Asymmetric cyclopropanation of allylic alcohols employing sulfonamide/schiff base ligands

Full text of DOI:10.1021/jo991704y

J . Org. Chem. 2000, 65, 5005-5008
5005
Notes
Asym m etr ic Cyclop r op a n a tion of Allylic
Alcoh ols Em p loyin g Su lfon a m id e/Sch iff
Ba se Liga n d s
asymmetric cyclopropanation of allylic alcohols using
sulfonamide/Schiff base ligands. Enantioselectivities as
high as 88% have been achieved at high catalyst loadings
J aume Balsells and Patrick J . Walsh*
P. Roy and Diane T. Vagelos Laboratories,
University of Pennsylvania, Department of Chemistry,
Resu lts a n d Discu ssion
Methods to monoderivatize trans-1,2-diaminocyclohex-
ane have generally resulted in formation of substantial
amounts of mono and bis(derivatized) products.
2
31 South 34th Street,
2
4-27
Philadelphia, Pennsylvania 19104-6323
We have found that formation of the aminosulfon-
amides (1-6) can be cleanly accomplished employing a
slight excess of the diamine (1.5 equiv) relative to the
sulfonyl chloride (Scheme 1).18 The reaction was per-
formed in the presence of triethylamine or diisopropyl-
ethylamine. Reaction of the aminosulfonamides with
salicylaldehyde derivatives cleanly afforded the sulfon-
amide/Schiff base ligands.
The conditions used for the asymmetric cyclopropana-
tion reactions were based on the two-flask method of
Denmark (Scheme 2).14 In a Schlenk flask under a
nitrogen atmosphere, trans-cinnamyl alcohol, the ligand,
dichloromethane, and diethylzinc were combined (solu-
tion A). In a second Schlenk flask iodine, dichloromethane
pwalsh@sas.upenn.edu
Received November 1, 1999
Many biologically active natural products contain
chiral cyclopropanes. Interest in the synthesis of these
and other products with cyclopropane subunits has fueled
the effort to develop improved methodology for the
enantioselective cyclopropanation of olefins. Much of this
work has employed diazo compounds to generate metal
carbenes that can add to olefins to provide cyclopro-
1
panes. However, this methodology has not found wide
application to asymmetric transfer of methylene units
2
(
2
CH ).
Efforts to develop methylene group transfer reagents
for cyclopropanation reactions have focused on the use
of diiodomethane. The stoichiometric transfer of a me-
thylene unit to allylic alcohols has been reported to give
high enantioselectivities.3 Successful catalytic asym-
metric cyclopropanation of allylic alcohols have been
2 2
and diethylzinc were mixed, followed by CH I (solution
B). Solution A was then combined with solution B. The
reactions were complete after 1 h at room temperature.
After workup, the reaction mixture was distilled. The
reactions were very clean, with isolated yields consis-
tently >90%. Using this procedure, the ligand was not
recovered. However, when the reaction mixture was
chromatographed after workup, the ligand was isolated
in 80-99% yield.
-7
8
9-12
achieved with TADDOL and bis(sulfonamide) ligands.
The bis(sulfonamide) system was developed by Kobaya-
shi9
-12
and improved by Denmark. The active reagent
13
in this cyclopropanation reaction is believed to be I-Zn-
-I.1
4-16
CH
We have been interested in the synthesis of sulfona-
2
The modular nature of sulfonamide/Schiff base ligands
permitted assembly of a wide range of ligand architec-
tures. The first generation was designed to determine
how R2 and R3 affected the enantioselectivity of the
1
7-19
mide-based ligands
and their application to asym-
Here we describe the catalytic
metric catalysis.2
0-23
1
(
1) Doyle, M. P.; McKervey, A. M.; T, Y. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley and Sons: New
catalyst. Ligands containing two sulfonamides (R ) and
2
3
three salicylaldehyde derivatives (R and R ) were ex-
amined in the asymmetric cyclopropanation reaction
using 10 mol % ligand (Scheme 2). The results (Table 1)
York, 1998.
(
(
2) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345.
3) Charette, A. B.; J uteau, H. J . Am. Chem. Soc. 1994, 116, 2651-
2
652.
(
4) Charette, A. B.; J uteau, H.; Lebel, H.; Molinaro, C. J . Am. Chem.
Soc. 1998, 120, 11943-11952.
5) Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. J pn.
(17) Diltz, S. I.; Aguirre, G.; Ortega, F.; Walsh, P. J . Tetrahedron:
Asymmetry 1997, 8, 3559-3562.
(18) Balsells, J .; Mejorado, L.; Phillips, M.; Ortega, F.; Aguirre, G.;
Somanathan, R.; Walsh, P. J . Tetrahedron: Asymmetry 1998, 9, 4135-
4142.
(
1
997, 70, 207-217.
(6) Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61-
6
4.
(
(
7) Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1227-1230.
8) Charette, A. B.; Brochu, C. J . Am. Chem. Soc. 1995, 117, 11367-
(19) Ho, D. E.; Betancort, J . M.; Woodmansee, D. H.; Larter, M. L.;
Walsh, P. J . Tetrahedron Lett. 1997, 38, 3867-3870.
(20) Pritchett, S.; Woodmansee, D. H.; Davis, T. J .; Walsh, P. J .
Tetrahedron Lett. 1998, 39, 5941-5944.
1
1368.
(
9) Imai, N.; Sakamoto, K.; Takahashi, H.; Kobayashi, S. Tetrahe-
dron Lett. 1994, 35, 7045-7048.
10) Imai, N.; Takahashi, H.; Kobayashi, S. Chem. Lett. 1994, 177-
80.
11) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tetra-
hedron Lett. 1992, 33, 2575-2578.
12) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai,
N.; Kobayashi, S. Tetrahedron 1995, 51, 12013-12026.
(21) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J . J .
Am. Chem. Soc. 1998, 120, 6423-6424.
(
1
(22) Balsells, J .; Walsh, P. J . J . Am. Chem. Soc. 2000, 122, 1802-
1803.
(23) Balsells, J .; Walsh, P. J . J . Am. Chem. Soc. 2000, 122, 3250-
3251.
(24) Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J . Tetrahedron Lett.
1995, 36, 7357-7360.
(25) Neumann, W. L.; Franklin, G. W.; Sample, K. R.; Aston, K. W.;
Weiss, R. H.; Riley, D. P.; Rath, N. Tetrahedron Lett. 1997, 38, 3143-
3146.
(
(
(
13) Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997, 62, 584-
5
94.
(14) Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997, 62, 3390-
3
401.
(
15) Denmark, S. E.; Edwards, J . P.; Wilson, S. R. J . Am. Chem.
Soc. 1992, 114, 2592-2602.
16) Charette, A. B.; Marcoux, J . F. J . Am. Chem. Soc. 1996, 118,
539-4549.
(26) Wennemers, H.; Yoon, S. S.; Still, W. C. J . Org. Chem. 1995,
60, 1108-1109.
(27) J entgens, C.; Bienz, S.; Hesse, M. Helv. Chim. Acta 1997, 80,
1133-1143.
(
4
1
0.1021/jo991704y CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/20/2000

5
006 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
Sch em e 1
F igu r e 1. Plots of the enantioselectivities of ligands 6a , 6b,
6
d , 6f, and 6g as a function of catalyst loading.
Sch em e 2
Ta ble 1. In itia l Exa m in a tion of th e Effect of R2 a n d R3
on th e En a n tioselectivities Usin g tr a n s-Cin n a m yl
Alcoh ol (Sch em e 2)
indicated the importance of the 3-methoxy group in 1a
and 2a . It is also clear from Table 1 that large substit-
uents on the Schiff base resulted in low enantioselectivi-
ties (1c and 2c).
ligand
R1
-Me
R2
R3
ee
The second generation of ligands maintained the
1
vanillin imine and optimized R . As illustrated in Table
1a
1b
4-C
4-C H -Me
4-C
6
H
4
OMe
H
Bu
OMe
H
Bu
H
H
Bu
H
H
Bu
44
22
2
56
37
0
1
2
, large sulfonamide groups such as R ) 2,4,6-trimeth-
6
4
t
t
1
2
c
a
6
H
4
-Me
1
ylbenzene (3a ) or R ) 2,4,6-triisopropylbenzene (4a ) led
1-naphthyl
1-naphthyl
1-naphthyl
to significant drops in the enantioselectivities. Smaller
2b
2c
t
t
groups such as Me (5a ) and nBu (6a ) give the highest
enantioselectivities, even surpassing the 1-naphthyl de-
rivative 2a in Table 1.
The methyl derivative 5a gave the highest enantiose-
lectivity of all the ligands at 10 mol % but the precursor
2
of the product, affirming the importance of R ) OMe.
At this point it is not known if the role of the methoxy
group is solely to define part of the chiral environment
of the catalyst or if the zinc is interacting with the lone
pair electrons on the oxygen.
5
was difficult to isolate due to its water solubility.
Because the n-butyl derivative 6a gave comparable
enantioselectivity to 5a (20 mol %) and was easily
prepared on large scale, it was used for the remainder of
the study.
Using 10, 20, 40, and 50 mol % ligand (Table 2), the
product ee values increased with increasing catalyst
loading. This indicates that the background reaction, the
reaction that occurs without the participation of the
It was thought that an electron-withdrawing substitu-
ent at R might increase the Lewis acidity and turnover
3
3
frequency of the catalyst. Changing from R ) H (6a ) to
3
R ) Br (6h ) had little effect on the enantioselectivity at
1
0-40 mol %. At 50 mol %, the enantioselectivity showed
3
a slight decrease with R ) Br while 6a climbed another
1% in enantioselectivity. Introduction of a nitro group
1
3
at R (6g) resulted in a marked decrease in enantiose-
lectivities at all ligand mole percents tested. A plot of
the catalyst loading vs product ee values is illustrated
in Figure 1. Unfortunately, little sign of a leveling off of
the enantioselectivities was observed with increasing
catalyst loadings indicating that the background reaction
chiral ligand and generates racemic product, was com-
petitive with the ligand accelerated process.28
The third generation ligands explored the use of
2
different substituents at R (OMe vs H, Cl, Br, and NO
2
)
and the effect of electron-withdrawing substituents at R3
(
H vs Br and NO
enantioselectivity (Table 3).
In these experiments, the sulfonamide R group was
2
) on the turnover frequency and the
2
8
is competitive with the ligand accelerated pathway.
1
Ligand 6a , which performed the best with trans-
cinnamyl alcohol, was then examined with a range of
allylic alcohols at 20 and 50 mol % ligand (Table 4).
Inspection of the results in Table 4 indicates that the
yields are high and the ee values are moderate except
for the trisubstituted allylic alcohol (Table 4, entry 3).
The bis(sulfonamide) system also exhibited low enanti-
oselectivity with this substrate (5% ee).29 The enantiose-
lectivities of trans allylic alcohols are superior to their
n
2
held constant ( Bu). Ligands with R ) H (6b), Cl (6d ),
Br (6e), and NO (6f) showed steep decreases in the ee
2
(
28) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059-1070.
29) Denmark, S. E.; Christenson, B. L.; O’Connor, S. P.; Noriaki,
M. Pure Appl. Chem. 1996, 68, 23-27.
30) Pritchett, S.; Gantzel, P.; Walsh, P. J . Organometallics 1999,
8, 823-831.
(
(
1

Notes
J . Org. Chem., Vol. 65, No. 16, 2000 5007
Ta ble 2. Secon d Gen er a tion Liga n d s. Op tim iza tion of th e Su lfon a m id e Gr ou p R1 w ith R2 ) OMe a n d R3 ) H in th e
Asym m etr ic Cyclop r op a n a tion of tr a n s-Cin n a m yl Alcoh ol
3a , R1 ) 2,4,6-C
H
-Me
4a , R1 ) 2,4,6-C
H
-iPr
1a , R1 ) 4-C
H
-Me
5a , R1 ) Me
6a , R1 ) Bu
n
catalyst mol %
6
2
3
6
2
3
6
4
1
2
4
5
0
0
0
0
5
6
8
9
44
54
68
74
49
72
79
88
81
Ta ble 3. Th ir d Gen er a tion Liga n d s. Reop tim iza tion of th e Sch iff Ba se Gr ou p (R2 a n d R ) a n d Exa m in a tion of th e Effect
3
of Electr on -With d r a w in g Su bstitu en ts on th e En a n tioselectivity w ith Su lfon a m id e R1
)
n
Bu
6a , R2 ) OMe,
6b, R ) H,
2
6d , R ) Cl,
2
6e, R ) Br,
2
6f, R ) NO
2
6g, R ) OMe,
3
2
6h , R ) OMe,
2
catalyst
mol %
2
3
3
3
3
3
3
R
) H
R
) H
R
) Cl
R
) Br
R
) NO
2
R
) Br
R
) NO
2
1
2
4
5
0
0
0
0
49
19
14
24
13
32
29
30
2
5
46
72
82
79
29
43
52
58
72
79
88
25
43
47
Ta ble 4. Asym m etr ic Cyclop r op a n a tion s w ith Liga n d 6a
catalyst (6g and 6h vs 6a ) does not lead to an increase
in turnover frequency is consistent with the idea that the
chiral assembly of the ligand and metal serve as a
scaffolding to bring the reacting partners together. This
is in contrast to the more common role of Lewis acid
catalysts, which is to electronically activate the substrate
through coordination.
1
3
Exp er im en ta l Section
Gen er a l. Details concerning handling of air-sensitive com-
pounds and purification of solvents have been previously re-
ported.30 Carbon multiplicities were assigned by DEPT experi-
ments at either 50 or 125 MHz. Elemental analyses were
performed at the University of Pennsylvania. Unless otherwise
specified, all reagents were purchased from Aldrich Chemical
Company and used without further purification. Diethylzinc
solutions (2 M) were prepared with hexanes in the drybox and
stored in glass vessels sealed with Teflon stoppers.
Enantiomeric excesses were determined using HPLC (25-cm
CHIRALCEL OD-H or 25 cm CHIRALCEL OB-H) or GC (30-m
Supelco â-DEX) methods.
a
See Supporting Information for details of ee determinations.
Syn t h esis a n d Ch a r a ct er iza t ion of t h e Am in osu lfon -
a m id es 1-6. The procedure for the preparation of compounds
cis analogues. Interestingly, the sense of enantioselec-
tivity of (R,R)-6a and (R,R)-bis(sulfonamide)-based cata-
lysts for trans allylic alcohols was the same. However,
the facial selectivity of these catalysts was opposite in
18
1
-4 has been described. An optimized procedure is described
for the synthesis of 5 and 6 that can be used to synthesize 1-4.
To a stirred solution of (R,R)-1,2-diaminocyclohexane tartrate
salt (5.28 g, 20.0 mmol) in 26 mL of a 2 N NaOH solution were
added 200 mL of dichloromethane and triethylamine (1.61 g,
1
3
the cyclopropanation of the cis allylic alcohols.
1
5.96 mmol). The mixture was cooled to 0 °C, and a solution of
n-butyl sulfonyl chloride (2.09 g, 13.3 mmol) in 133 mL of
dichloromethane was added dropwise over 90 min. After the
addition was complete, the mixture was allowed to warm to room
temperature and stirred overnight. The resulting solution was
washed with water (3 × 150 mL), and the organic phase was
dried. Finally, the solvent was removed at reduced pressure. In
Con clu sion s
The results of this investigation into the catalytic
asymmetric cyclopropanation of allylic alcohols represent
the first application of our sulfonamide/Schiff base ligands
to asymmetric catalysis. These ligands permit the cyclo-
propanation of trans allylic alcohols with good to high
enantioselectivities in most cases and excellent yields.
The modular nature of the ligands and their ease of
assembly allow rapid tailoring of the chiral environment.
The observation that increasing the Lewis acidity of the
this manner 6 was isolated as an oil in 61% yield (1.90 g, 8.12
1
mmol). Data for 6: [R]
D
) -35.5 (c 0.62, CHCl
3
); H NMR
(
CDCl
3
, 500 MHz) δ 0.95 (t, J ) 7.5 Hz, 3H), 1.1-1.2 (m, 4H),
.2-1.3 (m, 3H), 1.46 (q, J ) 7.5 Hz, 2H), 1.68-1.76 (m, 2H),
.78-1.86 (m, 2H), 1.96 (dd, J ) 2.0 Hz, J ) 13.0 Hz, 1H),
) 4.5
1
1
1
2
2.10-2.17 (m, 1H), 2.39 (t, J ) 10.5 Hz, 1H), 2.87 (td, J
1

5
008 J . Org. Chem., Vol. 65, No. 16, 2000
Notes
1
3
1
Hz, J
2
) 11.0 Hz, 1H), 3.0-3.1 (m, 2H) ppm; C { H} NMR
, 125 MHz) δ 13.5 (CH ), 21.5 (CH ), 24.8 (CH ), 25.0
), 25.7 (CH ), 33.6 (CH ), 35.7 (CH ), 53.6 (CH ), 55.0 (CH),
0.4 (CH) ppm; IR (film) 3436, 1639 cm ; ME (ES ) m/z 235.2
M + H, 100%).
Data for 5: the product was prepared as 6 above and obtained
+ H, 50%, 100%, 50%), 517.3, 519.3, 521.4 (M + Na, 30%, 60%,
(
(
CDCl
CH
3
3
2
2
2 2 3
30%). Anal. Calcd for C17H24Br N O S: C, 41.15; H, 4.87; N, 5.64.
2
2
2
2
2
+
Found: C, 41.11; H, 4.89; N, 5.30.
Data for 6e: 99% yield (1.28 g, 2.98 mmol); mp 99-101 °C;
-
1
6
(
1
[R]
D
3 3
) -69.3 (c 0.51, CHCl ); H NMR (CDCl , 200 MHz) δ 0.81
(t, J ) 7.2 Hz, 3H), 1.2-2.0 (m, 11H), 2.1-2.3 (m, 1H), 2.9-3.1
(m, 2H), 3.4-3.6 (m, 1H), 3.6-3.9 (m, 1H), 6.27 (b, 1H), 8.52 (d,
1
3
as an oil in 25% yield (100 mg, 0.52 mmol); H NMR (CDCl ,
1
3
2
2
00 MHz) δ 1.1-1.4 (m, 4H), 1.6-1.8 (m, 2H), 1.9-2.0 (m, 1H),
J ) 3.0 Hz, 2H),, 8.66 (s, 1H), 8.89 (d, J ) 3.0 Hz, 2H) ppm;
C
1
.0-2.2 (m, 1H), 2.3-2.5 (m, 1H), 2.6-3.0 (m, 3H), 3.02 (s, 3H)
{ H} NMR (CDCl
3
, 50 MHz) δ 13.3 (CH
3
), 21.3 (CH
2
), 23.7 (CH
2
),
1
3
1
ppm; C { H} NMR (CDCl
3.3 (CH ), 35.3 (CH ), 41.5 (CH
Syn th esis a n d Ch a r a cter iza tion of 1-6(a -g). The pro-
cedure for the preparation of compounds 1-6(a -g) has been
3
, 50 MHz) δ 24.6 (CH
2
), 24.9 (CH
2
),
24.6 (CH ), 25.5 (CH
2
2
), 31.2 (CH ), 33.2 (CH
2
2
), 54.3 (CH
2
), 56.7
3
2
2
3
), 54.7 (CH), 60.5 (CH) ppm.
(CH), 66.1 (CH), 117.6 (C), 128.5 (CH), 131.5 (CH), 137.0 (C),
-
1
140.2 (C), 166.7 (C), 170.7 (CH) ppm; IR (film) 3436, 1650 cm
;
-
ME (ES ) m/z 427.4 (M + H, 100%).
1
8
described in a previous paper. Data for the new compounds
Data for 6f: the product was recrystallized from CHCl
3
; 92%
5
a and 6a -g is described herein.
yield (1.15 g, 2.57 mmol); mp 193-194 °C; [R]
D
) -94.4 (c 0.50,
1
Data for 5a : the oily product was obtained as a 4:1 mixture
3 3
CHCl ); H NMR (CDCl , 200 MHz) δ 0.60 (t, J ) 7.4 Hz, 3H),
of diastereomers in 99% yield (171 mg, 0.52 mmol); [R]
D
) -158.0
, 200 MHz) δ 1.2-1.6 (m, 3H),
.6-2.0 (m, 4H), 2.2-2.3 (m, 1H), 2.70 (s, 3H), 2.9-3.1 (m, 2H),
0.9-2.0 (m, 11H), 2.2-2.4 (m, 1H), 2.6-3.1 (m, 3H), 3.2-3.4 (m,
1
(c 0.1.12, CHCl
3
); H NMR (CDCl
3
1H), 3.87 (s, 3H), 4.7-4.9 (m, 1H), 6.99 (s, 2H), 8.28 (s, 1H),
13.66 (s, 1H) ppm; 13C { H} NMR (CDCl
1
, 50 MHz) δ 13.2 (CH
), 25.5 (CH ), 33.6 (CH ), 34.4
), 57.7 (CH), 72.2 (CH), 109.5 (C),
117.3 (CH), 119.0 (CH), 124.9 (C), 149.6 (C), 151.2 (C), 164.5
1
3
7
{
2
3
3
),
.3-3.4 (m, 2H), 3.82 (s, 3H, minor), 3.85 (s, 3H, major), 6.7-
21.1 (CH
2
), 23.6 (CH
2
), 24.6 (CH
), 56.2 (CH
2
2
2
.0 (m, 3H), 8.24 (s, 1H, minor), 8.36, (s, 1H, major) ppm; 13
C
2
),
(CH ), 53.3 (CH
2
2
3
1
H} NMR (CDCl
), 33.5 (CH
), 114.3 (C), 118.0 (CH), 118.1 (CH), 123.1 (CH),
48.3 (C), 151.6 (C), 165.7 (CH) ppm; minor diastereomer δ 23.7
CH ), 24.4 (CH ), 32.7 (CH ), 33.8 (CH ), 40.9 (CH ), 55.8 (CH),
7.6 (CH), 71.9 (CH ), 113.9 (C), 117.6 (CH), 118.2 (CH), 123.1
3
, 50 MHz) major diastereomer δ 23.5 (CH
-1
+
4.4 (CH
2
2
), 33.8 (CH ), 40.9 (CH ), 55.8 (CH), 57.6
2
3
(CH) ppm; IR (film) 3280, 1631 cm ; ME (ES ) m/z 447.4, 449.5
2 4
(M + H, 100%). Anal. Calcd for C17H27BrN O S: C, 48.32; H,
6.08; N, 6.26. Found: C, 48.12; H, 6.05; N, 6.07.
(CH), 71.6 (CH
3
1
(
5
2
2
2
2
3
Data for 6g: the product precipitated from the reaction
mixture as a yellow powder, and after overnight stirring, the
3
(
CH), 148.1 (C), 151.7 (C), 164.7 (CH) ppm; IR (film) 3454, 1631
solid was vacuum filtered and dried; 92% yield (1.18 g, 2.85
-1
+
1
cm ; ME (ES ) m/z 327.4 (M + H, 100%), 349.3 (M + Na, 85%),
6
mmol); mp 267-269 °C; [R]
D
) -153.0 (c 0.10, CHCl
3
); H NMR
75.8 (2M + Na, 25%).
(DMSO, 500 MHz) δ 0.29 (t, J ) 7.0 Hz, 3H), 0.6-1.2 (m, 6H),
1.3-1.5 (m, 3H), 1.6-1.8 (m, 2H), 2.4-2.6 (m, 2H), 2.9-3.1 (m,
3H), 3.45 (s, 3H), 6.95 (d, J ) 8.5 Hz, 1H), 7.07 (d, J ) 2.0 Hz,
Data for 6a : 99% yield (735 mg, 1.99 mmol); mp 185-186
1
°
0
2
C; [R]
D
) -2.6 (c 0.51, CHCl
3
); H NMR (CDCl
3
, 200 MHz) δ
.50 (t, J ) 7.5 Hz, 3H), 0.8-2.0 (m, 11H), 2.2-2.4 (m, 1H), 2.6-
.9 (m, 2H), 2.9-3.1 (m, 1H), 3.2-3.4 (m, 1H), 3.84 (s, 3H), 5.23
1H), 7.80 (d, J ) 2.0 Hz, 1H), 8.30 (d, J ) 6.5 Hz, 1H), 13.5 (b,
1H) ppm; 13C { H} NMR (DMSO, 125 MHz) δ 13.6 (CH
1
), 21.1
), 34.4 (CH ),
), 56.1 (CH), 65.1 (CH), 106.2 (C), 112.0
(CH), 125.6 (C), 133.4 (CH), 152.3 (C), 166.7 (C), 172.0 (CH) ppm;
3
1
3
1
(d, J ) 8.0 Hz, 1H), 6.7-7.0 (m, 3H), 8.37 (s, 1H) ppm; C { H}
(CH
2
), 24.1 (CH
2
), 24.5 (CH
2
), 25.8 (CH
2
), 31.8 (CH
2
2
NMR (CDCl
CH ), 25.2 (CH
7.5 (CH), 71.7 (CH), 114.2 (C), 117.9 (CH), 118.1 (CH), 122.9
CH), 148.3 (C), 151.6 (C), 165.5 (CH) ppm; IR (film) 3047, 1642
3
, 50 MHz) δ 12.9 (CH
3
), 20.8 (CH
2
), 23.4 (CH
2
), 24.4
52.8 (CH
2
), 56.0 (CH
3
(
5
(
2
2
), 33.6 (CH ), 34.3 (CH
2
2
), 52.9 (CH
2
), 55.7 (CH
3
),
-
1
+
IR (film) 3453, 1642 cm ; ME (ES ) m/z 414.5 (M + H, 100%).
Anal. Calcd for C17 S: C, 52.29; H, 6.58; N, 10.16.
27 3 6
H N O
-1
+
cm ; ME (ES ) m/z 339.4 (M + H, 100%), 361.4 (M + Na, 10%).
Anal. Calcd for C18 S: C, 58.67; H, 7.66; N, 7.60. Found:
C, 58.40; H, 7.94; N, 7.31.
Data for 6b: 100% yield (603 mg, 1.78 mmol); mp 112-114
°
0
3
Found: C, 51.74; H, 6.57; N, 9.98.
H
28
N
2
O
4
(1R,2R)-2-P h en ylcyclop r op ylm eth a n ol. Gen er a l P r oce-
d u r e Usin g Differ en t P r om oter s. In a dry 25-mL round-
bottom flask (flask A) were combined trans-cinnamyl alcohol (123
mg, 0.91 mmol) and ligand (6b, 165 mg, 0.45 mmol). Vacuum
(0.5 Torr) was applied for 1 min, and then the flask was put
under atmosphere of nitrogen. This was repeated twice followed
1
C; [R]
D
) -132.3 (c 0.50, CHCl
.57 (t, J ) 7.4 Hz, 3H), 0.8-1.9 (m, 11H), 2.2-2.4 (m, 1H), 2.6-
.1 (m, 3H), 3.2-3.5 (m, 1H), 4.62 (d, J ) 8.2 Hz, 1H), 6.8-7.0
3 3
); H NMR (CDCl , 200 MHz) δ
1
3
1
(
(
2
(
m, 2H), 7.2-7.4 (m, 2H), 8.36 (s, 1H) ppm; C { H} NMR
CDCl , 50 MHz) δ 13.2 (CH ), 21.1 (CH ), 23.8 (CH ), 24.8 (CH ),
5.4 (CH ), 34.0 (CH ), 34.6 (CH ), 53.4 (CH ), 57.9 (CH), 72.9
CH), 117.1 (CH), 118.5 (C), 118.9 (CH), 131.5 (CH), 132.6 (CH),
2 2
by the addition of 10 mL of CH Cl . To this solution was slowly
3
3
2
2
2
added diethylzinc (143 µL, 1.4 mmol, 1.1 equiv) to give a colorless
solution, which was maintained at room temperature for another
30 min. To a 25-mL Schlenk flask similarly equipped (flask B)
2
2
2
2
61.0 (C), 165.4 (CH) ppm; IR (film) 3279, 1631 cm-1; ME (ES )
m/z 369.4 (M + H, 100%), 391.4 (M + Na, 10%). Anal. Calcd for
S: C, 60.33%; H, 7.74; N, 8.28. Found: C, 60.70; H,
+
1
2 2
were added iodine (456 mg, 1.80 mmol, 1.0 equiv) and CH Cl
(20 mL). When the iodine was completely dissolved, diethylzinc
(186 µL, 1.80 mmol, 2.0 equiv) was slowly added to give a white
slurry. After 5 min, diiodomethane (145 mL, 1.80 mmol, 1.0
equiv) was added, and the contents of the flask were stirred at
room temperature for an additional 5 min. After this time, the
contents of flask A were transferred via cannula to flask B. The
reaction was quenched after 1 h by addition of 13 mL of a 2 N
NaOH solution. The organic phase was separated, and the
17 26 2 3
C H N O
8
.01; N, 8.27.
Data for 6c: 99% yield (1.22 g, 2.99 mmol); mp 111-114 °C;
1
[
(
(
1
2
R]
D
) -113.7 (c 0.51, CHCl
3
); H NMR (CDCl
3
, 200 MHz) δ 0.64
t, J ) 7.2 Hz, 3H), 1.0-2.0 (m, 11H), 2.2-2.4 (m, 1H), 2.6-2.9
m, 2H), 3.1 (td, J ) 3.0 Hz, J ) 10.0 Hz, 1H), 3.2-3.5 (m,
H), 5.23 (b, 1H), 7.16 (d, J ) 2.6 Hz, 2H), 7.40 (d, J ) 2.6 Hz,
1
2
H), 8.30 (s, 1H) ppm; 13C { H} NMR (CDCl
), 21.1 (CH ), 23.6 (CH ), 24.6 (CH ), 25.5 (CH
4.3 (CH ), 53.3 (CH ), 57.7 (CH), 71.6 (CH), 119.1 (CH), 122.6
1
, 50 MHz) δ 13.2
), 33.5 (CH ),
3
2 2
aqueous solution was extracted twice with 30 mL of CH Cl . The
(CH
3
2
2
2
2
2
combined organic extracts were dried with sodium sulfate, and
the solvent was removed in vacuo. Distillation of the residue at
reduced pressure (bp 109 °C, 0.6 Torr) yielded 134 mg of (1R,2R)-
2-phenylcyclopropylmethanol (98%, 88.3% ee) as a colorless oil.
This procedure was used for the cyclopropanation of all other
allylic alcohols. Spectroscopic data for all cyclopropanes matched
those reported in the literature.4
3
2
2
(CH), 123.2 (C), 129.2 (C), 132.5 (C), 157.0 (C), 164.1 (CH) ppm;
-
1
+
IR (film) 2934, 1631 cm ; ME (ES ) m/z 407.3, 409.3 (M + H,
00%), 429.4, 431.3 (M + Na, 90%). Anal. Calcd for C17
Cl S: C, 50.13; H, 5.94; N, 6.88. Found: C, 50.48; H, 6.24;
N, 6.50%.
Data for 6d : 99% yield (1.48 g, 2.98 mmol); mp 117-120 °C;
1
24
H -
2
2 3
N O
,13
1
[
(
(
1
2
R]
t, J ) 7.4 Hz, 3H), 1.0-2.0 (m, 11H), 2.2-2.4 (m, 1H), 2.6-2.9
m, 2H), 3.1 (td, J ) 3.2 Hz, J ) 10.0 Hz, 1H), 3.2-3.5 (m,
H), 5.11 (b, 1H), 7.33 (d, J ) 2.2 Hz, 2H), 7.69 (d, J ) 2.2 Hz,
D
) -103.7 (c 0.51, CHCl
3
); H NMR (CDCl
3
, 200 MHz) δ 0.65
Ack n ow led gm en t. This work was supported by a
CAREER award to P.J .W. from the National Science
Foundation (CHE-9733274).
1
2
H), 8.28 (s, 1H) ppm; 13C { H} NMR (CDCl
), 21.1 (CH ), 23.6 (CH ), 24.6 (CH ), 25.5 (CH
4.3 (CH ), 53.3 (CH ), 57.7 (CH), 71.4 (CH), 109.4 (CH), 112.7
1
, 50 MHz) δ 13.2
), 33.6 (CH ),
3
Su p p or tin g In for m a tion Ava ila ble: Details of the ee
determinations. This material is available free of charge via
the Internet at http://pubs.acs.org.
(CH
3
2
2
2
2
2
3
2
2
(C), 119.5 (CH), 132.9 (C), 138.0 (C), 158.4 (C), 164.0 (CH) ppm;
-
1
+
IR (film) 3454, 1640 cm ; ME (ES ) m/z 495.3, 497.4, 499.3 (M
J O991704Y