Stereocontrol in N-directed hydroboration: Synthesis of amino alcohols related to the piperidine alkaloids

Article abstract of DOI:10.1021/ol802781c

Treatment of 2-(2'-alkenyl)-piperidine boranes with iodine or triflic acid induces internal hydroboration with high regiocontrol, even with a terminal alkene (R H). Good stereocontrol is possible for the N-benzyl substrates. Comparisons with acyclic model

Full text of DOI:10.1021/ol802781c

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1059-1061
Stereocontrol in N-Directed
Hydroboration: Synthesis of Amino
Alcohols Related to the Piperidine
Alkaloids
Guoqiang Wang and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
edVed@umich.edu
Received December 2, 2008
ABSTRACT
Treatment of 2-(2′-alkenyl)-piperidine boranes with iodine or triflic acid induces internal hydroboration with high regiocontrol, even with a
terminal alkene (R ) H). Good stereocontrol is possible for the N-benzyl substrates. Comparisons with acyclic model structures show that the
source of regiocontrol with the terminal alkene is due to a steric effect of the axial piperidine C(3,5) hydrogens that destabilize the competing
bridged bicyclic transition state.
Recent publications from our laboratory have described the
amine-directed intramolecular hydroboration reaction from
Scheme 1. Mechanistic Considerations
unsaturated amine borane complexes 1 activated by molec-
ular iodine.1,2 The key event is an SN2-like displacement of
a leaving group by the nucleophilic alkene, as shown in the
conversion of the activated iodoborane complex 2 to an olefin
π-complex ion pair 4, followed by 4-center hydroboration
(HB) to give 6 (Scheme 1). We now report applications of
this technique to piperidine substrates that provide opportuni-
ties for stereocontrol as well as regiocontrol in the HB step.3
The optimized methodology has been evaluated in the context
of amino alcohols related to the piperidine alkaloids where
(1) Scheideman, M.; Shapland, P.; Vedejs, E. J. Am. Chem. Soc. 2003,
125, 10502
.
diastereoselectivity of HB can be deduced by NMR com-
parisons with known structures.4-7
According to our prior investigation, the major product
of homoallylic amine borane activation with I2 is formed
via the fused bicyclic transition state 5, provided that the
(2) Scheideman, M.; Wang, G.; Vedejs, E. J. Am. Chem. Soc. 2008,
130, 8669
.
(3) Stereoselective amine HB: (a) Lyle, R. E.; Carle, K. R.; Ellefson,
C. R.; Spicer, C. K. J. Org. Chem. 1970, 35, 802. Stern, P.; Trska, P.;
Ferles, M. Collect. Czech. Chem. Commun. 1974, 39, 2267. Stereoselective
N-EWG HB: (b) Fujita, Y.; Irreverre, F.; Witkop, B. J. Am. Chem. Soc.
1964, 86, 1844. Dicko, A.; Montury, M.; Baboulene, M. Tetrahedron Lett.
1987, 28, 6041. Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1991, 56,
1027. Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042. Sibi,
M. P.; Li, B. Tetrahedron Lett. 1992, 33, 4115. Hodgson, D. M.; Thompson,
A. J.; Wadman, S.; Keats, C. J. Tetrahedron 1999, 55, 10815.
(4) Reviews: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957. Felpin,
F.-X.; Lebreton, J. Tetrahedron 2004, 60, 10127
.
(5) Takahata, H.; Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64, 8594
.
10.1021/ol802781c CCC: $40.75
Published on Web 01/30/2009
2009 American Chemical Society

substituent R is an alkyl group. Therefore, access to the
piperidine alkaloids 8 or 9 would be readily predicted from
a homoallylic amine precursor 10, but regiocontrol issues
would be expected in the case where R) H, corresponding
to sedridine (7; Scheme 2).
16b are not separable, we could not determine whether the
low dr is due to inherently low selectivity, or due to opposite
diastereofacial preferences for each diastereomer.
An alternative approach was pursued in an attempt to
improve diastereoselectivity at the stage of amine borane
complexation. Presumably, the reaction of 14b with THF/
borane occurs with low diastereoselectivity because there is
little energy difference between the nitrogen invertomers
(axial vs equatorial lone pairs in the chairlike structure).8
Better conformational control was expected starting with the
N-benzyl substrate, so 15b was evaluated in the complexation
step with THF/borane (Scheme 4). Assuming that 15b reacts
Scheme 2. Synthesis of rac-2-(2′-Alkenyl)-piperidines
Scheme 4. Intramolecular Hydroboration from 15
Our investigation began with conversion of racemic
2-piperidineethanol 11 into the protected aldehyde 12,
followed by Wittig olefination (KOtBu/THF) to afford the
alkenes 13a-c. Structures 13b and 13c were obtained as
9:1 and 13:1 Z:E mixtures, respectively, and were used as
such in the following steps. Deprotection and benzylation
then provided the desired 2-(2′-alkenyl)-piperidine substrates
14 and 15.
Treatment of the N-H piperidines 14 (Scheme 3) with
THF-borane at -20 °C afforded amine boranes 16 as
diastereomer mixtures. The terminal alkene 16a could not
via the more stable all-equatorial conformer (lone pair axial),
the major product should be 18b (axial BH3 subunit). The
exact dr was difficult to measure because the starting amine
15b contains 11% of the isomeric E-alkene, but comparison
of the N-benzyl signals indicated a ratio of ca. 8:1 in favor
of the isomer 18b as shown in Scheme 4.
Scheme 3. Intramolecular Hydroboration from 14
Upon activation of 18b with TfOH (-20 °C, 16 h)
followed by oxidative workup, the products 20 and 21 were
obtained in an improved ratio of 4:1, this time favoring the
(6) Maio, W. A.; Sinishtaj, S.; Posner, G. H. Org. Lett. 2007, 9, 2673.
(7) Extensive synthetic work targetting piperidine alkaloids is described
in ref 4. For selected recent studies, see: (a) Davis, F. A.; Prasad, K. R.;
Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5, 925. (b) Kochi, T.; Tang, T. P.;
Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276. (c) Lesma, G.; Crippa,
S.; Danieli, B.; Passarella, D.; Sacchetti, A.; Silvani, A.; Virdis, A.
Tetrahedron 2004, 60, 6437. (d) Passarella, D.; Barilli, A.; Belinghieri, F.;
Fassi, P.; Riva, S.; Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron:
Asymmetry 2005, 16, 2225.
be purified due to partial decomplexation at rt, but the
disubstituted alkene analogs 16b and 16c survived chroma-
tography and were isolated as diastereomer mixtures (ca. 2:1
dr). Activation of 16b with iodine or with TfOH gave
aminoalcohol products after oxidative workup. However, the
diastereomer ratio of 8:17 was only 1:1.2 according to NMR
comparisons.5 Because the diastereomers of the amine borane
(8) Allinger, N. L.; Carpenter, J. G. D.; Karkowski, F. M. J. Am. Chem.
Soc. 1965, 87, 1232. Bishop, R. J.; Sutton, L. E.; Dineen, D.; Jones, R. A. Y.;
Katritzky, A. R.; Wyatt, R. J. J. Chem. Soc. B 1967, 493.
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Org. Lett., Vol. 11, No. 5, 2009

stereochemistry corresponding to rac-8-ethylnorlobelol-I (8)
according to NMR comparisons after debenzylation with
Pd(OH)2/H2.5 Initial attempts to activate 18b with iodine gave
similar dr, but these experiments were less reproducible and
afforded variable amounts of recovered amine 15b. Our
earlier study demonstrated that the recovery of unreacted
amines is due to formation of ammonium salts via competing
protonation of the amine borane B-N bond by HI, formed
during the first stage of iodine activation of the B-H bond.2
Evidently, the TfOH activation procedure is more selective
for the desired protonation at B-H vs B-N for the tertiary
N-benzylamine 18b.
Scheme 5. Regioselectivity
The same sequence of complexation and TfOH activation
was also used with 15c. Amine borane 18c was obtained as
the major isomer (9:1 dr) and treatment with TfOH gave 22
with 5:1 dr. The assignment was confirmed by debenzylation
to give rac-9 (halosaline) as the major diastereomer.6 This
outcome corresponds to preferred hydroboration via the fused
transition state 19, and is consistent with the stereochemistry
assigned to 18b and 18c.
The major and minor amino alcohol diastereomers could
not be separated in the above examples (7, 8, 9). If isomer
separation is desired, this can be done as described in the
literature using N-protected analogues.7b,d
In both of the above examples (18b,c) the regioisomeric
amino alcohols could not be detected in the product mixture
as expected.2 However, the behavior of the terminal alkene
18a was more surprising. By analogy with the prior studies
using iodine activation of acyclic terminal alkenes such as
1 (R ) H), the primary alcohol should be the major product.
However, activation of 18a using TfOH afforded the
secondary alcohol 23 with high (>20:1) regioselectivity,
similar to the results with 18b and 18c. Furthermore, 23 was
obtained with the best dr (7:1) among the N-benzyl substrates
18a-c.
To better understand the improved regioselectivity with
18a, activation of the acyclic amine borane 24 was revisited,
but using the same TfOH conditions as for the experiment
with 18a (Scheme 5). After oxidative workup, the amino
alcohols 25 and 26 were obtained in a 3:1 ratio.2 Thus, the
TfOH activating agent is not responsible for the contrasting
regioselectivity observed with 18a.
An alternative explanation for the behavior of 18a was
considered, based on the steric environment adjacent to the
ring nitrogen. The preference for product formation via the
fused transition state 19a suggests that the alternative bridged
transition state 27 (Scheme 5) leading to a primary C-B
bond is destabilized by axial C-H interactions as shown.
Such interactions are absent in the analogous bridged TS 28
from 24, resulting in hydroboration with the usual preference
for boron bonding at the less substituted (primary) carbon.
On the other hand, the more highly substituted acyclic
substrate 29 would encounter the destabilizing steric repul-
sions in the bridged TS 30, but not in the fused TS 31.
Accordingly, 29 was studied under conditions of both the
iodine and TfOH activation conditions, followed by oxidative
workup. In contrast to 24, the secondary alcohol 32 was now
the major product, and was obtained with excellent 18:1
regioselectivity (85%) using TfOH activation (16 h at -20
°C). The analogous iodine experiment gave lower 10:1
selectivity.
Overall, our results are consistent with an intramolecular
HB process that occurs with moderate to good diastereose-
lectivity (4-7:1 dr). Excellent regioselectivity is observed
with all three substrates 18a-c, and also with the gem-
dimethyl-substituted acyclic terminal alkene 29. In all of
these examples, the major product corresponds to the
preferred reaction via a fused bicyclic transition state for
amine-directed hydroboration.
Acknowledgment. This work was supported by the
National Institutes of Health (GM067146).
Supporting Information Available: Characterization of
new compounds and key NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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