Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (-)-Deschloromytilipin A and (-)-Danicalipin A

Article abstract of DOI:10.1021/jacs.6b01643

A titanium-based catalytic enantioselective dichlorination of simple allylic alcohols is described. This dichlorination reaction provides stereoselective access to all common dichloroalcohol building blocks used in syntheses of chlorosulfolipid natural products. An enantioselective synthesis of ent-(-)-deschloromytilipin A and a concise, eight-step synthesis of ent-(-)-danicalipin A are executed and employ the dichlorination reaction as the first step. Extension of this system to enantioselective dibromination and its use in the synthesis of pentabromide stereoarrays relevant to bromosulfolipids is reported. The described dichlorination and dibromination reactions are capable of exerting diastereocontrol in complex settings allowing X-ray crystal structure analysis of natural and unnatural diastereomers of polyhalogenated stereohexads.

Full text of DOI:10.1021/jacs.6b01643

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Article
Catalytic Enantioselective Dihalogenation and the Selective
Synthesis of (–)-Deschloromytilipin A and (–)-Danicalipin A
Matthew L. Landry, Dennis X Hu, Grace M. McKenna, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01643 • Publication Date (Web): 28 Mar 2016
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Journal of the American Chemical Society
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Catalytic Enantioselective Dihalogenation and the Selective Synthe-
sis of (–)-Deschloromytilipin A and (–)-Danicalipin A
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Matthew L. Landry, Dennis X. Hu, Grace M. McKenna, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
ABSTRACT: A titanium-based catalytic enantioselective dichlorination of simple allylic alcohols is described. This dichlo-
rination reaction provides stereoselective access to all common dichloroalcohol building blocks used in syntheses of
chlorosulfolipid natural products. An enantioselective synthesis of ent-(−)-deschloromytilipin A and a concise, eight-step
synthesis of ent-(−)-danicalipin A are executed and employ the dichlorination reaction as the first step. Extension of this
system to enantioselective dibromination and its use in the synthesis of pentabromide stereoarrays relevant to bromo-
sufolipids is reported. The described dichlorination and dibromination reactions are capable of exerting diastereocontrol
in complex settings allowing X-ray crystal structure analysis of natural and unnatural diastereomers of polyhalogenated
stereohexads.
relies on the use of styrenyl olefins as substrates to elec-
tronically bias chloride delivery. Consequently, the selec-
1. INTRODUCTION
Although the addition of molecular chlorine to carbon–
carbon double bonds is one of the oldest known organic
reactions,1a the ability to control the enantioselectivity of
alkene dichlorination has largely eluded chemists.1b-d
Meanwhile, in recent years there has been a growing in-
terest in the stereoselective synthesis of polychlorinated
sulfolipid natural products. Due to the scarcity of meth-
ods for enantioselective dichlorination of alkenes, synthe-
ses of molecules within this class of natural products rely
on multistep routes for establishing chlorine-bearing chi-
ral centers in an enantioselective fashion. To date there is
a single report of using an enantioselective dichlorination
in the setting of complex molecule synthesis by Snyder,
which employs a super-stoichiometric chiral auxiliary.2a A
practical, catalytic, enantioselective dichlorination would
be of great value to the synthetic chemist.
tivity of this system is poor for non-styrenyl substrates
which limits its potential synthetic application and pre-
cludes its use in the synthesis of the chlorosulfolipids.
Scheme 1. A challenge in enantioselective dichlorina-
tion.
Slow progress in the area of enantioselective dichlorina-
tion is attributable to a number of factors. First, the high-
ly reactive nature of most commonly employed chlorinat-
ing reagents makes achieving catalysis over nonselective
background a challenge. Second, even if selectivity is
achieved in the formation of an enantiopure chloronium
ion (e.g. 1, Scheme 1), regiochemical control in chloride
delivery is still necessary. This is because non-
regioselective chloride delivery results in a racemic prod-
uct, since dichlorides formed from the two possible chlo-
ride deliveries to non-C2-symmetric chloronium ions are
enantiomers (e.g. 2 and ent-2, Scheme 1).2b
The enantioselective dichlorination of simple, alkyl di-
substituted allylic alcohols has been a long sought-after
transformation and would be a powerful means of entry
to the chlorosulfolipids, a class of acyclic, polychlorinated
natural products (Figure 1).4 In this area, dichlorinated
allylic alcohols have been identified as highly enabling
intermediates in the synthesis of mytilipin A (4), dan-
icalipin A (5), and malhamensilipin A (6).5,6 Highlighted
in Figure 1 are specific dichloroalcohols that have been
targeted and employed in syntheses of these molecules.
Given the lack of enantioselective dichlorination meth-
ods, these motifs are either generated in racemic fash-
ion6a,b or, as in the case of danicalipin A (5), prepared via
an enriched epoxide in 4 steps and 80% ee.6c The allylic
alcohol precursors to these dichlorides represent desira-
In 2011, Nicolaou reported the first catalytic enantiose-
lective dichlorination of allylic alcohols.2c In fact, Nico-
laou’s dichlorination constitutes the first catalytic enanti-
oselective dihalogenation of any kind.2d-f,3 This system
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ble, but challenging, settings for catalytic enantioselective dichlorination, the enantioselectivity of dichloride prod-
1
2
3
dichlorinations.
ucts would be limited to a modest 26% or 50% ee, respec-
tively, assuming the intermediacy of a discrete enantioen-
riched chloronium ion.
4
5
6
Table 1. Development of an Enantioselective Dichlo-
rination of Allylic Alcoholsa
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Figure 1. Structures of chlorosulolipid natural products (3–7)
and an analogous bromosulfolipid stereohexad (8). High-
lighted structures represent corresponding simple dichlorin-
ated allylic alcohols that have been targeted in synthesis.
Described herein is a catalytic enantioselective method
for the dichlorination of simple linear aliphatic allylic
alcohols. Specifically, our reported Schiff base-catalyzed
dihalogenation reaction is capable of accessing the enan-
tioenriched dichloroalcohols involved in all syntheses of
the chlorosulfolipids (Table 2). The utility of this method
is demonstrated in a synthesis of the unnatural enantio-
mer of deschloromytilipin A (3). X-ray crystallography is
used to confirm the relative configuration of the stereo-
hexad of this natural product. The ability of this method
to provide new diastereoselectivities in complex settings,
as well as access to enriched polybromides, allows com-
parison of the conformations of natural and unnatural
polychlorinated and polybrominated stereohexads in so-
lution and solid phase. A concise eight-step synthesis of
the unnatural enantiomer of danicalipin A (5) utilizing an
enantioenriched dichloride is additionally reported.
aReactions were conducted on 0.1 mmol scale with 1.1 equiv
X+ source and 1.1 equiv ClTi(Oi-Pr)3. Yields were assessed by
1H-NMR spectroscopy with 1,4-dinitrobenzene as an internal
standard; bRatio of bromochloride constitutional isomers.
Yields given for entries 1 and 2 are for both constitutional
isomers and ee is reported for the major isomer.
The viability of a selective dichlorination of trans-
disubstituted allylic alcohols was initially investigated by
replacing
N-bromosuccinimide
(NBS)
with
N-
chlorosuccinimide (NCS) as a source of electrophilic chlo-
rine in our titanium-mediated dihalogention reaction
(Table 1, entry 3). This provided dichloride product 10b in
fair yield and higher-than-predicted enantioselectivity
(i.e. greater than 26% ee). Such enantioselectivity could
originate from an increased regioselectivity in chloride
delivery in the case of trapping chloronium intermediates
by chlorotitanium species. Another possible explanation
is that diastereomeric chloronium-containing titanium
complexes are attacked by chloride with different regiose-
lectivity.
2. RESULTS AND DISCUSSION
2.1 Catalytic Enantioselective Dichlorination. Re-
cently, we reported a titanium-mediated enantioselective
bromochlorination of allylic alcohols catalyzed by Schiff
base 11 (Table 1).7 Trisubstituted, 1,1-disubsituted, and cis-
disubstituted allylic alcohols were bromochlorinated un-
der the described conditions with excellent regio- and
enantioselectivity. Unfortunately, application of this sys-
tem to disubstituted trans-allylic alcohol 9 provided bro-
mochloride 10a and its corresponding bromochloride
constituational isomer in a 1.7 to 1.0 ratio, respectively.
Reduced temperatures provided a slight improvement in
bromochloride product rations (3.0:1.0, Table 1, entry 2).
As depicted in Scheme 1, one would expect that if a 1.7 to
1.0 or a 3.o to 1.0 product ratio persisted for the case of
Subsequent
investigation
revealed
tert-
butylhypochlorite (t-BuOCl) as the most selective source
of electrophilic chlorine (Table 1, entries 4-8). This is sur-
prising given the highly reactive nature of t-BuOCl, which
exhibits substantial background reactivity in the absence
of a chiral catalyst. Mechanistically, we speculate that a
chiral titanium complex acts as an oxophilic Lewis acid on
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Table 2. Dichlorination Substrate Scopea
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aConditions unless otherwise noted: 1.1−1.5 equiv t-BuOCl, 1.1−1.6 equiv ClTi(Oi-Pr)3, 10–30 mol % (R,S)-11, hexanes, −20 °C, 4–
12 hours; b3:1 hexanes/CCl4; cisolated by distillation; dabsolute configuration unconfirmed.
t-BuOCl, accelerating transfer of the electrophilic chlo-
rine to the olefin of the titanium-bound allylic alcohol.
The higher selectivity for dichlorinations with t-BuOCl
compared with NCS could arise from the closer proximity
of the oxygen and chlorine in t-BuOCl, situating the chlo-
rine nearer the chiral ligand which is presumably also
titanium-bound. Use of ligands other than chiral imino-
diol 11 or solvents other than hexanes resulted in dimin-
ished selectivity (Table 1, entries 9-11). Decreased temper-
atures improved both the yield of and selectivity for di-
chloride 10b and permitted reduction in catalyst loading
(Table 1, entries 12-13). Further improvements in selectivi-
ty were observed in larger scale reactions employing more
controlled drop-wise additions of t-BuOCl solutions.
chloroalcohols on practical scale and in synthetically use-
ful yields and enantioselectivities. The low yield in the
dichlorination of 18 is likely due to the volatility of dichlo-
ride 19, which is isolated via distillation. Dichloroalcohol
21, which is used in our synthesis of ent-(−)-danicalipin A
(−)-5 (see Section 2.6), was prepared on 9.1 gram-scale in a
single run. The skipped diene 24 presents an interesting
chemoselectivity challenge and contains allylic protons
which could be acidic within a chloronium intermediate.
Our system can dichlorinate the more electron-deficient
olefin of 24 to produce 25 in fair yield and good enantiose-
lectivity (Table 2, entry 5); compound 25 maps on to nom-
inal undecachlorosulfolipid 7 (Figure 1). As previously
reported, our conditions can dihalogenate 1,1-
disubstituted allylic alcohol 26 to furnish 27 selectively
(Table 2, entry 6).7 Trisubstituted allylic alcohols are con-
verted to dichlorides with low yield using this method
due to facile deprotonation of trisubstituted chloronium
ions to give allylic chloride products.
As a benchmark substrate, cinnamyl alcohol 16 was
subjected to the dichlorination conditions and produced
dichloride (+)-17 in excellent yield and selectivity (Table
2, entry 1). Previously, enantioenriched (+)-17 and (–)-17
were prepared by Nicolaou in +61% and –81% ee, respec-
tively,
using
20
mol
%
pseudoenantiomeric
2.2 Catalytic Enantioselective Dibromination. En-
deavors to extend our system for dichlorination to the
dibromination of allylic alcohols was next undertaken.
Like dichlorination, alkene dibromination has been a
longstanding challenge in the area of enantioselective
catalysis. From a practical perspective, enantioenriched
dibromides could have great value as stereodefined build-
ing blocks for further functionalization. A palladium-
(DHQD)2PHAL or (DHQ)2PHAL.2c
Linear, aliphatic allylic dichloroalcohols 19, 21, and 23
are enantioenriched versions of intermediates that have
been used in syntheses of mytilipin A, danicalipin A, and
malhamensilipin A, respectively (Table 2, entries 2−4).6a–c
Dichlorination of allylic alcohols 18, 20, and 22 under our
developed conditions produced the aforementioned di-
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catalyzed enantioselective alkene dibromination was re-
chlorosulfolipid was isolated in 20104e and lacks the vinyl
ported in 2003 by Henry,3a but a subsequent report by
Denmark3b questioned these results. In their reinvestiga-
tion, all attempts to reproduce this chemistry returned
racemic dibromides. In 2013 our lab reported a TADDOL-
catalyzed enantioselective dibromination reaction which
was enantioselective only for electronically biased cin-
namyl alcohols.2d We envisioned that our success in the
enantioselective dichlorination of simple allylic alcohols
could translate back to enantioselective dibromination.
choride found in mytilipin A. Using a strategy similar to
that of Yoshimitsu6c and Vanderwal,6a,b oxidation and
chloroallylation8 of 19 provided known trichloroalcohol 34
as a single diastereomer. Although never previously elab-
orated to a chlorosulfolipid, alcohol 34 has been prepared
from crotyl alcohol in five chemical transformations in
66% ee using a kinetic resolution.6a,b Acryloylation of 34
and subsequent ring-closing metathesis yielded lactone
35, which was then reduced9 to enediol 36. The applica-
tion of a Z-selective cross metathesis between 1,4-
butenediol and chlorohydrin 34 to directly prepare diol 36
was attempted, but no reaction was observed.6a,10 In the
course of this synthesis, it was found that diol 36 is prone
to undergo facile intramolecular cyclization via an SN2’
displacement of the allylic chloride by the secondary al-
cohol. Hence, 36 was used directly after preparation to
prevent this unwanted decomposition. Dichlorination of
36 with Et4NCl311 furnished diol 37 with high diastereose-
lectivity. Silylation and triflation of 37 provided pen-
tachloride 38. Copper-catalyzed alkyl–alkyl cross cou-
pling12 of 38 followed by sulfation completed the first syn-
thesis of (−)-deschloromytilipin A (–)-3 in 11 steps from
crotyl alcohol. This route provides access to the unnatural
enantiomer of the natural product, which was targeted in
order to demonstrate the power and utility of enantiose-
lective catalysis when both ligand antipodes are readily
available. This work also represents the first use of an
enantioselective dihalogenation in the synthesis of a
chlorosulfolipid.13
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When NBS and BrTi(Oi-Pr)3 were used in place of t-
BuOCl and ClTi(Oi-Pr)3 in the halogenation reaction, di-
bromides were formed in high yield and selectivity (Table
3). As in the case of dichlorination, the origins of this
higher-than-predicted selectivity are unclear; possible
explanations parallel those discussed earlier for dichlorin-
ation (Section 2.1).
Dibromination of electronically biased allylic alcohol 16
proceeded smoothly, providing 28 in good yield and se-
lectivity2d (Table 3, entry 1). Electronically unbiased allylic
alcohols 18, 20, and 22 were also selectively dibrominated
providing 29, 30, and 31 in good yields (Table 3, entries 2-
4). 1,1-Disubstituted olefins such as 26 could be brominat-
ed as well, producing 32 efficiently and with good selectiv-
ity (Table 3, entry 5). In contrast to dichlorination, trisub-
stituted allylic alcohols are also viable substrates for di
bromination.7 It is anticipated that these enriched dibro-
mides could serve as useful chiral building blocks.
Table 3. Dibromination Substrate Scopea
2.4 Synthesis of a Polybrominated Precursor Rele-
vant to Bromosulfolipids. When the danicalipin A-
producing organism, O. danica, is grown in bromide-rich
media, the corresponding bromosulfolipid is purportedly
made.14a This curiosity raises questions about the path-
ways and molecular machinery responsible for halogena-
tion in these phytoflagellates, as well as fundamental
structural questions about these bromosulfolipids. The
salient barrier to the study of these peculiar molecules is
the limited data that exists for their characterization. In-
deed, isolation reports for most bromosulfolipids identify
these structures solely by mass spectrometry.14 Prompted
by a desire to provide structural and characterization data
for relevant polybrominated motifs, selective syntheses of
such stereoarrays were carried out.6k
The synthesis of the olefin precursor to pentabromodi-
ols proceeded in an analogous manner to the synthesis of
36 (Scheme 3). Oxidation of enantioenriched dibromide
29 provided dibromoaldehyde 39, which was particularly
capricious relative to its dichloroaldehyde counterpart
and rapidly eliminated HBr upon standing at room tem-
perature. Dibromoaldehyde 39, however, could be com-
bined immediately with preformed bromoaluminum rea-
gent 406a,b,15 to provide multi-gram quantaties of bromo-
hydrin 41. Allylic bromide 41 could be further elaborated
by acroylation and ring closing metathesis to provide lac-
tone 42. Cerium borohydride reduction9 afforded diol 43
on gram scale. The relatively high efficiencies of these
transformations were surprising given the generally per-
aConditions unless otherwise noted: 1.1−1.2 equiv NBS,
1.1−1.3 equiv BrTi(Oi-Pr)3, 15–20 mol % (R,S)-11, hexanes, −20
°C, 4–12 hours; b3:1 hexanes/CCl4; cabsolute configuration
unconfirmed.
2.3 Synthesis of (−)-Deschloromytilipin A. With >10
grams of enantioenriched 19, a synthesis of the enantio-
mer of natural product (+)-(3), herein refered to as
deschloromytilipin A, was executed (Scheme 2). This
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Scheme 2. Synthesis of (–)-Deschloromytilipin Aa
1
2
3
4
5
6
7
O
a. Dess–Martin
O
c.
B(pin)
Cl
b.
Cl
Cl
H
Cl
OH
Cl
O
Cl
OH
H
e. NaBH4, CeCl3
Cl
Cl
d. HG-II
33
Cl
H
(+)-19
Me
Me
Me
H
(51%)
(69%)
(97%)
H
H
Me
OH
Cl
OR
H
Cl
Cl
Cl
35
Cl
Cl
Cl
36
f. Et4NCl3 (65%, 18:1 dr)
OH
34
H
8
9
h. CuCl, TMEDA
;
BrMg
4
Cl
OSO3 Cl
Cl
OTESCl
OTf
Cl
OH Cl
OH
HCl, MeOH
(28%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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36
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41
42
43
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60
g. Tf2O; TESCl
≅
Me
Me
Me
(70%)
i. SO3⋅pyr (94%)
Cl
Cl
Cl
(−)-3
Cl
Cl
Cl
Cl
Cl
Cl
38
37
X-ray of derivative
aReagents and conditions: (a) Dess–Martin periodinane (1.3 equiv), NaHCO3 (3.0 equiv), CH2Cl2, 0 °C; (b) (Z)-
chloroallylpinacolborinate 33 (1.0 equiv), n-BuLi (1.2 equiv), trifluoroacetic anhydride (1.3 equiv), THF, −78 °C, 51% over two
steps; (c) acryloyl chloride (2.0 equiv), i-Pr2NEt (1.8 equiv), DMAP (0.2 equiv), CH2Cl2, 0 °C, 80%; (d) Hoveyda–Grubbs II (2 mol
%), toluene, 90 °C, 86%; (e) CeCl3•7H2O (2.4 equiv), NaBH4 (2.4 equiv), EtOH, rt, 97%; (f) Et4NCl3 (1.o equiv), 10:1 CH2Cl2/EtOH,
−78 °C, 65% (18:1 dr); (g) Tf2O (1.2 equiv), 2,6-lutidine (1.2 equiv), CH2Cl2, 0 °C, 82%; TESOTf (1.7 equiv), 2,6-di-tert-butylpyridine
(1.7 equiv), CH2Cl2, 0 °C, 85%; (h) CuCl (0.1 equiv.), N,N,N’,N’-tetramethylethylenediamine (0.3 equiv), 6-hepten-1-yl magnesium
bromide (1.2 equiv), THF, 0 °C to rt; 1 M aq. HCl, MeOH, rt, 28%; (i) SO3•pyridine (3.o equiv), THF, rt, 94%.
ceived sensitivity of allylic bromide, dibromide, and bro-
mohydrin functionalities.6k
was found that ferrocene carboxylate esters 44 and 46
were crystalline solids. Interestingly, 44 and 46 possess a
“bent” conformation in the solid state (Scheme 4, top).
This conformation is in agreement with that previously
predicted by computation and observed in NMR studies
for 3.4k Conversion of 37 to (–)-deschloromytilipin A (–)-3
(Scheme 2) confirms its absolute and relative configura-
tion. This represents a unique case wherein the absolute
and relative configuration of the complete stereoarray
within a chlorosulfolipid natural product has been con-
firmed by X-ray crystallography.16
2.5 Synthesis and Solid State Conformation of Poly-
chloride and Polybromide Stereohexads. Characteri-
zation and conformational data on stereohexad structures
of type 37 and its polybrominated analogues could prove
practically useful and academically insightful. First, syn-
thesis and characterization of polybromide stereohexads
would help confirm the existence of putative bromosul-
folipids.6k Second, conformational data on 37 could pro-
vide insight in to the manner in which these molecules
assemble in a lipid membrane. Third, investigation of
unnatural diastereomers of 37 would expand the reper-
toire of characterization data for complex polyhalostereo-
arrays. This could be particularly useful in the stereo-
chemical characterization of molecules like nominal un-
decachlorosulfolipid 7. For these reasons the syntheses of
chlorinated and brominated stereohexads was undertak-
en.
Scheme 3. Synthesis of Stereotetrad 43a
With pentachloride 37 already made, the completion of
the synthesis of the analogous pentabromide was con-
ducted (Scheme 4). This was effected through a diastere-
oselective dibromination of alkene 43 with pyridinium
tribromide and resulted in the predominant formation of
a stereohexad with the same relative configuration as
pentachloride 37. Such diastereoselectivity in dihalogena-
tion of 36 and 43 using trihalide reagents is in accordance
with previous reports concerning the dichlorination of
similar substrates.6a,b,h The high diastereoselectivity (18:1)
observed in the dichlorination suggests that strong sub-
strate bias exists for the halogenation of substrates of this
type.
aReagents and conditions: (a) Dess–Martin periodinane
(1.3 equiv.), NaHCO3 (3.0 equiv.), CH2Cl2, 0 °C; (b) 2,2,6,6-
tetramethylpiperidine (2.2 equiv.), n-BuLi (2.1 equiv.), allyl
bromide (2.1 equiv.), AlEt2Cl (4.0 equiv.), THF, −78 °C, 57%;
(c) acryloyl chloride (1.5 equiv.), i-Pr2NEt (1.0 equiv.), DMAP
(0.2 equiv.), CH2Cl2, 0 °C, 61%; (d) HG-II (2.5 mol%), toluene,
90 °C, 82%; (e) CeCl3ꢀ7H2O (2.4 equiv.), NaBH4 (2.4 equiv.),
EtOH, 0 °C, 66%.
During our studies on polyhalogenated stereohexads, it
was found that our reported catalytic system can overturn
inherent substrate bias to provide access to unnatural
diastereomers (36 to 45, and 43 to 47, Scheme 4). This
selectivity is particularly impressive considering the num-
ber of halogen atoms that could participate in anchimeric
Efforts were made to obtain X-ray quality crystals of
stereohexad 37 and its brominated analogue to compare
the conformations of these polyhalides in the solid state.
This presented a clear challenge due to the non-
crystalline nature of such lipids. After intensive efforts, it
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assistance.17 Treating tribromoenediol 43 with the titani-
um-based dihalogenation conditions in the absence of
ligand resulted in a reversal of inherent diastereoselectivi
These unnatural polychloride and polybromide stereo-
1
2
3
4
5
6
7
8
hexads could be crystallized as their p-bromobenzoates,
45 and 47. In contrast to the natural diastereomers, 45
and 47 possess a linear conformation in the solid state
(Scheme 4, bottom). The implications of the structural
differences between these polyhalide diastereomers for
biological systems are intriguing but at this point unclear.
Both pairs of crystal structures for the same diastereomers
of pentachlorides and pentabromides (i.e. 44 and 46, and
45 and 47, Scheme 4) show remarkable conformational
similarity at the unit cell level. This is unexpected given
the differences in Van der Waals radii, polarizability, C–X
bond length and electronegativity between chlorine and
bromine.18 Pentachlorides 44 and 45 also provide charac-
terization data for unnatural diastereomers of the stereo-
hexad contained within the putatively assigned stereooc-
tad of undecachlorosulfolipid 7.6h,i
Scheme 4. Synthesis of Stereohexads 44–47a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
OH Cl
OFcc
Br
OH Br
OFcc
Me
Me
Cl
Cl
Cl
Br
Br
46
Br
44
1) Et4NCl3
(65%, 18:1 dr)
2) Fcc-Cl
1) PyrHBr3
(88%, 7:1 dr)
2) Fcc-Cl
Scheme 5. Retrosynthesis of (–)-Danicalipin A
Cl
OH
Br
OH
Me
Me
Cl
Cl
36
Br
Br
OH
OH
43
1) (R,S)-11 (30 mol %)
t-BuOCl, ClTi(Oi-Pr)3
(55%, >20:1 dr)
1) (R,S)-11 (30 mol %)
NBS, BrTi(Oi-Pr)3
(67%, 11:1 dr)
2) p-Br(C6H4)COCl
2) p-Br(C6H4)COCl
Cl
OH Cl
OR
Br
OH Br
OR
Me
Me
Cl
Cl
Cl
Br
Br
47
Br
45
aX-ray crystal structures of the natural and unnatural dia-
stereomers of the polychloride stereohexad found within
mytilipin A, along with their polybrominated analogues. The
aryl carboxylate esters have been omitted in the crystal struc-
tures for clarity. Fcc = ferrocene carboxylate and R = p-
bromobenzoate.
2.6 Synthesis of (−)-Danicalipin A. The chlorosul-
folipid danicalipin A (5) is estimated to comprise >90% of
all polar lipids in the flagellar membrane of freshwater
Ochromonas danica algae.19 It possesses a unique struc-
ture for a lipid,4b containing two anionic sulfate moieties,
one at the terminus and one near the center of its other-
wise hydrophobic linear core. Owing to this unusual
structural feature and its complex halogenation pattern,
danicalipin A has attracted much synthetic interest. To
date there have been five reported syntheses of dan-
icalipin A, the most efficient of which are 9 and 12 linear
steps by Vanderwal6a and Carreira,6j respectively. Both of
these syntheses commence from allylic alcohol starting
materials. In the Vanderwal synthesis, access to an enan-
tioenriched dichlorinated intermediate is achieved via a
racemic dichlorination followed by resolution of a later
intermediate. In the Carreira synthesis, the vicinal dichlo-
ride motif is established through diastereoselective epoxi-
dation followed by chlorinolysis of the epoxide. We envi-
ty to 1:6 favoring diastereomer 47. Interestingly, the use of
ligand (S,R)-11 resulted in the formation of 47 as the major
diastereomer but in a lower diastereomeric ratio (2.3:1).
On the other hand, the use of ligand enantiomer (R,S)-11
resulted in the formation of 47 with higher diastereoselec-
tivity (11:1 dr). This suggests a matched/mismatched dia-
stereoselectivity scenario between the ligand and the tita-
nium-bound substrate – the inherent selectivity of titani-
um-based dibromination favors diastereomer 47, which is
either enhanced or counteracted by the appropriate chiral
ligand. Application of our dichlorination conditions to 36
with matched ligand enantiomer (R,S)-11 provided selec-
tive access to unnatural 45 in >20:1 dr. Prior to this work,
there was no way to overturn the inherent diastereoselec-
tivity of a given substrate in a dihalogenation without
changing the substrate itself.
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Scheme 6. Concise Synthesis of (−)-Danicalipin Aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReagents and conditions: (a) iodine monochloride (2.0 equiv), 2,6-lutidine (3.0 equiv), CH2Cl2, 0 °C to rt, 74%; (b) (R,R)-1,2-
dicyclohexyl-1,2-ethanediol 55 (1.1 equiv), aq. NaOH, THF, 0 ˚C, 85%; (c) CH2Cl2 (1.5 equiv), n-butyllithium (1.1 equiv), THF, –100
˚C; 56, ZnCl2 (1.0 equiv), –100 ˚C to rt; (d) 59 (1.0 equiv), t-butyllithium (1.1 equiv), Et2O/hexanes, –78 ˚C; magnesium bromide
ethyl etherate (1.2 equiv); then 57 (1.1 equiv), THF, –78 ˚C to rt, 24% from 56; (e) Dess–Martin periodinane (1.3 equiv), NaHCO3
(3.0 equiv), CH2Cl2, 0 °C to rt, 88%; (f) n-butyllithium (1.9 equiv), trifluoroacetic anhydride (1.9 equiv), THF, –78 ˚C; 49 (1.1
equiv), –78 ˚C to rt, 75% (g) methanol-d4, rt; concentrate; tetramethylammonium dichlorobromate (1.1 equiv), CH3CN, rt; (h)
tributyltin hydride (1.1 equiv), triethylborane (0.2 equiv), air, toluene, –78 ˚C, 22% over two steps; (i) chlorosulfonic acid, CH2Cl2,
rt, 93%.
sioned that our chemistry could be used to streamline the
synthesis of danicalipin by providing one-step, enantiose-
lecitve access to the requisite dichloride building block 21.
diol 55 provided chromatographically stable chlorovinyl-
boronic ester 56.20a
Homologation to 1,3-dichloroallyl boronic ester 57 was
next accomplished by treatment of 56 with dichloro-
methyllithium followed by zinc chloride according to
Matteson’s procedure.20b,c Boronic ester 57 was unstable
to chromatographic purification and prolonged storage,
but solutions of crude 57 could be advanced to fully func-
tionalized chloroallyl boronic ester 58 via a reaction in-
volving the Grignard reagent of alkyl iodide 59. Boronic
ester 58 was of >99% ee as determined by Mosher analysis
after oxidation of 58 to its corresponding alcohol. This
selectivity is particularly impressive as α-chloroallyl bo-
ronic esters have a high propensity to epimerize and de-
compose.20a,d Addition of magnesium bromide diethyl
etherate to the organolithiate was crucial, as solutions of
the intermediate organolithiate were found to be unstable
and rapidly undergo lithium-halogen exchange on the
gem-dichloride moiety.
Strategically, it was thought that the unnatural enanti-
omer of danicalipin A might be prepared through a for-
mal hydrochlorination of trans alkene 48, followed by
sulfation (Scheme 5). Enantioenriched chlorohydrin al-
kene 48 might then be synthesized through an enantiose-
lective chloroallylation reaction involving enantioen-
riched dichloroaldehyde 49 and a discrete, enantiopure
chloroallylboronate of general structure 50. Aldehyde 49
would arise from dichlorination and oxidation of allylic
alcohol 20. It was surmised that highly functionalized
chloroallylboronate 50 might be prepared stereoselective-
ly from a (Z)-chlorovinylboron reagent 51 and organome-
tallic species 52 and 53 via the homologation chemistry of
Matteson.20
The forward synthesis commenced with the develop-
ment of a scalable synthesis of an appropriate (Z)-
chlorovinylboron reagent (Scheme 6). The preparation of
an analogous (Z)-(2-bromovinyl)-MIDA boronate has
been accomplished previously by Burke.21 Following a sim-
ilar strategy it was found that (Z)-(2-chlorovinyl)-MIDA
boronate could be synthesized efficiently in one step by
treatment of commercially available 54 with iodine mon-
ochloride in the presence of 2,6-lutidine. The pure prod-
uct could be easily isolated by precipitation from diethyl
ether. Subsequent treatment with aqueous hydroxide in
the presence of one equivalent of commercial enantiopure
With chloroallyl boronic ester 58 in hand, allylation re-
actions were attempted with aldehyde 49 which was ob-
tained through oxidation of enantioenriched dichloroal-
cohol (–)-21. Initial attempts were low yielding and re-
quired excess dichloroaldehyde due to its propensity to
decompose under the reaction conditions. Gratifyingly, it
was found that chloroallyl boronic ester 58 could be in-
duced to react efficiently with aldehyde 49 at low temper-
ature by first activating it in situ as the borinate. This was
accomplished through the addition of n-butyllithium and
trifluoroacetic anhydride following a procedure developed
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by Aggarwal.22 Accordingly, this reaction afforded gram-
rationalization is that bromonium formation is reversible
1
2
3
4
quantaties of chlorohydrin alkene 60 as a single enantio-
and diastereomer in 75% yield. Serendipitously, it was
discovered that a kinetic resolution occurs during this
chloroallylation reaction, with the minor enantiomer of
dichloroaldehyde 49 being essentially unreactive.
and deprotonation of the alcohol during bromoetherifica-
tion is selectivity determining. Accordingly, the stronger
oxygen-deuterium bond would be harder to heterolytical-
ly cleave, effectively disfavoring the bromoetherification
pathway.
5
6
7
8
9
After failed attempts to directly hydrochlorinate 60,23
a
Our synthesis of the unnatural enantiomer of dan-
icalipin A was completed by radical debromination of 63
followed by sulfation (Scheme 6). It is noteworthy that
radical debromination can be carried out chemoselective-
ly (74% yield based on recovered starting material) in the
presence of alkyl chloride and geminal dichloride func-
tionalities. The described synthesis is 8 linear steps and
provides access to a single isomer of (–)-danicalipin A (–)-
5.
formal hydrochlorination was achieved through a bromo-
chlorination–radical debromination sequence.24 Initial
attempts to bromochlorinate 60 provided the desired
bromochloride in low yield due to competitive bromoeth-
erification arising from capture of an intermediate bro-
monium by the secondary alcohol of 60. Investigation of
bromochlorination conditions identified Me4N(Cl2Br)25 as
the best source of “BrCl,” providing the desired bromo-
chloride 63 in a mere 21% yield along with 65% yield of
bromoether 64, both as single diastereomers (Scheme 7).
Although low yielding, the clean reactivity was encourag-
ing as previous reports concerning the iodochlorination of
similar substrates gave complex mixtures of products.6a
Protection of the alcohol in 60 completely shut down any
desired reactivity and underscored the need for having a
free alcohol for this dihalogenation reaction. This led us
to hypothesize that the ratio of desired bromochloride to
undesired bromoether might be influenced by O-
deuteration of 60 as this should alter the nature of hydro-
gen bonding between substrate and halogenating agent.
In practice it was found that pretreatment of alcohol 60
with methanol-d4 followed by solvent removal and subse-
quent reaction with Me4N(Cl2Br) in acetonitrile increased
the yield of the bromochlorination to 44%.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. CONCLUSION
The enantioselective dichlorination and dibromination
of electronically unbiased, aliphatic allylic alcohols has
been demonstrated. The developed method is practical,
scalable, and provides access to valuable dichloroalcohols
used in the preparation of chlorosulfolipid natural prod-
ucts. Enantioselective syntheses of two chlorosulfolipids,
ent-(−)-deschloromytilipin (–)-3 and ent-(−)-danicalipin A
(–)-5, using this chemistry as the first step has been de-
scribed, highlighting the utility and practicality of the
system. We anticipate that this method could enable the
selective syntheses of all members of the chlorosulfolipid
family. Conversion of the dihaloalcohol products to the
relevant stereoarry of naturally occurring stereohexads
has provided insight into the absolute stereochemistry of
these molecules as well as their conformation. The tactics
reported here may be applied to both the synthesis and
structural assignment of undecachlorosulfolipid 7 whose
structure remains ambiguous.6h,i
Scheme 7. Rationale for the Effect of O-Deuteration
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterizations, spectral data,
and CIF files.
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
Rationale for this observed change in product ratio is
depicted in Scheme 7. Based on the subsequent transfor-
mation of bromochloride 63 to (–)-danicalipin A (–)-5
(Scheme 6) and NOE analysis of bromoether 64 (see Sup-
porting Information), it was determined that these prod-
ucts likely arise from diastereomeric bromonium inter-
mediates 61 and 62. Assuming bromonium formation oc-
curs on the conformer for 60 displayed in Scheme 7, the
undesired bromonium formation could be directed
through hydrogen bonding of the secondary alcohol; deu-
teration may then render this direction less effective, thus
reducing the amount of bromoether. Another possible
*nburns@stanford.edu
Funding Sources
This work was supported by Stanford University, the Nation-
al Institutes of Health (R01 GM114061), and the National Sci-
ence Foundation (DGE-114747 GRF to MLL and DXH).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to Dr. A. Oliver (University of Notre Dame)
for X-ray crystallographic analysis and Dr. S. Lynch (Stanford
University) for assistance with NMR spectroscopy.
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Journal of the American Chemical Society
(7) Hu, D. X.; Seidl, F. J.; Bucher, C.; Burns, N. Z. J. Am. Chem.
Soc. 2015, 137, 3795–3798.
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catalytic
enantioselective
OH
Cl
OH
6 steps
dichlorination
R
R
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X-ray
4 steps
4 steps
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O3SO
Cl
Cl
OSO3 Cl
Cl Cl
O3SO
Me
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(–)-danicalipin A
(–)-deschloromytilipin A
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