheme 5. Acetate Manipulation and Grob Fragmentationa
a Reagents and conditions: (a) KCN, MeOH, 94%; (b) LDA, THF,
75%; (c) TBSOTf, Et3N, 91%; (d) LiAlH4, Et2O, 62%; (e) Li0, NH3,
35%; (f) Na0, NH3, 83%.
a Reagents and conditions: (a) BF3 OEt2, ROH, CH2Cl2, 77%, 4:1 dr;
(b) LiAlH4, Et2O, 89%; (c) CDCl3, 48 h, 88%.
3
Having established the scope for this new intramolecular
cationic cascade replete with an unprecedented intermolecular
termination step, we now chose to pursue the synthesis of
compounds 1-3 from the tricyclic adduct 4a. The construction
of R-cedrene (1) would require global erasure of both the acetate
and the bridge ketone, whereas the synthesis of sec-cedrenol (3)
would require the selective removal of the ketone. R-Pipitzol (2),
on the other hand, would only require two oxidations of activated
regions, and thus seemed the most straightforward target.
Synthesis of r-Pipitzol (2). Submission of the allylic acetate
4a to a Jones oxidation smoothly proceeded to afford the enone
21 (Scheme 3).19 At this juncture, we had imagined dihydrox-
ylation followed by β-elimination would furnish R-pipitzol (2).
Treatment of 21 with osmium tetroxide (1 equiv) and subse-
quent reductive workup (NaHSO3) furnished the expected diol
22. However, its treatment with p-TsOH (0.3 equiv in benzene)
failed to deliver R-piptizol (2). Instead, the spirolactone 25
emerged in a respectable 85% yield. We believe this material
may result from a series of fragmentation reactions commen-
cing with an acid catalyzed retro-aldol reaction to afford the R-
hydroxy ketone 23. This intermediate undergoes hemiketali-
zation to give compound 24, whereupon a second retro-aldol
reaction furnishes the spirocyclic lactone 25.
To circumvent this rather debilitating series of events, we next
considered epoxidation of the enone 21. All typical nucleophilic
epoxidation reagents, as usually applied to enones, failed. Epox-
idation was eventually carried out by prolonged exposure of the
enone 21 to dimethyldioxirane (0.08 M in acetone, 4.5 equiv).
Application of Hu's mixed-acid catalyst (H2SO4, AcOH, 70 °C,
reduced pressure) for ring-opening of R,β-epoxyketones pro-
vided R-pipitzol (2) in good yield.20
Approaches for sec-Cedrenol (3) and R-Cedrene (1). Our
attention then turned toward the synthesis of sec-cedrenol (3),
which initially seemed to be a simple exercise, as it only required
selective erasure of the bridge ketone in 4a (Scheme 4). Attempts
to affect this transformation, however, were beset by two factors:
the congested nature of the ketone and the frailty of the allylic
acetate. For example, basic conditions, as required of most
Wolff-Kishner reductions, led to saponification and epimeriza-
tion of the allylic alcohol, presumably as a result of a retro-aldol/
aldol equilibration. This outcome even occurred under mild
conditions, such as deacylation by addition of KCN (0.5 equiv)
to the acetate 4a (0.2 M in MeOH). This prevented considera-
tion of any obvious alterations of the acetate protecting group on
the allylic alcohol. A second drawback to basic conditions was the
formation of the tetracycle 28, as observed upon treatment of 4
(0.5 M in THF) with lithium diisopropyl amide (1.2 equiv, 1.0 M
in THF).
On the other hand, the allylic acetate in compound 4a did not
fair better under acidic conditions, as might be required for for-
mation of certain hydrazones.21 Treatment of 4a with a number
of Lewis or Brønsted acids led to formation of the diene 29.
Optimal conditions involved treatment of 4a (0.05 M in Et3N)
with tert-butyldimethylsiliyltriflate (1.1 equiv). We suspect that
this reaction proceeds by regeneration of the corresponding
allylic cation 19, which undergoes elimination.
With our synthetic options disappearing before us, we next
considered removal of the bridge ketone by application of a
Barton-McCombie deoxygenation reaction of the properly
outfitted carbonyl reduction product. Unable to effect a chemo-
selective hydride reduction, we eventually found that both
carbonyls in 4a (0.48 M in THF, -78 °C) undergo reduction
with LiAlH4 (2.2 equiv) to produce the diol 30, as the result of
hydride addition to the least sterically encumbered face of the
bridge ketone. However, distinguishing between the alcohols in a
subsequent derivatization process was problematic. Application
of a single-electron reduction to 4a (16 equiv of Li0, 0.10 M in
NH3) solved this problem to some degree, resulting in a 41%
yield of the alcohol 31. Similarly, employing sodium (35 equiv of
Na0, 0.35 M in NH3) as the dissolving metal provided the
globally reduced product 32 in 83% yield.22 Despite our best
efforts, after conversion of 31 and 32 into their respective
xanthate ester,23 phosphite,24 or triflate25 derivatives, all attempted
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Scheme 6. Endgame for R-Cedrene (1) and sec-Cedrenol
upon the reaction's completion resulted in an allylic 1,3-transpo-
sition of the acetate. Because we ultimately desired the secondary
alcohol, we chose to reflux R-cedrene 1 (0.9 M in benzene) with
Pb(OAc)4 (1.05 equiv) for an extended time. The reaction
proceeded as expected, whereupon the initial tertiary allylic
acetate transformed entirely into the desired secondary allylic
acetate. Upon completion of the reaction as determined by TLC,
saponification with NaOMe afforded sec-cedrenol (3).
(3)a
’ CONCLUSION
The complexity created during the biosynthesis of cedrol (12)
inspired us to develop its synthetic equivalent. Phenols with
various ortho-(pent-4-enyl) motifs were directly prepared from
salicyaldehydes by a modification to our method for low tem-
perature o-QM generation and consumption. The key transfor-
mation features the oxidative dearomatization of an ortho-(pent-
4-enyl)-phenol (5a-h) followed by an intramolecular [5 þ 2]
cycloaddition of the respective phenoxonium intermediate
across the tethered olefin to afford the respective derivatives of
the tricyclo-[5.3.1.01,5]-undecane skeleton. This oxidative dearoma-
tization-induced cascade reaction is unique as it proceeds in the
absence of para-oxygen substituent. This distinction necessitates an
unprecedented termination step, whereby a nucleophile engages
the allylic cation that emerges from the [5 þ 2] cycloaddition in a
regioselective, diastereoselective, and intermolecular fashion,
much like water engages the cedryl cation 11 that concludes
the cascade leading to cedrol (12). Thus, by a combination of
these two methods, we have succinctly demonstrated an ability to
harness the reactivity of o-QMs and phenoxoniums, thereby
leading to an unprecedented streamlined construction of many
tricyclo-[5.3.1.01,5]-undecane derivatives.
In particular, three members of the cedranoid family were
synthesized from 4a and several remarkable fragmentations that
are unique to the tricyclo-[5.3.1.01,5]-undecane skeleton were
discovered from our efforts. R-Pipitzol (2) was constructed
(racemic, five pots, 28% overall yield; enantioselective, eight
pots, 14% overall yield). This is a significant improvement over
prior efforts toward R-pipitzol (2). A formal synthesis of
R-cedrene (1) was completed (racemic, four pots, 25% overall
yield; enantioselective, seven pots, 13% overall yield), signifying
the quickest and most efficient route to date. Finally, the first total
synthesis of sec-cedranol (3) was completed (racemic, five pots,
17% overall yield; enantioselective, eight pots, 9% overall yield)
and provides the first synthetic access to the most biologically
active member of the cedranoid family.
a Reagents and conditions: (a) BF3 OEt2, Et3SiH, CH2Cl2, 94%; (b)
KOH, H2NNH2, O(CH2CH2OH)2, 125-215 °C, 52%; (c) Pb(OAc)4,
benzene, 100 °C; NaOMe, MeOH, 68%.
3
radical erasures failed to provide the desired material and instead
afforded complex mixtures of unassigned products.
With the shortcomings of the allylic acetate as a protecting
group becoming all the more evident, we now sought to exchange
it for a more robust residue by regeneration of the allylic cation 19
and interception with another oxygen nucleophile (Scheme 5).
Several alcohols were investigated. However, of those tested, prenyl
alcohol 33 afforded the highest diastereoselectivity (∼4:1) to
provide the desired product 34. Lithium aluminum hydride
reduction of the ketone 34 proceeded with addition of the
hydride occurring from the more accessible face to furnish the
alcohol 35 (6.3:1 dr). However, the product proved unstable.
Prolonged exposure of 35 to acidic media (CDCl3) resulted in a
fragmentation to afford the fused-[5.3]-decane skeleton 36
found in the hydroazulene family of natural products.26 This
Grob-like fragmentation deviates from the classical orbital
alignment, and it is suggestive of a stepwise mechanism invol-
ving formation of corresponding allylic cationic intermediate.
We were able to convert the alcohol 35 under basic conditions
into its corresponding xanthate ester, phosphite, and triflate deri-
vatives. Once again, application of the customary radical reduction
reactions with these materials failed to afford the desired com-
pound 37.
We therefore chose to settle on a route to reach R-cedrene (1)
by intercepting the penultimate intermediate 38 from the
Wender synthesis,7 by using the propensity of the allylic acetate
in 4a to ionize to our advantage. We found that addition of
’ ASSOCIATED CONTENT
Et3SiH (4.5 equiv) and BF3 OEt2 (1.5 equiv) to compound 4a
3
S
Supporting Information. Detailed experimental proce-
b
(0.01 M in CH2Cl2) cleanly erased the acetate functionality and
afforded the corresponding ketone 38. Steric hindrance prohibits
the required anti-SN20 approach of palladium required for a
formate reduction of this allylic acetate. Treatment of 38 to a
Wolff-Kishner reduction, as previously outlined by Wender,
concluded our formal synthesis of R-cedrene (1).
Fortunately, an interesting observation that was reported
during the synthesis of verbenone suggested a means for us to
address sec-cedrenol (3) from R-cedrene (1) (Scheme 6).27
During the initial step of the verbenone synthesis, oxyplumbation
of R-pinene with Pb(OAc)4 in refluxing benzene resulted in the
formation of the corresponding allylic tertiary acetate. However,
in a footnote Paquette indicated that failure to remove lead oxide
dures, spectral characterization, and X-ray data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
pettus@chem.ucsb.edu
’ ACKNOWLEDGMENT
T.R.R.P. is deeply grateful that this work has been supported
by the National Science Foundation (CHE-0806356). J.C.G.
would like to thank the Robert H. DeWolfe Fellowship for
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ARTICLE
additional support and the ACS Division of Organic Chemistry
for the invitation to present this research at their inaugural
Graduate Research Symposium.
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