Total synthesis of motualevic acids A-F, (E) and (Z)-antazirines

Article abstract of DOI:10.1016/j.tet.2014.12.092

Total synthesis of motualevic acids A-F and (E) & (Z) geometrical isomers of antazirines has been achieved from a commercially available starting material, 1,10-decanediol. The synthesis of motualevic acid E served as a common key intermediate for the synthesis of most of these natural products. The key steps involved in this synthesis were Wittig olefination, Corey-Fuchs reaction, Neber reaction, amide coupling.

Full text of DOI:10.1016/j.tet.2014.12.092

Accepted Manuscript
Total synthesis of motualevic acids A-F, (E) and (Z)-antazirines
Vilas D. Kadam , Gangarajula Sudhakar
PII:
S0040-4020(14)01808-0
10.1016/j.tet.2014.12.092
TET 26313
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 December 2014
Revised Date: 26 December 2014
Accepted Date: 27 December 2014
Please cite this article as: Kadam VD, Sudhakar G, Total synthesis of motualevic acids A-F, (E) and (Z)-
antazirines, Tetrahedron (2015), doi: 10.1016/j.tet.2014.12.092.
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ACCEPTED MANUSCRIPT
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Total synthesis of motualevic acids A-F, (E)
and (Z)-antazirines
Leave this area blank for abstract info.
Vilas D. Kadam, and Gangarajula Sudhakar*
CPC Division (Organic Chemistry-II, and Academy of Scientific and Innovative Research, CSIR-Indian
Institute of Chemical Technology, Tarnaka, Hyedrabad-500007, India
Br
Br
O
Br
H
OH
N
CO R
2
Br
Br
R
Br
7
7
7
O
O
motualevic acid E
N
motualevic acid A: R = OH
motualevic acid C: R = NH2
motualevic acid F: R = H
OH
(R)-(E)-antazirine: R = CH3
motualevic acid D: R = N(CH )
3
2
CO R
Br
Br
2
O
OH
OH
N
1
,10-decanediol
Br
N
Br
7
7
H
starting material
motualevic acid B
O
(R)-(Z)-antazirine

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of motualevic acids A-F, (E) and (Z)-antazirines
a,b
a,b
Vilas D. Kadam and Gangarajula Sudhakar∗
a
b
CPC Division (Organic Chemistry-II), and Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad-500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Total synthesis of motualevic acids A-F and (E) & (Z) geometrical isomers of antazirines has
been achieved from a commercially available starting material, 1,10-decanediol. The synthesis
of motualevic acid E served as a common key intermediate for the synthesis of most of these
natural products. The key steps involved in this synthesis were Wittig-olefination, Corey-Fuchs
reaction, Neber reaction, amide coupling.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Azirine
Motualevic acids
Antazirine
Natural products
1. Introduction
The 2H-Azirine ring system contains highly strained
azacyclopropene ring and corresponds to the smallest of the
nitrogen-unsaturated heterocycles. Because of high reactivity, it
represents the first example of a long chain 2H-azirine containing
a C-2 carboxylic acid. The crude extracts from Siliquariaspongia
sp. are found to inhibit the growth of Staphalococcus aureus
(SA) and methecilline-resistant Staphalococcus aureus (MRSA)
in the disk diffusion assay. Antimicrobial disk diffusion assays
performed with pure motualevic acids A-F (9-14) and (4E)-(R)-
antazirine (ent-4) traced the MRSA-inhibitory activity to acids 9
and 14, which inhibited the growth of MRSA at loadings of 10
and 5 µg/disk, respectively. The same assay performed with SA
showed compounds 9, 10, 13, and 14 to be active at respective
loadings of 10, 10, 50, and 2 µg/disk. According to the
observations made by Bewley, the presence of a free carboxylic
acid is important for antimicrobial activity, which is supported by
the fact that the esters bearing antazirines and azirinomycine lack
the antimicrobial activity while motualevic acid F (14) and
azirinomycine (1) showed the significant antimicrobial activity in
its naturally occurring form.
became a key intermediate in the synthesis of various acyclic
1
functionalized
amino
derivatives
and
heterocycles.
Additionally, it also represents a very important class of bioactive
1
natural products (Figure 1). Azirinomycine (1), a naturally
occurring antibiotic and the first example of this class, was
2
isolated from a strain of the soil bacterium Streptomyces aureus.
The first long chain 2H-azirine carboxylic acid methyl ester,
2R)-(E)-dysidazirine (2), isolated from the marine sponge
(
Dysidea fragilis, is cytotoxic to L1210 cells and found to exhibit
potent antifungal activity against Candida albicans and
Saccharomyces cerevisiae at minimum concentration of 4µg per
3
disk in a standard paper disk assay. Later on Faulkner and co-
workers isolated (2S)-(4E)-dysidazirine (ent-2) and its
geometrical isomer, (Z)-dysidazirine (3) along with the (E) and
(
Z) geometrical isomers of brominated analogues, antazirines (4)
4
Important biological profile along with interesting structural
features, the synthesis of this class of molecules have been
reported in a reasonable number. The first enantioselective
synthesis of (R)-(E)-dysidazirine (2) was reported by Davis et. al.
and (5) from the same D. fragilis sponge. Molinski et al. isolated
another three heterogenous terminal halogenated antazirine
analogs 6-8 along with antazirines (4) and (5) from D. fragilis
and these are found to exhibit moderate cytotoxicity against
7
5
in 1995. The methyl ester of azirinomycine (1a) was reported by
HCT-116 cells.
8
Zwanenburg and co-workers in 1996. Recently, Molinski et al.
Recently, Bewley and co-workers isolated motualevic acids
A-F (9-14), a new class of ω-dibrominated unsaturated fatty
acids, along with an enantiomer of 4, (2R)-(4E)-antazirine (ent-4)
reported the synthesis of (R)-(Z)-dysidazirine (ent-3) and (R)-(E)-
dysidazirine (2) and their analogs. Very recently, the synthesis
9
of (S)-(E)-dysidazirine (ent-2) was reported by Takemoto et al.
6
10
from Siliquariaspongia sp. (Figure 1). Motualevic acid F (14)
using organocatalytic asymmetric Neber reaction.
—
——
∗
Corresponding author. Tel.: +91-40-27191435; e-mail: gsudhakar@iict.res.in

ACCEPTED MANUSCRIPT
2
Tetrahedron
CO Me
2
CO Me
2
CO Me
2
N
CO R
N
N
2
N
H
Br
azirinomycin (1) R = H
methyl ester of
azirinomycine (1a) R = Me (R)-(4E)-dysidazirine (2)
Br
(
S)-(E)-antazirine (4)
(
S)-(Z)-dysidazirine (3)
CO Me
2
CO Me
2
CO Me
2
CO Me
2
N
N
N
N
Br
Br
Cl
Cl
Br
Cl
Br
(
S)-(Z)-antazirine (5)
Cl
antazirine analog (6)
antazirine analog (7)
antazirine analog (8)
O
CO R
2
CO H
2
O
O
N
H
NH
Br
N
OH
CO H
2
Br
Br
Br
Br
Br
motualevic acid A (9) R = OH
motualevic acid C (11) R = NH2
Br
motualevic acid E (13)
Br
motualevic acid D (12) R = N(CH3)2 motualevic acid B (10)
motualevic acid F (14)
Figure 1. 2H-Azirine containing natural products and motualevic acids.
We communicated the first total synthesis of motualevic acids
the commercially available 1,10-decanediol (15) as shown in
Scheme 1. The diol 15 was, easily, converted to bromo-
11
A-E (9-13), and after our report, Bewley and co-workers
reported the synthesis of motualevic acids A (9), E (13), and their
1
3
functionality intermediate 16 (in 85% yield over 2 steps) by
bromination followed by THP ether protection. Treatment of 16
with KCN in the presence of catalytic amount of 18-crown-6 in
1
2
analogs along with structure-activity relationships. However, to
the best of our knowledge the synthesis of ω-dibromovinylidene
azirine-2-carboxylic acid (motualevic acid F) or its methyl ester,
1
4
CH
with DIBAL-H at −78 °C afforded aldehyde 17 in 75% yield
over two steps. Two carbon Wittig olefination of 17 in CH Cl at
room temperature furnished α,β-unsaturated ester 18 in 80%
3
CN at room temperature gave nitrile, which on reduction
15
(
E)-antazirine, and geometrical isomer of a latter one, (Z)-
antazirin, have not been reported. We report here full details of
total synthesis of motualevic acids A-E (9-13), and the first total
synthesis of motualevic acid F (14), and (E) & (Z)-antazirines
2
2
1
6
yield and with complete E selectivity. Deprotection of THP
ether moiety in 18 with a catalytic amount of PTSA in MeOH
resulted in a primary hydroxyl group 19 in excellent yield. Swern
oxidation was performed on 19 to give the corresponding
(
ent-4 and ent-5).
2
. Result and Discussion
1
7
aldehyde, which was subjected to Corey-Fuchs reaction to
We envisioned that the synthesis of motualevic acid E (13)
furnish 1,1-dibromoalkene 20 in 83% yield over two steps.
Hydrolysis of ester 20 using LiOH in THF/MeOH/H O system
2
resulted the desired motualevic acid E (13) in a yield of 72%. The
could serve as a key common intermediate in the synthesis of
several of these natural products such as motualevic acids A (9),
C (11), D (12), and F (14), and (E)-antazirine (4) by using
appropriate reactions. Then, we focused our attention on the
synthesis of motualevic acid E (13), which was commenced from
spectral data of synthetic motualevic acid E (13) has well
6
coincided
with
that
of
the
natural
material.
O
1
) KCN, 18-crown-6,
CH3CN, 50 h,
1
) HBr, toluene,
reflux, 16 h,
OH
OH
Br
Ph P=CHCO Et,
H
3
2
2
) DIBAL-H, CH Cl ,
CH Cl , 8 h,
2 2
2
) DHP, PPTS,
2
2
OTHP
OTHP
o
CH Cl , 16 h
8
−78 C, 2 h
80%
2
2
16
17
15
5% (2 steps)
75% (2 steps)
1
) (COCl) , DMSO,
2
O
O
O
LiOH.H O,
PTSA,
MeOH,
2
Et N, CH Cl ,
3
2
2
THF/MeOH/H O motualevic
o
2
OEt
OEt
OH
−78 C, 0.5 h,
OEt
acid E (13)
rt, 4 h,
OTHP 91%
(3:1:1), 5 h,
2
) CBr , Ph P,
Br
4
3
72%
CH Cl , 1 h,
2
2
19
20
Br
18
83% (2 steps)
Scheme 1. Synthesis of motualevic acid E (13).

ACCEPTED MANUSCRIPT
3
Having achieved the synthesis of motualevic acid E (13), we
turned our attention to the synthesis of other motualevic acids. In
this direction, motualevic acid E (13) was coupled with glycine
methyl ester hydrochloride using EDCI, HOBt as a coupling
2
NaOH and THF/H O (3:1) system at 0 °C was used to
accomplish the first total synthesis of motualevic acid F (14) in
85% yield. In spite of several reports for the synthesis of azirine
esters, this is the first report for the hydrolysis of azirine ester to
the corresponding carboxylic acid. Notably, hydrolysis of some
model azirine esters having saturated side chain, led to only some
unidentified mixture of compounds. This is supported by the fact
that the azirinomycin (1) is unstable in its naturally occurring
form (carboxylic acid), and it was characterized by spectral
measurements of its methyl ester 1a and other derivative. But,
whereas motualevic acid F with an unsaturated side chain, was
reported no issue with the stability in its naturally occurring form
(carboxylic acid). The data of synthetic motualevic acid F agree
well with the natural product and the optical purity is also
comparable with the natural product based on the specific
reagents in the presence of Et
motualevic acid A 21, which upon hydrolysis with LiOH in
THF/MeOH/H O system afforded motualevic acid A (9) in 75%
yield over two steps (Scheme 2). Motualevic acid A (9) on
treatment with ethyl chloroformate in the presence of Et N in
3 2 2
N in CH Cl to give methyl ester of
2
3
2
THF at −20 °C yielded motualevic acid C (11) in 83% yield,
whereas with N,N'-dimethylamine hydrochloride using EDCI,
HOBt in the presence of Et N in CH Cl afforded motualevic
3 2 2
6
acid D (12) in 65% yield. The spectral data of synthesized
motualevic acids A (9), C (11) and D (12) were in good
6
agreement with those of the natural products.
2
6
rotation (synthetic: [α]
=
= −78.8 (c 0.48, MeOH); natural: [α]
D D
Further, (E)-antazirine (ent-4) and motualevic acid F (14)
could be accessed from motualevic acid E (13) as shown in
Scheme 2. Hence, motualevic acid E (13) was reacted with
carbonyldiimidazole (CDI) to give the corresponding
imidazolide, which on treatment with the magnesium salt of
6
−74.0 (c 0.1, MeOH)) and 81% ee.
Having accomplished most of motualevic acids A (9), C-F
(11-14) and (R)-(E)-antazirine (ent-4)), we thought that the
bromo-functionality intermediate 16 encountered during the
synthesis of motualevic acid E (13) could serve as a starting
material for the synthesis of motualevic acid B (10) and (Z)-
antazirine (ent-5). Accordingly, intermediate 16 was treated with
dianion of propiolic acid, generated in situ by reacting propiolic
acid in HMPA:THF (1:1) with LDA at −40 °C and at −15 °C for
2 h, to give the acetylenic acid 24 in an improved yield of 86%
1
8
19
monomethyl malonic acid afforded β-ketoester 22 in moderate
yield. β-Keto-ester 22 was converted to oxime using
hydroxylamine hydrochloride in the presence of pyridine in
MeOH at 55 °C. Subsequently, oxime was treated with Ts
2
O,
pyridine and catalytic amount of DMAP in CH Cl to furnish
2
2
9
a
oxime-tosylate 23 in 40% yield over 2 steps. To induce the
chirality present in (E)-antazirine, we have selected a cinchona
1
1,20
(Scheme 3).
ester hydrochloride using EDCI and HOBt in the presence of
Et N in CH Cl to give a glycine residue coupled product 25 in
The acid 24 was reacted with glycine methyl
9
a,10
alkaloid, quinidine, to catalyze the asymmetric Neber reation.
The reaction of tosylated compound 23 with quinidine in toluene
at 0 °C went smoothly to give the desired (R)-(E)-antazirine (ent-
3
2
2
69% yield. Partial hydrogenation of acetylenic moiety in 25 using
Lindlar's catalyst in MeOH furnished the Z-olefin 26 in 72%
yield. Deprotection of the THP group of 26 using a catalytic
amount of PTSA in MeOH resulted in a primary hydroxyl group
27 in 89% yield. Oxidation of the hydroxyl group in 27 using
Swern oxidation reaction conditions resulted in aldehyde, which
4) in very good yield and 81% ee. The data of synthetic (R)-(E)-
antazirine (ent-4) was identical with the data reported for the
natural product, but the specific rotation of synthetic compound:
2
4
[
α]
D
= −85.1 (c 0.63, MeOH), is the same sign but higher value
= −7.3 (c 0.1, MeOH). This
than the natural compound: [α]
D
1
7
more magnitude is attributed to a higher optical purity of
was converted to terminal dibromide 28 in 66% yield over 2
steps. Subsequent hydrolysis of the methyl ester with LiOH in
6
synthetic compound than the natural compound.
THF/MeOH/H
2
O solvent system furnished the motualevic acid B
To achieve the synthesis of motualevic acid F (14), hydrolysis
of the methyl ester present in antazirine (ent-4), became the next
task. In this direction, optimized base mediated hydrolysis,
(
10) in a yield of 82%. The spectral data of motualevic acid B is
6
in accordance with the natural product.
O
CONH2
ClCO C H ,
2
2 5
NH OH, Et N,
4
3
N
H
THF, −20 °C,
.5 h, 83%
O
CO R
Br
Br
O
2
EDCI, HOBt,
glycine methyl ester,
1
N
OH
H
Et N, CH Cl , 3 h
motualevic acid C (11)
3
2
2
Br
Br
Br
85%
O
CONMe2
Br
LiOH.H O,
2
EDCI, HOBt,
21: R = Me
motualevic acid E
13)
THF/MeOH/H O
2
(CH ) NH.HCl,
N
3
2
(
(
3:1:1), 2 h,
89%
H
motualevic acid A
9): R = H
Et N, CH Cl ,
3
2
2
Br
i
CDI, PrMgBr,
CH O CCH CO H,
(
2 h, 65%
Br
3
2
2
2
motualevic acid D
12)
THF, 1.5 h, 46%
(
CO R
2
TsO
O
O
1
) NH OH.HCl, py,
2
N
O
quinidine
toluene, 48 h,
N
o
MeOH, 55 C, 1 h
OMe
Br
OMe
Br
Br
8
1% ee, 76%
2) (p-Ts)
CH Cl , rt, 2 h,
4
O, Py, DMAP,
2
(
R)-(E)-antazirine
Br
2
2
NaOH, THF:H O (3:1),
2
4
Br
Br
(ent- ): R = Me
0% (2 steps)
23
22
0 °C, 3 h, 81% ee, 85%
motualevic acid F
(
14): R = H
Scheme 2. Synthesis of motualevic acids A (9), C (11), D (12), F (14) and antazirine (ent-4).

ACCEPTED MANUSCRIPT
Tetrahedron
4
O
EDCI, HOBt,
glycine methyl ester
hydrochloride,
CO H
2
LDA, propiolic acid,
THF-HMPA (1:1),
CO2Me
Br
H ,
2
HN
OTHP
OTHP
Pd/CaCO3/Pb,
16 h, 86%
Et N, CH Cl ,
OTHP
3
2
2
MeOH, 0.25 h,
2
h, 69%
72%
16
24
25
O
1
) (COCl) , DMSO,
2
O
NH
O
Et N, CH Cl ,
3
2
2
NH
CO2R
NH
PTSA,
CO Me MeOH,
o
−
78 C, 0.5 h,
Br
CO Me
2
2
2
) CBr , Ph P,
4
3
o
5
h, 89%
OH
Br
28
OTHP
CH2Cl2, 0 C, 1 h,
LiOH.H O,
2
: R = Me
motualevic acid B
6
6% (2 steps)
THF/MeOH/H O
2
26
27
(
3:1:1), 1 h, 82%
(
10): R = H
Scheme 3. Synthesis of motualevic acids B (10).
The synthesis of (Z)-antazirine was attempted from the
intermediate 24 as shown in Scheme 4. Reaction of 24 with CDI
in THF provided corresponding imidazolide, which on treatment
with the magnesium salt of monomethyl malonic acid in THF
As before, the compound 16a was converted to acetylenic acid
20
24a, which was reacted with CDI, the magnesium salt of
monomethyl malonic acid in THF to give β-keto ester 29a
19
(57%). The ketoester 29a was converted to corresponding
1
9
9a
gave β-ketoester 29 in moderate yield. Treatment of 29 with
oxime-tosylate 30a (77%, 2 steps), which underwent quinidine-
hydroxylamine hydrochloride and pyridine in MeOH led to
mediated cyclization to give the desired 31a in 77% yield, but
only with low enantiomeric excess (51% ee) was observed in
alkynyl ketoxime tosylate 30a comparatively alkenyl ketoxime
tosylate 23. Then, deprotection of PMB group of 31a with DDQ
oxime, which was tosylated immediately with TS O, pyridine,
2
DMAP in CH
2
Cl
steps). Treatment of 30 with Et
in 78% yield. Disappointingly, attempts to deprotect the THP
ethereal moiety of 31 using PTSA or CSA in MeOH or CH Cl
2
to give oxime-tosylate 30 in 77% yield (2
9
a
3
N in toluene provided azirine 31
2 2 2
in CH Cl /H O solvent system provided primary hydroxyl
2
2
compound 32 in excellent yield without any problem. Oxidation
of 32 under Swern oxidation reaction conditions furnished
aldehyde, which was immediately and without further
found problematic due to the disturbances in azirine ring. To
overcome this difficulty, we had to switch over the primary
hydroxyl protecting group in 31 (P = THP) to 31a (P = PMB).
Here, the synthesis of 31a was achieved from 15 which was
converted to 16a in two steps: bromination followed by PMB
protection with p-methoxybenzyltrichloroacetimidate, and CSA
purification treated with PPh /CBr in CH Cl at 0 °C to give
3 4 2 2
17
dibromoalkene 33 in 54% yield over two steps. The acetylenic
compound 33 was selectively reduced with Lindlar catalyst at
lower temperature in hexane under a hydrogen atmosphere to
afford exclusively desired (Z)-antazirine (ent-5) in 82% yield.
21
in 1:2 mixture of CH
2
Cl
2
-cyclohexane (85% yield in 2 steps).
MeO C
2
1
)HBr, toluene
reflux, 16 h
CO H
2
LDA,
propiolic acid,
CDI,
iPrMgBr,
monomethyl
malonic acid,
THF, 1.5 h,
Br
O
OP
1
5
OP
2
) PMB-acetimidate,
CSA,
CH Cl : cyclohexane (1:2),
THF-HMPA
OPMB
6a
(
1:1),
1
16 h, 86%
24 P = THP
24a P = PMB
2
2
29 P = THP
29a P = PMB
5
7%
rt, 12 h, 85% (2 steps)
CO Me
2
N OTs
CO Me
Et N,
toluene, rt,
h, 78% or
3
1
) NH OH.HCl, py,
2
DDQ,
N
o
MeOH, 55 C, 1 h
2
5
CH2Cl2:H2O
OP
OP
2
) (p-Ts) O, py, DMAP,
2
quinidine, toluene,
52 h, 0 °C, 77%
51% ee
(
2:1), 95%
CH Cl , rt, 2 h,
2
2
7
7% (2 steps)
30 P = THP
0a P = PMB
31 P = THP
31a P = PMB
3
CO Me
2
CO Me
CO Me
2
2
H ,
2
N
1
) (COCl) , DMSO, Et N,
Pd/CaCO /Pb,
N
2
3
N
3
hexane,
0 oC, 2 h,
CH Cl , −78 °C, 0.5 h
2
2
OH
Br
Br
2
0
) CBr , Ph P, CH Cl ,
4 3 2 2
°C, 1 h, 54% (2 steps)
82%
Br
3
2
33
(R)-(Z)-antazirine (ent-5)
Br
Scheme 4. Synthesis of (Z)-antazirine (ent-5).

ACCEPTED MANUSCRIPT
5
The data of synthesised (Z)-antazirine (ent-5) is identical in all
concentrated under reduced pressure. Purification by flash
column (6% EtOAc/hexanes) yielded 16 (14.9 g, 92%) as a
4
,5
respects with the natural product data. The specific rotation of
2
4
1
synthetic (R)-(Z)-antazirine: [α] D = −63.6 (c 0.64, n-hexane)
shown the opposite sign and lower magnitude to the natural (S)-
colorless oil. R
MHz, CDCl ):
f
= 0.65 (10% EtOAc/hexanes); H NMR (500
4.54 (dd, J = 3.9, 2.9 Hz, 1H), 3.83 (ddd, J =
11.7, 8.7, 2.9 Hz, 1H), 3.69 (dt, J = 9.7, 6.8 Hz, 1H), 3.47 (m,
3
δ
2
4
5
(
Z)-antazirine (5): [α]
D
+98.9 (c 3.33, n-hexane), indicates low
enantiopurity (51% ee), which was retained from 31a, indicates
1H), 3.36 (m, 3H), 1.81 (m, 3H), 1.67 (m, 1H), 1.53 (m, 6H),
1
3
that no racemization and this is in accordance with the earlier
1.39 (m, 2H), 1.28 (m, 10H); C NMR (75 MHz, CDCl
3
): δ 98.7,
9
report.
67.5, 62.2, 33.9, 32.7, 30.6, 29.6, 29.3, 29.2, 28.6, 28.0, 26.1,
2
1
3
5.4, 19.5; IR (neat): νmax 2924, 2855, 1454, 1354, 1126, 1072,
3
. Conclusions
-1
+
028 cm ; HRMS (ESI): calcd for C15
H
29
O
2
NaBr [M+Na]
43.1248; found 343.1251.
In summary, we have accomplished the total synthesis of
motualevic acids A-F, and (E) and (Z) antazirines from a single
starting material, commercially available 1,10-decanediol.
Notably, motualevic acid F and (E) and (Z)-antazirines were
achieved for the first time. Motualevic acid E was used as a
common intermediate for the synthesis of several of this class of
molecules. The synthesis and biological activity of motualevic
acid and antazirine analogs are under progress in our laboratory
and will be reported in due course.
4.3. 1-((10-Bromodecyl)oxy)methyl)-4-methoxybenzene (16a): To
a suspension of NaH (60% dispersion in oil, 80 mg, 2.41 mmol)
in ether (30 mL) was added 4-methoxybenzyl alcohol (3 mL,
24.16 mmol) drop wise at 0 °C. After being stirred at 0 °C for 5
min, trichloroacetonitrile (2.5 mL, 25.37 mmol) was added and
then the reaction mixture was warmed to rt. The reaction mixture
was again cooled to 0 °C and stirred for another 15 min and
concentrated under reduced pressure. The resulting residue was
diluted with hexane and filtered through celite bed. The filtrate
was concentrated under reduced pressure to give crude p-
methoxybenzyltrichloroacetimidate (6.5 g), which was
immediately used for the reaction.
4. Experimental section
4.1. General methods
Anhydrous solvents were dried and distilled by standard
To a solution of bromoalcohol (5 g, 21.09 mmol) and the p-
methods prior to use. Commercially available reagents were used
without further purification unless otherwise specified. All the
reactions were performed under an atmosphere of nitrogen or
argon in oven-dried glassware under magnetic stirring. Column
chromatography was carried out using silica gel (60-120 or 100-
methoxybenzyltrichloroacetimidate (6.5 g, 23.20 mmol) in
CH Cl : cyclohexane (80 mL, 1:2) was added catalytic amount of
2 2
CSA (49 mg, 2.11 mmol) at 0 °C. The reaction mixture was
warmed to rt and stirred for 12 h while a white precipitate was
formed. The solution was filtered with celite bed and the solids
200 or 230-400 mesh) and the column was eluted with EtOAc-
were washed with 1:2 CH
filterate was washed with saturated aq NaHCO
over Na SO . The organic layer was concentrated under reduced
2
Cl
2
: cyclohexane (50 mL). The
hexanes, EtOAc-MeOH or EtOAc. Analytical thin layer
chromatography (TLC) was performed on precoated silica gel-60
F254 (0.5 mm) glass plates. Visualization of the spots on TLC
plates was achieved either by UV light or by staining the plates in
methanolic anisaldehyde-sulphuric acid-acetic acid or in
methanolphosphomolybdic acid-sulphuric acid solution and
charring on hot plate. Optical rotation values were measured on
Digipol 781 M6U NOVA high sensitive polarimeter using a 2
mL cell with a 10 mm path length. FTIR spectra were recorded
on Bruker (alpha) spectrometer. Mass spectra were recorded on
Micro Mass VG-7070H Mass spectrometer for ESI and are given
in mass units (m/z). High resolution mass spectra (HRMS)
3
, brine and dried
2
4
pressure to give a crude which was purified by flash column (6%
EtOAc/hexanes) to give compound 16a as a clear oil (6.9 g,
1
9
2%). R
f
= 0.6 (10% EtOAc/hexanes); H NMR (300 MHz,
CDCl ):
3
δ
7.19 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6, 2H), 4.38 (s,
2
1
1
2
1
H), 3.78 (s, 3H), 3.37 (m, 4H), 1.84 (m, 2H), 1.56 (m, 2H),
.45-1.25 (m, 12H); C NMR (75 MHz, CDCl ): δ 158.8, 130.5,
3
29.4, 128.8, 113.5, 113.4, 72.2, 69.9, 54.9, 33.6, 32.6, 29.5,
13
9.2, 29.2, 29.1, 28.5, 27.9, 25.9; IR (neat): νmax 2925, 2853,
-
1
608, 1511, 1456, 1246, 1098, 1036 cm ; HRMS (ESI): calcd for
+
C
18
H28BrO
2
[M-H] 355.1267, found 355.1269.
[
ESI+] were obtained using either a TOF or a double focusing
4.4. 11-((Tetrahydro-2H-pyran-2-yl)oxy)undecanal (17): To a
spectrometer.
solution of compound 16 (6 g, 18.69 mmol) in dry CH CN (75
3
4.2. 2-((10-Bromodecyl)oxy)tetrahydro-2H-pyran (16):1,10-
mL) were added KCN (1.46 g, 22.42 mmol) and 18-crown-6
(0.4 mL, 1.87 mmol) and stirred at rt for 50 h. The reaction
Decanediol 15 (10 g, 57.47 mmol) in toluene (600 mL) was
taken in a 1 L two neck round bottom flask equipped with a Dean
Stark apparatus, to which HBr (48%, 7.15 mL, 63.21 mmol) was
added and refluxed for 16 h. After cooling, the reaction mixture
mixture was diluted with H O, extracted with EtOAc, dried over
2
Na SO and concentrated in vacuo. The residue was purified
2
4
(10% EtOAc/hexanes) to give nitrile compound as a colorless oil
1
was washed with 1N HCl, 2M aq NaOH, H
2
O and brine. The
(4.44 g, 89%). R = 0.4 (10% EtOAc/hexanes); H NMR (300
f
organic layer was dried over Na SO , filtered and concentrated
2
4
3
MHz, CDCl ): δ 4.54 (dd, J = 3.7, 3.0 Hz, 1H), 3.81 (ddd, J =
under reduced pressure. The residue was purified by column
11.3, 8.3, 3.7 Hz, 1H), 3.68 (dt, J = 9.8, 6.7 Hz, 1H), 3.46 (m,
1H), 3.32 (dt, J = 9.8, 6.7 Hz, 1H), 2.32 (t, J = 6.7 Hz, 2H), 1.81
chromatography (15% EtOAc/hexanes) to give bromo-alcohol as
1
13
a clear oil (12.7 g, 93%). R
NMR (500 MHz, CDCl ):
.8 Hz, 2H), 1.85 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.38-1.27
f
= 0.45 (20% EtOAc/hexanes) H
3.63 (t, J = 5.8 Hz, 2H), 3.39 (t, J =
(m, 1H), 1.74-1.39 (m, 11H), 1.32 (m, 10H); C NMR (75 MHz,
3
δ
CDCl ):
3
δ
119.7, 98.7, 67.5, 62.2, 30.6, 29.6, 29.3, 29.1, 28.6,
6
28.5, 26.1, 25.4, 25.2, 19.6, 17.0; IR (neat): νmax 2926, 2856,
13
-
1
(
m, 10H); C NMR (125 MHz, CDCl
3
): δ 62.9, 33.9, 32.7, 32.6,
2246, 1728, 1455, 1355, 1265, 1127, 1072, 1028 cm ; HRMS
+
2
1
9.3, 29.2, 29.2, 28.6, 28.0, 25.6; IR (neat): νmax 2927, 2856,
(ESI): calcd for C H O NNa [M+Na] 290.2090, found
1
6
29
2
-
1
738, 1593, 1449, 1367, 1241 cm ; HRMS (ESI) calcd for
290.2088.
+
C H BrO [M+H] 237.0854, found 237.0845.
1
0
22
To a solution of nitrile compound (4 g, 14.98 mmol) in dry
DHP (6 mL, 65.82 mmol) and PPTS (127 mg, 0.50 mmol)
were added to a solution of bromo-alcohol (12 g, 50.63 mmol) in
00 mL of CH Cl and the mixture was stirred for 16 h. The
reaction mixture was quenched with 2M Na CO solution and
CH Cl (60 mL) was added 1M solution of DIBAL-H in toluene
16.5 mL, 16.47 mmol) drop wise at −78 °C and stirred at −78
2
2
(
1
2
2
°C for 2 h under argon. The reaction mixture was quenched with
2
3
MeOH, poured into saturated Rochelle's salt solution and
extracted with EtOAc. The organic layer was washed with brine,
2 2 2 4
extracted with CH Cl . The organic layer was dried over Na SO ,

ACCEPTED MANUSCRIPT
6
Tetrahedron
dried over Na
2
SO
4
and concentrated in vacuo. The residue was
To a stirred solution of PPh
(10 mL) was added CBr (4.18 g, 12.59 mmol) at 0 °C. After
being stirred for 15 min, a solution of aldehyde (1.6 g, 6.29
mmol) in CH Cl (8 mL) was added at 0 °C. The mixture was
3 2 2
(6.6 g, 25.19 mmol) in CH Cl
purified (8% EtOAc/hexanes) to give aldehyde 17 as a clear oil
4
1
(
3.4 g, 84%). R
MHz, CDCl ):
ddd, J = 11.7, 8.7, 3.9 Hz, 1H), 3.68 (dt, J = 9.7, 6.8 Hz, 1H),
f
= 0.55 (10% EtOAc/hexanes); H NMR (500
9.75 (s, 1H), 4.54 (dd, J = 3.9, 2.9 Hz, 1H), 3.81
3
δ
2
2
(
stirred at 0 °C for 10 min and quenched with cold hexane. The
suspension was filtered through a pad of celite. The filtrate was
concentrated and purified (4% EtOAc/hexanes) to give
dibromoalkene 20 as colorless oil (2.21 g, 86%). R
EtOAc/hexanes); H NMR (300 MHz, CDCl ): δ 6.94 (dt, J =
3.46 (m, 1H), 3.32 (dt J = 9.7, 6.8 Hz, 1H), 2.4 (t, J = 8.7 Hz,
13
2
H), 1.83 (m, 1H), 1.75-1.46 (m, 10H), 1.30 (m, 11H); C NMR
): 202.8, 98.7, 67.5, 62.2, 43.8, 30.7, 29.6,
9.4, 29.3, 29.2, 29.2, 29.0, 26.1, 25.4, 21.9, 19.6; IR (neat): νmax
(
75 MHz, CDCl
3
δ
f
= 0.4 (5%
1
2
2
3
-
1
925, 2856, 2715, 1727, 1456, 1355, 1127, 1029 cm ; HRMS
15.6, 6.9 Hz, 1H), 6.36 (t, J = 7.3 Hz, 1H), 5.78 (dt, J = 15.6, 1.3
Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.17 (q, J = 6.9 Hz, 2H), 2.06
+
(
ESI): calcd for C16
H
30
O
3
Na [M+Na] 293.2087, found 293.2086.
13
(
q, J = 7.3 Hz, 2H), 1.55-1.22 (m, 17H); C NMR (75 MHz,
CDCl ): 166.7, 149.3, 138.8, 121.1, 88.4, 60.0, 32.9, 32.1, 29.3,
9.2, 29.2, 29.0, 28.9, 27.9, 27.7, 14.2; IR (neat): ν-max 2922,
4.5. (E)-Ethyl 13-((tetrahydro-2H-pyran-2-yl)oxy)tridec-2-enoate
3
δ
(
18): (Carbethoxymethylene)triphenylphospharane (4.6 g, 13.33
mmol) was added to a solution of aldehyed 17 (3 g, 11.11 mmol)
in dry CH Cl (50 mL) and stirred at rt for 8 h. The reaction
mixture was concentrated under reduced pressure and purified
5% EtOAc/hexanes) to give 18 as colorless oil (3.05 g, 80%). R
2
2
1
854, 1720, 1654, 1456, 1367, 1266, 1179, 1043 cm ; HRMS
2
2
+
(
ESI): calcd for C16
H
27Br
2
O
2
[M+H] 409.0534, found 409.0546.
(
=
f
4.8. Motualevic acid E (13): To a solution of ester 20 (2 g, 4.87
1
0.4 (5% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
): δ 6.91
mmol) in 3:1:1 of THF: MeOH: H
(
2
O (20 mL) at 0 °C, LiOH.H
82 mg, 19.51 mmol) was added and stirred at rt for 5 h. The
reaction mixture was then acidified to PH 2 with 1N HCl and
extracted with EtOAc, washed with brine, dried over Na SO
2
O
(
3
3
dt, J = 15.6, 6.8 Hz, 1H), 5.77 (d, J = 15.6, 1H), 4.54 (dd, J =
.9, 2.9 Hz, 1H), 4.16 (q, J = 6.8, 2H), 3.82 (ddd, J = 11.7, 8.7,
.9 Hz, 1H), 3.69 (dt, J = 9.7, 6.8 Hz, 1H), 3.47 (m, 1H), 3.33 (dt
2
4
,
J = 9.7, 6.8 Hz, 1H), 2.19 (q, J = 6.8 Hz, 2H), 1.83 (m, 1H), 1.67
filtered and concentrated in vacuo. The crude was purified by
flash column (25% EtOAc/hexanes) to give motualevic acid E
(13) as colorless amorphous solid (1.34 g, 72%). R = 0.4 (30%
EtOAc/hexanes); H NMR (500 MHz, CDCl
13
(
m, 1H), 1.62-1.41 (m, 10H), 1.29 (m, 13H); C NMR (75 MHz,
CDCl ): 166.5, 149.2, 121.1, 98.6, 67.5, 62.1, 59.9, 32.0, 30.6,
9.6, 29.3, 29.3, 29.3, 29.2, 28.9, 27.8, 26.1, 25.4, 19.5, 14.1; IR
neat): νmax 2926, 2857, 1721, 1655, 1454, 1362, 1266, 1180,
δ
3
f
1
2
(
3
):
δ
7.04 (dt, J =
1
1
1
1
2
1
4
5.9, 6.7 Hz, 1H), 6.36 (t, J = 7.5 Hz, 1H), 5.81 (d, J = 15.9 Hz,
H), 2.24 (q, J = 6.7 Hz, 2H), 2.10 (dt, J = 7.5, 6.7 Hz, 2H), 1.53-
.40 (m, 4H), 1.37-1.20 (m, 10H); C NMR (75 MHz, CDCl ): δ
3
72.1, 152.1, 138.6, 120.5, 88.4, 32.8, 32.1, 29.2, 29.1, 29.0,
8.9, 28.8, 27.7, 27.6; IR (neat): νmax 2927, 2854, 1696, 1649,
222 cm ; HRMS (ESI): calcd for C H Br O Na [M+Na]
02.9884, found 402.9897.
-
1
+
1
3
033 cm ; HRMS (ESI): calcd for C20
63.2505, found 363.2504.
36 4
H O Na [M+Na]
1
3
4.6. (E)-Ethyl 13-hydroxytridec-2-enoate (19): To a solution of
1
8 (2.9 g, 8.53 mmol) in dry MeOH (30 mL) was added catalytic
-1
+
1
4
22
2
2
amount of PTSA (81 mg, 0.43 mmol) at 0 °C and stirred at rt for
h. The reaction mixture was quenched by the addition of
saturated aq NaHCO and extracted with EtOAc. The organic
layer was washed with brine, dried over Na SO , filtered and
concentrated under reduced pressure. The crude was purified
15% EtOAc/hexanes) to give alcohol 19 as colorless oil (1.98 g,
4
3
4.9. (E)-Methyl
2-(14,14-dibromotetradeca-2,13-
2
4
dienamido)acetate (21): To a solution of motualevic acid E (13)
300 mg, 0.78 mmol) in 8 mL of CH Cl was added sequentially
(
2
2
(
HOBt (212 mg, 1.57 mmol), EDCI (301 mg, 1.57 mmol) and
glycine methyl ester hydrochloride (148 mg, 1.17 mmol) at 0 °C.
1
91%). R
f
= 0.5 (20% EtOAc/hexanes); H NMR (500 MHz,
6.92 (dt, J = 15.6, 6.8 Hz, 1H), 5.77 (d, J = 15.6 Hz,
CDCl ):
3
δ
Then, Et
reaction mixture was stirred for 3 h at rt. After completion of the
reaction, diluted with CH Cl (100 mL), sequencially, washed
with 1N HCl, saturated aq NaHCO and brine. The organic layer
was dried with Na SO concentrated and purified (30%
3
N (0.65 mL, 4.71 mmol) was added at 0 °C and the
1
7
H), 4.17 (q, J = 6.8 Hz, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.2 (q, J =
13
.8 Hz, 2H), 1.53 (m, 2H), 1.46 (m, 1H), 1.31-1.25 (m, 16H);
): δ 166.8, 149.5, 121.1, 62.8, 60.1, 32.7,
2.1, 29.5, 29.3, 29.3, 29.0, 27.9, 25.7, 14.2; IR (neat): νmax 3424,
C
2
2
NMR (75 MHz, CDCl
3
3
3
2
2
4
,
-
1
923, 2854, 1715, 1652, 1458, 1369, 1269, 1181, 1042 cm ;
EtOAc/hexanes) to give amide compound 21 as colorless oil (300
mg, 85%). R = 0.3 (30% EtOAc/hexanes); H NMR (300 MHz,
CDCl
+
1
HRMS (ESI): calcd for C H O Na [M+Na] 279.1930, found
15
28
3
f
279.1927.
3
):
δ 6.87 (dt, J = 15.1, 6.7 Hz, 1H), 6.37 (t, J = 7.5 Hz,
1
5
7
H), 6.01 (bs, 1H), 5.83 (dt, J = 15.1, 1.5 Hz, 1H), 4.11 (d, J =
4
.7. (E)-Ethyl 14,14-dibromotetradeca-2,13-dienoate (20):
.2 Hz, 2H), 3.76 (s, 3H), 2.17 (q, J = 6.7 Hz, 2H), 2.07 (q, J =
Oxalyl chloride (0.9 mL, 10.54 mmol) was dissolved in CH
2
Cl
25 mL) and cooled to −78 °C. Then, DMSO (1.5 mL, 21.09
mmol) was added and the solution was stirred for 20 min at −78
C. The alcohol 19 (1.8 g, 7.03 mmol) dissolved in CH Cl (15
2
13
.5 Hz, 2H), 1.41 (m, 3H), 1.27 (m, 11H); C NMR (75 MHz,
(
CDCl
3
):
δ 170.2, 166.1, 145.2, 138.5, 122.6, 88.1, 51.8, 40.8,
3
2
2.6, 31.7, 29.0, 28.9, 28.8, 28.6, 27.8, 27.4; IR (neat): νmax 3292,
923, 2853, 1747, 1666, 1627, 1538, 1441, 1364, 1202 cm ;
°
2
2
-1
mL) was cannulated drop wise at −78 °C and stirred for 20 min.
Triethylamine (3.9 mL, 28.12 mmol) was added and the reaction
was stirred for 5 min at −78 °C. The mixture was allowed to
+
2 3
HRMS (ESI): calcd for C17H28Br NO [M+H] 452.0430, found
452.0435.
warm to 0 °C before quenching by the addition of H
CH Cl . The organic phase was washed with brine, dried over
Na SO , filtered and concentrated. The residue was purified (8%
2
O and
4
.10. Motualevic acid A (9): Motualevic acid A (9) was prepared
2
2
from amide compound 21 using the method described for the
preparation of motualevic acid E (13) from ester 20. The crude
product was purified (20% MeOH/EtOAc) to give motualevic
2
4
EtOAc/hexanes) to give aldehyde as a colorless oil (1.71 g,
1
9
6%). R
f
= 0.6 (15% EtOAc/hexanes); H NMR (300 MHz,
acid A (9), as colorless amorphous solid (258 mg, 89%). R
f
= 0.3
20% MeOH/EtOAc); H NMR (300 MHz, CD OD): δ 6.82 (dt,
3
1
CDCl ):
3
δ
9.75 (t, J = 1.5 Hz, 1H), 6.91 (dt, J = 15.8, 6.7 Hz,
(
1
2
H), 5.77 (dt, J = 15.8, 1.5 Hz, 1H), 4.16 (q, J = 6.7 Hz, 2H),
.40 (dt, J = 9.0, 1.5 Hz, 2H), 2.19 (m, 2H), 1.62 (m, 2H), 1.46
J = 15.8, 6.8 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 6.02 (d, J = 15.8
Hz, 1H), 3.92 (s, 2H), 2.24 (q, J = 6.8 Hz, 2H), 2.14 (dt, J = 7.5,
13
1
3
(
m, 2H), 1.29 (m, 13H); C NMR (75 MHz, CDCl
3
):
66.6, 149.2, 121.1, 59.9, 43.7, 32.0, 29.1, 28.9, 28.9, 27.8, 21.9,
4.1; IR (neat): νmax 2926, 2854, 2717, 1719, 1654, 1456, 1368,
+
δ 202.7,
6
.7 Hz, 2H), 1.56-1.30 (m, 14H); C NMR (75 MHz, CD
74.7, 168.6, 145.9, 140.3, 124.5, 89.1, 43.2, 33.9, 33.0, 30.5,
2919, 2849,
3
OD): δ
1
1
1
2
1
30.5, 30.4, 30.2, 30.1, 29.4, 28.8; IR (neat): ν
max
-1
-
1
267, 1180, 1043 cm ; HRMS (ESI): calcd for C15
55.1954, found 255.1953.
27 3
H O [M+H]
1
C
733, 1661, 1557, + 1262 cm ; HRMS (ESI): calcd for
16
H26Br
2
NO [M+H] 438.0274, found 438.0280.
3

ACCEPTED MANUSCRIPT
7
4.11. Motualevic acid C (11): To a solution of motualevic acid A
hydrochloride (122 mg, 1.75 mmol) and pyridine (0.14 mL,
(
9) (50 mg, 0.11 mmol) in dry THF (1 mL) at −20 °C, Et N (0.02
3
1.75 mmol). The reaction mixture was stirred at 55 °C for 1 h and
then concentrated under reduced pressure. The residue was taken
mL, 0.14 mmol) was added drop wise and stirred for 5 min. Then
ethyl chloroformate (0.013 mL, 0.14 mmol) was added and
up in H
2
O and extracted with EtOAc, washed with brine, dried
stirring was continued at −20 °C for 30 min. Then 25% NH
0.013 mL, 0.68 mmol) was added at the same temperature and
stirred for another 1.5 h. The reaction mixture was quenched by
adding saturated aq NH Cl solution and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
over Na SO and concentrated under reduced pressure. Column
purification (8% MeOH/EtOAc) gave motualevic acid C (11) as a
4
OH
over Na
2
SO , filtered and concentrated under reduced pressure.
4
(
2 2
The crude oxime was dissolved in dry CH Cl (10 mL) and p-
toluenesulfonic anhydride (778 mg, 2.38 mmol), pyridine (0.21
mL, 2.38 mmol) and catalytic amount of DMAP (9.7 mg, 0.08
mmol) were added at 0 °C. The reaction mixture was stirred at 0
°C for 2 h and quenched with aq NH
separated and aq layer was extracted with CH Cl . The combined
4
2
4
Cl. The layers were
4
colorless amorphous solid (40 mg, 83%). R
f
= 0.43 (10%
2
2
1
MeOH/EtOAc); H NMR (400 MHz, CDCl
3
):
δ
6.87 (dt, J =
2 4
organic layers were dried over Na SO and concentrated under
1
5
2
5.1, 6.8 Hz, 1H), 6.42-6.32 (m, 3H), 5.84 (d, J = 15.1 Hz, 1H),
.57 (bs, 1H), 4.05 (d, J = 5.2 Hz, 2H), 2.18 (dt, J = 7.5, 6.8 Hz,
H), 2.08 (dt, J = 7.5, 6.8 Hz, 2H), 1.50-1.37 (m, 4H), 1.35-1.24
reduced pressure. Purification by column chromatography (20%
EtOAc/hexanes) afforded tosylated compound 23 as a clear oil
1
(
386 mg, 40%). R
f
= 0.4 (20% EtOAc/hexanes); H NMR (500
1
3
(
m, 10H); C NMR (125 MHz, CDCl
3
): δ 171.5, 166.7, 146.4,
39.0, 122.8, 88.6, 43.1, 33.1, 32.2, 29.9, 29.5, 29.4, 29.3, 29.2,
8.3, 27.9; IR (neat): ν 2917, 2848, 1660, 1625, 1551, 1461,
+
MHz, CDCl ):
6
1
δ
7.86 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 7.7, 2H),
.67 (d, J = 15.4 Hz, 1H), 6.39 (t, J = 7.7 Hz, 1H), 6.29 (dt, J =
5.4, 6.6 Hz, 1H), 3.64 (s, 3H), 3.39 (s, 2H), 2.44 (s, 3H), 2.21
3
1
2
1
4
max
-
1
274, 1133 cm ; HRMS (ESI): calcd for C16
37.0433, found 437.0403.
2 2 2
H27Br N O [M+H]
(
q, J = 6.6 Hz, 2H), 2.09 (q, J = 7.7 Hz, 2H), 1.42 (m, 4H), 1.36-
.24 (m, 10H); C NMR (75 MHz, CDCl ): δ 168.7, 157.6,
3
13
1
1
3
46.4, 144.9, 138.8, 132.5, 129.5, 128.8, 118.1, 88.4, 52.4, 36.8,
3.2, 32.9, 29.6, 29.3, 29.2, 29.0, 28.9, 28.2, 27.7, 21.7; IR
4.12. Motualevic acid D (12): Motualevic acid D (12) was
prepared from motualevic acid A (9) using the same method
described for the preparation of amide compound 21 from
motualevic acid E (13). The crude product was purified (6%
MeOH/EtOAc) to give motualevic acid D (12) as colorless
-
1
(
neat): νmax 2921, 2854, 2355, 1742, 1594, 1453, 1218 cm ;
+
HRMS (ESI): calcd for C24
606.0521.
2 5
H34Br NO S [M+H] 606.0519, found
amorphous solid (34 mg, 65%). R = 0.6 (10% MeOH/EtOAc);
H NMR (300 MHz, CD OD): δ 6.81 (dt, J = 15.3, 6.8 Hz, 1H),
3
f
1
4.15. (R)-(E)-Antazirine (ent-4): To an oven dried round bottom
flask, quinidine (534 mg, 1.64 mmol) was taken and dissolved in
dry toluene (35 mL) and cooled to 0 °C. A solution of compound
23 (200 mg, 0.33 mmol) in toluene was cannulated and the
resulting mixture was stirred for 48 h at 0 °C. The reaction
mixture was quenched with 0.05 M HCl and extracted with
6
3
7
.47 (t, J = 7.1 Hz, 1H), 6.02 (d, J = 15.3 Hz, 1H), 4.11 (s, 2H),
.05 (s, 3H), 2.95 (s, 3H), 2.21 (q, J = 6.9 Hz, 2H), 2.11 (q, J =
1
3
.1 Hz, 2H), 1.53-1.35 (m, 2H), 1.35-1.25 (m, 12H); C NMR
OD): δ 170.5, 168.9, 146.4, 140.4, 124.5, 89.2,
(
125 MHz, CD
3
4
2
1
4
2.0, 36.7, 36.1, 34.1, 33.1, 30.6, 30.6, 30.5, 30.3, 30.2, 29.5,
2 4
EtOAc. Organic layer was washed with brine, dried over Na SO
8.9; IR (neat): νmax 2919, 2850, 1672, 1617, 1507, 1461, 1407,
-
1
+
and concentrated in vacuo. The crude was purified (5%
EtOAc/hexanes) to give (R)-(E)-antazirine (ent-4) as a light
yellowish foam (109 mg, 76% yield, 81% ee, (determined by
216 cm ; HRMS (ESI): calcd for C H N O [M+H]
1
8
31
2
2
65.0746, found 465.0734.
chiral HPLC, ciralpack-IC3, MeOH/CH
3
CN 90:10)). R
f
= 0.6
= −85.1 (c 0.63, MeOH); H NMR
6.68 (dt, J = 15.9, 7.0 Hz, 1H), 6.53 (d, J =
5.9 Hz, 1H), 6.37 (t, J = 7.0 Hz, 1H), 3.71 (s, 3H), 2.55 (s, 1H),
.35 (dd, J = 14.0, 7.0 Hz, 2H), 2.07 (dd, J = 14.9, 7.0 Hz, 2H),
4
.13. (E)-Methyl 16,16-dibromo-3-oxohexadeca-4,15-dienoate
2
4
1
(
(
10% EtOAc/hexanes); [α]
500 MHz, CDCl ):
D
(
22): To a solution of motualevic acid E (13) (1 g, 2.61 mmol) in
δ
dry THF (10 mL) at 0 °C was added CDI (509 mg, 3.14 mmol)
and stirred for 1 h at 0 °C. Parallelly in another round bottom
flask, monomethylmalonic acid (618 mg, 5.23 mmol) in dry THF
3
1
2
1
1
3
.50 (m, 2H), 1.40 (m, 2H), 1.35-1.24 (m, 10H); C NMR (125
): δ 172.6, 156.9, 156.1, 139.2, 113.2, 88.8, 52.6,
3.5, 33.3, 29.7, 29.6, 29.6, 29.5, 29.3, 28.6, 28.1, 28.1; IR
neat): νmax 2921, 2854, 1760, 1733, 1453, 1342, 1268, 1195,
(
10 mL) was taken and a solution of isopropylmagnesium
bromide (1M, 10.47 mL, 10.47 mmol) was added drop wise at 0
C and stirred for 30 min. The reaction mixture was cooled to
20 °C and previously prepared imidazolide solution was added
MHz, CDCl
3
(
3
°
−
-
1
+
1
4
028 cm ; HRMS (ESI): calcd for C17
34.0330, found 434.0321.
2 2
H26Br NO [M+H]
drop wise and the resulting mixture was stirred at −20 °C for 20
min at rt for 1.5 h. The reaction mixture was quenched by the
addition of 1N HCl and extracted with EtOAc (2 times). The
combined organic layers were washed with saturated aq NaHCO
and brine. The organic layer was dried over Na SO , filtered and
concentrated under reduced pressure. The residue was purified
4
.16. Motualevic acid F(14): To a solution of (R)-(E)-antazirine
3
(
ent-4) (50 mg, 0.11 mmol) in 3:1 of THF:H
2
O (4.4 mL) at 0 °C
2
4
was added NaOH (18.4 mg, 0.46 mmol). The reaction mixture
was stirred at 0 °C for 3 h and neutralized with 0.05 M HCl. The
mixture was extracted with EtOAc (3 times), the combined
(
(
10% EtOAc/hexanes) to give β-ketoester 22 as a colorless oil
525 mg, 46%, the ratio of keto:enol is 1:0.3). R = 0.5 (10%
11.81 (s, 0.3H),
.88 (dt, J = 15.8, 6.9 Hz, 1H), 6.66 (dt, J = 15.8, 6.9 Hz, 0.3H),
.38 (t, J = 7.3 Hz, 1.3H), 6.15 (d, J = 15.8 Hz, 1H), 5.78 (d, J =
5.8 Hz, 0.3H), 4.98 (s, 0.3H), 3.74 (s, 3.9H), 3.59 (s, 2H), 2.24
f
1
2 4
organic layers were washed with brine, dried over Na SO ,
3
EtOAc/hexanes); H NMR (300 MHz, CDCl ): δ
filtered and concentrated in vacuo. It was purified by flash
column chromatography (80% EtOAc/hexanes) to give
motualevic acid F (14) as light yellow foam (39.5 mg, 85% yield,
6
6
1
81% ee (determined by chiral HPLC, ciral column-ODH,
(
q, J = 6.7 Hz, 2.6H), 2.08 (q, J = 6.9 Hz, 2.6H), 1.43 (m, 4H),
.36-1.23 (m, 14H); C NMR (75 MHz, CDCl ):
26
D
1
3
hexane/isopropanol 80:20)). R
f
= 0.4 (EtOAc); [α]
= −78.8 (c
1
1
3
1
1
4
δ
192.0, 167.8,
1
3
0
7
2
.48, MeOH); H NMR (500 MHz, CDCl ): 6.72 (dt, J = 15.5,
.7 Hz, 1H), 6.53 (d, J = 15.5 Hz, 1H), 6.37 (t, J = 7.7 Hz, 1H),
.55 (s, 1H), 2.36 (dd, J = 15.4, 7.7 Hz, 2H), 2.07 (dd, J = 15.4,
3
δ
50.2, 141.2, 138.7, 129.4, 124.1, 89.5, 88.3, 52.2, 51.1, 46.4,
2.8, 32.4, 29.2, 29.1, 29.0, 28.8, 28.5, 28.3, 27.7, 27.6, 25.2,
7.0; IR (neat): νmax 2924, 2854, 1726, 1659, 1447, 1236, 1161+,
13
-
1
7.7 Hz, 2H), 1.51 (m, 2H), 1.40 (m, 2H), 1.35-1.21 (m, 10H);
NMR (125 MHz, CDCl ):
8.7, 33.5, 33.2, 29.6, 29.5, 29.5, 29.4, 29.2, 28.2, 28.0, 28.0; IR
C
025 cm ; HRMS (ESI): calcd for C H Br O Na [M+Na]
1
7
26
2
3
3
δ 177.6, 156.5, 156.2, 139.1, 112.8,
59.0146, found 459.0135.
8
-
1
(
neat): νmax 3424, 2925, 2853, 1771, 1698, 1458, 1213, 771 cm ;
4.14. (4E)-Methyl 16,16-dibromo-3-((tosyloxy)imino)hexadeca-
4,15-dienoate (23): To a solution of β-keto ester 22 (700 mg,
1.59 mmol) in methanol (10 mL) was added hydroxylamine
+
HRMS (ESI): calcd for C16
found 441.9981.
2 2
H23Br NO Na [M+Na] 441.9993,

ACCEPTED MANUSCRIPT
8
Tetrahedron
4
.17. 13-((Tetrahydro-2H-pyran-2-yl)oxy)tridec-2-ynoic acid
11.3, 7.5 Hz, 1H), 5.94 (bs, 1H), 5.71 (dt, J = 11.3, 1.5 Hz, 1H),
4.54 (dd, J = 3.7, 3.0 Hz, 1H), 4.05 (d, J = 5.2 Hz, 2H), 3.82
(ddd, J = 11.3, 8.3, 3.7 Hz, 1H), 3.77 (s, 3H), 3.67 (dt, J = 9.8,
6.7 Hz, 1H), 3.46 (m, 1H), 3.31 (dt J = 9.8, 6.7 Hz, 1H), 2.64 (m,
(24): A 250 mL round bottom flask equipped with a stirring bar
was flame dried under vacuum and filled with an argon. After
cooling, diisopropylamine (3.5 mL, 24.92 mmol) and 6 mL of
THF was added and cooled to 0 °C, while a solution of n-BuLi
1
3
2H), 1.88-1.47 (m, 7H), 1.45-1.22 (m, 15H); C NMR (75 MHz,
CDCl ): 170.4, 166.3, 147.1, 121.1, 98.7, 67.6, 62.2, 52.2, 40.8,
30.6, 29.6, 29.4, 29.3, 29.3, 29.2, 28.7, 26.1, 25.3, 19.5; IR(neat):
max 3320, 2923, 2854, 1750, 1665, 1530, 1448, 1361, 1202,
(
1.6M in hexanes, 14.3 mL, 22.92 mmol) was added dropwise.
3
δ
After 20 min, the reaction mixture was cooled to −40 °C and the
solution of propiolic acid (0.77 mL, 12.46 mmol) in 10 mL of
HMPA was cannulated. The resulting mixture was allowed to
warm to −15 °C and stirred for 2 h at the same temp. Then bromo
compound 16 (2 g, 6.2 mmol) was cannulated using THF (4 mL)
and warmed to rt. The reaction mixture was stirred at rt for 16 h
and then quenched by the addition of H O. The reaction mixture
2
was acidified to PH 2 using 1N HCl. The aq phase was extracted
with EtOAc, washed with brine, dried over Na SO4 and
concentrated in vacuo. The residue was purified by flash column
ν
-
1
+
1028 cm ; HRMS (ESI): calcd for C21
406.2569, found 406.2560.
5
H37NO Na [M+Na]
4
.21. (Z)-Methyl 2-(13-hydroxytridec-2-enamido)acetate (27):
Alcohol 27 was prepared from compound 26 using the same
method described for the preparation of alcohol 19 from
compound 18. The crude product was purified (35%
2
EtOAc/hexanes) to give alcohol 27 as pale yellow oil (277 mg,
1
8
9%). R
f
= 0.4 (50% EtOAc/hexanes); H NMR (300 MHz,
6.04 (dt, J = 11.3, 7.5 Hz, 1H), 5.88 (bs, 1H), 5.72 (dt,
chromatography (60% EtOAc/hexanes) to give acid 24 as pale
yellow oil (1.66 g, 86%). R
NMR (300 MHz, CDCl ):
1
CDCl ):
3
δ
f
= 0.2 (60% EtOAc/hexanes); H
δ
6.24 (bs, 1H), 4.58 (dd, J = 3.7, 3.0
3
Hz, 1H), 3.84 (ddd, J = 11.3, 8.3, 3.7 Hz, 1H), 3.68 (dt, J = 9.8,
13
3
): δ 170.5, 166.4, 147.1,
6
.7 Hz, 1H), 3.50 (m, 1H), 3.34 (dt J = 9.8, 6.7 Hz, 1H), 2.35 (t, J
13
=
6.7 Hz, 2H), 1.90-1.49 (m, 9H), 1.48-1.21 (m, 13H); C NMR
156.2, 98.6, 90.6, 73.0, 67.6, 62.0, 30.5,
9.5, 29.3, 29.2, 29.1, 28.8, 28.6, 27.3, 26.0, 25.2, 19.3, 18.5; IR
(
2
75 MHz, CDCl ): δ
3
-
1
+
1
207 cm ; HRMS (ESI): calcd for C H NO Na [M+Na]
16 29 4
3
22.1988, found 322.1984.
.22. (Z)-Methyl
(
1
3
neat): νmax 2925, 2856, 2235, 1711, 1455, 1364, 1247, 1071,
029 cm ; HRMS (ESI): calcd for C18
33.2036, found 333.2035.
-
1
+
30 4
H O Na [M+Na]
4
2-(14,14-dibromotetradeca-2,13-
dienamido)acetate (28): Compound 28 was synthesized from 27
using the same procedure described for 20 from 19.
4.18. 13-((4-Methoxybenzyl)oxy)tridec-2-ynoic acid (24a): Acid
2
4a was prepared from compound 16a using the same method
Data for oxidation product of 27 (aldehyde): Yield 94% (186
described for the preparation of compound 24. The residue was
purified by flash column chromatography (60% EtOAc/hexane)
to give acid 24a as pale yellow oil (3.3 g, 86%). R
EtOAc/hexanes); H NMR (500 MHz, CDCl
1
mg); pale yellow oil; R
300 MHz, CDCl ):
7.5 Hz, 1H), 5.88 (bs, 1H), 5.72 (dt, J = 11.3, 1.5 Hz, 1H), 4.06
f
= 0.6 (50% EtOAc/hexanes); H NMR
(
3
δ 9.74 (t, J = 1.7 Hz, 1H), 6.03 (dt, J = 11.5,
f
= 0.2 (60%
7.21 (d, J = 8.0
1
3
):
δ
(
1
(
d, J = 5.0 Hz, 2H), 3.78 (s, 3H), 2.65 (m, 2H), 2.40 (dt, J = 7.3,
Hz, 2H), 6.82 (d, J = 8.0, 2H), 5.44 (bs, 1H), 4.41 (s, 2H), 3.80
1
3
.7 Hz, 2H), 1.69-1.54 (m, 2H), 1.49-1.24 (m, 12H); C NMR
(
s, 3H), 3.40 (t, J = 7.0 Hz, 2H), 2.34 (t, J = 7.0 Hz, 2H), 1.58 (m,
13
75 MHz, CDCl
3
): δ 203.0, 170.5, 166.4, 147.1, 121.1, 52.3,
4
1
2
2
3
H), 1.45-1.25 (m, 12H); C NMR (75 MHz, CDCl ): δ 159.0,
56.9, 130.4, 129.2, 113.7, 91.6, 72.8, 72.3, 70.0, 55.2, 29.5,
9.3, 29.3, 29.2, 28.8, 28.7, 27.3, 26.0, 18.6; IR (neat): νmax 2924,
854, 2234, 1707, 1512, 1244, 1086, 1035 cm ; HRMS (ESI):
43.8, 40.9, 33.7, 29.1, 29.0, 28.8, 28.7, 24.6, 21.9; IR (neat): νmax
-
3361, 2921, 2854, 1734, 1720, 1659, 1531, 1443, 1365, 1209 cm
; HRMS (ESI): calcd for C16
296.1854.
-
1
1
+
4
H26NO [M-H] 296.1856, found
+
calcd for C21
30 4
H O Na [M+Na] 369.2036, found 369.2038.
4
.19. Methyl 2-(13-((tetrahydro-2H-pyran-2-yl)oxy)tridec-2-
Data of 28: Yield 70% (198 mg); as colorless oil; R
f
= 0.4
1
ynamido)acetate (25): Amide 25 was prepared from the
compound 24 using the same method described for the
preparation of amide compound 21 from motualevic acid E (13).
The crude product was purified (25% EtOAc/hexanes) to give
(30% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ 6.38 (t, J
3
= 7.7 Hz, 1H), 6.06 (dt, J = 11.2, 6.9 Hz, 1H), 5.91 (bs, 1H), 5.74
(d, J = 11.2, Hz, 1H), 4.09 (d, J = 5.1 Hz, 2H), 3.77 (s, 3H), 2.65
(q, J = 6.9 Hz, 2H), 2.08 (dd, J = 14.7, 7.7 Hz, 2H), 1.41 (m, 4H),
1
3
amide compound 25 as pale yellow oil (1.05 g, 69%). R
f
= 0.4
6.14 (bs,
H), 4.55 (dd, J = 3.9, 2.9 Hz, 1H), 4.05 (d, J = 4.8 Hz, 2H), 3.82
ddd, J = 11.7, 8.7, 3.9 Hz, 1H), 3.79 (s, 3H), 3.69 (dt, J = 9.7,
.8 Hz, 1H), 3.47 (m, 1H), 3.33 (dt J = 9.7, 6.8 Hz, 1H), 2.31 (t, J
6.8 Hz, 2H), 1.83 (m, 1H), 1.67 (m, 1H), 1.57 (m, 6H), 1.45-
1.36-1.24 (m, 10H); C NMR (125 MHz, CDCl ):
δ
170.5,
3
1
(
1
(
6
30% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ
3
166.4, 147.2, 138.9, 121.1, 88.3, 52.3, 40.9, 32.9, 29.6, 29.3,
2
1
C
9.2, 28.9, 28.8, 27.7; IR (neat): νmax 3312, 2920, 2853, 1748,
-1
664, 1530, 1454, 1364, 1207 cm ; HRMS (ESI): calcd for
+
17
H28Br
2
NO
3
[M+H] 452.0432, found 452.0421.
=
1
3
1
8
2
2
1
4
3
.25 (m, 14H); C NMR (75 MHz, CDCl ): δ 169.6, 153.3, 98.7,
4.23. Motualevic acid B (10): Motualevic acid B (10) was
prepared from ester 28 using the same method described for the
preparation of motualevic acid E (13) from ester 20. Yield: 82%
8.6, 74.8, 67.6, 62.2, 52.4, 41.2, 30.7, 29.6, 29.4, 29.3, 29.2,
8.9, 28.7, 27.6, 26.1, 25.4, 19.6, 18.5; IR (neat): νmax 3325,
923, 2854, 2232, 1751, 1651, 1526, 1449, 1364, 1279, 1203,
129 cm ; HRMS (ESI): calcd for C21
04.2407, found 404.2402.
(79 mg); as colorless amorphous solid; Rf = 0.4 (20%
-
1
+
1
H
35NO
5
Na [M+Na]
MeOH/EtOAc); H NMR (300 MHz, CD OD):
δ
6.49 (t, J = 7.5
3
Hz, 1H), 6.07 (dt, J = 11.3, 7.5 Hz, 1H), 5.87 (d, J = 11.3 Hz,
1
2
1
3
1
H), 3.94 (s, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.12 (q, J = 7.5 Hz,
H), 1.54-1.26 (m, 14H); C NMR (75 MHz, CD OD): δ 173.0,
3
69.0, 146.8, 140.0, 122.4, 88.7, 41.4, 33.6, 30.4, 30.2, 30.1,
4
.20. (Z)-Methyl 2-(13-((tetrahydro-2H-pyran-2-yl)oxy)tridec-2-
13
enamido) acetate (26): To a solution of amide 25 (900 mg, 2.36
mmol) in MeOH (30 mL) was added catalytic amount of Lindlar
catalyst (225 mg) and the resulting mixture was stirred
vigorously under a hydrogen atmosphere for 15 min at rt. The
mixture was filtered through celite and washed with EtOAc. The
filtrate was concentrated in vacuo. Purification of the residue
with flash column chromatography (25% EtOAc/hexanes) gave
0.0, 30.0, 29.7, 29.4, 28.4; IR (neat); νmax 2925, 2855, 1705,
-
1
670, 1607, 1460, + 1218 cm ; HRMS (ESI): calcd for
C
16
H26Br
2
NO [M+H] 438.0273, found 438.0268.
3
4
.24. Methyl 3-oxo-15-((tetrahydro-2H-pyran-2-yl)oxy)pentadec-
4-ynoate (29): Ketoester 29 was prepared from compound 24
compound 26 as pale yellow oil (650 mg, 72%). R
EtOAc/hexanes); H NMR (300 MHz, CDCl ):
f
= 0.4 (30%
using the same method described for the preparation of
1
δ 6.03 (dt, J =
3

ACCEPTED MANUSCRIPT
9
compound 22 from motualevic acid E (13). The residue was
4.28. Methyl 3-(12-((tetrahydro-2H-pyran-2-yl)oxy)dodec-1-yn-
purified by flash column chromatography (15% EtOAc/hexanes)
1-yl)-2H-azirine-2-carboxylate ((±)-31): To a solution of 30 (300
to give β-ketoester 29 as a pale yellow oil (471 mg, 57%; the
mg, 0.56 mmol) in dry toluene (10 mL) at 0 °C was added Et N
3
1
ratio of keto-enol is 1:0.3). R
NMR (400 MHz, CDCl ):
t, J = 3.8 Hz, 1.3H), 3.81 (ddd, J = 10.7, 8.4, 3.8 Hz, 1.3H), 3.75
s, 3.6H), 3.74 (s, 0.9H), 3.69 (dt, J = 9.2, 6.9 Hz, 1.3H), 3.51 (s,
f
= 0.6 (20% EtOAc/hexanes); H
(0.39 mL, 2.80 mmol). The reaction mixture was stirred at rt for
3
δ
11.75 (s, 0.3H), 5.23 (s, 0.3H), 4.54
5 h and then H
with brine and dried over Na
2
O was added and extracted with EtOAc, washed
SO . The organic layer was
(
(
2
4
concentrated in vacuo to give a crude compound which was
2
H), 3.47 (m, 1.3H), 3.32 (dt, J = 9.2, 6.9 Hz, 1.3H), 2.37 (t, J =
purified (15% EtOAc/hexanes) to give compound 31 as a pale
1
6
.9 Hz, 2.6H), 2.37 (t, J = 6.9 Hz, 0.6H), 1.83 (m, 1H), 1.72-1.49
m, 13.3H), 1.40-1.26 (m, 14.4H); C NMR (75 MHz, CDCl
yellow oil (159 mg, 78%). R
NMR (500 MHz, CDCl ):
f
= 0.55 (20% EtOAc/hexanes); H
4.53 (t, J = 4.4, Hz, 1H), 3.82 (ddd, J
1
3
(
3
):
δ
3
δ
1
7
2
1
1
78.6, 172.5, 166.5, 155.7, 98.7, 97.0, 96.3, 95.7, 94.5, 80.2,
= 11.0, 8.8, 3.3 Hz, 1H), 3.70 (s, 3H), 3.68 (m, 1H), 3.45 (m,
1H), 3.34 (dt, J = 8.8, 6.6 Hz, 1H), 2.67 (s, 1H), 2.54 (t, J = 7.7
Hz, 2H), 1.79 (m, 1H), 1.70-1.44 (m, 9H), 1.42-1.21 (m, 12H);
C NMR (125 MHz, CDCl ): δ 170.7, 149.2, 118.1, 98.7, 67.5,
3
64.5, 62.2, 52.3, 31.4, 30.6, 29.6, 29.3, 29.3, 29.2, 28.8, 28.7,
5.3, 67.5, 62.8, 62.2, 52.4, 52.3, 51.3, 51.0, 30.7, 30.6, 29.6,
9.4, 29.3, 29.2, 28.8, 28.7, 27.7, 27.4, 26.1, 25.4, 25.3, 19.6,
9.1, 18.9; IR (neat): ν-max 2926, 2856, 2215, 1748, 1676, 1609,
13
1
445, 1252, 1028 cm ; HRMS (ESI): calcd for C H O Na
2
1
34
5
+
[
M+Na] 389.2298, found 389.2297.
27.3, 26.0, 25.3, 20.2, 19.5; IR (neat): νmax 2930, 2855, 2227,
-
1
1
766, 1745, 1345, 1202, 1058 cm ; HRMS (ESI): calcd for
+
4
.25. Methyl 15-((4-methoxybenzyl)oxy)-3-oxopentadec-4-ynoate
21 4
C H33NO Na [M+Na] 386.2307, found 386.2319.
(29a): Ketoester 29a was prepared from 24a using the same
method described for the preparation of compound 22 from
motualevic acid E (13). The residue was purified by flash column
chromatography (15% EtOAc/hexanes) to give β-ketoester 29a as
4.29. (R)-Methyl 3-(12-((4-methoxybenzyl)oxy)dodec-1-yn-1-yl)-
2H-azirine-2-carboxylate (31a): To an oven dried round bottom
flask, quinidine (1.02 g, 3.15 mmol) was taken and dry toluene
(120 mL) was added and cooled to 0 °C. A solution of compound
30a (600 mg, 1.05 mmol) in toluene was cannulated at 0 °C. The
resulting mixture was stirred for 52 h at 0 °C. The reaction
mixture was quenched with 0.05 M HCl and extracted with
a pale yellow oil (662 mg, 57%; the ratio of keto:enol is 1:0.3).
1
R = 0.6 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl ):
δ
f
3
1
2
3
2
1.75 (s, 0.3H), 7.20 (d, J = 9.0 Hz, 2.6H), 6.82 (d, J = 9.0 Hz,
.6H), 5.23 (s, 0.3H), 4.39 (s, 2.6H), 3.79 (s, 3.9H), 3.75 (s, 3H),
.74 (s, 0.6H), 3.51 (s, 2H), 3.39 (t, J = 7.0 Hz, 2.6H), 2.37 (m,
2 4
EtOAc. Organic layer was washed with brine, dried over Na SO
13
.6H), 1.58 (m, 7H), 1.44-1.24 (m, 13H); C NMR (75 MHz,
): 178.6, 166.5, 158.9, 155.7, 130.6, 129.0, 113.6, 97.0,
5.7, 80.2, 72.4, 70.0, 67.7, 55.1, 52.3, 51.3, 51.0, 29.6, 29.4,
9.3, 29.2, 28.8, 28.7, 27.7, 27.4, 26.0, 19.1, 18.9; IR (neat): νmax
and concentrated in vacuo. The crude was purified (15%
EtOAc/hexanes) to give compound 31a as pale yellow oil (323
mg, 77% yield, 51% ee (chiral HPLC, ciral column-ODH,
CDCl
3
δ
9
2
2
hexane/isopropanol 80:20)). R = 0.55 (20% EtOAc/hexanes);
f
-
1
24
1
927, 2855, 2215, 1744, 1609, 1448, 1248, 1099 cm ; HRMS
[α]D = −58.1 (c 0.58, CHCl ); H NMR (500 MHz, CDCl ): δ
3 3
+
(
ESI): calcd for C24
H
34
O
5
Na [M+Na] 425.2298, found 425.2297.
7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.43 (s, 2H),
3
2
1
1
2
.80 (s, 3H), 3.75 (s, 3H), 3.43 (t, J = 7.6 Hz, 2H), 2.71 (s, 1H),
4
.26.
(Z)-Methyl
15-((tetrahydro-2H-pyran-2-yl)oxy)-3-
.58 (t, J = 7.6 Hz, 2H), 1.69-1.54 (m, 6H), 1.47-1.38 (m, 2H),
13
(
tosylimino)pentadec-4-ynoate (30): Oxime-tosylate 30 was
.38-1.25 (m, 8H); C NMR (75 MHz, CDCl ):
δ 170.9, 159.0,
3
prepared from ketoester 29 using the same method described for
the preparation of compound 23 from β-ketoester 22. The residue
was purified (20% EtOAc/hexanes) to give tosylated compound
49.3, 129.2, 118.2, 113.7, 72.5, 70.1, 64.6, 55.2, 52.4, 31.5,
9.7, 29.4, 29.4, 29.3, 28.9, 28.8, 27.4, 26.1, 20.3; IR (neat): νmax
-
2
;
921, 2852, 2223, 1753, 1735, 1602, 1446, 1344, 1196, 1094 cm
1
+
3
0 as a pale yellow oil (449 mg, 77%). R
f
= 0.4 (20%
7.85 (d, J = 7.9
Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 4.57 (t, J = 3.9 Hz, 1H), 3.87
ddd, J = 10.9, 8.9, 3.9 Hz, 1H), 3.72 (dt, J = 8.9, 6.9 Hz, 1H),
HRMS (ESI): calcd for C H NO [M+H] 400.2487, found
2
4
34
4
1
EtOAc/hexanes); H NMR (500 MHz, CDCl ):
δ
3
400.2490.
(
4.30. (R)-Methyl 3-(12-hydroxydodec-1-yn-1-yl)-2H-azirine-2-
carboxylate (32): To a solution of compound 31a (200 mg, 0.50
mmol) in CH Cl : H O (2:1, 2 mL) was added DDQ (156 mg,
0.68 mmol) at 0 °C. The reaction mixture was stirred at rt for 50
min and quenched by adding saturated aq NaHCO . The reaction
mixture was extracted with EtOAc and washed with aq NaHCO
(2 times). The organic layer was separated, dried over Na SO ,
3
2
1
.68 (s, 3H), 3.50 (m, 1H), 3.38 (dt, J = 8.9, 6.9 Hz, 1H), 3.35 (s,
H), 2.44 (s, 3H), 2.42 (t, J = 6.9 Hz, 2H), 1.82 (m, 1H), 1.76 (m,
2
2
2
1
3
H), 1.64-1.47 (m, 8H), 1.41-1.23 (m, 12H); C NMR (125
): 167.5, 145.0, 144.5, 132.2, 129.6, 129.5, 128.8,
28.7, 107.8, 98.7, 70.6, 67.5, 62.2, 52.3, 39.9, 30.6, 29.6, 29.4,
9.3, 29.2, 28.8, 28.6, 27.5, 26.1, 25.3, 21.5, 19.6; IR (neat): ν
MHz, CDCl
3
δ
3
1
2
2
3
max
2
4
-
1
930, 2856, 2223, 1746, 1597, 1379, 1186 cm ; HRMS (ESI):
filtered and concentrated in vacuo. The residue was purified
(30% EtOAc/hexanes) to give compound 32 as clear oil (133 mg,
+
calcd for C28
H41NO
7
SNa [M+Na] 558.2495, found 558.2491.
25
D
9
5%). R
f
= 0.4 (30% EtOAc/hexanes); [α]
= −106.4 (c 0.5,
3.75 (s, 3H), 3.64 (t, J =
.8 Hz, 2H), 2.71 (s, 1H), 2.58 (t, J = 7.8 Hz, 2H), 1.65 (m, 2H),
1
4
.27. (E,
Z)-Methyl 15-((4-methoxybenzyl)oxy)-3-
CHCl ); H NMR (500 MHz, CDCl ):
δ
3
3
(tosylimino)pentadec-4-ynoate (30a): Compound 30a was
6
1
1
3
prepared from β-ketoester 29a using the same method described
for the preparation of compound 23 from β-ketoester 22. The
crude product was purified (20% EtOAc/hexanes) to give
.56 (m, 2H), 1.43 (m, 2H), 1.38-1.28 (m, 10H); C NMR (75
): 170.8, 149.2, 118.2, 64.5, 62.8, 52.4, 32.6, 31.4,
9.3, 29.2, 29.2, 28.8, 28.7, 27.3, 25.6, 20.2; IR (neat): ν 3432,
MHz, CDCl
2
3
δ
max
-
1
tosylated compound 30a as a pale yellow oil (656 mg, 77%). R =
f
2927, 2855, 2227, 1768, 1747, 1438, 1345, 1204 cm ; HRMS
1
+
0.4 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
): δ 7.85
(
3
ESI): calcd for C16H26NO [M+H] 280.1907, found 280.1907.
(
d, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.6 Hz,
2
3
=
H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.68 (s,
4.31. (R)-Methyl 3-(13,13-dibromotridec-12-en-1-yn-1-yl)-2H-
azirine-2-carboxylate (33): Compound 33 was prepared from 32
following the same procedure described for the synthesis of 20
from 19. Dibromo alkene 33 was obtained as a clear oil (94 mg,
H), 3.43 (t, J = 6.7 Hz, 2H), 3.35 (s, 2H), 2.44 (s, 3H), 2.42 (t, J
1
3
7.6 Hz, 2H), 1.63-1.52 (m, 6H), 1.42-1.25 (m, 10H); C NMR
): 167.6, 159.0, 145.1, 144.5, 132.3, 130.7,
(
75 MHz, CDCl
3
δ
2
4
1
5
2
1
5
29.6, 129.5, 129.1, 128.9, 128.8, 113.6, 107.8, 72.4, 70.6, 70.1,
5.2, 52.3, 40.0, 29.7, 29.4, 29.3, 29.3, 28.9, 28.6, 27.6, 26.1,
1.6, 19.7; IR (neat): νmax 2930, 2856, 2223, 1746, 1598, 1379,
+
54% over two steps). R
f
= 0.4 (5% EtOAc/hexanes); [α]
D
=
1
−60.2 (c 0.16, CHCl ); H NMR (500 MHz, CDCl ): 6.39 (t, J
δ
3
3
= 7.8 Hz, 1H), 3.75 (s, 3H), 2.72 (s, 1H), 2.59 (t, J = 7.8 Hz, 2H),
-
1
186, 818 cm ; HRMS (ESI): calcd for C31
94.2495, found 594.2488.
7
H41NO SNa [M+Na]
2.09 (q, J = 7.8 Hz, 2H), 1.66 (m, 2H), 1.43 (m, 4H), 1.35-1.28
1
3
(m, 10H); C NMR (75 MHz, CDCl
3
): δ 170.8, 149.3, 138.8,
118.1, 88.4, 64.7, 52.4, 32.9, 31.5, 29.2, 29.2, 28.9, 28.9, 28.7,

ACCEPTED MANUSCRIPT
1
0
Tetrahedron
2
7.7, 27.4, 20.3; IR (neat): νmax 2925, 2854, 2227, 1744, 1731,
20. Bronk, B. S.; Lippard, S. J.; Danheiser, R. L. Organometallics
993, 12, 3340-3349.
-
1
1
1
437, 1272, 1202 cm ; HRMS (ESI): calcd for C17H24Br NO
M+H] 432.0168, found 432.0176.
2 2
+
21. Dahan, A.; Portnoy, M. J. Org. Chem. 2001, 66, 6480-6482.
[
4
.32. (R)-(Z)-Antazirine (ent-5): To a solution of compound 33
Supplementary Material
(
60 mg, 0.14 mmol) in dry hexane (6 mL) was added catalytic
amount of Lindlar catalyst (24 mg) and evacuated and purged
with H and cooled to 0 °C. The reaction mixture was stirred at 0
Supplementary data associated with this article can be found,
in the online version, at
2
°C for 2 h under hydrogen atmosphere. The reaction mixture was
then filtered through a pad of celite using hexane. The solvent
was concentrated under reduced pressure to afford crude which
was purified by column chromatography (10% EtOAc/hexanes)
to give (R)-(Z)-antazirine (ent-5) as a pale yellow foam (50 mg,
8
2% yield, 51% ee (chiral HPLC, ciral column-ODH,
24
hexane/isopropanol 80:20)). R
=
f
= 0.4 (5% EtOAc/hexane); [α]
6.57
D
1
−63.6 (c 0.64, n-hexane); H NMR (500 MHz, CDCl ):
δ
3
(
dt, J = 10.7, 7.7 Hz, 1H), 6.42 (d, J = 10.7 Hz, 1H), 6.38 (t, J =
7
.3 Hz, 1H), 3.73 (s, 3H), 2.62 (s, 1H), 2.50 (m, 2H), 2.08 (q, J =
13
7
.3 Hz, 2H), 1.48-1.37 (m, 4H), 1.33-1.24 (m, 10H); C NMR
172.2, 154.2, 152.5, 138.8, 111.2, 88.5,
2.2, 33.0, 29.7, 29.3, 29.2, 29.2, 29.2, 29.1, 28.9, 28.8, 27.7; IR
(
5
125 MHz, CDCl ): δ
3
(
1
4
neat): νmax 2926, 2853, 1762, 1730, 1618, 1436, 1269, 1196,
-
1
+
030 cm ; HRMS (ESI) calcd for C17
34.0324, found 434.0333.
2 2
H26Br NO [M+H]
Acknowledgments
This work was financially supported by the Ministry of Earth
Sciences (MoES), New Delhi, India. We thank CSIR, New Delhi,
India, for the Senior Research Fellowship (V. D. K)
References and notes
1
2
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.
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Supporting Information for
Total synthesis of motualevic acids A-F, (E) and (Z)-antazirines
a,b
a,b
Vilas D. Kadam and Gangarajula Sudhakar
aCPC Division (Organic Chemistry-II), and bAcademy of Scientific and Innovative Research (AcSIR),
CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India
Contents
Page No.s
1-70
1
13
1
. H and C NMR Spectra
2
. Chromatograms of compounds: 4, 14, 31a and 5
71-78

Corresponding author. Tel.: +91-40-27191435; e-mail: gsudhakar@iict.res.in
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