Manganese-Catalyzed Stereospecific Hydroxymethylation of Alkyl Tosylates

Article abstract of DOI:10.1021/acs.orglett.9b03706

The development of a stereospecific hydroxymethylation of alkyl tosylates using an inexpensive, first-row catalyst is described. The transformation proceeds under mild conditions with low pressure to deliver homologated alcohols as products. Chiral, nonracemic β-branched primary alcohols are obtained with high enantiospecificity from easily accessed secondary alkyl substrates. Simple modification of the reaction system also permits access to α-d₂ alcohols. These studies use anionic metal carbonyl catalysis to access a synthetic equivalent of the challenging hydroxymethyl anion from carbon monoxide.

Full text of DOI:10.1021/acs.orglett.9b03706

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Manganese-Catalyzed Stereospecific Hydroxymethylation of Alkyl
Tosylates
Hannah Shenouda and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: The development of a stereospecific hydrox-
ymethylation of alkyl tosylates using an inexpensive, first-row
catalyst is described. The transformation proceeds under mild
conditions with low pressure to deliver homologated alcohols
as products. Chiral, nonracemic β-branched primary alcohols
are obtained with high enantiospecificity from easily accessed
secondary alkyl substrates. Simple modification of the reaction
system also permits access to α-d2 alcohols. These studies use
anionic metal carbonyl catalysis to access a synthetic equivalent of the challenging hydroxymethyl anion from carbon monoxide.
he homologation of carbon chains by a single unit is
featured in a number of synthetic organic reactions.
control in reactions of secondary substrates is a significant
challenge.
T
Classic transformations of carbonyl compounds such as the
Killiani−Fisher and Arndt−Eistert syntheses are valued for
their simplicity and convenience and find widespread use in
synthesis.1−7 Conversely, few methods are available for the
formal homologation of alcohols, either directly or via their
conversion to alkyl halides or pseudohalides.8,9 Recent work
has demonstrated the potential of radical-mediated methods to
achieve this goal (Figure 1). For example, Ryu and co-workers
We targeted the development of an alternative, stereospecific
approach to the homologation of alkyl electrophiles using
anionic metal carbonyl catalysis.12 Chiral, nonracemic
branched primary alcohols are important building blocks in
asymmetric synthesis. This strategy would facilitate their
synthesis from easily accessed, chiral, nonracemic secondary
alkyl tosylates. Herein, we report the successful development of
a stereospecific hydroxymethylation using a commercially
available manganese carbonyl dimer. This mild, catalytic
transformation represents a unique and concise approach to
the one carbon homologation of alkyl tosylates with excellent
stereocontrol.
Our investigation commenced with the hydroxymethylation
of primary tosylate 1 (Table 1). We determined that a catalytic
system comprising 10 mol % Mn2(CO)10 and two equivalents
of NaBH4 provided the homologated alcohol 2 in good yield
(67%, entry 1). Substitution of Mn2(CO)10 with the putative
catalytic nucleophile Na[Mn(CO)5] was similarly effective
(entry 2). Interestingly, the use of Co2(CO)8the precatalyst
used in previous studies of stereospecific anionic metal
carbonyls catalysissignificantly reduced reaction efficiency,
likely owing to the lower nucleophilicity of Na[Co(CO)4]
(entry 3).12,13 Decreasing the catalyst loading to 5 mol %
(entry 4) or the CO pressure to 1 atm (balloon, entry 5)
slightly lowered efficiency. Increasing the CO pressure to 20
atm provided little improvement (entry 6). Performing the
reaction at room temperature decreased conversion (entry 7),
while excluding ambient light had little effect (entry 8).
Notably, omitting the dioxane cosolvent did not impact the
yield in this case, but was important with other tosylates (entry
Figure 1. Hydroxymethylations of alkyl electrophiles.
have developed a hydromethylation using formaldehyde and
cyanoborohydride in a radical chain process.10 More recently,
Mankad and co-workers reported a copper-catalyzed, radical-
mediated transformation of alkyl iodides to silyl ethers, which
upon deprotection with tetrabutylammonium fluoride yields
homologated alcohols.11 In each of these processes, the
intermediacy of carbon-centered radicals dictates that stereo-
Received: October 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03706
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reported copper-catalyzed hydroxymethylation protocol (entry
6).11
We continued with the hydroxymethylations of chiral,
nonracemic secondary tosylates (Table 3). We view the
Table 1. Manganese-Catalyzed Hydroxymethylation of an
Unactivated Alkyl Tosylate*
Table 3. Stereospecific, Manganese-Catalyzed
Hydroxymethylation of Chiral, Nonracemic Secondary
Alkyl Tosylates*
a
entry
variation from standard conditions above
yield (%)
1
2
3
4
5
6
7
8
9
10
none
67
68
50
61
60
70
48
64
66
0
20 mol % Na[Mn(CO)5]
10 mol % Co2(CO)8
5 mol % Mn2(CO)10
1 atm CO
20 atm CO
rt
dark
no dioxane
no Mn2(CO)10
*
a
Reactions were performed with [1]0 = 0.5 M. Yields determined by
1H NMR spectroscopy of crude reaction mixture using an internal
standard.
9).14 No product was formed in the absence of the catalyst
(entry 10).
Having identified a viable catalytic system, we turned our
attention to the scope of the hydroxymethylation, starting with
primary alkyl tosylates (Table 2). The hydroxymethylation of
Table 2. Manganese-Catalyzed Hydroxymethylation of
Primary Alkyl Tosylates
*
a
See Table 1 for conditions. Isolated yields unless otherwise noted.
Enantiospecificity (es) = (eeproduct/eesubstrate) × 100%, determined by
b
1
chiral HPLC. Reaction yield determined by H NMR spectroscopy
c
of crude reaction mixtures using an internal standard. Enantiospe-
cificity determined from the tosylated product (see Supporting
Information).
capability of our polar catalytic manifold to enable stereo-
specific hydroxymethylations as a powerful, unique aspect of
our approach. The hydroxymethylation of chiral, nonracemic
tosylate 13 delivered alcohol 14 in 58% yield and with
excellent enantiospecificity (97%, entry 1). Importantly, the
reaction is not limited to methyl-branched substrates as
demonstrated by the reaction of tosylate 15, which although
less efficient (40% 1H NMR yield, 31% isolated yield)
proceeds in >99% es (entry 2). The homologations of tosylates
derived from chiral, nonracemic 1,3-diols proceeded efficiently
with high enantiospecificities (entries 3 and 4) and
demonstrated reaction tolerance of electron-poor arenes.
Alkyl tosylate 21 containing thiophene underwent hydrox-
ymethylations in 54% yield. Finally, a simple aliphatic tosylate
(23) was also a viable substrate and provided the
hydroxymethylation product with good enantiospecificity
(entry 6). In general, the mass balance was a mixture of
unreacted starting material, elimination, or reduction by-
products. While the results of Tables 2 and 3 demonstrate that
the reaction yields of the hydroxymethylation are moderate,
the uniformly high stereoselectivities are an attractive feature of
this catalytic process.
*
a
See Table 1 for conditions. Isolated yields.
the tosylate derived from the monoterpenoid citronellol
provided homologated alcohol 4, demonstrating compatibility
with alkenyl substrates (entry 2). Common polar functionality
such as esters and Boc-protected amines are also tolerated in
the hydroxymethylation (entries 3 and 4). The homologation
of indolyl tosylate 9 yielded alcohol 10, demonstrating the
efficiency of the reaction in the presence of electron-rich
heterocycles (entry 5). Notably, the hydroxymethylation of a
lithocholic acid derivative is successful in the presence of a silyl
ether, which would undergo deprotection using a previously
α-Deuterated alcohols are important compounds due to
their use as drug analogs and internal standards in proteomic,
metabolomic, and LADMET studies.15 Common routes to
these α-deuterated products proceed via reduction of
B
DOI: 10.1021/acs.orglett.9b03706
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carboxylic acid derivatives using LiAlD4 or highly reactive
single-electron reductants.16 An alternative approach via direct
α-deuteration of an alcohol requires precious ruthenium
catalysts and can provide product regioisomers.17−19 Given
its commercial availability, we sought to apply NaBD4 in the
hydroxymethylation to achieve α-deuterium incorporation
under our mild catalytic conditions. As an initial demonstration
of our approach to α-deuterated alcohols, we performed the
hydroxymethylation of primary tosylate 1 with 2 equiv of
NaBD4. The hydroxymethylation proceeded in 50% isolated
yield and 94% deuterium incorporation (eq 1). This
Scheme 1. Plausible Catalytic Cycle for Stereospecific
Hydroxymethylation
modification of our catalytic system involves a nucleophilic
substitution with a formal deuterated hydroxymethyl anion
equivalent and offers a new concise approach to α-deuterated
alcohols under mild conditions.
We sought to uncover details regarding the reaction
mechanism by studying the reactivity of a putative
acylmanganese intermediate. The reaction of substrate 13
with 1 equiv of Na[Mn(CO)5]the active catalyst formed in
situin the absence of NaBH4 provided the acylmanganese 25
in 48% yield. This intermediate was subsequently reduced with
target the further development of valuable synthetic methods
using this unique mode of metal catalysis.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03706.
NaBH4 to deliver the homologated alcohol 14 in 56% H
NMR yield (eq 3), consistent with the viability of
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: eja@email.unc.edu.
ORCID
Erik J. Alexanian: 0000-0002-0256-2133
Notes
acylmanganese as a precursor to the hydroxymethylation
product. Furthermore, comparison of hydroxymethylation
product 14 (Table 3, entry 1) to an independently prepared
sample indicated that the reaction proceeded with inversion of
configuration at the stereogenic center.
A mechanistic proposal for the catalytic hydroxymethylation
is illustrated in Scheme 1. The dimanganese decacarbonyl
precatalyst is reduced in situ by NaBH4 to provide the active
sodium pentacarbonylmanganate species. Subsequent nucleo-
philic attack on the substrate forms an alkylmanganese
intermediate, which undergoes migratory insertion of CO
with retention of configuration. The resulting acyl manganese
is reduced by NaBH4 to regenerate the active catalyst. The
aldehyde initially formed in this step is further reduced to give
the hydroxymethylation product.
In conclusion, we have developed a stereospecific hydrox-
ymethylation of alkyl tosylates using manganese catalysis. This
approach leverages the reactivity of anionic metal carbonyl
catalysis to access a formal hydroxymethyl anion equivalent
from CO and hydride. A mild, stereospecific homologation of
alkyl electrophiles is achieved, providing direct access to chiral,
nonracemic β-branched primary alcoholsand α-deuterated
derivativesfrom simple starting materials. Future studies will
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported under award number R35
GM131708 from the National Institute of General Medical
Sciences. We thank the UNC Department of Chemistry Mass
Spectrometry Core Laboratory for assistance with MS analysis,
supported by the National Institute of General Medical
Sciences under award number R35 GM118055 and the
National Science Foundation under award number CHE
1726291. We thank Justin Marcum (University of North
CarolinaChapel Hill) for assistance with SFC and helpful
discussions.
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Org. Lett. XXXX, XXX, XXX−XXX