New reactivities of deltaline analogs: An efficient O-demethylation at C-1 and an unusual extrusion of the C-14 atom

Article abstract of DOI:10.1016/j.tet.2012.04.055

O-Demethylation at C-1 in the C₁₉-diterpenoid alkaloids is very challenging. In this paper, it was firstly observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction. After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be readily removed by treatment with HBr-HOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxidation, deformylation, and S_N2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.

Full text of DOI:10.1016/j.tet.2012.04.055

Tetrahedron 68 (2012) 5668e5676
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New reactivities of deltaline analogs: an efficient O-demethylation
at C-1 and an unusual extrusion of the C-14 atom
*
Pei Tang, Qi-Feng Chen, Ling Wang, Qiao-Hong Chen, Xi-Xian Jian, Feng-Peng Wang
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3, Renmin Nan Road, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
O-Demethylation at C-1 in the C19-diterpenoid alkaloids is very challenging. In this paper, it was firstly
observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction.
After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be
readily removed by treatment with HBreHOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be
extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxida-
tion, deformylation, and SN2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The
structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 28 February 2012
Received in revised form 3 April 2012
Accepted 12 April 2012
Available online 21 April 2012
Keywords:
C19-Diterpenoid alkaloids
Deltaline
O-Demethylation
Extrusion
1. Introduction
prolonged reaction time (5 days) according to our earlier study;16
(3) an unusual extrusion of the C-14 atom in a deltaline analog
Diterpenoid alkaloids are a group of structurally complex nat-
ural products, which have mainly been isolated from the genera
Aconitum and Delphinium (Ranunculaceae), and Spiraea (Rosa-
ceae).1 The diterpenoid alkaloids have attracted extensive and
lasting attention from researchers around the world due to their
varied bioactivities, structural complexity,1aef and intriguing
chemical reactions.1e Deltaline (1) was firstly isolated from Del-
phinium occidentale S. Wats in 1936,2 featuring an unique hydroxyl
group at C-10 and wide distribution. Numerous reactions of 1 and
its derivatives, including oxidation,3e6 reduction and deoxy-
genation,7e10 O-demethylation,11,12 and rearrangement,13,14 have
been extensively investigated for many years. In addition, an effi-
cient conversion of deltaline (1) to the A/B/C core system of taxane
has been recently presented by us.15 The reasons why these two
seems unrelated natural products can be synthesized from one to
another have been detailed in Ref. 15. In continuation of our con-
versional studies of deltaline to taxanes, the following interesting
reactions were observed: (1) treatment of deltaline (1) derivatives
with HBreHOAc provided a bromide in addition to the acetates that
were previously observed by us; (2) O-demethylation at C-1 in
deltaline (1) can proceed smoothly when 10-OH was removed. It is
worth noting that 1-O-methyl group in lycoctonine analogs can be
removed by treating with HBreHOAc only with heating and
via Grob fragmentation followed by deformylation. In this paper,
we wish to present the details on these interesting reactions.
2. Results and discussion
Regioselective O-demethylation of C19-diterpenoid alkaloids is
very important for their successful conversion to taxanes, and
also is meaningful for structureeactivity relationship studies. Es-
pecially, 1-O-demethylation is currently a bottleneck reaction dur-
ing our conversional synthesis of taxanes from deltaline. Initially,
O-demethylation reactions of deltaline (1) were carried out by
reacting with HBreHOAc, only leading to 14,16-O-demethyl prod-
uct with an intact 1-OCH3 group.11,15 However, the deoxygenated
analogs of 1, including 6-deoxydeltaline (2) (Scheme 1), 10-
deoxydeltaline (8) (Scheme 2), and 6,10-deoxydeltaline (13)
(Scheme 3), can generate interesting O-demethyl products by
treating with HBreHOAc. Specifically, heating 6-deoxydeltaline (2),
prepared from 1 using Barton deoxygenation method,9,19 with 6.5%
HBreHOAc for 33 h generated four products. Among them,14,16-O-
didemethyl derivative 5 and 16-O-demethyl derivative 6 (Scheme
1) are two major products, and bromides 3 and 4 are two minor
products. This result indicated that 1-O-methyl group in 1 cannot
be removed even at high reaction temperature and with prolong
reaction time. In contrast, 10-deoxydeltaline (8)17 was heated with
6.5% HBreHOAc for 33 h to furnish four products 9e12 (Scheme 2).
Among them, product 12 is 14,16-O-didemethyl product, and olefin
11 is the elimination product of 12; while products 9 and 10 are
* Corresponding author. Tel./fax: þ86 28 85501368; e-mail address: wfp@
scu.edu.cn (F.-P. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.055

P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
5669
Scheme 1. O-Demethylation of 6-deoxydeltaline (2).
Scheme 2. O-Demethylation of 10-deoxydeltaline (8).
bromides. The NMR data of bromide 10 showed that all methoxy
groups in the starting material have been completely removed,
suggesting that removal of 10-OH is beneficial to the removal of
1-O-methyl group. Finally, heating 6,10-deoxydeltaline (13)17 with
6.5% HBreHOAc (Scheme 3) generated a messy crude product,
which was subjected to column chromatography over silica gel to
furnish six products 14e19. Of them, product 14 is 14,16-O-
demethyl derivative; while products 15e19 are C-16 bromides.
Compound 15 is a bromide with intact methoxy groups at C-1 and
C-14; while the methoxy groups at C-1 and C-14 in bromides 16 and
17 have been partially removed, respectively. Bromides 18 and 19
do not contain any methoxy groups. After optimizing the reaction
condition, it was found that treatment of compound 13 with 3%
HBreHOAc at 60 ꢀC for 24 h furnished 16
a-bromide 15 (Scheme 3),
which directly reacted with 6.5% HBreHOAc without further puri-
fication to give 18 in a moderate yield (45% from 13).
The HR-ESIMS of 15 showed a pair of pseudomolecular ion peaks
at m/z 482.1897 and 484.1887 [MþH]þ with an abundance ratio of
1:1, indicating the existence of a bromine atom. Its NMR data (1H,
13C, and HMQC) exhibited the presence of an N-ethyl group (dC 14.1

5670
P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
Scheme 3. O-Demethylation of 6,10-deoxydeltaline (13).
q, dH 1.07, 3H, t, J¼7.2 Hz; dC 50.7 t, dH 2.70, 2.83, each 1H, m),
a tertiary methyl group (dC 25.7 q; dH 0.78, 3H, s), two methoxy
groups (dC 57.5 q, 56.2 q; dH 3.42, 3.33, each 3H, s), a methyl-
enedioxy group (dC 93.8 t; dH 5.05, 4.93, each 1H, s), and a methane
group (dC 51.6 d; dH 4.85, 1H, m). To confirm the bromine atom was
introduced through SN2 nucleophilic substitution into above-
mentioned bromides, the 2D-NMR spectra of bromide 15 were
acquired and analyzed. The bromine was assigned at C-16 based on
the critical correlations between H-16 (dH 4.85) and C-12 (dC 24.8),
and between H-14 (dH 3.56) and C-16 (dC 51.6) in the HMBC spec-
trum (Fig. 1). Two methoxy groups were located at C-1 and C-14
according to the respective key HMBC correlations between H-1 (dH
3.08) and OCH3-1 (dC 56.2), and between H-14 (dH 3.56) and OCH3-
14 (dC 57.5). Selective irradiation of H-16 resulted in signal en-
Hydrolysis of bromide 18 under alkali conditions normally gave
messy products. Only exception is that treatment of 18 with 5%
NaOH/MeOH at 0 ꢀC for 1 h generated exclusively product 20
(Scheme 4). To our surprise, reaction of 18 with sodium hydride in
DMF at room temperature for 12 h generated enone 21 (70%) and
oxetane 22 (14%). Under the similar reaction condition (NaHeTHF,
rt, 40 h), enone 21 (30%) and oxetane 22 (45%) can also be prepared
from compound 20. When the reaction time was shorten, a pair of
epimers 23a/b (29%) and trace amount of other unidentified
products were also obtained in addition to oxetane 22 (42%).
Treatment of oxetane 22 with Lewis acid TiCl4 in DCM can quickly
and quantitatively produce chloroalcohol 24.20 Reaction of 24 with
NaH, under the same reaction conditions as described for the
preparation of bromide 18, can yield enone 21 (65%) and oxetane 22
(17%) as well.
The molecular formula of 21 was established as C23H31NO5
according to its HR-ESIMS and 13C NMR data. Comparison of the
NMR data of 21 with those of starting material 20 indicated the
absence of an acetyl group and a bromine, and the presence of
a disubstituted double bond (dC 127.0 d, 123.5 d; dH 5.58 m, 5.54 m)
and a ketone carbonyl group (dC 208.1 s). The carbonyl group in 21
was assigned at C-9 according to the key HMBC correlations (Fig. 2)
of C-9 (dC 208.1) with H2-12 (dH 2.20, 2.37) and H2-15 (dH 2.28, 2.68).
The double bond was located at C-13 and C-16 based on the critical
correlations of H-10 (dH 2.35) with C-13 (dC 123.5), of H2-12 with
C-16 (dC 127.0), of H-16 (dH 5.58) with C-12 (dC 29.3), of H-13 (dH
5.54) with C-15 (dC 33.4), and of H2-15 with C-13 in its HMBC
spectrum. Comparison of its 13C NMR data with those of starting
material indicated the location of the only acetyl group at C-1. The
structure of 21 was confirmed by the X-ray crystallographic analysis
(Fig. 3).
hancement of 14
orientation of 16-Br (Fig. 1). Apparently, introduction of 16
can be ascribed to the SN2 nucleophilic substitution of the hydroxyl
group at C-16
a-OCH3 in its NOEds experiment, suggesting the
a
a
-Br
b.
The formation of compounds 21, 22, 23a/b, and 24 might be
explained by the mechanism depicted in Scheme 5: Grob
Fig. 1. Key 1He1H COSY, HMBC, and NOE correlations of 15.

P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
5671
Scheme 4.
products. The observation that removal of 10-OH in 1 is very ben-
eficial to 1-O-demethylation is very helpful in our further conver-
sional synthesis of taxanes starting from 1. Under the aerobic and
alkaline conditions, bromides 18 or 20 can undergo Grob frag-
mentation followed by oxidative deformylation to generate enone
21 with extrusion of the C-14 atom in the starting material. This
represents the first example of extrusion of the C-14 atom in the
C19-diterpenoid alkaloids. In addition, compound 18 or 20 can
undergo SN2 nucleophilic substitution under alkaline conditions to
form oxetane 22, which can undergo further SN2 nucleophilic
substitution with Lewis acid TiCl4 to generate chloroalcohol 24.
Compound 24 can also undergo Grob fragmentation and oxidative
deformylation to yield enone 21.
O
O
O
O
N
O
1H-1H COSY
HMBC
Fig. 2. Key 1He1H COSY and HMBC correlations of 21.
fragmentation of compound 20, prepared from 18 by partial hy-
drolysis, under alkali conditions (pathway a, Scheme 5) could
generate 23a/b. With the participation of aerobic oxidation, oxi-
dative deformylation21e23 of 23a/b in the presence of alkaline
might yield enone 21. In addition, SN2 nucleophilic substitution of
20 in the presence of alkaline could form oxetane 22 (pathway b).
Reaction of oxetane 22 with Lewis acid TiCl4 followed by SN2 nu-
cleophilic substitution could generate chloroalcohol 24. Similarly,
Grob fragmentation of 24 followed by oxidative deformylation can
also form enone 21 and oxetane 22.
3. Conclusion
In conclusion, treatment of the deoxygenated analogs prepared
from deltaline (1) with HBreHOAc produced various O-demethyl
Fig. 3. ORTEP drawing of 21.

5672
P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
Scheme 5. A plausible mechanism for the formation of 21, 22, 23a/b, and 24.
4. Experimental section
by column chromatography over silica gel, using petroleum
ether/acetone (10:1) as eluent, to yield compound 2 as a white
20
4.1. General methods
amorphous powder (7.6 g, 85% from 1). Mp: 125e127 ꢀC; [
ꢃ29.8 (c 0.50, CHCl3); IR (KBr): 3508, 2964, 2920, 2892, 1459, 1003,
955 cmꢃ1 1H NMR (400 MHz, CDCl3)
5.02, 4.94 (each 1H, s,
a]
D
Melting points were determined on
a
Kofler block (un-
;
d
corrected); optical rotations were measured in a 1.0 dm cell with a
PE-314 polarimeter at 20ꢁ1 ꢀC; IR spectra were recorded on
a Nicolet 200 SXV spectrometer; HRMS spectra were obtained
with a Bruker BioTOFQ mass spectrometer; 1H and 13C NMR spectra
were acquired on a Varian INOVA-400/54 spectrometer, with TMS
as internal standard; silica gel GF254 and H (10e40 mm, Qingdao
Sea Chemical Factory, China) were used for TLC and CC.
OCH2O), 4.12 (1H, t, J¼4.8 Hz, H-14
b), 3.45, 3.33, 3.27 (each 3H, s,
OCH3ꢂ3), 1.07 (3H, t, J¼7.2 Hz, H3-22), 0.81 (3H, s, H3-18); 13C NMR
(100 MHz, CDCl3) d 81.5 (d, C-1), 27.1 (t, C-2), 33.1 (t, C-3), 33.9 (s, C-
4), 53.7 (d, C-5), 39.2 (t, C-6), 90.2 (s, C-7), 83.3 (s, C-8), 43.7 (d, C-9),
80.1 (s, C-10), 56.4 (s, C-11), 34.0 (t, C-12), 33.1 (d, C-13), 78.3 (d, C-
14), 37.2 (t, C-15), 81.5 (d, C-16), 61.4 (d, C-17), 26.0 (q, C-18), 56.0 (t,
C-19), 50.5 (t, C-21), 14.0 (q, C-22), 93.6 (t, OCH2O), 55.6 (q, C-10),
57.9 (q, C-140), 56.3 (q, C-160); HR-ESIMS [MþH]þ m/z calcd for
C25H40NO6: 450.2856, found: 450.2866.
4.2. Preparation of compound 2
Deltaline (1, 10 g, 20 mmol) was dissolved in a solution of 5%
NaOH in MeOH (200 mL), and the reaction was allowed to proceed
at 50 ꢀC for 30 min. After removal of methanol under reduced
pressure, the residue was suspended with water (200 mL), and the
subsequent mixture was extracted with dichloromethane
(150 mLꢂ3). The combined extracts were rinsed with brine, dried
over anhydrous sodium sulfate, and concentrated to an alcohol
crude product (pale yellow amorphous powder, 9.08 g). To a solu-
tion of all this crude product in DMF (200 mL) at 0 ꢀC were se-
quentially added carbon disulfide (24 mL, 400 mmol) and
a solution of 20% NaOH in water (10 mL), and the reaction solution
(which was brown) was kept stirring at the same temperature for
1 h before slow addition of methyl iodide (12.5 mL, 200 mol). At
this point, the reaction mixture became pale yellow. The reaction
was kept to proceed at 0 ꢀC with stirring for an additional 5 h prior
to the addition of water (200 mL). The reaction mixture was
extracted with dichloromethane (200 mLꢂ3), the combined ex-
tracts were dried over anhydrous sodium sulfate, and the organic
solvent was removed under reduced pressure. The residue obtained
was subjected to column chromatography over silica gel, eluting
with petroleum ether/acetone (8:1), to furnish a xanthate (yellow
oil,10.8 g). To a solution of the xanthate (10.8 g) in toluene (200 mL)
were sequentially added AIBN (78 mg, 0.47 mmol) and n-Bu3SnH
(8.0 mL, 30 mmol), and the reaction mixture was kept refluxing for
3 h. After cooling down to room temperature, toluene was removed
in vacuo, and the residue was suspended with water (200 mL). The
subsequent mixture was extracted with dichloromethane
(250 mLꢂ3), and the combined extracts were dried (Na2SO4)
and concentrated in vacuo. The residue obtained was purified
4.3. Preparation of compounds 3, 4, 5, and 6
Compound 2 (200 mg, 0.44 mmol) was dissolved in a solution of
6.5% HBr in acetic acid (4 mL), and the reaction solution was kept
stirring at 80 ꢀC for 33 h prior to being poured into ice water
(20 mL). The subsequent mixture was basified with concd ammo-
nium hydroxide to pH >9, and extracted with dichloromethane
(30 mLꢂ3). The combined extracts were rinsed with brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure to furnish a residue. Column chromatography of the res-
idue over silica gel, employing cyclohexane/acetone (20:1) as elu-
ent, gave compounds 3 (white amorphous powder, 26 mg, 11%), 4
(white amorphous powder, 15 mg, 6%), 5 (white amorphous pow-
der, 78 mg, 32%), and 6 (white amorphous powder, 72 mg, 31%).
4.3.1. Compound 3. Mp: 110e112 ꢀC; [
a]
20 ꢃ45.6 (c 0.50, CHCl3); IR
D
(KBr): 2926, 2879, 1731, 1369, 1222, 1095 cmꢃ1; 1H NMR (400 MHz,
CDCl3)
d
5.04, 4.98 (each 1H, s, OCH2O), 4.87 (1H, td, J¼8.8, 2.4 Hz,
H-16
H-14
b
b
), 3.99 (1H, br d, J¼3.2 Hz, H-17), 3.74 (1H, dd, J¼6.0, 4.4 Hz,
), 3.42, 3.34 (each 3H, s, OCH3ꢂ2), 2.09 (3H, s, OAc), 1.08 (3H,
t, J¼7.2 Hz, H3-22), 0.77 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3)
see Table 1; ESIMS m/z 540 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd
for C26H39NO6Br: 540.1961, found: 540.1962.
4.3.2. Compound 4. Mp: 149e150 ꢀC; [
a]
20 ꢃ53.0 (c 0.50, CHCl3); IR
D
(KBr): 2924, 1737, 1367, 1232,1078 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
5.07 (1H, dd, J¼6.0, 4.4 Hz, H-14
4.74 (1H, td, J¼8.8, 2.8 Hz, H-16 ), 3.89 (1H, br d, J¼4.0 Hz, H-17),
3.34 (3H, s, OCH3), 2.12, 2.10 (each 3H, s, OAcꢂ2), 1.08 (3H, t,
b), 5.01, 4.97 (each 1H, s, OCH2O),
b

P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
5673
Table 1
give a residue, which was subjected to column chromatography
over silica gel, eluting with petroleum ether/acetone (6:1), to fur-
nish compound 7 as a white amorphous powder (8.2 g, 92% based
on the recovery of starting material), together with starting mate-
rial 1 (0.8 g).
13C NMR data of compounds 3, 4, 5, 6, 9, 10, 11, and 12 (100 MHz for 13C, CDCl3)
Position
3
4
5
6
9
10
11
12
1
2
3
81.4 d 78.7 d 78.7 d 78.7 d 83.8 d 77.8 d 83.0 d 82.3 d
26.2 t 26.2 t 36.8 t 26.9 t 24.8 t 24.3 t 26.9 t
32.8 t 32.7 t 33.0 t 33.1 t 25.9 t 27.4 t 36.1 t
26.9 t
27.0 t
4
5
6
7
8
9
33.9 s 33.9 s 33.7 s 33.7 s 34.3 s 34.3 s 34.2 s 34.0 s
46.8 d 47.3 d 47.9 d 48.6 d 55.0 d 55.1 d 55.6 d 55.5 d
37.9 t 37.9 t 37.4 t 37.3 t 75.8 d 75.6 d 74.4 d 74.0 d
92.0 s 91.9 s 90.5 s 90.3 s 73.8 s 93.5 s 91.3 s 92.1 s
81.2 s 81.1 s 80.0 s 80.1 s 83.2 s 83.4 s 82.4 s 82.7 s
45.5 d 45.5 d 45.3 d 45.2 d 47.2 d 46.4 d 47.7 d 47.5 d
95.7 s 94.2 s 94.7 s 95.9 s 42.2 d 42.0 d 38.9 d 39.5 d
58.5 s 58.5 s 58.3 s 58.3 s 50.0 s 49.0 s 49.4 s 50.2 s
4.4.1. Compound 7. Mp: 123e125 ꢀC; [
(KBr): 2932, 1742, 1240, 1090 cmꢃ1
a
]
D
20 ꢃ69.6 (c 0.50, CHCl3); IR
;
1H NMR (400 MHz, CDCl3)
d
6.09 (1H, d, J¼2.0 Hz, H-12), 5.47 (1H, s, H-6
s, OCH2O), 4.03 (1H, t, J¼4.8 Hz, H-14 ), 3.51, 3.37, 3.30 (each 3H, s,
OCH3ꢂ3), 2.08 (3H, s, OAc), 1.04 (3H, t, J¼7.2 Hz, H3-22), 0.87 (3H, s,
H3-18); 13C NMR (100 MHz, CDCl3)
79.0 (d, C-1), 25.9 (t, C-2), 36.2
a), 4.93, 4.95 (each 1H,
b
10
11
12
13
14
15
16
17
18
19
21
22
OCH2O
d
(t, C-3), 34.7 (s, C-4), 52.0 (d, C-5), 75.7 (d, C-6), 93.6 (s, C-7), 79.1 (s,
C-8), 43.6 (d, C-9), 147.5 (s, C-10), 49.9 (s, C-11), 129.8 (d, C-12), 43.4
(d, C-13), 80.3 (d, C-14), 35.8 (t, C-15), 80.3 (d, C-16), 70.2 (d, C-17),
25.5 (q, C-18), 56.7 (t, C-19), 49.9 (t, C-21), 13.8 (q, C-22), 93.9 (t,
OCH2O), 55.1 (q, C-10), 57.6 (q, C-140), 56.4 (q, C-160), 169.9 (s,
COCH3), 21.6 (q, COCH3); HR-ESIMS [MþH]þ m/z calcd for
C27H40NO7: 490.2805, found: 490.2802.
35.5 t 34.9 t 33.6 t 33.5 t 35.8 t 36.3 t 32.0 t
33.5 t
40.6 d 40.6 d 36.4 d 37.1 d 38.3 d 38.4 d 36.7 d 39.1d
78.8 d 74.1 d 72.9 d 80.5 d 77.8 d 76.4 d 78.1 d 75.1 d
37.3 t 37.3 t 37.3 t 36.9 t 36.6 t 36.6 t 122.9 d 36.7 t
50.9 d 50.0 d 73.3 d 73.6 d 50.8 d 51.2 d 132.7 d 78.3 d
63.0 d 62.9 d 61.9 d 61.6 d 65.3 d 64.2 d 65.7 d 64.3 d
25.6 q 25.6 q 25.7 q 25.7 q 25.3 q 25.2 q 25.6 q 25.5 q
55.7 t 55.7 t 55.9 t 55.9 t 56.9 t 57.5 t 56.8 t
50.4 t 50.5 t 50.4 t 50.3 t 50.6 t 50.1 t 50.5 t
56.9 t
50.5 t
14.0 q 13.9 q 13.9 q 13.9 q 14.1 q 14.0 q 13.9 q 14.1 q
4.5. Preparation of compound 8
94.2 t 94.1 t 93.8 t 93.8 t 94.0 t 94.3 t 94.2 t
93.6 t
1-OCH3 55.9 q 55.9 q 55.6 q 55.5 q 56.1 q
d
55.6 q 55.6 q
14-OCH3 57.8 q
d
d
d
d
d
d
d
d
d
d
57.9 q
d
d
d
d
d
d
d
d
d
d
d
To a solution of compound 7 (8.2 g, 16.77 mmol) in 95% EtOH/
EtOAc (1:1, 200 mL) were sequentially added acetic acid (8 mL) and
10% PdeC (410 mg), and the reaction mixture was kept stirring at
room temperature in the presence of hydrogen. The insoluble
material was filtered off, and the filtrate was concentrated to give
a residue. The residue was suspended with water (100 mL), and the
suspension was basified with concd ammonium hydroxide to pH
>9. The basic mixture was extracted with dichloromethane
(100 mLꢂ3), and the combined extracts were rinsed with brine,
dried (Na2SO4), and concentrated under reduced pressure to give
pure compound 8 as a white amorphous powder (8.2 g, 100%). Mp:
1-OAc
6-OAc
d
d
d
d
170.8 s
21.9 q
d
d
170.8 s 171.0 s 171.7 s 170.6 s
21.4 q 21.3 q 21.5 q 21.8 q
d
10-OAc 170.6 s 170.6 s 171.1 s 170.7 s
23.4 q 23.4 q 23.4 q 23.4 q
d
d
d
d
d
d
d
d
14-OAc
d
d
d
d
170.5 s 170.6 s
21.1 q 21.2 q
d
170.2 s 170.3 s 170.3 s 171.4 s
21.2 q 21.6 q 21.3 q 21.4 q
d
16-OAc
d
170.2 s 170.5 s
21.3 q 21.4 q
d
d
d
170.3 s
21.5 q
d
d
d
d
154e156 ꢀC; [
a
]
20 ꢃ23.2 (c 0.50, CHCl3); IR (KBr): 2936, 2823, 1740,
1368, 1246 cmꢃD1
;
1H NMR (400 MHz, CDCl3)
d
5.41 (1H, s, H-6
a),
J¼7.2 Hz, H3-22), 0.77 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3) see
Table 1; ESIMS m/z 568 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd for
C27H39NO7Br: 568.1910, found: 568.1913.
4.93, 4.90 (each 1H, s, OCH2O), 3.68 (1H, t, J¼4.8 Hz, H-14
b), 3.44,
3.34, 3.27 (each 3H, s, OCH3ꢂ3), 2.07 (3H, s, OAc), 1.05 (3H, t,
J¼7.2 Hz, H3-22), 0.85 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3)
d
82.0 (d, C-1), 26.9 (t, C-2), 27.9 (t, C-3), 33.8 (s, C-4), 55.8 (d, C-5),
20
4.3.3. Compound 5. Mp: 167e169 ꢀC; [
a
]
þ7.2 (c 0.50, CHCl3); IR
D
78.4 (d, C-6), 91.8 (s, C-7), 83.2 (s, C-8), 48.2 (d, C-9), 39.8 (d, C-10),
50.1 (s, C-11), 33.8 (t, C-12), 38.5 (d, C-13), 81.5 (d, C-14), 36.6 (t, C-
15), 83.3 (d, C-16), 64.2 (d, C-17), 25.4 (q, C-18), 56.7 (t, C-19), 50.3
(t, C-21), 13.9 (q, C-22), 93.9 (t, OCH2O), 55.3 (q, C-10), 57.6 (q, C-140),
56.1 (q, C-160), 170.0 (s, COCH3), 21.7 (q, COCH3); HR-ESIMS [MþH]þ
m/z calcd for C27H42NO7: 492.2961, found: 492.2968.
(KBr): 2969, 2923, 2880,1740, 1369, 1255, 1227,1081 cmꢃ1; 1H NMR
(400 MHz, CDCl3) ), 5.01, 4.99 (each
5.07 (1H, t, J¼5.6 Hz, H-14
), 3.99 (1H, d,
d
b
1H, s, OCH2O), 4.75 (1H, dd, J¼9.6, 4.0 Hz, H-16
a
J¼4.8 Hz, H-17), 3.27 (3H, s, OCH3), 2.13, 2.08, 2.00 (each 3H, s,
OAcꢂ3), 1.06 (3H, t, J¼7.2 Hz, H3-22), 0.78 (3H, s, H3-18); 13C NMR
(100 MHz, CDCl3) see Table 1; ESIMS m/z 548 [MþH]þ; HR-ESIMS
[MþH]þ m/z calcd for C29H42NO9: 548.2860, found: 548.2849.
4.6. Preparation of compounds 9, 10, 11, and 12
4.3.4. Compound 6. Mp: 132e134 ꢀC; [
(KBr): 2922, 1733, 1368, 1220 cmꢃ1
a]
20 ꢃ5.7 (c 0.30, CHCl3); IR
D
Compound 8 (100 mg, 0.20 mmol) was dissolved in a solution of
6.5% HBr in acetic acid (2 mL), and the reaction solution was kept
stirring at 80 ꢀC for 28 h. After cooling down to room temperature,
the reaction solution was poured into ice water (20 mL), which was
basified with concd ammonium hydroxide to pH >9. The sub-
sequent mixture was extracted with dichloromethane (20 mLꢂ3),
and the combined extracts were rinsed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue obtained
was purified by column chromatography over silica gel, eluting
with cyclohexane/acetone (20:1), to give compounds 9 (white
amorphous powder, 24 mg, 21%), 10 (white amorphous powder,
15 mg, 12%), 11 (white amorphous powder, 6 mg, 6%), and 12 (white
amorphous powder, 26 mg, 23%).
;
1H NMR (400 MHz, CDCl3)
d
5.00, 4.97 (each 1H, s, OCH2O), 4.70 (1H, dd, J¼9.6, 5.2 Hz, H-16
a
),
3.97 (1H, t, J¼4.4 Hz, H-14
b
), 3.81 (1H, br d, J¼4.8 Hz, H-17), 3.46,
3.26 (3H, s, OCH3ꢂ2), 2.08, 2.05 (each 3H, s, OAcꢂ2), 1.06 (3H, t,
J¼7.2 Hz, H3-22), 0.78 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3) see
Table 1; ESIMS m/z 520 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd for
C28H42NO8: 520.2910, found: 520.2919.
4.4. Preparation of compound 7
To a solution of deltaline (1, 10 g, 20 mmol) in pyridine (100 mL)
were sequentially added (Boc)2O (26 g, 120 mmol) and DMAP
(2.4 g, 20 mmol), and the reaction mixture was refluxed for 6 h.
After removal of pyridine under reduced pressure, the residue was
suspended with water (150 mL), and the suspension was extracted
with dichloromethane (100 mLꢂ3). The combined extracts were
dried over anhydrous sodium sulfate and concentrated in vacuo to
4.6.1. Compound 9. Mp: 121e123 ꢀC; [
(KBr): 2922, 1740, 1239, 1083 cmꢃ1
5.39 (1H, s, H-6
J¼5.6, 4.4 Hz, H-16
a
]
D
20 ꢃ90.0 (c 0.30, CHCl3); IR
;
1H NMR (400 MHz, CDCl3)
d
a
), 4.90, 4.89 (each 1H, s, OCH2O), 4.76 (1H, dd,
), 3.90 (1H, t, J¼5.2 Hz, H-14 ), 3.72 (1H, d,
b
b

5674
P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
J¼2.4 Hz, H-17), 3.34 (3H, s, OCH3), 2.08, 2.01 (each 3H, s, OAcꢂ2),
1.07 (3H, t, J¼7.2 Hz, H3-22), 0.83 (3H, s, H3-18); 13C NMR (100 MHz,
CDCl3) see Table 1; ESIMS m/z 568 [MþH]þ; HR-ESIMS [MþH]þ m/z
calcd for C27H39NO7Br: 568.1910, found: 568.1920.
OCH2O), 3.66 (1H, t, J¼4.8 Hz, H-14
b), 3.43, 3.34, 3.27 (each 3H, s,
OCH3ꢂ3), 1.06 (3H, t, J¼6.8 Hz, H3-22), 0.78 (3H, s, H3-18); 13C NMR
(100 MHz, CDCl3) d 83.0 (d, C-1), 27.2 (t, C-2), 27.9 (t, C-3), 34.0 (s, C-
4), 49.2 (d, C-5), 37.4 (t, C-6), 90.6 (s, C-7), 81.7 (s, C-8), 47.6 (d, C-9),
43.6 (d, C-10), 50.9 (s, C-11), 32.6 (t, C-12), 38.1 (d, C-13), 81.8 (d, C-
14), 33.1 (t, C-15), 83.9 (d, C-16), 61.7 (d, C-17), 25.8 (q, C-18), 55.9 (t,
C-19), 50.6 (t, C-21), 14.0 (q, C-22), 93.3 (t, OCH2O), 55.7 (q, C-10),
57.7 (q, C-140), 56.3 (q, C-160); HR-ESIMS [MþH]þ m/z calcd for
C25H40NO5: 434.2906, found: 434.2897.
4.6.2. Compound 10. Mp:155e157 ꢀC;[
a]
D
20 ꢃ101.7 (c0.35,CHCl3);IR
(KBr): 2921,1738,1238 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
5.42 (1H, s,
H-6
J¼5.2 Hz, H-14
a
), 4.90 (2H, br s, OCH2O), 4.85 (2H, m, H-1þH-16
b), 4.72 (1H, t,
), 3.76 (1H, br s, H-17), 2.12, 2.06, 2.01 (each 3H, s,
b
OAcꢂ3), 1.10 (3H, t, J¼7.2 Hz, H3-22), 0.84 (3H, s, H3-18); 13C NMR
(100 MHz, CDCl3) see Table 1; ESIMS m/z 596 [MþH]þ; HR-ESIMS
[MþH]þ m/z calcd for C28H39NO8Br: 596.1859, found: 596.1849.
4.8. Preparation of compounds 14, 15, 16, 17, 18, and 19
Method 1: compound 13 (600 mg, 1.39 mmol) was dissolved in
a solution of 6.5% HBr in acetic acid (12 mL), and the reaction solution
was kept stirring at 80 ꢀC for 28 h before being poured into ice water
(50 mL). The mixture was basified with concd ammonium hydroxide
to pH >9, and extracted with dichloromethane (60 mLꢂ3). The
combined organic layers were rinsed with brine, dried (Na2SO4), and
concentrated under reduced pressure to furnish a residue, which was
subjected to column chromatography over silica gel, eluting with
petroleum ether/ethyl acetate (15:1), to give compounds 14 (white
amorphous powder, 129 mg, 19%), 15 (white amorphous powder,
134 mg, 20%),16 (white amorphous powder,106 mg,15%),17 (whiter
amorphous powder, 35 mg, 5%), 18 (white amorphous powder,
194 mg, 26%), and 19 (white amorphous powder, 33 mg, 6%).
Method 2: compound 13 (1.00 g, 2.31 mmol) was dissolved in
a solution of 3% HBr in acetic acid (30 mL), and the reaction solution
was kept stirring at 60 ꢀC for 24 h prior to being poured into ice
water (20 mL). The mixture was basified with concd ammonium
hydroxide to pH >9, and extracted with dichloromethane
(30 mLꢂ3). The combined extracts were rinsed with brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure to yield the crude product of compound 15. A solution of
the crude product 15 in 6.5% HBreHOAc (30 mL) was kept stirring
at 60 ꢀC for 50 h. Employing the similar work-up procedure de-
scribed for that of compound 15, the residue obtained was chro-
matographed over silica gel, eluting with petroleum ether/ethyl
acetate (10:1), to furnish compound 18 as a white amorphous
powder (557 mg, 45% from starting material 13).
4.6.3. Compound 11. Mp: 183e185 ꢀC; [
(KBr): 2951, 2883, 1742, 1368 cmꢃ1
a
]
20 ꢃ61.3 (c 0.15, CHCl3); IR
D
;
1H NMR (400 MHz, CDCl3)
d
6.11 (1H, dd, J¼9.6, 7.2 Hz, H-16), 5.63 (1H, dd, J¼9.6, 2.0 Hz, H-15),
5.43 (1H, s, H-6a), 5.02, 4.94 (each 1H, s, OCH2O), 4.71 (1H, t,
J¼4.0 Hz, H-14 ), 3.25 (3H, s, OCH3), 2.05, 2.02 (each 3H, s, OAcꢂ2),
b
1.04 (3H, t, J¼7.2 Hz, H3-22), 0.87 (3H, s, H3-18); 3C NMR (100 MHz,
CDCl3) see Table 1; ESIMS m/z 488 [MþH]þ; HR-ESIMS [MþH]þ m/z
calcd for C27H38NO7: 488.2648, found: 488.2660.
20
4.6.4. Compound 12. Mp: 193e195 ꢀC; [
a
]
ꢃ40.2 (c 0.50, CHCl3);
D
IR (KBr): 2961, 2933, 1740, 1369, 1245, 1084 cmꢃ1
(400 MHz, CDCl3) 5.36 (1H, s, H-6 ), 4.90, 4.81 (each 1H, s,
OCH2O), 4.80 (2H, m, H-14 ), 3.24 (3H, s, OCH3), 2.07, 2.03,
þH-16
;
1H NMR
d
a
b
a
2.02 (each 3H, s, OAcꢂ3), 1.04 (3H, t, J¼7.2 Hz, H3-22), 0.82 (3H, s,
H3-18); 13C NMR (100 MHz, CDCl3) see Table 1; ESIMS m/z 548
[MþH]þ; HR-ESIMS [MþH]þ m/z calcd for C29H42NO9: 548.2860,
found: 548.2854.
4.7. Preparation of compound 13
Compound 8 (8.2 g, 16.70 mmol) was dissolved in a solution of
5% NaOH in methanol (150 mL), and the reaction mixture was kept
stirring at 50 ꢀC for 30 min before being cooled down to room
temperature. After removal of methanol, the residue was sus-
pended with water (100 mL), and the subsequent mixture was
extracted with dichloromethane (100 mLꢂ3). The combined ex-
tracts were rinsed with brine, dried (Na2SO4), and concentrated
under reduced pressure to furnish an alcohol product (pale yellow
amorphous powder, 7.45 g). To a solution of the alcohol (7.45 g)
made above in DMF (150 mL) were added carbon disulfide (20 mL,
332.8 mmol) and a solution of 20% NaOH in water (10 mL) at 0 ꢀC,
and the red-brown reaction solution was kept stirring at the same
temperature for 1 h prior to the slow addition of methyl iodide
(10.3 mL, 165.3 mmol). The reaction was allowed to proceed at 0 ꢀC
for an additional 4 h prior to being quenched with water (150 mL).
The subsequent mixture was extracted with dichloromethane
(150 mLꢂ3), and the combined extracts were dried (Na2SO4) and
concentrated under reduced pressure. The residue obtained was
purified by column chromatography, eluting with petroleum ether/
acetone (10:1), to give a xanthate (yellow oil, 8.5 g). To a solution of
the xanthate (8.5 g) prepared above in toluene (150 mL) were se-
quentially added AIBN (65 mg, 0.39 mmol) and n-Bu3SnH (6.3 mL,
23.64 mmol), and the reaction mixture was refluxed for 2 h. After
cooling down to room temperature and removal of toluene, the
residue was suspended with water (80 mL), and the mixture was
extracted with dichloromethane (100 mLꢂ3). The combined ex-
tracts were dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give a residue, which was subjected to
column chromatography over silica gel, using petroleum ether/ac-
etone (20:1) as eluent, to furnish compound 13 as a white amor-
phous powder (6.4 g, 88% from starting material 8). Mp: 99e101 ꢀC;
4.8.1. Compound 14. Mp: 99e101 ꢀC; [
a]
D
20 ꢃ16.7 (c 1.15, CHCl3); IR
(KBr): 2963, 2930, 2873, 1733, 1369, 1253, 1081 cmꢃ1
;
1H NMR
(400 MHz, CDCl3)
J¼5.2 Hz, H-14 ), 4.77 (1H, dd, J¼9.6, 4.8 Hz, H-16
), 3.23 (3H, s, OCH3), 2.11, 2.00
d
4.97, 4.92 (each 1H, s, OCH2O), 4.84 (1H, t,
), 3.05 (1H, br s, H-
b
a
17), 3.02 (1H, dd, J¼10.4, 7.2 Hz, H-1
b
(each 3H, s, OAcꢂ2), 1.05 (3H, t, J¼7.2 Hz, H3-22), 0.76 (3H, s, H3-18);
13C NMR (100 MHz, CDCl3) see Table 2; ESIMS m/z 490 [MþH]þ; HR-
ESIMS [MþH]þ m/z calcd for C27H40NO7: 490.2805, found: 490.2805.
20
4.8.2. Compound 15. Mp: 172e174 ꢀC; [
a
]
ꢃ65.0 (c 0.40, CHCl3);
D
IR (KBr): 2881, 1459, 1370, 1120, 1081 cmꢃ1
CDCl3)
3.08 (1H, dd, J¼10.8, 6.8 Hz, H-1), 1.98 (1H, m, H-2
(1H, overlapped, H-2 ), 1.20 (1H, m, H-3 ), 1.63 (1H, m, H-3
(1H, overlapped, H-5), 1.32 (1H, overlapped, H-6
;
1H NMR (400 MHz,
d
a), 2.35
b
a
b
), 1.32
a), 2.12 (1H, m, H-
6b
), 2.45 (1H, overlapped, H-9), 1.82 (1H, overlapped, H-10), 1.82
(1H, overlapped, H-12 ), 2.45 (1H, overlapped, H-12 ), 2.58 (1H, m,
H-13), 3.56 (1H, t, J¼4.4 Hz, H-14 ), 2.20 (1H, m, H-15 ), 2.35 (1H,
overlapped, H-15 ), 4.85 (1H, m, H-16), 3.57 (1H, s, H-17), 0.78 (3H,
a
b
b
a
b
s, H3-18), 2.45 (1H, overlapped, H-19a), 2.61 (1H, d, J¼11.6 Hz, H-
19b), 2.70 (1H, m, H-21a), 2.83 (1H, m, H-21b), 1.07 (3H, t, J¼7.2 Hz,
H3-22), 5.05, 4.93 (each 1H, s, OCH2O), 3.33 (3H, s, 1-OCH3), 3.42
(3H, s, 14-OCH3); 13C NMR (100 MHz, CDCl3) see Table 2; HR-ESIMS
[MþH]þ m/z calcd for C24H37NO4Br: 482.1906, found: 482.1897.
20
[
a]
20 ꢃ35.6 (c 0.50, CHCl3); IR (KBr): 2963, 2931, 2898, 2823, 1460,
4.8.3. Compound 16. Mp: 174e176 ꢀC; [
a
]
D
ꢃ70.8 (c 0.25, CHCl3);
D
1380, 1079 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
5.02, 4.92 (each 1H, s,
IR (KBr): 2926, 2882, 1741, 1368, 1239, 1083 cmꢃ1 1H NMR
;

P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
5675
Table 2
for 1 h prior to being diluted with water (10 mL). The subsequent
mixture was extracted with dichloromethane (15 mLꢂ3). The com-
bined extracts were rinsed with brine, dried (Na2SO4), and concen-
13C NMR data of compounds 14, 15, 16, 17, 18, and 19 (100 MHz for 13C, CDCl3)
Position
14
15
16
17
18
19
trated to give compound 20 as a white amorphous powder (99 mg,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
83.9 d
26.8 t
26.9 t
34.1 s
48.7 d
37.3 t
91.0 s
80.7 s
46.6 d
43.2 d
50.6 s
32.3 t
38.1 d
73.6 d
32.9 t
74.6 d
61.4 d
25.7 q
56.0 t
50.5 t
14.0 q
93.3 t
55.7 q
d
85.1 d
26.2 t
37.4 t
34.4 s
48.9 d
31.9 t
92.5 s
82.1 s
43.1 d
46.9 d
50.9 s
24.8 t
41.7 d
83.2 d
37.1 t
51.6 d
62.8 d
25.7 q
56.0 t
50.7 t
14.1 q
93.8 t
56.2 q
57.5 q
d
85.0 d
26.1 t
37.4 t
34.3 s
48.7 d
31.9 t
92.4 s
81.9 s
42.3 d
46.7 d
51.0 s
24.6 t
42.2 d
75.4 d
36.9 t
50.7 d
62.8 d
25.7 q
56.0 t
50.8 t
14.1 q
93.8 t
56.2 q
d
77.3 d
27.6 t
27.3 t
34.2 s
48.9 d
32.1 t
92.1 s
82.1 s
42.9 d
46.0 d
49.8 s
24.2 t
41.6 d
82.8 d
37.2 t
51.7 d
61.6 d
25.5 q
57.7 t
50.2 t
13.9 q
93.9 t
d
77.2 d
27.5 t
37.1 t
34.1 s
48.7 d
32.0 t
91.9 s
81.9 s
42.1 d
45.8 d
49.8 s
23.9 t
42.0 d
74.9 d
37.0 t
51.0 d
61.6 d
25.4 q
56.5 t
50.1 t
13.9 q
93.9 t
d
129.4 d
126.0 d
30.9 t
33.7 s
45.9 d
37.9 t
91.4 s
83.3s
41.9 d
42.3 d
50.3 s
24.3 t
41.6 d
75.5 d
40.3 t
50.6 d
61.3 d
26.0 q
59.9 t
50.1 t
13.8 q
93.5 t
d
20
quantitative yield): mp: 172e174 ꢀC; [
a
]
ꢃ85.1 (c 0.35, CHCl3); IR
D
(KBr): 3442, 2962, 2926, 2882, 1732, 1374, 1248, 1083 cmꢃ1; 1H NMR
(400 MHz, CDCl3) 5.06, 4.96 (each 1H, s, OCH2O), 5.04 (1H, m, H-16),
), 3.63
d
4.85 (1H, dd, J¼10.4, 7.2 Hz, H-1), 4.08 (1H, t, J¼4.4 Hz, H-14
b
(1H, brs, H-17), 2.12 (3H, s, OAc),1.12 (3H, t, J¼6.8 Hz, H3-22), 0.79(3H,
s, H3-18); 13C NMR see Table 3; HR-ESIMS [MþH]þ m/z calcd for
C24H35NO5Br: 496.1699, found: 496.1704.
Table 3
13C NMR data of compounds 20, 21, 22, 23a/b, and 24 (100 MHz for 13C, CDCl3)
Positon
20
21
22
23a
23b
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
77.2 d
27.5 t
37.3 t
34.2 s
48.9 d
32.0 t
92.1 s
82.2 s
45.3 d
46.1 d
49.7 s
24.5 t
44.2 d
73.9 d
37.1 t
51.8 d
61.7 d
25.4 q
56.5 t
50.1 t
13.9 q
94.0 t
d
75.0 d
27.6 t
36.9 t
33.1 s
50.9 d
32.9 t
88.0s
90.1 s
208.1 s
60.0 d
49.9 s
29.3 t
123.5 d
d
77.6 d
27.7 t
37.1 t
34.2 s
54.1 d
31.3 t
90.8 s
81.6 s
46.1 d
48.5 d
50.4 s
25.2 t
44.6 d
84.5 d
32.6 t
88.0 d
61.5 d
25.5 q
56.8 t
50.2 t
13.9 q
93.4 t
d
75.9 d
29.1 t
36.7 t
34.3 s
49.1 d
32.2 t
90.8 s
82.2 s
55.6 d
44.9 d
50.8 s
27.9 t
124.6 d
203.1 d
35.3 t
127.4 d
60.5 d
25.6 q
56.5 t
49.5 t
13.7 q
94.1 t
d
76.0 d
31.5 t
38.9 t
33.6 s
47.8 d
35.1 t
90.4 s
83.9 s
59.3 d
39.4 d
51.7 s
27.9 t
123.6 d
199.8 d
36.7 t
127.4 d
61.2 d
25.5 q
56.7 t
49.5 t
13.7 q
93.9 t
d
77.3 d
27.5 t
37.1 t
34.2 s
48.9 d
32.1 t
92.1 s
81.8 s
45.3 d
46.2 d
49.8 s
23.3 t
43.6 d
73.7 d
36.6 t
57.9 d
61.7 d
25.4 q
56.5 t
50.1 t
13.9 q
94.0 t
d
17
18
19
21
22
OCH2O
1-OCH3
14-OCH3
16-OCH3
1-OAc
56.5 q
d
d
d
d
d
d
d
d
d
d
171.0 s
21.9 q
d
170.9 s
21.8 q
170.7 s
21.2 q
d
d
d
d
d
d
14-OAc
16-OAc
170.3 s
21.3 q
171.2 s
21.3 q
d
170.8 s
21.2 q
d
170.6 s
21.9 q
d
d
d
33.4 t
127.0 d
60.8 d
25.3 q
56.1 t
49.4 t
13.7 q
94.7 t
d
d
d
d
d
d
d
d
17
18
19
21
(400 MHz, CDCl3)
d 5.02, 4.92 (each 1H, s, OCH2O), 4.81 (2H, m, H-
14 ), 3.56 (1H, br s, H-17), 3.33 (3H, s, OCH3), 3.09 (1H, dd,
b
þH-16
b
22
J¼10.8, 6.8 Hz, H-1 ), 2.12 (3H, s, OAc), 1.07 (3H, t, J¼7.2 Hz, H3-22),
b
OCH2O
1-OCH3
14-OCH3
1-OAc
0.77 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3) see Table 2; ESIMS
m/z 510 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd for C25H37NO5Br:
510.1855, found: 510.1854.
d
d
d
d
d
d
171.0 s
21.8 q
d
170.7 s
21.4 q
d
170.7 s
21.9 q
d
170.8 s
21.4 q
d
170.8 s
21.4 q
d
171.0 s
21.8 q
d
20
4.8.4. Compound 17. Mp: 165e167 ꢀC; [
IR (KBr): 2921, 2851, 1739 cmꢃ1
4.94 (each 1H, s, OCH2O), 4.85 (2H, m, H-1
a
]
ꢃ58.0 (c 0.15, CHCl3);
14-OAc
D
d
d
d
d
d
d
;
1H NMR (400 MHz, CDCl3)
þH-16 ), 3.61 (1H, br s,
), 3.41 (3H, s, OCH3), 2.12 (3H, s,
d 5.05,
b
b
H-17), 3.54 (1H, t, J¼4.8 Hz, H-14
b
4.10. Preparation of compounds 21, 22 and 23a/b
OAc), 1.11 (3H, t, J¼7.2 Hz, H3-22), 0.79 (3H, s, H3-18); 13C NMR
(100 MHz, CDCl3) see Table 2; HR-ESIMS [MþH]þ m/z calcd for
C25H37NO5Br: 510.1855, found: 510.1851.
Method 1: to a solution of compound 18 (2 g, 3.72 mmol) in DMF
(60 mL) was added NaH (60%, 893 mg, 22.32 mmol), and the mix-
ture was stirred at room temperature for 12 h before being poured
into ice water (100 mL). The mixture was extracted with
dichloromethane (100 mLꢂ3), and the combined organic layers
were rinsed with brine, dried (Na2SO4), and concentrated under
reduced pressure to give a residue. Column chromatography of the
residue eluting with petroleum ether/acetone (20:1) to provide
compounds 21 (white amorphous powder, 1.05 g, 70%) and 22
(white amorphous powder, 216 mg, 14%).
20
4.8.5. Compound 18. Mp: 103e105 ꢀC; [
a
]
ꢃ97.3 (c 0.30, CHCl3);
D
IR (KBr): 2962, 2928, 2878, 1738, 1372, 1241, 1081 cmꢃ1
(400 MHz, CDCl3) 5.00, 4.91 (each 1H, s, OCH2O), 4.85 (2H, m, H-
þH-16 ), 3.59 (1H, br s, H-17), 2.11
;
1H NMR
d
1
b
b
), 4.78 (1H, t, J¼4.4 Hz, H-14
b
(3H, s, OAc), 2.10 (3H, s, OAc), 1.11 (3H, t, J¼7.2 Hz, H3-22), 0.77 (3H,
s, H3-18); 13C NMR see Table 2; HR-ESIMS [MþH]þ m/z calcd for
C26H37NO6Br: 538.1804, found: 538.1812.
Method 2: to a solution of compound 20 (50 mg, 0.1 mmol) in
THF (2 mL) was added NaH (60%, 24 mg, 0.6 mmol), and the mix-
ture was stirred at room temperature for 40 h. Using the similar
work-up procedure as described in Method 1, the residue obtained
was purified by column chromatography over silica gel, eluting
with petroleum ether/acetone (20:1), to give compounds 21 (white
amorphous powder,12 mg, 30%) and 22 (white amorphous powder,
19 mg, 45%).
Method 3: to a solution of compound 20 (50 mg, 0.1 mmol) in
THF (2 mL) was added NaH (60%, 24 mg, 0.6 mmol), and the mix-
ture was kept stirring at room temperature for 2 h prior to being
poured into ice water (10 mL). The subsequent mixture was
extracted with dichloromethane (15 mLꢂ3), and the organic frac-
tions were rinsed with brine, dried over anhydrous sodium sulfate.
4.8.6. Compound 19. Mp: 158e160 ꢀC; [
a
]
D
20 ꢃ68.3 (c 0.75, CHCl3);
IR (KBr): 2961, 2885, 1741, 1649, 1373, 1237, 1082, 947 cmꢃ1
;
1H
NMR (400 MHz, CDCl3)
d
5.93 (1H, dt, J¼10.0, 3.6 Hz, H-2), 5.47 (1H,
d, J¼10.0 Hz, H-1), 4.97, 4.90 (each 1H, s, OCH2O), 4.92 (1H, t,
J¼5.2 Hz, H-14
b), 4.85 (1H, m, H-16b), 2.11 (3H, s, OAc), 1.07 (3H, t,
J¼7.2 Hz, H3-22), 0.85 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3) see
Table 2; ESIMS m/z 478 [MþH]þ; HR-ESIMS [MþH]þ m/z calcd for
C24H33NO4Br: 478.1593, found: 478.1590.
4.9. Preparation of compound 20
Compound 18 (107 mg, 0.2 mmol) was dissolved in a solution of
5%NaOHinmethanol(3 mL), andthesolutionwaskeptstirringat0 ꢀC

5676
P. Tang et al. / Tetrahedron 68 (2012) 5668e5676
After removal of organic solvent, the residue was subjected to
column chromatography over silica gel, eluting with petroleum
ether/acetone (20:1), to furnish compounds 23a (white amorphous
powder, 7 mg,16%), 23b (white amorphous powder, 5 mg,13%), and
22 (white amorphous powder, 18 mg, 42%).
Method 4: to a solution of compound 24 (100 mg, 0.22 mmol) in
DMF (3 mL) was added NaH (60%, 53 mg,1.32 mmol), and the mixture
waskept stirring atroom temperature for12 h. Using the similar work-
up procedure as described in Method 1, the residue was subjected to
column chromatography over silica gel, eluting with petroleum ether/
acetone (20:1), to give compounds 21 (white amorphous powder,
58 mg, 65%) and 22 (white amorphous powder, 16 mg, 17%).
TiCl4 (1 M in CH2Cl2, 0.18 mL, 0.18 mmol), and the reaction solu-
tion was stirred for 1 h before being quenched with saturated
sodium bicarbonate solution. After addition of dichloromethane
(10 mL) and water (10 mL), the subsequent mixture was extracted
with dichloromethane (10 mLꢂ2). The combined organic fractions
were rinsed with brine, dried over anhydrous sodium sulfate, and
concentrated to give compound 24 as a white amorphous powder
20
(67 mg, quantitative yield) Mp: 168e170 ꢀC; [
a]
ꢃ66.0 (c 0.40,
D
CHCl3); IR (KBr): 3446, 2963, 2892, 2852, 1727, 1251, 1103 cmꢃ1
1H NMR (400 MHz, CDCl3)
5.06, 4.96 (each 1H, s, OCH2O), 4.88
(1H, m, H-16), 4.84 (1H, dd, J¼14.4, 6.8 Hz, H-1), 4.12 (1H, t,
;
d
J¼4.4 Hz, H-14
b), 3.62 (1H, br s, H-17), 2.10 (3H, s, OAc), 1.12 (3H,
t, J¼7.2 Hz, H3-22), 0.79 (3H, s, H3-18); 13C NMR see Table 3; HR-
ESIMS [MþH]þ m/z calcd for C24H35NO5Cl: 452.2204, found:
452.2211.
4.10.1. Compound 21. Mp:159e161 ꢀC;[
a]
D
20 ꢃ98.4(c 0.25, CHCl3); IR
(KBr): 2966, 2926, 2892, 2852, 1727, 1251, 1103 cmꢃ1
;
1H NMR
(400 MHz, CDCl3)
), 2.44 (1H, m, H-2
H-3
), 1.46 (1H, d, J¼7.2 Hz, H-5), 1.70 (1H, m, H-6
), 2.35 (1H, m, H-10), 2.20 (1H, m, H-12 ), 2.37 (1H, m, H-12
(1H, m, H-13), 2.28 (1H, m, H-15 ), 2.68 (1H, m, H-15 ), 5.58 (1H, m,
H-16), 4.08(1H, s, H-17), 0.77 (3H, s, H3-18), 2.56 (2H, br s, H2-19), 2.62
(1H, m, H-21a), 2.83 (1H, m, H-21b),1.06 (3H, t, J¼6.8 Hz, H3-22), 5.19,
4.98 (each 1H, s, OCH2O), 2.05 (3H, s, OAc); 13C NMR see Table 3; HR-
ESIMS [MþH]þ m/z calcd for C23H32NO5: 402.2280, found: 402.2273.
The crystal structure for 139: a colorless orthorhombic crystal from
petroleum ether/ethyl acetate was mounted on a P4 four circle dif-
d
4.75 (1H, dd, J¼9.2, 7.6 Hz, H-1), 2.10 (1H, m, H-
),1.33 (1H, td, J¼14.8, 4.8 Hz, H-3 ),1.64 (1H, m,
), 1.88 (1H, m, H-
), 5.54
2
a
b
a
b
a
Acknowledgements
6b
a
b
a
b
We are grateful to the National Natural Science Foundation of
China (No. 30873147) for financial support of this research. We also
thank Mr. Dai-Bing Luo in Sichuan University for assisting in the X-
ray crystallographic analysis.
References and notes
fractometer and exposed to graphite-monochromated Mo Ka irradi-
ꢀ
ꢀ
1. For reviews, see: (a) Wang, F. P.; Liang, X. T. In The Alkaloids: Chemistry and
Biology; Cordell, G. A., Ed.; Elsevier Science: New York, NY, 2002; Vol. 59,
pp 1e280; (b) Wang, F. P.; Chen, Q. H.; Liang, X. T. In The Alkaloids: Chemistry and
Biology; Cordell, G. A., Ed.; Elsevier Science: San Diego, CA, 2009; Vol. 67,
pp 1e78; (c) Wang, F. P.; Chen, Q. H. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Elsevier Science: San Diego,CA, 2010; Vol. 69, pp 1e577; (d)
Wang, F. P.; Chen, Q. H.; Liu, X. Y. Nat. Prod. Rep. 2010, 27, 529e570; (e) Wang, F.
P.; Liang, X. T. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Aca-
demic: New York, NY, 1992; Vol. 42, pp 151e247; (f) Cherney, E.; Baran, P. S. Isr.
J. Chem. 2011, 51, 391e405.
ation. The unit cell parameters are a¼9.1939 (4) A, b¼9.4727 (4) A,
3
ꢀ
3
ꢀ
c¼23.6259 (11) A, V¼2057.60(15) A , Z¼4, dx¼1.296 g/cm , in space
group P212121, of the 3760 measured with 3.0815ꢄ
q
ꢄ28.9343ꢀ scan,
2672 were independently observed at the level of F0>4s(F0). The
structure was solved by the directed method using the program
SHELXL-97 and the atomic parameters were refined by the full-
matrix least squares on F2 method. The final R indices [I>2
s(I)] was
R1¼0.0451, WR2¼0.0711. CCDC reference number: CCDC 853699.
2. Couch, J. F. J. Am. Chem. Soc. 1936, 58, 684e685.
3. He, Y. M.; Zou, C. L.; Chen, Q. H.; Wang, F. P. J. Asian Nat. Prod. Res. 2007, 9,
713e720.
4.10.2. Compound 22. Mp: 185e187 ꢀC; [
IR (KBr): 2936, 1728, 1230 cmꢃ1
5.03 (each 1H, s, OCH2O), 4.92 (1H, m, H-16), 4.81 (2H, m, H-1, H-
14), 3.60 (1H, s, H-17), 2.04 (3H, s, OAc),1.12 (3H, t, J¼6.8 Hz, H3-22),
0.81 (3H, s, H3-18); 13C NMR see Table 3; HR-ESIMS [MþH]þ m/z
calcd for C24H33NO5Na: 438.2256, found: 438.2255.
a
]
20 ꢃ67.3 (c 0.35, CHCl3);
D
;
1H NMR (400 MHz, CDCl3)
d
5.14,
4. Zinurova, E. G.; Kabalnova, N. N.; Shereshovets, V. V.; Ivanova, E. V.; Shults, E. E.;
Tolstikov, G. A.; Yunusov, M. S. Russ. Chem. Bull., Int. Ed. 2001, 50, 720e723.
5. Desai, H. K.; Chokshi, H. P.; Pelletier, S. W. J. Nat. Prod. 1989, 52, 1296e1302.
6. Bai, Y. L.; Desai, H. K.; Pelletier, S. W. J. Nat. Prod. 1995, 58, 929e933.
7. Carmack, M.; Ferris, J. P.; Harvey, J.; Magat, P. T.; Martin, E. W.; Mayo, D. W. J. Am.
Chem. Soc. 1958, 80, 497.
8. Kulanthaivel, P.; Pelletier, S. W. Tetrahedron Lett. 1987, 28, 3883e3886.
9. Kulanthaivel, P.; Pelletier, S. W. Tetrahedron 1988, 44, 4313e4320.
10. Narzullaev, A. S.; Yunusov, M. S.; Moisenkov, A. M.; Sabirov, S. S. Khim. Prir.
Soedin. 1989, 372e375.
4.10.3. Compound 23a. Mp: 82e84 ꢀC; [
a
]
20 ꢃ24.7 (c 0.30, CHCl3);
D
IR (KBr): 2963, 2926, 1730, 1646, 1247 cmꢃ1
;
1H NMR (400 MHz,
11. Zou, C. L.; Ji, H.; Xie, G. B.; Chen, D. L.; Wang, F. P. J. Asian Nat. Prod. Res. 2008, 10,
CDCl3) d 9.89 (1H, s, H-14), 5.46 (2H, m, H-13, H-16), 5.11, 4.95 (each
1063e1067.
1H, s, OCH2O), 4.72 (1H, t, J¼8.8 Hz, H-1), 3.78 (1H, s, H-17), 2.02
(3H, s, OAc), 1.04 (3H, t, J¼6.8 Hz, H3-22), 0.80 (3H, s, H3-18); 13C
NMR see Table 3; HR-ESIMS [MþH]þ m/z calcd for C24H34NO5:
416.2437, found: 416.2431.
12. Liang, X. H.; Desai, H. K.; Joshi, B. S.; Pelletier, S. W. Heterocycles 1990, 31,
1889e1894.
13. Zou, C. L.; Liu, X. Y.; Wang, F. P.; Chen, Q. H. Chem. Pharm. Bull. 2008, 56,
250e253.
14. Srivastava, S. K.; Joshi, B. S.; Newton, M. G.; Lee, D.; Pelletier, S. W. Tetrahedron
Lett. 1995, 36, 519e522.
15. Zou, C. L.; Cai, L.; Ji, H.; Xie, G. B.; Wang, F. P.; Jian, X. X.; Song, L.; Liu, X. Y.; Chen,
D. L.; Chen, Q. H. Tetrahedron 2008, 64, 7594e7604.
20
4.10.4. Compound 23b. Mp: 123e125 ꢀC;
[
a
]
ꢃ43.3 (c 0.30,
1H NMR
10.18 (1H, s, H-14), 5.46 (2H, m, H-13, H-16),
D
CHCl3); IR (KBr): 2961, 2926, 1730, 1651, 1246 cmꢃ1
(400 MHz, CDCl3)
5.20, 5.00 (each 1H, s, OCH2O), 4.79 (1H, t, J¼9.2 Hz, H-1), 3.79 (1H,
s, H-17), 2.02 (3H, s, OAc), 1.02 (3H, t, J¼7.2 Hz, H3-22), 0.70 (3H, s,
H3-18); 13C NMR see Table 3; HR-ESIMS [MþH]þ m/z calcd for
C24H34NO5: 416.2437, found: 416.2445.
;
16. Liang, X. X.; Chen, Q. H.; Wang, F. P. J. Asian Nat. Prod. Res. 2011, 13, 624e633.
17. 10-Deoxydeltaline (8) and 6,10-deodeltaline (13) were prepared according to
the method described in the literature.8,9,19 Specifically, elimination of deltaline
(1) generated D10(12) olefin 718 in 92% yield based on the recovery of starting
material. Hydrogenation of the olefin produced 10-deoxydeltaline (8) in
a quantitative yield. 6,10-Deoxydeltaline (13) was prepared in 88% yield from8
through hydrolysis followed by Barton deoxydation.9,19
18. Cai, L. Ph.D. Dissertation. Sichuan University, 2006, p 46.
19. Schlessinger, R. H.; Gillman, K. W. Tetrahedron Lett. 1996, 37, 1331e1334.
20. Gao, F. Ph.D. Dissertation. Sichuan University, 2006, p 54.
21. Rheenen, V. V. Tetrahedron Lett. 1969, 985e988.
d
4.11. Preparation of compound 24
22. Sucrow, W. Chem. Ber. 1967, 100, 259e264.
23. Kuroda, C.; Murase, A.; Suzuki, H.; Endo, T.; Anzai, S. Bull. Chem. Soc. Jpn. 1998,
71, 1639e1647.
To a solution of compound 22 (62 mg, 0.15 mmol) in anhy-
drous dichloromethane (2 mL) at 0 ꢀC under argon was added