Highly Diastereoselective Synthesis of Decalin Skeletons with Quaternary Carbon Centers via the Tandem Oxy-Cope/Ene/Claisen Reaction

Article abstract of DOI:10.1021/ol025694q

(Formula Presented) The highly diastereoselective cascade sequence of three successive thermal pericyclic reactions of 1,2-divinylcyclohexanol allyl and propargyl ethers is described. This novel tandem process provides an efficient synthesis of sesqui- an

Full text of DOI:10.1021/ol025694q

ORGANIC
LETTERS
2
002
Vol. 4, No. 8
371-1374
Highly Diastereoselective Synthesis of
Decalin Skeletons with Quaternary
Carbon Centers via the Tandem
Oxy-Cope/Ene/Claisen Reaction
1
Louis Barriault* and Irina Denissova
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
lbarriau@science.uottawa.ca.
Received February 8, 2002
ABSTRACT
The highly diastereoselective cascade sequence of three successive thermal pericyclic reactions of 1,2-divinylcyclohexanol allyl and propargyl
ethers is described. This novel tandem process provides an efficient synthesis of sesqui- and diterpenoid skeletons having a quaternary
carbon at C9.
The creation of asymmetric quaternary carbon centers is a
problem frequently encountered in diterpene synthesis.
Although there exists a broad range of methods capable of
generating new carbon-carbon bonds, the establishment of
quaternary centers in the proper configuration is among the
most restrictive in organic chemistry. Herein, we present a
new synthetic method based on tandem oxy-Cope/trans-
annular ene/Claisen reaction sequences that can generate up
to four contiguous stereogenic centers including two qua-
ternary carbons at C5 and C9 (eq 1). The thermal oxy-Cope/
ene reaction of 1 generates in situ 1,5-hexadiene enol ether
intermediate 2, which is properly set up for a subsequent
Claisen rearrangement to afford bicyclic lactol 3.
1
This cascade reaction creates a quaternary carbon at C9
and gives direct access to the core of structurally complex
diterpenes such as tetrodecamycin (4) and dihydroxychili-
olide (5) (Figure 1). The combination of pericyclic reactions
constitutes a powerful synthetic strategy to make multiple
2
carbon-carbon bonds in an efficient manner. Previous work
from this laboratory established that the tandem combination
of oxy-Cope/ene reaction of 1,2-divinylcyclohexanols results
in rapid assembly of polycyclic compounds possessing a
(
1) Reviews: (a) Christoffers J.; Mann, A. Angew. Chem., Int. Ed. 2001,
4
3
0, 4591. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
7, 388. (c) Fuiji, K. Chem. ReV. 1993, 93, 2037. (d) Martin, S. F.
Tetrahedron 1980, 36, 419.
(
2) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
b) Ziegler, F. In ComprehensiVe Organic Synthesis, Combining C-C R
Bond; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5; Chapter
(
7
1
.3. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
31.
1
0.1021/ol025694q CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/16/2002

Table 1. Tandem Oxy-Cope/Ene/Claisen Reaction of
,2-Divinylcyclohexanols Allyl and Propargyl Ether
1
Figure 1. Structure of tetrodecamycin (4) and dihydroxychiolide
5).
(
3
bridgehead alcohol. The synthetic utility of this process in
organic synthesis was demonstrated by the total synthesis
of (+)-arteannuin M.4
Initial experiments were performed using allyl ether 7 to
establish the reaction conditions (Scheme 1). Allyl ether 7
Scheme 1a
a
2 2 2
(a) SeO , THPB, CH Cl . (b) AllylBr, NaH, THF. (c) DBU
2 2
(2 equiv), toluene 220 °C. (d) TPAP, NMO, MS 4 Å, CH Cl .
3
was readily prepared from 6 via allylic oxidation followed
by etherification. Substrate 7 was dissolved in deoxygenated
toluene and DBU (2 equiv) and heated in a sealed quartz
cell at 220 °C for 1 h in a CEM microwave to give lactol 8
a
1
b
5
-7
Diastereomeric ratio was determined by 500 MHz H NMR. Dias-
in 70% yield.
We have recently demonstrated that the
c
tereomeric ratio was determined using the corresponding lactone. Dias-
tereomeric ratio was determined using the corresponding diol.
(
3) (a) Barriault, L.; Warrington, J. M.; Yap, G. P. A. Org. Lett. 2000,
2
, 663. For other examples of tandem oxy-Cope/ene reaction, see: (b)
Paquette, L. A.; Nakatani, S.; Zydowsky, T. M.; Edmondson, S. D.; Sun,
Q.-L.; Skerlj, R. J. Org. Chem. 1999, 64, 3244. (c) Rajagopalan, K.;
Srinivasan, R. Tetrahedron Lett. 1998, 39, 4133. (d) Shanmugan, P.; Devan,
B.; Srinivasan, R.; Rajagopalan, K. Tetrahedron 1997, 53, 12637. (e)
Rajagopalan, K.; Shanmugam, P. Tetrahedron 1996, 52, 7737. (f) Rajago-
palan, K.; Janardhanam, S.; Devan, B. Tetrahedron Lett. 1993, 34, 6761.
tandem oxy-Cope/ene reaction of 1,2-divinylcyclohexanols
occurs 10- to 300-fold faster when irradiated with micro-
8
waves than heating with a conventional oven.
1
13
H and C NMR and GC-MS of the reaction mixture
(
g) Rajagopalan, K.; Janardhanam, S.; Balakumar, A. J. Org. Chem. 1993,
8, 5482. (h) Chorlton, A. P.; Morris, G. A.; Sutherland, J. K. J. Chem.
Soc., Perkin Trans. 1 1991, 1205.
indicated the presence of only two diastereomers (anomeric
position). To correctly determine the diastereomeric ratio of
the tandem process, the crude lactol mixture 8 was oxidized
with TPAP to afford the corresponding lactone 9 in 70%
yield as the sole diastereomer (dr > 98%).
5
(
4) Barriault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925.
(5) For review on microwaves in organic synthesis, see: (a) Loupy, A.;
Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Math e´ , D. Synthesis
995, 1213. (b) Majetich, G.; Hichs, R. J. J. MicrowaVe Power Electromagn.
Energy 1995, 30, 27. (c) Loupy, A.; Perreux, L. Tetrahedron 2001, 57,
1
9
2
199. (d) Lidstr o¨ m, P.; Tierny, J.; Wathey, B.; Westman, J. Tetrahedron
001, 57, 9225.
(7) Typical Procedure. A solution of 7 (80 mg, 0.36 mmol) in dry
deoxygenated toluene (10 mL) and DBU (110 mg, 0.72 mmol) was heated
in a quartz tube (previously washed with aqueous 2-propanol/NaOH solution,
water, and acetone) for 60 min for at 220 °C. The solution was cooled to
room temperature, and the solution was transferred and concentrated. The
residue was purified by flash chromatography (20% ethyl acetate in hexanes)
to afford 8 as colorless oil (60 mg, 75%).
(6) Nonpolar solvents such as toluene do not absorb microwaves;
therefore, a glass coated ferrite disk was placed inside the reaction cell.
Ferrite readily absorbs microwaves energy and transmits heat to the reaction
mixture through conduction. This microwave oven is equipped with fiber
optic probes placed inside the reaction cell to monitor the temperature and
pressure of the reaction.
(8) Deon, D. H., M.Sc. Thesis, University of Ottawa, 2001.
1372
Org. Lett., Vol. 4, No. 8, 2002

Figure 2. Proposed mechanism of the tandem oxy-Cope/ene/Claisen reaction.
Depending on the pattern of substitution on the terminal
allyl ether, additional tertiary or quaternary carbons adjacent
to C9 can be introduced onto the molecule.
27. Finally, the Claisen rearrangement proceeds anti to the
bridgehead alcohol at C5 to afford the desired bicyclic
product 17.
To prove this, differentially substituted allyl and propargyl
ethers were prepared according to Scheme 1. The ethers were
heated in toluene to give the corresponding lactols in 60-
To support the proposed mechanism, ether 28 was heated
at 220 °C for 1 h (Scheme 2). H NMR of the crude reaction
1
98% yield (Table 1). We were pleased to observe that the
tandem process is highly diastereoselective in all cases.
Indeed, the thermal transformation of 10 and 11 (entries 1
and 2) led to one-pot stereocontrolled syntheses of lactol 17
and 18 each possessing four contiguous stereogenic centers
Scheme 2
9
in 75% and 60% yield, respectively (dr > 98%). NMR
spectroscopy and X-ray analysis established the relative
configuration of the bicyclic products.
On the basis of these results, we turned our attention
toward the generation of a bicyclic core having two contigu-
ous quaternary centers at C9 and C11. Heating 12 at 200 °C
for 60 min gave the desired lactol 19 in 76% (entry 3).
Interestingly, enol ether 20 was isolated as a single isomer
in 15% yield (E/Z > 98%). Completion of the reaction
involves a prolonged exposure of 20 to heat, which resulted
in the formation of degradation products.
The high diastereoselectivity of this triple tandem reaction
can be explained by the mechanism depicted in Figure 2.
At first glance, the thermal oxy-Cope rearrangement of 10
leads to enol 25, which tautomerizes in situ to produce the
ketone 26. This ketone can adopt two chairlike conformations
at the transition state, A and B. A close examination of the
transition state B reveals a pseudo-1,3-diaxial O-allyl-ring
methylene interaction. Therefore, this favors the transition
state A over B as the reactive conformer to provide the enol
mixture indicated the formation of only one enol ether 29
1
0
(E/Z > 98%). This result confirms without ambiguity the
highly diastereoselective transannular ene reaction in the
tandem process.
Encouraged by these results, the synthesis of two contigu-
ous asymmetric quaternary carbons was investigated. Con-
trary to all expectations, the treatment of 13 under thermal
conditions gave 21 as the sole isomer (dr at C9 > 98% and
E/Z ) 89:11) (entry 4). The formation of this lactol can be
rationalized via a competitive 1,3-type rearrangement of the
enol intermediate 13a (Scheme 3) to give the rearrangement
1
1
product 21. The mechanism of this rearrangement is
currently under investigation. In the propargyl ether series
14 and 15, respectively, (Table 1, entries 5 and 6) gave upon
heating at 220 °C exclusively the expected tricyclic allene
(
9) It was observed that a prolonged exposure of 17 (entry 1) with DBU
(10) The olefin geometry was established by NOE experiment.
(11) The structure of 21 was elucidated by 2D-NMR COSY and NOESY
experiments.
at 220 °C resulted in a partial epimerization at C11 (23%). The replacement
of DBU by triethylamine afforded 17 in 75% without epimerization at C11.
Org. Lett., Vol. 4, No. 8, 2002
1373

In summary, we have developed a highly diastereoselective
tandem process based on a sequence of three successive
pericyclic reactions. The isolation of enol ether intermediates
Scheme 3
2
0 and 29 having an E olefin geometry strongly supports
the proposed mechanism depicted in Figure 2. This strategy,
which offers a simple and efficient method for the synthesis
of a bicyclic ring having a quaternary center at C9, is
currently being used in the total synthesis of tetrodecamycin
(4) and dihydroxychiliolide (5).
Acknowledgment. Financial support from the University
of Ottawa, NSERC, Canada Foundation for Innovation,
Ontario Innovation Trust, Bristol-Myers Squibb (Candiac,
Qu e´ bec), and Merck-Frosst is gratefully acknowledged.
Supporting Information Available: Spectroscopic data
for compounds 7-24, 28, and 29, the corresponding lactones
of 17, 18, 21-23 and the corresponding diol of 19, and
ORTEP views of the corresponding lactone of 17 and 18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2
2 and 23 in 98% and 68% yield. Interestingly, the thermal
tandem process of 16 provided tetracyclic acetal 24 (entry
) in 81% yield. This is rationalized by a subsequent addition
of the lactol hydroxyl moiety on the allene. The structures
7
1
13
of 22, 23, and 24 were established by H and C NMR
experiments.
OL025694Q
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Org. Lett., Vol. 4, No. 8, 2002