Formation of five- and six-membered carbocycles with nitrogenated tetrasubstituted carbons by radical addition-carbocyclization of alkynyl ketoxime ethers

Article abstract of DOI:10.1021/jo060883y

C3-Ketoxime ethers bearing alkynes with terminal δ-yne or internal γ-yne functions were prepared in five or six steps and ～20% overall yield from commercial glucofuranose derivatives. Their thiyl-, stannyl-, or carbon radical-promoted addition-carbocycliz

Full text of DOI:10.1021/jo060883y

Formation of Five- and Six-Membered Carbocycles with
Nitrogenated Tetrasubstituted Carbons by Radical
Addition-Carbocyclization of Alkynyl Ketoxime Ethers
Marta Ferna´ndez-Gonza´lez and Ricardo Alonso*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, UniVersidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
qoraa@usc.es
ReceiVed April 27, 2006
C3-Ketoxime ethers bearing alkynes with terminal δ-yne or internal γ-yne functions were prepared in
five or six steps and ∼20% overall yield from commercial glucofuranose derivatives. Their thiyl-, stannyl-,
or carbon radical-promoted addition-carbocyclization gave five- or six-membered carbocycles nitrogenated
at one of the bridgehead positions. For internal γ-yne ethers the tandem process was strongly dependent
on both the alkyne substituent and the radical-promoting species and could be directed toward either the
five- or the six-membered carbocycle. These results are presented and discussed in the context of studies
working toward (-)-tetrodotoxin.
Introduction
creation of nitrogen-bearing fully substituted carbon centers in
complex polycyclic frameworks.3 The study and development
of this latter type of transformation is called for by the existence
of a considerable number of useful or potentially useful
compounds endowed with a carbon center of this kind.4
One example is the natural product tetrodotoxin (TTX, 10,
Scheme 1), a compound with significant chemical, biological,
and pharmacological properties. Although it is a relatively small
molecule (MW ) 319), its structure is extremely complex.
Besides its nitrogenated tetrasubstituted carbon at C8a, it features
Free radical reactions are now well established in the synthetic
repertoire.1 In particular, the addition of carbon radicals to
CdN bonds has become a reliable procedure for the synthesis
of nitrogenated compounds.2 However, the full potential of this
reaction remains unrealized, especially its potential for the
* To whom correspondence should be addressed. Tel: +34 981547085.
Fax: +34 981595012.
(1) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH: Wein-
heim, Germany, 1996. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.;
Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301. (c) Ryu,
I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177. (d) Renaud, P.;
Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562. (e) Sibi, M. P.; Porter,
N. A. Acc. Chem. Res. 1999, 32, 163. (f) Naito, T. Heterocycles 1999, 50,
505. (g) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: New York, 2001; Vols. 1 and 2. (h) Bar, G.; Parsons, A. F. Chem.
Soc. ReV. 2003, 32, 251. (i) Sibi, M. P.; Manyam, S.; Zimmerman, J. Chem.
ReV. 2003, 103, 3263.
(3) Although radical addition onto ketimines is receiving increased
attention; see for example: (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y.
Synlett 2004, 2597. (b) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org.
Chem. 2005, 70, 3324. (c) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org.
Chem. 2006, 71, 2099 and references therein.
(4) Targets with fully substituted nitrogenated carbons include (-)-
huperzine A [(a) Jiang, H.; Luo, X.; Bai, D. Curr. Med. Chem. 2003, 10,
2231], (-)-cephalotaxine [(b) Taniguchi, T.; Ishita, A.; Uchiyama, M.;
Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005,
70, 1922], immunosuppressant FR901483 [(c) Panchaud, P.; Chabaud, L.;
Landais, Y.; Ollivier, C.; Renaud, P.; Zigmantas, S. Chem. Eur. J. 2004,
10, 3606], (+)-halichlorine [(d) Clive, D. L. J.; Yu, M.; Wang, J.; Yeh, V.
S. C.; Kang, S. Chem. ReV. 2005, 105, 4483], lactacystin [(e) Fukuda, N.;
Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem.
2006, 71, 1220], and myriocin [(j) Lee, K.-Y.; Oh, C.-Y.; Kim, Y.-H.; Joo,
J.-E.; Ham, W.-H. Tetrahedron Lett. 2002, 43, 9361. (k) Brunner, M.;
Koskinen, A. M. P. Curr. Org. Chem. 2004, 8, 1629].
(2) For reviews on addition of radicals to CdN bonds, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Mart´ınez-Grau, A.;
Marco-Contelles, J. Chem. Soc. ReV. 1998, 27, 155. (c) Friestad, G. K.
Tetrahedron 2001, 57, 5461. (d) Novel Radical Traps, Kim, S.; Joon, J.-Y.
In Radicals in Organic Synthesis, 1st ed.; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, New York, 2001; Vol. 2, Chapter 1. (e) Bertrand,
M.; Feray, L.; Gastaldi, S. C. R. Chimie 2002, 5, 623. (f) Miyabe, H.; Ueda,
M.; Naito, T. Synlett 2004, 7, 1140.
10.1021/jo060883y CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/08/2006
J. Org. Chem. 2006, 71, 6767-6775
6767

Ferna´ndez-Gonza´lez and Alonso
subunit of these channels,7 and it continues to be widely
employed in biological studies.8,9 Pharmacologically, tetrodo-
toxin is currently undergoing preclinical tests as a local and
topical anaesthetic and also phase II studies of its utility for
treatment of acute oncological or neuropathic pain and drug
abuse withdrawal symptoms.10,11
SCHEME 1. 5-exo Radical-Based Route toward
Tetrodotoxin via O-Tethered Alkyl and Vinyl Radicalsa
Ever since the elucidation of its structure,5 the unique,
complex architecture of tetrodotoxin has made it a test bench
for the development of synthetic methodologies.12-16 In par-
ticular, the challenging tetrasubstituted nitrogenated stereocenter
at C8a has been approached in different ways by a number of
research groups.17 Our own group, for example, has shown that
this center can be formed with complete stereocontrol through
5-exo radical addition to the imino carbon of ketoxime ethers,
as illustrated in Scheme 1 for the radical intermediates 5 and
6.18-20 This key transformation allows the conversion of â-D-
mannopyranose (1) into compounds 8 and 9, which have nine
of the 11 carbon atoms of tetrodotoxin (all except the hy-
droxymethyl and guanidine carbons) and four of its stereocenters
(C7, C8, C8a and C9) (Scheme 1).
The structural features of 8 and 9 and the relative short and
effective 5-exo radical-based synthetic sequence leading to these
structures (9 steps, 17% overall yield for 8, 12 steps, 9% overall
(7) Noda, M.; Shimizu, S.; Tanabe, T.; Takai, T.; Ikeda, T.; Takahashi,
H.; Hakayama, H.; Kanoaka, Y.; Minamino, N.; Kangawa, K.; Matsuo,
H.; Raftery, M. A.; Hirose, T.; Inayama, S.; Hayashida, H.; Miyata, T.;
Numa, S. Nature 1984, 312, 121.
(8) Hucho, F. Angew. Chem. 1995, 107, 23; Angew. Chem., Int. Ed. 1995,
34, 39.
(9) For the period 2000-2005, SciFinder Scholar retrieves between 270
and 400 references per year for tetrodotoxin in the CAS database. They
mostly relate to neurological and pharmacological studies.
(10) Pharmacological studies of tetrodotoxin under various trade names
are being conducted at Wex-Pharmaceuticals (Canada) and Esteve
(Spain): http://www.wexpharma.com/products/tectin.htm; http://www.wex
pharma.com/products/tocudin.htm; http://www.wexpharma.com/products/
tetrodin.htm; http://www.esteve.es/EsteveFront/Proyectos.do?op)DP&div)
id&con)14&cm)132.
(11) For recent papers on the therapeutic potential of sodium channel
blockers, see: (a) French, R. J.; Terlau, H. Curr. Med. Chem. 2004, 11,
3053. (b) Wood, J. N.; Boorman, J. Curr. Top. Med. Chem. 2005, 5, 529.
(12) For the first total synthesis of racemic tetrodotoxin, see: (a) Kishi,
Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino,
H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217. (b) Kishi, Y.;
Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.;
Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219.
(13) Enantioselective total syntheses of tetrodotoxin have been achieved
by the research groups led by Isobe and Du Bois: (a) Ohyabu, N.;
Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798. (b) Hinman,
A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. (c) Nishikawa, T.;
Urabe, D.; Isobe, M. Angew. Chem. 2004, 116, 4886; Angew. Chem., Int.
Ed. 2004, 43, 4782.
(14) The group led by Sato recently reported a new stereocontrolled
synthesis of racemic tetrodotoxin: Sato, K.-i.; Akai, S.; Sugita, N.; Ohsawa,
T.; Kogure, T.; Shoji, H.; Yoshimura, J. J. Org. Chem. 2005, 70, 7496.
(15) For syntheses of several deoxy-TTX forms, see: (a) Nishikawa,
T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.; Asai, M.; Isobe, M. Pure Appl.
Chem. 2003, 75, 251. (b) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi,
T.; Asai, M.; Isobe, M. Chem. Eur. J. 2004, 10, 452.
a For details, see ref 18. Tetrodotoxin numbering is used.
a high heteroatom content (50% of non-H atoms), nine stereo-
genic centers (including all the carbons of its six-membered
carbocycle), and the unique combination of an ortho-acid at C10
and a guanidine-hemiaminal ring.5 Biological interest in tetro-
dotoxin stems from its exceptional potency and selectivity in
blocking voltage-gated sodium channels.6 By virtue of this
property, tetrodotoxin has been instrumental in the identification,
isolation, purification, and subsequent sequencing of the main
(16) For other synthetic efforts towards tetrodotoxin see the following
articles and the references therein: (a) Keana, J. F. W.; Bland, J. S.; Boyle,
P. J.; Erion, M.; Hartling, R.; Husman, J. R.; Roman, R. B.; Ferguson, G.;
Parvez, M. J. Org. Chem. 1983, 48, 3627. (b) Nachman, R. J.; Honel, M.;
Williams, T. M.; Halaska, R. C.; Mosher, H. S. J. Org. Chem. 1986, 51,
4802. (c) Burgey, C. S.; Vollerthun, R.; Fraser-Reid, B. J. Org. Chem. 1996,
61, 1609. (d) Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 1323. (e)
Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619. (f) Taber, D. F.;
Storck, P. H. J. Org. Chem. 2003, 68, 7768. (g) Ozores, L.; Cagide, F.;
Alonso, R. Synlett 2004, 2746.
(17) Synthetic methods applied to the construction of the C8a stereocenter
of tetrodotoxin include Beckman rearrangement (ref 12), Rh-carbene C-H
insertion (ref 13b), Overman rearrangement (ref 13c), and azide opening
of spiro R-chloroepoxides (ref 14).
(5) The structural determination of tetrodotoxin was reported at the 3rd
IUPAC Symposium on the Chemistry of Natural Products, 13 April, 1964
(Kyoto, Japan), by the groups led by Hirata, Mosher, Tsuda and Woodward.
(a) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21,
2059. (b) Mosher, H. S.; Fuhrman, F. A.; Buchwald, H. D.; Fischer, H. G.
Science 1964, 144, 1100. (c) Tsuda, K.; Ikuma, S.; Kawamura, M.;
Tachikawa, R.; Sakai, K.; Tamura, C.; Amakasu, O. Chem. Pharm. Bull.
1964, 12, 1357. (d) Woodward, R. B. Pure Appl. Chem. 1964, 9, 49.
(6) (a) Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium
Channel; Kao, C. Y., Levinson, S. R., Eds.; New York Academy of
Sciences: New York, 1986; Vol. 479. (b) Tikhonov, D. B.; Zhorov, B. S.
Biophys. J. 2005, 88, 184. (c) Geffeney, S. L.; Fujimoto, E.; Brodie, E. D.;
Brodie, E. D.; Ruben, P. C. Nature 2005, 434, 759.
6768 J. Org. Chem., Vol. 71, No. 18, 2006

Formation of FiVe- and Six-Membered Carbocycles
SCHEME 2. Tandem Addition-6-exo Carbocyclization
Radical-Based Route toward Tetrodotoxin via a Ketoxime
Ether Bearing a Terminal Alkynea
SCHEME 3. Tandem Addition-6-exo Carbocyclization
Radical-Based Route toward Tetrodotoxin via a Ketoxime
Ether Bearing an Internal Alkyne (Pathway a); Alternative
5-exo Carbocyclization Leads to cis-Fused Cyclopentafurans
(Pathway b)a
a Sugar numbering is used except for 14.
yield for 9) suggest that both might serve as intermediates in
the total synthesis of tetrodotoxin. However, in this paper we
describe significant shorter routes to the alternative intermediates
14 (Scheme 2) and 20 (Scheme 3), both of which were prepared
by strategies featuring as their key step a tandem radical
addition-6-exo-carbocyclization undergone by a ketoxime ether
bearing an alkyne in which the triple bond was terminal in 12
(Scheme 2) and internal in 17 (Scheme 3, path a). Both 14 and
20 feature both the nitrogenated tetrasubstituted C8a stereocenter
of tetrodotoxin and its six-membered carbocycle with most of
its functionality, and they appear capable of mediating shorter
routes to the toxin than 8 or 9.21
As well as by its relevance to the synthesis of tetrodotoxin,
this work was strongly motivated by the novelty and potential
scope of the tandem radical processes 12 f 14 and 17 f 20
(+ 21), no examples of which have hitherto been reported.22-27
We envisage that the methodology described herein will find
increasing use for the formation of carbocyles with nitrogenated
quaternary carbons.28
a Sugar numbering is used except for 20.
Results and Discussion
Synthesis of Alkynyl Ketoxime Ethers 12a and 17a-c. The
δ-alkynyl ketoxime ether 12a [6R-12, P5 + P6 ) C(CH3)2,
Scheme 4] was obtained from commercial D-glucurono-γ-
lactone acetonide (11).29 Treatment of 11 with 1-trimethyl-
silylpropynyllithium30 afforded 24 in 88% yield as a mixture
of C6-epimeric hemiketals.31 Hydride reduction of the masked
carbonyl group in 24, carried out by treatment with NaBH3CN
(18) (a) Noya, B.; Alonso, R. Tetrahedron Lett. 1997, 38, 2745. (b) Noya,
B.; Paredes, M. D.; Ozores, L.; Alonso, R. J. Org. Chem. 2000, 65, 5960.
(19) Nitrogenated tetrasubstituted carbons can also be formed by
intermolecular radical addition of R-oxygenated carbon radicals to R-alkoxy-
carbonyl ketoxime ethers: Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985.
(20) The intra- and intermolecular 1,3-dipolar cycloaddition of ketoni-
trones has also proved to be a convenient method for stereoselective
formation of nitrogenated tetrasubstituted centres: (a) Torrente, S.; Noya,
B.; Paredes, M. D.; Alonso, R. J. Org. Chem. 1997, 62, 6710. (b) Torrente,
S.; Noya, B.; Branchadell, V.; Alonso, R. J. Org. Chem. 2003, 48, 4772.
(21) Although the total synthesis of a molecule as complex as tetrodotoxin
is a noteworthy achievement even if it involves a large number of steps,
particular emphasis is now placed on practicability and hence on brevity:
Koert, U. Angew. Chem. 2004, 116, 5690; Angew. Chem., Int. Ed. 2004,
43, 5572.
(22) There have been no reports of the formation of cyclohexane
derivatives with a fully substituted nitrogenated carbon by tandem radical
addition-6-exo carbocyclizations of ketimine derivatives with either a
terminal δ-yne or an internal γ-yne. Certain ketoxime ethers with a terminal
δ-yne derived from cyclobutanone have been reported to undergo a cascade
consisting in radical addition, 6-exo carbocyclization, fragmentation,
transannulation, ring expansion, and elimination, the ketoxime ether group
remaining unaltered or being hydrolyzed to a keto group overall. See: (a)
Pattenden, G.; Schulz, D. Tetrahedron Lett. 1993, 34, 6787. (b) Holling-
worth, G. J.; Pattenden, G.; Schulz, D. J. Aust. J. Chem. 1995, 48, 381.
J. Org. Chem, Vol. 71, No. 18, 2006 6769

Ferna´ndez-Gonza´lez and Alonso
SCHEME 4. Synthesis of δ-Alkynyl Ketoxime Ether 12aa
The cyclization precursors 17a-c were prepared from diace-
toneglucose (16) through the five-step sequence indicated in
Scheme 5. Oxidation39 and oxime ether formation40 at C3,
followed by hydrolysis of the terminal acetonide (best ac-
complished with Dowex 50W-X8),41 afforded the C5,C6 depro-
tected C3-ketoxime ether 28, which was then transformed into
epoxide 5S-29 under Mitsunobu-type conditions. [The config-
uration of 5S-29 at C5, which agrees with published prece-
(26) Tandem radical addition-cyclization processes not involving ketimine
derivatives have been reported by a number of groups. Selected examples:
the addition-5-exo carbocyclization of alkyne-tethered aldoxime ethers
derived from carbohydrates [(a) Marco-Contelles, J.; Destabel, C.; Gallego,
P.; Chiara, J. L.; Bernabe´, M. J. Org. Chem. 1996, 61, 1354]; the addition-
cyclization of allene-tethered aldoxime ethers and hydrazones [(b) Marco-
Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C.
D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997, 62, 1202]; the PhS•-
promoted addition-6-exo-carbocyclization of aldoxime ethers with a γ-Ct
C-Ar group [(c) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am.
Chem. Soc. 1999, 121, 5176]; the tandem cyclization of 2-azetidinone-
tethered enynes and allenynes [(d) Alcaide, B.; Rodr´ıguez-Campos, I. M.;
Rodr´ıguez-Lo´pez, J.; Rodr´ıguez-Vicente, A. J. Org. Chem. 1999, 64, 5377.
(e) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2003, 5, 3795];
a number of addition-heterocyclization processes of O- or N-tethered
unsaturated carbon chains [(f) Hanessian, S.; Ninkovic, S. J. Org. Chem.
1996, 61, 5418. (g) Gagosz, F.; Zard, S. Z. Org. Lett. 2002, 4, 4345. (h)
Pedrosa, R.; Andre´s, C.; Duque-Soladana, J. P.; Maestro, A.; Nieto, J.
Tetrahedron: Asymmetry 2003, 14, 2985. (i) Friestad, G. K.; Jiang, T.;
Fioroni, G. M. Tetrahedron Asymmetry 2003, 14, 2853. (j) Friestad, G. K.;
Massari, S. E. J. Org. Chem. 2004, 69, 863. (k) Sibi, M. P.; Patil, K.;
Rheault, T. R. Eur. J. Org. Chem. 2004, 372. (l) Miyabe, H.; Ueda, M.;
Fujii, K.; Nishimura, A.; Naito, T. J. Org. Chem. 2003, 68, 5618. (m)
Miyabe, H.; Naito, T. Org. Biom. Chem. 2004, 2, 1267. (n) Miyata, O.;
Kajisa, S.; Ueda, M.; Yamauchi, M.; Naito, T. Chem. Pharm. Bull. 2005,
53, 995]; the addition-cyclization of aromatic tertiary amines and furanones
[(o) Marinkovic, S.; Hoffmann, N. Eur. J. Org. Chem. 2004, 3102]; a
thiophenol-mediated addition-translocation-cyclization process [(p) Beaufils,
F.; Denes, F.; Renaud, P. Org. Lett. 2004, 6, 2563]; the addition-cyclization
of 2-indolylacyl radicals with electron-deficient alkenes [(q) Bennasar, M.-
Ll.; Roca, T.; Griera, R.; Bosch, J. J. Org. Chem. 2001, 66, 7547].
(27) For reviews on radical addition-cyclization processes and their
synthetic application, see: (a) Naito, T. Heterocycles 1999, 50, 505. (b)
Okiko, M.; Naito, T. C. R. Acad. Sci., Ser. IIc: Chim. 2001, 4, 401.
(28) We recently published a preliminary account of the thiyl-mediated
tandem radical addition and cyclization of ꢀ-substituted γ-yne-ketimines:
Ferna´ndez, M.; Alonso, R. Org. Lett. 2005, 7, 11.
a Sugar numbering is used.
and ZnCl2, gave the corresponding triols 25 with an average
yield of 49% and reasonable stereoselectivity (6R/6S ) 83/
17).32,33 Selective protection with 2,2-dimethoxypropane and
p-TsOH in acetone allowed the separation of the (6S)-C5,C6
isopropylidene derivative 26a (45%) from its (6S)-C3,C5
acetonide isomer 26b (24%) and its C6-epimer 26c (15%).34-36
A similar reaction path through the 5-O-methoxymethyl deriva-
tive of 11 gave 26a in 21% overall yield.37 Dess-Martin
oxidation38 of 26a at its free hydroxyl group, formation of the
benzyl oxime ether 27, and final TMS deprotection all proceeded
uneventfully in good yields, affording the desired ketoxime ether
12a (6 steps, 10-20% overall from 11).
(29) D-Glucurono-γ-lactone acetonide (11) is commercially available.
It can also easily be prepared from cheaper unprotected D-glucurono-γ-
lactone: (a) Kithihara, T.; Ogawa, T.; Naganuma, T.; Matsui, M. Agric.
Biol. Chem. 1974, 38, 2189. (b) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett
2002, 1532.
(30) (a) Corey, E. J.; Kirst, H. A. Tetrahedron Lett. 1968, 9, 5041. (b)
Stork, G.; Kowalski, C.; Garcia, G. J. Am. Chem. Soc. 1975, 97, 3258.
(31) For the reaction of the 5-O-tert-butyldimethylsilyl derivative of 11
with various anions to form the corresponding hemiketal intermediates as
C6-epimeric mixtures, see: (a) Graâberger, V.; Berger, A.; Dax, K.; Fechter,
M.; Gradnig, G.; Stu¨tz, A. E. Liebigs Ann. Chem. 1993, 379. (b) Ble´riot,
Y.; Veighey, C. R.; Smelt, K. H.; Cadefau, J.; Stalmans, W.; Biggadike,
K.; Lane, A. L.; Mu¨ller, M.; Watkin, D. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 1996, 7, 2761. (c) Ble´riot, Y.; Masaguer, C. F.; Charlwood, J.;
Winchester, B. G.; Lane, A. L.; Crook, S.; Watkin, D. J.; Fleet, G. W. J.
Tetrahedron 1997, 53, 15135. (d) Masaguer, C. F.; Ble´riot, Y.; Charlwood,
J.; Winchester, B. G.; Fleet, G. W. J. Tetrahedron 1997, 53, 15147. (e)
Morin, C.; Ogier, L. Tetrahedron: Asymmetry 2000, 11, 629. (f) Bessieres,
B.; Morin, C. Synlett 2000, 1691.
(32) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem.
1985, 50, 1927.
(33) Other reduction conditions (NaBH4/MeOH, LiAlH4/Et2O or NaBH4/
CeCl3/MeOH) gave lower yields.
(34) For details of the structural characterization of the synthetic
intermediates and the cyclized products resulting from the tandem radical
processes, see Experimental Section and Supporting Information.
(35) The relative stereochemistry of 26a at C6 was deduced from 1H
NMR coupling constants and NOE data obtained for its cyclized derivatives
14 (Scheme 2 and Table 1). See Supporting Information.
(36) Treatment of the mixture of 26b and 26c with 2,2-dimethoxypropane
and p-TsOH in acetone allowed partial conversion of 26b into 26a, which
was then separated from the remaining 26b and unaltered 26c by
chromatography.
(23) G. Fu and co-workers reported one example of simultaneous
formation of a nitrogenated quaternary centre and a cyclohexane ring by
tandem radical addition-6-exo carbocyclization of a ketoxime ether carrying
a ꢀ-formyl group (44%): (a) Tormo, J.; Hays, D. S.; Fu, G. C. J. Org.
Chem. 1998, 63, 201. For a related 6-endo case, see: (b) Tomaszewski, M.
J.; Warkentin, J. Tetrahedron Lett. 1992, 33, 2123.
(24) There have been two reported cases of the simultaneous formation
of a nitrogenated quaternary centre and a cyclohexane ring by 6-exo
carbocyclizations of a primary alkyl radical generated from either a C-Br
or a C-Se bonds to a ketimine group: (a) Della, E. D.; Knill, A. M. Aust.
J. Chem. 1994, 47, 1833. (b) Bowman, W. R.; Stephenson, P. T.; Young,
A. R. Tetrahedron Lett. 1995, 36, 5623.
(25) For the tandem radical addition-6-exo heterocyclization of benzyl
ketoxime ethers with an N-tethered terminal δ-yne to give benzo-fused
piperidines, see: (a) Enholm, E. J.; Burroff, J. A.; Jaramillo, L. M.
Tetrahedron Lett. 1990, 31, 3727. For analogous nontandem cyclizations
with O-tethered alkynes, see: (b) Booth, S. E.; Jenkins, P. R.; Swain, C. J.
J. Chem. Soc., Chem. Commun. 1991, 1248. (c) Booth, S. E.; Jenkins, P.
R.; Swain, C. J.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 1994, 3499.
6770 J. Org. Chem., Vol. 71, No. 18, 2006

Formation of FiVe- and Six-Membered Carbocycles
43
SCHEME 5. Synthesis of γ-Alkynyl Ketoxime Ethers 17
BF3‚OEt2 finally afforded the desired γ-alkynyl ketoxime
ethers 17a-c in 21-24% overall yields from 16.44
Tandem Radical Addition-Cyclizations. The tandem radi-
cal addition-cyclization of terminal alkyne 12a was first
attempted under conditions similar to those employed for the
successful 5-exo cyclization of the O-tethered γ-alkynyl-
ketoxime ether 4 (Scheme 1), i.e., using tin radicals as promoters
(R• in Schemes 2 and 3). Alkynes 12 were expected to behave
similarly to 4 in the first step of the tandem process, undergoing
intermolecular addition of tin radicals to form vinyl radical
intermediates 13 (Scheme 2) in much the same way as 4 gives
6 (Scheme 1). However, the second step appeared less likely
for 13 than for 6, because the 6-exo cyclization required for 13
is expected to be slower than the 5-exo process of 6.45 Moreover,
13 (but not 6) could undergo competitive reduction through
1,5-H transfer from position 4 (13 f 15, Scheme 2).46 In the
event, slow addition of n-Bu3SnH (2 equiv) to a 0.02 M solution
of 12a in toluene over 2.5 h resulted in no reaction, 12a being
essentially recovered unaltered (Table 1, entry 1). By contrast,
the whole desired tandem process took place when promoted
by photochemically generated thiyl radicals. Irradiation of a 0.02
M solution of 12a and PhSH (1 equiv) in toluene with a 450-W
medium-pressure mercury lamp led to cyclohexane derivative
14as, which was isolated in 33% yield as a 6:4 mixture of
geometric isomers (Table 1, entry 2).47 Among other minor
products, this reaction also produced what was tentatively
identified as a geometric mixture of noncyclic PhSH-addition
products (15as, 15%).48 The yield of 14as improved to 55%,
without affecting that of 15as, when the reaction was conducted
in benzene at greater dilution (0.014 M) and with a greater load
of PhSH, 1.3 equiv (Table 1, entry 3). Finally, we found that
tin radicals also promoted the tandem process if the stannane
precursor (2-2.4 equiv) was added in one portion at the
beginning of the reaction (Table 1, entries 4 and 5) instead of
slowly over a long period. Under these conditions, 12a afforded
the desired product in yields that were better than with PhSH
(60-61% as against 33-55%) and just slighter lower than the
yield of 8 obtained from 4 (68%, Scheme 1). Importantly, the
n-Bu3Sn-derived cyclohexyl derivative 14at was mainly ob-
tained as its E isomer (E/Z ratio 92:8) and the mixture was easily
separated. This is an advantage if subsequent vinyl couplings
are planned.49
dents,42 was eventually confirmed by spectroscopic studies of
its cyclic derivatives 20 (Table 2) and by an X-ray study of
20cs (vide infra)]. Epoxide opening at C6 by the lithium anions
derived from the terminal alkynes 30a-c in the presence of
(37) The alternative preparation of 26a from 11 was performed as shown
below; for details, see the Supporting Information.
(38) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Tojo, G.; Ferna´ndez, M. In Basic Reactions in Organic Synthesis, Oxidation
of Alcohols to Aldehydes and Ketones; Tojo, G., Ed.; Springer: New York,
2006; Chapter 3.
(39) Oxidation of diacetoneglucose has been carried out a number of
times. For selected examples, see: (a) Beynon, P. J.; Collins, P. M.;
Doganges, P. T.; Overend, W. G. J. Chem. Soc. C 1966, 1131. (b)
Czennecki, B.; Ceorcoulis, C.; Stevens, C. L.; Vijayakumapae, K. Tetra-
hedron Lett. 1985, 26, 1699. (c) Hodosi, G. Carbohydr. Res. 1994, 252,
291.
(40) (a) Plenkiewicz, J.; Szarek, W. A.; Sipos, P. A.; Phibbs, M. K.
Synthesis 1974, 56. (b) Denmark, S. E.; Dappen, M. S. J. Org. Chem. 1984,
49, 798.
(41) (a) Park, K. H.; Yoon, Y. J.; Lee, S. G. Tetrahedron Lett. 1994, 35,
9737. Hydrolysis of the terminal acetonide with 30% aqueous AcOH [(b)
Verheyden, J. P. H.; Richardson, A. C.; Bhatt, R. S.; Grant, B. D.; Fitch,
W. L.; Moffatt, J. G. Pure Appl. Chem. 1978, 50, 1363] and with thiourea
[(c) Majumdar, S.; Bhattacharjya, A. J. Org. Chem. 1999, 64, 5682] gave
lower yields (34% and 24%, respectively).
(42) For the conversion of terminal diols into epoxides with retention
under Mitsunobu conditions, see for example: (a) Achab, S.; Das, B. C.
Synth. Commun. 1982, 12, 931. (b) Takano, S.; Seya, K.; Goto, E.; Hirama,
M.; Ogasawara, K. Synthesis 1983, 116. (c) Robinson, P. L.; Barry, C. N.;
Bass, S. W.; Jarvis, S. E.; Evans, S. A. J. Org. Chem. 1983, 48, 5396. (d)
Abushanab, E.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1984, 25,
3841. (e) Mikkilineni, A. B.; Kumar, P.; Abushanab, E. J. Org. Chem. 1988,
53, 6005.
(43) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391. (b)
Le Merrer, Y.; Gravier-Pelletier, C.; Micas-Languin, D.; Mestre, F.;
Dure´ault, A.; Depezay, J.-C. J. Org. Chem. 1989, 54, 2409. (c) Ramana,
C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K. J. Org. Chem. 2005, 70,
8216.
(44) Ketoxime ethers 17a-c were obtained as a mixture of geometric
isomers. For details see Supporting Information.
(45) In general, 6-exo cyclizations (as required for intermediates 13 in
their conversion to 14, Scheme 2) are slower than 5-exo cyclizations (as
undergone by 6 to give 8, Scheme 1). Moreover, the presence of O and N
atoms in the chain connecting the carbon radical and the radical trap is
known to accelerate 5-exo radical cyclizations for stereoelectronic reasons.
The 6-exo process 13 f 14 is, on the contrary, a presumably slower
carbocyclization.
(46) ,5-Hydrogen transfers are especially favoured for stereoelectronic
reasons. Moreover, for the particular case of radical 13, the transfer of H4
is further facilitated by the presence of the ring oxygen (Scheme 2). This
factor was particularly worrying because even for intermediate 6, which
cannot be reduced by a 1,5-H transfer but only intermolecularly, reduction
partially competed with its 5-exo cyclization. See ref 18 for details.
(47) The major geometric isomer of 14at was shown to be the E-isomer,
in which the R group is oriented away from the crowded C8a quaternary
centre, according to NOE data (see Supporting Information); the major
geometric isomers of compounds 14as, 21bs, 21bt1, and 21bt2 were assumed
to have the same E-configuration.
J. Org. Chem, Vol. 71, No. 18, 2006 6771

Ferna´ndez-Gonza´lez and Alonso
TABLE 1. Tandem Addition-6-exo Carbocyclizations of δ-Alkynyl Ketoxime Ether 12a Promoted by Tin and Thiyl Radicalsa
entry
RH, equiv
initiation, equiv
[12a]b
timec
product yieldd (E/Z)
1
2
3i
4
5
n-Bu3SnH, 2,e
PhSH, 1
PhSH, 1.3
n-Bu3SnH, 2.4
n-Bu3SnH, 2
AIBN, 1.9, ∆
450-W Hgg
450-W Hgg
Et3B, 1.37, ∆
AIBN, 1, ∆
0.02
0.02
0.014
0.02
0.02
2.5
2.5
5.5
6.25
2
f
14as 33, (60/40) 15as 15h
14as 55, (56/44) 15as 15h
14at 60, (92/8)
14at 61j
a Unless otherwise indicated, reactions were carried out in toluene that had been deoxygenated by bubbling Ar for 15 min. b Molar concentration of 12a.
c Reaction time in h. d Isolated yield. e Added over 2.5 h. f Starting 12a was recovered. g A 450-W medium-pressure Hg UV lamp and Pyrex reaction vessels
were employed; temperature was maintained below 40 °C. h For the tentative identification of 15as as a mixture of geometric isomers of noncyclic PhSH-
addition products, see ref 48. i Solvent was benzene. j E-14at was isolated in 61% yield; the Z isomer was not quantified.
TABLE 2. Tandem Addition-5-exo Carbocyclizations and/or Tandem Addition-6-exo Carbocyclizations of δ-alkynyl Ketoxime Ethers 17a-c
Promoted by Tin, Thiyl, and 1,3-Dioxolan-2-yl Radicals
entry
substrate
RH, equiv
initiation, equiv, additives
[M]
timeb
product yieldc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
17a,b
17a,b
17a
17a
17b
17b
17b
17b
17c
17c
17c
17c
17b
17c
Ph3SnH, 1.5d
Ph3SnH, 2.6d
PhSH, 1.2d
AIBN, 2, ∆
0.015
0.015
0.06
0.02
0.08
0.08
0.04
0.04
0.08
0.075
0.036
0.02
0.027
0.08
0.08
0.02
0.02
0.02
14
14
6
6.5
9.5
19
6
2.25
9
7.5
9.5
3
e
e
e
g
Et3B, 1, ∆
AIBN, 0.1, ∆
PhSH, 3
sunlampf
PhSH, 1.3d
AIBN, 0.2, ∆
20bs 14, 21bs 41,h 17b 21
20bs 11, 21bs 29,h 17b 58
20bs 24, 21bs 20h
20bd 65
PhSH, 0.6 + 0.6i
PhSH, 1.1 + 0.4j
1,3-dioxolanel
PhSH, 1.3d
AIBN, 0.6, sunlampf
hν,k benzene
Ph2CO, 1, hνk
AIBN, 0.1, ∆
20cs 50
20cs 45-54
20cs 61
20cs 75, 7E+Z-22cs 6+6°
20bs 22, 21bs 5.7,h 17b 10
20cs 42
PhSH, 1.28,m
PhSH, 2.1
AIBN, 0.45, sunlampf
AIBN, 0.45, ultrasoundn
hν,k benzene
PhSH, 1.05
PhSSPh, 0.7
PhSH, 1.44,m
PhSH, 1.5,m
n-Bu3SnH, 2
Ph3SnH, 2
hν,k benzene
5
AIBN, 0.45,f Yb(OTf)3, 0.2
AIBN, 0.5,fMgBr2.OEt2, 0.6
AIBN, 1, ∆
11.5
19
1.25
4.5
1.75
17c
20cs 40
17b
17b
17c
20bt1 26, E-21bt1 53p
20bt2 9, E-21bt2 75p
20ct1 91
AIBN, 1, ∆
AIBN, 1, ∆
n-Bu3SnH, 2
a Unless otherwise stated, the solvent was deoxygenated toluene. b Reaction time in h. c Isolated yield. d Added over 2.5 h (entry 2) or 3.5 h (entries 1,
3, 5, and 9). e Starting 17 was recovered. f A 300-W sunlamp was used as the radiation source. g Complex mixture. h Isolated as E/Z mixtures; see ref 47.
i After 16 h. j After 4 h. k A 450-W medium-pressure Hg UV lamp and Pyrex reaction vessels were employed; temperature was maintained below 40 °C.
l 1,3-Dioxolane also acted as the solvent. m PhSH was added in 2-3 portions. n The flask was immersed in the bath of an ultrasound cleaning device. o See
ref 50. p See ref 47.
Initial uncertainty as to whether the γ-alkynyl ketoxime ethers
17 could be converted into cyclohexene derivatives 20 as in
Scheme 3 (steps a1 and a2) arose first from the unknown
influence of the terminal substituent R′, second from the
possibility of a competitive tandem process leading to the
exomethylenecyclopentane derivatives 21 (Scheme 3, steps b1
and b2), and third from the possibility of reduction of 17 to 22
or 23. In fact, as earlier reported,28 neither 17a (R′ ) CH(OEt)2)
nor 17b (R′ ) CO2Et) reacted with thermally generated Ph3Sn•
(1.5-2.6 equiv, slow addition, Table 2, entries 1 and 2), nor
was the cyclization of 17a promoted by PhS• radicals, which
either failed to react or gave a complex mixture (Table 2, entries
3 and 4). Gratifyingly, however, our preliminary study28 showed
that 17 could be cyclized to predominantly give either the
exomethylenecyclopentane derivatives 21 (R′ ) CO2Et and R•
) PhS•, Table 2, entries 5-7) or the cyclohexene derivatives
20 (R′ ) CO2Et and R• ) 1,3-dioxolanyl, entry 8; R′ ) Ph and
R• ) PhS•, entries 9-12)50 under a variety of reaction
conditions.
Now, we have performed additional experiments with the goal
of increasing the efficiency of the radical addition-carbocy-
clization process. In particular, we explored the use of PhSSPh
6772 J. Org. Chem., Vol. 71, No. 18, 2006

Formation of FiVe- and Six-Membered Carbocycles
instead of PhSH as the source of phenylthiyl radicals (entry
13) and the addition of Lewis acids51 (Yb(OTf)3, MgBr2‚OEt2,
0.2-0.6 equiv, entries 14 and 15) with no improvement. We
next found that, as with 12a, in the cases of of 17b and 17c,
stannane did promote the tandem process when added in one
portion at the beginning of the reaction, instead of over several
hours. Furthermore, the overall yields it achieved were very
good, 79-84% for 17b (entries 16 and 17) and 91% for 17c
(entry 18), though in the case of 17b the major product was
the cyclopentyl derivative 21bt [21bt:20bt ratio 53%:26%
(entry 16) or 75%:9% (entry 17)]. Interestingly, both 21bt1
(R ) n-Bu3Sn) and 21bt2 (R ) Ph3Sn) were isolated as a single
geometric isomer, whereas 21bs (R ) PhS) had been isolated
as a nearly equimolar mixture of two geometric isomers.47 The
91% of 20ct1 obtained from 17c with n-Bu3Sn• was the only
cyclized product (entry 18).
importance when dealing with highly functionalized compounds;
the possibility, when using γ-alkynylketoxime ethers, of direct-
ing the course of the process to obtain structurally diverse
products from a common precursor; the structural or functional
features of the final products (nitrogenated quaternary carbon,
vinyl tin or sulfide, allylamine, predictably located internal or
exocyclic double bonds, etc.), which can be of interest both in
themselves and with regard to further synthetic transformations;
and the possibility of further extending the scope of the
methodology by varying the CdN radical acceptor, the chain
connecting the alkyne and the CdN, and/or the reaction-
initiating free radical R•.
As regards the synthesis of tetrodotoxin, although compounds
such as 14 or 20 could probably be transformed into tetrodotoxin
analogues or perhaps into the toxin itself, the methodology
presented in this paper will probably be most efficiently
exploited if applied to ketoxime ethers bearing alkynes that
already contain more of the tetrodotoxin structure than is present
in 12 or 17. Research along these lines is being carried out and
progress will be reported in due course.
Conclusions
The above results show that ketoxime ethers bearing terminal
δ-yne or internal γ-yne functions can undergo tandem radical
addition-carbocyclization. These processes accomplish in a
single step both the formation of a carbocycle and the generation
of a fully substituted nitrogen-bearing carbon atom. With
terminal δ-ynes the product is an exomethylene cyclohexane;
with internal γ-ynes the formation of either an exomethylene
cyclopentane or a cyclohexene is possible. Tin radicals are more
efficient promoters than thiyl radicals in every case examined
and are also more selective when forming exomethylenes, giving
mainly or exclusively just one of the geometric isomers.
The attractive characteristics of this methodology include the
ease with which the ketoxime ether precursors can be prepared;
the robustness of the triple bond and ketoxime ether function-
alities; the smooth tandem reaction conditions, of critical
Experimental Section
Procedures for Tandem Radical Addition-Carbocyclizations.
Tin Radicals (Procedure A). A solution of 12a, 17b, or 17c and
AIBN (100 mol %) in dry toluene (0.02 M) was deoxygenated by
bubbling argon for 15 min. R3SnH (200 mol %) was added, and
the mixture was refluxed until the starting material was consumed
(TLC). Solvent removal, followed by flash chromatography using
EtOAc/hexane mixtures, afforded the corresponding carbocyclic
amine derivative.
Phenylthiyl Radicals (Procedure B). A solution of 12a, 17b,
or 17c in dry benzene (0.014-0.04 M) was deoxygenated by
bubbling argon for 10-15 min. Thiophenol (100-150 mol %) was
added either in one portion or in several portions at intervals through
the reaction, and the mixture, maintained at <40 °C, was externally
irradiated with a 450-W medium-pressure Hg UV lamp until the
starting material was consumed (TLC). Solvent removal, followed
by flash chromatography using EtOAc/hexane mixtures, afforded
the corresponding carbocyclic amine derivative.
Cyclohexanamine 14as. Prepared by procedure B from 12a (95
mg, 0.23 mmol) and thiophenol (0.31 mmol; 14 µL, followed by
two additional 9 µL portions 1.5 and 2.5 h later) in dry benzene
(17 mL). Irradiation time: 5.5 h. Flash chromatography (Et2O/
hexane 15:85) afforded 14as (67.7 mg, 55%, E/Z ) 56/44) as a
white solid, and 15as48 (19 mg, 15%). E-14as: 1H NMR (CDCl3,
400 MHz) δ 7.40-7.24 (m, 10H), 6.97 (d, J ) 1.8 Hz, 1H), 6.06
(br s, 1H), 5.79 (d, J ) 3.6 Hz, 1H), 4.69 (d, J ) 11.3 Hz, 1H),
4.62 (d, J ) 11.3 Hz, 1H), 4.52-4.49 (m, 2H), 4.42 (d, J ) 3.6
Hz, 1H), 4.33-4.27 (m, 1H), 3.16 (dd, J ) 14.1 Hz, J ) 6.6 Hz,
1H), 2.54 (ddd, J ) 14.1 Hz, J ) 8.6 Hz, J ) 1.8 Hz, 1H), 1.53
(s, 3H), 1.52 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 137.0, 135.4, 132.9, 129.7, 129.1, 128.4, 128.2, 128.0,
127.0, 126.9, 113.4, 109.0, 103.9, 87.2, 81.2, 77.3, 74.1, 72.3, 71.3,
31.5, 26.8, 26.7, 26.4, 24.7. LRMS (FAB+) m/z (%) 512 [11, (M
+ H)+], 454 [15, (M - C(CH3)2 - CH3)+], 393 (38), 322 (64).
HRMS (FAB+) calcd for C28H34NO6S (M + H)+ 512.2107, found
512.2097. E,Z-14as: 1H NMR (CDCl3, 400 MHz) δ 7.43-7.14
(m, 20HE,Z), 6.97 (d, J ) 1.8 Hz, 1HE), 6.54 (s, 1HZ), 6.06 (br s,
1HE), 6.03 (br s, 1HZ), 5.79 (d, J ) 3.6 Hz, 2HE,Z), 4.82-4.47 (m,
9HE,Z), 4.42 (d, J ) 3.6 Hz, 1HE), 4.34-4.16 (m, 2HE,Z), 3.16 (dd,
J ) 14.1 Hz, J ) 6.6 Hz, 1HE), 2.72 (m, 2HZ), 2.54 (ddd, J ) 14.1
Hz, J ) 8.6 Hz, J ) 1.8 Hz, 1HE), 1.53 (s, 6H), 1.52 (s, 6H), 1.32
(s, 3H), 1.31 (s, 3H), 1.28 (s, 6H).
(48) Although the 1H and the 13C NMR spectra of this chromatographic
fraction are both very complex, the presence of diagnostic resonances for
the carbon atom of the CdN group (δ 157.08 and 157.06 ppm) and for the
terminal vinyl proton in -CH2-CHdCHSPh [δ 6.29 ppm (dt, J ) 9.3 Hz,
J ) 1.4 Hz, J ) 1.4 Hz, 1H) for the CdC Z isomer and δ 6.14 ppm (dt,
J ) 15.0 Hz, J ) 1.2 Hz, J ) 1.2 Hz, 1H) for the CdC E isomer) strongly
suggest it contains a mixture of geometric isomers of the vinyl sulfide 15as
shown below.
(49) Alkenyltins can couple with a wide variety of organic halides and
triflates and with acid chlorides. For reviews see: Mitchell, T. N. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich,
F., Eds; Wiley-VCH: New York, 2004; Vol. 1, Chapter 3.
(50) When the cyclization of 17c (17, R′ ) Ph) to 20cs was performed
using a 450-W medium-pressure mercury lamp (Table 2, entry 12), the
reaction was clean enough to allow the isolation of two other products that
were tentatively identified (1H NMR, NOE data, and MS) as the noncyclized
PhSH adducts 7E-22cs and 7Z-22cs (20%). They both appear to be a mixture
of geometric isomers around the CdN bond. A NOE observed for H6 in
7Z-22cs, but not in 7E-22cs, on irradiation of H8, allowed assignation of
the configuration of the CdC bond. See Supporting Information for details.
Cyclohexanamine 14at. Prepared by procedure A from 12a (53
mg, 0.13 mmol), AIBN (22 mg, 0.13 mmol), and Bu3SnH (71 µL,
0.26 mmol) in dry toluene (6.6 mL). Reaction time: 2 h. Flash
(51) Protic and Lewis acids have been reported to favour addition of
radicals to ketoxime ethers, see for example ref 19.
J. Org. Chem, Vol. 71, No. 18, 2006 6773

Ferna´ndez-Gonza´lez and Alonso
chromatography (hexane to EtOAc/hexane 5:95) afforded E-14at
(56 mg, 61%) as a white solid: mp ) 68-69 °C (Et2O/hexane).
1H NMR (CDCl3, 400 MHz) δ 7.34-7.23 (m, 5H), 6.71 (d, J )
1.9 Hz, JSn-H ) 61.2 Hz, 1H), 6.03 (br s, 1H), 5.74 (d, J ) 3.5 Hz,
1H), 4.63 (d, J ) 11.0 Hz, 1H), 4.58 (d, J ) 11.0 Hz, 1H), 4.56-
4.53 (m, 2H), 4.34 (d, J ) 3.5 Hz, 1H), 4.27-4.20 (m, 1H), 2.72
(ddd, J ) 13.7 Hz, J ) 9.4 Hz, J ) 1.9 Hz, 1H), 2.64 (dd, J )
13.7 Hz, J ) 6.6 Hz, 1H), 1.56-1.48 (m, 12 H), 1.36-1.26 (m,
12 H), 1.07-0.94 (m, 6H), 0.88 (t, J ) 7.2 Hz, 9H). 13C NMR
(CDCl3, 100 MHz) δ 149.7, 137.3, 131.5, 128.3, 128.1, 127.8,
113.3, 108.8, 103.7, 88.1, 81.8, 77.4, 74.2, 73.5, 72.0, 38.9, 29.2,
27.3, 26.9, 26.6, 26.4, 24.5, 13.7, 10.3. LRMS (FAB+) m/z (%)
694 [78, (M120Sn + H)+], 693 [39, (M119Sn + H)+], 692 [61,
(M118Sn + H)+], 636 [87, (M120Sn - Bu)+], 635 [44, (M119Sn -
Bu)+], 634 [69, (M118Sn - Bu)+]. Anal. Calcd for C34H55NO6Sn,
C 58.97, H 8.01, N 2.02. Found: C 59.08, H 8.26, N 2.09. Z-14at:
1H NMR (CDCl3, 300 MHz) δ 7.38-7.29 (m, 5H), 6.13 (s, JSn-H
) 50.9 Hz, 1H), 5.59 (d, J ) 3.3 Hz, 1H), 4.98-4.95 (m, 2H),
4.88 (d, J ) 12.1 Hz, 1H), 4.79 (d, J ) 5.2 Hz, 1H), 4.27 (m, 1H),
4.19 (m, 1H), 3.48 (dd, J ) 15.5 Hz, J ) 4.1 Hz, 1H), 2.69 (dd, J
) 15.5 Hz, J ) 1.1 Hz, 1H), 1.65-1.27 (m, 24 H), 1.08-1.03 (m,
6H), 0.88 (t, J ) 7.2 Hz, 9H). 13C NMR (CDCl3, 75 MHz) δ 144.9,
135.4, 134.1, 128.5, 127.8, 126.5, 111.8, 109.5, 102.6, 82.9, 79.1,
78.7, 76.7, 73.9, 72.2, 39.2, 29.2, 27.3, 27.2, 26.6, 26.2, 24.3, 13.8,
10.5. LRMS (ESI-TOF) m/z (%) 625 [100, (M120Sn - Bn + Na)+],
624 [68, (M119Sn - Bn + Na)+], 623 [91, (M118Sn - Bn + Na)+].
HRMS (ESI-TOF) calcd for C27H48NNaO6120Sn (M - Bn + Na)+
625.2401, found 625.2219.
10.2 Hz, 1H), 1.70 (d, J ) 9.8 Hz, 1H), 1.60 (s, 3H), 1.37 (s, 3H).
13C NMR (CDCl3, 75 MHz) δ 168.0, 163.5, 139.7, 137.0, 136.9,
135.7, 128.8, 128.5, 128.4, 128.2, 127.9, 113.5, 104.4, 83.8, 83.5,
76.9, 72.0, 67.3, 52.0, 38.2, 27.0, 26.9. LRMS (FAB+) m/z (%)
742 [10, (M120Sn + H)+], 741 [6, (M119Sn + H)+], 740 [9,
(M118Sn + H)+], 664 [100, (M120Sn - Ph)+], 663 [50, (M119Sn -
Ph)+], 662 [76, (M118Sn - Ph)+]. HRMS (ESI-TOF) calcd for
C38H40NO7120Sn (M + H)+ 742.1829, found 742.1826. E-21bt2:
1H NMR (CDCl3, 300 MHz) δ 7.68-7.19 (m, 20H), 6.29 (s, 1H),
5.82 (d, J ) 3.4 Hz, 1H), 5.28 (d, J ) 3.4 Hz, 1H), 4.82 (d, J )
11.3 Hz, 1H), 4.68 (d, J ) 3.5 Hz, 1H), 4.61 (d, J ) 11.3 Hz, 1H),
4.22 (m, 1H), 3.35 (s, 3H), 2.65 (dd, J ) 16.3 Hz, J ) 6.9 Hz,
1H), 2.25 (dd, J ) 16.3 Hz, J ) 10.6 Hz, 1H), 2.05 (br s, 1H),
1.52 (s, 3H), 1.34 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 171.1,
157.0, 137.1, 137.0, 136.7, 135.3, 129.3, 128.7, 128.4, 128.0, 127.8,
113.7, 105.6, 88.1, 86.4, 78.3, 76.1, 71.9, 51.1, 42.8, 27.4, 27.0.
LRMS (FAB+) m/z (%) 742 [11, (M120Sn + H)+], 741 [7, (M119Sn
+ H)+], 740 [9, (M118Sn + H)+], 574 [4, (M120Sn - Bn - CO2Me
- OH)+], 573 [2, (M119Sn - Bn - CO2Me - OH)+], 572 [3, (M118
-
Sn - Bn - CO2Me - OH)+]. HRMS (FAB+) calcd for C38H40-
NO7119Sn (M + H)+ 741.1838, found 741.1848.
Cyclohexenamine 20bt1 and Cyclopentanamine 21bt1. Pre-
pared by procedure A from 17b (50.3 mg, 0.13 mmol), AIBN (23
mg, 0.14 mmol) and Bu3SnH (70 µL, 0.26 mmol) in dry toluene
(6.4 mL). Reaction time: 1.25 h. Flash chromatography (EtOAc/
hexane 5:95 to 10:90) afforded 20bt1 (23.5 mg, 26%) and E-21bt1
(47 mg, 53%) as colorless oils. 20bt1: 1H NMR (CDCl3, 500 MHz)
δ 7.32-7.22 (m, 5H), 6.45 (br s, 1H), 5.66 (d, J ) 3.4 Hz, 1H),
5.06 (d, J ) 3.4 Hz, 1H), 4.55 (ABq, J ) 11.5 Hz, 2H), 4.49 (d,
J ) 1.5 Hz, 1H), 4.11 (m, 1H), 3.77 (s, 3H), 2.76 (dd, J ) 18.3
Hz, J ) 5.4 Hz, 1H), 2.45 (dd, J ) 18.3 Hz, J ) 10.3 Hz, 1H),
1.76 (br s, 1H), 1.58 (s, 3H), 1.51-1.44 (m, 6H), 1.34 (s, 3H),
1.31-1.25 (m, 6H), 0.98-0.94 (m, 6H), 0.87 (t, J ) 7.3 Hz, 9H).
13C NMR (CDCl3, 125 MHz) δ 168.7, 167.5, 137.2, 133.4, 128.4,
128.3, 127.8, 113.3, 104.4, 83.8, 83.6, 76.9, 71.9, 67.4, 52.1, 37.7,
29.1, 27.3, 27.1, 26.8, 13.7, 11.4. LRMS (FAB+) m/z (%) 682 [6,
(M120Sn + H)+], 681 [3, (M119Sn + H)+], 680 [4, (M118Sn + H)+],
624 [100, (M120Sn - Bu)+], 623 [48, (M119Sn - Bu)+], 622 [81,
(M118Sn - Bu)+]. HRMS (FAB+) calcd for C28H42NO7120Sn (M
- Bu)+ 624.1983, found 624.1988. E-21bt1: 1H NMR (CDCl3,
500 MHz) δ 7.34-7.24 (m, 5H), 6.19 (s, 1H), 5.81 (d, J ) 3.3 Hz,
1H), 5.16 (d, J ) 3.3 Hz, 1H), 4.72 (d, J ) 11.4 Hz, 1H), 4.69 (d,
J ) 3.6 Hz, 1H), 4.56 (d, J ) 11.4 Hz, 1H), 4.29 (dddd, J ) 10.7
Hz, J ) 10.7 Hz, J ) 7.1 Hz, J ) 3.6 Hz, 1H), 3.71 (s, 3H), 2.64
(dd, J ) 15.8 Hz, J ) 7.1 Hz, 1H), 2.46 (dd, J ) 15.8 Hz, J )
10.7 Hz, 1H), 2.15 (d, J ) 10.7 Hz, 1H), 1.55-1.48 (m, 9H), 1.36-
1.28 (m, 9H), 1.08-1.01 (m, 6H), 0.88 (t, J ) 7.3 Hz, 9H). 13C
NMR (CDCl3, 125 MHz) δ 172.6, 152.5, 138.1, 137.4, 128.3, 128.1,
127.8, 113.6, 105.7, 88.1, 86.4, 78.0, 76.1, 72.1, 51.2, 42.2, 28.9,
Cyclohexenamine 20bs and Cyclopentanamine 21bs. Prepared
by procedure B from 17b (48 mg, 0.12 mmol) and thiophenol [14
µL + 5 µL (added after 4 h), 0.18 mmol] in dry benzene (3 mL).
Irradiation time: 6 h. Flash chromatography (EtOAc/hexane 20:
80 to 25:75) afforded 20bs (15 mg, 24%) and 21bs (12.3 mg, 20%)
as oils. 20bs: 1H NMR (CDCl3, 300 MHz) δ 7.29-7.21 (m, 10H),
6.29 (s, 1H), 5.89 (d, J ) 3.6 Hz, 1H), 5.09 (d, J ) 3.6 Hz, 1H),
4.66 (s, 2H), 4.63 (d, J ) 3.7 Hz, 1H), 4.38 (m, 1H), 3.46 (s, 3H),
3.09 (dd, J ) 18.4 Hz, J ) 7.5 Hz, 1H), 2.75 (dd, J ) 18.4 Hz, J
) 9.8 Hz, 1H), 2.10 (d, J ) 10.3 Hz, 1H), 1.55 (s, 3H), 1.32 (s,
3H). 13C NMR (CDCl3, 100 MHz) δ 165.7, 151.5, 136.8, 135.1,
129.7, 129.1, 128.7, 128.4, 128.1, 127.0, 127.5, 113.9, 105.8, 88.1,
83.8, 78.7, 77.4, 72.0, 52.2, 41.0, 27.2, 27.0. LRMS (FAB+) m/z
(%) 500 [33, (M + H)+], 442 [40, (M + H - OC(CH3)2)+]. HRMS
(FAB+) calcd for C26H30NO7S (M + H)+ 500.1743, found
500.1755. IR (CsI) 3486, 3272, 3061-2988-2950, 1720, 1583
cm-1. 21bs (isolated as an inseparable 55:45 mixture of geometric
isomers): 1H NMR (CDCl3, 300 MHz) δ 7.40-7.21 (m, 20H),
6.53 (br s, 1H), 6.30 (br s, 1H), 5.81 (d, J ) 3.4 Hz, 1H), 5.79 (d,
J ) 3.4 Hz, 1H), 5.18 (d, J ) 3.4 Hz, 1H), 5.05 (d, J ) 3.4 Hz,
1H), 4.77-4.55 (m, 5H), 4.40 (d, J ) 2.0 Hz, 1H), 4.30 (m, 1H),
4.08 (m, 1H), 3.84 (s, 3H), 3.54 (s, 3H), 3.22 (dd, J ) 17.7 Hz, J
) 7.3 Hz, 1H), 3.42-2.31 (m, 2H), 2.21 (dd, J ) 17.2 Hz, J )
10.4 Hz, 1H), 2.12 (d, J ) 10.5 Hz, 1H), 1.75 (br s, 1H), 1.54 (s,
6H), 1.35 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ 168.0, 166.3,
142.2, 137.0, 136.9, 133.4, 133.0, 131.7, 130.1, 129.6, 129.2, 129.0,
128.6, 128.4, 128.3, 128.3, 128.2, 127.8, 127.1, 126.3, 113.7, 113.3,
105.6, 104.2, 88.6, 86.1, 82.6, 82.2, 77.9, 77.2, 76.9, 72.4, 71.4,
67.5, 52.3, 52.1, 40.5, 34.1, 27.4, 27.3, 27.2, 26.8. LRMS (FAB+)
m/z (%) 500 [28, (M + H)+]. IR (CsI) 3484, 3276, 3061-2988-
27.5, 27.2, 27.0, 13.6, 11.0. LRMS (FAB+) m/z (%) 682 [38, (M120
-
Sn + H)+], 681 [21, (M119Sn + H)+], 680 [33, (M118Sn + H)+],
624 [42, (M120Sn - Bu)+], 623 [27, (M119Sn - Bu)+], 622 [49,
(M118Sn - Bu)+], 534 [100, (M120Sn - OC(CH3)2 - Bu - OH -
Me)+], 533 [45, (M119Sn - OC(CH3)2 - Bu - OH - Me)+], 532
[78, (M118Sn - OC(CH3)2 - Bu - OH - Me)+]. HRMS (FAB+)
calcd for C32H52NO7119Sn (M + H)+ 681.2687, found 681.2691.
Cyclohexenamine 20bd. A solution of 17b (40 mg, 0.10 mmol)
and benzophenone (19 mg, 0.10 mmol) in 1,3-dioxolane (2.5 mL,
0.04 M) was deoxygenated by bubbling argon for 10 min. The
mixture, maintained at <40 °C, was externally irradiated with a
450 W Hanovia medium-pressure mercury lamp until 17b was
consumed (TLC; irradiation time 2.25 h). Solvent removal, followed
by flash chromatography (EtOAc/hexane 35:65), afforded 20bd (31
mg, 65%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.34-
7.27 (m, 5H), 6.19 (s, 1H), 5.77 (d, J ) 3.4 Hz, 1H), 5.42 (s, 1H),
5.25 (d, J ) 3.4 Hz, 1H), 4.72 (d, J ) 11.1 Hz, 1H), 4.56 (d, J )
11.1 Hz, 1H), 4.41 (d, J ) 1.9 Hz, 1H), 4.13-4.09 (m, 1H), 4.05-
3.89 (m, 4H), 3.81 (s, 3H), 2.54 (dd, J ) 17.4 Hz, J ) 5.7 Hz,
1H), 2.26 (dd, J ) 17.4 Hz, J ) 10.5 Hz, 1H), 1.90 (d, J ) 9.8
2936, 1723, 1582 cm-1
.
Cyclohexenamine 20bt2 and Cyclopentanamine 21bt2. Pre-
pared by procedure A from 17b (53.5 mg, 0.14 mmol), AIBN (24
mg, 0.14 mmol) and Ph3SnH (70 µL, 0.27 mmol) in dry toluene
(6.8 mL). Reaction time: 4.5 h. Flash chromatography (EtOAc/
hexane 5:95 to 20:80) afforded 20bt2 (9.5 mg, 9%) as a colorless
oil and E-21bt2 (76.4 mg, 75%) as a white foam. 20bt2: 1H NMR
(CDCl3, 300 MHz) δ 7.61-7.23 (m, 20H), 6.57 (s, 1H), 5.79 (d, J
) 3.6 Hz, 1H), 5.09 (d, J ) 3.6 Hz, 1H), 4.65 (ABq, J ) 11.4 Hz,
2H), 4.55 (d, J ) 2.1 Hz, 1H), 4.18 (m, 1H), 3.29 (s, 3H), 2.78
(dd, J ) 18.9 Hz, J ) 5.3 Hz, 1H), 2.40 (dd, J ) 18.9 Hz, J )
6774 J. Org. Chem., Vol. 71, No. 18, 2006

Formation of FiVe- and Six-Membered Carbocycles
Hz, 1H), 1.55 (s, 3H), 1.34 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ
168.6, 141.6, 137.1, 128.9, 128.5, 128.2, 127.7, 113.2, 104.2, 101.6,
82.5, 82.2, 76.8, 71.9, 67.1, 65.7, 52.1, 27.2, 26.8, 26.7. LRMS
(FAB+) m/z (%) 464 [8, (M + H)+], 391 [22, (M + H -
dioxolanyl)+]. HRMS (FAB+) calcd for C23H30NO9 (M + H)+
464.1920, found 464.1924.
1H), 4.89 (d, J ) 11.3 Hz, 1H), 4.75 (d, J ) 11.3 Hz, 1H), 4.59
(d, J ) 2.3 Hz, 1H), 4.34 (dddd, J ) 10.1 Hz, J ) 10.1 Hz, J )
5.9 Hz, J ) 2.3 Hz, 1H), 4.24 (d, J ) 3.3 Hz, 1H), 2.73 (dd, J )
17.0 Hz, J ) 5.9 Hz, 1H), 2.37 (dd, J ) 17.0 Hz, J ) 10.1 Hz,
1H), 1.83 (J ) 10.1 Hz, 1H), 1.51 (s, 3H), 1.40-1.14 (m, 15 H),
0.83 (t, J ) 7.1 Hz, 9H), 0.55-0.46 (m, 6H). 13C NMR (CDCl3,
75 MHz) δ 147.2, 142.1, 141.8, 137.2, 130.8, 128.4, 128.2, 128.1,
127.9, 127.4, 113.4, 104.1, 83.9, 83.1, 75.9, 72.1, 67.7, 37.0, 29.0,
27.2, 27.1, 26.7, 13.6, 10.1. LRMS (FAB+) m/z (%) 700 [9,
(M120Sn + H)+], 699 [5, (M119Sn + H)+], 698 [7, (M118Sn + H)+],
642 [100, (M120Sn - Bu)+], 641 [48, (M119Sn - Bu)+], 640 [75,
(M118Sn - Bu)+]. HRMS (FAB+) calcd for C36H54NO5119Sn (M
+ H)+ 699.2946, found 699.2951.
Cyclohexenamine 20cs. Prepared by procedure B from 17c (76.6
mg, 0.18 mmol) and thiophenol (20.5 µL, 0.19 mmol, one portion)
in dry benzene (9.4 mL). Irradiation time: 3 h. Flash chromatog-
raphy (EtOAc/hexane 10:90 to 20:80) afforded 20cs (73 mg, 75%)
as a white solid, and 7E-22cs50 (6.1 mg, 6%) and 7Z-22cs50 (6.3
1
mg, 6%) as oils. 20cs: mp ) 168-170 °C (CH2Cl2/hexane). H
NMR (CDCl3, 300 MHz) δ 7.43-7.16 (m, 15H), 6.06 (s, 1H), 5.85
(d, J ) 3.3 Hz, 1H), 4.95 (d, J ) 11.1 Hz, 1H), 4.81 (d, J ) 11.1
Hz, 1H), 4.62 (d, J ) 2.2 Hz, 1H), 4.34 (d, J ) 3.3 Hz, 1H), 4.4-
4.3 (m, 1H), 2.51 (dd, J ) 16.8 Hz, J ) 6.3 Hz, 1H), 2.35 (dd, J
) 16.8 Hz, J ) 10.1 Hz, 1H), 1.81 (d, J ) 10.2 Hz, 1H), 1.55 (s,
3H), 1.24 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 137.5, 136.7,
134.9, 134.5, 133.5, 131.8, 130.3, 128.9, 128.5, 128.3, 128.0, 127.7,
127.1, 113.6, 104.0, 83.2, 82.9, 76.2, 72.3, 67.4, 34.4, 27.2, 26.8.
LRMS (FAB+) m/z (%) 518 [28, (M + H)+], 395 [100, (M -
NHOBn)+].
Acknowledgment. This work was supported by the Spanish
Ministries of Science and Technology (Project BQU2002-
01176) and Education and Science (Project CTQ2005-02338)
in collaboration with ERDF, the Xunta de Galicia (through
Project PGIDIT05BTF20901PR and a fellowship to M.F.) and
the University of Santiago de Compostela (through a postdoc-
toral contract to M.F.).
Cyclohexenamine 20ct1. Prepared by procedure A from 17c
(60.7 mg, 0.15 mmol), AIBN (26 mg, 0.15 mmol), and Bu3SnH
(80 µL, 0.29 mmol) in dry toluene (7.4 mL). Reaction time: 1.75
h. Flash chromatography (EtOAc/hexane 10:90 to 20:80) afforded
Supporting Information Available: Experimental procedures
and characterization data for 12a and 17a-c and their synthetic
precursors. NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
20ct1 (94.7 mg, 91%) as a colorless oil. H NMR (CDCl3, 300
MHz) δ 7.35-7.23 (m, 10H), 5.98 (s, 1H), 5.76 (d, J ) 3.3 Hz,
JO060883Y
J. Org. Chem, Vol. 71, No. 18, 2006 6775