6016
M. Haddad et al. / Tetrahedron Letters 46 (2005) 6015–6017
OH
O
O
O
CO2Me
CBz
a, b
a,b
PO
PO
c
MsO
CF3COHN
PO
HN
HN
N
N
N
CBz
CBz
CBz
CBz
5
9
3
d.e= 96%
2
(P = TBDPSi)
4
CO2Me
Scheme 1. Reagents and conditions: (a) Dibal-H, toluene, ꢀ78 °C, 6 h,
80%; (b) allyltrimethylsilane, SnCl4, ꢀ78 °C, 4 h, 70%; (c)
(CH3)2C(OCH3)2, APTS, benzene, reflux, 80%.
O
c, d
e
HN
CO2Me
CF3COHN
O
N
CBz
co-workers9 afforded the allylalcohol 3 which was pro-
tected under its acetonide form 4 (Scheme 1).
N
CBz
10
1
In a first approach, the silyl group was removed and the
free alcohol was activated with methanesulfonyl chlo-
ride to give 5. Next, the carbon chain was extended by
oxidative cleavage of the double bond followed by Wit-
tig reaction10 leading to the unsaturated ester 6. Substi-
tution of the mesylate group using sodium azide
afforded 7. Unfortunately, the azide 7 revealed to be
unstable and was converted on standing into the triazo-
line 8 as demonstrated by mass and IR spectra (Scheme
2). This result indicated that cyclization is possible even
under the acetonide form.
Scheme 3. Reagents and conditions: (a) NaN3, DMSO, 40–45 °C,
65%; (b) PPh3, H2O, THF, rt then (CF3CO)2O, NEt3, CH2Cl2, 76%;
(c) NaIO4, OsO4 cat, dioxane, H2O, 72%; (d) tetramethylguanidin,
(CH3O)2P(O)CH2CO2CH3, THF, ꢀ78 °C to rt, 80%; (e) NaBH4
(10 equiv), MeOH, 0 °C to rt, 50%.
NOE
H
6
H
2
CO2Me
N
H
CBzN
3
O
In view of these results, we decided to slightly modify
our strategy. For this purpose, compound 5 was reacted
in the following manner (Scheme 3): the mesyl group
was substituted with sodium azide, and the resulting
azide was reduced with triphenylphosphine in the pres-
ence of water to give the free amine.11 The latter was
used without purification and protected under its triflu-
oroacetate form 9. Compound 9 was treated in the same
conditions as described above to yield the unsaturated
ester 10.12 Deprotection of the trifluoroacetate group
was achieved by treatment of 10 with an excess of
sodium borohydride in methanol4 which was followed
by an intramolecular Michael reaction to form selec-
tively the cyclized product 1 as a single product.13
Figure 2.
ment; however, owing to the complexity of the signals, it
was not possible to calculate the coupling constant for
each proton. The NOE data revealed a clear interaction
between H-2 and H-6, indicating that all the substituents
of the piperidinic ring occupied an equatorial position in
a chair conformation as shown in Figure 2.
In conclusion, we have developed an efficient and highly
stereoselective method to access the conveniently substi-
tuted piperidine 1, a key intermediate toward the synthe-
sis of pseudodistomin D.
The stereochemistry of 1 was established by NMR
experiments: the COSY data allowed the proton assign-
Acknowledgment
We are grateful to Marie-Noe¨lle Rager for NMR experi-
ments and help for the determination of the stereochem-
istry of the final compound 1.
O
O
a, b
c, d
CO2Me
MsO
MsO
4
N
N
CBz
CBz
5
References and notes
6
1. Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.;
Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450–453.
2. Kobayashi, J.; Naito, K.; Doi, Y.; Deki, K.; Ishibashi, M.
J. Org. Chem. 1995, 60, 6941–6945.
3. Kiguchi, T.; Yumoto, Y.; Ninomiya, I.; Naito, T.; Deki,
K.; Ishibashi, M.; Kobayashi, J. Tetrahedron Lett. 1992,
33, 7389–7390.
CO2Me
N
O
N
N
e
CO2Me
N3
O
N
CBz
N
CBz
4. Knapp, S.; Hale, J. J. J. Org. Chem. 1993, 58, 2650–2651.
5. Freyer, A. J.; Patil, A. D.; Kilmer, L.; Troupe, N.;
Mentzer, M.; Carte, B.; Faucette, L.; Johnson, R. K. J.
Nat. Prod. 1997, 60, 986–990.
6. Trost, B. M.; Frandrick, D. R. Org. Lett. 2005, 7, 823–
826.
7
8
Scheme 2. Reagents and conditions: (a) nBu4 NF, THF, rt, 3 h, 90%;
(b) MsCl, NEt3, CH2Cl2, 85%; (c) NaIO4, OsO4 cat, dioxane, H2O,
70%; (d) tetramethylguanidin, (CH3O)2P(O)CH2CO2CH3, THF,
ꢀ78 °C to rt, 81%; (e) NaN3, DMSO, 40–45 °C, 12 h, 65%.
Haddad, Mansour
