Use of temporary tethers in the intramolecular [2+2] photocycloaddition reactions of tetrahydrophthalimide derivatives: a new approach to complex tricyclic lactones

Article abstract of DOI:10.1016/j.tet.2007.02.064

The intramolecular [2+2] photocycloaddition reactions of a series of alkenols tethered to ethanolamine, l-(+)-valinol and R-(-)-2-phenylglycinol derived 3,4,5,6-tetrahydrophthalimides via a carbonate or silicon linkage have been examined. These [2+2] phot

Full text of DOI:10.1016/j.tet.2007.02.064

Tetrahedron 63 (2007) 3659–3671
Use of temporary tethers in the intramolecular [2D2]
photocycloaddition reactions of tetrahydrophthalimide
derivatives: a new approach to complex tricyclic lactones
a
c
b
b,
*
€
Sxirin Gulten, Andrew Sharpe, James R. Baker and Kevin I. Booker-Milburn
aDepartment of Chemistry, Faculty of Arts and Sciences, C¸ anakkale Onsekiz Mart University, 17020 C¸ anakkale, Turkey
bSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
cSchool of Chemical Sciences & Pharmacy, University of East Anglia, Norwich, Norfolk NR4 7TJ, UK
Received 7 December 2006; revised 2 February 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—The intramolecular [2+2] photocycloaddition reactions of a series of alkenols tethered to ethanolamine, L-(+)-valinol and
R-(ꢀ)-2-phenylglycinol derived 3,4,5,6-tetrahydrophthalimides via a carbonate or silicon linkage have been examined. These [2+2]
photocycloadditions gave the corresponding cyclobutanes in high yield with complete endo control in all cases and with diastereoselectivities
as high as 8:1 with the chiral tethers. The cleavage of the temporary tethers by either desilylation or hydrolysis provided the endo diols.
Cleavage of the ethanolamine linkage by reduction/hydrolysis precipitated an acid-catalysed fragmentation/ring expansion sequence to
generate complex tricyclic lactones.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
been studied.9 For example, Piva and co-workers10 devel-
oped some promising results using chiral hydroxy acids as
spacers for controlling asymmetric intramolecular [2+2]
photocycloadditions. Around this time we also reported
highly diastereoselective [2+2] photocycloadditions of
alkenols tethered via a silicon or carbonate linkage to
L-(+)-valinol derived tetrahydrophthalimides.11
Inter- and intramolecular [2+2] photocycloaddition reac-
tions have long been recognised as important and efficient
synthetic transformations for the construction of cyclo-
butanes and cyclobutenes. As such they have found applica-
tion as pivotal steps in synthesis of natural products and
pharmacologically active compounds.1 Although simple in-
termolecular [2+2] cycloadditions (e.g., enone/alkene) can
be very efficient, they often suffer from poor stereocontrol
as a result of a typically stepwise triplet biradical reaction
manifold. In recent years, there has been increasing attention
given to the use of temporary silicon tethers as stereocontrol
elements for various reactions such as radical cyclisations,2
[4+2] cycloadditions3 and hydrosilylation reactions.4 Flem-
ing et al.,5 Crimmins and Guise6 and Penkett et al.7 have
reported the use of silicon tethers in [2+2] photocyclo-
additions as a regio- and stereocontrolled carbon–carbon
bond forming methodology. The use of disposable tethers
has also been widely applied to other cycloadditions.8
In the last 10 years, highly efficient intermolecular [2+2]
imide photocycloadditions have been investigated by us
for the synthesis of polycyclic cyclobutanes and cyclo-
butenes.12 For example, 3,4,5,6-tetrahydrophthalic anhydride
(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 10:1.12 The major product in
all cases was the exo isomer 3, which, due to the absence of
any absolute stereochemical control, was formed as a race-
mic mixture. We then elected to study the cycloaddition
reactions of alkenols linked to THPI derivatives in order to
achieve two goals: (a) the selective formation of the endo
isomer 4 and (b) by the use of chiral linkers to control the
absolute stereochemistry during [2+2] cycloaddition to 4.
If the cycloadducts 6 or 7 could be formed selectively
from 5 then cleavage of the linker ‘X’ would lead to synthe-
sis of enantiopure endo cycloadducts (Scheme 1). Our key
postulate involved the assumption that 5 could adopt a
‘double chairlike’ conformation whereby the chirality at
C* may control the facial selectivity during cycloaddition.
Asymmetric [2+2] photocycloaddition methodology using
chiral auxiliaries is far less developed than other areas of
asymmetric synthesis, although a number of systems have
Keywords: Photochemistry; Cycloadditions; Temporary tethers; Acid-
catalysed rearrangements.
* Corresponding author. Tel.: +44 117 928 8157; fax: +44 117 929 8611;
e-mail: k.booker-milburn@bristol.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.064

3660
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
Appropriate tuning of this selectivity could be engineered by
choice of R.
diphenyldichlorosilane in similar fashion.2,5,6 Irradiation of
14 again yielded the (ꢁ)-endo cycloadduct 15 as the sole
product in excellent yield (91%). Desilylation of 15 under
standard conditions yielded the racemic diol 11 in excellent
yield (95%) (Scheme 2).
O
O
O
X
X
O
O
h
H
+
OH
X
allyl alcohol
The highly selective endo mode of cycloaddition obtained in
these three experiments was confirmed by NOE experiments
on both the carbonate 10 and diol 11 as illustrated in Figure 1.
OH
( )-3 exo
H
O
( )-4 endo
1 X = O (THPA)
2 X = NH (THPI)
10:1 Ratio ( X = NH)
O
O
O
H
X
*
H
X
O
R
H
HO
*
O
R
H
R
O
N
O
O
O
h
N
O
N
*
O
O
O
CO
O
X
+
O
H
N
H
O
O
H
N
O
7
6
H
5
OH
H
H
X = Cleavable linker
R = H, alkyl, aryl
H
( )-10 endo
( )-11 endo
Scheme 1.
Figure 1. NOE correlations of (ꢁ)-10 and 11 endo isomers.
2. Results and discussion
2.1. Ethanolamine tethers
2.2. (R)-(L)-2-Phenylglycinol tether
Tethered chiral ethanolamines were then investigated as the
diastereoselective control element of the endo selective
cycloadditions as postulated in Scheme 1. Treatment of
THPA with (R)-(ꢀ)-2-phenylglycinol gave the correspond-
ing tetrahydrophthalimide 16 in excellent yield (99%).
Reaction of this with allyl chloroformate gave the carbonate
17 (56%),13 which upon irradiation gave an excellent yield
(98%) of the photocycloadducts 18 and 19. Hydrolysis was
very capricious and afforded (34%) an inseparable mixture
of the diols 20 and 21 in a poor diastereomeric ratio of
1.3:1 (13% de). To improve the diastereoselectivity of the
photocyclisation leading to 20 and 21, the alternative
SiPh2 linkage was studied. It was argued that the bulkier
diphenylsilane unit would afford less conformational mobil-
ity in the putative exited state (cf. 5, Scheme 1). Treatment of
16 with Cl2SiPh2 in MeCN followed by an excess of allyl
alcohol gave the corresponding diphenylsilane-linked tetra-
hydrophthalimide 22 in 46% overall yield. When 22 was
irradiated in MeCN, two diastereomeric cycloadducts 23
and 24 were isolated in excellent yield (89%). TBAF cleav-
age of the SiPh2 linkage afforded the diastereomeric diols 20
and 21 in excellent yield (93%) and in a greatly improved 3:1
ratio (Scheme 3).
We firstly elected to study the intramolecular [2+2] photo-
cycloaddition reactions of alkenols linked to THPI deriva-
tives with non-chiral derived tethers in order to ascertain if
complete endo selectivity could be achieved during cyclo-
addition. Initially the use of ethanolamine as the simplest
linker was investigated. Thus the tetrahydrophthalimide
derivative 8 was synthesised in excellent yield (98%) by
the reaction of THPA and ethanolamine at reflux in toluene.
In order to tether 8 to allyl alcohol, a mixed carbonate link-
age was investigated. Reaction of 8 with allyl chloroformate
yielded the carbonate 9 in excellent yield (95%). Irradiation
of 9 in MeCN for 2 h resulted in formation of the (ꢁ)-endo
cycloadduct 10 in excellent yield (95%). Pleasingly, none of
the corresponding exo isomer could be detected. Hydrolysis
of 10 formed the racemic endo diol 11 in good yield (75%)
(Scheme 2).13 Synthesis of the silicon-tethered variant 12
(X¼SiiPr2) was achieved, in overall moderate yield (53%),
by treatment of 8 with Cl2SiiPr2 followed by an excess of al-
lyl alcohol. A by-product in this reaction is the SiiPr2-linked
bisallyl ether.3,6,7 Irradiation of 12 in MeCN for 90 min
again gave the (ꢁ)-endo cycloadduct 13 as the sole product
in 74% yield. Treatment of 13 with Bu4NF yielded the
racemic diol 11 in good yield (82%) (Scheme 2). The use
of a diphenylsilyl linker was also investigated in this
series and the silaketal 14 was prepared by treatment of
The diastereoselectivity obtained in the formation of 20 and
21 from 22 (50% de), although good compared to the
O
O
OH
O
X
X
O
N
O
N
O
O
O
N
O
N
O
O
vi or vii
ii or iii or iv
v
i
OH
1
OH
H
O
8
( )-11 endo
( )-10 endo X=CO
( )-13 endo X=SiPri2
( )-15 endo X=SiPh2
9 X=CO
12 X=SiPri2
14 X=SiPh2
Scheme 2. Reagents and conditions: (i) ethanolamine, toluene, heat, 98%; (ii) allyl chloroformate, pyridine, THF, 0 ꢂC, 95% for 9; (iii) Cl2SiiPr2, Et3N, CH2Cl2,
rt, then allyl alcohol, 53% for 12; (iv) Cl2SiPh2, Et3N, DMF, rt, then allyl alcohol, 54% for 14; (v) hn, MeCN, 95% for 10, 74% for 13, 91% for 15; (vi) NaOH,
THF/H2O, rt, 75% from 10; (vii) Bu4NF, THF, rt, 82% from 13, 95% from 15.

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3661
O
O
O
O
H
Ph
O
H
X
X
X
O
O
N
O
O
H
O
Ph
O
N
O
iv
N
i
ii or iii
O
+
N
1
OH
H
Ph
Ph
H
O
H
16
17 X = CO; 22 X = SiPh2
18/19 X = CO; 23/24 X = SiPh2
v or vi
OH
O
OH
O
H
H
Ph
Ph
N
N
O
O
+
OH
OH
H
20
21
H
1.3:1 from 17
3:1 from 22
Scheme 3. Reagents and conditions: (i) (R)-(ꢀ)-2-phenylglycinol, toluene, heat, 99%; (ii) allyl chloroformate, pyridine, THF, 0 ꢂC, 56% for 17; (iii) Cl2SiPh2,
Et3N, MeCN, rt, then allyl alcohol, 46% for 22; (iv) hn, MeCN, 98% for 18/19, 89% for 23/24; (v) NaOH, THF/H2O (1:1), rt, 34% from 18/19; (vi) Bu4NF, THF,
rt, 93% from 23/24.
carbonate tether in 17, falls short of the standards expected
for a modern chiral auxiliary. This suggested to us that
(R)-(ꢀ)-2-phenylglycinol was not optimal and alternative
readily available auxiliaries were explored.
inseparable diastereomeric diols 30 and 31 in good yield
(79%) but in a ratio of 1:1. Although this result is disappoint-
ing in terms of asymmetric induction (on changing from Ph
to iPr), the yield of these photocycloaddition steps was high
and the irradiation times were short, thus indicating that the
basic photocycloaddition was not hampered by the introduc-
tion of either phenyl or isopropyl groups in the ethanolamine
tether. Attention was then focussed on a silicon linkage. Syn-
thesis of the SiiPr2-linked variant was carried out as before to
32 in 71% overall yield. Irradiation (90 min) of 32 gave
a mixture of the cycloadducts 33 and 34 (74%), which
upon treatment with TBAF gave the diols 30/31 as an in-
separable mixture of diastereoisomers (87%) with moderate
selectivity (2:1). Treatment of 25 with Cl2SiPh2 in DMF
followed by treatment with an excess of allyl alcohol gave
the SiPh2-tethered variant 35 (60%). Irradiation of 35 gave
an excellent yield (86%) of the cycloadducts 36/37. Removal
of the silicon linkage gave the diastereomeric diols 30 and 31
(99%) in a much improved ratio of 8:1 (Scheme 4).2,5,6
2.3. L-(D)-Valinol as a tether
Anhydride 1 was treated with L-(+)-valinol14 to afford the
corresponding tetrahydrophthalimide 25 in excellent yield
(95%). As an aside, irradiation of 25 with allyl alcohol in
an intermolecular cycloaddition was investigated. This pro-
vided a complex mixture (75%) of four cycloadducts,11
whose 1H NMR spectroscopy indicated a mixture of various
exo and endo diastereoisomers of 26. This result clearly
shows the poor stereocontrol exerted by the auxiliary in an
intermolecular reaction. Reaction of 25 with allyl chlorofor-
mate as before gave the carbonate 27 (61%).13 Irradiation
of 27 led efficiently (90%, 40 min) to two diastereomeric
cycloadducts 28 and 29. Hydrolysis afforded the two
O
O
H
O
O
O
H
X
X
O
X
O
iii or iv
O
H
O
i
or v
O
N
vi
O
N
1
N
O
O
OH
N
+
H
O
H
25
H
28/29 X = CO
33/34 X = SiPri2
36/37 X = SiPh2
27 X = CO
32 X = SiPri
35 X = SiPh2
ii
H
OH
H
O
OH
O
O
vii or viii
N
N
O
H
O
OH
O
OH
+
H
OH
O
OH
H
N
N
H
26 (4-isomers)
O
1:1 from 27
2:1 from 32
8:1 from 35
+
OH
OH
H
30
31
H
Scheme 4. Reagents and conditions: (i) L-(+)-valinol, toluene, heat, 95%; (ii) hn, allyl alcohol, MeCN, 6 h, 75%; (iii) allyl chloroformate, pyridine or 2,6-lu-
tidine, THF, 0 ꢂC, 61% for 27; (iv) Cl2SiiPr2, Et3N, CH2Cl2, rt, then allyl alcohol, 71% for 32; (v) Cl2SiPh2, Et3N, DMF, rt, then allyl alcohol, 60% for 35; (vi) hn,
MeCN, 90% for 28/29, 74% for 33/34, 86% for 36/37; (vii) KOH, THF/H2O (1:1), 79% from 28/29; (viii) Bu4NF, THF, rt, 87% from 33/34, 99% from 36/37.

3662
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
as in the allyl alcohol case 36/37, it is, to our knowledge,
the first reported example of this type of diastereoselective
cyclobutene formation (Scheme 5).
2.4. Tether cleavage
Although cleavage of the silicon/carbonate linkages was
straightforward, cleavage of the imide bound linkers was
much more difficult and was found to be not possible under
direct hydrolytic cleavage with aqueous hydroxide or min-
eral acid. Ganem and co-workers15 reported an easy and
near-neutral method for removing the amine group from
N-alkyl substituted phthalimides involving partial reduction
with NaBH4
15–17
followed by hydrolysis of the hydroxy-
Figure 2. X-ray structure of diastereomeric cycloadduct 36.
pyrrolidone with glacial acetic acid resulting in lactone for-
mation. Subjecting 11 to the same reaction conditions gave
the hydroxypyrrolidone derivative 43, in good yield (80%),
as a mixture of epimers (3:1) presumably arising from the
reduction of this least sterically encumbered imide carbonyl.
However, despite numerous attempts the hydroxypyrroli-
done derivative 43 failed to lactonise to 48 in glacial acetic
acid at reflux and gave only the recovered starting material
(Scheme 6). Heating 43 in 4 M H2SO4 at 80 ꢂC for 12 h
gave the rather unexpected and appealing formation of
the tricyclic keto-lactone 46 in 30% yield and tricyclic
1,2-diol-lactone 47 in 30% yield (Scheme 6).18,19 The
same acid-catalysed rearrangement was carried out using
trifluoroacetic acid instead of H2SO4. This gave the tricyclic
lactone 46 in higher isolated yield (50%) along with the
hydroxy-trifluoroacetate 50 in 30% yield (Scheme 6).
The direct absolute assignment of the stereochemistry of
30/31 formed from these cycloadditions proved extremely
difficult as even the 8:1 mixture was an oil and inseparable
by chromatographic methods. Attempts to carry out a direct
NOE analysis of this mixture did not yield conclusive re-
sults. Fortunately, although inseparable by chromatography,
recrystallisation of the 8:1 mixture of 36/37 from Et2O
1
yielded a pure sample (by H and 13C NMR spectroscopy)
of the major diastereoisomer (36), which was then slowly
crystallised to afford a single crystal of 36 of suitable quality
for X-ray analysis (Fig. 2), thus establishing the major
diastereoisomer formed in these photocycloadditions.
At the start of this study the conformation depicted for 5 in
Scheme 1 was only tentatively proposed to confer stereocon-
trol during cycloaddition and was considered as an adven-
turous but plausible model. It is intriguing therefore that in
light of the results confirmed by X-ray crystallography this
now serves as a useful explanation of the origin of the major
diastereomer 36 formed during the cycloaddition of 35.
Plausible mechanisms leading to the formation of 46 and 47
and other products are illustrated in Scheme 7. It is likely
that ring opening of the hydroxypyrrolidone in 43 leads
to the amide aldehyde 49, which undergoes lactonisation
with loss of ethanolamine. The reverse of this is probably
suppressed under the strongly acidic conditions by capture
of the ethanolamine by protonation. The resulting lactone-
aldehyde 48 then undergoes acid-catalysed cyclobutane
ring expansion by two classic Wagner–Meerwein type path-
ways. Pathway ‘a’ leads to the cation 51, which upon proton
loss and tautomerization gives the keto-lactone 46. The
alternative pathway ‘b’ leads to the cation 52, which upon
solvolysis yields the diol 47. Solvolysis of 52 with trifluoro-
acetate accounts for the formation of 49 observed during the
reaction of 43 in neat TFA.
In an attempt to explore the possibilities for the selective
synthesis of cyclobutenes, the valinol derivative 25 was
treated with Cl2SiPh2 followed by an excess of propargyl
alcohol to afford the SiPh2-tethered alkynol variant 38
(58%). Irradiation of 38 lead to the corresponding cyclo-
butenes 39 and 40 in only moderate yield (49%). Desilyla-
tion with TBAF gave the diastereomeric diols 41 and 42
(81%) in the ratio 4:1. Although this ratio was not as good
Ph
Si Ph
H
O
O
O
O
Ph
O
Ph
Ph
Si
H
Si
O
N
O
Ph
O
ii
O
+
N
N
O
O
O
H
39
40
38
iii
H
H
OH
O
OH
O
i
N
N
O
O
+
25
OH
4:1
OH
41
42
Scheme 5. Reagents and conditions: (i) Cl2SiPh2, Et3N, MeCN, rt, then prop-2-yn-1-ol, 58%; (ii) hn, MeCN, 49%; (iii) Bu4NF, THF, rt, 81%.

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3663
OH
O
OH
O
O
O
N
N
O
HO
OH
OH
iii
ii
i
H
H
( )-43
O
H
( )-48
( )-11 endo
iv
O
O
O
O
O
O
H
+
+ ( )-46 (50%)
OCOCF3
( )-50 (30%)
HO
HO
OH
H
O
( )-46 30%
( )-47 30%
Scheme 6. Reagents and conditions: (i) NaBH4, 2-propanol/H2O, rt, 80%; (ii) CH3COOH (glacial), heat; (iii) 4 M H2SO4 at 80 ꢂC for 12 h; (iv) TFA,
reflux, 12 h.
O
O
O
O
H
H
N
H
46
O
O
O
O
HO
OH
OH
a
b
51
H2SO4
43
b
a
H
48
H
H3N
O
O
49
O
O
OH
O
O
H+
HO
HO
OH
47
52
Scheme 7.
Assignment of 47 was further supported by the typical re-
actions of 1,2-diols such as the pinacol rearrangement and
oxidative cleavage. The pinacol rearrangement of 47 was
carried out in 4 M H2SO4 at 80 ꢂC and after four days
gave the rearranged keto-lactone 46 in 37% yield and recov-
ered the starting diol 47 (56%). This result clearly suggests
that the aldehyde 48 and diol 47 are actually in equilibrium
during the reaction as outlined in Scheme 7. Subjecting pure
keto-lactone 46 to the same conditions did not give any
evidence of reversibility. Pleasingly, the oxidative cleavage
of 47 using a sodium periodate/wet silica gel protocol20 af-
forded the desired eight-membered keto-aldehyde 53 in ex-
cellent yield (Scheme 8). Final confirmation of the structures
46 and 47 was obtained by X-ray crystallography (Fig. 3).
intermolecular reaction. Further studies using chiral, amino
acid derived tethers demonstrate that the valinol derived
tetrahydrophthalimide unit is superior to phenylglycinol in
controlling diastereoselectivity during photocycloaddition.
With the valinol tether, de as high as 78% was observed;
an impressive result compared to the corresponding inter-
molecular equivalent, which afforded no observable stereo-
control. Further synthetic studies on the cycloadducts have
shown that they can undergo useful synthetic transfor-
mations. The resulting cleaved and partially reduced diol
products undergo Wagner–Meerwien ring expansion reac-
tions yielding further polycyclic products as well as provid-
ing unique access to an 8,5-fused keto-lactone ring system.
3. Experimental section
3.1. General
In summary, the intramolecular photocycloaddition of alke-
nols attached via a temporary carbonate or silicon linkage
to ethanolamine-linked tetrahydrophthalimide derivatives
has been investigated. The cycloadditions have been shown
to proceed in excellent overall yields with complete con-
trol of endo selectivity in contrast to the exo-selective
NMR spectra were recorded using a Jeol JNM-EX 270 and
Varian NMR Gemini 300 spectrometers. Samples were dis-
solved in deuterochloroform (unless otherwise noted) using
O
O
O
O
O
0.65M NaIO4
SiO2/DCM
rt, 15 min
83%
4M H2SO4
46 (37%) + 47 (56%)
80 °C, 4 days
H
HO
O
OH
53
47
Scheme 8.

3664
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
Figure 3. X-ray structures of tricyclic keto-lactone 46 and 1,2-diol 47 (H-bonded pair in unit cell).
tetramethylsilane (TMS) as an internal reference. All car-
bon-13 spectra were assigned with the aid of DEPT experi-
ments. Infrared spectra were recorded on a Perkin–Elmer
1720 X FT spectrometer using sodium chloride plates.
Low-resolution electron impact mass spectra were run on
Kratos MS 25 and elemental microanalyses were carried
out on a Carlo Erba EA 1108. Optical rotations were
measured on Perkin–Elmer 141 Polarimeter. Flash chro-
matography was carried out using Matrix silica 60 (70–
200 mm). Camlab polygramÒ SIL G/UV254 plastic backed
plates (0.25 mm layer of silica) were used for TLC analyses.
Chromophoric compounds were visualised by UV light
(254 nm) and subsequent staining with alkaline potassium
permanganate solution or iodine. Melting points were
formed after completion of addition. The white reaction
mixture was stirred for 30 min at 0 ꢂC and then for 3 h at
rt, then the solution filtered and the solvent removed under
reduced pressure. Et2O was added and the solution filtered
again, washed with H2O and brine and dried over anhydrous
MgSO4. Filtration and concentration under reduced pressure
followed by purification via flash chromatography (petrol/
ethyl acetate) gave the carbonate product.
3.4. General procedure 3, silicon-tethered compounds
Part 1: to a stirred solution of the imido-alcohol in the spec-
ified solvent was added Et3N and the mixture allowed to stir
at rt for 20 min, after which time the dichlorosilane was
added dropwise. The reaction mixture was stirred overnight
at rt and then the solvent was concentrated under reduced
pressure to leave the crude product, which was used imme-
diately in part 2 without purification.
€
obtained using a Kopfler hot stage apparatus and are uncor-
rected. All reactions were carried out under an atmosphere of
oxygen-free nitrogen. Petroleum ether refers to light petro-
leum (bp 40–60 ꢂC). Evaporation of solvents was carried
€
out on a Buchi rotary evaporator. Toluene, acetonitrile, di-
chloromethane and petroleum ether were distilled from cal-
cium hydride; THF and diethyl ether were distilled from
sodium and benzophenone; DMF was initially dried using
Part 2: a mixture of allyl or propargyl alcohol and Et3N in
the solvent was added dropwise to a solution of the crude
product in the solvent. The resulting reaction mixture was
stirred overnight at rt and then the solvent was concentrated
under reduced pressure to leave a brown solid, which was
dissolved in saturated aqueous sodium bicarbonate, ex-
tracted with EtOAc, dried over MgSO4 and then concen-
trated under reduced pressure to afford a brown oil. The
residue was purified by flash chromatography (petrol/ethyl
acetate) to afford the silicon-tethered products.
˚
activated 4 A molecular sieves overnight followed by distil-
lation under reduced pressure. Photochemical reactions were
carried out in a 100 mL Pyrex immersion well photoreactor.
The reaction mixture was initially degassed by passage of ni-
trogen for 10 min and then irradiated for the specified length
of time under an atmosphere of nitrogen. The radiation
source was a 125 W medium pressure, water cooled, mer-
cury discharge lamp (Osram HQL (MBF-U) bulbs).
3.4.1. 2-(2-Hydroxyethyl)-4,5,6,7-tetrahydro-1H-isoin-
dole-1,3(2H)-dione 8. Following general procedure 1, using
THPA (3.51 g, 23.07 mmol), ethanolamine (1.39 mL,
23.07 mmol) and toluene (70 mL), afforded 8 as a pale
yellow oil, which slowly solidified to a white solid (4.40 g,
98%); mp 50–52 ꢂC. IR (DCM thin film): 3460, 1770,
3.2. General procedure 1, imide formation
To a solution of 3,4,5,6-tetrahydrophthalic anhydride
(THPA, 1) in toluene was added the amine (1 equiv). The re-
action flask was fitted with a condenser via a Dean–Stark
trap and heated at reflux for 3 h and then the solvent was con-
centrated under reduced pressure. The crude product was
subjected to flash chromatography (petrol/ethyl acetate) to
afford the imide.
1715 cmꢀ1 1H NMR (CDCl3, 270 MHz): d 3.73–3.60
;
(4H, m), 2.70 (1H, m), 2.34–2.25 (4H, m), 1.80–1.69 (4H,
m); 13C NMR (CDCl3, 67.80 MHz): d 171.6, 141.8, 61.2,
40.4, 21.3, 20.0; LRMS (EI): m/z 195 (18.6%, M+), 164
(100), 152 (15.4), 135 (5.6), 107 (11.6), 79 (16.2); Anal.
Calcd for C10H13O3N: C, 61.52; H, 6.71; N, 7.17. Found.
C, 61.34; H, 6.71; N, 7.12.
3.3. General procedure 2, carbonate formation
To a stirred solution of the imido-alcohol in THF was added
pyridine at 0 ꢂC. After stirring for 20 min allyl chlorofor-
mate was added dropwise at 0 ꢂC and a white precipitate
3.4.2. Carbonic acid-2-(1,3-dioxo-1,3,4,5,6,7-hexahydro-
2H-isoindole-2-yl)ethyl-2-propenyl ester 9. Following

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3665
general procedure 2, using 8 (2.20 g, 11.27 mmol), THF
(50 mL), pyridine (1.12 mL, 13.85 mmol), allyl chloro-
formate (1.47 mL, 13.85 mmol), afforded 9 as a pale yellow
(14H, m); 13C NMR (CDCl3, 75.45 MHz): d 183.0, 180.9,
61.6, 60.3, 46.6, 44.7, 42.0, 41.6, 28.6, 27.8, 26.4, 19.7,
19.4, 17.5, 17.1, 12.3, 11.2; LRMS (EI): m/z 365 (0.5%,
M+), 322 (100), 249 (3.4), 149 (5.9), 41 (16.2); Anal. Calcd
for C19H31O4NSi: C, 62.43; H, 8.54; N, 3.83. Found: C,
62.43; H, 8.67; N, 3.71.
1
oil (2.98 g, 95%). IR (neat): 1760, 1714, 1649 cmꢀ1; H
NMR (CDCl3, 300 MHz): d 6.00–5.80 (1H, m), 5.40 (1H,
dq, J¼17.3, 1.5 Hz), 5.30 (1H, dq, J¼10.5, 1.4 Hz), 4.65
(2H, dt, J¼5.7, 1.5 Hz), 4.29 (2H, t, J¼5.6 Hz), 3.89 (2H,
t, J¼5.6 Hz), 2.34 (4H, m), 1.76 (4H, m); 13C NMR
(CDCl3, 75.45 MHz): d 170.8, 154.7, 141.7, 131.5, 118.8,
68.5, 64.9, 36.2, 21.1, 19.8; LRMS (EI): m/z 279 (0.8%,
M+), 177 (100), 164 (70.9), 107 (10.8), 77 (12.4), 41
(20.8); Anal. Calcd for C14H17O5N: C, 60.20; H, 6.13; N,
5.01. Found: C, 60.42; H, 6.13; N, 5.18.
3.4.6. 2-[2-[[(Diphenyl)(2-propenyloxy)silyl]oxy]ethyl]-
4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione 14. Fol-
lowing general procedure 3, using in part 1; 8 (5.23 g,
26.8 mmol), DMF (70 mL), Et3N (7.45 mL, 53.6 mmol)
and diphenyldichlorosilane (11.23 mL, 53.6 mmol). Then
in part 2, allyl alcohol (16 mL, 236 mmol), Et3N (33 mL,
236 mmol), DMF (20 mL) and the crude product in DMF
(140 mL) were used to afford 14 (6.28 g, 54%) as a yellow
3.4.3. (2R*,8aS*,9aR*,13aS*)-Octahydro-1H,8H-2,9a-
methanobenzo[1,4]cyclobuta[1,2-h][1,3,6]-dioxazecine-
1,6,14-trione 10. A solution of 9 (2.40 g, 8.59 mmol) in
acetonitrile (100 mL) was irradiated for 2 h. The solvent
was removed under reduced pressure and the white solid
residue was purified by flash chromatography (petrol/ethyl
acetate 1:1) to afford 10 as a white solid (2.29 g, 95%);
1
oil. IR (neat): 1768, 1700, 1647 cmꢀ1; H NMR (CDCl3,
270 MHz): d 7.64 (4H, m), 7.35 (6H, m), 5.95 (1H, m),
5.35 (1H, dq, J¼17.2, 1.3 Hz), 5.13 (1H, dq, J¼10.2,
1.7 Hz), 4.30 (2H, dt, J¼4.6, 1.7 Hz), 3.95 (2H, t, J¼
5.6 Hz), 3.70 (2H, t, J¼5.6 Hz), 2.35 (4H, m), 1.73 (4H,
m); 13C NMR (CDCl3, 67.8 MHz): d 171.0, 141.4, 136.4,
134.9, 132.2, 130.4, 127.8, 114.7, 63.9, 60.4, 39.4, 21.3,
19.9; LRMS (EI): m/z 433 (2.7%, M+), 356 (80.8), 179
(100), 139 (94.5); Anal. Calcd for C25H27O4NSi: C, 69.25;
H, 6.27; N, 3.23. Found: C, 69.29; H, 6.10; N, 2.84.
mp 156.5–165 ꢂC. IR (DCM thin film): 1764, 1699 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 4.60 (2H, m), 4.30 (1H,
m), 4.11 (2H, m), 3.80 (1H, m), 2.75 (1H, m), 2.56 (1H,
dd, J¼13.3, 10.8 Hz), 2.46 (1H, dd, J¼13.3, 6.3 Hz), 2.30
(1H, m), 1.85 (1H, m), 1.80–1.50 (4H, m), 1.50–1.00 (2H,
m); 13C NMR (CDCl3, 75.45 MHz): d 182.5, 181.6, 151.9,
68.0, 66.7, 47.2, 43.1, 42.2, 40.1, 30.3, 27.8, 27.1, 19.5,
19.4; LRMS (EI): m/z 279 (6.9%, M+), 177 (10.3), 61
(21.4), 43 (100); Anal. Calcd for C14H17O5N: C, 60.20; H,
6.13; N, 5.01. Found: C, 59.96; H, 6.12; N, 4.84.
3.4.7. (2R*,8aS*,9aR*,13aS*)-6,6-Diphenyloctahydro-
1H,8H-2,9a-methanobenzo[1,4]cyclobuta[1,2-h][1,3,6,2]-
dioxazasilecine-1,14-dione 15. A solution of 14 (1.48 g,
3.41 mmol) in acetonitrile (100 mL) was irradiated for 7 h.
The solvent was concentrated under reduced pressure to
afford a white solid. This was subjected to flash chromato-
graphy (petrol/ethyl acetate 7:3) to afford 15 as a white solid
(1.35 g, 91%); mp 45–46 ꢂC. IR (DCM thin film): 1766,
3.4.4. 2-[2-[[Bis(1-methylethyl)(2-propenyloxy)silyl]-
oxy]ethyl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione
12. Following general procedure 3, using in part 1; 8 (0.35 g,
1.79 mmol), DCM (30 mL), Et3N (0.50 mL, 3.59 mmol) and
diisopropyldichlorosilane (0.64 mL, 3.59 mmol). Then
in part 2, allyl alcohol (0.90 mL, 13.26 mmol), Et3N
(1.85 mL, 13.26 mmol), DCM (10 mL) and the crude prod-
uct in DCM (60 mL) were used to afford 12 (0.345 g, 53%)
1
1699 cmꢀ1; H NMR (CDCl3, 300 MHz): d 7.60 (4H, m),
7.40 (6H, m), 4.15 (2H, m), 3.95 (2H, m), 3.65 (1H, dd,
J¼11.5, 4.0 Hz), 3.56 (1H, m), 2.75 (1H, dd, J¼12.2,
5.3 Hz), 2.55 (1H, m), 2.36 (1H, m), 2.34 (1H, m), 1.92–
1.20 (7H, m); 13C NMR (CDCl3, 75.45 MHz): d 183.4,
181.3, 135.4, 135.3, 132.5, 131.1, 130.8, 128.2, 128.1,
62.5, 61.3, 46.9, 44.3, 42.2, 41.2, 28.6, 27.7, 26.8, 19.5,
19.2; LRMS (EI): m/z 356 (10.1%, M+ꢀC6H5), 216 (51.9),
139 (100), 88 (7.8).
1
as a pale yellow oil. IR (neat): 1770, 1710, 1647 cmꢀ1; H
NMR (CDCl3, 270 MHz): d 5.96–5.82 (1H, m), 5.30 (1H,
dq, J¼17.2, 2.0 Hz), 5.20 (1H, dq, J¼10.7, 2.0 Hz), 4.20
(2H, m), 3.85 (2H, t, J¼6.0 Hz), 3.65 (2H, t, J¼6.0 Hz),
2.30 (4H, m), 1.80 (4H, m), 1.00 (14H, m); 13C NMR
(CDCl3, 67.8 MHz): d 171.1, 141.5, 137.1, 113.9, 63.6,
60.0, 39.5, 21.4, 20.0, 17.2, 12.0; LRMS (EI): m/z 322
(100%, M+ꢀCH(CH3)2), 296 (10.0), 134 (11.4), 99 (19.2),
41 (20.4); Anal. Calcd for C19H31O4NSi: C, 62.43; H,
8.54; N, 3.83. Found: C, 62.04; H, 8.77; N, 3.75.
3.4.8. (3aa,7aa,8S*)-3a,7a-Ethano-2-(2-hydroxyethyl)-8-
(hydroxymethyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-
dione 11. Method 1: the photocycloadduct 10 (1.33 g,
4.76 mmol) was dissolved in a mixture of THF (35 mL)
and H2O (15 mL) and then treated with NaOH (0.38 g,
9.52 mmol). After stirring for 3 h at rt, the reaction mixture
was neutralised by addition of 2 M HCl and the solvent
concentrated under reduced pressure to leave a white solid.
The crude product was dissolved in hot EtOH (200 mL),
the solution filtered and concentrated under reduced pressure
to leave a yellow liquid, which was purified by flash chroma-
tography (ethyl acetate/ethyl alcohol 9:1) to give 11 as a pale
yellow oil (0.90 g, 75%).
3.4.5. (2R*,8aS*,9aR*,13aS*)-6,6-Bis(1-methylethyl)-
octahydro-1H,8H-2,9a-methanobenzo[1,4]cyclobuta[1,2-
h][1,3,6,2]dioxazasilecine-1,14-dione 13. A solution of 12
(0.175 g, 0.48 mmol) in acetonitrile (100 mL) was irradiated
for 1.5 h. The solvent was concentrated under reduced pres-
sure and the yellow liquid residue was subjected to flash
chromatography (petrol/ethyl acetate 17:3) to afford 13 as
a pink solid (0.13 g, 74%); mp 91–95 ꢂC. IR (DCM thin
Method 2: to a stirred solution of 13 (93.7 mg, 0.256 mmol)
in THF (15 mL) was added, dropwise, Bu4NF (0.15 mL,
0.51 mmol) at rt. After 30 min all starting material had
been consumed. The solvent was concentrated under
reduced pressure to leave a pale yellow liquid. This was
film): 1763, 1694 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d 4.06 (4H, m), 3.81 (1H, dd, J¼6.8, 3.8 Hz), 3.75 (1H,
dd, J¼6.6, 4.5 Hz), 3.70 (1H, m), 3.65 (1H, m), 3.57 (1H,
m), 2.55 (1H, m), 2.30 (1H, m), 1.90–1.40 (6H, m), 1.00

3666
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
purified by flash chromatography (ethyl alcohol/ethyl
acetate 3:17) to give 11 as a pale yellow oil (53 mg, 82%).
give a white solid (0.83 g, 98%); mp 44.5–54.1 ꢂC. This
photocycloadduct was shown to be a mixture of two diaste-
reoisomers 18 and 19 in a 1.3:1 ratio as shown by integration
of signals in the 1H NMR spectrum.
Method 3: to a solution of 15 (2.90 g, 6.7 mmol) in
THF (60 mL) was added, dropwise, Bu4NF (3.90 mL,
13.40 mmol) and then the deep yellow reaction mixture
was stirred for 30 min at rt. The solvent was concentrated
under reduced pressure to leave a yellow oil. The yellow
oil residue was subjected to flash chromatography (pure
EtOAc) to give 11 as a pale yellow oil (1.60 g, 95%).
Major isomer 18. 1H NMR (CDCl3, 300 MHz): d 7.40 (2H,
m), 7.35 (3H, m), 5.65 (1H, m), 4.65 (1H, dd, J¼11.9,
2.2 Hz), 4.20 (2H, m), 4.00 (1H, dd, J¼11.8, 1.8 Hz), 2.70
(1H, m), 2.62 (1H, m), 2.45 (2H, m), 2.20 (2H, m), 1.70
(1H, m), 1.60 (2H, m), 1.50 (2H, m); 13C NMR (CDCl3,
75.45 MHz): d 181.3, 180.9, 152.5, 134.8, 129.1, 128.9,
128.8, 128.6, 68.6, 66.6, 57.2, 46.7, 43.4, 41.9, 31.8, 28.5,
26.7, 19.6, 18.9.
IR (neat): 3434, 1765, 1700 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 3.75 (5H, m), 3.60 (1H, dd, J¼12.0, 7.6 Hz),
3.0 (2H, br s), 2.85 (1H, m), 2.35 (1H, m), 2.16 (1H, dd,
J¼13.9, 9.2 Hz), 2.10 (1H, m), 2.00 (1H, m), 1.65 (2H,
m), 1.55 (3H, m), 1.10 (1H, m); 13C NMR (CDCl3,
75.45 MHz): d 183.2, 182.5, 62.6, 60.1, 47.1, 42.2, 41.5,
39.1, 32.4, 28.5, 27.6, 20.9, 20.2; LRMS (EI): m/z 253
(0.3%, M+), 210 (100), 165 (33.7), 121 (34.0), 84 (52.4);
Anal. Calcd for C13H19O4N: C, 61.64; H, 7.56; N. 5.53.
Found: C, 61.34; H, 7.64; N, 5.37.
Minor isomer 19. 1H NMR (CDCl3, 300 MHz): d 7.38 (5H,
m), 5.70 (1H, m), 5.55 (1H, dd, J¼13.0, 7.8 Hz), 4.76 (1H,
m), 4.51 (1H, d, J¼12.8 Hz), 4.40 (1H, m), 2.80 (1H, m),
2.52 (2H, m), 2.42 (2H, m), 1.85 (2H, m), 1.75 (2H, m),
1.60 (2H, m); 13C NMR (CDCl3, 75.45 MHz): d 183.6,
181.1, 151.8, 135.7, 128.3, 128.2, 128.1, 128.0, 69.0, 66.4,
56.2, 47.4, 43.6, 41.8, 31.8, 28.6, 27.2, 20.0, 18.9.
3.4.9. (2R)-2-[1-(Hydroxymethyl)-2-phenyl]-4,5,6,7-
tetrahydro-1H-isoindole-1,3(2H)-dione 16. Following
general procedure 1, using THPA (0.50 g, 3.3 mmol), (R)-
(ꢀ)-2-phenylglycinol (0.49 g, 3.6 mmol) and toluene
(20 mL), afforded 16 as a yellow oil (0.88 g, 99%). IR
Forthemixture. IR(DCMthinfilm):1761, 1701 cmꢀ1;LRMS
(EI): m/z 355 (3.6%, M+), 253 (4.7), 84 (94.6), 43 (100).
3.4.12. (1R)-2-[1-Phenyl-2-[[diphenyl(2-propenyloxy)-
silyl]oxy]ethyl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-
dione 22. Following general procedure 3, using in part 1;
16 (0.37 g, 1.36 mmol), MeCN (25 mL), Et3N (0.38 mL,
1
(neat): 3458, 1768, 1696, 1652 cmꢀ1; H NMR (CDCl3,
300 MHz): d 7.20–7.40 (5H, m), 5.20 (1H, dd, J¼8.9,
5.0 Hz), 4.50 (1H, dd, J¼11.6, 8.6 Hz), 4.10 (1H, dd,
J¼11.6, 5.0 Hz), 2.30 (5H, m), 1.70–1.80 (4H, m); 13C
NMR (CDCl3, 75.45 MHz): d 171.9, 142.0, 137.5, 128.9,
128.2, 128.0, 62.7, 57.2, 21.3, 20.0; LRMS (EI): m/z 253
(0.5%, M+ꢀH2O), 241 (48.7, M+ꢀCH2O), 240 (100,
M+ꢀCH2OH), 107 (8.6), 77 (14.9), 43 (23.6); Anal. Calcd
for C16H17O3N: C, 70.83; H, 6.31; N, 5.16. Found: C,
70.40; H, 6.39; N, 5.06.
2.73 mmol)
and
diphenyldichlorosilane
(0.57 mL,
2.73 mmol). Then in part 2, allyl alcohol (1.21 mL,
17.8 mmol), Et3N (2.48 mL, 17.8 mmol), MeCN (10 mL)
and the crude product in MeCN (50 mL) were used to afford
22 (0.32 g, 46%) as a pale yellow oil. IR (neat): 1770, 1710,
1647 cmꢀ1; 1H NMR (CDCl3, 270 MHz): d 7.60–7.20 (15H,
m), 5.99 (1H, m), 5.35 (2H, m), 5.14 (1H, dq, J¼10.6,
1.7 Hz), 4.70 (1H, t, J¼10.2 Hz), 4.30 (2H, dd, J¼6.0,
1.3 Hz), 4.25 (1H, m), 2.25 (4H, m), 1.71 (4H, m); 13C
NMR (CDCl3, 67.8 MHz): d 171.2, 141.4, 137.2, 136.4,
134.8, 134.6, 132.2, 130.4, 128.5, 128.2, 127.8, 114.7,
64.0, 61.94, 56.4, 21.3, 19.9.
3.4.10. Carbonic acid-2-(1,3-dioxo-1,3,4,5,6,7-hexa-
hydro-2H-isoindole-2-yl)-(1R)-phenylethyl-2-propenyl
ester 17. Following general procedure 2, using 16 (0.75 g,
2.8 mmol), THF (45 mL), pyridine (0.28 mL, 3.46 mmol)
and allyl chloroformate (0.37 mL, 3.46 mmol) afforded 17
as a yellow oil (0.55 g, 56%). IR (neat): 1752, 1702,
3.4.13. (2R,8aS,9aR,13aS)-Octahydro-3,6,6-triphenyl-
1H,8H-2,9a-methanobenzo[1,4]cyclobuta[1,2-h][1,3,6,2]-
dioxazasilecine-1,14-dione 23 and isomer 24. A solution of
22 (0.785 g, 1.54 mmol) in acetonitrile (100 mL) was irradi-
ated for 5 h. The solvent was removed under reduced pres-
sure to leave a pale yellow solid. The residue was then
subjected to flash chromatography (petrol/ethyl acetate
7:3) to give a pale yellow solid (0.70 g, 89%), mp 71.2–
73.8 ꢂC, which was shown to be a mixture of two diastereo-
isomers 23 and 24 in a 3:1 ratio as shown by integration of
signals in the 1H NMR spectrum.
1
1649 cmꢀ1; H NMR (CDCl3, 300 MHz): d 7.45 (2H, m),
7.35 (3H, m), 5.70 (1H, m), 5.40 (1H, dd, J¼10.5, 5.3 Hz),
5.30 (1H, dq, J¼17.2, 1.4 Hz), 5.25 (1H, dq, J¼10.3,
1.3 Hz), 5.10 (1H, t, J¼11.0 Hz), 4.70 (1H, dd, J¼11.0,
5.3 Hz), 4.60 (2H, dt, J¼5.9, 1.3 Hz), 2.3 (4H, m), 1.8
(4H, m); 13C NMR (CDCl3, 75.45 MHz): d 171.1, 154.8,
141.9, 136.5, 131.6, 129.0, 128.6, 128.2, 119.3, 68.8, 65.9,
53.4, 21.3, 20.0; LRMS (EI): m/z 254 (17.7%,
M+ꢀC4H5O3), 253 (46.8), 240 (100), 103 (8.0), 77 (12.1);
Anal. Calcd for C20H21O5N: C, 67.59; H, 5.95; N, 3.94.
Found: C, 67.71; H, 5.94; N, 4.0.
Major isomer 23. 1H NMR (CDCl3, 270 MHz): d 7.60 (4H,
m), 7.40 (6H, m), 7.10 (5H, m), 5.70 (1H, dd, J¼10.9,
3.3 Hz), 5.06 (1H, t, J¼11.2 Hz), 4.22 (1H, dd, J¼11.6,
3.3 Hz), 3.95 (1H, m), 3.61 (1H, dd, J¼11.6, 4.0 Hz), 2.47
(1H, m), 2.06 (2H, m), 1.50 (2H, m), 1.25 (4H, m), 0.99
(2H, m); 13C NMR (CDCl3, 67.8 MHz): d 183.2, 179.9,
136.0, 135.2, 135.0, 134.6, 134.3, 131.7, 130.9, 130.5,
130.3, 127.9, 127.8, 127.5, 62.4, 61.9, 56.8, 47.9, 44.9,
42.5, 29.6, 27.8, 24.6, 20.7, 19.9.
3.4.11. (2R,8aS,9aR,13aS)-Octahydro-3-phenyl-1H,8H-
2,9a-methanobenzo[1,4]cyclobuta[1,2-h][1,3,6]dioxaze-
cine-1,6,14-trione 18 and isomer 19. A solution of 17
(0.85 g, 2.4 mmol) in acetonitrile (100 mL) was irradiated
for 6 h. The solvent was concentrated under reduced pres-
sure to leave a pale yellow oil. The residue was then sub-
jected to flash chromatography (petrol/ethyl acetate 7:3) to

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3667
Minor isomer 24. 1H NMR (CDCl3, 270 MHz): d 7.70 (4H,
m), 7.50 (6H, m), 7.20 (5H, m), 5.60 (1H, dd, J¼11.22,
4.0 Hz), 5.30 (1H, t, J¼11.2 Hz), 4.15 (1H, m), 4.07 (1H,
dd, J¼11.6, 4.0 Hz), 3.91 (1H, m), 2.79 (1H, m), 2.62 (1H,
m), 2.55 (2H, m), 2.47 (1H, m), 1.78 (2H, m), 1.40 (2H,
m), 1.10 (2H, m); 13C NMR (CDCl3, 67.8 MHz): d 183.1,
180.40, 136.5, 135.2, 134.8, 134.5, 133.8, 132.4, 131.2,
130.7, 130.4, 130.3, 128.6, 128.4, 62.7, 62.6, 58.3, 46.4,
44.9, 43.4, 28.3, 28.0, 25.8, 21.0, 20.1.
8.8 mmol), L-(+)-valinol14 (0.91 g, 9.68 mmol) and toluene
(85 mL), afforded 25 [(1.98 g, 95%), [a]D +1.27ꢁ2 (c 1,
C2H5OH at 20 ꢂC)] as a yellow oil. IR (neat): 3448, 1767,
1699, 1640 cmꢀ1 1H NMR (CDCl3, 270 MHz): d 4.00
;
(1H, dd, J¼11.9, 7.25 Hz), 3.80–3.70 (2H, m), 3.00 (1H,
br s), 2.30 (5H, m), 1.70 (4H, m), 1.00 (3H, d, J¼6.6 Hz),
0.80 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3, 67.8 MHz):
d 172.1, 141.4, 62.3, 59.5, 27.2, 21.4, 20.2, 20.1, 20.0;
LRMS (EI): m/z 237 (4.0%, M+), 206 (100), 152 (15.2),
134 (4.4); Anal. Calcd for C13H19O3N: C, 65.80; H, 8.07;
N, 5.90. Found: C, 65.82; H, 8.00; N, 5.97.
For the mixture. IR (DCM thin film): 1770, 1700 cmꢀ1
;
LRMS (EI): m/z 509 (19.5%, M+), 432 (100), 390 (55.0),
199 (21.9), 91 (29.0); Anal. Calcd for C31H31O4NSi: C,
73.05; H, 6.13; N, 2.74. Found: C, 72.69; H, 6.12; N, 2.47.
3.4.16. (2S)-Carbonic acid-2-(1,3-dioxo-1,3,4,5,6,7-hexa-
hydro-2H-isoindole-2-yl)-3-methylbutyl-2-propenyl
ester 27. Following general procedure 2, using 25 (0.50 g,
2.1 mmol), THF (20 mL), pyridine (0.21 mL, 2.64 mmol)
and allyl chloroformate (0.28 mL, 2.64 mmol), afforded 27
as a pale yellow oil (0.41 g, 61%). IR (neat): 1751, 1706,
3.4.14. (3aR,7aS,8S)-3a,7a-Ethano-8-(hydroxymethyl)-2-
(2-hydroxy-1-phenylethyl)-4,5,6,7-tetrahydro-1H-isoin-
dole-1,3(2H)-dione 20 and isomer 21. Method 1: a mixture
of the diastereoisomers 18 and 19 (0.32 g, 0.9 mmol) was
dissolved in THF (15 mL), and then H2O (15 mL) and
NaOH (0.072 g, 1.8 mmol) were added to the solution. It
was stirred at rt for 2.5 h followed by treatment with 2 M
HCl until neutral. The solvent was concentrated in vacuo
to leave a pale yellow solid. Hot EtOH (150 mL) was poured
into the crude mixture, which was filtered and concentrated
to afford a yellow oil. The residue was then subjected to flash
chromatography (petrol/ethyl acetate 3:7) to give a pale yel-
low oil (99.5 mg, 34%). This compound was shown to be
a mixture of two diastereoisomers 20 and 21 in a 1.3:1 ratio
as shown by integration of signals in the 1H NMR spectrum.
1649 cmꢀ1 1H NMR (CDCl3, 270 MHz): d 5.80–6.00
;
(1H, m), 5.30 (1H, dq, J¼17.2, 1.3 Hz), 5.20 (1H, dd,
J¼17.1, 1.3 Hz), 4.58 (2H, dt, J¼5.6, 1.3 Hz), 4.45 (2H,
m), 3.99 (1H, m), 2.30 (5H, m), 1.70 (4H, m), 1.00 (3H, d,
J¼6.6 Hz), 0.80 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3,
67.8 MHz): d 171.2, 154.8, 141.2, 131.8, 118.6, 68.5, 65.9,
56.3, 27.9, 21.5, 20.2, 20.1, 20.0; LRMS (EI): m/z 321
(4.0%, M+), 206 (100), 164 (19.0); Anal. Calcd for
C17H23O5N: C, 63.53; H, 7.21; N, 4.36. Found: C, 63.61;
H, 7.22; N, 4.38.
3.4.17. (2R,8aS,9aR,13aS)-3-(1-Methylethyl)octahydro-
1H,8H-2,9a-methanobenzo[1,4]cyclobuta[1,2-h][1,3,6]-
dioxazecine-1,6,14-dione 28 and isomer 29. A solution of
27 (0.26 g, 0.82 mmol) in acetonitrile (100 mL) was irradi-
ated for 40 min. The solvent was concentrated under reduced
pressure to leave a yellow liquid. The liquid was purified by
flash chromatography (petrol/ethyl acetate 7:3) to give
a white solid (0.234 g, 90%); mp 108–116 ꢂC. It was shown
to be a mixture of two diastereoisomers 28 and 29 in a 1:1
Method 2: to a solution of 23 and 24 (0.44 g, 0.86 mmol) in
THF (20 mL) under a nitrogen atmosphere at rt was added,
dropwise, Bu4NF (0.49 mL, 1.73 mmol). The brown mixture
was stirred at rt for 1 h. The solvent was removed in vacuo to
leave a brown oil, which was purified by flash chromato-
graphy (EtOAc) to afford a mixture of 20 and 21 in a 3:1 ratio
as a pale yellow oil (0.26 g, 93%).
1
ratio as shown by integration of signals in the H NMR
spectrum.
Major isomer 20. 1H NMR (CDCl3, 300 MHz): d 7.40 (5H,
m), 5.30 (1H, m), 4.10 (1H, dd, J¼11.4, 4.9 Hz), 4.02 (1H,
dd, J¼11.5, 4.9 Hz), 3.75 (1H, dd, J¼11.9, 4.1 Hz), 3.65
(1H, dd, J¼12.0, 5.1 Hz), 3.40 (2H, br s), 2.70 (1H, m),
2.10 (2H, m), 1.90 (2H, m), 1.64 (2H, m), 1.58 (2H, m),
1.50 (2H, m); 13C NMR (CDCl3, 75.45 MHz): d 183.4,
182.5, 136.8, 128.4, 128.3, 127.8, 63.1, 61.5, 58.1, 46.7,
42.1, 38.8, 32.0, 28.5, 27.6, 20.8, 20.0.
For the mixture. IR (DCM thin film): 1761, 1695 cmꢀ1; 1H
NMR (CDCl3, 300 MHz): d 5.00 (2H, dd, J¼13.3, 7.6 Hz),
4.62 (2H, dd, J¼11.7, 2.1 Hz), 4.15 (2H, m), 4.00 (2H, m),
2.75 (2H, m), 2.55 (2H, m), 2.47 (2H, m), 2.41 (2H, m),
2.00–1.80 (8H, m), 1.60–1.40 (8H, m), 1.30 (2H, m), 1.08
(2ꢃ3H, 2ꢃd, J¼6.6 Hz), 0.80 (2ꢃ3H, 2ꢃd, J¼6.8 Hz);
13C NMR (CDCl3, 75.45 MHz): d 183.5, 182.4, 181.3,
154.5, 151.6, 68.2, 67.8, 61.2, 56.8, 47.4, 46.7, 43.0, 41.6,
31.5, 29.0, 28.0, 27.3, 26.8, 26.5, 26.2, 20.7, 20.4, 20.1,
19.8, 19.6, 19.3, 18.5; LRMS (EI): m/z 321 (47.6%, M+),
219 (65.5), 121 (67.0), 85 (100); Anal. Calcd for
C17H23O5N: C, 63.53; H, 7.21; N. 4.36. Found: C, 63.55;
H, 7.29; N, 4.07.
Minor isomer 21. 1H NMR (CDCl3, 300 MHz): d 7.35 (5H,
m), 5.40 (1H, m), 4.70 (1H, m), 4.60 (1H, m), 3.51 (1H, m),
3.49 (1H, m), 3.40 (2H, br s), 2.80 (1H, m), 2.30 (2H, m),
2.00 (2H, m), 1.85 (2H, m), 1.60 (2H, m), 1.45 (2H, m);
13C NMR (CDCl3, 75.45 MHz): d 183.4, 182.5, 136.6,
128.9, 127.9, 126.7, 62.2, 61.3, 57.9, 47.2, 42.0, 38.3,
32.7, 28.6, 27.5, 20.9, 20.1.
3.4.18. (2S)-2-[1-[[Bis(1-methylethyl)(2-propenyloxy)-
silyl]oxy]methyl-2-methylpropyl]-4,5,6,7-tetrahydro-1H-
isoindole-1,3(2H)-dione 32. Following general procedure
3, using in part 1; 25 (0.53 g, 2.25 mmol), DCM (30 mL),
Et3N (0.63 mL, 4.5 mmol) and diisopropyldichlorosilane
(0.79 mL, 4.5 mmol). Then in part 2, allyl alcohol
(1.13 mL, 16.6 mmol), Et3N (2.31 mL, 16.6 mmol), DCM
(10 mL) and the crude product in DCM (60 mL) were added
For the mixture. IR (neat): 3444, 1765, 1740, 1697 cmꢀ1
;
LRMS (EI): m/z 299 (1.0%, M+ꢀCH2O), 84 (63.8), 61
(18.0), 42 (100).
3.4.15. (2S)-2-[1-(Hydroxymethyl)-2-methylpropyl]-
4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione 25. Fol-
lowing general procedure 1, using THPA (1.34 g,

3668
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
to afford 32 (0.65 g, 71%) as a pale yellow oil. IR (neat):
1769, 1709, 1647 cmꢀ1 1H NMR (CDCl3, 270 MHz):
(75.2), 161 (25.5); Anal. Calcd for C28H33O4NSi: C,
70.70; H, 6.99; N, 2.94. Found: C, 70.61; H, 6.97; N, 2.86.
;
d 5.90 (1H, m), 5.30 (1H, dq, J¼17.2, 2.0 Hz), 5.00 (1H,
dd, J¼10.6, 1.7 Hz), 4.30 (2H, m), 4.10 (1H, m), 4.00 (1H,
dd, J¼10.23, 5.0 Hz), 3.80 (1H, td, J¼21.0, 10.2, 5.0 Hz),
2.30 (5H, m), 1.70 (4H, m), 1.00 (17H, m), 0.85 (3H, d,
J¼6.9 Hz); 13C NMR (CDCl3, 67.8 MHz): d 171.9, 141.0,
137.1, 113.8, 63.5, 61.0, 59.4, 27.7, 21.5, 20.3, 20.2, 20.0,
17.2, 12.1; LRMS (EI): m/z 365 (10.0%, M+ꢀC(CH3)2),
364 (38.6, M+ꢀCH(CH3)2), 275 (100), 191 (20.5), 135
(10.6); Anal. Calcd for C22H37O4NSi: C, 64.82; H, 9.15;
N, 3.44. Found: C, 64.96; H, 9.14; N, 3.43.
3.4.21. (2R,8aS,9aR,13aS)-6,6-Diphenyl-3-(1-methyl-
ethyl)octahydro-1H,8H-2,9a-methanobenzo[1,4]cyclo-
buta[1,2-h][1,3,6,2]dioxazasilecine-1,14-dione 36 and
isomer 37. A solution of 35 (0.71 g, 1.50 mmol) in aceto-
nitrile (100 mL) was irradiated for 2 h. The solvent was
concentrated in vacuo to leave a pale yellow oil. The oil
was purified by flash chromatography (petrol/ethyl acetate
17:3) to afford a white crystalline solid (0.61 g, 86%); mp
53.2–62.8 ꢂC; [a]D +4.3ꢁ2 (c 1, C2H5OH at 20 ꢂC). It was
shown to be a mixture of two diastereoisomers 36 and 37
in a 8:1 ratio as shown by comparison of the signals in the
1H NMR spectrum. Recrystallisation from Et2O gave
a pure sample of 36, which was slowly crystallised from
Et2O/petroleum ether to give a suitable single crystal for
X-ray diffraction.
3.4.19. (2R,8aS,9aR,13aS)-Octahydro-3,6,6-tris(1-meth-
yl)-1H,8H-2,9a-methanobenzo[1,4]cyclobuta[1,2-h]-
[1,3,6,2]dioxazasilecine-1,14-dione 33 and isomer 34. A
solution of 32 (0.41 g, 1.00 mmol) in acetonitrile (100 mL)
was irradiated for 1 h. The solvent was removed in vacuo
to leave a pale yellow crystalline solid. The residue was
then subjected to flash chromatography (petrol/ethyl acetate
8:2) to afford a white solid (0.305 g, 74%), mp 102–107 ꢂC,
which was shown to be a mixture of two diastereoisomers 33
and 34 in a 2:1 ratio as shown by integration of the 1H NMR
signals.
Major isomer 36. 1H NMR (CDCl3, 300 MHz): d 7.62 (4H,
m), 7.30 (6H, m), 4.39 (1H, dd, J¼11.4, 10.4 Hz), 4.15 (1H,
m), 3.99 (1H, m), 3.91 (1H, m), 3.57 (1H, dd, J¼11.4,
3.9 Hz), 2.55 (2H, m), 2.45 (2H, m), 1.90 (3H, m), 1.61–
1.47 (5H, m), 1.00 (3H, d, J¼6.6 Hz), 0.80 (3H, d, J¼
6.6 Hz); 13C NMR (CDCl3, 75.45 MHz): d 184.1, 181.0,
135.3, 135.2, 130.7, 128.1, 62.0, 62.0, 61.3, 47.7, 45.1,
42.2, 30.4, 28.6, 27.2, 25.2, 24.6, 21.0, 20.7, 20.5, 20.2, 20.0.
Major isomer 33. 1H NMR (CDCl3, 270 MHz): d 4.50 (1H, t,
J¼10.9 Hz), 4.00 (1H, m), 3.88 (1H, m), 3.70 (1H, dd,
J¼11.2, 4.6 Hz), 2.60 (2H, m), 2.45 (2H, m), 2.33 (4H,
m), 1.65 (3H, m), 1.10–0.70 (22H, m); 13C NMR (CDCl3,
67.8 MHz): d 183.9, 180.7, 61.6, 61.4, 61.0, 47.3, 45.0,
41.9, 30.1, 28.4, 25.4, 24.5, 20.8, 20.7, 20.3, 20.1, 17.5,
17.3, 12.0, 11.7.
Minor isomer 37. 1H NMR (CDCl3, 300 MHz): d 7.50 (4H,
m), 7.43 (6H, m), 4.65 (1H, dd, J¼11.4, 9.6 Hz), 4.20–4.10
(1H, m), 3.96 (1H, dd, J¼11.4, 2.9 Hz), 3.93 (1H, m), 3.80
(1H, dd, J¼11.6, 7.6 Hz), 2.78 (2H, m), 2.55 (2H, m), 2.41
(2H, m), 2.32 (2H, m), 1.95 (3H, m), 1.61–1.47 (4H, m),
1.00 (3H, d, J¼6.6 Hz), 0.80 (3H, d, J¼6.6 Hz); 13C NMR
(CDCl3, 75.45 MHz): d 184.1, 181.0, 135.5, 135.1, 132.2,
131.5, 62.8, 62.0, 60.6, 46.1, 44.8, 43.2, 30.9, 30.5, 28.4,
28.4, 26.4, 20.9, 20.8, 20.6, 20.2, 20.1.
Minor isomer 34. 1H NMR (CDCl3, 270 MHz): d 4.63 (1H, t,
J¼10.9 Hz), 4.05 (1H, m), 3.93 (2H, m), 2.65 (2H, m), 2.50
(2H, m), 2.33 (2H, m), 1.98 (2H, m), 1.60 (4H, m), 1.10–0.70
(21H, m); 13C NMR (CDCl3, 67.8 MHz): d 183.9, 180.7,
62.0, 60.7, 60.5, 47.3, 45.2, 41.9, 30.1, 28.9, 27.1, 26.0,
20.7, 20.4, 20.0, 19.8, 17.5, 17.1, 12.4, 10.6.
For the mixture. IR (DCM thin film): 1765, 1702 cmꢀ1
;
LRMS (EI): m/z 475 (1.7%, M+), 398 (100), 390 (30.4),
199 (15.5), 78 (14.3); Anal. Calcd for C28H33O4NSi: C,
70.70; H, 6.99; N, 2.94. Found: C, 70.64; H, 6.95; N, 3.02.
For the mixture. IR (DCM thin film): 1765, 1702 cmꢀ1
;
LRMS (EI): m/z 365 (26.3%, M+ꢀC(CH3)2), 364 (100,
M+ꢀCH(CH3)2), 275 (8.8); Anal. Calcd for C22H37O4SiN:
C, 64.82; H, 9.15; 3.44. Found: C, 64.80; H, 9.25; N, 3.32.
3.4.22. (3aR,7aS,8S)-3a,7a-Ethano-8-(hydroxymethyl)-2-
[1-(hydroxymethyl)-2-methylpropyl]-4,5,6,7-tetrahydro-
1H-isoindole-1,3(2H)-dione 30 and isomer 31. Method 1:
the photocycloadducts 28 and 29 (0.18 g, 0.57 mmol) were
dissolved in a mixture of EtOH (15 mL) and water
(15 mL) and treated with KOH (0.064 g, 1.14 mmol). After
stirring at rt for 3 h, the reaction mixture was neutralised by
the addition of 2 M HCl. The solvent was concentrated in va-
cuo to leave a brown oil. The oil was purified by flash chro-
matography (ethyl alcohol/ethyl acetate 1:9) to afford a pale
yellow oil (0.13 g, 79%). It was shown to be a mixture of two
diastereoisomers 30 and 31 in a 1:1 ratio as shown by inte-
gration of signals in the 1H NMR spectrum.
3.4.20. (2S)-2-[1-[[(Diphenyl)(2-propenyloxy)silyl]oxy]-
methyl-2-methylpropyl]-4,5,6,7-tetrahydro-1H-isoin-
dole-1,3(2H)-dione 35. Following general procedure 3,
using in part 1; 25 (1.69 g, 7.12 mmol), DMF (40 mL),
Et3N (1.97 mL, 14.2 mmol) and diphenyldichlorosilane
(2.45 mL, 14.2 mmol). Then in part 2, allyl alcohol
(4.2 mL, 52.8 mmol), Et3N (7.36 mL, 52.8 mmol), DMF
(10 mL) and the crude product in DMF (80 mL) were used
to afford 35 (2.01 g, 60%) as a pale yellow oil. IR (neat):
1768, 1704, 1647 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d 7.63 (4H, m), 7.30 (6H, m), 5.95 (1H, m), 5.34 (1H, dq,
J¼17.0, 1.8 Hz), 5.12 (1H, dq, J¼10.3, 2.0 Hz), 4.25 (2H,
m), 4.21 (1H, m), 4.01 (1H, dd, J¼10.3, 4.6 Hz), 3.85 (1H,
td, J¼20.1, 10.0, 4.5 Hz), 2.30 (5H, m), 1.72 (4H, m), 0.90
(3H, d, J¼6.6 Hz), 0.83 (3H, d, J¼6.6 Hz); 13C NMR
(CDCl3, 75.45 MHz): d 172.1, 141.3, 136.7, 134.9, 132.6,
130.6, 128.0, 114.8, 64.0, 61.4, 59.5, 27.6, 21.4, 20.3,
20.0; LRMS (EI): m/z 475 (7.6%, M+), 398 (100), 206
Method 2: to a solution of 33 and 34 (0.27 g, 0.67 mmol) in
THF (25 mL) was added, dropwise, Bu4NF (0.39 mL,
1.34 mmol) at rt. The reaction mixture was then stirred for
20 min at rt. The solvent was concentrated under reduced
pressure to leave a yellow oil. This was subjected to flash
chromatography (petrol/ethyl acetate 8:2) to give a pale

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3669
yellow oil (0.169 g, 87%), which was shown to be a mixture
of two diastereoisomers 30 and 31 in a 2:1 ratio.
Minor isomer 40. 1H NMR (CDCl3, 270 MHz): d 7.60 (4H,
m), 7.30 (6H, m), 6.20 (1H, s), 4.00 (4H, m), 2.50–2.00 (6H,
m), 1.80 (4H, m), 0.90 (6H, d, J¼6.6 Hz); 13C NMR (CDCl3,
67.8 MHz): d 179.7, 178.2, 156.3, 136.9, 135.2, 135.0,
134.7, 132.7, 131.9, 130.5, 127.9, 60.8, 59.1, 59.0, 52.5,
51.4, 27.3, 25.6, 23.4, 21.4, 20.4, 20.2, 19.9.
Method 3: to a solution 36 and 37 (0.18 g, 0.38 mmol) in
THF (25 mL) was added, dropwise, Bu4NF (0.22 mL,
0.76 mmol) and then the reaction mixture was stirred at rt
for 30 min. The solvent was concentrated in vacuo to leave
a yellow oil. The oil was then subjected to flash chromato-
graphy (petrol/ethyl acetate 7:3) to provide a pale yellow
oil (0.109 g, 99%), which was shown to be mixture of two
diastereoisomers 30 and 31 in a 8:1 ratio. [a]D +2.6ꢁ2
(c 1, C2H5OH at 20 ꢂC).
For the mixture. IR (DCM thin film): 1765, 1700,
1652 cmꢀ1
.
3.4.25. (2S)-3a,7a-Ethano-8-(hydroxymethyl)-2-[1-
(hydroxymethyl)-2-methylpropyl]-4,5,6,7-tetrahydro-
1H-isoindole-1,3(2H)-dione 41 and isomer 42. To a solu-
tion of 39 and 40 (0.30 g, 0.634 mmol) in THF (25 mL)
was added, dropwise, Bu4NF (0.36 mL, 1.26 mmol) and
the resulting brown solution was stirred at rt for 20 min.
The solvent was concentrated in vacuo to leave a brown
liquid. The residue was purified by flash chromatography
(petrol/ethyl acetate 6:4) to afford a colourless oil (0.15 g,
81%). It was shown to be a mixture of two diastereoisomers
41 and 42 in a 4:1 ratio as shown by integration signals in the
1H NMR spectrum.
For the mixture. IR (neat): 3439, 1764, 1700 cmꢀ1; 1H NMR
(CDCl3, 270 MHz): d 4.20 (2H, m), 3.90 (2H, m), 3.75 (1H,
m), 3.73 (1H, m), 3.65–3.40 (8H, m), 2.80 (1H+1H, m), 2.40
(2H, m), 2.35 (2H, m), 2.14 (4H, m), 2.00 (2H, m), 1.70 (4H,
m), 1.60 (2H, m), 1.55 (2H, m), 1.50 (4H, m), 1.00 (2ꢃ3H,
2ꢃd, J¼6.9 Hz), 0.82 (2ꢃ3H, d, J¼6.6 Hz); 13C NMR
(CDCl3, 67.8 MHz): d 184.1, 183.1, 182.9, 63.2, 62.6,
61.4, 61.3, 61.0, 47.2, 46.6, 42.1, 41.8, 38.7, 38.6, 32.0,
32.7, 29.7, 29.1, 28.9, 28.0, 27.8, 26.6, 26.2, 21.2, 21.2,
20.3, 20.1, 20.0, 20.0, 19.9; LRMS (EI): m/z 295 (2.1%,
M+), 210 (50.6), 165 (13.1), 121 (7.3), 84 (100); Anal. Calcd
for C16H25O4N: C, 65.06, H, 8.53; N, 4.74. Found: C, 64.99;
H, 8.14; N, 4.29.
Major isomer 41. 1H NMR (CDCl3, 270 MHz): d 6.20 (1H,
s), 4.20 (2H, s), 4.00 (1H, m), 3.80 (2H, m), 3.20 (2H, br s),
2.45 (1H, m), 1.90 (4H, m), 1.60 (2H, m), 1.35 (2H, m), 1.00
(3H, d, J¼6.6 Hz), 0.85 (3H, d, J¼6.6 Hz); 13C NMR
(CDCl3, 67.8 MHz): d 180.0, 179.3, 154, 134.1, 61.7, 59.8,
58.4, 53.4, 50.6, 26.2, 25.2, 24.7, 24.2, 19.8, 19.6, 19.5.
3.4.23. (2S)-2-[1-[[[Diphenyl(2-propynyloxy)silyl]oxy]-
methyl]-2-methylpropyl]-4,5,6,7-tetrahydro-1H-iso-
indole-1,3(2H)-dione 38. Following general procedure 3,
using in part 1; 25 (1.11 g, 4.67 mmol), MeCN (40 mL),
Et3N (1.3 mL, 9.35 mmol) and diphenyldichlorosilane
(1.96 mL, 9.33 mmol). Then in part 2, propargyl alcohol
(2.43 mL, 41.8 mmol), Et3N (5.83 mL, 41.8 mmol), MeCN
(10 mL) and the crude product in MeCN (80 mL) were
used to afford 38 (1.28 g, 58%) as a pale yellow oil. IR
Minor isomer 42. 1H NMR (CDCl3, 270 MHz): d 6.10 (1H,
s), 4.10 (2H, s), 4.00 (1H, m), 3.70 (2H, m), 2.40 (3H, br m),
2.00 (4H, m), 1.50 (2H, m), 1.40 (2H, m), 0.90 (3H, d,
J¼6.6 Hz), 0.80 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3,
67.8 MHz): d 180.0, 179.3, 154.6, 134.1, 61.7, 59.8, 58.3,
53.42, 50.6, 26, 25.12, 24.7, 24.2, 19.8, 19.6, 19.5.
1
(neat): 3289, 2125, 1770, 1705 cmꢀ1; H NMR (CDCl3,
270 MHz): d 7.50 (4H, m), 7.30 (6H, m), 4.40 (2H, s),
4.20 (1H, s), 4.05 (2H, m), 3.83 (1H, td, J¼20.1, 9.9,
4.6 Hz), 2.35 (5H, m), 1.70 (4H, m), 0.85 (3H, d, J¼
6.6 Hz), 0.77 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3,
67.8 MHz): d 171.0, 141.0, 134.9, 132.0, 130.5, 127.9,
82.0, 73.3, 61.5, 59.4, 51.5, 27.6, 21.4, 20.3, 20.0; LRMS
(EI): m/z 473 (1.1%, M+), 206 (100), 152 (24.9), 139 (37.6).
For the mixture. IR (neat): 3426, 1761, 1682, 1634 cmꢀ1
;
LRMS (EI): m/z 293 (3.3%, M+), 208 (83), 119 (100), 84
(28.4).
3.4.26. (3aa,7aa,8S*)-3a,7a-Ethano-3-hydroxy-2-(2-
hydroxyethyl)-8-(hydroxymethyl)-1-one-4,5,6,7-tetra-
hydro-1H-isoindole 43. To a stirred solution of 11 (0.45 g,
1.77 mmol) in 90% aqueous 2-propanol (10 mL) was added
NaBH4 (0.10 g, 2.63 mmol) in one portion. After stirring
overnight at rt, TLC indicated complete consumption of
the starting material. Excess NaBH4 was decomposed by
careful addition of glacial acetic acid. The mixture was con-
centrated, diluted with water (10 mL), extracted with Et2O
(3ꢃ25 mL), dried over Na2SO4 and concentrated under
reduced pressure. The resulting yellow oil was purified by
flash chromatography (ethyl alcohol/ethyl acetate 1:9) to
afford the product 43 as a pale yellow oil (0.36 g, 80%). It
was shown to be a mixture of diastereoisomers in a 1:2 ratio
as shown by integration of the 1H NMR signals.
3.4.24. (2R,8aS,9aR,13aS)-6,6-Diphenyl-3-(1-methyl-
ethyl)octahydro-1H,8H-2,9a-methanobenzo[1,4]cyclo-
butene[1,2-h][1,3,6,2]dioxazasilecine-1,14-dione 39 and
isomer 40. A solution of 38 (0.865 g, 1.82 mmol) in aceto-
nitrile (100 mL) was irradiated for 6 h. The solvent was
removed under reduced pressure to leave a yellow solid.
The solid residue was subjected to flash chromatography
(petrol/ethyl acetate 9:1) to afford a white solid (0.42 g,
49%); mp 42–47 ꢂC, which was shown to be a mixture of
two diastereoisomers 39 and 40 in a 4:1 ratio as shown by
integration of signals in the 1H NMR spectrum.
Major isomer 39. 1H NMR (CDCl3, 270 MHz): d 7.50 (4H,
m), 7.20 (6H, m), 5.90 (1H, s), 4.30 (4H, m), 2.40–2.20 (6H,
m), 1.20 (4H, m), 0.80 (6H, d, J¼6.6 Hz); 13C NMR (CDCl3,
67.8 MHz): d 179.7, 178.2, 156.3, 137.0, 135.1, 135.0,
134.8, 132.7, 131.9, 130.5, 127.9, 60.8, 59.1, 59.1, 52.5,
51.4, 27.4, 25.6, 23.4, 21.4, 20.4, 20.2, 19.9.
For the mixture. IR (neat): 3322, 1739, 1653 cmꢀ1; 1H NMR
(CDCl3, 300 MHz): d 5.45 (2H, br s), 5.01 (1H, s, minor iso-
mer), 4.96 (1H, s, major isomer), 4.40 (1H, br s), 3.8 (4H, m),
3.65 (4H, m), 3.55 (2H, m), 3.40 (2H, m), 2.65 (2H, m), 2.00
(4H, m), 1.70 (6H, m), 1.50 (8H, m), 1.05 (2H, m); 13C NMR
(CDCl3, 75.45 MHz): d 179.0, 178.4, 86.3, 84.6, 62.9, 60.3,

3670
xS. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
60.2, 59.8, 47.4, 46.7, 43.0, 42.5, 42.0, 39.9, 36.0, 34.3, 29.4,
28.7, 27.5, 26.7, 26.7 23.6, 21.1, 20.3, 20.2, 19.8; LRMS
(EI): m/z 255 (6.5%, M+), 237 (64.9), 206 (100), 194
(80.0), 180 (59.7).
silica thoroughly washed with DCM (2ꢃ15 mL). The
solvent was concentrated under reduced pressure to afford
a yellow oil. Purification was carried out by flash chromato-
graphy (ethyl alcohol/ethyl acetate 1:9) to give 53 as a yellow
1
oil (14 mg, 83%). IR (neat): 1777, 1710, 1698; H NMR
3.4.27. (1S*,6R*,9R*)-7-Oxobicyclo[4.3.0]nonane-1,9-
carbolactone 46 and (1R*,6S*,8R*,9R*)-6,9-dihydroxy-
bicyclo[4.2.1]nonane-1,8-carbolactone 47. A stirred solu-
tion of 43 (0.19 g, 0.74 mmol) in 4 M H2SO4 (5 mL) was
heated at 80 ꢂC for 12 h. The reaction mixture was cooled
to rt and neutralised by the addition of 2 M NaOH. The mix-
ture was concentrated under reduced pressure to leave a pale
yellow solid. The residue was dissolved in hot EtOH
(100 mL) and then filtered to remove Na2SO4. The solvent
was concentrated under reduced pressure to afford a yellow
oil, which was purified by flash chromatography (petrol/
ethyl acetate 1:1) to afford 46 as a pale yellow solid
(43 mg, 30%), mp 85 ꢂC, and 47 as a pale yellow solid
(48 mg, 30%), mp 100 ꢂC.
(CDCl3, 300 MHz): d 9.49 (1H, d, J¼2.2 Hz), 4.45 (1H,
m), 4.17 (1H, dd, J¼11.2, 8.5 Hz), 3.20 (1H, m), 2.90 (1H,
m), 2.73 (1H, m), 2.53 (1H, dd, J¼14.0, 3.8 Hz), 2.37 (2H,
m), 2.13 (1H, m), 1.89 (2H, m), 1.69 (2H, m); 13C NMR
(CDCl3, 75.45 MHz): d 211.2, 197.0, 173.1, 69.0, 61.6,
41.0, 40.8, 38.9, 29.3, 27.4, 22.2; LRMS (EI): m/z 210
(0.7%, M+), 182 (15.3), 84 (100), 67 (26).
3.4.30. (1S*,6R*,9R*)-7-Oxobicyclo[4.3.0]nonane-1,9-
carbolactone 46 and (1R*,6R*,8R*,9R*)-9-hydroxy-6-
trifluoroacetoxybicyclo[4.2.1]nonane-1,8-carbolactone
50. A stirred yellow solution of 43 (0.20 g, 0.78 mmol) in
anhydrous TFA (10 mL) was heated at reflux for 12 h. The
reaction mixture was cooled to rt and then the acid concen-
trated under reduced pressure to leave a brown oil. H2O
(10 mL) was added to the residue, which was then extracted
with Et2O (3ꢃ25 mL), the combined extracts washed with
saturated aqueous NaHCO3 solution (30 mL), dried over
Na2SO4, filtered and concentrated to give a pale brown oil.
This was subjected to flash chromatography (petrol/ethyl
acetate 1:1) to afford 46 as a pale yellow solid (76 mg,
50%) and 50 as a pale yellow solid (73 mg, 30%); mp
80 ꢂC. Data matched that reported above. IR (DCM thin
film): 3452, 1761, 1700, 1221–1163; 1H NMR (CDCl3,
300 MHz): d 4.50 (2H, m), 3.90 (1H, dd, J¼9.6, 6.3 Hz),
2.80 (2H, m), 2.40 (1H, m), 2.20 (2H, m), 1.85 (2H, m),
1.95 (1H, m), 1.70 (1H, m), 1.50 (2H, m), 1.41 (1H, m);
13C NMR (CDCl3, 75.45 MHz): d 179.9, 157.0, 110.0–
120.0 (very weak, CF3), 97.3, 79.8, 73.6, 51, 41.5, 38.4,
32.0, 31.1, 23.9, 21.5; 19F NMR (254 MHz, CDCl3):
d ꢀ74.6 (3F, s); LRMS (EI): m/z 306 (6.3%, M+ꢀ2ꢃH),
290 (14.7, M+ꢀH2O), 280 (30.8), 246 (27.3), 194 (59.1),
176 (78.7), 69 (100); Anal. Calcd for C13H15O5F3: C,
50.66; H, 4.90. Found: C, 50.78; H, 4.74.
Carbolactone 46. IR (DCM thin film): 1770, 1746 cmꢀ1; 1H
NMR (CDCl3, 300 MHz): d 4.45 (1H, dd, J¼9.6, 7.3 Hz),
4.07 (1H, dd, J¼9.6, 6.2 Hz), 2.99 (1H, m), 2.70 (1H, dd,
J¼19.7, 9.0 Hz), 2.50 (1H, t, J¼6.4 Hz), 2.30 (1H, ddd,
J¼19.8, 4.1, 1.0 Hz), 1.90 (2H, m), 1.75 (2H, m), 1.50
(4H, m); 13C NMR (CDCl3, 75.45 MHz): d 214.4, 179.83,
70.8, 49.4, 48.7, 39.6, 39.4, 28.5, 22.5, 22.5, 21.2; LRMS
(EI): m/z 194 (100%, M+), 166 (30.3), 139 (26.9), 79
(16.9); Anal. Calcd for C11H14O3: C, 68.03; H, 7.26. Found:
C, 68.20; H, 7.38.
Carbolactone 47. IR (DCM thin film): 3426, 1757; 1H NMR
(CDCl3, 300 MHz): d 4.56 (1H, t, J¼9.6 Hz), 4.16 (1H, d,
J¼4.0 Hz), 4.01 (1H, dd, J¼9.3, 6.9 Hz), 3.20 (1H, d, J¼
4.0 Hz), 2.70 (1H, m), 2.50 (1H, s), 2.40 (1H, m), 2.26
(1H, dd, J¼13.9, 9.90 Hz), 2.00 (2H, m), 1.70 (4H, m),
1.45 (2H, m); 13C NMR (CDCl3, 75.45 MHz): d 182.1,
83.7, 82.5, 74.9, 52.9, 41.8, 40.6, 37.7, 31.9, 24.6, 22.1;
LRMS (EI): m/z 212 (8.1%, M+), 194 (17.9), 91 (20.5), 79
(28.0), 43 (100).
3.4.28. Preparation of pinacol rearrangement product
from (1R*,6S*,8R*,9R*)-6,9-dihydroxybicyclo[4.2.1]-
nonane-1,8-carbolactone 47. A stirred solution of 47
(90 mg, 0.42 mmol) in 4 M H2SO4 (5 mL) was heated at
80 ꢂC for four days. The reaction mixture was cooled to rt
and neutralised by addition of 2 M NaOH. The mixture
was concentrated under reduced pressure to leave a pale yel-
low solid, which was dissolved in hot EtOH (80 mL) and
filtered to remove Na2SO4. The solvent was concentrated
under reduced pressure to leave a yellow oil. This was sub-
jected to flash chromatography (petrol/ethyl acetate 1:1) to
give product 46 (30 mg, 37%) as a pale yellow solid and
also 47 (50 mg, 56%) was recovered as a pale yellow solid.
Data matched that reported above.
Acknowledgements
We are grateful to the C¸ anakkale Onsekiz Mart University,
Turkey (Sx.G.) for financial support of this work. We also
thank Dr. Sigrid Wocadlo and Dr. Alexander Mandel for
performing the X-ray structural analysis.
References and notes
1. (a) Pirrung, M. C. J. Am. Chem. Soc. 1981, 103, 82–87; (b)
Crimmins, M. T. Chem. Rev. 1988, 88, 1453–1473; (c)
Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95,
2003–2020; (d) Samajdar, S.; Ghatak, A.; Ghosh, S. Tetra-
hedron Lett. 1999, 40, 4401–4402; (e) Lange, L. G.; Gottarado,
C.; Merica, A. J. Org. Chem. 1999, 64, 6738–6744; (f) Randall,
M. L.; Lo, P. J. Am. Chem. Soc. 1999, 121, 4534–4535; (g) Lo,
P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821; (h)
Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003,
125, 10772–10773; (i) Padwa, A.; Lipka, H.; Watterson,
S. H.; Murphree, S. S. J. Org. Chem. 2003, 68, 6238–6250.
3.4.29. (1S*,8R*)-8-Formyl-10-oxa-9-oxobicyclo[6.3.0]-
undecane 53. To a vigorously stirred suspension of chroma-
tographic grade silica gel (1.0 g) in DCM (5 mL) at rt, was
added a 0.65 M aqueous solution of NaIO4 (1 mL), dropwise
with stirring, at this time a flaky suspension was formed.
Carbolactone 47 (17 mg, 0.08 mmol) in DCM (3 mL) was
then added. After 15 min the mixture was filtered and the

Sx. Gu€lten et al. / Tetrahedron 63 (2007) 3659–3671
3671
2. Hutchinson, J. H.; Daynard, T. S.; Gillard, J. W. Tetrahedron
Lett. 1991, 32, 573–576.
11. Booker-Milburn, K. I.; Gulten, S.; Sharpe, A. Chem. Commun.
1997, 1385–1386.
3. Shea, K. J.; Staab, A. J.; Zandi, K. S.; Kathleen, S. Tetrahedron
Lett. 1991, 32, 2715–2718.
12. (a) Booker-Milburn, K. I.; Cowell, J. K.; Harris, L. J.
Tetrahedron Lett. 1994, 35, 3883–3886; (b) Booker-Milburn,
ꢀ
K. I.; Delgado Jimenez, F.; Sharpe, A. Synlett 1995, 735–
736; (c) Booker-Milburn, K. I.; Cowell, J. K.; Sharpe, A.;
4. (a) Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am.
Chem. Soc. 1992, 114, 2121–2128; (b) Hale, M. R.; Hoveyda,
A. H. J. Org. Chem. 1992, 57, 1643–1645.
ꢁ
Delgado Jimenez, F. Chem. Commun. 1996, 249–251; (d)
5. (a) Fleming, S. A.; Ward, S. C. Tetrahedron Lett. 1992, 33,
1013–1016; (b) Bradford, C. L.; Fleming, S. A.; Ward, S. C.
Tetrahedron Lett. 1995, 36, 4189–4192.
6. Crimmins, M. T.; Guise, L. E. Tetrahedron Lett. 1994, 35,
1657–1660.
7. Penkett, C. S.; Byrne, P. W.; Teobald, B. J.; Rola, B.; Ozanne,
A.; Hitchcock, P. B. Tetrahedron 2004, 60, 2771–2784.
8. (a) Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis
1997, 813–854; (b) Gauthier, D. R.; Zandi, K. S.; Shea, K. J.
Tetrahedron 1998, 54, 2289–2338.
Booker-Milburn, K. I.; Cowell, J. K.; Harris, L. J.
Tetrahedron 1997, 53, 12319–12338; (e) Booker-Milburn,
K. I.; Costin, N. J.; Dainty, R. F.; Patel, D.; Sharpe, A.
Tetrahedron Lett. 1998, 39, 7423–7426; (f) Booker-Milburn,
ꢁ
K. I.; Cowell, J. K.; Delgado Jimenez, F.; Sharpe, A.; White,
A. J. Tetrahedron 1999, 55, 5875–5888; (g) Booker-Milburn,
ꢁ
K. I.; Delgado Jimenez, F.; Sharpe, A. Tetrahedron 1999,
55, 5889–5902; (h) Booker-Milburn, K. I.; Anson, C. E.;
Clissold, C.; Costin, N. J.; Dainty, R. F.; Murray, M.; Patel,
D.; Sharpe, A. Eur. J. Org. Chem. 2001, 1473–1482.
13. Corey, E. J.; Sugss, J. W. J. Org. Chem. 1973, 38, 3223–3224.
14. Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc.
1985, 107, 7974–7978.
€
9. (a) Green, B. S.; Rabinsohn, Y.; Retjo, M. Carbohydr. Res.
1975, 45, 115–126; (b) Green, B. S.; Hagler, A. T.;
€
Rabinsohn, Y.; Retjo, M. Isr. J. Chem. 1976/77, 15, 124–130;
(c) Lange, G. L.; Decicco, C.; Lee, M. Tetrahedron Lett.
1987, 28, 2833–2836; (d) Meyers, A. I.; Fleming, S. A.
J. Am. Chem. Soc. 1986, 108, 306–307; (e) Herzog, H. D.;
Scharf, H. D.; Runsink, J. Tetrahedron 1986, 42, 3547–3558;
(f) Demuth, M.; Palomer, A.; Sluma, H. D.; Dey, A. K.;
Kruger, C.; Tsay, Y. H. Angew. Chem., Int. Ed. Engl. 1986,
25, 1117–1119; (g) Sato, M.; Takayama, K.; Abe, Y.; Furuya,
T.; Inukai, N.; Kaneko, C. Chem. Pharm. Bull. 1990, 38,
336–339; (h) Haag, D.; Scharf, H. D. J. Org. Chem. 1996, 61,
6127–6135; (i) Crimmins, M. T.; Reinhold, T. L. Org. React.
1993, 44, 297–588.
15. (a) Uhle, F. C. J. Org. Chem. 1961, 26, 2998–3001; (b) Osby,
J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25,
2093–2096.
16. (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437–1441; (b) Wijnberg, J. B. P. A.;
Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34,
179–187.
17. (a) Horii, Z.-I.; Iwata, C.; Tamura, Y. J. Org. Chem. 1961, 26,
2273–2276; (b) Dener, J. M.; Hart, D. J.; Ramesh, S. J. Org.
Chem. 1988, 53, 6022–6030; (c) Micouin, L.; Quirion, J.-C.;
Husson, H.-P. Synth. Commun. 1996, 26, 1605–1612.
18. Mukaiyama, T.; Yamashita, H.; Asami, M. Chem. Lett. 1983,
385–388.
10. (a) Faure, S.; Piva-Le Blanc, S.; Piva, O.; Pete, J.-P.
Tetrahedron Lett. 1997, 38, 1045–1048; (b) Piva-Le Blanc,
S.; Piva, O.; Pete, J.-P. Chem. Commun. 1998, 235–236;
(c) Faure, S.; Piva, O. Tetrahedron Lett. 2001, 42, 255–259;
(d) Faure, S.; Piva-Le Blanc, S.; Bertrand, C.; Pete, J.-P.;
Piva, O. J. Org. Chem. 2002, 67, 1061–1070.
19. Kang, J.; Lee, J. W.; Kim, J. I.; Pyun, C. Tetrahedron Lett. 1995,
36, 4265–4268.
20. Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Goffic, F. L.
Synthesis 1989, 64–65.