Asymmetric total synthesis of (+)-Hexachlorosulfolipid, a cytotoxin isolated from adriatic mussels

Article abstract of DOI:10.1021/jo100534d

The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph₃P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Full text of DOI:10.1021/jo100534d

pubs.acs.org/joc
Asymmetric Total Synthesis of (þ)-Hexachlorosulfolipid, a Cytotoxin
Isolated from Adriatic Mussels
Takehiko Yoshimitsu,* Naoya Fukumoto, Ryo Nakatani, Naoto Kojima, 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 March 21, 2010
The enantioselective total synthesis of (þ)-hexachlorosulfolipid, a cytotoxin found in the Adriatic
mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid
is successfully furnished by a series of dichlorination reactions of chiral epoxides with chloropho-
sphonium reagent generated in situ from Ph3P/NCS. The present total synthesis has allowed the
confirmation of the absolute configuration of the natural cytotoxic (þ)-hexachlorosulfolipid
originally proposed by Fattorusso, Ciminiello, and co-workers.
Introduction
lipids includes (þ)-hexachlorosulfolipid 1,2a undecachloro-
sulfolipid 2,2b malhamensilipin A (3),3a,d and danicalipin A
(4),1b all of which have drawn considerable attention as
substances of toxicological concern. In the quest for deeper
knowledge of their risks and effects on human health,
massive efforts have been made to establish chemical access
to chlorosulfolipids, which would allow the further evalua-
tion of their biological properties and functions. However,
the greatest difficulties in the chemical synthesis of chloro-
sulfolipids are those caused by the stereochemistry, which
poses significant challenges in the artificial production of
such molecules.
Polychlorinated sulfolipids have recently emerged as at-
tractive targets for biological investigations (Figure 1).1 They
are unique in featuring hydrocarbon motifs densely functio-
nalized with polar chlorine atoms, which are rarely seen in
other natural products. This unusual family of chlorine-rich
(1) For pioneering studies on this class of molecules, see: (a) Mayers,
G. L.; Haines, T. H. Biochemistry 1967, 6, 1665–1671. (b) Elovson, J.;
Vagelos, P. R. Proc. Natl. Acad. Sci. U.S.A. 1969, 62, 957–963. (c) Haines,
T. H.; Pousada, M.; Stern, B.; Mayers, G. L. Biochem. J. 1969, 113, 565–566.
(d) Elovson, J.; Vagelos, P. R. Biochemistry 1970, 9, 3110–3126. (e) Haines,
T. H. In Lipids and Biomembranes of Eukaryotic Microorganisms; Erwin, J. A.,
Ed.; Academic Press: New York; 1973; pp 197-232. (f) Haines, T. H. Annu. Rev.
Microbiol. 1973, 27, 403–412. (g) Hansen, J. A. Physiol. Plant. 1973, 29, 234–
238. (h) Elovson, J. Biochemistry 1974, 13, 3483–3487. (i) Mercer, E. I.; Davies,
C. L. Phytochemistry 1974, 13, 1607–1610. (j) Mercer, E. I.; Davies, C. L.
Phytochemistry 1975, 14, 1545–1548. (k) Mercer, E. I.; Davies, C. L. Phyto-
chemistry 1979, 18, 457–462.
(2) (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.; Di Meglio, P.; Ianaro, A.; Poletti, R.
Tetrahedron 2004, 60, 7093–7098. For reviews, see: (d) Ciminiello, P.;
Dell’Aversano, C.; Fattorusso, E.; Forino, M.; Magno, S. Pure Appl. Chem.
2003, 75, 325–336. (e) Ciminiello, P.; Fattorusso, E. Eur. J. Org. Chem. 2004,
2533–2551.
Vanderwal4 and Carreira5 have independently made sig-
nificant contributions to this emerging field of organic synth-
esis, which have led to the successful total syntheses of the
chlorosulfolipids. Carreira and co-workers were the first
to establish a route to (()-hexachlorosulfolipid 1 whose
(þ)-enantiomer is known as the causative substance of seafood
(4) An elegant methodology was developed by this group: (a) Shibuya,
G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 12514–
12518. (b) Kanady, J. S.; Nguyen, J. D.; Ziller, J. W.; Vanderwal, C. D.
J. Org. Chem. 2009, 74, 2175–2178. While the present paper was in review,
asymmetric total synthesis of malhamensilipine A was reported: (c) Bedke,
D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal, C. D.
J. Am. Chem. Soc. 2010, 132, 2542–2543.
(5) For the total synthesis of (()-hexachlorosulfolipid, see: (a) Nilewski,
C.; Geisser, R. W.; Carreira, E. M. Nature 2009, 457, 573–576. For an
account of this work, see: Bedke, D. K.; Vanderwal, C. D. Nature 2009, 457,
548–549. For related studies, see: (b) Nilewski, C.; Geisser, R. W.; Ebert,
M.-O.; Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 15866–15876.
(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. Recently,
the revised structure of this natural compound has been reported: (d) Pereira,
A. R.; Byrum, T.; Shibuya, G. M.; Vanderwal, C. D.; Gerwick, W. H. J. Nat.
Prod. 2010, 73, 279–283.
DOI: 10.1021/jo100534d
r
Published on Web 05/05/2010
J. Org. Chem. 2010, 75, 5425–5437 5425
2010 American Chemical Society

Yoshimitsu et al.
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FIGURE 1. Natural polychlorosulfolipids.
poisoning in the Adriatic mussel Mytilus galloprovincialis.2a
Carreira’s synthesis of sulfolipid 1 elegantly demonstrates that
the trimethylsilyl chloride-mediated ring opening of epoxides
effects the construction of the chlorinated architecture and an
anchimeric assistance of the distal chlorine atom takes place
during another carbon-chlorine bond formation.5a Vander-
wal and co-workers have also devised a general approach to
multiply chlorinated hydrocarbon units by diastereoselective
alkene dichlorinations in which the allylic strain (A1,3) of the
substrates directs the facial selectivity.4a,b In addition, their
recent efforts culminated in the first stereoselective total synth-
eses of danicalipin A (4), a major chlorosulfolipid isolated from
the freshwater alga Ochromonas danica,6,7 and malhamensili-
pin A (3), a protein tyrosine kinase (PTK) inhibitor found in
the cultured chrysophyte Poterioochromonas malhamensis.4c
We have also been engaged in the total synthesis of chloro-
sulfolipids as it would allow us to develop medicinal and
toxicological research associated with this class of naturally
occurring cytotoxins. Our avid interest in this area has been
directed toward (þ)-chlorosulfolipid 1 that exerts antiproli-
ferative activity on several cancer cell lines, including WEHI
164 (murine fibrosarcoma) and P388 (murine leukemia).2a
With a view to exploring further structure-activity relationship
studies on (þ)-hexachlorosulfolipid 1, we initiated a research
program aimed at establishing stereoselective access to natural
lipid 1 and its stereoisomers.8 In the present paper, we describe
the asymmetric total synthesis of (þ)-hexachlorosulfolipid 1
featuring the epoxide-chloride displacement strategy, which
allowed us to confirm the absolute configuration of lipid (þ)-1.
Results and Discussion
1. Key Transformations Leading to (þ)-Hexachlorosulfo-
lipid 1. Our approach to (þ)-hexachlorosulfolipid 1 is retro-
synthetically outlined in Scheme 1 and features the use of
Ph3P/NCS-mediated stereospecific dichlorinations of epoxi-
des (Scheme 1).8 In our approach, lipid (þ)-1 was traced
back to the (E)-alkenyl chloro triad 5 that would serve as a
suitable scaffold for alkene dichlorination and would be
readily derived from the simple allylic hydroxylation of
trichloride 6 followed by chain elongation. Prior to initiating
our investigations, however, we had little appreciation of
whether the dichlorination of an allylic double bond, which is
generally directed by the conformational strain (A1,3) of the
substrate,9 would provide the requisite configuration for
natural product 1: this is because the empirical rule might
favor the opposite stereochemistry over that of our target,10
and furthermore, in many cases, the degree of asymmetric
induction for the (E)-allylic substrate is unpredictable and
frequently low.9 Nevertheless, it was our belief that the
(9) For a pertinent review on the chemistry of allylic 1,3-strain, see:
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
(10) Chamberlin and co-workers (ref 10a) have reported that 2-iodo-1,3-
anti-diols are stereo- and regioselectively produced from 1,2-disubstituted
allylic alcohols via an intermediacy of cyclic iodonium ions generated
preferentially syn to the allylic hydroxyl group in the 1,3-allylic strain model,
followed by their nucleophilic hydration at the sterically more accessible
position. This observation suggested that dichlorination of our allylic alcohol
substrate 5 would favor the production of undesired (2S,3R)-pentachloride
21. (a) Chamberlin, A. R.; Mulholland, R. L., Jr. Tetrahedron 1984, 40,
2297–2302. (b) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C.
J. Am. Chem. Soc. 1983, 105, 5819–5825. Other related studies on the
diastereoselective halogenation of allylic alcohols, for instance: (c) Midland,
M. M.; Halterman, R. L. J. Org. Chem. 1981, 46, 1227–1229. (d) Liotta, D.;
Zima, G.; Saindane, M. J. Org. Chem. 1982, 47, 1258–1267. (e) Bartlett, P. A.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press, Inc.: New
York, 1984; Vol. 3, pp 411-454. (f) Kim, K. S.; Park, H. B.; Kim, J. Y.; Ahn,
Y. H.; Jeong, I. H. Tetrahedron Lett. 1996, 37, 1249–1252.
(6) Bedke, D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Haines,
T. H.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 7570–7572.
(7) Kawahara, T.; Kumaki, Y.; Kamada, T.; Ishii, T.; Okino, T. J. Org.
Chem. 2009, 74, 6016–6024.
(8) Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74,
696–702.
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SCHEME 1. Retrosynthesis of (þ)-Hexachlorosulfolipid 1
stereochemistry would be changeable and tunable to some
extent by modifying either the structural features of the
substrate or the reaction conditions. The present study
demonstrates that our prospect was indeed the case and that
the free hydroxyl group significantly altered the stereochem-
ical outcome of the alkene dichlorination, leading to the
desired polychloro motif. Then, we expected that trichloride
6 would be synthesized from simple starting material 9 by
epoxide-chloride displacement: the two chlorine atoms at
the C6/C7 positions (sulfolipid numbering) of target (þ)-1
would be readily installed by the dichlorination of enantio-
merically pure epoxide 9 with the Ph3P/NCS reagent system
to deliver dichloro alcohol 8. This compound 8, in turn,
would be transformed, upon oxidation followed by stereo-
selective allylation, into alcohol 7 that would serve as a
suitable precursor of trichloride 6. As described in detail in
the following section, initial attempts to simply chlorinate
the hydroxyl group of 7 were unsuccessful. However, the
Ph3P/NCS-mediated dichlorination of an epoxide derived
from 7 provided an efficient access to the chlorinated motif,
again showing the power of the epoxide-chloride displace-
ment strategy for the stereoselective construction of poly-
chlorinated scaffolds.
2. Synthesis of Alcohol 5 and Trichloroacetate 14. The
starting enantiomerically pure epoxide 9 (>98% ee) was
prepared from 10-tert-butyldiphenylsilyloxydec-2-en-1-ol11
via a two-step sequence comprising Sharpless asymmetric
epoxidation12 followed by protection of the hydroxyl group
as pivalic ester (Scheme 2). Installation of the vicinal dichloro
functionality into epoxide 9 was successfully achieved using
NCS/Ph3P in toluene at 90 °C to afford dichloride 11 in 85%
yield as a single isomer.13 Removal of the pivalic group of 11
with DIBAL efficiently took place, and the resultant alcohol 8
was then oxidized with Dess-Martin periodinane under
buffered conditions to deliver dichloroaldehyde i (shown in
brackets). As we had anticipated, this aldehyde i was easily
decomposed upon thin-layer silica gel chromatography,
showing its propensity for β-elimination of the chlorine atom.
Therefore, the crude aldehyde i was immediately reacted with
allyltrimethylsilane in the presence of BF3 OEt2 to afford
3
(11) Allylic alcohol 10 was prepared by a four-step protocol similar to the
known method; see: Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang,
Z. Org. Lett. 2006, 8, 1193–1196.
anti-chlorohydrin 7 along with the syn-diastereomer in an
anti/syn ratio of ds =3.8:1 (72% in two steps from 8).14 The
anti selectivity observed in the present case can be rationalized
(12) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. For reviews, see: (a) Finn, M. G.; Sharpless, K. B. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1985; Vol. 5, p
247-308. (b) Rossiter, B. E. Chem. Ind. 1985, 22, 295–308. (c) Pfenninger, A.
Synthesis 1986, 89–116. (d) Johnson, R. A.; Sharpless, K. B. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 7, pp 389-436. (e) Hoeft, E. Top. Curr. Chem. 1993, 164, 63–77. (f)
Schinzer, D. In Organic Synthesis Highlights II; Herbert, W., Ed.; VCH:
Weinheim, 1995; pp 3-8. (g) Katsuki, T.; Victor, M. Org. React. 1996, 48,
1–299. (h) Stephenson, G. R. Adv. Asymmetric Synth. 1996, 367–391. (i) Shum,
W. P.; Cannarsa, M. J. Chirality Ind. II 1997, 363–380. (j) Katsuki, T. Transition
Met. Org. Synth. 1998, 2, 261–271. (k) Kagan, H. B. Compr. Asymmetric Catal.
I-III 1999, 1, 9–30. (l) Katsuki, T. Compr. Asymmetric Catal. I-III 1999, 2,
621–648. (m) Mahrwald, R. J. Prakt. Chem. 1999, 341, 191–194. (n) Johnson,
R. A.; Sharpless, K. B. Catal. Asymmetric Synth. (2nd Ed.) 2000, 231–280.
(o) Liu, M. Rodd’s Chem. Carbon Compd. (2nd Ed.) 2001, 5, 1–32. (p) Martin,
V. S. Asymmetric Oxid. React. 2001, 50–69. (q) Bonini, C.; Righi, G. A.
Tetrahedron 2002, 58, 4981–5021. (r) Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2024–2032.
(13) The stereochemistry of dichloride 11 was established by its transfor-
mation into (E)-olefin by means of the known reductive olefination protocol.
Sonnet, P. E.; Oliver, J. E. J. Org. Chem. 1976, 41, 3284–3286. For details, see
the Supporting Information.
(14) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 16, 1295. Selected
reviews for Hosomi-Sakurai reactions: (a) Biamonte, M. A. In Name Reac-
tions for Homologations; Li, J. J., Ed.; John Wiley & Sons: Hoboken, NJ, 2009;
Part 1, pp 539-575. (b) Hosomi, A.; Miura, K. In Acid Catalysis in Modern
Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinhem, 2008; Vol. 1, pp 469-516. (c) Hosomi, A.; Miura, K.
Bull. Chem. Soc. Jpn. 2004, 77, 835–851. (d) Fleming, I. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; vol. 6, pp 563-593. (e) Fleming, I.; Dunogues, J.; Smithers, R. Org. React.
1989, 37, 57. (f) Hosomi, A. Acc. Chem. Res. 1988, 21, 200–206. (g) Schinzer, D.
Synthesis 1988, 263–273. (h) Sakurai, H. Pure Appl. Chem. 1982, 54, 1–22.
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SCHEME 2. Preparation of Alcohol 5 and Trichloroacetate 14
by considering either the Cornforth or the polar Felkin-Anh
transition-state model that preferentially undergoes allylation
reaction with allyltrimethylsilane to provide anti-alcohol 7
(Figure 2).15
The next process necessary for producing the chlorinated
skeleton was to displace the hydroxyl group of dichloro
alcohol 7 with a chloride ion at the position R to the bulky
vicinal dichloro motif. Contrary to our expectation, this
seemingly simple chlorination was difficult, and all our
efforts to deliver this all-syn chloro triad 6 were unfruitful
FIGURE 2. Rationale for anti selectivity of allylation of dichloro-
aldehyde i.
(15) For a theoretical investigation of the nucleophilic addition to R-
chloroaldehydes, see: Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem.
Soc. 2006, 128, 2920–2930. For a recent example, see: Kang, B.; Britton, R.
Org. Lett. 2007, 9, 5083–5086. and references cited therein.
due to the concomitant occurrence of elimination reactions.
Hexachloroacetone/Ph3P was among the most effective, but
the yield of trichloride 6 was still only 27%. The disappointing
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SCHEME 3. Determination of Stereochemistry of Trichloride 6
results prompted us to devise an alternative pathway to
produce chloro triad 6, and again, the epoxide-dichlorina-
tion method was found to be suitable for this process. Thus,
dichloro alcohol 7 was first transformed into trans-epoxide 12
by treatment with NaH,16 which, in turn, was subjected
to dichlorination under Ph3P/NCS conditions17,18 to fur-
nish trichloride 6 in 70% yield. This two-step protocol (7 f
12 f 6) could deliver triad 6 in a satisfactory overall yield,
indicating that the epoxide-dichlorination method serves
as a powerful means for the stereoselective construction
of polychloro motifs. The all-syn configuration of triad 6
was unambiguously confirmed by its transformation into
achiral meso-symmetrical trichloride 16 (Scheme 3). Thus,
trichloride 6 was initially subjected to a cross-olefin meta-
thesis with TBDPS-protected alkene 1519 in the presence
of Grubbs’ second-generation catalyst, giving rise to an
olefin (structure not indicated) in 58% yield. Hydrogena-
tion of the olefin under PtO2 conditions afforded symme-
trical meso-trichloride 16 in 91% yield, thereby unambiguously
establishing the all-syn arrangement of the chlorine atoms
embedded in trichloride 6.
eoselectivity (ca. 13a/13b = 3:5), each isomer was separable
by simple silica gel column chromatography, and further-
more, R-alcohol 13b could be isomerized to β-alcohol 13a.21
Thus, Dess-Martin oxidation of R-alcohol 13b was followed
by the reduction of the resultant ketone with NaBH4 in the
presence of CeCl3 7H2O to yield β-alcohol 13a in 81%
3
overall yield. Alcohol 13a was then assembled with 2-butene
in the presence of Grubbs’ second-generation catalyst to
efficiently deliver (E)-alkene 5 (E/Z = ca. 17:1) that bears an
internal unsaturated three-carbon unit suitable for the pro-
duction of a chloro pentad motif.
3. Synthesis of Chloro Pentad by Diastereoselective Di-
chlorination of Alkenes. As we approached even closer to the
target polychlorinated scaffold, the next task was to install
two more vicinal chlorine atoms at the 2/3 positions of allylic
alcohol 5, which allowed us to access pentad 20 that corre-
sponds to the C1-C14 portion of (þ)-hexachlorosulfolipid 1
(Table 1). As we mentioned earlier in this paper, it has
been well delineated that an asymmetric induction adjacent
to allylic substituents is predictable on the basis of allylic
strain (A1,3), particularly when the substrates possess a
substituent on the double bond Z to the allylic center.9
This is exactly exemplified by Vanderwal’s work in which
(Z)-allylic trichloroacetates exert high levels of diastereo-
selectivity in alkene dichlorination.4a Vanderwal’s work has
also revealed that the degree of selectivity depends on the
allylic hydroxyl protecting group. Accordingly, it was rea-
sonably assumed that, by considering such conformational
strain, dichlorination of the alkene in the present case would
favor the undesired configuration rather than the desired one
corresponding to that of the natural product.10 However, we
expected that (E)-allylic substrates would possibly undergo
dichlorination to provide pentachloride with the desired
configuration since our (E)-allylic substrates might be less
sensitive to the allylic strain. In addition to this prospect, we
also envisioned that the alteration of the hydroxyl protect-
ing group would significantly change the facial selectivity
in the initial chloronium formation as shown in Vaderwal’s
work, hopefully furnishing the natural configuration.
In this context, Vanderwal’s work has suggested that the
dichlorination of substrates with a free hydroxyl group
proceeds less selectively than that of protected variants4a
and shows a slight preference for chloronium formation that
occurs from anti to the hydroxyl group, which would
lead to the stereochemistry relevant to our target natural
product (þ)-1.
The stereoselective introduction of the allylic hydroxyl
group to compound 6 was achieved by selenium oxidation.
Numerous attempts to effect this transformation eventually
led to the discovery that the use of excess selenium dioxide
and tert-butyl hydroperoxide (TBHP) in the presence of
catalytic salicylic acid20 provided the highest product yield.
In this allylic oxidation, although the formation of unwanted
R-alcohol 13b was more pronounced with moderate diaster-
(16) The relative stereochemistry of epoxide 12 was unambiguously
determined by analyzing both NOEs and the coupling constants between
the protons Ha and Hb (J = 1.8 Hz) in the 1H NMR spectra.
(17) The dichlorination of epoxide 12 with Ph3P/hexachloroacetone
similarly gave desired trichloride 6 in 74% yield. However, partly because
side reactions occurred under this condition, the yields varied when the
reactions were performed on a large scale.
(18) In this case, dichloroethane was used as solvent because of the higher
solubility of the reagents and substrate. Dichlorination of epoxide 12 in
toluene, however, afforded trichloride 6 in a comparable yield (68%) to that
in dichloroethane.
(19) This material was readily prepared by silylating 5-hexen-1-ol with
TBDPSCl in the presence of imidazole in DMF (95% yield).
(20) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon,
Y. T. J. Am. Chem. Soc. 2002, 124, 9726–9728.
(21) The stereochemistry of β-alcohol 13a and R-alcohol 13b was deter-
mined by their transformation into the corresponding cis- and trans-epoxi-
des, respectively. For details, see the Supporting Information.
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TABLE 1. Dichlorination of Trichloroacetate 14 and Alcohol 5 under Marko’s Conditions
a
ꢀ
aThe reaction was performed with KMnO4 (1.2 equiv), BnEt3NCl (1.2 equiv), and TMSCl (7.4 equiv for trichloroacetate 14; 5.2 equiv for alcohol 5) in
CH2Cl2 at -78 to -10 °C. bThe stereochemistry of dichlorinated C2/C3 positions of chlorides 17, 18, and 20-22 was determined by chemical
correlations including epoxide formation. For details, see the Supporting Information. The rest of the materials were unidentified products whose
c
structures were difficult to elucidate. dThe yield of the material was determined after removal of the trichloroacetyl group.
ꢀ
The reagent that we chose for the dichlorination process
Marko’s conditions. The reaction of trichloroacetate 14
prepared by the reported procedure4a took place by gradu-
ally warming from -78 to -10 °C to provide a mixture of
(2R,3S)-pentachloride 17 (9%) and (2S,3R)-pentachloride
18 (45%) along with tetrachloride 19 (14%).23 The observed
stereochemical preference is in line with the prediction
ꢀ
was the Marko-Maguire (KMnO4/BnEt3NCl/TMSCl)
chlorination system (Table 1).22 Considering Vanderwal’s
observation that trichloroacetates are superior to other
allylic congeners in terms of yield and selectivity, we initially
examined the dichlorination of trichloroacetate 14 under
stemming from the consideration of the allylic strain (A1,3
)
of substrate 14 and suggests that chloronium formation
preferentially occurred syn to the trichloroacetyl substituent
that avoids steric repulsion caused by the bulky chlorinated
backbone, followed by attacking of a chloride ion at the
sterically more accessible 2 position (Scheme 4). Conforma-
tional analysis on a chlorinated hydrocarbon model that
possesses a shorter backbone with the requisite stereochem-
istry using Gaussian 03 program [B3LYP/6-31G(d)]24 sug-
gested that the most energetically favorable conformer of
trichloroacetate was in good agreement with the allylic strain
model as proposed.
ꢀ
(22) It has been proposed that both Marko-Maguire (KMnO4/
BnEt3NCl/TMSCl) and Mioskowski (Et4NCl3) reagents involve similar
reactive chlorinating species as exemplified by R4NCl3. In fact, Vanderwal’s
work has demonstrated that both Marko-Maguire (KMnO4/BnEt3NCl/
TMSCl) and Mioskowski (Et4NCl3) dichlorination protocols have nearly
identical levels of efficiency and selectivity. However, we assume that there
may be some differences in the Lewis acidities of the two reagent systems,
which possibly arise from the chemical species generated in the reaction
ꢀ
ꢀ
mixtures. (a) Marko, I. E.; Richardson, P. R.; Bailey, M.; Maguire, A. R.;
Coughlan, N. Tetrahedron Lett. 1997, 38, 2339–2342. (b) Schlama, T.;
Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew. Chem., Int. Ed. Engl.
1997, 36, 2342–2344.
(23) Compound 19 was possibly produced by the neighboring participa-
tion of the trichloroacetyl group followed by the elimination. Its stereochem-
istry at the 3 position has, however, yet to be determined.
We then expected that the free hydroxyl group of the
allylic substrate would considerably change the stereochem-
ical course of the dichlorination. Therefore, we evaluated
alcohol 5 as the substrate with a view to giving rise to the
desired pentachloro motif. Gratifyingly, the dichlorination
occurred under the same conditions to yield desired (2R,3S)-
pentachloride 20 (38%) as the major product together with
(2S,3R)-pentachloride 21 (10%) as well as (2S,3S)-penta-
chloride 22 (26%). Although further studies are necessary
for elucidating the origin of this moderate yet obvious
change in diastereoselectivity, it can be assumed that the
lack of streic demands of the protection-free (E)-allylic
alcohol system allows the greater conformational flexibility,
leading to the opposite facial selectivity. In this context, the
conformational analysis of the simple model of alcohol 5
(24) Conformational analysis on simple hydrocarbon models having a
shorter backbone was carried out using the Gaussian 03 program [B3LYP/
6-31G(d)]. For experimental details, see the Supporting Information. Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada.;
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision E.01; Gaussian,
Inc.: Wallingford, CT, 2004.
5430 J. Org. Chem. Vol. 75, No. 16, 2010

Yoshimitsu et al.
JOCFeatured Article
SCHEME 4. Rationale for the Stereochemical Outcome of Dichlorination of Trichloroacetate 14 Based on the Calculated Models
suggested that there was essentially no difference in energies
between the two favorable conformers a and b (∼ca. 0.5 kcal/
mol) (Figure 3).25 The dichlorination reaction of conformer
b was reasonably assumed to take place via an R-configura-
tional cyclic chloronium intermediate that avoids the severe
steric interaction with the bulky polychlorinated backbone,
giving rise to (2R,3S)-pentachloride 20 as a major product,
whereas it is difficult to rationalize preferential production
of (2R,3S)-20 from conformer a (Scheme 5).26 The produc-
tion of (2S,3S)-syn-pentachloride 22 may also indicate an
FIGURE 3. Energetically favorable conformers of model com-
pound of alcohol 5.
intermediacy of the R-configurational chloronium species
that possibly underwent the double inversion at the 2 or 3
position through anchimeric assistance of the distal chlorine
atom.5
HF-pyridine to provide primary alcohol 24 in 94% yield.
Dess-Martin oxidation of primary alcohol 24 afforded
aldehyde 25 (98%), which was subjected to CrCl2-mediated
chloroalkenylation27 to deliver alkenyl chloride 26 in 75%
yield. Deacetylation of alkenyl chloride 26 was successfully
carried out by DIBAL-mediated reduction to provide alco-
hol 27 in 96% yield. The final task necessary to yield target
molecule (þ)-1 was the sulfation of the hydroxyl group of
alcohol 27, which was successfully accomplished by conven-
4. Completion of the Asymmetric Total Synthesis of (þ)-
Hexachlorosulfolipid 1. To complete the total synthesis
of (þ)-hexachlorosulfolipid 1, pentachloride 20 possessing
requisite functionalities with the correct stereochemistry was
initially converted into acetate 23 quantitatively (Scheme 6).
The TBDPS group of pentachloride 23 was then removed by
(25) We currently assume that the low energy gap observed between the
two conformers a and b may arise from the relative instability of conformer a
that suffers from steric interaction between the hydrogen atom at C3 position
and the chlorine atom at C5. The interaction increases the relative energy of
conformer a, leading to the proximity in the conformational energy gap of the
two possible conformers.
(26) In this case, however, the observed stereochemical outcome may
possibly indicate an intermediacy of the coordination of a Lewis acidic
reagent to the hydroxyl group, such as the trimethylsilylated manganese
complex,22 which prevents substrate 5 from forming a β-chloronium inter-
mediate as in the case of substrate 14, eventually leading to (2R,3S)-
pentachloride 20 as the major product. We are currently making further
efforts to elucidate the origin of this stereochemical preference.
tional protocol using SO3 Py in DMF at room tempera-
3
ture to furnish (þ)-hexachlorosulfolipid 1 in 75% yield. The
spectroscopic and analytical data were in good agreement
with those reported in the literature.2a,5 The optical rota-
tion of our synthetic material 1 was [R]24 þ49 (c 0.59,
D
MeOH) [lit.2a [R]25 þ20.4 (c 0.0015, MeOH)], indicating
D
that the absolute configuration of natural sulfolipid was as
proposed by Ciminiello and Fattorusso.
Conclusions
We have accomplished the asymmetric total synthesis of
cytotoxic (þ)-hexachlorosulfolipid 1 isolated from the Adria-
tic mussel Mytilus galloprovincialis and successfully confirmed
the absolute stereochemistry as proposed by Fattorusso,
Ciminiello, and co-workers. In the present study, we estab-
lished a general method for the preparation of a polychloro
array, a structural feature commonly found in many classes of
natural chlorosulfolipids, and used it to synthesize (þ)-hexa-
chlorosulfolipid 1, one of the typical members of the family.
We are currently undertaking avid research to establish a
polychlorinated sulfolipid library that will open up further
structure-activity relationship studies on this class of natural
compounds.
(27) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–
7410. Also see ref 5a.
J. Org. Chem. Vol. 75, No. 16, 2010 5431

Yoshimitsu et al.
SCHEME 5. Rationale for the Opposite Stereoselection Observed in Dichlorination of Alcohol 5 Based on the Calculated Models
JOCFeatured Article
SCHEME 6. Completion of Asymmetric Total Synthesis of (þ)-Hexachlorosulfolipid 1
Experimental Section
addition of 10% NaOH and brine, the stirred mixture was
allowed to warm to room temperature. After 1 h, Celite and
MgSO4 were added, and stirring was continued for 15 min. The
mixture was filtered through a Celite pad, and the filtrate was
concentrated by rotary evaporation. The residue was purified by
silica gel column chromatography (EtOAc/n-hexane 1:3) to give
epoxide 10 (3.52 g, 96%) as a colorless oil. The enantiomeric
purity of this material was determined by the Mosher method to
[(2S,3S)-3-[7-[(tert-Butyldiphenylsilyl)oxy]heptyl]oxiran-2-yl]-
methanol (10). To a magnetically stirred suspension of 4A MS
(1.3 g) in CH2Cl2 (65 mL) at -25 °C were added L-diethyl tartrate
(0.12 mL, 0.70 mmol) and Ti(O-i-Pr)4 (0.13 mL, 0.44 mmol).
After 15 min, TBHP (5.5 M in decane, 3.1 mL, 17.1 mmol) was
added, and stirring was continued for an additional 1 h. To the
mixture was added a solution of (E)-10-[(tert-butyldiphenylsilyl)-
oxy]dec-2-en-1-ol (3.52 g, 8.59 mmol) in CH2Cl2 (15 mL), and
the mixture was stirred at -25 °C for further 10 h. Following
be >98% ee. Epoxide 10: colorless oil; [R]25 -13.4 (c 1.03,
D
CHCl3); IR (neat) ν 3420, 2930, 2857, 1427, 1111, 702 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.72-7.63 (m, 4H), 7.46-7.33 (m,
5432 J. Org. Chem. Vol. 75, No. 16, 2010

Yoshimitsu et al.
JOCFeatured Article
6H), 3.91 (ddd, 1H, J = 12.7, 5.5, 2.4 Hz), 3.65 (t, 2H, J = 6.6
Hz), 3.66-3.55 (m, 1H), 2.99-2.88 (m, 2H), 1.99 (t, 1H, J = 6.3
Hz), 1.61-1.51 (m, 4H), 1.47-1.26 (m, 8H), 1.05 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 135.5, 134.1, 129.4, 127.5, 63.9, 61.7,
58.4, 55.9, 32.5, 31.5, 29.3, 29.2, 26.8, 25.8, 25.6, 19.2; MS m/z
427 (MHþ), 199 (100); HRMS (FAB) calcd for C26H39O3Si
(MHþ) 427.2668, found 427.2644.
30 min and then filtered through a Celite pad. The filtrate was
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/n-hexane 1:8) to
give alcohol 8 (3.13 g, 95%) as a colorless oil. Alcohol 8: colorless
oil; [R]25D þ13.9 (c 0.27, CHCl3); IR (neat) ν 3383, 2932, 2857,
1427, 1111, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.73-7.63
(m, 4H), 7.47-7.33 (m, 6H), 4.28-4.13 (m, 2H), 3.96 (dd, 1H,
J = 11.7, 5.7 Hz), 3.88 (dd, 1H, J = 11.7, 7.0 Hz), 3.66 (t, 2H,
J = 6.4 Hz), 1.92-1.82 (m, 2H), 1.65-1.47 (m, 2H), 1.43-1.23
(m, 8H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.5,
134.1, 129.5, 127.5, 65.4, 64.5, 63.9, 62.0, 35.2, 32.4, 29.1, 28.9,
26.8, 26.5, 25.6, 19.2; MS m/z 481 (MHþ), 135 (100); HRMS
(FAB) calcd for C26H39O235Cl2Si (MHþ) 481.2096, found
481.2074.
(4R,5R,6R)-13-[(tert-Butyldiphenylsilyl)oxy]-5,6-dichlorotri-
dec-1-en-4-ol (7) and (4S,5R,6R)-13-[(tert-Butyldiphenylsilyl)-
oxy]-5,6-dichlorotridec-1-en-4-ol (syn-7). To a stirred solution of
alcohol 8 (5.13 g, 10.7 mmol) in CH2Cl2 (100 mL) were added
NaHCO3 (8.96 g, 106.7 mmol) and Dess-Martin periodinane
(6.71 g, 15.8 mmol) at room temperature. The mixture was
stirred for 20 min and then treated with satd NaHCO3 and
satd Na2S2O3. The mixture was poured into a separatory funnel
where it was extracted with Et2O. The organic phase was
separated, dried over MgSO4, filtered, and concentrated. The
residue was dissolved in CH2Cl2 (100 mL) and was subjected
to the next allylation reaction without further purification. To
thissolutionwereaddedallyltrimethylsilane (2.2mL, 13.8 mmol)
[(2S,3S)-3-[7-[(tert-Butyldiphenylsilyl)oxy]heptyl]oxiran-2-yl]-
methyl 2,2-dimethylpropanoate (9). To a stirred solution of epo-
xide 10 (3.58 g, 8.39 mmol) in CH2Cl2 (40 mL) at room tempera-
ture were added Et3N (1.8 mL, 12.9 mmol) and pivaloyl chloride
(1.4 mL, 11.1 mmol). After 2.5 h, DMAP (90 mg, 0.74 mmol) was
added, and stirring was continued for an additional 0.5 h.
Following addition of satd NaHCO3, the mixture was poured
into a separatory funnel and extracted with EtOAc. The organic
phase was separated, dried over MgSO4, filtered, and concen-
trated. Purification of the residue by silica gel column chroma-
tography (EtOAc/n-hexane 1:20) gave epoxide 9 (4.24 g, 99%) as
a colorless oil. Epoxide 9: colorless oil; [R]25 -14.8 (c 1.12,
D
CHCl3); IR (neat) ν 2957, 2932, 2857, 1732, 1153, 1111, 702
cm-1 1H NMR (300 MHz, CDCl3) δ 7.72-7.64 (m, 4H),
;
7.44-7.34 (m, 6H), 4.34 (dd, 1H, J = 12.2, 3.4 Hz), 3.93 (dd,
1H, J = 12.2, 6.0 Hz), 3.65 (t, 2H, J = 6.4 Hz), 2.96 (ddd, 1H,
J = 6.0, 3.4, 2.3 Hz), 2.84 (ddd, 1H, J = 5.5, 5.5, 2.3 Hz),
1.61-1.50 (m, 4H), 1.38-1.18 (m, 17H), 1.05 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 178.2, 135.5, 134.1, 129.4, 127.5, 64.6, 63.8,
56.4, 55.4, 38.8, 32.5, 31.5, 29.2, 27.1, 26.8, 26.5, 25.8, 25.6, 19.2;
MS m/z 511 (MHþ), 57 (100); HRMS (FAB) calcd for
C31H47O4Si (MHþ) 511.3244, found 511.3231.
and BF3 OEt2 (1.6 mL, 13.8 mmol) at -78 °C, and the mixture
was stirred for 30 min. Following addition of additional amo-
unts of allyltrimethylsilane (0.8 mL, 5.0 mmol) and BF3 OEt2
3
(2R,3R)-10-[(tert-Butyldiphenylsilyl)oxy]-2,3-dichlorodecyl 2,2-
dimethylpropanoate(11). To a stirredsolution ofepoxide 9 (4.14 g,
8.11 mmol) in toluene (80 mL) at room temperature were added
Ph3P (6.38 g, 24.3 mmol) and NCS (3.25 g, 24.3 mmol), and
the mixture was heated at 90 °C for 4.3 h. Additional amounts
of Ph3P (1.10 g, 4.05 mmol) and NCS (0.54 g, 4.06 mmol)
were added, and stirring was continued for a further 1 h. The
mixture was quenched with satd NaHCO3, poured into a separa-
tory funnel, and extracted with EtOAc. The organic phase was
separated, dried over MgSO4, filtered, and concentrated. The
following procedure was applied to ensure the removal of insepar-
able olefin byproducts: The residue obtained by the above-men-
tioned protocol was again dissolved in CH2Cl2 (40 mL), and solid
NaHCO3 was added to the solution. An outlet stream containing
O3 and O2 from an ozonizer was introduced into the mixture
at -78 °C for 30 min to oxidize chloroalkene that was produced
as a byproduct in the above-mentioned process. After being
quenched with Me2S, the mixture was allowed to warm to room
temperature and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(EtOAc/n-hexane 1:30) to give dichloride 11 (3.91 g, 85%)
3
(0.4 mL, 3.5 mmol) at the same temperature, the mixture was
stirred for 15 min and then allowed to warm to 0 °C. After 15 min
of stirring, the reaction was quenched with water. The mitxture
was poured into a separatory funnel where it was partitioned
between satd NaHCO3 and EtOAc. The organic phase was
separated, dried over MgSO4, filtered, and concentrated. TLC
analysis of the residue indicated that a trace of R,β-unsaturated
aldehyde was produced by β-elimination of dichloroaldehyde i.
Therefore, the crude residue was immediately dissolved in
MeOH-CH2Cl2 (5:3 v/v, 80 mL) without further purification
and was subjected to reduction with NaBH4 (100 mg, 2.64 mmol)
at 0 °C. After being stirred for 10 min, the solution was con-
centrated under reduced pressure. The residue was poured into
a separatory funnel where it was partitioned between satd
NH4Cl and EtOAc. The organic phase was separated, dried over
MgSO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (CH2Cl2/n-hexane 1:2) to give
less polar anti-alcohol 7 (3.18 g, 57%) as a colorless oil and more
polar syn-alcohol syn-7 (0.82 g, 15%) as a colorless oil. anti-Alcohol
7: colorless oil; [R]26 þ10.0 (c 0.51, CHCl3); IR (neat) ν 3447,
D
as a colorless oil. Dichloride 11: colorless oil; [R]25 þ18.3
2932, 2857, 1427, 1111, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.72-7.65 (m, 4H), 7.47-7.35 (m, 6H), 5.96-5.79 (m, 1H),
5.31-5.19 (m, 2H), 4.54 (ddd, 1H, J = 9.0, 5.3, 1.8 Hz),
4.02-3.91 (m, 1H), 3.79 (dd, 1H, J = 9.2, 1.7 Hz), 3.66 (t, 2H,
J = 6.5 Hz), 2.82-2.70 (m, 1H), 2.38-2.24 (m, 1H), 2.13 (d, 1H,
J= 4.9 Hz), 2.05-1.90 (m, 1H), 1.85-1.70 (m, 1H), 1.64-1.48 (m,
3H), 1.44-1.24 (m, 7H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 135.5, 134.1, 133.3, 129.5, 127.5, 119.7, 71.2, 66.5, 63.9, 61.9, 38.4,
36.3, 32.5, 29.1, 29.0, 26.8, 26.4, 25.6, 19.2; MS m/z 543 (MNaþ),
135 (100); HRMS (FAB) calcd for C29H42O235Cl2SiNa (MNaþ)
543.2229, found 543.2221. syn-7: colorless oil; [R]24D þ13.8 (c 1.02,
CHCl3); IR (neat) ν 3447, 2932, 2857, 1427, 1111, 702 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.46-7.34 (m,
6H), 5.94-5.77 (m, 1H), 5.24-5.13 (m, 2H), 4.14 (ddd, 1H, J =
8.1, 5.4, 3.3 Hz), 4.09-4.00 (m, 2H), 3.65 (t, 2H, J = 6.5 Hz),
2.55-2.42 (m, 1H), 2.42-2.28 (m, 1H), 2.22 (d, 1H, J = 2.9 Hz),
1.97-1.77 (m, 2H), 1.61-1.47 (m, 4H), 1.40-1.24 (m, 6H), 1.05
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.5, 134.1, 133.1, 129.5,
D
(c 0.67, CHCl3); IR (neat) ν 2932, 2859, 1738, 1148, 1111, 702
cm-1 1H NMR (300 MHz, CDCl3) δ 7.72-7.65 (m, 4H),
;
7.46-7.35 (m, 6H), 4.41-4.35 (m, 2H), 4.27 (ddd, 1H, J = 7.2,
6.0, 2.4 Hz), 4.18-4.10 (m, 1H), 3.66 (t, 2H, J = 6.4 Hz),
1.93-1.82 (m, 2H), 1.61-1.51 (m, 3H), 1.42-1.21 (m, 16H),
1.06 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 177.8, 135.5, 134.1,
129.5, 127.5, 64.9, 63.8, 61.8, 60.9, 38.8, 35.0, 32.4, 29.1, 28.8, 27.1,
26.8, 26.5, 25.6, 19.2; MS m/z 565 (MHþ), 57 (100); HRMS
(FAB) calcd for C31H47O335Cl2Si (MHþ) 565.2672, found
565.2662.
(2R,3R)-10-[(tert-Butyldiphenylsilyl)oxy]-2,3-dichlorodecan-1-
ol (8). To a stirred solution of dichloride 11 (3.87 g, 6.86 mmol)
in CH2Cl2 (54 mL) at -78 °C was added DIBAL (0.98 M in
n-hexane, 15.4 mL, 15.1 mmol), and the mixture was stirred
for 20 min. Following addition of satd NH4Cl, the whole mix-
ture was stirred at room temperature for 30 min. Celite was
added to the solution, and the mixture was stirred for further
J. Org. Chem. Vol. 75, No. 16, 2010 5433

Yoshimitsu et al.
JOCFeatured Article
127.5, 118.7, 71.3, 69.9, 63.9, 63.1, 38.4, 35.5, 32.5, 29.1, 28.9,
26.8, 26.3, 25.6, 19.2; MS m/z 543 (MNaþ), 135 (100); HRMS
(FAB) calcd for C29H42O235Cl2SiNa (MNaþ) 543.2229, found
543.2229.
1H, J = 4.8 Hz), 3.65 (t, 4H, J = 6.6 Hz), 1.98-1.74 (m, 4H),
1.63-1.49 (m, 4H), 1.39-1.22 (m, 16H), 1.04 (s, 18H); 13C
NMR (75 MHz, CDCl3) δ 135.6, 134.1, 129.5, 127.6, 69.1,
63.9, 63.7, 35.3, 32.5, 29.1, 28.9, 26.9, 26.3, 25.6, 19.2; MS m/z
853 (MHþ), 154 (100); HRMS (FAB) calcd for C49H70O235Cl3-
Si2 (MHþ) 853.3980, found 853.3972.
tert-Butyl[[(8R)-8-chloro-8-[(2S,3R)-3-(prop-2-en-1-yl)oxiran-
2-yl]octyl]oxy]diphenylsilane (12). To a solution of alcohol 7
(3.04 g, 5.84 mmol) in THF (58 mL) at 0 °C was added NaH
(60% in oil, 467 mg, 11.7 mmol). The mixture was stirred at room
temperature for 12.3 h. The mixture was poured into a separatory
funnel where it was partitioned between satd NH4Cl and Et2O.
The organic phase was separated, dried over MgSO4, filtered,
and concentrated. The residue was purified by silica gel column
chromatography (Et2O/n-hexane 1:30) to give epoxide 12 (2.74 g,
(3R,4S,5S,6R)-13-[(tert-Butyldiphenylsilyl)oxy]-4,5,6-trichlo-
rotridec-1-en-3-ol (13a) and (3S,4S,5S,6R)-13-[(tert-Butyldiphenyl-
silyl)oxy]-4,5,6-trichlorotridec-1-en-3-ol (13b). To a stirred solu-
tion of trichloride 6 (459 mg, 0.85 mmol) in dichloroethane
(14 mL) at room temperature were added SeO2 (379 mg, 3.42
mmol), TBHP (5.5 M TBHP in decane, 0.9 mL, 4.95 mmol), and
salicylic acid (46 mg, 0.33 mmol). The mixture was heated at
80 °C for 4 h and then cooled to room temperature. The mitxture
was poured into a separatory funnel, washed with satd NaHCO3
and satd Na2S2O3, and extracted with Et2O. The organic phase
was separated, dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography
(CH2Cl2/n-hexane 2:3) to give unreacted trichloride 6 (133 mg,
29%) as a colorless oil and syn-alcohol 13a (89 mg, 19%).
Further elusion with CH2Cl2/n-hexane (1:1 v/v) afforded anti-
alcohol 13b (143 mg, 30%) as a colorless oil. syn-Alcohol 13a:
colorlessoil;[R]22D þ15.3(c 0.49, CHCl3); IR (neat) ν 3414, 2930,
97%) as a colorless oil. Epoxide 12: colorless oil; [R]22 þ5.4
D
(c 0.55, CHCl3); IR (neat) ν 2932, 2857, 1427, 1111, 702 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.71-7.61 (m, 4H), 7.45-7.33 (m,
6H), 5.82(ddt, 1H, J = 17.2, 10.3, 6.6 Hz), 5.20 (dd, 1H, J = 17.2,
1.6 Hz), 5.13 (dd, 1H, J = 10.3, 1.4 Hz), 3.65 (t, 2H, J = 6.3 Hz),
3.46 (ddd, 1H, J = 8.4, 8.0, 4.5 Hz), 2.96 (dt, 1H, J = 5.4, 1.8 Hz),
2.88 (dd, 1H, J = 8.0, 1.8 Hz), 2.44-2.27 (m, 2H), 2.01-1.86 (m,
1H), 1.85-1.70 (m, 1H), 1.61-1.23 (m, 10H), 1.05 (s, 9H); 13
C
NMR (75MHz, CDCl3) δ 135.6, 134.1, 132.5, 129.5, 127.6, 117.9,
63.9, 62.0, 60.3, 57.7, 35.9, 35.5, 32.5, 29.1, 29.0, 26.9, 25.8, 25.6,
19.2; MS m/z 507 (MNaþ), 135 (100); HRMS (FAB) calcd for
C29H41O235ClSiNa (MNaþ) 507.2462, found 507.2480.
1
2857, 1427, 1111, 702 cm-1; H NMR (300 MHz, CDCl3) δ
7.70-7.64 (m, 4H), 7.46-7.34 (m, 6H), 5.91 (ddd, 1H, J = 17.3,
10.6, 5.5 Hz), 5.43 (d, 1H, J = 17.3 Hz), 5.35 (d, 1H, J = 10.6
Hz), 4.62-4.49 (m, 1H), 4.34-4.19 (m, 3H), 3.65 (t, 2H, J = 6.4
Hz), 2.15 (d, 1H, J = 7.9 Hz), 1.96-1.83 (m, 2H), 1.62-1.45 (m,
4H), 1.39-1.22 (m, 6H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 136.3, 135.5, 134.1, 129.5, 127.5, 118.3, 72.3, 69.1,
67.1, 63.8, 62.8, 35.9, 32.4, 29.0, 28.8, 26.8, 26.1, 25.6, 19.2; MS
m/z 579 (MNaþ), 135 (100); HRMS (FAB) calcd for
C29H41O235Cl237ClSiNa (MNaþ) 579.1810, found 579.1799.
tert-Butyldiphenyl[[(8R,9S,10S)-8,9,10-trichlorotridec-12-enyl]-
oxy]silane (6). To a stirred solution of epoxide 12 (1.05 g, 2.17
mmol) in dichloroethane (22 mL) at room temperature were
added Ph3P (1.36 g, 5.20 mmol) and NCS (694 mg, 5.20 mmol),
and the mixture was heated at 90 °C for 1 h. The mixture was
treated with satd NaHCO3, poured into a separatory funnel, and
extracted with CH2Cl2. The organic phase was separated, dried
over MgSO4, filtered, and concentrated. The residue was filtered
through a pad of silica gel (CH2Cl2/n-hexane 1:4), which allowed
the removal oftriphenylphosphineoxide togive amaterial(1.17 g)
comprising trichloride 6 and unidentified olefin as a colorless oil.
Further purification of the mixture using flash silica gel column
chromatography (CH2Cl2/n-hexane 1:40) furnished trichlor-
ide 6 (825 mg, 70%) as a colorless oil. Trichloride 6: colorless oil;
[R]26D þ9.6 (c 1.05, CHCl3); IR (neat) ν 2930, 2857, 1427, 1111,
anti-Alcohol 13b: colorless oil; [R]22 þ4.0 (c 0.79, CHCl3); IR
D
1
(neat) ν 3410, 2930, 2857, 1427, 1111, 702 cm-1; H NMR (300
MHz, CDCl3) δ 7.71-7.63 (m, 4H), 7.45-7.34 (m, 6H), 6.01 (ddd,
1H, J = 17.2, 10.3, 6.4 Hz), 5.45 (d, 1H, J = 17.2 Hz), 5.35 (d, 1H,
J = 10.3 Hz), 4.53 (dd, 1H, J = 6.6, 3.7 Hz), 4.48-4.36 (m, 1H),
4.20-4.07 (m, 2H), 3.65 (t, 2H, J = 6.4 Hz), 2.25 (brs, 1H),
2.01-1.86 (m, 1H), 1.84-1.68 (m, 1H), 1.60-1.21 (m, 10H), 1.05
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.9, 135.5, 134.1, 129.5,
127.5, 119.2, 73.4, 65.5, 64.6, 64.2, 63.8, 34.3, 32.4, 29.0, 28.8,
26.8, 26.1, 25.6, 19.2; MS m/z 579 (MNaþ), 135 (100); HRMS
(FAB) calcdfor C29H41O235Cl237ClSiNa (MNaþ) 579.1810, found
579.1823. The stereochemistry of syn-alcohol 13a and anti-alcohol
13b was determined by their transformation into the corresponding
epoxides (see the Supporting Information).
1
702 cm-1; H NMR (300 MHz, CDCl3) δ 7.72-7.62 (m, 4H),
7.48-7.33 (m, 6H), 5.84 (ddt, 1H, J = 17.1, 10.0, 7.2 Hz), 5.29-
5.17 (m, 2H), 4.30-4.10 (m, 3H), 3.65 (t, 2H, J = 6.5 Hz), 2.82-
2.57(m, 2H), 1.97-1.71 (m, 2H), 1.71-1.20 (m, 10H), 1.05 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 135.5, 134.1, 132.4, 129.5, 127.5,
119.5, 68.1, 63.8, 63.5, 62.0, 39.8, 35.2, 32.4, 29.0, 28.8, 26.8, 26.1,
25.6, 19.2; MS m/z 541 (MHþ), 154 (100%); HRMS (FAB) calcd
for C29H42O35Cl237ClSi (MHþ) 541.2041, found 541.2055.
Determination of Stereochemistry of Trichloride 6. To a stirred
solution of trichloride 6 (6 mg, 11 μmol) in CH2Cl2 (1 mL) at
room temperature were added olefin 15 (0.02 mL, 57 μmol) and
second-generation Grubbs catalyst (1.5 mg, 1.8 μmol). After
being heated at reflux for 2 h, the mixture was concentrated
under reduced pressure. The residue was purified by flash silica
gel column chromatography (CH2Cl2/n-hexane 1:10) to give
unreacted trichloride 6 (2.5 mg, 42%) as a colorless oil, and
further elution with CH2Cl2/n-hexane (1:3 v/v) afforded alkenyl
trichloride (5.5 mg, 58%) as a colorless oil. The alkenyl trichlo-
ride (5.5 mg, 6.5 μmol) was dissolved in n-hexane (1 mL), and
Pt2O (1.5 mg) was added to the solution. The mixture was stirred
at room temperature under hydrogen atmosphere for 10 min
and filtered through a pad of Celite to give meso-trichloride 16
(5 mg, 91%) as a colorless oil.
(4R,5S,6S,7R,E)-14-[(tert-Butyldiphenylsilyl)oxy]-5,6,7-trichlo-
rotetradec-2-en-4-ol (5). A round-bottomed flask equipped with
rubber balloon filled with 2-butene was charged with syn-alcohol
13a (268 mg, 0.48 mmol), CH2Cl2 (10 mL), and second-genera-
tion Grubbs catalyst (12 mg, 0.015 mmol) at room temperature.
The mixture was stirred at the same temperature for 1 h and
concentrated under reduced pressure. The residue was purified
by flash silica gel column chromatography (Et2O/n-hexane 1:10)
to give less polar (E)-olefin 5 (241 mg, 88%) as a colorless oil and
the more polar (Z)-isomer of 5 (14 mg, 5%) as a colorless oil. (E)-
5: colorless oil; [R]21D þ8.6 (c 1.01, CHCl3); IR (neat) ν 3447, 2932,
1
2857, 1427, 1111, 702 cm-1; H NMR (300 MHz, CDCl3) δ
7.69-7.64 (m, 4H), 7.46-7.34 (m, 6H), 5.88 (ddq, 1H, J = 15.4,
6.6, 0.7 Hz), 5.55 (ddq, 1H, J = 15.4, 6.6, 1.3 Hz), 4.52-4.42 (m,
1H), 4.31-4.22 (m, 2H), 4.16 (dd, 1H, J = 6.2, 4.4 Hz), 3.65 (t, 2H,
J = 6.2 Hz), 2.08 (d, 1H, J = 5.9 Hz), 1.94-1.83 (m, 2H), 1.76
(12R,13R,14S)-12,13,14-Trichloro-2,2,24,24-tetramethyl-3,3,
23,23-tetraphenyl-4,22-dioxa-3,23-disilapentacosan (16): color-
less oil; [R]24D ∼0 (c 0.23, CHCl3); IR (neat) ν 2930, 2857, 1427,
(dd, 3H, J = 6.6, 1.3 Hz), 1.61-1.23 (m, 11H), 1.05 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 135.5, 134.1, 130.9, 129.5, 129.0, 127.5,
72.6, 69.4, 67.1, 63.8, 63.1, 35.6, 32.4, 29.0, 28.8, 26.8, 26.1,
25.6, 19.2, 17.8; MS m/z: 571 (MHþ), 135 (100); HRMS (FAB)
calcd for C30H44O235Cl237ClSi (MHþ) 571.2147, found 571.2146.
1111, 702 cm-1 1H NMR (300 MHz, CDCl3) δ 7.71-7.62
;
(m, 8H), 7.47-7.33 (m, 12H), 4.22-4.13 (m, 2H), 4.10 (dd,
5434 J. Org. Chem. Vol. 75, No. 16, 2010

Yoshimitsu et al.
JOCFeatured Article
(Z)-Isomer of 5: colorless oil; [R]20D þ2.0 (c 0.30, CHCl3);IR (neat)
1.42-1.23 (m, 6H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
160.1, 135.6, 134.1, 129.5, 127.6, 77.7, 64.6, 64.4, 63.9, 63.7, 61.9,
54.8, 33.8, 32.4, 29.1, 28.7, 26.9, 25.7, 25.6, 22.8, 19.2; MS m/z 785
(MHþ), 135 (100); HRMS (FAB) calcd for C32H43O335Cl737ClSi
ν 3412, 2930, 2857, 1427, 1111, 702 cm-1; H NMR (300 MHz,
1
CDCl3) δ 7.69-7.64 (m, 4H), 7.45-7.34 (m, 6H), 5.78 (dq, 1H,
J = 10.8, 7.0 Hz), 5.48 (ddq, 1H, J = 10.8, 8.2, 1.7 Hz), 4.86 (dd,
1H, J = 8.2, 4.4 Hz), 4.34-4.24 (m, 2H), 4.17 (dd, 1H, J = 5.9, 4.2
Hz), 3.65 (t, 2H, J= 6.4 Hz), 1.96-1.84 (m, 2H), 1.77 (dd, 3H, J =
7.0, 1.7 Hz), 1.61-1.25 (m, 11H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 135.6, 134.1, 130.4, 129.5, 128.4, 127.6, 69.5, 67.5, 67.0,
(MHþ) 785.0460, found 785.0445. Olefin 19: colorless oil; [R]23
D
þ34.6 (c 0.23, CHCl3); IR (neat) ν 2930, 2857, 1773, 1427, 1225,
1111, 824, 702, 679 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.68-
7.63 (m, 4H), 7.44-7.35 (m, 6H), 5.86 (ddd, 1H J = 17.1, 9.8, 9.2
Hz), 5.48 (d, 1H, J =17.1 Hz), 5.43 (dd, 1H, J = 8.5, 2.4 Hz), 5.37
(d, 1H, J = 9.8 Hz), 4.88 (dd, 1H, J = 7.9, 2.4 Hz), 4.71 (dd, 1H,
J = 8.5, 9.2 Hz), 4.15 (dd, 1H, J = 7.9, 3.1 Hz), 4.04 (ddd, 1H,
J = 7.9, 4.9, 3.1 Hz), 3.64 (t, 2H, J = 6.4 Hz), 1.96-1.78 (m, 2H),
1.58-1.50 (m, 2H), 1.38-1.21 (m, 8H), 1.04 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 160.9, 135.6, 134.1, 132.4, 129.5, 127.6,
122.4, 77.3, 66.2, 63.9, 62.5, 61.2, 59.6, 36.1, 32.4, 29.0, 28.7,
26.9, 26.1, 25.6, 19.2; MS m/z 749 (MHþ), 135 (100%); HRMS
(FAB) calcd for C32H42O335Cl637ClSi (MHþ) 749.0693, found
749.0668.
63.9, 63.3, 35.7, 32.5, 29.1, 28.9, 26.9, 26.2, 25.6, 19.2, 13.8; MS m/z
571 (MHþ), 154 (100); HRMS (FAB) calcd for C30H44O235Cl2
37
-
ClSi (MHþ) 571.2147, found 571.2152.
(4R,5S,6S,7R,E)-14-[(tert-Butyldiphenylsilyl)oxy]-5,6,7-trichlo-
rotetradec-2-en-4-yl 2,2,2-Trichloroacetate (14). To a stirred solu-
tion of alcohol 5 (8 mg, 0.014 mmol) in THF (1 mL) were added
pyridine (20 μL, 0.25 mmol) and trichloroacetyl chloride (10 μL,
0.09 mmol) at 0 °C. After being stirred for 15 min, the mixture
was poured into a separatory funnel where it was partitioned
between satd NaHCO3 and Et2O. The organic phase was sepa-
rated, dried over MgSO4, filtered, and concentrated. The residue
was purified by silica gel column chromatography (EtOAc/
n-hexane 1:20) to give trichloroacetate 14 (10 mg, quant) as a
colorless oil. Trichloroacetate 14: colorless oil; [R]19D þ7.8 (c 1.58,
CHCl3); IR (neat) ν 2931, 2857, 1771, 1427, 1231, 1111, 824, 702,
(2R,3S,4R,5S,6S,7R)-14-[(tert-Butyldiphenylsilyl)oxy]-2,3,5,
6,7-pentachlorotetradecan-4-ol (20), (2S,3R,4R,5S,6S,7R)-14-
[(tert-Butyldiphenylsilyl)oxy]-2,3,5,6,7-pentachlorotetradecan-4-ol
(21), and (2S,3S,4R,5S,6S,7R)-14-[(tert-Butyldiphenylsilyl)oxy]-
2,3,5,6,7-pentachlorotetradecan-4-ol (22). To a stirred suspension
of KMnO4 (17 mg, 0.108 mmol) in CH2Cl2 (1.4 mL) was added
BnEt3NCl (25 mg, 0.108 mmol) at room temperature. After being
stirred for 30 min, the mixture was allowed to cool to 0 °C, and
TMSCl (60 μL, 0.47 mmol) was added. After 40 min, the mixture
was allowed to cool to -78 °C, and a solution of alcohol 5 (51 mg,
0.090 mmol) in CH2Cl2 (2.6 mL) was added. The mixture was
stirred for further 20 min at -78 °C and for an additional 2.5 h
during which time the mixture was allowed to gradually warm
to -10 °C. Then the mixture was stirred at -10 °C for an
additional 30 min and treated with satd NaHCO3 and satd
Na2S2O3. The whole mixture was poured into a separatory
funnel, where it was partitioned between Et2O and H2O. The
organic phase was separated, dried over MgSO4, filtered, and
concentrated. The residue was purified by flash silica gel column
chromatography (Et2O/n-hexane 1:20) to give less polar pen-
tachloride 21 (6 mg, 10%) as a colorless oil, pentachloride 20
(22 mg, 38%) as a colorless oil, and more polar pentachloride 22
(15 mg, 26%) as a pale yellow oil. Pentachloride 20: colorless oil;
[R]24D þ12.5 (c 0.23, CHCl3); IR (neat) ν 3524, 2930, 2857, 1427,
1111, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m,
4H), 7.46-7.34 (m, 6H), 4.85 (d, 1H, J = 8.4 Hz), 4.66 (dq, 1H,
J = 6.5, 2.6 Hz), 4.31 (dd, 1H, J = 9.5, 2.6 Hz), 4.26 (dd, 1H, J =
8.4, 2.2 Hz), 4.18 (ddd, 1H, J = 7.9, 5.7, 2.2 Hz), 4.01 (d, 1H, J =
9.5 Hz), 3.65 (t, 2H, J = 6.4 Hz), 2.28 (brs, 1H), 2.03-1.80 (m,
2H), 1.60 (d, 3H, J = 6.5 Hz), 1.63-1.50 (m, 2H), 1.41-1.24 (m,
8H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.5, 134.1,
129.5, 127.5, 71.9, 67.7, 67.5, 66.5, 63.8, 61.2, 56.1, 36.4, 32.4, 29.0,
28.9, 26.8, 26.2, 25.5, 19.2, 19.0; MS m/z 641 (MHþ), 135 (100);
HRMS (FAB) calcd for C30H44O235Cl437ClSi (MHþ) 641.1524,
1
683 cm-1; H NMR (300 MHz, CDCl3) δ 7.70-7.63 (m, 4H),
7.45-7.34 (m, 6H), 6.17 (dq, 1H, J = 15.0, 6.6 Hz), 5.62 (dd, 1H,
J = 8.1, 6.7 Hz), 5.51 (ddq, 1H, J = 15.0, 8.2, 1.6 Hz), 4.37 (dd,
1H, J = 6.6, 4.0 Hz), 4.19 (dd, 1H, J = 5.9, 4.1 Hz), 4.18-4.06
(m, 1H), 3.65 (t, 2H, J = 6.4 Hz), 2.01-1.87 (m, 1H), 1.81 (dd,
3H, J = 6.7, 1.5 Hz), 1.81-1.70 (m, 1H), 1.64-1.46 (m, 2H),
1.41-1.23 (m, 8H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 160.5, 137.1, 135.6, 134.1, 129.5, 127.6, 122.5, 89.7, 80.8,
65.4, 63.92, 63.86, 62.8, 34.5, 32.4, 29.0, 28.8, 26.9, 26.3,
25.6, 19.2, 18.1; MS m/z 715 (MHþ), 154 (100); HRMS (FAB)
calcd for C32H43O335Cl537ClSi (MHþ) 715.1083, found 715.
1068.
(2S,3R,4R,5S,6S,7R)-14-[(tert-Butyldiphenylsilyl)oxy]-2,3,5,
6,7-pentachlorotetradecan-4-yl 2,2,2-Trichloroacetate (18) and
(4R,5S,6S,7R)-14-[(tert-Butyldiphenylsilyl)oxy]-3,5,6,7-tetrachlo-
rotetradec-1-en-4-yl 2,2,2-Trichloroacetate (19). To a stirred sus-
pension of KMnO4 (4 mg, 0.025 mmol) in CH2Cl2 (0.8 mL) was
added BnEt3NCl (6 mg, 0.026 mmol) at room temperature. After
being stirred for 30 min, the mixture was allowed to cool to
0 °C, and TMSCl (20 μL, 0.16 mmol) was added. After 5 min,
the mixture was allowed to cool to -78 °C, and a solution of
trichloroacetate 14 (15 mg, 0.021 mmol) in CH2Cl2 (1.2 mL) was
added. The mixture was stirred for further 2.8 h at -78 °C and
for 1.5 h during which time the mixture was allowed to gradually
warm to -10 °C. Then the mixture was stirred at the same
temperature for an additional 1 h and treated with satd NaHCO3
and satd Na2S2O3. The whole mixture was poured into a sepa-
ratory funnel where it was partitioned between Et2O and H2O.
The organic phase was separated, dried over MgSO4, filtered,
and concentrated. The residue was purified by flash silica gel
column chromatography (CH2Cl2/n-hexane 1:5) to give an
inseparable mixture of less polar pentachloride 17 and olefin
19 (4.5 mg) as a colorless oil, and more polar pentachloride 18
(7.5 mg, 45%) as a colorless oil. Separation of compound 17
from compound 19 was quite difficult; therefore, the structure of
compound 17 has been elucidated after removal of the trichloro-
acetyl group (for details, see the Supporting Information). The
data of compound 19 given below are those obtained for the
material that could be partially separated. Pentachloride 18:
found 641.1528. Pentachloride 21: colorless oil; [R]23 þ6.4
D
(c 0.35, CHCl3); IR (neat) ν 3441, 2930, 2857, 1427, 1231, 1111,
702 cm-1; H NMR (300 MHz, CDCl3) δ 7.70-7.63 (m, 4H),
1
7.46-7.34 (m, 6H), 4.52 (dd, 1H, J = 6.4, 3.3 Hz), 4.42-4.29 (m,
2H), 4.27-4.18 (m, 2H), 4.11 (dd, 1H, J = 8.1, 3.3 Hz), 3.65 (t,
2H, J = 6.4 Hz), 1.99-1.85 (m, 1H), 1.84-1.72 (m, 1H), 1.69 (d,
3H, J = 6.6 Hz), 1.63-1.44 (m, 2H), 1.40-1.23 (m, 8H), 1.05 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 135.6, 134.1, 129.5, 127.6,
72.4, 66.8, 65.8, 65.3, 64.4, 63.9, 55.6, 34.4, 32.4, 29.1, 28.8, 26.9,
25.65, 25.60, 22.0, 19.2; MS m/z 641 (MHþ), 135 (100); HRMS
(FAB) calcd for C30H44O335Cl437ClSi (MHþ) 641.1524, found
colorless oil; [R]22 -1.0 (c 0.73, MeOH); IR (neat) ν 2932,
D
2857, 1786, 1427, 1220, 1111, 824, 702, 677 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.70-7.62 (m, 4H), 7.46-7.33 (m, 6H), 6.09 (dd,
1H, J = 7.7, 2.0Hz), 4.60 (d, 1H, J = 7.5Hz), 4.30-4.15 (m, 3H),
4.14-4.00 (m, 1H), 3.65 (t, 2H, J = 6.4 Hz), 2.01-1.84 (m, 1H),
1.83-1.66 (m, 1H), 1.74 (d, 3H, J = 6.2 Hz), 1.63-1.46 (m, 4H),
641.1527. Pentachloride 22: pale yellow oil; [R]22 þ9.9 (c 0.70,
D
CHCl3); IR (neat) ν 3524, 2932, 2857, 1427, 1111, 702 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.71-7.63 (m, 4H), 7.46-7.34 (m,
6H), 4.87 (dd, 1H, J = 9.6, 1.3 Hz), 4.71 (dq, 1H, J = 6.7, 1.7 Hz),
4.31 (dd, 1H, J = 8.6, 2.2 Hz), 4.30-4.18 (m, 2H), 4.07 (dd, 1H,
J. Org. Chem. Vol. 75, No. 16, 2010 5435

Yoshimitsu et al.
JOCFeatured Article
J = 9.5, 1.8 Hz), 3.65 (t, 2H, J = 6.4 Hz), 2.05-1.80(m, 2H), 1.66
(d, 3H, J = 6.7 Hz), 1.61-1.44 (m, 2H), 1.42-1.22 (m, 8H), 1.05
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.5, 134.1, 129.5, 127.6,
71.9, 67.6, 67.4, 65.6, 63.8, 61.2, 55.9, 36.5, 32.4, 29.0, 28.9, 26.9,
26.2, 25.6, 22.7, 19.2; MS m/z 641 (MHþ), 135 (100); HRMS
(FAB) calcd for C30H44O235Cl437ClSi (MHþ) 641.1524, found
641.1519. The stereochemistry of pentachlorides 18 and 20-22
was determined bytheir chemical correlations. For details, see the
Supporting Information.
4.07 (dd, 1H, J = 7.5, 2.8 Hz), 2.45 (dt, 2H, J = 7.3, 1.6 Hz), 2.20
(s, 3H), 1.97-1.77 (m, 2H), 1.73-1.56 (m, 2H), 1.55 (d, 3H, J =
6.6 Hz), 1.46-1.17 (m, 8H); 13C NMR (67.5 MHz, CDCl3) δ
202.6, 169.9, 72.1, 66.2, 64.8, 63.0, 61.7, 55.3, 43.8, 35.7, 28.8, 28.5,
26.1, 21.8, 20.8, 19.3; MS m/z 443 (MHþ), 154 (100); HRMS
(FAB) calcd for C16H26O335Cl437Cl (MHþ) 443.0295, found
443.0294.
(2R,3S,4R,5S,6S,7R,E)-2,3,5,6,7,15-Hexachloropentadec-14-
en-4-yl Acetate (26). To a stirred suspension of CrCl2 (35 mg, 0.27
mmol) in THF (0.8 mL) at room temperature was added a
premixed solution of aldehyde 25 (20 mg, 0.046 mmol) and
CHCl3 (0.01 mL, 0.13 mmol) in THF (1.7 mL). The mixture
was heated at 65 °C for 1.7 h and poured into a separatory funnel
where it was partitioned between H2O and Et2O. The organic
phase was separated, dried over MgSO4, filtered, and concen-
trated. The residue was purified by silica gel column chromatog-
raphy (Et2O/n-hexane 1:20) to give olefin 26 (16 mg, 75%) as a
colorless oil. Olefin 26: colorless oil; [R]24D þ48.1 (c 0.24, CHCl3);
IR(neat) ν 2930, 1749, 1211 cm-1; 1H NMR(300 MHz, CDCl3) δ
5.95 (d, 1H, J = 13.4 Hz), 5.88 (dt, 1H, J = 13.4, 6.6 Hz), 5.29
(dd, 1H, J = 9.7, 1.5 Hz), 4.96 (dd, 1H, J = 7.6, 1.5 Hz), 4.55 (dd,
1H, 9.7, 2.7 Hz), 4.30 (ddd, 1H, J =8.2, 5.5, 2.7 Hz), 4.24 (dq, 1H,
J = 6.6, 2.7 Hz), 4.07 (dd, 1H, J = 7.6, 2.7 Hz), 2.19 (s, 3H), 2.05
(dt, 2H, J = 6.8, 6.6 Hz), 1.94-1.79 (m, 2H), 1.55 (d, 3H, J = 6.6
Hz), 1.45-1.23 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 169.9,
133.8, 116.8, 72.1, 66.2, 64.8, 63.0, 61.7, 55.3, 35.7, 30.8, 28.7, 28.6,
28.5, 26.2, 20.8, 19.3; MS m/z 475 (MHþ), 154 (100); HRMS
(FAB) calcd for C17H27O235Cl537Cl (MHþ) 475.0113, found
475.0096.
(2R,3S,4R,5S,6S,7R)-14-[(tert-Butyldiphenylsilyl)oxy]-2,3,5,
6,7-pentachlorotetradecan-4-yl Acetate (23). To a stirred solu-
tion of pentachloride 20 (54 mg, 0.085 mmol) in CH2Cl2 (1.6 mL)
were added Et3N (0.03 mL, 0.22 mmol), Ac2O (0.015 mL, 0.16
mmol), and DMAP (1 mg, 0.008 mmol). After 10 min, the mixture
was poured into a separatory funnel where it was partitioned
between H2O and EtOAc. The organic phase was separated, dried
over MgSO4, filtered, and concentrated. The residue was purified
by silica gel column chromatography (EtOAc/n-hexane 1:6) to
give acetate 23 (57.5 mg, quant) as a pale yellow oil. Acetate 23:
pale yellow oil; [R]24 þ33.5 (c 0.18, CHCl3); IR (neat) ν 2932,
D
1
2859, 1751, 1427, 1213, 1111, 702 cm-1; H NMR (300 MHz,
CDCl3) δ 7.69-7.64 (m, 4H), 7.46-7.34 (m, 6H), 5.29 (dd, 1H,
J = 9.6, 1.5 Hz), 4.96 (dd, 1H, J = 7.6, 1.5 Hz), 4.54 (dd, 1H, J =
9.6, 2.7 Hz), 4.28 (ddd, 1H, J = 8.0, 5.7, 2.7 Hz), 4.23 (dq, 1H, J =
6.6, 2.7 Hz), 4.07 (dd, 1H, J = 7.6, 2.7 Hz), 3.65 (t, 2H, J = 6.6
Hz), 2.17 (s, 3H), 1.94-1.82 (m, 2H), 1.68-1.51 (m, 2H), 1.56 (d,
3H, J = 6.6 Hz), 1.42-1.22 (m, 8H), 1.05 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 169.8, 135.5, 134.1, 129.5, 127.5, 72.1, 66.2, 64.8,
63.8, 63.0, 61.7, 55.3, 35.8, 32.4, 29.0, 28.8, 26.8, 26.2, 25.6, 20.7,
19.3, 19.2; MS m/z 705 (MNaþ), 135 (100); HRMS (FAB) calcd
for C32H45O335Cl437ClSiNa (MNaþ) 705.1449, found 705.1451.
(2R,3S,4R,5S,6S,7R)-2,3,5,6,7-Pentachloro-14-hydroxytetra-
decan-4-yl Acetate (24). To a solution of pentachloride 23 (46 mg,
0.068 mmol) in THF (1.0 mL) at room temperature were added
pyridine (0.16 mL, 1.98 mmol) and 48% aq HF (0.05 mL, 1.38
mmol). After 25 h, the mixture was poured into a separatory
funnel where it was partitioned between satd NaHCO3 and
Et2O. The organic phase was separated, dried over MgSO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography (EtOAc/n-hexane 1:2) to give alcohol
24 (28 mg, 94%) as a pale yellow oil. Alcohol 24: pale yellow oil;
[R]23D þ57.8 (c 0.38, CHCl3); IR (neat) ν 3368, 2932, 2859, 1749,
1373, 1213, 1055, 1022 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.29
(dd, 1H, J = 9.5, 1.5 Hz), 4.96 (dd, 1H, J = 7.6, 1.5 Hz), 4.54 (dd,
1H, J = 9.5, 2.6 Hz), 4.30 (ddd, 1H, J = 8.1, 5.5, 2.8 Hz), 4.24
(dq, 1H, J = 6.6, 2.6 Hz), 4.08 (dd, 1H, J = 7.6, 2.8 Hz), 3.65 (t,
2H, J = 6.6 Hz), 2.19 (s, 3H), 1.97-1.82 (m, 2H), 1.64-1.51 (m,
2H), 1.56 (d, 3H, J = 6.6 Hz), 1.48-1.31 (m, 8H); 13C NMR (75
MHz, CDCl3) δ 169.9, 72.1, 66.2, 64.8, 63.0, 62.9, 61.7, 55.3, 35.7,
32.6, 29.0, 28.7, 26.2, 25.5, 20.8, 19.3; MS m/z 445 (MHþ), 154
(100); HRMS (FAB) calcd for C16H28O335Cl437Cl (MHþ)
445.0452, found 445.0456.
(2R,3S,4R,5S,6S,7R,E)-2,3,5,6,7,15-Hexachloropentadec-14-
en-4-ol (27). To a solution of acetate 26 (25 mg, 0.053 mmol)
in CH2Cl2 (1 mL) at -78 °C was added DIBAL (0.98 M in
n-hexane, 0.14 mL, 0.14 mmol). After 10 min, satd NH4Cl was
added, and the mixture was allowed to warm to room tempera-
ture. After 20 min, Celite was added, and the whole mixture was
stirred for an additional 50 min. After filtration of the mixture
through a Celite pad followed by concentration of the filtrate
under reduced pressure, the residue was purified by flash silica gel
column chromatography (EtOAc/hexane 1:10) to give alcohol 27
(22 mg, 96%) as a colorless oil. Alcohol 27: colorless oil; [R]25
D
þ27.4 (c 0.42, CHCl3); IR (neat) ν 3526, 2930, 2857, 1265, 1092
cm-1; 1H NMR(500 MHz, CD3OD) δ 6.04 (dd, 1H, J = 13.4, 1.2
Hz), 5.89 (dt, 1H, J = 13.4, 7.3 Hz), 4.71 (dq, 1H, J = 6.7, 2.4
Hz), 4.60 (dd, 1H, J = 9.2, 1.8 Hz), 4.42-4.34 (m, 3H), 3.99 (dd,
1H, J = 9.8, 1.2 Hz), 2.07 (dt, 2H, J = 7.3, 1.2 Hz), 2.01-1.85 (m,
2H), 1.54 (d, 3H, J = 6.7 Hz), 1.46-1.26 (m, 8H); 1H NMR (300
MHz, CDCl3) δ 5.94 (d, 1H, J = 13.2 Hz), 5.88 (dt, 1H, J = 13.2,
6.4 Hz), 4.85 (dd, 1H, J = 8.4, 1.1 Hz), 4.67 (dq, 1H, J = 6.6, 2.6
Hz), 4.32 (dd, 1H, J = 9.6, 2.6 Hz), 4.27 (dd, 1H, J = 8.4, 2.4 Hz),
4.19 (ddd, 1H, J = 8.1, 5.6, 2.4 Hz), 4.07-3.96 (m, 1H), 2.34
(d, 1H, J = 11.2 Hz), 2.09-1.82 (m, 4H), 1.61 (d, 3H, J = 6.6
Hz), 1.57-1.22 (m, 8H); 13C NMR(125 MHz, CD3OD) δ 135.12,
118.00, 71.99, 69.39, 69.12, 68.59, 62.56, 57.39, 38.08, 31.67,
29.89, 29.81, 29.78, 27.27, 18.88; 13C NMR (75 MHz, CDCl3) δ
133.81, 116.84, 71.94, 67.67, 67.50, 66.44, 61.19, 56.11, 36.41,
30.76, 28.69, 28.654, 28.646, 26.20, 19.07; MS m/z 455 (MNaþ),
176 (100); HRMS (FAB) calcd for C15H24O35Cl537ClNa (MNaþ)
454.9826, found 454.9840.
(2R,3S,4R,5S,6S,7R)-2,3,5,6,7-Pentachloro-14-oxotetradecan-
4-yl Acetate (25). To a stirred solution of alcohol 24 (25 mg, 0.057
mmol) in CH2Cl2 (1 mL) were added NaHCO3 (10 mg, 0.12
mmol) and Dess-Martin periodinane (36 mg, 0.085 mmol) at
room temperature. The mixture was stirred for 30 min and then
treated with satd NaHCO3 and satd Na2S2O3. The mixture was
poured into a separatory funnel where it was 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 (EtOAc/n-hexane
1:3) to give aldehyde 25 (25 mg, 98%) as a pale yellow oil.
(2R,3S,4R,5S,6S,7R,E)-2,3,5,6,7,15-Hexachloropentadec-14-
en-4-ylhydrogen Sulfate (1). To a solution of alcohol 27 (9 mg,
0.021 mmol) in DMF (1 mL) at room temperature was added
SO3 Py (50% active SO3, 67 mg, 0.21 mmol). After 1 h, MeOH
3
was added, and the mixture was concentrated under reduced
pressure. The residue was poured into a separatory funnel where
it was partitioned between H2O and Et2O. The organic phase was
separated, dried over MgSO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography
(AcOH/EtOAc 1:30) to give alcohol 27 (2 mg, 22%) as a colorless
Aldehyde 25: pale yellow oil; [R]23 þ46.2 (c 0.35, CHCl3); IR
D
(neat) ν 2934, 1751, 1722, 1211 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 9.77 (t, 1H, J = 1.7 Hz), 5.28 (dd, 1H, J = 9.6, 1.5
Hz), 4.96 (dd, 1H, J = 7.5, 1.5 Hz), 4.54 (dd, 1H, J = 9.6, 2.6 Hz),
4.30 (ddd, 1H, J = 8.2, 5.4, 2.8 Hz), 4.24 (dq, 1H, J = 6.6, 2.6Hz),
5436 J. Org. Chem. Vol. 75, No. 16, 2010

Yoshimitsu et al.
JOCFeatured Article
oil and hexachlorosulfolipid 1 (8 mg, 75%) as a pale yellow oil.
TLC analysis clearly indicated that sulfation of alcohol 27 took
place quantitatively to afford sulfolipid 1, which was, however,
somewhat unstable toward hydrolysis to again produce alcohol
27 duringthe workup. Hexachlorosulfolipid(þ)-1: pale yellow oil;
[R]24D þ49.0 (c 0.59, MeOH) (lit. [R]25D þ20.4 (c 0.0015, MeOH);
IR (neat) ν 3472, 2928, 2857, 1269, 1040, 937 cm-1; 1H NMR(500
MHz, acetone-d6) δ 6.13 (d, 1H, J = 13.4 Hz), 5.94 (dt, 1H, J =
13.4, 7.3 Hz), 5.16 (ddd, 1H, J = 8.5, 4.3, 1.8 Hz), 5.09 (dq, 1H,
J = 6.1, 1.8 Hz), 4.79 (dd, 1H, J = 9.8, 1.2 Hz), 4.73 (dd, 1H, J =
9.8, 1.8 Hz), 4.71 (dd, 1H, J = 9.8, 1.2 Hz), 4.43 (dd, 1H, J = 9.8,
1.8 Hz), 2.13-2.06 (m, 1H), 1.94-1.82 (m, 2H), 1.66-1.53 (m,
2H), 1.61 (d, 3H, J = 6.1 Hz), 1.45-1.27 (m, 7H); 13C NMR (125
MHz, acetone-d6) δ 135.11, 117.46, 75.62, 69.14, 68.92, 67.93,
63.19, 57.16, 37.80, 31.22, 29.44, 29.39, 29.24, 26.64, 19.25; MS
(negative ion mode) m/z 511 (M - Hþ), 153 (100); HRMS (FAB)
calcd for C15H23O435Cl537ClS (M - Hþ) 510.9419, found
510.9421. The spectroscopic data of synthetic (þ)-hexachloro-
sulfolipid 1 were in good agreement with those reported in the
literature.2a,5a However, it was found that there was a significant
Computational Methods
The fully optimized geometries calculated by the PM3 meth-
od using the Spartan Pro program (Wavefunction, Inc., Irvine,
CA, 2000) were used as starting geometries for DFT calcula-
tions. DFT calculations were carried out using the Gaussian 03
program. The geometries were fully optimized in vacuo by using
the B3LYP method with the standard 6-31G(d) basis set.
Frequency calculations were carried out at the B3LYP/6-31G(d)
level of theory and performed on all of the species to confirm
convergence to appropriate local minima on the energy surface.
For details, see the Supporting Information.
Acknowledgment. We are deeply indebted to Professor
Fattorusso and Professor Ciminiello for generous informa-
tion of the NMR data of natural hexachlorosulfolipid. This
work was supported by a Grant-in-Aid [KAKENHI No.
16790021] (T.Y.) funded by the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
1
change in the shape of the H NMR spectra depending on the
Supporting Information Available: Experimental details for
1
concentration of the material. The concentration dependence of
the spectra was particularly found in the area of 4.6-4.7 ppm.
(The spectra are provided in the Supporting Information.) At
lower concentrations of sulfolipid, the spectra showed good
agreement with those of natural product. For details, see the
Supporting Information.
the structural determination and copies of the H/13C NMR
spectra of products. Cartesian coordinates, total energies, and
zero-point vibrational energies of the energetically favorable
conformers of model compounds of alcohol 5 and trichloro-
acetate 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 16, 2010 5437