Haloacetal radical cyclizations of α- and β-hydroxyhydrazones

Article abstract of DOI:10.1021/ol050663r

(Chemical Equation Presented) Haloacetal radical cyclizations of α- and β-hydroxyhydrazones provide a direct access to aminosugarlike compounds. Stereocontrol of this process is influenced by stereogenic centers of both the hydroxyhydrazone and the acetal

Full text of DOI:10.1021/ol050663r

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2393-2396
Haloacetal Radical Cyclizations of
r-
and
â-Hydroxyhydrazones
Gregory K. Friestad*,† and Gina M. Fioroni‡
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242, and
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
gregory-friestad@uiowa.edu
Received March 28, 2005
ABSTRACT
Haloacetal radical cyclizations of
r- and â-hydroxyhydrazones provide a direct access to aminosugarlike compounds. Stereocontrol of this
process is influenced by stereogenic centers of both the hydroxyhydrazone and the acetal. The outcomes are consistent with chair and twist
transition states with the anomeric alkoxy group in pseudoaxial orientations.
Stereocontrolled construction of C-C bonds using radical
addition to imino acceptors1,2 may be accomplished using a
tether to transmit stereochemical information from a vicinal
stereocenter (Figure 1). Previously, we exploited silyl ethers
butyrolactones and by Stork5 for the construction of bicyclic
acetals and lactones in the early 1980s, and numerous
synthetic applications have followed.6 Despite the broad
utility of the Ueno-Stork haloacetal cyclization for addition
to alkenes, imine acceptors have rarely been used.7
(2) Selected recent examples: (a) Friestad, G. K.; Qin, J. J. Am. Chem.
Soc. 2000, 122, 8329-8330. Friestad, G. K.; Qin, J. J. Am. Chem. Soc.
2001, 123, 9922-9923. Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew.
Chem., Int. Ed. 2003, 42, 5061-5063. Friestad, G. K.; Deveau, A. M.;
Marie´, J.-C. Org. Lett. 2004, 6, 3249-3252. (b) Miyabe, H.; Ushiro, C.;
Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176-185.
Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 2003, 1, 381-390.
McNabb, S. B.; Ueda, M.; Naito, T. Org. Lett. 2004, 6, 1911-1914. (c)
Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron
2000, 56, 3951-3961. (d) Yamada, K.; Yamamoto, Y.; Maekawa, M.;
Tomioka, K. J. Org. Chem. 2004, 69, 1531-1534. (e) Ferna´ndez, M.;
Alonso, R. Org. Lett. 2003, 5, 2461-2464. (f) Halland, N.; Jørgensen, K.
A. J. Chem. Soc., Perkin Trans. 1 2001, 1290-1295.
(3) Friestad, G. K.; Massari, S. E. J. Org. Chem. 2004, 69, 863-875.
Friestad, G. K.; Jiang, T.; Fioroni, G. M. Tetrahedron: Asymmetry 2003,
14, 2853-2856. Friestad, G. K.; Massari, S. E. Org. Lett. 2000, 2, 4237-
4240. Friestad, G. K. Org. Lett. 1999, 1, 1499-1501.
(4) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J.
Am. Chem. Soc. 1982, 104, 5564-5566.
(5) Stork, G.; Mook, R.; Biller, S.; Rychnovsky, S. D. J. Am. Chem.
Soc. 1983, 105, 3741-3742. Stork, G. Bull. Soc. Chim. Fr. 1990, 127, 675-
680. Stork, G.; Ouerfelli, O. New J. Chem. 1992, 16, 95-98.
Figure 1. Use of a tether for stereocontrolled radical addition to
CdN bonds.
as temporary tethers for this purpose in an approach to anti-
1,2-amino alcohols.3 The C-C bond is formed under neutral
conditions without the complications associated with addi-
tions of basic organometallic reagents such as competing
enolization.
The Ueno-Stork reaction (haloacetal radical cyclization)
was first introduced by Ueno4 for the functionalization of
† University of Iowa.
(6) (a) For a comprehensive review, see: Salom-Roig, X. J.; De´ne`s, F.;
Renaud, P. Synthesis 2004, 1903-1928. (b) For more recent examples,
see: Yoshimitsu, T.; Sasaki, S.; Arano, Y.; Nagaoka, H. J. Org. Chem.
2004, 69, 9262-9268. Ward, D. E.; Gai, Y. Z.; Qiao, Q.; Shen, J. H. Can.
J. Chem. 2004, 82, 254-267. Itoh, T.; Kudo, K.; Yokota, K.; Tanaka, N.;
Hayase, S.; Renou, M. Eur. J. Org. Chem. 2004, 406-412. Clive, D. L. J.;
Yu, M. L.; Sannigrahi, M. J. Org. Chem. 2004, 69, 4116-4125. Yadav, J.
S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81-89.
‡ University of Vermont.
(1) Reviews of radical additions to imines and related acceptors: (a)
Friestad, G. K. Tetrahedron 2001, 57, 5461-5496. (b) Fallis, A. G.; Brinza,
I. M. Tetrahedron 1997, 53, 17543-17594. (c) For reviews of contributions
from the Naito and Bertrand groups, see: Miyabe, H.; Ueda, M.; Naito, T.
Synlett 2004, 1140-1157. Bertrand, M.; Feray, L.; Gastaldi, S. Compt. Rend.
Acad. Sci. Paris, Chim. 2002, 5, 623-638.
10.1021/ol050663r CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/11/2005

We envisioned application of 5- and 6-exo haloacetal cycli-
zations for direct access to aminosugars8 (Figure 2). As a
states with axial anomeric alkoxy groups, e.g., TS1-like and
TS1-unlike (Figure 3b). For cyclization of 1-like, the twist
transition state benefits from anomeric stabilization while
avoiding 1,3-diaxial interactions of the corresponding chair-
like transition state. Similarly, 6-exo cyclization of 3 via a
chairlike transition state with OEt axial is consistent with
exclusive formation of 4 (Figure 3c). These findings em-
phasize the important role of the anomeric effect in a refined
Beckwith-Houk model.
First, several cyclization substrates were prepared. For
5-exo cyclization substrates, the R-hydroxyhydrazones 5a and
5c (Scheme 1) were obtained from glycolaldehyde and (S)-
Figure 2. Potential access to aminopyranoside or aminofuranoside
structures via haloacetal radical cyclization.
prelude to aminosugar synthesis, we initiated a study of the
stereochemical outcome of these reactions with imino accep-
tors. Here we report haloacetal cyclizations of acyclic R-
and â-hydroxyhydrazones and their stereochemical conse-
quences.
Scheme 1. Access to R- and â-Hydroxyhydrazones
The stereoselectivity of haloacetal radical cyclizations
using acyclic precursors would be expected to be influenced
heavily by the anomeric acetal stereogenic center. Interest-
ingly, Renaud and co-workers showed that either relative
configuration of bromoacetal 1 (Figure 3a) leads to the same
lactate, respectively, as previously described.3 An achiral
â-hydroxyhydrazone was obtained from monosilyl ether 610
by Swern oxidation and condensation with diphenylhydrazine
hydrochloride in pyridine (59% yield, two steps). Desilylation
with tetrabutylammonium fluoride (TBAF) then provided 5b
in 76% yield.
Chiral â-hydroxyhydrazone 5d was synthesized from
methyl (S)-3-hydroxybutyrate (Scheme 1). Reduction of ester
711 with DIBAL afforded the aldehyde, which was condensed
with diphenylhydrazine to give the corresponding hydrazone
(8) Review: (a) Hauser, F. M.; Ellenberger, S. R. Chem. ReV. 1986, 86,
35-67. For selected references to synthesis and biological properties of
aminosugars, see: (b) Ge, M.; Chen, Z.; Onishi, H. R.; Kohler, J.; Silver,
L. L.; Kerns, R.; Fukuzawa, S.; Thompson, C.; Kahne, D. Science 1999,
284, 507-511. (c) Kong, F.; Zhao, N.; Siegel, M. M.; Janota, K.; Ashcroft,
J. S.; Koehn, F. E.; Borders, D. B.; Carter, G. T. J. Am. Chem. Soc. 1998,
120, 13301-13311. (d) Nicolaou, K. C.; Mitchell, H. J.; van Delft, F. L.;
Rubsam, F.; Rodriguez, R. M. Angew. Chem., Int. Ed. 1998, 37, 1871-
1874. (e) Rodriguez, M. J.; Snyder, N. J.; Zweifel, M. J.; Wilkie, S. C.;
Stack, D. R.; Cooper, R. D. G.; Nicas, T. I.; Mullen, D. L.; Butler, T. F.;
Thompson, R. C. J. Antibiot. 1998, 51, 560-569. (f) Sibi, M. P.; Lu, J.;
Edwards, J. J. Org. Chem. 1997, 62, 5864-5872.
(9) (a) Renaud, P.; Villar, F. Tetrahedron Lett. 1998, 39, 8655-8658.
(b) Renaud, P.; Villar, F.; Kolly-Kovac, T.; Equey, O. Chem. Eur. J. 2003,
9, 1566-1577. (c) Renaud, P.; Corminboeuf, O.; Schiesser, C. H. Chem.
Eur. J. 2003, 9, 1578-1584.
(10) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388-3390.
(11) Ishiyama, H.; Ishibashi, M.; Ogawa, A.; Yoshida, S.; Kobayashi, J.
J. Org. Chem. 1997, 62, 3831-3836.
Figure 3. Anomeric effect on the stereochemistry of haloacetal
radical cyclization.9 (a) Stereoconvergence of 1-like and 1-unlike,
inconsistent with the classical Beckwith-Houk model. (b) Calcu-
lated transition states (UHF/6-311G**) with axial alkoxy substit-
uents, introducing a twist transition state for cyclization of 1-like.
(c) Product 4 suggests a similar anomeric effect in 6-exo cyclization.
4,5-trans-lactone 2 after radical cyclization and oxidation.9
This apparent contradiction was resolved by calculations in
collaboration with Schiesser, which found only transition
(7) (a) Noya, B.; Paredes, M. D.; Ozores, L.; Alonso, R. J. Org. Chem.
2000, 65, 5960-5968. (b) Inokuchi, T.; Kawafuchi, H. Synlett 2001, 421-
423.
2394
Org. Lett., Vol. 7, No. 12, 2005

in 78% yield (two steps). Desilylation led to the correspond-
ing â-hydroxyhydrazone 5d in 92% yield.
The alcohols 5 were treated with either NBS or NIS and
ethyl vinyl ether to give the cyclization substrates 8 or 9,
respectively, in yields ranging from 38 to 49% (Table 1).
Table 1. Haloacetal Radical Cyclizations of Hydrazones
hydroxy-
hydrazone
haloacetal cyclization
(yield) (yield)
configurationsa
(product ratio)
R, X
5a (n ) 0) H, Br
5a (n ) 0) H, I
5b (n ) 1) H, Br
5b (n ) 1) H, I
8a (48%) 10a (69%) cis:transb (2:1)
9a (47%) 10a (68%) cis:transb (2:1)
8b (44%) 10b (48%) trans:cis (3:1)
9b (38%) 10b (70%) trans:cis (3:1)
5c (n ) 0) Me, Br 8c (36%) 10c (52%) 2R,4R:2â,4R (3:1)
5c (n ) 0) Me, I 9c (49%) 10c (64%) 2R,4R:2â,4R (3:1)
5d (n ) 1) Me, Br 8d (44%) 10d (47%) 2R,4â:2â,4R: 2â,4â
(3:1:1)
5d (n ) 1) Me, I
9d (44%) 10d (41%) 2R,4â:2â,4R: 2â,4â
(3:1:1)
a Assigned by 1H NMR spectra (coupling constants for 10b and 10d,
NOE difference for 10c). b Assigned by analogy with that reported by
Renaud et al.9
These were all obtained as inseparable 1:1 mixtures of
diastereomeric acetals. Although the bromides appeared to
be more stable during standard manipulations, they did not
offer any improvement in yield. Still, adequate quantities
were available to address our questions of stereocontrol.
Radical cyclizations of 8 and 9 were next examined (Table
1). Treatment of bromide 8a with tributyltin hydride and
AIBN in benzene (0.02 M) at reflux afforded 10a in 69%
yield (entry 1). The same reaction of iodide 9a gave 68%
yield (entry 2). Similarly, 8b and 9b were cyclized to afford
10b in 48 and 70% yields, respectively.
Figure 5. Proposed stereocontrol models for formation of 10c and
10d (X ) NPh2). (a) Alternative acetal configurations undergo 5-exo
cyclization via chair or twist transition states to the same 4,5-trans
relative configuration. (b) Alternative acetal configurations lead to
matched (R-anomer) and mismatched (â-anomer) double diaste-
reoselection in 6-exo cyclization. The R-anomer restricts the
conformational freedom of the hydrazone through dipole repulsion
between OEt and the imino nitrogen.
Having demonstrated both 5- and 6-exo cyclization, we
examined the diastereoselectivity of the process using chiral
cyclization substrates derived from enantiomerically pure
R-hydroxyhydrazones 5c and 5d. Upon 5-exo cyclization as
described above, haloacetals 8c and 9c each gave the same
mixture 10c, consisting of two of the four possible diaster-
eomers,12 with the 2R,4R configuration favored (dr 3:1). The
6-exo cyclizations of 8d and 9d formed 10d as three
diastereomers (dr 3:1:1), of which the 2R,4â relative con-
figuration was favored.
Relative configurations were determined by standard NMR
methods. For the 5-exo cyclization product 10c, the config-
uration was examined using the derived hemiacetal 11
(Figure 4), obtained as a mixture of diastereomers via acid-
catalyzed hydrolysis (47% yield, dr 3:1). For the major
diastereomer, a 5.2% NOE enhancement was found at the
vicinal hydrogen upon irradiating the methyl group, diag-
Figure 4. Selected diagnostic data for assignment of relative
configurations of the major diastereomers of 10b-d. Further data
are provided in Supporting Information.
(12) Formation of trace amounts of other diastereomers has not been
excluded.
Org. Lett., Vol. 7, No. 12, 2005
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nostic for the trans relative configuration C4 and C5. In the
6-exo haloacetal cyclization, the relative configurations of
the diastereomers of compounds 10b and 10d were deter-
mined through analysis of coupling constants (Figure 4).13
The stereocontrol in the cyclization reactions can be
rationalized using the Renaud-Schiesser model incorporating
twist transition states and the anomeric effect. For the 5-exo
cyclizations leading to 10c, both the chairlike and the twist
transition states offer stabilization from the anomeric effect
while minimizing steric repulsions, and both form the 4,5-
trans relative configuration (Figure 5a). In the case of 6-exo
cyclizations, the scenario is more complex because the R-
and â-anomers (acetal diastereomers) do not converge to the
same configuration at C4. The favored diastereomer (2R,4â-
10d) has an acetal configuration different from both of the
minor diastereomers. This shows that one acetal (2R) un-
dergoes cyclization with complete selectivity (or there would
be a fourth diastereomer found), while the other acetal (2â)
is nonselective, giving a 1:1 mixture of products. The effects
of the two stereocontrol elements are observed in matched
and mismatched double diastereoselection.
advantage of the excellent matched double diastereoselec-
tion available in 6-exo cyclization of 5d to 10d, a selec-
tive preparation of the 2R acetal configuration would be
required.
Broader application will benefit from further optimization
in two key aspects: First, the formation of haloacetals
requires improved methodology; yields under these condi-
tions were compromised by decomposition and incomplete
mass balance.14 Second, the method at present is limited to
aldehyde hydrazones; a 6-exo radical cyclization of an acyclic
ketone hydrazone was unsuccessful under these conditions,
leading only to reductive dehalogenation.
In conclusion, 5-exo and 6-exo haloacetal radical cycliza-
tions have been applied for the first time to aldehyde hy-
drazone acceptors. Analysis of the stereocontrol shows that
the cyclizations are influenced by stereogenic centers in both
the R- or â-hydroxyhydrazone precursor and the acetal.
Acknowledgment. We thank NSF (CHE-0096803) for
generous support of this work.
The synthetic implications of the stereoselectivity bear
further discussion. For the 5-exo cyclization sequence from
5c to 10c, the stereoconvergence renders the acetal config-
uration irrelevant for applications in which the acetal is
ultimately oxidized or hydrolyzed. In contrast, to take full
Supporting Information Available: General procedures
and characterization data for 5b, 5d, and 8-11. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050663R
(13) Silverstein, R. M.; Webster, F. X. Spectrometric Identification of
Organic Compounds, 6th ed.; Wiley: New York, 1998.
(14) We speculate that oxidative processes involving the hydrazone may
contribute to the incomplete mass balance.
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Org. Lett., Vol. 7, No. 12, 2005