Stevens Rearrangement of a Cyclic Hemiacetal System: Diastereoselective Approach to Chiral α-Amino Ketone

Article abstract of DOI:10.1055/s-2003-44998

The base-promoted reaction of ammonium ylide 1a, which forms a cyclic hemiacetal structure, is shown to afford the anti-hemiacetal 3a in high diastereopurity, via the Stevens rearrangement followed by efficient thermodynamic epimerization.

Full text of DOI:10.1055/s-2003-44998

LETTER
365
Stevens Rearrangement of a Cyclic Hemiacetal System: Diastereoselective
Approach to Chiral a-Amino Ketone
Diastereoselective
A
pp
a
r
oac
h
to
C
n
a
-Amin
ao Ketone bu Harada, Takeshi Nakai, Katsuhiko Tomooka*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152-8552, Japan
Fax +81(3)57343931; E-mail: ktomooka@apc.titech.ac.jp
Received 19 November 2003
moiety at the b-position. An alkoxide C derived from
hemiacetal A will isomerize to acyclic form D, which has
an alkoxide on the migrating group (Scheme 3). This
alkoxide moiety could act as the intramolecular base and/
or chelation counterpart in the rearrangement step and/or
the post-rearrangement step. Thus, it was expected that
the stereochemistry at the a-amino position of rearrange-
ment product B could be controlled by these intramolecu-
lar alkoxide effects.
Abstract: The base-promoted reaction of ammonium ylide 1a,
which forms a cyclic hemiacetal structure, is shown to afford the
anti-hemiacetal 3a in high diastereopurity, via the Stevens re-
arrangement followed by efficient thermodynamic epimerization.
Key words: acetal, amino alcohols, stereoselective synthesis,
ketones, rearrangements
The Stevens rearrangement is a general class of the 1,2-
alkyl shift from nitrogen or sulfur to carbon on a quater-
nary ylide system.1 This type of rearrangement is now
well recognized to proceed via a radical dissociation–re-
combination mechanism (Scheme 1).1,2
rearr.
post-rearr.
A
B
base
base
R
R
O
O
O
O
H (M)
R'2N
R"
R'2N
R"
R
R
X
R
base
R
C
F
O
H
R
R
OH
(M)
Y
R"
Y
R"
R'2Y
R"
R'2Y
R"
R'2N
R'2
R'2
R'2N
R: migrating group
Y=N,S
R"
O
R"
O
Scheme 1
E
D
M: Counter cation
Scheme 3
Despite the long history of the Stevens rearrangement, its
synthetic application as a diastereoselective approach to
chiral amines is limited due to the difficulty of stereocon-
trol at the a-amino position.3 Herein we wish to report a
novel Stevens rearrangement system using the hemiacetal
A (a tautomer of a hydroxy ketone A¢) as a substrate
which provides the a-amino ketone B and its tautomer,
acetal B¢, in good yield with excellent diastereoselectivity
(Scheme 2).
Based on this hypothesis, we designed the ammonium salt
1a (racemic) for the rearrangement substrate, and it was
readily prepared from phenylglycinol in two steps: N-me-
thylation followed by treatment with bromoacetophenone
(Scheme 4).5 According to the 1H NMR, C NMR, H-H
13
COSY NMR and HMQC NMR analyses and NOE experi-
ment, it was confirmed that the resulting salt 1a exists pre-
dominantly as a cyclic hemiacetal form.6
R
OH
O
R
R
R
Stevens
rearr.
1) HCHO,
O
Ph
OH
O
Ph
R'2N
OH
R"
OH
O
O
Ph
HCO2H
R'2N
O
OH
OH
base
R'2N *
R'2N
Me2N
X
Me2N
Br
1a
(67% in two steps)
*
2) BrCH2COPh
X
NH2
A
B
R"
R"
R" OH
Ph
Br
A'
B'
Ph
Scheme 2
Scheme 4
During the course of our study on acetal and hemiaminal
chemistry,4 we were interested in studying the rearrange-
ment of a hemiacetal A that has an ammonium ylide
A rearrangement of hemiacetal 1a was performed by
treatment with potassium tert-butoxide (2 equiv) in
ethanol at 0 °C to r.t.7,8 The reaction gave the expected
hydroxy ketone 2a5 in 35% yield as a single diastereomer
(>95% dr, anti) along with a hemiacetal 3a5 in 40%
yield also as a single diastereomer (>95% dr, anti,syn).9
SYNLETT 2004, No. 2, pp 0365–0367
0
2.
0
2.
2
0
0
4
Advanced online publication: 16.12.2003
DOI: 10.1055/s-2003-44998; Art ID: U24603ST
© Georg Thieme Verlag Stuttgart · New York

366
M. Harada et al.
LETTER
Furthermore, it was observed that the thus-obtained hy- control. The stereochemical outcome of the rearrange-
droxy ketone 2a easily tautomerized to a hemiacetal 3a on ment of 1a is explicable as a result of the efficient
silica gel (Scheme 5). These results reveal that the present thermodynamic control in the post-rearrangement step
hemiacetal rearrangement provides the single diastereo- that includes the base-catalyzed epimerization at the a-
mer of the product as expected.
amino position and the hydroxy ketone/hemiacetal tau-
tomerization. To evaluate the thermodynamic stability of
possible products, the potential energies were examined
by semiempirical calculation.11 As shown in Scheme 8,
the calculation predicted that anti,syn-3a (tautomer of
anti-2a) is favored over other isomers (>4.58 kcal/mol).
This result and experimental facts indicate that the forma-
tion of a stable cyclic acetal plays the key role in attaining
high stereoselectivity.
Ph
Ph
t-BuOK
OH
Ph
1a
O
+
EtOH
0 °C → rt
Me2N
Me2N
OH
Ph
anti-2a
anti,syn-3a
(40%)
O
(35%)
silica gel
Scheme 5
Ph
Ph
Ph
OH
Ph
To clarify the intramolecular alkoxide effect in the stereo-
control of the rearrangement, next we examined a similar
rearrangement of hydroxyl-protected derivative of 1a. In
sharp contrast to the above-mentioned result, the reactions
of methyl ether 1b and silyl ether 1c provide only a 1:1
diastereomer mixture of products 2b and 2c, respectively
(Scheme 6). However, interestingly enough, desilylation
of a diastereomer mixture of 2c with TBAF (2 equiv) gave
a mixture of anti-2a (17%) and its tautomer anti,syn-3a
(58%), did not give the syn-isomer.
O
O
Me2N
Me2N
Me2N
OH
OH
Ph
Ph
O
anti,syn-3a (–36.34)a
anti-2a (–30.10)a
anti,anti-3a (–30.96)a
Ph
Ph
Ph
OH
Ph
O
OH
O
Me2N
Me2N
Ph
syn,anti-3a (–27.61)a
Me2N
OH
Ph
O
syn-2a (–31.76)a
syn,syn-3a (–31.65)a
a Potential energy (kcal/mol)11
Ph
OR
Ph
t-BuOK
OR
Ph
Me2N
Scheme 8
EtOH
0 °C → r.t.
Br
Me2N
Ph
O
O
Next, we examined an asymmetric variant of the present
Stevens rearrangement using an optically active hemiace-
tal (2R,5R)-1a.12 The reaction performed in ethanol at
room temperature provides a mixture of (2S,3R)-2a and
(2S,3R,4R)-3a in 56% ee (Scheme 9). In contrast, when
water was used as a solvent, the enantiopurity of products
was raised to 72–82% ee. These results show that the
rearrangement proceeds predominantly with retention of
configuration at the migrating carbon13 and the degree
of asymmetric transmission is highly dependent on the
solvent used.14
dr=50:50
2b (75%)
2c (52%)
1b: R=Me
1c: R=TBS
TBAF
+
2c
dr=50:50
anti-2a
(17%)
anti,syn-3a
(58%)
THF
0 °C → r.t.
Scheme 6
Furthermore, we found that a similar reaction of g-hy-
droxy homologue 4 gave poor diastereoselectivity. Name-
ly, the Stevens rearrangement of ammonium salt 4, which
exists as an acyclic hydroxy ketone, provides a diastereo-
mer mixture of d-hydroxy ketone 5 and a hemiacetal
anti,syn-6,10 tautomer of anti-5 (Scheme 7).
5
Ph
Ph
Ph
3
2
4
O
OH
Ph
base
OH
O
2
+
Me2N
Br
2
3
Me2N
Me2N
Ph
OH
Ph
O
(2R,5R)-1a
(2S,3R)-2a
(2S,3R,4R)-3a
Ph
OH
t-BuOK
Ph
C2H4OH Ph
Ph
+
C2H4OH
80%a (56% ee)b
4%a (82% ee)b
86%a (72% ee)b
t-BuOK / EtOH, rt
+
Ph
Me2N
NaOH / H2O, 0 °C → rt
NaOH / H2O, 60 °C
O
Ph
O
EtOH
r.t.
Me2N
Me2N
Me2N
Br
a Combined yield of 2a and 3a.
b Determined by 1H NMR analysis of the MTPA ester of 2a.
Ph OH
O
Ph
O
4
anti-5
(20%: combined yield)
anti,syn-6
syn-5
(17%)
Scheme 9
Scheme 7
In summary, we have described a highly diastereoselec-
tive approach to the chiral hemiacetal, tautomer of b-
chiral a-amino ketone, based on a novel Stevens rear-
rangement of a cyclic hemiacetal system.
These results strongly suggest that the high level of dia-
stereoslectivity observed in the reaction of 1a is a result of
the base-catalyzed epimerization of the product, and the
properly positioned alkoxide is essential for this stereo-
Synlett 2004, No. 2, 365–367 © Thieme Stuttgart · New York

LETTER
Diastereoselective Approach to Chiral a-Amino Ketone
367
(6) The relative stereochemistry of 1a was determined by NOE
Acknowledgment
experiment as shown below (Figure 1).
This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element
Cyclic Molecules’, Basic Area (B) No. 14350473 and The 21st
Century COE Program ‘Creation of Molecular Diversity and
Development of Functionalities’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
0.3%
Hd'
OHa
0.3%
CH3 (ax)
Br
Hd
O
N
Ph
Hb
Ph
2.6%
References
CH3 (eq)
0.5%
Hb'
Hc
0.9%
(1) Reviews: (a) Pine, S. H. Org. React. 1970, 18, 404.
(b) Markó, I. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
913–974.
(2) Ollis, W. D.; Ray, M.; Sutherland, I. O. J. Chem. Soc.,
Perkin Trans. 1 1983, 1009.
5.0%
Figure 1
(7) It is considered that potassium ethoxide formed in the
reaction mixture acts as a base.
(8) Typical procedure: To a solution of the ammonium salt 1a
(50 mg, 0.137 mmol) in EtOH (5 mL) at 0 °C was added
potassium tert-butoxide (30.8 mg, 0.274 mmol). The
reaction mixture was allowed to warm to r.t. and stirred for
12 h. The mixture was quenched by the addition of
phosphate buffer (pH 7) and the organic layer was dried and
concentrated in vacuo. Purification of the residue by PTLC
(SiO2, hexane/EtOAc = 2/1) gave (2R*,3R*)-2-dimethyl-
amino-4-hydroxy-3-phenylbutyrophenone (anti-2a, 13.4
mg, 35% yield) and (2S*,3R*,4R*)-3-dimethylamino-
tetrahydro-2-hydroxy-2,4-diphenylfuran (anti,syn-3a, 15.6
mg, 40% yield).
(3) Only a few successful examples are reported so far. For these
the stereocontrol is based on the chirality transfer from
chiral nitrogen atom of the ammonium salt to carbon:
(a) Hill, R. K.; Chan, T.-H. J. Am. Chem. Soc. 1966, 88, 866.
(b) Naidu, B. N.; West, F. G. Tetrahedron 1997, 53, 16565.
(c) Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31.
(4) Selected examples: (a) Tomooka, K.; Okinaga, T.; Suzuki,
K.; Tsuchihashi, G. Tetrahedron Lett. 1989, 30, 1563.
(b) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem.
Soc. 1996, 118, 3317. (c) Tomooka, K.; Nakazaki, A.;
Nakai, T. J. Am. Chem. Soc. 2000, 122, 408. (d) Tomooka,
K.; Yamamoto, H.; Nakai, T. Angew. Chem. Int. Ed. 2000,
39, 4500.
(9) The relative stereochemistry of anti,syn-3a was determined
by NOE experiment as shown below (Figure 2).
(5) All new compounds were fully characterized by IR, 1H and
13C NMR analyses. Data for selected compounds are as
follows. Compound 1a: mp 202–204 °C (dec.). 1H NMR
(300 MHz, DMSO-d6): d = 2.96 (s, 3 H), 3.25 (s, 3 H), 3.55
(dd, J = 12.9, 2.4 Hz, 1 H), 3.93 (d, J = 12.9 Hz, 1 H), 4.05
(dd, J = 13.4, 2.6 Hz, 1 H), 4.99 (dd, J = 13.4, 11.6 Hz, 1 H),
2.3%
H
O
Ph
4.3%
H
H
H
Ph
5.13 (dd, J = 11.6, 2.6 Hz, 1 H), 7.40–7.70 (m, 11 H). 13
C
OH
NMe2
1.7%
NMR (75 MHz, DMSO-d6): d = 45.9, 54.1, 58.2, 67.2, 71.1,
95.0, 126.1, 128.2, 128.3, 129.2, 130.9, 131.4, 141.3. Anal.
Calcd for C18H22BrNO2: C, 59.35; H, 6.09; N, 3.85. Found:
C, 58.77; H, 5.96; N, 3.88. Compound anti-2a: mp 136–139
°C. 1H NMR (300 MHz, CDCl3): d = 2.42 (s, 6 H), 3.61
(ddd, J = 3.9, 9.0, 11.1 Hz, 1 H), 3.88 (dd, J = 3.9, 11.4 Hz,
1 H), 4.13 (dd, J = 9.0, 11.4 Hz, 1 H), 4.86 (d, J = 11.1 Hz,
1 H), 7.04–7.22 (m, 4 H), 7.34–7.51 (m, 4 H), 7.71 (d, J =
7.5 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 42.4, 45.0,
68.8, 70.4, 126.1, 127.1, 128.0, 128.4, 128.6, 133.1, 139.0,
139.5, 196.6. Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47;
N, 4.94. Found: C, 75.77; H, 7.37; N, 4.95. Compound
anti,syn-3a: 1H NMR (300 MHz, CDCl3): d = 2.12 (s, 6 H),
3.30 (d, J = 8.7 Hz, 1 H), 3.70 (ddd, J = 7.2, 8.7, 9.0 Hz, 1
H), 3.98 (dd, J = 7.2, 9.0 Hz, 1 H), 4.52 (dd, J = 9.0, 9.0 Hz,
1 H), 7.24–7.42 (m, 8 H), 7.71–7.74 (m, 2 H). 13C NMR (75
MHz, CDCl3): d = 45.0, 48.7, 74.4, 81.1, 104.2, 126.0,
126.9, 127.7, 128.1, 128.2, 129.0, 142.7, 143.8.
Figure 2
(10) Anti-5 and anti,syn-6 were obtained as a
chromatographically inseparable mixture.
(11) Conformational analysis of the rearrangement products was
carried out with the MacroModel 8.0 package and PC
Spartan Pro 1.0.5. Conformational search was performed
with Mixed MCMM/LowMode method (1000 structures)
using MM2* force field. Further geometry optimization and
the potential energy calculation of the most stable
conformers were performed by PM3 calculation using
Spartan.
(12) The hemiacetal (2R,5R)-1a was prepared from (R)-2-
phenylglycinol (99% ee) purchased from Aldrich.
(13) This result is consistent with the reported steric course of
Stevens rearrangement: see ref. 1.
(14) Similar solvent effect in terms of the asymmetric
transmission was reported by Ollis and colleagues, see ref. 2.
Synlett 2004, No. 2, 365–367 © Thieme Stuttgart · New York