Total synthesis of (+)-petromyroxol via tandem α-aminoxylation-allylation and asymmetric dihydroxylation-SN2 cyclization approach

Article abstract of DOI:10.1039/c5ra10405j

The total synthesis of (+)-petromyroxol, a tetrahydrofuran (THF)-diol fatty acid, isolated from sea lamprey larvae (Petromyzon marinus) is reported. The present synthesis employs a tandem α-aminoxylationallylation, cross metathesis and tandem asymmetric d

Full text of DOI:10.1039/c5ra10405j

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Total Synthesis of (+)-petromyroxol via tandem α-aminoxylation-
allylation and asymmetric dihydroxylation-S 2 cyclization
approach†‡
N
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
DOI: 10.1039/x0xx00000x
U. Nookaraju and Pradeep Kumar*
www.rsc.org/
The total synthesis of (+)-petromyroxol, a tetrahydrofuran (THF)-diol fatty acid, isolated from sea lamprey larvae
Petromyzon marinus) is reported. The present synthesis employs a tandem α-aminoxylation-allylation, cross metathesis
(
and tandem asymmetric dihydroxylation-S
N
2 cyclization as key steps.
Acetogenins, an important class of compounds containing
tetrahydrofuran ring systems (Fig 1), were isolated from
Annonaceae plants. They are known to exhibit a wide range of
could possibly help in development of eco-friendly pest
controlling agents.
biological
activities
such
as
antifeedant,
antitumor,
immunosuppressive and most significantly pesticidal and
pheromonal activities. This interesting biological profile along with
OH
Br
O
1
O
O
varied structural features of the acetogenin family has aroused a lot
of research interest in the synthesis of this class of compounds
among the organic chemists worlwide. Isolation of one such mono
Br
OH
O
OH
Br
O
2
(+)-Petromyroxol 1
Obtusine 2
O
HO
HO
acetogenin, petromyroxol containing a single THF ring has been
O
3
reported recently by Li et al. Petromyroxol was known to have a
6
6
OH
3
OH
4
possible biochemical role in study of communication among the sea
lamprey, which are parasitic fish that have known to cause damage
to the fish population especially in Great lakes area of North
America. Significant efforts have been made to maintain the
ecological balance and minimize the havoc caused by these invasive
species.
Anthelmintic oxylipids
OH
O
O
C
H
16 33
OH
O
O
3
OH Mucoxin 5
Towards this, many strategies have been employed to control
the growth of sea lamprey and one such study was to
understand the olfactory responses in these species. A non-
racemic mixture of petromyroxol (2.9 mg) has been isolated
from >100 000 L of water conditioned with the larvae of
Figure 1: Some of the acetogenins based natural products
In recent years organocatalysis has emerged as a powerful tool box
in the area of developing new methodologies and its application to
4
Petromyzon marinus. The (+)-enantiomer was found to be just the synthesis of biologically important natural products. It
0
.9 mg (~ 36%) of the isolated mixture, nevertheless, was compliments both the metal catalysis and expensive protein
5
found to trigger a better olfactory response among the catalysis. Proline is extensively used as organocatalyst since it is
6
commercially available in both the enantiomeric forms. It has an
lamprey fish than it’s (–)-antipode. The scarcity of the material
advantage of operational simplicity, moisture tolerance and often
has hampered further research in this area. The use of sex
products are obtained with high ee.
pheromones as a tool for biological control of pests has been
under active consideration and along these lines petromyroxol
3
is expected be a part of sex pheromones, of sea lamprey and
Petromyroxol is structurally interesting molecule with trisubstituted
tetrahydrofurandiol. The construction of stereochemically defined
THF ring has always been a major challenge which is evident from
2
various literature reports. The attractive structural features of
petromyroxol along with biological importance and its low
abundance drew our attention towards its synthesis. Accordingly
we devised a simple and efficient route to (+)-petromyroxol via
organocatalytic tandem process. While, the first synthesis of
7
a
petromyroxol was reported by Boyer using a protocol based on
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rhodium catalyzed denitrogenation and rearrangement of a 1- free alcohol was protected as its benzyl ether using NaHMDS and
7
b-c
sulfonyl-1,2,3-triazole, Ramana et al. described its synthesis from benzyl bromide at 0 °C to furnish the compound 10, which was then
7
d
carbohydrate using a chiral pool approach. Herein we report our desilylated using TBAF in THF to obtain homo allylic alcohol 11.
successful endeavors towards the total synthesis of 1 employing
proline catalyzed tandem α-aminoxylation-allylation, cross-
L-Proline, Nitrosobenzene,
DMSO, rt, 20 min
metathesis and tandem asymmetric dihydroxylation-S 2 cyclization
N
ONHPh
ONHPh
H
as key steps.
4
then In powder, allyl bromide,
NaI, 30 min, 70%
4
4
O
OH
6
OH
7
Heptanal
3
:2 - syn:anti
ONHPh
ONHPh
i) TBSOTf, TEA
CH Cl , 15 min, 0 °C
Cu(OAc)2
4
4
MeOH, 12h
2 Steps 82%
2
2
OTBS
OH
8
7
OH
4
OBn
NaHMDS, BnBr,
TBAF, THF,
rt, 12h, 95%
4
TBAI, THF, 0 °C
to rt, 2h, 92%
OTBS
OTBS
9
10
OBn
4
OH
1
1
Scheme 2: Synthesis of alcohol fragment 11
Our next task was to convert the major syn compound 6 into the
required homoallylic alcohol 11 (scheme 3). Towards this end
compound 15 was synthesized from 6 using a similar sequence of
reactions as described in scheme 2. Subsequently compound 15
was smoothly converted to the required fragment 11 via Mitsunobu
Scheme 1: Retrosynthetic analysis of (+)-petromyroxol 1
Our synthetic strategy for the synthesis of 1 is outlined in scheme 1. inversion.
We envisioned that the target molecule could be achieved by
hydrogenolysis of THF diol 20. The key tri-substituted THF moiety
could be constructed diastereoselectively by using tandem
ONHPh
ONHPh
TBSOTf, TEA,
CH Cl , 15 min,
0 °C, 97%
Cu(OAc)2
asymmetric dihydroxylation-S 2 cyclization of an olefin 19 which in
N
4
MeOH, 12h, 85%
4
2
2
OTBS
turn could be derived from the cross metathesis of ester 18 and
homoallylic alcohol 11. The homo allylic alcohol 11 could be
synthesized from commercially available heptanal via oragano
OH
6
12
OH
OBn
4
NaHMDS, BnBr,
TBAF,THF,
rt, 12h, 95%
8
catalytic tandem α-aminoxylation-allylation protocol developed by
4
TBAI, THF, 0 °C
to rt, 2h, 92%
Zhong. The ester fragment 18 could be readily accessible from
cyclohexanone.
OTBS
OTBS
1
3
1
4
OBn
4
OBn
PNBA, DIAD,
NO2
As illustrated in scheme 2, synthesis of petromyroxol started from
commercially available heptanal, which was subjected to α-
aminoxylation using L-proline as a catalyst and nitrosobenzene as
an oxygen source to provide chiral O-N-phenylaminoxyaldehyde.
This intermediate was then subjected to in situ indium mediated
allylation (In/allylbromide/NaI) to afford a mixture of O-amino-
substituted allylic alcohols 6 & 7 respectively with a diastereomeric
ratio of 3:2 (syn:anti) in 70% overall yield with excellent
Toluene, 0 °C
to rt, 97%
OH
4
O
15
16 O
OBn
LiOH.H2O
THF, MeOH, H2O, rt, 95%
4
OH
1
1
9
enantioselectivities. Both compounds 6 and 7 were cleanly
separated by silica gel chromatography and fully characterized by
spectroscopic means.
Scheme 3: Conversion of syn isomer 6 to desired anti alcohol
fragment 11
The anti compound 7 was then protected as its TBS ether using We then proceeded next to prepare the ester fragment, for that
TBSOTf and NEt to furnish the silyl ether 8. The crude compound 8 cyclohexanone was treated with 30% H O to give hydroperoxide
3
2 2
1
0
was subjected to N-O bond cleavage using copper (II) acetate in intermediate which was decomposed using ferrous sulfate-copper
methanol to get compound 9 in 82% yield (2 steps). Further, the sulfate system to give the acid 17 in 62% yield (scheme 4). The
1
1
2
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olefinic acid 17 was subjected to esterification using K CO /BnBr to OsO . Initially we carried out the reaction with standard conditions
2
3
4
furnish the benzyl ester 18 in 95% yield.
of Sharpless asymmetric dihydroxylation using 1 mol% ligand
(
DHQ) PHAL and 0.4mol% OsO , but reaction did not work even
2 4
after prolonged reaction time for a week at 0 °C. This prompted us
to increase the amount of OsO to 5 mol% in phased manner and to
4
our delight starting material was completely consumed to give the
crude diol. This crude product, without any extensive
characterization, was immediately subjected to cyclization using
pyridine as solvent. Though the reaction did not proceed at room
temperature, refluxing the same in pyridine for 16h furnished the
desired cyclized compound 20 in 80% yield (3 steps) with excellent
1
13
selectivity (single diastereomer, confirmed by H and C NMR).
Finally debenzylation of compound 20 using 10% wt/wt Pd/C under
hydrogen balloon pressure gave the target molecule (+)-
petromyroxol 1 in 95% yield.
Scheme 4: Synthesis of ester fragment 18
Conclusions
After few optimizations with temperature and catalyst loading, the
1
2
cross metathesis reaction was performed between alcohol 11 (1 In summary, we achieved the asymmetric synthesis of (+)-
equiv) and 18 (5 equiv) in CH
resulting in the cross coupled 19 as major product in 70% yield
scheme 5).
2 2
Cl using 15 mol% Grubb’s catalyst,
petromyroxol in 10 steps with an overall yield of 26.6% from
easily accessible starting materials. Depending upon the
catalyst (D/L-proline) used in the tandem aminoxylation-
allylation step along with variation in chain length and the
ligands (DHQ/DHQD) in the Sharpless asymmetric
dihydroxylation step, one can have easy access to various
stereoisomers of petromyroxol and its synthetic analogues.
(
OBn
OH
O
OBn
1
8
1
1
Grubbs 2nd generation
catalyst, CH Cl , rt, 16h,
2
2
70%
OBn
OH
O
Acknowledgements
OBn
i) MsCl, TEA, CH Cl , 0 °C, 15 min
19
2
2
U.N.R thanks UGC, New Delhi for a senior research fellowship.
The authors thank CSIR, New Delhi for financial support as part
of XII Five Year Plan under the title ORIGIN (CSC0108).
ii) OsO , (DHQ) PHAL, MeSO NH ,
4
2
2
2
K Fe(CN) , K CO , t-BuOH, H O,
3
6
2
3
2
0
°C, 24h
iii) pyridine, reflux, 16h
steps 80%
3
OBn
Experimental section
O
OBn
20
OH
O
(
4R, 5R)-5-((Phenylamino)oxy)hept-1-en-4-ol 6:
Pd/C, H2 Ballon,
EtOH, 3h, 95%
OH
To a stirred solution of heptanal (6.4 g, 56.0 mmol) and
nitrosobenzene (5.0, 46.6 mmol) in DMSO (94 mL), L-proline
O
(
1.07 g, 9.3 mmol) was added. After being stirred for 20 min at
OH
OH
+)-Petromyroxol 1
O
rt (The endpoint of the reaction was monitored by its color
change from green to orange), allyl bromide (6.05 ml, 70.0
mmol), NaI (10.5 g, 70.0 mmol), and indium powder (8.03 g,
(
7
0.0 mmol) were added at rt. The stirring was kept at room
Scheme 5: Synthesis of (+)-petromyroxol 1
temperature for 30 min. The reaction mixture was quenched
with 0.5 M aq HCl (50 mL) and the aqueous layer was
extracted with CH
were washed with brine (30 mL), dried over Na
concentrated under reduced pressure. The crude was purified
by flash column chromatography (EtOAc-petroleum ether,
2
Cl
2
(2 × 30 mL). The combined organic layers
SO and
After having substantial amounts of olefinic alcohol 19, the time
was set for the construction of trans trisubstituted tetrahydrofuran
ring 20 via intramolecular tandem Sharpless asymmetric
2
4
1
3
dihydroxylation-S 2 cyclization according to Marshall’s protocol.
N
3
1
:97) to afford compound (4R, 5R)-5-((phenylamino)oxy)hept-
6
Thus, the alcohol 19 was first converted into its mesylate and then
-en-4-ol
(5.1g, 42%) and the more quickly eluting (4S, 5R)-
(3.5 g, 28%). The diastereomeric ratios of the
1
4
subjected to Sharpless asymmetric dihydroxylation
using
isomer
products were determined by weighing the separated isomers.
7
commercially available AD-mix-α in t-BuOH–H O (1:1), however the
2
reaction did not work. So we considered to optimizing the
dihydroxylation reaction conditions with respect to ligand and
The enantiomeric excess of the anti and the syn-diastereomer
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1
was measured by HPLC analysis after separation of the isomers H), 0.91 (s, 12H), 0.08 (s, 6 H); C NMR (100MHz,
3
using column chromatography.
CDCl3) δ = 135.6, 116.8, 75.1, 74.6, 35.9, 31.9, 31.8, 25.8, 25.8,
+
22.6, 18.1, 14.0, -4.3, -4.6; HRMS (ESI) for C16
found 309.2228, calcd 309.2220.
34 2
H O Si (M + Na)
2
6.6
−1
Syn 6
:
275, 3074, 2929, 2863, 1640, 1600, 1484, 1459, 1375, 1320,
[α]D
: +28.7° (c 1.58, CHCl ); IR (neat, cm ) : ν 3394,
3 max
3
1
7
4
1
041; H NMR (500MHz, CDCl
3
)
.02 - 6.97 (m, 3 H), 5.95 - 5.85 (m, 1 H), 5.21 - 5.14 (m, 2 H), butyl)dimethylsilane 10:
δ = 7.28 (s, 2 H), 7.09 (s, 1 H), (((4S,
5R)-5-(Benzyloxy)dec-1-en-4-yl)oxy)(tert-
.03 (t, J = 5.6 Hz, 1 H), 3.89 (td, J = 2.9, 8.5 Hz, 1 H), 2.57 (br.
s., 1 H), 2.32 (t, J = 6.9 Hz, 2 H), 1.76 - 1.66 (m, 2 H), 1.65 - 1.56
(
1
3
m, 2 H), 1.55 - 1.36 (m, 4 H), 0.93 - 0.90 (m, 3 H); C NMR
Sodium bis(trimethylsilyl)amide (1M solution in THF, 10.48 mL,
0.48 mmol) was added to a stirred solution of (2.0 g, 6.9
1
9
(125MHz, CDCl3) δ = 148.3, 135.1, 129.0, 122.4, 117.7, 114.9,
mmol), tetrabutylammonium iodide (258 mg, 0.69 mmol) and
benzyl bromide (1.24 mL, 10.48 mmol) in THF (30 mL) at 0 °C.
The mixture was stirred at ambient temperature for 2h. The
reaction was quenched by the addition of saturated aqueous
ammonium chloride (25 mL) and extracted with EtOAc (3 × 50
85.8, 72.2, 36.9, 31.9, 28.2, 26.0, 22.5, 14.0; HRMS (ESI) for
C H O N (M + Na) found 286.1782, calcd 286.1778. The
+
1
6 25 2
enantioselectivity of compound
using chiral HPLC {Chiralcel OD-H (250mm x 4.6 mm),
6 was determined as 98% ee
−
1
R
iPrOH/hexane (10:90), flow rate 1 mL min , λ = 230 nm, t =
2 4
mL). The combined organic layers were dried over Na SO , and
R
5.40 (major), t = 6.31 (minor)}.
concentrated in vacuo. The crude product was purified by flash
column chromatography (EtOAc-pet ether, 1.5:98.5) to yield
2
6.6
−1
28.9
Anti 7
:
[α]
D
:
+20.4° (c 1.43, CHCl
3
); IR (neat, cm ) : νmax compound 10 as colourless oil (2.37 g, 92%). [α]
D
: +15.67° (c
−1
3
1
7
3
2
1
3
396, 3285,3075, 2929, 2863, 1640, 1600, 1480, 1459, 1375, 1.31, CHCl ); IR (neat, cm ): νmax 3075, 3029, 2940, 2861,
1
320, 1041; H NMR (500MHz, CDCl
1
3
)
3
δ = 7.31 - 7.27 (m, 2 H), 1462, 1370, 1317, 1252, 1208, 1095; H NMR (400MHz, CDCl )
.04 - 6.98 (m, 3 H), 5.98 - 5.82 (m, 1 H), 5.21 - 5.12 (m, 2 H), δ = 7.38 - 7.28 (m, 5 H), 5.88 (tdd, J = 7.2, 10.1, 17.1 Hz, 1 H),
.87 (ddd, J = 4.1, 5.7, 8.2 Hz, 1 H), 3.79 (q, J = 5.8 Hz, 1 H), 5.11 - 5.02 (m, 2 H), 4.71 (d, J = 11.5 Hz, 1 H), 4.51 (d, J = 11.5
.51 - 2.38 (m, 1 H), 2.33 - 2.25 (m, 1 H), 1.75 - 1.61 (m, 2 H), Hz, 1 H), 3.79 (td, J = 4.3, 6.3 Hz, 1 H), 3.38 (td, J = 3.6, 7.5 Hz, 1
.53 - 1.42 (m, 2 H), 1.38 - 1.30 (m, 4 H), 0.90 (t, J = 6.9 Hz, 3 H), 2.45 - 2.36 (m, 1 H), 2.32 - 2.24 (m, 1 H), 1.54 - 1.48 (m, 2
1
3
13
H); C NMR (125MHz, CDCl
3
)
δ = 148.0, 134.6, 129.0, 122.6, H), 1.36 - 1.24 (m, 6H), 0.92 - 0.87 (m, 12 H), 0.07 (s, 6 H);
17.9, 115.3, 85.4, 72.7, 38.2, 32.0, 29.4, 25.3, 22.5, 14.0; NMR (100MHz, CDCl δ = 139.1, 135.8, 128.2, 127.8, 127.4,
N (M + Na) found 286.1782, calcd 116.7, 82.3, 74.2, 72.5, 37.8, 32.0, 30.7, 25.9, 25.5, 22.6, 18.1,
C
1
3
)
+
25 2
HRMS (ESI) for C16H O
+
2
86.1778; The enantioselectivity of compound
determined as 98% ee using chiral HPLC {Chiralcel OD-H 399.2699, calcd 399.2690.
250mm x 4.6 mm), iPrOH/hexane (10:90), flow rate 1 mL
7
40 2
was 14.1, -4.4, -4.4; HRMS (ESI) for C23H O Si (M + Na) found
(
−
1
min , λ = 230 nm, t
R
= 6.32 (major), t
R
= 7.35 (minor)}.
(
4S, 5R)-5-(Benzyloxy)dec-1-en-4-ol 11:
(4S, 5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-ol 9:
To a stirred solution of 10 (2.0 g, 5.3 mmol) in THF (10 mL) was
added 1.0 M TBAF in THF (10.6 mL, 10.6 mmol) at 0 °C. After
To a stirred solution of compound
CH Cl
followed by TBDMSOTf (3.2 mL, 13.6 mmol) and the mixture EtOAc (2 × 20 mL). The combined organic layer was washed
was stirred for 15 min. The reaction mixture was quenched with brine (20 mL), dried over Na SO and concentrated under
with sat. NH
Cl solution (20 mL) and the aqueous layer was reduced pressure. The crude residue was purified by flash
extracted with CH Cl
(2 × 30 mL). The combined organic layers column chromatography (EtOAc–pet ether, 5:95) to afford
were washed with brine (20 mL), dried over Na
7
(3.0 g, 10.48 mmol) in being stirred for 12 h at rt, the reaction mixture was quenched
N (3.5 mL, 25.09 mmol), with H O (10 mL) and the aqueous layer was extracted with
2
2
2
(30.0 mL) at 0 °C was added Et
3
2
4
4
2
2
2
8.9
and compound 11 as colourless oil (1.3 g, 95%). [α]
:
-1.95° (c
2
SO
4
D
−1
concentrated under reduced pressure to give the crude
yellow oil.
8
as 0.6, CHCl
1696, 1635, 1455, 1372, 1084, 1037; H NMR (500MHz,
CDCl δ = 7.36 - 7.28 (m, 5 H), 5.95 - 5.79 (m, 1 H), 5.19 - 5.11
m, 2 H), 4.64 - 4.56 (m, 2 H), 3.87 - 3.81 (m, 1 H), 3.44 - 3.38
m, 1 H), 2.35 - 2.25 (m, 2 H), 1.93 (br. s., 1 H), 1.69 - 1.60 (m, 1
3
); IR (neat, cm ): νmax 3425, 3076, 3030, 2926, 2865,
1
3
)
(
(
To a stirred solution of the crude
added Cu(OAc) (720 mg, 3.96 mmol). The mixture was stirred
at rt for 16h. The reaction mixture was quenched with a cold
sat. NH Cl solution and extracted with ethyl acetate (3 x 30
mL). The combined organic layers were dried over Na SO and
8
in MeOH (50 mL) was
2
H), 1.50 (d, J = 7.6 Hz, 2 H), 1.38 - 1.25 (m, 5 H), 0.92 - 0.87 (m,
1
H); C NMR (125MHz, CDCl
3
3
1
2
3
) δ = 138.5, 135.1, 128.4, 127.8,
27.7, 117.6, 81.7, 77.3, 76.7, 72.1, 71.4, 36.9, 32.0, 29.1, 25.2,
2.6, 14.0; HRMS (ESI) for C17H O (M + Na) found 285.1830,
26 2
4
+
2
4
concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel (EtOAc-pet ether, 2:98)
calcd 285.1825.
to afford compound
:
9
+0.24° (c 1.74, CHCl ); IR (neat, cm ): νmax 3566, 3460, O-((4R, 5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-yl)-N-
as yellow colour oil (2.4 g, 2 steps 82%).
27.7
−1
[α]
D
3
1
3
076, 2942, 2862, 1462, 1392, 1258, 1080; H NMR (400MHz, phenylhydroxylamine 12:
δ = 5.90 - 5.77 (m, 1 H), 5.12 - 5.01 (m, 2 H), 3.70 - 3.64
m, 1 H), 3.61 - 3.56 (m, 1 H), 2.35 - 2.26 (m, 1 H), 2.25 - 2.17
m, 1 H), 1.92 (br. s., 1 H), 1.45 - 1.39 (m, 2 H), 1.37 - 1.29 (m, 6
3
CDCl )
(
(
4
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Procedure as described in the preparation of 9. Yellow colour 135.0, 128.4, 127.8, 127.7, 117.3, 81.4, 72.3, 72.0, 38.1, 32.1,
2
D
5.8
+
liquid. Yield: 5.57 g, 97%. [α]
: +22.7° (c 1.7, CHCl
3 26 2
); IR (neat, 30.1, 24.8, 22.6, 14.0; HRMS (ESI) for C17H O (M + Na) found
−1
cm ) : ν
3296, 3074, 2942, 2861, 1641, 1601, 1463, 1421, 285.1831, calcd 285.1825.
max
1
1
372, 1252, 1081, 1010, 913, 835, 772, 728, 687; H NMR
500MHz, CDCl δ = 7.32 - 7.26 (m, 3 H), 7.02 - 6.94 (m, 3 H),
.90 (tdd, J = 7.2, 10.0, 17.1 Hz, 1 H), 5.15 - 5.06 (m, 2 H), 4.00
ddd, J = 2.1, 5.0, 7.2 Hz, 1 H), 3.87 - 3.82 (m, 1 H), 2.41 (td, J =
(
3
)
(
4S, 5R)-5-(Benzyloxy)dec-1-en-4-yl 4-nitrobenzoate 16:
5
(
7
-
.1, 14.3 Hz, 1 H), 2.34 - 2.27 (m, 1 H), 1.73 - 1.62 (m, 2 H), 1.56
1.44 (m, 2 H), 1.42 - 1.34 (m, 4 H), 0.98 - 0.93 (m, 12 H), 0.13
To a stirred solution of alcohol 15 (1.0 g, 3.8 mmol) in dry
toluene (15 mL) were added PPh (0.393 g, 15.2 mmol), p-
nitrobenzoic acid (PNBA) (0.143 g, 19.0 mmol) and
diisopropylazodicarboxylate (DIAD) (0.29 ml, 15.2 mmol) at 0
1
3
3
(s, 6 H); C NMR (125MHz, CDCl3) δ = 148.8, 135.7, 128.8,
121.6, 116.9, 114.3, 86.6, 74.0, 37.6, 32.0, 29.4, 26.2, 25.9,
+
39 2
22.6, 18.2, 14.1, -4.3, -4.4; HRMS (ESI) for C22H O N Si (M+H)
°
C and it was stirred for 2h at rt. Toluene was concentrated
found 378.2830, calcd 378.2823.
and directly transferred into silica gel column and it was
purified by silica gel column chromatography using (EtOAc-
petroleum ether, 3 : 97) as eluent to furnish 16 as a yellow
(4R, 5R)-4-((Tert-butyldimethylsilyl)oxy)dec-1-en-5-ol 13:
2
D
8.9
colour oil (1.5 g, 97%). [α]
: +9.13° (c 1.18, CHCl ); IR (neat,
3
−
1
cm ): νmax 3074, 3027, 2937, 2863, 1724, 1643, 1641, 1530,
1
Procedure as described in the preparation of
9
. Yellow colour 1456, 1348, 1275; H NMR (400MHz, CDCl
: -7.8° (c 1.61, CHCl
); IR (neat, J = 8.8 Hz, 2 H), 8.22 - 8.16 (m, J = 8.8 Hz, 2 H), 7.38 - 7.27 (m, 5
cm ): νmax 3568, 3460, 3076, 2942, 2862, 1463, 1392, 1255, H), 5.82 (tdd, J = 7.0, 10.0, 17.1 Hz, 1 H), 5.41 (td, J = 4.0, 8.4
3
) δ = 8.32 - 8.26 (m,
2
6.0
oil. 1Yield: 3.2 g, 85%. [α]
D
3
−
1
1
079; H NMR (500MHz, CDCl ) δ = 5.80 (tdd, J = 7.1, 10.1, 17.2 Hz, 1 H), 5.17 - 5.04 (m, 2 H), 4.70 (d, J = 11.5 Hz, 1 H), 4.55 (d,
3
Hz, 1 H), 5.12 - 5.05 (m, 2 H), 3.56 (td, J = 4.3, 7.0 Hz, 1 H), 3.47 J = 11.5 Hz, 1 H), 3.64 (td, J = 3.7, 7.8 Hz, 1 H), 2.66 - 2.56 (m, 1
3.43 (m, 1 H), 2.43 (td, J = 7.1, 14.1 Hz, 1 H), 2.25 - 2.18 (m, 1 H), 2.56 - 2.48 (m, 1 H), 1.73 - 1.48 (m, 4 H), 1.46 - 1.29 (m, 4
-
H), 1.91 (br. s., 1 H), 1.53 - 1.44 (m, 1 H), 1.43 - 1.39 (m, 2 H), H), 0.89 (t, J = 6.8 Hz, 3 H); C NMR (100MHz, CDCl
1
3
3
) δ = 164.2,
1
.37 - 1.28 (m, 5 H), 0.92 - 0.89 (m, 12 H), 0.10 (d, J = 7.3 Hz, 6 150.5, 138.2, 135.8, 133.6, 130.7, 128.4, 127.9, 127.7, 123.5,
H); C NMR (125MHz, CDCl
1
3
3
)
δ = 134.4, 117.4, 74.6, 72.4, 38.7, 118.1, 79.6, 75.7, 72.4, 34.2, 31.8, 30.5, 25.3, 22.5, 14.0; HRMS
+
N (M + Na) found 434.1949, calcd 434.1938.
3
3.9, 31.9, 25.9, 25.5, 22.6, 18.1, 14.1, -4.1, -4.7; HRMS (ESI) (ESI) for C24
for C16
H
29
O
5
+
Si (M + Na) found 309.2226, calcd 309.2220.
H
34
O
2
Conversion of nitrobenzoate 16 to alcohol fragment 11:
(((4R, 5R)-5-(Benzyloxy)dec-1-en-4-yl)oxy)(tert-
butyl)dimethylsilane 14:
To a stirred solution of p-nitro benzoate ester 16 (1.1 g, 2.6
2 2
mmol) in THF:MeOH:H O (3:2:1, 12 mL) was added LiOH.H O
Procedure as described in the preparation of 10. Colourless oil. (0.168 g, 4.0 mmol) and stirred at rt for 1h. After completing
2
D
7.6
−1
Yield: 3.4 g, 92 %. [α]
max 3074, 3029, 2941, 2862, 1462, 1370, 1319, 1253, 1208, quenched with water and extracted with EtOAc (3 x 10 ml).
: +22.3° (c 2.8, CHCl
3
); IR (neat, cm ): the starting material (monitored by TLC), reaction was
ν
1
1
094; H NMR (500MHz, CDCl ) δ = 7.37 - 7.28 (m, 5 H), 5.84 The combined organic layers were washed with brine, dried
tdd, J = 7.2, 10.0, 17.2 Hz, 1 H), 5.09 - 5.01 (m, 2 H), 4.62 (d, J = over Na SO and concentrated in vacuum. The crude was
2 4
3
(
1
1
3
1
1
1.9 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 3.81 (td, J = 3.9, 8.3 Hz, purified by column chromatography using an eluent (EtOAc-
H), 3.33 (ddd, J = 2.9, 4.4, 9.2 Hz, 1 H), 2.41 (dddd, J = 1.8, petroleum ether, 5:95) to give 11 as colourless oil (659 mg,
.4, 5.1, 14.0 Hz, 1 H), 2.17 - 2.10 (m, 1 H), 1.67 - 1.61 (m, 1 H), 95%).
.55 - 1.48 (m, 1 H), 1.42 (dtd, J = 4.6, 9.0, 13.5 Hz, 1 H), 1.34 -
1
3
.27 (m, 5 H), 0.89 (s, 12 H), 0.02 (s, 3 H), 0.04 (s, 3 H); C NMR
δ = 139.3, 136.7, 128.5, 128.1, 127.8, 116.7,
2.3, 77.3, 72.8, 72.6, 36.7, 32.2, 29.0, 26.3, 26.1, 22.9, 18.3,
Hex-5-enoic acid 17:
(
3
125MHz, CDCl )
8
1
3
+
4.3, -4.2, -4.2; HRMS (ESI) for C23
99.2699, calcd 399.2690.
40 2
H O Si (M + Na) found
To a stirred solution of cyclohexanone (20.0 g, 203.7 mmol) in
MeOH (20 mL), hydrogen peroxide (46 mL, 407.4 mmol) was
added slowly at rt. The mixture was then added to a stirred
solution of FeSO
51 g, 203.7 mmol) in water (370 mL), maintaining the reaction
temperature at 18-20 °C. The aqueous phase was separated
and extracted with Et O (3 x 40 mL). The combined Et
extracts were washed with 20% NaOH (3 x 20 mL). The alkaline
extract was acidified with 20% H SO to pH 2 and extracted
with Et O (3 x 40 mL), dried over Na SO and concentrated
4 2 4 2
.7H O (56.7 g, 203.7 mmol) and CuSO .5H O
(4R, 5R)-5-(Benzyloxy)dec-1-en-4-ol 15:
(
2
O
Procedure as described in the preparation of 11. Colourless oil.
2
2
D
8.8
−1
Yield: 1.3 g, 95%. [α]
νmax 3421, 3073, 3030, 2927, 2862, 1638, 1695, 1457, 1373,
3
: -18.6° (c 2.27, CHCl ); IR (neat, cm ):
2
4
1
080; H NMR (400MHz, CDCl
tdd, J = 7.0, 10.3, 16.9 Hz, 1 H), 5.16 - 5.07 (m, 2 H), 4.67 (d, J =
1
3
) δ = 7.38 - 7.29 (m, 5 H), 5.88
2
2
4
under reduced pressure. The crude residue was purified by
flash column chromatography (EtOAc–petroleum ether, 10:90)
to afford compound 17 as colourless oil (14.4 g, 62%). IR (neat,
(
1
1
1.2 Hz, 1 H), 4.52 (d, J = 11.2 Hz, 1 H), 3.65 (td, J = 4.8, 7.8 Hz,
H), 3.35 (q, J = 5.5 Hz, 1 H), 2.40 - 2.31 (m, 1 H), 2.30 - 2.21
−
1
1
cm ): νmax 3077, 2933, 2670, 1711, 1420, 1251, 1110; H NMR
(
(
m, 1 H), 2.16 (br. s., 1 H), 1.72 - 1.53 (m, 2 H), 1.43 - 1.28 (m, 6
1
3
200MHz, CDCl
3
)
δ = 5.95 - 5.67 (m, 1 H), 5.14 - 4.96 (m, 2 H),
3
H), 0.91 (t, J = 6.8 Hz, 3 H); C NMR (100MHz, CDCl ) δ = 138.4,
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C5RA10405J
ARTICLE
Journal Name
2.45 - 2.33 (m, 2 H), 2.13 (q, J = 7.1 Hz, 2 H), 1.75 (quin, J = 7.4 The combined organic layers were washed with water (3 x 5
Hz, 2 H).
mesylate.
2 4
mL), brine, dried over Na SO and concentrated to give crude
Benzyl hex-5-enoate 18:
To a mixture of K
g, 0.58 mmol) and (DHQ) PHAL (1.5 mg, 0.002 mmol, 1 mol%)
3 6 2 3
Fe(CN) (0.192 g, 0.580 mmol), K CO (0.081
2
To a stirred solution of compound 17 (4.0 g, 35.04 mmol), in
DMF (50 mL), K CO (12.1 g, 87.6 mmol) was added under
in t-BuOH–H O (1:1, 10 mL) at 0 °C was added osmium
tetroxide (95 ꢀL, 0.1 M solution in toluene, 5 mol%), followed
2
2
3
argon atmosphere at 0 °C. After 10 min stirring at 0 °C, BnBr
6.2 mL, 52.5 mmol) was added to the reaction mixture and
by methane sulfonamide (0.079 g, 0.83 mmol). After stirring
for 5 min at 0 °C, the crude mesylate (0.100 g, 0.19 mmol) was
added in one portion. The reaction mixture was stirred at 0 °C
for 24h and then quenched with solid sodium sulphite (286
mg, 1.48 mg/mmol). Stirring was continued for an additional
15 min and then the solution was extracted with EtOAc (3 × 10
mL). The combined extracts were washed with brine, dried
(
stirred for 2h at rt. After completion of reaction cold water
was added into the reaction mixture and extracted with EtOAc
(2 x 50 mL). The combined organic layers were dried over
Na SO and concentrated in vacuo. The crude product was
2
4
purified by flash column chromatography (EtOAc-petrolium
ether, 5:95) to yield compound 18 as colourless oil (6.8 g,
2 4
over Na SO and concentrated under reduced pressure to give
−
1
9
1
5
2
2
1
+
5%). IR (neat, cm ): νmax 3074, 2940, 1737, 1638, 1596, 1451,
the crude diol.
1
234, 1162, 1111; H NMR (200MHz, CDCl
H), 5.91 - 5.65 (m, 1 H), 5.13 (s, 2 H), 5.09 - 4.94 (m, 2 H),
.39 (t, J = 7.5 Hz, 2 H), 2.10 (q, J = 7.3 Hz, 2 H), 1.88 - 1.65 (m, The crude diol was refluxed in pyridine at 150 °C for 16h gave
3
) δ = 7.47 - 7.32 (m,
1
3
3
H); C NMR (50MHz , CDCl )
δ = 173.4, 137.6, 136.0, 128.5, the cyclized compound. After completion of the reaction 10%
28.2, 115.4, 66.1, 33.5, 33.0, 24.0; HRMS (ESI) for C13
H
16
O
2
(M CuSO
extracted with EtOAc. The combined organic layers were
washed with water (2 x 5 mL), brine, dried over Na SO and
concentrated to give crude cyclized compound. The crude
Benzyl (8S, 9R, E)-9-(benzyloxy)-8-hydroxytetradec-5-enoate material was purified by flash column chromatography
9:
(EtOAc–petroleum ether, 15:85) to give compound 20 as
4 2
.5H 0 solution was added to the reaction mixture and
+
Na) found 227.1047, calcd 227.1043.
2
4
1
2
D
4.8
colourless oil (59 mg, 80%). [α]
(neat, cm ): νmax 3441, 2928, 2861, 1733, 1455, 1249, 1161,
: +15.2° (c 1.49, CHCl ); IR
3
−1
To a stirred solution of 11 (600 mg, 2.28 mmol) in CH
mL) was added compound 18 (2.3 g, 11.44 mmol) and
2
Cl
2
(7.0
1
1
3
083; H NMR (400MHz, CDCl ) δ = 7.38 - 7.28 (m, 10 H), 5.13
(s, 2 H), 4.70 (d, J = 11.7 Hz, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.32
degassed for 15 min. Then Grubb’s II catalyst (290 mg, 15 mol
%) was added to the reaction mixture and stirred for 16h at rt.
(td, J = 6.2, 9.1 Hz, 1 H), 4.27 (t, J = 2.9 Hz, 1 H), 3.81 (dt, J =
2
1
3
1
3
.6, 6.5 Hz, 1 H), 3.34 - 3.28 (m, 1 H), 2.53 - 2.38 (m, 2 H), 2.05 -
.83 (m, 5 H), 1.83 - 1.57 (m, 6 H), 1.53 - 1.41 (m, 4 H), 0.88 (s,
After completion of reaction solvent was removed under
reduced pressure. The crude material was purified by flash
column chromatography (EtOAc–petroleum ether, 8:92) to
13
H); C NMR (100MHz, CDCl3) δ = 173.7, 139.0, 135.9, 128.5,
28.2, 127.9, 127.4, 82.1, 81.1, 79.3, 72.9, 72.7, 66.3, 37.5,
3.9, 32.0, 30.6, 28.4, 25.3, 22.6, 21.3, 14.0; HRMS (ESI) for
2
D
8.9
afford compound 19 as yellow colour oil (700 mg, 70%). [α]
−1
:
2
-1.11° (c 1.64, CHCl
861, 1734, 1598, 1454, 1378, 1219, 1155, 1083; H NMR
δ =7.42 - 7.28 (m, 10 H), 5.56 - 5.40 (m, 2 H),
3
); IR (neat, cm ): νmax 3456, 3030, 2930,
+
(M + Na) found 477.2621, calcd 477.2611.
C
28
H
38
O
5
1
(
400MHz, CDCl
3
)
5
3
2
2
.15 - 5.10 (m, 2 H), 4.64 - 4.53 (m, 2 H), 3.82 - 3.72 (m, 1 H),
.45 - 3.33 (m, 1 H), 2.41 - 2.34 (m, 2 H), 2.29 - 2.16 (m, 2 H),
.14 - 2.01 (m, 2 H), 1.92 - 1.84 (m, 1 H), 1.74 (quin, J = 7.5 Hz,
(
+)-Petromyroxol 1:
H), 1.68 - 1.57 (m, 1 H), 1.54 - 1.45 (m, 2 H), 1.36 - 1.28 (m, 5 To a stirred solution of 20 (14 mg, 0.03 mmol) in EtOH (3 mL)
1
3
H), 0.89 (t, J = 6.8 Hz, 3 H); C NMR (100MHz, CDCl
3
)
δ = 173.4, was added 10% w/w Pd/C (2 mg, 0.1 w/w) and the mixture
38.5, 136.0, 132.5, 131.4, 128.5, 128.4, 128.2, 127.8, 127.6, was stirred for 3h under H atmosphere. Then, the Pd/C was
27.4, 126.7, 81.7, 72.1, 71.6, 66.1, 35.6, 33.6, 32.0, 31.9, 29.1, filtered off and the solvent was evaporated under reduced
5.2, 24.5, 22.6, 14.0; HRMS (ESI) for C28
61.2672, calcd 461.2662.
1
1
2
4
2
+
38 4
H O
(M + Na) found pressure. The residue was purified by flash column
chromatography (MeOH:CH Cl
as a colourless liquid (8 mg, 95%). [α]
{
, 15:85) to afford compound
1
),
2
2
2
5.9
D
: +8.5° (c 0.64, CHCl
3
3
25
−1
(lit . [α] = +17° (c 0.36, CHCl )}; IR (neat, cm ): ν 3400,
D 3 max
1
Benzyl 3S,
hydroxytetrahydrofuran-2-yl)butanoate 20:
4-((2S,
5R)-5-((R)-1-(benzyloxy)hexyl)-3- 2935, 2861, 1710, 1408, 1248, 1072, 1065; H NMR (500MHz,
3
CDCl ) δ = 4.32 - 4.27 (dd, J = 3.5, 3.5, 1 H), 4.10 - 4.04 (ddd, J =
6
3
=
1
=
7
.4, 6.7, 8.9, 1 H), 3.82 - 3.77 (ddd, J = 2.4, 6.5, 6.5, 1 H), 3.43 -
.37 (ddd, J = 4.0, 6.4, 7.3, 1 H), 2.49 - 2.37 (m, 2 H), 2.04 (dd, J
6.6, 13.3 Hz, 1 H), 1.89 (ddd, J = 4.6, 9.1, 13.5 Hz, 1 H), 1.80 -
.63 (m, 4 H), 1.55 - 1.47 (m, 1 H), 1.44 - 1.28 (m, 7 H), 0.89 (t, J
13
3
6.9 Hz, 3 H). C NMR (125MHz, CDCl ) δ = 177.7, 82.4, 80.5,
To a stirred solution of compound 19 (72 mg, 0.164 mmol) in
dry CH Cl was added triethylamine (0.057 ml, 0.41 mmol),
2 2
followed by slow addition of mesyl chloride (0.018 ml, 0.246
mmol) at 0 °C, with further stirring for 15 min at the room
temperature. The reaction mixture was quenched with
addition of cold water at 0 °C. The two phases were separated
4.1, 73.3, 37.6, 33.5, 33.1, 31.8, 28.2, 25.2, 22.6, 21.2, 14.0;
+
HRMS (ESI) for C14
97.1672.
26 5
H O (M + Na) found 297.1678, calcd
2
2 2
and the aqueous phase was extracted with CH Cl (3 x 5 mL).
6
| J. Name., 2012, 00, 1-3
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Page 7 of 8
PleaseRd So Cn oA t da vd aj un s ct ems argins
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DOI: 10.1039/C5RA10405J
Journal Name
ARTICLE
Stephen and B. Siegfried, Angew. Chem. Int. Ed., 2003,
, 1900.
13 (a) J. A. Marshall and J. J. Sabatini, Org. Lett., 2005, 7,
Notes and references
4
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Address: CSIR-National Chemical Laboratory, Division of Organic
4819; (b) J. A. Marshall, G. Schaaf and A. Nolting, Org.
Lett., 2005, 7, 5331; (c) U. Nookaraju, E. Begari and P.
Chemistry, Dr. Homi Bhabha Road, Pune, 411008, India. Fax: +91 20
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Kumar, Org. Biomol. Chem., 2014, 12, 5973.
14 (a) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless,
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Jeong, H. L. Kwong, K. Morikawa and Z. M. Wang, J. Org.
Chem., 1992, 57, 2768.
E-mail: pk.tripathi@ncl.res.in
‡
Electronic Supplementary Information (ESI) available: Copies
1
13
of NMR spectra ( H & C) of all compounds. See DOI:
0.1039/c000000x/
1
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a) J. K. Rupprecht, Y. H. Hui and J. L. McLaughlin, J. Nat.
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Estornell and D. Cortes, Nat. Prod. Rep., 2005, 22, 269;
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Álvarez, Chem. Rev., 2013, 113, 4567.
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The enantioselectivity of compound
as 98% ee using chiral HPLC {Chiralcel OD-H (250mm x
6, 1637.
6
was determined
i
−1
4
=
.6 mm), PrOH/hexane (10:90), flow rate 1 mL min , λ
230 nm, t = 5.40 (major), t = 6.31 (minor)}. The
was determined as
8% ee using chiral HPLC {Chiralcel OD-H (250mm x 4.6
R
R
enantioselectivity of compound
7
9
i
−1
mm), PrOH/hexane (10:90), flow rate 1 mL min , λ =
30 nm, t = 6.32 (major), t = 7.35 (minor)}.
a) N. Momiyama and H. Yamamoto, J. Am. Chem. Soc.,
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R
R
1
0
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2
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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DOI: 10.1039/C5RA10405J
Total Synthesis of (+)-petromyroxol via tandem α-aminoxylation-allylation
and asymmetric dihydroxylation-S 2 cyclization approach†‡
N
U. Nookaraju and Pradeep Kumar*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008, India
Tandem Asymmetic
Tandem
Dihydroxylation-
SN2 cyclization
Aminoxylation
Allylation
OH
O
H
O
OH
OH
Cross metathesis
Heptanal
O
(+)-Petromyroxol