The role of the achiral template in enantioselective transformations. Radical conjugate additions to α-methacrylates followed by hydrogen atom transfer

Article abstract of DOI:10.1021/ja016839b

We have evaluated various achiral templates (1a-g, 10, and 16) in conjunction with chiral Lewis acids in the conjugate addition of nucleophilic radicals to α-methacrylates followed by enantioselective H-atom transfer. Of these, a novel naphthosultam templ

Full text of DOI:10.1021/ja016839b

Published on Web 01/19/2002
The Role of the Achiral Template in Enantioselective
Transformations. Radical Conjugate Additions to
r-Methacrylates Followed by Hydrogen Atom Transfer
Mukund P. Sibi* and Justin B. Sausker
Contribution from the Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
Received August 14, 2001
Abstract: We have evaluated various achiral templates (1a-g, 10, and 16) in conjunction with chiral Lewis
acids in the conjugate addition of nucleophilic radicals to R-methacrylates followed by enantioselective
H-atom transfer. Of these, a novel naphthosultam template (10) gave high enantioselectivity in the H-atom-
transfer reactions with ee’s up to 90%. A chiral Lewis acid derived from MgBr
the highest selectivity in the enantioselective hydrogen-atom-transfer reactions. Non-C
20-25) have also been examined as ligands, and of these, compound 25 gave optimal results (87% yield
2
and bisoxazoline (2) gave
2
symmetric oxazolines
(
and 80% ee). Insights into rotamer control in R-substituted acrylates and the critical role of the tetrahedral
sulfone moiety in realizing high selectivity are discussed.
Introduction
examples of H-atom transfer to chiral Lewis acid-complexed
radicals have been noted in the literature. We have recently
5
The development of new synthetic methodology for the
preparation of enantiomerically pure compounds (EPC) is an
important goal. In contrast to the large amount of literature
available on ionic and neutral methods for the synthesis of EPCs,
only in the past couple of years have methodologies for absolute
reported that chiral Lewis acid-complexed protected glycine
radicals undergo H-atom transfer with good to excellent
1
6
selectivity.
7
8
In the past couple of years, we and others have reported
examples of enantioselective conjugate radical additions using
catalytic amounts of chiral Lewis acids. The enantioselectivity
in our work employing bisoxazolines as chiral ligands was as
high as 97% using 30 mol % of the catalyst. With the success
of the bisoxazoline-derived chiral Lewis acid system at control-
ling the â center, a logical progression would be an attempt to
establish the stereochemistry of the R-methyl group in an
appropriately chosen R-methacrylate substrate. Selectivity could
in principle be achieved through the addition of a nucleophilic
radical to the terminal olefinic carbon followed by an enantio-
selective hydrogen atom transfer (Figure 1).
2
stereocontrol using radical intermediates been reported.
A
majority of them involve C-C bond formations using chiral
3
Lewis acids. Another area of focus, although less actively
pursued, is H-atom-transfer reactions. In principle, these reac-
tions can be carried out in two distinct ways: (1) by H-atom
transfer from a chiral reagent to a radical or (2) alternatively
by H-atom transfer from an achiral reagent to a radical
4a
4b,c
4d
complexed to a chiral source. Curran, Metzger, Roberts,
4
e
and Schiesser have reported examples of reactions using chiral
H-atom-transfer reagents. On the other hand, only a few
(
1) (a) For recent monographs see: Catalytic Asymmetric Synthesis, Ojima, I.
Ed.; Wiley-VCH: New York; 2000. ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York;
The high enantioselectivity observed in the radical conjugate
additions can be attributed to the control of the various rotamers
of the starting material with reaction occurring from one reactive
conformation. In contrast, preferred conformations in R-alkyl-
substituted systems such as A (Figure 1) are not so easily
1
999. For a recent review on enantioselective protonation see: Eames, J.;
Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1.
(
2) For recent reviews on enantioselective radical reactions see: Sibi, M. P.;
Porter, N. A. Acc. Chem. Res. 1999, 32, 163. Sibi, M. P.; Rheault, T. R. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
New York, 2001; Vol. 1, Chapter 4.5. For an excellent review on Lewis
acid mediated radical reactions see: Renaud, P.; Gerster, M. Angew. Chem.,
Int. Ed. 1998, 37, 2562.
9
predicted. Will an s-cis (A), an s-trans (B), or a strongly twisted
conformer predominate? X-ray analysis by Giese on a pyrro-
lidinone methacrylamide showed strong twisting.10 Similarly,
(
3) For work from other laboratories see: Mero, C.; Porter, N. A. J. Am. Chem.
Soc. 1999, 121, 5155. Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem.
Soc. 1995, 117, 11029. Wu, J. H.; Zhang, G.; Porter, N. A. Tetrahedron
Lett. 1997, 38, 2067. Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D. J.
Org. Chem. 1997, 62, 6702. Porter, N. A.; Feng, H.; Kavrakova, I. K.
Tetrahedron Lett. 1999, 40, 6713. Fhal, A.-R.; Renaud, P. Tetrahedron
Lett. 1997, 38, 2661. Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J.
Am. Chem. Soc. 1997, 119, 11713.
(5) (a) Murakata, M.; Tsutsui, H.; Hoshino, O. J. Chem. Soc., Chem. Commun.
1995, 481. (b) Murakata, M.; Tsutsui, H.; Takeuchi, N.; Hoshino, O.
Tetrahedron 1999, 55, 10295. (c) Urabe, H.; Yamashita, K.; Suzuki, K.;
Kobayashi, K.; Sato, F. J. Org. Chem. 1995, 60, 3576.
(6) Sibi, M. P.; Asano, Y.; Sausker, J. B. Angew. Chem., Int. Ed. 2001, 40,
1263. For a review on free radical reactions in the synthesis of amino acids
see: Easton, C. J. Chem. ReV. 1997, 97, 53.
(7) For a review on enantioselective conjugate additions including radical
reactions see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(8) Iserloh, U.; Curran, D. P.; Kanemasa, S. Tetrahedron: Asymmetry 1999,
10, 2417. Kikukawa, T.; Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1999,
40, 7497. Mikami, K.; Yamaoka, M. Tetrahedron Lett. 1998, 39, 4501.
Murakata, M.; Tsutsui, H.; Hoshino, O. Org. Lett. 2001, 3, 299.
(9) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585.
(
4) (a) Nanni, D.; Curran, D. P. Tetrahedron: Asymmetry 1996, 7, 2417. (b)
Schwarzkopf, K.; Blumenstein, M.; Hayen, A.; Metzger, J. O. Eur. J. Org.
Chem. 1998, 177. (c) Blumenstein, M.; Schwarzkopf, K.; Metzger, J. O.
Angew. Chem., Int. Ed. Engl. 1997, 36, 235. (d) Dang, H.-S.; Kim, K.-M.;
Roberts, B. P. J. Chem. Soc., Chem. Commun. 1998, 1413. (e) Dakternieks,
D.; Dunn, K.; Perchyonok, T.; Schiesser, C. H. Chem. Commun. 1999,
1
665. For some very recent work see: Curran, D. P.; Gualtieri, G. Synlett
001, 1038.
2
984 VOL. 124, NO. 6, 2002
9
J. AM. CHEM. SOC.
10.1021/ja016839b CCC: $22.00 © 2002 American Chemical Society

Radical Conjugate Additions to R-Methacrylates
A R T I C L E S
Giese10 and Taber20 have independently shown that using
pyrrolidinone auxiliaries highly diastereoselective H-atom-
transfer reactions are indeed possible in R-methacrylate systems.
Diastereoselective H-atom-transfer reactions to captodative
2
1
radicals derived from N-acylamido acrylates in both acyclic
2
2
and cyclic systems have also been investigated, and they
proceed with moderate to good selectivity. A few examples of
enantioselective H-atom transfer to chiral Lewis acid-complexed
prochiral radicals with achiral donors are known; however,
none involve R-methacrylate systems.
5
,6
Evaluation of the effect of achiral templates on reactivity and/
or selectivity in stereoselective transformations has been reported
2
3
in the literature but only in a sporadic nature. The diastereo-
selective H-atom-transfer reactions described above with R-meth-
acrylates suggested that development of enantioselective variants
might indeed be possible. Our goal was to examine a series of
achiral templates, which are used as anchors for the acrylate
fragment, with the expectation of controlling the reactive
conformers. By systematic change of the ring size and nature
of the achiral template (variation of heteroatoms in the ring)
we surmised that additional space for either the R-methyl group
or the methylene could be available. Alterations in the steric
environment, it was hoped, would also assist in providing
rotamer control for the olefin side chain.
This paper details the evaluation of various achiral templates
in conjunction with chiral Lewis acids in the conjugate addition
of nucleophilic radicals to R-methacrylates followed by
enantioselective H-atom transfer. Of these, a novel sultam
template gave high enantioselectivity in the H-atom-transfer
reactions with ee’s up to 90%. Insights into rotamer control in
R-substituted acrylates and the critical role of the tetrahedral
sulfone moiety in realizing high selectivity are discussed below.
Figure 1.
crystal structure analyses of R-methacryloyl camphor sultam9
and R,â-dimethylacryloyl camphor sultam show significant
deviation of the alkene from planarity. The relief of steric strain
in the substrate apparently overcame any additional stabilization
otherwise obtained by π conjugation. Non-coplanarity of the
R,â-unsaturated fragment could manifest itself in reduced
11
12
reactivity toward nucleophilic additions.
In the system shown in Figure 1, after conjugate addition,
H-atom transfer to the intermediate chiral Lewis acid complexed
radical should occur from one reactive conformation to realize
high selectivity. Additionally, conformational interconversion
C to D, Figure 1)1 of the radical intermediate should be slower
3
(
than intermolecular hydrogen atom transfer. Since hydrogen
atom transfer from tributyltin hydride occurs with high rates,
1
4
we were hopeful that conformer interconversion of the inter-
mediate radical may not be an issue. Thus maximum face
shielding from a substrate-chiral Lewis acid complex and
reactions occurring from one ground-state conformer should
provide for high selectivity in conjugate radical addition
followed by H-atom-transfer experiments.
Several groups have reported important results on the
preferred conformation in R-methacrylates in diastereoselective
transformations. The seminal work of Oppolzer15 and Curran
with chiral sultams is of relevance. Additional support for the
preference for s-trans rotamer of the R-methacrylate fragment
comes from the work of Murahashi and co-workers17 who have
examined the Pd(II)-catalyzed asymmetric acetalization of the
Results and Discussion
Our work began with the screening of a series of templates
attached to the R-methacryloyl group. The required side chain
was attached to the templates using standard conditions. The
initial goals were to identify templates that would provide good
reactivity and selectivity. Reactions were carried out under a
set of standard conditions: addition of nucleophilic isopropyl
radical at -78 °C employing magnesium bromide as the Lewis
acid and the cyclopropyl bisoxazoline (2) as the chiral ligand
16
1
8
terminal olefin carbon of a number of Evans oxazolidinones.
(19) Diels-Alder reaction of R-methacrylates derived from camphor lactam
proceeded through an s-trans geometry. Boeckman, R. K., Jr.; Nelson, S.
G.; Gaul, M. D. J. Am. Chem. Soc. 1992, 114, 2258.
(20) Taber, D. F.; Gorski, G. J.; Liable-Sands, L. M.; Rheingold, A. L.
Tetrahedron Lett. 1997, 36, 6317.
The sense of stereoinduction suggests that the reaction occurs
from an s-trans rotamer.19 This was further supported by CAChe
calculations at the MM2 level.
(
21) (a) Crich, D.; Davies, J. W. Tetrahedron 1989, 45, 5641. (b) Kessler, H.;
Wittmann, V.; K o¨ ck, M.; Kottenhahn, M. Angew. Chem., Int. Ed. Engl.
1992, 31, 902. For additions to a polymer supported system see: Yim,
A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Lett. 1999, 40,
4535.
(
(
(
10) Giese, B.; Hoffmann, U.; Roth, M.; Veit, A.; Wyss, C.; Zehnder, M.; Zipse,
H. Tetrahedron Lett. 1993, 34, 2445.
11) Oppolzer, W.; Poli, G.; Starkmann, C.; Bernardelli, G. Tetrahedron Lett.
1
988, 29, 3559.
(22) (a) Axon, J. R.; Beckwith, A. L. J. J. Chem. Soc., Chem Commun. 1995,
549. (b) Goodal, K.; Parsons, A. F. Tetrahedron Lett. 1997, 38, 491. (c)
Goodal, K.; Parsons, A. F. Tetrahedron 1996, 52, 6739. (d) Chai, C. L. L.;
King, A. R. Tetrahedron Lett. 1995, 36, 4295. (e) Manzoni, L.; Belvisi,
L.; Scolastico, C. Synlet 2000, 1287. (f) Baker, S. R.; Parsons, A. F.; Wilson,
M. Tetrahedron Lett. 1998, 39, 2815. For reactions at a center remote to
the carbonyl see: Beaulieu, F.; Arora, J.; Veith, U.; Taylor, N. J.; Chapell,
B. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 8727. Pyne, S. G.; Schafer,
K. Tetrahedron 1998, 54, 5709. For reactions with lactones see: Piber,
M.; Leahy, J. W. Tetrahedron Lett. 1998, 39, 2043.
(23) (a) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393. (b) Evans, D. A.; Miller,
S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559. (c)
Jensen, K. B.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1997, 62, 2471. (d) Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122,
10710. (e) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S-i.; Yamamoto,
H.; Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120,
3074.
12) Curran has carried out several relative reactivity studies of R-methacryloyl
systems. These clearly show reduced reactivity for R-alkylacrylates. See
ref 9.
(
13) Only two conformers are shown. It is quite likely that the actual
conformation is an intermediate of these two extreme structures.
14) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry;
Wiley: Chichester, U.K., 1995; Chapter 7. Also see: Chatgilialoglu, C.;
Newcomb, M. AdV. Organomet. Chem. 1999, 44, 67.
(
(15) (a) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. HelV. Chim. Acta 1984,
6
7, 1397. (b) Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.;
Bernardinelli, G. HelV. Chim. Acta 1987, 70, 2201. (c) ref 11.
(
(
(
16) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett.
1
988, 29, 3555.
17) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-I. J. Org. Chem.
995, 60, 6159.
18) Evans, D. A. Aldrichim. Acta 1982, 15, 23.
1
J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002 985

A R T I C L E S
Sibi and Sausker
Table 1. Investigation of Various Templates
heterocycles were selected for the study. Commercially available
2
-azetidinone as a template was examined first. Curran and
Porter have previously shown that radical addition to N-acryloyl-
2
8
2
-azetidinone is very facile. In our experiments, 2-(R-
methacryloyl)azetidinone was also extremely reactive and the
noncatalyzed reaction occurred at a similar rate as the Lewis
acid-catalyzed reaction. The enantioselectivity obtained with this
template was disappointing (entry 4). Our laboratory has shown
that oxazolidinone-derived templates can indeed provide high
2
9
30
levels of both diastereoselectivity and enantioselectivity in
free radical chemistry. The readily available 2-oxazolidinone
was chosen as the next template for study. In the absence of a
Lewis acid, the reaction does proceed, but at a much slower
rate. The enantioselective additions using this template were
encouraging providing the best enantioselectivity at 65% (entry
5
). The stereochemistry of the addition product was shown to
have (S) configuration by hydrolysis of 3e to the known acid.
Thus templates which lead to five-membered chelates give
enantiomeric products in contrast to templates which form six-
3
1
membered chelates with the chiral Lewis acid. Isopropyl
radical addition to the pyrrolidinone derived substrate 1f was
also facile, and the product 3f was isolated in 76% yield (entry
6
). The observed enantioselectivity was lower than that for the
oxazolidinone template (compare entries 5 and 6). Hydrolysis
23
of 3f to the known acid indicated that the S isomer was formed
in these reactions as well. One additional template, the com-
mercially available N-phenylpyrazolone, was examined. The
nitrogen at the 3-position was appealing since it could have an
impact on the rotamer population of the side chain. However,
radical addition to 1g proceeded with poor selectivity (entry
7
). On the basis of the above results, templates 1e and 1f were
chosen for more detailed scrutiny.
Reactions aimed at determining which Lewis acid would offer
the best combination of yield and enantioselectivity for the
addition of isopropyl radical to substrate 1e was undertaken (eq
2, Table 2). In the absence of a Lewis acid, the reaction does
proceed, but at a much slower rate (entry 1). Zinc based Lewis
acids failed in both respects; the yields and enantioselectivities
were unacceptable (entries 2 and 3). Of the magnesium Lewis
acids, the counterion was important with MgBr2‚Et2O providing
the best enantioselectivity at 65% (entry 6). After establishing
a
Isolated yield. b ee determined by optical rotation of the hydrolysis
c
product: see Supporting Information. ee determined by chiral HPLC
analysis.
and tributyltin hydride as a H-atom donor and chain carrier.
We have previously established that conjugate radical additions
using chiral Lewis acids derived from bisoxazolines and Mg or
Zn Lewis acids proceed with high selectivity.24
that MgBr ‚Et O as a Lewis acid of choice, the next series of
2
2
experiments were undertaken in an attempt to discern if the size
of the attacking radical exhibited any effect on the selectivity
of the reaction. A series of nucleophilic radicals that differed
in size were examined. No definitive trend was observed (entries
Three templates, pyrazole, 3,5-dimethylpyrazole, and inda-
zole, capable of forming five-membered chelates with the Lewis
acid were chosen for the initial study (eq 1). These results are
shown in Table 1. All of these templates showed moderate
reactivity and low selectivity (entries 1-3) in radical addition
6
-9). The above results suggest that oxazolidinone is an
2
5
ineffective template in controlling the stereochemistry at the
R-carbon.
reactions. The stereochemistry for the conjugate product 3b
2
6
was determined to be (R) by hydrolysis to a known acid. We
Results from radical additions to the pyrrolidinone derived
acrylate 1f (eq 3) are shown in Table 3. Different radicals were
have previously shown that 3,5-dimethylpyrazole is a good
template for enantioselective conjugate addition.27 Thus the low
selectivity for reactions with 1a-c is most likely due to poor
rotamer control.
We then examined templates capable of forming six-
membered chelates. Readily available four- and five-membered
(27) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997, 38, 5955.
(
28) Curran, D. P.; Qi, H.; Porter, N. A.; Su, Q.; Wu, W.-X. Tetrahedron Lett.
1
993, 34, 4489.
(29) (a) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc. 1995, 117, 10779.
b) Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl. 1996, 35, 190. (c) Sibi,
M. P.; Ji, J.; Sausker, J. B.; Jasperse, C. P. J. Am. Chem. Soc. 1999, 121,
(
7517.
(
24) Sibi, M. P.; Ji, J.; Wu, J. H.; Gurtler, S.; Porter, N. A. J. Am. Chem. Soc.
996, 118, 9200.
25) We have carried out extensive studies on all the templates shown in Table
(30) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800.
1
(31) We have previously hypothesized that formation of enantiomeric products
from pyrazole and oxazolidinone derived templates is most likely due to
changes in the geometry of the reactive complex: trans octahedral for
pyrazoles and cis octahedral for oxazolidinone. For a review on reversal
of stereochemistry see: Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 5,
719.
(
1. For brevity, only the most pertinent results are shown. The reader should
consult the following for additional information: Sausker, J. B. MS thesis,
North Dakota State University, Fargo, 2001.
(26) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233.
986 J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002

Radical Conjugate Additions to R-Methacrylates
A R T I C L E S
Table 2. Radical Additions to 2-Oxazolidinone R-Methacrylatea
in temperature to 0 °C gave racemic material (entry 6). Results
from these studies suggest that there is very little rotamer control
at higher temperatures or a poorly organized structure for the
complex derived from Lewis acid + ligand + substrate.
A more interesting result was obtained by altering the H-atom
donor from Bu3SnH to tris(trimethylsilyl)silane (TTMSS); the
opposite enantiomeric product was obtained (compare entry 2
3
2
with entry 8). This inversion of stereochemistry based solely
on H-atom donor was completely unexpected. The stronger
Si-H bond as compared to the Sn-H bond could potentially
allow for a slower trap of the radical intermediate. This in turn
could provide the radical enough time to interconvert to a more
stable conformation. Unfortunately, the reaction was unsuc-
cessful at -78 °C (entry 7). The reaction was extremely slow,
and at the higher temperature of -40 °C (entry 8), 35% of the
cyclohexyl conjugate addition product was obtained along with
c
d
entry
product
Lewis acidb
none
ZnBr2
Zn(OTf)2
MgI2
Mg(OTf)2
MgBr2‚Et2O
MgBr2‚Et2O
MgBr2‚Et2O
MgBr2‚Et2O
yield, %
ee, %
1
2
3
4
5
6
7
8
9
3e
3e
3e
3e
3e
3e
4
27
48
50
85
98
80
65
75
57
0
7
4
10
2
65
20
38
50
5
6
5
5% yield of recovered starting material after 8 h. As temper-
a
b
Reactions were performed on a 0.2 mmol scale at -78 °C. Stoichio-
c
d
ature was increased further to 0 °C (entry 9), the yield improved
to 45%. Starting material was still recovered in these reactions.
Enantioselectivity was highest at -40 °C (entry 8). This
phenomenon was not unique to cyclohexyl radical addition. The
addition of acetyl radical experienced this strange effect as well
metric amount of chiral Lewis acid. Isolated yield. ee’s determined from
chiral HPLC analysis.
Table 3. Reactions on the 2-Pyrrolidinone R-Methacrylatea
(entry 10). At this time, we have no explanation for these
unexpected results.
It appeared that achieving practical levels of enantioselectivity
utilizing templates that form six-membered chelates with the
chiral Lewis acid would be difficult. One final modification to
these types of templates was initiated in the hope of solving
the problem of obtaining synthetically useful levels of enantio-
selectivity. Alteration of the geometry of substrate-Lewis acid-
c
d
entry
product
temp, °C
hydride
yield, %
ee, %
1
2
3
4
5
6
7
8
9
3f
7
8
9
7
7
7
7
7
9
-78
-78
-78
-78
-40
0
-78
-40
0
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
(MeSi)3SiH
(MeSi)3SiH
(MeSi)3SiH
(MeSi)3SiH
76
92
75
75
82
75
42
45
40
75
34
2
ligand superstructure by replacing the sp carbon of the template
3
carbonyl with an sp center was envisaged. To maintain the
0
0
possibility of two-point binding in the template, it was decided
trace
e
33
35 (55)
45 (47)
53 (43)
-39
-35
-20
to utilize a sulfone oxygen as the second Lewis basic site.
e
e
The application of sultams as chiral auxiliaries has been well
10
0
3
4
established by Oppolzer. In contrast, there are only limited
reports on the use of sulfones as templates in enantioselective
a
b
Reactions were performed on a 0.2 mmol scale. Stoichiometric amount
of chiral Lewis acid. Isolated yield. ee’s were determined from chiral
HPLC analysis. Numbers in parentheses indicate recovered starting
c
d
35
transformations. Wada and Kanemasa have shown that R,â-
e
unsaturated ketones appended with a phenyl sulfonyl group
undergo highly selective Diels-Alder reactions.36 The two
sulfonyl oxygens in differentially substituted sulfones are
enantiotopic. Wada and Kanemasa hypothesized on the pref-
erential coordination of one of the sulfonyl oxygen to the chiral
Lewis acid and for the phenyl group to provide face selectivity.
material.
screened utilizing a stoichiometric amount of magnesium
bromide as the Lewis acid, which provided good yields of the
desired reaction products. Enantioselectivity varied on the basis
of the choice of the radical precursor. Alkyl radicals gave only
moderate levels of enantioselectivity between 40 and 45%
entries 1 and 2). Heteroatom functionalized radicals such as
methoxymethyl and acetyl could be added in good yields (entries
and 4). The addition of acetyl radical gave the product with
the highest level of enantioselectivity (entry 4). This is similar
to the results observed with the oxazolidinone template where
the acetyl radical again provided good selectivity. The limited
success with the addition of cyclohexyl and acetyl radicals to
(
32) Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. Tris(trimethylsilyl)silane in
organic synthesis. In The Chemistry of Organic Silicon Compounds;
Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, U.K., 1997; Vol. 2,
Chapter 25, p 1539. Also see: Chatgilialoglu, C. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinhem, Germany,
2001; Chapter 1.3.
33) For an excellent review on sultam derived acrylates and issues related to
geometry and reactivity see: Kim, B. H.; Curran, D. P. Tetrahedron 1993,
49, 293.
34) References 13, 14, and 33. Sultams have been used as an auxiliary in a
variety of transformations including radical reactions. For the use of
Oppolzer sultam in radical reactions see (a) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim,
Germany, 1995. (b) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem.
Res. 1991, 24, 296. (c) Smadja, W. Synlett 1994, 1. For the use of sulfones
in diastereoselective reactions see: (d) Marcantoni, E.; Cingolani, S.;
Bartoli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 1998, 63, 3624. (e)
Marino, J. P.; Viso, A.; Lee, J.-D. J. Org. Chem. 1997, 62, 645. (f) Enders,
D.; Muller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2000, 879.
(g) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741.
(
3
(
(
1
f led us to modify reaction conditions with respect to Lewis
acid, temperature, and H-atom donor. The addition of acetyl
radical to 1f was carried out using two other Lewis acids,
Zn(OTf)2 and Mg(OTf)2. Both of these gave nearly racemic
products (data not shown in table). Temperature had an adverse
effect on selectivity. Increasing the reaction temperature from
(35) (a) Wada, E.; Yasuoka, H.; Kanemasa, S. Chem. Lett. 1994, 1637. (b) Wada,
-
78 to -40 °C for the cyclohexyl radical addition to 1f led to
a small decrease in ee (compare entry 2 with 5). Further increase
E.; Yasuoka, H.; Kanemasa, S. Chem. Lett. 1994, 145.
(36) Wada, E.; Pei, W.; Kanemasa, S. Chem. Lett. 1994, 2345.
J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002 987

A R T I C L E S
Sibi and Sausker
Table 4. Reactions on the 1,8-Naphthosultam Templatea
crude reaction product indicated the formation of less than 5%
of the product (entry 1)). In contrast, addition of isopropyl
radical occurred with both high yield and excellent selectivity
in the presence of MgBr2‚Et2O (1 equiv) and ligand 2 (entry
2
). The product ee of 78% was the highest yet obtained for
these addition/H-atom-transfer reactions. Catalytic reactions
were attempted using 30 mol % of the chiral Lewis acid and at
this loading, the yield and ee were similar (entry 3). Increasing
the temperature to -40 °C (entry 4) or 0 °C (entry 5) led to
deterioration in both yield and selectivity. An alternate H-atom
donor, triphenyltin hydride, was examined. The chemical
efficiency with this reagent was slightly lower as compared to
tributyltin hydride; however, the enantioselectivity was quite
similar (compare entry 2 with 6 and 3 with 7). As was the case
with tributyltin hydride, reaction at -40 °C gave lower
selectivity with triphenyltin hydride also (compare entry 3 with
c
d
entry product temp, °C
Lewis acid (eqiv)
hydride
yield, % ee, %
noneb
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
11
11
11
11
11
11
11
11
12
12
12
13
13
13
14
14
14
14
15
-78
-78
-78
-40
0
Bu3SnH
<5
90
80
71
52
59
55
51
91
84
32
96
71
72
91
89
95
93
<25
0
78
80
59
5
MgBr2‚Et2O (1.0) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (1.0) Ph3SnH
MgBr2‚Et2O (0.3) Ph3SnH
MgBr2‚Et2O (1.0) Ph3SnH
MgBr2‚Et2O (1.0) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (1.0) Ph3SnH
MgBr2‚Et2O (1.0) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (1.0) Ph3SnH
MgBr2‚Et2O (1.0) Bu3SnH
MgBr2‚Et2O (0.3) Bu3SnH
MgBr2‚Et2O (1.0) Ph3SnH
MgBr2‚Et2O (0.3) Ph3SnH
MgBr2‚Et2O (1.0) Bu3SnH
e
-78
-78
-40
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
88
80
42
80
89
78
89
82
83
86
90
87
88
18
4
and 7 with 8). TTMSS was ineffective in reactions with 10.
Other alkyl radicals that are reasonably nucleophilic add
e
e
1
1
1
1
1
1
1
1
1
1
efficiently using stoichiometric or catalytic amounts of the Lewis
acid (entries 9, 10, 12, and 13). The enantioselectivities in these
experiments were quite good ranging between 80 and 89%.
Methoxymethyl radical addition followed by H-atom transfer
occurred with exceptionally high selectivity (entries 15 and 16).
Triphenyl and tributyltin hydrides showed similar efficiency in
H-atom-transfer selectivity, although chemical yields differed
from substrate to substrate (entries 11, 14, 17, and 18). The
addition of acetyl radical (entry 19) was extremely slow and
ethyl radical did not add under any of the reaction conditions
utilized (data not shown).
a
b
Reactions were performed on a 0.2 mmol scale. No Lewis acid was
added. Isolated yields. ee’s were determined from chiral HPLC analysis.
Reactions were performed on a 0.5 mmol scale with 30 mol % of the
c
d
e
chiral Lewis acid.
The absolute configuration of the isopropyl radical addition
product 11 was determined by hydrolysis. The sign of the optical
rotation for the product acid was compared with that reported
Porter has shown that radical additions to acrylates attached to
an achiral cyclic sultam proceeds in good yields.37 Recently,
Hiroi has reported an interesting example of enantiocontrol in
radical cyclization using sulfones.38 The selectivity in the
cyclization was attributed to the coordination of one of the
enantiotopic sulfonyl oxygen to the chiral Lewis acid. An
additional example on the use of sulfones in radical reactions
was recently reported by Toru and co-workers.39 We surmised
that the formation of one of the two possible diastereomeric
complexes between enantiotopic sulfonyl oxygen in N-acyl
sultams and the chiral Lewis acid could allow for conformer
control of the acyl side chain. This in turn could allow for
selectivity in H-atom-transfer reactions.
23
in the literature and was determined to be (S). The absolute
stereochemistry for the isopropyl radical addition product was
identical for the various templates which form a six-membered
chelate with the magnesium Lewis acids.
Control experiments were in order to probe the importance
of the tetrahedral nature of the sulfone group and reactions with
a template in which SO2 group is replaced by a trigonal CO
group were undertaken. The 1,8-naphtholactam is also a
commercially available compound, and the required substrate
(16) was prepared uneventfully. This template proved to be
much more reactive than the naphthosultam, and this caused a
small problem (eq 5, Table 5). Due to its enhanced reactivity,
the reduced starting material, 17, contaminated the conjugate
addition products, especially when alkyl radicals were used.
However, it was possible to separate 17 from the products
resulting from the addition of the more polar heteroatom
containing radicals (entries 1-3, Table 5). The data in the table
clearly indicate that the lactam template is ineffective in
providing even marginal levels of selectivity. This is in marked
contrast to the high levels of selectivity observed with the sultam
template.
A commercially available achiral template that would meet
our needs was the 1,8-naphthosultam. This offered advantages
as a potential achiral template. Both the starting material and
the desired products were UV-active, simplifying isolation. The
radical addition compounds were considerably less polar than
the other templates investigated thus far, again simplifying
isolation of the product from polar organotin reaction byprod-
ucts. This new template was tested with the addition of isopropyl
radical and the enantioselectivity of the product was measured
(eq 4, Table 4). We were pleased by the results for radical
additions to this template. In the absence of a Lewis acid,
isopropyl radical addition did not occur (NMR spectrum of the
Other Chiral Ligands
Until now the only class of ligands we have investigated in
some detail in enantioselective radical reactions are the C2
symmetric bisoxazolines. Two working models with the mag-
nesium Lewis acid in a tetrahedral or an octahedral environment
have been formulated to explain results obtained in conjugate
(
37) Porter, N. A.; Carter, R. L.; Mero, C. L.; Roepel, M. G.; Curran, D. P.
Tetrahedron 1996, 52, 4181.
(38) Hiroi, K.; Ishii, M. Tetrahedron Lett. 2000, 41, 7071.
39) Watanabe, Y.; Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42,
(
2
981.
988 J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002

Radical Conjugate Additions to R-Methacrylates
A R T I C L E S
Table 5. Reactions on the 1,8-Naphtholactam Templatea
Table 6. Enantioselective H-Atom Transfers Catalyzed by
Acyloxazoline Complexes
Lewis acidb
temp, °C
yield, %
c
ee, %
d
entry
product
entry
ligand
Lewis acid
compda
yield, %
b
ee, %
c
1
2
3
4
18
19
18
19
MgBr2
MgBr2
MgBr2
Mg(ClO4)2
-78
-78
-40
-78
55 (36)
61 (27)
00 (86)
31 (62)
22
6
0
1
2
3
4
5
6
7
8
9
2
20
21
22
23
24
25
25
25
25
25
25
25
MgBr2‚Et2O
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
11
11
11
11
11
11
11
11
11
11
11
13
14
90
85
62
68
85
60
87
80
76
88
72
87
77
78
34
9
10
18
8
80
75
68
14
0
6
a
b
Reactions were performed on a 0.2 mmol scale. Stoichiometric amount
c
of chiral Lewis acid utilized. Isolated yield. Numbers in parentheses
represent reduced starting material 17. ee’s determined from chiral HPLC
analysis.
d
d
MeMgI
MeMgIe
MeMgBr
MeMgCl
MeMgI
1
1
0
1
additions. To gain further insight into the nature of the geometry
around the Lewis acid, we decided to explore alternative ligands.
Fujisawa40 has reported on the use of chiral complexes of
12
13
75
35
MeMgI
2
-arylsulfonyloxazoline-based ligands for enantioselective
a
Reaction performed on 0.3 mmol scale. b Isolated yield. c ee’s obtained
Diels-Alder reactions. In these reactions, the chiral Lewis acid
was formed in situ, via the addition of Grignard reagents to
solutions of the ligand. Fujisawa postulated an octahedral Mg
complex in the Diels-Alder reaction between cyclopentadiene
and an oxazolidinone acrylate to account for the high selectivity.
We hoped that reaction of 10 catalyzed by Mg complexes
derived from ligands 20-25 would serve two purposes: (1)
offer a new ligand system for selective H-atom-transfer reactions
and (2) provide us with additional information on ligand +
Lewis acid + substrate superarchitecture.
d
from chiral HPLC analysis. Reaction performed with 50 mol % chiral
Lewis acid, 0.5 mmol scale. e Reaction performed with 30 mol % chiral
Lewis acid, 0.5 mmol scale.
(
entries 3 and 4). Fujisawa noted in his Diels-Alder reactions
that sulfonamides similar to ligand 21 furnished superior yield
and enantioselectivity. Unfortunately when ligand 24 (entry 6)
was utilized, the same effect was not observed. The yield was
moderate, and enantioselectivity was poor.
Surprisingly, the parent compound 25, catalyzed the H-atom-
transfer reaction quite well (entries 7-13). In fact, the observed
8
0% ee (entry 7) was similar to that with ligand 2 (entry 1).
With a highly selective ligand for H-atom-transfer reactions,
attempts to further optimize the reaction were undertaken. With
ligand 25, a pronounced counterion effect was observed with
iodide > bromide . chloride (entries 9-11). All of the
counterions tested showed good ability to activate the substrate
with excellent yields of the product 11 obtained in all cases.
An examination of the enantioselectivity shows that ee’s drop
rapidly as the size of the counterion decreases. The stereochem-
istry for the addition product 11 was determined to be (R)
(note: ligand 25 has the 1R,2S stereochemistry; opposite to that
in ligand 2). Thus the sense of stereoinduction in the addition
reaction leading to 11 is the same with ligands 2 and 25.
A series of ligands 20-25 were prepared following literature
procedures.41 The chiral Lewis acids were prepared by the
addition of methyl Grignard reagents to the aryl oxazoline of
interest. This solution was then cooled to -78 °C, and 10 was
added. Results from conjugate addition of nucleophilic radicals
to 10 followed by H-atom transfer are tabulated in Table 6 (eq
Stereochemical Model for Selectivity
Radical reactions are known to proceed by an early transition
state, and thus its structure closely resembles that of the starting
material (complex). In our analysis (vide infra) it is assumed
that the H-atom transfer occurs rapidly in relation to any rotamer
interconversion, and thus precursor geometry impacts on product
stereochemistry. Thus the enoate conformation in the Lewis
acid-coordinated complex is critical to determining product
stereochemistry.
Oxazolidinone and Pyrrolidinone Templates. None of the
traditional templates were successful in providing good to high
levels of selectivity. Literature precedents for predominance of
s-trans rotamer geometry in R-methacryloyl amides and the
formation of the (S) enantiomer allow us to propose stereo-
6
). From the results a number of trends are apparent. The Mg
Lewis acid that is formed in situ by the addition of the MeMgI
to ligands 20 and 23 are quite successful in activating the
substrate for conjugate addition (entries 2 and 5). Unfortunately,
the enantioselectivity was poor. The chiral catalyst formed by
the reaction of the amine containing ligands 21 and 22 gave
lower yields and also suffered from low enantioselectivity
(
40) Ichiyanagi, T.; Shimizu, M.; Fujisawa, T. J. Org. Chem. 1997, 62, 7937.
(
41) See Supporting Information for experimental details.
J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002 989

A R T I C L E S
Sibi and Sausker
Figure 2.
Figure 3.
chemical models for the H-atom-transfer reactions with 1e and
of the substrate with the nitrogen atom slightly above this plane.
The facility of conjugate additions to 10 lends support to this
conclusion. The single bond of the enoate is also restricted in
its motion in the complex. For example, clockwise motion is
less sterically encumbered than an anticlockwise rotation. This
is in contrast to the rotamers postulated with the oxazolidinone
and pyrrolidinone templates.
1
f. Assuming a tetrahedral Mg(II) species and a bidentate
coordination of the substrate, the enoate resides in a twisted
4
2
s-trans conformation to minimize adverse steric interactions.
The enoate can twist in either a clockwise (E, Figure 2) or an
anticlockwise (F, Figure 2) manner (from an ideal s-trans
conformer) to relieve steric strain, and both rotamers seem
reasonable. The relative ease of conjugate addition to the
oxazolidinone methacrylate suggests that the deviation of the
OdCCdC dihedral angle from 180° is not large. The â-carbon
is easily accessible for conjugate addition. In the subsequent
H-atom-transfer step, both faces of the intermediate radical are
open, with a small preference for re face addition. This accounts
for the moderate selectivity observed with templates 1e and 1f.
Sultam and Lactam Templates. The high selectivities with
the sultam template raises questions related to enoate geometry.
Molecular models indicate that both s-trans and s-cis rotamers
are relatively free from steric interactions in a tetrahedral Mg
chelate with the substrate (G, Figure 3). The tetrahedral nature
of the sulfone also imparts a near planarity to the enoate portion
Product stereochemistry analysis suggests that the reaction
should occur from conformer G (Figure 3) with H-atom transfer
taking place from the re face of the radical intermediate. The
reasons for the preference for this rotamer are not apparent.
Models suggest that higher selectivities may be possible with
the s-cis rotamer.
In the case of the lactam-based template 16, coordination to
the Lewis acid results in the carbonyls again aligning syn to
one another. To remove unfavorable steric interactions, the olefin
assumes an s-trans geometry (H, Figure 3). The methyl group
twists up and rotates clockwise to move the methylene further
away from the hydrogen atom of the naphthalene ring system.
However, unlike the sultam, the trigonal nature of the CO group
in the lactam system pushes the naphthalene ring system into a
planar arrangement with the CONCO atoms (chelated ring). The
rotation of the enoate opens the back face to attack by both the
(
42) Other geometries, such as cis octahedral structures, are also possible. We
have been unable to arrive at an exact geometry for the ternary complex in
these radical reactions. Experiments are underway to gain a better
understanding
990 J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002

Radical Conjugate Additions to R-Methacrylates
A R T I C L E S
3
H11NSO : C, 61.53; H,
incoming radical and to the H-atom donor. The exposed nature
of the olefin should result in a nonselective reaction. The results
substantiate this hypothesis. Comparison of the results for the
addition of methoxymethyl radical to both the lactam and the
sultam (Table 4, entry 4 and Table 5, entry 16) clearly suggests
the requirement for the sulfone group for high selectivity.
131.8, 131.9, 139.6, 169.3. Anal. Calcd for C14
.07; N, 5.12. Found: C, 61.26; H, 4.44; N, 5.08.
2S)-N-(2,4-Dimethy1pentanoyl)-1,8-naphthosultam (11). Accord-
ing to the general procedure outlined above, 10 was alkylated to provide
1 ( yield, 90%; yellow solid); mp 63-65 °C. R ) 0.55 (30% EtOAc:
): δ 0.95 (d, J ) 6.7 Hz, 3H),
.97 (d, J ) 6.7 Hz, 3H), 1.02 (d, J ) 6.7 Hz, 3H), 1.72-1.80 (m,
4
(
1
f
1
hexanes). H NMR (500 MHz, CDCl
3
0
1
3
H), 2.22-2.29 (m, 1H), 2.92-2.98 (dd, J ) 16.5, 8.7 Hz, 1H), 3.14-
.18 (dd, J ) 16.3, 4.7 Hz, 1H), 7.62-7.69 (m, 2H), 7.75-7.79 (dd,
Conclusions
In conclusion, an effective enantioselective H-atom-transfer
reaction has been developed by the utilization of the 1,8-
naphthosultam achiral template. Reactions with this template
could be conducted with catalytic amounts of the chiral Lewis
acid and maintain the high levels of enantioselectivity. Other
templates that formed six-membered chelates with the chiral
Lewis acid were unsuccessful in providing high levels of
enantioselectivity. Pyrazole-based templates that form a five-
membered chelate offered products with the opposite configu-
ration for the newly formed chiral center, but with reduced levels
of enantioselectivity. A series of new chiral aryloxazoline-based
ligands were found to be effective for the addition of alkyl
radicals to the 1,8-naphthosultam template. Achieving high
levels of enantioselectivity for H-atom-transfer reactions is more
difficult than for radical conjugate addition reactions.
J ) 8.2, 7.4 Hz, 1H), 7.98 (d, J ) 7.4 Hz, 1H), 8.13 (d, J ) 8.4 Hz,
13
1
H), 8.25-8.27 (dd, J ) 7.4 Hz, 0.7 Hz, 1H). C NMR (125 MHz,
CDCl ): δ 16.0, 18.6, 20.3, 32.3, 35.5, 41.0, 113.8, 119.5, 122.1, 127.9,
3
26
128.8, 130.0, 130.6, 132.0, 132.2, 170.9. [R]
D
2
: +23.2 (c 0.66 CH -
Cl ). Anal. Calcd for C17 S: C, 64.33; H, 6.03; N, 4.41. Found:
2
H19NO
3
C, 64.55; H, 6.42; N, 4.65. ee 78% (S) by HPLC (Chiralcel OJ, hexanes:
propan-2-ol ) 9:1 (0.4 mL/min), 254 nm). (Absolute configuration
determined by hydrolysis to the acid and comparison of the sign of the
optical rotation to that reported in the literature; see below.)
Hydrolysis of 11 to (2S)-2,4-Dimethylpentanoic Acid. To a flask
containing 11 (111 mg, 0.35 mmol), tetrahydrofuran (THF) (5 mL),
2
and H O (5 mL) under N
2 2 2
was added H O (30%, 0.16 mL, 1.4 mmol)
2
at 0 °C. LiOH‚H O (29 mg, 70 mmol) was then added, and the reaction
mixture was stirred at 0 °C for 1 h. After completion of the reaction
(TLC) most of the THF was evaporated. The aqueous solution (pH )
12) was extracted with CH
template). The aqueous solution was acidified with HCl (3 M) until
pH ∼ 1 and extracted again with CH Cl (4 × 15 mL). The organic
solution was dried (MgSO ) and concentrated to yield (2S)-2,4-
dimethylpentanoic acid (34 mg, 74%). H NMR (300 MHz, CDCl
δ 0.83-0.88 (overlapping doublets, 6H), 1.12 (d, J ) 7.25 Hz, 3H),
2
Cl
2
(3 × 10 mL; removal of achiral
Experimental Section
2
2
For general experimental details, see Supporting Information.
General Procedure for the Chiral Lewis Acid Mediated Inter-
molecular r-Selective Hydrogen Atom Transfer Reaction Utilizing
Chiral Ligand 2 at -78 ˚C (2/Lewis Acid/Substrate ) 1:1:1). A
solution of the substrate (0.20 mmol), Lewis acid (0.20 mmol), ligand
4
1
3
):
1
3
1
.17-1.25 (m, 1H), 1.52-1.64 (m, 2H), 2.43-2.54 (m, 1H). C NMR
2
6
(75 MHz, CDCl
3
): δ 17.5, 22.6, 22.7, 26.0, 37.7, 42.9, 183.4; [R]
D
:
26
+
17.1 (c 0.99 Et
General Procedure for Enantioselective H-Atom-Transfer Reac-
tions Catalyzed by Aryl Oxazoline Ligands. A solution of the desired
ligand (0.15 mmol) in 3 mL of CH Cl was cooled to 0 °C in an ice
bath. To the solution was added the appropriate methyl Grignard reagent
0.05 mL (0.15 mmol) of 3.0 M Et O). The solution bubbled and
changed from clear to pale yellow and was allowed to stir at 0 °C for
0 min. The flask was transferred to a dry ice acetone bath and cooled
to -78 °C. The substrate, 18, was added as a solution in 2 mL of
CH Cl followed by the radical precursor RX [passed through basic
alumina] (1.0 mmol), Bu SnH (88 mg, 0.30 mmol), and Et B (1 M in
hexane, 1 mL, 1 mmol) at -78 °C. A 5 mL aliquot of O was then
added via syringe over 2 h. The reaction mixture was stirred at -78
C for 2 h. After completion (TLC), Et O (20 mL) was added to the
reaction mixture. It was then washed with brine (3 × 3 mL) and dried
with MgSO . The crude compound was purified by flash column
2
O) [lit.23 [R]
D
: -21.86 (c 5.39, Et
2
O) (R) isomer].
2 2 2
(71 mg, 0.20 mmol), and CH Cl (3 mL) under N was allowed to stir
at room temperature for 30 min. The solution was cooled to -78 °C in
a dry ice acetone bath. To the solution was added the radical precursor
RX [passed through basic alumina] (1.0 mmol), Bu
mmol), and Et B (1 M in hexane, 1 mL, 1 mmol) at -78 °C. A 5 mL
aliquot of O was then added via syringe over 2 h. The reaction mixture
was stirred at -78 °C for 2 h. After completion (TLC), Et O (20 mL)
was added to the reaction mixture. It was then washed with brine (3 ×
mL) and dried with MgSO . The crude product was purified by flash
3
SnH (116 mg, 0.40
2
2
3
(
2
2
2
3
3
4
column chromatography to yield the alkylated products.
N-(2-Methylpropenoyl)-1,8-naphthosultam (10). A suspension of
2
2
3
3
1
,8-naphthosultam (10.26 g, 50 mmol) in THF (200 mL) and under N
2
2
atmosphere was cooled to 0 °C in an ice bath. To this suspension was
added NaH (3.0 g, 75 mmol, 60% in mineral oil) portionwise over a
period of 20 min. The solution bubbled upon the addition of NaH, and
the dark brown suspension turned clear and was allowed to stir at room
temperature for 1.5 h. A solution of freshly distilled methacryloyl
chloride (7.6 mL, 75 mmol) was added dropwise over 10 min. After
stirring at room temperature overnight, the solution was carefully
°
2
4
chromatography to furnish the alkylated product.
Acknowledgment. Financial support for this program was
provided by NIGMS (Grant GM-54656). We thank Tara Rheault
and Shankar Manyem for experimental assistance and Prof.
Craig Jasperse for helpful discussions.
quenched by the slow addition of saturated aqueous NH
The mixture was extracted with ethyl acetate, washed with brine, dried
over MgSO , and concentrated. The crude product was a brown solid
and was purified by recrystallization using EtOAc:hexanes (11.89 g,
7%, brown solid); mp 160-162 °C. R ) 0.40 (30% EtOAc:hexanes).
): δ 2.16 (s, 3H), 5.78-5.80 (m, 1H), 5.96
s, 1H), 7.67-7.81 (m, 3H), 7.94 (d, J ) 7.2 Hz, 1H), 7.97 (d, J ) 7.2
4
Cl (30 mL).
4
Supporting Information Available: Characterization data for
compounds 1-25 and experimental procedures. See any current
masthead page for ordering information and Web access
instructions.
8
f
1
H NMR (400 MHz, CDCl
3
(
1
3
Hz, 1H), 8.15 (d, J ) 8.3 Hz, 1H). C NMR (125 MHz, CDCl
3
): δ
1
9.4, 114.7, 119.5, 120.1, 122.5, 123.7, 128.1, 129.5, 129.7, 130.7,
JA016839B
J. AM. CHEM. SOC.
9
VOL. 124, NO. 6, 2002 991