Concise synthesis and antitumor activity of Bengamide e and its analogs

Article abstract of DOI:10.1016/j.tet.2012.11.004

Bengamide E (1a) and C-2 epimer (1b), free hydroxyl analogs (1c) and (1d), and shorter chain analog (1e) were synthesized by utilizing (2R,3S,4R)-2,3,4- tris(benzyloxy)hex-5-enal (2a) as the chiral building block. Preliminary biological studies revealed that only compound 1c showed slightly weaker activity than Bengamide E (1a) against MDA-MB-453 human breast carcinoma cells, MCF-7 human breast cancer cells and HCT-116 colon cancer cells, with the others being inactive. These results suggest that the correct stereochemistry at C-2, the alkylation on C-2 hydroxyl group, as well as the length of the carbon chain of Bengamide E are critical for structural recognition and binding to the target(s).

Full text of DOI:10.1016/j.tet.2012.11.004

Tetrahedron 69 (2013) 664e672
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise synthesis and antitumor activity of Bengamide E and its
analogs
*
*
Wenxuan Zhang, Qingzhao Liang, Hui Li, Xiangbao Meng , Zhongjun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2012
Received in revised form 10 September 2012
Accepted 2 November 2012
Available online 16 November 2012
Bengamide E (1a) and C-2 epimer (1b), free hydroxyl analogs (1c) and (1d), and shorter chain analog (1e)
were synthesized by utilizing (2R,3S,4R)-2,3,4-tris(benzyloxy)hex-5-enal (2a) as the chiral building
block. Preliminary biological studies revealed that only compound 1c showed slightly weaker activity
than Bengamide E (1a) against MDA-MB-453 human breast carcinoma cells, MCF-7 human breast cancer
cells and HCT-116 colon cancer cells, with the others being inactive. These results suggest that the correct
stereochemistry at C-2, the alkylation on C-2 hydroxyl group, as well as the length of the carbon chain of
Bengamide E are critical for structural recognition and binding to the target(s).
Keywords:
Bengamide E
Carbohydrate
Ó 2012 Elsevier Ltd. All rights reserved.
Stereoselective reduction
Antitumor activity
1. Introduction
The bengamides, first isolated by Crews and co-workers from
Jaspis sponges in 1986,1 display a wide range of biological activities,
including antitumor, antibiotic, and anthelmintic properties.2 These
interesting biological activities have made bengamides popular tar-
gets for synthesis3 and biological studies.2,4 The cytotoxic mechanism
of bengamides has been investigated, and it showed that they arrest
cells at the G1 and G2/M phases of the cell cycle by binding to either
methionine aminopeptidase type 1 (Met-Ap1) or type 2 (Met-Ap2).5
Carbohydrates have been used as chiral building blocks in
asymmetric synthesis because of their known absolute stereo-
chemistry and availability.6 Hex-5-enals derived from carbohydrates
are valuable synthons in the total synthesis of natural products and
chiral compounds.7 Herein we report a concise synthesis of Benga-
mide E (1a) and its analogs for biological evaluations. Our synthetic
Fig. 1. The structure of Bengamide E and retrosynthetic analysis.
under strong acidic conditions. Meanwhile, reduction of TBDMS
protected cyanohydrin 3b with DIBAL-H10 failed to produce the
aldehyde 3d but resulted in an amine. Nef reaction was then tried to
convert the nitro group in compound 411 into an acid 3c12 or
aldehyde 4a.13 Unfortunately, all tested conditions14 could not yield
the desired product.
scheme was to utilize the polyhydroxyl carbon skeleton of D-glucose
for preparation of the side chain of Bengamide E, as shown in Fig. 1.
Dondoni’s group employed 2-(trimethylsily1)thiazole as a for-
myl anion equivalent to prepare extended carbohydrates.15 Treat-
ment of 2a with 2-(trimethylsilyl)thiazole yielded a mixture of
alcohols 5a and 5b and their TMS derivatives. Exposure of the
reaction mixture to nBu4NþFꢀ afforded 5a and 5b as a 1:l mixture of
diastereoisomers in 85% yields, which can be separated by silica gel
chromatography (Scheme 2).
In our attempts to improve the stereoselective synthesis of 5a
and 5b, a two-step oxidation/reduction procedure was planned.16
The Swern oxidation of alcohols mixture led to ketone 5c, which
was supposed to be stereoselectively reduced to the desired
2. Results
(2R,3S,4R)-2,3,4-Tris(benzyloxy)hex-5-enal (2a)8 was prepared
from methyl
a-D-glucoside. Initially, we attempted to prepare
a
-hydroxy carboxylic acid 3c from cyanohydrin 3a by hydrolysis
(Scheme 1).9 However, the starting material was decomposed
* Corresponding authors. Tel.: þ86 10 82801714; fax: þ86 10 82805496; e-mail
addresses: xbmeng@bjmu.edu.cn (X. Meng), zjli@bjmu.edu.cn (Z. Li).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.004

W. Zhang et al. / Tetrahedron 69 (2013) 664e672
665
Scheme 1. Reagents and conditions: (a) (i) TMSCN, K2CO3, THF, 23 ꢁC, 12 h; (ii) nBu4NþFꢀ, CH2Cl2, 23 ꢁC, 20 min; (b) TBDMSCl, imidazole, DMF, 12 h; (c) from 3a: 6 N HCl (aq),
CH3OH, reflux, 24 h; (d) from 3b; DIBAL-H, toluene, ꢀ78 ꢁC, 1 h; (e) CH3NO2, tBuOK, tBuOH, THF, rt, 12 h; (f) NaNO2, HOAc, DMSO, rt, 24 h; (g) KMnO4, KOH/KH2PO4 buffer, tBuOH, rt,
1 h; (h) 1 N HCl (aq), tBuOH, rt, 12 h; (i) NaOH, H2SO4, CH3OH, 30 min.
Scheme 2. Reagents and conditions: (a) (i) 2-(trimethylsilyl)thiazole (2-TST), CH2Cl2, 23 ꢁC, 6 h, (ii) nBu4NþFꢀ, CH2Cl2, 23 ꢁC, 20 min, 43% yield for 5a and 43% yield for 5b;(b) NaH,
MeI, THF, rt, 12 h, 95% yield for 6a and 96% yield for 6b; NaH, BnBr, THF, rt, 12 h, 92% yield for 6c and 95% yield for 6d; (c) (i) MeI, 4 A MS, MeCN, reflux, 12 h, (ii) NaBH4, MeOH, 0 ꢁC,
ꢀ
30 min, (iii) AgNO3, MeCN/H2O (4:1), 23 ꢁC, 10 min; (d)NaClO2, NaH2PO4$H2O, H2O2, MeCN/tBuOH/H2O (2:2:1), rt, 3 h, 80% yield for 7a, 78% yield for 7b, 76% yield for 7c, 73% yield
for 7d; (e) L-(ꢀ)-
a-amino-d-caprolactam, EDCI, HOBt, Et3N, DMF, rt, 12 h, 85% yield for 8a, 78% yield for 8b, 72% yield for 8c, 78% yield for 8d; (f) HoveydaeGrubbs catalysts second
generation, 3-methyl-1-butene, CH2Cl2, reflux, 24 h, 93% yield for 9a, 88% yield for 9b, 89% yield for 9c, 90% yield for 9d; (g) Na, NH3, THF, ꢀ78 ꢁC, 1 h, 58% yield for 1a, 71% yield for
1b, 43% yield for 1c, 50% yield for 1d.
anti-alcohol 5a or syn-alcohol 5b with a satisfactory yield. Although
it was highly efficient to afford the syn-diastereomer 5b when
treated with DIBAL-H, ZnBH4, or DIBAL/ZnCl2, no stereoselection in
favor of the anti-diastereomer 5a was observed in the presence of
required the conversion of the thiazole moiety into an aldehyde.
This procedure was carried out in a one-pot, three-step sequence
developed by Dondoni.15 Hence, 6a was first N-methylated by
treatment with methyl iodide in the presence of molecular sieves in
acetonitrile for 12 h at 82 ꢁC. Subsequent reduction of the thiazo-
linium with sodium borohydride in MeOH at 0 ꢁC for 30 min
afforded thiazolidine. Initially, mercury(II) chloride was used to
NaBH4, LiBH4, L-selecrtide, as well as LiAlH4 (Table 1). The syn-
diastereoselectivity observed could be explained that borohydride
attacked the less hindered face of the carbonyl of 5c in the con-
formation B, according to the Cram chelate model (Fig. 2).16 In the
nonchelated conformation A (FelkineAhneHouk model), si-face
and re-face could be attacked by borohydride at the same time.
Mitsunobu reaction was then tried to invert secondary hydroxyl
group at C-2 of 5b, but no reaction was observed when PPh3/DIAD/
p-NO2BzOH condition was employed.
convert the thiazolidine to a-methyloxyaldehyde, but the yield was
disappointing. Silver nitriate17 was then tried and a better yield was
obtained. Oxidation of the aldehyde by sodium chlorite and sodium
dihydrogen phosphate in the presence of hydrogen peroxide
afforded acid 7a in 80% overall yield.
Coupling of acid 7awith commerciallyavailable
L
-(þ)-
a-amino-d-
Methylation of alcohol 5a with methyl iodide in the presence of
sodium hydride formed methyl ether 6a in 95% yield. The next step
caprolactam18 was achieved by using EDCI/HOBt, and the amide 8a
was thereby obtained in 85% yield. In order to introduce the terminal

666
W. Zhang et al. / Tetrahedron 69 (2013) 664e672
Table 1
Reduction of ketone 5c
Entry
Reducing agent
5b/5ag
Yieldh (%)
1
2
3
4
5
6
7
DIBAL-Ha,d
DIBAL-H/ZnCl2
>95:5
>95:5
>95:5
50:50
50:50
50:50
50:50
94%
93%
96%
93%
94%
97%
96%
a,b
a,f
Zn(BH4)2
d,e
NaBH4
b,c
LiBH4
L
-Selecrtideb,c
a,b
LiAlH4
a
Et2O used as solvent.
b
Reaction was at ꢀ78 ꢁC.
c
THF used as solvent.
Reaction was at 0 ꢁC.
d
e
MeOH used as solvent.
f
Reaction was at ꢀ20 ꢁC.
g
Diastereomer ratio determined by 1H NMR analysis on crude mixture of both diastereomers.
h
Yield refers to the column purified product.
Bengamide E analogs without C-2 were also prepared. Com-
pound 2a, (2S,3S,4R)-2,3,4-tris(benzyloxy) hex-5-ena (2b)8 or
(2R,3S,4S)-2,3,4-tris(benzyloxy)hex-5-ena (2c),8 was oxidized to
acid 10aec by the Pinnick oxidation in a satisfied yield (83e88%).
(b)
(a)
Coupling of acid 10aec with
L-(þ)-
a-amino-d-caprolactam afforded
11aec in 72e81% yield. Olefin cross metathesis of 11aec and 3-
methyl-1-butene with second-generation HoveydaeGrubbs cata-
lyst afforded compound 12aec in 75e88% yield. Birch reduction
(Na/NH3) of 12aec afforded 1eeg in 40e42% yield (Scheme 3).
All these compounds were tested with MDA-MB-453 human
breast carcinoma cells, MCF-7 human breast cancer cells and HCT-
116 colon cancer cells for their antitumor activities (Table 2).2a
Compound 1c showed almost two fold less activity than Benga-
mide E (1a). No growth inhibitions were observed for other com-
Fig. 2. Nonchelated (A) and chelated (B) model in the reduction of ketone 5c.
pounds at concentrations up to 100 mM.
isopropyl group of Bengamide E, olefin cross metathesiswastried.3d,g
Treating 8a and 3-methyl-1-butene with second-generation Hov-
eydaeGrubbs catalyst afforded compound 9a in 93% yield with an
excellent selectivity (>19:5 mixture of E:Z isomers, as determined by
1H NMR spectroscopy). Removal of benzyl groups in 9a with Na/
NH319 afforded Bengamide E (1a) in 58% yield after purification over
silicagel.The 1H NMR andl3C NMR datawereingood agreementwith
those reported for natural Bengamide E.3 The optical rotation of our
3. Conclusion
In conclusion, we have achieved a concise synthesis of Benga-
mide E and its analogs with modifications at C-2 position. The side
chain was constructed by utilizing (2R,3S,4R)-2,3,4-tris(benzyloxy)
hex-5-enal (2a) as the chiral building block, with a Dondoni re-
action and E-olefination by olefin cross metathesis. Compared with
natural Bengamide E (1a), only compound 1c showed slightly
weaker cytotoxic activity, with the rest being inactive. These reveal
the significance of the stereochemistry at C-2 position, alkylation
on C-2 hydroxyl group and the length of carbon chain of Bengamide
E for structural recognition and binding to the target(s).2b,3g
synthetic sample([
reported by Crews ([
a
]
a
29 þ36.0(c1.33, MeOH))wascomparabletothat
D
]
29 þ37.0 (c 0.043, MeOH)).1
D
Bengamide E analogs with modifications at the C-2 position
were prepared using the synthetic route outlined in Scheme 2. (2S)-
Bengamide E (1b) was synthesized from S-methoxylthiazoles (6b),
using the similar synthetic route as Bengamide E (1a). For free
hydroxyl analogs, benzyl ether was employed to protect the C-2
hydroxyl group of alcohol 5a or 5b temporarily. Treatment of 5a or
5b with benzyl bromide and sodium hydride afforded 6c or 6d in
92% and 95% yield. Compounds 7ce9c and 7de9d were prepared in
a similar way to 7ae9a. Finally, 2-OH-Bengamide E (1c) and (1d)
were prepared via deprotection of per-benzyl ether of 9c and d.
4. Experimental
4.1. Synthesis
1H and 13C NMR spectra were recorded on a Bruker 400 in-
strument using TMS as the internal standard. Mass spectra were
obtained on an IBIMDS Sciex QStar mass spectrometer. Optical

W. Zhang et al. / Tetrahedron 69 (2013) 664e672
667
Scheme 3. Reagents and conditions: (a) NaClO2, NaH2PO4$H2O, H2O2, MeCN/tBuOH/H2O (2:2:1), rt, 3 h, 88% yield for 10a, 83% yield for 10b, 84% yield for 10c; (b) L-(ꢀ)-
a-amino-d-
caprolactam, EDCI, HOBt, Et3N, DMF, rt, 12 h, 81% yield for 11a, 79% yield for 11b, 72% yield for 11c; (c) HoveydaeGrubbs catalysts second generation, 3-methyl-1-butene, CH2Cl2,
reflux, 24 h, 88% yield for 12a, 88% yield for 12b, 75% yield for 12c; (d)Na, NH3, THF, ꢀ78 ꢁC, 1 h, 48% yield for 1e, 42% yield for 1f, 40% yield for 1g.
Table 2
(d, J¼3.2 Hz, 1H), 7.24e7.36 (m, 16H), 7.04e7.06 (m, 2H), 6.02 (ddd,
Antitumor activities of 1aeg against three cancer cell lines (IC50 in mM)
J¼17.6, 10.7, 7.3 Hz, 1H), 5.41 (s, 1H), 5.37 (d, J¼9.5 Hz, 1H), 5.16 (d,
J¼3.5 Hz, 1H), 4.76 (d, J¼2.2 Hz, 2H), 4.66e4.72 (m, 5H), 4.41e4.50
(m, 3H), 4.18e4.21 (m, 3H), 3.90 (dd, J¼6.3, 4.7 Hz, 1H). 13C NMR
Entry
HCT-116
MDA-MB-453
MCF-7
1a
1b
1c
1d
1e
1f
9.02
6.71
3.36
>100
8.35
>100
>100
>100
>100
(100 MHz, CDCl3)
d 174.1, 142.5, 138.1, 137.7, 134.8, 128.5, 128.4,
>100
25.49
>100
>100
>100
>100
>100
11.36
>100
>100
>100
>100
128.3, 128.2 (2), 128.0, 127.8 (2), 127.6, 119.4, 119.1, 82.4, 81.6, 80.0,
75.0, 74.9, 72.0, 70.8. HRMS (ESI) m/z calcd for C30H32NO4S (MþH)
502.20462, found 502.20466.
1g
4.3. General procedure for the synthesis of 6a,b
rotations were measured at 25 ꢁC using an Optical Activity AA10R
automatic polarimeter. TLC was performed on glass plates coated
with Silica Gel GF254 (Merck). Column chromatography was per-
formed on Silica Gel H60 (Haiyang Chemical Factory, Qingdao,
Shandong, China). Solvents were purified by standard procedures.
To a solution of compound 5a,b (1 equiv) in dry THF (2 mL) was
added portionwise NaH 60% (3 equiv) at room temperature. The
reaction mixture was stirred for 20 min and then methyl iodide
(2 equiv) was added sequentially. The solution was stirred at room
temperature overnight until MeOH was added. The solvent was
concentrated at reduced pressure, saturated aqueous NaHCO3 was
then added, and the mixture was extracted with dichloromethane.
After drying (anhydrous Na2SO4), the solvent was removed under
vacuum and the residue was chromatographed on silica gel (10:1
PE/ethyl acetate) to give the O-methyl derivative 6a,b.
4.2. General procedure for the synthesis of 5a, 5b
A solution of the aldehyde 2a (2.1 g, 5.05 mmol) and 2-(trime-
thylsilyl) thiazole (1.6 mL, 10.1 mmol) in dry dichloromethane
(25 mL) was stirred for 6 h at 23 ꢁC. The solvent was treated with
tetra-n-butylammonium fluoride (10.1 mmol). After 20 min of
stirring, the solution was extracted with dichloromethane, dried
with Na2SO4 and the solvent was removed in vacuo. The residue
was chromatographed on silica gel (10:1 PE/ethyl acetate) to give
the anti-isomer 5a (1.09 g, 43%) as a colorless syrup and syn-isomer
5b (1.07 g, 43%) as a colorless syrup.
4.3.1. 2-((1R,2R,3S,4R)-2,3,4-Tris(benzyloxy)-1-methoxyhex-5-en-1-
yl)thiazole (6a). Yield: 95%, colorless syrup; 1H NMR (400 MHz,
CDCl3)
d
7.80 (d, J¼3.2 Hz, 1H), 7.14e7.52 (m, 16H), 5.90e5.93 (m,
1H), 5.34 (d, J¼1.5 Hz,1H), 5.31 (d, J¼9.0, Hz,1H), 4.71e4.80 (m,1H),
4.69 (dd, J¼11.6, 4.3 Hz, 1H), 4.55 (d, J¼11.1 Hz, 1H), 4.44 (dd, J¼11.5,
3.4 Hz 2H), 4.24 (t, J¼6.6 Hz, 1H), 4.17 (t, J¼5.3 Hz, 1H), 3.74 (t,
J¼5.4 Hz, 1H), 3.21 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 169.8, 142.2,
138.9, 138.6, 138.5, 135.6, 128.4, 128.2, 128.2, 128.1, 128.1, 127.8,
127.5, 127.4, 127.3, 120.3, 119.2, 81.6, 81.3, 81.1, 80.7, 75.3, 74.3, 70.5,
57.2. HRMS (ESI) m/z calcd for C31H34NO4S (MþH) 516.22031, found
516.22007.
4.2.1. (1R,2S,3S,4R)-2,3,4-Tris(benzyloxy)-1-(2-thiazolyl)hex-5-en-1-
ol (5a). [
a
]
25 ꢀ3.8(c 2.12, CHCl3);1H NMR (400 MHz, CDCl3)
d 7.80(d,
D
J¼3.2 Hz, 1H), 7.22e7.49 (m, 15H), 5.73e5.85 (m, 1H), 5.28e5.44 (m,
3H), 4.91 (t, J¼10.2 Hz, 2H), 4.73 (d, J¼11.4 Hz,1H), 4.61 (d, J¼11.4 Hz,
1H), 4.55 (d, J¼11.4 Hz,1H), 4.33e4.50 (m, 3H), 4.21 (dd, J¼4.4, 2.9 Hz,
4.3.2. 2-((1S,2R,3S,4R)-2,3,4-Tris(benzyloxy)-1-methoxyhex-5-en-1-
1H), 3.72 (dd, J¼7.1, 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
174.0,
yl)thiazole (6b). Yield: 96%, colorless syrup; [
a]
ꢀ25.3 (c 1.58,
25
D
143.0,138.1, 137.9,134.8,128.4,128.4,128.4,128.0,127.9,127.8,127.6,
119.8, 119.0, 82.4, 82.0, 79.8, 74.9, 72.3, 71.8, 70.8. HRMS (ESI) m/z
calcd for C30H32NO4S (MþH) 502.20462, found 502.20466.
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.82 (d, J¼3.2 Hz,1H), 7.13e7.46
(m, 15H), 5.95e6.04 (m, 1H), 5.40 (s, 1H), 5.36 (d, J¼7.5 Hz, 1H),
4.63e4.77 (m, 3H), 4.45 (d, J¼11.9 Hz, 1H), 4.29 (d, J¼10.9 Hz, 1H),
4.09 (dd, J¼6.8, 3.9 Hz, 1H), 4.04 (dd, J¼7.0, 4.5 Hz, 1H), 3.83 (dd,
4.2.2. (1S,2S,3S,4R)-2,3,4-Tris(benzyloxy)-1-(2-thiazolyl)hex-5-en-1-
J¼6.8, 4.4 Hz, 1H), 3.24 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 171.2,
ol (5b). [
a
]
25 ꢀ18.5 (c 1.08, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.77
138.0, 137.8, 137.4, 134.8, 128.7, 128.4, 128.3, 128.1 (2), 127.7 (2),
D

668
W. Zhang et al. / Tetrahedron 69 (2013) 664e672
119.6, 82.1, 81.3, 80.8, 80.3, 75.4, 74.5, 70.6, 58.5. HRMS (ESI) m/z
calcd for C31H34NO4S (MþH) 516.22031, found 516.22007.
(d, J¼11.1 Hz, 1H), 4.37 (d, J¼11.7 Hz, 1H), 4.18 (t, J¼4.0 Hz, 1H), 3.99
(dd, J¼5.6, 2.5 Hz, 1H), 3.79 (t, J¼5.6 Hz, 1H), 3.74 (d, J¼2.4 Hz, 1H),
3.25 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 171.2, 138.0, 137.8, 137.4,
4.4. General procedure for the synthesis of 6c,d
134.8,128.7,128.4, 128.3,128.1,128.1,127.7 (2),119.6, 82.1, 81.3, 80.3
(2), 75.4, 74.5, 70.6, 58.5. HRMS (ESI) m/z calcd for C29H32NaO6
(MþNa) 499.20911, found 499.21042.
To a solution of compound 5c,d (1 equiv) in dry THF (2 mL) was
added portionwise NaH 60% (3 equiv) at room temperature. The
reaction mixture was stirred for 20 min and then benzyl bromide
(2 equiv) was added sequentially. The solution was stirred at room
temperature overnight until MeOH was added. The solvent was
concentrated at reduced pressure, saturated NaHCO3 was added,
and the mixture was extracted with dichloromethane. After drying
(anhydrous Na2SO4), the solvent was removed under vacuum and
the residue was chromatographed on silica gel (10:1 PE/ethyl ace-
tate) to give the O-benzyl derivative 6c,d.
4.5.2. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methoxyhept-6-enoic
25
acid (7b). Yield: 78%, colorless syrup; [
a
]
ꢀ27.7 (c 1.01, CHCl3);
D
1H NMR (400 MHz, CDCl3)
d
7.17e7.34 (m, 15H), 5.92e6.00 (m,
1H), 5.36 (s, 1H), 5.32 (d, J¼6.7 Hz, 1H), 4.55e4.75 (m, 5H), 4.37
(d, J¼12.0 Hz, 1H), 4.17 (dd, J¼7.2, 3.1 Hz, 1H), 3.82e3.84 (m, 2H),
3.62 (d, J¼3.1 Hz, 1H), 3.15 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
174.1, 138.2, 137.9, 137.5, 135.0, 128.7, 128.4, 128.2, 128.1 (2),
127.9, 127.5 (2), 118.9, 81.5, 80.1, 79.9, 78.8, 75.5, 75.3, 70.1, 58.7.
HRMS (ESI) m/z calcd for C29H32NaO6 (MþNa) 499.20911, found
499.21001.
4.4.1. 2-((1R,2R,3S,4R)-1,2,3,4-Tetra(benzyloxy)hex-5-en-1-yl)thia-
zole (6c). Yield: 92%, colorless syrup; [
NMR (400 MHz, CDCl3)
a
]
25 ꢀ6.6 (c 1.20, CHCl3); 1H
D
d
7.73 (d, J¼3.2 Hz, 1H), 7.18e7.31 (m,
4.5.3. (2S,3R,4S,5R)-2,3,4,5-Tetra(benzyloxy)hept-6-enoic acid (7c).
25
20H), 5.83e5.92 (m, 1H), 5.26 (s, 1H), 5.23 (d, J¼6.3 Hz, 1H), 4.98
(d, J¼5.3 Hz, 1H), 4.48e4.70 (m, 5H), 4.41 (d, J¼11.5 Hz, 1H), 4.31
(d, J¼11.8 Hz, 1H), 4.21e4.24 (m, 2H), 3.69 (t, J¼5.3 Hz, 1H). 13C
Yield: 76%, colorless syrup; [
a
]
ꢀ22.9 (c 0.35, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
7.07e7.22 (m, 21H), 5.76 (ddd, J¼17.7, 10.3,
7.6 Hz,1H), 5.16 (d, J¼11.0 Hz,1H), 5.01 (d, J¼17.4 Hz,1H), 4.46e4.67
(m, 6H), 4.16 (dd, J¼7.5, 3.4 Hz, 1H), 4.04 (d, J¼12.0 Hz, 1H), 3.91 (d,
J¼11.7 Hz, 1H), 3.77 (d, J¼3.3 Hz, 1H), 3.72 (dd, J¼7.5, 3.5 Hz, 1H),
NMR (100 MHz, CDCl3)
d 169.9, 142.1, 138.8, 138.6, 138.4, 137.6,
135.5, 128.4, 128.2, 128.1, 128.1, 128.0, 127.9, 127.7, 127.7, 127.6,
127.4, 120.5, 119.2, 81.8, 81.4, 81.1, 79.0, 75.3, 74.5, 71.3, 70.5. HRMS
(ESI) m/z calcd for C37H38NO4S (MþH) 592.25161, found
592.25250.
3.49 (dd, J¼7.5, 3.4 Hz,1H). 13C NMR (100 MHz, CDCl3)
d 174.4,138.2,
138.0, 137.7, 136.9, 135.2, 128.7, 128.5, 128.5, 128.3, 128.3, 128.1,
127.9, 127.7, 127.6, 127.0, 119.1, 81.6, 80.0, 78.9, 77.5, 75.6, 75.5, 73.1,
70.0. HRMS (ESI) m/z calcd for C35H36NaO6 (MþNa) 575.24041,
found 575.24121.
4.4.2. 2-((1S,2R,3S,4R)-1,2,3,4-Tetra(benzyloxy)hex-5-en-1-yl) thia-
zole (6d). Yield: 95%, colorless syrup; [
a
]
25 ꢀ40.9 (c 4.70, CHCl3); 1H
D
NMR (400 MHz, CDCl3)
d
7.89e7.90 (m, 1H), 7.30e7.43 (m, 20H),
4.5.4. (2R,3R,4S,5R)-2,3,4,5-Tetra(benzyloxy)hept-6-enoic acid (7d).
25
7.23e7.24 (m, 2H), 5.88e5.94 (m, 1H), 5.33 (d, J¼10.4 Hz, 1H), 5.18
(d, J¼17.4 Hz, 1H), 5.07 (dd, J¼3.8, 2.5 Hz, 1H), 4.63e4.84 (m, 5H),
4.45 (dd, J¼10.9, 2.0 Hz, 1H), 4.31 (dd, J¼11.8, 1.6 Hz, 1H), 4.23e4.26
Yield: 73%, colorless syrup; [
a
]
ꢀ8.2 (c 0.49, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
7.27e7.34 (m, 22H), 5.83e5.92 (m, 1H), 5.37 (s,
1H), 5.33 (d, J¼3.8 Hz, 1H), 4.61e4.86 (m, 6H), 4.39 (d, J¼11.7 Hz,
(m, 2H), 3.82 (d, J¼1.9 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 170.9,
1H), 4.32 (d, J¼11.5 Hz, 1H), 4.22 (t, J¼5.8 Hz, 1H), 4.12 (d, J¼5.8 Hz,
142.7, 138.8, 138.5, 138.1, 137.3, 135.5, 128.7, 128.6, 128.5, 128.4,
128.2, 128.2, 128.0, 127.8, 127.5, 127.4, 120.0, 119.1, 82.3, 82.0, 80.0,
78.9, 75.6, 75.4, 72.1, 70.3. HRMS (ESI) m/z calcd for C37H38NO4S
(MþH) 592.25161, found 592.25196.
2H), 3.83 (t, J¼5.3 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 172.1, 138.0,
137.9, 137.0, 134.8, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0 (3), 127.9,
127.2 (2), 119.5, 81.4, 81.0, 80.7, 79.6, 75.4, 74.6, 72.6, 70.6. HRMS
(ESI) m/z calcd for C35H36NaO6 (MþNa) 575.24041, found
575.24097.
4.5. General procedure for the synthesis of 7aed
4.6. General procedure for the synthesis of 8aed
A mixture of the thiazole derivative 6aed, methyl iodide
ꢀ
(5 equiv) and activated 4 A powdered molecular sieves in CH3CN
To a solution of the acid 7aed in dry DMF were added EDCI
(5 mL) was refluxed for 12 h. The suspension was filtered and then
concentrated. The residue was dissolved in CH3OH (2 mL), cooled
(ice bath), and treated with NaBH4 (2 equiv). The resulting mix-
ture was stirred at 0 ꢁC for 30 min, diluted with acetone (1 mL),
filtered through Celite, and concentrated. To a solution of the
residue in 4:1 CH3CN/H2O (2 mL) was added AgNO3 (1 equiv). The
mixture was stirred at 23 ꢁC for 10 min and then filtered through
Celite and concentrated to give the crude aldehyde (90% pure by
1H NMR) as clear yellow syrup. The syrup was dissolved in
(2 equiv), HOBt (2 equiv), and Et3N (3 equiv). After 30 min,
L
-(ꢀ)-
a-
amino- -caprolactam (1.5 equiv) was added and the mixture was
d
stirred at room temperature overnight. The reaction mixture was
concentrated, dissolved in dichloromethane and 1 N HCl was
added. The resultant solution was then partitioned between
dichloromethane and water. The combined organic layers were
dried (Na2SO4) and the solvent was evaporated in vacuo. The crude
was purified by flash chromatography on silica gel (5:1 PE/ethyl
acetate) to give 8aed.
MeCN/tBuOH/H2O (2:2:1), treated with NaClO2 (3 equiv), NaH2
-
PO4$H2O (3 equiv) and 35% H2O2 (10 equiv). The mixture was
stirred at room temperature for 3 h, Na2SO3 and 1 N HCl (aq) were
added, and the solution was extracted with dichloromethane. The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuo. The crude was purified by flash chroma-
tography on silica gel (50:1 dichloromethane/methanol) to give
7aed.
4.6.1. (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methoxy-N-((S)-2-
oxoazepan-3-yl)hept-6-enamide (8a). Yield: 85%, colorless syrup;
25
[a
]
þ15.5 (c 2.33, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.01 (d,
D
J¼6.0 Hz, 1H), 7.21e7.37 (m, 15H), 6.61 (t, J¼6.2 Hz, 1H), 6.02 (m,
1H), 5.41 (d, J¼17.3 Hz, 1H), 5.35 (d, J¼10.4 Hz, 1H), 4.83 (d,
J¼11.1 Hz, 1H), 4.75 (d, J¼11.0 Hz, 1H), 4.63e4.69 (m, 3H), 4.54 (dd,
J¼10.0, 6.0 Hz, 1H), 4.37 (d, J¼11.9 Hz, 1H), 4.25 (dd, J¼7.5, 3.8 Hz,
1H), 4.16 (dd, J¼7.2, 2.8 Hz, 1H), 3.90 (dd, J¼7.2, 3.9 Hz 1H), 3.76 (d,
J¼2.8 Hz, 1H), 3.25 (s, 3H), 3.17e3.20 (m, 2H), 2.10 (d, J¼6.0 Hz, 1H),
1.97e2.00 (m, 1H), 1.46e1.55 (m, 1H), 1.32e1.42 (m, 1H). 13C NMR
4.5.1. (2S,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methoxyhept-6-enoic
acid (7a). Yield: 80%, colorless syrup; [
NMR (400 MHz, CDCl3)
a
]
25 ꢀ16.0 (c 1.0, CHCl3); 1H
D
d
7.14e7.44 (m, 16H), 5.85 (m, 1H),
(100 MHz, CDCl3)
d 175.1, 169.4, 138.9, 138.4, 135.8, 128.3, 128.2,
5.20e5.47 (m, 2H), 4.68e4.83 (m, 3H), 4.61 (d, J¼11.7 Hz, 1H), 4.54
128.0, 127.5, 127.3, 127.2, 118.9, 82.3, 82.1, 80.9, 80.7, 75.6, 74.9, 70.3,

W. Zhang et al. / Tetrahedron 69 (2013) 664e672
669
58.0, 51.8, 42.0, 31.5, 28.9, 27.9. HRMS (ESI) m/z calcd for
C35H43N2O6 (MþH) 587.31156, found 587.31177.
HRMS (ESI) m/z calcd for C38H49N2O6 (MþH) 629.36014, found
629.35851.
4.6.2. (2S,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methoxy-N-((S)-2-
4.7.2. (2S,3R,4S,5R,E)-3,4,5-Tris(benzyloxy)-2-methoxy-8-methyl-N-
oxoazepan-3-yl)hept-6-enamide (8b). Yield: 78%, colorless syrup;
((S)-2-oxoazepan-3-yl)non-6-enamide (9b). Yield: 88%, brown
78% [
a]
25 ꢀ27.4 (c 2.63, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.78 (d,
foam; [
a
]
25 ꢀ58.9 (c 1.90, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.80
D
D
J¼7.0 Hz, 1H), 7.21e7.39 (m, 15H), 6.30 (t, J¼6.2 Hz, 1H), 5.98e6.07
(m, 1H), 5.38 (d, J¼2.1 Hz, 1H), 5.35 (d, J¼9.5 Hz, 1H), 4.68e4.81 (m,
3H), 4.53e4.63 (m, 3H), 4.39 (d, J¼12.0 Hz, 1H), 4.22 (dd, J¼7.8,
2.3 Hz, 1H), 3.84e3.86 (m, 2H), 3.60 (d, J¼2.4 Hz,1H), 3.20e3.28 (m,
5H), 1.77e1.88 (m, 4H), 1.27e1.39 (m, 2H). 13C NMR (100 MHz,
(d, J¼6.9 Hz, 1H), 7.22e7.40 (m, 15H), 6.59 (s, 1H), 5.70 (dd, J¼15.7,
6.4 Hz,1H), 5.60 (dd, J¼7.6, 1.1 Hz, 1H), 4.79 (dd, J¼20.7, 11.2 Hz, 2H),
4.54e4.70 (m, 4H), 4.38 (d, J¼12.1 Hz, 1H), 4.25 (dd, J¼8.1, 2.6 Hz,
1H), 3.75e3.82 (m, 2H), 3.57 (d, J¼2.6 Hz, 1H), 3.19e3.30 (m, 5H),
2.32e2.43 (m, 1H), 1.72e1.89 (m, 4H), 1.27e1.38 (m, 2H), 1.06 (dd,
CDCl3)
d
175.3, 169.6, 138.6, 138.5, 137.6, 135.3, 128.8, 128.4, 128.2
J¼11.2, 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 175.4, 169.6, 142.8,
(2), 128.0, 127.9, 127.7, 127.5, 118.7, 82.2, 82.0, 80.8, 78.9, 75.7, 75.4,
70.2, 59.1, 51.7, 42.1, 31.3, 30.9, 28.9, 28.0. HRMS (ESI) m/z calcd for
C35H43N2O6 (MþH) 587.31156, found 587.31262.
138.6, 138.7, 137.8, 128.9, 128.4, 128.2 (2), 127.8, 127.6, 127.5, 127.2,
123.9, 82.9, 82.2, 81.0, 78.4, 75.7, 75.5, 69.6, 59.1, 51.7, 42.0, 31.4,
31.0, 28.9, 28.0, 22.4. HRMS (ESI) m/z calcd for C38H49N2O6 (MþH)
629.36014, found 629.35851.
4.6.3. (2R,3R,4S,5R)-2,3,4,5-Tetra(benzyloxy)-N-((S)-2-oxoazepan-3-
yl)hept-6-enamide (8c). Yield: 72%, colorless syrup; 1H NMR
4.7.3. (2R,3R,4S,5R,E)-2,3,4,5-Tetra(benzyloxy)-8-methyl-N-((S)-2-
(400 MHz, CDCl3)
d
7.98 (d, J¼7.0 Hz,1H), 7.25e7.41 (m, 21H), 7.13 (t,
oxoazepan-3-yl)non-6-enamide (9c). Yield: 89%, brown foam; 1H
J¼5.8 Hz, 1H), 5.89e5.98 (m, 1H), 5.31 (d, J¼11.0 Hz, 1H), 5.14 (d,
J¼17.4 Hz, 1H), 4.85 (d, J¼11.2 Hz, 1H), 4.78 (d, J¼11.0 Hz, 1H),
4.58e4.68 (m, 5H), 4.34 (dd, J¼8.2, 2.5 Hz, 1H), 4.26 (d, J¼12.0 Hz,
1H), 3.97 (d, J¼11.1 Hz, 1H), 3.81e3.85 (m, 2H), 3.58 (dd, J¼7.3,
2.6 Hz,1H), 3.13e3.28 (m, 2H),1.73e1.91 (m, 4H),1.32e1.36 (m, 2H).
NMR (400 MHz, CDCl3)
d
7.96 (d, J¼7.0 Hz, 1H), 7.23e7.41 (m, 21H),
7.02 (s, 1H), 5.49 (dd, J¼15.7, 7.6 Hz, 1H), 5.41 (dd, J¼15.7, 6.0 Hz,
1H), 4.85 (d, J¼11.3 Hz, 1H), 4.78 (d, J¼11.1 Hz, 1H), 4.58e4.67 (m,
5H), 4.34 (dd, J¼8.1, 2.6 Hz, 1H), 4.26 (d, J¼12.1 Hz, 1H), 3.92 (d,
J¼11.1 Hz, 1H), 3.76e3.82 (m, 2H), 3.50 (dd, J¼7.6, 2.8 Hz, 1H),
3.18e3.28 (m, 2H), 2.28e2.36 (m, 1H), 1.73e1.90 (m, 4H), 1.27e1.38
(m, 3H), 1.04 (dd, J¼13.1, 6.7 Hz, 6H), 0.88e0.95 (m, 1H). 13C NMR
13C NMR (100 MHz, CDCl3)
d 175.7, 169.6, 138.7, 138.5, 137.7, 136.8,
135.5, 129.0, 128.9, 128.5, 128.5, 128.3, 128.2, 128.2, 128.1, 127.9,
127.7, 127.5, 127.3, 119.0, 82.3, 80.7, 79.9, 78.6, 77.6, 77.4, 77.2, 76.9,
75.8, 75.6, 73.4, 70.0, 51.8, 42.0, 31.3, 28.8, 28.1.
(100 MHz, CDCl3)
d 175.7, 169.6, 138.8, 138.6, 137.9, 136.9, 129.0 (2),
128.5, 128.4, 128.2, 128.1 (2), 127.8, 127.7, 127.5, 127.2, 123.9, 82.7,
80.9, 80.1, 78.0, 75.8, 75.7, 73.5, 69.3, 51.8, 42.0, 31.4, 30.9, 28.8, 28.1,
22.4, 22.3. HRMS (ESI) m/z calcd for C44H53N2O6 (MþH) 705.38981,
found 705.39074.
4.6.4. (2S,3R,4S,5R)-2,3,4,5-Tetra(benzyloxy)-N-((S)-2-oxoazepa-3-
yl)hept-6-enamide (8d). Yield: 78%, colorless syrup; 1H NMR
(400 MHz, CDCl3)
d
8.22 (d, J¼5.9 Hz, 1H), 7.23e7.39 (m, 21H), 7.07
(t, J¼6.0 Hz, 1H), 6.05 (ddd, J¼17.7, 10.3, 7.7 Hz, 1H), 5.43 (d,
J¼17.4 Hz, 1H), 5.37 (d, J¼10.6 Hz, 1H), 4.89 (d, J¼11.1 Hz, 1H),
4.66e4.78 (m, 4H), 4.57 (dd, J¼10.3, 5.8 Hz, 1H), 4.49 (d, J¼11.8 Hz,
1H), 4.41 (d, J¼11.8 Hz, 1H), 4.36 (d, J¼12.0 Hz, 1H), 4.27e4.31 (m,
2H), 4.09 (d, J¼2.7 Hz, 1H), 3.96 (dd, J¼7.0, 3.9 Hz, 1H), 3.10e3.22
(m, 2H), 2.09 (d, J¼13.1 Hz, 1H), 2.00 (d, J¼14.2 Hz, 1H), 1.78e1.89
(m, 2H), 1.50 (dd, J¼8.0, 16.0 Hz, 1H), 1.37 (dd, J¼21.9, 11.3 Hz, 1H).
4.7.4. (2S,3R,4S,5R,E)-2,3,4,5-Tetra(benzyloxy)-8-methyl-N-((S)-2-
25
oxoazepan-3-yl)non-6-enamide (9d). Yield: 90%, brown foam; [a]
D
ꢀ7.9 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.22 (d, J¼4.8 Hz,
1H), 7.22e7.35 (m, 20H), 7.01e7.07 (m, 1H), 5.82 (dd, J¼15.7, 6.4 Hz,
1H), 5.62 (dd, J¼15.7, 8.2 Hz, 1H), 4.89 (d, J¼11.1 Hz, 1H), 4.63e4.77
(m, 4H), 4.56 (dd, J¼26.4, 11.8 Hz, 2H), 4.47 (d, J¼11.8 Hz, 1H), 4.41
(d, J¼11.8 Hz, 1H), 4.24e4.34 (m, 3H), 4.06 (s, 1H), 3.90e3.93 (m,
1H), 3.15e3.21 (m, 2H), 2.33e2.42 (m, 1H), 1.97e2.10 (m, 2H),
1.78e1.89 (m, 1H), 1.49 (dd, J¼24.0, 11.3 Hz, 1H), 1.36 (dd, J¼23.3,
11.9 Hz, 2H), 1.05 (td, J¼6.6, 1.3 Hz, 6H), 0.93 (dd, J¼15.8, 9.1 Hz, 1H).
13C NMR (100 MHz, CDCl3)
d 175.3, 169.5, 138.9, 138.8, 138.4, 137.5,
135.7, 128.5, 128.4, 128.2 (2), 128.1, 127.8, 127.6, 127.5, 127.4 (2),
119.1, 82.1, 81.5, 80.9, 80.4, 75.7, 75.1, 72.3, 70.3, 51.9, 41.9, 31.4,
28.9, 28.0.
13C NMR (100 MHz, CDCl3)
d 175.3, 169.5, 143.0, 139.0, 138.9, 138.7,
137.6, 128.4, 128.3 (2), 128.1, 128.1, 127.7, 127.5, 127.4, 127.3, 124.4,
82.8, 81.7, 80.7, 80.6, 75.8, 75.2, 72.2, 69.8, 51.9, 41.9, 31.4, 31.0, 28.9,
28.0, 22.4. HRMS (ESI) m/z calcd for C44H53N2O6 (MþH) 705.38981,
found 705.39093.
4.7. General procedure for the synthesis of 9aed
Compound 8aed was dissolved in a 1:2 CH2Cl2/3-methyl-1-
butene mixture (3 mL), and HoveydaeGrubbs catalysts second
generation (0.3 equiv) was added. The flask was then capped and
the mixture was refluxed for 24 h, after which the crude mixture
was concentrated and purified by flash column chromatography on
silica gel (5:1 PE/acetone) to yield 9ae9d.
4.8. General procedure for the synthesis of 1aed
To a solution of 9aed in a mixture of THF (3 mL) and liquid
ammonia (15 mL) at ꢀ78 ꢁC was added sodium metal until the blue
color persisted. After 1 h, the reaction finished and the NH3 (g) was
evaporated. The residue was then partitioned between dichloro-
methane and water. The combined organic layers were dried
(Na2SO4) and the solvent was evaporated in vacuo. The crude was
purified by flash chromatography on silica gel (5:1 ethyl acetate/
methanol) to give 1aed.
4.7.1. (2R,3R,4S,5R,E)-3,4,5-Tris(benzyloxy)-2-methoxy-8-methyl-N-
((S)-2-oxoazepan-3-yl)non-6-enamide (9a). Yield: 93%, brown
foam; 1H NMR (400 MHz, CDCl3)
d
7.97 (d, J¼5.8 Hz, 1H), 7.22e7.34
(m, 15H), 6.09 (s, 1H), 5.78 (dd, J¼15.7, 6.4 Hz, 1H), 5.58 (dd, J¼15.7,
8.0 Hz,1H), 4.81 (d, J¼11.2 Hz,1H), 4.74 (d, J¼11.0 Hz,1H), 4.61e4.68
(m, 3H), 4.54 (dd, J¼10.2, 6.1 Hz, 1H), 4.33 (d, J¼12.0 Hz, 1H),
4.14e4.20 (m, 2H), 3.84 (dd, J¼3.8, 7.2 Hz, 1H), 3.72 (d, J¼2.6 Hz,
1H), 3.22 (s, 4H), 2.34 (dd, J¼13.2, 6.5 Hz, 1H), 2.08 (d, J¼13.7 Hz,
1H), 1.99 (d, J¼15.5 Hz, 1H), 1.82e1.88 (m, 2H), 1.39e1.51 (m, 3H),
1.35 (s, 3H), 1.28 (s, 2H), 1.02 (t, J¼6.9 Hz, 6H). 13C NMR (100 MHz,
4.8.1. Bengamide E (1a). Yield: 58%, white foam; [
MeOH); 1H NMR (400 MHz, CDCl3)
a
]
29 þ36.0 (c 1.33,
D
d
7.87 (d, J¼6.9 Hz, 1H), 6.17 (t,
J¼6.0 Hz, 1H), 5.81 (dd, J¼15.6, 6.5 Hz, 1H), 5.44 (ddd, J¼15.5, 7.1,
1.2 Hz, 1H), 4.58 (dd, J¼10.1, 7.0 Hz, 1H), 4.25 (t, J¼6.3 Hz, 1H), 4.03
(d, J¼6.6 Hz, 1H), 3.96 (t, J¼5.3 Hz, 1H), 3.83 (d, J¼5.5 Hz, 1H), 3.60
(s, 1H), 3.53 (s, 3H), 3.41e3.21 (m, 2H), 3.18e2.99 (m, 2H), 2.32 (dq,
J¼12.7, 6.4 Hz, 1H), 2.05 (dd, J¼25.1, 9.8 Hz, 2H), 1.95e1.64 (m, 5H),
CDCl3)
d 175.3, 169.5, 143.0, 139.0, 138.6, 128.3, 128.3, 128.3, 128.3,
128.1,128.0,127.5,127.4,127.2,124.4, 82.7, 82.3, 81.2, 80.5, 77.5, 77.4,
77.2, 76.9, 75.8, 75.1, 69.7, 57.9, 51.9, 41.9, 31.5, 31.0, 28.9, 28.0, 22.4.

670
W. Zhang et al. / Tetrahedron 69 (2013) 664e672
1.64e1.49 (m, 1H), 1.49e1.35 (m, 1H), 1.01 (dd, J¼6.8, 1.0 Hz, 6H). 13
C
4.80 (d, J¼11.4 Hz, 1H), 4.60e4.70 (m, 5H), 4.51 (d, J¼2.0 Hz, 1H),
NMR (100 MHz, CDCl3)
d
175.1, 171.6, 141.7, 125.5, 81.5, 74.0, 72.6,
4.44 (d, J¼11.4 Hz, 1H), 4.18e4.24 (m, 2H), 4.05 (d, J¼8.4 Hz, 1H). 13
C
59.6, 51.9, 42.0, 41.9, 31.0, 30.8, 28.7, 27.9, 22.2, 22.1. HRMS (ESI) m/z
calcd for C17
31N2O6 (MþH) 359.21766, found 359.21771.
NMR (100 MHz, CDCl3) d 174.8, 140.7, 138.1, 137.6, 137.1, 135.9, 128.6,
H
128.5, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.1, 120.4, 81.9,
79.2, 77.9, 77.6, 77.3, 76.9, 74.7, 73.7, 70.3, 65.0. HRMS (ESI) m/z calcd
for C27 H28NaO5 (MþNa) 455.18290, found 455.18367.
4.8.2. (2S,3R,4S,5R,E)-3,4,5-Trihydroxy-2-methoxy-8-methyl-N-((S)-
2-oxoazepan-3-yl)non-6-enamide (1b). Yield: 71%, white foam;
25
[
a]
ꢀ24.4 (c 1.97, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.87 (d,
4.9.3. (2R,3S,4S)-2,3,4-Tris(benzyloxy)hex-5-enoic acid (10c). Yield:
D
J¼6.9 Hz, 1H), 6.17 (t, J¼6.0 Hz, 1H), 5.81 (dd, J¼15.6, 6.5 Hz, 1H),
5.44 (ddd, J¼15.5, 7.1, 1.2 Hz, 1H), 4.58 (dd, J¼10.1, 7.0 Hz, 1H), 4.25
(t, J¼6.3 Hz,1H), 4.03 (d, J¼6.6 Hz,1H), 3.96 (t, J¼5.3 Hz,1H), 3.83 (d,
J¼5.5 Hz, 1H), 3.60 (s, 1H), 3.53 (s, 3H), 3.24e3.37 (m, 2H), 3.08 (d,
J¼4.7 Hz, 1H), 3.03 (s, 1H), 2.28e2.36 (m, 1H), 2.01e2.10 (m, 2H),
1.50e1.59 (m, 1H), 1.38e1.48 (m, 1H), 1.01 (dd, J¼6.8, 1.0 Hz, 6H). 13C
84%, colorless syrup; [
a
]
25 ꢀ15.5 (c 1.03, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
7.28e7.41 (m, 15H), 5.92e6.10 (m, 1H), 5.48 (d, J¼17.2 Hz,
1H), 5.40 (d, J¼10.4 Hz, 1H), 4.70e4.86 (m, 4H), 4.45e4.50 (m, 2H),
4.34 (s, 1H), 4.25 (s, 1H), 4.01 (s, 1H). 13C NMR (100 MHz, CDCl3)
d
174.2, 138.2, 138.1, 137.2, 135.0, 132.4, 132.3, 128.5, 128.5, 128.4,
128.3, 128.2, 128.1 (2), 127.8, 82.7, 80.9, 78.8, 74.9, 72.8, 70.9. HRMS
(ESI) m/z calcd for C27 H28NaO5 (MþNa) 455.18290, found
455.18337.
NMR (100 MHz, CDCl3)
d 175.2, 170.1, 141.8, 125.4, 82.1, 73.9, 73.0,
71.9, 59.2, 51.7, 42.1, 31.1, 30.7, 28.8, 27.9, 22.2, 22.1. HRMS (ESI) m/z
calcd for C17H30N2NaO6 (MþNa) 381.20046, found 381.20046.
4.10. General procedure for the synthesis of 11aec
4.8.3. (2R,3R,4S,5R,E)-2,3,4,5-Tetrahydroxy-8-methyl-N-((S)-2-
oxoazepan-3-yl)non-6-enamide (1c). Yield: 43%, colorless syrup;
To the solution of the acid 10aec in dry DMF were added EDCI
þ34.7 (c 1.5, CH3OH); 1H NMR (400 MHz, D2O)
d
5.86 (dd,
(2 equiv), HOBt (2 equiv), and Et3N (3 equiv). After 30 min,
L
-(ꢀ)-
a-
25
[
a]
D
J¼15.5, 6.4 Hz, 1H), 5.39 (dd, J¼15.6, 8.1 Hz, 1H), 4.64 (d, J¼10.4 Hz,
1H), 4.28 (d, J¼6.5 Hz, 1H), 4.15 (t, J¼8.1 Hz, 1H), 3.85 (d, J¼5.5 Hz,
1H), 3.70 (d, J¼8.0 Hz, 1H), 3.27e3.39 (m, 2H), 2.28e2.36 (m, 1H),
2.02 (d, J¼12.4 Hz, 1H), 1.66e1.93 (m, 4H), 1.40 (dd, J¼25.0, 11.8 Hz,
amino- -caprolactam (1.5 equiv) was added and the mixture was
d
stirred at room temperature overnight. The reaction mixture was
concentrated, dissolved in dichloromethane and 1N HCl was added.
The resultant solution was then partitioned between dichloro-
methane and water. The combined organic layers were dried
(Na2SO4) and the solvent was evaporated in vacuo. The crude was
purified by flash chromatography on silica gel (5:1 PE/acetone) to
give 11aec.
1H), 0.99 (d, J¼6.8 Hz, 6H). 13C NMR (100 MHz, D2O)
d 177.0, 173.3,
143.7, 124.3, 73.7, 72.9, 72.7, 70.8, 52.1, 41.4, 30.3, 30.0, 27.6, 27.4,
21.3. HRMS (ESI) m/z calcd for C16H28N2NaO6 (MþNa) 367.18396,
found 367.18445.
4.8.4. (2S,3R,4S,5R,E)-2,3,4,5-Tetrahydroxy-8-methyl-N-((S)-2-
oxoazepan-3-yl)non-6-enamide (1d). Yield: 50%, colorless syrup;
4.10.1. (2R,3S,4R)-2,3,4-Tris(benzyloxy)-N-((S)-2-oxoazepan-3-yl)
25
hex-5-enamide (11a). Yield: 81%, white solid; [
a
]
þ37.1 (c 1.4,
D
25
[
a]
ꢀ24.0 (c 0.5, CH3OH); 1H NMR (400 MHz, D2O)
d
5.82 (dd,
CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.03 (d, J¼5.2 Hz, 1H),
D
J¼15.5, 6.5 Hz, 1H), 5.45 (ddd, J¼15.6, 7.7, 1.2 Hz, 1H), 4.62 (dd,
J¼11.2, 1.5 Hz, 1H), 4.31 (d, J¼3.5 Hz, 1H), 4.16 (t, J¼7.8 Hz, 1H), 3.94
(t, J¼3.8 Hz, 1H), 3.66 (dd, J¼6.0, 4.4 Hz, 1H), 3.23e3.36 (m, 2H),
2.26e2.34 (m, 1H), 1.97e2.02 (m, 1H), 1.63e1.89 (m, 4H), 1.31e1.41
7.19e7.32 (m, 15H), 6.31 (t, J¼6.1 Hz, 1H), 5.73e5.82 (m, 1H), 5.29
(dd, J¼10.3, 1.3 Hz, 1H), 5.24 (d, J¼17.2 Hz, 1H), 4.84 (d, J¼11.6 Hz,
1H), 4.54e4.62 (m, 3H), 4.41e4.44 (m, 2H), 4.23 (dd, J¼10.7, 5.3 Hz,
1H), 4.17 (t, J¼7.9 Hz, 1H), 4.03 (d, J¼2.4 Hz, 1H), 3.95 (dd, J¼7.8,
2.4 Hz,1H), 3.17e3.21 (m, 2H),1.95e2.01 (m, 2H),1.76e1.83 (m, 2H),
(m, 1H), 0.96 (d, J¼6.8 Hz, 6H). 13C NMR (100 MHz, D2O)
d 177.0,
173.3, 143.0, 124.5, 74.4, 73.0, 72.7, 71.1, 51.9, 41.3, 30.2, 30.0, 27.5,
27.3, 21.3, 21.2. HRMS (ESI) m/z calcd for C16H28N2NaO6 (MþNa)
367.18396, found 367.18439.
1.37 (dd, J¼23.6, 11.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 175.2,
170.1, 138.8, 138.6, 136.8, 135.1, 128.9, 128.5, 128.3, 128.2, 128.0,
127.8, 127.4, 127.3, 119.7, 82.8, 82.5, 80.3, 77.5, 77.1, 76.8, 75.8, 73.9,
71.1, 52.1, 41.9, 31.3, 28.9, 27.9. HRMS (ESI) m/z calcd for C33H39N2O5
(MþH) 543.28535, found 543.28524.
4.9. General procedure for the synthesis of 10aec
The aldehyde 2aec was dissolved in MeCN/tBuOH/H2O (2:2:1),
and treated with NaClO2 (3 equiv), NaH2PO4$H2O (3 equiv) and 35%
H2O2 (10 equiv). The mixture was stirred at room temperature for
3 h, Na2SO3 and 1 N HCl (aq) were added, and the mixture was
extracted with dichloromethane. The combined organic layers
were dried (Na2SO4) and the solvent was evaporated in vacuo. The
crude was purified by flash chromatography on silica gel (50:1
dichloromethane/methanol) to give 10aec.
4.10.2. (2S,3S,4R)-2,3,4-Tris(benzyloxy)-N-((S)-2-oxoazepan-3-yl)
25
hex-5-enamide (11b). Yield: 79%, white solid; [
a
]
þ23.9 (c 0.67,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.16 (d, J¼5.4 Hz,1H), 7.42e7.11
(m, 17H), 5.79e6.01 (m, 1H), 5.49 (d, J¼17.2 Hz, 1H), 5.43 (d,
J¼10.3 Hz, 1H), 4.67e4.41 (m, 5H), 4.37 (s, 1H), 4.28 (dd, J¼10.6,
5.6 Hz, 1H), 4.21 (d, J¼11.6 Hz, 1H), 4.13 (t, J¼8.1 Hz, 1H), 3.98 (d,
J¼8.2 Hz, 1H), 3.08e3.16 (m, 1H), 1.94 (d, J¼11.3 Hz, 2H), 1.71e1.77
(m, 2H), 1.35 (dd, J¼25.2, 13.1 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
175.4, 170.8, 138.3, 138.1, 137.0, 136.2, 128.8, 128.5, 128.4, 128.2,
4.9.1. (2R,3S,4R)-2,3,4-Tris(benzyloxy)hex-5-enoic acid (10a). Yield:
128.1, 128.0, 127.7, 127.5, 127.5, 120.2, 82.5, 79.6, 79.3, 75.4, 74.3,
70.0, 51.9, 41.9, 31.2, 28.8, 27.9. HRMS (ESI) m/z calcd for C33H39N2O5
(MþH) 543.28535, found 543.28543.
88%, colorless syrup; 1H NMR (400 MHz, CDCl3)
d 7.14e7.29 (m,
15H), 5.64e5.74 (m, 1H), 5.16e5.23 (m, 2H), 4.78 (d, J¼11.2 Hz, 1H),
4.66 (d, J¼11.3 Hz, 1H), 4.52e4.59 (m, 2H), 4.29e4.37 (m, 2H), 4.15
(t, J¼7.5 Hz, 1H), 4.08 (d, J¼2.9 Hz, 1H), 3.88 (dd, J¼7.2, 3.1 Hz, 1H).
4.10.3. (2R,3S,4S)-2,3,4-Tris(benzyloxy)-N-((S)-2-oxoazepan-3-yl)
25
13C NMR (100 MHz, CDCl3)
d
174.5, 138.1, 137.8, 136.7, 134.5, 128.5,
hex-5-enamide (11c). Yield: 72%, white solid; [
a
]
ꢀ9.2 (c 0.87,
D
128.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.6, 119.9, 81.7, 81.3, 78.2,
75.3, 73.5, 71.7. HRMS (ESI) m/z calcd for C27 H28NaO5 (MþNa)
455.18290, found 455.18360.
CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.06 (d, J¼6.6 Hz, 1H),
7.27e7.41 (m, 15H), 5.88 (ddd, J¼17.6, 10.3, 7.7 Hz, 1H), 5.48 (d,
J¼17.2 Hz, 1H), 5.33 (d, J¼11.3 Hz, 1H), 4.83 (dd, J¼28.2, 11.5 Hz, 2H),
4.46e4.72 (m, 4H), 4.47 (d, J¼11.7 Hz, 1H), 4.32 (t, J¼7.4 Hz, 1H),
4.20 (d, J¼2.9 Hz, 1H), 3.99 (dd, J¼7.2, 2.9 Hz, 1H), 3.16e3.20 (m,
2H), 2.05 (d, J¼13.4 Hz, 1H), 1.95 (d, J¼14.2 Hz, 1H), 1.76e1.81 (m,
4.9.2. (2S,3S,4R)-2,3,4-Tris(benzyloxy)hex-5-enoic acid (10b). Yield:
83%, colorless syrup; [
a
]
25 þ13.6 (c 0.88, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
7.28e7.43 (m, 15H), 5.91e6.00 (m, 1H), 5.49e5.56 (m, 2H),
2H), 1.29e1.44 (m, 2H). 13C NMR (100 MHz, CDCl3)
d 175.7, 169.1,

W. Zhang et al. / Tetrahedron 69 (2013) 664e672
671
138.8, 138.7, 137.3, 135.2, 132.2, 132.1, 128.7, 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 127.4, 127.4, 119.7, 83.4, 81.6, 80.0, 77.6,
74.7, 72.9, 70.9, 51.9, 41.9, 31.22, 28.9, 28.1. HRMS (ESI) m/z calcd for
C33H39N2O5 (MþH) 543.28535, found 543.28547.
purified by flash chromatography on silica gel (5:1 ethyl acetate/
methanol) to give 1eeg.
4.12.1. (2R,3S,4R,E)-2,3,4-Trihydroxy-7-methyl-N-((S)-2-oxoazepan-
25
3-yl)oct-5-enamide (1e). Yield: 48%, colorless syrup; [
a
]
þ21.4 (c
D
0.56, CHCl3);1HNMR (400 MHz, CDCl3)
d
7.74 (d, J¼6.9 Hz,1H), 6.63(s,
4.11. General procedure for the synthesis of 12aec
1H), 5.81(dd, J¼15.5, 6.5 Hz,1H), 5.52 (dd, J¼15.5, 7.1 Hz,1H), 4.60 (dd,
J¼10.7, 7.3 Hz, 1H), 4.44 (s, 1H), 4.42e4.28 (m, 3H), 3.96 (d, J¼5.0 Hz,
1H), 3.24e3.37 (m, 3H), 2.28e2.37 (m, 1H), 1.79e2.06 (m, 5H), 1.61
(dd, J¼23.8,12.3 Hz,1H),1.43 (dd, J¼22.7,12.5 Hz,1H),1.01 (dd, J¼6.7,
Compound 11aec was dissolved in a 1:2 CH2Cl2/3-methyl-1-
butene mixture (3 mL), and HoveydaeGrubbs catalysts second
generation (0.3 equiv) was added. The flask was then capped and
the mixture was refluxed for 24 h, after which the crude mixture
was concentrated and purified by flash column chromatography
(silica gel, 5:1 PE/acetone) to yield 12aec.
1.6Hz, 6H).13C NMR (100 MHz, CDCl3)
d 175.9,172.2,142.3,125.4, 74.2,
74.1, 73.4, 52.1, 42.0, 30.8, 30.6, 28.6, 28.0, 22.1, 22.1. HRMS (ESI) m/z
calcd for C15H26N2NaO5 (MþNa) 337.17339, found 337.17384.
4.12.2. (2S,3S,4R,E)-2,3,4-Trihydroxy-7-methyl-N-((S)-2-oxoazepan-
4.11.1. (2R,3S,4R,E)-2,3,4-Tris(benzyloxy)-7-methyl-N-((S)-2-
25
3-yl)oct-5-enamide (1f). Yield: 42%, colorless syrup; [
a
]
ꢀ12.3 (c
D
25
oxoazepan-3-yl)oct-5-enamide (12a). Yield: 88%, brown foam; [a]
D
0.65, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.10 (d, J¼6.6 Hz,1H), 6.60
þ31.1 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.10 (d, J¼5.3 Hz,
(s, 1H), 5.77 (dd, J¼15.5, 6.2 Hz, 1H), 5.58 (dd, J¼15.7, 6.3 Hz, 1H),
4.57 (dd, J¼10.8, 6.9 Hz, 1H), 4.39 (d, J¼6.0 Hz, 1H), 4.15 (d, J¼7.5 Hz,
1H), 3.67 (d, J¼7.5 Hz, 1H), 3.18e3.35 (s, 2H), 2.27e2.35 (m, 1H),
2.00e2.04 (m, 2H), 1.76e1.87 (m, 3H), 1.57 (dd, J¼23.4, 12.0 Hz, 1H),
1.40 (dd, J¼21.7, 11.0 Hz, 1H), 0.99 (d, J¼6.8 Hz, 6H). 13C NMR
1H), 7.13e7.41 (m, 16H), 5.69 (dd, J¼15.6, 6.6 Hz, 1H), 5.37 (ddd,
J¼15.5, 8.6, 0.8 Hz, 1H), 4.91 (d, J¼11.6 Hz, 1H), 4.58 (t, J¼10.8 Hz,
3H), 4.44 (dd, J¼11.3, 2.8 Hz, 2H), 4.25 (dd, J¼10.6, 5.3 Hz, 1H), 4.19
(t, J¼8.4 Hz, 1H), 4.04 (d, J¼2.2 Hz, 1H), 3.98 (dd, J¼8.3, 2.2 Hz, 1H),
3.10e3.23 (m, 2H), 2.31e2.39 (m, 1H), 1.99 (t, J¼15.0 Hz, 3H),
1.74e1.83 (m, 2H),1.34e1.43 (m, 2H),1.04 (dd, J¼6.8, 3.0 Hz, 6H). 13C
(100 MHz, CDCl3)
d 175.4, 172.9, 140.7, 126.0, 74.8, 71.8, 71.2, 70.5,
52.2, 42.1, 31.3, 30.8, 28.8, 28.0, 22.2, 22.2. HRMS (ESI) m/z calcd for
C15H26N2NaO5 (MþNa) 337.17339, found 337.17398.
NMR (100 MHz, CDCl3)
d 180.2, 175.2, 149.0, 143.9, 143.8, 141.9,
133.7, 133.5, 133.3, 133.1, 133.0, 133.0, 132.8, 132.3, 132.1, 128.9, 88.2,
87.5, 85.7, 82.4, 82.1, 81.8, 81.0, 79.0, 75.7, 57.0, 46.9, 36.2, 36.0, 33.9,
32.9, 27.4, 27.3. HRMS (ESI) m/z calcd for C36H45N2O5 (MþH)
585.33230, found 585.33372.
4.12.3. (2R,3S,4S,E)-2,3,4-Trihydroxy-7-methyl-N-((S)-2-oxoaze-
25
pan-3-yl)oct-5-enamide (1g). Yield: 40%, colorless syrup; [a]
D
ꢀ32.4 (c 0.37, CH3OH); 1H NMR (400 MHz, D2O)
d
5.75 (dd, J¼15.5,
6.2 Hz, 1H), 5.32 (dd, J¼16.9, 7.7 Hz, 1H), 4.45 (d, J¼11.1 Hz, 1H), 4.20
(d, J¼4.0 Hz, 1H), 4.13 (t, J¼6.9 Hz, 1H), 3.71 (dd, J¼6.3, 4.0 Hz, 1H),
3.18e3.24 (m, 2H), 2.13e2.21 (m, 1H), 1.86e1.96 (m, 1H), 154e1.80
(m, 5H), 1.28 (ddd, J¼14.0, 11.6, 3.1 Hz, 1H), 0.87 (dd, J¼6.8, 1.4 Hz,
4.11.2. (2S,3S,4R,E)-2,3,4-Tris(benzyloxy)-7-methyl-N-((S)-2-
25
oxoazepan-3-yl)oct-5-enamide (12b). Yield: 88%, brown foam; [a]
D
þ15.2 (c 0.79, CHCl3); 1H NMR (400 MHz, CDCl3)
8.12 (d, J¼5.1 Hz,
d
1H), 7.21e7.33 (m, 17H), 6.74 (s, 1H), 5.85 (dd, J¼15.5, 6.5 Hz, 1H),
5.40 (dd, J¼15.2, 8.2 Hz, 1H), 4.36e4.60 (m, 6H), 4.26 (dd, J¼10.3,
5.4 Hz, 1H), 4.18 (d, J¼11.6 Hz, 1H), 4.06 (t, J¼8.5 Hz, 1H), 3.95 (dd,
J¼8.5, 1.6 Hz, 1H), 3.07e3.25 (m, 2H), 2.34e2.42 (m, 1H), 1.69e1.96
(m, 5H), 1.28e1.47 (m, 2H), 1.03 (dd, J¼6.6, 2.3 Hz, 6H). 13C NMR
6H). 13C NMR (100 MHz, D2O)
d 177.0, 173.0, 143.0, 124.2, 75.1, 72.8,
72.1, 52.1, 41.3, 30.1, 29.7, 27.5, 27.4, 21.3, 21.0. HRMS (ESI) m/z calcd
for C15H26N2NaO5 (MþNa) 337.17339, found 337.17409.
4.13. Methods for bioactivity assays
(100 MHz, CDCl3)
d 180.1, 175.8, 149.3, 143.6, 142.1, 133.8, 133.4,
133.3, 133.0, 132.6, 132.4, 129.9, 87.7, 84.6, 84.1, 82.4, 82.1, 81.8, 80.3,
79.3, 74.5, 56.9, 47.0, 36.3, 36.1, 33.9, 32.9, 27.4, 27.1. HRMS (ESI) m/z
calcd for C36H45N2O5 (MþH) 585.33230, found 585.33364.
Each test solution for in vitro assay was prepared by diluting with
DMSO. All cells used in the research were prepared at 3.5ꢂ104 cells/
mL concentration and each 100 mL cells suspension was seeded in
96-well cell microplate for 24 h (37 ꢁC, 5% CO2). Then each solution
was added and incubated for another 72 h. For the control group,
equivalent concentration of DMSO (final concentration 0.5%) was
added. MTT (3-[4,5-dimethylthiazol-2yl]-diphenyl tetrazolium
bromide) method was employed to measure the number of surviv-
ing cells and recorded the OD value at 492/620 nm. The IC50 values
were calculated using Prism Graph pad software of the triplicate
experiment.
4.11.3. (2R,3S,4S,E)-2,3,4-Tris(benzyloxy)-7-methyl-N-((S)-2-
25
oxoazepan-3-yl)oct-5-enamide (12c). Yield: 75%, brown foam; [a]
D
ꢀ10.8 (c 1.11, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.01 (d, J¼6.6 Hz,
1H), 7.25e7.40 (m, 15H), 7.06 (s, 1H), 5.83 (dd, J¼15.6, 6.6 Hz, 1H),
5.36 (dd, J¼15.6, 8.2 Hz, 1H), 4.82 (q, J¼11.6 Hz, 2H), 4.69 (d,
J¼11.7 Hz, 1H), 4.57 (dt, J¼19.0, 11.7 Hz, 3H), 4.44 (d, J¼11.7 Hz, 1H),
4.27 (t, J¼7.7 Hz, 1H), 4.14 (d, J¼2.9 Hz, 1H), 3.89 (dd, J¼7.2, 2.9 Hz,
1H), 3.17e3.27 (m, 2H), 2.26e2.34 (m, 1H), 2.04 (d, J¼13.8 Hz, 1H),
1.95 (dd, J¼11.3, 3.0 Hz,1H),1.80 (d, J¼13.1 Hz, 2H),1.31e1.47 (m, 2H),
0.99 (t, J¼6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 175.7, 169.2, 143.5,
Acknowledgements
139.0, 137.3, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.3, 123.9, 83.6,
81.3, 79.9, 77.5, 77.2, 76.9, 74.8, 72.5, 70.5, 51.8, 42.0, 31.5, 30.9, 28.9,
28.1, 22.3. HRMS (ESI) m/z calcd for C36H45N2O5 (MþH) 585.33230,
found 585.33372.
This work was supported by grants from the National Natural
Science Foundation of China (NSFC No. 21072017) and the National
Basic Research Program of China (Grant No. 2012CB822100).
Supplementary data
4.12. General procedure for the synthesis of 1eeg
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.004.
To a solution of 12aec in a mixture of THF (3 mL) and liquid
ammonia (15 mL) at ꢀ78 ꢁC was added sodium metal until the blue
color persisted. After 1 h, the reaction finished and the NH3 (g) was
evaporated. The residue was then partitioned between dichloro-
methane and water. The combined organic layers were dried
(Na2SO4) and the solvent was evaporated in vacuo. The crude was
References and notes
~
ꢁ
1. (a) Quinoa, E.; Adamczeski, M.; Crews, P.; Bakus, G. J. Org. Chem. 1986, 51,
~
ꢁ
4494e4497; (b) Adamczeski, M.; Quinoa, E.; Crews, P. J. Am. Chem. Soc. 1989,

672
W. Zhang et al. / Tetrahedron 69 (2013) 664e672
~
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