Asymmetric route to spirotetracyclic (1S)-5′,11′-dihydro-3H- spiro[cyclopentane-1,10′-dibenzo[a,d]cyclohepten]-3-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.11.039

A new synthetic pathway to the final compound 1-[(1S)-5′,11′- dihydrospiro[cyclopentane-1,10′-dibenzo[a,d]cyclohepten]-3-yl] -3-azetidinecarboxylic acid (1) was set up. The two preparative chiral HPLC separations needed in the first route were successfully avoided and replaced by two diastereomeric crystallizations of intermediate compounds 5 and 10.

Full text of DOI:10.1016/j.tetlet.2010.11.039

Tetrahedron Letters 52 (2011) 329–331
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric route to spirotetracyclic (1S)-50,110-dihydro-3H-
spiro[cyclopentane-1,100-dibenzo[a,d]cyclohepten]-3-one derivatives
⇑
Massimo Gianotti , Daniele Andreotti, Davide Casotto, Mario Mattioli, Anna Mingardi,
Francesca Pavone, Roberto Profeta, Filippo Valente
Neurosciences CEDD, GlaxoSmithKline, Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new synthetic pathway to the final compound 1-[(1S)-5’,11’-dihydrospiro[cyclopentane-1,10’-
Received 15 October 2010
Revised 4 November 2010
Accepted 9 November 2010
Available online 27 November 2010
dibenzo[a,d]cyclohepten]-3-yl]-3-azetidinecarboxylic acid (1) was set up. The two preparative chiral
HPLC separations needed in the first route were successfully avoided and replaced by two diastereomeric
crystallizations of intermediate compounds 5 and 10.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diazo-insertion
Diastereomeric crystallization
Spirotetracyclic compounds
Sleep disorders
Zwitterion
Research aiming to identify new and potent dual H1/5-HT2A
antagonists for the treatment of sleep disorders,1 led to new chem-
ical entities characterized by a spirotetracyclic scaffold substituted
with a cyclic aminoacid moiety. Compound 1 (Fig. 1) emerged as
one of our most interesting and promising molecules, endowed
as it was with appropriate, well balanced, dual H1/5-HT2A poten-
cies and a good developability profile.2
Substance 1 and congeners appeared to be available by reduc-
tive amination of ketone (S)-9, which, therefore constitutes the
major subgoal en route to the target molecules. It soon became
apparent that the preparation of this spiroketone was an interest-
ing chemical challenge, especially because no literature precedent
could be found for the synthesis of such a novel structure.
The first original route used to prepare 1 entailed the elabora-
tion of 5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one to (S)-
9 (Fig. 1).2 While this approach enabled the conduct of all planned
structure–activity relationship (SAR) studies, it provided only lim-
ited amounts of material. The major problems with this route were
that it required two preparative chiral HPLC separations, and that it
involved steps that were difficult to scale-up. Significantly larger
quantities of material were required to support the full preclinical
characterization of the most promising compounds, including 1.
Accordingly, a completely new enantioselective avenue to (S)-9
had to be developed. In this Letter, we describe a practical route
to 1 that is suitable for large scale production and that requires
no preparative chiral HPLC.
This new route relies on a key CH insertion reaction of a carbe-
noid. As detailed in Scheme 1, the precursor of the requisite carb-
enoid was diazoacetoacetate 7. The choice of 7, instead of a more
straightforward diazoketone,3 was dictated by the fact that the
Buchner reaction (namely the cyclopropanation of the aromatic
ring) of the carbenoid derived from the latter would have been
highly competitive with the desired CH insertion.4 The synthesis
thus started from 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one 2
(Scheme 1), easily obtained by bromination/dehydro-bromination
of dibenzosuberenone.5 The bromo derivative 2 was then reacted
with methylacrylate under Heck conditions to give compound 3
in very high yield and exclusively as the E-geometric isomer.
O
HO
O
N
O
(S)-9
1
Figure 1. Key intermediate spiro tetracyclic (1S)-5’,11’-dihydro-3H-spiro[cyclo-
pentane-1,10’-dibenzo[a,d]cyclohepten]-3-one (S)-9 in the previous retrosynthetic
approach.
⇑
Corresponding author.
E-mail address: masgian@libero.it (M. Gianotti).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.039

330
M. Gianotti et al. / Tetrahedron Letters 52 (2011) 329–331
OH
OMe
OMe
O
O
O
Br
iii
i
ii
4
5
3
O
2
O
iv
OEt
O
O
N2
O
O
OEt
OEt
O
O
O
v
vii
vi
6
7
9
8
Scheme 1. Synthesis of the key Intermediate 9. Reagents and conditions: (i) DMF, methyl acrylate, TEA, PdCl2(PPh3)2, 75 °C; (ii) acetic acid, Pd/C, H2 10 atm, 90 °C; (iii) H2O/
THF, LiOH; (iv) MeCN, TEA, CDI, MgCl2, potassium monoethyl malonate; (v) p-acetamidobenzenesulfonyl azide, TEA; (vi) DCM, Rh2(OAc)4; (vii) toluene/H2O, DMAP, 92 °C.
All attempts to promote an enantioselective hydrogenation of 3
that would introduce the requisite chirality at the benzylic carbon
OEt
O
met with failure. Even reduction in the presence of cinchonidine
(CD)6 was unsuccessful. Therefore, compound 3 was hydrogenated
over Pd(C) under more traditional conditions, resulting in satura-
tion of the double bonds and hydrogenolysis of the aromatic keto
function. This afforded ester 4, the hydrolysis of which to the cor-
responding acid 5 was straightforward. The latter, in turn, was con-
verted into b-keto ester 6 under Masamune conditions,7 and then
advanced to the diazo derivative 78 by reaction with p-acet-
amidobenzenesulfonyl azide.9 Exposure of diazoacetoacetate 7 to
a catalytic amount of Rh2(OAc)4 resulted in a clean and smooth
cyclization to the desired spiro intermediate 8, obtained as the
exclusive product. A final decarbethoxylation gave the desired
key intermediate, ( )-9.
It is well established that carbenoid CH insertion reactions of
the type leading to compound 8 proceed with retention of config-
uration.10 Consequently, the use of enantioenriched acid 5 in the
above sequence materialized as a good strategy for the production
of nonracemic 9. This prompted us to study the resolution of acid
( )-5 by crystallization of diastereomeric salts obtained by reaction
with chiral, enantiopure amines.
Table 1 reports a selection of amines and solvents used in rep-
resentative crystallization experiments. All the precipitates were
filtered and analyzed by chiral HPLC to evaluate the enantiomeric
excess of the acid component. Best results were obtained with
(2-naphthyl)ethylamine in both THF and dioxane. The desired (S)
-5 was readily obtained by using (R)-(+)-1-(2-naphthyl)ethylamine
and dioxane was the solvent of choice for the recrystallization, be-
cause of the better recovery obtained compared to THF. The requi-
site enantiomeric excess (98% ee) for progressing with the
chemical route required up to five crystallizations.11
O
OH
N2
O
O
S
(S)-9
(S)-5
(S)-7
Figure 2. Stereo-conservative diazo-insertion.
cyclization step via carbenoid CH insertion had occurred with com-
plete retention of configuration.
The final step on the way to 1 was the reductive amination of
(S)-9 with methyl 3-azetidinecarboxylate, a reaction leading to
the formation of the second stereogenic center of the molecule
(Scheme 2).12 This transformation was carried out using the cus-
tomary NaBH(OAc)3 as the reductant, resulting in formation of a
favorable 80/20 diastereomeric ratio of products 10. Separation
of the two diastereoisomers by conventional chromatography
proved to be extremely tedious. In order to avoid resorting to the
use of preparative HPLC, the separation of the two diastereomers
of 10 by crystallization of salts prepared using chiral acids was
investigated. As shown, in Table 2, best results were obtained using
D
-malic acid and acetone as solvent. Four consecutive crystalliza-
tions were required to obtain a single diastereoisomer.13
The last step, the hydrolysis to give the desired final compound
1, proceeded smoothly under standard conditions using potassium
hydroxide in methanol/water (3:1).
In conclusion, a new synthesis of lead compound 1 that avoids
two preparative chiral HPLC separations was achieved. Key to the
success of the new route were the resolution of ( )-5 with (R)-
(+)-1-(2-naphtyl)ethylamine, leading to an efficient multigram
The sequence of Figure 2 permitted the efficient conversion of
enantioenriched (S)-5 into (S)-7, which in turn underwent Rh-
catalyzed cyclization to (S)-9. In accord with the literature,10 the
O
O
Table 1
Resolution of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)propanoic acid (5)
with chiral amines
O
N
Chiral amines
Ethyl acetate MeCN
THF
Dioxane
ii
i
S-(ꢀ)-1-(2-
4% ee
2% ee
55% ee 47% ee
1
Naphtyl)ethylamine
S-(ꢀ)-1-Aminotetralin
S-(ꢀ)-1-Phenylpropylamine
Cinchonidin
S
4% ee
Sol.
0% ee
—
2% ee
10% ee Sol.
0% ee
—
Sol.
—
(S)-9
—
10
Sol.
—
—
46% ee
R-(+)-1-(2-Naphtyl)ethylamine
Scheme 2. Synthesis of the final compound 1: (i) methyl 3-azetidinecarboxylate,
Sol. solution (no precipitation was observed), — not performed.
DCE, NaBH(OAc)3, rt, (ii) KOH, MeOH.

M. Gianotti et al. / Tetrahedron Letters 52 (2011) 329–331
331
Table 2
(i) DCM, oxalyl chloride, DMF; (ii) (a) Et2O, TMSCHN2; (b) KF/MeOH; (iii) DCM,
Rh2(OAc)4.
Crystallization of 10 with chiral acids
4. (a) Maguire, A. R.; Buckley, N. R.; O’Leary, P.; Ferguson, G. J. Chem. Soc., Perkin
Trans. 1 1998, 24, 4077–4091; (b) Maguire, A. R.; O’Leary, P.; Harrington, F.;
Lawrence, S. E.; Blake, A. J. J. Org. Chem. 2001, 66, 7166–7177.
5. Taljaard, B.; Taljaard, J. H.; Imrie, C.; Caira, M. R. Eur. J. Org. Chem. 2005, 12,
2607–2619.
6. Nitta, Y.; Watanabe, J.; Okuyama, T.; Sugimura, T. J. Catal. 2005, 236, 164–167.
7. (a) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1979, 18,
72–74; (b) Mansour, T. S.; Evans, C. A. Synth. Commun. 1990, 20, 773–781.
Chiral acids
Ethyl acetate
IPA
THF
Acetone
Tartaric acid (+)
53% de
54% de
54% de
60% de
58% de
78% de
Sol.
Sol.
84% de
Sol.
Sol.
84% de
Tartaric acid (ꢀ)
D-Malic acid
Sol.
Sol.
35% de
56% de
Sol.
Sol.
Sol.
Sol.
L
-Malic acid
Dibenzoyl-
D
-tartaric acid
8. The a-diazo-b-ketoester intermediate 7 demonstrated to be thermically stable
up to 90 °C by means of DSC (Differential Scanning Calorimetry) analysis.
Sol. solution (no precipitation was observed).
9. Bollinger, F. W.; Tuma, L. D. Synlett 1996, 407–413.
10. Muller, P.; Bolea, C. Helv. Chim. Acta 2002, 85, 483–494.
11. Resolution of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)propanoic
acid (5) by crystallization of the (R)-(+)-1-(2-naphtyl)ethylamine salt. 3-
(10,11-Dihydro-5H-dibenzo[a,d] cyclohepten-10-yl)propanoic acid (5, 1.22 Kg,
procedure to obtain enantiopure acid intermediate (S)-5, and the
separation of the diastereomers of compound 10 by crystallization
of the corresponding salts of D-malic acid. Besides enabling the
conduct of the full preclinical characterization, the new synthesis
demonstrates the yet undocumented resolution of substances of
type 5 and the enantioselective assembly of spiroketones such as
9. These advances are likely to be of interest to medicinal and syn-
thetic organic chemists alike.
4.56 mol)
was
dissolved
in
dioxane
(30 L)
and
(R)-(+)-1-(2-
naphthyl)ethylamine (781 g, 4.56 mol) was added portionwise. Soon a white
precipitate appeared. The mixture was stirred for 2 h and then the precipitate,
a white solid, was filtered and oven-dried at 55 °C under vacuum overnight.
This afforded 1240 g of a white solid, which was suspended in 10 L of dioxane
and heated to 95 °C in order to achieve complete dissolution. The solution was
left to cool to room temperature and stirred for 1 h. The white precipitate was
filtered and dried as described before to provide 994 g of a white solid, which
was suspended in 10 L of dioxane and heated to 95 °C in order to achieve
complete dissolution. The solution was cooled to about 40 °C and the white
precipitate that formed was filtered and dried as detailed above to furnish
760 g of a white solid. Two additional recrystallizations (five crystallizations
total) gave 580 g of (S)-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-
yl)propanoic acid, [(1R)-1-(2-naphthalenyl)ethyl]amine salt, as a white solid.
A chiral HPLC assay indicated that the optical purity of the acid corresponded
to 98% ee.
Supplementary data
Supplementary data (all the experimental procedures, charac-
terization, for compounds 3–9) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.11.039.
Preparation of free acid (S)-5. The above salt (667.8 g, 1.53 mol) was dissolved
in ethyl acetate (7 L) and treated with aqueous 1 M HCl solution (2 ꢁ 7 L and
1 ꢁ 4 L). Separation of the aqueous layers and evaporation of the organic phase
afforded 337 g (83% yield) of (S)-3-((10S)-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-10-yl)propanoic acid, (S)-5.
References and notes
12. The absolute configuration of the amino ester 10 and of the final amino acid 1
was not determined. During the exploration of the SAR, few attempts have
been done to determine stereochemistry on the final amino acids or the
precursor amino esters and we were successful only in one example, by VCD
analysis, whose results are still under consideration.
1. (a) Renger, J. J. Curr. Top. Med. Chem. 2008, 8, 937–953; (b) Gianotti, M.; Corti,
C.; Delle Fratte, S.; Di Fabio, R.; Leslie, C. P.; Pavone, F.; Piccoli, L.; Stasi, L.;
Wigglesworth, M. J. Bioorg. Med. Chem. Lett. 2010, 20, 5069–5073.
2. Gianotti, M.; Botta, M.; Brough, S.; Carletti, R.; Castiglioni, E.; Corti, C.; Dal-Cin,
M.; Delle Fratte, S.; Korajac, D.; Lovric, M.; Merlo, G.; Mesic, M.; Pavone, F.;
Piccoli, L.; Rast, S.; Roscic, M.; Sava, A.; Smehil, M.; Stasi, L.; Togninelli, A.;
Wigglesworth, M. J. J. Med. Chem. 2010, 53, 7778–7795.
13. Separation of the diastereomers of 10 by crystallization of its salt with D-malic
acid. Methyl 1-(50,110-dihydrospiro [cyclopentane-1,10’-dibenzo[a,d]cyclo-
hepten]-3-yl)-3-azetidine-carboxylate (10, 1.2 g, 3.32 mmol) was dissolved in
3.
acetone (12 mL), then
yellow solution was left at rt. overnight, whereupon
D
-malic acid (1 equiv) was added. The resulting light
white precipitate
N+
N
a
Cl
formed. This solid was filtered and triturated four times with acetone (12–
15 mL) to give a diastereomerically pure malate salt (840 mg, white solid) of
10. This solid was then treated with aqueous saturated NaHCO3 solution and
the aqueous phase was extracted with DCM to give pure 10 (592 mg, 49%
yield).
O
O
i
9
ii
iii
5
+
by-products