Photochemistry of 4-(2′-aminoethyl)quinolones: Enantioselective synthesis of tetracyclic tetrahydro-1aH-pyrido[4′,3′:2,3]- cyclobuta[1,2-c] quinoline-2,11(3H,8H)-diones by intra- and intermolecular [2 + 2]-photocycloaddition reactions in solution

Article abstract of DOI:10.1021/jo0606608

Enantioselective [2 + 2]-photocycloaddition reactions on 4-(2′-aminoethyl)quinolones in solution were studied using the enantiomerically pure complexing agent 1 as source of chirality. The intermolecular reactions of fully N-protected substrates 5a-5c wit

Full text of DOI:10.1021/jo0606608

Photochemistry of 4-(2′-Aminoethyl)quinolones: Enantioselective
Synthesis of Tetracyclic Tetrahydro-1aH-pyrido[4′,3′:2,3]-
cyclobuta[1,2-c] Quinoline-2,11(3H,8H)-diones by Intra- and
Intermolecular [2 + 2]-Photocycloaddition Reactions in Solution
Philipp Selig and Thorsten Bach*
Lehrstuhl fu¨r Organische Chemie I, Technische UniVersita¨t Mu¨nchen, D-85747 Garching, Germany
thorsten.bach@ch.tum.de
ReceiVed March 28, 2006
Enantioselective [2 + 2]-photocycloaddition reactions on 4-(2′-aminoethyl)quinolones in solution were
studied using the enantiomerically pure complexing agent 1 as source of chirality. The intermolecular
reactions of fully N-protected substrates 5a-5c with different 2-alkyl-substituted acrylates 12-15 represent
the first systematic study on the diastereoselectivity of their intermolecular [2 + 2]-photocycloadditions
to unsymmetrically 1,1-disubstituted olefins (75-91% yield, d.r. ) 58/42-95/5). N-Benzylic-protected
photoproducts exo-16a/b-19a/b could easily be converted into lactams 20a/b-23a/b by a sequence of
Boc deprotection and thermal lactamization (74-98% yield). Identical products 20a-22a were directly
accessible by the intramolecular [2 + 2]-photocycloaddition of acrylic acid amides 2-4 (41-61% yield).
The suitability of both pathways for an enantioselective reaction variant was proven (70-92% ee). Thus,
tetracyclic lactams possessing the carbon framework C were obtained with good yields and enantiose-
lectivities of up to 92% ee in intramolecular reactions. Comparative investigation of both routes showed
that quinolone dimerization was the single most decisive factor preventing a complete chirality transfer.
Functional group manipulations were successfully conducted with the primary photoproduct exo-17a.
Finally, a new and unexpected type of benzylic hydrogen abstraction-radical cyclization reaction was
discovered for substrate 5a, which explains the photochemical instability of substrates 2-5 under short
wavelength irradiation (λ ) 300 nm).
Introduction
remained limited to the upper [5,6,5] tricyclic core structure.6
All of the above-mentioned biomimetic and total synthetic
methods rely on the formation of the quinoline moiety in a late
or final step of the synthesis.
Following a fundamentally different approach and starting
from intact 2-quinolones, we plan to access the lower part of
the Melodinus ring system B using a 1,2-rearrangement of
precursor structure C (Figure 1).7 The envisioned diastereose-
lective 1,2-σ-bond shift should ideally conserve the stereogenic
centers on the quinolone c-bond. Thus, complete stereocontrol
The incorporation of a quinoline moiety within a monoter-
penoid alkaloid skeleton represents a very rare structural feature
in the world of natural products, uniquely found in a small group
of alkaloids from the Apocynacea species Melodinus spp.1
Following its close structural relationship with indole alkaloids
of the Aspidospermine2 and Leuconolam type, several biomi-
metic syntheses of the pentacyclic Melodinus ring system A
have been accomplished.3 However, only a single racemic total
synthesis of the prototypical compound (()-meloscine4 has been
reported to date,5 and attempts at an asymmetric synthesis have
(2) For reviews of Aspidospermine alkaloids and numerous syntheses,
see: (a) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, CA, 1998; Vol. 51, pp 1-197. (b) Kutney, J. P. In The
total synthesis of natural products; ApSimon, J., Ed.; Wiley & Sons: New
York, 1977; Vol. 3, pp 372-397. (c) Do¨pke, W. In Ergebnisse der Alkaloid-
Chemie 1960-1968; Akademie-Verlag: Berlin, 1976; pp 1049-1077.
(1) Reviews: (a) Cordell, G. A. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1979; Vol. 17, p 261. (b) Cordell, G. A.;
Saxton, J. E. In The Alkaloids; Academic Press: New York, 1981; Vol.
20, p 183.
10.1021/jo0606608 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/28/2006
5662
J. Org. Chem. 2006, 71, 5662-5673

Photochemistry of 4-(2′-Aminoethyl)quinolones
FIGURE 1. General structures of the Melodius alkaloid ring system
A and the envisioned precursor structures B and C.
of the [3.3.0]-bicyclic structure B should be feasible via a
stereoselective synthesis of the preceding [4.2.0]-bicyclic ring
system C.
FIGURE 2. Structure of the chiral complexing agent 1 and the
quinolone substrates for the intra- (2-4) and intermolecular (5a-5c)
enantioselective [2 + 2]-photocycloadditions.
Cyclobuta[1,2-c]quinolones such as C are well-known to be
accessible by the [2 + 2]-photocycloaddition reaction8 of olefins
and 2-quinolone.9,10 This reaction has been thoroughly inves-
tigated for simple 4-alkoxyquinolones by Kaneko and Naito.11
Preliminary investigations in our group suggested the applicabil-
ity of this method also for bulky N-protected 4-(2′-aminoethyl)-
quinolones.12 As an important feature of the photochemical
synthesis of structure C, the 2-quinolone substrates allow for
the [2 + 2]-photocycloaddition to be conducted in an enantio-
selective fashion. Enantioselectivity arises from the efficient
hydrogen bond-mediated complexation to the chiral complexing
agent 1 (Figure 2). In such a complex, the bulky tetrahy-
dronaphthalene shield effectively blocks one of the two enan-
tiotopic faces of the prochiral, planar quinolone substrates and
thus creates the necessary chiral environment for the enantio-
selective reaction to occur.13
employ, for example, inclusion complexes,15 ionic auxiliaries,16
or chirally modified zeolites.17 While these solid-state reactions
are generally limited to intramolecular transformations,18 reac-
tions in solution naturally greatly expand the scope of suitable
substrates.19 However, these synthetically more useful enantio-
selective photoreactions in solution, achieved for example by
means of chiral solvents20 or circularly polarized light,21 until
recently gave only mediocre results with respect to both yields
and enantioselectivities.22,23 The advent of the chiral complexing
(14) Reviews: (a) Sakamoto, M. In Chiral Photochemistry; Inoue, Y.,
Ramamurthy, V., Eds.; Dekker: New York, 2004, pp 415-461. (b) Ito, Y.
Synthesis 1998, 1-32. (c) Toda, F. Acc. Chem. Res. 1995, 28, 480-486.
(15) Review: Toda, F. Aust. J. Chem. 2001, 54, 573-582.
(16) Reviews: (a) Scheffer, J. R.; Xia, W. Top. Curr. Chem. 2005, 254,
233-262. (b) Scheffer, J. R. Can. J. Chem. 2001, 79, 349-357. (c) Gamlin,
J. N.; Jones, R.; Leibovitch, M.; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc.
Chem. Res. 1996, 29, 203-209.
(17) Review: Sivaguru, J.; Natarajan, A.; Kaanumalle, L. S.; Shailaja,
J.; Uppili, S.; Joy, A.; Ramamurthy, V. Acc. Chem. Res. 2003, 36, 509-
521.
Enantioselective photochemical reactions have long been and
still are an especially challenging field of synthetic organic
chemistry. Creation of a chiral environment around achiral
substrates has been successfully achieved in the solid state,
especially in homochiral crystals.14 Alternative approaches
(18) For an interesting exception of an enantioselective intermolecular
reaction in the solid state, see: Koshima, H.; Ding, K.; Chisaka, Y.;
Matsuura, T. J. Am. Chem. Soc. 1996, 118, 12059-12065.
(3) (a) Hugel, G.; Le´vy, J. J. Org. Chem. 1984, 49, 3275-3277. (b)
Hugel, G.; Le´vy, J. J. Org. Chem. 1986, 51, 1594-1595. (c) Palmisano,
G.; Danieli, B.; Lesma, G.; Riva, R.; Riva, S.; Demartin, F.; Masciocchi,
N. J. Org. Chem. 1984, 49, 4138-4143. (d) Goh, S. H.; Ali, A. R. M.
Tetrahedron Lett. 1986, 27, 2501-2504. (e) Goh, S. H.; Ali, A. R. M.;
Wong, W. H. Tetrahedron 1989, 45, 7899-7920.
(4) (a) Bernauer, K.; Englert, G.; Vetter, W. Experientia 1965, 21, 374-
375. (b) Bernauer, K.; Englert, G.; Vetter, W.; Weiss, E. HelV. Chim. Acta
1969, 52, 1886-1905. (c) Oberha¨nsli, W. E. HelV. Chim. Acta 1969, 57,
1905-1911.
(5) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem.
Soc. 1991, 113, 2598-2610.
(6) Schultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645-648.
(7) For examples of similar 1,2-rearrangements, see: (a) Connolly, P.
J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 4135-4144. (b) Crimmins,
M. T.; Carroll, C. A.; Wells, A. J. Tetrahedron Lett. 1998, 39, 7005-7008.
(8) For general reviews of [2 + 2]-photocycloaddition reactions, see:
(a) Fleming, S. A. In Molecular and Supramolecular Photochemistry:
Synthetic Organic Photochemistry; Griesbeck, A. G., Mattay, J., Eds.;
Dekker: New York, 2005; Vol. 12, pp 141-160. (b) Margaretha, P. In
Molecular and Supramolecular Photochemistry: Synthetic Organic Pho-
tochemistry; Griesbeck, A. G., Mattay, J., Eds.; Dekker: New York, 2005;
Vol. 12, pp 211-237. (c) Bach, T. Synthesis 1998, 683-703. (d) Fleming,
S. A.; Bradford, C. L.; Gao, J. J. In Molecular and Supramolecular
Photochemistry: Organic Photochemistry; Ramamurthy, V., Schanze, K.
S., Eds.; Dekker: New York, 1997; Vol. 1, pp 187-243. (e) Pete, J.-P.
AdV. Photochem. 1996, 21, 135-216. (f) Crimmins, M. T.; Reinhold, T.
L. Org. React. 1993, 44, 297-583. (g) Baldwin, S. W. Org. Photochem.
1981, 5, 123-225.
(9) Evanega, G. R.; Fabiny, D. L. J. Org. Chem. 1970, 35, 1757-1761.
(10) Buchardt, O.; Christensen, J. J.; Harrit, N. Acta Chem. Scand. B
1976, 30, 189-192.
(11) Review: Kaneko, C.; Naito, T. Heterocycles 1982, 19, 2183-2206.
(12) Brandes, S.; Selig, P.; Bach, T. Synlett 2004, 2588-2590.
(13) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc.
2002, 124, 7982-7990.
(19) For general reviews of enantioselective photochemisty in solution,
see: (a) Everitt, S. R. L.; Inoue, Y. In Organic Molecular Photochemistry;
Ramamurthy, V., Schanze, K. S., Eds.; Dekker: New York, 1999; pp 71-
130. (b) Inoue, Y. Chem. ReV. 1992, 92, 741-770. (c) Rau, H. Chem. ReV.
1983, 83, 535-547.
(20) Examples: (a) Seebach, D.; Oei, H.-A.; Daum, H. Chem. Ber. 1977,
110, 2316-2333. (b) Boyd, D. R.; Campbell, R. M.; Coulter, P. B.;
Grimshaw, J.; Neill, D. C.; Jennings, W. B. J. Chem. Soc., Perkin Trans.
1 1985, 849-855.
(21) Examples: (a) Bernstein, W. J.; Calvin, M.; Buchardt, O. J. Am.
Chem. Soc. 1973, 95, 527-532. (b) Buchardt, O. Angew. Chem. 1974, 86,
222-228. (c) Moradpour, A.; Kagan, H.; Baes, M.; Morren, G.; Martin, R.
H. Tetrahedron 1975, 31, 2139-2143. (d) Zandomeneghi, M.; Cavazza,
M. J. Am. Chem. Soc. 1984, 106, 7261-7262. (e) Shimizu, Y.; Kawanishi,
S. J. Chem. Soc., Chem. Commun. 1996, 819-820. (f) Nishino, H.; Kosaka,
A.; Hembury, G. A.; Aoki, F.; Miyauchi, K.; Suitomi, H.; Onuki, H.; Inoue,
Y. J. Am. Chem. Soc. 2002, 124, 11618-11627.
(22) For representative references related to the photochemical synthesis
of enantiomerically pure materials by an auxiliary approach, see: (a) Tolbert,
L. M.; Ali, M. B. J. Am. Chem. Soc. 1982, 104, 1742-1744. (b) Koch, H.;
Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217-3220. (c)
Meyers, A. I.; Fleming, S. A. J. Am. Chem. Soc. 1986, 108, 306-307. (d)
Demuth, M.; Palomer, A.; Sluma, H.-D.; Dey, A. K.; Kru¨ger, C.; Tsay,
Y.-H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1117-1119. (e) Bertrand,
S.; Hoffmann, N.; Pete, J.-P. Tetrahedron 1998, 54, 4873-4888. (f) Chen,
C.; Chang, V.; Cai, X.; Duesler, E.; Mariano, P. S. J. Am. Chem. Soc. 2001,
123, 6433-6434. (g) Faure, S.; Piva-Le-Blanc, S.; Bertrand, C.; Pete, J.-
P.; Faure, R.; Piva, O. J. Org. Chem. 2002, 61, 1061-1070 and references
therein. (h) Saito, H.; Mori, T.; Wada, T.; Inoue, Y. J. Am. Chem. Soc.
2004, 126, 1900-1906. (i) Mori, T.; Weiss, R. G.; Inoue, Y. J. Am. Chem.
Soc. 2004, 126, 8961-8975.
(23) For examples of catalytic enantioselective photoreactions, see: (a)
Kim, J.-I.; Schuster, G. B. J. Am. Chem. Soc. 1992, 114, 9309-9317. (b)
Hoffmann, R.; Inoue, Y. J. Am. Chem. Soc. 1999, 121, 10702-10710. (c)
Asaoka, S.; Wada, T.; Inoue, Y. J. Am. Chem. Soc. 2003, 125, 3008-
3027.
J. Org. Chem, Vol. 71, No. 15, 2006 5663

Selig and Bach
SCHEME 1
agent 1 has significantly changed this picture and enabled both
intra- and intermolecular photochemical reactions in solution
to be performed with unprecedented yields and enantiomeric
purities.24
Compound 1 derived from Kemp’s triacid25 was originally
designed in our laboratories to enable enantioselective [2 +
2]-photocycloadditions,26,27 but additional applications for vari-
ous types of photochemical transformations have been estab-
lished.28 Recently, the application of 1 has been successfully
expanded to enantioselective radical cyclizations,29 and it has
been used as an NMR analytical tool.30 To date, complexing
agent 1 is the most efficient compound for enantioselective
photoreactions mediated by hydrogen bonding to a chiral
receptor,31 although its use is naturally limited to sufficiently
complexable substrate structures such as quinolones or pyri-
dones.32
Results and Discussion
Following our preliminary studies on the synthesis of
compounds possessing the carbon skeleton C,12 we present here
in detail our work on the intra- and intermolecular racemic and
enantioselective [2 + 2]-photocycloadditions of quinolones 2-5
(Figure 2). Until now (with the single exception of diketene
photocycloaddition33) no example of an intermolecular [2 +
2]-photocycloaddition between a quinolone and an unsymmetri-
cally 1,1-substituted olefin has been reported, and only the
simple 4-methoxyquinolone has been studied in the enantiose-
lective intermolecular [2 + 2]-photocycloaddition using the
chiral complexing agent 1.13,27 Thus, a first detailed study was
conducted on the intermolecular [2 + 2]-photocycloaddition
between N-protected quinolones 5a-5c and different 2-alkyl-
substituted acrylates, both under racemic and chiral reaction
conditions. Leading to identical tetracyclic 1,9,10,11a-tetrahy-
dro-1aH-pyrido[4′,3′:2,3]-cyclobuta[1,2-c]quinoline-2,11-
(3H,8 H)-diones of structure C, a detailed comparison between
inter- and intramolecular reaction pathways was possible. In
addition to the anticipated [2 + 2]-photocycloaddition, benzyl-
protected substrate 5a was shown to undergo a new and
unexpected type of photochemical hydrogen abstraction-radical
cyclization reaction. Finally, different precursors for the desired
1,2-rearrangement were accessible from functional group ma-
nipulations on cyclobuta[c]quinolone carboxylates.
Preparation of Starting Materials. All starting materials
2-5 were synthesized starting from the common precursor
4-bromoethylquinolone (6), which was easily available using a
literature-known four-step transformation of inexpensive 4-me-
thylquinolone (7).34 The synthesis of the chiral complexing agent
1 has been reported previously.35
As depicted in Scheme 1, reaction of 6 with neat primary
amines gave the intermediate N-alkylamines 8a-8c in high
yields. For all following substances differing only in the N-alkyl
protecting group, lower case letters a-c will be used to
distinguish between the benzyl (a), para-methoxybenzyl (PMB,
b), and tert-butyl (c) residue. Acylation of amine 8a with acrylic
acid chlorides 9-11 to the corresponding amides 2-4 proceeded
surprisingly well, despite the methylenic R,â-unsaturation of
the acid chlorides. The substrates for intramolecular reactions
already incorporate an N-acyl protecting group necessary for
successful [2 + 2]-photocycloadditions. Simple amines generally
suffer from severe side reactions due to photoinduced electron
transfer under irradiation.36 Thus, amines 8a-8c were N-Boc-
protected to give the desired substrates 5a-5c for the intermo-
lecular reactions. The Boc protective group was chosen because
of its high stability, a significant enhancement of substrate
solubility in apolar solvents, and the possibility of mild cleavage
orthogonal to the N-alkyl groups.37 While 8a,8b were easily
protected in high yields (>90%) using di-tert-butyldicarboxylate
(Boc2O) in CH2Cl2, the attempted acylation of sterically
hindered tert-butylamine 8c either showed insufficient substrate
conversion or lacked selectivity if more drastic reaction condi-
tions were employed. Selective Boc protection to 5c was finally
achieved in acceptable yields (67%) under solvent-free condi-
tions using an excess of Boc2O at 100 °C.38 All desired 4-(2′-
aminoethyl)quinolones were thus obtained in high yields and
multigram quantities by simple and robust two-step sequences.
To grant a maximum of comparability with the intramolecular
[2 + 2]-photocycloadditions of acrylic acid amides 2-4, 2-alkyl-
substituted acrylates were chosen as olefin components in the
intermolecular reactions. Methyl acrylate (12), methyl meth-
(24) Reviews: (a) Grosch, B.; Bach, T. In Organic Photochemistry and
Photobiology; Horspool, W., Lenci, E., Eds.; CRC Press: Boca Raton, FL,
2004; pp 61/1-61/14. (b) Grosch, B.; Bach, T. In Chiral Photochemistry;
Inoue, Y., Ramamurthy, V., Eds.; Dekker: New York, 2004; pp 315-340.
(c) Wessig, P. Angew. Chem., Int. Ed. 2006, 45, 2168-2171.
(25) Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140-5143.
(26) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem., Int. Ed. 2000,
39, 2302-2304.
(27) Bach, T.; Bergmann, H. J. Am. Chem. Soc. 2000, 122, 11525-
11526.
(28) (a) Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Kaneda, M.; Wada,
T.; Inoue, Y.; Bach, T. Chem.-Eur. J. 2004, 10, 2179-2189. (b) Bach,
T.; Grosch, B.; Strassner, T.; Herdtweck, E. J. Org. Chem. 2003, 68, 1107-
1116. (c) Bauer, A.; Westka¨mper, F.; Grimme, S.; Bach, T. Nature 2005,
436, 1139-1140.
(29) Aechtner, T.; Dressel, M.; Bach, T. Angew. Chem., Int. Ed. 2004,
43, 5849-5851.
(30) Bergmann, H.; Grosch, B.; Sitterberg, S.; Bach, T. J. Org. Chem.
2004, 69, 970-973.
(34) Uchida, M.; Tabusa, F.; Komatsu, M.; Morita, S.; Kanabe, T.;
Nakagawa, K. Chem. Pharm. Bull. 1985, 33, 3775-3786.
(35) Bach, T.; Bergmann, H.; Grosch, B.; Harms, K.; Herdtweck, E.
Synthesis 2001, 1395-1405.
(36) For a review of PET reactions, see: Lewis, F. D. Acc. Chem. Res.
1986, 19, 401-405.
(37) Greene, T. W.; Wuts, P. G. M. ProtectiVe groups in organic
synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(38) Kabalka, G. W.; Li, N.-S.; Pace, D. R. Synth. Commun. 1995, 25,
2135-2143.
(31) For an alternative approach towards a chiral receptor for [2 +
2]-photocycloadditions, see: Cauble, D. F.; Lynch, V.; Krische, M. J. J.
Org. Chem. 2003, 68, 15-21.
(32) For an example of enantioselective reactions on pyridones, see:
Bach, T.; Bergmann, H.; Harms, K. Org. Lett. 2001, 3, 601-603.
(33) (a) Chiba, T.; Okada, M.; Kato, T. J. Heterocycl. Chem. 1982, 19,
1521-1525. (b) Chiba, T.; Kato, T.; Yoshida, A.; Moroi, R.; Shimomura,
N.; Momose, Y.; Naito, T.; Kaneko, C. Chem. Pharm. Bull. 1984, 32, 4707-
4720.
5664 J. Org. Chem., Vol. 71, No. 15, 2006

Photochemistry of 4-(2′-Aminoethyl)quinolones
head-to-head (HH) products for acceptor-substituted olefins.42,43
The exclusive formation of cis-fused cyclobuta[c]quinolones is
most conveniently explained by the steric rigidity of the
quinolone ring.9 As with simple 4-methoxyquinolone, the
reaction with 2-unsubstituted methyl acrylate (12) additionally
displayed a high degree of simple diastereoselectivity,44 with
the exo-HT products 16a-16c formed almost exclusively
(entries 1, 5, and 9). With increasingly bulky 2-substituents at
the acrylate, however, this selectivity was systematically
diminished (entries 2, 3, 6, 7, 10, and 11) by the formation of
endo-diastereoisomers. With R2 ) Et only a slight preference
for the exo-products was preserved. Fortunately, the diastereo-
isomeric mixtures were at least partly separable using simple
flash chromatography, with the separation becoming increasingly
difficult for unpolar, especially tBu-protected photoproducts. In
contrast, the most polar diastereomeric tulipaline cycloadducts
19a-19c were separable without problem. Sufficiently pure
samples of all exo-diastereoisomers 16a/b/c-19a/b/c could thus
be obtained, yet isolation of pure endo-diastereoisomers of 17c,
18b, and 18c was not achieved. While the diastereoselectivity
of the reactions was profoundly dependent on the nature of
acrylate substituents R2, sterically constraining the acrylate ester
moiety in a cyclic system exhibited no significant effect. The
spirocyclic lactones 19a-19c displayed nearly identical dia-
stereomeric ratios (d.r.) as their open-chain analogues 17a-
17c. While the strong influence of the acrylate substitution was
not unexpected, the observed effect of the N-alkyl protecting
groups on the diastereomeric ratios came as a surprise. These
groups are both electronically separated and sterically distant
from the reacting quinolone double bond. However, N-tBu-
protected quinolone 5c repeatedly exhibited a degree of exo-
diastereoselectivity (entries 9-12) higher than that of the
benzylic-protected substrates 5a and 5b (entries 1-8). The
surplus of exo-isomers generally consisted of 15-20%. In
contrast, only a slight electronic modification of the benzyl
protective group (Bn vs PMB) left the obtained diastereomeric
ratios unaffected. The influence of the tBu group can therefore
best be explained by its steric influence on the intermediate 1,4-
diradical species formed in the course of the [2 + 2]-photocy-
cloaddition. The competition between diradical cleavage and
ring closure is well-known to decisively affect both the regio-
and the diastereoselectivity of [2 + 2]-photocycloadditions.42,45
SCHEME 2
TABLE 1. Intermolecular [2 + 2]-Photocycloaddition Reactions
between Quinolones 5a-5c (5-30 mM) and Acrylates 12-15 (5-20
Equiv) in Toluene at λ ) 350 nm (RPR 3500 Å, 35 °C)
yielda
d.r.b
entry substrate acrylate R1
R2
R3 product (%) (exo/endo)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5b
5b
5b
5c
5c
5c
5c
12
13
14
15
12
13
14
15
12
13
14
15
Bn
Bn
Bn
Bn
H
CH3 16a
CH3 17a
80
89
75
82
87
84
91
74
91
77
76
83
92/8
CH3
73/27
58/42
72/28c
>90/10
71/29
60/40
71/29c
>95/5
83/17
69/31
80/20c
CH2CH3 CH3 18a
-CH2CH2- 19a
PMB
H
CH3 16b
CH3 17b
PMB CH3
PMB CH2CH3 CH3 18b
PMB -CH2CH2- 19b
tBu
tBu CH3
H
CH3 16c
CH3 17c
10
11
12
tBu CH2CH3 CH3 18c
tBu
-CH2CH2-
19c
a Yield of isolated products (sum of both diastereoisomers). b d.r.
determined by HPLC and NMR analysis of the crude product mixture.
c Diastereoisomers were completely separated. The given d.r.’s correspond
to isolated, pure exo- and endo-diastereoisomers.
acrylate (13), and its cyclic analogue tulipaline (15) were
commercially available. Methyl-2-ethyl acrylate (14) was
prepared according to established procedures39 and converted
to its acyl chloride 11 by straightforward reaction with SOCl2.40
Racemic [2 + 2]-Photocycloaddition Experiments. For
intermolecular [2 + 2]-photocycloadditions, the N-protected
quinolones 5a-5c were irradiated with a moderate excess of
acrylates 12-15 to give an array of 12 (3 × 4) photoproducts
(Scheme 2). In contrast to our previous experiments on similar
aminoethylquinolones, irradiation at λ ) 300 nm proceeded
sluggishly and gave complex mixtures without defined cycload-
dition products (vide infra). Hence, irradiations were conducted
in toluene solution in a Rayonet photoreactor with a wavelength
of λ ) 350 nm (RPR 3500 Å) at 35 °C. These irradiations
proceeded smoothly in the concentration range of 5-30 mM
of quinolone and with 5-20 equiv of acrylate to give the desired
photoproducts 16a/b/c-19a/b/c in high yields. In addition to a
linear correlation between quinolone concentration and the
reaction time until complete conversion (5-30 mM T 0.5-
3.0 h), variations of substrate concentration were without
significant influence on the outcome of the reactions. The results
of the racemic intermolecular [2 + 2]-photocycloaddition
reactions are summarized in Table 1.
t
A steric effect of the Bu group on the corresponding relative
rate constants does not seem unlikely.46
Intramolecular racemic [2 + 2]-photocycloaddition reactions
of acrylic acid amides 2-4 were carried out under the same
conditions established for intermolecular irradiations (toluene
solution, RPR 3500 Å, λ ) 350 nm, 35 °C). However, in
contrast to the high yields of photoproducts obtained in the
intermolecular reactions, the six-membered lactams 20a-22a
could only be isolated in moderate yields (Scheme 3, upper
section). Due to steric constraints, cis-cis-annelated tetracyclic
products with a straight cyclobutane and a six-membered lactam
All [2 + 2]-photocycloadditions resulted exclusively in the
formation of cis-annelated head-to-tail (HT) products. The
observed regioselectivity is in clear contrast to the so-called
Corey-De Mayo rules,41 predicting a favored formation of
(42) Erickson, J. A.; Kahn, S. D. Tetrahedron 1993, 49, 9699-9712.
(43) For alternative mechanistic explanations of the regioselectivity of
intermolecular [2 + 2]-photocycloaddtions, see: (a) Schuster, D. I.; Lem,
G.; Kaprinidis, N. A. Chem. ReV. 1993, 93, 3-22. (b) Bauslaugh, P. G.
Synthesis 1970, 2, 287-300.
(44) Kaneko, C.; Naito, T. Chem. Pharm. Bull. 1979, 27, 2254-2256.
(45) Andrew, D.; Hastings, D. J.; Weedon, A. C. J. Am. Chem. Soc.
1994, 116, 10870-10882.
(46) For studies about the importance of intermediate diradicals in
Paterno-Bu¨chi photocycloaddition, see: Abe, M.; Kawakami, T.; Ohata,
S.; Nozaki, K.; Nojima, M. J. Am. Chem. Soc. 2004, 126, 2838-2846.
(39) (a) Iwakura, Y.; Sato, M.; Matsuo, Y. Chem. Abstr. 1961, 3427-
3228. (b) Attu-Ur-Rahman; Beisler, J. A.; Harley-Mason, J. Tetrahedron
1979, 36, 1063-1070.
(40) Marshalok, G. A.; Yatchishin, I. I.; Tolopko, D. K. Russ. J. Org.
Chem. 1981, 17, 603-608.
(41) (a) Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am.
Chem. Soc. 1964, 86, 5570-5583. (b) De Mayo, P. Acc. Chem. Res. 1971,
4, 41-47.
J. Org. Chem, Vol. 71, No. 15, 2006 5665

Selig and Bach
SCHEME 3
FIGURE 3. Significant NOE contacts in cyclobuta[c]quinolones 17a-
17c and tetracyclic lactams 21a,21b (solid line: strong; broken line:
weak).
to 110 °C. In contrast, R-alkyl-substituted aminoesters 25a,25b
and 26a,26b were stable substances, indicating a profound
influence of the alkyl substituent on the preferred relative
conformation of the carboxylic ester. Even prolonged refluxing
in toluene resulted only in traces of the desired product 22a,22b
for R2 ) Me, and free amines 26a,26b (R2 ) Et) remained
completely unchanged under these conditions. Lactamization
of these hindered substrates could eventually be achieved by
simple heating of the crude aminoesters above their respective
melting points under Ar.48 The condensation was clearly
apparent by the evolution of gaseous methanol at 170-220 °C,
and yields were high to excellent in all cases. Neat heating in
an inert atmosphere generally proved to be the quickest and
highest-yielding method of lactamization for all intermediates
24a/b-27a/b regardless of their residues R2. All N-Bn and
N-PMB-protected amines were thus easily converted to the
corresponding eight tetracyclic lactams 20a/b-23a/b in high
ring were formed exclusively.47 Crossed products or trans-
annelation could not be detected in any case. Even at substrate
concentrations as low as 5 mM, formation of polar side products
was evident, indicated by the occurrence of insoluble, yellow
precipitates. The effect was most pronounced for R-unsubstituted
substrate 2, yielding only 41% of the desired product 20a, but
yields did not exceed 61% for R-methyl and R-ethyl lactams
21a and 22a, either. Since the N-benzyl aminoethylquinolones
have already shown a high reactivity in intermolecular reactions
even with a comparably low amount of olefinic reaction partner,
these precipitates most probably originate from intermolecular
oligomerization of the substrate molecules. However, further
reduction of the substrate concentration to values as low as 0.5
mM did not significantly drive back these undesired reactions.
A strong tendency toward the formation of associates even in
very dilute solutions was therefore assumed, which was
confirmed in consecutive experiments (vide infra).
Tetracyclic lactams 20a/b-23a/b could also be synthesized
from the products of the intermolecular [2 + 2]-photocycload-
dition using a two-step sequence of Boc deprotection and
thermal lactamization (Scheme 3, lower section). Thus, lactams
20a-22a were accessible by both inter- and intramolecular [2
+ 2]-photocycloaddition and proved identical in both physical
and spectroscopic properties regardless of the synthetic method
applied. Cleavage of the N-Boc-group with 10% v/v trifluoro-
acetic acid (TFA) in CH2Cl2 proceeded smoothly with yields
generally >80% for all photoproducts. Due to the steric
constraints mentioned before, only photoproducts with the
carboxyl group exo relative to the bicyclic cyclobutane system
were suitable for lactamization. The endo substituents R2 showed
a remarkably strong influence on the reactivity of the free
secondary amines 24a/b-27a/b. Spirocyclic lactones 27a and
27b already cyclized to a large extent under the standard workup
conditions of the Boc deprotection due to relief of ring strain.
Conversion could be completed by short heating of the product
to 70 °C in toluene. Crude amines 24a and 24b with no endo
substituent (R2 ) H) also showed a moderate amount of
condensation products 20a and 20b after N-Boc deprotection,
yet completion of the reaction required longer heating in toluene
t
overall yields. As expected, Bu-protected amines were com-
pletely unreactive toward lactamization, due to the steric bulk
of the N-substituent. Even prolonged heating of model com-
pound 24c (R2 ) H) to 220 °C only resulted in a slow
decomposition with no cyclization product being observable.
The synthesis of the desired lactams was generally higher
yielding by the intermolecular than by the intramolecular [2 +
2]-photocycloaddition route. The efficiency of the intermolecular
route was, however, somewhat limited by the diastereomeric
ratios of the photocycloaddition step. Thermal lactamization was
not significantly impaired when the reaction was carried out in
a diastereoisomeric mixture. However, the decomposition of
endo-diastereoisomers to various polar side products made the
separation of pure lactams much more difficult. In summary,
synthesis of the desired lactams was most efficient via the
intermolecular route for R2 ) H and R2 ) CH2CH2OH (20a,20b
and 23a,23b). Unfavorable diastereoselectivities in intermo-
lecular [2 + 2]-photocycloadditions with R2 ) Me and R2 )
Et rendered the intramolecular route more favorable for lactams
21a and 22a. Unfortunately, this alternative route showed
inferior yields in both the acylation and the cycloaddition steps.
Lactamization finally served as an ultimate proof of the
assignment of relative configurations to exo- and endo-diaste-
reoisomers, which was previously conducted on the basis of
observable NOE contacts in photocycloaddition products 16-
19 (Figure 3).
Kinetic Studies, H-Abstraction, and Intramolecular Radi-
cal Cyclization of Substrate 5a. As discussed earlier, N-benzyl-
protected aminoethylquinolones 2-4 and 5a were nicely suited
(47) For the regioselectivity of intramolecular [2 + 2]-photocycloaddi-
tions, see: Liu, R. S. H.; Hammond, J. S. J. Am. Chem. Soc. 1967, 89,
4936-4944.
(48) Schnell, H.; Nentwig, J. In Methoden der Organischen Chemie
(Houben-Weyl); Thieme: Stuttgart, 1958; Vol. XI/2, p 529.
5666 J. Org. Chem., Vol. 71, No. 15, 2006

Photochemistry of 4-(2′-Aminoethyl)quinolones
SCHEME 4
for [2 + 2]-photocycloaddition reactions using an irradiation
wavelengths of λ ) 350 nm. To elucidate the unexplained side
reactions arising from irradiations at λ ) 300 nm, model
compound 5a was irradiated without an olefinic reaction partner
at both wavelengths. Detailed HPLC studies of the reaction
mixtures unexpectedly indicated the formation of three new
substances, all of which could be isolated in pure form
(Scheme 4).
FIGURE 4. Time profile of the irradiation of pure quinolone 5a (10
mM, toluene) at λ ) 350 nm. The relative amounts of substrate and
products were determined by HPLC analysis of the reaction mixture.
Product 28 arose from a reversible [2 + 2]-photocycloaddition
of two molecules of 5a and could clearly be identified as a
substrate dimer by means of NMR and ESI-MS spectroscopy.
As even small substituents in the 4-position of 2-quinolones
have been reported to severely hinder quinolone dimerization,49
the occurrence of up to 36% yield of isolated substrate dimer
came as a surprise. Spectroscopic methods remained futile in
the assignment of dimer stereochemistry, and thus an HH-cis-
anti-cis connection can only be assumed following earlier
studies.50 The two remaining products were identified as the
diastereoisomeric spiro-pyrrolidines 29 and 30. These products
possibly resulted from an initial hydrogen abstraction at the
N-benzylic position via a seven-membered transition state and
a subsequent radical process. An alternative mechanism involv-
ing a photoelectron transfer (PET) from the N-Boc-protected
nitrogen atom to the excited quinolone and subsequent benzylic
H-abstraction seems unlikely due to the high oxidation potential
of amides and especially carbamates.51 While PET-promoted
photocyclization reactions are well-known for alkylamines,52
corresponding reactions of alkylcarbamates have not been
reported, and the only carbamates successfully employed in
PET-promoted radical cyclization reactions thus far were
additionally stabilized by R-silyl substituents.53,54 As NOE
spectroscopy again could give no clear configuration assignment
for either 29 and 30 or their respective N-Boc-deprotected
derivatives 31 and 32, the attribution of relative configuration
was based on the strong anisotropic effect of the aromatic phenyl
At first glance, Figure 4 seems to indicate a consecutive
reaction with dimer 28 serving as an intermediate. This could
be disproved by the following observations. First, reduction of
the substrate concentration to 2.5 mM did markedly lower the
amount of dimer 28 but was without any effect on the rate of
formation of 29 and 30. Second, in all irradiation experiments
substrate 5a was never entirely consumed but remained present
in different, albeit small, equilibrium amounts. Hydrogen
abstraction and [2 + 2]-dimerization therefore most likely
constitute two independent types of reaction. Upon switching
the irradiation wavelength from λ ) 350 nm to λ ) 300 nm,
only minimal amounts of [2 + 2]-photodimer 28 could be
observed and the formation of radical cyclization products was
accelerated. A total of 66% of analytically pure spiro-pyrro-
lidines 29/30 (d.r. ) 50/50) could be isolated. Thus, irradiation
at λ ) 300 nm seems to favor H-abstraction, while λ ) 350
nm favors [2 + 2]-photocycloaddition. The pronounced influ-
ence of the excitation wavelength on the type of dominant
photoreaction suggests that different types of excited states give
rise to photocycloaddition and H-abstraction. [2 + 2]-Photo-
cycloadditions on 2-quinolones are thought to originate from
the lowest-lying triplet state,10 resulting primarily in 1,4-
diradicals after reaction with the olefin component. In contrast,
the observed type of H-abstraction could be the result of
electronically different intermediates formed by higher-energy
excitation. tBu-substituted quinolone 5c was irradiated to
measure the efficiency of the [2 + 2]-photocycloaddition without
the concurrence of H-abstraction. As expected, only an equi-
librium between substrate and dimer was observed. The amount
of dimer was 6.5% at λ ) 300 nm and 69% at λ ) 350 nm.
Contrary to benzylic amine 5a, addition of 5 equiv of methyl
acrylate (12) gave high yields of the [2 + 2]-product 16c for
both 350 and 300 nm. The reaction of 5c at λ ) 300 nm
proceeded approximately 2-3 times more slowly than at λ )
350 nm. This can conveniently be explained by the overall
smaller integral overlap of the long wavelength absorption
spectrum of quinolone 5c and the emission spectrum of RPR
3000 Å compared to RPR 3500 Å lamps.
1
ring on H chemical shifts of different parts of the quinolone
residue. While the two spirocyclic products were always
obtained in a ratio of roughly 50/50, the relative ratios of
pyrrolidines vs dimerization product were strongly dependent
on the reaction time (Figure 4). Irradiation of isolated dimer 28
resulted in the formation of both products 29 and 30 and the
substrate 5a, the former two being unreactive toward further
irradiation in pure form.
(49) Buchardt, O. Acta Chem. Scand. 1964, 18, 1389-1396.
(50) Taylor, E. C.; Paudler, W. W. Tetrahedron Lett. 1960, 25, 1-3.
(51) Yoshida, J.-I.; Isoe, S. Tetrahedron Lett. 1987, 28, 6621-6624.
(52) Example: Xu, W.; Zhang, X.-M.; Mariano, P. S. J. Am. Chem. Soc.
1991, 113, 8863-8878.
(53) Example: Jeon, Y. T.; Lee, C.-P.; Mariano, P. S. J. Am. Chem.
Soc. 1991, 113, 8847-8863.
(54) For the lowering effect of R-silyl substituents on oxidation potentials,
see: (a) Cooper, B. E.; Owen, W. J. J. Organomet. Chem. 1971, 29, 33-
40. (b) Yoshida, J.-I.; Maekawa, T.; Murata, T.; Matsunaga, S.-I.; Isoe, S.
J. Am. Chem. Soc. 1990, 112, 1962-1970.
The competition of hydrogen abstraction from the N-benzylic
position and subsequent radical reactions was therefore un-
doubtedly the decisive reason for futile [2 + 2]-photocycload-
dition attempts of substrates 5a and 5b at λ ) 300 nm. This
undesired reaction is considerably slowed at λ ) 350 nm in
favor of [2 + 2]-cycloaddition and can be completely suppressed
J. Org. Chem, Vol. 71, No. 15, 2006 5667

Selig and Bach
compared to the alkyl-substituted products (-)-17a-19a. This
might be a further hint for a different, more lactam-like confor-
mation of the carboxylic ester moiety, as was already indicated
by the very facile ring closure in the thermal lactamization. As
expected, conducting the reaction at higher temperatures lowered
the obtained enantiomeric excesses dramatically (entry 1).
However, variation of both quinolone and acrylate concentration
left the observed ee’s virtually unchanged (entries 2-5). Only
at very low quinolone concentrations of c ) 0.5 mM, reactions
proceeded slowly and uncleanly because of an apparent substrate
limitation. Possible side reactions due to hydrogen abstraction
were completely undetectable at -60 °C. Consequently, the type
of the N-alkyl protecting group R1 was expected to be without
significant influence. This was confirmed by the reaction of
methyl acrylate (12) with the tBu-protected quinolone 5c, which
gave basically identical results compared to its N-Bn counterpart
5a (entries 5 and 6). 2-Substitution in the acrylate component
showed to be without any effect on the enantioselectivity for
R2 ) Et (entry 8). Interestingly, a somewhat higher enantiose-
lectivity was obtained in the reaction with methyl methacrylate
(13), and ee’s were further increased with its cyclic analogue
14. Thus, spirocyclic product (-)-19a showed the highest
obtained enantiomeric excess with 81% ee. In comparison with
the previously reported intermolecular [2 + 2]-photocycload-
ditions on 4-methoxyquinolone (81-98% ee),13 however, all
observed enantioselectivities were slightly reduced.
FIGURE 5. Photochemical product formation via [2 + 2]-photocy-
cloaddition and/or hydrogen abstraction from substrate 5a (c ) 10 mM)
using different excitation wavelengths.
with a slight excess of a suitable olefinic reaction partner. A
comparison of reaction kinetics is depicted in Figure 5.
Remarkably, both types of photoreactions displayed zero-order
kinetics. It was therefore concluded that the reaction rates were
mainly limited by the photon flux over a broad concentration
range. Substrate limitation was a crucial factor only at the end
of the reaction, that is, at substrate concentrations <10% (rel.)
or <1 mM, respectively.
Formation of the undesired, minor enantiomers can theoreti-
cally arise from both incomplete complexation of the quinolone
itself and from incomplete chiral shielding of the complexed
quinolone. Acrylates might thus attack through a gap between
the quinolone and the tetrahydronaphthalene shield of 1. This
gap attack should be hindered by increasing the steric bulk of
R2. Such a limitation of enantioselectivity by incomplete
shielding is obviously contradicted by the comparably low ee
in the reaction with bulky methyl-2-ethyl acrylate (14). Con-
sequently, insufficient H-bonding between quinolones 5a/c and
the chiral complexing agent 1, probably due to competing strong
self-association of the quinolone, seems to be the dominant cause
for the incomplete chirality transfer from complexing agent to
photoproduct. NMR titration studies showed no weakening of
the quinolone complexation by the addition of up to 1000 mM
of methyl acrylate (13). A simple polar solvent effect of the
excess acrylates is therefore also unlikely. The nature of the
influence of R2 and R3 on the enantioselectivity of the reaction
thus remains unclear until now.
Enantioselective [2 + 2]-Photocycloaddition Experiments.
Enantioselective intra- and intermolecular [2 + 2]-photocy-
cloadditions with the chiral complexing agent 1 were performed
using conditions previously established to grant a maximum of
substrate complexation.27 Most importantly, an excess of 2.5
equiv of 1 was necessary to override self-association of the
2-quinolones. It is important to note here that self-association
of enantiopure 1 itself is effectively zero (see Supporting
Information), due to the steric bulk of the tetrahydronaphthalene
shield.13 To further diminish impairment of hydrogen bond
formation by solvent molecules or thermal movement, the
reactions were conducted in the aprotic, non-polar solvent
toluene at -60 °C, using a slightly modified Rayonet reactor
RPR 3500 Å with a low-temperature immersion well. As
concentration effects were expected to influence host-guest
association to a considerable degree, the enantioselective
intermolecular [2 + 2]-photocycloaddition was extensively
investigated with respect to both quinolone and acrylate
concentrations (Table 2). In general, neither cooling nor the
presence of 2.5 equiv of complexing agent 1 had any noticeable
influence on the reaction times, on the diastereomeric ratios
obtained, or on the product yields in comparison with the
corresponding racemic reactions at room temperature. Unfor-
tunately, endo-diastereoisomers could not be completely sepa-
rated from the complexing agent 1 due to similar polarities
(Scheme 5). However, compound 1 could be recovered in 70-
90% yield after the reactions, thus lowering the amount of
actually used receptor to 25-75 mol %. Complexing agent 1
can therefore reasonably be considered a “quasi-catalyst” in the
enantioselective reactions.
The obtained cycloaddition products (+)-16a and (-)-17a-
19a were further converted to the corresponding enantio-
enriched lactams (+)-20a-23a using established thermal condi-
tions (Scheme 3.) Not surprisingly, these transformations fully
conserved the enantiomeric excesses of the photoproducts
within the margin of error of chiral HPLC. (+)-20a-23a
were thus isolated with 71% ee (R2 ) H, Et) to 81% ee (R2 )
CH2CH2OH).
As in the racemic reactions at room temperature, yields of
intramolecular [2 + 2]-photocycloadditions using enantioselec-
tive standard conditions were noticeably reduced by undesired
intermolecular oligomerization. Amazingly, enantioselectivities
of these intramolecular reactions were uniformly higher or at
least equal to their intermolecular counterparts (Scheme 6).
All exo-products (+)-16a,16c and (-)-17a-19a could be
obtained with good enantioselectivities of 70-81% ee if the
reactions were conducted at low temperature. (+)-16a was
chosen as a model compound for further studies because of its
high d.r. and thus most facile product isolation. Interestingly,
(+)-16a showed the opposite sign of optical rotation as
The observed yields and ee’s can consistently be explained
by the competition between quinolone self-association and
complexation to the chiral receptor 1. While quinolone dimers
5668 J. Org. Chem., Vol. 71, No. 15, 2006

Photochemistry of 4-(2′-Aminoethyl)quinolones
TABLE 2. Enantioselective [2 + 2]-Photocycloaddition Reactions: 2.5 Equiv 1, RPR 3500 Å (Toluene)
entry
quinolone
cquin (mM)
acrylate
cacr (mM)
product
R1
R2
R3
T (°C)
yielda (%)
eeb(%)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5c
5a
5a
5a
20
5
20
20
5
5
5
5
5
12
12
12
12
12
12
13
14
15
200
25
100
55
25
25
25
25
25
(+)-16a
(+)-16a
(+)-16a
(+)-16a
(+)-16a
(+)-16c
(-)-17a
(-)-18a
(-)-19ac
Bn
Bn
Bn
Bn
Bn
tBu
Bn
Bn
Bn
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
+35
-50
-60
-60
-60
-60
-60
-60
-60
76
77
86
74
86
80
63
44
45c
32
70
71
73
72
70
76
71
81
CH3
CH2CH3
-CH2CH2-
a Yield of isolated exo-diastereoisomer. b ee determined by chiral HPLC. (Chiralpak, AD/AD-H). c Additional purification by chromatography on Alox
(neutral) was necessary.
SCHEME 5
single crystals for X-ray analysis could be obtained. However,
the absolute stereochemistry depicted in Schemes 5 and 6 is
very strongly supported by previous X-ray crystallographic
results on the [2 + 2]-photocycloaddition products of similar
2-methoxyquinolones which employed the very same complex-
ing agent 1.13
All experimental results indicated a pronounced tendency of
the employed aminoethylquinolones (2-5) toward self-associa-
tion. This was finally confirmed by means of NMR titration
experiments at room temperature in toluene-d6 (see Supporting
Information). Quantification of the obtained data was achieved
using the HOSTEST computer program.55 As expected, a 1:1
binding stoichiometry between 5a and 1 was evident. The
association constant of KA = 390 M-1 was comparable with
the value obtained for the complexation of 4-unsubstituted
2-quinolone and 1 (KA = 580 M-1).13 Thus, the bulky
4-substituent entails no hindering of host-guest complexation.
However, optimal curve-fit of the binding isotherm 5a/1 required
the assumption of an unusually large dimerization constant of
5a (KDim = 900 M-1). This high value was also confirmed by
a separate dilution experiment of pure 5a. Although a high
dimerization constant was indeed expected from the previous
observations, the fact that dimerization is even stronger than
host complexation came as a surprise. A casual role of secondary
π-stacking interactions in N-benzyl-protected quinolone 5a could
be ruled out by the fact that N-tBu-substituted 5c showed an
even larger dimerization constant.56 Substrate self-association
thus clearly represents the single most decisive factor for
incomplete complexation and chirality transfer from compound
1. Considering that dimerization is about twice as strong as
complexation, the ee values of >70% corresponding to a
substrate complexation of >85% might seem illogically high.
However, host-guest complexation is clearly enthalpically
favored over guest dimerization as self-association of complex-
ing agent 1 (KDim = 0 M-1) is completely suppressed by the
bulky tetrahydronaphthalene shield. Consequently, with an
excess of complexing agent 1, complexation of 5a and 1 gives
rise to two hydrogen bonds per quinolone molecule, while
dimerization of the substrate only results in two hydrogen bonds
per two quinolone molecules. Uncomplexed or excess 1 remains
uninvolved in hydrogen bonding. With the breaking of quinolone
dimers and the formation of host-guest complexes effectively
doubling the number of hydrogen bonds, enthalpy of complex-
ation is expected to override dimerization, despite the adverse
complexation constants KA , KDim. In addition to the mere
SCHEME 6
exclusively lead to the formation of racemic product in the
intermolecular case, association of amides 2-4 predominantly
results in the formation of intermolecular oligomerization
products. This difference in reactivity is further emphasized by
the fact that, in contrast to the intermolecular case, intramo-
lecular [2 + 2]-photocycloadditions are markedly slowed by
cooling to -60 °C. The difference in temperature dependence
is easily explained by the obvious requirement of close proximity
between the quinolone ring and the acrylate C,C-double bonds
for intramolecular reactions to occur. This is only likely in
strongly bent, comparably high-energy conformations of the
aminoethyl side chain. With these conformations being less
populated at low temperatures, the efficiency of intramolecular
reactions is markedly reduced. Lactams (+)-20a-22a produced
by intramolecular [2 + 2]-photocycloaddition are therefore
chiefly the product of monomeric and complexed substrates.
Hence, a widespread intermolecular oligomerization, although
lowering the yields, results in higher ee values of the lactam
products by reducing racemic intramolecular reactions. This
connection was confirmed by the irradiation of R-unsubstituted
quinolone 2, which gave both the lowest yield and the highest
ee, according to the most pronounced and visible formation of
insoluble, oligomeric precipitates.
The assignment of the absolute configuration of products (+)-
16a, (-)-17a-19a, and (+)-20a-23a is based mainly on logical
considerations about the geometry of H-bond mediated com-
plexes of the quinolones 2-5 and the chiral complexing agent
1. These should most certainly result in a selective shielding of
the re-side with respect to C-3. Diastereomeric (-)-menthyl
derivatives of lactam 21a could be synthesized. Unfortunately,
these compounds proved unexpectedly unstable, and no suitable
(55) Wilcox, C. S. In Frontiers in supramolecular organic chemistry
and photochemistry; Schneider, H.-J., Du¨rr, H., Eds.; VCH Verlagsgesell-
schaft: Weinheim, Germany, 1991; pp 123-145.
(56) For the importance of π-stacking in molecular recognition, see:
Hunter, C. A. Chem. Soc. ReV. 1994, 23, 101-109.
J. Org. Chem, Vol. 71, No. 15, 2006 5669

Selig and Bach
SCHEME 7
Conclusion
In summary, we have achieved the first enantioselective
syntheses of complex, tetracyclic, cyclobutane annelated lactams
(+)-20a-23a. Products (+)-20a-22a were comparatively
synthesized by both inter- and intramolecular [2 + 2]-photo-
cycloaddition reactions employing the chiral complexing agent
1. The 2-quinolone substrates exhibited an unexpectedly strong
self-association, as was shown by NMR titration studies of
model compound 5a. The enantioselective [2 + 2]-photocy-
cloaddition reactions gave good to very good enantiomeric
excesses (70-92% ee) in intermolecular and intramolecular
reactions. The methodology of enantioselective [2 + 2]-pho-
tocycloadditions in solution by hydrogen bond mediated com-
plexation to 1 thus proved to be very robust and well-suited
even for bulky substrates of problematic complexation behavior.
In addition to these enantioselective syntheses, a detailed study
on intermolecular [2 + 2]-photocycloadditions of unsymmetri-
cally 1,1-disubstituted quinolones was conducted by the syn-
thesis of a (3 × 4)-matrix of photoproducts. Model compound
exo-17a proved to be suitable for selective functional group
transformations, thus greatly widening the scope of obtainable
cyclobutanes. Finally, an unexpected hydrogen abstraction-
radical cyclization reaction was discovered for N-benzyl qui-
nolone 5a. Studies concerning its kinetics and selectivity were
conducted, as were for [2 + 2]-photocycloadditions in com-
parison. The results indicated different modes of photochemical
excitation for both reactions. The possibility of an envisioned
1,2-rearrangement reaction of compounds possessing the tetra-
cyclic carbon skeleton C and their use for an enantioselective
synthesis of Melodinus alkaloids is currently being investigated
in our laboratories.
number of formed hydrogen bonds, hydrogen bonding between
5a and 1 might further be favored energetically over quinolone
dimerization by secondary interactions. However, as both
complexation and dimerization result from the interaction of
two six-membered lactams, simple models based on secondary
electrostatic interactions57 or empirical rules derived thereof58
show no significant energetic difference between these two
possibilities.59 Preliminary microcalorimetric titration experi-
ments between unsubstituted 2-quinolone and 1 indicated a
highly positive association entropy.13 A crucial role of additional
solvent interactions with both host and guest molecules thus
seems also possible,60 although no reliable microcalorimetric
data of the complexation of 5a to 1 could yet be obtained due
to the problematic solubility and dimerization behavior of
quinolone 5a.
Further Transformations of Photocycloaddition Product
exo-17a. With the successful syntheses of enantioenriched
lactams (+)-20a-23a, we proved the general accessibility of
the desired tetracyclic carbon skeleton C. However, the N-
benzyl-protected lactams were remarkably stable substances, and
therefore only of limited use in the planned 1,2-rearrangement
to [3.3.1]-bicyclic systems of structure B. Thus, functional group
transformations of the open-chain methyl ester exo-17a were
examined. To our delight, both the corresponding alcohol 33a
and the aldehyde 34a were easily accessible in high yields using
standard LAH reduction and subsequent IBX oxidation reactions
(Scheme 7). The variability of functional groups certainly
broadens the scope of possible rearrangement routes.
Experimental Section
Preparation of Starting Materials. Acryloyl chloride (9),
methacryloyl chloride (10), methyl acrylate (12), methyl methacry-
late (13), tulipaline (15), and 4-methyl-2(1H)-quinolone (7) are
commercially available. Methyl-2-ethyl acrylate (14),39 2-ethyl
acryloyl chloride (11),40,62 4-bromoethyl-2(1H)-quinolone (6),34,63
and the chiral complexing agent 135 were synthesized according to
reported procedures. Alternative literature-known syntheses for
high-priced tulipaline (15)64 and 4-methyl-2(1H)-quinolone (7)65
were employed to obtain larger quantities from inexpensive starting
materials.
General Procedure for the Amination of Bromide 6.
Bromide 6 was suspended in an excess (5-20 equiv) of the
respective neat amine, and the suspension was stirred at the given
temperature until complete conversion of the starting material was
observed by TLC. After cooling to room temperature, crystallization
from ether solutions and washing with H2O and Et2O gave the
desired products as white crystalline solids.
Similar to ester 17a, alcohol 33a was easily N-Boc depro-
tected with 10% TFA in CH2Cl2 to give the corresponding free
amine (35a) in high yields. Contrary to all hitherto synthesized
cyclobuta[c]quinolones, aldehyde 34a was a comparably un-
stable substance. Even under mild acidic conditions (1% TFA,
CH2Cl2), which left the N-Boc group completely untouched,
34a exhibited a very fast, cycloreversive [2 + 2]-fragmentation
of the cyclobutane ring to the parent quinolone 5a.61 Boc
deprotection of aldehyde 34a was therefore impossible, and the
intriguing intramolecular condensation of an N-deprotected
aldehyde could not be achieved.
Alcohol 33a is currently being investigated as a substrate for
an oxidation ring closure sequence to imines and iminium ions
possessing a tetracyclic ring system C more prone to the planned
rearrangement. First results seem promising and will be reported
in due course.
4-[2-(Benzylamino)ethyl]-2(1H)-quinolone (8a). 6 (3.00 g, 11.9
mmol) and BnNH2 (25.0 mL, 24.5 g, 229 mmol, 19 equiv) were
stirred for 4 h at 65 °C to give 3.26 g (11.7 mmol, 99%) of 8a. Rf
1
) 0.24 (CH2Cl2/MeOH ) 10/1); mp 132-133 °C; H NMR (500
MHz, CDCl3) δ 12.60 (br, 1 H), 7.65 (d, 3J ) 7.0 Hz, 1 H), 7.42-
7.35 (m, 2 H), 7.30-7.10 (m, 6 H), 6.55 (s, 1 H), 3.81 (s, 2 H),
3.10-2.90 (m, 4 H), 1.93 (br, 1 H); 13C NMR (90 MHz, CDCl3)
(57) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112,
2008-2010. (b) Jorgensen, W. L.; Severance, S. L. J. Am. Chem. Soc. 1991,
113, 209-216. (c) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am.
Chem. Soc. 1991, 113, 2810-2819.
(58) Sartorius, J.; Schneider, H.-J. Chem.-Eur. J. 1996, 2, 1446-1452.
(59) For possible differences in hydrogen bond basicity, see: Questel,
J. Y. L.; Laurence, C.; Lachkar, A.; Helbert, M.; Berthelot, M. J. Chem.
Soc., Perkin Trans. 2 1992, 2091-2094.
(60) Susi, H. J. Phys. Chem. 1965, 69, 2799-2801.
(61) For a similar fragmentation under drastic thermal conditions, see:
Lange, G. L.; Lee, M. Synthesis 1986, 117-120.
(62) Borszeky, K.; Mallat, T.; Baiker, A. Tetrahedron: Asymmetry 1997,
8, 3745-3753.
(63) Wolfe, J. F.; Trimitsis, G. B.; Morris, D. R. J. Org. Chem. 1969,
34, 3263-3268.
(64) Murray, A. W.; Reid, R. G. Synthesis 1985, 35-38.
(65) Lauer, W. M.; Kaslow, C. E. In Organic Syntheses; Horning, E.
C., Ed.; Wiley: New York, 1955; Collect. Vol. III, pp 580-581.
5670 J. Org. Chem., Vol. 71, No. 15, 2006

Photochemistry of 4-(2′-Aminoethyl)quinolones
δ 164.2 (C), 150.9 (C), 139.7 (C), 138.6 (C), 130.5 (CH), 128.4
(CH), 128.0 (CH), 127.1 (CH), 124.1 (CH), 122.5 (CH), 120.0 (CH),
119.7 (C), 116.9 (CH), 53.8 (CH2), 48.0 (CH2), 32.7 (CH2); HRMS
(EI) calcd for C18H18N2O 278.1419, found 278.1419; Anal. Calcd
for C18H18N2O (278.35): C, 77.67; H, 6.52; N, 10.06. Found: C,
77.35; H, 6.70; N, 10.01.
General Procedure for Boc Protection of Amines 8a/b. The
respective amine was suspended in CH2Cl2, 1.15 equiv of NEt3
and 1.15 equiv Boc2O were added, and the solution was stirred at
room temperature until complete conversion of the starting material
was observed by TLC. Water (30-50 mL) was added, the aqueous
phase was extracted with 3 × 20 mL of CH2Cl2, and the combined
organic layers were dried over Na2SO4 and filtered. Evaporation
of the solvent and purification by column chromatography
(CH2Cl2/MeOH ) 20/1 as eluent) gave the desired Boc-protected
amines.
rac-(1S,2aS,8bR)-8b-{2-[Benzyl(tert-butoxycarbonyl)amino]-
ethyl}-1-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]-
quinoline-1-methylcarboxylate (exo-17a). 5a (767 mg, 2.04 mmol)
and methyl methacrylate (13) (4.30 mL, 4.05 g, 40.5 mmol, 20
equiv) in 67.5 mL of PhMe were irradiated to give 500 mg (1.04
mmol, 51%) of exo-17a, 234 mg (489 µmol, 12%) of a mixture of
diastereoisomers, and 132 mg (276 µmol, 14%) of endo-17a as
white foams. d.r. (exo/endo) ) 73/27, 89% overall, 51% exo-17a.
1
Rf ) 0.35 (P/EtOAc ) 1/1); mp 77-78 °C; H NMR (360 MHz,
DMSO-d6, 80 °C) δ 9.85 (br, 1 H), 7.35-7.20 (m, 3 H), 7.20-
3
7.10 (m, 3 H), 7.00-6.95 (m, 2 H), 6.88 (d, J ) 7.8 Hz, 1 H),
2
2
4.31 (d, J ) 15.2 Hz, 1 H), 4.24 (d, J ) 15.2 Hz, 1 H), 3.64 (s,
2
3
3 H), 3.03 (dd, J ) 12.1 Hz, J ) 11.0 Hz, 1 H), 3.05-2.90 (m,
1 H), 2.90-2.85 (m, 1 H), 2.70-2.60 (m, 1 H), 2.15-2.05 (m, 1
H), 1.86 (dd, 2J ) 12.1 Hz, 3J ) 5.0 Hz, 1 H), 1.80-1.65 (m, 1H),
1.42 (s, 9 H), 0.92 (s, 3 H); 13C NMR (90 MHz, DMSO-d6, 80 °C)
δ 173.8 (C), 169.7 (C), 154.3 (C), 138.5 (C), 138.1 (C), 127.9 (CH),
127.8 (CH), 127.1 (CH), 126.6 (CH), 126.4 (CH), 121.9 (CH), 120.0
(C), 115.2 (CH), 78.7 (C), 51.0 (CH3), 49.9 (CH2), 49.9 (C), 47.6
(C), 42.6 (CH2), 36.6 (CH), 34.4 (CH2), 32.5 (CH2), 27.7 (CH3)3,
21.4 (CH3); HRMS (EI) calcd for C28H34N2O5 478.2468, found
478.2463. Anal. Calcd for C28H34N2O5 (478.58): C, 70.27; H, 7.16;
N, 5.85. Found: C, 69.93; H, 7.21; N, 5.62 (Anal. of diastereoi-
someric mixture).
tert-Butyl-N-benzyl-N-[2-(2-oxo-1,2-dihydro-4-quinolinyl)eth-
yl]carbamate (5a). 8a (4.77 g, 17.1 mmol) was Boc-protected to
give 6.28 g (16.6 mmol, 97%) of 5a as a white solid. Rf ) 0.60
1
(CH2Cl2/MeOH ) 10/1); mp 149-151 °C; H NMR (360 MHz,
3
DMSO-d6, 80 °C) δ 11.39 (br, 1 H), 7.70 (d, J ) 8.2 Hz, 1 H),
7.46 (virt t, 3J ) 7.6 Hz, 1 H), 7.35-7.15 (m, 6 H), 7.15 (virt t, 3J
3
) 7.6 Hz, 1 H), 6.30 (s, 1 H), 4.45 (s, 2 H), 3.47 (t, J ) 6.8 Hz,
2 H), 3.04 (t, 3J ) 6.8 Hz, 2 H), 1.52 (s, 9 H); 13C NMR (90 MHz,
DMSO-d6, 80 °C) δ 161.0 (C), 155.4 (C), 148.3 (C) 138.7 (C),
138.0 (C), 129.6 (CH), 127.9 (CH), 127.0 (CH), 126.6 (CH), 123.8
(CH), 121.0 (C), 121.0 (CH), 118.5 (CH), 115.3 (CH) 78.6 (C),
49.4 (CH2), 45.9 (CH2), 30.0 (CH2), 27.5 (CH3); HRMS (EI) calcd
for C23H26N2O3 378.1943, found 378.1948; Anal. Calcd for
C23H26N2O3 (378.46): C, 72.99; H, 6.92; N, 7.40. Found: C, 72.86;
H, 6.94; N, 7.37.
rac-(1R,2aS,8bR)-8b-{2-[Benzyl(tert-butoxycarbonyl)amino]-
ethyl}-1-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]-
quinoline-1-methylcarboxylate (endo-17a). Rf ) 0.25 (P/EtOAc
1
) 1/1); H NMR (360 MHz, DMSO-d6, 80 °C) δ 9.73 (br, 1 H),
7.30-7.15 (m, 3 H), 7.15-7.00 (m, 3 H), 6.95-6.85 (m, 2 H),
3
2
6.82 (d, J ) 7.8 Hz, 1 H), 4.32 (d, J ) 15.0 Hz, 1 H), 4.24 (d,
2J ) 15.0 Hz, 1 H), 3.27 (s, 3 H), 2.95 (virt t, J ) 9.0 Hz, 1 H),
2.90-2.85 (m, 1 H), 2.67 (virt t, J ) 11.0 Hz, 1 H), 2.60-2.50
3
3
General Procedure for the Acylation of Amine 8a. Amine 8a
was suspended in CH2Cl2 and cooled to 0 °C, 1.1 equiv of NEt3
and 1.1 equiv of the corresponding freshly distilled acrylic acid
chloride were added, and the mixture was stirred at room temper-
ature for 1 h. The reaction was quenched with saturated NaHCO3,
and the aqueous phase was extracted with 3 × 20 mL of CH2Cl2.
The organic phase was dried over Na2SO4, filtered, and evaporated
to dryness. Column chromatography (CH2Cl2/MeOH ) 20/1 as
eluent) of the crude product gave the desired acrylic acid amides
as white solids or foams.
(m, 1 H), 2.10-1.95 (m, 3 H), 1.42 (s, 3 H), 1.39 (s, 9 H); 13C
NMR (90 MHz, DMSO-d6, 80 °C) δ 173.1 (C), 168.5 (C), 154.3
(C), 138.0 (C), 137.8 (C), 127.9 (CH), 127.6 (CH), 127.0 (CH),
126.6 (CH), 121.7 (CH), 115.1 (CH), 78.6 (C), 51.7 (C), 50.7 (CH3),
49.3 (CH2), 48.2 (C), 41.5 (CH2), 38.0 (CH), 34.2 (CH2), 31.6
(CH2), 27.7 (CH3), 18.8 (CH3). (One C and CH signal were not
resolved due to superimposition.); HRMS (EI) calcd for C28H34N2O5
478.2468, found 478.2462. Anal. Calcd for C28H34N2O5 (478.58):
C, 70.27; H, 7.16; N, 5.85. Found: C, 69.93; H, 7.21; N, 5.62 (Anal.
of diastereoisomeric mixture).
N-Benzyl-N-[2-(2-oxo-1,2-dihydro-4-quinolinyl)ethyl]acryla-
mide (2). Amine 8a (209 mg, 751 µmol) was reacted with 70 µL
(77.7 mg, 0.86 mmol, 1.1 equiv) of acryloyl chloride (9) to give
185 mg (557 µmol, 74%) of 2 as a white solid. Rf ) 0.38 (CH2-
General Procedure for Intramolecular Racemic [2 + 2]-Pho-
tocycloadditions. The respective acrylic acid amide (5 mM) was
dissolved in toluene, and the solution was irradiated (light source:
RPR 3500 Å, 35 °C, Duran filter) until complete conversion of the
starting material was observed by TLC. The solution was evaporated
to dryness, and the residue was purified by column chromatography
(P/EtOAc ) 50/50 as eluent) to give the desired lactams as white
solids or foams.
1
Cl2/MeOH ) 10/1); mp 57/168 °C; H NMR (360 MHz, DMSO-
d6) δ 11.38 (br, 1 H), 7.90-7.60 (br, 1 H), 7.47 (t, 3J ) 7.6 Hz, 1
H), 7.38-7.23 (m, 6 H), 7.16 (t, 3J ) 7.6 Hz, 1 H), 6.71 (dd, 3J )
16.4 Hz, 3J ) 10.1 Hz, 1 H), 6.34 (s, 1 H), 6.17 (d, 3J ) 16.4 Hz,
3
3
1 H), 5.64 (d, J ) 10.1 Hz, 1 H), 4.69 (s, 2 H), 3.63 (t, J ) 7.5
Hz, 2 H), 3.02 (t, 3J ) 7.5 Hz, 2 H); 13C NMR (90 MHz, DMSO-
d6) δ 165.7/165.5 (C), 161.4/161.3 (C), 148.7/147.9 (C), 138.9 (C),
137.8 (C), 130.3/130.2 (CH), 128.6/ 128.4 (CH), 128.2/128.1 (CH),
128.0/127.5 (CH2), 127.8/127.3 (CH), 127.1/126.7 (CH), 124.4/
124.1 (CH), 121.7/121.5 (CH), 121.6/121.0 (CH), 118.7/118.4 (C),
115.7/115.6 (CH), 50.6/47.9 (CH2), 46.4/46.0 (CH2), 30.8/29.8
(CH2) (broad signals and/or doubled set of signals due to Boc
coalescence); HRMS (EI) calcd for C21H20N2O2 332.1525, found
332.1524.
General Procedure for Intermolecular Racemic [2 + 2]-Pho-
tocycloadditions. The respective quinolone and the corresponding
acrylic acid esters were dissolved in toluene, and the solution was
irradiated (light source: RPR 3500 Å, 35 °C, Duran filter) until
complete conversion of the starting material was observed by TLC.
The solution was evaporated to dryness, and the residue was purified
by column chromatography (P/EtOAc ) 50/50 f EtOAc as eluent)
to give the exo-photocycloaddition products as unpolar and the
endo-products as polar fractions.
rac-(1aS,7bS,11aS)-10-Benzyl-11a-methyl-1,9,10,11a-tetrahy--
dro-1aH-pyrido-[4′,3′:2,3] cyclobuta[1,2-c]quinoline-2,11(3H,8H)-
dione (21a). 3 (125 mg, 361 µmol) was irradiated to give 76 mg
(219 µmol, 61%) of 21a. Rf ) 0.35 (EtOAc); mp 208-210 °C; 1H
NMR (360 MHz, CDCl3) δ 9.32 (br, 1 H), 7.40-7.27 (m, 5 H),
7.19 (virt t, 3J ) 7.4 Hz, 1 H), 7.08 (virt t, 3J ) 7.0 Hz, 1 H), 7.04
3
3
2
(virt t, J ) 7.0 Hz, 1 H), 6.83 (d, J ) 7.9 Hz, 1 H), 4.83 (d, J
) 14.5 Hz, 1 H), 4.61 (d, 2J ) 14.5 Hz, 1 H), 3.67 (ddd, 2J ) 13.0
3
3
2
3
Hz, J ) 12.5 Hz, J ) 3.1 Hz, 1 H), 3.39 (ddd, J ) 13.0 Hz, J
) 5.0 Hz, 3J ) 3.0 Hz, 1 H), 3.22 (dd, 3J ) 11.0 Hz, 3J ) 7.9 Hz,
1 H), 2.78 (dd, J ) 12.6 Hz, J ) 11.0 Hz, 1 H), 2.27 (dd, J )
2
3
2
3
2
3
12.6 Hz, J ) 7.9 Hz, 1 H), 2.21 (ddd, J ) 14.5 Hz, J ) 12.5
Hz, 3J ) 5.0 Hz, 1 H), 1.92 (ddd, 2J ) 14.5 Hz, 3J ) 3.1 Hz, 3J )
3.0 Hz, 1 H), 1.15 (s, 3 H); 13C NMR (90 MHz, CDCl3) δ 174.0
(C), 171.0 (C), 137.0 (C), 136.0 (C), 128.8 (CH), 128.5 (CH), 128.1
(CH), 127.6 (CH), 123.4 (CH), 123.3 (C), 116.2 (CH), 51.2 (CH2),
46.6 (C), 46.4 (C), 43.3 (CH2), 37.6 (CH2), 37.1 (CH), 34.3 (CH2),
22.4 (CH3). (One C signal was not resolved due to superimposition);
HRMS (EI) calcd for C22H22N2O2 346.1681, found 346.1676. Anal.
J. Org. Chem, Vol. 71, No. 15, 2006 5671

Selig and Bach
Calcd for C22H22N2O2 (346.42): C, 76.28; H, 6.40. Found: C,
76.13; H, 6.52.
µmol, 5.0 mM), 1 (81.5 mg, 231 µmol, 2.5 equiv), and 13 (49.0
µL, 46.1 mg, 460 µmol, 5.0 equiv) in 18.5 mL of PhMe were
irradiated to give 28.0 mg (58.5 µmol, 63%) of (-)-exo-17a (76%
ee), 6.0 mg (12.5 µmol, 14%) of a mixture of diastereoisomers,
General Procedure for N-Boc Deprotection. The respective
N-Boc-protected substrate was stirred in 10% v/v TFA in CH2Cl2
for 2 h and then quenched with 25 mL of saturated NaHCO3. The
aqueous phase was extracted with 3 × 20 mL of CH2Cl2. The
organic phase was dried over Na2SO4, filtered, and evaporated to
dryness to give the crude free amines which were sufficiently pure
for further reactions.
and 69 mg (196 µmmol, 85%) of recovered 1. [R]20 -20.4 (c
D
0.93, CH2Cl2); HPLC (Chiralpak AD, Hex/i-PrOH ) 90/10, 1 mL/
min) tR ) 15.5 min ((-), 88%), tR ) 28.4 min ((+), 12%).
(-)-(1S,2aS,8bR)-8b-2-[Benzyl(tert-butoxycarbonyl)amino]et-
hyl-1-ethyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-
1-methylcarboxylate ((-)-exo-18a). 5a (35.0 mg, 92.5 µmol, 5.0
mM), 1 (81.5 mg, 231 µmol, 2.5 equiv), and 14 (57.1 µL, 52.5
mg, 460 µmol, 5.0 equiv) in 18.5 mL of PhMe were irradiated to
give 20.0 mg (40.6 µmol, 44%) of (-)-exo-17a (71% ee), 11.0 mg
(22.4 µmol, 24%) of a mixture of diastereoisomers, and 67 mg
rac-(1S,2aS,8bR)-8b-[2-(Benzylamino)ethyl]-1-methyl-3-oxo-
1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-1-methylcarboxy-
late (25a). exo-17a (355 mg, 742 µmol) was N-Boc-deprotected
to give 227 mg (600 µmol, 81%) of 25a as slightly yellow solid.
1
Rf ) 0.35 (CH2Cl2/MeOH ) 10/1); mp 152-153 °C; H NMR
(190 µmol, 82%) of recovered 1. [R]20 -14.4 (c 1.0, CH2Cl2);
(500 MHz, CDCl3) δ 9.22 (br, 1 H), 7.20-7.15 (m, 2 H), 7.15-
7.10 (m, 4 H), 7.07 (d, 3J ) 7.6 Hz, 1 H), 6.97 (virt t, 3J ) 6.5 Hz,
1 H), 6.77 (d, 3J ) 7.9 Hz, 1 H), 3.69 (s, 3 H), 3.56 (s, 2 H), 3.19
(dd, 2J ) 12.0 Hz, 3J ) 11.0 Hz, 1 H), 3.05 (dd, 3J ) 11.0 Hz, 3J
D
HPLC (Chiralpak AD, Hex/i-PrOH ) 90/10, 1 mL/min) tR ) 15.5
min ((-), 85.5%), tR ) 29.4 min ((+), 14.5%).
(-)-(1S,2aS,8bR)-8b-{2-[Benzyl(tert-butoxycarbonyl)amino]-
ethyl}-1-[spiro-( 4-γ-butyrolactonyl)]-3-oxo-1,2,2a,3,4,8b-hexahy-
drocyclobuta[c]quinoline ((-)-exo-19a). 5a (35.0 mg, 92.5 µmol,
5.0 mM), 1 (81.5 mg, 231 µmol, 2.5 equiv), and 15 (40.3 µL, 45.1
mg, 460 µmol, 5.0 equiv) were irradiated in 18.5 mL of PhMe.
Double column chromatography (1st: silica: 2.5 × 10 cm, P/EtOAc
) 50/50 f EtOAc as eluent, 2nd: ALOX neutral: 2.5 × 10 cm,
CH2Cl2 f CH2Cl2/MeOH ) 98/2 as eluent) gave 20.0 mg (42.0
µmol, 45%) of (-)-exo-19a (81% ee) and 38 mg (108 µmmol, 45%)
of recovered 1. [R]20 -28.4 (c 0.89, CH2Cl2); HPLC (Chiralpak
AD, Hex/(i-PrOH +D0.1% w/v NEt3) ) 60/40, 0.8 mL/min) tR )
8.7 min ((-), 90.5%), tR ) 11.2 min ((+), 9.5%).
General Procedure for Enantioselective, Intramolecular [2
+ 2]-Photocycloadditions. The respective acrylic acid amide (5
mM) and the chiral complexing agent 1 (2.5 equiv, 12.5 mM) were
dissolved in toluene, and the solution was irradiated at -60 °C
(light source: RPR 3500 Å, Duran filter) until complete conversion
of the starting material was observed by TLC (2-3 h). The solution
was evaporated to dryness, and the residue was purified by column
chromatography (P/EtOAc ) 1/1 f EtOAc as eluent) to give
compound 1 as unpolar fraction and the desired lactam as polar
fraction.
2
3
3
) 5.0 Hz, 1 H), 2.42 (ddd, J ) 10.7 Hz, J ) 10.2 Hz, J ) 5.0
2
3
3
Hz, 1 H), 2.27 (ddd, J ) 10.7 Hz, J ) 10.0 Hz, J ) 5.0 Hz, 1
H), 2.21 (ddd, 2J ) 11.5 Hz, 3J ) 10.2 Hz, 3J ) 5.0 Hz, 1 H), 1.98
(dd, 2J ) 12.0 Hz, 3J ) 5.0 Hz, 1 H), 1.81 (ddd, 2J ) 11.5 Hz, 3J
) 10.0 Hz, J ) 5.0 Hz, 1 H), 0.98 (s, 3 H); 13C NMR (90 MHz,
3
CDCl3) δ 175.1 (C), 172.5 (C), 138.7 (C), 137.7 (C), 128.4 (CH),
128.4 (CH), 128.1 (CH), 127.4 (CH), 127.1 (CH), 123.5 (CH), 121.3
(C), 116.1 (CH), 53.6 (CH2), 51.9 (CH3), 51.3 (C), 48.8 (C), 45.0
(CH2), 38.2 (CH), 37.2 (CH2), 33.5 (t, CH2), 22.5 (CH3); HRMS
(EI) calcd for C23H26N2O3 378.1943, found 378.1946.
General Procedure for Lactamization of exo-[2 + 2]-PCA
Products. The respective crude N-Boc-deprotected amine was
heated under Ar (Bu¨chi Kugelrohr, GKR-50) to 200 °C for 20 min,
cooled to room temperature, and purified by column chromatog-
raphy (EtOAc or CH2Cl2/MeOH ) 20:1 as eluent) to give the
desired lactams as white solids or foams.
For example, 200 mg (418 µmol) of exo-17a were N-Boc-
deprotected and thermally lactamized to give 116 mg (335 µmol,
80%) of 21a (see above).
General Procedure for Enantioselective Intermolecular [2 +
2]-Photocycloadditions. The respective quinolone (5-20 mM), the
chiral complexing agent 1 (2.5 equiv), and the corresponding
acrylate (5 equiv) were dissolved in toluene, and the solution was
irradiated at -60 °C (light source: RPR 3500 Å, Duran filter) until
complete conversion of the starting material was observed by TLC
(usually <1 h). The solution was evaporated to dryness, and the
residue was purified by column chromatography (P/EtOAc ) 50/
50 as eluent) to give the enantioenriched exo-product as unpolar
and recovered compound 1 as polar fraction. Isolation of pure endo-
diastereoisomers was not attempted.
(+)-(1S,2aS,8bS)-8b-{2-[Benzyl(tert-butoxycarbonyl)amino]-
ethyl}-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-1-
methylcarboxylate ((+)-exo-16a). 5a (19.1 mg, 50.4 µmol, 20
mM), 1 (52.9 mg, 150 µmol, 2.5 equiv), and 12 (11.5 µL, 10.8
mg, 137 µmol, 2.7 equiv) in 2.5 mL of PhMe were irradiated to
give 17.3 mg (37.3 µmol, 74%) of (+)-exo-16a (73% ee) and 32.1
mg (89.8 µmol, 65%) of recovered 1. [R]20D +4.0 (c 1.0, CH2Cl2);
HPLC (Chiralpak AD, Hex/i-PrOH ) 90/10, 1 mL/min) tR ) 22.4
min ((+), 86.5%), tR ) 26.4 min ((-), 13.5%).
(+)-(1S,2aS,8bS)-8b-[2-(tert-butoxycarbonyl)(tert-butylamino)-
ethyl]-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-1-
methylcarboxylate ((+)-exo-16c). 5c (20.0 mg, 58.1 µmol, 5 mM),
1 (21.2 mg, 145 µmol, 2.5 equiv), and 12 (26.0 µL, 25.0 mg, 290
µmol, 5 equiv) in 2.5 mL of PhMe were irradiated to give 20.0 mg
(46.5 µmol, 80%) of (+)-exo-16c (71% ee) and 43 mg (122 µmol,
84%) of recovered 1. [R]20D +5.2 (c 1.0, CH2Cl2); HPLC (Chiralpak
AD, Hex/i-PrOH ) 97/3, 1 mL/ min) tR ) 29.9 min ((+), 85.5%),
tR ) 35.0 min ((-), 14.5%).
(+)-(1aS,7bS,11aS)-10-Benzyl-1,9,10,11a-tetrahydro-1aH-py-
rido[4′,3′:2,3]-cyclobuta[1,2-c] quinoline-2,11(3H,8H)dione ((+)-
20a). 19.9 mg (60.0 µmol, 5.0 mM) 2 and 52.9 mg (150 µmol, 2.5
eq) 1 were irradiated to give 40 mg (113 µmol, 75%) recovered 1
20
and 9.2 mg (27.7 µmol, 46%) (+)-20a (92% ee). [R]D +57.0 (c
) 0.5, CH2Cl2); HPLC (Chiralpak AD-H, Hex/(i-PrOH+0.1% w/v
NEt3) ) 40/60, 0.8 mL/min) tR ) 9.6 min ((+), 96.0%), tR ) 12.5
min ((-), 4.0%).
(+)-(1aS,7bS,11aS)-10-Benzyl-11a-methyl-1,9,10,11a-tetrahy-
dro-1aH-pyrid o-[4′,3′:2,3] cyclobuta[1,2-c]quinoline-2,11(3H,8H)-
dione ((+)-21a). 3 (20.8 mg, 60.0 µmol, 5.0 mM) and 1 (52.9 mg,
150 µmol, 2.5 equiv) were irradiated to give 43 mg (122 µmol,
81%) of recovered 1 and 11.0 mg (31.8 µmol, 53%) of (+)-20a
(76% ee). [R]20 +57.1 (c 0.69, CH2Cl2); HPLC (Chiralpak AD-
D
H, Hex/(i-PrOH + 0.1% w/v NEt3) ) 40/60, 0.8 mL/min) tR
8.1 min ((-), 12%), tR ) 13.8 min ((+), 88%).
)
(+)-(1aS,7bS,11aS)-10-Benzyl-11a-ethyl-1,9,10,11a-tetrahydro-
1aH-pyrido[ 4′,3′:2,3] cyclobuta[1,2-c]quinoline-2,11(3H,8H)-
dione ((+)-22a). 4 (21.6 mg, 60.0 µmol, 5.0 mM) and 1 (52.9 mg,
150 µmol, 2.5 equiv) were irradiated to give 45 mg (128 µmol,
85%) of recovered 1 and 12.0 mg (33.3 µmol, 55%) of (+)-20a
(74% ee). [R]20 +68.1 (c 0.75, CH2Cl2); HPLC (Chiralpak AD-
D
H, Hex/(i-PrOH + 0.1% w/v NEt3) ) 40/60, 0.8 mL/min) tR
8.0 min ((-), 13%), tR ) 11.5 min ((+), 87%).
)
(+)-(1aS,7bR,11aR)-10-Benzyl-11a-(2-hydroxyethyl)-1,9,10,-
11a-tetrahydro-1aH-pyrido [4′,3′:2,3]cyclobuta[1,2-c]quinoline-
2,11(3H,8H)dione ((+)-23a). According to general procedures, 15
mg (30 µmol) of (-)-exo-19a (81% ee) were N-Boc-deprotected
and thermally lactamized to give 8 mg (21 µmol, 73%) of (+)-22a
(81% ee). [R]20D +55.4 (c 0.5, CH2Cl2); HPLC (Chiralpak AD-H,
(-)-(1S,2aS,8bR)-8b-{2-[Benzyl(tert-butoxycarbonyl)amino]-
ethyl}-1-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quin-
oline-1-methylcarboxylate ((-)-exo-17a). 5a (35.0 mg, 92.5
5672 J. Org. Chem., Vol. 71, No. 15, 2006

Photochemistry of 4-(2′-Aminoethyl)quinolones
Hex/(i-PrOH + 0.1% w/v NEt3) ) 40/60, 0.8 mL/min) tR ) 7.7
min ((-), 9.5%), tR ) 31.1 min ((+), 90.5%).
9.65 (br, 1 H), 7.30-7.21 (m, 3 H), 7.10-7.00 (m, 3 H), 7.03 (d,
3J ) 7.6 Hz, 1 H), 6.92 (virt t, 3J ) 7.3 Hz, 1 H), 6.82 (d, 3J ) 7.8
2
Hydrogen Abstraction-Radical Cyclization and Dimerization
of 5a. 5a (500 mg, 1.32 mmol, 30 mM) in 44.0 mL of PhMe was
irradiated (light source: RPR 3500 Å, 35 °C, Duran filter) for 6 h.
After evaporation to dryness, the crude product mixture was
separated by column chromatography (silica, 3.0 × 20 cm, P/EtOAc
) 50/50 f 20/80 as eluent) to give 62 mg (164 µmol, 12%) of 29,
80 mg (211 µmol, 16%) of a diastereomeric mixture, 58 mg (153
µmol, 12%) of 30, and 180 mg (239 µmol, 36%) of the dimeric
product 28.
Hz, 1 H), 4.78 (br, 1 H), 4.33 (d, J ) 15.3 Hz, 1 H), 4.20 (d,
2J ) 15.3 Hz, 1 H), 3.59 (d, 2J ) 10.8 Hz, 1 H), 3.38 (d, 2J ) 10.8
Hz, 1 H), 2.88-2.82 (m, 2 H), 2.57-2.50 (m, 1 H), 2.30-2.18
(m, 2 H), 2.13-2.08 (m, 1 H), 1.66-1.61 (dd, 2J ) 10.8 Hz, 3J )
7.1 Hz, 1 H), 1.40 (s, 9 H), 0.73 (s, 3 H); 13C NMR (90 MHz,
DMSO-d6, 80 °C) δ 169.9 (C), 154.4 (C), 138.1 (C), 129.9 (C),
127.9 (CH), 127.8 (CH), 127.0 (CH), 126.7 (CH), 126.6 (CH), 122.9
(C), 121.5 (CH), 114.9 (CH), 78.5 (C), 65.7 (CH2), 49.3 (CH2),
46.9 (C), 45.3 (C), 42.3 (CH2), 37.7 (d, CH), 33.6 (CH2), 33.3
(CH2), 27.8 (CH3), 22.1 (CH3); Anal. Calcd for C27H34N2O4
(450.57): C, 71.97; H, 7.61. Found: C, 71.68; H, 7.71.
Dimeric Product (28), Presumably HH-cis-anti-cis. Rf ) 0.50
1
(EtOAc); mp 193-196 °C (dec); H NMR (360 MHz, DMSO-d6,
80 °C) δ 9.55 (br, 1 H), 7.20 (br, 4 H), 7.00-6.85 (m, 5 H), 4.09
(s, 2 H), 2.97 (s, 1 H), 2.86 (br, 1 H), 2.37 (br, 1 H), 1.71 (br, 1
H), 1.30 (m, 10 H); 13C NMR (90 MHz, DMSO-d6, 80 °C) 166.8
(C), 154.1 (C), 138.0 (C), 137.7 (C), 127.8 (CH), 127.7 (CH), 127.1
(CH), 126.9 (CH), 126.6 (CH), 122.0 (CH), 120.5 (C), 115.4 (CH),
78.6 (C), 49.8 (C), 49.6 (CH2), 45.1 (CH), 42.0 (CH2), 37.9 (CH2),
27.6 (CH3); Anal. Calcd for C46H52N4O6 (756.43): C, 72.99; H,
6.92. Found: C, 72.88; H, 7.25.
rac-N-2-[(1S,2aS,8bR)-1-Formyl-1-methyl-3-oxo-1,2,2a,3,4,8b-
hexahydro-cyclobuta[c] quinoline-8b-yl]ethyl-N-benzyl-tert-bu-
tylcarbamate (34a). Alcohol 33a (50.0 mg, 111 µmol) and IBX
(93.2 mg, 333 µmol, 3 equiv) in 3.0 mL of DMSO were stirred for
22 h. To this mixture were added 60 mL of H2O and 10 mL of
saturated NaHCO3, phases were separated, and the aqueous layer
was extracted with 3 × 30 mL of EtOAc. The combined organic
phases were washed with 50 mL of H2O and 50 mL of brine, dried
over Na2SO4, and filtered. The solvent was removed in a vacuum.
Purification of the residue by column chromatography (silica, 3.0
× 10 cm, P/EtOAc ) 50/50 f EtOAc as eluent) afforded 40 mg
(89 µmol, 80%) of aldehyde 34a as a white foam. Rf ) 0.65
rac-(4R,2′S)-3,4-Dihydroquinoline-2(1H)-on-4-spiro-3′-(2′-
phenyl)pyrrolidine-1-tert-butylcarbamate (29). Rf ) 0.64 (EtOAc);
1
mp 235 °C (dec); H NMR (500 MHz, DMSO-d6, 80 °C) δ 9.97
3
(s, 1 H), 7.37-7.32 (m, 2 H), 7.32-7.26 (m, 1 H), 7.22 (t, J )
7.3 Hz, 1 H), 7.20-7.14 (m, 3 H), 7.05 (t, 3J ) 7.5 Hz, 1 H), 6.98
(d, 3J ) 7.7 Hz, 1 H), 4.95 (s, 1 H), 3.78 (virt t, 3J ) 9.2 Hz, 1 H),
3.36 (ddd, 2J ) 10.0 Hz, 3J ) 10.4 Hz, 3J ) 7.3 Hz, 1 H), 2.27 (d,
2J ) 15.8 Hz, 1 H), 2.07 (ddd, 2J ) 12.5 Hz, 3J ) 9.7 Hz, 3J ) 9.6
(EtOAc); H NMR (360 MHz, DMSO-d6, 80 °C) δ 9.86 (s, 1 H),
1
3
9.76 (s, 1 H), 7.31-7.18 (m, 4 H), 7.18 (t, J ) 7.7 Hz, 1 H),
3
3
7.13-7.08 (m, 2 H), 7.00 (t, J ) 7.5 Hz, 1 H), 6.90 (d, J ) 7.9
Hz, 1 H), 4.30 (d, 2J ) 15.3 Hz, 1 H), 4.21 (d, 2J ) 15.3 Hz, 1 H),
2
3
Hz, 1 H), 1.98-1.92 (m, 1 H), 1.50 (d, J ) 15.8 Hz, 1 H), 1.26
2.97 (virt t, J ) 10.9 Hz, 1 H), 2.95-2.85 (m, 2 H), 2.63-2.56
(br, 9 H); 13C NMR (90 MHz, DMSO-d6, 80 °C) δ 167.9 (C), 152.8
(C), 136.8 (C), 129.1 (C), 127.8 (C), 127.6 (CH), 127.3 (CH), 126.8
(CH), 126.4 (CH), 123.5 (CH), 122.0 (CH), 115.6 (CH), 78.3 (C),
67.8 (CH), 46.3 (C), 44.4 (CH2), 39.5 (CH2), 33.1 (CH2), 27.6
(CH3); HRMS (EI) calcd for C23H26N2O3 378.1943, found 378.1944.
rac-(4R,2′R)-3,4-Dihydroquinoline-2(1H)-on-4-spiro-3′-(2′-
phenyl)pyrrolidine-1-tert-butylcarbamate (30). Rf ) 0.60 (EtOAc);
mp 225 °C (dec); 1H NMR (500 MHz, DMSO-d6, 80 °C) δ 10.09
(m, 1 H), 2.22 (ddd, J ) 12.1 Hz, J ) 10.7 Hz, J ) 4.9 Hz, 1
2 3
2
3
3
H), 1.87-1.79 (m, 1 H), 1.75 (dd, J ) 10.8 Hz, J ) 5.5 Hz, 1
H), 1.39 (s, 9 H), 0.86 (s, 3 H); 13C NMR (90 MHz, DMSO-d6, 80
°C) δ 204.1 (C), 169.1 (C), 154.3 (C), 138.3 (C), 137.9 (C), 127.9
(CH), 127.8 (CH), 127.3 (CH), 127.0 (CH), 126.6 (CH),121.9 (CH),
120.1 (C), 115.3 (CH), 78.7 (C), 53.4 (C), 49.4 (CH2), 48.9 (C),
42.0 (CH2), 37.6 (CH), 34.5 (CH2), 29.7 (CH2), 27.7 (CH3) 18.3
(CH3); HRMS (EI) calcd for C27H32N2O4 448.23621, found
448.23637.
3
(s, 1 H), 7.03-6.98 (m, 4 H), 6.88 (d, J ) 7.7 Hz, 1 H), 6.63-
3
6.59 (m, 2 H), 6.51 (t, J ) 7.5 Hz, 1 H), 6.46-6.43 (m, 1 H),
3
2
4.68 (s, 1 H), 3.78 (dd, J ) 10.4 Hz, J ) 10.3 Hz, 1 H), 3.36
Acknowledgment. Support of this research by the Deutsche
Forschungsgemeinschaft (SPP 1179 Organokatalyse) and by the
Fonds der Chemischen Industrie is gratefully acknowledged.
P.S. is grateful for a scholarship from the Studienstiftung des
Deutschen Volkes. We cordially thank Craig S. Wilcox (Uni-
versity of Pittsburgh) for making his HOSTEST program
available to us. We also thank Olaf Ackermann for assistance
with HPLC experiments and Christine Schwarz for conducting
high-temperature NMR experiments.
3
2
3
(ddd, J ) 10.7 Hz, J ) 10.3 Hz, J ) 7.1 Hz, 1 H), 2.76 (ddd,
2J ) 12.3 Hz, J ) 10.7 Hz, J ) 10.4 Hz, 1 H), 2.60 (s, 2 H),
3
3
2
3
1.77 (dd, J ) 12.3 Hz, J ) 7.1 Hz, 1 H), 1.23 (br, 9 H); 13C
NMR (90 MHz, DMSO-d6, 80 °C) δ 170.5 (C), 154.7 (C), 140.8
(C), 136.9 (C), 128.3 (CH), 127.5 (CH), 126.7 (CH), 125.9 (CH),
125.7 (CH), 124.3 (C), 122.8 (CH), 115.6 (CH), 79.8 (C), 66.6
(CH), 49.0 (C), 43.9 (CH2), 41.5 (CH2), 30.2 (CH2), 28.0 (CH3);
HRMS (EI) calcd for C23H26N2O3 378.1943, found 378.1945.
Further Transformations of Photocycloaddition Product exo-
17a. rac-N-2-[(1S,2aS,8bR)-1-(Hydroxymethyl)-1-methyl-3-oxo-
1,2,2a,3,4,8b-hexahydrocyclo-buta[c]quinoline-8b-yl]ethyl-N-
benzyl-tert-butylcarbamate (33a). Ester exo-17a (252 mg, 527
µmol) in 20 mL of dry Et2O at 0 °C was treated dropwise with
0.66 mL of 1.0 M LAH in THF (659 µmol, 1.25 equiv), and the
mixture was stirred for an additional 30 min. The excess hydride
was destroyed by the addition of several drops of H2O. The solution
was filtered, washed with 3 × 20 mL of Et2O, and evaporated.
Purification by column chromatography (silica, 3.0 × 10 cm,
P/EtOAc ) 50/50 f EtOAc as eluent) of the residue afforded 191
mg (424 µmol, 80%) of alcohol 33a as a white foam. Rf ) 0.33
Supporting Information Available: General experimental
methods. NOESY NMR, HPLC, and UV data for selected
1
compounds. Fully assigned H and 13C NMR spectroscopic data
for compounds 5b, 5c, 8b, 8c, exo-16a-16c, exo-17b,17c, exo-
18a-18c, exo-19a-19c, endo-17b, endo-18a, endo-19a-19c, 25a,
25b, 26a, 26b, 31, 32, and 35a. 13C NMR spectra, IR and MS data
for all compounds. NMR titration data of compounds 1 and 5a.
UV-vis spectra of compounds 1, 3, 5a-5c, exo-17a, 28, and 29.
NOE charts of compounds 16c and 21a. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
(EtOAc); mp 105 °C; H NMR (360 MHz, DMSO-d6, 80 °C) δ
JO0606608
J. Org. Chem, Vol. 71, No. 15, 2006 5673