A new approach for construction of quarternary chiral centers: Preparation of α-branched serine derivatives

Article abstract of DOI:10.3987/COM-00-8863

In the presence of a Lewis acid, the Michael-type reaction of (3R)-5- tert-butyldimethylsiloxy-3-phenyl-1H-pyrrolo[1,2-c]oxazole (1) with nitro olefins smoothly occurred to give 7a-alkylated pyrrolo[1,2-c]oxazol-5-ones (2) in good yields. The products (2)

Full text of DOI:10.3987/COM-00-8863

HETEROCYCLES, Vol. 53, No. 5, 2000, pp. 1011 - 1016, Received, 2nd February, 2000
A NEW APPROACH FOR CONSTRUCTION OF QUARTERNARY
CHIRAL CENTERS:
DERIVATIVES
PREPARATION OF α-BRANCHED SERINE
†
Hidemitsu Uno,* Ken-ichi Kasahara, and Noboru Ono
Advanced Instrumentation Center for Chemical Analysis, Ehime University,
Bunkyo-cho 2-5, Matsuyama 790-8577, Japan
†
Department of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2-
5, Matsuyama 790-8577, Japan
Abstract—In the presence of a Lewis acid, the Michael-type reaction of (3R)-5-
tert-butyldimethylsiloxy-3-phenyl-1H-pyrrolo[1,2-c]oxazole (1) with nitro olefins
smoothly occurred to give 7a-alkylated pyrrolo[1,2-c]oxazol-5-ones (2) in good
yields. The products (2) were successfully transformed to a α-branched serine
derivatives via reductive denitration followed by lactam-ring cleavage.
In the synthesis of amino acids, use of the nucleophilic reaction at a nitrogen-bearing carbon is very
important, and many successful examples1 have been reported for this purpose. Methods1 utilizing
diastereoselective reactions of chiral auxiliaries or building blocks represented by Evans' oxazolones,
Schöllkopf's bislactims, Williams' piperadinones, and Seebach's oxazolones deserve attention due to their
wide applicability and high reliability. In some cases, however, construction of quarternary chiral centers
by these methods still encounter low selectivity and/or poor yields mainly due to reversible nature of such
reactions. Great attention has been paid for the Mukaiyama-type aldol reactions2 to overcome this problem.
We have reported the selective construction of chiral quartenary centers based on the Lewis acid-promoted
reactions of chiral siloxypyrroles (1 and ent-1) derived from (L)- and (D)-glutamic acid leading to
lactacystin and its analogues.3 This method can be utilized for the construction of the quarternary center of
4
α-branched serine derivatives, if the lactam ring is cleaved. In this communication we would like to
describe the novel synthesis of these abnormal amino acids via this route.

R"O C
2
R"'OH C
2
HO C
2
R
R
R
2
R'N
Ph
R N
H N
2
O
O
HO
Ph
Oxidative
Clevage
Reductive
Clevage
α-Branched (R)-Serine
1
1
1
R
R
R
6
Alkylation
Alkylation
R
O
R
7a
O
TBSO
O
N
N
N
1
O
O
Ph
Ph
Ph
syn-2
1
anti-2
Reductive
Clevage
Oxidative
Clevage
R"O C
2
R"'OH C
2
HO C
2
R
R
R
R'N
R'N
Ph
H N
2
O
O
HO
Ph
α-Branched (S)-Serine
Scheme 1. Synthetic Strategy to the α-Branched Serines
Our strategy to the synthesis of serine derivatives is shown in Scheme 1. If we achieve the alkylation at the
7a position of the siloxypyrrole (1) stereoselectively, we can get both S and R α-branched serine
derivatives via the oxidative and reductive cleavage of the γ-lactam ring of 2. First, we attempted to alkylate
the siloxypyrrole (1) under the similar conditions employed for the alkylation of 1-tert-butoxycarbonyl-2-
5
tert-butyldimethylsilyl-oxypyrrole.
In spite of all our efforts, however, no reaction or complete
decomposition was observed and no alkylated product such as 2 was obtained. Next, we examined the
Michael-type reaction of 1 with various Michael acceptors such as α,β-unsaturated carbonyl compounds,
and the reaction took place at the 7a position of 1 (Eq 1 and Table 1).
2
1
1
1
R
R
R
R
2
2
X
R
R
+
(1)
TBSO
O
O
N
N
N
Lewis acid
-78 ˚C
X
X
O
O
O
Ph
Ph
syn-2
Ph
1
1a: R = Me
1
anti-2
1b: R = H

Table 1. The Reaction of Siloxypyrrole (1) with Michael Acceptors
Entry Siloxy-
pyrrole
Michael Acceptor
Lewis Acid
(equiv)
Solvent Products Yield Ratio
(%a) syn/antib
R2
H
X
equiv
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
COMe
COMe
COMe
COMe
CHO
NO2
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
2.0
2.0
1.0
2.0
TiCl4 (1.2)
SnCl4 (1.2)
SnCl4 (1.2)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
SnCl4 (1.0)
SnCl4 (1.0)
BF3·OEt2 (1.2)
SnCl4 (0.5)
SnCl4 (1.0)
SnCl4 (0.1)
SnCl4 (1.0)
SnCl4 (0.1)
SnCl4 (0.1)
b
ether
ether
2aa
2aa
2aa
2aa
2abd
2ac
62c
36
1/12
1/4
1/3
1/11
-/1e
2/1
7/1
2/1
6/1
7/1
19/1
1/2
1/2
1/3
H
3
H
CH2Cl2
ether
66
4
H
49c
35c
30
5
Me
H
ether
6
ether
7
H
NO2
CH2Cl2
ether
2ac
62
8
H
NO2
2ac
21
9
H
NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2ac
73
10
11
12
13
14
H
NO2
2ac
62
H
NO2
2ac
66c
54f
60
H
NO2
2bc
2adg
2aeg
Me
Et
NO2
NO2
37
a
Combined yield of the chromatographed material. The ratio was calculated by the NMR analysis of the
c
d
reaction mixture.
e
Isolated yield of the major isomer(s).
This product was obtained as a TBS enol
f
ether. The ratio could not be estimated due to complexity of the reaction mixture.
g
The product reacted at
the 6 position was obtained in 13% yield.
The product was obtained as a mixture of four diastereomers,
additional chiral center of which could not be assigned.
In the presense of TiCl4, the siloxypyrrole (1a) reacted with methyl vinyl ketone only at the 7a position to
give anti-2aa in 62% yield (syn-2aa : anti-2aa = ca. 1 : 12, Entry 1). The face selectivity was not affected
by the choice of Lewis acid and solvent (Entries 2, 3, and 4), although lower yields were realised in ether.
The reactions with 1,1-unsubstituted 2-nitroalkenes occurred smoothly to give nitro compounds in
moderate to good yields (Entries 6-14), while β-nitrostyrene, ethyl acrylate, acrylonitrile, and ethyl
propiolate did not react. In the cases of 2-nitropropene, 2-nitrobutene, and 3-methyl-2-nitrobutene, syn-
and anti-isomers were determined by the NOE experiments, although the additional stereogenic center at the
nitro-substituted carbon could not be assigned. In the reaction of 1b, the Michael-type reaction with
nitroethylene occurred at both 7a and 6 positions, although the major product was 2bc (Entry 12).

We turned our attention to the face selectivity in the Michael-type addition of siloxypyrroles (1). All
reactions except for the reaction of 1a with nitroethylene took place at the 7a position from the opposit face
against the 3-phenyl group. This approach of the Michael acceptors seems to be reasonable (Figure 1, T1),
if we consider the steric requirement only around the 7a carbon in the synclinal transition states; the 3-
6
phenyl group would interfere the approach of the Michael acceptors from the same site (Figure 1, T2). In
our previous papers, we have discussed about the importance of the Diels-Alder-type transition states in the
3,7
reactions of 2-siloxypyrroles.
In the case of highly reactive Michael acceptors such as nitroalkenes, the
orbital interaction of the starting materials should be important and the Diels-Alder-like transition states
could become very important, if the steric requirement allows the transitiion states (Figure 1, T3 and T4).
The TBS group of 1a (not 1b) is thought to be fixed in the opposite site to the 3-phenyl group due to the
stericinteraction with 3-phenyl and 6-methyl groups. In fact, the diastereotopic methyl groups of the TBS
of 1a were observed in similar fields (0.02 and 0.09 ppm), while the methyl groups of 1b were observed
in well-separated places (-0.04 and 0.17 ppm) probably due to the anisotropic effect of the 3-phenyl group.
Thus, in the case of 1a, nitroethylene would preferably approach from the same face to the 3-phenyl group
(T4) to give the syn product. In other nitroalkenes, the alkyl groups (R2) would interact with the 3-phenyl
group, so the synclinal transition state (T1) would be favored to give the anti products.
-
2
O
N
L.A.
TBS
O
R
+
N
L.A.
1
X
R
2
R
TBS
2
1
1
R
R
R
O
O
O
N
N
X
O
O
O
Ph
Ph
Ph
anti-2
Diels-Alder Like
Transition State (T3)
Synclinal Tansition State (T1)
X = NO or COEt
2
TBS
1
+
TBS
1
1
R
O
R
R
O
2
-
N
N
R
L.A.
O
O
N
O
O
2
N
O
R
X
2
L.A.
O
1
Ph
R
R = Me
2
Ph
X
Ph
R = H
syn-2
Diels-Alder Like
Transition State (T4)
Synclinal Tansition State (T2)
X = NO or COEt
2
Figure 1. Proposed Transition States

Next, cleavage of the γ-lactam ring in the major adducts (2) was examined (Scheme 2). However,
dihydroxylation of 2ac and 2ae by OsO4 did not occur, and no reaction or decompositon was observed.
Since both types of the ring system was dihydroxylated in the synthesis of lactacystin and its analogues,3
the nitro group would interfere the osmylation.8 Therefore, the adducts were refluxed with n-Bu3SnH in
the presence of AIBN in toluene to remove the nitro group.9
The secondary nitro group of 2ad and 2ae
was easily removed to give the corresponding compounds (3d and 3e) in good yields, while no product
was obtained from the reaction of the primary nitro compound 2ac. These products (3d and 3e) were
succesfully dihydroxylated under the usual osmylation conditions to give diols (4d and 4e), which were
transformed to the aimed α-branched serine derivatives (7d and 7e) by cleavage10 with Pb(OAc)4
followed by oxidation11 with NaClO2 and deprotection with 6 N HCl. The specific rotation of 7d and 7e
was [α]D23 = +10˚ (c 0.160, 1 N HCl) and +27˚ (c 0.253, 1 N HCl) , respectively.
O H
N
Me
O
Me
O
O H
O
Me
O
2
2
2
2
R
R
R
i
ii
N
N
N O
O
O
Ph
Ph
Ph
2
2
2
anti-2ad: R = Me
2
3d: R = Me; 83%
2
4d: R = Me; 60%
2
anti-2ae: R =Et
3e: R =Et; 69%
4e: R =Et; 49%
O
O
C O H
CHO
2
2
2
R
R
H O C
2
Me
iii
Me
2
iv
v
R
N
N
+
H
N
O
O
3
O
O
-
H O
Ph
Ph
Cl
2
2
2
5d: R = Me; 98%
2
6d: R = Me; 50%
2
7d: R = Me; 90%
2
5e: R =Et; 96%
6e: R =Et; 46%
7e: R =Et; 89%
Scheme 2. Reagents and Conditions: i) n-Bu SnH, AIBN, toluene, reflux; ii) OsO , NMO, t-BuOH, rt; iii)
3
4
Pb(OAc) , K C O , benzene, rt; iv) NaClO , NaH PO , 2-methyl-2-butene, t-BuOH, rt; v) 6 N HCl, reflux.
4
2
3
2
2
4
In conclusion, the Michael-type reaction of (3R)-5-tert-butyldimethylsiloxy-6-methyl-3-phenyl-1H-
pyrrolo[1,2-c]oxazole (1) with 1,1-unsubstituted 2-nitroalkenes occurred at the 7a position preferentially
from the opposite face to the 3-phenyl group. The adducts were successfully converted to the α-branched
serine derivatives.

ACKNOWLEDGEMENT
Financial support from Grant-in-Aid for Scientific Research from the Ministry of Education, Science,
Sports, and Culture is greatly acknowledged.
REFERENCES AND NOTES
1.
2.
3.
R. M. Williams, "Synthesis of Optically Active α-Amino Acids" Pergamon Press, 1989, London.
T. Mukaiyama, Organic Reactions, 1982, 28, Chap. 3.
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and N. Ono, Heterocycles, 1998, 48, 635.
4.
For other examples, see: S. Sano, X. -K. Liu, M. Takebayashi, Y. Kobayashi, K. Tabata, M. Shiro,
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1982, 1756.
5.
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1995, 2471.
6.
7.
8.
G. Casiraghi and G. Rassu, Synthesis, 1995, 607.
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Am. Chem. Soc., 1988, 110, 621.
9.
N. Ono, H. Miyake, R. Tamura, and A. Kaji, Tetrahedron Lett., 1981, 22, 1705.
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4
761) was carried out in the presence of K CO according to the modified procedure by G. Stork and
2
3
T. Takahashi. "Yuukikagaku jikkenn no tebiki (Handbook for Organochemical Experiments)" T.
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