Stereoselective nucleophilic substitution of 6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetate: application to the synthesis of a NK1 receptor antagonist

Article abstract of DOI:10.1016/j.tetlet.2007.03.104

Reaction of chiral cis- and trans-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetates with various nucleophiles (allyltrimethylsilane, bistrimethylsilylacetylene, benzyl alcohol, benzyl carbamate etc.) in the presence of a Lewis acid gave th

Full text of DOI:10.1016/j.tetlet.2007.03.104

Tetrahedron Letters 48 (2007) 3723–3726
Stereoselective nucleophilic substitution of
6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetate:
application to the synthesis of a NK1 receptor antagonistI
Kazutoshi Sugawara* and Tomiki Hashiyama
Medicinal Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
Received 15 February 2007; revised 15 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—Reaction of chiral cis- and trans-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetates with various nucleo-
philes (allyltrimethylsilane, bistrimethylsilylacetylene, benzyl alcohol, benzyl carbamate etc.) in the presence of a Lewis acid gave
the corresponding 2,3-unsaturated pyran derivatives in good to excellent yield with trans selectivity. Application to the synthesis
of NK1 antagonist is also described.
Ó 2007 Elsevier Ltd. All rights reserved.
In our previous paper,1 we have reported that the reac-
tion of cis-(3S,6S)-6-(tert-butyldimethylsilyloxy)-3,6-
dihydro-2H-pyran-3-yl acetate (1a) with allyltrimethyl-
silane in the presence of a Lewis acid gave a 6-allyl
substituted pyran derivative (2a) in a highly trans selec-
tive manner (Scheme 1). In this reaction, the tert-butyl-
dimethylsilyloxy group works as a good leaving group.
The remarkable stereoselectivity observed in this
reaction prompted us to investigate the reactivity and
stereoselectivity with various nuculeophiles, including
C-Nucleophiles, O-Nucleophiles, and N-Nucleophiles,
in the presence of a Lewis acid.
kinetic resolution method, followed by the Mitsunobu
reaction (Scheme 2).
Lewis-acid-promoted nucleophilic substitution of 1b or
5b with various nucleophiles is summarized in Table 1.
The use of catalytic amounts of Sc(OTf)32 showed com-
parable yield and selectivity to the stoichiometric use of
BF3ÆOEt2 (entry 1 vs 2). When allylsilane or bistrimeth-
ylsilyl acetylene was used as a nucleophile, the Lewis-
acid-promoted reaction proceeded with high trans
selectivity in good to excellent yields irrespective of the
stereochemistry of C-6 (entry 1 vs 3, 4 vs 5).3 The stereo-
chemistry observed in these reactions can be explained
by a common oxo-carbeniumion intermediate (Fig. 1).
In the intermediate, the acetoxy substituent preferen-
tially adopts a pseudo axial conformation (Aax) over
As substrates, (3R,6R)-cis (1b) and (3R,6S)-trans (5b)
were employed in order to investigate the influence of
the stereochemistry at C-6; they were synthesized from
rac-4 in a multi-gram scale through a Lipase-catalyzed
OH
OH
OH
ref.1
+
TBSO
O
TBSO
O
TBSO
O
(44%)
(44%)
OAc
+
OAc
OAc
4a >99% ee
4b >99% ee
TMS
rac-4
O
O
i
ii
TBSO
O
BF3·OEt2
1a
2a (91%)
3a (trace)
OAc
OAc
Scheme 1. Nucleophilic substitution reaction reported.1
TBSO
O
TBSO
O
1b
5b
q Numbering of the products follows pyranone numbering.
*
Scheme 2. Reagents and conditions: (i) Ac2O, NEt3, CH2Cl2, quant.;
Corresponding author. Tel.: +81 48 433 2503; fax: +81 48 433
(ii) diisopropylazodicarboxylate, PPh3, AcOH, THF, rt, 80%.
2610; e-mail: k-suga@tanabe.co.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.104

3724
K. Sugawara, T. Hashiyama / Tetrahedron Letters 48 (2007) 3723–3726
Table 1. Nucleophilic substitution reaction of 1b or 5ba
Run
1
Substrates
Nucleophiles
Conditions
Major productsb (trans:cis)
Yieldc (%)
91
Reference
1,3
OAc
OAc
TMS
BF3ÆOEt2 (1.3 equiv)
CH2Cl2, À40 °C
O
(2.0 equiv)
TBSO
O
1b
2b (95:5>)
TMS
2
3
1b
Sc(OTf)3 (0.5 mol %)
CH2Cl2, À40 to 0 °C
2b (92:8)
85
91
3
(2.0 equiv)
OAc
OAc
OAc
TMS
BF3ÆOEt2 (1.3 equiv)
CH2Cl2, À40 °C
2b (95:5>)
1,3
(2.0 equiv
)
TBSO
TBSO
TBSO
O
O
O
5b
1b
5b
OAc
TMS
TMS
TMS
4
5
TiCl4 (1.3 equiv)
CH2Cl2, À40 °C
O
66
72
3
3
(1.3 equiv
)
TMS
6b (95:5>)
TMS
TiCl4 (1.3 equiv)
CH2Cl2, À40 °C
6b (95:5>)
(1.3 equiv
)
OAc
OAc
6d
TMSCN
(5.0 equiv)
BF3ÆOEt2 (1.5 equiv)
CH2Cl2, À40 to 0 °C
or Sc(OTf)3 (0.5 mol %),
CH2Cl2, rt
Trace
O
N
TBSO
O
1b
7
OAc
O
O
7
1b
BnOH
(1.2 equiv)
BF3ÆOEt2 (20 mol %)
CH2Cl2, À40 °C
88
5
8b (82:18)
OAc
O
8e
1b
1b
BnOCONH2
(1.0 equiv)
BF3ÆOEt2 (1.0 equiv)
CH2Cl2, À40 to 0 °C
71
12
O
N
O
H
9b (79:21)
OAc
9
Et3SiH (2.0 equiv)
BF3ÆOEt2 (1.2 equiv)
CH2Cl2, À30 to 0 °C
75
12
O
10
a All reactions were performed in 0.22 M substrate concentration.
b Product ratio was estimated by using 1H NMR (300 MHz) analysis of the crude material.
c Isolated yield.
d When D-xyral was used as a substrate instead of 1b, 7 was obtained in 84% yield as shown below.
OAc
OAc
TMSCN
OAc
NC
O
Sc(OTf)3 (0.5 mol%)
(84%)
7
O
α:β = ca. 3:1
D-xyral
e Structures of 9 were elucidated by using NOE analysis shown below.
H
H
O
O
O
Ha
Hb
O
Ha
Hb
HN
O
HN
O
H
O
H
O
BnO
BnO
9b (trans
)
9b (cis)

K. Sugawara, T. Hashiyama / Tetrahedron Letters 48 (2007) 3723–3726
3725
AcO
H
These results suggest that an equilibrium between the
cis- and trans-isomers exists under these conditions.6
The OTBS group can be easily removed by Et3SiH in
the presence of BF3ÆOEt2 (entry 9).
O+
AcO
H
O+
Nu
Aeq
Aax
Next, we tried to apply this chemistry to the synthesis of
a selective human neurokin-1 (hNK1) receptor antago-
nist, which has been reported by a group at Merck7
(Scheme 3). In the synthetic scheme, 12 is a key interme-
diate in their synthetic array for tetrahydropyran NK1
antagonists, including 13.8 Thus, we chose this com-
pound as a synthetic target. Staring from 1b, treatment
with the known phenethyl alcohol 149 in the presence of
a catalytic amount of BF3ÆOEt2 afforded 15 as an insep-
arable mixture of epimers (8:1). After hydrolysis of the
acetate group, these epimers were readily separated by
SiO2 chromatography to give 16. The allyl alcohol moi-
ety of 16 was then oxidized with O-iodoxybenzoic acid
(IBX)10 to give enone 18, which was then subjected to
phenylcuprate-mediated 1,4-addition in the presence of
TMSCl. Crude silyl enol ether was then treated with
an aqueous solution of formaldehyde in the presence
Figure 1. Oxocarbenium intermediate.
an equatorial one (Aeq) due to the stabilization of the
electrostatic interactions between the partially nega-
tively charged oxygen of the substituent and the posi-
tively charged carbon of the oxocarbenium ion.
Therefore, the nucleophiles can attack the C-6 carbon
anti to the acetoxy group.4
It is noteworthy that the reaction with TMSCN gave
only trace amount of the desired product, in contrast
to the same reaction with D-xyral (footnote d and entry
6). When benzyl alcohol or benzylcarbamate was used
as a nucleophile, the reaction proceeded smoothly in
the presence of a catalytic amount of Lewis acid,
although with moderate selectivity (entry 7 and 8).
Me
O-
OH
+
H
O
N
O
9 steps
OBn
11
F
O
O
F
F
F
O
see ref. 6
(11% overall yield)
O
F
F
12
F
F
13
F
F
F
F
Scheme 3. Synthesis of NK1 antagonists reported by a group at Merck.
F
OH
O
F
F
OH
iii
O
F
O
O
F
O
O
F
F
F
F
14
O
F
F
ii
F
O
O
TBSO
i
F
F
F
F
F
1b
F
16
17
15
+
C-6 epimer
O
O
OH
OH
O
O
F
O
O
OH
F
F
vii
vi
F
iv
v
O
O
F
O
O
F
F
F
F
F
O
O
F
F
F
F
F
18
F
F
19
20
F
F
12
F
F
F
F
F
Scheme 4. Reagents and conditions: (i) BF3ÆOEt2 (20 mol %), CH2Cl2, À30 °C, 93%; (ii) K2CO3, MeOH, rt, 16: 82%, 17: 10%; (iii) IBX, DMSO, rt,
91%; (iv) PhMgBr, HMPA, CuBrÆSMe2, THF, À78 °C, then TMSCl; (v) 37% HCHO, Yb(OTf)3 (10 mol %), THF, rt; (vi) MS4A, toluene reflux, 72%
from 18; (vii) NH2NHTs, TsOH, MeOH, then NaBH3(CN), MS4A, THF, 50%.

3726
K. Sugawara, T. Hashiyama / Tetrahedron Letters 48 (2007) 3723–3726
of Yb(OTf)3 as a catalyst.11 Under these conditions,
hemiacetal 19 was obtained as an inseparable mixture
with the desired 20. Fortunately, 19 was readily con-
verted to the desired alcohol 20 by simply heating it in
toluene in the presence of MS4A. Finally, modified
Wolff–Kishner procedure, involving the formation of
tosylhydrazone, followed by its reduction with
NaBH3CN, afforded 12 (Scheme 4). As a result, we syn-
thesized 12 via a seven-step sequence with a 25% overall
yield from 1b.
3. Synthesis of 7a and 7b from Pentose glycals see: Hoso-
kawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett.
1998, 39, 1917, and reference cited therein.
4. Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am.
Chem. Soc. 2005, 127, 5322, and reference cited therein.
5. Synthesis of the enantiomers of 8b from 3,4-di-O-acetyl-D-
xylal, see: Cristina, F.; Roberta, G.; Giovanna, M.; Matio,
O. T. Tetrahedron: Asymmetry 2001, 12, 2731, and
reference cited therein.
6. When 8b was treated with BF3ÆOEt2 in CH2Cl2 at À40 °C,
formation of cis-8b was detected by HPLC analysis (ca.
15%). In the case of 9b, cis-isomer was detected in CDCl3
medium after allowing to stand at room temperature for
1 week.
7. Nelson, T. D.; Rosen, J. D.; Smitrovich, J. H.; Payack, J.;
Craig, B.; Matty, L.; Huffman, M. A.; McNamara, J. Org.
Lett. 2005, 7, 55, and reference cited therein.
In conclusion, we investigated the reactivity and stereo-
selectivity of the nucleophilic substitution reaction of
1b and 5b in the presence of a Lewis acid. Furthermore,
we showed the utility of this chemistry by the short ste-
reocontrolled synthesis of a NK1 antagonist. The chem-
istry developed during the course of this study should
allow access to a range of highly substituted tetrahydro-
pyran derivatives, as well as hNK1 antagonists.
8. Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams, B. J.
U.S. Patent 6,458,830 B1, 2001.
9. Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T.
D.; Candelario, A.; Huffman, M. A.; Zhao, M.; Li, J.;
Craig, B.; Song, Z.; Tschaen, D. M.; Hansen, K.;
Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P.; Reamer,
R. A.; Welch, C. J.; Mathre, D.; Tsou, N. N.; McNamara,
J. M.; Reider, P. J. J. Am. Chem. Soc. 2003, 125,
2129.
References and notes
10. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019.
1. Sugawara, K.; Imanishi, Y.; Hashiyama, T. Tetrahedron:
Asymmetry 2000, 11, 4529.
11. Kobayashi, S. Chem. Lett. 1991, 12, 2187.
12. All new compounds were fully characterized.
2. Aggarwal, V. K.; Vennall, G. P. Tetrahedron Lett. 1996,
37, 3745.