Substituted cis-hydrindan-4-ones by sequential cycloadditions

Article abstract of DOI:10.1055/s-0034-1378880

The synthesis of substituted cis-hydrindan-4-ones is reported. Particular emphasis was placed on the diastereoselective construction of quaternary stereogenic ring carbon atoms. An intermolecular asymmetric Al(III)-promoted (4+2)-cycloaddition served as the principal C/C-connecting tool. Opportunities for the further structural elaboration of the (4+2)-cycloadducts were explored.

Full text of DOI:10.1055/s-0034-1378880

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3489–3504
paper
3489
S. Steffen et al.
Paper
Synthesis
Substituted cis-Hydrindan-4-ones by Sequential Cycloadditions
O
O
Sara Steffen
OBn
Andreas Schäfer
Martin Hiersemann*
XBn
O
Xi-Pr
O
O
N
OBn
OBn
Me2AlCl
MeAlCl2
R
Fakultät für Chemie und Chemische Biologie, Technische
Universität Dortmund, 44227 Dortmund, Germany
martin.hiersemann@tu-dortmund.de
R = i-Pr
59% (3.9 g)
R = Bn
36% (1.9 g)
OTBS
OTBS
TBSO
endo
exo
Xi-Pr
O
XBn
O
1. Et2Zn, CH2I2
2. p-TsOH·H2O
3. H2, Pd/C
1. Et2Zn, CH2I2
2. p-TsOH·H2O
3. H2, Pd/C
OH
OH
single
diastereomer
mixture of
four diastereomers
O
O
Received: 04.06.2015
Accepted after revision: 07.07.2015
Published online: 20.08.2015
O
O
8
DOI: 10.1055/s-0034-1378880; Art ID: ss-2015-t0360-op
9
10
10b
O
O
7
6
C
H
Abstract The synthesis of substituted cis-hydrindan-4-ones is report-
ed. Particular emphasis was placed on the diastereoselective construc-
tion of quaternary stereogenic ring carbon atoms. An intermolecular
asymmetric Al(III)-promoted (4+2)-cycloaddition served as the princi-
pal C/C-connecting tool. Opportunities for the further structural elabo-
ration of the (4+2)-cycloadducts were explored.
5a
10a
1
2
OH
O
O
A
B
3a
5
3
4
O
O
homoverrucosane scaffold
and numbering system
(+)-gagunin E (1)
(phorbas sp.)
Key words cycloaddition, Diels–Alder reaction, Lewis acids, ring
opening, Grignard reaction
Figure 1 Proposed structure of (+)-gagunin E (1). The absolute config-
uration of 1 is unknown. The illustrated homoverrucosane numbering
system is used throughout this article.
In the context of a research program aimed at the devel-
opment of C/C-bond forming transformations that are use-
ful for the total synthesis of architecturally challenging and
biologically active terpenoids of marine and terrestrial ori-
gin,1 our attention was recently drawn to a report by Shin
and co-workers on the isolation of gagunin E (1) from a
sponge of the genus Phorbas.2 The homoverrucusane diter-
penoid 1 is characterized by a densely substituted 5(A)-
6(B)-7(C)-tricyclic cyclohepta[e]hydrindane scaffold featur-
ing an A,B-cis-B,C-trans annulation pattern, which is rare
within the family of homoverrucosanoids (Figure 1).
From our retrosynthetic point of view, the cis-hydrin-
dane nucleus represents the key element to the architec-
ture of gagunin E. As outlined in Scheme 1, we envisioned a
sequence of two intermolecular cycloadditions as a suitable
answer to the synthetic challenge and decided to explore
the feasibility of such a synthetic approach.3 In light of the
exploratory nature of our endeavor, we selected the easily
accessible silyl enol ether 54 as an A-ring building block.
The (4+2)-cycloaddition between 5 and a suitable dieno-
phile 6 would afford the desired hydrindane architectural
R1
R1
H
10a
R2
5a
R2
10b
3a
5
4
O
OSiR3
3
2
(2+1)
R1
6
R1
R1
H
H
5a
R2
R2
(4+2)
R2
5a
5a
10b
3a
10b
3a
10b
3a
OSiR3
OSiR3
exo-4
OSiR3
endo-4
5
Scheme 1 Proposed sequence of diastereoselective cycloadditions to
the 3a,5a-dimethyl substituted cis-hydrindan-4-one scaffold 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3490
S. Steffen et al.
Paper
Synthesis
motif 4, fittingly substituted with the angular methyl group
at carbon atom C5a. By controlling the exo/endo diastereo-
selectivity of the (4+2)-cycloaddition, the relative configu-
ration of the carbon atoms C10b and C5a would be prede-
termined; internal or external asymmetric induction would
be required to render the (4+2)-cycloaddition enantioselec-
tive. With respect to the stereochemical course of the sub-
sequent (2+1)-cycloaddition, we ventured to assume that
the configuration of the carbon atom C10b of the (4+2)-cy-
cloadduct would trigger an electrophilic cyclopropanation
from the convex face of the bicyclic silyl enol ether 4. Subse-
quent regioselective ring-opening of the siloxycyclopro-
pane moiety would finalize our approach to the substituted
B-ring of gagunin E (1).
Our planning with respect to the structure of the dieno-
phile and the reaction conditions was guided by examples
for exo diastereoselective intermolecular (4+2)-cycloaddi-
tions from the literature (Scheme 2);5–10 thus, α,β-unsatu-
rated carbonyl compounds were used as dienophiles in con-
junction with aluminum(III) Lewis acid activation. The de-
sired exo diastereoselectivity was experimentally observed
regardless of the nature of the Al(III) Lewis acid promoter.
Evans type N-acryloyl oxazolidinones as deployed by Keay
(10) appeared particularly promising to us because of the
solid experimental and mechanistic basis provided by
Evans as well as by the opportunity for auxiliary-induced
diastereoselectivity.11 Thus, we decided to study the Al(III)
promoted (4+2)-cycloaddition between cross-conjugated
silyl dienol ether 5 and an appropriately substituted 3-ac-
ryloyloxazolidin-2-one 6.
Jung (2005):
Me3Al (0.05 equiv)
The synthesis of silyl enol ether 5 commenced with the
one-pot oxidative cleavage of cyclohexane-1,2-diol (15) and
subsequent 5-enolexo aldol condensation to provide the
crude 1-cyclopentene-1-carbaldehyde as a solution in ether
(Scheme 3).12 Reacting the crude aldehyde with methyl-
magnesium bromide delivered allylic alcohol 16 on a gram
scale after chromatographic purification (64%, 12.4 g of an-
alytically pure compound isolated).13 Oxidation of the allyl-
ic alcohol 16 with manganese(IV) oxide afforded the crude
volatile enone as a solution in CH2Cl2. Formation of the de-
sired acid labile silyl enol ether 5 was then accomplished by
treatment of the crude enone with an excess of triethyl-
amine and tert-butyldimethylsilyl trifluoromethansulfon-
ate (89%, 6.18 g).14 The crude silyl enol ether 5 was purified
by Kugelrohr distillation and could be stored for several
weeks at low temperature and under the rigorous exclusion
of acid.15
O
AlBr3 (0.5 equiv)
toluene–CH2Cl2 (2:1)
– 9 °C, 15 min
8 (1.5 equiv)
O
0 °C, 4 h
7
88% (370 mg)
exo:endo = 72:28
OTBS
OTBS
( )-exo-9
8
Keay (2009):
MeAlCl2 (1.4 equiv)
CH2Cl2, – 78 °C, 10 min
11a (1.9 equiv)
O
Xi-Pr
O
O
– 78 °C to r.t.; r.t., 5 h
N
O
OBn
60% (213 mg)
exo/endo = 20:1
OBn
i-Pr
R
exo-12
10
11a: R = Me
11b: R = H
1. NaIO4 (1.3 equiv)
H2O, Et2O (1:1)
r.t., 30 min
Snider (2010):
aq KOH (1.4 equiv)
r.t., 1 h
2. MeMgBr (1.2 equiv)
THF, 0 °C, 25 min
64% (12.4 g)
Me2AlCl (1.9 equiv)
CH2Cl2, – 78 °C, 10 min
11b (1.0 equiv)
– 78 °C to 4 °C
4 °C, 48 h
OH
O
XH
O
O
N
OH
OH
O
54% (330 mg)
exo/endo = 10:1
15
16
1. MnO2 (10.8 equiv)
CH2Cl2, reflux, 3 h
2. Et3N (2.2 equiv)
TBSOTf (1.2 equiv)
CH2Cl2, 0 °C; r.t., 1.5 h
( )-exo-14
13
this work:
O
XR
R3Al
5
O
O
conditions
89% (6.18 g)
BnO
OBn
OTBS
N
O
5
R
OTBS
endo/exo-4
Scheme 3 Preparation of silyl enol ether 5 on a gram scale requires
only a single column chromatographic purification; the acid-labile silyl
enol ether can be purified by Kugelrohr distillation.
6
5
TBSO
Scheme 2 Guiding literature examples and the object of this work
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

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Synthesis
The synthesis of N-acryloyl oxazolidinones required ac-
cess to (E)-4-(benzyloxy)-3-methylbut-2-enoic acid (20) for
covalent attachment to the corresponding chiral auxiliaries
(Scheme 4). The synthesis of the acid 20 started with the
commercially available ethyl (E)-3-methyl-4-oxobut-2-
enoate (17), which was chemoselectively reduced with so-
dium borohydride to afford allylic alcohol 18 (90%, 24.3 g).
The allylic alcohol was subjected to a silver(I) oxide mediat-
ed and tetra-n-butylammonium iodide catalyzed benzyla-
tion to provide benzylic ether 19 (92%, 13.08 g).16 Saponifi-
cation by exposure to aqueous lithium hydroxide at elevat-
ed temperature finally delivered the desired acid 20 (90%,
9.66 g).
PivCl (1.3 equiv)
Et3N (2.6 equiv)
THF, 0 °C, 30 min
HX (1 equiv)
n-BuLi (1.1 equiv)
r.t., 12 h
O
O
OH
X
OBn
OBn
6a–d
20
(1.1 equiv)
O
O
O
O
O
N
O
N
O
N
O
N
O
N
O
Ph
Bn
NaBH4 (3 equiv)
MeOH, r.t., 16 h
O
O
XRiPr
(R)-6a
81%
XSiPr
XBn
XH
XPh
(S)-6a
68%
(6.47 g)
(S)-6b
78%
(9.76 g)
6d
64%
(1.72 g)
(R)-6c
83%
(1.79 g)
OEt
OEt
90% (24.3 g)
O
OH
(6.61 g)
18
17
Scheme 5 Preparation of (E)-3-[4-(benzyloxy)-3-methylbut-2-
enoyl]oxazolidin-2-ones 6a–d
Ag2O (0.8 equiv)
TBAI (0.1 equiv)
BnBr, r.t., overnight
92%
(13.08 g)
O
Me2AlCl
or
MeAlCl2
(CH2Cl)2
OBn
LiOH·H2O (3 equiv)
H2O, THF (4:5)
reflux, 14 h
X
O
X
X
O
OBn
OBn
O
O
6a–d
OH
OEt
90% (9.66 g)
OBn
OBn
20
19
OTBS
OTBS
Scheme 4 Preparation of carboxylic acid 20 from commercially avail-
able aldehyde 17
TBSO
endo-4a–d
exo-4a–d
5
OTBS
Re
Model studies by Evans have revealed that the phenylal-
aninol-derived auxiliary exerted an enhanced auxiliary-
induced diastereoselectivity in the Et2AlCl promoted (4+2)-
cycloaddition of N-acryloyl oxazolidinones with acyclic
dienes.11 To test the significance of this auxiliary effect, we
set out to synthesize a small collection of 3-acryloyloxazoli-
din-2-ones using differently substituted 1,3-oxazolidin-2-
ones (Scheme 5). In our hands, reacting the mixed anhy-
dride of acid 20 with pivalic acid and the lithiated 1,3-oxaz-
olidin-2-one in the absence of additional lithium chloride
delivered the desired 3-acryloyloxazolidin-2-ones 6a–d
most effectively.17,18
TBSO
BnO
R2
Al
Si
Si
Si
R2
Al
BnO
O
N
Si
Si
O
N
O
O
H
O
O
H
H
S
H
S
proposed exo-type
transition-state structure
proposed endo-type
transition-state structure
Scheme 6 Diastereoselective (4+2)-cycloadditions promoted by
Me2AlCl or MeAlCl2. Absolute configuration proposed for (S)-configured
auxiliaries (X). For conditions see Table 1 (Me2AlCl) and Table 2 (MeAlCl2).
With diene 5 and a collection of dienophiles 6a–d in
hand, we proceeded to investigate the envisioned (4+2)-cy-
cloaddition (Scheme 6, Table 1 and Table 2). By following
the reported procedures (Scheme 2), N-acryloyl oxazolidi-
nones 6a–d were treated at low temperature with an excess
of dimethylaluminum chloride (1.4 equiv) to allow for che-
late formation (1,2-dichloroethane, –25 °C, 10 min). Subse-
quent addition of diene 5 (2 equiv) at –25 °C followed by
stirring at ambient temperature delivered the cycloadducts
4a–d (Table 1). The (4+2)-cycloaddition promoted by
Me2AlCl proceeded in a highly endo diastereoselective fash-
ion and with complete auxiliary-induced diastereoselectivi-
ty.19 The valinol-based auxiliary XiPr was particularly effec-
tive in this regard, and a single endo diastereomer (endo-4a)
was obtained after chromatographic purification (Table 1,
entries 1 and 2). Diminished endo/exo diastereoselectivities
were detected for the dienophiles 6b or 6c, equipped with
phenylalanine- and phenylglycine-based auxiliaries XBn or
XPh (Table 1, entries 3 and 4). To determine the intrinsic en-
do/exo diastereoselectivity without interference by a chiral
auxiliary, the achiral dienophile 6d, containing the simple
1,3-oxazolidin-2-one XH, was subjected to our standard
conditions for the dimethylaluminum chloride-promoted
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3492
S. Steffen et al.
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Synthesis
trophilic cyclopropanation of the silyl enol ether moiety.
Departing from our initial expectations, given that the exo-
and endo-configured cycloadducts 4 were available, we opt-
ed to address the (2+1)-cycloaddition for both diastereo-
mers.
Table 1 Endo-Diastereoselective (4+2)-Cycloadditions Promoted by
Me2AlCl (Scheme 4)a
Entry
Dienophile
X
endo/exob
opt. rot.c endo-4a–db
1
2
3
4
5
(S)-6a
(R)-6a
(S)-6b
(R)-6c
6d
XSiPr
>95:5
>95:5
83:17
87:13
>95:5
(+)
(–)
(+)
(–)
(±)
59% (3.94 g)
50% (2.13 g)
38% (70 mg)
50% (651 mg)
54% (107 mg)
Installation of the siloxycyclopropane moiety by Furukawa
type cyclopropanation of (–)-endo-4a proceeded unevent-
fully and provided imide (–)-3a (88%, 2.96 g) as a single di-
astereomer (Scheme 7).17 Subsequent Brønsted acid medi-
ated ring-opening of the siloxycyclopropane (–)-3a deliv-
XRiPr
XBn
XPh
XH
ered the cis-hydrindan-4-one
2
(79%, 1.87 g).20 In
a Reaction conditions: 6a–d (1 equiv), (CH2Cl)2, Me2AlCl (1.4 equiv), –25 °C,
10 min; 5 (2 equiv), –25 °C to r.t., then r.t., 2 h.
accordance with our original plan (Scheme 1), the cyclopro-
panation proceeded from the convex face of the bicyclic silyl
enol ether endo-4a leading to the trans-arrangement of the
3a- and 5a-methyl groups on the six-membered B-ring of 2.
b Determined by 1H NMR spectroscopic analysis.
c Sign of optical rotation of the pure endo diastereomer determined as
specified in the Experimental Section.
d Isolated yield (isolated mass) of pure endo diastereomer after purification
by chromatography.
Et2Zn (4 equiv)
XRiPr
O
XRiPr
O
CH2I2 (8 equiv)
CH2Cl2, toluene (5:1)
r.t., 12 h
OBn
OBn
Table 2 Exo-Diastereoselective (4+2)-Cycloadditions Promoted by
MeAlCl2 (Scheme 4)a
88% (2.96 g)
Entry
Dienophile
X
endo/exob
opt. rot.c exo-4a–cd
OTBS
OTBS
1
2
3
(S)-6a
(S)-6b
(R)-6c
XSiPr
XBn
XPh
17:83
6:94
(–)
(–)
(+)
29% (98 mg)
36% (1.9 g)
(–)-3a
(–)-endo-4a
13:87
43% (70 mg)
p-TsOH·H2O (1.2 equiv)
CH2Cl2, reflux, 2 h
79%
(1.87 g)
a Reaction conditions: 6a–c (1 equiv), (CH2Cl)2, MeAlCl2 (1.4 equiv), –25 °C,
10 min; 5 (2 equiv), –25 °C to r.t., then r.t., 12 h.
b Determined by 1H NMR spectroscopic analysis.
XRiPr
O
XRiPr
O
c Sign of optical rotation of the pure exo diastereomer determined as speci-
fied in the Experimental Section.
OH
OBn
H2, Pd/C (0.08 equiv)
10a
d Isolated yield (isolated mass) of pure exo diastereomer after purification
by chromatography.
EtOAc, r.t., 4 h
5a
10b
3a
4
83%, (747 mg)
O
O
(4+2)-cycloaddition (Table 1, entry 5). In the event, the endo
configured cycloadduct 4d was obtained exclusively. In light
of the examples from the literature (Scheme 2), the high
endo-diastereoselectivity of the dimethylaluminum chlo-
ride-promoted (4+2)-cycloaddition between 5 and 6 caught
us by surprise. We speculate that diene 5 is sterically less
demanding compared with dienophiles such as 11a,b and,
hence, the intrinsic preference for an endo-type transition-
state prevails.
(–)-21
(–)-2a
91%
(216 mg)
LAH (0.3 equiv)
toluene, r.t., 4 h
NaBH4
O
O
O
(3 equiv)
O
O
O
MeOH
0 °C, 2 h
Somewhat surprisingly, switching the Lewis acid to
methylaluminum dichloride had a profound influence on
the exo/endo diastereoselectivity of the (4+2)-cycloaddition
(Table 2). Regardless of the nature of the chiral auxiliary, the
formation of the exo-configured cycloadducts 4a–c was fa-
vored, albeit in inferior isolated yields (29−43%) compared
with the dimethylaluminum chloride promoted endo dia-
stereoselective (4+2)-cycloaddition (38−59%). Nevertheless,
by employing the phenylalanine-derived chiral auxiliary
XBn, the diastereomerically pure (4+2)-cycloadduct exo-4b
was accessible on a gram scale (Table 2, entry 2).
O
OH
(4S)-23
15% (13 mg)
OH
(4R)-23
(–)-22
58% (49 mg)
O
O
5a-Me
H4
OH
O
O
10b
H
10b
H
H4 H10a
10a
OH
H
3a-Me
3a-Me
(4R)-23: selected NOE
3a-Me ↔ 4-H
(4S)-23: selected NOE
3a-Me↔ 10a-H
3a-Me ↔10b-H
4H ↔ 5a-Me
3a-Me ↔ 10a-H
3a-Me ↔ 10b-H
10a-H ↔ 10b-H
We next set out to evaluate opportunities for structural
elaboration of the diastereomerically pure (4+2)-cycload-
ducts 4. According to our plan (Scheme 1), we initially fo-
cused on the introduction of the 3a-methyl group by elec-
10a-H ↔ 10b-H
Scheme 7 Introduction of the 3a-methyl group and subsequent struc-
tural elaboration
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3493
S. Steffen et al.
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Synthesis
We next focused on the extrusion of the chiral auxiliary by
lactonization.21 Accordingly, the benzyl protecting group
was removed by hydrogenolysis to afford the γ-hydroxy im-
ide (–)-21 (83%, 747 mg). In our hands, lactonization was
then triggered by treatment of the γ-hydroxy imide (–)-21
with substoichiometric amounts (0.3 equiv) of lithium alu-
minum hydride in toluene at ambient temperature (91%,
216 mg) and without reduction of the C4 carbonyl group.22
We hypothesized that aluminum alkoxide formation and a
directing effect could be responsible for the success of the
lactonization. Having established conditions for extrusion
of the chiral auxiliary, we finally investigated the chemo-
and diastereoselective reduction of ketone 22. Preliminary
experiments revealed that the application of L- or K-Selec-
tride,23 DIBAL-H,24 or Red-Al at low temperature in tetrahy-
drofuran (THF) led to no conversion, possibly as a conse-
quence of the steric congestion in 22. Exposure of ketone 22
to an excess of sodium borohydride in methanol finally de-
livered the desired alcohol 23 as a mixture of diastereomers
(4R/4S ratio 4:1) that were separable by chromatography.
This result indicates a moderate preference for an equatori-
al attack of the hydride from the convex face of the mole-
cule. A similar result was obtained for the reduction of ke-
tone 22 by using NaBH4 (1.5 equiv) in the presence of CeCl3
(1.5 equiv) in MeOH at –30 °C (86%, dr = 69:31).25
1. Et2Zn (6 equiv)
CH2I2 (12 equiv)
CH2Cl2, r.t., 12 h
2. p-TsOH·H2O (1.1 equiv)
CH2Cl2, reflux, 2 h
XSiPr
O
XSiPr
O
OBn
OBn
53% (731 mg)
O
OTBS
(+)-2a
(+)-endo-4a
H2, Pd/C (0.08 equiv)
EtOAc, r.t., 4 h
85%
(1.98 g)
Me(OMe)NH2Cl (3.3 equiv)
N
O
XSiPr
O
i-BuMgCl (6.6 equiv)
THF, Et2O (4:1)
r.t., 12 h
O
OH
OH
86% (418 mg)
O
O
(+)-24
(+)-21
DMP (1.5 equiv)
K2CO3 (3 equiv), CH2Cl2, 0 °C; r.t., 4 h
94%
(140 mg)
BrMg
O
N
O
(18 equiv)
O
O
O
Aiming to add structural elements of the homoverru-
cosane scaffold to the cis-hydrindan-4-one building block 2,
we next set out to explore additional opportunities for the
structural elaboration of the (4+2)-cycloadducts. Thus, ex-
posure of (+)-endo-4a to the chemistry described above de-
livered alcohol (+)-21 (Scheme 8). Treatment of the γ-hy-
droxy imide (+)-21 with an excess of magnesium chloride
methoxy(methyl)amide led to the exposure of the auxiliary
and formation of the corresponding Weinreb amide 24
(86%, 418 mg).26 Notably, attempts to convert the benzyl
ether (–)-2a into the corresponding Weinreb amide had
proven unsuccessful. Dess–Martin oxidation of alcohol 24
proceeded uneventfully and delivered the aldehyde 25 (94%,
140 mg).27 The aldehyde was then subjected to reaction
with (3-methylbut-3-en-1-yl)magnesium bromide28 to af-
ford the trans-γ-lactones (6S)- and (6R)-26 as an equimolar
but separable mixture of diastereomers (84%, 45 mg). The
thus installed C7 to C9 tether could later serve as a handle
for the annulation of the seven-membered C-ring of the ho-
moverrucosane scaffold.
Et2O, THF (1:1)
–78 °C; r.t., 30 min
84% (45 mg)
dr = 1:1
O
O
(+)-25
26
10a
3a-Me
10a
H
H
3a-Me
H10b
H10b
O
H
O
O
O
H
6
6
O
O
5a-Me
5a-Me
(6R)-26: selected NOE
10a-H ↔ 6-H
(6S)-26: selected NOE
5a-Me ↔ 6-H
3a-Me ↔ 10a-H
3a-Me ↔ 10b-H
10a-H ↔ 10b-H
3a-Me ↔ 10a-H
3a-Me ↔ 10b-H
10a-H ↔ 10b-H
Scheme 8 Structural elaboration of cycloadduct (+)-endo-4a by chain
elongation at carbon atom C6
The productive combination of substrate- and auxiliary-
induced diastereoselectivity enabled access to the diaste-
reomerically pure cis-hydrindan-4-ones (+)-2a and (–)-2a
(Scheme 7 and Scheme 8). To explain the complete diastere-
oselectivity of the Furukawa cyclopropanation of endo-4a,
we propose the qualitative stereochemical model depicted
in Scheme 9.29 Assuming that the absolute configuration of
the carbon atom C10b induces a curvature in the bicyclic si-
lyl enol ether scaffold of endo-4a, the convex face should be
more easily accessible by the cyclopropanation reagent. The
preference for an attack from the convex face may be rein-
forced, or at least not attenuated, because of the concavely
directed 5a-methyl group. We then utilized the stereo-
chemical model to predict the outcome of the (2+1)-cy-
cloaddition of the exo-configured (4+2)-cycloadduct exo-4b
(Scheme 9). Accordingly, we expected a preference for the
attack of the cyclopropanation reagent from the convex face
of exo-4b to deliver the desired cis-hydrindan-4-one build-
ing block 2b. In this case, however, the pseudo-axial 5a-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3494
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XSiPr
H
O
XBn
H
O
1. Et2Zn (6 equiv)
CH2I2 (12 equiv)
CH2Cl2
OBn
OBn
10b
3a
10b
3a
0 °C, 1 h, r.t., 12 h
2. p-TsOH·H2O (1.1 equiv)
CH2Cl2, reflux, 2 h
3. H2, Pd/C (0.08 equiv)
EtOAc, r.t., 4 h
5a-Me
5a-Me
XBn
O
XBn
O
4
4
OBn
OH
OTBS
OTBS
(-)-exo-4b
expected:
(+)-endo-4a
exp. verified (Scheme 8):
H
(3aSi,4Re): "convex"
OTBS
O
XBn
OBn
21ba,bb
34% (500 mg)
dr = 77:23
21bc,bd
11% (171 mg)
dr = 91:9
(–)-exo-4b
H
H
TBSO
H
O
5a-Me
XSiPr
OBn
ZnLn
ZnLn
O
(3aRe,4Si): "convex"
1. "ICH2ZnEt"
5a-Me
TBSO
XBn
O
XBn
O
1. "ICH2ZnEt"
2. p-TsOH·H2O
2. p-TsOH·H2O
OBn
OBn
H
3a-MeH
H
XBn
XSiPr
OTBS
OTBS
3a-Me
OBn
O
OBn
O
H
Scheme 10 Cyclopropanation of exo-4b delivered a mixture of four
diastereomers 21ba–bd
O
O
5a-Me
5a-Me
(+)-2a
2b
Scheme 9 Stereochemical model used to explain and predict the dia-
stereoface-differentiation of the electrophilic cyclopropanation using
conditions reported by Furukawa
that the high diastereoselectivities of the initial (4+2)-cy-
cloadditions between 5 and 6 originate from a certainly
asynchronous but still concerted bond reorganization pro-
cess (Diels–Alder reaction).
methyl group is directed toward the convex face of the bicy-
clic silyl enol ether. Thus, we could not a priori preclude an
attenuated diastereoselectivity for the Furukawa cyclopro-
panation of exo-4b.
In conclusion, we have studied a sequence composed of
consecutive (4+2)- and (2+1)-cycloadditions that provides
access to substituted cis-hydrindan-4-one building blocks
from simple starting materials. Deploying a chiral dieno-
phile, the aluminum(III)-promoted (4+2)-cycloaddition
proceeded with complete auxiliary-induced diastereoselec-
tivity. The exo/endo-diastereoselectivity of the (4+2)-cy-
cloaddition could be controlled by the appropriate choice of
the Lewis acid promoter. The diastereoselectivity of the
subsequent Furukawa cyclopropanation turned out to de-
pend on the relative configuration of the (4+2)-cycloadduct.
The (2+1)-cycloaddition of the endo-configured (4+2)-cy-
cloadduct was highly diastereoselective, whereas the cyclo-
propanation of the exo-configured (4+2)-cycloadduct af-
forded a complex mixture of diastereomers. A stereochemi-
cal model was proposed to account for this experimental
finding. Removal of the auxiliary by functional group inter-
conversion, redox chemistry, and C/C-bond formation by
Grignard reaction served to illustrate opportunities for
structural elaboration of the available cis-hydrindan-4-one
building block.
Being confident of the validity of our stereochemical
model (Scheme 9), we proceeded to investigate the (2+1)-
cycloaddition of exo-4b (Scheme 10). Much to our dismay,
however, exposure of the exo-4b cycloaddition product to
the Furukawa cyclopropanation led to the formation of an
inseparable mixture of four diastereomers. Exposure of the
diastereomeric mixture to Brønsted acidic conditions trig-
gered siloxycyclopropane ring-opening. Subsequent benzyl
ether cleavage by hydrogenolysis delivered two separable
pairs of two diastereomers each (21ba,bb and 21bc,bd).
Chromatographic purification allowed isolation of one pure
diastereomer 21bc, however, NOE studies of the mixtures
as well as the pure diastereomer 21bc were inconclusive or
ambiguous; thus, we refrain from assigning relative config-
urations for 21ba–bd.
The formation of four diastereomers and the failure of
our stereochemical model to predict the outcome of the cy-
clopropanation of exo-4b may be explained by assuming
that the orientation of the 5a-methyl group toward the con-
vex face of the bicyclic silyl enol ether decelerates the cyclo-
propanation of exo-4b to a degree that a Lewis acid (ZnLn)-
mediated retro-Michael/Michael reaction equilibrium
emerges as a competitive reaction pathway. Retrospective-
ly, this result and its interpretation support the assumption
Unless otherwise stated, commercially available reagents, catalysts
and solvents were used as purchased. Tetrahydrofuran, dichloro-
methane, acetonitrile, and diethyl ether were dried by deploying a
commercially available solvent purification system. Triethylamine
(Et3N) was dried over KOH followed by distillation from CaH2 and
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3495
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stored under an atmosphere of Argon. CDCl3 was stored over activat-
ed 4 Å molecular sieves. All moisture-sensitive reactions were per-
formed in flame-dried septum-sealed glassware under an atmo-
sphere of argon. Reagents were transferred by using a syringe. Solids
were introduced under a counter-flow of argon. The concentration of
commercially available n-BuLi solutions were confirmed by titration
against diphenylacetic acid.30
tivated 4 Å MS (20 g, beads) were added. To the ethereal solution was
added MeMgBr (1 M in THF, 202.22 mL, 202.22 mmol 1.17 equiv) at
0 °C over a period of 25 min. After addition of the Grignard reagent
was complete, the reaction mixture was diluted by the addition of sat.
aq NH4Cl (200 mL). The phases were separated and the aqueous layer
was extracted with Et2O. The combined organic phases were dried
(MgSO4) and concentrated. Purification of the residue by chromatog-
raphy (cyclohexane–EtOAc, 50:1→20:1→10:1) afforded allylic alcohol
(±)-16.
Analytical TLC was performed using precoated silica gel foils (4 cm).
Visualization was achieved by using 254 nm ultraviolet irradiation
followed by staining with the Kägi–Miescher reagent (p-anisaldehyde
2.53% v/v, acetic acid 0.96% v/v, EtOH 93.06% v/v, concd H2SO4 3.45%
v/v) or the KMnO4 reagent [KMnO4 (3 g), K2CO3 (20 g), NaOH (0.25 g in
5 mL H2O), H2O (300 mL)].31 Unless otherwise specified, chromato-
graphic purification32 was performed on silica gel (particle size
0.040–0.063 mm). Mixtures of cyclohexane and EtOAc or n-pentane
and diethyl ether were used as eluents.
Yield: 12.42 g (110.72 mmol, 64%); colorless liquid; Rf = 0.48 (cyclo-
hexane–EtOAc, 2:1).
IR (film): 3345 (s), 2970 (s), 2950 (s), 2930 (s), 2895 (s), 2845 (s), 1365
(s), 1070 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.28 (d, J = 6.5 Hz, 3 H), 1.88 (m, 3 H),
2.31 (t, J = 7.6 Hz, 4 H), 4.40 (q, J = 6.5 Hz, 1 H), 5.56 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 22.1, 23.4, 31.4, 32.2, 67.3, 124.2,
1H NMR spectra were recorded at 400 or 500 MHz. Chemical shifts (δ)
are reported in ppm relative to chloroform (δ = 7.26 ppm).33 Signal
splitting patterns are labeled as: s = singlet, d = doublet, t = triplet,
q = quartet, quint = quintuplet, sext = sextet, sept = septet, oct = octet,
m = multiplet or overlap of nonequivalent resonances, br = broad,
Ar = aryl, cPr = cyclopropyl, iPr = isopropyl. Coupling constants (Hz)
are given as reported by the NMR processing and analysis software.
13C NMR spectra were recorded at 101 or 126 MHz. Unless otherwise
reported, all 13C NMR spectra were obtained with broadband proton
decoupling. Chemical shifts are reported in ppm relative to CDCl3 (δ =
77.16 ppm); the total number of reported 13C atom signals may fall
short of the expected number because of coincidental chemical shifts,
even for constitutopic or diastereotopic carbon atoms. The NMR peak
assignment as well as the assignment of the relative configuration
rests on the interpretation of 1H1H COSY, 1H13C HSQC and 1H1H NOESY
experiments. Atom numbering is based on the homoverrucosane
numbering system (Figure 1).
148.3.
Anal. Calcd for C7H12O: C, 74.95; H, 10.78. Found: C, 74.9; H, 10.8.
Silyl Enol Ether 5
MnO2 Oxidation: To a solution of allylic alcohol 16 (12.42 g, 110.72
mmol, 1 equiv) in CH2Cl2 (600 mL) at ambient temperature was added
pretreated (2 d at 150 °C) MnO2 (90% w/w, 115.54 g, 103.99 g MnO2,
1196.07 mmol, 10.8 equiv). The reaction mixture was heated to reflux
for 3 h and subsequently filtered through a pad of Celite. The filter
cake was rinsed with CH2Cl2 and the filtrate was concentrated at 800
mbar and 40 °C to a volume of 100 mL. According to NMR analysis,
the solution contained the corresponding enone (11.20 g, 101.68
mmol, 92%) that was sufficiently pure for further transformation. For
analytical purposes, a sample of the enone was purified by chroma-
tography (pentane–Et2O, 50:1→20:1, solvent evaporation at 700 mbar
and 40 °C) to deliver the enone as a clear colorless liquid; Rf = 0.65
(cyclohexane–EtOAc, 2:1).
Unless stated otherwise, IR spectra were recorded as a thin film on a
KBr disk. Infrared absorptions are reported in reciprocal wavelength ν
(cm–1) and are adjusted down- or upward to 0 or 5 cm–1. Relative in-
tensities are indicated as they appeared as: s = strong, m = medium,
w = weak.
IR (film): 2955 (s), 2855 (m), 1705 (m), 1665 (s), 1615 (s), 1375 (s),
1295 (s), 1265 (s), 1045 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.93 (tt, J = 7.6, 7.6 Hz, 2 H), 2.32 (s,
3 H), 2.52–2.58 (m, 4 H), 6.73 (tt, J = 2.0, 2.0 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 23.0, 26.8, 30.6, 34.0, 144.4, 146.3,
Molecular formula assignment was confirmed by combustion ele-
mental analysis using the elemental analyzers Leco CHNS-932 or Ele-
mentar Vario Micro Cube.
196.9.
Silyl Enol Ether Formation: To a solution of the enone (3.12 g, 28.33
mmol, 1 equiv) in CH2Cl2 (200 mL) at 0 °C was successively added Et3N
(0.73 g/mL, 8.70 mL, 6.35 g, 62.76 mmol, 2.2 equiv) and tert-butyldi-
methylsilyl trifluoromethanesulfonate (1.151 g/mL, 7.81 mL, 8.99 g,
34.0 mmol, 1.2 equiv). The reaction mixture was stirred at r.t. for 1.5
h. Evaporation of the volatiles afforded a biphasic residue; the lower
layer was discarded whereas the upper layer was subjected to
Kugelrohr distillation to deliver the acid-labile silyl enol ether 5 at
0.66 mbar and 95–100 °C. The silyl enol ether could be stored up to
four weeks under an atmosphere of argon at –30 °C.15
High-resolution mass spectra were recorded with a LTQ Orbitrap
mass spectrometer using electrospray ionization (ESI).
Melting points (m.p.) are uncorrected and were recorded with a Büchi
B-540 melting point apparatus.
Synthesis of Allylic Alcohol 16 from Cyclohexan-1,2-diol
To a solution of NaIO4 (47.90 g, 223.95 mmol, 1.3 equiv) in H2O (300
mL), was added at r.t. a solution of cyclohexan-1,2-diol (20.0 g, 172.18
mmol, 1 equiv) in Et2O (300 mL). The pH of the reaction mixture was
measured and, if necessary, adjusted to pH 4 by the addition of aq
HNO3 (25% v/v). After being stirred for 30 min at ambient tempera-
ture, a solution (20% w/v, 67 mL) of KOH (13.4 g, 238.8 mmol, 1.4
equiv) in H2O was added and the resulting mixture was stirred at r.t.
for 1 h. The layers were separated and the aqueous phase was extract-
ed with Et2O. The combined organic phases were dried (MgSO4) and
concentrated at 900 mbar and 40 °C bath temperature to a volume of
100 mL. The ethereal solution was diluted with THF (150 mL) and ac-
Yield: 6.18 g (27.54 mmol, 97%); pale-yellow oil; Rf = 0.72 (cyclohex-
ane–EtOAc, 2:1)
1H NMR (500 MHz, CDCl3): δ = 0.18 (s, 6 H), 0.97 (s, 9 H), 1.93 (tt,
J = 7.5, 7.5 Hz, 2 H), 2.43 (t, J = 7.5 Hz, 4 H), 4.27 (d, J = 2.5 Hz, 2 H),
6.00 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 4.6, 18.3, 23.7, 25.9, 32.2, 33.0, 92.6,
128.8, 141.3, 154.1.
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Synthesis
Allylic Alcohol 18 by NaBH4 Reduction
IR (film): 3300–2500 (br. s), 3065 (s), 3030 (s), 2920 (s), 2860 (s),
1695 (s), 1650 (s), 1455 (s), 1425 (s), 1365 (s), 1295 (s), 1255 (s), 1170
To a solution of ethyl (E)-3-methyl-4-oxobut-2-enoate (17) (1.063
g/mL, 25.0 mL, 26.575 g, 186.95 mmol, 1 equiv) in MeOH (500 mL) at
0 °C was added NaBH4 (20.84 g, 550.89 mmol, 3 equiv). After stirring
at ambient temperature for 16 h, the reaction mixture was diluted
with sat. aq NaHCO3 (400 mL). The phases were separated and the
aqueous layer was extracted with EtOAc. The combined organic
phases were dried (MgSO4) and concentrated. The residue was puri-
fied by chromatography (cyclohexane–EtOAc, 10:1→5:1) to give allyl-
ic alcohol 18.
(s), 1105 (s), 735 (s), 700 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.13 (d, J = 1.1 Hz, 3 H), 4.03 (d,
J = 1.4 Hz, 2 H), 4.56 (s, 2 H), 6.08 (tq, J = 1.1, 1.4 Hz, 1 H), 7.29–7.40
(m, 5 H), 11.80 (br. s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 16.2, 72.7, 74.0, 114.5, 127.7, 127.9,
128.6, 137.7, 157.8, 172.3.
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.0; H, 7.2.
Yield: 24.30 g (168.55 mmol, 90%); colorless liquid; Rf = 0.33 (cyclo-
hexane–EtOAc, 2:1).
Preparation of 3-Acryloyloxazolidin-2-ones 6a–d from Carboxylic
Acid 20; General Procedure
IR (film): 3440 (br. s), 2985 (s), 2905 (s), 1715 (s), 1660 (s), 1445 (s),
1385 (s), 1370 (s), 1320 (s), 1280 (s), 1225 (s), 1150 (s), 1080 (s), 1045
To a solution of acid 20 (1.1 equiv) and Et3N (0.73 g/mL, 2.6 equiv) in
THF at 0 °C was added freshly distilled pivaloyl chloride (PivCl; 0.98
g/mL, 1.3 equiv). The resulting suspension was stirred for 30 min at
0 °C. Meanwhile, to a solution of the representative oxazolidin-2-one
(1 equiv) in THF was added n-BuLi (1.1 equiv) at 0 °C. The reaction
mixture was stirred at 0 °C for 10 min and subsequently transferred
to the suspension by syringe. After stirring for 12 h at r.t., the mixture
was diluted with H2O (10 mL/mmol oxazolidin-2-one). The phases
were separated and the aqueous layer was extracted three times with
EtOAc. The combined organic phases were dried (MgSO4) and concen-
trated under reduced pressure. The residue was purified by chroma-
tography (cyclohexane–EtOAc, 50:1→20:1→10:1→5:1) to give the
corresponding imide.
(s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H), 1.95 (t, J =
6.0 Hz, 1 H), 2.08 (d, J = 1.1 Hz, 3 H), 4.13 (dd, J = 7.1 Hz, 2 H), 4.16 (q,
J = 7.1 Hz, 2 H), 5.98 (tq, J = 1.1, 1.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 14.4, 15.7, 59.8, 67.1, 113.7, 157.3,
166.9.
Anal. Calcd for C7H12O3: C, 58.32; H, 8.39. Found: C, 58.3; H, 8.6.
Benzyl Ether 19
To a solution of allylic alcohol 18 (8.75 g, 60.69 mmol, 1 equiv) in ben-
zyl bromide (36 mL) was added at r.t. tetra-n-butyl-ammonium io-
dide (2.24 g, 6.06 mmol, 0.1 equiv). After stirring for 20 min at r.t., the
reaction mixture was chilled to 0 °C and Ag2O (11.24 g, 48.50 mmol,
0.8 equiv) was added in portions. The cooling bath was removed and
the reaction mixture was stirred at r.t. overnight. The mixture was fil-
tered through a plug of Celite and the filter cake was rinsed with Et2O.
The filtrate was dried (MgSO4) and concentrated. The residue was pu-
rified by chromatography (cyclohexane–EtOAc, 100:1→50:1) to give
benzyl ether 19.
(R,E)-3-[4-(Benzyloxy)-3-methylbut-2-enoyl]-4-isopropyloxazoli-
din-2-one [(R)-6a]
According to the general procedure, (R)-6a was prepared from acid 20
(6.03 g, 29.24 mmol, 1.1 equiv), Et3N (0.73 g/mL, 9.63 mL, 7.03 g,
69.47 mmol, 2.7 equiv) and PivCl (0.98 g/mL, 4.25 mL, 4.165 g, 34.54
mmol, 1.3 equiv) in THF (230 mL) as well as (R)-4-isopropyloxazoli-
din-2-one (HXRiPr; 3.32 g, 25.70 mmol, 1 equiv) and added n-BuLi
(2.48 M in hexanes, 11.77 mL, 29.19 mmol, 1.1 equiv) in THF (93 mL)
to give imide (R)-6a.
Yield: 13.08 g (55.83 mmol, 92%); clear colorless oil; Rf = 0.68 (cyclo-
hexane–EtOAc, 2:1).
Yield: 6.61 g (20.83 mmol, 81%); colorless solid; mp 88 °C; Rf = 0.51
(cyclohexane–EtOAc, 2:1); [α]D20 –64.7 (c 0.97, CHCl3).
IR (film): 2980 (s), 2855 (s), 1715 (s), 1660 (s), 1455 (s), 1370 (s), 1320
(s), 1270 (s), 1225 (s), 1150 (s), 1105 (s), 1030 (s) cm–1
.
IR (film): 1775 (s), 1680 (s), 1640 (s), 1385 (s), 1365 (s), 1255 (s), 1210
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz, 3 H), 2.11 (d,
J = 1.1 Hz, 3 H), 4.00 (d, J = 1.4 Hz, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.54
(s, 2 H), 6.01 (tq, J = 1.1, 1.4 Hz, 1 H), 7.28–7.38 (m, 5 H).
13C NMR (126 MHz, CDCl3): δ = 14.4, 15.9, 59.8, 72.6, 74.2, 115.4,
127.7, 127.8, 128.5, 137.9, 154.5, 166.8.
(s), 1185 (s), 1105 (s), 1065 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J = 7.0 Hz, 3 H), 0.92 (d,
J = 7.0 Hz, 3 H), 2.11 (d, J = 1.1 Hz, 3 H), 2.38–2.46 (m, 1 H), 4.07 (d,
J = 1.3 Hz, 2 H), 4.21 (dd, J = 9.0, 3.4 Hz, 1 H), 4.28 (dd, J = 9.0, 8.4 Hz,
1 H), 4.48–4.52 (m, 1 H), 4.58 (s, 2 H), 7.27 (tq, J = 1.1, 1.3 Hz, 1 H),
7.26–7.40 (m, 5 H).
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.7; H, 7.8.
13C NMR (101 MHz, CDCl3): δ = 14.8, 16.8, 18.1, 28.6, 58.4, 63.2, 72.6,
74.5, 115.3, 127.8, 127.8, 128.5, 137.9, 154.0, 156.5, 165.2.
Carboxylic Acid 20 by Saponification
To a solution of LiOH·H2O (6.48 g, 154.43 mmol, 3 equiv) in H2O (117
mL) was added at r.t. a solution of the ester 19 (12.14 g, 51.81 mmol, 1
equiv) in THF (149 mL). After heating to reflux for 14 h, the reaction
mixture was cooled to r.t. and the phases were separated. The organic
layer was extracted twice with H2O. The combined clear yellow aque-
ous solutions were acidified (pH 1) with aq HCl (1 M) and the result-
ing white suspension was extracted three times with EtOAc. The
combined organic phases were dried (MgSO4) and concentrated. The
residue was purified by chromatography (cyclohexane–EtOAc, 20:1)
to give carboxylic acid 20.
Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.3; H,
7.3; N, 4.2.
(S,E)-3-[4-(Benzyloxy)-3-methylbut-2-enoyl]-4-isopropyloxazoli-
din-2-one [(S)-6a]
According to the general procedure, (S)-6a was prepared from acid 20
(7.0 g, 33.94 mmol, 1.1 equiv), Et3N (0.73 g/mL, 11.18 mL, 8.16 g,
80.64 mmol, 2.7 equiv) and PivCl (0.98 g/mL, 4.94 mL, 4.84 g, 40.14
mmol, 1.3 equiv) in THF (230 mL) as well as (S)-4-isopropyloxazoli-
din-2-one (HXSiPr; 3.86 g, 29.89 mmol, 1 equiv) and added n-BuLi
(2.48 M in hexanes, 13.69 mL, 33.95 mmol, 1.1 equiv) in THF (93 mL)
to give imide (S)-6a.
Yield: 9.66 g (46.84 mmol, 90%); colorless oil that solidified at r.t. to
afford colorless crystals; mp 27–28 °C; Rf = 0.23 (cyclohexane–EtOAc,
2:1).
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3497
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Synthesis
Yield: 6.47 g (20.39 mmol, 68%); colorless solid; mp 85 °C; Rf = 0.50
(cyclohexane–EtOAc, 2:1); [α]D20 +63.4 (c 1.0, CHCl3). The spectrocop-
ic data were identical to those reported for (R)-6a.
stirred for 30 min at 0 °C, then the suspension was added to the above
solution at 0 °C over 10 min. The reaction mixture was warmed to r.t.
and, after stirring for 17 h at r.t., the reaction mixture was diluted
with sat. aq NH4Cl (150 mL). The phases were separated and the aque-
ous layer was extracted with CH2Cl2 (3 × 150 mL). The combined or-
ganic phases were extracted with sat. aq NaHCO3 (250 mL), and the
organic layer was separated, dried (MgSO4), and concentrated. The
residue was purified by chromatography (cyclohexane–EtOAc,
10:1→5:1) to give imide 6d.
Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.5; H,
7.5; N, 4.3.
(S,E)-3-[4-(Benzyloxy)-3-methylbut-2-enoyl]-4-benzyloxazolidin-
2-one [(S)-6b]
According to the general procedure, (S)-6b was prepared from acid 20
(7.70 g, 37.34 mmol, 1.1 equiv), Et3N (0.73 g/mL, 12.33 mL, 9.0 g,
88.95 mmol, 2.6 equiv) and PivCl (0.98 g/mL, 5.41 mL, 5.30 g, 43.95
mmol, 1.3 equiv) in THF (360 mL) as well as (S)-4-benzyloxazolidin-
2-one (HXBn; 6.03 g, 34.03 mmol, 1 equiv) and added n-BuLi (2.46 M
in hexanes, 15.22 mL, 37.44 mmol, 1.1 equiv) in THF (200 mL) to give
imide (S)-6b.
Yield: 1.72 g (6.24 mmol, 64%); clear colorless oil; Rf = 0.43 (cyclohex-
ane–EtOAc, 1:1).
IR (film): 3030 (w), 2920 (m), 2855 (m), 1775 (s), 1680 (s), 1640 (s),
1385 (s), 1360 (s), 1270 (s), 1220 (s), 1185 (s), 1110 (s), 1045 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.13 (d, J = 1.3 Hz, 3 H), 4.06 (dd,
J = 8.8, 7.4 Hz, 2 H), 4.07 (d, J = 1.6 Hz, 2 H), 4.40 (dd, J = 8.8, 7.4 Hz,
2 H), 4.57 (s, 2 H), 7.26 (tq, J = 1.3, 1.6 Hz, 1 H), 7.26–7.39 (m, 5 H).
Yield: 9.76 g (26.71 mmol, 78%); colorless solid; mp 53 °C; Rf = 0.47
(cyclohexane–EtOAc, 2:1); [α]D20 +38.9 (c 1.315, CHCl3).
13C NMR (126 MHz, CDCl3): δ = 16.8, 42.7, 61.9, 72.6, 74.5, 114.8,
127.8, 128.5, 137.9, 153.4, 156.8, 165.3.
IR (film): 3030 (w), 2915 (w), 2855 (w), 1775 (s), 1685 (s), 1385 (s),
1325 (s), 1250 (s), 1200 (s), 1180 (s), 1110 (s), 1065 (s) cm–1
.
Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.2; H,
6.5; N, 5.1.
1H NMR (500 MHz, CDCl3): δ = 2.03 (d, J = 1.1 Hz, 3 H), 2.78 (dd,
J = 13.4, 9.8 Hz, 1 H), 3.37 (dd, J = 13.4, 3.3 Hz, 1 H), 4.09 (d, J = 1.3 Hz,
2 H), 4.16 (dd, J = 9.0, 3.1 Hz, 1 H), 4.18–4.22 (m, 1 H), 4.59 (s, 2 H),
4.71–4.76 (m, 1 H), 7.28 (tq, J = 1.1, 1.3 Hz, 1 H), 7.28–7.40 (m, 10 H).
Me2AlCl-Promoted Endo-Diastereoselective (4+2)-Cycloadditions:
General Procedure
13C NMR (101 MHz, CDCl3): δ = 16.9, 38.1, 55.3, 66.1, 72.6, 74.4, 115.2,
127.3, 127.8, 128.5, 129.0, 129.5, 135.6, 137.9, 153.4, 157.0, 165.1.
To a solution of dienophile 6 (1 equiv) in 1,2-dichloroethane (4
mL/mmol dienophile) was slowly added Me2AlCl (0.9 M in heptane,
1.4 equiv) at –25 °C. The reaction mixture was stirred at –25 °C for 10
min. A solution of silyl enol ether 5 (2 equiv) in 1,2-dichloroethane (4
mL/mmol dienophile) was added. The reaction mixture was warmed
to r.t. and stirred for 2 h, then the reaction mixture was diluted with
sat. aq NaHCO3. The phases were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic phases were dried
(MgSO4) and concentrated. The residue was first purified by chroma-
tography on basic Al2O3 (cyclohexane–EtOAc, 100:0→100:1→50:1)
and then by chromatography on silica gel (cyclohexane–EtOAc,
100:1→75:1→50:1) to afford the cycloaddition product endo-4.
Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.2; H,
6.3; N, 3.7.
(R,E)-3-[4-(Benzyloxy)-3-methylbut-2-enoyl]-4-phenyloxazolidin-
2-one [(R)-6c]
According to the general procedure, (R)-6c was prepared from acid 20
(1.39 g, 6.74 mmol, 1.1 equiv), Et3N (0.73 g/mL, 2.22 mL, 1.62 g, 16.0
mmol, 2.6 equiv) and PivCl (0.98 g/mL, 0.98 mL, 0.96 g, 7.96 mmol, 1.3
equiv) in THF (70 mL) as well as (R)-4-phenyloxazolidin-2-one (HXPh
;
1.0 g, 6.13 mmol, 1 equiv) and added n-BuLi (2.48 M in hexanes, 2.72
mL, 6.75 mmol, 1.1 equiv) in THF (mL) to give imide (R)-6c.
MeAlCl2-Promoted Exo-Diastereoselective (4+2)-Cycloadditions:
General Procedure
Yield: 1.79 g (5.09 mmol, 83%); colorless solid; mp 91 °C; Rf = 0.45
(cyclohexane–EtOAc, 2:1); [α]D20 –44.2 (c 0.965, CHCl3).
To a solution of dienophile 6 (1 equiv) in 1,2-dichloroethane (4
mL/mmol dienophile) was added MeAlCl2 (1 M in hexane, 1.4 equiv)
between –25 and –30 °C. After stirring the reaction mixture for 10
min at –25 to –30 °C, a solution of silyl enol ether 5 (2 equiv) in 1,2-
dichloroethane (4 mL/mmol dienophile) was added. After stirring for
12 h at r.t., the reaction mixture was diluted with sat. aq NaHCO3. The
phases were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic phases were dried (MgSO4) and con-
centrated. The residue was first purified by chromatography on basic
Al2O3 (cyclohexane–EtOAc, 100:0→100:1→50:1) and then by chroma-
tography on silica gel (cyclohexane–EtOAc, 100:1→50:1→20:1) to de-
liver cycloaddition product exo-4.
IR (film): 3065 (m), 3030 (m), 2915 (m), 2855 (m), 1780 (s), 1680 (s),
1640 (s), 1495 (s), 1455 (s), 1385 (s), 1325 (s), 1250 (s), 1180 (s), 1110
(s), 1065 (s), 1030 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.03 (d, J = 1.2 Hz, 3 H), 4.05 (s, 2 H),
4.25 (dd, J = 8.8, 4.1 Hz, 1 H), 4.58 (d, J = 1.8 Hz, 2 H), 4.69 (dd, J = 8.8,
8.8 Hz, 1 H), 5.48–5.51 (m, 1 H), 7.29 (tq, J = 1.2, 1.8 Hz, 1 H), 7.28–
7.40 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 16.8, 57.7, 69.9, 72.7, 74.4, 115.0,
126.0, 127.8, 128.5, 128.7, 129.2, 137.9, 139.3, 153.7, 157.3, 164.6.
Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.4; H,
6.3; N, 3.9.
Me2AlCl-Promoted (4+2)-Cycloaddition of (S,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-isopropyloxazolidin-2-one [(+)-6a]: Silyl
Enol Ether (+)-endo-4a (Table 1, entry 1)
(E)-3-[4-(Benzyloxy)-3-methylbut-2-enoyl]oxazolidin-2-one (6d)
To a solution of oxazolidin-2-one (HXH; 2.08 g, 23.9 mmol, 2.46 equiv)
in THF (50 mL) was added n-BuLi (2.3 M in n-hexane, 10.5 mL, 24.15
mmol, 2.5 equiv) at 0 °C. The colorless suspension was stirred at 0 °C
for 15 min and at r.t. for 15 min. Meanwhile, to a solution of acid 20
(2.00 g, 9.70 mmol, 1 equiv) in THF (70 mL) at 0 °C was added Et3N
(0.73 g/mL, 3.25 mL, 2.36 g, 23.3 mmol, 2.4 equiv) and, slowly, PivCl
(0.98 g/mL, 1.43 mL, 1.41 g, 11.6 mmol, 1.2 equiv). The mixture was
To a solution of dienophile (+)-6a (3.91 g, 12.32 mmol, 1 equiv) in 1,2-
dichloroethane (50 mL) was added Me2AlCl (0.9 M in heptane, 19.20
mL, 17.28 mmol, 1.4 equiv) at –25 °C. The reaction mixture was
stirred for 10 min at –25 °C and a solution of silyl enol ether 5 (5.54 g,
24.67 mmol, 2 equiv) in 1,2-dichloroethane (50 mL) was added. After
stirring for 2 h at r.t., the reaction mixture was diluted with sat. aq
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3498
S. Steffen et al.
Paper
Synthesis
NaHCO3 (80 mL). The phases were separated and the aqueous layer
was extracted four times with CH2Cl2. The combined organic phases
were dried (MgSO4) and concentrated. The residue was first purified
by chromatography on basic Al2O3 (particle size 0.05–0.20 mm, cyclo-
hexane–EtOAc, 100:0→100:1→50:1) and then by chromatography on
silica gel (cyclohexane–EtOAc, 100:1→50:1→20:1) to deliver (+)-
endo-4a.
MeAlCl2-Promoted (4+2)-Cycloaddition of (S,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-isopropyloxazolidin-2-one [(+)-6a]: Silyl
Enol Ether (–)-exo-4a (Table 2, entry 1)
To a solution of dienophile (+)-6a (200 mg, 0.63 mmol, 1 equiv) in
1,2-dichloroethane (2 mL) was slowly added MeAlCl2 (1 M in hexane,
0.88 mL, 0.88 mmol, 1.4 equiv) at –30 °C, and the reaction mixture
was stirred at –30 °C for 10 min. A solution of silyl enol ether 5 (282
mg, 1.26 mmol, 2 equiv) in 1,2-dichloroethane (2 mL) was added and
the reaction mixture was warmed to r.t. After stirring for 12 h at r.t.,
the reaction mixture was diluted with sat. aq NaHCO3 (2 mL). The
phases were separated and the aqueous layer was extracted four
times with CH2Cl2. The combined organic phases were dried (MgSO4)
and concentrated. The residue was first purified by chromatography
on basic Al2O3 (particle size 0.05–0.20 mm, cyclohexane–EtOAc,
100:0→100:1→50:1) and then by chromatography on silica gel (cy-
clohexane–EtOAc, 100:1→75:1→50:1) to afford a mixture of diaste-
reomers (35%, dr = 83:17). Further purification delivered the pure cy-
cloadduct (–)-exo-4a.
Yield: 3.94 g (7.27 mmol, 59%); viscous oil that solidified upon stor-
age in the refrigerator; mp 113 °C; Rf = 0.65 (cyclohexane–EtOAc, 2:1);
[α]D20 +77.4 (c 1.0, CHCl3).
IR (film): 2960 (s), 2930 (s), 1780 (s), 1700 (s), 1385 (s), 1360 (s), 1095
(s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.12 (s, 3 H, TBS-CH3), 0.13 (s, 3 H,
TBS-CH3), 0.87 (d, J = 7.0 Hz, 3 H, XiPr-CH3), 0.90 (d, J = 7.0 Hz, 3 H,
XiPr-CH3), 0.93 (s, 9 H, TBS-CH3), 0.93–0.99 (m, 1 H, 1-CH2), 1.03 (s,
3 H, 5a-CH3), 1.37–1.48 (m, 1 H, 2-CH2), 1.71 (dddd, J = 12.3, 7.1, 5.6,
2.3 Hz, 1 H, 2-CH2), 1.80 (dddd, J = 16.9, 2.6, 2.6, 1.3 Hz, 1 H, 5-CH2),
1.90 (ddd, J = 10.9, 6.1, 5.6 Hz, 1 H, 1-CH2), 2.13–2.18 (m, 1 H, 3-CH2),
2.21–2.27 (m, 1 H, 3-CH2), 2.31 (dddd, J = 16.9, 2.6, 2.6, 3.1 Hz, 1 H, 5-
CH2), 2.33–2.39 (m, 1 H, XiPr-CH), 2.48–2.55 (m, 1 H, 10b-CH), 3.18 (d,
J = 8.7 Hz, 1 H, 6-CH2), 3.36 (d, J = 8.7 Hz, 1 H, 6-CH2), 4.17 (dd, J = 9.2,
3.3 Hz, 1 H, XiPr-CH2Re), 4.20 (dd, J = 9.2, 7.3 Hz, 1 H, XiPr-CH2Si), 4.45
(ddd, J = 7.3, 3.6, 3.3 Hz, 1 H, XiPr-CH), 4.46 (d, J = 10.5 Hz, 1 H, 6-
OCH2Ph), 4.52 (d, J = 4.9 Hz, 1 H, 10a-CH), 4.54 (d, J = 10.5 Hz, 1 H, 6-
OCH2Ph), 7.24–7.37 (m, 5 H, Ar-CH).
Yield: 98 mg (0.181 mmol, 29%); viscous oil that solidified upon stor-
age in the refrigerator; mp 113 °C; Rf = 0.69 (cyclohexane–EtOAc, 2:1);
[α]D20 –60.5 (c 0.7, CHCl3).
IR (film): 2955 (s), 2930 (s), 2855 (s), 1775 (s), 1700 (s), 1385 (s), 1375
(s), 1360 (s), 1250 (s), 1205 (s), 1120 (s), 1095 (s), 1025 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.12 (s, 3 H, TBS-CH3), 0.13 (s, 3 H,
TBS-CH3), 0.77 (d, J = 7.0 Hz, 3 H, XiPr-CH3), 0.78 (d, J = 7.0 Hz, 3 H,
13C NMR (126 MHz, CDCl3): δ = –4.0 (TBS-CH3), –3.6 (TBS-CH3), 14.5
(XiPr-CH3), 18.2 (TBS-C), 18.3 (XiPr-CH3), 23.5 (5a-CH3), 24.2 (2-CH2),
25.9 (TBS-CH3), 26.0 (3-CH2), 28.4 (XiPr-CH), 30.3 (1-CH2), 37.7 (5-
CH2), 39.5 (5a-C), 40.8 (10b-CH), 42.6 (10a-CH), 58.9 (XiPr-CH), 62.6
(XiPr-CH2), 73.2 (6-OCH2Ph), 76.7 (6-CH2), 116.1 (3a-C), 127.4 (Ar-CH),
127.5 (Ar-CH), 128.3 (Ar-CH), 138.8 (Ar-C), 140.8 (4-C), 154.1 (XiPr-C),
172.7 (10-C).
X
iPr-CH3), 0.94 (s, 9 H, TBS-CH3), 1.13 (ddd, J = 11.5, 7.8, 3.9 Hz, 1 H, 1-
CH2), 1.28 (s, 3 H, 5a-CH3), 1.50–1.58 (m, 1 H, 2-CH2), 1.67 (dddd,
J = 16.7, 2.6, 2.6, 1.9 Hz, 1 H, 5-CH2), 1.71–1.78 (m, 2 H, 1-CH2, 2-CH2),
2.09 (dddd, J = 16.7, 2.6, 2.6, 3.5 Hz, 1 H, 5-CH2), 2.18–2.25 (m, 2 H,
X
iPr-CH, 3-CH2), 2.31–2.38 (m, 1 H, 3-CH2), 2.70–2.76 (m, 1 H, 10b-
CH), 3.11 (dd, J = 8.8, 8.8 Hz, 1 H, XiPr-CH2Si), 3.24 (d, J = 8.7 Hz, 1 H, 6-
CH2), 3.57 (d, J = 8.6 Hz, 1 H, 6-CH2), 3.76 (dd, J = 8.8, 3.3 Hz, 1 H, XiPr
-
CH2Re), 3.80 (d, J = 10.5 Hz, 1 H, 10a-CH), 4.06 (ddd, J = 8.8, 3.6, 3.3 Hz,
1 H, XiPr-CH), 4.38 (d, J = 12.0 Hz, 1 H, 6-OCH2Ph), 4.47 (d, J = 12.0 Hz,
1 H, 6-OCH2Ph), 7.24–7.34 (m, 5 H, Ar-CH).
Anal. Calcd for C31H47NO5Si: C, 68.72; H, 8.74; N, 2.59. Found: C, 68.8;
H, 8.9; N, 2.6.
13C NMR (126 MHz, CDCl3): δ = –3.8 (TBS-CH3), –3.7 (TBS-CH3), 14.6
(XiPr-CH3), 17.9 (XiPr-CH3), 18.2 (TBS-C), 19.6 (5a-CH3), 23.9 (2-CH2),
25.8 (TBS-CH3), 26.4 (3-CH2), 28.4 (XiPr-CH), 32.0 (1-CH2), 41.3 (5a-C),
Me2AlCl-Promoted (4+2)-Cycloaddition of (R,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-isopropyloxazolidin-2-one [(–)-6a]: Silyl
Enol Ether (–)-endo-4a (Table 1, entry 2)
41.8 (5-CH2), 43.1 (10b-CH), 48.3 (10a-CH), 58.5 (XiPr-CH), 62.2 (XiPr
-
To a solution of the dienophile (–)-6a (2.49 g, 7.85 mmol, 1 equiv) in
1,2-dichloroethane (30 mL) was added Me2AlCl (0.9 M in heptane,
12.21 mL, 10.99 mmol, 1.4 equiv) at –25 °C. The reaction mixture was
stirred for 10 min at –25 °C and a solution of silyl enol ether 5 (3.0 g,
13.37 mmol, 1.7 equiv) in 1,2-dichloroethane (30 mL) was added. Af-
ter stirring for 2 h at r.t., the reaction mixture was diluted with sat. aq
NaHCO3 (50 mL). The phases were separated and the aqueous layer
was extracted four times with CH2Cl2. The combined organic phases
were dried (MgSO4) and concentrated. The residue was first purified
by chromatography on basic Al2O3 (particle size 0.05–0.20 mm, cyclo-
hexane–EtOAc, 100:0→100:1→50:1) and then by chromatography on
silica gel (cyclohexane–EtOAc, 100:1→50:1→20:1) to deliver (–)-
endo-4a.
CH2), 72.9 (6-OCH2Ph), 79.9 (6-CH2), 120.0 (3a-C), 126.8 (Ar-CH),
127.5 (Ar-CH), 128.3 (Ar-CH), 138.8 (Ar-C), 138.8 (4-C), 154.7 (XiPr-C),
175.4 (10-C).
Anal. Calcd for C31H47NO5Si: C, 68.72; H, 8.74; N, 2.59. Found: C, 68.4;
H, 8.7; N, 2.5.
MeAlCl2-Promoted (4+2)-Cycloaddition of (S,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-benzyloxazolidin-2-one [(+)-6b]: Silyl
Enol Ether (–)-exo-4b (Table 2, entry 2)
To a solution of the dienophile (+)-6b (3.29 g, 9.0 mmol, 1 equiv) in
1,2-dichloroethane (35 mL) was slowly added MeAlCl2 (1 M in hex-
ane, 12.6 mL, 12.6 mmol, 1.4 equiv) at –25 °C. The mixture was
stirred at –25 °C for 10 min, then a solution of silyl enol ether 5 (4.04
g, 18.0 mmol, 2 equiv) in 1,2-dichloroethane (2 mL) was added. The
reaction mixture was warmed to r.t. and stirred for 12 h and then di-
luted with sat. aq NaHCO3 (30 mL). The phases were separated and
the aqueous layer was extracted four times with CH2Cl2. The com-
bined organic phases were dried (MgSO4) and concentrated. The resi-
due was first purified by chromatography on basic Al2O3 (particle size
0.05–0.20 mm, cyclohexane–EtOAc, 100:0→100:1→50:1) and then by
Yield: 2.13 g (3.93 mmol, 50%); viscous oil that solidified upon stor-
age in the refrigerator; mp 113 °C; Rf = 0.64 (cyclohexane–EtOAc, 2:1);
20
[α]D –78.4 (c 1.085, CHCl3). The spectrocopic data were identical to
those reported for (+)-endo-4a.
Anal. Calcd for C31H47NO5Si: C, 68.72; H, 8.74; N, 2.59. Found: C, 69.1;
H, 9.0; N, 2.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3499
S. Steffen et al.
Paper
Synthesis
chromatography
on
silica
gel
(cyclohexane–EtOAc,
CH2Ph), 3.19 (d, J = 8.8 Hz, 1 H, 6-CH2), 3.39 (d, J = 8.8 Hz, 1 H, 6-CH2),
3.42 (dd, J = 13.1, 3.0 Hz, 1 H, XBn-CH2Ph), 4.09 (dd, J = 9.4, 3.5 Hz, 1 H,
X
100:1→75:1→50:1) to afford a mixture of diastereomers (dr = 94:6).
Further purification delivered the pure cycloadduct (−)-exo-4b.
Bn-CH2Re), 4.11 (dd, J = 9.4, 7.0 Hz, 1 H, XBn-CH2Si), 4.48 (d, J = 12.1 Hz,
1 H, 6-CH2OBn), 4.51 (d, J = 7.0 Hz, 1 H, 10a-CH), 4.55 (d, J = 12.1 Hz,
1 H, 6-OCH2Ph), 4.65–4.69 (m, 1 H, XBn-CH), 7.24–7.37 (m, 10 H, Ar-
CH).
13C NMR (126 MHz, CDCl3): δ = –4.1 (TBS-CH3), –3.5 (TBS-CH3), 18.2
(TBS-C), 23.6 (5a-CH3), 24.2 (2-CH2), 25.9 (TBS-CH3), 26.1 (3-CH2),
30.3 (1-CH2), 37.8 (5-CH2), 38.2 (XBn-CH2Ph), 39.5 (5a-C), 40.8 (10b-
CH), 42.8 (10a-CH), 56.0 (XBn-CH), 65.6 (XBn-CH2), 73.2 (6-OCH2Ph),
76.7 (6-CH2), 116.2 (3a-C), 127.3 (Ar-CH), 127.4 (Ar-CH), 127.6 (Ar-
CH), 128.3 (Ar-CH), 129.0 (Ar-CH), 129.5 (Ar-CH), 135.9 (Ar-C), 138.7
(Ar-C), 140.9 (4-C), 153.4 (XBn-C), 172.6 (10-C).
Yield: 1.90 g (3.22 mmol, 36%); viscous oil; Rf = 0.76 (cyclohex-
ane−EtOAc, 2:1); [α]D20 −8.3 (c 1.1, CHCl3).
IR (film): 2955 (s), 2930 (s), 1780 (s), 1695 (s), 1375 (s), 1350 (s), 1250
(s), 1205 (s), 1100 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.13 (s, 3 H, TBS-CH3), 0.14 (s, 3 H,
TBS-CH3), 0.94 (s, 9 H, TBS-CH3), 1.09–1.21 (m, 1 H, 1-CH2), 1.31 (s,
3 H, 5a-CH3), 1.50–1.61 (m, 1 H, 2-CH2), 1.69 (dddd, J = 16.8, 2.6, 2.6,
1.9 Hz, 1 H, 5-CH2), 1.74–1.84 (m, 2 H, 2-CH2, 1-CH2), 2.12 (dddd,
J = 16.8, 2.6, 2.6, 3.3 Hz, 1 H, 5-CH2), 2.20–2.28 (m, 1 H, 3-CH2), 2.31–
2.40 (m, 1 H, 3-CH2), 2.51 (dd, J = 13.2, 10.1 Hz, 1 H, XBn-CH2Ph), 2.72–
2.82 (m, 1 H, 10b-CH), 3.12 (dd, J = 8.8, 8.8 Hz, 1 H, XBn-CH2Si), 3.25
(dd, J = 13.2, 3.0 Hz, 1 H, XBn-CH2Ph), 3.26 (d, J = 8.6 Hz, 1 H, 6-CH2),
3.57 (d, J = 8.6 Hz, 1 H, 6-CH2), 3.71 (dd, J = 8.8, 3.2 Hz, 1 H, XBn-CH2Re),
3.79 (d, J = 10.6 Hz, 1 H, 10a-CH), 4.26–4.32 (m, 1 H, XBn-CH), 4.36 (d,
J = 12.0 Hz, 1 H, 6-OCH2Ph), 4.46 (d, J = 12.0 Hz, 1 H, 6-OCH2Ph), 7.11–
7.31 (m, 10 H, Ar-CH).
Anal. Calcd for C35H47NO5Si: C, 71.27; H, 8.03; N, 2.37. Found: C, 71.4;
H, 8.2; N, 2.3.
MeAlCl2-Promoted (4+2)-Cycloaddition of (R,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-phenyloxazolidin-2-one [(–)-6c]: Silyl
Enol Ether (+)-exo-4c (Table 2, entry 3)
13C NMR (101 MHz, CDCl3): δ = –3.8 (TBS-CH3), –3.7 (TBS-CH3), 18.2
(TBS-C), 19.5 (5a-CH3), 23.9 (2-CH2), 25.8 (TBS-CH3), 26.4 (3-CH2),
32.0 (1-CH2), 38.4 (XBn-CH2Ph), 41.4 (5a-C), 41.7 (5-CH2), 43.0 (10b-
CH), 48.5 (10a-CH), 55.3 (XBn-CH), 65.3 (XBn-CH2), 73.0 (6-OCH2Ph),
79.8 (6-CH2), 120.0 (3a-C), 126.8 (Ar-CH), 127.1 (Ar-CH), 127.5 (Ar-
CH), 128.3 (Ar-CH), 128.8 (Ar-CH), 129.3 (Ar-CH), 135.8 (Ar-C), 138.6
(Ar-C), 138.8 (4-C), 154.1 (XBn-C), 175.5 (10-C).
To a solution of dienophile (–)-6c (100 mg, 0.28 mmol, 1 equiv) in
1,2-dichloroethane (1 mL) was slowly added MeAlCl2 (1 M in hexane,
0.39 mL, 0.39 mmol, 1.4 equiv) at –25 °C. The reaction mixture was
stirred at –25 °C for 10 min and then a solution of silyl enol ether 5
(128 mg, 0.57 mmol, 2 equiv) in 1,2-dichloroethane (1 mL) was add-
ed. The reaction mixture was warmed to r.t. and stirred for 12 h, then
diluted with sat. aq NaHCO3 (2 mL). The phases were separated and
the aqueous layer was extracted four times with CH2Cl2. The com-
bined organic phases were dried (MgSO4) and concentrated. The resi-
due was first purified by chromatography on basic Al2O3 (particle size
0.05–0.20 mm, cyclohexane–EtOAc, 100:0→100:1→50:1) and then
Anal. Calcd for C35H47NO5Si: C, 71.27; H, 8.03; N, 2.37. Found: C, 71.1;
H, 8.2; N, 2.3.
Me2AlCl-Promoted (4+2)-Cycloaddition of (S,E)-3-(4-(benzyloxy)-
3-methylbut-2-enoyl)-4-benzyloxazolidin-2-one (+)-6b: Silyl Enol
Ether (+)-endo-4b (Table 1, entry 3)
by
chromatography
on
silica
gel
(cyclohexane–EtOAc,
100:1→75:1→50:1) to afford a mixture of diastereomers (dr = 87:13).
Further purification delivered the pure cycloadduct (+)-exo-4c.
To a solution of dienophile (+)-6b (115 mg, 0.315 mmol, 1 equiv) in
1,2-dichloroethane (1.5 mL) was slowly added Me2AlCl (0.9 M in hep-
tane, 0.48 mL, 0.43 mmol, 1.4 equiv) at –25 °C. The reaction mixture
was stirred at –25 °C for 10 min, then a solution of silyl enol ether 5
(141 mg, 0.63 mmol, 2 equiv) in 1,2-dichloroethane (1.5 mL) was add-
ed. The reaction mixture was warmed to r.t. and stirred for 12 h, then
diluted with sat. aq NaHCO3 (1.5 mL). The phases were separated and
the aqueous layer was extracted four times with CH2Cl2. The com-
bined organic phases were dried (MgSO4) and concentrated. The resi-
due was first purified by chromatography on basic Al2O3 (particle size
0.05–0.20 mm, cyclohexane–EtOAc, 100:0→100:1→50:1) and then
Yield: 70 mg (0.12 mmol, 43%); viscous oil; Rf = 0.72 (cyclohexane–
EtOAc, 2:1); [α]D20 +15.4 (c 0.98, CHCl3).
IR (film): 2955 (s), 2929 (s), 1780 (s), 1705 (s), 1383 (s), 1175 (s), 1099
(s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.11 (s, 3 H, TBS-CH3), 0.11 (s, 3 H,
TBS-CH3), 0.93 (s, 9 H, TBS-CH3), 0.93–1.02 (m, 1 H, 1-CH2), 1.24 (s,
3 H, 5a-CH3), 1.24–1.40 (m, 2 H, 1-CH2, 2-CH2), 1.60–1.67 (m, 1 H, 2-
CH2), 1.67 (dddd, J = 16.8, 2.7, 2.7, 1.7 Hz, 1 H, 5-CH2), 2.10 (dddd,
J = 16.8, 2.7, 2.7, 3.2 Hz, 1 H, 5-CH2), 2.13–2.19 (m, 1 H, 3-CH2), 2.23–
2.34 (m, 1 H, 3-CH2), 2.49–2.57 (m, 1 H, 10b-CH), 3.29 (d, J = 8.6 Hz,
1 H, 6-CH2), 3.57 (dd, J = 8.9, 8.9 Hz, 1 H, XPh-CH2Re), 3.66 (d, J = 8.9 Hz,
1 H, 6-CH2), 3.74 (d, J = 10.5 Hz, 1 H, 10a-CH), 3.79 (dd, J = 8.9, 4.8 Hz,
by
chromatography
on
silica
gel
(cyclohexane–EtOAc,
100:1→75:1→50:1) to afford a mixture of diastereomers (dr = 83:17).
Further purification delivered the pure cycloadduct (+)-endo-4b.
1 H,
X
Ph-CH2Si), 4.40 (d, J = 11.8 Hz, 1 H, 6-OCH2Ph), 4.52 (d,
J = 11.8 Hz, 1 H, 6-OCH2Ph), 4.79 (dd, J = 8.9, 4.8 Hz, 1 H, XPh-CH),
7.13–7.42 (m, 10 H, Ar-CH).
Yield: 70 mg (0.12 mmol, 38%); viscous oil; Rf = 0.74 (cyclohexane–
EtOAc, 2:1); [α]D20 +159.7 (c 0.85, CHCl3).
13C NMR (101 MHz, CDCl3): δ = –3.9 (TBS-CH3), –3.8 (TBS-CH3), 18.2
(TBS-C), 19.7 (5a-CH3), 23.8 (2-CH2), 25.8 (TBS-CH3), 26.3 (3-CH2),
31.7 (1-CH2), 41.4 (5a-C), 41.7 (5-CH2), 43.0 (10b-CH), 48.6 (10a-CH),
58.0 (XPh-CH), 68.9 (XPh-CH2), 73.0 (6-OCH2Ph), 80.0 (6-CH2), 120.1
(3a-C), 125.9 (Ar-CH), 127.1 (Ar-CH), 127.6 (Ar-CH), 128.3 (Ar-CH),
128.4 (Ar-CH), 129.0 (Ar-CH), 138.6 (Ar-C), 138.8 (Ar-C), 139.9 (4-C),
154.4 (XPh-C), 174.8 (10-C).
IR (film): 3065 (w), 3030 (w), 2955 (s), 2930 (s), 2855 (s), 1780 (s),
1700 (s), 1455 (s), 1385 (s), 1350 (s), 1260 (s), 1210 (s), 1175 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.16 (s, 3 H, TBS-CH3), 0.16 (s, 3 H,
TBS-CH3), 0.95 (s, 9 H, TBS-CH3), 0.97–1.05 (m, 1 H, 1-CH2), 1.08 (s,
3 H, 5a-CH3), 1.40–1.50 (m, 1 H, 2-CH2), 1.73 (dddd, J = 12.3, 7.3, 6.2,
2.2 Hz, 1 H, 2-CH2), 1.82 (dddd, J = 16.9, 2.7, 2.7, 1.3 Hz, 1 H, 5-CH2),
1.94 (ddd, J = 11.0, 6.0, 5.5 Hz, 1 H, 1-CH2), 2.16–2.24 (m, 1 H, 3-CH2),
2.23–2.31 (m, 1 H, 3-CH2), 2.40 (dddd, J = 16.9, 2.7, 2.7, 3.0 Hz, 1 H, 5-
Anal. Calcd for C34H45NO5Si: C, 70.92; H, 7.88; N, 2.43. Found: C, 71.0;
H, 7.7; N, 2.4.
CH2), 2.52–2.58 (m, 1 H, 10b-CH), 2.57 (dd, J = 13.1, 10.9 Hz, 1 H, XBn
-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3500
S. Steffen et al.
Paper
Synthesis
Me2AlCl-Promoted (4+2)-Cycloaddition of (R,E)-3-[4-(Benzyloxy)-
3-methylbut-2-enoyl]-4-phenyloxazolidin-2-one [(–)-6c]: Silyl
Enol Ether (–)-endo-4c (Table 1, entry 4)
Yield: 107 mg (0.214 mmol, 54%); colorless viscous oil; Rf = 0.24 (cy-
clohexane–EtOAc, 5:1).
IR (film): 3065 (m), 3030 (m), 2930 (s), 2855 (s), 1770 (s), 1700 (s),
1470 (s), 1385 (s), 1360 (s), 1335 (s), 1255 (s), 1220 (s), 1175 (s), 1100
To a solution of dienophile (−)-6c (800 mg, 2.28 mmol, 1 equiv) in 1,2-
dichloroethane (12 mL) was slowly added Me2AlCl (0.9 M in heptane,
3.54 mL, 3.19 mmol, 1.4 equiv) at –25 °C. The reaction mixture was
stirred at –25 °C for 10 min and then a solution of silyl enol ether 5
(1.02 g, 4.55 mmol, 2 equiv) in 1,2-dichloroethane (12 mL) was added.
The reaction mixture was warmed to r.t. and stirred for 2 h, then the
reaction mixture was diluted with sat. aq NaHCO3 (10 mL). The phases
were separated and the aqueous layer was extracted four times with
CH2Cl2. The combined organic phases were dried (MgSO4) and con-
centrated. The residue was first purified by chromatography on basic
(s), 1040 (s), 1010 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.13 (s, 3 H, TBS-CH3), 0.13 (s, 3 H,
TBS-CH3), 0.84 (m, 1 H, 1-CH2Re), 0.93 (s, 9 H, TBS-CH3), 1.06 (s, 3 H,
5a-CH3), 1.42 (m, 1 H, 2-CH2Re), 1.70 (dddd, J = 12.7, 7.8, 5.6, 2.4 Hz,
1 H, 2-CH2Si), 1.79 (dddd, J = 17.0, 2.6, 2.6, 1.5 Hz, 1 H, 5-CH2Re), 1.84
(ddd, J = 11.4, 6.8, 5.6 Hz, 1 H, 1-CH2Si), 2.14–2.27 (m, 2 H, 3-CH2),
2.35 (dddd, J = 17.0, 2.6, 2.6, 3.2 Hz, 1 H, 5-CH2Si), 2.49 (m, 1 H, 10b-
CH), 3.18 (d, J = 8.8 Hz, 1 H, 6-CH2Re), 3.38 (d, J = 8.8 Hz, 1 H, 6-CH2Si),
3.98 (m, 2 H, XH-CH2), 4.34 (m, 2 H, XH-CH2), 4.47 (d, J = 12.3 Hz, 1 H,
6-OCH2PhRe), 4.55 (d, J = 12.3 Hz, 1 H, 6-OCH2PhSi), 4.56 (d, J = 7.0 Hz,
1 H, 10a-CH), 7.24–7.37 (m, 5 H, Ph-CH).
13C NMR (101 MHz, CDCl3): δ = –4.0 (TBS-CH3), –3.5 (TBS-CH3), 18.2
(TBS-C), 23.6 (5a-CH3), 24.1 (2-CH2), 25.9 (TBS-CH3), 26.1 (3-CH2),
30.4 (1-CH2), 37.7 (5-CH2), 39.4 (5a-C), 40.6 (10b-CH), 42.6 (XH-CH2),
42.9 (10a-CH), 61.4 (XH-CH2), 73.2 (6-OCH2Ph), 76.6 (6-CH2), 115.9
(3a-C), 127.4 (Ar-CH), 127.5 (Ar-CH), 128.3 (Ar-CH), 138.7 (Ar-C),
140.9 (4-C), 153.5 (XH-C), 173.1 (10-C).
Al2O3
(particle
size
0.05–0.20
mm,
cyclohexane–EtOAc,
100:0→100:1→50:1) and then by chromatography on silica gel (cy-
clohexane–EtOAc, 100:1→75:1→50:1) to afford a mixture of diaste-
reomers (dr = 83:17). Further purification delivered the pure cycload-
duct (–)-endo-4c.
Yield: 651 mg (1.13 mmol, 50%); viscous oil; Rf = 0.70 (cyclohexane–
EtOAc, 2:1); [α]D20 –125.9 (c 0.75, CHCl3).
IR (film): 2955 (s), 2929 (s), 2855 (s), 1780 (s), 1705 (s), 1385 (s), 1320
(s), 1260 (s), 1175 (s), 1100 (s) cm–1
.
Anal. Calcd for C28H41NO5Si: C, 67.30; H, 8.27; N, 2.80. Found: C, 67.6;
H, 8.5; N, 2.7.
1H NMR (500 MHz, CDCl3): δ = 0.03 (s, 3 H, TBS-CH3), 0.07 (s, 3 H,
TBS-CH3), 0.39–0.48 (m, 1 H, 1-CH2), 0.89 (s, 9 H, TBS-CH3), 1.08 (s,
3 H, 5a-CH3), 1.20–1.31 (m, 1 H, 2-CH2), 1.36–1.43 (m, 1 H, 2-CH2),
1.65 (ddd, J = 11.1, 6.1, 5.5 Hz, 1 H, 1-CH2), 1.75 (dddd, J = 16.9, 2.7,
2.7, 1.3 Hz, 1 H, 5-CH2), 1.93–2.04 (m, 2 H, 3-CH2), 2.27 (dddd,
J = 16.9, 2.7, 2.7, 3.1 Hz, 1 H, 5-CH2), 2.41–2.47 (m, 1 H, 10b-CH), 3.16
(d, J = 8.8 Hz, 1 H, 6-CH2), 3.35 (d, J = 8.8 Hz, 1 H, 6-CH2), 4.28 (dd,
J = 8.8, 2.8 Hz, 1 H, XPh-CH2Si), 4.45 (d, J = 12.4 Hz, 1 H, 6-OCH2Ph),
4.53 (d, J = 6.8 Hz, 1 H, 10a-CH), 4.54 (d, J = 12.4 Hz, 1 H, 6-OCH2Ph),
4.62 (dd, J = 8.8, 8.8 Hz, 1 H, XPh-CH2Re), 5.43 (dd, J = 2.8, 8.8 Hz, 1 H,
Siloxycyclopropane (–)-3a by Cyclopropanation
To a solution of (–)-endo-4a (3.29 g, 6.07 mmol, 1 equiv) in CH2Cl2
(135 mL) was successively added Et2Zn (1.1 M in toluene, 22.07 mL,
24.28 mmol, 4 equiv) and CH2I2 (3.325 g/mL, 3.91 mL, 13.0 g 48.54
mmol, 8 equiv) at 0 °C. The cooling bath was removed and the reac-
tion mixture was stirred at r.t. for 12 h, then sat. aq NaHCO3 (100 mL)
was added and the phases were separated. The aqueous layer was ex-
tracted three times with CH2Cl2 and the combined organic layers
were extracted once with aq NaS2O3 and then dried (MgSO4) and con-
centrated. The residue was purified by chromatography (cyclohex-
ane–EtOAc, 100:1→50:1) to provide siloxycyclopropane (−)-3a.
X
Ph-CH), 7.24–7.37 (m, 10 H, Ar-CH).
13C NMR (126 MHz, CDCl3): δ = –4.2 (TBS-CH3), –3.7 (TBS-CH3), 18.1
(TBS-C), 23.5 (5a-CH3), 24.0 (2-CH2), 25.8 (3-CH2), 25.9 (TBS-CH3),
29.7 (1-CH2), 37.7 (5-CH2), 39.5 (5a-C), 41.0 (10b-CH), 42.7 (10a-CH),
57.9 (XPh-CH), 69.3 (XPh-CH2), 73.2 (6-OCH2Ph), 76.7 (6-CH2), 116.2
(3a-C), 126.7 (Ar-CH), 127.4 (Ar-CH), 127.5 (Ar-CH), 128.3 (Ar-CH),
128.7 (Ar-CH), 128.9 (Ar-CH), 138.8 (Ar-C), 139.4 (Ar-C), 140.5 (4-C),
153.7 (XPh-C), 172.1 (10-C).
Yield: 2.96 g (5.33 mmol, 88%); colorless viscous oil that solidified
upon storage in the refrigerator; mp 74 °C; Rf = 0.52 (cyclohexane–
EtOAc, 5:1); [α]D20 –52.8 (c 1.0, CHCl3).
IR (film): 2955 (s), 2935 (s), 2855 (m), 1780 (s), 1700 (s), 1245 (s),
1225 (s), 1205 (s) cm–1
.
Anal. Calcd for C34H45NO5Si: C, 70.92; H, 7.88; N, 2.43. Found: C, 70.8;
H, 7.8; N, 2.5.
1H NMR (500 MHz, CDCl3): δ = 0.04 (s, 3 H, TBS-CH3), 0.13 (s, 3 H,
TBS-CH3), 0.60 (d, J = 5.2 Hz, 1 H, cPr-CH2), 0.76 (d, J = 5.2 Hz, 1 H, cPr-
CH2), 0.83 (d, J = 6.9 Hz, 3 H, XiPr-CH3), 0.86 (d, J = 6.9 Hz, 3 H, XiPr
-
Me2AlCl-Promoted (4+2)-Cycloaddition of (E)-3-[4-(Benzyloxy)-3-
methylbut-2-enoyl]oxazolidin-2-one (6d): Silyl Enol Ether
(±)-endo-4d (Table 1, entry 5)
CH3), 0.86 (s, 9 H, TBS-CH3), 1.23 (s, 3 H, 5a-CH3), 1.43–1.53 (m, 2 H,
3-CH2, 1-CH2), 1.60–1.67 (m, 1 H, 2-CH2), 1.72 (d, J = 14.3 Hz, 1 H, 5-
CH2), 1.76–1.83 (m, 2 H, 1-CH2, 2-CH2), 1.96 (d, J = 14.3 Hz, 1 H, 5-
CH2), 2.10–2.16 (m, 1 H, 3-CH2), 2.22–2.29 (m, 1 H, XiPr-CH), 2.55
(ddd, J = 10.1, 7.4, 2.7 Hz, 1 H, 10b-CH), 3.05 (d, J = 8.8 Hz, 1 H, 6-CH2),
3.38 (d, J = 8.8 Hz, 1 H, 6-CH2), 3.73 (d, J = 7.4 Hz, 1 H, 10a-CH), 3.81
To a solution of dienophile 6d (110 mg, 0.40 mmol, 1 equiv) in 1,2-
dichloroethane (1 mL) was slowly added a solution of Me2AlCl (0.9 M
in n-heptane, 0.62 mL, 0.56 mmol, 1.4 equiv). The colorless turbid re-
action mixture was stirred at –25 °C for 10 min. A stock solution of
the silyl enol ether 5 in 1,2-dichloroethane (0.1 M, 1.2 mL, 1.2 mmol,
3 equiv) was added. The reaction mixture was warmed to r.t., stirred
for 21.5 h, then diluted with sat. aq potassium sodium tartrate (2 mL).
The mixture was diluted with H2O (2 mL) and CH2Cl2 (2 mL), and sub-
sequently stirred at r.t. for 3 h. The phases were separated and the
aqueous layer was extracted three times with CH2Cl2. The combined
organic phases were extracted with sat. aq NaCl (10 mL) and then
dried (MgSO4). Evaporation of all volatiles delivered a residue that
was purified by chromatography on silica gel (cyclohexane–EtOAc,
100:1) to afford the silyl enol ether (±)-endo-4d.
(dd, J = 8.8, 8.8 Hz, 1 H, XiPr-CH2Re), 4.02 (dd, J = 8.8, 2.6 Hz, 1 H, XiPr
-
CH2Si), 4.23 (ddd, J = 8.8, 3.1, 2.6 Hz, 1 H, XiPr-CH), 4.30 (d, J = 12.2 Hz,
1 H, 6-OCH2Ph), 4.47 (d, J = 12.2 Hz, 1 H, 6-OCH2Ph), 7.22–7.33 (m,
5 H, Ph-CH).
13C NMR (126 MHz, CDCl3): δ = –3.5 (TBS-CH3), –3.3 (TBS-CH3), 14.5
(XiPr-CH3), 17.9 (TBS-C), 18.1 (XiPr-CH3), 19.3 (5a-CH3), 25.5 (2-CH2),
25.8 (TBS-CH3), 26.5 (cPr-CH2), 28.3 (XiPr-CH), 29.4 (3a-C), 31.7 (1-
CH2), 31.9 (3-CH2), 38.6 (5a-C), 40.1 (10b-CH), 42.1 (10a-CH), 47.5 (5-
CH2), 57.1 (4-C), 58.2 (XiPr-CH), 62.6 (XiPr-CH2), 73.0 (6-OCH2Ph), 77.7
(6-CH2), 126.9 (Ar-CH), 127.3 (Ar-CH), 128.3 (Ar-CH), 138.9 (Ar-C),
153.5 (XiPr-C), 174.5 (10-C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3501
S. Steffen et al.
Paper
Synthesis
Anal. Calcd for C32H49NO5Si: C, 69.15; H, 8.89; N, 2.52. Found: C, 69.3;
H, 9.1; N, 2.4.
J = 11.0 Hz, 1 H, 6-CH2), 4.20 (dd, J = 9.0, 3.2 Hz, 1 H, XiPr-CH2Si), 4.29
(dd, J = 9.0, 9.0 Hz, 1 H, XiPr-CH2Re), 4.52 (ddd, J = 9.0, 3.5, 3.2 Hz, 1 H,
XiPr-CH), 4.71 (d, J = 6.0 Hz, 1 H, 10a-CH).
13C NMR (126 MHz, CDCl3): δ = 14.6 (XiPr-CH3), 18.1 (XiPr-CH3), 19.9
(5a-CH3), 23.3 (2-CH2), 25.9 (3a-CH3), 28.3 (XiPr-CH), 28.8 (1-CH2),
36.0 (3-CH2), 41.5 (10a-CH), 43.6 (5a-C), 47.7 (5-CH2), 49.1 (10b-CH),
55.5 (3a-C), 58.4 (XiPr-CH), 63.0 (XiPr-CH2), 70.7 (6-CH2), 154.1 (XiPr-C),
174.1 (10-C), 215.0 (4-C).
Ketone (–)-2a by Brønsted Acid Mediated Cyclopropane Ring-
Opening
To a solution of siloxycyclopropane (–)-3 (2.96 g, 5.33 mmol, 1 equiv)
in CH2Cl2 (70 mL) was added p-toluenesulfonic acid monohydrate
(1.22 g, 6.41 mmol, 1.2 equiv). The reaction mixture was heated to re-
flux for 2 h and subsequently diluted with H2O (10 mL) at r.t. The pH
of the resulting mixture was adjusted to 8–9 by the addition of aq
NaOH (1 M). The phases were separated and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated. Purification of the residue by chro-
matography (cyclohexane–EtOAc, 50:1→20:1→10:1) delivered ketone
(–)-2a.
Anal. Calcd for C19H29NO5: C, 64.93; H, 8.32; N, 3.99. Found: C, 64.7; H,
8.2; N, 3.9.
γ-Lactone (–)-22 by LAH-Mediated Lactonization
To a solution of alcohol (–)-21 (375 mg, 1.07 mmol, 1 equiv) in tolu-
ene (17 mL) was added LiAlH4 (12 mg, 0.32 mmol, 0.3 equiv) at
–78 °C. After 10 min, the reaction mixture was warmed to r.t., stirred
for 4 h and then diluted with sat. aq NH4Cl (10 mL). The layers were
separated and the aqueous phase was extracted three times with
EtOAc. The combined organic phases were dried and concentrated.
Purification of the residue by chromatography (cyclohexane–EtOAc,
10:1→5:1→3.5:1) delivered lactone (–)-22.
Yield: 1.87 g (4.23 mmol, 79%); colorless viscous oil; Rf = 0.57 (cyclo-
hexane–EtOAc, 2:1); [α]D20 –103.5 (c 1.05, CHCl3).
IR (film): 2965 (s), 2875 (s), 1780 (s), 1735 (m), 1705 (s), 1455 (s),
1385 (s), 1375 (s), 1300 (s), 1225 (s), 1205 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.84 (d, J = 7.0 Hz, 3 H, XiPr-CH3), 0.86
(d, J = 7.0 Hz, 3 H, XiPr-CH3), 1.20 (s, 3 H, 5a-CH3), 1.26–1.32 (m, 1 H, 3-
CH2), 1.33 (s, 3 H, 3a-CH3), 1.48–1.60 (m, 1 H, 1-CH2; 2 H, 2-CH2),
1.73–1.80 (m, 1 H, 1-CH2), 1.99 (d, J = 14.1 Hz, 1 H, 5-CH2), 2.20–2.27
(m, 1 H, XiPr-CH), 2.47–2.52 (m, 1 H, 3-CH2), 2.54 (ddd, J = 12.7, 5.8,
3.0 Hz, 1 H, 10b-CH), 2.84 (d, J = 14.0 Hz, 1 H, 5-CH2), 3.10 (d,
J = 8.9 Hz, 1 H, 6-CH2), 3.36 (d, J = 8.9 Hz, 1 H, 6-CH2), 3.91 (dd, J = 9.0,
9.0 Hz, 1 H, XiPr-CH2Re), 4.07 (dd, J = 9.0, 3.0 Hz, 1 H, XiPr-CH2Si), 4.26
(ddd, J = 9.0, 3.5, 3.0 Hz, 1 H, XiPr-CH), 4.41 (d, J = 12.3 Hz, 1 H, 6-
OCH2Ph), 4.49 (d, J = 12.3 Hz, 1 H, 6-OCH2Ph), 4.78 (d, J = 5.8 Hz, 1 H,
10a-CH), 7.26–7.35 (m, 5 H, Ar-CH).
13C NMR (126 MHz, CDCl3): δ = 14.7 (XiPr-CH3), 18.0 (XiPr-CH3), 20.6
(5a-CH3), 23.3 (2-CH2), 25.9 (3a-CH3), 28.4 (XiPr-CH), 28.7 (1-CH2),
36.0 (3-CH2), 41.8 (10a-CH), 42.9 (5a-C), 48.5 (5-CH2), 49.0 (10b-CH),
55.6 (3a-C), 58.2 (XiPr-CH), 62.8 (XiPr-CH2), 73.2 (6-OCH2Ph), 78.1 (6-
CH2), 127.4 (Ar-CH), 127.6 (Ar-CH), 128.4 (Ar-CH), 138.4 (Ar-C), 153.7
(XiPr-C), 173.8 (10-C), 214.9 (4-C)
Yield: 216 mg (0.97 mmol, 91%); colorless solid; mp 80 °C; Rf = 0.5
(cyclohexane–EtOAc, 1:1); [α]D20 –58.3 (c 1.0, CHCl3).
IR (film): 2965 (s), 1780 (s), 1705 (s), 1115 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.10 (s, 3 H, 5a-CH3), 1.26 (s, 3 H, 3a-
CH3), 1.39–1.47 (m, 1 H, 3-CH2), 1.48–1.61 (m, 1 H, -CH2; 2 H, 2-CH2),
2.06–2.12 (m, 1 H, 1-CH2), 2.36–2.41 (m, 1 H, 3-CH2), 2.40 (d,
J = 13.8 Hz, 1 H, 5-CH2), 2.46–2.51 (m, 1 H, 10b-CH), 2.68 (d,
J = 13.8 Hz, 1 H, 5-CH2), 3.03 (d, J = 6.0 Hz, 1 H, 10a-CH), 4.01 (d,
J = 8.5 Hz, 1 H, 6-CH2), 4.05 (d, J = 8.5 Hz, 1 H, 6-CH2).
13C NMR (126 MHz, CDCl3): δ = 20.7 (5a-CH3), 24.5 (2-CH2), 26.7 (3a-
CH3), 28.3 (1-CH2), 36.9 (3-CH2), 44.0 (10b-CH), 44.0 (5a-C), 47.2
(10a-CH), 48.8 (5-CH2), 55.3 (3a-C), 78.5 (6-CH2), 174.7 (10-C), 212.5
(4-C).
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 69.9; H, 7.8.
Hydroxylactones (4R)-23 and (4S)-23 by NaBH4 Reduction
Anal. Calcd for C26H35NO5: C, 70.72; H, 7.99; N, 3.17. Found: C, 70.6; H,
8.2; N, 3.0.
To a solution of lactone (–)-22 (85 mg, 0.38 mmol, 1 equiv) in MeOH
(8 mL) was added NaBH4 (43 mg, 1.14 mmol, 3 equiv) at 0 °C. After
stirring at 0 °C for 2 h, the reaction mixture was diluted with sat. aq
NH4Cl (6 mL), the layers were separated and the aqueous phase was
extracted three times with EtOAc. The combined organic phases were
dried (MgSO4) and concentrated. The residue was purified by chro-
matography (cyclohexane–EtOAc, 2:1→1:1→0:1) to deliver a mixture
of the diastereomeric alcohols (73%, dr = 4:1). The diastereomers
were separated by chromatography to provide the major diastereo-
mer (4R)-23 and the minor diastereomer (4S)-23 as colorless solids.
Alcohol (–)-21 by Benzyl Ether Cleavage
To a solution of the ketone (–)-2a (1.13 g, 2.56 mmol, 1 equiv) in
EtOAc (20 mL) was added Pd/C (10% w/w, 218 mg, 22 mg Pd, 106.42
g/mol, 0.20 mmol, 0.08 equiv). The flask was evacuated and vented
with argon three times. Hydrogen was then passed through the reac-
tion mixture at r.t. for 4 h, then the reaction mixture was filtered
through a plug of Celite. The Celite cake was rinsed with EtOAc and
the solvent was evaporated. The residue was purified by chromatog-
raphy (cyclohexane–EtOAc, 10:1→5:1) to give alcohol (–)-21.
Major Diastereomer (4R)-23
Yield: 747 mg (2.12 mmol, 83%); colorless solid; mp 134 °C; Rf = 0.63
(cyclohexane–EtOAc, 0:1); [α]D20 –147.8 (c 1.0, CHCl3).
Yield: 49 mg (0.22 mmol, 58%); colorless solid; mp 196 °C; Rf = 0.4
(cyclohexane–EtOAc, 1:1); [α]D20 –45.7 (c 1.0, CHCl3).
IR (film): 3435 (m), 2965 (s), 2930 (m), 2875 (m), 1770 (s), 1705 (s),
IR (film): 3515 (s), 2960 (m), 2930 (m), 1760 (s) cm–1
.
1385 (s), 1375 (s), 1205 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.07 (s, 3 H, 3a-CH3), 1.44 (s, 3 H, 5a-
CH3), 1.51 (ddd, J = 13.3, 10.4, 6.4 Hz, 1 H, 3-CH2), 1.64 (br. s, 1 H, OH),
1.65–1.73 (m, 1 H, 2-CH2), 1.78–1.84 (m, 1 H, 2-CH2), 1.86 (d,
J = 4.0 Hz, 2 H, 5-CH2), 1.84–1.90 (m, 1 H, 1-CH2), 1.98–2.02 (m, 1 H,
1-CH2), 2.00–2.04 (m, 1 H, 3-CH2), 2.13–2.18 (m, 1 H, 10b-CH), 2.52
(d, J = 4.9 Hz, 1 H, 10a-CH), 3.78 (t, J = 4.0 Hz, 1 H, 4-CH), 3.82 (d,
J = 7.8 Hz, 1 H, 6-CH2), 3.98 (d, J = 7.8 Hz, 1 H, 6-CH2).
1H NMR (500 MHz, CDCl3): δ = 0.88 (d, J = 7.0 Hz, 3 H, XiPr-CH3), 0.91
(d, J = 7.0 Hz, 3 H, XiPr-CH3), 1.15 (s, 3 H, 5a-CH3), 1.28–1.32 (m, 1 H, 3-
CH2), 1.33 (s, 3 H, 3a-CH3), 1.48–1.64 (m, 2 H, 2-CH2; 1 H, 1-CH2),
1.72–1.80 (m, 1 H, 1-CH2), 1.95 (d, J = 14.0 Hz, 1 H, 5-CH2), 1.99 (br,
1 H, OH), 2.26–2.32 (m, 1 H, XiPr-CH), 2.50 (ddd, J = 12.6, 6.4, 6.0 Hz,
1 H, 3-CH2), 2.58 (ddd, J = 12.6, 6.0, 3.2 Hz, 1 H, 10b-CH), 2.78 (d,
J = 14.0 Hz, 1 H, 5-CH2), 3.25 (d, J = 11.0 Hz, 1 H, 6-CH2), 3.50 (d,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3502
S. Steffen et al.
Paper
Synthesis
13C NMR (126 MHz, CDCl3): δ = 22.7 (5a-CH3), 24.2 (2-CH2), 27.2 (1-
CH2), 27.6 (3a-CH3), 36.4 (3-CH2), 38.2 (5-CH2), 40.3 (5a-C), 42.9 (10b-
CH), 47.1 (3a-C), 47.4 (10a-CH), 74.9 (4-CH), 82.1 (6-CH2), 176.3 (10-
C)
Yield: 1.98 g (5.63 mmol, 85%); colorless solid; mp 137 °C; Rf = 0.63
(cyclohexane–EtOAc, 0:1); [α]D20 +131.2 (c 1.55, CHCl3).
Anal. Calcd for C19H29NO5: C, 64.93; H, 8.32; N, 3.99. Found: C, 65.3; H,
8.5; N, 4.0.
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.2; H, 8.9.
The NMR and IR data matched those reported for (–)-21.
Minor Diastereomer (4S)-23
Weinreb Amide (+)-24
Yield: 13 mg (0.06 mmol, 15%); colorless solid; mp 176 °C; Rf = 0.22
(cyclohexane–EtOAc, 1:1); [α]D20 –121.5 (c 0.75, CHCl3).
To a solution of alcohol (+)-21 (600 mg, 1.71 mmol, 1 equiv) in THF
(22 mL) was successively added N,O-dimethylhydroxylamine hydro-
chloride (549 mg, 5.63 mmol, 3.3 equiv) and i-BuMgCl (2 M in Et2O,
5.64 mL, 11.3 mmol, 6.6 equiv) at 0 °C. The cooling bath was removed
and the reaction mixture was stirred at r.t. for 12 h. Sat. aq NH4Cl (16
mL) was added, the phases were separated, and the aqueous layer was
extracted three times with EtOAc. The combined organic phases were
dried (MgSO4) and concentrated. Purification of the residue by chro-
matography (cyclohexane–EtOAc, 5:1→2:1→1:1) provided amide (+)-
24.
IR (film): 3515 (s), 2960 (m), 2930 (m), 1760 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.06 (s, 3 H, 3a-CH3), 1.23 (s, 3 H, 5a-
CH3), 1.41 (ddd, J = 13.1, 9.3, 5.4 Hz, 1 H, 3-CH2), 1.53 (dd, J =12.0,
12.0 Hz, 1 H, 5-CH2), 1.55–1.61 (m, 1 H, 1-CH2), 1.69–1.76 (m, 2 H, 2-
CH2), 1.83 (dd, J = 12.0, 4.4 Hz, 1 H, 5-CH2), 1.92–2.04 (m, 2 H, 3-CH2,
1-CH2), 2.21 (ddd, J = 10.1, 5.0, 5.1 Hz, 1 H, 10b-CH), 2.51 (d,
J = 5.0 Hz, 1 H, 10a-CH), 3.82 (dd, J = 12.0, 4.4 Hz, 1 H, 4-CH), 3.89 (d,
J = 8.2 Hz, 1 H, 6-CH2), 3.98 (d, J = 8.2 Hz, 1 H, 6-CH2); no OH-signal
detected.
13C NMR (126 MHz, CDCl3): δ = 19.0 (3a-CH3), 20.7 (5a-CH3), 23.1 (2-
CH2), 26.0 (1-CH2), 38.0 (3-CH2), 39.4 (5-CH2), 42.9 (5a-C), 43.8 (10b-
CH), 47.4 (3a-C), 47.6 (10a-CH), 69.9 (4-CH), 80.6 (6-CH2), 175.8 (10-
C).
Yield: 418 mg (1.48 mmol, 86%); colorless solid; mp 98 °C; Rf = 0.38
(cyclohexane–EtOAc, 0:1); [α]D20 +80.2 (c 1.05, CHCl3).
IR (film): 3445 (s), 2960 (s), 2875 (s), 1700 (s), 1650 (s), 1455 (s), 1425
(s), 1375 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.08 (s, 3 H, 5a-CH3), 1.26 (s, 3 H, 3a-
CH3), 1.34 (ddd, J = 12.7, 7.7, 6.4 Hz, 1 H, 3-CH2), 1.46–1.62 (m, 2 H, 2-
CH2), 1.78 (dt, J = 8.5, 7.6 Hz, 2 H, 1-CH2), 2.09 (dd, J = 5.8, 4.5 Hz, 1 H,
OH), 2.17 (d, J = 14.8 Hz, 1 H, 5-CH2), 2.36–2.44 (m, 2 H, 10b-CH, 3-
CH2), 2.65 (d, J = 14.8 Hz, 1 H, 5-CH2), 3.19 (s, 3 H, N-CH3), 3.26 (dd,
J = 10.9, 5.8 Hz, 1 H, 6-CH2), 3.47 (dd, J = 10.9, 4.5 Hz, 1 H, 6-CH2), 3.67
(d, J = 5.7 Hz, 1 H, 10a-CH), 3.77 (s, 3 H, N-OCH3).
13C NMR (126 MHz, CDCl3): δ = 20.6 (5a-CH3), 23.3 (2-CH2), 26.5 (3a-
CH3), 29.5 (1-CH2), 32.2 (N-CH3), 36.3 (3-CH2), 39.1 (10a-CH), 43.1
(5a-C), 46.9 (5-CH2), 48.9 (10b-CH), 54.6 (3a-C), 61.8 (N-OCH3), 70.5
(6-CH2), 175.0 (10-C), 215.6 (4-C).
Ketone (+)-2a
Cyclopropanation: To a solution of (+)-endo-4a (1.70 g, 3.14 mmol, 1
equiv) in CH2Cl2 (70 mL) were successively added Et2Zn (1.1 M in tolu-
ene, 17.13 mL, 18.84 mmol, 6 equiv) and CH2I2 (3.325 g/mL, 3.04 mL,
10.11 g, 37.75 mmol, 12 equiv) at 0 °C. The cooling bath was removed
and the reaction mixture was stirred at r.t. for 12 h. Sat. aq NaHCO3
(60 mL) was added, the phases were separated, and the aqueous layer
was extracted three times with CH2Cl2. The combined organic phases
were extracted with aq Na2S2O3 and then dried (MgSO4). The solvents
were removed and the residue was purified by chromatography (cy-
clohexane–EtOAc, 100:1→50:1) to afford the corresponding siloxycy-
clopropane (1.16 g, 2.09 mmol, 67%).
Anal. Calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C, 63.7; H,
9.0; N, 4.9.
Siloxycyclopropane Ring-Opening: To a solution of the siloxycyclopro-
pane (1.16 g, 2.09 mmol, 1 equiv) in CH2Cl2 (27 mL) was added p-tol-
uenesulfonic acid monohydrate (477 mg, 2.51 mmol, 1.2 equiv). After
stirring and heating to reflux for 2 h, the reaction mixture was diluted
with H2O (5 mL). The pH of the biphasic mixture was adjusted to 8–9
by the addition of aq NaOH (1 M). The phases were separated and the
aqueous layer was extracted three times with CH2Cl2. The combined
organic phases were dried (MgSO4) and the solvents were evaporated.
The residue was purified by chromatography (cyclohexane–EtOAc,
50:1→20:1→10:1) to give ketone (+)-2a.
Aldehyde (+)-25 By Dess–Martin Oxidation
To a solution of amide (+)-24 (150 mg, 0.53 mmol, 1 equiv) in CH2Cl2
(12 mL) at 0 °C was added K2CO3 (219 mg, 1.59 mmol, 3 equiv) and
Dess–Martin periodinane (337 mg, 0.80 mmol, 1.5 equiv). After stir-
ring at r.t. for 4 h, sat. aq Na2S2O3 (10 mL) was added. The phases were
separated and the aqueous layer was extracted three times with
CH2Cl2. The combined organic phases were dried (MgSO4) and con-
centrated. The residue was purified by chromatography (cyclohex-
ane–EtOAc, 5:1→2:1→1:1) to deliver aldehyde (+)-25.
Yield: 140 mg (0.50 mmol, 94%); colorless solid; mp 80 °C; Rf = 0.52
(cyclohexane–EtOAc, 0:1); [α]D20 +45.4 (c 1.1, CHCl3).
IR (film): 2960 (s), 1725 (s), 1700 (s), 1650 (s), 1460 (s) cm–1
Yield: 731 mg (1.66 mmol, 79%); colorless viscous oil; Rf = 0.57 (cyclo-
hexane–EtOAc, 2:1); [α]D20 +105.5 (c, 1.0 CHCl3).
.
The NMR and IR data matched those reported for (–)-2a.
1H NMR (500 MHz, CDCl3): δ = 1.07 (s, 3 H, 3a-CH3), 1.19 (s, 3 H, 5a-
CH3), 1.37–1.51 (m, 2 H, 1-CH2, 2-CH2), 1.52–1.62 (m, 2 H, 3-CH2, 2-
CH2), 1.89–1.95 (m, 1 H, 1-CH2), 2.07–2.13 (m, 1 H, 3-CH2), 2.16 (ddd,
J = 9.8, 8.3, 6.2 Hz, 1 H, 10b-CH), 2.33 (d, J = 17.3 Hz, 1 H, 5-CH2), 2.95
(d, J = 17.3 Hz, 1 H, 5-CH2), 3.20 (s, 3 H, N-CH3), 3.68 (d, J = 6.2 Hz, 1 H,
10a-CH), 3.76 (s, 3 H, N-OCH3), 9.48 (s, 1 H, 6-H).
13C NMR (126 MHz, CDCl3): δ = 21.0 (5a-CH3), 23.4 (2-CH2), 27.5 (3a-
CH3), 31.2 (1-CH2), 32.7 (N-CH3), 37.0 (3-CH2), 40.6 (10a-CH), 41.2 (5-
CH2), 47.0 (10b-CH), 50.9 (5a-C), 52.5 (3a-C), 61.6 (N-OCH3), 161.7
(10-C), 202.7 (6-C), 212.9 (4-C).
Alcohol (+)-21 by Benzyl Ether Cleavage
To a solution of the ketone (+)-2 (2.92 g, 6.61 mmol, 1 equiv) in EtOAc
(52 mL) was added Pd/C (10% w/w, 562.7 mg, 56.3 mg Pd, 106.42
g/mol, 0.53 mmol, 0.08 equiv) at r.t.. The reaction mixture was de-
gassed three times by evacuation and venting with argon. Hydrogen
was then bubbled through the reaction mixture over 4 h, then the re-
action mixture was filtered through a plug of Celite. The filter cake
was rinsed with EtOAc. The solvent was removed and the residue was
purified by chromatography (cyclohexane–EtOAc, 10:1 to 5:1) to de-
liver the alcohol (+)-21.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

3503
S. Steffen et al.
Paper
Synthesis
Anal. Calcd for C15H23NO4: C, 64.03; H, 8.24; N, 4.98. Found: C, 64.2; H,
8.2; N, 4.8.
sic mixture was adjusted to 8–9 by the addition of aq NaOH (1 M).
The phases were separated and the aqueous layer was extracted three
times with CH2Cl2. The combined organic phases were dried (MgSO4)
and concentrated. The residue was purified by chromatography (cy-
clohexane–EtOAc, 50:1→20:1) to afford the corresponding ketone as
an inseparable mixture of four diastereomers (934 mg, 1.91 mmol,
72%).
Lactone 26 by Grignard Reaction
To a solution of aldehyde (+)-25 (52 mg, 0.185 mmol, 1 equiv) in THF
(2 mL) at –78 °C was slowly added a solution of Grignard reagent pre-
pared from Mg (81 mg, 3.33 mmol, 18 equiv) and 4-bromo-2-methyl-
but-1-ene (500 mg, 3.35 mmol, 18 equiv) in Et2O (2 mL). When the
addition was complete, the cooling bath was removed and the reac-
tion mixture was stirred at r.t. for 30 min. The reaction mixture was
diluted with sat. aq NH4Cl (1 mL), the phases were separated, and the
aqueous layer was extracted three times with EtOAc. The combined
organic phases were dried (MgSO4) and concentrated. The residue
Alcohol 21bc by Benzyl Ether Cleavage: To a solution of the ketone (934
mg, 1.91 mmol, 1 equiv) in EtOAc (30 mL) at ambient temperature
was added Pd/C (10% w/w, 162 mg, 16.2 mg Pd, 106.42 g/mol, 0.152
mmol, 0.08 equiv). The flask was evacuated and vented with argon
three times. Hydrogen from a balloon was bubbled through the reac-
tion mixture over 4 h, then the reaction mixture was filtered through
Celite and the filter cake was rinsed with EtOAc. The solvent was re-
moved and the residue was purified by chromatography (cyclohex-
ane–EtOAc, 10:1→5:1→3.5:1) to deliver alcohol 21ba−bd (C23H29NO5,
399.49 g/mol) as two mixtures (21ba,bb: colorless viscous oil, 500
mg, 1.25 mmol, 66%, dr = 77:23; 21bc,bd: colorless viscous oil, 171
mg, 0.43 mmol, 22%, dr = 91:9) of two diastereomers each. A diaste-
reomerically pure sample of 21bc [Rf = 0.48 (cyclohexane–EtOAc,
1:1)] was obtained and its analytical data are listed below.
was
purified
by
chromatography
(cyclohexane–EtOAc,
10:1→5:1→2:1→1:1) to provide lactone 26.
Yield: 45 mg (0.155 mmol, 84%); colorless solid; mixture of C-6 dia-
stereomers (1:1); mp 71 °C; Rf = 0.57 (cyclohexane–EtOAc, 1:1).
IR (film): 2965 (s), 1780 (s), 1705 (s), 1450 (s), 1370 (s) cm–1
.
NMR data are listed for the mixture of diastereomers using the label
‘*’ to assign distinguishable signals.
1H NMR (500 MHz, CHCl3): δ = 0.92 (s, 3 H, 5a*-CH3), 1.11 (s, 3 H, 5a-
CH3), 1.25 (s, 3 H, 3a-CH3; 3 H, 3a*-CH3), 1.38–1.45 (m, 1 H, 3-CH2;
1 H, 3*-CH2), 1.47–1.56 (m, 1 H, 1-CH2; 1 H, 1*-CH2), 1.54–1.67 (m,
2 H, 2-CH2; 2 H, 2*-CH2; 1 H, 7-CH2; 1 H, 7*-CH2), 1.72 (s, 3 H, 9*-CH3),
1.73 (s, 3 H, 9-CH3), 1.75–1.86 (m, 1 H, 7-CH2; 1 H, 7*-CH2), 2.07–2.14
(m, 1 H, 1-CH2; 1 H, 1*-CH2; 1 H, 8-CH2; 1 H, 8*-CH2), 2.21–2.29 (m,
1 H, 8-CH2; 1 H, 8*-CH2), 2.26 (d, J = 13.5 Hz, 1 H, 5-CH2), 2.34 (d,
J = 13.7 Hz, 1 H, 5*-CH2), 2.36–2.41 (m, 1 H, 3-CH2; 1 H, 3*-CH2), 2.45–
2.51 (m, 1 H, 10b*-CH; 1 H, 10b-CH), 2.61 (d, J = 13.7 Hz, 1 H, 5*-CH2),
2.69 (d, J = 13.5 Hz, 1 H, 5-CH2), 3.06 (d, J = 5.9 Hz, 1 H, 10a*-CH), 3.18
(d, J = 6.0 Hz, 1 H, 10a-CH), 4.06 (dd, J = 3.6, 10.8 Hz, 1 H, 6-CH), 4.11
(dd, J = 3.7, 9.3 Hz, 1 H, 6*-CH), 4.71 (s, 2 H, 9*-CH2), 4.78 (s, 2 H, 9-
CH2).
13C NMR (126 MHz, CDCl3): δ = 15.8 (5a*-CH3), 22.4 (9*-CH3), 22.6 (9-
CH3), 23.6 (5a-CH3), 24.4 (2-CH2), 24.5 (2*-CH2), 26.7 (7*-CH2), 26.7
(3a*-CH3), 26.9 (3a-CH3), 27.3 (7-CH2), 28.6 (1*-CH2), 28.7 (1-CH2),
33.7 (8-CH2), 33.9 (8*-CH2), 36.9 (3-CH2), 36.9 (3*-CH2), 43.9 (10a-
CH), 44.0 (10b-CH), 44.0 (10b*-CH), 45.0 (5a-C), 46.5 (5a*-C), 47.1 (5-
CH2), 48.6 (5*-CH2), 49.3 (10a*-CH), 55.1 (3a*-C), 55.3 (3a-C), 87.3
(6*-CH), 87.7 (6-CH), 111.1 (9-CH2), 111.2 (9*-CH2), 144.0 (9*-C),
144.1 (9-C), 174.5 (10-C), 174.6 (10*-C), 212.6 (4*-C), 213.1 (4-C).
IR (film): 3500 (m, OH), 2965 (s), 1775 (s), 1700 (s), 1385 (s), 1350 (s),
1210 (s), 1100 (s), 1050 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.00 (s, 3 H, 5a-CH3), 1.15 (s, 3 H, 3a-
CH3), 1.32–1.43 (m, 1 H, 1-CH2), 1.52 (ddd, J = 12.9, 8.9, 3.5 Hz, 1 H, 3-
CH2), 1.79–1.87 (m, 1 H, 1-CH2), 1.89–1.97 (m, 1 H, 2-CH2), 1.97 (d,
J = 14.7 Hz, 1 H, 5-CH2), 2.00–2.08 (m, 1 H, 2-CH2; 1 H, 3-CH2), 2.60
(dd, J = 11.9, 6.7 Hz, 1 H, 10b-CH), 2.67 (dd, J = 10.6, 13.3 Hz, 1 H, XBn
-
CH2Ph), 2.72 (br. s, 1 H, 6-OH), 2.96 (d, J = 14.7 Hz, 1 H, 5-CH2), 3.35
(d, J = 12.0 Hz, 1 H, 6-CH2), 3.40 (d, J = 12.0 Hz, 1 H, 6-CH2), 3.43 (dd,
J = 3.4, 13.3 Hz, 1 H, XBn-CH2Ph), 4.21 (dd, J = 9.4, 6.8 Hz, 1 H, XBn
-
CH2Si), 4.22 (dd, J = 9.4, 3.2 Hz, 1 H, XBn-CH2Re), 4.27 (d, J = 11.9 Hz, 1 H,
10a-CH), 4.73–4.78 (m, 1 H, XBn-CH), 7.23–7.37 (m, 5 H, Ar-CH).
13C NMR (126 MHz, CDCl3): δ = 17.6 (5a-CH3), 21.8 (2-CH2), 21.9 (3a-
CH3), 30.2 (1-CH2), 36.6 (3-CH2), 38.0 (XBn-CH2Ph), 44.5 (5a-C), 46.1
(10a-CH), 46.4 (5-CH2), 50.4 (10b-CH), 54.9 (3a-C), 56.4 (XBn-CH),
66.4 (XBn-CH2), 70.6 (6-CH2), 127.5 (Ar-CH), 129.1 (Ar-CH), 129.4 (Ar-
CH), 135.4 (Ar-C), 154.7 (XBn-C), 174.1 (10-C), 213.9 (4-C).
Acknowledgment
Anal. Calcd for C18H26O3: C, 74.45; H, 9.02. Found: C, 74.4; H, 9.2.
Financial Support by the TU Dortmund is gratefully acknowledged.
Hydroxyketone 21bc
Supporting Information
Cyclopropanation: To a solution of cycloadduct (–)-exo-4b (2.20 g,
3.73 mmol, 1 equiv) in CH2Cl2 (88 mL) at 0 °C were successively added
CH2I2 (3.325 g/mL, 3.61 mL, 12.0 g, 44.80 mmol, 12 equiv) and Et2Zn
(1.1 M in toluene, 20.34 mL, 22.37 mmol, 6 equiv). After stirring at
0 °C for 1 h and at r.t. for 12 h, the reaction mixture was diluted with
sat. aq NaHCO3 (60 mL). The phases were separated and the aqueous
layer was extracted three times with CH2Cl2. The combined organic
phases were dried (MgSO4) and concentrated. The residue was puri-
fied by chromatography (cyclohexane–EtOAc, 100:1→50:1) to deliver
the corresponding siloxycyclopropane as an inseparable mixture of
four diastereomers (1.60 g, 2.65 mmol, 71%).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378880.
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References
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Siloxycyclopropane Ring-Opening: To a solution of the siloxycyclopro-
pane (1.60 g, 2.65 mmol, 1 equiv) in CH2Cl2 (35 mL) was added p-tol-
uenesulfonic acid monohydrate (557 mg, 2.93 mmol, 1.1 equiv). After
stirring and heating to reflux for 2 h, the reaction mixture was cooled
to r.t. and subsequently diluted with H2O (5 mL). The pH of the bipha-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504

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Synthesis
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tion of diagnostic 1H NMR signals. The assignment of the rela-
tive configuration rests on the interpretation of NOESY experi-
ments. The absolute configuration of the (4+2)-cycloaddition
products is proposed based on the transition-state model
depicted in Scheme 6.
(2) (a) Rho, J.-R.; Lee, H.-S.; Sim, C. J.; Shin, J. Tetrahedron 2002, 58,
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(3) For selected examples for intermolecular (4+2)-cycloaddition
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(8) For the MeAlCl2-promoted exo diastereoselective (4+2)-
cycloaddition between an acyclic diene and a chiral (XSiPr) N-
acryloyl oxazolidinone, see: Roush, W. R.; Limberakis, C.; Kunz,
R. K.; Barda, D. A. Org. Lett. 2002, 4, 1543.
(9) Waldmann has reported the Et2AlCl-promoted (4+2)-cycloaddi-
tion between tiglic aldehyde and diene 11b in toluene (−20 to 5
°C) to proceed with a diastereoselectivity of endo/exo = 84:16
(68%); the dr improved upon deployment of EtAlCl2•THF in
CH2Cl2 at −78 °C to endo/exo = 99:1 (81%), see: Brohm, D.;
Waldmann, H. Tetrahedron Lett. 1998, 39, 3995.
(10) A completely exo diastereoselective (4+2)-cycloaddition
between the diene 11b and an elaborated enone promoted by
EtAlCl2 (1.5 equiv) and THF (1 equiv) in CH2Cl2 at r.t. was
revealed by Danishefsky, see: Yoon, T.; Danishefsky, S. J.; de
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(21) All attempts to remove the auxiliary from benzyl ether (–)-2a
were unsuccessful. Application of DIBAL-H or LAH led to the
reductive opening of the oxazolidinone and isolation of the cor-
responding amide. No notable conversion was obtained using
various alternative reagents: LiBH4, NaBH4, NaOMe, LiOOH,
MeOMgBr as well as Me(OMe)NH2Cl/AlMe3 or Me(OMe)NH2Cl/
i-PrMgCl.
(22) Running the reaction in ethereal solvents or in the presence of
more than 0.3 equiv of LAH or DIBAL-H led to the undesired
reductive ring-opening of the auxiliary and hydroxy amide for-
mation.
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7512.
(15) Brønsted acidic impurities triggered the decomposition of diene
5. However, complete recovery was possible after stirring a
solution of 5 in CH2Cl2 and H2O (1:1) at r.t. overnight. After
Kugelrohr distillation of 5, residual water was removed under
fine vacuum conditions at 5 × 10−2 mbar.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3489–3504