Enantioselective synthesis of 4-heterosubstituted cyclopentenones

Article abstract of DOI:10.1021/jo400409f

Racemic 4-hydroxycyclopentenone, readily derived from furfuryl alcohol, can be transformed via its O-Boc derivative to 4-acyloxy, 4-aryloxy-, 4-amino-, or 4-thio-substituted cyclopentenones with high enantioselectivity by palladium-catalyzed kinetic resolution via nucleophilic allylic substitutions. Applying this methodology, a short formal synthesis of ent-noraristeromycin was readily accomplished.

Full text of DOI:10.1021/jo400409f

Subscriber access provided by University of British Columbia Library
Note
Enantioselective Synthesis of 4-Heterosubstituted Cyclopentenones
Kathrin Ulbrich, Peter Kreitmeier, Tirayut Vilaivan, and Oliver Reiser
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400409f • Publication Date (Web): 25 Mar 2013
Downloaded from http://pubs.acs.org on April 1, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
Enantioselective Synthesis of 4-Heterosubstituted Cyclopentenones
7
Kathrin Ulbrich,† Peter Kreitmeier,† Tirayut Vilaivan,‡* Oliver Reiser†*
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Institut für Organische Chemie, Universitätsstr. 31, 93053 Regensburg, Germany
‡Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn
University, Phayathai Road, Patumwan, Bangkok 10330, Thailand
vtirayut@chula.ac.th;
oliver.reiser@chemie.uni-regensburg.de
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
In Memoriam Robert E. Gawley#
O
Pd2(dba)3
O
O
(1-2 mol% Pd)
+
(R,R)-DACH phenyl
(Trost's Ligand)
(2-4 mol%)
OBoc
Nu
S up to 500
OBoc
+
NuH
(O, N, S-nucleophiles)
Racemic 4-hydroxycyclopentenone, readily derived from furfuryl alcohol, can be transformed via its O-
Boc derivative to 4-acyloxy, 4-aryloxy-, 4-amino-, or 4-thio-substituted cyclopentenones with high
enantioselectivity by palladium-catalyzed kinetic resolution via nucleophilic allylic substitutions.
Applying this methodology, a short formal synthesis of ent-noraristeromycin was readily accomplished.
Enantiopure 4-hydroxycyclopentenone (2) has been recognized as a most versatile chiral
intermediate,1 having been used as a key synthon for the synthesis of natural products and
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 13
1
2
3
4
5
6
pharmaceutical drugs. Prominent examples are found in the synthesis of prostaglandin PGE1 methyl
a
ester,2 the HIV protease inhibitor GRL-065792b or the farnesyltransferase inhibitor Arglabin™.2c
7
8
9
Figure 1. 4-Hydroxycyclopentenone as synthon in the synthesis of drugs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
H
CH3
CO2Me
5
H
O
Pentn
OH
O
O
H
HO
H3C
Arglabin™
PGE1 methyl ester
O
Ph
O
O
O
S
O
N
H
N
OH
Pri
OH
GRL-06579 A
Consequently, a considerable number of synthetic approaches towards racemic3 and enantiopure 2 and
derivatives thereof utilizing the chiral pool4, chiral reagents5 or catalysts6 have been developed. A
majority of these transformations involve selective changing the oxidation state of the corresponding
1,3-cis-diol7 or 1,3-diketone.8
The direct deracemization of (±)-2 or its O-acyl derivative was achieved by enzymatic resolution with
lipases9 or penicillin G acylase.10 Kinetic resolution of (±)-2 had also been achieved by catalytic
asymmetric isomerization11 or hydrogenation.12 Surprisingly in light of the well-established
methodology for asymmetric nucleophilic substitutions of cyclic and acyclic allylic alcohols, as well as
,
, ,
their esters, by chiral palladium catalysts (Tsuji-Trost reaction),13 14 15 16 this approach was not
investigated with (±)-2. Arguably, the most direct access to racemic (±)-2 is the transformation of
furfuryl alcohol (1) under aqueous acidic conditions,17 a process that could recently be greatly improved
moving from batch to flow conditions in microreactors (Scheme 1).18 We report here the easily prepared
O-Boc derivative (±)-3b as an excellent substrate for resolving (±)-2 by regioselectively introducing
oxygen, nitrogen, and sulfur nucleophiles with high asymmetric induction.
ACS Paragon Plus Environment
2

Page 3 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
Scheme 1. Facile and high-yielding synthesis of starting materials (±)-3 from furfuryl alcohol 1.
7
8
9
O
Ac2O
AcOH / H2O (pH 4)
Toluene (10%)
240 °C, 34 bar, < 1 min
80%
Ref. 9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
OAc
Continuous Flow
O
(±)-3a
OH
87%
O
OH
Boc2O
Ref. 18
1
(±)-2
87-90%
OBoc
(±)-3b
We started our investigation by converting (±)-2 to its corresponding acetate (±)-3a, which was
subjected to palladium catalyzed allylations with various nucleophiles using Trost’s ligand (R,R)-5.
However, under various conditions tried, (±)-3a turned out to be a sluggish substrate for the title
transformation, resulting in low selectivities which was accompanied by decomposition of the starting
material at extended reaction times (Table 1, entries 1, 2). Obviously, the allyl acetate moiety in (±)-3a
is deactivated by the conjugated carbonyl group, making a more activated derivative necessary.
Gratifyingly, turning to the O-Boc derivative (±)-3b, the allyl palladium complex formation occurred
readily even at –78 °C, allowing the introduction of various O-, S- and N-nucleophiles. Initially, the
nucleophiles were used in stoichiometric quantities with the aim to achieve a dynamic kinetic
resolution, which had been proven possible for hydroxybutenolide and related substrates.14,15,16,20
However, for (±)-3b as substrate, the reaction only took place in a kinetic resolution mode because the
reaction did not proceed to completion even when the nucleophiles (acetate and phthalimide) were
present in excess, and moreover, the products were obtained with low optical purities in such cases. On
the other hand, good to excellent enantioselectivities were obtained when the amount of the
nucleophiles was decreased to 0.5 equiv or less (Table 1). Carboxylic acids (entries 3, 5, 7) and phenol
(entry 4) proved to be suitable nucleophiles, giving generally selectivity factors of > 30 in the kinetic
resolution at room temperature within 1 hour reaction time. For 1-naphthoic acid (entry 6), a scale-up to
5 mmol of the substrate (±)-3b with concurrent lowering of the temperature to –20 °C allowed the
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 13
1
2
3
4
5
6
7
8
isolation of both recovered starting material (R)-3b and product 6c in enantiopure forms (> 99% ee)
with almost perfect yield.
9
Table 1. Palladium-catalyzed allylic substitutions of 3.[a]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Pd2(dba)3
(2.3 mol% Pd)
O
O
NuH
+
+
(R,R)-5 (3.7 mol%)
OR
OR
CH2Cl2
Nu
(S)-6a-g
(R)-3a-b
(±)-3a (R = Ac)
(±)-3b (R = Boc)
4a: CH3CO2H
4b: PhOH
O
O
4c: 1-naphthyl-CO2H
4d: 4-BrC6H4CO2H
4e: BnSH
NH HN
4f: n-C12H25SH
4g: Phthalimide
PPh2Ph2P
(R,R)-5
entry
3
4
t
T
3
6
S[b]
(h) (°C)
yield
(%)
yield
(%)
%ee
26
% ee
91
1
2
3a
3a
4b
4c
18
4
25
0
23
50
12
24
11
25
30
77
35
3
3b
4a
1
0
46
96
90
31
(3a)
4
5
6
7
8
9
3b
3b
3b
3b
3b
3b
4b
4c
2
1
4
1
0
0
34
31
43
44
33
38
31
42
99
90
34
46
45
41
42
39
93
90
44
44
4c[c]
4d
4e
–20
0
>99
95
>99
91
501
41
17 –78
17 –78
>99
92
93
56
4f
93
50
10 3b
11 3b
4g
18
rt
rt
>99 50[d] 96[d]
>99
48[e] 95[e]
194
113
4g[c] 16
[a]
(±)-3 (0.5 mmol), 4 (0.24 mmol), Pd2(dba)3 (1.2 mol%, 2.3 mol% Pd based on the nucleophile),
(R,R)-5 (3.7 mol% based on the nucleophile) in dichloromethane (2 mL). Absolute configurations of 6a
and 6d were obtained by comparison of specific rotation values with literature (see experimental part) as
[b]
well as by X-ray crystallography (6g, see supporting information).
Selectivity factor.19 [c]5 mmol
scale, Pd2(dba)3 (0.5 mol%; 1 mol% Pd based on the nucleophile), (R,R)-5 (2 mol% based on the
nucleophile).[d]36%, 99% ee after single recrystallization from ethanol. [e]43%, 97% ee after single
recrystallization from ethanol.
ACS Paragon Plus Environment
4

Page 5 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Likewise, sulfur nucleophiles (entries 8,9) were also successfully employed, however, due to their
greater reactivity we found that the reactions are best carried out at –78 °C to give 6e and 6f with
8
9
selectivity factors around 50. This successful use of thiols as nucleophiles in a palladium-catalyzed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
allylic substitution represents new examples of the very rare reactions of this type.13, Finally,
20
phthalimide allowed the enantioselective introduction of a nitrogen nucleophile into the cyclopentenone
moiety (entries 10, 11), being especially relevant for the synthesis of carbocyclic nucleosides.
Indeed, starting from (±)-3b a short formal synthesis of the enantiomer of the antiviral and antitumor
drug noraristeromycin was readily accomplished. The key intermediate 8, previously synthesized from
,
from desymmetrized cis-4-cyclopentene-1,3-diol,21 22 can be obtained in one step from (±)-3b and 6-
chloropurine (7) in 46% yield (92% yield based on 7) and in 94% ee, which can be raised to 98% ee
(39% yield) by a single recrystallization. In addition, (R)-3b was also recovered in 47% yield and 98%
ee.
Scheme 2. Formal synthesis of (ent)-noraristeromycin 9.
(R)-3b
O
47%, 98% ee
+
N
N
OBoc
Pd2(dba)3
(1 mol% Pd)
N
N
Cl
NH2
(±)-3b
O
HO
+
N
N
N
N
N
Cl
(R,R)-5 (2 mol%)
CH2Cl2
Ref. 21,22
N
HO
OH
N
H
46%, 94% ee
N
7
8
9
In summary, we have demonstrated a successful kinetic resolution of (±)-3 via Pd-catalyzed asymmetric
allylic substitution. Excellent enantioselectivities of both substitution products and recovered starting
materials were obtained even at low catalyst loading (1–2 mol% Pd, 2–4 mol% (R,R)-5 based on the
nucleophile). The scope of participating nucleophiles is very broad - phenols, carboxylic acids, thiols
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 13
1
2
3
4
5
6
7
8
and nitrogen-containing heterocycles. This method should provide a potentially useful access to a
variety of optically active 4-substituted-2-cyclopentenone derivatives.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Information. All reagents of which the preparation is not described were obtained from
commercial suppliers and used without further purification. 4-Hydroxy-2-cyclopentenone (±)-2, 4-
acetoxy-2-cyclopentenone (±)-3, and the (R,R)-5 were prepared according to published proce-
dures.9,18,23 CH2Cl2 and THF were obtained from a solvent purification system. CH2Cl2 was degassed by
three freeze-pump-thaw cycles. Hexanes and EtOAc were distilled before use. Chemical shifts are
reported in ppm from CHCl3 (7.26 ppm) as internal standard on the δ scale. 13C chemical shifts are
13
reported in ppm from CHCl3 (77 ppm) as internal standard on the δ scale. The C signals assignment
were assisted by DEPT 90 and DEPT 135 experiments. The optical rotation was determined on a
polarimeter at 589 nm wavelength (sodium-d-line) in a 0.5 dm measuring cell of ca. 1 mL volume.
General procedure for Pd-catalyzed kinetic resolution. To a solution of (±)-3b (0.50 mmol) and the
nucleophile (0.24 mmol) in dry, degassed CH2Cl2 (2 mL) under nitrogen at the specified temperature
was added the catalyst solution, which was separately prepared by stirring Pd2(dba)3 (2.6 mg, 0.0028
mmol, 2.3 mol% Pd based on 4) and (R,R)-5 (6.1 mg, 0.0088 mmol, 3.7 mol% based on 4) in dry,
degassed CH2Cl2 (1 mL) under nitrogen until the initially purple solution turned yellow-brown (2–3
min). The progress of the reaction was monitored by TLC. Once the reaction was complete, the reaction
mixture was directly loaded onto a silica gel column and the product eluted by an appropriate PE:EtOAc
mixture.
General procedure for Pd-catalyzed kinetic resolution on larger scale. To a solution of (±)-3b (5
mmol) and the nucleophile (2.4 mmol) in dry, degassed CH2Cl2 (20 mL) under nitrogen at the specified
temperature was added the catalyst solution, which was separately prepared by stirring Pd2(dba)3 (11
ACS Paragon Plus Environment
6

Page 7 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
mg, 0.012 mmol, 1 mol% Pd based on 4) and (R,R)-5 (33 mg, 0.048 mmol, 2 mol% based on 4) in dry,
degassed CH2Cl2 (10 mL) under nitrogen until the initially purple solution turned yellow-brown (2–3
min). The reaction mixture was monitored by TLC. Once the reaction was complete, the solvent was
evaporated and the crude product was purified by column chromatography with PE:EtOAc as eluent
mixture.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(tert-Butoxycarbonyloxy)-2-cyclopentenone (±)-3b. To a solution of 4-hydroxy-2-cyclopentenone
(±)-2 (0.500 g, 5 mmol) and Boc2O (1.167 g, 6 mmol) in THF (5 mL), triethylamine (0.84 mL, 6 mmol)
and DMAP (10 mg) were added. After stirring at room temperature for 30 min, the solvent was removed
and the residue purified by column chromatography to give the product as a white solid (0.865 g, 87%).
1
M.p. 38–39 °C. Rf = 0.33 (PE/EtOAc 90:10). H NMR (300 MHz, CDCl3): δ = 1.47 (s, 9H), 2.41 (dd,
1H, J = 18.7, 2.3 Hz), 2.84 (dd, 1H, J = 18.7, 6.4 Hz), 5.72 (dtd, 1H, J = 6.1, 2.3, 1.3 Hz), 6.34 (dd, 1H,
J = 5.7, 1.3 Hz), 7.60 (dd, 1H, J = 5.7, 2.4 Hz). 13C NMR (75 MHz, CDCl3): δ = 27.8, 41.0, 74.2, 83.3,
137.2, 152.7, 158.6, 204.6. IR (solid): νmax(cm-1) = 1731, 1716. HRMS (EI-quadrupole): m/z calcd for
C10H14O4: 198.0892 [M·+]; found: 198.0896.
Recovered starting material from kinetic resolution: (R)-4-(tert-Butoxycarbonyloxy)-2-cyclopentenone
(R)-3b. 99% ee (tR major, minor = 12.9, 14.2 min, Chiralcel OJ-H, 4.6×250 mm, 10 µm, heptane:i-
PrOH 99:1, 1.0 mL/min). [α]22D = +85.0 (c = 1.60, CHCl3).
(S)-4-Acetoxycyclopent-2-enone 3a. Colorless oil (Table 1, entry 3: 35%, 50 mg, 1 mmol of starting
material (±)-3b applied). 90% ee (tR major, minor = 28.7, 18.1 min, Chiralcel AS-H 4.6×250 mm 10
µm, heptane:i-PrOH 90:10, 1.0 mL/min). Rf = 0.22 (PE/EtOAc 80:20). [α]23 = –103.9 (c = 1.22,
D
CHCl3) ([α]20D = –111 (c = 0.51, CHCl3))24. 1H NMR (300 MHz, CDCl3): δ = 2.09 (s, 3H), 2.32 (dd, 1H,
J = 18.7, 2.2 Hz), 2.83 (dd, 1H, J = 18.8, 6.4 Hz), 5.85 (dtd, 1H, J = 6.1, 2.3, 1.4 Hz), 6.33 (dd, 1H, J =
13
5.7, 1.3 Hz), 7.57 (dd, 1H, J = 5.7, 2.4 Hz). C NMR (75 MHz, CDCl3): δ = 20.9, 41.1, 72.0, 137.1,
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 13
1
2
3
4
5
6
7
159.0, 170.5, 204.9. IR (film): νmax(cm-1) = 1717; HRMS (EI-quadrupole): m/z calcd for C7H8O3:
140.0473 [M·+]; found: 140.0476.
8
9
(S)-4-Phenoxycyclopent-2-enone 6b. Colorless oil (Table 1, entry 4: 34%, 28 mg). 93% ee (tR major,
minor = 13.5, 12.4 min, Phenomenex Lux Cellulose-1 4.6×250 mm 5 µm, heptane:i-PrOH 90:10, 1.0
mL/min). Rf = 0.20 (PE/EtOAc 90:10). [α]22D = –7.2 (c = 1.36, CHCl3). 1H NMR (300 MHz, CDCl3): δ
= 2.47 (dd, 1H, J = 18.4, 2.1 Hz), 2.90 (dd, 1H, J = 18.4, 6.0 Hz), 5.47 (dtd, 1H, J = 5.8, 2.2, 1.3 Hz),
6.38 (dd, 1H, J = 5.7, 1.2 Hz), 6.93 (dd, 2H, J = 8.7 Hz), 7.01 (t, 1H, J = 7.4 Hz), 7.33 (dd, 2H, J = 8.6,
7.5 Hz), 7.72 (dd, 1H, J = 5.7, 2.3 Hz). 13C NMR (75 MHz, CDCl3): δ = 41.9, 75.1, 115.3, 121.8, 129.8,
136.6, 157.3, 159.7, 205.1. IR (film): νmax(cm-1) = 1720. HRMS (EI-quadrupole): m/z calcd for
C11H10O2: 174.0681 [M·+]; found: 174.0677.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-4-(1-Naphthoyl)oxycyclopent-2-enone 6c. White solid (Table 1, entry 6: 45%, 566 mg). M.p. 60–
62 °C. >99% ee (tR major, minor = 14.7, 16.9 min, Phenomenex Lux Cellulose-1 4.6×250 mm 5 µm,
heptane:i-PrOH 90:10, 1.0 mL/min). Rf = 0.44 (PE/EtOAc 80:20). [α]22D = –143.7 (c = 1.05, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 2.56 (dd, 1H, J = 18.8, 2.2 Hz), 3.01 (dd, 1H, J = 18.8, 6.4 Hz), 6.20 (tdd,
1H, J = 4.6, 3.6, 1.8 Hz), 6.42 (dd, 1H, J = 5.7, 1.3 Hz), 7.47–7.57 (m, 2H), 7.64 (ddd, 1H, J = 8.6, 6.9,
1.5 Hz), 7.76 (dd, 1H, J = 5.7, 2.4 Hz), 7.90 (dd, 1H, J = 8.1, 1.4 Hz), 8.05 (d, 1H, J = 2.0 Hz), 8.20 (dd,
1H, J = 7.3, 1.3 Hz), 8.94 (d, 1H, J = 8.8 Hz). 13C NMR (75 MHz, CDCl3): δ = 41.3, 72.5, 124.5, 125.6,
125.9, 126.5, 128.1, 128.8, 130.7, 131.4, 133.9, 134.1, 137.3, 159.1, 166.8, 205.0. IR (film): νmax(cm-1)
= 1712. HRMS (EI-quadrupole): m/z calcd for C16H12O3: 252.0786 [M·+]; found: 252.0784.
(S)-4-(4-Bromobenzoyl)oxycyclopent-2-enone 6d. White solid (Table 1, entry 7: 41%, 58 mg). M.p.
92–93 °C (lit. m.p. 89 °C)25 91% ee (tR major, minor = 13.8, 15.3 min, Phenomenex Lux Cellulose-1
4.6×250 mm 5 µm, heptane:i-PrOH 70:30, 0.5 mL/min). Rf = 0.20 (PE/EtOAc 90:10). [α]22D = –166.0 (c
= 1.46, CHCl3) ([α]D= –167.7 (c = 0.43, CHCl3))25. 1H NMR (300 MHz, CDCl3): δ = 2.48 (dd, 1H, J =
18.8, 2.2 Hz), 2.95 (dd , 1H, J = 18.8, 6.4 Hz), 6.10 (dtd, 1H, J = 6.1, 2.2, 1.2 Hz), 6.41 (dd, 1H, J = 5.7,
ACS Paragon Plus Environment
8

Page 9 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.2 Hz), 7.60 (d, 2H, J = 8.6 Hz), 7.68 (dd, 1H, J = 5.7, 2.4 Hz), 7.89 (d, 2H, J = 8.6 Hz). 13C NMR (75
MHz, CDCl3): δ = 41.1, 72.7, 128.2, 128.8, 131.3, 132.0, 137.4, 158.7, 165.3, 204.7. IR (solid):
νmax(cm-1) = 1704. HRMS (EI-quadrupole): m/z calcd for C12H9BrO3: 279.9733 [M·+]. found: 279.9740.
(S)-4-(Benzylthio)cyclopent-2-enone 6e. Colorless oil (Table 1, entry 8: 42%, 42 mg). 93% ee (tR
major, minor = 16.0, 14.8 min, Chiralcel OJ-H 4.6×250 mm 10 µm, heptane:i-PrOH 85:15, 1.0
mL/min). Rf = 0.15 (PE/EtOAc 90:10). [α]26D = –163.2 (c = 1.13, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 2.30 (dd, 1H, J = 19.2, 2.1 Hz), 2.73 (dd, 1H, J = 19.2, 6.5 Hz), 3.74–3.84 (m, 2H), 3.91 (tdd, 1H, J
= 6.5, 2.6, 2.0 Hz), 6.19 (dd, 1H, J = 5.6, 1.8 Hz), 7.24–7.37 (m, 5H), 7.46 (dd, 1H, J = 5.6, 2.6, Hz).
13C NMR (75 MHz, CDCl3): δ= 35.7, 42.7, 43.3, 127.5, 128.8, 128.9, 134.6, 137.6, 163.4, 207.3. IR
(film): νmax(cm-1) = 1715. HRMS (EI-quadropol): m/z calcd for C12H12OS: 204.0609 [M·+]; found:
204.0606.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-4-(Dodecylthio)cyclopent-2-enone 6f. Colorless oil (Table 1, entry 9: 39%, 54 mg). 93% ee (tR
major, minor = 18.47, 15.60 min, Chiralcel AS-H 4.6×250 mm 10 µm, heptane:i-PrOH 85:15, 1.0
mL/min). Rf = 0.18 (PE/EtOAc 90:10). [α]22D = –193.8 (c = 1.56, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 0.87 (t, 3H, J = 6.7 Hz), 1.25 (m, 16H), 1.36 (m, 2H), 1.58 (m, 2H), 2.37 (dd, 1H, J = 19.2, 2.1 Hz),
2.51 (dd, 2H, J = 7.7, 7.1 Hz), 2.84 (dd, 1H, J = 19.2, 6.6 Hz), 4.01 (tdd, 1H, J = 6.5, 2.5, 2.0 Hz), 6.22
13
(dd, 1H, J = 5.6, 1.8 Hz), 7.57 (dd, 1H, J = 5.6, 2.6 Hz). C NMR (75 MHz, CDCl3): δ = 14.2, 22.7,
29.0, 29.2, 29.5, 29.6, 29.7, 29.7, 29.7, 32.0, 42.8, 43.5, 134.3, 163.9, 207.6. IR (KBr): νmax(cm-1) =
2923, 2853, 1720. HRMS (EI-quadrupole): m/z calcd for C17H30OS: 282.2017 [M·+]; found: 282.2021.
(S)-4-Phthalimidocyclopent-2-enone 6g. Long white needles (Table 1, entry 10: 50%, 56 mg). M.p.
156–159 °C (dec.). 96% ee (tR major, minor = 27.2, 30.2 min, Phenomenex Lux Cellulose-1 4.6×250
mm 5 µm, heptane:i-PrOH 90:10, 1.0 mL/min). Rf = 0.15 (PE/EtOAc 80:20). [α]23D = –230.8 (c = 1.07,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 2.75 (dd, 1H, J = 18.3, 3.5 Hz), 2.85 (dd, 1H, J = 18.2, 6.8
Hz), 5.54 (tdd, 1H, J = 6.8, 3.5, 2.3 Hz), 6.44 (dd, 1H, J = 5.7, 2.2 Hz), 7.52 (dd, 1H, J = 5.7, 2.4 Hz),
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 13
1
2
3
4
5
6
7
8
9
7.72–7.78 (m, 2H), 7.82–7.89 (m, 2H). 13C NMR (75 MHz, CDCl3): δ = 39.6, 49.7, 123.6, 131.7, 134.4,
136.2, 159.6, 167.6, 205.2. IR (solid): νmax(cm-1) = 1777, 1700. HRMS (EI-quadrupole): m/z calcd for
C13H9NO3: 227.0582 [M·+]; found: 227.0583.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-4-(6-chloro-9H-purin-9-yl)cyclopent-2-enone 8. To a solution of (±)-3b (991 mg, 5 mmol) and 6-
chloropurine (7) (371 mg, 2.4 mmol) in dry, degassed dichloromethane (20 mL) under nitrogen at 0 °C
the catalyst solution was added. It was separately prepared by stirring Pd2(dba)3 (11 mg, 0.012 mmol, 1
mol% Pd based on 7) and (R,R)-5 (33 mg, 0.048 mmol, 2 mol% Pd based on 7) in dry, degassed
dichloromethane (10 mL) under nitrogen until the initially purple solution turned yellow-brown (2–3
min). After 24 h stirring at 0 °C the solvent was evaporated. The crude product was purified by column
chromatography with PE:EtOAc (10:1) for recovering starting material 3b (47% yield, 466 mg, 98% ee)
and EtOAc for product as eluent mixture. 8 was obtained as a white solid (46% yield, 536 mg, 94% ee)
which gave colourless crystals after recrystallization (39% yield, 463 mg, 98% ee). M.p. 131–133 °C
(135.5–136 °C)21. 98% ee (tR major, minor = 24.43, 20.55 min, Chiralcel AS-H 4.6×250 mm 10 µm,
1
heptane:i-PrOH 50:50, 0.5 mL/min). Rf = 0.25 (EtOAc). [α]22D = –114.5 (c = 0.98, CHCl3). H NMR
(300 MHz, CDCl3): δ = 2.69 (dd, 1H, J = 18.8, 2.8 Hz), 3.18 (dd, 1H, J = 18.8, 7.2 Hz), 6.01 (ddd, 1H, J
= 7.2, 4.8, 2.5 Hz), 6.65 (dd, 1H, J = 5.7, 2.0 Hz), 7.69 (dd, 1H, J = 5.7, 2.5 Hz), 8.08 (s, 1H), 8.76 (s,
1H).13C NMR (75 MHz, CDCl3): δ = 41.7, 54.5, 131.9, 138.4, 142.8, 151.4, 151.6, 152.3, 157.0, 203.5.
IR (solid): νmax(cm-1) = 1720. HRMS (ESI-TOF): m/z calcd for C10H7ClN4O: 235.0381 [M+H]+; found:
235.0384. The experimental data are in accordance with literature.21
ACKNOWLEDGMENT. This work was supported by the Alexander von Humboldt Foundation
(fellowship for TV) and the Deutsche Bundesumweltstiftung (KONAROM AZ26920).
SUPPORTING INFORMATION PARAGRAPH. Full experimental details and characterization of all
new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment
10

Page 11 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
# This work was greatly inspired by the many insightful discussions on “Principles of Asymmetric
Synthesis” with Prof. Robert E. Gawley, mentor, colleague and friend. For an insightful article on the
sensibility of the term % ee, which is nevertheless used throughout our article since no issues of
diastereoselectivity arise and optically pure catalysts are employed, see R. E. Gawley, J. Org. Chem.
2006, 71, 2411–2146. He will be dearly missed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1) Leading Review: Roche, S. P.; Aitken, D. J. Eur. J. Org. Chem. 2010, 28, 5339–5358.
(2) (a) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244–7254; (b)
Mihara, H.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2008, 3, 359–366; (c) Kalidindi,
S.; Jeong, W. B; Schall, A.; Bandichhor, R.; Nosse, B.; Reiser, O. Angew. Chem. Int. Ed. 2007, 46,
6361–6363.
(3) (a) Barton, D. H. R.; Hulshof, L. A. J. Chem. Soc. Perkin Trans. 1 1977, 1103–1106; (b) Corey, E.
J.; Mehrotra, M. M. J. Am. Chem. Soc. 1984, 106, 3384–3384; (c) Kao, T.-C.; Chuang, G. J.; Liao, C.-
C. Angew. Chem. Int. Ed. 2008, 47, 7325–7327; (d) Shono, T.; Matsumura, Y.; Hamaguchi, H.;
Nakamura, K. Chem. Lett. 1976, 5, 1249–1252; (e) Mucha, B.; Hoffmann, H. M. R. Tetrahedron Lett.
1989, 30, 4489–4492; (f) Caddick, S.; Khan, S. J. Chem. Soc., Chem. Commun. 1995, 1971–1972; (g)
Vassilikogiannakis, G.; Stratakis, M. Angew. Chem. Int. Ed. 2003, 42, 5465–5468; (h) Takeda, K.;
Fujisawa, M.; Makino, T.; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351–9352.
(4) (a) Ogura, K.; Yamashita, M.; Tsuchihashi, G. Tetrahedron Lett. 1976, 17, 759–762; (b) Khanapure,
S. P.; Najafi, N.; Manna, S.; Yang, J.-J.; Rokach, J. J. Org. Chem. 1995, 60, 7548–7551; (c) McAllister,
G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197–1200; (d) Paul, K. G.; Johnson, F.; Favara, D.
J. Am. Chem. Soc. 1976, 98, 1285–1286; (e) Gallos, J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 13
1
2
3
4
5
6
7
8
9
Lett. 2001, 42, 5769–5771; (f) Ingate, S. T.; Marco-Contellers, J. Org. Prep. Proced. Int. 1998, 30, 121–
143.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) (a) Morita, A.; Kuwahara, S. Org. Lett. 2006, 8, 1613–1616; (b) Rivero, M. R.; de la Rosa, J. C.;
Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992–14993.
(6) (a) Dickmeiss, G.; De Sio, V.; Udmark, J.; Poulsen, T. B.; Marcos, V.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2009, 48, 6650–6653; (b) Batsanov, A. S.; Knowles, J. P.; Lightfoot, A. P.; Maw, G.;
Thirsk, C. E.; Twiddle, S. J. R.; Whiting, A. Org. Lett. 2007, 9, 5565–5568.
(7) Sih, C. J. WO 8607611A1 (31 Dec 1986).
(8) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717–6725.
(9) Ghorpade, S. R.; Bastawade, K. B.; Gokhale, D. V.; Shinde, P. D.; Mahajan, V. A.; Kalkote, U. R.;
Ravindranathan, T. Tetrahedron: Asymmetry 1999, 10, 4115–4122.
(10) Kumaraguru, T.; Fadnavis, N. W. Tetrahedron: Asymmetry 2012, 23, 775–779.
(11) Kitamura, M.; Manabe, K.; Noyori, R.; Takaya, H. Tetrahedron Lett. 1987, 28, 4719–4720.
(12) Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori, R.; Takaya, H. J. Org. Chem. 1988, 53, 708–710.
(13) (a) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427–440; (b) Trost, B. M.; van
Vranken, D. L. Chem. Rev. 1996, 96, 395–422.
(14) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543–3544; (b) Trost, B. M.; Crawley,
M. L. Chem. Eur. J. 2004, 10, 2237–2252.
(15) (a) Shan, M.; O’Doherty, G. A. Org. Lett. 2010, 12, 2986–2989; (b) Babu, R. S.; O’Doherty, G. A.
J. Am. Chem. Soc. 2003, 125, 12406–12407.
(16) (a) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125,
8714–8715; (b) van der Deen, H.; van Oeveren, A.; Kellogg, R. M.; Feringa, B. L. Tetrahedron Lett.
1999, 40, 1755–1758.
ACS Paragon Plus Environment
12

Page 13 of 13
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(17) Piancatelli, G.; Scettri, A.; Barbardoro, S. Tetrahedron Lett. 1976, 17, 3555–3558.
(18) Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037–2040.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) Kagan, H. B.; Fiaud, J.-C. Top. Stereochem. 1988, 18, 249–330.
(20) (a) Gais, H.-J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe, G. Chem. Eur. J. 2003,
9, 4202–4221; (b) Lüssem, B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041–4052.
(21) Boojamra, C. G.; Parrish, J. P.; Sperandio, D.; Gao, Y.; Petrakovsky, O. V.; Lee, S. K.;
Markevitch, D. Y.; Vela, J. E.; Laflamme, G.; Chen, J. M.; Ray, A. S.; Barron, A. C.; Sparacino, M. L.;
Desai, M. C.; Kim, C. U.; Cihlar, T.; Mackman, R. L. Bioorg. Med. Chem. 2009, 17, 1739–1746.
(22) Kitade, Y.; Kozaki, A.; Miwa, T.; Nakanishi, M. Tetrahedron 2002, 58, 1271–1277.
(23) Trost, B. M.; van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327–9343.
(24) Mandai, T.; Matsumoto, S.; Kohama, M.; Kawada, M.; Tsuji, J.; Saito, S.; Moriwake, T. J. Org.
Chem. 1990, 55, 5671–5673.
(25) Iguchi, K.; Kaneta, S.; Tsune, C.; Yamada, Y. Chem. Pharm. Bull. 1989, 37, 1173–1175.
ACS Paragon Plus Environment
13