Solvent-controlled intramolecular [2 + 2] photocycloadditions of α-substituted enones

Article abstract of DOI:10.1021/ja060968g

The regio- and stereoselectivity of intramolecular [2 + 2] photocycloadditions of 2′-hydroxyenones are shown to be solvent-dependent. In the presence of aprotic solvents, 2′-hydroxyenones undergo photocycloadditions in a manner consistent with the presenc

Full text of DOI:10.1021/ja060968g

Published on Web 05/12/2006
Solvent-Controlled Intramolecular [2 + 2] Photocycloadditions
of r-Substituted Enones
Stephanie M. Ng, Scott J. Bader, and Marc L. Snapper*
Contribution from the Department of Chemistry, Merkert Chemistry Center,
Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467
Received February 9, 2006; E-mail: marc.snapper@BC.edu
Abstract: The regio- and stereoselectivity of intramolecular [2 + 2] photocycloadditions of 2′-hydroxyenones
are shown to be solvent-dependent. In the presence of aprotic solvents, 2′-hydroxyenones undergo
photocycloadditions in a manner consistent with the presence of an intramolecular hydrogen bond between
the carbonyl group and the tether’s hydroxy functionality. In protic solvents, intermolecular interactions
appear to disrupt the intramolecular hydrogen bond, providing products with complementary diastereo-
selectivity. If the facial accessibility of the R-tethered olefin is limited, the cycloadditions proceed to give
head-to-tail or head-to-head regioisomers, depending on the nature of the solvent employed.
Scheme 1. Crimmins’ Solvent-Dependent Intramolecular [2 + 2]
Photocycloadditions
Introduction
Intramolecular [2 + 2] photocycloadditions between enones
and olefins provide rapid and powerful entries into complex
polycyclic ring systems.1 While numerous examples of selective
photocycloadditions have been presented,2 there are only a few
examples of solvent-controlled [2 + 2] photocycloadditions,3
particularly involving intramolecular hydrogen bonds that can
direct the course of the reaction. Bach and co-workers observed
high enantioselectivity in intra- and intermolecular [2 + 2]
photocycloadditions in the presence of a chiral host, which
hydrogen bonds to a prochiral substrate or guest.4 Likewise,
Crimmins and co-workers have demonstrated important solvent
effects on diastereoselective intramolecular [2 + 2] photocy-
cloadditions through intramolecular hydrogen bonds with â-di-
carbonyl compounds (Scheme 1).5 The γ-hydroxyl group was
proposed to hydrogen bond with the exocyclic carbonyl moiety
and direct the facial selectivity, based on choice of solvent. This
strategy was used in the total synthesis of gingkolide B.6
In a study of intramolecular photocycloadditions of func-
tionalized cyclobutenes, we noted a solvent-dependent intramo-
lecular [2 + 2] photocycloaddition of 2′-hydroxyenone 1
(Scheme 2).7 Photocycloadditions of 1 in protic solvents, such
as acetone/water, led to a preference of the “head-to-head”
(straight) coupling product 2 over the “head-to-tail” (crossed)
cycloadduct 3 in a 7:1 ratio.8 Alternatively, when the photocy-
cloaddition was carried out in an aprotic solvent, such as
methylene chloride, the crossed product was favored by a 10:1
ratio. It was speculated that an intramolecular hydrogen bond
between the enone carbonyl and the 2′-hydroxy group in this
substrate was responsible for this solvent-controlled regiose-
lectivity.
(1) For select reviews on applications of [2 + 2] photocycloadditions, see:
(a) Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297-588. (b)
Keukeleire, D. D.; He, S. L. Chem. ReV. 1993, 93, 359-380. (c) Bauslaugh,
P. G. Synthesis 1970, 287-300. (d) Schreiber, S. L. Science 1985, 227,
857-863. (e) Crimmins, M. T. Chem. ReV. 1988, 88, 1453-1473.
(2) For a review on stereoselective intermolecular [2 + 2] photocycloadditions,
see: (a) Bach, T. Synthesis 1998, 683. For examples of [4+4], see: (b)
Sieburth, S. M.; Joshi, P. V. J. Org. Chem. 1993, 58, 1661-1663. (c)
Sieburth, S. M.; McGee, K. F. Org. Lett. 1999, 1, 1775-1777. (d) Sieburth,
S. M.; McGee, K. F., Jr.; Al-Tel, T. H. J. Am. Chem. Soc. 1998, 120, 587-
588. Paterno Buchi: (e) Adam, W.; Peters, K.; Peters, E. M.; Stegmann,
V. R. J. Am. Chem. Soc. 2000, 122, 2958-2959. (f) Griesbeck, A. G.;
Bondock, S. J. Am. Chem. Soc. 2001, 123, 6191-6192. Other: (g) Rigby,
J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655-12656. For
representative examples of regioselective photocycloadditions, see: (h)
Matlin, A. R.; George, C. F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc.
1986, 108, 3385-3394. (i) Gleiter, R.; Fischer, E. Chem. Ber. 1992, 125,
1899-1911.
Unfortunately, the role of 2′-substituents in these [2 + 2]
photocycloadditions is unclear. In an approach to the guana-
(6) Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas,
J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc. 2000, 122,
8453-8463.
(7) Bader, S. J.; Snapper, M. L. J. Am. Chem. Soc. 2005, 127, 1201-1205.
(8) For related studies on steric effects in cyclopentenone [2 + 2] photocy-
cloadditions, see: (a) Matlin, A. R.; George, C. F.; Wolff, S.; Agosta, W.
C. J. Am. Chem. Soc. 1986, 108, 3385. (b) Becker, D.; Klimovich, N.
Tetrahedron Lett. 1994, 35, 261.
(3) For example, see: (a) Yokoyama, A.; Mizuno, K. Org. Lett. 2000, 2, 3457-
3459. (b) Mizuno, K.; Kagano, H.; Otsuji, Y. Tetrahedron Lett. 1983, 24,
3849.
(4) (a) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem., Int. Ed. 2000, 39,
2302-2303. (b) Bach, T.; Bergmann, H.; Harms, K. J. Am. Chem. Soc.
1999, 121, 10650-10651.
(5) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1997, 119, 10237-10238.
9
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J. AM. CHEM. SOC. 2006, 128, 7315-7319
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A R T I C L E S
Ng et al.
or cyclohexenyl bromide 7 (Scheme 3).10 Lithium-halogen
exchange of 4 or 7 occurred after addition of n-BuLi at -78
°C, at which time 4-pentenal was added, followed by acidic
workup to afford enone 5 and 8, respectively, in a 60-80%
yield. Enone 5 was further transformed to methyl ether 6 using
Trost’s methylation conditions.11 This substrate should provide
insight into the [2 + 2] photocycloaddition for systems lacking
an intramolecular hydrogen bond.
Scheme 2. Solvent-Dependent Regioselective Intramolecular [2 +
2] Photocycloadditions
In a similar fashion, enones 10 and 12, with one-carbon longer
olefin tethers, were also generated. The addition of Weinreb
amide 13, which was readily prepared from 5-hexenoic acid,
to the respective vinyllithium reagent derived from five- or six-
membered rings afforded products 9 and 11 in moderate yields.
Luche reduction,12 followed by acidic workup, provided sub-
strates 10 and 12 in >80% yields.
With functionalized 2′-hydroxyenones in hand, we examined
the photocycloaddition of these systems in a variety of solvents.
As shown in Table 1, enone 5 was irradiated with a 450 W
medium-pressure lamp through Pyrex filters in various solvents
to yield mixtures of cycloadducts 14a and 14b. Resubjection
of either cycloadduct to the photolysis conditions did not lead
to formation of the other diastereomer, an observation indicating
that the products were not equilibrating under the photolysis
conditions. The ratio of cycloadducts obtained in these photo-
cycloadditions suggested that an intramolecular hydrogen bond
between the 2′-hydroxy group and the enone carbonyl can
influence the facial selectivity of the interacting π-systems.13
castepenes, Sorensen observed a highly selective intramolecular
[2 + 2] photocycloaddition of a 2′-substituted system (eq 1).9
In this case, only one diastereomer was a competent substrate
in the [2 + 2] photocycloaddition. Given these observations,
we sought to explore the role of 2′-functionalization in these
cycloadditions. We were particularly interested in examining
the generality of solvent effects on intramolecular [2 + 2]
photocycloadditions of 2′-hydroxyenones. Accordingly, the
regio- and stereochemical results of photochemical cycloaddi-
tions of 2′-hydroxyenones in protic and aprotic solvents are
described herein.
Table 1. Intramolecular [2 + 2] Photocycloadditions’ Solvent
Screen
Results and Discussion
As illustrated in Scheme 3, enones with acyclic 2′-hydroxy-
containing tethered olefins were synthesized in order to observe
the role that steric effects and hydrogen bonding play in the
regio- and stereochemical preference of intramolecular [2 + 2]
photocycloadditions. Enones 5 and 8 were prepared in a
straightforward manner from either cyclopentenyl bromide 4
entry
solvent
14a
14b
yield (%)
1
2
3
4
5
6
7
acetone/H2O
methanol
acetonitrile
diethyl ether
dichloromethane
pentane
>20
>20
1
1
3
1
6
2
3
60
65
77
90
80
63
42
5
2
1
1
1
Scheme 3. Synthesis of 2′-Hydroxyenonesa
cyclohexane
The results summarized in Figure 1 point to a role that solvent
may play in controlling these intramolecular photocycloaddi-
tions. In aprotic solvents, such as methylene chloride, an
intramolecular hydrogen bond between the 2′-hydroxyl and the
carbonyl groups can orient the enone and pendent olefin to
provide a particular facial selectivity between the two reactive
π-systems, leading to adduct 14b. In protic solvents, however,
hydrogen bonding with the solvent competes effectively with
the intramolecular interaction, affording the opposite facial
selectivity between the enone and tethered olefin. This orienta-
tion leads to diastereomer 14a. As indicated in entry 2 of Table
(9) Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063.
(10) (a) Kowalski, C.; Weber, A.; Fields, K. J. Org. Chem. 1982, 47, 5088-
5093. (b) House, H.; McDaniel, W. J. Org. Chem. 1977, 42, 2155-2160.
(11) Trost, B.; Yang, H.; Probst, G. D. J. Am. Chem. Soc. 2004, 126, 48-49.
(12) (a) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454. (b)
Wang, X. J.; Hart, S. A.; Xu, B.; Mason, M. D.; Goodell, J. R.; Etzkorn,
R. A. J. Org. Chem. 2003, 68, 2343.
(13) For a related observation with intramolecular [4 + 4] photocycloadditions,
see: Zhu, M.; Qiu, Z.; Hiel, G. P.; Sieburth, S. M. J. Org. Chem. 2002,
67, 3487 and references therein.
a Conditions: (a) (1) n-BuLi, -78 °C, THF; (2) 4-pentenal, 1 M HCl
(60-80% over 3 steps). (b) Ag2O, MeI, 58 °C, 48 h (60-70%). (c) (1)
n-BuLi, -78 °C, Et2O; (2) N-methoxy-N-methylhex-5-enamide 13 (57%,
2 steps). (d) (1) CeCl3, NaBH4, MeOH, 0 °C; (2) 1 M HCl (80%, 2 steps).
9
7316 J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006

[2
+
2] Photocycloadditions of
R
-Substituted Enones
A R T I C L E S
group in the pendent olefin are shown in entries 4 and 5. In
these examples, the solvent-dependent facial control improved
in protic and aprotic solvents; however, the overall efficiency
of the photocycloaddition appeared to suffer as indicated by
the lower yields.15
Conformation of the structures for cycloadducts 14a and 14b
was accomplished through the correlation studies illustrated in
Scheme 4. Compounds 14a and 14b were shown to be
diastereomers through oxidation of both secondary alcohols to
the same diketone 17. Derivatization of 14a to bromobenzoate
16 allowed for confirmation of relative stereochemistry for
diastereomer 14a through X-ray crystallographic studies. The
structures and stereochemistry of the remaining cycloadducts
were confirmed in a related fashion. As shown in Scheme 4,
photoadducts 18a, 18b, 19a, and 19b could all be transformed
into the same diketone 21. Likewise, the diastereomeric
relationship between adducts 20a and 20b was demonstrated
through a PCC oxidation to diketone 22. These studies,
combined with additional X-ray crystallographic information,16
allowed for the unambiguous structural assignment for each of
the photoadducts.
Figure 1. Photocycloaddition facial selectivity controlled by intra- and
intermolecular hydrogen bonding.
2, [2 + 2] photocycloaddition of methyl ether 6 provides only
cycloadduct 15 regardless of the solvent employed. The rela-
tive stereochemistry of this photoproduct is similar to that of
adduct 14a, where the intramolecular hydrogen bond is not
present.
Table 2. Solvent-Dependent Intramolecular [2 + 2]
Photocycloadditionsa
Scheme 4. Structural Confirmation of Photocycloadductsa
a Conditions: (a) PCC (20% on basic alumina), CH2Cl2 (75-85%). (b)
DMAP, DCC, p-bromobenzoic acid, CH2Cl2 (60%). (c) Ag2O, MeI, CH3CN
(67%).
These diastereoselective cycloadditions differ from the solvent-
dependent straight and crossed photocycloadditions observed
with enone 1. We suspect this disparity arises from structural
constraints imposed by compound 1’s polycyclic ring system.
That is, regardless of solvent, only one face of the isolated olefin
is available to the excited enone. For substrate 5, the presence
or absence of an intramolecular hydrogen bond dictates the facial
selectivity of both the isolated olefin and enone; however, only
the enone facial selectivity is influenced in substrate 1. The
generality of these solvent-controlled regio- and diastereose-
lective photocycloadditions was probed with substrates that limit
olefin accessibility.
a All reactions: hV, Pyrex filter, 3 mM in solvent.
The transformations described in entries 3-5 of Table 2
explore the scope of the solvent-controlled photocycloadditions
with 2′-hydroxyl-containing substrates with larger cyclic enones
and longer tethered olefins. In all cases, the two reactive
π-systems interact in a head-to-head fashion, where their facial
selectivity is dictated by the presence or absence of an
intramolecular hydrogen bond.14 Cyclohexenone 8, shown in
entry 3 for example, reacted in a manner very similar to that of
substrate 5. Protic solvents favored photoadduct 18a, while
aprotic solvents led to 18b as the major product. The results of
photocycloadditions of substrates with an additional methylene
(15) For representative examples of tether length effects on rates of cyclization,
see: (a) Johnson, C. C.; Horner, J. H.; Tronche, C.; Newcomb, M. J. Am.
Chem. Soc. 1995, 117, 1684. (b) Salomon, G. Trans. Faraday Soc. 1938,
34 1311.
(14) While other minor products were observed, we were not able to identify
any head-to-tail regioisomers in this series of photocycloadditions.
(16) See Supporting Information for additional information.
9
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A R T I C L E S
Ng et al.
Table 3. [2 + 2] Photocycloadditions of 27 and 28a
a All reactions: hV, Pyrex filter, 3 mM concentration.
lithium reagent derived from cyclopentene 4 to Weinreb amide
30 then yielded substrate 31 in 51% yield. CBS reductions using
each antipode of the catalyst, followed by mild hydrolysis,
produced the diastereomeric enones 27 and 28 in >10:1
diastereomeric purity as determined by chiral HPLC analysis.
Enone 27 underwent an intramolecular photochemical cy-
cloaddition in an aprotic solvent (CH2Cl2) to give the head-to-
head cycloadduct 32 as the major product, albeit in low yield
(Table 3). In contrast, using an acetone/water mixture as solvent
to disrupt the intramolecular hydrogen bond in 27 forced the
cycloaddition to go in a head-to-tail fashion to provide
compound 33 as the major isolable product, again with low
efficiency. These results follow the reactivity trends discussed
in Figure 2.
Likewise, when diastereomer 28 was subjected to the same
set of reaction conditions, a similar, but less pronounced,
selectivity trend was observed. Irradiation of enone 28 in a protic
environment afforded mainly the head-to-head cycloadduct 35
in 64% yield. Switching the solvent to CH2Cl2 generated more
of the head-to-tail regioisomer 36, but still in a minor amount
compared to 35. While the regioselectivity in this series is
influenced by the presence or absence of an intramolecular
hydrogen bond, there are also other factors,19 such as steric
effects that play an important role in dictating the facial and
regioselectivity in these intramolecular [2 + 2] photocycload-
ditions.8
Figure 2. Regioselectivity controlled by hydrogen bonding and olefin
accessibility in [2 + 2] photocycloaddition.
As illustrated in Figure 2, substrate 23, with a tethered
cyclopentenyl ring, offers a system that restricts the pendent
olefin’s accessibility. As shown in eq 2, conditions that allow
an intramolecular hydrogen bond between the enone and
2′-hydroxyl group should lead to photoadduct 24, with a head-
to-head coupling between the enone and accessible face of
the tethered olefin. If the intramolecular hydrogen bond is
broken through intermolecular interactions, the stereogenic
center on the cyclopentenyl ring prohibits the other face of the
enone from interacting (in a low energy manner) with the
opposite face of the tethered olefin (eq 3), as was observed with
substrate 5. Instead, the opposite face of the enone interacts
with the accessible face of the attached olefin to yield the head-
to-tail (crossed) product 26 shown in eq 4. To test this
hypothesis, enones 27 and 28 were prepared and studied in
intramolecular [2 + 2] photocycloadditions in protic and aprotic
solvents.
Scheme 5. Synthesis of Diastereomers 27 and 28a
a Conditions: (a) N,O-dimethylhydroxylamine hydrochloride, CDI,
CH2Cl2, 0 °C (79%). (b) 4, n-BuLi, -78 °C, THF (51%). (c) (R)-1-Methyl-
3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxasaborole, BH3-THF, toluene,
0 °C; then 1 M HCl (50-70%). (d) (S)-1-Methyl-3,3-diphenyl-1H,3H-
pyrrolo[1,2-c][1,3,2]oxasaborole, BH3-THF, toluene, 0 °C; then 1 M HCl
(50-70%).
Figure 3. ORTEPs of p-bromobenzoic esters of photoadducts 33 and 35.
As outlined in Scheme 5, enones 27 and 28 were generated
in three steps from enantiopure acid 29.17 Weinreb amide 30
was prepared employing Scheffer’s protocol.18 Addition of the
As with the previous substrates, the diastereoisomeric rela-
tionship between photoadducts 32 and 35, as well as 33 and
36, was demonstrated by oxidation to the same diketones. This
(17) The saturated alcohol was the minor product in a ratio of 30:1 by NMR
analysis of the reaction mixture. (a) Liotta, D.; Zima, G.; Saindane, M. J.
Org. Chem. 1982, 47, 1258-1267. (b) He, F.; Bo, Y.; Altom, J. D.; Corey,
E. J. J. Am. Chem. Soc. 1999, 121, 6771-6772. (c) Trost, B.; Van Vranken,
D.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327-9343. (d) Campos, K.;
Journet, M.; Lee, S.; Grabowski, E.; Tillyer, R. J. Org. Chem. 2005, 70,
268.
(19) For examples of other factors influencing intramolecular [2 + 2] photo-
cycloadditions, see: (a) Becker, D.; Cohen-Arazi, Y. J. Am. Chem. Soc.
1996, 118, 8278. (b) Becker, D.; Morlender, N.; Haddad, N. Tetrahedron
Lett. 1995, 36, 1921. (c) Tanaka, N.; Yamazaki, H.; Sakuragi, H.;
Tokumaru, K. Bull. Chem. Soc. Jpn. 1994, 67, 1434. (d) Becker, D.;
Haddad, N. Tetrahedron 1993, 49, 947.
(18) Chong, K.; Scheffer, J. R. J. Am. Chem. Soc. 2003, 125, 4040.
9
7318 J. AM. CHEM. SOC. VOL. 128, NO. 22, 2006

[2
+
2] Photocycloadditions of
R
-Substituted Enones
A R T I C L E S
Representative Procedure for the Oxidation of Photocycload-
ducts: To a stirred solution of the photocycloadduct (1.0 equiv) in
CH2Cl2 (0.1-0.01 M) was added pyridinium chlorochromate (PCC 20%
on basic alumina, 2.0 equiv). The reaction was stirred at room
temperature until the starting material was deemed consumed by TLC
analysis. The reaction mixture was filtered through a plug (1 cm) of
Celite, and the filtrate was washed with a solution of saturated CuSO4
(2 mL), dried with MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by Kugelrohr distillation.
Representative Procedure for the Derivatization of the [2 + 2]
Photocycloadducts: To a solution of cycloadduct (1 equiv) in CH2Cl2
(0.1 M) cooled to 0 °C were added 4-bromobenzoic acid (1.1 equiv),
4-(dimethylamino)pyridine (DMAP, 0.5 equiv), and N,N′-dicyclohexyl-
carbodiimide (DCC, 1.1 equiv). The reaction was warmed slowly to
room temperature. After the reaction was deemed finished by TLC
analysis, the mixture was diluted with CH2Cl2 and dried with MgSO4.
The solution was filtered, concentrated, and purified through silica gel
chromatography. The product was then recrystallized under the ap-
propriate conditions.
information, coupled with X-ray crystallographic studies sum-
marized in Figure 3, allowed for unambiguous assignment of
relative stereochemistry of these cycloadducts.
Summary
There has been a longstanding interest in the factors influenc-
ing [2 + 2] photocycloadditions of cyclic enones.20 For
2′-hydroxyenones, the regio- and diastereoselective outcome of
intramolecular [2 + 2] photocycloadditions can be dictated by
solvent. An intramolecular hydrogen bond between the carbonyl
and 2′-hydroxyl group can govern the facial selectivity between
the two interacting π-systems under photochemical [2 + 2]
conditions. Changing the tether to a conformationally restricted
olefin, however, limits one π-system, affording complementary
regioselective cycloadditions in protic and aprotic media.
Experimental Section
Representative Procedure for the Intramolecular [2+2] Photo-
cycloaddition: To a thick-walled, flame-dried, Pyrex reaction tube were
added the R,â-unsaturated ketone (1 equiv) and solvent (3.7 mM). The
solution was degassed by bubbling N2 through the solution for 15 min
and then irradiated through a 4 mm barrier of Pyrex with a 450 W
medium-pressure Hanovia mercury lamp until the reaction was deemed
finished by TLC analysis. The reaction was concentrated under reduced
pressure and purified through silica gel flash chromatography.
Acknowledgment. We thank the National Institute of General
Medical Sciences (National Institutes of Health, GM62824) for
financial support. We are grateful to Schering-Plough for X-ray
facility support, and Keith Griswold, Wayne Lo, and Dr. Richard
J. Staples for substantial assistance with X-ray crystallographic
studies.
Supporting Information Available: Complete experimental
procedures and data on new compounds are provided (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For representative examples, see: (a) Wilsey, S.; Gonza´lez, L.; Robb, M.
A.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 5866. (b) Schuster, D. I.;
Heibel, G. E.; Brown, P. B.; Turro, N. J.; Kumar, C. V. J. Am. Chem. Soc.
1988, 110, 8261. (c) Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B.
J. Am. Chem. Soc. 1964, 86, 5570.
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