Solid-phase synthesis of 3,5-disubstituted 2,3-dihydro-1,5- benzothiazepin-4(5H)-ones

Article abstract of DOI:10.1021/jo981567p

A solid-phase route affording novel 3,5-disubstituted 1,5- benzothiazepin-4(5H)-ones in optically pure form has been enabled. S(N)Ar reaction of polymer-bound 4-fluoro-3-nitrobenzoic acid, 12, with L-Fmoc- cysteine, L-13, under basic conditions, followed by tin(II) chloride mediated nitro group reduction, furnished the primary aniline 15. Reductive alkylation of 15 to the corresponding secondary anilines 17 was shown to be feasible for a wide range of aldehydes, using an optimized solvent system composed of CH(OMe)₃, DMF, MeOH, and HOAc, with NaCNBH₃ as the reducing agent. In cases of enolizable aldehydes, benzotriazole was found to be a beneficial additive for the suppression of side-products due to imine-enamine tautomerization. Subsequent cyclization of the secondary anilines 17 using DIC in apolar solvents furnished the corresponding N(5)-alkylated 1,5-benzothiazepin-4- ones 19. Following Fmoc removal from 19, the primary amino group was finally reacted with carboxylic acids, isocyanates, sulfonyl chlorides, or aldehydes to afford the respective amides 32, ureas 33, sulfonamides 34, or secondary amines 35. Performing the synthesis with the D-form of Fmoc-cysteine, D-13, resulted in the corresponding antipodal products, with no detectable scrambling at C(3). The solid-phase assembly of 1,5-benzothiazepin-4-ones was also shown to be compatible with chemical encoding based on dialkylamine tags, enabling the construction of large combinatorial libraries of the title compounds.

Full text of DOI:10.1021/jo981567p

J . Org. Chem. 1999, 64, 2219-2231
2219
Solid -P h a se Syn th esis of 3,5-Disu bstitu ted
2
,3-Dih yd r o-1,5-ben zoth ia zep in -4(5H)-on es
,
‡
Matthias K. Schwarz,* David Tumelty, and Mark A. Gallop
Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, California 94304
Received August 4, 1998
A solid-phase route affording novel 3,5-disubstituted 1,5-benzothiazepin-4(5H)-ones in optically
pure form has been enabled. S Ar reaction of polymer-bound 4-fluoro-3-nitrobenzoic acid, 12, with
N
L-Fmoc-cysteine, L-13, under basic conditions, followed by tin(II) chloride mediated nitro group
reduction, furnished the primary aniline 15. Reductive alkylation of 15 to the corresponding
secondary anilines 17 was shown to be feasible for a wide range of aldehydes, using an optimized
3 3
solvent system composed of CH(OMe) , DMF, MeOH, and HOAc, with NaCNBH as the reducing
agent. In cases of enolizable aldehydes, benzotriazole was found to be a beneficial additive for the
suppression of side-products due to imine-enamine tautomerization. Subsequent cyclization of the
secondary anilines 17 using DIC in apolar solvents furnished the corresponding N(5)-alkylated
1
,5-benzothiazepin-4-ones 19. Following Fmoc removal from 19, the primary amino group was finally
reacted with carboxylic acids, isocyanates, sulfonyl chlorides, or aldehydes to afford the respective
amides 32, ureas 33, sulfonamides 34, or secondary amines 35. Performing the synthesis with the
D-form of Fmoc-cysteine, D-13, resulted in the corresponding antipodal products, with no detectable
scrambling at C(3). The solid-phase assembly of 1,5-benzothiazepin-4-ones was also shown to be
compatible with chemical encoding based on dialkylamine tags, enabling the construction of large
combinatorial libraries of the title compounds.
In tr od u ction
Over the past two decades, substituted 1,5-benzo-
thiazepin-4-ones have elicited considerable pharmaco-
logical interest, primarily as a result of their role as
calcium antagonists interacting with the L-type voltage-
gated Ca2 channel. Along with the dihydropyridines
+
1
(
e.g., nifedipine) and the phenylalkylamines (e.g.,
verapamil), the 1,5-benzothiazepinones (e.g., diltiazem,
) are nowadays among the most widely used drugs in
1
2
the treatment of cardiovascular disorders. Moreover,
further potential therapeutic applications can be inferred
from literature data on different representative benzo-
thiazepinones, most notably the 3-amino-substituted
analogues 2.3
retrosynthetic disconnection of the basic skeleton 3. In
strategy A (by far the most frequently employed), 3 was
derived from nucleophilic attack of substituted 2-ami-
nothiophenols, 4, or 2-nitrothiophenols, 5, on aliphatic
5
Spurred by the success of 1 in clinical studies, a wealth
electrophiles, 6, such as â-halo-propionic acids, R,â-
6
7
of synthetic procedures affording 1,5-benzothiazepin-4-
unsaturated carboxylic acids, â-propiolactones, malonic
4
8
9
ones have been developed. These can formally be sub-
acids, or phenylglycidic esters. In the converse scenario
B, a â-mercapto acid (typically a cysteine derivative), 8,
was allowed to react with substituted 2-fluoronitroarenes,
divided into three classes, A, B, and C, based on the
3
‡
7, followed by nitro group reduction and cyclization.
Present address: Serono Pharmaceutical Research Institute S.A.,
CH-1228 Plan-les-Ouates, Geneva, Switzerland.
Finally, in C, the 6,7-fused ring system 3 was shown to
also be accessible from 6,6-fused systems, 9, such as
§
Abbreviations: Fmoc ) 9-fluorenylmethoxycarbonyl; HATU )
2
-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate; DIEA ) N,N-diisopropylethylamine; DIC ) 1,3-diisopropyl-
carbodiimide; HOBt ) 1-hydroxybenzotriazole; DMAP ) 4-(dimethyl-
amino)pyridine; EDC ) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride; DECP ) diethyl cyanophosphonate; NMM ) 4-meth-
ylmorpholine; Alloc ) allyloxycarbonyl; NMP ) 1-methyl-2-pyrrolidi-
none.
(5) (a) Floyd, D. M.; Moquin, R. V.; Atwal, S. K.; Ahmed, S. Z.;
Spergel, S. H.; Gougoutas, J . Z.; Malley, M. F. J . Org. Chem. 1990, 55,
5572. (b) L e´ vai, A.; Puzicha, G. Synth. Commun. 1985, 15, 623. (c)
Mayer, F.; Horst, C. Ber. Dtsch. Chem. Ges. 1923, 56, 1415.
(6) See for example: (a) Ambrogi, V.; Giampietri, A.; Grandolini,
G.; Perioli, L.; Ricci, M.; Tuttobello, L. Arch. Pharm. 1992, 325, 569.
(b) L e´ vai, A.; Duddeck, H. Pharmazie 1983, 38, 827. (c) Krapcho, J .;
Spitzmiller, E. R.; Turk, C. F. J . Med. Chem. 1963, 6, 544. (d) Mills,
W. H.; Whitworth, J . B. J . Chem. Soc. 1927, 2738.
(
1) (a) Rampe, D.; Triggle, D. J . Prog. Drug Res. 1993, 40, 191. (b)
Chaffman, M.; Brogden, R. N. Drugs 1985, 29, 387.
2) (a) Pitt, B. Clin. Ther. 1997, 19 (Suppl. A), 3. (b) Ferrari, R. Eur.
Heart J . 1997, 18 (Suppl. A), A56.
3) See for example: (a) Slade, J .; Stanton, J . L.; Ben-David, D.;
(
(
(7) Ambrogi, V.; Grandolini, G. Synthesis 1987, 724.
Mazzenga, G. C. J . Med. Chem. 1985, 28, 1517. (b) Wyvratt, M.; Devita,
R.; Bochis, R.; Schoen, W. U.S. Patent 5,672,596, 1997. (c) Nagel, A.
A. PCT Int. Appl. WO 9401421, 1994.
(8) Ried, W.; Sell, G. Chem. Ber. 1980, 113, 2314.
(9) See for example: (a) Schwartz, A.; Madan, P. B.; Mohacsi, E.;
O’Brien, J . P.; Todaro, L. J .; Coffen, D. L. J . Org. Chem. 1992, 57, 851.
(b) Hashiyama, T.; Inoue, H.; Takeda, M.; Murata, S.; Nagao, T. Chem.
Pharm. Bull. 1985, 33, 2348. (c) Kugita, H.; Inoue, H.; Ikezaki, M.;
Konda, M.; Takeo, S. Chem. Pharm. Bull. 1971, 19, 595.
(
4) For a recent review, see: L e´ vai, A. Trends Heterocycl. Chem.
1
995, 4, 51. See also: W u¨ nsch, K.-H.; Ehlers, A. Z. Chem. 1970, 10,
3
61.
1
0.1021/jo981567p CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/06/1999

2
220 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
Sch em e 1
a
Product derived from TFA cleavage of 14. bProduct derived from TFA cleavage of 15.
1
-thioflavanones or thiochromanones, by ring enlarge-
However, in contrast to the previously reported solution
protocols, we planned to introduce the substituents at
N(5) by reductive alkylation with aldehydes prior to
cyclization, with a view to gaining access to novel
functionalities at this critical position. The present report
details the results of these studies, which culminated in
high-yielding syntheses of novel, optically pure 1,5-
benzothiazepin-4-ones on solid support, as well as in the
construction of large combinatorial libraries of such
compounds. We also disclose a new method for perform-
ing reductive alkylations with enolizable aliphatic alde-
hydes that was developed during the course of this work.
1
0
ment via Beckmann or Schmidt-type rearrangements.
As a notable common feature of all these approaches,
functionalization of N(5) was invariably effected after
formation of the seven-membered ring had been com-
pleted, using alkyl halides under basic conditions.
Resu lts a n d Discu ssion
Following Fmoc deprotection, ArgoGel-Rink resin, 10,12
was allowed to react with 4-fluoro-3-nitrobenzoic acid, 11,
in the presence of HATU and DIEA in DMF (Scheme 1).
The resulting intermediate 12, which has previously been
1
3
N
shown to undergo facile S Ar-type reactions with sulfur
1
4
and/or nitrogen-nucleophiles, was then exposed to a
solution of L-Fmoc-cysteine, 13,15 and DIEA in DMF.
With as little as 1.5 equiv of 13 relative to the theoretical
loading of the resin, HPLC analysis16 showed complete
conversion of 12 to 14 after a reaction time of 24 h at
ambient temperature. The presence of an Fmoc group in
the majority of the synthetic intermediates provided a
convenient means of determining the amount of desired
compound present on the resin. In conjunction with
HPLC data on the purity of the crude compounds after
TFA cleavage, this was used as an estimate of the yields
To date, no solid-phase synthesis of substituted 1,5-
benzothiazepin-4-ones has been reported. Based on our
previous experience with solid-phase syntheses of 1,5-
benzodiazepin-2-ones from polymer-bound 4-fluoro-3-
nitrobenzoic acid, 12,11 and inspired by the solution-phase
strategy B above, a related approach leading to 1,5-
benzothiazepin-4-ones was envisaged (see Scheme 1).
Thus, the benzothiazepine skeleton was to be assembled
from 12 and a suitably protected form of cysteine.
(12) Loading: 0.33 mmol/g.
(
(
13) Yan, B.; Kumaravel, G. Tetrahedron 1996, 52, 843.
14) See for example: (a) ref 11. (b) Wei, G. P.; Phillips, G. B.
Tetrahedron Lett. 1998, 39, 179. (c) Lee, J .; Murray, W. V.; Rivero, R.
A. J . Org. Chem. 1997, 62, 3874.
(15) 13 was obtained from the corresponding commercially available
(
10) See for example: (a) Kaye, P. T.; Mphahlele, M. J . Synth.
Commun. 1995, 25, 1495. (b) L e´ vai, A. Acta Chim. Acad. Sci. Hung.
1
1
981, 107, 361.
11) Schwarz, M. K.; Tumelty, D.; Gallop, M. A. Tetrahedron Lett.
998, 39, 8397. A synopsis of all results obtained was presented at
2 2
N-Fmoc-S-trityl-protected form by treatment with TFA in CH Cl (see
Experimental Section).
(
(16) At every stage of the synthetic sequence, an aliquot of resin
was subjected to TFA cleavage conditions (90% TFA/CH Cl ) to liberate
the 2nd Canadian Conference of Combinatorial Chemistry, Montreal,
Canada, Oct. 6 and 7, 1997. Described were solid-phase syntheses of
2
2
the products for the purpose of analysis. After thorough evaporation
of the solvent and gravimetric estimation of the crude yields, the
residues were routinely analyzed by HPLC (UV detection at 220/280
nm) and ESI-MS.
1
,5-benzothiazepin-4-ones, 1,6-benzothiazocin-5-ones, 1,5-benzodiaz-
epin-2-ones, 4-alkoxy-1,4-thiazin-3-ones, quinoxalin-2-ones, and of a
thieno-thiazepine.

3
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2221
Ta ble 1. Yield s of Secon d a r y An ilin es 22, Obta in ed a fter TF A Clea va ge of Resin 17 Der ived fr om Red u ctive Alk yla tion
of 15, a n d of N(5)-Su bstitu ted 1,5-Ben zoth ia zep in -4-on es 23, Obta in ed fr om Cycliza tion of 17 F ollow ed by TF A Clea va ge,
1
a s a F u n ction of th e Ald eh yd e Str u ctu r e (R -CHO)
a
Conditions: A ) 10 equiv aldehyde (0.2 M), CH(OMe)3/DMF/MeOH 9:1:2 (1% HOAc), 50 °C, 18 h; then added 50 equiv NaCNBH3 (1
M), THF, 50 °C, 6 h; B ) 10 equiv aldehyde + 10 equiv benzotriazole (0.2 M), CH(OMe)3/DMF/MeOH 9:1:2 (1% HOAc), rt, 18 h; then
added 50 equiv NaCNBH3 (1 M), THF, rt, 6 h; reagent equivalents are given relative to theoretical resin loading (see ref 12). b Determination
of yields (all in percent): x ) yields, as determined from Fmoc number readings in conjunction with analytical HPLC (UV detection at
λ ) 220 nm); y ) yields of isolated, HPLC-purified compounds, derived from cleavage of 100-200 mg of resin; calculations relative to
c
resin loading based on Fmoc numbers. For certain electron-rich aldehydes, TFA treatment was found to cause partial dealkylation of
the secondary anilines 17 (affording 15) but not of the corresponding cyclic products 19.
associated with a given reaction step (Table 1, footnote
b). Reduction of the nitro group of 14 with SnCl ‚2H
in DMF smoothly afforded the primary aniline 15.
In accordance with literature data, the subsequent
reductive alkylation of 15 proved to be problematic, as a
result of the poor nucleophilicity of the aniline nitrogen
as compared with aliphatic amino groups. Thus, using a
high molar excess of aldehyde in a mixture of trimethyl-
orthoformate, MeOH, and acetic acid (HOAc) at room
2
2
O
1
7
1
8
19
temperature afforded low yields of the corresponding
secondary anilines 17 for aromatic aldehydes bearing
either electron-donating or ortho substituents, as well as
for all aliphatic aldehydes. By adding small amounts
(
17) Pinori, M.; Di Gregorio, G.; Mascagni, P. In Innovation and
Perspectives in Solid-Phase Synthesis; Epton, R., Ed.; Mayflower
Worldwide: Kingswinford, 1994; pp 635-638.
(19) (a) Szardenings, A. K.; Burkoth, T. S.; Look, G. C.; Campbell,
D. A. J . Org. Chem. 1996, 61, 6720. (b) Look, G. C.; Murphy, M. M.;
Campbell, D. A.; Gallop, M. A. Tetrahedron Lett. 1995, 36, 2937.
(
18) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849.

2
222 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
(10% v/v) of DMF to the above solvent system and raising
Sch em e 2
the temperature to 50 °C, the majority of reactions
involving aromatic aldehydes could be driven to comple-
tion (Table 1).
The only significant side-product occasionally present
in minor amounts (5-10%) was identified as the N-
methyl-aniline 16, arising from incorporation of the
2
0
methine carbon of the orthoformate. As a notable
exception, highly electron-rich aldehydes such as N-
alkylamino-benzaldehydes (e.g., 21f) and, by analogy,
N-methylated indole- and pyrrole-carboxaldehydes (21q
and 21s) did not give satisfactory results, presumably
because of failure in imine formation.21 The related
N-acetylated and/or N-sulfonylated aldehydes 21g, 21r ,
and 21t, however, readily afforded the desired products
in high purities. A drop in yields ascribable to steric
factors was observed only in cases with substituents in
both ortho positions (21j, 21k ). Ortho monosubstitution,
such as in 21h or 21i, however, did not adversely affect
the outcome of the reaction, regardless of the size of the
substituents. Under the above conditions, both at 50 °C
and at room temperature, aliphatic aldehydes such as
2
1u -z invariably afforded complex mixtures of products,
among which only few could tentatively be identified (on
the basis of their molecular weights) as dialkylated and
dehydro-dialkylated compounds, 31. The latter products
were rationalized as being derived from tautomerization
of the initially formed imine 26 to the thermodynamically
more stable enamine 27, followed by reaction with a
second aldehyde molecule 25 and subsequent reduction
the primary aniline 15 failed when applied to the
secondary anilines 17, among them HATU/DIEA, DIC/
HOBt, DIC/DMAP, and EDC, as well as some noncarbo-
diimide-type reagents such as DECP and Mukaiyama’s
reagent. A breakthrough was the finding that DIC
solutions in DMF, devoid of any additives such as HOBt
or DMAP, were able to furnish the desired N(5)-alkylated
benzothiazepinones 19 as major products, along with
varying amounts (20-50%) of the corresponding N-
acylureas, 18. Common byproducts in carbodiimide-
(see Scheme 2).
We explored addition of benzotriazole (BtH) to the
reaction mixture to suppress formation of enamine-
derived side-products, because of the known ability of
BtH to form stable adducts with imines.22 Thus, by
blocking the tautomerization of 26 to 27 through in situ
formation of the benzotriazolyl derivative 28, it was
hoped that subsequent hydride displacement of the Bt
moiety would cleanly afford the desired monoalkylated
products 30. Indeed, the analytical HPLC traces revealed
a remarkable improvement in terms of product purity,
especially for reactions carried out at room temperature,
with the desired secondary anilines 30 being essentially
the only detectable products. In further studies, the
benzotriazole-mediated suppression of enamine-derived
side-product formation was shown to be of broad scope,
failing only in those cases in which the driving force for
tautomerization was particularly strong (such as for
aldehydes 21y and 21z).
23
mediated peptide coupling reactions, N-acylureas arise
via rearrangement of the initially formed O-acylisourea
intermediates in competition with amide bond formation.
In further studies, formation of 18 could almost com-
pletely be suppressed in favor of the desired cyclization
reaction by replacing DMF with solvents of lower polar-
24
2 2
ity, such as CH Cl or benzene. Gratifyingly, the newly
established cyclization conditions proved to be of wide
generality, allowing essentially all secondary anilines 17
to be smoothly converted into the corresponding N(5)-
substituted 1,5-benzothiazepinones 19 (Table 1). It was
found to be imperative, however, that the resin batches
The reductive alkylation of the primary aniline 15
could be expected to render N(5) more basic but less
nucleophilic because of increased steric crowding and
hence less amenable to cyclization to form the seven-
membered ring. Indeed, most of the coupling reagents
that had successfully been used to effect cyclization of
1
7 originating from reductive alkylation be subjected to
a wash with aqueous acetic acid (2% v/v) prior to
cyclization. Omitting the washing step completely inhib-
ited cyclization of the secondary anilines 17. It appeared
that under the reductive alkylation conditions the car-
boxyl function in 17 had been converted into its sodium
salt, which was unreactive toward carbodiimide-type
reagents.
(20) (a) Crotchet, R. A.; Blanton, C. D. Synthesis 1974, 55. (b)
Perrault, W. R.; Shephard, K. P.; Lapean, L. A.; Krook, M. A.;
Dobrowolski, P. J .; Lyster, M. A.; McMillan, M. W.; Knoechel, D. J .;
Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process Res. Dev. 1997,
1
3
, 106. For mechanistically related reactions of CH(OMe) see: (c)
Zupet, R.; Tisler, M.; Golic, L. J . Heterocycl. Chem. 1991, 28, 1731. (d)
Wentrup, C.; Briehl, H.; Lorencak, P.; Vogelbacher, U. J .; Winter, H.-
W.; Maquestiau, A.; Flammang, R. J . Am. Chem. Soc. 1988, 110, 1337.
(23) Kiso, Y.; Yajima, H. Amide-Formation, Deprotection, and
Disulfide Formation in Peptide Synthesis. In Peptides: Synthesis,
Structures, and Applications; Gutte, B., Ed.; Academic Press: San
Diego, New York, Boston, London, Sydney, Tokyo, Toronto, 1995; pp
40-93.
(24) The importance of solvent choice with regard to limiting the
extent of N-acylureas formation has long been appreciated: Sheehan,
J . C.; Goodman, M.; Hess, G. P. J . Am. Chem. Soc. 1956, 78, 1367.
(
21) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
971, 93, 2897.
22) (a) Katritzky, A. R.; Lan, X.; Fan, W.-Q. Synthesis 1994, 445.
b) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron 1991,
7, 2683.
1
(
(
4

3
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2223
Sch em e 3
approach in terms of the sequence of steps and the
reaction conditions used, it was desirable to accumulate
additional data on the optical purity of the compounds
originating from synthesis on solid support. To that end,
pairs of selected benzothiazepines, (R)-20 and (S)-20,
derived from L- and D-Fmoc-cysteine, respectively, were
reacted with optically pure entities such as L-amino acids
to afford, after cleavage from the resin, pairs of diaster-
eomers, e.g., (R,S)-41w and (S,S)-41w (Figure 1).
Subsequent analysis by RP-HPLC showed no detect-
able amounts of (R,S)-41w present in sample (S,S)-41w
and vice versa. Analogous experiments carried out for
1
different R groups, as well as for 1,5-benzothiazepinones
of the general structures 33-35, furnished no evidence
of racemization in any of the samples examined.
We have previously described how the use of chemical
encoding strategies greatly facilitates the identification
of bioactive compounds from large combinatorial librar-
ies.27 To explore the compatibility of our dialkylamine
encoding method with the 1,5-benzothiazepinone chem-
istry, synthesis on an orthogonally differentiated resin
4
2 was carried out according to Scheme 4.
Thus, differentiated TentaGel resin 4228 was submitted
to the conditions outlined in Scheme 1, using n different
1
aldehydes R -CHO in the reductive alkylation step, to
afford n batches of resin bearing Fmoc-protected N(5)-
substituted 1,5-benzothiazepin-4-ones, 43. Removal of the
Alloc group was followed by coupling of the first set of
1
1
The remaining steps completing the synthetic sequence
tags, T , encoding the R position. Subsequently, all
batches were pooled and split anew into m aliquots,
involved further functionalization of the exocyclic amino
group of the 1,5-benzothiazepinone template. This in-
cluded Fmoc removal from 19 and treatment of the
resulting primary amines 20 with carboxylic acids, iso-
cyanates, sulfonyl chlorides, and/or aldehydes to generate
the corresponding amides 32, ureas 33, sulfonamides 34,
and/or secondary amines 35, respectively (see Scheme 3).
These four transformations reliably afforded the de-
sired 3,5-disubstituted 1,5-benzothiazepin-4-ones in high
purities and yields, showing full compatibility with all
types of functional groups examined, whether already
2
which were provided with the second set of tags, T ,
defining the R2 position. Functionalization at the R
position proceeded according to the protocols summarized
in Scheme 3 and afforded the final two-position-encoded
resin batches carrying 3,5-disubstituted 1,5-benzothiaz-
epin-4-ones, 44. In model studies, it was shown that the
extra steps devoted to the introduction of the chemical
codes did not adversely affect the purity of the ligands,
further validating the robustness of this chemical encod-
ing strategy.27
2
1
2-5
present as R or newly introduced as R . In one model
study (Table 2, top), large resin batches of selected
benzothiazepinones 20 with five different R1 groups
spanning a broad range of functionalities were each split
into four aliquots to be reacted with 3-methoxypropionic
acid and DIC in DMF, 2-chloroethyl isocyanate and NMM
In summary, an efficient, high-yielding solid-phase
route to 3,5-disubstitued 1,5-benzothiazepin-4(5H)-ones
has been developed, which lends itself to both the
synthesis of discrete, optically pure compounds and the
generation of large (>10K member) encoded libraries. In
the two key steps of the synthetic sequence (and in
contrast to previous solution-phase approaches) alkyla-
tion of N(5) was effected prior to cyclization, using
aldehydes under reductive alkylation conditions. Benzo-
triazole was found to be a beneficial additive in reductive
alkylation reactions with enolizable aliphatic aldehydes.
In subsequent experiments, the underlying synthetic
strategy of assembling benzo-fused heterocycles via SN-
Ar chemistry from resin-bound 4-fluoro-3-nitrobenzoic
acid, 12, has been extended to the synthesis of related
in CH
NMM in CH
CH(OMe) (0.3% v/v HOAc), followed by NaCNBH
2
Cl
2
, 3,5-dimethylisoxazole-4-sulfonyl chloride and
Cl , and 3-(methylthio)propionaldehyde in
in
2
2
3
3
THF. The products 36-39 were purified by RP-HPLC
2
5
and fully characterized. A parallel study based on 21c
1
as the R aldehyde component was designed to compare
analytical data, in particular the optical rotations, of the
respective benzothiazepines (R)-36c-40c and (S)-36c-
4
0c,26 derived from L-Fmoc-cysteine, L-13, and D-Fmoc-
cysteine, D-13, respectively (Table 2, bottom).
The [R] values obtained corroborate the results of
earlier solution-phase studies showing that 1,5-benzo-
thiazepin-4-ones can be assembled from cysteine deriva-
tives and fluoronitroarenes without racemization at the
R-carbon atom.3 Given, however, that these solution
protocols differ substantially from the present solid-phase
D
(
27) (a) Ni, Z.-J .; Maclean, D.; Holmes, C. P.; Murphy, M. M.;
Ruhland, B.; J acobs, J . W.; Gordon, E. M.; Gallop, M. A. J . Med. Chem.
996, 39, 1601. (b) Maclean, D.; Schullek, J . R.; Murphy, M. M.; Ni,
Z.-J .; Gordon, E. M.; Gallop, M. A. Proc. Natl. Acad. Sci. U.S.A. 1997,
1
9
4, 2805.
2
(28) TentaGel HL-NH (loading: 0.41 mmol/g) was differentiated
using a 9:1 molar ratio of Fmoc-Cl and Alloc-Cl and, following Fmoc
deprotection, coupled with the Rink-type, acid-labile linker p-[(R,S)-
[
1-(9H-fluoren-9-yl)-methoxyformamido]-2,4-dimethoxybenzyl]-phe-
(
25) See Experimental Section.
noxyacetic acid (Bernatowicz, M. S.; Daniels, S. B.; K o¨ ster, H.
Tetrahedron Lett. 1989, 30, 4645). Fmoc removal from the latter
furnished the starting resin 42.
(26) Terminology based on the absolute configuration at C(3).
Compound 38c was not synthesized.

2
224 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
Ta ble 2. (Top ) Yield s of Rep r esen ta tive 3,5-Disu bstitu ted 1,5-Ben zoth ia zep in -4-on es, 36-39 (Bottom ) Yield s of
2
6
Rep r esen ta tive En a n tiom er ic 3,5-Disu bstitu ted 1,5-Ben zoth ia zep in -on es, (R)-36-40 a n d (S)-36-40, Der ived fr om L- a n d
D-F m oc-cystein e, Resp ectively
a
See Table 1. b Yields of isolated, RP-HPLC-purified products derived from cleavage of 300 mg of resin; in percent relative to resin
c
loading based on Fmoc numbers. Purity of the crude product derived from TFA cleavage; in percent as determined by analytical HPLC
(UV detection at λ ) 220 nm).
structures such as 1,5-benzodiazepin-2-ones,11 2,2-di-
methyl-1,5-benzothiazepin-4-ones, 1,6-benzothiazocin-5-
ones, and 4-alkoxy-1,4-thiazin-3-ones. The results of
these studies will be reported in detail soon.
(Alltech Associates) placed on a vortex shaker. For reactions
performed at elevated temperature, screw-cap borosilicate
glass vials (Wheaton) were used, which had previously been
silanated by brief (10 min) exposure to a 10% solution of TMS-
Cl in hexane, rinsed several times with CH
2 2
Cl , and oven-
dried. Charged with the resin and reagents, the vials were then
Exp er im en ta l Section
1
13
placed in a heat block situated on a shaker. H and C NMR
spectra were recorded in DMSO-d on a Varian Mercury at
00 and 75 MHz, respectively. Chemical shifts were internally
referenced to the residual proton resonance of DMSO-d (δ
.50) and to the signal corresponding to the C methyl
resonance in DMSO-d (δ 39.51). ESI mass spectra were
6
Gen er a l. Reagents were purchased in the highest quality
available from Aldrich, Lancaster, Maybridge, Novabiochem,
and Advanced ChemTech and were used as received unless
otherwise stated. ArgoGel-Rink resin was purchased from
Argonaut Technologies (loading: 0.33 mmol/g), and TentaGel
3
5
1
3
2
6
HL-NH
mmol/g). Resins were washed twice each with DMF and CH
Cl prior to use. All reactions carried out at room temperature
were conducted in either glass standard peptide vessels
Chemglass) or polypropylene Extract-CleanTM filter tubes
2
was purchased from Rapp Polymere (loading: 0.41
recorded on a Hewlett-Packard Series 1100MSD instrument.
High-resolution mass spectra were run by the UC Berkeley
Mass Spectrometry Facility on a double focusing high-resolu-
tion Micromass ZAB2 EQ @ 8000 v accelerator potential using
FAB ionization. Optical rotations were determined using a
2
-
2
(

3
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2225
and H
2
O, containing 0.1% (v/v) TFA, were used as the solvent
system, with a gradient starting at 15% acetonitrile and
increasing to 95% within 30 min.
Gen er a l P r oced u r e for Deter m in a tion of F m oc Nu m -
ber s. A measured quantity n of resin (0.002 g < n < 0.010 g)
was placed in a 4 mL Alltech tube and allowed to react with
5
00 µL of a solution of 30% (v/v) piperidine in NMP for 30 min.
The solution was collected, and an aliquot (20 µL) was
removed, diluted by a factor of 50 with 30% piperidine in NMP,
and analyzed in a Hewlett-Packard 8452A Diode Array spec-
trophotometer (d ) 1 cm), measuring the absorbance D at λ )
3
02 nm. Given the molar extinction coefficient of the piperi-
-
1
-1
dine/dibenzofulvene adduct of 8100 L mol cm , the loading
L in mmol of compound per g of resin was then calculated as
L ) (25 × D)/(8100 × n).
Gen er a l Meth od for Isola tion a n d P u r ifica tion of th e
P r od u cts. From the dry resin, an aliquot of 300 mg was
removed and submitted to TFA cleavage by adding 6 mL of a
9
3
0% (v/v) solution of TFA in CH
0 min, the supernatant was collected, the resin was washed
Cl , and the combined filtrates were
2 2
Cl at room temperature. After
with another 6 mL of CH
2
2
concentrated on a SpeedVac. The dried residue was subse-
quently redissolved in 3-4 mL of DMSO for purification by
preparative RP-HPLC (vide supra). The product fractions were
lyophilized to afford the desired compound as a white to off-
white powder, in purities exceeding 99% based on HPLC
analysis with UV detection at λ ) 220 nm. Yields were
calculated on the basis of the loading of the resin as deter-
mined from its Fmoc number value.
Cou p lin g of 11 to Resin (12). To 25 g of ArgoGel-Rink
resin (8.25 mmol) in a 250 mL peptide vessel was added 100
mL of a 20% (v/v) solution of piperidine in DMF at room
temperature. The suspension was allowed to mix at room
temperature for 20 min. The supernatant was drained off and
replaced by another 100 mL of fresh reagent. After another
2
0 min mixing time, the solution was drained off, and the resin
was washed with DMF (6×), CH Cl (2×), MeOH (2×), and
CH Cl
added a solution of 11 (5.55 g, 30 mmol), HATU (11.40 g, 30
mmol), and DIEA (10.2 mL, 60 mmol) in anhydrous DMF (150
mL) at room temperature, and the mixture allowed to react
at room temperature for 12 h. The supernatant was drained
2
2
2
2
(4×) and then dried in vacuo. To the dry resin was
F igu r e 1. RP-HPLC analysis of (R,S)-41w (assembled from
L-Fmoc-cysteine and L-Boc-Phe) vs (S,S)-41w (from D-Fmoc-
cysteine and L-Boc-Phe), with UV detection at λ ) 220 nm. A:
Chromatogram of (R,S)-41w (solid line) superimposed with
that of (S,S)-41w (dotted line); B: Chromatogram obtained
by co-injection of (R,S)-41w and (S,S)-41w .
off, and the resin was washed with DMF (5×), CH
2
Cl
2
(3×),
MeOH (3×), and CH
2
Cl
2
(3×) and dried in vacuo.
L-N-(F lu or en ylm eth yloxyca r bon yl)-cystein e a n d D-N-
Sch em e 4
(
F lu or en ylm eth yloxyca r bon yl)-cystein e (L-13 a n d D-13).
To a solution of L-Fmoc-Cys(Trt)-OH (10.0 g, 17 mmol) in 50
mL of CH Cl were added triethylsilane (13.6 mL, 85 mmol)
2
2
and TFA (6.5 mL, 85 mmol) at room temperature. After 60
min, the mixture was concentrated in vacuo to afford a
yellowish oil. The latter was redissolved in CH Cl and again
2 2
concentrated several times, until a white precipitate formed,
at which point the suspension was diluted with an equal
volume of hexane. After removal of the solvents, the dry white
solid was placed in a B u¨ chner funnel and washed twice with
8
0 mL of toluene to remove most of the triphenylmethane. The
remaining white solid (4.9 g, 84%, purity >92% by HPLC),
L-13, was dried in vacuo and used without further purification
2
3
for the ensuing fluorine displacement. [R]
D
) -24.8 (c 2.3,
) δ 2.73 (m, broad, 1H),
.0 (m, 1H), 3.1 (m, 1H), 4.15 (m, 1H), 4.2-4.3 (m, 3H), 7.6
1
DMF); H NMR (300 MHz, DMSO-d
6
3
(
1
3
m, 4H), 7.9 (m, 3H), 8.1 (m, 2H), 13.1 (s, broad, 1H); C NMR
75 MHz, DMSO-d ) δ 25.5, 46.6, 56.6, 65.7, 120.1, 125.3, 127.1,
27.6, 140.7, 143.8, 156.0, 171.9. The same protocol was used
(
6
1
2
3
for D-Fmoc-Cys(Trt)-OH, providing D-13. [R]
D
) +26.3 (c 2.0,
DMF); all other analytical data identical to those of L-13.
(R)-N-(F lu or en ylm eth yloxyca r bon yl)-S-(2-n itr o-4-ca r -
ba m oylp h en yl)-cystein e ((R)-14a ). To 2.0 g of resin 12
(approximately 0.6 mmol) placed in a 25 mL peptide vessel
was added a solution of L-13 (340 mg, 1.0 mmol) and DIEA
(350 µL, 2.0 mmol) in 15 mL of anhydrous DMF at room
temperature. After a 24 h mixing period at ambient temper-
ature, the supernatant was drained off, and the resin (R)-14
J apan Spectroscopic Digital Polarimeter, model DIP-370.
Analytical HPLC relied on the use of a Beckman System Gold
module 126, equipped with a diode array module 168 detector
(
detection at λ ) 220/280 nm), and a Vydac RP column 218TP
(4.6 mm × 250 mm), used at a flow-rate of 1 mL/min.
Preparative HPLC was carried out using a Beckman System
Gold module 126, equipped with a Waters PrepPak column
charged with DeltaPak cartridges (40 mm × 100 mm, C18, 15
µm, 100 Å), monitoring at λ ) 220 nm. Mixtures of acetonitrile
was washed with DMF (5×), CH
2
Cl
2
(1×), MeOH (2×), and
CH Cl
2
2
(5×) and dried in vacuo. The product was isolated

2
226 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
according to the standard method (vide supra) to yield 29 mg
(S)-N-(F lu or en ylm et h yloxyca r b on yl)-S-(2-{[(4-m et h -
ylt h iop h en yl)m et h yl]a m in o}-4-ca r b a m oylp h en yl)-cys-
tein e ((S)-22c). The product was synthesized from resin (S)-
15 and aldehyde 21c by means of the general synthetic
procedure and isolated according to the standard method (vide
2
3
(
76%) of (R)-14a as a yellow powder. [R]
D
) +11.1 (c 0.97,
1
DMF); H NMR (300 MHz, DMSO-d
1
(
1
2
8
NMR (75 MHz, DMSO-d
1
1
6
) δ 3.34 (dd, 1H, J ) 13.8,
0.2 Hz), 3.62 (dd, 1H, J ) 13.5, 4.2 Hz), 4.2-4.3 (m, 4H), 7.31
t, 2H, J ) 7.2 Hz), 7.41 (t, 2H, J ) 7.5 Hz), 7.68 (s, broad,
2
3
H), 7.69 (d, 2H, J ) 8.1 Hz), 7.78 (d, 1H, J ) 9.0 Hz), 7.89 (d,
H, J ) 7.2 Hz), 7.97 (d, 1H, J ) 8.7 Hz), 8.19 (dd, 1H, J )
supra): 21 mg (51%) of (S)-22c as an off-white powder. [R]
D
) +59.3 (c 1.35, DMF); all other analytical data identical to
those of (R)-22c.
.7, 1.5 Hz), 8.29 (s, broad, 1H), 8.68 (d, 1H, J ) 1.5 Hz); 13
C
6
) δ 33.0, 46.5, 52.3, 65.8, 120.0, 124.9,
(R)-N-(F lu or en ylm eth yloxyca r bon yl)-S-(2-{[(3,4-m eth -
ylen ed ioxyp h en yl)m eth yl]a m in o}-4-ca r ba m oylp h en yl)-
cystein e ((R)-22e). The product was synthesized from resin
(R)-15 and aldehyde 21e by means of the general synthetic
procedure and isolated according to the standard method (vide
25.0, 125.1, 126.9, 127.0, 127.5, 130.9, 132.3, 139.1, 140.5,
43.5, 145.3, 155.7, 165.0, 171.3; HR-FABMS m/z calcd for
+
+
MH (C25
22 3 7
H N O S ) 508.1178, obsd 508.1168.
(
S)-N-(F lu or en ylm eth yloxyca r bon yl)-S-(2-n itr o-4-ca r -
2
3
ba m oylp h en yl)-cyst ein e ((S)-14a ). The same synthetic
protocol was followed as for (S)-14a , using D-13 (340 mg, 1.0
mmol) instead of l-13. The product was isolated according to
the standard method (vide supra): 30 mg (79%) of (S)-14a as
supra): 16 mg (35%) of (R)-22e as an off-white powder. [R]
D
1
) -52.9 (c 0.51, DMF); H NMR (300 MHz, DMSO-d ) δ 2.99
6
(dd, 1H, J ) 13.5, 10.2 Hz), 3.22 (dd, 1H, J ) 13.5, 3.9 Hz),
4.0 (m, 1H), 4.2-4.3 (m, 3H), 4.34 (s, 2H), 5.935 (s, 1H), 5.941
(s, 1H), 6.2 (s, broad, 1H), 6.80 (s, 2H), 6.89 (s, 1H), 7.02 (m,
2H), 7.25 (s, broad, 1H), 7.3-7.45 (m, 5H), 7.74 (d, 2H, J )
6.9 Hz), 7.84 (s, broad, 1H), 7.86 (d, 1H, J ) 8.4 Hz), 7.90 (d,
2
3
a yellow powder. [R]
analytical data identical to those of (R)-14a .
R)-N-(Flu or en ylm eth yloxycar bon yl)-S-(2-am in o-4-car -
ba m oylp h en yl)-cystein e ((R)-15a ). To 2.0 g of resin (R)-14
approximately 0.5 mmol) placed in a 25 mL peptide vessel
was added a solution of SnCl O (6.77 g, 30 mmol) in 15
D
) -8.6 (c 1.01, DMF); all other
(
2H, J ) 7.2 Hz); 13C NMR (75 MHz, DMSO-d
) δ 34.9, 45.8,
6
(
46.6, 53.3, 65.6, 100.6, 107.3, 107.9, 109.2, 114.9, 119.0, 119.7,
120.0, 125.1, 126.9, 127.5, 133.3, 134.4, 135.3, 140.5, 143.6,
145.8, 147.1, 147.8, 155.8, 167.6, 171.8; ESI-MS m/z calcd for
2
‚2H
2
mL DMF at room temperature. After 24 h, the solution was
+
+
drained off, and the resin (R)-15 was washed with DMF (5×),
30 3 7
MH (C33H N O S ) 612.18, obsd 612.25.
CH
2
Cl
2
(1×), MeOH (2×), and CH
2
Cl
2
(4×) and dried in vacuo.
(R)-N-(F lu or en ylm et h yloxyca r b on yl)-S-(2-{[(t h ien -3-
yl)m eth yl]am in o}-4-car bam oylph en yl)-cystein e ((R)-22m ).
The product was synthesized from resin (R)-15 and aldehyde
21m by means of the general synthetic procedure and isolated
according to the standard method (vide supra): 20 mg (47%)
The product was isolated according to the standard method
(
vide supra): 30 mg (84%) of (R)-15a as an off-white powder.
2
3
1
[R]
D
6
) -57.8 (c 0.83, DMF); H NMR (300 MHz, DMSO-d )
δ 2.98 (dd, 1H, J ) 13.5, 9.9 Hz), 3.18 (dd, 1H, J ) 13.5, 3.9
Hz), 4.0 (m, 1H), 4.2-4.35 (m, 3H), 7.05 (dd, 1H, J ) 8.1, 2.1
Hz), 7.2-7.45 (m, 7H), 7.73 (d, 2H, J ) 7.5 Hz), 7.8-7.9 (m,
2
3
of (R)-22m as an off-white powder. [R]
D
) -48.0 (c 1.00,
1
DMF); H NMR (300 MHz, DMSO-d
6
) δ 2.99 (dd, 1H, J ) 13.5,
1
3
4
1
1
H); C NMR (75 MHz, DMSO-d
6
) δ 34.7, 46.6, 53.3, 65.7,
10.2 Hz), 3.21 (dd, 1H, J ) 13.5, 4.5 Hz), 3.99 (m, 1H), 4.2-
4.35 (m, 3H), 4.43 (s, 2H), 7.0-7.1 (m, 3H), 7.25-7.45 (m, 8H),
7.74 (d, 2H, J ) 7.2 Hz), 7.85 (s, broad, 1H), 7.86 (d, 1H, J )
14.3, 115.8, 120.0, 125.1, 126.9, 127.5, 133.9, 135.2, 140.5,
43.6, 147.5, 155.7, 167.7, 171.9; HR-FABMS m/z calcd for
MH (C25
+
+
13
H
24
N
3
O
5
S ) 478.1437, obsd 478.1430.
8.4 Hz), 7.90 (d, 2H, J ) 7.2 Hz); C NMR (75 MHz, DMSO-
(
S)-N-(Flu or en ylm eth yloxycar bon yl)-S-(2-am in o-4-car -
6
d ) δ 35.0, 42.1, 46.6, 53.3, 65.7, 109.2, 115.0, 119.1, 120.0,
ba m oylp h en yl)-cyst ein e ((S)-15a ). The same synthetic
protocol was followed as for (R)-15a , starting from 2.0 g of resin
121.1, 125.1, 126.2, 126.9, 127.0, 127.5, 134.5, 135.3, 140.5,
140.6, 143.6, 147.9, 155.8, 167.7, 171.9; ESI-MS m/z calcd for
+
+
(
S)-14. The product was isolated according to the standard
MH (C30H N O S ) 574.15, obsd 574.15.
28 3 5 2
method (vide supra): 27 mg (76%) of (S)-15a as an off-white
(R)-N-(F lu or en ylm eth yloxyca r bon yl)-S-(2-{[(N-a cetyl-
in d ole -3-yl)m e t h yl]a m in o }-4-ca r b a m oylp h e n yl)-cys-
tein e ((R)-22r ). The product was synthesized from resin (R)-
15 and aldehyde 21r by means of the general synthetic
procedure and isolated according to the standard method (vide
2
3
powder. [R]
D
) +62.7 (c 1.17, DMF); all other analytical data
identical to those of (R)-15a .
Gen er a l P r oced u r e for t h e R ed u ct ive Alk yla t ion of
th e P r im a r y An ilin e (15) w ith Non en oliza ble Ald eh yd es.
To 200 mg portions (approximately 50 µmol) of resin 15 in 8
mL screw-cap glass vials were added 3.0 mL of a 0.2M solution
2
3
supra): 16 mg (33%) of (R)-22r as an off-white powder. [R]
D
1
) -40.5 (c 0.57, DMF); H NMR (300 MHz, DMSO-d ) δ 2.57
6
of the respective aldehydes in dry CH(OMe)
3
/DMF 9:1 and 600
(s, 3H), 2.98 (dd, 1H, J ) 13.5, 9.9 Hz), 3.18 (dd, 1H, J ) 13.5,
4.5 Hz), 3.99 (m, 1H), 4.2-4.3 (m, 3H), 4.57 (s, 2H), 6.1 (s,
broad, 1H), 7.38 (dd, 1H, J ) 8.1, 1.8 Hz), 7.2-7.45 (m, 9H),
7.71 (d, 2H, J ) 7.5 Hz), 7.75-7.9 (m, 6H), 8.29 (d, 1H, J )
µL of a 6% (v/v) solution of HOAc in MeOH at room temper-
ature. The vials were then placed in a heat block heated to
4
5-50 °C, and the reactions were allowed to proceed under
gentle agitation from a shaker for 18 h. After this time, 3.0
mL of a 1 M solution of NaCNBH in THF was added, and
7.5 Hz); 13C NMR (75 MHz, DMSO-d
) δ 23.8, 35.1, 38.5, 46.6,
6
3
53.3, 65.6, 109.3, 115.2, 115.8, 119.0, 119.3, 119.4, 120.0, 123.1,
124.5, 124.7, 125.1, 126.9, 127.5, 129.2, 134.5, 135.2, 135.3,
140.5, 143.5, 147.9, 155.7, 167.6, 168.9, 171.8; HR-FABMS
agitation at 45-50 °C was continued for another 6 h. The
resulting resin batches 17 were then transferred to 8 mL
+
+
polypropylene filter tubes and washed with MeOH (3×), H
2×), 2% HOAc (aqueous) (4×), H O (2×), MeOH (2×), CH
Cl Cl (4×). The secondary anilines
(1×), DMF (3×), and CH
2 were isolated from 17 according to the standard method
described above.
R)-N-(F lu or en ylm et h yloxyca r b on yl)-S-(2-{[(4-m et h -
2
O
33 4 6
m/z calcd for MH (C36H N O S ) 649.2120, obsd 649.2128.
(
2
2
-
Gen er a l P r oced u r e for t h e R ed u ct ive Alk yla t ion of
th e P r im a r y An ilin e (15) w ith En oliza ble Ald eh yd es. To
200 mg portions (approximately 50 µmol) of resin 15 in 8 mL
screw-cap glass vials were added 3.0 mL of a 0.2 M solution
of the respective aldehydes and benzotriazole (24 mg per ml)
2
2
2
2
(
ylt h iop h en yl)m et h yl]a m in o}-4-ca r b a m oylp h en yl)-cys-
tein e ((R)-22c). The product was synthesized from resin (R)-
3
in dry CH(OMe) /DMF 9:1 and 600 µL of a 6% (v/v) solution
of HOAc in MeOH at room temperature. The reactions were
allowed to proceed at room temperature under gentle agitation
from a shaker for 18 h. After this time, 3.0 mL of a 1 M solution
1
5 and aldehyde 21c by means of the general synthetic
procedure and isolated according to the standard method (vide
2
3
supra): 18 mg (46%) of (R)-22c as an off-white powder. [R]
D
3
of NaCNBH in THF was added, and agitation at ambient
temperature continued for another 6 h. The resulting resin
batches 17 were then transferred to 8 mL polypropylene filter
1
)
-53.3 (c 0.15, DMF); H NMR (300 MHz, DMSO-d
s, 3H), 2.99 (dd, 1H, J ) 13.5, 10.2 Hz), 3.25 (dd, 1H, J )
3.8, 4.2 Hz), 3.99 (m, 1H), 4.2-4.35 (m, 3H), 4.41 (s, 2H), 6.2
6
) δ 2.41
(
1
tubes and washed with MeOH (3×), H
(aqueous) (4×), H O (2×), MeOH (2×), CH
and CH Cl
17 according to the standard method described above.
(R)-N-(F lu or en ylm eth yloxyca r bon yl)-S-[2-(isop en tyl)-
a m in o]-4-ca r ba m oylp h en yl)-cystein e ((R)-22v). The prod-
uct was synthesized from resin (R)-15 and aldehyde 21v by
2
O (2×), 2% HOAc
(
)
s, broad, 1H), 7.0 (m, 2H), 7.15-7.45 (m, 10H), 7.74 (d, 2H, J
2
2
Cl
2
(1×), DMF (3×),
1
3
7.5 Hz), 7.8-7.9 (m, 4H); C NMR (75 MHz, DMSO-d
6
) δ
2
2
(4×). The secondary anilines 22 were isolated from
1
1
1
4.8, 34.8, 45.5, 46.6, 53.3, 65.7, 109.2, 114.9, 118.8, 120.0,
25.1, 125.9, 126.9, 127.3, 127.5, 134.6, 135.4, 135.9, 136.2,
40.5, 143.6, 147.8, 155.8, 167.6, 171.9; HR-FABMS m/z calcd
+
+
32 3 5 2
H N O S ) 614.1783, obsd 614.1778.
for MH (C33

3
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2227
6
MHz, DMSO-d ) δ 3.17 (t, 1H, J ) 11.5 Hz), 3.51 (dd, 1H, J )
means of the general synthetic procedure and isolated accord-
ing to the standard method (vide supra): 30 mg (73%) of (R)-
2
11.4, 7.2 Hz), 4.15-4.3 (m, 4H), 4.77 (d, 1H, J ) 15.1 Hz), 5.35
(d, 1H, J ) 15.4 Hz), 5.92 (s, 2H), 6.65 (dd, 1H, J ) 7.8, 0.9
Hz), 6.74 (d, 1H, J ) 7.8 Hz), 6.82 (d, 1H, J ) 0.9 Hz), 7.32 (t,
2H, J ) 7.5 Hz), 7.41 (t, 2H, J ) 7.2 Hz), 7.58 (s, broad, 1H),
7.65-7.75 (m, 4H), 7.88 (d, 2H, J ) 7.5 Hz), 8.00 (s, 1H), 8.01
2
3
1
2v as an off-white powder. [R]
D
) -60.1 (c 1.34, DMF); H
NMR (300 MHz, DMSO-d
6
) δ 0.88 (d, 6H, J ) 6.6 Hz), 1.45
(m, 2H), 1.64 (non, 1H, J ) 6.6 Hz), 2.97 (dd, 1H, J ) 13.5,
1
1
1
2
0.2 Hz), 3.15 (m, 3H), 3.97 (m, 1H), 4.3 (m, 3H), 7.06 (dd,
H, J ) 7.5, 1.8 Hz), 7.09 (d, 1H, J ) 1.8 Hz), 7.3 (s, broad,
H), 7.33 (t, 2H, J ) 7.2 Hz), 7.35 (d, 1H, J ) 7.5 Hz), 7.42 (t,
H, J ) 7.2 Hz), 7.74 (d, 2H, J ) 7.5 Hz), 7.84 (d, 1H, J ) 8.1
1
3
(d, 1H, J ) 8.1 Hz), 8.15 (s, broad, 1H); C NMR (75 MHz,
DMSO-d ) δ 37.2, 46.5, 50.5, 51.4, 65.8, 100.7, 107.7, 108.1,
6
120.0, 121.0, 123.2, 125.0, 125.9, 126.9, 127.5, 130.2, 130.3,
135.3, 136.2, 140.5, 143.47, 143.54, 144.3, 146.1, 146.8, 155.3,
1
3
Hz), 7.90 (d, 2H, J ) 7.5 Hz), 7.9 (s, broad, 1H); C NMR (75
MHz, DMSO-d ) δ 22.47, 22.50, 25.5, 35.4, 37.4, 41.1, 46.6,
3.4, 65.7, 108.8, 114.9, 119.0, 120.0, 125.1, 126.9, 127.5, 134.5,
35.5, 140.5, 143.5, 143.6, 148.2, 155.8, 167.7, 171.8; HR-
+
+
6
166.2, 170.8; ESI-MS m/z calcd for MH (C33
H
28
N
3
O
6
S )
5
1
594.17, obsd 594.25.
(R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
am in o]-N(5)-[(th ien -3-yl)m eth yl]-1,5-ben zoth iazepin -4(5H)-
on e ((R)-23m ). The product was derived from the correspond-
ing secondary aniline according to the general synthetic
procedure and isolated following the standard method (vide
+
+
FABMS m/z calcd for MH (C30
48.2213.
R)-N-(F lu or en ylm eth yloxyca r bon yl)-S-(2-{[3-(4-m eth -
34 3 5
H N O S ) 548.2219, obsd
5
(
oxyp h e n yl)p r op yl]-a m in o}-4-ca r b a m oylp h e n yl)-cys-
tein e ((R)-22x). The product was synthesized from resin (R)-
1
procedure and isolated according to the standard method (vide
supra): 33 mg (72%) of (R)-22x as an off-white powder. [R]
2
3
supra): 23 mg (69%) of (R)-23m as a snow-white powder. [R]
D
1
5 and aldehyde 21x by means of the general synthetic
3 6
) -86.1 (c 1.45, CHCl ); H NMR (300 MHz, DMSO-d ) δ 3.15
(1H, t, J ) 11.7 Hz), 3.51 (dd, 1H, J ) 11.7, 6.9 Hz), 4.1-4.3
(m, 4H), 4.91 (d, 1H, J ) 15.3 Hz), 5.32 (d, 1H, J ) 15.6 Hz),
6.96 (dd, 1H, J ) 4.9, 0.8 Hz), 7.2-7.4 (m, 6H), 7.58 (s, broad,
1H), 7.5 (m, 4H), 7.88 (d, 2H, J ) 7.4 Hz), 7.99 (d, 1H, J ) 1.4
Hz), 8.02 (s, broad, 1H), 8.14 (s, broad, 1H); 13C NMR (75 MHz,
2
3
D
1
)
-44.6 (c 1.42, DMF); H NMR (300 MHz, DMSO-d
6
) δ 1.83
(
quin, 2H, J ) 7.5 Hz), 2.58 (t, 2H, J ) 7.5 Hz), 2.98 (dd, 1H,
J ) 13.5, 10.2 Hz), 3.15 (m, 3H), 3.68 (s, 3H), 3.98 (m, 1H),
4
7
.2-4.3 (m, 3H), 6.0 (s, broad, 1H), 6.78 (d, 2H, J ) 8.4 Hz),
.07 (m, 4H), 7.3-7.45 (m, 6H), 7.72 (d, 2H, J ) 7.2 Hz), 7.85
6
DMSO-d ) δ 37.1, 46.5, 46.8, 51.4, 65.8, 120.0, 122.5, 123.2,
125.0, 125.9, 126.0, 126.9, 127.3, 127.5, 130.1, 135.2, 136.2,
(
d, 1H, J ) 8.7 Hz), 7.9 (s, broad, 1H), 7.90 (d, 2H, J ) 7.2
137.4, 140.5, 143.47, 143.54, 144.4, 155.3, 166.2, 170.5; ESI-
1
3
+
+
2
Hz); C NMR (75 MHz, DMSO-d
6
) δ 30.4, 31.7, 35.5, 42.4, 46.6,
26 3 4
MS m/z calcd for MH (C30H N O S ) 556.14, obsd 556.15.
5
1
1
3.4, 54.9, 65.7, 108.7, 113.5, 114.9, 119.0, 120.0, 125.1, 126.9,
(R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
a m in o]-N(5)-[(N-a cetylin d ole-3-yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-23r ). The product was derived from
the corresponding secondary aniline according to the general
synthetic procedure and isolated following the standard method
27.5, 129.0, 133.3, 134.6, 135.6, 140.5, 143.5, 143.6, 148.2,
+
55.8, 157.2, 167.8, 171.9; ESI-MS m/z calcd for MH
+
(C
35
H
36
N
3
O
6
S ) 626.23, obsd 626.20.
Gen er a l P r oced u r e for th e Cycliza tion of th e Secon d -
a r y An ilin es (17). To 300 mg resin portions of the general
structure 17 (approximately 75 µmol) in 15 mL polypropylene
filter tubes was added 6 mL of a 1% (v/v) solution of DIC in
(vide supra): 33 mg (70%) of (R)-23r as a snow-white powder.
[R]23
) -52.5 (c 1.65, CHCl
); H NMR (300 MHz, DMSO-d
1
)
D
3
6
δ 2.47 (s, 3H), 3.18 (t, 1H, J ) 11.5 Hz), 3.54 (dd, 1H, J )
11.3, 4.4 Hz), 4.1-4.3 (m, 4H), 5.19 (d, 1H, J ) 16.2 Hz), 5.28
(d, 1H, J ) 16.2 Hz), 7.2-7.4 (m, 6H), 7.54 (d, 1H, J ) 7.7
Hz), 7.57 (s, broad, 1H), 7.7 (m, 5H), 7.9 (m, 2H), 8.01 (d, 1H,
J ) 1.7 Hz), 8.10 (d, 1H, J ) 8.0 Hz), 8.16 (s, broad, 1H), 8.27
2 2
CH Cl /benzene (1:1 v/v) at room temperature, and the mix-
tures were gently agitated for 6 h at ambient temperature.
After this time, the supernatants were removed, and the
resulting resin batches of general structure 19 were washed
with CH
in vacuo. The 1,5-benzothiazepin-4-ones 23 were isolated from
9 according to the standard method described above.
R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
2
Cl
2
(3×), DMF (3×), and CH
2
Cl
2
(3×) and finally dried
(d, 1H, J ) 8.0 Hz); 13C NMR (75 MHz, DMSO-d
) δ 23.6, 36.9,
6
43.7, 46.6, 51.8, 65.8, 115.7, 117.3, 119.4, 119.93, 119.99, 123.0,
124.8, 124.9, 125.0, 125.9, 126.9, 127.4, 127.5, 128.7, 129.8,
135.0, 135.3, 136.4, 140.48, 140.54, 143.4, 143.5, 144.8,
1
(
+
a m in o]-N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-23c). The product was derived from
the corresponding secondary aniline according to the general
synthetic procedure and isolated following the standard method
155.5, 166.3, 168.8, 170.8; HR-FABMS m/z calcd for MH
+
(C36
H
31
N
4
O
5
S ) 630.2015, obsd 630.2005.
(R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
am in o]-N(5)-isopen tyl-1,5-ben zoth iazepin -4(5H)-on e ((R)-
23v). The product was derived from the corresponding sec-
ondary aniline according to the general synthetic procedure
and isolated following the standard method (vide supra): 25
(
vide supra): 22 mg (61%) of (R)-23c as a snow-white powder.
2
3
1
[R]
D
3 6
) -79.0 (c 1.04, CHCl ); H NMR (300 MHz, DMSO-d )
δ 2.39 (s, 3H), 3.16 (t, 1H, J ) 11.8 Hz), 3.52 (dd, 1H, J )
1.3, 6.9 Hz), 4.1-4.3 (m, 4H), 4.83 (d, 1H, J ) 15.4 Hz), 5.39
d, 1H, J ) 15.4 Hz), 7.09 (d, 2H, J ) 8.5 Hz), 7.20 (d, 2H, J
8.2 Hz), 7.32 (t, 2H, J ) 7.4 Hz), 7.41 (t, 2H, J ) 7.4 Hz),
.58 (s, broad, 1H), 7.7 (m, 4H), 7.88 (d, 2H, J ) 7.4 Hz), 8.01
2
3
1
(
)
mg (62%) of (R)-23v as a snow-white powder. [R]
D
) -134.9
1
(c 1.03, CHCl ); H NMR (300 MHz, DMSO-d ) δ 0.77 (d, 3H,
3
6
J ) 6.6 Hz), 0.83 (d, 3H, J ) 6.6 Hz), 1.19 (m, 1H), 1.35 (m,
1H), 1.54 (m, 1H), 3.10 (t, 1H, J ) 11.5 Hz), 3.5 (m, 2H), 4.08
(m, 1H), 4.15-4.35 (m, 4H), 7.32 (t, 2H, J ) 7.4 Hz), 7.41 (t,
2H, J ) 7.1 Hz), 7.60 (s, broad, 1H), 7.68 (dd, 2H, J ) 6.9, 5.5
Hz), 7.73 (d, 1H, J ) 8.0 Hz), 7.79 (dd, 1H, J ) 8.1, 1.4 Hz),
7.88 (d, 2H, J ) 7.1 Hz), 7.90 (d, 1H, J ) 6.9 Hz), 7.99 (d, 1H,
7
1
3
(m, 2H), 8.15 (s, broad, 1H); C NMR (75 MHz, DMSO-d
6
) δ
1
1
1
4.5, 37.2, 46.5, 50.5, 51.4, 65.8, 120.0, 123.2, 125.0, 125.4,
25.9, 126.9, 127.5, 128.2, 130.1, 133.1, 135.3, 136.2, 136.6,
40.5, 143.46, 143.54, 144.4, 155.2, 166.1, 170.8; HR-FABMS
+
+
13
m/z calcd for MH (C33
H
30
N
3
O
4
S
2
) 596.1678, obsd 596.1675.
J ) 1.5 Hz), 8.18 (s, broad, 1H); C NMR (75 MHz, DMSO-
(
S)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
6
d ) δ 22.2, 22.4, 25.3, 36.2, 37.0, 46.5, 46.6, 51.1, 65.7, 119.9,
a m in o]-N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((S)-23c). The product was derived from
the corresponding secondary aniline according to the general
synthetic procedure and isolated following the standard method
123.5, 125.0, 126.0, 126.9, 127.5, 130.7, 135.1, 136.3, 140.5,
143.5, 144.7, 155.2, 166.1, 169.9; HR-FABMS m/z calcd for
+
+
MH (C30
32 3 4
H N O S ) 530.2114, obsd 530.2115.
(R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
a m in o]-N(5)-[3-(4-m eth oxyp h en yl)p r op yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-23x). The product was derived from
the corresponding secondary aniline according to the general
synthetic procedure and isolated following the standard method
(vide supra): 25 mg (55%) of (R)-23x as a snow-white powder.
(
vide supra): 27 mg (69%) of (S)-23c as a snow-white powder.
2
3
[R]
D
3
) +77.4 (c 1.87, CHCl ); all other analytical data
identical to those of (R)-23c.
R)-7-Ca r ba m oyl-3-[N-(flu or en ylm eth yloxyca r bon yl)-
(
am in o]-N(5)-[(3,4-m eth ylen edioxyph en yl)m eth yl]-1,5-ben -
zoth ia zep in -4(5H)-on e ((R)-23e). The product was derived
from the corresponding secondary aniline according to the
general synthetic procedure and isolated following the stan-
dard method (vide supra): 29 mg (65%) of (R)-23e as a snow-
2
3
1
[R]
6
D
3
) -113.0 (c 0.85, CHCl ); H NMR (300 MHz, DMSO-
d
) δ 1.66 (m, 2H), 2.47 (m, 2H), 3.13 (t, 1H, J ) 12.0 Hz), 3.5
(m, 2H), 3.68 (s, 3H), 4.1 (m, 1H), 4.15-4.3 (m, 4H), 6.77 (d,
2H, J ) 8.4 Hz), 6.97 (d, 2H, J ) 8.7 Hz), 7.31 (t, 2H, J ) 7.2
Hz), 7.41 (t, 2H, J ) 7.5 Hz), 7.60 (s, broad, 1H), 7.68 (t, 2H,
2
3
1
white powder. [R]
D
3
) -68.9 (c 1.35, CHCl ); H NMR (300

2
228 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
J ) 6.6 Hz), 7.75 (d, 1H, J ) 8.1 Hz), 7.80 (dd, 1H, J ) 8.1,
J ) 8.1, 1.8 Hz), 7.99 (d, 1H, J ) 1.8 Hz), 8.14 (s, broad, 1H),
1
7
.5 Hz), 7.88 (d, 2H, J ) 7.5 Hz), 7.92 (d, 1H, J ) 8.1 Hz),
8.50 (d, 1H, J ) 7.8 Hz); 13C NMR (75 MHz, DMSO-d
) δ 35.4,
6
.96 (d, 1H, J ) 1.5 Hz), 8.16 (s, broad, 1H); 1 C NMR (75 MHz,
3
37.4, 46.6, 49.0, 57.8, 67.9, 122.5, 123.3, 125.9, 126.0, 127.4,
DMSO-d
6
) δ 29.6, 31.6, 37.0, 46.5, 47.9, 51.2, 54.8, 65.7, 113.5,
130.2, 135.2, 136.2, 137.4, 144.4, 166.2, 169.4, 170.1; HR-
+
+
1
1
20.0, 123.7, 125.0, 126.1, 126.9, 127.5, 128.9, 130.6, 133.1,
35.1, 136.3, 140.5, 143.5, 144.7, 155.2, 157.1, 166.2, 170.0;
FABMS m/z calcd for MH (C19
H
22
N
3
O
4
S
2
) 420.1052, obsd
420.1057.
+
+
ESI-MS m/z calcd for MH (C35
08.20.
Gen er a l P r oced u r e for th e Syn th esis of th e 3-(Acyl-
H
34
N
3
O
5
S ) 608.22, obsd
(R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
(5)-[(N-acetylin dole-3-yl)m eth yl]-1,5-ben zoth iazepin -4(5H)-
on e ((R)-36r ). The product was isolated according to the
standard method (vide supra): 20 mg (53%) of (R)-36r as a
6
a m in o)-1,5-ben zoth ia zep in -4-on es (32). To 300 mg resin
portions of the general structure 19 (approximately 75 µmol)
in 15 mL polypropylene filter tubes was added 6 mL of a 20%
2
3
1
snow-white powder. [R]
D
) -80.1 (c 0.60, CHCl
3
); H NMR
(300 MHz, DMSO-d ) δ 2.36 (t, 2H, J ) 6.6 Hz), 2.55 (s, 3H),
6
(v/v) solution of piperidine in DMF at room temperature, and
3.10 (t, 1H, J ) 11.4 Hz), 3.17 (s, 3H), 3.47 (t, 2H, J ) 6.3 Hz),
3.49 (m, 1H), 4.46 (m, 1H), 5.13 (d, 1H, J ) 16.5 Hz), 5.32 (d,
1H, J ) 16.5 Hz), 7.21 (td, 1H, J ) 7.8, 1.2 Hz), 7.31 (td, 1H,
J ) 7.4, 1.2 Hz), 7.64 (d, 1H, J ) 7.5 Hz), 7.58 (s, broad, 1H),
7.65 (d, 1H, J ) 8.1 Hz), 7.72 (dd, 1H, J ) 8.1, 1.8 Hz), 7.72
(s, 1H), 8.03 (d, 1H, J ) 1.8 Hz), 8.16 (s, broad, 1H), 8.25 (d,
the mixtures were gently agitated for 20 min. After removal
of the supernatants, the resulting resin batches of general
structure 20 were washed with DMF (6×), CH
2
Cl
2
(4×), and
DMF (3×) and subsequently resuspended in a solution con-
taining 3-methoxypropionic acid (76 µL, 0.8 mmol), DIC (128
µL, 0.8 mmol), and a spatula tip of DMAP in 4 mL of
anhydrous DMF. After a reaction time of 2 h at ambient
temperature, the supernatants were removed, and the result-
ing resin batches of general structure 32 were washed with
1
3
1H, J ) 8.1 Hz), 8.58 (d, 1H, J ) 7.5 Hz); C NMR (75 MHz,
DMSO-d
6
) δ 23.7, 35.4, 37.1, 43.4, 49.5, 57.8, 67.8, 115.6, 117.2,
119.4, 123.0, 123.2, 124.7, 125.2, 125.9, 128.8, 130.0, 135.0,
135.2, 136.3, 144.7, 166.3, 168.9, 169.7, 170.3; HR-FABMS
+
+
DMF (5×), CH
2
Cl
2
(1×), MeOH (2×), and CH
2
Cl
2
(4×) and
26 4 5
m/z calcd for M (C25H N O S ) 494.1624, obsd 494.1623.
finally dried in vacuo. The 3-(acylamino)-1,5-benzothiazepi-
nones 36 were isolated from 32 according to the standard
method described above.
(R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
(5)-isop en tyl-1,5-ben zoth ia zep in -4(5H)-on e ((R)-36v). The
product was isolated according to the standard method (vide
2
3
(
R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
5)-[(4-m et h ylt h iop h en yl)m et h yl]-1,5-b en zot h ia zep in -
(5H)-on e ((R)-36c). The product was isolated according to
the standard method (vide supra): 20 mg (72%) of (R)-36c as
supra): 22 mg (73%) of (R)-36v as a snow-white powder. [R]
D
1
(
4
) N/A; H NMR (300 MHz, DMSO-d ) δ 0.77 (d, 3H, J ) 6.6
6
Hz), 0.83 (d, 3H, J ) 6.6 Hz), 1.19 (m, 1H), 1.35 (m, 1H), 1.54
(non, 1H, J ) 6.6 Hz), 2.32 (t, 2H, J ) 6.3 Hz), 3.01 (t, 1H, J
) 11.7 Hz), 3.16 (s, 3H), 3.45 (m, 4H), 4.3 (m, 2H), 7.59 (s,
broad, 1H), 7.73 (d, 1H, J ) 8.1 Hz), 7.78 (dd, 1H, J ) 8.1, 1.5
Hz), 7.98 (d, 1H, J ) 1.5 Hz), 8.17 (s, broad, 1H), 8.39 (d, 1H,
2
3
1
a snow-white powder. [R]
D
) -106.5 (c 0.84, CHCl
) δ 2.35 (t, 2H, J ) 6.3 Hz), 2.40 (s, 3H),
.09 (t, 1H, J ) 11.7 Hz), 3.17 (s, 3H), 3.45 (m, 1H), 3.46 (t,
H, J ) 6.3 Hz), 4.45 (m, 1H), 4.81 (d, 1H, J ) 15.6 Hz), 5.42
3
); H NMR
(
300 MHz, DMSO-d
6
3
2
(
)
(
J ) 8.1 Hz); 13C NMR (75 MHz, DMSO-d
) δ 22.2, 22.4, 25.3,
6
d, 1H, J ) 15.9 Hz), 7.10 (d, 2H, J ) 8.4 Hz), 7.20 (d, 2H, J
8.4 Hz), 7.58 (s, broad, 1H), 7.65 (d, 1H, J ) 8.1 Hz), 7.71
dd, 1H, J ) 8.1, 1.8 Hz), 8.01 (d, 1H, J ) 1.8 Hz), 8.15 (s,
broad, 1H), 8.50 (d, 1H, J ) 8.1 Hz); C NMR (75 MHz,
DMSO-d ) δ 14.5, 35.4, 37.5, 48.9, 50.3, 57.8, 67.9, 123.3, 125.4,
25.9, 128.3, 130.2, 133.1, 135.2, 136.2, 136.7, 144.3, 166.1,
35.4, 36.2, 37.3, 46.5, 48.6, 57.8, 67.9, 123.6, 126.1, 130.7, 135.1,
136.3, 144.6, 166.1, 169.3, 169.5; HR-FABMS m/z calcd for
+
+
28 3 4
MH (C19H N O S ) 394.1801, obsd 394.1789.
1
3
(R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
(5)-[3-(4-m eth oxyph en yl)pr opyl]-1,5-ben zoth iazepin -4(5H)-
on e ((R)-36x). The product was isolated according to the
standard method (vide supra): 19 mg (54%) of (R)-36x as a
6
1
1
4
+
+
26 3 4 2
H N O S )
69.4, 170.3; HR-FABMS m/z calcd for MH (C22
60.1365, obsd 460.1366.
2
3
1
snow-white powder. [R]
D
) -151.9 (c 0.49, CHCl
3
); H NMR
(
S)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
5)-[(4-m et h ylt h iop h en yl)m et h yl]-1,5-b en zot h ia zep in -
(5H)-on e ((S)-36c). The product was isolated according to
the standard method (vide supra): 18 mg (64%) of (S)-36c as
(300 MHz, DMSO-d ) δ 1.66 (m, 2H), 2.33 (t, 2H, J ) 6.3 Hz),
6
(
4
2.5 (m, 2H), 3.04 (t, 1H, J ) 12.0 Hz), 3.17 (s, 3H), 3.4-3.55
(m, 4H), 3.68 (s, 3H), 4.29 (m, 1H), 4.38 (m, 1H), 6.77 (d, 2H,
J ) 8.4 Hz), 6.97 (d, 2H, J ) 8.4 Hz), 7.59 (s, broad, 1H), 7.75
(d, 1H, J ) 8.1 Hz), 7.80 (dd, 1H, J ) 8.1, 1.8 Hz), 7.95 (d, 1H,
2
3
a snow-white powder. [R]
analytical data identical to those of (R)-36c.
R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
5)-[(3,4-m eth ylen ed ioxyp h en yl)m eth yl]-1,5-ben zoth ia z-
D
) +111.5 (c 0.82, CHCl
3
); all other
1
3
J ) 1.5 Hz), 8.15 (s, broad, 1H), 8.41 (d, 1H, J ) 8.1 Hz);
C
(
NMR (75 MHz, DMSO-d ) δ 29.6, 31.6, 35.4, 37.3, 47.7, 48.7,
54.9, 57.7, 67.9, 113.5, 123.8, 126.1, 128.9, 130.7, 133.0, 135.1,
6
(
ep in -4(5H)-on e ((R)-36e). The product was isolated according
to the standard method (vide supra): 23 mg (67%) of (R)-36e
136.3, 144.6, 157.1, 166.2, 169.4, 169.6; HR-FABMS m/z calcd
+
+
for MH (C24
30 3 5
H N O S ) 472.1906, obsd 472.1908.
2
3
1
as a snow-white powder. [R]
NMR (300 MHz, DMSO-d ) δ 2.35 (t, 2H, J ) 6.3 Hz), 3.09 (t,
H, J ) 12.0 Hz), 3.16 (s, 3H), 3.45 (m, 3H), 4.45 (m, 1H),
D
) -91.9 (c 1.00, CHCl
3
); H
Gen er a l P r oced u r e for th e Syn th esis of th e 3-Ur eid o-
1,5-ben zoth ia zep in -4-on es (33). To 300 mg resin portions
of the general structure 19 (approximately 75 µmol) in 15 mL
polypropylene filter tubes was added 6 mL of a 20% (v/v)
solution of piperidine in DMF at room temperature, and the
mixtures were gently agitated for 20 min. After removal of
the supernatants, the resulting resin batches of general
6
1
4
2
1
7
.76 (d, 1H, J ) 15.3 Hz), 5.36 (d, 1H, J ) 15.0 Hz), 5.93 (dd,
H, J ) 3.0, 1.2 Hz), 6.69 (dd, 1H, J ) 7.8, 1.8 Hz), 6.74 (d,
H, J ) 7.8 Hz), 6.82 (d, 1H, J ) 1.2 Hz), 7.58 (s, broad, 1H),
.65 (d, 1H, J ) 8.1 Hz), 7.71 (dd, 1H, J ) 8.1, 1.8 Hz), 8.00
(
d, 1H, J ) 1.8 Hz), 8.15 (s, broad, 1H), 8.50 (d, 1H, J ) 8.1
structure 20 were washed with DMF (6×), CH
DMF (2×), CH Cl (3×) and subsequently resuspended in a
solution of 2-chloroethyl isocyanate (104 µL, 1.2 mmol) and
NMM (132 µL, 1.2 mmol) in 4 mL of anhydrous CH Cl . After
2
Cl
2
(1×), and
1
3
Hz); C NMR (75 MHz, DMSO-d
6
) δ 35.4, 37.5, 49.0, 50.4, 57.8,
7.9, 100.7, 107.7, 108.1, 121.1, 123.3, 125.9, 130.28, 130.30,
35.2, 136.2, 144.2, 146.1, 146.8, 166.2, 169.5, 170.4; HR-
2
2
6
1
2
2
+
+
FABMS m/z calcd for MH (C22
58.1397.
R)-7-Ca r ba m oyl-3-[N-(3-m eth oxyp r op ion yl)a m in o]-N-
5)-[(th ien -3-yl)m eth yl]-1,5-ben zoth iazepin -4(5H)-on e ((R)-
6m ). The product was isolated according to the standard
method (vide supra): 15 mg (58%) of (R)-36m as a snow-white
H
24
N
3
O
6
S ) 458.1386, obsd
a reaction time of 2 h at ambient temperature, the superna-
tants were removed, and the resulting resin batches of general
4
(
structure 33 were washed with CH
Cl Cl
2
2
Cl
2
(3×), DMF (3×), CH
2
-
(
3
2
(1×), MeOH (2×), and CH
2
(4×) and finally dried in
vacuo. The 3-ureido-1,5-benzothiazepinones 37 were isolated
from 33 according to the standard method described above.
(R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
a m in o}-N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-37c). The product was isolated ac-
cording to the standard method (vide supra): 17 mg (61%) of
2
3
1
powder. [R]
DMSO-d ) δ 2.34 (t, 2H, J ) 6.3 Hz), 3.08 (t, 1H, J ) 11.4
Hz), 3.16 (s, 3H), 3.45 (m, 3H), 4.45 (m, 1H), 4.91 (d, 1H, J )
D
) -126.7 (c 0.36, CHCl
3
); H NMR (300 MHz,
6
1
5.6 Hz), 5.31 (d, 1H, J ) 15.9 Hz), 6.96 (dd, 1H, J ) 5.1, 1.2
2
3
Hz), 7.26 (dd, 1H, J ) 3.0, 1.2 Hz), 7.39 (dd, 1H, J ) 4.8, 3.0
Hz), 7.57 (s, broad, 1H), 7.66 (d, 1H, J ) 8.1 Hz), 7.72 (dd, 1H,
(R)-37c as a snow-white powder. [R]
D
) -86.0 (c 0.61,
1
MeOH); H NMR (300 MHz, DMSO-d
6
) δ 2.40 (s, 3H), 3.02 (t,

3
1
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2229
H, J ) 11.7 Hz), 3.25 (m, 2H), 3.5 (m, 3H), 4.36 (m, 1H), 4.82
6.61 (d, broad, 1H, J ) 8 Hz), 7.58 (s, broad, 1H), 7.73 (d, 1H,
J ) 8.1 Hz), 7.78 (dd, 1H, J ) 8.1, 1.5 Hz), 7.97 (d, 1H, J )
(d, 1H, J ) 15.3 Hz), 5.43 (d, 1H, J ) 15.3 Hz), 6.55 (t, broad,
1
8
1
H, J ) 6 Hz), 6.71 (d, broad, 1H, J ) 8 Hz), 7.10 (d, 2H, J )
.7 Hz), 7.21 (d, 2H, J ) 8.4 Hz), 7.57 (s, broad, 1H), 7.65 (d,
H, J ) 8.1 Hz), 7.70 (dd, 1H, J ) 8.1, 1.5 Hz), 8.00 (d, 1H, J
1.5 Hz), 8.16 (s, broad, 1H); 13C NMR (75 MHz, DMSO-d
22.2, 22.4, 25.3, 36.2, 38.3, 41.3, 44.4, 46.4, 49.4, 123.7, 126.1,
6
) δ
130.9, 135.0, 136.2, 144.6, 156.2, 166.2, 170.3; HR-FABMS
1.5 Hz), 8.14 (s, broad, 1H); 13C NMR (75 MHz, DMSO-d
)
+
+
)
6
4 3
m/z calcd for MH (C18H26ClN O S ) 413.1414, obsd 413.1415.
δ 14.5, 38.5, 41.3, 44.4, 49.8, 50.3, 123.3, 125.4, 125.9, 128.3,
(R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
a m in o}-N(5)-[3-(4-m eth oxyp h en yl)p r op yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-37x). The product was isolated ac-
cording to the standard method (vide supra): 21 mg (56%) of
1
30.4, 133.1, 135.1, 136.1, 136.6, 144.3, 156.2, 166.2, 171.2;
+
+
HR-FABMS m/z calcd for MH (C21H24ClN O S ) 479.0978,
obsd 479.0974.
4 3 2
2
3
(
S)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
(R)-37x as a snow-white powder. [R]
D
) -112.4 (c 0.11,
1
a m in o}-N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((S)-37c). The product was isolated ac-
MeOH); H NMR (300 MHz, DMSO-d ) δ 1.66 (m, 2H), 2.50
6
(m, 2H), 2.97 (t, 1H, J ) 11.4 Hz), 3.24 (m, 2H), 3.5 (m, 4H),
3.68 (s, 3H), 4.28 (m, 2H), 6.54 (t, broad, 1H, J ) 6 Hz), 6.63
(d, broad, 1H, J ) 8 Hz), 6.77 (d, 2H, J ) 8.7 Hz), 6.97 (d, 2H,
J ) 8.4 Hz), 7.59 (s, broad, 1H), 7.75 (d, 1H, J ) 8.1 Hz), 7.79
(dd, 1H, J ) 8.1, 1.5 Hz), 7.93 (d, 1H, J ) 1.5 Hz), 8.14 (s,
cording to the standard method (vide supra): 19 mg (61%) of
S)-37c as a snow-white powder. [R]2
3
) +81.1 (c 0.32, MeOH);
(
D
all other analytical data identical to those of (R)-37c.
R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
(
a m in o}-N(5)-[(3,4-m et h ylen ed ioxyp h en yl)m et h yl]-1,5-
ben zoth ia zep in -4(5H)-on e ((R)-37e). The product was iso-
lated according to the standard method (vide supra): 25 mg
broad, 1H); 13C NMR (75 MHz, DMSO-d
41.3, 44.4, 47.7, 49.5, 54.9, 113.5, 123.8, 126.1, 128.9, 130.8,
6
) δ 29.7, 31.6, 38.2,
133.0, 135.0, 136.3, 144.6, 156.2, 157.2, 166.2, 170.4; HR-
2
3
+
+
(
0
70%) of (R)-37e as a snow-white powder. [R]
D
) -72.9 (c
) δ 3.03 (t, 1H, J
11.7 Hz), 3.25 (m, 2H), 3.5 (m, 3H), 4.33 (m, 1H), 4.76 (d,
FABMS m/z calcd for MH (C23
H
28ClN
4
O
4
S ) 491.1520, obsd
1
.53, MeOH); H NMR (300 MHz, DMSO-d
6
491.1508.
)
1
2
Gen er a l P r oced u r e for th e Syn th esis of th e 3-(Su lfo-
n yla m in o)-1,5-ben zoth ia zep in -4-on es (34). To 300 mg resin
portions of the general structure 19 (approximately 75 µmol)
in 15 mL polypropylene filter tubes was added 6 mL of a 20%
(v/v) solution of piperidine in DMF at room temperature, and
the mixtures were gently agitated for 20 min. After removal
of the supernatants, the resulting resin batches of general
H, J ) 15.0 Hz), 5.38 (d, 1H, J ) 15.6 Hz), 5.93 (dd, 2H, J )
.4, 1.2 Hz), 6.55 (t, broad, 1H, J ) 6 Hz), 6.71 (d, broad, 1H,
J ) 8 Hz), 6.70 (dd, 1H, J ) 7.8, 1.8 Hz), 6.74 (d, 1H, J ) 7.8
Hz), 6.83 (d, 1H, J ) 1.2 Hz), 7.57 (s, broad, 1H), 7.66 (d, 1H,
J ) 8.1 Hz), 7.70 (dd, 1H, J ) 8.1, 1.5 Hz), 7.99 (d, 1H, J )
1
3
1
1
4
.5 Hz), 8.13 (s, broad, 1H); 13C NMR (75 MHz, DMSO-d
) δ
6
8.5, 41.3, 44.4, 49.8, 50.4, 100.7, 107.7, 108.1, 121.0, 123.4,
25.9, 130.3, 130.4, 135.1, 136.1, 144.2, 146.1, 146.8, 156.3,
structure 20 were washed with DMF (6×), CH
2
Cl
2
(1×), DMF
(2×), and CH
2
Cl
2
(3×) and subsequently resuspended in a
+
+
66.3, 171.2; HR-FABMS m/z calcd for MH (C21
H
22ClN
4
O
5
S )
solution of 3,5-dimethylisoxazole-4-sulfonyl chloride (235 mg,
77.0999, obsd 477.1001.
1.2 mmol) and NMM (132 µL, 1.2 mmol) in 4 mL of anhydrous
CH Cl . In the case of the 1,5-benzothiazepinones derived from
2 2
(
R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
a m in o}-N (5)-[(t h ie n -3-yl)m e t h yl]-1,5-b e n zot h ia ze p in -
(5H)-on e ((R)-37m ). The product was isolated according to
the standard method (vide supra): 15 mg (57%) of (R)-37m
aldehyde 21c, a solution of 1-propanesulfonyl chloride (136 µL,
4
1.2 mmol) and NMM (132 µL, 1.2 mmol) in 4 mL of anhydrous
2 2
CH Cl was used. After a reaction time of 2 h at ambient
2
3
1
as a snow-white powder. [R]
D
) -108.0 (c 0.40, MeOH); H
) δ 3.01 (t, 1H, J ) 11.7 Hz), 3.25
m, 2H), 3.5 (m, 3H), 4.33 (m, 1H), 4.91 (d, 1H, J ) 15.3 Hz),
temperature, the supernatants were removed, and the result-
ing resin batches of general structure 34 were washed with
NMR (300 MHz, DMSO-d
(
5
6
CH
Cl
2
Cl
2
(3×), DMF (3×), CH
2
Cl
2
(1×), MeOH (2×), and CH
2
-
.34 (d, 1H, J ) 15.3 Hz), 6.55 (t, broad, 1H, J ) 5 Hz), 6.71
2
(4×) and finally dried in vacuo. The 3-(sulfonylamino)-1,5-
(
(
d, broad, 1H, J ) 8 Hz), 6.97 (dd, 1H, J ) 5.1, 1.2 Hz), 7.28
d, 1H, J ) 1.2 Hz), 7.39 (dd, 1H, J ) 5.1, 3.0 Hz), 7.56 (s,
benzothiazepinones 38 and 40 were isolated from 34 according
to the standard method described above.
broad, 1H), 7.67 (d, 1H, J ) 8.1 Hz), 7.71 (dd, 1H, J ) 8.1, 1.5
(R)-7-Ca r ba m oyl-3-[N-(p r op a n esu lfon yl)a m in o]-N(5)-
[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth ia zep in -4(5H)-
on e ((R)-40c). The product was isolated according to the
standard method (vide supra): 17 mg (59%) of (R)-40c as a
1
3
Hz), 7.99 (d, 1H, J ) 1.5 Hz), 8.13 (s, broad, 1H); C NMR (75
MHz, DMSO-d ) δ 38.3, 41.3, 44.4, 46.6, 49.8, 122.6, 123.4,
25.9, 126.0, 127.4, 130.4, 135.1, 136.1, 137.4, 144.4, 156.2,
6
1
1
4
+
+
23
1
66.3, 170.9; HR-FABMS m/z calcd for MH (C18
H
20ClN
4
O
3
S
2
)
snow-white powder. [R]
D
) -72.2 (c 0.49, MeOH); H NMR
39.0665, obsd 439.0668.
(300 MHz, DMSO-d ) δ 0.89 (t, 3H, J ) 7.5 Hz), 1.6 (m, 2H),
6
(
R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
2.40 (s, 3H), 2.85 (m, 2H), 3.10 (t, 1H, J ) 11.7 Hz), 3.57 (dd,
1H, J ) 11.1, 6.9 Hz), 3.98 (m, 1H), 4.87 (d, 1H, J ) 15.3 Hz),
5.32 (d, 1H, J ) 15.6 Hz), 7.11 (d, 2H, J ) 8.4 Hz), 7.20 (d,
2H, J ) 8.1 Hz), 7.59 (s, broad, 1H), 7.67 (d, 1H, J ) 8.4 Hz),
7.73 (dd, 1H, J ) 8.4, 1.8 Hz), 7.91 (d, 1H, J ) 9.0 Hz), 8.01
a m in o}-N(5)-[(N-a cetylin d ole-3-yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-37r ). The product was isolated ac-
cording to the standard method (vide supra): 22 mg (58%) of
2
3
(
R)-37r as a snow-white powder. [R]
D
) -54.2 (c 0.71,
) δ 2.55 (s, 3H), 3.04 (t,
H, J ) 11.7 Hz), 3.27 (m, 2H), 3.5 (m, 3H), 4.36 (m, 1H), 5.13
d, 1H, J ) 16.2 Hz), 5.35 (d, 1H, J ) 16.2 Hz), 6.54 (t, broad,
H, J ) 6 Hz), 6.78 (d, broad, 1H, J ) 8 Hz), 7.22 (td, 1H, J
1
13
MeOH); H NMR (300 MHz, DMSO-d
1
(
1
6
(d, 1H, J ) 1.8 Hz), 8.16 (s, broad, 1H); C NMR (75 MHz,
6
DMSO-d ) δ 12.6, 14.6, 16.8, 51.0, 53.1, 54.5, 123.3, 125.4,
126.0, 128.2, 130.0, 133.2, 135.4, 136.3, 136.7, 144.3, 166.1,
+
+
170.5; HR-FABMS m/z calcd for MH (C21
H
26
N
3
O
4
S
3
)
)
7.8, 1.2 Hz), 7.30 (td, 1H, J ) 7.5, 1.4 Hz), 7.55 (d, 1H, J )
480.1085, obsd 480.1081.
7
1
8
.2 Hz), 7.57 (s, broad, 1H), 7.65 (d, 1H, J ) 8.1 Hz), 7.70 (dd,
H, J ) 8.1, 1.5 Hz), 7.75 (s, 1H), 8.02 (d, 1H, J ) 1.5 Hz),
(S)-7-Ca r b a m oyl-3-[N-(p r op a n esu lfon yl)a m in o]-N(5)-
[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth ia zep in -4(5H)-
on e ((S)-40c). The product was isolated according to the
standard method (vide supra): 21 mg (65%) of (S)-40c as a
1
3
.14 (s, broad, 1H), 8.25 (d, 1H, J ) 8.1 Hz); C NMR (75 MHz,
DMSO-d
1
1
6
) δ 23.7, 38.0, 41.4, 43.2, 44.3, 50.2, 115.6, 117.2,
19.4, 123.0, 123.3, 124.7, 125.2, 125.9, 128.8, 130.2, 135.0,
35.1, 136.2, 144.6, 156.5, 166.4, 168.8, 171.2; HR-FABMS
snow-white powder. [R]23
) +62.2 (c 1.11, MeOH); all other
D
analytical data identical to those of (R)-40c.
+
+
m/z calcd for M (C24
R)-7-Ca r ba m oyl-3-{N-[(2-ch lor oeth yla m in o)ca r bon yl]-
am in o}-N(5)-isopen tyl-1,5-ben zoth iazepin -4(5H)-on e ((R)-
7v). The product was isolated according to the standard
method (vide supra): 26 mg (83%) of (R)-37v as a snow-white
H
24ClN
5
O
4
S ) 513.1238, obsd 513.1249.
(R)-7-Ca r b a m oyl-3-[N-(3,5-d im et h ylisoxa zole-4-su lfo-
n yl)a m in o]-N(5)-[(3,4-m et h ylen ed ioxyp h en yl)m et h yl]-
1,5-ben zoth ia zep in -4(5H)-on e ((R)-38e). The product was
isolated according to the standard method (vide supra): 26
(
3
2
3
mg (67%) of (R)-38e as a snow-white powder. [R]
D
) -38.9
2
3
1
1
powder. [R]
D
) -154.6 (c 0.93, MeOH); H NMR (300 MHz,
) δ 0.77 (d, 3H, J ) 6.6 Hz), 0.83 (d, 3H, J ) 6.6 Hz),
.20 (m, 1H), 1.36 (m, 1H), 1.54 (non, 1H, J ) 6.6 Hz), 2.93 (t,
H, J ) 11.7 Hz), 3.24 (m, 2H), 3.43 (dd, 1H, J ) 10.8, 6.6
(c 1.13, DMF); H NMR (300 MHz, DMSO-d ) δ 2.30 (s, 3H),
6
DMSO-d
1
1
6
2.41 (s, 3H), 3.14 (t, 1H, J ) 11.7 Hz), 3.55 (dd, 1H, J ) 11.4,
6.9 Hz), 3.76 (m, 1H), 4.57 (d, 1H, J ) 15.0 Hz), 5.08 (d, 1H,
J ) 15.3 Hz), 5.91 (d, 2H, J ) 1.2 Hz), 6.58 (dd, 1H, J ) 7.8,
1.7 Hz), 6.69 (m, 2H), 7.64 (s, broad, 1H), 7.67 (d, 1H, J ) 7.8
Hz), 3.5 (m, 3H), 4.3 (m, 2H), 6.55 (t, broad, 1H, J ) 6 Hz),

2
230 J . Org. Chem., Vol. 64, No. 7, 1999
Schwarz et al.
Hz), 7.75 (dd, 1H, J ) 7.8, 1.8 Hz), 8.01 (d, 1H, J ) 1.8 Hz),
(v/v) solution of piperidine in DMF at room temperature, and
the mixtures were gently agitated for 20 min. After removal
of the supernatants, the resulting resin batches of general
.19 (s, broad, 1H), 8.92 (d, 1H, J ) 9.6 Hz); 1 C NMR (75 MHz,
DMSO-d ) δ 10.5, 12.1, 38.4, 49.8, 52.7, 100.7, 107.7, 108.2,
15.6, 121.2, 122.9, 126.3, 129.7, 130.0, 135.8, 136.2, 143.4,
46.2, 146.8, 157.4, 165.8, 169.2, 172.0; HR-FABMS m/z calcd
3
8
6
1
1
structure 20 were washed with DMF (6×), CH
2
Cl
2
(2×), DMF
(2×), and THF (3×) and subsequently resuspended in a
+
+
22 4 7 2
H N O S ) 530.0930, obsd 530.0931.
for M (C23
R)-7-Ca r ba m oyl-3-[N-(3,5-d im et h ylisoxa zole-4-su lfo-
n yl)a m in o]-N(5)-[(th ien -3-yl)m eth yl]-1,5-ben zoth ia zep in -
(5H)-on e ((R)-38m ). The product was isolated according to
the standard method (vide supra): 19 mg (64%) of (R)-38m
solution of 3-(methylthio)propionaldehyde (40 µL, 0.4 mmol)
(
and benzotriazole (48 mg, 0.4 mmol) in 4 mL of CH(OMe)
0.3% HOAc. After a reaction time of 6 h at ambient temper-
ature, 4 mL of a 0.5 M solution of NaCNBH in THF was
3
/
4
3
added, and the reactions were allowed to continue for another
2 h at room temperature. The supernatants were removed, and
the resulting resin batches of general structure 35 were
2
3
1
as a snow-white powder. [R]
D
) -58.6 (c 0.50, MeOH); H
) δ 2.30 (s, 3H), 2.40 (s, 3H), 3.12
t, 1H, J ) 11.7 Hz), 3.54 (dd, 1H, J ) 11.1, 6.6 Hz), 3.9 (m,
NMR (300 MHz, DMSO-d
(
1
6
washed with MeOH (5×), CH
2
Cl
2
(1×), DMF (3×), and CH
2
-
H), 4.73 (d, 1H, J ) 15.3 Hz), 5.05 (d, 1H, J ) 15.0 Hz), 6.82
Cl
2
(4×) and finally dried in vacuo. The 3-(alkylamino)-1,5-
(
dd, 1H, J ) 5.1, 1.5 Hz), 7.16 (d, 1H, J ) 1.8 Hz), 7.35 (dd,
H, J ) 5.1, 3 Hz), 7.63 (s, broad, 1H), 7.68 (d, 1H, J ) 7.8
Hz), 7.76 (dd, 1H, J ) 8.1, 1.8 Hz), 8.00 (d, 1H, J ) 1.8 Hz),
.18 (s, broad, 1H), 8.92 (d, 1H, J ) 9.9 Hz); 13C NMR (75
benzothiazepinones 39 were isolated from 35 according to the
standard method described above.
1
(R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth ia zep in -
4(5H)-on e ((R)-39c). The product was isolated according to
the standard method (vide supra): 14 mg (51%) of (R)-39c as
8
MHz, DMSO-d
1
1
6
) δ 10.5, 12.1, 38.2, 46.0, 52.7, 115.6, 122.9,
23.0, 126.0, 126.3, 127.3, 129.9, 135.7, 136.3, 136.6, 143.6,
57.4, 165.8, 168.9, 172.0; HR-FABMS m/z calcd for MH
+
23
1
a snow-white powder. [R]
D
) -52.8 (c 0.61, MeOH); H NMR
+
(C
20
H
21
N
4
O
5
S
3
) 493.0674, obsd 493.0663.
(300 MHz, DMSO-d ) δ 1.82 (quin, 2H, J ) 7.2 Hz), 2.01 (s,
6
(
R)-7-Ca r ba m oyl-3-[N-(3,5-d im et h ylisoxa zole-4-su lfo-
3H), 2.40 (s, 3H), 2.5 (m, 2H), 2.9 (m, 2H), 3.24 (t, 1H, J )
11.7 Hz), 3.82 (dd, 1H, J ) 11.1, 6.9 Hz), 4.19 (m, 1H), 4.88
(d, 1H, J ) 15.6 Hz), 5.46 (d, 1H, J ) 15.3 Hz), 7.11 (d, 2H, J
) 8.7 Hz), 7.20 (d, 2H, J ) 8.7 Hz), 7.62 (s, broad, 1H), 7.69
n yl)a m in o]-N(5)-[(N-a cet ylin d ole-3-yl)m et h yl]-1,5-b en -
zoth ia zep in -4(5H)-on e ((R)-38r ). The product was isolated
according to the standard method (vide supra): 21 mg (50%)
2
3
of (R)-38r as a snow-white powder. [R]
D
) -11.6 (c 0.89,
(d, 1H, J ) 7.8 Hz), 7.77 (dd, 1H, J ) 8.1, 1.8 Hz), 8.08 (d, 1H,
1
13
DMF); H NMR (300 MHz, DMSO-d
6
) δ 2.32 (s, 3H), 2.43 (s,
J ) 1.8 Hz), 8.20 (s, broad, 1H), 9.2-9.6 (s, broad, 1H);
C
3
1
1
H), 2.50 (s, 3H), 3.11 (t, 1H, J ) 11.7 Hz), 3.52 (dd, 1H, J )
6
NMR (75 MHz, DMSO-d ) δ 14.3, 14.5, 25.0, 29.8, 35.0, 44.5,
50.9, 56.4, 124.2, 125.4, 126.5, 128.5, 129.5, 132.3, 135.3, 136.5,
137.1, 143.1, 166.0, 167.0; HR-FABMS m/z calcd for MH
1.1, 6.9 Hz), 3.8 (m, 1H), 4.82 (d, 1H, J ) 15.3 Hz), 5.27 (d,
H, J ) 15.6 Hz), 7.16 (td, 1H, J ) 7.5, 1.2 Hz), 7.26 (td, 1H,
+
+
J ) 7.4, 1.2 Hz), 7.41 (d, 1H, J ) 7.5 Hz), 7.62 (d, 1H, J ) 8.1
Hz), 7.64 (s, 1H), 7.65 (s, broad, 1H), 7.74 (dd, 1H, J ) 8.1, 1.8
Hz), 8.11 (d, 1H, J ) 1.8 Hz), 8.18 (d, 1H, J ) 8.1 Hz), 8.20 (s,
(C22
H
28
N
3
O
2
S
3
) 462.1344, obsd 462.1353.
(S)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[(4-m eth ylth iop h en yl)m eth yl]-1,5-ben zoth ia zep in -
4(5H)-on e ((S)-39c). The product was isolated according to
the standard method (vide supra): 11 mg (41%) of (S)-39c as
1
3
broad, 1H), 8.94 (d, 1H, J ) 9.9 Hz); C NMR (75 MHz,
DMSO-d ) δ 10.5, 12.1, 23.7, 38.1, 41.9, 53.0, 115.5, 115.7,
16.2, 122.9, 123.3, 124.7, 125.9, 126.4, 128.8, 130.1, 134.7,
35.8, 136.2, 143.4, 157.3, 165.9, 168.7, 169.1, 172.0; HR-
6
1
1
a snow-white powder. [R]23
) +48.3 (c 0.56, MeOH); all other
D
analytical data identical to those of (R)-39c.
+
+
FABMS m/z calcd for M (C26
67.1255.
R)-7-Ca r ba m oyl-3-[N-(3,5-d im et h ylisoxa zole-4-su lfo-
H
25
N
5
O
6
S
2
) 567.1246, obsd
(R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[(3,4-m eth ylen ed ioxyp h en yl)m eth yl]-1,5-ben zoth i-
a zep in -4(5H)-on e ((R)-39e). The product was isolated ac-
cording to the standard method (vide supra): 18 mg (51%) of
5
(
n yl)a m in o]-N (5)-isop e n t yl-1,5-b e n zot h ia ze p in -4(5H )-
on e ((R)-38v). The product was isolated according to the
standard method (vide supra): 28 mg (80%) of (R)-38v as a
2
3
(R)-39e as a snow-white powder. [R]
D
) -34.5 (c 0.53,
1
MeOH); H NMR (300 MHz, DMSO-d
6
) δ 1.82 (quin, 2H, J )
2
3
1
snow-white powder. [R]
300 MHz, DMSO-d ) δ 0.73 (d, 3H, J ) 6.3 Hz), 0.79 (d, 3H,
J ) 6.6 Hz), 1.07 (m, 1H), 1.27 (m, 1H), 1.45 (m, 1H), 2.28 (s,
H), 2.37 (s, 3H), 3.07 (t, 1H, J ) 11.7 Hz), 3.5 (m, 2H), 3.68
m, 1H), 3.83 (m, 1H), 7.63 (s, broad, 1H), 7.75 (d, 1H, J ) 8.1
Hz), 7.81 (dd, 1H, J ) 8.1, 1.8 Hz), 7.89 (d, 1H, J ) 1.5 Hz),
D
) -110.4 (c 1.01, DMF); H NMR
7.2 Hz), 2.01 (s, 3H), 2.5 (m, 2H), 2.9 (m, 2H), 3.25 (t, 1H, J )
11.4 Hz), 3.81 (dd, 1H, J ) 11.4, 6.6 Hz), 4.20 (dd, 1H, J )
12.0, 7.5 Hz), 4.82 (d, 1H, J ) 15.0 Hz), 5.43 (d, 1H, J ) 15.0
Hz), 5.95 (dd, 2H, J ) 2.4, 0.9 Hz), 6.70 (dd, 1H, J ) 7.8, 1.5
Hz), 6.76 (d, 1H, J ) 8.1 Hz), 6.82 (d, 1H, J ) 1.5 Hz), 7.63 (s,
broad, 1H), 7.70 (d, 1H, J ) 8.1 Hz), 7.78 (dd, 1H, J ) 8.1, 1.8
Hz), 8.08 (d, 1H, J ) 1.5 Hz), 8.20 (s, broad, 1H), 9.2-9.5 (s,
(
6
3
(
8
.21 (s, broad, 1H), 8.80 (d, 1H, J ) 9.9 Hz); 1 C NMR (75 MHz,
DMSO-d ) δ 10.5, 12.0, 22.1, 22.3, 25.2, 36.0, 38.1, 46.6, 52.6,
15.6, 122.9, 126.3, 130.1, 135.7, 136.4, 144.4, 157.3, 165.8,
68.4, 171.9; HR-FABMS m/z calcd for MH (C20
67.1423, obsd 467.1421.
3
broad, 1H); 13C NMR (75 MHz, DMSO-d
35.0, 44.6, 51.0, 56.4. 100.8, 107.8, 108.3, 121.4, 124.2, 126.5,
) δ 14.3, 25.0, 29.8,
6
6
1
1
4
+
+
H
27
N
4
O
5
S
2
)
129.5, 135.3, 136.5, 142.9, 146.3, 146.9, 166.0, 167.1; HR-
+
+
FABMS m/z calcd for MH (C22
H
26
N
3
O
4
S
2
) 460.1365, obsd
(
R)-7-Ca r ba m oyl-3-[N-(3,5-d im et h ylisoxa zole-4-su lfo-
460.1366.
n yl)a m in o]-N(5)-[3-(4-m et h oxyp h en yl)p r op yl]-1,5-b en -
zoth ia zep in -4(5H)-on e ((R)-38x). The product was isolated
according to the standard method (vide supra): 23 mg (56%)
(R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[(t h ien -3-yl)m et h yl]-1,5-b en zot h ia zep in -4(5H )-on e
((R)-39m ). The product was isolated according to the standard
method (vide supra): 11 mg (42%) of (R)-39m as a snow-white
2
3
of (R)-38x as a snow-white powder. [R]
D
) -75.9 (c 1.00,
) δ 1.56 (m, 2H), 2.28 (s,
H), 2.37 (s, 3H), 2.39 (m, 2H), 3.09 (t, 1H, J ) 11.7 Hz), 3.44
quin, 1H, J ) 6.9 Hz), 3.53 (dd, 1H, J ) 11.1, 6.9 Hz), 3.69 (s,
H), 3.69 (m, 1H), 3.86 (m, 1H), 6.76 (d, 2H, J ) 8.7 Hz), 6.94
d, 2H, J ) 8.4 Hz), 7.64 (s, broad, 1H), 7.77 (d, 1H, J ) 8.1
Hz), 7.84 (dd, 1H, J ) 8.1, 1.8 Hz), 7.90 (d, 1H, J ) 1.5 Hz),
1
23
1
DMF); H NMR (300 MHz, DMSO-d
6
powder. [R]
D
) -71.4 (c 0.51, MeOH); H NMR (300 MHz,
3
(
3
(
DMSO-d ) δ 1.82 (quin, 2H, J ) 7.2 Hz), 2.01 (s, 3H), 2.5 (m,
6
2H), 2.9 (m, 2H), 3.24 (t, 1H, J ) 11.7 Hz), 3.81 (dd, 1H, J )
11.1, 6.9 Hz), 4.19 (dd, 1H, J ) 11.4, 6.9 Hz), 4.97 (d, 1H, J )
15.3 Hz), 5.39 (d, 1H, J ) 15.3 Hz), 6.97 (dd, 1H, J ) 4.8, 0.9
Hz), 7.31 (d, 1H, J ) 1.8 Hz), 7.43 (dd, 1H, J ) 5.1, 2.7 Hz),
7.62 (s, broad, 1H), 7.71 (d, 1H, J ) 8.1 Hz), 7.79 (dd, 1H, J )
8.1, 1.8 Hz), 8.06 (d, 1H, J ) 1.5 Hz), 8.19 (s, broad, 1H), 9.2-
3
8
.20 (s, broad, 1H), 8.82 (d, 1H, J ) 9.9 Hz); 1 C NMR (75 MHz,
DMSO-d ) δ 10.5, 12.0, 29.3, 31.4, 38.1, 47.9, 52.6, 54.9, 113.5,
15.6, 123.2, 126.4, 128.8, 130.1, 132.9, 135.7, 136.5, 144.3,
57.2, 157.3, 165.8, 168.5, 171.9; HR-FABMS m/z calcd for
6
1
1
M
9.6 (s, broad, 1H); 13C NMR (75 MHz, DMSO-d
29.8, 34.9, 44.6, 47.0, 56.4, 123.2, 124.2, 126.2, 126.5, 127.4,
6
) δ 14.3, 25.0,
+
+
(C25
H
28
N
4
O
6
S
2
) 544.1450, obsd 544.1449.
129.5, 135.3, 136.5, 143.1, 166.0, 166.8; HR-FABMS m/z calcd
+
+
24 3 2 3
H N 0 S ) 422.1031, obsd 422.1039.
Gen er a l P r oced u r e for th e Syn th esis of th e 3-(Alk yl-
for MH (C19
a m in o)-1,5-ben zoth ia zep in -4-on es (35). To 300 mg resin
portions of the general structure 19 (approximately 75 µmol)
in 15 mL polypropylene filter tubes was added 6 mL of a 20%
(R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[(N-a cet ylin d ole-3-yl)m et h yl]-1,5-b en zot h ia zep in -
4(5H)-on e ((R)-39r ). The product was isolated according to

3
,5-Disubstituted 1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 64, No. 7, 1999 2231
the standard method (vide supra): 14 mg (37%) of (R)-39r as
(R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
N(5)-[3-(4-m et h oxyp h en yl)p r op yl]-1,5-b en zot h ia zep in -
4(5H)-on e ((R)-39x). The product was isolated according to
the standard method (vide supra): 17 mg (46%) of (R)-39x as
2
3
1
a snow-white powder. [R]
D
) -13.6 (c 0.45, MeOH); H NMR
) δ 1.83 (quin, 2H, J ) 7.2 Hz), 2.02 (s,
H), 2.5 (m, 2H), 2.52 (s, 3H), 2.95 (m, 2H), 3.22 (t, 1H, J )
1.4 Hz), 3.78 (dd, 1H, J ) 11.1, 6.9 Hz), 4.23 (m, 1H), 5.11
(300 MHz, DMSO-d
6
3
1
23
1
a off-white powder. [R]
300 MHz, DMSO-d ) δ 1.70 (quin, 2H, J ) 7.5 Hz), 1.79 (quin,
H, J ) 7.2 Hz), 2.00 (s, 3H), 2.5 (m, 4H), 2.9 (m, 2H), 3.22 (t,
D
) -75.2 (c 0.11, MeOH); H NMR
(
d, 1H, J ) 15.3 Hz), 5.53 (d, 1H, J ) 15.6 Hz), 7.20 (td, 1H,
J ) 7.2, 1.2 Hz), 7.31 (td, 1H, J ) 7.2, 1.2 Hz), 7.50 (d, 1H, J
7.2 Hz), 7.65 (s, broad, 1H), 7.68 (d, 1H, J ) 8.1 Hz), 7.73
s, 1H), 7.79 (dd, 1H, J ) 8.1, 1.8 Hz), 8.15 (d, 1H, J ) 1.5
Hz), 8.20 (s, broad, 1H), 8.24 (d, 1H, J ) 8.4 Hz), 9.2-9.6 (s,
(
6
2
1
1
)
(
H, J ) 11.7 Hz), 3.6 (m, 1H), 3.69 (s, 3H), 3.78 (dd, 1H, J )
1.1, 6.9 Hz), 4.12 (m, 1H), 4.33 (m, 1H), 6.87 (d, 2H, J ) 9.0
1
3
Hz), 6.98 (d, 2H, J ) 8.7 Hz), 7.64 (s, broad, 1H), 7.80 (d, 1H,
J ) 8.1 Hz), 7.86 (dd, 1H, J ) 8.4, 1.5 Hz), 7.99 (d, 1H, J )
broad, 1H); C NMR (75 MHz, DMSO-d
6
) δ 14.3, 23.8,
2
1
1
5.0, 29.8, 34.9, 43.1, 44.6, 56.5, 115.6, 116.3, 119.3, 123.0,
24.5, 124.8, 125.9, 126.6, 128.8, 129.6, 134.9, 135.3, 136.5,
1
3
1
.5 Hz), 8.19 (s, broad, 1H), 9.1-9.3 (s, broad, 1H); C NMR
+
43.0, 166.1, 166.9, 168.8; HR-FABMS m/z calcd for MH
(75 MHz, DMSO-d ) δ 14.3, 25.0, 29.4, 29.8, 31.5, 34.7, 44.6,
6
+
(C
25
H
29
N
4
O
3
S
2
) 497.1681, obsd 497.1672.
48.2, 54.9, 56.3, 113.6, 124.4, 126.6, 128.9, 129.8, 132.8, 135.3,
(
R)-7-Ca r ba m oyl-3-{N-[(3-(m eth ylth io)p r op yl]a m in o}-
136.6, 143.4, 157.2, 166.0, 166.5; HR-FABMS m/z calcd for
MH (C H N O S ) 474.1885, obsd 474.1888.
24 32 3 3 2
+
+
N(5)-isop en t yl-1,5-b en zot h ia zep in -4(5H )-on e ((R)-39v).
The product was isolated according to the standard method
(
[
vide supra): 15 mg (49%) of (R)-39v as a snow-white powder.
2
3
1
Ack n ow led gm en t. The authors would like to thank
Dr. W. L. Fitch and G. Detre for providing MS and NMR
data, respectively, Dr. C. P. Holmes for numerous
helpful suggestions, and S. Ferla for technical as-
sistance.
R]
D
6
) -91.6 (c 0.39, MeOH); H NMR (300 MHz, DMSO-d )
δ 0.79 (d, 3H, J ) 6.6 Hz), 0.86 (d, 3H, J ) 6.6 Hz), 1.25 (m,
1
H), 1.38 (m, 1H), 1.58 (non, 1H, J ) 6.6 Hz), 1.79 (quin, 2H,
J ) 7.2 Hz), 2.00 (s, 3H), 2.5 (m, 2H), 2.9 (m, 2H), 3.20 (t, 1H,
J ) 11.4 Hz), 3.6 (m, 1H), 3.76 (dd, 1H, J ) 11.4, 6.9 Hz), 4.11
(
m, 1H), 4.37 (m, 1H), 7.64 (s, broad, 1H), 7.79 (d, 1H, J ) 8.1
Hz), 7.85 (dd, 1H, J ) 8.1, 1.5 Hz), 8.02 (d, 1H, J ) 1.8 Hz),
.20 (s, broad, 1H), 9.1-9.3 (s, broad, 1H); 13C NMR (75 MHz,
DMSO-d ) δ 14.3, 22.1, 22.4, 25.0, 25.3, 29.8, 34.7, 36.0, 44.5,
7.0, 56.2, 124.2, 126.6, 129.8, 135.3, 136.6, 143.3, 166.0, 166.3;
HR-FABMS m/z calcd for MH (C19
obsd 396.1780.
8
Su p p or tin g In for m a tion Ava ila ble: Copies of the H and
1
13
6
C NMR spectra of new compounds. This material is available
4
free of charge via the Internet at http://pubs.acs.org.
+
+
30 3 2 2
H N O S ) 396.1779,
J O981567P