Synthesis of Spirocyclic Imines: Key Pharmacophores in the Shellfish Toxins Spirolides and Gymnodimine

Article abstract of DOI:10.1055/s-2003-41481

The efficient synthesis of several spirocyclic imines of similar structure to that present in the shellfish toxins, the spirolides and gymnodimine, is described. The key steps involved double α-alkylation of simple lactam starting materials, Grubbs' ring closing metathesis of the resultant bis-alkylated lactams and LiEt₃BH reduction of the TEOC protected lactams to imines.

Full text of DOI:10.1055/s-2003-41481

2
042
LETTER
Synthesis of Spirocyclic Imines: Key Pharmacophores in the Shellfish Toxins
Spirolides and Gymnodimine
S
M
ynthesis of Spirocycl
i
ic Imin
ce s hael Trzoss, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 14 August 2003
2
spirolides B 2 and D 4 were elucidated together with two
Abstract: The efficient synthesis of several spirocyclic imines of
similar structure to that present in the shellfish toxins, the spirolides
and gymnodimine, is described. The key steps involved double a-
more related, but biologically inactive, compounds,
3
spirolides E and F. Recently, isolation and culture of a
alkylation of simple lactam starting materials, Grubbs’ ring closing toxic clone of the dinoflagellate Alexandrium ostenfeldii,
metathesis of the resultant bis-alkylated lactams and LiEt BH obtained from the same aquaculture site, allowed
3
4
reduction of the TEOC protected lactams to imines.
structural elucidation of spirolides A 1 and C 3. The
Key words: lactam, spirocyclic imine, shellfish toxin, spirolides A–D 1–4 cause potent and characteristic
gymnodimine, spirolides
symptoms in the mouse bioassay (spirolide A, LD 250
100
–1
mg kg ) and are activators of L-type calcium channels.
These toxins possess an unusual 7,6-spirocyclic imine
moiety within a macrocycle that also contains a novel
The production of shellfish toxins (phycotoxins) is
associated with dinoflagellate blooms (‘red tide’
phenomenon) that can result in massive kills of fish and
6
,5,5-bis-spiroacetal ring system and they closely
5,6
resemble the related shellfish toxins, the pinnatoxins
and pteriatoxin.7
1
marine animals in temperate waters. The shellfish feed
upon the micro-algae and concentrate the toxins, thereby
acting as a vector by transferring these toxins further up
the food chain. During algal blooms the level of toxins
within healthy shellfish can reach a level that is harmful to
humans causing symptoms ranging from diarrhoea to
extreme cardiovascular and neurotoxic effects at
exposures as low as a few parts per billion.
In 1994, commercial oyster beds in Southland, New
Zealand were closed due to the high levels of the marine
biotoxin gymnodimine found in the
Gymnodimine 5 contains a 6,6-spirocyclic imine ring
system analogous to that present in spiro-prorocentrimine
oysters.8
that was isolated from
a
laboratory-cultured
Prorocentrum species of Taiwan.9
The spirolides A–D, 1–4 (Figure 1), comprise a novel
family of macrocycles found in the polar lipid fraction
obtained from the digestive glands of contaminated
mussels (Mytilus edulis), scallops (Placopecten
magellanicus) and toxic plankton from the eastern coast
of Nova Scotia, Canada. Initially the structures of
The spirocyclic imine functionality is thought to be the
active pharmacophore in these toxins based on the
observations that an analogue of gymnodimine wherein
10
the imine has been reduced was inactive and that
spirolides E and F that are keto amine hydrolysis
derivatives of spirolides A–D, are also inactive.3
Me
R1
N
H
OH
O
O
O
O
H
O
O
O
Me
Me
HO
N
Me
O
Me
HO
R3
1
Gymnodimine 5
2
Spirolide A 1: ∆ R =H, R =Me
2
1
,3,
2
Spirolide B 2: R =H, R =Me
1
2
Spirolide C 3: ∆2,3, R =Me, R =Me
1
2
Spirolide D 4: R =Me, R =Me
Figure 1
SYNLETT 2003, No. 13, pp 2042–2046
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41481; Art ID: D20603ST.pdf
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spirocyclic Imines
2043
O
O
O
double alkylation
Grubbs RCM
( )n
(
)n
HN
HN
( )m
HN
(
)m
(
)m
O
protection
( )n
LiEt3BH
( )n
Me3Si
O
N
N
(
)m
( )m
O
Scheme 1
16
Diels–Alder cycloaddition of dienes to a-methylene and enantiopure spirocycles. Focusing our initial atten-
lactams has provided an efficient method for the tion on the lactam double a-alkylation step, it was noted
construction of the spirocyclic imine unit in that often the lactams are protected 17as tert-
1
1
12
15
gymnodimine and pinnatoxin A. Other approaches to butoxycarbamates or N-benzyl derivatives, thereby
form the spirocyclic imine in pinnatoxin A include necessitating a deprotection step after the ring closing
intramolecular cyclization of an epoxy-nitrile followed by metathesis. Therefore, we were prompted by the use of the
1
3
aza-Wittig reaction of an azidoketone and thermolysis labile N-trimethylsilyl lactam derivatives, as reported by
of an aminoketone. Given the importance of the Covey et al. for the synthesis of 3,3-dialkyl-e-capro-
spirocyclic imines as key structural features in these lactams, wherein the N-trimethylsilyl lactams were pre-
1
4
18
complex, highly toxic shellfish toxins, we directed our pared (benzene, Et N, trimethylsilyl chloride) and isolated
3
attention to the synthesis of a range of hindered before the alkylation step.
spirocyclic imines as potential pharmacological probes.
In the present work the N-trimethylsilyl lactams were
Towards this end, we herein report the efficient synthesis
prepared using butyllithium in THF at –78 ºC and
of spirocyclic imines from simple lactams via double
trimethylsilyl chloride before immediate subjection to the
alkylation to generate a diene precursor followed by
first a-alkylation step without isolation and purification.
In the case of the unsymmetrically disubstituted dienes 6,
Grubbs’ ring closing metathesis and reduction of the
lactam to an imine (Scheme 1).
8
and 10 the alkylations steps were performed
Support for adopting this versatile method for the sequentially whereas in the case of the symmetrically
preparation of spirocyclic imines was provided by the use substituted dienes 7, 9, and 11 the double alkylation was
of an analogous double alkylation – ring closing metathe- effected in one step using two equivalents of base with
sis strategy to construct bicyclic lactam peptidomimetics15 excess electrophile (Table 1).
Table 1 Preparation of Spirolactams19,20
PCy3
Cl
Ru
O
HN
Ph
O
O
Cl
method A or B
PCy3 5%
(
)n
( )n
HN
CH Cl r.t., 3 h.
HN
(
)m
2
2,
(
)m
( )m
Entry
m
1
1
2
2
3
3
Methoda,b
n
No.
6
Yield (%)
No.
Yield (%)
1
2
3
4
5
A
B
A
B
A
B
1
2
1
2
1
2
74
71
81
78
67
77
12
13
14
15
16
17
86
93
90
95
88
92
7
8
9
10
11
6
a
Method A: i) n-BuLi (1.05 equiv), THF, –78 °C, SiMe Cl (1.05 equiv) –78 °C to 0 °C;
3
ii) LDA (1 equiv), THF, –78 °C, 4-bromo-1-butene (1.05 equiv) –78 °C to 0 °C; iii) LDA (1.1 equiv) –78 °C, allyl iodide (1.25 equiv), –78 °C
to 0 °C.
b
Method B: i) n-BuLi (1.05 equiv), –78 °C, SiMe Cl (1.05 equiv), –78 °C to 0 °C;
3
ii) LDA (2.3 equiv) –78 °C, 4-bromo-1-butene (2.5 equiv), –78 °C to 0 °C.
Synlett 2003, No. 13, 2042–2046 © Thieme Stuttgart · New York

2
044
M. Trzoss, M. A. Brimble
LETTER
With the a,a-dialkylated dienes in hand, ring closing
O
N
O
2
1
H
metathesis
using the standard Grubbs’ catalyst
H
H
OR
proceeded readily at ambient temperature to produce
spirolactams 12–17 in high yield (Table 1). Whilst the
metathesis step proceeded uneventfully, subsequent
OR
β
O
N
δ
O
2
0
22
2
2
conversion of the lactams to imines proved more
difficult. After much experimentation, it was found that
the optimum procedure involved protection of the lactam
R = (CH ) SiMe
2 2 3
Figure 2 Proposed structures for attack of hydride on the lactam
carbonyl group of compounds 20 and 22.
as
TEOC) group followed by reduction of the amide
carbonyl using lithium triethylborohydride as described
a
fluoride-labile b-trimethylsilylethoxycarbonyl
23
(
carbons a and d to the lactam carbonyl group thus forcing
the hydride to attack the more accessible carbonyl group
of the carbamate protecting group. However, the six-
membered ring in spirolactam 20 adopts a chair
conformation in which the carbonyl group is readily
accessible to the incoming hydride source resulting in
smooth conversion to the desired spirocyclic imine 26
after treatment with tetrabutyl ammonium fluoride.
2
4
by Grieco and Kaufman.
Introduction of the TEOC group employing butyllithium
and 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate25
provided the TEOC protected lactams 18–23. Subsequent
reduction with lithium triethylborohydride at –78 °C
followed by immediate exposure to tetrabutylammonium
fluoride afforded the spirocyclic imines 24–27 in good
yield (Table 2). Spirocyclic imines 24–27 were stable
compounds that were readily purified by flash
chromatography.
In summary, an efficient method for the construction of a
range of spirocyclic imines similar to that present in the
shellfish toxins, the spirolides and gymnodimine, has
been developed. The procedure combines the use of a
convenient lactam double alkylation protocol with a
The only drawback to this reduction procedure surfaced in
the reduction of spirolactams 22 and 23 in which the
lactam was embedded in a seven-membered ring. In these
cases reduction of the carbamate carbonyl group took
place in preference to the lactam carbonyl group resulting
in formation of the corresponding N-formyl spirolactams
highly
efficient
ring-closing
metathesis
step.
Additionally, a useful method for the reduction of the
sterically hindered spirolactams to spirocyclic imines has
been extended from the work of Grieco and Kaufmann.24
2
8 and 29. This result is readily rationalized by
examination of the minimum energy conformation of the Acknowledgement
7
,6-spirolactam 22 compared to the 6,6-spirolactam 20
We thank the Royal Society of New Zealand Marsden Fund for
financial support of this work.
(
Figure 2). Simple molecular models and semi-empirical
calculations (computed for R = Me on the PM3 level)
suggest that in the seven-membered spirolactam 22 the
carbonyl group experiences considerable steric hindrance
due to transannular interactions with the hydrogens on the
Table 2 Preparation of Spiroimines26,a
O
O
(
)n
1
( )n
2
( )n
( )n
or
O
Me Si
HN
3
N
N
N
H
(
)m
( )m
( )m
4, 25, 26, 27
( )m
O
2
O
2
8, 29
Entry
M
n
1
2
1
2
1
2
No.
18
19
20
21
22
23
Yield (%)
No.
24
25
26
27
28
29
Yield (%)
1
2
3
4
5
1
1
2
2
3
3
98
99
97
98
96
97
83
70
86
84
71
74
6
a
1
. (i) n-BuLi (1.05 equiv), THF, –78 °C; (ii) 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate (1.15 equiv), –78 °C to r.t. 2. (i) LiEt H (1.2 equiv),
3
–
78 °C then work-up; (ii) Bu NF (2 equiv), THF, r.t., 12 h.
4
Synlett 2003, No. 13, 2042–2046 © Thieme Stuttgart · New York

LETTER
Synthesis of Spirocyclic Imines
2045
References
dialkylated lactam 8 (0.78 g, 4.05 mmol, 81%) was obtained
as a colorless oil after purification of the residue by column
chromatography.
(
1) Garthwaite, I. Trends in Food Science and Technology 2000,
1, 235.
1
FTIR (thin film): 3211, 3074, 2942, 1659, 1489, 1448, 997,
(
2) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter,
J. A.; Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc.,
Chem. Commun. 1995, 2159.
–1
9
11 cm .
1
H NMR (300 MHz, CDCl ): d = 6.00 (br s, 1 H, NH), 5.84–
3
5
.73 (m, 2 H, 2 × CH), 5.09–4.91 (m, 4 H, 2 × CH=CH ),
2
(
(
3) Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C.
Tetrahedron Lett. 1996, 37, 7671.
4) (a) Hu, T.; Burton, I. W.; Cembella, A. D.; Curtis, J. M.;
Quilliam, M. A.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod.
3
2
1
.28–3.23 (m, 2 H, NHCH ), 2.53–2.47 (m, 1 H, CHH),
.25–2.19 (m, 1 H, CHH), 2.15–1.99 (m, 2 H, CH ), 1.84–
2
2
.67 (m, 5 H, 2 × CH and CHH), 1.57–1.47 (m, 1 H, CHH).
2
13
C NMR (75 MHz, CDCl ): d = 176.4 (C=O), 138.6, 134.3
3
2
1
001, 64, 308. (b) Cembella, A. D.; Lewis, N. I. Nat. Toxins
999, 7, 197.
(
CH), 118.1, 114.4 (CH=CH ), 44.4 (C), 43.0, 42.7, 37.6,
2
29.3, 28.7, 19.7 (CH2).
(
5) Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng, S.;
Chen, H. J. Am. Chem. Soc. 1995, 117, 1155.
6) Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023.
7) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D.
Tetrahedron Lett. 2001, 42, 3495.
HRMS (EI): m/z for C H NO: 193.1467, found: 193.1468
1
2
19
+
[
M] .
(
(
+
MS (EI): m/z = 193 (4%) [M] , 139(100).
(
20) Typical Procedure for Metathesis Reaction:
2-Azaspiro[5.5]undec-8-en-1-one (14) - To a stirred
(
8) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H.; Yasumoto,
T. Tetrahedron Lett. 1995, 36, 7093.
solution of dialkylated lactam 8 (0.58 g, 3 mmol) in anhyd
CH Cl (30 mL) was added benzylidene-bis-(tricyclohexyl-
2
2
(
9) Lu, C.-K.; Lee, G.-H.; Huang, R.; Chou, H.-N. Tetrahedron
Lett. 2001, 1713.
phosphine)-dichlororuthenium (0.12 g, 0.15 mmol) at 23 °C
and the reaction mixture stirred for 3 h. DMSO (0.5 mL) was
added and stirring continued for 12 h. The solvents were
removed under reduced pressure and bicyclic lactam 14
(10) Stewart, M.; Blunt, J. W.; Munro, M. H. G.; Robinson, W.
T.; Hannah, D. J. Tetrahedron Lett. 1997, 38, 4889.
(
11) (a) Tsujimoto Ishihara, J.; Horie, M.; Murai, A. Synlett 2002,
(
0.45 g, 90%) was obtained as a colourless oil after
399. (b) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2,
purification of the residue by column chromatography.
763.
–1
FTIR (thin film): 2948, 1650, 1489, 1265, 729, 704 cm .
(
(
(
12) Ishihara, J.; Horie, M.; Shingo, T.; Murai, A. Synlett 2002,
03.
13) Wang, J.; Sakamoto, S.; Kamada, K.; Nitta, A.; Noda, T.;
Oguri, H.; Hirama, M. Synlett 2003, 891.
14) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S.
G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120,
1
H NMR (300 MHz, CDCl ): 5.93 (br s, 1 H, NH); 5.68–5.58
3
4
(
(
m, 2 H, 2 × CH); 3.29–3.26 (m, 2 H, NHCH ); 2.60–2.56
2
m, 1 H, CHH); 2.14–1.54 (m, 9 H, 4 × CH and CHH).
2
13
C NMR (75 MHz, CDCl ): 178.2 (C=O), 125.3, 124.6
3
(
CH), 39.7 (C), 42.6, 33.3, 30.1, 28.9, 21.3, 19.0 (CH2).
HRMS (EI): m/z for C H NO: 165.1154, found: 165.1155
1
0
15
7647.
+
[
M] .
(
(
(
15) Colombo, L.; Di Giacomo, M.; Vinci, V.; Colombo, M.;
Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59, 4501.
16) Hughes, R. C.; Dvorak, C. A.; Meyers, A. I. J. Org. Chem.
+
MS (EI): m/z = 165 (100%) [M] , 136 (80).
(
(
21) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Schuster, M.; Blechert, S. Angew. Chem.,
2001, 66, 5545.
Int. Ed. Engl. 1997, 36, 2037. (c) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371. (d) Grubbs, R. H.; Chang,
S. B. Tetrahedron 1998, 54, 4413. (e) Fürstner, A. Angew.
Chem., Int. Ed. Engl. 2000, 39, 3012. (f) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
17) (a) Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M.
H.; Price, A. T. J. Org. Chem. 1994, 59, 1418. (b) Daoust,
B.; Lessard, J. Tetrahedron 1999, 55, 3495.
(
(
18) Reddy, P. A.; Woodward, K. E.; McIlheran, S. M.; Hsiang,
B. C. H.; Latifi, T. N.; Hill, M. W.; Rothman, S. M.;
Ferrendelli, J. A.; Covey, D. F. J. Med. Chem. 1997, 40, 44.
19) Typical Dialkylation Procedure (Method A):
22) (a) Katsifis, A. G.; McPhee, M. E.; Ridley, D. D. Aust. J.
Chem. 1998, 51, 1121. (b) Hu, W.-P.; Wang, J.-J.; Lin,
F.-L.; Lin, Y.-C.; Lin, S. R.; Hsu, M.-H. J. Org. Chem. 2001,
3-Allyl-3-(3-butenyl)tetrahydro-2(1H)-pyridinone (8):
66, 2881. (c) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org.
To a stirred solution of d-valerolactam (0.49 g, 5 mmol) in
anhyd THF (30 mL) was added dropwise n-BuLi (1.6 M
solution in hexane, 3.28 ml, 5.25 mmol) at –78 °C. After
stirring for 15 min at –78 °C trimethylsilyl chloride (0.67
mL, 5.25 mmol) was added dropwise and stirring continued
for 30 min while the solution was allowed to warm to 0 °C.
The reaction mixture was then cooled to –78 °C and
transferred (via cannula) to a solution of freshly prepared
LDA (5 mmol) in anhyd THF (20 mL) at –78 °C. After
stirring for 30 min at –78 °C, 4-bromo-1-butene (0.53 mL,
Chem. 1996, 61, 4115.
23) Carpino, L. A.; Tsao, J. H. J. Chem. Soc., Chem. Commun.
(
(
(
1
978, 358.
24) Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64,
041.
25) Typical Procedure for TEOC-Protection:
-(Trimethylsilyl)ethyl 1-oxo-2-azaspiro[5.5]undec-8-
6
2
ene-2-carboxylate (20): To a stirred solution of bicyclic
lactam 14 (0.49 g, 3 mmol) in anhyd THF (30 mL) was
added dropwise a 1.6 M solution of n-BuLi in hexane (1.97
mL, 3.15 mmol) at –78 °C. After stirring for 30 min at –78
5.25 mmol) was added dropwise and stirring continued for 1
h while the solution was allowed to warm to 0 °C. The
reaction mixture was then cooled to –78 °C and transferred
to a solution of freshly prepared LDA (5.5 mmol) in anhyd
THF (20 mL) at –78 °C. After stirring for 45 min at –78 °C,
allyl iodide (0.57 ml, 6.25 mmol) was added dropwise and
stirring continued for 3 h while the solution was allowed to
warm to 23 °C. The reaction mixture was quenched by the
addition of sat. aq NH Cl solution and extracted with Et O.
°
C a solution of 2-(trimethylsilyl)ethyl 4-nitrophenyl
carbonate (0.98 g, 3.45 mmol) in anhyd THF (5 mL) was
added dropwise and stirring continued for 1.5 h while the
solution was allowed to warm up to 23 °C. The reaction
mixture was quenched by the addition of sat aq NH Cl
solution and extracted with Et O. The combined organic
4
2
layers were dried over MgSO . The solvents were removed
4
4
2
under reduced pressure and TEOC protected lactam 20 (0.90
g, 97%) was obtained as a white solid after purification of
the residue by column chromatography.
The combined organic layers were dried over MgSO . The
4
solvents were removed under reduced pressure and
Synlett 2003, No. 13, 2042–2046 © Thieme Stuttgart · New York

2
046
M. Trzoss, M. A. Brimble
LETTER
FTIR (thin film): 3025, 2952, 2899, 1769, 1713, 1438, 1379,
and extraction of the aq phase with Et O. The combined
2
–
1
1
295, 1268, 1237, 1162, 1049, 944, 860, 838 cm .
organic layers were dried over MgSO and the solvents
4
1
H NMR (300 MHz, CDCl ): 5.69–5.58 (m, 2 H, 2 × CH),
removed under reduced pressure. The crude residue was
dissolved in THF (10 mL) and treated with a 1 M solution of
TBAF in THF (2 ml, 2 mmol). After stirring for 12 h at 23
°C toluene (10 mL) was added and all solvents removed
under reduced pressure. Spiroimine 26 (0.13 g, 86%) was
obtained as a colorless oil after purification of the residue by
column chromatography.
3
4.34–4.28 (m, 2 H, OCH ), 3.76–3.60 (m, 2 H, NHCH ),
2
2
2
.65–2.57 (m, 1 H, CHH), 2.12–1.62 (m, 9 H, 4 × CH and
2
CHH); 1.13–1.06 (m, 2 H, CH Si); 0.03 (s, 9 H, SiMe ).
2
3
13
C NMR (75 MHz, CDCl ): 177.8 (C=Oamide), 155.3
3
(
C=Ocarbamate), 125.4, 124.5 (CH), 65.4 (OCH ), 43.3 (C),
2
4
7.4, 33.6, 30.7, 29.7, 21.6, 19.4 (CH ), 17.5 (CH Si), –1.6
2 2
(
SiMe3).
FTIR (thin film): 3023, 2923, 2852, 1649, 1438, 1047, 923
–
1
HRMS (EI): m/z for C H NO Si: 309.1760 (–0.8 ppm
error), found: 309.1763 [M] .
cm .
1
6
27
3
+
1
H NMR (300 MHz, CDCl ): d = 7.52 (br s, 1 H, CHN),
3
+
MS (EI): m/z = 309 (1%) [M] , 281(30), 73(100).
26) Typical Procedure for Imine Preparation:
-Azaspiro[5.5]undeca-1,8-diene (26): To a stirred
5.73–5.70 (m, 1 H, CH), 5.63–5.57 (m, 1 H, CH), 3.61–3.43
(m, 2 H, NCH ); 2.11–1.99 (m, 3 H, CH and CHH); 1.89–
(
2
2
2
1.82 (m, 1 H, CHH); 1.72–1.39 (m, 6 H, 3 × CH ).
2
1
3
solution of TEOC protected lactam 20 (0.31 g, 1 mmol) in
anhyd THF (10 mL) was added dropwise a 1 M solution of
C NMR (75 MHz, CDCl ): d = 169.6 (C=N), 126.3, 124.0
3
(CH), 34.8 (C), 49.9, 33.4, 31.1, 29.6, 21.2, 19.0 (CH ).
2
LiEt BH in THF (1.2 mL, 1.2 mmol) at –78 °C. After stirring
for 45 min at –78 °C the reaction mixture was quenched by
dropwise addition of water followed by aqueous work up
HRMS (EI): m/z for C H N: 149.1205, found: 149.1204
3
10 15
+
[M] .
+
MS (EI): m/z = 149 (95%) [M] , 120(100).
Synlett 2003, No. 13, 2042–2046 © Thieme Stuttgart · New York