Studies towards the diastereoselective spiroannulation of phenolic derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00552-X

The oxidative spiroannulation of simple phenols bearing a chiral center was carried out. Good yields (61-83%) of spirocompounds were obtained. An increase in diastereomeric ratios from 55/45 to 81/19 was observed as the steric factor surrounding the chiral carbon increased.

Full text of DOI:10.1016/S0040-4039(02)00552-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3597–3599
Studies towards the diastereoselective spiroannulation of
phenolic derivatives
Guy L. Plourde*
University of Northern British Columbia, Department of Chemistry, 3333 University Way, Prince George, British Columbia,
Canada V2N 4Z9
Received 28 February 2002; accepted 14 March 2002
Abstract—The oxidative spiroannulation of simple phenols bearing a chiral center was carried out. Good yields (61–83%) of
spirocompounds were obtained. An increase in diastereomeric ratios from 55/45 to 81/19 was observed as the steric factor
surrounding the chiral carbon increased. © 2002 Elsevier Science Ltd. All rights reserved.
As part of our ongoing research focusing on oxaspiro-
compounds such as 1 and 2 (Fig. 1),1,2 we wanted to
use these simple molecules as starting materials in the
asymmetric synthesis of natural products from the
manumycin family.3 To accomplish this task we
required optically pure spirocompounds as starting
materials. Unfortunately, to our knowledge the asym-
metric synthesis of this type of spirocompounds does
not exist. Hence, our first goal was to find a synthetic
route to carry out the asymmetric spiroannulation of
phenolic derivatives. We now wish to report our prelim-
inary findings towards the asymmetric synthesis of sim-
ple oxaspirocompounds.
than spirolactones would be synthesized since we had
previously observed that spirolactones are sometimes
unstable to purification by column chromatography.2
We expected that the spiroether counterparts would
eliminate this problem since the ether moiety should be
less susceptible to acid hydrolysis.
We prepared the necessary phenolic derivatives 6a–c in
racemic forms according to Scheme 1. The synthesis of
the starting materials 6a was straightforward and first
involved the condensation of vanillin 3 with acetone [3
M NaOH, rt], followed by hydrogenation [H2, Pd/C,
EtOAc] to afford the ketone 5a in 68% yield as a white
solid (33–34°C). In the case of 5b and 5c, all attempts
to synthesize these compounds using a similar method
failed [3, isopropylmethylketone or pinacolone, 3 M
NaOH, THF or EtOH or THF/EtOH], presumably due
to the lack of solubility of the phenoxide salts in these
solvents. This problem was quickly eliminated by pro-
tecting the phenolic hydroxyl of 3 as a benzyl ether
[K2CO3, CH3CN, PhCH2Cl, NaI], giving 4 as a white
solid (60–61°C) in 99% yield according to known litera-
ture procedure.4 Condensation of 4 with pinacolone
[NaOH, THF/EtOH, reflux] afforded 5c in 54% yield as
a white solid (65–66°C) after hydrogenation [H2, Pd/C,
EtOAc]. The synthesis of 5b according to this proce-
dure was more difficult and provided a mixture of
many products as observed by thin-layer chromatogra-
phy (at least seven spots) and the crude 1H NMR
spectrum. Eventually, we were able to isolate 5b in 22%
yield as a colorless oil using LDA as the base at low
temperature (−94°C). Reduction of ketones 5a–c
[NaBH4, EtOH] proceeded uneventfully and provided
good yields of alcohols 6a–c (6a 91%, 6b 90%, 6c 96%)
as colorless oils.
As a first approach, we decided to study the effect of
having a stereocontrol element located on the propyl
side chain of the starting phenols. More accurately, we
decided to investigate the effect of having a chiral
center next to the nucleophile during the spiroannula-
tion reaction. It was also decided that spiroethers rather
Figure 1.
Keywords: asymmetric; spiroannulation; phenols.
* Tel.: 250-960-6694; fax: 250-960-5545; e-mail: plourde@unbc.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00552-X

3598
G. L. Plourde / Tetrahedron Letters 43 (2002) 3597–3599
Scheme 1. (a) PhCH2Cl, NaI, CH3CN, K2CO3, reflux (99%); (b) 1. acetone, 3 M NaOH, rt; 2. H2, Pd/C, EtOAc (68% 5a); (c)
1. 4, isopropyl methyl ketone, LDA, THF, −94°C; 2. H3O+; 3. H2, Pd/C, EtOAc (22% 5b); (d) 1. 4, pinacolone, THF/EtOH,
NaOH, reflux; 2. H2, Pd/C, EtOAc (54% 5c); (e) EtOH, NaBH4 (91% 6a, 90% 6b, 96% 6c); (f) oxidant, acetone, 2.5 h, see Table
1 for details.
The oxidative spiroannulation of these racemic alcohols
was first attempted on 6a in order to optimize the
conditions. The results and reaction conditions for
these spiroannulations are summarized in Table 1. All
spiroannulation reactions were performed in acetone
for 2.5 h using three different oxidants.† Entry 1 shows
that at room temperature the spiroannulation pro-
ceeded nicely with lead tetraacetate as the oxidant
giving 7a as a colorless oil in 64% yield. The
diastereomeric ratio was estimated to be 56/44 using the
Table 1, was also confirmed by GC analysis. Unfortu-
nately, these diastereomers were not separable and
characterization of the products was carried out using
the diastereomeric mixture which was first purified by
column chromatography. This reaction was also per-
formed at lower temperatures (entries 2–4). In these
cases, the yields stayed constant at around 60%, but the
diastereomeric ratio slightly increased to 65/35 (entry 4)
when performed at −45°C. This increase in diastereose-
lectivity suggests that the preference for the formation
of one diastereomer over the other is kinetically con-
trolled, although we cannot exclude other causes such
as selective product decomposition. We also used two
1
signals for H6 (5.75 l major, 5.70 l minor) from the H
NMR spectrum of the crude reaction mixture. This
diastereomeric ratio, as well as all others found in
Table 1. Spiroannulation of 6 to 7.
Entry
R
T (°C)
Oxidant
Product
% Yielda,b
Diastereomeric ratioc
1
2
3
4
5
6
7
8
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Isopropyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
22
Pb(OAc)4
Pb(OAc)4
Pb(OAc)4
Pb(OAc)4
PIDA
7a
7a
7a
7a
7a
7a
7be
7cf
6c
7c
6c
7c
64
62
61
61
30
32
83
69
100
30
56/44
62/38
64/36
65/35
53/47
54/46
71/29d
81/19d
n/a
0
−15
−45
0
0
0
0
0
22
0
22
PIFA
Pb(OAc)4
Pb(OAc)4
PIDA
PIDA
PIFA
9
10
11
12
55/45
n/a
57/43
100
31
PIFA
a Yields are based on total isolated products.
b All reactions were performed in acetone for 2.5 h.
c Diastereomeric ratios were measured from the 1H NMR spectrum of the crude reaction mixture using the signals for H6 of both diastereomers.
d Major and minor isomers were partially separable by column chromatography and were fully characterized.
e 1H NMR (CDCl3) l: major 7b: 0.94 (d, 3H, J=6.8 Hz, CH3), 1.01 (d, 3H, J=6.6 Hz, CH3), 1.70–1.88 (m, 2H, H3), 2.10–2.20 (m, 3H, H4 and
isopropyl CH), 3.69 (s, 3H, OCH3), 3.96 (m, 1H, H2), 5.76 (d, 1H, J=2.7 Hz, H6), 6.12 (d, 1H, J=10.0 Hz, H9), 6.79 (dd, 1H, J=2.7, 10.0 Hz,
H10); minor 7b: 0.94 (d, 1H, J=6.8 Hz, CH3), 1.00 (d, 1H, J=6.7 Hz, CH3), 1.73–1.88 (m, 2H, H3), 2.06–2.23 (m, 3H, H4 and isopropyl CH),
3.72 (s, 3H, OCH3), 3.90 (m, 1H, H2), 5.67 (d, 1H, J=2.6 Hz, H6), 6.13 (d, 1H, J=9.9 Hz, H9), 6.87 (dd, 1H, J=2.6, 9.9 Hz, H10).
f 1H NMR (CDCl3) l: major 7c: 0.95 (s, 9H, CH3), 1.91–2.13 (m, 4H, H3 and H4), 3.69 (s, 3H, OCH3), 3.95 (dd, 1H, J=5.8, 9.0 Hz, H2), 5.77
(d, 1H, J=2.7, H6), 6.13 (d, 1H, J=10.0 Hz, H9), 6.80 (dd, 1H, J=2.7, 10.0 Hz, H10); minor 7c: 0.92 (s, 9H, CH3), 1.90–2.10 (m, 4H, H3 and
H4), 3.67 (s, 3H, OCH3), 3.89 (dd, 1H, J=5.9, 8.7 Hz, H2), 5.67 (d, 1H, J=2.7 Hz, H6), 6.14 (d, 1H, J=9.9 Hz, H9), 6.89 (dd, 1H, J=2.7, 9.9
Hz, H10).
† Typical procedure for Pb(OAc)4 oxidation: A solution of phenol 6a–c (ꢀ200 mg) was dissolved in acetone (10 mL) and cooled to the appropriate
temperature. The oxidant (2.5 equiv.) was added in one portion and the solution was stirred for 2.5 h. The precipitate was filtered through Celite,
ethylene glycol (10 drops) was added and the solution was stirred for 24 h. The precipitate was filtered through Celite and the solvent was
evaporated in vacuo. The resulting product was purified by chromatography on silica gel using a mixture of ethyl acetate and hexanes as eluant.

G. L. Plourde / Tetrahedron Letters 43 (2002) 3597–3599
3599
other oxidants for the spiroannulation of 6a, iodoben-
zene diacetate (PIDA) and [bis(trifluoroacetoxy)iodo]-
benzene (PIFA). These two oxidants have been used
before in similar spiroannulation reactions.2,5–9 Con-
trary to what was expected, when the reaction was
performed at 0°C with either PIDA or PIFA, the
isolated yields decreased to about 30% (entries 5–6).
This was surprising since in the synthesis of 2 (Fig. 1),
we obtained higher yields of spiroannulated products
with either PIDA or PIFA (46%), when compared with
lead tetraacetate (10%).2 However, more important is
the fact that the diastereomeric ratio decreased to 54/46
(entries 5–6), suggesting that a change in oxidant results
in different transition states being involved in the for-
mation of these spiroethers. We are presently investigat-
ing this hypothesis.
30% yield was obtained while the diastereoselectivity
(55/45) significantly decreased when compared to the
lead tetraacetate reaction (81/19) (entry 8).
We have shown that in the spiroannulation of phenolic
derivatives bearing a chiral carbon on the alkyl side
chain a preference exists for the selective formation of
one of the two possible diastereomers. To our knowl-
edge, the syntheses of 7a–c represent the first examples
of diastereoselective spiroannulation of simple phenolic
derivatives. We believe that the electron-donating char-
acter of the methoxy group is directly affecting the
diastereoselectivity when Pb(OAc)4 is used as the oxi-
dant, and we are presently attempting to proof this
hypothesis by changing the nature and location of this
group. We are also working on the asymmetric synthe-
sis of 7c, in order to unambiguously assign the structure
of the major isomer.
Having found good conditions [acetone, 0°C,
Pb(OAc)4] for the transformation of 6a to 7a, the size
of the alkyl moiety adjacent to the hydroxyl group was
increased to isopropyl 6b and t-butyl 6c. Spiroannula-
tion of 6b [acetone, 0°C, Pb(OAc)4, 2.5 h] afforded 7b
in 83% yield, with an estimated diastereomeric ratio of
71/29 (5.76 l H6-major, 5.67 l H6-minor). In this case
we were able to partially separate the racemic
diastereomers and obtained the major product (5.76 l)
as a white solid (77–78°C) and the minor product as a
colorless oil. Changing the alkyl moiety to t-butyl 6c
also improved on the diastereoselectivity of the reaction
and we obtained 7c in 69% yield with an estimated
diastereomeric ratio of 81/19 (5.77 l H6-major, 5.62 l
H6-minor). These diastereomers were also partially sep-
arated by column chromatography and we isolated the
major product (5.77 l) as a white solid (60–61°C) and
the minor product (5.62 l) as a colorless oil. In both of
these cases, the major and minor isomers of 7b and 7c
were fully characterized. All attempts to carry out this
reaction with PIDA or PIFA at 0°C (entries 9 and 11)
failed and only the alcohol 6c was recovered. Only
when the reactions were performed at room tempera-
ture did we obtain spiroannulation products (entries 10
and 12). However, as previously observed with 6a, only
Acknowledgements
The author is grateful to the University of Northern
British Columbia for the financial support of this work.
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