A column-based 'flush and flow' system for the asymmetric α-chlorination of acid halides

Article abstract of DOI:10.1016/j.tetasy.2005.09.014

We describe a column based flow system in which a cinchona alkaloid based reagent/catalyst solid-phase promotes the asymmetric α-chlorination of acid chlorides to afford highly optically active α-chloroesters in high enantiomeric excess and in good yields

Full text of DOI:10.1016/j.tetasy.2005.09.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3481–3483
A column-based ‘flush and flow’ system for the asymmetric
a-chlorination of acid halides
Daniel Bernstein, Stefan France, Jamison Wolfer and Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
Received 11 August 2005; accepted 13 September 2005
Available online 11 November 2005
Abstract—We describe a column based flow system in which a cinchona alkaloid based reagent/catalyst solid-phase promotes the
asymmetric a-chlorination of acid chlorides to afford highly optically active a-chloroesters in high enantiomeric excess and in good
yields.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
eluting at the bottom of the column in a fairly pure
form. The most interesting aspect of this particular sys-
Herein, we report a simple, solid-phase ÔflowÕ system for
the enantioselective chlorination of acid halides, in
which resin beads derivatized with a cinchona alkaloid
serve as both the asymmetric promoter of the reaction
and the stoichiometric dehydrohalogenating agent for
enolate formation (Scheme 1). In most solid-phase1
methodologies, the substrates are immobilized on solid
support while the reagents are passed through in the
mobile phase.2 Our system, however, features the
attachment of the reagent/catalyst to the solid support.3
The beads are loaded into a jacketed column, which
serves as the reaction vessel, and are flushed with solvent
to ensure complete saturation. The substrates are then
added to the column in solution and allowed to flow
through the solid-phase reagent with the products
tem is that by alternating a HunigÕs base ÔflushÕ cycle
¨
with the introduction of the substrates, the cinchona
alkaloid-derived beads can be completely regenerated.
Given the robustness of the beads to the flow of reagents
and solvents, a theoretically unlimited number of flush/
flow cycles can be done sequentially to afford the prod-
uct again and again. This methodology thus provides an
example of a process that is rendered catalytic by the
addition of a periodic physical/chemical regeneration
step. Also of note, by linking such columns together in
sequence, a Ôsynthesis machineÕ can be fashioned in
which each column carries out a discrete step of the
overall synthesis. We recently demonstrated this concept
via the convergent, five-step synthesis of BMS-275294
entirely through a column-based flow system.5
Cl
O
O
Cl
Cl
In previous work, we discovered that when a solution of
phenylketene is treated with 1 equiv of electrophilic
chlorinating agent 2 in the presence of 10 mol % ben-
zoylquinine, a-chloroester 4 is formed in 80% yield
and high enantiomeric excess (99% ee) after purification
by column chromatography.6 Under these conditions,
the catalyst is difficult to recover from the reaction mix-
ture in its pure form, so we looked to a solid-phase sys-
tem based on our earlier success with reactive columns.7
N
and
Cl
R
Cl
N
H
N
4
Cl
Cl
O
"Flush" cycle
"Flow" cycle
R
O
Cl
Cl
Cl
O
H
Cl
Cl
N
N
R
Cl
Cl
3
1
2
Cl
Scheme 1. Column Ôflush and flowÕ system for the enantioselective
a-chlorination of acid chlorides.
2. Results and discussion
*
After our initial success with column asymmetric synthe-
Corresponding author. Tel.: +1 410 516 6448; e-mail: lectka@
jhu.edu
sis of b-lactams,7 we envisioned the extension of our
0957-4166/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.09.014

3482
D. Bernstein et al. / Tetrahedron: Asymmetry 16 (2005) 3481–3483
Table 1. Reactions of acid chlorides 1 with chlorinating agent 2 using
polymer-bound quinine derivative 3
methodology to other reactions and eventually onto
more complex syntheses of medicinally or biologically
important molecules. The linking and interchanging of
columns could ultimately lead to the synthesis of a num-
ber of complex molecules.
Entry Acid chloride
Product
Yielda eeb
(%)
(%)
Cl
O
O
1
58
94
Ph
OPhCl5
Ph
Cl
The column assembly is depicted in Figure 1. First, a
nitrogen-flushed, fritted, jacketed chromatography
column8 was slurry-packed with quinine-loaded Wang
resin 3.9 THF was added via syringe until the solvent
reached just above the surface. Phenylacetyl chloride
1a (1.3 equiv) and 2,2,3,4,5,6-hexachloro-3,5-cyclohexa-
dien-1-one 2 (1 equiv) were independently dissolved in a
minimal amount of THF, and the jacketed column
cooled to 0 °C with an ice/water bath. A small amount
of the acid chloride (20%) was then added to the col-
umn. At this stage, the flow was started at a rate of
0.1 mL/min. It was necessary to provide a steady stream
of nitrogen to ensure a constant flow rate. After the
small primer of acid chloride was forced into the beads,
small, equal amounts of acid chloride 1a and chlorinat-
ing agent 2 in THF were loaded on top of the column
packing. Once the level of the solution dropped to di-
rectly above the level of the surface, 1 mL of THF was
added and forced into the beads. Then the next portions
of reagents were added. Once all of the substrate mix-
ture was added, THF was used to flush the product off
the column. The entire process was complete in about
4 h. The eluent was collected, concentrated, and purified
to afford 4a in 58% yield and 94% ee (Table 1, entry 1).
1a
4a
Cl
O
O
2
3
4
5
52
50
40
61
93
92
90
93
PhO
1-Np
Cl
PhO
OPhCl5
1b
4b
O
Cl
O
Cl
1-Np
OPhCl5
O
4c
1c
O
Cl
4-ClPh
Cl
4-ClPh
OPhCl5
1d
4d
Cl
O
O
4-Tol
OPhCl5
4-Tol
Cl
1e
4e
O
Cl
O
Cl
OPhCl5
O
O
6
55
88
4f
1f
N
N
O
O
N
N
a Isolated yield after column chromatography.
b Determined by chiral-phase HPLC.
acid chloride and
chlorinating agent
OMe
First, it eliminates the need to isolate and/or manipulate
highly reactive ketenes. No ketene preformation steps or
precautions, other than an ice bath are necessary. Sec-
ondly, the catalyst can be easily recycled for innumera-
ble additional runs and we avoid degradation of the
catalyst beads that can be caused by vigorous mechani-
cal stirring. Even the reaction time is drastically reduced.
Most importantly, the system can ultimately be adapted
to automation through the use of computer-mediated
solvent pumps and flow meters.
N
dehydrohalogenation
reagent and
N
H
asymmetric catalyst
O
O
O
O
ice
bath
3
O
Cl
Cl
Cl
O
Cl
O
Cl
R
Cl
Cl
R
OPhCl5
4
Cl
1
2
50-61% yield
88-94% ee
product elution
after ~3 h
3. Conclusion
Figure 1. Column-based asymmetric synthesis of a-chloroesters.
In conclusion, we have expanded our column asymmet-
ric methodology to include the enantioselective a-halo-
genation of acid chlorides, affording optically-active a-
chloroesters in high enantioselectivity. It is noteworthy
that the process has been rendered catalytic by an inter-
To prepare the apparatus for another cycle, the column
was flushed in sequence with THF, HunigÕs base in THF
¨
solution (ꢀ10%), and two more times with THF.10
These beads have shown no loss of activity after numer-
ous cycles; in fact, we have used one batch of beads
more than 100 times.
mittent flush cycle using HunigÕs base to deprotonate the
¨
beads and remove any hydrochloride salts.
To demonstrate the utility of this methodology, we have
employed a variety of acid chlorides, ranging from aryl
to aliphatic substituents.11 The results of the screening
can be seen in Table 1. There are several important
advantages to conducting this type of reaction on a col-
umn as opposed to the conventional batch method.
Acknowledgements
T.L. thanks the NIH (GM 064559), the Dreyfus and
Sloan Foundations, and Merck for support. S.F. thanks
the Ford Foundation, GlaxoSmithKline, and NOBC-
ChE, for support.

D. Bernstein et al. / Tetrahedron: Asymmetry 16 (2005) 3481–3483
3483
5. France, S.; Bernstein, D.; Weatherwax, A.; Lectka, T.
Org. Lett. 2005, 7, 3009–3012.
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¨
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