A stereocontrolled approach to substituted piperidones and piperidines: Flavopiridol D-ring analogs

Article abstract of DOI:10.1016/S0040-4039(00)02350-9

A stereocontrolled approach to substituted piperidones and piperidines is presented, and their utility as intermediates for the synthesis of flavopiridol D-ring analogs is described.

Full text of DOI:10.1016/S0040-4039(00)02350-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1631–1633
A stereocontrolled approach to substituted piperidones and
piperidines: flavopiridol D-ring analogs
Alexandre Gross, David R. Borcherding, Dirk Friedrich and Jeffrey S. Sabol*
Aventis Pharmaceuticals Inc., Route 202-206, PO Box 6800, Bridgewater, NJ 08807-0800, USA
Received 13 November 2000; accepted 1 December 2000
Abstract—A stereocontrolled approach to substituted piperidones and piperidines is presented, and their utility as intermediates
for the synthesis of flavopiridol D-ring analogs is described. © 2001 Elsevier Science Ltd. All rights reserved.
Cyclin-dependent kinases (CDKs) belong to a class of
enzymes that control the ability of a cell to enter into
and proceed through the cell division cycle. These
kinases are regulated by cyclin activators and endoge-
nous CDK inhibitors. The loss of this regulation can
result in proliferative disorders such as those found in
cancers, which make the CDKs attractive therapeutic
targets.1 Flavopiridol (Fig. 1) is a synthetic flavone
currently in phase II clinical trials as an anticancer
agent whose mechanism of action is believed to be
through the inhibition of CDKs.2 We were interested in
preparing flavopiridol D-ring analogs for SAR studies
while maintaining the necessary cis relationship
between the 3-hydroxyl and 4-flavone substituents. We
wish to communicate an approach which allows us to
stereoselectively prepare substituted piperidones and
piperidines, leading to the synthesis of flavopiridol D-
ring analogs.
described by Bartlett et al.4 was completely stereoselec-
tive, and the resulting g-iodolactones were treated with
sodium azide to afford multigram quantities of scaf-
folds 4a and 4b. The enolate of g-azidolactone 4a was
generated using lithium bis(trimethylsilyl)amide (LiH-
MDS) as the base and treatment with iodomethane
afforded the trans–trans lactone 5, whose relative stereo-
chemistry was unambiguously determined from 1H
NMR NOESY and NOE difference data.5 In addition,
other electrophiles such as allyl bromide, benzyl bro-
mide, and ethyl bromoacetate also reacted with the
enolate of 4a in a stereocontrolled fashion, and these
results will be described elsewhere. Hydrogenation of
azide 5 did not produce piperidone 6, however, treat-
ment of the hydrogenation product with catalytic
sodium methoxide in methanol6 readily afforded piperi-
done 6 whose relative stereochemistry was assigned
from NMR data.5 The potential of piperidone 6 for
further functionalization is being explored. The
hydroxyl group of 6 can be protected or manipulated,
and the lactam is useful for N-alkylation or for the
introduction of carbon nucleophiles by N-carbamate
formation, followed by nucleophilic lactam ring open-
ing and intramolecular reductive amination.
The synthesis (Scheme 1) commences with the
Wadsworth–Emmons olefination of aldehyde 1 with
trimethyl phosphonoacetate followed by reduction of
the resulting a,b-unsaturated ester with diisobutylalu-
minum hydride (DIBAL) to afford allylic alcohol 2a.
Similarly, olefination of 1 with the anion of dimethyl
(2-oxopropyl)phosphonate and reduction of the unsatu-
rated ester with lithium triethylborohydride afforded
allylic alcohol 2b. Johnson ortho ester Claisen
rearrangement3 of alcohols 2a and 2b provided interme-
diate g,d-unsaturated esters, which were saponified to
acids 3a and 3b. Stereocontrolled iodocyclization of
acids 3a and 3b under thermodynamic control as
* Corresponding author. Tel.: 1-908-231-3092; fax: 1-908-231-3577;
e-mail: jeff.sabol@aventis.com
Figure 1. Flavopiridol.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02350-9

1632
A. Gross et al. / Tetrahedron Letters 42 (2001) 1631–1633
Scheme 1. Conditions: (i) (CH3O)2P(O)CH2CO2CH3, THF, LiHMDS, 0°C–rt, 90%; (ii) DIBAL, toluene, rt (1 h), 98%; (iii) NaH,
dioxane, (CH3O)2P(O)CH2C(O)CH3, 100°C (1 h), 80%; (iv) LiEt3BH3, THF, 0°C, 95%; (v) CH3C(OC2H5)3, t-BuCO2H (5%),
o-xylene, 135°C (2 h), a=60%, b=70%; (vi) 1N NaOH, MeOH, 50°C (4 h), a=85%, b=75%; (vii) I2 (3 equiv.) CH3CN, 0°C (24
h), a=80%, b=75%; (viii) NaN3, DMF, 100°C (3 h), a=88%, b=95%; (ix) LiHMDS, THF, −70°C (0.5 h), then CH3I (−70°C–rt),
60%; (x) H2 (60 psi), EtOH, 10% Pd/C, quant.; (xi) NaOMe (cat.), MeOH, 65°C (2 h), 75%.
Scheme 2. Conditions: (i) t-Butyldimethylsilyl chloride, imidazole, DMAP, DMF, rt, 95%; (ii) LAH, THF, 65°C (3 h), 90%; (iii)
aq. CH2O, NaBH3CN, CH3CN, pH 5.0, 90%; (iv) Ac2O, BF3·OEt2, then 10% aq. NaOH, 30°C (6 h), 30–50%; (v) DMF, 95%
NaH (5 equiv.), rt (1 h), then methyl 2-chlorobenzoate, rt (16 h), 30%; (vi) 4N HCl/dioxane, rt (16 h); (vii) pyr·HCl, quinoline,
160°C (1 h).

A. Gross et al. / Tetrahedron Letters 42 (2001) 1631–1633
1633
Scheme 3.
5. Selected NMR data: 5 1H NMR (400 MHz, CDCl3): l
6.15 s (2H; H-3%/H-5%), 4.80 ddd (J=9.5, 5.5, 3 Hz; H-4a),
3.82 s (3H; 4%-OMe), 3.80 s (6H; 2%-OMe/6%-OMe), 3.69 dd
(J=11, 9.5 Hz; H-3b), 3.44 dd (J=13.5, 3 Hz; H-5), 3.33
dd (J=13.5, 5.5 Hz; H-5), 3.32 dq (J=11, 7 Hz; H-2a),
The utilization of piperidone 6 in the synthesis (Scheme
2) of a flavopiridol D-ring analog begins with the
conversion of 6 to piperidine 7 in 76% yield using a
three-step sequence of hydroxyl group protection as a
t-butyldimethylsilyl ether, lactam reduction with
lithium aluminum hydride, and N-methylation with
concomitant loss of the protecting group. At this point,
the published procedure for the synthesis of the flavone
portion of flavopiridol was followed.7 The B-ring annu-
lation was initiated by the conversion of 7 to hydroxy-
acetophenone 8 via a selective demethylation-Fries
1
significant NOE between H-2a and H-4a. 6 H NMR (400
MHz, CDCl3): l 6.18 s (2H; H-3%/H-5%), 5.86 brs (NH),
4.12 brs (4a-OH), 4.08 brs (H-4b), 3.82 s (9H; 2%-OMe/4%-
OMe/6%-OMe), 3.72 dd (J=12, 1.5 Hz; H-3b), 3.50 brdd
(J=12.5, 2.5 Hz; H-5b), 3.37 ddd (J=12.5, 3.5, 2.5 Hz;
H-5a), 3.33 dq (J=12, 7 Hz; H-2a), 1.04 d (3H; J=7 Hz;
H-6), NOEs between axial H-2a and 4a-OH, and between
rearrangement sequence. Condensation of
8 with
1
axial H-3b and H-5b. 10 H NMR (500 MHz, CDCl3): l
methyl 2-chlorobenzoate was followed by cyclodehy-
dration, yielding flavone 9. Demethylation with pyri-
dinium hydrochloride completed the synthesis of
flavopiridol analog 10.5 Likewise (Scheme 3), azidolac-
tone 4b was stereoselectively converted to piperidone 11
in 57% overall yield utilizing the two-step sequence used
in the conversion of 5 to 6. The cis–cis relative stereo-
chemistry of 11 was confirmed by NMR.5 Finally,
piperidone 11 was transformed to flavopiridol analog
125 by the same reaction sequence used to convert 6 to
10.
7.55 dd (J=8, 1.5 Hz; H-6¦), 7.54 dd (J=7.5, 2 Hz; H-3¦),
7.48 ddd (J=8, 7.5, 2 Hz; H-5¦), 7.42 ddd (J=7.5, 7.5, 1.5
Hz; H-4¦), 6.40 s (H-3%), 6.30 s (H-7%), 4.15 brs (H-3b), 3.16
dd (J=12, 1 Hz; H-4b), 3.09 brd (J=12 Hz; H-2a), 3.05
brd (J=11.5 Hz; H-6a), 2.85 dddq (J=12, 11, 4, 6.5 Hz;
H-5a), 2.46 s (3H; N-CH3), 2.41 brd (J=12 Hz; H-2b),
1.94 dd (J=11.5, 11 Hz; H-6b), 0.65 d (3H; J=6.5 Hz;
H-7). 11 1H NMR (300 MHz, CDCl3); l 6.18 s (2H;
H-3%/H-5%), 5.72 brs (NH), 4.16 brs (4a-OH), 3.97 ddd
(J=13, 6, 1 Hz; H-3b), 3.82 s (6H; 2%-OMe/6%-OMe), 3.81
s (3H; 4%-OMe), 3.80 brs (H-4b), 3.65 brdq (J=2, 6.5 Hz;
H-5b), 3.24 dd (J=18, 13 Hz; H-2a), 2.28 dd (J=18, 6 Hz;
H-2b), 1.27 d (3H; J=6.5 Hz; H-6), NOEs between axial
H-2a and 4a-OH, and between axial H-3b and H-5b. 12
1H NMR (500 MHz, CDCl3): l 7.57 ddd (J=7.5, 2, 0.5
Hz; H-3¦), 7.56 ddd (J=8, 1.5, 0.5 Hz; H-6¦), 7.49 ddd
(J=8, 7.5, 2 Hz; H-5¦), 7.43 ddd (J=7.5, 7.5, 1.5 Hz;
H-4¦), 6.42 s (H-3%), 6.31 s (H-7%), 3.85 brs (H-3b), 3.63
ddd (J=13, 4.5, 1.5 Hz; H-4b), 3.08 m (H-6a), 2.58 m
(H-5a), 2.45 brq (J=6.5 Hz; H-2b), 2.41 s (3H; N-CH3),
2.40 m (H-6b), 1.54 m (H-5b), 1.26 d (3H; J=6.5 Hz;
H-7), NOEs between axial H-4b and axial H-2b, H-6b.
6. The authors thank Drs. Philip Weintraub and Ronald
Bernotas for helpful discussions.
In conclusion, we have outlined a stereocontrolled
approach to useful, substituted piperidones and pipe-
ridines, which were further elaborated to flavopiridol
D-ring analogs. Additional work and SAR studies will
be communicated elsewhere.
References
1. Sielecki, T. M.; Boylan, J. F.; Benfield, P. A.; Trainor, G.
L. J. Med. Chem. 2000, 43, 1–18.
2. Sedlacek, H. H.; Czech, J.; Naik, R.; Kaur, G.; Worland,
P.; Losiewicz, M.; Parker, B.; Carlson, B.; Smith, A. Int. J.
Oncol. 1996, 9, 1143–1168.
3. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brock-
som, T. J.; Li, T.; Faulkner, D. J.; Petersen, M. R. J. Am.
Chem. Soc. 1970, 92, 741–743.
4. Gonzalez, F. B.; Bartlett, P. A. Org. Synth. 1986, 64,
175–181.
7. (a) Kattige, S. L.; Naik, R. G.; Lakdawalla, A. D.;
Dohadwalla, A. N.; Rupp, R. H.; Desouza, N. J. US
Patent 4,900,727, 1990; (b) Naik, R.; Lal, B.; Rupp, R. H.;
Sedlacek, H. H.; Dickneite, G.; Czech, J. US Patent 5,284,
856, 1988; (c) Naik, R.; Kattige, S. I.; Bhat, S. V.; Alrejy,
B.; DeSouza, N. J.; Rupp, R. H. Tetrahedron 1988, 44,
2081.
.