Photochemistry of MTM- and MTE-esters of ωphthalimido carboxyhc acids: Macrocyclization versus deprotection

Article abstract of DOI:10.1021/jo001089u

The photochemistry of five linear methylthiomethyl (MTM)-esters of ω-phthalimido carboxylic acids Pht=N-(CH₂)_nCOOCH₂SCH₃ 1a-e (n = 1, 2, 3, 5, and 10), of the two methylthioethyl (MTE)-esters Pht=N- (CH₂)_nCOOCH₂CH₂SCH₃ 2a,b (n = 1, 2), and of the two methyl-substituted MTM/MTE esters 3a and 3b was investigated. Two reaction channels were observed: (i) photocyclization to give medium-sized and macrocyclic rings, (ii) photochemical deprotection to give the free carboxylic acids. Photocyclization of 1b and 1c (n = 2, 3) resulted in 4b,c in excellent yields whereas the substrates 1a and 1d,e with shorter as well as longer spacer groups (n = 1, 5, 10) gave preferentially the deprotected products 5a,d,e. Subsequent photolysis afforded N-methylphthalimide (6) from 5a. The MTE-esters 2a and 2b gave the macrocyclic lactones 7 and E-8. Thus, the competition between cyclization and deprotection strongly depended on the chain length of the hydrocarbon linker between phthalimido chromophore and ester group. To examine the influence of the position of the ester group in the linker chain the model substrates 3a and 3b with identical number of atoms separating electron donor and acceptor group were investigated. The more flexible MTE-derivative 3b cyclized to give a 4:1 diastereoisomeric mixture of cis/trans-9b, whereas photolysis of the more reluctant MTM-ester 3a resulted in cis-9a only after prolonged irradiation. These results show that MTM can function as a photolabile protecting group whereas MTE cannot be removed photochemically. The distance dependence of the secondary reaction steps indicates that the primary electron transfer is not necessarily induced starting from close contact geometries.

Full text of DOI:10.1021/jo001089u

9028
J . Org. Chem. 2000, 65, 9028-9032
P h otoch em istr y of MTM- a n d MTE-Ester s of ω-P h th a lim id o
Ca r boxylic Acid s: Ma cr ocycliza tion ver su s Dep r otection 1
Axel G. Griesbeck,* Michael Oelgemo¨ller,† and J ohann Lex
Institut fu¨r Organische Chemie, Universita¨t zu Ko¨ln, Greinstrasse 4, D-50939 Ko¨ln, Germany
griesbeck@uni-koeln.de
Received J uly 19, 2000
The photochemistry of five linear methylthiomethyl (MTM)-esters of ω-phthalimido carboxylic acids
PhtdN-(CH2)nCOOCH2SCH3 1a -e (n ) 1, 2 , 3, 5, and 10), of the two methylthioethyl (MTE)-
esters PhtdN-(CH2)nCOOCH2CH2SCH3 2a ,b (n ) 1, 2), and of the two methyl-substituted MTM/
MTE esters 3a and 3b was investigated. Two reaction channels were observed: (i) photocyclization
to give medium-sized and macrocyclic rings, (ii) photochemical deprotection to give the free carboxylic
acids. Photocyclization of 1b and 1c (n ) 2, 3) resulted in 4b,c in excellent yields whereas the
substrates 1a and 1d ,e with shorter as well as longer spacer groups (n ) 1, 5, 10) gave preferentially
the deprotected products 5a ,d ,e. Subsequent photolysis afforded N-methylphthalimide (6) from
5a . The MTE-esters 2a and 2b gave the macrocyclic lactones 7 and E-8. Thus, the competition
between cyclization and deprotection strongly depended on the chain length of the hydrocarbon
linker between phthalimido chromophore and ester group. To examine the influence of the position
of the ester group in the linker chain the model substrates 3a and 3b with identical number of
atoms separating electron donor and acceptor group were investigated. The more flexible MTE-
derivative 3b cyclized to give a 4:1 diastereoisomeric mixture of cis/trans-9b, whereas photolysis
of the more reluctant MTM-ester 3a resulted in cis-9a only after prolonged irradiation. These results
show that MTM can function as a photolabile protecting group whereas MTE cannot be removed
photochemically. The distance dependence of the secondary reaction steps indicates that the primary
electron transfer is not necessarily induced starting from close contact geometries.
In tr od u ction
linker structure of the substrate, especially for precursors
to medium-sized ring systems. In the context of decar-
boxylative cyclization of N-phthaloyl peptides3,9 and
esters,10 we have recently found that rigid linker groups
(with, as well as without, hydrogen bonding activity)
strongly influence the efficiency of photochemical mac-
rocyclizations.
The MTM- and MTE-protected phthalimides 1, 2 of a
series of amino acids, whose photochemical reactions are
described in this publication, were expected to show
preferentially oxidation at sulfur and subsequent radical
combination reactions. To study the influence of the less
conformationally flexible (in comparison with simple
alkyl spacers) ester group on the cyclization selectivity,
we focused on N-phthaloyl amino acid derivatives with
relatively short hydrocarbon linker chains. For additional
studies of the cyclization diastereoselectivity, we synthe-
sized two model substrates 3a ,b with identical number
of atoms separating electron donor and acceptor group
differing only in the position of the ester group in the
spacer chain.
The photochemical macrocyclization of N-alkylated
phthalimides has been investigated by us in the last
years for sulfur-,2 carboxylate-,3 and aryl-substituted
derivatives.4 Due to low-lying oxidation potentials thio-
ethers are excellent substrates for electron transfer
initiated cyclizations (Eox. of dialkylsulfides approxi-
mately 1.3 V vs SCE in MeCN5).6 Especially interesting
compounds in this context are the methylthiomethyl
(MTM) and methylthioethyl (MTE) esters of phthaloyl
amino acids which allow the investigation of conforma-
tional restricted linkers such as esters or amides. Al-
though this concept has already been realized by Kanao-
ka and co-workers for macrocyclization reactions using
ester7 as well as peptide8 linked substrates and the
thiomethyl group as electron donor, little is known about
the relationship between cyclization efficiency and the
† Present address: Inoue Photochirogenesis Project, ERATO, J ST,
4-6-3, Kamishinden, Toyonaka 565-0085, J apan.
(1) Part of the doctoral thesis of M. O., University of Cologne, 1999.
(2) (a) Griesbeck, A. G.; Hirt, J .; Kramer, W.; Dallakian, P. Tetra-
hedron 1998, 54, 3169. (b) Griesbeck, A. G.; Hirt, J .; Peters, K.; Peters,
E.M.; von Schnering, H. G. Chem. Eur. J . 1996, 2, 1388.
(3) (a) Griesbeck, A. G.; Kramer, W.; Oelgemo¨ller, M. Synlett 1999,
1169. (b) 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.
Resu lts a n d Discu ssion
All starting materials were easily available in moder-
ate to good yields from the corresponding N-phthaloyl
(4) (a) Henz, A.; Griesbeck, A. G. J . Inf. Rec. 1994, 21, 567. (b)
Griesbeck, A. G.; Henz, A.; Hirt, J .; Ptatschek, V.; Engel, T.; Lo¨ffler,
D.; Schneider, F. W. Tetrahedron 1994, 50, 701.
(5) Pienta, N. J . In Photoinduced Electron Transfer; Fox, M. A.,
Chanon, M., Eds.; Elsevier: Amsterdam, 1988; Part C, p 427.
(6) (a) Hatanaka, Y.; Sato, Y.; Nakai, H.; Wada, M.; Mizoguchi, T.;
Kanaoka, Y. Liebigs Ann. Chem. 1992, 1113. (b) Sato, Y.; Nakai, H.;
Wada, M.; Mizoguchi, T.; Hatanaka, Y.; Migita, Y.; Kanaoka, Y. Liebigs
Ann. Chem. 1985, 1099.
(7) (a) Wada, M.; Nakai, H.; Aoe, K.; Kotera, K.; Sato, Y.; Hatanaka,
Y.; Kanaoka, Y. Tetrahedron 1983, 39, 1273. (b) Wada, M.; Nakai, H.;
Aoe, K.; Kotera, K.; Sato, Y.; Kanaoka, Y. Chem. Pharm. Bull. 1982,
30, 2275.
(8) Sato, Y.; Nakai, H.; Wada, M.; Mizoguchi, T.; Hatanaka, Y.;
Kanaoka, Y. Chem. Pharm. Bull. 1992, 40, 3174.
(9) Griesbeck, A. G.; Kramer, W.; Lex, J . Angew. Chem., in press.
(10) Griesbeck, A. G.; Nerowski, F.; Lex, J . J . Org. Chem. 1999, 64,
5213.
10.1021/jo001089u CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

Photochemistry of MTM- and MTE-Esters
J . Org. Chem., Vol. 65, No. 26, 2000 9029
Sch em e 1. P r ep a r a tion of th e Sta r tin g Ma ter ia ls
Sch em e 2. P h otoch em istr y of th e MTM-Ester s 1a -e
Ta ble 1. P h otolysis of 1a -e. P r od u ct Com p osition a
amino acids according to literature methods described for
MTM (m ) 1)11,12 and MTE (m ) 2) ester derivatives.13
The photolyses of the MTM substrates 1a -e resulted
in two groups of products: cyclization and “deprotection”
products, respectively. The deprotection products, i.e., the
free N-phthaloyl amino acids, were photostable under the
reaction conditions; only the glycine derivative 5a was
rapidly photodecarboxylated to give N-methylphthal-
imide (6) in acetone whereas photolysis in acetonitrile
resulted in a 2:1 mixture of 5a and 6. These were the
only products formed from 1a and no trace of photocy-
clization compound was detected in the NMR spectra of
the crude material. Substrates 1b and 1c gave the
corresponding macrocycles 4b (also confirmed by X-ray
structure analysis)14 and 4c in excellent yields of 84%
(100% conversion) and 51% (after 61% conversion). The
deprotection products were not detected from these
substrates; thus, the cyclization/deprotection selectivity
is >95:5 for nine- and ten-membered ring formation.
Much to our surprise and in contrast to our results
reported for the decarboxylative macrocyclization,3 the
MTM-esters 1d and 1e mainly gave the free N-phthaloyl
amino acids 5d ,e. In the case of 1d , the cyclization
product 4d was identified in minor amounts (<10%) by
GC-MS from the crude product mixture after transfor-
mation into the corresponding TMS-ether, but could not
be isolated. No such product could be detected from 1e,
i.e., the 17-membered lactone is formed in less than 2%
relative yield.
1
solvent
conversion (%)
4 (%)
5 (%)
6 (%)
a
a
b
c
d
e
acetone
acetonitrile
acetone
acetone
acetone
acetone
55
100
100
61
100
100
-
-
100
100
<10
-
-
66
100
34
-
-
-
-
>80c
>90c
-
-
a
b
Normalized to 100%. 0.01-0.02 M solution of 1/Pyrex/13 °C/
24-48 h/RPR-208 Rayonet photoreactor. c Higher amounts of
decomposition products (ca. 10%).
Only cyclization was observed when the more flexible
MTE-esters 2a and 2b were irradiated. From 2a , the
nine-membered heterocycle 7 was produced in 82% yield
whereas photolysis of 2b resulted in the cyclization/
dehydration product E-8 in 72% yield. The Z-isomer of 8
was identified in minor amounts (E:Z ) 87:13) in the
proton NMR of the crude product mixture, but could not
be isolated. Both structures were confirmed by X-ray
structure analyses.14
Cycliza tion Efficien cy ver su s Dia ster eoselectiv-
ity. To study the diastereoselectivity of the radical
combination step, the two regioisomeric model systems
3a and 3b were examined. These two starting materials
differ only in the relative position of the linking ester
group. Irradiation of 3a resulted in highly diastereose-
lective formation of cis-9a (61% yield). After transforma-
tion into the corresponding TMS-ether the trans-diaste-
reoisomer could not even be detected in the crude product
mixture by GC-MS analysis. Prolonged irradiation was
necessary to run the reaction to 100% conversion. In
contrast, the MTE-ester 3b was readily transferred into
the corresponding macrocyclic mixture 9b after relatively
short irradiation. After 18 h the two diastereoisomers cis-
and trans-9b were isolated in a 79:21 ratio in 88% yield.
(11) Mora, N.; Lacombe, J . M.; Pavia, A. A. Tetrahedron Lett. 1993,
34, 2461.
(12) (a) Dossena, A.; Marchelli, R.; Casnati, G. J . Chem. Soc. Chem.
Commun. 1979, 370. (b) Dossena, A.; Marchelli, R.; Casnati, G. J .
Chem. Soc., Perkin Trans. 1 1981, 2737.
(13) Amaral, M. J . S. A.; Rydon, H. N. J . Chem. Soc. (C) 1966, 807.
(14) X-ray data: Enraf-Nonius CAD4-diffractometer, Mo KR, graph-
ite monochromator. Crystallographic data available as Supporting
Information.

9030 J . Org. Chem., Vol. 65, No. 26, 2000
Sch em e 3. P h otoch em istr y of th e MTE-Ester s 2a a n d 2b
Griesbeck et al.
Sch em e 4. Dia ster eoselectivity Stu d ies w ith 3a
a n d 3b
Sch em e 5. P r op osed Rea ction Mech a n ism
the final product of the leaving group in the photodepro-
tection path of MTM esters. The cleavage can be initiated
already at the stage of the radical cation A or after proton
transfer from the highly acidic R-CH-position. In the
former case, the formation of a cyclic distal radical cation
B is energetically possible.16 Further reduction and
hydrolysis can lead to dimethyl sulfoxide and the proto-
nated carboxylic acidsa photochemical retro-Pummerer
rearrangement. Alternatively, back electron transfer can
occur at the stage of the R-thioalkyl radical C. Intramo-
lecular SN reaction can result in thiirane and the
carboxylate anion. If the radical centers in C have
optimal distances, C-C bond formation which results in
the cyclization products 4 or 7 can efficiently compete. A
further important aspect is the multiplicity of the biradi-
cal C: from time-resolved laser flash investigation it was
deduced that triplet intermediates are formed in the PET
reaction of phthalimidoalkyl-substituted thioethers.15
Thus, spin inversion is necessary prior to bond formation,
and this process competes also with the (spin-unre-
stricted) cleavage process. As already mentioned, the
efficiency of the photocyclization reaction of phthalimi-
doalkyl-substituted carboxylates3a,10 as well as the cor-
responding thioethers7,8 does not depend on the spacer
chain length. The distance dependence of the secondary
reaction steps of the MTM substrates 1 indicates that
the primary electron transfer is not necessarily induced
starting from close contact geometries. In case of sub-
strates with larger alkyl chains connecting the electron-
donating thioether group with the electron-accepting
phthalimide, long-range electron transfer can generate
radical ion pairs separated in space. In these cases, the
cleavage of the MTM group functions as a radical clock
and competes with conformational dynamics necessary
for the approach of the two radical centers in C. The
reduced conformational flexibility due to the linking ester
group in 1a and the resulting low tendency for the
approach of the two radical centers in substrates 1d and
1e favor cleavage reactions.17 In these cases the MTM-
protecting group acts as a p hotor emovable p rotecting
After chromatography the pure cis-9b was obtained in
67% yield, and its structure was confirmed by X-ray
analysis.14
Mech a n istic Discu ssion . Both photocyclization and
photodeprotection reactions of phthalimido-activated di-
alkyl sulfides are initiated via one-electron oxidation
(PET) of the sulfur atom. The strongest evidence comes
from the position of CH-activation: the homolytic Norrish
bond cleavage should involve either adjacent (γ- or δ-)-
hydrogens or the weaker secondary R-thio CH bonds. In
contrast to that, kinetic deprotonation of a thioether
radical cation occurs preferentially from the thiomethyl
group. This effect was observed in case of the MTM as
well as the MTE substrates. When acetone is present as
solvent (or alternatively other triplet sensitizers), inter-
molecular PET can generate the acetone radical anion
in the first step.15 Prior to formation of cyclization
products, a second electron transfer which reduces the
phthalimide electrophore has to occur in this case. A
direct intramolecular PET can also be assumed for
photoreactions in acetonitrile which, however, proceeds
dramatically less efficient.2 Kanaoka and co-workers have
described a series of photocyclizations reactions involving
long alkyl spacers separating the phthalimide electro-
phore and the thioether group.6-8 In these cases, efficient
radical combination was observed for nearly all spacer
lengths (except for the shortest one: PhtdN-CH2-S-
CH3). The same insensitivity was also observed for the
PET-decarboxylation/cyclization sequence of ω-phthal-
imido alkylcarboxylates.3b
The MTM-substrates (1a -e and 3a ) investigated in
this work were sensitive concerning the competition
between photocyclization and photodeprotection with
respect to the length of the hydrocarbon spacer. In
contrast, irradiation of MTE esters (2a ,b and 3b) cleanly
resulted in the corresponding macrocyclic products with-
out loss of the MTE group. Consequently, the R-relation-
ship between ester and thioether group makes the radical
cation sensitive toward cleavage of the MTM protecting
group.
(15) Go¨rner, H.; Griesbeck, A. G.; Heinrich, T.; Kramer, W.; Oel-
gemo¨ller, M. Chem: Eur. J . 2001, in press.
At present, we can only speculate about the nature and
(16) Kutateladze A., personal communication of unpublished results.

Photochemistry of MTM- and MTE-Esters
J . Org. Chem., Vol. 65, No. 26, 2000 9031
group (PRPG).18 For the glycine compound 1a , deprotec-
tion is followed by rapid photochemical R-decarboxyla-
tion, a process which has been described by us19 and
others20,21 for N-phthaloyl R-amino acids.
was added slowly to a suspension of the N-phthaloylamino acid
(1.0 mmol) and NaHCO3 (10.0 mmol) in 50 mL of DMSO. After
stirring overnight at rt, water (ca. 50 mL) was added. The
reaction mixture was extracted with ether (3 × 100 mL); the
combined organic layers were washed with brine and dried
over MgSO4. After removal of the solvent, the residue was
dried in vacuo.
The corresponding MTE esters did not show cleavage
reactions which is probable due to higher conformational
flexibility at the stage of the triplet biradicals and/or
reduced tendency to undergo side-reactions such as the
formation of intermediates such as B. Similar substrates
to the MTE-esters (2-hydroxymethyl-1,3-dithiane esters)
have been investigated by Kutateladze and co-workers
and used for efficient electrochemical deprotection.22
Concerning the diastereoselectivity of the photocycliza-
tion of chiral substrates 3, we have recently shown that
R-alkyl substituents effect the diastereoselectivity in the
cyclization step of the decarboxylative photocyclization.10
The preferred formation of the cis product 9a from 3a
might be due to a stereoelectronic effect that favors the
axial position of the hydroxy group in the macrocyclic
lactone ring and leads to the thermodynamically favored
cis diastereoisomer. Compared to the result obtained for
the compound 3a , the additional methylene group in the
thioalkyl fragment in 3b increases the tendency for
cyclization but on the other hand lowers the degree of
stereoselectivity.
P h th a lim id oa cetic a cid m eth ylth io m eth yl ester (1a ):
1
mp: 67-69 °C. H NMR (300 MHz, CDCl3): δ ) 2.22 (s, 3H),
4.47 (s, 2H), 5.20 (s, 2H), 7.74 (dd, J ) 5.6, 3.1 Hz, 2H), 7.87
(dd, J ) 5.6, 3.1 Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ )
15.5 (q), 38.9 (t), 69.8 (t), 123.7 (d), 131.9 (s), 134.3 (d), 167.1
(s), 167.4 (s). Anal. Calcd for C12H11NO4S (268.06): C 54.33,
H 4.18, N 5.28. Found: C 54.47, H 4.31, N 5.11.
P h th a lim id op r op ion ic a cid m eth ylth io m eth yl ester
(1b): mp: 34-36 °C. 1H NMR (300 MHz, CDCl3): δ ) 2.18 (s,
3H), 2.76 (t, J ) 7.2 Hz, 2H), 3.99 (t, J ) 7.2 Hz, 2H), 5.11 (s,
2H), 7.70 (dd, J ) 5.7, 3.1 Hz, 2H), 7.83 (dd, J ) 5.7, 3.1 Hz,
2H, H). 13C NMR (75.5 MHz, CDCl3): δ ) 15.4 (q), 33.0 (t),
33.6 (t), 68.7 (t), 123.3 (d), 132.0 (s), 134.0 (d), 167.9 (s), 170.5
(s). Anal. Calcd for C13H13NO4S (279.31): C 55.90, H 4.69, N
5.01. Found: C 56.12, H 4.77, N 5.30.
4-P h t h a lim id ob u t yr ic a cid m et h ylt h io m et h yl est er
(1c): mp: 63-65 °C. 1H NMR (300 MHz, CDCl3): δ ) 2.02
(quin, J ) 7.2 Hz, 2H), 2.22 (s, 3H), 2.41 (t, J ) 7.2 Hz, 2H),
3.75 (t, J ) 7.2 Hz, 2H), 5.10 (s, 2 H), 7.70 (dd, J ) 5.6, 3.1
Hz, 2H), 7.83 (dd, J ) 5.6, 3.1 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3): δ ) 15.3 (q), 23.7 (t), 31.5 (t), 37.0 (t), 68.2 (t), 123.2
(d), 131.9 (s), 133.9 (d), 168.3 (s), 172.2 (s). Anal. Calcd for
C14H15NO4S (293.34): C 57.32, H 5.15, N 4.77. Found: C 57.22,
H 5.34, N 5.00.
Exp er im en ta l Section
6-P h th a lim id oh exa n oic a cid m eth ylth io m eth yl ester
(1d ): oil. H NMR (300 MHz, CDCl3): δ ) 1.32 (m, 2H), 1.62
The starting materials were synthesized from the N-
phthaloyl amino acids according to literature procedures by
Mora et al.,11 Dossena at al.,12 and Amaral and Rydon.13 The
photochemical reactions were performed in Pyrex vessels
(100-250 mL) using a RPR-208 Rayonet photochemical reactor
equipped with 3000 Å lamps (approximately 800 W) at 13 °C
under a nitrogen atmosphere. All solvents used for photore-
actions (acetone and acetonitrile) were puriss. p.a. (Fluka).
Analyses of the crude product mixtures were performed using
1H and 13C NMR spectroscopy. Product mixtures were sepa-
rated (when necessary) by means of silica gel column chro-
matography (Macherey & Nagel, 230-240 mesh). Analyses of
1
(m, 4H), 2.14 (s, 3H), 2.28 (t, J ) 7.4 Hz, 2H), 3.60 (t, J ) 7.1
Hz, 2H), 5.04 (s, 2H), 7.64 (dd, J ) 5.4, 3.0 Hz, 2H), 7.76 (dd,
J ) 5.4, 3.0 Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ ) 15.2
(q), 24.2 (t), 26.1 (t), 27.6 (t), 28.1 (t), 33.9 (t), 37.5 (t), 67.8 (t),
123.0 (d), 131.9 (s), 133.7 (d), 168.2 (s), 172.9 (s). MS (EI, 70
eV): m/z (%) ) 274 (M+ - SCH3, 1), 260 (1), 245 (1), 217 (12),
160 (100), 130 (18), 77 (17), 69 (5), 61 (40), 55 (12), 50 (4). HR-
MS (PI-FAB): 321.1042 (calcd 321.1035).
11-P h th a lim id ou n d eca n oic a cid m eth ylth io m eth yl
1
ester (1e): mp: 47-48 °C. H NMR (300 MHz, CDCl3): δ )
1
the purified photoproducts were performed using H and 13C
1.25 (m, 12H), 1.62 (m, 4H), 2.21 (s, 3H), 2.31 (t, J ) 7.4 Hz,
2H), 3.63 (t, J ) 7.2 Hz, 2H), 5.10 (s, 2H), 7.68 (dd, J ) 5.4,
3.2 Hz, 2H), 7.82 (dd, J ) 5.4, 3.2 Hz, 2H). 13C NMR (75.5
MHz, CDCl3): δ ) 15.3 (q), 24.8 (t), 26.8 (t), 28.5 (t), 28.9 (t),
29.0 (t), 29.1 (t), 29.2 (t), 29.3 (t), 34.3 (t), 38.0 (t), 67.8 (t),
123.1 (d), 132.1 (s), 133.8 (d), 168.4 (s), 173.4 (s). MS (EI, 70
eV): m/z (%) ) 391 (M+, 1), 377 (1), 331 (1), 315 (21), 287 (30),
244 (1), 188 (2), 160 (100), 130 (13), 77 (11), 69 (4), 61 (38), 55
(17), 50 (2). HR-MS (PI-FAB): 391.1809 (calcd 391.1817).
NMR (Bruker DPX 300, and Bruker AC 300 F) spectroscopy,
IR (Perkin-Elmer FT-IR-S 1600), UV (Perkin-Elmer Lambda
7), mp (Bu¨chi No. B-535; uncorrected), MS (Finnigan MAT 500)
and HR-MS (Finnigan MAT H-SQ 30) spectroscopy, and
combustion analyses (Elementar Vario EL). For GC-MS stud-
ies the products were transferred into the corresponding TMS-
ethers and esters using N-methyl-N-trimethylsilyltrifluoro-
acetamide (MSTFA).23
r a c-3-P h th a lim id obu tyr ic a cid m eth ylth io m eth yl es-
ter (3a ): mp: 73-75 °C. 1H NMR (300 MHz, CDCl3): δ ) 1.50
(d, J ) 6.9 Hz, 3H), 2.11 (s, 3H), 2.83 (dd, J ) 16.0, 5.9 Hz,
1H), 3.22 (dd, J ) 16.0, 9.2 Hz, 1H), 4.80 (ddd, J ) 5.9, 6.9,
9.2 Hz, 1H), 5.05 (s, 2H), 7.69 (dd, J ) 5.6, 3.1 Hz, 2H), 7.81
(dd, J ) 5.6, 3.1 Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ )
15.4 (q), 18.8 (q), 38.1 (d), 43.5 (t), 68.5 (t), 123.2 (d), 131.9 (s),
133.9 (d), 168.0 (s), 170.5 (s). IR (CsI): vj (cm-1) ) 1742, 1703,
1698, 1694, 1393, 1375, 1169, 1024, 718. MS (EI, 70 eV): m/z
(%) ) 293 (M+, 3), 265 (1), 247 (2), 232 (5), 217 (27), 189 (3),
174 (100), 147 (10), 130 (27), 104 (9), 76 (17), 69 (17), 61 (30),
50 (5). UV (MeCN): λ (nm, ꢀ) ) 218.4 (18950), 239.8 (4702),
291.4 (803). HR-MS (PI-FAB): 293.0726 (calcd 293.0722).
Sta n d a r d P r oced u r e for th e Syn th esis of th e MTE-
Ester s. N-Phthalimidocarboxylic acid (10 mmol), 2.0 mL (14.3
mmol) of triethylamine, and 2.0 mL (20.3 mmol) of methyl-2-
chloroethyl sulfide in 50 mL of ethyl acetate were heated to
reflux for 3 days. After cooling to rt, ethyl acetate (50 mL) was
added, and the reaction mixture was filtered. The filtrate was
washed with sat. NaHCO3, water, and brine and dried over
MgSO4. After evaporation of the solvent, the residue was dried
in vacuo.
Sta n d a r d P r oced u r e for th e Syn th esis of th e MTM-
Ester s. tert-Butyl bromide (10.0 mmol) in 25 mL of DMSO
(17) C-S bond cleavage has been described for other systems, e.g.:
(a) Fleming, S. A.; J ensen, A. W. J . Org. Chem. 1996, 61, 7040. (b)
Bobrowski, K.; Marciniak, B.; Hug, G. L. J . Photochem. Photobiol. A:
Chem. 1994, 81, 159. (c) Wagner, P. J .; Lindstrom, M. J . J . Am. Chem.
Soc. 1987, 109, 3062.
(18) (a) Banerjee, A.; Falvey, D. E. J . Org. Chem. 1997, 62, 6245.
(b) J ones, P. B.; Pollastri, M. P.; Porter, N. A. J . Org. Chem. 1996, 61,
9455. (c) Pillai, V. N. R. Org. Photochem. 1987, 9, 225.
(19) Griesbeck, A. G.; Henz, A. Synlett 1994, 931.
(20) (a) Yoon, U. C.; Sung, J . C.; Lee, Y.J .; Mancheno, M. J .; Mariano,
P. S. J . Org. Chem. 1995, 60, 2353. (b) 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.
(21) (a) Sato, Y.; Nakai, H.; Mizoguchi, T.; Kawanishi, M.; Hatanaka,
Y.; Kanaoka, Y. Chem. Pharm. Bull. 1982, 30, 1263. (b) Sato, Y.; Nakai,
H.; Mizoguchi, T.; Kawanishi, M.; Hatanaka, Y.; Kanaoka, Y. Chem.
Pharm. Bull. 1973, 21, 1164.
(22) Barnhurst, L. A.; Wan, Y.; Kutateladze, A. G. Org. Lett. 2000,
2, 799.
(23) (a) Donike, M. Chromatographia 1976, 9, 440. (b) Donike, M.
J . Chromatogr. 1975, 115, 591. (c) Donike, M.; Gola, R.; J aenicke, L.
J . Chromatogr. 1977, 134, 385.

9032 J . Org. Chem., Vol. 65, No. 26, 2000
Griesbeck et al.
P h th a lim id oa cetic a cid m eth ylth ioeth yl ester (2a ):
mp: 71-73 °C. H NMR (300 MHz, CDCl3): δ ) 2.10 (s, 3H),
168.2 (s), 170.7 (s). IR (CsI): vj (cm-1) ) 3324, 1763, 1708, 1692,
1684, 1672, 1469, 1437, 1364, 1202, 989, 707. MS (EI, 70 eV):
m/z (%) ) 275 (M+-H2O, 7), 245 (50), 230 (2), 202 (20), 188
(85), 161 (12), 147 (3), 76 (10), 69 (100), 51 (7). MS (EI, 70 eV,
TMS-derivative): m/z (%) ) 365 (M+, 12), 350 (2), 335 (1), 319
(20), 276 (2), 261 (48), 160 (12), 73 (100). UV (MeCN): λ (nm,
ꢀ) ) 230.8 (6324), 246.2 (3382). Anal. Calcd for C14H15NO4S
(293.33): C 57.32, H 5.15, N 4.77. Found: C 56.89, H 5.08, N
4.32.
4b-Hyd r oxy-4b,5,7,8-tetr a h yd r o-10-oxa -6-th ia -11a -a za -
cyclon on a [a ]in d en e-9,12-d ion e (7): mp: 186-188 °C (de-
comp.). 1H NMR (300 MHz, acetone-d6/DMSO-d6 (ca. 10%)):
δ ) 2.72 (ddd, J ) 15.3, 2.9, 5.1 Hz, 1H), 2.88 (ddd, J ) 15.3,
5.4, 10.1 Hz, 1H), 2.93 (br. d, J ) 13.8 Hz, 1H), 3.53 (br. d, J
) 13.8 Hz, 1H), 3.77 (m, 1H), 3.78 (d, J ) 16.0 Hz, 1H), 4.59
(ddd, J ) 10.9, 2.9, 5.4 Hz, 1H), 4.77 (d, J ) 16.0 Hz, 1H),
6.70 (s, 1H, OH), 7.50 (ddd, J ) 7.3, 1.3 Hz, 1H), 7.55 (dd, J )
7.3, 1.0 Hz, 1H), 7.61 (ddd, J ) 7.3, 1.2 Hz, 1H), 7.68 (dd, J )
7.3, 1.0 Hz, 1H). 13C NMR (75.5 MHz, acetone-d6/DMSO-d6 (ca.
10%)): δ ) 29.4 (t), 36.8 (t), 40.6 (t), 63.4 (t), 90.2 (s), 122.3
(d), 122.9 (d), 129.7 (d), 131.3 (s), 132.7 (d), 147.3 (s), 166.4
(s), 170.8 (s). IR (CsI): vj (cm-1) ) 3376, 1746, 1700, 1682, 1419,
1245, 1059, 961, 699, 577. UV (MeCN): λ (nm, ꢀ) ) 222.2
(10833), 230.8 (7833), 253.2 (4000). Anal. Calcd for C13H13NO4S
(279.31): C 55.90, H 4.69, N 5.01. Found: C 55.78, H 4.52, N
4.91.
E -8,11,12,13-Te t r a h yd r o-7H -9-oxa -6-t h ia -13a -a za cy-
clou n d eca [a ]in d en e-10,14-d ion e (8). This compound was
detected in the proton NMR spectrum of the crude reaction
product in mixture of the two isomers E-/Z-8 (ca. 87:13). After
purification, only E-8 was isolated. E-8: mp: 166-170 °C. 1H
NMR (300 MHz, acetone-d6/DMSO-d6 (ca. 10%)): δ ) 2.12 (m,
4H), 3.25 (t, J ) 5.2 Hz, 2H), 3.87 (t, J ) 5.7 Hz, 2H), 4.35 (t,
J ) 5.3 Hz, 1H), 6.14 (s, 1H), 7.54 (ddd, J ) 7.5, 0.8 Hz, 1H,
7.67 (ddd, J ) 7.8, 1.1 Hz, 1H), 7.75 (d, J ) 7.5 Hz, 1H), 8.26
(d, J ) 7.8 Hz, 1H). 13C NMR (75.5 MHz, acetone-d6/DMSO-
d6 (ca. 10%)): δ ) 23.9 (t), 31.7 (t), 34.6 (t), 37.8 (t), 65.4 (t),
107.5 (d), 123.5 (d), 125.3 (d), 129.9 (d), 132.1 (s), 132.8 (d),
135.6 (s), 137.3 (s), 173.5 (s).
1
2.71 (t, J ) 6.9 Hz, 2H), 4.30 (t, J ) 6.9 Hz, 2H), 4.44 (s, 2H),
7.72 (dd, J ) 5.4, 3.0 Hz, 2H), 7.86 (dd, J ) 5.4, 3.0 Hz, 2H).
13C NMR (75.5 MHz, CDCl3): δ ) 15.7 (q), 32.2 (t), 38.8 (t),
64.3 (t), 123.6 (d), 132.0 (s), 134.2 (d), 167.1 (s), 167.4 (s). Anal.
Calcd for C13H13NO4S (279.31): C 55.90, H 4.69, N 5.01.
Found: C 55.78, H 5.01, N 4.89.
4-P h th a lim id obu tyr ic a cid m eth ylth ioeth yl ester (2b):
1
oil. H NMR (300 MHz, CDCl3): δ ) 1.95 (quin, J ) 7.2 Hz,
2H), 2.06 (s, 3H), 2.33 (t, J ) 7.4 Hz, 2H), 2.63 (t, J ) 6.9 Hz,
2H), 3.68 (t, J ) 6.8 Hz, 2H), 4.15 (t, J ) 6.9 Hz, 2H), 7.65
(dd, J ) 5.7, 3.1 Hz, 2H), 7.77 (dd, J ) 5.7, 3.1 Hz, 2H). 13C
NMR (75.5 MHz, CDCl3): δ ) 15.5 (q), 23.6 (t), 31.3 (t), 32.3
(t), 37.0 (t), 62.8 (t), 123.1 (d), 131.9 (s), 133.8 (d), 168.1 (s),
172.2 (s). Anal. Calcd for C15H17NO4S (307.36): C 58.62, H
5.57, N 4.56. Found: C 58.38, H 5.71, N 4.44.
R-2-P h th a lim id op r op ion ic a cid m eth ylth ioeth yl ester
(3b): oil. 1H NMR (300 MHz, CDCl3): δ ) 1.67 (d, J ) 7.4 Hz,
3H), 2.06 (s, 3H), 2.66 (m, 2H), 4.28 (m, 2H), 4.96 (q, J ) 7.4
Hz, 1H), 7.71 (dd, J ) 5.4, 3.1 Hz, 2H), 7.84 (dd, J ) 5.4, 3.1
Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ ) 15.2 (q), 15.7 (q),
32.1 (t), 47.4 (d), 64.3 (t), 123.5 (d), 131.9 (s), 134.1 (d), 167.3
(s), 169.5 (s). HR-MS (PI-FAB): 293.0731 (calcd 293.0722).
Sta n d a r d Ir r a d ia tion P r oced u r e. A solution of 2.0 mmol
of the substrate in 200 mL of the appropriate solvent in a Pyrex
vessel purged with a constant stream of dry nitrogen was
irradiated for 24 h. After evaporation of the solvent, the pure
products were obtained by column chromatography or recrys-
tallization. Compounds 5a ,d ,e and 6 are described in ref 3 and
19.
4b-Hydr oxy-4b,5,10,11-tetr ah ydr o-8-oxa-6-th ia-11a-aza-
1
cyclon on a [a ]in d en e-9,12-d ion e (4b): mp: 163-165 °C. H
NMR (300 MHz, CDCl3/DMSO-d6 (ca. 10%)): δ ) 3.17 (d, J )
15.3 Hz, 1H), 3.31 (ddd, J ) 13.0, 5.6 Hz, 1H), 3.52 (d, J )
15.3 Hz, 1H), 3.53-3.74 (m, 3H), 4.86 (d, J ) 10.3 Hz, 1H),
5.25 (d, J ) 10.3 Hz, 1H), 7.36 (d, J ) 7.5 Hz, 1H), 7.41 (ddd,
J ) 7.5, 1.1 Hz, 1H), 7.53 (ddd, J ) 7.5, 1.1 Hz, 1H), 7.61 (d,
J ) 7.5 Hz, 1H). 13C NMR (75.5 MHz, CDCl3/DMSO-d6 (ca.
10%)): δ ) 34.1 (t), 36.0 (t), 38.0 (t), 64.2 (t), 91.2 (s), 121.4
(d), 122.7 (d), 129.4 (d), 131.7 (s, d), 132.2 (d), 146.6 (s), 169.6
(s), 172.5 (s). IR (CsI): vj (cm-1) ) 3211, 1751, 1676, 1670, 1420,
1328, 1203, 1078, 764, 703. MS (EI, 70 eV): m/z (%) ) 261
(M+ - H2O, 1), 217 (2), 203 (12), 188 (1), 160 (17), 104 (7), 77
(13), 61 (100), 46 (8). UV (MeCN): λ (nm, ꢀ) ) 215.6 (10194),
(4bR,11S)-4b-Hyd r oxy-11-m eth yl-4b,5,7,8-tetr a h yd r o-
10-oxa-6-th ia-11a-azacyclon on a[a ]in den e-9,12-dion e (9b).
This compound was detected in the proton NMR spectrum of
the crude reaction product in mixture of the two diastereo-
isomers cis-/trans-9b (ca. 80:20). After purification, only cis-
9b was isolated. cis-9b: mp: 145-148 °C. 1H NMR (300 MHz,
CDCl3): δ ) 1.61 (d, J ) 7.5 Hz, 3H), 2.71 (ddd, J ) 15.6, 0.9,
5.1 Hz, 1H), 2.89 (d, J ) 15.4 Hz, 1H), 3.07 (ddd, J ) 15.6,
5.7, 12.1 Hz, 1H), 3.59 (ddd, J ) 11.0, 5.1, 12.1 Hz, 1H), 3.83
(d, J ) 15.4 Hz, 1H), 4.65 (ddd, J ) 11.0, 0.9, 5.7 Hz, 1H),
5.46 (q, J ) 7.5 Hz, 1H), 5.59 (s, 1H, OH), 7.48-7.65 (m, 3H),
7.69 (m, 1H). 13C NMR (75.5 MHz, acetone-d6): δ ) 15.4 (q),
33.2 (t), 41.8 (d), 48.2 (t), 63.2 (t), 93.2 (s), 122.2 (d), 123.6 (d),
130.2 (d), 133.0 (s), 133.3 (d), 148.2 (s), 167.5 (s), 174.1 (s). IR
(CsI): vj (cm-1) ) 3412, 1743, 1696, 1472, 1388, 1170, 1073,
776, 703. UV (MeCN): λ (nm, ꢀ) ) 220.4 (16104), 226.8 (12593),
209.6 (4187), 206.6 (4240). Anal. Calcd for
C13H13NO4S
(279.31): C 55.90, H 4.69, N 5.01. Found: C 55.39, H 4.83, N
4.82.
4b -H yd r oxy-4b ,10,11,12-t et r a h yd r o-5H -8-oxa -6-t h ia -
12a -a za cyclod eca [a ]in d en e-9,13-d ion e (4c): mp: 175-178
°C. 1H NMR (300 MHz, CDCl3/DMSO-d6 (ca.10%)): δ ) 2.11-
2.20 (m, 2H), 2.31 (m, 1H), 2.46 (m, 1H), 3.07 (d, J ) 14.3 Hz,
1H), 3.28 (d, J ) 14.3 Hz, 1H), 3.29 (m, 1H), 3.55 (m, 1H),
4.71 (d, J ) 10.4 Hz, 1H), 4.89 (d, J ) 10.4 Hz, 1H), 6.22 (s,
1H, OH), 7.23 (dd, J ) 7.5, 1.0 Hz, 1H), 7.27 (ddd, J ) 7.4,
7.5, 1.0 Hz, 1H), 7.36 (ddd, J ) 7.4, 7.5, 1.0 Hz, 1H), 7.54 (dd,
J ) 7.4, 1.0 Hz, 1H). 13C NMR (75.5 MHz, acetone-d6/DMSO-
d6 (ca.10%)): δ ) 24.1 (t), 32.9 (t), 36.1 (t), 38.4 (t), 62.9 (t),
90.6 (s), 121.0 (d), 122.4 (d), 129.0 (d), 131.8 (s, d), 147.1 (s),
170.7 (s), 171.3 (s). IR (CsI): vj (cm-1) ) 3294, 1728, 1674, 1481,
1424, 1345, 1156, 1066, 779, 703. UV (MeCN): λ (nm, ꢀ) )
244.8 (6156), 282.8 (2575), 306.4 (2224). Anal. Calcd for C14H15
-
NO4S (293.33): C 57.32, H 5.15, N 4.77. Found: C 57.35, H
5.18, N 4.62.
1
tr a n s-9b: H NMR (300 MHz, acetone-d6, in mixture with
cis-9b): δ ) 1.81 (d, J ) 7.2 Hz, 3H), 2.57 (ddd, J ) 15.1, 1.3,
3.6 Hz, 1H), 2.96 (m, 1H), 3.30 (d, J ) 13.9 Hz, 1H), 3.72 (d,
J ) 13.9 Hz, 1H), 4.23 (ddd, J ) 11.0, 3.6, 11.9 Hz, 1H), 4.33
(ddd, J ) 11.0, 0.8, 5.3 Hz, 1H), 5.39 (q, J ) 7.2 Hz, 1H), 5.79
(s, 1 H, OH), 7.46-7.65 (m, 4H).
239.6 (3555), 271.6 (1591), 281.2 (1027). Anal. Calcd for C14H15
-
NO4S (293.33): C 57.32, H 5.15, N 4.77. Found: C 57.28, H
5.24, N 4.70.
cis-4b-Hyd r oxy-11-m eth yl-4b,5,10,11-tetr a h yd r o-8-oxa -
6-t h ia -11a -a za cyclon on a [a ]in d en e-9,12-d ion e (cis-9a ):
mp: 152-154 °C. H NMR (300 MHz, CDCl3): δ ) 1.48 (d, J
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft, the Fonds der Che-
mischen Industrie, and Bayer AG.
1
) 6.8 Hz, 3H), 2.63 (dd, J ) 13.5, 5.2 Hz, 1H), 3.22 (d, J )
14.9 Hz, 1H), 3.46 (d, J ) 14.9 Hz, 1H), 3.57 (dd, J ) 13.5,
12.0 Hz, 1H), 4.13 (qdd, J ) 5.2, 6.8, 12.0 Hz, 1H), 4.90 (d, J
) 10.1 Hz, 1H), 5.06 (d, J ) 10.1 Hz, 1H), 6.25 (s, 1H, OH),
7.31 (d, J ) 7.1 Hz, 1H), 7.41-7.48 (m, 2H), 7.69 (dd, J ) 6.8,
0.7 Hz, 1H). 13C NMR (75.5 MHz, acetone-d6/DMSO-d6 (ca.
10%)): δ ) 18.8 (q), 35.5 (t), 40.1 (t), 47.6 (d), 64.0 (t), 91.5 (s),
121.3 (d), 122.5 (d), 129.2 (d), 131.9 (d), 132.7 (s), 146.1 (s),
Su p p or tin g In for m a tion Ava ila ble: Tables of crystal-
lographic data of compounds 4b, 7, E-8, and cis-9b; 1H and
13C NMR spectra of compounds 4b, 7, E-8, cis-9a , and cis-9b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O001089U