Synthesis of Majusculamides A and B

Article abstract of DOI:10.1055/s-0037-1611805

The synthesis of two marine lipodipeptides, majusculamides A and B, is described. The key feature of this synthesis is the stereoselective construction of an α-methyl-β-keto-carboxamide moiety.

Full text of DOI:10.1055/s-0037-1611805

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
Synlett
D. Nakajima et al.
Letter
Synthesis of Majusculamides A and B
Daisuke Nakajimaa
Kosuke Sueyoshib
Kensuke Oriharaa
Toshiaki Teruya*b
Satoshi Yokoshima*a
NH2
NH2
N
N
O
O
O
O
O
O
N
O
N
O
MeO
MeO
0
0
0
0-
0
0
0
3-4
0
3
6-0
0
6
2
R
S
a
Graduate School of Pharmaceutical Sciences, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
yokosima@ps.nagoya-u.ac.jp
Faculty of Education, University of Ryukyus, 1 Senbaru, Nishihara,
Okinawa, 903-0213, Japan
majusculamide A
13% from L-valine
majusculamide B
18% from L-valine
b
t-teruya@edu.u-ryukyu.ac.jp
Received: 28.02.2019
Accepted after revision: 02.04.2019
Published online: 12.04.2019
comprising N,O-dimethyl-D-tyrosine and N-methyl-L-va-
line, with a C-terminal primary amide. The -methyl--
keto-decanoyl group is bonded to the N terminus of the di-
peptide to form a tertiary amide. The methyl group in the
decanoyl group generates two diastereomers, and the (R)
and (S) diastereomers are majusculamides A (1) and B (2),
respectively.
DOI: 10.1055/s-0037-1611805; Art ID: st-2019-u0118-l
Abstract The synthesis of two marine lipodipeptides, majusculamides
A and B, is described. The key feature of this synthesis is the stereose-
lective construction of an -methyl--keto-carboxamide moiety.
Key words marine natural products, peptides, polyketides, -ketoam-
ide, asymmetric aldol reaction
Although the -methyl--keto-carboxamide moiety ap-
pears to be stereochemically labile, these two isomers could
be separated. Isomerization of either isomer under heating
4,5
Marine natural products show a wide range of biologi-
in dimethyl sulfoxide at 140 °C was reported to be slow.
cal activities because of their structural diversity, which of-
fers a rich source of biological tools as well as new drugs.1
Although the evaluation of their biological activities is
sometimes restricted by their limited natural supply, chem-
ical synthesis can provide sufficient amounts of samples
and might expand the possibility of identifying the poten-
cies of the molecules. In connection with our campaign to
discover biologically active molecules, we developed syn-
theses of the marine natural products, majusculamides A
and B (Figure 1).
Conformational insights into the -methyl--keto-imide
moiety by Evans and coworkers explain the stereochemical
6
stability of the system, in which the C–H bond at the  po-
sition is arranged almost coplanar with the plane of the
amide so as to minimize the 1,3-allylic strain of the amide
moiety (Figure 2).7 This insight also suggests that the alkyl
chains of the decanoyl groups in majusculamides A and B
are oriented in different directions relative to the dipeptide
core in preferable conformations, thereby differentiating
,8
9
the shapes of the two molecules. The structural differences
might confer distinct biological activities. In fact, a differ-
ence in cell cytotoxicity measured with an MTT assay was
observed between majusculamides A and B. Majusculamide
A showed cytotoxicity at 10 M in cultured Hela S3 cells,
while majusculamide B showed no cytotoxicity under the
NH2
NH2
N
N
O
O
O
O
O
O
N
O
N
O
MeO
MeO
10
same conditions.
R
S
The synthesis of majusculamides A and B began with
the preparation of methylated amino acid units (Scheme 1).
majusculamide A (1)
majusculamide B (2)
11
Protection of D-tyrosine (3) with a Boc group, followed by
Figure 1 Structures of majusculamides A and B
methylation with iodomethane in the presence of sodium
hydride in tetrahydrofuran afforded N,O-dimethyl-N-Boc-
tyrosine (4).12 After protecting L-valine (5) with a Boc
group, N-methylation was conducted under the same con-
ditions.13 The carboxylic acid moiety in 6 was then activat-
ed by treatment with isobutyl chloroformate and N-meth-
The first isolation of the majusculamides from cyano-
bacteria, Lyngbya majuscula, and their structural elucida-
tion were reported by Moore, Clardy, and co-workers in
2,3
1
977. These natural products feature a dipeptide moiety
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
Synlett
D. Nakajima et al.
Letter
OH
OH
a, b
O
O
NH2
D-tyrosine (3)
N
HO
MeO
Boc
4
c, d
e
OH
OH
NH2
H2N
N
N
O
Boc
O
Boc
O
L-valine (5)
6
7
NH2
N
R
f
4
O
NH2
O
N
H
g
N
O
MeO
·HCl
8
9
: R = Boc
h
Figure 2 Structural comparison of majusculamides A and B. The dipep-
tide core, shown in gray, is based on the X-ray crystal structure of
majusculamide B. The alkyl chains, shown in green and violet for majus-
culamides A and B, respectively, are presented in extended forms.
1
0: R = H·HCl
Scheme 1 Preparation of methylated amino acid units. Reagents and
conditions: (a) Boc O, NaOH, 1,4-dioxane–H O, rt; (b) NaH, MeI, THF, 0
2
2
°
C to rt, 84% (2 steps); (c) Boc O, NaOH, THF–H O, rt; (d) NaH, MeI,
2
2
THF, 0 °C to rt; (e) i-BuOCOCl, N-methylmorpholine, Et O, –15 °C; NH
2
3
(
gas), –15 °C to rt, 50% (3 steps); (f) HCl, MeOH, 0 °C to rt, 98%; (g) 4,
ylmorpholine in diethyl ether, and the resulting mixed an-
hydride was treated with ammonia gas to furnish
COMU, DMF, 0 °C, then 8, Et N, 0 °C to rt, 74%; (h) HCl, MeOH, rt,
quant.
3
14
carboxamide 7. Compound 7 was subjected to deprotec-
tion by treatment with methanolic hydrogen chloride, giv-
ing the hydrogen chloride salt of N-methylvaline carboxam-
ide 8. Condensation of these amino acid units thus obtained
could be successfully carried out by using (1-cyano-2-
ethoxy-2-oxoethylidenaminooxy)dimethylamino-mor-
pholino-carbenium hexafluorophosphate (COMU) to give
dipeptide 9 in 74% yield. Employing other condensation
reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-te-
tramethyluronium-hexafluorophosphate (HATU) or EDCI–
HOBt (EDCI = ethyl-3-(3-dimethylaminopropyl)carbodiim-
ide) resulted in a lower yield because of the steric hindrance
at the units. The Boc group in 9 was cleaved with methano-
lic hydrogen chloride to give 10.
O
O
OH
O
N
a
10
O
X
O
c
R
Bn
1
O
O
(
)6
1
1
H
13: X =
Bn
2
N
b
15
14: X = OH
NH2
NH2
N
N
O
O
d
Ar
O
O
O
N
O
N
O
MeO
(
)6
R
OH
5: Ar = p-C6H4OMe
The decanoic acid unit was prepared by an asymmetric
aldol reaction (Scheme 2). Sequential treatment of (R)-pro-
panoyloxazolidinone 11 with titanium(IV) chloride, TME-
DA, and then octanal (12) afforded -hydroxy-imide 13,16
1
majusculamide A (1)
O
O
NH2
N
N
O
which was hydrolyzed with lithium hydroperoxide to give
O
S
carboxylic acid 14.17 Condensation of 14 with dipeptide 10
Bn
4 steps
O
O
16
N
O
was conducted by using HATU to furnish 15 in 72%
MeO
O
18,19
yield.
Since the primary carboxamide moiety in 10 was
S
(
)6
H
affected by HATU, premixing 14 and HATU before adding 10
effectively improved the yield. Finally, oxidation of the sec-
ondary alcohol moiety with Dess–Martin periodinane20 in
the presence of sodium bicarbonate produced majuscu-
12
majusculamide B (2)
Scheme 2 Syntheses of majusculamides A and B. Reagents and condi-
tions: (a) TiCl , TMEDA, CH Cl , 0 °C, then octanal (12), 0 °C, 68%; (b)
4
2
2
21
lamide A (1). Starting from (S)-propanoyloxazolidinone
6, majusculamide B (2) could be obtained according to the
LiOH·H
C, then 10, 0 °C to rt, 72%; (d) Dess–Martin periodinane, NaHCO3,
CH Cl , 0 °C to rt, 51%
2
O, H O , THF–H O, 0 °C, quant.; (c) 14, HATU, i-Pr NEt, DMF, 0
2
2
2
2
°
1
22
2
2
same procedure. The spectral data of the synthetic mate-
rials were identical to those of the natural samples.
In summary, we achieved syntheses of majusculamides
A and B with a longest linear sequence of eight steps in 13
and 18% overall yields, respectively. The characteristic -
methyl--keto-carboxamide moiety could be constructed
in a two-step sequence, which includes condensation of the
amine moiety in the peptide unit and the -hydroxy-car-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
Synlett
D. Nakajima et al.
Letter
boxylic acid units, followed by oxidation of the hydroxy
group. The sequence can be used to synthesize analogues of
majusculamides. Other biological evaluation of the natural
products and the analogues is currently underway and will
be reported in due course.
Org. Lett. 2011, 13, 3028. (b) Sun, Y.; Ding, Y.; Li, D.; Zhou, R.; Su,
X.; Yang, J.; Guo, X.; Chong, C.; Wang, J.; Zhang, W.; Bai, C.;
Wang, L.; Chen, Y. Angew. Chem. Int. Ed. 2017, 56, 14627.
(
8) In the case of N,O-dimethylhydroxamic acids, also known as
Weinreb amides, -methyl--keto compounds could be
employed in further transformation under the appropriate con-
ditions without isomerization, whereas the -methyl--keto
compounds could be used as substrates for asymmetric transfer
hydrogenation with dynamic kinetic resolution. For examples,
see: (a) Takamura, H.; Kadonaga, Y.; Kadota, I.; Uemura, D. Tet-
rahedron 2010, 66, 7569. (b) Kumaraswamy, G.; Narayanarao,
V.; Shanigaram, P.; Balakishan, G. Tetrahedron 2015, 71, 8960.
9) The structure of the -methyl--keto-carboxamide moiety was
supported by DFT calculations and NOESY experiments of sim-
plified molecules. For details, see Supporting Information.
10) Glucose uptake enhancement activity was also investigated.
Both compounds had no effect on the glucose uptake up to a
concentration of 30 M in cultured L6 myotubes.
11) Partial formation of an N,O-bis(Boc) product was observed
under those conditions. The Boc group on the phenolic hydroxy
group was easily cleaved during the ensuing methylation. For
related reports, see: (a) Nakamura, K.; Nakajima, T.; Kayahara,
H.; Nomura, E.; Taniguchi, H. Tetrahedron Lett. 2004, 45, 495.
(b) Nishiyama, Y.; Ishizuka, S.; Shikama, S.; Kurita, K. Chem.
Pharm. Bull. 2001, 49, 233.
Funding Information
This work was financially supported by JSPS KAKENHI (Grant Num-
bers 17H01523 and 18H04399) and by the Platform Project for Sup-
porting Drug Discovery and Life Science Research (Basis for
Supporting Innovative Drug Discovery and Life Science Research;
BINDS) from the Japan Agency for Medical Research and Development
(
(AMED) under Grant Number JP18am0101099.
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Supporting information for this article is available online at
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References and Notes
(
1) (a) Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat.
(12) Boger, D. L.; Yohannes, D. J. Org. Chem. 1988, 53, 487.
(13) Malkov, A. V.; Vranková, K.; Černý, M.; Kočovský, P. J. Org. Chem.
2009, 74, 8425.
(14) Lim, H. J.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2010, 12,
2162.
Rev. Drug Discov. 2009, 8, 69. (b) Montaser, R.; Luesch, H. Future
Med. Chem. 2011, 3, 1475. (c) Blunt, J. W.; Copp, B. R.; Keyzers, R.
A.; Munro, M. H. G.; Prinsep, M. R. Nat. Prod. Rep. 2017, 34, 235.
(d) Blunt, J. W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R.
A.; Prinsep, M. R. Nat. Prod. Rep. 2018, 35, 8. (e) Carroll, A. R.;
Copp, B. R.; Davis, R. A.; Keyzers, R. A.; Prinsep, M. R. Nat. Prod.
Rep. 2019, 36, 122.
(15) El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F. Chem. Eur.
J. 2009, 15, 9404.
(16) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883.
(
2) Marner, F.-J.; Moore, R. E.; Hirotsu, K.; Clardy, J. J. Org. Chem.
1
977, 42, 2815.
(17) (a) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957. (b) Evans, D. A.; Britton, T. C.; Ellman, J. A.
Tetrahedron Lett. 1987, 28, 6141.
(18) (a) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. (b) Carpino,
L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.; Zhang, C.; Lee, Y.;
Foxman, B. M.; Henklein, P.; Hanay, C.; Mügge, C.; Wenschuh,
H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem. Int. Ed.
2002, 41, 441.
(19) (2R,3S)-N-[(R)-1-{[(S)-1-amino-3-methyl-1-oxobutan-2-
yl](methyl)amino}-3-(4-methoxyphenyl)-1-oxopropan-2-
yl]-3-hydroxy-N,2-dimethyldecanamide (15)
To a solution of carboxylic acid 14 (51.0 mg, 0.252 mmol) and
(
3) Majusculamides A and B were also recently isolated by us from
the marine cyanobacterium Moorea producens collected from
the coast of Bise Okinawa.
(
4) No isomerization was observed in 1H NMR spectra of the pure
amides in DMSO-d at 140 °C after heating for 10 minutes.
6
(
5) The -methyl--keto-carboxamide moiety is observed in the
macrocyclic systems of some natural products. For synthetic
studies toward such natural products, see: (a) Rinehart, K. L.;
Kishore, V.; Nagarajan, S.; Lake, R. J.; Gloer, J. B.; Bozich, F. A.; Li,
K.-M.; Maleczka, R. E.; Todsen, W. L.; Munro, M. H. G.; Sullins, D.
W.; Sakai, R. J. Am. Chem. Soc. 1987, 109, 6846. (b) Plaza, A.;
Garcia, R.; Bifulco, G.; Martinez, J. P.; Hüttel, S.; Sasse, F.;
Meyerhans, A.; Stadler, M.; Müller, R. Org. Lett. 2012, 14, 2854.
i-Pr NEt (0.048 mL, 0.28 mmol) in DMF (1.62 mL) was added
2
HATU (106 mg, 0.278 mmol) at 0 °C. After stirring for 30 min, a
(
5
c) Ghosh, A. K.; Rao, K. V.; Akasapu, S. Tetrahedron Lett. 2014,
5, 5191. (d) Qi, N.; Allu, S. R.; Wang, Z.; Liu, Q.; Guo, J.; He, Y.
Org. Lett. 2016, 18, 4718. (e) Revu, O.; Prasad, K. R. J. Org. Chem.
017, 82, 438. (f) Seo, C.; Yim, J. H.; Lee, H. K.; Park, S. M.; Sohn,
solution of amine hydrochloride 10 (90.3 mg, 0.252 mmol) and
i-Pr NEt (0.097 mL, 0.56 mmol) in DMF (1.54 mL) was added
2
dropwise at 0 °C. After the resulting mixture was stirred for 4 h
at 25 °C, the reaction was quenched with NaCl solution (10%) in
water. The resulting mixture was extracted three times with
AcOEt. The combined organic phases were washed with
aqueous NaHCO , dried with Na SO , and concentrated under
2
J.-H.; Oh, H. Tetrahedron Lett. 2008, 49, 29. (g) Ghosh, A. K.; Xu,
C.-X. Org. Lett. 2009, 11, 1963. (h) Reddy, K. M.; Shashidhar, J.;
Pottireddygari, G. R.; Ghosh, S. Tetrahedron Lett. 2011, 52, 5987.
3
2
4
(i) Kaneda, M.; Inuki, S.; Ohno, H.; Oishi, S. J. Org. Chem. 2018,
reduced pressure. The crude product was purified by silica gel
8
3, 3047.
column chromatography (AcOEt–n-hexane 1:5 to 1:0) to give 15
(91.4 mg, 0.181 mmol, 72%) as a colorless oil. []D −1.78 (c
23
(
6) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am.
Chem. Soc. 1984, 106, 1154.
7) Tertiary amides are essential for the stereochemical stabilities
of -keto-carboxamides. For examples of isomerization of sec-
ondary amides, see: (a) Satoh, N.; Yokoshima, S.; Fukuyama, T.
0.310, CHCl ). IR (film): 3397, 3205, 2929, 2856, 1691, 1627,
3
1514, 1466, 1405, 1301, 1249, 1178, 1095, 1036, 824 cm–1
.
1
H
(
NMR (400 MHz, CDCl , mixture of rotamers):  = [7.14 (d, J = 8.8
3
Hz), 7.10 (d, J = 8.8 Hz), all sum to 2 H), [6.81 (d, J = 8.8 Hz), 6.79
(d, J = 8.8 Hz), all sum to 2 H], [6.71 (br s), 6.13 (br s), all sum to 1
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
Synlett
D. Nakajima et al.
Letter
H], [5.70 (dd, J = 8.0, 7.6 Hz), 5.68 (dd, J = 8.0, 7.6 Hz), all sum to
mixture of rotamers):  = 206.9 (C), 206.7 (C), 172.5 (C), 172.0
(C), 171.7 (C), 171.6 (C), 171.2 (C), 169.3 (C), 158.5 (C), 130.3
(CH), 130.1 (CH), 128.3 (C), 128.2 (C), 113.9 (CH), 113.8 (CH),
1 H], [5.58 (br s), 5.35 (br s), all sum to 1 H], [4.50 (d, J = 10.8 Hz),
3.72 (d, J = 10.4 Hz), all sum to 1 H], 3.80–3.60 (m, 1 H), 4.15–
4.06 (br s, 1 H), [3.76 (s), 3.76 (s), all sum to 3 H], 3.18–2.84 (m, 2
63.7 (CH), 62.5 (CH), 55.7 (CH), 55.3 (CH ), 54.3 (CH), 51.2 (CH),
3
H), [some signals including the following: 3.06 (s), 2.99 (s), 2.96
s), 2.91 (s), all sum to 6 H], [2.57 (qd, J = 7.2, 2.0 Hz), 2.48 (qd,
J = 7.2, 2.0 Hz), 1 H], 2.34–2.15 (m, 1 H), 1.48 (m, 2 H), 1.34–1.17
50.6 (CH), 40.5 (CH ), 40.1 (CH ), 34.9 (CH ), 34.6 (CH ), 31.6
2
2
2
2
(
(CH ), 31.2 (CH ), 30.9 (CH ), 30.7 (CH ), 29.6 (CH ), 29.1 (CH ),
2 3 3 3 3 2
27.6 (CH), 25.5 (CH), 23.5 (CH ), 23.3 (CH ), 22.6 (CH ), 19.9
2
2
2
(
[
(
m, 10 H), [0.97 (d, J = 6.4 Hz), 0.74 (d, J = 6.4 Hz), all sum to 3 H],
(CH ), 18.8 (CH ), 18.6 (CH ), 18.4 (CH ), 14.1 (CH ), 13.4 (CH ).
3 3 3 3 3 3
0.93–0.81 (m), 0.65 (d, J = 6.4 Hz), 0.63 (d, J = 6.4 Hz), 6 H], 0.89
HRMS (ESI+): m/z calcd for C28H45N NaO : 526.3257; found:
3
5
13
t, J = 7.7 Hz, 3 H). C NMR (100 MHz, CDCl , mixture of rotam-
526.3252.
3
ers):  = 178.6 (C), 178.1 (C), 172.1 (C), 171.8 (C), 171.6 (C),
(22) Majusculamide B (2)
1
1
69.1 (C), 158.6 (C), 158.5 (C), 130.3 (CH), 130.1 (CH), 128.2 (C),
28.0 (C), 113.9 (CH), 113.8 (CH), 71.2 (CH), 70.8 (CH), 63.5
To a solution of -hydroxy amide (17.6 mg, 0.0348 mmol), pre-
pared by condensation of ent-14 with 10, in CH Cl (0.232 mL),
2
2
(
CH), 62.4 (CH), 55.3 (CH ), 54.3 (CH), 53.9 (CH), 39.4 (CH), 39.0
were added NaHCO3 (4.8 mg, 0.0568 mmol) and Dess–Martin
periodinane (19.2 mg, 0.0453 mmol) at 0 °C. After stirring for 1
h at 25 °C, NaHCO aq and Na S O aq were added to the reac-
3
(CH), 34.7 (CH ), 34.6 (CH ), 33.9 (CH ), 33.5 (CH ), 31.8 (CH ),
2
2
2
2
2
3
1.1 (CH ), 31.0 (CH ), 30.7 (CH ), 30.4 (CH ), 29.6 (CH ), 29.2
3 3 3 3 2
3
2
2
3
(
CH ), 27.3 (CH), 26.0 (CH ), 25.9 (CH ), 25.4 (CH), 22.6 (CH ),
tion mixture. The resulting solution was extracted three times
2
2
2
2
1
9.7 (CH ), 19.3 (CH ), 19.2 (CH ), 18.3 (CH ), 14.1 (CH ), 9.3
with AcOEt. The combined organic layer was dried with Na SO4
3
3
3
3
3
2
(
CH ), 8.5 (CH ). HRMS (ESI+): m/z calcd for C28H47N NaO :
and concentrated under reduced pressure. The crude product
3
3
3
5
5
28.3413; found: 528.3427.
was purified by preparative TLC (AcOEt–n-hexane 5:1) to give 2
23
(
20) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
21) Majusculamide A (1)
(10.8 mg, 0.0215 mmol, 62%) as a colorless oil. []D +25.5 (c
0.580, EtOH). IR (film): 3336, 3209, 2958, 2931, 2856, 1722,
1691, 1633, 1514, 1467, 1400, 1301, 1249, 1178, 1128, 1101,
(
–1
1
To a solution of -hydroxy amide 15 (26.1 mg, 0.0517 mmol) in
CH Cl (0.344 mL), were added NaHCO (8.15 mg, 0.0971 mmol)
and Dess–Martin periodinane (32.9 mg, 0.0775 mmol) at 0 °C.
After stirring for 1 h at 25 °C, NaHCO aq and Na S O aq were
added to the reaction mixture. The resulting solution was
extracted three times with AcOEt. The combined organic layer
was dried with Na SO and concentrated under reduced pres-
1073, 1038, 825 cm . H NMR (400 MHz, CDCl , mixture of
3
rotamers):  = [7.16 (d, J = 8.6 Hz), 7.12 (d, J = 8.6 Hz), all sum to
2 H], [6.80 (d, J = 8.6 Hz), 6.78 (d, J = 8.4 Hz), all sum to 2 H],
[6.74 (br s), 6.09 (br s), all sum to 1 H], [5.77 (dd, J = 7.4, 7.4 Hz),
5.73 (dd, J = 8.8, 6.4 Hz), all sum to 1 H], [5.48 (br s), 5.32 (br s),
all sum to 1 H], [4.48 (d, J = 10.8 Hz), 3.62 (d, J = 10.8 Hz), all sum
to 1 H], [3.76 (s), 3.75 (s), all sum to 3 H], 3.61–3.43 (m, 1 H),
3.18–2.85 (m, 2 H), [some signals including the followings: 3.04
(s), 3.04 (s), 3.02 (s), 2.91 (s), all sum to 6 H], 2.32–2.15 (m, 1 H),
[1.99 (dt, J = 17.6, 7.2 Hz), 1.93 (dt, J = 17.6, 7.2 Hz), 1.65–1.53
(m), all sum to 2 H], 1.50–1.32 (m, 2 H), 1.32–1.06 (m, 8 H), 1.28
(d, J = 7.2 Hz, 3 H), [0.97 (d, J = 6.4 Hz), 0.92 (d, J = 6.4 Hz), 0.91–
0.84 (m), 0.75 (d, J = 6.8 Hz), 0.63 (d, J = 6.8 Hz), all sum to 6 H],
2
2
3
3
2
2
3
2
4
sure. The crude product was purified by preparative TLC
AcOEt–n-hexane 5:1) to give 1 (13.3 mg, 0.0264 mmol, 51%) as
(
23
a colorless oil. []D +33.2 (c 0.715, EtOH). IR (film): 3335, 3208,
2930, 2863, 1688, 1635, 1510, 1463, 1400, 1297, 1250, 1178,
–1
1
1107, 1040, 829 cm
. H NMR (400 MHz, CDCl , mixture of
3
rotamers):  [7.14 (d, J = 8.4 Hz), 7.08 (d, J = 8.4 Hz), all sum to 2
H], [7.01 (br s), 6.16 (br s), all sum to 1 H], [6.80 (d, J = 8.4 Hz),
13
0.88 (t, J = 7.2 Hz, 3 H). C NMR (100 MHz, CDCl , mixture of
3
6.79 (d, J = 8.4 Hz), all sum to 2 H], [5.71 (dd, J = 8.0, 8.0 Hz), 5.65
rotamers):  = 206.6 (C), 205.5 (C), 172.2 (C), 171.8 (C), 171.5
(dd, J = 9.2, 6.0 Hz), all sum to 1 H], [5.50 (br s), 5.27 (br s), all
(C), 171.4 (C), 171.0 (C), 169.2 (C), 158.5 (C), 130.3 (CH), 130.1
sum to 1 H], [4.54 (d, J = 10.8), 3.71 (d, J = 10.8 Hz), all sum to 1
H], 3.77 (s, 3 H), [3.59 (q, J = 7.0 Hz), 3.44 (q, J = 7.2 Hz), all sum
to 1 H], 3.20–2.85 (m, 2 H), [some signals including the follow-
ing: 3.08 (s), 3.00 (s), 2.94 (s), 2.91 (s), all sum to 6 H], 2.48–2.30
(CH), 128.3 (C), 113.9 (CH), 63.7 (CH), 62.4 (CH), 55.1 (CH ), 55.0
3
(CH ), 54.9 (CH), 54.3 (CH), 51.4 (CH), 50.7 (CH), 39.4 (CH ), 39.3
3
2
(CH ), 34.8 (CH ), 34.6 (CH ), 31.2 (CH ), 31.6 (CH ), 30.9 (CH ),
2
2
2
2
3
3
30.5 (CH ), 29.5 (CH ), 29.2 (CH ), 29.1 (CH ), 29.0 (CH ), 28.9
3
3
2
2
2
(
2
m, 2 H), [2.34–2.24 (m), 2.26–2.14 (m), all sum to 1 H], 1.51 (m,
H), 1.35–1.10 (m, 8 H), [1.00–0.91 (m), 0.90–0.78 (m) 0.59 (d,
J = 6.4 Hz), all sum to 6 H], [1.22 (d, J = 7.0 Hz), 0.93 (d, J = 7.0
(CH ), 27.4 (CH), 25.4 (CH), 23.4 (CH ), 23.4 (CH ), 22.6 (CH ),
19.7 (CH ), 19.2 (CH ), 19.2 (CH ), 18.3 (CH ), 14.1 (CH ), 13.7
3 3 3 3 3
2
2
2
2
(CH ), 13.6 (CH ). HRMS (ESI+): m/z calcd for C28H45N NaO :
3
3
3
5
13
Hz), all sum to 3 H] 0.85 (m, 3 H). C NMR (100 MHz, CDCl3,
526.3257; found: 526.3278.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D