A new approach to the C28 fatty acid chain of the marine natural products schulzeines B and C: A concise diastereoselective total synthesis of(-)-schulzeine B

Article abstract of DOI:10.1016/j.tet.2011.06.023

An enantioselective approach to the C₂₈ fatty acid chain of the marine natural products schulzeines B and C was established based on the l-tartaric acid derived C₄ chiron 11 via successive 1,4-bis-chain elongation reactions and catal

Full text of DOI:10.1016/j.tet.2011.06.023

Tetrahedron 67 (2011) 6281e6288
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A new approach to the C28 fatty acid chain of the marine natural products
schulzeines B and C: a concise diastereoselective total synthesis of
(ꢀ)-schulzeine B
*
Chao Yang, Yu-Hui Bao, Pan Liang, Jian-Liang Ye, Ai-E Wang, Pei-Qiang Huang
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2011
Received in revised form 31 May 2011
Accepted 10 June 2011
Available online 16 June 2011
An enantioselective approach to the C28 fatty acid chain of the marine natural products schulzeines B and
C was established based on the
reactions and catalytic asymmetric hydrogenation. The chiral tricyclic core 8 was constructed via a dia-
stereoselective PicteteSpengler cyclization reaction (dr ¼ 89:11) of the -glutamic acid derived precursor
13. On this basis, a concise total synthesis of (ꢀ)-schulzeine B (5) was disclosed.
Ó 2011 Elsevier Ltd. All rights reserved.
L-tartaric acid derived C4 chiron 11 via successive 1,4-bis-chain elongation
L
Keywords:
Marine natural products
Total synthesis
Tartaric acid
Glycosidase inhibitors
benzo[a]quinolizidine
1. Introduction
Up to date, the asymmetric total synthesis of penarolide sulfate
6
A1 and schulzeines AeC (4e6),7e9 as well as the enantioselective
synthesis of the hydroxy acid segment of schulzeines B/C10 and the
3-aminobenzo[a]quinolizidine moiety of schulzeines AeC11 have
been reported. Although Wardrop and Bowen have shown that
construction of the tricyclic isoquinoline core by PicteteSpengler
cyclization could reach a 9:1 cis/trans diastereoselectivity,9a how-
ever, in all the reported total syntheses of schulzeine B,7e9 the
diastereoselectivities in the construction of the benzo[a]quinolizi-
dine core11 were low, which varied from 1:1 to 2:1.9b With a pro-
gram aiming at the synthesis of glycosidases inhibitors,12 we now
report an efficient and highly diastereoselective synthesis of the C28
fatty acid chain of schulzeines B and C, as well as the total synthesis
of (ꢀ)-schulzeine B via the chiron approach.13
Glycosidases play key roles in many biological processes.1 Many
sugar-related natural products, such as azasugars show potent in-
hibitory activity against glycosidases, and are considered to be
promising leads for drug development against metabolites-related
diseases.1 Recently, marine invertebrates have been shown to be
a new source of potent
proline-containing macrolide trisulfates penarolide sulfates A1 (1)
and A2 (2) were isolated from the marine sponge Penares sp. They
a
-glucosidase inhibitors.2 In 2000, two
show potent anti-yeast
a
-glucosidase activity (IC50¼1.2 and 1.5
mg/
mL, respectively).3 Later on, penasulfate A (3) (Fig. 1), a pipecolate-
containing disulfate was isolated from the same source. It shows ten
times more potent thanpenarolide sulfates A1 and A2 against yeast a-
glucosidase.4 Then schulzeines AeC (4e6), three benzo[a]quinolizi-
dine-containing trisulfates were isolated, which exhibit potent in-
2. Results and discussion
hibitory activities toward yeast
viral neuraminidase (IC50¼60
inhibitory activities toward
a
m
-glucosidase (IC50¼48e170 nM) and
M).5 Noteworthy is that, remarkable
-glucosidase (IC50 values of 2.5 and
Our synthetic approach to schulzeine B (5) is displayed retro-
synthetically in Scheme 1. As schulzeine B consists of a 3-
aminobenzo[a]quinolizidine and a C28 fatty acid chain, the assem-
bly of two properly protected segments via amide bond formation
is the direct and general strategy for its total syntheses.7e11 For the
a
1.1 mM, respectively) are still retained by the desulfated analogues of
schulzeines A and B.5
synthesis of the C28 fatty acid chain, a L-tartaric acid-based chiron
approach14 was envisaged. The known tosyl-triflate15 11 was cho-
sen as the proper chiron, which includes both the requisite 2,3-diol
* Corresponding author. Fax: þ86 592 2186400; e-mail address: pqhuang@
xmu.edu.cn (P.-Q. Huang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.023

6282
C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
pathway.5 On the basis of our recent studies on the
L-glutamic acid-
O
30
based synthetic approach to protected 3-amino-6-hydroxy-2-
piperidone derivatives,19 we selected dibenzyl derivative 13 as
the precursor for PicteteSpengler reaction, which could be avail-
able from the known compound 147 and 15.19 According to recent
reports on PicteteSpengler reactions of O,O-dimethyl analogue11
and N-Phth protected analogue9 of 13, cis-diastereoselectivity was
expected for PicteteSpengler reaction of 13.
1'
1
O
O
26
N
N
OSO3Na
NaO3SO 16
5'
15
14 OSO3Na
penarolide sulfate A1 (1)
O
30
The synthesis of the hydroxy acid segment (9) of schulzeines B
OSO3Na
17
and C started from the known C4 building block 11,15 readily
1'
1
O
O
27
NaO3SO 15
available from L-tartaric acid in 53% overall yield. Treatment of the
OSO3Na
16
5'
tosyl triflate 11 with organocopper reagent, generated in situ from
1.1 equiv of Grignard reagent n-C9H19MgBr and a catalytic amount
of CuBr, at 0 ꢁC for 1.5 h produced chemoselectively the desired
coupling product 16 in 80% yield (Scheme 2). For the second chain
elongation, tosylate 16 was treated with the dianion generated in
situ from methyl acetoacetate (NaH; n-BuLi).20 Unfortunately the
penarolide sulfate A2 (2)
CO2Me
O
OSO3Na
N
7
desired
g-alkylation product was not obtained. Considering the
OSO3Na
success in the similar
g
-alkylation with 4,5-bis(iodomethyl)-2,2-
dimethyl-1,3-dioxolane,21 it was envisioned that both electronic
and steric hindrance of the tosyl group might be responsible for the
penasulfate A (3)
20'
HO
OSO3Na
H
11b
R1 R2
NaO3SO
failure of the
g-alkylation with tosylate 16, and replacement of
N
O
tosyloxy with iodide as the leaving group would be beneficial. In-
deed, after converting the tosylate 16 into the corresponding iodide
(NaI, DMF), the alkylation proceeded smoothly to give the desired
product 10 in 70% yield. Under the catalytic8,16 asymmetric hy-
drogenation conditions (0.5 mol % of (R)-(BINAP)RuCl2, H2, 6 atm,
O
14'
OH
N
H
OSO3Na
Schulzeine A (4, 11b R, R1 = Me, R2 = H)
Schulzeine B (5, 11b S, R1 = R2 = H)
Schulzeine C (6, 11b R, R1 = R2 = H)
MeOH, 70 ꢁC, 20 min),
b-ketoester 10 was reduced to give the b-
hydroxyester 17 as the only observable diastereomer in 80% yield.
The diastereoselectivity of the reduction was estimated to be higher
than 95:5 at the limits of the method (NMR). O-Protection of the
hydroxyl group with TESCl gave compound 18 in 98% yield. Che-
moselective reduction of the ester with DIBAL-H at ꢀ78 ꢁC yielded
the corresponding aldehyde, which reacted with the Wittig re-
agent, generated in situ from phosphonium salt 19 and KHMDS in
THF to produce the Z-olefin 20 in 89% overall yield. The geometry of
the olefin could not be determined from the 1H NMR data, but
Fig. 1. Marine sulfates exhibiting inhibitory activities toward
a
-glucosidase.
moiety with syn-stereochemistry and 1,4-difunctionalities for
a straightforward bis-chain elongation. After coupling with the
dienolate 12, the third carbinolic chiral center could be established
by catalytic asymmetric hydrogenation.8,16 As for the synthesis of
the 3-aminobenzo[a]quinolizidine moiety, L-glutamic acid-based
chiron aproach7,9,11,17,18 appeared attractive in light of its biogenetic
8
BnO
OH
6
H
17'
N
O
schulzeine B
O
HO
11b
(5)
3
1
OBn
14'
N
H
7
OH
BnO
O
O
n-C9H19
H
N
O
O
9
HO
OBn
OTES
NH2
9
8
Noyori catalytic
asymmetric
hydrogenation
BnO
NH2
O
O
BnO
n-C9H19
MeO
N
O
OBn
14
HO
O
O
10
BnO
OH
NBn2
1,4-bis-chain
elongation
CO2Bn
NBn2
15
13
n-C9H19
OM OM'
OMe
M
O
OTf
OTs
+
O
11
12
Scheme 1. Retrosynthetic analysis of schulzeine B.

C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
6283
O
O
NH2
DIBAL-H
BnO
n-C9H19MgBr
OH
OH
DIBAL-H•14
ref. 15
HO
HO
O
O
CuBr, THF
TfO
TsO
THF, 0 °C, 3 h
5 steps
53%
+
OBn
14
0 °C, 1.5 h
80%
NBn2
ref. 19
11
L-tartaric acid
OH
L-Glu
BnO2C
2 steps
74%
i. NaI, DMF, refl.
ii. NaH, n-BuLi, THF
MeO
3
15
O
O
n-C9H19
3"
BnO
1'
(COCl)2, DMSO
CH2Cl2, -78 °C;
1
TsO
THF, refl., 4 h
HN
O
5"
16
O
O
98%
Et3N, -78 °C
71% for two steps
OBn
2
NBn2
5
84%
(R)-(BINAP)RuCl2
OH
O
O
21
n-C9H19
0.5 mol%
1
BnO
MeO
3"
BnO
H2, 6 atm
1'
6
6
MeOH, 70 °C, 20 min
HN
O
O
O
N
O
80% (dr > 95:5)
CHO
6
5"
BnO
HO
10
OBn
NBn2
3
NBn2
O
O
n-C9H19
13
TESCl, CH2Cl2
98%
22
1
MeO
MeO
8
3"
5"
BnO
BnO
HOAc
O
OH
17
6
1'
H
CH2Cl2
N
O
N
O
+
6
11b
DIBAL-H, –78 °C;
KHMDS,THF
3
1
OBn
OBn
O
O
3
NBn2
NBn2
n-C9H19
23 (43%)
24 (46%)
1
or
BnO2C
(19)
6
PPh3Br
9
BnO
BnO
+
O
OTES
89%
H
N
H
N
18
O
HOAc, TFA
O
18
O
CH2Cl2, refl.
96%
O
n-C9H19
OBn
OBn
NBn2
NBn2
14
O
1
BnO
6
11
cis-23 (89:11, inseparable) trans-23
OTES
20
Scheme 3. Diastereoselective construction of the 3-aminobenzo[a]quinolizidine
moiety cis-23.
Scheme 2. Synthesis of the precursor of the C28 fatty acid chain of schulzeines B and C.
deduced from the observed absorption at 736 and 689 cmꢀ1 in the
IR spectrum of compound 20, which is an indication of a Z-olefin.22
Having accomplished the diastereoselective synthesis of the
diastereomer 20 as a precursor of the C28 fatty acid residue, we next
turned our attention to the synthesis of the cis-3-aminobenzo[a]
quinolizidine moiety 8. The synthesis started from the known 2-
(3,5-bis(benzyloxy)phenyl)ethanamine (14)7 and hydroxylated
amino ester 1519 (Scheme 3). Using the method developed in our
laboratory,23 the O-unprotected hydroxyl ester 15 was treated with
a DIBAL-H$amine complex, prepared in situ from amine 14 and
DIBAL-H, to afford the desired hydroxy amide 21 in 98% yield.
Oxidation of alcohol 21 with either PDC or DesseMartin period-
inane gave aldehyde 22 in only 20e30% and 50e60% yields, re-
spectively. Swern oxidation24 [(COCl)2, DMSO, CH2Cl2; NEt3] at
ꢀ78 ꢁC afforded the cyclic tautomer 13 as a separable di-
astereomeric mixture in 10:1 ratio with a 84% combined yield.
Because both diastereomers can be used for the subsequent cycli-
zation, their stereochemistries were not determined. Next, the key
diastereoselective PicteteSpengler cyclization reaction was in-
vestigated.9,11,17 Treatment of the diastereomeric N,O-acetals 13
with a catalytic amount of HOAc in CH2Cl2 at room temperature for
48 h led to the formation of the desired cyclization product 23 as
a diastereomeric mixture in 43% yield, along with the dehydrated
product 24 in 46% yield. The formation of the enamide 24 might be
attributed to the slow rate of the cyclization reaction that makes the
dehydration reaction possible. It was thus envisioned that the
conditions allowing an enhancement of the cyclization reaction,
such as use of a stronger acid and running the reaction at a higher
temperature would increase the yield of the cyclization. Indeed,
when 2.0 equiv of TFA17c,9 were added and the reaction run at reflux
for 24 h, the desired product 23 was obtained as a diastereomeric
mixture in 89:11 ratio with 96% combined yield. The two di-
astereomers were inseparable by column chromatography and the
ratio was determined by 1H NMR and HPLC analyses. 2D NOESY
experiments on the major diastereomer of 23 showed a NOE cor-
relation between the protons at C-3 and C-11b, indicating a cis-
relationship between these two protons. The observed cis-diaster-
eoselectivity of PicteteSpengler reaction is in agreement with the
reported similar systems,9,11 but much higher diastereoselectivity
was obtained, compared with the corresponding O,O-dimethyl
analogue (8:1 vs 1.7:1 and 2.2:1).11
To get two diastereomers separated, a conversion of the N-
dibenzyl group to a carbamate group7,9 was envisioned. Thus, se-
lective N-monodebenzylation of 23 was first attempted. To our
disappointment, treatment of the diastereomeric mixture of 23
with either ceric ammonium nitrate (CAN)25 or DDQ26 did not give
the desired product. An alternative approach was then investigated.
The 8:1 diastereomeric mixture of 23 was subjected to catalytic
hydrogenolytic conditions (10% Pd/C, H2 1 atm, room temperature)
in the presence of (Boc)2O, which afforded, in one-pot, the fully
debenzylated and N-Boc protected compound 25 as an inseparable
diastereomeric mixture in 90:10 ratio with a combined yield of 89%.
O,O-Dibenzylation of this diastereomeric mixture with benzyl
bromide (K2CO3, DMF) at room temperature for 12 h led to the
known carbamates7,9 cis-26 (yield: 82%) and trans-26 (yield: 10%)
that were easily separated by flash column chromatography
(Scheme 4). Thus, compound cis-26 was synthesized in five steps
from the known compound 15 with an overall yield of 58%.

6284
C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
BnO
3. Conclusion
H
10% Pd/C, H2
N
O
In summary, by taking advantage of the multiple functionalities
of the -tartaric acid derived C4 building block 11, a flexible and
(Boc)2O, MeOH
89%
OBn
L
NBn2
highly diastereoselective approach for the synthesis of the C28 fatty
acid chain of schulzeines B and C has been achieved. In combination
with a highly diastereoselective (dr ¼ 89: 11) synthesis of the 3-
aminobenzo[a]quinolizidine moiety, we have developed a concise
and highly diastereoselective total synthesis of the marine natural
product (ꢀ)-schulzeine B (5). The synthesis was achieved in 14
chromatographic separation steps with 12.7% overall yield from the
known compounds 15 and 11.
23 (cis/trans = 89:11)
HO
HO
H
H
N
O
N
O
+
OH
trans-25
BnO
OH
cis-25
NHBoc
NHBoc
BnO
BnBr
4. Experimental section
4.1. General methods
H
N
H
O
N
O
+
K2CO3, DMF
92%
OBn
OBn
NH
NH
Boc
Boc
(separable)
(10%)
trans-26
cis-26
(82%)
Melting points were uncorrected. Infrared spectra were mea-
sured using film KBr pellet techniques. 1H and 13C NMR spectra
were recorded in CDCl3 or in CD3CN or in CD3OD with tetrame-
thylsilane as an internal standard. Silica gel (300e400 mesh) was
used for flash column chromatography, eluting (unless otherwise
stated) with ethyl acetate/petroleum ether (PE) (60e90 ꢁC) mix-
ture. Ether and THF were distilled over sodium benzophenone ketyl
under N2. Dichloromethane was distilled over calcium hydride
under N2.
Scheme 4. Synthesis of 3-aminobenzo[a]quinolizidine derivative cis-26.
In order to assemble the benzo[a]quinolizidine moiety cis-26
with the protected hydroxy acid segment 20, cis-26 was depro-
tected (3 M HCl, EtOAc) to give the free amine 8,7 and compound 20
was hydrogenated under basic conditions8 (H2, Pd/C, 2,6-lutidine,
EtOH) to give the protected C28 fatty acid residue of schulzeines B
and C (9)8 (Scheme 5). The coupling of the two fragments was
undertaken by treatment of carboxylic acid 9 with EDCI, HOBt, and
Et3N to form an activated ester, which reacted with amine 8 to
afford the amide 27 in 89% yield. Removal of the acetal and TES
protecting groups by heating compound 27 in a 2 N HCl solution in
methanol at 90 ꢁC for 2 h gave the desired triol 7 in 95% yield.
Sulfation7e9 of triol 7 using SO3$pyridine complex in anhydrous
DMF provided the trisulfated compound 28. Finally, hydrogenolysis
of the benzyl groups afforded schulzeine B (5) (Scheme 5). The
spectral data of the synthetic schulzeine B (5) are identical with
those reported.5,9
4.2. ((4S,5S)-5-Decyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl-
4-methylbenzenesulfonate (16)
To a suspension of CuBr (76 mg, 0.53 mmol) inTHF (10 mL) at 0 ꢁC
were added n-C9H19MgBr (0.5 M in THF, 5.2 mL, 2.60 mmol) and
a THF solution (3 mL) of the known tosyl triflate 11.15 After being
stirred at the same temperature for 1.5 h, the reaction was quenched
with a saturated NH4Cl/aqueous NH3 (9:1) solution (5 mL). The in-
soluble substance was removed by filtration through Celite. The
filtrate was concentrated under vacuum and extracted with ether
(10 mLꢂ5). The combined extracts were washed successively with
water (3 mL) andbrine (1 mL), dried overanhydrousNa2SO4, filtered,
and concentrated under vacuum. Filtration of the residue through
a short pad of silica gel column eluting with EtOAc/PE ¼ 1:10 yielded
BnO
3N HCl
H
cis-26
N
O
EtOAc
OBn
EDCI, HOBt, NEt3
NH2
8
compound 16 (817 mg, yield: 80%) as a colorless oil. [
a
]
20 ꢀ15.8 (c 1.3,
D
CH2Cl2, rt, 20 h
89%
CHCl3); IR (film) nmax: 2986, 2926, 2854, 1598, 1458, 1182 cmꢀ1; 1H
over three steps
NMR (400 MHz, CDCl3)
d
7.80 (d, J¼8.0 Hz, 2H, Ar), 7.34 (d, J¼8.0 Hz,
O
O
H2, Pd/C
O
O
n-C9H19
2H, Ar), 4.15e4.04 (m, 2H, OCH), 3.82e3.74 (m, 2H, eOCH2), 2.45 (s,
3H, PhCH3), 1.56e1.48 (m, 2H, CH2), 1.36 (s, 6H, C(CH3)2), 1.32e1.24
(m, 19H,), 0.88 (t, J¼6.4 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
20
2,6-lut., EtOH HO
9
OTES
9
BnO
d
145.0, 132.8, 129.8, 128.0, 109.3, 78.2, 77.9, 69.2, 33.1, 31.9, 29.58,
H
29.55, 29.5, 29.3, 27.3, 26.7, 25.8, 22.7, 21.6, 14.1; MS (ESI) m/z 427
(MþHþ, 100%); HRESIMS calcd for C23H38O5SNa (MþNa)þ:
449.2338; found: 449.2332.
N
N
O
O
O
2N HCl, 90 °C, reflux
95%
n-C9H19
OBn
OBn
N
H
9
OTES
27
4.3. Methyl 5-((4S,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-oxopentanoate (10)
BnO
H
O
OH
i. SO3·pyridine, DMF
O
n-C9H19
Compound 16 (1.58 g, 3.70 mmol) was added slowly to a hot
(80e90 ꢁC) and vigorously stirred solution of NaI (833 mg,
5.6 mmol) in DMF (7.5 mL). The mixture was stirred at the same
temperature for 2 h, then cooled to room temperature and poured
into water (75 mL). The resulting mixture was extracted with Et2O
(30 mLꢂ6). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under vacuum.
The crude iodide was used immediately in the next step without
further purification.
ii. H2, Pd/C
N
H
OH
yield over two steps 69%
9
OH
7
HO
H
N
O
OSO3Na
OSO3Na
O
n-C9H19
OH
N
H
9
OSO3Na
(–)-schulzeine B (5)
To a suspension of NaH (178 mg, 7.43 mmol) in THF (25 mL) at
Scheme 5. Synthesis of (e)-schulzeine B (5).
0 ꢁC was added methyl acetoacetate (0.80 mL, 7.43 mmol) and the

C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
6285
mixture was stirred at 0 ꢁC for 15 min before n-butyl lithium was
added dropwise. After the addition, the mixture was stirred at 0 ꢁC
for another 15 min before the solution of the iodide (1.42 g,
3.72 mmol) in THF (2 mL) was added to the reaction mixture. The
reaction was allowed to warm to room temperature and stirred for
1 h. Then the reaction was quenched with saturated NH4Cl (5 mL).
The resulting mixture was extracted with ethyl ether (20 mLꢂ3).
The combined extracts were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under vacuum. The resi-
due was purified by flash chromatography. The combined extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash
chromatography eluting with 5% EtOAc in PE to give the ketoester
16H), 0.95 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 0.88 (t, J¼6.4 Hz, 3H, CH3),
0.60 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3); 13C NMR (100 MHz, CDCl3)
d
172.0, 107.8, 81.0, 80.9, 69.1, 51.4, 42.6, 34.1, 33.0, 31.9, 29.8, 29.6,
29.5, 29.3, 28.5, 27.28, 27.25, 26.1, 22.7, 14.1, 6.8, 4.9; MS (ESI): m/z
509 (MþNaþ, 100%); HRESIMS calcd for C27H54O5SiNa (MþNa)þ:
509.3638; found: 509.3638.
4.6. Benzyl (R,Z)-16-((4S,5S)-5-decyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-14-((triethylsilyl)oxy)hexadec-11-enoate (20)
To a solution of ester 18 (186 mg, 0.38 mmol) in CH2Cl2 (4 mL) at
ꢀ78 ꢁC was added a solution of DIBAL-H (0.57 mL of a 1.0 M solu-
tion in hexane, 1.0 mmol) dropwise. The reaction mixture was
stirred at ꢀ78 ꢁC for 0.5 h and then quenched by dropwise addition
of methanol (0.6 mL) before the reaction was allowed to warm to
23 ꢁC slowly. To the reaction mixture was added a 1 M solution of
Rochelle’s salt (4 mL). After being stirred overnight, the mixture
was extracted with CH2Cl2 (5 mLꢂ3). The combined extracts were
dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum to give the aldehyde as a yellowish oil (164 mg, 94%), which
was used as such in the next step.
10 as a colorless oil (1.02 g, yield: 74%). [
a
]
D
20 ꢀ28.5 (c 1.2, CHCl3); IR
(film) nmax: 2983, 2929, 2855, 1756, 1714, 1378, 1246 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 3.74 (s, 3H, OCH3), 3.62e3.54 (m, 2H, OCH), 3.48
(s, 2H, OCCH2CO), 2.83e2.63 (m, 2H, COCH2), 1.98e1.89 (m, 1H,
CHH-5), 1.74e1.64 (m, 1H, CHH-5), 1.54e1.48 (m, 2H, CH2-8), 1.36 (s,
6H, C(CH3)2), 1.31e1.19 (m, 16H), 0.88 (t, J¼6.8 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3)
d 202.1, 167.5, 108.0, 80.9, 79.8, 52.3, 49.0,
39.5, 32.7, 31.9, 29.7, 29.6, 29.5, 29.3, 27.3, 27.2, 26.4, 26.0, 22.6, 14.1;
MS (ESI): m/z 393 (MþNaþ, 100%); HRESIMS calcd for C21H38O5Na
(MþNa)þ: 393.2617; found: 393.2607.
To a suspension of the phosphonium salt 19 (651 mg,1.08 mmol)
in THF (2.5 mL) at ꢀ78 ꢁC was added KHMDS (0.7 M in toluene,
1.2 mL, 0.86 mmol) dropwise. The resulting mixture was stirred at
4.4. Methyl (R)-5-((4S,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-
4-yl)-3-hydroxypentanoate (17)
0
ꢁC for 1 h, and cooled to ꢀ78 ꢁC. To the resulting mixture was
added dropwise a solution of aldehyde (164 mg, 0.36 mmol) in THF
(1 mL). The reaction was allowed to warm to room temperature and
stirred for 5 h before quenching with water (1.5 mL). The resulting
mixture was extracted with ethyl ether (5 mLꢂ3). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash
column chromatography (eluent: 2% EtOAc in PE) to give Z-olefin 20
A vial containing catalyst (R)-BinapRuCl2 (11 mg, 0.014 mmol,
0.5% equiv) and ketoester 10 (1.00 g, 2.7 mmol) in MeOH (2 mL) was
placed in an autoclave and the autoclave was placed in an oil bath
pre-warmed to 70 ꢁC. After being purged with hydrogen for 5 min,
the pressure of hydrogen was raised to 6 atm, and the mixture was
stirred for 20 min. The reaction was stopped and the mixture di-
luted with CH2Cl2, passed through a pad of silica gel, concentrated
under vacuum. The residue was purified by flash column chroma-
tography (SiO2, eluting with 5% EtOAc in hexane) to give the alcohol
as a colorless oil (245 mg, yield: 95%). [
a
]
D
20 ꢀ5.27 (c 1.4, CHCl3); IR
(film) nmax: 2925, 2851, 1735, 1461, 1096, 736, 689 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d 7.45e7.38 (m, 5H, Ar), 5.56e5.51 (m, 2H, CH]
CH), 5.19 (s, 2H, OCH2Ph), 3.81e3.73 (m, 1H, SiOCH), 3.70e3.59 (m,
2H, OCH), 2.42 (t, J¼7.6 Hz, 2H, OCCH2), 2.35e2.22 (m, 2H, CH2-13),
2.13e2.04 (m, 2H, CH2-10), 1.79e1.67 (m, 4H, CH2-15, CH2-16),
1.62e1.47 (m, 4H, CH2-13, CH2-19), 1.44 (s, 6H, C(CH3)2), 1.40e1.31
(m, 28H), 1.04 (t, J¼8.0 Hz, 9H, Si(CH2CH3)3), 0.95 (t, J¼6.4 Hz, 3H,
CH3), 0.68 (q, J¼8.0 Hz, 6H, Si(CH2CH3)3); 13C NMR (100 MHz,
17 as a colorless oil (800 mg, yield: 80%). [
a
]
20 ꢀ25.0 (c 1.2, CHCl3);
D
IR (film) nmax: 3469, 2983, 2925, 2851, 1731, 1441, 1158 cmꢀ1 1H
;
NMR (400 MHz, CDCl3)
d 4.09e4.01 (m, 1H, HOCH), 3.71 (s, 3H,
OCH3), 3.63e3.55 (m, 2H, OCH), 3.21 (d, J¼4.4 Hz, 1H, OH, D2O
exchangeable), 2.55e2.42 (m, 2H, OCCH2CO), 1.87e1.76 (m, 1H,
CHH-4), 1.75e1.66 (m, 1H, CHH-4), 1.62e1.45 (m, 4H, CH2-5, CH2-8),
1.38 (s, 6H, C(CH3)2), 1.34e1.23 (m, 16H), 0.88 (t, J¼6.8 Hz, 3H, CH3);
CDCl3) d 173.6, 136.2, 131.8, 128.5, 128.1, 125.4, 107.7, 81.2, 81.1, 72.2,
66.0, 35.5, 34.3, 33.3, 33.1, 31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.34,
29.31, 29.2, 29.1, 29.0, 27.5, 27.3, 26.1, 24.9, 22.7, 14.1, 6.9, 5.1, 1.0; MS
(ESI): m/z 737 (MþNaþ, 100%); HRESIMS calcd for C44H78O3SiNa
(MþNa)þ: 737.5530; found: 737.5516.
13C NMR (100 MHz, CDCl3)
d 173.2, 108.0, 81.1, 81.0, 67.8, 51.7, 41.3,
33.4, 32.8, 31.9, 29.72, 29.65, 29.6, 29.5, 29.3, 28.9, 27.3, 27.2, 26.1,
22.7, 14.1; MS (ESI): m/z 395 (MþNaþ, 100%); HRESIMS calcd for
C21H40O5Na (MþNa)þ: 395.2773; found: 395.2770.
4.7. (S)-N-[3,5-Bis(benzyloxy)phenethyl]-2-(dibenzylamino)-
4.5. Methyl 5-(R)-((4S,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-
5-hydroxypentanamide (21)
4-yl)-3-((triethylsilyl) oxy)pentanoate (18)
A solution of DIBAL-H (1 M in hexane, 1.33 mL, 1.33 mmol) was
added, under a nitrogen atmosphere, to a cooled (0e5 ꢁC) THF
solution (0.5 mL) of the known amine 149 (403 mg, 1.2 mmol). The
mixture was allowed to warm up and stirred at room temperature
for 3 h. The concentration of the thus formed DIBAL-H$14 complex
was about 0.75 M, and was used directly for aminolysis.
To a solution of compound 17 (1.02 g, 2.8 mmol), TESCl (0.94 mL,
5.6 mmol), and DMAP (34 mg, 0.28 mmol) in CH2Cl2 (40 mL) at 0 ꢁC
was added dropwise triethylamine (0.78 mL, 5.6 mmol). The mix-
ture was then allowed to warm to room temperature and stirred for
12 h. The reaction was quenched with methanol (1 mL) at 0 ꢁC. The
mixture was diluted with ether, washed successively with water
(1 mL) and brine (1 mL). The organic phase was dried over Na2SO4,
filtered, and concentrated under vacuum. The residue was purified
by flash column chromatography eluting with 2% EtOAc in PE, to
To a solution of the known hydroxy amino ester 1519 (487 mg,
1.0 mmol) in THF (3 mL) was added the DIBAL-H$14 complex under
nitrogen at room temperature. After being refluxed for 17 h, the re-
action was cooled down to 0 ꢁC, and then quenched with 1 M HCl
(2 mL). The mixture was extracted with ethyl acetate (3 mLꢂ3). The
combined extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by flash chromatography (eluent: ethyl acetate/PE ¼ 1:1) to
give the silyl ether 18 as a colorless oil (1.31 g, yield: 98%). [a 20
]
D
ꢀ27.4 (c 1.35, CHCl3); IR (film) nmax: 2925, 2876, 2847, 1735, 1457,
1084 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 4.22e4.15 (m, 1H, SiOCH),
3.67 (s, 3H, OCH3), 3.62e3.53 (m, 2H, OCH), 2.53e2.40 (m, 2H,
OCCH2CO), 1.79e1.71 (m, 1H, CHH-4), 1.68e1.60 (m, 1H, CHH-4),
1.59e1.42 (m, 4H, CH2-5, CH2-8), 1.37 (s, 6H, C(CH3)2), 1.30e1.19 (m,
afford amide 21 (799 mg, yield: 98%) as a colorless oil. [
0.7, CHCl3); IR (film) nmax: 3393, 2927, 2869, 2366, 1647, 1588, 1570,
a
]
20 ꢀ35.9 (c
D

6286
C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
1159,1110,1027 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.50e7.18 (m, 20H,
55.1, 49.8, 38.0, 29.9, 29.6, 23.5; MS (ESI): m/z 609 (MþHþ, 100%);
Ar), 7.02 (t, J¼5.4 Hz, 1H, NH), 6.60 (t, J¼2.0 Hz, 1H, CH-400), 6.55 (d,
J¼2.0 Hz, 2H, CH-200, CH-600), 5.04 (s, 4H, OCH2Ph), 3.66 (d, J¼13.6 Hz,
2H, NCH2Ph), 3.69e3.58(m, 4H, CH2-5, CH2-10), 3.50(d, J¼13.6 Hz, 2H,
NCH2Ph), 3.11 (dd, J¼8.3, 3.3 Hz,1H, CH-2), 2.92e2.73 (m, 3H, CH2-20,
OH, D2O exchangeable), 2.04e1.83 (m, 2H, CH2-3), 1.81e1.64 (m, 2H,
HRESIMS calcd for [C41H40N2O3þHþ]: 609.3117; found: 609.3103.
4.10. (S)-1-(3,5-Bis(benzyloxy)phenethyl)-3-(dibenzylamino)-
3,4-dihydropyridin-2(1H)-one (24)
CH2-4); 13C NMR (100 MHz, CDCl3)
d
173.8, 160.4, 141.1, 138.8, 136.8,
To a solution of 13 (318 mg, 0.50 mmol) in anhydrous CH2Cl2
(15 mL) was added acetic acid (2 mL, 35 mmol). After stirring at
room temperature for 48 h, the mixture was concentrated under
vacuum, and the residue was purified by flash chromatography on
silica gel (EtOAc/PE ¼ 1:5) to give compound 23 (142 mg, yield:
43%) as a pale yellow solid, and compound 24 (133 mg, yield: 46%)
130.0, 128.62, 128.60, 128.0, 127.6, 127.3, 108.0, 100.2, 70.1, 61.8, 61.7,
54.4, 39.8, 35.7, 31.5, 20.2; MS (ESI): m/z 629 (MþHþ,100%); HRESIMS
calcd for [C41H44N2O4þHþ]: 629.3379; found: 629.3364.
4.8. (3S,6R/S)-1-[3,5-Bis(benzyloxy)phenethyl]-3-
(dibenzylamino)-6-hydroxypiperidin-2-one (13)
as a pale yellow oil. [
a
]
20 ꢀ93.3 (c 0.33, CHCl3); IR (film) nmax: 3061,
D
3024, 2927, 2853, 1661, 1591, 1448, 1366, 1232, 1146, 1046,
To a stirring, cooled (ꢀ78 ꢁC) solution of oxalyl chloride (0.13 mL,
1.47 mmol) in CH2Cl2 (5 mL) was added dropwise DMSO (0.2 mL,
2.4 mmol). After stirring for 10 min, a solution of compound 21
(739 mg, 1.18 mmol) in CH2Cl2 (1.5 mL) was transferred into the re-
action mixture via a canula. The resultant mixture was stirred at
ꢀ78 ꢁC for 40 min, then NEt3 (1 mL) was added. After stirring for
15 min at ꢀ78 ꢁC, an additional NEt3 (1 mL) was added and the
mixture was stirred at 0e5 ꢁC for 15 min. The reaction was quenched
with water (1 mL), and the mixture extracted with CH2Cl2 (3 mLꢂ3).
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel
(EtOAc/PE ¼ 1:5) to give compound 13 (673 mg, yield: 91%) as a pale
yellow oil, which is a 10:1 mixture of two diastereomers (determined
by 1H NMR). IR (film) nmax: 3414, 3061, 3024, 2923, 2866, 1634, 1589,
1451, 1381, 1369, 1143, 1049, 1024 cmꢀ1; 1H NMR (400 MHz, CD3CN)
1024 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.45e7.12 (m, 20H, Ar), 6.45
(s, 3H, CH-200, CH-400, CH-600), 5.68 (dd, J¼7.9, 2.6 Hz, 1H, CH-6), 4.95
(s, 5H, OCH2Ph, CH-5), 4.04 (d, J¼14.2 Hz, 2H, NCH2Ph), 3.88e3.80
(m, 1H, CH-3), 3.78 (d, J¼14.2 Hz, 2H, NCH2Ph), 3.53e3.43 (m, 2H,
CH2-10), 2.78 (t, J¼7.2 Hz, 2H, CH2-20), 2.51e2.39 (m, 1H, CHH-4),
2.36e2.21 (m, 1H, CHH-4); 13C NMR (100 MHz, CDCl3)
d 170.0,
160.0, 140.9, 140.6, 136.9, 129.1, 128.6, 128.5, 128.3, 128.0, 127.6,
126.8, 108.2, 105.1, 100.2, 70.0, 57.3, 55.1, 47.6, 35.3, 25.8; MS (ESI):
m/z 609 (MþHþ, 100%); HRESIMS calcd for [C41H40N2O3þHþ]:
609.3117; found: 609.3103.
4.11. tert-Butyl (3S,11bS)-9,11-dihydroxy-4-oxo-2,3,4,6,7,11b-
hexahydro-1H-pyrido[2,1-a]isoquinolin-3-ylcarbamate (cis-
25) and trans-25
A suspension of the diastereomeric mixture of 23 (188 mg,
0.31 mmol) and 10% Pd/C (19 mg) in methanol (2 mL) was stirred
under 1 atm of H2 at room temperature for 12 h. Boc2O (0.093 mL,
0.39 mmol) was added and the mixture was stirred for 10 h at room
temperature. The catalyst was removed by filtration through a pad
of Celite, and the filtrate was concentrated under vacuum. The
residue was purified by flash chromatography on silica gel (EtOAc/
PE ¼ 1:1) to give cis-25 (white gummy paste, 87 mg, yield: 80%),
(data of the major diastereomer)
d 7.48e7.19 (m, 20H, Ar), 6.51 (d,
J¼6.5 Hz, 2H, CH-200, CH-600), 6.49 (t, J¼2.2 Hz,1H, CH-400), 5.05 (s, 4H,
OCH2Ph), 4.61 (m, 1H, CH-6), 3.97 (d, J¼14.1 Hz, 2H, NCH2Ph),
3.88e3.80 (m,1H, CH2-3), 3.75 (d, J¼14.1 Hz, 2H, NCH2Ph), 3.38e3.28
(m, 1H, CHH-10), 3.22e3.13 (m, 1H, CHH-10), 2.89e2.74 (m, 2H, CH2-
20), 2.22e2.14 (m, 3H, CH2-4, OH, D2O exchangeable), 1.80e1.67 (m,
1H, CHH-5), 1.54e1.43 (m, 1H, CHH-5); 13C NMR (100 MHz, CD3CN)
(data of the major diastereomer)
d
171.8, 160.7, 143.3, 141.6, 138.2,
and trans-25 (white gummy paste, 10 mg, yield: 9%). cis-25: [a 20
]
D
129.3, 129.2, 128.9, 128.6, 128.4, 127.5, 108.9, 100.9, 80.1, 70.4, 59.7,
55.9, 47.5, 35.0, 30.2, 21.7; MS (ESI): m/z 627 (MþHþ,100%); HRESIMS
calcd for [C41H42N2O4þHþ]: 627.3223; found: 627.3215.
ꢀ50.8 (c 0.8, MeOH) {lit.7 [a 20
]
ꢀ49.1 (c 0.9, MeOH)}; IR (film) nmax
:
D
3338, 2975, 2923, 1594, 1466, 1421, 1412, 1381, 1366, 1314, 1116,
1046 cmꢀ1; 1H NMR (400 MHz, CD3OD)
d
6.18 (d, J¼2.3 Hz, 1H, CH-
10), 6.11 (d, J¼2.3 Hz, 1H, CH-8), 4.86e4.74 (br s, 3H, OH, NH), 4.80
(d, J¼3.7 Hz, 1H, CH-11b), 4.63e4.52 (m, 1H, CHH-6), 4.34e4.26 (m,
1H, CH-3), 2.72e2.55 (m, 3H, CHH-1, CH2-7), 2.53e2.42 (m, 1H,
CHH-6), 2.34e2.23 (m, 1H, CHH-2), 1.46 (s, 9H, CH3), 1.57e1.27 (m,
4.9. (3S)-9,11-Bis(benzyloxy)-3-(dibenzylamino)-2,3,6,7-
tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one (23)
Acetic acid (4 mL, 70 mmol) was added to a mixture of 13
(622 mg, 0.99 mmol) in anhydrous CH2Cl2 (40 mL). After stirring for
10 min, trifluoroacetic acid (0.15 mL, 2.0 mmol) was added. The
reaction was heated to reflux for 24 h. After the reaction was
allowed to cool down to room temperature, the mixture was con-
centrated under vacuum, and the residue was purified by flash
chromatography on silica gel (EtOAc/PE ¼ 1:5) to give compound
23 as a pale yellow solid (580 mg, yield: 96%), which is an in-
separable mixture of C-6 epimers (trans/cis ¼ 11:89, determined by
HPLC). IR (film) nmax: 3058, 3021, 2923, 2856,1655,1601,1491, 1448,
1372, 1305, 1265, 1149, 1095, 1021 cmꢀ1; 1H NMR (400 MHz, CDCl3)
2H, CHH-2, CHH-1); 13C NMR (100 MHz, CD3OD)
d 172.4, 158.0,
157.9, 156.1, 138.4, 115.0, 107.3, 101.9, 80.5, 51.1, 50.8, 40.4, 30.2, 29.2,
28.7, 26.3; MS (ESI): m/z 349 (MþHþ, 72%), 371 (MþNaþ, 100%).
Data for trans-25: [a 20
]
D
þ115.8 (c 0.2, MeOH) {lit.7 [
a
]
20 þ122 (c
D
1.4, MeOH)}; IR (film) nmax: 3335, 2972, 2917, 1610, 1427, 1421, 1412,
1381, 1274, 1253, 1146, 1119, 1061 cmꢀ1; 1H NMR (400 MHz, CD3OD)
d
6.17 (d, J¼2.2 Hz,1H, CH-10), 6.08 (d, J¼2.2 Hz,1H, CH-8), 4.89e4.78
(br s, 3H, OH, NH), 4.82e4.70 (m, 2H, CH-11b, CHH-6), 3.96 (m, 1H,
CH-3), 3.13e3.01 (m, 1H, CHH-1), 2.73e2.47 (m, 3H, CHH-6, CH2-7),
2.14e2.04 (m, 1H, CHH-2), 2.01e1.85 (m, 1H, CHH-2), 1.45 (s, 9H,
CH3), 1.39e1.27 (m, 1H, CHH-1); 13C NMR (100 MHz, CD3OD)
(data of the major diastereomer)
d
7.51e7.17 (m, 20H, Ar), 6.46 (d,
d 171.0, 158.1, 157.6, 156.7, 138.7, 116.0, 107.6, 102.2, 80.4, 57.2, 53.2,
J¼2.1 Hz, 1H, CH-10), 6.37 (d, J¼2.1 Hz, 1H, CH-8), 5.03e4.96 (m, 4H,
OCH2Ph), 4.86e4.79 (m, 1H, CHH-6), 4.62 (dd, J¼10.9, 3.4 Hz, 1H,
CH-3), 4.23 (d, J¼14.6 Hz, 2H, NCH2Ph), 3.85 (d, J¼14.6 Hz, 2H,
NCH2Ph), 3.52 (t, J¼9.4 Hz, 1H, CH-11b), 2.85e2.73 (m, 1H, CHH-6),
2.73e2.63 (m, 2H, CH2-7), 2.46e2.34 (m, 1H, CHH-2), 2.15e2.01 (m,
1H, CHH-1), 1.93e1.81 (m, 1H, CHH-1), 1.47e1.33 (m, 1H, CHH-2);
40.8, 31.0, 29.5, 28.8 (2C); MS (ESI): m/z 371 (MþNaþ, 100%).
4.12. tert-Butyl (3S,11bS)-9,11-bis(benzyloxy)-4-oxo-2,3,4,6,7,11b-
hexahydro-1H-pyrido[2,1-a]isoquinolin-3-ylcarbamate (cis-26)
and trans-26
13C NMR (100 MHz, CDCl3) (data of the major diastereomer)
158.2, 155.9, 140.9, 137.6, 136.7, 136.6, 136.5, 128.3, 128.0, 127.9,
127.8, 127.4, 126.9, 126.6, 126.5, 117.8, 105.8, 99.0, 70.0, 69.8, 56.5,
d
172.3,
To a mixture of the above mentioned diastereomeric mixture 25
(400 mg, 1.15 mmol) and K2CO3 (635 mg, 4.6 mmol) in dry DMF
(6 mL) was added benzyl bromide (0.3 mL, 2.53 mmol) at room

C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
6287
temperature. After stirring for 12 h, the reaction was diluted with
(film) nmax: 3423, 2921, 2855, 1644, 1615, 1100 cmꢀ1
(400 MHz, CDCl3)
;
1H NMR
ice-water (50 mL) and the resulting mixture extracted with Et2O
(20 mLꢂ3). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under vacuum.
The residue was filtered through a short pad of silica gel column
eluting with EtOAc:PE ¼ 1:5 to afford compound cis-26 (498 mg,
yield: 82.3%) as a white power, and trans-26 (62 mg, yield: 10.2%) as
a pale yellow gummy paste.
d
7.42e7.30 (m, 10H, Ar), 6.81 (d, J¼5.2 Hz, 1H,
NH), 6.48 (d, J¼2.4 Hz, 1H, CH-10), 6.38 (d, J¼2.4 Hz, 1H, CH-8), 5.08
(d, J¼1.2 Hz, 2H, OCH2Ph), 4.99 (s, 2H, OCH2Ph), 4.96e4.91 (m, 1H,
CH-11b), 4.76e4.70 (m, 1H, CHH-6), 4.58e4.50 (m, 1H, CH-3),
3.70e3.63 (m, 1H, CH-140), 3.63e3.53 (m, 2H, CH-170, CH-180),
2.87e2.64 (m, 4H, CH2-7, CHH-6, CHH-2, CHH-7), 2.54e2.45 (m, 1H,
CHH-1), 2.25 (t, J¼7.2 Hz, 2H, CH2-20), 1.71e1.60 (m, 4H), 1.55e1.42
(m, 8H), 1.38 (s, 6H, C(CH3)2), 1.33e1.24 (m, 34H), 0.97 (t, J¼8.0 Hz,
9H, Si(CH2CH3)3), 0.88 (t, J¼6.8 Hz, 3H, CH3), 0.60 (q, J¼8.0 Hz, 6H,
Compound cis-26: mp 117.0e120 ꢁC (EtOAc/PE) {lit.7 mp 118 ꢁC};
[
a 20
]
ꢀ102.8 (c 1.01, CHCl3) {lit. [a 20
]
ꢀ102 (c 1.1, CHCl3);7
[ ]
a 24
D
D
D
ꢀ108.1 (c 1.97, CHCl3)9}; IR (film) nmax: 3399, 3064, 3033, 2975,
Si(CH2CH3)3); 13C NMR (100 MHz, CDCl3)
d 173.0, 170.5, 158.4,
2927, 2869,1713,1658,1610,1494,1427,1363,1311,1274,1162,1095,
155.9, 137.1, 136.6, 136.4, 128.7, 128.6, 128.1, 128.0, 127.4, 127.0, 117.2,
107.7, 105.8, 99.0, 81.2, 81.0, 72.2, 70.1, 48.7, 38.8, 37.4, 36.7, 33.5,
33.0, 31.8, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.24, 29.21, 28.9, 28.5,
27.3, 26.0, 25.7, 25.2, 22.6,14.0, 6.9, 5.1; MS (ESI): m/z 1059 (MþNaþ,
100%); HRESIMS calcd for C64H100N2O7SiNa (MþNa)þ: 1059.7198;
found: 1059.7182.
1058, 1024, 1003 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.43e7.29 (m,
10H, Ar), 6.48 (s, 1H, CH-10), 6.39 (s, 1H, CH-8), 5.75 (d, J¼5.1 Hz,1H,
NH), 5.09 (d, J¼12.4 Hz, 1H, OCHHPh), 5.05 (d, J¼12.4 Hz, 1H,
OCHHPh), 4.99 (s, 2H, OCH2Ph), 4.94e4.85 (m, 1H, CH-11b),
4.78e4.67 (m, 1H, CHH-6), 4.40e4.26 (m, 1H, CH2-3), 2.87e2.74
(m, 2H, CHH-7, CHH-1), 2.74e2.65 (m, 1H, CHH-7), 2.62e2.51 (m,
1H, CHH-6), 2.51e2.40 (m, 1H, CHH-2), 1.46 (s, 9H, CH3), 1.43e1.33
4.14. (14S,17S,18S)-N-((3S,11bS)-9,11-Bis(benzyloxy)-4-oxo-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)-
14,17,18-trihydroxyoctacosanamide (7)
(m, 2H, CHH-1, CHH-2); 13C NMR (100 MHz, CDCl3)
d 170.6, 158.4,
155.9, 155.7, 137.3, 136.7, 136.5, 128.8, 128.6, 128.11, 128.05, 127.5,
127.1, 117.4, 105.9, 99.0, 79.4, 70.2, 49.8, 48.8, 38.8, 29.7, 28.5, 28.4,
25.8; MS (ESI): m/z 529 (MþHþ, 4%), 551 (MþNaþ, 100%).
A mixture compound 27 (225 mg, 0.217 mmol) and 2 M HCl
(2 mL) in methanol (2 mL) was refluxed at 90 ꢁC for 3 h. The re-
action was then quenched with a 2 M NaOH solution (4 mL). The
resulting mixture was extracted with EtOAc (5 mLꢂ3). The com-
bined extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash
column chromatography (SiO2, eluting with 80% EtOAc in PE)
to give triol 7 (180 mg, yield: 95%) as a white solid. Mp 88e89 ꢁC;
Compound trans-26: [a 20
]
þ178.5 (c 0.5, CHCl3) {lit. [a 20
þ116
]
D
D
(c 1.35, CHCl3);7 [a 24
]
þ182.2 (c 1.33, CHCl3)9}; IR (film) nmax: 3399,
D
3067, 3027, 2972, 2930, 2863,1707,1640,1607,1497,1427,1363,1314,
1268, 1247, 1152, 1095, 1046, 1006 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.45e7.29 (m, 10H, Ar), 6.50 (d, J¼2.2 Hz, 1H, CH-10), 6.37
(d, J¼2.2 Hz, 1H, CH-8), 5.37 (s, 1H, NH), 5.06 (d, J¼11.8 Hz, 1H,
OCHHPh), 5.02 (d, J¼11.8 Hz, 1H, OCHHPh), 5.00 (d, J¼11.8 Hz, 1H,
OCHHPh), 4.99 (d, J¼11.8 Hz, 1H, OCHHPh), 4.95e4.88 (m, 1H, CHH-
6), 4.78 (dd, J¼11.0, 3.2 Hz, 1H, CH-11b), 4.06e3.96 (m, 1H, CH-3),
3.10e3.02 (m, 1H, CHH-1), 2.91e2.81 (m, 1H, CHH-7), 2.66e2.55
(m, 2H, CHH-6, CHH-7), 2.49e2.40 (m,1H, CHH-2),1.80e1.67 (m,1H,
CHH-2), 1.45 (s, 9H, C(CH3)3), 1.53e1.35 (m, 1H, CHH-1); 13C NMR
[
a 20
]
ꢀ61.0 (c 2.2, CHCl3) {lit.9
[
a 24
]
ꢀ60.0 (c 7.8, CHCl3)}; IR (film)
D
D
nmax
: 3340, 2917, 2847, 1648, 1602, 1465, 1436, 1146, 1092,
1047 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.41e7.30 (m, 10H, Ar), 6.86
(d, J¼4.8 Hz,1H, NH), 6.47 (d, J¼1.6 Hz, 1H, CH-10), 6.38 (d, J¼1.6 Hz,
1H, CH-8), 5.08 (s, 2H, OCH2Ph), 4.98 (s, 2H, OCH2Ph), 4.96e4.91 (m,
1H, CH-11b), 4.75e4.69 (m, 1H, CHH-6), 4.58e4.51 (m, 1H, CH-3),
3.66e3.59 (m, 1H, CH-140), 3.42 (d, J¼4.4 Hz, 2H, CH-170, CH-180),
2.96e2.73 (m, 2H, CHH-7, CHH-6), 2.73e2.62 (m, 2H, CHH-2, CHH-
7), 2.53e2.45 (m, 1H, CHH-1), 2.25 (t, J¼6.4 Hz, 2H, CH2-20),
1.70e1.61 (m, 4H,), 1.58e1.40 (m, 8H), 1.35e1.20 (m, 34H), 0.88 (t,
(100 MHz, CDCl3) d 168.7,158.1,156.7,156.1,137.8,136.7,136.4,128.6,
128.5, 128.0, 127.4, 127.1, 118.3, 106.0, 99.1, 79.4, 70.1, 70.0, 56.1, 52.7,
39.4, 30.5, 28.3, 28.0, 27.7; MS (ESI): m/z 551 (MþNaþ, 100%).
4.13. (S)-N-((3S,11bS)-9,11-Bis(benzyloxy)-4-oxo-2,3,4,6,7,11b-
hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)-16-((4S,5S)-5-
decyl-2,2-dimethyl-1,3-dioxolan-4-yl)-14-((triethylsilyl)oxy)
hexadecanamide (27)
J¼5.6Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3)
d 173.09, 170.45,
158.38, 155.83, 137.03, 136.59, 136.36, 128.68, 128.49, 128.01, 127.95,
127.35, 126.90, 117.08, 105.80, 99.00, 74.27, 74.21, 71.63, 70.03,
48.75, 48.67, 38.79, 37.38, 36.60, 33.41, 32.99, 31.79, 29.65, 29.54,
29.52, 29.48, 29.43, 29.32, 29.22, 29.14, 28.46, 25.66, 25.63, 25.17,
22.56, 14.00; HRESIMS calcd for C55H82N2O7Na (MþNa)þ:
905.6020; found: 905.6018.
A mixture of benzyl ester 20 (244 mg, 0.34 mmol), 10% Pd/C
(24 mg), and 2,6-lutidine (0.084 mL, 0.72 mmol) in EtOH (1 mL) was
stirred under an atmosphere of hydrogen (10 atm) for 3 h. The
mixture was then filtered and concentrated under vacuum to give
carboxylic acid 9 as a colorless oil, which was used immediately in
the next step without further purification.
4.15. Schulzeine B (5)
A mixture of compound cis-26 (168 mg, 0.34 mmol) and 3 M HCl
in ethyl acetate (3 mL) was stirred for 30 min at room temperature.
The reactionwas neutralized with a 1 M NaOH solution. The aqueous
phase was extracted with ethyl acetate (10 mLꢂ3). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum to give the free amine 8, which was
used directly in the next step without further purification.
A mixture of triol 7 (54 mg, 0.061 mmol) and sulfur triox-
ideepyridine complex (98 mg, 0.61 mmol) in dry DMF (1 mL) was
stirred at room temperature for 6 h then quenched with an
aqueous NaOH solution (0.5 M, 0.25 mL). After being stirred for
1 h, the reaction mixture was concentrated under vacuum and
passed through a Waters C18 Sep-Pak VacÒ solid phase extraction
cartridge and the cartridge was eluted with H2O (5 mL), H2O/
MeOH (8:1, 5 mL), H2O/MeOH (4:1, 5 mL), H2O/MeOH (7:3, 5 mL),
H2O/MeOH (3:2, 5 mL), H2O/MeOH (1:1, 5 mL), H2O/MeOH (2:3,
5 mL), H2O/MeOH (3:7, 5 mL), H2O/MeOH (1:4, 5 mL), H2O/MeOH
(1:8, 5 mL) and MeOH (5 mL) to give an essentially pure com-
pound 28, which was immediately dissolved with methanol
(3 mL) and 10% Pd/C (15 mg). Then the reaction mixture was
placed under an atmosphere of H2. After being stirred for 3 h, the
mixture was then passed through a Waters C18 Sep-Pak VacÒ solid
phase extraction cartridge to remove the catalyst and the filtrate
A mixture of amine 8 (143 mg, 0.34 mmol), acid 9 (210 mg,
0.34 mmol), HOBt (54 mg, 0.40 mmol), EDCI (77 mg, 0.40 mmol),
and NEt3 (0.08 mL, 0.55 mmol) in CH2Cl2 (3 mL) was stirred at room
temperature for 20 h. The mixture was then poured into water
(2 mL), and extracted with EtOAc (5 mLꢂ3). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by flash column chromatography
(SiO2, eluting with 30% EtOAc/PE) to give amide 27 (310 mg, 89%
yield over three steps) as a colorless oil: [
a
]
D
20 ꢀ55.0 (c 1.3, CHCl3); IR

6288
C. Yang et al. / Tetrahedron 67 (2011) 6281e6288
7. Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana, C. V.; Mohapatra, D. K. J. Org.
Chem. 2007, 72, 6591e6594.
8. Liu, G.; Romo, D. Org. Lett. 2009, 11, 1143e1146.
9. (a) Bowen, E. G.; Wardrop, J. J. Am. Chem. Soc. 2009, 131, 6062e6063; (b) For the
construction of the tricyclic isoquinoline core, although a 9:1 cis/trans stereo-
selectivity has been achieved (cf. Ref. 9a), but this has not been used for the
total synthesis of (ꢀ)-schulzeines B, instead, a 2:1 diastereomeric mixture was
used (cf. SI in Ref. 9a).
concentrated under vacuum to give schulzeine B (5) (43 mg, 69%
over two steps) as a white powder. Mp 183e185 ꢁC;22[a
]
20 e87.5 (c
D
24
0.8, MeOH) {lit. [
a
]
ꢀ87.1 (c 0.10, MeOH);9
[
a
]
ꢀ23 (c 0.1,
D
D
MeOH)5}; IR (film) nmax: 3365, 2917, 2847, 1623, 1611, 1470, 1441,
1241, 1063 cmꢀ1
;
1H NMR (500 MHz, CD3OD):
d
6.20 (d, J¼1.6 Hz,
1H, CH-10), 6.13 (d, J¼1.6 Hz, 1H, CH-8), 4.90e4.78 (m, 1H, CH-
11b), 4.70e4.60 (m, 4H, CH-3, CHH-6, OCH-170, OCH-180),
4.42e4.36 (m, 1H, CH-140), 2.78e2.67 (m, 2H, CHH-6, CHH-7),
2.67e2.53 (m, 2H, CHH-7, CHH-1), 2.29 (t, J¼6.4 Hz, 3H, CH2-20,
CHH-2), 1.98e1.87 (m, 2H, CHH-150, CHH-160), 1.80e1.50 (m, 9H,
CH2-30, CH2-130, CHH-150, CHH-160, CH2-190, CHH-2), 1.47e1.20 (m,
35H, CHH-1, CH2-40e120, CH2-200e270), 0.88 (t, J¼5.6 Hz, 3H, CH3);
10. Biswas, S.; Chattopadhyay, S.; Sharma, A. Tetrahedron: Asymmetry 2010, 21,
27e32.
11. Kuntiyong, P.; Akkarasamiyo, S.; Eksinitkun, G. Chem. Lett. 2006, 1008e1009.
12. (a) Wei, B.-G.; Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62, 190e198; (b) Zhou,
X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. Tetrahedron 2007, 63, 6346e6357; (c) Wu,
T.-J.; Huang, P.-Q. Tetrahedron Lett. 2008, 49, 383e386; (d) Wu, S.-F.; Zheng, X.;
Ruan, Y.-P.; Huang, P.-Q. Org. Biomol. Chem. 2009, 7, 2967e2975; (e) Fu, R.; Du,
Y.; Li, Z.-Y.; Xu, W.-X.; Huang, P.-Q. Tetrahedron 2009, 65, 9765e9771; (f) Wu,
S.-F.; Ruan, Y.-P.; Zheng, X.; Huang, P.-Q. Tetrahedron 2010, 66, 1653e1660; (g)
Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. Org. Biomol. Chem. 2010, 8, 2085e2091; (h) Liu,
G.; Wu, T.-J.; Ruan, Y.-P.; Huang, P.-Q. Chem.dEur. J. 2010, 16, 5755e5768.
13. For a review, see: Hanessian, S. Pure Appl. Chem. 1993, 65, 1189e1204.
14. For reviews on the use of tartaric acid-derived chirons, see: (a) Coppola, G. M.;
13C NMR (125 MHz, CD3OD)
d 176.19, 171.85, 157.94, 156.13, 138.32,
115.01, 107.36, 102.02, 81.27, 80.06, 80.02, 51.74, 49.61, 40.47, 37.02,
35.45, 33.02, 31.64, 30.83, 30.76, 30.73, 30.70, 30.67, 30.64, 30.56,
30.43, 30.39, 30.33, 30.32, 30.25, 29.89, 28.96, 26.88, 26.84, 26.10,
25.89, 25.86, 23.67, 14.41; HRESIMS calcd for C41H67N2O16S3Na2
(MꢀNa)ꢀ: 985.3448; found: 985.3440.
Schuster, H. a-Hydroxyacids in Synthesis; Wiley-VCH: New York, NY, 1997; (b)
Gawronski, J.; Gawronska, K. Tartaric and Malic Acids in Synthesis; John Wiley:
New York, NY, 1999; (c) Ghosh, A. K.; Koltum, E. S.; Blicer, G. Synthesis 2001,
1281e1301.
15. Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417e4422.
16. (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345e350; (b) Noyori, R.;
Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.
J. Am. Chem. Soc. 1987, 109, 5856e5858.
17. (a) Fang, H. H.; Wu, X. Y.; Nie, L. L.; Dai, X. Y.; Chen, J.; Cao, W. G.; Zhao, G. Org.
Lett. 2010, 12, 5366e5369; (b) Lee, Y. S.; Cho, D. J.; Kim, S. N.; Choi, J. H.; Park, H.
J. Org. Chem. 1999, 64, 9727e9731; (c) Ducrot, P.; Thal, C. Tetrahedron Lett. 1999,
40, 9037e9040; (d) Lee, Y. S.; Kang, S. S.; Choi, J. H.; Park, H. Tetrahedron 1997,
53, 3045e3049.
Acknowledgements
The authors are grateful to the NSF of China (20832005;
21072160), the NFFTBS (No. J1030415), and the National Basic Re-
search Program (973 Program) of China (Grant No. 2010CB833200)
for financial support.
18. For two recent reviews on the PicteteSpengler-type reactions, see: (a) Cox, E.
D.; Cook, J. M. Chem. Rev. 1995, 95, 1797e1842; (b) Chrzanowska, M.; Rozwa-
dowska, M. D. Chem. Rev. 2004, 104, 3341e3370.
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