Enantioselective total synthesis of (S)-nakinadine B

Article abstract of DOI:10.1039/c6ra03915d

A novel approach for the synthesis of α-phenyl-β²-amino acid core unit 1 and its application to the total synthesis of (S)-nakinadine B 3, a marine natural product, is described. The synthesis utilizes the optimized combination of diphenylprolinol silyl ether mediated asymmetric Michael addition and a proline catalyzed aminoxylation reactions as key steps.

Full text of DOI:10.1039/c6ra03915d

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‡
Enantioselective total synthesis of (S)-nakinadine B
Yuvraj Garg and Satyendra Kumar Pandey*
Received 00th February 20xx,
Accepted 00th February 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
2
2
A novel approach for the synthesis of an α-phenyl-β -amino acid activities. The nakinadine alkaloids possess an α-phenyl-β-
core unit 1 and its application to the total synthesis of (S)- amino acid moiety with a long chain N-alkyl substituent
nakinadine B 3, a marine natural product is described. The capped by a terminal 3-pyridyl moiety. The nakinadine B
3
and
which is
) having an α-
. The nakinadine A-C (
2
synthesis utilizes the optimized combination of diphenylprolinol
silyl ether mediated asymmetric Michael addition and proline different from the nakinadines A
C
4
possess an α-phenyl-β -amino acid core unit
and D−F (
1
5
6-8
2
,3
catalyzed aminoxylation reactions as key steps.
phenyl-β -amino acid core unit
2
3-5)
alkaloids have been shown to possess significant cytotoxicity
against a variety of tumour cell lines including L1210 murine
leukaemia and KB human epidermoid carcinoma cells.
1
Introduction
The absolute configuration of (S)-nakinadine B
3 was
determined by Kobayashi and co-workers with the help of 2D
NMR spectroscopic studies. The paucity of the material in
Over the recent years, marine sponges have been recognized
as a rich source of bioactive natural products with fascinating
chemical structures. The nakinadine A-F (3-8) alkaloids were
isolation has hampered further studies of the biochemistry of
1
nakinadine A-F
(
3
-
8
). Therefore, in order to achieve
recently isolated from an Okinawan marine sponge
1
nakinadine alkaloids in larger quantities for further biological
evaluation, it is highly desirable to develop a general,
convergent and enantiopure synthetic approach which
Amphimedon sp. (SS-1059) (Fig. 1). Metabolites from an
Okinawan marine sponge family illicit a myriad of biological
activities that includes antimicrobial, cardiotonic, cytotoxic and
antitumor
involves stable intermediates. The nakinadine A-F (3-8) have
been synthetic targets of considerable interest due to its high
3
HO
O
cytotoxic activity and with an array of functionalities. More
N
R1 =
H
N
2
12
recently, Davies and co-workers reported the first asymmetric
R1
nakinadine B 3
synthesis of the (S)-nakinadine B
3 in nine steps employing
N
=
1
R1
conjugate addition of lithium dibenzylamide to an N-α-
phenylacryloyl SuperQuat derivative with in situ
9
nakinadine C 4
3
b
diastereoselective enolate protonation as the key step. As
part of our research on the asymmetric synthesis of bioactive
HO
O
3
H
N
R2 =
R3 =
N
4
2
compounds, we wish to report herein, a new, general and
1
2
R2
N
highly efficient synthetic approach for enantiopure α-phenyl-
2 R3
8
2
β -amino acid core unit
1
and its application to the total
employing diphenylprolinol silyl
nakinadine A 5
synthesis of (S)-nakinadine B
3
nakinadine D 6 R2 = R3, m = 12
ether mediated asymmetric Michael addition and proline
catalyzed aminoxylation reactions as key steps.
N
nakinadine E 7 R2, m = 13; R3, m = 12
nakinadine F 8 R2, n = 9
m
N
R3, n = 8
n
Results and discussion
Fig. 1 Structures of nakinadine A-F alkaloids
2
Our synthetic approach for the synthesis of α-phenyl-β -amino
acid core unit
1
and (S)-nakinadine B
3
was envisioned via the
was
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India.
Phone: +91-175-239-3832, Fax: +91-175-236-4498 E-mail: skpandey@thapar.edu
Dedicated to Prof. Bhisma K. Patel in recognition of his seminal contributions
retrosynthetic route as shown in Scheme 1. The diol
visualized as a synthetic intermediate from which α-phenyl-β -
9
2
‡
to so many aspects of organic chemistry.
1
13
†
Electronic Supplementary Information (ESI) available: Copies of H and C NMR
spectra of compounds 3, 11 and 13-17. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C6RA03915D
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1
0
conditions,
subsequent treatment of aldehyde with
Reductive
alkylation
nitrosobenzene in the presence of catalytic amount of L-
proline (20 mol %) in DMSO at room temperature furnished α-
OH Aminoxylation
OH
HO
O
HO
aminoxylated aldehyde, which on spontaneous reduction with
H
N
Boc
N
R1
Boc
N
R1
NaBH
afforded the diol 17 as a single diastereomer in 61% yield.
The diol 17 on smooth oxidative cleavage in the presence of
4 4 2
and cleavage of phenylamine moiety with CuSO .5H O
R1
1
1
Michael
addition
1
9
1
0
1
2
13
NaIO
4
followed by oxidation with oxone and finally
OH
deprotection of N-Boc with TFA furnished the sponge
NO2
NO2
25
metabolite (S)-nakinadine B
3
in 81% yield {[α]
-6.3 (c 1, CHCl )]}. The physical and
spectroscopic data of (S)-nakinadine B
D
-6.4 (c 1,
3
20
CHCl
3
) [Lit. [α]
D
3
1
1
12
3
were found in full
1
,3
agreement with those reported in the literature.
Scheme
synthesis of α-phenyl-β -amino acid core unit
nakinadine B
1. Retrosynthetic approach for the asymmetric
OH
OTBS
NO2
2
1
and (S)-
NO2
NO 2
3
.
a
b
c
1
OH
3
amino acid core unit
cleavage followed by oxidation of the intermediate aldehyde.
The diol in turn could be synthesized from alcohol derivative
through proline catalyzed α-aminoxylation of aldehyde
1
could be synthesized by oxidative
12
11
OTBS
9
Boc
N
Boc
1
0
N
d
12
e
12
derived from 10 followed by standard organic transformations.
The alcohol 10 could be obtained from nitroalcohol derivative
1
5
N
N
16
1
1 by employing hydrogenation to get amine intermediate
OH
followed by reductive N-alkylation. The key intermediate
nitroalcohol 11 could be easily prepared from commercially
available nitrostyrene 12 via diphenylprolinol silyl ether
HO
O
OH
Boc
N
H
N
12
f
12
mediated asymmetric Michael addition with acetaldehyde. The
1
7
N
3
N
2
(
S)- and (R)- configuration of α-phenyl-β -amino acid core unit
1
could be manipulated by simply changing the (S)- and (R)- Scheme 2. Reagents and conditions: (a) i) Acetaldehyde, (S)-
o
configuration of the catalyst diphenylprolinol silyl ether during diphenylprolinol silyl ether, 1,4-dioxane, 4 C to rt, 18 h, ii)
asymmetric Michael addition step.
As outlined in Scheme 2, the synthesis of (S)-nakinadine B
commenced with commercially available nitrostyrene 12
o
NaBH
imidazole, dry CH
(20%), CH OH, rt, 6 h, ii) Ar(CH
4 3
, CH OH, 0 C, 15 min, 75% (over two steps) (b) TBSCl,
o
3
,
2
Cl
2
, 0 C to rt, 6 h, 95% (c) i) H
12CHO 14, Na(CN)BH
OH, 0 C to rt, 48 h, iii) (Boc) O, NaH, DMAP, dry DMF, 0 C
to rt, 12 h, 82% (over three steps) (d) TBAF, THF, rt, 6 h, 96%
2
, Pd(OH)
2
/C
3
2
)
3
, Na SO
2
4
,
o
o
which can be easily synthesized from base catalyzed5
C
2
H
5
2
condensation of benzaldehyde with nitromethane.
o
Asymmetric Michael addition of acetaldehyde with (e) i) (COCl)
2
,
DMSO, Et
3 2 2
N, CH Cl , -78 C, 3 h, ii)
nitrostyrene 12 in the presence of catalytic amount of (S)- Nitrosobenzene,
L
-proline, DMSO, rt, 30 min, iii) NaBH ,
4
6
o
o
diphenylprolinol silyl ether in a sealed tube afforded the CH
nitroaldehyde adduct, which on subsequent reduction with 61% (over four steps) (f) i) NaIO
3
OH, 0 C, 15 min, iv) CuSO
4
.5H
, dioxane:water 3:1 v/v, rt, 3
Cl , rt, 12 h, 81% (over
2 3
O, CH OH, 0 C to rt, 12 h,
7
4
NaBH
with 96% ee {[α]
CH Cl )]}. With enantiomerically pure nitroalcohol 11 in hand,
4
delivered the nitroalcohol derivative 11 in 75% yield h, ii) Oxone, DMF, rt, 12 h, iii) TFA, CH
2
2
2
5
8
25
D
-13.8 (c 0.5, CH
2
Cl
2
) [Lit. [α]
D
-13.7 (c 0.5, three steps).
2
2
we then performed base catalyzed silyl ether protection of
free alcohol which afforded the TBS protected derivative 13 in
Conclusions
9
5% yield. Our next aim was to carry out N-alkylation at
In conclusion, we have described an expeditious approach for
2
terminal nitro group site. To this end, compound (S)-13 was
subjected to hydrogenation in the presence of catalytic
amount of Pd(OH)
Reductive N-alkylation of the synthesized amine intermediate
the synthesis of α-phenyl-β -amino acid core unit
1 and its
application to the total synthesis of (S)-nakinadine B
3
2
to afford the terminal amine intermediate.
employing diphenylprolinol silyl ether mediated asymmetric
Michael addition and proline catalyzed aminoxylation
9
with 13-(pyridin-3-yl)tridecanal 14 using Na(CN)BH
the N-alkylated amine intermediate which on subsequent
protection with (Boc) O in the presence of NaH and catalytic
amount of DMAP furnished the Boc protected derivative 15 in
2% yield. The cleavage of silyl ether in compound (S)-15 with
3
afforded
reactions as key steps. The overall yield for (S)-nakinadine B
3
was 28% after six column chromatography steps. Moreover,
the synthetic strategy described has significant potential for
stereochemical variation of substituents at the 2-aryl and N-
alkyl sites to synthesize other analogues of nakinadine
alkaloids. Currently, the work is in progress, and the results will
be disclosed in due course.
2
8
TBAF afforded the alcohol derivative 16 quantitatively.
Oxidation of alcohol (S)-16 to aldehyde under Swern
2
| RSC Adv., 2016, 00, 1-3
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-
1 1
2
7
3
932, 2402, 1552, 1362, 735 cm ; H NMR (400 MHz, CDCl ) δ:
Experimental
.20-7.36 (m, 5H), 4.58-4.72 (m, 2H), 3.68-3.74 (m, 1H), 3.56-
All reactions were carried out under argon or nitrogen in oven-
dried glassware using standard glass syringes and septa. The
solvents and chemicals were purchased from Merck and Sigma
Aldrich chemical company. Solvents and reagents were
purified and dried by standard methods prior to use. Progress
of the reactions was monitored by TLC using precoated
aluminium plates of Merck kieselgel 60 F254. Column
chromatography was performed on silica gel (60-120 and 100-
3
.61 (m, 1H), 3.42-3.47 (m, 1H), 1.83-1.97 (m, 2H), 0.89 (s, 9H),
13
0.009 (s, 6H); C NMR (100 MHz, CDCl
3
) δ: 139.1, 128.8, 127.6,
+
80.6, 59.9, 41.1, 35.8, 25.8, 18.1, -5.5; HRMS (ESI ) m/z calcd
+
+
3
for C16H28NO Si ([M + H] ) 310.1833; Found 310.1833.
1
3-(Pyridin-3-yl)tridecanal, 14
To a solution of oxalyl chloride (685 mg, 460 µL, 5.4 mmol) in
dry CH Cl (10 mL) at -78 °C was added dropwise DMSO (870
mg, 790 µL, 11.2 mmol) in CH Cl (10 mL) over 15 min. The
reaction mixture was stirred for 30 min and a solution of 13-
2
2
2
2
200 mesh) using a mixture of n-hexane/ethyl acetate and
Dichloromethane/MeOH. Optical rotations were measured on
9
(
pyridin-3-yl)tridecan-1-ol (1.0 g, 3.6 mmol) in CH
was added dropwise over 15 min. The reaction mixture was
stirred for 30 min at same temperature, then added Et N (1.6
g, 2.2 mL, 15.84 mmol) in CH Cl (10 mL) dropwise and stirred
for 3 h. The reaction mixture was diluted with water (20 mL),
organic layer separated, extracted with CH Cl (3 x 20 mL)
washed with brine, dried over anhydrous Na SO and
2 2
Cl (10 mL)
1
13
automatic polarimeter AA-65. H and C NMR spectra were
recorded in CDCl (unless otherwise mentioned) on JEOL ECS
3
3
operating at 400 and 100 MHz, respectively. Chemical shifts
are reported in δ (ppm), referenced to TMS. HRMS were
recorded on Agilent 6530 Accurate-Mass Q-TOF using Electron
Spray Ionization. IR spectra were recorded on Agilent
resolution Pro 600 FT-IR spectrometer, fitted with a beam-
condensing ATR accessory.
2
2
2
2
2
4
concentrated under reduced pressure. Purification by silica gel
column chromatography (EtOAc/hexane 1:1 v/v) as eluent
afforded aldehyde derivative 14 (940 mg, 95%) as pale yellow
(
S
)-4-Nitro-3-phenylbutan-1-ol, 11
To 1,4-dioxane (2.0 mL)
diphenyltrimethylsiloxymethyl pyrrolidine (265 mg, 0.81 mmol,
0 mol %) and nitrostyrene 12 (1.2 g, 8.05 mmol) was added
a
solution
of
(S)-
1
oil. H NMR (400 MHz, CDCl
3
) δ: 9.76 (t, J = 1.84 Hz, 1H), 8.42-
8
7
1
1
2
.43 (m, 2H), 7.48-7.50 (m, 1H), 7.19-7.22 (m, 1H), 2.60 (t, J =
.32 Hz, 2H), 2.42 (td, J = 1.80, 7.76 Hz, 2H), 1.59-1.64 (m, 4H),
.25-1.30 (m, 16H); C NMR (100 MHz, CDCl ) δ: 203.0, 149.7,
3
46.9, 137.9, 135.8, 123.2, 43.8, 32.9, 31.1, 29.5, 29.4, 29.4,
9.3, 29.2, 29.0, 22.0.
1
o
acetaldehyde (4.5 mL, 80.5 mmol) in a sealed tube at 4 C. The
reaction mixture was stirred at room temperature for 18 h and
then quenched with 1N HCl (10 mL). The aqueous phase was
extracted with EtOAc (3 x 20 mL) washed with brine, dried
13
(S
)-tert-Butyl-4-(tert-butyldimethylsilyloxy)-2-phenylbutyl(13-
2 4
over anhydrous Na SO , concentrated in vacuo, and used as
such for the next step without further purification.
(pyridin-3-yl)tridecyl) carbamate, 15
To a solution of compound 13 (750 mg, 2.42 mmol) in MeOH
12 mL) was added catalytic amount of 20% Pd(OH) /C. The
To the above crude product were added MeOH (20 mL), NaBH
4
(
2
(
460 mg, 12.1 mmol) and the reaction mixture stirred for 15
reaction mixture was then subjected to hydrogenation under 1
atmospheric pressure for 6 h. After this time, the reaction
mixture was filtered through a pad of Celite and washed with
additional MeOH (30 mL). The resulting organic layer was
concentrated in vacuo, which was used as such for the next
step without further purification.
Pyridyl aldehyde 14 (665 mg, 2.42 mmol) in ethanol (10 mL)
was added to the above synthesized TBS-protected amine
intermediate in ethanol (10 mL) followed by addition of
o
min at 0 C. The reaction was quenched with saturated
aqueous NH Cl solution, extracted with ethyl acetate (3 x 20
mL), dried over anhydrous Na SO , concentrated in vacuo and
purified by silica gel column chromatography (EtOAc/hexanes
:7 v/v) as eluent to afford the nitro alcohol 11 (1.18 g, 75%).
4
2
4
3
2
5
8
{
(
[α]
CH
D
-13.8 (c 0.5, CH
) ν: 3378, 2940, 2415, 1549, 1379, 1265, 733 cm ; H
) δ: 7.23-7.34 (m, 5H), 4.61-4.65 (m, 2H),
.66-3.74 (m, 1H), 3.59-3.64 (m, 1H), 3.46-3.52 (m, 1H), 1.87-
2 2 2 2
Cl ) [Lit. -13.7 (c 0.5, CH Cl )]}; IR
-
1 1
2 2
Cl
NMR (400 MHz, CDCl
3
3
o
anhydrous Na
2
SO
4
(2.1 g, 14.6 mmol) at 0 C. The reaction
1
3
2.04 (m, 2H), 1.66 (s, 1H); C NMR (100 MHz, CDCl
3
) δ: 138.7,
mixture was then stirred at room temperature for 36 h. After
this time, Na(CN)BH (305 mg, 4.84 mmol) was added to the
+
129.0, 127.7, 127.5, 80.6, 59.8, 41.0, 35.5; HRMS (ESI ) m/z
+
+
3
calcd for C10
H
13NO
3
Na ([M + Na] ) 218.0787; Found 218.0784.
o
reaction mixture at 0 C and the reaction mixture was stirred
at room temperature for additional 12 h. The ethanol from the
reaction mixture was evaporated in vacuo. The reaction
mixture was then diluted with water and the aqueous phase
was extracted with EtOAc (3 x 20 mL). The combined organic
phase was dried over anhydrous Na SO , concentrated in
2 4
vacuo, and used as such for the next step without further
purification.
(
S
)-tert-Butyldimethyl(4-nitro-3-phenylbutoxy)silane, 13
To a solution of nitro alcohol 11 (1.0 g, 5.13 mmol) in CH
20 mL) was added imidazole (525 mg, 7.7 mmol) followed by
2
Cl
2
(
o
tert-butyldimethylsilyl chloride (940 mg, 6.2 mmol) at 0 C. The
reaction was then stirred under N for 6 h at room
temperature, after which it was quenched by adding saturated
aqueous NH Cl (20 mL) solution. The aqueous layer was
extracted with CH Cl (3 x 20 mL), organic layer separated,
washed with brine, dried over anhydrous Na SO and
2
4
2
2
NaH (87 mg, 3.63 mmol) was added to the solution of above
coupled amine derivative in 20 mL of dry DMF at 0 °C. After
the solution was stirred for 10 min, di-tert-butyl dicarbonate
2
4
concentrated under reduced pressure. Purification by silica gel
column chromatography (EtOAc/hexane 1:9 v/v) as eluent
furnished TBS protected derivative 13 (1.5 g, 95%) as pale
(790 mg, 3.63 mmol) and DMAP (150 mg, 1.2 mmol) were
added at the same temperature. The reaction mixture was
stirred at room temperature for 12 h. After completion of the
2
5
yellow oil. [α]
D
2 2 2 2
-71.2 (c 1, CH Cl ); IR (CH Cl ) ν: 3012, 2945,
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reaction as monitored by TLC, the reaction was quenched with To a DMSO solution (5 mL) of
RSC Advances
L
-proline (12 mg, 0.104 mmol, 20
water and extracted with diethyl ether (3 x 20 mL). The organic mol %) was added above synthesized aldehyde and
extract was washed with brine, dried over anhydrous Na SO nitrosobenzene (62 mg, 0.572 mmol) successively at room
and concentrated under reduced pressure. Purification of the temperature. After stirring the reaction mixture for 30 min,
crude product by silica gel column chromatography MeOH (5 mL) and NaBH (30 mg, 0.78 mmol) were added and
2
4
4
o
(
(
(
(
7
(
EtOAc/hexane 1:9 v/v) as eluent furnished the compound 15 the reaction mixture was stirred for 15 min at 0 C. The
2
5
1.27 g, 82%) as yellow oil. [α]
CH Cl ) ν: 3075, 2982, 2431, 1567, 1383, 775 cm ; H NMR NH
400 MHz, CDCl ) δ: 8.45-8.47 (m, 2H), 7.51-7.54 (dt, J = 1.84, over anhydrous Na
.76 Hz, 1H), 7.29-7.33 (m, 3H), 7.17-7.25 (m, 3H), 3.39-3.64 residue thus obtained above was dissolved in MeOH (5 mL)
m, 3H), 3.02-3.30 (m, 3H), 2.85-2.91 (m, 1H), 2.63 (t, J = 8.28 and subjected to treatment with CuSO .5H O (33 mg, 0.13
Hz, 2H), 1.84-1.96 (m, 4H), 1.61-1.68 (m, 2H), 1.44 (s, 9H), mmol) at 0 C and stirred at room temperature for 12 h. After
D
-45.2 (c 0.8, CH
2
Cl
2
); IR reaction mixture was then quenched with saturated aqueous
Cl solution, extracted with ethyl acetate (3 x 10 mL), dried
SO , and concentrated in vacuo. The
-
1 1
2
2
4
3
2
4
4
2
o
1
3
1
.19-1.34 (m, 18H), 0.89 (s, 9H), -0.01 (s, 6H); C NMR (100 completion of reaction as monitored by TLC, it was quenched
MHz, CDCl ) δ: 149.8, 147.0, 142.6, 137.9, 135.7, 128.3, 128.2, with saturated aqueous NH Cl solution. The organic layer was
28.0, 126.4, 123.2, 79.0, 60.9, 60.7, 53.4, 52.7, 47.3, 41.3, separated and the aqueous phase extracted with EtOAc (3 x 10
3
4
1
4
2
(
(
0.7, 35.8, 32.9, 31.1, 29.5, 29.5, 29.3, 29.1, 28.3, 28.1, 27.7, mL). The combined organic phase was dried over anhydrous
+
+
6.8, 25.8, 18.2, -5.4; HRMS (ESI ) m/z calcd for C39
[M + H] ) 639.4916; Found 639.4921.
H
67
N
2
O
3
Si
Na
2 4
SO , concentrated in vacuo, and purified by silica gel
column chromatography (EtOAc/hexanes 7:3 v/v) as eluent to
)-tert-Butyl-4-hydroxy-2-phenylbutyl(13-(pyridin-3-yl)tridec afford the diol 17 (170 mg, 61%). [α]
IR (CH Cl ) ν: 3369, 2942, 2855, 1467, 1312, 920 cm ; H NMR
To a solution of compound 15 (1.0 g, 1.56 mmol) in THF (10 (400 MHz, CDCl ) δ: 8.43 (m, 2H), 7.48-7.50 (m, 1H), 7.22-7.31
+
2
5
S
D
2 2
-42.2 (c 1.02, CH Cl );
-
1 1
yl)carbamate, 16
2
2
3
mL) was added TBAF solution (3.12 mL, 1.0 M in THF, 3.12 (m, 6H), 4.18-4.24 (m, 1H), 3.87 (bs, 1H), 3.20-3.48 (m, 3H),
mmol) dropwise via syringe. The reaction mixture was stirred 2.77-2.98 (m, 3H), 2.59 (t, J = 7.7 Hz, 2H), 1.59-1.61 (m, 4H),
1
3
for 6 h at room temperature, after which the reaction mixture 1.48 (s, 9H), 1.25-1.29 (m, 18H); C NMR (100 MHz, CDCl
was quenched with saturated aqueous NH Cl solution (15 mL) 157.5, 149.7, 146.9, 138.8, 135.9, 129.0, 128.3, 127.0, 80.5,
and extracted with ethyl acetate (2 x 20 mL). The combined 70.4, 65.1, 49.0, 47.6, 46.7, 32.9, 31.1, 29.6, 29.5, 29.5, 29.3,
3
) δ:
4
+
2 4
organic fractions were dried over anhydrous Na SO and 29.2, 29.1, 28.3, 26.8, 14.1; HRMS (ESI ) m/z calcd for
+
+
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane
C
33
H
53
N
2
O
4
([M + H] ) 541.4000; Found 541.4012.
(S)-Nakinadine B, 3
4
:6 v/v) as eluent to give the alcohol derivative 16 (770 mg, To a solution of diol 17 (100 mg, 0.185 mmol) in dioxane-water
25
9
6%) as pale yellow oil. [α]
D
-55.8 (c 0.5, CH
2
Cl
2
); IR (CH
2
Cl
2
)
)
(3:1, 2 mL) was added NaIO
4
(80 mg, 0.37 mmol). The reaction
was stirred at 25 C for 3 h. After completion of reaction, water
Cl (10 mL) were added. The organic layer was
.31 (m, 2H), 7.18-7.24 (m, 4H), 3.48-3.72 (m, 3H), 2.86-3.25 separated, and the water layer extracted with CH Cl (3 x 10
m, 4H), 2.59 (t, J = 7.76 Hz, 2H), 1.81-1.88 (m, 5H), 1.57-1.64 mL). The combined organic layer was washed with brine and
-
1
1
o
ν: 3362, 2961, 1589, 1269, 732 cm ; H NMR (400 MHz, CDCl
δ: 8.40-8.42 (m, 2H), 7.48-7.50 (dt, J = 1.40, 7.32 Hz, 1H), 7.27- (5 mL) and CH
7
3
2
2
2
2
(
(
1
3
m, 2H), 1.42 (s, 9H), 1.22-1.30 (m, 18H); C NMR (100 MHz, dried over anhydrous Na
) δ: 149.6, 146.8, 138.0, 135.9, 128.4, 127.8, 126.5, 123.2, crude aldehyde which was used as such for the next step
9.2, 60.6, 52.8, 47.8, 41.3, 35.7, 32.9, 31.0, 29.6, 29.5, 29.4, without further purification.
2 4
SO , concentrated in vacuo to give
CDCl
7
3
+
29.4, 29.3, 29.0, 28.3, 28.1, 26.7, 22.6, 14.0; HRMS (ESI ) m/z The above aldehyde was dissolved in DMF followed by
+
+
calcd for C33
H
53
N
O
2 3
([M + H] ) 525.4051; Found 525.4056.
)-3,4-dihydroxy-2-phenylbutyl(13-(pyridin-3-
yl)tridecyl)carbamate, 17
addition of oxone (57 mg, 0.185 mmol) and stirred at room
temperature for 12 h. The resulting solution was diluted with
water, filtered through a Celite pad, washed and extracted
tert-Butyl(2S,3R
To a solution of oxalyl chloride (100 mg, 68 µL, 0.78 mmol) in with diethyl ether (3 x 10 mL). The organic extract was washed
dry CH Cl (5 mL) at -78 °C was added dropwise DMSO (125 with brine, dried over anhydrous Na SO , and the solvent was
mg, 115 µL, 1.6 mmol) in CH Cl (5 mL) over 15 min. The removed in vacuo to obtain the crude product which was used
reaction mixture was stirred for 30 min and a solution of for the next step without further purification.
alcohol 16 (270 mg, 0.52 mmol) in CH Cl (5 mL) was added To the above acid product in CH Cl (2 mL) was added
dropwise over 15 min. The reaction mixture was stirred for 30 trifluoroacetic acid (2 mL) and the reaction mixture was stirred
min, then Et N (230 mg, 320 µL, 2.3 mmol) in CH Cl (5 mL) at room temperature for 12 h. The reaction was quenched
was added dropwise and stirred for 3 h. The reaction mixture with saturated aqueous NaHCO and extracted with
was diluted with water and the organic layer separated. The dichloromethane (3 x 5 mL). The combined organic layers were
aqueous layer was extracted with CH Cl (3 x 10 mL) and the washed with brine, dried over anhydrous Na SO and
combined organic layer was washed with brine, dried over concentrated under reduced pressure to near dryness. The
anhydrous Na SO and concentrated in vacuo to give the crude crude product was purified by silica gel column
aldehyde, which was used in the next step without further chromatography using (CH OH/CH Cl 1:9 v/v) as eluent to give
purification. title compound (63 mg, 81%) as a white solid compound. mp
2
2
2
4
2
2
2
2
2
2
3
2
2
3
2
2
2
4
2
4
3
2
2
3
2
5
3
120-122 °C; {[α]
D
3 3
-6.4 (c 1, CHCl ) [Lit. -6.3 (c 1, CHCl )]}; IR
4
| RSC Adv., 2016, 00, 1-3
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DOI: 10.1039/C6RA03915D
RSC Advances
COMMUNICATION
-
1 1
by Swern oxidation; see: (a) B. J. Shorey, V. Lee and J. E.
Baldwin, Tetrahedron, 2007, 63, 5587.
(
CH
2
Cl
2
) ν: 3032, 2925, 2853, 1652, 1562 cm ; H NMR (400
) δ: 8.41-8.42 (m, 2H), 7.47-7.49 (m, 1H), 7.12-7.34
m, 6H), 3.99 (m, 1H), 3.38-3.48 (m, 1H), 2.78-2.87 (m, 3H),
MHz, CDCl
(
2
1
1
3
3
1
0 (a) T. T. Tidwell, Synthesis, 1990, 10, 857; (b) T. T. Tidwell,
Org. React., 1990, 39, 297.
.57-2.61 (t, J = 7.56 Hz, 2H), 1.57-1.67 (m, 4H), 1.20-1.29 (m,
1
1 The diastereoselectivity of compound 17 was determined by
1
3
1
13
8H); C NMR (100 MHz, CDCl
3
) δ: 173.2, 149.8, 147.0, 138.0,
37.8, 135.8, 128.7, 128.1, 127.2, 123.2, 52.3, 51.1, 47.8, 32.9,
1.1, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.1, 29.1, 26.7, 25.7;
H-NMR and C-NMR spectroscopy. For aminoxylation
reactions see: (a) Y. Hayashi, J. Yamaguchi, T. Sumiya, K.
Hibino and M. Shoji, J. Org. Chem., 2004, 69, 5966; (b) A.
Cordova, H. Sunden, A. Bogevig, M. Johansson and F. Himo,
Chem. Eur. J., 2004, 10, 3673; (c) L. Yang, R. Liu, B. Wang, L.
Weng and H. Zheng, Tetrahedron Lett., 2009, 50, 2628.
+
+
+
HRMS (ESI ) m/z calcd for C27
Found 425.3163.
41 2 2
H N O ([M + H] ) 425.3163;
1
2 (a) W. Yu, Y. Mei, Y. Kang, Z. Hua and Z. Jin, Org. Lett., 2004,
6, 3217.
Acknowledgements
13 (a) R. T. Benjamin, S. Meenakshi, G. O. Hollist and B. Borhan,
Org. Lett., 2003, , 1031.
5
Y.G. thanks UGC, New Delhi for a senior research fellowship.
S.K.P. is thankful to Department of Science and Technology,
New Delhi, for generous funding of the project (Grant No.
SB/FT/CS-178/2011). We are grateful to Prof. Prakash Gopalan
for his support and encouragement.
Notes and references
1
(a) T. Kubota, T. Nishi, E. Fukushi, J. Kawabata, J. Fromont
and J. Kobayashi, Tetrahedron Lett., 2007, 48, 4983; (b) T.
Nishi, T. Kubota, J. Fromont, T. Sasaki and J. Kobayashi,
Tetrahedron, 2008, 64, 3127.
2
(a) D. M. Roll, P. J. Scheuer, G. K. Matsumot and J. Clardy, J.
Am. chem. Soc., 1983, 105, 6177; (b) H. Nakamura, J.
Kobayashi, M. Kobayashi, Y. Ohizumi and Y. Hirata, Chem.
Lett., 1985, 14, 713; (c) F. J. Schmitz and S. J. Bloor, J. Org.
Chem., 1988, 53, 3922; (d) I. Shin and M. J. Krische, Org.
Lett., 2015, 17, 4786; (e) D. B. Abdjul, H. Yamazaki, S. Kanno,
O. Takahashi, R. Kirikoshi, K. Ukai and M. Namikoshi, J. Nat.
Prod., 2015, 78, 1428; (f) J. Uenishi, T. Iwamoto and J.
Tanaka, Org. Lett., 2009, 11, 3262; (g) Y. Takahashi, T.
Kubota, J. Fromont and J. Kobayashi, Org. Lett., 2009, 11, 21.
3
4
For synthesis of nakinadine-A 5, see: (a) S. G. Davies, A. M.
Fletcher, P. M. Roberts, R. S. Shah, A. L. Thompson and J. E.
Thomson, Org. Lett., 2014, 16, 1354; For synthesis of
nakinadine-B 3, see: b) S. G. Davies, J. A. Lee, P. M. Roberts,
R. S. Shah and J. E. Thomson, Chem. Commun., 2012, 48
236; For synthesis of nakinadine-C , see: c) S. G. Davies, P.
M. Roberts, R. S. Shah and J. E. Thomson, Tetrahedron Lett.,
,
9
4
2
013, 54, 6423; For synthesis of nakinadine-D-F 6-8, see: d)
S. G. Davies, A. M. Fletcher, R. S. Shah, P. M. Roberts and J. E.
Thomson, J. Org. Chem., 2015, 80, 4017.
(a) Y. Garg and S. K. Pandey, J. Org. Chem., 2015, 80, 4201;
(
b) Y. Garg, S. Gahalawat and S. K. Pandey, RSC Adv., 2015,
5
5
,
,
3
8846; (c) S. Gahalawat and S. K. Pandey, RSC Adv., 2015,
4
1013; (d) S. Gahalawat, Y. Garg and S. K. Pandey, Asian J.
Org. Chem., 2015,
4
, 1025.
5
6
(a) D. E. Worrall, Org. Synth., 1929, 9, 66.
(S)-diphenylprolinol silyl ether was prepared from (S)-
diphenylprolinol and TMSCl using a known procedure; see:
(
a) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew.
Chem. Int. Ed., 2005, 44, 4212.
7
(a) P. Garcia-Garcia, A. Ladepeche, R. Halder and B. List,
Angew. Chem. Int. Ed., 2008, 47, 4719; (b) Y. Hayashi, T. Itoh,
M. Ohkubo and H. Ishikawa, Angew. Chem. Int. Ed., 2008, 47
,
4
722; (c) Y. Qiao, J. He, B. Ni and A. D. Headley, Adv. Synth.
Catal., 2012, 354, 2849.
8
9
(a) C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente
and S. Vera, Angew. Chem. Int. Ed., 2007, 46, 8431.
13-(Pyridin-3-yl)tridecanal 14 was prepared from dodecane-
1
,12-diol and 3-picoline using a known procedure followed
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DOI: 10.1039/C6RA03915D
Graphical Abstract:
2
A novel approach for the synthesis of an αꢀphenylꢀβ ꢀamino acid core unit 1 and its application
to the total synthesis of (S)ꢀnakinadine B 3, a marine natural product is described. The synthesis
utilizes the optimized combination of diphenylprolinol silyl ether mediated asymmetric Michael
addition and proline catalyzed aminoxylation reaction as key steps.