Asymmetric syntheses of pectenotoxins-4 and -8, Part II: Synthesis of the C20-C30 and C31-C40 subunits and fragment assembly

Full text of DOI:10.1002/1521-3773(20021202)41:23<4560::AID-ANIE4560>3.0.CO;2-B

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product syntheses[5] and as novel scaffolds for combinatorial
libraries.[6]
To examine the facility of this process, a series of
oxabicyclo[3.2.1]octan-3-one derivatives with an olefinic teth-
er at the bridgehead were prepared by oxyallyl cation
cycloaddition of 2-substituted furans (Scheme 2). Reaction
Synthesis of Functionalized Pyrans by Domino
Metathesis Reaction of Oxabicyclo Derivatives:
Dramatic Effect of Remote Substituents on
Reactivity and Selectivity**
Lynn C. Usher, Maria Estrella-Jimenez,
Ion Ghiviriga, and Dennis L. Wright*
O
O
O
Highly substituted pyrans are a common structural feature
found in natural products and have been the focus of many
synthesis studies.[1] They are often present as an integral part
of macrocyclic structures of marine origin. We previously
reported[2] a general method for the preparation of cis-2,6-
disubstitued-4-pyrones through the intermolecular ring-open-
ing cross-metathesis reaction of 8-oxabicyclo[3.2.1]octene
derivatives, which are conveniently prepared by the [4þ3]
cycloaddition between furan and an oxyallyl cation equiv-
alent.[3] A more advanced variation occurs when the donor
olefin is tethered to the bicyclic ring system. The second
metathesis process would effect a ring closure, thereby
resulting in the synthesis of annulated pyran systems. In
principle, there are three manifolds for this bond-reorganiza-
tion process, determined by placement of the tether
(Scheme 1).[4]
O
Cl
CHCl2
Cl
R
ClH2C
CF3
Zn(Cu)
NH4Cl
R
R
CH2ONa
CF3CH2OH
O
O
3a-d
2a: R = (CH2)2CH=CH2
2b: R = (CH2)3CH=CH2
2c: R = CH2OCH2CH=CH2
2d: R = (CH2)4CH=CH2
4a, 69% for two steps
4b, 72% for two steps
4c, 65% for two steps
4d, 68% for two steps
Scheme 2. Synthesis of substituted bicyclic ethers.
of the furans under the conditions of Fˆhlisch et al.[7] led to a
smooth conversion into the oxabicyclo[3.2.1]octenes 3a d.
Direct dechlorination upon exposure to zinc copper couple
gave the metathesis precursors 4a d in good yields. With a
series of dienes in hand, we were able to study the domino
metathesis process (Table 1).
Table 1. Synthesis of spirocyclic pyrans.
Type I
Type II
Type III
O
Alkene
Product[a]
Yield [%][b]
56 (16)
O
3
O
2
4a
4b
5a
5b
1
O
O
O
O
N
N
Mes
Cl
Mes
Ru
1
82 (10)
Ph
Cl
PCy3
O
O
O
O
O
4c
4d
5c
5d
80
spiro
bridged
linear
Scheme 1. Synthesis of fused pyrans by metathesis-promoted bond reor-
ganization.
< 15 (44)[c]
A type I bond-reorganization process would arise if the
tether was attached at C3, leading to the synthesis of bridged
fused pyrans. Placement of the tether at C2 leads to a linear
fused system, whereas a type III cyclization from the C1
position would lead to spiro-fused pyrans. Herein, we wish to
report our studies on the type III cyclization and the dramatic
influence of remote substituents on the domino process. These
compounds are of interest as building blocks for natural
[a] Reaction conditions: substrate in CH2Cl2 (0.01m), 1 (2 mol%). [b] Yield
of recovered starting material in parentheses. [c] The dimer was also
isolated (38%).
Exposure of a dilute solution of the dienes 4a c to the
Grubbs catalyst 1[8] led to rearrangement to the corresponding
five- and six-membered spirocycles 5a c in good yield.
Cyclization to form the seven-membered homologue 5d was
extremely poor, the major product arising from dimerization
of the terminal vinyl groups. Furthermore, much of the
starting alkene was recovered unchanged. Increased catalyst
or elevated temperatures did little to improve the yield of the
reaction.
[*] Prof. Dr. D. L. Wright, L. C. Usher, M. Estrella-Jimenez,
Dr. I. Ghiviriga
Department of Chemistry, University of Florida
Gainesville, FL 32611-7200 (USA)
Fax : (þ 1)352-846-0296
E-mail: dwright@chem.ufl.edu
[**] We thank the National Science Foundation for support of this work.
MEJ thanks the University of Florida for a graduate minority
fellowship. We thank Professor Merle A. Battiste and Professor
William R. Dolbier for helpful discussions.
This method is also compatible with the analogous oxabi-
cyclo[2.2.1]heptene derivatives leading to perhydro-spirofur-
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ans. The substrates were easily prepared from furans 2a d by
Diels Alder reaction with N-phenylmaleimide. The major exo
adducts were treated with the Grubbs catalyst to trigger
rearrangement (Table 2). The reactions of these derivatives
delivered the rearranged furans 7a d in moderate to excellent
yields. Again, five- and six-membered cyclizations were the
most efficient. Interestingly, the formation of the seven-
membered ring 7d was significantly better in this series. This
could be related to the enhanced reactivity of the more
strained oxabicyclo[2.2.1]heptene nucleus.
N
N
Mes
Ph
Mes
Cl
O
1
Ru
8a: R=CH3
8b: R=CH2OCH3
8c: R=CH2OCH2CH2CH3
Cl
trace amounts
of product
PCy3
R
O
Ph
Scheme 4. Attempted ring-opening of substituted systems.
offered an opportunity to probe these regiochemical issues
(Scheme 4).
Surprisingly, exposure of the substituted compounds 8a c
to catalyst and styrene gave only trace amounts of product,
even after prolonged reaction times and elevated temper-
atures. In fact, the compounds could not even be forced to
undergo ROMP in refluxing toluene. The inability to effect
ring-opening of these systems may be related to shielding of
the exo face of the olefin by the bridgehead group. This
suggests that the intramolecular reaction proceeded by initial
reaction with the terminal olefin. Since ensuing attack at the
bridge alkene would be intramolecular, it would be less
sensitive to these steric effects.
In previous studies,[2] an unusual influence of the group at
C3 was observed: reduction/silylation of the ketone greatly
increased the reactivity of the bicyclic alkene towards ring
opening. It seemed possible that this remote effect may be
used to induce reactivity in the unreactive olefins. To examine
this possibility, a series of reduced derivatives was prepared[11]
and subjected to metathesis conditions (Table 3).
Table 2. Synthesis of spirocyclic perhydrofurans.
Alkene
Product[a]
Yield [%][b]
6a
6b
7a
7b
84
78
6c
6d
7c
7d
95
Table 3. Intermolecular cross-metathesis of reduced derivatives.
54 (19)
N
N
Mes
Mes
Cl
Cl
Y
X
Ru
Y
X
Y
X
1
Ph
PCy3
R
R
[a] Conditions: substrate in CH2Cl2 (0.01m), 1 (2 mol%). [b] Yield of
recovered starting material in parentheses.
R
O
Ph
O
Ph
Ph
O
11a–e
10a–e
9a–e
Alkene[a]
R
X
Y
Yield [%]
10/11[b]
One possible mechanism[9] involves initial reaction with the
vinyl group followed by cyclization to close the carbocyclic
ring and open the bicyclic olefin simultaneously (Scheme 3).
An alternative path would require a regioselective opening of
the bridged olefin followed by cyclization onto the pendant
olefin. Since the reactions had proceeded cleanly and in high
yield, we favored the former mechanism. However, there is
little information regarding the influence of bridgehead
substituents,[10] and we felt that the intermolecular variant
9a
9b
9c
9d
9e
Me
CH2OMe
Me
CH2OMe
Me
OTBS
OTBS
OH
OH
H
H
H
H
H
83
65
85
66
15
6:1
1:1
20:1
20:1
6:1
OH
[a] Conditions: substrate in CH2Cl2 (0.3m), styrene (3 4 equiv),
(1.5 mol%). [b] Ratios approximated by NMR spectroscopy and GC
analysis.
1
Reduction/silylation of ketones 8a and 8b gave adducts 9a/
9b. As previously observed, this structural change resulted in
a dramatic change in reactivity. Both compounds opened
readily with styrene to give the cross-metathesis products 10/
11. The methyl-substituted compound 9a showed good
regioselectivity, giving the more substituted isomer 10a as
the major product (6:1). The methoxymethyl derivative 9b
was not selective, thus giving an almost equal mixture of the
two regioisomers. In a very surprising result, opening of the
endo alcohols 9c/9d with styrene, although a much slower
reaction, showed a dramatic increase in regioselectivity,
producing the more substituted derivatives 10c/10d in an
approximately 20:1 predominance. This high selectivity was
lost when the reactions were run at higher temperatures or in
O
O
O
O
LnRu=CHPh
RuLn
4a
A
4a
A
O
O
LnRu
O
O
H
O
LnRu
5a
O
H
Scheme 3. Proposed mechanism for the domino metathesis reaction.
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the presence of a larger excess of catalyst. The origin of this
enhanced reactivity and selectivity appears to be an exclusive
endo effect. Opening of the exo alcohol 9e was extremely
sluggish, only proceeding to about 15%. Moreover, the
regioselectivity of the product had decreased to a ratio of
about 6:1. These effects could be a result of the steric
interaction of the axial group with the bridged alkene or an
electronic effect similar to those seen in norbornyl systems.[12]
Although the nature of the effect is unclear, we proposed
that this rate acceleration could be used to improve some of
the previous spirocyclizations. If the reaction proceeds as in
Scheme 3, then the second ring-closing step should be
accelerated by similar structural changes. Therefore, we
examined the spirocyclization with reduced forms of dienes
4a and 4d (Table 4). We examined the five- and seven-
membered ring closures, since these were less efficient than
metathesis reactions. Further studies on these effects and the
synthesis of other types of annulated pyrans are currently
under investigation.
Received: July 8, 2002 [Z19679]
[1] M. C. Elliot, J. Chem. Soc. Perkin Trans. 1 1998, 4175 4200, and
references therein.
[2] D. L. Wright, L. C. Usher, M. Estrella-Jimenez, Org. Lett. 2001, 3,
4275 4277;a) for other approaches to pyrans by RCM, see: M. E.
Maier, M. Bugl, Synlett 1998, 1390 1392; b) B. Schmidt, H. Wild-
emann, J. Org. Chem. 2000, 65, 5817 5822; c) B. Schmidt, H.
Wildemann, J. Chem. Soc. Perkin Trans. 1 2000, 2916 2925.
[3] For excellent reviews, see: a) H. M. R. Hoffmann, Angew. Chem.
1984, 96, 29 48; Angew. Chem. Int. Ed. Engl. 1984, 23, 1 19; b) J. H.
Rigby, F. C. Pigge in Organic Reactions, Vol. 51 (Ed.: L. A. Paquette),
Wiley, New York, 1997, p. 351.
[4] For examples of domino metathesis reactions, see: a) N. Buschmann,
A. R¸ckert, S. Blechert, J. Org. Chem. 2002, 67, 4325 4329; b) O.
Arjona, A. G. Csaky, R. Medel, J. Plumet, J. Org. Chem. 2002, 67,
1380 1383; c) R. Stragies, S. Blechert, J. Am. Chem. Soc. 2000, 122,
9584 9591; d) O. Arjona, A. G. Csaky, M. C. Murcia, J. Plumet,
Tetrahedron Lett. 2000, 41, 9777 9779; e) R. Stragies, S. Blechert,
Tetrahedron, 1999, 55, 8179 8188; f) R. Stragies, S. Blechert, Synlett
1998, 169 170.
[5] a) S. W. Pelletier, N. V. Mody, Z. Djarmati, S. D. Lajsic, J. Org. Chem.
1976, 41, 3042 3044; b) D. J. Aberhart, K. H. Oberton, S. Huneck, J.
Chem. Soc. C. 1970, 11, 1612 1614.
[6] M. A. Walters, F. La, P. Desmukh, D. O. Omencinsky, J. Comb. Chem.
2002, 4, 125 130.
[7] B. Fˆhlisch, E. Gehrlach, B. Geywitz, Chem. Ber. 1987, 120, 1815
1824.
[8] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953
956.
Table 4. Spirocyclizations with reduced derivatives.
Alkene
Product[a]
Yield[b]
83%
12
14
13
15
48%
80%
[9] M. F. Schneider, N. Lucas, J. Velder, S. Blechert, Angew. Chem. 1997,
109, 257 259; Angew. Chem. Int. Ed. Engl. 1997, 36, 257 259; for a
review, see: A. F¸rstner, Angew. Chem. 2000, 112, 3140 3172; Angew.
Chem. Int. Ed. 2000, 39, 3012 3043.
15
17
[10] a) J. Plumet, O. Arjona, A. G. Csaky, Synthesis 2000, 6, 857 861;
b) M. L. Randall, J. A. Tallarico, M. L. Snapper, Tetrahedron, 1997, 48,
16511 16520; c) M. L. Randall, J. A. Tallarico, M. L. Snapper, J. Am.
Chem. Soc. 1995, 117, 9610 9611; d) O. Arjona, A. G. Csaky, M. C.
Murcia, J. Plumet, J. Org. Chem. 1999, 64, 9739 9741; e) J. G.
Hamilton, K. J. Ivin, M. McCann, J. J. Rooney, J. Chem. Soc. Chem.
Commun. 1984, 1379 1381.
[11] Reduction with L-selectride at ꢀ788C gave exclusively the endo
alcohols in 80 90% yield. The exo alcohol was prepared by reduction
with SmI2 (60% yield, one isomer).
cyclizations to form cyclohexyl rings. In the case of cyclo-
pentyl rings it may be somewhat difficult for the shorter tether
to reach the bridged alkene, whereas the seven-membered
ring may be slowed by nonbonded interactions in the tether.
Diene 4a was reduced to the endo alcohol 12, and rearrange-
ment gave 13 in an improved yield of 83%. The more difficult
cyclization to form the seven-membered ring systems was also
better with endo alcohol 14, tripling the yield to 48%. Since
the silyl ethers were more reactive in the intermolecular case,
it seemed possible that an even better rate enhancement could
be produced. Treatment of 16 with the ruthenium catalyst
resulted in a rapid reaction, delivering the spiro product 17 in
80% yield. This study nicely illustrates the potential of tuning
alkene reactivity in these types of reactions.
[12] For some examples, see: a) G. Mehta, G. Gunasekaran, S. R. Gadre,
R. N. Shirsat, B. Ganguly, J. Chandrasekhar, J. Org. Chem. 1994, 59,
1953 1955; b) G. Mehta, F. A. Khan, J. Am. Chem. Soc. 1990, 112,
6140 6142.
Olefin-metathesis reactions have become important bond-
forming reactions in contemporary synthetic chemistry. Dom-
ino ring-opening/ring-closing reactions are a convenient way
to construct polycyclic systems from readily available bridged
bicyclic alkenes. We have been able to develop a method to
prepare spiro-annulated pyrans from furan. An important
aspect of this study is the finding that the reactivity and
selectivity of the metathesis reactions can be tuned by
manipulation of functional groups on the substrate. Although
the origins of these effects are still under investigation, it is
clear that they can play an extremely important part in
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