Syntheses of the hexahydroindene cores of indanomycin and stawamycin by combinations of iridium-catalyzed asymmetric allylic alkylations and intramolecular diels-alder reactions

Article abstract of DOI:10.1002/chem.201202822

Short and concise syntheses of the hexahydroindene cores of the antibiotics indanomycin (X-14547 A) and stawamycin are presented. Key methods used are an asymmetric iridium-catalyzed allylic alkylation, a modified Julia olefination, a Suzuki-Miyaura coupling, and an intramolecular Diels-Alder reaction.

Full text of DOI:10.1002/chem.201202822

DOI: 10.1002/chem.201202822
Syntheses of the Hexahydroindene Cores of Indanomycin and Stawamycin by
Combinations of Iridium-Catalyzed Asymmetric Allylic Alkylations and
Intramolecular Diels–Alder Reactions
Martin Gꢀrtner,[a] Gedu Satyanarayana,[b] Sebastian Fçrster,[a] and Gꢁnter Helmchen*[a]
Abstract: Short and concise syntheses of the hexahydroindene cores of the antibi-
otics indanomycin (X-14547 A) and stawamycin are presented. Key methods used
are an asymmetric iridium-catalyzed allylic alkylation, a modified Julia olefination,
a Suzuki–Miyaura coupling, and an intramolecular Diels–Alder reaction.
Keywords: alkylation · Diels–Alder
reaction · hexahydroindenes · iridi-
um · Julia olefination · Suzuki–
Miyaura coupling
Introduction
The enantioselective Ir-catalyzed allylic substitution is a
powerful tool in organic synthesis.[1] We are interested in
widening the scope of this method by exploration of new al-
lylic substrates and nucleophiles as well as application of the
substitution products in natural products synthesis. Herein,
we present a combination of the Ir-catalyzed allylic alkyla-
tion with the Julia–Kocienski olefination;[2] this method was
applied in very short and efficient syntheses of the hexahy-
droindene cores of the antibiotics indanomycin and stawa-
mycin (Figure 1).
Indanomycin was isolated from the fermentation broth of
Streptomyces antibioticus and exhibits antibiotic activity
against Gram-positive bacteria.[3] Its relative and absolute
configuration was determined by X-ray crystal-structure
Figure 1. Antibiotics containing a hexahydroindene moiety.
anal
G
et al.[9] The key step of all syntheses is an intramolecular
Diels–Alder reaction, which has been considered to be a
step in the biosynthesis of indanomycin.[10] The previous syn-
theses were carried out at a time when the methodology of
acyclic stereocontrol was not yet far developed. Accordingly,
many steps were required for the syntheses of the cy
AHCTUNGTREGzNNNU ation precursors. Herein, we now describe a fully stereo-
controlled approach based on asymmetric catalysis, which
allows the cyclization precursors of both targets to be availa-
ble in only four steps.
ces strain and has shown moderate inhibitory activity against
Epstein–Barr virus BZLF1 transcription factor.[4] stawamy-
cin was obtained as an amorphous solid; its structure was
determined by NMR spectroscopy, however, the relative
configurations of the hydroxylated centers remain unknown.
Up to now, four total syntheses of indanomycin have been
reported by the groups of Nicolaou,[5] Ley,[6] Roush,[7] and
Burke.[8] The synthesis of a building block representing the
hexahydroindene core of stawamycin was described by Dias
ACHTUNGTRENNUNGcli-
The concept of our synthesis of the trans-fused hexahy-
droindene ring system is outlined in Scheme 1. The key step
is an intramolecular Diels–Alder reaction, yielding the hexa-
hydroindene-core structure of stawa- and indanomycin with
the desired relative configuration.[11] The chiral linchpin unit
of the precursor was envisaged to be obtained by an enan-
tioselective Ir-catalyzed allylic alkylation with a heteroaro-
matic sulfone as nucleophile. This would allow the conjugat-
ed diene to be constructed with high E selectivity by Julia-
type olefination. The enoate moiety was planned to be in-
troduced by selective hydroboration of the vinyl group, fol-
lowed by Suzuki–Miyaura coupling with a 3-haloacrylate.
[a] Dr. M. Gꢀrtner, Dr. S. Fçrster, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
E-mail: g.helmchen@oci.uni-heidelberg.de
[b] Prof. Dr. G. Satyanarayana
Indian Institute of Technology (IIT) Hyderabad
Ordnance, Factory Estate (ODF)
Yedduaram 502205, Medak District, Andhra Pradesh (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202822.
400
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 400 – 405

FULL PAPER
Figure 2. Phosphoramidites used for Ir-catalyzed allylic substitutions.
conversion in conjunction with the particularly active ligand
L2.
The methoxycarbonyl group, which was required as auxili-
ary group to reach sufficient acidity in the allylic substitu-
Scheme 1. Retrosynthetic concept (S=protecting group).
Table 1. Results of the allylic alkylations according to Scheme 2.
Entry Carbonate Pronucleo- Products L* Catalyst
Results and Discussion
t
T
Yield
Regio-
ee
phile
ACHTUNGTRENNUNG
The pronucleophile Nu1 was
introduced by Trost et al. and
used in a Pd-catalyzed allylic
alkylation with 1,3-dimethylal-
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1c
1a
1b
Nu1
Nu1
Nu1
Nu1
Nu1
Nu1
Nu2
Nu2
2a+3a
2a+3a
2a+3a
2b+3b
2b+3b
2c+3c
4a+5a
4b+5b
L1
L2
L3
L2
L3
L2
L2
L2
2
1
2
2
4
4
4
4
72
50
86[e]
90
92
93
91
89
93
77
91:9
91:9
95
95.5
93
92
91
97.5
96
97
3.5 50
3.5 RT
2.5 40
3
5
93:7
87:13
90:10
93:7
95:5
86:14
50
RT
ACHTUNGTRENNUNGlyl ethyl carbonate in conjunc-
tion with a total synthesis of
amphidinolide A.[12] We have
now tested its applicability in
the asymmetric Ir-catalyzed al-
lylic substitution (Scheme 2).
Methyl carbonates 1a–c were
used as substrates. The phos-
2.5 RT
50
3
[a] The catalyst was prepared from [{IrACTHUNGTERN(NUGN cod)Cl}2] (2 mol%), L* (4 mol%), and TBD (8 mol%). [b] Combined
1
yield of regioisomers. [c] Ratio of regioisomers (2/3 or 4/5), determined by H NMR spectroscopy of the crude
product. [d] Determined by HPLC after demethoxycarbonylation.
phoramidites[13] L1–L3 with R,R,aR configuration were em-
ployed as chiral ligands (Figure 2); it was anticipated[1] that
these would induce the desired configuration of the substitu-
tion products. “Salt-free” reaction conditions, that is, the use
of the conjugate acid of the nucleophile in combination with
only a catalytic amount of base, were employed through-
out.[14] When initial tests with Nu1 gave encouraging results,
the sulfone Nu2 was included into the test set (Table 1).
However, this was found to be less reactive and gave lower
yields than Nu1. Reactions with Nu2 only gave complete
tion, was removed after the alkylation by Krapcho de-
ACHUTNGERNmNUG ethoxyACHTUTGNRENcNUGN arbonylation (Scheme 3) by using conditions
(NaCl, H2O, DMSO, 1508C)[15] that have been previously
Scheme 3. Demethoxycarbonylation using the Krapcho reaction.
applied for related substrates by the Trost group.[12] Several
unidentified side products were observed, which could be
suppressed in the case of the tetrazolylsulfones 2 by omit-
ting NaCl from the reaction mixtures, while this additive
was required for the reactions of the benzothiazolylsulfones,
because otherwise no reaction occurred. Finally, the sulfones
6 and 7 were obtained in yields of 63–82%.
The Julia–Kocienski olefinations of the O-protected alde-
hydes 8a and 8b[16] with the sulfones 6 and 7 were carried
out with 1,2-dimethoxyethane (DME) as solvent and
KHMDS or LiHMDS (HMDS=hexamethyl disilazide) as
base at ꢀ788C. In each case the E isomer was obtained with
Scheme 2. Ir-catalyzed allylic alkylation (TBD=1,5,7-triazabicyclo-
ACHTUNGTRENNUNG[4.4.0]dec-5-ene).
Chem. Eur. J. 2013, 19, 400 – 405
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
401

G. Helmchen et al.
a purity of ꢁ90% (Table 2). The minor component could
not be separated. Its tentative structural assignment as Z
isomer is supported by, in every case, a clearly discernable
Table 2. Julia–Kocienski olefination (PMB=p-methoxybenzyl).
Scheme 4. Hydroboration/Suzuki–Miyaura coupling (a: nBu4NF, THF,
RT).
used by Nicolaou et al. (toluene, sealed tube, temp.>1008C;
Table 3).[5] Isomerically pure products could not be isolated,
however, column chromatography yielded two fractions in
all cases. The major fraction contained a mixture of the two
endo products (a+b), the individual ratio of which (com-
pare Table 3) could be determined by NMR spectroscopy.[21]
The minor fraction contained a mixture of the two exo prod-
ucts (g+d); their individual configurations were not as-
signed. The endo and exo configuration was determined by
treatment of products 14 with tetrabutylammonium fluoride
(TBAF) to effect desilylation (Scheme 5), which gave lac-
tones 17 from the endo products and hydroxy esters 18
Entry Aldehyde Sulfone Base
([equiv])
Product E/Z[a] Yield
G
[%]
1
8a (1.0)
8a (1.0)
8a (1.1)
8a (1.1)
8a (1.0)
8a (1.0)
8b (1.1)
8b (1.0)
8b (1.0)
8b (1.5)
8b (1.1)
8b (1.0)
8b (1.0)
6a
6a
6a
7a
6b
6b
6a
6a
6a
6a
7a
6b
7b
KHMDS
KHMDS
LiHMDS
KHMDS
KHMDS
LiHMDS
KHMDS
KHMDS
9a
9a
9a
90:10 54 (75)[b]
81:19 55 (73)[b]
88:12 82
2[c]
3
4
9a
9b
n.d.
80
5
6
84:16 54 (92)[b]
9b
10a
10a
93:7
97
7[c]
8
69:31 58 (73)[b]
88:12 47
9
10
LiHMDS 10a
LiHMDS 10a
84:16 71
88:12 88
11
12
13
KHMDS
LiHMDS 10b
LiHMDS 10b
10a
n.d.
80
85:15 93
89:11 83
1
[a] Determined by H NMR spectroscopy. [b] Incomplete conversion, cor-
rected yield in brackets. [c] The reaction was carried out with THF as sol-
vent. n.d.=not determined.
Table 3. Thermal Diels–Alder reaction.
13
1
ꢀ
C NMR resonance of R CH upfield by dꢁ5 ppm from
the corresponding signal of the E isomer (9 or 10). Since the
heteroarylsulfones were the more valuable components, an
excess of sulfone was avoided. With LiHMDS superior re-
sults with respect to conversion and yield were obtained. By
using KHMDS as base, the reaction with 8a proceeded with
high E selectivity, however, conversion was modest (en-
tries 1, 2, 5, 7, and 8). In the reactions with aldehyde 8b, the
E/Z ratios were slightly lower than those obtained with the
more bulky 8a.
According to our synthetic route, hydroboration selective-
ly at the vinyl group of the trienes 9 and 10, as described in
Table 2, was required. This was accomplished with 9-
borabicycloACHTUNGTRENNUNG[3.3.1]nonan (9-BBN) after some experimenta-
tion. As was previously observed with other trienes,[17] the
best results were obtained with a reaction time of 5 min
(Scheme 4). For the Suzuki–Miyaura coupling,[18] methyl
(2E)-3-iodoacrylate[19] served as coupling partner in conjunc-
Entry
Starting
material
T [8C]
t [h]
endo/exo[a]
a/b[b]
Yield [%][c]
1
2
3
4
5
6
7
11a
11b
11b
11b
12a
12b
13b
125
130
100
160
130
130
130
63
48
96
25
60
52
63
5.1:1
3:1
5:1
2.4:1
4:1
4:1
60
85
50 (86)[d]
tion with [PdACHTUNGTRENNUNG(dppf)Cl2]/Ph3As as catalyst and Cs2CO3 as
6:1
1:1
50
90
88
74
base (Scheme 4).[20] The trienes 11 and 12 were obtained in
reasonable yields; they proved to be sensitive to air and
were stored under argon at ꢀ208C. The free alcohols 13a
and b were prepared from the tBuPh2Si-protected substrates
11 by treatment with nBu4NF.
3.6:1
4.2:1
3.4:1
3.2:1
8:1
7:1[e]
[a] Based on isolated yields. [b] Determined by 1H NMR (14a and 15a)
or 13C NMR spectroscopy (14b, 15b, and 17b). The major isomer pos-
sesses the 1S,3aR,4S,5R,7aR configuration (a). [c] Combined isolated
yields. [d] Corrected yield. [e] Spontaneous lactonization to 17b occur-
red.
The intramolecular Diels–Alder (IMDA) reaction was
first carried out under thermal conditions, as previously
402
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 400 – 405

Synthesis of Hexahydroindene Cores
FULL PAPER
Table 4. Et2AlCl-catalyzed IMDA reaction.
Entry
Starting
material
Et2AlCl
[equiv]
T
[8C]
t
a/b[a]
Yield
[%]
[h]
1
2
3
4
12a
12b
13a
13b
2
5
2
3
ꢀ30!RT
0!RT
60
53
60
21
2.5:1
9:1
2.7:1
9:1
41
35
58
41
ꢀ30!RT
0!RT
[a] Determined by H NMR (17a) or 13C NMR spectroscopy (17b).
1
Scheme 5. Desilylation of 14a and 14b; upper part: endo isomers, lower
part: exo isomers.
from the exo products in high yields. The configurations of
the PMB derivatives 15 were determined by analogy of the
NMR spectra of 14 and 15.
Scheme 6. Suzuki–Miyaura coupling with 3-O-(bromoacryloyl)-(R)-pan-
tolactone.
The following aspects of the results described in Table 3
are worth noting. a) The endo/exo ratio was within the
range previously reported for IMDA reactions yielding
hexaACHTUNGTRENNUNG
hydroindenes.[5–9,11] b) The endo/exo selectivity was
found to be almost independent of the reaction temperature
(entries 3 and 4). c) The IMDA reactions of the fully pro-
tected triene 12b and the triene 13b, containing a OH
group, proceeded with the same facial selectivity (a/b); in
the last case spontaneous cyclization of the primarily
formed endo-16b (not observed) to the lactone 17b (isolat-
ed) occurred.[22]
Lewis acid catalyzed Diels–Alder reactions, anticipated to
display improved stereoselectivities, were investigated next
(Table 4). The tBuPh2Si-protected substrates 11 gave rise to
decomposition. The PMB-protected trienes 12 and the alco-
hols 13 tolerated Et2AlCl as Lewis acid and gave diastereo-
meric lactones 17 as products in modest yields.[21]
Scheme 7. IMDA reaction with esters of (R)-pantolactone.
As obvious from Table 4, diastereoselectivities were excel-
lent for the ethyl but unsatisfactory for the methyl deriva-
tives. To improve facial selection at the enoate moiety, a
chiral auxiliary was introduced. (R)-Pantolactone was select-
ed, which was known to give rise to high degrees of
the cyclization in Scheme 7 represents the matched case.
Compared to all other cyclizations leading to lactone 17aa,
the facial selectivity was significantly improved.
diastereo
selectivity in intermolecular Diels–Alder reactions,
In the text above, routes using various protecting and aux-
iliary groups are described. The following routes most effi-
ciently access the target lactones 17. The preferred route to
17aa involves allylic alkylation of 1a with Nu1 (Table 1,
entry 3), demethoxycarbonylation to give 6a, Julia-Kocien-
ski olefination of 6a with 8b to give 10a (Table 2, entry 10),
Suzuki–Miyaura coupling with 19 to give 20a, and Et2AlCl-
catalyzed IMDA reaction yielding 17a with a 5:1 diastereo-
favoring aRe-face attack at the enoate moiety, as required
here.[23] The requisite enoate 19 (Scheme 6) was readily pre-
pared.[23b] Suzuki–Miyaura coupling with the PMB-protected
substrates 10 gave the trienoates 20 (Scheme 6).
The Et2AlCl-catalyzed IMDA reaction yielded the lac-
tones 17 as the only isolable products (Scheme 7). Judged by
the intermolecular reaction of 19 and cyclopentadiene,[23]
Chem. Eur. J. 2013, 19, 400 – 405
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
403

G. Helmchen et al.
In all cases, the branched dienes 9 or 10 were accompanied by the corre-
sponding linear dienes, which could not be separated by chromatography.
The mixtures of isomers were carried on to the next step.
selectivity and an overall yield of 19%. The lactone 17ba is
best obtained by allylic alkylation of 1b with Nu1 (Table 1,
entry 4), demethoxycarbonylation, olefination with 8b
(Table 2, entry 12), Suzuki–Miyaura coupling with 19, and
Et2AlCl-catalyzed IMDA reaction. This route provides 17b
in 28% overall yield and a diastereofacial selectivity of 20:1.
To test the reproducibility, ent-17aa was also prepared, em-
ploying ligand (S,S,aS)-L2 in the allylic alkylation step.
General procedure 4—Suzuki–Miyaura reaction: Under an atmosphere
of argon, a solution of diene 9 or 10 (1.0 equiv) and 9-BBN (2 equiv) in
dry THF (2 mLmmolꢀ1) was heated at 658C for 5 min (solution A). In a
separate flask,
a
suspension of [PdACHTUNGTERNNU(G dppf)Cl2] (5 mol%), Ph3As
(10 mol%), Cs2CO3 (1.8 equiv), and the alkenyl halide (1.1 equiv) in
DMF/H2O (15:1, 2.5 mLmmolꢀ1, degassed with helium) was vigorously
stirred for 15 min under an atmosphere of argon. At RT, solution A was
added, and the resulting mixture was stirred for 16 h. Then, water was
added, and the solution was extracted with diethyl ether, dried over
MgSO4, and concentrated in vacuo. The residue was subjected to flash
chromatography to yield 11, 12 or 19. In all cases, the coupling product
contained Z isomers (resulting from the olefination), and impurities de-
rived from the linear isomers were separated off.
Conclusion
We have developed a five-step sequence to access the hexa-
hydroindene core present in the antibiotics stawamycin and
indanomycin. Highly enantioselective iridium-catalyzed
asymmetric allylic alkylations with an a-sulfonylacetic ester
as nucleophile served as source of chirality. Subsequent
Krapcho reaction and E-selective Julia–Kocienski olefina-
tion gave a triene that was suitable for one-pot hydrobora-
tion with 9-BBN, which proceeded selectively at the vinyl
group, and Suzuki–Miyaura coupling generated the diene/
enoate precursor of the subsequent intramolecular Diels–
Alder reaction. The reaction was controlled by (R)-panto-
lactone as chiral auxiliary and proceeded upon Lewis acid
catalysis with good to excellent diastereoselectivity and
General procedure 5—thermal intramolecular Diels–Alder reaction:
Under an atmosphere of argon, a solution of 11 or 12 in dry toluene (de-
gassed with argon) was heated at the temperature stated in Table 4 in a
sealed tube until TLC monitoring indicated complete conversion. The
solution was concentrated in vacuo, and the residue was subjected to
flash chromatography to yield two fractions of cycloaddition products 14
or 15. The endo/exo ratio was determined from the isolated yields; the
ratio a/b was determined by NMR spectroscopy.
General procedure 6—Lewis acid catalyzed intramolecular Diels–Alder
reaction: Et2AlCl (1.8m in toluene, 2–5 equiv) was added dropwise to a
solution of 12, 13 or 19 (1 equiv) in dry CH2Cl2 at the stated temperature.
The solution was allowed to warm to RT and stirred until TLC monitor-
ing indicated complete conversion. Water was added, and the solution
was extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography
yielded lactones 17 as a mixture of diastereoisomers. The ratio a/b was
determined by NMR spectroscopy.
simul
ACHTUNGTRENNUNGtaneous in situ removal of the protecting group and
the chiral auxiliary.
For experimental details and analytical data, see the Supporting Informa-
tion.
Experimental Section
General procedure 1—iridium-catalyzed allylic alkylation: Under an at-
mosphere of argon, a solution of [{Ir(cod)Cl}2] (2 mol%), L* (4 mol%),
and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 8 mol%) in dry THF was
stirred at RT for 5 min (L2), 30 min (L3), or 90 min (L1). Then, carbon-
ate 1 (1 equiv) and pronucleophile Nu1 or Nu2 (1.1 equiv) were added,
and the solution was stirred at the temperature stated in Table 1 until
TLC monitoring showed complete conversion. The solvent was removed
in vacuo, and the ratio of regioisomers 2/3 or 4/5 was determined by
1H NMR spectroscopy of the crude product. Purification by flash chro-
matography yielded the branched alkylation products 2 or 4 as a mixture
of diastereoisomers (1:1) accompanied by the linear alkylation products 3
or 5, which could not be separated by chromatography. The mixtures of
isomers were carried on to the next step.
AHCTUNGTRENNUNG
Acknowledgements
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
623 and GK 850). We thank O. Tverskoy for experimental assistance,
Prof. K. Ditrich (BASF SE) for enantiomerically pure 1-arylethylamines,
and Dr. F. Rominger for crystal-structure analyses.
ACHTUNGTRENNUNG
[1] Reviews: a) G. Helmchen, A. Dahnz, P. Dꢂbon, M. Schelwies, R.
Weihofen, Chem. Commun. 2007, 675–691; b) R. Takeuchi, S.
Kezuka, Synthesis 2006, 3349–3366; c) G. Helmchen, in Iridium
Complexes in Organic Synthesis (Eds.: L. A. Oro, C. Claver), Wiley-
VCH, Weinheim, 2009, pp. 211–250; d) J. F. Hartwig, L. M. Stanley,
Acc. Chem. Res. 2010, 43, 1461–1475; e) W.-B. Liu, J.-B. Xia, S.-L.
You, Top. Organomet. Chem. 2012, 155–208; f) P. Tosatti, A.
Nelson, S. P. Marsden, Org. Biomol. Chem. 2012, 10, 3147–3163.
[2] Reviews: a) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1 2002,
2553–2585; b) C. Aissa, Eur. J. Org. Chem. 2009, 1831–1844.
[3] a) C.-M. Liu, T. E. Hermann, M. Liu, D. N. Bull, N. J. Palleroni,
B. L. T. Prosser, J. W. Westley, P. A. Miller, J. Antibiot. 1979, 32, 95–
99; b) J. W. Westley, R. H. Evans Jr., L. H. Sello, N. Troupe, C.-M.
Liu, J. F. Blount, J. Antibiot. 1979, 32, 100–107; c) J. W. Westley,
R. H. Evans, Jr., C.-M. Liu, T. Herman, J. F. Blount, J. Am. Chem.
Soc. 1978, 100, 6784–6786.
General procedure 2—Krapcho demethoxycarbonylation: Water (9% v/
v) or NaCl (1.5 equiv) was added to a solution of 2 or 4 (1 equiv) in
DMSO, and the resulting mixture was heated at 1508C until TLC moni-
toring indicated complete conversion. After cooling to RT, water was
added, and the solution was extracted with Et2O. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. Purification by
flash chromatography yielded 6 or 7. The enantiomeric excesses of 6 or 7
were determined by chiral HPLC. In all cases, the branched sulfones
were accompanied by the corresponding linear sulfones, which could not
be separated by chromatography. The mixtures of isomers were carried
on to the next step.
General procedure 3—Julia–Kocienski olefination (Barbier conditions):
LiHMDS (1.1 equiv, 1m in toluene) was added dropwise to a solution of
6 or 7 (1 equiv) and 8 (1–1.5 equiv) in dry DME at ꢀ788C. The solution
was allowed to warm to RT overnight. Water was added, and the solution
was extracted with Et2O. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography
[4] S. Miao, M. R. Anstee, V. Baichwal, A. Park, Tetrahedron Lett.
1995, 36, 5699–5702.
[5] K. C. Nicolaou, D. P. Papahatjis, D. A. Claremon, R. L. Magolda,
R. E. Dolle, J. Org. Chem. 1985, 50, 1440–1456.
[6] M. P. Edwards, S. V. Ley, S. G. Lister, B. D. Palmer, D. J. Williams, J.
Org. Chem. 1984, 49, 3503–3516.
1
yielded 9 or 10. The E/Z ratio was determined by H NMR spectroscopy.
404
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 400 – 405

Synthesis of Hexahydroindene Cores
FULL PAPER
[7] W. R. Roush, S. M. Peseckis, A. E. Walts, J. Org. Chem. 1984, 49,
3429–3432.
[8] S. D. Burke, A. D. Piscopio, M. E. Kort, M. A. Matulenko, M. H.
Parker, D. M. Armistead, K. Shankaran, J. Org. Chem. 1994, 59,
332–347.
[16] a) W. R. Roush, J. A. Straub, M. S. VanNieuwenhze, J. Org. Chem.
1991, 56, 1636–1648; b) J. Murga, J. Garcꢃa-Fortanet, M. Carda,
J. A. Marco, Synlett 2004, 2830–2832.
[17] M. Gꢀrtner, D. Kossler, D. Pflꢀsterer, G. Helmchen, J. Org. Chem.
2012, 77, 4491–4495.
[9] a) L. C. Dias, L. S. A. Jardim, A. A. Ferreira, H. U. Soarez, J. Braz.
Chem. Soc. 2001, 12, 463–466; b) L. C. Dias, G. Z. Melgar, L. S. A.
Jardim, Tetrahedron Lett. 2005, 46, 4427–4431.
[10] K. E. Roege, W. L. Kelly, Org. Lett. 2009, 11, 297–300.
[11] Review: W. R. Roush, in Advances In Cycloadditions, Vol. 2 (Ed.:
D. P. Curran), JAI Press, London, 1990, pp. 91–146.
[12] a) B. M. Trost, J. D. Chisholm, S. J. Wrobleski, M. Jung, J. Am.
Chem. Soc. 2002, 124, 12420–12421; b) B. M. Trost, S. T. Wrobleski,
J. D. Chisholm, P. E. Harrington, M. Jung, J. Am. Chem. Soc. 2005,
127, 13589–13597.
[13] a) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346–353; b) K. Tissot-
Croset, D. Polet, A. Alexakis, Angew. Chem. 2004, 116, 2480–2482;
Angew. Chem. Int. Ed. 2004, 43, 2426–2428; c) J. F. Teichert, B. L.
Feringa, Angew. Chem. 2010, 122, 2538–2582; Angew. Chem. Int.
Ed. 2010, 49, 2486–2528.
[14] a) R. Weihofen, O. Tverskoy, G. Helmchen, Angew. Chem. 2006,
118, 5673; Angew. Chem. Int. Ed. 2006, 45, 5546; b) S. Spiess, J. A.
Raskatov, C. Gnamm, K. Brçdner, G. Helmchen, Chem. Eur. J.
2009, 15, 11087–11090; c) J. A. Raskatov, S. Spiess, C. Gnamm, K.
Brçdner, F. Rominger, G. Helmchen, Chem. Eur. J. 2010, 16, 6601–
6615; d) S. Spiess, C. Welter, G. Franck, J.-P. Taquet, G. Helmchen,
Angew. Chem. 2008, 120, 7764–7767; Angew. Chem. Int. Ed. 2008,
47, 7652–7655.
[18] Reviews: a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–
2483; b) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58,
9633–9695; c) S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew.
Chem. 2001, 113, 4676–4701; Angew. Chem. Int. Ed. 2001, 40, 4544–
4568.
[19] D. J. Dixon, S. V. Ley, D. A. Longbottom, Org. Synth. 2003, 80, 123.
[20] C. R. Johnson, M. P. Braun, J. Am. Chem. Soc. 1993, 115, 11014–
11015.
[21] The endo-fraction contained an unidentified side product (<10%),
presumed to originate from the Z-olefin contained in the starting
material.
[22] Lactones 17aa and 17ba were characterized by crystal-structure
analysis (see the Supporting Information). CCDC-894766 (17aa)
and CCDC-894765 (17ba) contain the supplementary crystallo-
graphic 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.
[23] a) T. Poll, A. Sobczak, H. Hartmann, G. Helmchen, Tetrahedron
Lett. 1985, 26, 3095–3098; b) G. Linz, J. Weetmann, A. F. Abdel
Hady, G. Helmchen, Tetrahedron Lett. 1989, 30, 5599–5602; c) G.
Helmchen, A. F. Abdel Hady, H. Hartmann, R. Karge, A. Krotz, K.
Sartor, M. Urmann, Pure Appl. Chem. 1989, 61, 409–412.
[15] Reviews: a) A. P. Krapcho, Synthesis 1982, 805–822; b) A. P. Krap-
cho, Synthesis 1982, 893–914.
Received: August 6, 2012
Published online: November 23, 2012
Chem. Eur. J. 2013, 19, 400 – 405
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
405