Enantioselective dichlorination of allylic alcohols

Article abstract of DOI:10.1021/ja202555m

The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration of the substrate scope, and a model for stereoinduction are presented.

Full text of DOI:10.1021/ja202555m

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pubs.acs.org/JACS
Enantioselective Dichlorination of Allylic Alcohols
K. C. Nicolaou,* Nicholas L. Simmons, Yongcheng Ying, Philipp M. Heretsch, and Jason S. Chen
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037,
United States
Department of Chemistry and Biochemistry, University of California—San Diego, La Jolla, California 92093, United States
S Supporting Information
b
ABSTRACT: The development of an enantioselective
allylic alcohol dichlorination catalyzed by dimeric cinchona
alkaloid derivatives and employing aryl iododichlorides as
chlorine sources is reported. Reaction optimization, explora-
tion of the substrate scope, and a model for stereoinduction
are presented.
Figure 1. Molecular structure of chlorosulfolipid cytotoxin 1 and
opportunities for asymmetric allylic alcohol dichlorination.
espite tremendous advances in the development of chiral
D
methods, asymmetric olefin dichlorination1 remains a chal-
lenging problem. Such a reaction would be useful for the synthesis
of oligo- and polychlorinated compounds.2 Originally discovered
from the membranes of freshwater algae,3 chlorosulfolipids have
gained significant attention since 20014 due to their putative link
to diarrhetic shellfish poisoning. Their biosynthesis likely pro-
ceeds through a series of site-selective and stereoselective enzy-
matic chlorinations of unfunctionalized positions on sulfolipid
precursors.5 In contrast, synthetic chemists generally can control
chlorination only at functionalized sites. Evaluation of existing
synthetic approaches1 and the structure of chlorosulfolipid cyto-
toxin 1 (the most complex member of the family; see Figure 1)6
suggested a need for asymmetric olefin dichlorination methods,
especially those applicable to allylic alcohols. Most recent ap-
proaches have relied on substrate control of stereochemistry and
required substrate derivatization (e.g., epoxidation of the olefin1eꢀg
or esterification of an allylic alcohol1h). In the Snyder group’s total
synthesis of napyradiomycin A1,1c there is an isolated example of a
practical enantioselective olefin dichlorination employing a stoi-
chiometric chiral auxiliary. Although the above methods have been
employed in total syntheses of several chlorosulfolipids,7 there
remains a need for additional asymmetric dichlorination methods.
We present herein the development of an enantioselective dichlor-
ination of allylic alcohols.
Scheme 1. Mechanism of Olefin Dichlorination and Chal-
lenges for Enantioselectivity
regiocontrolled chloride attack. The hydroxyl moiety might
hydrogen bond with a catalyst or reagent, rigidifying the system
and potentially improving stereocontrol. Our first clue suggest-
ing a direction for catalyst screening came from observations that
electrophilic halogenation is dramatically accelerated by tertiary
amines.10 Screening of common amine catalysts (e.g., proline and
imidazolidinone derivatives,11 small peptides,12 and cinchona
alkaloids1a,8,13) and a range of chlorine sources (e.g., Cl2 gas,
Et4NCl3, and PhICl2) revealed the dimeric cinchona alkaloid
derivative (DHQ)2PHAL (commonly employed as a ligand for
Sharpless asymmetric dihydroxylation) and PhICl2 as a uniquely
promising reagent combination for further studies.
Interestingly, the quality of PhICl2 proved to be critical, with
the use of PhICl2 generated from PhI and NaOCl (Chlorox bleach
or a solution from SigmaꢀAldrich) resulting in poor reproduci-
bility. However, employing PhICl2 freshly prepared from PhI and
Cl2 gas yielded consistent results. Furthermore, catalyst aging in
the presence of PhICl2 degraded both reactivity and selectivity.
As shown in Scheme 1, olefin dichlorination is a challenging
reaction to renderenantioselective. Thereaction proceeds through
an initial electrophilic chlorination (see 2) to form chloronium
species 3. Even if this process is rendered facial-selective,8 there
remains a regioselectivity challenge in the subsequent nucleo-
philic chlorination; attack of the two chloronium positions of
homochiral species 3 leads to opposite antipodes of 4. Addition-
ally, the configurational stability of chloronium species 3 may be
degraded by reversibility and/or direct chlorenium transfer to
another molecule of the olefinic substrate (2).9
In view of these potential challenges, we selected trans-
cinnamyl alcohol (5, Table 1) as a model substrate. The benzylic
nature of the intermediate chloronium species would enforce a
Received: March 23, 2011
Published: May 04, 2011
r
2011 American Chemical Society
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Table 1. Screeningof ReactionConditionsforEnantioselective
Dichlorinationa
Table 2. Generality and Scope of Enantioselective
Dichlorinationa
entry
ArICl2
PhICl2
solvent
temp (°C) ee (%)b
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
0
22
23
41
82
<5
10
<5
75
75
56
85
73
2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
3
ꢀ40
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
4
5
6
EtOAc
Et2O
7
8
CH2Cl2:hexanes (1:1)
CH2Cl2:PhMe (1:1)
9
10
11
12
o-Me(C6H4)ICl2 CH2Cl2
p-Ph(C6H4)ICl2 CH2Cl2
p-t-Bu(C6H4)ICl2 CH2Cl2
a Reactions were performed on 7 mg (50 μmol) scale and run to
completion (TLC analysis). b Determined by chiral HPLC analysis.
Therefore, since the uncatalyzed reaction is very slow, the catalyst
was added last to a reaction mixture already containing the
substrate and PhICl2. An initial addition of 10 mol % catalyst
followed by slow addition of another 10 mol % catalyst gave the
best results.
Under these conditions, (DHQ)2PHAL-catalyzed dichlorina-
tion of trans-cinnamyl alcohol (5) by PhICl2 at ambient tem-
perature (Table 1, entry 1) afforded dichloride 6 in 22% ee.
Lowering the temperature (entries 2ꢀ4) prolonged reaction times
but improved enantioselectivity. A solvent screen (entries 4ꢀ7)
revealed CH2Cl2 to be uniquely suitable. Mixed solvents contain-
ing CH2Cl2 could also be used (entries 8 and 9), but the reactions
became more sluggish (likely due to reduced solubility of the
catalyst and PhICl2), and selectivities were not improved. An
exploration of alternative aryl iododichlorides (entries 10ꢀ12)
revealed some effects on the level of enantioselectivity, with the
use of p-Ph(C6H4)ICl2 (entry 11) delivering dichloride 6 in
85% ee.
Scaling up the reaction conditions in entry 11 of Table 1 and
reducing the amount of aryl iododichloride to 1.6 equiv gave
dichloride 6 in 63% yield and 81% ee (see entry 1a, Table 2).
Under otherwise identical conditions, but employing the pseu-
doenantiomeric catalyst (DHQD)2PHAL, dichloride ent-6 was
obtained in 58% yield and 61% ee. As shown in Table 2, the
reaction was tolerant of some changes in electronics (entries
1aꢀe). Very electron-deficient olefins failed to react. Electron-
rich cinnamyl substrates underwent rapid dichlorination, but
the products were prone to epimerization, chloride elimination,
and other decomposition reactions, presumably due to facile
benzylic SN1-type reactions. This is not a limitation of the
method but of compound stability; racemic reference samples
were similarly labile. Naphthyl substrates reacted in the same
a Reactions were performed on 40ꢀ50 mg scale using 20 mol % of
(DHQ)2PHAL and 1.6 equiv of p-Ph(C6H4)ICl2 in CH2Cl2 (0.05 M) at
ꢀ78 °C and run to completion (TLC analysis). b Isolated yield after flash
action performed at ꢀ40 °C. e PhICl2 used in place of p-Ph(C6H4)ICl2.
f Absolute configuration not determined. g Incomplete reaction. Yield
and ee determined after desilylation. h Determined by NMR analysis of
the corresponding Mosher ester.
c
column chromatography. Determined by chiral HPLC analysis. d Re-
manner (entries 2 and 3). Steric congestion was tolerated both
on the aryl ring (entry 4) and near the allylic alcohol (entry 5).
Importantly, the reaction is stereospecific. Thus, as shown in
entry 6, although the efficiency and enantioselectivity of the
reaction of cis-cinnamyl alcohol (8) left much to be desired, it
proceeded to give the opposite diastereoisomer (9) as compared
with the dichlorination of the trans isomer (contrast with
entry 1a). Furthermore, the allylic alcohol proved to be a critical
substrate feature; masking of this moiety as a TES ether (entry 7)
abolished enantioselectivity.
We also investigated the suitability of our reaction conditions
on selected non-cinnamyl substrates in order to ensure that we
were developing a generally useful catalytic system. We decided
to investigate the reactions of monobenzylated cis- and trans-
butenediol since differentially protected hydroxyl moieties might
be useful for further elaboration of the products.14 The use of
p-Ph(C6H4)ICl2 resulted in impractically long reaction times
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Figure 3. Proposed stereoinduction model (11) and molecular struc-
ture of (DHQ)2AQN.
outlined model is speculative; ongoing studies will test and refine
this working model.
In conclusion, we have developed an enantioselective dichlor-
ination of allylic alcohols employing the dimeric cinchona alkaloid
derivative (DHQ)2PHAL [or its pseudoenantiomer (DHQD)2-
PHAL] and aryl iododichlorides. Further screening of catalyst and
iododichloride modifications is under way and promises to lead to
improved enantioselectivity and generality.
Figure 2. Molecular structures and ORTEPs of p-nitrobenzoate esters
70 and ent-100.
’ ASSOCIATED CONTENT
at ꢀ78 °C, so the more reactive oxidant PhICl2 was employed
instead. Pleasingly, as shown in entries 8 and 9 of Table 2, the
reactions proceeded with efficiency and enantioselectivity com-
parable to those of cinnamyl substrates.
S
Supporting Information. Experimental procedures and
b
characterization data for key compounds (CIF, PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Enantiopure dichlorination products 7 (entry 1d, Table 2) and
ent-10 (see entry 9, Table 2) (obtained by preparative chiral
HPLC) were converted into p-nitrobenzoate esters 70 and ent-100
(Figure 2). X-ray crystallographic analysis of the p-nitrobenzoates
allowed assignment of their absolute configurations. The other
dichlorination products of trans-cinnamyl alcohols were pre-
sumed to have the same absolute configuration as 7; however,
we currently have no experimental proof of these assignments.
Since the dichlorination is stereospecific, it likely proceeds
through the intermediacy of a chloronium species in the manner
outlined in Scheme 1. Furthermore, the relative configuration of
the products eliminates the possibility of anchimeric assistance in
chloronium attack (see 3f4, Scheme 1). The sense of absolute
stereoinduction is consistent with preferential chloronium for-
mation on the face of the olefin that would react in a Sharpless
asymmetric dihydroxylation employing (DHQ)2PHAL as a li-
gand. We propose a chlorenium ion transfer from an electrophilic
chlorinating reagent generated through attack of the aryl iodo-
dichloride by one of the quinuclidine nitrogens of the catalyst
(see 11, Figure 3).10,15 Chlorenium delivery might then proceed
in a manner analogous to that proposed by Corey and Noe16 for
the Sharpless asymmetric dihydroxylation. Since an unmasked
allylic alcohol is required, we postulate the presence of a hydrogen
bond to one of the phthlazine nitrogens of the catalyst (see 11,
Figure 3). Consistent with this hypothesis, (DHQ)2AQN
(Figure 3), lacking the phthlazine nitrogens, provides minimal
stereoinduction (10% ee in favor of ent-6, compare with 85% ee
in favor of 6; entry 11, Table 1). We acknowledge that the
’ AUTHOR INFORMATION
Corresponding Author
kcn@scripps.edu
’ ACKNOWLEDGMENT
We thank Drs. D. H. Huang, L. Pasternack, and R. Chadha for
NMR spectroscopic and X-ray crystallographic assistance. This
work was supported by the National Institutes of Health
(R01ES013314), the Skaggs Institute for Research, the National
Science Foundation (predoctoral fellowship to N.L.S.), and the
Deutsche Akademie der Naturforscher Leopoldina (postdoctoral
fellowship to P.M.H.).
’ REFERENCES
(1) Enantioselective approaches: (a) Julia, S.; Ginebreda, A. Tetra-
hedron Lett. 1979, 20, 2171. (b) Adam, W.; Mock-Knoblauch, C.; Saha-
M€oller, C. R.; Herderich, M. J. Am. Chem. Soc. 2000, 122, 9685. (c)
Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131,
5744. (d) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303. Diastereospecific approaches: (e) Iranpoor, N.;
Firouzabadi, H.; Azadi, R.; Ebrahimzadeh, F. Can. J. Chem. 2006, 84, 69.
(f) Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009,
74, 696. (g) Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010,
12, 4678. Diastereoselective approach: (h) Shibuya, G. M.; Kanady, J. S.;
Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 12514.
8136
dx.doi.org/10.1021/ja202555m |J. Am. Chem. Soc. 2011, 133, 8134–8137

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COMMUNICATION
(2) (a) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141. (b) Kladi, M.;
Vagias, C.; Roussis, V. Phytochem. Rev. 2004, 3, 337.
(3) (a) Elovson, J.; Vagelos, P. R. Proc. Natl. Acad. Sci. U.S.A. 1969,
62, 957. (b) Elovson, P. R.; Vagelos, P. R. Biochemistry 1970, 9, 3110. (c)
Haines, T. H.; Pousada, M.; Stern, B.; Mayers, G. L. Biochem. J. 1969,
113, 565.
(4) Ciminiello, P.; Fattorusso, E.; Forino, M.; Di Rosa, M.; Ianaro,
A.; Poletti, R. J. Org. Chem. 2001, 66, 578.
(5) Mooney, C. L.; Haines, T. H. Biochemistry 1973, 12, 4469.
(6) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.;
Magno, S.; Di Rosa, M.; Ianaro, A.; Poletti, R. J. Am. Chem. Soc. 2002,
124, 13114.
(7) (a) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature 2009,
457, 573. (b) Bedke, D. K.; Shibuya, G. M.; Pereira, A.; Gerwick, W. H.;
Haines, T. H.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 7570. (c)
Bedke, D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal,
C. D. J. Am. Chem. Soc. 2010, 132, 2542. (d) Yoshimitsu, T.; Fukumoto,
N.; Nakatani, R.; Kojima, N.; Tanaka, T. J. Org. Chem. 2010, 75, 5425.
(e) Umezawa, T.; Shibata, M.; Kaneko, K.; Okino, T.; Matsuda, F. Org.
Lett. 2011, 13, 904. (f) Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.;
Tanaka, T. Org. Lett. 2011, 13, 908.
(8) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298. (b) Yousefi, R.; Whitehead, D. C.;
Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608.
(9) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010,
132, 1232.
(10) Zhang, W.; Xu, H.; Xu, H.; Tang, W. J. Am. Chem. Soc. 2009,
131, 3832.
(11) (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.
(12) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem.
Rev. 2007, 107, 5759.
(13) (a) Tommaso, M.; Hiemstra, H. Synthesis 2010, 1229. (b)
Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J., III; Lectka, T. J. Am.
Chem. Soc. 2001, 123, 1531. (c) France, S.; Wack, H.; Taggi, A. E.; Hafez,
A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.; Lectka, T. J. Am. Chem.
Soc. 2004, 126, 4245. (d) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli,
M.; Melchiorre, P.; Sambra, L. Angew. Chem., Int. Ed. 2005, 44, 6219.
(14) β,γ-Dichloroalcohols are amenable to DessꢀMartin oxidation
and elaboration of the resulting aldehyde without loss of configurational
stability.7d
(15) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560.
(16) (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579.
(b) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (c) Corey,
E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
8137
dx.doi.org/10.1021/ja202555m |J. Am. Chem. Soc. 2011, 133, 8134–8137