A highly efficient synthesis of potent and selective butyrolactam inhibitors of 11β-Hsd1

Article abstract of DOI:10.1021/ol061429j

A convergent synthesis of structurally novel butyrolactam 11β-HSD1 inhibitors is described. The approach features an efficient Ireland-Claisen reaction to construct a highly substituted aldehyde building block which is converted to a lactam via a tandem r

Full text of DOI:10.1021/ol061429j

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3963-3966
A Highly Efficient Synthesis of Potent
and Selective Butyrolactam Inhibitors of
11â
-Hsd1†
Vince S. C. Yeh,*,‡ Ravi Kurukulasuriya,§ and Francis A. Kerdesky
|
Metabolic Disease Research, Target and Lead DiscoVery Research, and Process
Chemistry Research, Abbott Laboratories, 100 Abbott Park Road, Dept R4MC, AP-10,
Abbott Park, Illinois 60064-6113
Vince.yeh@abbott.com
Received June 11, 2006
ABSTRACT
A convergent synthesis of structurally novel butyrolactam 11â-HSD1 inhibitors is described. The approach features an efficient Ireland−
Claisen reaction to construct a highly substituted aldehyde building block which is converted to a lactam via a tandem reductive amination/
cyclization sequence. The generality of the synthetic sequence is demonstrated during the preparation of two additional potent 11
â-HSD1
inhibitors.
11â-Hydroxysteroid dehydrogenase 1 (11â-HSD1) converts
the inactive glucocorticoid cortisone into the active hormone
cortisol. Cortisol mediates a wide variety of physiological
functions such as inflammatory and stress responses, growth
and development, and gluconeogenesis.1 A related enzyme,
11â-HSD2, catalyzes the reverse reaction which in tissues
such as kidney protects the mineralocorticoid receptor from
activation by cortisol. The current hypothesis is that tissue
excess production of cortisol by 11â-HSD1 can lead to
symptoms of metabolic syndrome, and selective inhibition
of 11â-HSD1 over 11â-HSD2 may have potential for
therapeutic intervention for diabetes.2
Our drug discovery program sought to identify potent and
selective 11â-HSD1 inhibitors that possess desirable phar-
macokinetic properties. This led us to a series of butyrolac-
tams exemplified by 13 (Figure 1). Lactam 1 is highly potent
against human 11â-HSD1 and over 7600-fold in selectivity
against 11â-HSD2. The biological evaluation and the struc-
† This paper is dedicated to professor Barry M. Trost on the occasion of
his 65th birthday.
‡ Metabolic Disease Research.
§ Target and Lead Discovery Research.
(2) (a) For a review on recent patents, see: Fotsch, C.; Askew, B. C.;
Chen, J. J. Expert Opin. Ther. Pat. 2005, 3, 289. (b) For a general review
on type 2 diabetes, see: Ross, S. A.; Gulve, E. A.; Wang, M. Chem. ReV.
2004, 104, 1255.
(3) All of the lactam compounds discussed in this paper are chiral racemic
mixtures derived from the center denoted by * in Figure 1. Asymmetric
synthesis of 1 will be published elsewhere.
| Process Chemistry Research.
(1) For recent reviews, see: (a) Draper, N.; Stewart, P. M. J. Endocrinol.
2005, 186, 251. (b) Thieringer, R.; Hermanowski-Vosatka, A. Expert ReV.
CardioVasc. 2005, 3, 911. (c) Morton, N. M.; Paterson, J. M.; Masuzaki,
H.; Holmes, M. C.; Staels, B.; Fievet, C.; Walker, B. R.; Flier, J. S.; Mullins,
J. J.; Seckl, J. R. Diabetes 2004, 53, 931.
10.1021/ol061429j CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/05/2006

sequential reductive amination/ring cyclization sequence5
between amino ester 36 and aldehyde 4. The highly substi-
tuted aldehyde 4 could be built from an Ireland-Claisen
rearrangement of ester 5.7
The synthesis commenced with monosilylation8 of com-
mercially available diol 6. Crude alcohol 7 was esterified
with isobutyryl chloride to give ester 5 in 90% yield after
purification (Scheme 2). We found the crucial Ireland-
Scheme 2. Synthesis of Acid 8
Figure 1. Lactam 11â-HSD1 inhibitor.
ture-activity relationships (SAR) of these lactams will be
reported elsewhere.4 We now report the development of an
efficient and scalable route to these functionally dense and
structurally unique lactams.
Lactam 1 features a highly substituted core with an R-gem-
dimethyl quaternary center and a â-alkoxymethylene group.
When we began, there was not a general synthetic route to
this type of structure. We needed a route that would allow
us to vary both group 1 and group 2 for SAR studies, as
well as high convergency so that we could prepare these
compounds on a multigram scale for in vivo studies. The
design of our synthetic strategy is outlined in Scheme 1. We
Claisen rearrangement of 5 nontrivial since the formation
of the silylenolether intermediate required the abstraction of
a hindered R proton. Screening of common enolization
reaction conditions using strong bases such as LDA, LiH-
MDS, or NaHMDS in THF gave either no desired product
or <20% conversion along with decomposition products such
as alcohol 7. Soft enolization methods such as addition of
TMSOTf to a CH2Cl2 solution of 5, followed by the addition
of i-Pr2NEt, gave no observable silylenol either.9 Ultimately,
we achieved clean enolization with KHMDS in toluene. The
reaction was optimal when a solution of ester 5 was added
to a cold (-78 °C) suspension of KHMDS.10 After the
addition of TMSCl, the silyl enol ether was allowed to warm
to room temperature followed by gentle heating (80 °C) to
complete the rearrangement. After workup, acid 8 was
isolated in 85-90% yield. This reaction has been scaled up
to 50 g scale with reproducible yields.11 Acid 8 was converted
into the corresponding methyl ester using TMS-diazomethane
Scheme 1. Retrosynthesis of 1
(5) Butyrolactam synthesis examples: (a) Duan, J. J.-W.; Chen, L.;
Wasserman, Z. R.; Lu, Z.; Liu, R.-Q.; Convington, M. B.; Qian, M.;
Hardman, K. D.; Magolda, R. L.; Newton, R. C.; Christ, D. D.; Wexler, R.
R.; Decicco, C. P. J.Med. Chem. 2002, 45, 4954. (b) Duan, J. J.-W.; LU,
Z.; Xue, C.-B.; He, X.; Seng, J. L.; Roderick, J. J.; Wasserman, Z. R.; Liu,
R.-Q.; Convington, M. R.; Magolda, R. L.; Newton, R. C.; Trzaskos, J.
M.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2003, 13, 2035. (c) Dolbeare,
K.; Pontoriero, G. F.; Gupta, S. K.; Mishra, R. K.; Johnson, R. L. J. Med.
Chem. 2003, 46, 727.
(6) Link, J. T.; Pliushchev, M. A.; Rohde, J. J.; Wodka, D.; Patel, J. R.;
Shuai, Q. U.S. Patent 0245534, 2005.
(7) For reviews on Ireland-Claisen rearrangements, see: (a) Chai, Y.;
Hong, S.-P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905. (b) Wipf, P. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5, p 827.
(8) a) Li, X.; Lantrip, D.; Fuchs, P. L. J. Am. Chem. Soc. 2003, 125,
14262. (b) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
(9) Kobayashi, M.; Masumoto, K.; Nakai, E.; Nakai, T. Tetrahedron Lett.
1996, 37, 3005.
planned to make the heteroaryl ether bond near the end of
the synthesis via a nucleophilic aromatic substitution reaction
between alcohol 2 and a heteroaryl halide. The lactam core
2 was envisioned to be formed convergently through a
(4) (a) Yeh, V. S. C.; Kurukulasuriya, R.; Fung, S.; Monzon, K.; Chiou,
W.; Wang, J.; Stolarik, D.; Imade, H.; Brune, M.; Jacobsen, P.; Link, J. T.
Bioorg. Med. Chem. Lett. 2006, submitted for publication. (b) The bridged
bicyclic structures on the nitrogen of the lactam ring significantly contribute
to potency and selectivity for 11â-HSD1. The current synthetic route
crucially impacted our ability to determine the SAR of these inhibitors.
(10) Hong, S.-P.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh,
M. C. J. Org. Chem. 2002, 67, 2042.
(11) See the Supporting Information for experimental details.
3964
Org. Lett., Vol. 8, No. 18, 2006

(Scheme 3). The olefin was cleaved with O3 to give a labile
Table 1. Optimization of Lactam Formation (Scheme 3)
Scheme 3. Ozonolysis and Lactam Formation
% yield
entry
1
conditionsa
of 10b
(i) 3, 9, NaCNBH3, AcOH, MeOH, rt, 12 h;
(ii) reflux, 6 h
(i) 3, 9, NaHB(OAc)3, THF, rt, 12 h;
20
2
3
4
35
60
(ii) reflux, 6 h
(i) 3, 9, 4 Å MS, THF, 5 h; then add NaBH4,
rt, 12 h; (ii) reflux, 6 h
(i) 3, 9, 4 Å MS, THF, 5 h; then add NaHB(OAc)3,
rt, 12 h; (ii) toluene, 90 °C, 2 h
>85
a 1.1 equiv of 3 and 1 equiv of 9 were used. b Isolated yields.
Scheme 4. Synthesis of Lactam 1
aldehyde 9.12 This reaction was at first problematic due to
irreproducible yields on scales larger than 0.5 g. One of the
side products isolated from the ozonolysis reaction mixture
was lactone 11 (Figure 2). Ease of 11 formation is probably
Figure 2. Lactone byproducts.
reaction of alcohol 2 and chloropyridine 13 was carried out
by the addition of NaH to a solution of the two components
in THF/DMPU to give ether 14 in 85% yield. Preformation
of alkoxide of 2 led to dimerization of the starting material
and lower isolated yield of the product 14. Methyl ester 14
was then hydrolyzed by KOTMS, and the corresponding acid
was converted into the final product 1 in good yield.
With a reliable route in hand, we were able to synthesize
a variety of lactams with different N-substituents.4 Here we
demonstrate the synthesis of two lactams with unique
functionalized bridged bicycles such as the bicyclo[3.3.1]-
nonane amine 15 and the bicyclo[2.2.2]octane amine 16
shown in Figure 3.
aided by the Thorp-Ingold effect13 from the R-gem-dimethyl
groups of aldehyde 9. Upon optimization, we found that it
was crucial to buffer the reaction mixture with NaHCO3 and
closely monitor the end point of ozonolysis with a dye
indicator (Sudan III). Under optimized conditions, multigram
amounts of aldehyde 9 were routinely obtained in >85%
yield.
With aldehyde in hand, the stage was set for the lactam
formation. Table 1 shows selected optimization results from
the tandem reductive amination/cyclization reaction. Low
yields were observed under standard reductive amination
conditions where amine 3 and aldehyde 9 were stirred in
the presence of a borohydride reagent (entries 1 and 2).
Lactone 12 (Figure 2) was isolated as a major byproduct.
The optimal conditions involved the preformation of an
intermediate imine aided by molecular sieves followed by
reduction with NaHB(OAc)3. After filtration, concentration,
and heating the residue in toluene, lactam 10 was obtained
in >85% yield. The silyl group was then removed by TBAF
giving alcohol 2 which served as a key intermediate for the
SAR studies (Scheme 3).
Figure 3. Functionalized bridged bicycle amines.
The completion of the synthesis of inhibitor 1 is depicted
in Scheme 4. The nucleophilic heteroaromatic substitution
The bicyclo[2.2.2]octane amine 16 was synthesized fol-
lowing a literature procedure.14 Scheme 5 shows the conver-
(12) Aldehyde 9 was usually prepared fresh before use.
(13) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Org. Chem. 1915,
107, 1080.
(14) a) Reynolds, R. C.; Johnson, C. A.; Piper, J. R.; Sirotnak, F. M.
Eur. J. Med. Chem. 2001, 36, 237. (b) Nuding, G.; Vogtle, F.; Danielmeier,
K.; Stechhan, E. Synthesis 1996, 71.
Org. Lett., Vol. 8, No. 18, 2006
3965

Scheme 5. Synthesis of Bicyclo[3.3.1]nonane Amine 15
Scheme 6. Syntheses of Lactam Inhibitors 22 and 23
sion of bicyclo[3.3.1]nonane ketone 1715 to amine 15.
Protection of ketone 17, followed by NaOMe mediated
epimerization and deprotection, gave the exo-ester 19 in good
overall yield. Ketone 19 was condensed with methoxyamine
to give an intermediate methoxyimine which was directly
subjected to Raney Ni catalyzed hydrogenation to give the
desired anti-amine 15 with high selectivity (>10:1) and yield.
The stereochemistry of 15 was confirmed by NOE studies
of a lactam derivative (see below).
The bicyclo[3.3.1]nonane amine 15 and aldehyde 9 were
joined via the tandem reductive amination/lactam formation
procedure that we developed (Scheme 6). The process
worked reproducibly, giving a 90% yield of lactam 20. NOE
signals were observed between proton 1 and proton 3 (lactam
20), as well as proton 4 and proton 5, hence confirming the
stereochemistry of the substituents on the bicyclo[3.3.1]-
nonane. Lactam 20 was converted into the final product
following the reaction sequences shown in Scheme 4 giving
inhibitor 22 in very good overall yield. Similarly, the bicyclo-
[2.2.2]octane amine 16 was also carried forward to give
lactam inhibitor 23 in similar overall yield. Similar to lactam
1, both 22 and 23 are highly potent and selective inhibitors
of 11â-HSD1.4
In conclusion, we have developed an efficient and scalable
synthetic route to a series of highly substituted lactam 11â-
HSD1 inhibitors. The synthesis features an Ireland-Claisen
reaction to give an aldehyde with a R-gem-dimethyl qua-
ternary center and a â-alkoxymethylene group. The aldehyde
was then converted to the lactam core through a tandem
reductive amination/cyclization reaction sequence. The cur-
rent synthesis provided the flexibility of varying both ends
of the lactam for SAR studies. These lactam inhibitors were
instrumental in our study of 11â-HSD1 as a therapeutic
target.
Acknowledgment. We thank David Wittern and the
Structural Chemistry group at Abbott Laboratories for
obtaining NMR spectra and for data analysis. We also thank
Dr. Andrew Judd, J. T. Link, John Lynch, and Bruce
Szczepankiewicz of Abbott Laboratories for helpful discus-
sion.
Supporting Information Available: Detailed experi-
1
mental procedures and H and 13C NMR spectra of the
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Peters, J. A.; Van de Graaf, B.; Schuyl, J. W.; Wortel, T. H.; Van
Bekkum, H. Tetrahedron 1976, 32, 2735.
OL061429J
3966
Org. Lett., Vol. 8, No. 18, 2006