Decarboxylative Photocyclization: Synthesis of Benzopyrrolizidines and Macrocyclic Lactones

Article abstract of DOI:10.1021/jo990390b

The benzopyrrolizidines 2, 6a, and 6b were synthesized from the enantiomerically pure γ-amino acid derivatives 1, 5a, and 5b by decarboxylative photocyclization of the corresponding potassium salts in aqueous acetone. The diastereoselectivity of the radical coupling step was low (dr = 60:40) for the N-phthaloylglutamic acid methyl ester 1, whereas the α-benzyl- and the α-methyl-substituted γ-phthalimido butyric acid derivatives 5a,b cyclized with high cis diastereoselectivity (dr = 91:9 and 97:3, respectively). Acid-catalyzed epimerization of the cis/trans-2 mixture gave exclusively cis-2. The benzopyrrolizidines cis/trans-2 mixture was transformed with high stereoselectivity (dr = 93:7, ee >98%) into the cis methyl ether 3 via the corresponding acyliminium cation and subsequently into the allyl derivative 4 (dr = 86:14) with trimethylallylsilane catalyzed by titanium tetrachloride. The structures of the benzopyrrolizidines rac-3, (+)-3, rac-4, and 6a were determined by X-ray structure analyses. The macrocyclic lactones 8a,b were formed in high yields from the precursors 7a,b. The diastereoselectivity for the valine-derived substrate (in contrast to the reactions of 5a and 5b) was only moderate (dr = 64:36). The structure of the macrolide 9a (from 8a) was determined by X-ray structure analysis.

Full text of DOI:10.1021/jo990390b

J . Org. Chem. 1999, 64, 5213-5217
5213
Deca r boxyla tive P h otocycliza tion : Syn th esis of
Ben zop yr r olizid in es a n d Ma cr ocyclic La cton es
Axel G. Griesbeck,* Frank Nerowski,1 and J ohann Lex
Institut fu¨r Organische Chemie der Universita¨t zu Ko¨ln, Greinstr. 4, D-50939 Ko¨ln, Germany
Received March 4, 1999
The benzopyrrolizidines 2, 6a , and 6b were synthesized from the enantiomerically pure γ-amino
acid derivatives 1, 5a , and 5b by decarboxylative photocyclization of the corresponding potassium
salts in aqueous acetone. The diastereoselectivity of the radical coupling step was low (dr ) 60:40)
for the N-phthaloylglutamic acid methyl ester 1, whereas the R-benzyl- and the R-methyl-substituted
γ-phthalimido butyric acid derivatives 5a ,b cyclized with high cis diastereoselectivity (dr ) 91:9
and 97:3, respectively). Acid-catalyzed epimerization of the cis/trans-2 mixture gave exclusively
cis-2. The benzopyrrolizidines cis/trans-2 mixture was transformed with high stereoselectivity (dr
) 93:7, ee >98%) into the cis methyl ether 3 via the corresponding acyliminium cation and
subsequently into the allyl derivative 4 (dr ) 86:14) with trimethylallylsilane catalyzed by titanium
tetrachloride. The structures of the benzopyrrolizidines rac-3, (+)-3, rac-4, and 6a were determined
by X-ray structure analyses. The macrocyclic lactones 8a ,b were formed in high yields from the
precursors 7a ,b. The diastereoselectivity for the valine-derived substrate (in contrast to the reactions
of 5a and 5b) was only moderate (dr ) 64:36). The structure of the macrolide 9a (from 8a ) was
determined by X-ray structure analysis.
We have recently described the synthesis of medium-
and large-sized heterocyclic compounds via decarboxy-
lative intramolecular photocyclization of ω-phthalimido
carboxylic acids.2 An essential prerequisite for this reac-
tion is the use of alkali metal carboxylates, which were
prepared in situ or prior to the reaction. The in situ
method uses heterogeneous conditions and is superior for
base-labile substrates. Many starting materials could be
deprotonated prior to photolysis and irradiated in homo-
geneous solvent mixtures of organic solvents and water.3
Most probably, these reactions are of triplet-state origin;
the use of a sensitizing solvent such as acetone or a triplet
sensitizer, however, is not necessary. To evaluate this
ring annulation methodology and to further widen the
scope of the reaction, we have studied the synthesis of
benzopyrrolizidines and macrocyclic lactones. Both groups
of compounds originate retrosynthetically from R-amino
acids as enantiomerically pure building blocks.
course of the reaction, and consequently, only racemic
products are obtained. By activation of remote carboxy-
late groups via photoinduced electron transfer this
disadvantage can be overcome.
The photocyclization of the glutamic acid derivative 1
has been described previously.2 After completion of the
four-step synthesis, we isolated the methoxy-substituted
compound 3 as a racemic mixture (space group P21/n).6
Reexamination of the reaction protocol led to the conclu-
sion that racemization had occurred at the (thermal)
phthaloylation stage. Thus, we prepared enantiomerically
pure (S)-1 by an alternative route and converted it into
the diastereoisomeric benzopyrrolizidines 2. The in situ
method gave approximately 20% of a simple decarboxy-
lation product (i.e., the methyl ester of N-phthaloyl
R-amino butyric acid) beside a 3:2 mixture of cis- and
trans-2. When using the potassium salt of 1 in a 1:1
mixture of water directly and acetone as solvent, less
than 5% of the decarboxylation product was observed
after quantitative conversion. Treatment of the product
mixture with catalytic trifluoroacetic acid or formic acid
led to near-quantitative epimerization to give the cis
diastereoisomer (Scheme 1).
Epimerization at the stereogenic center of hydroxy
lactams resulting in a 1:1 equilibrium has already been
reported by us for the product of the N-phthaloylvaline
ester photolysis.7 In the glutamic acid case reported
herein, however, the epimerization equilibrium is >9:1
in favor of cis-2. Further treatment of cis-2 with formic
acid in methanol led to the methoxybenzopyrrolizidine
3 with high (93:7) diastereoselectivity.6 This reaction
Benzopyrrolizidines of the type mentioned above have
also been synthesized using the azomethine ylide route
using N-trialkylsilylmethylimides or phthaloylglycine as
1,3-dipole precursors.4 This highly useful route developed
by Mariano, Yoon, and co-workers5 has the disadvantage
that the stereogenic R-center is epimerized during the
* To whom correspondence should be addressed. Tel.: (xx) 221 470
30 83. Fax: (xx) 221 470 50 57. E-mail: griesbeck@uni-koeln.de.
(1) Part of the dissertation of F.N., University of Cologne, 1999.
(2) Griesbeck, A. G.; Henz, A.; Peters, K.; Peters, E.-M.; von
Schnering, H. G. Angew. Chem. 1995, 107, 498; Angew. Chem., Int.
Ed. Engl. 1995, 34, 474.
(3) Griesbeck, A. G.; Henz, A.; Kramer, W.; Lex, J .; Nerowski, F.;
Oelgemo¨ller, M.; Peters, K.; Peters, E.-M. Helv. Chim. Acta 1997, 80,
912.
(4) Takahashi, Y.; Miyashi, T.; Yoon, U. C.; Oh, S. W.; Mancheno,
M.; Su, Z.; Falvey, D. F.; Mariano, P. S. J . Am. Chem. Soc. 1999, 121,
3926. Yoon, U. C.; Kim, D. U.; Lee, J . G.; Ammon, H. L.; Mariano, P.
S. J . Am. Chem. Soc. 1995, 117, 2698.
(5) Yoon, U. C.; Kim, D. U.; Kim, J . C.; Lee, C. W.; Choi, Y. S.;
Mariano, P. S.; Lee, Y. J .; Ammon, H. L. Tetrahedron Lett. 1993, 34,
5859. Yoon, U. C.; Cho, S. J .; Lee, Y.-J .; Mancheno, M. J .; Mariano, P.
S. J . Org. Chem. 1995, 60, 2353.
(6) X-ray analyses of rac-3, cis-(+)-3, (+)-4, cis-6a , and 9a . Data
collection: Enraf-Nonius-CAD4 diffractometer, Mo KR graphite mono-
chromator, Wyckoff-scan, θ range (deg) 1.75-27.5. Structural analysis
and refinement: solution by direct-phase determination, method of
refinement full-matrix LSQ, hydrogen positions of riding model with
fixed isotropic U, program used Siemens SHELXL-93.
(7) Griesbeck, A. G.; Mauder, H.; Mu¨ller, I. Chem. Ber. 1992, 125,
2467.
10.1021/jo990390b CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

5214 J . Org. Chem., Vol. 64, No. 14, 1999
Griesbeck et al.
Sch em e 1. Syn th esis of N-P h th a loylglu ta m ic
Acid r-Meth yl Ester
major diastereomer could be crystallized and the cis
configuration additionally proven by X-ray structure
analysis.6 Even higher was the stereoselectivity in the
case of the R-methyl-GABA derivative 5b: a 97:3 mixture
of cis- and trans-6b was formed in 81% yield (Scheme
3). The preferred formation of the cis products might be
due to a stereoelectronic effect that favors the axial
position of the hydroxy group in the pyrrolizidine ring
and leads to the thermodynamically favored cis products.
Although total thermodynamic control did not seem to
occur for the glutamic acid derivative 1, it might for a
yet unknown reason operate, however, for the starting
materials 5a ,b.
Sch em e 2. P h otocycliza tion of 1 a n d
Tr a n sfor m a tion s of 2
As another strategy for the use of R-amino acids as
building blocks in decarboxylative photocyclization, we
investigated ester-linked substrates with N-phthaloyl-
glycine and N-phthaloylvaline as the carboxylic acid
components. The substrates 7a ,b were easily available
from the amino acids via three-step syntheses involving
phthaloylation, esterification with benzyl 6-bromohex-
anoate, and hydrogenation. Using the homogeneous
reaction conditions, photocyclization of these substrates
afforded the macrocyclic lactones 8a ,b in excellent yields
(77%, 81%) (Scheme 4). Asymmetric induction from the
isopropyl group in 7a was only marginal: a 60:40
cis,trans mixture resulted. To gain definitive structural
proof for the macrolide structures, the hydroxy lactone
8a was transformed via acid-catalyzed methanol addition
into the methoxy compound 9a from which an X-ray
structure analysis was obtained (Figure 2, Table 1).6
proceeds via an intermediary acyl iminium cation, which
is known to be reactive with a multitude of nucleophiles.8
The enantiomeric purity of (+)-3 was determined by
chiral HPLC to be >98%.9 Allylation of the methoxy
derivative (+)-3 by TiCl4-catalyzed reaction with tri-
methylsilylallylsilane10 proceeded smoothly to give an 86:
14 mixture of cis and trans diastereoisomers of 4 (Scheme
2). An X-ray structure of the major isomer cis-4 was
obtained as additional structural proof (from the racemic
series).6 The low diastereoselectivity of the C-C coupling
step in the photodecarboxylation of 1 thus can be
“repaired” by nucleophilic addition or substitution reac-
tions involving acyliminium cations. In both cases, the
asymmetric induction originates from the ester group,
which probably directs the methanol addition (by hydro-
gen-bonding interaction) as well as the allylation (prob-
ably by complexation with the Lewis acid). Steric con-
straints seem not to determine the stereoselectivity of
the nucleophilic addition since the intermediary acylimin-
ium cation is essentially planar.
To investigate the stereoselectivity of the C-C coupling
step in the presence of other directing groups, we
synthesized the benzyl- and the methyl-substituted start-
ing materials 5a and 5b from N-Boc-phenylalanine and
N-Boc-alanine, respectively, by a literature-known six-
step synthesis11 involving chain-elongation by reaction
with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione)
and subsequent reduction. Photocyclization of the benzyl
derivative 5a resulted in a 91:9 diastereomeric mixture
of benzopyrrolizidinones 6a in 74% yield (Figure 1). The
As remarkable features of these photochemical trans-
formations it should be noted that in no case did we
observe the formation of either “simple” decarboxylation
products or dimerization reactions when homogeneous
photolysis conditions were used and the benzopyrroli-
zidines, as well as the macrocyclic lactones, were isolated
in chemical yields >74%. Additionally, dilution condi-
tions, which are often necessary for the synthesis of
macrocyclic compounds, are not necessary, and substrate
concentrations up to 0.1 M could be applied.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR: 300 and 500 MHz. 13C
NMR: 75 and 125 MHz, carbon multiplicities were determined
by DEPT. IR: Perkin-Elmer 1605 FT-IR spectrophotometer.
Column chromatography: silica gel (Merck) 60-230 mesh;
petroleum ether (PE, 40-60 °C), ethyl acetate (EA). UV/vis:
Perkin-Elmer Lambda 7 spectrophotometer. MS: Finnigan
Incos 500. All melting points were determined with a Bu¨chi
melting point apparatus (type Nr. 535) and are uncorrected.
Combustion analyses: Institut fu¨r Anorganische Chemie der
Universita¨t zu Ko¨ln and in-house. Rayonet chamber photore-
actors RPR-208 (8 × 3000 Å lamps, ca. 800 W, λ ) 300 ( 10
nm) were used for irradiations.
(2S)-2-(1,3-Dioxo-1,3-d ih yd r oisoin d ol-2-yl)p en ta n ed io-
ic Acid R-Meth yl Ester (1). To a solution of (S)-N-phtha-
loylglutamic acid (27.72 g, 100 mmol) and triethylamine (14
mL, 100 mmol) in chloroform (150 mL) was added dimethyl
sulfate (10.5 mL, 110 mmol) at rt. After the solution was
stirred at rt for 40 h, the solvent was removed and the residue
treated with water (150 mL) and extracted with ethyl acetate.
The combined organic extracts were extracted with saturated
NaHCO3. The aqueous solutions were combined and acidified
with concentrated HCl. The colorless precipitate was collected
and, after drying (MgSO4), dissolved in methanol and crystal-
lized by adding hexane to give 17.4 g (60%) of the monoester
(8) De Koning, H.; Speckamp, W. N. Methods Org. Chem. (Houben-
Weyl) 1995, 21b, 1953. Hiemstra, H.; Speckamp, W. N. In Compre-
hensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, 1047.
(9) Nucleosil-Chiral 2 column, cyclohexane/1% propanol, ∆tR ) 1.2
min.
(10) Shono, T.; Matsumura, Y.; Uchida, K.; Kobayashi, J . Org. Chem.
1985, 50, 3243.
(11) Smrcina, M.; Majer, P.; Majerova´, E.; Guerassina, T. A.;
Eissenstat, M. A. Tetrahedron 1997, 53, 12867.

Decarboxylative Photocyclization
J . Org. Chem., Vol. 64, No. 14, 1999 5215
F igu r e 1. Structures of 3 and cis-6a in the crystal.
Sch em e 3. Syn th esis a n d P h otocycliza tion of 5a
a n d 5b
F igu r e 2. Structure of 9a in the crystal.
of most of the acetone, the residual solution was extracted with
CHCl3 (3 × 100 mL). After drying (MgSO4) and evaporation
of the solvent, the resulting product was (if not indicated
otherwise) crystallized from acetone.
Sch em e 4. Syn th esis a n d P h otocycliza tion of 7a
a n d 7b
(3S,9bRS)-Meth yl 2,3,5,9b-Tetr a h yd r o-9b-h yd r oxy-1H-
p yr r olo[2,1-a ]isoin d ol-5-on e-3-ca r boxyla te (2). Following
the general reaction protocol, 1.46 g (5 mmol) of (S)-1 was
irradiated in a mixture of 100 mL of acetone and 100 mL of
water for 6 h. After evaporation of the solvent and recrystal-
lization of the residue from acetone, 982 mg (80%) of a 3:2
mixture of cis- and trans-23 resulted as a colorless powder.
(3S,9bR)-Meth yl 2,3,5,9b-Tetr a h yd r o-9b-m eth oxy-1H-
p yr r olo[2,1-a ]isoin d ol-5-on e-3-ca r boxyla te (3). A solution
of 1.12 g (4.5 mmol) of a 3:2 cis/trans mixture of the 9b-
hydroxybenzopyrrolizidines 2 in 50 mL of methanol was
treated with 1 mL of formic acid. The solution was heated to
reflux for 3 h, cooled to rt, and diluted with 10 mL of water.
After extraction with CH2Cl2, the organic phase was dried over
MgSO4 and the solvent rota-evaporated. The crude solid
material was recrystallized from acetone to give 882 mg (75%)
of 3: colorless needles; mp 121-122 °C; [R]20 ) +55.8° (c )
D
1, MeOH); IR (cm-1) 1759, 1752, 1716, 1712, 1708, 1365, 1202,
772; UV (CH3CN) λ (log ꢀ) ) 229.6 (3.90), 222.2 (3.84), 209.2
(4.08); 1H NMR (CDCl3) δ 1.60 (ddd, 1H J ) 8.8, 9.5, 14.1 Hz),
2.36 (ddd, 1H, J ) 2.3, 9.5, 11.8 Hz), 2.66-2.75 (m, 2H), 3.03
(s, 3H, OMe), 3.78 (s, 3H, COOMe), 4.58 (dd, 1H, J ) 8.8, 8.8
Hz, NCH), 7.44-7.62 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 32.7,
35.6, 50.5, 52.4, 55.6, 100.7, 122.7, 124.1, 130.1, 132.5, 133.0,
143.7, 170.1, 172.2. Anal. Calcd for C14H15NO4: C, 64.36; H,
5.79; N, 5.36. Found: C, 64.13; H, 5.78; N, 5.33.
as colorless crystals: mp 134-136 °C (from acetone, lit.12 mp
134-136 °C); IR (cm-1) 2936, 2905, 1743, 1704, 1373, 710; 1H
NMR (methanol-d4) δ 2.39-2.49 (m, 2H), 2.52-2.70 (m, 2H),
3.76 (s, 3H, OCH3), 5.02 (dd, 1H, J ) 4.9, 10.0 Hz), 7.85-8.05
(m, 4H, Ar-H); 13C NMR (63 MHz, methanol-d4) δ 25.2, 29.2,
50.3, 51.0, 122.3, 130.8, 133.6, 166.8, 168.9, 173.8.
Gen er a l P r oced u r e for P h otod eca r boxyla tion of N-
P h th a loyl ω-Am in o Ca r boxylic Acid Der iva tives. A mix-
ture of potassium carbonate (1 mmol) and the substrate (2
mmol) in water (1 mL) was heated to 60-70 °C for 1 min and
dissolved in a 1:1 (vol) mixture of water and acetone (100-
200 mL). A homogeneous solution resulted that was irradiated
in a Pyrex tube for 6-16 h while being purged with a slow
stream of nitrogen and cooled to ca. 15 °C. After evaporation
(3S,9bR)-Meth yl 2,3,5,9b-Tetr a h yd r o-9b-2′-p r op en yl-
1H-p yr r olo[2,1-a ]isoin d ol-5-on e-3-ca r b oxyla t e (4). To a
solution of 261 mg (1.0 mmol) of 3 in 6 mL of methylene
chloride was added simultaneously 0.13 mL (1.2 mmol) of
titanium tetrachloride and 0.24 mL (1.5 mmol) of trimethyl-
allylsilane. The solution was stirred for 1 h at rt and quenched
with 10 mL of water. After extraction of methylene chloride,
the organic phase was dried over MgSO4 and the solvent rota-
evaporated. The crude solid material was purified by column
chromatography (CH2Cl2/MeOH 20:1) and recrystallization
from acetone to give 234 mg (75%) of cis-4 as colorless
needles: mp 68-69 °C; [R]20 ) -94.0° (c ) 1, MeOH); IR
D
(cm-1) 1751, 1746, 1702, 1698, 1687, 1373, 1360, 1201, 1187,
(12) Hanus, J .; Tolman, V.; Veres, K. Collect. Czech. Chem. Commun.
1973, 38, 1212.
1173; UV (CH3CN) λ (log ꢀ) ) 225.0 (4.0), 207.8 (3.80). Anal.

5216 J . Org. Chem., Vol. 64, No. 14, 1999
Ta ble 1. Cr ysta llogr a p h ic Da ta for Com p ou n d s r a c-3, (+)-3, (+)-4, cis-8b, a n d 9a
Griesbeck et al.
no.
rac-3
(+)-3
rac-4
cis-6a
9a
emp formula
C
14H15NO4
C14H15NO4
261.27
C16H17NO3
271.30
C18H17NO2
279.33
C16H19NO4
289.32
molecular mass
cryst dimens (mm)
a (pm)
b (pm)
c (pm)
261.27
0.25 × 0.15 × 0.1
1068.4(3)
1323.7(4)
965.9(2)
0.25 × 0.2 × 0.18
0.2 × 0.18 × 0.15
0.2 × 0.1 × 0.1
0.2 × 0.15 × 0.12
702.3(1)
689.4(2)
743.1(1)
1145.0(1)
1123.7(2)
1673.3(2)
1248.0(3)
1676.2(5)
790.3(1)
1249(2)
1117.7(1)
1209.1(1)
R (deg)
â (deg)
106.84(2)
90.68(2)
94.91(1)
108.26(1)
γ (deg)
V (106pm3)
Z
1307.4(6)
4
1320.5(3)
4
1442.1(7)
2
730.9(2)
2
1469.4(2)
4
F(calcd)
1.327
monoclinic
P21/n
2916
2844
2187
0.047
0.117
0.21/-0.21
1.320
1.250
monoclinic
Pc
3219
3135
1.269
monoclinic
P21
5170
2935
1.308
monoclinic
P21/c
5803
2983
2365
0.039
0.098
0.18/-0.16
cryst syst
space grp
no. reflns measd
no. unique reflns
no. obsd reflnsa)
R
orthorhombic
P212121
1664
1664
1146
0.049
0.104
0.13/-0.15
2398
1361
0.046
0.094
0.15/-0.17
0.068
0.080
0.12/-0.14
b
Rw
largest diff peak/hole (e Å-3
)
For F > 2σ(F). Rw ) [∑w(Fo - Fc2)2/∑w(Fo2)2]1/2 with w ) 1/σ2 (F).
a
b
2
Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.62; H, 6.48; N, 5.13.
acetone, 129 mg (81%) of 6a (pure cis isomer) resulted as a
yellowish oil that could not be crystallized: 1H NMR (acetone-
d6) δ 1.38 (d, 3H, J ) 6.5 Hz), 1.45-1.57 (m, 1H), 2.19-2.33
(m, 2H), 2.50 (ddd, J ) 4.4, 7.7, 15.9 Hz), 3.87 (ddd, 1H, J )
6.5, 7.8, 10.9 Hz), 5.38 (s, 1H, OH), 7.44-7.62 (m, 4H, Ar-H);
13C NMR (acetone-d6) δ 23.4, 36.5, 36.9, 51.9, 97.0, 123.3, 123.6,
130.0, 132.8, 133.2, 149.0, 170.5; HREIMS (C12H13NO3) calcd
219.0895, found 219.0891.
Major diastereoisomer (cis, from the crude 84:16 diastereo-
isomeric mixture): 1H NMR (CDCl3) δ 1.46 (ddd, 1H, J ) 8.8,
12.0, 12.1 Hz), 2.11 (dd, 1H, J ) 7.2, 12.2 Hz), 2.59 (mc, 2H),
2.66 (mc, 2H), 3.70 (s, 3H, COOMe), 4.63 (dd, 1H, J ) 8.7, 8.8
Hz, NCH), 4.88-4.95 (m, 2H), 5.53 (dddd, 1H, J ) 6.6, 7.6,
11.6, 17.7 Hz), 7.44-7.62 (m, 4H, Ar-H). 13C NMR (CDCl3) δ
32.7, 33.9, 39.9, 52.2, 55.4, 73.6, 118.7, 121.8, 124.0, 128.2,
131.6,131.9, 132.1, 149.7, 171.5, 172.5.
Minor diastereoisomer (trans, from the crude 84:16 diaste-
reoisomeric mixture): 1H NMR (CDCl3) δ 1.88 (ddd, 1H, J )
7.6, 12.3, 12.4 Hz), 2.07 (dd, 1H, J ) 6.6, 12.2 Hz), 2.31 (dd,
1H, J ) 8.1, 13.6 Hz), 2.45 (dd, 1H, J ) 7.2, 13.9 Hz), 2.50
(dd, 1H, J ) 7.2, 13.9 Hz), 2.55-2.77 (m, 1H), 3.63 (s, 3H,
COOMe), 4.29 (dd, 1H, J ) 9.0, 9.1 Hz, NCH), 4.80-4.88 (m,
2H), 5.33 (dddd, 1H, J ) 7.2, 7.5, 9.8, 13.6 Hz), 7.29-7.35 (m,
2H, Ar-H), 7.45 (dd, 1H, J ) 1.1, 7.5 Hz), 7.64-7.66 (m, 1H,
Ar-H). 13C NMR (CDCl3) δ 31.2, 33.8, 42.1, 52.0, 55.8, 73.8,
119.2, 121.8, 123.9, 128.0, 131.6, 131.8, 132.9, 149.5, 169.9,
171.4.
(3R,9bS)-3-Ben zyl-9b-h yd r oxy-1,2,3,9b-tetr a h yd r op yr -
r olo[2,1-a ]isoin d ol-5-on e (6a ). (R)-4-amino-5-phenylpen-
tanoic acid13 was synthesized in a five-step synthesis from (S)-
phenylalanine11 and condensed with phthalic anhydride to give
5a . A 307 mg (0.95 mmol) portion of 5a in 100 mL of acetone
and 100 mL of water was converted into 285 mg of crude
reaction product (diastereoisomeric mixture: 91:9) following
the general reaction protocol (16 h irradiation time). After
recrystallization from acetone, 196 mg (74%) of 6a (pure cis
4b-Hyd r oxy-4b,5,6,7,8,9-h exa h yd r o-10-oxa -12a -a za cy-
clod eca [a ]in d en e-11,13-d ion e (8a ). A solution of 4.1 g (20
mmol) of N-phthaloylglycine potassium salt and 5.7 g (20
mmol) of benzyl 6-bromohexanoate in 100 mL of DMF was
treated with 21 mmol of K2CO3 and stirred for 16 h at r.t. After
filtration, the solvent was rota-evaporated and the residue
dissolved in diethyl ether and washed with saturated aqueous
NaHCO3. After drying over MgSO4 and evaporation of the
solvent, 2.53 g (31%) of the coupled benzyl ester resulted as a
colorless oil. This compound was dissolved in 200 mL of
methanol, treated with 250 mg of Pd on charcoal, and
hydrogenated for 16 h in a Parr apparatus (3 bar hydrogen
pressure). After evaporation of the solvent under reduced
pressure, the residue was dissolved in 100 mL of ether, washed
with 50 mL of 1 N HCl, and extracted into 100 mL of saturated
aqueous NaHCO3. After acidification to pH ) 1, 2.11 g (73%)
of the free acid 7a resulted as colorless needles: mp 94-95
°C; IR (cm-1) 1745, 1740, 1731, 1221; UV (CH3CN) λ (log ꢀ) )
293.0 (1.3), 217.0 (4.0); 1H NMR (CDCl3) δ 1.38 (mc, 2H), 1.60-
1.71 (m, 4H), 2.33 (t, 2H, J ) 7.4 Hz), 4.15 (t, 2H, J ) 6.6 Hz),
4,42 (s, 2H), 7.72-7.88 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 24.1,
25.2, 28.1, 33.6, 38.9, 65.5, 123.6, 132.0, 134.3, 167.3, 167.5,
178.7. Anal. Calcd for C16H17NO6: C, 60.18; H, 5.37; N, 4.39.
Found: C, 60.05; H, 5.32; N, 4.29.
isomer) resulted as colorless plates: mp 154-155 °C; IR (cm-1
)
3320, 1678, 1617, 1425, 764, 702; 1H NMR (acetone-d6) δ 1.49-
1.60 (m, 1H), 2.23-2.46 (m, 3H), 2.86 (dd, 1H, J ) 9.1, 13.2
Hz), 3.30 (dd, 1H, J ) 5.5, 13.2 Hz), 4.10 (dddd, 1H, J ) 1.3,
5.6, 8.1, 14.9 Hz), 7.17-7.64 (m, 9H, Ar-H); 13C NMR (acetone-
d6) δ 34.9, 36.5, 44.6, 57.6, 97.1, 123.5, 123.7, 127.0, 129.0,
A 319 mg (1 mmol) portion of 7a in 50 mL of acetone and
50 mL of water was converted into 260 mg of crude reaction
product following the general reaction protocol (12 h irradia-
tion time). After recrystallization from acetone, 213 mg (77%)
of 8a resulted as colorless needles: mp 174-175 °C; IR (cm-1
)
129.1, 130.1, 130.2, 133.3, 139.9, 170.4. Anal. Calcd for C18H17
-
NO2: C, 76.40; H, 6.13; N, 5.01. Found: C, 76.48; H, 6.17; N,
5.00.
3297, 1741, 1736, 704; UV (CH3CN) λ (log ꢀ) ) 244.4 (3.68),
228.0 (3.87); 1H NMR (CDCl3) δ 0. 80-0.87 (m, 2H), 1.26-
1.48 (m, 3H), 1.75 (ddd, 1H, J ) 4.4, 7.0, 14.6 Hz), 1.83-1.87
(m, 1H), 2.08 (ddd, 1H, J ) 9.7, 10.0, 14.8 Hz), 3.59 (d, 1H, J
) 17.1 Hz), 3.64 (t, 1H, J ) 11.2 Hz), 4.15 (d, 1H, J ) 17.1
Hz), 4.21 (s, 1H, OH), 4.73 (dt, 1H, J ) 0.7, 11.2 Hz), 7.40-
7.59 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 21.9, 23.5, 25.2, 31.2,
39.6, 66.9, 91.7, 121.9, 123.4, 129.6, 130.3, 132.8, 146.1, 167.2,
168.9. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.26; H, 6.21; N, 5.00.
(3S,9bS)-9b-Hyd r oxy-3-m eth yl-1,2,3,9b-tetr a h yd r op yr -
r olo[2,1-a ]isoin d ol-5-on e (6b). (S)-4-Aminopentanoic acid14
was synthesized in a five-step synthesis from (S)-alanine11 and
condensed with phthalic anhydride to give 5b. A 194 mg (0.79
mmol) portion of 5b in 50 mL of acetone and 50 mL of water
was converted into 154 mg of crude reaction product (diaste-
reoisomeric mixture: 97:3) following the general reaction
protocol (16 h irradiation time). After recrystallization from
4b-Hyd r oxy-4b,5,6,7,8,9-h exa h yd r o-10-oxa -11-(1′-m eth -
yleth yl)-12a -a za cyclod eca [a ]in d en e-11,13-d ion e (8b). A
solution of 12.4 g (50 mmol) of (S)-N-phthaloylvaline potassium
(13) Tseng, C. C. Chem. Pharm. Bull. 1977, 25, 29. ) 5a .
(14) Okomoto, S. Bull. Chem. Soc. J pn. 1979, 52, 2670. ) 5b.

Decarboxylative Photocyclization
J . Org. Chem., Vol. 64, No. 14, 1999 5217
salt and 14.2 g (50 mmol) of benzyl 6-bromohexanoate in 400
mL of DMF was treated with 51 mmol of K2CO3 and stirred
for 16 h at rt. After filtration, the solvent was rota-evaporated,
the residue dissolved in diethyl ether and washed with
saturated aqueous NaHCO3. After drying over MgSO4 and
evaporation of the solvent, 17.9 g (79%) of the coupled benzyl
ester resulted as a colorless oil. A 5.0 g (11 mmol) portion of
this compound was dissolved in 200 mL of methanol, treated
with 250 mg of Pd on charcoal, and hydrogenated for 16 h in
a Parr apparatus (3 bar hydrogen pressure). After evaporation
of the solvent under reduced pressure, the residue was
dissolved in 100 mL of ether, washed with 50 mL of 1 N HCl,
and extracted into 100 mL of saturated aqueous NaHCO3.
After acidification to pH ) 1, 1.26 g (31%) of the free acid 7b
resulted as a colorless oil: 1H NMR (CDCl3) δ 0.88 (d, 3H, J )
6.8 Hz), 1.12 (d, 3H, J ) 6.7 Hz), 1,27 (m, 2H), 1.54 (mc, 4H),
2.21 (t, 2H, J ) 7.4 Hz), 2.67-2.78 (m, 1H), 4.03-4.17 (m, 2H),
4.53 (d, 1H, J ) 8.2 Hz), 7.71-7.86 (m, 4H, Ar-H); 13C NMR
(CDCl3) δ 19.4, 20.9, 24.0, 25.2, 28.0, 28.5, 33.7, 57.7, 65.1,
123.5, 131.6, 134.2, 167.8, 168.8, 179.3. Following the general
irradiation procedure, 1.13 g (3.1 mmol) of 7b in 100 mL of
acetone and 100 mL of water were converted into 980 mg of
crude reaction product (16 h irradiation time). After recrys-
tallization from acetone, 807 mg (81%) of a 3:2 cis/trans
mixture of 8b resulted as a colorless powder: mp 184-186
°C; IR (cm-1) 1735, 1722, 1668, 1468, 1211, 1200, 1127, 1066,
Hz), 1.00 (d, 3H, J ) 2.3 Hz), 1.28.1.61 (m, 6H), 2.09-2.14
(m, 2H), 2.29-2.37 (m, 1H), 3.71 (d, 1H, J ) 11.0 Hz), 4.16-
4.21 (m, 1H), 4.29 (ddd, 1H, J ) 1.6, 10.7, 11.2 Hz), 5.43 (s,
1H, OH), 7.45-7.71 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 20.0,
20.3, 21.6, 24.5, 25.3, 29.7, 33.3, 62.1, 65.7, 92.2, 121.4, 123.6,
129.8, 132.2, 132.5, 145.4, 167.5, 169.7.
4b-Meth oxy-4b,5,6,7,8,9-h exa h yd r o-10-oxa -12a -a za cy-
clod eca [a ]in d en e-11,13-d ion e (9a ). To a solution of 100 mg
(0.36 mmol) of 8a in 25 mL of methanol was added 0.1 mL of
trifluoroacetic acid. The resulting solution was heated to reflux
for 3 h. After addition of 3 mL of water and drying over MgSO4,
the solvent was rota-evaporated and recrystallized from
acetone to give 77 mg (74%) of 9a as colorless needles: mp
144-145 °C; 1H NMR (CDCl3) δ 0.82-0.94 (m, 1H), 0.95-1.08
(m, 1H), 1.28-1.49 (m, 3H), 1.76 (ddd, 1H, J ) 0.9, 10.4, 12.6
Hz), 1.83-1.96 (m, 1H), 2.07 (ddd, 1H, J ) 1.4, 11.8, 11.9 Hz),
2.71 (s, 3H, OMe), 3.55 (d, 1H, J ) 17.0 Hz), 3.72 (ddd, 1H, J
) 1.8, 5.6, 9.2 Hz), 4.79-4.82 (m, 1H), 4.84 (d, 1H, J ) 17.0
Hz), 7.38-7.83 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 21.8, 23.5,
25.3, 31.4, 39.9, 49.9, 67.1, 95.9, 122.1, 123.7, 129.7, 132.4,
132.5, 142.5, 167.4, 169.0. Anal. Calcd for C16H19NO4: C, 66.42;
H, 6.62; N, 4.84. Found: C, 66.32; H, 6.80; N, 5.05.
Ack n ow led gm en t. This research project has been
financially supported by the Deutsche Forschungs-
gemeinschaft (research grants GR 881/7-2 and 7-3), the
Fonds der Chemischen Industrie, Bayer AG, Degussa
AG, and Merck KGaA. The analyses of enantiomeric
purity were performed at the Max-Planck-Institute of
radiation research (Mu¨lheim a. d. Ruhr) in the group
of Prof. M. Demuth.
700; UV (CH3CN) λ (log ꢀ) ) 244.8 (3.7). Anal. Calcd for C18H23
-
NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 67.83; H, 7.32; N,
4.34.
Major diastereoisomer (cis, from the crude 60:40 diastereo-
isomeric mixture): 1H NMR (CDCl3) δ 0.87 (d, 3H, J ) 2.3
Hz), 1.07 (d, 3H, J ) 2.2 Hz), 1.28-1.61 (m, 6H), 2.09-2.14
(m, 2H), 2.62-2.75 (m, 1H), 3.86 (ddd, 1H, J ) 2.1, 11.0, 11.2
Hz), 4.70-4.74 (m, 1H), 4.79 (d, 1H, J ) 11.3 Hz), 5.50 (s, 1H,
OH), 7.45-7.71 (m, 4H, Ar-H); 13C NMR (CDCl3) δ 19.8, 21.1,
22.1, 24.7, 25.1, 28.7, 32.6, 58.4, 67.3, 93.6, 121.0, 123.9, 129.7,
131.7, 132.8, 146.1, 167.5, 170.2.
Su p p or tin g In for m a tion Ava ila ble: 1H- and 13C NMR
data of compounds 3, 4, 6a ,b, 8a ,b, and 9a and X-ray data of
compounds rac-3, (+)-3, (+)-4, cis-6a , and 9a . This material
is available free of charge via the Internet at http://pubs.acs.org.
Minor diastereoisomer (trans, from the crude 60:40 diaste-
reoisomeric mixture): 1H NMR (CDCl3) δ 0.89 (d, 3H, J ) 2.2
J O990390B