Highly stereoselective intermolecular radical addition to aldehyde hydrazones from a chiral 3-amino-2-oxazolidinone [16]

Full text of DOI:10.1021/ja002173u

J. Am. Chem. Soc. 2000, 122, 8329-8330
Highly Stereoselective Intermolecular Radical
8329
Addition to Aldehyde Hydrazones from a Chiral
3-Amino-2-oxazolidinone
Figure 1. Retrosynthetic analysis of chiral R-branched amines according
to a radical addition strategy and potential origins of stereocontrol.
Gregory K. Friestad* and Jun Qin
Department of Chemistry, UniVersity of Vermont
Burlington, Vermont, 05405
ReceiVed June 19, 2000
Asymmetric synthesis of chiral R-branched amines, ubiquitous
substructures within natural products and other biologically active
synthetic targets, is underdeveloped relative to that of other
functional groups. Consequently, commonly used indirect syn-
thetic methods exploit stepwise introduction of carbon-carbon
bonds, stereogenic centers, and nitrogen (e.g., epoxide opening
with N-nucleophiles). Direct asymmetric amine synthesis by
addition of carbon nucleophiles to the CdN bond of carbonyl
imino derivatives holds promise for improved efficiency by
introducing the stereogenic center and carbon-carbon bond in
one step. However, employing basic organometallic reagents for
this purpose1 often results in competing aza-enolization2 and can
lack generality or functional group tolerance, while Strecker3a and
Mannich3b reactions restrict the incoming nucleophile to cyanide
and enolizable carbonyl compounds, respectively. Versatile new
stereocontrolled carbon-carbon bond construction methods for
direct asymmetric amine synthesis under mild conditions are
therefore in high demand.3
To address the general problem of asymmetric amine synthesis,
nonpolar radical additions to CdN bonds4,5 (Figure 1) would (a)
circumvent imine enolization problems, (b) efficiently construct
crowded C-C bonds, and (c) avoid some functional group
restrictions associated with ionic transformations. Stereocontrolled
intermolecular radical addition6 to CdN bonds was unknown until
Naito7 and Bertrand8 independently reported additions to chiral
glyoxylate and malonate imino derivatives. In these cases the
nearby carbonyl groups were required to activate the radical
Figure 2. (a) Design of a hypothetical N-linked auxiliary approach for
stereocontrolled radical addition to CdN bonds, with Lewis acid (LA)
chelation inducing a rigid, electronically activated radical acceptor. (b)
Implementation with N-acylhydrazones derived from 4-benzyl-2-oxazo-
lidinone.
acceptor or attach a chiral auxiliary. Obviating these requirements
would considerably enhance the versatility of radical additions
for asymmetric amine synthesis. Toward this end, we envisioned
a nitrogen-linked auxiliary approach incorporating Lewis acid
activation and restriction of rotamer populations as key design
elements. We now disclose preparation of novel N-acylhydrazones
from N-amino-4-benzyl-2-oxazolidinone and their implementation
for highly enantioselective intermolecular radical addition reac-
tions.
We first focused on incorporating features desirable for stereo-
control, namely restricted rotamer populations and Lewis acid
actiVation, beginning with a hydrazone with a proximal stereo-
genic center (A, Figure 2). Constraining the C-N bond within a
ring and including a carbonyl group would enable two-point
binding of a Lewis acid to afford a rigid structure (B) with the
stereocontrol element localized over one face of the hydrazone.
The Lewis acid would also increase reactivity toward nucleophilic
radicals9 by lowering the LUMO energy of the CdN bond.
Finally, we noted the facility of reductive cleavage of N-N
bonds,1d,10 whereby the N-linked auxiliary would be released for
reuse after stereoisomer purification. Oxazolidinones11,12 emerged
as obvious initial candidates to test our hypothesis. Surprisingly,
N-amino derivatives of oxazolidinones have appeared in the
literature only rarely,13 and to our knowledge have never been
used for asymmetric synthesis.
(1) Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(b) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c)
Bloch, R. Chem. ReV. 1998, 98, 1407. (d) Enders, D.; Reinhold: U.
Tetrahedron Asymmetry 1997, 8, 1895. (e) Denmark, S. E.; Nicaise, O. J.-C.
J. Chem. Soc., Chem. Commun. 1996, 999.
(2) Aza-enolization of imines with Grignard reagents: Stork, G.; Dowd,
S. R. J. Am. Chem. Soc. 1963, 85, 2178. Less basic organocerium reagents
also exhibit aza-enolization: Enders, D.; Diez, E.; Fernandez, R.; Martin-
Zamora, E.; Munoz, J. M.; Pappalardo, R. R.; Lassaleta, J. M. J. Org. Chem.
1999, 64, 6329.
(3) For selected recent examples, 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: 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)
Allylation: Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942.
(d) Imino-ene reaction: Drury, W. J., III; Ferraris, D.; Cox, C.; Young, B.;
Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006. Yamanaka, M.; Nishida, A.;
Nakagawa, M. Org. Lett. 2000, 2, 159.
(4) (a) Review of radical cyclizations involving nitrogen: Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) 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.
(5) For representative nonstereoselective intermolecular radical additions
to CdN, see: Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631.
Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991, 32, 525. Hanamoto,
T.; Inanaga, J. Tetrahedron Lett. 1991, 32, 3555. Kim, S.; Yoon, J.-Y. J. Am.
Chem. Soc. 1997, 119, 5982. Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T.
Tetrahedron Lett. 1998, 39, 631. Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro,
C.; Naito, T. Tetrahedron 1998, 54, 11431. Bertrand, M. P.; Feray, L.;
Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189. Miyabe, H.; Ueda,
M.; Yoshioka, N.; Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413.
(6) For reviews of acyclic stereocontrol in radical addition to CdC bonds,
see: (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163 and references
therein. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; Concepts, Guidelines, and Synthetic Applications; VCH: New
York; 1995.
(7) (a) Miyabe, H.; Ushiro, C.; Naito, T. J. Chem. Soc., Chem. Commun.
1997, 1789. (b) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569. (c)
Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem.
2000, 65, 176. (d) Miyabe, H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2,
1443.
(8) 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.
(9) Protonation of imines leads to improved yields in radical addition.
Russell, G. A.; Yao, C.-F.; Rajaratnam, R.; Kim, B. H. J. Am. Chem. Soc.
1991, 113, 373. For a review of Lewis acid effects in radical reactions, see:
Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562.
(10) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266. Sturino,
C. F.; Fallis, A. G. J. Am. Chem. Soc. 1994, 116, 7447.
(11) Evans, D. A.; Kim, A. S. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 1, pp 345-
356.
(12) Oxazolidinones have been used previously for stereocontrolled radical
addition to alkenes. (a) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc.
1995, 117, 10779. (b) Sibi, M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am.
Chem. Soc. 1999, 121, 7517.
10.1021/ja002173u CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

8330 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Communications to the Editor
Table 2. Radical Addition Reactions of Various Alkyl Iodides
with Hydrazones 3 and 7 in the Presence of ZnCl2
Scheme 1
c
product,
diastereomer
ratiob
entry
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Ph
Ph
Ph
Ph
iPr
9c, 60
9d, 59
9e, 28
99:1
96:4
97:3
95:5
99:1
96:4
99:1
93:7
cC5H9
cC6H11
tBu
9f, 54
iPr
10c, 42
10d, 59
10e, 30
10f, 83
cC5H9
cC6H11
tBu
a Isolated yield. b Ratios by HPLC (9c-f) or GCMS (10c-f) versus
authentic mixtures. In separate reactions, diastereomer ratios of 9e and
9f were reproduced within 0.5%. c Reaction conditions: see Table 1.
Table 1. Survey of Lewis Acids for Promotion of Radical
Addition to Propionaldehyde Hydrazone 3 (Scheme 1)
yield of
recovery
of 3, %
product ratio
entry
Lewis acid
9c, %a
(9c:9b:9a)b
Scheme 2
1
2
3
4
5
6
7
none
NR
0
NR
32
55
60
53
BF3‚Et2O
MgBr2
Yb(OTf)3
InCl3
ZnCl2
Zn(OTf)2
0:0:100
96:4:0
92:8:0
91:9:0
93:7:0
29
24
i
a Isolated yield of pure 9c (R2 ) Pr). NR ) no reaction. Reaction
conditions: Bu3SnH (5 equiv) and O2 (7 mL/mmol 3) by syringe pump,
iPrI (10 equiv), Et3B (10 equiv), and Lewis acid (2 equiv), 2:1 CH2Cl2/
ether, -78 °C f room temperature. b 9a: R2 ) H. 9b: R2 ) Et. Ratios
(Table 2). With various secondary and tertiary alkyl iodide radical
precursors, we were delighted to find that additions to both 3
and 7 occurred with excellent stereocontrol in all cases to afford
N-acylhydrazines 9c-f and 10c-f.16 Chemical correlation and
X-ray crystallographic analysis confirmed the absolute configura-
tions of 9c and 10f.17 After N-benzoylation of 9c (Scheme 2),
1
by H NMR spectra after removal of tin residues.
Experimental evaluation of our design hypothesis began with
preparation of the requisite hydrazones. Amination of com-
mercially available (S)-4-benzyl-2-oxazolidinone (1, Scheme 1)
with n-butyllithium and O-(mesitylenesulfonyl)hydroxylamine13a,d
gave N-aminooxazolidinone 2 (75% yield). Condensation with
various aldehydes (toluene; p-toluenesulfonic acid catalyst) af-
forded chiral N-acylhydrazones 3-8 as single isomers in 92-
96% yield from 2. Alternatively, introduction of aldehydes directly
to the amination reaction mixture gave hydrazones via a conve-
nient one-pot protocol.
A survey of a variety of simple Lewis acids in isopropyl radical
addition (Bu3SnH, Et3B/O214) to hydrazone 3 (Scheme 1, Table
1) revealed initially that Lewis acid was required for the reaction
(entry 1). With BF3‚OEt2, undesired CdN reduction occurred to
afford 9a in quantitative yield within 5 min, indicating that 3
was remarkably prone to Lewis acid activation.15 Magnesium salts
did not promote radical addition (entry 3), while ytterbium triflate
(entry 4) gave modest yields. On the other hand, InCl3 and Zn(II)
salts afforded clean (albeit incomplete) conversion to desired
adduct 9c (entries 5-7).16 Gratifyingly, initial examination by
1H NMR spectroscopy showed a single diastereomer (dr >98:2).
For diastereoselectivity analysis in radical additions, we selected
hydrazones 3 and 7 with ZnCl2 as the Lewis acid promoter
10
exposure of 11 to SmI2 cleanly afforded 12 (99% yield) and 1
(97% yield) within 5 min.
In conclusion, a novel N-acylhydrazone auxiliary approach
gives excellent stereocontrol in radical addition to CdN bonds.
Notably, this is the first such radical addition that does not require
adjacent carbonyl functionality for auxiliary linkage or acceptor
activation. In contrast to related additions to R,â-unsaturated
amides which require a larger blocking group,12,18 the simple
benzyl control element affords high selectivity in all cases
examined. This distinction can be attributed to the closer proximity
of the control element and acceptor carbon in hydrazones 3 and
7 relative to N-enoyloxazolidinones, resulting in more effective
steric blocking while limiting rotational freedom. With excellent
stereocontrol now at hand, evaluation of additional hydrazones,
reaction optimization, and modifications to facilitate direct
auxiliary removal are underway, as are efforts toward chiral Lewis
acid catalysis.
Acknowledgment. We thank the Research Corporation, the Petroleum
Research Fund, NSF Vermont EPSCoR, and the University of Vermont
for generous support. We also thank Professors J. S. Madalengoitia and
M. E. Kuehne (University of Vermont) for sharing instrumentation and
Dr. Patrick J. Carroll (University of Pennsylvania) for X-ray crystal-
lography.
(13) (a) Kim, M.; White, J. D. J. Am. Chem. Soc. 1977, 99, 1172. (b)
Ciufolini, M. A.; Shimizu, T.; Swaminathan, S.; Xi, N. Tetrahedron Lett. 1997,
38, 4947. (c) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (d) The
more convenient N-electrophile O-(diphenylphosphinyl)hydroxylamine also
gives reliable results in the amination of 1 (73-79%). Details will be reported
elsewhere.
(14) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64,
403. Brown, H. C.; Midland, M. M. Angew. Chem., Int. Ed. Engl. 1972, 11,
692.
(15) Reduction (Bu3SnH, BF3‚OEt2) of N-acylhydrazones proved to be
generally efficient; from appropriate ketone N-acylhydrazones, both diaster-
eomers of 9c-f and 10c-f were acquired for characterization purposes (see
Supporting Information).
(16) Separable ethyl radical adduct 9b (or 10b) was observed (<10% yield)
in all cases. The remaining mass balance was unreacted hydrazone 3 (or 7).
Primary halides have thus far given low yields in these reactions, presumably
due to ineffective chain transfer.7 Preliminary experiments with 8 gave 1 as
the major product (57% yield).
Supporting Information Available: Characterization data for 2-12
and selected experimental procedures (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA002173U
(17) Configurations of 9d-f and 10c-e are assigned by analogy with 9c
and 10f. These are consistent with model B (Figure 2), although the available
data do not permit rigorous exclusion of alternative substrate-Lewis acid
binding modes. (a) (S)-Valinol was converted to 12 with [R]D +10.0 (c 1.0,
CHCl3) by treatment of its N-Boc-O-tosylate derivative with Me2CuLi followed
by interchange of the carbamate to benzamide. (b) Benzoylation of 10f (81%
yield) as indicated in Scheme 2 gave material suitable for X-ray crystallography
(see Supporting Information).
(18) Sibi et al. found that 4-(diphenylmethyl)-2-oxazolidinone was needed
for good stereocontrol (dr ) 45:1) in isopropyl radical addition to N-cinnamoyl
derivatives (4-benzyl-2-oxazolidinone gave dr ) 2:1).12b