Stereoselective dichlorination of allylic alcohol derivatives to access key stereochemical arrays of the chlorosulfolipids

Article abstract of DOI:10.1021/ja804167v

Dichlorination of (Z)-allylic trichloroacetates efficiently and stereoselectively generates the syn,syn hydroxydichloride stereotriad that is prevalent in the understudied polychlorinated sulfolipid class of natural products. Further, the dichlorination of a (2)-allylic chlorohydrin affords with high selectivity a stereotetrad present in one of the chlorosulfolipids.

Full text of DOI:10.1021/ja804167v

Published on Web 08/22/2008
Stereoselective Dichlorination of Allylic Alcohol Derivatives to
Access Key Stereochemical Arrays of the Chlorosulfolipids
Grant M. Shibuya, Jacob S. Kanady, and Christopher D. Vanderwal*
Department of Chemistry, 1102 Natural Sciences II, The UniVersity of California,
IrVine, California 92697-2025
Received June 2, 2008; E-mail: cdv@uci.edu
Abstract: Dichlorination of (Z)-allylic trichloroacetates efficiently and stereoselectively generates the syn,syn
hydroxydichloride stereotriad that is prevalent in the understudied polychlorinated sulfolipid class of natural
products. Further, the dichlorination of a (Z)-allylic chlorohydrin affords with high selectivity a stereotetrad
present in one of the chlorosulfolipids.
Introduction
Over 2000 chlorine-containing natural products are currently
known,1 and many of these display potent antibiotic or cytotoxic
properties. Therefore, it is noteworthy that the development of
methods for the stereoselective introduction of chlorine into
organic compounds significantly lags behind nearly all other
aspects of stereoselective synthesis.2-4 The lack of sophistication
in this area, coupled with the broad range of important
chlorinated natural and non-natural products, drives our labora-
tory to develop new methods for the stereoselective introduction
of chlorine into organic scaffolds.
(1) The status of organohalogen natural product isolation has been
consistently monitored by Professor Gordon W. Gribble:(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. Acc. Chem. Res. 1998, 31,
141–152. (d) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353–1395. (e)
From 1995 through 2002, Professor Gribble frequently reviewed the
literature pertaining to the isolation of organochlorine natural products.
The results were published on the internet in a series of 18 “Natural
Chlorine Updates”. See: http://www.eurochlor.org/index.asp?page)84,
accessed June 2, 2008.
(2) For several breakthrough examples of catalytic asymmetric R-chlorina-
tion of carbonyl compounds, see:(a) Hintermann, L.; Togni, A. HelV.
Chim. Acta 2000, 83, 2425–2435. (b) Wack, H.; Taggi, A. E.; Hafez,
A. M.; Drury, W. J.; Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531–
1532. (c) Hafez, A. M.; Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka,
T. Org. Lett. 2001, 3, 2049–2051. (d) Brochu, M. P.; Brown, S. P.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108–4109. (e)
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A.
J. Am. Chem. Soc. 2004, 126, 4790–4791.
Figure 1. Unnamed chlorosulfolipids isolated from Adriatic mussels (1-3)
and from freshwater algae (4) and algae-derived protein kinase inhibitor
malhamensilipin A (5).
Chlorosulfolipids 1-55,6 (Figure 1) represent a particularly
daunting challenge for synthesis. Ciminiello, Fattorusso, and
co-workers isolated compounds 1-3 from Adriatic mussels that
caused diarrhetic shellfish poisoning upon ingestion;5 these
fascinating molecules were deemed to be the causative agents
of this illness. The NMR method developed by Murata’s group
was used to arrive at the relative stereochemistry shown.7 An
efficient synthesis of these compounds would allow confirmation
of their stereochemistry and, by extension, a validation of this
NMR method in complex polychlorinated molecules. Related
chlorosulfolipids have been isolated from freshwater algae,
(3) For representative chiral auxiliary- and reagent-based protocols for
stereoselective introduction of chlorine, see:(a) Evans, D. A.; Sjogren,
E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39–42.
(b) Evans, D. A.; Ellman, J. A.; Dorow, R. L. Tetrahedron Lett. 1987,
28, 1123–1126. (c) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org.
Chem. 1996, 61, 7513–7520. (d) Hu, S.; Jayaraman, S.; Oehlschlager,
A. C. J. Org. Chem. 1998, 63, 8843–8849, and references therein.
(4) There have been innumerable reports of the introduction of single
chloride-bearing stereogenic centers using alcohol to chloride conver-
sion protocols.
(5) (a) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.; Di Rosa,
M.; Ianaro, A.; Poletti, R. J. Org. Chem. 2001, 66, 578–582. (b)
Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.; 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. (e)
Ciminiello, P.; Fattorusso, E. Eur. J. Org. Chem. 2004, 2533–2551.
(6) (a) Elovson, J.; Vagelos, P. R. Proc. Natl. Acad. Sci. U.S.A. 1969, 62,
957–963. (b) Haines, T. H.; Pousada, M.; Stern, B.; Mayers, G. L.
Biochem. J. 1969, 113, 565–566. (c) Elovson, J.; Vagelos, P. R.
Biochemistry 1970, 9, 3110–3126. (d) Haines, T. H. In Lipids and
Biomembranes of Eukaryotic Microorganisms; Erwin, J. A., Ed.;
Academic Press: New York, 1973; pp 197-232. (e) Haines, T. H.
Annu. ReV. Microbiol. 1973, 27, 403–412.
(7) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866–876.
9
12514 J. AM. CHEM. SOC. 2008, 130, 12514–12518
10.1021/ja804167v CCC: $40.75
2008 American Chemical Society

Stereoselective Dichlorination
A R T I C L E S
Figure 2. Probable conformational preference of chlorosulfolipid 1. g )
gauche, a ) anti.
though their relative stereochemistry remains unknown.6,8 In
at least one species of freshwater algae, chlorosulfolipids such
as 46c account for 15% of the total lipid content of the organism,
and they are the primary lipids found in the cell membranes, to
the exclusion of phospholipids.6 The related algae-derived
compound malhamensilipin A (5) was found to be a protein
kinase inhibitor.9,10
Figure 3. Possible stereochemical outcomes of the vicinal dichlorination
of (Z)-allylic alcohol derivatives.
valuable. Ready access to enantiomerically enriched allylic
alcohols of both E and Z geometry makes this approach
appealing.15-17 To our surprise, and to the best of our
knowledge, a comprehensive study of the diastereoselective
vicinal dichlorination of chiral acyclic alkenes has never been
reported.18,19 Progress toward this goal, in the form of the
diastereoselective synthesis of syn,syn hydroxydichloride motifs
from allylic alcohol derivatives, is reported here.
On the assumption that allylic strain (A1,3) might serve as a
valuable stereocontrol element,20 we opted to study the dichlo-
rination of a series of (Z)-allylic alcohol derivatives (Figure 3).
We surmised that the right combination of steric and electronic
effects required for high diastereoselectivity might be unveiled
by varying substituent groups on the allylic alcohol oxygen;
the choice of reagents for either syn or anti dichlorination,
These polychlorinated lipids may be viewed as electronically
distinct isosteres of polyketide natural products. The enormous
family of polyketides includes many important pharmaceutical
agents, including antibiotic and antitumor compounds. Their
complex stereochemical arrays confer substantial conformational
organization to what appear to be very flexible molecules. The
resulting preferred conformations, which dictate overall mo-
lecular shape, are critical to the biological activity of these
compounds.11 The chlorosulfolipids contain arrays of adjacent
stereogenic carbon atoms that each bear an electronegative atom;
in addition to the avoidance of syn-pentane-like interactions that
is important in the context of polyketides, dipolar and stereo-
electronic effects might be important. For example, the well-
known stereoelectronic preference for mutual gauche orienta-
tions of electronegative substituents12 might further limit the
number of low-energy conformers of these molecules. Indeed,
(14) In our work focusing on the chlorosulfolipids, we wish to avoid the
potentially problematic conversion of acyclic polyols into the corre-
sponding polychlorides; this procedure could suffer from serious issues
of regiocontrol as targets 1-5 bear a mixture of chlorides and
hydroxyl/sulfate groups, and potential problems of partial retention
in the chlorination reactions would be devastating. In the context of
hexapyranose sugars, some beautiful work for the conversion of
multiple hydroxyl groups into chlorides, with inversion, has been
reported:(a) Jennings, H. J.; Jones, J. K. N. Can. J. Chem. 1965, 43,
2372–2385. (b) Cottrell, A. G.; Buncel, E.; Jones, J. K. N. Chem.
Ind. 1966, 552.
3
the JH-H coupling constants reported for 15a perfectly match
the three-dimensional structure predicted simply on the basis
of avoidance of syn-pentane-like interactions and maximization
of relative gauche orientations (Figure 2).13 Methodology that
enables the synthesis of 1-5 and non-natural polychlorinated
alkanes will enable study of the conformational aspects of these
fascinating molecules and could eventually proVide opportunities
for the control of molecular shape.
As targets for synthesis, these complex lipids will necessarily
elicit substantial methodology development for stereoselective
polychlorination.14 Given the nearly regular interspersion of
hydroxyl (or sulfated hydroxyl) groups among the many
chlorides of the chlorosulfolipids (see 2 and 3, in particular)
we reasoned that a method for the diastereoselective vicinal
dichlorination of allylic alcohols would be both relevant and
(15) For state-of-the-art enantioselective syntheses of propargylic alcohols,
which can be reduced to either the (E)- or (Z)-allylic alcohols, see:(a)
Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738–8739. (b) Boyall, D.; Frantz, D. E.; Carreira,
E. M. Org. Lett. 2002, 4, 2605–2606.
(16) For a seminal contribution in the area of direct enantioenriched (E)-
allylic alcohol synthesis, see: Oppolzer, W.; Radinov, R. N. HelV.
Chim. Acta 1992, 75, 170–173.
(17) For direct syntheses of enantioenriched (Z)-allylic alcohols, see: Salvi,
L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2007, 129, 16119–16125.
(18) Studies of related processes, including dibromination, haloetherifica-
tion, halolactonization, and selenofunctionalization of alkenes have
all been studied in some detail. For some representative examples,
see:(a) Liotta, D.; Zima, G.; Saindane, M. J. Org. Chem. 1982, 47,
1258–1267. (b) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills,
M. C. J. Am. Chem. Soc. 1983, 105, 5819–5825. (c) Chamberlin, A. R.;
Mulholland, R. L., Jr Tetrahedron 1984, 40, 2297–2302. (d) Bartlett,
P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press,
Inc.: New York, 1984; Vol. 3, pp 411-454. (e) Kim, K. S.; Park,
H. B.; Kim, J. Y.; Ahn, Y. H.; Jeong, I. H. Tetrahedron Lett. 1996,
37, 1249–1252.
(8) A survey of the distribution of chlorosulfolipids among 30 species of
algae has shown that these chlorosulfolipids are present in a significant
number of freshwater algae. See:Mercer, E. I.; Davies, C. L.
Phytochemistry 1979, 18, 457–462.
(9) 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.
(10) Increasingly common occurrences of halogenated fatty acids in a
variety of organisms have prompted a review article on the subject:
Dembitsky, V. M.; Srebnik, M. Prog. Lipid Res. 2002, 41, 315–367.
(11) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054–2070.
(12) For an excellent lead reference, see: Sonntag, L.-S.; Schweizer, S.;
Ochsenfeld, C.; Wennemers, H. J. Am. Chem. Soc. 2006, 128, 14697–
14703.
(19) The significantly different behavior among the halides and related
reagents means that previously studied stereoselective halogenation/
halofunctionalization reactions of allylic alcohols do not necessarily
translate to the corresponding dichlorination process. High selectivities
in the selenofunctionalization of allylic alcohols are thought to derive
from Se-O attractive interactions; analogous interactions are not likely
to be operative in chlorination reactions. For an excellent study of the
diastereoselective dibromination of chiral allylic alcohols, which
resulted in high levels of selectivity in alcoholic solvents with an excess
of added bromide ion, see:(a) Midland, M. M.; Halterman, R. L. J.
Org. Chem. 1981, 46, 1227–1229. Attempts to adapt this procedure
with the chlorine equivalent Et4NCl3 in alcoholic solvents, with added
chloride, led to predominant chloroetherification and apparent low
selectivity in the small amount of dichlorinated product observed.
(13) O’Hagan and coworkers have pioneered the stereocontrolled synthesis
of polyfluorinated alkanes with three or four adjacent fluorine-bearing
stereogenic centers. For details, and a discussion of the conformations
of these interesting polyfluorides, see: (a) Nicoletti, M.; O’Hagan, D.;
Slawin, A. M. Z. J. Am. Chem. Soc. 2005, 127, 482–483. (b) Hunter,
L.; O’Hagan, D.; Slawin, A. M. Z. J. Am. Chem. Soc. 2006, 128,
16422–16423. (c) Hunter, L.; Slawin, A. M. Z.; Kirsch, P.; O’Hagan,
D. Angew. Chem., Int. Ed. 2007, 46, 7887–7890.
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A R T I C L E S
Shibuya et al.
Table 1. Comparison of the Marko´-Maguire and Mioskowski
Reagents for Diastereoselective Vicinal Dichlorination of Allylic
Alcohol Derivatives (TBS ) tert-Butyldimethylsilyl, Piv ) Pivaloate)
Table 2. Evaluation of the Optimal O-Substituent for Dichlorination
Diastereoselectivity (TBS ) tert-Butyldimethylsilyl, Boc )
tert-Butoxycarbonyl, Ac ) Acetate, Piv ) Pivaloate)
X
temp (°C)
dr (7:8)a
X
temp (°C)
dr (7:8)a
H
Me
TBS
CO2Me
Boc
-78
-78
-78
-78
-78
-78
1.0:1
2.0:1
2.0:1
5.0:1b
5.0:1b
5.0:1b
Piv
Piv
Cl3CCO
Cl3CCO
F3CCO
-78
-90
-78
-90
-78
-90
7.5:1b
7.7:1b
5.0:1
6.5:1
6.0:1
7.0:1
X
method
dr (5:6)a
H
H
TBS
TBS
Piv
Piv
A
B
A
B
A
B
1.2:1
1.1:1
1.2:1
1.5:1
2.5:1
2.4:1
Ac
F3CCO
a Diastereomeric ratio (dr) determined by 1H NMR analysis of crude
reaction mixtures. b In addition to 7 and 8, rearranged products such as
9 were produced with unconfirmed stereochemistry in varying quantities;
all other reactions proceeded cleanly to complete conversion.
a Diastereomeric ratio (dr) determined by 1H NMR analysis of crude
reaction mixtures.
combined with diastereofacial selectivity, might eventually
enable access to all four stereotriads shown. In particular,
stereoselective access to the syn,syn isomer by anti dichlori-
nation would be directly relevant to targets 1-3 (see highlighted
substructures in Figure 1).
reagent; the soluble permanganate salt could oxidize chloride
ion, generating molecular chlorine, and thence a tetraalkylam-
monium trichloride reagent.25,26 Although our evidence is at
best circumstantial, we feel that this is a plausible explanation
for the reactivity of the Marko´-Maguire reagent.27
Results and Discussion
Screening of a variety of groups of differing steric and
electronic nature on the allylic hydroxyl (Table 2) indicated that
the steric bulk of the substituent had little impact on selectivity.
However, electron-deficient (acyl-type) groups led to reasonable
margins of selectivity. In particular, pivaloyl, trichloroacetyl,
and trifluoroacetyl groups showed significant diastereoselec-
tivities, with best results at -90 °C. However, dichlorinations
of the less electron-deficient acyl groups, including pivaloyl,
suffered from substantial side product formation resulting from
ester carbonyl participation/rearrangement to afford compounds
tentatively assigned as 9. The good selectivity and clean
reactivity of the allylic trihaloacetates is particularly noteworthy
given the ease of introduction and removal of these acyl groups.
As a result of the lability of trifluoroacetate esters to chromato-
graphic purification, the more stable trichloroacetate group was
deemed optimal, despite the slightly diminished selectivities.
A screen of solvents (not shown) demonstrated that the use of
dichloromethane at -90 °C was optimal for both clean
conversion and diastereoselectivity.
Consideration of stereospecific processes for the anti dichlo-
rination of alkenes led us to two seemingly distinct procedures,
in addition to the less appealing direct use of molecular chlorine.
Marko´, Maguire, and co-workers reported the use of an
uncharacterized reagent generated by premixing a tetraalkyl-
ammonium permanganate with TMSCl; this reagent effectively
dichlorinates a range of alkenes with quite reasonable functional
group tolerance and apparent anti stereospecificity.21,22 Miosk-
owski’s group pioneered the use of tetraethylammonium trichlo-
ride, an easily prepared, bench-stable solid for vicinal anti
dichlorinations of both alkenes and alkynes, which also dem-
onstrates good functional group compatibility.23 We were
hopeful that the reagent of Marko´ and Maguire, which might
proceed via some sort of chloromanganese reagent,22b could
coordinate to an allylic alcohol or a Lewis basic derivative
(ether, ester, carbonate, etc.) to afford useful levels of stereo-
control based on a substrate-directed mechanism.24 To our
surprise, we found nearly identical levels of efficiency and
diastereoselectivity with both reagents, using several different
allylic alcohol derivatives (three examples shown, Table 1). As
a result, we considered that the reagent made in situ by the
Marko´-Maguire procedure might simply be a Mioskowski-type
The results in Table 3 indicate that, after some further
optimization, the reaction affords usable selectivities (from
4.6:1 to 10.9:1 diastereomeric ratio (dr) for crude reaction
mixtures) across a range of structurally different substrates
and is tolerant of a variety of functional groups (see also
Table 2 and ref 23 for further compatibility of the reagent).
There appears to be little effect from steric modulation in
(20) For an excellent review, see:(a) Hoffmann, R. W. Chem. ReV 1989,
89, 1841–1860. For seminal applications of A1,3-strain minimization
for acyclic stereocontrol in natural product synthesis, see the first
synthesis of monensin by Kishi and coworkers: (b) Schmid, G.;
Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101,
259–260.
(24) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307–
1370.
(21) Marko´, I. E.; Richardson, P. R.; Bailey, M.; Maguire, A. R.; Coughlan,
N. Tetrahedron Lett. 1997, 38, 2339–2342.
(25) In ref 21, the Marko´-Maguire reagent is also reported to open epoxides
to the corresponding chlorohydrins and oxidize sufides to sulfoxides.
We have not evaluated the reactivity of the Mioskowski reagent in
these transformations, as the presence of manganese salt byproducts
in the former procedure might well be critical.
(22) An earlier variant of this protocol used oxalyl chloride as a chlorine
source and generated a thermally unstable reagent of unknown structure
that lost chlorination activity above -35 °C: (a) Marko´, I. E.;
Richardson, P. F. Tetrahedron Lett. 1991, 32, 1831–1834. (b)
Richardson, P. F.; Marko´, I. E. Synlett 1991, 733–736.
(26) As an important historical note, Scheele’s discovery of molecular
chlorine resulted from the oxidation of chloride ion by manganese
oxides. See: Weeks, M. E. DiscoVery of the Elements, 3rd ed.; Journal
of Chemical Education: Easton, PA, 1935; pp 253-257.
(23) Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew.
Chem., Int. Ed. 1997, 36, 2341–2344.
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Stereoselective Dichlorination
A R T I C L E S
Table 3. Scope of the Stereoselective Dichlorination Reaction
(TCA ) Trichloroacetate, TBS ) tert-Butyldimethylsilyl, Bn )
Benzyl)
Scheme 1. Diastereoselective Synthesis of a Stereotetrad
Relevant to Chlorosulfolipid 1 (TCA ) Trichloroacetate)
Scheme 2. Synthesis of Pyran 16 to Confirm the Relative
Stereochemistry of Dichlorination
a Yield refers to isolated yield of indicated diastereomeric
composition. Diastereomeric ratios (d.r.) determined by integration using
1H NMR; d.r. in parentheses refers to crude product when different
from purified product.
the vicinity of the trichloroacetate group (see 11a-11c), and
useful functional group handles were tolerated at the other
terminus (see 11d and 11e). These two examples provide
means for chain extension for applications to complex
polychlorinated targets. Product 11f, formed in a 4.6:1 dr,
demonstrates that synthetically useful heteroatom functional
groups are tolerated at the trichloroacetate terminus. Removal
of the trichloroacetyl group, which is necessary for stereo-
control, occurs in nearly quantitative yield without disruption
of the chlorides (NH3 in MeOH/Et2O) to afford product of
sufficient purity to obviate chromatography.28 In several cases
we have run the three-step sequence of acylation, dichlori-
nation, and deacylation and obtained diastereoselectivities
identical to those shown in Table 3 in good overall yields.28
We were aware that this methodology would need to be
applied in even more complex contexts, so we generated racemic
trichloroacetylated allylic chlorohydrin 14 as shown in Scheme
1. According to the method of Kang and Britton,29 acetylide
addition to R-chloroaldehyde 13 provided anti chlorohydrin in
up to 30:1 dr, consistent with the polar Felkin-Anh model;30
semihydrogenation and trichloroacetylation completed the simple,
unoptimized sequence. Fortunately, the extra chlorine-bearing
stereogenic center had little effect on selectivity, as stereotetrad
15 was produced in 10.5:1 dr in 76% yield. The relative
stereorelationships in 15 match perfectly the central stereotetrad
of chlorosulfolipid 1.
Although the Mioskowski reagent is known to effect ste-
reospecific anti dichlorination reactions,23 we clearly needed to
unambiguously assign the relative stereochemistry of our
products. Unfortunately, the majority of our dichlorinated
products were oils, and preliminary screens of derivatives did
not lead to promising candidates for X-ray crystallographic
analysis. In principle, the NMR method developed by Murata’s
group,7 which was used to assign the relative stereochemistry
of lipids 1-3, could be used; however, we desired independent
means of stereochemical analysis to be certain of our assign-
ments. To elucidate the stereorelationship between the trichlo-
roacetoxy-bearing carbon and the newly formed chlorine-bearing
centers, we turned to the stereospecific epoxidation reaction of
chlorohydrins; differentiation of cis- and trans-epoxides is
readily accomplished on the basis of coupling constant analysis
and nuclear Overhauser effect (nOe) experiments.31 The conver-
sion of product 11a and its anti,syn-diastereomer to the
corresponding cis- and trans-epoxides, respectively, supported
our assignment of the syn,syn stereochemistry of the major
reaction products.28 To further solidify our assignment, we
converted product 11e into dichloropyran 16 (Scheme 2);
coupling constant analysis on the six-membered ring scaffold
clearly supported our analysis.28
(27) Et4NCl3 effects smooth anti dichlorination of alkynes (ref 23). We
have found that the Marko´-Maguire reagent performs the same
transformation. This is also consistent with these reagents being similar
in nature and argues against a possible mechanism involving syn
chloromanganation of the π-system, followed by invertive SN2
displacement of manganese by chloride (see reference 22a); in the
case of alkyne substrates, SN2 displacement on an sp2 carbon would
need to be invoked.
(28) Please see the Supporting Information for details.
(29) For a recent account of highly stereroselective alkynyllithium additions
to R-chloroaldehydes, see: Kang, B.; Britton, R. Org. Lett. 2007, 9,
5083–5086.
(30) The addition of organometallic nucleophiles to R-chloroaldehydes
generally proceeds to afford the anti product, consistent with the polar
Felkin-Anh model (hyperconjugative stabilization of the transition
state/steric control), though the Cornforth model (dipole minimization/
steric control) also accounts for the stereochemistry of the products.
For an excellent discussion and lead reference, see: Cee, V. J.; Cramer,
C. J.; Evans, D. A. J. Am. Chem. Soc. 2006, 128, 2920–2930.
(31) For one example of the determination of halohydrin relative stereo-
chemistry by stereospecific conversion to the corresponding epoxides,
see:(a) Besse, P.; Sokoltchik, T.; Veschambre, H. Tetrahedron:
Asymmetry 1998, 9, 4441–4457. See also refs 3c,d, and 29.
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A R T I C L E S
Shibuya et al.
Inspired by polychlorinated sulfolipids 1-5, we have outlined
a direct solution to the synthesis of syn,syn hydroxydichloride
stereotriads by the dichlorination of allylic alcohol derivatives
using tetraethylammonium trichloride. Readily available (Z)-
allylic trichloroacetates have demonstrated high levels of
diastereocontrol across a range of substrates; the ease of
deprotection without interference of the chlorides is noteworthy.
We are currently studying the extent to which (Z)-allylic
trichloroacetates are competent substrates for the stereoselective
additions of other reagents that react via anti addition processes.
We have also synthesized a stereotetrad relevant to chlorosul-
folipid 1 using our methodology, and we have firmly established
the relative stereochemistry of our products. Further methods
for the stereoselective introduction of chlorine into carbon
scaffolds, application of these methods to the synthesis of the
chlorosulfolipids, and studies on the conformational aspects and
membrane behaviors of polychlorinated alkanes will be the
subjects of future disclosures.
Acknowledgment. The authors thank the School of Physical
Sciences of University of California, Irvine for generous startup
funding. New Faculty Awards from Amgen and Eli Lilly are also
gratefully acknowledged. J.S.K. thanks Pfizer for a 2007 Summer
Undergraduate Research Fellowship and The Camille & Henry
Dreyfus Foundation for a 2008 Jean Dreyfus Boissevain Under-
graduate Scholarship for Excellence in Chemistry.
Supporting Information Available: Complete experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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12518 J. AM. CHEM. SOC. VOL. 130, NO. 37, 2008