Diastereoselective intramolecular photochemical [2 + 2] cycloaddition reactions of tethered L-(+)-valinol derived tetrahydrophthalimides

Article abstract of DOI:10.1039/a702386c

Intramolecular photochemical [2 + 2] cycloaddition of allyl alcohol linked to amino acid derived 3,4,5,6-tetrahydrophthalimides, either via a carbonate or silicon tether, gives the corresponding cyclobutanes in excellent yield with diastereoselectivities

Full text of DOI:10.1039/a702386c

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Diastereoselective intramolecular photochemical [2 + 2] cycloaddition reactions
of tethered l-(+)-valinol derived tetrahydrophthalimides
Kevin I. Booker-Milburn,* Sirin Gulten and Andrew Sharpe
School of Chemical Sciences, University of East Anglia, Norwich, Norfolk, England, UK NR4 7TJ
Intramolecular photochemical [2 + 2] cycloaddition of allyl
alcohol linked to amino acid derived 3,4,5,6-tetrahydro-
phthalimides, either via a carbonate or silicon tether, gives
the corresponding cyclobutanes in excellent yield with
diastereoselectivities as high as 8:1.
(95%, only one enantiomer drawn for clarity). Hydrolysis to the
diol 11, followed by NOE studies, confirmed the highly
selective endo mode of cycloaddition obtained by use of a
carbonate tether. Synthesis of the silicon tethered2 variant 12
(X = SiPri2) was achieved by treatment of 8 with 2 equiv. of
Cl2SiPri2 followed by an excess of allyl alcohol (53% overall).
Irradiation of 12 again gave the (±)-endo cycloadduct 13 as the
sole product in 74% yield. Treatment of 13 with Bu4NF yielded
the diol 11 in excellent yield (82%) (Scheme 2).
Asymmetric [2 + 2] photocycloaddition using chiral auxiliaries
and chiral additives is far less developed than other areas of
asymmetric synthesis. Although a number of systems have been
studied,1 there exist very few methods for the preparation of
enantiomerically pure cyclobutanes compared to the corre-
sponding thermal [4 + 2] and [3 + 2] cycloaddition reactions.
Both Fleming2 and Crimmins3 have reported the use of silicon
tethers in controlling regio- and stereo-selectivity in [2 + 2]
photocycloadditions. Very recently Piva and Pete4 reported
some promising results using chiral hydroxy acids as spacers for
controlling asymmetric intramolecular [2 + 2] photocycloaddi-
tions. We now disclose our own results in this area involving the
diastereoselective intramolecular [2 + 2] cycloaddition reac-
tions of alkenols tethered to l-(+)-valinol derived tetra-
hydrophthalimides.
With the exo/endo selectivity problem solved we then turned
our attention to the use of tethered chiral ethanolamines to
control the diastereoselectivity of the endo selective cycloaddi-
tions and ultimately the enantioselectivity upon removal of the
chiral ethanolamine. Treatment of 1 with l-(+)-valinol gave the
tetrahydrophthalimide 14 in excellent yield (95%). Irradiation
of 14 with allyl alcohol gave rise to a complex mixture (75%) of
four cycloadducts which by NMR spectroscopy appeared to be
the various possible exo and endo diastereoisomers of 15. This
was not too surprising as it would be expected that there would
be little stereochemical control exerted by the valinol unit
during an intermolecular photocycloaddition. Reaction of 14
with allyl chloroformate as before gave the carbonate 16 in
moderate yield (61%). Irradiation of 16 gave two cycloadducts
We recently reported5 that 3,4,5,6-tetrahydrophthalic anhy-
dride (THPA, 1) and the corresponding imide (THPI, 2)
underwent efficient intermolecular photocycloaddition with
alkenols to give the corresponding cyclobutanes in excellent
yields with diastereoselectivities as high as 10:1. The major
isomer in all cases was the exo isomer 3 which, due to the
absence of any absolute stereochemical control, was formed as
a racemic mixture (only one enantiomer drawn for clarity). We
then elected to study the cycloaddition reactions of alkenols
linked to THPI derivatives in order to achieve two goals: (i) the
selective formation of the endo isomer 4 and (ii) by the use of
chiral linkers, control the absolute stereochemistry of 4. If the
cycloadducts 6 or 7 could be formed selectively from 5 then
cleavage of the tether (X) would lead to the synthesis of
enantiopure endo cycloadducts (Scheme 1).
Initially we investigated the use of ethanolamine as a linker
and found that heating THPA with ethanolamine in toluene
gave the tetrahydrophthalimide derivative 8 in 96% yield.
Reaction of 8 with allyl chloroformate gave the carbonate
tethered tetrahydrophthalimide 9 in good yield (84%). Irradia-
tion† of 9 in MeCN for just 90 min resulted in the exclusive
formation of the (±)-endo cycloadduct 10 in excellent yield
1
(17 and 18) which upon hydrolysis (74%) were shown by H
NMR spectroscopy to be an inseparable 1:1 mixture‡ of the
diastereomeric diols 19 and 20. Although this result was
disappointing in terms of asymmetric induction, the overall
yield in the photocycloaddition step was high (90%) and the
irradiation times were short (60 min), thus indicating that the
basic photocycloaddition was not hampered by the introduction
of a chiral centre in the linker. Synthesis of the SiPri2 tethered
variant was carried out as before to give 21 in 71% yield.
Irradiation (90 min) of 21 gave a mixture of the cycloadducts 22
and 23 (74%) which, upon treatment with Bu4NF, gave the diols
19 and 20 as an inseparable mixture of diastereoisomers (87%)
in a ratio of 2:1 although it was not possible to assign which
was the major isomer. Encouraged by these results we decided
X
O
O
O
O
HO
i
ii or iii
1
N
N
O
O
O
9 X = CO; 12 X = SiPri2
O
O
O
8
OH
X
X
iv
O
O
hν
X
+
HO
O
O
H
allyl
X
alcohol
(ref. 5)
O
v or vi
HO
(±)-3 exo 10:1 (X = NH)
H
X
O
O
N
N
O
1 X = O THPA
2 X = NH THPI
(±)-4 endo
HO
O
O
O
O
R
R
X
H
H
(±)-11
O
R
H
H
(±)-10 X = CO; (±)-13 X = SiPri2
O
N
N
hν
O
O
or
O
N
O
H
X
Scheme 2 Reagents and conditions: i, ethanolamine, toluene, heat, 96%; ii,
allyl chloroformate, pyridine, THF, 0 °C, 84% for 9; iii, Cl2SiPri2 (2 equiv.),
Et3N, CH2Cl2, then allyl alcohol (4 equiv.), 53% for 12; iv, hn, MeCN, 95%
for 10, 74% for 13; v, KOH (1.2 equiv.), EtOH–H2O (1:1), 64% from 10;
vi, Bu4NF, THF, 82% from 13
H
O
5
6
7
H
Scheme 1
Chem. Commun., 1997
1385

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In order to study the effects of other chiral ethanolamines, 1
was treated with (R)-(2)-2-phenylglycinol to give the corre-
sponding tetrahydrophthalimide (97%). Treatment of this with
Cl2SiPh2 in DMF followed by an excess of allyl alcohol gave
the SiPh2 tethered phthalimide 27 in 46% overall yield.
Irradiation gave a high yield of cycloaddition products (89%)
which, upon cleavage with Bu4NF (93%), afforded the
diastereoisomeric diols 28 and 29 in a ratio of 3:1. This clearly
demonstrates that the valinol unit is superior to phenylglycinol
in controlling diastereoselectivity during photocycloaddition.
Finally, treatment of the valinol derivative 14 with Cl2SiPh2
followed by treatment with an excess of prop-2-ynyl alcohol
gave the SiPh2 tethered alkynol variant 30 in moderate overall
yield (58%). Irradiation of 30 gave a 46% yield of the
corresponding cyclobutenes which, upon desilylation with
Bu4NF (81%), gave the diastereoisomeric diols 31 and 32 in a
ratio of 4:1. Although the ratio was not as good as in the allyl
alcohol case (24) this is, to the best of our knowledge, the first
example of this type of diastereoselective cyclobutene forma-
tion (Scheme 4).
In summary, l-(+)-valinol derived tetrahydrophthalimides
containing silicon tethered alkenol and alkynol units have been
shown to undergo efficient, diastereoselective intramolecular [2
+ 2] photocycloadditions. Present studies are concerned with
the assignment of the absolute configuration of the major
diastereoisomer from these cycloadditions in order gain some
information about the transition state, and hopefully increase
the diastereoselectivity by investigating different reaction
conditions. We are also investigating the efficient hydrolytic
removal of the valinol linker so that ultimately it can be used as
a true chiral auxiliary in the enantioselective, photochemical
synthesis of highly substituted cyclo-butanes and -butenes.
We would like to thank the Canakkale Onsekiz Mart
University, Turkey (S. G.) and the EPSRC (GR/K15985) (A. S.)
for financial support of this work.
to try and increase the diastereoselectivity of the cycloaddition
by changing the nature of the groups on silicon. Thus treatment
of 14 with Cl2SiPh2 in DMF followed by treatment with an
excess of allyl alcohol gave the SiPh2 tethered variant 24 in 60%
overall yield. Irradiation (60 min) of 24 gave an excellent yield
(82%) of the two cycloadducts 25 and 26 which, upon treatment
with Bu4NF, gave the diastereomeric diols 19 and 20 in 97%
yield and in a very pleasing ratio of 8:1. Again it was not
possible to assign which was the major diastereoisomer,
although it was the same as that obtained with the diisopropyl
tether (Scheme 3).
O
HO
HO
H
O
ii
i
1
N
N
O
H
HO
15
O
14
H
iii or iv
or v
O
O
O
O
X
X
X
H
O
O
O
H
H
N
vi
O
N
O
O
O
+
N
H
O
H
17 X = CO
18 X = CO
16 X = CO
22 X = SiPri2
25 X = SiPh2
23 X = SiPri2
26 X = SiPh2
21 X = SiPri2
24 X = SiPh2
vii or viii
HO
HO
H
O
H
O
+
N
N
O
O
HO
1:1 from 16
2:1 from 21
8:1 from 24
HO
H
20
19
H
Footnotes
* E-mail: k.booker-milburn@uea.ac.uk
Scheme 3 Reagents and conditions: i, l-(+)-valinol, toluene, heat, 95%; ii,
hn, allyl alcohol, MeCN, 6 h, 75%; iii, allyl chloroformate, pyridine, THF,
3 h, 0 °C, 61% for 16; iv, Cl2SiPri2, Et3N, CH2Cl2, then allyl alcohol (4
equiv.), 71% for 21; v, Cl2SiPh2 (2 equiv.), Et3N, DMF, then allyl alcohol
(4 equiv.), 60% for 24; vi, hn, MeCN, 60–90 min, 90% for 17/18, 74% for
22/23, 82% for 25/26; vii, KOH (1.2 equiv.), EtOH–H2O (1:1), 74% from
17/18; viii, Bu4NF, THF, 87% from 22/23, 97% from 25/26
† Glassware consisted of a standard, water cooled, pyrex immersion well
photochemical apparatus of 100 ml reaction volume. All reactions were
carried out in dry, degassed MeCN (100 ml) with concentrations of between
0.01–0.036 m in substrate. Irradiations were performed using a 125 W
medium-pressure mercury vapour lamp obtained from Osram HQL (MBF-
U) bulbs. All new compounds were fully characterised by IR, 1H NMR and
13C NMR spectroscopy, and either elemental analysis or HRMS.
‡ The diastereoisomeric ratio was readily ascertained by 1H NMR
spectroscopy from comparison of the integrals of the two pairs of
diastereotopic Me groups present in the various mixtures of 19 and 20.
Ph Ph
HO
H
Ph
Si
O
O
O
O
i, ii
iv
N
O
1
HO
N
Ph
H
H
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O
27
Ph
28
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+
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iii
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N
14
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HO
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Scheme 4 Reagents and conditions: i, (R)-(2)-2-phenylglycinol, toluene,
heat, 97%; ii, Cl2SiPh2 (2 equiv.), Et3N, MeCN, then allyl alcohol (4
equiv.), 46%; iii, Cl2SiPh2 (2 equiv.), Et3N, MeCN, then prop-2-yn-1-ol (4
equiv.), 58%; iv, hn, MeCN, 5–6 h, then Bu4NF, THF, 83% overall for
28/29 and 38% overall for 31/32
Received in Liverpool, UK, 8th April 1997; 7/02386C
1386
Chem. Commun., 1997