Stereospecific Construction of Chiral Quaternary α-Oxygenated Aldehydes from Chiral Secondary Alcohol Derivatives

Article abstract of DOI:10.1055/s-2004-815406

Chiral tertiary dichloromethylcarbinol derivatives 2, prepared from protected chiral secondary alcohols 1, were converted stereospecifically into chiral quaternary α-oxygenated aldehyde derivatives 4 and 11 via intermediary α-chloroepoxides 3 under weakly

Full text of DOI:10.1055/s-2004-815406

546
LETTER
Stereospecific Construction of Chiral Quaternary a-Oxygenated Aldehydes
from Chiral Secondary Alcohol Derivatives
S
tereospecific Con
i
structio
d
nof
C
hiral
e
Quaternary
k
a
-Oxygenate
i
d
A
ldehyde
s
Arasaki, Masashi Iwata, Daisuke Nishimura, Akichika Itoh, Yukio Masaki*
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan
Fax +81(58)2375979; E-mail: masaki@gifu-pu.ac.jp
Received 18 November 2003
through an absolute double inversion of the quaternary
stereogenic center.
Abstract: Chiral tertiary dichloromethylcarbinol derivatives 2, pre-
pared from protected chiral secondary alcohols 1, were converted
stereospecifically into chiral quaternary a-oxygenated aldehyde
derivatives 4 and 11 via intermediary a-chloroepoxides 3 under
weakly basic conditions (K2CO3/MeOH/r.t.). The fashion generat-
ing the quaternary centers was proved to be quite different depend-
ing on the substrates: inversion of configuration of non-benzylic
substrate 2a and apparent retention with benzylic one 2b.
Chiral quaternary dichloromethylcarbinols 2a and 2b5
were obtained in 54% and 81% yield with 31% and 10%
recovery of the starting alcohols, respectively, by dichlo-
rocarbene insertion reaction of TMS-ethers of (R)-(–)-2-
octanol (1a) and (R)-(+)-1-phenylethanol (1b) under ul-
trasonic conditions with CHCl3 and powdered NaOH/
Ca(OH)2 (4:1) in the presence of a catalytic amount of
cetyltrimethylammonium chloride (CTAC) at 20–50 °C,
followed by acidic hydrolysis (aq HCl and MeOH/r.t./2 h)
of the crude products (Scheme 1).6
Key words: a,a-disubstituted a-oxyaldehyde, chiral synthesis, a-
chloroepoxide, ring opening, methoxide anion
Although much effort has been devoted to synthesize
chiral carbon compounds, it still has been a great chal-
lenge in organic synthesis to create chiral quaternary car-
bon stereocenters1 highly enantioselectively by facile
manipulations. Contrary to the scarcity of widely applica-
ble enantioselective synthetic methods for chiral tertiary
alcohol derivatives,2 several excellent practical methods
have been developed to obtain chiral secondary alcohol
derivatives with nearly perfect enantioselectivity.3 In the
context, we have found protected secondary alcohols to
undergo stereospecific a-C-H insertion reaction with
dichlorocarbene generated from chloroform and 50%
aqueous NaOH in the presence of a phase transfer cata-
lyst,4 providing chiral tertiary dichloromethylcarbinol
functional group which is believed to be a promising
chiral building block. In the extension of the work facile
stereospecific transformation of chiral tertiary dichloro-
methylcarbinols to a-azide-aldehydes and a-cyano-alde-
hydes has been reported recently.5
1. TMS-Cl, Et3N, THF, r.t., 2 h
H-O
H-O
2. NaOH/Ca(OH)2 (4/1),
CHCl3, CTAC (cat.),
20–50 °C, 2 h, ))))
CHCl2
H
Me
R
Me
R
2
1
3. 2% HCl, MeOH, r.t., 2 h
a: 54% (SM 31%)
b: 81% (SM 10%)
a: R: n-C6H13
b: R: Ph
CTAC:
(C16H33(Me)3N+ Cl–)
Scheme 1
The dichloromethylcarbinol 2a was treated with 3 equiv-
alents of K2CO3 in MeOH at room temperature for 10
minutes, providing a crude a-chloroepoxide 3a, which
was converted into an a-methoxy-aldehyde 4 in 75%
overall yield on treatment with 3 equivalents of K2CO3 in
MeOH at room temperature for 10 hours. The aldehyde
was also obtained directly in a higher yield (79%) by treat-
ment of 2a with 5 equivalents of K2CO3 in MeOH at room
temperature for 10 hours (Scheme 2).6
In this paper we report on stereospecific ring opening re-
actions of chiral a-chloroepoxides 3, which were prepared
from stereochemically defined dichloromethylcarbinols 2
derived via dichlorocarbene C-H insertion reaction of
TMS-protected chiral secondary alcohols 1, with methox-
ide anion under weakly basic conditions. The product ob-
tained from the non-benzylic substrates 3a was found
to be configurationally inverted quaternary carbon com-
pounds, a-methoxyaldehyde 4 resulted from epoxide-ring
opening in complete SN2 fashion. On the other hand, a
benzylic substrate 3b was found to provide a configura-
tionally retained a-hydroxyaldehyde derivative 11
Stereochemistry of S-configuration and stereochemical
homogeneity of the product 4 were verified by derivation
to (S)-1,2-dimethoxy-2-methyloctane (6) and (S)-1-(p-
methoxybenzyloxy)-2-methoxy-2-methyloctane (7) via a
methoxy-aldehyde 5, followed by comparison of [a]D and
chiral HPLC7 with those of the corresponding authentic
samples prepared through Sharpless dihydroxylation of 2-
methyloctene (8) with AD-mix-b,8 which was known to
produce selectively (R)-glycol 9 according to Scheme 3.
The treatment of the benzylic one 2b under the same con-
ditions gave (R)-2-hydroxy-2-phenylpropanal dimethyl
acetal (11) in an excellent yield (92%). Stereochemical
homogeneity of 11 was characterized by chiral HPLC7 in
comparison with the corresponding racemic one. The
SYNLETT 2004, No. 3, pp 0546–0548
1
8.
0
2.
2
0
0
4
Advanced online publication: 12.01.2004
DOI: 10.1055/s-2004-815406; Art ID: U24503ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereospecific Construction of Chiral Quaternary a-Oxygenated Aldehydes
547
c
O
OH
Cl
MeO
Me
a
CHO
n-C6H13
b
CHCl2
S
R
n-C6H13
Me
Me
n-C6H13
2a
3a
4
d
f
MeO
Me
O-PMB
n-C6H13
MeO
Me
OMe
MeO
Me
OH
e
n-C6H13
n-C6H13
6
5
7
PMB: CH2C6H4-OMe(p)
Scheme 2 a) K2CO3 (3 equiv), MeOH, r.t., 10 min; b) K2CO3 (3 equiv), MeOH, r.t., 10 h (two steps 75%); c) K2CO3 (5 equiv), MeOH, r.t.,
10 h (79%); d) NaBH4, MeOH, r.t., 1 h (92%); e) NaH, MeI, DMF, r.t., 10 h (88%); f) NaH, PMBCl, DMF, r.t., 10 h (78%).
HO
Me
OMe
MeO
Me
OH
O
Cl
OH
CHCl2
a
b
Cl
CHO
Ph
d
b
R
n-C6H13
n-C6H13
n-C6H13
Me
Me
Me
Ph
Ph
Me
2b
3b
12
8
(R)-6
9
c
CH(OMe)2
c
HO
Me
a
Ph
O
OMe
Ph
11
MeO
Me
(R)-7
O-PMB
HO
Me
O-PMB
n-C6H13
10
d
f
Me
n-C6H13
16
MeO
Me
MeO
Me
CH(OMe)2
MeO
Me
CO2H
Ph
CHO
Ph
h
g
Ph
Scheme 3 a) AD-mix-b, H2O–t-BuOH, 0 °C, 18 h (89%); b) NaH,
MeI, DMF, r.t., 18 h (82%); c) NaH, PMBCl, DMF, r.t, 18 h (67%);
d) NaH, MeI, DMF, r.t., 18 h (63%).
13
14
15
Scheme 4 a) K2CO3 (5 equiv), MeOH, r.t., 10 h (92%); b) K2CO3 (3
equiv), MeOH, r.t., 10 min; c) K2CO3 (3 equiv), MeOH, r.t., 10 h (two
steps 86%); d) THF, r.t., 10 h (76%); e) K2CO3 (5 equiv), MeOH, r.t.,
10 h (95%); f) NaH, MeI, DMF, r.t., 10 h (95%); g) 5% aq H2SO4,
THF, reflux, 5 h (75%); h) Jones reagent, acetone, r.t., 10 min (85%).
acetal 11 was obtained via a-chloroaldehyde 12, which
was produced from dichloromethylcarbinol 2b through an
unstable a-chloroepoxide 3b, as illustrated in Scheme 4.
Although several chemists have reported formations and
reactions of 3-substituted 2-chlorooxiranes including 3-
methyl-3-phenyl-2-chlorooxirane (racemic 3b) with
NaOMe in MeOH affording a-hydroxyaldehyde dimethyl
acetals, no stereochemistry in the reaction has been ad-
dressed.9 The configuration of the stereogenic center of
the acetal 11 was determined to be R by conversion into a-
methoxyaldehyde 14 through the methyl ether 13 fol-
lowed by acidic hydrolysis, and comparison of [a]D with
the corresponding data {[a]D} for the known (S)-2-meth-
oxy-2-phenylpropanal (14).10 Furthermore, Jones oxida-
tion of the aldehyde 14 led to (R)-2-methoxy-2-
phenylpropionic acid (15).10 Stereospecific double inver-
sion of configuration of the a-chloroepoxide 3b was pos-
tulated to explain the results. Thus, the crude a-
chloroepoxide 3b was rearranged with inversion of con-
figuration to an a-chloroaldehyde 12 which was converted
into 11 by successive nucleophilic attack of methoxide an-
ion on the aldehyde 12 and on the generated a-methoxy-
epoxide 169 as shown in Scheme 4.
In conclusion, a dramatic change of behavior of 3,3-disub-
stituted 2-chlorooxirane 3 was observed depending on
pattern of the substituents, non-benzylic and benzylic one,
to give opposite stereochemical outcome. A new method
for preparation of stereochemically defined quaternary a-
oxygenated non-benzylic and benzylic aldehydes such as
4 and 14 from chiral secondary alcohols has been devel-
oped.
Acknowledgment
This study was financially supported in part by a Grant-in-Aid for
Scientific Research (No.14657566) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
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Synlett 2004, No. 3, 546–548 © Thieme Stuttgart · New York

548
H. Arasaki et al.
LETTER
3460, 2941, 2922, 2914, 2861, 1457 cm–1. 1H NMR (270
MHz, CDCl3): d = 0.99 (s, 3 H), 1.40–1.87 (m, 13 H), 2.15
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filtered through a short column of silica gel to give a crude
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Synlett 2004, No. 3, 546–548 © Thieme Stuttgart · New York