A silicon tether approach for diastereocontrol in radical addition to chiral hydrazones

Article abstract of DOI:10.1021/ol991059h

(formula presented) A radical carbon-carbon bond construction approach to chiral α-branched amines is presented. Stereocontrolled radical addition to chiral hydrazones can be achieved by virtue of conformational constraints imposed during cyclizations usi

Full text of DOI:10.1021/ol991059h

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1499-1501
A Silicon Tether Approach for
Diastereocontrol in Radical Addition to
Chiral Hydrazones
Gregory K. Friestad
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
gregory.friestad@uVm.edu
Received September 16, 1999
ABSTRACT
A radical carbon−carbon bond construction approach to chiral r-branched amines is presented. Stereocontrolled radical addition to chiral
hydrazones can be achieved by virtue of conformational constraints imposed during cyclizations using a temporary silicon connection. Oxidative
removal of the tether completes the hydroxymethylation process to afford anti-2-hydrazino-1,3-diols in good yield. The 1,2-induction increases
with increasing A values of the appended groups, consistent with prediction by the Beckwith−Houk model for stereocontrol in 5-hexenyl
radical cyclizations.
Chiral R-branched amines are key features within bioactive
amino alcohols such as sphingolipids and aminosugars; direct
and efficient synthetic strategies exploiting carbon-carbon
bond construction with acyclic stereocontrol hold consider-
able promise for streamlined preparation of these valuable
targets.1 Currently common are indirect routes involving
stepwise C-C and C-N bond constructions and often a third
separate asymmetric induction step (e.g., alkene epoxidation
or carbonyl reduction).2 In contrast, a strategy exploiting
retrosynthetic C-C bond disconnection of R-branched
amines (Figure 1) creates both a stereocenter and a C-C
bond in one synthetic transformation.
ionic reagents to aldehyde imino derivatives3 (azomethines)
often suffer competing aza-enolization.4 New C-C bond
constructions for chiral R-branched amine synthesis are
consequently in high demand.5
To address the general problem of acyclic chiral R-branched
amine synthesis, nonpolar radical additions to CdN bonds6
(1) Reviews of methods for amino alcohol synthesis: Reets, M. T. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1531. Ager, D. J.; Prakash, I.; Schaad, D.
R. Chem. ReV. 1996, 96, 835. For ionic C-C bond construction approaches,
see: Enders, D.; Reinhold, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 1219.
Barrett, A. G. M.; Seefeld, M. A.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 1996, 61, 2677. Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima,
M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. Trost, B. M.; Lee, C.
B. J. Am. Chem. Soc. 1998, 120, 6818. Petasis, N. A.; Zavialov, I. A. J.
Am. Chem. Soc. 1998, 120, 11798.
(2) Recent examples in natural product synthesis: 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. Deng, J.; Hamada, Y.; Shioiri, T. Synthesis
1998, 627.
(3) 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: Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portunovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555. Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268. Kobayashi, S.; Sugita, K.; Oyamada, H. Synlett
1999, 138.
Figure 1. Carbon-carbon disconnection for synthesis of chiral
R-branched amines.
(4) Even organocerium reagents, considered relatively nonbasic nucleo-
philes, can promote aza-enolization of hydrazones. Enders, D.; Diez, E.;
Fernandez, R.; Martin-Zamora, E.; Munoz, J. M.; Pappalardo, R. R.;
Lassaleta, J. M. J. Org. Chem. 1999, 64, 6329.
Application of the C-C bond construction strategy has
been underdeveloped, largely because additions of carban-
10.1021/ol991059h CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/01/1999

(Figure 1) could (a) circumvent imine aza-enolization
problems, (b) efficiently construct crowded C-C bonds, and
(c) tolerate highly functionalized precursors. However,
acyclic stereocontrol of radical additions to CdN is virtually
unknown.7 Could the well-known high internal conforma-
tional diastereocontrol of 5-hexenyl radical cyclizations8 be
harnessed for formal acyclic stereocontrol of radical addition
to CdN bonds? To test this hypothesis, the preexisting
stereocenter of a chiral R-hydroxy ester would serve to direct
the 5-exo-trig cyclization of a radical tethered via a temporary
silicon connection9 (Figure 2). Subsequent oxidative removal
Cyclization of bromides 4 using standard tin hydride
conditions (1.4 equiv of Bu3SnH, 10 mol % of AIBN, PhH,
0.02 M) resulted in very clean, efficient C-C bond construc-
tion to furnish unstable cyclic silanes 5 (Scheme 2). In the
Scheme 2. Silicon-Tethered Radical Addition to Hydrazones
Figure 2. Silicon tether approach to stereocontrolled radical
addition to CdN bonds.
same flask, Tamao oxidation17 (KF, KHCO3, H2O2) then
smoothly delivered anti-2-hydrazino-1,3-diols 613 in good
yields. The cyclic silane intermediates were unstable to
normal silica gel chromatography but were examined easily
of the tether10 would afford acyclic chiral R-branched
amines.11 Here I disclose initial experiments which confirm
the viability of the silicon tether approach for stereoselective
hydroxymethylation of hydrazones and explore substituent
effects on diastereocontrol.
From readily available enantiomerically pure R-silyloxy
esters 1a-d,12 standard transformations led conveniently to
cyclization substrates 4 in good overall yields (Scheme 1).
(6) (a) Review of radical cyclizations to CdN acceptors: Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Intermolecular radical
addition to CdN acceptors: Miyabe, H.; Fujishima, Y.; Naito, T. J. Org.
Chem. 1999, 64, 2174 and references therein. (c) General reviews of radical
reactions in organic synthesis: 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.
(7) Only two studies showing acyclic stereocontrol in radical addition
to CdN acceptors have appeared to date: Miyabe, H.; Ushiro, C.; Naito,
T. J. Chem. Soc., Chem. Commun. 1997, 1789. Bertrand, M. P.; Feray, L.;
Nouguier, R.; Stella, L. Synlett 1998, 780. For acyclic stereocontrol in radical
addition to CdC bonds, see: Sibi, M. P.; Porter, N. A. Acc. Chem. Res.
1999, 32, 163 and references therein.
Scheme 1. Preparation of Hydrazone Cyclization Substrates
(8) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH: New
York; 1995.
(9) 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: 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. For a recent nonradical
application to amino alcohol synthesis, see: Righi, P.; Marotta, E.; Rosini,
G. Chem. Eur. J. 1998, 4, 2501.
(10) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1.
(11) Importantly, the silicon tether should permit introduction of a variety
of functionalized fragments in addition to hydroxymethyl. Tamao, K.;
Maeda, K.; Yamaguchi, T.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 4984.
(12) Esters 1 are prepared easily by standard methods from commercially
available hydroxy acids or amino acids.
(13) All structures 2, 3, 6, and 7 are consistent with combustion analyses,
spectroscopic data (1H and 13C NMR, IR, MS), and optical rotation. See
Supporting Information.
(14) Hydrazones 2-4 were essentially single isomers (>98:2) with
respect to the CdN bond; only 2a-4a contained detectable traces (<5%)
of a minor isomer. Aldehyde hydrazones are generally obtained as E isomers.
Enders, D. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press:
New York, 1984; pp 275-339.
Silylation and DIBAL reduction gave aldehydes which
condensed readily with N,N-diphenylhydrazine to afford the
corresponding hydrazones 2.13,14 Desilylation gave R-hydroxy
hydrazones 3,13 which upon treatment with bromometh-
yldimethylsilyl chloride in the presence of triethylamine
provided radical cyclization substrates 4.15,16
(15) Cyclization substrates 4 were purified rapidly by flash chromatog-
raphy and used immediately in the next step.
(16) Mosher ester analysis confirmed that the integrity of the preexisting
stereocenter was maintained through the sequence to diols 6b and 6c (>96%
ee). However, alcohol 3d, wherein the phenyl group can promote enolization,
suffered significant racemization en route to 6d. The R-hydroxy and
R-silyloxy hydrazones without additional carbanion-stabilizing functionality
are configurationally stable under these conditions.
(5) Mild, stereoselective additions to aldehyde imino derivatives are a
prominent current challenge. For notable efforts and leading references,
see: Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. Kobayashi, S.;
Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942. Fujii, A.; Hagiwara,
E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
(17) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. 8, p 315.
1500
Org. Lett., Vol. 1, No. 9, 1999

by 1H NMR spectroscopy and stored indefinitely in benzene
at -5 °C without significant decomposition.
Table 1. Correlation of Cyclization Diastereoselectivity with
Relative configuration was ascertained upon conversion
of diols 6 to the corresponding 1,3-diol acetonides 713
(Scheme 3). Large vicinal coupling constants (1H NMR, J2,3
Substituent A Values
Scheme 3. Relative Configurations of 2-Hydrazino-1,3-diols
entry
R
A valuea (kcal/mol)
product, ratio (anti:syn)b
1
2
3
4
Me
iBu
iPr
Ph
1.6
1.8 (est.)
2.2
5a , 80:20 [6a , 79:21]
5b, 88:12 [6b, 85:15]
5c, 95:5 [6c, 96:4]c
5d , >98:2d [6d , >98:2]d
2.9
a
A values are free energy differences between equatorial and axial chair
cyclohexanes.21 Values for R are assumed similar here in order to show
the trend within the series. Ratios from integration of H NMR spectra.
Gravimetric ratio of separated diastereomers. Minor isomer not detected.
b
1
c
d
) 8.7-9.7 Hz) revealed anti configurations.18 Predominant
chair conformations were confirmed by appropriate acetonide
chemical shifts (13C NMR).19
In conclusion, a method for stereocontrolled radical
addition to chiral hydrazones has been designed and imple-
mented which, in conjunction with established methods for
reductive cleavage of hydrazine N-N bonds,23 constitutes a
novel nonpolar complement to ionic methods for acyclic
amino alcohol synthesis. This carbon-carbon bond construc-
tion approach to chiral R-branched amine synthesis features
the temporary silicon connection for formal acyclic stereo-
control of radical addition to CdN bonds.
The Beckwith-Houk model20 predicts enhancement of
diastereoselectivity upon increasing substituent steric demand
in 4-substituted 5-hexenyl radical cyclizations. The present
method was conceived in expectation that a similar transition
state model would apply. Indeed, experimental support for
this is seen in the correlation of diastereoselectivity with
substituent A values21 (Table 1). A preferred chairlike
transition state with a pseudoequatorial substituent minimiz-
ing allylic strain is consistent with the observed product
distributions; the minor syn product would be expected from
disfavored chair-axial and/or boat conformations.22
Acknowledgment. I thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this research. Additional
support was provided by the University of Vermont.
(18) Mori, K.; Uenishi, K. Liebigs Ann. Chem. 1994, 41. Barrett, A. G.
M.; Rys, D. J. Chem. Soc., Perkin Trans. 1 1995, 1009. Han, B. H.; Kim,
J. C.; Park, M. K.; Park, J. H.; Go, H. J.; Yang, H. D.; Suh, D.-Y.; Kang,
Y.-H. Heterocycles 1995, 41, 1909. Herold, P. HelV. Chim. Acta 1988, 71,
354.
(19) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
Supporting Information Available: Experimental pro-
cedures and complete analytical data for compounds 2, 3, 6,
and 7. This material is available free of charge via the Internet
at http://pubs.acs.org.
(20) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
(21) Bushweller, C. H. In Conformational BehaVior of Six-Membered
Rings; Juaristi, E., Ed.; VCH: New York, 1995.
(22) Cyclohexane terminology for 5-hexenyl radical transition states is
the current convention. See ref 8 for discussion.
OL991059H
(23) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266.
Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc. 1996, 116, 7447. Martin, S.
F.; Hom, R. K. Tetrahedron Lett. 1999, 40, 2887. Enders, D.; Reinhold, U.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1219.
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