Selective synthesis of α,α-dideuterio alcohols by the reduction of carboxylic acids using Smi2 and D2O as deuterium source under set conditions

Article abstract of DOI:10.1021/ol502404e

The first general method for the chemoselective synthesis of α,α-dideuterio alcohols directly from feedstock carboxylic acids under single electron transfer conditions using SmI₂ is reported. This reaction proceeds after the activation of Sm(II

Full text of DOI:10.1021/ol502404e

Letter
pubs.acs.org/OrgLett
Selective Synthesis of α,α-Dideuterio Alcohols by the Reduction of
Carboxylic Acids Using SmI2 and D2O as Deuterium Source under SET
Conditions
Michal Szostak,*,† Malcolm Spain,‡ and David J. Procter*,‡
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: The first general method for the chemoselective
synthesis of α,α-dideuterio alcohols directly from feedstock carboxylic
acids under single electron transfer conditions using SmI2 is reported.
This reaction proceeds after the activation of Sm(II) with a Lewis base,
results in excellent levels of deuterium incorporation across a wide
range of substrates, and represents an attractive alternative to processes
mediated by pyrophoric alkali metal deuterides.
ecent studies demonstrate that the introduction of
deuterium as a hydrogen bioisostere can have a major
ment of new general protocols for the selective incorporation of
deuterium is an important goal.
R
impact on improving pharmacokinetic properties (ADMET) of
a large variety of drugs.1 Most importantly, due to the primary
deuterium kinetic isotope effect,2 deuterium substitution at the
metabolically labile sites can significantly increase stability of
active pharmaceutical ingredients and reduce their toxicity by
impeding formation of toxic metabolites (Figure 1).3 As such,
Significant progress on the deuteration of organic molecules
has been reported,8 including pH-dependent9a,b and transition
metal mediated9c−f protocols. However, the vast majority of
these methods employ harsh reaction conditions, are limited in
scope, or afford isotopically labeled products with moderate
levels of deuterium incorporation.8,9 Additional problems
include nonselective labeling of several positions and lack of
methods that would afford high selectivity in labeling of
functional groups with similar reactivities. In addition,
compared with deuteration of sp2 or sp bonds (e.g.
aromatic,9a,c,g vinylic,9d alkynyl9b), mild general methods for
deuteration of unactivated sp3 bonds are underdeveloped.8,9e,f
There is no general deuteration method that involves a SET
pathway.10
Since the pioneering studies by Kagan, SmI2 has emerged as
one of the most important single electron transfer reagents in
organic synthesis.11−13 Several methods employing SmI2 to
introduce deuterium to organic molecules have been
reported.14 In particular, Concello
́
n and Rodrıguez-Solla
́
disclosed protocols for deuteration of activated π-bonds (Figure
2A);14a−e however, the potential of SmI2 for the synthesis of
isotopically labeled compounds has yet to be fully realized.11
We recently disclosed a practical method for the reduction of
carboxylic acids via acyl-type radical intermediates using a
reagent system prepared by activation of SmI2 by Lewis base
and water.15 Crucially, the reaction was successfully applied to
the reduction of a wide range of carboxylic acid feedstock
materials bearing sensitive functional groups.16
Figure 1. Recent examples of deuterated drug analogues. Deuterium
used as a bioisostere of hydrogen to improve pharmacokinetic
properties (ADMET = absorption, distribution, metabolism, excretion,
toxicity).
deuterium incorporation has experienced a renaissance of
interest in the pharmaceutical industry,1,4 and several
deuterated drugs have been advanced to clinical trials.1d In
addition, deuterated molecules are of high synthetic interest
because of their use as tools for studying reaction mechanisms5
and their application as functional materials6 and as analytical
standards in mass spectrometry.7 Consequently, the develop-
To further expand this methodology, here we report the
development of the synthesis of α,α-dideuterio alcohols by a
Received: August 13, 2014
© XXXX American Chemical Society
A
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Table 1. Effect of Additives on D2 Incorporation in the
Reduction of Unactivated Carboxylic Acids with SmI2−
a
D2O
b
b
equiv
(R3N)
equiv
(ROH)
yield
(%)
[D2]
entry
amine
Et3N
ROH
(%)
1
2
D2O
D2O
D2O
D2O
D2O
D2O
D2O
D2O
MeOD
D2O
D2O
D2O
D2O
D2O
D2O
36
36
36
36
12
72
36
36
36
36
36
36
36
36
36
9.9
>98
>98
>98
>98
>98
>98
>98
21.5
>98
>98
>98
>98
>98
>98
<2.0
92.0
94.5
93.5
84.5
94.0
92.5
96.0
34.0
52.0
27.5
20.5
36.0
67.5
43.5
Et3N
36
36
c
3
d
Et3N
4
Et3N
36
5
6
7
Et3N
18
Et3N
72
Et3N
144
288
36
e
8
Et3N
9
Et3N
10
11
12
13
n-BuNH2
C5H10NH
C4H8NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
36
Figure 2. (a) Previous studies: dideuteration of activated π-bonds with
SmI2−D2O. (b) This work: chemoselective synthesis of α,α-dideuterio
alcohols via acyl-type radicals using SmI2− D2O−base.
36
36
36
c
14
d
36
direct reduction of carboxylic acids via radical intermediates
using SmI2 and D2O as deuterium source (Figure 2B). There
are several noteworthy features of this protocol: (i) very mild
reaction conditions;8 (ii) high functional group tolerance;13
(iii) excellent levels of deuterium incorporation;7 and (iv) the
use of nonpyrophoric reagents in aqueous media.17 In contrast
to the synthesis of dideuterio alcohols using alkali metal
deuterides, the current protocol can be readily applied to
chemoselectively differentiate between functional groups with
similar reactivities.13 Furthermore, we demonstrate the
preparation of deuterated compounds with a gradually
increasing amount of deuterium label by exploiting a single
electron transfer mechanism based on reversibility of electron
transfer and formation of well-defined SmI2−alcohol complexes
with high affinity for Sm(II).18 Finally, studies carried out
during the development of the reaction suggest that in the
Sm(II) reagents, amines can play a dual role as an
intramolecular base and as a proton source, an observation
that may have important implications for the future design and
optimization of Sm(II) reagents.
We started our investigation by studying the effect of Lewis
base and protic additives on D2 incorporation in the reduction
of 3-phenylpropanoic acid (Table 1). Because of its low price
and ready availability,19 D2O was used as a preferred deuterium
source. No reaction occurred in the absence of a proton source
(entry 1). Pleasingly, the reaction in the presence of Et3N as a
Lewis base and D2O as a proton source afforded the alcohol
product in quantitative yield with 92.0% D2 incorporation
(entry 2). Premixing of acid with D2O increases D2
incorporation, presumably as a result of proton exchange
(entries 2−4).14a
15
36
a
Conditions: carboxylic acid (1 equiv), SmI2 (6 equiv), THF, 23 °C.
Addition order: acid, SmI2, amine, D2O. Determined by H NMR.
Addition order: acid, SmI2, D2O, amine. Preformed solution of
SmI2/D2O/amine. Addition order: acid, D2O, SmI2, amine.
b
1
c
d
e
reduction.18 Experiments conducted to investigate the potential
for reagent complexation and proton exchange (entries 13−15)
showed that proton transfer from amine occurs independently
under the reaction conditions. Taken together, these experi-
ments suggest that in reactions mediated by SmI2−amine−
water, amine can play a dual role as an intramolecular base and
as a proton source before or after H+ exchange, which is in
contrast to previous studies suggesting that the major role of
amine is to increase the redox potential of the reagent.5a,15,18
+
The D2 incorporation is consistent with the relative pKBH of
amines.18d
Scope studies showed that high levels of D2 incorporation are
general across a range of substrates, resulting in a broadly useful
protocol (Table 2). Primary, secondary, tertiary, and aromatic
ring-containing substrates afforded the dideuterated products
with excellent D2 incorporation (entries 1−4). Decarboxylation
and aromatic reduction were not observed. Examination of a
wide range of functional groups further demonstrates the broad
scope of this protocol (entries 5−11). Importantly, several
functional groups that are not compatible with other SET
reagents were tolerated in the reaction (entries 5−8 and 11).
The sequential aryl bromide/acid reduction indicates the
potential of this protocol for aryl-selective introduction of a
deuterium label (entry 9).21 Terminal olefins (entry 12) and
heterocycles (entry 13) were tolerated. Moreover, protection of
free N−H groups is not required to afford high levels of D2
incorporation (entries 10 and 13). Finally, more complex
substrates featuring activated benzylic and homobenzylic
positions (entries 14 and 15) and unprotected alcohols, such
as ursodeoxycholic acid (entry 16), readily participated in the
reaction, maintaining excellent levels of D2 incorporation.
One of the advantages of using Sm(II) reagents to introduce
deuterium lies in the ability to fine-tune the redox potential (E°
= 0.9 to 2.8 V) to a specific moiety.11−13 This can result in high
Deuterium incorporation depends on the reagent stoichi-
ometry (entries 5−8). The best results were obtained in the
presence of excess of D2O (entry 8); however, all reaction
conditions in which the additives were present in the required
stoichiometry18a resulted in high levels of D2 incorporation.
The use of highly coordinating MeOD-d4 was less effective
(entry 9).20 Primary and secondary amines promoted the
reduction in excellent yields and in an instantaneous reaction
time; however, much lower D2 incorporation was observed
(entries 10−15), consistent with the relative rates of the
B
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Table 2. Effect of Structure on D2 Incorporation in the
Reduction of Carboxylic Acids with SmI2−D2O
Table 3. Application of SmI2−D2O/H2O to Targeted
a
a
Incorporation of Deuterium Content
D2O/H2O
(x:y, %)
entry
conv (%)
yield of 2s (%)
[H1/D1] (%)
1
2
3
4
5
6
100
0
20
>98
>98
>98
>98
>98
>98
96
94
93
92
94
93
<2
80
60
40
20
0
31.5
54.5
70.5
85.5
>98
40
60
80
100
a
Conditions: substrate, SmI2, THF, D2O/H2O (200 equiv), 23 °C.
Figure 3. Calibration curve for targeted incorporation of deuterium
using SmI2−D2O/H2O in the reduction of 1s.
To further demonstrate the synthetic utility of the reaction,
we examined deuteration of lovastatin,16d a cholesterol-
lowering drug, featuring a six-membered lactone and acyclic
ester in a sensitive decalin ring (Scheme 1). The dideuterated
Scheme 1. Chemoselective Dideuteration of Lovastatin
a
Conditions: carboxylic acid, SmI2 (6 equiv), THF, D2O (36 equiv),
b
c
Et3N (36 equiv), 23 °C. Determined by 1H NMR. 96:4 ratio of 2f to
1,1-D,D-3-(p-tolyl)propan-1-ol. 88:12 ratio of 2h to 1,1-D,D-3-
phenylpropan-1-ol. >95% conversion to 1,1-D,D-3-(4-
d
e
deuteriophenyl)propan-1-ol; 76% [D1] at the aromatic ring.
chemoselectivity simply by changing the required additive. The
developed SmI2−D2O conditions can be applied to the
synthesis of α-mono and α,α-dideuterio alcohols from a variety
of functions, such as aldehydes (1q), chlorides (1r), ketones
(1s), esters (1t), and amides (1u) (Table 1-SI, Supporting
Information).
Furthermore, the present reaction can be readily applied to
the targeted titration of deuterium content to afford products
with increasing amount of deuterium simply by using a
combination of H2O and D2O (Table 3 and Figure 3:
correlation curve, R2 = 0.99).8,9 Note that this outcome is
possible on the basis of rate-limiting electron transfer,18 low
kinetic isotope effect to carbon,5,15,18 and the use of user-
friendly aqueous conditions in the reaction.17 A similar titration
would be difficult to achieve using pyrophoric metal deuterides.
product resulting from lactone reduction was obtained with
complete selectivity (>98% D2),13 demonstrating the potential
of this protocol to chemoselectively introduce D2 in complex
settings.
In conclusion, α,α-Dideuterio alcohols can be synthesized
directly from carboxylic acid feedstocks using SmI2 and D2O as
deuterium source. The reaction conditions are mild and result
in high levels of deuterium incorporation to give alcohol
products via a general single electron transfer mechanism. The
protocol can also be extended to other functional groups,
targeted titration of deuterium, and deuteration of complex
molecules. Amines can serve as an intramolecular proton
source, which could lead to the discovery of novel two-
component Sm(II) reagents and the development of catalytic
Sm(II) protocols.
C
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Organic Letters
Letter
pathways typically proceeds with low deuterium incorporation due to
ASSOCIATED CONTENT
* Supporting Information
■
́
hydrogen atom transfer mechanism: (c) Jimenez, T.; Barea, E.; Oltra,
S
J. E.; Cuerva, J. M.; Justicia, J. J. Org. Chem. 2010, 75, 7022.
(d) Paradas, M.; Campana, A. G.; Jimen
́
ez, T.; Robles, R.; Oltra, J. E.;
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
̃
Bunuel, E.; Justicia, J.; Car
2010, 132, 12748.
́
denas, D. J.; Cuerva, J. M. J. Am. Chem. Soc.
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(11) (a) Kagan, H. B. Tetrahedron 2003, 59, 10351. (b) Nicolaou, K.
C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140.
(c) Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2011, 50, 7737.
(d) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev.
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(12) For reviews on additives to SmI2, see: (a) Szostak, M.; Spain,
M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330.
́
(b) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: michal.szostak@rutgers.edu.
*E-mail: david.j.procter@manchester.ac.uk.
Notes
The authors declare no competing financial interest.
Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155.
(14) (a) Concellon
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Rodríguez-Solla, H. Eur. J. Org. Chem. 2006, 1613. (e) Davies, S. G.;
Rodríguez-Solla, H.; Tamayo, J. A.; Garner, A. C.; Smith, A. D. Chem.
Commun. 2004, 2502. For other SmI2-mediated deuteration protocols,
see: (f) Schmalz, H. G.; Siegel, S.; Bernicke, D. Tetrahedron Lett. 1998,
39, 6683. (g) Dutta, D.; Hadd, H.; Vander Velde, D. G.; Georg, G. I.
Bioorg. Med. Chem. Lett. 1999, 9, 3277. (h) Chiara, J. L.; Sesmilo, E.
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, J. M.; Rodríguez-Solla, H. Chem.Eur. J. 2002,
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ACKNOWLEDGMENTS
■
́
We thank the EPSRC and Leverhulme Trust for support. M.S.
thanks Rutgers University for support during the preparation of
this manuscript.
́
́
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