Gassman's cationic [2 + 2] cycloadditions using temporary tethers

Article abstract of DOI:10.1021/ol3026796

An intermolecular equivalent of Gassman's cationic [2 + 2] cycloaddition through the use of temporary tethering is described. Notably, hydrazine and hydroxyamide proved to be robust under the acidic conditions required for the cycloaddition, leading to unique cyclobutane manifolds in a highly regio- and stereoselective manner. This development represents a rare usage of hydrazine and hydroxyamide in the capacity as temporary tethers.

Full text of DOI:10.1021/ol3026796

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5562–5565
Gassman’s Cationic [2 þ 2]
Cycloadditions Using Temporary Tethers
Jun Deng, Richard P. Hsung,* and Changhong Ko
Division of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222,
United States
rhsung@wisc.edu
Received September 28, 2012
ABSTRACT
An intermolecular equivalent of Gassman’s cationic [2 þ 2] cycloaddition through the use of temporary tethering is described. Notably, hydrazine
and hydroxyamide proved to be robust under the acidic conditions required for the cycloaddition, leading to unique cyclobutane manifolds in a
highly regio- and stereoselective manner. This development represents a rare usage of hydrazine and hydroxyamide in the capacity as temporary
tethers.
While intramolecular reactions can bring forth complex
structural motifsexpeditiouslyvia highly regio- and stereo-
selective reaction pathways, intermolecular reactions often
lack regio- and/or stereochemical control despite being
equally important. An elegant solution to this problem has
been the use of a temporary and removable tether that
renders intermolecular reactions intramolecular in nature,
thereby allowing improved regio- and/or stereochemical
control in addition to an enhanced reaction rate.1 In
particular, intermolecular [2 þ 2] cycloadditions, photo-
chemically2ꢀ5 or thermally driven,5ꢀ7 are known to suffer
from poor regiochemical control. Our long-standing interest8
in developing synthetically useful thermalꢀ[2 þ 2] cyclo-
additions led us to uncover a Lewis acid catalyzed intramo-
lecular version of Gassman’s cationic [2 þ 2] cycloaddi-
tion [1f2f3 in Scheme 1]9,10 amenable for the synthesis
of raikovenal.10a,11 To date, Gassman’s work and ours
(1) For leading reviews, see: (a) Bols, M.; Skrydstrup, T. Chem. Rev.
1996, 96, 1253. (b) Gauthier, D. R.; Zandi, K. S.; Shea, K. J. Tetrahedron
1998, 54, 2289.
(2) Crimmins, M. T. In Comprehensive Organic Synthesis; Trost,
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33, 157.
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1995, 78, 1747. For total syntheses, see: (c) Snider, B.; Lu, Q. Synth.
Commun. 1997, 27, 1583. (d) Rosini, G.; Laffi, F.; Marotta, E.; Pagani,
I.; Righi, P. J. Org. Chem. 1998, 63, 2389.
(4) Bach, T. Synthesis 1998, 683 and refs 1ꢀ15 cited within.
(5) Also see (a) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103,
1449. (b) De Keukeleire, D.; He, S.-L. Chem. Rev. 1993, 93, 359.
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Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Pattenden,
G., Eds.; Pergamon Press: New York, 1991; Vol. 5, p 63.
(7) For some reviews on metal mediated cycloadditions and cycliza-
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ꢀ
(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.;
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r
10.1021/ol3026796
Published on Web 10/25/2012
2012 American Chemical Society

Scheme 1. Temporary Tethered Cationic [2 þ 2] Cycloaddition
Scheme 2. Hydrazine Tether Cycloaddition Precursor
represent the only examples of such cycloadditions that
involve vinyl oxocarbenium ion 2.12 Given the prevalence
of cyclobutanes among alkaloids,13 and that a cationic [2 þ 2]
pathway has a biosynthetic origin,14 developing a temporary
tethered manifold would be of great significance in providing
a thermally driven intermolecular equivalent of the [2 þ 2]
cycloaddition [4f5f6f7]. While many different tethering
systems have been documented with siloxane tethers being
the most well-known especially in DielsꢀAlder cycloaddi-
tions,1,15 we intended to explore unusual temporary
tethers that can (1) sustain acidic conditions required for
these cationic cycloadditions and (2) bring in unique
functionalities. We wish to report here our success in
achieving temporary tethered Gassman’s cationic [2 þ 2]
cycloadditions.
containing alkaloids.13 It is noteworthy that, based on
calculations and X-ray structure, bis-N-acyl-hydrazines
[right box in Scheme 2] possess a dihedral or torsional
angle of ∼90° with respect to the C(O)ꢀNꢀNꢀC(O) bond
sequence.18 Therefore, although deceptively far apart when
drawn two-dimensionally, reactive partners A and B on the
hydrazinyl nitrogen atoms would assume a gauche-like
conformational relationship. With the rotational barrier
Inspired by Lee’s elegant work for hydrazine-tethered
ring-closing metathesis,16,17 we elected to first examine
hydrazines as a possible tether for the Gassman’s cationic
[2 þ 2] cycloadditions. We were intrigued by hydrazines
because they are pharmacologically important structural
entities18 and because of our interest in cyclobutane
around the NꢀN bond being ΔE = 19 kcal mol
,
ꢀ1 19 this
gauche-like conformational preference should entropically
promote the reactivity between A and B.
Toward this goal, we assembled the Gassman’s cationic
[2 þ 2] cycloaddition precursor 12 from bis-N-ethoxycar-
bonyl hydrazine 8 in five steps [Scheme 2].20 Selective
monofunctionalization on one of the two hydrazinyl ni-
trogen atoms was readily achieved with a very high overall
efficiency [see 10], and Noyori’s conditions21 remain the
best for the acetal formation from aldehyde 11. The
ensuing cationic [2 þ 2] cycloaddition of 12 was success-
fully carried out as shown in Scheme 3. After screening
some Lewis and Brønsted acids,10 SnCl4 proved to be
the most effective here, leading to the desired cycloadduct
13 as a single diastereomer. FeCl3ꢀSiO2,22 used quite
successfully in our intramolecular study,10 is also feasible
(12) For reviews, see: (a) Harmata, M.; Rashatasakhon, P. Tetrahedron
2003, 59, 2371. (b) Harmata, M. Tetrahedron 1997, 53, 6235.
(13) For a leading review, see: Dembitsky, V. M. J. Nat. Med. 2008,
62, 1.
(14) For a leading reference, see: Thulasiram, H. V.; Erickson, H. K.;
Poulter, C. D. Science 2007, 316, 73.
(15) For siloxane tethering, see: (a) Stork, G.; Chan, T. Y.; Breault,
G. J. Am. Chem. Soc. 1992, 114, 7578. (b) Gillard, J. A.; Fortin, R.;
Grimm, E. L.; Maillard, M.; Tjepkema, M.; Bernstein, M. A.; Glaser, R.
Tetrahedron Lett. 1991, 32, 1145. (c) Shea, K. J.; Zandi, K. S.; Staab,
A. J.; Carr, R. Tetrahedron Lett. 1990, 31, 5885. (d) Tamao, K.;
Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478. (e) Ainsworth,
P. J.; Craig, D.; Reader, J. C.; Slawin, A. M. Z.; White, A. J. P.; Williams,
D. J. Tetrahedron 1995, 51, 11601. For some examples of other tethering
strategies, see: (f) Mg and Al cation: Stork, G.; Chan, T. Y. J. Am. Chem.
Soc. 1995, 117, 6595. (g) Diester: Craig, D.; Ford, M. J.; Stones, J. A.
Tetrahedron Lett. 1996, 37, 535. (h) Cu-Box: Evans, D. A.; Johnson, J. S.
J. Org. Chem. 1997, 62, 786.
(19) (a) Reynolds, C.; Hormann, R. E. J. Am. Chem. Soc. 1996, 118,
9395 and references therein. Also see: (b) Nelsen, S. F. In Acyclic
Organonitrogen Stereodynamics; Lambert, J. B., Takeuchi, Y., Eds.; VCH
Publishers: New York, 1992; Chapter 3, pp 89ꢀ121.
(20) See Supporting Information.
(16) For a leading reference, see: Kim, Y. J.; Lee, D. Org. Lett. 2004,
6, 4351.
(17) For some examples in which hydrazine is used as an anchor with
(21) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(22) For a preparation of FeCl3ꢀSiO2, see: Chavan, S. P.; Sharma,
ꢁ
a focus toward constructing heterocycles, see: (a) Tsupova, S.; Lebedev,
€
A. K. Synlett 2001, 667.
O.; Maeorg, U. Tetrahedron 2012, 68, 1011. (b) Matteis, V. D.; van Delft,
F. L.; Tiebes, J.; Rutjes, F. P. J. T. Synlett 2008, 354. (c) Lim, A.; Choi,
C. H.; Tae, J. Tetrahedron Lett. 2008, 49, 4882. (d) Tae, J.; Hahn, D.-H.
Tetrahedron Lett. 2004, 45, 3757.
(18) For a leading reference, see: Billas, I. M.; Iwema, T.; Garnier,
J.-M.; Mitschler, A.; Rochel, N.; Moras, D. Nature 2003, 426, 91.
(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.
(24) Also see Ko, C.; Hsung, R. P. Organic Biomol. Chem. 2007, 7,
431.
Org. Lett., Vol. 14, No. 21, 2012
5563

design (1) could lead to an orthogonal approach to con-
structing cyclobutane manifolds and (2) would represent a
rare usage of hydroxyamide as a temporary tether.26,27
Scheme 3. A Hydrazine Tethered Cationic [2 þ 2] Cycloaddition
Scheme 5. A Diversified Assembly of Hydroxyamide Tethers
23,24
here at 0.5 equiv, while HNTf2
ineffective.
was essentially
Relative stereochemistry in the cyclic hydrazine fused
cyclobutane 13 was unambiguously assigned using the
single crystal X-ray structure [Scheme 3]. It is noteworthy
that the torsional angle for the (O)CꢀNꢀNꢀC(O) bond
sequence here in the cycloadduct is also precisely at 90.1°,
thereby suggesting a 90° dihedral angle is also present in
the cycloaddition precursor 12. To complete the concept of
temporary tethering, we were able to first hydrolyze the
acetal motif and then reduce the intermediate aldehyde to
afford alcohol 14 [Scheme 4]. The final reductive cleavage
of the hydrazine tether was best exercised using dissolving
metal reduction16,25 to afford diaminomethyl cyclobutane
15, while standard hydrogenation conditions were not
effective.
As shown in Scheme 5, this orthogonal design can be
achieved through the synthesis of hydroxyamide contain-
ing bis-olefins 18a and 18b with N-hydroxy-phthalamide
serving as the diverging point. The assembly features two
opposite sequences of O-allylation via Mistunobu reaction
and N-allylation with the use of hydrazine to liberate the
hydroxyl-amine followed by acylation in between. The
cycloaddition precursors 20a and 20b could then be pre-
pared, respectively, from 18a and 18b, using the same
sequence for the hydrazine tether [Scheme 6]. The antici-
pated cationic [2 þ 2] cycloadditions of 20a and 20b were
the most successful when using 3.0 equiv of HNTf2,23,24
leading to bicyclic cyclobutanes 21a and 21b as single
diastereomers. The latter yielded a single crystal that
allowed us to obtain an X-ray structure to unambiguously
assign the relative stereochemistry of the three contiguous
carbon centers. On the other hand, the use of SnCl4 or
FeCl3 activated with SiO2 led to recovery of the starting
material along with products resulting from hydrolysis
of the starting material. We are not sure of the precise
Scheme 4. A Diaminomethyl Cyclobutane Manifold
(26) For two related examples on hydroxyamide as a tether, see:
(a) Yang, Y.-K.; Choi, J.-H.; Tae, J. J. Org. Chem. 2005, 70, 6995.
(b) Miyata, O.; Namba, M.; Ueda, M.; Naito, T. Org. Biomol. Chem.
2004, 2, 1274.
(27) For some examples of using hydroxyamides as an anchor to
build heterocycles, see: (a) Reddy, V. K.; Miyabe, H.; Yamauchi, M;
Takemoto, Y. Tetrahedron 2008, 64, 1040. (b) Shustov, G. V.; Chandler,
M. K.; Wolfe, S. Can. J. Chem. 2005, 83, 93. (c) Yang, Y.-K.; Lee, S.;
Tae, J. Bull. Korean Chem. Soc. 2004, 25, 1307. (d) Flohic, A. L.; Meyer,
C.; Cossy, J.; Desmurs, J.-R. Tetrahedron Lett. 2003, 44, 8577. (e)
Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.; Takemoto,
Y. Synlett 2003, 567. (f) Yang, Y.-K.; Tae, J. Synlett 2003, 1043, 2017.
(g) Koide, K.; Finkelstein, J. M.; Ball, Z.; Verdine, G. L. J. Am. Chem.
Soc. 2001, 123, 398.
Having established the feasibility of hydrazine as a
temporary tether for the Gassman’s cationic [2 þ 2]
cycloaddition, we were compelled to expand the scope of
the tethering system for this study, as this would be more
significant than expanding the substrate scope for one
tether. We contemplated adopting hydroxyamides as an-
other unique tether for this cycloaddition because this
(25) Veldhuizen, J. J. V.; Gillingham, D. G.; Garber, S. B.; Kataoka,
O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502.
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Org. Lett., Vol. 14, No. 21, 2012

Scheme 6. Hydroxyamide Tethered [2 þ 2] Cycloadditions
Scheme 7. Aminomethyl-Hydroxymethyl Cyclobutanes
NiCl2ꢀ6H2O and NaBH4,28 while the acetal motif could
be preserved here for further transformations.
We have described here the concept of an intermolecular
equivalent of Gassman’s cationic [2 þ 2] cycloaddition
through temporary tetherings. In particular, hydrazine
and hydroxyamide tethering systems proved to be tolerant
of the Lewis and Brønsted acidic conditions required
for the cycloaddition, leading to substituted cyclobutane
manifolds in a highly regio- and stereoselective manner.
This work represents a rare adaptation of hydrazine and
hydroxyamide as temporary tethers. Applications of this
unique intermolecular cationic [2 þ 2] cycloaddition
equivalent specifically in the synthesis of cyclobutane-
containing alkaloids are currently underway.
Acknowledgment. We thank The National Science
Foundation [NSF-CHE1012198] for support of this work
and Dr. Vic Young and Mr. Gregory T. Rohde of the
University of Minnesota for providing X-ray structural
analysis.
rationale for thiscontrastwiththe reaction conditions used
for the hydrazine-tethered system 12.
Although these two hydroxyamide-tethered cycloaddi-
tions afforded lower yields than the hydrazine tether, these
two cycloadditions provide a useful strategy for construct-
ing orthogonally substituted cyclobutane manifolds in a
highly stereo- and regioselective manner that is otherwise
difficult for an intermolecular [2 þ 2] cycloaddition. As
demonstrated in Scheme 7, the NꢀO tether could be
released in good yields through reductive cleavage using
Supporting Information Available. Experimental pro-
1
cedures as well as H NMR spectra, X-ray structural
data, and characterizations. This material is available free
of charge via the Internet at http://pubs.acs.org.
(28) Hardy, S.; Martin, S. F. Org. Lett. 2011, 12, 3102.
The authors declare no competing financial interest.
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