Siloxacyclopentenes as dienophile-linked directing groups in intramolecular diels-alder reactions

Article abstract of DOI:10.1021/ol802266s

(Chemical Equation Presented) The synthesis and intramolecular Diels-Alder reactions of trienes 5 and 6 with a siloxacyclopentene-constrained dienophile are described. These reactions provide the primary cycloadducts 7 and 8 with high diastereoselectivity. These cycloadducts possess trans-relationships between the ring fusion proton and the adjacent C(1) alkoxy group and can be further elaborated to alcohols 9 and 11 (via protiodesilylation) or to 10 and 12 (via Fleming- Tamao oxidation) depending on the substitutent R.

Full text of DOI:10.1021/ol802266s

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5313-5316
Siloxacyclopentenes as
Dienophile-Linked Directing Groups in
Intramolecular Diels-Alder Reactions
Geoff T. Halvorsen and William R. Roush*
Department of Chemistry, Scripps-Florida, Jupiter, Florida 33458
roush@scripps.edu
Received September 29, 2008
ABSTRACT
The synthesis and intramolecular Diels-Alder reactions of trienes 5 and 6 with a siloxacyclopentene-constrained dienophile are described.
These reactions provide the primary cycloadducts 7 and 8 with high diastereoselectivity. These cycloadducts possess trans-relationships
between the ring fusion proton and the adjacent C(1) alkoxy group and can be further elaborated to alcohols 9 and 11 (via protiodesilylation)
or to 10 and 12 (via Fleming-Tamao oxidation) depending on the substitutent R.
Intramolecular Diels-Alder (IMDA) reactions of 1,3,8-
nonatrienes and 1,3,9-decatrienes have been extensively
applied to the synthesis of hexahydroindene and octahy-
dronaphthalene substructures found in a wide array of natural
products.1-4 Addition of temporary stereochemical directing
groups has been used to increase stereoselectivity of certain
IMDA reactions.5,6
Boeckman and our group introduced the steric directing
group strategy for diastereocontrol of IMDA reactions of
trienes with alkoxy substituents at the internal dienylic
position (e.g., 1). Introduction of the diene substituent “X”
in triene substrates allows for selective access to cycloadducts
in which the alkoxy substituent of the product is in a cis-
relationship with the adjacent ring fusion proton.5,6 For
example, trienes 1 (X ) Br or SiMe3) react through transition
state A to give cycloadducts 2 with excellent diastereose-
lectivity. Our group has applied this methodology to the
synthesis of chlorothricolide6-8 and spinosyn A model
systems.9,10
Complementary stereochemical control can be achieved
by locking the diene and an adjacent hydroxyl group by
way of a conformationally constraining siloxacyclopentene
unit.11 For example, trienes 3 react through transition state
B to give cycloadducts 4 in which the heteroatom is in a
trans-relationship with the adjacent ring fusion proton
(Scheme 1).
In connection with an ongoing effort in natural product
synthesis, we became interested in the possibility that use
of a dienophile-tethered siloxacyclopentene unit could pro-
(1) Ciganek, B. Org. React. 1983, 32, 1
.
(2) Craig, D. Chem. Soc. ReV. 1986, 16, 187
.
(7) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411
(8) Roush, W. R.; Brown, B. B. J. Am. Chem. Soc. 1993, 115, 2268
(9) (a) Frank, S. A.; Roush, W. R. J. Org. Chem. 2002, 67, 4316. (b)
Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157
.
(3) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 513-550.
(4) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779
(5) Boeckman, R. K., Jr.; Barta, T. E. J. Org. Chem. 1985, 50, 3421
(6) (a) Roush, W. R.; Kageyama, M. Tetrahedron Lett. 1985, 26, 4327.
(b) Roush, W. R.; Riva, R. J. Org. Chem. 1988, 53, 710. (c) Roush, W. R.;
Kageyama, M.; Riva, R.; Brown, B. B.; Warmus, J. S.; Moriarty, K. J. J.
.
.
.
.
(10) Winbush, S. M.; Mergott, D. J.; Roush, W. R. J. Org. Chem. 2008,
73, 1818
.
(11) (a) Halvorsen, G. T.; Roush, W. R. Org. Lett. 2007, 9, 2243. (b)
For related studies, see: Pidaparthi, R. R.; Welker, M. E. Tetrahedron Lett.
2007, 48, 7853.
Org. Chem. 1991, 56, 1192
.
10.1021/ol802266s CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

silylation13 or Fleming-Tamao oxidation,14 would then lead
to 9-12. Cycloadducts 10 and 12 are of considerable interest
Scheme 1
.
Stereochemical Directing Group Strategies for IMDA
Reactions
Scheme 2. Strategy for Intramolecular Diels-Alder Cyclizations
of Siloxacyclopentene-Constrained Trienes 5 and 6
vide a general strategy for control of the stereochemistry of
bicycles 9-12 (Scheme 2). On the basis of the limited
number of literature examples of IMDA reactions of trienes
with unconstrained alkoxy units allylic to the dienophile,1-4
it appears that synthetically useful control of the stereo-
chemistry of the alkoxy group relative to the ring fusion in
cycloadducts analogous to 9 and 11 cannot always be
achieved.12 In contrast, it was anticipated that IMDA
cyclizations of 5 and 6 should proceed via transition states
C and D to give trans-fused cycloadducts 7 and 8, respec-
tively, with excellent stereochemical control. The constraint
imposed by the siloxacyclopentene unit makes it impossible
for these reactions to proceed with pseudoequatorial place-
ment of the alkoxyl group, which would lead to the C(1)-
epimers of 9-12. Moreover, it was anticipated that the
IMDA cyclizations of 5 and 6 should show excellent control
for trans-ring-fused cycloadducts, as the alternative cis-fused
transition states (not shown) suffer from nonbonded interac-
tions between the diene and the dimethylsilyl unit. Elabora-
tion of the primary cycloadducts 7 and 8, either by protiode-
as they are the formal products of intramolecular Diels-Alder
reactions of enol-containing dienophiles.
We report herein the synthesis and IMDA reactions of
siloxacyclopentene-constrained trienes 5a-c and 6a-c to
illustrate this strategy. The ethylene glycol acetal units in
5c and 6c serve as excellent dienophiles under Lewis acidic
conditions.15
Synthesis of nonatrienes 5a-c began with the known
Claisen rearrangement16 of commerically available 1,4-
pentadien-3-ol (13) (Scheme 3). Aldehyde 14 was then
treated with the lithium acetylides generated from either
phenylacetylene, 2-furylacetylene, or propionaldehyde acetal
1617 to give alcohols 15a-c respectively. These intermedi-
ates were then elaborated to trienes 5a-c in good yield by
treatment with tetramethyldisilazane, followed by catalytic
potassium tert-butoxide in THF to effect intramolecular
hydrosilylation (Scheme 3).18
(12) (a) Funk has shown that decatriene i undergoes a highly stereose-
lective cycloaddition under Lewis acid promoted conditions to give
cycloadducts ii, as a result of a presumed hyperconjugation of the CsO
bond with the dienophile in the transition state. However, lower selectivity
is observed in the thermal cyclization and with the substrate lacking a TBS
protecting group: Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982, 47, 180.
(b) The IMDA cyclizations of nonatrienes iii display a less pronounced
preference for cycloadducts iW, and selectivity in this series is strongly
influenced by substituents on the tether: Suzuki, T.; Tanaka, N.; Matsumura,
T.; Hosoya, Y., Nakada, M. Tetrahedron Lett. 2006, 47, 1593.
Syntheses of decatrienes 6a-c were performed by using
similar procedures (Scheme 4). Commercially available
(13) (a) Stork, G.; Mah, R. Tetrahedron Lett. 1989, 30, 3609. (b)
Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J. M.;
Va, P.; Roush, W. R. Org. Lett. 2004, 7, 2405.
(14) Jones, G. R. Tetrahedron 1996, 52, 7599.
(15) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S. P.
J. Am. Chem. Soc. 1987, 109, 2182.
(16) Reed, S. F. J. Org. Chem. 1965, 30, 1663.
(17) Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.
(18) Maifeld, S. V.; Lee, D. Org. Lett. 2005, 7, 4995.
5314
Org. Lett., Vol. 10, No. 22, 2008

2-methoxytetrahydropyran (17) was converted into dienol
18 via the known procedure.19 Alcohol 18 was oxidized using
the Swern protocol,20 and the resulting aldehyde was treated
with the lithium acetylide generated from either phenylacety-
lene, 2-furylacetylene or 16 to give alcohols 19a-c. Prop-
argyl alcohols 19a-c were then converted to the trienes
6a-c by treatment with HN(SiMe2H)2 followed by catalytic
KOtBu in THF.18
Scheme 4. Synthesis of Decatrienes 6a-c
Scheme 3. Synthesis of Nonatrienes 5a-c
Scheme 5. Attempted Hydrosilylation of 19d
Although the results summarized in Schemes 3 and 4 (as
well as those in our previous study11) demonstrate that the
intramolecular hydrosilylation procedure, originally devel-
oped by Lee,18 works well for a range of substrates, one
limitation is for substrates like 19d (Scheme 5). Attempted
hydrosilylation of 19d under a variety of conditions gave
only small amounts (<10%) of 6d, which proved to be highly
unstable to attempted chromatographic purification, as well
as to acidic, basic, and thermal (e.g., Diels-Alder) reaction
conditions. Consequently, acetals 5c and 6c serve as sur-
rogates for conventional dienophile-activated trienes in this
study.
(H2O2, KF, KHCO3 in 1:1 THF/MeOH),14 as indicated.21,22
Remarkably, all cycloadditions were highly stereoselective
for the trans-fused cycloadducts, with no observable cis-
fused cycloadducts by 1H NMR analysis of the crude reaction
mixtures (g20:1 dr).
The intramolecular cycloaddition of phenyl-substituted
triene 5a required 7 days at 190 °C to proceed to completion
but nevertheless gave a single diastereomeric cycloadduct
1
according to H NMR analysis of the reaction mixture.
Oxidation of crude 7a under standard Fleming-Tamao
conditions gave diol 10a in 72% overall yield. The stereo-
chemistry of 10a (as with all isolated cycloadducts in this
study) was assigned by NMR methods (see Supporting
Information). Thermal cycloaddition of 2-furyl-substituted
triene 5b was also sluggish and required three days at 170
°C to go to completion. Again, standard Fleming-Tamao
oxidation of the crude cycloadduct 7b gave a single diol 10b
in 43% yield.
The results of intramolecular Diels-Alder reactions of
trienes 5 and 6 are summarized in Table 1. Thermal
cycloadditions were performed in toluene (0.03 M) in a
sealed tube in the presence of a catalytic amount of BHT.
Lewis acid promoted cycloadditions were carried out by
addition of the reagent to a solution of triene in CH2Cl2 (0.02
M) at -78 °C, and then the solution was warmed to the
final reaction temperature. In both sets of reactions, the crude
cycloadducts were subjected either to protiodesilylation
(TBAF in THF, 60 °C)13 or to Fleming-Tamao oxidation
Attempted thermal cycloaddition of triene 5c led only to
decomposition. Fortunately, TMS-OTf promoted cycload-
(21) The siloxacyclopentane units of the primary cycloadducts 7 and 8,
and especially those of ethylene glycol acetals 7c and 8c, are unstable.
Therefore, all cycloadditions were processed as described in text to give
9-12 as the isolated reaction products.
(22) Protiodesilylation of cycloadduct 7a with TBAF was unselective,
giving a ca. 1.5:1 mixture of benzylic epimers.
(19) Margo, C.; Schlosser, M. Tetrahedron Lett. 1985, 26, 1035.
(20) Tidwell, T. T. Org. React. 1990, 39, 297.
Org. Lett., Vol. 10, No. 22, 2008
5315

Table 1. Thermal and Lewis Acid Promoted Intramolecular Diels-Alder Reactions of Trienes 5 and 6
entry
substrate
R
Diels-Alder conditions
190 °C, 7 days
170 °C, 72 h
170 °C, 72 h
0.4 equiv TMS-OTf, -78 to 0 °C, 2 h
190 °C, 5 days
170 °C, 48 h
170 °C, 72 h
0.4 equiv TMS-OTf, -78 to 0 °C, 2 h
workup conditions
producta
product yield (%)b
1
2
3
4
5
6
7
8
5a
5b
5c
5c
6a
6b
6c
6c
Ph
KF, KHCO3, H2O2
KF, KHCO3, H2O2
10a
10b
10c
9c
12a
12b
11c
11c
72
43
0
85
64
45
0
2-furyl
-CH(OCH2)2
-CH(OCH2)2
Ph
2-furyl
-CH(OCH2)2
-CH(OCH2)2
TBAF, THF, 60 °C, 2 h
KF, KHCO3, H2O2
KF, KHCO3, H2O2
TBAF, THF, 60 °C, 2 h
91
a Each cycloaddition was highly diastereoselective (g20:1 by 1H NMR analysis of the crude reaction mixtures.) b Yield of cycloadducts after purification
by silica gel column chromatography.
dition of 5c proceeded smoothly at -78 to 0 °C. The
resulting cycloadduct 7c was converted to alcohol 9c (85%
yield) by treatment with TBAF in THF. Again 9c was
obtained as a single isomer by 1H NMR analysis of the crude
reaction mixture. Unfortunately, all attempts to oxidize the
carbon-silicon bond of 7c under a variety of conditions
failed to give diol 10c. All attempted oxidations of 7c under
conditions containing a fluoride source or a strong base led
only to desilylated 9c (H2O2, KF, KHCO3 in 1:1 THF/MeOH
or t-BuOOH, NaH in THF), while no reaction was observed
under milder conditions (Me3NO in DMF).
Decatrienes 6a-c behaved analogously to their nonatriene
counterparts. Thermal cycloaddition of 6a required 5 days
at 190 °C. Fleming-Tamao oxidation of the primary
cycloadduct 8a gave diol 12a in 64% yield. Thermal
cycloaddition of 6b was complete after 2 days at 170 °C.
Fleming-Tamao oxidation of 8b provided the diol 12b in
45% yield. Finally, treatment of decatriene 6c with TMS-
OTf at -78 °C with warming to 0 °C led to smooth
cycloaddition. Protiodesilylation of the primary cycloadduct
8c by treatment with TBAF in THF at 60 °C then provided
alcohol 11c in 91% yield and as a single diastereomer. All
attempts to effect Fleming-Tamao oxidation of 8c were
unsuccessful.
dronaphthalene cycloadducts 9-12 via the intramolecular
Diels-Alder cyclizations of siloxacyclopentene-constrained
trienes 5 and 6. The silacyclopentene units of 5 and 6 permit
the stereochemistry of the C(1) hydroxyl group of the
cycloadducts to be controlled relative to the ring fusion and
also serve as a handle for subsequent Fleming-Tamao
oxidation (in the case of cycloadducts 7a,b and 8a,b). Also
of interest is the ability of triene acetals 5c and 6c to undergo
TMS-OTf promoted cycloadditions to give cycloadducts 9c
and 11c after protiodesilylation of the initial products, 7c
and 8c. Applications of this new strategy for stereochemical
control of the intramolecular Diels-Alder reaction in the
synthesis of biologically active natural products synthesis
will be reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM026782) is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and full charactization data (1H NMR, 13C NMR,
IR, and HRMS) for all new compounds, as well as summaries
of stereochemical assignments for cycloadducts. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed a strategy for the
stereocontrolled synthesis of hexahydroindene and octahy-
OL802266S
5316
Org. Lett., Vol. 10, No. 22, 2008