General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form

Article abstract of DOI:10.1021/jo5000829

A second-generation synthesis of three structurally related chlorosulfolipids has been developed. Key advances include highly stereocontrolled additions to α,β-dichloroaldehydes, kinetic resolutions of complex chlorinated vinyl epoxide intermediates, and Z-selective alkene cross metatheses of cis-vinyl epoxides. This strategy facilitated the synthesis of enantioenriched danicalipin A, mytilipin A, and malhamensilipin A in nine, eight, and 11 steps, respectively.

Full text of DOI:10.1021/jo5000829

Article
pubs.acs.org/joc
General Approach to the Synthesis of the Chlorosulfolipids
Danicalipin A, Mytilipin A, and Malhamensilipin A in Enantioenriched
Form
Won-jin Chung, Joseph S. Carlson, and Christopher D. Vanderwal*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
*
S Supporting Information
ABSTRACT: A second-generation synthesis of three structur-
ally related chlorosulfolipids has been developed. Key advances
include highly stereocontrolled additions to α,β-dichloro-
aldehydes, kinetic resolutions of complex chlorinated vinyl
epoxide intermediates, and Z-selective alkene cross metatheses
of cis-vinyl epoxides. This strategy facilitated the synthesis of
enantioenriched danicalipin A, mytilipin A, and malhamen-
silipin A in nine, eight, and 11 steps, respectively.
INTRODUCTION AND BACKGROUND
attractive research problems. Since 2009, the groups of
■
3
4
5
6
1
,2
Carreira, Yoshimitsu, Matsuda, and our own have
contributed syntheses of chlorosulfolipids and, in so doing,
have taken what once looked like intractable problems for
synthesis and found multiple creative ways for their
construction. With the exception of Carreira’s tour de force
Almost 40 years after the first report of their existence,
intense activity aimed at the chemical synthesis of the
chlorosulfolipids (1−5, Figure 1) began independently and
essentially simultaneously in at least four research groups
around the world. Apparently purely coincidental, this
confluence of research might well have stemmed from the
fact that truly novel and unstudied classes of natural product
targets are extremely rare in current times and make very
2i
synthesis of the proposed structure of mytilipin C (5) that
3c
determined the incorrectness of that structure, all of the
published work to date has been focused on the three
3
a,4b,6e
structurally similar chlorosulfolipids mytilipin A (3),
danicalipin A (1),
4c,5,6b
6d
and malhamensilipin A (2). At the
outset of our work, we sought a general strategy toward these
three targets; however, the unknown relative configuration of
danicalipin A and malhamensilipin A prevented the develop-
ment of such an approach at the time. Our productive
collaboration with the Gerwick group unveiled the relative and
6
b,c
absolute configuration of these two lipids and revealed that a
central” stereotriad was conserved among the three lipids (1−
), but that there were important differences at other centers.
“
3
Indeed, the difference at C16 between danicalipin A and
malhamensilipin A precluded the direct translation of our
successful synthesis of the former to the latter.
3a
The approaches adopted for mytilipin A by Carreira and for
6b,d
danicalipin A and malhamensilipin A by our group
took
advantage of alkene oxidation reactions for the introduction of
all of the polar atoms in the stereochemically rich regions of
these targets. However, since shortly after our interest in the
chlorosulfolipids began, we have been keenly interested in an
approach involving diastereoselective carbonyl additions to α,β-
Received: January 13, 2014
Figure 1. Representative chlorosulfolipids.
©
XXXX American Chemical Society
A
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Scheme 1. a. Previous Synthesis of Racemic Danicalipin A. b. General Approach to Danicalipin A, Malhamensilipin A, and
Mytilipin A Featuring Carbonyl Additions to α,β-Dichloroaldehydes and Convergent Z-selective Alkene Cross Metathesis
dichloroaldehydes. Conceptually, this approach was attractive
because these starting materials are easy to accessat least in
racemic formand additions to the aldehyde should be highly
could be generalized to targets 1−3 that obviates the
troublesome Wittig olefination and that takes advantage of
the common stereotriad highlighted in Figure 1. The synthesis
plan that was most attractive is shown in Scheme 1b.
Stereospecific anti-dichlorination of either an (E)- or a (Z)-
allylic alcohol will lead to anti- or syn-dichloroalcohol products,
7
stereocontrolled. However, the poor stability of the these
aldehydes, which eliminate HCl easily, prevented our early
attempts to use this tactic. To our knowledge, only Yoshimitsu
and co-workers had successfully added nucleophiles to α,β-
7,8
respectively. Assuming high levels of 1,2-stereoinduction,
a
4
b,c
dichloroaldehydes prior to the work that we describe here. It
was that significant challenge in implementation that led us
instead to the alkene oxidation approach that permitted the first
haloallylation reaction would afford either syn-halohydrin 15 or
cis-vinyl epoxide 16, depending upon workup conditions. Either
of these intermediates could be productive substrates for Z-
selective alkene cross metathesis as a replacement for the Wittig
olefination; the products that result would intersect with the
late stages of our previous syntheses. The major impediments
to the implementation of this plan were: (1) it was not certain
that an efficient and stereoselective carbonyl addition to
dichloroaldehydes would be possible; (2) there was no obvious
way to render the synthesis enantioselective; and (3) Z-
selective alkene cross metathesis was, at the time we began this
work, very much in its infancy and was not certain to work on
such unusual and potentially reactive substrates.
6
b,d
syntheses of danicalipin A and malhamensilipin A.
Although effective, our first-generation syntheses of 1 and 2
were fraught with the several problems: (1) the critical
convergent Wittig reaction was both poorly stereocontrolled
and somewhat erratic in terms of reproducibility; (2) the
enantioselective route to malhamensilipin A could not be
applied to danicalipin A because of a stereochemical difference
in the targets; and (3) the routes were longer than we had
hoped. In this article, we describe the evolution of our second-
generation strategy that is applicable to chlorosulfolipids 1−3 in
enantioenriched forms by virtue of an interesting kinetic
resolution of chlorinated cis-vinyl epoxides. This approach also
obviates the troublesome Wittig reaction, which is replaced by a
convergent Z-selective alkene cross metathesis reaction. The
results are (1) for danicalipin A, eight steps racemic, nine steps
RESULTS AND DISCUSSION
■
Because of our familiarity with its late-stage chemistry, we
aimed to first apply our new strategy to an enantioselective
synthesis of danicalipin A. As a result, in the following sections,
we will first discuss the solutions to the three key unknowns
described above in the context of this target. We will then
demonstrate the generality of the approach with the syntheses
of all three targets in subsequent sections.
6b
enantioselective (previous best 12 steps racemic or 13 steps
4
c
enantioselective ); (2) for mytilipin A, seven steps racemic,
3
a,d
eight steps enantioselective (previous best 10 steps racemic
4b
or 19 steps enantioselective ); and (3) for malhamensilipin A,
1 steps formal enantioselective (previous best was our
1
6d
Additions to α,β-Dichloroaldehydes. For our new
synthetic route, it was necessary to develop conditions for
mild and highly diastereoselective haloallylation of α,β-
dichloroaldehydes to establish an efficient route toward the
requisite cis-vinyl epoxide of type 16. In our earliest studies,
attempted Grignard, organolithium, or alkali metal enolate
additions to these aldehydes were met with failure, as were
previous 12-step route, which was the only prior synthesis ).
SYNTHESIS PLAN
■
To put the second-generation approach into perspective, our
first synthesis of racemic danicalipin A is shown in Scheme 1a.
As alluded to above, we were aiming for a shorter synthesis that
B
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Lewis acid-catalyzed addition of π-nucleophiles. While the
Preparation of Enantioenriched Intermediates via
Kinetic Resolution. Because we were clearly beholden to
starting our synthesis from α,β-dichloroaldehydes, we required
either enantioselective access to these key intermediates, or a
means to resolve them, if we were to render our synthesis
enantioselective. Although technology for asymmetric alkene
chlorination is improving, with Nicolaou’s recent enantiose-
4
b,c
Yoshimitsu group had some success in this area,
Carreira
alludes to similar problems in their disclosure of the mytilipin A
3
a
synthesis. On the other hand, additions to α-chloroaldehydes
were generally quite efficient and often stereoselective; these
outcomes were not surprising given the lack of elimination
pathways and the rather well-known stereocontrol imparted by
8
11
α-acceptor groups on carbonyl additions. For example, the
lective dichlorination of allylic alcohols being particularly
chloroallylation of α-chloroisovaleraldehyde (19) with (Z)-γ-
noteworthy, there is not currently a method that would prove
economical enough in the preparation of highly enantioen-
riched dichloroalcohols to service a natural product synthesis
endeavor of this type.
9
chloroallylstannane 20 in the presence of BF ·OEt provided
3
2
undesired syn,syn-21 with high diastereoselectivity (Scheme 2a).
Scheme 2. a. Chloroallylation of α-Chloroaldehyde.
b. Synthesis of Racemic cis-Vinyl Epoxide (± )-30
Certainly, we spent some time trying to develop just such a
reaction, but with no success. Attempts to obtain enantioen-
riched material via enantioselective dichlorination with
12
Cinchona alkaloid-derived chiral variants of Mioskowski’s
1
3
reagent (Et NCl ) or resolution of dichlorinated primary
4
3
14
alcohols by peptide-catalyzed or enzymatic means were
unsuccessful. Of course, highly effective examples of enzymatic
15
resolution of chiral primary alcohols are few.
Clearly, either resolution methods of later stage intermedi-
ates or Yoshimitsu’s elegant stereospecific dichlorodeoxy-
4a
genation reactions of epoxides were the most promising
ways to access enantioenriched intermediates. Owing to the
single additional step involved in resolutions compared with the
multiple steps involved in the epoxide-based strategy, we took
the former approach to solve our problem.
The Carreira group developed an asymmetric variant of their
synthesis of mytilipin A (3) via (parallel) resolution of racemic
3d
dichloride 31 (eq 1). Sharpless asymmetric epoxidation of the
allylic alcohol functional group afforded epoxide 32 in 1.3:1 dr;
the enantiopurity of the desired diastereomer was moderate at
8
9:11 er.
We undertook an extensive investigation into asymmetric
Not surprisingly, this reaction type was not successfully
extended to electrophiles with β-chlorides. In contrast, 19
could be converted to desired anti,syn-21 by chloroallylation
carbonyl additions to α,β-dichloroaldehydes using chiral
reagents or catalysts. The kinetic resolutions of racemic α,β-
dichloroaldehyde (±)-27 via enantioselective haloallylation
with chiral Oehlschlager/Brown haloallylborane reagents (33/
10
with (Z)-γ-chloroallylborane 22. However, the base-pro-
moted epoxide formation surprisingly proceeded with poor site
selectivity to give a mixture of constitutional isomers 23 and 24.
Nonetheless, this haloallylborane reactivity could be extended
to α,β-dichloroaldehydes (see below), and this outcome was
the first hint that this type of electrophile tends to survive the
milder conditions associated with closed transition structure
allylations and related reactions. These observations were
important in the eventual discovery that bromoallylaluminum
10
34) proceeded with poor enantioselectivity (Scheme 3a).
According to the enantioselective chloroallylation procedure of
16
Kobayashi, the chiral zinc catalyst derived from the bipyridine
ligand 38 afforded the product (−)-35 in moderate
enantiopurity, and useful selectivity factors were achieved
(Scheme 3b). However, the resolved starting material, which is
always easier to obtain in higher enantiopurity via kinetic
17
resolution, was unstable to the reaction conditions and could
not be isolated, leaving only partially resolved product 35.
Furthermore, as we showed in Scheme 2a, epoxide formation
from α,α′-dichloroalcohols of type 35 was not selective, and the
bromoallylation corresponding to that shown in Scheme 3b was
never successfully implemented.
9
reagents of type 28 were optimal from the perspectives of
efficiency, stereoselectivity, and ease of preparation. An
attractive sequence resulted: after dichlorination of (E)-2-
nonen-1-ol (25) and careful oxidation with the Dess−Martin
periodinane, bromoallylation followed by basic workup afforded
vinyl epoxide 30 as a single regioisomer in high yield and with
essentially perfect diastereoselectivity consistent with both the
Felkin−Anh and Cornforth models (Scheme 2b). This
sequence could produce racemic 30 in multigram scale in
about 70% yield from the commercially available allylic alcohol
precursor.
We next considered resolving racemic vinyl epoxide 30
derived from diastereoselective haloallylation/epoxide forma-
tion of the α,β-dichloroaldehyde (Scheme 2b). This type of
vinyl epoxide was readily prepared on multigram scale and
should be easily recovered after kinetic resolution. Furthermore,
it has a strong bias for regiocontrol of ring opening; clearly the
C
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1
9a
Scheme 3. a. Haloallylation of Dichloroaldehyde with a
Chiral Boron Reagent. b. Chloroallylation of
Dichloroaldehyde with Chiral Zinc Lewis Acid
(1S,2S)-42 in high enantiopurity (Scheme 4a). Later, it was
found that the dimeric phosphoramide Lewis base (R,R)-41,
which is typically more selective for other SiCl -mediated
4
enantioselective transformations, provided (1S,2S)-42 with
19b
notably diminished enantiopurity. The stereochemical out-
come of desymmetrization of meso-epoxide suggested that the
(
R)-BINAM-derived phosphoramde Lewis base catalysts would
enrich our cis-vinyl epoxide reactants in the desired enantiomer
by selectively catalyzing ring-opening chlorinolysis of the
undesired enantiomer.
Under Denmark’s conditions, the cis-vinyl epoxide (±)-30
was found to be less reactive than meso-epoxides, probably
because of the more sterically congested environment
presented by the proximal chlorine bearing carbons. Con-
sequently, the kinetic resolution with (R)-40 was carried out at
slightly elevated temperature (−50 °C) with higher catalyst
loading (20 mol%) (Scheme 4b). Unfortunately, the resolution
with (R)-40 proceeded with poor selectivity (selectivity factor,
S = 4). Surprisingly, in contrast to Denmark’s result, the
dimeric chiral Lewis base (R,R)-41 was more selective (S = 14)
for our kinetic resolution than the monomeric chiral Lewis base
allylic terminus is activated while the other epoxide carbon is
deactivated by the proximal chlorides. Therefore, we postulated
that some of the many available enantioselective meso-epoxide
desymmetrization protocols should be plausibly extended to
kinetic resolution of substrates of type 30.
(
R)-40. Interestingly and unexpectedly, the resolved vinyl
epoxide from the kinetic resolutions with (R)-40 and (R,R)-41
were enriched in the opposite enantiomers. Other chiral Lewis
bases such as trans-cyclohexanediamine-derived phosphoramide
(
R,R)-43 and (R)-BINAPO ((R)-44) were also tested. These
We began with Jacobsen’s epoxide opening chemistry, using
18
Lewis bases were more reactive than (R)-40 or (R,R)-41 but
virtually unselective (S < 3). Clearly, we had a good lead with
catalyst (R,R)-41 at this point.
highly reactive (R,R)-(oligosalen)Co catalysts. To the best of
our knowledge, resolutions of internal epoxides with the
Jacobsen system have not been reported; however, we felt
that the cis-vinyl epoxide might be a close structural mimic of
competent cyclic meso-epoxides that are frequently desymme-
trized using Jacobsen chemistry. Surprisingly, substrate 30
proved unreactive toward nucleophiles such as water, phenol,
or benzyl alcohol under published conditions for desymmet-
rization of meso-epoxides. For reasons that we do not
understand, Denmark’s catalytic system for desymmetrization
During the optimization of the kinetic resolution, it was
found that the selectivity is highly dependent on the reaction
temperature. When (±)-30 was resolved with 10 mol% of
(R,R)-41 at −78 °C, a substantially improved selectivity factor
of 33 was obtained (Table 1, entry 1). However, the reaction
was even more sluggish and proceeded to only 24% conversion
after 24 h. Even with higher catalyst loading (20 mol%) and
extended reaction time (48 h), the conversion was improved to
only 42% and the reaction became increasingly slower as the
1
9a,b
of meso-epoxides via ring-opening chlorinolysis,
“
using the
1
9c
Lewis base activation of Lewis acids” concept, proved much
more successful. In the original Denmark group study, meso-
stilbene oxide (39) was effectively desymmetrized in the
presence of a chiral phosphoramide Lewis base catalyst (R)-40
reaction progressed (entry 2). The amounts of SiCl and i-
4
Pr NEt seem to have little effect on the conversion and
2
selectivity. Because it is reasonable to postulate that the rate of
chlorinolysis would be increased at higher concentration of
and SiCl , a weak Lewis acid, to afford the syn-1,2-chlorohydrin
4
Scheme 4. a. Denmark’s Desymmetrization of meso-Epoxides. b. Preliminary Study of Chiral Lewis Base-Catalyzed Kinetic
Resolution of cis-Vinyl Epoxide (± )-30. Selectivity Factor, S = k /k
= ln[(1 − conversion)(1 − ee)]/ln[(1 −
fast slow
conversion)(1 + ee)]. c. Chiral Lewis Bases Studied for Kinetic Resolution
D
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a
Table 1. Optimization of Kinetic Resolution of (± )-30
b
c
d
entry
1
concentration (M)
time (h)
conversion (%)
er (reactant)
er (product)
S
0.1
0.1
0.1
0.2
0.4
1.0
0.05
0.2
24
48
48
48
24
24
72
24
24
42
61
41
44
66
32
53
66.0:34.0
84.5:15.5
93.1:6.9
3.9:96.1
5.3:94.7
22.2:77.8
5.8:94.2
10.0:90.0
31.9:68.1
2.5:97.5
88.1:11.9
33
37
9
e
2
f
3
4
5
6
7
83.9:16.1
83.7:16.3
88.7:11.3
72.4:27.6
33
18
5
61
27
,
eg
8
2.7:97.3
a
b
1
c
All reactions employed 1.0 equiv of SiCl and 0.1 equiv of i-Pr NEt on 0.1−2.0 mmol scale. Determined by H NMR analysis. Determined by
4
2
d
e
f
g
CSP-GC. Determined by CSP-SFC after 2,4-dinitrobenzoylation. 20 mol% of catalyst. 1.0 equiv of Et NCl. Preparative scale, using (S,S)-41, to
4
preferentially recover (−)-30.
chloride nucleophile, the kinetic resolution was conducted in
the presence of exogenous soluble chloride (entry 3). Although
the conversion was improved to 61% in the presence of 1 equiv
Scheme 5. Synthesis of Racemic cis-Vinyl Epoxide (± )-49
of Et NCl, the selectivity factor diminished significantly. It was
4
also possible to improve the conversion by adopting higher
concentrations. The kinetic resolution could be efficiently
carried out at 0.2 M with little attenuation of selectivity (entry
4). The reaction could be further accelerated by further
increasing the concentration; however, the selectivity factor
decreased substantially (entries 5 and 6). On the other hand,
the selectivity factor could be improved by performing the
reaction in more diluted condition. A selectivity factor of 61
was obtained at 0.05 M even though the reaction was too slow
to be practical (entry 7). Unfortunately, the mechanistic origin
for the drastic effects of the exogenous chloride and the
reaction concentration on the selectivity was unclear.
Eventually, an ideal 53% conversion was achieved with 20
mol% of (S,S)-41 after 24 h at 0.2 M, and the desired
enantiomer of unreacted vinyl epoxide (−)-30 was isolated in
Surprisingly, the kinetic resolution of (±)-49, which differs
only by alkyl chain length compared to (±)-30, was only
moderately efficient with catalyst (R,R)-41. Under the
optimized conditions developed for (±)-30, a selectivity factor
of only 6 was obtained (Table 2, entry 1). Although it was
a
Table 2. Optimization of Kinetic Resolution of (± )-49
43% yield with 97.3:2.7 er on a preparative scale (entry 8 and
eq 2). The catalyst could be fully recovered after reaction.
b
concentration
(M)
time
(h)
conversion
(%)
er
c
entry
(reactant)
S
1
2
3
4
0.2
24
36
72
72
56
66
65
57
84.6:16.4
6
d
0.2
92.4:7.6
6
8
0.15
0.1
94.8:5.2
93.4:6.6
13
The optimized kinetic resolution conditions were next
applied to a substrate that was destined for the enantioselective
synthesis of mytilipin A. The cis-vinyl epoxide (±)-49 was
prepared in a similar manner to that used to make (±)-30
a
All reactions employed 1.0 equiv of SiCl and 0.1 equiv of i-Pr NEt
4
2
b
1
and were conducted on 0.25−0.54 mmol scale. Determined by H
NMR analysis. Determined by CSP-GC. Determined by CSP-SFC
after benzoylation.
c
d
(
Scheme 5). (E)-Crotyl alcohol (45) was treated with
molecular chlorine in the presence of Et NCl to give the
4
anti-1,2-dichloride (±)-46. Oxidation with the Dess−Martin
periodinane followed by a careful workup afforded the sensitive
and volatile α,β-dichloroaldehyde (±)-47 in crude form, which
was immediately converted to volatile cis-vinyl epoxide (±)-49
via bromoallylalumination and epoxide formation, again with
near perfect diastereocontrol. The moderate yield in this case
can be attributed to volatility of the intermediate aldehyde and
the vinyl epoxide product.
possible to recover (+)-49 with an improved enantiopurity at
higher conversion (entry 2), a more practical level of selectivity
was desired. Similarly to the case of (±)-30, higher selectivity
could be achieved at lower concentration. Consequently, the
selectivity factor was improved to 8 at 0.15 M concentration
(entry 3). Furthermore, a selectivity factor of 13 at 57%
conversion was realized at 0.1 M concentration, and
enantioenriched (+)-49 was isolated in 93.4:6.6 er and 43%
E
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yield (entry 4 and eq 3). The monomeric phosphoramide (R)-
exogenous chloride, while likely to accelerate the reaction,
would equally likely attenuate the already very low
enantioselectivity, as we had previously observed in the study
of (±)-30. When (±)-55 was resolved with the typically more
reactive (S)-BINAPO ((S)-44), a much higher reaction rate
was indeed observed. Contrary to previous cases, the selectivity
factor was also improved, although it was still moderate (S = 8−
40 and (R)-BINAPO ((R)-44) were even less selective (S =
9
). From a preparative scale reaction, the resolved vinyl epoxide
−)-55 was obtained in 3.4:96.6 er and 34% yield. Several
related chiral bis(phosphine oxide)s such as (S)-Tol-BINAPO,
S)-H -BINAPO, and (R)-SEGPHOS dioxide were also tested,
(
(
8
but the selectivity was not improved.
Convergent Z-Selective Alkene Cross Metathesis.
Concurrent with the development of an effective kinetic
resolution method, the key convergent metathesis step was
investigated with (±)-30, a potential precursor to danicalipin A.
At the time of conception of our metathesis-based second-
generation approach, only the first hint that Z-selective alkene
cross metathesis was a viable reaction had appeared in the
literature. Moreover, whereas a Z-configured alkene is
required en route to malhamensilipin A and mytilipin A so
that stereospecific anti-dichlorination would afford the correct
relative syn-configuration (at C11/C12 and C9/C10, respec-
tively), it was not obviously a necessity for danicalipin A
because of the unchlorinated carbon at C12. Therefore, the
feasibility of the alkene cross metathesis approach was initially
evaluated with normal alkene metathesis catalysts.
∼
4, not shown), although (R)-BINAPO was more reactive than
dimeric phosphoramide catalyst (R,R)-41. Curiously, it was
difficult to reliably analyze the enantiopurity of the chlorohy-
drin product (+)-50 because of apparently facile selective
sublimation of the major enantiomer under vacuum, which
2
1
20
resulted in enantiodepletion of the sample (eq 4).
The same kinetic resolution strategy was also examined for
the enantioselective synthesis of (+)-malhamensilipin A. The
corresponding cis-vinyl epoxide (±)-55, which differs from
substrates 30 and 49 by virtue of its syn-1,2-dichloride moiety,
was prepared from (Z)-2-undecen-1-ol (51) via the same
sequence used for previous substrates (Scheme 6a). Unfortu-
Two different orders of operations were considered for
alkene cross metathesis and ring-opening chlorinolysis (Scheme
7
). The left-hand sequence involves the alkene cross metathesis
Scheme 6. a. Synthesis of Racemic cis-Vinyl Epoxide (± )-55.
b. Kinetic Resolution of (± )-55
Scheme 7. Possible Orders of Operations for Alkene Cross
Metathesis and Ring-Opening Chlorinolysis
of a vinyl epoxide (16) followed by chlorinolysis of the
resulting internal alkenyl epoxide, which might be plagued by
double inversion at the allylic center and S 2′ side reactions, as
N
seen in previous studies. On the other hand, the right-hand
sequence is initiated with chlorinolysis of the terminal vinyl
epoxide, which might proceed as a clean S 2 reaction under
N
certain conditions, for example, the “racemic version” of the
vinyl epoxide chlorinolysis resolution using SiCl and an achiral
4
Lewis base catalyst such as HMPA. The resulting allylic
chlorohydrin 15 would then be a potential substrate for
subsequent alkene cross metathesis to deliver 58. With the
latter sequence, the enantioenriched 1,2-chlorohydrin product
from the kinetic resolution could also be conveniently utilized
for the synthesis of enantiomeric chlorosulfolipids.
nately, (±)-55 was considerably less reactive toward chlor-
inolysis than the other vinyl epoxide substrates, and the
enantioselectivity was very poor (Scheme 6b). Under the
general conditions with 20 mol% of (R,R)-41, the resolution
proceeded to only 15% conversion even after 72 h and afforded
a selectivity factor of only 4. Modified reaction conditions with
higher concentrations, higher temperatures, or addition of
Electron-poor allylic chloride (±)-35 underwent alkene cross
metathesis with 1-decene in the presence of 10 mol% of the
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Grubbs second-generation catalyst (G II) at room temperature
to afford the (E)-alkene product 59 in 43% yield along with
dimeric side products (Scheme 8); because of the relatively
Scheme 9. Alkene Cross Metathesis of 35 with Z-Selective
Catalyst 60
Scheme 8. Alkene Cross Metathesis of (± )-35
Scheme 10. Alkene Cross Metathesis between 30 and Simple
Terminal Alkenes
complex crude reaction mixture, it was difficult to determine
the inherent E/Z selectivity of this reaction. The Hoveyda−
Grubbs second-generation catalyst (HG II) promoted slower
but cleaner alkene cross metathesis to give an 84:16 E:Z
mixture of alkene isomers in 85% conversion and 60% yield of
isomerically pure 59. Unfortunately, iodochlorination of 59
with ICl provided a complex crude mixture (not shown), in
contrast to the case of the corresponding Z-isomer that had
been iodochlorinated with high efficiency in our first-generation
approach, although with low diastereoselectivity. Attempts to
directly hydrochlorinate the unactivated alkene under iron-
mediated radical hydrofunctionalization conditions recently
22
reported by Boger was also unsuccessful, probably because of
the low reactivity of the electron-deficient alkene.
To generate the more desirable (Z)-alkene isomer, Z-
selective alkene cross metathesis of allylic chloride 35 with
various terminal alkene partners in the presence of recently
∼57 and 10%, respectively based on NMR integration). In
contrast, a complex mixture was obtained from the similar
reaction with HG II. While the desired product was not
detected, one of the major components in the crude mixture
was identified as the unsaturated chloroaldehyde 65, which
implies the formation of α,β-dichloroaldehyde 27 (Scheme 2b)
under the reaction conditions. Additionally, the presence of
chlorohydrin 66 as a minor component in the crude mixture
further suggests the formation of 27 followed by elimination of
HCl, which is presumably responsible for epoxide chlorinolysis
of a small amount of desired alkene cross metathesis product.
The formation of 65 was confirmed from the reactions between
30 and HG II (10 and 100 mol%) in the absence of other
metathesis partners. At this stage, we cannot put forth a
reasonable mechanism for this interesting three-carbon
degradation of vinyl epoxides. We have not investigated the
generality of this reaction type.
23
developed Grubbs cycloadamantyl catalyst 60, which was
generously provided first by the Grubbs group and later by
Materia, was investigated. However, not only 35 but also
hydroxy-protected substrates and the less chlorinated substrate
6
2 exhibited no reactivity (Scheme 9). Ruthenium metathesis
catalysts are clearly able to execute cross metatheses of allylic
chlorides; at this stage, we have no reasonable understanding of
the apparent limitation of the Z-selective catalysts toward allylic
chlorides, nor do we know if it is a truly general limitation.
Alternatively, the corresponding cis-vinyl epoxide was
examined as a substrate for alkene cross metathesis. Similarly
to the corresponding allylic chloride, cis-vinyl epoxide (±)-30
underwent alkene cross metathesis with 1-decene in the
presence of 10 mol% of G II to afford 64 with moderate
8
2:18 E:Z-selectivity (Scheme 10). Unlike the case of
Gratifyingly, cis-vinyl epoxide 30 turned out to be a
competent substrate for Z-selective alkene cross metathesis.
In the presence of 1 mol% of catalyst 60, 30 underwent alkene
cross metathesis with an excess of 1-hexene to 12% conversion
at 35 °C in 1 h (Scheme 11). The Z-isomer of vinyl epoxide 67
chlorohydrin substrates, it was difficult to separate the internal
alkenyl epoxide product from the unreacted terminal vinyl
epoxide reactant. These compounds were isolated as a mixture
(
estimated yields of the product and the recovered reactant:
G
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Scheme 11. Z-Selective Alkene Cross Metathesis of 30 with
Scheme 12. a. Preparation of Potential Alkene Cross
Metathesis Partners 70 and 71 for the Synthesis of
1-Hexene
Danicalipin A and Malhamensilipin A. b. Z-Selective Alkene
Cross Metathesis of 30 for the Synthesis of Danicalipin A
(
all compounds shown are racemic)
was produced with exquisite selectivity. Such exceptionally high
23
Z-selectivity had only been rarely observed with this catalyst.
Other solvents such as toluene or dichloromethane had no
significant impact on the conversion and selectivity. The
catalytic activity was typically lost within a few hours, and the
reactions would proceed no further. The conversion could be
improved to about 50−60% (NMR estimate) with higher
loading of catalyst (10 mol%), and the use of chlorinated
solvents such as dichloromethane or 1,2-dichloroethane proved
beneficial because of the poor solubility of 60 in other solvents.
However, the decomposition of the starting vinyl epoxide was a
serious side reaction, and significant amounts of an as yet
unidentified decomposition product were formed.
With this preliminary success in hand, we turned to the use
of the relevant alkene 71 as the metathesis partner, which was
24
made from known aldehyde 68 via a slight modification of
4c
Yoshimitsu’s procedure as shown in Scheme 12a. This high
molecular weight compound could not be used in as large
excess as the model alkenes owing to effects on reaction
concentration; initial reactions suffered from very low
efficiencies, and the decomposition of the starting vinyl epoxide
remained problematic. The related alkene 70, with a free
hydroxyl group and attendant lower molecular weight that
could potentially be used in greater excess, was unreactive
and drive these reactions to higher conversion. Therefore, the
reaction was carried out under static vacuum, continuous
vacuum, and in an open vessel inside a glovebox, but to no
avail. More rigorous removal of ethylene was attempted by
vigorously bubbling argon through the reaction mixture, and
gratifyingly, the formation of the unknown was finally
prevented. Under optimized conditions, with 10 mol% of 60,
(±)-10 was obtained in 19% yield along with 74% recovered
starting material (Scheme 12b). It was more challenging to
suppress the decomposition with higher catalyst loadings, and
the mass balance was poorer. The decomposition could be
minimized by slowing down the reaction rate via a portionwise
addition of catalyst, giving the product 10 in 29% yield with
40% recovered starting material using 30 mol% of 60. Although
we were unable to achieve more than the equivalent of a single
turnover, this sequence still stands as a marked improvement
over the previous Wittig-based route. Access to enantioenriched
10 now requires only five steps, compared with our previous
eight-step approach that afforded racemic material. As a result,
this moderate success completed a much shorter, enantiose-
lective formal synthesis of danicalipin A because of the
interception of intermediate 10 from our first-generation
synthesis. However, more improvements in the end-game
were still possible (see below).
(
Scheme 12b).
To achieve higher conversion and suppress the decom-
position, an extensive optimization of the reaction conditions
was conducted. A variety of reaction solvents including
tetrahydrofuran, diethyl ether, t-butyl methyl ether, toluene,
25
25
chlorobenzene, hexafluorobenzene, α,α,α-trifluorotoluene,
25
and octafluorotoluene, as well as neat conditions were
employed, but the reaction efficiency was not improved. The
reaction was even slower at room temperature, and performing
the reaction at higher temperature (60 °C) only resulted in
greater decomposition.
A wide range of additives were also evaluated. Amine bases
such as i-Pr NEt and di-tert-butylpyridine promoted decom-
2
position. 1,4-Benzoquinone, known to scavenge ruthenium
2
6
hydride species that might be formed during reaction and
cause decomposition, only attenuated the catalytic reactivity of
60. The reaction became slightly cleaner in the presence of 3 or
4
Å molecular sieves, but substrate decomposition could not be
27
28
completely avoided. Ti(Oi-Pr)4 and hexachloroethane,
which have been used to improve the reactivity of other alkene
cross metathesis reactions, had no influence on the reaction.
Portionwise addition of catalyst and 1-hexene also provided
no advantage. We hoped that removal of ethylene from the
reaction mixture would shift the cross metathesis equilibrium
Convergent Z-selective alkene cross metathesis for mytilipin
A with the corresponding cis-vinyl epoxide 49 proceeded
H
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similarly to the corresponding reaction for danicalipin A.
Alkene metathesis partner 74 was obtained in two steps from 8-
bromo-1-octene (73) via formylation of Grignard reagent
followed by Takai-Utimoto chloroolefination (eq 5). The
of 60 with respect to the specific chlorinated cases relevant to
the chlorosulfolipids, we tested the reactivity of unchlorinated
cis-vinyl epoxide 79 with 1-decene (Scheme 13). In the
convergent metathesis reactions were carried out with vigorous
bubbling of argon to prevent the decomposition of starting
vinyl epoxide, and the desired alkene (±)-(Z)-75 was produced
as a single geometrical isomer. Again, we were unable to
achieve more than a single turnover with 10−30 mol% of
catalyst 60 (Table 3, entries 1 and 2). The use of fluorinated
Scheme 13. a. Synthesis of Simple Vinyl Epoxide 79. b. Z-
Selective Alkene Cross Metathesis of (± )-79
Table 3. Z-Selective Alkene Cross Metathesis for the
a
Synthesis of Mytilipin A
entry
60 (mol%)
solvent
time (h)
yield (%)
1
2
3
4
10
30
DCE/CH Cl
2
3
3
4
3
10
32
33
34
39
2
2
DCE/CH Cl
2
2
30
PhCF /CH Cl
3 2
2
50
PhCF /CH Cl
3 2
2
b
5
100
DCE
a
b
All reactions were carried out on 0.15−0.25 mmol scale. 5 equiv of
4 was employed. Catalyst 60 was added in one portion.
7
presence of 10 mol% of 60, complete conversion to (Z)-vinyl
epoxide 80 was observed (83% isolated yield, >20:1 Z:E). Even
with only 1 mol% of catalyst, the reaction proceeded to 46%
conversion and the product was isolated in 43% yield with
equal selectivity. Therefore, it appears that cis-vinyl epoxides are
subject to highly Z-selective alkene cross metathesis with 60,
and that the poor efficiency observed in the convergent steps
for chlorosulfolipids is likely specific to chlorinated substrates.
Recently, the Grubbs group also demonstrated that vinyl
epoxides are excellent substrates for Z-selective metathesis
2
5
solvents such as α,α,α-trifluorotoluene did not result in any
improvement (entry 3). Unfortunately, higher loading of
catalyst only resulted in significant loss of mass balance and
the yield of product was only marginally improved (entries 4
and 5). Despite the low efficiency of the Z-selective alkene
cross metathesis, the direct incorporation of the vinyl chloride
is a marked improvement over previous syntheses because it
eliminates at least three postconvergence steps. Cross meta-
thesis partner 74 might appear upon cursory analysis to be
poised for side reactivity because as a 1,9-diene cyclooctene
formation could occur via ring-closing metathesis. However,
vinyl chlorides are relatively slow to react in metathesis
processes, and cyclo-octene formation can also be a sluggish
reaction. Almost certainly, however, the high kinetic selectivity
of catalyst 60 for (Z)-alkenes is presumably the most important
factor that prevents reaction with the (E)-vinyl chloride in
either RCM or cross metathesis events.
23o
using these catalysts.
Postconvergent Manipulations and Completion of
the Syntheses. Completion of the synthesis of (+)-danicalipin
A took advantage of a similar reaction sequence to that
previously developed in the context of our first-generation
approach (Scheme 1a). Lewis acid-mediated chlorinolysis of
the internal alkenyl epoxide 10 typically afforded a diastereo-
meric mixture of the desired S 2 product 11 and the double
N
3a,6b
inversion
product 81 as well as the constitutional isomer 82
Unfortunately, the convergent Z-selective alkene cross
metathesis was even less efficient for malhamensilipin A. The
metathesis product (+)-76 was isolated only in 19% yield from
the reaction of (−)-55 with 71 under the analogous conditions
to those used for danicalipin A (eq 6). Cursory attempts to
improve the efficiency of this reaction were unsuccessful. For
reasons explained below, the improvement of this convergent
step was not a priority.
While admittedly not as efficient as desired, the convergent
Z-selective alkene cross metathesis is noteworthy for its
complete diastereoselectivity in all cases examined. To see if
the extremely high selectivity we observed was general for cis-
vinyl epoxides, as well as to investigate the low catalytic activity
formed via S 2′ substitution (Scheme 14a). The extent of side
N
product formation was highly dependent on the choice of Lewis
acid and the concentration of chloride anion. Because exclusive
SN2 reactivity was observed from the reaction of terminal cis-
vinyl epoxide with SiCl4 in the presence of HMPA, a
combination of SiCl and a number of Lewis base activators
4
including pyridine, DMAP, pyridine N-oxide, HMPA, DMPU,
DMI, and TMU was evaluated with or without Et NCl. In all
4
cases, a variable amount of side products were produced and a
useful level of selectivity was not accomplished (90:10−31:69
dr, 2−50% S 2′). Both undesired pathways were reasonably
N
attenuated when the epoxide was opened using dry HCl;
however, high selectivity was desired specifically for the
I
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Scheme 14. a. Completion of the Synthesis of (+)-Danicalipin A. b. Completion of the Synthesis of (−)-Mytilipin A
exclusion of double inversion product 81, which is more
difficult to separate from the desired product. Double inversion
could be completely overcome by employing BF ·OEt at −78
steps (3.7% overall yield). These results compare favorably to
the previously reported syntheses.
It is indeed fortuitous that we chose to first pursue
danicalipin A with this new approach. The choice of
malhamensilipin A as a first target could easily have discouraged
us from pursuing this strategy. Although, as described above,
this strategy led to much improved syntheses of mytilipin A and
danicalipin A, there was ultimately little improvement in the
synthesis of malhamensilipin A, for which we had already
established an enantioselective synthesis, via the same number
of steps, and for which the Wittig reaction was not improved
upon with the metathesis option. Therefore, while we are
pleased to claim a formal enantioselective synthesis of
malhamensilipin A as part of this second-generation, general
strategy for chlorosulfolipid synthesis, we would suggest that
our first enantioselective synthesis of this single target would
likely be the preferred method to access samples of this natural
product. However, if new catalysts become available that can
better effect these challenging Z-selective cross metatheses, and
if a truly effective method for asymmetric dichlorination of
allylic alcohols is discovered, the strategy described here would
be hard to beat for any of these three chlorosulfolipid targets.
Indeed, this approach has the distinct advantage that it can be
rendered enantioselective without recourse to resolution once
asymmetric catalysis technology is developed for allylic alcohol
dichlorination.
3
2
°
C with a high concentration of Et NCl. Despite the presence
4
of a rather large amount of S 2′ product 82, the desired isomer
N
11 could be isolated in 73% yield as a single diastereomer. A
major problem of our first-generation synthesis was the poorly
diastereoselective iodochlorination reaction of 11 (∼1.8:1 dr),
which was compounded further by the very painstaking
separation of diastereomers at that stage or after deiodination.
We found that transient introduction of a trimethylsilyl group
on the C14 hydroxyl permitted high diastereocontrol (95:5 dr)
in the iodochlorination, and because the silyl group could be
introduced and removed in the same pot, this result had a
significantly positive impact on the synthesis. Overall, the new
approach facilitated a nine-step synthesis of enantioenriched
(
+)-danicalipin A (4.6% overall yield), which is a significant
improvement over our 12-step racemic first-generation syn-
thesis.
Completion of the synthesis of mytilipin A required only
three postconvergence steps (Scheme 14b). BF ·OEt -mediated
3
2
vinyl epoxide chlorinolysis with inversion of configuration
proceeded with exclusive diastereoselectivity and delivered
diene 85. Dichlorination of the electron-deficient allylic
chloride afforded hexachloride 86 in 86% yield with high
diastereoselectivity (93:7 dr of crude product, purified to 97:3)
and complete chemoselectivity with respect to the isolated vinyl
chloride. Sulfation of the secondary alcohol according to
CONCLUSIONS
■
We have developed a concise and general approach for the
enantioselective synthesis of three chlorosulfolipid targets that
takes strategic advantage of a common stereotriad. Diastereo-
selective carbonyl addition to sensitive α,β-dichloroaldehydes,
Z-selective alkene cross metatheses, and kinetic resolution of
3a
Carreira’s conditions completed the synthesis of mytilipin A.
In this way, racemic chlorosulfolipid could be accessed in 8.6%
yield over the seven linear steps sequence, and enantioenriched
mytilipin A is available via a longest linear sequence of eight
J
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chlorinated vinyl epoxides are key advances that permitted
success in this second-generation approach. Enantioenriched
danicalipin A, mytilipin A, and malhamensilipin A are accessed
in nine, eight, and 11 steps, respectively.
Given the paucity of efforts toward this class of natural
products until about five years ago, it is remarkable that so
many effective solutions to these targets from multiple research
groups have appeared in such short order. Certainly, poly-
chlorinated natural products are not to be feared as objectives
for chemical synthesis and are rather well-behaved in the
contexts of many different reaction types. We look forward to
extending our efforts toward other polyhalogenated natural
products.
Synthesis of Danicalipin A. (±)-(2S,3R)-2,3-Dichloro-1-non-
4c
30
anol (26): To a stirred solution of Et NCl (6.63 g, 40.0 mmol) and
(
4
E)-2-nonen-1-ol (2.84 g, 20.0 mmol) in CH Cl2 (60 mL) was
2
bubbled Cl at 0 °C until the reaction mixture turned yellow (∼2
2
min). Ethylene was bubbled until the yellow color disappeared (∼2
min). The resulting colorless solution was diluted with CH Cl (50
2
2
mL) and shaken with a mixture of saturated aqueous NaHCO3
solution (50 mL) and saturated aqueous Na S O solution (50 mL).
2
2
3
The organic layer was separated, and the aqueous layer was extracted
with CH Cl (50 mL). The combined organic extracts were shaken
2
2
with saturated aqueous NaCl solution (100 mL). The organic layer
was separated, and the aqueous layer was extracted with CH Cl (50
2
2
mL). The combined organic extracts were dried over Na SO , filtered,
2
4
and concentrated in vacuo (25 mmHg). The residue was purified by
bulb-to-bulb distillation under reduced pressure (0.25 mmHg, ABT
1
23−126 °C) to afford (±)-26 (4.04 g, 95%, contained ∼1.5% of 1,3-
1
EXPERIMENTAL SECTION
dichloro-2-nonanol) as a colorless oil. Data for (±)-26: H NMR (600
■
MHz, CDCl ) δ 4.12 (app td, J = 8.7, 8.7, 2.7 Hz, 1H), 4.09−4.06 (m,
3
General Experimental Protocols. All reactions were performed
in oven-dried (140 °C) or flame-dried glassware under an atmosphere
of dry argon unless otherwise noted. Reaction solvents including
dichloromethane, toluene, N,N-dimethylformamide, and tetrahydro-
furan were dried by percolation through a column packed with neutral
alumina and a column packed with Q5 reactant, a supported copper
catalyst for scavenging oxygen, under a positive pressure of argon.
Dichloroethane (DCE) was heated to reflux over CaH2 for 3 h,
distilled under argon, and stored over 3 Å molecular sieves prior to
use. Column chromatography was performed using 60 Å (0.040−
1
H), 4.024 (d, J = 6.6 Hz, 1H), 4.017 (d, J = 6.6 Hz, 1H), 2.11−2.02
(
m, 1H), 1.97 (app t, J = 6.9, 6.9 Hz, 1H), 1.82−1.75 (m, 1H), 1.64−
1
6
3
1
.54 (m, 1H), 1.48−1.39 (m, 1H), 1.39−1.23 (m, 6H), 0.89 (dd, J =
13
.8, 6.8 Hz, 3H); C NMR (126 MHz, CDCl ) δ 66.4, 64.5, 61.8,
3
4.9, 31.6, 28.6, 25.5, 22.5, 14.0; IR (thin film) 3390, 2924, 2858, 1463,
−1
455, 1434, 1379, 1066, 725, 655 cm ; HRMS (CI-TOF) m/z calcd
35
18
+
for C H Cl ONH [M + NH ] 230.1078, found 230.1071.
9
2
4
4
(
±)-(2S,3R)-2,3-Dichlorononanal (27): To a stirred suspension of
(
±)-26 (2.13 g, 10.0 mmol) and NaHCO (2.52 g, 30.0 mmol) in
3
CH Cl2 (10 mL, saturated with H O) was added Dess−Martin
2
2
0
.063 mm) mesh silica gel (SiO ). The following reagents were
2
periodinane (6.36 g, 15.0 mmol) slowly over 1 min at 0 °C under air.
After stirring for 10 min, the ice bath was removed and the reaction
mixture was stirred at rt for 30 min prior to the addition of n-pentane
distilled from the indicated drying agents under argon prior to use:
,2,6,6-tetramethylpiperidine (Na), allyl bromide (CaH ), triethyl-
2
2
amine (CaH ), N,N-diisopropylethylamine (CaH ), trimethylsilyl
2
2
(100 mL). The resulting mixture was filtered, washed with saturated
chloride (TMSCl, CaH ), and ethylene diamine (CaH ). Silicon
2
2
aqueous NaHCO3 (50 mL), dried over Na SO , filtered, and
2
4
tetrachloride was heated at reflux for 2 h under a flow of argon and
then distilled prior to use. Z-Selective Grubbs cycloadamantyl catalyst
60, Materia) was stored in the glovebox and used as received. Dimeric
Denmark catalysts ((R,R)-41 and (S,S)-41, Obiter) were used as
received and recovered by recrystallization from boiling benzene. (E)-
concentrated in vacuo (25 mmHg) to give 27 (1.99 g) as a pale
yellow oil. The crude material was used directly for the next reaction
(
31
without further purification (∼3% 2-chloro-2-nonenal). Data for
1
(
(
1
±)-27: H NMR (600 MHz, CDCl ) δ 9.43 (d, J = 3.1 Hz, 1H), 4.25
3
dd, J = 7.4, 3.1 Hz, 1H), 4.24−4.21 (m, 1H), 2.02−1.97 (m, 1H),
2
-Nonen-1-ol (25), boron trifluoride diethyl etherate, and tri-n-
.84−1.77 (m, 1H), 1.63−1.54 (m, 1H), 1.48−1.39 (m, 1H), 1.39−
butyltin hydride were distilled prior to use. Tetraethylammonium
chloride was heated to reflux in benzene with a Dean−Stark trap for 3
h and dried at 0.25 mmHg before use. Chlorine gas, Dess−Martin
periodinane, diethylaluminum chloride, n-butyllithium, imidazole,
iodine monochloride (1.0 M in CH Cl ), camphorsulfonic acid
13
1
.27 (m, 6H), 0.90 (dd, J = 6.9, 6.9 Hz, 3H); C NMR (126 MHz,
CDCl ) δ 191.4, 64.9, 59.8, 34.0, 31.5, 28.5, 25.5, 22.5, 14.0; IR (thin
3
−1
film) 2926, 2858, 1734, 1458 cm ; HRMS (CI-TOF) m/z calcd for
35
+
C H ClONH [M − HCl + NH ] 192.1155, found 192.1158.
9
15
4
4
2
2
(±)-(3S,4S,5S,6R)-5,6-Dichloro-3,4-epoxy-1-dodecene (30): To
(
CSA), triethylborane (1.0 M in THF), chlorosulfonic acid, nickel(II)
a stirred solution of TMP (3.71 mL, 22.0 mmol) in THF (50 mL) was
added n-BuLi (2.50 M in hexanes, 8.40 mL, 21.0 mmol) at −78 °C.
After being stirred for 30 min, the LiTMP solution was cannulated into
acetate tetrahydrate, sodium borohydride, magnesium (20−100
mesh), 1,2-dibromoethane, 1-bromo-10-undecene, N-chloro-
succinimide, t-butyldimethylsilyl chloride, and paraformaldehyde
were used without further purification. Tetraethylammonium tri-
a solution of allyl bromide (1.82 mL, 21.0 mmol) and Et AlCl (1.0 M
2
in hexanes, 40.0 mL, 40.0 mmol) in THF (100 mL) at −78 °C over 5
min. The resulting solution was stored at −78 °C, while (±)-27 was
prepared (see above). A solution of (±)-27 in THF (10 mL + rinsed
with 5 mL × 2) was added dropwise over 15 min. After being stirred at
−78 °C for 4 h, the reaction mixture was poured into an ice-cold 5 M
13
29
chloride and (S)-BINAPO were prepared according to literature
procedures.
1
13
H and 1 C spectra were referenced to residual solvent (CDCl :
3
13
1
7
.26 ppm, H, 77.00 ppm, C; CD OD: 3.31 ppm, H, 49.00 ppm,
3
1
3
C). Chemical shifts are reported in parts per million, and
multiplicities are indicated by s (singlet), d (doublet), t (triplet), q
quartet), m (multiplet), br s (broad singlet), and app (apparent).
aq NaOH solution (200 mL). Et NCl (17 mg, 0.10 mmol) was
4
3
2
added. The biphasic mixture was vigorously stirred at rt for 1 h prior
to the dilution with n-pentane (100 mL) and filtration. The organic
layer was separated, and the aqueous layer was extracted with n-
pentane (100 mL × 2). The combined organic extracts were washed
(
Coupling constants, J, are reported in Hertz. Infrared (IR) spectra
were recorded on an FT-IR instrument on NaCl plates, and peaks are
−1
reported in cm . High-resolution mass spectra (HRMS) data are
reported in the form of (m/z). Kugelrohr distillation temperatures
reported are air bath temperatures (ABT). Visualization of analytical
thin-layer chromatography was accomplished with UV(254) and
with saturated aqueous NH Cl solution (200 mL × 2), dried over
4
Na SO , filtered, and concentrated in vacuo (25 mmHg). The residue
2
4
was purified by column chromatography (SiO , ϕ = 5.0 cm, l = 13.5
2
cm, n-pentane/CH Cl , 9/1, R = 0.29, p-anisaldehyde) and bulb-to-
2
2
f
potassium permanganate (KMnO ) or p-anisaldehyde staining
bulb distillation under reduced pressure (0.25 mmHg, ABT 123−127
4
solutions. Optical rotation data were obtained on a digital polarimeter
and are reported as follows: concentration (c = g/100 mL) and
solvent. Analytical gas chromatography (CSP-GC) was performed on a
gas chromatograph equipped with a flame ionization detector and a
dimethylated β-cyclodextrin (B-DM, 30 m) capillary column. The
injector temperature and the detector temperature were 200 °C with a
split ratio of approximately 100:1.
°C) to give (±)-30 (1.89 g, 75% from (±)-26, 98:2 dr) as a colorless
1
oil. Data for (±)-30: H NMR (600 MHz, CDCl ) δ 5.82 (ddd, J =
3
17.1, 10.6, 5.6 Hz, 1H), 5.52 (d, J = 17.1 Hz, 1H), 5.45 (d, J = 10.7 Hz,
1H), 4.21 (ddd, J = 9.4, 4.6, 4.1 Hz, 1H), 3.76 (dd, J = 9.0, 4.2 Hz,
1H), 3.57 (app t, J = 4.9, 4.9 Hz, 1H), 3.46 (dd, J = 9.0, 4.3 Hz, 1H),
1.98−1.87 (m, 2H), 1.65−1.59 (m, 1H), 1.47−1.39 (m, 1H), 1.36−
1.26 (m, 6H), 0.89 (dd, J = 6.9, 6.9 Hz, 3H); 13C NMR (126 MHz,
K
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The Journal of Organic Chemistry
Article
CDCl ) δ 130.4, 121.2, 65.2, 60.6, 57.7, 56.0, 34.5, 31.6, 28.6, 26.5,
pentane/CH Cl , 5/1 to 3/1 to 1/1, p-anisaldehyde) to give (+)-11
3
2
2
2
9
2.5, 14.0; IR (thin film) 2956, 2928, 2858, 1463, 1455, 1250, 981,
(27 mg, 73%, R = 0.25 in 3/1, >20:1 dr) as a colorless oil and S 2′
f
N
−
1
34, 783, 668, 597 cm ; HRMS (CI-TOF) m/z calcd for
product 82 (9.6 mg, 26%, R = 0.33 and 0.24 in 1/1, 6:4 dr) as a
f
35
20
+
25
1
C H Cl ONH [M + NH ] 268.1235, found 268.1236.
colorless oil. Data for (+)-11: [α]D = +62.5 (c 1.00, CHCl ); H
12
2
4
4
3
(
−)-(3S,4S,5S,6R)-5,6-Dichloro-3,4-epoxy-1-dodecene (30),
NMR (600 MHz, CDCl ) δ 5.73 (app t, J = 10.3, 10.3 Hz, 1H), 5.66
3
(
−)-(3S,4R,5R,6S)-3,5,6-trichloro-1-dodecen-4-ol (35): To a stirred
(app dt, J = 10.7, 7.4, 7.4 Hz, 1H), 5.38 (dd, J = 9.9, 1.7 Hz, 1H), 4.49
(app dt, J = 10.3, 2.9, 2.9 Hz, 1H), 4.29 (dd, J = 9.0, 3.1 Hz, 1H), 3.92
(s, 2H), 3.83−3.78 (m, 1H), 2.34 (d, J = 10.5 Hz, 1H), 2.21−2.09 (m,
4H), 1.91−1.83 (m, 1H), 1.83−1.76 (m, 1H), 1.67−1.62 (m, 1H),
1.61−1.56 (m, 2H), 1.46−1.36 (m, 3H), 1.36−1.25 (m, 14H), 0.91 (s,
solution of (±)-30 (126 mg, 0.502 mmol) and (S,S)-41 (84 mg, 0.10
mmol) in CH Cl (2.5 mL) were added i-Pr NEt (9 μL, 0.05 mmol)
2
2
2
and SiCl (57 μL, 0.50 mmol) at −78 °C. After 24 h, a solution of
4
CH OH/Et N/CH Cl (1/1/5, 4 mL) was added quickly at −78 °C.
3
3
2
2
1
3
The resulting solution was vigorously stirred with a saturated aqueous
9H), 0.89 (app t, J = 6.8, 6.8 Hz, 3H), 0.11 (s, 6H); C NMR (126
NaHCO solution (20 mL) at rt for 2 h prior to filtration. The organic
layer was separated, and the aqueous layer was extracted with CH Cl2
10 mL). The combined organic extracts were dried over Na SO ,
filtered, and concentrated in vacuo (25 mmHg). (S,S)-41 was
recovered from the residue by column chromatography (SiO , ϕ =
.2 cm, l = 7 cm, CH Cl /i-PrOH, 10/1, R = 0.37, UV). The fractions
that contained 30 and 35 were combined and purified by column
chromatography (SiO , ϕ = 2.2 cm, l = 11 cm, n-pentane/CH Cl , 8/1
MHz, CDCl ) δ 135.7, 125.8, 93.5, 75.1, 66.8, 62.4, 60.1, 43.5, 32.5,
3
3
2
31.6, 29.3, 29.2, 29.1, 29.0 (2C), 28.6, 27.6, 26.5, 25.7, 24.7, 22.6, 18.3,
1
(
14.0, −5.4. Data for 82 (a 6:4 mixture of diastereomers): H NMR
2
4
(600 MHz, CDCl ) δ 5.97−5.90 (m, 1H), 5.79 (ddd, J = 15.2, 13.9,
3
2
6.8, 1H), 4.77 (app td, J = 7.3, 7.3, 3.9 Hz, 0.4H), 4.72 (app td, J = 7.2,
7.2, 4.3 Hz, 0.6H), 4.39 (app quintet, J = 7.4, 7.4, 7.4, 7.4 Hz, 1H),
4.18 (ddd, J = 8.8, 6.7, 4.1 Hz, 1H), 3.92 (s, 2H), 3.91−3.88 (m, 1H),
2.20−2.14 (m, 2H), 2.13−2.04 (m, 2H), 1.89−1.73 (m, 3H), 1.65−
1.51 (m, 3H), 1.50−1.37 (m, 3H), 1.37−1.23 (m, 14H), 0.91 (s, 9H),
0.89 (app t, J = 6.8, 6.8 Hz, 3H), 0.11 (s, 6H); 13C NMR (126 MHz,
2
2 2 f
2
2
2
to 4/1, p-anisaldehyde) to give (−)-35 (70 mg, 49%, R = 0.12 in 8/1,
f
8
8.1:11.9 er) as a colorless oil and (−)-30 as a colorless oil, which was
purified again by column chromatography (54 mg, 43%, R = 0.30 in
CDCl ) δ 136.0, 135.7, 128.22, 128.17, 93.5, 72.1, 72.0, 71.7, 69.4,
f
3
26
8
/1, 2.7:97.3 er). Data for (−)-30: [α] = −29.9 (c 1.00, CHCl );
GC (B-DM, 30 psi, 145 °C) t 15.5 min (2.7%), 16.5 min (97.3%).
Data for (−)-35: [α] = −60.6 (c 1.00, CHCl ); GC (B-DM, 30 psi,
65 °C) t 18.5 min (88.1%), 19.1 min (11.9%); H NMR (500 MHz,
CDCl ) δ 6.03 (ddd, J = 16.9, 10.2, 7.7 Hz, 1H), 5.49 (d, J = 16.9 Hz,
H), 5.35 (d, J = 10.2 Hz, 1H), 5.07 (d, J = 7.6 Hz, 1H), 4.51 (app dt,
69.1, 61.9, 61.7, 61.6, 43.5, 38.4, 38.3, 34.7, 34.5, 31.6, 29.30, 29.26,
29.0, 28.9, 28.61, 28.60, 26.43, 26.35, 25.7, 25.3, 25.2, 24.7, 22.5, 18.3,
14.1, −5.4; IR (thin film) 3403, 2929, 2857, 1463, 1256, 1153, 1120,
D
3
R
25
D
3
1
−1
1
970, 840, 780 cm .; HRMS (ESI-TOF) m/z calcd for
R
3
5
+
3
C H Cl O SiNa [M + Na] 647.2155, found 647.2143.
28 53 5 2
1
(−)-(11S,12R,13S,14R,15S,16R)-1-tert-Butyldimethylsiloxy-2,2,-
6b
J = 10.5, 2.7, 2.7 Hz, 1H), 4.31 (dd, J = 9.4, 2.7 Hz, 1H), 3.89 (app td,
J = 9.8, 9.8, 1.3 Hz, 1H), 2.23 (d, J = 9.9 Hz, 1H), 1.92−1.83 (m, 1H),
11,13,15,16-hexachloro-14-hydroxy-12-iododocosane (83): To
a stirred solution of (+)-11 (27 mg, 0.043 mmol) and imidazole (8.8
1
(
1
.83−1.74 (m, 1H), 1.68−1.58 (m, 1H), 1.46−1.23 (m, 7H), 0.89
mg, 0.13 mmol) in CH
mmol) at rt. After being stirred for 10 min, the reaction mixture was
cooled to −78 °C and ICl (1.0 M in CH Cl , 215 μL, 0.215 mmol)
was added. After being stirred for 20 min at −78 °C, a solution of CSA
(100 mg, 0.43 mmol) in CH OH (645 μL) was added and the cold
bath was removed. After being stirred for 30 min, the brown solution
was poured into a stirred mixture of saturated aqueous NaHCO
solution (5 mL) and saturated aqueous Na S O solution (5 mL). The
2 2
Cl (430 μL) was added TMSCl (11 μL, 0.086
app t, J = 6.6, 6.6 Hz, 3H); 13C NMR (126 MHz, CDCl ) δ 134.4,
3
19.6, 74.5, 66.5, 65.0, 62.5, 32.4, 31.6, 28.6, 26.5, 22.6, 14.0; IR (thin
2
2
film) 3540, 2956, 2927, 2857, 1465, 1379, 1265, 1096, 1069, 987, 935
−
1
35
cm ; HRMS (CI-TOF) m/z calcd for C H Cl ONH4 [M +
3
12
21
3
+
NH ] 304.1002, found 304.1000.
4
(
+)-(11Z,13S,14S,15S,16R)-1-tert-Butyldimethylsiloxy-2,2,-
3
6
b
1
5,16-tetrachloro-13,14-epoxy-11-docosene (10): The solvents
2
2
3
were bubbled with argon for 15 min before use. To a stirred solution
resulting colorless biphasic mixture was diluted with CH Cl (10 mL)
2 2
of (−)-30 (52 mg, 0.21 mmol) and 71 (152 mg, 0.414 mmol) in DCE
and H O (10 mL). The organic layer was separated, and the aqueous
2
(
(
1
210 μL) in a test tube (12 mm × 75 mm) was added a solution of 60
layer was extracted with CH Cl (10 mL × 2). The combined organic
2
2
39 mg, 0.062 mmol) in CH Cl (210 μL) in three portions (0, 0.5,
extracts were washed with saturated aqueous NH Cl solution (20 mL),
2
2
4
.0 h) at 35 °C while the reaction mixture was vigorously bubbled with
and the aqueous layer was extracted with CH Cl (10 mL × 2). The
2
2
33
argon (saturated with DCE). After being stirred at 35 °C with argon
bubbling for an additional 2 h, the reaction mixture was cooled to rt,
filtered through silica gel (ϕ = 2.2 cm, l = 9 cm, CH Cl , 40 mL), and
combined organic extracts were dried over Na SO , filtered, and
2 4
concentrated in vacuo (25 mmHg). The residue was purified by
2
2
column chromatography (SiO , ϕ = 1.1 cm, l = 5.5 cm, n-pentane/
2
concentrated in vacuo (25 mmHg). The residue was purified by
CH Cl , 5/1 to 3/1, R = 0.29 in 3/1, p-anisaldehyde) to give (−)-83
2
2
f
2
6
column chromatography (SiO , ϕ = 3.8 cm, l = 15 cm, n-pentane/
(28 mg, 82%, 95:5 dr) as a colorless oil. Data for (−)-83: [α]
=
2
D
1
CH Cl , 8/1, R = 0.24, p-anisaldehyde) to give (+)-10 (35 mg, 29%,
−7.6 (c 1.00, CHCl ); H NMR (600 MHz, CDCl ) δ 4.98 (d, J =
2
2
f
3
3
2
6
>
20:1 = Z:E) as a colorless oil. Data for (+)-10: [α]D = +14.2 (c
.00, CHCl ); H NMR (600 MHz, CDCl ) δ 5.86 (app dt, J = 10.9,
.6 Hz, 7.6, 1H), 5.26−5.20 (m, 1H), 4.21 (ddd, J = 9.6, 4.4, 4.0 Hz,
H), 3.92 (s, 2H), 3.76 (dd, J = 9.1, 4.0 Hz, 1H), 3.74 (dd, J = 7.9, 4.3
10.9 Hz, 1H), 4.72 (app t, J = 10.6, 10.6 Hz, 1H), 4.56 (dd, J = 10.9,
1.8 Hz, 1H), 4.48 (app dt, J = 10.5, 2.6, 2.6 Hz, 1H), 4.38 (dd, J = 9.8,
2.4 Hz, 1H), 3.92 (s, 2H), 3.75−3.71 (m, 1H), 2.19−2.16 (m, 2H),
2.14 (d, J = 11.3 Hz, 1H), 2.04−1.97 (m, 1H), 1.97−1.88 (m, 1H),
1.83−1.78 (m, 1H), 1.77−1.71 (m, 1H), 1.69−1.62 (m, 1H), 1.62−
1.56 (m, 2H), 1.53−1.46 (m, 1H), 1.46−1.38 (m, 3H), 1.38−1.27 (m,
1
1
7
1
3
3
Hz, 1H), 3.44 (dd, J = 9.1, 4.2 Hz, 1H), 2.27−2.19 (m, 2H), 2.19−
2
3
3
7
2
.14 (m, 2H), 1.99−1.86 (m, 2H), 1.66−1.55 (m, 3H), 1.46−1.39 (m,
1
3
H), 1.39−1.26 (m, 14H), 0.91 (s, 9H), 0.89 (app t, J = 6.9, 6.9 Hz,
13H), 0.92 (s, 9H), 0.90 (app t, J = 6.8, 6.8 Hz, 3H), 0.11 (s, 6H);
C
1
3
H), 0.11 (s, 6H); C NMR (126 MHz, CDCl ) δ 139.6, 121.5, 93.5,
NMR (126 MHz, CDCl ) δ 93.5, 74.6, 72.1, 66.3, 66.0, 62.9, 62.8,
3
3
2.1, 65.2, 61.5, 57.4, 52.5, 43.5, 34.3, 31.6, 29.29, 29.27, 29.26, 29.1,
43.5, 42.6, 40.6, 32.8, 31.6, 29.2 (2C), 29.0, 28.9, 28.6, 26.6, 26.2, 25.7,
9.0, 28.6, 28.1, 26.5, 25.7, 24.7, 22.5, 18.3, 14.0, −5.4.
24.7, 22.6, 18.3, 14.1, −5.3.
(
+)-(7R,8S,9S,10R,11Z)-22-tert-Butyldimethylsiloxy-7,8,10,21,-
(+)-(11S,13S,14R,15S,16R)-1-tert-Butyldimethylsiloxy-2,2,-
6
b
6b
2
1-pentachloro-11-docosen-9-ol (11): To a stirred solution of
11,13,15,16-hexachloro-14-hydroxydocosane (84): Toluene was
(
+)-10 (35 mg, 0.059 mmol) and Et NCl (30 mg, 0.18 mmol) in
bubbled with argon for 20 min before use. To a stirred solution of
4
CH Cl (240 μL) was added BF ·OEt (15 μL, 0.12 mmol) at −78 °C.
(−)-83 (28 mg, 0.035 mmol) in toluene (355 μL) were added n-
3 6 6
2
2
3
2
1
34
After being stirred for 1 h, the reaction mixture was poured into an ice-
Bu SnH (11 μL, 0.041 mmol, 99% pure by H NMR in C D ) and
cold saturated aqueous NaHCO solution (10 mL). To the biphasic
Et B (1.0 M in THF, 7 μL, 0.007 mmol) at −78 °C. After being stirred
3
3
mixture were added CH Cl (10 mL) and H O (10 mL). The organic
for 2 h at −78 °C, n-pentane (3.55 mL) was added and the resulting
2
2
2
layer was separated, and the aqueous layer was extracted with CH Cl2
solution was concentrated in vacuo (25 mmHg). The residue was
2
(
10 mL × 2). The combined organic extracts were dried over Na SO ,
purified by column chromatography (SiO , ϕ = 1.1 cm, l = 5.5 cm, n-
2
4
2
filtered, and concentrated in vacuo (25 mmHg). The residue was
purified by column chromatography (SiO , ϕ = 1.5 cm, l = 9 cm, n-
pentane/CH Cl , 1/0 to 4/1, R = 0.25 in 4/1, p-anisaldehyde) to give
2
2
f
2
5
(+)-84 (21.5 mg, 91%) as a colorless oil. Data for (+)-84: [α]D =
2
L
dx.doi.org/10.1021/jo5000829 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1
+
34.3 (c 1.00, CHCl ); H NMR (600 MHz, CDCl ) δ 4.96 (d, J =
for (±)-52: H NMR (500 MHz, CDCl ) δ 4.22 (ddd, J = 8.1, 5.4, 2.6
3
3
3
1
2
1
1
3
1
6
7
2
0.3 Hz, 1H), 4.51 (app dt, J = 10.6, 2.4, 2.4 Hz, 1H), 4.30 (dd, J = 9.7,
.4 Hz, 1H), 4.17−4.13 (m, 1H), 3.92 (s, 2H), 3.77 (app t, J = 10.7,
0.7 Hz, 1H), 2.35−2.28 (m, 1H), 2.20−2.16 (m, 2H), 2.16 (d, J =
1.6 Hz, 1H), 2.02−1.95 (m, 1H), 1.94−1.85 (m, 1H), 1.83−1.73 (m,
H), 1.68−1.62 (m, 1H), 1.62−1.57 (m, 2H), 1.57−1.49 (m, 1H),
.49−1.39 (m, 2H), 1.39−1.26 (m, 14H), 0.91 (s, 9H), 0.89 (app t, J =
Hz, 1H), 4.18 (m, 1H), 3.95 (ddd, J = 11.9, 7.7, 6.0 Hz, 1H), 3.89
(ddd, J = 12.1, 7.5, 5.6 Hz, 1H), 1.94 (dd, J = 7.7, 5.4 Hz, 1H), 1.90−
1.84 (m, 2H), 1.57−1.51 (m, 1H), 1.44−1.22 (m, 11H), 0.88 (app t, J
= 6.6, 6.6 Hz, 3H); 13C (126 MHz, CDCl ) δ 65.6, 64.7, 62.2, 35.3,
3
32.0, 29.5, 29.3, 29.1, 26.7, 22.8, 14.3; IR (thin film) 3363, 3923, 2855,
−
1
35
22
1455, 1041 cm ; HRMS (CI-TOF) m/z calcd for C H Cl ONH
11
2
4
.8, 6.8 Hz, 3H), 0.11 (s, 6H); 13C NMR (126 MHz, CDCl ) δ 93.5,
[M + NH ] 258.1392, found 258.1401.
+
3
4
5.1, 72.1, 66.5, 63.0, 62.7, 60.4, 44.3, 43.5, 38.7, 32.4, 31.6, 29.3, 29.2,
(±)-(2S,3S)-2,3-Dichloroundecanal (53): To a stirred suspension
9.0 (2C), 28.6, 26.6, 26.2, 25.7, 24.7, 22.6, 18.3, 14.0, −5.3.
of (±)-52 (2.20 g, 9.12 mmol) and NaHCO (2.30 g, 27.4 mmol) in
3
2
k,5,4c,6b
(
+)-Danicalipin A Disodium Salt (1):.
To a stirred
CH Cl2 (46 mL, saturated with H O) was added Dess−Martin
2
2
solution of (+)-84 (21.5 mg, 0.0324 mmol) in CH Cl (650 μL)
was added ClSO H (5 drops) via a Pasteur pipet at rt under air. After
being stirred for 10 min, the reaction mixture was slowly poured into a
periodinane (5.80 g, 13.7 mmol) portionwise over 1 min at 0 °C under
air. After being stirred for 5 min, the ice bath was removed and the
reaction mixture was stirred at rt for 25 min prior to the addition of
2
2
3
vigorously stirred mixture of a saturated aqueous NaHCO solution
hexanes (20 mL) and saturated aqueous NaHCO solution (100 mL).
3
3
(
6.5 mL) and solid NaHCO (650 mg). The resulting heterogeneous
The organic layer was separated, and the aqueous layer was extracted
3
mixture was diluted with EtOH (26 mL), filtered, and concentrated in
vacuo (30 mmHg). The residue was suspended in THF (20 mL),
filtered, and concentrated in vacuo (25 mmHg). The residue purified
by column chromatography (SiO , ϕ = 2.2 cm, l = 14.5 cm, CH Cl /
with hexanes (50 mL × 3). The combined organic extracts were
filtered, dried over MgSO , filtered, and concentrated in vacuo (5
4
mmHg) to give (±)-53 as a pale yellow oil. The crude material was
generally used directly for the next reaction within 30 min and without
2
2
2
CH OH, 3/1, R = 0.38, p-anisaldehyde) to give (+)-1 (23.4 mg, 96%)
further purification (it was often contaminated with up to 5% 2-chloro-
3
f
25
1
as a colorless amorphous solid. Data for (+)-1: [α] = +34.2 (c 2.34,
2-undecenal). Data for (±)-53: H NMR (500 MHz, CDCl ) δ 9.55
D
3
2
D
6
4c
28
CH OH) (lit. [α] +33.0 (c 0.40, CH OH), [α]D +31.5 (c 0.25,
(s, 1H), 4.40 (app s, 2H), 1.92−1.86 (m, 2H), 1.55−1.48 (m, 1H),
3
3
5
25
D
2k
1
13
CH OH), [α]
+12.8 (c 0.2, CH OH) ); H NMR (600 MHz,
1.40−1.22 (m, 11H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (126 MHz,
3
3
CD OD) δ 4.89 (d, J = 11.2 Hz, 1H), 4.75 (d, J = 10.7 Hz, 1H), 4.55
CDCl ) δ 194.8, 67.0, 60.1, 35.1, 31.8, 29.3, 29.1, 28.8, 26.1, 22.6, 14.1;
3
3
−1
(
d, J = 10.2 Hz, 1H), 4.45 (dd, J = 10.2, 1.5 Hz, 1H), 4.31 (s, 2H),
IR (thin film) 2927, 2856, 1736, 1465 cm ; HRMS (ESI-TOF) m/z
calcd for C H ClONa [M − HCl + Na] 225.1022, found
225.1013.
35
19
+
4
2
1
1
.23−4.19 (m, 1H), 2.56−2.49 (m, 1H), 2.27−2.24 (m, 2H), 2.15−
.06 (m, 1H), 1.99−1.92 (m, 1H), 1.85−1.76 (m, 2H), 1.76−1.69 (m,
H), 1.69−1.62 (m, 2H), 1.61−1.52 (m, 2H), 1.51−1.42 (m, 2H),
11
(±)-(3S,4S,5S,6S)-5,6-Dichloro-3,4-epoxy-1-tetradecene (55):
To a stirred solution of TMP (3.39 mL, 20.1 mmol) in THF (46
mL) was added n-BuLi (2.47 M in hexanes, 7.75 mL, 19.2 mmol) at
−78 °C. After being stirred for 15 min, the LiTMP solution was
cannulated into a solution of allyl bromide (1.66 mL, 19.2 mmol) and
13
.42−1.27 (m, 14H), 0.90 (app t, J = 6.9, 6.9 Hz, 3H); C NMR (126
MHz, CD OD, 313 K) δ 91.3, 80.9, 75.6, 68.4, 63.3, 62.4, 62.2, 45.5,
3
4
2
5.1, 39.9, 33.5, 32.9, 30.4, 30.3, 30.07, 30.05, 30.0, 27.6, 27.4, 25.8,
3.6, 14.4. The analytical data for (+)-1 were in agreement with the
data given in refs 2k, 4c, 5, and 6b.
Et AlCl (1.0 M in hexanes, 36.5 mL, 36.5 mmol) in THF (46 mL) at
2
Synthesis of Malhamensilipin A. (Z)-2-Undecen-1-ol (51): To
−78 °C over 15 min. The resulting solution was stored at −78 °C,
while (±)-53 was prepared (see above). A solution of (±)-53 in THF
(10 mL + rinsed with 8 mL × 2) was added dropwise down the side of
the flask. After being stirred at −78 °C for 5 h, the cooling bath was
removed and a 6 M aq NaOH solution (100 mL) was added. After
stirring vigorously for 1 h, the biphasic mixture was diluted with
hexanes (100 mL) and shaken in a separatory funnel. The organic
layer was separated, and the aqueous layer was extracted with hexanes
(100 mL × 3). The combined organic extracts were washed with
saturated aqueous NaCl solution (50 mL × 3), filtered through silica
gel (CH Cl , 300 mL), and concentrated in vacuo (5 mmHg). The
a stirred solution of Ni(OAc) ·4H O (9.12 g, 36.7 mmol) in CH OH
2
2
3
(
500 mL) was added NaBH (1.38 g, 36.7 mmol) portionwise over 5
4
min at 0 °C. The blue solution immediately turned black upon
addition of NaBH . After being stirred for an additional 5 min, the ice
4
bath was removed and ethylene diamine (4.90 mL, 36.7 mmol) was
3
5
added. After being stirred for 5 min, a solution of undec-2-yn-1-ol
24.7 g, 147 mmol) in CH OH (230 mL) was added. The reaction
(
3
mixture was quickly purged with H three times and stirred overnight
2
under a balloon of H prior to the dilution with H O (100 mL) and n-
2
2
pentane (100 mL). After filtration through Celite, the organic layer
was separated and the aqueous layer was extracted with n-pentane
2
2
residue was purified by column chromatography (500 mL of SiO , 5%
2
(
(
100 mL × 3). The combined organic extracts were washed with H O
CH Cl /hexanes, R = 0.2, KMnO ) and bulb-to-bulb distillation under
2
2
2
f
4
50 mL) and saturated aqueous NaCl solution (50 mL), dried over
reduced pressure (0.1 mmHg, ABT 150 °C) to give (±)-55 as a
1
MgSO , filtered, and concentrated in vacuo (5 mmHg) to afford 51
colorless oil (1.83 g, 72% from (±)-52). Data for (±)-55: H NMR
4
(
25.0 g, 98%) as a colorless oil. The crude material was used for the
(500 MHz, CDCl ) δ 5.82 (ddd, J = 17.0, 10.6, 5.3 Hz, 1H), 5.49 (d, J
3
1
next reaction without any further purification. Data for 51: H NMR
= 17.2 Hz, 1H), 5.45 (d, J = 10.7 Hz, 1H), 4.26 (ddd, J = 8.3, 4.9, 2.7
Hz, 1H), 3.67 (dd, J = 8.9, 2.7 Hz, 1H), 3.64 (app t, J = 4.7 Hz, 1H),
3.54 (dd, J = 9.7, 4.7 Hz, 1H), 1.94 (app dtd, J = 14.2, 9.5, 4.8 Hz, 1H),
1.83, (app ddt, J = 14.0, 10.1, 5.4 Hz, 1H), 1.58−1.50, (m, 1H), 1.43−
(
600 MHz, CDCl ) δ 5.62−5.52 (m, 2H), 4.19 (d, J = 6.4 Hz, 2H),
3
2
0
5
3
.07 (q, J = 7.2 Hz, 2H), 1.38−1.32 (m, 2H), 1.32−1.23 (m, 10H),
.88 (t, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl ) δ 133.5, 128.4,
3
1
3
8.8, 32.0, 29.8, 29.6, 29.42, 29.38, 27.6, 22.8, 14.3; IR (thin film)
1.35 (m, 1H), 1.35−1.22 (m, 10H), 0.88 (app t, J = 6.6 Hz, 3H); C
−1
347, 3938, 3857, 1015 cm ; HRMS (CI-TOF) m/z calcd for
NMR (126 MHz, CDCl ) δ 130.5, 121.3, 63.5, 60.4, 58.6, 57.4, 35.8,
3
+
C H ONH [M + NH ] 188.2014, found 188.2023.
32.0, 29.5, 29.3, 29.1, 26.5, 22.8, 14.3; IR (thin film) 2926, 2855, 932
1
1
22
4
4
−
1
35
(
±)-(2S,3S)-2,3-Dichloro-1-undecanol (52): To a stirred solution
cm ; HRMS (CI-TOF) m/z calcd for C H Cl ONH [M +
14 24 2 4
+
of (4.96 g, 29.1 mmol) in CH Cl (70 mL) was added Et NCl (13.8
NH ] 296.1548, found 296.1560.
4
2
2
4
3
g, 58.3 mmol) portionwise over 5 min at rt. After the yellow color
(−)-(3S,4S,5S,6S)-5,6-Dichloro-3,4-epoxy-1-tetradecene (55),
(+)-(3S,4R,5R,6R)-3,5,6-trichloro-1-tetradecen-4-ol (56): To a
stirred solution of (±)-55 (500 mg, 1.79 mmol) and (S)-BINAPO
(234 mg, 0.358 mmol) in CH Cl (36 mL) were added i-Pr NEt (31.0
disappeared over the course of 10 min, another portion of Et NCl3
4
(
6.89 g, 29.1 mmol) was added portionwise over 3 min. After being
stirred for 30 min, the reaction mixture was poured into a mixture of
2
2
2
saturated aqueous NaHCO solution (15 mL) and saturated aqueous
μL, 0.179 mmol) and SiCl (144 μL, 1.25 mmol) slowly at −78 °C.
3
4
Na S O solution (15 mL). The organic layer was separated, and the
After 39 h, a solution of CH OH/Et N/CH Cl (1/1/5, 5 mL) was
2
2
3
3
3
2
2
aqueous layer was extracted with hexanes (30 mL × 3). The combined
added quickly at −78 °C. The resulting solution was vigorously stirred
organic extracts were dried over MgSO , filtered, and concentrated in
with a saturated aqueous NaHCO solution (20 mL) at rt for 2 h. The
4
3
vacuo (5 mmHg). The residue was purified by column chromatog-
raphy (150 mL of SiO , 10% EtOAc/hexanes, R = 0.6 in 30% EtOAc/
organic layer was separated, and the aqueous layer was extracted with
CH Cl (20 mL × 3). The combined organic layers were dried over
2
f
2
2
hexanes, KMnO ) to give (±)-52 (5.79 g, 82%) as a colorless oil. Data
MgSO , filtered, and concentrated in vacuo (5 mmHg). The residue
4
4
M
dx.doi.org/10.1021/jo5000829 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−
1
+
was purified by column chromatography (SiO , 5% EtOAc/hexanes,
cm ; HRMS (ESI-TOF) m/z calcd for C H ONa [M + Na]
2
12 22
KMnO ) to give (−)-55 (165 mg, 33%, 3.4:96.6 er, R = 0.7 in 10%
205.1568, found 205.1561.
4
f
4c
EtOAc/hexanes) as a colorless oil and (+)-56 (367 mg, 65%, 71.4:28.6
2,2-Dichloro-11-dodecenal (69): To a flask containing t-
butylamine (634 μL, 6.03 mmol) was added 11-dodecenal (68)
(1.00 g, 5.49 mmol) dropwise at 0 °C. After being stirred at rt for 45
min, the cloudy reaction mixture was dried over K CO (3.79 g, 27.4
mmol), filtered, and concentrated in vacuo (25 mmHg). The residue
was purified by bulb-to-bulb distillation under reduced pressure (0.25
er, R = 0.5 in 10% EtOAc/hexanes) as pale yellow crystals. The
f
enantiopurity of the recovered reactant (−)-55 was measured after
2
5
ring-opening chlorinolysis to form (−)-56. Data for (−)-55: [α]
=
D
2
3
−
23.5 (c 1.74, CHCl ); GC (B-DM, 30 psi, 180 °C) t 23.9 min
2.6%), 25.1 min (97.4%). Data for (+)-56: mp 34.0−36.0 °C; [α]
+1.6 (c 2.01, CHCl ); GC (B-DM, 30 psi, 180 °C) t 23.7 min
3
R
24
(
D
4c
=
(
mmHg, ABT 128−135 °C) to give the corresponding t-butylimine
3
R
1
71.4%), 25.3 min (28.6%); H NMR (600 MHz, CDCl ) δ 6.07 (ddd,
(1.21 g, ∼92:8 imine:aldehyde) as a colorless oil. The t-butylimine was
dissolved in CH Cl (15 mL), and N-chlorosuccinimide (2.04 g, 15.3
3
J = 17.1, 10.3, 7.4 Hz, 1H), 5.49 (dd, J = 16.1, 1.0 Hz, 1H), 5.35 (dd, J
10.3, 0.8 Hz, 1H), 5.10 (dd, J = 7.4, 1.0 Hz, 1H), 4.56 (ddd, J = 9.0,
.2, 1.4 Hz, 1H), 4.10 (dd, J = 9.4, 1.5 Hz, 1H), 4.05 (dd, J = 9.1, 1.1
Hz, 1H), 2.18 (d, J = 8.8 Hz, 1H), 2.00 (app dtd, J = 14.0, 10.0, 4.7 Hz,
2
2
=
5
mmol) was added at rt under air. After being stirred for 24 h, the
reaction mixture was shaken with saturated aqueous Na S O solution.
2
2
3
The organic layer was separated, and the aqueous layer was extracted
with CH Cl . The combined organic extracts were washed with
1
1
H), 1.80 (app ddt, J = 15.5, 10.7, 5.5 Hz, 1H), 1.58−1.51 (m, 1H),
2
2
.45−1.38 (m, 1H), 1.36−1.24 (m, 10H), 0.89 (app t, J = 6.9 Hz, 3H);
saturated aqueous NaCl solution, dried over Na SO , filtered, and
concentrated in vacuo (25 mmHg). The residue was diluted with
2 4
1
3
C NMR (126 MHz, CDCl ) δ 134.9, 119.5, 74.5, 64.7, 64.5, 61.7,
3
3
2
6.5, 32.0, 29.5, 29.3, 29.2, 26.7, 22.8, 14.3; IR (thin film) 3390, 2925,
hexanes, filtered, and concentrated in vacuo (25 mmHg) to give the
4
c
−1
35
855, 933 cm ; HRMS (ESI-TOF) m/z calcd for C H Cl O [M +
corresponding α,α-dichloro-t-butylimine as a yellow oil (1.54 g,
∼94:6 dichloride:monochloride). The crude material was dissolved in
THF (10 mL), and 6 M aq HCl (10 mL) was added at rt. The biphasic
14
25
4
−
Cl] 349.0659, found 349.0665.
+)-(11Z,13S,14S,15S,16S)-1-tert-Butyldimethylsiloxy-2,2,-
5,16-tetrachloro-13,14-epoxy-11-tetracosene (76): The solvents
(
1
mixture was stirred for 2 h prior to dilution with Et O. The organic
2
were bubbled with argon for 15 min before use. To a stirred solution
of (−)-55 (134 mg, 0.481 mmol) and 71 (530 mg, 1.44 mmol) in
DCE (480 μL) was added a solution of 60 (91.3 mg, 0.144 mmol) in
CH Cl (600 μL) in six portions (0, 15, 30, 45, 60, 75 min) at 35 °C
layer was separated, and the aqueous layer was extracted with Et O.
The combined organic extracts were washed with saturated aqueous
2
NaHCO solution, dried over MgSO , filtered, and concentrated in
3
4
vacuo (25 mmHg). The residue was purified by column chromatog-
raphy (SiO , ϕ = 2.2 cm, l = 7 cm, n-pentane/CH Cl , 2/1, R = ∼0.20,
2
2
while the reaction mixture was vigorously bubbled with argon
2
2
2
f
6
(
saturated with DCE). After being stirred at 35 °C with argon
streaky, KMnO ) and bulb-to-bulb distillation under reduced pressure
4
bubbling for an additional 105 min, the reaction mixture was cooled to
(0.25 mmHg, ABT 129−135 °C) to give 69 (1.01 g, 73% over three
1
rt, filtered through a plug of silica gel (CH Cl , 10 mL), and
steps, ∼94% pure) as a colorless oil. Data for 69: H NMR (500 MHz,
2
2
concentrated in vacuo (5 mmHg). The residue was purified via
column chromatography (140 mL of SiO , 5% CH Cl /hexanes, R =
CDCl ) δ 9.25 (s, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 4.99 (dd,
3
J = 17.1, 1.9 Hz, 1H), 4.93 (dd, J = 10.2, 1.0 Hz, 1H), 2.31−2.23 (m,
2H), 2.04 (dd, J = 14.4, 6.9 Hz, 2H), 1.66−1.58 (m, 2H), 1.43−1.24
(m, 10H).
2
2
2
f
0
.23 in 10% CH Cl /hexanes) to give (+)-76 (57.1 mg, 19%, >20:1 =
2 2
25
Z:E) as a colorless oil. Data for (+)-76: [α]D = +0.088 (c 2.65,
CHCl ); H NMR (499 MHz, CDCl ) δ 5.86 (app td, J = 8.9, 8.4 Hz,
1
2,2-Dichloro-11-dodecen-1-ol (70): To a stirred solution of 69
3
3
1
3
1
1
1
(
3
2
H), 5.22 (app t, J = 8.7 Hz, 1H), 4.29−4.24 (m, 1H), 3.92 (s, 2H),
.82−3.77 (m, 1H), 3.65 (d, J = 8.9 Hz, 1H), 3.52 (dd, J = 8.0, 2.2 Hz,
H), 2.22 (app q, J = 7.2 Hz, 2H), 2.19−2.15 (m, 2H), 1.98−1.89 (m,
H), 1.86−1.78 (m, 1H), 1.62−1.52 (m, 3H), 1.45−1.39 (m, 3H),
.37−1.23 (m, 18H), 0.91 (s, 9H), 0.88 (app t, J = 6.3 Hz, 3H), 0.11
(1.00 g, 3.98 mmol) in ethanol (12 mL) was added NaBH
3.98 mmol) at 0 °C under air. After being stirred for 30 min at rt, 1 M
aq HCl (12 mL) was added. The cloudy mixture was diluted with H
and extracted with hexanes twice. The combined organic extracts were
dried over Na SO , filtered, and concentrated in vacuo (25 mmHg).
The residue was purified by column chromatography (SiO , ϕ = 2.2
cm, l = 13 cm, n-pentane/CH Cl , 1/1, R = 0.29, p-anisaldehyde) to
give 70 (934 mg, 93%) as a colorless oil. Data for 70: H NMR (500
MHz, CDCl ) δ 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 4.99 (dd, J =
4
(151 mg,
O
2
2
4
s, 6H); 13C NMR (126 MHz, CDCl ) δ 139.8, 121.6, 93.7, 72.3, 63.5,
3
2
1.3, 58.3, 54.0, 43.7, 35.9, 32.0, 29.5, 29.45, 29.43 (2C), 29.32, 29.28,
2
2
f
1
9.18, 29.12, 28.4, 26.5, 25.9, 24.9, 22.8, 18.4, 14.2, −5.2; IR (thin
−1
film) 2927, 2855, 1119, 939, 779 cm ; HRMS (ESI-TOF) m/z calcd
for C H O Cl SiNa [M + Na] 639.2701, found 639.2719.
3
35
+
17.1, 1.5 Hz, 1H), 4.93 (d, J = 10.2 Hz, 1H), 3.90 (d, J = 7.6 Hz, 2H),
2.29 (t, J = 7.6 Hz, 1H), 2.24−2.18 (m, 2H), 2.04 (dd, J = 14.3, 6.9 Hz,
30
56
2
4
Preparation of Alkene Cross Metathesis Partner for
36
13
Danicalipin A and Malhamensilipin A. 11-Dodecenal (68):
2H), 1.68−1.59 (m, 2H), 1.42−1.26 (m, 10H); C NMR (126 MHz,
To a flask containing magnesium (3.43 g, 141 mmol) in THF (10 mL)
was added 1,2-dibromoethane (275 μL, 3.19 mmol) slowly. The
mixture was allowed to sit at rt until gray precipitate formed. After
dilution with additional THF (70 mL), a solution of 1-bromo-10-
undecene (10.0 mL, 45.6 mmol) in THF (20 mL) was added over 1 h
via a syringe pump. After being stirred for 1 h, the mixture was cooled
to 0 °C and allowed to settle. The liquid phase was transferred via a
cannula to a rapidly stirred solution of DMF (53 mL, 684 mmol) and
THF (53 mL) at 0 °C. After being stirred for 20 min at rt, the reaction
mixture was diluted with hexanes (200 mL) and poured into 1 M aq
HCl (200 mL). The organic layer was separated, and the aqueous layer
was extracted with hexanes (200 mL × 3). The combined organic
CDCl ) δ 139.1, 114.2, 94.7, 72.1, 43.5, 33.8, 29.28, 29.27, 29.02,
3
−1
28.98, 28.8, 24.8; IR (thin film) 3484, 2926, 2854 cm ; HRMS (CI-
TOF) m/z calcd for C H O Cl NH [M + NH ] 270.1392, found
35
+
12
22
2
4
4
270.1390.
12-tert-Butyldimethylsiloxy-11,11-dichloro-1-dodecene (71):
4
c
To a stirred solution of 70 (348 mg, 1.37 mmol) and imidazole (187
mg, 2.75 mmol) in CH Cl (2 mL) was added TBSCl (228 mg, 1.51
2
2
mmol) at rt. After being stirred for 48 h, the reaction mixture was
diluted with CH Cl2 (5 mL) and shaken with saturated aqueous
2
NaHCO (5 mL). The organic layer was separated, and the aqueous
3
layer was extracted with hexanes (10 mL × 3). The combined organic
extracts were washed with saturated aqueous NaCl (3 mL),
concentrated in vacuo (5 mmHg), and passed through a pad of silica
gel (5% EtOAc in hexanes, 10 mL). The residue was purified by bulb-
to-bulb distillation under reduced pressure (0.05 mmHg, ABT 170−
extracts were washed with brine (100 mL), dried over MgSO , filtered,
and concentrated in vacuo (5 mmHg). The residue was purified by
column chromatography (300 mL of SiO , 5% EtOAc in hexanes) to
afford 68 (6.33 g, 76%) as a colorless oil. Data for 68: H NMR (500
4
2
1
1
180 °C) to afford 71 (453 mg, 90%) as a colorless oil. Data for 71: H
MHz, CDCl ) δ 9.76 (s, 1H), 5.81 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H),
NMR (500 MHz, CDCl ) δ 5.81 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H), 4.99
3
3
4
.99 (dd, J = 17.0, 1.4 Hz, 1H), 4.92 (dd, J = 10.2, 0.8 Hz, 1H), 2.41
(dd, J = 17.3, 1.7 Hz, 1H), 4.93 (dd, J = 10.2, 1.0 Hz, 1H), 3.92 (s,
2H), 2.15−2.19 (m, 2H), 2.04 (app q, J = 7.2 Hz, 2H), 1.55−1.62 (m,
(
td, J = 7.6, 1.7 Hz, 2H), 2.03 (app q, J = 7.1 Hz, 2H), 1.62 (tt, J = 7.3,
13
13
6
.6 Hz, 2H), 1.39−1.35 (m, 2H), 1.33−1.25 (m, 10H); C NMR
2H), 1.27−1.40 (m, 10H), 0.91 (s, 9H), 0.11 (s, 6H); C NMR (126
(
126 MHz, CDCl ) δ 203.0, 139.2, 114.1, 43.9, 33.8, 29.4, 29.34,
MHz, CDCl ) δ 139.2, 114.1, 93.5, 72.1, 43.5, 33.8, 29.30, 29.29, 29.1,
3
3
29.31, 29.13, 29.07, 28.9, 22.1; IR (thin film) 2926, 2854, 2715, 1727
29.0, 28.9, 25.7, 24.7, 18.3, −5.4; IR (thin film) 2928, 2856, 1118, 838
N
dx.doi.org/10.1021/jo5000829 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−
1
35
cm ; HRMS (CI-TOF) m/z calcd for C H Cl OSiNH [M +
(d) Bedke, D. K.; Shibuya, G. M.; Pereira, A.; Gerwick, W. H.;
Vanderwal, C. D. J. Am. Chem. Soc. 2010, 132, 2542−2543. (e) Chung,
W.-j.; Carlson, J. S.; Bedke, D. K.; Vanderwal, C. D. Angew. Chem., Int.
Ed. 2013, 52, 10052−10055. (f) Chung, W.-j.; Vanderwal, C. D. Acc.
Chem. Res. 2014, DOI: 10.1021/ar400246w.
18
36
2
4
+
NH ] 384.2256, found 384.2257.
4
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
7) Carbonyl additions to simple α-chloroaldehydes are often highly
diastereoselective. See: Britton, R.; Kang, B. Nat. Prod. Rep. 2013, 30,
27−236.
8) The addition of organometallic nucleophiles to α-chloro-
Copies of NMR spectra for all new compounds and relevant
chromatograms are available. This material is available free of
charge via the Internet at http://pubs.acs.org.
2
(
aldehydes generally proceeds to afford the anti product, consistent
with the polar Felkin−Anh model (hyperconjugative stabilization of
the transition state/steric control), though the Cornforth model
AUTHOR INFORMATION
Corresponding Author
E-mail: cdv@uci.edu.
Notes
■
(dipole minimization/steric control) also accounts for the stereo-
*
chemistry of the products. For an excellent discussion and lead
reference, see: Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc.
The authors declare no competing financial interest.
2
(
006, 128, 2920−2930.
9) The corresponding chloroallylaluminum reagents have been
ACKNOWLEDGMENTS
This work was supported by the National Institutes of Health
R01 GM086483). J.S.C. is supported by a National Science
Foundation Graduate Research Fellowship. We thank Materia
for generous donation of metathesis catalyst 60, and Dr. Martin
Schnermann, Dr. Paresma Patel, Dr. Vanessa Marx, and Prof.
Robert Grubbs for assistance with the convergent metathesis
step. We thank Prof. Scott Miller (Yale) and Dr. Matthew
Tudge (Merck) for assistance with our attempts to resolved
■
(
previously reported: Hosomi, A.; Kohra, S.; Tominaga, Y.; Ando, M.;
Sakurai, H. Chem. Pharm. Bull. 1987, 35, 3058−3061.
(10) (a) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem.
1
996, 61, 7513−7520. (b) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J.
Org. Chem. 1998, 63, 8843−8849.
11) (a) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch, P. M.;
(
Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134−8137. For
enantioselective dibromination of alkenes, see: (b) Hu, D. X.;
Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc. 2013, 135, 12960−
1
(
2963.
12) Halpern, O. S. M.S. Dissertation, UC Irvine, 2008.
(13) Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C.
2
,3-dichloroalcohols. We acknowledge the intellectual contri-
butions made to this project by Dr. D. Karl Bedke.
Angew. Chem., Int. Ed. 1997, 36, 2341−2344.
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30) At the initial stage of optimization, a catalytic amount of Et NCl
2
(
(
(
̈
9
(
́
́
(
3
(
4
was employed as an indicator of the completion of the reaction. After
all the alkene substrate is consumed, Et NCl is formed with an excess
4
3
of Cl and shows deep yellow color as a sign of completion. In the
2
experiment described here, an excess of Et NCl was employed to
4
suppress the formation of oligomeric side products, which is usually
−
problematic in the absence of an excess of exogenous Cl source.
(
31) An NMR sample of crude (±)-27 showed no noticeable further
decomposition after standing at rt overnight.
32) Although the epoxide formation can proceed without a phase
(
transfer catalyst, the addition of a catalytic amount of Et NCl facilitates
4
the epoxide formation and ensures complete conversion.
(
33) The vinyl epoxide decomposed significantly during reactions
without argon bubbling.
34) In the presence of an excess of n-Bu SnH, dechlorination of one
(
3
of the gem-dichlorides was often observed.
(
(
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2
P
dx.doi.org/10.1021/jo5000829 | J. Org. Chem. XXXX, XXX, XXX−XXX