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M. E. B. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 703–705
MeO2C NHBoc
O
O
MeO2C
NH
NH
NH
HO2C
NH2
i
i
O
+
O
Br
3a
4a
racemic
ii, iii
iv, v
2
ii,iii
MeO2C
NHBoc
MeO2C
NHBoc
MeO2C
NHBoc
HO2C
NHBoc
3b
3a
iv
OH
OH
Scheme 1. Reagents and conditions: (i) lactamase; (ii) SOCl2,
MeOH, 14 h, 0°C then room temp., 100%; (iii) (tert-
BuO2C)2O, NEt3, CH2Cl2, 2 h, 0°C, 98%; (iv) SOCl2, MeOH,
2 h, 0°C then room temp., 85%; (v) (tert-BuO2C)2O, NEt3,
CH2Cl2, 2 h, 0°C, 96%.
6a
5a
1a
1b
vii
v, vi
MeO2C
NHBoc
MeO2C
NHBoc
Cyclopentene 3a was subjected to an NBS-promoted
bromocyclisation, whereby formation of a cyclic carba-
mate 4a in high yield introduced the oxygen atom with
defined stereochemistry.6 Its treatment with alkali
effected elimination of HBr and the hydrolysis of both
the ester and carbamate functions. tert-Butoxycarbonyl-
ation in situ gave the key intermediate 5a as a white
solid in an overall 80% yield from 3a (Scheme 2). While
the hydrobromide elimination removes a stereocentre, it
gives the opportunity to form either of two new isomers
by way of stereodirected hydrogenation. Usefully,
hydrogenation over palladium on charcoal delivered
hydrogen to the least hindered olefin face to provide the
all cis-stereoisomer with a d.e. of 76% in a yield of 98%.
The purity could be raised by formation of the tert-
butylamine salt giving a d.e. of 98% in 65% yield, which
was then esterified using methyl chloroformate in
methanol to provide the requisite scaffold 1a in 92% as
a colourless oil. Its enantiomer 1c was generated using
an identical synthetic sequence from 3b. In contrast,
homogeneous hydrogenation in the presence of cata-
OH
OH
1e
xi, xii, xiii
viii, ix, x
MeO2C
NHBoc
MeO2C
NHBoc
OH
OH
1f
Scheme 2. Reagents and conditions: (i) NBS, THF–H2O
(10:1), room temp., 18 h, 95%; (ii) KOH, MeOH–H2O (1:1),
90°C, 3 days; (iii) (tert-BuO2C)2O, H2O–THF (5:1), pH 10.5,
5°C to room temp., 18 h, 84% (overall for steps (ii) and (iii));
(iv) MeOCOCl, NEt3, MeOH, 5°C then room temp., 18 h,
81%; (v) H2 (35 psi), Pd/C, MeOH, room temp., 18 h (d.e.
76%, 98%); (vi) MeOCOCl, NEt3, MeOH, 5°C then room
temp., 18 h, 86%; (vii) H2 (75 psi) {(R,R)-[MeDuPHOS]-
Rh(COD)}BF4, MeOH, room temp. (d.e. >97%, 100%); (viii)
MeSO2Cl, TEA, DMAP, CH2Cl2, 5°C, 3 h, 97%; (ix) KOAc,
DMF, 60°C, 48 h, 85%; (x) NaOMe, MeOH, 5°C, 7 h, 98%;
(xi) MeSO2Cl, TEA, DMAP, CH2Cl2, 5°C, 5 h, 94%; (xii)
KOAc, DMF, 60°C, 8 days, 88%; (xiii) NaOMe, MeOH, 5°C,
6 h, 98%.
7
lytic (R,R)-{[MeDuPHOS]-Rh(COD)}BF4 gave the
opposite stereoisomer. Hydrogenation was sluggish
using the carboxylic acid 5a, attributed to unproductive
co-ordination of the carboxylic acid function with the
rhodium catalyst,8 but with ester 6a reaction was rapid
giving 1e (d.e. 98, 100%).2 Likewise the opposite enan-
tiomer 1g was obtained from the 3b derived allylic
alcohol using the (S,S)-catalyst. The scope of this high
selectivity, which we attribute to secondary coordina-
tion to the catalyst from the butoxycarbonylamino
functionality, has been explored separately.2
3. Conclusion
We have demonstrated a scaleable synthesis of all eight
stereoisomers of a scaffold useful for the pharmaceuti-
cal industry. Interestingly, halogenated products
derived from scaffold 1d have been shown to be potent
conformationally rigid deactivators of g-aminobutyric
acid aminotransferase.10
Access to the scaffolds having the hydroxyl function in
a trans-relationship to the amino function 1b, 1d, 1f
and 1h was easily gained via a mesylation–acetate dis-
placement inversion sequence performed on 1a, 1c, 1e
and 1g using standard procedures. Scaffolds 1b, 1d, 1f
and 1h were isolated as white solids in 81–83% overall
yields. The absolute stereochemistry of all scaffolds is
assumed to be related to that of lactam 2.9 The relative
stereochemistry of scaffolds 1a, 1b, 1e and 1f was
determined by NOE experiments performed on the
Acknowledgements
We thank Dr. Mark Suto of DuPont Pharmaceuticals
for valuable discussions related to the choice of func-
tionality protection in these scaffolds for use to prepare
multi-compound libraries.
1
respective O-acetylated derivatives. H NMR spectral
data for 1d are in agreement with those previously
reported.10