The synthesis of fused and spiro annulated carbohydrate structures using copper(I) catalysed intramolecular photoannulation of glucose derivatives

Article abstract of DOI:10.1039/b315623k

Intramolecular [2 + 2] photoannulation catalysed by copper(I)triflate has been applied to a series of carbohydrate derivatives obtained from glucose. Dienes 1a and 1b lead to cyclobutanes 3a and 3b whereas the diastereoisomeric dienes 5a and 5b gave diastereoisomeric products 7a and 7b. These results demonstrate that the reaction is stereo-specific. Products 3a and 7a were converted into bromoesters 4 and 9 respectively. The Vasella elimination of 8 lead to the expected bicyclic aldehyde 10 and the ring expanded hydroxy ketone 12. The stereospecific formation of enantiomerically pure spiro annulated carbohydrates 18a and 18b was demonstrated whereas in example 19 no selectivity in the formation of 20 and 21 was observed.

Full text of DOI:10.1039/b315623k

View Article Online / Journal Homepage / Table of Contents for this issue
The synthesis of fused and spiro annulated carbohydrate structures
using copper(I) catalysed intramolecular photoannulation of
glucose derivatives†
David J. Holt, William D. Barker, Subrata Ghosh‡ and Paul R. Jenkins*
Department of Chemistry, The University of Leicester, Leicester, UK LE1 7RH
Received 2nd December 2003, Accepted 5th February 2004
First published as an Advance Article on the web 25th February 2004
Intramolecular [2 ϩ 2] photoannulation catalysed by copper()triflate has been applied to a series of carbohydrate
derivatives obtained from glucose. Dienes 1a and 1b lead to cyclobutanes 3a and 3b whereas the diastereoisomeric
dienes 5a and 5b gave diastereoisomeric products 7a and 7b. These results demonstrate that the reaction is stereo-
specific. Products 3a and 7a were converted into bromoesters 4 and 9 respectively. The Vasella elimination of 8 lead
to the expected bicyclic aldehyde 10 and the ring expanded hydroxy ketone 12. The stereospecific formation of
enantiomerically pure spiro annulated carbohydrates 18a and 18b was demonstrated whereas in example 19 no
selectivity in the formation of 20 and 21 was observed.
Intra and intermolecular [2 ϩ 2] photocycloaddition reactions
have been used to synthesise a wide variety of cyclobutane
containing natural products and to generate cyclobutane
intermediates, which subsequently undergo ring expansion
in routes to other important target molecules.1 Light absorbtion
at a practical wavelength is usually achieved in the [2 ϩ 2]
photocyclisation by using an enone chromophore in reaction
with an alkene. The stereochemistry of this process has
been studied extensively with varying degrees of success.2 The
[2 ϩ 2] photocyclisation of two non-conjugated alkenes is also
possible using a metal catalyst;3 the most successful catalyst
for this reaction is bis(copper()trifluoromethanesulfonate)-
benzene complex [(CuSO3CF3)2.C6H6](CuOTf ) first reported
by Salomon and Kochi.4
Attempts to achieve asymmetric induction of the copper()
catalysed [2 ϩ 2] reaction with a chiral auxilliary have met
with some success, with ee’s up to 60%, however reactions in
Scheme 1 Reagents and conditions: i) hν, CuOTf, benzene; ii) NBS,
the presence of a chiral ligand gave very poor results, with ee’s
< 5%.5 As part of our interest in new methods of carbohydrate
annulation.6,7 we were attracted to the idea of using carbo-
hydrate substrates8 as a means of synthesising chiral cyclo-
butanes. We report here in full the first successful synthesis
of chiral cyclobutane derivatives in enantiomerically pure
form using carbohydrate substrates in the copper() catalysed
[2 ϩ 2] photcycloaddition reaction.9 Recently a related study
using furanose sugars has appeared.10
BaCO3, CHCl3, reflux.
determination. A similar result was obtained with alcohol 1b,
which was converted into product 3b in 18% yield, the structure
3b follows by comparison with the NMR spectra of 3a. The low
yield of 3b may be due to the extra steric hinderance of the
quaternary centre in 1b making cyclisation to 3b more difficult.
Finally, tetracyclic-alcohol 3a was reacted with NBS according
to the procedure by Hannessian and Plessas13 to produce the
tricyclic-bromoester 4 in 72% yield.
The stereospecific nature of the photoannulation process
became clear when the cis- isomer 5a was subjected to irradi-
ation in the presence of copper() triflate (Scheme 2) to give a
single isomer of tetracyclic alcohol 7a in 86% yield. In this
example the same explanation applies as in Scheme 1. Both
double bonds and the OH coordinate to the copper () as shown
in transition state 6. The cyclobutane ring forms on the same
side as the OH group leading to structure 7a. The structure of
this compound was determined by spectroscopic comparison
with compound 3a on which an X-ray crystal structure
had been determined. A similar result was obtained using the
alcohol 5b leading to the product 7b in 89% yield.
Results and discussion
When the two trans-alcohol 1a was irradiated in the presence of
bis(copper()trifluoromethane sulfonate) [(CuSO3CF3)2.C6H6] =
CuOTf according to the method introduced by Salomon and
Kochi4 a single diastereoisomer of the product 3a was obtained
in 86% yield, Scheme 1. We account for this result by applying
the explanation given for simpler cases put forward by Salomon
et al.11 The Cu() from the copper triflate coordinates both
double bonds and the OH before the photoannulation takes
place, as shown in the proposed transition state 2. This causes
the cyclobutane ring to form on the same side as the OH
leading to product 3a. The structure of product 3a was
confirmed by an X-ray crystallography12 crystal structure
Further transformations of tetracyclic alcohol 7a were
carried out to remove the sugar ring from the molecule.
Reaction with NBS13 gave the bromoester 8 in 73% yield
followed by a Vasella elimination14 with zinc in aqueous
isopropanol to give a 29% yield of the expected aldehyde 10.
A second product was also obtained via a ring expansion
reaction of α-hydroxy aldehyde 10. We reasoned that Zn2ϩ was
† Electronic supplementary information (ESI) available: NMR data
and ORTEP diagrams. See http://www.rsc.org/suppdata/ob/b3/
b315623k/
‡ On leave from: Organic Chemistry Department, Indian Association
for the Cultivation of Science, Jadavpur, Calcutta 700 032, India.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 3 – 1 0 9 7
1093

View Article Online
Scheme 2 Reagents and conditions: i) hν, CuOTf, benzene; ii) NBS, BaCO3, CHCl3, reflux; iii) activated Zn, 2-propanol : H2O (10 : 1), reflux.
present in the Vasella reaction and that it is likely to coordinate
the OH and carbonyl oxygen to give intermediate 11, migration
of the carbon–carbon bond will then take place leading to
the hydroxyketone 12. The configurational assignment for
compound 12 was based on the NOESY spectrum in which
protons 2, 4-axial, 5, 8, 9 show strong NOE effects.
We observed a related reaction to this in our work on the
transformation of annulated carbohydrates obtained by ring
closing metathesis.7 To the best of our knowledge the closest
analogy to this reaction in the literature is the rearrangement
of 17α-hydroxy-2O-oxopregnanes 13, into 17α-hydroxy-17β-
methyl-17a-ketones 14.15 This reaction occurs in Lewis acid
conditions using BF3, alumina or Al(tBuO)3 and involves the
migration of the less substituted carbon, a in structure 13
leading to 14. Subsequent work by Gros, Seldes and co-
workers16 has demonstrated that with ZnI2 a stereospecific
rearrangement takes place with exclusive migration of the
more substituted carbon, b in structure 13, leading to the
17aα-hydroxy-17aβ-methyl-17-oxo derivative 15. In our case
the selective migration of the carbon not bearing the cyclo-
butane in the proposed chelated intermediate 11 occurs.
When structure 16a was irradiated in the presence of
copper() triflate another stereospecific cyclobutanation took
place via the proposed transition state 17, Scheme 3. In this
case the coordination of the copper() is with the oxygen of
the sugar ring and the ‘outside edge’ of the vinyl group which
prevents its free rotation, suprafacial approach of the second
double bond then takes place as shown in 17 to produce a
cis-fused 5–6 ring system of the spiro-tetracyclic structure 18a
in 72% yield. A similar result was obtained starting from diene
16b leading to 18b in 61% yield. Structures 18a and 18b were
proved by X-ray crystallography.12 This method provides a
useful route to spiro-annulated sugar derivatives in enantio-
merically pure form.
Scheme 3 Reagents and conditions: i) hν, CuOTf, benzene.
Scheme 4 Reagents and conditions: i) hν, CuOTf, benzene.
possible. Structure 19 gave spiro product 20 in 33% yield and a
30% yield of its isomer 21.
In conclusion we report full details of our study of
carbohydrate annulation of glucose derivatives using
copper()triflate catalysed photoannulation. The results
demonstrate the synthesis of fused and spiro-tetracyclic
carbohydrate derivatives in enantiomerically pure form. We
have further demonstrated that a combination of Hanessian
bromination13 and Vasella elimination14 removes the sugar ring
from the tetracyclic structure and produces functionalised
enantiomerically pure bicyclic structures that could be readily
transformed further.
Stereoselectivity is lost in Scheme 4 where simultaneous
coordination of the Cu() and the two double bonds is not
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 3 – 1 0 9 7
1094

View Article Online
(2R,4aR,6S,6aR,6bR,8aR,9aS,9bS )-6-Methoxy-2-phenyl-
Experimental
octahydro-1,3,5-trioxacyclobuta[3,4]-cyclopenta[1,2-a]naph-
thalen-6a-ol (7a). In the same way as for the preparation of
3a above (CF3SO3Cu)2.C6H6 (23 mg, 0.046 mmol, 13 mol%),
methyl (R)-4,6-O-benzylidene-2-C-ethenyl-3-deoxy-3-C-pro-
penyl-α--glucopyranoside7 5a (118 mg, 0.36 mmol) in dry
benzene (10 mL) was irradiated for 5.5 h. The reaction mixture
was worked up as described for 3a above to leave a yellow oil.
Chromatography on silica gel with petroleum ether–diethyl
ether (4 : 1) as the eluent yielded 7a as a colourless oil (101 mg,
86%): Rf 0.52, petroleum ether–diethyl ether (1 : 1); [α]2D0 ϩ 4.3
(c 1.0, CHCl3); νmax (CHCl3)/cmϪ1 3580w, 3010w, 1090s, 1060s,
1030s; δH (400 MHz, CDCl3) 1.74–1.90 (2H, m), 1.94–2.07 (1H,
m), 2.13–2.34 (4H, m), 2.71 (1H, s), 2.75–2.83 (1H, m), 2.83–
2.95 (1H, m), 2.96 (1H, dd, overlapping, J 9.7, 10.5), 3.48 (3H,
s), 3.65 (1H, t, J 10.3), 3.80 (1H, ddd, J 4.8, 9.7, 10.3), 4.28 (1H,
dd, J 4.8, 10.3), 4.46 (1H, s), 5.45 (1H, s), 7.32–7.54 (5H);
δC (62.9 MHz, CDCl3) 16.6 (CH2), 28.6 (CH2), 34.1 (CH2), 36.3
(CH), 44.0 (CH), 52.7 (CH), 55.8 (CH3), 62.8 (CH), 69.8 (CH2),
78.9 (CH), 80.9 (C), 100.5 (CH), 102.2 (CH), 126.6 (CH), 128.7
(CH), 129.4 (CH), 138.1 (C); m/z (FAB) 333 (MHϩ, 18%)
(found MHϩ, 333.1703; C19H25O5 requires 333.1702).
All reactions were performed under an atmosphere of nitrogen
(unless otherwise stated in the text) and solvent extractions
dried with anhydrous magnesium sulfate. Tetrahydrofuran and
diethyl ether were freshly distilled from sodium benzophenone
ketyl. Benzene was distilled form sodium under nitrogen.
Chloroform was distilled from phosphorous pentoxide and
stored under nitrogen. Dichloromethane was distilled from
calcium hydride. Petroleum ether refers to the 40–60 ЊC boiling
fraction. Flash chromatography was performed on Sorbsil C-60
silica gel (Crosfield Chemicals), 40–60 µM. Melting points
are uncorrected. All chemical shifts were taken directly from
the spectra, and J values are given in hertz. Specific optical
rotations are measured in units of 10Ϫ1 deg cm2 gϪ1
.
General procedure for the copper(I) triflate catalysed
photoannulation reaction
(2R,4aR,6S,6aS,6bS,8aS,9aS,9bS)-6-Methoxy-2-phenyl-
octahydro-1,3,5-trioxacyclobuta-[3,4]cyclo-penta[1,2-a]naph-
thalen-6a-ol (3a) (CF3SO3Cu)2.C6H6 (10 mg, 0.020 mmol, 5
mol%) was added to a solution of methyl (R)-4,6-O-benzyl-
idene-2-C-ethenyl-3-deoxy-3-C-propenyl-α--glucopyrano-
side7 1a (140 mg, 0.42 mmol) in dry benzene (10 mL), in a
quartz photolysis tube, water-cooled by a cold finger extending
into the solution. Irradiation was carried out at 254 nm, using a
Rayonet photochemical reactor, for 6 h. The reaction mixture
was diluted with diethyl ether (40 mL) and washed with aque-
ous ammonia solution (35%, 2 × 20 mL). The organic layer was
washed with water (20 mL), dried and concentrated under
reduced pressure to leave a yellow oil. Chromatography on
silica gel with petroleum ether–diethyl ether (3 : 1) as the eluent
yielded 3a as a white solid (121 mg, 86%): mp 101–103 ЊC
(2R,4aR,6S,6aR,6bR,8aR,9aS,9bS )-6-Methoxy-9a-methyl-
2-phenyl-octahydro-1,3,5-trioxa-cyclobuta[3,4]cyclopenta-
[1,2-a]naphthalen-6a-ol (7b). In the same way as for 3a above
(CF3SO3Cu)2.C6H6 (20 mg, 0.040 mmol, 14 mol%) methyl (R)-
4,6-O-benzylidene-2-C-ethenyl-3-deoxy-3-C-methyl-3-C-pro-
penyl-α--glucopyranoside7 5b (96 mg, 0.28 mmol) in dry
benzene (10 mL), was irradiated for 6 h. The reaction was
worked out as described for 3a above to leave a yellow oil.
Chromatography on silica gel with petroleum ether–diethyl
ether (3 : 1) as the eluent yielded 7b as a colourless oil (85 mg,
89%): Rf 0.69, petroleum ether–diethyl ether (1 : 1); [α]2D0 ϩ 13.6
(c 7.0, CHCl3); νmax (CHCl3)/cmϪ1 3580w, 3010w, 1090s, 1060s,
1030s; δH (250 MHz, CDCl3) 1.20 (3H, s), 1.50 (1H, dd, J 6.3,
13.2), 1.60–1.82 (1H, m), 1.86–2.09 (1H, m), 2.12–2.31 (3H, m),
2.70–2.98 (2H, m), 2.75 (1H, broad s), 3.11 (1H, d, J 9.4), 3.42
(3H, s), 3.62 (1H, t, J 10.1), 3.86 (1H, ddd, J 5.0, 9.4, 10.1), 4.27
(1H, dd, J 5.0, 10.1), 4.37 (1H, s), 5.44 (1H, s), 7.28–7.55 (5H,
m); δC (62.9 MHz, CDCl3) 14.3 (CH3), 16.9 (CH2), 28.2 (CH2),
35.5 (CH), 43.4 (CH2), 45.7 (CH), 53.3 (C), 56.1 (CH3), 59.3
(CH), 70.0 (CH2), 80.1 (CH), 80.3 (C), 101.8 (CH), 102.1 (CH),
126.6 (CH), 128.6 (CH), 129.3 (CH), 138.3 (C); m/z (FAB)
347 (MHϩ, 20%) (found MHϩ, 347.1858; C20H27O5 requires
347.1859).
(ethanol); Rf 0.36, petroleum ether–diethyl ether (1 : 1); [α]2D0
ϩ
34.2 (c 4.1, CHCl3); νmax (CHCl3)/cmϪ1 3580w, 3010w, 1090s,
1060s, 1030s; δH (400 MHz, CDCl3) 1.58 (1H, dt, J 5.7, 12.3),
1.81 (1H, m), 1.97–2.08 (3H, m), 2.15 (1H, br s), 2.15–2.29 (2H,
overlapping m), 2.73–2.84 (2H, m), 3.42 (3H, s), 3.70 (1H, ddd,
J 4.7, 9.2, 10.2), 3.87 (1H, t, J 10.2), 3.88 (1H, dd, overlapping,
J 9.2, 11.0), 4.31 (1H, dd, J 4.7, 10.2), 4.60 (1H, s), 5.59 (1H, s),
7.33–7.55 (5H, m); δC (100.6 MHz, CDCl3) 17.2 (CH2), 29.4
(CH2), 33.6 (CH2), 37.1 (CH), 42.7 (CH), 48.0 (CH), 55.6
(CH3), 65.1 (CH), 69.6 (CH2), 81.4 (CH), 81.9 (C), 102.3 (CH),
102.9 (CH), 126.6 (CH), 128.7 (CH), 129.3 (CH), 138.2 (C); m/z
(FAB) 333 (MHϩ, 15%) (found MHϩ, 333.1703; C19H25O5
requires 333.1702). Anal. found: C, 68.75; H, 7.32. C19H24O5
requires C, 68.66; H, 7.28%.
General procedure for NBS bromination of benzylidene acetals
(2R,4aR,6S,6aS,6bS,8aS,9aS,9bS )-6-Methoxy-9a-methyl-2-
phenyl-octahydro-1,3,5-trioxacyclobuta-[3,4]cyclopenta[1,2-a]-
naphthalen-6a-ol (3b). In the same was as for the preparation
of 3a (CF3SO3Cu)2.C6H6 (22 mg, 0.044 mmol, 13mol%) methyl
(R)-4,6-O-benzylidene-2-C-ethenyl-3-deoxy-3-C-methyl-3-C-
propenyl-α--mannopyranoside7 1b (118 mg, 0.34 mmol)
in dry benzene (10 mL) was irradiated for 22 h. The reaction
mixture was worked up as described in the preparation of 3a
above to produce a yellow oil. Chromatography on silica gel
with petroleum ether–diethyl ether (3 : 1) as the eluent yielded
3b as a colourless oil (21 mg, 18%): Rf 0.50, petroleum ether–
diethyl ether (1 : 1); [α]2D0 Ϫ59.2 (c 2.1, CHCl3); νmax (CHCl3)/
cmϪ1 3580w, 3010w, 1090s, 1060s, 1030s; δH (250 MHz, CDCl3)
0.93 (3H, s), 1.72–1.94 (4H, m), 2.00–2.26 (2H, m), 2.57 (1H, s),
2.57–2.69 (1H, m), 2.80–3.00 (1H, m), 3.50 (3H, s), 3.79 (1H,
ddd,J4.1,9.1,9.8),3.87(1H,t,J9.8),4.23(1H,d,J9.1),4.33(1H,
dd, J 4.1, 9.8), 4.71 (1H, s), 5.58 (1H, s), 7.29–7.54 (5H, m); δC
(100.6 MHz, CDCl3) 15.8 (CH3), 17.4 (CH2), 28.4 (CH2), 37.2
(CH), 42.5 (CH2), 42.9 (CH), 51.6 (C), 57.2 (CH3), 66.9 (CH),
70.1 (CH2), 82.2 (C), 82.7 (CH), 102.1 (CH), 103.3 (CH), 126.7
(CH), 128.6 (CH), 129.3 (CH), 138.4 (C); m/z (FAB) 347 (MHϩ,
12%) (found MHϩ, 347.1859; C20H27O5 requires 347.1859).
(2aS,2bS,3S,5S,6S,6aS,7aS )-Benzoic acid 5-bromomethyl-
2b-hydroxy-3-methoxy-decahydro-4-oxa-cyclobuta[a]inden-6-yl
ester (4). Barium carbonate (542 mg, 2.75 mmol) and
N-bromosuccinimide (135 mg, 0.76 mmol) were added sequen-
tially to a solution of (2R,4aR,6S,6aS,6bS,8aS,9aS,9bS)-
6-methoxy-2-phenyl-octahydro-1,3,5-trioxa-cyclobuta[3,4]-
cyclopenta[1,2-a]naphthalen-6a-ol, 3a (228 mg, 0.69 mmol)
in dry chloroform (30 mL). The mixture was heated under
reflux for 23 h, allowed to cool to room temperature, barium
carbonate removed by filtration and the residue washed
with dichloromethane (2 × 20 mL). The filtrate was washed
with water (2 × 50 mL), dried and concentrated under reduced
pressure to leave a yellow oil. Chromatography on silica gel with
petroleum ether–diethyl ether (3 : 1) as the eluent yielded 4 as a
colourless oil (204 mg, 72%): Rf 0.60, petroleum ether–diethyl
ether (1 : 1); νmax (CHCl3)/cmϪ1 3580w, 1725s, 1275s, 1115s,
1030s; δH (300 MHz, CDCl3) 1.63–2.27 (7H, 3-H, m), 2.33 (1H,
broad s), 2.63–2.80 (2H, m), 3.41 (3H, s), 3.44 (1H, dd,
overlapping, J 6.7, 11.0), 3.52 (1H, dd, J 2.5, 11.0), 3.83 (1H,
ddd, J 2.5, 6.7, 10.2), 4.59 (1H, s), 5.29 (1H, t, J 10.2), 7.37 (2H,
m), 7.49 (1H, m), 7.94 (2H, m); δC (75.8 MHz, CDCl3) 17.3
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 3 – 1 0 9 7
1095

View Article Online
(CH2), 29.1 (CH2), 33.1 (CH2), 34.5 (CH2), 36.9 (CH), 42.3
(CH), 48.8 (CH), 55.9 (CH3), 70.6 (CH), 73.7 (CH), 81.0 (C),
102.1 (CH), 128.9 (CH), 130.0 (C), 130.1 (CH), 133.8 (CH),
165.9 (C).
Methyl (R)-4,6-O-benzylidene-2,3-dideoxy-2(S )-spiro(2,7Ј-
3Ј(R), 6Ј(R)-1Ј-oxa-bicyclo-[3.2.0]-heptane)-ꢀ-D-glucopyrano-
side (18a). In the same way as for 3a above (CF3SO3Cu)2.C6H6
(10 mg, 0.020 mmol, 6 mol%) methyl-(R)-4,6-O-benzylidene-
2-C-ethenyl-2-O-propenyl-3-deoxy-α--glucopyranoside7 16a
(208 mg, 0.33 mmol) in dry benzene (10 mL) was irradiated
for 8 h. The reaction mixture was worked up as described for
3a to leave a yellow solid. Chromatography on silica gel with
petroleum ether–diethyl ether (3 : 1) as the eluent yielded 18a as
a white solid (143 mg, 86%): mp 141.5–143 ЊC; Rf 0.26, petrol-
eum ether–diethyl ether (1 : 1); [α]2D0 ϩ 36.6 (c 3.3, CHCl3); νmax
(CHCl3)/cmϪ1 2900m br, 1410m, 1250s, 1080m br; δH (250MHz,
CDCl3) 1.67 (1H, m), 1.87 (2H, m), 2.01 (2H, m), 2.22 (1H, m),
2.93–3.16 (2H, m), 3.49 (1H, m), 3.49 (3H, s), 3.70 (1H, t,
J 10.1), 3.80–3.98 (3H, m), 4.24 (1H, dd, J 4.4, 10.1), 4.67 (1H,
s), 5.50 (1H, s), 7.30–7.55 (5H, m); δC (62.9 MHz, CDCl3) 19.6
(CH2), 24.1 (CH2), 32.7 (CH2), 39.1 (CH), 45.6 (CH), 55.4
(CH3), 64.1 (CH), 69.9 (CH2), 73.1 (CH2), 77.4 (CH), 83.8 (C),
99.6 (CH), 102.3 (CH), 126.6 (CH), 128.7 (CH), 129.5 (CH),
137.8 (C); m/z (FAB) 333 (MHϩ, 56), 301 (MHϩ Ϫ MeOH,
100); elemental analysis found C 68.46, H 7.22, C19H24O5
requires C 68.66, H 7.30%.
(2aR,2bR,3S,5S,6S,6aS,7aR)-Benzoic acid 5-bromomethyl-
2b-hydroxy-3-methoxy-decahydro-4-oxa-cyclobuta[a]inden-6-yl
ester (8). In the same way as for 4 above barium carbonate (552
mg, 2.80 mmol) and N-bromosuccinimide (137 mg, 0.77 mmol),
(2R,4aR,6S,6aR,6bR,8aR,9aS,9bS)-6-methoxy-2-phenyl-octa-
hydro-1,3,5-trioxa-cyclobuta[3,4]cyclopenta[1,2-a]naphthalen-
6a-ol 7a (232 mg, 0.70 mmol) in dry chloroform (30 ml) were
reacted together for 23 h. The reaction was worked up as
described for 4 above to leave a yellow oil. Chromatography on
silica gel with petroleum ether–diethyl ether (3 : 1) as the eluent
yielded 8 as a colourless oil (211 mg, 73%): Rf 0.62, petroleum
ether–diethyl ether (1 : 1); [α]2D0 ϩ 54.3 (c 1.1, CHCl3); νmax
(CHCl3)/cmϪ1 3580w, 1725s, 1275s, 1115s, 1030s; δH (250 MHz,
CDCl3) 1.61–2.47 (7H, 3-H, m), 2.65 (1H, broad s), 2.76–2.98
(2H, m), 3.35 (1H, dd, J 8.2, 11.0), 3.47 (1H, dd, J 2.5, 11.0),
3.57 (3H, s), 4.10 (1H, ddd, J 2.5, 8.2, 9.8), 4.53 (1H, s), 4.64
(1H, dd, J 9.1, 9.8), 7.47 (2H, m), 7.59 (1H, m), 8.04 (2H, m);
δC (62.9 MHz, CDCl3) 16.6 (CH2), 27.5 (CH2), 32.9 (CH2), 35.3
(CH2), 35.9 (CH), 43.7 (CH), 52.4 (CH), 56.0 (CH3), 69.7 (CH),
71.7 (CH), 80.5 (C), 100.2 (CH), 128.9 (CH), 129.8 (C), 130.2
(CH), 133.9 (CH), 166.4 (C); m/z (EI) 410/412 (Mϩ, 1%), 105
(PhCOϩ, 84) (found Mϩ, 410.0728; C19H23O5Br requires
410.0729).
Methyl (R)-4,6-O-benzylidene-2,3-dideoxy-2(S )-spiro(2,7Ј-
3Ј(R),
6Ј(R)-3Ј-methyl-1Ј-oxa-bicyclo-[3.2.0]-heptane)-ꢀ-D-
glucopyranoside (18b). In the same way as for 3a above
(CF3SO3Cu)2.C6H6 (10 mg, 0.020 mmol, 4 mol%) was added
to a solution of methyl(R)-4,6-O-benzylidene-2-C-ethenyl-2-O-
(2-methylpropenyl)-3-deoxy-α--glucopyranoside7 16b (165
mg, 0.47 mmol) in dry benzene (10 ml) was irradiated for 6 h.
The reaction was worked up as described for 3a above to leave a
yellow solid. Chromatography on silica gel with petroleum
ether–diethyl ether (3 : 1) as the eluent yielded starting material
16b as a white solid (48 mg, 29%) and 18b as a white solid (83
mg, 50%): mp 165.5–167 ЊC; Rf 0.29, petroleum ether–diethyl
ether (1 : 1); [α]2D0 ϩ 11.2 (c 4.9, CHCl3); νmax (CHCl3)/cmϪ1
2940s br, 1450m, 1395m, 1100s; δH (250 MHz, CDCl3) 1.25 (3H,
s), 1.71–1.99 (6H, m), 2.54 (1H, m), 3.42 (3H, s), 3.46 (1H, m),
3.51 (1H, d, J 9.1), 3.63 (1H, t, J 10.2), 3.76 (1H, ddd, over-
lapping, J 4.4, 8.6), 3.79 (1H, d, J 9.1), 4.17 (1H, dd, J, 4.4,
10.2), 4.58 (1H, s), 5.45 (1H, s), 7.22–7.55 (5H, m); δC
(62.9MHz, CDCl3) 16.1 (CH2), 24.9 (CH3), 30.7 (CH2), 31.3
(CH2), 46.8 (C), 51.4 (CH), 55.4 (CH3), 64.1 (CH), 69.8 (CH2),
77.9 (CH), 78.7 (CH2), 84.2 (C), 99.8 (CH), 102.4 (CH), 126.6
(CH), 128.8 (CH), 129.5 (CH), 137.8 (C); m/z (ES) 369 (MNaϩ,
100); elemental analysis found C 69.34, H 7.56, C20H26O5
requires C 69.35, H 7.35%.
(1S,1ЈR,3ЈS,4ЈR,5ЈR)-Benzoic acid 1-(4Ј-formyl-4Ј-hydroxy-
bicyclo[3.2.0]hept-3Ј-yl)-allyl ester (10) and (1S,1ЈR,3ЈR,4ЈS,-
6ЈR)-benzoic acid 1-(4Ј-hydroxy-5Ј-oxo-bicyclo[4.2.0]oct-3Ј-yl)-
allyl ester (12). Zinc powder (60 g) was activated by washing
sequentially with 2 M hydrochloric acid (6 × 30 mL), water
(5 × 35 mL), 10% w/v aqueous potassium carbonate solution
(30 mL), water (4 × 40 mL), isopropanol (2 × 35 mL) and
diethyl ether (3 × 35 mL). The bromo compound (2aR,2bR,3S,-
5S,6S,6aS,7aR)-benzoic acid 5-bromomethyl-2b-hydroxy-3-
methoxy-decahydro-4-oxa-cyclobuta[a]inden-6-yl ester 8 (200
mg, 0.49 mmol) was heated under reflux with the activated zinc
(4.14 g, 0.063 mol) in isopropanol : water (20:2 mL) for 2.5 h.
The zinc was removed by filtration, washed with diethyl ether
(3 × 25 mL), the combined organic layers washed with water
(2 × 50 mL), saturated sodium chloride solution (50 mL), dried,
and evaporated to leave a colourless oil. Chromatography on
kieselgel silica with petroleum ether–diethyl ether (4 : 1 to 3 : 1)
as the eluent yielded 10 as a colourless oil (42 mg, 29%) and 12
as a colourless oil (43 mg, 29%): 10 Rf 0.49, petroleum ether–
diethyl ether (1 : 1); [α]2D0 Ϫ38.9 (c 1.6, CHCl3); νmax (CHCl3)/
cmϪ1 3510w, 1715s, 1610w, 1275s; δH (250 MHz, CDCl3) 1.69–
1.93 (2H, m), 2.08–2.37 (3H, m), 2.38–2.58 (1H, m), 2.64–2.77
(1H, m), 2.90–3.05 (1H, m), 3.12 (1H, ddd, J 3.6, 6.9, 13.4), 3.41
(1H, s), 5.19–5.38 (2H, m), 5.67–5.75 (1H, m), 5.83–6.01 (1H,
m), 7.44 (2H, m), 7.58 (1H, m), 7.99 (2H, m), 9.52 (1H, s); δC
(100.6 MHz, CDCl3) 18.5 (CH2), 26.2 (CH2), 31.2 (CH2), 34.8
(CH), 42.0 (CH), 51.6 (CH), 72.5 (CH), 86.5 (C), 117.5 (CH2),
128.9 (CH), 129.9 (CH), 130.3 (C), 133.6 (CH), 135.5 (CH),
165.2 (C), 200.3 (CH); m/z (FAB) 301 (MHϩ, 5%), 323 (MNaϩ,
7) (found MHϩ, 301.1440; C18H21O4 requires 301.1440).
Methyl (R)-4,6-O-benzylidene-2,3-dideoxy-3(R)-spiro(3,7Ј-
3Ј(R), 6Ј(R)-1Ј-oxa-bicyclo-[3.2.0]-heptane)-ꢀ-D-glucopyrano-
side (20) and methyl (R)-4,6-O-benzylidene-3(R)-2,3-dideoxy-
spiro(3,7Ј-3Ј(S ),
6Ј(S )-1Ј-oxa-bicyclo-[3.2.0]-heptane)-ꢀ-D-
glucopyranoside (21). In the same way as for 3a above
(CF3SO3Cu)2.C6H6 (10 mg, 0.020 mmol, 5 mol%) was added to
a solution of methyl (R)-4,6-O-benzylidene-2-deoxy-3-C-ethe-
nyl-3-O-propenyl-α--allopyrano-side6 19 (147 mg, 0.45 mmol)
in dry benzene (10 mL) was irradiated for 6 h. The reaction
mixture was worked up as described for 3a above to leave a
yellow solid. Chromatography by chromatatron with chloro-
form–ethyl acetate (4 : 1) as the eluent yielded 20 as a white
solid (48 mg, 33%) and 21 as a white solid (40 mg, 30%): 20: mp
141–143 ЊC; Rf 0.36, petroleum ether–diethyl ether (1 : 1); [α]2D0
ϩ 87.9 (c 4.2, CHCl3); νmax (CHCl3)/cmϪ1 2950m, 1390m, 1100s,
1050s; δH (400MHz, CDCl3) 1.72 (1H, m), 1.85 (1H, dd, J 4.6,
14.6), 1.95 (1H, m), 2.03 (1H, m), 2.19 (1H, m), 2.21 (1H, dd,
overlapping, J 0.6, 14.6), 2.93–2.98 (2H, m), 3.46 (3H, s), 3.47
(1H, m), 3.69 (1H, t, J 11.7), 3.97 (1H, d, J 8.0), 4.31 (1H, m),
4.31 (2H, d), 4.79 (1H, d, J 4.6), 5.45 (1H, s), 7.35–7.58 (5H, m);
δC (100.6MHz, CDCl3) 18.4 (CH2), 24.8 (CH2), 36.8 (CH2), 40.2
(CH), 46.9 (CH), 56.0 (CH3), 59.6 (CH,), 69.7 (CH2), 77.8
12 Rf 0.46, petroleum ether–diethyl ether (1 : 1); [α]2D0 ϩ 5.5
(c 1.0, CHCl3); νmax (CHCl3)/cmϪ1 3490w, 1725s, 1715s, 1610w,
1275s, 1115s; δH (400 MHz, CDCl3) 1.72–2.30 (7H, 3-H, m),
2.87–2.97 (1H, m), 3.20–3.31 (1H, m), 3.87 (1H, broad s), 4.05
(1H, dd, J 1.3, 11.5), 5.23–5.38 (2H, m), 5.86–5.98 (1H, m),
6.04–6.10 (1H, m), 7.48 (2H, m), 7.60 (1H, m), 8.11 (2H, m);
δC (100.6 MHz, CDCl3) 23.0 (CH2), 25.2 (CH2), 25.6 (CH2),
36.6 (CH), 45.4 (CH), 45.5 (CH), 73.8 (CH), 76.0 (CH), 117.2
(CH2), 128.9 (CH), 130.1 (CH), 130.7 (C), 133.5 (CH), 135.1
(CH), 165.7 (C), 215.2 (C); m/z (FAB) 301 (MHϩ, 15%), 323
(MNaϩ, 13).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 3 – 1 0 9 7
1096

View Article Online
3 R. G. Salomon, Tetrahedron, 1983, 39, 485.
4 R. G. Salomon and J. K. Kochi, J. Am. Chem. Soc., 1973, 95,
1889.
(CH2), 81.3 (C), 86.3 (CH), 98.8 (CH), 102.4 (CH), 126.4 (CH),
128.6 (CH), 129.3 (CH), 138.3 (C); m/z (ES) 355 (MNaϩ, 100);
elemental analysis found C 68.58, H 6.88, C19H24O5 requires C
68.66, H 7.30%.
5 K. Langer and J. Mattay, J. Org. Chem., 1995, 60, 7256.
6 R. V. Bonnert and P. R. Jenkins, J. Chem. Soc., Chem. Commun.,
1987, 6; R. V. Bonnert, J. Howarth, P. R. Jenkins and N. J. Lawrence,
J. Chem. Soc., Perkin Trans. 1, 1991, 1225; A. J. Wood, P. R. Jenkins,
J. Fawcett and D. R. Russell, J. Chem. Soc., Chem. Commun., 1995,
1567; A. J. Wood, D. J. Holt, M.-C. Dominguez and P. R. Jenkins,
J. Org. Chem., 1998, 63, 8522; R. J. Bonnert, M. J. Davies,
J. Howarth and P. R. Jenkins, J. Chem. Soc., Chem. Commun., 1990,
148; R. J. Bonnert, M. J. Davies, J. Howarth and P. R. Jenkins,
J. Chem. Soc., Perkin Trans. 1, 1992, 27; A. J. Wood and P. R.
Jenkins, Tetrahedron Lett., 1997, 38, 1853; A. N. Boa, J. Clark, P. R.
Jenkins and N. J. Lawrence, J. Chem. Soc., Chem. Commun., 1993,
151.
21: mp 168–169 ЊC; Rf 0.25, petroleum ether–diethyl ether
(1 : 1); [α]2D0 ϩ 58.3 (c 4.6, CHCl3); νmax (CHCl3)/cmϪ1 2960m br,
1390m, 1200m, 1100s; δH (400MHz, CDCl3) 1.61 (1H, dd, J 4.6,
14.8), 1.79 (1H, m), 2.01 (1H, dd, J 0.8, 14.8), 1.98–2.12 (2H,
m), 2.54–2.66 (2H, m), 2.95 (1H, m), 3.38 (3H, s), 3.71–3.79
(2H, m), 4.01 (1H, dd, J 3.4, 9.3), 4.07 (1H, dd, J 7.0, 9.3), 4.35
(2H, m), 4.66 (1H, d, J 4.6), 5.61 (1H, s), 7.38–7.57 (5H, m); δC
(100.6MHz, CDCl3) 20.6 (CH2), 24.1 (CH2), 38.6 (CH2), 39.2
(CH), 48.7 (CH), 55.9 (CH3), 60.6 (CH), 70.2 (CH2), 73.8
(CH2), 81.4 (C), 81.5 (CH), 98.8 (CH), 101.9 (CH), 126.5 (CH),
128.5 (CH), 129.1 (CH), 138.3 (C); m/z (ES) 355 (MNaϩ, 100);
elemental analysis found C 68.41, H 7.27, C19H24O5 requires C
68.66, H 7.30%.
7 D. J. Holt, W. D. Barker, P. R. Jenkins, J. Panda and S. Ghosh, J. Org.
Chem., 2000, 65, 482; D. J. Holt, W. D. Barker, P. R. Jenkins,
D. L. Davies, S. Garratt, J. Fawcett, D. R. Russell and S. Ghosh,
Angew. Chem., Int. Ed. Eng., 1998, 104, 3298.
Configuration of diastereoisomers was confirmed by 2-D
NOESY experiments. 20 showed a significant NOE signal
between 7-H and 4-H, whereas 21 showed a significant NOE
signal between 7-H and 2ax-H.
8 S. Hanessian, Total Synthesis of Natural Products; The Chiron
Approach, Pergamon, Oxford, 1983; R. J. Ferrier and S. Middleton,
Chem. Rev., 1993, 93, 2779; J. C. Lopez and B. Fraser-Reid,
Chem.Commun., 1997, 2251.
9 For our preliminary communication of these results see : D. J. Holt,
W. D. Barker, P. R. Jenkins, S. Ghosh, D. R. Russell and J. Fawcett,
Synlett., 1999, S1, 1003.
10 S. Banerjee and S. Ghosh, J. Org. Chem., 2003, 68, 3981.
11 R. G. Salomon, M. F. Salomon, M. G. Zargorski, J. M. Reuter and
D. J. Coughlin, J. Am. Chem. Soc., 1982, 104, 998.
12 Crystallographic data for compounds 3a, 18a and 18b have been
deposited with the Cambridge Crystallographic Data Centre as
deposition numbers CCDC 110883, 110884 and 110885 respectively.
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: ϩ44
(0)1223–336–033; deposit@ccdc.cam.ac.uk].
Acknowledgements
We are grateful to the Engineering and Physical Sciences
Research Council, Pharmachemie BV (Haarlem, Holland) and
to the Indian National Science Academy/Royal Society (study
visit grant to S. Ghosh).
References
1 M. T. Crimmins, Chem. Rev., 1988, 88, 1453.
13 S. Hanessian and N. R. Plessas, J. Org. Chem., 1969, 34, 1035.
14 A. Vasella and B. Bernet, Helv. Chim. Acta, 1979, 62, 1990;
A. Vasella and B. Bernet, Helv. Chim. Acta, 1984, 67, 1328.
15 D. N. Kirk and C. R. McHugh, J. Chem. Soc., Perkin Trans. 1, 1978,
173.
16 L. Schor, S. M. Seldes and E. G. Gros, J. Chem. Soc., Perkin Trans.1,
1990, 163; L. Schor, S. M. Seldes and E. G. Gros, J. Chem. Soc.,
Perkin Trans.1, 1992, 453.
2 T. Bach, Synthesis, 1998, 683. For carbohydrate examples of the
enone olefin reaction see : D. R. Hicks, J. L. Primeau and B. Fraser-
Reid, Carbohydr. Res., 1982, 108, 41; M. Fetizon, D. D. Khac and
N. D. Tho, Tetrahedron Lett., 1986, 26, 1777; A. Tenaglia and
D. Barille, Synlett, 1995, 776; A. M. Gioomez, S. Mantecon,
S. Velazquez, S. Valerde, P. Herczegh and J. C. Lopez, Synlett, 1998,
1402.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 9 3 – 1 0 9 7
1097