Enantiocontrolled synthesis of polychlorinated hydrocarbon motifs: A nucleophilic multiple chlorination process revisited

Article abstract of DOI:10.1021/jo802093d

Polychlorinated hydrocarbon motifs have been synthesized in enantiomerically pure forms by means of nucleophilic multiple chlorinations of chiral epoxides, which stereospecifically incorporate halogen atoms into oxygenated molecular scaffolds. The present

Full text of DOI:10.1021/jo802093d

Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs:
A Nucleophilic Multiple Chlorination Process Revisited
Takehiko Yoshimitsu,* Naoya Fukumoto, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
yoshimit@phs.osaka-u.ac.jp
ReceiVed September 20, 2008
Polychlorinated hydrocarbon motifs have been synthesized in enantiomerically pure forms by means of
nucleophilic multiple chlorinations of chiral epoxides, which stereospecifically incorporate halogen atoms
into oxygenated molecular scaffolds. The present study demonstrates the scope of the N-chlorosuccinimide
(NCS)/organophosphine reagent system that forms multiple sp3C-Cl bonds in a regularly repeating pattern
with proper stereochemical configurations and evaluates its applicability to various epoxides having
elaborate structures. It is noteworthy that tetrachlorinated motifs are produced in one step from bisepoxides
by using NCS/Ph3P. Furthermore, Ph2PCl used in combination with NCS has been found to serve as a
potentially useful alternative to NCS/Ph3P, especially for promoting dichlorination reactions of alkenyl-
substituted epoxides.
Introduction
Fattorusso, and co-workers,4 all of which possess chlorine-
substituted multiple stereogenic centers as their structural feature
(Figure 1).5
Naturally occurring polychlorinated hydrocarbons have re-
cently been garnering considerable attention for their potential
use as lead compounds for drug discovery as well as their unique
toxicological profiles.1,2 This class of bioactive molecules
includes chlorosulfolipids, such as malhamensilipin A (1), a
protein tyrosine kinase (PTK) inhibitor isolated in 1994 by
Gerwick and Slate,3 and cytotoxic polychlorosulfolipids 2 and
3 recently isolated from Adriatic mussels by Ciminiello,
In addition to the difficulty of acquiring sufficient quantities
of chiral polychlorides from natural resources, access to these
compounds by chemical synthesis has been hampered because
of the limited availability of methods capable of incorporating
an array of chlorine atoms into hydrocarbon skeletons with
correct absolute stereochemistries.6,7 To address this problem,
we initiated a research program aimed at establishing stereo-
selective approaches to polychlorinated hydrocarbons.8,9
(1) For pertinent reviews on natural halogenated compounds, see: (a) Gribble,
G. W. J. Chem. Educ. 2004, 81, 1441–1449. (b) Gribble, G. W. Am. Sci. 2004,
92, 342–349. (c) Gribble, G. W. Chemosphere 2003, 52, 289–297. (d) Gribble,
G. W. Prog. Heterocycl. Chem. 2003, 15, 58–74. (e) Gribble, G. W. Acc. Chem.
Res. 1998, 31, 141–152. (f) Gribble, G. W. J. Chem. Educ. 1994, 71, 907–911.
(g) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353–1395.
(2) For synthetic studies on bioactive polyhalogenated natural compounds,
see: (a) Jung, M. E.; Parker, M. H. J. Org. Chem. 1997, 62, 7094–7095. (b)
Durow, A. C.; Long, G. C.; O’Connell, S. J.; Willis, C. L. Org. Lett. 2006, 8,
5401–5404. (c) Sotokawa, T.; Noda, T.; Pi, S.; Hirama, M. Angew. Chem., Int.
Ed. 2000, 39, 3430–3432. (d) Schlama, T.; Baati, R.; Gouverneur, V.; Valleix,
A.; Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2085–2087.
(e) Sheldrake, H. M.; Jamieson, C.; Burton, J. W. Angew. Chem., Int. Ed. 2006,
45, 7199–7202. (f) Frankie, M. S.; Curtis, N. R.; Payne, A. N.; Congreve, M. S.;
Francis, C. L.; Burton, J. W.; Holmes, A. B. Synthesis 2005, 3199–3201. (g)
Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem. 1993, 58, 2468–
2477. (h) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem. Soc. 1991,
113, 5378–5384. (i) Williard, P. G.; De Laszlo, S. E. J. Org. Chem. 1985, 50,
3738–3749. Also see: Murai, A. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier Science B. V.: New York, 1997; Vol. 19, pp 411-
461.
(3) (a) Chen, J. L.; Proteau, P. J.; Roberts, M. A.; Gerwick, W. H.; Slate,
D. L.; Lee, R. H. J. Nat. Prod. 1994, 57, 524–527. (b) Gerwick, W. H. Biochim.
Biophys. Acta 1994, 1211, 243–255. (c) Gerwick, W. H.; Roberts, M. A.; Proteau,
P. J.; Chen, J. L. J. Appl. Phycol. 1994, 6, 143–149.
(4) (a) Ciminiello, P.; Fattorusso, E.; Forino, M.; Di Rosa, M.; Ianaro, A.;
Poletti, R. J. Org. Chem. 2001, 66, 578–582. (b) Ciminiello, P.; Dell’Aversano,
C.; Fattorusso, E.; Forino, M.; Magno, S.; Di Rosa, M.; Ianaro, A.; Poletti, R.
J. Am. Chem. Soc. 2002, 124, 13114–13120. (c) Ciminiello, P.; Dell’Aversano,
C.; Fattorusso, E.; Forino, M.; Magno, S. Pure Appl. Chem. 2003, 75, 325–336.
(d) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.; Magno, S.; Di
Meglio, P.; Ianaro, A.; Poletti, R. Tetrahedron 2004, 60, 7093–7098.
(5) For pioneering studies on this class of molecules, see: (a) Elovson, J.;
Vagelos, P. R. Biochemistry 1970, 9, 3110–3126. (b) Haines, T. H. Annu. ReV.
Microbiol. 1973, 27, 403–411. (c) Hansen, J. A. Physiol. Plant. 1973, 29, 234.
(d) Mercer, E. I.; Davies, C. L. Phytochemistry 1974, 13, 1607–1610. (e) Mercer,
E. I.; Davies, C. L. Phytochemistry 1975, 14, 1545–1548. (f) Mercer, E. I.; Davies,
C. L. Phytochemistry 1979, 18, 457.
(6) For recent reviews on enantioselective halogenations, see: (a) Ibrahim,
H.; Togni, A. Chem. Commun. 2004, 1147–1155. (b) Guilena, G.; Ramon, D. J.
Tetrahedron: Asymmetry 2006, 17, 1465–1492.
696 J. Org. Chem. 2009, 74, 696–702
10.1021/jo802093d CCC: $40.75 2009 American Chemical Society
Published on Web 11/19/2008

Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs
a first set of experiments, racemic trans- and cis-epoxides 4a
and 4b were subjected to nucleophilic substitution reactions
using various chlorinating agents (Tables 1 and 2). Tables 1
and 2 indicate that NCS/Ph3P was best suited for the dichlori-
nation of each epoxide in terms of reaction time and product
yield.
In general, dichloride 5a or 5b was produced in moderate to
good yield, together with small amounts of olefins.12 Com-
mercially available Cl2PPh3 also promoted the dichlorination
reaction;9c,d however, this reagent showed somewhat limited
utility because of low reproducibility that possibly stems from
its susceptibility to hydrolytic decomposition upon exposure to
moisture (Table 1, entry 1, and Table 2, entry 1). The use of
(c-Hex)3P or n-Bu3P in combination with NCS also gave
dichloride 5a or 5b but required longer reaction times, and when
trans-epoxide 4a was used as substrate, the yield of dichloride
5a decreased (Table 1, entries 4 and 5, and Table 2, entries 4
and 5). Interestingly, dichlorination of epoxides 4a and 4b with
NCS/t-Bu3P gave chlorohydrins 7/8 and 9/10 rather than the
desired dichlorides 5a and 5b, respectively (Table 1, entry 6,
and Table 2, entry 6). The reason for the preferential production
of the chlorohydrins in these particular cases is currently unclear;
however, the severe steric demand of bulky tert-butylphospho-
nium intermediates (vide infra) that retarded subsequent nu-
cleophilic substitution may be responsible for their formation.
Reagent amount also affected product yield (Table 1, entry 3):
a small reagent amount (NCS 2.5 equiv/Ph3P 2.5 equiv) led to
poor yield. The reaction rate decreased at low temperature (i.e.,
7 h at 45 °C vs 1 h at 90 °C) (Table 2, entry 3). Use of the
Isaacs reagent system, Ph3P/CCl4,9a efficiently transformed cis-
epoxide 4b into dichloride 5b, but it was less effective for trans-
epoxide 4a (Table 1, entry 7, and Table 2, entry 7). An attempted
dichlorination of epoxide 4a using PCl5 under buffered condi-
tions resulted in significant decomposition of the starting epoxide
(Table 1, entry 8).
Reaction Mechanism. The dichlorination by NCS/organo-
phosphine is reasonably assumed to involve sequential substitu-
tion reactions as proposed by Iranpoor et al. (Scheme 1).9g The
stereospecific displacement of epoxide oxygen atoms with a
chloride ion begins with the activation of the epoxide via
coordination of phosphonium salt i generated from the chlorina-
tion of R3P with NCS (i f ii). The initial nucleophilic attack
of a chloride ion that comes from 1 equiv of phosphonium salt
i provides oxyphosphonium intermediate iii (ii f iii). Then,
another chloride ion reacts with intermediate iii via the SN2
pathway, giving rise to dichloride iv along with organophosphine
oxide and its derivative v. If the phosphonium intermediate iii
undergoes E2 elimination, chloroalkene vi is stereospecifically
produced (iii f vi).
FIGURE 1. Natural bioactive polychlorides.
Isaacs and Kirkpatrick have demonstrated a potential direct
approach to chiral vicinal dichlorides from epoxides in a
stereospecific manner using organophosphonium chlorides
prepared in situ from Ph3P/CCl4.9a,b Recently, Iranpoor et al.
have also reported that NCS/Ph3P promotes dichlorination of
terminal epoxides as well as cyclohexene oxide.9g However,
little is known about the general scope of the dichlorination
reactions of structurally complex internal epoxides. Conse-
quently, some questions occurred to us: do stereospecific
dichlorinations take place with internal epoxides carrying various
functional groups that might affect stereospecificity and reactiv-
ity? Is it possible to install more than two chlorine atoms
stereospecifically into consecutive epoxy groups in a similar
manner? In the present study, new insights to these questions
were provided through the evaluations of several N-chlorosuc-
cinimide (NCS)/organophosphine reagents that form sp3C-Cl
bonds in terms of selectivity and reactivity, and attempts were
made to apply the multiple chlorination method to various
internal epoxides.10 We also explored new reagent systems for
the dichlorination of epoxides and found that NCS/Ph2PCl,11
highly reactive chlorinating reagent, was suitable for this purpose
in some cases.
a
Results and Discussion
Evaluation of Reagent Scope and Reaction Conditions.
We initially evaluated the reagent scope and reaction conditions
for the dichlorination of simple alkyl-substituted epoxides. As
(7) For a pertinent review on the use of epoxides as precusor for chiral
halohydrins, see: Bonini, C.; Righi, G. Synthesis 1994, 225–238.
(8) Recently, Vanderwal and co-workers established the stereoselective
dichlorination-basedaccesstothisclassofpolychlorinatednaturalproducts:Shibuya,
G. M.; Kanady, J. S.; Vanderwal, C. D J. Am. Chem. Soc. 2008, 130, 12514–
12518.
(9) For the stereospecific dichlorination of epoxides, see: (a) Isaacs, N. S.;
Kirkpatrick, D. Tetrahedron Lett. 1972, 13, 3869–3870. (b) Croft, A. P.; Bartsch,
R. A. J. Org. Chem. 1983, 48, 3353–3354. (c) Oliver, J. E.; Sonnet, P. E. Org.
Synth. 1978, 58, 64–67. (d) Sonnet, P. E.; Oliver, J. E. J. Org. Chem. 1976, 41,
3279–3283. (e) Echigo, Y.; Watanabe, Y.; Mukaiyama, T. Chem. Lett. 1977,
1013–1014. (f) Iranpoor, N.; Firouzabadi, H.; Aghapour, G.; Nahid, A. Bull.
Chem. Soc. Jpn. 2004, 77, 1885–1891. (g) Iranpoor, N.; Firouzabadi, H.; Azadi,
R.; Ebrahimzadeh, F Can. J. Chem. 2006, 84, 69–75.
(10) O’Hagan and co-workers have reported an enantioselective synthesis
of polyfluorinated motifs by means of nucleophilic displacement of oxygen
functionalities: (a) Hunter, L.; Slawin, A. M. Z.; Kirsch, P.; O’Hagan, D. Angew.
Chem., Int. Ed. 2007, 46, 7887–7890. (b) Hunter, L.; O’Hagan, D.; Slawin,
A. M. Z. J. Am. Chem. Soc. 2006, 128, 16422–16423. (c) Nicoletti, M.; O’Hagan,
D.; Slawin, A. M. Z. J. Am. Chem. Soc. 2005, 127, 482–483.
(11) Ph2PCl itself is known to serve as a chlorinating reagent for alcohols;
see: (a) Hiebel, M.; Pelotier, B.; Piva, O. Tetrahedron 2007, 63, 7874–7878. (b)
Hayashi, T.; Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada, M. J. Org. Chem.
1986, 51, 3772–3781.
Dichlorination of 1,4-Dioxygenated 2,3-Epoxides. Then, the
dichlorination of chiral epoxides 4c-h possessing oxygen
functionalities at 1,4-positions was examined under NCS/Ph3P
conditions (Table 3). The reaction of trans-epoxide 4c and cis-
epoxide 4d with NCS/Ph3P afforded corresponding dichlorides
syn-5c and anti-5d in good yields along with olefins 6c/6c′ and
6d/6d′, respectively (Table 3, entries 1 and 2). The reaction
times were significantly shortened at 90 °C, as expected, and
the dichloride/olefin ratio showed a slight decrease at this
(12) The stereochemistry of each chloroalkene (6a and 6b) was unambigu-
ously confirmed by NOE experiments. The selective production of 3-chloro-
substituted alkene is presumably attributed to the preferential attack of a chloride
ion at the less hindered site where interaction with the bulky tert-butyldiphe-
nylsilyl substituent is avoidable.
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Yoshimitsu et al.
TABLE 1. Dichlorination of trans-Epoxide 4a with Various Chlorinating Reagents
entry
reagents (equiv)
solvent
T (°C)
time (h)
productsa,b (%)
5a (79), 6a (18)
1
2
3
4
5
6
7
8
Cl2PPh3 (4)
toluene
toluenec
toluene
toluene
toluene
toluene
CCl4
80
90
90
90
90
90
reflux
rt
0.5
0.7
13
6
6
22
7
NCS/Ph3P (3/3)
NCS/Ph3P (2.5/2.5)
NCS/(c-Hex)3P (3/3)
NCS/n-Bu3P (3/3)
NCS/t-Bu3P (3/3)
Ph3P (3)
5a (76), 6a (17)
5a (69), 6a (19), 7 (9)
5a (65), 6a (11), 7 (4), 8 (2)
5a (66), 6a (11), 7 (19)
7 (65), 8 (32)
d
7 (47), 8 (10)
PCl5 (3), NaHCO3
CH2Cl2
1
complex mixture
b
a Isolated yield. Ratio determined by H NMR analysis. c When MeCN was used as solvent, 5a (65%) and 6a (24%) were produced. d Unreacted 4a
1
(43%) was recovered.
TABLE 2. Dichlorination of cis-Epoxide 4b with Various Chlorinating Reagents
entry
reagents (equiv)
solvent
T (°C)
time (h)
productsa,b (%)
1
2
3
4
5
6
7
Cl2PPh3 (4)
toluene
toluene
toluene
toluene
toluene
toluene
CCl4
80
90
45
90
90
90
reflux
0.5
1
7
4.5
6
22
7
5b (82), 6b (17)
5b (88), 6b (9)
5b (90), 6b (6)
5b (86), 6b (7)
5b (82), 6b (7)
9 (72), 10 (17)
5b (81), 6b (7)
NCS/Ph3P (3/3)
NCS/Ph3P (3/3)
NCS/(c-Hex)3P (3/3)
NCS/n-Bu3P (3/3)
NCS/t-Bu3P (3/3)
Ph3P (3)
b
a Isolated yield. Ratio determined by H NMR analysis.
1
reaction temperature compared to that at 45 °C. It was revealed
that tert-butyldimethylsilyl and pivaloyl substituents were
compatible with the present conditions, without accompanying
undesired deprotection (Table 3, entries 3 and 4).
Dichlorination of Aryl Epoxides 4i and 4j. Further applica-
tions of the present method to various epoxides revealed that
subtle differences in the structures of epoxides significantly
affected yields and selectivities (Table 4). When phenyl-
substituted epoxide 4i was subjected to dichlorination using
NCS/Ph3P in toluene at 90 °C, desired dichloride 5i was
produced in 57% yield (syn:anti ) 1:50), together with olefin
6i (38%) (Table 4, entry 1). The reaction of trans-epoxide 4j
under the same conditions, however, produced olefin 6j as the
major product (68%) and dichloride 5j in low yield (19%; syn:
anti ) 14:1) (Table 4, entry 2). The preferential formation of
the undesired olefin from epoxide 4j, which markedly contrasts
the result obtained with cis-epoxide 4i, could be rationalized
by considering the steric hindrance of the initially introduced
chlorine atom as well as the stability of the product; the bulky
chlorine atom installed at the benzylic position covered the
R-face of the staggered alkyl chain to disrupt the second
nucleophilic attack of another chloride ion at the same face of
the intermediate, favoring an elimination reaction to give stable
conjugated olefins.
Epoxides 4g and 4h, both having a ketal group, were
moderately transformed with Ph3P/NCS into dichlorides 5g and
5h (Table 3, entries 5 and 6). In those cases, however, the yields
of alkenes 6g and 6g′ slightly increased, reflecting that the steric
hindrance of the ketal oxygen adjacent to the epoxide retarded
the second nucleophilic substitution and led to E2 elimination
of the oxyphosphonium intermediates. Thus, epoxide 4g un-
derwent dichlorination with NCS/Ph3P to afford dichloride 5g
in moderate yield (56%) along with regioisomeric alkenes 6g/
6g′ (Table 3, entry 5). The selective production of alkene 6g′
over 6g indicated the occurrence of an exclusive C2 attack with
a chloride ion rather than a nucleophilic displacement at C3-
position. Interestingly, under the same conditions, epoxide 4h
gave dichloride 5h (42%) as a stereoisomeric mixture (syn:anti
) 3:1), suggesting that the participation of the neighboring ketal
oxygen occurred (Table 3, entry 6). Thus, anti-5h was probably
produced through the double inversion at the C3 center, which
led to net configurational retention of the stereogenic center
(Scheme 2).
NCS/Ph2PCl, a New Dichlorinating Reagent for Alkenyl
Epoxides. A marked difference in product ratios of cis- and
trans-epoxides was also observed for alkenyl epoxides 4k-m
698 J. Org. Chem. Vol. 74, No. 2, 2009

Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs
SCHEME 1. Plausible Mechanism of Dichlorination
TABLE 3. Dichlorination of 1,4-Dioxygenated 2,3-Epoxides 4c-h
a All reactions were carried out using NCS (3 equiv) and PPh3 (3 equiv) in toluene. b Isolated yield. c Ratio determined by 1H NMR analysis.
d Accompanied by small amounts of deprotected compounds (1-6%).
(Table 4, entries 3-5). Alkenyl cis-epoxide 4k was transformed
into dichloride 5k in 58% yield, together with diene 6k in 34%
yield (entry 3). In contrast, trans-epoxide 4l predominantly
underwent SN2′ substitution reaction to give dichloride 6l (52%)
and desired dichloride 5l was produced in only 33% yield (entry
4). This was also the case for trans-epoxide 4m having a simple
alkyl substituent (entry 5). To our delight, however, byproduct
formation could be circumvented to some extent by using NCS/
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Yoshimitsu et al.
SCHEME 2. Rationale for Configurational Retention at the C3 Position
TABLE 4. Dichlorination of Aryl Epoxides 4i/4j and Alkenyl Epoxides 4k-m
c
a All reactions were carried out using NCS (3 equiv) and PPh3 (3 equiv) in toluene at 90 °C. b Isolated yield. Ratio determined by H NMR analysis.
d The use of MeCN as solvent gave similar yields: 16% of 5j (syn/anti ) 25:1) and 76% of 6j (E/Z ) 12:1). e NCS/Ph2PCl was used (see Scheme 3).
f Stereochemistry has yet to be determined.
1
SCHEME 3. Dichlorination of Alkenyl Epoxides 4l and 4m with NCS/Ph2PCl
Ph2PCl, a new chlorinating reagent that promoted the reaction
efficiently at room temperature (Scheme 3). Thus, a solution of
epoxide 4l or 4m in CH2Cl2 at room temperature was added
slowly over 5 min to the chlorinating reagent that was prepared
by premixing NCS (3.5 equiv) and Ph2PCl (3.0 equiv) in
CH2Cl2, and the mixture was stirred for an additional 5 min to
furnish desired dichloride 5l in 53% yield or 5m in 58% yield
(entries 4 and 5). We also evaluated the applicability of this
new reagent system to substrates 4a, 4b, 4i, and 4j and found
that the reactions with NCS/Ph2PCl showed unique substrate
scope (Table 5). Dichlorination of alkyl-substituted epoxides
4a and 4b smoothly took place at room temperature to give
dichlorides 5a and 5b in acceptable yields along with alkenes
6a and 6b, respectively (Table 5: entries 1 and 2), whereas the
reactions with phenyl-substituted epoxides 4i and 4j led to only
moderate yields of dichlorides 5i and 5j (Table 5, entries 3 and
4).
Tetrachlorination of Bisepoxides. As an extension of our
multiple chlorination strategy, we then applied the NCS/Ph3P
(13) The stereochemistry of each compound 5n and 5p was tentatively
assigned on the basis of the stereochemical outcomes obtained for other substrates.
700 J. Org. Chem. Vol. 74, No. 2, 2009

Enantiocontrolled Synthesis of Polychlorinated Hydrocarbon Motifs
TABLE 5. Dichlorination of Epoxides 4a, 4b, 4i, and 4j with NCS/Ph2PCl
a The reaction was carried out using NCS (3 equiv) and Ph2PCl (2 equiv) in CH2Cl2 at rt. b Racemic substrate was used. c The reaction was carried
out using NCS (3 equiv) and Ph2PCl (3 equiv) in CH2Cl2 at rt. d Isolated yield. e Ratio determined by 1H NMR analysis. f Phosphinate (14%) was also
produced. For the details, see the Supporting Information. g Phosphinate (5%) was produced. h No phosphinate was produced. i Phosphinate (6%) was
produced.
6, entry 3).13 Although bisepoxide 4q was found to be a poor
TABLE 6. Tetrachlorination of Bisepoxides 4n-q with NCS/Ph3P
substrate (Table 6: entry 4),14 the present one-step tetrachlori-
nation of bisepoxides potentially serves as a useful methodology
for synthesizing chiral polychlorinated hydrocarbons.
Determination of Stereochemistry of Chiral Polychlo-
rides. The stereochemistry of the products was unambiguously
confirmed by chemical correlations with known compounds as
well as NMR analysis (Scheme 4). syn-Dichloride 5c was
converted into chiral C2-symmetric diol 11c ([R]21D +6.6 (c 0.54,
MeOH)) in 96% yield over two steps by sequential removal of
TBDPS and benzyl groups.15 Similar conversion of anti-isomer
5d afforded meso-diol 11d in 90% yield, thereby establishing
its relative configuration. Tetrachloride 5o was converted into
meso-acetate 11o in 58% overall yield, while by deprotection
and subsequent acetylation, tetrachloride 5q gave chiral C2-
symmetric acetate 11q ([R]24 +8.8 (c 0.16, MeOH)). Stereo-
D
chemical assignments of all other dichlorides were deduced from
NMR analyses of olefins that were stereospecifically prepared
with known olefination procedures using NaI in refluxing HMPA
(for details, see the Supporting Information).
a The reaction was carried out using NCS (6 equiv) and PPh3 (6
equiv) in toluene at 90 °C. b NCS (10 equiv) and PPh3 (10 equiv) were
used. c The reaction mixture was initially heated at 45 °C for 1.3 h then
at 90 °C for 3.7 h. d Accompanied by olefin byproducts. e Isolated yield.
f Stereochemistry has yet to be determined.
Conclusions
We have demonstrated that chiral polychlorides were acces-
sible stereospecifically by nucleophilic multiple chlorination
reactions of internal epoxides using NCS/organophosphine. The
fact that various chiral epoxides are readily obtainable by
asymmetric epoxidation reactions of alkenes is evidence that
the organochlorination process disclosed here provides signifi-
cant opportunities for preparing an array of chiral chlorinated
stereocenters. Further applications of the present technique to
system to tetrachlorination, which would provide a novel short
access to the structural motifs of polychlorosulfolipids. To our
delight, despite the limited substrate scope at the present time,
tetrachlorination of bisepoxides 4n and 4o under NCS/Ph3P
conditions provided chiral tetrachlorides 5n and 5o, respectively
(Table 6, entries 1 and 2).13 Bisepoxide 4n was transformed
with NCS/Ph3P into tetrachloride 5n in 40% yield as a single
diastereomer. Benzyloxy derivative 4o was also stereospecifi-
cally chlorinated under the same conditions, giving compound
5o in 42% yield. Bisepoxide 4p possessing cis/trans configu-
ration was moderately transformed into tetrachloride 5p (Table
(14) The rest of the material was a complex mixture of many products,
including alkenes and dichlorides, and was difficult to analyze.
(15) Werner, F. P. DE Patent 10933345, 1960.
J. Org. Chem. Vol. 74, No. 2, 2009 701

Yoshimitsu et al.
SCHEME 4. Determination of Structure of Polychlorides
into the corresponding aldehydes (for details, see the Supporting
Information).
the synthesis of natural bioactive polychlorides are currently
being evaluated in this laboratory.
Representative Procedure for Dichlorination of Epoxides
with NCS/Ph2PCl. Ph2PCl (27 µL, 0.15 mmol) was added to a
magnetically stirred solution of NCS (24 mg, 0.18 mmol) in CH2Cl2
(0.4 mL) at room temperature, followed by a solution of alkenyl
epoxide 4m (21 mg, 0.05 mmol) in CH2Cl2 (0.6 mL) over 5 min.
The mixture was stirred for an additional 5 min and then transferred
to a separatory funnel where it was neutralized with satd NaHCO3
and extracted with EtOAc. The organic phase was separated, dried
over MgSO4, filtered, and concentrated. The residue was purified
by silica gel column chromatography (hexane) to give dichloride
5m (14 mg, 58%) as a colorless oil and olefin 6m (6.3 mg, 27%)
as a colorless oil. tert-Butyl({[(E,4R,5R)-4,5-dichlorodec-2-en-1-
Experimental Section
Representative Procedure for Dichlorination of Epoxides
with NCS/Ph3P. To a magnetically stirred solution of epoxide 4c
(204 mg, 0.47 mmol) in toluene (5 mL) at room temperature were
added Ph3P (367 mg, 1.40 mmol) and NCS (190 mg, 1.39 mmol),
and the mixture was heated at 90 °C for 3.4 h. The mixture was
then poured into a separatory funnel and partitioned between satd
NaHCO3 and EtOAc. The organic phase was separated, dried over
MgSO4, filtered, and concentrated. The residue was purified by silica
gel column chromatography (CH2Cl2/hexane 1:8) to give dichloride
5c (188 mg, 82%) as a colorless oil and an inseparable mixture of
alkenes 6c/6c′ (29 mg, 14%; 6c:6c′ ) 4:1 determined by 1H
analysis) as a colorless oil. The stereo- and regiochemistry of each
olefin were determined by NOE experiments. We sometimes
encountered difficulties in separating dichlorides from Ph3P remain-
ing in the crude reaction mixture. In such cases, treatment of the
reaction mixture with satd NaHCO3 and t-BuOOH (80 µL; ca. 1.5
equiv; 80% solution in di-tert-butyl peroxide) prior to workup
oxidized the remaining Ph3P to give Ph3PdO that was easily
removable. [(2R,3R)-4-(Benzyloxy)-2,3-dichlorobutoxy](tert-bu-
tyl)diphenylsilane (5c): colorless oil; [R]22D -4.6 (c 3.10, CHCl3);
yl]oxy})diphenylsilane (5m): colorless oil; [R]24 +20.1 (c 0.86,
D
1
CHCl3); IR (neat) ν 1957, 1892, 1822, 1464, 1113 cm-1; H (300
MHz, CDCl3) δ 7.71-7.62 (m, 4H), 7.50-7.33 (m, 6H), 6.02 (ddt,
1H, J ) 15.1, 8.2, 1.5 Hz), 5.89 (dt, 1H, J ) 15.2, 3.8 Hz), 4.62
(dd, 1H, J ) 8.2, 3.8 Hz), 4.25 (dd, 2H, J ) 3.8, 1.5 Hz), 4.04 (dt,
1H, J ) 9.7, 3.7 Hz), 2.03-1.84 (m, 1H), 1.78-1.63 (m, 1H),
1.50-1.24 (m, 6H) 1.07 (s, 9H), 0.91 (t, 3H, J ) 6.7 Hz); 13C
NMR (67.5 MHz, CDCl3) δ 135.4, 134.3, 133.3, 129.6, 127.6,
125.6, 65.5, 64.9, 63.2, 33.9, 31.2, 26.9, 26.2, 22.5, 19.3, 14.1;
MS m/z 485 (MNa+), 135 (100); HRMS (FAB) calcd for
C26H36O35Cl2SiNa (MNa+) 485.1810, found: 485.1819.
IR (neat) ν 2931, 1589, 1471, 1113, 700 cm-1; H (300 MHz,
1
Acknowledgment. This work was supported by a Grant-in-
Aid (KAKENHI No. 16790021) funded by the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
CDCl3) δ 7.63-7.53 (m, 4H), 7.40-7.20 (m, 11H), 4.67 (ddd, 1H,
J ) 8.2, 6.0, 2.0 Hz), 4.62 (d, 1H, J ) 12.1 Hz), 4.58 (d, 1H, J )
12.3 Hz), 4.42 (ddd, 1H, J ) 8.8, 5.7, 2.0 Hz), 3.93 (dd, 1H, J )
10.2, 8.9 Hz), 3.88-3.70 (m, 3H), 0.98 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 137.5, 135.6, 135.5, 132.8, 132.6, 129.9, 128.5, 127.9,
127.8, 127.7, 73.4, 70.9, 64.3, 59.9, 58.0, 26.8, 19.2; MS m/z 487
(MH+), 91 (100); HRMS (FAB) calcd for C27H33O235Cl2Si (MH+)
487.1627, found 487.1634. Due to the difficulty of separation of
alkenes 6c/6c′, the structures were elucidated by their transformation
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802093D
702 J. Org. Chem. Vol. 74, No. 2, 2009