Enantioselective Iridium-catalyzed allylic alkylations - Improvements and applications based on salt-free reaction conditions

Article abstract of DOI:10.1055/s-2007-970754

Simplified procedures for the Ir-catalyzed asymmetric allylic alkylation reaction are described that often allow substitution products to be obtained with ≥99% ee. Applications to syntheses of important chiral building blocks, such as the Taniguchi lacton

Full text of DOI:10.1055/s-2007-970754

790
LETTER
Enantioselective Iridium-Catalyzed Allylic Alkylations – Improvements and
Applications Based on Salt-Free Reaction Conditions
Ir-Catalyzed
A
lly
h
lic Substitut
r
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: g.helmchen@oci.uni-heidelberg.de
Received 5 January 2007
Dedicated to Professor Rolf Gleiter on the occasion of his 70th birthday
We have now found that these problems can be solved by
Abstract: Simplified procedures for the Ir-catalyzed asymmetric
allylic alkylation reaction are described that often allow substitution
products to be obtained with ≥99% ee. Applications to syntheses of
important chiral building blocks, such as the Taniguchi lactone and
dimethyl 2-vinylcyclopropane-1,1-dicarboxylate, are presented.
the use of salt-free reaction conditions, which have been
advantageous already for reactions with N,N-diacyl-
amines and reactions of nitro compounds.8 In this variant
of the allylic substitution, which was introduced by Tsuji
for Pd-catalyzed substitutions,9 the alkoxide generated
from the leaving group acts as base and, therefore, soluble
b-dicarbonyl compounds rather than their salts can be
employed. Due to a low concentration of base, additives
previously used in alkylations (see below) can be omitted.
Key words: Taniguchi lactone, iridium, enantioselectivity, allylic
substitution, catalysis
In recent years, the Ir-catalyzed allylic substitution has be-
come a reliable method to synthesize chiral compounds 2
(Scheme 1) with high degrees of regio- and enantioselec-
tivity from easily available monosubstituted allylic car-
bonates 1.1 Iridium complexes of phosphorus amidites2
have proven to be the so far best suited catalysts for
alkylations,3 aminations4 and etherifications.5,6 The Ir-
catalyzed variant supplements the well-established Pd-
catalyzed allylic substitution, which gives rise to linear
achiral substitution products 3, with a few exceptions.7
R
S
S
O
O
O
O
aS
aS
P
N
P
N
S
S
R
L1: R = H
L2: R = OMe
L3
Nu
HNu
[ML*Ln]
+
Figure 1 Phosphorus amidites used as ligands
R
X
*
R
Nu
R
1
2
3
As one of several applications of this salt-free variant, we
have carried out a highly enantioselective synthesis of 4-
vinylbutyrolactone (Taniguchi lactone),10 the starting
material of Stork’s quinine synthesis11a (Scheme 2) and
other natural product syntheses. So far the enantiomerical-
ly pure lactone has been available only via resolution.
Thus, the ‘flaw’ of the Stork synthesis, namely the lack of
enantioselectivity, is rectified.11b
Alkylation of 1a (Scheme 3 and the General Procedure12)
with dimethyl malonate under salt-free conditions gave
distinctly better results than the reaction with sodium di-
methyl malonate (Table 1, entries 1–4); however, longer
Scheme 1 Allylic substitution
A scale of 0.5–1 mmol has been typically used for Ir-
catalyzed allylic substitutions so far. Scale-up (≥10 mmol)
disclosed a number of problems: (a) highest selectivities
were generally obtained with THF as solvent. Difficulties
arose because of generally low solubility of alkali-metal
salts of b-dicarbonyl compounds. For example, reactions
with the malonic acid derivative CH2(CN)CO2Me have
failed until now. While working on a small scale, solubil-
ity problems are often not noticed because of temporary
oversaturation. (b) Iridium catalysts usually employed,
which are prepared from [Ir(COD)Cl]2 and a phosphorus
amidite (Figure 1) by base-induced CH activation, are not
stable against base in the long term. (c) In cyclizations
according to Scheme 6 (see below), deprotonation of the
malonate gives rise to the competitive non-catalyzed reac-
tion pathway, which leads to reduced enantioselectivity.
OMe
O
H
N
O
S
OH
N
Taniguchi
lactone
quinine
SYNLETT 2007, No. 5, pp 0790–0794
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970754; Art ID: G00607ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
3.
2
0
0
7
Scheme 2 Taniguchi lactone, starting material of Stork’s quinine
synthesis

LETTER
Ir-Catalyzed Allylic Substitution
791
entries 9–18).13 Reactions were run on a 10 mmol or 20
mmol scale without difficulty (entries 14 and 15).
MeO2C
R
CO2Me
1. [Ir(COD)Cl]2,
L*, TBD
OCO2Me
Application of the salt-free reaction conditions allows the
salt content to be reduced; furthermore, additives like
tetrahydrothiophene and CuI3c or LiCl3a,e are unnecessary.
The precatalyst [Ir(COD)L*Cl], which is formed sponta-
neously from [Ir(COD)Cl]2 and L*, still has to be acti-
vated with base. Strong bases induce an irreversible
cyclometallation by CH activation at the CH3 group in the
case of L1, as can be easily proved by 31P NMR spectros-
copy.3c,6 With TBD (cf. Scheme 3) as base, an activation
time of two hours was found to be optimal. In the case of
L2, the corresponding CH activation could not be detect-
ed and start of the allylic substitution five minutes after
addition of TBD was found to be optimal.
2
3
R
2. CH2(CO2Me)2 or
NaCH(CO2Me)2
THF
CO2Me
CO2Me
1
R
1–3 a R = Ph
b
c
d
R = CH2OSiPh2t-Bu
R = CH2OCPh3
R = CH3
Scheme 3 Ir-catalyzed alkylations with dimethyl malonate
{TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene}
reaction times were required. Increase of temperature led
to significantly shortened reaction times (entries 5–8). On
reducing the catalyst loading from 4 mol% to 1 mol% the
reaction time was only slightly prolonged but yields and
selectivities were still very high (entries 6 and 8). Similar
results were obtained with substrates 1b–d (Table 1,
For the synthesis of the Taniguchi lactone (Scheme 4),
chromatographically purified 2c was subjected to a
Krapcho reaction to give methyl 3-[(trityloxy)meth-
yl]pent-4-enoate (2c¢),14 which upon cleavage of the trityl
Table 1 Ir-Catalyzed Allylic Alkylation with Dimethyl Malonate According to Scheme 3 and the General Procedure12
Entry Substrate Pronucleophile
Ir (mol%)
L*
L1
L1
L2
L2
L1
L1
L2
L2
L1
L1
L2
L1
L1
L2
L2
L1
L1
L2
Temp (°C) Time (h)
Yield (%)a Ratio 2:3b
ee (%)c
96
1d
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
NaHC(CO2Me)2
CH2(CO2Me)2
NaCH(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
NaCH(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
NaCH(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
NaCH(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
4
4
4
4
4
1
4
1
4
4
4
4
4
4
2
4
4
4
r.t.
r.t.
r.t.
r.t.
50
50
50
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
1
88
92
92
96
94
89
96
92
88
88
86
96
96
88
97
92
90
90
99:1
99:1
9
97.5
98
3d
4
0.5
2
>99:1
99:1
>99
96
5
0.75
1
99:1
6
97:3
96.5
>99
>99
97
7
0.33
0.66
2.5
99:1
8
98:2
9e
88:12
86:14
76:24
84:16
81:19
78:22
78:22
98:2
10
21
21
2.5
97
11
>99
96
12e
13
24
22
45
98.5
>99
98.5
95
14f
15g
16e
17
1.5
8
3
98:2
97.5
98.5
18
98:2
a Combined isolated yield of regioisomers 2 and 3.
b Determined by 1H NMR spectroscopy of the crude products.
c Determined by HPLC on chiral columns.16 In case of 2b and 2c, the absolute configuration was verified by synthesis of (S)-4-vinylbutyro-
lactone (4).
d Data taken from ref.3d
e The reaction was carried out with tetrahydrothiophene and CuI according to the procedure of ref.3c
f The reaction was carried out on a 10 mmol scale.
g The reaction was carried out on a 20 mmol scale with only 2 mol% of Ir {1 mol% of [Ir(COD)Cl]2, 2 mol% of L2 and 4 mol% of TBD,
c 0.4 M}.
Synlett 2007, No. 5, 790–794 © Thieme Stuttgart · New York

792
C. Gnamm et al.
LETTER
O
Table 2 Ir-Catalyzed Allylic Alkylation of 1b with Methyl
1. Krapcho demethoxy-
carbonylation
Cyanoacetate and Malononitrile According to Scheme 5 and the
MeO2C
Ph3CO
CO2Me
General Procedure12
O
2. ZnCl2
Entry Pronucleophile
L*
Time Yield
Ratio
ee
of 5 (%)a 5:6b
(%)c
2c
(S)-4
(h)
30
18
15
5
Scheme 4 Synthesis of (S)-4-vinylbutyrolactone (Taniguchi
1
2
3
4
CH2(CO2Me)(CN) L1
CH2(CO2Me)(CN) L2
72
63
77
70
88:12
85:15
84:16
73:27
99
lactone)
98.5
98
CH2(CN)2
CH2(CN)2
L1
L2
NC
R
H2C(CN)R
R
96
1b
[Ir(COD)Cl]2,
L*, TBD,
THF, r.t.
OTBDPS
CN
a Isolated yield of 5a or 5b.
OTBDPS
b Determined by 1H NMR spectroscopy of the crude products.
c Determined by HPLC on chiral columns.18
5a R = CO2Me
5b R = CN
6a R = CO2Me
6b R = CN
Scheme 5 Allylic alkylation with methyl cyanoacetate and malono-
nitrile
Furthermore, salt-free conditions allowed the known
vinylcyclopropane 8a as well as the so far unknown vinyl-
cyclobutane 8b to be prepared with high enantio-
selectivity (Scheme 6). For the syntheses of the vinyl-
cyclopentane and vinylcyclohexane homologues of 8a
and 8b, we had previously3d used the following proce-
dure: the lithiomalonate was prepared with n-BuLi at low
temperature, the Ir catalyst was added and the reaction
mixture allowed to warm to room temperature. Under
these conditions vinylcyclopropane 8a was not formed at
all and vinylcyclobutane 8b was formed only in very poor
yield. In contrast, under salt-free conditions at room tem-
perature, 8a was obtained in good yield, but the enantio-
meric excess of 55–88% ee was moderate (Table 3,
entries 1–3). Lowering the reaction temperature to 0 °C to
–10 °C led to increased ee of 97% (entries 4–7).19 Ester 8a
is a useful chiral building block in organic synthesis20 that
has been prepared by means of auxiliary control,21
resolution22 and an enantioselective synthesis, which,
group with ZnCl2 spontaneously gave lactone (S)-4 in an
overall yield of 77%.15 Within the range of precision,
enantiomeric purities of 4 and the starting material 2c
were identical. Using the ligand ent-L2, the enantiomeric
lactone (R)-4 was prepared in the same manner in 81%
yield.
Salt-free reaction conditions were particularly effective in
the case of methyl cyanoacetate (Scheme 5). With the
sodium salt no reaction occurred due to its very low solu-
bility in THF. Under salt-free conditions, the carbonate 1b
was alkylated with high degrees of regio- and enantio-
selectivity (Table 2).17 Similar to the case of dimethyl
malonate, the reaction rate was higher with L2 than with
L1, but regio- as well as enantioselectivity were lower.
Similar results were obtained with malononitrile as pro-
nucleophile as well as with carbonate 1c.
Table 3 Salt-Free Ir-Catalyzed Cyclizations According to Scheme 6a
Entry
L*
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
Substrate
L1
Time (h)
24
Temp (°C)
Yield (%)b
67
ee (%)c (abs. config.)d
63 (R)
1
2
r.t.
r.t.
r.t.
0
ent-L2
L3
4.5
3.5
22
91
55 (S)
3
69 (95)
89
88 (R)
4
ent-L2
L3
84 (S)
5
24
0
85 (>99)
56 (77)
92 (97)
24 (29)
55
94 (R)
6
L2
47
–10
–10
r.t.
r.t.
50
97 (R)
7e
8
L2
46
93 (R)
L1
24
96 (R)
9f
ent-L2
ent-L2
18
99 (S)
10
0.75
65
98.5 (S)
a All reactions were carried out on a 0.5 mmol scale according to the general procedure.19
b Isolated yield; in parentheses: corrected yield referring to recovered substrate.
c Determined by gas chromatography on chiral columns.25
d In the case of 8a, the absolute configuration was confirmed by comparison of the optical rotation with reported data.26
e After 24 h catalyst was added again {2 mol% of [Ir(COD)Cl]2, 4 mol% of ligand L2 and 8 mol% of TBD}.
f The reaction was carried out on a 2 mmol scale.
Synlett 2007, No. 5, 790–794 © Thieme Stuttgart · New York

LETTER
Ir-Catalyzed Allylic Substitution
793
however, gave rise to only 70% ee.23 The cyclization of 7b
gave the cyclobutane 8b with enantiomeric excess of
>98% (entries 8–10); cooling was not required here.24
(9) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron
Lett. 1982, 23, 4809.
(10) Ishibashi, F.; Taniguchi, E. Bull. Chem. Soc. Jpn. 1988, 61,
4361.
(11) (a) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec,
J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123,
3239. (b) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 706.
CO2Me
OCO2Me
MeO2C
( )
CO2Me
[Ir(COD)Cl]2,
L*, TBD
( )
n
MeO2C
n
THF
(12) General Procedure for the Ir-Catalyzed Allylic
Alkylation under Salt-Free Conditions
7a n = 1
7b n = 2
8a n = 1
8b n = 2
Under argon, a solution of [Ir(COD)Cl]2 (13.4 mg, 0.02
mmol) and L* (0.04 mmol) in anhyd THF (1.0 mL, content
of H2O <30 mg/L, Karl-Fischer titration) was treated with
anhyd 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 11.1 mg,
0.08 mmol) and stirred for 5 min (L2) or 2 h (L1, L3).
Then, carbonate 1 (1.0 mmol), anhyd THF (4 mL) and the
pronucleophile (1.4 mmol) were added, and the solution was
stirred for the time and at the temperature stated in Table 1.
Conversion was monitored by TLC or GC. The solvent was
removed under reduced pressure and the residue was
analyzed with respect to the ratio of branched and linear
product by 1H NMR. Pure reaction products were obtained
by flash column chromatography.
Scheme 6 Ir-catalyzed cyclization
In conclusion, simplified procedures for asymmetric allyl-
ic alkylations are described that often allow substitution
products to be obtained with ≥99% ee. The new proce-
dures have been used to prepare chiral building blocks,
such as the Taniguchi lactone and the vinylcyclopropane
8a, that are of interest for syntheses of biologically active
compounds.
(13) Analytical Data for (+)-(R)-Dimethyl {1-[(Trityl-
oxy)methyl]prop-2-en-1-yl}malonate (2c)
Acknowledgment
Oil; [a]D20 +38.9 (c 0.99, CHCl3; 99.5% ee (R)]. 1H NMR
(300 MHz, CDCl3): d = 3.05–3.25 (m, 3 H, OCH2CH,
OCH2), 3.61, 3.67 (2 s, 6 H, OCH3), 3.84 [d, J = 8.4 Hz, 1 H,
CH(CO2CH3)2], 5.14 (d, J = 8.4, 1 H, CH=CHEHZ), 5.16 (d,
J = 17.3 Hz, 1 H, CH=CHEHZ), 5.94 (ddd, J = 17.1, 10.3, 8.8
Hz, 1 H, CH=CH2), 7.25–7.34 (m, 9 H, Ph), 7.41–7.44 (m, 6
H, Ph). 13C NMR (75 MHz, CDCl3): d = 44.46 (d,
OCH2CH), 52.22, 52.34 (2 s, OCH3), 53.29 [d,
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623), the Fonds der Chemischen Industrie and the Studien-
stiftung des Deutschen Volkes. We thank Johannes Schröder for
motivated and competent experimental assistance and Prof. Klaus
Ditrich (BASF AG) for enantiomerically pure 1-arylethylamines.
References and Notes
CH(CO2CH3)2], 64.25 (t, OCH2), 86.68 (s, CPh3), 118.01 (t,
CH=CH2), 126.97, 127.73, 128.68 (3 d, Ph), 135.67 (d,
CH=CH2), 143.78 (s, Ph), 168.53, 168.62 (2 s, CO2CH3).
Anal. Calcd for C28H28O5: C, 75.65; H, 6.35. Found: C,
75.52; H, 6.56. HRMS–FAB: m/z calcd for C28H27O5
[M – H]+: 443.1858; found: 443.1838.
(1) (a) Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.;
Weihofen, R. Chem. Commun. 2007, 675. (b) Takeuchi, R.;
Kezuka, S. Synthesis 2006, 3349.
(2) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(b) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.;
Alexakis, A. Synthesis 2004, 2586.
(14) Synthesis of (+)-(S)-Methyl 3-[(Trityloxy)methyl]pent-4-
enoate (2c¢)
(3) (a) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741.
(b) Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen,
G. Eur. J. Inorg. Chem. 2002, 2569. (c) Lipowsky, G.;
Miller, N.; Helmchen, G. Angew. Chem. Int. Ed. 2004, 43,
4595; Angew. Chem. 2004, 116, 4695. (d) Streiff, S.;
Welter, C.; Schelwies, M.; Lipowsky, G.; Miller, N.;
Helmchen, G. Chem. Commun. 2005, 2957. (e) Polet, D.;
Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich,
K. Chem. Eur. J. 2006, 12, 3596; and references cited
therein.
(4) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 122,
15164. (b) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen,
G. Chem. Commun. 2004, 896. (c) Leitner, A.; Shu, C.;
Hartwig, J. F. Org. Lett. 2005, 7, 1093; and references cited
therein. (d) Polet, D.; Alexakis, A. Org. Lett. 2005, 7, 1621;
and references cited therein. (e) Weihofen, R.; Dahnz, A.;
Tverskoy, O.; Helmchen, G. Chem. Commun. 2005, 3541.
(5) (a) López, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 3426. (b) Shu, C.; Hartwig, J. F. Angew. Chem.
Int. Ed. 2004, 43, 4794; Angew. Chem. 2004, 116, 4898.
(6) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272.
A suspension of (+)-(R)-2c (2.23 g, 5.01 mmol), NaCl (0.44
g, 7.52 mmol) and H2O (0.56 mL, 31.06 mmol) in DMSO
(8.2 mL) was stirred for 22 h at 160 °C. Then, the reaction
mixture was cooled to r.t., diluted with H2O (45 mL), and the
aqueous layer was extracted with Et2O (3 ꢀ 90 mL). The
organic layers were combined, washed with brine (45 mL),
dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash column chromatog-
raphy.
HPLC Data for 2c¢
Daicel Chiralcel AD-H, 250 ꢀ 4.6 mm, 5 mm, with guard
cartridge 10 ꢀ 4 mm, 5 mm, n-hexane–i-PrOH 98:2,
flow = 0.5 mL min–1, r.t., 210 nm: tR[(+)-(S)-2c¢] = 13 min,
tR[(–)-(R)-2c¢] = 18 min.
Analytical Data for (+)-(S)-(2c¢)
Oil; [a]D20 +12.9 [c 1.00, CHCl3; >99% ee (S)]. 1H NMR
(300 MHz, CDCl3): d = 2.37 (dd, J = 15.0, 8.2 Hz, 1 H,
CHaHbCO2CH3), 2.67 (dd, J = 15.3, 5.9 Hz, 1 H,
CHaHbCO2CH3), 2.82–2.96 (m, 1 H, CHCH2O), 3.03 (dd,
J = 8.7, 6.9 Hz, 1 H, CHaHbO), 3.16 (dd, J = 8.8, 5.3 Hz, 1
H, CHaHbO), 3.63 (s, 3 H, OCH3), 5.06 (ddd, J = 10.3, 1.4,
0.9 Hz, 1 H, CH=CHEHZ), 5.09 (ddd, J = 17.2, 1.4, 1.3 Hz, 1
H, CH=CHEHZ), 5.78 (ddd, J = 17.4, 10.1, 7.4 Hz, 1 H,
CH=CH2), 7.20–7.37 (m, 9 H, Ph), 7.39–7.50 (m, 6 H, Ph).
13C NMR (75 MHz, CDCl3): d = 36.58 (t, CH2CO2CH3),
40.68 (d, CHCH2O), 51.42 (q, OCH3), 65.91 (t, CH2O),
86.49 (s, CPh3), 116.05 (t, CH=CH2), 126.93, 127.72, 128.70
(7) (a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L.
Acc. Chem. Res. 2003, 36, 659. (b) Trost, B. M.; Jiang, C.
Org. Lett. 2003, 5, 1563; and references cited therein.
(8) (a) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew.
Chem. Int. Ed. 2006, 45, 5546; Angew. Chem. 2006, 118,
5673. (b) Dahnz, A.; Helmchen, G. Synlett 2006, 697.
Synlett 2007, No. 5, 790–794 © Thieme Stuttgart · New York

794
C. Gnamm et al.
LETTER
(3 d, Ph), 138.22 (d, CH=CH2), 144.05 (s, Ph), 172.91 (s,
CO2CH3). Anal. Calcd for C26H26O3: C, 80.80; H, 6.78.
Found: C, 80.50; H, 6.82. HRMS–FAB: m/z calcd for
C26H26O3Na [M + Na]+: 409.1779; found: 409.1784.
by TLC or GC. When conversion was complete or no further
conversion was detected, Et2O (5 mL) and sat. NH4Cl
solution (5 mL) were added without warming, and the
mixture was extracted with Et2O (2 ꢀ 20 mL). The combined
organic phases were washed with brine (20 mL), dried over
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography.
As the reaction is reversible, work-up has to be started at low
temperature by adding aq NH4Cl solution. In order to prove
reversibility, an enantiomerically enriched sample of (R)-7a
(91% ee) was treated at r.t. according to the general
procedure with ent-L2. In doing so, the ee decreased to 39%
(R) within 19 h.
(15) Synthesis of the Taniguchi Lactone (+)-(S)-(4)
ZnCl2 (0.71 g, 5.15 mmol) was added to a solution of (+)-
(S)-2c¢ (1.89 g, 4.90 mmol) in CH2Cl2 (10 mL). The
suspension was stirred at r.t. for 15 h. Phosphate buffer (pH
7, 100 mL) was added and the aqueous layer was extracted
with Et2O (3 ꢀ 100 mL). The organic layers were combined,
dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash column chromatog-
raphy.
GC Data for 4
(b) Preparation of 8b
Chrompack permethyl-b-cyclodextrin, 25 m ꢀ 0.25 mm,
temperature program: 70 °C (20 min), then gradient 10 °C/
min (11 min), then 180 °C (10 min), injector temperature
200 °C: tR [(+)-(S)-4] = 27.0 min, tR [(–)-(R)-4] = 27.1 min.
Analytical Data for (+)-(S)-4
Carbonate 7b (0.5 mmol) was added to the catalyst solution
prepared as described above, and the reaction mixture was
stirred for the time stated in Table 3. For work-up, the
mixture was concentrated under reduced pressure, and the
crude product was purified by flash column
Colorless oil; [a]D20 +7.6 [c 1.10, EtOH, >99% ee (S)]. 1H
NMR (250 MHz, CDCl3): d = 2.35 (dd, J = 17.2, 8.9 Hz, 1
H, CHaHbCO2), 2.64 (dd, J = 17.4, 8.2 Hz, 1 H, CHaHbCO2),
3.07–3.30 (m, 1 H, CH), 3.98 (dd, J = 8.4, 8.4 Hz, 1 H,
CHaHbO), 4.40 (dd, J = 8.4, 8.2 Hz, 1 H, CHaHbO), 5.13 (d,
J = 10.1 Hz, 1 H, CH=CHEHZ), 5.15 (d, J = 17.1 Hz, 1 H,
CH=CHEHZ), 5.74 (ddd, J = 17.3, 9.9, 7.5 Hz, 1 H,
CH=CH2). 13C NMR (75 MHz, CDCl3): d = 34.04 (d, CH),
39.69 (t, CH2CO2), 72.11 (t, CH2O), 117.35 (t, CH=CH2),
135.72 (d, CH=CH2), 176.35 (s, CO2). HRMS (EI): m/z
calcd for C6H8O2 [M]+: 112.0524; found: 112.0523.
(16) HPLC and GC Data for 2 and 3 (Table 1)
HPLC (Daicel columns, 250 ꢀ 4.6 mm, 5 mm with guard
cartridge, 10 ꢀ 4 mm, 0.5 mL min–1): 2a (Chiralcel OJ-H, n-
hexane–i-PrOH 97:3, r.t., 210 nm) tR[(–)-(S)-2a] = 58 min,
tR[(+)-(R)-2a] = 64 min; 2b (Chiralcel AD-H, n-hexane–i-
PrOH 99:1, 20 °C, 220 nm) tR[(+)-(R)-2b] = 12 min, tR[(–)-
(S)-2b] = 14 min, tR[3b] = 15 min; 2c (Chiralcel OD-H, n-
hexane–i-PrOH 98:2, 20 °C, 210 nm) tR[(+)-(R)-2c] = 16
min, tR[(–)-(S)-2c] = 19 min, tR[3c] = 22 min.
chromatography.
(20) (a) Carson, C. A.; Kerr, M. A. Angew. Chem. Int. Ed. 2006,
45, 6560; Angew. Chem. 2006, 118, 6710. (b) Quinkert, G.;
Schmalz, H.-G.; Dzierzynski, E. M.; Dürner, G.; Bats, J. W.
Angew. Chem., Int. Ed. Engl. 1986, 25, 992; Angew. Chem.
1986, 98, 1023.
(21) Quinkert, G.; Schwartz, U.; Stark, H.; Weber, W. D.; Adam,
F.; Baier, H.; Frank, G.; Dürner, G. Liebigs Ann. Chem.
1982, 1999.
(22) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem.
Commun. 1972, 821.
(23) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988,
29, 669.
(24) Analytical Data for (–)-(S)-Dimethyl 2-Vinylcyclo-
butane-1,1-dicarboxylate (ent-8b)
Colorless oil; [a]D20 –154.7 [c 1.00, CHCl3; 98.8% ee (S)].
1H NMR (500 MHz, CDCl3): d = 1.97–2.04 (m, 1 H,
CHCHaHb), 2.06–2.19 (m, 2 H, CHCHaHb, CHCH2CHaHb),
2.54–2.61 (m, 1 H, CHCH2CHaHb), 3.64 (ddd, J = 8.0, 8.0,
8.0 Hz, 1 H, CHCH2CH2), 3.67, 3.72 (2 s, 6 H, CO2CH3),
5.06 (dt, J = 10.2, 1.3 Hz, 1 H, CH=CHEHZ), 5.07 (dt,
J = 17.2, 1.4 Hz, 1 H, CH=CHEHZ), 5.82 (ddd, J = 17.1,
10.5, 6.7 Hz, 1 H, CH=CH2). 13C NMR (75 MHz, CDCl3):
d = 21.03 (t, CHCH2), 25.69 (t, CHCH2CH2), 43.51 (d,
CHCH2), 52.17, 52.47 (2 q, CO2CH3), 57.84 [s,
C(CO2CH3)2], 116.37 (t, CH=CH2), 136.42 (d, CH=CH2),
170.00, 171.90 (2 s, CO2CH3). Anal. Calcd for C10H14O4: C,
60.59; H, 7.12. Found: C, 60.46; H, 7.18. HRMS (EI): m/z
calcd for C10H14O4 [M]+: 198.0892; found: 198.0890.
(25) GC Data for 8a and 8b (Table 3)
GC [Chiraldex g-Trifluoroacetyl (G-TA), 30 m ꢀ 0.25 mm ꢀ
0.125 mm, 50–100 °C, 1 °C/min, injector temperature
200 °C, detector temperature 250 °C]: tR[(+)-(R)-2d] = 33
min, tR[(–)-(S)-2d] = 34 min.
(17) Product 5a was obtained as a ca. 2:1 mixture of
diastereomers, which were not individually characterized.
(18) HPLC Data for 5 (Table 2)
For 5a determined after demethoxycarbonylation to give
(S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)pent-4-
enenitrile (5a¢).
Daicel Chiralcel OD-H, 250 ꢀ 4.6 mm, 5 mm, with guard
cartridge 10 ꢀ 4 mm, 5 mm, n-hexane–i-PrOH 99:1, flow =
0.5 mL min–1, 20 °C, 210 nm: tR[(–)-(R)-5¢a] = 15 min,
tR[(+)-(S)-5¢a] = 24 min; tR[(–)-(S)-5b] = 18 min, tR[(+)-(R)-
5b] = 22 min.4b
Compound 8a [Chiraldex g-Trifluoroacetyl (G-TA), 30 m ꢀ
0.25 mm ꢀ 0.125 mm, 70 °C isothermal, injector temperature
200 °C, detector temperature 250 °C]: tR[(–)-(S)-8a] = 45
min, tR[(+)-(R)-8a] = 54 min.
Compound 8b [Varian CP-Chirasil-Dex (b-CD), 25 m ꢀ
0.25 mm ꢀ 0.25 mm, 100 °C isothermal, injector temperature
200 °C, detector temperature 250 °C]: tR[(–)-(S)-8b] = 16
min, tR[(+)-(R)-8b] = 17 min.
(19) Procedure for the Ir-Catalyzed Cyclization According to
Scheme 6
The catalyst solution was prepared as described above12 and
was diluted with anhyd THF (4 mL).
(26) The absolute configuration is as expected4b and was verified
in the case of 8a by comparison of the optical rotation of (S)-
8a {95.5 % ee, [a]D20 –54.6 (c 0.98, CCl4)} with reported21
data: [a]D25 –55.2 (c 0.98, CCl4).
(a) Preparation of 8a
The solution of the catalyst was cooled to the temperature
stated in Table 3 and carbonate 7a (0.5 mmol) was added
through a septum with a syringe. Conversion was monitored
Synlett 2007, No. 5, 790–794 © Thieme Stuttgart · New York

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