Accelerating effect induced by the structure of α-amino acid in the copper-catalyzed coupling reaction of aryl halides with α-amino acids. Synthesis of benzolactam-V8

Article abstract of DOI:10.1021/ja981662f

The coupling of optically pure α-amino acids with aryl halides produces enantiopure N-aryl-α-amino acids with retention of configuration under the catalysis of CuI. This reaction can complete at much lower temperature than typical Ullmann condensation even for electron-rich aryl halides, which indicates that an accelerating effect induced by the structure of the α- amino acid exists in this reaction. α-Amino acids with larger hydrophobic groups give higher coupling yields, while those with smaller hydrophobic groups only deliver lower yields and no coupling products were detected for those with hydrophilic groups. No racemization was observed in most cases of this coupling reaction. After some controlled experiments, a possible mechanism including the π-complex and the intramolecular substitution reaction is proposed. Based on this catalyzed reaction, a facile and stereoselective synthesis of benzolactam-V8, a new PKC activator, is achieved.

Full text of DOI:10.1021/ja981662f

J. Am. Chem. Soc. 1998, 120, 12459-12467
12459
Accelerating Effect Induced by the Structure of R-Amino Acid in the
Copper-Catalyzed Coupling Reaction of Aryl Halides with R-Amino
Acids. Synthesis of Benzolactam-V8
Dawei Ma,*,† Yongda Zhang,‡ Jiangchao Yao,† Shihui Wu,‡ and Fenggang Tao‡
Contribution from the State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China, and the
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China
ReceiVed May 13, 1998
Abstract: The coupling of optically pure R-amino acids with aryl halides produces enantiopure N-aryl-R-
amino acids with retention of configuration under the catalysis of CuI. This reaction can complete at much
lower temperature than typical Ullmann condensation even for electron-rich aryl halides, which indicates that
an accelerating effect induced by the structure of the R-amino acid exists in this reaction. R-Amino acids
with larger hydrophobic groups give higher coupling yields, while those with smaller hydrophobic groups
only deliver lower yields and no coupling products were detected for those with hydrophilic groups. No
racemization was observed in most cases of this coupling reaction. After some controlled experiments, a
possible mechanism including the π-complex and the intramolecular substitution reaction is proposed. Based
on this catalyzed reaction, a facile and stereoselective synthesis of benzolactam-V8, a new PKC activator, is
achieved.
Introduction
Furthermore, many R-amino acids are commercially available
in optically pure form. On the other hand, chiral N-aryl-R-
amino acids are of the common core structures for a number of
synthetically challenging and medicinally important agents.
These agents include protein kinase C (PKC) activators,
indolactam-V,10 and its analogue benzolactam-V8;11 (see Figure
1) Ciba’s phenylamide fungicides (R)-metalaxyl;12 fibrinogen
receptor antagonist SB 214857;13 NMDA receptor antagonist
L68956014 and tricyclic quinoxalinediones;15 ACE inhibitors;16
and antiulcer agents.17 In the past two decades, these structures
Recently, the formation of the carbon-nitrogen bond by the
palladium-catalyzed coupling of aryl halides with amines has
been achieved.1 Buchwald2 and Hartwig3 independently re-
ported that Pd/P(o-tolyl)3 complex under the action of sterically
bulky bases such as t-BuONa or LHDMS efficiently catalyzed
the amination of aromatic bromides. By varying the catalytic
systems and reaction conditions, aryl iodides,4 aryl triflates,5
and aryl chlorides6 could be also used as effective amination
reagents. Because these palladium-catalyzed reactions could
be carried out at much lower temperature than the copper-
mediated Ullmann condensation, these results represented a
major advance in the development of aromatic amination
methodology.1 Recently, much attention has also been directed
to seeking the arylation of more complex amines7 that may
expand the scope of this methodology. However, few reports
dealt with optically pure amines.8 Among numerous function-
alized amines, R-amino acid is one of the best building blocks
in organic synthesis because of its further transformations.9
(8) (a) Ma, D.; Yao, J. Tetrahedron: Asymmetry 1996, 7, 3075. (b)
Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
8451.
(9) For reviews, see: (a) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996,
96, 1825. (b) Coppola, G. M.; Schuster, H. F.; Asymmetric Synthesis.
Construction of Chiral Molecules Using Amino Acids; Wiley: New York,
1987.
(10) (a) Endo, Y.; Shudo, K.; Furuhata, K.; Ogura, H.; Sakai, S.; Aimi,
N.; Hitotsuyanagi, Y.; Koyama, Y. Chem. Pharm. Bull. 1984, 32, 358. (b)
Kogan, T. P.; Somers, T. C.; Venuti, M. C. Tetrahedron 1990, 46, 6623.
(c) Semmelhack, M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1395. (d)
Quick, J.; Saha, B.; Driedger, P. E. Tetrahedron Lett. 1994, 35, 8549.
(11) (a) Endo, Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. J. Am.
Chem. Soc. 1996, 118, 1841 and references therein. (b) 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. (c) Endo, Y.; Yamaguchi, M.; Hirano, M.; Shudo, K. Chem. Pharm.
Bull. 1996, 44, 1138.
† Shanghai Institute of Organic Chemistry.
‡ Fudan University.
(1) For reviews, see: Hartwig, J. F. Synlett 1997, 329.
(2) Guram, S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1348.
(3) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(4) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133.
(5) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (b)
Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1997,
62, 1268. (c) Torisawa, Y.; Hashimoto, A.; Furuta, T.; Minamikawa, J.
Bioorg. Med. Chem. Lett. 1997, 14, 1821.
(12) Voss, G. CHEMTECH 1997, (Apr), 17.
(13) Miller, W. H.; Ku, T. W.; Ali, F. E.; Bondinell, W. E.; Calvo, R.
R.; Davis, L. D.; Erhard, K. F.; Hall, L. B.; Huffman, W. F.; Keenan, R.
M.; Kwon, C.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Takata, T.
D.; Yuan, C. Tetrahedron Lett. 1995, 36, 9433.
(6) Reddy, N. P.; Tanaka, M.Tetrahedron Lett. 1997, 38, 4807.
(7) (a) Beletskaya, I. P.; Bessmertnykh, A. G.; Guilard, R. Tetrahedron
Lett. 1997, 38, 2287. (b) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.;
Putman, D. G. Tetrahedron Lett. 1998, 39, 1313. (c) Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617. (d) Singer, R.
A.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 213. (e)
Zhao, S.; Miller, A. K.; Berger, J.; Fippin, L. A. Tetrahedron Lett. 1996,
37, 7217.
(14) (a) Kemp, J. A.; Leeson, P. D. Trends Pharmacol. Sci. 1993, 14,
20. (b) Leeson, P. D.; Carling, R. W.; Smith, J. D.; Baker, R.; Foster, A.
C.; Kemp, J. A. Med. Chem. Res. 1991, 1, 64.
(15) Nagata, R.; Ae, N.; Tanno, N. Bioorg. Med. Chem. Lett. 1995, 5,
1527.
(16) De Lombaert, S.; Blanchard, L.; Stamford, L. B.; Sperback, D. M.;
Grim, M. D.; Jenson, T. M.; Rodriguez, H. R. Tetrahedron Lett. 1994, 35,
7513.
10.1021/ja981662f CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/19/1998

12460 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Ma et al.
Table 1. Copper-Catalyzed Couplings of Aryl Halides and
R-Amino Acidsa
yieldb
(%)
entry
aryl halide
amino acid
L-valine
D-valine
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhCl
PhI
3-MeOC6H4Br
4-BrC6H4CO2H
2,5-Me2C6H3Br
2,6-Me2C6H3Br
2,6-Me2C6H3Br
4-MeOC6H3Br
2-MeOC6H4Br
2-HOC6H4Br
4-ClC6H4Br
3-BrC6H4CO2H
2-BrC6H4CO2H
2-IC6H4CO2H
1
2
3
5
6
7
8
4
9
81
75
80
92
65
76
60
46
73
0
0
0
3
83
85
75
74
14
5
L-proline
L-phenylalanine
L-alanine
L-methionine
L-tyrosine
N-methyl-L-valine
L-tryptophen
L-glutamic acid
L-serine
glycine
L-valine
L-valine
L-valine
L-valine
L-valine
L-valine
L-alanine
L-valine
L-valine
L-valine
L-valine
L-valine
1
1
10
11
16
17
12
Figure 1.
were assembled via several steps to get the enantiomerically
pure form. For example, in the synthesis of indolactam-V8 and
its analogues, the chiral N-aryl-R-amino acid subunit was built
inconveniently by an SN2 displacement10,11 of chiral triflate
derived from D-valine with arylamine. In the synthesis of
L689560,14b the corresponding subunit was obtained from the
addition of arylamine to dimethyl acetylenedicarboxylate fol-
lowed by chemical resolution. However, as a more direct and
economical way, the coupling of an aryl halide with an R-amino
acid derivative was achieved only when the aromatic ring was
activated.10c,13 Therefore, a general coupling reaction of aryl
halides with R-amino acids appears attractive and of great value.
Stimulated by recent progress on palladium-catalyzed amination,
we have developed a Pd/Cu-catalyzed coupling reaction of
R-amino acids with aryl halides.8a Because this reaction could
be carried at 95 °C to give coupling product in high yield even
for bromobenzene, which was much different with a typical
Ullmann condensation reaction18 (for unsubstituted aryl halides,
the reaction is generally carried out at a temperature in excess
of 150 °C), palladium was initially realized to play a key role
in this reaction. However, after careful reinvestigation, we
found that palladium catalyst was not necessary in this reaction
and CuI itself could catalyze the coupling reaction of R-amino
acids with aryl halides, which gave enantiomerically pure N-aryl-
R-amino acids in moderate to excellent yields in most cases.
This reaction proceeded under much lower temperature even
for electron-rich aryl halides, which provided an unprecedented
example of Ullmann-type amination.18 This result indicated that
an accelerating effect induced by the structure of R-amino acid
existed in this reaction. In addition, by using this reaction, a
facile and stereoselective synthesis of benzolactam-V8, a new
protein kinase C activator, was developed. Herein, we disclose
our results.
c
18a
18b
13
82
61
83
92
64
83
14
L-valine
L-valine
15d
15
a Reaction conditions: 10 mol % CuI, 150 mol % K2CO3, ArX (3.2
mmol), amino acid (3.2 mmol), DMA (4 mL), 90 °C, 48 h. b Isolated
yield. c Product decomposed during the isolation. d Salicyclic acid was
isolated in 30% yield.
of R-amino acids with aryl halides were effective,8a after some
controlled experiments, it was found that CuI alone could
catalyze this coupling reaction (eq 1). Thus, heating a mixture
(1)
of L-valine (1 equiv), bromobenzene (1 equiv), CuI (10 mol
%), and K2CO3 (1.5 equiv) in DMA at 90 °C for 48 h, we could
isolate the coupling product 1 in 81% yield. Other solvents
were also checked for this reaction. Over 80% yields were
obtained when tert-butyl alcohol, DMF, or NMPO was used as
solvent, respectively. However, much lower yields were
observed if pyridine (33% yield) or water (16% yield) instead
of DMA was used as a solvent.
On the basis of these results, the coupling reaction was also
tested by a number of different amino acids and aryl halides.
The results were summarized in Table 1. It was found that
both electron-rich and electron-deficient aryl bromides or aryl
iodides worked for this reaction. However, aryl chlorides were
poor coupling reagents (entry 13). The yields of the coupling
reaction were influenced greatly by the types of R-amino acids.
Those with larger hydrophobic groups gave higher coupling
yields, while those with smaller hydrophobic groups delivered
lower yields, and those with hydrophilic groups even yielded
no coupling products at all (entries 10-12). These differences
might result from the different solubilities of the R-amino acids
or their related intermediates formed during the coupling reaction
in the reaction solvent. Cyclic amino acid gave high yield.
However, acyclic N-alkyl-amino acid gave low yield (entries 3
Results and Discussion
Copper-Catalyzed Coupling Reaction of R-Amino Acids
with Aryl Halides. We chose the coupling reaction of L-valine
with bromobenzene as the model reaction to investigate suitable
reaction conditions. Although the original Pd/Cu reaction
conditions developed by our laboratory for the coupling reaction
(17) Hosokami, T.; Kuretani, M.; Higashi, K.; Asano, M.; Ohya, K.;
Takasugi, N.; Mafune, E.; Miki, T. Chem. Pharm. Bull. 1992, 40, 2712.
(18) (a) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496. (b) Lindley, J.
Tetrahedron, 1984, 40, 1433. (c) For an example of Ullmann-like reductive
coupling of aryl, heteroaryl, and alkenyl halides under mild conditions,
see: Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312.

Synthesis of Benzolactam-V8
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12461
Figure 3. Structures of dipeptides 19 and 20 and potassium salt 21.
tions seemed mild enough to avoid the racemization of either
the starting material or the product in most cases. The poorer
optical purity of 7 might result from its special structural feature.
In 7, the methylthio group might facilitate the formation of
potassium salt 21 and therefore accelerate the racemization (see
Figure 3).
The utility of the present reaction could be illustrated by some
reaction products. For example, N-phenyl-L-proline (3), the
direct coupling product of L-valine with iodobenzene, was found
as a key precursor for synthesizing antiulcer agents,17 while the
original synthesis for this compound took several steps to give
racemic product. N-(2,6-Dimethylphenyl)-D-alanine (12) could
be used in synthesizing Ciba’s phenylamide fungicide (R)-
metalaxyl.12 Although the yield for this compound by our
method is low, the methodology opens a new avenue for
synthesizing this class of compounds. Obviously, these N-aryl-
R-amino acids are also valuable building blocks for peptido-
mimetic studies. In addition, an example using this reaction
for efficient synthesis of a biologically important compound
would be discussed here later.
Mechanism Studies. To study the possible mechanism of
the present reaction and seek its scope, the coupling reactions
of other amines with aryl halides under different copper catalysts
were carried out. From the results summarized in Table 2, we
could observe that the present reaction had the typical charac-
teristics of an Ullmann condensation in many aspects.18 First,
although the yields were all over 80% after 48 h when CuSO4,
Cu(OAc)2, or CuI was used as the catalyst, respectively (entries
1-3), the reaction catalyzed by CuI was faster than those
catalyzed by CuSO4 or Cu(OAc)2 (compare entries 4, 5, and
6), while molecular oxygen could inhibit the reaction (entry 13).
These results implied that Cu(I) or a related complex might serve
as the active catalyst. Second, a strong o-carboxylate accelerat-
ing effect was also observed while p-carboxylate had no similar
effect (entries 7-9). Finally, the ease of halogen displacement
from the aromatic ring was also found in following order: I >
Br > Cl (compare entries 7, 14, and 15). The only exception
was that the present reaction could occur at much lower
temperature even for unsubstituted or electron-rich aryl halides.
For example, the coupling reaction of bromobenzene with
L-valine could give 43% conversion at 75 °C after 24 h (entry
7). In contrast, the coupling reaction of bromobenzene with
benzylamine only gave 5% conversion at 110 °C after 32 h
(entry 10). It was reported that amines with a hydroxyl group
at the â- or γ-position were more reactive than butylamine in
the Ullmann condensation reaction of haloanthraquinones with
amines.21 We tried the coupling reaction of (S)-valinol with
bromobenzene and found only 5% conversion at 110 °C after
32 h (entry 12), which was much slower than the reaction of
L-valine and bromobenzene (entry 7). These results demon-
strated that a strong accelerating effect induced by the structure
of R-amino acid existed in the coupling reaction of R-amino
acids with aryl halides. As a nucleophilic agent, the reactivity
Figure 2. Structures of the coupling products catalyzed by CuI.
and 8). This phenomenon was similar with that found by Driver
and Hartwig19 in Pd-catalyzed coupling of aryl halides and
amines. Steric hindrance about the methyl of aryl halides
disfavored this reaction. For example, the coupling reaction
of 2,6-dimethylbromobenzene with L-valine gave much lower
yield than that of 2,5-dimethylbromobenzene with L-valine
(entries 17 and 18). In the case of 4-bromoanisole as substrate,
although the coupling product was monitored by TLC, it was
too unstable to be isolated under ordinary conditions (entry 20).
In contrast, the coupling products from 2-bromoanisole or
2-bromophenol could be isolated in 82% and 61% yields,
respectively (entries 21 and 22). When 2-bromobenzoic acid
was used to couple with L-valine under the same conditions,
besides the expected coupling product in 64% yield, a side
product, salicylic acid, was also isolated in 30% yield (Table
1, entry 20). However, when 2-iodobenzoic acid was used as
substrate, the formation of salicylic acid was not observed.
It is well-known that an optically pure R-amino acid will
racemize on heating it under high temperature and strong basic
condition.20 Considering that the present coupling reaction was
also carried out under basic conditions and higher temperature,
it was possible that the racemization might occur during the
course of coupling reaction. To check the optical purity of each
coupling product, we transformed the coupling products to their
peptide derivatives to see if any diastereoisomers existed.
Accordingly, the coupling product 5 (see Figure 2) was coupled
with L-alanine methyl ester hydrochloride using EDC to produce
19. Analysis of 19 by 1H NMR revealed that only one isomer
existed, while analysis of 20, the coupling product of the racemic
5 (prepared from the coupling of DL-phenylalanine with bro-
mobenzene) with L-alanine methyl ester, showed clearly the
existence of two isomers by 1H NMR. These results illustrated
that the optical purity of 5 was over 97%. In a similar manner,
the other products were checked and we found that each of them
had over 97% optical purity except for the coupling products 6
and 7. These two products showed 93% and 71% optical purity,
respectively. Thus, we could conclude that the present condi-
(19) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217.
(20) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; Wiley:
New York, 1961; Vol. 3.
(21) Arai, S.; Yamagishi, T.; Ototake, S.; Hida, M. Bull. Chem. Soc.
Jpn. 1977, 50, 547.

12462 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Ma et al.
Table 2. Copper Ions-Catalyzed Coupling Reactions of Aryl Halides and Aminesa
temp
(°C)
time
(h)
product
entry
ArX
RNH2
L-valine
catalyst
CuI
CuSO4
Cu(OAc)2
CuI
CuSO4
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
(yieldb(%))
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
90
90
90
90
90
90
75
75
75
110
110
110
90
75
75
48
48
48
24
24
24
24
24
24
32
32
32
24
24
24
48
1 (80)
1 (79)
1 (82)
1 (81)
1 (44)
1 (51)
1 (45)
15 (66c)
11 (0)
(5g)
L-valine
L-valine
L-valine
L-valine
L-valine
L-valine
L-valine
L-valine
PhCH2NH2
PhCH2NH2
(S)-valinol
L-phenylalanine
L-valine
L-valine
f
2-BrC6H4CO2H
4-BrC6H4CO2H
PhBr
PhBr
PhBr
PhBr
PhCl
PhI
PhBr
(9d,g
(5h)
)
CuI
CuI
CuI
CuI
5 (0e)
1 (0)
1 (80)
5 (43)
f
90
a Reaction conditions: 10 mol % CuI, 150 mol % K2CO3, ArX (3.2 mmol), amine (3.2 mmol), DMA (4 mL). b Isolated yield. c Salicylic acid
d
was isolated in 28% yield. L-Valine (10 mol %) was added in this reaction. e Reaction was carried out under air. f Cu(II)-L-phenylalanine complex
(Cu(H2NCH(Bn)COO)2) was used. g Product was N-benzylaniline and 80% benzylamine was recovered. h Product was (S)-N-phenylvalinol and
84% (S)-valinol was recovered.
Scheme 1. Possible Catalytic Cycle
energy of this step. This hypothesis could be used to explain
the accelerating effect induced by the structure of the R-amino
acid. Finally, HX was removed from C with the assistance of
potassium carbonate to deliver another π-complex D, which
could decompose to produce the coupling product and regenerate
the cuprous ion.
This proposed mechanism was also supported by following
experiments: (i) L-Phenylalanine-Cu(II) complex was reacted
with bromobenzene in the presence of potassium carbonate in
DMA under a nitrogen atmosphere. Although the solubility of
this complex was very low in this reaction system, it was found
that the coupling product 1 could be isolated in 43% yield after
48 h (Table 2, entry 16). However, the reaction of L-
phenylalanine and bromobenzene catalyzed by CuI under air
did not give any coupling product and the blue L-phenylalanine-
Cu(II) complex was isolated after 24 h (Table 2, entry 13). These
results indicated that the active catalyst might be L-phenyl-
alanine-Cu(I) complex but not L-phenylalanine-Cu(II) com-
plex. It was known that Cu(II) could be reduced to Cu(I) by
the nucleophile.18 (ii) Addition of 10 mol % L-valine in the
CuI-catalyzed reaction of benzylamine with bromobenzene did
not cause a marked accelerating effect (Table 2, entry 11).
Because the nucleophilic ability of benzylamine was higher than
that of L-valine, this result ruled out the intermolecular substitu-
tion mechanism. (iii) It was reported that the glycine-Cu(II)
complex was much more stable than the N-phenylglycine-Cu-
(II) complex.22 Thus, it was reasonable to understand that
complex A is easier to form than the Cu(I)-coupling product
complex in order to make the catalytic cycle continue. Of
course, because of the complexity of the Ullmann condensation
reaction,18 the present catalytic cycle was still not completely
satisfactory. Other reasonable mechanisms may exist and more
detailed studies should be carried out to investigate the true
mechanism.
of an R-amino acid is obviously much weaker than a simple
aliphatic amine because of the electron-withdrawing effect of
the carboxylate in an R-amino acid. Thus, the structural feature
of the R-amino acids could contribute to the formation of the
present accelerating effect. It is known that copper ions can
form chelates with amino acids through the carboxyl and amino
groups.22 These chelates might play a key role in the catalytic
cycle. On the basis of this analysis and the known π-complex
mechanism18a of Ullmann condensation, we proposed the
possible catalytic cycle for the present reaction as shown in
Scheme 1. First, cuprous ion reacted with an R-amino acid salt
to form the chelate A, which coordinated with a suitable aryl
halides to provide the π-complex B. Next, intramolecular
nucleophilic substitution occurred at the aromatic ring to give
the transition state C. This step might be the rate-determining
step, and the intramolecular attack would lower the activation
Synthesis of Benzolactam-V8. Benzolactam-V8 (Figure 1)
is a core structure of a new class of protein kinase C activators.11
Although the activity of benzolactam-V8 itself is not so potent,
its derivatives with a side chain at the 8 or 9 position showed
potency similar to that of teleocidin B4.11 From benzolactam-
(22) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; Wiley:
New York, 1961; Vol. 1; p 569.

Synthesis of Benzolactam-V8
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12463
Scheme 3a
Scheme 2a
a Reagents: (a) ClCOOMe, then NaBH4; (b) NaOH, then BnBr; (c)
CuI, K2CO3, DMA, 90 °C, 48 h.
a Reagents and conditions: (a) DCC, HOBt, Et3N, CH2Cl2, rt, 82%;
(b) NaBH3CN, 37% HCHO, AcOH, CH3CN, 0 °C, 83%; (c) (i) 1 N
NaOH, (ii) NaH, BnBr, (iii) 1 N NaOH; (d) (i) EDC, HOBt, diethyl
aminomalonate hydrochloride, Et3N, CH2Cl2, rt, 81%; (ii) Pd/C, H2,
42%; (e) MsCl, Et3N; (f) PBu3, ADDP, 32%; (g) t-BuOK, THF, 50%.
V8, 8-decynyl-benzolactam-V8 (DM50) (Figure 1) was syn-
thesized through iodination followed by a Pd-catalyzed coupling
reaction with 1-decyne.11b Biological studies indicated that
DM50 could selectively downregulate PKCâ in MCF-7 and
MDA-231 cells and had antiproliferative activity against breast
carcinoma cell lines MCF-7 and MDA-MB-231.11b However,
previous synthesis of benzolactam-V8, using the SN2 displace-
ment11 of chiral triflate derived from D-valine with arylamine
to introduce the N-aryl-valine moiety, was not very efficient.
After being successful in directly coupling of L-valine with aryl
halides, we believed that the present methodology could provide
us a good chance to develop a new synthetic protocol to
benzolactam-V8 and its derivatives. Thus, the studies on the
CuI-catalyzed coupling reaction of L-valine or N-methyl-L-valine
with some ortho-substituted iodobenzenes were conducted.
As outlined in Scheme 2, 2-iodobenzoic acid was reduced to
2-iodobenzyl alcohol (22) with ClCOOMe/NaBH4. Considering
that the hydroxy group could give some trouble in further
transformation, it was protected with benzyl group to afford
23. Initially, the coupling reaction of N-methyl-L-valine with
22 under the above typical conditions was tried. Like the
coupling of N-methyl-L-valine with bromobenzene (Table 1,
entry 8), coupling product 24 was obtained in lower yield. Next,
the reaction of 23 and L-valine was carried out to produce 25.
However, the yield (47%) was still not satisfactory. Finally, it
was found that the coupling reaction of 22 with L-valine could
provide the desired product 26 in high yield (86%).
To introduce the amino alcohol moiety necessary for syn-
thesizing benzolactam-V8, some functional groups in 26 should
be protected in advance. Thus, 26 was lactonized with DCC
and then reduction methylation was carried out with NaBH3-
CN and HCHO to produce 27. After the lactone ring was
opened by aqueous NaOH, the resultant sodium salt was dried
and then directly reacted with 1 equiv of benzyl bromide under
the action of sodium hydride to afford acid 28 in 90% overall
yield. Condensation of 28 with diethyl aminomalonate under
the ordinary conditions followed by removal of the benzyl
protecting group by Pd/C-catalyzed hydrogenation afforded the
alcohol 29. At this stage, we planned to build an eight-
membered lactam ring by an intramolecular alkylation. It was
reported23 that PBu3/ADDP could promote the alkylation of
malonate esters with suitable alcohols. Under similar conditions,
cyclization of 29 was tried. However, no desired product 31
was obtained but a side product 32 was isolated. Base-mediated
alkylation of 30 was also tried. Unfortunately, the similar
undesired result was observed (Scheme 3).
Because the intramolecular alkylation was not successful in
obtaining product 31, another route was designed to synthesize
the target molecule in which the cyclization would be carried
out by amide bond formation (Scheme 4). Accordingly, the
lactone 27 was treated with 1 equiv of NaOH to open the ring
and then the resultant sodium salt was reacted with benzyl
bromide to afford ester 33. Subjecting 33 to Swern oxidation
produced aldehyde 34, which was condensed with methyl
2-nitroacetate under the action of TiCl4 and NMM to furnish
1
olefin 35.24 By H NMR it was found that both cis and trans
isomers were formed in a ratio of about 1/1.7 and the mixture
was directly used for the next step without further separation.
Next, reduction of the CdC double bond and nitro group and
deprotection of benzyl ester were carried out in one pot by Pd/
C-catalyzed hydrogenation to yield crude amino acid, which
was cyclized under the action of DPPA to afford a mixture of
diastereoisomers 36 (35% overall yield from 35) and 37 (17%
overall yield from 35). Finally, LiBH4 reduction of 37 afforded
benzolactam-V8 in 88% yield. The overall yield was about
17.7% from L-valine, which was better than either of the
previous two synthetic routes11 (overall yields are 7% and
(23) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
1639.
(24) Lehnert, W. Tetrahedron 1972, 28, 663.

12464 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Ma et al.
Scheme 4a
reactions were run in flame-dried glassware under nitrogen atmosphere
unless stated otherwise.
General Procedure for the CuI-Catalyzed Coupling Reaction of
Amino Acids with Aryl Halides. A Schlenk tube was charged with
amino acid (3.2 mmol), aryl halide (3.2 mmol), K2CO3 (4.8 mmol),
and CuI (0.32 mmol). Under N2 atmosphere, DMA (4 mL) was added
by syringe. The tube was sealed and heated at 90 °C for 48 h. After
being cooled to room temperature, the reaction mixture was diluted
with 10 mL of ethyl acetate and 5 mL of water. Under cooling with
ice/water, concentrated HCl was added to adjust the pH to 3. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (5 × 20 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated to dryness by
Rotavapor. The residual oil was loaded on a silica gel column and
eluted with ethyl acetate/petroleum ether (1/5 to 1/1) to afford the
coupling product.
N-Phenyl-L-valine (1): 81% yield; [R]D25 ) -49.1 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.18 (t, J ) 7.8 Hz, 2H), 6.68 (t, J )
7.5 Hz, 1H), 6.65 (d, J ) 7.8 Hz, 2H), 3.89 (d, J ) 5.4 Hz, 1H), 2.18
(m, 1H), 1.05 (d, J ) 9.4 Hz, 6H); MS m/z 193 (M+), 150, 148, 132,
104; HRMS found m/z 193.167 (M+), C11H15NO2 requires 193.167.
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.24. Found: C,
68.06; H, 7.76, N, 6.88.
N-Phenyl-D-valine (2): 75% yield; [R]D25 ) +47.2 (c 0.11, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.18 (t, J ) 7.8 Hz, 2H), 6.68 (t, J )
7.5 Hz, 1H), 6.65 (d, J ) 7.8 Hz, 2H), 3.89 (d, J ) 5.4 Hz, 1H), 2.18
(m, 1H), 1.05 (d, J ) 9.4 Hz, 6H); MS m/z 193 (M+), 150, 148, 132,
104, 77, 43; HRMS found m/z 193.168 (M+), C11H15NO2 requires
193.167.
N-Phenyl-L-proline (3): 80% yield; [R]D25 ) -46.8 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.05 (t, J ) 8.2 Hz, 2H), 6.79 (t, J )
7.6 Hz, 1H), 6.64 (d, J ) 8.3 Hz, 2H), 4.23 (dd, J ) 8.5, 3.0 Hz, 1H),
3.30 (t, J ) 7.2 Hz, 2H), 2.35 (m, 2H), 2.12 (m, 2H); MS m/z 191
(M+), 146, 117, 104, 77. Anal. Calcd for C11H13NO2: C, 69.13; H,
6.81; N, 7.33. Found: C, 68.81; H, 6.97; N, 7.11.
a Reagents and conditions: (a) 1 N NaOH, then BnBr, 98%; (b)
oxalyl chloride, DMSO, -65 °C, then Et3N 97%; (c) MeOOCCH2NO2,
TiCl4, then NMM, 82%; (d) (i) Pd/C, H2, MeOH, (ii) DPPA, DMF,
35% for 36, 17% for 37; (e) LiBH4, THF, 88%.
25
N-Phenyl-N-methyl-L-valine (4): 46% yield; [R]D ) -88.6 (c
0.93, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.28 (t, J ) 7.8 Hz, 2H),
6.98 (d, J ) 7.9 Hz, 2H), 6.82 (t, J ) 7.8 Hz, 1H), 3.95 (d, J ) 10.1
Hz, 1H), 3.07 (s, 3H), 2.29 (m, 1H), 1.01 (d, J ) 6.9 Hz, 3H), 0.92 (d,
J ) 6.9 Hz, 3H); MS m/z 207 (M+), 176, 162, 146, 120, 106, 91, 77,
42; HRMS found m/z 206.1185 (M+ - 1), C12H16NO2 requires
206.1182.
10.3%, respectively). It is obvious that we could synthesize 8-
or 9-substituted analogues of benzolactam-V8 by this methodol-
ogy if we started from a suitable substituted 2-iodobenzyl
alcohol. Thus, the discovery of the present reaction provides
us a very efficient protocol to synthesize this class of compounds
with potential therapeutic value.
In summary, we have found CuI is an effective catalyst for
direct coupling of aryl halides and R-amino acids under
relatively mild conditions. This reaction provides a short and
economic way to synthesize chiral N-aryl-R-amino acids, which
are common core structures for a number of biologically
important molecules. The discovery of the accelerating effect
induced by the structure of the R-amino acid for the Ullmann
condensation reaction would be of benefit for its mechanism
studies, as well as catalyst design for aryl amination at lower
temperature. Using this methodology to synthesize other
complex molecules such as substituted benzolactam-V8 as well
as the detailed mechanism studies are being pursued in our
laboratory and will be reported in due course.
N-Phenyl-L-phenylalanine (5): 92% yield; [R]D25 ) +2.5 (c 0.50,
CH3COCH3); 1H NMR (300 MHz, CDCl3) δ 7.05 (t, J ) 8.2 Hz, 2H),
6.79 (t, J ) 7.6 Hz, 1H), 6.64 (d, J ) 8.3 Hz, 2H), 4.23 (dd, J ) 8.5,
3.0 Hz, 1H), 3.30 (t, J ) 7.2 Hz, 2H), 2.35 (m, 2H), 2.12 (m, 2H); MS
m/z 191 (M+), 146, 117, 104, 77. Anal. Calcd for C15H15NO2: C,
74.70; H, 6.22; N, 5.81. Found: C, 74.38; H, 6.51, N, 5.58.
N-Phenyl-L-alanine (6): 65% yield; [R]D25 ) -44.8 (c 0.84, CH3-
1
COCH3); H NMR (300 MHz, CDCl3) δ 7.22 (t, J ) 7.5 Hz, 2H),
6.78 (t, J ) 7.4 Hz, 1H), 6.62 (d, J ) 8.2 Hz, 2H), 5.70 (br s, 2H),
4.13 (q, J ) 7.2 Hz, 1H), 1.53 (d, J ) 7.2 Hz, 3H); MS m/z 165 (M+),
120, 104, 91, 77, 65, 51, 42. Anal. Calcd for C9H11NO2: C, 65.48;
H, 6.67; N, 8.48. Found: C, 65.51; H, 6.73; N, 8.55.
N-Phenyl-L-methionine (7): 76% yield; [R]D25 ) -11.8 (c 1.0, CH3-
1
COCH3); H NMR (300 MHz, CD3SOCD3) δ 7.06 (t, J ) 8.1 Hz,
2H), 6.56 (d, J ) 7.5 Hz, 2H), 6.54 (m, 1H), 3.99 (dd, J ) 7.1, 5.2 Hz,
1H), 2.58 (m, 2H), 2.05 (s, 3H), 1.96 (m, 2H); MS m/z 225 (M+), 207,
192, 180, 159, 132, 118, 104, 91, 77, 61, 43; HRMS found m/z 225.0813
(M+), C11H15NO2S requires 225.0821.
Experimental Section
N-Phenyl-L-tyrosine (8): 60% yield; [R]D25 ) +23.9 (c 0.86, CH3-
OH); 1H NMR (300 MHz, CD3SOCD3) δ 7.09-7.02 (m, 4H), 6.64(d,
J ) 8.2 Hz, 2H), 6.53 (d, J ) 8.2 Hz, 2H), 6.50 (m, 1H), 4.00 (t, J )
7.6 Hz, 1H), 2.92 (dd, J ) 13.9, 7.0 Hz, 1H), 2.85 (dd, J ) 12.8, 7.0
Hz, 1H); MS m/z 257 (M+), 212, 150, 132, 118, 104, 91, 77, 51. Anal.
Calcd for C15H15NO3: C, 70.03; H, 5.88; N, 5.44. Found: C, 70.05;
H, 5.85; N, 5.21.
General Procedures. IR spectra were measured on a Schimadzu
440 spectrometer. 1H NMR spectra were recorded with TMS as an
internal standard at a Brucker AM-300 spectrometer. MS spectra were
determined on a Finnigan 4201 spectrometer or a VG Quattro MS/MS
spectrometer. Optical rotations were obtained on a Perkin-Elmer 241
Autopol polarimeter. Analytically pure DMF, DMA and NMPO were
used directly without further purification. CH2Cl2 was distilled from
CaH2, and THF was distilled from a deep blue ketyl prior to use. All
other solvents were of reagent grade quality and used as received. Na2-
SO4 was used as the drying agent in all workup procedures. All
N-Phenyl-L-tryptophen (9): 73% yield; [R]D25 ) +9.2 (c 0.77, CH3-
1
OH); H NMR (300 MHz, CD3SOCD3) δ 10.86 (s, 1H), 7.56 (d, J )
7.6 Hz, 1H), 7.34 (d, J ) 7.6 Hz, 1H), 7.20 (d, J ) 1.9 Hz, 1H), 7.08-
6.93 (m, 4H), 6.57 (d, J ) 8.4 Hz, 2H), 6.53 (t, J ) 7.4 Hz, 1H), 4.15

Synthesis of Benzolactam-V8
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12465
25
(t, J ) 7.1 Hz, 1H), 3.24 (dd, J ) 14.4, 6.0 Hz, 1H), 3.12 (dd, J )
14.4, 6.4 Hz, 1H); MS m/z 225 (M+), 207, 192, 180, 159, 132, 118,
104, 91, 77, 61, 43; HRMS found m/z 225.0813 (M+), C11H15NO2S
requires 225.0821.
N-(2′-Benzyloxymethylphenyl)-L-valine (25): 47% yield; [R]D
)
-13.8 (c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m,
5H), 7.21 (t, J ) 7.7 Hz, 1H), 7.08 (d, J ) 7.6 Hz, 1H), 6.73 (t, J )
7.7 Hz, 1H), 6.59 (d, J ) 7.8 Hz, 1H), 4.67 and 4.60 (AB q, d, J )
12.0 Hz, 2H), 4.52 and 4.45 (AB q, d, J ) 11.5 Hz, 1H), 3.86 (d, J )
5.6 Hz, 1H), 2.19 (m, 1H), 1.02 (d, J ) 7.1 Hz, 3H), 1.00 (d, J ) 7.1
Hz, 3H); MS m/z 313 (M+), 237, 219, 199, 183, 150, 135, 122, 107,
91, 77, 51; HRMS found m/z 313.1663 (M+), C19H23NO3 requires
25
N-(3′-Methoxyphenyl)-L-valine (10): 85% yield; [R]D ) -38.5
1
(c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.12 (t, J ) 8.1 Hz,
1H), 6.33 (dd, J ) 8.1, 2.1 Hz, 1H), 6.27 (dd, J ) 8.1, 2.0 Hz, 1H),
6.21 (t, J ) 2.0 Hz, 1H), 3.87 (d, J ) 7.6 Hz, 1H), 3.76 (s, 3H), 2.19
(m, 1H), 1.05 (d, J ) 7.2 Hz, 6H); MS m/z 223 (M+), 178, 162, 152,
134, 123, 107, 92, 83, 77, 43; HRMS found m/z 223.1175 (M+), C12H17-
NO3 requires 223.1204.
313.1678.
25
N-(2′-Hydroxymethylphenyl)-L-valine (26): 86% yield; [R]D
)
-59.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.21 (t, J ) 7.8
Hz, 1H), 7.07 (dd, J ) 7.7, 1.5 Hz, 1H), 6.71 (t, J ) 7.7 Hz, 1H), 6.59
(d, J ) 7.8 Hz, 1H), 4.95 (br s, 3H), 4.72 and 4.67 (AB q, d, J ) 12.3
Hz, 2H), 3.86 (d, J ) 5.6 Hz, 1H), 2.23 (m, 1H), 1.06 (d, J ) 7.1 Hz,
6H); MS m/z 223 (M+), 206, 134, 107, 77, 43; HRMS found m/z
223.1198 (M+), C12H17NO3 requires 223.1209.
General Procedure for the Catalytic Coupling Reaction of
Benzylamine or (S)-Valinol with Aryl Halides. A mixture of amine
(3.2 mmol), aryl halide (3.2 mmol), K2CO3 (4.8 mmol), CuI (0.32
mmol), and DMA (4 mL) in a sealed tube was heated at 110 °C for 32
h. After being cooled to room temperature, the reaction mixture was
diluted with 30 mL of 1/2 ethyl acetate/petroleum ether and 10 mL of
water. The organic layer was separated, washed with brine, dried over
Na2SO4, and concentrated to dryness by Rotavapor. The residual was
chromatographed to afford the coupling product and starting material.
N-(4′-Carboxyphenyl)-L-valine (11): 75% yield; [R]D25 ) -114.1
(c 0.93, CH3COCH3); 1H NMR (300 MHz, CD3SOCD3) δ 12.35 (br s,
1H), 7.65 (d, J ) 8.4 Hz, 2H), 6.63 (d, J ) 8.4 Hz, 2H), 3.73 (m, 1H),
2.06 (m, 1H), 1.00 (d, J ) 7.2 Hz, 3H), 0.96 (d, J ) 7.2 Hz, 3H); MS
m/z 237 (M+), 220, 192, 176, 148, 132, 121, 104, 77, 65, 44. Anal.
Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.94;
H, 6.40; N, 6.01.
N-(2′,6′-Dimethylphenyl)-L-alanine (12): 74% yield; [R]D
+39.6 (c 0.50, CHCl3); H NMR (300 MHz, CDCl3) δ 6.98 (d, J )
7.5 Hz, 2H), 6.83 (t, J ) 7.6 Hz, 1H), 5.25 (br s, 2H), 3.97 (q, J ) 7.2
Hz, 1H), 2.29 (s, 6H), 1.42 (d, J ) 7.1 Hz, 3H); MS m/z 193 (M+),
132, 118, 105, 91, 77, 65, 51, 44; HRMS found m/z 193.1076 (M+),
C11H15NO2 requires 193.1100.
25
)
1
25
N-(4′-Chlorophenyl)-L-valine (13): 83% yield; [R]D ) -47.8 (c
25
(S)-N-Phenylvalinol: 5% yield; [R]D ) -29.6 (c 0.84, CHCl3);
1
0.94, CHCl3); H NMR (300 MHz, CDCl3) δ 7.12 (d, J ) 8.2 Hz,
1H NMR (300 MHz, CDCl3) δ 7.16 (t, J ) 7.8 Hz, 2H), 6.73 (t, J )
7.7, 1H), 6.66 (d, J ) 7.7 Hz, 2H), 3.77 (dd, J ) 10.8, 4.2 Hz, 1H),
3.53 (dd, J ) 10.8, 6.9 Hz, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 0.98 (d,
J ) 7.1 Hz, 3H), 0.95 (d, J ) 7.2 Hz, 3H); MS m/z 179 (M+), 148,
136, 118, 92, 77, 55, 43; HRMS found m/z 179.1302 (M+), C11H17NO
requires 179.1311.
2H), 6.58 (d, J ) 8.2 Hz, 2H), 6.28 (br s, 2H), 3.83 (d, J ) 5.6 Hz,
1H), 2.17 (m, 1H), 1.06 (d, J ) 6.5 Hz, 6H); MS m/z 229 (M+, 37Cl),
227 (M+, 35Cl), 184, 182, 166, 147, 140, 138, 127, 111, 99, 75, 55, 43;
HRMS found m/z 227.0743 (M+, 35Cl), C11H14ClNO2 requires 227.0714.
25
N-(3′-Carboxyphenyl)-L-valine (14): 92% yield; [R]D ) -59.7
1
(c 1.1, CH3COCH3); H NMR (300 MHz, CDCl3) δ 7.46 (d, J ) 7.7
Lactone 27. To a solution of 26 (8.31 g, 36.7 mmol) in 100 mL of
anhydrous methylene chloride was added triethylamine (5.5 mL, 40.4
mmol) and HOBt (4.90 g, 36.7 mmol). The resultant mixture was
cooled with ice/water, and a solution of DCC (7.60 g, 36.7 mmol) in
50 mL of methylene chloride was added dropwise. After the addition,
the solution was allowed to be stirred at room temperature overnight.
The resultant solid was filtered off, and the filtrate was washed with
water and brine, dried over Na2SO4, and concentrated to dryness to
give an oily product (6.2 g, 82% crude yield).
The above oil was dissolved in 60 mL of acetonitrile and then 37%
aqueous HCHO (24 mL) and NaBH3CN (7.2 g, 114 mmol) were added.
The solution was cooled with ice/water, and a solution of AcOH (5
mL) in 10 mL of acetonitrile was added dropwise. After being stirred
at this temperature for 30 min, the reaction mixture was warmed to
room temperature and stirring was continued overnight. Ether extract
workup followed by column chromatography (silica gel, 1/5 ethyl
Hz, 1H), 7.43 (s, 1H), 7.24 (t, J ) 7.7 Hz, 1H), 6.88 (dd, J ) 7.9, 2.0
Hz, 1H), 3.95 (d, J ) 5.7 Hz, 1H), 2.20 (m, 1H), 1.09 (d, J ) 6.9 Hz,
6H); MS m/z 237 (M+), 192, 176, 148, 132, 121, 103, 93, 77, 43; HRMS
found m/z 237.0982 (M+), C12H15NO4 requires 237.1001.
25
N-(2′-Carboxyphenyl)-L-valine (15): 83% yield; [R]D ) -89.9
1
(c 1.1, CH3COCH3); H NMR (300 MHz, CDCl3) δ 8.00 (d, J ) 7.8
Hz, 1H), 7.41 (t, J ) 7.5 Hz, 1H), 6.68 (t, J ) 7.6 Hz, 1H), 6.65 (d,
J ) 7.7 Hz, 1H), 4.03 (d, J ) 5.1 Hz, 1H), 2.33 (m, 1H), 1.13 (d, J )
6.9 Hz, 3H), 1.10 (d, J ) 6.9 Hz, 3H); MS m/z 237 (M+), 192, 174,
148, 132, 119, 104, 92, 65, 43; HRMS found m/z 237.1009 (M+),
C12H15NO4 requires 237.1001.
N-(2′,5′-Dimethylphenyl)-L-valine (16): 74% yield; [R]D25 ) -41.5
1
(c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 6.95 (d, J ) 7.6 Hz,
1H), 6.55 (d, J ) 7.7 Hz, 1H), 6.40 (s, 1H), 6.10 (br s, 2H), 3.92 (d,
J ) 5.4 Hz, 1H), 2.27 (s, 3H), 2.24 (m, 1H), 2.18 (s, 3H), 1.11 (d, J
) 6.9 Hz, 3H), 1.09 (d, J ) 6.9 Hz, 3H); MS m/z 221 (M+), 178, 132,
104, 65, 45; HRMS found m/z 221.1414 (M+), C13H19NO2 requires
221.1416.
25
acetate/petroleum ether as eluent) afforded 5.47 g (82%) of 27: [R]D
) -519 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.24 (t, J )
1
7.6 Hz, 1H), 7.05 (d, J ) 7.6 Hz, 1H), 7.03 (d, J ) 7.6 Hz, 1H), 6.87
(t, J ) 7.5 Hz, 1H), 5.55 and 5.00 (AB q, d, J ) 14.9 Hz, 2H), 3.79
(d, J ) 10.3 Hz, 1H), 2.81 (s, 3H), 2.27 (m, 1H), 1.03 (d, J ) 7.0 Hz,
3H), 1.00 (d, J ) 7.0 Hz, 3H); MS m/z 219 (M+), 192, 175, 148, 132,
117, 105, 91, 77, 43; HRMS found m/z 219.1233 (M+), C13H17NO2
requires 219.1256.
N-(2′,6′-Dimethylphenyl)-L-valine (17): 14% yield; [R]D25 ) +9.5
1
(c 0.86, CHCl3); H NMR (300 MHz, CDCl3) δ 6.95 (d, J ) 7.8 Hz,
2H), 6.78 (t, J ) 7.8 Hz, 1H), 3.80 (d, J ) 5.7 Hz, 1H), 2.29 (s, 6H),
2.13 (m, 1H), 1.14 (d, J ) 6.9 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H); MS
m/z 221 (M+), 178, 132, 120, 105, 77, 65; HRMS found m/z 221.1415
(M+), C13H19NO2 requires 221.1416.
(S)-N-Methyl-N-(2′-benzyloxymethylphenyl)valine (28). A mix-
ture of 27 (4.21 g, 19.3 mmol), 20 mL of 1 N NaOH, and 40 mL of
THF was stirred at room temperature until the starting material
disappeared as monitored by TLC. The solution was concentrated, and
the residual solid was dried in vacuo for 4 h and then dissolved in 120
mL of anhydrous THF. To this solution, NaH (60%, 1.5 g, 38.6 mmol)
was added and the mixture was stirred until no more bubbles appeared.
After cooling with ice/water, benzyl bromide (2.5 mL, 21.2 mmol) was
added and the reaction mixture was stirred overnight. The solution
was acidified to pH 2 by adding 1 N HCl and extracted with ethyl
acetate (3 × 150 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated via Rotavapor. The residual
oil was chromatographed (silica gel, 1/3 ethyl acetate/petroleum ether
as eluent) to afford 5.40 g (90%) of 28: [R]D25 ) -4.8 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.43 (d, J ) 7.6 Hz, 1H), 7.39-7.19
N-(2′-Methoxyphenyl)-L-valine (18a): 83% yield; [R]D25 ) -12.0
(c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.82 (dt, J ) 7.8, 1.4
Hz, 1H), 6.76 (dd, J ) 7.7, 1.4 Hz, 1H), 6.72 (dt, J ) 7.7, 1.4 Hz,
1H), 6.56 (dd, J ) 7.6, 1.4 Hz, 1H), 5.89 (br s, 2H), 3.86 (s, 3H), 3.83
(d, J ) 5.8 Hz, 1H), 2.24 (m, 1H), 1.08 (d, J ) 6.9 Hz, 3H), 1.06 (d,
J ) 6.9 Hz, 3H); MS m/z 223 (M+), 179, 148, 136, 121, 107, 92, 77,
65; HRMS found m/z 223.1203 (M+), C12H17NO3 requires 223.1204.
N-Methyl-N-(2′-hydroxymethylphenyl)-L-valine (24): 17% yield;
[R]D25 ) +17.0 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.27-
7.08 (m, 4H), 6.10 (br s, 2H), 4.94 and 4.63 (AB q, d, J ) 12.9 Hz,
2H), 3.64 (d, J ) 6.9 Hz, 1H), 2.77 (s, 3H), 2.16 (m, 1H), 1.08 (d, J
) 7.2 Hz, 3H), 0.95 (d, J ) 7.2 Hz, 3H); MS m/z 237 (M+), 220, 192,
176, 148, 136, 120, 106, 91, 77; HRMS found m/z 237.1355 (M+),
C13H19NO3 requires 237.1365.

12466 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Ma et al.
(m, 7H), 7.15 (t, J ) 7.5 Hz, 1H), 4.69 and 4.63 (AB q, d, J ) 13.7
Hz, 2H), 4.61 (s, 2H), 3.57 (d, J ) 8.5 Hz, 1H), 2.78 (s, 3H), 2.19 (m,
1H), 1.12 (d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 7.1 Hz, 3H); MS m/z 328
(M+ + H+), 310, 282, 236, 220, 190, 148, 132, 91, 77, 43; HRMS
found m/z, 327.1825 (M+), C20H25NO3 requires 327.1835.
-78 °C. After stirring for 15 min from -78 to -65 °C, a solution of
33 (100 mg, 0.3 mmol) in 3 mL of methylene chloride was added. The
resultant reaction mixture was stirred for 30 min at -65 °C for 30
min, and then 0.2 mL of triethylamine was added by syringe. The
solution was allowed to warm to room temperature, and then water
was added to quench the reaction. After being extracted with methylene
chloride, the crude product was chromatographed to afford 96 mg (97%)
of aldehyde 34: [R]D ) -127 (c 1.2, CHCl3); H NMR (300 MHz,
CDCl3) δ 10.21 (s, 1H), 7.70 (dd, J ) 7.7, 1.6 Hz, 1H), 7.29 (t, J )
7.7 Hz, 1H), 7.27 (m, 2H), 7.13 (m, 2H), 7.06 (d, J ) 7.6 Hz, 2H),
6.97 (d, J ) 7.7 Hz, 1H), 5.04 and 4.96 (AB q, d, J ) 12.6 Hz, 2H),
3.42 (d, J ) 10.6 Hz, 1H), 2.92 (s, 3H), 2.25 (m, 1H), 1.07 (d, J ) 6.9
Hz, 3H), 0.87 (d, J ) 6.8 Hz, 3H); MS m/z 326 (M+ + H+), 296, 254,
190, 172, 146, 132, 91, 77, 42; HRMS found m/z 325.1671 (M+),
C20H23NO3 requires 325.1679.
Condensation of 28 with Diethyl Aminomalonate. In a 500-mL
bottle were placed diethyl aminomalonate hydrochloride (5.11 g, 24.1
mmol) and 150 mL of anhydrous methylene chloride. The suspension
solution was stirred, and triethylamine (9 mL, 66.2 mmol) was added.
After the stirring was continued for 30 min, the solution was cooled
with ice/water and then HOBt (2.60 g, 19.3 mmol), and 28 (5.30 g,
16.2 mmol) were added, respectively. To this stirred solution was added
a solution of EDC (3.71 g, 19.3 mmol) in 20 mL of methylene chloride
dropwise. After the addition, the reaction mixture was allowed to warm
to room temperature and stirred overnight. Water (100 mL) was added
to quench the reaction and organic layer was separated. The aqueous
layer was extracted with methylene chloride (2 × 100 mL), and the
combined organic layers were washed with water and dried over Na2-
SO4. After removal of solvent, the residue was loaded onto a silica
gel column and eluted with 1/3 ethyl acetate/petroleum ether to afford
6.31 g (81%) of condensed product, which was dissolved in 100 mL
of ethanol, and then 0.6 g of 10% Pd/C was introduced. The suspension
solution was stirred under hydrogen (55 atm) at 50 °C for 2 days. The
catalyst was filtered off, and the filtrate was condensed via Rotavapor.
25
1
Condensation of 34 with Methyl 2-Nitroacetate. At room
temperature, TiCl4 (0.5 mL, 4.8 mmol) was added to 5 mL of 1,4-
dioxane and a yellow solid was formed immediately. To this suspension
was added a solution of 34 (200 mg, 0.6 mmol) and methyl
2-nitroacetate (0.06 mL, 0.6 mmol) in 2 mL of 1,4-dioxane dropwise.
After stirring for 2 h at room temperature, NMM (1 mL, 9.6 mmol)
was added slowly. The reaction mixture was stirred for another 2 h
and then partitioned between 20 mL of ethyl acetate and 20 mL of
water. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated.
Chromatography (silica gel, 1/10 ethyl acetate/petroleum ether as eluent)
of the residual oil afforded 210 mg (82%) of the olefin 35 as a mixture
25
Chromatography of the residual oil afforded 2.67 g (52%) of 29: [R]D
1
) -8.4 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.36 (d, J )
7.5 Hz, 1H), 7.24-7.04 (m, 4H), 5.05 (d, J ) 7.0 Hz, 1H), 4.97 and
4.63 (AB q, d, J ) 12.5 Hz, 2H), 4.20 (m, 4H), 3.51 (d, J ) 8.1 Hz,
1H), 2.74 (s, 3H), 2.30 (m, 1H), 1.28 (t, J ) 7.2 Hz, 3H), 1.23 (t, J )
7.2 Hz, 3H), 1.10 (d, J ) 7.1 Hz, 3H), 0.96 (d, J ) 7.2 Hz, 3H); MS
m/z 395 (M+ + H+), 377, 349, 192, 174, 148, 95, 77, 43; HRMS found
m/z 394.2122 (M+), C20H30N2O6 requires 394.2105.
Mitsunobu Reaction of 29. Under nitrogen atmosphere, alcohol
29 (50 mg, 0.13 mmol) and tributyl phosphine (60 µL, 0.23 mmol)
were dissolved in 5 mL of dry THF. The solution was cooled with
ice/water and then ADDP (50 mg, 0.21 mmol) was added. After 10
min, the reaction mixture was warmed to room temperature and the
stirring was continued for 24 h. Hexane was added to the reaction
mixture and the dihydro-ADDP separated out was filtered off. After
25
1
of cis and trans isomers: [R]D ) -160 (c 0.74, CHCl3); H NMR
(300 MHz, CDCl3) δ 8.30 (s, 0.37H), 7.86 (s, 0.63H), 7.20 (m, 5H),
7.08-6.86 (m, 4H), 4.95 (s, 1.26H), 4.90 (s, 0.74H), 3.80 (s, 1.89H),
3.62 (s, 1.11H), 3.25 (d, J ) 10.5 Hz, 0.63H), 3.20 (d, J ) 10.5 Hz,
0.37H), 2.85 (s, 1.11H), 2.82 (s, 1.89H), 2.27 (m, 1H), 1.08 (d, J )
6.9 Hz, 1.89 H), 1.03 (d, J ) 7.0 Hz, 1.11H), 0.83 (d, J ) 6.9 Hz,
1.89H), 0.79 (d, J ) 7.0 Hz, 1.11H); MS m/z 426 (M+), 410, 383,
291, 222, 202, 174, 132, 91, 43; HRMS found m/z 426.1775 (M+),
C23H26N2O6 requires 426.1791.
Esters 36 and 37. A suspension of 35 (350 mg, 0.8 mmol) and 30
mg of 10% Pd/C in 20 mL of methanol was stirred under hydrogen
(40 atm) at room temperature for 3 days. The catalyst was filtered
off, and the filtrate was condensed via Rotavapor. The resultant white
solid was dried in vacuo for 1 day and then dissolved in 80 mL of dry
DMF. The solution was cooled with ice/water and then triethylamine
(0.22 mL, 1.6 mmol) and DPPA (0.21 mL, 0.96 mmol) were added,
respectively. After the reaction mixture was stirred for 18 h, the solvent
was removed at reduced pressure. The residue was partitioned between
80 mL of ethyl acetate and 20 mL of water, and then the organic layer
was separated, washed with water and brine, and dried over Na2SO4.
After removal of solvent, the residual oil was chromatographed (silica
gel, 1/4 ethyl acetate/petroleum ether as eluent) to afford 80 mg (35%)
of 36 and 39 mg (17%) of 37.
36: [R]D25 ) -145 (c 0.77, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.24 (t, J ) 7.8 Hz, 1H), 7.14 (d, J ) 7.7 Hz, 1H), 7.09 (d, J ) 7.7
Hz, 1H), 6.95 (t, J ) 7.6 Hz, 1H), 6.26 (m, 1H), 5.20 (m, 1H), 3.82 (s,
3H), 3.58 (dd, J ) 16.3, 4.2 Hz, 1H), 3.36 (d, J ) 7.3 Hz, 1H), 2.97
(dd, J ) 16.4, 8.7 Hz, 1H), 2.77 (s, 3H), 2.38 (m, 1H), 1.09 (d, J )
6.9 Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H); MS m/z 290 (M+), 263, 247,
219, 204, 159, 132, 117, 91, 77, 42; HRMS found m/z 290.1650 (M+),
C16H22N2O3 requires 290.1632.
evaporating the filtrate under reduced procedure, the residual oil was
25
purified by chromatography to afford 15 mg (32%) of 32: [R]D
)
-163 (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.16 (t, J ) 7.8
Hz, 1H), 6.98 (d, J ) 7.8 Hz, 1H), 6.91 (d, J ) 7.6 Hz, 1H), 6.78 (t,
J ) 7.7 Hz, 1H), 6.06 (s, 1H), 5.19 (d, J ) 17.6 Hz, 1H), 4.35 (d, J )
17.7 Hz, 1H), 4.23 (m, 2H), 3.92 (m, 1H), 3.80 (d, J ) 8.9 Hz, 1H),
3.71 (m, 1H), 2.80 (s, 3H), 2.33 (m, 1H), 1.25 (t, J ) 6.9 Hz, 3H),
1.00 (d, J ) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 0.85 (t, J ) 6.8
Hz, 3H); MS m/z 377 (M+ + H+), 333, 305, 219, 189, 161, 120, 92,
78, 63, 45; HRMS found m/z 376.2010 (M+), C20H28N2O5 requires
376.1999.
(S)-N-Methyl-N-(2′-hydroxymethylphenyl)valine, Benzyl Ester
(33). A mixture of lactone 27 (1.5 g, 6.8 mmol) and 1 N NaOH (6.8
mL, 6.8 mmol) in 20 mL of THF was stirred at room temperature for
3 h. After the solution was concentrated, the obtained residual solid
was dried in vacuo for 10 h and then dissolved in 15 mL of anhydrous
DMF. The solution was cooled with ice/water, and then benzyl bromide
(0.9 mL, 7.4 mmol) was added. The stirring was continued at room
temperature for 18 h, and the reaction mixture was partitioned between
70 mL of ethyl acetate and 30 mL of water. The organic layer was
washed with water and brine and dried over Na2SO4. After the removal
of solvent, the residual oil was chromatographed to afford 2.2 g (98%)
of 33: [R]D25 ) +27.9 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.21 (m, 4H), 7.05 (m, 5H), 4.93 and 4.86 (AB q, d, J ) 12.4 Hz, 2H),
4.84 and 4.45 (AB q, d, J ) 12.8 Hz, 2H), 3.78 (br s, 1H), 3.35 (d, J
) 9.2 Hz, 1H), 2.71 (s, 3H), 2.20 (m, 1H), 1.03 (d, J ) 6.8 Hz, 3H),
0.85 (d, J ) 6.8 Hz, 3H); MS m/z 327 (M+), 310, 284, 192, 174, 148,
118, 95, 77, 43; HRMS found m/z 327.1834 (M+), C20H25NO3 requires
327.1836.
25
1
37: [R]D ) -93.6 (c 0.47, CHCl3); H NMR (300 MHz, CDCl3)
δ 7.23 (t, J ) 7.8 Hz, 1H), 7.21 (d, J ) 7.5 Hz, 1H), 7.19 (d, J ) 7.6
Hz, 1H), 6.98 (t, J ) 7.7 Hz, 1H), 6.44 (d, J ) 6.4 Hz, 1H), 4.37 (t,
J ) 6.6 Hz, 1H), 3.82 (s, 3H), 3.23 (d, J ) 15.2 Hz, 1H), 3.07 (dd, J
) 15.6, 6.9 Hz, 1H), 3.03 (d, J ) 10.2 Hz, 1H), 2.91 (s, 3H), 2.44 (m,
1H), 0.96 (d, J ) 6.7 Hz, 3H), 0.87 (d, J ) 6.7 Hz, 3H); MS m/z 290
(M+), 263, 231, 219, 204, 174, 159, 144, 132, 117, 91, 77, 42; HRMS
found m/z 290.1650 (M+), C16H22N2O3 requires 290.1632.
(S)-N-Methyl-N-(2′-formalphenyl)valine, Benzyl Ester (34). To
a solution of DMSO (0.16 mL, 2.2 mmol) in 5 mL of anhydrous
methylene chloride was added oxalyl chloride (0.12 mL, 1.4 mmol) at
(2S,5S)-Benzolactam-V8. To a solution of 36 (15 mg, 0.052 mmol)
in 1 mL of THF was added LiBH4 (3 mg, 0.14 mmol). The reaction
mixture was stirred at room temperature until the reaction was

Synthesis of Benzolactam-V8
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12467
completed as monitored by TLC. After quenching the reaction by
adding 1 mL of water, ethyl acetate extract workup followed by
chromatography (silica gel, 1/1 ethyl acetate/petroleum ether as eluent)
(m, 1H), 1.06 (d, J ) 6.8 Hz, 3H), 0.88 (d, J ) 6.6 Hz, 3H); MS m/z
262 (M+), 235, 219, 191, 176, 158, 144, 132, 117, 91, 57, 43.
25
afforded 12 mg (88%) of benzolactam-V8: [R]D ) -346 (c 0.44,
Acknowledgment. We thank Professor Xiyan Lu for helpful
discussion and the Chinese Academy of Sciences and National
Natural Science Foundation of China (Grants 29402016 and
29725205) for financial supports.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.21 (t, J ) 7.7 Hz, 1H), 7.04
(d, J ) 7.6 Hz, 1H), 7.02 (d, J ) 7.7 Hz, 1H), 6.88 (t, J ) 7.7 Hz,
1H), 6.86 (br s, 1H), 4.05 (m, 1H), 3.70 (dd, J ) 10.7, 3.7 Hz, 1H),
3.52 (m, 1H), 3.48 (d, J ) 8.9 Hz, 1H), 3.40 (br s, 1H), 3.08 (dd, J )
16.9, 8.0 Hz, 1H), 2.83 (dd, J ) 15.2, 2.4 Hz, 1H), 2.80 (s, 3H), 2.43
JA981662F