A stereoselective approach to functionalized cyclohexenones

Article abstract of DOI:10.1002/ejoc.201300752

A catalytic enantioselective approach to 4-hydroxy-6-methylcyclohex-2- enones is presented herein. The stereogenic information is generated through a copper-catalyzed 1,4-addition to p-benzoquinone monoketal using a chiral, BINOL-based (BINOL = 1,1′-bi-2-

Full text of DOI:10.1002/ejoc.201300752

FULL PAPER
DOI: 10.1002/ejoc.201300752
A Stereoselective Approach to Functionalized Cyclohexenones
Anne C. Meister,[a] Paul F. Sauter,[a] and Stefan Bräse*[a,b]
Keywords: Asymmetric catalysis / Natural products / Enantioselectivity / Diastereoselectivity / Quinones
A catalytic enantioselective approach to 4-hydroxy-6-meth-
ylcyclohex-2-enones is presented herein. The stereogenic in-
cording to the procedure of Feringa et al. A CBS (Corey–
Bakshi–Shibata) reduction of the 1,4-adducts gave the four
formation is generated through a copper-catalyzed 1,4-ad- possible isomers in two steps and 82–97%ee (enantiomeric
dition to p-benzoquinone monoketal using a chiral, BINOL-
based (BINOL = 1,1Ј-bi-2-naphthol) phosphane ligand, ac-
excess), starting from commercially available 4,4-dimeth-
oxycyclohexa-2,5-dien-1-one (7).
sented a flexible pathway in only six steps towards both
cyclohexenones 1 and 2.[11] Earlier, an enantioselective
seven-step synthesis of the trans isomer of 2 was pub-
lished.[12] Piers and co-workers described an eight-step syn-
thesis towards racemic PMB-protected cis-2 (PMB = para-
methoxybenzyl).[13] A six-step synthesis of diastereomeric
cis-1 and trans-1 was presented by Edwards and co-
workers.[14] Carreño et al. described a stereoselective ap-
proach in eight steps to both cis enantiomers of TBDMS-
protected 1 (TBDMS = tert-butyldimethylsilyl).[15] By using
the chiral pool substance d-quinic acid, Shan and
O’Doherty synthesized trans-1 in 10 steps and Boc-pro-
tected cis-1 (Boc = tert-butyloxycarbonyl) in 9 steps.[16]
Until now, the syntheses of either cyclohexenone 1 or 2
required at least six steps. As they are used as building
blocks for natural product synthesis,[3,11] quick access to
these compounds will be indubitably advantageous. Herein,
we present a two-step synthesis to the four isomers of 1,
which are produced with high enantiomeric excess values
(82–97%ee).
Introduction
Substituted cyclohexenones similar to 1 and 2 are valu-
able building blocks for the synthesis of natural products
(see Figure 1). These structural motifs appear in many small
molecules such as epoxydine A (3),[1] gabosine B (4),[2] di-
hydroepiepoformin,[3] and ampelomin A.[4] These cyclohex-
enone units are also part of more complex natural products
such as blennolide A (5) and B,[5,6] secalonic acids A–G,[7]
ergochrysin A and B,[8] the phomoxanthones,[9] and leptos-
phaerin A, B, F (6), and G.[10]
Results and Discussion
Inspired by the work of Feringa and co-workers,[17] we
planned a short and simple approach to both cyclohex-
enones 1 and 2. Starting from commercially available
benzoquinone monoketal 7,[18] the enantioselective 1,4-ad-
dition of Feringa et al. was realized by using dimethylzinc
in the presence of a copper(II) catalyst and the chiral
BINOL-based (BINOL = 1,1Ј-bi-2-naphthol) phosphane li-
gand (S,R,R)-9 (see Scheme 1). The 1,4-adduct (R)-8 was
obtained in 97%ee. We then adapted this procedure by
using the enantiomeric ligand (R,S,S)-9 to give (S)-8, which
was obtained in good yield and 98%ee. The enantiomeric
excess (ee) values of both 1,4-adducts 8 were determined by
GC analysis on a chiral modified column.
Figure 1. Cyclohexenones 1 and 2 and some of the natural products
that contain them.
In the literature, some syntheses of cyclohexenones 1 and
2 have been described. For example, our group recently pre-
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
http://www.ioc.kit.edu/braese/
[b] Institute of Toxicology and Genetics, Karlsruhe Institute of
Technology,
Hermann-von-Helmholtz Platz 1,
76344 Eggenstein-Leopoldshafen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300752.
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A Stereoselective Approach to Functionalized Cyclohexenones
Scheme 1. Synthesis of enantiomeric 1,4-adducts (R)- and (S)-8.
Reagents and conditions: (a) Cu(OTf)2, (S,R,R)-9, absolute tolu-
ene, room temp., 1 h, then –25 °C, 7, ZnMe2, 12 h, 61%, 97%ee;[17]
(b) Cu(OTf)2, (R,S,S)-9, absolute toluene, room temp., 1 h, then
–25 °C, 7, ZnMe2, 15 h, 53%, 98%ee.
Scheme 2. Synthesis of cyclohexenones (R)- and (S)-1. Only the
main diastereomers are shown. Reagents and conditions: (a) (R)-
CBS, BH3·THF, absolute tetrahydrofuran (THF), 0 °C, 1 h, then
HCl (1 m), room temp., 30 min, 69%, cis/trans, 4.1:1.0, 95%ee for
cis, 86%ee for trans; (b) (S)-CBS, BH3·THF, absolute THF, 0 °C,
1 h, then HCl (1 m), room temp., 30 min, 65%, cis/trans, 1.0:1.8,
82%ee for trans, 92%ee for cis; (c) (R)-CBS, BH3·THF, absolute
THF, 0 °C, 1 h, then HCl (1 m), room temp., 30 min, 46%, cis/trans,
1.0:2.1, 96%ee for trans, 96%ee for cis; (d) (S)-CBS, BH3·THF,
absolute THF, 0 °C, 1 h, then HCl (1 m), room temp., 20–30 min,
61%, cis/trans, 3.5:1.0, 97%ee for cis, 60%ee for trans.
First, we focused on the synthesis of cyclohexenone 1
(see Scheme 2). The reduction of 1,4-adduct (R)-8 with the
(R)-CBS ligand (CBS = Corey–Bakshi–Shibata) and a bor-
ane–THF complex gave cyclohexenone (R)-1 as a mixture
of two inseparable diastereomers with a preference for the
cis isomer [see Scheme 2, (a)]. The catalyst [(R)-CBS] prefer-
entially afforded the (S)-configured stereocenter, which in at the stereocenter with the methyl group. The reduction
this case is the cis diastereomer (catalyst control). In ad- conditions are very mild, so racemization probably occurs
dition, the cis diastereomer is also preferred through sub- during the acidic deprotection of the ketal. The methyl and
strate control, and the attack of the hydride donor mainly hydroxy substituents of the cis diastereomer are in equato-
occurs on the side opposite to the methyl group, as there is rial positions, however one substituent in the trans dia-
less steric hindrance (kinetic control). Furthermore, the cis stereomer must be in an axial position. As a result, the trans
product is also more stable than the trans product, as both isomer is less stable and probably undergoes racemization
substituents on the ring can be in an equatorial position easier than the cis isomer. Therefore, the ee value of cis
(thermodynamic control). The catalyst and substrate isomer is higher than that of the trans isomer.
formed a matched pair. The fact that not only the cis but
The same reactions as those with (R)-8 were conducted
also the trans product is formed is possibly a result of a fast with 1,4-adduct (S)-8, Again, the diastereomeric products
background reaction without the participation of the CBS were inseparable. When (R)-CBS was used as the catalyst,
ligand. The enantiomeric excess values of the cis and the there was a minor selectivity for the trans isomer, which was
trans isomers were obtained by converting them into the the same as that observed with (R)-8 and (S)-CBS [mis-
corresponding Mosher esters (see Exp. Section) and deter- matched substrate-catalyst pair, see Scheme 2, (c)]. In this
mined to be 95 and 86%ee for the cis and trans isomer, case, both diastereomers were produced in 96%ee. Nearly
respectively.
no racemization of the trans isomer took place, which was
When (R)-8 was treated with the enantiomeric ligand (S)- probably a result of the slightly shorter stirring time with
CBS, a preference for the trans isomer of 1 was observed, HCl during workup.
although it was less distinct than that of (R)-CBS for the
The treatment of (S)-8 with (S)-CBS gave the cis dia-
cis isomer [see Scheme 2, (b)]. (S)-CBS preferentially af- stereomer with a high enantiomeric excess value and nearly
forded the (R)-configured stereocenter, which in this case the same diastereoselectivity as that obtained for the reac-
is the trans diastereomer, although the cis diastereomer is tion of (R)-8 with (R)-CBS [matched substrate-catalyst pair,
preferred through substrate control. The catalyst and sub- see Scheme 2, (d)]. The enantioselectivity of the cis isomer
strate formed a mismatched pair, even though catalyst con- was 97%ee and that of the trans isomer was 60%ee. This
trol appears to be stronger than substrate control. These very low ee value was probably a result of the longer stirring
inseparable diastereomers were formed in 82 and 92%ee for time with HCl during workup. In summary, we were able
the trans and cis isomer, respectively. Interestingly, the ee to synthesize cyclohexenones (R)-1 and (S)-1 in 29–61%de
values were very high for the cis and lower for trans dia- (de = diastereomeric excess) and 82–97%ee in only two
stereomer in both reactions. As the ee value of the substrate steps from commercially available benzoquinone monoketal
[(R)-8, 97%ee] was very high, racemization must take place 7.
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We then turned our attention to the synthesis of cyclo-
hexenone 2. Under very mild deprotection conditions (Am-
berlyst® 15[19] in acetone), (R)-8 afforded the unusual diket-
one (R)-10 (see Scheme 3) as a slightly yellow oil, which
remained stable for several hours at 7 °C without under-
going a tautomerization. Under the same conditions, we
also converted (S)-8 into (S)-10. In both cases, the yields
were quantitative. The synthesis of racemic diketone 10 was
already known,[20] but the preparation presented herein is
the shortest [two steps from commercially available 4,4-di-
methoxycyclohexa-2,5-dien-1-one (7)] and the only stereo-
selective one. The preparations of the unsubstituted and the
racemic 5-vinyl-substituted dione have also been described
in the literature, but through different synthetic path-
ways.[21] The enantiomeric excess values of (R)- and (S)-10
could not be determined by chiral modified GC or HPLC
columns, because aromatization occurred during the mea-
surements. Nevertheless, optical rotations of both enantio-
Scheme 3. Synthesis of diketone 10. Reagents and conditions:
(a) Amberlyst 15®, water (2 drops), acetone, room temp., 10 min,
mers of 10 could be measured, and they were opposite to quantitative yield of crude product; (b) Amberlyst 15®, water
(2 drops), MeOH, room temp., 10 min, quantitative yield of crude
each other with the same absolute value (see Exp. Section).
product; (c) cyclopentadiene, MeOH, 0 °C to room temp., 3 d,
We then conducted the deprotection step with methanol as
32%, endo/exo, 1.4:1.0; (d) cyclopentadiene, MeOH, 0 °C to room
temp., 18 h, 28%, endo/exo, 1.0:1.0.
the solvent, instead of acetone, which allowed us to react
diketone 10 in situ. In this manner, diketones (R)- and (S)-
10 were subjected to a Diels–Alder reaction with cyclopen-
of trans-2 was much lower (31%de). By using the bulky
Alpine-hydride, cyclohexenone 1 was obtained nearly exclu-
sively in good yield, which is probably a result of the steric
tadiene to determine their enantiomeric excess values. This
conversion has already been described using racemic dione
10,[20a,20b] and the preparation of the racemic adduct 11 has
hindrance from the methyl group (see Table 1, Entry 5). The
also been performed through different synthetic routes.[22]
cis isomer of 1 was mainly formed in 77%de. The reduction
of (R)-10 by treatment with diisobutylaluminium hydride
(DIBAL-H) only yielded a small amount of a mixture of
Again, the enantiomeric excess values could not be deter-
mined, as this time there was a lack of separation on the
chiral modified columns (GC and HPLC). However, as the
both regioisomers 1 and 2, and again with a preference for
racemization of dione 10 would occur with aromatization,
1 (see Table 1, Entry 6). Cyclohexenone 1 mainly had the
it can be assumed that the enantiomeric excess value of 10
cis configuration, whereas cyclohexenone 2 again was
should be equivalent to that of 8.
With the assumption that the oxygen at C-4 is more nu-
cleophilic than the one at C-1 because of the presence of
the adjacent methyl group, the reduction of diketone (R)-
10 under Luche conditions with 1 equiv. of reagent was per-
formed to yield cyclohexenone (R)-2 (see Table 1, Entry 1).
Thereby, a mixture of isomers 1 and 2 with a preference for
1 was observed. For 1, mainly the cis diastereomer was
formed (92%de). No diastereoselectivity was observed for
2. Next, the same reaction was performed at a lower tem-
perature (see Table 1, Entry 2), which again yielded a mix-
ture of both regioisomers with a slight preference for 1.
Both regioisomers were preferentially formed with the trans
configuration (29%de for 1 and 74%de for 2). We then con-
ducted the reduction without the addition of the ce-
rium(III) reagent. The overall yield was much lower, and no
preference between the two regioisomers was observed (see
Table 1, Entry 3). Cyclohexenone 1 was formed with a high
de value (89%de for cis isomer), whereas the diastereoselec-
tivity of 2 was much lower (43%de for trans isomer). The
treatment of diketone (R)-10 with the milder reducing agent
triacetoxyborohydride afforded product in only a very low
yield and with no preference observed between the two re-
gioisomers (see Table 1, Entry 4). Here again, the cis isomer
Table 1. Reaction conditions for reduction of diketone 10.
Entry Reagents
Conditions
Yield[a] 2 (% de)/1 (% de)
(%)
1
2
3
4
5
6
7
NaBH4, CeCl3
NaBH4, CeCl3
NaBH4
MeOH, 0 °C
44
33
17
6.7
50
6.7
6.6
1.0 (4.8):4.1 (92)
1.0 (74):1.2 (29)
1.0 (43):1.0 (89)
1.0 (31):1.1 (91)
1.0 (33):15 (77)
1.0 (39):3.8 (71)
1.0 (9.0):8.4 (95)
MeOH, –78 °C
MeOH, –10 °C
MeOH, –78 °C
NaBH(OAc)3
Alpine-hydride[b] THF, –78 °C
DIBAL-H
menthol,
NaBH4,
THF, –78 °C
THF, –78 °C
DIBAL-H
(R)-CBS
(S)-CBS
8
9
THF, 0 °C
THF, 0 °C
15
46
1.0 (4.8):4.4 (93)
1.0 (44):1.4 (90)
[a] Yield determined over two steps from cyclohexenone 8. [b] Al-
pine-hydride = lithium B-isopinocampheyl-9-borabicyclo[3.3.1]-
of 1 was formed in a high de (91%). The diastereoselectivity nonyl hydride.
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A Stereoselective Approach to Functionalized Cyclohexenones
mainly the trans isomer. The addition of menthol and so- ducted on a gram-scale and are, therefore, suitable for
dium borohydride to DIBAL-H gave only low yields, but building block synthesis. In addition, the (R)- and (S)
with a strong preference for cyclohexenone 1 (see Table 1, enantiomers of diketone 10, suitable reactants for Diels–
Entry 7), which also diastereoselectively formed as the cis Alder reactions, were obtained stereoselectively. From di-
isomer (95%de). Finally, the (R)- and (S)-CBS reagents ketone 10, cyclohexenone 1 was also obtained regioselec-
were applied to the reduction reaction, but, again, mixtures tively by reduction with Alpine-hydride. Under various con-
of regioisomers were obtained. In both cases, the formation ditions, regioisomer 2 was obtained as a mixture with 1.
of 1 was preferred over 2, although this preference was
Experimental Section
stronger with (R)-CBS (see Table 1, Entry 8). Again, the cis
diastereomer of 1 was formed with high diastereomeric ex-
cess values [93%de with (R)-CBS and 90%de with (S)-
CBS]. In the formation of 2 with (R)-CBS, no diastereo-
selectivity could be observed. This changed with (S)-CBS,
where the trans diastereomer of 2 was formed in 44%de.
Overall, the methyl group does not appear to bring about
a strong difference in the reduction of either of the carbonyl
groups. In every case, however, it did effect a preference for
cyclohexenone 1 instead of the desired cyclohexenone 2. In
one case (see Table 1, Entry 5), cyclohexenone 1 was ob-
tained in good yield with high regioselectivity. The methyl
and the hydroxy groups of 1 are preferentially arranged cis
to each other. This is probably a consequence of the steric
hindrance from the methyl group during the reduction reac-
General Methods: The NMR spectroscopic data were recorded as
solutions with a Bruker Avance 300 or a Bruker AM 400 spectrom-
eter. Chemical shifts are expressed in parts per million (ppm, δ)
downfield from tetramethylsilane (TMS) and are referenced to the
residual solvent peaks. All coupling constants (J) are absolute val-
ues and are expressed in Hertz (Hz). The descriptions of signals
include s (singlet), d (doublet), m (multiplet), mc (centered mul-
tiplet), br. s (broad singlet), dd (doublet of doublet), ddd (doublet
of doublet of doublet), and so forth. The assignment of different
diastereomers or regioisomers was done by COSY experiments and
by comparison to the literature (see ref.[11]). The spectra were ana-
lyzed according to first order. The signal structure in the 13C NMR
spectra was analyzed by DEPT and is described according to +
(primary or tertiary C atom, positive DEPT signal), – (secondary
C atom, negative DEPT signal), and Cq (quaternary C atom, no
tion. The reducing agent attacks the carbonyl group on the DEPT signal). MS [EI (electron impact mass spectrometry)] was
performed with a FINNIGAN MAT 90 (70 eV). The mass peak
[M]+ and characteristic fragment peaks are given as a mass to
charge ratio (m/z), and the intensity of the signals are indicated as
a percent that is relative to the intensity of the base signal (100%).
IR (infrared spectroscopy) was recorded with a FTIR Bruker al-
pha, and the intensities of the signals are characterized as vs (very
strong, 0–10% transmission), s (strong, 11–30% transmission), m
(medium, 31–70% transmission), w (weak, 71–90% transmission),
and vw (very weak, 91–100% transmission). Optical rotations were
measured with a Perkin–Elmer 241 polarimeter and are given as
side opposite to the methyl group. In addition, cis-1 is more
stable than trans-1, as both substituents in cis-1 can be ar-
ranged in the equatorial position. For cyclohexenone 2, the
preference changes, and the trans diastereomer is mainly
formed, although the diastereoselectivities are much lower
than that for cyclohexenone 1. In this case, the steric hin-
drance from the methyl group does not appear to be that
effective. Furthermore, trans-2 is more stable than cis-2, as
both substituents of trans-2 can be in the equatorial posi-
tion. The yields are moderate to low, as there is a problem [α]2D0 = α/(β·d). The concentration (c) is given in g/100 mL, and α is
the measured value in degrees (°). β is the concentration in g/mL,
and d is the length of the cuvette in dm. Melting points of solid
substances were measures with a Mel-Temp II (Laboratory Devices
Inc.). Some of the enantiomeric excess values were measured by
using a Bruker GC 430 with a chiral modified column (Zebron
ZB-5MS), hydrogen as carrier gas, and a flame ionization detector
(oxygen). Solvents, reagents, and chemicals were purchased from
Aldrich, ABCR, Acros, and Maybridge. All solvents, reagents, and
chemicals were used as purchased unless stated otherwise.
with the reactivity of diketone 10 in all these reactions. Un-
der the reaction conditions, the diketone can tautomerize
into 2-methylhydroquinone (12). This conversion was ob-
served for all the reactions, even in the formation of Diels–
Alder adducts 11 (see Scheme 3). Furthermore, the double
reduction to diol 13 was also observed, but this was usually
produced in low amounts as the reactions were quenched
as soon as the double-reduced product was detectable by
TLC. The results in Table 1 show that this synthetic path-
way is only suitable for the synthesis of cyclohexenone 1
(see Table 1, Entries 5 and 7) and not for cyclohexenone 2.
1,4-Adduct [(S)-8]:[23] A solution of copper(II) triflate (56 mg,
0.156 mmol, 0.0240 equiv.) and (R,S,S)-9 (168 mg, 0.311 mmol,
0.0480 equiv.) in absolute toluene (30 mL) was stirred at room
temp. under argon for 1 h. The mixture was then cooled to –25 °C,
and benzoquinone monoketal 7[24] (1.00 g, 6.49 mmol, 1.00 equiv.)
and dimethylzinc (1.2 m in toluene, 8.92 mL, 1.02 g, 10.7 mmol,
1.65 equiv.) were added. After stirring at –25 °C for 15 h, a satu-
rated ammonium chloride solution (16 mL) was added, and the
mixture was extracted with ethyl acetate (3ϫ 120 mL). The com-
bined organic layers were washed with NaOH (1 m solution,
150 mL) and a saturated sodium chloride solution (150 mL) and
then dried with sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give (S)-8
(580 mg, 3.41 mmol, 53%) as a colorless oil. The enantiomeric ex-
cess (98%ee) was determined by GC analysis on a chiral modified
Conclusions
We presented the shortest synthetic pathway towards 4-
hydroxy-6-methylcyclohex-2-enone (1) through an asym-
metric Michael addition to benzoquinone monoketal 7.
Both enantiomeric 1,4-adducts 8 were obtained with high
enantiomeric excess values (97–98%ee). Each enantiomer
could then be converted into the corresponding cyclohex-
enone 1 through reduction by treatment with a CBS rea-
gent. By choosing (R)- or (S)-CBS, the trans or cis isomers
of cyclohexenones 1 were achieved. They were obtained in
82–97%ee and 29–61%de. All the reactions could be con- column. Rf = 0.69 (cyclohexane/ethyl acetate, 1:1). 1H NMR
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A. C. Meister, P. F. Sauter, S. Bräse
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3
(300 MHz, CDCl3): δ = 0.97 (d, J = 7.1 Hz, 3 H, CH3), 2.28 (dd, General Procedure for Determination of Enantiomeric Excess Values
2J = 16.8 Hz, 3J = 3.1 Hz, 1 H, CH2), 2.51–2.62 (m, 1 H, CH), of Cyclohexenones 1 by Mosher Method:[25] To cyclohexenone 1
2.83 (dd, 2J = 16.8 Hz, 3J = 4.8 Hz, 1 H, CH2), 3.27 (s, 6 H, 2
(5.0 mg, 39.6 μmol, 1.00 equiv.) in deuterated pyridine (0.5 mL) in
a NMR tube was added Mosher chloride (15 μL, 79.2 μmol,
3
3
CH3O), 6.02 (d, J = 10.4 Hz, 1 H, =CH), 6.65 (dd, J = 10.4 Hz,
4J = 2.0 Hz, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 2.00 equiv.). The mixture was shaken for 1 h, and the NMR spec-
14.88 (+, CH3), 35.52 (+, CH), 42.24 (–, CH2), 47.64 (+, CH3O),
49.80 (+, CH3O), 99.18 [Cq, C(OMe)2], 130.59 (+, =CH), 146.53
troscopic data were recorded. The enantiomeric excess values were
determined by integration of the signals. Full analytical data have
already been reported by the authors (see ref.[11]).
(+, =CH), 198.92 (C , CO) ppm. IR (KBr): ν = 2943 (m), 2833
˜
q
(w), 1685 (m), 1630 (w), 1459 (w), 1413 (w), 1383 (m), 1349 (w),
1293 (w), 1264 (w), 1233 (w), 1203 (m), 1133 (m), 1112 (m), 1069
(m), 1045 (m), 993 (w), 971 (m), 931 (m), 848 (vw), 771 (vw), 706
(vw), 593 (vw) cm–1. MS (FAB): m/z = 171 [M + H]+, 155 [M –
CH3]+, 139 [M – CH3O]+, 137 [C9H13O]+, 136 [C8H9O2]+, 123
[C7H7O2]+, 107 [C7H7O]+. HRMS (FAB): calcd. for C9H15O3
171.1021; found 171.1023. [α]2D0 = +2.21 (c = 0.895, ethyl acetate).
General Procedure A for Deprotection of 1,4-Adduct 8: To a solution
of 1,4-adduct 8 (20 mg, 118 μmol, 1.00 equiv.) in acetone (1 mL)
were added water (2 drops) and then Amberlyst 15® (10 mg). The
mixture was stirred at room temp. for 10 min and then diluted with
Et2O (5 mL). The resulting solution was dried with sodium sulfate,
and then the solvent was removed under reduced pressure at room
temp. to give product 10 (14.6 mg, 118 μmol, quantitative yield) as
a yellow oil, which was used without further purification. Note:
The product was stable at 7 °C for several hours. 1H NMR
(300 MHz, CDCl3): δ = 1.25 (d, 3J = 6.6 Hz, 3 H, CH3), 2.63 (ddd,
General Procedure for the Synthesis of Cyclohexenones 1: To a solu-
tion of CBS reagent (65.1 mg, 235 μmol, 1.00 equiv.) in absolute
THF (2 mL) under argon were added 1,4-adduct 8 (40.0 mg,
235 μmol, 1.00 equiv.) in absolute THF (2 mL) at 0 °C, and the
reaction mixture was stirred for 5 min. Then, BH3·THF (1 m in
THF, 470 μL, 470 μmol, 2.00 equiv.) was added dropwise, and the
mixture was stirred at 0 °C for 1 h. After this time, HCl (1 m solu-
tion, 2 mL) was added, and the resulting mixture was stirred for
30 min and extracted with ethyl acetate (20 mL). The organic layer
was dried with sodium sulfate, and the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 1:1). The full analytical data of
cyclohexenone 1 have already been reported by the authors (see
ref.[11] and Supporting Information).
2J = 12.3 Hz, J = 12.3 Hz, J = 3.1 Hz, 1 H, CH2), 2.94–3.03 (m,
2 H, CHCH3, CH2), 6.70 (dd, 3J = 10.3 Hz, 4J = 0.7 Hz, 1 H,
=CH), 6.74 (d, 3J = 10.3 Hz, 1 H, =CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 15.68 (+, CH3), 41.98 (+, CH), 45.00 (–,
CH2), 140.68 (+, =CH), 140.88 (+, =CH), 197.66 (Cq, CO), 200.21
(Cq, CO) ppm. For [(R)-10], [α]2D0 = –134.68 (c = 0.496, acetone)
and for [(S)-10], [α]2D0= +130.85 (c = 0.496, acetone). No further
analytical data were recorded because the molecule was very sensi-
tive to aromatization.
General Procedure B for Deprotection of 1,4-Adduct 8: To a solution
of 1,4-adduct 8 (20 mg, 118 μmol, 1.00 equiv.) in MeOH (1 mL)
were added water (2 drops) and then Amberlyst 15® (10 mg). The
mixture was stirred at room temp. for 10 min, and then it was dried
with sodium sulfate and filtered. The filtrate was used directly for
the next reaction with the assumption of a quantitative yield for 10.
3
4
Cyclohexenone cis-(R)-1: According to the general procedure, (R)-
CBS and (R)-8 were used to yield the product (20.4 mg, 162 μmol,
69%) as a colorless oil and as a mixture of two inseparable dia-
stereomers (cis-1/trans-1, 4.1:1.0, 95%ee for cis-1, 86%ee for trans-
Reduction of Diketone 10
1
3
1). H NMR (300 MHz, CDCl3, cis-1): δ = 1.15 (d, J = 6.5 Hz, 3
H, CH3), 1.74 (mc, 1 H, CH2), 2.33–2.46 (m, 3 H, OH, CHCH3,
(a) Using NaBH4 and CeCl3 at 0 °C: According to general pro-
cedure B, (R)-8 was deprotected. The methanolic solution was co-
oled to 0 °C, and then CeCl3·7H2O (44.0 mg, 118 μmol, 1.00 equiv.)
was added. After stirring for 5 min, NaBH4 (1.1 mg, 29.5 μmol,
0.250 equiv.) was added. The stirring was continued at this tem-
perature for 90 min, and then NaBH4 (1.1 mg, 29.5 μmol,
0.250 equiv.) was added again. After 30 min at this temperature,
the mixture was quenched with a saturated ammonium chloride
solution (2 mL). The resulting solution was extracted with ethyl
acetate (3ϫ 5 mL), and the combined extracts were dried with so-
dium sulfate. The solvent was removed under reduced pressure. The
residue was purified by column chromatography (cyclohexane/ethyl
acetate, 1:1) to give the product as a mixture of (R)-1 (5.2 mg,
41.5 μmol, 35% over 2 steps; cis/trans, 25.3:1.0) and (R)-2 (1.3 mg,
10.1 μmol, 8.6% over 2 steps; cis/trans, 1.1:1.0) as a yellow oil.
3
CH2), 4.64 (mc, 1 H, CHOH), 5.95 (d, J = 10.2 Hz, 1 H, =CH),
6.88 (mc, 1 H, =CH) ppm.
Cyclohexenone trans-(R)-1: According to the general procedure,
(S)-CBS and (R)-8 were used to yield the product (19.3 mg,
153 μmol, 65%) as a colorless oil and as a mixture of two insepa-
rable diastereomers (cis-1/trans-1, 1.0:1.8, 82%ee for trans-1,
92%ee for cis-1). 1H NMR (300 MHz, CDCl3, trans-1): δ = 1.16
(d, 3J = 7.1 Hz, 3 H, CH3), 2.02–2.23 (m, 3 H, OH, CH2), 2.76
3
(mc, 1 H, CHCH3), 4.55 (mc, 1 H, CHOH), 5.95 (d, J = 10.1 Hz,
1 H, =CH), 6.87 (mc, 1 H, =CH) ppm.
Cyclohexenone trans-(S)-1: According to the general procedure,
(R)-CBS and (S)-8 were used to yield the product (13.6 mg,
108 μmol, 46%) as a colorless oil and as a mixture of two insepa-
rable diastereomers (cis-1/trans-1, 1.0:2.1, 96%ee for trans-1,
96%ee for cis-1). 1H NMR (300 MHz, CDCl3, trans-1): δ = 1.16
(b) Using NaBH4 and CeCl3 at –78 °C: According to the general
procedure B, (R)-8 was deprotected. The methanolic solution was
cooled to –78 °C, and then CeCl3·7H2O (44.0 mg, 118 μmol,
1.00 equiv.) was added. After stirring for 5 min, NaBH4 (4.5 mg,
118 μmol, 1.00 equiv.) was added. The stirring was continued at
this temperature for 60 min, and then the mixture was quenched
with a saturated ammonium chloride solution (2 mL). The re-
sulting solution was extracted with ethyl acetate (3ϫ 5 mL), and
the combined extracts were dried with sodium sulfate. The solvent
3
(d, J = 7.1 Hz, 3 H, CH3), 2.02–2.18 (m, 2 H, CH2), 2.76 (mc, 1
3
H, CHCH3), 4.55 (mc, 1 H, CHOH), 5.95 (d, J = 10.1 Hz, 1 H,
3
=CH), 6.88 (d, J = 10.1 Hz, 1 H, =CH) ppm.
Cyclohexenone cis-(S)-1: According to the general procedure, (S)-
CBS and (S)-8 were used to yield the product (18.1 mg, 143 μmol,
61%) as a colorless oil and as a mixture of two inseparable dia-
stereomers (cis-1/trans-1, 3.5:1.0, 97%ee for cis-1, 60%ee for trans- was removed under reduced pressure. The residue was purified by
1
3
1). H NMR (300 MHz, CDCl3, cis-1): δ = 1.16 (d, J = 6.2 Hz, 3
column chromatography (cyclohexane/ethyl acetate, 1:1) to give the
H, CH3), 1.73 (mc, 1 H, CH2), 1.95 (br. s, 1 H, OH), 2.34–2.44 (m, product as a mixture of (R)-1 (2.7 mg, 21.2 μmol, 18%; cis/trans,
2 H, CHCH3, CH2), 4.65 (mc, 1 H, CHOH), 5.95 (d, 3J = 10.2 Hz, 1.0:1.8) and (R)-2 (2.2 mg, 17.7 μmol, 15%; cis/trans, 1.0:6.6) as a
1 H, =CH), 6.88 (mc, 1 H, =CH) ppm.
7114
yellow oil.
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7110–7116

A Stereoselective Approach to Functionalized Cyclohexenones
(c) Using NaBH4: According to general procedure B, (R)-8 was de-
protected. The methanolic solution was cooled to –10 °C, and then
NaBH4 (1.1 mg, 29.5 μmol, 0.250 equiv.) was added. The mixture
was stirred at this temperature for 90 min and then quenched with
a saturated ammonium chloride solution (2 mL). The resulting
mixture was extracted with ethyl acetate (3ϫ 5 mL), and the com-
bined extracts were dried with sodium sulfate. The solvent was re-
moved under reduced pressure. The residue was purified by column
chromatography (cyclohexane/ethyl acetate, 1:1) to give the product
as a mixture of (R)-1 (1.3 mg, 9.9 μmol, 8.4%; cis/trans, 17.1:1.0)
and (R)-2 (1.3 mg, 9.9 μmol, 8.4%; cis/trans, 1.0:2.5) as a yellow
oil.
residue was purified by column chromatography (cyclohexane/ethyl
acetate, 1:1) to give the product as a mixture of (R)-1 (0.9 mg,
7.0 μmol, 5.9% over 2 steps; cis/trans, 41.5:1.0) and (R)-2 (0.1 mg,
0.9 μmol, 0.7% over 2 steps; cis/trans, 1.0:1.2) as a yellow oil.
(h) Using (R)-CBS: According to general procedure A, (R)-8 was
deprotected. Crude 10 was dissolved in absolute THF (2 mL), and
the mixture was cooled to 0 °C. Then, (R)-CBS reagent (32.7 mg,
118 μmol, 1.00 equiv.) was added. After 5 min, BH3·THF (1 m in
THF, 118 μL, 118 μmol, 1.00 equiv.) was added. The mixture was
stirred at 0 °C for 1 h and then quenched with HCl (1 m solution,
2 mL). The resulting mixture was extracted with ethyl acetate (3ϫ
5 mL), and the combined extracts were dried with sodium sulfate.
The solvent was removed under reduced pressure. The residue was
purified by column chromatography (cyclohexane/ethyl acetate,
1:1) to give the product as a mixture of (R)-1 (1.8 mg, 13.9 μmol,
12% over 2 steps; cis/trans, 26.0:1.0) and (R)-2 (0.4 mg, 3.2 μmol,
2.7% over 2 steps; cis/trans, 1.1:1.0) as a yellow oil.
(d) Using NaBH(OAc)3: According to general procedure B, (R)-8
was deprotected. The methanolic solution was cooled to –78 °C,
and then NaBH(OAc)3 (25.0 mg, 118 μmol, 1.00 equiv.) was added.
After stirring for 90 min at this temperature, the mixture was
quenched with a saturated ammonium chloride solution (2 mL).
The resulting mixture was extracted with ethyl acetate (3ϫ 5 mL),
and the combined extracts were dried with sodium sulfate. The sol-
vent was removed under reduced pressure. The residue was purified
by column chromatography (cyclohexane/ethyl acetate, 1:1) to give
the product as a mixture of (R)-1 (0.52 mg, 4.1 μmol, 3.5%;
cis/trans, 22.4:1.0) and (R)-2 (0.48 mg, 3.8 μmol, 3.2%; cis/trans,
1.0:1.9) as a yellow oil.
(i) Using (S)-CBS: According to general procedure A, (R)-8 was
deprotected. Crude 10 was dissolved in absolute THF (2 mL), and
the mixture was cooled to 0 °C. Then, (S)-CBS reagent (32.7 mg,
118 μmol, 1.00 equiv.) was added. After 5 min, BH3·THF (1 m in
THF, 118 μL, 118 μmol, 1.00 equiv.) was added. The mixture was
stirred for 1 h at 0 °C and then quenched with HCl (1 m solution,
2 mL). The resulting mixture was extracted with ethyl acetate (3ϫ
5 mL), and the combined extracts were dried with sodium sulfate.
The solvent was removed under reduced pressure. The residue was
purified by column chromatography (cyclohexane/ethyl acetate,
1:1) to give the product as a mixture of (R)-1 (4.0 mg, 31.7 μmol,
27% over 2 steps; cis/trans, 19.1:1.0) and (R)-2 (2.9 mg, 23.0 μmol,
19% over 2 steps; cis/trans, 1.0:2.6) as a yellow oil. The full analyti-
cal data of cyclohexenone 2 have already been reported by the au-
thors (see ref.[11] and Supporting Information).
(e) Using Alpine-Hydride: According to general procedure A, (R)-8
was deprotected. The crude 10 was dissolved in absolute THF
(2 mL), and the mixture was cooled to –78 °C. Alpine-hydride
(0.5 m in THF, 118 μL, 118 μmol, 1.00 equiv.) was then added. Af-
ter stirring for 60 min at this temperature, the mixture was
quenched with a saturated ammonium chloride solution (2 mL),
and the resulting solution was extracted with ethyl acetate (3ϫ
5 mL). The combined extracts were dried with sodium sulfate, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (cyclohexane/ethyl acetate,
1:1) to give the product as a mixture of (R)-1 (7.0 mg, 55.0 μmol,
47%; cis/trans, 7.6:1.0) and (R)-2 (0.5 mg, 3.7 μmol, 3.1%; cis/trans,
1.0:2.0) as a yellow oil.
Diels–Alder Adduct (S)-11: To a solution of 1,4-adduct (S)-8
(50.0 mg, 295 μmol, 1.00 equiv.) in acetone (2 mL) were added
water (2 drops) and then Amberlyst 15® (10 mg). The mixture was
stirred at room temp. for 10 min then diluted with Et2O (10 mL).
The resulting solution was dried with sodium sulfate, and the sol-
vent was removed under reduced pressure at room temp. to give
(S)-10 as a yellow oil (14.6 mg, 118 μmol, quantitative yield). The
product was dissolved in methanol (5 mL), and the solution was
cooled to 0 °C. Freshly distilled cyclopentadiene (25 mg, 378 μmol,
1.28 equiv.) was added. The mixture was stirred at room temp. for
18 h, and then the solvent was removed under reduced pressure.
The residue was purified by column chromatography (cyclohexane/
ethyl acetate, 20:1). One fraction of pure endo-(S)-11 (5.4 mg,
28.4 μmol, 10%) and a mixed fraction of endo- and exo-(S)-11
(10.4 mg, 54.7 μmol, 19%; endo/exo, 1.0:4.2) were obtained. Data
for endo-(S)-11: Rf = 0.53 (cyclohexane/ethyl acetate, 2:1); m.p.
(f) Using DIBAL-H: According to general procedure A, (R)-8 was
deprotected. The crude 10 was dissolved in absolute THF (2 mL),
and the mixture was cooled to –78 °C. DIBAL-H (1 m in dichloro-
methane, 118 μL, 118 μmol, 1.00 equiv.) was added. After stirring
for 60 min at this temperature, the mixture was quenched with a
saturated ammonium chloride solution (2 mL), and the resulting
solution was extracted with ethyl acetate (3ϫ 5 mL). The combined
extracts were dried with sodium sulfate, and the solvent was re-
moved under reduced pressure. The residue was purified by column
chromatography (cyclohexane/ethyl acetate, 1:1) to give the product
as a mixture of (R)-1 (0.8 mg, 6.3 μmol, 5.3% over 2 steps; cis/trans,
5.9:1.0) and (R)-2 (0.2 mg, 1.7 μmol, 1.4% over 2 steps; cis/trans,
1.0:2.3) as a yellow oil.
3
76 °C. 1H NMR (400 MHz, CDCl3): δ = 1.10 (d, J = 6.7 Hz, 3 H,
3
CH3), 1.38 (d, 2J = 8.7 Hz, 1 H CH2), 1.50 (ddd, 2J = 8.6 Hz, J =
(g) Using (–)-menthol, DIBAL-H, and NaBH4: According to general 1.7 Hz, 3J = 1.7 Hz, 1 H, CH2), 2.26–2.52 (m, 3 H, CHCH3, CH2),
procedure A, (R)-8 was deprotected. To absolute THF (2 mL) were
added (–)-menthol (18.4 mg, 236 μmol, 2.00 equiv.) and DIBAL-H
(1 m in dichloromethane, 0.12 mL, 118 μmol, 1.00 equiv.), and the
3.18 (dd, 3J = 9.8 Hz, 3J = 3.8 Hz, 1 H, CH), 3.25 (dd, 3J = 9.8 Hz,
3J = 3.9 Hz, 1 H, CH), 3.42 (mc, 1 H, CH), 3.48 (mc, 1 H, CH),
6.12 (dd, 3J = 5.6 Hz, 3J = 2.9 Hz, 1 H, =CH), 6.25 (dd, 3J =
reaction mixture was stirred at room temp. for 1 h. The mixture 5.6 Hz, 3J = 2.9 Hz, 1 H, =CH) ppm. 13C NMR (100 MHz,
was cooled to –78 °C. Then, a solution of crude 10 in absolute
CDCl3): δ = 15.34 (+, CH3), 41.97 (+, CHCH3), 46.00 (–, CH2),
THF (0.5 mL) and NaBH4 (1.5 mg, 29.5 μmol, 0.250 equiv.) were 47.00 (+, CH), 48.52 (+, CH), 49.24 (–, CH2), 50.66 (+, CH), 52.64
added to the reaction mixture. The mixture was stirred at –78 °C
for 1.5 h and then quenched with a saturated ammonium chloride
solution (2 mL). The resulting mixture was extracted with ethyl
acetate (3ϫ 5 mL), and the combined extracts were dried with so-
dium sulfate. The solvent was removed under reduced pressure. The
(+, CH), 135.74 (+, =CH), 137.37 (+, =CH), 208.94 (Cq, CO),
212.05 (Cq, CO) ppm. Data for exo-(S)-11: Rf = 0.47 (cyclohexane/
ethyl acetate, 2:1); m.p. 89 °C. 1H NMR (400 MHz, CDCl3): δ =
3
2
1.00 (d, J = 6.5 Hz, 3 H, CH3), 1.35 (d, J = 8.7 Hz, 1 H CH2),
2
3
3
1.58 (ddd, J = 8.9 Hz, J = 1.7 Hz, J = 1.7 Hz, 1 H, CH2), 1.95
Eur. J. Org. Chem. 2013, 7110–7116
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7115

A. C. Meister, P. F. Sauter, S. Bräse
FULL PAPER
(dd, 2J = 16.9 Hz, 3J = 14.4 Hz, 1 H, CH2), 2.55 (ddd, 2J = 16.9 Hz,
[4]
[5]
H. Zhang, J. Xue, P. Wu, L. Xu, H. Xie, X. Wie, J. Nat. Prod.
2009, 72, 265–269.
4
3J = 5.4 Hz, J = 1.5 Hz, 1 H, CH2), 2.73–2.83 (m, 1 H, CHCH3),
3.17 (dd, 3J = 10.1 Hz, 3J = 3.8 Hz, 1 H, CH), 3.32 (ddd, 3J =
a) W. Zhang, K. Krohn, Zia-Ullah, U. Flörke, G. Pescitelli, L.
Di Bari, S. Antus, T. Kurtán, J. Rheinheimer, S. Draeger, B.
Schulz, Chem. Eur. J. 2008, 14, 4913–4923; b) for the first total
synthesis of blennolide B, see: T. Qin, R. P. Johnson, J. A.
Porco Jr., J. Am. Chem. Soc. 2011, 133, 1714–1717; c) for the
first total synthesis of blennolide A, see: L. F. Tietze, L. Ma,
J. R. Reiner, S. Jackenkroll, S. Heidemann, Chem. Eur. J. 2013,
19, 8610–8614.
3
4
10.0 Hz, J = 3.9 Hz, J = 1.3 Hz, 1 H, CH), 3.40 (mc, 1 H, CH),
3.50 (mc, 1 H, CH), 6.04 (dd, 3J = 5.6 Hz, 3J = 2.8 Hz, 1 H, =CH),
6.25 (dd, 3J = 5.6 Hz, 3J = 2.9 Hz, 1 H, =CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.75 (+, CH3), 41.49 (+, CHCH3), 45.45
(+, CH), 45.67 (–, CH2), 48.47 (+, CH), 48.56 (–, CH2), 52.20 (+,
CH), 52.55 (+, CH), 135.07 (+, =CH), 138.26 (+, =CH), 210.11
(Cq, CO), 210.30 (Cq, CO) ppm. IR [attenuated total reflectance
[6]
[7]
a) K.-S. Masters, S. Bräse, Chem. Rev. 2012, 112, 3717–3776;
b) S. Bräse, A. Encinas, J. Keck, C. F. Nising, Chem. Rev. 2009,
109, 3903–3990.
(ATR) platinium, mixture of diastereomers]: ν = 2972 (vw), 2946
˜
(vw), 1695 (w), 1458 (vw), 1412 (vw), 1373 (vw), 1339 (vw), 1299
(vw), 1261 (vw), 1244 (vw), 1223 (vw), 1181 (vw), 1157 (vw), 1104
(vw), 1057 (vw), 991 (vw), 910 (vw), 860 (vw), 781 (vw), 751 (vw),
729 (vw), 613 (vw), 576 (vw), 501 (vw) cm–1. MS (EI, 70 eV, mix-
ture of diastereomers): m/z (%) = 190 (44) [M]+, 91 (19) [C7H7]+,
66 (100) [C5H6]+. HRMS (EI, mixture of diastereomers): calcd. for
C12H14O2 190.0994; found 190.0995.
a) B. Franck, E.-M. Gottschalk, U. Ohnsorge, F. Hüper, Chem.
Ber. 1966, 99, 3842–3862; b) P. S. Steyn, Tetrahedron 1970, 26,
51–57; c) C. C. Howard, R. A. W. Johnstone, I. D. Entwistle, J.
Chem. Soc., Chem. Commun. 1973, 464; d) I. Kurobane, L. C.
Vining, G. McInnes, Tetrahedron Lett. 1978, 19, 4633–4636.
B. Franck, G. Baumann, Chem. Ber. 1966, 99, 3863–3874.
a) M. Isaka, A. Jaturapat, K. Rukseree, K. Danwisetkanjana,
M. Tanticharoen, Y. Thebtaranonth, J. Nat. Prod. 2001, 64,
1015–1018; b) B. Elsässer, K. Krohn, U. Flörke, N. Root, H.-
J. Aust, S. Draeger, B. Schulz, S. Antus, T. Kurtán, Eur. J. Org.
Chem. 2005, 4563–4570.
J. Lin, S. Liu, B. Sun, S. Niu, E. Li, X. Liu, Y. Che, J. Nat.
Prod. 2010, 73, 905–910.
A. C. Meister, M. Nieger, S. Bräse, Eur. J. Org. Chem. 2012,
5373–5380.
U. K. Ohnemüller (née Schmid), C. F. Nising, M. Nieger, S.
Bräse, Eur. J. Org. Chem. 2006, 1535–1546.
[8]
[9]
Diels–Alder Adduct (R)-11: To a solution of 1,4-adduct (R)-8
(50.0 mg, 295 μmol, 1.00 equiv.) in acetone (2 mL) were added
water (2 drops) and then Amberlyst 15® (10 mg). The mixture was
stirred at room temp. for 10 min and then diluted with of Et2O
(10 mL). The resulting mixture was dried with sodium sulfate, and
then the solvent was removed under reduced pressure at room
temp. to give (R)-10 (14.6 mg, 118 μmol, quantitative yield) as a
yellow oil. The product was dissolved in methanol (5 mL), and the
solution was cooled to 0 °C. Freshly distilled cyclopentadiene
(25 mg, 378 μmol, 1.28 equiv.) was added. The mixture was stirred
at room temp. for 18 h, and then the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 10:1). One fraction of pure endo-
(S)-11 (5.7 mg, 30.0 μmol, 10%) and a mixed fraction of endo- and
exo-(S)-11 (12.0 mg, 63.1 μmol, 21%; endo/exo, 1.0:1.6) were ob-
tained. The analytical data of endo-(R)-11 corresponds with endo-
(S)-11, and the data for exo-(R)-11 corresponds with exo-(S)-11.
Therefore, they are not listed.
[10]
[11]
[12]
[13]
[14]
E. Piers, S. Caillé, G. Chen, Org. Lett. 2000, 2, 2483–2486.
M. G. Edwards, M. N. Kenworthy, R. R. A. Kitson, M. S.
Scott, R. J. K. Taylor, Angew. Chem. 2008, 120, 1961; Angew.
Chem. Int. Ed. 2008, 47, 1935–1937.
[15] a) M. C. Carreño, M. Ribagorda, Á. Somoza, A. Urbano, An-
gew. Chem. 2002, 114, 2879; Angew. Chem. Int. Ed. 2002, 41,
2755–2757; b) M. C. Carreño, M. Pérez-Gonzalés, M. Riba-
gorda, Á. Somoza, A. Urbano, Chem. Commun. 2002, 3052–
3053; c) M. C. Carreño, M. Ribagorda, A. Somoza, A. Ur-
bano, Chem. Eur. J. 2007, 13, 879–890.
[16] a) M. Shan, G. A. O’Doherty, Org. Lett. 2008, 10, 3381–3384;
b) M. Shan, E. U. Sharif, G. A. O’Doherty, Angew. Chem.
2010, 122, 9682; Angew. Chem. Int. Ed. 2010, 49, 9492–9495.
[17] a) R. Imbos, M. H. G. Brilman, M. Pineschi, B. L. Feringa,
Org. Lett. 1999, 1, 623–625; b) see also: L. C. Konkol, F. Guo,
A. A. Sarjeant, R. J. Thomson, Angew. Chem. 2011, 123,
10105; Angew. Chem. Int. Ed. 2011, 50, 9931–9934.
Supporting Information (see footnote on the first page of this arti-
cle): Further experimental and analytical data as well as 1H and
13C NMR spectra are presented.
Acknowledgments
[18] For the synthesis from a diketal, see: D. R. Henton, J. An-
derson, M. J. Manning, J. S. Swenton, J. Org. Chem. 1980, 45,
3422–3433; for the synthesis from a hydroquinone, see: A.
Pelter, S. Elgendy, Tetrahedron Lett. 1988, 29, 677–680.
[19] G. M. Coppola, Synthesis 1984, 1021–1023.
[20] a) D. D. Chapman, W. J. Musliner, J. W. Gates Jr., J. Chem.
Soc. C 1969, 124–128; b) D. D. Chapman, J. W. Gates Jr., W. J.
Musliner, French Patent FR 2004838, 1969; c) M. Sainsbury,
in: Science of Synthesis 2008, vol. 32, p. 299–334.
The authors acknowledge the Fonds der Chemischen Industrie and
the Deutsche Forschungsgemeinschaft (DFG) (BR 1750-12-1) for
the financial support.
[1] S. Qin, H. Hussain, B. Schulz, S. Draeger, K. Krohn, Helv.
Chim. Acta 2010, 93, 169–174.
[2] a) G. Bach, S. Breiding-Mack, S. Grabley, P. Hammann, K.
Huetter, R. Thiericke, H. Uhr, J. Wink, A. Zeeck, Liebigs Ann.
Chem. 1993, 241–250; b) for the first total synthesis of gabos- [21] a) E. W. Garbisch Jr., J. Am. Chem. Soc. 1965, 87, 4971–4972;
ine B, see: T. Shinada, T. Fuji, Y. Ohtani, Y. Yoshida, Y.
Ohfune, Synlett 2002, 1341–1343; c) for a review about gabos-
ines, see: P. Bayón, M. Figueredo, Chem. Rev. 2013, 113, 4680–
4707.
b) S. Jarupinthusophon, U. Thong-In, W. Chavasiri, J. Mol.
Catal. A: Chem. 2007, 270, 289–294.
[22] a) D. B. G. Williams, K. Blann, C. W. Holzapfel, J. Chem. Soc.
Perkin Trans. 1 2001, 219–220; b) M. Ghandi, M. Shahidzadeh,
J. Organomet. Chem. 2006, 691, 4918–4925.
[23] The synthesis was adapted from ref.[17]
[24] For its synthesis see ref.[18]
[3] a) M.-S. Kuo, D. A. Yurek, S. A. Mizsak, V. P. Marshall, W. F.
Liggett, J. I. Cialdella, A. L. Laborde, J. A. Shelly, S. E. Trues-
dell, J. Antibiot. 1995, 48, 888–890; b) for the first total Synthe-
sis see: M. C. Carreño, E. Merino, M. Ribagorda, Á. Somoza,
A. Urbano, Org. Lett. 2005, 7, 1419–1422; c) M. C. Carreño,
E. Merino, M. Ribagorda, A. Somoza, A. Urbano, Chem. Eur.
J. 2007, 13, 1064–1077.
[25] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543–2549.
Received: May 22, 2013
Published Online: September 13, 2013
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