A chiral benzyl group as a chiral auxiliary and protecting group for the synthesis of optically active 1,2-Diols and (+)-Frontalin

Article abstract of DOI:10.1055/s-0033-1340163

Chelation-controlled asymmetric nucleophilic addition of a Grignard reagent to chiral α-benzyloxy ketones gives the corresponding alcohols with high diastereoselectivities (up to 96% de) by 1,4-asymmetric induction. A chiral benzyl group is used as a chiral auxiliary as well as a protecting group for the synthesis of optically active 1,2-diols and (+)-frontalin. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340163

LETTER
▌251
lAetteCr hiral Benzyl Group as a Chiral Auxiliary and Protecting Group for the
Synthesis of Optically Active 1,2-Diols and (+)-Frontalin
A Chiral Benzyl Group as a Chiral Auxiliary for 1,2-Diols
Tae Hyun Kim,a Young-Kyo Kim,a Zunhua Yang,a Jung Wha Jung,a Lak Shin Jeong,b Hee-Doo Kim*a
a
College of Pharmacy, Sookmyung Women’s University, Yongsan-ku, Seoul 140-742, Republic of Korea
Fax +82(2)7030736; E-mail: hdkim@sm.ac.kr
b
College of Pharmacy, Seoul National University, Kwanak-ku, Seoul 151-742, Republic of Korea
Received: 22.08.2013; Accepted after revision: 30.09.2013
dition reaction. Herein, we describe nucleophilic addition
Abstract: Chelation-controlled asymmetric nucleophilic addition
to α-alkoxy ketones in which a chiral benzyl group is at-
of a Grignard reagent to chiral α-benzyloxy ketones gives the corre-
tached as both a protecting group and a chiral auxiliary in
proximity to a prochiral functionality by means of an ether
sponding alcohols with high diastereoselectivities (up to 96% de) by
1,4-asymmetric induction. A chiral benzyl group is used as a chiral
auxiliary as well as a protecting group for the synthesis of optically linkage (Scheme 1).
active 1,2-diols and (+)-frontalin.
We chose methyl and phenyl ketone derivatives as the
Key words: nucleophilic addition, diols, α-benzyloxy ketones,
(+)-frontalin, stereoselective synthesis
α-alkoxy ketones for our investigation. The preparation of
α-benzyloxy ketone 1 was simple and straightforward as
shown in Scheme 2. Chiral benzyl alcohol 4, prepared di-
rectly from D-glyceraldehyde acetonide, according to the
literature method,7 was converted into the benzyl ethers 6,
in good yields, by O-alkylation using allyl bromides 5.
Ozonolyzis of alkenes 6 produced the corresponding α-
alkoxy carbonyl compounds 1a and 1b in good yields.
O-Alkylation of alcohol 4 with the corresponding α-bro-
mo ketone also provided an alternative and direct entry to
ketones 1a and 1b.
The widespread use of 1,2-diols and their derivatives as
chiral synthons in organic synthesis has grown in line with
advances in methods for their asymmetric synthesis.1
Sharpless asymmetric dihydroxylation of alkenes is a
well-known method for the preparation of optically active
1,2-diols.2 The nucleophilic addition of a Grignard re-
agent to α-alkoxy carbonyl compounds offers an alterna-
tive and important route to chiral 1,2-diols, especially
those not accessible via Sharpless asymmetric dihydrox-
ylation.3
The feasibility of 1,4-asymmetric induction in this nucleo-
philic 1,2-addition was first examined using methyl ke-
tone 1a. The reactions were performed with or without
pre-complexation of the ketone, using the respective met-
al salts as Lewis acids. In addition, the nucleophiles and
solvents were varied. The addition of nucleophiles to the
carbonyl compounds was performed by utilizing the fol-
lowing standard procedure: a mixture of the ketone and
additive (4 equiv, pre-dried with a heat gun under vacu-
um) in a solvent was irradiated in an ultrasonic water bath
for 10 minutes, and then cooled to –78 °C. To this mixture
was added dropwise a solution of the appropriate nucleo-
phile (2 equiv). The mixture was quenched after two hours
with water to afford, following extraction and chromato-
graphy, the respective addition products in good yields
Our recent development of a chelation-controlled asym-
metric alkylation process that permits efficient syntheses
of chiral α-hydroxy esters prompted us to investigate
whether this process would be readily adaptable to the
synthesis of chiral 1,2-diols.4 It was envisioned that the
chelation-controlled asymmetric nucleophilic 1,2-addi-
tion to an α-alkoxy ketone, followed by removal of the
chiral auxiliary would provide optically active diols.5 Our
initial attempt toward the synthesis of (+)-flutriafol via a
chiral 1,2-diol was found to be successful.6 Encouraged
by this result, we investigated the scope and limitations of
our chelation-controlled asymmetric nucleophilic 1,2-ad-
O
OH
O
O
R2MgX
O
OH
O
O
O
R2
R1
HO
R1
R2
chelation-
controlled
debenzylation
R1
stereoselective
addition
3
OMe
OMe
1
2
Scheme 1 A chiral benzyl moiety as a chiral auxiliary and protecting group for the synthesis of optically active 1,2-diols
SYNLETT 2014, 25, 0251–0254
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340163; Art ID: ST-2013-U0803-L
© Georg Thieme Verlag Stuttgart · New York

252
T. H. Kim et al.
LETTER
O
O
O
O
O
OH
O3
R1
1a R1 = Me
1b R1 = Ph
Br
+
R1
5
OMe
OMe
4
6
Scheme 2 Synthesis of chiral α-benzyloxy ketones 1a and 1b
(75–97%). The stereochemical results of the transforma- tion occurred under the same conditions. According to the
tions are summarized in Table 1.
Schlenk equilibrium,8 two equivalents of RMgX are in
equilibrium with R2Mg and MgX2. Thus, the MgX2 spe-
cies in the phenylmagnesium halide seems to play a piv-
otal role in inducing the diastereoselective reaction. Even
better selectivity was obtained by changing the solvent
from tetrahydrofuran to dichloromethane. The solvation
ability of tetrahydrofuran or 1,2-dimethoxyethane (DME)
seems to be correlated with the stereoselectivity, presum-
ably destroying the chelated complex. The use of
Grignard reagents, combined with pre-complexation of
As shown in Table 1, preferential formation of 2 over 2′
was observed, and the ratio was found to be highly depen-
dent on the additive, solvent, and nucleophiles. In the ab-
sence of an additive, addition of phenyllithium (PhLi) to
the methyl ketone derivative afforded the corresponding
alcohol in good yield, but without any diastereoselection
(Table 1, entry 1). However, when using phenylmagne-
sium chloride (Table 1, entry 2), diastereoselective addi-
Table 1 Asymmetric Nucleophilic 1,2-Addition to α-Alkoxy Ketonesa
R2
HO R2
O
O
O
O
OH
R1
O
O
R2M
O
O
O
O
R1
R1
+
additive, solvent
–78 °C, )))
OMe
OMe
OMe
1
2
2'
Entry
R1
R2M
PhLi
Solvent
Additive
2:2′b
Yield (%)c
1
2
Me
Me
Me
Me
Me
Me
Me
Ph
THF
none
1:1
8:1
95
83
85
80
97
92
81
81
92
87
80
90
87
75
PhMgCl
THF
none
3
PhMgCl
PhMgCl
DME
none
5:1
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
none
18:1
16:1
16:1
50:1
11:1
11:1
16:1
10:1
15:1
18:1
35:1
5
PhMgCl
LiBr
6
PhMgCl
MgCl2
7
PhMgCl
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
8
MeMgCl
vinylMgBr
allylMgCl
i-PrMgBr
c-hexMgCl
9
Ph
10
11
12
13
14
Ph
Ph
Ph
Ph
4-FC6H4MgBr
Ph
t-BuMgCl
a Additive (4 equiv) and R2M (2 equiv) in THF were used based on ketone 1 (1 equiv).
b The 2:2′ ratios were measured by HPLC analysis.
c Combined yield of the two diastereoisomers.
Synlett 2014, 25, 251–254
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Chiral Benzyl Group as a Chiral Auxiliary for 1,2-Diols
253
the ketone with magnesium bromide–diethyl etherate chelation complex, resulting in lower stereoselectivities.
(MgBr2·OEt2) in a poorly-donating solvent, turned out to The absolute configurations of the newly created stereo-
represent the best conditions (Table 1, entry 7). Under the genic centers in 2 and 2′ were assigned after removal of
optimized conditions, we applied various types of nucleo- the chiral auxiliary with cerium(IV) ammonium nitrate
philes in reactions with phenyl ketone derivative 1b. The (CAN) or trimethylsilyl chloride (TMSCl),9 and compari-
bulkiness of the nucleophile was important to the selectiv- son of the optical rotations of the resulting 1,2-diols with
ity. The bulkier the R2 group, the higher the selectivity at- literature values.3,10 For example, treatment of a mixture
tained in the alkylation. When R2 was a tert-butyl group, of 2 and 2′ (Table 1, entry 7) with cerium(IV) ammonium
the selectivity ratio reached up to 35. Overall, methyl ke- nitrate in 10% aqueous acetonitrile at room temperature
tone 1a was found to serve as a more efficient substrate for five hours afforded (R)-2-phenylpropane-1,2-diol
than phenyl ketone 1b (Table 1, entries 7 and 13).
{[α]D25 –5.6 (c 1.0, EtOH)} in 67% yield.3b,5c During the
removal of the chiral auxiliary on 2 with cerium(IV) am-
monium nitrate, intermediate 4 was oxidized into the cor-
responding ketone, which on treatment with L-Selectride,11
can be readily recovered for reuse. Encouraged with this
result, we applied the present method to the synthesis of
optically active (+)-frontalin, as outlined in Scheme 3.
The preferential formation of 2 over 2′ and the high level
of stereoselection associated with this asymmetric alkyla-
tion can be rationalized by considering the plausible tran-
sition state model of a highly organized chelation
complex, resulting from tridentate chelation of the three
internal oxygens with the magnesium ion (Figure 1). In
this model, the five-membered ring containing the carbon- Due to the unique structure and its biological activity,
yl group is puckered upwards minimizing the steric inter- frontalin has attracted intense interest from synthetic
action with the nearby aromatic ring. Therefore, chemists, which has led to more than 50 syntheses of the
nucleophilic attack is preferred from the convex side of natural and unnatural products.12 Our diastereoselective
the chelated complex, which is syn to the aryl ring.
synthesis of unnatural (+)-frontalin is simple and straight-
forward. Only two steps were required to complete the
synthesis of the target molecule starting from α-benzyloxy
ketone 1a. Performing the nucleophilic addition of
Grignard reagent 8, pre-complexed with magnesium
bromide–diethyl etherate in dichloromethane at –78 °C, to
methyl ketone derivative 1a followed by hydrolysis gave
a 15:1 ratio of 7a and 7b, isolated in 70% and 4% yield,
respectively. Finally, upon exposure of the mixture to eth-
anethiol (EtSH) and tin(II) chloride (SnCl2) in dichloro-
methane,9b the alcohol 7a underwent debenzylation and
deacetalization, followed by concomitant cyclization to
afford (+)-frontalin in 65% yield. This synthetic sample of
(+)-frontalin was identical in all respect (1H NMR, 13C
NMR, IR), except for the optical rotation, to those report-
ed for natural (–)-frontalin. The specific rotation of the
R1
O
O
Nu–
O
Mg+
nucleophile approaches
from the convex side
of the complex
O
H
OMe
Figure 1 Hypothetical chelated transition state showing the pre-
ferred attack by the nucleophile
As shown in Table 1, external polar ligands such as tetra-
hydrofuran and 1,2-dimethoxyethane could destroy the
MgBr
O
O
OH
O
O
O
O
O
O
O
O
O
8
MgBr2⋅OEt2
CH2Cl2
–78 °C
OMe
1a
OMe
7b
+
OH
O
O
O
O
O
O
EtSH, SnCl2
CH3
O
CH2Cl2
65%
Me
(+)-frontalin
OMe
7a
Scheme 3 Stereoselective synthesis of (+)-frontalin
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 251–254

254
T. H. Kim et al.
LETTER
synthetic sample {[α]D25 +52.3 (c 0.5, Et2O)}13 was almost
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In conclusion, we have shown that optically active 1,2-di-
ols and the natural product, (+)-frontalin, can be prepared
efficiently from our chiral auxiliary through a stereoselec-
tive nucleophilic 1,2-addition reaction. A high degree of
1,4-asymmetric induction has been realized during the al-
kylation step via the chelation-controlled mechanism. The
chiral benzyl group employed in this reaction was shown
to act efficiently as a protecting group as well as a chiral
auxiliary. Thus, our synthetic method might offer an alter-
native route to chiral diols that are not easily accessible
through Sharpless asymmetric dihydroxylation.
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Acknowledgment
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2011-0010857).
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2014, 25, 251–254
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