The combination of diallylboration and ring-closing metathesis in the synthesis of spiro-β-amino alcohols and (±)-cephalotaxine

Article abstract of DOI:10.1002/ejoc.200800755

A convenient and practical methodology for the preparation of various spiro-β-amino alcohols has been elaborated. The approach involves allylboration and ring-closing methathesis to prepare spirobicyclic compounds and their subsequent modification to spiro-β-amino alcohols containing four- to six-membered azacycles. N-Boc-protected azaspirocyclic olefins reacted with NBS in solvent under reflux to give tricyclic bromocyclocarbamates. The structure of one of the bromides was established by single-crystal X-ray analysis. The dehydrobromination of the tricyclic bromides with tBuOK produced olefins in good yields, which underwent allylic-type rearrangement in the presence of MgBr₂Et₂O. Alkaline hydrolysis of the rearranged carbamates led to diastereomerically pure spiro-β-amino alcohols. The structure of the dimethyl-substituted amino alcohol was proved by single-crystal X-ray analysis. rac-(5R*,6S*)-1-Azaspiro[4.4]non-7- en-6-ol was used in the formal synthesis of cephalotaxine. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800755

FULL PAPER
DOI: 10.1002/ejoc.200800755
The Combination of Diallylboration and Ring-Closing Metathesis in the
Synthesis of Spiro-β-Amino Alcohols and (؎)-Cephalotaxine
Nikolai Yu. Kuznetsov,[a] Galina D. Kolomnikova,[a] Victor N. Khrustalev,[a]
Denis G. Golovanov,[a] and Yuri N. Bubnov*[a]
Keywords: Allylboration / Metathesis / Spiro compounds / Cephalotaxine / Allylic compounds / Rearrangement / Amino
alcohols
A convenient and practical methodology for the preparation
of various spiro-β-amino alcohols has been elaborated. The
approach involves allylboration and ring-closing methathesis
to prepare spirobicyclic compounds and their subsequent
modification to spiro-β-amino alcohols containing four- to
six-membered azacycles. N-Boc-protected azaspirocyclic
olefins reacted with NBS in solvent under reflux to give tricy-
clic bromocyclocarbamates. The structure of one of the bro-
mides was established by single-crystal X-ray analysis. The
dehydrobromination of the tricyclic bromides with tBuOK
produced olefins in good yields, which underwent allylic-
type rearrangement in the presence of MgBr2·Et2O. Alkaline
hydrolysis of the rearranged carbamates led to dia-
stereomerically pure spiro-β-amino alcohols. The structure of
the dimethyl-substituted amino alcohol was proved by sin-
gle-crystal X-ray analysis. rac-(5R*,6S*)-1-Azaspiro[4.4]non-
7-en-6-ol was used in the formal synthesis of cephalotaxine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The family of Cephalotaxus alkaloids has attracted con-
siderable attention since their first isolation in 1963.[1] Many
works devoted to the preparation of cephalotaxine (CPT)
and its close analogues can be found in the literature.[2] The
interest shown by synthetic chemists in its synthesis can be
attributed to two main reasons. First, CPT (Figure 1) pos-
sesses a unique pentacyclic skeleton that contains a 1-azas-
piro[4.4]nonane unit, which serves as a useful model for the
development of new approaches to azaspiranes. Secondly,
the esters of CPT, harringtonines, are the main components
of drugs used to cure several types of human leukemia
(passing the third phase of clinical trials) and have also been
investigated for application in the treatment of chloroquine-
resistant malaria.[3] Despite the relatively simple structure
of CPT, the construction of the azaspiro fragment is a
somewhat challenging task,[2] whereas other steps of the
CPT synthesis are well established.
Recently we have demonstrated the utility of the dial-
lylboration and ring-closure metathesis (RCM) sequence in
the preparation of various spiro[4a] and bridged[4b,4c] aza-
bicycles starting from aromatic heterocycles (pyridines, iso-
quinolines, and pyrrole) and lactams. Having such a
straightforward access to azaspirobicycles we decided to de-
velop the synthesis of CPT. Our first attempt to use the
Figure 1. Cephalotaxus alkaloids.
Heck-type reaction to form the azepine cycle of CPT re-
sulted in a novel eight-membered cyclization that led to a
structural isomer of the main pentacyclic core of CPT.[5]
However, this approach was unsuitable for CPT prepara-
tion. Accordingly we concentrated our attention on the
modification of the spirobicycles to give products that have
already found application in the synthesis of CPT.
Isono and Mori[2l] have shown that the azepine cycle of
CPT can be formed by electrophilic cyclization under the
action of polyphosphoric acid (PPA) on a mixture of dia-
stereomeric allylic-type spiro-β-amino alcohols. Moreover,
some spiro-β- and -γ-amino alcohols or their parent
ketones are very interesting compounds because they serve
as intermediates in a number of syntheses of natural prod-
ucts, such as histrionicotoxine,[6a] sibirine,[6b] halichlori-
ne,[6c,6f] fasicularine,[6d,6e] and pinnaic acid.[6f] Therefore the
elaboration of new and practical methods to this type of
compound is an important task. This report reveals a route
to the spiro-β-amino alcohols of the azaspiro[4,n]nonene
series.
[a] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
Vavilov 28, 119991 Moscow, Russia
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5647–5655
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FULL PAPER
Results and Discussion
We first prepared a set of spiranes by our conventional
approach. The spirane 1a with a four-membered aza ring
was prepared from 3-chloropropionitrile (Scheme 1).
The diallylboration of nitriles[7a,7b] with triallylborane
(TAB) was carried out by heating at 110 °C and proceeded
via the formation of diazadiboretidines, which after alkaline
treatment released diallylated primary amines. In the case
of 3-chloropropionitrile, diallylboration followed by debo-
ronation of the reaction mixture with NaOH liberated the
2,2-diallylazetidine (Scheme 1) in 91% yield in a one-pot
reaction. Protection of 2,2-diallylazetidine with Boc2O fol-
lowed by RCM (Grubbs’ catalyst I, 1.3 mol-%) provided
spirocycle 1a. Spiranes with a five- (2a–4a) or six-membered
(5a) aza ring were prepared from lactams[4a] (Scheme 2).
The lactams readily reacted with TAB in THF or benzene
solution under reflux to give 2,2-diallylated heterocycles af-
ter alkaline treatment.[7c] Further protection of the amino
function and RCM furnished the required spiranes 2a–5a.
Bicycle 4a was prepared in an enantiomerically pure form
starting from (S)-2-(hydroxymethyl)pyrrolidone. The N-
Boc-protected diallylated precursor of 4a was subjected to
RCM (catalyst I, 2.0 mol-%) without protection of the OH
group to give a crystalline product (85%).
Scheme 3. Modification of 1a–5a with NBS.
ing under reflux in CHCl3 with NBS produced tricyclic bro-
mides 2b (80%), 3b (86%), and 4b (mixture of dia-
stereomers, 98%), respectively. The structure of 2b was es-
tablished by single-crystal X-ray analysis (Figure 2).
Scheme 2. Synthesis of pyrrolidine- and piperidine-type spiranes.
The protected azaspiro-olefins 1a–5a were modified by
intramolecular bromocyclocarbamation using NBS
(Scheme 3).
Halocyclization is a common approach to the stereose-
lective introduction of hydroxy or amino groups into mole-
cules.[8] However, spiro systems have not been modified this
Figure 2. Molecular structure of 2b.
The reaction of 1a (DCE at reflux) proved the most diffi-
way previously as the reaction requires rather harsh condi- cult and was accompanied by partial decomposition of the
tions, with the exception of the six-membered spirane 5a; substrate, which reduced the yield of 1b (73%). This obser-
the tricyclic bromide 5b (80%) was formed at room tem- vation can be rationalized by taking into account the
perature. Bicycles with contracted rings, 2a–4a, upon heat- strained nature of the azetedine ring in the tricyclic system.
Scheme 1. Synthesis of the azetidine-type spirane.
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Synthesis of Spiro-β-Amino Alcohols and (Ϯ)-Cephalotaxine
Note that an α substituent, even a bulky TBS group as Table 1. Preparation of spiro-β-amino alcohols; summary of chemi-
cal yields and conditions.
in 4a, has little effect on the diastereoselectivity of the bro-
mocyclization due to the coplanarity of the amidic carbonyl
group; its deviation from the plane of the pyrrolidine cycle
is 1.80° (X-ray data of 2b). The diastereoisomers 4b_min
and 4b_max obtained from the reaction with NBS in
MeCN were separated by flash chromatography and their
structures were assigned by NMR experiments.
n
R
Product, % yield
tBuOK[a]
MgBr2·Et2O[b]
NaOH[c]
0
1
1
2
H
H
CH3
H
52, 1c
93, 2c
95, 3c
87, 5c
53, 1d
84, 2d
99, 3d
93, 5d
82, 1e
84, 2e
90, 3e[d]
89, 5e
[a] 1.2 equiv. of tBuOK, –15 °CǞr.t., 2 h. [b] 10–12 mol-%
MgBr2·Et2O. [c] 6 equiv. of NaOH, 2 h, reflux. [d] 12 equiv. of
NaOH, 4 h reflux.
The bromides 1b–5b were subjected to a dehydrobromi-
nation reaction. Previously, DBU was used in a test reaction
with 2b, however, prolonged reaction times even with an
excess of DBU and the formation of a mixture of products
makes it unsuitable for the dehydrobromination step. Fortu-
nately, we found that the dehydrobromination proceeded
smoothly under the action of tBuOK in THF giving rise to
spiro-olefin 2c in 93% yield (Scheme 4, Table 1). The other
olefins 1c–5c were prepared analogously, but in the case of
1c only a moderate yield (52%) was determined due to a
partial decomposition of the substrate. We attempted to
convert the carbamates to spiro-γ-amino alcohols by simple
hydrolysis, however, 2c was highly resistant to hydrolytic
splitting under the action of methanolic NaOH and even
after 6 h of heating under reflux a mixture of products
along with remains of 2c were obtained. On the other hand
we observed allylic-type isomerization of the double bond
in 2c in the presence of MgBr2·Et2O (10–12 mol-%) in
DCM at ambient temperature leading to the sole isomer
2d. A similar acid-catalyzed isomerization (in a non-spiro
system) has been observed previously.[9] Importantly, the
same isomerization process did not allow the correct assign-
ment of the structure of carbamate 2c in a recent publica-
tion.[2k] The acidic treatment of the N-Boc-spiro-γ-amino
alcohol did not produce carbamate 2c as the authors con-
cluded, but instead its isomer 2d. This was confirmed by its
13C NMR spectrum which coincides with our spectroscopic
data for 2d. The carbamate 2d, in contrast to that of 2c,
was easily hydrolyzed to produce diastereomerically pure
spiro-β-amino alcohol 2e.
state that were stabilized by O–H···N contacts with an
O···N distance equal to 2.797(3) Å.
Figure 3. Molecular structure of 3e.
The two diastereomers of 4b were transformed to the en-
antiomerically pure amino alcohols 9a and 9b (Scheme 5).
Dehydrobromination of the isomers of 4b proceeded well in
the presence of 2 equiv. of tBuOK for 3 h and after purifica-
tion by chromatography 6a and 6b were isolated in 94 and
82% yields, respectively. Allylic isomerization gave the pure
isomers 7a and 7b in 91 and 82% yields after recrystalli-
zation. The hydroxy group in 7 was deprotected by using
AcOH with gentle heating followed by recrystallization (in
the case of 8a) or by treatment with TBAF at room tem-
perature (in the case of 8b). Evidently these compounds are
suitable for further modification of the hydroxy group giv-
ing access to a new pool of chiral products. Hydrolysis of
the carbamates 8 produced the target spiro-β-amino diols
9a and 9b as only one isomer. Note that some of the spiro-
β-amino alcohols (1e, 2f, 9a, and 9b) have an unusual ability
to induce deuterium–proton exchange between NH, OH,
Scheme 4. Preparation of spiro-β-amino alcohols.
This protocol worked equally well for all the other com-
pounds, although slight differences in reactivity were ob-
served for the hindered carbamates 3c and 3d. The isomeri-
zation of 3c only started upon heating the DCM solution
and the reaction of 3d required 12 equiv. of NaOH to com-
plete the hydrolysis. The structure of amino alcohol 3e was
unambiguously established by single-crystal X-ray analysis
Scheme 5. Preparation of chiral spiro-β-amino diols. Reagents and
conditions: i. 2 equiv. of tBuOK, –15 °CǞr.t., 3 h, 6a (94%), 6b
(82%); ii. 10 mol-% MgBr2·Et2O, 7a (91%), 7b (82%), iii. AcOH/
THF/H2O, 8a (94%); TBAF/THF 8b (93%); iv. 6 equiv. of NaOH,
(Figure 3). The molecules of 3e formed dimers in the crystal 2 h, reflux, 9a (99%), 9b (93%).
Eur. J. Org. Chem. 2008, 5647–5655
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FULL PAPER
Scheme 6. Preparation of the saturated spiro-β-amino alcohol 2f and the tetracyclic core of cephalotaxine (12).
corded with Bruker Avance-300, 400, or 600 MHz instruments.
Mass spectra were recorded with a Finnigan Polaris Q Ion Trap
spectrometer. Melting points were obtained from recrystallized sol-
ids and are uncorrected. All solvents and reagents were purified
using standard methods. N-tert-Butoxycarbonyl-1-azaspiro[4.4]-
non-7-ene (2a) and N-tert-butoxycarbonyl-6-azaspiro[4.5]dec-2-ene
(5a) were prepared in accordance with the literature procedure.[4a]
and CDCl3. As a result, a residual solvent signal of high
intensity is observed in their H NMR spectra and a signal
1
corresponding to CHCl3 in the 13C NMR spectra. This is
an interesting phenomenon that is currently under study.
Although the alcohols 1e–5e can be obtained and stored
in pure form, it is convenient to prepare them just before
their functionalization from stable cyclic carbamates. We
performed such a one-pot procedure (hydrolysis and acyl-
ation) for carbamate 2d (Scheme 6). The excess NaOH from
the hydrolysis reaction was used as base in the acylation
step. Amide 10 was obtained as a crystalline solid and can
be purified either by chromatography or crystallization. Re-
duction of amide 10 by LAH in THF at 0 °C gave rise to
amino alcohol 11 which in fact is one of the isomers of
Mori’s substrate.[2l] We found that 11 was the minor compo-
nent in a mixture of diastereomeric alcohols.[2l] A compari-
son of the spectroscopic data allowed us to identify the con-
figuration of the two isomers of Mori’s substrate because
of the known stereochemistry of the OH group in our iso-
mer. Thus, to ensure the identity of the substrate in the
cyclization step a control experiment with 11 was carried
out. Heating 11 in the presence of PPA led to the tetracyclic
product 12 in 77% yield, which was isolated by chromatog-
raphy. Its NMR spectrum was identical to that reported
by Isono and Mori and hence the formal synthesis of rac-
cephalotaxine was complete. Also, 2d was hydrogenated
N-(tert-Butoxycarbonyl)-1-azaspiro[3.4]oct-6-ene (1a): Grubbs’ cat-
alyst I (0.08 g, 0.097 mmol, 1.3 mol-%) was added in two equal
portions, 2 h apart, to a deoxygenated solution of N-Boc-2,2-dial-
lylazetidine (1.8 g, 7.6 mmol) in DCM (40 mL) at 40 °C. After the
disappearance of the starting material the mixture was concen-
trated and the residual oil was purified by FC on silica gel in hex-
ane/EtOAc = 6:1 to give 1.52 g (96%) of 1a as an oil. 1H NMR
(400 MHz, [D6]DMSO, 353 K): δ = 5.62 (s, 2 H), 3.69 (t, J =
7.4 Hz, 2 H), 2.90 (d, J = 15.7 Hz, 2 H), 2.45 (d, J = 15.3 Hz, 2
H), 2.16 (t, J = 7.4 Hz, 2 H), 1.37 (s, 9 H) ppm. Owing to the
hindered rotation of the amide group the signals are doubled in the
13C NMR spectrum. 13C NMR (CDCl3, 100 MHz): δ = 155.53,
154.59, 128.81, 128.63, 79.54, 79.33, 73.32, 73.05, 45.66, 45.32,
44.42, 43.87, 33.96, 29.09 ppm. MS (EI, 70 eV): m/z (%) = 209 (3)
[M]+, 194 (2), 183 (2), 170 (2), 154 (10), 153 (8), 140 (28), 136 (7),
120 (3), 108 (28), 107 (8), 94 (33), 93 (22), 92 (100), 91 (86), 80
(25), 79 (32), 77 (39), 67 (8), 57 (10), 53 (6), 51 (11), 41 (25), 39
(19). C12H19NO2 (209.2): calcd. C 68.87, H 9.15, N 6.69; found C
68.84, H 9.14, N 6.65.
N-(tert-Butoxycarbonyl)-2,2-dimethyl-1-azaspiro[4.4]non-7-ene (3a):
The procedure followed was similar to that used for the preparation
and after hydrolysis the saturated amino alcohol 2f was ob- of 1a. A mixture of N-tert-butoxycarbonyl-2,2-diallyl-5,5-dimethyl-
pyrrolidine (5.6 g, 20 mmol), Grubbs’ catalyst I (162 mg, 0.2 mmol,
1.0 mol-%), and CH2Cl2 (80 mL) was heated under reflux for 4 h.
Flash chromatography was performed on silica gel (hexane/AcOEt
= 6:1; Rf = 0.56) to give 4.86 g (97%) of 3a as a colorless oil. Owing
to the hindered rotation of the amide group the signals are doubled
tained in 86% yield for the two steps.
Conclusions
We have elaborated a new method for the synthesis of in the 1H NMR spectrum and most of the signals are poorly re-
spiro-β-amino alcohols, which are valuable reagents in nat-
ural product synthesis. The method is based on the trans-
formation of Boc-protected azaspiro-olefins to amino
alcohols by the halocyclocarmabation–dehydrohalogena-
tion–isomerization–hydrolysis sequence. Most of the steps
solved multiplets in the 13C NMR spectrum. 1H NMR (CDCl3,
300 MHz): δ = 5.68 and 5.61 (both s, total 2 H), 3.13 and 2.95
(both d, J = 15.1 and 15.3 Hz, total 2 H), 2.25–2.13 (m, 2 H), 1.88
and 1.76 (both m, total 4 H), 1.50, 1.43, 1.38 (all s, total 15 H) ppm.
MS (EI, 70 eV): m/z (%) = 252 (2) [MH]+, 196 (35), 195 (100), 183
(12), 180 (17), 166 (33), 164 (20), 155 (29), 150 (24), 140 (22), 138
do not require chromatography and were performed on the
(19), 136 (51), 134 (51), 122 (20), 119 (45), 107 (16), 94 (36), 91
mmol scale. The mild conditions used for the allylic-type
isomerization may be compatible with other functional
groups in similar substrates.
(34), 79 (20), 77 (21), 67 (12), 41 (21), 39 (17). C15H25NO2 (251.4):
calcd. C 71.67, H 10.02, N 5.57; found C 71.74, H 10.10, N 5.52.
Procedure for the Reaction of 1a–5a with NBS
(1R*,7S*,9R*)-9-Bromo-2-oxa-4-azatricyclo[5.2.1.04.7]decan-3-one
(1b): NBS (2.31 g, 12 mmol) was added to a solution of 1a (2.09 g,
10 mmol) in 1,2-dichloroethane (30 mL). The mixture was stirred
at reflux for 2 h. Then the solvent was removed under reduced pres-
sure. The residue was treated with Et2O (20 mL) and 10% NaOH
(10 mL) and stirred for 15 min. The organic layer was separated,
Experimental Section
General: All reactions and manipulations with triallylborane[10]
were carried out under dry Ar. Flash chromatography was per-
formed on silica gel (60–230 mesh, Merck). NMR spectra were re-
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Synthesis of Spiro-β-Amino Alcohols and (Ϯ)-Cephalotaxine
washed with brine (10 mL), dried with K2CO3, and the solvents
evaporated. The residual oil was purified by flash chromatography
in hexane/EtOAc = 1:1 (TLC, hexane/EtOAc = 1:1, Rf = 0.42) to
give 1.70 g (73 %) of tricyclic bromide 1b as a colorless oil. 1H
4.0, 14.8 Hz, 1 H), 1.98–1.87 (m, 4 H), 0.87 (s, 9 H), 0.03 and 0.02
(both s, total 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.24,
84.27, 68.75, 62.26, 59.43, 51.19, 47.46, 34.89, 32.35, 26.22, 25.92
(3 CH3), 18.19, –5.36, –5.56 ppm. C16H28BrNO3Si (390.4): calcd.
NMR (300 MHz, CDCl3): δ = 4.88 (d, J = 3.0 Hz, 1 H), 4.37 (ddd, C 49.23, H 7.23, Si 7.19; found C 49.25, H 7.21, Si 7.20.
J = 2.0, 4.8, 7.8 Hz, 1 H), 4.09–3.94 (m, 2 H), 3.08 (ddd, J = 2.3,
4b_min: Transparent needles, m.p. 78–79 °C (hexane). [α]2D5 = –87.2
7.8, 14.0 Hz, 1 H), 2.52 (dd, J = 6.6, 8.7 Hz, 2 H), 2.37 (dd, J =
(c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.75 (d, J =
3.0, 12.5 Hz, 1 H), 2.20 (dd, J = 4.8, 14.2 Hz, 1 H), 2.08 (d, J =
2.3 Hz, 1 H), 4.30 (ddd, J = 1.8, 4.3, 8.0 Hz, 1 H), 4.01 (dd, J =
12.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.1; 85.69;
3.9, 10.3 Hz, 1 H), 3.94–3.90 (m, 1 H), 3.54 (dd, J = 2.3, 10.3 Hz,
72.56; 49.60; 46.84; 46.38; 34.64; 22.62 ppm. MS (EI, 70 eV): m/z
1 H), 3.09 (ddd, J = 2.1, 7.8, 14.4 Hz, 1 H), 2.41 (dd, J = 2.7,
12.6 Hz, 1 H), 2.09–1.87 (m, 5 H), 1.80 (d, J = 12.6 Hz, 1 H), 0.86
(%) = 234/232 (8) [MH]+, 173/171 (2), 153 (8), 152 (79), 124 (15),
109 (11), 108 (77), 106 (17), 96 (8), 95 (6), 94 (4), 93 (6), 82 (9), 81
(s, 9 H), 0.03 and 0.02 (both s, total 6 H) ppm. 13C NMR
(26), 80 (100), 79 (48), 77 (36), 67 (7), 65 (10), 53 (44), 51 (13), 39
(100 MHz, CDCl3): δ = 150.41, 84.19, 69.01, 62.00, 60.64, 50.67,
(12). C8H10BrNO2 (232.0): calcd. C 41.40, H 4.34, N 6.04, Br 34.43;
found C 41.46, H 4.34, N 5.99, Br 34.34.
47.54, 35.60, 31.82, 25.93 (3 CH3), 25.18, 18.32, –5.29, –5.55 ppm.
MS (EI, 70 eV): m/z (%) = 392/390 (0.8) [MH]+, 334/332 (40), 290/
(1R*,8S*,10R*)-10-Bromo-2-oxa-4-azatricyclo[6.2.1.04.8]undecan-3-
288 (18), 209 (13), 208 (63), 134 (10), 118 (10), 117 (21), 116 (100),
75 (11). C16H28BrNO3Si (390.4): calcd. C 49.23, H 7.23, Si 7.19;
found C 49.21, H 7.19, Si 7.26.
one (2b): The procedure followed was similar to that used for the
preparation of 1b. A mixture of 2a (2.23 g, 10 mmol) and NBS
(2.31 g, 12 mmol) in CHCl3 (30 mL) was stirred under reflux for
1.5 h. After work-up residual oil was crystallized from hexane/Et2O
mixture to give 1.96 g (80%) of the tricyclic bromide 2b as white
crystals, m.p. 123.5–124 °C. Rf = 0.47 (hexane/EtOAc = 1:1). 1H
NMR (300 MHz, CDCl3): δ = 4.43 (d, J = 2.3 Hz 1 H), 3.91 (ddd,
J = 2.0, 4.4, 7.9 Hz, 1 H), 3.19–3.14 (m, 2 H), 2.02 (ddd, J = 2.4,
7.9, 14.3 Hz, 1 H), 1.70 (dd, J = 2.8, 12.3 Hz, 1 H), 1.39 (dd, J =
4.4, 14.3 Hz, 1 H), 1.20–1.01 (m, 5 H) ppm. 13C NMR (75 MHz,
C6D6): δ = 149.66, 83.82, 67.23, 50.49, 48.03, 46.36, 34.81, 32.69,
22.28 ppm. MS (EI, 70 eV): m/z (%) = 248/246 (10) [MH]+, 166
(22), 122 (40), 120 (100), 94 (6), 92 (5), 67 (3), 39 (4). C9H12BrNO2
(246.1): calcd. C 43.92, H 4.91, N 5.69, Br 32.47; found C 43.90,
H 4.87, N 5.77, Br 32.54.
(1R*,9S*,11R*)-9-Bromo-2-oxa-4-azatricyclo[7.2.1.04.9]dodecan-3-
one (5b): The procedure followed was similar to that used for the
preparation of 1b. A mixture of 5a (1.0 g, 4.3 mmol) and NBS
(0.9 g, 5 mmol) in DCM (15 mL) was stirred at 25 °C for 2 h. Work
up followed by FC gave 0.9 g (80.5%) of the tricyclic bromide 5b
as white crystals, m.p. 124–124.5 °C. 1H NMR (300 MHz, CDCl3):
δ = 4.73 (m, 1 H), 4.46 (ddd, J = 2.0, 4.3, 8.0 Hz, 1 H), 4.11 (dm,
J = 13.5 Hz 1 H), 3.21 (ddd, J = 2.1, 7.8, 15.1 Hz, 1 H), 2.8 (dt, J
= 3.4, 13.5 Hz, 1 H), 2.39 (dd, J = 4.4, 14.3 Hz, 1 H), 2.14 (d, J =
13.0 Hz, 1 H), 1.98 (dd, J = 4.3, 15.1 Hz, 1 H), 1.84–1.77 (m, 4 H),
1.54–1.31 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.15,
82.89, 63.32, 47.83, 47.57, 41.42, 38.82, 33.48, 24.57, 20.73 ppm.
MS (EI, 70 eV): m/z (%) = 262/260 (0.5) [MH]+, 218/216 (3), 180
(37), 137/135 (11), 136 (60), 134 (100), 108 (6), 94 (9), 93 (9), 91
(5), 55 (6), 39 (3). C10H14BrNO2 (260.1): calcd. C 46.17, H 5.42, N
5.38, Br 30.72; found C 46.24, H 5.32, N 5.42, Br 30.68.
(1S*,8S*,10S*)-10-Bromo-5,5-dimethyl-4-azatricyclo[6.2.1.04,8]un-
decan-3-one (3b): The procedure followed was similar to that used
for the preparation of 1b. A mixture of 3a (2.86 g, 11.4 mmol) and
NBS (2.63 g, 14.8 mmol) in CHCl3 (6 mL) was stirred under reflux
for 30 min. The yield of 3b after recrystallization was 2.56 g
Procedure for the Reaction of 1b–5b with tBuOK
(1R*,7S*)-2-Oxa-4-azatricyclo[5.2.1.04.7]dec-8-en-3-one (1c): A
solution of bromide 1b (1.1 g, 4.7 mmol) in THF (3 mL) was added
to a solution of tBuOK (1.06 g, 9.4 mmol) in THF (10 mL) at
–15 °C under Ar with stirring. The mixture was warmed to room
temperature and stirring was continued for 1.5 h [TLC, hexane/
EtOAc = 1:1; Rf = 0.27]. The solvent was removed under reduced
pressure and water (3 mL) and DCM (15 mL) were added to the
residue and shaken. The organic layer was separated and the aque-
ous one extracted with DCM (10 mL). The combined extracts were
dried with Na2SO4 and the solvents evaporated. The residue was
purified by FC in hexane/EtOAc = 3:2 to give 0.37 g (52%) of 1c
1
(86.4%), m.p. 102–103 °C (hexane), Rf = 0.62 (EtOAc). H NMR
(300 MHz, CDCl3): δ = 4.71 (s, 1 H), 4.37–4.34 (m, 1 H), 2.89 (ddd,
J = 1.8, 7.8, 14.4 Hz, 1 H), 2.50 (dd, J = 2.5, 12.6 Hz, 1 H), 2.14
(td, J = 10.7, 12.1 Hz, 1 H), 2.05 (dd, J = 4.3, 14.8 Hz, 1 H), 1.92
(dm, J = 12.3 Hz, 1 H), 1.81–1.73 (m, 3 H), 1.50 (s, 3 H), 1.29 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.44, 83.86, 69.57,
63.00, 51.77, 47.59, 38.66, 36.38, 30.60, 28.08, 24.56 ppm. MS (EI,
70 eV): m/z (%) = 276/274 (2) [MH]+, 260/258 (3), 232/230 (14),
216/214 (12), 204/202 (4), 194 (66), 159/157 (3), 151/149 (12), 150/
148 (100), 134 (23), 117 (7), 107 (10), 106 (14), 105 (14), 94 (25),
93 (20), 91 (20), 81/79 (8), 80 (13), 77 (14), 39 (6). C11H16BrNO2
(274.1): calcd. C 48.19, H 5.88, N 5.11, Br 29.15; found C 48.24,
H 5.87, N 5.13, Br 29.01.
1
as a solid, m.p. 62–63 °C. H NMR (400 MHz, CDCl3): δ = 6.66
(d, J = 5.6 Hz, 1 H), 6.19 (dd, J = 2.5, 5.5 Hz, 1 H), 5.16 (s, 1 H),
4.05 (d, J = 8.4 Hz, 1 H), 4.04 (d, J = 8.3 Hz, 1 H), 2.78 (dt, J =
8.6, 12.1 Hz, 1 H), 2.49 (dt, J = 6.8, 12.2 Hz, 1 H), 2.17 (dd, J =
2.4, 10.8 Hz, 1 H), 2.11 (d, J = 10.5 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.97, 145.01, 132.23, 81.89, 73.43, 47.95,
44.56, 24.06 ppm. MS (EI, 70 eV): m/z (%) = 151 (17) [M]+; 136
(4), 123 (5), 122 (14), 120 (11), 108 (10), 107 (29), 106 (100), 95
(24), 94 (34), 92 (13), 81 (7), 80 (22), 79 (59), 78 (41), 77 (62), 67
(14), 65 (17), 53 (10), 52 (18), 51 (25), 50 (19), 39 (17). C8H9NO2
(151.2): calcd. C 63.56, H 6.00, N 9.27; found C 63.53, H 6.20, N
9.19.
(1R,5S,8S,10R)-10-Bromo-5-{[tert-butyl(dimethyl)silyl]oxymethyl}-
2-oxa-4-azatricyclo[6.2.1.04,8]undecan-3-one (4b_max) and
(1S,5S,8R,10S)-10-Bromo-5-{[tert-butyl(dimethyl)silyl]oxymethyl}-
2-oxa-4-azatricyclo[6.2.1.04,8]undecan-3-one (4b_min): A solution of
4a (0.90 g, 2.45 mmol) and NBS (0.55 g, 3.12 mmol) in MeCN
(5 mL) was stirred for 30 min at 40 °C. TLC [hexane/EtOAc = 1:1;
Rf (4b_max) = 0.61, Rf (4b_min) = 0.46]. Work-up followed by FC
gave 0.40 g of 4b_max and 0.54 g of 4b_min (total yield 98%).
4b_max: Transparent plates, m.p. 98–99 °C (hexane). [α]2D5 = +34.8
(c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.78 (narrow m, (1R*,8S*)-2-Oxa-4-azatricyclo[6.2.1.04.8]undec-9-en-3-one (2c): The
1 H), 4.38 (ddd, J = 1.9, 3.8, 7.9 Hz, 1 H), 3.93–3.90 (m, 2 H), 3.60 procedure followed was similar to that used for the preparation of
(dd, J = 4.0, 11.8 Hz, 1 H), 2.94 (ddd, J = 2.1, 7.9, 14.8 Hz, 1 H),
2.54 (dd, J = 2.6, 12.6 Hz, 1 H), 2.42–2.33 (m, 1 H), 2.10 (dd, J =
1c. Bromide 2b (1.23 g, 5.0 mmol) produced 0.77 g (93%) of olefin
2c as a solid, m.p. 63–64 °C (hexane). 1H NMR (300 MHz,
Eur. J. Org. Chem. 2008, 5647–5655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5651

Yu. N. Bubnov et al.
FULL PAPER
CDCl3): δ = 6.32 (d, J = 5.5 Hz, 1 H), 6.19 (unresolved dd, J =
5.5 Hz, 1 H), 5.13 (s, 1 H), 3.62–3.56 (m, 1 H), 3.44–3.56 (m, 1 H),
122 (17), 120 (15), 119 (10), 118 (18), 106 (17), 94 (10), 93 (21), 92
(17), 91 (10), 80 (9), 79 (11), 77 (8), 65 (7), 39 (6). C10H13NO2
2.26–2.21 (m, 1 H), 2.14 (d, J = 11.4 Hz, 1 H), 2.10–1.90 (m, 3 H), (179.2): calcd. C 67.02, H 7.31, N 7.82; found C 66.98, H 7.34, N
1.85 (d, J = 10.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 7.79.
151.44, 142.85, 131.00, 80.73, 69.12, 45.25, 43.69, 31.65, 22.98 ppm.
Procedure for the Isomerization of 1c–5c with MgBr2·Et2O
(1R*,7S*)-2-Oxa-4-azatricyclo[5.3.01.7.04.7]dec-9-en-3-one (1d):
MgBr2·Et2O (80 mg, 0.3 mmol, 12 mol-%) was added to a solution
of 1c (0.35 g, 2.4 mmol) in DCM (5 mL). The mixture was stirred
at room temperature for 1 h (TLC, hexane/EtOAc = 3:2; Rf = 0.42).
After the rearrangement was complete water (0.2 mL) was added
to separate the magnesium salt. The solution obtained was passed
through a layer of Super-cel Hyflo, which after evaporation and
MS (EI, 70 eV): m/z (%) = 165 (18) [M]+; 136 (21), 121 (16), 120
(100), 118 (8), 109 (6), 108 (11), 93 (12), 92 (24), 80 (8), 77 (5), 66
(9), 65 (12), 39 (7). C9H11NO2 (165.2): calcd. C 65.44, H 6.71, N
8.48; found C 65.41, H 6.71, N 8.37.
(1S*,8S*)-5,5-Dimethyl-4-azatricyclo[6.2.1.04,8]undec-9-en-3-one
(3c): The procedure followed was similar to that used for the prepa-
ration of 1c. Bromide 3b (2.34 g, 8.5 mmol) produced 1.64 g
(100%) of olefin 3c as a solid. The yield after recrystallization was
FC purification gave 0.18 g (53%) of 1d as a solid, m.p. 69–70 °C
1.56 g (95%), m.p. 100–100.5 °C (hexane). 1H NMR (300 MHz,
CDCl3): δ = 6.28 (d, J = 5.2 Hz, 1 H), 6.04 (m, 1 H), 5.01 (s, 1 H),
2.08 (d, J = 10.7 Hz, 1 H), 2.04–2.02 (m, 2 H), 1.87–1.85 (m, 2 H),
1.73 (d, J = 10.9 Hz, 1 H), 1.46 (s, 3 H), 1.31 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 150.14, 142.31, 130.47, 80.19, 70.78,
61.54, 44.65, 39.22, 28.76, 28.13, 24.90 ppm. MS (EI, 70 eV): m/z
(%) = 193 (4) [M]+, 178 (39), 164 (6), 149 (16), 148 (46), 135 (11),
134 (100), 133 (10), 132 (70), 117 (20), 107 (9), 106 (25), 94 (9), 93
(22), 91 (30), 80 (8), 79 (7), 77 (17), 65 (15), 39 (8). C11H15NO2
(193.2): calcd. C 68.37, H 7.82, N 7.25; found C 68.42, H 7.79, N
7.27.
(hexane). 1H NMR (300 MHz, CDCl3): δ = 6.05–6.03 (m, 1 H),
5.82 (ddd, J = 2.1, 4.1, 5.9 Hz, 1 H), 5.35 (s, 1 H), 4.22 (dt, J =
9.3, 7.5 Hz, 1 H), 3.82 (td, J = 3.9, 9.3 Hz, 1 H), 3.19 (dt, J = 9.6,
11.9 Hz, 1 H), 3.11 (ddd, J = 1.8, 3.9, 18.1 Hz, 1 H), 2.69 (dm, J
= 18.0 Hz, 1 H), 2.50 (ddd, J = 3.9, 7.6, 11.9 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.30, 135.46, 128.37, 90.43, 74.33,
51.49, 43.41, 31.40 ppm. MS (EI, 70 eV): m/z (%) = 152 (10)
[MH]+, 151 (1) [M]+, 150 (4), 138 (4), 123 (10), 122 (21), 108 (7),
107 (16), 106 (89), 105 (6), 104 (9), 96 (5), 95 (68), 94 (26), 92 (61),
81 (12), 80 (24), 79 (94), 78 (61), 77 (100), 68 (14), 67 (43), 65 (33),
53 (13), 52 (40), 51 (54), 50 (28), 41 (12), 39 (28). C8H9NO2 (151.2):
calcd. C 63.56, H 6.00, N 9.27; found C 63.75, H 6.07, N 9.10.
(1R,5S,8S)-5-{[tert-Butyl(dimethyl)silyl]oxymethyl}-2-oxa-4-azatri-
cyclo[6.2.1.04,8]undec-9-en-3-one (6a): The procedure followed was
similar to that used for the preparation of 1c. Bromide 4b_max
(1.4 g, 3.6 mmol) produced 1.03 g (94%) of olefin 6a as solid, trans-
parent crystals, m.p. 58–59 °C (hexane). [α]2D5 = –17.0 (c = 1,
(1R*,8S*)-2-Oxa-4-azatricyclo[6.3.01.8.04.8]undec-10-en-3-one (2d):
The procedure followed was similar to that used for the preparation
of 1d. Olefin 2c (0.25 g, 1.5 mmol) produced 0.21 g (84%) of 2d as
1
a solid, m.p. 58–59 °C (hexane). H NMR (300 MHz, CDCl3): δ =
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 6.23 (d, J = 5.2 Hz, 1
6.06–6.04 (m, 1 H), 5.87 (ddd, J = 1.8, 4.1, 5.9 Hz, 1 H), 5.22 (s, 1
H), 3.61 (ddd, J = 6.8, 8.0, 11.6 Hz, 1 H), 3.19 (ddd, J = 4.3, 8.4,
11.6 Hz, 1 H), 2.68 (ddd, J = 2.1, 4.3, 17.3 Hz, 1 H), 2.35 (dm, J
= 17.3 Hz, 1 H), 2.21–2.08 (m, 1 H), 2.07–1.83 (m, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.56, 135.55, 128.88, 87.88, 73.96,
44.75, 44.28, 34.74, 25.78 ppm. MS (EI, 70 eV): m/z (%) = 165 (4)
[M]+, 148 (4), 136 (11), 121 (23), 120 (100), 118 (6), 106 (4), 93
(11), 92 (9), 80 (5), 66 (6), 65 (7), 39 (5). C9H11NO2 (165.2): calcd.
C 65.44, H 6.71, N 8.48; found C 65.59, H 6.74, N 8.54.
H), 6.08 (m, 1 H), 5.04 (s, 1 H), 3.88 (br. s, 1 H), 3.80 (dd, J = 4.8,
10.0 Hz, 1 H), 3.60 (d, J = 10.0 Hz, 1 H), 2.21 (m, 1 H), 2.06–1.97
(m, 4 H), 1.81 (d, J = 10.7 Hz, 1 H), 0.81 (s, 9 H), 0.01 (s, 6 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 150.93, 142.44, 131.01, 80.82,
70.17, 62.85, 58.22, 43.37, 30.24, 26.40, 25.91, 18.17, –5.38,
–5.56 ppm. MS (EI, 70 eV): m/z (%) = 309(0.1) [M]+, 264 (3), 252
(11), 250 (7), 209 (20), 208 (100), 180 (12), 120 (5), 118 (5), 75 (4).
C
16H27NO3Si (309.5): calcd. C 62.10, H 8.79, Si 9.08; found C
62.03, H 8.85, Si 9.09.
(1R*,8S*)-5,5-Dimethyl-2-oxa-4-azatricyclo[6.3.01.8.04.8]undec-10-
en-3-one (3d): The procedure followed was similar to that used for
the preparation of 1d. Olefin 3c (1.454 g, 5.53 mmol) produced
1.451 g (99 %) of 3d as a solid, m.p. 85.5–86.5 °C. 1H NMR
(CDCl3, 300 MHz): δ = 6.09–6.07 (m, 1 H), 5.89–5.85 (m, 1 H),
5.06 (s, 1 H), 2.81 (d, J = 17.6 Hz, 1 H), 2.47 (d, J = 17.6 Hz, 1
H), 2.10–1.98 (m, 3 H), 1.89–1.81 (m, 1 H), 1.48 (s, 3 H), 1.41 (s,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 156.78, 136.75, 128.40,
87.10, 75.09, 60.46, 47.79, 43.10, 35.97, 29.78, 24.41 ppm. MS (EI,
70 eV): m/z (%) = 193 (17) [M]+, 164 (11), 150 (11), 149 (60), 148
(99), 134 (100), 132 (53), 122 (10), 121 (13), 120 (12), 117 (20), 106
(44), 93 (45), 91 (40), 80 (16), 77 (19), 65 (20), 39 (11). C11H15NO2
(193.2): calcd. C 68.37, H 7.82, N 7.25; found C 68.25, H 7.78, N
7.15.
(1S,5S,8R)-5-{[tert-Butyl(dimethyl)silyl]oxymethyl}-2-oxa-4-azatri-
cyclo[6.2.1.04,8]undec-9-en-3-one (6b): Bromide 4b_min (1.98 g,
5.07 mmol) produced 1.28 g (82%) of olefin 6b as a solid, m.p. 33–
1
34 °C. [α]2D5 = –88.7 (c = 1, CHCl3). H NMR (300 MHz, CDCl3):
δ = 6.22 (d, J = 5.2 Hz, 1 H), 6.08 (dd, J = 2.0, 5.2 Hz, 1 H), 4.98
(s, 1 H), 3.88 (m, 1 H), 3.82 (dd, J = 4.8, 10.0 Hz, 1 H), 3.58 (dd,
J = 2.0, 9.9 Hz, 1 H), 2.25–2.13 (m, 1 H), 2.08–1.90 (m, 4 H), 1.75
(d, J = 10.7 Hz, 1 H), 0.79 (s, 9 H), –0.04 and –0.06 (both s, 6
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 151.16, 144.29, 130.20,
80.64, 70.01, 62.58, 59.18, 44.05, 30.16, 25.92, 25.79, 18.28, –5.30,
–5.56 ppm. C16H27NO3Si (309.5): calcd. C 62.10, H 8.79, Si 9.08;
found C 62.14, H 8.76, Si 9.11.
(1R*,9S*)-2-Oxa-4-azatricyclo[7.2.1.04.9]dodec-10-en-3-one (5c):
The procedure followed was similar to that used for the preparation
of 1c. Bromide 5b (0.35 g, 1.35 mmol) produced 0.22 g (87%) of
olefin 5c as a solid, m.p. 83.5–84.5 °C. 1H NMR (600 MHz,
CDCl3): δ = 6.60 (d, J = 6.0 Hz, 1 H), 6.21 (dd, J = 2.3, 5.5 Hz, 1
H), 4.92 (s, 1 H), 4.00 (dt, J = 1.8, 13.3 Hz, 1 H), 2.72 (td, J = 3.2,
13.3 Hz, 1 H), 2.03 (d, J = 11.4 Hz, 1 H), 1.86 (dd, J = 2.3, 11.5 Hz,
1 H), 1.83–1.71 (m, 4 H), 1.51–1.43 (m, 2 H) ppm. 13C NMR
(1R,5S,8S)-5-{[tert-Butyl(dimethyl)silyl]oxymethyl}-2-oxa-4-azatri-
cyclo[6.3.01.804.8]undec-10-en-3-one (7a): The procedure followed
was similar to that used for the preparation of 1d. Olefin 6a (0.96 g,
3.1 mmol) produced 0.87 g (91%) of 7a as a solid, m.p. 56–57 °C.
[α]2D5 = –55.3 (c = 1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ =
6.02 (m, 1 H), 5.85 (m, 1 H), 5.19 (s, 1 H), 3.86 (m, 1 H), 3.70 (m,
2 H), 2.95 (d, J = 17.6 Hz, 1 H), 2.32 (d, J = 17.6 Hz, 1 H), 2.23–
(150 MHz, CDCl3): δ = 153.73, 141.78, 132.68, 79.14, 64.52, 46.40, 2.02 (m, 2 H), 1.95–1.84 (m, 2 H), 0.89 (s, 9 H), 0.05 (s, 6 H) ppm.
42.61, 31.20, 24.72, 21.00 ppm. MS (EI, 70 eV): m/z (%) = 179 (11) 13C NMR (CDCl3, 75 MHz): δ = 161.09, 135.64, 128.63, 87.99,
[M]+, 160 (8), 158 (8), 150 (12), 138 (9), 136 (9), 135 (27), 134 (100),
74.17, 64.67, 60.61, 45.03, 36.18, 28.75, 25.92, 18.39, –5.36,
5652
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5647–5655

Synthesis of Spiro-β-Amino Alcohols and (Ϯ)-Cephalotaxine
–5.48 ppm. C16H27NO3Si (309.5): calcd. C 62.10, H 8.79, N 4.53, 46.12, 45.39, 37.78, 25.89 ppm. MS (EI, 70 eV): m/z (%) = 139 (45)
Si 9.08; found C 62.08, H 8.74, N 4.56, Si 9.12.
[M]+, 138 (59), 123 (31), 122 (58), 120 (87), 117 (61), 110 (51), 109
(32), 97 (43), 95 (45), 91 (37), 83 (100), 82 (95), 80 (42), 79 (47), 77
(37), 67 (51), 57 (32), 55 (26), 41 (34), 39 (25). C8H13NO (139.2):
calcd. C 69.03, H 9.41, N 10.06; found C 68.99, H 9.46, N 10.01.
(1S,5S,8R)-5-{[tert-Butyl(dimethyl)silyl]oxymethyl}-2-oxa-4-azatri-
cyclo[6.3.01.804.8]undec-10-en-3-one (7b): The procedure followed
was similar to that used for the preparation of 1d. Olefin 6b (1.10 g,
3.6 mmol) produced 0.90 g (82 %) of 7b as a solid, m.p. 43.5–
44.5 °C. [α]2D5 = +30.4 (c = 0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 6.05 (dt, J = 2.4, 5.9 Hz, 1 H), 5.83 (ddd, J = 2.2,
(5R*,6S*)-1-Azaspiro[4.4]nonan-6-ol (2f): The procedure followed
was similar to that used for the preparation of 1e. A carbamate
(0.30 g, 1.8 mmol) obtained after hydrogenation of 2d produced
1
4.5, 5.9 Hz, 1 H), 5.08 (t, J = 2.0 Hz, 1 H), 4.38 (dd, J = 3.8, 0.233 g (92%) of amino alcohol 2f as an oil. H NMR (400 MHz,
10.1 Hz, 1 H), 3.70 (dd, J = 2.2, 10.2 Hz, 1 H), 3.64 (dddd, J =
1.6, 2.2, 3.8, 8.5 Hz, 1 H), 2.73 (ddd, J = 2.3, 4.5, 17.6 Hz, 1 H),
2.38 (dt, J = 2.3, 17.6 Hz, 1 H), 2.28–2.09 (m, 3 H), 1.71–1.67 (m,
1 H), 0.86 (s, 9 H), 0.04 and 0.03 (both s, total 6 H) ppm. A split-
ting of several signals was observed in the 13C NMR spectrum and
are shown in parentheses. 13C NMR (CDCl3, 75 MHz): δ = 156.94,
136.59, 128.55, 87.35, 75.14, 60.90, (57.21, 57.13), 47.00, 35.55,
CDCl3): δ = 3.36 (dd, J = 2.2, 4.2 Hz, 1 H), 2.92 (dt, J = 5.1,
8.0 Hz, 1 H), 2.71 (dt, J = 4.9, 8.0 Hz, 1 H), 1.80–1.42 (m, 10
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 75.53, 71.76, 46.10,
36.78 2C, 32.36, 26.49, 20.90 ppm. MS (EI, 70 eV): m/z (%) = 141
(12) [M]+, 125 (10), 123 (34), 119 (41), 112 (31), 110 (31), 97 (45),
95 (40), 91 (31), 83 (100), 82 (98), 80 (50), 79 (37), 76 (22), 57 (29),
55 (16), 41 (24), 39 (32). C8H15NO (141.2): calcd. C 68.04, H 10.71,
31.97, (26.09, 25.82, 25.79, 25.52), 18.15, (–5.58, –5.62), (–5.71, N 9.92; found C 67.93, H 10.75, N 9.91.
–5.74) ppm. MS (EI, 70 eV): m/z (%) = 309(0.1) [M]+, 252 (16), 250
(6), 209 (17), 208 (100), 206 (5), 180 (12), 134 (6), 132 (5), 75 (4).
C16H27NO3Si (309.5): calcd. C 62.10, H 8.79, N 4.53, Si 9.08; found
C 62.19, H 8.77, N 4.54, Si 9.01.
(5R*,6S*)-2,2-Dimethyl-1-azaspiro[4.4]non-7-en-6-ol (3e): The pro-
cedure followed was similar to that used for the preparation of 1e.
Carbamate 3d (1.253 g, 6.5 mmol) produced 0.978 g (90%) of 3e as
an oil. 1H NMR (CDCl3, 300 MHz): δ = 5.81 (dtd, J = 0.5, 2.1,
(1R*,9S*)-2-Oxa-4-azatricyclo[7.3.0.1.904.9]dodec-11-en-3-one (5d): 6.1 Hz, 1 H), 5.77 (ddd, J = 2.1, 3.7, 5.9 Hz, 1 H), 3.93 (s, 1 H),
The procedure followed was similar to that used for the preparation
3.12 (br. s, 2 H), 2.45 (dtd, J = 0.7, 2.3, 16.7 Hz, 1 H), 2.39 (ddd,
J = 1.8, 3.7, 16.7 Hz, 1 H), 1.99–1.84 (m, 2 H), 1.72–1.58 (m, 2 H),
1.22 (s, 3 H), 1.48 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 133.89, 131.97, 79.28, 70.56, 59.14, 46.75, 39.59, 37.69, 30.34,
of 1d. Olefin 5c (0.21 g, 1.2 mmol) produced 0.19 g (93%) of 5d as
1
a solid, m.p. 88.5–89.5 °C. H NMR (300 MHz, CDCl3): δ = 6.07–
6.05 (m, 1 H), 5.84 (ddd, J = 2.04, 4.1, 5.7 Hz, 1 H), 5.00 (s, 1 H),
3.89 (dd, J = 4.35, 13.5 Hz, 1 H), 2.91 (td, J = 3.4, 13.5 Hz, 1 H), 30.19 ppm. MS (EI, 70 eV): m/z (%) = 167 (17) [M]+, 166 (15), 150
2.80 (ddd, J = 2.1, 4.3, 17.6 Hz, 1 H), 2.40 (dd, J = 2.0, 17.6 Hz, (30), 149 (48), 148 (85), 134 (73), 132 (54), 117 (22), 111 (45), 106
1 H), 1.94–1.91 (m, 1 H), 1.81–1.44 (m, 5 H) ppm. 13C NMR
(45), 96 (100), 94 (26), 93 (47), 91 (44), 82 (16), 81 (16), 80 (22), 79
(100 MHz, CDCl3): δ = 155.73, 135.54, 128.31, 88.40, 65.35, 41.84, (22), 77 (27), 65 (22), 39 (14). C10H17NO (167.2): calcd. C 71.81,
39.35, 34.94, 24.90, 21.07 ppm. MS (EI, 70 eV): m/z (%) = 179 (23) H 10.25, N 8.37; found C 71.89, H 10.26, N 8.21.
[M]+, 135 (28), 134 (100), 120 (16), 107 (11), 106 (17), 93 (9), 92
(5), 80 (5), 79 (7), 77 (5), 65 (4), 39 (4). C10H13NO2 (179.2): calcd.
C 67.02, H 7.31, N 7.82; found C 66.85, H 7.38, N 7.77.
(2S,5S,6R)-2-(Hydroxymethyl)-1-azaspiro[4.4]non-7-en-6-ol (9a):
The procedure followed was similar to that used for the preparation
of 1e. Carbamate 8a (0.37 g, 1.9 mmol) produced 0.318 g (99%) of
Procedure for the Alkaline Hydrolysis of 1d–5d with NaOH
amino alcohol 9a as an oil. [α]2D5 = +82.7 (c = 1, MeOH). 1H NMR
(CDCl3, 300 MHz): δ = 5.29 (m, 1 H), 5.81 (s, 1 H), 4.03 (s, 1 H),
3.60 (dd, J = 3.0, 11.0 Hz, 1 H), 3.41 (dd, J = 7.5, 11.0 Hz, 1 H),
3.30–3.27 (m, 1 H), 2.50 (d, J = 16.7 Hz, 1 H), 2.33 (d, J = 16.7 Hz,
1 H), 1.91–1.68 (m, 3 H), 1.62–1.53 (m, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 134.01, 132.56, 79.15, 70.05, 65.21, 59.33,
45.14, 37.45, 27.60 ppm. MS (EI, 70 eV): m/z (%) = 169 (8) [M]+,
168 (5), 152 (21), 150 (17), 138 (58), 121 (11), 120 (75), 118 (59),
113 (34), 106 (17), 103 (25), 95 (12), 94 (24), 93 (16), 91 (34), 82
(100), 80 (23), 79 (14), 77 (29), 67 (20), 39 (11). C9H15NO2 (169.2):
calcd. C 63.88, H 8.93, N 8.28; found C 63.69, H 9.06, N 8.16.
(4R*,5S*)-1-Azaspiro[3.4]oct-6-en-5-ol (1e): Solid NaOH (0.26 g,
6.5 mmol) was added to a solution of carbamate 1d (0.20 g,
1.3 mmol) in a mixture of MeOH (2.0 mL) and water (0.5 mL).
The mixture was heated at reflux with stirring for 2.5 h, until the
disappearance of a spot of 1d on a TLC plate (hexane/EtOAc =
1:1). Then the MeOH was evaporated under reduced pressure,
DCM (30 mL) was added, and the resulting suspension was dried
with K2CO3, filtered, and concentrated in vacuo to afford 0.13 g
(82%) of pure amino alcohol 1e as an oil. 1H NMR (400 MHz,
CDCl3): δ = 5.66 (s, 1 H), 5.61 (s, 1 H), 4.16 (s, 1 H), 3.39 (dd, J
= 8.0, 15.7 Hz, 1 H), 3.21 (dd, J = 8.0, 13.4 Hz, 1 H) 2.55 (d, J =
17.0 Hz, 1 H), 2.43 (d, J = 16.8 Hz, 1 H), 2.27–2.20 (m, 1 H),
(2R,5S,6S)-2-(Hydroxymethyl)-1-azaspiro[4.4]non-7-en-6-ol (9b):
The procedure followed was similar to that used for the preparation
2.15–2.09 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 133.32, of 1e. Carbamate 8b (0.137 g, 0.7 mmol) produced 0.11 g (93%) of
130.89, 79.23, 69.90, 45.03, 41.20, 29.92 ppm. MS (EI, 70 eV): the
product was too volatile to record a mass spectrum. C7H11NO
(125.2): calcd. C 67.17, H 8.86, N 11.19; found C 67.32, H 9.06, N
11.13.
amino alcohol 9b as an oil. [α]2D5 = –48.9 (c = 0.5, MeOH). 1H
NMR (CDCl3, 400 MHz): δ = 5.82 (s, 1 H), 5.77 (s, 1 H), 3.99 (s,
1 H), 3.55 (br. s, 1 H), 3.38–3.36 (br. m, 2 H), 2.45 (d, J = 16.5 Hz,
1 H), 2.32 (d, J = 16.5 Hz, 1 H), 1.83 (br. m, 2 H), 1.72–1.70 (m,
1 H), 1.54 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
133.48, 132.62, 79.40, 70.15, 65.80, 59.18, 45.14, 37.37, 27.34 ppm.
C9H15NO2 (169.2): calcd. C 63.88, H 8.93, N 8.28; found C 63.70,
H 9.10, N 8.12.
(5R*,6S*)-1-Azaspiro[4.4]non-7-en-6-ol (2e): The procedure fol-
lowed was similar to that used for the preparation of 1e. Carbamate
2d (0.33 g, 2.0 mmol) produced 0.24 g (84%) of amino alcohol 2e
1
as a solid, m.p. 34–35 °C. H NMR (300 MHz, CDCl3): δ = 5.86
(dtd, J = 0.7, 2.3, 5.9 Hz, 1 H), 5.79 (ddd, J = 2.0, 3.9, 5.9 Hz, 1
(1S*,5R*)-6-Azaspiro[4.5]dec-2-en-1-ol (5e): The procedure fol-
H), 4.01 (s, 1 H), 3.37 (br. s, 2 H, NH and OH), 3.03 (dt, J = 7.1, lowed was similar to that used for the preparation of 1e. Carbamate
10.0 Hz 1 H) 2.60 (dt, J = 6.2, 10.0 Hz 1 H), 2.41 (s, 2 H), 1.88–
1.70 (m, 4 H) ppm. A splitting of one signal was observed in the
13C NMR spectrum and is shown in parentheses. 13C NMR
(75 MHz, CDCl3): δ = 133.72, 132.32, (79.87, 79.33, 78.88), 69.84,
5d (0.18 g, 1.0 mmol) produced 0.13 g (89%) of amino alcohol 5e
as a solid, m.p. 87–88 °C. H NMR (300 MHz, CDCl3): δ = 5.84–
5.82 (m, 1 H), 5.77–5.75 (m, 1 H), 4.24 (br. s, 2 H, OH and NH),
4.11 (s, 1 H), 2.89 (d, J = 11.4 Hz 1 H), 2.66 (t, J = 10.7 Hz, 1 H),
1
Eur. J. Org. Chem. 2008, 5647–5655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5653

Yu. N. Bubnov et al.
FULL PAPER
2.31 (t, J = 17.8 Hz, 2 H), 1.64–1.42 (m, 6 H) ppm. A splitting of
tively determined by the refinement of the Flack parameter which
was equal 0.035(13). The hydrogen atoms were placed in calculated
one signal was observed in the 13C NMR spectrum and is shown
in parentheses. 13C NMR (75 MHz, CDCl3): δ = 132.51, 132.08, positions and refined in riding mode with fixed thermal parameters.
(81.51, 81.14, 81.05, 80.67), 60.98, 42.56, 40.70, 35.03, 25.64,
The final R factors were R1 = 0.0340 for 1488 independent reflec-
tions with IϾ2σ(I) and wR2 = 0.0772 for all 1854 independent
21.66 ppm. MS (EI, 70 eV): m/z (%) = 153(7) [M]+, 152 (7), 137
(6), 136 (48), 134 (31), 132 (5), 125 (5), 124 (14), 122 (12), 120 (6), reflections.
118 (5), 117 (6), 110 (14), 108 (13), 106 (14), 97 (100), 96 (84), 94
X-ray Crystal Structure Determination for 3e: Owing to the low
(15), 93 (11), 91 (13), 82 (18), 80 (14), 79 (10), 77 (11), 68 (9), 67
(9), 54 (11), 41 (7), 39 (8). C9H15NO (153.2): calcd. C 70.55, H
9.87, N 9.14; found C 70.71, H 10.15, N 8.98.
melting point of the sample crystallization was performed by an in
situ method. Liquid was sealed in a glass capillary with an inner
diameter of 0.3 mm. The desired crystal of acceptable quality was
grown close to the melting point. Afterwards the crystal with an
outer liquid layer was slowly cooled to 100 K. The experiment was
performed at a sample temperature equal to 100 K, which pro-
duced data for a twinned sample. The major domain of the twin
was selected by the RLatt module of the APEX2 software.[11]
Preparation of the Tetracycle 12 – Precursor for Cephalotaxine Syn-
thesis
(5R*,6S*)-1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-azaspiro[4.4]non-7-
en-6-ol (11): A solution of amide 10 (0.40 g, 1.26 mmol) in THF
(8 mL) was added dropwise to a solution of LAH (0.38 g,
1.0 mmol) in THF (6 mL) at 0–5 °C. The mixture was stirred for
1.5 h at 25 °C and then one more portion of LAH (0.38 g,
1.0 mmol) was added and the mixture was stirred for a further
0.5 h. TLC control (hexane/EtOAc = 1:1, Rf = 0.15). After the reac-
tion was complete, 10% NaOH (2 mL) was added, the precipitated
salt was filtered, washed with THF (4 ϫ5 mL), and the filtrate
evaporated under reduced pressure. The residual oil was subjected
to FC in hexane/EtOAc = 1:1 to give 0.31 g (80%) of amine 11 as
an oil. 1H NMR (400 MHz, CDCl3):[2l] δ = 6.80–6.70 (m, 3 H),
5.78 (t, J = 7.68 Hz, 2 H), 4.19 (s, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H),
3.37–3.32 (m, 1 H), 2.96 (ddd, J = 7.4, 9.6, 11.4 Hz, 1 H), 2.79
(ddd, J = 4.4, 9.0, 13.4 Hz, 1 H), 2.70 (d, J = 16.4 Hz 1 H), 2.74–
2.66 (m, 1 H), 2.59–2.49 (m, 2 H), 2.12 (d, J = 17.6 Hz, 1 H),
2.09–2.03 (m, 1 H), 1.89–1.73 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.81, 147.42, 134.37, 132.32, 131.17, 120.60, 112.05,
111.17, 80.63, 72.30 (2 C), 55.86, 52.91, 52.74, 39.28, 38.23, 35.70,
23.16 ppm. C18H25NO3 (303.4): calcd. C 71.26, H 8.31, N 4.62;
found C 71.31, H 8.20, N 4.57.
C10H10NO, M = 160.19, monoclinic, space group P21/n, 100 K, a
= 10.249(3), b = 6.019(2), c = 15.492(4) Å, V = 90.947(7) Å3, Z =
4 (ZЈ = 1), dcalcd. = 1.113 g/cm3, µ(Mo-Kα) = 0.73 cm–1, F(000) =
340. The intensities of 9837 reflections were measured with a
Bruker SMART APEX2 diffractometer [λ(Mo-Kα) = 0.71072 Å, ω
scans, 2θ Ͻ 58°] and were integrated by using the SAINT soft-
ware.[12] A set of 2521 independent reflections [Rint = 0.0571] were
used for further refinement. Absorption correction was applied
semi-empirically with the SADABS software.[13] The structure was
solved by a direct method and refined by the full-matrix least-
squares technique against F2 in the anisotropic–isotropic approxi-
mation. The hydrogen atoms were located by using the Fourier syn-
thesis of electron density and refined in the isotropic approxi-
mation. Refinement converged to wR2 = 0.0879 and GOF = 0.956
for all independent reflections [R1 = 0.0424 was calculated against
F for 1754 observed reflections with IϾ2σ(I)].
All the calculations performed for 2b and 3e were carried out by
using the SHELXTL PLUS program (PC Version 5.10).[14]
(3aS*,13bS*)-3,5,6,8,9,13b-Hexahydro-11,12-dimethoxy-4H-cyclo-
penta[a]pyrrolo[2,1-b][3]benzazepine (12):[2l] Amine 11 (0.318 g,
1.05 mmol) was mixed with PPA (9 g) and stirred at 60 °C for 30 h.
The reaction mixture was treated with satd. NaHCO3 (15 mL) and
then solid NaOH was added to adjust the pH to 10. The mixture
was extracted with DCM (20 mLϫ3) and then the extracts were
dried with K2CO3, filtered, and the solvent evaporated. The resid-
ual oil was purified by chromatography with hexane/EtOAc/Et3N
= 70:50:1 as eluent to afford 0.23 g (77%) of tetracycle 12 as an
CCDC-679404 (for 2b) and -696293 (for 3e) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, 1H/13C NMR spectra for the
prepared compounds, and X-ray data for compound 2b and 3e.
1
oil. H NMR (400 MHz, CDCl3): δ = 6.67 (s, 1 H), 6.62 (s, 1 H),
Acknowledgments
5.80–5.77 (m, 1 H), 5.55–5.52 (m, 1 H), 3.89 (m, 1 H), 3.86 (s, 3
H), 3.84 (s, 3 H), 3.21 (ddd, J = 7.6, 12.6, 13.5 Hz, 1 H), 3.08 (ddd,
J = 4.8, 8.9, 9.3 Hz, 1 H), 2.94 (ddd, J = 6.8, 11.6, 12.1 Hz, 1 H),
2.76 (ddd, J = 2.5, 4.8, 17.6 Hz, 1 H), 2.56 (dd, J = 7.5, 11.4 Hz,
1 H), 2.43–2.32 (m, 2 H), 2.04–1.95 (m, 3 H), 1.80–1.67 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.43, 147.07, 132.43,
130.98, 130.79, 128.53, 113.99, 112.95, 68.08, 62.24, 56.02, 55.93,
53.65, 49.07, 43.31, 34.71, 30.37, 19.88 ppm.
We are grateful to the President of the Russian Federation (Sci.
School 3834.2008.3), the Russian Foundation for Basic Research
(Grant no. 08-03-00790), and the Presidium of the R.A.S. (8, coor-
dinator: V. A. Tartakovsy) for financial support. Special thanks go
to Prof. R. H. Grubbs and J. Kibler (Materia Inc.) for a valuable
gift of metathesis catalysts.
X-ray Crystal Structure Determination for 2b: C9H12BrNO2, M =
246.11, orthorhombic, space group Pna21, T = 293 K, a =
9.0704(11), b = 13.3202(16), c = 7.9647(10) Å, V = 962.3(2) Å3, Z
= 4, F(000) = 496, dcalcd. = 1.699 g/cm3, µ = 4.238 mm–1. Data were
collected with a Bruker three-circle diffractometer equipped with a
SMART 1K CCD detector [λ(Mo-Kα) radiation, graphite mono-
chromator, φ and ω scan mode, θmax = 26°] and corrected for Lo-
rentzian and polarization effects and for absorption. The structure
was determined by direct methods and refined by a full-matrix le-
ast-squares technique on F2 with anisotropic displacement param-
eters for all non-hydrogen atoms. The absolute structure was objec-
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Received: July 30, 2008
Published Online: October 13, 2008
Eur. J. Org. Chem. 2008, 5647–5655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5655