Synthesis of spirolactams and spiropiperidines as CCR4 receptor antagonists

Article abstract of DOI:10.1016/j.tetlet.2005.10.139

The synthesis of racemic and non-racemic spirocyclic lactams that display high binding affinity toward CCR4 is described. Two distinct series of spirocycles were prepared from the common intermediate 9.

Full text of DOI:10.1016/j.tetlet.2005.10.139

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 69–72
Synthesis of spirolactams and spiropiperidines as CCR4
receptor antagonists
Joshua D. Hansen,a,* Bradley J. Newhouse,a Shelley Allen,a Aaron Anderson,a
Todd Eary,a Justin Schiro,a John Gaudino,a Ellen Laird,a Andrew C. Allen,a
David Chantry,b Christine Eberhardtb and Laurence E. Burgessa
aArray BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA
bIcos Corporation, 22021 20th Avenue S.E., Bothell, WA 98021, USA
Received 16 September 2005; revised 25 October 2005; accepted 26 October 2005
Available online 14 November 2005
Abstract—The synthesis of racemic and non-racemic spirocyclic lactams that display high binding affinity toward CCR4 is
described. Two distinct series of spirocycles were prepared from the common intermediate 9.
ꢀ 2005 Elsevier Ltd. All rights reserved.
CCR4 is a G-protein coupled receptor that binds two
chemokines, macrophage derived chemokine (MDC)
and thymus and activation regulated chemokine
(TARC).1 CCR4 is expressed primarily by Th2 T cells,
and there is considerable evidence that CCR4 regulates
the migration of Th2 cells in disease settings.2 Because
CCR4 is preferentially expressed by Th2 cells, and its
ligands are induced at sites of allergic inflammation,
we and others have pursued CCR4 antagonists as novel
agents for the treatment of asthma and atopic dermati-
tis.3 Recent reports from these laboratories described a
series of 2,3,5-trisubstituted thiazolidinone4 and 1,3,5-
trisubstituted pyrrolidinone5 CCR4 inhibitors as novel
therapeutic agents of allergic inflammation. As a con-
tinuation of these series, we have evaluated rigidified
analogs such as spirolactam 2 (Fig. 1). Herein, we dis-
close the synthetic details in which both racemic and
enantiomerically pure spirolactams as well as racemic
spiropiperidines were constructed.
Cl
Cl
Cl
Cl
X
O
O
NHR'
O
NHR'
N
N
RHN
RHN
O
O
1
2
X = O, H2
Figure 1. Previously explored lactam (1) and proposed spirocyclic
template (2).
by the same method, were accessed by employment of
(S)- or (R)-phenylglycinol to afford bicyclic lactam 5
(R = Ph) as one diastereomer. In our work, we required
the use of (S)-phenylglycinol as the (R) derived lactam
gave analogs much less potent.5 Titanium(IV)chloride/
triethylsilane mediated ring opening and N-acyliminium
ion reduction7 provided lactam 6 in 80% yield. When
R = Ph for lactam 6, only one diastereomer was
observed by NMR. The alcohol of racemic lactam 6
(R = H) was protected as its silyl ether 9. To obtain
enantiopure lactams, the general synthetic scheme
briefly diverges to remove the chiral auxiliary. A modi-
fied procedure of auxiliary removal8 was used that
involved conversion of the alcohol bearing moiety of
lactam 6 to its corresponding chloride and subsequent
treatment with sodium ethoxide in ethanol at 45 ꢁC to
provide enamide 7. Hydrolysis of the enamide was then
easily accomplished with HCl to afford lactam 8 in an
Taking a cue from our previous work,5 we envisioned a
route to the scaffold (2,8-diaza-spiro[4.5]decane-1,7-
dione) via the bicyclic lactam methodology developed
by Meyers and Brengel.6 As outlined in Scheme 1, race-
mic lactams were attained by the condensation of etha-
nolamine with ketoacid 4 in refluxing toluene and
azeotropic removal of water. The enantiopure lactams,
*
Corresponding author. Tel.: +1 303 386 1312; e-mail:
josh.hansen@arraybiopharma.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.139

70
J. D. Hansen et al. / Tetrahedron Letters 47 (2006) 69–72
with (2-bromoethoxy)-tert-butyldimethylsilane afforded
X1
X1
enantiopure lactam 9 in 75% yield. Chiral HPLC of
enantiopure lactam 9 (X1 = Cl, X2 = H or X1 =
X2 = Cl) indicated it to be >95% ee.9 It is at this point
the racemic and enantiomeric syntheses converge.
NH2
R
X2
X2
i
HO
O
O
HO
3
N
R = H, Ph
X1 =Cl, X2 =H
X1 = X2 = Cl
4
R
O
As detailed in Scheme 2, the spirocycle was assembled
by sequential di-alkylation of lactam 9 with LDA and
allylbromide at À78 ꢁC to afford di-allyllactam 10 in 50%
overall yield. Ring closing metathesis utilizing GrubbsÕ
second generation catalyst10 at 0.05 or 0.10 molar con-
centration in refluxing 1,2-dichloroethane yielded spiro-
lactam 11 in 80% yield after filtration through a silica gel
plug. At this point, we envisioned opening the cyclic
olefin of the spirolactam via ozonolysis followed by
a reductive workup method described by Claus and
Schreiber,11 to achieve differentiated oxidation states.
Therefore, ozonolysis of lactam 11 in DCM/MeOH at
À78 ꢁC followed by workup with acetic anhydride and
triethylamine in DCM at 0 ꢁC provided ester-aldehyde
12 as a 1:1 mixture of diastereomers in 75% yield.
Reductive cyclization occurred by subjecting ester-alde-
hyde 12 to 3-chloro-2-methyl benzylamine in the pres-
ence of sodium triacetoxyborohydride. Silica gel
chromatography provided each spirolactam 13 and 14
in 50% combined overall yield. Alternatively, separation
of the diastereomers could be performed at a later stage.
NMR studies on lactam 13 confirmed the stereochemis-
try at the spirocyclic carbon.12 During the course of our
work, several benzyl amines were incorporated to
expand the structure–activity relationships.
5
O
ii
X1
X2
X1
X2
iv
R = Ph
N
N
HO
X1
O
6
R
7
Ph
O
iii
v
R = H
X1
X2
X2
vi
N
O
HN
TBSO
8
9
O
Scheme 1. Reagents and conditions: (i) toluene, reflux, Dean–Stark,
16 h, 100%; (ii) TiCl4, DCM, Et3SiH, À78 ꢁC to rt, 16 h, 80%; (iii)
TBDMSCl, imidazole, DMF, 95%; (iv) a—SOCl2, THF, 0 ꢁC to rt,
95%; b—NaOEt, EtOH, 45 ꢁC, 80%; (v) 1 N HCl (aq), THF, reflux,
85%; (vi) KH, DMF, (2-bromoethoxy)-tert-butyldimethylsilane, rt,
1 h, 75%.
overall conversion of 65%. Treatment of lactam 8
with potassium hydride in DMF, followed by alkylation
X1
X1
X1
X2
X2
X2
O
i
ii
iii
9
TBSO
N
O
TBSO
N
TBSO
N
O
O
O
O
10
11
12
iv
X1
X1
X2
O
X2
O
N
N
O
N
N
O
v
NH
O
TBSO
X1
Cl
N
Cl
15
13
+
X1
X2
O
N
X2
O
N
N
O
N
O
TBSO
O
14
NH
Cl
Cl
N
16
Scheme 2. Reagents and conditions: (i) a—LDA, THF, À78 ꢁC then allylbromide, 70%, b—LDA, THF, À78 ꢁC then allylbromide, 70%; (ii) GrubbsÕ
second generation catalyst, 1,2-DCE, reflux, 80%; (iii) a—ozone, DCM/MeOH, NaHCO3, À78 ꢁC; b—Ac2O, TEA, DCM, 0 ꢁC, 75%; (iv) (3-chloro-
2-methylphenyl)methanamine, NaBH(OAc)3, 1,2-DCE, 50%; (v) a—Jones reagent, acetone, 80%; b—CDI, CH2Cl2, 3-(piperidin-1-yl)propan-1-
amine, 40%.

J. D. Hansen et al. / Tetrahedron Letters 47 (2006) 69–72
71
With the spirocycle in place, we now focused on function-
alizing the left arm of the molecule. Immersing spirolac-
tam 13 and 14 (as a mixture of diastereomers or
separate) in Jones reagent in acetone facilitated the depro-
tection of the TBS ether and oxidation of the resultant
alcohol to the acid in one pot. Amide bond formation
on the crude acid with carbonyl diimidazole in DCM with
3-(piperidin-1yl)propane-1-amine and preparative thin
layer chromatography to separate diastereomers pro-
vided diastereomerically and enantiomerically pure spiro-
lactams 15 and 16 in 40% combined yield. It should be
noted that the carbonyl in the six-membered ring of lac-
tam 15 is in a trans disposition to the aromatic ring on
the five-membered ring lactam. This diastereomer proved
to be more potent1 than its counterpart 16, an observation
we made in our non-spiroseries.4,5 Again, several amines
were used at this stage in order to expand the scope of
our SAR studies.
(spiropiperidines), where the carbonyl is removed as
exemplified in Figure 2. Recent studies have utilized this
scaffold as HIV-1 protease inhibitors.13
As outlined in Scheme 3, we employed racemic lactam
10 (from Scheme 2, X1 = X2 = Cl) as a starting point.
Ozonolysis of di-allyllactam 10 at À78 ꢁC in DCM fol-
lowed by reductive workup using polymer bound triphe-
nylphosphine conveniently afforded di-aldehyde 16.
Reductive amination of 16 with benzyl amine provided
the spiropiperidine in 55% yield. With the requisite spi-
ropiperdine ring structure complete, it was desirable to
switch protecting groups to avoid oxidation of piperi-
dine. To this end, a von Braun like N-debenzylation14
was performed by refluxing 17 in acetonitrile with allyl-
chloroformate affording the spiropiperidine 18 in 98%
yield. Functionalization of the TBS ether was then
smoothly accomplished using the sequence described in
Scheme 2.
To ascertain the role of the carbonyl of the six-mem-
bered ring on spirolactam 2, we undertook a program
to prepare a series of 2,8-diaza-spiro[4.5]decan-1-ones
To further functionalize the piperidine nitrogen, palla-
dium mediated deprotection of the allylcarbamate
provided spiropiperidine 20, a useful intermediate for
acylations, sulfonylations, or reductive aminations.
Piperidine was treated with 3-chlorobenzaldehyde and
sodium triacetoxyborohydride in 1,2-dichloroethane to
give spiropiperidine 21. Again, several acid chlorides,
sulfonyl chlorides, and aldehydes were employed to
expand the SAR of this series.
Cl
Cl
O
NHR'
N
RHN
O
In conclusion, we have demonstrated efficient racemic
and chiral syntheses of spirolactams and spiropiperi-
dines. Both series of compounds can take advantage of
Figure 2. Spirocyclic core with carbonyl excised or placed outside of
ring.
Cl
Cl
Cl
Cl
Cl
Cl
O
i
ii
N
TBSO
N
TBSO
N
TBSO
N
Ph
O
O
O
O
17
10
16
iii
Cl
Cl
Cl
Cl
O
O
O
iv
N
N
N
O
TBSO
N
O
O
19
18
OH
O
v
Cl
Cl
Cl
Cl
Cl
vi
O
O
N
NH
N
N
N
N
N
N
O
H
O
H
20
21
Scheme 3. Reagents and conditions: (i) ozone, DCM, À78 ꢁC then PS-TPP, warm to rt, 100%; (ii) benzyl amine, NaBH(OAc)3, 1,2-DCE, 55%;
(iii) allylchloroformate, AcCN, reflux, 98%; (iv) Jones reagent, acetone, 79%; (v) a—PyBop, DIEA, 3-(piperidin-1-yl)propan-1-amine, 40%;
b—Pd(PPh3)4, THF–DEA; (vi) 3-chlorobenzaldehyde, NaHB(Oac)3, 1,2-DCE.

72
J. D. Hansen et al. / Tetrahedron Letters 47 (2006) 69–72
5. Newhouse, B.; Allen, S.; Fauber, B.; Anderson, A. S.;
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di-allyllactam 10, an intermediate that can be readily
synthesized on large scale racemically or in enantiomeri-
cally pure form. Three crucial steps are required to gen-
erate the spirolactams: ring closing metathesis,
ozonolytic cleavage, and reductive cyclization. From
lactam 10, spiropiperidines require ozonolysis to
dialdehyde and reductive cyclization to create the
six-membered ring which conveniently circumvents
diastereomeric mixtures.
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