Stereoinversion of Stereocongested Carbocyclic Alcohols via Triflylation and Subsequent Treatment with Aqueous N,N-Dimethylformamide

Article abstract of DOI:10.1021/acs.orglett.6b02675

A convenient method for the stereoinversion of secondary alcohols, applicable to stereocongested carbocyclic substrates, is reported. A simple three-step procedure, including triflylation of the hydroxy group, nucleophilic oxygenative displacement by the treatment with aqueous N,N-dimethylformamide (DMF), and methanolysis, allowed for efficient stereoinversion of various substrates, including sugar derivatives, in one pot.

Full text of DOI:10.1021/acs.orglett.6b02675

Letter
pubs.acs.org/OrgLett
Stereoinversion of Stereocongested Carbocyclic Alcohols via
Triflylation and Subsequent Treatment with Aqueous
N,N‑Dimethylformamide
Hidenori Ochiai, Takashi Niwa, and Takamitsu Hosoya*
Chemical Biology Team, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies,
6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
S
* Supporting Information
ABSTRACT: A convenient method for the stereoinversion
of secondary alcohols, applicable to stereocongested carbocyclic
substrates, is reported. A simple three-step procedure, including
triflylation of the hydroxy group, nucleophilic oxygenative dis-
placement by the treatment with aqueous N,N-dimethyl-
formamide (DMF), and methanolysis, allowed for efficient
stereoinversion of various substrates, including sugar derivatives, in one pot.
group in 1a did not proceed even under reflux conditions in
tereoinversion of secondary alcohols is a fundamental and
Simportant transformation in organic synthesis. The 1,2-dichloroethane, indicating severe steric congestion around
the hydroxy group (Scheme 1B). These results demonstrated
the difficulty of achieving stereoinversion of sterically congested
alcohols. Herein, we report a convenient method that increases
options for stereoinversion of stereocongested secondary alcohols.
To achieve stereoinversion of stereocongested alcohols, we
revisited the SN2 displacement approach. We assumed that
using small-sized reagents for both hydroxy group activation
and nucleophilic displacement would be advantageous to
achieve the desired transformation. More specifically, we con-
sidered that triflylation of the hydroxy group followed by
stereoinvertive formyloxylation of the resulting triflate 6 with
DMF via iminium salt 78 would be a promising approach
(Scheme 2). We expected that the undesired β-elimination
Mitsunobu reaction is the most widely used method for this
purpose.1 This method has been successfully applied for the
stereoinversion of alcohols bearing a broad range of functional
groups, including intermediates for the synthesis of complex
molecules. Another occasionally used approach is the SN2 dis-
placement by oxygen nucleophiles, performed after converting
the hydroxy group to a good leaving group such as a sulfonyl-
oxy group.2−4 For some substrates, stereoinversion of alcohols
has been achieved through a sequence of reactions comprising
oxidation of the starting alcohols to ketones followed by their
stereoselective reduction.5
These conventional methods, however, have substrate limi-
tations; in particular, they are often inapplicable to stereo-
congested carbocyclic alcohols.2d,f,5i,6 Indeed, some of our trials
to invert the stereochemistry of the hydroxy group in ribose
derivative 1a with two neighboring cis-benzoyloxy groups were
unsuccessful (Scheme 1). For example, under typical Mitsunobu
conditions,7 a stereoretained O-acylated product 3 was obtained
in low yield instead of the desired stereoinverted arabinose
derivative 2 (Scheme 1A). Furthermore, tosylation of the hydroxy
Scheme 2. Working Hypothesis
reaction in 6 to form the corresponding alkene,9 which often
competes with the intended nucleophilic displacement, would
be avoidable because of the superior leaving group ability of the
triflyloxy group and low Brønsted basicity of DMF. If the SN2
displacement with DMF can be conducted in an acidic aqueous
solution, the iminium intermediate 7 can be hydrolyzed in situ
to furnish the desired stereoinverted formate 8.
Scheme 1. Initial Attempts
Based on these considerations, we examined the reaction con-
ditions for stereoinversion of alcohol 1a (Table 1). Triflylation of
1a with triflic anhydride (Tf2O) proceeded smoothly at a low
Received: September 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02675
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Organic Letters
Letter
Table 1. Screening of Reaction Conditions
Scheme 3. Stereoinvertive Oxygenation Using [18O]H2O
a
yield (%)
b
entry
aq acid or water
temp (°C) time (h)
8a
9a
total
1
2
3
4
5
6
7
10 wt % aq HBr
10 wt % aq HCl
10 wt % aq HF
10 wt % aq HOTf
water
100
100
100
100
100
100
60
5
nd
nd
45
51
50
nd
nd
nd
44
39
41
85
52
−
−
89
90
91
85
99
5
5
subsequent hydrolysis provides 9a with 50 atom%18O incor-
poration (Scheme S5A). However, ESI-MS analyses of the
oxygenated products showed that the content ratios of 18O in
8a and 9a were ≥98% and 14%, respectively (Scheme 3A).
Considering that nucleophilic substitution with DMF provides
9a without incorporation of the 18O atom (Scheme S5B), this
result indicated that the reaction proceeded mainly based
on our scenario (Scheme 2).14 Furthermore, performing the
reaction using a preheated mixture of DMF and [18O]H2O
(10/1, v/v) without or with HOTf (1 equiv) at 100 °C for
5 h also afforded 9a that contained a small amount of 18O
(Scheme 3B and 3C), suggesting that involvement of formate
as a nucleophile is a minor pathway in this reaction.
Using the additive-free conditions (Table 1, entry 5), the
stereochemistry of a hydroxy group in various sugar derivatives
was invertible via the corresponding triflates 6 (Table 2).15
A commercial tetraacetyl mannose triflate 6b, which has been
utilized as a radiolabeling precursor of 18F-fluorodeoxyglucose
([18F]FDG),16 was successfully converted to glucose formate
8b. In this case, selective methanolysis of the formate moiety
proceeded in the absence of triethylamine to afford 9b. In
addition to benzoyl and acetyl protecting groups, a wide variety
of functional groups such as an imide and ethers bearing benzyl,
methyl, 4-methoxyphenyl, and allyl moieties tolerated this trans-
formation, considerably expanding the scope of this method. Not
only 2,3,6-tri-O-benzoyl-D-galactoside triflate 6c but also 2,3,6-tri-
O-benzyl-D-galactoside triflate 6d was converted efficiently to its
corresponding glucosides 9c and 9d, respectively.17 Protected
glucosamine triflate 6e was also efficiently transformed to a
galactosamine derivative 9e.17 Notably, the interconversion
between the glucosamine derivative and the galactosamine deriv-
ative was successfully conducted by using this method; 1f (= 9g)
was converted into 9f (= 1g) and vice versa with high yields.
The method was also applied to a disaccharide; cellobiose deriv-
ative 9h was obtained in high yield from a protected lactose
triflate 6h. Through these stereoinversion sequences, neither
epimerized nor hydrolyzed products with the functional groups
at the anomeric position were detected, despite the likely gen-
eration of triflic acid.18
5
5
water
24
120
water
47
b
a
Isolated yields are shown. nd = not detected. Total yields of
stereoinverted products (8a + 9a).
temperature to afford triflate 6a almost quantitatively. Triflate
6a was sufficiently stable to be purified using silica-gel column
chromatography and could be stored at room temperature
under open-air conditions for more than a month without any
decomposition. We then aimed for the realization of stereo-
invertive formyloxylation of the triflyloxy group in 6a by
performing the reaction in a 10:1 (v/v) mixture of DMF and
an acidic aqueous solution with heating at 100 °C (Table 1).
Neither the desired stereoinverted formate 8a nor alcohol 9a
was obtained on using aqueous hydrobromic acid or hydro-
chloric acid; however, 6a was consumed completely and a
mixture of unidentified compounds was obtained (entries 1
and 2). Efficient results were obtained on using aqueous hydro-
fluoric acid or trifluoromethanesulfonic acid (HOTf), both of
which afforded oxygenated products 8a and 9a in high com-
bined yields (entries 3 and 4).10 Treatment of formate 8a with
triethylamine in methanol at room temperature afforded the
corresponding alcohol 9a in high yield, leaving the benzoyl
groups intact. Further examination revealed that the reaction
proceeded efficiently even without adding an acid (entries 5
and 6) and may have been promoted by triflic acid, which
generated gradually in situ as the SN2 displacement progressed.
The reaction also proceeded efficiently at a lower temperature
of 60 °C; however, a significant prolongation of the reaction
time was required to obtain the desired oxygenated products
with high yield (entry 7).11
Supportive experiments suggested that alcohol 9a was
generated mainly through deformylation of 8a.12 For example,
heating 8a at 100 °C for 9 h in a mixture of DMF and aqueous
HOTf or water afforded 9a (Scheme S3).
From the mechanistic viewpoint, there was a possibility that
dimethylammonium formate, which could be generated in situ
via the decomposition of DMF, served as an oxygen nucleo-
phile in this transformation. Thus, to trace the origin of oxygen
incorporated in the oxygenated products, we conducted the
inversion reaction using [18O]H2O (≥98 atom%18O) as the
water source (Schemes 3 and S4).13 Theoretically, if the in situ
generated formate serves as an oxygen nucleophile, the 18O
atom in 8a is introduced randomly in the formyloxy group and
A sequence of reactions for the stereoinversion could be
simply performed in a one-pot procedure, as demonstrated by
an efficient gram-scale transformation of 1a to 9a (Scheme 4),
demonstrating the practicality of the method.13
The one-pot procedure was particularly effective for the
stereoinversion of sterically less-hindered alcohols for which
the corresponding triflates were too labile to be isolated.
B
DOI: 10.1021/acs.orglett.6b02675
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a
Table 2. Substrate Scope
a
b
c
Isolated yields are shown. See Supporting Information for details of reaction conditions. Commercial. Methanolysis was performed under reflux
d
e
conditions without using triethylamine. The reaction was performed using MeOH−CH2Cl2 as a solvent. Reaction time or yields when the reaction
was performed at 60 °C are shown in the parentheses. PMP = p-methoxyphenyl. 46% of 1h was recovered.
f
g
In summary, we have developed a simple method for the
Scheme 4. One-Pot Procedure in Gram Scale
stereoinversion of carbocyclic alcohols applicable to stereo-
congested substrates. This method is unique in that the oxy-
genative displacement proceeds under acidic conditions, provid-
ing a new option for the stereoinversion of alcohols.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02675.
Experimental procedures, characterization for new
compounds including NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: takamitsu.hosoya@riken.jp.
ORCID
Figure 1. Stereoinversion of alcohols via labile triflates using a one-pot
procedure.
For example, by using this method, monobenzoyl-protected
5- and 6-membered cycloalkane cis-1,2-diols 1i and 1j were suc-
cessfully converted to trans-1,2-diols 9i and 9j, respectively
(Figure 1).13,19,20
Takamitsu Hosoya: 0000-0002-7270-351X
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02675
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Organic Letters
Letter
1987, 43, 2523. (f) Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J.
Org. Chem. 1997, 62, 8294.
ACKNOWLEDGMENTS
■
The authors thank Central Glass Co., Ltd. for providing Tf2O.
This research was supported by JSPS KAKENHI Grant Number
15K05509 (T.N.) and a Special Postdoctoral Researchers
Program Fellowship from RIKEN (H.O.).
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