A tandem organocatalytic α-chlorination-aldol reaction that proceeds with dynamic kinetic resolution: A powerful tool for carbohydrate synthesis

Article abstract of DOI:10.1021/ol401370b

A tandem, proline-catalyzed α-chlorination/aldol reaction is described that involves a dynamic kinetic resolution of α-chloroaldehyde intermediates. The resulting syn-chlorohydrins are produced with good to excellent diastereoselectivity in high enantiopurity and provide new opportunities for the synthesis of carbohydrates.

Full text of DOI:10.1021/ol401370b

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3554–3557
A Tandem Organocatalytic
r‑ChlorinationÀAldol Reaction That
Proceeds with Dynamic Kinetic Resolution:
A Powerful Tool for Carbohydrate Synthesis
Milan Bergeron-Brlek, Timothy Teoh, and Robert Britton*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
rbritton@sfu.ca
Received May 15, 2013
ABSTRACT
A tandem, proline-catalyzed R-chlorination/aldol reaction is described that involves a dynamic kinetic resolution of R-chloroaldehyde intermediates.
The resulting syn-chlorohydrins are produced with good to excellent diastereoselectivity in high enantiopurity and provide new opportunities for the
synthesis of carbohydrates.
Carbohydrates play a vital role in regulating biological
events that range from cell recognition to pathogen/host
adhesion and are essential components of many biomole-
cules (e.g., DNA, RNA, and glycoproteins).1 Not surpris-
ingly, inhibitors of carbohydrate binding and cleaving
processes have been identified as leads in various thera-
peutic areas, and several glycomimetic drugs have been
approved for use.2 Progress in glycomimetic research is
often closely tied to advances in the de novo synthesis
of unnatural carbohydrates, with much success being
realized through the use of organocatalytic reactions.3
In particular, the pioneering work of List, Lerner, and
Barbas III,4,5 MacMillan,6 Enders,7 and others8 have
demonstrated that biomimetic transformations such as
aldol reactions involving dihydroxy acetone derivatives
can be catalyzed by chiral amines with excellent enantio-
selectivity (e.g., 1 f 3,7a Scheme 1). These processes
facilitate the rapid synthesis of carbohydrates and their
analogues, but necessarily require the use of optically pure
R-alkoxyaldehydes7a (e.g., 2) or a subsequent aldol reac-
tion (e.g., 6 f 8).6 Access to heterocyclic C-glycoconju-
gates, which continue to attract attention as drug leads and
biological probes,9 is also limited by the availability of
suitably functionalized aldehydes. Our continued interest
in the use of R-chloroaldehydes as building blocks for
natural product synthesis10 led us to probe their organo-
catalytic aldol reactions with the dioxanone 1,5c,7,11À13
(1) Varki, A. Glycobiology 1993, 3, 97.
(2) (a) Asano, N. Glycobiology 2003, 13, 93R. (b) Gustafsson, A.;
Holgersson, J. Expert Opin. Drug Discovery 2006, 1, 161.
(3) For recent reviews, see: (a) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) Guillena, G.;
Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249.
(c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
(d) Scheffler, U.; Mahrwald, R. Synlett 2011, 1660.
(6) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752.
(7) (a) Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210.
(b) Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329. (c) Grondal, C.;
Enders, D. Synlett 2006, 20, 3507. (d) Enders, D.; Terteryan, V.; Palecek,
J. Synthesis 2010, 17, 2979.
(8) Mlynarski, J.; Gut, B. Chem. Soc. Rev. 2012, 41, 587.
(9) Bottcher, T.; Sieber, S. A. J. Am. Chem. Soc. 2010, 132, 6964.
(10) (a) Halperin, S. D.; Britton, R. Org. Biomol. Chem. 2013, 11,
1702. (b) Britton, R.; Kang, B. Nat. Prod. Rep. 2013, 30, 227. (c) Chang,
S.; Britton, R. Org. Lett. 2012, 14, 5844. (d) Draper, J. A.; Britton, R.
Org. Lett. 2010, 12, 4034. (e) Kang, B.; Chang, S.; Decker, S.; Britton, R.
Org. Lett. 2010, 12, 1716. (f) Kang, B.; Mowat, J.; Pinter, T.; Britton, R.
Org. Lett. 2009, 11, 1717.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
(5) (a) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.
2002, 3024. (b) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III. Org.
Lett. 2005, 7, 1383. (c) Suri, J. T.; Mitsumori, S.; Albertshofer, K.;
Tanaka, F.; Barbas, C. F., III. J. Org. Chem. 2006, 71, 3822. (d)
Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2007, 46, 5572. (e) Utsumi, N.; Imai,
M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F., III. Org. Lett. 2007,
9, 3445. (f) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas,
C. F., III. Org. Lett. 2008, 10, 1621.
r
10.1021/ol401370b
Published on Web 07/02/2013
2013 American Chemical Society

Scheme 1. De Novo Synthesis of Carbohydrates and a Tandem
R-ChlorinationÀAldol Reaction with Dynamic Kinetic
Resolution
Scheme 2. Proline-Catalyzed Aldol Reactions of
2-Chloropentanal
enantiomeric chlorohydrins were produced in similar yield
and only slightly diminished diastereoselectivity, with the
major product (ent-12) bearing the opposite configuration
at the chloromethine stereocenter to that of the starting
chloroaldehyde (R)-11. As we suspected the proline
catalysts effected racemization of chloroaldehyde (R)-11
during the course of these reactions,14c a sample of (R)-11
was treated independently with (S)-proline (Scheme 2,
Chart A, solid line) and (R)-proline (Chart A, long
dash), and its enantiomeric excess was monitored over
time. As depicted in Chart A, both antipodes of proline
were equally efficient at promoting racemization of (R)-2-
chloropentanal (11), with samples of the latter substance
degrading to 40% ee over the course of one day. Likewise,
a sample of (R)-11 prepared by (S)-proline-catalyzed
chlorination of pentanal (20% ee) was racemic after 10 h
of stirring with (S)-proline (Chart A, short dash).
Based on the sense of diastereoselectivity in the aldol
reactions depicted in Scheme 2, there is an inherent sub-
strate bias for the reaction of the R-chloroaldehyde (R)-11
with the chiral enamine derived from (S)-proline.17,18 While
it is well documented that proline-catalyzed aldol reactions
involving dioxanone 1 are highly selective for anti-aldol
products7 as predicted by the HoukÀList model,7a,19 the
observed syn-chlorohydrin selectivity is opposite to that
expected from EvansÀCornforth models of stereo-
induction.20 A potential explanation for the preferential
reaction of (R)-chloropentanal with the (S)-proline-derived
which would provide a launching point for the preparation
of various cabohydrates. These efforts resulted in the
discovery of a one-pot R-chlorination/aldol reaction that
involves the dynamic kinetic resolution of an in situ gener-
ated R-chloroaldehyde. As described below, this process
provides direct access to novel, optically enriched building
blocks (e.g., 9) for the synthesis of carbohydrates and
C-glycoconjugates.
As depicted in Scheme 2, we first investigated the (S)-
proline catalyzed reaction of 2,2-dimethyl-1,3-dioxan-5-
one (1) with (R)-2-chloropentanal (11) (78% ee), prepared
following Jørgensen’s R-chlorination protocol.14b We were
delighted to find that this double diastereodifferentiating15
aldol reaction produced a ca. 6:1 mixture of the chlorohy-
drins 12 and 13 (63% yield), respectively.16 Surprisingly,
when the reaction was repeated with (R)-proline catalysis,
(11) Several examples of organocatalytic aldol reactions involving
chloroacetaldehyde have been reported; see: (a) Markert, M.; Scheffler,
U.; Mahrwald, R. J. Am. Chem. Soc. 2009, 131, 16642. (b) Hayashi, Y.;
Yasui, Y.; Kawamura, T.; Kojima, M.; Ishikawa, H. Angew. Chem., Int.
Ed. 2011, 50, 2804. (c) Fanton, J.; Camps, F.; Castillo, J. A.; Guerard-
Helaine, C.; Lemaire, M.; Charmantray, F.; Hecquet, L. Eur. J. Org.
Chem. 2012, 203. (d) Rohr, K.; Mahrwald, R. Org. Lett. 2012, 14, 2180.
(12) For cross aldol reactions involving R-chloroaldehydes where the
chloromethine is directly reduced following the reaction, see: Kano, T.;
Sugimoto, H.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 18130.
(13) (a) Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int. Ed.
2005, 44, 1304. (b) Niewczas, I.; Majewski, M. Eur. J. Org. Chem. 2009,
33. (c) Palyam, N.; Majewski, M. J. Org. Chem. 2009, 74, 4390.
(14) For the asymmetric R-chlorination of aldehydes, see: (a) Brochu,
M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
4108. (b) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (c) Amatore, M.;
Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int.
Ed. 2009, 48, 5121.
(17) For an example of kinetic resolution in the reaction of a racemic
R-chloroaldehyde with a chiral enolate, see: Shinoyama, M.; Shirokawa,
S.-i.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2009, 11, 1277.
(18) For examples of aldol reactions that proceed with kinetic
resolution, see: Ward, D. E.; Becerril-Jimenez, F.; Zahedi, M. M. J.
Org. Chem. 2009, 74, 4447 and references cited therein.
(19) (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475. (b) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16.
(15) For reviews, see: (a) Masamune, S.; Choy, W.; Petersen, J. C.;
Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1. (b) Kolodiazhnyi,
O. I. Tetrahedron 2003, 59, 5953.
(16) See Supporting Information for full details.
Org. Lett., Vol. 15, No. 14, 2013
3555

Table 1. Optimization of One-Pot R-Chlorination/Aldol Reactiona
(S)-proline
temp
time
(h)
yield
(%)b
entry
solvent
(equiv)
(°C)
12:13c
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.2
0.2
0.2
0.2
0.2
1.2
0.8
0.8
0.8
0.8
0.8
0.8
À15d
0
72
144
144
72
48
24
24
24
24
24
24
24
0
À
2
36
55
13
49
63
72
51
34
32
63
49
6:1
3
20
30
20
20
20
20
20
20
20
20
5:1
nde
4
f
5
CH2Cl2
CH2Cl2
CH2Cl2
DCE
6:1
Figure 1. Potential HoukÀList transition structures leading to
aldol adducts 12 and 13.
6
4:1
7
6:1
8
2.6:1
2.6:1
3.8:1
1.5:1
2.2:1
enamine (TS-1, Figure 1) involves avoidance of steric
interactions as well as the destabilizing electrostatic inter-
actions that exist between the Cl and O atoms in the merged
EvansÀCornforth/HoukÀList model (TS-2). The diaste-
reomeric excess of both aldol adducts 12 and ent-12 was
also found to change considerably throughout the course
of the reactions (Scheme 1, Chart B), further indicating
that racemization of R-chloroaldehyde (R)-11 is competi-
tive with the desired aldol reaction. Importantly, these
results confirm that the proline-catalyzed aldol reac-
tion between dioxanone 1 and (R)-2-chloropentanal (11)
proceeds via a dynamic kinetic resolution (DKR)21 of the
R-chloroaldehyde.
Based on the observations detailed above, we investi-
gated one-pot variations of the reaction described in
Scheme 2 (top) in which proline-catalyzed aldehyde chlo-
rination is followed directly by a DKR proline-catalyzed
aldol reaction. As depicted in eq 1, (S)-proline catalyzed
chlorination of pentanal was complete in 3 h (ee ≈ 15%),
after which time the dioxanone 1 was added directly to the
reaction mixture. Alternatively, the experimental protocol
could be further simplified by adding all reagents together
at once. In both cases, this tandem process delivered the
aldol adduct 12 in good yield, diastereoselectivity (dr = 5:1),
and enantiopurity (94% ee).
9
THF
10
11
12
PhCH3
MeCN
EtOAc
a Reaction conditions: Pentanal (1 equiv), 1 (1.05 equiv), NCS (1.05
equiv), and (S)-proline (0.8 equiv) added to solvent (≈ 0.2 M) at 0 °C and
allowed to warm gradually to designated temperature. b Combined
isolated yield of 12 and 13. c From analysis of 1H NMR spectra recorded
on crude reaction mixtures. d Reaction maintained at À15 °C. e Not
determined. f 0.5 equiv of H2O added.
As H2O has been reported to accelerate organocatalytic
aldol reactions,3,22 the addition of 0.5 equiv of H2O was
also examined (entry 5) and the reaction time was reduced
without significantly impacting the overall yield or
diastereoselectivity.23 Increasing the amount of (S)-proline
to 1.2 equiv further reduced the reaction time to 24 h, albeit
with a slight decrease in diastereoselectivity. While the
entire process can be promoted effectively by 0.2 equiv
of (S)-proline (entry 3), optimally, the use of 0.8 equiv of
(S)-proline delivered the aldol adducts 12 and 13 in a
combined yield of 72% in 24 h (entry 7). Notably, follow-
ing the conditions described in entry 7, this reaction could
be run on multigram scale without a decrease in yield,
diastereoselectvity, or product enantiopurity. As summar-
ized in entries 8 to 12, a variety of solvents were also
examined. Notably, access to significant quantities of the
anti-chlorohydrin 13 could be gained by simply using
MeCN (entry 11), in which near equal amounts of the
diastereomeric aldol adducts were produced in 63% yield.
Having identified an optimal set of reaction conditions
for the formation of the aldol adduct 12 (Table 1, entry 7),
we next evaluated the scope of this one-pot reaction. As
highlighted in Figure 2, 10 additional aldehydes were
reacted with dioxanone 1 and NCS in the presence of
(S)-proline, providing a range of enantiomerically en-
riched and functionally diverse chlorohydrins 16aÀj. The
diastereoselectivity of these reactions ranged from modest
to excellent depending on the electronic and steric features
of the aldehyde. For example, in the series propanal f
butanal f pentanal, the diastereomeric ratio of the
resulting chlorohydrins increases from 2.5:1 (16a) to
3.8:1 (16b) to 6:1 (12). As exemplified by the reaction of
As summarized in Table 1, we next surveyed reaction
conditions in an effort to decrease the reaction time and
probe the effect of solvent on both diastereoselectivity and
yield of 12. Whenthe reaction depicted ineq1 was repeated
at À15 or 0 °C, very little product was formed, while
increasing the temperature above 20 °C resulted in signifi-
cant degradation of the R-chloroaldehyde (entries 1À4).
(20) (a) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem.
Soc. 1959, 112. (b) Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem.
Soc. 2006, 128, 2920.
(21) For examples of organocatalytic dynamic kinetic resolutions,
see: (a) Pellissier, H. Adv. Synth. Catal. 2011, 353, 659. (b) Ward, D. E.;
Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7, 1181. (c) Reyes, E.;
Cordova, A. Tetrahedron Lett. 2005, 46, 6605. (d) Ward, D. E.; Jheengut,
V.; Beye, G. E.; Gillis, H. M.; Karagiannis, A.; Becerril-Jimenez, F.
Synlett 2011, 508.
(22) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G.
J. Am. Chem. Soc. 2007, 129, 15100.
(23) Other additives that had little effect on the diastereoselectivity or
yield of this process include H2O, succinimide, and benzoic acid.
3556
Org. Lett., Vol. 15, No. 14, 2013

Scheme 3. Conversion of Aldol Adducts 16i, 16h, and 16g into
Carbohydrate Analogues
1,3-syn- or 1,3-anti-selective manner and heated in a
mixture of MeOHÀH2O to effect cyclization to the corre-
sponding D-ribose analogues 17À20 and 22. Impressively,
this methodology permits the de novo synthesis of these
carbohydrates in excellent optical purity in only three
steps from commercially or readily available aldehydes.
Furthermore, the protected 2-chloro-2-deoxyaltrose 21
was produced from the 1,3-syn reduction product (not
shown) of aldol adduct 16h by simple deprotection and
oxidation of the resulting primary alcohol function.
In summary, we have developed a robust, asymmetric
organocatalytic aldehyde chlorination/aldol process that
proceeds with dynamic kinetic resolution of in situ formed
R-chloroaldehydes. This sequence of reactions proceeds with
modest to excellent levels of diastereoselectivity, favoring the
formation of syn-chlorohydrin products with high enantio-
purity. Importantly, this process avoids the isolation and
purification of R-chloroaldehydes and is sufficiently general
to allow incorporation of branched alkyl, aryl, propargyl,
and benzyl groups adjacent to the chloromethine stereocen-
ter. The products of this reaction are excellent building blocks
for the synthesis of carbohydrates and C-glycoconjugates as
demonstrated by the formation of several derivatives of D-
ribose and 2-deoxy-2-chloroaltrose. These aldol adducts
should also find use in the preparation of other classes of
natural products and glycomimetics, work that is ongoing in
our laboratory.
Figure 2. Scope of proline-catalayzed chlorination/aldol reac-
tion (combined isolated yield). a Reaction carried out at 5 °C for
16 h. b Reaction carried out at 0 °C for 48 h.
isovaleraldehyde, the incorporation of a branching posi-
tion adjacent to the choloromethine stereocenter also led
to increased diastereoselectivity (16c, dr = 22:1) without
significantly impacting the overall yield of the process.
Remarkably, reactions involving the silyl protected
3-hydroxypropanal or phenylacetaldehyde both afford
the corresponding chlorohydrins 16h and 16i in excellent
enantiopurity. These results are notable since we have
not been able to effect the asymmetric R-chlorination14
of either aldehyde. While the reactions depicted in Figure 2
generallyproceedwith excellent enantioselectivity at20°C,
both that of isovaleraldehyde and phenylacetaldehyde
provided the corresponding chlorohydrins 16c and 16i
in 86% ee and 78% ee, respectively, at rt. In both cases,
however, repetition of the reaction at lower temperatures
(0 or 5 °C) significantly improved the enantiopurity of
these products.
Acknowledgment. This work was supported by an NSERC
Discovery Grant, the Michael Smith Foundation for Health
Research Career Investigator Award to R.B., and NSERC
and FQRNT Scholarships for M.B.-B. The authors thank
Regine Gries (SFU) for assistance with chiral GC analysis.
Finally, with direct access to the unique series of en-
antiomerically enriched chlorohydrins 16aÀj (Figure 2),
several of these compounds were converted into carbo-
hydrate analogues and C-glycoconjugates (Scheme 3).
Building on our previous efforts in the preparation of
tetrahydrofurans from ketochlorohydrins,10e,f each of the
aldol adducts 16i, 16h, and 16g were reduced in either a
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3557