Total Synthesis of (-)-Luminacin D

Article abstract of DOI:10.1021/acs.joc.6b00489

A second-generation synthesis of (-)-luminacin D based on an early stage introduction of the trisubstituted epoxide group is reported, allowing access to the natural product in an improved yield and a reduced number of steps (5.4%, 17 steps vs 2.6%, 19 steps). A full account of the optimization work is provided, with the reversal of stereoselection in the formation of the C4 alcohol in equally excellent diastereoselectivity as the key improvement.

Full text of DOI:10.1021/acs.joc.6b00489

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Article
Total Synthesis of (–)-Luminacin D
Julien Malassis, Nathan Bartlett, Kane Hands, Matthew Duncan Selby, and Bruno Linclau
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00489 • Publication Date (Web): 07 Apr 2016
Downloaded from http://pubs.acs.org on April 9, 2016
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Total Synthesis of (–)ꢀLuminacin D
a
a
a
b
,a
Julien Malassis, Nathan Bartlett, Kane Hands, Matthew D. Selby and Bruno Linclau*
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Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK). UCB, 216 Bath
Road, Slough, Berkshire, SL1 WE (UK).
bruno.linclau@soton.ac.uk
RECEIVED DATE
Abstract—A second generation synthesis of (−)ꢀluminacin D based on an early stage introduction of
the trisubstituted epoxide group is reported, allowing access to the natural product in an improved yield
and a reduced number of steps (5.4%, 17 steps vs 2.6%, 19 steps). A full account of the optimization
work is provided, with the reversal of stereoselection in the formation of the C4 alcohol in equally
excellent diastereoselectivity as the key improvement.
1
. Introduction
1
Angiogenesis is defined as the formation of new blood vessels from the preꢀexisting vascular network.
Through its involvement in numerous pathologies, including tumor growth and metastasis,
angiogenesis and its associated regulation mechanisms have emerged as promising targets in drug
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discovery. In particular, remarkable efforts have been directed towards the identification of angiogenic
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modulators among the natural products.
The luminacin family of natural products, originally isolated from bacterial fermentation, contains
numerous members that have been shown to exhibit potent antiangiogenic activity in several assays.
Wakabayashi et al. notably demonstrated that luminacins operate by blocking the initial stages of the
capillary tube formation in vitro, with luminacin D 1a (Chart 1) being the most active among the 12
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members tested. Later on, additional in vivo studies using luminacin C2 1b revealed that this molecule
effectively inhibited the phosphorylation activity of Src tyrosine kinases, and was found to exert its
5
,6
unique mode of action by disrupting Src mediated proteinꢀprotein interactions. Src tyrosine kinases
play key roles in the regulation of numerous processes associated to angiogenesis, including growth,
7
differentiation, migration and survival. In addition, luminacin C2 was also found to inhibit breast
cancer cell invasion and metastasis in vitro by disrupting the AMAP1ꢀcortactin binding (proteinꢀprotein
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interactions). The recent isolation of two cancer cell migration inhibitors of similar structure
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(migracins A and B, 1c, 1d), highlighted once more the therapeutic potential of these molecules.
Chart 1. Structure of luminacins
Despite its promising antiꢀangiogenic activity as revealed by the original work of Wakabayashi,
luminacin D has been less extensively studied in comparison with some other members of its family,
and little information can be found regarding its mode of action and biological functions. To obtain
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further material to enable further biological investigations, chemical synthesis is the most efficient way
given the modest yield from extraction (and the fact that a new extraction campaign would be
required).
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Apart from our recent contribution, so far there have been four reported syntheses of luminacin
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11,12,13,14,15
derivatives,
each presenting shortcomings in term of length or selectivity. In particular, the
efficiency of three from these four syntheses was dramatically compromised by the low or undesired
stereoselectivity associated with the epoxidation step which, in addition, in each case took place at a
late stage of the synthesis. In this context, we achieved a highly diastereoselective synthesis of (–)ꢀ
1
0
luminacin D in 19 steps. As shown in Scheme 1, our synthetic approach relied on the stereoselective
introduction of the epoxide moiety at an early stage of the synthesis starting from the enantiopure
sulfoxide 5, and subsequently to utilize the chirality of the epoxide group in 4 for the diastereoselective
completion of the aliphatic fragment. This was achieved via a chelationꢀcontrolled allylation procedure
of the enantiopure αꢀepoxy aldehyde 4a, which proceeded in excellent yield and diastereoselectivity.
Unfortunately, the reaction led to the formation of the undesired diastereoisomer 6, and thus an
inversion of the obtained alcohol stereocentre was required to complete the synthesis. As further shown
in the retrosynthetic analysis, the formation of Luminacin D 1a was realized via arylation of the fully
functionalized fragment 2, whose construction was envisaged via spontaneous hemiacetal formation
and synꢀaldol reaction from the key compound 3. A full account of the different approaches for the
formation of the cyclic hemiacetal moiety, and further optimizations of several other steps are disclosed
here. In particular, this includes our efforts towards the development of methodology that resulted in
direct access to the key intermediate 3 from 4.
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Scheme 1. Retrosynthetic analysis and new diastereoselective methodologies developed
O
HO
OH
O
O-
S+
O
O
O
X
OH
R
O
O
O
O
OH
O
tBuO
OH
O
Tol
H
H
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tBuO
tBuO
O
O
5
H
H
3
R=H 4a
R=Allyl 4b
OH
OP
1
a
2
(_
incorrect stereochemistry
)-luminacin D
O
H
OH
O
O
SnBu3
O
O
Chelation-controlled
allylation
Previous work:
tBuO
MgBr , DCM
2
78 °C
87%, d.r >95:5
tBuO
6
-
4
a
O
OH
O
O
L-selectride
THF
O
O
Diastereoselective
reduction
tBuO
tBuO
3
3
4
b
This work:
O
B
O
H
OH
O
O
O
O
O
Non chelation-controlled
allylation
DCM
tBuO
tBuO
4a
Results and discussion
Synthesis of the epoxide precursor (ester-sulfoxide 9)
Starting from the αꢀsulfoxyꢀesters 5, we initially investigated the oneꢀpot Knoevenagel procedure
1
6
described by Tanikaga et al. in order to access to the desired (E)ꢀalkenes 8 and (±)-8 . This method
Tol
Ph
proved unsuccessful when applied to our substrates (recovery of starting material). Hence, as described
1
0
in our previous communication, the formation of racemic and enantiopure α,βꢀunsaturated (E)ꢀ
alkenes (±)-8Ph and 8Tol was then accomplished in 2 steps from the corresponding βꢀsulfoxyꢀester, as
1
7
shown in Scheme 2. At first, following a known procedure, an aldolꢀtype condensation of 5 with
propanal led to the βꢀhydroxy ester 7 as an impure mixture of diastereoisomers. It was found that
treatment of this mixture with MsCl in pyridine afforded alkenes 8 in excellent yield and
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stereoselectivity. Further to Tanikaga’s stereochemical assignment by chemical shift differences, the E
configuration of 8 is now further confirmed by NOE analysis (see SI).
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Scheme 2. Synthesis of (E)-alkenes 8
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The subsequent epoxidation step had been achieved in a diastereoselective manner in our previous
synthesis, using a procedure that was adapted from De La Pradilla’s vinyl sulfoxide methodology
1
8
(
Table 1, entries 1 and 2). The reaction proceeded in excellent yield and diastereoselectivity with the
phenyl derivative 8Ph (90%, dr 94:6), while the same reaction conditions applied with tolyl derivative
8Tol led to lower yield and diastereoselectivity (77%, dr 88:12). In addition, the product 12 was
obtained in 19% yield as mixture of diastereoisomers (Table 1). The latter was thought to arise from the
nucleophilic attack of nꢀBuLi onto the Michael intermediate 11, since an excess of nꢀBuLi was used
compared to tꢀBuOOH (5 vs 4 equiv., respectively).
We then decided to investigate modified conditions for the epoxidation reaction. The first experiment
was carried out with 8Tol by using an excess of tꢀBuOOH compared to nꢀBuLi (Entry 3). Although the
reaction proceeded without any formation of 12, the formation of undesired byꢀproducts could be
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observed by H NMR, alongside with the expected transꢀepoxides syn-9Tol and anti-9 . After column
Tol
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chromatography, the epoxides were isolated as a mixture of diastereoisomers in moderate yield (60%,
dr syn-9Tol /anti-9Tol 95:5). A mixture of two unexpected products was also isolated in 16% yield,
which allowed their assignment as the cisꢀepoxide isomers syn-10Tol and anti-10 . Following this, it
Tol
was found that using a 1:1 ratio of tꢀBuOOH and nꢀBuLi, and reducing the reaction time allowed to
minimize the formation of the cisꢀepoxides 10Tol (Entry 4). The transꢀepoxide 9Tol was isolated in both
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excellent yield and diastereselectivity in these conditions (82%, dr syn-9 /anti-9
91:9).
Tol
Tol
Interestingly, the replacement of nꢀBuLi by NaH as base with the racemic derivative (±)-8 resulted in
ph
promoting the formation of cisꢀisomers 10 , with a good selectivity towards the synꢀepoxide (±)-syn-
ph
10ph (Entry 5). The same outcome was observed when an excess of NaH compared to tꢀBuOOH was
used with the tolyl derivative 8Tol (Entry 6). The epoxidation reaction was carried out on 3 g scale (10
mmol) with the tolyl derivative 8Tol using the optimised conditions, and enabled isolation of the
expected transꢀepoxides 9Tol in a slightly improved yield and diastereoselectivity compared to our
earlier procedure (Entry 7, 82%, dr syn/anti 92:8 vs 77% dr syn/anti 88:12). A minor quantity of the
cisꢀepoxides 10Tol was also obtained after separation (<2% yield).
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Table 1. Optimisation of the epoxidation reaction. Prefixes syn/anti refer to the relative position
of the sulfoxide aryl group compared to the epoxide function. Prefixes trans/cis (as used in the
discussion) refer to the relative arrangement of the epoxide substituents
3
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8
9
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2
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3
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5
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0
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0
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Base
tꢀBuOOH
dr syn-9/anti-9/
Overall Yield
Yield 9
Yield 10
Entry Ar.
t (h)
0.4
0.4
1.5
0.4
0.4
0.4
0.4
a
b
b
b
(
equiv.)
(equiv.)
syn-10/anti-10
(%)
(%)
(%)
nꢀBuLi
5)
c
d
e e
f
f
1
2
Ph
Tol
Tol
Tol
Ph
4
94:6: :
89
77
91
88
78
78
88
89
77
60
82
(
nꢀBuLi
5)
c
d
e e
4
88:12: :
(
nꢀBuLi
4)
g
3
4.9 – 6
72 : 4 : 16 : 8
81 : 8 : 6 : 6
35 : 4 : 54 : 7
45 : 2 : 50 : 3
86 : 7 : 4 : 3
16
(
nꢀBuLi
3)
d
h
4
5
6
3
(
NaH
(2.5)
g
3.2 – 3.9
23
53
25
<2
NaH
(3.2)
d
h
Tol
Tol
3
nꢀBuLi
c
d
7
3
82
(3)
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a
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b
c
d
Determined by H NMR; Isolated yield; Reaction carried out on 3ꢀ6g (10ꢀ20 mmol) scale; A commercial solution of tꢀBuOOH in
e
f
1
g
decane (5.5M) was used; Not detected; Traces were observed in H NMR; A commercial solution of tꢀBuOOH in decane (5ꢀ6M) was
h
used; Not isolated
The assignment of configuration of all the epoxide stereomers was achieved by a combination of Xꢀray
crystallographic analysis and a chemical correlation experiment. The configuration of the crystalline
C3 (“pseudo”ꢀ) epimers syn-9Tol and (±)-syn-10Ph was established by Xꢀray analysis (see supporting
information), as the synꢀisomers for both 9 and 10 crystallized as pure diastereomers. The
stereochemical relationship between the synꢀ and antiꢀepoxides was established by the oxidation
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(
Scheme 3) of a mixture of isomers syn-10Tol and anti-10Tol (dr ~1:1), which led to a single sulfone 13
1
(
as observed by H NMR), which allowed unambiguous assignment of anti-10 as the cisꢀantiꢀ
Tol
epoxide (and by inference, also that of anti-10Ph).
Scheme 3. Sulfone formation
Synthesis of the intermediate 3: the diastereoselective reduction approach
As already mentioned, we previously reported the development of chelationꢀcontrolled allylation
methodology, which, when applied to aldehydes possessing a αꢀoxygenated center, proceeded with
10
excellent diastereoselectivity. The selectivity outcome was found consistent with the formation of a
1,3ꢀchelated transition state, in which facial selectivity is dictated by a CornforthꢀEvans (CE) type
model. With the aim of developing a complementary approach to the aforementioned allylation step,
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our investigations were directed towards a chelationꢀmediated reduction involving 1,3ꢀketo esters such
3
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as 4b, in which the stereoselection would be equally predicted by the CE model. Hence, by invoking
1
4, hydride attack of the least congested Siꢀface would directly lead to the key intermediate 3 (Scheme
4
). We were encouraged in this approach by the work of Castle et al. regarding the selective addition of
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various nucleophiles to a 1,3ꢀalkoxy ketone containing an αꢀOTBS substituent, which was found to
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operate via a 1,3ꢀchelation controlled transition state combined with CEꢀtype stabilization.
Furthermore, a number of methodologies for the metalꢀmediated diastereoselective reduction of βꢀketo
esters, βꢀhydroxy ketones and α-epoxy ketones have been described, leading in general to excellent
facial selectivity.20,21,22,23,24,25,26
Scheme 4. Proposed reduction approach
In order to simplify the optimization studies, we first focused on the synthesis of the βꢀpropyl keto ester
4c, whose formation was envisaged via acylation reaction of the sulfoxide 9Tol (Table 2). This was
achieved in moderate yield, via treatment of 9Tol with tꢀBuLi and subsequent trapping of the resulting
oxiranyl anion with methyl butyrate, under Barbier conditions. As these reactions were carried out on
the 92:8 syn/anti mixture, an 84% product enantiopurity was obtained. Unfortunately, the selective
crystallization procedure of 9 as explained above was only achieved after carrying out the experiments
given in Table 2, but would give access to enantiopure material. As shown in table 2, several trials
1
9
involving a Lewis acid to induce chelationꢀcontrol during the reduction reaction were undertaken. As
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5
6
a first experiment, treatment of 4c with NaBH and MgBr , in a mixture of THF/DCM gave no
4
2
expected product. Instead, these conditions resulted in the formation of the bromohydrin 17 as major
product (48% isolated yield), alongside with the reduced bromohydrin 18 as a mixture of
diasteroisomers. The antiꢀproduct 18a was isolated in 9% yield. The epoxide opening issue was
overcome by performing the reaction at 0 °C in MeOH, leading to the exclusive formation of products
16. To our surprise, the undesired antiꢀdiastereoisomer 16a was obtained as major product (dr 16a/16b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1:29, Entry 2), which is not consistent with reaction via the transition state 14 (cf. Scheme 4).
2
1,22
Replacing MgBr by CaCl as chelating metal
resulted in a similar outcome, with 15a obtained in
2
2
good isolated yield and excellent diastereoselectivity (70%, dr 16a/16b 97:3, Entry 3). Following this,
the use of Et SiH or Lꢀselectride as reducing agents with MgBr was also attempted at ꢀ78 °C, though
3
2
both conditions led to the exclusive formation of the bromohydrin 17 (Entry 4 and 5). Since the
involvement of MgBr /CaCl led to undesired diastereoselectivity or unexpected reactivity, the
2
2
reduction of the ketone 4c was attempted using Lꢀselectride only (Entry 6). This time, the reaction
proceeded in good yield and excellent diastereoselectivity towards the desired synꢀproduct 16b (Entry
6
, 90%, dr 16a/16b 1:9). Interestingly, employing the more hindered LSꢀselectride led to a drop of
conversion and selectivity.
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9
Table 2. Acylation and attempted conditions for the reduction reaction
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
Yield
Yield
Yield
Entry
1
Conditions
1
6 (%) (dr)
17 (%)
18 (%) (dr)
NaBH (1.05 equiv.), MgBr ,
4
2
b
c
22 (9)
a
b
c
(1.6equiv), DCM/THF 2:1,
78 °C to rt, 3 h
78 (48)
a
(
dr 18a/18b 93:7)
ꢀ
b
NaBH (1.2 equiv.), MgBr (2
100
4
2
a
a
a
2
3
4
5
6
7
b
equiv.), MeOH, 0 °C, 30 min.
(dr 16a/16b 71:29)
b
c
NaBH (0.6 equiv.), CaCl (2
100 (72)
4
2
a
a
a
a
a
b
equiv.), MeOH, 0 °C, 30 min
(dr 16a/16b 97:3)
Et SiH (1.05 equiv.), MgBr (1.6
3
2
a
b
c
83 (64)
equiv), DCM, ꢀ78 °C, 2 h
Lꢀselectride (1.05 equiv.), MgBr2,
1.6 equiv), DCM, ꢀ78 °C, 2 h
a
b
100
(
b
c
Lꢀselectride (1.05 equiv.), THF,
ꢀ78 °C, 30 min.
100 (90)
a
a
b
(dr 16a/16b 1:9)
b
LSꢀselectride (1.3 equiv.), THF,
48
b
ꢀ
78 °C, 45 min.
(dr 16a/16b 33:67)
a
b
1
c
Not formed; Determined by H NMR; Isolated yield.
As shown in Figure 1, the selectivity observed when NaBH /CaCl and MgBr were used could be
4
2
2
explained by the 1,2ꢀchelated transition state 19, assuming that the metal salt catalyzes the formation
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
6
2+
formation of alkoxyborohydrides NaBH ꢀn(OMe)n in MeOH. The coordination between a Ca and
4
the methoxy group of the borohydride species would therefore direct the hydride attack to the Reꢀface,
leading to the antiꢀcompound 16a. On the other hand, the models 20 and 21 are consistent with the
selectivity observed when L or LSꢀselectride are employed, assuming that the Li cation is able to
chelate between the carbonyl groups (model 20) or between the carbonyl group and the epoxide (model
21). Hydride attack from the least hindered Siꢀface in both cases would lead to the observed formation
of the synꢀcompound 16b.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Possible rationalization of the selectivity outcome
The relative configuration of 16a and 16b was assigned by NMR comparison with the antiꢀalcohol,
which was obtained after reduction of the double bond of previously synthesized 3 (Scheme 5). The
regioselectivity of bromide mediated epoxide opening on 4c, and the relative configuration of the
resulting 18a, were determined thanks to Xꢀray crystallographic analysis (See SI).
Scheme 5. Hydrogenation of 3 to allow assignment of the relative stereochemistry
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2
Motivated by these results, the acylation/diastereoselective reduction procedure was then applied
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
7
towards the luminacin D synthesis, using methyl butꢀ3ꢀeneoate 22 and Lꢀselectride (Scheme 6). Since
the intermediate 4b proved unstable to purification on silica gel (with double bond isomerization
occurring during silica gel chromatography, not shown), the reduction reaction was attempted on the
crude material, immediately after workꢀup. A first experiment was conducted on small scale with the
racemic epoxide (±)-9Ph and Lꢀselectride as reducing agent. The synꢀαꢀepoxy alcohol (±)-3 was
obtained as major product in an encouraging yield (19 % over 2 steps), together with a minor quantity
of the antiꢀdiastereoisomer (±)-7 (1% over 2 steps, separation achieved by column chromatography).
Unfortunately, the reaction proved less efficient on 1 g scale, resulting in a drop of yield (14% for (±)-3
over 2 steps). Several parameters, including the volatility of intermediate 4b and the purification issues
induced by the formation of numerous byꢀproducts over the 2 steps, made the process cumbersome.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Formation of 3 and 7 via the reduction approach
Synthesis of the intermediate 3: the allylation approach
Given the moderate yield obtained with the previous approach, the original strategy involving an
allylation reaction was reconsidered, with the aim of developing new conditions allowing access to the
opposite selectivity outcome compared to the MgBr ꢀpromoted allylation procedure. Given the
2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
unexpected stereochemical outcome of the reduction process using CaCl as explained above, this
2
additive was now used in a reinvestigation of the allylation of 4a. Hence, the aldehyde 4a (and (±)-4a)
was reꢀsynthesized through formylation of the epoxide precursors 9, applying similar conditions as
used for the acylation procedure (Table 3). Pleasingly, the reaction proceeded in an improved yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
compared to our previous procedure, and is generally more efficient as it can be conducted at ꢀ78 °C
(instead of ꢀ120 °C) without the need of CeCl , which had to be dried under vacuum prior to the
3
reaction and made the work up difficult.
We then examined the use of a modified procedure for the allylation reaction (Table 3). The conditions
of the reported procedure (Entry 1), but with CaCl instead of MgBr , were investigated first (Entry 2).
2
2
Despite the poor conversion obtained, we were pleased to notice that only the desired synꢀ
1
diastereoisomer 3 was formed during the reaction, as observed by H NMR of the reaction mixture
before chromatography. Increasing the temperature, concentration and reaction time resulted in a better
conversion, with 3 obtained in a very good diastereoselectivity (Entry 3, dr 3/7 92:8). Based on these
results, it was envisaged that CaCl might not be involved in a chelated transition state, but would only
2
act as a weak activator of the reaction. To confirm this hypothesis, investigations were directed towards
the use of nonꢀchelating conditions for the allylation reaction. A first experiment involving the reaction
of 4a with allyltrimethylsilane and a subꢀstoichiometric amount of TBAF led to the recovery of the
28
starting material (Entry 4). However, the allylation of 4a occurred using the more reactive pinacolyl
2
9
allylboronate 23 in DCM, by raising the temperature from ꢀ78 °C to rt overnight (entry 5). As
predicted, the nonꢀchelation control promoted the formation of the desired synꢀdiastereoisomer 3, in an
excellent diastereoselectivity and isolated yield. This result mirrors the work of Mulzer and Prantz, who
recently demonstrated that the selectivity of the allylation of 2,2ꢀdialkylꢀ3ꢀoxopropionates could be
3
0
reverted by switching from chelation (TiCl ) to nonꢀchelation (BF •OEt ) mediated allylation. It
4
3
2
should be noted that both these Lewis acids are not compatible with the epoxideꢀcontaining substrate 4.
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The optimised twoꢀsteps procedure was then carried out on 1.5 g (5 mmol) scale of sulfoxide 9Tol (dr
2:8)(Entry 6). The slow addition of tꢀBuLi to the mixture via syringe pump over a period of 1 h was
found to give the best results for the formylation reaction. After column chromatography, the aldehyde
a was obtained in a mixture with minor impurities. Subsequent treatment with the pinacolyl
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
allylboronate 23 using the optimised conditions enabled isolation of the synꢀalcohol 3 as major product
in 33 % yield over 2 steps, together with the minor antiꢀdiastereoisomer 7, isolated in 1% yield.
1
Although an accurate dr determination was not possible by H NMR due to the presence of impurities,
the ratio of isolated yields of 7 and 3 is consistent with that observed on small scale. Similar results
were obtained when the racemic phenyl epoxide (±)ꢀ9 was used as starting material (Entry 7).
Ph
Table 3. Formylation and attempted conditions for the allylation reaction
Conversion
Yield 7
(%)
Yield 3
(%)
Ar
Tol
Ph
Ph
Ph
M
Entry
Conditions
a
dr 7/3
b
b
(
%)
c
MgBr
2
(1.6 equiv.), DCM (0.2 M),
d
a
e
e
SnBu3
1
> 95:5
87
4
ꢀ78 °C, 2 h
CaCl (1.6 equiv.), DCM (0.2 M), ꢀ
2
2
3
4
SnBu3
4
n.d
ꢀ78 °C, 2h
CaCl (1 equiv.), DCM (0.7M), rt,
a
2
SnBu3
35
8:92
28
<1
30h
TBAF (0.1 equiv.), MS 4Å, DCM
f
f
f
TMS
s.m recovered
(
0.05 M), rt, 48h
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
5
Ph
Tol
Ph
DCM (0.3 M), ꢀ78 °C to rt, 16 h
100
100
100
< 5:95
2
80
33
g
d
1
6
7
DCM (0.3 M), ꢀ78 °C to rt, 16 h
<5:95
<5:95
(
2 steps)
(2 steps)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
g
d
e
33
(2 steps)
DCM (0.3 M), ꢀ78 °C to rt, 16 h
a
f
1
b
c
d
e
Determined by H NMR; Isolated yield; Reaction carried out on 3 mmol of 4a; Based on isolated yields; Not isolated;
g
Not detected; Reaction carried out on 5 mmol of 8 (2 steps procedure)
In the context of the luminacin D synthesis, this new procedure represents a significant improvement
compared to the previous route reported by our laboratory, which required two extra steps for the
formation of 3, in a lower overall yield (24% over 4 steps). The excellent substrate control of this
allylation reaction under nonꢀchelating conditions can be rationalized (Figure 2) by invoking the classic
CornforthꢀEvans (24) or polar FelkinꢀAnh (25) models, assuming that the CꢀO bond of the epoxide acts
as the “polar substituent” in preference to the ester.
Figure 2. CornforthꢀEvans (24) and polar FelkinꢀAnh (25) models to explain the observed
diastereoselectivity.
Completion of the aliphatic fragment: aldol reaction and attempted lactonization.
With access to the pure intermediate 3 (and (±)-3), the synthesis was pursued towards the formation of
aldehyde 26 (and (±)ꢀ26), which was accomplished in two steps, following the reported procedure
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(Scheme 7). The βꢀchiral silyl ether center on 26 offered the possibility for remote stereocontrol, which
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
15
had been exploited in the luminacin D synthesis by Shipman et al. However, the use of a titanium
enolate derived from an aromatic ketone (already containing the luminacin D aliphatic moiety) only led
to modest stereocontrol (dr ~2:1, in favor of the desired isomer). Interestingly, while this type of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31
remote stereocontrol has been mainly investigated for Mukaiyama aldol reactions, we found no
related investigations of the extent of remote stereocontrol for aldol reactions involving classic Nꢀacyl
oxazolidinone boron enolate reagents. Hence, at this juncture, it was decided to investigate this process
using simplified model compounds in order to evaluate its potential usefulness in the luminacin D
3
2
32
synthesis (Table 4). Aldehydes (±)ꢀ27 and (±)ꢀ28 were prepared according to standard procedures
and subjected to aldol reactions with the boron enolate of 29. For the reaction between the ethyl
oxazolidinone 28a and (±)-26, a low stereocontrol was obtained (Entry 1). As predicted from the Evans
model, the major isomer contained the desired relative stereochemistry for our purposes (see SI for the
determination of the product relative stereochemistry). Increasing the size of the protecting group (as in
(±)ꢀ28) led to a slight increase of the desired selectivity (Entry 2). A further increase of the steric bulk
by using 29b, the reagent required for the luminacin D synthesis, did give a reasonable 5:1 ratio (Entry
3
).
Scheme 7. Synthesis of aldehyde 26
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4. Investigation of remote stereocontrol for the aldol reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry dr 30/31
R
P
c
1
2:1
3:1
Me
Bn
2
Me TBDPS
Pr TBDPS
3
5:1
a
1
Determined by H NMR.
With this level of selectivity obtained, this diastereoselective aldol reaction was then performed on the
racemic natural product intermediate (±)ꢀ32 with a TBDPS protecting group (Scheme 8).
Unfortunately, a slightly diminished level of selectivity (4:1) was obtained for the desired aldol
diastereomer (±)ꢀ33.
Scheme 8.Translation of the diastereoselective aldol reaction to the natural product system
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6
7
8
9
10
11
12
13
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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
Given the modest diastereoselectivity favoured the desired stereomer, a matched double
diastereodifferentiation process using a chiral oxazolidinone based auxiliary was then investigated.
14
This approach has also been used in the luminacin D synthesis by Maier et al. Hence, the enantiopure
3
3
oxazolidinone 35 was required (Scheme 9). For atom economy reasons, it was decided to use a TES
protecting group as opposed to a TBDPS group. Initially, the racemic aldehyde (±)-26 was engaged in
Evansꢀaldol reaction with the acyl chiral oxazolidinone, which led to the formation of two (among the
1
four possible) aldol adducts ( H NMR analysis) in a 1:1 dr. The two isomers could be separated by
preparative HPLC after TES protection of the formed alcohol, allowing isolation of the expected aldol
1
0
product 38 as well as the isomer 39, the latter resulting from the aldol reaction of the oxazolidinone
3
5 with the enantiomer of 26, since racemic starting material was employed. Given the low remote
stereocontrol exerted by the alcohol chiral centre as shown above, it is thought that the auxiliary
dominates the stereoselection, leading to the C2’,C3’ꢀsynꢀC3’,C5’ꢀsyn diastereoisomer 37. With
enantioenriched aldehyde 26 (er 92:8), exclusive formation of the aldol products 36 and 37 in a 91:9 dr
was observed. From that mixture, alcohol protection and HPLC separation allowed isolation of 38 and
39 in 86 and 6% yields, respectively. As mentioned above, applying the selective crystallization
procedure of 9 would avoid this separation issue, as in this case only aldol product 36 would be formed.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 9. Evans-aldol reaction and subsequent separation of the diastereoisomers
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cyclization of the aliphatic fragment: first approach
It was envisaged that the synthesis of the aliphatic fragment could be completed at this stage by acidꢀ
catalyzed tꢀBu deprotection, which would initiate lactone formation that then could be reduced to the
luminacin D lactol ring. The lactone formation was first investigated using the racemic aldol product 33
was used as model substrate (Scheme 10). To our surprise, heating with CSA in toluene led to a
product with the tꢀBu ester intact, but in which cyclization towards the epoxide group had occurred,
leading to 41 in excellent yield (81%). When TFA in DCM was used, the desired lactone formation did
occur, but only 11% of the 43 was isolated. Under these conditions, the same alternative cyclization
leading to a tetrahydropyran group occurred, even if the resulting product 44 was isolated as the
carboxylic acid. Presumably the slow tꢀbutyl ester deprotection promoted tetrahydropyran over lactone
formation, and the COOH deprotection leading to 44 could have occurred after the ring formation.
20
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Assignment of the different cyclisation products was achieved by HMBC and NOE analyses (see
supporting information).
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9
1
1
1
1
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1
1
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6
Scheme 10. Deprotection and unexpected cyclisation of the aldol product 33
O
O
O
O
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N
O
N
O
O
CO tBu
CSA
Tol
2
TBDPSO
OH
OTBDPS
O
OTBDPS
O H
OH
CO tBu
2
tBuOOC
OH
40a
33
41
81%
O
O
N
O
O
TBDPSO
OH
OTBDPS
O
O
O
O
H O
O
2
N
O
O
4
2
43
11%a
OTBDPS
O
TFA / DCM
O
OH
O
tBuOOC
N
O
CO R
3
3
2
TBDPSO
OH
OTBDPS
CO H
O H
O
2
OH
40b
44
67%
a
Isolated in a mixture with 44 (see experimental section)
Cyclization under basic conditions was also unsuccessful (Scheme 11). Treatment of the aldol product
33 with sodium hydride resulted in the formation of a product 45 in low yield, in which both
elimination and oxazolidinone ring opening had occurred. Interestingly, when 33 was subjected to
lithium ethylthiolate (see next section), the same elimination product was obtained in quantitative yield.
A mechanism of formation for this product 45 is proposed: deprotonation of the hydroxyl group
initiates cyclization to the carbamate group, expelling the primary alkoxide 48, which could then be
involved in carbon dioxide elimination to give 49, possibly via an intramolecular deprotonation
pathway as shown. Finally, amide anion protonation, either by reaction with 33, or in the workup, leads
to 45. The fact that no elimination/oxazolidinone opening product such as 45 was formed with lithium
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6
ethylthiolate when the alcohol group was protected (see next section) is consistent with the proposed
mechanism.
Scheme 11. Base catalysed elimination of aldol product 33
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Cyclization of the aliphatic fragment: second approach
Given the unsuccessful lactone formation, it was envisaged to postpone this step until after the
introduction of the aryl fragment (Scheme 12). Hence, oxazolidinone removal was attempted via
thioester formation. At high reagent concentration, the product 52, resulting from oxazolidinone
opening with lithium ethyl thiolate was sometimes observed, alongside with the expected thioester 50.
Nevertheless, a fully chemoselective conversion of TESꢀprotected aldol product 38 to the thioester 50
was achieved in excellent yield using dilute [EtSLi] conditions. The subsequent palladiumꢀmediated
reduction reaction produced the final aldehyde fragment 51. The yield of the reduction was
significantly increased by adding the reagents at 0 °C rather than rt as reported in the previous
procedure (96% vs 66ꢀ75%).
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Scheme 12. Completion of the aliphatic fragment synthesis
3
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9
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0
Completion of the synthesis
With the aliphatic fragment in hand, we pursued our efforts towards the synthesis of the bromoaryl
derivatives 55 and 58, as potential substrates for the coupling reaction. As depicted in Scheme 13, these
1
0,34,35
two compounds could be synthesized from the same intermediate 53,
and only differ from the
choice of protecting groups. In the first case, Oꢀlithiation of 53 and treatment with BOMCl enabled
1
0
introduction of the benzyloxy moiety in moderate yield. The obtained 54 was then brominated with
NBS to yield the desired bromoaryl 55. For 58, an Oꢀformylation reaction was followed by aldehyde
reduction, silylation and finally bromination.
Scheme 13. Synthesis of aromatic fragments
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6
The coupling reaction was then carried out in the presence of tꢀBuLi and an excess of the bromoaryl
derivative (Scheme 14), leading in each case to the desired product 59 as a mixture of benzylic alcohol
epimers in excellent yield. Pleasingly, the excess of aromatic compound could be easily recovered by
column chromatography as an inseparable mixture of 57 and 58, and treatment with NBS allowed
complete recycling of 58. The mixture of epimers 59a and 59b was then subjected to DIBALꢀH
reduction in order to convert the tꢀbutyl ester to the corresponding aldehydes 60a-b (Scheme 14).
Surprisingly, the minor benzylic alcohol epimer was found to be unreactive towards reduction, and
aldehydes 60a and 60b were obtained as a single diastereoisomer, together with the remaining
isomerically pure starting material 59a-b (the alcohol configuration at C1’ could not be determined).
Aldehyde 60b could separated from 59b by preparative HPLC, and was subsequently converted to the
hemiacetal 61b after treatment with TBAF and spontaneous cyclisation. In the case of 60a, separation
from its starting material was not possible, and the TBAF treatment was thus applied to the mixture.
This led to the formation of the desired hemiacetal derivative 61a, together with the residual starting
material 62a, with separation now achieved by column chromatography.
0
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Scheme 14. Formation of hemiacetals 61
10
11
12
13
14
15
16
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18
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48
49
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51
52
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54
55
56
57
58
59
60
Assuming that the lack of reactivity observed for the minor epimer 59a (and 59b) was due to
conformational restrictions imposed by the alcohol configuration at C1’, a sequential
oxidation/reduction process towards the formation of 60a was attempted (Scheme 26). Thus, the
benzylic alcohol was oxidised using DessꢀMartin periodinane (DMP) in 73% yield, and the resulting
ketone 63 was then treated with an excess of DIBALꢀH. Although the benzylic ketone in C1’ was
effectively reduced, only trace amount of the aldehyde 60a could be observed by NMR. Instead, the
compound 59a was obtained as a single epimer, whose configuration unfortunately corresponds to that
of the previously observed unreactive isomer. Following this, no further investigation was attempted on
this sequence, and the synthesis was pursued on the major epimer 61a.
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Scheme 15. Attempted sequential oxidation/reduction process
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Completion of the luminacin D synthesis was achieved in 2 further steps from the intermediate 61a
(Scheme 16). At first, the treatment of 61a using DMP in the presence of NaHCO enabled oxidation of
3
the benzylic alcohols to give 64 in moderate yield. The oxidation step proved cumbersome, with the
best yield (56%) obtained after termination of the reaction prior to completion (5 min), separation of
the product from the starting material, and reꢀsubjecting the remaining starting material to DMP. A
longer reaction time (10 min or 1.5 h) led to a drop in yield (43% in each case). Finally, subsequent
deprotection provided (–)ꢀluminacin D 1a in 92% yield after column chromatography, and in 80% after
HPLC purification.
Scheme 16: Completion of the synthesis from the first protecting group strategy
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The final sequence was then investigated with the triꢀbenzylated 61b, as simultaneous deprotection of
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the benzyl ethers would enable to complete the synthesis with only bisꢀbenzylic oxidation left to do
(Scheme 17). However, the hydrogenolysis attempts were associated with numerous selectivity issues,
and 65 was never obtained in a meaningful yield. It was found that the primary benzylic alcohol could
easily be fully reduced to a methyl group, while the secondary benzyl alcohol was also found to be
labile.
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Scheme 17. Attempted hydrogenolysis of the tribenzylated 61b
In view of these unexpected results, deprotection conditions were investigated on a simple model
substrate 66 (Scheme 18), resulting from the coupling reaction between 55 and propionaldehyde (not
shown). It was envisioned that DDQ oxidation of the electron rich aromatic ring, similar to pꢀmethoxy
3
6,37
benzyl cleavage, would directly lead to the corresponding C1 aldehyde 68, alongside with BnOH.
However, despite considerable experimentation, this was not achieved. Surprisingly, this process did
yield the ketone 67, which, though potentially useful for our purposes, was judged too lowꢀyielding for
application on the luminacin D system. Hence, the hydrogenolysis approach was reinvestigated, using
the same model system.
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Scheme 18. DDQ promoted debenzylation/oxidation of the secondary benzyl alcohol
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Given its perceived instability, the secondary benzylic alcohol group was first oxidized to the ketone 69
(Scheme 19). Manganese dioxide was found ineffective at this transformation on small scale. The full
1
1
debenzylation was now achieved under acidic conditions previously as used by Tatsuda to give the
triol 70 in excellent yield. In this reaction, control of the reaction time was required, as overꢀreduction
1
1
to 71 occurred with longer reaction times, a sideꢀreaction not reported by Tatsuda.
Scheme 19. Oxidation/reduction sequence
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Finally, these successful reactions were applied to 61b (Scheme 20). Pleasingly, the initial oxidation to
ketone 72 proceeded in quantitative yield, as did the subsequent debenzylation reaction to triol 73.
Luminacin D 1a was then obtained by a second DessꢀMartin oxidation.
3
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Scheme 20. Completion of the synthesis from the second protecting group strategy
Conclusions
A successful second generation synthesis of enantiopure (–)ꢀluminacin D is reported in full. The
synthetic strategy relies on a conventional key disconnection to give an aromatic and aliphatic
fragment. The synthesis of the chiral aliphatic fragment relies on the diastereoselective introduction of
the trisubstituted epoxide subunit, which is achieved by modified de la Pradilla sulfoxide methodology,
with the sulfoxide then becoming a reactive handle for introduction of a formyl group. A key step is the
subsequent diastereoselective allylation of this formyl group. Initial methodology relying on chelation
control achieved this allylation in very high diastereoselectivity, but with the wrong relative
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