Diastereoselective phenol para-alkylation: Access to a cross-conjugated cyclohexadienone en route to resiniferatoxin

Article abstract of DOI:10.1021/ol0480832

(Chemical Equation Presented) We document a route for the synthesis of a densely functionalized spiro-fused 2,5-cyclohexadienone as an intermediate for the synthesis of resineferatoxin. The strategy is based on an unprecedented diastereoselective, intramolecular phenol para-alkylation to a cross-conjugated cyclohexadienone. In the course of these synthetic studies we developed rapid access to a chiral nitrile possessing a quaternary stereocenter and disclose an unusual acetal rearrangement from a dioxane, which favors the corresponding dioxepane.

Full text of DOI:10.1021/ol0480832

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4371-4374
Diastereoselective Phenol
para-Alkylation: Access to a
Cross-Conjugated Cyclohexadienone en
Route to Resiniferatoxin
Tobias Ritter, Pablo Zarotti, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg, HCI, H335,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received September 20, 2004
ABSTRACT
We document a route for the synthesis of a densely functionalized spiro-fused 2,5-cyclohexadienone as an intermediate for the synthesis of
resineferatoxin. The strategy is based on an unprecedented diastereoselective, intramolecular phenol para-alkylation to a cross-conjugated
cyclohexadienone. In the course of these synthetic studies we developed rapid access to a chiral nitrile possessing a quaternary stereocenter
and disclose an unusual acetal rearrangement from a dioxane, which favors the corresponding dioxepane.
The diterpene natural product resiniferatoxin (1, Figure 1)
is a prominent member of the daphnane structure class, in
field of organic synthesis over the past 30 years, resulting
in completed total syntheses of both resiniferatoxin and
phorbol.2 We have demonstrated that the daphnane structure
class could be accessed quickly through the photorearrange-
ment of tricyclic cross-conjugated 2,5-cyclohexadienones (eq
1).3,4 In this letter we report our results in the development
Figure 1. The daphnane resiniferatoxin with a cyclohexadienone.
and synthesis of densely functionalized bicyclic cyclohexa-
dienone-ring systems in our efforts to gain fast access to a
variety of different photoprecursors for their use in the
synthesis of daphnanes and tiglianes. In the course of the
synthetic studies we have made a number of interesting
observations: (1) a highly diastereoselective para-alkylation
large part because of its high irritant activity.1 The structurally
related tigliane phorbol has inspired great innovation in the
(1) (a) Appendino, G.; Szallasi, A. Life Sci. 1997, 60, 681. (b) Szallasi,
A.; Blumberg, P. M. Pain 1996, 68, 195.
10.1021/ol0480832 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/13/2004

of a phenol, (2) the use of a chiral nitrile-substituted dioxane
to establish a quaternary center, and (3) an unusual rear-
rangement of a hydroxylmethyl-substituted dioxane that
favors the formation of the seven-memberred ring acetal.
As part of a projected investigation of the photochemistry
of cross-conjugated cyclohexadienones in the context of the
synthesis of resineferatoxin and analogues, we designed a
strategy to access a highly functionalized carbocyclic core
distinct from the route we had previously employed for the
tricyclic system. We aimed at a route in which an intramo-
lecular, diastereoselective phenol para-alkylation5 would
generate the requisite bicyle incorporating the cyclohexadi-
enone chromophore. In this approach the stereogenic center
C-11 (Figure 2, resiniferatoxin numbering) would be set by
Unlike the reported uses of this elegant chemistry in which
the nitrile is excised to give a methine stereocenter, however,
we aimed to retain the quaternary stereocenter and transform
the nitrile into an aldehyde. The synthesis of 9 commenced
with commercially available (S)-3-hydroxy butyric acid ethyl
ester (3) (Scheme 1). The hydroxyl butyrate was protected
Scheme 1
as its trimethylsilyl ether, and the resulting ester was reduced
to the aldehyde (DIBALH). Subsequent cyanide-catalyzed
trimethylsilyl cyanide addition to the aldehyde followed by
ketal formation afforded the two diastereomeric acetonides
4 and 5 in 75% combined yield over four steps. Alkylation
of the derived nitrile enolate with benzyl chloromethyl ether
(BOMCl) afforded the desired ether 6 in 60% yield as a
Figure 2. Retrosynthetic analysis for the formation of the
cyclohexadienone via diastereoselective Winstein alkylation.
1
single diastereomer as assayed by analysis of the H NMR
appropriate selection of the starting material 2 and trans
formed to the product through an invertive displacement. By
contrast, the configuration at the quaternary center necessarily
needs to be controlled in the alkylation reaction. Our previous
study provided little guidance in this respect, because the
bicyclic intermediate dictated the facial selectivity in the
intramolecular alkylation. A stereoselective phenol para-
alkylation in an unconstrained acyclic intermediate has not
been previously addressed, and thus we became interested
in investigating the stereochemical consequences of this
critical step.
spectrum. The reaction sequence (3 f 6) could conveniently
be accomplished on a 100-g scale. Further functionalization
of the benzyl-protected primary alcohol ultimately required
cleavage of the benzyl ether. We found this deprotection step
to be problematic under reductive conditions (Na/NH3, H2/
Pd) at this as well as at later stages in the synthesis. However,
7
selective C-H oxidation using RuO4/NaIO4 transformed the
benzyl ether to the corresponding benzoate 7. Reduction of
this benzoate with DIBALH and protection of the resulting
alcohol as its tert-butyldimethylsilyl ether afforded nitrile 8
in 88% yield. Nitrile reduction to aldehyde 9 using DIBALH,
a common reducing agent for this transformation,8 afforded
the product in only 30-40% yield. However, using the alum-
inate complex formed from n-BuLi and DIBALH,9 the de-
sired aldehyde could be isolated in 94% yield.
The synthesis of the requisite coupling partner for 9, cin-
namyl bromide 10, was pursued next (Scheme 2). The syn-
thesis started with regioselective acetylation of inexpensive
3,4-dihydroxybenzaldehyde (11) to afford the mono 3-acyl
ester along with its 4-acyl regioisomer as a 9:1 mixture in
66% yield after recrystallization. Protection of the residual
phenol group as its methanesulfonic acid ester yielded ben-
zaldehyde 12. Horner-Wadsworth-Emmons reaction with
In selecting a viable route to the C-8-C-11 fragment (2,
Figure 2), we decided to employ the method developed by
Rychnovsky for the synthesis of protected 1,3-diol units.6
(2) Phorbol: (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams,
P. D. J. Am. Chem. Soc. 1989, 111, 8954. (b) Wender, P. A.; Kogen, H.;
Lee, H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem.
Soc. 1989, 111, 8957. (c) Wender, P. A.; Rice, K. D.; Schnute, M. E. J.
Am. Chem. Soc. 1997, 119, 7897. (d) Lee, K.; Cha, J. K. J. Am. Chem.
Soc. 2001, 123, 5590. Resiniferatoxin: Wender, P. A.; Jesudason, C. D.;
Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997,
119, 12976.
(3) Jackson, S. R.; Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira,
E. M. Angew. Chem., Int. Ed. 2001, 40, 2694.
(4) For the closely related photorearrangement of R-santonin, see: (a)
Barton, D. H. R.; DeMayo, P.; Shafiq, M. J. Chem. Soc. 1957, 929; J.
Chem. Soc. 1958, 141; J. Chem. Soc. 1958, 3314; Proc. Chem. Soc. 1957,
205. (b) Arigoni, D.; Bosshard, H.; Bruderer, H.; Bu¨chi, G.; Jeger, O.;
Krebaum, L. J. HelV. Chim. Acta 1957, 40, 1732.
(5) Winstein, S.; Baird, R. J. Am. Chem. Soc. 1957, 79, 756.
(6) (a) Rychnovsky, S. D.; Zeller, S.; Skalitzky D. J.; Griesgraber, G. J.
Org. Chem. 1990, 55, 5550. (b) Rychnovsky, S. D.; Griesgraber, G. J. Org.
Chem. 1992, 57, 1559. (c) Rychnovsky, S. D.; Powers, J. P.; LePage, T. J.
J. Am. Chem. Soc. 1992, 114, 8375.
(7) (a) Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838. (b)
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem.
1981, 46, 3936.
(8) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th
ed.; John Wiley & Sons: New York, 2001; p 1204.
(9) Sunggak, K.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717.
4372
Org. Lett., Vol. 6, No. 23, 2004

because 1,3-syn-diaxial interactions in the [1,3]-dioxane ring
are avoided in the corresponding five-membered hetero-
cycle.12 To our surprise, acid-catalyzed rearrangement of 19
did not afford the expected [1,3]-dioxolane 20 but instead
[1,3]-dioxepane 21 in 80% yield. In seven-membered car-
bocycles, an important source of strain results from tran-
sannular interactions wherein substituents on opposite sides
of the ring may approach within van der Waals distances.
This unfavorable interaction is in large part responsible for
the strain energy of cycloheptane of 6.2 kcal/mol.13 In [1,3]-
dioxepanes this transannular interaction is in part attenuated,
because one hydrogen atom in the carbocycle is replaced
by a lone pair in the heterocycle. The observation of the
unusual ketal rearrangement was fortuitously exploited in
the synthesis of diol 22 (Scheme 3). Isopropylidene ketal
Scheme 2
Scheme 3
trimethyl-phosphono acetate10 furnished ethyl cinnamate 13
in 99% yield. Methanolysis of the acetate followed by
O-allylation gave 14 in 72% yield over two steps. Claisen
rearrangement proceeded smoothly in refluxing p-cymene.
Ethylation of the phenol functionality gave ethyl cinnamate
16, which was reduced to cinnamyl alcohol 17 (60% yield
over three steps). Treatment of this alcohol with mesyl
anhydride and LiBr furnished cinnamyl bromide 10. The use
of the mesylate as a phenol protecting group in 10 is essential
for the stability of the cinnamyl bromide.11
Treatment of 10 with activated zinc in DMF at -20 °C
furnished an intermediate allyl zinc, which underwent addi-
tion to aldehyde 9 to afford 19. It was most convenient to
determine the yield of the addition reaction following de-
silylation; thus 18 was isolated in 41% yield, after two steps.
Initially, we envisaged rearranging the six-membered
isopropylidene ketal 19 to the five-membered isopropylidene
ketal 20 (eq 2). Such rearrangements are generally favorable,
18 underwent acid-catalyzed rearrangement to the corre-
sponding dioxepane, and the resulting diol protected with
benzaldehyde dimethyl acetal to give dioxepane 23. To
confirm the structure of the initially formed rearrangement
product, [1,3]-dioxepane 24 was prepared by HCl-catalyzed
ketal transposition of diol 18.
1
Analysis of the H NMR and COSY NMR spectra of 24
gave instructive information about the conformation of the
(10) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499. (b) Wadsworth, W.; Emmons, W. D. J. Am. Chem.
Soc. 1961, 83, 1733. (c) Blanchette, M. A.; Choy, W.; Davis, J. T.;
Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(11) Ritter, T.; Stanek, K.; Larrosa, I.; Carreira, E. M. Org. Lett. 2004,
6, 1513.
(12) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons: New York, 1994; p 758. (b) Angyal, S. J.; Beveridge,
R. J. Carbohydr. Res. 1978, 65, 229.
(13) Anet, F. A. L. Medium-Sized Oxygen Heterocycles. In Conforma-
tional Analysis of Medium Sized Heterocycles; Glass, R. S., Ed.; VCH
Publishers: New York, 1988.
Org. Lett., Vol. 6, No. 23, 2004
4373

dioxepane. Strong W-coupling of 2.5 Hz between the two
equatorial hydrogen atoms of both methylene groups in the
seven-membered ring indicated a rigid chair conformation.
Subsequent acid-catalyzed methanolysis of the more labile
isopropylidene ketal in the presence of the benzylidene acetal
in 23 furnished diol 22. LDA-mediated cleavage of the aryl
methanesulfonate11 to phenol diol 25 followed by selective
bisbenzoylation afforded 26.
pentane-like interaction renders B significantly higher in
energy with respect to A and thus accounts for the high
selectivity. Of additional importance, careful choice of
solvent mixture and base proved essential to obtain the
optimized reaction outcome. The use of methanol as solvent
accelerated the reaction but delivered substantial amounts
of material resulting from double-bond isomerization to
produce conjugated enone 28 (eq 4) (ratio 27 to 28: 2/3).
For the crucial phenol para-alkylation, the secondary
alcohol in 26 needed to be converted into a good leaving
group. After sulfonylation of the alcohol as its 3,5-bistri-
fluoromethylbenzenesulfonate ester, the key transformation
could be promoted by K2CO3 in 2-propanol/ethanol at 23
°C, and the desired spirocycle 27 could be isolated in 95%
yield over two steps (eq 3). Most importantly, the reaction
The same observations could be found with ethanol as
solvent, albeit to a smaller extent (ratio 4/1). 2-Propanol
dramatically reduced the overall rate of reaction and thus
was not practical. K2CO3 was found to be the optimal base,
because weaker bases such as triethylamine did not initiate
the reaction and stronger bases such as NaOMe, KOt-Bu,
and Cs2CO3 resulted in double-bond isomerization.
In conclusion, we have documented a route that provides
rapid access to densely functionalized spiro-fused cyclo-
hexadienones through a novel series of transformations. Key
to the successful approach was a highly diastereoselective
phenol para-alkylation, which affords the desired spirocycle
as a single diasteomer in 95% yield, generating an otherwise
difficult-to-prepare quaternary center. The combination of
the phenol alkylation with the unexpected formation of a
dioxepane-derived acetal and the nitrile alkylation chem-
istry yields a serviceable strategy. We are in a position to
prepare a variety of cyclohexadienones and examine their
behavior in photorearrangement reactions to provide useful
intermediates for the synthesis of daphnane and tigliane
structures.
afforded the product including a new quaternary stereogenic
center diastereoselectively. Hence, the product cyclohexa-
dienone was isolated as a single isomer as assayed by H
NMR. The observed selectivity at the quaternary stereocenter
can be rationalized by analysis of the two diastereomeric
transition states depicted in Figure 3. An unfavorable syn-
1
Acknowledgment. We thank the Swiss National Science
Foundation and F. Hoffmann-La Roche Ltd., as well as
Merck & Co., Inc. and Eli Lilly and Company. T.R.
thanks the Fonds der Chemischen Industrie for a Kekule´
Fellowship.
Supporting Information Available: Experimental de-
tails and characterization for new compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Rationale for the selectivity in the phenol para-alkylation
illustrated by the diastereomeric transition states A and B.
OL0480832
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Org. Lett., Vol. 6, No. 23, 2004