Formal synthesis of schulzeines B and C

Article abstract of DOI:10.1016/j.tet.2011.07.085

A formal synthesis of schulzeines B and C, marine natural products with inhibitory effect against α-glucosidase, has been achieved. The key reactions of the synthesis are N-acyliminium ion cyclization, Sharpless asymmetric dihydroxylation, olefin cross me

Full text of DOI:10.1016/j.tet.2011.07.085

Tetrahedron 67 (2011) 8034e8040
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Formal synthesis of schulzeines B and C
*
Punlop Kuntiyong , Sunisa Akkarasamiyo, Nuanpan Piboonsrinakara, Chitlada Hemmara,
Poramate Songthammawat
Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of schulzeines B and C, marine natural products with inhibitory effect against
a-
Received 18 February 2011
Received in revised form 24 June 2011
Accepted 26 July 2011
glucosidase, has been achieved. The key reactions of the synthesis are N-acyliminium ion cyclization,
Sharpless asymmetric dihydroxylation, olefin cross metathesis, and asymmetric allylboration.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 31 July 2011
Keywords:
Schulzeines B and C
Formal synthesis
N-Acyliminium ion cyclization
28-Carbon fatty acid side chain
1. Introduction
Schulzeines AeC (1e3) are marine natural products isolated
from Japanese sponge, Penares schulzeii.1 These natural products
exhibit potent activity against
a-glucosidase, an enzyme, which
plays pivotal roles in carbohydrate metabolism and cell cycle.1,2
This intriguing biological activity renders them potential leads for
medicinal investigation for treatment of various diseases, such as
diabetes, cancers, and viral infections. There have been several
synthetic studies3 of these natural products resulting in three total
syntheses of schulzeines B and C4,5 and one total synthesis of
schulzeine A.5 We have reported a synthesis of the 9,11-dimethyl
ether of the tricyclic core of schulzeines utilizing N-acyliminium
ion cycliaztion.3a,b Herein we present a formal synthesis of schul-
zeines B and C featuring N-acyliminium ion cyclization, Sharpless
asymmetric dihydroxylation, asymmetric allylboration and olefin
cross metathesis as key reactions (Fig. 1).
Fig. 1. Schulzeines AeC.
subunit 10 possessing three stereogenic centers at C14, 17, and 18
would be derived from asymmetric allylboration of C14-aldehyde
11. The C17e18 protected diol functionality could be installed by
Sharpless asymmetric dihydroxylation of alkene 12.
2. Results and discussion
Our retrosynthetic analysis of schulzeines, as shown in
Scheme 1, divides the molecule into two major subunits, namely,
the tricyclic core 4 and 28-carbon fatty acid side chain 5. The tri-
cyclic core 4 could be obtained from intramolecular cyclization of
N-acyliminium ion 6, which in turn could be prepared from ary-
lethylamine 7 and benzylated glutamic acid 8. The 28-carbon fatty
acid side chain would be constructed from benzyl 11-dodecenoate
(9)6 and C12eC28 subunit 10 via olefin cross metathesis. The
Synthesis of the tricyclic core 4 began with known 2-(3,5-
dibenzyloxyphenyl)ethylamine (7),7 prepared in five steps from
3,5-dihydroxybenzoic acid (Scheme 2). This amine was coupled
with ( )-glutamic acid derivative 8 to give amide 13 in good yield.
L
Treatment of this amide with lithium aluminum hydride gave im-
ide 14.8 DIBAL-H reduction of the imide occurred selectively at the
less hindered carbonyl group to give hydroxylactam 15.9 Sub-
sequent treatment of this compound with TMSOTf yielded the
protected tricyclic core 16 of schulzeines as an inseparable mixture
of two diastereomers at C11b. This mixture was converted into N-
Boc-carbamates 17a and 17b (ca. 3:1) and the two diastereomers
were readily separable by flash chromatography and their
* Corresponding author. Tel.: þ66 3 425 5797; fax: þ66 3 427 1356; e-mail
address: punlop@su.ac.th (P. Kuntiyong).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.085

P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
8035
as dibenzyl ether 18a and 18b and the N-Boc-carbamate was re-
moved to give the desired tricyclic core 4a and 4b of schulzeines.
The synthesis of C28-fatty acid side chain commenced with
olefin cross metathesis of 1-dodecene (19) and benzyl-4-pentenyl
ether (20) in the presence of Grubbs’ first generation catalyst
(Scheme 3).11 The product was obtained as a mixture of E/Z olefin
12 (ca. 3:1) and was treated with AD-mix-a
to yield diol 21.12 The
diol was obtained from Sharpless asymmetric dihydroxylation of E-
olefin and was separated from the mixture of unreacted mixture of
olefin, which had an increased ratio of Z-isomer. The diol was
protected as bis-TBS ether 22 and the benzyl ether was sub-
sequently removed to give primary alcohol 23. The alcohol was
oxidized to give aldehyde 11 using Swern oxidation and subsequent
asymmetric allylboration using Brown’s conditions13 gave the
homoallylic alcohol 24 with the desired (R)-configuration in a di-
astereomeric ratio of 6:1. This sets up the stereogenic center at C14
of the 28-carbon fatty acid side chain. The homoallylic alcohol was
protected as TBS ether 10, which subsequently underwent olefin
cross metathesis with benzyl 11-dodecenoate (9)6 to give a mixture
of inconsequential E/Z alkene product 25 possessing the full carbon
skeleton of C28-fatty acid side chain of schulzeines B and C.
Treatment of this mixture with hydrogen gas and palladium on
activated carbon resulted in simultaneous reduction of the olefin
and hydrogenolysis of the benzyl ester. The resulting 28-carbon
fatty acid side chain 5 with the correct absolute configuration of
14S, 17S, and 18S was therefore in hand for coupling with the tri-
cyclic core 4 of schulzeines.
Scheme 1. Retrosynthetic analysis of schulzeines B and C.
configurations at C11b were assigned based on NOESY experiments
and comparison of NMR results with a related dimethoxy de-
rivative whose configuration has been confirmed by X-ray crystal
analysis.10,3b The separated diastereomers were then re-protected
Scheme 3. Synthesis of the 28-carbon fatty acid side chain 5.
With both key fragments in hand we proceeded to the coupling
of the tricyclic core 4a or 4b and the C28-fatty acid side chain 5
(Scheme 4). Amide 26 was obtained from the coupling in good yield
in the presence of DCC and DMAP in CH2Cl2. The tris-TBS ether was
removed using 1 N HCl to furnish the corresponding triol 27. These
advancedintermediates are in commonwith thosein two previously
reported syntheses of schulzeines B and C and our spectral data
match perfectly with those reported results.4 Thus a formal syn-
thesis of schulzeines B and C was achieved with the remaining steps
for the completion of the synthesis of the natural products being
sulfate formation and debenzylation using the reported procedure.4
Scheme 2. Synthesis of the tricyclic core 4.

8036
P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
and the crude material was purified by flash column chromatog-
raphy (silica gel, 2:1 hexane/ethyl acetate) to give amido-ester 13
(1.02 g, 62%) as a yellow-brown oil; Rf (2:1 hexane/ethyl acetate)
0.39; dH (300 MHz, CDCl3) 7.50e7.10 (25H, m), 6.50 (1H, t, J¼2.2 Hz),
6.40 (2H, d, J¼2.2 Hz), 5.24 (1H, d, J¼12.2 Hz), 5.13 (1H, d, J¼12.2 Hz)
5.00 (4H, s), 3.85 (2H, d, J¼13.7 Hz), 3.50 (2H, d, J¼13.7 Hz),
3.44e3.10 (3H, m), 2.60 (2H, t, J¼7.0 Hz), 2.25e1.70 (4H, m); dC
(75 MHz, CDCl3) 172.4,172.3,160.2 (2C),141.4,139.4 (2C),136.9 (2C),
136.0, 129.0 (4C), 128.7 (2C), 128.6 (4C), 128.5 (2C), 128.4, 128.3 (4C),
128.0 (2C), 127.6 (4C), 127.2 (2C), 108.0 (2C), 100.2, 70.1 (2C), 66.2,
60.3, 54.6 (2C), 40.4, 35.9, 33.1, 25.4; ½a D25
ꢂ39.2 (c 2.4, CHCl3);
ꢁ
nmax(film) 3425, 3033, 2934, 2857, 1727, 1664, 1594, 1519, 1496,
1455, 1265, 1214, 1158, 1070 cmꢂ1; ESI-HRMS calculated for
C48H49N2O5 [MþH]þ 733.3641 found 733.3492.
4.1.2. Imide 14. To
a solution of amido-ester 13 (216 mg,
0.295 mmol) in THF (6 mL) was added lithium aluminum hydride
(34.0 mg, 0.896 mmol) in one portion at 0 ꢀC. The resulting sus-
pension was stirred at 0 ꢀC under argon for 45 min. The reaction
was quenched by drop-wise addition of satd aq NaHCO3 into the
mixture until all bubbling subsided. Water (5 mL) was added and
the mixture was then extracted with Et2O (3ꢃ20 mL). The com-
bined organic layers were dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography (silica gel, 4:1 hexane/
ethyl acetate) to give imide 14 (94.0 mg, 52%) as a colorless oil, and
the unreacted amide was also recovered; Rf (2:1 hexane/ethyl ac-
etate) 0.66; dH (300 MHz, CDCl3) 7.38e7.15 (20H, m), 6.43 (2H, d,
J¼2.2 Hz), 6.36 (1H, t, J¼2.2 Hz), 4.88 (4H, s), 4.07e3.94 (1H, m),
3.91e3.82 (1H, m), 3.82 (2H, d, J¼13.9 Hz), 3.55 (2H, d, J¼13.9 Hz),
3.39e3.29 (1H, m), 2.80e2.65 (3H, m), 2.37e2.22 (1H, m),1.94e1.81
(2H, m); dC (75 MHz, CDCl3) 173.1, 171.7, 159.9 (2C), 140.7, 139.6 (2C),
136.9 (2C), 128.6 (4C), 128.5 (4C) 128.4 (4C), 127.9 (2C), 127.6 (4C),
127.2 (2C), 108.3 (2C), 100.2, 70.0 (2C), 59.3, 55.0 (2C), 40.5, 34.3,
Scheme 4. Fragment coupling and conversion to triol 27.
3. Conclusion
In summary, the triol intermediates of schulzeines B and C were
synthesized with N-acyliminium ion cyclization, Sharpless asym-
metric dihydroxylation, olefin cross metathesis, and asymmetric
allylboration as the key steps. There were 24 total steps with the
longest linear sequence of 14 steps from 3,5-dihydroxybenzoic acid
and the overall yield of 2.6% and 0.9% for 27a and 27b, respectively.
4. Experimental
4.1. General
32.3, 22.7; ½a 2D5
ꢂ39.3 (c 1.0, CHCl3); nmax (film) 2879, 1725, 1674,
ꢁ
1595, 1495, 1455,1376,1344,1264,1151, 1051,1027 cmꢂ1; ESI-HRMS
calculated for C41H41N2O4 [MþH]þ 625.3066 found 625.2927.
Starting materials and reagents were obtained from commercial
sources and were used without further purification. Solvents were
dried by distillation from the appropriate drying reagents imme-
diately prior to use. Tetrahydrofuran and ether were distilled from
sodium and benzophenone under argon. Toluene, triethylamine,
and dichloromethane were distilled from calcium hydride under
argon. Moisture- and air-sensitive reactions were carried out under
an atmosphere of argon. Reaction flasks were oven dried at 105 ꢀC
overnight. Unless otherwise stated, concentration was performed
under reduced pressure using a rotary evaporator at water aspirator
pressure. Analytical thin-layer chromatography (TLC) was con-
ducted using Fluka precoated TLC plates (0.2 mm layer thickness of
silica gel 60 F-254). Compounds were visualized by ultraviolet light
and/or by heating the plate after dipping in a 1% solution of vanillin
in 0.1 M sulfuric acid in ethanol. Flash chromatography was carried
4.1.3. Hydroxylactam 15. To a solution of imide 14 (93.0 mg,
0.149 mmol) in toluene (2 mL) was added diisobutyl aluminum
hydride (1.0 M solution in THF, 0.750 mL, 0.750 mmol) via syringe at
ꢂ78 ꢀC under argon. The mixture was stirred for 1 h at ꢂ78 ꢀC then
MeOH (5 mL) was added. The reaction mixture was allowed to
warm to room temperature and satd aq NaHCO3 was added. The
mixture was extracted with CH2Cl2 (3ꢃ20 mL) and the combined
organic layers were dried over anhyd Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography (silica gel, 2:1 hexane/ethyl ace-
tate) to give hydroxylactam 15 (68.0 mg, 73% mixture of two di-
astereomers) as a colorless oil; Rf (2:1 hexane/ethyl acetate) 0.42;
dH (300 MHz, CDCl3) 7.40e7.10 (20H, m), 6.43 (2H, t, J¼2.0 Hz), 6.37
(1H, t, J¼2.0 Hz), 4.85 (4H, s), 4.54 (1H, t, J¼7.3 Hz), 3.91 (2H, d,
J¼14.0 Hz), 3.84e3.70 (1H, m), 3.68e3.52 (3H, m), 3.22 (1H, q,
J¼5.8 Hz), 2.86e2.73 (2H, m), 2.11e1.99 (1H, m), 1.88e1.74 (2H, m),
1.69e1.46 (1H, m); dC (75 MHz, CDCl3) 171.2, 159.9 (2C), 141.7, 140.4
(2C), 136.9 (2C), 128.7 (4C), 128.6 (4C), 128.2 (4C), 127.9 (2C), 127.5
(4C), 126.8 (2C), 108.1 (2C), 100.2, 80.4, 70.0 (2C), 58.2, 55.2 (2C),
43.8, 34.4, 31.4, 23.2; nmax(film) 3429, 2832, 1644, 1606, 1552, 1495,
1375, 1265, 1055, 1027 cmꢂ1; ESI-HRMS calculated for C41H43N2O4
[MþH]þ 627.3223 found 627.3069.
out using Scientific Absorbents Inc. silica gel (40 mm particle size).
Optical rotations were measured with a PerkineElmer 243 polar-
imeter at ambient temperature using a 0.9998 dm cell with 1 mL
capacity. Infrared (IR) spectra were recorded on a Nicolet 5DXB FT-
IR spectrometer. Proton and carbon nuclear magnetic resonance
(NMR) spectra were obtained using a Bruker AC-300 spectrometer.
4.1.1. Amido-ester 13. A mixture of 2-(3,5-dibenzyloxyphenyl)eth-
ylamine (7) (1.81 g, 5.43 mmol), N,N-dibenzyl-L-glutamic acid-5-
4.1.4. Tricyclic core 16. To a solution of hydroxylactam 15 (68.0 mg,
benzyl ester (5) (0.940 g, 2.25 mmol), DCC (1.49 g, 7.22 mmol),
and DMAP (55.0 mg, 0.450 mmol) in CH2Cl2 (60 mL) was stirred at
room temperature under argon for 48 h, after which the mixture
was filtered. The filtrate was concentrated under reduced pressure
0.108 mmol) in CH2Cl2 (9 mL) was added TMSOTf (39.0 mL,
0.215 mmol) via syringe at 0 ꢀC under argon. The mixture was
stirred at this temperature for 4 h and satd aq NaHCO3 was added
drop-wise. The mixture was extracted with CH2Cl2 (3ꢃ10 mL). The

P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
8037
combined organic layers were dried over anhyd Na2SO4, filtered,
and concentrated under reduced pressure to give tricyclic core 16
(inseparable mixture of two diastereomers in approximately 3:1
ratio as determined by 1H NMR, 60.0 mg, 91%) as a colorless oil; Rf
(2:1 hexane/ethyl acetate) 0.68; major product dH (300 MHz, CDCl3)
7.50e7.20 (20H, m), 6.47 (1H, d, J¼2.0 Hz), 6.37 (1H, d, J¼2.0 Hz),
5.05e4.95 (4H, m), 4.85 (1H, dd, J¼10.3, 3.9 Hz), 4.57 (1H, dd,
J¼10.9, 3.2 Hz), 4.26 (2H, d, J¼14.6 Hz), 3.89 (2H, d, J¼14.6 Hz), 3.55
(1H, dd, J¼9.9, 9.1 Hz), 2.88e2.52 (3H, m), 2.01e1.77 (2H, m),
1.30e1.18 (2H, m); dC (75 MHz, CDCl3) 171.5, 157.3, 154.9, 140.0 (2C),
136.7, 135.7, 135.6, 127.7 (2C), 127.6 (4C), 127.4 (2C), 127.1 (4C), 127.0,
126.9, 126.5 (2C), 125.7 (2C), 125.6 (2C), 116.8, 104.8, 97.9, 69.1, 68.9,
55.6, 54.2 (2C), 48.9, 37.1, 29.0, 28.6, 22.6; minor product dH
(300 MHz, CDCl3) 7.50e7.20 (20H, m), 6.38 (1H, d, J¼2.1 Hz), 6.34
(1H, d, J¼2.1 Hz), 5.05e4.95 (5H, m), 4.70 (1H, dd, J¼10.6, 2.1 Hz),
4.08 (2H, d, J¼13.9 Hz), 3.84 (2H, d, J¼13.9 Hz), 3.42 (1H, dd, J¼11.1,
7.3 Hz), 2.87e2.52 (3H, m), 2.47e2.30 (1H, m), 2.19e2.03 (1H, m),
1.99e1.79 (1H, m), 1.46e1.34 (1H, m); dC (75 MHz, CDCl3) 169.8,
157.1, 155.5, 139.5 (2C), 137.1, 135.7, 135.5, 127.7 (2C), 127.6 (4C),
127.4 (2C), 127.1 (4C), 127.0, 126.9, 126.5 (2C), 126.0 (2C), 125.7 (2C),
117.5, 105.0, 98.0, 69.1, 69.0, 57.7, 54.4 (2C), 54.2, 37.5, 29.5, 28.4,
26.0; nmax(film) 2874, 2833, 2254, 1703, 1641, 1609, 1542,
1493 cmꢂ1; ESI-HRMS calculated for C41H41N2O3 [MþH]þ 609.3117
found 609.2977.
a colorless oil; Rf (2:1 hexane/ethyl acetate) 0.50; dH (300 MHz,
CDCl3) 7.60e7.18 (10H, m), 6.45 (1H, d, J¼2.2 Hz), 6.36 (1H, d,
J¼2.2 Hz), 5.75 (1H, d, J¼5.3 Hz), 5.05 (2H, s), 4.97 (2H, s), 4.89 (1H,
dd, J¼10.3, 4.0 Hz), 4.69e4.60 (1H, m), 4.32e4.17 (1H, m),
2.79e2.56 (3H, m), 2.54e2.31 (2H, m), 1.50 (9H, s,), 1.34e1.23 (2H,
m); dC (75 MHz, CDCl3) 170.1, 158.2, 155.7, 155.4, 137.0, 136.5, 136.2,
128.5, 128.3 (2C), 127.9, 127.8 (2C), 127.2 (2C), 126.8 (2C), 117.1, 105.7,
98.8, 79.0, 69.9, 69.8, 49.5, 48.5, 38.6, 29.5, 28.3, 28.2 (3C), 25.9;
½
a 2D5
ꢁ
ꢂ83.4 (c 1.4, CHCl3); nmax(film) 3413, 2983, 2931, 1710, 1655,
1609, 1497, 1432, 1367, 1162, 1060 cmꢂ1; ESI-HRMS calculated for
C32H37N2O5 [MþH]þ 529.2702 found 529.2624.
4.1.7. N-Boc benzylated tricyclic core 18b. To a solution of N-Boc
debenzylated tricyclic core 17b (73.0 mg, 0.210 mmol), Cs2CO3
(205 mg, 0.629 mmol), and TBAI (12.0 mg, 32.5
mmol) in DMF (3 mL)
at 0 ꢀC was added benzyl bromide (55.0
mL, 0.462 mmol). This so-
lution was stirred at 0 ꢀC under argon for 1 h. Water was added and
the mixture was extracted with ethyl acetate (3ꢃ10 mL). The com-
bined organic phases were dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The crude material was pu-
rified by flash column chromatography (silica gel, 2:1 hexane/ethyl
acetate) to give dibenzyl ether 18b (74.0 mg, 81%) as a colorless oil; Rf
(2:1 hexane/ethyl acetate) 0.30; dH (300 MHz, CDCl3) 7.40e7.20
(10H, m), 6.47 (1H, d, J¼2.3 Hz), 6.35 (1H, d, J¼2.3 Hz), 5.33 (1H, d,
J¼5.0 Hz), 5.04e4.94 (4H, m), 4.92e4.38 (1H, m), 4.78 (1H, dd,
J¼11.0, 3.7 Hz), 4.03e3.91 (1H, m) 3.08e2.97 (1H, m), 2.89e2.72 (1H,
m), 2.64e2.51 (2H, m), 2.46e2.35 (1H, m), 1.79e1.59 (2H, m), 1.50
(9H, s); dC (75 MHz, CDCl3) 168.8, 158.1, 156.7, 156.1, 137.8, 136.6,
136.4,128.6,128.5 (2C),128.0 (2C),128.1 (2C),127.4 (2C),127.1,118.3,
106.0, 99.0, 79.4, 70.1, 70.0, 56.1, 52.7, 39.4, 30.5, 28.3 (3C), 27.9, 27.8;
4.1.5. N-Boc debenzylated tricyclic core 17a and 17b. To a solution of
tricyclic core 9 (292 mg, 0.480 mmol) in methanol (9 mL) was
added palladium on activated carbon (29.0 mg, 10% w/w) and the
resulting suspension was stirred under a hydrogen atmosphere for
3 h (a balloon of hydrogen gas was equipped to the reaction flask,
ca. 1.1 atm). Then Boc2O (210 mg, 0.962 mmol) was added and the
reaction mixture was stirred for 5 h. The mixture was then filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
2:1 ethyl acetate/hexane) to give two separated diastereomers of
the tricyclic core 17a (97.5 mg, 58%) and 17b (32.5 mg, 19%) as
a colorless oil; 17a Rf (1:1 hexane/ethyl acetate) 0.19; dH (300 MHz,
CD3OD) 6.10 (1H, d, J¼2.3 Hz), 6.02 (1H, d, J¼2.3 Hz), 4.69 (1H, dd,
J¼10.8, 3.2 Hz), 4.47 (1H, d, J¼6.82 Hz), 4.22 (1H, t, J¼10.1 Hz),
2.64e2.49 (3H, m), 2.47e2.32 (1H, m), 2.26e2.11 (1H, m), 1.37e1.31
(1H, m), 1.36 (9H, s), 1.30e1.15 (1H, m); dC (75 MHz, CD3OD) 171.0,
156.7, 156.5, 154.7, 137.0, 113.7, 105.9, 100.6, 79.3, 49.7, 49.4, 39.0,
½
a 2D5
ꢁ
þ96.9 (c 2.8, CHCl3); nmax(film) 3413, 2983, 2931, 1710, 1655,
1609, 1497, 1432, 1367, 1162, 1060 cm1; ESI-HRMS calculated for
C32H37N2O5 [MþH]þ 529.2702 found 529.2556.
4.1.8. Tricyclic core 4a. A solution of N-Boc tricyclic core 18a
(62.0 mg, 0.117 mmol) was treated with 3 N HCl in ethyl acetate
(1.10 mL) at room temperature. The solution was stirred for 3 h,
after which ethyl acetate (5 mL) and satd aq NaHCO3 (10 mL) were
added. The phases were separated and the aqueous layer was
extracted with ethyl acetate (3ꢃ10 mL). The combined organic
layers were dried over anhyd Na2SO4, filtered, and concentrated
under reduced pressure to give amine 4a (44.0 mg, 88%) as a col-
orless oil; Rf (1:1 hexane/ethyl acetate) 0.20; dH (300 MHz, CDCl3)
7.50e7.30 (10H, m), 6.49 (1H, d, J¼2.2 Hz), 6.38 (1H, d, J¼2.1 Hz),
5.07 (2H, d, J¼2.9 Hz), 5.00 (2H, s), 4.85 (1H, dd, J¼11.3, 3.6 Hz), 4.72
(1H, dd, J¼8.2, 1.8 Hz), 3.89e3.76 (1H, m), 2.88e2.62 (3H, m),
2.57e2.33 (2H, m), 1.79e1.59 (1H, m), 1.54e1.38 (1H, m); dC
(75 MHz, CDCl3) 170.9, 158.5, 156.0, 137.4, 136.7, 136.5, 128.8 (2C),
128.6 (2C), 128.1 (2C), 127.5 (2C), 127.0 (2C), 117.0, 105.7, 99.1, 70.2,
70.1, 49.8, 49.2, 39.0, 29.7, 28.2, 25.1. This amine was used imme-
diately, without further purification, in the next step.
28.9, 27.8, 27.4 (3C), 24.9; ½a D25
ꢂ76.0 (c 0.9, MeOH); nmax (film)
ꢁ
3274, 2924, 2854, 1683, 1646, 1511, 1464, 1376, 1277, 1251, 1159,
1055, 947, 842 cmꢂ1; ESI-HRMS calculated for C18H24N2NaO5
[MþNa]þ 371.1583 found 371.1463; 17b Rf (2:1 hexane/ethyl ace-
tate) 0.10; dH (300 MHz, CD3OD) 6.08 (1H, d, J¼2.3 Hz), 5.99 (1H, d,
J¼2.3 Hz),4.69 (1H, dd, J¼10.8, 3.2 Hz), 4.63 (1H, dd, J¼11.0, 2.5 Hz),
3.94e3.77 (1H, m), 2.97 (1H, dd, J¼13.8, 3.1 Hz), 2.66e2.37 (3H, m),
2.06e1.94 (1H, m), 1.89e1.73 (1H, m), 1.40 (9H, s), 1.30e1.20 (1H,
m); dC (75 MHz, CD3OD) 169.6,156.7,156.3, 155.3, 137.3, 114.6, 106.2,
100.7, 79.0, 55.8, 51.8, 39.4, 29.7, 28.1, 27.4 (3C), 27.3; ½a D25
þ30.2 (c
ꢁ
0.8, MeOH); nmax(film) 3274, 2924, 2854, 1683, 1646, 1511, 1464,
1376, 1277, 1251, 1159, 1055, 947, 842 cmꢂ1; ESI-HRMS calculated
for C18H25N2O5 [MþH]þ 349.1763 found 349.1708.
4.1.9. Tricyclic core 4b. A solution of N-Boc tricyclic core 18b
(74.0 mg, 0.140 mmol) was treated with 3 N HCl in ethyl acetate
(1.40 mL) at room temperature. The solution was stirred for 3 h,
after which ethyl acetate (5 mL) and satd aq NaHCO3 (10 mL) were
added. The phases were separated and the aqueous layer was
extracted with ethyl acetate (3ꢃ10 mL). The combined organic
layers were dried over anhyd Na2SO4, filtered, and concentrated
under reduced pressure to give amine 4b (59.0 mg, 98%) as a col-
orless oil; Rf (1:1 hexane/ethyl acetate) 0.10; dH (300 MHz, CDCl3)
7.48e7.30 (10H, m), 6.50 (1H, d, J¼2.2 Hz), 6.37 (1H, d, J¼2.1 Hz),
5.05 (2H, d, J¼3.9 Hz), 5.00 (2H, s), 4.92 (1H, dd, J¼11.3, 2.5 Hz), 4.80
(1H, dd, J¼8.3, 1.7 Hz), 3.44e3.31 (1H, m), 3.01 (1H, d, J¼13.3 Hz),
2.93e2.76 (1H, m), 2.68e2.54 (1H, m), 2.51e2.29 (1H, m),
2.28e2.17 (1H, m), 1.75e1.55 (1H, m), 1.49e1.31 (1H, m); dC
4.1.6. N-Boc benzylated tricyclic core 18a. To a solution of N-Boc
debenzylated tricyclic core 17a (23.0 mg, 66.0
(65.0 mg, 0.199 mmol) and TBAI (4.0 mg, 10.8 mol) in DMF (1 mL)
at 0 ꢀC was added benzyl bromide (17.0
L, 0.143 mmol). This so-
mmol), Cs2CO3
m
m
lution was stirred at 0 ꢀC under argon for 1 h. Water was added and
the mixture was extracted with ethyl acetate (3ꢃ10 mL). The
combined organic phases were dried over anhyd Na2SO4, filtered,
and concentrated under reduced pressure. The crude material was
purified by flash column chromatography (silica gel, 2:1 hexane/
ethyl acetate) to give dibenzyl ether 18a (20.0 mg, 69%) as

8038
P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
(75 MHz, CDCl3) 172.1, 158.2, 156.7, 138.0, 136.8, 136.6, 128.7 (2C),
128.4 (2C), 128.1, 128.0, 127.5 (2C), 127.0 (2C), 118.5, 106.2, 99.1, 70.1
(2C), 56.1, 52.5, 39.2, 30.6, 29.3, 28.5. This amine was used imme-
diately, without further purification, in the next step.
hexane (17 mL) was added palladium on activated carbon (85.0 mg,
10% w/w) and the resulting suspension was stirred under a hydro-
gen atmosphere for 3 h (a balloon of hydrogen gas was equipped to
the reaction flask, ca. 1.1 atm). The mixture was then filtered and
the solvent was removed under reduced pressure. Purification by
flash column chromatography (silica gel, 4:1 hexane/ethyl acetate)
gave primary alcohol 23 (561 mg, 78%) as a colorless oil; Rf (4:1
hexane/ethyl acetate) 0.75; dH (300 MHz, CDCl3) 3.57 (2H, t,
J¼6.2 Hz), 3.53e3.50 (1H, m), 3.50e3.47 (1H, m), 2.30 (1H, br s),
1.75e1.33 (4H, m), 1.21 (18H, br s), 0.84 (21H, br s), 0.06e0.00 (12H,
m); dC (75 MHz, CDCl3) 75.4, 75.3, 63.1, 30.1, 29.8, 29.7, 29.6 (2C),
29.5, 29.3, 26.6, 26.3, 26.0, 25.8 (6C), 22.6, 17.9 (2C), 14.1, ꢂ4.2 (2C),
4.1.10. Benzyl-1-(4-pentadecenyl) ether (12). To a solution of ben-
zyloxy-4-pentene (20) (757 mg, 4.28 mmol) and 1-dodecene (19)
(9.60 mL, 42.8 mmol) in CH2Cl2 (150 mL) was added Grubbs’ first
generation catalyst (176 mg, 0.214 mmol) in CH2Cl2 (10 mL). The
reaction was heated to reflux under argon for 4 h and then allowed
to cool to room temperature. Silica gel was added, and the mixture
was concentrated. Purification by flash column chromatography
(silica gel, 20:1 hexane/ethyl acetate) gave alkene 12 (1.15 g, 85%, E/
Z¼3:1) as a colorless oil; Rf (20:1 hexane/ethyl acetate) 0.61; dH
(300 MHz, CDCl3) 7.33e7.20 (5H, m), 5.44e5.31 (2H, m), 4.50 (2H,
s), 3.50e3.41 (2H, m), 2.17e1.91 (4H, m), 1.72e1.60 (2H, m), 1.39
(16H, br s), 0.88 (3H, t, J¼6.7 Hz); dC (75 MHz, CDCl3) (E isomer)
139.2, 131.5, 129.9, 128.8 (2C), 128.1 (2C), 127.9, 73.3, 70.3, 33.1, 32.5,
30.2 (2C), 30.1 (2C), 29.9, 29.7, 29.6, 27.7, 23.2, 14.6; (Z-isomer)
139.2, 131.1, 129.4, 128.8 (2C), 128.1 (2C), 127.9, 73.4, 70.4, 33.1, 32.5,
30.3 (2C), 30.1 (2C), 29.9, 29.7, 29.6, 27.7, 24.3, 14.6; nmax(film) 2929,
2856, 1715, 1603, 1467, 1456, 1316, 1099 cmꢂ1; ESI-HRMS calculated
for C22H36NaO [MþNa]þ 339.2664 found 339.3338.
ꢂ4.6 (2C); ½a 2D5
ꢂ17.0 (c 0.6, CHCl3); nmax(film) 3429, 2955, 2929,
ꢁ
2857, 1471, 1463, 1361, 1258, 1097, 836, 759 cmꢂ1; ESI-HRMS cal-
culated for C27H61O3Si2 [MþH]þ 489.4159 found 489.4010.
4.1.14. (4S,5S)-4,5-Bis-(tert-butyldimethylsilanyloxy)penta-decanal
(11). To a solution of oxalyl chloride (0.300 mL, 3.49 mmol) in dry
CH2Cl2 (25 mL) at ꢂ78 ꢀC under argon was added DMSO (0.500 mL,
7.04 mmol) drop-wise. After 30 min, alcohol 23 (561 mg,
1.15 mmol) in dry CH2Cl2 (5 mL) was added. The mixture was stirred
at ꢂ78 ꢀC for 1 h. Et3N (1.44 mL, 10.3 mmol) was added at ꢂ78 ꢀC
and the reaction mixture was allowed to warm to room tempera-
ture over 45 min. The reaction was quenched with water and
extracted with CH2Cl2 (3ꢃ50 mL). The combined organic layers
were dried over anhyd Na2SO4, filtered, and concentrated to give
aldehyde 11 (550 mg, 98%) as a colorless oil; Rf (10:1 hexane/ethyl
acetate) 0.64; dH (300 MHz, CDCl3) 9.70 (1H, s), 3.56e3.52 (1H, m),
3.52e3.48 (1H, m), 2.56e2.38 (2H, m), 1.99e1.90 (1H, m), 1.66e1.50
(2H, m), 1.49e1.34 (1H, m), 1.22 (16H br s), 0.82 (21H, br s), 0.00
(12H, s); dC (75 MHz, CDCl3) 202.2, 75.1, 74.5, 41.1, 31.9, 29.7, 29.6
(2C), 29.5, 29.3, 26.6, 25.9, 25.8 (6C), 22.8, 22.6, 17.9 (2C), 14.0, ꢂ4.2
(2C), ꢂ4.7, ꢂ5.0; nmax(film) 2928, 2857, 2710, 1716, 1520, 1471, 1463,
1389, 1361, 1256, 1217, 1075, 835, 773 cmꢂ1. This aldehyde was used
immediately, without further purification, in the next step.
4.1.11. (4S,5S)-1-Benzyloxypentadecane-4,5-diol (21). To a solution
of AD-mix-a (0.920 g) and methansulfonamide (60.0 mg) in tert-
butanol and water (15 mL,1:1) at 0 ꢀC was added alkene 12 (0.210 g,
0.663 mmol). The reaction mixture was stirred vigorously at 0 ꢀC for
2 days and quenched with sodium sulfite (1.70 g). Ice bath was
removed and the mixture was stirred at room temperature for
45 min. The resulting mixture was extracted with ethyl acetate
(3ꢃ25 mL). The combined organic layers were dried over anhyd
Na2SO4, filtered, and concentrated. Purification by flash column
chromatography (silica gel, 2:1 hexane/ethyl acetate) gave diol 21
(162 mg, 70%) as a colorless oil; Rf (2:1 hexane/ethyl acetate) 0.40;
dH (300 MHz, CDCl3) 7.34e7.22 (5H, m), 4.50 (2H, s), 3.65 (2H, br s),
3.49 (2H, t, J¼6.0 Hz), 3.42e3.29 (2H, m), 1.87e1.54 (2H, m),
1.54e1.33 (4H, m),1.30 (16H br s), 0.88 (3H, t, J¼6.7 Hz); dC (75 MHz,
CDCl3) 138.1, 128.4 (2C), 127.7 (3C), 74.7, 74.1, 73.0, 70.4, 33.5, 31.9,
4.1.15. (4R,7S,8S)-7,8-Bis-(tert-butyldimethylsilanyloxy)octadec-1-
en-4-ol (24). To a solution of (ꢂ)-methoxydiisopinocampheylbor-
ane (743 mg, 2.35 mmol) in dry Et2O (25 mL) at 0 ꢀC was added allyl
magnesium bromide solution (1 M in THF, 2.10 mL, 2.10 mmol). The
mixture was stirred at room temperature for 1 h and then cooled to
ꢂ78 ꢀC. Aldehyde 11 (564 mg, 1.16 mmol) in dry Et2O (10 mL) was
added drop-wise into the solution. The mixture was stirred at
ꢂ78 ꢀC for 1 h. MeOH (1.30 mL) was added and the solution was
allowed to warm to room temperature. NaOH (3 M, 11.0 mL,
33.0 mmol) and H2O2 (30%, 40.0 mL) were added and the solution
was stirred overnight. To this mixture was added brine and the
layers were separated. The aqueous layer was extracted with Et2O
(3ꢃ50 mL). The combined organic layers were dried over anhyd
Na2SO4, filtered, and concentrated. Purification by flash column
chromatography (silica gel, 20:1 hexane/ethyl acetate) gave
homoallylic secondary alcohol 24 (563 mg, 92%) as a colorless oil; Rf
(20:1 hexane/ethyl acetate) 0.38; dH (300 MHz, CDCl3) 5.86e5.69
(1H, m), 5.08 (1H, d, J¼16.2 Hz), 5.07 (1H, d, J¼11.1 Hz), 3.64e3.52
(1H, m), 3.52e3.49 (1H, m), 3.49e3.46 (1H, m), 2.32e2.19 (1H, m),
2.18e2.05 (1H, m), 1.82e1.51 (4H, m), 1.50e1.25 (3H, m), 1.21 (16H
br s), 0.82 (21H, br s), 0.00 (12H, s); dC (75 MHz, CDCl3) 134.9, 117.9,
75.7, 75.3, 71.1, 41.8, 34.2, 31.9, 29.7, 29.6 (2C), 29.5, 29.3, 26.6, 26.2,
30.6, 29.8 (2C), 29.7 (2C), 29.4, 26.1, 25.8, 22.7, 14.1; ½a D25
ꢂ8.1 (c 1.1,
ꢁ
CHCl3); nmax(film) 3423, 2930, 2856, 1717, 1316, 1279, 1115, 1071,
1001, 892 cmꢂ1; ESI-HRMS calculated for C22H39O3 [MþH]þ
351.2899 found 351.2772.
4.1.12. (4S,5S)-1-Benzyloxy-4,5-bis-(tert-butyldimethyl silanyl-oxy)
pentadecane (22). To an ice-cold solution of diol 21 (690 mg,
1.97 mmol) in dry CH2Cl2 (21 mL) under argon atmosphere were
added 2,6-lutidine (0.680 mL, 5.93 mmol) and TBSOTf (1.60 mL,
5.93 mmol) The mixture was stirred at room temperature for 2 h.
The reaction was quenched with satd aq NaHCO3 and extracted
with CH2Cl2 (3ꢃ50 mL). The combined organic layers were dried
over anhyd Na2SO4, filtered, and concentrated. Purification by flash
column chromatography (silica gel, 20:1 hexane/ethyl acetate) gave
bis-TBS ether 22 (853 mg, 75%) as a colorless oil; Rf (2:1 hexane/
ethyl acetate) 0.90; dH (300 MHz, CDCl3) 7.30e7.10 (5H, m), 4.42
(2H, s), 3.58e3.46 (2H, m), 3.41 (2H, t, J¼6.1 Hz), 1.84e1.62 (2H, m),
1.62e1.35 (2H, m), 1.22 (18H, br s), 0.84 (21H, br s), 0.00 (12H, s); dC
(75 MHz, CDCl3) 138.8, 128.3 (2C), 127.6 (2C), 127.4, 75.5, 75.4, 72.8,
70.8, 32.0, 29.8, 29.7 (2C), 29.6, 29.5, 27.2, 26.9, 26.7, 26.1, 26.0
26.0, 25.8 (6C), 22.7, 18.0 (2C), 14.1, ꢂ4.1 (2C), ꢂ4.6 (2C); ½a D25
ꢂ27.7
ꢁ
(6C),22.8, 18.1 (2C), 14.2, ꢂ4.0 (2C), ꢂ4.5 (2C); ½a D25
ꢁ
ꢂ22.7 (c 1.9,
(c 2.2, CHCl3); nmax(film) 3429, 2929, 2856, 1639, 1520, 1472, 1424,
1361, 1257, 1218, 1006, 928, 771 cmꢂ1; ESI-HRMS calculated for
C30H65O3Si2 [MþH]þ 529.4472 found 529.4292.
CHCl3); nmax (film) 2928, 2857, 2710, 1716, 1520, 1471, 1463, 1389,
1361, 1256, 1217, 1075, 835, 773 cmꢂ1; ESI-HRMS calculated for
C34H67O3Si2 [MþH]þ 579.4629 found 579.4402.
4.1.16. (4R,7S,8S)-4,7,8-Tris-(tert-butyldimethylsilanyloxy)-octadec-
1-ene (10). To an ice-cold solution of secondary alcohol 24 (495 mg,
0.936 mmol) in dry CH2Cl2 (10 mL) under argon were added 2,6-
4.1.13. (4S,5S)-4,5-Bis-(tert-butyldimethylsilanyloxy) pentadecan-1-
ol (23). To a solution of benzyl ether 22 (850 mg, 1.47 mmol) in

P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
8039
lutidine (0.140 mL, 1.22 mmol) and TBSOTf (0.260 mL, 0.964 mmol).
The mixture was stirred at room temperature for 2 h. The reaction
was quenched with satd aq NaHCO3 and extracted with CH2Cl2
(3ꢃ50 mL). The combined organic layers were dried over anhyd
Na2SO4, filtered, and concentrated. Purification by flash column
chromatography (silica gel, hexane) gave tris-TBS ether 10 (590 mg,
73%) as a colorless oil; Rf (20:1 hexane/ethyl acetate) 0.83; dH
(300 MHz, CDCl3) 5.87e5.69 (1H, m), 5.06e4.92 (2H, m), 3.68e3.57
(1H, m), 3.52e3.36 (2H, m), 2.17 (2H, t, J¼6.5 Hz),1.78e1.49 (4H, m),
1.21 (18H, br s), 0.83 (30H, br s), 0.00 (18H, s); dC (75 MHz, CDCl3)
135.5, 116.5, 76.0, 75.4, 72.6, 42.2, 34.4, 31.9, 29.7, 29.6 (2C), 29.5,
29.4, 26.6, 26.3, 25.9, 25.8 (9C), 22.7, 18.1, 18.0 (2C), 14.1, ꢂ4.1, ꢂ4.2,
(1H, d, J¼2.7 Hz), 6.35 (1H, d, J¼2.1 Hz), 5.06 (2H, s), 4.96 (2H, s),
4.94e4.86 (1H, m), 4.75e4.65 (1H, m), 4.58e4.46 (1H, m),
3.65e3.53 (1H, m), 3.53e3.38 (2H, m), 2.74e2.62 (2H, m),
2.54e2.42 (2H, m), 2.22 (2H, t, J¼7.4 Hz), 1.98e1.82 (2H, m),
1.74e1.49 (10H, m), 1.35 (34H, br s), 0.84 (30H, s), 0.00 (18H, s); dC
(75 MHz, CDCl3) 173.2, 170.6, 158.5, 155.9, 137.2, 136.7, 136.4, 128.8
(2C), 128.6 (2C), 128.2, 128.1, 127.5 (2C), 127.1 (2C), 117.2, 105.9, 99.1,
76.1, 75.4, 72.9, 70.1 (2C), 48.8, 38.9, 37.1, 36.8, 36.6, 34.7, 33.7, 32.7,
31.9, 30.8, 29.9, 29.7 (4C), 29.6 (4C), 29.5, 29.4, 29.3 (2C), 26.6, 26.1,
25.9 (3C), 25.8 (6C), 25.7, 25.5, 25.2, 22.7, 18.2, 18.0 (2C), 14.1, ꢂ4.0,
ꢂ4.1, ꢂ4.4, ꢂ4.5 (2C), ꢂ4.6; ½a D25
ꢂ29.4 (c 3.0, CHCl3); nmax(film)
ꢁ
3401, 2928, 2860, 2253, 1790, 1645, 1611, 1499, 1464, 1376, 1257,
1149, 1093, 1010 cmꢂ1; ESI-HRMS calculated for C73H125N2O7Si3
[MþH]þ 1225.8795 found 1225.9003.
-4.4, ꢂ4.5, ꢂ4.6 (2C); ½a D25
ꢂ19.5 (c 1.8, CHCl3); nmax(film) 2956,
ꢁ
2857, 1639, 1472, 1463, 1361, 1257, 1218, 1091, 1006 cmꢂ1; ESI-HRMS
calculated for C36H79O3Si3 [MþH]þ 643.5337 found 643.5108.
4.1.20. Amide intermediate 26b of schulzeine C. A mixture of tri-
cyclic amine 4b (70.0 mg, 0.163 mmol), 28-carbon fatty acid side
chain 5 (133 mg, 0.163 mmol), DCC (108 mg, 0.523 mmol), and
4.1.17. 28-Carbon alkene 25. To a solution of C12eC28 alkene 10
(35.0 mg, 53.0
0.533 mmol) in CH2Cl2 (1.8 mL) was added Grubbs’ first generation
catalyst (4.4 mg, 5.34 mol) in CH2Cl2 (1 mL). The reaction was
mmol) and benzyl 11-dodecenoate (9) (154 mg,
DMAP (4.0 mg, 32.7 mmol) in CH2Cl2 (2 mL) was stirred at room
m
temperature under argon for 48 h after which the mixture was
filtered. The filtrate was concentrated under reduced pressure and
the crude material was purified by flash column chromatography
(silica gel, 2:1 hexane/ethyl acetate) to give amide 26b (174 mg,
89%) as a colorless oil; Rf (2:1 hexane/ethyl acetate) 0.38; dH
(300 MHz, CDCl3) 7.40e7.23 (10H, m), 6.46 (1H, d, J¼2.1 Hz), 6.38
(1H, d, J¼5.1 Hz), 6.33 (1H, d, J¼2.1 Hz), 5.00 (2H, d, J¼6.0 Hz), 4.98
(2H, s), 4.88 (1H, dd, J¼12.0, 4.1 Hz), 4.77 (1H, dd, J¼10.5, 3.0 Hz),
4.24e4.12 (1H, m), 3.65e3.53 (1H, m), 3.54e3.43 (2H, m), 3.04 (1H,
d, J¼11.4 Hz), 2.81(1H, d, J¼12.6 Hz), 2.69e2.44 (3H, m), 2.19 (2H, t,
J¼7.2 Hz), 1.96e1.83 (2H, m), 1.76e1.49 (10H, m), 1.30 (34H, br s),
0.84 (30H, s), 0.00 (18H, s); dC (75 MHz, CDCl3) 173.9, 170.0, 158.3,
156.8, 137.8, 136.7, 136.5, 128.7 (2C), 128.6 (2C), 128.1 (2C), 127.3
(2C), 127.2 (2C), 118.2, 106.1, 99.2, 76.1, 75.4, 72.9, 70.2 (2C), 56.2,
52.0, 49.2, 39.6, 37.3, 36.8, 34.7, 34.1, 31.9, 30.6, 29.7 (2C), 29.6 (2C),
29.5 (2C), 29.4, 29.3 (2C), 29.2, 27.9, 27.2, 26.6, 26.2, 26.1 (3C), 26.0
(6C), 25.7, 25.6, 25.5, 24.7, 22.7, 18.1, 18.0 (2C), 14.1, ꢂ4.1 (2C), ꢂ4.4,
heated to reflux under argon for 4 h and then allowed to cool to
room temperature. Silica gel was added, and the mixture was
concentrated. Purification by flash column chromatography (silica
gel, 30:1 hexane/ethyl acetate) gave internal alkene 25 (35.0 mg,
73%) as a colorless oil; Rf (30:1 hexane/ethyl acetate) 0.75; dH
(300 MHz, CDCl3) 7.39e7.27 (5H, m), 5.43e5.32 (2H, m), 5.08 (2H,
s), 3.67e3.53 (1H, m), 3.52e3.39 (2H, m), 2.32 (2H, t, J¼6.4 Hz),
2.22e2.05 (2H, m), 2.05e1.87 (2H, m), 1.77e1.51 (4H, m), 1.24 (32H,
br s), 0.85 (30H, br s), 0.01 (18H, s); dC (75 MHz, CDCl3) 173.7, 136.1,
132.7, 132.6, 128.5 (2C), 128.2 (2C), 126.6, 76.0, 75.4, 73.2, 66.0, 41.0,
40.2, 35.6, 34.4, 34.3, 32.7, 31.9, 30.0, 29.7, 29.6 (2C), 29.5, 29.4, 29.3,
29.2, 29.1, 27.5, 26.6, 26.4, 25.9 (9C), 25.0, 22.7, 18.2, 18.0 (2C), 14.1,
ꢂ4.1, ꢂ4.2, ꢂ4.4, ꢂ4.5 (2C), ꢂ4.6; ½a D25
ꢂ7.0 (c 1.0, CHCl3); nmax(film)
ꢁ
2929, 2856, 1732, 1602, 1520, 1471, 1463, 1434, 1361, 1257, 1218,
1093, 1006, 929, 836, 771 cmꢂ1
; ESI-HRMS calculated for
C53H103O5Si3 [MþH]þ 903.7113 found 903.7093.
ꢂ4.5 (2C), ꢂ4.6; ½a D25
þ22.5 (c 2.0, CHCl3); nmax(film) 3401, 2928,
ꢁ
4.1.18. 28-Carbon fatty acid side chain 5. To a solution of alkene 25
(130 mg, 0.144 mmol) in hexane (2.5 mL) was added palladium on
activated carbon (13.0 mg, 10% w/w) and the resulting suspension
was stirred under a hydrogen atmosphere for 12 h (a balloon of
hydrogen gas was equipped to the reaction flask, ca. 1.1 atm). The
mixture was then filtered and the solvent was removed under re-
duced pressure. Purification by flash column chromatography (sil-
ica gel, 10:1 hexane/ethyl acetate) gave 28-carbon fatty acid 5
(81.0 mg, 69%) as a colorless oil; Rf (20:1 hexane/ethyl acetate) 0.12;
dH (300 MHz, CDCl3) 3.64e3.53 (1H, m), 3.53e3.40 (2H, m), 2.30
(2H, t, J¼7.5 Hz), 1.76e1.49 (6H m), 1.47e1.34 (4H, m), 1.25 (34H, br
s), 0.85 (30H, br s), 0.00 (18H, s); dC (75 MHz, CDCl3) 180.2, 76.1,
75.4, 72.9, 37.3, 36.6, 34.7 (2C), 34.1, 31.9, 29.9 (2C), 29.8, 29.7, 29.6
(2C), 29.5, 29.4, 29.3, 29.1, 26.6, 26.2, 26.1, 26.0 (3C), 25.9 (6C), 25.5,
25.2, 24.7, 22.7, 18.1, 18.0 (2C), 14.1, ꢂ4.1, ꢂ4.4, ꢂ4.5 (2C), ꢂ4.6 (2C);
2856, 2253, 1794, 1645, 1610, 1499, 1464, 1376, 1257, 1149, 1093,
1006 cmꢂ1; ESI-HRMS calculated for C73H125N2O7Si3 [MþH]þ
1225.8795 found 1225.9071.
4.1.21. Triol intermediate 27a of schulzeine B. A solution of amide
26a (13.0 mg, 10.6 mmol) in 1 N HCl in THF (0.500 mL) was stirred at
room temperature for 30 min. Ethyl acetate (3 mL) and satd aq
NaHCO3 (3 mL) were added and the phases were separated. The
aqueous layer was extracted with ethyl acetate (3ꢃ5 mL). The
combined organic layers were dried over anhyd Na2SO4, filtered,
and concentrated under reduced pressure to give triol 27a (7.2 mg,
74%) as a colorless oil; dH (300 MHz, CDCl3) 7.43e7.29 (10H, m), 6.83
(1H, d, J¼5.6 Hz), 6.47 (1H, d, J¼2.2 Hz), 6.38 (1H, d, J¼2.2 Hz), 5.09
(2H, s), 4.99 (2H, s), 4.93 (1H, dd, J¼10.8, 4.0 Hz), 4.77e4.66 (1H, m),
4.60e4.48 (1H, m), 3.79e3.55 (1H, m), 3.49e3.36 (2H, m),
2.86e2.61 (4H, m), 2.57e2.41 (1H, m), 2.26 (2H, t, J¼7.9 Hz),
1.77e1.40 (15H, m), 1.37e1.25 (31H, m), 0.88 (3H, t, J¼6.3 Hz); dC
(75 MHz, CDCl3): 173.1, 170.5, 158.5, 155.9, 137.1, 136.7, 136.4, 128.8
(2C), 128.6 (2C), 128.2, 128.1, 127.5 (2C), 127.0 (2C), 117.2, 105.8, 99.1,
74.6, 74.4, 71.9, 70.1 (2C), 48.8, 38.9, 37.5, 36.7, 33.5, 33.0, 31.8, 29.6,
29.5 (6C), 29.5 (5C), 29.4, 29.3 (2C), 29.2, 28.5, 25.7 (2C), 25.6, 25.2,
½
a 2D5
ꢁ
ꢂ16.1 (c 1.7, CHCl3); nmax(film) 2927, 2856, 1709, 1463, 1388,
1361, 1256, 1215, 1091, 835, 774, 669 cmꢂ1; ESI-HRMS calculated for
C46H99O5Si3 [MþH]þ 815.6800 found 815.6810.
4.1.19. Amide intermediate 26a of schulzeine B. A mixture of tri-
cyclic amine 4a (40.0 mg, 93.3
chain 5 (81.5 mg, 0.100 mmol), DCC (62.0 mg, 0.300 mmol), and
DMAP (2.5 mg, 20.5 mol) in CH2Cl2 (1 mL) was stirred at room
mmol), 28-carbon fatty acid side
22.6, 14.0; ½a 2D5
ꢂ47.4 (c 2.4, CHCl3); nmax(film) 3430, 3016, 2925,
ꢁ
m
2853, 1791, 1636, 1608, 1498, 1465, 1375, 1358, 1308, 1271, 1151,
1090, 1048 cmꢂ1; ESI-HRMS calculated for C55H83N2O7 [MþH]þ
883.6200 found 883.6119.
temperature under argon for 48 h after which the mixture was
filtered. The filtrate was concentrated under reduced pressure and
the crude material was purified by flash column chromatography
(silica gel, 2:1 hexane/ethyl acetate) to give amide 26a (105 mg,
91%) as a colorless oil; Rf (2:1 hexane/ethyl acetate) 0.62; dH
(300 MHz, CDCl3) 7.40e7.25 (10H, m), 6.79 (1H, d, J¼5.4 Hz), 6.47
4.1.22. Triol intermediate 27b of schulzeine C. A solution of amide
26b (18.0 mg, 14.7
mmol) in 1 N HCl in THF (0.700 mL) was stirred at
room temperature for 30 min. Ethyl acetate (3 mL) and satd aq

8040
P. Kuntiyong et al. / Tetrahedron 67 (2011) 8034e8040
6. Takaya, Y.; Kikuchi, H.; Terui, Y.; Komiya, J.; Furukawa, K.-I.; Seya, K.; Motomura,
S.; Ito, A.; Oshima, Y. J. Org. Chem. 2000, 65, 985e989.
7. Zhao, H.; Neamati, N.; Mazumder, A.; Sunder, S.; Pommier, Y.; Burke, T. R., Jr. J.
NaHCO3 (3 mL) were added and the phases were separated. The
aqueous layer was extracted with ethyl acetate (3ꢃ5 mL). The
combined organic layers were dried over anhyd Na2SO4, filtered,
and concentrated under reduced pressure to give triol 27b (10.1 mg,
78%) as a colorless oil; dH (300 MHz, CDCl3) 7.44e7.29 (10H, m), 6.51
(1H, d, J¼2.9 Hz), 6.50e6.38 (1H, m), 6.37 (1H, d, J¼2.9 Hz), 5.05
(1H, s), 5.03 (1H, s), 5.01 (2H, s), 4.96e4.84 (1H, m), 4.80 (1H, dd,
J¼11.0, 3.4 Hz), 4.28e4.14 (1H, m), 3.72e3.56 (1H, m), 3.51e3.45
(2H, m), 3.11e2.77 (2H, m), 2.74e2.49 (3H, m), 2.22 (2H, t, J¼7.4 Hz),
1.83e1.37 (15H, m), 1.38e1.19 (31H, m), 0.88 (3H, t, J¼7.1 Hz); dC
(75 MHz, CDCl3) 173.7, 168.8, 158.2, 156.8, 137.7, 136.6, 136.4, 128.8
(2C), 128.7 (2C), 128.1 (2C2C), 127.5 (2C), 127.2 (2C), 118.1, 106.1, 99.1,
74.5, 74.4, 71.8, 70.2, 70.1, 56.2, 51.9, 39.5, 37.4, 36.7, 33.5, 33.1, 31.9,
30.6, 29.7, 29.6 (5C), 29.4 (4C), 29.3 (2C), 29,2 (2C), 27.9, 27.2, 25.7,
Med. Chem. 1997, 40, 1186e1194.
8. The use of LiAlH4 as the reagent for the conversion of amido-ester 13 to imide
14 was discovered serendipitously. As reported in Ref. 3a, initially, we planned
to reduce the dimethyl ether analog of amido-ester 13 to the corresponding
primary alcohol and subsequently oxidize it to yield the hydroxylactam.
However, the imide was obtained as the product along with recovered starting
material. The intended primary alcohol was not observed.
9. Maryanoff, B. B.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431e1628.
10. NOESY experiment shows correlation between H11b (d 4.48 ppm) and H3 (d 2.
57 ppm) in 17a. This correlation is not present in 17b.
HO
O
O
11b
O
N
N
25.6, 25.5, 22.7, 14.1; ½a D25
ꢁ
þ59.1 (c 2.2, CHCl3); nmax(film) 3422,
OH
H
3
H
H
3016, 2925, 2855, 1790, 1636, 1608, 1498, 1465, 1375, 1358, 1308,
1271, 1151, 1090, 1050 cmꢂ1; ESI-HRMS calculated for C55H83N2O7
[MþH]þ 883.6200 found 883.6129.
NOESY
X-ray crystallographic analysis was performed on a related compound dimethyl
ether 28 and the relative configuration of H3 and H11b is clearly shown as cis.
Acknowledgements
This project is funded by the Thailand Research Fund. Scholar-
ships for S.A., N.P., C.H., and P.S. are provided by the department of
Chemistry, Faculty of Science, Silpakorn University, Thailand.
Supplementary data
Supplementary data containing nuclear magnetic resonance
(NMR) spectra of compounds synthesized in this study are available
for online publication. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2011.07.085.
MeO
References and notes
H
N
O
O
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OMe
28
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