Regiodivergent epoxide opening (REO) via electron transfer: Control elements

Article abstract of DOI:10.1016/j.tetasy.2010.03.052

The first regiodivergent opening of unbiased epoxides (REO) providing the ring-opened products in high enantiomeric excess from racemic and exceptionally high enantiomeric excess from enantioenriched substrates in a double asymmetric process has been devised. It constitutes a more general case of the very important enantioselective openings of meso-epoxides. The dependence of the selectivity of ring opening on the epoxides substitution pattern was studied.

Full text of DOI:10.1016/j.tetasy.2010.03.052

Tetrahedron: Asymmetry 21 (2010) 1361–1369
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Regiodivergent epoxide opening (REO) via electron transfer: control elements
a
a
a
b,
Andreas Gansäuer a, , Lei Shi , Florian Keller , Peter Karbaum , Chun-An Fan
*
*
a Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
b State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first regiodivergent opening of unbiased epoxides (REO) providing the ring-opened products in high
enantiomeric excess from racemic and exceptionally high enantiomeric excess from enantioenriched
substrates in a double asymmetric process has been devised. It constitutes a more general case of the very
important enantioselective openings of meso-epoxides. The dependence of the selectivity of ring opening
on the epoxide’s substitution pattern was studied.
Received 1 March 2010
Accepted 14 March 2010
Available online 11 May 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
and electronically unbiased groups.4 The two examples shown in
Scheme 2 highlight the problems. It seems difficult to combine
Epoxides are amongst the most versatile compounds in organic
chemistry. This is because they are not only important synthetic
endpoints,1 but also key intermediates for further manipulation.2
Due to the oxiranes’ high ring strain (about 27 kcal molꢀ1), they
are ‘spring loaded’ for a number of interesting ring-opening
reactions. In the past, this field has been heavily dominated by
nucleophilic substitution reactions.3 The usefulness of epoxides
in SN2-reactions has been expanded even further by the develop-
ment of transition metal-catalyzed desymmetrizations of meso-
epoxides3 and kinetic resolutions3 mainly of monosubstituted
and 1,1-disubstituted epoxides. In this manner, a wide range of
important 1,2-difunctionalized compounds has been obtained with
high enantio- and diastereoselectivity through the back-side ap-
proach of the nucleophile. Two of the many excellent examples
of catalytic epoxide openings are shown in Scheme 1.
the high regioselectivity of the epoxide opening with a high reac-
tivity of both enantiomers of the substrate even with today’s most
successful catalysts. Hence, either rather unselective reactions or
kinetic resolutions are observed. Nevertheless, such reactions are
in principle extremely attractive for applications in the synthesis
of complex molecules and also very interesting conceptually.
In a more general context, Kagan has described the underlying
principles of such transformations. For racemic substrates such
processes have been termed ‘parallel resolutions’ or ‘divergent
reactions of racemic mixtures’.5 A mathematical treatment has also
been provided by Kagan.5c Synthetic applications of such regiodi-
vergent reactions are still relatively rare. They include examples
from Baeyer–Villiger oxidations mediated by biological and chem-
ical catalysts, cyclopropanations, acylations with hetero and car-
bon nucleophiles, hydroacylations, and cycloadditions.6
Despite the success of these catalytic processes, important lim-
itations are caused by the key mechanistic aspect of all SN2-reac-
tions. The displacement of the leaving group is sensitive to both
the substitution pattern of the carbon atom involved and the bulk
of the nucleophile employed. Hence a number of potentially useful
reactions are kinetically hindered or even outright impossible.
Two simple examples underline these restrictions: first, epoxide
openings via SN2 usually occur at the least substituted carbon. Sec-
ond, reactions with sterically demanding substituents are often too
slow to be useful.
Another more subtle limitation has emerged more recently. To
date, it has not been possible to observe the high regioselectivities
obtained in the enantioselective opening of meso-epoxides in reac-
tions of other epoxides. Surprisingly, this is even so for the most
similar case, cis-1,2-disubstituted epoxides with two sterically
Herein we report some synthetic and mechanistic aspects of our
approach to these reactions that feature a titanocene-catalyzed elec-
tron transfer7 to alkyl-substituted epoxides. The catalytic method is
based on Nugent’s and RajanBabu’s stoichiometric transformation.8
After our initial report,9 the regiodivergent reactions of strained het-
erocycles, such as oxabicyclic alkenes10 and aziridines11 via different
mechanisms have been reported. We propose the name ‘regiodiver-
gent epoxide opening’ (REO) for such transformations if the ring
opening constitutes the stereodifferentiating event.
Complementary reactions of vinyloxiranes with dialkylzinc re-
agents have been reported by Pineschi and Feringa.12 Reductive
elimination from an allyl copper complex constitutes the stereodif-
ferentiating step and not the ring opening that we concentrate on
here.
2. Results and discussion
* Corresponding authors. Tel.: +49 228 732800; fax: +49 228 734760 (A.G.), tel./
fax: +86 931 891 5516 (C.-A.F.).
The decoupling of the ring opening from the trapping of the rad-
ical intermediate generated through electron transfer circumvents
E-mail addresses: andreas.gansaeuer@uni-bonn.de (A. Gansäuer), fanchunan@
lzu.edu.cn (C.-A. Fan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.052

1362
A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
OSiMe2iPr
N3
[(L-Zr-OH)2 t BuOH]n (8 mol%)
iPrMe2SiN3
O
CF3CO2SiMe3 (2 mol%)
1,2-dichlorobutane, 0 °C
86% yield
er = 96.5:3.5
HO
N
OH
OH
(S,S,S)-H3L
(S,S)-Cat
(0.2 mol%)
OH
O
O
H2O
OH
0.55 equiv
( )
44% yield
er > 99:1
50% yield
er = 99:1
H
H
N
O
N
O
M
tBu
tBu
tBu
tBu
(S,S)-Cat:M = Co(OAc)(H2O)
Scheme 1. Catalytic desymmetrization and kinetic resolution in epoxide opening.
the problems associated with the SN2 mechanism. In this manner,
the selectivity of the REO is reduced to a high selectivity of the
breaking of one of the two C–O bonds. Thus, for the opening of
epoxide 1 to 2 and 3 we chose Kagan’s complex 413 that had al-
ready been established as highly selective catalyst for the opening
of meso-epoxides via electron transfer.14 The opening of meso-
epoxides constitutes a special case of the REO, because both sub-
stituents of the epoxide are identical. The results of the REO of 1
are summarized in Table 1.
Clearly, 4 catalyzes the desired REO efficiently. As expected for
reactions of racemic mixtures, the product formed in higher yields
is obtained with lower enantioselectivity (entry 1). The reactions of
the enantiomerically enriched substrates demonstrate that the
regioselectivity of the REO is reagent controlled. With 4, the prod-
uct 3 is obtained preferentially and with very high selectivity,
whereas ent-4 results in the preferred formation of 2 with high
selectivity. The influence of the substrate is negligible. The minor
isomers are formed with low selectivity (entries 2 and 3).
To understand the influence of the regioselectivity of ring open-
ing on the steric demand of the epoxide’s substitution, we studied
the REOs of 5 and 6 which both contain n-alkyl substituents
(Table 2).
selectivity of the REO, albeit at the cost of a slower reaction. Most
likely, this is due to a slower heterogeneous reduction of the
titanocene (IV) species by Mn. A similar observation has been
made in titanocene-catalyzed pinacol couplings.15 For enantiome-
rically enriched 6 the reagent controlled nature of the REO was
demonstrated by the inversion of the selectivity of ring opening
(entries 4 and 5).
The bicyclic epoxide 11 displays a REO with even lower enanti-
oselectivity (Scheme 3). This indicates that a reduction of the steric
interaction compared to non-cyclic alkyl substituents, that can ro-
tate freely, is detrimental for selectivity. This is in line with the re-
sults from the opening of meso-epoxides.14
We next turned our attention to the influence of secondary and
tertiary substituents. To this end, substrates 14 with a cyclohexyl
group directly attached to the epoxide and 17 with a tertiary group
separated from the epoxide by a methylene group were investi-
gated, as summarized in Table 3.
From these results, it is clear that the introduction of substitu-
ents with a different steric bulk has a noticeable influence on the
outcome of the REO. The results of both racemic epoxides show
that the C–O bond closer to the bulky substituent is preferentially
broken. This is in line with our proposed model of steric control of
ring opening because the bulky substituent will interact more
strongly with the ligands of the catalyst. It is interesting to note
that the effect of the tertiary substituent is more pronounced even
though it is positioned at a greater distance from the epoxide than
the secondary substituent. In the case of the enantiomerically
For 5, the selectivity of the REO is noticeably lower than that for
the substrates 1 and 6. Thus, a rather subtle fine-tuning of the ste-
ric interactions of the catalyst and the substrate is occurring that is
hard to explain quantitatively. As demonstrated in entry 3, lower-
ing of the reaction temperature leads to a distinct increase in the

A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
1363
Table 2
N3
O
OSiMe3
Me
(R,R)-Cat (2 mol%)
Regiodivergent epoxide opening (REO) of 5 and 6 catalyzed by Kagan’s complex 4
+
Me3SiN3
Me
Me
Et2O, r.t.
Me
OH CO2tBu
65% yield
er = 91:9
CO2tBu
O
( )n
( )n
10 mol% 4 or ent-4
n = 4: 7; n = 5:9
OH
( )n
O
Cat (5 mol%)
tBuOMe, 20 ºC
Mn, Coll*HCl
1,4-C6H8
Me3SiN3
+
CO2tBu
Me
nBu
n = 3, (4S*,5R*)-5;
n = 4, (4S*,5R*)-6a;
n = 4, (4S,5R)-6b: er = 94:6
er = 97.5:2.5
n = 3: 8; n = 4:10
N3
OSiMe3
nBu
Me3SiO
Me
N3
nBu
Entry
Sub
Cat
Prod/%, ee
Prod/%, ee
+
Me
A
1
2
3
4
5
5
ent-4
7, 38, 79
9, 40, 87
9, 23, 93
9, 66, 98
9, 16, 30
8, 44, 79
6a
6aa
6b
6b
4
4
4
10, 40, 80
10, 24, 86
10, 11, 32
10, 72, 98
B
( )-Cat
A:B = 1:1, 81% yield
A:B = 2:1, 79% yield
A:B = 1:4, 77% yield
ent-4
er not reported
(R,R)-Cat
(S,S)-Cat
a
0 °C.
O
HO
O
H
N
H
N
O
O
12, 45%, ee = 73
M
O
10 mol% 4
tBu
tBu
O
O
Mn, Coll*HCl
1,4-C6H8
O
tBu
tBu
O
OH
(4S*,5R*)-11
(R,R)-Cat: M = CrCl
13, 19%, ee = 82
Scheme 3. REO of the bicyclic epoxide 11.
Scheme 2. Catalytic regioselective epoxide opening of a meso-epoxide versus an
enantiomerically enriched substrate.
enriched 17b, the catalyst is unable to completely override this ef-
fect (entries 3 and 4). Thus matched and mismatched cases of re-
agent and substrate control are observed.
We next investigated as to whether the chelating groups in the
substrate had an influence on the REO with Kagan’s complex. For
trans-disubstituted epoxides it is well documented that the pres-
ence of such groups has a profound influence on the regioselectiv-
ity of ring opening for both stoichiometric and catalytic
reactions.8,16 The results of our investigations with epoxides 20
and 23 are summarized in Scheme 4.
Table 3
Regiodivergent epoxide opening (REO) of epoxides with secondary and tertiary
substituents
OH CO2tBu
CO2tBu
O
10 mol% 4
15
OH
Mn, Coll*HCl
1,4-C6H8
(4S*,5R*)-14
16
CO2tBu
Table 1
Regiodivergent epoxide opening (REO) of 1 catalyzed by Kagan’s complex 4
OH CO2tBu
OH CO2tBu
CO2tBu
O
( )5
( )4
10 mol% 4 or ent-4
18
OH
CO2tBu
O
( )3
( )2
( )4
10 mol% 4 or ent-4
2
OH
Mn, Coll*HCl
1,4-C6H8
( )2
(4S*,5R*)-1a;
(4S*,5R*)-17a
Mn, Coll*HCl
1,4-C6H8
(4S,5R)-17b: e.r. = 92.5:7.5
19
CO2tBu
(4S,5R)-1b: er = 90:10
3
CO2tBu
Entry
Sub
Cat
Prod/%, ee
15, 39, 70
18, 23, 94
18, 5, 30
Prod/%, ee
4
=
1
2
3
4
14
4
4
4
16, 21, 94
19, 66, 62
19, 82, 94
19, 25, 26
TiCl2
)
2
17a
17b
17b
ent-4
18, 55, >99
Entry
Sub
Cat
2/%, eea
3/%, eea
1
2
3
1a
1b
1b
ent-4
4
ent-4
45, ꢀ81
13, ꢀ8
76, 94
42, 93
71, >99
10, ꢀ50
For the simple alkoxy substituent in 20, no significant effect on
the regioselectivity of the ring opening was observed
(21:22 = 46:54) compared to the similar epoxides 1, 5, and 6 (reg-
a
(R)–(S).

1364
A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
OH CO2tBu
steric bulk leads to situations where matched and mismatched
cases of reagent and substrate control of ring opening are observed.
Chelation does not seem to play a major role in the cases investi-
gated. The REO of cis-disubstituted epoxides with alkyl groups of
similar steric demand can lead to highly enantioselective reactions,
especially when conducted under double asymmetric conditions.
We are currently using the REO concept for the realization of
usual18 and unusual19 cyclizations and in reactions with titanocene
catalysts possessing additional binding sites.20
nBuO
21, 39%, ee = 92
OH
CO2tBu
O
10 mol% 4
nBuO
Mn, Coll*HCl
1,4-C6H8
(4S*,5R*)-20
nBuO
CO2tBu
22, 46%, ee = 81
4. Experimental
CO2tBu
OH
All reactions were performed in oven-dried (100 °C) glassware
under Ar. THF was freshly distilled from K. CH2Cl2 was freshly dis-
tilled from CaH2. The products were purified by flash chromatogra-
phy on Merck Silica Gel 50 (eluents given in brackets, EE refers to
ethyl acetate, CH to cyclohexane) according to the procedure of
Still.21 Yields refer to analytically pure samples. Isomer ratios were
determined by suitable 1H NMR integrals of cleanly separated sig-
nals. NMR: Bruker DRX 300, AMX 300, AM 400; DRX 500 1H NMR,
CHCl3 (7.26 ppm) or C6D5H (7.16 ppm) in the indicated solvent as
internal standard in the same solvent; 13C NMR, CDCl3
(77.16 ppm), or C6D6 (128.06 ppm) as internal standard in the
same solvent; integrals in accordance with assignments, coupling
constants are measured in Hertz and always constitute J(H,H) cou-
pling constants. IR spectra: Perkin–Elmer 1600 series FT-IR and
Thermo Nicolet 380 as neat films on KBr plates or via ATR measure-
ments. Mass Spectrometry: EI Thermoquest Finningan MAT 95 XL,
calibration against PFK; ESI Bruker Daltonics microTOF-Q, calibra-
tion against HCO2Na. Combustion analytics was performed on a
vario micro cube from Elementar, Hanau.
O
CO2tBu
O
10 mol% 4
24, 52%, ee = 62
OH CO2tBu
O
Mn, Coll*HCl
1,4-C6H8
(2'S*,3'R*)-23
O
25, 27%, ee = 98
Scheme 4. Influence of chelating groups on the REO.
ioselectivities of 48:52–50:50). Thus, no effects on chelation can be
observed. The situation changes markedly for 23. Here, the ‘left’ C–
O bond is broken with a selectivity of 66:34. This can be explained
by a slight preference for the formation of an eight-membered che-
late with the epoxide and carbonyl oxygen acting as donor atoms.
As a consequence, the minor isomer is formed with very high
enantioselectivity as expected for any resolution. These results
are in sharp contrast to the reactions of similar trans-disubstituted
effects, where chelation of the catalyst by the substrate has been
used to explain the highly regioselective opening of the oxiranes
that yield the derivative of the 1,3-diols.
Epoxides 1a,9 1b,9 5,9 6a,9 6b,9 14,9 17a,9 17b,9 20,9 23, and 2617
were prepared according to the literature procedures indicated.
Only the physical data are given.
Finally, the effect of a stereogenic center adjacent to the epoxide
was studied for the silylated epoxide17 26 (Scheme 5). While the
use of Cp2TiCl2 resulted in the selective formation of the protected
derivative of the 1,2-diol 27 in 67% yield, the use of 4 did not lead
to the desired REO. The protected 1,3-diol 28 was formed exclu-
sively, albeit in a very low yield (14%). Thus, epoxides of the type
of 26 do not seem to be suitable substrates for our REO. Presum-
ably, the OTBS group is too bulky to allow substrate binding to
the catalyst.
4.1. General procedure for the REO
To a mixture of collidine hydrochloride (236 mg, 1.5 mmol,
1.5 equiv), titanocene catalyst (0.1 equiv), and Mn (83 mg,
1.5 equiv) in THF were added 1,4-cyclohexadiene (350 mg,
4.4 equiv) and the epoxide (1 equiv). After stirring at room temper-
ature overnight, the reaction was quenched by the addition of
phosphate buffer. The mixture was then extracted (twice with
EtOAc and twice with CH2Cl2). The organic layers were dried
(MgSO4) and the volatiles removed in vacuo. The crude product
was purified by SiO2 chromatography in the given eluents.
OTBS
10 mol% Cp2TiCl2
OH
Comopound (4S*,5R*)-1: 1H NMR (400 MHz, CDCl3): d = 2.96–
2.89 (m, 2H), 2.46–2.31 (m, 2H), 1.85 (dddd, 2J = 14.0 Hz, 3J = 4.9,
7.4, 8.4 Hz, 1H), 1.76–1.65 (m, 1H), 1.56–1.45 (m, 4H), 1.44 (s,
9H), 0.96 ppm (t, 3J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d = 172.4, 80.6, 57.3, 56.2, 32.6, 29.9, 28.2, 23.7, 20.0, 14.1 ppm;
OTBS
Mn, Coll*HCl
1,4-C6H8
27, 67%
O
OTBS
(1R*,2R*,3R*)-26
10 mol% 4
IR (KBr):
m = 2967, 2874, 1732, 1457, 1392, 1367, 1257, 1155,
1099, 990, 942, 848, 801, 755 cmꢀ1; HRMS (EI): m/z calcd for
C8H14O3: 158.0943; found: 158.0944. For preparation of
(4S*,5R*)-1a and (4S,5R)-1b and see:9a
Mn, Coll*HCl
1,4-C6H8
OH
28, 14%
Table 1, entry 1: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, (4S*,5R*)-1a (215.0 mg, 1.0 mmol), and
1,4-cyclohexadiene in THF (3 mL) were treated with ent-4
(53.0 mg, 0.1 mmol) overnight. Purification (cyclohexane/AcOEt
90:10?80:20) gave (S)-2 (97.2 mg, 45%) and (R)-3 (90.0 mg, 42%).
Scheme 5. Attempted REO of a silylated Sharpless-epoxide.
3. Conclusion
Comopound (S)-2:
½
a 2D0
ꢁ
¼ þ1:0 (c 0.2, CHCl3); 1H NMR
(300 MHz, CDCl3): d = 3.64–3.51 (m, 1H), 2.34 (t, J = 7.0 Hz, 2H),
2.07 (s, 1H), 1.77(dddd, J = 14.3 Hz, 3.8, 7.2, 7.2 Hz, 1H), 1.63 (dddd,
J = 14.6 Hz, J = 7.4, 7.5, 7.7 Hz, 1H), 1.50–1.20 (m, 15H), 0.88 ppm (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 173.9, 80.5, 71.4,
In conclusion, we have provided further experimental support
for the correctness of our hypothesis of steric control of the REO
of alkyl-substituted epoxides via electron transfer catalyzed by Ka-
gan’s complex 4. The introduction of substituents with a different

A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
1365
37.4, 32.4, 32.2, 28.2, 27.9, 22.8, 14.2 ppm; IR (KBr):
m
= 3436, 2931,
1,4-cyclohexadiene in THF (3 mL) were treated with ent-4
(53.0 mg, 1.0 mmol) overnight. Purification (cyclohexane/AcOEt
90:10) gave (S)-7 (83.4 mg, 38%) and (R)-8 (97.9 mg, 44%).
1731, 1456, 1367, 1226, 1154, 1085, 949, 848, 755 cmꢀ1; HRMS
(EI): m/z calcd for C8H15O3: 159.1021; found: 159.1024.
Compound (R)-3: ½a D20
ꢁ
¼ ꢀ1:0 (c 0.1, CHCl3), 1H NMR (300 MHz,
Comopound (S)-7:
½
a 2D0
ꢁ
¼ þ2:0 (c 0.1, CHCl3); 1H NMR
CDCl3): d = 3.64–3.53 (m, 1H), 2.23 (t, J = 7.1 Hz, 2H), 1.85–1.55 (m,
3H), 1.50–1.25 (m, 15H), 0.91 ppm (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 173.4, 80.3, 71.2, 39.7, 36.9, 35.5, 28.2, 21.2,
(300 MHz, C6D6): d = 3.38–3.27 (m, 1H), 2.14 (t, J = 7.3 Hz, 2H),
1.81–1.56 (m, 2H), 1.39 (s, 9H), 1.37–1.13 (m, 9H), 0.87 ppm (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, C6D6): d = 172.8, 79.6, 71.1,
37.7, 37.3, 35.6, 28.2, 28.2, 23.2, 21.5, 14.3 ppm; IR (KBr):
18.9, 14.2 ppm; IR (KBr):
m = 3436, 2959, 2872, 1731, 1456, 1392,
1367, 1253, 1153, 848 cmꢀ1; HRMS (EI): m/z calcd for C8H15O3:
159.1021; found: 159.1018.
m = 3430, 2956, 2929, 2860, 1729, 1456, 1392, 1366, 1254, 1148,
848 cmꢀ1; HRMS (EI): m/z calcd for C9H17O3: 173.1178; found:
The enantiomeric ratios of (S)-2 and (R)-3 in entry 1 of Table 1
were determined by Chiral GC analysis after the following lacton-
ization process.
173.1180.
Compound (R)-8: ½a D20
ꢁ
¼ ꢀ2:0 (c 0.2, CHCl3), 1H NMR (400 MHz,
CDCl3): d = 3.65–3.57 (m, 1H), 2.27 (ddd, J = 7.1, 7.1, 0.3 Hz, 2H),
1.79 (dddd, J = 14.4, 7.2 Hz, 7.2, 3.6 Hz, 1H), 1.65 (dddd, J = 14.2,
8.4, 7.1, 7.1 Hz, 1H), 1.58 (s, 1H), 1.50–1.23 (m, 17H), 0.89 ppm
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 173.5, 79.8,
71.1, 38.0, 32.9, 32.3, 32.3, 28.1, 25.8, 23.1, 14.3 ppm; IR (KBr):
Compound (S)-2-Lactone:22 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (S)-2 (70.0 mg,
32.3 ꢂ 10ꢀ2 mmol), benzene (10 mL), and p-toluenesulfonic acid
monohydrate (3.0 mg, 1.6 ꢂ 10ꢀ2 mmol). The reaction mixture
was refluxed at around 85 °C for 4 h and then cooled to room tem-
perature. The solvent was removed under reduced pressure, and
the residue was directly subjected to flash column chromatogra-
phy on silica gel eluting with cyclohexane/AcOEt (80:20) to afford
m
= 3433, 2956, 2929, 2859, 1729, 1456, 1366, 1255, 1149, 1084,
951, 847 cmꢀ1; HRMS (EI): m/z calcd for C9H17O3: 173.1178;
found: 173.1179.
The enantiomeric ratios of (S)-7 and (R)-8 in entry 1 of Table 2
were determined by Chiral GC analysis after the following lacton-
ization process.
(S)-2-Lactone (38.0 mg, 83% yield) ½a D20
¼ þ33:3 (c 1.0, CHCl3);
ꢁ
(R):(S) = 9.5:90.5). The enantiomeric ratio was accurately mea-
sured by Chiral GC using Cyclodextrin TA column (70 kPa pressure,
140 °C isotherm for 30 min, major enantiomer 17 min, minor enan-
tiomer 15 min). 1H NMR (400 MHz, CDCl3): d = 4.42 (dddd, J = 5.9,
6.5, 7.5, 7.5 Hz, 1H), 2.46 (dd, J = 7.0, 9.4 Hz, 2H), 2.26 (ddd,
J = 13.4, 6.6, 12.9 Hz, 1H), 1.84–1.73 (m, 1H), 1.68 (dddd, J = 13.7,
Hz, 5.1, 7.5, 10.0 Hz, 1H), 1.59–1.48 (m, 1H), 0.85 ppm (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 177.4, 81.1, 35.3,
28.9, 28.1, 27.4, 22.5, 14.0 ppm.
Compound (S)-7-Lactone:25 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (S)-7 (15.0 mg), ben-
zene (5 mL), and p-toluenesulfonic acid monohydrate (2.0 mg). The
reaction mixture was refluxed at around 85 °C for 4 h, and then
cooled to room temperature. The solvent was removed under re-
duced pressure, and the residue was directly subjected to flash col-
umn chromatography on silica gel eluting with cyclohexane/AcOEt
(80:20) to afford (S)-7-Lactone (9.0 mg, 90% yield; ½a D20
¼ ꢀ36:4 (c
ꢁ
Compound (R)-3-Lactone:23 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (R)-3 (50.0 mg,
23.1 ꢂ 10ꢀ2 mmol), benzene (10 mL), and p-toluenesulfonic acid
monohydrate (3.0 mg, 1.6 ꢂ 10ꢀ2 mmol). The reaction mixture
was refluxed at around 85 °C for 4 h, and then cooled to room tem-
perature. The solvent was removed under reduced pressure, and
the residue was directly subjected to flash column chromatogra-
phy on silica gel eluting with cyclohexane/AcOEt (80:20) to afford
4.0, CHCl3); (R):(S) = 10.5:89.5). The enantiomeric ratio was accu-
rately measured by Chiral GC using Cyclodextrin TA column
(70 kPa pressure, 120 °C isotherm for 60 min, major enantiomer
51 min, minor enantiomer 54 min). 1H NMR (400 MHz, CDCl3):
d = 4.26 (dddd, J = 10.6, 7.7, 5.0, 2.7 Hz, 1H), 2.57 (dtd, J = 17.6,
6.1, 1.2 Hz, 1H), 2.42 (dtd, J = 17.9, 7.9, 0.9 Hz, 1H), 1.95–1.76 (m,
3H), 1.75–1.64 (m, 1H), 1.62–1.26 (m, 6H), 0.89 ppm (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3): d = 172.1, 80.7, 35.6, 29.6, 27.9,
27.2, 22.6, 18.6, 14.0 ppm.
(R)-3-Lactone (30.0 mg, 91% yield; ½a D20
¼ ꢀ45:3 (c 14.6, CHCl3);
ꢁ
(R):(S) = 96.5:3.5). The enantiomeric ratio was accurately mea-
sured by Chiral GC using Cyclodextrin TA column (70 kPa pressure,
120 °C isotherm for 60 min, major enantiomer 35 min, minor enan-
tiomer 39 min). 1H NMR (400 MHz, CDCl3): d = 4.28 (dddd, J = 3.0,
4.7, 7.6, 10.7 Hz, 1H), 2.62–2.52 (m, 1H), 2.49–2.38 (m, 1H),
1.95–1.76 (m, 3H), 1.75–1.63 (m, 1H), 1.60–1.35 (m, 4H),
0.93 ppm (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 172.1,
80.5, 38.0, 29.6, 27.9, 18.6, 18.3, 14.0 ppm.
Compound (R)-8-Lactone:24 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (R)-8 (10.0 mg), ben-
zene (5 mL), and p-toluenesulfonic acid monohydrate (2.0 mg). The
reaction mixture was refluxed at around 85 °C for 4 h, and then
cooled to room temperature. The solvent was removed under re-
duced pressure, and the residue was directly subjected to flash col-
umn chromatography on silica gel eluting with cyclohexane/AcOEt
(80:20) to afford (R)-8-Lactone (5.0 mg, 70% yield; ½a D20
¼ þ28:3 (c
ꢁ
Table 1, entry 2: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, (4S,5R)-1b (217.0 mg, 1.0 mmol), and
1,4-cyclohexadiene in THF (3 mL) were treated with 4 (53.0 mg,
0.1 mmol) overnight. Purification gave (cyclohexane/AcOEt
90:10?80:20) (S)-2 (29.0 mg, 13%) and (R)-3 (155.0 mg, 71%).
4.5, CHCl3); (R):(S) = 89.5:10.5). The enantiomeric ratio was accu-
rately measured by Chiral GC using Cyclodextrin TA column
(70 kPa pressure, 140 °C isotherm for 60 min, major enantiomer
25 min, minor enantiomer 27 min). 1H NMR (400 MHz, CDCl3):
d = 4.47 (dddd, J = 7.3, 7.0, 7.0, 6.2 Hz, 1H), 2.51 (dd, J = 9.5,
6.9 Hz, 2H), 2.30 (dtd, J = 13.1, 6.6, 6.6 Hz, 1H), 1.84 (dtd, J = 12.7,
9.5, 8.1 Hz, 1H), 1.77–1.66 (m, 1H), 1.63–1.52 (m, 1H), 1.51–1.23
(m, 6H), 0.88 ppm (t, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d = 177.4, 81.1, 35.6, 31.5, 28.9, 28.0, 24.9, 22.5, 14.0 ppm.
(S)-2: ½a 2D0
ꢁ
¼ þ1:0 (c 0.2, CHCl3); (R)-3: ½a D20
¼ ꢀ0:5 (c 0.7, CHCl3).
ꢁ
For the analytical data, see the synthesis of (S)-2 and (R)-3 in entry
1 of Table 1. The enantiomeric ratios of (S)-2 and (R)-3 in entry 2 of
Table 1 were determined by Chiral GC analysis after lactonization.
Table 1, entry 3: Procedure according to entry 2. (4S,5R)-1b
Compound (4S,5R)-6b: ½a D20
¼ ꢀ11:9 (c 0.9, CHCl3); er = 94:6) as
ꢁ
(222.0 mg, 1.0 mmol), (R)-2 (170.0 mg, 76% yield; ½a D20
ꢁ
¼ þ0:7 (c
colorless oil. 1H NMR (300 MHz, C6D6): d = 2.76 (ddd, 3J = 4.4, 4.8,
7.3 Hz, 1H), 2.67 (m, 1H), 2.31 (ddd, 2J = 16.1 Hz, 3J = 7.1, 8.0 Hz,
1H), 2.24 (ddd, 2J = 16.0 Hz, 3J = 7.5, 7.5 Hz, 1H), 1.77 (dddd,
2J = 14.1 Hz, 3J = 5.0, 7.2, 8.0 Hz, 1H), 1.67 (dddd, 2J = 14.3 Hz,
3J = 7.1, 7.2, 7.2 Hz, 1H), 1.41–1.12 (m, 17H), 0.83 ppm (t,
3J = 6.9 Hz, 3H); 13C NMR (75 MHz, C6D6): d = 171.9, 79.9, 57.0,
55.7, 32.7, 31.9, 30.6, 28.1, 26.7, 24.0, 22.9, 14.2 ppm; IR (KBr):
0.9, CHCl3)) and (S)-3 (23.0 mg, 10% yield; ½a D20
¼ þ0:5 (c 0.3,
ꢁ
CHCl3)). For the analytical data, see the synthesis of (S)-2 and
(R)-3 in entry 1 of Table 1. The enantiomeric ratios of (S)-2 and
(R)-3 in entry 2 of Table 1 were determined by Chiral GC after
lactonization.
Table 2, entry 1: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, (4S*,5R*)-5 (220.0 mg, 1.0 mmol), and
m
= 2960, 2930, 2860, 1730, 1460, 1390, 1370, 1260, 1160, 900,

1366
A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
850 cmꢀ1; HRMS (EI): m/z calcd for C10H17O3: 185.1178; found:
185.1181. For preparation of (4S*,5R*)-6a and (4S,5R)-6b and see:9a
Table 2, entry 2: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, (4S*,5R*)-6a (242.0 mg, 1.0 mmol) and
1,4-cyclohexadiene in THF (3 mL) was treated with 4 (53.0 mg,
0.1 mmol) overnight. Purification (cyclohexane/AcOEt 88:12) gave
(R)-9 (97.6 mg, 40%) and (S)-10 (98.0 mg, 40%).
yield, ½a 2D0
¼ ꢀ1:0 (c 0.1, CHCl3)). For the analytical data, see the
ꢁ
synthesis of (R)-9 and (S)-10 in entry 2 of Table 2. The enantiomeric
ratios of (R)-9 and (S)-10 in entry 4 of Table 2 were determined by
Chiral GC analysis after lactonization.
Table 2, entry 4: By following the general procedure described
above, the mixture of 2,4,6-collidine hydrochloride (166.0 mg,
10.5 ꢂ 10ꢀ1 mmol), Mn (57.0 mg, 10.4 ꢂ 10ꢀ1 mmol), (4S,5R)-6b
(170.0 mg, 0.7 mmol), and 1,4-cyclohexadiene (245.0 mg,
30.6 ꢂ 10ꢀ1 mmol) in THF (6 mL) was treated with the catalyst 4
(36.0 mg, 0,07 mmol) overnight. Silica gel chromatography (cyclo-
Compound (R)-9: ½a D20
ꢁ
¼ þ1:5 (c 0.6, CHCl3); 1H NMR (400 MHz,
C6D6): d = 3.47–3.37 (m, 1H) 2.35 (ddd, J = 15.9, 7.0, 7.6 Hz, 1H),
2.30 (ddd, J = 16.0, 7.3, 7.4 Hz, 1H) 1.71 (dddd, J = 14.0, 3.7, 7.4,
7.4 Hz, 1H), 1.60 (dddd, J = 14.2, 7.1, 8.5, 7.1 Hz, 1H), 1.49 (s, 1H),
1.44–1.16 (m, 19H), 0.90 ppm (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, C6D6): d = 173.4, 79.8, 71.1, 38.1, 32.9, 32.3, 32.3, 29.8,
hexane/AcOEt 90:10) gave (R)-9 (114.0 mg, 67% yield; ½a D20
¼ þ1:5
ꢁ
(c 0.6, CHCl3)) and (R)-10 (18.8 mg, 11% yield; ½a D20
¼ þ1:0 (c 0.1,
ꢁ
CHCl3). For the analytical data, see the synthesis of (R)-9 and (S)-
10 in entry 2 of Table 2. The enantiomeric ratios of (R)-9 and (S)-
10 in entry 4 of Table 2 were determined by Chiral GC analysis
after lactonization.
28.2, 26.0, 23.1, 14.3 ppm; IR (KBr):
m = 3440, 2930, 1730, 1460,
1390, 1370, 1150, 960, 850, 760 cmꢀ1; HRMS (EI): m/z calcd for
C
10H20O3: 188.1413; found: 188.1417.
Compound (S)-10:
½
a 2D0
ꢁ
¼ ꢀ1:0 (c 0.1, CHCl3); 1H NMR
Table 2, entry 5: By following the general procedure described
above, the mixture of 2,4,6-collidine hydrochloride (237.0 mg,
1.5 mmol), Mn (82.4 mg, 1.5 mmol), (4S,5R)-6b (242.0 mg,
1.0 mmol), and 1,4-cyclohexadiene (349.0 mg, 43.5 ꢂ 10ꢀ1 mmol)
in THF (6 mL) was treated with the catalyst ent-3 (53.0 mg,
0.1 mmol) overnight. Silica gel chromatography (cyclohexane/
(400 MHz, C6D6): d = 3.34 (dddd, J = 5.7, 5.7, 5.8, 5.8 Hz, 1H), 2.14
(dd, J = 7.3, 7.3 Hz, 2H), 1.72 (ddddd, J = 13.6, 6.7, 6.9, 6.9, 8.6 Hz,
1H), 1.63 (ddddd, J = 13.8, 7.0, 7.0, 7.0, 9.0 Hz, 1H), 1.40–1.15 (m,
19H), 1.06 (s, 1H), 0.90 ppm (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, C6D6): d = 172.8, 79.6, 71.1, 38.0, 37.3, 35.6, 32.3, 28.2,
25.8, 23.1, 21.6, 14.3 ppm; IR (KBr):
m
= 3440, 2930, 1730, 1460,
AcOEt 90:10) gave (S)-9 (38.0 mg, 16% yield; ½a D20
¼ ꢀ1:0 (c 0.1,
ꢁ
1370, 1250, 1150, 850 cmꢀ1; HRMS (EI): m/z calcd for C10H20O3:
188.1413; found: 188.1415.
CHCl3)) and (R)-10 (175.0 mg, 72% yield; ½a D20
¼ þ1:2 (c 0.4 CHCl3)).
ꢁ
For the analytical data, see the synthesis of (R)-9 and (S)-10 in en-
try 2 of Table 2. The enantiomeric ratios of (R)-9 and (S)-10 in entry
The enantiomeric ratios of (R)-9 and (S)-10 in entry 2 of Table 2
were determined by Chiral GC analysis after the following lacton-
ization process.
4
of Table
2 were determined by Chiral GC analysis after
lactonization.
Compound (R)-9-Lactone:26 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (R)-9 (17.0 mg,
69.6 ꢂ 10ꢀ3 mmol), benzene (10 mL) and p-toluenesulfonic acid
monohydrate (3.0 mg, 1.6 ꢂ 10ꢀ2 mmol). The reaction mixture
was refluxed at around 85 °C for 4 h, and then cooled to room tem-
perature. The solvent was removed under reduced pressure, and
the residue was directly subjected to flash column chromatogra-
phy on silica gel eluting with cyclohexane/AcOEt (80:20) to afford
To a solution of the corresponding olefin28 (4.0 g, 35.7 mmol) in
CH2Cl2 (100 mL) were added MCPBA (11.4 g, 46.4 mmol) and NaO-
Ac (8.8 g, 107.3 mmol) at 0 °C. The mixture was diluted with
CH2Cl2 and washed with a saturated aqueous solution of K2CO3.
After drying (MgSO4) and evaporation of the volatiles, the crude
product was purified by SiO2 chromatography (CH/EtOAc 2:1) to
give 11 (2.0 g, 15.6 mmol, 44%). 1H NMR (300 MHz, CDCl3):
d = 3.44–3.34 (m, 2H), 2.69 (dd, J = 6.9, 16.2 Hz, 1H), 2.60–2.54
(m, 2H), 2.48–2.46 (m, 1H), 1.70–1.64 (m, 1H), 1.49–1.40 ppm
(m, 1H); 13C NMR (75 MHz, CDCl3): d = 169.5, 62.5, 52.7, 48.9,
34.0, 28.0 ppm.
REO of 11: By following the general procedure: 2,4,6-collidine
hydrochloride, Mn, 11 (128.0 mg, 1.0 mmol), and 1,4-cyclohexadi-
ene in THF (3 mL) were treated with 4 (53.0 mg, 1.0 mmol) over-
night. Silica gel chromatography (cyclohexane/AcOEt 80:20) gave
an inseparable mixture product 12/13 (66: 34, 81.0 mg, 64%,
(R)-9-Lactone (10.0 mg, 84% yield; ½a D20
¼ ꢀ42:8 (c 2.2, CHCl3)). The
ꢁ
enantiomeric ratio, (R):(S) = 93.5:6.5, was accurately measured by
Chiral GC using Cyclodextrin TA column (70 kPa pressure, 140 °C
isotherm for 60 min, major enantiomer 39 min, minor enantiomer
43 min). 1H NMR (400 MHz, C6D6): d = 3.76 (dddd, J = 5.2, 6.6, 7.7,
7.7 Hz, 1H), 1.92 (ddd, J = 17.4, 4.3, 9.5 Hz, 1H), 1.82 (ddd,
J = 17.4 Hz, 9.5, 9.6 Hz, 1H), 1.34 (dddd, J = 12.6, 4.3, 6.5, 9.4 Hz,
1H), 1.30–1.05 (m, 10H), 0.98 (dddd, J = 12.6, 8.0, 9.5, 9.5 Hz, 1H),
0.88 ppm (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, C6D6): d = 175.7,
79.9, 35.8, 32.0, 29.3, 28.6, 27.8, 25.6, 22.9, 14.3 ppm.
½
a 2D0
ꢁ
¼ ꢀ20:0, (c 3.0, CHCl3). 1H NMR (400 MHz, CDCl3): d = 4.68–
4.61 (m, 1H), 4.22 (ddd, J = 1.8, 7.2, 12.8 Hz, 1H), 4.14 (ddd,
J = 1.5, 7.9, 12.8 Hz, 1H), 4.11–4.04 (m, 1H), 3.74 (dd, J = 5.8,
5.9 Hz, 2H), 3.01 (br s, 1H; OH), 2.89 (dd, J = 8.4, 13.6 Hz, 1H),
2.82 (dd, J = 1.6, 13.6 Hz, 1H), 2.51–2.47 (m, 2H), 2.36–2.28 (m,
2H), 2.09–1.70 ppm (m, 4H); 12: 13C NMR (75 MHz, CDCl3):
d = 173.3, 69.3, 64.8, 42.8, 36.5, 24.5 ppm. Compound 13: 13C
NMR (100 MHz, CDCl3): d = 177.4, 78.6, 59.1, 38.2, 28.8, 28.2 ppm.
For chiral GC of 12: TA column, 200 kPa pressure, 80 °C iso-
therm for 10 min, 10 °C/min rate, 100 °C isotherm for 170 min,
10 °C/min rate, 140 °C isotherm for 260 min, 10 °C/min rate,
160 °C isotherm for 10 min, minor enantiomer 387 min, major
enantiomer 362 min. For chiral GC of 13: TA column, 200 kPa pres-
sure, 80 °C isotherm for 10 min, 10 °C/min rate, 100 °C isotherm for
170 min, 10 °C/min rate, 140 °C isotherm for 260 min, 10 °C/min
rate, 160 °C isotherm for 10 min, major enantiomer 245 min, minor
enantiomer 255 min.
Compound (S)-10-Lactone:27 To a 10-mL round-bottomed flask
equipped with a reflux condenser were added (S)-10 (75.0 mg,
30.9 ꢂ 10ꢀ2 mmol), benzene (10 mL), and p-toluenesulfonic acid
monohydrate (3.0 mg, 1.6 ꢂ 10ꢀ2 mmol). The reaction mixture
was refluxed at around 85 °C for 4 h, and then cooled to room tem-
perature. The solvent was removed under reduced pressure, and
the residue was directly subjected to flash column chromatogra-
phy on silica gel eluting with cyclohexane/AcOEt (80:20) to afford
(R)-7a-Lactone (41.0 mg, 78% yield; ½a D20
¼ þ31:6 (c 1.1, CHCl3)).
ꢁ
The enantiomeric ratio, (R):(S) = 90:10, was accurately measured
by Chiral GC using Cyclodextrin TA column (70 kPa pressure,
120 °C isotherm for 120 min, major enantiomer 92 min, minor
enantiomer 89 min). 1H NMR (400 MHz, C6D6): d = 3.62 (dddd,
J = 3.0, 4.6, 7.6, 10.7 Hz, 1H), 2.08 (dddd, J = 17.2, 1.3, 5.8, 6.9 Hz,
1H), 1.98 (ddd, J = 17.2, 7.1, 8.1 Hz, 1H), 1.46–0.98 (m, 12H),
0.86 ppm (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, C6D6): d = 169.9,
79.3, 36.1, 32.0, 29.6, 27.8, 25.0, 22.9, 18.6, 14.2 ppm.
Table 3, entry 1: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, racemic-14 (254.0 mg, 1.0 mmol), and
1,4-cyclohexadiene in THF (3 mL) were treated with 4 (53.0 mg,
1.0 mmol) overnight. Silica gel chromatography (cyclohexane/
AcOEt 20:1?7:1) gave 15 (100.0 mg, 39%) and 16 (54.0 mg, 21%).
Table 2, entry 3: Procedure according to entry 2, but stirring at
0 °C overnight. (4S*,5R*)-6b (240.0 mg, 1.0 mmol), (R)-9 (55.0 mg,
23% yield, ½a 2D0
¼ þ1:5 (c 0.6, CHCl3)) and (S)-10 (57.0 mg, 24%
ꢁ

A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
1367
Compound 15: ½a 2D0
ꢁ
¼ ꢀ6:0 (c 1.6, CHCl3), 1H NMR (300 MHz,
40.4, 35.8, 31.7, 29.0, 25.3, 25.1, 24.5, 22.5, 14.0 ppm; IR (KBr):
CDCl3): d = 3.70 (m, 1H), 2.34 (dt, J = 1.3, 7.3 Hz, 2H), 1.92 (br s,
1H; OH), 1.80–1.55 (m, 7H), 1.43 (s, 9H), 1.42–1.31 (m, 2H),
1.30–1.10 (m, 4H), 0.98–0.77 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3): d = 173.8, 80.5, 68.8, 45.6, 34.3, 34.2, 33.0, 32.9, 32.2,
m = 2961, 2932, 2860, 1772, 1466, 1386, 1206, 1148, 1116, 1034,
1018, 912 cmꢀ1; HRMS (EI): m/z calcd for C12H22O2: 198.1620;
found: 198.1618 [M]+.
Compound 19-Lactone: ½a D20
¼ þ13:7 (c 2.0, CHCl3), ee = 62,
ꢁ
28.2, 28.2, 28.2, 26.7, 26.5, 26.3 ppm; IR (KBr):
m
= 3434, 2977,
enantiomeric ratio was accurately measured by Chiral GC using
Cyclodextrin TA column (40 kPa pressure, 80 °C isotherm for
15 min, 10 °C/min rate, 90 °C isotherm for 60 min, 10 °C/min rate,
100 °C isotherm for 60 min, 10 °C/min rate,110 °C isotherm for
30 min, 10 °C/min rate,120 °C isotherm for 30 min, 10 °C/min rate,
160 °C isotherm for 10 min, major enantiomer 176 min, minor
enantiomer 174 min).1H NMR (300 MHz, CDCl3): d = 4.25–4.17
(m, 1H), 1.78–1.99 (m, 12H), 1.22 (s, 3H), 1.20 (s, 3H), 0.82 ppm
(t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 177.6, 81.7, 38.1,
36.2, 34.6, 31.6, 27.9, 27.8, 26.0, 24.5, 22.5, 14.0 ppm; IR (KBr):
2922, 2851, 1731, 1448, 1367, 1256, 1152, 848 cmꢀ1; HRMS (EI):
m/z calcd for C11H20O3: 200.1412; found: 200.1414 [M+HꢀtBu]+.
For chiral GC of 15: TA column, 50 kPa pressure, 100 °C isotherm
for 15 min, 10 °C/min rate, 120 °C isotherm for 30 min, 10 °C/min
rate, 140 °C isotherm for 100 min, 10 °C/min, 160 °C isotherm for
15 min, major enantiomer 99.5 min, minor enantiomer 100.6 min.
Compound 16: ½a 2D0
ꢁ
¼ ꢀ10:5 (c 0.5, MeOH), 1H NMR (400 MHz,
CDCl3): d = 3.34 (ddd, J = 3.4, 5.4, 8.8 Hz, 1H), 2.24 (t, J = 7.3 Hz,
2H), 1.80–1.47 (m, 8H), 1.44 (s, 9H), 1.42–0.95 ppm (m, 8H); 13C
NMR (100 MHz, CDCl3): d = 173.4, 80.3, 75.8, 43.7, 35.6, 33.6,
29.4, 28.3, 28.3, 28.3, 27.9, 26.7, 26.5, 26.3, 21.5 ppm; IR (KBr):
m
= 2934, 2865, 1732, 1459, 1386, 1287, 1190, 1130, 1017 cmꢀ1
;
HRMS (EI): m/z calcd for C12H22O2: 198.1620; found: 198.1626
m
= 3435, 2925, 2852, 1731, 1450, 1367, 1254, 1151 cmꢀ1; HRMS
[M]+.
(EI): m/z calcd for C11H19O3: 199.1334; found: 199.1338 [MꢀtBu]+.
For chiral GC of 16: TA column, 50 kPa pressure, 100 °C isotherm
for 15 min, 10 °C/min rate, 120 °C isotherm for 30 min, 10 °C/min
rate, 140 °C isotherm for 100 min, 10 °C/min, 160 °C isotherm for
15 min, major enantiomer 105.1 min, minor enantiomer
106.6 min.
Table 3, entry 3: Procedure according to entry 2. Compound 18
(14.0 mg, 5%), ½a D20
¼ ꢀ7:0 (c 0.7, CHCl3) and 19 (223.0 mg, 82%),
ꢁ
½
a 2D0
ꢁ
¼ ꢀ0:8 (c 1.5, CHCl3).
Table 3, entry 4: Procedure according to entry 2. Compound 18
(150.0 mg, 55%), ½a D20
¼ þ3:2 (c 2.0, CHCl3) and 19 (68.0 mg, 25%),
ꢁ
½
a 2D0
ꢁ
¼ þ0:6 (c 1.5, CHCl3).
Compound (4S,5R)-17b: ½a D20
ꢁ
¼ ꢀ14:8 (c 2.0, CHCl3). 1H NMR
Scheme 4, REO of 20: By following the general procedure: 2,4,6-
(300 MHz, C6D6): d = 7.73 (d, J = 8.3 Hz, 2H) 6.74 (d, J = 7.9 Hz,
2H), 4.03 (dd, J = 11.1, 5.0 Hz, 1H), 3.95 (dd, J = 11.1, 6.4 Hz, 1H),
2.85 (ddd, J = 4.2, 4.9, 6.2 Hz, 1H), 2.53–2.48 (m, 1H), 1.86 (s, 3H),
1.21–0.94 (m, 8H), 0.80 ppm (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
C6D6): d = 144.6, 133.9, 128.2, 68.5, 56.3, 53.0, 31.6, 27.9, 26.5,
collidine hydrochloride, Mn, 20 (258.0 mg, 1.0 mmol), and 1,4-
cyclohexadiene in THF (3 mL) were treated with 4 (53.0 mg,
1.0 mmol) overnight. Silica gel chromatography (cyclohexane/
AcOEt 20:1?7:1) gave an inseparable mixture of 21/22 (46:54,
221.0 mg, 85% yield;
½
a 2D0
ꢁ
¼ þ6:6 (c 2.5, CHCl3)). IR (KBr):
22.7, 21.2, 14.1 ppm; IR (KBr):
m
= 2963, 2930, 2873, 1725, 1472,
m = 3436, 2958, 2933, 2870, 1731, 1456, 1392, 1367, 1254, 1153,
1391, 1368, 1312, 1255, 1221, 1148, 852 cmꢀ1; HRMS (EI): m/z
calcd for C12H22O3: 214.1569; found: 214.1575 [MꢀC4H8]+.
Table 3, entry 2: By following the general procedure: 2,4,6-col-
lidine hydrochloride, Mn, 17a (270.0 mg, 1.0 mmol), and 1,4-cyclo-
hexadiene in THF (3 mL) were treated with 4 (53.0 mg, 1.0 mmol)
overnight. Purification (cyclohexane/AcOEt 90:10?80:20) gave 18
(63.0 mg, 23%) and 19 (179 mg, 66%).
1119, 849 cmꢀ1; HRMS (EI): m/z calcd for C10H20O4: 204.1362;
found: 204.1369 [M+HꢀtBu]+.
Compound 21: 1H NMR (300 MHz, CDCl3): d = 3.80–3.69 (m, 1H),
3.65–3.48 (m, 2H), 3.46–3.36 (m, 2H), 2.41–2.26 (m, 2H), 1.77–1.24
(m, 9H), 1.40 (s, 9H), 0.86 ppm (t, 3J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 173.5, 80.2, 71.1, 70.9, 69.8, 36.4, 32.5, 31.9,
31.8, 28.2, 28.2, 28.2, 19.3, 13.9 ppm.
Compound 18: ½a 2D0
ꢁ
¼ ꢀ3:0 (c 1.5, CHCl3), 1H NMR (300 MHz,
Compound 22: 1H NMR (300 MHz, CDCl3): d = 3.80–3.69 (m, 1H),
3.48–3.39 (m, 2H), 3.40 (dd, 2J = 9.4 Hz, 3J = 3.2 Hz, 1H), 3.22 (dd,
2J = 9.4 Hz, 3J = 7.9 Hz, 1H), 2.20 (t, 3J = 7.3 Hz, 2H), 1.77–1.24 (m,
9H), 1.40 (s, 9H), 0.88 ppm (t, 3J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d = 173.1, 80.1, 75.0, 71.3, 70.0, 35.4, 32.6, 31.8, 28.2,
28.2, 28.2, 21.2, 19.4, 14.0 ppm.
CDCl3): d = 3.62 (br s, 1H), 2.12 (d, J = 2.4 Hz, 1H), 1.77 (dd,
J = 9.6, 14.5 Hz, 1H), 1.42–1.14 (m, 11H), 1.37 (s, 9H), 1.12 (s, 3H),
1.11 (s, 3H), 0.81 ppm (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 178.6, 80.3, 69.1, 47.7, 41.8, 39.0, 31.9, 29.3, 27.9, 27.8, 25.6,
24.3, 22.6, 14.1 ppm; IR (KBr):
m = 3500, 2960, 2930, 2858, 1724,
1709, 1473, 1391, 1368, 1311, 1253, 1226, 1142, 852 cmꢀ1; HRMS
The enantiomeric ratios of 21 and 22 were determined by Chiral
GC analysis after lactonization process.
(EI): m/z calcd for
[MꢀC4H8]+.
C12H24O3: 216.1725; found: 216.1728
Compound 21-Lactone: ½a D20
¼ ꢀ46:0 (c 3.1, CHCl3), ee = 92, the
ꢁ
Compound 19: ½a 2D0
ꢁ
¼ ꢀ0:7 (c 1.5, CHCl3),.1H NMR (300 MHz,
enantiomeric ratio was measured by Chiral GC using Cyclodextrin
TA column (60 kPa pressure, 100 °C isotherm for 15 min, 10 °C/min
rate, 140 °C isotherm for 80 min, 10 °C/min rate, 160 °C isotherm
for 15 min, major enantiomer 73.1 min, minor enantiomer
70.3 min). 1H NMR (400 MHz, CDCl3): d = 4.65 (ddt, 3J = 5.2, 6.5,
7.9 Hz, 1H), 3.53 (dd, 3J = 5.3, 6.9 Hz, 2H), 3.40 (t, 3J = 6.7 Hz, 2H),
2.52 (dd, 3J = 6.8, 9.7 Hz, 2H), 2.34 (dt, 3J = 6.7, 19.5 Hz, 1H), 1.98–
1.84 (m, 3H), 1.56–1.49 (m, 2H), 1.41–1.30 (m, 2H), 0.90 ppm (t,
3J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 177.3, 78.5, 71.1,
CDCl3): d = 3.50–3.42 (m, 1H), 1.73 (s, 1H; OH), 1.61–1.15 (m, 12
H), 1.36 (s, 9H), 1.06 (s, 3H), 1.05 (s, 3H), 0.82 ppm (t, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): d = 177.3, 79.8, 72.0, 42.4, 37.3,
36.4, 32.7, 31.9, 28.0, 25.6, 25.3, 24.9, 22.6, 14.0 ppm; IR (KBr):
m
= 3443, 2931, 2860, 1725, 1474, 1457, 1390, 1368, 1322, 1255,
1142, 1076, 1052, 853 cmꢀ1; HRMS (EI): m/z calcd for C12H23O2:
199.1698; found: 199.1700 [MꢀOHꢀC4H8]+.
The enantiomeric ratios of 18 and 19 were determined by Chiral
GC analysis after lactonization process.
66.7, 35.9, 31.8, 28.9, 28.2, 19.4, 14.0 ppm; IR (KBr):
m = 2957,
Compound 18-Lactone: ½a D20
ꢁ
¼ ꢀ24:9 (c 2.0, CHCl3), ee = 94,
2868, 1770, 1462, 1367, 1183, 1115, 1018, 969, 904, 653 cmꢀ1
;
enantiomeric ratio was accurately measured by Chiral GC using
Cyclodextrin TA column (50 kPa pressure, 100 °C isotherm for
15 min, 10 °C/min rate, 140 °C isotherm for 150 min, 10 °C/min
rate, 160 °C isotherm for 10 min, minor enantiomer 34 min, major
enantiomer 33 min.). 1H NMR (300 MHz, CDCl3): d = 4.38–4.29 (m,
1H), 2.07 (dd, J = 5.8, 12.6 Hz, 1H), 1.64 (dd, J = 9.8, 12.6 Hz, 1H),
1.72–1.17 (m, 10H), 1.20 (s, 3H), 1.18 (s, 3H), 0.82 ppm (t,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 182.1, 77.2, 43.6,
HRMS (EI): m/z calcd for C10H18O3: 186.1256; found: 186.1263
[M]+.
Compound 22-Lactone: ½a D20
¼ þ9:6 (c 2.5, CHCl3), ee = 81, the
ꢁ
enantiomeric ratio was measured by Chiral GC using Cyclodextrin
TA column (50 kPa pressure, 100 °C isotherm for 15 min, 10 °C/min
rate, 130 °C isotherm for 100 min, 10 °C/min rate, 160 °C isotherm
for 15 min, major enantiomer 93 min, minor enantiomer 91 min).
1H NMR (400 MHz, CDCl3): d = 4.42 (ddt, 3J = 3.4, 4.8, 10.4 Hz,

1368
A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
1H), 3.57, 3.52 (dABq, 3J = 4.8 Hz, 2J = 10.4 Hz, 2H), 3.47, 3.46 (tABq,
3J = 6.6 Hz, 2J = 9.3 Hz, 2H), 2.61–2.53 (m, 1H), 2.49–2.40 (m, 1H),
1.99–1.90 (m, 2H), 1.88–1.78 (m, 1H), 1.74–1.62 (m, 1H), 1.57–
1.50 (m, 2H), 1.41–1.30 (m, 2H), 0.90 ppm (t, 3J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d = 171.4, 79.3, 72.6, 71.7, 31.8, 29.8,
References
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Scheme 4, REO of 23: By following the general procedure de-
scribed above, the mixture of 2,4,6-collidine hydrochloride
(71.9 mg, 45.6 ꢂ 10ꢀ2 mmol), Mn (25.1 mg, 45.6 ꢂ 10ꢀ2 mmol),
racemic epoxide 23 (70.0 mg, 30.4 ꢂ 10ꢀ2 mmol), and 1,4-cyclo-
hexadiene (0.13 mL, 1.37 mmol) in THF (4 mL) was treated with
4 (16.0 mg, 30.4 ꢂ 10ꢀ3 mmol) for 3 days. Silica gel chromatogra-
phy (cyclohexane/AcOEt 10:1) gave an inseparable mixture prod-
uct 24/25 (66:34, 54.4 mg, 77% yield; ½a D20
¼ ꢀ4:4 (c 3.5, CHCl3)).
ꢁ
IR (KBr):
m = 3478, 2932, 2863, 1747, 1462, 1394, 1368, 1246,
1148, 1034, 942, 846, 732 cmꢀ1
; HRMS (EI): m/z calcd for
C8H16O4: 176.1049; found: 176.1055 [M+HꢀtBu]+.
Compound 24: 1H NMR (300 MHz, C6D6): d = 3.83–3.74 (m, 1H),
3.76 (s, 2H), 3.41 (br s, 1H; OH), 3.36 (dd, 3J = 3.0 Hz, 2J = 9.4 Hz,
1H), 3.23 (dd, 3J = 7.6 Hz, 2J = 9.4 Hz, 1H), 1.65–1.20 (m, 6H), 1.30
(s, 9H), 0.86 ppm (t, 3J = 7.3 Hz, 3H); 13C NMR (75 MHz, C6D6):
d = 170.3, 81.3, 77.2, 70.3, 69.1, 33.2, 28.2, 28.0, 28.0, 28.0, 23.2,
14.3 ppm. The enantiomeric ratio of 24 (ee = 62) was measured
by Chiral GC using Cyclodextrin TA column (50 kPa pressure,
80 °C isotherm for 10 min, 10 °C/min rate, 90 °C isotherm for
390 min, 10 °C/min rate, 120 °C isotherm for 70 min, 10 °C/min
rate, 160 °C isotherm for 10 min, major enantiomer 352.8 min,
minor enantiomer 343.8 min).
Compound 25: 1H NMR (300 MHz, C6D6): d = 4.00–3.90 (m, 1H),
3.72, 3.65 (ABq, 2J = 16.6 Hz, 2H), 3.60–3.54 (m, 2H), 3.41 (br s, 1H;
OH), 1.65–1.20 (m, 6H) 1.29 (s, 9H), 0.91 ppm (t, 3J = 7.3 Hz, 3H);
13C NMR (75 MHz, C6D6): d = 170.3, 81.3, 69.5, 69.2, 68.6, 40.2,
37.5, 28.0, 28.0, 28.0, 19.4, 14.4 ppm. The enantiomeric ratio of 25
(ee = 98) was measured by Chiral GC using Cyclodextrin TA column
(50 kPa pressure, 80 °C isotherm for 10 min, 10 °C/min rate, 100 °C
isotherm for 300 min, 10 °C/min rate, 160 °C isotherm for 10 min,
major enantiomer 198.2 min, minor enantiomer 195.0 min).
Compound 24/25 (66:34, 54.4 mg, 77% yield; ½a D20
¼ ꢀ4:4 (c 3.5,
ꢁ
CHCl3)). IR (KBr):
m = 3478, 2932, 2863, 1747, 1462, 1394, 1368,
1246, 1148, 1034, 942, 846, 732 cmꢀ1; HRMS (EI): m/z calcd for
C8H16O4: 176.1049; found: 176.1055 [M+HꢀtBu]+.
Scheme 5, entry 1, REO of (1R*,2R*,3R*)-26: By following the
general procedure described above, the mixture of 2,4,6-collidine
hydrochloride (472 mg, 3 mmol), Mn (166 mg, 3 mmol),
(1R*,2R*,3R*)-2617,29 (435 mg, 2 mmol), and 1,4-cyclohexadiene
(700 mg, 8.7 mmol) in THF (6 mL) was treated with Cp2TiCl2
(50 mg, 0.2 mmol). Silica gel chromatography (cyclohexane/AcOEt
9:1) gave 2730 (293 mg, 67%). All analytical data are in agreement
with the literature values.30
14. (a) Gansäuer, A.; Lauterbach, T.; Bluhm, H.; Noltemeyer, M. Angew. Chem., Int.
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6916–6917.
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Scheme 5, entry 2, REO of (1R*,2R*,3R*)-26: By following the
general procedure described above, the mixture of 2,4,6-collidine
hydrochloride (436 mg, 1.5 mmol), Mn (83 mg, 1.5 mmol),
(1R*,2R*,3R*)-26 (223 mg, 1 mmol), and 1,4-cyclohexadiene
(350 mg, 4.4 mmol) in THF (3 mL) was treated with 4 (53 mg,
0.1 mmol). Silica gel chromatography (cyclohexane/AcOEt 9:1)
gave 28 (31 mg, 14%). All analytical data are in agreement with
the literature values.31
Acknowledgments
We are indebted to the SFB 813 (‘Chemistry at Spin Centers’),
the Fonds der Chemischen Industrie (‘Sachbeihilfen’), and the Alexan-
der von Humboldt-Stiftung for financial support.
18. (a) Gansäuer, A.; Pierobon, M. Synlett 2000, 1357–1359; (b) Gansäuer, A.;
Pierobon, M.; Bluhm, H. Synthesis 2001, 2500–2520; (c) Barrero, A. F.; Quílez
del Moral, J. F.; Sánchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641.

A. Gansäuer et al. / Tetrahedron: Asymmetry 21 (2010) 1361–1369
1369
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