(±)-trans, cis -4-Hydroxy-5,6-di-O -isopropylidenecyclohex-2-ene-1- one: Synthesis and facile dimerization to decahydrodibenzofurans

Article abstract of DOI:10.1021/jo102314w

An efficient synthesis of (±)-trans,cis-4-hydroxy-5,6-di-O- isopropylidenecyclohex-2-ene-1-one (3) has been developed from acetonide-protected meso-1,2-dihydrocatechol derivative 1 via photooxygenation, then Kornblum-DeLaMare rearrangement. The product is

Full text of DOI:10.1021/jo102314w

pubs.acs.org/joc
desymmetrization [(-)-ent, R = Ac; (þ)-ent, R = TBS),3-5
(()-trans,cis-4-Hydroxy-5,6-di-O-
isopropylidenecyclohex-2-ene-1-one: Synthesis and
Facile Dimerization to Decahydrodibenzofurans
from D-galactose [(þ)-ent, R = Ac)6 and from (-)-quinic acid
[(-)-ent, R = TBS).7-9 These routes employ either allylic
alcohol oxidation or β-hydroxyketone elimination as the
final step to establish the enone function and, therefore, do
not provide enone 3 free of protection at the 4-OH group
directly. By contrast, a shorter route pioneered by
Hudlicky10-13 from Pseudomonas putida chlorobenzene
metabolite14,15 (þ)-cis-1-chloro-4,6-cyclohexadiene-2,3-diol
via photooxygenation, then thiourea-mediated hydrogeno-
lysis of the resulting endoperoxide, does provide the unpro-
tected (-)-4-hydroxy enone 3 but has the drawback that this
starting material is expensive (due to its nontrivial isolation
from the fermentation broth). Vexed by the high cost and
apparent instability2 of (-)-4-hydroxy enone 3 obtained via
this route, we sought to develop a new route to racemic enone
3. Here, we describe these studies and also the structural
elucidation of two diastereomeric dimers of this compound,
the facile formation of which explains its instability in
solution in the presence of base.
Victoria L. Paddock, Robert J. Phipps,
Almudena Conde-Angulo, Araceli Blanco-Martin,
ꢀ
~
Carles Giro-Manas, Laetitia J. Martin, Andrew J. P. White,
and Alan C. Spivey*
Department of Chemistry, Imperial College, London,
SW7 2AY, U.K.
a.c.spivey@imperial.ac.uk
Received November 23, 2010
Inspired by the syntheses of various conduritols by Balci,16
we envisaged that (()-4-hydroxy enone 3 could be prepared
from meso-1,2-dihydrocatechol derivative 1 by photooxy-
genation17,18 and then Kornblum-DeLaMare (KDLM)19
rearrangement (Scheme 1).20
Although meso-1,2-dihydrocatechol (a Pseudomonas puti-
da benzene metabolite14,15) is commercially available, it is
expensive and prone to aromatization on storage, and so we
required a more economic source of its acetonide derivative
1. Nonenzymatic syntheses have been reported by Yang21,22
An efficient synthesis of (()-trans,cis-4-hydroxy-5,6-di-
O-isopropylidenecyclohex-2-ene-1-one (3) has been deve-
loped from acetonide-protected meso-1,2-dihydrocatechol
derivative 1 via photooxygenation, then Kornblum-
DeLaMare rearrangement. The product is unstable un-
less its 4-hydroxy group is protected, as it undergoes facile
dimerization in solution to a 1:1 mixture of diastereoiso-
meric decahydrodibenzofurans 8 and 9. A new synthesis
of the dihydrocatechol 1 from 1,3-cyclohexadiene has
also been developed.
(4) Johnson, C. R.; Ple, P. A.; Adams, J. P. J. Chem. Soc., Chem.
Commun. 1991, 1006–1007.
(5) Dumortier, L.; Liu, P.; Dobbelaere, S.; Van der Eycken, J.; Vandewalle,
M. Synlett 1992, 243–245.
(6) Mereyala, H. B.; Gaddam, B. R. J. Chem. Soc., Perkin Trans. 1 1994,
2187–2190.
(7) Katoh, T.; Izuhara, T.; Yokota, W.; Inoue, M.; Watanabe, K.;
Nobeyama, A.; Suzuki, T. Tetrahedron 2006, 62, 1590–1608.
(8) Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651–7655.
(9) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem.
1999, 64, 6443–6458.
(10) Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen, C.; Nugent, T.;
Price, J. D. J. Chem. Soc., Perkin Trans. 1 1991, 2907–2917.
(11) Hudlicky, T.; Fan, R. L.; Tsunoda, T.; Luna, H.; Andersen, C.; Price,
J. D. Isr. J. Chem. 1991, 31, 229–238.
(12) Oppolzer, W.; Spivey, A. C.; Bochet, C. G. J. Am. Chem. Soc. 1994,
116, 3139–3140.
(13) Banwell, M. G.; De Savi, C.; Hockless, D. C. R.; Pallich, S.; Watson,
K. G. Synlett 1999, 885–888.
(14) Boyd, D. R.; Sharma, N. D.; Belhocine, T.; Malone, J. F.; McGregor,
S.; Allen, C. C. R. Chem. Commun. 2006, 4934–4936.
(15) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichimica Acta 1999,
32, 35–62.
(16) Balci, M. Pure. Appl. Chem. 1997, 69, 97–104.
(17) Sutbeyaz, Y.; Secen, H.; Balci, M. J. Chem. Soc., Chem. Commun.
1988, 1330–1331.
During the course of ongoing studies toward the total
asymmetric synthesis of the Amaryllidaceae alkaloid (-)-
lycorine,1,2 we required an efficient preparation of racemic
4-hydroxy enone 3 for development work. Syntheses of this
versatile enone in an enantiomerically pure form, with
various protecting groups (R) on the 4-hydroxy function,
have been described previously from meso-1,2-dihydro-
catechol derivative 1 via enzymatic acylative/deacylative
(18) Secen, H.; Gultekin, S.; Sutbeyaz, Y.; Balci, M. Synth. Commun.
1994, 24, 2103–2108.
(1) For leading references to previous syntheses of lycorine and regarding
its biological activity, respectively, see: (a) Jones, M. T.; Schwartz, B. D.;
Willis, A. C.; Banwell, M. G. Org. Lett. 2009, 11, 3506. (b) Hayden, R. E.;
Pratt, G.; Drayson, M. T.; Bunce, C. M. Haematologica 2010, 95, 1889–1896.
(19) Kornblum, N.; De La Mare, H. E. J. Am. Chem. Soc. 1951, 73, 880–
881.
(20) It is possible that, by applying the organocatalytic, asymmetric
Kornblum-DeLaMare rearrangement protocol developed by Toste et al.
to endoperoxide 2, this synthesis could be rendered enantioselective; see:
Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658.
(21) Yang, N. C.; Chen, M.-J.; Chen, P. J. Am. Chem. Soc. 1984, 106,
7310–7315.
ꢀ
(2) Spivey, A. C.; Giro-Manas, C.; Mann, I. Chem. Commun. 2005, 4426–
~
4428.
(3) Johnson, C. R.; Adams, J. P.; Collins, M. A. J. Chem. Soc., Perkin
Trans. 1 1993, 1–2.
DOI: 10.1021/jo102314w
r
Published on Web 01/25/2011
J. Org. Chem. 2011, 76, 1483–1486 1483
2011 American Chemical Society

Paddock et al.
JOCNote
SCHEME 1. Envisaged Synthesis of 4-Hydroxy Enone 3
SCHEME 3. Synthesis of 4-Hydroxy Enone 3
SCHEME 2. Synthesis of meso-1,2-Dihydrocatechol Derivative 1
Hunig’s base (1 equiv) in either CH2Cl2 or DMF (∼0.4 M)
effected KDLM rearrangement to give 4-hydroxyenone 3
1
essentially quantitatively within 40 min, as judged by H
(four steps, 26% yield overall from 1,4-cyclohexadiene23)
and by Fabris24 (three steps, 36% yield overall from myo-
inositol)25, but these proved unsatisfactory in our hands.
Consequently, we developed an alternative three-pot synthe-
sis from 1,3-cyclohexadiene (Scheme 2).
NMR and TLC. However, if left for longer, a new substance
started to form, which was slightly less polar than enone 3
and non-UV-active by TLC. This substance also formed
during solvent evaporation and significantly impaired isola-
tion of enone 3 (66% yield). It displays a m/z (MNH4þ) of
386 Da, which corresponds to a dimer of enone 3, but the
Thus, photooxidation of 1,3-cyclohexadiene in CCl4 at
0 °C (300 W sun lamp, 5.5 h) using tetraphenylphorphyrin
(TPP, 2 mol %) as a photosensitizer gave endoperoxide
4,26,27 which was not isolated but treated directly with
cobalt-TPP (2 mol %) to give bis-epoxide 5.28 Efficient
isolation of bis-epoxide 5 is hampered by its low boiling
point, but direct treatment of the crude reaction mixture with
a solution of dilithium tetrabromocuprate (Li2CuBr4)29
allows in situ bis-ring-opening to give cis-dibromide 6 in
68% overall yield from 1,3-cyclohexadiene.30 Protection of
the diol unit using DMP/p-TsOH gives acetonide 7 (88%
yield); then, bis-elimination of HBr using DBU/TBAI in
CH2Cl2 at reflux gives the desired diene 1 in 83% yield after
distillation. The relative stereochemistry of compound 7 was
confirmed by a single-crystal X-ray structure determination
(see the Supporting Information). Overall, this three-pot
sequence of reactions gives diene 1 in ∼50% yield on a
preparative scale from 1,3-cyclohexadiene.
1
complexity of the H NMR fingerprint was suggestive of
more than one isomer. A single-crystal X-ray structure deter-
mination on a crystalline component of this product (see the
Supporting Information) revealed it to be the pentacyclic cis,
trans,cis-decahydrodibenzofuran derivative 8 (Scheme 3).
1
This compound accounts for exactly half of the H NMR
signals in the crude spectrum; the remaining signals are those
of the diastereomeric cis,cis,cis-decahydrodibenzofuran 9,
which is noncrystalline, is chromatographically inseparable
from cis,trans,cis-decahydrodibenzofuran 8, and is formed
in a close to equal amount (i.e., 8/9 1:1).31 The stereochemical
assignments for dimers 8 and 9 were confirmed by NOESY
NMR: dimer 8 shows nOe crosspeaks for H4a T H9b, H5a
H9a, and H9b T H9β, whereas dimer 9 shows them for H4a
H9b, H4a T H5a, H5a T H9a, H5a T H9b, H5a T H6, and H9a
T
T
T
H9b. These are consistent with the crystal structure of dimer 8
and a MMFF94 minimized structure for dimer 9 (Scheme 3).
Formation of these dimers probably results from a double
Michael addition cascade: first, intermolecular addition of
the alcohol/alkoxide to the enone, then intramolecular addi-
tion of the resulting enol/enolate to the remaining enone,
effecting 5-exo-trig cyclization to give the central THF ring.
There appears to be no preference for which face of the enone
is attacked in the initial conjugate addition step to form the
C4a stereocenter, but the enol/enolate reacts with complete
facial selectivity for the formation of the C8a and C8b
Photooxygenation of diene 1 in CCl4 at RT (300 W sun
lamp, 7.5 h, TPP, 5 mol %)17,18 gave the known endoperoxide
2 (95% yield). Pleasingly, treatment of this compound with
(22) Yang, N. C.; Chen, M. J.; Chen, P.; Mak, K. T. J. Am. Chem. Soc.
1982, 104, 853–855.
(23) The Chan sequence of reactions (ref 21) has been reported by
Johnson et al. to proceed in 87% overall yield. In our hands, however, the
original yields are reproduced; see: Johnson, C. R.; Ple, P. A.; Adams, J. P.
J. Chem. Soc., Chem. Commun. 1991, 1006.
(24) Fabris, F.; Rosso, E.; Paulon, A.; De Lucchi, O. Tetrahedron Lett.
2006, 47, 4835–4837.
stereocenters. An analogous dimerization process has pre-
~
4-substituted-4-hydroxycyclohexen-2-one using NaH in
CH2Cl2, which was reported to give a cis,trans,cis-decahy-
drodibenzofuran exclusively.
(25) The Fabris route (ref 24) is based on one developed by Mereyala for
the synthesis of the cyclohexylidene analogue; see: Mereyala, H. B.; Pannala,
M. Tetrahedron Lett. 1995, 36, 2121.
(26) Schenck, G. O.; Dunlap, D. E. Angew. Chem. 1956, 68, 248–249.
(27) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876–877.
(28) Boyd, J. D.; Foote, C. S.; Imagawa, D. K. J. Am. Chem. Soc. 1980,
102, 3641–3642.
32
viously been reported by Carreno and Ribagorda for a
(29) Ciaccio, J. A.; Heller, E.; Talbot, A. Synlett 1991, 248–250.
(30) CuBr2 can also be employed to affect this transformation, but the
yield is slightly lower. Interestingly, if any 1,3-cyclohexadiene is carried
through into this step (due to incomplete photooxygenation), CuBr2 affects
efficient conversion of this compound to 1,4-dibromocyclohex-2-ene, pre-
dominantly as the crystalline trans isomer. This compound has been prepared
previously by treatment of 1,3-cyclohexadiene with Br2 at -70 °C and a
crystal structure reported; see: Han, X.; Khedekar, R. N.; Masnovi, J.;
Baker, R. J. J. Org. Chem. 1999, 64, 5245–5250.
(31) Dimers 8 and 9 are also formed as an ∼1:1 mixture from the
decomposition of the enantiomerially pure (-)-3 formed by the Hudlicky
route (ref 2), as judged by 1H NMR following attempted isolation. However,
this is only a minor component of the decomposition pathway in those
reactions; the major decomposition product is highly polar and results from
reaction of the enone 3 with the thiourea (or derived carbodiimide) employed
to affect the final endoperoxide hydrogenolysis.
(32) Carreno, M. C.; Ribagorda, M. Org. Lett. 2003, 5, 2425–2428.
1484 J. Org. Chem. Vol. 76, No. 5, 2011

Paddock et al.
JOCNote
Because 4-hydroxyenone 3 is prone to dimerization, par-
ticularly during solvent evaporation, in situ protection
proved to be the preferred method for obtaining its O-pro-
tected derivatives. For example, if further Hunig’s base
(1 equiv) and TBSCl (2 equiv) are added immediately after
the disappearance of endoperoxide 2 in the KDLM rearran-
gement reaction and the solution is left to stir overnight, the
TBS ether 10 is isolated in 78% yield (Scheme 3).
CDCl3): δC 29.9 (ꢀ2), 52.6 (ꢀ2, broad), 72.9 (ꢀ2); IR νmax
(neat): 675, 1040, 1077, 2946, 3395 cm -1; m/z (EIþ) 276
[{M(81Br, 81Br)}þ•, 21%], 274 [{M(81Br, 79Br)}þ•, 45%)], 272
[{M(79Br, 79Br)}þ•, 22%], 256 (30), 175 (39), 113 (51), 84 (77), 67
(100); HRMS (EIþ) m/z calcd for C6H10O279Br2 [Mþ•] 271.9048,
found 271.9042 (Δ = -2.0 ppm).
(3aR*,4R*,7S*,7aS*)-4,7-Dibromo-2,2-dimethylhexahydro-
1,3-benzodioxole 7. To a solution of diol 6 (1.52 g, 5.55 mmol) in
CH2Cl2 (60 mL) was added a solution of DMP (4.10 mL, 33.30
In conclusion, a new synthesis of (()-4-hydroxyenone 3
has been developed utilizing a KDLM rearrangement. The
reason for its known, but previously unexplained, instability
in solution has been shown to be at least partly due to the
facile formation of a pair of diastereoisomeric decahydrodi-
benzofurans 8 and 9 in the presence of base. In situ hydroxyl
protection, however, allows for efficient preparation of
protected derivatives (e.g., 10) that are established synthetic
intermediates en route to Amaryllidaceae alkaloids,2,11,12
conduritols,4-6,10 shikimate derivatives,3 scyphostatin ana-
logues,7,8 and aldopentoses.13
mmol) and p-TsOH H2O (211 mg, 1.11 mmol) in CH2Cl2
3
(5 mL) at 0 °C, and the resultant solution was allowed to stir
at this temperature for 2 h. After this time, the reaction mixture
was quenched with aqueous NaOH (100 mL, 1 M). The phases
were separated and the aqueous phase extracted further with
CH2Cl2 (2 ꢀ 50 mL). The combined organic phases were dried
over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by FC (SiO2, 100% hexane f hexane/Et2O, 99:1 f
hexane/Et2O, 98:2 f hexane/Et2O, 97:3 f hexane/Et2O, 9:1) to
give acetonide 7 as a white crystalline solid, which was recrys-
tallized from n-hexane to give colorless blocks (1.53 g, 88%). mp
74-77 °C; Rf = 0.42 (hexane/Et2O, 9:1); 1H NMR (400 MHz,
CDCl3): δH 1.34 (3H, s), 1.47 (3H, s), 2.07-2.22 (4H, m),
4.18-4.26 (2H, m), 4.40-4.44 (2H, m); 13C (125 MHz, CDCl3):
δC 26.3, 28.6, 30.0 (ꢀ2), 50.0 (ꢀ2), 79.3 (ꢀ2), 110.1; IR νmax
(neat): 864, 1050, 1063, 1220, 1211, 1382, 2986 cm -1; m/z (CIþ)
334 [M(81Br, 81Br)NH4þ, 23%], 332 [M(81Br, 79Br)NH4þ, 46%],
330 [M(79Br, 79Br)NH4þ, 24%], 317 [M(81Br, 81Br)Hþ, 48%],
315 [M(81Br, 79Br)Hþ, 100%], 313 [M(79Br, 79Br)Hþ, 50%];
HRMS (CIþ) m/z calcd for C9H15O2Br2 [MHþ] 312.9439, found
312.9449 (Δ = 3.3 ppm). A single-crystal X-ray structure
determination was performed on this product (see the Support-
ing Information).
Experimental Section
(1R*,2R*,3S*,4S*)-3,6-Dibromocyclohexane-1,2-diol 6.
A
solution of TPP (65 mg, 0.11 mmol) in CCl4 (20 mL) was purged
with O2 and 1,3-cyclohexadiene (0.5 mL, 5.25 mmol) added. The
solution was cooled to 0 °C and irradiated with a 300 W lamp at
this temperature under an atmosphere of O2 for 5.5 h. After this
1
time, full conversion to endoperoxide 42 was observed by H
NMR analysis. 1H NMR (400 MHz, CDCl3): δH 1.46 (2H, dm,
J = 9.4), 2.27 (2H, dm, J = 9.4), 4.63 (2H, m), 6.66 (2H, dd, J =
4.4, 3.3). CoTPP (71 mg, 0.11 mmol) was added to the solution,
and the reaction mixture was stirred at 25 °C under an inert
atmosphere. After 2.5 h, full conversion to bis-epoxide 5 was
observed by TLC. This solution of crude bis-epoxide was used
directly in the next step. An aliquot of the solution was taken and
purified by FC (SiO2, 100% hexane f 95:5 hexane/Et2O f 2:1
hexane/Et2O) to give an analytical sample of bis-epoxide 533 as a
yellow oil. Rf = 0.28 (Et2O/hexane, 2:1); 1H NMR (400 MHz,
CDCl3): δH 1.77-1.79 (4H, m), 3.04-3.05 (2H, m), 3.31 (2H,
dm, J = 4.3); 13C NMR (100 MHz, CDCl3): δC 19.65 (ꢀ2),
47.30 (ꢀ2), 47.94 (ꢀ2); IR νmax (neat): 761, 779, 796, 888, 917,
938, 1267, 1415, 1440, 2935, 3004 cm -1; m/z (CIþ) 130
(MNH4þ, 100%) 52 (10); HRMS (CIþ) m/z calcd for
C6H12NO2 [MNH4þ] 130.0868, found 130.0870 (Δ = 1.5 ppm).
A solution of dilithium tetrabromocuprate (Li2CuBr4) was
prepared according to the method of Ciaccio29 by dissolving
CuBr2 (1.88 g, 8.4 mmol) and LiBr (1.46 g, 16.8 mmol) in MeCN
(10 mL) at 0 °C and warming to 25 °C. To this dark purple
solution was added a solution of the crude bis-epoxide 5
(∼5.25 mmol) in CCl4 (∼20 mL) via cannular. The bis-epoxide
containing flask was washed with MeCN (10 mL) and cannu-
lated likewise and the reaction mixture allowed to stir at 25 °C
for 1 h. The solvent was then removed in vacuo and the crude
mixture partitioned between H2O (20 mL) and Et2O (20 mL).
The phases were separated and the aqueous phase extracted
further with Et2O (2 ꢀ 60 mL). The combined organic phases
were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by FC (SiO2, 100% hexane f hexane/
Et2O, 99:1 f hexane/Et2O, 97:3 f hexane/Et2O, 95:5 f
hexane/Et2O, 2:1f hexane/Et2O, 1:1 f hexane/Et2O, 1:2) to
give diol 6 as a white crystalline solid (983 mg, 68% from
cyclohexadiene). mp 80-82 °C; Rf = 0.42 (Et2O/hexane, 2:1);
1H NMR (400 MHz, CDCl3): δH 2.10 (2H, m), 2.21-2.27 (2H,
m), 3.06 (2H, s), 4.21 (2H, m), 4.28 (2H, m); 13C (100 MHz,
(3aR*,7aS*)-2,2-Dimethyl-3a,7a-dihydro-1,3-benzodioxole 134.
Into a dry two-neck flask containing TBAI (3.87 g, 9.76 mmol)
was cannulated a solution of acetonide 7 (1.53 g, 4.87 mmol) in
CH2Cl2 (10 mL); the flask was washed with CH2Cl2 (3.6 mL)
and cannulated likewise. To this solution was added DBU
(7.28 mL, 48.73 mmol), and the solution was heated to reflux.
After 2 h, the reaction mixture was quenched with a citric acid
monohydrate solution (15.40 g, 73.05 mmol in 20 mL of H2O)
and allowed to stir for 10 min. The phases were separated and
the aqueous phase extracted further with CH2Cl2 (3 ꢀ 15 mL).
The combined organic phases were washed with brine (3 ꢀ
50 mL) and H2O (2 ꢀ 50 mL), dried over Na2SO4, and filtered.
The crude product was isolated by distillation at 55 °C to give
diene 1 as a yellow oil (617 mg, 83%). Rf = 0.83 (petrol/EtOAc,
1:1); 1H NMR (300 MHz, CDCl3): δH 1.38 (3H, s), 1.40 (3H, s),
4.63-4.64 (2H, m), 5.85-5.90 (2H, m), 5.96-6.00 (2H, m); 13
C
NMR (75 MHz, CDCl3): δC 23.7, 25.7, 69.3 (ꢀ2), 103.5, 122.7
(ꢀ2), 122.2 (ꢀ2); IR νmax (neat): 694, 872, 1027, 1045, 1159,
1208, 1238, 1370, 1381, 2886, 2935, 2986, 3045 cm -1; m/z (CIþ)
322 (2M þ NH4þ, 25%), 305 (2M þ Hþ, 10%), 264 (100), 247
(58), 170 (MNH4þ, 85%); HRMS (CIþ) m/z calcd for C18-
H25O4 [2M þ Hþ] 305.1753, found 305.1751 (Δ = -0.6 ppm).
(1R*,2S*,6R*,7R*)-4,4-Dimethyl-3,5,8,9-tetraoxa-tricyclo-
[5.2.2.02,6]undec-10-ene 217,18. A solution of diene 1 (2.74 g,
18 mmol) and TPP (221 mg, 0.36 mmol) in CCl4 (73 mL) was
irradiated with light from a 300 W lamp for 5.5 h while oxygen
was bubbled through the solution. TTP (300 mg, 0.49 mmol)
and CCl4 (40 mL) were added, and the reaction mixture was
irradiated with light from a 300 W lamp for an extra 2 h while
oxygen was bubbled through the solution. The reaction mixture
was concentrated in vacuo. The residue was dissolved in ice-cold
EtOAc/hexane (2:8) and was stirred with activated carbon. The
mixture was filtered through a pad of Celite and then concentrated
(33) Suzuki, M.; Ohtake, H.; Kameya, Y.; Hamanaka, N.; Noyori, R.
J. Org. Chem. 1989, 54, 5292–5302.
(34) Ramesh, K.; Wolfe, M. S.; Lee, Y.; Velde, D. V.; Borchardt, R. T.
J. Org. Chem. 1992, 57, 5861–5868.
J. Org. Chem. Vol. 76, No. 5, 2011 1485

Paddock et al.
JOCNote
in vacuo to give endoperoxide 2 as white/light pink needles
14.0, 8.8), 2.70 (1H, bs), 3.04 (1H, dd, J = 14.0, 8.2), 3.16 (1H,
m), 3.57 (1H, dd, J = 10.9, 7.2), 4.01 (1H, dd, J = 3.6, 2.2), 4.30
(1H, d, J = 7.5), 4.32 (1H, d, J = 7.5), 4.40 (1H, d, J = 6.6), 4.63
(1H, dd, J = 7.5, 3.7), 4.70 (1H, dd, J = 6.6, 2.2), 4.79 (1H, dd,
qJ = 10.9, 2.1); 13C NMR (125 MHz, CDCl3): δC 23.5, 25.1,
26.0, 26.7, 33.7, 38.5, 48.6, 66.4, 76.9, 77.0, 77.2, 77.3, 77.5, 77.8,
110.8, 111.6, 202.6, 210.7.
1
(3.05 g, 95%). Rf = 0.30 (EtOAc/petrol 1:9); H NMR (400
MHz, CDCl3): δH 1.36 (6H, s), 4.59 (2H, m), 4.91 (2H, m), 6.58
(2H, m); 13C NMR (100 MHz, CDCl3): δC 25.4, 25.7, 71.5 (ꢀ2),
71.9 (ꢀ2), 110.3, 130.6 (ꢀ2); m/z (CIþ) 202 (MNH4þ, 100%).
(7R*)-Hydroxy-2,2-dimethyl-(7,7aS*)-dihydro-(3aR*)H-benzo-
[1,3]dioxol-4-one 3,11 (4R*)-Hydroxy-(2S*,3R*,6S*,7S*)-bis-[di-
O-isopropylidene]deca-[4aR*,5aR*,9aS*,9bS*]hydrodibenzofuran-
1,8-dione 8, and (4R*)-Hydroxy-(2S*,3R*,6S*,7S*)-bis-[di-O-
isopropylidene]deca-[4aS*,5aR*,9aS*,9bR*]hydrodibenzofuran-
1,8-dione 9. To a stirred solution of endoperoxide 2 (400 mg, 2.17
mmol) in CH2Cl2 (10 mL) was added triethylamine (304 μL, 2.71
mmol), and the resulting solution was stirred for 2 h at 25 °C.
The reaction mixture was then washed with water (2 ꢀ 20 mL)
and the aqueous washings extracted with CH2Cl2 (2 ꢀ 20 mL).
The combined organic extracts were washed with brine (50 mL),
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by FC (SiO2, EtOAc/hexane, 1:9 f 1:1) to give the
following:
Enone 3 as a colorless oil (265 mg, 1.80 mmol, 66%). Rf = 0.4
(EtOAc/hexane 2:1); 1H NMR (400 MHz, CDCl3): δH 1.46 (3H,
s), 1.47 (3H, s), 4.51 (2H, m), 4.63 (1H, m), 6.17 (1H, dd, J =
10.3, 1.5), 6.92 (1H, dd, J = 10.3, 3.3, CH) (OH absent), [lit.11];
1H NMR (270 MHz, CDCl3): δH 6.87 (1H, dd, J = 10.3, 3.2),
6.11 (1H, dd, J = 10.3, 1.6), 4.58 (1H, br s), 4.46 (2H, m), 1.40
(6H, s)]; m/z (CIþ) 202 (MNH4þ, 100%), 185 (MHþ, 47%), 162
(16), 146 (9), 129 (5); HRMS (CIþ) m/z calcd for C9H16NO4
[MNH4þ] 202.1079, found 202.1079 (Δ = 0.0 ppm).
Decahydrodibenzofurans 8 and 9 as a colorless oil (105 mg,
0.28 mmol, 26%, 8/9, 1:1 as determined by NMR). Rf = 0.45
(EtOAc/hexane 2:1); νmax (thin film): 734, 863, 909, 1062, 1087,
1161, 1212, 1384, 1732, 2935, 2989, 3452 cm-1; m/z (CIþ) 386
(MNH4þ, 25%), 202 (100), 185 (45); HRMS (CIþ) m/z calcd for
C18H28NO4 (MNH4þ) 386.1815, found 386.1811 (Δ = 1.1
ppm.). cis,trans,cis-Decahydrodibenzofuran 8 was isolated by
crystallization from CH2Cl2/pentane as colorless prisms. mp
184.6-186.0 °C; 1H NMR (400 MHz, CDCl3): δH 1.36 (3H, s),
1.38 (3H, s), 1.51 (3H, s), 1.57 (3H, s), 2.23 (1H, dd, J = 13.3,
8.8), 2.31 (1H, d, J = 2.2), 2.75 (1H, dd, J = 13.3, 7.2), 3.26 (1H,
dd, J = 9.5, 3.3), 3.33 (1H, m), 4.29 (1H, dd, J = 5.4, 3.7), 4.34
(1H, d, J = 7.5), 4.37 (1H, m), 4.43 (1H, d, J = 6.7), 4.70 (1H,
dd, J = 7.5, 3.9), 4.73 (1H, dd, J = 6.7, 3.7), 4.87 (1H, dd, J =
9.5, 3.4); 13C NMR (100 MHz, CDCl3): δC 23.6, 25.1, 26.1, 26.9,
37.5, 39.0, 51.3, 67.4, 76.3, 77.3, 77.4, 78.0, 78.4, 78.4, 110.7,
112.1, 202.4, 205.9. A single-crystal X-ray structure determina-
tion was performed on this product (see the Supporting
Information). The noncrystalline cis,cis,cis-decahydrodibenzo-
furan 9 was not obtained pure, but its 1H and 13C NMR
characteristics can be deduced by comparison of data for that
of isolated 8 with that of the mixture of 8 and 9. 1H NMR (500
MHz, CDCl3): δH 1.39 (6H, s), 1.53 (6H, s), 2.49 (1H, dd, J =
(7R*)-(tert-Butyldimethylsilanyloxy)-2,2-dimethyl-(7,7aS*)-
dihydro-(3aR*)H-benzo[1,3]dioxol-4-one 1011. To a solution of
endoperoxide 2 (0.5 g, 2.71 mmol) in DMF (7.5 mL) was added
diisopropylethylamine (470 μL, 2.71 mmol), and this solution
was stirred for 40 min at 25 °C. During this time, a solution of
TBSCl (813 mg, 5.42 mmol) in DMF (2.5 mL) was degassed to
remove HCl by bubbling through with N2 for 10 min prior to
addition of diisopropylethylamine (470 μL, 2.71 mmol) and a
further 10 min degassing. This TBSCl solution was then added
to the first solution after the aforementioned 40 min, and the
reaction was stirred for 14 h. EtOAc (30 mL) and brine (30 mL)
were added, the layers were separated, and the aqueous phase
was extracted with further EtOAc (2 ꢀ 30 mL). The combined
organic extracts were washed with brine (2 ꢀ 50 mL), dried over
Na2SO4, and concentrated in vacuo to give a yellow oil. This was
initially purified by FC (SiO2, EtOAc/pentane, 0:100 f 5:95 f
10:90) to give a mixture of 4-silyloxy enone 10 and TBSOH,
which was removed by heating to 70 °C for 1 h under high
vacuum to leave 4-silyloxy enone 10 as a waxy solid upon
storage at -20 °C (630 mg, 78%). Rf = 0.85 (EtOAc/hexane
2:1); 1H NMR (400 MHz, CDCl3): δH 0.16 (3H, s), 0.19 (3H, s)
0.93 (9H, s), 1.42 (3H, s), 1.43 (3H, s), 4.45 (2H, m), 4.55 (1H, dt,
J = 3.5, 1.0), 6.10 (1H, dd, J = 0.8, 10.3), 6.78 (1H, ddd, J =
10.3, 3.8, 1.1); 13C NMR (400 MHz, CDCl3): δC -4.7 (ꢀ2),
18.08, 25.7 (ꢀ3), 25.9, 27.4, 67.0, 74.3, 79.6, 110.17, 127.9, 148.5,
194.6; IR νmax (thin film): 515, 669, 727, 779, 838, 891, 1075,
1220, 1252, 1383, 1472, 1694, 2858, 2932 cm-1; m/z (CIþ) 316
(M-NH4þ, 100%), 299 (MHþ, 20), 241 (7), 186 (8), 145 (15),
132 (15), 126 (32); HRMS (CIþ) m/z calcd for C15H27O4Si
[MHþ] 299.1679, found 299.1676 (Δ = 1.0 ppm.).
Acknowledgment. We thank GlaxoSmithKline, sano-
fi-aventis, and the EPSRC for provision of studentships
(V.L.P., C.G-M. and L.J.M.), Imperial College London for
MSci research project support (R.J.P.), and the University
of Salamanca for providing Summer scholarships (A.C-A.
and A.B-M.).
Supporting Information Available: General experimental
directions, NMR spectra for compounds 1-3 and 6-9, and
details of the crystallographic analyses, including CIF files for
structures 7 and 8. This material is available free of charge via
the Internet at http://pubs.acs.org.
1486 J. Org. Chem. Vol. 76, No. 5, 2011