Tetrahedron 62 (2006) 9446–9455

A general approach to crinine-type Amaryllidaceae

alkaloids: total syntheses of (±)-haemanthidine,
(±)-pretazettine, (±)-tazettine, and (±)-crinamine
Fu-Min Zhang, Yong-Qiang Tu,* Jian-Dong Liu, Xiao-Hui Fan, Lei Shi,
Xiang-Dong Hu, Shao-Hua Wang and Yong-Qiang Zhang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 14 June 2006; revised 6 July 2006; accepted 7 July 2006
Available online 10 August 2006

Abstract—A general strategy for synthesizing the crinine-type Amaryllidaceae alkaloids was developed. And total syntheses of four repre-
sentative crinine-type Amaryllidaceae alkaloids: (
)-haemanthidine, (
)-pretazettine, (
)-tazettine, and (
)-crinamine, were accomplished
via a common intermediate 17. This crucial precursor was achieved on the basis of the NBS-promoted semipinacol rearrangement recently
developed by our group and an intramolecular Michael addition, which efficiently constructed the sterically congested quaternary carbon
center and the hydroindole skeleton of the crinine-type alkaloids, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.

1. Introduction As a part of our ongoing research program for synthesizing

Amaryllidaceae alkaloids,8 we report herein a new general
The crinine-type Amaryllidaceae alkaloids possess a wide approach to the more complex crinine-type alkaloid mem-
range of biological activities.1,2 For example, (
)-haeman- bers 1–4 (Fig. 1).
thidine (1),3 (
)-tazettine (3),4 and (
)-crinamine (4)5
show high analgesic, mild anticancer, and cytotoxic activi- Our retrosynthetic analysis is shown in Scheme 1. We envi-
ties, respectively. In particular, (
)-pretazettine (2),3 which sioned that all four target molecules could be synthesized
exhibits high anticancer activity, has recently stimulated from the same crucial arylhydroindole enone 5, which might
extremely the interest of chemists.3,6 The important struc- be prepared from 6 through an intramolecular Michael addi-
tural features of these alkaloids include an arylhydroindole tion. The requisite double bond and 1,2-amino alcohol unit
core and a cis or trans hydroxyl group in the pyrrolidine of intermediate 6 would be derived from the bromine and
ring, which represent central synthetic challenges. To date, aldehyde functions in compound 7, respectively. The key
several creative strategies had emerged to address these sterically congested quaternary carbon center in 7 could be
problems.3–5,7 Despite the availability of many synthetic constructed by the NBS-promoted semipinacol rearrange-
methods, it is necessary to develop more general procedures. ment of allylic alcohol 8.

O O O O
O O O O
OH
OH
OH O O OH
OH
6a
3
H3CO N H3CO N H3CO N H3CO N
H H CH3 H CH3 H

(±)-haemanthidine (1) (±)-pretazettine (2) (±)-tazettine (3) (±)-crinamine (4)

Figure 1. Representative member of the crinine-type Amaryllidaceae alkaloids.

* Corresponding author. Tel.: +869318912410; fax: +869318912582; e-mail: tuyq@lzu.edu.cn

0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.027
 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455 9447

Ar
OR1 OR3 aldehyde 7 was easily prepared from the alcohol 8 in excel-
Michael Ar
addition
lent yield (95%) and with high diastereoselectivity
1-4 (d.r.>99:1). In order to introduce the hydroxyl group at
O NR2 NHR 4
H O C-6a position and extend a nitrogen-containing carbon
5 6 chain, the cyanation method was applied. The addition of
trimethylsilylcyanide (TMSCN) to the aldehyde 7 set the
Ar
Cyanosilylation CHO Semipinacol OH hydroxyl group at C-6a position, and the corresponding
O rearrangement trimethylsilyl ether adducts (11, a mixture of two isomers),
O
Elimination Br
O
O which could not be separated by silica gel chromatography,
O
7 O were then reduced with LiAlH4. After protection of the
8
amino alcohol with acetone, two separable diastereoisomers
Scheme 1. Retrosynthetic analysis of target molecules 1–4; Ar¼3,4-methyl- (11a and 11b) were obtained in 85% yield over three steps
enedioxyphenyl. (path A in Scheme 3). However, the diastereoselectivity
was very low (11a/11b¼1.2:1) when triethylamine (Et3N)
was used as a base. To increase the diastereoselectivity of
2. Results and discussion the initial addition reaction, other conditions were investi-
gated (Table 1). The cinchona alkaloids were selected as
2.1. Preparation of allylic alcohol 8 the base in place of Et3N. Notably, in all tests with different
cinchona alkaloids, only the cyanohydrin products, but none
The starting allylic alcohol 8 was prepared by two means. of the corresponding TMS adduct were isolated (Scheme 3).
One was the addition of aldehyde 99 to the Grignard reagent The use of a stoichiometric quantity of the hydroquinine was
of 4-bromo-1,2-(methylenedioxy)benzene, the other was the necessary (entries 9–11, Table 1). Evaluation of bases and
Shapiro reaction between 108d and piperonal (Scheme 2). solvents showed that the best conditions for the reaction,

CHO Table 1. Preparation of cyanohydrin in different conditionsa

O Br O
O NNHTris
Entry Solvent Base/equiv Time Ratiob 110 /1100 Yieldc (%)
O O O 10
1) 9 1 Et2O Quinine/1 2d —d Trace
2) M DA
9
g,
T ME 2 THF Quinine/1 2d —d Trace
TH i, al
92 F uL ron 3 Toluene Quinine/1 2d 2.1:1 62
% OH ) n-B pipe % 4 CH2Cl2 Quinine/1 2d 2.8:1 83
1 2) 69
5 CH2Cl2 Quinidine/1 2d 2.3:1 81
O
6 CH2Cl2 Cinchonine/1 2d 2.0:1 78
O
O 7 CH2Cl2 Cinchonidine/1 2d 2.6:1 76
O 8 CH2Cl2 Hydroquinidine/1 2d 3.28:1 79
9 CH2Cl2 Hydroquinine/0.1 4d 1.61:1 56
Scheme 2. Preparation of allylic alcohol 8. 10 CH2Cl2 Hydroquinine/0.5 3d 1.88:1 63
11 CH2Cl2 Hydroquinine/1 2d 3.5:1 82
12 CH2Cl2 Hydroquinine/2 10 h 2.7:1 90
2.2. Preparation of aldehyde 7 and compounds 11a and
a
11b Reaction was carried out on a 0.1 mmol scale with 1.2 equiv of TMSCN in
2 mL of solvent for 2 d, unless noted otherwise.
By utilizing the work recently developed by our group on the
b
Determined by 1H NMR.
c
The yield was overall yields of 110 and 1100 , based on the recovered mate-
use of N-bromosuccinimide (NBS)-promoted semipinacol rial.
rearrangement to build the quaternary carbon center,8b the d
Not determined.

OH OH
TMSCN, rt Ar Ar
Ar
CHO cinchona CN
NBS 6a CN
alkaloids O
8 O O +
CH3CN
Br path B Br Br
O O
95% O

7 11' 11''
TMSCN, rt 1. LiAlH4, THF
CH2Cl2, Et3N path A 2. acetone, SiO2
> 99% 90%

OTMS O O
Ar Ar Ar
NH NH
6a CN 1. LiAlH , Et O
O 4 2
O + O
Br 2. acetone, SiO2 Br Br
O O O
85%
11 (β:α = 1.2:1) 11a 11b
used without purification
Ar = 3,4-methylenedioxyphenyl

Scheme 3. Preparation of aldehyde 7 and compounds 11a and 11b.

9448 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455

which provided product 110 and 1100 (ratio¼3.5:1), were our group.13 Due to the failure of the one-pot operation,
hydroquinine as base and CH2Cl2 as solvent (entry 11, Table the hydroxyl of 13a was first protected as the silyl ether un-
1). Interestingly, the decrease in diastereoselectivity was der the Sweeley’s condition,14 giving compound 15 in excel-
observed when a twofold hydroquinine was employed (entry lent yield. Enolization of 15 and trapping with TMSCl
12, Table 1). As shown in Scheme 3, 11a and 11b were also afforded the silyl enol ether 16, which was oxidized directly
obtained from 110 and 1100 under the similar reaction condi- by Pd(OAc)215 to furnish the desired enone 17 in 70% yield
tions. The major isomer 11a was identified to be the desired (Scheme 5).
intermediate (as will be discussed below).

2.3. Construction of arylhydroindole framework 13a Ar

NBoc
LDA, -78 °C O
13a O
The major isomer 11a was dehydrobrominated by treatment THF, TMSCl N
H
TMSO
with 1,8-diazabicyclo[5.4.0]under-7-ene (DBU) in refluxing H Boc Ar OTMS
toluene, and the requisite double bond of 12a was introduced 14
in 82% yield. Under acidic condition, 12a was deprotected Ar OTMS
and transformed into the corresponding secondary amine in HMDS, pyridine LDA, -78 °C
nearly quantitative yield,4c and without purification this 13a
TMSCl, 90% N THF, TMSCl
O
Michael addition product was treated with di-tert-butyl di- H Boc
carbonate (Boc2O) to provide the crucial intermediate 13a 15
in 81% yield (Scheme 4).10 Successively, the transformation Ar OTMS Ar OTMS
Pd(OAc)2 1
of the minor isomer 11b into the intermediate 13a was also CH 3CN 2
investigated (Scheme 4). The diastereoisomer 13b (6a-epi- 70%
TMSO N O N
13a) was prepared in the same fashion from 11b in 62% yield H Boc (2 steps) H Boc
(two steps). With the isomer 13b in hand, we next focused on 16 17
the inversion of the configuration at C-6a position. Under the Ar = 3,4-Methylenedioxyphenyl
standard Mitsunobu conditions,11 the reactions did not
provide the expected product 13a, but resulted only in the Scheme 5. Determination of b-OH at C-6a position and preparation of
decomposition of the starting material. enone 17.

2.5. Total syntheses of haemanthidine (1), pretazettine

O (2), and tazettine (3)
Ar NH
1. DBU, toluene 1. 2 N HCl, THF,
11a O
2. acetone, SiO2 2. Boc2O, CH2Cl2 Having introduced the correct C1–C2 double bond, we then
82% O 81%.
Ar OH proceeded to set the methyloxy group at the C-3 position in
12a
stereoselective manner. Enone 17 was reduced with L-Selec-
N
tride in THF at 78  C to afford allylic alcohol 18a as a
O
Ar OH H Boc single diastereoisomer in excellent yield, whose formation
Mitsunobu 13a
two steps transformation
arose from the attack of hydride on the exo face of the hydro-
11b indole system. Using Whitlock’s method,16 we inverted
62% O N
H Boc the b-hydroxyl group of 18a into the required a-methoxy
13b derivative 19a in 93% yield. The alcohol 20 was easily pre-
Ar = 3,4-Methylenedioxyphenyl pared from compound 19a and converted into the N-formyl
derivative 22 via acetate 21 (86% yield for four steps).
Scheme 4. Construction of the arylhydroindole framework (13a and 13b).
Following the known procedures,3i,3j we achieved the total
syntheses of 1, 2, and 3 from derivative 22 (Scheme 6),
2.4. Preparation of enone 17 and determination of b-OH whose spectral data were identical to those reported in the
at C-6a position literature.3i,3j
With the rapid construction of the arylhydroindole frame- Ar OTMS Ar OTMS
work 13a, installation of the C1–C2 double bond was inves- L- Selectride Ms2O, THF
tigated. Initially we anticipated that the silyl enol ether 16 17
THF then CH3OH 3
HO N N
could be synthesized from 13a by silylation of the hydroxyl 95% H Boc 93% H3CO
H Boc
group and enolization of the carbonyl group in a one-pot 18a 19a
process (Scheme 5). However, unexpected compound 14 1. TBAF, THF, 99%; Ar OR1
was isolated in excellent yield under the conditions of 20 R1 = H, R2 = Boc
2. Ac2O, pyridine, DMAP, 99%;
21 R1 = Ac, R2 = Boc
lithium diisopropylamine (LDA) and chlorotrimethylsilane 3. TFA, ClCH2CH2Cl; 1 2
NR2 22 R = Ac, R = Formyl
(TMSCl). The formation of 14 is a fortuitous proof of the then DMF, HCO2Me, 88% H3CO H
relative stereochemistry of the hydroxyl group at C-6a
ref 3i
position, since the secondary alcohol of opposite configura- ref 3j ref 3j
(±)-3 (±)-2 (±)-1
tion cannot form an oxygen bridge at C-3 position.12 To our
Ar = 3,4-Methylenedioxyphenyl
knowledge, as an efficient chemical method to determine the
key hydroxyl group configuration at C-6a position in this Scheme 6. Total syntheses of haemanthidine (1), pretazettine (2), and tazet-
hydroindoline system, this conversion is first reported by tine (3).
 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455 9449

2.6. Total synthesis of crinamine (4) 4.1.1. Benzo[1,3]dioxol-5-yl-(1,4-dioxa-spiro[4.5]dec-7-

en-8-yl)-methanol (8). Process A: to a stirred suspension
Additionally, enone 17 was reduced under Luche condi- of magnesium turnings 240 mg (10 mmol) in dry THF
tion17 at room temperature to afford allylic alcohol 18 in (20 mL) was added 1.2 mL 4-bromo-1,2-(methylenedi-
95% yield (18b/18a¼2:1), albeit with disappointing dia- oxyl)benzene (10 mmol) in 10 mL THF at room tempera-
stereoselectivity. Allylic ether 19b was obtained from 18b ture. The reaction mixture was stirred for 2 h until the
using the same method as in the preparation of 19a. After magnesium turnings had disappeared. Then a solution of
removal of the Boc and TMS protecting groups of 19b aldehyde 99 1.7 g (10 mmol) in THF (20 mL) was added
with CF3COOH, the followed Pictet–Spengler reaction in to the above mixed solution at 0  C. After 30 min, the reac-
a one-pot procedure readily gave crinamine 4 in 76% yield, tion mixture was quenched by addition of saturated aqueous
whose spectral data were agreed with those reported in the NH4Cl (30 mL) and allowed to stir for another 1 h. The
literature (Scheme 7).3i,2b aqueous solution was extracted with CH2Cl2 (320 mL).
The combined extracts were washed with water, brine, and
dried over Na2SO4, then concentrated under reduced pres-
NaBH4 Ar OTMS sure. Recrystallization from petroleum/EtOAc afforded the
CeCl3.7H2O Ms2O, THF allylic alcohol 8 (2.67 g, 92%) as a white crystal. Mp 104–
17
MeOH HO N then MeOH, 106  C; 1H NMR (300 MHz, CDCl3): d 6.86–6.75 (m,
95% H Boc 97% 3H), 5.95 (d, J¼2.7 Hz, 2H), 5.77 (s, 1H), 5.05 (s, 1H),
18b:18a = 2:1
3.98–3.95 (m, 4H), 2.35 (br s, 2H), 2.10–2.08 (m, 2H),
Ar OTMS 1.71 (t, J¼6.6 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3):
TFA, ClCH2CH2Cl, d 147.6, 146.8, 139.3, 136.2, 120.1, 119.9, 108.0, 107.9,
(±)-4
H3CO N then HCHO-MeOH, 107.0, 100.9, 77.0, 64.3, 35.4, 30.8, 23.5 ppm; IR (KBr):
H Boc 6 N HCl, 76% n 3418, 1500, 1488, 1442, 1251, 1231, 1115, 1051, 1037,
19b 938, 926 cm1; MS (70 eV, EI): m/z (%) 290 (M+, 12),
Ar = 3,4-Methylenedioxyphenyl
272 (1), 226 (3), 151 (23), 122 (24), 99 (16), 93 (15), 86
Scheme 7. Total synthesis of crinamine (4). (100), 77(11); HRMS (ESI) calcd for C16H18O5Na:
313.1046 [M+Na]+; found: 313.1044.

Process B: to a cold (78  C) suspension of 10 (4.36 g,

3. Conclusion
10 mmol) in dried tetramethylethylenediamine (TMEDA,
30 mL) was added dropwise n-BuLi (2.0 M in hexane,
In summary, we successfully synthesized the crinine-type
12.0 mL, 24 mmol) under an argon atmosphere (10 min).
Amaryllidaceae alkaloids including (
)-haemanthidine,
The reaction mixture was stirred at room temperature for
(
)-pretazettine, (
)-tazettine, and (
)-crinamine using an
4 h, and then cooled to 78  C again. The solution of piper-
NBS-promoted semipinacol rearrangement developed by
onal (3.0 g, 20 mmol) in dried TMEDA (15 mL) was added
our group and a Michael addition as the key steps, and
dropwise. After 1 h, the mixture was poured into saturated
disclosed a general strategy for synthesizing the crinine-
aqueous solution of NH4Cl (100 mL). The organic layer
type Amaryllidaceae alkaloids.
was separated, and the aqueous layer was extracted with
CH2Cl2 (3100 mL). The combined organic phases were
washed with brine, dried over Na2SO4, and concentrated in
4. Experimental vacuo. Purification of the residue by column chromato-
graphy on silica gel (petroleum/EtOAc¼5:1) provided the
4.1. General allylic alcohol 8 (2.0 g, 69%).

Melting points were measured on X-4 melting point appara- 4.1.2. 8-Benzo[1,3]dioxol-5-yl-7b-bromo-1,4-dioxa-
tus and are uncorrected. IR spectra were measured on KBr spiro[4.5]decane-8-carbaldehyde (7). To a solution of
disks by using a Nicolet NEXUS 670 FTIR spectrometer. allylic alcohol 8 (290 mg, 1 mmol) in CH3CN (15 mL)
NMR spectra were recorded with TMS as an internal stan- was added NBS (196 mg, 1.1 mmol) at room temperature.
dard in CDCl3 by a Mercury-plus 300BB spectrometer The reaction mixture was stirred for 6 h until the allylic
(300 MHz for 1H NMR and 75 MHz for 13C NMR spectra), alcohol had disappeared completely as monitored by TLC.
a Brucker AM-400 spectrometer (400 MHz for 1H NMR and The solution was concentrated in vacuum and the residue
100 MHz for 13C NMR spectra). The EIMS spectra were was purified by flash column chromatography on silica gel
recorded on a HP5988A mass spectrometer, and the high- (petroleum/EtOAc¼6:1) to give the aldehyde 7 as a white
resolution mass spectra were recorded on Brucker Daltonics crystal (350 mg, 95%). Mp 84–86  C; 1H NMR (300 MHz,
APEX II 49e spectrometer by means of the ESI technique. CDCl3): d 9.93 (s, 1H), 6.80–6.75 (m, 2H), 6.63 (dd,
Silica gel (200–300 mesh) for column chromatography and J¼8.3, 2.3 Hz, 1H), 5.96 (s, 2H), 4.71 (dd, J¼12.9, 4.2 Hz,
silica GF254 for TLC were produced by Qingdao Marine 1H), 3.99–3.90 (m, 4H), 2.52–2.47 (m, 1H), 2.35–2.31 (m,
Chemical Company (China). Solvents for reaction were 1H), 2.22 (t, J¼12.9 Hz, 1H), 1.84 (dd, J¼12.9, 9.9 Hz,
distilled prior to use: THF and Et2O from Na and benzo- 2H), 1.67–1.64 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3):
phenone, MeOH from Mg and I2, CH2Cl2, Et3N, and d 202.1, 148.3, 147.0, 132.1, 120.3, 108.4, 108.0, 107.0,
DMF from CaH2, and toluene from LiAlH4. All air- or 101.3, 64.6, 64.4, 56.5, 51.0, 43.6, 32.1, 31.8 ppm; IR
moisture-sensitive reactions were conducted under an argon (KBr): n 3405, 1712, 1501, 1439, 1241, 1150, 1093, 1036,
atmosphere. 938, 622 cm1; MS (70 eV, EI): m/z (%) 370 (M+, 3), 368
9450 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455

(M+, 3), 289 (9), 260 (41), 259 (34), 215 (37), 187 (57), 174 CDCl3): d 6.85–6.78 (m, 3H), 6.01 and 6.00 (2s, 2H), 5.20
(100), 157 (26), 128 (43), 115 (63), 108 (52), 99 (70), 80 (m, 1H), 4.96 (d, J¼11.4 Hz, 0.67H), 4.76 (d, J¼10.8 Hz,
(93), 63 (33); HRMS (ESI) calcd for C16H17O5BrNa: 0.19H), 4.07–4.00 (m, 2H), 3.85–3.81 (m, 2H), 2.27–2.09
391.0152 [M+Na]+; found: 391.0158. (m, 4H), 1.83–1.79 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d 148.9, 148.5, 147.8, 147.6, 127.0, 121.7, 117.9,
4.1.3. 5-(8-Benzo[1,3]dioxol-5-yl-7b-bromo-1,4-dioxa- 117.6, 108.9, 108.6, 107.0, 101.6, 101.5, 70.2, 69.7, 64.5,
spiro[4.5]decane-8-yl)-2,2-dimethyl-oxazolidine (11a 63.6, 60.5, 53.2, 52.7, 48.9, 48.8, 38.4, 38.0, 31.0, 30.5,
and 11b). Path A: to a solution of the above aldehyde 7 24.8, 24.3 ppm; IR (KBr): n 3389, 1710, 1506, 1437, 1244,
(1.11 g, 3 mmol) in CH2Cl2 (30 mL) was added dropwise 1091, 1039, 940, 845 cm1; MS (70 eV, EI): m/z (%) 259
TMSCN (0.48 mL, 3.6 mmol) at room temperature, and (1), 174 (1), 88 (11), 86 (69), 84 (100), 82 (15), 80 (13),
then Et3N (0.52 mL, 3.8 mmol) was added. The mixture 49 (16), 47 (18), 43 (13).
was stirred and the reaction was monitored by 1H NMR.
After the material had disappeared completely, the reaction 4.1.5. 5-(8-Benzo[1,3]dioxol-5-yl-7b-bromo-1,4-dioxa-
mixture was concentrated in vacuo. The solution of the resi- spiro[4.5]decane-8-yl)-2,2-dimethyl-oxazolidine (11a
due in Et2O (30 mL) was added dropwise to a solution of and 11b). Path B: to a solution of LiAlH4 (32 mg,
LiAlH4 (228 mg, 6 mmol) in dry Et2O (50 mL) at 0  C. 0.84 mmol) in THF (10 mL) was added dropwise a solution
After the mixture was stirred for 2 h at room temperature, of the mixtures of 110 and 1100 (160 mg, 0.4 mmol) in THF
the reaction mixture was quenched with H2O, 15% NaOH, (10 mL) at 0  C. After 20 min, the reaction was quenched
and H2O, and the resulting mixture was filtered. The solid with H2O, 15% NaOH, and H2O, and the resulting mixture
residue was washed well with CHCl3, and the combined was filtered. The solid residue was washed well with
organic phases were concentrated. The residue was purified CHCl3, the combined organic phases were concentrated,
by flash column chromatography silica gel (petroleum/ and the residue was purified by silica gel (petroleum/
acetone¼5:1) to give white gem 11a (612 mg, 46.4%) and acetone¼5:1) to give white gem 11a (124 mg, 70%) and
11b (510 mg, 38.6%). Compound 11a: 1H NMR 11b (35 mg, 20%).
(400 MHz, CDCl3): d 6.89 (br, 2H), 6.79 (d, J¼8.0 Hz,
1H), 5.96 (d, J¼3.6 Hz, 2H), 5.22 (s, 1H), 4.26 (dd, J¼7.4, 4.1.6. 5-(8-Benzo[1,3]dioxol-5-yl-1,4-dioxa-spiro[4,5]-
4.2 Hz, 1H), 4.05–3.98 (m, 2H), 3.82–3.78 (m, 2H), 3.03 dec-6-en-8-yl)-2,2-dimethyl-oxazolidine (12a). A mixture
(dd, J¼12.6, 7.4 Hz, 1H), 2.70 (dd, J¼12.4, 4.4 Hz, 1H), of 11a (516 mg, 1.18 mmol) and DBU (1.8 mL,
2.15 (dd, J¼11.4, 3.0 Hz, 2H), 2.05–2.01 (m, 1H), 1.92– 11.8 mmol) in toluene (20 mL) was refluxed for 2 d. The
1.81 (m, 2H), 1.74 (d, J¼14 Hz, 1H), 1.20 (s, 3H), 1.18 (s, mixture was concentrated in vacuo. The residue was puri-
3H) ppm; 13C NMR (100 MHz, CDCl3): d 147.5, 146.4, fied directly by flash column chromatography on silica
129.6, 122.4, 109.6, 107.7, 107.3, 101.1, 95.5, 82.1, 77.2, gel (petroleum/acetone¼3:1) to afford compound 12a
64.4, 63.4, 56.6, 47.5, 47.0, 37.9, 30.7, 26.5, 25.3 ppm; IR (347 mg, 82%, two steps) as a white gum. 1H NMR
(KBr): n 3304, 1491, 1434, 1374, 1243, 1093, 1040, 933, (400 MHz, CDCl3): d 7.00 (s, 1H), 6.80 (dd, J¼8.2,
911, 732, 644 cm1; MS (70 eV, EI): m/z (%) 360 (1), 260 3.0 Hz, 1H), 6.69 (dd, J¼8.2, 3.0 Hz, 1H), 6.02 (dd,
(23), 174 (41), 115 (8), 100 (100), 71 (25), 70 (16), J¼11.2, 2.4 Hz, 1H), 5.90 (t, J¼2.8 Hz, 2H), 5.75 (d, J¼
43 (15); HRMS (ESI) calcd for C20H27NBrO5: 440.1067 10.8 Hz, 1H), 4.04–3.83 (m, 5H), 3.01–2.95 (m, 1H),
[M+H]+; found: 440.1073. Compound 11b: 1H NMR 2.89–2.83 (m, 1H), 2.00–1.95 (m, 2H), 1.78–1.75 (m, 1H),
(300 MHz, CDCl3): d 7.01 (d, J¼1.8 Hz, 1H), 6.91 (d, 1.65–1.58 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H) ppm; 13C
J¼8.1 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 5.94–5.93 (m, NMR (100 MHz, CDCl3): d 147.4, 145.9, 136.9, 135.3,
2H), 4.85 (t, J¼7.3 Hz, 1H), 4.33 (dd, J¼7.4, 5.0 Hz, 1H), 128.6, 120.9, 108.6, 107.5, 105.4, 100.8, 95.8, 83.1, 64.6,
4.02–3.94 (m, 2H), 3.87–3.83 (m, 2H), 3.21 (dd, J¼12.5, 64.3, 47.7, 45.8, 30.0, 29.8, 27.1, 25.7 ppm; IR (KBr):
7.7 Hz, 1H), 2.79 (dd, J¼12.6, 5.1 Hz, 1H), 2.40–2.31 (m, n 3313, 1487, 1434, 1240, 1099, 1038, 936, 814 cm1; MS
3H), 2.16 (br, 1H), 1.83–1.80 (m, 1H), 1.61–1.54 (m, 2H), (70 eV, EI): m/z (%) 260 (3), 187 (2), 128 (3), 115 (3), 100
1.51 and 1.11 (2s, 6H) ppm; 13C NMR (100 MHz, CDCl3): (100); HRMS (ESI) calcd for C20H26NO5: 360.1805
d 147.5, 146.1, 133.5, 120.6, 108.9, 107.8, 107.6, 101.0, [M+H]+; found: 360.1801.
95.1, 80.1, 65.8, 64.5, 63.8, 54.4, 47.9, 47.5, 41.1, 31.0,
26.6, 25.0 ppm; IR (KBr): n 3307, 1712, 1490, 1435, 1240, 4.1.7. 5-(8-Benzo[1,3]dioxol-5-yl-1,4-dioxa-spiro[4,5]-
1038, 940, 827, 662 cm1; MS (70 eV, EI): m/z (%) 360 dec-6-en-8-yl)-2,2-dimethyl-oxazolidine (12b). The same
(1), 292 (1), 260 (24), 174 (42), 115 (9), 100 (100), 71 method was applied to the preparation of compound 12b
(26), 70 (16), 55 (9), 43 (13). (79%, two steps). 1H NMR (400 MHz, CDCl3): d 6.93 (d,
J¼1.6 Hz, 1H), 6.80 (dd, J¼8.2, 1.4 Hz, 1H), 6.70 (dd, J¼
4.1.4. (8-Benzo[1,3]dioxol-5-yl-7b-bromo-1,4-dioxa- 7.8, 3.0 Hz, 1H), 5.99 (d, J¼10.0 Hz, 1H), 5.90 (s, 2H),
spiro[4.5]decane-8-yl)-hydroxy-acetonitrile (11 0 and 5.86 (d, J¼10.0 Hz, 1H), 4.15–4.12 (m, 1H), 4.00–3.94
1100 ). To a solution of the above aldehyde 7 (312 mg, (m, 3H), 3.86 (dd, J¼6.4, 5.8 Hz, 1H), 3.16 (dd, J¼12.0,
0.85 mmol) in CH2Cl2 (10 mL) was added dropwise 7.2 Hz, 1H), 2.91 (dd, J¼12.0, 5.4 Hz, 1H), 2.00–1.92 (m,
TMSCN (0.14 mL, 1.05 mmol) at room temperature, and 2H), 1.69–1.65 (m, 2H), 1.58–1.52 (m, 1H), 1.33 (s, 3H),
then hydroquinine (278 mg, 0.85 mmol) was added. The 1.27 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d 147.4,
mixture was stirred for 2 d at room temperature, and then 145.9, 136.4, 134.3, 130.3, 121.1, 108.3, 107.5, 105.3,
concentrated in vacuo. The residue was purified by flash col- 100.8, 95.6, 82.3, 64.7, 64.3, 47.8, 46.1, 31.9, 29.5, 26.8,
umn chromatography on silica gel (petroleum/EtOAc¼5:1) 25.2 ppm; IR (KBr): n 3313, 1653, 1610, 1487, 1434,
to give 263 mg white solid (110 and 1100 , ratio¼3.5:1) and re- 1240, 1038, 936, 814 cm1; MS (70 eV, EI): m/z (%) 360
covered the starting material 12 mg. 1H NMR (300 MHz, (M+, 1), 260 (23), 174 (41), 115 (8), 100 (100), 71 (25), 70
 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455 9451

(16), 43 (15); HRMS (ESI) calcd for C20H26NO5: 360.1805 then slowly warmed to 20  C, and quenched after 1 h
[M+H]+; found: 360.1801. with saturated NaHCO3 solution (2 mL). After dilution
with ether (30 mL), the organic layer was separated, and
4.1.8. 3a-Benzo[1,3]dioxol-5-yl-3b-hydroxy-6-oxo-octa- the aqueous layer was extracted with ether (310 mL).
hydro-indole-1-carboxylic acid tert-butyl ester (13a). The combined organic layers were washed successively
A solution of the above protected amino alcohol 12a with saturated NaHCO3 solution, brine, dried over
(277 mg, 0.77 mmol), THF (15 mL), and 2 N HCl (2.2 mL) Na2SO4, and concentrated in vacuum. Purification of the
was heated at reflux for 6 h. After cooled to room tempera- residue by flash column chromatography on silica gel (petro-
ture, the reaction was quenched by addition solid of K2CO3 leum/EtOAc¼10:1) provided the acetal 14 (109 mg, 90%)
until pH¼8. The resulting layers were separated and the as a white film. 1H NMR (400 MHz, CDCl3): d 6.73–6.63
aqueous layer was extracted with CHCl3 (510 mL). The (m, 3H), 5.90 (s, 2H), 4.60 (dd, J¼3.6, 1.6 Hz, 1H), 4.52
combined organic layers were washed with brine, dried (d, J¼6.8 Hz, 0.59H), 4.39 (d, J¼7.6 Hz, 0.42H), 3.31 (d,
(MgSO4), and concentrated. The residue was dissolved in J¼11.4 Hz, 0.5H), 3.26 (d, J¼11.6 Hz, 0.5H), 2.95–2.87
CH2Cl2 (10 mL), and triethylamine (0.33 mL, 2.4 mmol) (m, 1H), 2.28–2.24 (m, 1H), 2.16–2.13 (m, 1H), 2.10–2.02
was added to the solution. The solution was stirred for (m, 1H), 1.98–1.86 (m, 2H), 1.79–1.72 (m, 1H), 1.48 (s,
10 min, then added (Boc)2O 252 mg (1.16 mmol) at 0  C. 4H), 1.39 (s, 5H), 0.14 (s, 9H) ppm; 13C NMR (100 MHz,
The reaction mixture was stirred at room temperature for CDCl3): d 154.4, 154.0, 147.9, 146.3, 135.2, 118.8, 108.2,
1 h, whereupon H2O (3 mL) was added and the organic 106.5, 106.3, 101.0, 96.4, 96.2, 80.6, 79.9, 79.5, 79.4,
layers were separated and the aqueous layer was extracted 60.2, 57.0, 56.5, 52.9, 52.4, 45.4, 44.9, 43.7, 43.2, 34.8,
with CH2Cl2 (310 mL). The combined organic layers 34.7, 28.5, 28.3, 1.89 ppm; IR (KBr): n 1693, 1402, 1245,
were washed with brine, dried (Na2SO4), and concentrated. 1174, 1041, 923, 873, 844 cm1; MS (70 eV, EI): m/z (%)
The residue was purified by flash column chromatography 447 (M+, 1), 288 (14), 246 (19), 202 (22), 73 (49), 57
on silica gel (petroleum/EtOAc¼1:1) to give 13a as a white (100); HRMS (ESI) calcd for C23H34NSiO6: 448.2150
gum (234 mg, 81%). 1H NMR (400 MHz, CDCl3): d 6.95 [M+H]+; found: 448.2150.
(br, 0.64H), 6.78 (br, 2.30H), 5.96 (s, 2H), 4.64–4.58 (br,
0.74H), 4.46 (br, 0.60H), 4.28 (br, 0.64H), 3.67 (br, 4.1.11. 3a-Benzo[1,3]dioxol-5-yl-6-oxo-3b-trimethyl-
0.56H), 3.34 (d, J¼10.4 Hz, 1H), 3.06–2.85 (br, 2H), 2.60 silanyloxy-octahydro-indole-1-carboxylic acid tert-butyl
(br, 0.77H), 2.38 (br, 1H), 2.23–1.85 (br, 3H), 1.15 and ester (15). To a solution of 13a (107 mg, 0.29 mmol) in
1.42 (2s, 9H) ppm; 13C NMR (100 MHz, CDCl3): d 211.1, dried pyridine (1.5 mL) were added hexamethyl disilazane
154.4, 148.3, 148.0, 146.5, 137.1, 134.8, 119.1, 118.9, (HMDS) (0.4 mL, 1.92 mmol) and TMSCl (0.3 mL,
108.2, 106.9, 106.5, 106.3, 101.2, 94.9, 94.6, 81.0, 80.1, 2.36 mmol) subsequently. The reaction mixture was stirred
79.7, 77.2, 59.4, 56.9, 56.2, 53.0, 52.5, 52.2, 51.6, 51.1, for 30 min and H2O (0.5 mL) was added carefully. After
45.6, 45.1, 43.5, 43.0, 42.7, 42.1, 36.5, 33.3, 33.2, 28.4, dilution with CH2Cl2 (30 mL), the organic layer was sepa-
26.4 ppm; IR (KBr): n 3405, 1689, 1506, 1488, 1402, rated, and the aqueous layer was extracted with CH2Cl2
1237, 1167, 1039, 932, 732 cm1; MS (70 eV, EI): m/z (310 mL). The combined organic layers were washed
(%) 375 (M+, 3), 319 (3), 229 (4), 216 (8), 188 (9), 174 with saturated CuSO4 solution, water, brine, dried over
(14), 115 (11), 77 (10), 57 (100); HRMS (ESI) calcd for Na2SO4, and concentrated in vacuum. Purification of the
C20H25NO6Na: 398.1574 [M+Na]+; found: 398.1580. residue by flash column chromatography on silica gel (petro-
leum/EtOAc¼12:1) provided 15 (115 mg, 90%) as a white
4.1.9. 3a-Benzo[1,3]dioxol-5-yl-3a-hydroxy-6-oxo-octa- film. 1H NMR (400 MHz, CDCl3): d 6.81–6.74 (m, 3H),
hydro-indole-1-carboxylic acid tert-butyl ester (13b). 5.95 (s, 2H), 4.68–4.59 (br, 1H), 3.99 (s, 1H), 3.67 (br,
The same method was applied to the preparation of com- 1H), 3.41–3.34 (br, 1H), 3.21 (br, 0.4H), 3.04 (br, 0.5H),
pound 13b (yield: 78%). 1H NMR (400 MHz, CDCl3): 2.68 (dd, J¼16.8, 5.2 Hz, 1H), 2.23–2.09 (m, 4H), 1.49 (s,
d 6.86–6.79 (m, 3H), 5.99 (s, 2H), 4.62 (br, 1H), 4.13 (br, 9H), 0.10 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
1H), 3.70 (br, 2H), 3.26 (br, 0.5H), 2.99 (br, 0.5H), 2.81 d 210.2, 155.9, 148.1, 146.5, 133.4, 121.0, 108.4, 108.2,
(br, 1H), 2.25–2.00 (m, 4H), 1.48 (s, 9H) ppm; 13C NMR 101.3, 80.6, 77.4, 59.1, 55.1, 53.7, 42.6, 41.4, 36.9, 31.0,
(100 MHz, CDCl3): d 209.9, 155.4, 148.9, 147.1, 131.7, 28.7, 0.00 ppm; IR (KBr): n 1693, 1491, 1393, 1250, 1167,
120.8, 108.9, 107.4, 101.4, 80.6, 77.4, 57.8, 54.2, 53.2, 936, 845 cm1; MS (70 eV, EI): m/z (%) 447 (M+, 0.5),
43.1, 41.4, 36.2, 31.4, 28.4 ppm; IR (KBr): n 3426, 1711, 216 (100), 174 (16), 73 (30), 57 (50); HRMS (ESI) calcd
1690, 1490, 1396, 1235, 1037, 931 cm1; MS (70 eV, EI): for C23H33NSiO6Na: 470.1969 [M+Na]+; found: 470.1960.
m/z (%) 375 (M+, 1), 229 (4), 216 (40), 174 (14), 115 (5),
70 (8), 57 (84), 43 (100). 4.1.12. 3a-Benzo[1,3]dioxol-5-yl-6-oxo-3b-trimethylsila-
nyloxy-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid
4.1.10. 7-Benzo[1,3]dioxol-5-yl-1b-trimethylsilanyloxy- tert-butyl ester (17). A solution of n-butyllithium (2 M so-
2-oxa-5-aza-tricyclo[4.3.1.03,7]decane-5-carboxylic acid lution in hexane, 0.23 mL) was added dropwise to a solution
tert-butyl ester (14). A solution of n-butyllithium (2 M of diisopropylamine (0.065 mL, 0.46 mmol) in THF (5 mL)
solution in hexane, 0.3 mL) was added dropwise to a solution at 0  C under argon atmosphere. The solution was stirred at
of diisopropylamine (0.084 mL, 0.6 mmol) in THF (5 mL) 0  C for 45 min before being cooled to 78  C and treated
at 0  C under argon atmosphere. The solution was stirred with a solution of silyl ether 15 (195 mg, 0.44 mmol) in
at 0  C for 45 min before being cooled to 78  C and treated THF (2 mL). After 30 min, TMSCl (0.07 mL, 0.55 mmol)
with a solution of 13a (101 mg, 0.27 mmol) in THF (2 mL). was added. The reaction mixture was stirred at 78  C for
After 30 min, TMSCl (0.080 mL, 0.63 mmol) was added. 30 min, slowly warmed to 20  C, and quenched with satu-
The reaction mixture was stirred at 78  C for 30 min, rated NaHCO3 solution (2 mL) after 1 h. After diluting with
9452 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455

ether (30 mL), the organic layer was separated, and the was stirred at 0  C for 3 d. Ethyl acetate (30 mL) was added
aqueous layer was extracted with ether (310 mL). The to this solution, and the organic layer was washed with
combined organic layers were washed successively with saturated aqueous NaHCO3, water, and brine, dried over
saturated NaHCO3 solution, brine, dried over Na2SO4, and Na2SO4, and concentrated. The residue was purified by flash
concentrated in vacuum to give the silyl enol ether 16, which column chromatography on silica gel (petroleum/EtOAc¼
was used in the next reaction without further purification. A 3:1) to give 19a as a colorless amorphous (21 mg, 93%).
1
mixture of this residue, Pd(OAc)2 (160 mg, 0.71 mmol) in H NMR (300 MHz, CDCl3): d 6.90 (d, J¼1.6 Hz, 1H),
CH3CN (20 mL) was stirred at room temperature overnight. 6.63 (dd, J¼10.0, 1.8 Hz, 1H), 6.76 (d, J¼7.2 Hz, 1H),
The mixture was then concentrated and the brown residue 6.20 (d, J¼10.5 Hz, 1H), 5.95 (d, J¼10.5 Hz, 1H), 5.95 (s,
was purified by flash column chromatography on silica gel 2H), 4.49–4.44 (m, 1H), 4.05 (br, 0.4H), 3.88–3.78 (m,
(petroleum/EtOAc¼3:1) to afford enone 17 as a white foamy 2.3H), 3.68–3.61 (m, 0.4H), 3.38–3.32 (m, 3H), 2.98 (t,
solid (137 mg, 70%). 1H NMR (300 MHz, CDCl3): d 7.11 J¼10.0 Hz, 1H), 2.85 (br, 0.33H), 2.60 (br, 0.64H), 1.48
(d, J¼10.5 Hz, 1H), 6.84 (s, 1H), 6.78 (s, 2H), 6.29 (d, (s, 9H), 0.067 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3):
J¼10.8 Hz, 1H), 5.95 (s, 2H), 4.51–4.46 (m, 1H), 4.24 (br, d 154.6, 154.3, 147.8, 146.3, 135.3, 131.7, 131.3, 128.3,
0.45H), 4.11 (br, 0.76H), 3.89–3.81 (m, 1H), 3.67 (br, 127.9, 120.9, 108.0, 107.8, 101.1, 80.0, 79.6, 76.1, 75.3,
0.44H), 3.30–3.24 (br, 0.61H), 3.09–2.94 (m, 1H), 2.45– 72.6, 61.5, 56.0, 53.4, 52.5, 51.9, 51.3, 28.5, 27.2, 25.8,
2.30 (br, 1H), 1.44 (s, 9H), 0.05 (s, 9H) ppm; 13C NMR 0.11 ppm; IR (KBr): n 1694, 1488, 1395, 1249, 1101,
(75 MHz, CDCl3): d 197.7, 197.4, 154.4, 148.3, 147.7, 936, 879, 843 cm1; MS (70 eV, EI): m/z (%) 231 (9), 199
147.4, 147.0, 132.2, 132.0, 130.8, 120.5, 108.3, 107.1, (13), 198 (51), 73 (48), 57 (100), 41 (27); HRMS (ESI) calcd
101.3, 80.7, 80.1, 76.6, 75.7, 61.7, 54.0, 52.9, 52.3, 52.0, for C24H35O6NSiNa: 484.2126 [M+Na]+; found: 484.2129.
37.8, 36.4, 28.3, 0.23 ppm; IR (KBr): n 1697, 1504,
1488, 1394, 1250, 1164, 1113, 1040, 934, 912, 844, 4.1.15. 3a-Benzo[1,3]dioxol-5-yl-3b-hydroxy-6a-
733 cm1; MS (70 eV, EI): m/z (%) 215 (14), 214 (100), methoxy-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic
73 (27), 57 (43), 41 (13); HRMS (ESI) calcd for acid tert-butyl ester (20). To a solution of silyl ether 19a
C23H31NSiO6Na: 468.1813 [M+Na]+; found: 468.1817. (43 mg, 0.095 mmol) in THF (3 mL) was added dropwise
a solution of Bu4NF (1 M solution in THF, 0.1 mL,
4.1.13. 3a-Benzo[1,3]dioxol-5-yl-6b-hydroxy-3b-tri- 0.10 mmol) at room temperature. After 10 min, the solution
methylsilanyloxy-2,3,3a,6,7,7a-hexahydro-indole-1-car- was concentrated under reduced pressure. Purification of the
boxylic acid tert-butyl ester (18a). To a well-stirred residue by flash column chromatography on silica gel (petro-
solution of enone 17 (24 mg, 0.054 mmol) in THF (2 mL) leum/EtOAc¼1:1) afforded the alcohol 20 (36.5 mg, 99%).
at 78  C under argon atmosphere was added dropwise a 1
H NMR (300 MHz, CDCl3): d 6.94 (s, 1H), 6.88 (d,
solution of L-Selectride (1.0 M solution in THF, 0.07 mL, J¼8.1 Hz, 1H), 6.78 (d, J¼8.4 Hz, 1H), 6.26 (d, J¼
0.07 mmol) by syringe and the resulting solution was stirred 10.5 Hz, 1H), 5.96 (s, 2H), 5.92 (d, J¼11.1 Hz, 1H), 4.60
for 15 min at this temperature. The reaction mixture was (br, 1H), 4.06 (br, 0.7H), 3.93–3.86 (br, 2.73H), 3.40 (s,
quenched by the addition of CH3OH (0.2 mL) over 1 min. 3H), 3.13 (t, J¼9.3 Hz, 1H), 2.77 (br, 0.6H), 2.57 (br,
The resulting slurry was allowed to warm to room tempera- 0.8H), 1.76 (br, 1H), 1.54 (s, 1H), 1.48 (s, 8H) ppm; 13C
ture slowly, and H2O (3 mL) was added. The aqueous layer NMR (75 MHz, CDCl3): d 154.5, 148.1, 146.7, 134.8,
was extracted with CHCl3 (320 mL), and the combined 132.4, 127.6, 120.7, 109.8, 108.3, 107.6, 101.2, 80.1, 74.7,
organic layers were dried over Na2SO4, and concentrated 72.4, 61.2, 56.1, 53.6, 50.8, 28.5, 27.6 ppm; IR (KBr):
under reduced pressure. Purification of the residue by flash n 3404, 1674, 1605, 1487, 1409, 1320, 1132, 930 cm1;
column chromatography on silica gel (petroleum/EtOAc MS (70 eV, EI): m/z (%) 389 (M+, 1), 259 (1), 249 (21),
10:1) afforded the allylic alcohol 18a as white crystal 230 (19), 199 (10), 198 (13), 115 (10), 57 (100), 41 (26);
(24 mg, 95%). Mp 168–170  C; 1H NMR (400 MHz, HRMS (ESI) calcd for C21H31N2O6: 407.2177 [M+NH4]+;
CDCl3): d 6.81 (s, 1H), 6.75 (s, 2H), 6.26 (dd, J¼9.9, found: 407.2174.
3.6 Hz, 1H), 6.20 (d, J¼9.9 Hz, 1H), 5.94 (s, 2H), 4.40 (t,
J¼10.0 Hz, 1H), 4.10 (br, 1H), 3.94 (br, 1H), 3.73 (br, 4.1.16. 3b-Acetoxy-3a-benzo[1,3]dioxol-5-yl-6a-meth-
1H), 3.07 (dd, J¼13.6, 8.4 Hz, 1H), 2.60 (br, 0.7H), 1.84 oxy-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid
(br, 0.6H), 1.68–1.47 (m, 1H), 1.48 (s, 9H), 0.02 (s, 9H) tert-butyl ester (21). A solution of alcohol 20 (30 mg,
ppm; 13C NMR (100 MHz, CDCl3): d 155.2, 148.0, 146.5, 0.077 mmol), DMAP (2 mg), pyridine (0.03 mL), and
135.1, 131.8, 128.3, 120.5, 108.1, 107.6, 101.1, 80.3, 77.3, Ac2O (0.04 mL) in CH2Cl2 (2 mL) was stirred at 0  C for
63.6, 60.3, 52.9, 51.8, 29.7, 28.5, 0.11 ppm; IR (KBr): 2 h. Ethyl acetate (20 mL) was added to the solution and
n 3424, 1690, 1399, 1248, 1111, 1037, 936, 844 cm1; the organic phase was washed with 1 N HCl, water, saturated
MS (70 eV, EI): m/z (%) 447 (M+, 0.2), 198 (100), 199 aqueous NaHCO3, water, and brine, dried over Na2SO4, and
(14), 73 (21), 57 (31), 41 (10); HRMS (ESI) calcd for concentrated. Purification of the residue by flash column
C23H33NSiO6Na: 470.1969 [M+Na]+; found: 470.1974. chromatography on silica gel (petroleum/EtOAc¼2:1) pro-
vided 21 (33 mg, 99%). 1H NMR (400 MHz, CDCl3):
4.1.14. 3a-Benzo[1,3]dioxol-5-yl-6a-methoxy-3b-tri- d 6.93 (d, J¼1.6 Hz, 1H), 6.87 (dd, J¼8.2, 1.8 Hz, 1H),
methylsilanyloxy-2,3,3a,6,7,7a-hexahydro-indole-1-car- 6.77 (d, J¼8.2 Hz, 1H), 6.17 (dd, J¼10.2, 2.8 Hz, 1H),
boxylic acid tert-butyl ester (19a). To a solution of allylic 5.96 (s, 2H), 5.86 (d, J¼10.2 Hz, 1H), 5.59 (t, J¼6.4 Hz,
alcohol 18a (22 mg, 0.049 mmol) and NEt3 (0.10 mL, 0.5H), 5.52 (t, J¼6.4 Hz, 0.5H), 4.12 (d, J¼3.6 Hz, 0.5H),
0.72 mmol) in THF (2 mL) was added Ms2O (54 mg, 4.05 (d, J¼4.4 Hz, 0.5H), 3.98–3.92 (m, 1H), 3.85 (br,
0.31 mmol) at 0  C and the solution was stirred for 1 h. To 1H), 3.40 (s, 3H), 3.17 (dd, J¼11.2, 6.0 Hz, 0.5H), 3.08
this solution was added MeOH (2 mL) and the solution (dd, J¼10.8, 7.2 Hz, 0.5H), 2.61 (t, J¼6.0 Hz, 0.5H),
 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455 9453

2.40–2.33 (m, 0.5H), 2.02 (s, 3H), 1.86–1.81 (m, 0.5H), J¼13.6, 4.4 Hz, 0.6H), 2.24 (td, J¼13.6, 4.4 Hz, 1H), 2.05
1.76–1.71 (m, 0.5H), 1.47 and 1.25 (2s, 9H) ppm; 13C (dd, J¼13.6, 4.0 Hz, 1H), 2.02 (br, 0.5H) ppm; 13C NMR
NMR (100 MHz, CDCl3): d 170.1, 154.2, 148.1, 146.8, (100 MHz, CDCl3): d 147.9, 147.8, 146.9, 146.6, 135.7,
134.5, 131.3, 130.5, 129.3, 128.5, 120.4, 108.2, 107.6, 134.1, 132.9, 132.5, 128.0, 127.3, 126.2, 126.0, 109.5,
101.2, 80.2, 75.8, 75.1, 72.0, 59.8, 56.2, 49.3, 49.1, 28.5, 108.4, 102.9, 102.8, 101.1, 88.4, 85.8, 78.6, 78.1, 72.4,
27.8, 26.5, 20.9 ppm; IR (KBr): n 2975, 1744, 1694, 1489, 72.1, 62.0, 58.0, 56.9, 56.6, 56.5, 51.9, 50.7, 50.3, 27.7,
1392, 1238, 1039, 935 cm1; MS (70 eV, EI): m/z (%) 431 27.4 ppm; IR (KBr): n 3383, 2924, 1482, 1246, 1087,
(M+, 1), 291 (13), 198 (20), 71 (20), 57 (100), 43 (54), 41 1036, 933, 732 cm1; MS (70 eV, EI): m/z (%) 317 (M+,
(26); HRMS (ESI) calcd for C23H33N2O7: 449.2282 9), 284 (14), 268 (16), 227 (11), 209 (17), 201 (11), 200
[M+NH4]+; found: 449.2276. (13), 199 (11), 103 (12), 102 (11), 88 (28), 73 (38), 71
(44), 47 (55), 41 (71), 39 (24); HRMS (ESI) calcd for
4.1.17. 3b-Acetic acid-3a-benzo[1,3]dioxol-5-yl-1-for- C17H20NO5: 318.1337 [M+H]+; found: 318.1334.
myl-6a-methoxy-2,3,3a,6,7,7a-hexahydro-1H-indol-3-yl
ester (22). To a solution of 21 (26 mg, 0.06 mmol) in 4.1.19. (±)-Pretazettine (2). To a well-stirred solution of 1
ClCH2CH2Cl (2 mL) was added CF3COOH (0.1 mL, (7.0 mg, 0.022 mmol) in MeOH (3 mL) was added methyl
1.3 mmol) at room temperature. After 3 h, solid K2CO3 iodine (0.38 mL, 6.2 mmol). The reaction mixture was
(ca. 200 mg) was added to the solution, and a small amount stirred for 6 h before removing the methanol in vacuum.
of Na2SO4 was also added. The undissolved material was The residue was treated with aqueous hydrochloric acid
filtered off and the solvent was removed. DMF (1 mL) and (2 mL, 0.01 M) for 1 min and the pH of the solution was
HCO2Me (2 mL) were added to this crude amine and the adjusted to 8 with saturated aqueous NaHCO3. The mixture
solution was warmed at 90  C for 6 h. The solvent was was extracted with CHCl3 (65 mL), and the organic
removed under reduced pressure and the crude product portions were combined, dried, and concentrated. The crude
was purified by flash column chromatography on silica gel product was purified by flash column chromatography on
(petroleum/EtOAc¼3:1) to give 22 as a white film (19 mg, silica gel (MeOH/Et3N/CHCl3¼10:3:87) to afford 2 as a
88%). 1H NMR (400 MHz, CDCl3): d 8.31 (s, 0.62H), white film (6.9 mg, 95%). 1H NMR (400 MHz, CDCl3):
8.25 (s, 0.46H), 6.89 (dd, J¼4.8, 1.6 Hz, 1H), 6.86–6.83 d 6.87 (s, 1H), 6.77 (s, 1H), 6.13 (s, 1H), 5.93 (s, 2H), 5.89
(m, 1H), 6.77 (dd, J¼8.4, 2.8 Hz, 1H), 6.24–6.19 (m, 1H), (d, J¼10.8 Hz, 1H), 5.52 (d, J¼10.4 Hz, 1H), 4.34 (dd,
5.96 (s, 2H), 5.88 (d, J¼10.4 Hz, 1H), 5.67 (t, J¼6.0 Hz, J¼11.2, 7.2 Hz, 1H), 4.18–4.14 (m, 1H), 3.44 (s, 3H),
0.63H), 5.50 (t, J¼7.2 Hz, 0.5H), 4.22 (dd, J¼8.0, 3.4 Hz, 3.01–2.96 (m, 2H), 2.67 (dd, J¼9.6, 8.0 Hz, 1H), 2.55–
1H), 4.09–4.02 (m, 1H), 3.89 (dd, J¼12.4, 4.0 Hz, 1H), 2.48 (m, 1H), 2.50 (s, 3H), 1.77 (dd, J¼11.2, 10.0 Hz, 1H)
3.40 (s, 1.35H), 3.39 (s, 1.70H), 3.31–3.25 (m, 1H), 2.75 ppm; 13C NMR (100 MHz, CDCl3): d 147.7, 146.5, 135.4,
(t, J¼8.4 Hz, 0.48H), 2.31–2.24 (m, 0.56H), 2.03 (s, 129.1, 128.9, 127.4, 108.1, 104.9, 101.2, 93.9, 73.9, 73.1,
1.75H), 1.99 (s, 1.35H), 1.99–1.95 (m, 0.64H), 1.69–1.65 64.1, 56.1, 54.1, 46.2, 43.3, 30.2 ppm; IR (KBr): n 3350,
(m, 0.68H) ppm; 13C NMR (100 MHz, CDCl3): d 170.3, 1482, 1254, 1089, 1036, 934 cm1; MS (70 eV, EI): m/z
170.0, 161.6, 160.6, 148.3, 147.0, 133.9, 133.6, 132.3, (%) 331 (M+, 4), 316 (3), 247 (25), 225 (7), 201 (9), 139
129.6, 129.3, 127.7, 120.3, 120.0, 108.4, 108.3, 107.4, (8), 128 (9), 115 (18), 85 (60), 83 (100), 82 (10), 77 (12),
101.3, 75.0, 74.9, 71.6, 71.1, 59.5, 59.4, 56.5, 56.3, 52.8, 74 (18), 70 (27), 57 (16), 55 (16), 44 (37), 42 (31); HRMS
51.5, 48.5, 47.3, 30.9, 26.1, 20.9, 20.8 ppm; IR (KBr): (ESI) calcd for C18H22NO5: 332.1492 [M+H]+; found:
n 3385, 2922, 1741, 1668, 1378, 1237, 1069, 1037 cm1; 332.1486.
MS (70 eV, EI): m/z (%) 359 (M+, 2), 198 (8), 115 (8), 84
(67), 49 (35), 47 (42), 43 (100); HRMS (ESI) calcd for 4.1.20. (±)-Tazettine (3). To a well-stirred solution of 2
C19H22NO6: 360.1442 [M+H]+; found: 360.1437. (6.9 mg, 0.0208 mmol) in MeOH (1.0 mL) was added
0.1 M NaOH (0.7 mL, 0.07 mmol), and the reaction mixture
4.1.18. (±)-Haemanthidine (1). A solution of formamide 22 was stirred for 30 min before removing the MeOH in
(15 mg, 0.042 mmol) in freshly distilled POCl3 (0.5 mL) vacuum. The aqueous layer was extracted with CHCl3
was stirred at 80  C under sealed tube. After 4 h, the mixture (75 mL), and the organic portions were combined, dried,
was cooled to room temperature and the excess POCl3 was and concentrated. The crude product was purified by flash
removed in vacuum. Aqueous THF (1:1, 1.0 mL) was added column chromatography on silica gel (MeOH/CHCl3¼1:9)
and the solution was stirred at room temperature for 1 h. The to afford 3 as a white film (6.3 mg, 91%). 1H NMR
solvent was removed under reduced pressure. The residue (400 MHz, CDCl3): d 6.86 (s, 1H), 6.51 (s, 1H), 6.16 (d,
was dissolved in MeOH (1.0 mL), and K2CO3 (50 mg, J¼10.2 Hz, 1H), 5.91 (s, 2H), 5.62 (d, J¼10.2 Hz, 1H),
0.36 mmol) was added to the solution. The mixture was 4.97 (d, J¼15.0 Hz, 1H), 4.65 (d, J¼15.0 Hz, 1H), 4.16–
stirred at room temperature for additional 1 h, and filtered. 4.13 (m, 1H), 3.47 (s, 3H), 3.32 (d, J¼10.2 Hz, 1H), 2.88
The filtrate was removed under vacuum and the resulted (br, 1H), 2.70 (d, J¼10.2 Hz, 1H), 2.42 (s, 3H), 2.28–2.22
crude product was purified by flash column chromatography (m, 1H), 1.67–1.60 (m, 1H) ppm; 13C NMR (100 MHz,
on silica gel (CHCl3/MeOH¼6:1) to give 1 (10 mg, 76%) as CDCl3): d 146.7, 146.5, 130.8, 128.6, 128.1, 125.5, 109.3,
an opaque film. 1H NMR (400 MHz, CDCl3): d 6.98 (s, 104.0, 102.1, 101.0, 72.9, 70.1, 65.6, 62.1, 56.1, 49.9,
0.40H), 6.83 (s, 0.50H), 6.81 (s, 0.41H), 6.78 (s, 0.48H), 41.9, 26.8 ppm; IR (KBr): n 3196, 1475, 1453, 1380, 1127,
6.44–6.35 (m, 2H), 5.94–5.92 (m, 2H), 5.76 (s, 0.42H), 883, 706 cm1; MS (70 eV, EI): m/z (%) 331 (M+, 6), 316
5.11 (s, 0.47H), 4.24 (dd, J¼14.4, 7.0 Hz, 0.43H), 3.95– (3), 298 (5), 247 (56), 201 (13), 199 (15), 185 (10), 152
3.90 (m, 2.5H), 3.66 (dd, J¼12.8, 4.4 Hz, 0.5H), 3.40 and (20), 113 (12), 112 (11), 97 (23), 71 (64), 57 (87), 55 (51),
3.39 (2s, 3H), 3.42–3.38 (m, 0.5H), 3.28 (dd, J¼12.4, 49 (60), 43 (100), 42 (95), 41 (80); HRMS (ESI) calcd for
2.8 Hz, 0.5H), 3.03 (dd, J¼13.6, 2.0 Hz, 0.5H), 2.36 (td, C18H22NO5: 332.1492 [M+H]+; found: 332.1490.
9454 F.-M. Zhang et al. / Tetrahedron 62 (2006) 9446–9455

4.1.21. 3a-Benzo[1,3]dioxol-5-yl-6a-hydroxy-3b-tri- mixture was stirred for 8 h at room temperature, saturated

methylsilanyloxy-2,3,3a,6,7,7a-hexahydro-indole-1-car- aqueous NaHCO3 (1 mL) was added, and the organic layer
boxylic acid tert-butyl ester (18b). To a solution of 17 was separated, and the aqueous layer was extracted with
(150 mg, 0.52 mmol) in methanol (10 mL) was added CHCl3 (35 mL). The combined organic phases were dried
CeCl3$7H2O (193 mg, 0.52 mmol) at room temperature over Na2SO4 and concentrated under reduced pressure to
and then NaBH4 (49 mg, 1.3 mmol) was added. After stir- give crude amine. A solution of formalin (0.05 mL) in
ring for 5 min, the reaction mixture was quenched with MeOH (0.1 mL) was added to this amine. After the solution
H2O (0.5 mL). The solution was concentrated, and the resi- was stirred for 10 min, 6 M aqueous hydrochloric acid
due was dissolved in CH2Cl2 (50 mL) and washed with H2O (2.5 mL) was added. The mixture was warmed to 40  C
(10 mL) back extracting the aqueous phase with CH2Cl2 for 10 h, cooled to room temperature, and then basified by
(50 mL). The combined organic portions were concentrated the dropwise addition of NH3$H2O. The resultant mixture
and the residue was purified by flash column chromato- was extracted with CHCl3 (510 mL), and the organic layer
graphy on silica gel (petroleum/EtOAc¼3:1) to give 18b was dried (Na2SO4) and concentrated. The residue was puri-
as a white amorphous (90 mg, 63%) and 18a as white crystal fied by column chromatography on silica gel (CHCl3/
(46 mg, 32%). Compound 18b: 1H NMR (400 MHz, MeOH¼10:1) to afford 4 (10 mg, 76%, two steps). 1H
CDCl3): d 6.90 (d, J¼1.6 Hz, 1H), 6.85 (dd, J¼8.0, NMR (400 MHz, CDCl3): d 6.81 (s, 1H), 6.49 (s, 1H),
2.0 Hz, 1H), 6.78 (br, 1H), 6.11 (d, J¼10.8 Hz, 1H), 5.92 6.27 (s, 2H), 5.91 (d, J¼2.0 Hz, 2H), 4.34 (d, J¼17.0 Hz,
(d, J¼10.0 Hz, 1H), 5.92 (s, 2H), 4.41 (br, 1H), 4.28 (br, 1H), 4.02 (dd, J¼10.0, 6.0 Hz, 1H), 3.98–3.97 (m, 1H),
1H), 3.99 (br, 0.5H), 3.88 (br, 0.5H), 3.81 (dd, J¼10.0, 3.72 (d, J¼17.0 Hz, 1H), 3.41 (s, 3H), 3.39–3.37 (m, 2H),
7.2 Hz, 1H), 3.63 (br, 0.5H), 2.95 (t, J¼10.0 Hz, 1H), 2.79 3.23 (dd, J¼13.2, 4.4 Hz, 1H), 2.15–2.05 (m, 2H) ppm;
13
(br, 0.5H), 2.57 (d, J¼12.4 Hz, 0.5H), 1.62 (br, 1H), 1.46 C NMR (100 MHz, CDCl3): d 146.6, 146.3, 136.2,
(s, 9H), 0.08 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): 135.5, 126.8, 123.6, 106.9, 103.2, 100.9, 80.1, 76.1, 66.2,
d 154.7, 147.9, 146.4, 135.5, 133.9, 128.0, 127.7, 120.8, 63.6, 61.3, 55.8, 50.3, 30.3 ppm; IR (KBr): n 3363, 2920,
118.9, 108.0, 107.7, 106.8, 101.1, 80.1, 79.6, 76.2, 75.5, 1654, 1481, 1238, 1036, 935 cm1; MS (70 eV, EI): m/z
61.6, 53.1, 53.0, 52.3, 51.9, 51.4, 28.54, 28.46, (%) 270 (17), 269 (87), 268 (30), 240 (40), 224 (27), 211
0.12 ppm; IR (KBr): n 3405, 1690, 1488, 1397, 1250, (19), 181 (84), 153 (26), 115 (47), 77 (31), 71 (40), 69
879, 843 cm1; MS (70 eV, EI): m/z (%) 447 (M+, 0.3), (44), 57 (59), 55 (63), 43 (100), 41 (48); HRMS (ESI) calcd
216 (100), 198 (37), 73 (45), 57 (78); HRMS (ESI) calcd for C17H20NO4: 302.1387 [M+H]+; found: 302.1382.
for C23H33NSiO6Na: 470.1969 [M+Na]+; found: 470.1977.

4.1.22. 3a-Benzo[1,3]dioxol-5-yl-6b-methoxy-3b-tri- Acknowledgements

methylsilanyloxy-2,3,3a,6,7,7a-hexahydro-indole-1-car-
boxylic acid tert-butyl ester (19b). To a solution of 18b This work was financially supported by the NSFC (No.
(34 mg, 0.076 mmol) and NEt3 (0.15 mL, 1.08 mmol) in 20021001, 203900501) and Chang Jiang Scholars of
THF (2 mL) was added Ms2O (92 mg, 0.53 mmol) at 0  C Program of China.
and the solution was stirred for 1 h. To this solution was
added MeOH (2 mL) and the solution was stirred at 0  C
for 3 d. Ethyl acetate (50 mL) was added to this solution, References and notes
and the organic layer was washed with saturated aqueous
NaHCO3, water, and brine, dried over Na2SO4, and concen- 1. (a) Martin, S. F. The Alkaloids; Brossi, A., Ed.; Academic:
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graphy on silica gel (petroleum/EtOAc¼3:1) to give 19b The Alkaloids; Cordell, G. A., Ed.; Academic: New York,
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2H), 6.16 (dd, J¼12.3, 4.2 Hz, 1H), 6.01 (d, J¼11.7 Hz, 111–126.
1H), 5.95 (s, 2H), 4.34 (t, J¼6.3 Hz, 1H), 4.05–3.96 (br, 2. (a) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.; Matsuda, H.;
1H), 3.71–3.66 (m, 2H), 3.55 (dd, J¼10.5, 6.3 Hz, 0.5H), Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119–1124; (b)
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