Diastereoselective spiroannulation of phenolic substrates: Synthesis of (±)-2-tert-butyl-6-methoxy-1-oxaspiro[4,5]deca-6,9-diene-8-one. http://www.mdpi.org

Article abstract of DOI:10.3390/10101335

The synthesis of a new spiroether is described. The title compound is obtained as a diastereomeric mixture in 45% yield.

Full text of DOI:10.3390/10101335

Molecules 2005, 10, 1335-1339
molecules
ISSN 1420-3049
http://www.mdpi.org
Diastereoselective Spiroannulation of Phenolic Substrates:
Synthesis of (±)-2-tert-Butyl-6-methoxy-1-oxaspiro[4,5]deca-6,9-
diene-8-one.
Guy L. Plourde* and Nadine J. English
University of Northern British Columbia, Department of Chemistry, 3333 University Way, Prince
George, British Columbia, Canada, V2N 4Z9. Tel: +1-250-960-6694, Fax: +1-250-960-5845.
* Author to whom correspondence should be addressed; Email: plourde@unbc.ca.
Received: 23 June 2005 / Accepted: 9 August 2005 / Published: 31 October 2005
Abstract: The synthesis of a new spiroether is described. The title compound is obtained as a
diastereomeric mixture in 45% yield.
Keywords: Spiroannulation, oxidation, phenol, diastereoslective, lead tetraacetate.
Introduction
We recently published our results related to the diastereoselective spiroannulation of phenolic
substrates producing spiroethers 1-3, as shown in Figure 1 [1,2].
Figure 1
O
O
O
OMe
+
OMe
OMe
O
O
O
R
R
t
Bu
1 R= methyl (dr 64/36)
2 R=isopropyl (dr 71/29)
3 R= tert-butyl (dr 81/19)
4
We had observed that increasing the size of the alkyl group on the side chain of the phenol
increased the diastereoselectivity from 64/36, when the alkyl group was a methyl, to 81/19 for a
tertiary butyl group. Furthermore, the oxidant used to carry out these transformations also played a
role in the outcome of the reactions. For instance, oxidation with lead tetraacetate (LTA) gave higher

1336
Molecules 2005, 10
chemical yields as well as higher diastereoselectivity than either [bis(trifluoroacetoxy)iodo]benzene
(PIFA) or (Diacetoxyiodo)benzene (PIDA). We speculated that the nature and the location of the
substituent on the aromatic ring of the phenol had a strong influence on the reaction outcomes. We
now wish to report the synthesis of the isomeric spiroether 4 and show that indeed, the position of the
methoxy substituent does affect the results of this reaction.
Results and Discussion
The synthesis of phenol 8 was performed as described in Scheme 1. We have previously reported
the synthesis of aldehyde 5, which we prepared from the corresponding catechol aldehyde in 78%
yield [3]. Following its synthesis, aldehyde 5 was condensed with pinacolone to afford the α,β-
unsaturated ketone 6 in 65% yield after purification by chromatography. Hydrogenation of 6 was
carried out under a slight positive pressure of hydrogen to afford 7 as an oil in 98% yield. Reduction of
the ketone carbonyl, followed by acid workup, provided the necessary deprotected phenol 8 as a
racemate in 82% yield (Scheme 1).
Scheme 1
OMOM
OMOM
OH
O
O
OMOM
a
c
b
d
+
OMe
OMe
OMe
OMe
OMe
OMe
O
O
CHO
t
t
Bu
Bu
t
t
t
Bu
O
Bu
O
Bu
HO
4 (50%dr )
5
7
6
8
(a) 50% THF/EtOH, pinacolone, NaOH, reflux(65%); (b) EtOAc, H , Pd/C (98%);
2
1
(c) [1] EtOH, NaBH ; [2] 10% HCl (82%); (d) Acetone, Pb(OAc) (45%) (50%dr from H-NMR)
4
4
We treated phenol 8 under reaction conditions seemingly identical to those previously described in
the synthesis of 1-3 (Figure 1) [1,2], and we obtained racemic 4 in 45% yield with a 50/50
1
diastereomeric ratio. This ratio was determined by analysis of the H-NMR spectrum of the crude
reaction mixture. The signals for H10 located at 6.55 and 6.63 ppm for each of these diastereomers
were used to determine the diastereomeric ratio, while signals for H7 (5.44 and 5.46) and H9 (6.01 and
6.05) as well as the signals for the methoxy group (3.74 and 3.77) were used as a confirmation of the
stereoselectivity observed. Contrary to compounds 1-3, which were partially separable by column
chromatography [1,2], the diastereomers of 4 were not separable and characterization of the products
was carried out from the diastereomeric mixture. In this case, only one spot was observed by thin layer
chromatography. We did not attempt the spiroannulation with either PIFA and PIDA since results
with these oxidants did not previously show any diastereoselectivity [1,2].
While the lower yield of 4 (45%) compared to 3 (69%) can be partially attributed to the greater
steric factors near the reactive site in 8 [1,2], the diastereoselectivity observed does suggest that the
position of the methoxy group has an influence on the approach of the nucleophile in this
spiroannulation reaction, since it is the only difference between the two starting phenols. It has been

1337
Molecules 2005, 10
shown that oxidation of phenolic substrates produces a phenoxonium ion (9a) such as the one shown
in Figure 2 [4].
Figure 2
O
+
O
O
+
+
OMe
OMe
OMe
t
t
t
HO
Bu
HO
Bu
HO
Bu
9a
9b
10
When the methoxy group is located at the 3-position on the phenol, as in the case previously
studied for 1-3 [1,2], the phenoxonium ion can be stabilized by resonance giving rise to structure 9b as
shown in Figure 2. On the other hand, when the methoxy group is located at the 2-position on the
phenol, as seen in 8, the second resonance structure (equivalent to 9b) for the phenoxonium ion 10
cannot be formed and the intermediate is hence less stable and most likely less reactive as well. This
lower reactivity may also partially explain the poor yield obtained. Furthermore, assuming that 10 is
the reacting intermediate, one would not expect any stereoselectivity in the formation of the
spirocenter since the steric factors influencing the approach of the nucleophilic hydroxyl would be
identical from either side of the cyclic carbocation.
Conclusions
We have reported the synthesis of a new spiroether 4 and have shown that the location of the
methoxy group on the phenol influences the diastereoselectivity of this spiroannulation reaction, most
likely via the resonance stabilization of the reactive intermediate. It is expected that other electron
donating groups located at the 3-position on the phenol will have a similar effect in terms of
stereoselectivity. We are presently investigating this possibility, as well as the influence the size of the
3-subtituent may have on the diastereoselectivity of this reaction.
Acknowledgements
We acknowledge the financial contribution of the University of Northern British Columbia in
support of this work.
Experimental
General
Melting points were determined on a hot stage instrument and are uncorrected. Infrared spectra
1
were recorded either as KBr pellets or neat on a Perkin Elmer System 2000 FTIR. H-NMR spectra
were recorded on a Bruker AMX300 spectrometer at 300MHz and chemical shifts are expressed in

1338
Molecules 2005, 10
ppm using TMS as internal standard. 13C-NMR spectra were recorded on a Bruker AMX300
spectrometer at 75.4MHz and chemical shifts are expressed in ppm using chloroform as internal
standard. Mass spectra were recorded on a Hewlett Packard 5898B spectrometer. Elemental analysis
was performed at the Central Equipment Laboratory of the University of Northern British Columbia.
1-(2-Methoxy-4-O-methoxymethylphenyl)-4,4-dimethyl-1-penten-3-one (6).
To a solution of 2-methoxy-4-O-methoxymethylbenzaldehyde (5, 848 mg, 4.3 mmol) in 50%
ethanol/tetrahydrofuran (80 mL) was added pinacolone (964 mg, 9.6 mmol) and sodium hydroxide
(376 mg, 9.4 mmol). The resulting mixture was refluxed for 24 hours. Water (50 mL) was added, the
solution was concentrated in vacuo to about 50% of its original volume and the aqueous residue was
extracted with dichloromethane (3 x 40 mL). The organic fractions were combined, washed with brine
(30 mL), dried (anhydrous MgSO4) and the solvent was evaporated in vacuo to give a yellow oil.
Chromatography on silica gel (15% EtOAc/hexanes) afforded an oil (860 mg, 72%). IR (neat): 1681
(CO); 1H-NMR (CDCl3) δ: 1.22 (s, 9H, t-butyl), 3.50 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 5.25 (s, 2H,
OCH2O), 6.60 (d, 1H, J=2.2Hz, Ar-H3), 6.65 (dd, 1H, J=2.2, 8.6Hz, Ar-H5), 7.13 (d, 1H, J=15.7Hz,
13
H1), 7.49 (d, 1H, J=8.6Hz, Ar-H6), 7.93 (d, 1H, J=15.7Hz, H2); C-NMR (CDCl3) δ: 26.7 (C5), 43.3
(C4), 55.7 (OCH3), 56.4 (OCH3), 94.5 (OCH2O), 100.2 (Ar-C3), 107.9 (Ar-C5), 118.2 (C2), 119.7 (Ar-
C1), 130.5 (Ar-C6), 138.3 (C1), 160.3 (Ar-C2 and Ar-C4), 205.0 (C3); MS m/e (relative %):278 [M+]
(2), 221 (100), 191 (16), 189 (16), 176 (6); Anal. Calc’d for C16H22O4: C 69.04, H 7.97; found C
69.14, H 7.91.
1-(2-Methoxy-4-O-methoxymethylphenyl)-4,4-dimethyl-3-pentanone (7)
To a solution of ketone 6 (860 mg, 3.1 mmol) in ethyl acetate (75 mL) was added Pd/C (279 mg)
and the resulting mixture was stirred under a positive pressure of hydrogen for 6 hours. The
suspension was filtered through Celite® and the solvent was evaporated in vacuo to give a yellowish
oil. Chromatography on silica gel (20% EtOAc/hexanes) afforded a colorless oil (812 mg, 94%); IR
1
(neat) cm-1: 1702 (CO); H-NMR (CDCl3) δ: 1.12 (s, 9H, t-butyl), 2.76 (m, 4H, H1 and H2), 3.48 (s,
3H, OCH3), 3.80 (s, 3H, OCH3), 5.16 (s, 2H, OCH2O), 6.56 (m, 2H, Ar-H3 and Ar-H5), 7.03 (d, 1H,
J=9.1, Ar-H6); 13C-NMR (CDCl3) δ: 25.1 (C1), 25.5 (C5), 37.1 (C2), 44.3 (C4), 55.5 (OCH3), 56.2
(OCH3), 94.9 (OCH2O), 100.3 (Ar-C3), 107.2 (Ar-C5), 123.6 (Ar-C1), 130.5 (Ar-C6), 158.5 (Ar-C2 and
Ar-C4), 216.0 (C3); MS m/e (relative %): 280 [M+] (51), 223 (20), 182 (12), 181 (100), 151 (52); Anal.
Calc’d for C16H24O4: C 68.55, H 8.63; found C 68.43, H 8.54.
o1-(4-hydroxy-2-methoxyphenyl)-4,4-dimethyl-3-pentanol (8)
To a cold (0oC) solution of ketone 7 (810 mg, 2.9 mmol) in ethanol (50 mL) was added sodium
borohydride (139 mg, 3.7 mmol). The resulting mixture was stirred at 0oC for 30 minutes then at room
temperature for 2 hours. HCl (10%, 50 mL) was added and the solution was stirred at room
temperature for 20 hours. The solution was concentrated in vacuo to about half its original volume
and the residue was extracted with dichloromethane (3 x 40 mL), dried (MgSO4) and evaporated in
vacuo to give a yellowish oil. Chromatography on silica gel (25% EtOAc/hexanes) afforded a clear oil

1339
Molecules 2005, 10
1
(564 mg, 82%). IR (neat) cm-1: 3382 (OH); H-NMR (CDCl3) δ: 0.87 (s, 9H, t-butyl), 1.62 (m, 2H,
H2), 2.69 (m, 2H, H1), 3.78 (s, 3H, OCH3), 6.35 (dd, 1H, J=2.4, 8.0Hz, Ar-H5), 6.41 (d, 1H, J=2.4Hz,
Ar-H3), 6.99 (d, 1H, J=8.0Hz, Ar-H6); 13C-NMR (CDCl3) δ: 26.0 (C5), 26.6 (C2), 32.2 (C1), 34.9 (C4),
55.5 (OCH3), 79.6 (C3), 99.3 (Ar-C3), 107.3 (Ar-C5), 121.9 (Ar-C1), 130.6 (Ar-C6), 155.7 (Ar-C4),
158.3 (Ar-C2); MS m/e (relative %): 238 [M+] (8), 236 (29), 179 (12), 137 (100), 107 (12), 77 (9);
Anal. Calc’d for C14H22O3: C 70.56, H 9.30; found C 70.43, H 9.19.
(±)-2-tert-Butyl-6-methoxy-1-oxaspiro[4,5]deca-6,9-diene-8-one (4)
To a cold (0oC) solution of phenol 8 (156 mg, 0.7 mmol) in acetone (20 mL) was added lead
tetraacetate (954 mg, 2.2 mmol). The solution was stirred at 0oC for 2 hours, the mixture was filtered
through Celite® and ethylene glycol (10 drops) was added. The solution was stirred at room
temperature for 20 hours, filtered through Celite® and the solvent was evaporated in vacuo to give a
1
pale yellow oil. H-NMR of the crude reaction mixture indicated that two diastereomers were
produced in a 50/50 ratio. Chromatography on silica gel (25% EtOAc/hexanes) afforded a pale yellow
oil (70 mg, 45%) as a mixture of diastereomers (only one spot by thin layer chromatography).
Characterization was performed on the mixture. Whenever distinguishable, values given are for one
1
isomer with those of the second one listed in square brackets. IR (neat) cm-1: 1680 (CO); H-NMR
(CDCl3) δ: 0.93 [0.95] (s, 9H, t-butyl); 2.10 (m, 5H, H2, H3 and H4), 3.74 [3.77] (s, 3H, OCH3), 5.44
(d, 1H, J=1.7Hz, H7) [5.46 (J=1.7 Hz)], 6.01 (dd, 1H, J=1.7, 9.7Hz, H9) [6.05 (J=1.7, 9.7Hz)], 6.55 (d,
1H, J=9.7, H10) [6.63 (J=9.7Hz)]; 13C-NMR (CDCl3) δ: 26.0 [26.2] (t-butyl CH3), 27.6 [28.1] (C3),
29.8 [33.7] (t-butyl C), 36.8 [37.1] (C4), 55.7 [55.9] (OCH3), 78.2 (C5), 89.5 [91.3] (C2), 101.1 (C7),
126.0 (C9), 147.1 (C10), 175.7 [176.8] (C6), 187.7 (C8); MS m/e (relative %): 236 [M+] (100), 180 (24),
179 (32), 178 (19), 151 (22), 137 (44), 91 (19); Anal. Calc’d for C10H10O4: C 61.81, H 5.19; found C
61.52, H 5.40.
References
1. Plourde G.L. Tetrahedron Lett. 2002, 43, 3597.
2. Plourde G.L. Molbank 2003 M315-M322.
3. Plourde G.L.; Fisher B.B. Molecules 2003, 8, 315.
4. Quideau S.; Metthew A.L.; Pouységu L. Org. Lett., 1999, 1, 1651.
Sample availability: Available from the authors.
© 2005 by MDPI (http:www.mdpi.org). Reproduction is permitted for noncommercial purposes.