Intramolecular condensation via an o-quinone methide: Total synthesis of (±)-heliol

Article abstract of DOI:10.1021/ol301092w

An acid-catalyzed intramolecular [4 + 2] cycloaddition of a non-natural bisabolene is reported. The key cyclocondensation was developed to access cyclic sesquiterpenes from linear phenolic precursors by generating a reactive o-quinone methide intermediate to initiate a cascade reaction. The new method was applied to the first total synthesis of (±)-heliol.

Full text of DOI:10.1021/ol301092w

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2929–2931
Intramolecular Condensation via an
o-Quinone Methide: Total Synthesis
of (()-Heliol
Jason C. Green, Eric R. Brown, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
pettus@chem.ucsb.edu
Received April 24, 2012
ABSTRACT
An acid-catalyzed intramolecular [4 þ 2] cycloaddition of a non-natural bisabolene is reported. The key cyclocondensation was developed to
access cyclic sesquiterpenes from linear phenolic precursors by generating a reactive o-quinone methide intermediate to initiate a cascade
reaction. The new method was applied to the first total synthesis of (()-heliol.
Nature has produced an array of cyclic natural products
from the bisabolene skeleton manifested in curcuphenol (6)
(Scheme 1).1 The major distinction between each sesquiter-
Scheme 1. Variations of the Bisabolene Framework
pene is the resulting connectivity across the original prenyl
functionality, producing an assortment of three- to eight-
membered rings (1ꢀ5, 7ꢀ11).2 For some time, we have seen
this array as a remarkable opportunity for chemical study in
the hopes of developing new dearomatization methods that
might access members of these structurally related natural
products from a common linear phenolic system in a
selective fashion.
One of our first studies delved into the biosynthesis of
helianane, the putative des-hydroxy des-phenoxy
(1) (a) Bohlmann, F.; Lonitz, M. Chem. Ber. 1978, 111, 843–952. (b)
Wright, A. E.; Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.;
McCarthy, P. J. J. Nat. Prod. 1987, 50, 976–978. (c) Fusetani, N.;
Sugano, M.; Matsunaga, S.; Hashimoto, K. Experientia 1987, 43,
1234–1235. (d) Butler, M. S.; Capon, R. J.; Nadeson, R.; Beveridge,
A. A. J. Nat. Prod. 1991, 54, 619–623.
(2) (a) Irie, T.; Suzuki, M.; Hayakawa, Y. Bull. Chem. Soc. Jpn. 1969,
42, 843–844. (b) Ishikawa, N. K.; Yamaji, K.; Tahara, S.; Fukushi, Y.;
Takahashi, K. Phytochemistry 2000, 54, 77–782. (c) Ishikawa, N. K.;
Fukishi, Y.; Yamaji, K.; Tahara, S.; Takakashi, K. J. Nat. Prod. 2001,
64, 932–934. (d) Suzuki, M.; Kurosawa, E. Tetrahedron Lett. 1978, 28,
2503–2506. (e) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo,
J. M. G.; Fronzek, F. R. Tetrahedron Lett. 1993, 34, 1999–2002. (f) We
assigned the name “heliol” to a natural product reported in: de Nys,
R.; Coll, J. C.; Bowden, B. F. Aust. J. Chem. 1992, 45, 1611–1623.
(g) Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–2648.
(h) Jakupovic, J.; Warning, U.; Bohlmann, F.; King, R. M. Rev. Latinoam.
enantiomeric antipode of heliannuol A (7).3 Our attempts
ultimately led to the repudiation of the entire helianane
familyand a new putative biosynthesisfor heliannuol D (4)
and A (7). The efforts also provided syntheses of the
(3) Green, J. C.; Jiminez-Alonso, S.; Brown, E. R.; Pettus, T. R. R.
Org. Lett. 2011, 13, 5500–5503.
Quim. 1987, 18, 75–76. (i) Walter, P. Annalen 1841, 39, 246.
r
10.1021/ol301092w
2012 American Chemical Society
Published on Web 05/31/2012

benzopyran natural products 8 and 9 and three cedrenoids
from linear phenolic precursors.4
Figure 2. Synthesis of various diol precursors.
Figure 1. Proposed cyclocondensation reaction.
heated to 80 °C for 10.5 h, the yield of 15a increased to 91%
(Table 1, entry 2). Optimal conditions, 1.1 equiv of the acid
at 80 °C, afforded the desired product in 93% yield in 15 min
(Table 1, entry 4). The cyclization could be carried out in
open atmosphere, and the reaction consistently afforded
excellent yields on both millimolar and molar scales.
Continuing along in this direction, we imagined that
access to structures resembling laurinterol (1), enokipodin
A (2), 3, or heliol (5) would require the development of a
new procedure to render the benzylic position as an
electrophile so that the prenyl residue might serve as an
intramolecular nucleophile. We devised that the non-natural
phenol 12a, which possesses a terminal olefin and a tertiary
benzylic alcohol, should undergo an acid-catalzyed, step-
wise, intramolecular [4 þ 2] cycloaddition to afford the
desired 3,4-benzo-fused 2-oxabicyclo[3.3.1]nonane frame-
work found in the structure 15a (Figure 1).
Table 1. Acid-Catalyzed Cyclocondensation
The syntheses of the starting diol 12a and various
analogues are described in Figure 2. The alkyl iodide 17
was accessed by a known four-step sequence from methal-
lyl alcohol 16.5 The resulting alkyllithium was added to a
number of commercially available acetophenones 18a-d
(R = CH3) and salicylaldehydes18eꢀi (R = H). Variation
at the benzylic position was accomplished by oxidation of
diol 12e (R1 = H, X = H) with MnO2 followed by addi-
tion of the appropriate organolithium or Grignard reagent
to ketone 19, thereby arriving at the respective tertiary
benzyl alcohols 12jꢀm.
TsOH
product
3
entry
1
H2O (equiv)
temp (°C)
time
30 h
(yield, %)
0.1
25
15a (35)
14 (29)
13 (9)
2b
3
4c
0.1
1.1
1.1
80
25
80
10.5 h
19.5 h
15 min
15a (91)
15a (91)
15a (93)
a Reaction conditions: 12a (0.05 M in CH3CN), p-TsOH H2O, open
Next, we turned our attention toward affecting the
desired intramolecular cyclization (Table 1). We found
that numerous Lewis and Brønsted acids served to cata-
lyze the desired cyclocondensation in good yields. We
3
to the atmosphere at designated temperature. b Catalytic procedure.
c General procedure.
Various neutral and electron-donating substituents on
the aromatic ring were tolerated under the reaction condi-
tions (Figure 3, 15bꢀd). Removal of the benzylic methyl
substituent slightly diminished the yield to afford com-
pounds 15eꢀi. Ethyl, isopropyl, vinyl, and aryl substitu-
tion at the benzylic junction similarly afforded high yields
of the desired cycloadducts 15jꢀm.
chose toluenesulfonic acid hydrate (TsOH H2O) in aceto-
3
nitrile for its simplicity and ease of use. Catalytic amounts
(0.1 equiv) of the acid afforded a mixture of the desired
cycloadduct 15a (35%) and cyclohexenes 13 (9%) and 14
(29%) (Table 1, entry 1). When the identical reaction was
(4) Green, J. C.; Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133, 1603–
1609.
(5) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org.
Chem. 1994, 59, 4172–4178.
While testing the reaction scope, we found that the
monosubstituted olefin 20 failed to participate in the cycli-
zation (Figure 4). This observation provides additional
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Org. Lett., Vol. 14, No. 12, 2012

Figure 5. Total synthesis of (()-heliol (5).
Application to the total synthesis of (()-heliol (5) began
by iodination of 3-pentyn-1-ol 23 (Figure 5). Enyne cross
metathesis of this product with ethylene provided the
diene 25. Upon undergoing lithiumꢀhalogen exchange
by the addition of tert-butyllithium to diene 25, addition
to 2-hydroxy-4-methylacetophenone 18d afforded the diol
26. Subjecting this material to the cyclization conditions
resulted in formation of the methylenated tricycle 27 in
91% yield. Ozonolysis of the exocyclic olefin followed by
reductive workup furnished ketone 28. Reduction of the
ketone with LiAlH4 provided 3-epi-heliol as the major
diastereomer. Stereochemical inversion of the secondary
alcohol afforded (()-heliol (5), which was identical in all
spectroscopic respects to the natural product.
In conclusion, we developed an acid-catalyzed, stepwise,
cyclocondensation reaction involving an o-quinone methide
intermediate as means to access the 3,4-benzofused
2-oxabicyclo[3.3.1]nonane skeleton. We examined the scope
of this cyclocondensation and demonstrated its utility with
the first total synthesis of (()-heliol (5).
Figure 3. Analogues made from respective starting materials
12bꢀm. Isolated yields given in parentheses.
support to the stepwise mechanism postulated within
Figure 1 that involves the tertiary cationic intermediate D.
Reduction of the tether length, as shown with diol 21,
resulted in the formation of the seven-membered ether 22
as the major product.
Acknowledgment. We are deeply grateful for past
support from the National Science Foundation (CHE-
0806356).
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 4. Observed limitations.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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