Gassman's intramolecular [2 + 2] cationic cycloaddition. Formal total syntheses of raikovenal and epi-raikovenal

Article abstract of DOI:10.1021/ol8004968

The first intramolecular version of Gassman's cationic [2 + 2] cycloaddition employing vinyl acetals tethered to an unactivated olefin and its application in the formal syntheses of raikovenal and epi-raikovenal are described.

Full text of DOI:10.1021/ol8004968

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1971-1974
Gassman’s Intramolecular [2 + 2]
Cationic Cycloaddition. Formal Total
Syntheses of Raikovenal and
epi-Raikovenal
Changhong Ko, John B. Feltenberger, Sunil K. Ghosh, and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received March 5, 2008
ABSTRACT
The first intramolecular version of Gassman’s cationic [2 + 2] cycloaddition employing vinyl acetals tethered to an unactivated olefin and its
application in the formal syntheses of raikovenal and epi-raikovenal are described.
In the past half-century, a diverse array of elegant work from
the synthetic community has established the [2 + 2]
cycloaddition along with Diels-Alder-type cycloadditions
as one of the most powerful cycloaddition manifolds in
organic synthesis.1 With the Woodward-Hoffmann rules as
the fundamental guiding principles,2 photochemical [2 + 2]
cycloadditions3–7 have naturally taken center stage and
played a significant role in establishing the current promi-
nence of this cycloaddition in synthesis. On the other hand,
a nonphotochemical or thermal [2 + 2] cycloaddition strategy
remains less developed.8 Some elegant advances have been
made in this area with most being stepwise transformations
whether mediated by metals or acids.9–11 However, what has
been under-explored is Gassman’s cationic [2 + 2] cycload-
(1) For general reviews on cycloadditions, see: (a) Chapters on cycload-
ditions in: ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: New York, 1991; Vols. 4 and 5. (b) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Oxford and
New York, 1990. (c) Padwa, A.; Schoffstall, A. In AdVances in Cycload-
dition; Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1990; Vol. 2.
(2) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969,
8, 781.
(8) For a review on thermal [2 + 2], see: (a) Baldwin, J. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Pattenden,
G., Ed.; Pergamon Press: New York, 1991; Vol. 5, p 63. (b) Narasaka, K.;
Hayashi, Y. In AdVances in Cycloaddition; Lautens, M., Ed.; JAI Press:
Greenwich, CT, 1997; Vol. 4, pp 87–120.
(9) For recent reviews on metal-mediated cycloadditions and cyclizations,
see: (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (b)
Varela, J A.; Saa´, C. Chem. ReV. 2003, 103, 3787. (c) Rubin, M.; Sromek,
A. W.; Gervorgyan, V. Synlett 2003, 2265. (d) Aubert, C.; Buisine, O.;
Malacria, M. Chem. ReV. 2002, 102, 813. (e) Saito, S.; Yamamoto, Y. Chem.
ReV. 2000, 100, 2901.
(3) Crimmins, M. T. In ComprehensiVe Organic Synthesis; Trost,B. M.,
Fleming, I., Pattenden, G., Eds.; Pergamon Press: New York, 1991; Vol.
5, p 123.
(4) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. ReV. 1995, 95, 2003.
(5) Bach, T. Synthesis 1998, 683. and refs 1-15 cited within. .
(6) (a) Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103, 1449. (b)
De Keukeleire, D.; He, S.-L. Chem. ReV. 1993, 93, 359. (c) Lukina, M.
Yu. Russ. Chem. ReV. 1963, 32, 635.
(10) For recent examples, see: (a) Sweel, R. F.; Schramm, M. P.;
Kozimin, S. A. J. Am. Chem. Soc. 2004, 126, 7442. (b) Marion, F.; Coulomb,
J.; Courillon, C.; Fensterbank, L.; Malacria, M. Org. Lett. 2004, 6, 1509.
(c) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681. (d) Couty,
S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726.
(7) Wong, H. N. C.; Lau, K. L.; Tam, K. F. Top. Curr. Chem. 1986,
133, 83.
10.1021/ol8004968 CCC: $40.75
Published on Web 04/19/2008
2008 American Chemical Society

dition12 via Brønsted or Lewis acid activation of vinyl acetals
113 en route to cyclobutane 2 or 3 (Scheme 1).
Scheme 2. Gassman’s Intramolecular [2 + 2] Cycloaddition
Scheme 1. Gassman’s Cationic [2 + 2] Cycloaddition
Although such activations of vinyl acetals for inter- and
intramolecular [4 + 2] cycloadditions14 and for oxyallyl [4
+ 3] cycloadditions15,16 have been extensively investigated,
an intramolecular variant of Gassman’s cationic [2 + 2]
cycloaddition employing vinyl acetals 4 tethered to an
unactivated olefin for preparations of cyclobutanes 7 has not
been reported. Given a number of recently isolated cyclobu-
tane-containing natural products with biological rel-
evance17,18 and that a cationic [2 + 2] cycloaddition pathway
has a biosynthetic origin,19 we recognized this as an excellent
opportunity to develop useful thermal [2 + 2] cycloadditions.
We report here an intramolecular version of Gassman’s
cationic [2 + 2] cycloaddition.
To establish feasibility, we initially examined vinyl acetal
9 containing an ether tethering that was prepared from readily
available 5-bromo-3-methyl-2-pentene and cis-2-butene-1,4-
diol featuring Noyori’s mild protocol for the acetal forma-
tion20 (Scheme 2). The initial usage of BF3·OEt2- as Lewis
acid brought forth immediate success to the proposed
intramolecular cationic [2 + 2] cycloaddition, leading to
cycloadduct 1021 in 66% yield as a single diastereomer when
using 1.0 equiv of BF3·OEt2 along with 4 Å MS with the
reaction being run in CH2Cl222 at 0 °C for 10 min (entry 2).
Overall, the addition of 4 Å MS was the most critical, as
its presence reduces the competing hydrolysis of the acetal
moiety both in the starting vinyl acetal 9 and cycloadduct
10 (entry 1 vs 2). In addition, the reaction temperature and
concentration appear to be more optimal at 0 °C and 0.005
M, respectively (entries 3 and 4). Finally, the reaction was
found to be slow and sluggish when using <0.5 equiv of
BF3·OEt2 (entries 5 and 6). The relative stereochemistry of
cycloadduct 10 was unambiguously established through
X-ray structure of p-bromobenzoyl ester 12 prepared from
10 via hydrolysis and NaBH4 reduction followed by acylation
(Figure 1).
(11) Also see: (a) Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007,
129, 12686. (b) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005,
127, 3668. (c) Boxer, M. B.; Yamamoto, H. Org. Lett. 2005, 7, 3127. (d)
Takasu, K.; Ueno, M.; Inanaga, K.; Ihara, M. J. Org. Chem. 2004, 69, 517.
(e) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Nihata, S. J. Am. Chem. Soc.
1992, 114, 8869. (f) Engler, T. A.; Letavic, M. A.; Reddy, J. P. J. Am.
Chem. Soc. 1991, 113, 5068. (g) Ichikawa, Y.; Narita, A.; Shiozawa, A.;
Hayashi, Y.; Narasaka, K. J. Chem. Soc., Chem. Commun. 1989, 1919. (h)
Narasaka, K.; Hayashi, K.; Hayashi, Y. Tetrahedron 1994, 50, 4529–4542.
(12) (a) Gassman, P. G.; Chavan, S. P.; Fertel, L. B. Tetrahedron Lett.
1990, 31, 6489. (b) Gassman, P. G.; Lottes, A. C. Tetrahedron Lett. 1992,
33, 157.
(13) For reviews, see: (a) Mukaiyama, T.; Murakami, M. Synthesis 1987,
1043. (b) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1,
477.
Figure 1. X-ray structure of ester 12.
(14) For reviews, see: (a) Harmata, M.; Rashatasakhon, P. Tetrahedron
2003, 59, 2371. (b) Harmata, M. Tetrahedron 1997, 53, 6235.
(15) For reviews on oxyallyl cation [4 + 3] cycloadditions, see: (a)
Harmata, M. Acc. Chem. Res. 2001, 7, 595. (b) Davies, H. M. L. In AdVances
in Cycloaddition; Harmata, M., Ed.; JAI Press: Greenwich, 1998; Vol. 5,
p 119. (c) West, F. G. In AdVances in Cycloaddition; Lautens, M., Ed.;
JAI: Greenwich, 1997; Vol. 4, p 1. (e) Rigby, J. H.; Pigge, F. C. Org.
React. 1997, 51, 351. (f) Harmata, M. Recent Res. DeV. Org. Chem. 1997,
1, 523.
We then proceeded to evaluate other Lewis acids as well
as Brønsted acids. As summarized in Table 1, SnCl4 appears
to be another useful Lewis acid (entries 3-6) and gave 10
in comparable yield when the reaction was carried out at
-20 °C (entry 5). For Brønsted acids, although TfOH had
1972
Org. Lett., Vol. 10, No. 10, 2008

Having established the feasibility, we focused on some
mechanistic probing and synthetic application. Mecha-
nistically, this intramolecular [2 + 2] cycloaddition should
be stepwise as illustrated in Scheme 3. The key activation
of the acetal motif in 9 by Lewis Acid would give vinyl
oxocarbenium ion 13 likely complexed (shown by the
dashed line) to the Lewis acid coordinated oxygen (in
red).26 The ensuing addition of the unactivated olefin would
complete the first bond formation shown in 14. While
trapping of the resulting carbocation in 14 (the red arrow)
represents the desired cycloaddition pathway and the proper
stereochemical course, an E1-elimination (the blue arrow)
would afford alkenes 12 and 16 (not observedsif formed, it
could isomerize rapidly to 12 under the reaction conditions)
in a cationic ene or vinylogous-Prins manner. Alkene 12
could be derived from 14 directly via E1-elimination through
an external proton scavenger or sponge.27 It is noteworthy
that the high level of diastereoselectivity suggests the
cycloaddition proceeds through 13 with a high degree of
conformational control.
Table 1. Evaluations of Lewis and Brønsted Acids
a 4 Å MS was used in all reactions except in entry 3. b CH2Cl2 was the
solvent in all reactions. c Isolated yields. d A side product was isolated and
identified as the half-cycloaddition product 12 (see Scheme 3). e NR: no
reaction with full or partial recovery of the starting vinyl acetal 9.
To further support the stepwise nature of this cycloaddi-
tion, we prepared both cis- and trans-vinyl acetals 17 and
cis- and trans- olefins 19 (Scheme 4). Cycloadditions of both
been found useful in Gassman’s intermolecular work,12 it
was poor for our intramolecular cycloaddition (entry 10).
23,24
However, HNTf2
was suitable for the cycloaddition
Scheme 4. cis- and trans-Vinyl Acetals
(entry 9) while TFA was moderately useful (entry 13). Again,
these reactions required one full equivalent of the acid and
4 Å MS. In addition, we isolated half-cycloaddition product
(12, see Scheme 3) in 40% and 20% yield, respectively, when
Scheme 3. [2 + 2] Versus Ene-Like Pathway
sets of isomers provided identical stereochemical outcome
in the respective cycloadducts 18 and 20. This suggests that
(17) For bielschowskysin, see: (a) Marrero, J.; Rodr´ıguez, A. D.; Baran,
P.; Raptis, R. G.; Sa´nchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org.
Lett. 2004, 6, 1661. For biyouyanagin A, see: (b) Tanaka, N.; Okasaka,
M.; Ishimaru, Y.; Takaishi, Y.; Sato, M.; Masato Okamoto, M.; Oshikawa,
T.; Ahmed, S. U.; Consentino, L. M.; Lee, K.-H. Org. Lett. 2005, 7, 2997.
(18) For an elegant approach to bielschowskysin, see: (a) Doroh, B.;
Sulikowski, G. A. Org. Lett. 2006, 8, 903.
using TMSOTf and TfOH (entries 1 and 10). We note here
that the nature of the acetal motif, i.e., 1,3-dioxolane used
in 9 versus 1,3-dioxane,25 bears no impact on the cycload-
dition.
(19) For a leading reference, see: (a) Thulasiram, H. V.; Erickson, H. K.;
Poulter, C. D. Science 2007, 316, 73.
(20) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(16) For some recent examples, see: (a) Sakai, T.; Ishibashi, Y.; Ohno,
M. Tetrahedron Lett. 1982, 23, 1693. (b) Fo¨hlisch, B.; Krimmer, D.;
Gehrlach, E.; Kashammer, D. Chem. Ber. 1988, 121, 1585. (c) Murray,
D. H.; Albizati, K. Tetrahedron Lett. 1990, 31, 4109. (d) Harmata, M.;
Elomari, S.; Barnes, C. J. J. Am. Chem. Soc. 1996, 118, 2860, and references
cited within.
(21) See the Supporting Information.
(22) Hexane and THF were examined but not useful.
(23) For a study on the acidity of HNTf2, see: Thomazeau, C.; Olivier-
Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003,
125, 5264, and references cited therein.
Org. Lett., Vol. 10, No. 10, 2008
1973

scrambling through these cationic intermediates (in brackets)
is facile and that the stereochemical information of both the
vinyl acetal and the olefin is readily lost during the stepwise
pathway. It is noteworthy that the olefin stereochemistry in
cis- or trans-17 was not scrambled prior to the first bond
formation. 1H NMR of the crude mixture attained within the
first 20 s of the reaction course revealed no erosion of the
double-bond geometry in the unreacted cis- or trans-17.
Likewise, the olefin in cis-19 also did not isomerize under
the reaction conditions.28
raikovenal and epi-raikovenal.31,32 The key vinyl acetal 25
could be constructed from δ-enal 23 in four steps featuring
Otera’s conditions for the vinyl acetal formation (Scheme
6).33 Again, constructing the acetal motif in these all-carbon
Scheme 6. Formal Synthesis of Raikovenal
To render this cationic [2 + 2] cycloaddition useful
toward natural product synthesis, we examined vinyl acetal
21 with an all-carbon tether. As shown in Scheme 5, the
Scheme 5. Fused Carbocyclic Systems
tethered vinyl acetals [including 21] was also surprisingly
different, as Noyori’s protocol was not useful. The ensuing
cycloaddition gave the desired cyclobutane 26 and epi-26
in 60% yield as a separable isomeric mixture with a ratio of
2:1 in favor of epi-26. Chromatographic separation and
hydrolysis gave aldehydes 27 and epi-27 for which both
spectroscopically matched the reported literature values.32
NOE experiments of 26 and epi-26 also confirmed their
respective relative stereochemistry. The major isomer epi-
26 is likely a result of the cycloaddition proceeding through
the more favored conformation shown in brackets.
reaction of 21 behaved differently, as neither BF3·OEt2
nor SnCl4 was useful in promoting this cycloaddition.
After much screening, 0.5 equiv of FeCl3 adsorbed on
activated silica gel (5% w/w)29 was found to be the most
optimal Lewis acid at 0 °C to give the desired cycloadduct
22 in 64% yield, although neither SiO2 nor 0.1 equiv of
FeCl3 alone at 0 °C to rt afforded any desired product.
On the other hand, trans-vinyl acetal 17 with the oxygen
atom-containing tether could also undergo cycloaddition
in a comparable yield when using 0.5 equiv of
FeCl3-SiO2. We are currently investing this intriguing
comparison.30
We have described Gassman’s intramolecular cationic
[2 + 2] cycloaddition of vinyl acetals tethered to an
unactivated olefin and its application in formal syntheses
of raikovenal and epi-raikovenal.
Acknowledgment. We thank ACS-PRF-AC and UW-
Madison for funding. We thank Dr. Vic Young and Ben
Kucera at the University of Minnesota for providing X-ray
structural analysis.
Having established this new protocol for cycloaddition of
a vinyl acetal containing an all-carbon tether, we pursued
an application of this reaction in formal total syntheses of
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectral and characterizations.
(24) Ko, C.; Hsung, R. P. Organic Biomol. Chem. 2007, 7, 431.
(25) 1,3-Dioxane based vinyl acetal i led to a comparable outcome.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8004968
(26) (a) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043. (b)
Alexakis, A.; Mangeney, P. Tetrahedron Asymmetry 1990, 1, 477.
(27) In response to an excellent suggestion by a reviewer, with 1.0 equiv
of 2,6-di-tert-butyl-4-methylpyridine, it gave 55% yield of 10 when using
SnCl4 with no changes in the yield of alkene 12 (or 16).
(30) Preliminarily, cycloadditions of vinyl acetals with nitrogen atom-
containing tethers could also be accomplished in a comparable manner using
SnCl4, BF3·OEt2, or FeCl3-SiO2.
(31) For isolation, see: (a) Guella, G.; Dini, F.; Erra, F.; Pietra, F.
J. Chem. Soc., Chem. Commun. 1994, 2585. (b) Guella, G.; Dini, F.; Pietra,
F. HelV. Chim. Acta 1995, 78, 1747.
(28) The crude reaction mixture from cis-19 was analyzed within the
first 5 s, and the ratio of unreacted cis-19/20 was 2:1. The reaction of trans-
19 was too fast and completed within 5 s. Thus, it was inconclusive in
assessing the integrity of olefin stereochemistry in this case. We are again
grateful for the reviewers’ insightful suggestions.
(32) For total syntheses, see: (a) Snider, B.; Lu, Q. Synth. Commun.
1997, 27, 1583. (b) Rosini, G.; Laffi, F.; Marotta, E.; Pagani, I.; Righi,
P. J. Org. Chem. 1998, 63, 2389.
(33) Conditions: 2.0 equiv of MgSO4, 10 mol
%
of
(29) For a preparation of FeCl3-SiO2, see: (a) Chavan, S. P.; Sharma,
A. K. Synlett 2001, 667.
HOBu2SnOSnBu2NCS, 20 equiv of HOCH2CH2OH, benzene, 80 °C, 48 h.
See: Otera, J.; Dan-Oh, N.; Nozaki, H. Tetrahedron 1992, 48, 1449.
1974
Org. Lett., Vol. 10, No. 10, 2008