Enantioselective Desymmetrization of Tropinone Derivatives by Hydroboration

Article abstract of DOI:10.1055/s-2003-42080

N-Protected tropenone derivatives 3, prepared from the respective pyrroles 5 and tetrabromoacetone (6), were used as starting materials for desymmetrization by hydroboration of the C-C double bond. Hydroboration of 3a with (-)-(Ipc)₂BH followed

Full text of DOI:10.1055/s-2003-42080

LETTER
2175
Enantioselective Desymmetrization of Tropinone Derivatives by
Hydroboration
Enantioselective
D
i
esymm
c
etrization of
T
ropinone
l
D
eriva
a
tives i Cramer, Sabine Laschat,* Angelika Baro, Wolfgang Frey
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)6854285; E-mail: sabine.laschat@po.uni-stuttgart.de
Received 17 July 2003
Dedicated to Prof. Larry Overman on the occasion of his 60th birthday.
selective hydroboration. Up to now hydroboration has
been utilized for desymmetrization purposes only in one
case. Marchionni and Vogel realized the asymmetric syn-
thesis of complex tricyclic polypropanoates in this way.4
Abstract: N-Protected tropenone derivatives 3, prepared from the
respective pyrroles 5 and tetrabromoacetone (6), were used as start-
ing materials for desymmetrization by hydroboration of the C–C
double bond. Hydroboration of 3a with (–)-(Ipc)2BH followed by
oxidation, however, gave the desired 6-hydroxylated product 4a Thus, it was tempting to investigate desymmetrization via
only in low yield due to byproduct formation. After acetalization of
the carbonyl group in 3, the corresponding acetals 8 were desymme-
trized with (Ipc)2BH and oxidative workup to chiral alcohols 11 in
hydroboration for meso alkaloids. The preliminary results
towards this goal are reported in this paper.
As shown in Scheme 2, N-protected tropenones 3 were
prepared via [4+3] cycloaddition from pyrroles 5 and
tetrabromoacetone (6).5 The required oxyallyl cation was
generated from 6 following a methodology developed by
Mann.6 In order to improve the yields, benzene was re-
placed by toluene as the solvent, and a twofold excess of
the oxyallyl component 6 was applied. This modification
resulted in decreased reaction temperatures (from 0 °C to
–12 °C). Derivatives 3a–c were isolated in moderate
yields of 40–60%.
good yields with excellent enantiomeric excesses in most cases.
Key words: desymmetrization, hydroboration, tropenone, enantio-
selectivity
Tropane alkaloids represent a class of naturally occurring
compounds which have been intensively studied due to
their variety of pharmacological activity.1 Among the
most prominent derivatives are atropine, cocaine and sco-
polamine, and well-known pharmaceuticals such as atro-
vent® and buscopan® are chemically related to the natural
products atropine and scopolamine. The synthesis of
tropane derivatives relied mostly on derivatization of the
natural compounds, e.g., scopolamine.2 In contrast, de-
symmetrization of Cs-symmetrical precursors such as 1 or
3 have been only rarely used. One important example is
the enantioselective deprotonation and subsequent aldol
reaction of tropinone 1 developed by Simpkins using a
chiral lithium amide base as the key step (Scheme 1).3
In an initial attempt functionalization of the double bond
by hydroboration was investigated preliminary with the
tropenone derivative 3a (Scheme 2). However, hydrobo-
ration of carbamate-protected 3a with (–)-diisopino-
R
N
O
Br
Br
+
Br
Br
5a−c
6 (2 equiv)
We were interested to investigate if tropenone 3 could be
desymmetrized to the chiral alcohol 4 by using enantio-
ZnEt2 (1.8 equiv)
toluene, -12 °C→r.t., 18 h
R
R
R
N
1) Ph
N
Li
Ph
Ph
N
N
1, 3
R
Yield (%) of 3
LiCl, −78 °C, THF
2) PhCHO
a
CO2Me
40
57
60
OH
b
c
Z
Ts
3a−c
O
1
2 (90% ee)
O
O
O
R
1. (−)-(Ipc)2BH, THF, −28 °C, 18 h
2. MeOH, NaOH, H2O2, 55 °C, 1 h
R
for 3a
N
N
CO2Me
CO2Me
N
HO
N
Y
3
4
X
+
HO
HO
Scheme 1
O
OH
4a, 9%
7a, 64%
SYNLETT 2003, No. 14, pp 2175–2177
Advanced online publication: 15.10.2003
0
6
.1
1
.2
0
0
3
endo/exo = 96:4; endo: >96% ee
DOI: 10.1055/s-2003-42080; Art ID: G17403ST.pdf
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

2176
N. Cramer et al.
LETTER
R
R
campheylborane (Ipc)2BH and subsequent oxidation with
H2O2 in MeOH/NaOH7 afforded a mixture of the desired
alcohol 4a in only 9% yield, diastereomeric diols 7a as
major products (endo/exo = 96:4), and 18% of unreacted
starting material 3a. In contrast to Molander’s experi-
ments on acyclic b,g-unsaturated ketones8 a hydrobora-
tion/intramolecular reduction sequence leading to the diol
7a is not possible for steric reasons. However, an intermo-
lecular pathway might be conceivable, because Molander
demonstrated that alkenes react much faster with dialkyl-
boranes than ketones. The major diastereomer of 7a could
be separated from the minor one by recrystallization from
CHCl3, and after derivatization with (S)-(+)-Mosher’s
reagent, an enantiomeric excess of >96% was determined
for endo-7a by NMR spectroscopy.
N
N
1. (−)-(Ipc)2BH, THF,
−28 °C, 18 h
HO
2. MeOH, NaOH, H2O2,
55 °C, 1 h
X'
X'
8a−c,
9b,10b
11a−c,
12b,13b
X
X
Compd
R
X
X'
Yield (%) ee (%)
CO2Me OCH2CH2O
77
96
76
72
96
>99
>99
21
11a
11b
11c
12b
13b
Z
Ts
Z
OCH2CH2O
OCH2CH2O
OTBS H
>99
81
Z
H
OTBS
Scheme 4
To avoid the formation of byproducts 7, the carbonyl sis alcohols 11a, 11b11 and 11c and 12b, 13b were acces-
group in 3 was protected prior to hydroboration. As out- sible in good yields (72–96%). In the case of 11a and 11b
lined in Scheme 3, two different protection strategies, i.e. the ee-values were determined by GC on a chiral station-
acetalization and reduction/silylation were used. The ace- ary phase.12 Compounds 11c, 12b and 13b were deriva-
talization of compound 3a with ethylene glycol in the tized with Mosher’s reagent,13 and their enantiomeric
presence of catalytic amounts of p-TsOH in boiling ben- excesses were determined by NMR spectroscopy and ad-
zene under Dean–Stark conditions was accompanied by ditionally by GC of the diastereomers.14 The carbamate-
side-reactions, giving the acetal 8a only in 17% yield. and Z-protected tropenone derivatives 11a,b and 12b gave
Fortunately, clean acetalization of 3a–c was achieved very high enantioselectivities (>99% ee). The enantiomer-
with pyridinium p-toluenesulfonate (PPTS) as a catalyst ic excess of compound 13b was somewhat decreased to
in boiling benzene. Acetals 8a, 8b9 and 8c were obtained 81%. In contrast, N-tosyl-protected tropenone 11c dis-
in high yields of 84–93%.
played only very low enantioselectivity (21% ee). Apply-
ing Mosher’s method, the absolute configuration of
alcohols 11–13 was determined to be (S).13 In case of 11c,
X-ray diffraction confirmed this assignment.15
The reduction/silylation approach was studied for com-
pound 3b (Scheme 3). Reduction of ketone 3b with
NaBH4 in MeOH10 and subsequent silylation with tert-bu-
tyldimethylchlorosilane (TBSCl) and imidazole gave the The decreased enantioselectivity in the case of the N-to-
derivatives 9b and 10b in 85% yield in a ratio of syl-protected tropenone 8c is probably caused by steric
9b:10b = 64:36, which could be separated by chromato- hindrance of the phenyl ring of the tosyl group, being ar-
graphy.
ranged directly above the double bond, as can be seen
from the X-ray crystal structure of 8c (Figure 1).15
The protected tropenone derivatives 8a–c, 9b and 10b
were submitted to hydroboration with (Ipc)2BH in THF at
–28 °C as depicted in Scheme 4. After oxidative hydroly-
R
R
N
N
PPTS, benzene
(CH2OH)2
reflux, 8 h
O
O
O
3a−c
8a (85%)
8b (84%)
8c (93%)
1) NaBH4, MeOH, rt, 3 h
2) TBSCl, imidazole, DMF, r.t., 16 h
for 3b
85%
Z
Z
N
N
+
OTBS
9b
10b
OTBS
:
64
36
Figure 1 ORTEP view of the N-tosyl protected tropenone derivati-
ve 8c
Scheme 3
Synlett 2003, No. 14, 2175–2177 © Thieme Stuttgart · New York

LETTER
Enantioselective Desymmetrization of Tropinone Derivatives
2177
(C-6, C-7), 136.6 (Ar), 152.2 (CO) ppm. FT-IR (ATR): 2958
(m), 2926 (m), 2881 (m), 2360 (m), 2341 (m), 1695 (vs),
1411 (s), 1345 (s), 1300 (vs), 1088 (vs)cm–1. MS (EI): m/z
(%) = 301 (15) [M+], 257 (10) [M+ – C2H6O2], 170 (10), 91
Thus, during attack of the bulky borane reagent from the
exo-face interactions with the tosyl group result in a de-
creased energy difference between diastereomeric transi-
tion states (i.e. attack at the Re carbon versus Si carbon of
the double bond). It should be noted that the observed
conformation of the N-tosyl group in 8c is not merely a
crystal packing effect, but it is also present in solution, as
evidenced by the significant high field shift of the olefinic
signals in the 1H NMR spectrum of the tosyl derivative 8c
(d = 5.68 ppm) compared to the carbamate- and Z-protect-
ed compounds 8a (d = 6.15 ppm) and 8b (d = 6.09–6.22
ppm).
+
(100) [C7H7 ]. Anal. Calcd for C17H19NO4 (301.3): C, 67.76;
H, 6.36; N, 4.65. Found: C, 67.56; H, 6.44; N, 4.60.
(10) Burke, S. D.; Danheiser, R. L. Handbook of Reagents for
Organic Synthesis, Oxidizing and Reducing Agents; Wiley
Verlag: New York, 1999.
(11) (–)-N-Benzyloxycarbonyl-6-exo-hydroxy-{spiro-8-
azabicyclo[3.2.1]octane-3,2¢-[1,3]dioxolane} (11b). A
solution of 8b (5.08 mg, 16.88 mmol) in absolute THF (8
mL) was added at –28 °C to crystalline (Ipc)2BH (7.4 g,
25.96 mmol), and the reaction mixture stirred at –28 °C for
18 h. After hydrolysis of excess borane with MeOH (2.3
mL), a 3 N NaOH solution (10 mL) and 30% H2O2 (10.7 mL)
were added and the reaction mixture heated to 55 °C with
vigorous stirring. EtOAc (100 mL) was added and the
solution washed with a NaCl solution (50 mL). The aqueous
layer was extracted with EtOAc (3 × 50 mL). The combined
organic layers were dried (Na2SO4) and concentrated.
Purification by flash chromatography on SiO2 (EtOAc)
(Rf = 0.55) gave 5.21 g (96%) of 11b as a colorless solid. Mp
112 °C (i-Pr2O/CH2Cl2), [a]D20 = –8.2 (c 1.0, CHCl3), >99%
ee. 1H NMR (500 MHz, CDCl3): d = 1.65–1.78 (br m, 2 H,
2-Heq,4-Heq), 1.79–2.08 (br m, 4 H, OH, 2-Hax,4-Hax,7-Hexo),
2.65 (dd, J = 13.4 Hz, J = 7.0 Hz, 1 H, 7-Hendo), 3.75–3.85
(m, 2 H, OCH2), 3.90–3.95 (m, 2 H, OCH2), 4.15 (br, 1 H, 1-
H), 4.44 (br, 1 H, 5-H), 4.54 (br t, J = 5.7 Hz, 1 H, 6-H), 5.13
(s, 2 H, CH2Ar), 7.28–7.37 (m, 5 H, Ar) ppm. 13C NMR (125
MHz, CDCl3): d = 38.1 (br, C-2), 39.7 (br, C-4), 40.3 (br, C-
7), 53.3 (CH2Ar), 62.3 (C-1), 63.4, 64.5 (OCH2), 67.0 (C-5),
73.8 (br, C-6), 106.8 (C-3), 127.9, 128.0, 128.5, 136.6 (Ar),
154.2 (CO) ppm. FT-IR (ATR): 3375 (s), 3288 (s), 2950 (s),
2874 (s), 2360 (vs), 2341 (vs), 1699 (vs), 1654 (vs), 1442 (s),
1408 (s), 1108 (vs), 1063 (s)cm–1. MS (EI): m/z (%) = 319
(8) [M+], 228 (30) [M+ – benzyl], 184 (20), [M+ – Z], 140
In conclusion, desymmetrization of tropenones using (–)-
diisopinocampheylborane followed by oxidation gave
convenient access to chiral tropinone derivatives.
Acknowledgment
This work was generously supported by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the Wissen-
schaftsministerium des Landes Baden-Württemberg.
References
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2676.
(9) N-Benzyloxycarbonyl-spiro{8-azabicyclo[3.2.1]oct-6-
ene-3,2¢-[1,3]dioxolane} (8b). A solution of 3b (5.63 g, 21.9
mmol), ethylene glycol (15 mL) and PPTS (0.8 g, 2.3 mmol)
in benzene (200 mL) was heated under Dean–Stark
conditions at reflux for 8 h. The reaction mixture was then
diluted with EtOAc (250 mL) and washed with H2O and a
solution of NaCl (100 mL each). The organic layer was dried
(Na2SO4) and concentrated. Flash chromatography on SiO2
with EtOAc/hexanes, 3:1 (Rf = 0.14) gave 3.49 g (84%
referred to conversion) of 8b and 2.11 g of unreacted 3b. 1H
NMR (300 MHz, CDCl3): d = 1.83 (dd, J = 13.7 Hz, J = 5.3
Hz, 2 H, 2-Heq,4-Heq), 2.10 (dd, J = 13.7 Hz, J = 3.4 Hz, 1
H, 2-Hax), 2.21 (dd, J = 13.7 Hz, J = 3.4 Hz, 1 H, 4-Hax),
3.75–3.92 (m, 4 H, OCH2), 4.65 (br, 1 H, 5-H), 4.70 (br, 1 H,
1-H), 5.12 (d, J = 12.1 Hz, 1 H, CH2Ar), 5.19 (d, J = 12.1
Hz, 1 H, CH2Ar), 6.09–6.22 (br m, 2 H, 6-H, 7-H), 7.27–7.38
(m, 5 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): d = 38.6,
39.5 (C-2, C-4), 56.4 (C-1, C-5), 63.2, 64.3 (OCH2), 66.7
(CH2Ar), 106.9 (C-3), 127.8, 127.9, 128.4 (Ar), 132.5, 132.9
+
(15), 98 (20), 91 (100) [C7H7 ]. Anal. Calcd for C17H21NO5
(319.4): C, 63.94; H, 6.63; N, 4.39. Found: C, 63.94; H, 6.67;
N, 4.30.
(12) GC was performed on a Bondex unb column (20 m × 0.25
mm) with 0.4 bar H2 as carrier gas. Compound 11a:
temperature program: 3 min at 60 °C, then 1 °C min–1
gradient to 200 °C, tR(R-11a) = 106.35 min, tR(S-
11a) = 107.26 min, >99% ee. Compound 11b: temperature
program: 3 min at 150 °C, then 2.5 °C min–1 gradient to
200 °C, tR(R-11b) = 49.32 min, tR(S-11b) = 49.93 min,
>99% ee.
(13) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 113, 4092. (c) Ward, D. E.; Rhee,
C. K. Tetrahedron Lett. 1991, 32, 7165.
(14) GC was performed on a HP-5 TA column (30 m × 0.32 mm)
with a temperature program: 16 °C min–1 gradient from
80 °C to 300 °C. Compound 12b: tR(R-12b) = 19.54 min,
tR(S-12b) = 19.62 min, >99% ee. Compound 13b: tR(R-
13b) = 19.85 min, tR(S-13b) = 19.99 min, 81% ee.
(15) CCDC 215377(11a), CCDC 215376(8c) and CCDC
217879(11c) contain the supplementary crystallographic
data of these structures. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
Synlett 2003, No. 14, 2175–2177 © Thieme Stuttgart · New York