Practical synthesis of structurally important spirodiamine templates

Article abstract of DOI:10.1080/00397910701571599

A general, concise, four-step synthetic sequence for the preparation of spirodiamine templates is described herein. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701571599

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Practical Synthesis of Structurally Important
Spirodiamine Templates
F.‐Y. Tang a , L.‐Q. Qu a , Y. Xu a , R.‐J. Ma a , Dr. Shu‐Hui Chen a & G. Li a
a Chemistry Division, WuXi PharmaTech Co., Ltd., Shanghai, P. R. China
Version of record first published: 19 Oct 2007.
To cite this article: F.‐Y. Tang, L.‐Q. Qu, Y. Xu, R.‐J. Ma, Dr. Shu‐Hui Chen & G. Li (2007): Practical Synthesis
of Structurally Important Spirodiamine Templates, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:21, 3793-3799
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Synthetic Communicationsw, 37: 3793–3799, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701571599
Practical Synthesis of Structurally
Important Spirodiamine Templates
F.-Y. Tang, L.-Q. Qu, Y. Xu, R.-J. Ma, S.-H. Chen, and G. Li
Chemistry Division, WuXi PharmaTech Co., Ltd.,Shanghai, P. R. China
Abstract: A general, concise, four-step synthetic sequence for the preparation of spiro-
diamine templates is described herein.
Keywords: a-aza-bicyclo templates, a-“N”-bearing spirodiamies, spirodiamines
INTRODUCTION
The incorporation of spiro-bicyclic ring systems into many bioactive molecules
is one of the key strategies in modern medicinal chemistry. This is due primarily
to their structural rigidity along with feasibility for further structural elaboration
through three-dimensional drug space. A recent survey reveals the popularity of
the spirodiamine scaffolds with heteroatom attached directly to the nearby
spiro-carbon atom as shown in Fig. 1. For example, the [6,6]-spiro scaffold A
showed pharmacological activity on synaptic conductance and was believed
to confer neurotoxic activities.[1] The recent interest in [5,7]-aza-bicyclic
system B stemmed from the successful use of aza-siprolactams as beta-turn
mimetics.[2] Furthermore, the discovery of quinolone antibacterial agents con-
taining the [5,5]-spirodiamine moiety (e.g., compound C) has garnered
further interest in the synthesis of such aza-spiro scaffolds (see Fig. 1).
Prompted by intriguing biological and pharmacological activities
exhibited by the spirodiamine scaffolds as shown in Fig. 1, we decided to
devise practical synthetic routes for those a-nitrogen-containing spirodia-
mines as outlined in Fig. 2, namely [5,5]-, [6,5]-, [5,6]-, and [6,6]-scaffolds.
Received January 25, 2007
Address correspondence to Dr. Shu-Hui Chen, Chemistry Division, WuXi Pharma-
Tech Co., Ltd., Building No. 1, 288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone,
Shanghai 200131, China. E-mail: chen_shuhui@pharmatechs.com
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F.-Y. Tang et al.
Figure 1. Examples of spirodiamine structures.
We believe that these structural motifs can be incorporated into diverse bio-
logically active molecules.
Figure 2. Spirodiamine templates of interest.
Despite their growing popularity in medicinal chemistry, a practical
synthetic method directed toward spirodiamines with a-heteroatom is sub
optimal. For example, the reported four-step procedure (consisting of C-alky-
lation, cyano reduction, second ring closure, and amido-reduction) for the
synthesis of [5,5]-spiro template as shown in Fig. 3 suffers from poor
overall yield (only 2.6%).[3]
With the intention of designing a high-yielding and general methodology,
we have devised an efficient route as shown in Scheme 1.[4] In this event, N-
Boc proline 1 was converted to its carboxamide 2 (60%) and thereafter the
cyano derivative 3 in 85% yield via trifluoro acetic anhydride/triethyl
amine (TFAA/TEA)-mediated dehydration reaction. Treatment of 3 with
lithium diisopropyl amine (LDA) followed by 1-bromo-2-chloro-ethane led
to the C-1 alkylated compound 4 (55%), which was further transformed to
the [5,5]-spirodiamine template 5 (90%) via Raney Ni–mediated cyano
Figure 3. Literature route toward the synthesis of [5,5]-template: (a) ClCH2CN,
LDA, 40%; (b) H2, Raney Ni; (c) heat, 36% two steps; (d) LAH, 18%.

Spirodiamine Templates
3795
Scheme 1. Efficient synthetic routes for [5,5]- and [5,6]-templates: (a) i-PrOC (O)Cl,
NH3-H2O, 60%; (b) TFAA, Et3N, 85%; (c) LDA, BrCH2CH2Cl, 55%; (d) H2,
Raney Ni, NH3-H2O, 90%; (e) LDA, ClCH2CH2CH2Cl, 75%; (f) H2, Raney Ni,
NH3-H2O, 95%.
reduction and subsequent ring closure. Following the same sequence as
described for the target template 5, compound 3 was subjected to C-alkylation
with ClCH2CH2CH2Cl to afford the desired C-1 alkylated product 6 in 75%
yield. This intermediate was further converted to the target [6,5]-spirodiamine
template 7 via an one-pot process in 95% yield. It is worthwhile to mention
that the four-step overall yields for the templates 5 and 7 are 25 and 36%,
respectively. This represents a significant improvement over that reported
(2.6%) in Ref. [3].
Following the same strategy as outlined in Scheme 1, the syntheses of [5,6]-
and [6,6]-spirodiamines employed N-Boc pipcolic acid 8 as the starting
material. A two-step procedure was used to convert the acid 8 into its C-1
cyano derivative 10 in 50% overall yield. Subsequent C-1 alkylation on 10
Scheme 2. Efficient synthetic routes for [6,5]- and [6,6]-templates: (a) i-PrOC (O)Cl,
NH3-H2O, 60%; (b) TFAA, TEA, 89%; (c) LDA, BrCH2CH2Cl, 50%; (d) H2,
Raney Ni, NH3-H2O, 92%; (e) LDA, BrCH2CH2CH2Cl, 65%; (f) H2, Raney Ni,
NH3-H2O, 90%.

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F.-Y. Tang et al.
with appropriate alkyl halides afforded the expected products 11 (50%) and 13
(65%), which were further converted to the desired templates 12 (92%) and 14
(90%) via Raney Ni–mediated cyano reduction and ammonia–water–
mediated ring-closure reaction. The overall four-step yields for the [5,6]- and
[6,6]-spirodiamine templates are 25% and 31% (Scheme 2).
In summary, we have designed an efficient four-step sequence for the
preparation of a-nitrogen containing spirodiamine templates 5, 7, 12, and
14. The overall yields for the target templates range between 25 and 36%.
It is conceivable that the synthetic route reported herewith will allow for
synthesis of related spirodiamines bearing different ring sizes.
EXPERIMENTAL
Unless otherwise mentioned, reagents were obtained commercially and used
1
1
without further purification. H NMR, 13C NMR and H-13C HMQC were
taken with Bruker AM-400 Hz spectrometer in CDCl3. MS was taken with
Shimadzu 2010.
tert-Butyl 2-Carbamoylpyrrolidine-1-carboxylate (2)
A solution of Boc-proline (10.75 g, 0.05 mol) and Et3N (22.5 g, 0.225 mol) in
dichloromethane (50 ml) was cooled to 2308C and then treated with
isopropyl chloroformate (12.2 g, 0.1 mol) at 2308C. After complete
addition, the resulting mixture was stirred at 230 to 2208C for 30 min, and
.
this mixture was treated with conc. NH3 H2O (11 ml, 0.15 mol) at 2308C
in a period of 30 min. This mixture was allowed to warm up to room tempera-
ture and stirred overnight. The reaction mixture was washed with water
(3 ꢀ 50 ml), dried over Na2SO4, filtered, and concentrated under reduced
1
pressure to give 2 (6.45 g, yield 60%) as a white solid. H NMR (400 MHz,
CDCl3): 5.50–7.01 (m, 2H), 4.87 (m, 1H), 4.35 (m, 1H), 3.44 (m, 1H),
1.75–1.99 (m, 4H), 1.43 (s, 9H): MS (m/z): 215 (M þ 1).
tert-Butyl 2-Cyanopyrrolidine-1-carboxylate (3)
A solution of compound 2 (10.70 g, 0.05 mol) in dichloromethane (300 ml)
and Et3N (22.7 g, 0.225 mol) was cooled to 08C and then treated with
TFAA (21.0 g, 0.1 mol) at 08C. After complete addition, the mixture was
allowed to warm up to room temperature and stirred overnight. The reaction
mixture was washed with water (3 ꢀ 50 ml), 0.5 M HCl, and aqueous
NaHCO3; dried over Na2SO4; filtered; and concentrated under reduced
pressure to give compound 3 (8.33 g, yield 85%) as a yellow solid.
1H NMR (400 MHz, CDCl3): 4.43 (m, 1H), 3.31–3.55 (m, 2H), 1.96–2.30
(m, 4H), 1.49 (s, 9H): MS (m/z): 197 (M þ 1).

Spirodiamine Templates
3797
tert-Butyl 2-(2-Chloroethyl)-2-cyanopyrrolidine-1-carboxylate (4)
A solution of n-BuLi (2.5 M, 12 ml, 0.03 mol) in THF was added to a
solution of diisopropylamine (5.6 ml, 0.04 mol) in THF (30 ml) under an
N2 atmosphere at 2 788C. After 30 min, compound 3 (4.91 g, 0.025 mol)
was added to the mixture at 2788C. After complete addition, the resulting
mixture was stirred at 2788C for 45 min. 1-Bromo-2-chloro-ethane (4.1 ml,
0.05 mol) was added to the mixture at 2788C. After complete addition, the
mixture was allowed to warm up to room temperature and stirred overnight.
The reaction mixture was quenched by aqueous NH4Cl and extracted with
EtOAc (50 ml ꢀ 3). The combined organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to give crude compound 4
(5.4 g) as a brown liquid. The crude product was purified by silica column
chromatography to afford compound 4 (3.5 g, yield 55%) as a yellow solid.
1H NMR (400 MHz, CDCl3): 3.41–3.95 (m, 4H), 2.21–2.65 (m, 2H), 1.71–
2.35 (m, 4H), 1.50 (s, 9H): MS (m/z): 203 (M-23), 259 (M þ 1).
tert-Butyl 1,7-Diazaspiro[4.4]nonane-1-carboxylate (5)
A solution of compound 4 (1.1 g, 4.4 mmol) in methanol (40 ml) and conc.
.
NH3 H2O (2.8 ml) was stirred with Raney Ni (1 g) under an H2 atmosphere
(30 psi) at 508C for 6 h. After filtrating off Raney Ni, the filtrate was concen-
trated under reduced pressure to give compound 5 (1.0 g, yield 90%). 1H NMR
(400 MHz, CDCl3): 3.20–3.50 (m, 3H), 2.16–2.67 (m, 4H), 1.62–1.89
(m, 5H), 1.49 (s, 9H): 13C NMR (400 MHz, CDCl3): 154.7, 81.1, 67.4,
1
53.7, 47.8, 46.0, 39.8, 36.1, 28.5, 23.2; H-13C HMQC: H3.22, 3.48/C53.7;
H3.23, 2.67/C47.8; H2.16, 2.43/C47.8; H2.23, 1.89/C46.0; H1.76, 1.80/
C36.1; H1.62, 1.70/C23.2; MS (m/z): 227 (M þ 1).
tert-Butyl 2-(3-Chloropropyl)-2-cyanopyrrolidine-1-carboxylate (6)
General procedure for compound 4 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 3.31–3.75 (m, 4H), 2.35–2.51 (m, 2H), 1.70–2.25
(m, 6H), 1.51 (s, 9H): MS (m/z): 295 (M þ 23).
tert-Butyl 1,7-Diazaspiro[4.5]decane-1-carboxylate (7)
General procedure for compound 5 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 2.80–3.48 (m, 6H), 1.60–2.67 (m, 8H), 1.49
(s, 9H): 13C NMR (400 MHz, CDCl3): 154.3, 80.3, 62.3, 48.3, 43.4, 37.3,
31.4, 28.7, 28.5, 21.8, 20.8; 1H-13C HMQC: H3.48, 3.02/C48.3; H3.15,
2.92/C43.4; H3.20, 2.80/C37.3; H2.67, 2.25/C31.4; H2.05, 1.90/H28.7;
H1.98, 1.85/21.8; H1.65, 1.60/C20.8; MS (m/z): 241 (M þ 1).

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F.-Y. Tang et al.
tert-Butyl 2-Carbamoylpiperidine-1-carboxylate (9)
General procedure for compound 2 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 6.12 (m, 2H), 4.70 (m, 1H), 4.11 (m, 1H), 2.70
(m, 1H), 2.25 (m, 1H), 1.46 (s, 9H), 1.38–1.70 (m, 5H): MS (m/z): 229
(M þ 1).
tert-Butyl 2-Cyanopiperidine-1-carboxylate (10)
1H NMR (400 MHz, CDCl3): 5.25 (m, 1H), 4.02 (m, 1H), 3.61 (m, 1H), 2.98
(m, 1H), 1.45–1.85 (m, 6H), 1.47 (s, 9H): MS (m/z): 155 (M-56), 211
(M þ 1), 233 (M þ 23).
tert-Butyl 2-(2-chloroethyl)-2-cyanopiperidine-1-carboxylate (11)
General procedure for compound 4 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 3.75 (d, 1H), 3.64 (t, 2H, J ¼ 10 Hz), 3.10 (m, 1H),
2.50 (m, 1H), 2.05 (m, 1H), 1.45–1.70 (m, 6H), 1.51 (s, 9H): MS (m/z): 217
(M-56), 295 (M þ 23).
tert-Butyl 2,6-Diazaspiro[4.5]decane-6-carboxylate (12)
General procedure for compound 5 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 2.99–3.69 (m, 6H), 1.52–2.18 (m, 8H), 1.43
(s, 9H); 13C NMR (400 MHz, CDCl3): 156.2, 80.4, 62.3, 58.3, 43.0, 41.2,
36.8, 29.6, 28.4, 23.5, 20.5; 1H-13C HMQC: H3.69, 2.89/C58.3; H3.21,
3.20/C43.0; H3.45, 3.05/C41.2; H2.18, 1.95/C36.8; H2.00, 1.93/C29.6;
H1.72, 1.59/C23.5; H1.65, 1.52/C20.5; MS (m/z): 241 (M þ 1).
tert-Butyl 2-(3-chloropropyl)-2-cyanopiperidine-1-carboxylate (13)
General procedure for compound 4 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 3.75 (dd, 1H, J ¼ 4 Hz), 3.59 (tetra, 2H,
J ¼ 6.4 Hz), 3.10 (m, 1H), 2.14–2.20 (m, 2H, J ¼ 5.2 Hz), 1.60–2.05
(m, 8H), 1.51 (s, 9H): MS (m/z): 231 (M-56), 309 (M þ 23).
tert-Butyl 1,8-Diazaspiro[5.5]undecane-1-carboxylate (14)
General procedure for compound 5 was followed to afford the title product. 1H
NMR (400 MHz, CDCl3): 2.44–4.01 (m, 6H), 1.50–1.75 (m, 10H), 1.43
(s, 9H); 13C NMR (400 MHz, CDCl3): 156.4, 81.6, 63.4, 52.3, 42.0, 36.8,

Spirodiamine Templates
3799
29.4, 28.7, 28.5, 28.4, 24.6, 19.0; 1H-13C HMQC: H4.01, 3.25/C52.3; H3.55,
2.46/C42.0; H3.16, 2.65/C36.8; H1.58, 1.55/C29.4; H1.75, 1.65/C28.5;
H1.70, 1.63/C28.4; H1.68, 1.59/C24.6; H1.50, 1.55/C19.0; MS (m/z): 255
(M þ 1).
ACKNOWLEDGMENT
We thank Kai Gu and Ning Zhao for analytic support.
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1. Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1993, 58, 6451–6456.
2. Pettersen, D.; Ahlberg, P. Tetrahedron: Asymmetry 2005, 16, 2075–2080.
3. Culbertson, T. P.; Sanchez, J. P.; Gambino, L.; Sesnie, J. A. J. Med. Chem. 1990, 33,
2270–2275.
4. Tang, F.-Y.; Qu, L.-Q.; Xu, Y.; Ma, R.; Chen, S. H.; Li, G. Preparation of a-aza
spiro-bicyclo templates, application no. 200610027069.9, May 30, 2006.