Angewandte
Chemie
Table 4: Acid-mediated methanolysis of the THP* auxiliary and pro-
duction of amino alcohols 22–28.
in the case of 9 and by chemical correlation methods for 12
and 13.
Reductive manipulation of the nitro group and non-
destructive removal of the THP* group was necessary to
confirm the effectiveness of this reaction as an asymmetric
method for the synthesis of amino alcohols. It was eventually
found that the most reliable way to reduce the nitro group was
a one-pot nickel boride reduction[9] with concomitant in situ
tert-butyloxycarbonyl (Boc) protection. The THP* group
functions as both a protecting group and a stereochemical
marker: Any epimerization of the newly formed stereogenic
Entry R1
1
Product Yield [%] ee [%] [a]2D5 (c)[a]
22
97
>98
À57.5 (1.01)
2
3
23
24
94
99
>98
>98
À19.9 (1.45)
À20.0 (1.00)
1
center would be observable in the H NMR spectra of the
products. Gratifyingly, no epimerization was observed, and
the N-Boc-protected amine products 15–21 were afforded in
good to excellent yields in all cases (Table 3).
4
25
84
>98
À37.8 (1.03)
À27.4 (1.06)[b]
À19.2 (1.00)[c]
À10.2 (1.00)
Table 3: Nickel boride reduction and in situ N-Boc-protection of the oxy-
Michael adducts 7 and 9–14.
5
6
7
26
27
28
74
84
99
>97
>96
>97
[a] Measured in CHCl3. [b] Ref. [a]2D5 =À28.8 (CHCl3, c=1.19)[4b]. [c] Ref.
[a]2D5 =À19.4 (CHCl3, c=0.94)[4b]
.
Entry
1
R1
Product
Yield [%]
98
15
1,2-amino alcohols. Further studies to ascertain the origin of
stereoselectivity and the scope of the reaction are ongoing.
2
3
16
17
57
80
Received: May 30, 2003 [Z52007]
Keywords: amino alcohols · diastereoselectivity · lactols ·
.
Michael addition · nitroalkenes
4
18
81
5
6
7
19
20
21
85
90
83
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Removal of the THP* group in the presence of methanol
and polymer-bound acid resin (MPTsOH II) was straightfor-
ward and afforded the N-Boc-protected amino alcohol
products 22–28 in good to excellent yields in all cases
following filtration and concentration in vacuo. Owing to
the high efficiency of the reaction and high volatility of the 6-
methyltetrahydropyranyl methyl ether side products, no
further purification was required. The ee values of the
products were determined by derivatization as their Mosher
esters[10] and were found to be superior to or equivalent to the
diastereomeric ratios obtained in the oxy-Michael addition
reactions (Table 4).
In summary, the “naked” alkoxide of 6-methyl-d-lactol,
formed by deprotonation with KHMDS and sequestering
with [18]crown-6, undergoes highly diastereoselective oxy-
Michael additions to a range of nitroalkene acceptors to give
the O-protected Henry products in good yields. Subsequent
reduction of the nitro group and acidic methanolysis of the
THP* group affords the desired enantiomerically enriched
Angew. Chem. Int. Ed. 2003, 42, 4241 –4244
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