Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2010.09.049

We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is

Full text of DOI:10.1016/j.bmcl.2010.09.049

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6524–6532
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of highly potent and efficacious MC4R agonists with spiroindane
N-Me-1,2,4-triazole privileged structures for the treatment of obesity
Shuwen He a, , Zhixiong Ye a, Peter H. Dobbelaar a, Raman K. Bakshi a, Qingmei Hong a, James P. Dellureficio a,
⇑
Iyassu K. Sebhat a, Liangqin Guo a, Jian Liu a, Tianying Jian a, Yingjie Lai a, Christopher L. Franklin a,
Mikhail Reibarkh a, Mark A. Holmes a, David H. Weinberg b, Tanya MacNeil b, Rui Tang b,
Constantin Tamvakopoulos c, Qianping Peng c, Randy R. Miller c, Ralph A. Stearns c, Howard Y. Chen b,
Airu S. Chen b, Alison M. Strack d, Tung M. Fong b, Matthew J. Wyvratt Jr. a, Ravi P. Nargund a
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
b Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
c Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
d Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 May 2010
Revised 8 September 2010
Accepted 10 September 2010
Available online 19 September 2010
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Com-
pound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obes-
ity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R.
Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound
32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Spiroindane
Triazole
Privileged structure
Melanocortin subtype-4 receptor
MC4R
Agonist
Obesity
The melanocortin receptors are a family of seven-transmem-
brane G-protein coupled receptors (GPCR’s) with five subtypes
(MC1R–MC5R). The endogenous peptides (melanocortins), derived
from common precursor proopiomelanocortin (POMC), interact
with the melanocortin receptors to regulate many important
physiological functions, including energy homeostasis, skin pig-
mentation, steroidogenesis, sexual functions, and exocrine gland
secretion.1
There have been intense efforts from our laboratories and other
research groups to identify selective small molecule MC4R ago-
nists.3,4 Recently, we disclosed the analogs based on spiroindane
amide privileged structures as potent and selective MC4R agonists
N
N
The evidence linking MC4R with energy balance and feeding
behaviors is compelling.2 The agouti mouse which expresses an
antagonist of MC1R, MC3R, and MC4R is obese, indicating that
blocking the actions of these receptors can lead to obesity. MC4R
knockout mice recapitulate the phenotype of the agouti mice, they
are hyperphagic and obese. Most convincingly, both non-sense and
frame shift variants in MC4R gene in humans lead to inherited
obesity.
F
F
O
O
(R)
(R)
(S)
(S)
N
N
F
F
Cl
Cl
(R)
(S)
O
N
R2
NHAc
R1
MK-0489
reverse amide analogs
⇑
Corresponding author. Tel.: +1 732 594 0881; fax: +1 732 594 3007.
E-mail address: shuwen_he@merck.com (S. He).
Figure 1. Structures of MK-0489 and the reverse amide analogs.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.049

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
6525
(Fig. 1).3h,3i In particular, MK-0489 has excellent pharmacokinetics
profiles in pre-clinical species. It shows excellent pro-erectile
activity in a mouse model and good efficacy in rodent obesity mod-
els. Furthermore, in the reverse amide series, analogs with S config-
uration significantly improve the potency on MC4R. Herein, we
describe the replacements of the amide with heterocycles (Fig. 2)
and the effects on MC4R activity.
N
N
F
F
O
O
N
OH
F
F
1
We carried out an SAR study varying heterocycles on the spiro-
indane privileged structure (Fig. 2), while keeping acid 1 top piece
intact.3f These heterocyclic privileged structures were synthesized
from the corresponding acid or acid equivalents.3i
Cl
NH
N
O
F
O
First we prepared the 1,3,4-oxadiazole analogs (Scheme 1). The
racemic acid 2 was converted to the acyl hydrazine 3, which was
then cyclized to form 1,3,4-oxadiazole privileged structure 4. This
racemic material was resolved by chiral HPLC to give two enantio-
mers 4e1 (first peak) and 4e2 (second peak). Boc group on each
enantiomer was removed.5 The resulting amines were coupled
with acid 1 to give single compounds 5d1 and 5d2.6
N
F
N
F
Cl
O
Het
N
F
We then synthesized analog 8 with methyl substituted 1,3,4-
oxadiazole (Scheme 2). The synthesis began with enantiomerically
pure acid 2a with S configuration since previously we showed that
reversed amide analogs (Fig. 1) with S configuration were much
more potent than their R isomers.3i Acid 2a was converted to amide
6 tethered with acetyl amide group, which cyclized to give a
methyl-1,3,4-oxadiazole intermediate, which was Boc protected
Cl
O
R1
N
R2
Figure 2. Design of spiroindane heterocyclic privileged structure.
O
O
N
N
N
N
F
F
F
F
O
O
O
O
OH
OH
OH
OH
F
F
F
F
1
27
28
29
Figure 3. Acid top pieces.
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
Cl
O
O
N
CO2H
N
HN NH2
2 (racemic)
3
4
c
4e1
4e2
N
d
F
O
N
F
Cl
O
N
N
5d1
5d2
Scheme 1. Preparation of 1,3,4-oxadiazole analog 5d1 and 5d2. Reagents and conditions: (a) (1) HOAt, EDC, DMF; (2) hydrazine monohydrate; (b) triethyl orthoformate,
155 °C; (c) chiral AS column, 9% 2-propanol in heptane; (d) (1) CAN, MeCN, 100 °C; (2) acid 1, HATU, HOAt, NMM, CH2Cl2.

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S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
Cl
O
O
N
(S)
CO2H
N
HN NH
O
2a (S)
6
7
N
F
O
N
c
F
Cl
O
N
N
8
Scheme 2. Preparation of 1,3,4-oxadiazole analog 8. Reagents and conditions: (a) (1) HOAt, EDC, DMF; (2) acetylhydrazine; (b) (1) POCl3, 100 °C; (2) NaOH (2 M, aqueous),
dioxane, Boc2O; (c) (1) 4 M HCl in dioxane; (2) acid 1, HATU, HOAt, NMM, CH2Cl2.
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
O
a
b
Cl
Cl
Cl
N
OH
N O
CN
NH2
NH2
10
11
9
N
F
CO2t-Bu
O
N
N
F
c
d
Cl
N
N
O
Cl
N
N
O
12
13
Scheme 3. Preparation of 1,2,4-oxadiazole analog 13. Reagents and conditions: (a) NH2OH HCl salt, NaOH (5 N, aqueous), EtOH, reflux; (b) acetic acid, diisopropylcar-
bodiimide, HOBt; (c) TBAF, THF; (d) (1) 4 M HCl in dioxane; (2) acid 1, HATU, HOAt, NMM, CH2Cl2.
to give 7 for the purpose of isolation since the Boc group is unstable
under POCl3 cyclization conditions. The privileged structure 7 was
then coupled with the acid 1 top piece to give analog 8.
We also prepared analog 13 with 1,2,4-oxadiazole (Scheme 3).
Racemic nitrile 9 was converted to amide oxime 10, which was
then acetylated to give intermediate 11. Upon treating with TBAF,
11 cyclized to give racemic privileged structure 12 with 1,2,4-oxa-
diazole, which was coupled with acid 1 to analog 13 containing
two diastereomeric isomers.
We then synthesized analog 16 with a privileged structure con-
taining oxazole (Scheme 4). Acid 2a was converted to amide 14,
which underwent AuCl3 catalyzed cyclization to give privileged
structure 15.7 A routine coupling with acid 1 afforded analog 16.
Analog 21 with 1,2,3-triazole was prepared from aldehyde 17
(Scheme 5), which was available from racemic nitrile 9 by DIBAL
reduction. Henry reaction of aldehyde 17 with nitromethane fol-
lowed by dehydration afforded nitroalkene 19, which was then
coupled with acid 1 to give 20. The nitroalkene moiety was then
transformed to 1,2,3,-triazole by treating with sodium azide. Since
the starting material nitrile 9 was racemic, analog 21 was a mix-
ture of two diastereomers.
Finally, we prepared analog 26 with N-Me-1,2,4-triazole (Scheme 6).
Primary amide 22 prepared from acid 2a, was condensed with N,N-
dimethylformamide dimethyl acetal to give intermediate 23,
which upon treatment of methyl hydrazine give the privileged
structure 24.8 The other possible regioisomer 25 was formed in
negligible amount and was not isolated. Routine coupling of 24
with the acid 1 afforded analog 26.
The in vitro potency of these analogs on human MC4R versus
MC1bR are summarized in Table 1.9 Agonism of MC1bR, an isoform
of MC1R involved in regulating skin and hair color, can lead to
undesirable skin darkening.9d To our excitement, analog 26 is

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
6527
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
Cl
O
O
N
(S)
CO2H
NH
15
2a
14
N
F
O
(R)
(S)
N
c
F
Cl
(S)
O
N
16
Scheme 4. Preparation of oxazole analog 16. Reagents and conditions: (a) (1) HOAt, EDC, DMF; (2) propargylamine hydrochloride, NMM; (b) AuCl3 (cat.), CH2Cl2; (c) (1) 4 M
HCl in dioxane; (2) acid 1, HATU, HOAt, NMM, CH2Cl2.
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
c
Cl
Cl
Cl
NO2
OH
CN
CHO
9 (racemic)
17
18
N
N
CO2t-Bu
N
F
F
O
O
N
N
d
e
F
Cl
F
NO2
Cl
Cl
N
NO2
N
19
N
H
20
21
Scheme 5. Preparation of 1,2,3-triazole analog 21. Reagents and conditions: (a) DIBAL, À78 °C; (b) MeNO2, NaOH (aq, 10 N, 1.5 equiv), EtOH; (c) Et3N, MsCl, EtOAc; (d) (1) 4 M
HCl in dioxane; (2) acid 1, HATU, HOAt, NMM, CH2Cl2; (e) NaN3, DMSO.
exceptional in that it is more than a magnitude more potent than
other analogs! Its rat pharmacokinetics profile is excellent, with
a half life of 9.4 h as well as excellent exposure (Table 2). It is also
highly efficacious in diet induced obese mouse obesity model.
Unfortunately, 26 also lowers food intake and body weight in
MC4R/3R double knockout mouse10 (see Supplementary data).
These results indicate that the efficacy observed is not solely med-
iated through MC4R.
To address this problem, we continued with the SAR study
keeping N-Me-1,2,4-triazole privileged structure while changing
the acid top piece. The structures of the top acid pieces are listed
in Figure 3. Acid 27 was previously incorporated in the structure
of RY-767, a potent MC4R agonist.11,12 Acid 28 was independently
discovered by us and a Neurocrine group.13,4e Acid 29 was origi-
nally identified in our laboratories as a MC4R potency enhancing
moiety exemplified in some analogs, which nevertheless were dia-
stereomeric mixtures at the stereogenic carbon next to the nitro-
gen atom on the cyclopentyl ring.13
We synthesized the top piece 29 in its pure form from enantio-
merically pure alkene acid 30 (Scheme 7). First, alkene acid 30 was
protected as the benzyl ester 31.14 Then the double bond was
cleaved oxidatively to give ketone 32. Reduction amination with
methyl amine followed Boc protection gave intermediate 33 as a
2:1 mixture of two diastereomers, which were separated by chiral
HPLC. Deprotection of the major isomer 33a (also the first peak
from chiral HPLC) followed by reductive amination with tetrahy-
dro-4H-pyran-4-one installed the tetrahydropyran group. Removal
of the Bn group by hydrogenolysis afforded the acid top piece 29 as
a homogenous material. The configuration of the newly created
stereogenic carbon was determined by NOE studies.

6528
S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
CO2t-Bu
N
CO2t-Bu
N
CO2t-Bu
N
a
b
Cl
Cl
Cl
O
O
(S)
CO2H
NH2
N
N
2a (S)
22
23
N
CO2t-Bu
N
F
O
N
c
d
F
Cl
N
N
Cl
N
N
N
24
N
26
CO2t-Bu
N
Cl
N
N
N
25
Scheme 6. Preparation of N-Me 1,2,4-triazole analog 26. Reagents and conditions: (a) (1) HOAt, EDC, DMF; (2) concd NH3 in H2O; (b) N,N-dimethylformamide dimethyl
acetal, 120 °C; (c) methylhydrazine, HOAc, 90 °C; (d) (1) 4 M HCl in dioxane; (2) acid 1, HATU, HOAt, NMM, CH2Cl2.
O
Boc
N
a
b
c
F
F
F
F
F
F
HO
BnO
BnO
F
F
BnO
O
O
O
O
30
31
32
33
Boc
Boc
N
N
F
F
F
F
d
+
BnO
BnO
O
O
33a
33b
NOE
e
O
H3C
O
O
N
H
H3C
N
NOE
HO
NOE
N
H
H
F
F
f
F
F
F
F
O
H
BnO
HO
O
O
29
34
29
Scheme 7. Preparation of acid top piece 29. Reagents and conditions: (a) BnOCOCl, Et3N, DAMP (cat.), CH2Cl2; (b) NaIO4, OsO4 (cat.), t-BuOH–H2O; (c) (1) MeNH2 HCl salt,
NaBH(OAc)3, Et3N, molecular sieves, CH2Cl2; (2) Boc2O, Et3N, NaOH (2 N, aqueous), CH2Cl2; (d) chiral OJ column, eluted with 20% 2-propanol in heptane; (e) (1) 4 M HCl in
dioxane; (2) tetrahydro-4H-pyran-4-one, NaBH(OAc)3, Et3N, molecular sieves, CH2Cl2; (f) Pd/C (cat.), HCl (1 M, aqueous), 2-propanol.

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
6529
Table 1
Analogs with spiroindane heterocyclic privileged structures: in vitro potency on human MC4R and MC1bR
Het
N
F
O
a
a
a
hMC4R binding IC50
(nM)
hMC4R agonism EC50 (nM)
(% activation)
hMC1bR agonism EC50 (nM)
(% activation)
Compound
N
F
Cl
Het
O
5d1
5d2
8
49
211 (117%)
2.2 (92%)
2.3 (97%)
14 (71%)
48 (99%)
NDb (10%)
138 (57%)
1145 (88%)
855 (46%)
1650 (57%)
N
N
N
O
N
O
1.3
1.9
5.7
9.7
N
O
N
N
13c
16
N
O
N
N
N
21c
26
16
4.2 (82%)
1040 (31%)
125 (80%)
N
H
N
0.41
0.23 (106%)
N
N
a
b
c
The reported data are the average of at least three repeated experiments.
Not determined.
A mixture of two diastereomers.
From acids 27, 28, and 29, we synthesized analogs 30, 31, and
32. Their structures and potency data are listed in Table 3 together
with data of analog 26 as a comparison. Compared with analog 26,
piperidine analog 30 is about 5–10-folds less potent on MC4R. Ana-
log 31 has slight loss of MC4R potency. However, analog 32 is more
potent than 26 on MC4R while its off-target activity on MC1bR is
also diminished.
Analogs 30, 31, and 32 were further evaluated in rat pharmaco-
kinetics (Table 4). Analogs 31 and 32 had good pharmacokinetic
profiles while analog 30 was outstanding with a long half life
(11 h) and excellent bioavailability (86%).
Table 2
Rat pharmacokinetic data for 26a
PK parameter
26
F (%)
26
Cl (mL minÀ1 kgÀ1
)
6.7
5.0
9.4
1.1
Vdss (L kgÀ1
t1/2 (h)
)
AUCn (lM h/mpk)
a
Compound dosed in Sprague–Dawley rats as a solution in EtOH/PEG400/water
(10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.
DIO-veh
DIO-veh
0.75
4
3
2
1
0
DIO-cpd A, 20mpk
DIO-cpd 32, 6mpk
DIO-cpd 32, 2mpk
15%
*
DIO-cpd A, 20mpk
17%
*
28%
**
DIO-cpd 32, 6mpk
0.25
DIO-cpd 32, 2mpk
*
-0.25
31%
39%
***
56%
***
***
*
*
-0.75
**
-1.25
4-hr FI
18-hr FI
Figure 4. Food intake (FI) and body weight (BW) in DIO mouse after oral dosing of analog 32 (*P <0.05; **P <0.01).

6530
S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
WT-veh
WT-cpd A, 20mpk
WT-cpd 32, 10mpk
KO-veh
0.75
0.25
5
4
3
2
1
0
KO-cpd 32, 10mpk
18%
**
30%
**
-0.25
-0.75
-1.25
WT-veh
35%
46%
WT-cpd A, 20mpk
WT-cpd 32, 10mpk
KO-veh
***
***
***
KO-cpd 32, 10mpk
***
4-hr FI
18-hr FI
Figure 5. Food intake (FI) and body weight (BW) in wild type (WT) mouse and MC4R/3R knockout (KO) mouse after oral dosing of analog 32 ( P <0.05; P <0.01).
**
*
25
20
15
10
5
PO Vehicle
cpd A,, 1100mmgg//kkgg
cpd 32 ,, 11mmgg//kkgg
cpd 32 ,, 33mmgg//kkgg
% suppr
31 9*
32 7*
56 5*
0
4:39:43 PM
8:39:42 PM
12:39:40 AM
4:39:40 AM
8:39:43 AM
Figure 6. Food intake (FI) in diet induced obese (DIO) rats after oral dosing of analog 32.
Table 3
Potency of triazole analogs on human MC4R and MC1bR
O
R
O
R
N
a
a
a
hMC4R binding IC50
(nM)
hMC4R agonism EC50 (nM)
(% activation)
hMC1b-R agonism EC50 nM
(% activation)
Compound
Cl
N
N
N
N
F
26
0.41
0.23 (106%)
125 (80%)
O
F
N
F
30
1.7
2.4 (96%)
1050 (37%)
O
F

S. He et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6524–6532
6531
Table 3 (continued)
O
R
O
R
N
a
a
a
hMC4R binding IC50
(nM)
hMC4R agonism EC50 (nM)
(% activation)
hMC1b-R agonism EC50 nM
(% activation)
Compound
Cl
N
N
N
O
N
31
0.84
0.90 (105%)
708 (54%)
F
O
F
O
N
32
0.43
0.11 (99%)
250 (49%)
F
O
F
The reported data are the average of at least three repeated experiments.
a
Table 4
Rat pharmacokinetic data for 30, 31, and 32a
intake by 56% and 32% at 3 mpk and 1 mpk, respectively. The effi-
cacy of analog 32 at 1 mpk was comparable to that of the positive
control (compound A) at 10 mpk. Therefore, analog 32 showed po-
tent efficacy in the DIO rat obesity model.
In summary, we have described our SAR study of MC4R agonists
in the spiroindane heterocyclic privileged structure series. This
work culminates in the identification of N-Me-1,2,4-triazole moi-
ety which significantly enhances MC4R in vitro potency. This priv-
ileged structure, in combination with an appropriate acid top piece,
results in MC4R agonists with excellent efficacy in rodent models
of obesity.
PK parameter
30
31
32
F (%)
86
22
19
11
1.1
35
37
10
3.4
0.24
20
24
9.7
5.1
0.20
Cl (mL minÀ1 kgÀ1
)
Vdss (L kgÀ1
t1/2 (h)
AUCn (lM h/mpk)
)
a
Compound dosed in Sprague–Dawley rats as a solution in EtOH/PEG400/water
(10:40:50) at 1 mg/kg, iv and 4 mg/kg, po.
These analogs were then tested in DIO mouse obesity model
and MC4R/3R double knockout (KO) versus wild type (WT) mouse
model. Similar to analog 26, analog 30 showed excellent efficacy in
DIO mice (see Supplementary data for data of analogs 30 and 31).
But it also reduced food intake and body weight in KO mice (see
Supplementary data), indicative of non-MC4R mediated effects.
Analog 31 had good efficacy in DIO mice. It slightly reduced food
intake in MC4R/3R knockout mice by 20% at 4 h time point
although the reduction was not statistically significant (P = 0.0
56). We were delighted to find that analog 32 was highly effica-
cious in the DIO mouse obesity model and that the efficacy was
mediated through MC4R. In the DIO mouse study, when dosed or-
ally at 6 mpk and 2 mpk, analog 32 reduced food intake by 56% and
31% at the 4 h time point, followed by 28% and 15% at 18 h time
point (Fig. 4). It also lowered body weight significantly. The efficacy
of 32 at 2 mpk was similar to that of compound A dosed at
20 mpk.15 In a KO mouse versus WT mouse study, analog 32 re-
duced food intake at 4 and 18 h, as well as body weight in WT mice,
but not in KO mice (Fig. 5). Therefore, analog 32 demonstrated M4R
mediated efficacy in mouse obesity models, resolving the off-target
issue associated with analog 26.16
Supplementary data
Supplementary data (NMR spectra of privileged structure 24
and efficacy data of analogs 26, 30, and 31 in DIO mouse as well
as MC4R/3R KO vs WT mouse) associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.2010.09.049.
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intake during 18 h after oral dosing (Fig. 6). Analog 32 reduced food

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15. Compound A was discovered previously in our laboratories. Ujjainwalla, F;
Sings, H. L. unpublished results.
F
F
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N
O
N
O
N
H
Cl
compound A
hMC4R binding IC50 70 nM
agonism EC50 18 nM
(97% act.)
5. Attempt to remove Boc group under routine conditions (e.g., 4 M HCl in
dioxane) was unsuccessful probably due to the instability of the oxadiazole
moiety. For Boc deprotection using ceric ammonium nitrate (CAN), see: Hwu, J.
R.; Jain, M. L.; Tsay, S.-C.; Hakimelahi, G. H. Tetrahedron Lett. 1996, 37, 2035.
6. The configurations of 5d1 and 5d2 were not firmly established. However, based
16. Analog 32 is potent on MC3R (hMC3R EC50 7.2 nM, 110% act.). It is highly
potent on murine MC4R (mMC4R EC50 0.052 nM, 117% act.). Its potency on
murine MC3R was not determined. If we assume the potency is similar to the
data on human MC3R, the possible involvement of MC3R in the efficacy
observed can not be ruled out completely, although analog 32 is over 100-fold
more potent on MC4R than MC3R.
on the potency on MC4R (Table 1), 5d1 likely has
spiroindane while 5d2 has S configuration.
R configuration on
7. Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
8. The structure of privileged structure 24 was established by NMR studies. See
the Supplementary data.