Formal synthesis of (-)-cephalotaxine

Article abstract of DOI:10.1002/hlca.201200486

A formal synthesis of (-)-cephalotaxine (1) by means of a highly stereoselective radical carboazidation process is reported. The synthesis begins with the protected (S)-cyclopent-2-en-1-ol derivative 10 and uses the concept of self-reproduction of a stereogenic center (Schemes5 and 6). For this purpose, the double bond adjacent to the initial chiral center in 10 is converted into an acetonide after stereoselective dihydroxylation. The initial alcohol function is used to build an exocyclic methylene group suitable for the carboazidation process 8→7 (Scheme7). Finally the protected diol moiety is converted back to an alkene (14→15→6) and used for the formation of ring B via a Heck reaction (6→(-)-16; Scheme8). Copyright

Full text of DOI:10.1002/hlca.201200486

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Formal Synthesis of (ꢀ)-Cephalotaxine
by Monica G. GonÅalves-Martin, Sarunas Sigmantas, and Philippe Renaud*
University of Bern, Department of Chemistry and Biochemistry, Freiestrasse 3, CH-3012 Bern
(phone: þ 41-31-6314359; e-mail: philippe.renaud@ioc.unibe.ch)
Dedicated with great admiration to Prof. Dieter Seebach on the occasion of his 75th birthday
A formal synthesis of (ꢀ)-cephalotaxine (1) by means of a highly stereoselective radical
carboazidation process is reported. The synthesis begins with the protected (S)-cyclopent-2-en-1-ol
derivative 10 and uses the concept of self-reproduction of a stereogenic center (Schemes 5 and 6). For this
purpose, the double bond adjacent to the initial chiral center in 10 is converted into an acetonide after
stereoselective dihydroxylation. The initial alcohol function is used to build an exocyclic methylene
group suitable for the carboazidation process 8 ! 7 (Scheme 7). Finally the protected diol moiety is
converted back to an alkene (14 ! 15 ! 6) and used for the formation of ring B via a Heck reaction (6 !
(ꢀ)-16; Scheme 8).
Introduction. – (ꢀ)-Cephalotaxine (1) is the parent structure of the Cephalotaxus
alkaloids, a unique class of benzazepine alkaloids [1]. Its original pentacyclic structure
and the clinically established therapeutic potential of its ester derivatives (i.e.,
harringtonine and homoharringtonine) as antileukemia agents make it a popular target
for synthesis as illustrated by the early work of Auerbach and Weinreb [2] and
Semmelhack and co-workers [3]. Several strategies for the construction of the ABCD
ring system have been developed. One of the most common strategy, pioneered by
Semmelhack and co-workers, consists of forming the B-ring by starting from a
spirocyclic precursor containing the ACD rings (Scheme 1) [3]. Several different
cyclization procedures leading to ring B involving radical cyclization [4], ketone
arylation [3][5], FriedelꢀCrafts alkylation [6], intramolecular Heck reactions [7],
intramolecular Schmidt reaction [8], and transannular conjugate addition [9] have been
reported.
Scheme 1. (ꢀ)-Cephalotaxine (1) and the B-Ring-Closing Synthetic Strategy
The synthesis of the key spirocyclic intermediates containing the rings ACD in
optically pure form is of primary importance for the efficacy of the whole synthesis, and
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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improvement of this part of the synthesis is still strongly desired. Recently, we have
reported a radical carboazidation procedure very well suited for the preparation of
secondary and tertiary C-atom centers substituted by an amino group [10]. This process
was the key step of our recent synthesis of lepadiformines [11], cylindricine C [12],
hyacinthacine A1 [13], and indolizidines [14]. The preparation of the spirocyclic
systems such as the core of (ꢁ)-des(methylamino)-FR901483 via carboazidation of a
methylenecycloalkane derivative followed by reductive lactamization was reported
(Scheme 2) [10c]. Here, we extend this approach to the synthesis of optically pure (ꢀ)-
cephalotaxine (1). A method allowing an efficient control of the configuration of the
amino-substituted spiro center was developed.
Scheme 2. Preparation of the Spirocyclic Core of (ꢁ)-Des(methylamino)-FR901483 [10c]
Nagasakaꢀs Intermediate 2 from 2-Methylenecyclopentanol (3; R ¼ H). – The
spirocyclic amide 2, an intermediate in Nagasaka and co-workersꢂ synthesis of
cephalotaxine [15], was selected as target for our approach. Compound 2 has been
prepared with moderate diastereoselectivities by Royer and co-workers. [16] and was
expected to be readily prepared from protected (1S)-2-methylenecyclopentanol
derivative (S)-3 according to Scheme 3. The stereochemical outcome of the key
carboazidation step was examined first on protected methylenecyclopentanol deriv-
atives. Racemic 2-methylenecyclopentanol was protected as an acetate ester 3a, a (tert-
butyl)dimethylsilyl ether 3b, and a (tert-butyl)diphenylsilyl ether 3c. The carboazida-
tion of the protected allylic alcohols 3a – 3c afforded the expected azido derivatives 4a –
4c in 63 – 88% yield. However, the level of stereoselectivity did not exceed a trans/cis
1.2 :1 ratio even with the large (tert-butyl)diphenylsilyl protecting group [17]. A 1:1
diastereoisomer mixture 4a was reduced with H2 over Pd/C to the amine that
underwent lactamization upon heating in the presence of triethylamine to afford 5a as a
single trans-isomer. The cis-isomer was isolated as a noncyclized amino ester. Under
similar conditions, trans-4b and trans-4c afforded the spirolactams 5b and 5c in 75% and
87% yield, respectively.

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Scheme 3. Retrosynthesis of Nagasaka Intermediate 2 and Configuration of the Carboazidation Step
The silylated (1S)-2-methylenecyclopentanol derivative (S)-3c (96.5% ee) was
prepared from racemic cyclopentanol via enzymatic enantioselective acetylation with
hog-pancreas lipase (PPL) according to the procedure developed by Burgess and
Jennings for allylic alcohols [18]. Carboazidation of (S)-3c afforded, as expected from
the racemic series, azido derivative 4c in 89% yield as a 1.2 :1 mixture of isomers
(Scheme 4). After separation by flash chromatography1), the major azido ester (þ)-
(1R,2S)-4c was converted into the spirolactam (ꢀ)-(5R,6S)-5c by reductive lactamiza-
tion. Desilylation with Bu4NF and oxidation of the free alcohol with pyridinium
chlorochromate (PCC) of the free alcohol afforded Nagasaka intermediate (ꢀ)-(R)-2.
Conversion of this intermediate into (ꢀ)-cephalotaxine (1) according to Kuehneꢂs
procedure [6b] has been reported by Nagasaka and co-workers [15] and requires 10
steps.
Scheme 4. Synthesis of Optically Pure Nagasaka Intermediate (ꢀ)-(R)-2
1
)
When the flash chromatography was run with AcOEt/hexane as eluent, the minor diastereoisomer
decomposed on the column, and only the trans-isomer (þ)-(1R,2S)-4c was isolated in 59% yield
from (S)-3c.

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Moriꢀs Intermediate (ꢀ)-16 from (1S)-Cyclopent-2-en-1-ol (9). – Since the first
approach leading to Nagasakaꢂs intermediate did not allow an efficient control of the
configuration of the spiro center, another approach starting from (1S)-cyclopent-2-en-
1-ol (9) [19] was developed. The key disconnections are depicted in Scheme 5.
Formation of the B ring will be performed from 6 via a Heck intramolecular cross-
coupling reaction according to the work of Tietze and Schirok [7a][7b] and Yoshida and
co-workers [7d]. The C¼C bond necessary for the Heck cross-coupling process
corresponds to the one of cyclopentenol 9. Remarkably, this C¼C bond was used to
control the configuration of the carboazidation step by temporary formation of an
acetonide protected diol in compounds 7 and 8. A high level of stereoselectivity is
expected for the carboazidation step due to the bicyclic nature of alkene 8. Thus, the
stereogenic center of cyclopentenol 9 will be used to control the configuration of the
diol, then be destroyed when the methylenecyclopentane derivative 8 is built, and
finally by formed again during the carboazidation step leading to 7. This strategy
corresponds to the self-regeneration of stereogenic centers (SRS), a general concept of
asymmetric synthesis developed by Seebach and co-workers [20].
Scheme 5. Key Disconnections for a Stereoselective Synthesis of (ꢀ)-Cephalotaxine (1) by Means of the
SRS Concept
The synthesis of the methylenecyclopentane derivative 8 started with the silyl ether
10, easily prepared on large scale in 96% ee according to our recently published
procedure [19] (Scheme 6). Dihydroxylation of the C¼C bond of 10 with OsO4
afforded diol 11 as a single diastereoisomer that was protected as an acetonide.
Desilylation with Bu4NF fluoride, oxidation of the alcohol to the corresponding ketone
with pyridinium dichromate (PDC), and finally Wittig-type methylenation afforded the
bicyclic alkene 8.
Scheme 6. Preparation of the Methylenecyclopentane 8
The carboazidation of 8 was run under tin-free conditions with ethyl iodoacetate
and pyridine-3-sulfonyl azide by using triethylborane and air to initiate the radical
process (Scheme 7) [21]. As anticipated, the azido ester 7 was obtained with a very high

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diastereoselectivity (drꢂ 97:3). This high stereoselectivity resulted from an exo-
selective azidation of the bicyclic radical according to model A (Scheme 7). Reduction
of the azide with H2 and Pd/CaCO3 as a catalyst afforded directly the desired
spirolactam 12. The whole sequence depicted in Schemes 6 and 7 allowed to convert the
protected allyl alcohol 10 into the spirolactam 12 in 7 steps and ꢂ 35% yield with
excellent control of the configuration.
Scheme 7. Preparation of the Key Lactam 12 via Highly Stereoselective Carboazidation
For the conversion of 12 to (ꢀ)-cephalotaxine (1), spirolactam 12 was first reduced
with Red-Alꢃ to the corresponding spirocyclic amine (Scheme 8). The crude amine was
N-alkylated with nosylate 13 to afford 14 in 83% yield from 12. After hydrolysis of the
acetonide, several procedures were examined for the direct conversion of the diol to the
alkene but none of them was successful. Finally, conversion of the diol to the
thiocarbonate 15 with 1,1’-(thiocarbonyl)bis[1H-imidazole] followed by treatment with
1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (CoreyꢀHopkins reagent) [22] afford-
ed the desired alkene 6 in 80% yield. As anticipated and in contrast to the approach
developed by Hayes and co-workers [6j], no racemization took place during the
synthesis of 6. Optically active 6 has been recently prepared by Zhao and Mariano [23],
but the key Heck cyclization has only been reported for racemic 6 by Yoshida and co-
workers [7d]. Formation of ring B via Heck intramolecular reaction according to Tietze
and Schirokꢂs procedure [7a][7b] with Hermann and co-workersꢂ catalyst [24] afforded
(ꢀ)-16 in 46% yield2), an advanced intermediate for the synthesis of (ꢀ)-cephalotaxine
(1). The physical and spectroscopic properties of 1 matches the one reported by Mori,
Tietze, Hayes, and their co-workers [6d][6j][7a][7b]. Conversion of 16 to (ꢀ)-
cephalotaxine (1) in 4 steps has been described by Isono and Mori [6d].
Conclusions. – We developed a formal synthesis of (ꢀ)-cephalotaxine (1) based on a
radical carboazidation process. The starting material was (1S)-cyclopent-2-en-1-ol, a
chiral building block easily available on a large scale. Remarkably, all chemical
2
)
Tietze and Schirok reported the cyclization of the corresponding aryl bromide to 16 in 81% yield
[7a][7b]. Yoshida and co-workers obtained 16 from iodide 6 in 60% yield [7d]. In our case, no
attempt to optimize the cyclization was undertaken.

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Scheme 8. Cephalotaxine Synthesis, Formation of Ring B
transformations occured with excellent stereoselectivity. The stereogenic center of
(1S)-cyclopent-2-en-1-ol was used to control all the asymmetric centers of the target
molecules. For this purpose, it was destroyed and rebuilt as a quaternary amino-
subtituted C-atom center following the concept of self-regeneration of stereogenic
centers.
This work was supported by the Swiss National Science Foundation (Grant 20-135087).
Experimental Part
1. General. All reactions were performed under N2, heat-gun dried glassware were used, and
standard precautions against moisture were taken. Commercial reagents were used as received. Solvents
for reactions (distilled THF, Et2O, benzene, toluene, and CH2Cl2) were purified and dried by filtration
through columns of dried alumina under a positive pressure of Ar. Solvents for extraction and flash
column chromatography were of technical grade and were distillated prior to use. TLC: SiO2 60 F254
plates. Flash column chromatography (FC): Silica gel 60 (SiO2; 40 – 60 mm). GC: CE-Instruments HR-
GC, series 8532; Macherey-Nagel Optima d-3 column i.d. 0.25 mm, 30 m. M.p.: Bꢀchi-B-545 apparatus;
uncorrected. IR Spectra: Jasco-FT-IR-460-Plus spectrometer, equipped with a Specac-MKII-Golden-
1
Gate single-reflection diamond ATR system; ˜n in cmꢀ1. H- and 13C-NMR Spectra: Bruker-Avance-300
spectrometer, at 300 (1H) and 75 MHz (13C), or Bruker-Avance-II-400 spectrometer, at 400 (1H) and
100 MHz (13C); at 228 unless otherwise stated, d in ppm rel. to CHCl3 as internal standard (d(H) 7.26 and
d(C) 77.0), J in Hz. Low and high-resolution MS: Waters-Micromass-Autospec-Q spectrometer in the EI
mode at 70 eV; in m/z (rel. %). GC/MS: Finnigan-Trace-GC-2000 gas chromatograph equipped with an
autosampler and a Finnigan-Trace-MS mass-selective detector.

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2. General Procedure A. To a stirred soln. of a methylenecyclopentane derivative (1.0 mmol) in dry
benzene (2.0 ml) were added PhSO2N3 (550 mg, 3.0 mmol), ethyl iodoacetate (124 mg, 0.12 ml,
t
1.0 mmol), Bu6Sn2 (870 mg, 0.76 ml, 1.5 mmol), and BuON¼NOtBu (6 mg, 0.03 mmol). The resulting
mixture was heated under reflux and N2. After 2 h, a second portion of tBuON¼NOtBu (6 mg,
0.03 mmol) was added, and the mixture was further heated under reflux for 2 h. The solvent was
evaporated and the crude product filtered through SiO2. Elution with hexane allowed to remove tin
residues, and a mixture of hexane/AcOEt 9 :1 afforded a crude product that was further purified by FC
(hexane/AcOEt).
Caution: Since organic azides are capable of exploding, it is strongly recommended to apply standard
safety rules and to use a safety shield.
3. General Procedure B. To a stirred soln. of azido derivative (1.0 mmol) in dry EtOH (4.0 ml) was
added 10% Pd/C (30 wt.-%). The mixture was stirred under H2 (30 bar) for 36 h. The slurry was filtered
through Celiteꢃ, and the resulting soln. was treated with Et3N (5.0 mmol, 0.70 ml) and heated under
reflux for 4 h. Then the solvent was evaporated and the residue purified by FC (AcOEt/MeOH).
4. Synthesis of the Nagasaka Intermediate 2. 2-Methylenecyclopentyl Acetate (3a). Acetic anhydride
(10 ml, 106 mmol) and pyridine (2 ml, 24 mmol) were added to 2-methylenecyclopentanol [25] (0.98g,
10 mmol). After stirring for 18 h at r.t., 1n aq. NaHCO3 was added slowly. The resulting mixture was
extracted with AcOEt (3 ꢃ 50 ml), the combined org. phase washed with dil. HCl soln. (3 ꢃ 30 ml) and
brine (2 ꢃ 50 ml), dried (Na2SO4), and concentrated, and the residue purified by FC (hexane/AcOEt
95 :5): 3a (1.24 g, 89%). Colorless oil. Physical and spectral data: in accordance with [26].
(tert-Butyl)dimethyl[(2-methylenecyclopentyl)oxy]silane (¼1-{[1,1-Dimethylethyl)dimethylsilyl]-2-
methylenecyclopentane; 3b). To a soln. of 2-methylenecyclopentanol (672 mg, 7 mmol) and 2,6-lutidine
t
(¼2,6-dimethylpyridine; 0.89 ml, 7.7 mmol) in CH2Cl2 (10 ml) at 08 was added dropwise BuMe2SiO-
SO2CT3 (1.77 ml, 7.7 mmol). The mixture was stirred at 08 for 2 h, and the reaction was stopped by adding
20 ml of sat. aq. NH4Cl soln. The aq. phase was extracted with CH2Cl2 (3 ꢃ 20 ml), the combined org.
phase washed with brine (20 ml), dried (Na2SO4), and concentrated, and the residue purified by FC
(hexane/AcOEt 98.5 :1.5): 3b (1.08 g, 73%). Colorless oil. Rf (hexane/AcOEt 98 :2) 0.26. IR (film): 3080,
1
2955, 1664, 835. H-NMR (300 MHz, CDCl3): 5.05 – 5.02 (m, 1 H); 4.95 – 4.92 (m, 1 H); 4.42 – 4.38 (m,
1 H); 2.48 – 2.26 (m, 2 H); 1.98 – 1.88 (m, 1 H); 1.84 – 1.71 (m, 1 H); 1.62 – 1.43 (m, 2 H); 0.93 (s, 9 H);
0.11 (s, 3 H); 0.09 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 154.1; 106.2; 75.5; 35.4; 29.3; 25.9; 20.7; ꢀ 4.6;
ꢀ 4.7. HR-EI-MS: 212.1595 (C12H24OSiþ; calc. 212.1596). Physical and spectral data: in accordance with
[27].
(tert-Butyl)[(2-methylenecyclopentyl)oxy]diphenylsilane (¼{[(1,1-Dimethylethyl)diphenylsilyl]-
oxy}-2-methylenecyclopentane; 3c). To a stirred soln. of 2-methylenecyclopentanol (1.31 g, 13.3 mmol)
t
and 1H-imidazole (2.00 g, 29.3 mmol) in DMF (15 ml) at r.t. was added BuPh2Si (5.6 ml, 14.7 mmol).
The mixture was stirred for 5 h at r.t. Then the soln. was diluted with CH2Cl2 (50 ml), washed with 1n
NaHSO4 (2 ꢃ 50 ml), H2O (2 ꢃ 50 ml), and brine (50 ml), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by FC (hexane/AcOEt 99 :1): 3c (3.88 g, 87%). Rf (hexane/AcOEt 9 :1) 0.77. IR
1
(film): 3446, 2957, 1728, 1112. H-NMR (300 MHz, CDCl3): 7.75 – 7.69 (m, 4 H), 7.48 – 7.38 (m, 6 H);
5.09 – 5.06 (m, 1 H); 4.48 – 4.43 (m, 1 H); 2.49 – 2.36 (m, 1 H); 2.31 – 2.19 (m, 1 H); 1.82 – 1.72 (m, 1 H);
1.70 – 1.39 (m, 3 H); 1.12 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 153.8; 135.9; 135.8; 129.6; 127.5; 127.5;
106.7; 76.2; 35.2; 29.2; 27.0; 20.7. HR-EI-MS: 336.1909 (C22H28OSiþ; calc. 336.1909).
(þ)-(tert-Butyl)[(2-methylenecyclopentyl)oxy]diphenylsilane ((S)-3c) and (þ)-2-Methylenecyclo-
pentyl Acetate ((þ)-3a). Hog-pancreas lipase (PPL; 2.0 g), vinyl acetate (14.7 ml, 160 mmol)), and 2-
methylenecyclopentanol (3.92 g, 40 mmol) were added to ground, activated 4-ꢄ molecular sieves (5 g) in
hexane (350 ml) [18]. The mixture was stirred at 258 and the reaction was followed by GC. After 8 h
(51% conversion by CC), the soln. was filtered and the filtrate concentrated. The crude mixture of
alcohol and acetate (4.5 g) was dissolved in DMF (15 ml) and treated with tBuPh2SiCl (5.55 g, 5.17 ml)
and 1H-imidazole (2.75 g) and stirred for 6 h at r.t. The soln. was diluted with CH2Cl2 (100 ml), the org.
phase washed with 1m NaHSO4 (2 ꢃ 30 ml) and brine (30 ml), dried (Na2SO4), and concentrated, and the
crude product purified by FC (cyclohexane/tBuOMe 95 :5): (S)-3c (4.07 g, 33%) and (þ)-3a (2.00 g,
39%). (S)-3c: [a]D25 ¼ þ13 (c ¼ 0.9, CHCl3). The optical purity and the abs. configuration were
determined after desilylation of (S)-3c to (þ)-(1S)-2-methylenecyclopentanol [28].

Helvetica Chimica Acta – Vol. 95 (2012)
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Ethyl 2-(Acetyloxy)-1-azidocyclopentanepropanoate (4a). According to the General Procedure A,
from alkene derivative 3a (420 mg, 3.0 mmol), ethyl iodoacetate (642 mg, 0.35 ml 3.0 mmol), PhSO2N3
t
(1.65 g, 9.0 mmol), Bu6Sn2 (2.27 ml, 4.5 mmol), and BuON¼NOtBu (35 mg, 0.18 mmol). The crude
product was purified by FC (hexane/AcOEt 93 :7): 4a (518 mg, 64%; 1:1 diastereoisomer mixture).
Colorless oil . Rf (hexane/AcOEt 9 :1) 0.2. IR (film): 2981, 2108 (N3), 1738, 1236. 1H-NMR (300 MHz,
CDCl3): 4.93 – 4.88 (m, 1 H); 4.15 – 4.08 (m, 2 H); 2.49 – 2.30 (m, 2 H); 2.25 – 1.98 (m, 6 H); 1.88 – 1.56 (m,
6 H); 1.26 – 1.22 (m, 3 H). 13C-NMR (75 MHz, CDCl3): 173.0; 172.8; 170.3; 169.8; 80.1; 78.7; 73.7; 70.7;
60.6; 60.5; 33.2; 32.2; 30.6; 30.5; 29.6; 29.5; 28.6; 28.1; 21.1; 20.8; 20.5; 18.9; 14.1. HR-ESI-MS: 292.1263
(C12H19N3NaOþ4 ; calc. 292.1273).
Ethyl 1-Azido-2-{[(tert-butyl)dimethylsilyl]oxy}cyclopentanepropanoate (4b). According to the
General Procedure A, from alkene derivative 3b (637 mg, 3.0 mmol), ethyl iodoacetate (642 mg, 0.35 ml
3.0 mmol), PhSO2N3 (1.65 g, 9.0 mmol), Bu6Sn2 (2.27 ml, 4.5 mmol), and tBuON¼NOtBu (35 mg,
0.18 mmol). Purification by FC (hexane/AcOEt 98.5 :1.5) gave 4b (717 mg, 70%) as a 1.2 :1 mixture of
diastereoisomers. Further purification by FC (hexane/AcOEt 98.5 :1.5) allowed the isolation of the
major trans-4b as a single diastereoisomer.
trans-4b: Colorless oil. Rf (hexane/AcOEt 9 :1) 0.52. IR (film) 2105 (N3), 1729. 1H-NMR (300 MHz,
CDCl3): 4.14 (q, J ¼ 7.4, 2 H); 3.87 (dd, J ¼ 5.1, 2.8, 1 H). 2.43 – 2.38 (m, 2 H); 2.11 – 1.92 (m, 3 H); 1.84 –
1.55 (m, 5 H); 1.25 (t, J ¼ 7.4, 3 H); 0.87 (s, 9 H); 0.07 (s, 3 H); 0.06 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
173.4; 78.1; 75.0; 60.4; 32.9; 32.2; 29.9; 28.2; 25.7; 20.2; 17.9; 14.2; ꢀ 4.3; ꢀ 5.1. HR-ESI-MS: 364.2016
(C16H31N3NaO3Siþ; calc. 364.2032).
Ethyl 1-Azido-2-{[(tert-butyl)diphenylsilyl]oxy}cyclopentanepropanoate (4c). According to the
General Procedure A, from alkene derivative 3c (1.01 g, 3.0 mmol), ethyl iodoacetate (642 mg, 0.35 ml
3.0 mmol), PhSO2N3 (1.65 g, 9.0 mmol), Bu6Sn2 (2.27 ml, 4.5 mmol), and tBuON¼NOtBu (35 mg,
0.18 mmol). Purification by FC (hexane/AcOEt 98.8 :1.2) gave 4c (1.24 g, 89%) as a 1.2 :1 mixture of
diastereoisomers. Further purification by FC (hexane/AcOEt 98.5 :1.5) enabled to isolate the major
trans-4c (0.82 g, 59%). The minor decomposed slowly during FC and could not be isolated. trans-4c:
1
Colorless oil. Rf (hexane/AcOEt 9 :1) 0.39. IR (film): 2104 (N3), 1735. H-NMR (300 MHz, CDCl3):
7.69 – 7.62 (m, 4 H); 7.48 – 7.35 (m, 6 H); 4.15 (q, J ¼ 7.0, 2 H); 3.97 – 3.94 (m, 1 H); 2.42 – 2.39 (m, 2 H);
2.23 – 2.05 (m, 2 H); 1.93 – 1.51 (m, 6 H); 1.27 (t, J ¼ 7.0, 3 H); 1.07 (s, 9 H). 13C-NMR (75 MHz, CDCl3):
173.2; 135.8; 135.7; 134.2; 132.9; 129.8; 129.7; 127.7; 127.5; 79.2; 75.0; 60.4; 32.2; 32.1; 29.8; 28.2; 26.9; 20.0;
19.2; 14.2. HR-ESI-MS: 488.2347 (C26H35N3NaO3Siþ; calc. 488.2345).
(þ)-(1R,2S)-Ethyl 1-Azido-2-{[(tert-butyl)diphenylsilyl]oxy}cyclopentanepropanoate ((þ)-(1R,2S)-
4c). According to the procedure described for racemic 4c, from (S)-3c (1.01 g, 3.0 mmol). [a]2D5 ¼ þ18
(c ¼ 1.0, CHCl3).
2-Oxo-1-azaspiro[4.4]non-6-yl Acetate (¼6-(Acetyloxy)-1-azaspiro[4.4]nonan-2-one; 5a). Accord-
ing to the General Procedure B, from 4a (269 mg, 1.0 mmol) and 10% Pd/C (80 mg). Purification by FC
(AcOEt) gave 5a (85 mg, 43%, one diastereoisomer) together with the uncyclized amino ester (22 mg).
Data of 5a: White solid. M.p. 120 – 1238. Rf (AcOEt/MeOH 99 :1) 0.4. IR (CHCl3): 3423, 3019, 1731,
1690. 1H-NMR (300 MHz, CDCl3): 7.02 (br. s, 1 H); 4.90 (dd, J ¼ 7.0, 5.7, 1 H); 2.46 – 2.24 (m, 3 H); 2.21 –
2.03 (m, 1 H); 2.05 (s, 3 H); 1.87 – 1.58 (m, 6 H). 13C-NMR (100 MHz, CDCl3): 177.9; 170.4; 79.3; 68.1;
35.7; 30.6; 28.3; 27.4; 21.1; 18.7. HR-EI-MS: 197.1052 (C10H15NOþ3 ; calc. 197.1052).
Data of Uncyclized Amino Ester: Yellow oil. Rf (AcOEt/MeOH 99 :1) 0.5. 1H-NMR (300 MHz,
CDCl3): 4.44 (d, J ¼ 5.5, 1 H); 4.08 (q, J ¼ 7.0, 2 H); 2.43 – 2.26 (m, 2 H); 2.11 – 1.99 (m, 1 H); 1.93 – 1.77
(m, 6 H); 1.68 – 1.36 (m, 4 H); 1.21 (t, J ¼ 7.0, 3 H). 13C-NMR (75 MHz, CDCl3): 173.6 (C); 163.8 (C);
87.6 (CH); 81.0 (C); 60.3 (CH2); 39.13 (CH2); 34.63 (CH2); 34.13 (CH2); 30.13 (CH2); 23.03 (CH2); 14.13
(Me); 13.73 (Me). HR-ESI-MS: 266.1375 (C12H21NNaOþ4 ; calc. 266.1368).
t
The relative configuration of 5a was confirmed by converting it to the corresponding BuPh2Si-
protected compound 5c: To the soln. of 5a (60 mg, 0.3 mmol) in MeOH (1.5 ml) was added K2CO3
(138 mg, 1.0 mmol), and the mixture was stirred for 18 h at r.t. Upon completion (TLC monitoring),
MeOH was evaporated, and the residue was dissolved in DMF (1 ml) and treated with 1H-imidazole
t
(45 mg, 0.06 mmol) followed by dropwise addition of BuPh2SiCl (84 ml, 0.33 mmol). The mixture was
stirred for 4 h at r.t. The soln. was diluted with CH2Cl2 and washed with 1n NaHSO4 and brine, dried

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Helvetica Chimica Acta – Vol. 95 (2012)
(Na2SO4), and concentrated. Purification by FC (hexane/AcOEt 99 :1) gave 5c (73 mg, 62% over 2
steps).
6-{[(tert-Butyl)dimethylsilyl]oxy}-1-azaspiro[4.4]nonan-2-one (5b). According to the General
Procedure B, from trans-4b (33 mg, 0.1 mmol) and 10% Pd/C (16 mg). Purification by FC (AcOEt)
gave 5b (23 mg, 88%). Pale yellow solid. M.p. 34 – 368. Rf (AcOEt) 0.48. IR (CHCl3) 3423, 3018, 1686.
1H-NMR (300 MHz, CDCl3): 5.89 (br. s, 1 H); 3.84 (t, J ¼ 7.4, 1 H); 2.49 – 2.25 (m, 3 H); 1.93 – 1.82 (m,
1 H); 1.77 – 1.48 (m, 6 H); 0.87 (s, 9 H); 0.04 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 178.4; 78.5; 69.1; 35.2;
30.9; 30.8; 27.0; 25.7; 18.0; 17.9; ꢀ 4.7; ꢀ 4.9. HR-ESI-MS: 292.1704 (C14H27NNaO2Siþ; calc. 292.1708).
6-{[(tert-Butyl)diphenylsilyl]oxy}-1-azaspiro[4.4]nonan-2-one (5c). According to the General
Procedure B, from trans-4c (major diastereoisomer; 300 mg, 0.66 mmol) and 10% Pd/C (100 mg).
Purification by FC (AcOEt) gave 5c (219 mg, 87%). White solid. M.p. 122 – 1248. Rf (AcOEt) 0.53. IR
(CHCl3): 3423, 3017, 1690. 1H-NMR (300 MHz, CDCl3): 7.65 – 7.63 (m, 4 H); 7.45 – 7.34 (m, 6 H); 6.49 (br.
s, 1 H); 3.91 (t, J ¼6.6, 1 H); 2.62 – 2.53 (m, 1 H); 2.42 – 2.24 (m, 2 H); 1.82 – 1.42 (m, 7 H); 1.06 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 178.0; 135.8; 135.8; 134.1; 133.2; 129.8; 129.7; 127.7; 127.5; 78.6; 69.3; 35.1;
30.7; 30.5; 26.9; 26.8; 19.2; 17.8. HR-ESI-MS: 394.2219 (C24H32NO2Siþ; calc. 394.2202).
(5R,6S)-6-{[(tert-Butyl)diphenylsilyl]oxy}-1-azaspiro[4.4]nonan-2-one ((ꢀ)-(5R,6S)-5c). Accord-
ing to the procedure reported for racemic 4c, from (þ)-(1R,2S)-4c (300 mg, 0.66 mmol). Purification by
FC (AcOEt) gave (ꢀ)-(5R,6S)-5c (189 mg, 75%). Viscous oil. [a]2D5 ¼ ꢀ19 (c ¼ 1.0, CHCl3).
(5R)-1-Azaspiro[4.4]nonane-2,6-dione ((ꢀ)-(R)-2). To a stirred soln. of (ꢀ)-(5R,6S)-5c (393 mg,
1.0 mmol) in THF (2 ml) was added 1m Bu4NF in THF (2.0 ml, 2.0 mmol). The mixture was stirred for 5 h
at r.t. and then concentrated. The residue was purified by FC (AcOEt/MeOH 99 :1) to obtain the
corresponding alcohol (135 mg, 87%) [15][16b]. White solid. Rf (AcOEt) 0.1. 1H-NMR (300 MHz,
CDCl3): 7.35 (br. s, 1 H); 4.01 (br. s, 1 H); 3.94 (td, J ¼ 8.1, 3.5, 1 H); 2.52 – 2.27 (m, 3 H); 2.01 – 1.93 (m,
1 H); 1.80 – 1.53 (m, 6 H). 13C-NMR (75 MHz, CDCl3): 179.0; 77.2; 69.2; 35.2; 31.1; 28.9; 26.5; 17.2. HR-
EI-MS: 155.0946 (C8H13NOþ2 ; calc. 155.0946).
A soln. of the above-described alcohol (39 mg, 0.25 mmol) in CH2Cl2 (1 ml) was added dropwise to a
slurry of PCC (81 mg, 0.375 mmol, 1.5 equiv.) in CH2Cl2 (2 ml). The mixture was stirred for 2 h at r.t.
After evaporation, the residue was purified by FC (AcOEt): (ꢀ)-(R)-2 (30 mg, 79%). White solid. M.p.
131 – 1338. ([15]: m.p. 133 – 1348). [a]D25 ¼ ꢀ65 (c ¼ 0.46, CHCl3) ([15] and [16a]: [a]2D5 ¼ ꢀ68 (c ¼ 1.0,
CHCl3) and ꢀ 64, resp.). Physical and spectral data: in accordance with [15].
5. Synthesis of Mori Intermediate (ꢀ)-16. (þ)-3-{[(tert-Butyl)dimethylsilyl]oxy}cyclopentane-1,2-diol
(11). To a soln. of (ꢀ)-(S)-(cyclopent-2-en-1-yloxy)(1,1-dimethylethyl)dimethylsilane (¼(ꢀ)-(3S)-
3-{[1,1-dimethylethyl)dimethylsilyl]oxy}cyclopentene; 10) [19] (10.0 g, 50.4 mmol) and trimethylamine
N-oxide hydrate (8.40 g, 76 mmol) in acetone/H2O 10 :1 (505 ml) was added K2Os4 · H2O (93 mg,
0.25 mmol). The mixture was stirred at r.t. for 6 h. Acetone was evaporated and the crude product
poured into sat. aq. NaHSO3 soln. Extraction with Et2O, drying of the combined org. extract (Na2SO4),
and concentration afforded a crude product that was purified by FC (pentane/Et2O 6 :4): 11 (9.84 g,
84%). Colorless oil. [a]2D2 ¼ þ24.5 (c ¼ 1.0, CHCl3). IR (film): 3382, 1251, 1053, 833, 774. 1H-NMR
(300 MHz, CDCl3): 4.16 (m, 1 H); 4.07 (m, 1 H); 3.72 (m, 1 H); 3.03 (m, 2 H); 2.10 – 1.97 (m, 2 H); 1.63 –
1.52 (m, 1 H); 1.46 – 1.36 (m, 1 H); 0.86 (s, 9 H); 0.05 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
79.5 (CHOSi); 77.4 (CHOH); 71.6 (CHOH); 29.7 (CH2); 28.9 (CH2), 25.8 (Me3C); 18.1 (Me3C); ꢀ 4.7
(2 SiMe). EI-MS (70 eV): 231 (15, [M ꢀ H]þ), 175 (25), 158 (66), 157 (81), 131 (37), 119 (41), 101 (48),
75 (100), 73 (59), 57 (37). HR-EI-MS: 232.14939 (C11H24O3Siþ; calc. 232.14947).
(þ)-Tetrahydro-2,2-dimethyl-4-methylene-4H-cyclopenta-1,3-dioxole (8). To a suspension of 11
(600 mg, 2.60 mmol) in 2,2-dimethoxypropane (6.5 ml) was added a catalytic amount of p-toluenesul-
fonic acid (90 mg, 470 mmol). The mixture was stirred at r.t. for 30 min, and 1m NaOH was added. The
mixture was extracted with Et2O, the org. phase washed with H2O, dried (Na2SO4), and concentrated,
and the crude product purified by FC (pentane/Et2O 95 :5): corresponding acetonide (670 mg, 95%).
Colorless oil. [a]2D2 ¼ þ12.4 (c ¼ 1.0, CHCl3). IR (film): 1068, 1040, 831, 775. 1H-NMR (300 MHz,
CDCl3): 4.71 (m, 1 H); 4.27 (dd, J ¼ 5.64, 1.32, 1 H); 4.09 (m, 1 H); 1.97 – 1.72 (m, 3 H); 1.53 – 1.48 (m,
1 H); 1.40 (s, 3 H); 1.27 (s, 3 H); 0.86 (s, 9 H); 0.05 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
109.5 (Me2C); 86.9 (CHOC); 80.4 (CHOC); 76.9 (CHOSi); 31.1 (CH2); 30.1 (CH2); 26.2 (Me); 25.7 (3
Me); 23.9 (Me); 18.0 (Me3C); ꢀ 4.8 (Me2Si); ꢀ 4.8 (Me2Si). EI-MS (70 eV): 258 (37, [M ꢀ CH2]þ), 158

Helvetica Chimica Acta – Vol. 95 (2012)
2511
(67), 157 (100), 127 (54), 101 (68), 75 (93), 73 (56). HR-EI-MS: 272.18093 (C14H28O3Siþ; calc.
272.18077).
To a soln. of the acetonide (670 mg, 2.46 mmol) in THF (5.5 ml) was added 1.0m Bu4NF in THF
(3 ml) dropwise at 08. After stirring at r.t. for 2 h, the mixture was extracted with Et2O. The extract was
washed with brine, dried (Na2SO4), and concentrated, and the crude product purified by FC (pentane/
Et2O 60 :40): expected alcohol (345 mg, 89%). White solid. M.p. 63 – 658. [a]2D2 ¼ þ39.7 (c ¼ 1.0, CHCl3).
1
IR (film): 3415, 1041, 1012. H-NMR (300 MHz, CDCl3): 4.74 (m, 1 H); 4.33 (m, 1 H); 4.14 (m, 1 H),
1.97 – 1.82 (m, 4 H); 1.61 – 1.48 (m, 1 H); 1.40 (s, 3 H); 1.28 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 109.8
(Me2C); 86.5 (CHO); 80.3 (CHO); 76.5 (CHOH); 30.7 (CH2); 30.0 (CH2); 26.1 (Me); 23.8 (Me). EI-MS
(70 eV): 158(12), 144 (44), 143 (67), 83 (72), 59 (74), 55 (72). HR-EI-MS: 158.09429 (C8H14Oþ3 ; calc.
158.09407).
To freshly activated and grounded 3 ꢄ molecular sieve (2 g) in dry CH2Cl2 (12 ml) was added the
alcohol (400 mg, 2.53 mmol), pyridinium dichromate (927 mg, 4.3 mmol), and anh. AcOH (250 ml).
After stirring for 1 h at r.t., the mixture was filtered through a short pad of Celiteꢃ (Et2O as eluent). The
reddish brown filtrate was evaporated, and toluene was added to the filtrate to remove traces of AcOH
by evaporation. The resulting dark brown residue was dissolved in CH2Cl2, and AcOEt was added to
precipitate the CrIII species. The soln. was filtered through a pad of SiO2 (Et2O as eluent). The brownish
filtrate was concentrated and the crude product purified by FC (pentane/Et2O 7:3): tetrahydro-2,2-
dimethyl-4H-cyclopenta-1,3-dioxol-4-one (395 mg, 79%). White crystals. IR (film): 1736, 903. M.p. 48 –
508. [a]2D2 ¼ þ41.2 (c ¼ 1.0, CHCl3). 1H-NMR (300 MHz, CDCl3): 4.82 (t, J ¼ 4.62, 1 H); 4.17 (d, J ¼ 4.85,
1 H); 2.66 – 2.52 (m, 1 H); 2.32 – 2.20 (m, 2 H); 2.10 – 1.97 (m, 1 H); 1.42 (s, 3 H); 1.35 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 214.6 (CO); 111.7 (Me2C); 78.7 (CHO); 77.2 (CHO); 32.8 (CH2); 26.5 (CH2); 24.6
(Me); 23.2 (Me). EI-MS (70 eV): 156 (62), 152 (64), 141 (74), 123 (100), 99 (97), 85 (63), 69 (53), 59
(85), 43 (84), 41 (98). HR-EI-MS: 156.07811 (C8H12Oþ3 ; calc.156.07864).
t
Methyltriphenylphosphonium bromide (687 mg, 1.92 mmol) and BuOK (215 mg, 1.92 mmol) were
dissolved in Et2O (5 ml) and heated at 408 during 1 h. The cyclopentadioxolone (150 mg, 1.28 mmol) in
Et2O (1.33 ml) was added to the yellow suspension, and the soln. was stirred for 2 h at 408. After cooling,
more Et2O was added and the soln. was washed with H2O and dried (Na2SO4). Evaporation of the
solvent afforded a crude product that was purified by FC (pentane/Et2O 95 :5): 8 (177 mg, 90%).
1
Colorless oil. [a]2D2 ¼ þ112.5 (c ¼ 1.0, CHCl3). IR (film): 1738, 1366, 905. H-NMR (300 MHz, CDCl3):
4.51 (d, J ¼ 2.64, 1 H); 4.45 (m, 1 H); 4.10 – 4.03 (m, 2 H); 2.02 – 1.89 (m, 1 H); 1.55 – 1.48 (m, 1 H); 1.34 –
1.27 (m, 1 H); 1.04 – 0.90 (m, 1 H); 0.82 (s, 3 H); 0.69 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 150.5
(C¼CH2); 111.5 (C¼CH2); 110.1 (Me2C); 82.0 (CHO); 80.4 (CHO); 31.1 (CH2); 29.3 (CH2); 26.4 (Me);
24.3 (Me). TOF-MS (pos., 70 eV): 177.0889 (2.4, [M ꢀ Na]þ), 157.0778 (0.6). HR-ESI-MS: 177.0891
(C9H14NaOþ2 ; calc. 177.0889).
(þ)-4-Azido-tetrahydro-2,2-dimethylcyclopenta-1,3-dioxol-4)-propanic Acid Ethyl Ester (7). Hex-
abutyldistannane Procedure. To a stirred soln. of 8 (100 mg, 0.65 mmol) in dry benzene (1.3 ml) were
added pyridine-3-sulfonyl azide (360 mg, 1.95 mmol), ethyl iodoacetate (0.77 ml, 0.65 mmol), Bu3Sn2
(0.49 ml, 0.97 mmol), and di(tert-butyl) hyponitrite (7.34 mg, 0.04 mmol). The resulting mixture was
heated reflux and N2. After 2 h, another portion of di(tert-butyl) hyponitrite (7.34 mg, 0.04 mmol) was
added, and the mixture was further heated under reflux for 2 h. Upon completion, the solvent was
evaporated, the crude product filtered with cyclohexane/tBuOMe 80 :20 through SiO2, the filtrate
evaporated, and the crude product purified by FC (SiO2 mixed with KF [29], cyclohexane/tBuOMe
95 :5): 7 (148 mg, 80%).
Et3B Procedure. Freshly prepared 2m Et3B in dry EtOH was added via syringe pump within 1 h at r.t.
to an air-exposed vigorously stirred mixture of 8 (100 mg, 0.65 mmol), pyridine-3-sulfonyl azide (360 mg,
1.95 mmol), and ethyl iodoacetate (0.77 ml, 0.65 mmol) in H2O (Caution: the needle must be immersed
into the mixture to avoid a direct contact of Et3B drops with air). After 1 h, hexane was added, the aq.
layer extracted with Et2O, the combined org. phase washed with H2O, dried (MgSO4), and concentrated,
and the crude product purified by FC (cyclohexane/tBuOMe 95 :5): 7 (141 mg, 76%). Colorless oil.
[a]2D2 ¼ þ145.6 (c ¼ 1.0, CHCl3). IR (film): 2098, 1447, 1160, 1039. H-NMR (300 MHz, CDCl3): 4.70 –
1
4.67 (m, 1 H); 4.17 (q, J ¼ 7.14, 14.31, 21.45, 2 H); 4.07 (d, J ¼ 5.64, 1 H); 2.51 – 2.45 (m, 2 H); 2.10 –
2.04 (m, 2 H); 1.81 – 1.74 (m, 4 H); 1.40 (s, 3 H); 1.28 – 1.23 (m, 6 H). 13C-NMR (75 MHz, CDCl3):

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Helvetica Chimica Acta – Vol. 95 (2012)
173.1 (COO); 110.2 (Me2C); 83.8 (CHO); 80.5 (CHO); 74.0 (CN3); 60.5 (MeCH2O); 31.9 (CH2); 30.2
(CH2); 29.7 (CH2); 28.5 (CH2); 26.1 (Me); 23.9 (Me); 14.2 (Me). EI-MS (70 eV): 284 (7, [M ꢀ H]þ), 268
(71), 183 (72), 169 (83), 152 (76), 123 (81), 100 (82), 96 (100), 81 (96), 69 (96), 56 (87), 39 (89). HR-EI-
MS: 283.15334 (C13H21N3Oþ4 ; calc. 283.15321).
(þ)-(2’R,3aR,6aS)-Tetrahydro-2,2-dimethylspiro[4H-cyclopenta-1,3-dioxole-4,2’-pyrrolidin]-5’-one
(12). To a stirred soln. of 7 (566 mg, 2.0 mmol) in dry EtOH (8 ml) was added 5% Pd/CaCO3 (60 wt.-%).
The mixture was stirred under 30 bar of H2 for 48 h at 908. The slurry was filtered through Celiteꢃ, the
solvent evaporated, and the residue purified by FC (AcOEt/EtOH 97.5 :2.5): 12 (422 mg, > 95%). White
solid. M.p. 111 – 1138. [a]2D2 ¼ þ22.8 (c ¼ 1.0, CHCl3). IR (neat): 1688, 1435, 1035, 896. 1H-NMR
(300 MHz, CDCl3): 7.22 (s, 1 H); 4.75 (t, J ¼ 4.53, 1 H); 4.23 (m, 1 H); 2.46 – 2.32 (m, 3 H); 1.99 – 1.68 (m,
6 H); 1.44 (s, 3 H); 1.29 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 178.7 (CO); 110.4 (Me2C); 85.8 (CHO);
80.2 (CHO); 69.2 (CN); 34.7 (CH2CO); 30.4 (CH2); 30.3 (CH2); 26.7 (CH2); 26.1 (CH2); 23.9 (Me).
B.p. 112 – 1148. EI-MS (70 eV): 211 (14, Mþ), 196 (6), 153 (22), 136 (14), 110 (15), 101 (20), 97 (100), 69
(39), 43 (41) 41 (16). HR-EI-MS: 211.12084 (C11H17NOþ3 ; calc. 211.12085).
(þ)-(2’S,3aR,6aS)-Tetrahydro-1’-[2-(6-iodo-1,3-benzodioxol-5-yl)ethyl]-2,2-dimethylspiro[4H-cyclo-
penta-1,3-dioxole-4,2’-pyrrolidine] (14). A soln. of 12 (400 mg, 2.0 mmol) in dry benzene (20 ml) was
added dropwise to a slurry of sodium bis(2-methoxyethoxy)aluminium hydride (1 ml, 3.80 mmol) in dry
benzene (20 ml). The mixture was stirred for 3 h under reflux. After hydrolysis with H2O and 1m aq.
NaOH, the mixture was filtered, the filtrate extracted with Et2O, and the extract dried (Na2SO4) and
concentrated spiro[cyclopentadioxol-pyrrolidine] to afford the crude that was used for the next step
1
without further purification. Pale yellow oil. IR (neat): 1693, 1205, 1035. H-NMR (300 MHz, CDCl3):
4.73 (t, J ¼ 4.71, 1 H); 4.03 (dd, J ¼ 5.46, 1.32, 1 H); 3.04 – 2.99 (m, 1 H); 2.82 – 2.77 (m, 1 H); 2.10 – 1.48
(m, 9 H); 1.42 (s, 3 H); 1.28 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 109.5 (Me2C); 85.3 (CHO); 81.0
(CHO); 72.5 (CN); 46.3 (CH2N); 34.8 (CH2); 31.3 (CH2); 30.9 (CH2); 26.3 (Me); 26.0 (CH2); 24.0 (Me).
To a stirred soln. of the crude spiro[cyclopentadioxole-pyrrolidine] (395 mg, 2.0 mmol) in dry MeCN
(4 ml) were added the 4-nitrobenzenesulfonate 13 (1.12 g, 3.2 mmol) and iPr2EtN (4 ml, 8 mmol) at r.t.
t
Stirring was continued under reflux for 20 h, then the mixture was diluted with BuOMe and extracted
with 1m aq. NaOH. The org. layer was dried (Na2SO4), the solvent evaporated, and the residue purified
by FC (AcOEt/cyclohexane 85 :15): 14 (785 mg, 83%). Colorless oil. [a]2D2 ¼ þ17.3 (c ¼ 1.0, CHCl3). IR
(neat): 1473, 1224, 1036. 1H-NMR (300 MHz, CDCl3): 7.20 (s, 1 H); 6.73 (s, 1 H); 5.94 (s, 2 H); 4.62 (t,
J ¼ 12.06, 6.03, 1 H); 4.26 (d, J ¼ 6.42, 1 H); 3.03 – 2.67 (m, 4 H); 2.60 – 2.43 (m, 2 H); 2.23 – 2.14 (m, 1 H);
1.85 – 1.49 (m, 7 H); 1.45 (s, 3 H); 1.29 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 148.4 (CO); 146.9 (CO);
136.4 (C); 118.5 (C); 110.5 (Me2C); 109.7 (C); 101.5 (CH2); 87.7 (CHO); 83.7 (CHO); 80.5 (CN); 77.4
(CI); 51.5 (CH2N); 50.5 (CH2N); 41.0 (CH2); 32.5 (CH2); 31.0 (CH2); 30.6 (CH2); 26.3 (Me); 24.3 (Me);
21.8 (CH2). TOF-MS (pos., 70 eV): 472.0963 (1.2, [M ꢀ H]þ), 313.2810 (1.1). HR-ESI-MS: 472.0984
(C20H27INOþ4 ; calc. 472.0963).
(þ)-(2’S,3aR,6aS)-Tetrahydro-1’-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]spiro[4H-cyclopenta-1,3-di-
oxole-4,2’-pyrrolidine]-2-thione (15). Acetonide 14 (200 mg, 424 mmol) was heated under reflux in 2m
HCl and 95% EtOH for 2.5 h. Then the solvent was evaporated and the residue purified by FC (Et2O/
NH3): corresponding diol (160 mg, 88%). Viscous oil. [a]2D2 ¼ þ24.8 (c ¼ 1.0, CHCl3). IR (neat): 3388,
1472, 1225, 1036. 1H-NMR (300 MHz, CDCl3): 7.22 (s, 1 H); 6.75 (s, 1 H); 5.94 (s, 2 H); 4.13 – 4.08 (dt, J ¼
11.85, 5.82, 2.43, 1 H); 3.80 (d, J ¼ 6.42, 1 H); 3.32 – 3.25 (m, 1 H); 2.90 – 2.41 (m, 7 H); 2.21 – 2.11 (m,
1 H); 1.96 – 1.78 (m, 3 H); 1.63 – 1.47 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 148.5 (CO); 147.0 (CO);
136.1 (C); 118.6 (C); 109.7 (C); 101.6 (CH2O); 87.7 (CHO); 77.2 (CHO); 73.7 (CI); 70.1 (CN); 51.9
(CH2N); 49.3 (CH2N); 40.3 (CH2); 32.0 (CH2); 29.2 (CH2); 25.8 (CH2); 21.6 (CH2). HR-ESI-MS:
432.0671 (C17H23INOþ4 ; calc. 432.0681).
To a stirred soln. of diol (566 mg, 1.30 mmol) in dry CH2Cl2 (5 ml) was added 1,1’-(thiocarbonyl)-
bis[1H-imidazole] (¼di-1H-imidazol-1-ylmethanethione; 715 mg, 4.0 mmol) and iPr2EtN (15 ml,
13 mmol). The mixture was stirred under reflux for 5 h and then diluted with CH2Cl2. The CH2Cl2
phase was washed with H2O, dried (Na2SO4), and concentrated and the residue subjected to FC (AcOEt/
EtOH 97.5 :2.5): 15 (474 mg, 77%). Colorless liquid. [a]2D2 ¼ þ114.3 (c ¼ 1.0, CHCl3). IR (neat): 1472,
1277, 1223. 1H-NMR (300 MHz, CDCl3): 7.20 (s, 1 H); 6.69 (s, 1 H); 5.94 (s, 2 H); 5.22 (m, 1 H); 4.82 (d,
J ¼ 6.42, 1 H); 3.50 – 2.46 (m, 6 H); 2.17 – 1.60 (m, 8 H). 13C-NMR (75 MHz, CDCl3): 191.4 (CS); 148.4

Helvetica Chimica Acta – Vol. 95 (2012)
2513
(CO); 147.0 (CO); 135.7 (C); 118.5 (C); 109.8 (C); 101.6 (CH2O); 89.6 (CO); 87.6 (CO); 86.7 (CI); 75.4
(CN); 51.4 (CH2N); 50.0 (CH2N); 40.7 (CH2); 32.1 (CH2); 31.1 (CH2); 29.4 (CH2); 21.9 (CH2). EI-MS
(70 eV): 474 (12, [M ꢀ H]þ), 473 (46, Mþ), 396 (64), 274 (68), 212 (100), 168 (94), 96 (83). HR-ESI-MS:
474.0236 (C18H21INO4Sþ; calc. 474.0221).
(ꢀ)-(5R)-1-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]-1-azaspiro[4.4]non-6-en-2-one (6). Thione 15
(300 mg, 634 mmol) was heated at 408 in neat 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (420 ml,
1.9 mmol) for 4 h. Then the solvent was evapoarated and the residue purified by FC (AcOEt/EtOH
95 :5): 6 (217 mg, 83%). Colorless liquid. [a]2D2 ¼ ꢀ74.0 (c ¼ 1.0, CHCl3); [23]: [a]D22 ¼ ꢀ32.0 (c ¼ 0.08,
CHCl3)). Spectral data: in accordance with [6j][7d][23]. 1H-NMR (300 MHz, CDCl3): 7.20 (s, 1 H); 6.74
(s, 1 H); 5.92 (s, 2 H); 5.82 – 5.78 (m, 1 H); 5.58 – 5.54 (m, 1 H); 3.01 – 2.94 (m, 1 H); 2.84 – 2.78 (m, 3 H);
2.47 – 2.36 (m, 2 H); 2.35 – 2.27 (m, 2 H); 1.90 – 1.75 (m, 5 H); 1.68 – 1.58 (m, 1 H). 13C-NMR (75 MHz,
CDCl3): 148.5 (C); 147.0 (C); 135.9 (C); 134.3 (C); 132.6 (C); 118.6 (C); 109.7 (C); 101.5 (CH2O); 89.0
(CI); 78.8 (C); 51.4 (CN); 50.1 (CH2); 40.8 (CH2); 38.8 (CH2); 31.7 (CH2); 30.0 (CH2); 21.8 (CH2).
(3aS,14bS)-3,5,6,8,9,14b-Hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzaze-
pine (¼2,3-Didehydro-2-demethoxy-3-deoxy-1,2-dihydrocephalotaxine; (ꢀ)-16). According to the pro-
cedure reported by Tietze, Yoshida and co-workers [7b][7d]: A mixture containing MeCN (5 ml), DMF
(5 ml), H2O (1 ml), 6 (150 mg, 510 mmol), Bu4NOAc (301 mg, 1.0 mmol), and palladium catalyst (18 mg,
t
2 · 10ꢀ2 mmol) was stirred for 7 h at 1208. The soln. was poured into BuOMe and washed with dil. aq.
NaOH soln. The org. layer was extracted with HCl soln. The acidic phase was basified with NaOH and
extracted with tBuOMe. The combined org. layer was dried (Na2SO4) and concentrated. Purification by
FC (AcOEt) gave Moriꢂs intermediate (ꢀ)-16 (68.4 mg, 46%) [6d][6j][7b][7d][7e]. Colorless liquid.
Physical and spectral data: in accordance with [6d]. [a]2D2 ¼ ꢀ196.7 (c ¼ 1.0, CHCl3) ([6d]: ꢀ 230.8 (c ¼
1.22, CHCl3); [7b]: ꢀ 200.4 (c ¼ 1.0, CHCl3); [6j]: ꢀ 210.5 (c ¼ 0.25, CHCl3)). 1H-NMR (300 MHz,
CDCl3): 6.63 (s, 1 H); 6.58 (s, 1 H); 5.87 (s, 1 H); 5.86 (s, 1 H); 5.78 (dddd, J ¼ 5.9, 2.6, 2.9, 2.2, 1 H); 5.52
(dddd, J ¼ 5.9, 2.6, 2.9, 2.2, 1 H); 3.85 (m, 1 H); 3.21 (m, 1 H); 3.08 (m, 1 H); 2.98 – 2.75 (m, 2 H); 2.60 (d,
1 H); 2;45 (m, 1 H); 2.36 (d, 1 H); 1.58 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 148.2 (C); 147.1 (C); 134.5
(C); 133.6 (C); 132.9 (C); 129.1 (C); 110.9 (C); 110.0 (C); 101.5 (CH2O); 69.5 (C); 63.2 (CN); 54.6
(CH2); 50.0 (C); 43.6 (CH2); 35.9 (CH2); 31.3 (CH2); 20.5 (CH2).
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Received August 20, 2012