Intramolecular [2+2] photocycloaddition reactions as an entry to the 2-oxatricyclo[4.2.1.04,9]nonan-3-one skeleton of lactiflorin

Article abstract of DOI:10.1002/asia.201200295

Two [2+2] photocycloaddition routes were evaluated as possible ways to access the tricyclic core structure found in the terpene monoglycoside lactiflorin. While the first route via γ-substituted cyclopentenones was quickly discarded, the reactions of racemic (5R*)-3-benzyloxy-5-but-3'- enyl-4-methoxycarbonylfuran-2(5H)-ones proceeded in high yields and with perfect diastereoselectivity. However, it turned out that the regioselectivity was strongly dependent on the substitution pattern within the but-3'-enyl chain, which connects the terminal olefinic double bond to the photoexcited butenolide chromophor. If the chain was unsubstituted or if a tert-butyldimethylsilyloxy group was placed at the 2' position in a syn-relationship to the existing stereogenic center (5R*,2'S*), the crossed product prevailed with regioselectivities of 89:11 to 69:31. If the tert-butyldimethylsilyloxy group was positioned at 2' in an anti-relationship to the existing stereogenic center (5R*,2'R*), the desired straight products were obtained in regioselectivities of 74:24 to 55:45 (61-83% yield). Following this route, the aglycon part of lactiflorin was obtained by an intramolecular [2+2] photocycloaddition and a subsequent hydrogenolysis in 53% yield. Its further conversion into the natural product after glycosylation included a methyl addition to the lactone carbonyl group, which was optimized to give the desired key intermediate in a yield of 70%. The further conversion to lactiflorin was achieved in four steps and with an overall yield of 49%.

Full text of DOI:10.1002/asia.201200295

DOI: 10.1002/asia.201200295
Intramolecular [2+2] Photocycloaddition Reactions as an Entry to the
2-Oxatricyclo[4.2.1.04,9]nonan-3-one Skeleton of Lactiflorin
Ping Lu, Eberhardt Herdtweck, and Thorsten Bach*[a]
Abstract: Two [2+2] photocycloaddi-
tion routes were evaluated as possible
ways to access the tricyclic core struc-
ture found in the terpene monoglyco-
side lactiflorin. While the first route via
g-substituted cyclopentenones was
quickly discarded, the reactions of rac-
emic (5R*)-3-benzyloxy-5-but-3’-enyl-
nolide chromophor. If the chain was
unsubstituted or if a tert-butyldimethyl-
silyloxy group was placed at the 2’ posi-
tion in a syn-relationship to the existing
stereogenic center (5R*,2’S*), the
crossed product prevailed with regiose-
lectivities of 89:11 to 69:31. If the tert-
butyldimethylsilyloxy group was posi-
tioned at 2’ in an anti-relationship to
ucts were obtained in regioselectivities
of 74:24 to 55:45 (61–83% yield). Fol-
lowing this route, the aglycon part of
lactiflorin was obtained by an intramo-
lecular [2+2] photocycloaddition and
a subsequent hydrogenolysis in 53%
yield. Its further conversion into the
natural product after glycosylation in-
cluded a methyl addition to the lactone
carbonyl group, which was optimized
to give the desired key intermediate in
a yield of 70%. The further conversion
to lactiflorin was achieved in four steps
and with an overall yield of 49%.
4-methoxycarbonylfuran-2ACTHUNTGRENNG(U 5H)-ones
proceeded in high yields and with per-
fect diastereoselectivity. However, it
turned out that the regioselectivity was
strongly dependent on the substitution
pattern within the but-3’-enyl chain,
which connects the terminal olefinic
double bond to the photoexcited bute-
the
existing
stereogenic
center
(5R*,2’R*), the desired straight prod-
Keywords: cycloaddition · glycosy-
lation · photochemistry · regioselec-
tivity · total synthesis
Introduction
alternative structures could be found in the literature for
this compound[9] added further zest to the synthetic efforts,
which we recently completed successfully.[10] The structure
of the natural product, as it was eventually proven by syn-
thesis, is depicted in Figure 1.
Terpenoid natural products frequently display a cyclobutane
ring as part of their structure, the formation of which occurs
biosynthetically by olefinic attack at a cationic carbon
center.[1] Synthetic access to cyclobutanes has been achieved
in many total syntheses by inter- and intramolecular [2+2]
photocycloaddition reactions of cyclic a,b-unsaturated car-
bonyl compounds.[2,3] Intermolecular [2+2] photocycloaddi-
tion reactions offer more versatility in the choice of poten-
tial substrates but they lack the regioselectivity, which is
commonly associated with intramolecular [2+2] photocy-
cloaddition reactions.[4] For the latter reactions, the forma-
tion of five-membered rings seems to be generally favored[5]
as a consequence of a fast ring closure from an intermediate
excited triplet species.[6] Exceptions to this ꢀrule of fiveꢁ are
known,[7] although it is difficult to predict when to expect
these exceptions.
Figure 1. Absolute and relative configuration of (+)-lactiflorin (1) as es-
tablished by total synthesis.
Regarding the synthesis of lactiflorin it is apparent that
the molecule can be dissected into a glycosidic part, which is
derived from d-glucose, and an aglycon, which bears an in-
teresting 2-oxatricyclo[4.2.1.04,9]nonan-3-one skeleton. Ret-
rosynthetically, a further disconnection of the tricyclic skele-
ton invites the use of intramolecular [2+2] photocycloaddi-
tion reactions. The core structure A, as depicted in
Scheme 1, can be disconnected horizontally to provide pre-
cursors of type B or vertically to lactones of type C. In both
cases the stereogenic center within the five-membered ring
was expected to provide a high facial diastereoselectivity. In
addition, the previously mentioned ꢀrule of five’[5] appeared
The unique structure of (+)-lactiflorin (1) as proposed by
Liang et al.[8] made this monoterpene glycoside an intriguing
target for total synthetic studies. The fact that two additional
[a] Dr. P. Lu, Dr. E. Herdtweck, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universitꢂt Mꢃnchen
Lichtenbergstraße 4, 85747 Garching (Germany)
Fax : (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200295.
Chem. Asian J. 2012, 00, 0 – 0
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Scheme 1. Retrosynthetic
disconnection
of
the
2-oxatricy-
clo[4.2.1.04,9]nonan-3-one core (A) related to the lactiflorin aglycon.
Scheme 2. Preparation of substrates rac-4 and rac-5 for an intramolecular
[2+2] photocycloaddition according to disconnection (i) (Scheme 1).
Exact reaction conditions: a) NEt3 (1.5 equiv), CH3COCOCl (2 equiv),
CH2Cl2, 08C!rt, overnight, 76%; b) TMSCl (1.3 equiv), NEt3
(1.5 equiv), CH2Cl2, 08C!rt, overnight, 83%; c) BzCl (2 equiv), NEt3
(3 equiv), DMAP (0.5 equiv), CH2Cl2, 79%. Bz=benzoyl, DMAP=4-di-
methylaminopyridine, TMS=trimethylsilyl.
to make the formation of the desired regioisomer likely. The
simple diastereoselectivity in [2+2] photocycloaddition reac-
tions is determined by the geometric restrictions of the cy-
clobutane ring and five-membered rings are normally found
to be cis-anellated to the four-membered ring.[2,11]
Further considerations concerned the introduction of the
functional group at C-7. In compounds of type B it seemed
reasonable to introduce the keto group from the very begin-
ning because cyclopentenones are known to be excellent
substrates for [2+2] photocycloaddition reactions.[2] In com-
pounds of type C the introduction of a vinyl ketone at an
early stage was discouraged due to its sensitivity to nucleo-
philic attack and due to its undesired, long-wavelength ab-
sorption. It seemed therefore sensible to introduce the func-
tional group at C-7 as protected hydroxy group.
In this manuscript we describe in detail our photosynthet-
ic studies towards the core of lactiflorin. It turned out that
the disconnection according to (i) in Scheme 1 was not feasi-
ble and, even more surprisingly, that the disconnection ac-
cording to (ii) led to severe regioselectivity issues in the
[2+2] photocycloaddition. In addition, we discuss the final
stages of our enantioselective lactiflorin synthesis comple-
menting our previous communication[10] on this topic.
tion appears to be the limited conformational freedom of
the carboxylate linkage, which prevents a proper positioning
of the acrylate double bond to the photoexcited enone.
Indeed, there is no precedent for this type of ring closure in
the literature.
Preliminary Experiments with Substrates of Type C
The intramolecular reaction of substrates of type C was
slightly better precedented. In our own work on tetronate
[2+2] photocycloadditon chemistry, we had successfully em-
ployed a g-butenyl-substituted tetronate that produced a dia-
stereomerically pure product in good yield (75%).[14] The re-
gioselectivity was in line with the ꢀrule of fiveꢁ and only
a straight [2+2] photoproduct could be detected. Support
for a successful [2+2] photocycloaddition was also found by
previous [2+2] photocycloaddition reactions of other g-bu-
tenyl-substituted a,b-unsaturated g-lactones (butenolides)[15]
and by a related intramolecular allene [2+2] photocycload-
dition.[16] In the work of Figueredo, Font et al. three g-substi-
tuted a,b-unsaturated butenolides were studied. The [2+2]
photocycloaddition proceeded with high diastereoselectivity
and with a clear preference for the straight product.[15c]
a,b,g-Trisubstituted a,b-unsaturated lactones rac-8 and
rac-10, unsubstituted at the allylic position, were chosen as
initial model substrates of type C. The syntheses began with
the known b-hydroxy ester methyl 3-hydroxyhept-6-enoate
(rac-6)[17] (Scheme 3). Cyclization of an in situ generated
Results and Discussion
Access to Precursors of Type B
The syntheses of g-substituted cyclopentenones of type B
commenced with the known enone 4-hydroxy-2-cyclopent-
en-1-one (rac-2)[12] (Scheme 2). Esterification with pyruvic
acid chloride afforded rac-3, which was exposed to TMSCl
or BzCl under basic conditions furnishing the corresponding
enol derivatives rac-4 or rac-5 in high yields.
Pyruvate-derived silyl enol ethers have been shown to be
reliable olefin components in intermolecular [2+2] photocy-
cloaddition reactions with quinolone or cyclohexenone.[13]
The intramolecular reaction of rac-4 or rac-5 was not feasi-
ble, however. The irradiation of rac-4 at l=254 nm or l=
300 nm led exclusively to its decomposition. We initally as-
sumed that the low chemoselectivity may be attributable to
the labile trimethylsilyl group. Disappointingly, precursor
rac-5, in which the trimethylsilyl group was replaced by
a more stable benzoyl group, did not give any isolable cyclo-
addition products either. For both substrates the irradiation
conditions (solvent, wavelength, and sensitizer) were broad-
ly varied. The most likely reason for the failure of the reac-
1,3-bisACHTNUTRGNE(NUG silyloxy)alk-1-ene with oxalyl chloride provided bu-
tenolide 7.[18] The latter was subsequently O-benzylated,
giving lactone rac-8 in 71% yield. Butenolide rac-10 was ob-
tained in a three-step sequence involving saponification, re-
duction to primary alcohol,[19] and benzoylation in 47%
overall yield.
Irradiation of rac-8 smoothly afforded [2+2] photocy-
cloaddition products at l=300 nm in moderate to excellent
yields (entries 1–6, Table 1). Various solvents were screened
and the reaction provided the best yield when acetonitrile
was used as solvent together with acetone as sensitizer
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ACHTUNGTRENNUNG[2+2] Photocycloaddition of Butenolides
tries 3 and 4, Table 1) to 15:85 in acetone (entry 5, Table 1).
The reaction was much slower without acetone as sensitizer
but the sensitization did not significantly change the regiose-
lectively. Sensitization also helped to increase the reaction
rate in the [2+2] photocycloaddition of the benzoyloxymeth-
yl-substituted substrate rac-10 (entries 7–10, Table 1). The
relative ratio of straight-to-crossed isomer (rac-13:rac-14)
was slightly enhanced compared with rac-8 but still re-
mained unfavorable in view of the intended application.
These preliminary experiments were performed only on ana-
lytical scale but it was shown for the best examples (en-
tries 6 and 9, Table 1) that yields of isolated products are in
the same range as the NMR yields.
The separation of the regioisomers was facile and the
products could be obtained as spectroscopically homoge-
nous compounds. Since there were some contradictory sig-
nals in the HMBC (heteronuclear multiple bond correla-
tion) spectra of the photocycloaddition products and no ob-
vious conclusions could be drawn from NOE (nuclear Over-
hauser effect) experiments, we sought to prove the constitu-
tion and configuration of the products by single-crystal X-
ray crystallography. The assignment was based on alcohol
rac-16 (Scheme 4), which was prepared from product rac-14
Scheme 3. Preparation of [2+2] photocycloaddition substrates from b-hy-
droxyketoester rac-6. Exact reaction conditions: a) LDA (2.2 equiv),
TMSCl (2.5 equiv), THF, ꢀ788C!rt, 19 h; then (COCl)2 (1 equiv),
CH2Cl2, ꢀ788C!rt, 21 h, 69%; b) NaH (2 equiv), BnBr (2 equiv), DMF,
rt, 21 h, 71%; c) Ba(OH)2·8H2O (5 equiv), THF/H2O, 48 h, 74%;
d) NMM (1 equiv), ClCO2Me (1 equiv), THF, ꢀ108C, 0.5 h; then NaBH4
(3 equiv), MeOH, 08C, 0.5 h, 68%; e) BzCl (1.5 equiv), DMAP
(0.2 equiv), NEt3 (2 equiv), CH2Cl2, 08C ! rt, 1 h, 96%. Bn=benzyl,
LDA=lithium diisopropylamide, NMM=N-methylmorpholine.
Table 1. Preliminary [2+2] photocycloaddition experiments with sub-
strates rac-8 (R=COOMe) and rac-10 (R=CH2OBz).
Entry[a] Substrate Solvent(s)
t [h][b] Product Yield [%][c] r.r.[d]
[rac-]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
rac-8
rac-8
rac-8
rac-8
rac-8
rac-8
rac-10
rac-10
rac-10
rac-10
Et2O
3
3
3
3
0.5
1.5
22
8
2
2
11:12
11:12
11:12
11:12
11:12
11:12
13:14
13:14
13:14
13:14
53
75
46
86
19:81
25:75
26:74
26:74
15:85
18:82
31:69
33:67
33:67
35:65
toluene
MeOH
CH2Cl2
ac
MeCN/ac
CH2Cl2
CH2Cl2/ac
MeCN/ac
MeCN/ac[g]
92
97[e]
70
Scheme 4. Structure proof of [2+2] photocycloaddition products rac-12
and rac-14 by conversion to alcohol rac-16. Exact reaction conditions:
a) K2CO3 (5 equiv), MeOH, rt, 16 h, 87%; b) NMM (1 equiv), ClCO2Me
(1 equiv), THF, ꢀ108C, 0.5 h; then NaBH4 (3 equiv), MeOH, 08C, 0.5 h,
83%; c) BzCl (1.5 equiv), DMAP (0.2 equiv), NEt3 (2 equiv), CH2Cl2,
08C!rt, 1 h, 94%; d) 10% Pd/C (0.5 equiv), H2, EtOH, 2 h, 84%.
70
78[f]
63
10
[a] All reactions were conducted using a RPR-100 reactor with 16 Rayo-
net RPR-3000 ꢅ lamps (Duran filter) as the irradiation source in deaer-
ated solvent (c=5 mm). Solvent mixtures included acetonitrile/acetone
(11:1) or dichloromethane/acetone (1:1). [b] Elapsed reaction time to
achieve 100% conversion of the starting material. [c] The product yield
was determined by crude NMR using mesitylene as internal standard.
[d] The regioisomeric ratio (r.r.) of the crude product was determined by
1H NMR spectroscopy. [e] 91% Yield in a preparative run. [f] 70% Yield
in a preparative run. [g] The reaction was performed in quartz but not in
Duran tubes.
by hydrogenolysis. In turn, compound rac-12 could be easily
transformed to rac-14 in a three-step sequence (saponifica-
tion, reduction, and benzoylation)[19] via primary alcohol
rac-15 (68% overall yield), thus establishing an immediate
correlation between the two major regioisomers of the
[2+2] photocycloaddition.
Tertiary alcohol rac-16 turned out to be a crystalline solid
and its core structure was shown to be the 9-oxatricy-
clo[4.3.0.04,7]nonan-8-one skeleton of a crossed photocy-
cloaddition product by single-crystal X-ray crystallography.
In addition, the crystal structure confirmed unambiguously
the relative configuration (Figure 2).
(ratio 11:1; entry 6, Table 1). In contrast to the above-men-
tioned literature precedent,[14–16] the main product in these
reactions was found to be the crossed product rac-12 (see
below). The regioisomeric ratio (r.r.=rac-11:rac-12) varied
minimally ranging from 26:74 in MeOH and CH2Cl2 (en-
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Figure 2. Structure of alcohol rac-16 in the crystal (ORTEP drawing with
50% ellipsoids).
ACHTUNGTRENNUNG
Since the regioselectivity of the [2+2] photocycloaddition
can depend on minimal changes in the substitution pattern
of the substrate and although the photocycloaddition reac-
tion of butenolides rac-8 and rac-10 had favored crossed
products, we performed a more comprehensive study with
substrates that already bear the oxygen functionality at C-7
of the desired skeleton (Scheme 1). Along these lines, lac-
tones rac-21 and rac-23, which show an opposite 1,3-diol-
type relationship to the stereogenic center at the lactone,
were synthesized.
Scheme 6. Preparation of [2+2] photocycloaddition substrates from syn-
diol rac-18a and anti-diol rac-18b. Yields on top refer to the syn-series,
yields on the bottom to the anti-series. Exact reaction conditions:
a) TBSOTf (1.05 equiv), 2,6-lutidine (3 equiv), CH2Cl2, ꢀ788C, 4 h, 77%
(rac-19a) or 90% (rac-19b); b) LDA (2.2 equiv), TMSCl (2.5 equiv),
THF, ꢀ788C!rt, 19 h; then (COCl)2 (1 equiv), CH2Cl2, ꢀ788C!rt, 21 h,
55% (rac-20a) or 61% (rac-20b); c) NaH (2 equiv), BnBr (2 equiv),
DMF, rt, 21 h, 60% (rac-21a) or 67% (rac-21b); d) Ba(OH)2·8H2O
(5 equiv), THF/H2O, 60 h; e) NMM (1 equiv), ClCO2Me (1 equiv), THF,
ꢀ108C, 0.5 h; then NaBH4 (3 equiv), MeOH, 08C, 0.5 h, 61% (rac-22a
from rac-21a) or 45% (rac-22b from rac-21b); f) BzCl (1.5 equiv),
DMAP (0.2 equiv), NEt3 (2 equiv), CH2Cl2, 08C!rt, 1 h, 99% (rac-23a)
or 91% (rac-23b). TBSOTf=tert-butyldimethylsilyl trifluoromethanesul-
fonate.
Selective syn-reduction of the known methyl 5-hydroxy-3-
oxo-6-heptenoate (rac-17)[20] to product rac-18a could be
easily realized with Et2BACTHNUTRGNEUNG
(OMe)/NaBH4,[21] and reduction
with NMe4BHACHTUNGTRENNUNG(OAc)3 led anti-selectively to 1,3-diol rac-18b
(Scheme 5).[22] The syntheses of syn- and anti-photocycload-
Table 2) the photocycloaddition was — under identical con-
ditions — much slower than with the unsubstituted precur-
sors. Specifically, in the case of rac-23a the reaction did not
go to completion (entries 3 and 4, Table 2). Sensitization im-
proved the performance of the reactions and product forma-
tion was complete within two (entry 2, Table 2) or two and
a half hours (entry 5, Table 2). The preference in favor of
the crossed products was even more pronounced than ob-
served with the unsubstituted substrates rac-8 and rac-10.
The NOE analysis of crossed product rac-25a or rac-27a
showed a characteristic signal (see below) between two hy-
drogen atoms at each of the two methylene groups. The
HMBC spectra, however, led to considerable ambiguities.
Thus, further transformations were conducted to confirm
the product structures.
The conversion of rac-25a into rac-27a was achieved in
high yield following a procedure (Scheme 7) similar to that
depicted in Scheme 4. Saponification of ester rac-25a deliv-
ered the free carboxylic acid rac-28a, which was reduced
after activation via the respective anhydride to a primary al-
cohol,[19] which in turn was O-benzoylated to compound rac-
27a. Upon hydrogenolysis, the liberated tertiary alcohol rac-
29a could be obtained in 87% yield.
Scheme 5. Preparation of the syn-diol rac-18a and the anti-diol rac-18b
from b-hydroxyketone rac-17. Exact reaction conditions: a) NaBH4
(1.05 equiv), Et2BOMe (1.05 equiv), THF/MeOH, ꢀ788C, 74%;
b) Me4NHB
(OAc)3 (5 equiv), CH3CN/HOAc, ꢀ358C, 44 h, 88%.
dition precursors followed an identical synthetic scheme
starting from the corresponding diols (Scheme 6). Selective
mono-TBS protection[23] of the 1,3-diols rac-18 led to b-hy-
droxy esters rac-19 in good yield. Treatment of compounds
rac-19 with LDA and TMSCl generated 1,3-bisACTHUNRTGNEUNG(silyloxy)alk-
1-enes, which were cyclized with oxalyl chloride[18] to pro-
vide butenolides rac-20. Subsequent O-benzylation pro-
duced lactones rac-21 in moderate yields. The photocycload-
dition precursors rac-23 were subsequently obtained in
a three-step sequence[19] in good overall yields.
In close analogy to the above-mentioned model studies,
the reaction of syn-substrates rac-21a and rac-23a favored
the corresponding crossed products rac-25a and rac-27a (en-
tries 1–5, Table 2). Without sensitization (entries 1, 3, and 4,
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ACHTUNGTRENNUNG[2+2] Photocycloaddition of Butenolides
Table 2. Diastereoselective [2+2] photocycloaddition of syn-substrates
rac-21a (R=COOMe) and rac-23a (R=CH2OBz).
Figure 3. Structure of alcohol rac-30a in the crystal (ORTEP drawing
with 50% ellipsoids).
Entry[a] Substrate Solvent(s) t [h][b] Product Yield [%][c] r.r.[d]
AHCTUNGTRENGN[UN rac-]
Table 3. Diastereoselective [2+2] photocycloaddition of anti-substrates
rac-21b (R=COOMe), rac-22b (R=CH2OH), and rac-23b (R=
CH2OBz).
1
2
3
4
5
rac-21a
rac-21a
rac-23a
rac-23a
rac-23a
CH2Cl2
MeCN/ac
CH2Cl2
CH2Cl2
9
2
24
46
24a:25a 66
24a:25a 64
26a:27a 45[e]
26a:27a 53[f]
26a:27a 66
26:74
19:81
21:79
11:89
15:85
MeCN/ac 2.5
[a] All reactions were conducted using a RPR-100 reactor with sixteen
Rayonet RPR-3000 ꢅ lamps (Duran filter) as the irradiation source in
deaerated dichloromethane or acetonitrile/acetone (11:1) as the solvent
(c=5 mm). [b] Elapsed reaction time to achieve 100% conversion of the
starting material. [c] Yield of isolated product. [d] The regioisomeric
ratio (r.r.) of the crude product was determined by 1H NMR spectrosco-
py. [e] Incomplete reaction; 34% of the starting material was recovered.
[f] Incomplete reaction; 11% of the starting material was recovered.
Entry[a] Substrate Solvent(s) t [h][b] Product Yield [%][c] r.r.[d]
AHCTUNGTRENGN[UN rac-]
1
2
3
4
5
rac-21b
rac-21b
rac-22b
rac-23b
rac-23b
CH2Cl2
9
2
2
22
2
24b:25b 75
24b:25b 67
31b:32b 61
26b:27b 80
26b:27b 83
49:51
55:45
66:34
70:30
72:28
MeCN/ac
MeCN/ac
CH2Cl2
MeCN/ac
[a] All reactions were conducted using a RPR-100 reactor with 16 Rayo-
net RPR-3000 ꢅ lamps (Duran filter) as the irradiation source in deaer-
ated dichloromethane or acetonitrile/acetone (11:1) as the solvent (c=
5 mm). [b] Elapsed reaction time to achieve 100% conversion of the
starting material. [c] Yield of isolated product. [d] The regioisomeric
ratio (r.r.) of the crude product was determined by 1H NMR spectrosco-
py.
reaction of rac-23b in different solvents with or without ace-
tone as sensitizer (entries 4 and 5, Table 3). The reaction of
debenzoylated alcohol rac-22b gave a similar regioselectivi-
ty, but the product yield was lower (entry 3, Table 3).
NOE experiments of crossed product rac-25b also showed
a characteristic signal (see below) between two hydrogen
atoms at the two methylene groups. The structure was fur-
ther unambiguously confirmed by single-crystal X-ray crys-
tallography (Figure 4).
However, the photocycloaddition products rac-26b and
rac-27b were inseparable at this stage. It has to be stressed
that this was the only instance in all cases studied, in which
the regioisomers were not separable. Therefore, the subse-
quent hydrogenolysis of the product mixture was performed
with the expectation that the tertiary alcohols might be
better separable. Indeed, this turned out to be feasible and
further optimization studies were performed aiming at a con-
venient two-step access to diastereomerically pure alcohol
rac-33b (Table 4). The ratio of regioisomers varied slightly
but there was no apparent trend to be observed (entries 1–4,
Table 4). The higher reaction rate observed with acetone as
co-solvent (entry 5, Table 4) and the satisfactory regioselec-
Scheme 7. Structural proof of [2+2] photocycloaddition products rac-25a
and rac-27a by conversion into alcohol rac-29a. Exact reaction condi-
tions: a) K2CO3 (7 equiv), MeOH, 608C, 9 h, 89%; b) NMM (1 equiv),
ClCO2Me (1 equiv), THF, ꢀ108C, 0.5 h; then NaBH4 (3 equiv), MeOH,
08C, 0.5 h; c) BzCl (1.5 eq), DMAP (0.2 eq), NEt3 (2 equiv), CH2Cl2,
08C!rt, 1 h, 72% (over two steps); d) 10% Pd/C, H2, EtOH, 87%.
Compound rac-29a turned out to be a crystalline solid. Its
constitution and relative configuration was unambiguously
proven by single-crystal X-ray crystallography (see the Sup-
porting Information). In addition, the structure of straight
product rac-30a, which was obtained upon treatment of rac-
26a with Pd/C under 1 atm of hydrogen (99%), was con-
firmed by single-crystal X-ray crystallography (Figure 3).
Gratifyingly, the reaction of anti-precursors rac-21b–rac-
23b largely enhanced the ratio of straight relative to crossed
products (entries 1–5, Table 3). As in the previous cases,
a significant rate increase was observed when acetone was
used as a sensitizing co-solvent. The reaction of rac-21b af-
forded a 1:1 mixture of regioisomers in good yield (entries 1
and 2, Table 3). The straight product rac-27b dominated the
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Figure 4. Structure of alcohol rac-25b in the crystal (ORTEP drawing
with 50% ellipsoids).
tivity made these conditions the conditions of choice. Even-
tually, the reaction delivered aglycon rac-33b as a single dia-
stereomer in 53% yield over two steps.
Despite the fact that NMR experiments suggested the
constitution and relative configuration of tertiary alcohol
rac-33b¸ it was — given its importance for the progress of
the total synthesis — extremely useful that this compound
Figure 5. Structure of alcohol rac-33b in the crystal (ORTEP drawing
with 50% ellipsoids).
2
ple, it was observed that the J coupling constant of protons
H-5 within the cyclobutane ring provides clear evidence of
the product constitution (straight or crossed). All straight
products D (Figure 6) display a geminal coupling constant
Table 4. Conversion of substrate rac-23b into diastereomerically pure al-
cohol rac-33b by [2+2] photocycloaddition and subsequent hydrogenoly-
sis.
2
of J=12.5–14.0 Hz, while crossed products E exhibit a cou-
Entry[a]
Solvent(s)
t [h][b]
r.r.[c]
Yield [%][d]
1
2
3
4
5
6
CH2Cl2
CH2Cl2
MeCN
CH2Cl2/hex
MeCN/ac
MeCN/ac
22
74:26
72:28
69:31
74:26
71:29
72:28
40
36
45
40
53
43
8.5[e]
15.5
14
Figure 6. Three-dimensional
representation
of
the
2-oxatricy-
clo[4.2.1.04,9]nonan-3-one skeleton
D
and of the 9-oxatricy-
clo[4.3.0.04,7]nonan-8-one skeleton E formed in the intramolecular [2+2]
photocycloaddition. Characteristic JHH couplings and the characteristic
NOE contact between H-2 and H-5 in crossed skeleton E are marked.
The CH2OBz/COOMe group was omitted for clarity.
2
1[e]
[a] All photochemcial reactions were conducted using a RPR-100 reactor
with 16 Rayonet RPR-3000 ꢅ lamps (Duran filter) as the irradiation
source in deaerated solvent (c=5 mm). Solvent mixtures included aceto-
nitrile/acetone (11:1) or dichloromethane/hexane (1:1). [b] Elapsed reac-
tion time to achieve 100% conversion of the starting material in the
[2+2] photocycloaddition. [c] The regioisomeric ratio (r.r.) of the crude
product mixture (rac-33b/rac-34b) was determined by H NMR spectros-
copy. [d] Yield of isolated product rac-33b. [e] The reaction was per-
formed in quartz but not in Duran tubes.
pling constant of 2J=10.1–10.5 Hz (see the Supporting Infor-
mation for further details). Further coupling constants of hy-
drogen atoms H-5 proved that proton H-6 and its adjacent
cis-proton at C-5 are almost synperiplanar in structure D.
The coupling constant 3Jc varies between 10.5 Hz and
11.1 Hz. The trans coupling constant in the straight products
1
3
turned out to be a crystalline solid, the relative configura-
tion of which was unambiguously proven by single-crystal
X-ray crystallography (Figure 5).
D is clearly detectable at Jt ffi 4 Hz, whereas the coupling is
not observed for the trans-protons H-5 and H-4 in com-
ꢀ
pound E. The dihedral angle between the respective C H
bonds appears to be close to 908. The cis coupling for H-4
and the respective proton H-5 was found to be 3Jc =6.1–
6.8 Hz in structure E. The coupling constant of H-6 and H-7
is relatively large (3J ffi 7 Hz) for straight products D derived
from syn-diol rac-18a and smaller (3J ffi 3.5 Hz) for straight
products derived from anti-diol rac-18b. A similar trend was
observed for the coupling of H-4 to the vicinal proton H-3
in structure E.
Structure and Mechanistic Discussion
All cycloaddition products could be safely assigned based
on crystallographic data and based on synthetic transforma-
tions connecting the individual products. With these data in
hand, it was possible to analyze in retrospective the NMR
data of the cyclobutane products in more detail. For exam-
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ACHTUNGTRENNUNG[2+2] Photocycloaddition of Butenolides
COSY (correlation spectroscopy) data allowed us to dis-
Font et al., who detected a similar but less pronounced
tinguish the methylene protons at C-8 in structure D and at
C-2 in structure E. In a similar fashion the methylene pro-
tons at C-5 could be distinguished in both structures (see
above). The characteristic NOE contact between H-2 and
H-5, which was mentioned previously, is depicted in struc-
ture E. A more extensive discussion of relevant NOESY sig-
nals can be found in the Supporting Information.
effect with a methyl substituent at the a-carbon atom.[15c]
Enantioselective Preparation of Starting Materials, Lactol
Formation, and Completion of the Synthesis
The synthesis of enantiopure aglycon 33b commenced with
known
(2’R)-2,2-dimethyl-6-(2’-hydroxybut-3-enyl)-1,3-
The efficient sensitization with acetone as a co-solvent
strongly suggests that the [2+2] photocycloaddition occurs
via an excited triplet state intermediate, which is best de-
scribed by a pp* state located at the a,b-unsaturated lactone
double bond. Further product formation should occur via
1,4-biradicals to the respective cyclobutanes.[24] When ana-
lyzing the different regioselectivities in the photocycloaddi-
tion of b-benzoyloxymethyl-substituted substrates 10, 23a,
and 23b, it is evident that a chair-like conformation is feasi-
ble, in which the internal carbon atom of the olefin and the
b-carbon atom of the lactone are ideally positioned to form
a 1,4-biradical by five-membered ring closure (path I in
Scheme 8). Biradicals of this type lead to the respective
straight products 13, 26a, and 26b. A distortion of the con-
dioxin-4-one (35)[25] (Scheme 9). Refluxing of dioxinone 35
and methanol in toluene provided ketoester 18 in 78%
yield. The further conversion of compound 18 into product
33b was performed as depicted for the racemic compound
in Scheme 6 and Table 4.
Scheme 9. Preparation of enantiomerically pure alcohol 18 from litera-
ture-known[25] 1,3-dioxin-4-one 35. Exact reaction conditions: Methanol
(2.8 equiv), toluene, reflux, 3 h, 78%.
Glucosylation attempts were extensively surveyed with
various glycosyl donors bearing different leaving groups (at
C-1’) and neighboring groups (at C-2’) derived from d-glu-
cose. Glucosyl donor 36 with N-phenyltrifluoroacetimidate
(PTFAI)[26] as leaving group at C-1’ and the 2-chloro-2-
methylpropanoyl group[27] as protecting group for the alco-
hol at C-2’ delivered the highest yield of b-glucoside 37b
(26%) together with a-anomer 37a (Scheme 10), which was
obtained in 44% yield.
The lactone moiety in 37b was supposed to be strained
and was expected to react most readily with methyl lithi-
um.[28] It was found, however, that the benzoate group in
37b was much more easily removed under addition condi-
tions. Exposure to four equivalents of methyl lithium gave
three products in varying amounts (Figure 7): diol 38 with
the lactone ring intact, lactol 39 with the C-2’ ester group
intact, and the completely deacylated lactol 40. Lactol 40
could be smoothly cyclized to the single diastereomer 41
under mild acidic conditions in quantitive yield.
Scheme 8. Conformations of substrates 10 and 23 and putative 1,4-biradi-
cals en route to straight products 13 and 26 and crossed products 14 and
27. Major products are underlined.
formation that brings the terminal carbon atom of the olefin
closer to the b-carbon atom of the lactone can lead to the al-
ternative crossed 1,4-biradical, which should be thermody-
namically favored (secondary vs. primary radical). It appears
that the required conformation in favor of path I is best en-
forced in compound 23b because the TBSO group is equa-
torially positioned. In the absence of this enforcing effect
and, most severely, in a situation in which the TBSO group
suffers severe 1,3-diaxial interactions with the Cg-oxygen
bond of the lactone, as for substrate 23a, the internal
carbon atom moves away from the b-carbon atom of the lac-
tone and path II is preferred. The relative high stability of
the radical center in a-position to the lactone may increase
this preference because it allows for the correction of a disfa-
vored 1,4-biradical formation by retrocleavage.
Even in CDCl3 solution, a rapid conversion of lactol 40
into product 41 was observed and no lactol signal was de-
1
tected in the H NMR spectrum. Lactol 39 could be trans-
formed to acetal 41 after removal of the 2-chloro-2-methyl-
propanoyl group (K2CO3, MeOH/THF) via lactol 40. The
best way to convert compound 37b into the pentacyclic
product 41 was found to be the successive treatment of the
former compound with an excess of methyl lithium (13
equiv) at ꢀ788C in THF and then with pyridinium para-tol-
uenesulfonate (PPTS) in CH2Cl2. By this means, acetal 41
could be obtained in 70% yield. Methyl addition to the in-
termediate lactol or its open aldehyde form was not ob-
served under these conditions.
The fact that the benzyloxy group at the a-carbon atom
of the butenolide partially deteriorates the expected ꢀrule of
fiveꢁ selectivity is in line with the findings of Figueredo,
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Scheme 11. Completion of the total synthesis of (+)-lactiflorin (1) in four
steps, starting from primary alcohol 41. Exact reaction conditions:
a) NEt3 (5 equiv), DMAP (1 equiv), BzCl (5 equiv), CH2Cl2, 18 h, 88%;
b) TBAF (3.4 equiv), THF, rt, 2 h; c) DMP (3 equiv), NaHCO3 (8 equiv),
CH2Cl2, rt, 4 h, 81%; d) Pd(OH)2/C, H2, EtOH, rt, 4 h, 99%. TBAF=
tetra-n-butylammonium fluoride, DMP=Dess–Martin periodinane.
Scheme 10. Glycosylation of alcohol with glucosyl donor 36 to form b-
anomer 37b together with a-anomer 37a. Exact reaction conditions: 36
(3 equiv), TBSOTf (0.4 equiv), 4 ꢅ MS, hexane/CH2Cl2, 08C, 12 h, 26%
for 37b, and 44% for 37a.
can significantly alter the regioselectivity of a [2+2] photo-
cycloaddition. In our specific example, model studies with
unsubstituted substrates such as rac-8 and rac-10 had hinted
clearly at an undesired regiochemical outcome and might
have led to a premature change in synthetic strategy. Thus,
the need for substrates that are not only close to the real
target molecules but are indeed intermediates in a projected
total synthesis has been — once again — manifested and
seems to be particular important for photocycloaddition re-
actions as key steps in natural product synthesis. With the
appropriately substituted [2+2] photocycloaddition precur-
sor 23b, it was possible to establish the desired 2-oxatricy-
clo[4.2.1.04,9]nonan-3-one skeleton en route to lactiflorin.
The three stereogenic centers at the cyclobutane core of the
natural product were all established with perfect diastereo-
selectivity in the [2+2] photocycloaddition step. The effi-
cient synthesis of the aglycon (nine steps from known com-
pound 35; 6% overall yield) makes this approach very at-
tractive, in particular if the biological activity of aglycon is
to be studied separately. The yield in the further conversion
into (+)-lactiflorin was hampered by the unsatisfactory glu-
cosylation reaction, which could not be improved. The fur-
ther transformation could be optimized, however, and ena-
bled the synthesis to be completed in five steps from glyco-
side 37b and in an overall yield of 49%.
Figure 7. Possible products 38–41 in the reaction of glucoside 37b with
methyl lithium.
Benzoylation of the primary alcohol 41 followed by liber-
ation of the secondary alcohol at C-7 and oxidation with
Dess–Martin periodinane (DMP)[29] smoothly gave the triply
benzylated ketone 43 (Scheme 11). Global debenzylation
with Pearlmanꢁs catalyst[30] gave lactiflorin 1.
The structure of lactiflorin was finally confirmed by com-
parison with the reported spectra.[10] The assignment was
further corroborated by the preparation of lactiflorin triace-
tate, which was obtained upon treatment of triol 1 with
acetic anhydride in pyridine (59% yield).
Experimental Section
General
Conclusions
All reactions involving moisture-sensitive chemicals were carried out in
flame-dried glassware in dried solvents with magnetic stirring under
argon. Tetrahydrofuran (THF), diethyl ether (Et2O), and dichlorome-
thane (CH2Cl2) were purified by using a SPS-800 solvent purification
system (M. Braun). Diisopropylamine was distilled over calcium hydride.
All other chemicals were used as received. TLC was performed on silica-
In summary, the present study has shown the subtle differ-
ences that can influence the outcome of an intramolecular
[2+2] photocycloaddition. Conformational factors, which
disfavor five-membered ring closure, together with stabiliz-
ing substituents at the putative 1,4-biradical intermediates
coated glass plates (silica gel 60 F254
) with detection by UV light
(254 nm) or ceric ammonium molybdate (CAM) with subsequent heat-
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ACHTUNGTRENNUNG[2+2] Photocycloaddition of Butenolides
ing. Flash chromatography was performed on silica gel 60 (Merck, 230–
400 mesh) with the indicated eluent. All solvents for chromatography
were distilled prior to use. Compounds rac-2,[12] rac-6,[17] rac-17,[20] rac-
18a[21], and 35[25] are literature-known. The preparation and analytical
data of all new compounds are reported below or in the Supporting In-
formation. IR spectra were recorded on a JASCO IR-4100 spectrometer
(ATR) and MS/HRMS measurements were performed on a Finnigan
MAT 8200 (EI), a Finnigan MAT 95S (HR-EI), a Finnigan LCQ classic
(ESI), or a Thermo Finnigan LTQ FT mass spectrometer (HRMS-ESI),
respectively. 1H and 13C NMR spectra were recorded in CDCl3 at 303 K,
either on a Bruker AV-360 or a Bruker AV-500 spectrometer. The chemi-
cal shifts are reported relative to CHCl3 (d=7.26 ppm) or C6H6 (d=
7.16 ppm). Apparent multiplets that occur as a result of the accidental
equality of coupling constants to those of magnetically nonequivalent
protons are marked as virtual (virt). If clearly visible, virtual doublets in
para-substituted arenes were also assigned and marked as virtual (virt).
The multiplicities of 13C NMR signals were determined by DEPT experi-
ments, and assignments are based on COSY, HMBC, and HSQC experi-
ments. Melting points were measured on a Koffler Thermopan and are
uncorrected.
Intramolecular photocycloaddition reaction of butenolide rac-8: The re-
action of butenolide rac-8 (20.0 mg, 0.0662 mmol) in CH3CN/acetone
(11:1, 13 mL) afforded straight product rac-11 (3.2 mg, 16%) and crossed
product rac-12 (15.0 mg, 75%) after flash chromatography (eluent: pen-
tane/EtOAc=7:1).
(1R*,4R*,6R*,9R*)-4-Benzyloxy-9-methoxycarbonyl-2-oxatricy-
clo[4.2.1.04,9]nonan-3-one (rac-11): Rf =0.22 (Pentane/EtOAc=7:1,
CAM); 1H NMR (500 MHz, CDCl3): d=7.35–7.27 (m, 5H, CH2Ph), 5.38
(d, J=3.6 Hz, 1H, H-1), 4.58 (d, J=10.8 Hz, 1H, CHHPh), 4.52 (d, J=
10.8 Hz, 1H, CHHPh), 3.73 (s, 3H, CO2Me), 3.10 (virt. tdd, Jffi9.7, 6.9,
2.8 Hz, 1H, H-6), 2.84 (dd, J=12.8, 10.5 Hz, 1H, HH-5), 2.35–2.21 (m,
2H, HH-7, HH-8), 2.13 (dd, J=12.8, 2.8 Hz, 1H, HH-5), 1.80 (dddd, J=
14.3, 12.1, 8.3, 3.6 Hz, 1H, HH-8), 1.68–1.58 ppm (m, 1H, HH-7);
13C NMR (91 MHz, CDCl3): d=175.2 (C-3), 169.0 (CO2Me), 136.8 (Ph),
128.3 (Ph), 127.9 (Ph), 127.6 (Ph), 85.0 (C-1), 79.7 (C-4), 68.0 (CH2Ph),
63.4 (C-9), 52.6 (CO2Me), 36.6 (C-8), 35.4 (C-5), 33.2 (C-6), 29.9 ppm (C-
7); IR (ATR): n˜ =2951, 2941, 2878, 1770, 1725, 1497, 1435 cmꢀ1; MS (EI,
70 eV): m/z (%)=302 (0.8) [M+], 91 (100) [C7H7+]; HRMS (EI):
C17H18O5 [M+] calcd. 302.1149, found 302.1150.
(1R*,4S*,6R*,7R*)-7-Benzyloxy-6-methoxycarbonyl-9-oxatricy-
clo[4.3.0.04,7]nonan-8-one (rac-12): Rf =0.11 (Pentane/EtOAc=7:1,
CAM); 1H NMR (500 MHz, C6D6): d=7.51 (d, J=7.4 Hz, 2H, CH2Ph),
7.27 (t, J=7.4 Hz, 2H, CH2Ph), 7.18 (t, J=7.4 Hz, 1H, CH2Ph), 4.95 (d,
J=11.2 Hz, 1H, CHHPh), 4.91 (s, 1H, H-1), 4.83 (d, J=11.2 Hz, 1H,
CHHPh), 3.37 (s, 3H, CO2Me), 2.91 (dd, J=10.3, 6.7 Hz, 1H, HH-5),
2.42 (virt. t, J ffi 5.6 Hz, 1H, H-4), 1.68 (ddd, J=14.2, 10.6, 7.0 Hz, 1H,
HH-3), 1.55 (ddd, J=14.2, 7.0, 1.1 Hz, 1H, HH-2), 1.45 (dd, J=10.3,
1.0 Hz, 1H, HH-5), 1.44–1.37 (m, 1H, HH-3), 1.34–1.23 ppm (m, 1H,
HH-2); 13C NMR (91 MHz, C6D6): d=172.0 (C-8), 169.7 (CO2Me), 138.2
(Ph), 128.6 (Ph), 128.1 (Ph), 128.0 (Ph), 90.0 (C-7), 81.1 (C-1), 69.0
(CH2Ph), 54.5 (C-6), 51.9 (CO2Me), 39.3 (C-4), 24.4 (C-5), 23.3 (C-2),
22.1 ppm (C-3); IR (ATR): n˜ =2953, 2873, 1770, 1728, 1497, 1455,
1436 cmꢀ1; MS (EI, 70 eV): m/z (%)=302 (0.66) [M+], 91 (100) [C7H7+];
HRMS (EI): C17H18O5 [M+] calcd. 302.1149, found 302.1136.
Single-crystal X-ray Structure Determinations
rac-16: colorless fragment, C16H16O5, Mr =288.29; orthorhombic, space
group Pbcn (No. 60), a=23.5346(6), b=9.4007(2), c=12.5110(3) ꢅ, V=
2767.96(11) ꢅ3, Z=8, l
ACHTUNGTRENNUNG
(MoKa)=0.71073 ꢅ, m=0.103 mmꢀ1, 1calcd =1.384
gcmꢀ3, T=123(1) K, F
ACHTUNGTRENNUNG(000)=1216, qmax: 25.358, R1=0.0321 (2462 ob-
served data), wR2=0.0801 (all 2528 data), GOF=1.054, 255 parameters,
D1max/min =0.32/ꢀ0.20 eꢅꢀ3
.
rac-25b: colorless fragment, C23H32O6Si, Mr =432.58; monoclinic, space
group P21/n (No. 14), a=14.7334(4), b=7.8565(2), c=20.5340(5) ꢅ, b=
92.7607(10)8, V=2374.11(11) ꢅ3, Z=4,
lACHTUNGETRNNU(G MoKa)=0.71073 ꢅ, m=
0.133 mmꢀ1, 1calcd =1.210 gcmꢀ3, T=123(1) K, F (000)=928, qmax: 25.358,
R1=0.0315 (4167 observed data), wR2=0.0856 (all 4335 data), GOF=
1.060, 399 parameters, D1max/min =0.32/ꢀ0.28 eꢅꢀ3
.
Intramolecular photocycloaddition reaction of butenolide rac-10: The re-
action of rac-10 (22.0 mg, 68.1 mmol) in CH3CN/acetone (11:1, 12 mL) af-
forded straight product rac-13 (5.3 mg, 24%) and crossed product rac-14
(10.2 mg, 46%) after flash chromatography (eluent: pentane/EtOAc=
9:1).
rac-29a: colorless plate, C22H30O6Si, Mr =418.55; monoclinic, space group
P21/c (No. 14), a=28.4443(8), b=12.4627(4), c=12.6023(4) ꢅ, b=
97.6806(14)8,
V=4427.3(2) ꢅ3, Z=8,
l
N
m=
0.140 mmꢀ1, 1calcd =1.256 gcmꢀ3, T=123(1) K, F
AHCTUNGTRENNUNG
R1=0.0313 (7434 observed data), wR2=0.0847 (all 8116 data), GOF=
1.051, 763 parameters, D1max/min =0.34/ꢀ0.25 eꢅꢀ3
.
(1R*,4R*,6R*,9R*)-9-Benzoyloxymethyl-4-benzyloxy-2-oxatricy-
clo[4.2.1.04,9]nonan-3-one (rac-13): Rf =0.50 (Pentane/EtOAc=6:1,
CAM); 1H NMR (500 MHz, CDCl3): d=8.00 (d, J=8.2 Hz, 2H, COPh),
7.61 (t, J=7.4 Hz, 1H, COPh), 7.46 (virt. t, J ffi 7.8 Hz, 2H, COPh),
7.36–7.27 (m, 5H, CH2Ph), 5.01 (d, J=3.7 Hz, 1H, H-1), 4.90 (d, J=
11.3 Hz, 1H, CHHPh), 4.69 (d, J=11.3 Hz, 1H, CHHPh), 4.67 (d, J=
11.9 Hz, 1H, CHHOCO), 4.63 (d, J=11.9 Hz, 1H, CHHOCO), 2.78–2.63
(m, 2H, HH-5, H-6), 2.35–2.27 (m, 2H, HH-7, HH-8), 2.22–2.10 (m, 1H,
HH-5), 1.91 (dddd, J=14.2, 12.1, 8.4, 3.7 Hz, 1H, HH-8), 1.77–1.58 ppm
(m, 1H, HH-7); 13C NMR (91 MHz, CDCl3): d=176.7 (C-3), 166.2
(COPh), 137.4 (Ph), 133.3 (Ph), 129.49 (Ph), 128.51 (Ph), 128.3 (Ph),
127.7 (Ph), 127.4 (Ph), 86.2 (C-1), 77.4 (C-4), 67.7 (CH2Ph), 62.0
(CH2OCO), 58.5 (C-9), 36.3 (C-8), 34.0 (C-5), 32.1 (C-6), 30.2 ppm (C-7);
IR (ATR): n˜ =3033, 2963, 2877, 1767, 1717, 1452, 1267 cmꢀ1; MS (EI,
70 eV): m/z (%)=378 (1) [M+], 91 (100) [C7H7+]; HRMS (EI): C23H22O5
[M+] calcd. 378.1462, found 378.1466; C16H15O5 [M+-91] calcd. 287.0914,
found 287.0913.
rac-30a: colorless plate, C22H30O6Si, Mr =418.55; monoclinic, space group
P21/c (No. 14), a=17.6456(14), b=10.5766(8), c=11.8548(9) ꢅ, b=
93.124(4)8, V=2209.2(3) ꢅ3, Z=4, l(MoKa)=0.71073 ꢅ, m=0.141 mmꢀ1
ACHTUNGTERNUNNG ,
1calcd =1.258 gcmꢀ3, T=123(1) K, F
ACHTNUGTRNEGNU(000)=896, qmax: 25.378, R1=0.0300
(3797 observed data), wR2=0.0790 (all 4049 data), GOF=1.052, 382 pa-
rameters, D1max/min =0.33/ꢀ0.28 eꢅꢀ3
.
rac-33b: colorless fragment, C22H30O6Si, Mr =418.55; triclinic, space
group P1 (No. 2), a=10.2014(4), b=10.4234(4), c=11.5998(4) ꢅ, a=
82.6260(15)8, b=78.5574(16)8, g=65.7693(15)8, V=1100.90(7) ꢅ3, Z=2,
lACHTUNGTRENNUNG
(MoKa)=0.71073 ꢅ, m=0.141 mmꢀ1, 1calcd =1.263 gcmꢀ3, T=123(1) K, F-
ACHTUNGTRENNUNG(000)=448, qmax: 25.448, R1=0.0338 (3899 observed data), wR2=0.0917
(all 4043 data), GOF=1.027, 382 parameters, D1max/min =0.37/ꢀ0.27 eꢅꢀ3
.
CCDC 870803 (rac-16), CCDC 870804 (rac-25b), CCDC 870805 (rac-
29a), CCDC 870807 (rac-30a), and CCDC 870806 (rac-33b) contain the
supplementary crystallographic data for this paper. These data can be ob-
tained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(1R*,4S*,6R*,7R*)-6-Benzoyloxymethyl-7-benzyloxy-9-oxatricy-
clo[4.3.0.04,7]nonan-8-one (rac-14): Rf =0.34 (Pentane/EtOAc=6:1,
CAM); 1H NMR (500 MHz, CDCl3): d=8.03 (d, J=8.4 Hz, 2H, COPh),
7.59 (t, J=7.4 Hz, 1H, COPh), 7.47 (virt. t, J ffi 8.0 Hz, 2H, COPh), 7.42
(d, J=7.2 Hz, 2H, CH2Ph), 7.36 (t, J=7.2 Hz, 2H, CH2Ph), 7.31 (t, J=
7.2 Hz, 1H, CH2Ph), 5.09 (d, J=11.5 Hz, 1H, CHHPh), 5.09 (s, 1H, H-
1), 4.85 (d, J=11.5 Hz, 1H, CHHPh), 4.85 (d, J=11.7 Hz, 1H,
General Procedure for the Photocycloaddition Reactions
A deaerated solution of butenolide (5 mm) was irradiated in a Rayonet
RPR 100 merry-go-round reactor, equipped with 16 Rayonet RPR
3000 ꢅ lamps (Duran filter unless otherwise stated, l=300 nm), at room
temperature. Unless otherwise stated, the reaction was stopped when the
starting material was fully consumed according to TLC analysis. Subse-
quently, the reaction mixture was concentrated in vacuo to afford the res-
idue, which was purified by flash chromatography (eluent: pentane/
EtOAc) on silica gel to afford the cycloaddition products.
CHHOCO), 4.41 (d, J=11.7 Hz, 1H, CHHOCO), 2.93 (virt. t,
J
ffi 5.3 Hz, 1H, H-4), 2.41 (dd, J=10.1, 6.5 Hz, 1H, HH-5), 2.11 (ddd, J=
9.0, 7.9, 3.4 Hz, 1H, HH-3), 2.08–1.95 (m, 3H, HH-3, H-2), 1.89 ppm (d,
J=10.1 Hz, 1H, HH-5); 13C NMR (91 MHz, CDCl3): d=174.1 (C-8),
166.2 (COPh), 138.0 (Ph), 133.2 (Ph), 129.6 (Ph), 129.4 (Ph), 128.5 (Ph),
Chem. Asian J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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Thorsten Bach et al.
FULL PAPERS
128.3 (Ph), 127.6 (Ph), 127.4 (Ph), 85.2 (C-7), 82.6 (C-1), 68.2 (CH2Ph),
63.2 (CH2OCO), 51.5 (C-6), 38.1 (C-4), 25.0 (C-5), 23.2 (C-2), 22.7 ppm
(C-3); IR (ATR): n˜ =3065, 3031, 2964, 2871, 1769, 1717, 1601, 1584, 1453,
1268 cmꢀ1; MS (EI, 70 eV): m/z (%)=378 (1) [M+], 91 (100) [C7H7+];
HRMS (EI): C23H22O5 [M+] calcd. 378.1462, found 378.1454.
(%)=417 (2) [M+-91], 91 (100) [C7H7+]; HRMS (EI): C22H29O6Si [M+
-91] calcd. 417.1728, found 415.1745.
(1R*,3S*,4R*,6R*,7R*)-6-Benzoyoxymethyl-7-benzyloxy-3-(tert-butyldi-
metheylsilyl-oxy)-9-oxatricyclo[4.3.0.04,7]nonan-8-one (rac-27a): Rf =0.2
(Pentane/EtOAc=10:1, CAM); m.p.=112–1158C; 1H NMR (500 MHz,
CDCl3): d=8.00 (d, J=7.8 Hz, 2H, COPh), 7.55 (t, J=7.1 Hz, 1H,
COPh), 7.43 (virt. t, J ffi 7.6 Hz, 2H, COPh), 7.40 (d, J=7.8 Hz, 2H,
CH2Ph), 7.33 (virt. t, J ffi 7.5 Hz, 2H, CH2Ph), 7.29 (t, J=7.3 Hz, 1H,
CH2Ph), 5.22 (d, J=11.8 Hz, 1H, CHHPh), 5.03 (s, 1H, H-1), 4.80 (d, J=
11.8 Hz, 1H, CHHPh), 4.52 (d, J=11.8 Hz, 1H, HH-10), 4.45 (virt. t, J
ffi 5.6 Hz, 1H, H-3), 4.39 (d, J=11.8 Hz, 1H, HH-10), 3.02 (virt. t, J
ffi 6.0 Hz, 1H, H-4), 2.34 (dd, J=10.5, 6.7 Hz, 1H, HH-5), 2.21 (ddd, J=
15.3, 6.2, 2.8 Hz, 1H, HH-2), 2.04 (d, J=15.3 Hz, 1H, HH-2), 1.60 (d, J=
10.5 Hz, 1H, HH-5), 0.92 (s, 9H, SiMe2CMe3), 0.09 (s, 3H, SiMe-
MeCMe3), 0.08 ppm (s, 3H, SiMeMeCMe3); 13C NMR (91 MHz, CDCl3):
d=174.0 (C-3), 166.3 (COPh), 138.4 (Ph), 133.2 (Ph), 129.7 (Ph), 129.6
(Ph), 128.5 (Ph), 128.3 (Ph), 127.6 (Ph), 127.4 (Ph), 82.2 (C-7), 81.3 (C-
1), 69.5 (C-3), 67.7 (CH2Ph), 63.0 (C-10), 52.9 (C-6), 46.7 (C-4), 33.5 (C-
2), 25.6 (SiMe2CMe3), 25.1 (C-5), 17.9 (SiMe2CMe3), ꢀ4.9 (SiMe-
MeCMe3), ꢀ5.0 ppm (SiMeMeCMe3); IR (ATR): n˜ =2953, 2929, 2857,
1772, 1720, 1342, 1272 cmꢀ1; MS (EI, 70 eV): m/z (%)=451 (1) [M+-57],
91 (100) [C7H7+]; HRMS (EI): C25H27O6Si [M+-57] calcd. 415.1571,
found 415.1565.
Intramolecular photocycloaddition reaction of butenolide rac-21a: The
reaction of butenolide rac-21a (28.0 mg, 64.7 mmol) in CH2Cl2 (13 mL)
afforded straight product rac-24a (5.0 mg, 18%) and crossed product rac-
25a (13.4 mg, 48%) after flash chromatography (eluent: pentane/
EtOAc=9:1).
(1R*,4R*,6R*,7S*,9R*)-4-Benzyloxy-9-methoxycarbonyl-7-(tert-butyldi-
methylsilyl-oxy)-2-oxatricyclo[4.2.1.04,9]nonan-3-one (rac-24a): Rf =0.39
(Pentane/EtOAc=8:1, CAM); m.p.=103–1058C; 1H NMR (500 MHz,
CDCl3): d=7.36–7.26 (m, 5H, CH2Ph), 5.33 (d, J=4.7 Hz, 1H, H-1), 4.61
(d, J=11.0 Hz, 1H, CHHPh), 4.55 (d, J=11.0 Hz, 1H, CHHPh), 4.49
(virt. t, J ffi 6.4 Hz, 1H, H-7), 3.72 (s, 3H, CO2Me), 3.25 (ddd, J=10.8,
7.2, 3.1 Hz, 1H, H-6), 2.66 (dd, J=12.5, 3.1 Hz, 1H, HH-5), 2.56 (dd, J=
12.5, 10.8 Hz, 1H, HH-5), 2.28 (d, J=15.0 Hz, 1H, HH-8), 1.96 (ddd, J=
15.0, 5.5, 4.7 Hz, 1H, HH-8), 0.90 (s, 9H, SiMe2CMe3), 0.08 (s, 3H, SiMe-
MeCMe3), 0.04 ppm (s, 3H, SiMeMeCMe3); 13C NMR (91 MHz, CDCl3):
d=174.3 (C-3), 168.9 (CO2Me), 137.1 (Ph), 128.3 (Ph), 127.8 (Ph), 127.6
(Ph), 83.6 (C-1), 80.1 (C-4), 71.7 (C-7), 67.9 (CH2Ph), 63.5 (C-9), 52.7
(CO2Me), 44.8 (C-8), 39.2 (C-6), 26.9 (C-5), 25.7 (SiMe2CMe3), 18.1(Si-
Me2CMe3), ꢀ4.9 (SiMeMeCMe3), ꢀ5.2 ppm (SiMeMeCMe3); IR (ATR):
n˜ =2952, 2927, 2856, 1770, 1719, 1498, 1436 cmꢀ1; MS (EI, 70 eV): m/z
(%)=375 (2.8) [M+-57], 91 (100) [C7H7+]; HRMS (EI): C19H23O6Si [M+
-57] calcd. 375.1258, found 375.1256; C19H23O6Si [M+] calcd. 432.1963,
found 432.1951.
Intramolecular photocycloaddition reaction of butenolide rac-21b: The
reaction of rac-21b (28.0 mg, 64.7 mmol) in CH2Cl2 (13 mL) afford
straight product rac-24b (10.0 mg, 36%) and crossed product rac-25b
(11.0 mg, 39%) after flash chromatography (eluent: pentane/EtOAc=
10:1).
(1R*,3S*,4R*,6R*,7R*)-7-Benzyloxy-6-methoxycarbonyl-3-(tert-butyldi-
metheylsilyl-oxy)-9-oxatricyclo[4.3.0.04,7]nonan-8-one (rac-25a): Rf =0.21
(Pentane/EtOAc=8:1, CAM); m.p.=57–598C; 1H NMR (500 MHz,
CDCl3): d=7.40 (d, J=7.1 Hz, 2H, CH2Ph), 7.34 (virt. t, J ffi 7.2 Hz, 2H,
CH2Ph), 7.28 (t, J=7.3 Hz, 1H, CH2Ph), 5.21 (s, 1H, H-1), 4.82 (d, J=
11.6 Hz, 1H, CHHPh), 4.75 (d, J=11.6 Hz, 1H, CHHPh), 4.41 (virt. t, J
ffi 4.5 Hz, 1H, H-3), 3.72 (s, 3H, CO2Me), 2.89–2.82 (m, 2H, HH-5, H-4),
2.18 (ddd, J=15.3, 6.1, 2.8 Hz, 1H, HH-2), 2.05 (dd, J=15.3, 1.5 Hz, 1H,
HH-2), 1.66–1.60 (m, 1H, HH-5), 0.89 (s, 9H, SiMe2CMe3), 0.07 (s, 3H,
SiMeMeCMe3), 0.05 ppm (s, 3H, SiMeMeCMe3); 13C NMR (91 MHz,
CDCl3): d=171.8 (C-8), 169.8 (CO2Me), 137.8 (Ph), 128.3 (Ph), 127.7
(Ph), 127.5 (Ph), 86.3 (C-7), 80.1 (C-1), 69.0 (C-3), 68.0 (CH2Ph), 55.8
(C-6), 52.4 (CO2Me), 47.6 (C-4), 33.4 (C-2), 25.5 (SiMe2CMe3), 24.4 (C-
5), 17.9 (SiMe2CMe3), ꢀ5.0 (SiMeMeCMe3), ꢀ5.1 ppm (SiMeMeCMe3);
(1R*,4R*,6R*,7R*,9R*)-4-Benzyloxy-9-methoxycarbonyl-7-(tert-butyldi-
methylsilyl-oxy)-2-oxatricyclo[4.2.1.04,9]nonan-3-one (rac-24b): Rf =0.56
(Pentane/EtOAc=10:1, CAM); 1H NMR (360 MHz, CDCl3): d=7.40–
7.26 (m, 5H, CH2Ph), 5.42 (dd, J=5.2, 2.0 Hz, 1H, H-1), 4.60 (d, J=
10.9 Hz, 1H, CHHPh), 4.48 (d, J=10.9 Hz, 1H, CHHPh), 4.29 (ddd, J=
6.8, 5.6, 3.3 Hz, 1H, H-7), 3.73 (s, 3H, CO2Me), 3.01 (virt. dt, Jffi11.0,
3.8 Hz, 1H, H-6), 2.83 (dd, J=13.5, 11.0 Hz, 1H, HH-5), 2.45 (ddd, J=
14.6, 5.6, 2.0 Hz, 1H, HH-8), 2.21 (dd, J=13.5, 4.0 Hz, 1H, HH-5), 2.08
(ddd, J=14.6, 6.8, 5.2 Hz, HH-8), 0.85 (s, 9H, SiMe2CMe3), 0.04 ppm (s,
6H, SiMe2CMe3); 13C NMR (91 MHz, CDCl3): d=174.4 (C-3), 168.7
(CO2Me), 136.8 (Ph), 128.4 (Ph), 127.9 (Ph), 127.5 (Ph), 83.3 (C-1), 79.6
(C-4), 78.3 (C-7), 68.2 (CH2Ph), 61.6 (C-9), 52.7 (C-11), 44.6 (C-8), 42.0
(C-6), 32.9 (C-5), 25.6 (SiMe2CMe3), 17.9 (SiMe2CMe3), ꢀ4.87 (SiMe-
MeCMe3), ꢀ4.92 ppm (SiMeMeCMe3); IR (ATR): n˜ =2952, 2935, 2926,
2856, 1777, 1730, 1435 cmꢀ1; MS (EI, 70 eV): m/z (%)=375 (78) [M+
-57], 91 (100) [C7H7+]; HRMS (EI): C19H23O6Si [M+-57] calcd. 375.1258,
found 375.1256.
IR (ATR): n˜ =2960, 2929, 2888, 2854, 1776, 1740, 1453, 1343, 1259 cmꢀ1
;
MS (EI, 70 eV): m/z (%)=375 (45) [M+-57], 91 (100) [C7H7+]; HRMS
(EI): C19H23O6Si [M+-57] calcd. 375.1258, found 375.1251.
Intramolecular photocycloaddition reaction of butenolide rac-23a: The
reaction of rac-23a (30.0 mg, 59.0 mmol) in CH3CN/acetone (11:1, 12 mL)
afforded straight product rac-26a (7.2 mg, 24%) and crossed product rac-
27a (12.6 mg, 42%) after flash chromatography (eluent: pentane/
EtOAc=10:1!8:1).
(1R*,3R*,4R*,6R*,7R*)-7-Benzyloxy-6-methoxycarbonyl-3-(tert-butyldi-
methylsilyl-oxy)-9-oxatricyclo[4.3.0.04,7]nonan-8-one (rac-25b): Rf =0.36
(Pentane/EtOAc=10:1, CAM); m.p.=78–808C; 1H NMR (500 MHz,
CDCl3): d=7.40 (d, J=7.2 Hz, 2H, CH2Ph), 7.36 (t, J=7.2 Hz, 2H,
CH2Ph), 7.30 (t, J=7.2 Hz, 1H, CH2Ph), 5.19 (virt. t, J ffi 2.4 Hz, 1H, H-
1), 4.76 (d, J=11.0 Hz, 1H, CHHPh), 4.56 (d, J=11.0 Hz, 1H, CHHPh),
4.22 (virt. t, J ffi 7.0 Hz, 1H, H-3), 3.72 (s, 3H, CO2Me), 2.87 (dd, J=10.5,
6.4 Hz, 1H, HH-5), 2.67 (dd, J=6.4, 1.5 Hz, 1H, H-4), 2.44 (ddd, J=14.5,
6.7, 2.0 Hz, 1H, HH-2), 2.07 (d, J=10.5 Hz, 1H, HH-5), 1.85 (ddd, J=
14.5, 7.8, 2.8 Hz, 1H, HH-2), 0.85 (s, 9H, SiMe2CMe3), 0.04 (s, 3H, SiMe-
MeCMe3), 0.03 ppm (s, 3H, SiMeMeCMe3); 13C NMR (91 MHz, CDCl3):
d=171.4 (C-8), 169.7 (CO2Me), 137.0 (Ph), 128.4 (Ph), 128.0 (Ph), 127.7
(Ph), 87.9 (C-7), 79.6 (C-1), 68.7 (CH2Ph), 66.2 (C-3), 54.8 (C-6), 52.5
(CO2Me), 46.9 (C-4), 34.3 (C-2), 25.7 (SiMe2CMe3), 21.7 (C-5), 17.9 (Si-
Me2CMe3), ꢀ4.8 (SiMeMeCMe3), ꢀ4.9 ppm (SiMeMeCMe3); IR (ATR):
n˜ =2952, 2933, 2857, 1776, 1738, 1471, 1234 cmꢀ1; MS (EI, 70 eV): m/z
(%)=375 (6) [M+-57], 91 (100) [C7H7+]; HRMS (EI): C19H23O6Si [M+
-57] calcd. 375.1258, found 375.1252; C23H32O6Si [M+] calcd. 432.1963,
found 432.1952.
(1R*,4R*,6R*,7S*,9R*)-9-Benzoyoxymethyl-4-benzyloxy-7-(tert-butyldi-
methylsilyl-oxy)-2-oxatricyclo[4.2.1.04,9]nonan-3-one (rac-26a): Rf =0.40
(Pentane/EtOAc=10:1, CAM); m.p.=79–818C; 1H NMR (500 MHz,
CDCl3): d=7.99 (d, J=8.2 Hz, 2H, COPh), 7.61 (t, J=7.4 Hz, 1H,
COPh), 7.47 (virt. t, J ffi 7.8 Hz, 2H, COPh), 7.37–7.26 (m, 5H, CH2Ph),
4.94 (d, J=4.4 Hz, 1H, H-1), 4.94 (d, J=11.4 Hz, 1H, CHHPh), 4.73 (d,
J=11.4 Hz, 1H, CHHPh), 4.67 (d, J=11.9 Hz, 1H, HH-10), 4.60 (d, J=
11.9 Hz, 1H, HH-10), 4.55 (virt. t, J ffi 5.9 Hz, 1H, H-7), 2.86 (ddd, J=
10.8, 7.1, 3.2 Hz, 1H, H-6), 2.68 (dd, J=12.7, 3.2 Hz, 1H, HH-5), 2.47
(dd, J=12.7, 10.8 Hz, 1H, HH-5), 2.30 (d, J=14.9 Hz, 1H, HH-8), 2.08
(ddd, J=14.9, 5.9, 4.4 Hz, 1H, HH-8), 0.94 (s, 9H, SiMe2CMe3), 0.11 (s,
3H, SiMeMeCMe3), 0.06 ppm (s, 3H, SiMeMeCMe3); 13C NMR
(91 MHz, CDCl3): d=175.9 (C-3), 166.3 (COPh), 137.6 (Ph), 133.4 (Ph),
129.51 (Ph), 129.49 (Ph), 128.6 (Ph), 128.3 (Ph), 127.7 (Ph), 127.5 (Ph),
84.6 (C-1), 77.5 (C-4), 72.2 (C-7), 67.5 (CH2Ph), 62.3 (C-10), 58.3 (C-9),
44.6 (C-8), 38.7 (C-6), 25.7 (SiMe2CMe3), 25.6 (C-5), 18.1 (SiMe2CMe3),
ꢀ4.8 (SiMeMeCMe3), ꢀ5.1 ppm (SiMeMeCMe3); IR (ATR): n˜ =2957,
2950, 2926, 2855, 1769, 1718, 1602, 1453, 1273 cmꢀ1; MS (EI, 70 eV): m/z
Intramolecular photocycloaddition reaction of butenolide rac-22b: The
reaction of rac-22b (24.0 mg, 59.3 mmol) in CH3CN/acetone (11:1, 12 mL)
was irradiated at l=300 nm for 2 h. The reaction mixture was concen-
trated in vacuo to afford a residue, which was purified by flash chroma-
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ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

ACHTUNGTRENNUNG[2+2] Photocycloaddition of Butenolides
tography (eluent: pentane/EtOAc=6:1) on silica gel to afford straight
product rac-31b (10.7 mg, 45%) and crossed product rac-32b (4.0 mg,
17%).
in CRC Handbook of Organic Photochemistry and Photobiology,
2nd ed. (Eds.: W. Horspool, F. Lenci), CRC Press, Boca Raton, 2004,
S. 71/1–71/14; e) T. Bach, Synthesis 1998, 683–703; f) J.-P. Pete,
Adv. Photochem. 1996, 21, 135–216; g) J. Mattay, R. Conrads, R.
Hoffmann in Methoden der Organischen Chemie (Houben-Weyl) 4te
Aufl., Band E 21c (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer,
E. Schaumann); Thieme, Stuttgart 1995, pp. 3085–3132; h) M. T.
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[5] a) R. Srinivasan, K. H. Carlough, J. Am. Chem. Soc. 1967, 89, 4932–
4936; b) R. S. H. Liu, G. S. Hammond, J. Am. Chem. Soc. 1967, 89,
4936–4944.
(1R*,4R*,6R*,7R*,9R*)-4-Benzyloxy-9-hydroxymethyl-7-(tert-butyldime-
thylsilyloxy)-2-oxatricyclo[4.2.1.04,9]nonan-3-one
(rac-31b):
Rf =0.40
(Pentane/EtOAc=4:1, CAM); 1H NMR (500 MHz, CDCl3): d=7.40–
7.28 (m, 5H, CH2Ph), 5.01 (d, J=11.3 Hz, 1H, CHHPh), 5.00 (d, J=
2.6 Hz, 1H, H-1), 4.66 (d, J=11.3 Hz, 1H, CHHPh), 4.29 (virt. td, J
ffi 5.4, 2.9 Hz, 1H, H-7), 3.95 (dd, J=11.9, 6.4 Hz, 1H, HH-10), 3.81 (dd,
J=11.9, 6.4 Hz, 1H, HH-10), 2.66 (dd, J=13.7, 10.8 Hz, 1H, HH-5), 2.49
(virt. dt, J ffi 10.8, 3.5 Hz, 1H, H-6), 2.40 (ddd, J=14.9, 5.4, 2.6 Hz, 1H,
HH-8), 2.34 (t, J=6.4 Hz, 1H, OH), 2.17–2.10 (m, 2H, HH-8, HH-5),
0.87 (s, 9H, SiMe2CMe3), 0.054 (s, 3H, SiMeMeCMe3), 0.047 ppm (s, 3H,
SiMeMeCMe3); 13C NMR (91 MHz, CDCl3): d=176.3 (C-3), 137.4 (Ph),
128.5 (Ph), 128.0 (Ph), 127.7 (Ph), 83.8 (C-1), 78.5 (C-7), 77.1 (C-4), 67.7
(CH2Ph), 61.2 (C-10), 59.5 (C-9), 44.1 (C-8), 41.4 (C-6), 30.3 (C-5), 25.7
(SiMe2CMe3), 18.0 (SiMe2CMe3), ꢀ4.9 ppm (SiMe2CMe3); IR (ATR): n˜ =
3503, 2928, 2856, 1770, 1471, 1462, 1254 cmꢀ1; MS (ESI): 405 [M+H]+;
HRMS (ESI): C22H33O5Si [M+H]+ calcd. 405.2092, found 405.2092.
[6] D. J. Maradyn, A. C. Weedon, J. Am. Chem. Soc. 1995, 117, 5359–
5360.
[7] For exceptions, see: a) R. T. LaLonde, R. I. Aksentijevich, Tetrahe-
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Acta 1976, 59, 2244–2248; c) M. J. Begley, M. Mellor, G. Pattenden,
Chem. Commun. 1979, 235–236; d) A. Alder, N. Bꢃhler, D. Bellus,
Helv. Chim. Acta 1982, 65, 2405–2412; e) M. Ikeda, M. Takahashi,
T. Uchino, K. Ohno, Y. Tamura, M. Kido, J. Org. Chem. 1983, 48,
4241–4247; f) A. R. Matlin, C. F. George, S. Wolff, W. C. Agosta, J.
Am. Chem. Soc. 1986, 108, 3385–3394; g) N. W. A. Geraghty, M. J.
Monaghan, N. Hanley, Tetrahedron Lett. 1987, 28, 4729–4732;
h) M. T. Crimmins, E. B. Hauser, Org. Lett. 2000, 2, 281–284;
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7.1 Hz, 1H, CH2Ph), 5.11 (d, J=11.3 Hz, 1H, CHHPh), 4.79–4.75 (m,
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1.93 (d, J=10.5 Hz, 1H, HH-5), 1.86 (ddd, J=14.3, 7.8, 2.3 Hz, 1H, HH-
2), 0.86 (s, 9H, SiMe2CMe3), 0.05 (s, 3H, SiMeMeCMe3), 0.04 ppm (s,
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(Ph), 128.5 (Ph), 128.0 (Ph), 127.6 (Ph), 85.1 (C-7), 80.3 (C-1), 68.4
(CH2Ph), 67.3 (C-3), 61.9 (C-10), 54.1 (C-6), 45.0 (C-4), 34.4 (C-2), 25.7
(SiMe2CMe3), 21.1 (C-5), 18.0 (SiMe2CMe3), ꢀ4.7 (SiMeMeCMe3),
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Acknowledgements
This project was supported by the Alexander von Humboldt Foundation
(research fellowship to P. L.).
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Received: April 5, 2012
Published online: && &&, 0000
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FULL PAPERS
Substitution matters in the [2+2] pho-
tocycloaddition of butenolides 1: For
X,Y=H and X=OTBS, Y=H the
crossed products were formed as major
regioisomers (r.r.=89:11 to 65:35),
whereas the straight products prevailed
in the case of X=H, Y=OTBS in par-
ticular for R=CH2OBn (r.r.=70:30).
The latter product (X=H, Y=OTBS,
R=CH2OBn) was successfully con-
verted into the monoterpene glycoside
lactiflorin.
Cycloaddition
Ping Lu, Eberhardt Herdtweck,
Thorsten Bach*
&&&& — &&&&
Intramolecular [2+2] Photocycloaddi-
tion Reactions as an Entry to the 2-
Oxatricyclo[4.2.1.04,9]nonan-3-one
Skeleton of Lactiflorin
Chem. Asian J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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