Synthesis of 7-methoxybenzolactam-V8 using a diastereoselective Strecker synthesis

Article abstract of DOI:10.1039/b008970m

7-Methoxybenzolactam-V8 (4) was synthesized using a diastereoselective Strecker reaction as the key step employing an ortho-substituted phenylacetaldehyde and (R)-phenylglycinol as the chiral auxiliary.

Full text of DOI:10.1039/b008970m

Synthesis of 7-methoxybenzolactam-V8 using a diastereoselective Strecker
synthesis
Sukumar Sakamuri and Alan P. Kozikowski*
Drug Discovery Program, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC
20007-2197, USA. E-mail: kozikowa@giccs.georgetown.edu; Fax: +1-202-687-5065, Tel: +1-202-687-0686
Received (in Corvallis, OR, USA) 3rd November 2000, Accepted 19th January 2001
First published as an Advance Article on the web 19th February 2001
7-Methoxybenzolactam-V8 (4) was synthesized using a
diastereoselective Strecker reaction as the key step employ-
ing an ortho-substituted phenylacetaldehyde and (R)-phe-
nylglycinol as the chiral auxiliary.
the conditions of a subsequent nitrile methanolysis step,
resulting in the formation of an undesired six-membered
lactam.6 We therefore masked the amine as a 2,5-dime-
thylpyrrole which can be easily cleaved under mild conditions
but is stable to the conditions of acidic nitrile methanolysis.
Accordingly, compound 10 was deprotected to give aniline 11,
which on treatment with acetonylacetone in toluene utilizing a
Dean–Stark trap for azeotropic water removal gave compound
12 in 72% yield.7 Compound 12 was converted to the aldehyde
in a two step sequence. First, compound 12 on treatment with
osmium tetroxide in acetone in the presence of NMO at rt gave
diol 13 in 74% yield. Compound 13 was oxidized to the
aldehyde 14 using sodium metaperiodate in a 1+1 mixture of
tBuOH and H2O at rt in 69% yield. Compound 14 was now
subjected to the Strecker synthesis using (R)-phenylglycinol.8 It
is important to note that previously Chakraborty et al.8 reported
Protein kinase C (PKC) consists of a growing family of closely
related isozymes that mediate a wide range of cellular signal
transduction processes.1 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. However, very few
isozyme-selective activators have been reported to date. The
teleocidins (e.g. indolactam V, 1) are potent PKC activators,
however, they show little selectivity.2 Endo’s group and ours
have reported3 that the benzolactam-V8 derivative 3, a mimic of
the twist-like conformation of indolactam V, is a potent
activator of PKC. Recently, our group has shown that
introduction of a methoxy substituent at the C7-position of
benzolactam-V8 leads to a compound (5) that retains potency at
PKCa, PKCd and PKCe.4 The total synthesis of benzolactam-
V8 analogs depends mainly on the effective construction of the
8-membered lactam ring, which in turn depends on an efficient
synthesis of a suitably substituted phenylalanine moiety. An
improved synthesis of 7-methoxybenzolactam-V8 (4) would
permit access to further analogs by making use of the
heteroatom at the 7-position. We have recently developed the
first synthesis of 7-methoxybenzolactam-V8,4 which makes use
of a catalytic asymmetric alkylation. The poor selectivity in this
step induced us to explore an alternative approach. In the
present communication, we describe a diastereoselective
Strecker reaction for the synthesis of the required substituted
phenylalanine which after a series of further reactions leads to
the title compound 4.
Our synthetic sequence began with the introduction of an
allyl group in the ortho position to the hydroxy group using the
Claisen rearrangement. Thus, 3-hydroxyacetanilide (6) was
transformed into its allyl ether 7 using allyl bromide and
potassium carbonate in refluxing acetone in 88% yield (Scheme
1). Compound 7 was subjected to the Claisen rearrangement in
refluxing dimethylaniline for 6 h to give a mixture of products
8 and 9 in a 1+1 ratio.5 The required regioisomer 8 was isolated
by fractional crystallization and protected as its methyl ether in
82% yield. The N-acetyl group in compound 10 was unstable to
Scheme 1 Reagents and conditions: (a) K2CO3, allyl bromide, acetone,
reflux, 88%; (b) PhNMe2, reflux, 6 h, 84%; (c) K2CO3, MeI, acetone, reflux,
82%; (d) 7% HCl, reflux, 2 h, 81%; (e) acetonylacetone, toluene, reflux,
24 h, 72%; (f) OsO4, NMO, rt, acetone, 74%; (g) NaIO4, t-BuOH–H2O, rt,
69%; (h) i, (R)-phenylglycinol, CHCl3, ii, Me3SiCN, 0 °C–rt, 10 h, iii,
TBAF, 66% for three steps; (i) HCl in ether, MeOH, 0 °C–rt, 48 h, 81% (j)
i, Pb(OAc)4, CH2Cl2–MeOH (2+1), 15 min; ii, 20% Pd(OH)2/C, EtOH, 50
psi of H2, overnight; iii, BOC2O, Et3N, THF, rt, 44% for three steps; (k)
LiBH4, THF, 0 °C–rt, 8 h, 96%; (l) NH2OH·HCl, Et3N, i-PrOH–H2O,
reflux, 24 h, 81%; (m) 2,6-lutidine, 1,2-dichloroethane, 87%; (n) H2, Pd/C,
EtOH, quantitative; (o) i, N-hydroxysuccinimide–DCC, CH2Cl2, ii, tri-
fluoroacetic acid, then NaHCO3, EtOAc, 82%; iii, HCHO, NaCNBH3,
AcOH, CH3CN, reflux, 87%.
DOI: 10.1039/b008970m
Chem. Commun., 2001, 475–476
This journal is © The Royal Society of Chemistry 2001
475

that the Strecker reaction of phenylacetaldehyde with (R)-
phenylglycinol gave a 1+1 ratio of isomers. The poor selectivity
was attributed to steric factors. Compound 14 on reaction with
(R)-phenylglycinol in chloroform at rt overnight gave the imine
which on reaction with Me3SiCN at rt for 10 h followed by
treatment with tetrabutylammonium fluoride gave the amino
nitriles 15 and 16 in a 4+1 ratio in 66% yield over the three steps.
The amino nitriles 15 and 16 were easily separated by column
chromatography. The structure of the isomer 15 was confirmed
by X-ray crystallography. This compound was subjected to
acidic hydrolysis to afford the ester 17 in 81% yield based on
recovered starting material. No cyclization product was formed
in the hydrolysis reaction, thus supporting our choice of
protecting group. Oxidative removal of the phenylglycinol
moiety was carried out with lead tetraacetate in CH2Cl2–MeOH
to give a Schiff’s base, which on catalytic hydrogenation over
Pd(OH)2/C gave the free amine. The amine was isolated as the
BOC-protected intermediate 18, and the overall yield for the
three steps was 44%.
Notes and references
1 (a) Y. Nishizuka, Science, 1992, 258, 607; (b) Y. Nishizuka, Nature,
1988, 334, 661; (c) S. Bhagavan, D. Ibarreta, D. Ma, A. P. Kozikowski
and R. Etcheberrigaray, Neurobiol. Disease, 1998, 5, 177.
2 (a) Y. Endo, K. Shudo and T. Okamoto, Chem. Pharm. Bull., 1982, 30,
3457; (b) Y. Endo, K. Shudo, K. Furuhata, H. Ogura, S. Sakai, N. Aimi,
Y. Hitotsuyanagi and Y. Koyama, Chem. Pharm. Bull., 1984, 32, 358;
(c) K. Irie, T. Isaka, Y. Iwata, Y. Yanai, Y. Nakamura, F. Koizumi, H.
Ohigashi, P. A. Wender, Y. Satomi and H. Nishino, J. Am. Chem. Soc.,
1996, 118, 10733.
3 (a) Y. Endo, M. Ohno, M. Hirano, A. Itai and K. Shudo, J. Am. Chem.
Soc., 1996, 118, 1841; (b) A. P. Kozikowski, S. Wang, D. Ma, J. Yao,
S. Ahmad, R. I. Glazer, K. Bogi, P. Acs, S. Modarres, N. E. Lewin and
P. M. Blumberg, J. Med. Chem., 1997, 40, 1316.
4 D. Ma, T. Zhang, G. Wang, A. P. Kozikowski, N. E. Lewin and P. M.
Blumberg, Bioorg. Med. Chem. Lett., 2001, 11, 99.
5 (a) Chem. Abstr., 1955, 49, 3880; (b) Z. Budesinsky and E. Rockova,
Chem. Listy, 1954, 48, 427.
6 Compound 10 after a sequence of reactions as reported in Scheme 1
gave compound A, which on acid hydrolysis gave lactam B.
With the substituted phenylalanine fragment in hand, we now
needed to add the valine fragment. Compound 18 was reduced
to alcohol 19 using LiBH4 in THF in near quantitative yield.
The aromatic amino group was unmasked in good yield by
i
refluxing in a solvent mixture of PrOH–H2O with hydrox-
ylamine hydrochloride and triethylamine. The aniline 20 was
reacted with the
-valine derived triflate 219 to give compound
D
22 in 87% yield. Compound 22 on hydrogenation gave the
carboxylic acid in quantitative yield, which was converted to the
eight-membered lactam using the active ester method as
reported previously.3b N-Methylation using HCHO–
NaCNBH3–HOAc gave 7-methoxybenzolactam 4 in 87%
yield.10
In conclusion, we report an improved synthesis of
7-methoxybenzolactam-V8 making use of a diastereoselective
Strecker synthesis. This compound may serve as an inter-
mediate in the preparation of a variety of C7-substituted
benzolactam analogs, which may exhibit better isozyme
selectivity.
7 J. E. Macor, B. L. Chenard and R. J. Post, J. Org. Chem., 1994, 59,
7496.
8 T. K. Chakraborty, A. Hussain and G. V. Reddy, Tetrahedron, 1995, 51,
9179.
9 T. P. Kogan, T. C. Somers and M. C. Venuti, Tetrahedron, 1990, 46,
6623.
10 Selected data for compound 4: [a]2D2 2 262° (c 0.6, CHCl3), lit4: [a]2D2
2 275° (c 0.82, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.12 (1H, t, J
= 8.3 Hz), 6.65 (1H, d, J = 8.0 Hz), 6.61 (1H, br s), 6.49 (1H, d, J =
8.0 Hz), 4.36 (1H, s), 3.80 (3H, s), 3.71 (1H, dd, J = 10.9, 4.2 Hz), 3.57
(1H, d, J = 8.5 Hz), 3.50 (1H, d, J = 9.3 Hz), 3.24 (1H, d, J = 17.5 Hz),
2.80 (3H, s), 2.76–2.64 (2H, m), 2.45–2.38 (1H, m), 1.04 (3H, d, J = 6.3
Hz), 0.83 (3H, d, J = 6.9 Hz); 13C NMR (CDCl3) d 19.7, 20.7, 27.8,
28.2, 34.9, 54.2, 55.6, 66.4, 69.7, 103.4, 112.3, 118.7, 127.3, 157.9,
173.9.
We are indebted to the National Institutes of Health for
support of this work (CA 79601).
476
Chem. Commun., 2001, 475–476