Diastereoselective vinyl addition to chiral hydrazones via tandem thiyl radical addition and silicon-tethered cyclization

Article abstract of DOI:10.1021/ol0067991

(equation presented) A diastereoselective method for addition of a vinyl group to α-hydroxy hydrazones under neutral tin-free radical cyclization conditions, leading to substituted vinylglycinols, is presented. Tandem thiyl radical addition/cyclization up

Full text of DOI:10.1021/ol0067991

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4237-4240
Diastereoselective Vinyl Addition to
Chiral Hydrazones via Tandem Thiyl
Radical Addition and Silicon-Tethered
Cyclization
Gregory K. Friestad* and Sara E. Massari
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
gregory.friestad@uVm.edu
Received October 30, 2000
ABSTRACT
A diastereoselective method for addition of a vinyl group to r-hydroxy hydrazones under neutral tin-free radical cyclization conditions, leading
to substituted vinylglycinols, is presented. Tandem thiyl radical addition/cyclization upon a silicon-tethered vinyl group followed by treatment
with potassium fluoride accomplishes a one-pot neutral vinyl addition process to afford acyclic allylic anti-hydrazino alcohols in good yield.
Chiral R-branched amines are a key feature of bioactive
naturally occurring amino alcohols such as sphingolipids,1
hydroxylated pyrrolidines and piperidines (“azasugars”),2 and
aminosugars.3 Amino alcohols4,5 are also components of
commonly used chiral building blocks, auxiliaries, and
ligands in asymmetric synthesis4 and have been proposed
as key binding motifs for design of biomimetic recognition
processes.6 When not available by direct reduction of amino
acids, amino alcohols are often prepared by indirect routes
involving various permutations of stepwise C-C and C-N
bond constructions with a separate asymmetric induction step
(e.g., alkene oxidation or carbonyl reduction).7,8 In contrast,
(1) For a review, see: Kolter, T.; Sandhoff, K. Angew. Chem., Int Ed.
1999, 38, 1532.
(2) Reviews: (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. 1999, 38, 750-770. (b) Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-
VCH: Weinheim, 1998. (c) Nash, R. J.; Watson, A. A.; Asano, N. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Pergamon: Tarrytown, NY, 1996; pp 345-376.
(3) (a) Review: Hauser, F. M.; Ellenberger, S. R. Chem. ReV. 1986, 86,
35-67. (b) For selected recent syntheses, see: Sibi, M.; Lu, J.; Edwards,
J. J. Org. Chem. 1997, 62, 5864. Nicolaou, K. C.; Mitchell, H. J.; van Delft,
F. L.; Rubsam, F.; Rodriguez, R. M. Angew. Chem., Int. Ed. 1998, 37,
1871.
(6) Wong, C.-H.; Hendrix, M.; Manning, D. D.; Rosenblum, C.;
Greenberg, W. A. J. Am. Chem. Soc. 1998, 120, 8319 and references therein.
(7) Alkene oxidation methods demand isomerically pure alkenes, which
can in turn require nontrivial syntheses and/or separations.
(8) Representative examples: Barrett, A. G. M.; Beall, J. C.; Braddock,
D. C.; Flack, K.; Gibson, V. C.; Salter, M. M. J. Org. Chem. 2000, 65,
6508. Zhou, B.; Edmondson, S.; Padron, J.; Danishefsky, S. J. Tetrahedron
Lett. 2000, 41, 2039. Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H.
J. Org. Chem. 2000, 65, 1623. Boger, D. L.; Ledeboer, M. W.; Kume, M.
J. Am. Chem. Soc. 1999, 121, 1098. Ghosh, A. K.; Wang, Y. J. Org. Chem.
1999, 64, 2789.
(9) Reviews: Bloch, R. Chem. ReV. 1998, 98, 1407. Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. Denmark, S. E.;
Nicaise, O. J.-C. J. Chem. Soc., Chem. Commun. 1996, 999. Selected recent
examples: Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875.
Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. Kobayashi,
S.; Sugita, K.; Oyamada, H. Synlett 1999, 138. Davis, F. A.; Reddy, R. E.;
Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.;
Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555.
(4) Reviews: Bergmeier, S. C. Tetrahedron 2000, 56, 2561. Ager, D.
J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. Reetz, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531.
(5) Selected recent C-C bond construction approaches for synthesis of
1,2-amino alcohols: Matsuda, F.; Kawatsura, M.; Dekura, F.; Shirahama,
H. J. Chem. Soc., Perkin Trans. 1 1999, 2371. Petasis, N. A.; Zavialov, I.
A. J. Am. Chem. Soc. 1998, 120, 11798. Trost, B. M.; Lee, C. B. J. Am.
Chem. Soc. 1998, 120, 6818. Kobayashi, S.; Furuta, T.; Hayashi, T.;
Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. Barrett, A.
G. M.; Seefeld, M. A.; White, A. J. P.; Williams, D. J. J. Org. Chem. 1996,
61, 2677. Enders, D.; Reinhold, U. Angew. Chem., Int. Ed. Engl. 1995,
34, 1219.
10.1021/ol0067991 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/05/2000

retrosynthetic C-C bond disconnection of R-branched
amines (Figure 1) suggests inherently efficient syntheses may
and Bertrand.16 Furthermore, a synthetically viable intermo-
lecular addition of vinyl or aryl radicals to CdN bonds has
not yet been developed. Here we disclose a temporary silicon
tether approach that formally achieves vinyl radical addition
to hydrazones via a diastereoselective tandem addition,
cyclization, and elimination process.
We have previously shown that conformational constraints
can be harnessed via a temporary silicon connection17 to
achieve formal acyclic stereocontrol of radical addition to
R-hydroxyhydrazones, leading to anti-hydrazino-1,3-diols
(Figure 2).18 Along with the hydroxymethyl group addition
Figure 1. Carbon-carbon radical disconnection for synthesis of
chiral R-branched amines.
be available by creating both a stereogenic center and a C-C
bond in a single synthetic transformation involving addition
to a CdN bond. Application of such a C-C bond construc-
tion strategy has been underdeveloped, largely because
additions of carbanionic reagents to aldehyde imino deriva-
tives9 (azomethines) under basic conditions often suffer
competing aza-enolization.10 New C-C bond constructions
for chiral R-branched amine synthesis under mild conditions
are consequently in high demand.11
Nonpolar radical addition reactions12 with aldimine deriva-
tives13 (Figure 1) should avoid imine aza-enolization and
tolerate highly functionalized precursors, complementing
carbanion reagents. However, acyclic stereocontrol of alkyl
radical addition to CdN acceptors is rare, appearing only in
recent reports from our laboratories14 and those of Naito15
Figure 2. Silicon-tethered synthetic equivalents of hydroxymethyl
and vinyl groups and their stereocontrolled radical addition to
CdN bonds.
(10) (a) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178. (b)
Even organocerium reagents, considered relatively nonbasic nucleophiles,
can promote aza-enolization of hydrazones. Enders, D.; Diez, E.; Fernandez,
R.; Martin-Zamora, E.; Munoz, J. M.; Pappalardo, R. R.; Lassaletta, J. M.
J. Org. Chem. 1999, 64, 6329. (c) Wittig, G.; Frommeld, H. D.; Suchanek,
P. Angew. Chem., Int. Ed. Engl. 1963, 2, 683. Wittig, G.; Reiff, H. Angew.
Chem., Int. Ed. Engl. 1968, 7, 7.
exemplified in these previous results, our synthetic objectives
called for a method to introduce a functionalized two-carbon
fragment. Intermolecular addition of heteroatom radicals to
an alkene or alkyne can initiate a cyclization event when a
second radical acceptor moiety is appropriately situated.19
We hypothesized that thiyl radical addition to a vinylsilane
temporarily tethered to a chiral R-hydroxyhydrazone would
facilitate such a cyclization with excellent stereocontrol.20,21
(11) The goal of mild, stereoselective C-C bond constructions with imino
derivatives has generated significant research activity. For selected asym-
metric approaches, see (a) Strecker reactions: Porter, J. R.; Wirschun, W.
G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 2657. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J.
Am. Chem. Soc. 2000, 122, 762. Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157. (b) Mannich reactions: Saito, S.; Hatanaka, K.; Yamamoto,
H. Org. Lett. 2000, 2, 1891. Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi,
A. Angew. Chem., Int. Ed. 2000, 39, 1958. Fujii, A.; Hagiwara, E.; Sodeoka,
M. J. Am. Chem. Soc. 1999, 121, 5450. Ferraris, D.; Dudding, T.; Young,
B.; Drury, W. J., III; Lectka, T. J. Org. Chem. 1999, 64, 2168. (c)
Organostannane additions: Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc.
2000, 122, 976. Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999,
121, 6942. Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844. Nakamura, H.;
Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 4242. (d)
Imino-ene reactions: Drury, W. J., III; Ferraris, D.; Cox, C.; Young, B.;
Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006. (e) Organotitanium
additions: Teng, X.; Takayama, Y.; Okamoto, S.; Sato, F. J. Am. Chem.
Soc. 1999, 121, 11916. (f) Nitrone cycloadditions: Ishikawa, T.; Kudo, T.;
Shigemori, K.; Saito, S. J. Am. Chem. Soc. 2000, 122, 7633. Denmark, S.
E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875.
(15) Miyabe, H.; Ushiro, C.; Naito, T. J. Chem. Soc., Chem. Commun.
1997, 1789. Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569. Miyabe,
H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000,
65, 176.
(16) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998,
780. Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148. Bertrand, M. P. Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P.
Tetrahedron 2000, 56, 3951.
(17) Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh, K. J. Org. Chem.
1984, 49, 2298. Stork, G.; Kahn, M. J. Am. Chem. Soc. 1985, 107, 500.
Reviews of silicon-tethered reactions: Gauthier, D. R., Jr.; Zandi, K. S.;
Shea, K. J. Tetrahedron 1998, 54, 2289. Fleming, I.; Barbero, A.; Walter,
D. Chem. ReV. 1997, 97, 2063. Bols, M.; Skrydstrup, T. Chem. ReV. 1995,
95, 1253.
(12) Recent reviews of stereocontrol in radical reactions: Curran, D.
P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions: Concepts,
Guidelines, and Synthetic Applications; VCH: New York, 1995. Sibi, M.
P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2562. General reviews of radical reactions
in organic synthesis: Hart, D. J. Science 1984, 223, 883. Giese, B. Radicals
in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon
Press: New York, 1986. Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem.
ReV. 1991, 91, 1237. Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301.
(18) Friestad, G. K. Org. Lett. 1999, 1, 1499.
(19) Review: Naito, T. Heterocycles 1999, 50, 505. Recent examples
involving CdN bonds: Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T.
Tetrahedron 2000, 56, 6199. Depature, M.; Diewok, J..; Grimaldi, J.; Hatem,
J. Eur. J. Org. Chem. 2000, 275. Ryu, I.; Ogura, S.; Minakata, S.; Komatsu,
M. Tetrahedron Lett. 1999, 40, 1515. Depature, M.; Siri, D.; Grimaldi, J.;
Hatem, J.; Faure, R. Tetrahedron Lett. 1999, 40, 4547. Marco-Contelles,
J.; Rodriguez, M. Tetrahedron Lett. 1998, 39, 6749.
(20) This exploits a vinylsilane as a source of a tethered radical.
Previously, intramolecular trapping of various cyclic radicals with a
vinylsilane as a tethered radical acceptor has been reported. Shuto, S.;
Yahiro, Y.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2000, 65, 5547 and
references therein.
(13) Review of radical cyclizations to CdN acceptors: Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543.
(14) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329.
4238
Org. Lett., Vol. 2, No. 26, 2000

Subsequent thiolate elimination during excision of the tether
would complete a tandem process comprising stereoselective
vinyl addition to a hydrazone. The potentially valuable
differentially functionalized allylic amino alcohol products
may be regarded as substituted vinylglycinols; the parent
structure (R ) H) is a chiral building block of well-
documented utility.22
For an initial feasibility study, we began with glycol-
aldehyde dimer, which was condensed with diphenylhydra-
zine to provide R-hydroxyhydrazone 1a23 (78%). Silylation
with commercially available chlorodimethylvinylsilane (2,
Scheme 1) provided the addition/cyclization substrate 3a23
1b-e18 by silylation with 2. Sequential treatment with
thiophenol/AIBN and KF led to allylic anti-hydrazino
alcohols 5b-e23 (Table 1).26,27 The diastereoselectivity,
Table 1. Yields and Selectivities of Radical Addition/
Cyclization with Various R Groupsa
Scheme 1. Preparation of Hydrazone Cyclization Substrates
entry
R
yield,b product
ratio (anti:syn)c
1
2
3
4
5c
6
H
54%, 5a
77%, 5b
67%, 5c
61%, 5d
89%, 5d
49%, 5e
Me
iBu
iPr
iPr
Ph
90:10
94:6
98:2
>98:2d,e
(93% yield). Although treatment of 3a with tributyltin
hydride and AIBN [2,2′-azobis(isobutyronitrile)] appeared
in preliminary experiments to lead to the desired addition/
>98:2e
a Conditions: 1.2 equiv of PhSH, 10 mol % AIBN, 0.1-0.3 mmol
hydrazone in refluxing cyclohexane (0.1 M); 2-3 h with TLC monitoring.
If necessary (TLC), additional AIBN was added and the reaction was
continued until complete. b Isolated yields of diastereomeric mixtures.
c Ratios from integration of 500 MHz 1H NMR spectra. d Reaction run on
5 g scale; isolated yield and ratio were determined after crystallization (single
diastereomer). e Minor isomer not detected.
1
cyclization process as judged by H NMR spectra, further
attempted transformations of the cyclic product gave complex
mixtures and low yields. In contrast, treatment with thiophe-
nol and AIBN (cyclohexane, reflux) resulted in very clean,
efficient C-C bond construction to furnish cyclic silane 4a
1
(mixture of diastereomers by H NMR), which was not
90:10 or higher in all cases, is attributable to conformational
constraints imposed by the silicon tether, leading to distinc-
tions among transition states according to the Beckwith-
Houk model28 for 4-substituted 5-hexenyl radical cycliza-
tions. A transition state resembling chairlike conformation
A, wherein the pseudoequatorial orientation of substituent
R minimizes allylic strain, is consistent with the observed
anti diastereoselection. The minor syn product would be
expected from disfavored chair-axial and/or boat conforma-
tions.29,30
amenable to standard flash chromatography on silica gel. In
the same flask, 4a was smoothly converted to allylic
hydrazino alcohol 5a23 (R ) H, racemic) by the action of
KF (54% yield, two steps). Presumably â-elimination of
thiolate occurs from an intermediate fluorosilicate, regenerat-
ing the alkene functionality.24 This one-pot process achieves
vinyl addition to a CdN bond under neutral conditions,
without toxic and difficult-to-remove stannane reagents.
Next we explored the diastereoselectivity of the process
using cyclization substrates 3b-e23,25 (Scheme 1), easily
prepared from enantiomerically pure R-hydroxy hydrazones
(26) Relative configuration of 5d was assigned by chemical correlation:
Acetonide formation, Lemieux-Johnson oxidation, reduction, and acetonide
equilibration led to known anti-2-hydrazino-1,3 diol acetonide i (see
Supporting Information).
(21) A nonradical silicon-tethered strategy using BF3‚OEt2-induced
vinylsilane addition to an acyliminium ion has been reported. Hioki, H.;
Izawa, T.; Yoshizuka, M.; Kunitake, R.; Ito, S. Tetrahedron Lett. 1995,
36, 2289.
(22) For selected alternative preparations and applications, see: Trost,
B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99 and references
therein. See also: Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem.
2000, 65, 5887. Harris, M. C. J.; Jackson, M.; Lennon, I. C.; Ramsden, J.
A.; Samuel, H. Tetrahedron Lett. 2000, 41, 3187. Monache, G. D.; Misiti,
D.; Salvatore, P.; Zappia, G.; Pierini, M. Tetrahedron: Asymmetry 2000,
11, 2653.
(23) Structures of new compounds 1a, 1f, 3, and 5 are consistent with
combustion analyses and spectroscopic data (1H and 13C NMR, IR, MS)
provided in the Supporting Information.
(27) Previous work established that epimerization of R-hydroxy hydra-
zones during a related sequence did not occur except when the anion-
stabilizing phenyl group was present (i.e., 1e). See ref 18.
(28) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
(29) Cyclohexane terminology for 5-hexenyl radical transition states is
the current convention, see ref 12.
(30) We did not attempt to determine the relative configuration of the
phenylthiomethyl substituent in 4; this stereogenic center is lost during the
subsequent elimination.
(24) For a similar fluorodesilylative â-elimination of a â-phenylseleno
group, see: Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org. Chem. 1999, 64,
7153.
(25) Hydrazones were obtained as single CdN bond isomers (>98:2).
Org. Lett., Vol. 2, No. 26, 2000
4239

We expected that a D-glyceraldehyde hydrazone containing
two tethered vinyl groups would also undergo vinyl transfer
stereoselectively through the proximal silyl ether linkage via
the more rapid 5-exo cyclization.31 To test this hypothesis,
hydrazone 1f 23 (Scheme 2) was prepared by condensation
5f,23 a potentially useful chiral building block with differ-
entially functionalized termini. It is worth noting that the
two hydroxyls of D-glyceraldehyde do not require protection
or differentiation prior to this radical vinylation sequence.
Finally, a promising indication for multigram material
throughput was observed upon increasing the scale to ca. 5
g (Table 1, entry 5). Crystalline, diastereomerically pure 5d
was obtained in a significantly improved yield (89% after
crystallization). Further scale-up has not yet been attempted.
Scheme 2. Vinyl Addition to d-Glyceraldehyde Hydrazone
without Prior Hydroxyl Protection or Differentiation
In conclusion, we have developed a carbon-carbon bond
construction approach toward synthesis of chiral R-branched
aminessspecifically, substituted vinylglycinolsswhich ex-
ploits the temporary silicon connection and a tandem radical
process for stereocontrolled vinyl addition to CdN bonds.
This novel nonpolar acyclic amino alcohol synthesis comple-
ments existing methods, and its synthetic utility is under
further examination.
Acknowledgment. We thank the University of Vermont
for support of this research. Partial support has been provided
by the Petroleum Research Fund, administered by the
American Chemical Society, and the Research Corporation
(Research Innovation Award to G.K.F.).
of commercially available aqueous D-glyceraldehyde with
diphenylhydrazine. Silylation of both hydroxyls afforded
vinylation substrate 3f,23 wherein 5-exo or 6-exo cyclization
could be initiated by thiyl addition to either of the vinylsi-
lanes. In fact, radical vinylation proceeded as before with
high selectivity (dr 91:9) to provide allylic hydrazino diol
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(31) For kinetic data, see: Sturino, C. F.; Fallis, A. G. J. Org. Chem.
1994, 59, 6514.
OL0067991
4240
Org. Lett., Vol. 2, No. 26, 2000