General and stereospecific route to 9-substituted, 8,9-disubstituted, and 9,10-disubstituted analogues of benzolactam-V8

Article abstract of DOI:10.1021/jo990605h

Nitration of the L-tyrosine derivative 9 provides the 3-nitro compound 13, which is converted into amide 15 by reduction and protection. Nitration of 15 either ortho or para to the acetamido group gives 16 and 17. After reduction of the nitro group, the anilines 21b and 29b are coupled with triflate 22a, and then cyclized to afford lactams 24 and 31, respectively. By means of a Pd-catalyzed coupling reaction, 8-acetamido-9-decynylbenzolactam- V8 (26) and 9-decynyl-10-acetamidobenzolactam-V8 (33) are obtained. The regioisomers 16 and 17 are transformed into a single isomer, 34, which is converted into 9-decynylbenzolactam-V8 (4). The K(i) values for 4, 26, and 33 to displace PDBU binding from recombinant PKCα (PKC = protein kinase C) are about 6, 173, and 46 nM. These results demonstrate that while the introduction of a substituent at either the 8- or 10-position of the 9- substituted benzolactam-V8s lowers their binding affinity, these newly generated analogues still retain reasonably good potency for PKC.

Full text of DOI:10.1021/jo990605h

6366
J . Org. Chem. 1999, 64, 6366-6373
Gen er a l a n d Ster eosp ecific Rou te to 9-Su bstitu ted ,
8,9-Disu bstitu ted , a n d 9,10-Disu bstitu ted An a logu es of
Ben zola cta m -V8
Dawei Ma,*,† Wenjun Tang,† Alan P. Kozikowski,*,‡ Nancy E. Lewin,§ and
Peter M. Blumberg§
State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China,
Drug Discovery Program, Institute for Cognitive & Computational Sciences,
Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, D.C. 20007-2197,
and National Cancer Institute, Bethesda, Maryland 20892
Received April 8, 1999
Nitration of the L-tyrosine derivative 9 provides the 3-nitro compound 13, which is converted into
amide 15 by reduction and protection. Nitration of 15 either ortho or para to the acetamido group
gives 16 and 17. After reduction of the nitro group, the anilines 21b and 29b are coupled with
triflate 22a , and then cyclized to afford lactams 24 and 31, respectively. By means of a Pd-catalyzed
coupling reaction, 8-acetamido-9-decynylbenzolactam-V8 (26) and 9-decynyl-10-acetamidobenzolac-
tam-V8 (33) are obtained. The regioisomers 16 and 17 are transformed into a single isomer, 34,
which is converted into 9-decynylbenzolactam-V8 (4). The Ki values for 4, 26, and 33 to displace
PDBU binding from recombinant PKCR (PKC ) protein kinase C) are about 6, 173, and 46 nM.
These results demonstrate that while the introduction of a substituent at either the 8- or 10-position
of the 9-substituted benzolactam-V8s lowers their binding affinity, these newly generated analogues
still retain reasonably good potency for PKC.
1
In tr od u ction
structure, and H NMR studies have revealed that ILV
exists as two major conformations in solution; these are
the twist conformer (with a cis-amide bond) and the sofa
conformer (with a trans-amide bond) in solution.8 In
seeking to identify the PKC active conformation of ILV,
as well as to investigate the possibility to create isoform-
selective modulators, Kozikowski and Ma first explored
the use of a benzolactam nucleus to replace the indo-
lactam core. They showed that an analogue that mim-
icked the sofa conformation of ILV was incapable of
activating PKC.9 Later, Endo reported that another type
of benzolactam, such as the 9-decylbenzolactam-V8 (5)
(Figure 1), could mimic the twist conformation, and that
this compound was a potent PKC activator.10 The side
chain at the 9-position of 5 was important for PKC
Protein kinase C (PKC) consists of a growing family
of closely related isozymes that mediate a wide range of
cellular signal transduction processes.1,2 Compounds that
are able to selectively modulate the individual PKC
isozymes can serve as valuable research tools in the
elucidation of their physiological roles. Additionally, such
compounds hold promise in the development of novel
therapeutics for the treatment of human diseases, such
as cancer and Alzheimer’s dementia.1-3 Among the
known PKC activators, the teleocidins are a family of
natural products possessing relatively simple structures,
but imbued with a remarkable affinity for PKC.4 The
teleocidins thus offer a chemically manipulable class of
molecules that serve as important lead structures in the
search for isoform-selective modulators of PKC.5,6 This
class of compounds has indolactam V (ILV)7 as the core
(5) For studies directed toward the synthesis of the teleocidin family,
see: (a) Endo, Y.; Shudo, K.; Furuhata, K.; Ogura, H.; Sakai, S.; Aimi,
N.; Hitotsuyanagi, Y.; Koyama, Y. Chem. Pharm. Bull. 1984, 32, 358.
(b) Naktsuka, S.; Masuda, T.; Goto, T. Tetrahedron Lett. 1987, 28, 3671.
(c) Okabe, K.; Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 5113.
(d) Kogan, T. P.; Somers, T. C.; Venuti, M. C. Tetrahedron 1990, 46,
6623. (e) Okabe, K.; Natsume, M. Tetrahedron 1991, 47, 7615. (f)
Semmelhack, M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1395. (g)
Quick, J .; Saha, B.; Driedger, P. E. Tetrahedron Lett. 1994, 35, 8549.
(6) For studies directed toward the modifications of the teleocidin
family, see: (a) Irie, K.; Koshimizu, K. Mem. Coll. Agric., Ktoto Univ.
1988, No. 132, 1. (b) Kozikowski, A. P.; Sato, K.; Basu, A.; Lazo, J . S.
J . Am. Chem. Soc. 1989, 111, 6228. (c) Webb II, R. R.; Venuti, M. C.;
Eigenbrot, C. J . Org. Chem. 1991, 56, 4706. (d) Irie, K.; Isaka, T.; Iwata,
Y.; Yanai, Y.; Nakamura, Y.; Koizumi, F.; Ohigashi, H.; Wender, P.
A.; Satomi, Y.; Nishino, H. J . Am. Chem. Soc. 1996, 118, 10733.
(7) Irie, I.; Okuno, S.; Kajiyama, S.; Koshimizu, K.; Nishino, H.;
Iwashima, A. Carcinogenesis 1991, 12, 1883 and references therein.
(8) (a) Endo, Y.; Shudo, K.; Itai, A.; Hasegawa, M.; Sakai, S.;
Tetrahedron 1986, 42, 5905. (b) Kawai, T.; Ichinose, T.; Takeda, M.;
Tomioka, N.; Endo, Y.; Yamaguchi, K.; Shudo, K.; Itai, A. J . Org. Chem.
1992, 57, 6150.
† Chinese Academy of Sciences.
‡ Georgetown University Medical Center.
§ National Cancer Institute.
(1) (a) Nishizuka, Y. Science 1992, 258, 607. (b) Nishizuka, Y. Nature
1988, 334, 661.
(2) (a) Dekker: L. V.; Parker, P. J . Trends Biochem. Sci. 1994, 19,
73. (b) Protein Kinase C, Current Concepts and Future Perspectives;
Lester, D. S.; Epand, R. M., Eds.; Ellis Horwood Ltd.: New York, 1992.
(c) Hoffman, J . FASEB J . 1997, 11, 649.
(3) (a) Stabel, S.; Parker, P. J . Pharmacol. Ther. 1991, 51, 71. (b)
Gescher, A. Br. J . Cancer 1992, 66, 10. (c) Basu, A. Pharmacol. Ther.
1993, 59, 257. (d) Wilkinson, S. E.; Hallan, T. J . Trends Pharmacol.
Sci. 1994, 15, 53. (e) O′Brian, C. A. Oncol. Rep. 1998, 5, 305. (f)
Caponigro, F.; French, R. C.; Kaye, S. B. Anti-Cancer Drugs 1997, 8,
26. (g) Nambi, P.; Amegadzie, B.; Mattern, M. Pharmacol. Rev.
Commun. 1996, 8, 29.
(4) For reviews, see: (a) Rando, R.; Kishi, Y. Biochemistry 1992,
31, 2211. (b) Wender, P. A.; Cribbs, C. M. Computer assisted molecular
design related to the protein kinase C receptor. In Advances in
Medicinal Chemistry; J AI Press: Greenwich, CT, 1992; Vol. 1, pp 1-53.
(c) Kishi, Y.; Rando, R. Acc. Chem. Res. 1998, 31, 163. (d) Waldmann,
H.; Alonsi-Diaz, D.; Hinterding, K. Angew. Chem., Int. Ed. Engl. 1998,
37, 688.
(9) Kozikowski, A. P.; Ma, D.; Pang, Y.-P.; Shum, P.; Likic, V.;
Mishra, P. K.; Macura, S.; Basu, A.; Lazo, J . S.; Ball, R. G. J . Am.
Chem. Soc. 1993, 115, 3957.
10.1021/jo990605h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

Analogues of Benzolactam-V8
J . Org. Chem., Vol. 64, No. 17, 1999 6367
Sch em e 1
F igu r e 1. Structures of the teleocidin family and benzolac-
tam-V8 analogues.
activity, since benzolactam-V8 (1), without this side
chain, demonstrated considerably reduced ability to
activate PKC.10 As it has been reported that different side
chain appendages can alter isoform selectivity in the
phorbol family,11 we realized that 1 can be a new core
structure for pursuing the design of isoform-selective
PKC modulators through side chain variations. In con-
nection with such efforts,9,12-16 we reported that 8-decyn-
ylbenzolactam-V8 (2) exhibited improved isozyme selec-
tivity in comparison with its saturated side-chain coun-
terpart, 8-decylbenzolactam-V8 (3).13 Compound 2 also
showed isoform selectivity in down-regulating PKCâ and
in vivo antitumor activity that indolactam V did not
have.17 These findings promoted us to develop a general
route for the synthesis of 9-substituted, 8,9-disubstituted,
and 9,10-disubstituted analogues of benzolactam-V8,
with the notion to investigate the effects of the aryl ring
substitution pattern on PKC isoform selectivity.
Sch em e 2
Resu lts a n d Discu ssion s
Our strategy for synthesizing the desired analogues A
is shown in Scheme 1. We envisaged that L-tyrosine was
a good starting material, because the 4′-hydroxy group
of L-tyrosine could be used to introduce various substit-
uents via the corresponding triflate by palladium-
catalyzed coupling reactions,18 while its amino acid
moiety could be transformed into the amino alcohol part
of the cyclization precursor. The key problem was how
to introduce a nitro group at the 2′-position of L-tyrosine,
which would in turn allow us to build up the “valine-
like” appendage according to a known protocol. As it is
obvious that direct nitration of L-tyrosine will take place
in an undesirable manner, we concluded that the elec-
tronic distribution of the benzene ring of L-tyrosine must
be altered to fit our chemical needs. As the nitration19 of
6 is known to produce a mixture of 7 and 8 (eq 1), we
(1)
(10) (a) Ohno, M.; Endo, Y.; Hirano, M.; Itai, A.; Shudo, K.
Tetrahedron Lett. 1993, 34, 8119. (b) Endo, Y.; Ohno, M.; Hirano, M.;
Itai, A.; Shudo, K. J . Am. Chem. Soc. 1996, 118, 1841.
(11) Kazanietz, M. G.; Areces, L. B.; Bahador, A.; Mischak, H.;
Goodnight, J .; Mushinski, F.; Blumberg, P. M. Mol. Pharmacol. 1993,
44, 298.
(12) Kozikowski, A. P.; Ma, D.; Du, L.; Lewin, N. E.; Blumberg, P.
M. J . Am. Chem. Soc. 1995, 117, 6666.
(13) Kozikowski, A. P.; Wang, S.; Ma, D.; Yao, J .; Ahmad, S.; Glazer,
R. I.; Bogi, K.; Acs, P.; Modarres, S.; Lewin, N. E.; Blumberg, P. M. J .
Med. Chem. 1997, 40, 1316.
(14) Ma, D.; Zhang, Y.; Yao, J .; Wu, S.; Tao, F. J . Am. Chem. Soc.
1998, 120, 12459.
reasoned that our desired products B and C could be
obtained through the nitration of D. The acetamido group
present in the intermediates B and C could at a later
stage be converted to other substituents through diazo-
tization methods.
As outlined in Scheme 2, we prepared 9 in quantitative
yield by esterification of L-tyrosine with thionyl chloride
in methanol followed by protection of the amino group
with methyl chloroformate in an aqueous NaHCO3 solu-
tion. Reduction of 9 with NaBH4/LiI20 followed by protec-
(15) Part of the results have been reported as a communication: Ma,
D.; Tang, W. Tetrahedron Lett. 1998, 39, 7369.
(16) Qiao, L.; Wang, S.; George, C.; Lewin, N. E.; Blumberg, P. M.;
Kozikowski, A. P. J . Am. Chem. Soc. 1998, 120, 6629.
(17) Kozikowski, A. P.; Ma, D.; Glazer, R. I. Unpublished results.
(18) (a) Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27, 1171.
(b) Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108, 3033. (c)
Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
(d) Ritter, K. Synthesis 1993, 735. (e) Powell, N. A.; Rychnovsky, S. D.
Tetrahedron Lett. 1996, 37, 7901.
(19) Sannie, C.; Lapin, H. Bull. Soc. Chim. Fr., 1952, 369.
(20) Sudharshan, M.; Hultin, P. G. Synlett 1997, 171.

6368 J . Org. Chem., Vol. 64, No. 17, 1999
Ma et al.
Sch em e 3
Sch em e 4
tion of the two hydroxy groups to their acetates afforded
10 in 72% yield. Unfortunately, nitration of 10 under
standard conditions (HNO3/Ac2O) provided the desired
product 12 in low yield, together with some unidentified
products. After a multitude of failures to improve the
reaction yield of this step using other nitration conditions
such as HNO3/Cu(OAc)2/Ac2O21 and NaNO3/TMSCl/
AlCl3,22 we considered to remove the 4′-acetyl group of
10 to enhance the activity of the substrate, thus allowing
the use of other mild nitration conditions. Accordingly,
treatment of 10 with diethylamine produced 11, which
was subjected to nitration using La(NO3)3 as a phase-
transfer catalyst and NaNO3/HCl as the nitration re-
agent.23 However, no nitration occurred under this
condition. After prolonged experimentation, we eventu-
ally found that this method was quite workable if
compound 9 was used as the substrate. In this way the
desired product 13 could be isolated in 85% yield (Scheme
3). The reason for the unexpected difference in reactivity
between 9 and 11 was not clear.
found to give very complex products. However, on lower-
ing the reaction temperature to -13 °C two major
separable products in a 1/1 ratio were produced in a total
1
yield of 76%. As the signals in the H NMR spectra of
both 16 and 17 are all very broad, we were unable to
make a determination of the location of the nitro group
in these compounds. Fortunately, their reduction prod-
ucts 18a and 19 gave clear 1H NMR spectra, thus
permitting us to make regiochemical assignments. The
1
structure of 19 was confirmed by its H NMR spectrum
in which clear doublets at 6.64 and 7.17 were observed,
while the structure of 18a was confirmed by its NOESY
spectrum in which only one aromatic proton (Hb) has a
NOE with Ha. This result ruled out the formation of 18b
and indicated that the regioselectivity of this nitration
step was in agreement with our initial proposal.
After confirming the structures of both products, we
could transform them to the corresponding disubstituted
analogues of benzolactam-V8. First, it was necessary to
change the protecting groups in compound 17 (Scheme
4). To avoid any possible problems in subsequent chemi-
cal manipulations stemming from the 4′-hydroxy group
of 17, its protecting group was switched to the more
stable benzyl group to afford 20. Also, in consideration
Hydrogenation of the nitro group of 13 catalyzed by
Pd/C and then protection by N-acetylation afforded 14
in 80% yield. Reduction of the amino ester group of 14
to the corresponding amino alcohol using LiBH4 followed
by treatment with Ac2O produced the precursor for
second nitration 15 in 78% overall yield. Initial attempts
to nitrate 15 using concentrated HNO3/Ac2O at 0 °C was
(21) Suzuki, H. Synthesis 1977, 217.
(22) Olah, G. A.; Ramaiah, P.; Sandford, G.; Orlinkov, A.; Prakash,
G. K. S. Synthesis 1994, 468.
(23) Ouertani, M.; Girard, P.; Kagan, H. B. Tetrahedron Lett. 1982,
23, 4315.

Analogues of Benzolactam-V8
Sch em e 5
J . Org. Chem., Vol. 64, No. 17, 1999 6369
Sch em e 6
Similarly, 8-acetamido-9-decynylbenzolactam-V8 (33)
was synthesized from nitrate 16 employing the reaction
sequence outlined in Scheme 5. Some noteworthy points
regarding this scheme are as follows. The N-acetyl
protecting group of 28 was cleanly removed by hydrolysis
with 10% potassium hydroxide. Reduction25 of the nitro
group of 29b with SnCl2 was found to give higher yields
than use of the NaBH4/CuSO4 method. After hydrolysis
of 30 with aqueous NaOH and removal of the Boc group
with TFA, the newly generated amino acid salt was
directly treated with diphenylphosphoryl azide (DPPA)
to give the lactam 31 in 63% overall yield. In this case,
use of the previous procedure for N-methylation worked
well and gave 32 in 96% yield. The divergent chemical
behavior of 31 and 24 might result from the differences
in the steric accessibility of their nitrogen atoms.
To investigate whether the acetamido group of 16 or
17 could be converted into other substituents by diazo-
tization chemistry, we undertook the studies shown in
Scheme 6. After nitration of 15, the mixture of 16 and
17 was directly treated with 3 N H2SO4 at 70 °C to
remove the acetyl groups. The resultant aniline salt was
subjected to diazotization and then reduction with H3PO2
at 70 °C to afford a single nitro compound, 34, in 61%
overall yield. By combining the results indicated in
Schemes 2 and 3, we may conclude that the 2′-nitro-
tyrosine derivative 34 can be obtained from l-tyrosine in
25% overall yield by “six working-up steps” with the key
strategy involving introduction of an orientation-directing
functional group. This methodology may be useful for
preparing various 2′-substituted tyrosine derivatives,
compounds which are well-known to be pharmacologi-
cally important amino acids as well as building blocks
for the synthesis of modified peptides.26
With the intermediate 34 in hand, we could synthesize
9-decynylbenzolactam-V8 (4) on the basis of the proce-
dure as discussed above (Scheme 7). Protection of phenol
34 with benzyl bromide afforded 37. Reduction of 37 with
Cu(OAc)2/NaBH4 followed by coupling with triflate 22b
provided 38. The ester 38 was hydrolyzed in 2 N KOH
at 70 °C with simultaneous removal of both the amine
protecting groups and the carboxylic acid protecting
group, and then neutralized with HCl, concentrated, and
dried over P2O5. Without any separation, this mixture
was directly treated with DPPA and Et3N in DMF
of the difficulty in cleaving the N-methyl carbamate
protecting group of 20, we planned to switch it to an
N-Boc protecting group. This transformation was con-
firmed necessary because extensive decomposition was
observed when 27 was hydrolyzed to remove the N-
methyl carbamate protecting group. Hence, treatment of
20 with 10% potassium hydroxide followed by reprotec-
tion with di-tert-butyl dicarbamate provided a mixture
of the 3′-amino product 21a and 3′-acetamido product
21b. The former product could be converted into the
latter one by reaction with acetyl anhydride. Next, the
nitro group of 21b was reduced with NaBH4/Cu(OAc)2
to an amino group,24 which was reacted with the D-valine-
derived triflate 22a 5d to deliver ester 23. After compound
23 was transformed into the lactam 24 using a standard
activated ester protocol, N-methylation was carried out.
It was found that the previous procedure13 for this
conversion (HCHO/NaCNBH3/HOAc) did not work well.
Some byproducts formed before the starting material
disappeared. However, if NaBH4/HCHO/3N H2SO4 were
employed for methylation, and the reaction were carried
out at 50 °C for 15 min, the desired product 25 could be
obtained in 89% yield. Finally, the side chain at the
9-position was introduced by the following steps: (i)
protection of the hydroxy group with TBSCl and imid-
azole in DMF; (ii) removal of the benzyl group by
hydrogenation followed by transformation of the result-
ant phenol into its triflate; (iii) coupling the triflate with
1-decyne under the catalysis of PdCl2(PPh3)2, CuI, and
Bu4NI;18 (iv) removal of the silyl group by TsOH/MeOH.
The overall yield from 25 to 9-decynyl-10-acetamidoben-
zolactam-V8 (26) was about 80%.
(25) Cowan, J . A. Tetrahedron Lett. 1986, 27, 1205.
(26) (a) Davis, A. L.; Zaun, J . W.; Reeves, P. C.; Hance, R. L.;
McCord, T. J . J . Med. Chem, 1966, 9, 828. (b) Hara, H.; Inoue, T.;
Endoh, M.; Nakamura, H.; Takahashi, H.; Hoshino, O. Heterocycles
1996, 42, 445. (c) Dugave, C. J . Org. Chem. 1995, 60, 601. (d)
Hinterding, K.; Hagenbuch, P.; Retey, J .; Waldmann, H. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 1236. (e) Schmidt, U. Leitenberger, V.;
Griesser, H.; Schmidt, J .; Meyer, R. Synthesis 1992, 1248.
(24) Bellamy, F.; Ou, K. Tetrahedron Lett. 1984, 25, 839.

6370 J . Org. Chem., Vol. 64, No. 17, 1999
Ma et al.
Sch em e 7
F igu r e 2. Structures of 5-substituted analogues of indolac-
tam-V.
studies on these benzolactams together with their activity
toward other PKC isozymes will be reported in due
course.
Exp er im en ta l Section
(S)-3-(4-Hyd r oxyp h en yl)-2-[(m eth oxyca r bon yl)a m in o]-
1-p r op a n oic Acid , Meth yl Ester (9). To a suspension
solution of L-tyrosine (30 g, 0.17 mol) in 200 mL of methanol
was added thionyl chloride (36.5 mL, 0.5 mol) in a dropwise
manner at -30 °C. After the addition the solution was allowed
to warm to room temperature. The reaction mixture was
heated at reflux overnight and then concentrated via rotary
evaporator to afford the crude ester, which was dissolved in
200 mL of water. The resultant solution was neutralized with
NaOH (6.64 g, 0.17 mol) before NaHCO3 (21 g, 0.25 mol) was
added. After the solution was cooled with ice-water, a solution
of methyl chloroformate (15.4 mL, 0.2 mol) in 100 mL of CHCl3
was added. The reaction mixture was stirred for 2 h and then
extracted with CHCl3 (3 × 150 mL). The combined organic
layers were washed with water and dried over Na2SO4. After
Sch em e 8
removal of solvent in vacuo, 41.5 g (100%) of 9 was obtained
1
as a pale yellow oil: [R]18 +9.3 (c 0.6, CHCl3); H NMR (300
D
MHz, CDCl3) δ 6.98 (d, J ) 8.1 Hz, 2H), 6.74 (d, J ) 8.1 Hz,
2H), 5.22 (br s, 1H), 4.66 (m, 1H), 3.73 (s, 3H), 3.67 (s, 3H),
3.05 (d, J ) 6.4 Hz, 2H); MS (EI) m/z 254 (M+ + H+). Anal.
Calcd for C12H15NO5: C, 56.91; H, 5.97; N, 5.51. Found: C,
56.72; H, 5.96; N, 5.11.
(S)-3-(4-H yd r oxy-3-n it r op h en yl)-2-[(m et h oxyca r b on -
yl)a m in o]-1-p r op a n oic Acid , Meth yl Ester (13). NaNO3
(13.8 g, 163 mmol) and La(NO3)3‚6H2O (0.7 g, 1.6 mmol) were
dissolved in 260 mL of 6 N HCl. To this solution was added a
solution of 9 (41 g, 163 mmol) in 500 mL of methylene chloride
at 0 °C over 2 h. After the addition the solution was warmed
to room temperature, and the stirring was continued for 4 h.
The organic layer was separated, and the aqueous layer was
extracted with methylene chloride. The combined organic
layers were washed with water and brine, dried over Na2SO4,
and concentrated. The residual oil was chromatographed,
followed by N-methylation to afford benzolactam 39 in
82% overall yield. Finally, the decynyl group was intro-
duced in four steps as described in the synthesis of 26
from 25. Thus, we have found a convenient and ste-
reospecific route to 9-substituted benzolactam-V8 4 by
using L-tyrosine as the chiral building block. The overall
yield of 4 from L-tyrosine was 8.8%.
The acetamido group of 16 and 17 can also be con-
verted into an iodo substituent, which provides flexibility
for further modification (Scheme 8) Thus, upon heating
a mixture of 16 with 2 N H2SO4 in methanol at 70 °C to
remove all the acetyl protecting group, the resulting
aniline salt was oxidized with NaNO2/H2SO4 to afford the
diazonium ion. This ion was treated with potassium
iodide to provide 35 in 45% yield. In a similar manner,
36 was obtained from 17 in 42% yield.
eluting with 1/4 ethyl acetate/petroleum ether to afford 41 g
1
(85%) of 13: [R]18 +83.6 (c 3.5, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 10.5 (d, J ) 3.0 Hz, 1H), 7.86 (s, 1H), 7.36 (dd, J )
8.7, 1.6 Hz, 1H), 7.08 (dd, J ) 8.7, 3.0 Hz, 1H), 5.33 (br s, 1H),
4.62 (m, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 3.12 (dd, J ) 13.6, 5.1
Hz, 1H), 2.98 (dd, J ) 13.6, 9.1 Hz, 1H); MS (EI) m/z 299 (M+
+ H+); HRMS found m/z 298.0808 (M+), C12H14N2O7 requires
298.0801.
Compounds 4, 26, and 33 were evaluated for their
ability to displace phorbol 12,13-dibutyrate (PDBU) bind-
ing from recombinant PKCR. The Ki values for these
analogues were about 6, 173, and 46 nM. These results
demonstrate that while the introduction of a substituent
at either the 8- or 10-position of the 9-substituted
benzolactam-V8s lowers their binding affinity, these
newly generated analogues still retain reasonably good
potency for PKC. It is known that certain 5-substituted
indolactam-Vs 40 (Figure 2) fail to activate PKC, results
that have been explained by the preference of these
molecules to adopt a sofa-restricted conformation.6a,d
Thus, the potent activity found for 26 suggests that the
10-substituent of benzolactam-V8 does not play a similar
role in altering the conformation. Further modeling-based
(S)-3-(4-Acetoxy-3-a ceta m id op h en yl)-2-[(m eth oxyca r -
bon yl)a m in o]-1-p r op a n oic Acid , Meth yl Ester (14). A
suspension solution of 13 (40 g, 143 mmol) and Pd/C (10%, 1
g) in 400 mL of ethyl acetate was stirred under hydrogen
atmosphere (30 atm) until no more hydrogen was taken in.
The catalyst was filtered off, and the filtrate was concentrated
to afford the crude aniline, which was dissolved in 400 mL of
methylene chloride. After triethylamine (70 mL, 0.5 mol) was
added, the solution was cooled to -10 °C, and acetyl chloride
(20 mL, 280 mmol) was added dropwise. The resultant mixture
was stirred for 2 h before it was quenched by adding 200 mL
of water. The organic layer was separated, and the aqueous
layer was extracted. The combined organic layers were washed
with water and brine, dried over Na2SO4, and concentrated
via rotary evaporator. Column chromatography (2/1 ethyl

Analogues of Benzolactam-V8
J . Org. Chem., Vol. 64, No. 17, 1999 6371
acetate/petroleum ether as eluent) of the residual oil afforded
2 h, the solution was neutralized with HCl to pH 7. Ethyl
acetate extraction and workup followed by concentration
provided an oil, which was dissolved in 30 mL of dry DMF. To
this solution were added anhydrous K2CO3 (1.93 g, 14 mmol)
and freshly distilled benzyl bromide (1.44 g, 8.4 mmol),
respectively. After the reaction mixture was heated at 50 °C
for 3 h, DMF was removed at reduced pressure. The residue
was partitioned between 100 mL of ethyl acetate and 20 mL
of water. The organic layer was washed with brine, dried over
Na2SO4, and concentrated. Column chromatography (2/1 ethyl
1
36 g (80%) of 14: [R]19 +69.1 (c 0.3, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.91 (s, 1H), 7.56 (s, 1H), 7.00 (d, J ) 8.1 Hz,
1H), 6.85 (d, J ) 8.0 Hz, 1H), 5.47 (br s, 1H), 4.57 (m, 1H),
3.71 (s, 3H), 3.60 (s, 3H), 3.02 (m, 2H), 2.26 (s, 3H), 2.12 (s,
3H); MS (EI) m/z 353 (M+ + H+); HRMS found m/z 352.1271
(M+), C16H20N2O7 requires 352.1271.
(S)-O-Acetyl-3-(4-acetoxy-3-acetam idoph en yl)-2-[(m eth -
oxyca r bon yl)a m in o]-1-p r op a n ol (15). To a stirring solution
of 14 (15.1 g, 42.6 mmol) in 350 mL of anhydrous THF was
added LiBH4 (2.8 g, 128 mmol) at 0 °C. The solution was
warmed to room temperature, and the stirring was continued
for 5 h. The reaction was quenched by adding HOAc with
cooling by ice-water, and then the mixture was concentrated.
The residue was partitioned between 300 mL of ethyl acetate
and 50 mL of water. The organic layer was separated, washed
with brine, and concentrated to dryness to afford the crude
reduction product, which was dissolved in 200 mL of dry
pyridine. After the solution was cooled to 0 °C, acetic anhydride
(16.3 g, 160 mmol) was added dropwise. The reaction mixture
was stirred for 8 h at room temperature and then concentrated
via rotary evaporator. The residual oil was partitioned between
400 mL of ethyl acetate and 100 mL of water. The organic
layer was separated, washed with brine, dried over Na2SO4,
and concentrated. The residue was chromatographed, eluting
with 2/1 ethyl acetate/petroleum ether to afford 12.2 g (78%)
acetate/petroleum ether as eluent) of the residual oil afforded
1
2.4 g (79%) of 20: [R]19 -28.4 (c 0.9, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.35 (m, 5H), 7.18 (d, J ) 8.7 Hz, 1H), 7.08 (d,
J ) 8.7 Hz, 1H), 5.31 (br s, 1H), 5.13 (s, 2H), 3.89 (m, 1H),
3.68 (m, 2H), 3.64 (s, 3H), 2.80 (m, 2H), 2.12 (s, 3H); MS (EI)
m/z 418 (M+ + H+); HRMS found m/z 417.1542 (M+),
C
20H23N3O7 requires 417.1547.
(S)-3-(4-Ben zoxy-3-a m in o-2-n it r op h en yl)-2-[(ter t-b u -
t oxyca r bon yl)a m in o]-1-p r op a n ol (21a ). A mixture of 20
(2.0 g, 4.8 mmol) in 30 mL of methanol and 30 mL of 10%
KOH was stirred at 50 °C until the starting material disap-
peared as monitored by TLC. After the solution was neutral-
ized with HCl to pH 7, di-tert-butyl dicarbonate (1.3 g, 5.8
mmol) and NaHCO3 (1.0 g, 11.9 mmol) were added. The
resultant mixture was stirred for 32 h before it was extracted
with ethyl acetate. The extracts were washed with brine, dried
over Na2SO4, and concentrated. The residue was chromato-
graphed (2/1 ethyl acetate/petroleum ether as eluent) to afford
0.92 g (46%) of 21a , together with 0.88 g (44%) of 21b. Data
for 21a : [R]18D -38.4 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.40 (m, 5H), 6.86 (d, J ) 8.1 Hz, 1H), 6.57 (d, J ) 8.1 Hz,
1H), 5.13 (s, 2H), 3.90 (m, 1H), 3.11 (dd, J ) 13.8, 4.4 Hz, 1H),
2.89 (dd, J ) 13.8, 9.8 Hz, 1H), 1.37 (s, 9H); MS (EI) m/z 367
(M+ + H+). Anal. Calcd for C21H27N3O6: C, 60.42; H, 6.52; N,
10.07. Found: C, 60.36; H, 6.50; N, 9.94.
of 15: [R]18 -10.5 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3)
D
δ 8.02 (s, 1H), 7.17 (s, 1H), 7.09 (d, J ) 7.8 Hz, 1H), 6.97 (d, J
) 7.8 Hz, 1H), 4.89 (d, J ) 7.5 Hz, 1H), 4.13 (m, 1H), 4.06 (m,
2H), 3.65 (s, 3H), 2.85 (m, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 2.10
(s, 3H); MS (EI) m/z 367 (M+). Anal. Calcd for C17H22N2O7: C,
55.73; H, 6.05; N, 7.65. Found: C, 55.50; H, 5.94; N, 7.19.
Nitr a tion of 15. To a suspension of 15 (16.5 g, 45.1 mmol)
in 160 mL of acetic anhydride was added HNO3 (65%, 9.4 mL,
142 mmol) in a dropwise manner at -13 °C. After the addition
the reaction mixture was stirred at the same temperature until
the starting material disappeared as monitored by TLC. The
solution was partitioned between 300 mL of ethyl acetate and
300 mL of water. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (3 × 100 mL).
The combined organic layers were washed with water and
brine and then dried over Na2SO4. After removal of solvent
the residual oil was chromatographed (2/1 ethyl acetate/
petroleum ether as eluent) to afford 6.5 g (36%) of 16 and 7.5
g (40%) of 17. Data for 16: [R]21D -61.1 (c 0.9, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 8.41 (s, 1H), 7.92 (s, 1H), 7.61 (br s, 1H),
5.20 (br s, 1H), 4.23 (m, 1H), 4.15 (m, 2H), 3.54 (s, 3H), 3.18
(m, 2H), 2.38 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H); MS (EI) m/z
412 (M+ + H+); HRMS found m/z 411.1278 (M+), C17H21N3O9
(2S)-N-[2-Acet a m id o-3-b en zoxy-6-[(S)-2-(ter t-b u t oxy-
ca r bon yl)a m in o-3-h yd r oxyp r op yl]p h en yl]va lin e Meth yl
Ester (23). To a solution of 21b (780 mg, 1.7 mmol) in 30 mL
of methanol was added 10 mL of Cu(OAc)2-saturated methanol.
The resultant solution was cooled with ice-water while NaBH4
(1.0 g, 26 mmol) was added in four partitions. The stirring
was continued for 30 min, and then the reaction mixture was
passed over a short column of silica gel. The filtrate was
concentrated before it was partitioned between 100 mL of ethyl
acetate and 20 mL of water. The organic layer was washed
with brine, dried over Na2SO4, and concentrated to provide
the crude aniline, which was dissolved in 20 mL of 1,2-
dichloroethane. To the resulting solution were added 2,6-
lutidine (310 µL, 2.7 mmol) and 22a (520 mg, 2.0 mmol). The
mixture was heated at 70 °C for 72 h before the solvent was
evaporated. The residual oil was chromatographed (1/1 ethyl
acetate/petroleum ether as eluent) to provide 581 mg (63%) of
requires 411.1276. Data for 17: [R]21 -50.7 (c 0.1, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.28 (m, 2H), 5.28
(br s, 1H), 4.09 (m, 1H), 4.04 (m, 2H), 3.57 (s, 3H), 2.84 (m,
2H), 2.24 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H); MS (EI) m/z 412
(M+ + H+); HRMS found m/z 411.1277 (M+), C17H21N3O9
requires 411.1276.
23: [R]19 -78.2 (c 0.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.61 (br s, 1H), 7.36 (m, 5H), 7.11 (d, J ) 8.4 Hz, 1H), 6.73 (d,
J ) 8.4 Hz, 1H), 5.29 (br s, 1H), 5.04 (AB q, J ) 11.1, 2H),
3.67 (d, J ) 5.4 Hz, 1H), 3.57 (s, 3H), 3.48 (m, 2H), 3.00 (m,
1H), 2.85 (m, 1H), 2.21 (s, 3H), 1.46 (m, 9H), 1.09 (d, J ) 6.8
Hz, 3H), 1.04 (d, J ) 6.8 Hz, 3H); MS (EI) m/z 544 (M+ + H+);
HRMS found m/z 543.2945 (M+), C29H41N3O7 requires 543.2949.
La cta m 24. A mixture of 23 (350 mg, 0.64 mmol) in 3 mL
of methanol and 3 mL of 10% NaOH was stirred overnight.
The solution was neutralized with 10% aqueous citric acid to
pH 5 before it was extracted with ethyl acetate. The extracts
were washed with brine, dried over Na2SO4, and concentrated
to afford the crude acid. This product and N-hydroxysuccin-
imide (89 mg, 0.77 mmol) were dissolved in 15 mL of meth-
ylene chloride. To this solution was added a solution of DCC
(159 mg, 0.77 mmol) in 2 mL of methylene chloride. After it
was stirred for 2 h, the mixture was filtered. The filtrate was
purified by passing it over a short column of silica gel to afford
the corresponding activated ester.
Gen er a l P r oced u r e for Hyd r ogen a tion of 16 a n d 17.
A suspension of 16 (190 mg, 0.5 mmol) and 10 mg of 10% Pd/C
in 5 mL of ethyl acetate was stirred under hydrogen at room
temperature and ordinary pressure for 3 h. The catalyst was
filtered off, and the filtrate was purified by column chroma-
tography (2/1 ethyl acetate/petroleum ether as eluent) to
provide 190 mg (100%) of 18a : 1H NMR (300 MHz, CDCl3) δ
8.05 (s, 1H), 6.57 (s, 1H), 6.33 (s, 1H), 5.48 (m, 1H), 4.13 (m,
1H), 4.38 (dd, J ) 12.5, 3.4 Hz, 1H), 3.89 (m, 1H), 3.70 (s, 3H0,
271 (d, J ) 12.3 Hz, 1H), 2.39 (dd, J ) 12.3, 10.1 Hz, 1H),
2.17 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H); MS (EI) m/z 381 (M+).
Data for 19: 1H NMR (300 MHz, CD3OD) δ 7.17 (d, J ) 8.3
Hz, 1H), 6.64 (d, J ) 8.3 Hz, 1H), 4.44 (m, 1H), 4.38 (m, 2H),
3.85 (s, 3H), 3.02 (dd, J ) 12.4, 5.2 Hz, 1H), 2.92 (dd, J )
12.4, 7.9 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H); MS
(EI) m/z 381 (M+).
(S)-3-(4-Ben zoxy-3-a ceta m id o-2-n itr op h en yl)-2-[(m eth -
oxyca r bon yl)-a m in o]-1-p r op a n ol (20). To a mixture of 17
(3.0 g, 7.2 mmol) in 60 mL of methanol and 40 mL of water
was added Na2CO3 (2.0 g, 18.8 mmol). After it was stirred for
The above product was dissolved in 5 mL of methylene
chloride. With cooling by ice-water, 5 mL of TFA was added
slowly. After the stirring was continued for 2 h at 0 °C, the
solvents were evaporated at reduced pressure. The residue was

6372 J . Org. Chem., Vol. 64, No. 17, 1999
Ma et al.
dissolved in 60 mL of ethyl acetate and 6 mL of saturated
aqueous NaHCO3. After the resultant mixture was stirred for
10 min at room temperature, it was heated at reflux for 30
min. The cooled mixture was separated, and the organic layer
was washed with brine and dried over Na2SO4. After removal
of solvent, the residual oil was chromatographed (4/1 ethyl
acetate/petroleum ether as eluent) to provide 210 mg (80%) of
3H); MS (EI) m/z 455 (M+); HRMS found m/z 455.3147 (M+),
C
27H41N3O3 requires 455.3148.
(S)-3-(5-Aceta m id o-4-ben zoxy-2-n itr op h en yl)-2-[(m eth -
oxyca r bon yl)a m in o]-1-p r op a n ol (28). Following the pro-
cedure for preparing 20 from 17, 28 was obtained in 81% yield
from 16: [R]19 -53.2 (c 0.64, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 8.47 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.43 (m, 5H),
5.38 (m, 1H), 5.17 (s, 2H), 4.03 (m, 1H), 3.75 (m, 2H), 3.67 (s,
3H), 3.15 (dd, J ) 13.8, 4.4 Hz, 1H), 3.08 (dd, J ) 13.8, 9.8
Hz, 1H), 2.19 (s, 3H); MS (EI) m/z 418 (M+ + H+); HRMS found
m/z 417.1540 (M+), C20H23N3O7 requires 417.1547.
24: [R]21 -47.3 (c 0.13, CH3OH); 1H NMR (300 MHz, CDCl3)
D
δ 7.37 (m, 5H), 7.28 (s, 1H), 6.89 (d, J ) 8.4 Hz, 1H), 6.61 (d,
J ) 8.4 Hz, 1H), 6.59 (br s, 1H), 5.01 (s, 2H), 4.91 (m, 1H),
3.72 (dd, J ) 11.3, 3.4 Hz, 1H), 3.57 (dd, J ) 11.3, 5.2 Hz,
1H), 3.53 (d, J ) 6.6 Hz, 1H), 3.01 (dd, J ) 13.8, 4.4 Hz, 1H),
2.89 (dd, J ) 13.8, 9.8 Hz, 1H), 2.17 (s, 3H), 2.16 (m, 1H), 1.08
(d, J ) 6.8 Hz, 3H), 0.99 (d, J ) 6.8 Hz, 3H); MS (EI) m/z 411
(M+); HRMS found m/z 411.2140 (M+), C23H29N3O4 requires
411.2158.
(S)-O-Acetyl-3-(5-a ceta m id o-4-ben zoxy-2-n itr op h en yl)-
2-[(ter t-bu toxyca r bon yl)a m in o]-1-p r op a n ol (29b). Follow-
ing the procedure for synthesizing 21a for 20, 29a was
prepared from 28 in 81% yield. To a mixture of 29a (0.81 g,
1.94 mmol) and 30 mL of pyridine was added acetyl chloride
(0.37 g, 4.66 mmol) at 50 °C. After the addition the stirring
was continued for 10 min at the same temperature. The solvent
was removed in vacuo, and the residue was partitioned
between 70 mL of ethyl acetate and 20 mL of water. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. Column chromatography (1/2 ethyl acetate/
petroleum ether as eluent) of the residual oil afforded 870 mg
(90%) of 29b: [R]17D -29.5 (c 0.76, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 8.46 (s, 1H), 7.89 (s, 1H), 7.70 (s, 1H), 7.43 (m, 5H),
5.15 (s, 2H), 4.87 (d, J ) 9.3 Hz, 1H), 4.19 (m, 1H), 4.11 (m,
2H), 3.22 (dd, J ) 13.2, 4.8 Hz, 1H), 3.02 (dd, J ) 13.3, 9.4
Hz, 1H), 2.19 (s, 3H), 2.13 (s, 3H), 1.37 (s, 9H); MS (EI) m/z
502 (M+ + H+). Anal. Calcd for C25H31N3O8: C, 59.87; H, 6.27;
N, 8.38. Found: C, 59.68; H, 6.20; N, 8.18.
(S,S)-9-Ben zoxy-10-acetam idoben zolactam -V8 (25). The
lactam 24 (130 mg, 0.32 mmol) and NaBH4 (60 mg, 1.58 mmol)
were mixed in 5 mL of THF. The resultant suspension solution
was added dropwise into a freshly prepared mixture of
formalin (0.6 mL, 7.4 mmol) and 3 N H2SO4 (1.0 mL, 0.32
mmol) with vigorous stirring. During the addition the reaction
temperature should be kept below 20 °C by cooling with ice-
water. After the addition the stirring was continued for 5 min.
NaOH powder was added to quench the reaction, and then
the mixture was partitioned between 50 mL of ethyl acetate
and 10 mL of water. The organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography (4/1 ethyl
acetate/petroleum ether as eluent) to afford 120 mg (89%) of
(2S)-N-[5-Ben zoxy-4-a cet a m id o-(S)-2-[2-(ter t-b u t oxy-
ca r bon yl)a m in o-3-a cetoxyp r op yl]p h en yl]va lin e Meth yl
Ester (30). To a solution of 29b (670 mg, 1.33 mmol) in 30
mL of ethanol was added SnCl2 (1.27 g, 6.71 mmol). The
resulting solution was refluxed for 1 h before it was cooled
and poured onto ice-water. The mixture was neutralized with
saturated NaHCO3 to pH 8 and then extracted with ethyl
acetate. After the extraction the product was purified by
column chromatography (1/2 ethyl acetate/petroleum ether as
eluent) to afford the corresponding aniline. This aniline was
coupled with 22a according to the procedure for preparing 23
25: [R]21 -193 (c 0.53, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.37 (m, 5H), 6.92 (br s, 2H), 6.89 (d, J ) 7.7 Hz, 1H), 6.63 (d,
J ) 8.4 Hz, 1H), 5.01 (s, 2H), 3.74 (m, 1H), 3.57 (m, 2H), 3.45
(m, 1H), 2.88 (m, 1H), 2.73 (s, 3H), 2.41 (m, 1H), 2.16 (s, 3H),
1.00 (d, J ) 6.8 Hz, 6H); MS (EI) m/z 425 (M+); HRMS found
m/z 425.2299 (M+), C24H31N3O4 requires 425.2314.
(S,S)-9-Decyn yl-10-a ceta m id oben zola cta m -V8 (26). To
a solution of 25 (80 mg, 0.19 mmol) in 5 mL of DMF were
added imidazole (26 mg, 0.38 mmol) and tert-butyldimethylsilyl
chloride (58 mg, 0.38 mmol), respectively. After the mixture
was stirred overnight, DMF was removed in vacuo. The residue
was partitioned between 20 mL of ethyl acetate and 5 mL of
water. The organic layer was washed with brine, dried over
Na2SO4, and concentrated. After column chromatography (1/2
ethyl acetate/petroleum ether as eluent), the silyl ether was
obtained. This product was dissolved in 5 mL of ethyl acetate,
and then 5 mg of 10% Pd/C was added. The resultant
suspension was stirred under hydrogen atmosphere (ordinary
pressure) until no more starting material was determined by
TLC. Pd/C was filtered off, and the filtrate was concentrated
to dryness to provide an oil, which was dissolved in 1 mL of
dry methylene chloride. To this solution was added triethyl-
amine (84 µL, 0.6 mmol) before trifluoromethanesulfonic
anhydride (86 mg, 0.3 mmol) was added at -78 °C. After the
solution was stirred for 10 min at the same temperature, the
reaction was quenched by adding water. Methylene chloride
extraction and workup followed by column chromatography
afforded 77 mg (70% from 25) of the corresponding triflate.
to provide 30 in 81% overall yield: [R]19 -114.5 (c 0.17,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.90 (br s, 1H), 7.38 (m,
6H), 6.28 (s, 1H), 5.18 (d, J ) 7.1 Hz, 1H), 5.04 (s, 2H), 4.06
(d, J ) 5.6 Hz, 2H), 3.90 (m, 1H), 3.75 (d, J ) 7.0 Hz, 1H),
3.61 (s, 3H), 2.98 (m, 1H), 2.52 (m, 1H), 2.23 (m, 1H), 2.09 (s,
3H), 2.04 (s, 3H), 1.44 (s, 9H), 1.13 (d, J ) 6.8 Hz, 3H), 1.04
(d, J ) 6.8 Hz, 3H); MS (EI) m/z 585 (M+); HRMS found m/z
585.3045 (M+), C31H43N3O8 requires 585.3050.
La cta m 31. A mixture of 30 (250 mg, 0.43 mmol), 5 mL of
methanol, and 5 mL of 2 N NaOH was stirred overnight. After
the solution was neutralized with 10% aqueous citric acid to
pH 6, it was extracted with methylene chloride. The organic
layer was cooled to -10 °C, and 6 mL of TFA was added
dropwise. The resultant solution was stirred for 1 h at the
same temperature before it was concentrated. The residue was
dried in vacuo and then dissolved in 60 mL of DMF. At 0 °C
triethylamine (91 mg, 0.91 mmol) and DPPA (141 mg, 0.51
mmol) were added. The solution was stirred for 1 h at 0 °C
and 17 h at room temperature. DMF was removed in vacuo,
and the residual oil was partitioned between 50 mL of ethyl
acetate and 20 mL of water. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. Column
chromatography (4/1 ethyl acetate/petroleum ether as eluent)
The above triflate (50 mg, 0.086 mmol), 1-decyne (78 mL,
0.43 mmol), and 1 mL of triethylamine were dissolved in 5
mL of DMF. Under nitrogen PdCl2(PPh3)2 (24 mg, 0.017 mmol),
CuI (6.5 mg, 0.034 mmol), and n-Bu4NI (95 mg, 0.17 mmol)
were added, respectively. The mixture was heated at 70 °C
for 2 days under nitrogen before it was passed over a short
column of silica gel. The filtrate was mixed with a solution of
10 mg of TsOH in 2 mL of methanol, and then the mixture
was stirred for 3 h. The solvents were removed in vacuo, and
the residue was chromatographed (1/3 ethyl acetate/petroleum
ether as eluent) to afford 28 mg (71% from the triflate) of 26:
[R]21D -168 (c 0.36, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.02
(m, 1H), 6.84 (m, 1H), 6.66 (m, 1H), 3.79 (m, 1H), 3.50 (m,
3H), 2.79 (m, 2H), 2.64 (s, 3H), 2.30 (m, 1H), 2.29 (t, J ) 7.0
Hz, 2H), 2.12 (s, 3H), 1.87 (m, 1H), 1.48 (m, 2H), 1.32 (m, 2H),
1.19 (m, 8H), 0.94 (d, J ) 6.6 Hz, 6H), 0.79 (t, J ) 6.4 Hz,
of the residual oil afforded 110 mg (63%) of 31: [R]21 -22.9
D
1
(c 0.36, CH3OH); H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H),
7.49 (s, 1H), 7.31 (m, 5H), 6.33 (s, 1H), 6.30 (d, J ) 7.3 Hz,
1H), 4.89 (s, 2H), 3.98 (m, 1H), 3.73 (d, J ) 8.4 Hz, 1H), 3.65
(dd, J ) 11.3, 4.3 Hz, 1H), 3.56 (dd, J ) 11.3, 6.2 Hz, 1H),
3.03 (dd, J ) 14.2, 11.6 Hz, 1H), 2.79 (dd, J ) 14.2, 6.5 Hz,
1H), 2.15 (m, 1H), 2.09 (s, 3H), 1.03 (d, J ) 6.8 Hz, 3H), 0.91
(d, J ) 6.8 Hz, 3H); MS (EI) m/z 411 (M+); HRMS found m/z
411.2189 (M+), C23H29N3O4 requires 411.2158.
(S,S)-8-Aceta m in d o-9-ben zoxyben zola cta m -V8 (32). To
a mixture of 31 (100 mg, 0.24 mmol) in 5 mL of CH3CN were

Analogues of Benzolactam-V8
J . Org. Chem., Vol. 64, No. 17, 1999 6373
added 0.2 mL of formalin, NaCNBH3 (46 mg, 0.73 mmol), and
23 µM HOAc at 0 °C, sequentially. After the stirring was
continued for 30 min at the same temperature, the reaction
mixture was partitioned between 50 mL of ethyl acetate and
10 mL of water. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was chro-
matographed (4/1 ethyl acetate/petroleum ether as eluent) to
added benzyl bromide (456 mg, 2.67 mmol) in a dropwise
manner. After the reaction mixture was heated at 50 °C for 2
h, DMF was removed in vacuo. The residue was partitioned
between 100 mL of ethyl acetate and 20 mL of water. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. The crude product was purified by column
chromatography (2/1 ethyl acetate/petroleum ether as eluent)
afford 100 mg (96%) of 32: [R]21 -244 (c 0.24, CHCl3); 1H
to provide 720 mg (90%) of 37: [R]18 +9.3 (c 0.2, CH3OH); 1H
D
D
NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.62 (s, 1H), 7.39 (m,
5H), 6.77 (d, J ) 4.1 Hz, 1H), 6.61 (s, 1H), 5.08 (AB q, J )
11.7 Hz, 2H), 4.89 (s, 2H), 3.98 (m, 1H), 3.73 (d, J ) 8.4 Hz,
1H), 3.65 (dd, J ) 11.3, 4.3 Hz, 1H), 3.56 (dd, J ) 11.3, 6.2
Hz, 1H), 3.03 (dd, J ) 14.2, 11.6 Hz, 1H), 2.79 (dd, J ) 14.2,
6.5 Hz, 1H), 2.15 (m, 1H), 2.09 (s, 3H), 1.03 (d, J ) 6.8 Hz,
3H), 0.91 (d, J ) 6.8 Hz, 3H); MS (EI) m/z 425 (M+); HRMS
found m/z 425.2306 (M+), C24H31N3O4 requires 425.2314.
(S,S)-8-Aceta m in d o-9-decyn ylben zola cta m -V8 (33). Fol-
lowing the procedure for preparing 26 from 25, 33 was
NMR (300 MHz, CDCl3) δ 7.53 (d, J ) 2.6 Hz, 1H), 7.38 (m,
6H), 7.17 (dd, J ) 8.4, 2.6 Hz, 1H), 5.24 (d, J ) 7.6 Hz, 1H),
5.10 (s, 2H), 3.98 (m, 1H), 3.70 (m, 2H), 3.60 (s, 3H), 3.11 (dd,
J ) 13.8, 6.1 Hz, 1H), 2.73 (dd, J ) 13.8, 9.1 Hz, 1H); MS (EI)
m/z 361 (M+ + H+). Anal. Calcd for C18H20N2O6: C, 59.99; H,
7.77; N,5.59. Found: C, 59.75; H, 7.49; N, 5.64.
(2S)-N-[5-Ben zoxy-2-[(S)-2-(ter t-bu toxycar bon yl)am in o-
3-h yd r oxyp r op yl] p h en yl]va lin e Ben zyl Ester (38). Fol-
lowing the procedure for synthesizing 23 from 21b, 38 was
obtained from 37 in 64% yield: [R]21 -92.2 (c 0.54, CHCl3);
D
obtained from 32 in 61% overall yield: [R]21 -153 (c 0.34,
1H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 7.29 (m, 5H), 7.00
(d, J ) 8.2 Hz, 1H), 6.33 (dd, J ) 8.2, 2.4 Hz, 1H), 6.24 (d, J
) 2.4 Hz, 1H), 5.34 (d, J ) 8.2 Hz, 1H), 5.10 (AB q, J ) 12.0
Hz, 2H), 4.94 (AB q, J ) 11.6 Hz, 2H), (d, J ) 8.5 Hz, 1H),
6.99 (d, J ) 8.5 Hz, 1H), 3.76 (m, 1H), 3.49 (m, 2H), 3.42 (s,
3H), 3.53 (d, J ) 8.1 Hz, 1H), 3.44 (d, J ) 8.7 Hz, 1H), 2.79
(dd, J ) 13.8, 4.8 Hz, 1H), 2.70 (dd, J ) 13.8, 9.8 Hz, 1H),
2.12 (m 1H), 1.04 (d, J ) 7.1 Hz, 3H), 0.99 (d, J ) 7.1 Hz, 3H);
MS (EI) m/z 520 (M+); HRMS found m/z 520.2545 (M+),
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.76 (s, 1H),
7.03 (s, 1H), 6.53 (d, J ) 3.6 Hz, 1H), 4.22 (m, 1H), 3.68 (dd,
J ) 10.8, 3.8 Hz, 1H), 3.50 (dd, J ) 10.9, 8.1 Hz, 1H), 3.38 (d,
J ) 8.0 Hz, 1H), 2.95 (dd, J ) 15.3, 8.2 Hz, 1H), 2.85 (dd, J )
15.4, 2.1 Hz, 1H), 2.73 (s, 3H), 2.48 (d, J ) 7.3 Hz, 2H), 2.37
(m, 1H), 2.18 (s, 3H), 1.66 (m, 2H), 1.47 (m, 2H), 1.30 (m, 8H),
1.06 (d, J ) 6.6 Hz, 6H), 0.90 (m, 6H); MS (EI) m/z 455 (M+);
HRMS found m/z 455.3146 (M+), C27H41N3O3 requires 455.3148.
(S)-3-(4-H yd r oxy-2-n it r op h en yl)-2-[(m et h oxyca r b on -
yl)a m in o]-1-p r op a n ol (34). After nitration of 15 according
to the procedure as described above, the generated mixture of
16 and 17 (1.5 g, 3.6 mmol) was dissolved in 30 mL of methanol
and 30 mL of 1 N H2SO4. The resultant solution was heated
at 70 °C for 1 day, and then methanol was removed via
rotavapor. The aqueous solution was cooled to 0 °C, and
NaNO2 (262 mg, 3.8 mmol) was added. After the stirring was
continued for 30 min, 0.5 mL of 30% H3PO2 was added. The
solution was heated at 70 °C for 5 h, and then the cooled
solution was extracted with ethyl acetate. The extracts were
washed with brine, dried over Na2SO4, and concentrated.
Column chromatography (2/1 ethyl acetate/petroleum ether as
C
30H36N2O6 requires 520.2574.
(S,S)-9-Ben zoxyb en zola ct a m -V8 (39). A mixture of 38
(180 mg, 0.35 mmol), 6 mL of methanol, and 3 mL of 2 N KOH
was heated at 70 °C for 1 day. The cooled solution was
neutralized with 2 N HCl to pH 7 and then concentrated. The
residual solid was dried in vacuo for 1 day before it was
dissolved in 10 mL of DMF. To this solution were added
triethylamine (97 µM, 0.73 mmol) and DPPA (90 µM, 0.42
mmol) at 0 °C. After the stirring was continued for 1 h at 0 °C
and 17 h at room temperature, DMF was evaporated at
reduced pressure. The residue was partitioned between 50 mL
of ethyl acetate and 10 mL of water. The organic layer was
washed with brine, dried over Na2SO4, and concentrated. The
residual oil was chromatographed (2/1 ethyl acetate/petroleum
ether as eluent) to provide 100 mg (82%) of cyclization product,
which was subjected to reduction methylation following the
procedure for preparing 32 from 31 to provide 39 in 95%
eluent) of the residual oil afforded 601 mg (61%) of 34: [R]21
D
-17.1 (c 0.62, CH3OH); 1H NMR (300 MHz, CD3OD) δ 7.51
(d, J ) 2.6 Hz, 1H), 7.44 (d, J ) 8.4 Hz, 1H), 7.18 (dd, J ) 8.4,
2.6 Hz, 1H), 4.09 (m, 1H), 3.75 (m, 2H), 3.70 (s, 3H), 3.15 (dd,
J ) 13.8, 4.4 Hz, 1H), 2.71 (dd, J ) 13.8, 9.8 Hz, 1H); MS (EI)
m/z 271 (M+ + H+); HRMS found m/z 270.0852 (M+),
yield: [R]21 -279.2 (c 0.08, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.40 (m, 5H), 6.94 (d, J ) 8.3 Hz, 1H), 6.61 (m, 2H),
6.49 (dd, J ) 8.3, 2.5 Hz, 1H), 5.02 (s, 2H), 3.92 (m, 1H), 3.68
(m, 1H), 3.52 (m, 1H), 3.49 (d, J ) 9.1 Hz, 1H), 3.03 (m, 1H),
2.98 (m, 1H), 2.76 (s, 3H), 2.68 (m, 1H), 2.41 (m, 1H), 1.04 (d,
J ) 6.6 Hz, 3H), 0.84 (d, J ) 6.6 Hz, 3H); MS (EI) m/z 368
(M+); HRMS found m/z 368.2101 (M+), C22H28N2O3 requires
368.2105.
C
11H14N2O6 requires 270.0851.
(S)-3-(5-Iod o-4-h yd r oxy-2-n it r op h en yl)-2-[(m et h oxy-
ca r bon yl)a m in o]-1-p r op a n ol (35). A mixture of 16 (100 mg,
0.24 mmol), 5 mL of methanol, and 3 mL of 2 N H2SO4 was
heated at 70 °C for 16 h. Methanol was removed by rotavapor,
and the remaining aqueous solution was cooled to 0 °C. To
this stirring solution was added NaNO2 (20 mg, 0.28 mmol).
After the stirring was continued for 30 min, KI (120 mg, 0.72
mmol) was added, and the resultant mixture was heated at
70 °C for 5 h. Extraction workup followed by column chroma-
tography (2/1 ethyl acetate/petroleum ether as eluent) afforded
(S,S)-9-Decyn ylben zola cta m -V8 (4). Following the pro-
cedure for preparing 26 from 25, 4 was obtained from 39 in
1
80% overall yield: [R]19 ) -140.6 (c 0.03, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.01 (d, J ) 1.3 Hz, 1H), 6.95 (d, J ) 7.8
Hz, 1H), 6.89 (dd, J ) 7.8, 1.3 Hz, 1H), 6.51 (m, 1H), 3.95 (br
s, 1H), 3.71 (dd, J ) 10.6, 3.9 Hz, 1H), 3.53 (dd, J ) 10.6, 9.1
Hz, 1H), 3.09 (dd, J ) 17.0 Hz, 7.8 Hz, 1H), 2.79 (s, 3H), 2.74
(m, 1H), 2.51 (m, 1H), 2.38 (t, J ) 7.1 Hz, 2H), 1.60 (m, 2H),
1.45 (m, 2H), 1.29 (m, 8H), 1.05 (d, J ) 6.4 Hz, 3H), 0.89 (d, J
) 6.4 Hz, 3H), 0.87 (t, J ) 7.0 Hz, 3H). MS (EI) m/z 398 (M+);
HRMS found m/z 398.2928 (M+), C25H38N2O2 requires 398.2934.
43 mg (45%) of 35: [R]21 -55 (c 0.35, CH3OH); 1H NMR (300
D
MHz, CD3COCD3) δ 7.91 (s, 1H), 7.47 (s, 1H), 6.28 (d, J ) 9.2
Hz, 1H), 3.92 (m, 1H), 3.60 (d, J ) 5.0 Hz, 2H), 3.47 (s, 3H),
3.25 (dd, J ) 14.0, 4.3 Hz, 1H), 2.80 (dd, J ) 13.9, 10.0 Hz,
1H); MS (EI) m/z 396 (M+); HRMS found m/z 395.9808 (M+),
C
11H13N2O6I requires 395.9818.
(S)-3-(4-H yd r oxy-3-iod o-2-n it r op h en yl)-2-[(m et h oxy-
ca r bon yl)a m in o]-1-p r op a n ol (36). Following the procedure
for preparing 35 from 16, 36 was obtained from 17 in 42%
Ack n ow led gm en t. We are grateful to the Chinese
Academy of Sciences, National Natural Science Founda-
tion of China (Grant 29725205), and Qiu Shi Science &
Technologies Foundation for their financial support.
yield: [R]21 -29.3 (c 0.35, CH3OH); 1H NMR (300 MHz,
D
CD3OD) δ 7.51 (d, J ) 2.4 Hz, 1H), 7.43 (d, J ) 8.5 Hz, 1H),
7.18 (dd, J ) 8.4, 2.4 Hz, 1H), 4.08 (m, 1H), 3.73 (m, 2H), 3.70
(s, 3H), 3.38 (dd, J ) 13.8, 4.5 Hz, 1H), 2.71 (dd, J ) 13.8, 9.5
Hz, 1H); MS (EI) m/z 396 (M+); HRMS found m/z 395.9821
(M+), C11H13N2O6I requires 395.9818.
(S)-3-(4-Ben zoxy-2-n it r op h en yl)-2-[(m et h oxyca r b on -
yl)a m in o]-1-p r op a n ol (37). To a solution of 34 (600 mg, 2.22
mmol) and K2CO3 (612 mg, 4.44 mmol) in 20 mL of DMF was
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4, 16, 24, 26, 32-36, and 39. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O990605H