Chlorine, an atom economical auxiliary for asymmetric aldol reactions

Article abstract of DOI:10.1039/c3ob27462d

An auxiliary strategy has been developed for asymmetric reactions of aldehydes in which the auxiliary itself is not chiral, but a single chlorine atom introduced via organocatalytic α-chlorination. The stereodirecting influence of the chlorine atom is then exploited prior to its removal by radical reduction. This strategy is demonstrated in the synthesis of several aldols (92-99% ee) and the natural products (+)-dihydroyashabushiketol and (+)-solistatin.

Full text of DOI:10.1039/c3ob27462d

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Chlorine, an atom economical auxiliary for asymmetric
aldol reactions†
Cite this: Org. Biomol. Chem., 2013, 11,
1702
Shira D. Halperin and Robert Britton*
An auxiliary strategy has been developed for asymmetric reactions of aldehydes in which the auxiliary
itself is not chiral, but a single chlorine atom introduced via organocatalytic α-chlorination. The stereo-
directing influence of the chlorine atom is then exploited prior to its removal by radical reduction. This
strategy is demonstrated in the synthesis of several aldols (92–99% ee) and the natural products
(+)-dihydroyashabushiketol and (+)-solistatin.
Received 19th December 2012,
Accepted 10th January 2013
DOI: 10.1039/c3ob27462d
www.rsc.org/obc
Introduction
Chiral auxiliaries play an important role in organic synthesis
by enabling many transformations to proceed with a predict-
able sense and level of enantioselectivity.1 Perhaps most recog-
nizable are the Evans auxiliaries2 that are routinely exploited
in polyketide synthesis, and variants of this classic reaction
facilitate the enantioselective synthesis of most stereoisomeric
aldols.3 Despite the successes of these and other chiral auxili-
aries, their use in asymmetric synthesis is often disfavoured
due to costs associated with employing a stoichiometric
amount of chiral reagent, and the inherently low overall atom
economy4 of these processes. Considering that the primary
role of a chiral auxiliary is to impart diastereoselectivity to
otherwise non-selective reactions,1 we envisioned an alterna-
tive auxiliary approach to asymmetric synthesis in which the
auxiliary itself is not chiral, but a single atom introduced through
a catalytic asymmetric reaction. In this way, the use of stoichio-
metric amounts of expensive chiral pool materials would be
avoided, and the overall mass balance of the asymmetric
process improved. For example, temporary replacement of an
α-hydrogen of an aldehyde with a halogen atom (e.g., 1 → 2,
Scheme 1) via organocatalysis5,6 could be coupled with a well-
established diastereoselective reaction of the resulting α-halo-
aldehyde (e.g., crotylation,7 aldol reaction,8 or 1,2-addition9). Sub-
sequent removal of the halogen (e.g., 3 → 4) would then
provide optically enriched secondary alcohols relevant to poly-
ketide synthesis (e.g., 5–7). The development of this strategy
and its demonstration in atom and step economical syntheses
Scheme 1 A single atom auxiliary for asymmetric synthesis.
of the natural products (+)-dihydroyashabushiketol and (-
+)-solistatin are described below.
Results and discussion
Considering the relative stability, stereodirecting ability,9a,10
and ease of asymmetric synthesis of individual α-haloalde-
hydes,5 we began these investigations with the preparation of
several racemic α-chloroaldehydes using the procedure
described by Jørgensen.6b Addition of lithium enolates8g or
lithium derivatives of acetonitrile to these compounds pro-
vided the chlorohydrins 10–14 in good to excellent yield and
diastereoselectivity. While reduction of the C–Cl bond in
α-chlorocarbonyl compounds with Zn/HOAc is well known,11
and the C–Cl bond in a number of chlorohydrin-containing
carbohydrates has been reduced,12 only one report documents
the reduction of a racemic β-ketochlorohydrin using Bu3SnH/
AIBN, in which no yields were provided.8b This latter reaction
is likely complicated by competing furan formation at elevated
temperatures8b,8i and, unfortunately, radical reduction of 10
using a combination of AIBN and Bu3SnH resulted largely in
decomposition. Based on the improved halogen-abstracting
ability of the radical generated from tris(trimethylsilyl)silane
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia,
Canada, V55 1S6. E-mail: rbritton@sfu.ca; Fax: +1-778-782-3765;
Tel: +1-778-782-4889
†Electronic supplementary information (ESI) available: Full experimental pro-
cedures, characterization data and copies of NMR spectra. See DOI:
10.1039/c3ob27462d
1702 | Org. Biomol. Chem., 2013, 11, 1702–1705
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
(TTMSS),13 the reduction of β-keto- and β-nitrilechlorohydrins
10–14 were also examined using TTMSS and, after some optim-
ization, we were delighted to find that the chloromethine func-
tion in each of these compounds could be reduced without
competing formation of furans or side reactions involving
other functional groups in the molecules (e.g., ketone, nitrile,
acetonide). In this way, the β-hydroxyketones 15–19 were pro-
duced in good to excellent yield.
The results summarized in Scheme 2 inspired us to apply
this chlorine-auxiliary approach to asymmetric methyl ketone
aldol reactions, which are among the more challenging asym-
metric aldol reactions.14 As depicted in Scheme 3, chlorination
of pentanal, hydrocinnamaldehyde, and isovaleraldehyde
using MacMillan’s asymmetric SOMO α-chlorination proce-
dure6c afforded the corresponding α-chloroaldehydes, which
subsequently engaged in high yielding aldol reactions with
lithium enolates8g derived from 2-undecanone, 4-phenyl-2-
butanone, and 5-(t-butyldimethylsilyloxy)-2-pentanone to
afford a small collection of optically enriched β-ketochloro-
hydrins. Radical reduction of the chloromethine function in
each of these latter compounds proceeded smoothly using the
optimized reaction conditions to provide the β-hydroxyketones
24–29 in good to excellent overall yield and enantiomeric
excess, as determined by chiral GC or HPLC analysis. Based on
the relative ease with which this process is executed, its func-
tional group tolerability, and the high level of optical purity of
the resulting β-hydroxyketones, this approach represents a
viable alternative to existing chiral auxiliary-based strategies
for asymmetric aldol synthesis.
Scheme 3 Chlorine auxiliary approach to asymmetric aldol reactions.
As depicted in Scheme 4, the chlorine-auxiliary strategy was
applied to a short asymmetric synthesis of (+)-dihydroyasha-
bushiketol (32), a diarylheptanoid that was originally isolated15
from the deciduous plant Alnus firma and has demonstrated a
variety of potentially useful biological activities.16 In 2011, the
first asymmetric synthesis of (+)-32 was reported that involved
a six-step sequence of reactions including the use of Oppol-
zer’s sultam auxiliary to control the absolute stereochemistry
Scheme 4 A short synthesis of (+)-dihydroyashabushiketol (32).
of a 1,3-dipolar cycloaddition.16a Notably, the chiral auxiliary
represented 49% of the molecular weight of the cycloaddition
product. As depicted in Scheme 4, treatment of (S)-2-chloro-
hydrocinnamaldehyde (30)6c with the lithium enolate derived
from 4-phenyl-2-butanone, afforded the ketochlorohydrin 31
in good yield. Reduction of the chloromethine function in 31
proceeded smoothly to provide (+)-dihydroyashabushiketol
(32) in excellent yield and optical purity (98% ee). It is worth
highlighting that this three-step synthesis (from hydrocinna-
maldehyde) also proceeds in excellent overall yield (58%), and
that the auxiliary (Cl) represents only 11% of the molecular
weight of the aldol adduct 31.
The chlorine-auxiliary approach was further demonstrated
in a short total synthesis of (+)-solistatin (40). Isolated from
the cheese-associated fungus Penicillium solitum,17 solistatin is
an inhibitor of cholesterol biosynthesis and structurally
similar to other HMG CoA reductase inhibitors (e.g., simvasta-
tin and lovastatin).18 In 2007 a 17-step synthesis of solistatin
was reported that exploited sequential catalytic asymmetric
Overman esterification reactions.19 As outlined in Scheme 5,
chlorination of 34 using MacMillan’s SOMO α-chlorination
Scheme 2 TTMSS reduction of β-keto- and β-nitrilechlorohydrins.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 1702–1705 | 1703

View Article Online
Paper
Organic & Biomolecular Chemistry
asymmetric transformations of aldehydes is currently under-
way in our laboratory, and the results of these efforts will be
reported in due course.
Acknowledgements
This work was supported by an NSERC Discovery Grant to
R. B., a Michael Smith Foundation for Health Research Career
Investigator Award to R. B., and a NSERC Postgraduate Scholar-
ship to S. D. H. The authors thank Regine Gries, Department
of Biological Sciences (SFU) for assistance with chiral
G. C. analysis.
References
1 Y. Gnas and F. Glorius, Synthesis, 2006, 1899–1930.
2 (a) D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc.,
1981, 103, 2127–2129; (b) D. A. Evans, J. M. Takacs,
L. R. McGee, M. D. Ennis, D. J. Mathre and J. Bartroli, Pure
Appl. Chem., 1981, 53, 1109–1127; (c) D. A. Evans, Aldrichi-
mica Acta, 1982, 15, 23–41.
Scheme 5 Total synthesis of (+)-solistatin (40).
3 For examples, see: (a) M. A. Walker and C. H. Heathcock,
J. Org. Chem., 1991, 56, 5747–5750; (b) D. A. Evans,
H. P. Ng, J. S. Clark and D. L. Rieger, Tetrahedron, 1992, 48,
2127–2142; (c) M. Nerz-Stormes and E. R. Thornton, J. Org.
Chem., 1991, 56, 2489–2498.
4 B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259–281.
5 B. Kang and R. Britton, Nat. Prod. Rep., 2013, 30, 227–236.
6 (a) M. P. Brochu, S. P. Brown and D. W. C. MacMillan,
J. Am. Chem. Soc., 2004, 126, 4108–4109; (b) N. Halland,
A. Braunton, S. Bachmann, M. Marigo and K. A. Jørgensen,
J. Am. Chem. Soc., 2004, 126, 4790–4791; (c) M. Amatore,
T. D. Beeson, S. P. Brown and D. W. C. MacMillan, Angew.
Chem., Int. Ed., 2009, 48, 5121–5124; (d) S. Dekeukeleire,
M. D’hooghe, K. W. Tornroos and N. De Kimpe, J. Org.
Chem., 2010, 75, 5934–5940.
procedure6c afforded the chloroaldehyde 36. Reaction of 36
with the dianion derived from methyl acetoacetate gave the
corresponding β-ketochlorohydrin (not shown) in modest yield
(40%) and diastereoselectivity (dr = 3 : 1). While use of the enol
silyl ether 3720 failed to improve the diastereoselectivity of this
reaction, the Mukaiyama aldol8d reaction depicted in
Scheme 5 provided the desired chlorohydrin 38 in good iso-
lated yield (63%). Methanolysis, followed by 1,3-syn-selective
reduction21 of the resulting β-hydroxyketone gave the chloro-
diol 39. Radical reduction of the chloromethine function in 39
proceeded smoothly to provide a mixture of (+)-solistatin (40)
and the corresponding methylester (not shown). Brief treat-
ment of this mixture with p-TsOH afforded (+)-solistatin (40) in
good yield and enantiomeric excess (94% ee).
7 H. Brinkmann and R. W. Hoffmann, Chem. Ber., 1990, 123,
2395–2401.
8 For examples of aldol reactions of α-haloaldehydes, see:
(a) M. Yasuda, T. Oh-Hata, I. Shibata, A. Baba and
H. Matsuda, J. Chem. Soc., Perkin Trans. 1, 1993, 859–865;
(b) K. Maruoka, A. B. Concepcion, N. Murase, M. Oishi,
N. Hirayama and H. Yamamoto, J. Am. Chem. Soc., 1993,
115, 3943–3949; (c) B. Kang, J. Mowat, T. Pinter and
R. Britton, Org. Lett., 2009, 11, 1717–1720; (d) T. Borg,
J. Danielsson and P. Somfai, Chem. Commun., 2010, 46,
1281–1283; (e) M. Shinoyama, S.-i. Shirokawa, A. Nakazaki
and S. Kobayashi, Org. Lett., 2009, 11, 1277–1280;
(f) J. Saadi, M. Akakura and H. Yamamoto, J. Am. Chem.
Soc., 2011, 133, 14248–14251; (g) S. D. Halperin, B. Kang
and R. Britton, Synthesis, 2011, 1946–1953; (h) T. Kano,
H. Sugimoto and K. Maruoka, J. Am. Chem. Soc., 2011, 133,
18130–18133; (i) S. Chang and R. Britton, Org. Lett., 2012,
14, 5844–5847.
Conclusion
We have demonstrated that the asymmetric chlorination of
aldehydes can be partnered sequentially with diastereoselec-
tive aldol reactions and chloromethine reduction to afford
β-hydroxyketones in excellent overall yield and enantioselectiv-
ity. This process should serve as an alternative to chiral auxili-
ary-based aldehyde coupling reactions. Specifically, in contrast
to traditional chiral auxiliary approaches, stoichiometric
amounts of chiral pool materials are not required, and the
overall mass balance of the asymmetric process is significantly
improved. The efficiency of the chlorine-auxiliary approach has
been demonstrated in short total syntheses of both
(+)-dihydroyashabushiketol (32) (3 steps) and (+)-solistatin (40)
(6 steps). The extension of this work to include other
1704 | Org. Biomol. Chem., 2013, 11, 1702–1705
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
9 For examples of 1,2-additions to α-haloaldehydes, see ref.
5, and: (a) J. W. Cornforth, R. H. Cornforth and
K. K. Mathew, J. Chem. Soc., 1959, 112–127;
(b) T. Takahashi, H. Kataoka and J. Tsuji, J. Am. Chem. Soc.,
(b) H. Lerchen, J. Baumgarten, N. Piel and V. Kolb-Bacho-
fen, Angew. Chem., Int. Ed., 1999, 38, 3680–3683;
(c) R. P. van Summeren, B. L. Feringa and A. J. Minnaard,
Org. Biomol. Chem., 2005, 3, 2524–2533.
1983, 105, 147–149; (c) D. Bernard, A. Doutheau, J. Gore, 13 (a) C. Chatgilialoglu, D. Griller and M. Lesage, J. Org.
J. Moulinoux, V. Quemener, J. Chantepie and G. Quash,
Tetrahedron, 1989, 45, 1429–1439; (d) J. Barluenga,
Chem., 1988, 53, 3641–3642; (b) C. Chatgilialoglu,
Chem.–Eur. J., 2008, 14, 2310–2320.
L. Llavona, P. L. Bernad and J. M. Concellon, Tetrahedron 14 (a) J. M. Goodman and R. S. Paton, Chem. Commun., 2007,
Lett., 1993, 34, 3173–3176; (e) A. V. Kel’in and
O. G. Kulinkovich, Russ. J. Org. Chem., 1998, 34, 1446–1448;
2124–2126; (b) S. E. Denmark, R. A. Stavenger and
K.-T. Wong, J. Org. Chem., 1998, 63, 918–919.
(f) B. Kang and R. Britton, Org. Lett., 2007, 9, 5083–5086; 15 Y. Asakawa, Bull. Chem. Soc. Jpn., 1970, 43, 2223–2229.
(g) J. Mowat, R. Gries, G. Khaskin, G. Gries and R. Britton, 16 (a) J. Romanski, P. Nowak, C. Chapuis and J. Jurczak, Tetra-
J. Nat. Prod., 2009, 72, 772–776; (h) B. Kang, S. Chang,
S. Decker and R. Britton, Org. Lett., 2010, 12, 1716–1719;
(i) J. Draper and R. Britton, Org. Lett., 2010, 12, 4034–4037;
hedron: Asymmetry, 2011, 22, 787–790; (b) H. Matsuda,
S. Nakashima, Y. Oda, S. Nakamura and M. Yoshikawa,
Bioorg. Med. Chem., 2009, 17, 6048–6053.
( j) T. Yoshimitsu, R. Nakatani, A. Kobayashi and T. Tanaka, 17 D. Sørensen, T. O. Larsen, C. Christophersen, P. H. Nielsen
Org. Lett., 2011, 13, 908–911. and U. Anthoni, Phytochemistry, 1999, 51, 1027–1029.
10 (a) M. Cherest, H. Felkin and N. Prudent, Tetrahedron Lett., 18 H. Oka, A. Terahara and A. Endo, US Patent 4,255,444,
1968, 9, 2199–2204; (b) N. T. Anh and O. Eisenstein, 1981.
Nouv. J. Chim., 1977, 1, 61–70; (c) D. A. Evans, S. J. Siska 19 J. T. Binder and S. F. Kirsch, Chem. Commun., 2007,
and V. J. Cee, Angew. Chem., Int. Ed., 2003, 42, 1761–1765. 4164–4166.
11 For example, see: D. A. Evans, D. M. Fitch, T. E. Smith and 20 A. Fettes and E. M. Carreira, J. Org. Chem., 2003, 68,
V. J. Cee, J. Am. Chem. Soc., 2000, 122, 10033–10046. 9274–9283.
12 For examples, see: (a) K.-P. Chan, Y.-H. Ling, J. L.-T. Chan 21 K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic and
and T.-P. Loh, J. Org. Chem., 2007, 72, 2127–2132;
M. J. Shapiro, Tetrahedron Lett., 1987, 28, 155–158.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 1702–1705 | 1705