Triphosgene-pyridine mediated stereoselective chlorination of acyclic aliphatic 1,3-diols

Article abstract of DOI:10.1039/c5cc06365e

We describe a strategy to chlorinate stereocomplementary acyclic aliphatic 1,3-diols using a mixture of triphosgene and pyridine. While 1,3-anti diols readily led to 1,3-anti dichlorides, 1,3-syn diols must be converted to 1,3-syn diol monosilylethers to access the corresponding 1,3-syn dichlorides. These dichlorination protocols were operationally simple, very mild, and readily tolerated by advanced synthetic intermediates.

Full text of DOI:10.1039/c5cc06365e

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Triphosgene-Pyridine Mediated Stereoselective Chlorination of
Acyclic Aliphatic 1,3-Diols†
Andrés Villalpando, Mirza A. Saputra, Thomas H. Tugwell,‡ and Rendy Kartikaa
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We describe a strategy to chlorinate stereocomplementary acyclic stereochemical arrays.2
While the fundamental tactics
aliphatic 1,3-diols using a mixture of triphosgene and pyridine. undertaken by these studies generally focused on the
While 1,3-anti diols readily led to 1,3-anti dichlorides, 1,3-syn diols stereoselective construction of vicinal dichloride structural
must be converted to 1,3-syn diol monosilylethers to access the motifs, stereocomplementary synthesis to access both
corresponding 1,3-syn dichlorides. These dichlorination protocols diastereomers of unactivated, acyclic aliphatic 1,3-dichlorides
were operationally simple, very mild, and readily tolerated by essentially remained significant problems.2c,3 To bridge this
advanced synthetic intermediates.
gap of knowledge, this communication describes our unifying
strategy for the production of both 1,3-anti and 1,3-syn
dichlorides from their corresponding unreactive aliphatic 1,3-
diols in a single synthetic operation and, most importantly, in a
stereoselective manner.
Chlorosulfolipids are one of the major classes of naturally
occurring organohalogens.1 These natural products are
essentially a long hydrocarbon chain containing multiple
chlorine, sulfate, and/or hydroxy substituents along their
Recently, we reported
a new method to chlorinate
aliphatic backbone.
The inherent structural complexity
significant
challenge for total synthesis, thus prompting the development
sterically encumbered primary and secondary aliphatic
alcohols via activation with triphosgene and pyridine.4 These
operationally simple reactions were very clean, high yielding,
and did not generate any chromatographically nuisance
byproducts. As shown in Scheme 1, the mechanism of this
reaction was proposed to proceed via an intermediacy of
exhibited by these biomolecules presents
a
Figure 1. Examples of Chlorosulfolipid Natural Products
pyridinium carbamate ion
upon nucleophilic activation of chloroformate
Under the reaction conditions, the putative pyridinium
carbamate intermediate was susceptible to nucleophilic
5, which was presumably produced
4
with pyridine.
5
substitution by chloride ions at the carboxyl position to
generate the target alkyl chlorides with an inversion of
stereochemistry, while regenerating pyridine as the
nucleophilic promoter and releasing CO2 as the sole byproduct.
Scheme 1. Triphosgene-Pyridine Promoted Chlorination of
Secondary Alcohols.
of contemporary strategies to access the intricate polychloride
Our chlorination methodology naturally placed us in a
strategic position to contribute a viable solution to the
synthesis of alkyl 1,3-anti and 1,3-syn dichlorides. We
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proposed that these stereocomplementary compounds should
be readily generated by subjecting the corresponding aliphatic
1,3-diol precursors to our triphosgene-pyridine activation. For
proof of concept, we proceeded to explore the reactivity of
1,3-anti diol
6 and 1,3-syn diol 9. We were cognizant that 1,3-
diols are known to readily undergo carbonate cyclization with
triphosgene and amine bases.5 Interestingly, treatment of 1,3-
anti diol 6 with 1.0 equivalent of triphosgene and 4.0
equivalents of pyridine in dichloromethane at reflux produced
7
1,3-anti dichloride
carbonate byproduct
in a quantitative yield, and cyclic
8 was detected only in a trace amount.
This result suggested that in the presence of excess
triphosgene and pyridine, 1,3-anti diol rapidly underwent
double chloroformylation, ultimately leading to dichlorination.
In contrast, the use of 1,3-syn diol produced cyclic carbonate
11 as the major product, indicating that monochloro-
formylation in 1,3-syn diol was immediately captured by the
facile 6-membered ring cyclization to form thermodynamically
favorable chair conformation in cyclic carbonate 11
6
9
9
.
[a] Starting materials are racemic with >20:1 dr. [b] Products
Scheme 2. Initial Studies of Triphosgene-Pyridine Chlorination
with 1,3-Diols.[a,b]
were isolated as
a single diastereomer with presumed
stereochemical inversion. [c] Yields are based on product
isolation after flash column chromatography.
We then continued our investigation towards solving the
challenges associated with the dichlorination of 1,3-syn diols,
particularly in controlling the rate of chlorination vs. carbonate
cyclization. We envisioned that the competitive carbonate
cyclization could be inhibited by simply masking one of the
hydroxy groups in 1,3-syn diol to a monosilylether, viz. 14. The
rationale is illustrated in Scheme 3. Exposure of substrate 14
to triphosgene-pyridine should rapidly chlorinate the free
secondary alcohol via pyridinium carbamate 15. During this
process, excess chloride ions liberated from decomposition of
triphosgene should slowly cleave the silylether moiety to
[a] Starting materials are racemic with >20:1 dr. [b] The ratio
of dichloride and cyclic carbonate products was determined
via GC-MS analyses of the crude reaction mixtures.
furnish putative chloroalcohol 16 6
chloroformylation of the newly unmasked alcohol, followed by
.
The ensuing in situ
With these preliminary results in hand, we then explored
the conversion of several exemplary 1,3-anti diols to 1,3-anti
dichlorides in preparative scales. As depicted in Table 1,
substrates bearing aromatic, allylic, and aliphatic groups as
represented in 1,3-anti diols 12a and 12b afforded 1,3-anti
dichlorides 13a and 13b in 90% and 65% yields, respectively.
This dichlorination protocol was found to be compatible with
structurally complex substrates, such as 1,3-anti diol 12c. We
found that primary TBS ether remained intact under the
reaction conditions, and product 13c was isolated in 80% yield.
Our chemistry also enabled the production of synthetically
daunting 1,3-dichloro compounds, most notably exemplified
Scheme 3.
Chlorination Strategy with 1,3-syn Diol
Monosilylether.
by the conversion of 1,3-anti
β,γ
β
anti -dichloroester 13d in 73% isolated yield.
,
γ
-dihydroxyester 12d to 1,3-
The
tolerability of this highly sensitive starting material and
product under the reaction conditions underscore the
mildness of our chlorination method. It is noteworthy that
chlorination of these 1,3-anti diol substrates proceeded very
cleanly. In fact, analysis of the crude reaction mixtures by both
GC-MS and NMR essentially revealed quantitative conversion
of the starting material to the corresponding 1,3-anti
dichlorides without formation of any other byproducts.
pyridine activation should then form pyridinium carbamate 17
and furnish the desired 1,3-syn dichloride.
Table 1. Chlorination of 1,3-anti Diols.
2 | J. Name., 2012, 00, 1-3
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concentration up to 500 mM profoundly improved the
selectivity to 99:1, favoring formation of 1,3-syn dichloride 10
Table 2. Screening and Reaction Optimization with 1,3-syn
.
Diol Monosilylether.
Application of these optimized conditions towards several
1,3-syn diol substrates in preparative scale reactions is
demonstrated in Table 3.
For instance, the use of
monosilylated 1,3-syn diols 19a and 19b readily generated 1,3-
syn dichlorides 20a and 20b, respectively, in high yields.
Exposure of advanced synthetic intermediate 1,3-syn diol
monosilylether 19c to the reaction conditions successfully
produced the corresponding 1,3-syn dichloride 20c in an
excellent yield. Furthermore, we were also able to convert
monosilylated 1,3-syn β,γ-dihydroxy ester 19d to synthetically
challenging and highly sensitive 1,3-syn dichloride 20d in 92%
yield using this methodology.7
Our success in the installation of 1,3-dichlorides inspired us
to push this method towards the construction of
stereocomplementary alkyl 1,3,5-trichlorides from the
corresponding aliphatic triols. As shown in Scheme 4, 1,3,5-
anti triol 21 was treated with 1.5 equivalents of triphosgene
and 6.0 equivalents of pyridine in dichloromethane at reflux.
Gratifyingly, the GC-MS and NMR analyses of the crude
reaction mixture revealed a full conversion to 1,3,5-anti
trichloride 22, corresponding to 75% isolation yield. Similarly,
when 1,3,5-syn triol 23 was reacted with identical molar
equivalence of triphosgene-pyridine mixture at the optimal
500 mM concentration, the crude reaction mixture also
indicated the complete consumption of the starting material to
[a] Concentration was based on starting material 18. [b] The
ratio of dichloride 10 and cyclic carbonate 11 was determined
via GC-MS analyses of the crude reaction mixtures.
Table 2 describes a series of experiments to test this
hypothesis. As shown in Entries 2-5, we prepared several
monosilylethers 18
triethylsilyl ether,
,
ranging from trimethylsilyl ether,
dimethylphenylsilyl ether, and
diphenylmethylsilyl ether. Each of these substrates was
subjected to identical dichlorination conditions, i.e. 1.0
equivalent of triphosgene, 4.0 equivalents of pyridine in
dichloromethane (25 mM concentration based on starting
material) at reflux. We identified that dimethylphenylsilyl
ether was the most suitable functionality as it yielded the best
ratio between 1,3-syn dichloride 10 and cyclic carbonate 11
the corresponding 1,3,5-syn trichloride 24
.
An attempt to
isolate this sensitive compound using column chromatography
resulted in 55% yield.
Scheme 4. Chlorination of Stereocomplementary 1,3,5-Triols.
[a,b]
Table 3. Chlorination of 1,3-syn Diol Monosilylether.
[a] Starting materials are racemic with >20:1 dr. [b] Products
were isolated as
a single diastereomer with presumed
stereochemical inversion.
The relative stereochemistry of these acyclic chlorinated
compounds was readily deduced by an analysis developed by
Carman and Nouguier,8 which involved a direct comparison of
the 13C NMR signals of the 1,3-anti and 1,3-syn diastereomers.
Carman and Nouguier observed that in deuterated chloroform,
the chemical shifts belonging to the 1,3-anti dichlorides, in
[a] Starting materials are racemic with >20:1 dr. [b] Products
particular those of the chlorinated carbon centers (C
and their immediate neighboring carbons (C
α
and C
α
’)
were isolated as
a single diastereomer with presumed
β
and Cβ
’),
stereochemical inversion. [c] Yields are based on product
isolation after flash column chromatography.
(entry 4). Further reaction optimization revealed that the
selectivity between dichlorination and carbonate cyclization
was evidently modulated by the reaction concentration. As
appeared more downfield in the 13C NMR spectrum by
approximately 1 ppm than those produced by the comparable
carbons in 1,3-syn dichlorides. Application of the Carman-
Nouguier analysis to our alkyl 1,3-dichloride products revealed
similar patterns (Table 4). We indeed observed that the 13C
indicated in entries
4 and 6-8, increasing the reaction
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NMR signals for both chlorinated carbons and their respective
adjacent carbons for 1,3-anti dichlorides 13a-13d and 22 were
Prod. Rep., 2011, 28, 15-25; d) T. Umezawa and F. Matsuda,
Tetrahedron Lett., 2014, 55, 3003-3012.
consistently ~1 ppm more downfield than the signals from the 2. a) W.-j. Chung, J. S. Carlson and C. D. Vanderwal, J. Org.
corresponding 1,3-syn dichlorides 20a 20d and 24
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respectively. These comparative chemical shifts data thus
supported the stereoselectivity in our dichlorination reactions,
i.e. 1,3-anti diols lead to 1,3-anti dichlorides, 1,3-syn diols lead
to 1,3-syn dichlorides.
Table 4. Carman-Nouguier 13C NMR Analyses.[a]
3. While there are ample of precedents on the preparation of
activated 1,3-dichloride systems, i.e. benzylic, α-carbonyl, etc.,
to the best of our knowledge, complementary stereoselective
methods to access both diastereomers of unactivated, acyclic
aliphatic 1,3-dichlorides are not well precedented in the
literature. Rare examples on the conversion of aliphatic 1,3-
anti diol to the corresponding 1,3-anti dichlorides using PPh3-
NCS activation: Hoffmann, R. W.; Stenkamp, D. Tetrahedron
1999, 55, 7169, and ref 2c.
[a] Chemical shifts are reported relative to residual CHCl3 as an
internal reference (77.0 ppm).
4
a) A. Villalpando, C. E. Ayala, C. B. Watson and R. Kartika, J.
Org. Chem., 2013, 78, 3989-3996; b) C. E. Ayala, A. Villalpando,
A. L. Nguyen, G. T. McCandless and R. Kartika, Org. Lett., 2012,
14, 3676-3679.
In conclusion, we have developed a general tactic for the
synthesis of stereocomplementary aliphatic 1,3-anti and 1,3-
syn dichlorides, enabled by our triphosgene-pyridine
chlorination conditions. The mild nature of this highly
stereoselective method readily tolerated sensitive functional
groups, allowing for the construction of synthetically
challenging complex molecules. Extension of the strategy to
vicinal diols and synthetic application towards chlorosulfolipid
natural products are currently underway in our laboratory.
This publication is based upon work supported by the NSF
under CHE-1464788 and the NIGMS of the NIH under Award
Number R25GM069743 through the Initiative for Maximizing
Student Development (LSU-IMSD) Fellowship award to A.V.
Generous financial support from Louisiana State University
(LSU) College of Science is greatly appreciated. We thank
Professor George Stanley for kindly allowing us to use the GC-
MS instrument in his laboratories.
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7. The position of the silylether group in the 1,3-syn diols did not
affect the outcome of our dichlorination reaction. We exposed
a mixture of γ- monosilylated 1,3-syn dihydroxy ester 19d and
its β-variant to the reaction conditions, and the GC-MS analysis
of the crude mixture revealed a quantitative conversion of
both substrates to the corresponding 1,3-syn dichloride 20d.
8. C. J. Carman, A. R. Tarpley Jr. and J. H. Goldstein. J. Am. Chem.
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Notes and References
‡
Undergraduate research participant
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718-728; b) C. Nilewski and E. M. Carreira, Eur. J. Org. Chem,
2012, 1685-1698; c) D. K. Bedke and C. D. Vanderwal, Nat.
4 | J. Name., 2012, 00, 1-3
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