Stereospecific construction of chiral quaternary carbon compounds from chiral secondary alcohol derivatives

Article abstract of DOI:10.1246/cl.2003.4

Chiral tertiary dichloromethylcarbinol derivatives, prepared by stereospecific α C-H insertion reaction of dichlorocarbene with protected chiral secondary alcohols, were converted into intermediary α-chloroepoxides which gave stereospecifically chiral qua

Full text of DOI:10.1246/cl.2003.4

4
Chemistry Letters Vol.32, No.1 (2003)
Stereospecific Construction of Chiral Quaternary Carbon Compounds from Chiral Secondary
Alcohol Derivatives
Yukio Masaki,ꢀ Hideki Arasaki, and Masashi Iwata
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585
(Received September 13, 2002;CL-020785)
Chiral tertiary dichloromethylcarbinol derivatives, prepared
a-chloro-, a-hydroxy-, and a-azide-aldehydes proceeded in net
SN2 mechanism or took place highly diastereoselectively,
because the substitution reactions proceeded in the highly
diastereotopic environment of the sugar derivatives used as the
substrate. Thus, intrinsic stereochemical behavior of the sub-
stituted a-chloroepoxide functionality in ring opening substitu-
tion reactions remains to be cleared.
In this paper we report on stereospecific ring opening
reactions of chiral a-chloroepoxides 3, prepared from stereo-
chemically defined dichloromethylcarbinols 2 derived via
dichlorocarbene C–H insertion reaction of TMS-protected chiral
secondary alcohols 1. The products obtained from the non-
benzylic substrates 3a and 3b were found to be configurationally
inverted quaternary carbon compounds, a-azide- 4a,b and a-
cyano-aldehyde derivatives 7a,b resulted from epoxide-ring
opening in complete SN2 fashion. On the other hand, a benzylic
one 3c was found to provide configurationally retained 4c and 7c
through an absolute double inversion of the quaternary stereo-
genic center.
Treatment of (R)-(ꢁ)-2-octanol 1a with chloro-trimethylsi-
lane (TMS-Cl) and Et3N in THF at room temperature for 2 h gave
the corresponding crude TMS-ether which underwent dichlor-
ocarbene C–H insertion reaction by stirring with CHCl3 and 50%
aqueous NaOH in the presence of a catalytic amount of
cetyltrimethylammonium chloride (CTAC) for 18 h at 80 ꢂC.5
The crude product obtained was treated with aq. conc. HCl and
MeOH at room temperature for 2 h to give a dichloromethylcar-
binol 2a in 39% overall yield with a 52% recovery of the starting
alcohol 1a. Other substrates 1b and 1c were transformed to the
corresponding dichloromethylated products 2b and 2c in 31 and
60% overall yield with 61 and 23% recovery of the starting
alcohols, respectively, as shown in Scheme 1. Stereochemistry of
the C–H insertion reaction proceeding with complete retention of
configuration of the starting alcohols has been established with
non-benzylic as well as benzylic alcohol derivatives.5 Stereo-
specificity of the reaction performed on TMS-ethers was also
verified by homogeneity of 2c observed in chiral HPLC
analysis.10
by stereospecific a C–H insertion reaction of dichlorocarbene
with protected chiral secondary alcohols, were converted into
intermediary a-chloroepoxides which gave stereospecifically
chiral quaternary carbon compounds, a-aminoacids via a-azide-
aldehydes and a-cyanoacetic acids through cyanation, respec-
tively. The fashion generating the quaternary centers from
dichloromethylcarbinols via a-chloroepoxides was proved to be
quite different depending on the substrates: inversion of
configuration of non-benzylic substrates and apparent retention
with benzylic one.
Optically active compounds which contain quaternary
carbon stereocenters including tertiary alcohol derivatives, a,a-
disubstituted amino acids and their derivatives, and compounds
with a quaternary carbon bearing four different carbon sub-
stituents are widely distributed in biologically active compounds
including medicine.1 Although much effort has been devoted to
synthesize chiral carbon compounds, it still has been a great
challenge in organic synthesis to create chiral quaternary carbon
stereocenters2 highly enantioselectively by facile manipulations.
Contrary to the scarcity of widely applicable enantioselective
synthetic methods for chiral tertiary alcohol derivatives,3 several
excellent practical methods have been developed to obtain chiral
secondary alcohol derivatives with nearly perfect en-
antioselectivity.4 In the context, we have recently 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 catalyst,5
providing chiral tertiary dichloromethylcarbinol functional group
which is believed to be a promising chiral building block. Tertiary
dichloromethylcarbinol group has hitherto been made by addition
reaction of ketones with dichloromethyl lithium prepared from
dichloromethane and LDA,6 and the group was known to be
transformed to a-chloro- and a-hydroxy-aldehyde moieties via
a-chloroepoxide functionality albeit with stereochemical
ambiguity.7 Recently Sato, et al.,8a Deloisy, et al.,8b Nakamura,
et al.,8c and Yoshikawa, et al.8d have reported diastereoselective
addition reactions of dichloromethyl lithium with cyclic ketones
derived from a sugar and with a carbonyl group on the side chain
of a sugar derivative to give dichloromethylcarbinol intermedi-
ates which were led to a-chloro-, a-hydroxy-, and a-azide-
aldehydes via unstable a-chloroepoxides. More recently, Satoh
has developed another route to a-chloroepoxides by oxidation of
2,2-disubstituted 1-chloroolefins with m-chloroperbenzoic acid.9
They have claimed that the transformations of a-chloroepoxides
to the functional groups mentioned above proceeded in SN2
fashion. It, however, still has been unclear whether the reaction of
a-chloroepoxide under weakly basic conditions providing with
1) TMS-Cl,Et N, THF,
3
r.t, 2 h
H-O
H-O
CHCl2
H
R
2) CHCl , 50% aq. NaOH
3
Me
Me
R
.
CTAC (cat.), 80 C, 18 h
2
1
3) 2% HCl, MeOH, r.t, 2 h
a R: n-C6H13 39% (SM 52%)
b R: CH2Ph 31% (SM 61%)
c R: Ph
60% (SM 23%)
Scheme 1.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.1 (2003)
5
Unexpectedly, the derived amino acid 6c and cyanoacetic acid
d
2a R: n-C6H13
9c were identified with (R)-(ꢁ)-a-methylphenylglycine14 and
(S)-(þ)-2-cyano-2-methylphenylacetic acid,15 respectively.
Stereospecific double inversion of configuration of the a-
chloroepoxide 3c was postulated to explain the results. Thus,
the crude a-chloroepoxide 3c was stirred for 12 h in THF at room
temperature to give a good yield (79%) of an a-chloroaldehyde
10c, which was converted into 4c by treatment with NaN3 and 7c
with KCN, respectively.
b R: CH2Ph
c R: Ph
N3
N3
CH2OH
H2N
Me
b
CHO
R
c
CO2H
R
Me
R
Me
4a (78%)
4b (81%)
NC
Me
7a (66%)
7b (67%)
5a (91%)
5b (95%)
NC CH2OH
6a (76%)
6b (79%)
a
R: Alkyl
CH(CN)OH
NC CO2H
e
O
f
c
Cl
Me
R
R
R
Me
9a (94%)
9b (88%)
Me
R
8a (81%)
8b (73%)
3
d (71%)
In conclusion, a new method for construction of chiral
quaternary stereogenic centers, substituted with amino group and
with four different carbon ligands was developed by way of
tertiary dichloromethylcarbinols derived stereospecifically from
chiral secondary alcohols.
g (79%)
R: Ph
N3
N3 CH2OH
H2N
Me
CHO
CO2H
Ph
b
c
(77% directly
(94%)
Me
Ph
Me
Ph
5c
from 3c)
4c
6c
Cl
CHO
Ph
10c
(79% from 10c)
Me
CH(CN)OH
CH2OH
NC
NC
Me
NC
CO2H
e
c
f
References and Notes
(71% directly
Ph
9c
(90%)
(73%)
Me
Ph
7c
Me
Ph
1
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Scheme 2. Reagents and conditions: a: K2CO3 (5 eq.), MeOH., r.t., 10 min,
b: NaN3 (3 eq.), 15-crown-5 (1 eq.), THF, r.t., 12 h, c: NaBH4 (5 eq.), MeOH,
r.t., 10 min, d: 1) Jones’ reagent, acetone, 0 ꢂC, 15 min, 2) H2, Pd/C, EtOH,
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chloroepoxide 3a, which was converted into an a-azide-aldehyde
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substrate 2c. The crude unstable a-chloroepoxide 3c analogously
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azide-aldehyde 4c in 77% yield or a diastereomeric mixture of
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