Asymmetric homoaldol reactions with cyclohex-2-enyl N,N- diisopropylcarbamate: Kinetic resolution, elucidation of the stereochemical course and applications in the synthesis of hexahydroisobenzofuran-4-(1H)-ones

Article abstract of DOI:10.1002/ejoc.200700219

Enantio-enriched cyclohex-2-enyl N,N-diisopropylcarbamate (5) is stereospecifically deprotonated by sec-butyllithium/(-)-sparteine (9) to form the configurationally stable lithium complex 7.9. A kinetic resolution of rac-5 by n-butyllithium/(-)-sparteine (9) yielded (R)-5 with up to 99 % ee. Electrophilic substitution with tin electrophiles proceeds in a anti-S _E′ fashion as shown by chemical correlations. The synthesized allylstannanes 10 undergo a highly stereospecific TiCl₄-mediated homoaldol reaction with various aldehydes, yielding syn-configured homoaldol products 12. These were transferred into all-cis-configured hexahydroisobenzofuran-4(1H)-ones 22 by BF₃·OEt ₂-mediated reactions with aldehydes. The configurations of several products were determined by X-ray structure analysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700219

FULL PAPER
DOI: 10.1002/ejoc.200700219
Asymmetric Homoaldol Reactions with Cyclohex-2-enyl N,N-Diisopropyl-
carbamate: Kinetic Resolution, Elucidation of the Stereochemical Course and
Applications in the Synthesis of Hexahydroisobenzofuran-4-(1H)-ones
[a]
[a][‡]
Kirsi Salorinne,[b][‡] and and Dieter Hoppe*[a]
Jochen Becker, Roland Fröhlich,
Keywords: Asymmetric synthesis / Kinetic resolution / Metallated allyl carbamates / Homoaldol reactions / Tetra-
hydrofuran synthesis
Enantio-enriched cyclohex-2-enyl N,N-diisopropylcarba-
mate (5) is stereospecifically deprotonated by sec-butyllith-
ium/(–)-sparteine (9) to form the configurationally stable lith-
ium complex 7·9. A kinetic resolution of rac-5 by n-butyllith-
ium/(–)-sparteine (9) yielded (R)-5 with up to 99% ee. Elec-
trophilic substitution with tin electrophiles proceeds in a anti-
4
TiCl -mediated homoaldol reaction with various aldehydes,
yielding syn-configured homoaldol products 12. These were
transferred into all-cis-configured hexahydroisobenzofuran-
4(1H)-ones 22 by BF ·OEt -mediated reactions with alde-
3 2
hydes. The configurations of several products were deter-
mined by X-ray structure analysis.
S
E
Ј fashion as shown by chemical correlations. The synthe-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
sized allylstannanes 10 undergo a highly stereospecific
Introduction
to form persistent, configurationally stable lithium com-
pounds 2. These are usually attacked by tin-electrophiles in
Enantio-enriched lithiated alk-2-enyl N,N-diisopro-
pylcarbamates are valuable homoenolate reagents and have
often been used, after lithium–titanium exchange, in highly
stereoselective homoaldol reactions.[ As we have recently
demonstrated, alkyl-substituted cyclohex-2-enyl carbamates
of type 1, under certain structural preconditions, are
smoothly deprotonated by means of alkyllithium/diamine
an anti-S Ј fashion (Scheme 1) to yield diastereomerically
pure allylstannanes 3.
E
[3]
1,2]
Results and Discussion
Synthesis of Chiral Carbamates 5
From our recent studies, carried out with racemic cy-
clohex-2-enyl N,N-diisopropyl carbamate (rac-5), no con-
clusion could be drawn about the configurational stability
of lithiated intermediate rac-7 that may undergo stereospec-
ific substitution reactions as found for alkyl-substituted cy-
[
3]
clohex-2-enyl carbamates like 1. The carbamate rac-5 was
[
4]
[5]
prepared by the usual method, from the alcohol rac-4
and N,N-diisopropylcarbamoyl chloride (6), in 87% yield
Scheme 2). In the same way, (R)-5 (96% ee) and (S)-5 (90%
ee) were synthesized from the optically active cyclohex-2-
(
[
6]
[7]
enols (R)-4 and (S)-4.
Scheme 1.
[
a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-
versität Münster,
Corrensstr. 40, 48149 Münster
Fax: +49-251-83-36531
E-mail: dhoppe@uni-muenster.de
b] Nanoscience Center, University of Jyväskylä,
[
[
4
0014, Finland
Scheme 2. Synthesis of optically active cyclohex-2-enyl carbamates
5.
‡] X-ray crystal structure analysis.
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3337

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
Deprotonation and Stannylation
(S)-10a was obtained with 90% and 95% optical yield,
respectively (entries 7 and 8).
The lithiated complexes 7·rac-8 have only a limited con-
figurational stability, resulting in a slow epimerisation. Af-
ter 5 h, the enantio-enrichment decreases from 96% ee to
Carbamates rac-5, (R)-5, and (S)-5 were subjected to dif-
ferent deprotonation conditions and the lithiated species
were trapped by Bu SnCl or Ph SnCl to afford the stann-
3
3
anes 10a or 10b, respectively (Scheme 3, Table 1). Depro-
tonation in presence of N,N,NЈ,NЈ-tetramethylethylenedi-
amine (TMEDA) as chelating ligand resulted in low yields
and stereoselectivities of the stannane 10a (entries 1–3).
Better yields of rac-10a (75%) were obtained when using
nBuLi and rac-trans-1,2-bis(dimethylamino)cyclohexane
73% ee (Entry 9). After lithiation times of 30 min and
60 min the stannane (S)-10a was obtained with 90% and
95% OY, respectively (Entries 7 and 8). Obviously, the
minor enantiomer (S)-5 is lithiated faster than (R)-5 be-
cause of matched and mismatched interactions of the chiral
substrates and the racemic ligand rac-8. Here also a kinetic
resolution of the diastereomeric lithium complexes takes
place during the substitution step: the ee decreases, if the
amount of the electrophile and the substitution time are
decreased (Entries 8 and 10). When sBuLi/(–)-sparteine (9)
were used for deprotonation, (R)-5 or (S)-5 afforded stann-
anes (S)-10a or (R)-10a in high yields and without loss of
optical purity (Entries 12–16). The complex (R)-7·9 is con-
figurationally stable for more than 3 h at –78 °C. As fre-
quently observed, the rate of epimerisation of chiral
organolithium compounds decreases with increasing the
(
TMCDA, rac-8) (Entry 4). Starting from (R)-5 (92% ee)
or (S)-5 (90% ee) under the same reaction conditions, (S)-
0a or (R)-10a were obtained with lower enantiomeric ex-
1
cesses, 73% ee or 72% ee, respectively (Entries 5 and 6).
After lithiation times of 30 min and 60 min, the stannane
[
8]
bulk of the complexing diamine.
The reaction of the (–)-sparteine/lithium complex (R)-7·9
with Ph SnCl yielded a semicrystalline sample of stannane
3
(R)-10b in 73% yield and 90% ee (Entry 18). Unfortunately,
the crystals turned out to be racemic, whereas the (R)-en-
antiomer remained as an oil. Although, no direct proof for
the configuration of stannanes (R)-10a and (R)-10b was
possible at this stage, the above assignments were concluded
from the anti-S Ј-substitution of substituted cyclohex-2-
E
[
3]
enyl carbamates and the stereochemical results of Lewis
acid catalysed homoaldol reactions of stannanes 10 (vide
infra).
Scheme 3. Lithiation and subsequent stannylation; reagents and
We also investigated the possibility of a kinetic resolution
conditions: (a) 1.3 equiv. nBuLi/rac-8, Et
for R = Ph), –78 °C, 4–5 h; (b) 1.3 equiv. sBuLi/9, Et
or toluene (R = Ph), –78 °C, 30–180 min; (c) i) 2.0 equiv. R
78 °C, 1–2 h; ii) NH Cl/H O.
2
O (for R = Bu) or toluene of rac-5 by use of equimolar amounts of nBuLi/(–)-sparte-
O (R = Bu)
SnCl,
(
2
ine (9), combined with subsequent trapping of the lithium
3
[
9,10]
intermediate by Bu SnCl (Scheme 4, Table 2).
3
–
4
2
Table 1. Deprotonation of 5 and subsequent stannylation.
Entry
5 (% ee)[a]
R–Li/Diamine (t [min])
Equiv. R
3
SnCl (t [min])
10 (% yield)[b]
% ee[a]
% OY[c]
1
2
3
4
5
6
7
8
9
rac-5
nBuLi/TMEDA (300)
sBuLi/TMEDA (120)
sBuLi/TMEDA (60)
nBuLi/rac-8 (240)
nBuLi/ rac-8 (300)
nBuLi/rac-8 (240)
sBuLi/rac-8 (30)
sBuLi/rac-8 (60)
sBuLi/rac-8 (300)
sBuLi/rac-8 (60)
sBuLi/rac-8 (60)
sBuLi/9 (30)
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
1.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
2.0 Bu
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
SnCl (60)
SnCl (120)
SnCl (60)
SnCl (60)
SnCl (120)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (10)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (60)
SnCl (120)
SnCl (120)
rac-10a (21)
rac-10a (36)
(R)-10a (54)
rac-10a (75)
(S)-10a (76)
(R)-10a (78)
(S)-10a (57)
(S)-10a (64)
(S)-10a (42)
(S)-10a (58)
(S)-10a (72)
(S)-10a (68)
(S)-10a (61)
(S)-10a (86)
(R)-10a (85)
(R)-10a (66)
rac-10b (68)
(S)-10b (73)
rac
rac
45
rac
73
72
86
91
73
85
54
95
97
95
90
87
rac
90
–
–
50
–
rac-5
(S)-5 (90)
rac-5
(R)-5 (92)
(S)-5 (90)
(R)-5 (96)
(R)-5 (96)
(R)-5 (96)
(R)-5 (96)
(R)-5 (96)
(R)-5 (96)
(R)-5 (99)
(R)-5 (96)
(S)-5 (90)
(S)-5 (90)
rac-5
79
80
90
95
76
89
56
99
98
99
Ͼ99
97
–
10
11
12
13
14
15
16
17
18
[
d]
sBuLi/9 (60)
sBuLi/9 (180)
sBuLi/8 (30)
sBuLi/9 (60)
[
[
d]
d]
nBuLi/rac-8 (360)
sBuLi/9 (60)
2.0 Ph
2.0 Ph
3
(R)-5 (99)
3
91
[
a] Enantiomeric excesses were determined by HPLC. [b] Isolated yields. [c] OY: optical yield, conservation of the original enantio-
enrichment of 5. [d] Toluene was used as solvent.
3338
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348

Asymmetric Homoaldol Reactions
FULL PAPER
12a was obtained in 58% yield; but, as usual for the lithium
method, only moderate diastereoselectivity favoring rac-
syn-12a over rac-anti-12a was observed. The configuration
of rac-syn-12a was secured by comparison of the analytical
data with that of the corresponding homoaldol product re-
sulting from the Lewis acid-mediated homoaldol reaction
Scheme 4. Kinetic resolution of rac-5; reagents and conditions: (a)
3
i) 1.0 equiv. nBuLi/9, –78 °C, t; ii) 1.3 equiv. or 2.0 equiv. Bu SnCl,
1
h.
(vide infra).
Table 2. Results of the kinetic resolution of 5.
Entry solvent
t
(R)-10a (% ee)[a] (R)-5 (% ee)[a]
[
[
[
[
[
[
[
b,c]
1
2
3
4
5
6
7
toluene
toluene
toluene
2 h
4 h
8 h
8 h
8 h
8 h
21.5 h
11 (77)
33 (66)
36 (68)
37 (66)
22 (78)
18 (82)
58 (35)
71 (11% op)
56 (46)
53 (54)
44 (68)
69 (30)
54 (23% op)
28 (99)
b]
b]
b]
Et
2
O
d]
toluene
n-pentane
toluene
d]
b]
[
a] Isolated yields. Enantiomeric excesses were determined by
HPLC. [b] nBuLi was added to a solution of the carbamate rac-5
and 9 at –78 °C. [c] 0.5 equiv. nBuLi/9. [d] rac-5 was added to a
solution of nBuLi/9 at –90 °C.
Scheme 5. Homoaldol reactions of the lithiated species; reagents
O, –78 °C, 5 h; ii)
.0 equiv. acetone, –78 °C, 2 h; (b) i) 1.3 equiv. nBuLi/rac-8, Et O,
78 °C, 4 h; ii) 3.0 equiv. PhCHO, –78 °C, 3 h.
and conditions: (a) i) 1.3 equiv. nBuLi/rac-8, Et
2
3
2
–
After lithiation of rac-5 with 1.0 equiv. nBuLi/9 for 8 h
in toluene half of the starting material was consumed (En-
try 3). The enantiomer (S)-5 is lithiated faster than (R)-5,
leading to an enantio-enrichment of the stannane (R)-10a
[
9a,11]
The TiCl -mediated homoaldol reaction
of stann-
anes 10a proceeded with high yields and stereoselectivities
Scheme 6, Table 3). For this purpose, a solution of (R)-10a
or (S)-10a and 1.3 equiv. of aldehyde 14 was stirred for 10–
0 min at –78 °C after addition of 1.3 equiv. TiCl . After
4
(
after stereospecific syn-S Ј substitution of the lithiated spe-
E
2
cies with Bu SnCl.
4
3
‡
aqueous work up, syn-configured homoaldol products 12
were obtained with 50 to 88% yield with essentially no loss
of enantiomeric purity (Table 3). The simple diastereoselec-
The difference of the free enthalpies ∆∆G at –78 °C of
the deprotonation transition states of (S)-5 and (R)-5 is not
sufficient to allow complete differentaion of the enantio-
mers by the chiral base nBuLi/9. Thus, (R)-10a was
achieved with 68% ee (36% yield) and (R)-5 with 54% ee
tivity was excellent (Ͼ98:2) in all TiCl -mediated homoal-
4
(53% yield). At –90 °C in n-pentane or toluene the conver-
sion is slower but more selective; up to 82% ee (18% yield)
were achieved for the allylstannane (R)-10a (entries 5 and
6). Lithiation of rac-5 for 21.5 h in toluene at –78 °C af-
forded the carbamate (R)-5 with a synthetically useful en-
richment of 99% ee and 28% yield (max. yield 50%, Entry
7).
Homoaldol Reactions with 5
Addition of acetone to the solution of rac-7·TMCDA re-
sulted in γ-addition product rac-11 in 58% yield besides
starting material (Scheme 5). Using benzaldehyde, rac-syn- (14), –78 °C, 10–20 min.
Scheme 6. TiCl
4
-mediated homoaldol reaction of allylstannane
, 1.3 equiv. RCHO
10a; reagents and conditions: (a) 1.3 equiv. TiCl
4
Table 3. Results of the homolaldol reactions.
Entry
Stannane 10a (% ee)[a] Aldehyde, R
Product 12
Configuration
% Yield[b,c]
% ee
% OY[d]
a]
1
2
3
4
5
6
7
(S)-10a (95)
(S)-10a (70)
(R)-10a (90)
(S)-10a (84)
(R)-10a (87)
(S)-10a (97)
(S)-10a (84)
14a, Ph
12a
[3R,3(1S)]
[3R,3(1S)]
[3S,3(1R)]
[3R,3(1S)]
[3S,3(1R)]
[3R,3(1R)]
[3R,3(1R)]
82 (88)
72 (77)
80 (82)
81 (74)
50 (60)
74 (86)
72 (70)
92[
97
Ͼ99
98
Ͼ99
98
99
14b, 2-naphthyl
14c, p-BrPh
14d, p-MeOPh
14e, 2-furyl
14f, Me
12b
70[
a]
[a]
ent-12c
12d
ent-12e
12f
12g
88
84[
85[
a]
a]
[e]
96
e,f]
14g, CH(CH
3
)
2
85[
Ͼ95
[
a] Enantiomeric excesses were determined by HPLC. [b] Isolated yields. Yields of the racemate strarting from rac-10a are given in
brackets. [c] dr Ͼ98:2 For all reactions as determined from the crude product by GC (HP-5). [d] OY: Optical yield, conservation of the
original enantio-enrichment of 10a. [e] Enantiomeric excesses were determined by GC. [f] +/–5% ee.
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3339

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
Figure 1. Solid state structure of [3S,3(1R)]-3-[1-(4-bromophenyl)-1-hydroxymethyl]cyclohex-1-enyl N,N-diisopropylcarbamate (ent-
[
12,13]
12c).
dol reactions which were investigated here. Product ent-12c,
formed from (R)-10a and p-bromobenzaldehyde 14c, gave
suitable crystals for an X-ray analysis with anomalous dis-
[
12,13]
persion (Figure 1).
It clearly shows the (3S)-configuration. Overall, Bu Sn
3
was substituted by the hydroxyalkyl residue with inversion
of the configuration. The stereochemical course is in
accordance with an exchange of Bu Sn for TiCl in an anti-
3
3
S Ј manner and a syn addition of the aldehyde via a
E
[14]
Zimmerman–Traxler transition state TS-15.
strong Lewis acidity of the trichlorotitanium complex, TS-
5 may be a tighter transition state as a result of the shorter
Due to the
1
O–Ti bond than in the Li-mediated carbonyl addition,
which results in a high syn-selectivity of products 12.
Scheme 7. Synthesis of cis,trans,cis-3-acyl-tetrahydrofurans 17.
occurred in a cis-fashion via the intermediate 21.[16] The
syn-configured homoaldol products lead to all-cis-substi-
tuted tetrahydrofurans 22. The (E)-oxonium ion in TS-21a
Synthesis of all-cis-Hexahydroisobenzofuran-4(1H)-ones
Several years ago, we reported that the condensation of
(Z)-anti-5-hydroxy-1-alkenylcarbamates 16 with aldehydes
takes place under the influence of boron trifluoride etherate
to form tetrahydrofurans 17 with high stereoselectivity
[
15]
(Scheme 7).
The Mukaiyama-type cyclocondensation
proceeds through an (E)-oxonium ion that adopts the most
preferential conformation 18. The highly ordered transition
state leads to the cis,trans,cis-substituted cation 19, which
affords the stereohomogeneous product 17 after hydrolytic
decarbamoylation.
The homoaldol products rac-12a–g and achiral aldehydes
18a–e were subjected to the standard conditions affording,
after aqueous work up, the all-cis-configured bicycles 22 in
good yields and with excellent diastereoselectivities
1
(
Scheme 8, Table 4). The H NMR coupling constants
Scheme 8. Synthesis of all-cis-hexahydroisobenzofuran-4(1H)-ones
22; reagents and conditions: (a) 1.3 equiv. BF ·OEt , 1.3 equiv.
3
J3a,7a of the products 22a–g are in the range of 7.2–9.7 Hz
3
2
confirming, that the annulation of the five-membered ring RЈCHO (20), CH
2 2 4 2
Cl , 0 °C Ǟ r.t., 15–330 min; (b) NH Cl/H O.
Table 4. Synthesis of annulated all-cis-tetrahydrofurans 22.
Entry
12
R
Aldehyde, RЈ
20a, p-BrPh
22[b]
% Yield[a]
dr[c]
1
2
rac-12b
ent-12c
2-naphthyl
p-BrPh
rac-22a
ent-22b
(89% ee)[
rac-22b
rac-22c
22d
(96% ee)
ent-22d
(75% ee)
rac-22e
71
84
Ͼ98:2
Ͼ98:2
20b, C(CH
3
)
3
d]
(
88% ee)
3
4
5
rac-12c
rac-12d
12f
p-BrPh
p-OCH
CH
20b, C(CH
20c, CH(CH
20d, furyl
3
)
3
)
3 2
73
67
68
Ͼ98:2
45:55
Ͼ98:2
3
Ph
3
(
96% ee)
ent-12f
76% ee)
rac-12g
6
CH
3
20d, furyl
20e, vinyl
72
Ͼ98:2
(
7
3 2
CH(CH )
84
Ͼ98:2
[
a] Isolated Yields. [b] Enantiomeric excesses were determined by HPLC. [c] The diastereomeric ratio was determined from the crude
product by GC. [d] Recrystrallisation from n-pentane afforded crystals of ent-22b with Ͼ99% ee (HPLC).
3340
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348

Asymmetric Homoaldol Reactions
FULL PAPER
avoids 1,3-allylic strain which results in preferential forma- diastereomer 22f was formed from the (3R)-enantiomer
tion of products 22 with 1,3-cis-configuration. 12b, whereas 22g was formed from the (3S)-configured car-
The enantio-enrichments of the isobenzofurans 22 are es- bamate ent-12b.
sentially equal to those of their corresponding homoaldol
products 12. The absolute configuration of ent-22b was de-
termined by an X-ray analysis with anomalous dispersion
[
12,17]
(Figure 2).
In general, a single diastereomer is formed,
with exception of the 4-methoxyphenyl-substituted homoal-
dol product 12d, which yielded a nearly 1:1 ratio of the
1,3a-cis- and 1,3a-trans-substituted hexahydroisobenzofu-
ran-4(1H)-ones 22c and epi-22c, respectively. The configu-
ration of epi-22c was deduced from the typical coupling
3
[16]
constant J
= 9.7 Hz, as well as an nOe effect of the
3
a,7a
3a-proton and the o-protons of the aromatic substituent at
C-1 (Figure 3). The electron-rich aromatic substituent
might cause a dehydroxylation of the homoaldol product
by the Lewis acid to form the highly stabilized benzylic cat-
ion 23. Next, the cation 23 adds unstereoselectively to the
aldehyde 20c, which leads to an epimeric configuration of
the stereogenic C-1 of epi-22c. This pathway is an exception Scheme 9. Reaction of the enantio-enriched homoaldol product
and was not observed in the other THF cyclocondensation 12b with (–)-myrtenal (20f).
reactions, where the configuration of the stereogenic sec-
ondary alcohol remained unchanged.
Figure 2. Solid state structure of (1R,3S,3aR,7aS)-1-(4-bro-
mophenyl)-3-tert-butyl-hexahydroisobenzofuran-4(1H)-one (ent-
Figure 4. Solid-state structures: [1S,3R,3(1R,5R),3aS,7aR]- and
[1R,3S,3(1R,5R),3aR,7aS]-3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-
[
12,17]
22b).
2
left)
-yl)-1-(naphthalen-2-yl)-hexahydroisobenzofuran-4(1H)-one (22f,
[12,18] [12,19]
and (22g, right).
Conclusions
The homoaldol reaction of metallated cyclohex-2-enyl
N,N-diisopropylcarbamate 10 with aldehydes leads to dia-
stereomerically pure 3-(1-hydroxyalkyl)cyclohex-1-enyl car-
bamates of type 12. Starting from enantio-enriched metallo-
carbamates, optically active addition products are formed.
These undergo smooth condensation with aldehydes
to form the hexahydroisobenzofuran-4(1H)ones 22,
Figure 3. nOe experiments with 22c and epi-22c.
When optically active homoaldol product 12b (70% ee, (Scheme 10) providing a facile, flexible, and stereoselective
er = 85:15) was allowed to react with enantiopure (–)-myrt-
enal (20f), two separable diastereomers 22f and 22g (ratio
88:12, determined by GC of the crude product) were iso-
lated (Scheme 9). Both compounds afforded suitable crys-
tals for an X-ray crystal structure analysis (Figure 4), which
shows that they have the opposite configuration at the ste-
reogenic 1, 3, 3a, and 7a carbon atoms.[
12,18,19]
The major Scheme 10.
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3341

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
access to an important class of compounds. In the subse- colourless liquid. t
R
= 11.34 min (HP-5). R
F 2
= 0.32 (Et O/PE =
1
1
:9). H NMR (300 MHz, CDCl
3
): δ = 1.19, 1.22 (2s, 12 H, iPr
quent paper we report on the enantioselective synthesis of
higher substituted hexahydroisobenzofuran-4(1H)-ones.
[
20]
3 2
(CH ) ), 1.57–2.16 (m, 6 H, 4-H, 5-H, 6-H), 3.91 (br. s, 2 H, iPr
CH), 5.22 (m, 1 H, 1-H), 5.78 (m, 1 H, 2-H), 5.88 (m, 1 H, 3-H)
1
3
ppm. C NMR (75 MHz, CDCl
iPr (CH ), 24.9 (CH , C-6), 28.8 (CH
7.9 (CH, C-1), 126.9 (CH, C-2), 131.4 (CH, C-3), 155.5 (C
ppm. IR (film): ν˜ = 2968 (s), 2935 (m), 2871 (s) [ν(Caliph–H)], 1682
3
): δ = 19.1 (CH
, C-4), 45.7 (CH, iPr CH),
, C=O)
2 3
, C-5), 21.1 (CH ,
3
)
2
2
2
Experimental Section
6
q
General Remarks: All solvents were dried and purified prior to use:
toluene and Et O were distilled from sodium benzophenone ketyl,
THF was distilled from potassium benzophenone ketyl and CH Cl
was distilled from powdered CaH . N,N,NЈ,NЈ-Tetramethylethyl-
enediamine (TMEDA) was distilled from powdered CaH and
–
1
+
(s) [ν(N–C=O)] cm . MS (ESI): m/z = 248.1600 [M + Na] .
(225.33): calcd. C 69.29, H 10.29, N 6.22; found
C 69.16, H 10.63, N 6.12.
2
13 2
C H23NO
2
2
2
2
(
R)-Cyclohex-2-enyl N,N-Diisopropylcarbamate ((R)-5): According
stored under Ar in the dark. rac-trans-1,2-Bis(dimethylamino)cy-
clohexane (TMCDA, rac-8)[ was stored under Ar at 4 °C. (–)-
Sparteine (9) was kept under Ar in a refrigerator after the original
bottles had been opened. Solutions of sec-butyllithium (ca. 1.3 
in cyclohexane/hexane, 92:8) were filtered through a pad of Celite
under Ar in order to remove any precipitate and were stored in a
freezer (–30 °C); only a slight yellow hue is acceptable. The content
of sBuLi was determined by titration.[22] n-Butyllithium (1.6  in
hexanes) and all other commercially available reagents were used
as received. All reactions were performed under Ar in flame dried
glassware sealed with a rubber septum. Flash column chromatog-
raphy (FCC) was performed on Merck 60 silica gel (40–60 µm,
to GP A NaH (1.09 g, 27.2 mmol, 1.2 equiv.), (R)-cyclohex-2-
enol ((R)-4, 96% ee, 2.23 g, 22.7 mmol) and 6 (5.21 g, 32 mmol,
21]
[6]
1
.4 equiv.) were refluxed in THF (68 mL) for 13 h. Purification by
FCC (Et O/PE = 1:9) yielded 4.63 g (20.6 mmol, 91%) (R)-5 as a
colourless liquid. [α]
2
20
D
3
= +147.3 (c = 1.07, CHCl ) at 96% ee;
HPLC Chiralcel OD-H (4.6ϫ250 mm), λ = 200 nm, iPrOH/n-hex-
ane = 1:2000, 0.5 mL/min, 24.57 min ((R)-5), 28.17 min ((S)-5).
(S)-Cyclohex-2-enyl N,N-Diisopropylcarbamate ((S)-5): According
to GP A NaH (302 mg, 7.56 mmol, 1.2 equiv.), (S)-cyclohex-2-
enol[ ((S)-4, 90% ee, 600 mg, 6.3 mmol) and 6 (1.45 g, 140 mmol,
1.4 equiv.) were refluxed in THF (18 mL) for 13 h. Purification by
7]
2
30–400 mesh ASTM), and monitored by thin-layer chromatog-
raphy (TLC) on Merck 60 F254 TLC plates. NMR: Bruker ARX
00 or ARX 400 (routine 2D spectra) and Varian Unity Plus 600
2
FCC (Et O/PE = 1:9) yielded 1.317 g (5.85 mmol, 93%) (S)-5 as a
2
0
D 3
colourless liquid. [α] = –135.4 (c = 1.03, CHCl ) at 90% ee; HPLC
3
Chiralcel OD-H.
1
(2D spectra). H shifts are related to SiMe
4
(δ
H
= 0.00 ppm) or to
Deprotonation of Cyclohex-2-enyl Carbamate 5 and Stannylation.
General Procedure B (GP B): A solution of cyclohex-2-enyl carba-
mate 5 (225 mg, 1.0 mmol), TMEDA (151 mg, 1.3 equiv.) [or
TMCDA rac-8 (221 mg, 1.3 equiv.) or (–)-sparteine (9, 305 mg,
13
the residual content of CHCl
3
(δ
H
= 7.24 ppm) and C shifts to
1
CDCl
abbreviated as s (singlet), d (doublet), t (triplet), sept (septet), oct
octet), m (multiplet), and br (broad). Diastereotopic methylene
protons with different chemical shifts are abbreviated as H and
. IR: Nicolet 5DCX, Bruker IFS 28 or Varian 3100 Excalibur
3 C
(δ = 77.0 ppm). Peak multiplicities in H NMR spectra are
(
2
1.3 equiv.)] in Et O (5 mL) was cooled to –78 °C. 1.23  sBuLi
A
solution (1.04 mL, 1.3 equiv.) [or 1.6  nBuLi solution (0.81 mL,
H
B
1
3
.3 equiv.)] were added dropwise and the solution was stirred for
0 min–6 h. Bu SnCl (650 mg, 2.0 equiv.) was then added dropwise
Series with Specac Golden Gate Single Reflection ATR. MS:
Bruker MicroTof (ESI). Optical rotation: Perkin–Elmer 341. Melt-
ing point: Stuart Scientific SMP3. Melting points are not corrected.
Elemental analysis: Elementar-Analysensysteme Vario EL III. GC:
3
by syringe and stirring at –78 °C was continued for 1–2 h. The reac-
tion was quenched at –78 °C with satd. aq. NH Cl solution (2 mL)
4
and the mixture was warmed to room temperature. The layers were
separated and the aqueous layer was extracted with TBME
Agilent 6890; 30 mϫ0.32 mm HP-5; 1.5 mL/min H
2
; start at 50 °C,
10 °C/min, end 300 °C, 15 min at 300 °C. HPLC: Waters 600E
(
3ϫ10 mL). The combined organic layers were dried with MgSO
4
,
Multisolvent Delivery System and 996 PDA detector or Knauer
Smartline UV detector 2600, Pump 1000 and Manager 5000 or
Agilent Technologies 1200 Series (Bin Pump, ALS, TCC, DAD).
filtered and the solvent was removed in vacuo. FCC on silica gel
2
(Et O/PE = 1:19) yielded the pure stannane 10.
(
(
S)-3-(Tributylstannyl)cyclohex-1-enyl N,N-Diisopropylcarbamate
(S)-10a): Representative procedure: According to GP B (R)-cy-
Carbamoylation of Cyclohex-2-enol. General Procedure A (GP A):
Sodium hydride (60% in mineral oil, 480 mg, 12 mmol, 1.2 equiv.)
was suspended in THF (20 mL) at 0 °C. A solution of cyclohex-2-
enol (4, 981 mg, 10 mmol) in THF (1 mL) was added to the stirred
clohex-2-enyl carbamate (R)-5 (96% ee, 113 mg, 0.5 mmol) and (–)-
sparteine (9, 152 mg, 0.65 mmol, 1.3 equiv.) were dissolved in Et
2.5 mL). The solution was cooled to –78 °C and 1.23  sBuLi
2
O
(
suspension by syringe and stirring was continued for 1 h at room
solution (0.52 mL, 0.65 mmol, 1.3 equiv.) was added dropwise over
a period of 5 min. The solution was stirred for additional 3 h.
temperature. N,N-Diisopropylcarbamoyl chloride[
23]
(6, 2.29 g,
14 mmol, 1.4 equiv.) was added over a period of 5 min and the
Bu
ring was continued for 1 h. The reaction was quenched with satd.
aq. NH Cl solution (1 mL) and worked up according to GP B.
FCC on silica gel (Et O/PE = 1:19) yielded 222 mg (0.43 mmol,
6%) (S)-10a (95% ee) as a colourless liquid. rac-10a was obtained
from rac-5 (225 mg, 1.0 mmol), after lithiation with TMCDA rac-8
221 mg, 1.3 mmol, 1.3 equiv.) and 1.6  nBuLi solution (0.81 mL,
3
SnCl (325 mg, 1.0 mmol, 2.0 equiv.) was then added and stir-
reaction mixture was heated to reflux (90 °C) for 11–13 h. After
complete consumption of the starting material (TLC) the solution
was cooled to room temperature and treated with aq. 2  HCl solu-
tion (25 mL). The aqueous layer was extracted with tert-butyl
methyl ether (TBME, 3ϫ20 mL). The combined organic layers
4
2
8
were washed with satd. aq. NaHCO
MgSO , and concentrated in vacuo. FCC on silica gel (Et
:9) yielded pure cyclohex-2-enyl N,N-diisopropylcarbamate (5).
3
solution (25 mL), dried with
(
4
2
O/PE =
1
2
.3 mmol, 1.3 equiv.), by stannylation with Bu
.0 mmol, 2.0 equiv.) as colourless liquid; yield 384 mg
= 20.24 min (HP-5). R = 0.33 (Et O/PE =
1:9). H NMR (400 MHz, CDCl ): δ = 0.89 (t, J1Ј,4Ј = 7.3 Hz, 9
H, 4Ј-H), 0.90 (m, 6 H, 1Ј-H), 1.22, 1.23 (2 br. s, 12 H, iPr
3
SnCl (650 mg,
1
a
rac-Cyclohex-2-enyl N,N-Diisopropylcarbamate (rac-5): According
(0.75 mmol, 75%). t
R
F
2
1
3
to GP A NaH (4.80 g, 120 mmol, 1.2 equiv.), racemic cyclohex-2-
3
[
5]
enol
.4 equiv.) were refluxed in THF (210 mL) for 11 h. Purification by
FCC (Et O/PE = 1:9) yielded 19.53 g (87 mmol, 87%) rac-5 as a
(rac-4, 9.82 g, 100 mmol) and 6 (22.90 g, 140 mmol,
3
3
1
(CH
3
)
2
), 1.32 (dt, J1Ј,4Ј = 7.3 Hz, J2Ј,3Ј = 7.2 Hz, 6 H, 3Ј-H), 1.48
/5-H), 1.98 (m, 1 H, 4-
2
(m, 6 H, 2Ј-H), 1.62–1.82 (m, 3 H, 4-H
A
3342
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348

Asymmetric Homoaldol Reactions
FULL PAPER
H
B
), 2.08 (m, 1 H, 6-H
A
), 2.21 (m, 1 H, 3-H), 2.33 (m, 1 H, 6-H
B
),
br. s, 12 H, iPr (CH
3
)
2
), 1.77 (m, 2 H, 5-H), 1.99–2.19 (m, 3 H, 6-
13
2
3.81, 4.00 (2 br. s, 2 H, iPr CH), 5.44 (m, 1 H, 2-H) ppm. C NMR H/4-H
A
), 2.35 (m, 1 H, 4-H
B
), 2.96 (m, J3,Sn = 80.7 Hz, 1 H, 3-
1
(
(
100 MHz, CDCl
CH , C-4Ј), 21.1 (CH
, C-6), 27.3 (CH
, C-3Ј), 46.2 (CH, iPr CH), 117.6 (CH, C-2), 144.3 (C
54.3 (C , C=O) ppm. IR (ATR): ν˜ = 2957 (m), 2926 (s), 2873 (w)
852 (w) (ν(Caliph–H), 1707 (s) [ν(N–C=O)] cm . MS (ESI): m/z = 47.9 Hz, m-Ph), 128.8 (CH, Jp-Ph,Sn = 10.9 Hz, p-Ph), 137.3 (CH,
3
): δ = 9.1 ( J1Ј,Sn = 295.4 Hz, C-1Ј, CH
, iPr (CH ), 23.2 (CH, C-3), 23.5 (CH
, C-4), 27.5 (CH , C-2Ј), 29.2 NMR (100 MHz, CDCl
, C-1), C-5), 26.0 (CH , C-6), 26.4 (CH, C-3), 27.2 (CH
iPr CH), 116.2 (CH, J2,Sn = 41.7 Hz, C-2), 128.5 (CH, Jm-Ph,Sn
2
), 13.6 H), 3.77, 4.05 (2 br. s, 2 H, iPr CH), 5.69 (m, 1 H, 2-H), 7.37 (m,
1
3
2
3
3
)
2
2
,
4 H, m-PhCH, p-PhCH), 7.52–7.64 (m, 1 H, o-PhCH) ppm.
): δ = 21.1 (CH , iPr (CH ), 23.3 (CH
, C-4), 46.1(CH,
C
C-5), 26.2 (CH
CH
2
2
2
3
3
3
)
2
2
,
(
2
q
2
2
2
3
1
2
5
9
q
=
–1
4
+
2
1
38.2684 [M + Na] . C25
.60, N 2.72 found C 58.28, H 9.92, N 2.59. [α]
) at 95% ee HPLC Chira Grom 1 (2ϫ250 mm), λ = 210 nm,
iPrOH/n-hexane 1:2000, 0.3 mL/min, 6.55 min ((S)-10a),
5.13 min ((R)-10a).
H49NO
2
Sn (514.37): calcd. C 58.38, H
Jo-Ph,Sn = 33.9 Hz, o-Ph), 138.7 (C
q
,
Ji-C-Ph,Sn = 464.8 Hz,
20
D
= –55.9 (c = 1.00,
444.0 Hz, i-C-Ph), 146.1 (C , C-1), 146.1 (C , C=O) ppm. (IR
q
q
CHCl
3
(film): ν˜ = 3063 (m), 3048 (m), 3042 (m) [ν(Carom–H)], 2992 (m),
2969 (m), 2943 (m), 2928 (m) [ν(Caliph–H)], 1707 (s) [ν(N–C=O)]
=
–
1
+
1
cm . MS (ESI): m/z = 598.1743 [M + Na] . C31
H37NO
2
Sn
(
574.34): calcd. C 64.83, H 6.49, N 2.44; found C 64.71, H 6.54, N
.50. [α] = –34.1 (c = 1.05, CHCl ) at 90% ee; HPLC Chira Grom
D 3
(2ϫ250 mm), λ = 210 nm, iPrOH/n-hexane = 1:500, 0.3 mL/min,
.00 min ((R)-10b), 7.22 min ((S)-10b).
Kinetic Resolution of rac-Cyclohex-2-enyl N,N-Diisopropylcarba-
mate (rac-5): Representative procedure I (Table 2, Entry 7): rac-
cyclohex-2-enyl carbamate rac-5 (4.50 g, 20.0 mmol) and (–)-spar-
teine (9, 4.68 g, 20.0 mmol, 1.0 equiv.) were dissolved in toluene
20
2
1
5
rac-3-(1-Hydroxy-1-methylethyl)cyclohex-1-enyl N,N-Diisopropyl-
carbamate (rac-11): rac-Cyclohex-2-enyl carbamate rac-5 (225 mg,
1
(
1
(
50 mL) in a Schlenk tube, equipped with a rubber septum, and
the solution was cooled to –78 °C. 1.6  nBuLi solution (12.5 mL,
0.0 mmol) was added dropwise over a period of 20 min. The tube
was sealed with a glass stopper and the solution was stirred for
1 h 30 min at –78 °C. Bu SnCl (8.4 g, 26.0 mmol, 1.3 equiv.) was
.0 mmol) was lithiated according to GP B with TMCDA rac-8
226 mg, 1.30 mmol, 1.3 equiv.) and 1.6  nBuLi solution (0.81 mL,
.3 mmol, 1.3 equiv.) in Et O (5 mL) at –78 °C. The solution was
2
2
3
2
stirred for additional 5 h. Acetone (174 mg, 3.0 mmol, 3.0 equiv.)
was added and stirring was continued for 1 h. The reaction was
added over a period of 10 min and the solution was stirred for
additional 50 min. The reaction was quenched with satd. aq.
quenched with satd. aq. NH
ing to GP B and FCC on silica gel (Et
0.58 mmol, 58%) rac-11 as a colourless oil. t
4
Cl solution (4 mL). Work up accord-
O/PE = 1:2) yielded 165 mg
= 14.52 min (HP-
5). RF = 0.30 (Et O/PE = 1:1). H NMR (300 MHz, CDCl ): δ =
NH
4
Cl solution (20 mL) and worked up according to GP B. FCC
O/PE 1:19, then 1:10) yielded 5.935 g
11.53 mmol, 58%) (R)-10a with 35% ee (HPLC) and 1.278 g
on silica gel (Et
(
2
=
2
(
R
1
2
0
(5.67 mmol, 28%) (R)-5 with 99% ee (HPLC). (R)-10a: [α]
D
=
2
3
+
CHCl
24.3 (c = 1.11, CHCl
) at 99% ee.
3
) at 35% ee; (R)-5: [α]2
D
0
= +150.3 (c = 1.00,
3 3 3 2
1.19 (s, 3 H, 2Ј-CH ), 1.22, 1.25 (br. s, 2Ј-CH , iPr (CH ) , 15 H,
br. s), 1.58–1.91 (m, 4 H, 4-H/5-H), 2.06, 2.14 (2 m, 2 H, 6-H),
.33 (m, 1 H, 3-H), 3.91 (br. s, 2 H, iPr CH), 5.44 (s, 1 H, 2-H)
3
2
Representative procedure II (Table 2, Entry 6): To a solution of
–)-sparteine (9, 468 mg, 2.0 mmol, 1.0 equiv.) in n-pentane (10 mL)
13
ppm. C NMR (75 MHz, CDCl
3
): δ = 20.9 (CH
, C-2Ј), 26.2, 27.3, 28.1 (CH
/C-6), 46.2 (CH, iPr CH), 46.4 (CH, C-3), 72.7 (C , C-OH), 113.9
, C-1), 153.8 (C , C=O) ppm. IR (film): ν˜ =
970 (s), 2936 (m), 2866 (s) [ν(Caliph–H)], 1690 (s) [ν(N–C=O)]
3
, iPr (CH
3 2
) ),
(
2
5
2.2 (CH
3
, C-2Ј), 23.8 (CH
3
2
, C-4/C-
at –90 °C was added 1.6  nBuLi solution (1.25 mL, 2.0 mmol).
rac-Cyclohex-2-enyl carbamate rac-5 (450 mg, 2.0 mmol) was
added dropwise over a period of 20 min and the solution was
q
(
CH, C-2), 150.5 (C
q
q
2
stirred for 8 h at –90 °C. Bu
3
SnCl (1.3 g, 4.0 mmol, 2.0 equiv.) was
–1
+
cm . MS (ESI): m/z = 306.2049 [M + Na] . C16
3
H29NO (283.41):
added over a period of 10 min and the solution was stirred for
additional 60 min and worked up as described in Representative
procedure I. Yield 185 mg (0.36 mmol, 18%) (R)-10a with 82% ee
calcd. C 67.81, H 10.31, N 4.94; found C 67.57, H 10.43, N 4.71.
[3RS,3(1SR)]- and [3RS,3(1RS)]-3-[(1-Hydroxyphenyl)methyl]cy-
clohex-1-enyl N,N-Diisopropylcarbamate (rac-syn-12a and rac-anti-
12a): rac-Cyclohex-2-enyl carbamate rac-5 (450 mg, 2.00 mmol)
was lithiated according to GP B with TMCDA rac-8 (452 mg,
(
1
HPLC) and 242 mg (1.08 mmol, 54%) (R)-5 with 23% op. (R)-
0a: [α]2
0
20
D
3 D
= +53.0 (c = 1.00, CHCl ) at 82% ee; (R)-5: [α] = +34.4
(c = 0.99, CHCl
3
) (23% op).
2.60 mmol, 1.3 equiv.) and 1.6  nBuLi solution (0.81 mL,
(
(
S)-3-(Triphenylstannyl)cyclohex-1-enyl N,N-Diisopropylcarbamate
(S)-10b): According to GP B, (R)-cyclohex-2-enyl carbamate (R)-
2.60 mmol, 1.3 equiv.) in Et O (5 mL) at –78 °C for 4 h. Benzalde-
hyde (14a, 636 mg, 6.0 mmol, 3.0 equiv.) was then added and stir-
2
5
(99% ee, 113 mg, 0.5 mmol) and (–)-sparteine (9, 152 mg,
ring was continued for 3 h. The reaction was quenched with satd.
0
.65 mmol, 1.3 equiv.) were dissolved in toluene (3 mL). To the
aq. NH
on silica gel (Et
4
Cl solution (8 mL). Work up according to GP B and FCC
O/PE = 1:1) yielded 386 mg (1.17 mmol, 58%) of
cooled solution (–78 °C) 1.23  sBuLi solution (0.52 mL,
.65 mmol, 1.3 equiv.) was added dropwise over a period of 5 min.
The solution was stirred for additional 1 h. Ph SnCl (385 mg,
.0 mmol, 2.0 equiv.), dissolved in toluene (5 mL), was added and
stirring was continued for 1 h. The reaction was quenched with
satd. aq. NH Cl solution (3 mL). Work up according to GP B and
FCC on silica gel (Et O/PE = 1:6) yielded 210 mg (0.37 mmol,
3%) (S)-10b with 90% ee as a colourless oil. The racemate crys-
2
0
an inseparable mixture of rac-syn-12a/rac-anti-12a = 86:14 as a
colourless solid. rac-syn-12a: see above. rac-anti-12a: M.p. 93–95 °C
3
1
(Et
(HP-5). R
3 2
δ = 1.21 (br. s, 12 H, iPr (CH )
2
O/PE for rac-syn-12a/rac-anti-12a = 86:14). t
R
= 18.81 min
O/PE = 1:1). H NMR (400 MHz, CDCl ):
), 1.42–1.66 (m, 2 H, 4-H), 1.88
1
F
= 0.33 (Et
2
3
4
2
(m, 1 H, 5-H
(m, 1 H, 5-H
A
), 2.08–2.21 (m, 2 H, 6-H), 2.33 (m, 1 H, 3-H), 2.65
), 3.80, 3.96 (2 br. s, 2 H, iPr CH), 4.47 (d, J3,CH-O
3
7
B
tallized from a solution of the product in n-pentane, whereas the
enantio-enriched product remained as an oil.[ rac-10b was ob-
tained from rac-5 (113 mg, 0.5 mmol) after lithiation with TMCDA
= 6.9 Hz, 1 H, CH-O), 5.52 (s, 1 H, 2-H), 7.26 (m, 1 H, p-PhCH),
24]
13
7.34 (m, 4 H, o-/m-PhCH) ppm. C NMR (100 MHz, CDCl
= 20.6 (CH , iPr (CH ), 21.6, 25.7, 27.4 (CH , C-4/C-5/C-6), 42.6
(CH, C-3), 46.2 (CH, iPr CH), 76.8 (C , C-OH), 113.5 (CH, C-2),
126.3, 127.2, 128.1 (CH, o-/m-/p-Ph), 143.6 (C , i-C-Ph), 150.6 (C
C-1), 153.8 (C , C=O) ppm. IR (KBr): ν˜ = 3426 (s) [ν(O–H)], 2971
(m), 2938 (m), 2873 (s) [ν(Caliph–H)], 1683 (s) [ν(N–C=O)] cm .
3
): δ
3
3
)
2
2
(
(
(
rac-8, 111 mg, 0.65 mmol, 1.3 equiv.) and 1.6  nBuLi solution
0.41 mL, 0.65 mmol, 1.3 equiv.) by stannylation with Ph SnCl
385 mg, 1.0 mmol, 2.0 equiv.), yield 193 mg (0.24 mmol, 67%).
= 25.36 min (HP-5). R = 0.37
O/PE = 1:9). H NMR (400 MHz, CDCl ): δ = 1.22, 1.24 (2
q
3
q
q
,
q
–
1
M.p. 100 °C (PE for rac-10b). t
R
F
1
+
(Et
2
3
MS (ESI): m/z = 354.2044 [M + Na] . C20
H29NO
3
(331.45, mixture
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
3343

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
of diastereomers): calcd. C 72.47, H 8.82, N 4.23; found C 72.47,
H 8.86, N 4.13.
(C
ppm. IR (ATR): ν˜ = 3421 (m) [ν(O–H)], 3053 (w) [ν(Carom–H)],
973 (m), 2949 (m), 2869 (w) [ν(Caliph–H)], 1669 (s) [ν(N–C=O)]
q q q q
, C-Ar), 140.4 (C , i-C-Ar), 151.1 (C , C-1): 153.8 (C , C=O)
2
Synthesis of syn-Homoaldol Products 12. General Procedure C (GP
C): To a stirred solution of 3-(tributylstannyl)cyclohex-1-enyl N,N-
diisopropylcarbamate (10a, 514 mg, 1.0 mmol) and the aldehyde 14
–1
+
cm . MS (ESI): m/z = 404.2193 [M + Na] . C24
3
H31NO (381.51):
calcd. C 75.56, H 8.19, N 3.67; found C 75.51, H 8.09, N 3.54.
20
[α]
D
= –23.8 (c = 1.01, CHCl
3
) at 70% ee; HPLC Chira Grom 2
(
1
1.3 equiv.) in CH
2
Cl
.3 equiv.) was added dropwise by syringe. After complete con-
Cl solution (2 mL) was added
and the reaction mixture was warmed to room temperature.
CH Cl (5 mL) was added, the aqueous layer was extracted with
TBME (3ϫ10 mL) and dried with MgSO . After removal of the
solvent in vacuo, the residue was purified by flash column
2
(4 mL) at –78 °C, TiCl
4
(247 mg,
(
2ϫ250 mm), λ = 227 nm, iPrOH: n-hexane = 1:80, 0.3 mL/min,
[
25]
22.15 min (12b), 24.93 min (ent-12b).
sumption of 10a (TLC) satd. aq. NH
4
[
3S,3(1R)]-3-(1-(4-Bromophenyl)-1-hydroxymethyl)cyclohex-1-enyl
N,N-Diisopropylcarbamate (ent-12c): According to GP C (R)-10a
90% ee, 195 mg, 0.38 mmol), 4-bromobenzaldehyde (14c, 91 mg,
.49 mmol, 1.3 equiv.), and TiCl (93 mg, 0.49 mmol, 1.3 equiv.)
were stirred in CH Cl (2 mL) for 15 min at –78 °C. Purification
by FCC (Et O/PE = 2:1) yielded 124 mg (0.30 mmol, 80%) ent-12c
as a colourless solid. rac-12c was obtained from rac-10a (1.058 g,
2
2
4
(
0
4
[
26]
chromatography
2
on silica gel (Et O/PE mixtures) to yield the
2
2
homoaldol products 12.
2
[3R,3(1S)]-3-(1-Hydroxyphenylmethyl)cyclohex-1-enyl N,N-Diiso-
2
2
.0 mmol), TiCl
.6 mmol, 1.3 equiv.) as a colourless solid; yield 674 mg
O/PE for rac-12c), m.p. 102–
O/PE for ent-12c at 88% ee). t = 20.04 min (HP-5),
O/PE = 3:2). H NMR (300 MHz, CDCl ): δ = 1.20,
.23 (2 br. s, 12 H, iPr (CH ), 1.43–1.66 (m, 3 H, 4-H/5-H ), 1.85
m, 1 H, 5-H ), 2.04–2.23 (m, 2 H, 6-H), 2.53 (br. s, 1 H, OH),
4
(543 mg, 2.6 mmol, 1.3 equiv.), and 14c (461 mg,
propylcarbamate (12a): According to GP C (S)-10a (95% ee,
1
1
CH
38 mg, 0.27 mmol), benzaldehyde (14a, 37 mg, 0.35 mmol,
.3 equiv.), and TiCl (67 mg, 0.35 mmol, 1.3 equiv.) were stirred in
Cl (2 mL) for 15 min at –78 °C. Purification by FCC (Et O/
PE = 1:1) yielded 73 mg (0.22 mmol, 82%) 12a as a colourless so-
lid. rac-12a was obtained from rac-10a (514 mg, 1.0 mmol), TiCl
(
0.82 mmol, 82%). M.p. 95 °C (Et
2
4
104 °C (Et
2
R
2
2
2
1
R
1
(
F
= 0.32 (Et
2
3
3
)
2
A
4
B
(209 mg, 1.1 mmol, 1.1 equiv.), and 14a (117 mg, 1.1 mmol,
3
2.63 (m, 1 H, 3-H), 3.89 (br. s, 2 H, iPr CH), 4.59 (d, J3,CH–O
=
1
.1 equiv.) as a colourless solid; yield 293 mg (0.88 mmol, 88%).
O/PE for rac-12a), m.p. 87 °C (Et O/PE for 12a at
= 18.52 min (HP-5). R = 0.33 (Et O/PE = 1:1). H
NMR (400 MHz, CDCl ): δ = 1.19, 1.22 (2 br. s, 12 H, iPr
), 1.53–1.66 (m, 2 H, 4-H), 1.86 (m, 1 H, 5-H ), 2.08–2.21
m, 2 H, 6-H), 2.53 (dd, J3,CH–O = 5.9 Hz, J = 2.7 Hz, 1 H, 3-H),
.67 (m, 1 H, 5-H ), 3.80, 3.96 (2 br. s, 2 H, iPr CH), 4.61 (d,
3,CH–O = 5.9 Hz, 1 H, CH-O), 5.10 (s, 1 H, 2-H), 7.26 (m, 1 H,
5
.9 Hz, 1 H, CH-O), 5.10 (s, 1 H, 2-H), 7.24 (d, J = 8.6 Hz, 2 H,
M.p. 100 °C (Et
2% ee). t
2
2
1
3
1
Ar-H), 7.45 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. C NMR (75 MHz,
CDCl ): δ = 20.9 (CH , iPr (CH ), 21.2 (CH , C-5), 22.6 (CH
C-4), 27.5 (CH , C-6), 42.6 (CH, C-3), 46.2 (CH, iPr CH), 76.1
(CH, C-OH), 114.4 (CH, C-2), 120.9 (C , C-Ar), 128.2, 131.2 (CH,
C-Ar), 141.8 (C , i-C-Ar), 151.3 (C , C-1), 153.7 (C , C=O) ppm.
IR (ATR): ν˜ = 3450 (s) [ν(O–H)], 2969 (m), 2935 (m), 2870 (w)
9
R
F
2
3
3
3
)
2
2
2
,
3
2
(CH
3
)
2
A
3
q
(
q
q
q
2
B
3
J
–
1
13
[ν(Caliph–H)], 1688 (s) [ν(N–C=O)] cm . MS (ESI): m/z = 432.1146
p-PhCH), 7.34 (m, 4 H, o-/m-PhCH) ppm. C NMR (100 MHz,
CDCl ): δ = 21.1 (CH , iPr (CH ), 21.4, 23.1, 27.6 (CH , C-4/C-
/C-6), 42.8 (CH, C-3), 46.4 (CH, iPr CH), 77.5 (CH, C-OH), 114.8
CH, C-2), 126.6, 127.4, 128.3 (CH, o-/m-/p-Ph), 142.9 (C , i-C-
Ph), 151.2 (C , C-1), 153.9 (C , C=O) ppm. IR (ATR): ν˜ = 3426
s) [ν(O–H)], 2971 (m), 2938 (m), 2873 (s) [ν(Caliph–H)], 1683 (s)
+
[
M + Na] . C20
found C 58.43, H 6.92, N 3.39. [α]
8% ee; HPLC Chira Grom 2 (2ϫ250 mm), λ = 223 nm, iPrOH: n-
3
H28BrNO (410.35): calcd. C 58.54, H 6.88, N 3.41;
3
3
3
)
2
2
2
0
D
3
= +23.7 (c = 1.12, CHCl ) at
5
(
8
q
hexane = 1:100, 0.3 mL/min, 14.73 min (ent-12c), 18.10 min (12c).
q
q
(
–1
+
[3R,3(1S)]-3-[1-Hydroxy-1-(4-methoxyphenyl)methyl]cyclohex-1-
enyl N,N-Diisopropylcarbamate (12d): According to GP C (S)-10a
(84 % ee, 1.058 g, 2.00 mmol), 4-methoxybenzaldehyde (14d,
[ν(N–C=O)] cm . MS (ESI): m/z = 354.2041 [M + Na] .
20 3
C H29NO
(331.45): calcd. C 72.47, H 8.82, N 4.23; found
20
D 3
C 72.37, H 8.79, N 4.12. [α] = –20.5 (c = 1.01, CHCl ) at 92%
3
54 mg, 2.60 mmol, 1.3 equiv.), and TiCl
.3 equiv.) were stirred in CH Cl (8 mL) for 10 min at –78 °C. Pu-
O/PE = 3:1) yielded 585 mg (1.62 mmol,
81%) 12d as a colourless solid. rac-12d was obtained from rac-10a
(1.058 g, 2.0 mmol), TiCl (543 mg, 2.6 mmol, 1.3 equiv.), and 14d
(354 mg, 2.6 mmol, 1.3 equiv.) as a colourless solid; yield 536 mg
(1.48 mmol, 74%). M.p. 95 °C (Et O/PE for rac-12d), m.p. 100–
102 °C (Et O/PE for 12d at 84% ee). t = 20.75 min (HP-5). R
PE = 3:2) yielded 136 mg (0.36 mmol, 72%) 12b as a colourless 0.29 (Et O/PE = 2:1). H NMR (300 MHz, CDCl ): δ = 1.21, 1.22
solid. rac-12b was obtained from rac-12a (514 mg, 1.0 mmol), TiCl (2 br. s, 12 H, iPr (CH ), 1.51 (m, 1 H, 4-H ), 1.57–1.67 (m, 2
209 mg, 1.1 mmol, 1.1 equiv.), and 14b (172 mg, 1.1 mmol, H, 5-H), 1.86 (m, 1 H, 4-H ), 2.05–2.25 (m, 3 H, 6-H/OH), 2.67
(m, 1 H, 3-H), 3.81 (br. s and s, 4 H, iPr CH, Ar-OCH ), 3.97 (br.
4
(543 mg, 2.60 mmol,
ee; HPLC Chira Grom 2 (2ϫ250 mm), λ = 210 nm, iPrOH/n-hex-
ane = 1:80, 0.3 mL/min, 9.21 min (ent-12a), 13.63 min (12a).
1
2
2
rification by FCC (Et
2
[
3R,3(1S)]-3-[1-Hydroxy-1-(naphthalen-2-yl)methyl]cyclohex-1-enyl
N,N-Diisopropylcarbamate (12b): According to GP C (S)-10a (70%
ee, 257 mg, 0.5 mmol), 2-naphthaldehyde (14b, 101 mg, 0.65 mmol,
4
1
.3 equiv.), and TiCl
4
(123 mg, 0.65 mmol, 1.3 equiv.) were stirred
O/
2
in CH Cl (2 mL) for 15 min at –78 °C. Purification by FCC (Et
2
2
2
2
R
F
=
1
2
3
4
3
)
2
A
(
B
1
.1 equiv.) as a colourless solid; yield 295 mg (0.77 mmol, 77%).
O/PE for rac-12b), m.p. 131–132 °C (Et O/PE for
= 22.56 min (HP-5). R = 0.37 (Et O/PE = 3:2).
H NMR (400 MHz, CDCl
CH ), 1.54–1.68 (m, 3 H, 4-H/5-H
br. d, J6-HA,6–HB = 16.7 Hz, 1 H, 6-H
16.7 Hz, 1 H, 6-H ), 2.77 (m, 1 H, 3-H), 2.98 (br. s, 1 H, OH), O-CH
.77, 3.92 (2 br. s, 2 H, iPr CH), 4.76 (d, J3,CH–O = 6.3 Hz, 1 H,
CH-O), 5.13 (s, 1 H, 2-H), 7.46 (m, 3 H, Ar-H), 7.80 (m, 4 H, Ar-
H) ppm. 13C NMR (100 MHz, CDCl
): δ = 20.7 (CH , iPr (CH ), [ν(O–H)], 2962 (m), 2937 (m), 2929 (m), 2857 (m), [ν(Caliph–H)],
, C-4), 27.6 (CH , C-6), 42.6 (CH, C- 1692 (s) [ν(N–C=O)] cm . MS (ESI): m/z = 384.2140 [M + Na] .
3
3
M.p. 145 °C (Et
2b at 70% ee). t
2
2
s, 1 H, iPr CH), 4.60 (d, J3,CH–O = 6.0 Hz, 1 H, CH-O), 5.12 (s, 1
1
R
F
2
H, 2-H), 6.79 (d, J = 8.4 Hz, 1 H, Ar-H), 6.93 (d, J = 8.4 Hz, 2 H,
1
13
3
): δ = 1.17, 1.19 (2 br. s, 12 H, iPr Ar-H), 7.23 (d, J = 8.4 Hz, 1 H, Ar-H) ppm. C NMR (75 MHz,
(
(
=
3
)
2
A
), 1.85 (m, 1 H, 5-H
B
), 2.08 CDCl
), 2.19 (br. d, J6-HA,6–HB 4), 27.5 (CH
), 76.7 (CH, C-OH), 111.8, 113.0 (CH, C-Ar), 114.7 (CH,
C-2), 118.8, 129.1 (CH, C-Ar), 144.4 (C , i-C-Ar), 151.0 (C , C-1),
153.7 (C , C=O), 159.6 (C , C-Ar) ppm. IR (ATR): ν˜ = 3431 (m)
3 3 3 2 2 2
): δ = 20.8 (CH , iPr (CH ) ), 21.3 (CH , C-5), 22.9 (CH , C-
2
2
A
2
, C-6), 42.6 (CH, C-3), 46.2 (CH, iPr CH), 55.2 (CH
3
,
B
3
3
3
q
q
q
q
3
3
3 2
)
–
1
+
2
3
1
1.4 (CH
2
, C-5), 23.1 (CH
2
2
), 46.3 (CH, iPr CH), 77.5 (CH, C-OH), 114.8 (CH, C-2), 124.8,
25.4, 125.6, 126.0, 127.7, 127.9, 128.1 (CH, C-Ar), 133.0, 133.3
21 4
C H31NO (361.48): calcd. C 69.78, H 8.64, N 3.87; found C
2
0
69.45, H 8.60, N 3.73. [α]
D 3
= –15.0 (c = 1.02, CHCl ) at 84% ee;
3344
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348

Asymmetric Homoaldol Reactions
FULL PAPER
HPLC Chira Grom 2 (2ϫ250 mm), λ = 226 nm, iPrOH/n-hexane
M.p. 61 °C (Et
(Et O/PE = 1:1). H NMR (300 MHz, CDCl
Ј-H, 3
CH
2
O for rac-12g). t
R
= 15.17 min (HP-5). R
): δ = 0.87, 0.94 (d,
2Ј-H,3Ј–H = 6.8 Hz, 6 H, d), 1.18, 1.21 (2 br. s, 12 H, iPr
F
= 0.30
1
=
1:80, 0.3 mL/min, 16.94 min (ent-12d), 23.35 min (12d).
2
3
3
J
[
3S,3(1R)]-3-[1-(Furan-2-yl)-1-hydroxymethyl]cyclohex-1-enyl N,N-
3
(
3
)
2
), 1.49–1.65 (m, 3 H, 4-H/5-H
A
), 1.76 (oct, J2Ј,3Ј = 6.8 Hz,
Diisopropylcarbamate (ent-12e): According to GP C (R)-10a
87% ee, 676 mg, 1.30 mmol), furan-2-carbaldehyde (14e, 162 mg,
.69 mmol, 1.3 equiv.), and TiCl (320 mg, 1.69 mmol, 1.3 equiv.)
were stirred in CH Cl (5 mL) for 15 min at –78 °C. Purification
by FCC (Et O/PE = 2:1) yielded 207 mg (0.65 mmol, 50%) ent-12e
as a colourless liquid. rac-12e was obtained from rac-10a (1.058 g,
3
J2Ј,CH–O = 6.8 Hz, 1 H, 2Ј-H), 1.87 (m, 1 H, 5-H ), 1.93 (br. s, 1
B
(
H, OH), 2.10 (m, 2 H, 6-H), 2.47 (m, 1 H, 3-H), 3.16 (dd,
1
4
3
3
J
2Ј,CH–O = 6.8 Hz, J3,CH–O = 5.1 Hz, 1 H, CH-O), 3.87 (br. s, 2
2
2
13
H, iPr CH), 5.15 (s, 1 H, 2-H) ppm. C NMR (75 MHz, CDCl
3
):
, C-
, C-6), 30.0 (CH, C-2Ј), 38.1 (CH,
C-3), 46.2 (CH, iPr CH), 79.2 (CH, C-OH), 115.4 (CH, C-2), 150.9
, C-1), 153.8 (C , C=O) ppm. IR (film): ν˜ = 3468 (w) [ν(O–H)],
965 (m), 2935 (m), 2872 (w) [ν(Caliph–H)], 1693 (s) [ν(N–C=O)]
2
δ = 17.9, 19.4 (CH
3 3 3 2 2
, C-3Ј), 21.0 (CH , iPr (CH ) ), 21.4 (CH
), 21.7 (CH , C-4), 27.5 (CH
5
2
2
2
2
.0 mmol), TiCl
.6 mmol, 1.3 equiv.) as a colourless liquid; yield 388 mg
= 16.95 min (HP-5), R = 0.18 (Et O/PE =
:2). H NMR (400 MHz, CDCl ): δ = 1.17, 1.19 (2 br. s, 12 H,
), 1.44 (m, 1 H, 4-H ), 1.62 (m, 1 H, 5-H ), 1.73–1.86
m, 2 H, 4-H /5-H ), 2.07–2.20 (m, 2 H, 6-H), 2.63 (m, 1 H, 3-H),
.77, 3.95 (2 br. s, 2 H, iPr CH), 4.55 (d, J3,CH–O = 7.1 Hz, 1 H,
4
(543 mg, 2.6 mmol, 1.3 equiv.), and 14e (250 mg,
(
C
q
q
(1.21 mmol, 60%). t
R
F
2
2
1
3
3
–1
+
cm . MS (ESI): m/z = 320.2193 [M + Na] . C17
3
H31NO (297.43):
iPr (CH
(
3
3
)
2
A
A
calcd. C 68.65, H 10.51, N 4.71; found C 68.36, H 10.34, N 4.62.
B
B
20
α]
D 3
[ = –10.7 (c = 1.09, CHCl ) at 85 (+/–5)% ee. GC DEX β-120,
3
120 °C isotherm, 1090 min (12g), 1109 min (ent-12g).
CH-O), 5.07 (s, 1 H, 2-H), 6.27 (d, J = 3.3 Hz, 1 H, Ar-H), 6.30
(
dd, J = 3.3 Hz, J = 1.8 Hz, 1 H, Ar-H), 7.33 (dd, J = 1.8 Hz, J =
Synthesis of Hexahydroisobenzofuran-4(1H)-ones 22. General Pro-
13
0
.9 Hz, 2 H, Ar-H) ppm. C NMR (75 MHz, CDCl
, iPr (CH ), 21.2 (CH , C-5), 23.6 (CH
C-6), 40.3 (CH, C-3), 46.1 (CH, iPr CH), 71.0 (CH, C-OH), 106.8,
10.1 (CH, C-Ar), 113.8 (CH, C-2), 141.6 (Cq, i-C-Ar), 150.8 (C
C-1), 153.7 (C , C=O), 155.4 (C , C-Ar) ppm. IR (film): ν˜ = 3422 temperature and stirring was continued until complete consump-
w) [ν(O–H)], 2969 (m), 2934 (m), 2871 (w) [ν(Caliph–H)], 1695 (s) tion of the starting material (TLC). The reaction was quenched
3
): δ = 20.9 cedure D (GP D): To a stirred solution of the homoaldol product
(CH
3
3
)
2
2
2
, C-4), 27.4 (CH
2
,
12 (0.5 mmol) and aldehyde 20 (0.65 mmol, 1.3 equiv.) in CH
(2 mL) at 0 °C, BF ·OEt (92 mg, 0.65 mmol, 1.3 equiv.) was added
through a syringe within 1 min. The solution was warmed to room
2 2
Cl
3
2
1
q
,
q
q
(
[
ν(N–C=O)] cm–1. MS (ESI): m/z = 344.1835 [M + Na] . with satd. aq. NaCl solution (3 mL), diluted with CH
+
2
2
Cl (5 mL)
C
18
H
27NO
4
(321.41): calcd. C 67.26, H 8.47, N 4.36; found C
and the aqueous layer was extracted with TBME (3ϫ10 mL). The
combined organic layers were washed with satd. NaHCO solution
3
20
6
7.33, H 8.77, N 4.14. [α]
HPLC Chira Grom 2 (2ϫ250 mm), λ = 210 nm, iPrOH/n-hexane
1:80, 0.3 mL/min, 9.71 min (ent-12e), 11.51 min (12e).
D
= +1.9 (c = 1.02, CHCl
3
) at 85% ee;
(5 mL), dried with MgSO
product was purified by FCC on silica gel (Et
4
and concentrated in vacuo. The crude
O/PE mixtures).
=
2
[
3R,3(1R)]-3-(1-Hydroxyethyl)cyclohex-1-enyl N,N-Diisopropyl- (1SR,3RS,3aSR,7aRS)-3-(4-Bromophenyl)-1-(naphthalen-2-yl)hexa-
carbamate (12f): According to GP C (S)-10a (97 % ee, 571 mg,
.11 mmol), acetaldehyde (14f, 64 mg, 1.44 mmol, 1.3 equiv.), and
TiCl (275 mg, 1.44 mmol, 1.3 equiv.) were stirred in CH Cl
5 mL) for 15 min at –78 °C. Purification by FCC (Et O/PE = 3:2)
yielded 221 mg (0.82 mmol, 74%) 12f as a colourless oil. rac-12f
was obtained from rac-10a (1.058 g, 2.0 mmol), TiCl (543 mg,
.6 mmol, 1.3 equiv.), and 14f (114 mg, 2.6 mmol, 1.3 equiv.) as a
hydroisobenzofuran-4(1H)-one (rac-22a): According to GP D rac-
12b (190 mg, 0.50 mmol), 4-bromobenzaldehyde (20a, 120 mg,
1
4
2
2
0.65 mmol, 1.3 equiv.), and BF
1.3 equiv.) were stirred for 2 h. FCC (Et
150 mg (0.36 mmol, 71 %) rac-22a as a colourless oil. t
3
·OEt
2
(92 mg, 0.65 mmol,
(
2
2
O/PE = 2:1) yielded
R
=
1
4
25.17 min (HP-5). R
CDCl ): δ = 1.03 (m, 1 H, 5-H
1.73 (m, 1 H, 7-H
F 2
= 0.33 (Et O/PE = 2:1). H NMR (300 MHz,
2
3
A
2
), 1.15–1.41 (m, 3 H, 6-H/7-H
A
),
colourless oil; yield 465 mg (1.73 mmol, 86%). t
R
= 14.01 min (HP-
): δ =
B
), 2.03 (br. d, J5A,5B = 15.8 Hz, 1 H, 5-H
B
), 2.84
1
3
3
3
3
5
1
). R
F
= 0.34 (Et
2
O/PE = 3:2). H NMR (400 MHz, CDCl
3
(ddt, J1,7a = J1,7A = 5.9 Hz, J3a,7a = 8.9 Hz, J7B,7a = 11.8 Hz, 1
3
H, 7a-H), 3.66 (dd, J3,3a = 11.4 Hz, 3J3a,7a = 7.4 Hz, 1 H, 3a-H),
3
.20 (d, J2Ј,CH–O = 6.2 Hz, 3 H, 2Ј-H), 1.23, 1.24 (2 br. s, 12 H,
), 1.48 (m, 1 H, 4-H ), 1.66 (m, 1 H, 5-H ), 1.74 (m, 1
), 1.88 (m, 1 H, 5-H ), 2.07–2.24 (m, 3 H, 6-H/OH), 2.32 3-H), 7.38 (d, J = 8.6 Hz, 2 H, Ar-H), 7.46–7.54 (m, 2 H, Ar-H),
3
3
iPr (CH
H, 4-H
m, 1 H, 3-H), 3.76 (dq, J2Ј,CH–O = 6.2 Hz, J3,CH–O = 1.3 Hz, 1
H, CH-O), 3.81, 4.01 (2 br. s, 2 H, iPr CH), 5.27 (s, 1 H, 2-H) ppm. (75 MHz, CDCl
3
)
2
A
A
5.31 (d, J1,7a = 4.1 Hz, 1 H, 1-H), 5.50 (d, J3,3a = 11.4 Hz, 1 H,
B
B
3
3
13
(
7.85–7.94 (m, 3 H, Ar-H), 8.02 (s, 1 H, Ar-H) ppm. C NMR
): δ = 22.9 (CH , C-6), 23.4 (CH , C-7), 41.5 (CH
C-5), 47.2 (CH, C-7a), 58.5 (CH, C-3a), 79.9 (CH, C-3), 83.6 (CH,
, C-6), C-1), 121.5 (C , C-Ar), 123.8, 124.3, 125.9, 126.3, 127.7, 127.9,
2.3 (CH, C-3), 46.1 (CH, iPr CH), 70.3 (CH, C–OH), 114.7 (CH, 128.1, 131.4 (CH, C-Ar), 132.7, 133.2, 135.3, 138.3 (C , C-Ar),
C-2), 150.6 (C , C-1), 153.8 (C , C=O) ppm. IR (film): ν˜ = 3450 210.7 (C , C-4) ppm. IR (film): ν˜ = 3061 (w), 3053 [ν(Carom–H)],
w) [ν(O–H)], 2970 (m), 2934 (m), 2870 (w) [ν(Caliph–H)], 1695 (s) 2940 (m), 2865 (m) [ν(Caliph–H)], 1703 (s) [ν(C=O)] cm . MS (ESI):
3
3
2
2
,
13
C NMR (100 MHz, CDCl
3
): δ = 20.0 (CH
3 3
, C-2Ј), 20.9 (CH ,
iPr (CH ), 21.4 (CH , C-5), 22.7 (CH
3
)
2
2
2
, C-4), 27.5 (CH
2
q
4
q
q
q
q
–
1
(
[
–
1
+
+
ν(N–C=O)] cm . MS (ESI): m/z = 292.1869 [M + Na] . m/z = 443.0609 [M + Na] . C24
(269.38): calcd. C 66.88, H 10.10, N 5.20; found C H 5.02; found C 68.67, H 5.12.
2
H21BrO (421.33): calcd. C 68.42,
15 3
C H27NO
20
D 3
66.78, H 10.34, N 5.14. [α] = –6.5 (c = 1.03, CHCl ) at 96% ee.
(
1R,3S,3aR,7aS)-1-(4-Bromophenyl)-3-(tert-butyl)hexahydroisoben-
GC DEX β-120, 125 °C isotherm, 461 min (12f), 481 min (ent-12f).
zofuran-4(1H)-one (ent-22b): According to GP D ent-12c (88% ee,
62 mg, 0.15 mmol), pivaldehyde (20b, 27 mg, 0.31 mmol,
[
3R,3(1R)]-3-(1-Hydroxy-2-methylpropyl)cyclohex-1-enyl N,N-Di-
isopropylcarbamate (12g): According to GP C (S)-10a (84 % ee,
2.1 equiv.), and BF (40 mg, 0.28 mmol, 1.9 equiv.) were
3
·OEt
2
5
1
29 mg, 1.00 mmol), isobutyraldehyde (14g, 93 mg, 1.30 mmol,
.3 equiv.), and TiCl (247 mg, 1.30 mmol, 1.3 equiv.) were stirred
Cl (4 mL) for 15 min at –78 °C. Purification by FCC (Et O/
stirred for 90 min. FCC (Et O/PE = 1:2) yielded 44 mg (0.13 mmol,
84%) ent-22b as a colourless solid. rac-22b was obtained from rac-
12c (205 g, 0.5 mmol), pivaldehyde (20b, 90 mg, 1.05 mmol,
2
4
in CH
2
2
2
PE = 3:2) yielded 213 mg (0.72 mmol, 72%) 12g as a colourless 2.1 equiv.), and BF
oil. rac-12g was obtained from rac-10a (1.058 g, 2.0 mmol), TiCl colourless solid; yield 128 mg (0.37 mmol, 73%). M.p. 87 °C (Et
543 mg, 2.6 mmol, 1.3 equiv.), and 14g (187 mg, 2.6 mmol, PE for rac-22b), m.p. 116–118 °C (Et O/PE for ent-22b at 89% ee),
.3 equiv.) as a colourless solid; yield 417 mg (1.40 mmol, 70%). m.p. 122 °C (Et O/PE for ent-22b at Ͼ99% ee). t
3
·OEt
2
(135 mg, 0.95 mmol, 1.9 equiv.) as a
4
2
O/
(
2
1
2
R
= 21.10 min
3345
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
1
B
5-H =
), 2.31 (m, 1 H, 7a-H), 3.24 (dd, 3J3,3a = 11.0 Hz, 3J3a,7a
(
HP-5). R
δ = 0.99 (s, 9 H, C(CH
.63 (2 m, 2 H, 6-H /7-H
F
= 0.53 (Et
2
O/PE = 2:1). H NMR (300 MHz, CDCl
), 1.10–1.19 (m, 2 H, 5-H , 6-H ), 1.36, 8.3 Hz, 1 H, 3a-H), 4.00 (dq, J1,1Ј–CH3 = 6.3 Hz, J1,7a = 10.5 Hz,
), 2.28 (m, 1 H, 7-H ), 2.40 (m, 1 H, 5- 1 H, 1-H), 5.19 (d, J3,3a = 11.0 Hz, 1 H, 3-H), 6.24 (m, 2 H, Ar-
3
):
3
3
3
)
3
A
A
3
1
H
1
B
A
B
3
3
3
3
13
B
), 2.70 (ddt, J1,7a = J1,7A = 5.9 Hz, J3a,7a = 8.9 Hz, J7B,7a
=
H), 7.25 (m, 1 H, Ar-H) ppm. C NMR (75 MHz, CDCl
15.1 (CH , 1Ј-CH ), 21.2 (CH , C-6), 23.7 (CH , C-7), 39.8 (CH
C-5), 46.1 (CH; C-7a), 57.0 (CH, C-3a), 75.6 (CH, C-3), 78.6 (CH,
, C-Ar), 210.5 (C
, C-6), C-4) ppm. IR (film): ν˜ = 3143 (w), 3117 [ν(Carom–H)], 2939 (m),
3
): δ =
1.8 Hz, 1 H, 7a-H), 3.16 (dd, J3,3a = 9.8 Hz, 3J3a,7a = 8.9 Hz, 1
3
3
3
2
2
2
,
3
H, 3a-H), 3.78 (d, J3,3a = 9.8 Hz, 1 H, 3-H), 4.71 (d, J = 5.9 Hz,
1
H, 1-H), 7.18 (d, J = 8.4 Hz, 2 H, Ar-H), 7.41 (J = 8.4 Hz, 2 H, C-1), 108.2, 110.4, 142.2 (CH, C-Ar), 152.4 (C
q
q
,
13
Ar-H) ppm. C NMR (75 MHz, CDCl
3.2 (CH , C-7), 27.4 (CH , C(CH ), 34.3 (CH
C(CH
CH, C-1), 120.8 (C
C-Ar), 213.6 (C , C-4) ppm. IR (film): ν˜ = 2933 (m), 2861 (m) 96% ee; ent-22d: [α]
3
): δ = 22.2 (CH
2
–
1
2
2
3
3
)
3
2
, C-5), 41.6 (C
q
,
2869 (m) [ν(Caliph–H)], 1702 (s) [ν(C=O)] cm . MS (ESI): m/z =
+
3
)
3
), 46.0 (CH, C-7a), 55.0 (CH, C-3a), 81.0 (CH, C-3), 90.5 243.0989 [M + Na] . C13
16 3
H O (220.26): calcd. C 70.89, H 7.32;
2
0
(
q
, C-Ar), 127.5, 131.2 (CH, C-Ar), 137.9 (C found C 70.59, H 7.51. 22d: [α]
q
,
D
= –169.1 (c = 1.03, CHCl
3
) at
2
0
q
D
= +141.0 (c = 1.06, CHCl ) at 75% ee; HPLC
3
–1
[
[
ν(Caliph–H)], 1689 (s) [ν(C=O)] cm . MS (ESI): m/z = 373.0766
2
Chiralcel OJ-RH (150 ϫ 4.6 mm), λ = 230 nm, MeCN/H O =
(351.28): calcd. C 61.54, H 6.60; found 38:62, 0.5 mL/min, 13.88 min (ent-22d), 14.66 min (22b).
+
M + Na] . C18
H
23BrO
2
2
0
C 61.37, H 6.48. [α]
Chira Grom 1 (2ϫ250 mm), λ = 224 nm, iPrOH/n-hexane = 1:80,
.3 mL/min, 8.39 min (22b), 9.78 min (ent-22b).
D 3
= +168.7 (c = 0.98, CHCl ) at 89% ee; HPLC
(
1RS,3SR,3aSR,7aRS)-1-Isopropyl-3-vinyl-hexahydroisobenzo-
furan-4(1H)-one (rac-22e): According to GP D rac-12g (74 mg,
.25 mmol), acroleine (20e, 19 mg, 0.33 mmol, 1.3 equiv.), and
·OEt (46 mg, 0.33 mmol, 1.3 equiv.) were stirred for 5 h
O/PE = 1:2) yielded 44 mg (0.21 mmol, 84%) rac-
0
0
(
(
1SR,3SR,3aSR,7aRS)- and (1RS,3SR,3aSR,7aRS)-3-Isopropyl-1- BF
4-methoxyphenyl)hexahydroisobenzofuran-4(1H)-one (rac-22c and 30 min. FCC (Et
3
2
2
epi-rac-22c): According to GP D rac-12d (180 mg, 0.50 mmol), iso-
butyraldehyde (20c, 47 mg, 0.65 mmol, 1.3 equiv.), and BF ·OEt
O/PE
2:1) yielded 97 mg (0.34 mmol, 67%) of an inseparable mixture
22e as a colourless oil. t
R
= 10.30 min (HP-5). R
F
= 0.36 (Et
): δ = 0.88, 1.05 (2 d,
), 1.43 (m, 1 H, 5-H ), 1.56
2
O/PE
= 1:2). 1H NMR (300 MHz, CDCl
3
2
3
3
(
=
92 mg, 0.65 mmol, 1.3 equiv.) were stirred for 4 h. FCC (Et
2
J
iPr(Me),iPrCH = 6.6 Hz, 6 H, iPr (CH
), 1.86 (dsept, JiPr(Me),iPrCH
6.6 Hz, J1,iPrCH = 3.5 Hz, 1 H, iPr CH), 1.98–2.11 (m, 2 H, 7-H),
3
)
2
A
3
(m, 1 H, 6-H
A
), 1.73 (m, 1 H, 6-H
B
=
[27]
3
of rac-22c: epi-rac-22c = 45:55 as a colourless oil. t
minor diastereomer: rac-22c, t = 17.40 min major diastereomer:
epi-rac-22c (HP-5). R = 0.29 (Et
300 MHz, CDCl ): δ (rac-22c) = 0.80, 1.03 (2 d, JiPr(Me),iPrCH
.4 Hz, 6 H, iPr (CH ), 1.10–1.33, 1.48–1.87, 2.05–2.44 (3 m, 8
H, 5-H/6-H/7-H/3a-H/iPr CH), 2.57 (m, 1 H, 7a-H), 3.18 (br. t,
R
= 17.28 min
3
3
R
B
2.31–2.43 (m, 2 H, 5-H /7a-H), 3.17 (dd, J3,3a = 11.5 Hz, J3a,7a
1
= 7.1 Hz, 1 H, 3a-H), 3.30 (dd, J1,iPrCH = 3.5 Hz, 3J1,7a = 9.8 Hz,
3
F
2
O/PE = 2:1). H NMR
3
1 H, 1-H), 4.62 (ddt, J1Ј,3 = 5.8 Hz, 3J3,3a = 11.5 Hz, J = 1.3 Hz,
3
(
3
=
3
2
6
3
)
2
1 H, 3-H), 5.12 (dt, J1Ј,2ЈA = 10.5 Hz, J2ЈA,2ЈB = 1.6 Hz, 1 H, 2Ј-
3
2
H
A
), 5.33 (dt, J1Ј,2ЈB = 17.2 Hz, J2ЈA,2ЈB = 1.6 Hz, 1 H, 2Ј-H
B
),
3
3
3
3
3
3
3
J
3,3a = J3a,7a = 8.8 Hz, 1 H, 3a-H), 3.18 (br. t, J3,3a = J3a,7a
.2 Hz, 1 H, 3a-H), 3.72 (s, 3 H, O-CH ), 3.76 (m, 1 H, 3-H), 4.74
d, J1,7a = 5.1 Hz, 1 H, 1-H), 6.79 (m, 2 H, Ar-H), 7.16 (m, 2 H, iPr (CH
=
5.71 (ddd, J1Ј,2ЈA = 10.5 Hz, J1Ј,2ЈB = 17.2 Hz, J1Ј,3 = 5.8 Hz, 1
1
3
9
(
3
H, 1Ј-H) ppm. C NMR (75 MHz, CDCl
), 21.6 (CH , C-6), 23.7 (CH , C-7), 28.2 (CH, iPr CH),
, C-5), 44.1 (CH; C-7a), 57.3 (CH, C-3a), 79.2 (CH, C-
3 3
): δ = 19.0, 20.1 (CH ,
3
3
)
2
2
2
3
Ar-H) ppm. δ (epi-rac-22c) = 0.89, 0.95 (2 d, JiPr(Me),iPrCH
=
42.1 (CH
3), 88.9 (CH, C-1), 116.5 (CH
C-4) ppm. IR (film): ν˜ = 2958 (m), 2943 (m), 2873 (m) [ν(Caliph
2
6
5
.8 Hz, 6H, iPr (CH
-H/6-H/7-H/7a-H/iPr CH), 2.63 (dd, J3,3a = 5.2 Hz, J3a,7a
.7 Hz, 1H, 3a-H), 3.71 (s, 3-H, O-CH
3
)
2
), 1.10–1.33, 1.48–1.87, 2.05–2.44 (3 m, 8 H,
2
, C-2Ј), 136.6 (CH, C-1Ј), 211.2 (C
q
,
3
3
=
–
), 4.23 (dd, 3J3,3a = 5.2 Hz,
H)], 1704 (s) [ν(C=O)] cm . MS (ESI): m/z = 231.1346 [M +
–1
9
J
6
3
3
3,iPrCH = 5.9 Hz, 1H, 3-H), 4.26 (d, 3
.79 (m, 2H, Ar-H), 7.16 (m, 2 H, Ar-H) ppm. C NMR (75 MHz,
CDCl ): δ (rac-22c) = 19.7, 20.3 (CH , iPr (CH ), 23.0 (CH , C-
), 23.3 (CH , C-7), 31.1 (CH , C-5), 42.1 (CH, iPr CH), 47.2 (CH,
C-7a), 54.1 (CH, C-3a), 81.7 (CH, C-3), 85.6 (CH, C-1), 113.5,
26.9 (CH, C-Ar), 130.6, 158.6 (C , C-Ar), 212.5 (C , C-4) ppm. δ
epi-rac-22c) = 18.1, 18.7 (CH , iPr (CH ), 22.0 (CH , C-6), 23.7
CH , C-7), 32.5 (CH , C-5), 40.7 (CH, iPr CH), 49.2 (CH, C-7a),
5.2 (CH, C-3a), 82.0 (CH, C-3), 82.5 (CH, C-1), 113.7, 127.4 (CH,
C-Ar), 132.6, 159.3 (C , C-Ar), 210.7 (C , C-4) ppm. IR (film): ν˜
2956 (m), 2934 (m), 2865 (m) [ν(Caliph–H)], 1706 (s) [ν(C=O)]
+
20 2
J1,7a = 9.4 Hz, 1H, 1-H), Na] . C13H O (208.30): calcd. C 74.96, H 9.68; found C 74.96, H
13
9.94.
3
3
3
)
2
2
[
1S,3R,3(1R,5R),3aS,7aR]- and [1R,3S,3(1R,5R),3aR,7aS]-3-(6,6-
6
2
2
Dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1-(naphthalen-2-yl)-hexa-
hydro-isobenzofuran-4(1H)-one (22f) and (22g): According to GP D
1
(
(
q
q
12b (70% ee, 95 mg, 0.25 mmol), (1R)-(–)-myrtenal (49 mg,
0.33 mmol, 1.3 equiv.), and BF ·OEt (46 mg, 0.33 mmol,
1.3 equiv.) were stirred for 1 h. FCC (Et O/PE = 1:2) yielded 57 mg
3
3
)
2
2
3
2
2
2
2
5
(
0.15 mmol, 59%) 22f and 13 mg (0.04 mmol, 14%) 22g (total yield
q
q
[27]
7
3%, dr = 88:12 ) as colourless crystalline solids. 22f: M.p. 205 °C
Et O/PE). t = 24.11 min (HP-5). R = 0.56 (Et O/PE = 3:2).
H NMR (500 MHz, CDCl ): δ = 0.90 (s, 3 H, 6Ј-CH ), 1.03 (d, J
9.2 Hz, 1 H, 5-H ), 1.11 (m, 1 H, 6-H ), 1.28 (s, 3 H, 6Ј-CH ),
.34–1.47 (m, 2 H, 6-H /7-H ), 1.89 (m, 1 H, 7-H ), 1.97 (dt, J =
=
(
2
R
F
2
–1
+
cm . MS (ESI): m/z = 311.1620 [M + Na] . C18
H
24
O
3
(288.38,
1
3
3
mixture of diastereomers): calcd. C 74.97, H 8.39; found C 74.78,
H 8.57.
=
1
A
A
3
B
A
B
(
1S,3S,3aS,7aR)-3-(Furan-2-yl)-1-methyl-hexahydroisobenzofuran- 5.6 Hz, J = 1.6 Hz, 1 H, 5Ј-H), 2.08 (m, 1 H, 1Ј-H), 2.31–2.40 (m,
3
4
0
1
(1H)-one (22d): According to GP D 12f (96 % ee, 86 mg,
.32 mmol), furan-2-carbaldehyde (20d, 46 mg, 0.48 mmol,
B 3,3a
5 H, 4Ј-H, 5-H , 7Ј-H), 2.77 (m, 1 H, 7a-H), 3.41 (dd, J =
3
3
11.2 Hz, J3,7a = 7.5 Hz, 1 H, 3a-H), 4.64 (dq, J3,3a = 11.2 Hz, J
3
.5 equiv.), and BF
3
·OEt
2
(59 mg, 0.42 mmol, 1.5 equiv.) were
O/PE = 1:1) yielded 48 mg (0.22 mmol,
= 2.2 Hz, 1 H, 3-H), 5.08 (d, J1,7a = 4.3 Hz, 1 H, 1-H), 6.08 (m,
stirred for 15 min. FCC (Et
6
ent-12f (76 % ee, 46 mg, 0.17 mmol), furan-2-carbaldehyde (20d,
2
1
2
2
1 H, 3Ј-H), 7.44–7.52 (m, 3 H, Ar-H), 7.83 (d, J = 8.5 Hz, 2 H,
Ar-H), 7.88 (d, J = 7.9 Hz, 1 H, Ar-H), 7.94 (s, 1 H, Ar-H) ppm.
8%) 22d (96% ee) as a colourless oil. ent-22d was obtained from
1
3
C NMR (500 MHz, CDCl
C-6), 23.9 (CH , C-7), 26.1 (CH
(CH , C-7Ј), 38.5 (C , C-6Ј), 40.7 (CH, C-1Ј), 42.3 (CH
2
3
): δ = 20.8 (CH
3
, 6Ј-CH
3
), 23.4 (CH
, C-5), 31.6
, C-4Ј),
2
,
5 mg, 0.26 mmol, 1.5 equiv.), and BF
.3 equiv.) as a colourless oil; yield 27 mg (0.13 mmol, 72%) ent-
2d (75% ee), colourless oil. t = 12.03 min (HP-5). R = 0.29
O/PE = 2:1). 1H NMR (300 MHz, CDCl
): δ = 1.31 (d,
), 1.44–1.54 (m, 2 H, 5-H /6-H
), 1.92 (m, 1 H, 7-H ), 2.11 (m, 1 H, 145.7 (C
3
·OEt
2
(31 mg, 0.22 mmol,
2
3
, 6Ј-CH ), 30.9 (CH
3
2
2
q
R
F
44.8 (CH, C-5Ј), 47.6 (CH, C-7a), 56.5 (CH, C-3a), 81.6 (CH, C-
3), 82.6 (CH, C-1), 118.4 (CH, C-3Ј), 124.1, 124.5, 125.7, 126.1,
(
Et
2
3
3
J1,1-CH3 = 6.3 Hz, 3 H, 1-CH
3
A
A
), 127.7, 127.8, 127.9 (CH, C-Ar), 132.7, 133.2, 135.7 (C
q
, C-Ar),
1
.63–1.74 (m, 3 H, 6-H
B
/7-H
A
B
q
, C-2Ј), 211.5 (C , C-4) ppm. IR: ν˜ = (ATR) [= 3049 (w)
q
3346
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348

Asymmetric Homoaldol Reactions
FULL PAPER
ν(Carom–H)], 2990 (m), 2929 (s), 2860 (m) [ν(Caliph–H)], 1694 (s)
1990, 29, 296–298; b) O. Zschage, J.-R. Schwark, T. Krämer,
D. Hoppe, Tetrahedron 1992, 48, 8377–8388; c) O. Zschage, J.-
R. Schwark, T. Krämer, D. Hoppe, Tetrahedron 1992, 48, 8389–
–1
+
[
(
–
2
0
30 2
ν(C=O)] cm . MS (ESI): m/z = 409.2133 [M + Na] . C27H O
2
0
386.52): calcd. C 83.90, H 7.82; found C 83.82, H 7.82. [α]
D
=
=
8392.
127.6 (c = 1.03, CHCl
3.98 min (HP-5). R
= 0.34. 1H NMR (400 MHz, CDCl
.94 (s, 3 H, 6Ј-CH ), 1.08 (d, J = 8.2 Hz, 1 H, 5-H
), 1.36 (s, 3 H, 6Ј-CH ), 1.44 (m, 1 H, 6-H
), 1.83 (m, 1 H, 7-H ), 2.08–2.18 (m, 2 H, 1Ј-H, 5Ј-H),
.29–2.40 (m, 5 H, 4Ј-H, 5-H
3 2 R
). 22g: M.p. 150 °C (Et O/PE). t
[
10] For kinetic resolution of allyltitanium carbamates by chiral al-
dehydes, see: a) R. W. Hoffmann, J. Lanz, R. Metternich, G.
Tarara, D. Hoppe, Angew. Chem. 1987, 99, 1196–1197; Angew.
Chem. Int. Ed. Engl. 1987, 26, 1145–1146; b) I. Berque, P.
Le Ménez, P. Razon, C. Anies, A. Pancrazi, J. Ardisson, A.
Neuman, T. Prangé, J.-D. Brion, Synlett 1998, 1132–1134; c) I.
Berque, P. Le Ménez, P. Razon, C. A. Pancrazi, J. Ardisson, J.-
D. Brion, Synlett 1998, 1135–1137; d) P. Razon, S. Dhulut, S.
Bezzenine-Lafollée, J. Courtieu, A. Pancrazi, J. Ardisson, Syn-
thesis 2005, 102–108; application in total synthesis: E.
de Lemos, F.-H. Porée, A. Commerçon, J.-F. Betzer, A.
Pancrazi, J. Ardisson, Angew. Chem. 2007, 119, 1949–1953; An-
F
3
): δ =
), 1.24 (m, 1
B
), 1.63 (m, 1
3
A
H, 6-H
H, 7-H
2
A
3
A
B
3
3
B
, 7Ј-H), 2.77 (ddt, J1,7a = J7A,7a
=
3
3
5
.4 Hz, J3a,7a = 7.2 Hz, J7B,7a = 12.8 Hz, 1 H, 7a-H), 3.36 (dd,
3
3,3a = 11.2 Hz, 3
1.2 Hz, 1 H, 3-H), 5.05 (d, J1,7a = 5.4 Hz, 1 H, 1-H), 5.74 (s, 1
H, 3Ј-H), 7.37–7.50 (m, 3 H, Ar-H), 7.80–7.83 (m, 4 H, Ar-H) ppm.
3
J
3,3a
J3a,7a = 7.2 Hz, 1 H, 3a-H), 4.85 (d, J =
3
1
1
3
C NMR (100 MHz, CDCl
C-6), 23.6 (CH , C-7), 26.5 (CH
CH , C-7Ј), 37.9 (C , C-6Ј), 40.3 (CH, C-1Ј), 41.0 (CH
3.2 (CH, C-5Ј), 45.9 (CH, C-7a), 56.1 (CH, C-3a), 82.5 (CH, C-
), 83.9 (CH, C-1), 122.9 (CH, C-3Ј), 124.0, 124.4, 125.7, 126.1,
27.7, 127.8, 127.9 (CH, C-Ar), 132.7, 133.2, 135.9 (C , C-Ar),
44.5 (C , C-2Ј), 211.3 (C , C-4) ppm. IR (ATR): ν˜ = 3049 (w)
3
): δ = 21.5 (CH
3
, 6Ј-CH
3
), 22.8 (CH
, C-5), 31.7
, C-4Ј),
2
,
2
3
, 6Ј-CH ), 31.5 (CH
3
2
[10d]
gew. Chem. Int. Ed. 2007, 46, 1917–1921; see also ref.
(
2
q
2
[
11] a) T. Krämer, J.-R. Schwark, D. Hoppe, Tetrahedron Lett. 1989,
4
3
1
1
30, 7037–7040; b) H. Paulsen, C. Graeve, R. Fröhlich, D.
Hoppe, Synthesis 1996, 1, 145–149.
q
[12] Data sets were collected with a Nonius KappaCCD dif-
fractometer. Programs used: data collection COLLECT (Non-
ius B. V., 1998), data reduction Denzo-SMN (Z. Otwinowski,
W. Minor, Methods in Enzymology, 1997, 276, 307–326), ab-
sorption correction Denzo (Z. Otwinowski, D. Borek, W. Ma-
jewski, W. Minor, Acta Crystallogr. 2003, A59, 228–234), struc-
ture solution SHELXS-97 (G. M. Sheldrick, Acta Crystallogr.
q
q
[
[
(
ν(Carom–H)], 2993 (m), 2940 (s), 2861 (m) [ν(Caliph–H)], 1698 (s)
–1
+
30 2
ν(C=O)] cm . MS (ESI): m/z = 409.2129 [M + Na] . C27H O
2
0
386.52): calcd. C 83.90, H 7.82; found C 83.79, H 7.88. [α]
D
=
+
94.8 (c = 0.63, CHCl ).
3
1
990, A46, 467–473), structure refinement SHELXL-97 (G. M.
Sheldrick, University of Göttingen, 1997), graphics
Acknowledgments
SCHAKAL (E. Keller, University of Freiburg, 1997). CCDC-
6
39293 to -639296 contain the supplementary crystallographic
This work was supported by the Deutsche Forschungsgemeinschaft
SFB 424) and the Fonds der Chemischen Industrie (stipend for
J. B.). J. B. thanks M. Renger for her skilful experimental assist-
ance.
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(
[13] X-ray crystal structure analysis for 12c: formula C H BrNO ,
2
0
28
3
M = 410.34, colorless crystal 0.10ϫ0.05ϫ0.03 mm, a =
3
7
=
.465(1), b = 10.067(1), c = 27.851(1) Å, V = 2093.0(4) Å , ρcalc
[
1] For reviews, see: a) D. Hoppe, T. Hense, Angew. Chem. 1997,
–3
–1
1.302 gcm , µ = 2.810 mm , empirical absorption correc-
1
09, 2376–2410; Angew. Chem. Int. Ed. Engl. 1997, 36, 2282–
tion (0.766ՅTՅ0.921), Z = 4, orthorhombic, space group
P2 (No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans,
8
2316; b) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365–390; c)
1 1 1
2 2
D. Hoppe, F. Marr, M. Brüggemann, Organolithiums in Enan-
tioselective Synthesis in Top. Organomet. Chem. (Ed.: D. M.
Hodgson), Springer, Berlin, 2003, vol. 5, pp. 61–138; d) P.
Beak, T. A. Johnson, D. D. Kim, S. H. Lim, Organolithiums in
Enantioselective Synthesis in Top. Organomet. Chem. (Ed.:
D. M. Hodgson), Springer, Berlin, 2003, vol. 5, pp. 139–176; e)
D. Hoppe, G. Christoph in The Chemistry of Organolithium
Compounds (Eds.: Z. Rappoport, I. Marek), Wiley, Chichester,
–1
000 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å ,
039 independent (Rint = 0.060) and 2225 observed reflections
3
[IՆ2σ(I)], 231 refined parameters, R = 0.056, wR
2
= 0.114,
Flack parameter –0.07(4), max. residual electron density 0.32
–3
(
–0.26) e·Å , hydrogen atoms calculated and refined as riding
atoms.
[
[
14] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
1
920–1923.
2
004, vol. 2, pp. 1055–1164.
15] a) D. Hoppe, T. Krämer, C. Freire Erdbrügger, E. Egert, Tetra-
hedron Lett. 1989, 30, 1233–1236; b) S. Ünaldi, M. Özlügedik,
R. Fröhlich, D. Hoppe, Adv. Synth. Catal. 2005, 347, 1621–
[
2] Recent examples: a) D. Hoppe, M. Özlügedik, J. Kristensen, B.
Wibbeling, R. Fröhlich, Eur. J. Org. Chem. 2002, 414–427; b)
M. Seppi, R. Kalkofen, J. Reupohl, R. Fröhlich, D. Hoppe,
Angew. Chem. 2004, 116, 1447–1451; Angew. Chem. Int. Ed.
1
626.
[
16] For determination of the configuration of hydroisobenzofurans
2004, 43, 1423–1427; c) J. Reuber, R. Fröhlich, D. Hoppe, Org.
3
via JH,H couplings see: Y. Chai, D. A. Vicic, M. C. McIntosh,
Org. Lett. 2003, 5, 1039–1042.
Lett. 2004, 6, 783–786; d) R. Bou Chedid, R. Fröhlich, D.
Hoppe, Org. Lett. 2006, 8, 3061–3064.
3] J. Becker, S. Grimme, R. Fröhlich, D. Hoppe, Angew. Chem.
[
17] X-ray crystal structure analysis for ent-22b: formula
[
2
007, 119, 1672–1676; Angew. Chem. Int. Ed. 2007, 46, 1645–
C
18
H23BrO
2
,
M
=
351.27,
colorless
crystal
1
649.
0.15ϫ0.03ϫ0.03 mm, a = 6.5993(1), b = 31.6292(6), c =
7.7836(1) Å, β = 90.256(1)°, V = 1624.66(4) Å , ρcalc =
1.436 gcm , µ = 3.457 mm , empirical absorption correction
(0.625ՅTՅ0.903), Z = 4, monoclinic, space group P2 (No.
4), λ = 1.54178 Å, T = 223 K, ω and φ scans, 6351 reflections
collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å , 4030 independent
(Rint = 0.050) and 3832 observed reflections [IՆ2σ(I)], 385
3
[
4] J. A. Marshall, S. B. DeHoff, Tetrahedron Lett. 1986, 27, 4873–
–
3
–1
4876.
[
5] C. L. Kissel, B. Rickborn, J. Org. Chem. 1972, 37, 2060–2063.
1
[
6] N. Holub, J. Neidhöfer, S. Blechert, Org. Lett. 2005, 7, 1227–
–
1
1
229.
7] M. K. Södergren, P. G. Andersson, J. Am. Chem. Soc. 1998,
20, 10760–10761.
[
[
[
1
2
refined parameters, R = 0.049, wR = 0.132, Flack parameter
–
3
8] G. A. Weisenburger, N. C. Faibish, D. J. Pippel, P. Beak, J. Am.
Chem. Soc. 1999, 121, 9522–9530.
0.03(3), max. residual electron density 0.97 (–0.36) e·Å , two
almost identicalmolecules in the asymmetric unit, hydrogen
atoms calculated and refined as riding atoms.
9] For kinetic resolution of open-chained carbamates by nBuLi/
(
–)-sparteine (9) see: a) O. Zschage, J.-R. Schwark, D. Hoppe, [18] X-ray crystal structure analysis for 22f: formula C27
H
30
O
2
, M
Angew. Chem. 1990, 102, 336–337; Angew. Chem. Int. Ed. Engl.
= 386.51, colorless crystal 0.40ϫ0.25ϫ0.10 mm, a = 6.907(1),
Eur. J. Org. Chem. 2007, 3337–3348
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3347

J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe
FULL PAPER
3
b = 8.946(1), c = 16.886(1) Å, β = 96.83(1)°, V = 1036.0(2) Å ,
[20] J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe, Eur. J. Org.
Chem. 2007, 3349–3364, following article.
[21] C. Benson, P. Cai, M. Colon, M. A. Haiza, M. Tokles, J. K.
Snyder, J. Org. Chem. 1988, 53, 5335–5341.
[22] W. G. Konfron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–
–3
–1
ρ
calc = 1.239 gcm , µ = 0.590 mm , empirical absorption cor-
rection (0.798ՅTՅ0.943), Z = 2, monoclinic, space group P2
No. 4), λ = 1.54178 Å, T = 223 K, ω and φ scans, 8144 reflec-
1
(
–1
tions collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å , 2652 inde-
pendent (Rint 0.030) and 2622 observed reflections
IՆ2σ(I)], 264 refined parameters, R = 0.035, wR = 0.093,
Flack parameter 0.0(3), max. residual electron density 0.12
=
1880.
[
2
[23] D. Hoppe, R. Hanko, A. Brönneke, F. Lichtenberg, E.
van Hülsen, Chem. Ber. 1985, 118, 2822–2851.
[24] Samples of the crystalline product had 23% ee (HPLC), the
oily residue had 94% ee (HPLC).
–3
(
–0.11) e·Å , hydrogen atoms calculated and refined as riding
atoms.
[
19] X-ray crystal structure analysis for 22g: formula C27
H
30
O
2
, M
[25] For larger scale reactions (Ͼ1 mmol) 1.1 equiv. of the aldehyde
=
386.51, colorless crystal 0.20ϫ0.20ϫ0.15 mm, a = 6.479(1),
and TiCl
reactions 1.3 equiv. are recommended because of some hydroly-
sis of TiCl by atmospheric moisture.
4
are sufficient for complete conversions. In small scale
3
b = 8.790(1), c = 18.784(1) Å, β = 98.24(1)°, V = 1058.7(2) Å ,
–
3
–1
ρ
calc = 1.212 gcm , µ = 0.577 mm , empirical absorption cor-
rection (0.893ՅTՅ0.918), Z = 2, monoclinic, space group P2
No. 4), λ = 1.54178 Å, T = 223 K, ω and φ scans, 11912 reflec-
4
1
[26] In order to remove all traces of the liberated stannanes the
crude products were purified two times by flash column
chromatography.
[27] The diastereomeric ratio was determined from the crude prod-
ucts by GC (HP-5).
(
–1
tions collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å , 3613 inde-
pendent (Rint 0.048) and 3226 observed reflections
IՆ2σ(I)], 264 refined parameters, R = 0.070, wR = 0.190,
Flack parameter –0.4(5), max. residual electron density 0.13
=
[
2
Received: March 12, 2007
Published Online: May 10, 2007
–3
(
–0.15) e·Å , hydrogen atoms calculated and refined as riding
atoms.
3348
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3337–3348