Synthesis and characterization of all four diastereomers of 3,4-dichloro-2-pentanol, motifs relevant to the chlorosulfolipids

Article abstract of DOI:10.1021/jo802390e

All four diastereomers of 3,4-dichloro-2-pentanol were synthesized by anti-dichlorination of the precursor allylic alcohols; their stereochemistry was elucidated by X-ray crystallographic analysis of tosylate derivatives. Complete NMR data is provided in

Full text of DOI:10.1021/jo802390e

Synthesis and Characterization of All Four
Diastereomers of 3,4-Dichloro-2-pentanol, Motifs
Relevant to the Chlorosulfolipids
Jacob S. Kanady, John D. Nguyen, Joseph W. Ziller, and
Christopher D. Vanderwal*
1102 Natural Sciences II, Department of Chemistry,
UniVersity of California, IrVine, California, 92697-2025
cdV@uci.edu
ReceiVed October 27, 2008
FIGURE 1. Unnamed chlorosulfolipids isolated from Adriatic mussels
(1-3) and from freshwater algae (4) and algae-derived protein kinase
inhibitor malhamensilipin A (5).
rination of allylic alcohol derivatives to afford preferentially
the syn,syn hydroxydichloride stereorelationship (6 f 7, eq
1).4 Although the stereochemistry shown in Figure 1 for 1-3
had been elucidated using the powerful J-based configura-
tional analysis of Murata,3f,g,5 the accuracy of this method
has not yet been validated in the context of polychlorinated
compounds; therefore, we rigorously assigned the relative
stereochemistry of our hydroxydichloride products by chemi-
cal manipulations that included epoxide- and pyran-forming
schemes. To further solidify these and future stereochemical
assignments, we describe in this Note the synthesis, spec-
troscopic characterization, and unambiguous structure de-
termination by X-ray crystallography of the four diastereo-
meric hydroxychloride stereotriads on a minimal five-carbon
chain. We hope that the data provided might enable stereo-
chemical correlations by those who pursue the synthesis of
the chlorosulfolipids. These data should certainly enable
facile determination of the stereochemical outcomes of any
allylic alcohol dichlorination reactions that are developed
from this point on and could prove useful in the elucidation
of the stereochemistry of chlorosulfolipids such as 4 and 5.
All four diastereomers of 3,4-dichloro-2-pentanol were
synthesized by anti-dichlorination of the precursor allylic
alcohols; their stereochemistry was elucidated by X-ray
crystallographic analysis of tosylate derivatives. Complete
NMR data is provided in the hope that this information will
facilitate structural elucidation and synthesis studies on the
chlorosulfolipid family of natural products, such as malha-
mensilipin A.
Databases of spectral information can be powerful tools
for structural determination. For example, the Kishi group’s
NMR database for polyketide natural products1 was devel-
oped by the independent synthesis of stereochemical motifs
common to this important group and compilation of the NMR
data for each. The advent of this data collection has enabled
simplified protocols for the structure determination of newly
discovered polyketides and synthetic fragments thereof.2
The chlorosulfolipids (1-5, Figure 1) are an unusual class
of polychlorinated alkanes that represent particularly daunting
challenges for chemical synthesis.3 The obvious dearth of
methodology for the stereocontrolled introduction of multiple
chlorine atoms onto acyclic scaffolds poses a significant
problem; however, the less obvious problem of stereochem-
ical elucidation of these natural products and synthetic
intermediates presents an equally important challenge. As
part of our program targeting the chlorosulfolipids, we
recently introduced a method for the stereoselective dichlo-
(3) (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 Microorgan-
isms; Erwin, J. A., Ed.; Academic Press: New York; 1973; pp 197-232. (e)
Haines, T. H. Annu. ReV. Microbiol. 1973, 27, 403–412. (f) 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. (g) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.;
Di Rosa, M.; Ianaro, A.; Poletti, R. J. Org. Chem. 2001, 66, 578–582. (h)
Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.; Di Rosa, M.; Ianaro,
A.; Poletti, R. J. Am. Chem. Soc. 2002, 124, 13114–13120. (i) Ciminiello, P.;
Dell’Aversano, C.; Fattorusso, E.; Forino, M.; Magno, S. Pure Appl. Chem. 2003,
75, 325–336. (j) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.;
Magno, S.; Di Meglio, P.; Ianaro, A.; Poletti, R. Tetrahedron 2004, 60, 7093–
7098. (k) Ciminiello, P.; Fattorusso, E. Eur. J. Org. Chem. 2004, 2533–2551.
(4) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008,
130, 12514–12518.
(1) (a) Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2177–
2180. (b) Lee, J.; Kobayashi, Y.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2181–
2184. (c) Kishi, Y. Tetrahedron 2002, 58, 6239–6258.
(2) For a recent review that emphasizes the NMR Universal Database, see:
Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. ReV. 2007,
107, 3744–3779.
(5) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K.
J. Org. Chem. 1999, 64, 866–876.
10.1021/jo802390e CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2175–2178 2175

SCHEME 2. Synthesis of syn,syn and anti,syn
Dichlorotosylates
The chlorosulfolipids have never been crystallized, and di-
and trichlorinated alkanes related to 7 are oils; these properties
are likely the result of the long alkyl chains in each. We posited
that the use of the minimal five-carbon chain (3,4-dichloropen-
tan-2-ols) might best enable the generation of crystalline
compounds. Derivatization of each diastereomer with groups
known to impart crystallinity would then have the greatest
chance of overriding any inherent lack of order of the hydroxy-
dichloride-containing molecule. We were also inspired by a
single report of the X-ray diffraction of the p-toluenesulfonate
ester of one diastereomer of 3,4-dichloropentan-2-ol, though the
crystal structure was not provided, nor were any characterization
data.6 That disclosure focused only on the vibrational spectra
of one isomer of 2,3,4-trichloropentane, derived from the
tosylate in question.
TABLE 1. 1H and 13C NMR Assignments for All
Hydroxydichloride Stereotriadsa
To access the syn,anti and anti,anti stereotriads, com-
mercially available (E)-3-penten-2-ol (8) was dichlorinated
(Scheme 1) with anti stereospecificity using the reagent
pioneered by Mioskowski, Et4NCl3,7 which serves as a bench-
stable equivalent to chlorine. The resulting dichloroalcohol
diastereomers 9a and 9b were separated by careful flash
chromatography, and the individual isomers were converted
into their corresponding tosylates, p-bromobenzoates, and
p-nitrobenzoates. The tosylates (10a and 10b) of both isomers
readily provided crystals appropriate for X-ray diffraction
analysis, and the resulting structures are shown in the scheme.
The tosylate derived from the first eluting hydroxydichloride
isomer (pentane/Et2O on SiO2) had syn,anti stereochemistry
(10a), and that derived from the slower eluting isomer had
anti,anti stereochemistry (10b).
H1 [C1]
H2 [C2]
H3 [C3]
H4 [C4]
H5 [C5]
1.70 (d)
9a
1.33 (d)
J ) 6.4
[21.2]
4.46 (m) 3.82 (dd)
4.29 (dq)
J ) 9.2, 2.0 J ) 9.2, 6.6 J ) 6.6
[72.7]
[66.4]
[56.8]
[22.9]
9b
1.31 (d)
J ) 6.2
[17.8]
4.29 (m) 4.09 (dd)
4.16 (dq)
1.68 (d)
J ) 8.0, 4.7 J ) 8.0, 6.4 J ) 6.4
[72.4]
[68.1]
[56.6]
[22.4]
13a
1.32 (d)
J ) 6.4
[20.0]
4.11 (m) 3.86 (dd)
4.31 (dq)
1.65 (d)
J ) 5.7, 3.7 J ) 6.7, 3.7 J ) 6.8
[73.5]
[68.8]
[57.9]
[22.8]
13b 1.42 (d)
J ) 6.2
4.00 (m) 3.71 (dd)
4.69 (dq)
1.62 (d)
J ) 8.5, 2.4 J ) 6.7, 2.4 J ) 6.7
[70.4] [56.9] [22.8]
[20.8]
[69.3]
a From COSY and HMQC experiments, CDC13, 500 MHz.
SCHEME 1. Synthesis of syn,anti and anti,anti
Dichlorotosylates
stereomers by silica gel chromatography was typically
challenging but that the resulting TBS ethers were easily
separable. Racemic (Z)-2-tert-butyldimethylsilyloxy-3-pen-
tene (11) was prepared according to known protocols by
addition of 1-propynylmagnesium bromide to acetaldehyde,
followed by alkyne semireduction and silylation. As antici-
pated, the diastereomeric products of anti-dichlorination (12a
and 12b, Scheme 2) were readily isolated in stereoisomeri-
cally pure form following flash chromatography. No great
effort was made to optimize silyl ether cleavage, which
proceeded in low yield; nonetheless, significant quantities
of each hydroxydichloride isomer were available for deriva-
tization and crystallization studies. The tosylate 14a of the
slower eluting hydroxydichloride isomer 13a was crystallized
and shown to have syn,syn stereochemistry; several deriva-
tives of the other isomer (13b) including the tosylate proved
difficult to crystallize. However, by process of elimination,
we had now secured the relative configurations of all of the
diastereomers of 3,4-dichloropentan-2-ol. The complete
proton and carbon NMR assignments can be found in
Table 1.
We knew from previous studies in our group that the
separation of syn,syn and anti,syn hydroxydichloride dia-
1
Selected H NMR data for each tosylate are provided in
Table 2. It is noteworthy that the coupling constants between
the methine protons do not change dramatically upon
introduction of the tosyl group onto the dichloroalcohols. It
(6) Chough, S. H.; Krimm, S. Spectrochim. Acta 1990, 46A, 1405–1418.
(7) Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1997, 36, 2341–2344.
2176 J. Org. Chem. Vol. 74, No. 5, 2009

1
TABLE 2. Selected H NMR Data for Dichlorotosylates 10a, 10b,
SCHEME 3. Synthesis of 13a by Diastereoselective
Dichlorination of (Z)-Allylic Trichloroacetate 15
(Unoptimized)
14a, and 14b, Including Methine Methine Coupling Constants
H2
H3
H4
10a
10b
14a
14b
5.36 (dq)
JH2-H3 ) 1.8
3.73 (dd)
JH3-H4 ) 9.7
4.00 (dq)
5.10 (dq)
JH2-H3 ) 4.5
4.07 (dd)
JH3-H4 ) 8.3
3.98 (dq)
4.26 (dq)
4.32 (dq)
4.88 (dq)
JH2-H3 ) 6.4
3.89 (dd)
JH3-H4 ) 3.6
4.84 (dq)
JH2-H3 ) 8.5
3.86 (dd)
JH3-H4 ) 1.5
is apparent from analysis of the coupling constant data that
the solution conformations of these stereochemically rich
small molecules are not all strongly biased toward single,
low-energy conformations. While the coupling constants
observed for 10a and 14b suggest the predominant population
of a single low energy conformer for each molecule, the
intermediate coupling constant values observed for 10b and
14a point to the absence of a single preferred conformation.
From the perspective of using these stereotriads for prediction
of stereochemistry of the chlorosulfolipids, this result is both
surprising and unfortunate. For chlorosulfolipid 1, coupling
constants of the vicinal protons throughout the C9-C14
region are either very large (ca. 10 Hz) or very small (e1.5
Hz),3g indicating a strong conformational preference for anti
or gauche disposition of these protons, respectively (Figure
2). The stereotriads 14a and 10b that correspond to the
C10-C12 and C12-C14 regions of chlorosulfolipid 1 (with
the tosylate group representing a sulfate surrogate), respec-
tively, are the ones for which the coupling constants are
indicative of multiple low energy conformations; therefore,
any hope of performing stereochemical elucidations of lipids
4 and 5 using this small database is unlikely. On the other
hand, we have learned that the high degree of conformational
order that characterizes the chlorosulfolipids might only be
possible when more than three contiguous stereogenic centers
are present and working in concert.
which was applied to five-carbon substrate 15 (Scheme 3).
The major product of the 5:1 ratio that resulted, after cleavage
of the trichloroacetate ester, was found to be identical with
syn,syn-diastereomer 13a, as expected on the basis of our
previous studies.4
We hope that these data will enable correlation in the event
that new methods for the stereoselective dichlorination of
allylic alcohols are developed and that they will prove useful
to other researchers engaged in studies toward the chloro-
sulfolipids.8
Experimental Section
(2R*,3S*,4R*)-3,4-Dichloropentan-2-ol (9a). To a solution of
(E)-3-penten-2-ol (1.5 g, 17 mmol) in CH2Cl2 (58 mL), was
added Et4NCl3 (5.7 g, 24 mmol) at -78 °C. The mixture was
stirred for 1.5 h as the temperature warmed to -40 °C. The
reaction was quenched with a 1:1 solution of 10% aqueous
Na2S2O3/saturated aqueous NaHCO3 (50 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 80 mL). The combined organic
extracts were washed with brine (50 mL), dried with MgSO4,
and concentrated. 1H NMR spectroscopic analysis revealed a
1.4:1 (9a:9b) ratio of diastereomers. The diastereomers were
separated by flash chromatography (SiO2, 9:1 pentane/Et2O) to
yield 9a (1.2 g, 44%) and 9b (0.83 g, 30%) as yellow oils. 9a:
1H NMR (500 MHz, CDCl3) δ 1.33 (d, J ) 6.4, 3H), 1.70 (d, J
) 6.6, 3H), 1.75 (d, J ) 9.4, 1H), 3.82 (dd, J ) 9.2, 2.0, 1H),
4.29 (dq, J ) 9.2, 6.6, 1H), 4.46 (m, 1H); 13C NMR (500 MHz,
CDCl3) δ 21.2, 22.9, 56.8, 66.4, 72.7; IR (neat) 3402, 2984,
2936, 1453, 1380, 1122, 755, 668; HRMS (CI/CH2Cl2) m/z calcd
for C5H10OCl2 (M + Na)+ 179.0006, found 179.0005.
(2R*,3S*,4R*)-3,4-Dichloropentan-2-yl 4-Methylbenzene-sul-
fonate (10a). To a solution of 9a (54 mg, 0.34 mmol) in CH2Cl2
(2.1 mL) were added triethylamine (0.17 mL, 1.2 mmol), 4-dim-
ethylaminopyridine (83 mg, 0.68 mmol), and tosyl chloride (0.23
g, 1.2 mmol) at room temperature. The reaction mixture was stirred
at room temperature for 22 h and monitored by TLC. The remaining
tosyl chloride was quenched with 1,3-propanediol (0.12 mL, 1.7
mmol). The crude product was diluted with Et2O and filtered
through cotton. The organic phase was washed with 0.5 M CuSO4
(3 × 5 mL), saturated aqueous NaHCO3 (3 × 5 mL), and brine (5
mL) and dried with Na2SO4. The crude product was purified by
flash chromatography (SiO2, 9:1 hexanes/ethyl acetate) to yield 10a
as a viscous yellow oil (75 mg, 70%), which could be crystallized
as small rods from 5:1 hexanes/acetone using a hexane exchange
FIGURE 2. Comparison of the C10-C12 and C12-C14 regions of 1
with 10b and 14a, respectively. The simple stereotriads do not share
the conformational characteristics of the complete lipid.
Nonetheless, this study had a second purpose, for which
it is still useful. Syntheses of the chlorosulfolipids are likely
to rely, at least in part, on stereoselective dichlorination
reactions of allylic alcohols. Our database can be used to
determine the stereochemical outcome of dichlorination
reactions of chiral allylic alcohols by correlation. This idea
is illustrated using our previously described method for
stereoselective dichlorination of (Z)-allylic trichloroacetates,
1
chamber: H NMR (500 MHz, CDCl3) δ 1.46 (d, J ) 6.4, 3H),
1.64 (d, J ) 6.5, 3H), 2.45 (s, 3H), 3.73 (dd, J ) 9.7, 1.8, 1H),
(8) While this manuscript was in review, an excellent study of the conversion
of epoxides into dichlorides with inversion of configuration at both centers
appeared. This method has clear relevance to the chlorosulfolipids: Yoshimitsu,
T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696–702.
J. Org. Chem. Vol. 74, No. 5, 2009 2177

4.00 (dq, J ) 9.7, 6.5 1H), 5.36 (dq, J ) 1.8, 6.4, 1H), 7.35 (d, J
) 8.0, 2H), 7.83 (dd, J ) 6.7, 1.6, 2H); 13C NMR (500 MHz,
CDCl3) δ 19.2, 21.6, 23.1, 55.9, 68.5, 76.1, 127.8, 129.8, 133.9,
144.9; IR (neat) 2992, 2936, 1599, 1453, 1360, 1176, 1096, 810;
HRMS (CI/CH2Cl2) m/z calcd for C12H16O3Cl2S (M + Na)+
333.0095, found 333.0104.
thanks Pfizer for a Summer Undergraduate Research Fellowship
and the Dreyfus Foundation for a Jean Dreyfus Boissevain
Fellowship.
Supporting Information Available: General experimental
details, synthesis procedures and characterization data for all
new compounds, including copies of 1H and 13C NMR spectra,
and crystallographic information files in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. J.S.K. and J.D.N. contributed equally to
this work. Funding was provided by the School of Physical
Sciences of the University of California, Irvine through startup
funds and a grant from the Committee on Research. J.S.K.
JO802390E
2178 J. Org. Chem. Vol. 74, No. 5, 2009