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T. Spangenberg et al.
LETTER
(5) (a) Ella-Menye, J.-R.; Dobbs, W.; Billet, M.; Klotz, P.;
Rh(CO)2acac (1 mol%)
biphephos (2 mol%)
MeI
LiHMDS
OTBS
Mann, A. Tetrahedron Lett. 2005, 46, 1897. (b) Billet, M.;
Schoenfelder, A.; Klotz, P.; Mann, A. Tetrahedron Lett.
2002, 43, 1453. (c) Billet, M.; Klotz, P.; Mann, A.
Tetrahedron Lett. 2001, 42, 631.
6b
NBoc
Me
H2/CO (1:1), 5 bar
THF, 65 °C, 18 h
THF–DMF
H
–10 °C, 88%
9
(6) Orientating experiments with different protecting groups on
the alcohol were performed with TBS (5e/6e = 85:15), Bn
(5e/6e = 75:25), Me (5e/6e = 70:30) using conditions from
Table 1, entry 1.
O
PPh3
11
CHO
OTBS
(7) (a) Keck, G. E.; Murry, J. A. J. Org. Chem. 1991, 56, 6606.
(b) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J.
Synthesis 2000, 990.
NBoc
16 h, 65 °C, 77%
H
Me
10
(8) Typical Procedure for an Aza-Sakurai–Hosomi
Reaction: In a dry flask under argon were introduced 4
(0.756 mmol) and R2NH2 (0.756 mmol) in anhydrous
CH2Cl2 (4 mL, 0.2 M). The mixture was cooled to 0 °C by
means of an ice bath. Allylsilane (0.765 mmol) was then
added followed by a dropwise addition of a 1 M solution of
BF3·OEt2 in CH2Cl2 (0.756 mmol). The reaction was stirred
for 1 h at 0 °C before addition of sat. NaHCO3. The organic
layer was extracted with CH2Cl2 (3 ×) and dried over
Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by silica gel chromatography.
Spectroscopic data for 6a: IR(film): 2952, 2928, 2856, 1696,
1508, 1250 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.23–
7.39 (m, 10 H), 5.70–5.80 (m, 1 H), 5.05–5.21 (m, 5 H), 4.82
(dd, J = 2.0, 9.1 Hz, 1 H), 3.80–3.91 (m, 1 H), 2.26–2.40 (m,
2 H), 1.93 (ddd, J = 2.9, 10.0, 13.8 Hz, 1 H), 1.68 (br d, J =
O
OTBS
Ph
HCl, i-PrOH, 60 °C
72%
( )-2
NBoc
H
Me
12
Scheme 4 Preparation of ( )-2
vored diastereomer.17 Finally ( )-allo-lobeline was pre-
pared for the first time in seven steps (from benzaldehyde)
with an overall yield of 25%.
Thus we have reported that implementation of the aza-
Sakurai–Hosomi three-component reaction (aSH-R3C)
on 1,3-O-protected aldehydes delivered homoallylamines
in good yields and with moderate anti 1,3-diastereoselec-
tivities in an acyclic stereocontrol. The anti-allylamines
6a and 6b were used for the expeditious syntheses of two
piperidine alkaloids ( )-allo-sedamine (1a; 7 steps) and
( )-allo-lobeline (2; 7 steps), respectively, by using a cy-
clohydrocarbonylation or a one-pot hydroformylation–
Wittig reaction. We are currently focusing our efforts on
the rapid access to other biomolecules using hydroformy-
lation.
9.1 Hz, 1 H), 0.88 (s, 9 H), 0.05 (s, 3 H), –0.26 (s, 3 H). 13
C
NMR (75 MHz, CDCl3): d = 155.9 (C), 145.0 (C), 136.9 (C),
134.5 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 128.0
(CH), 127.3 (CH), 125.9 (CH), 117.8 (CH2), 72.7 (CH), 66.5
(CH2), 48.4 (CH), 44.4 (CH2), 39.7 (CH2), 25.8 (Me), 18.1
(C), –4.5 (Me), –5.1 (Me). HRMS (ESI, positive, HCOOLi):
m/z [M + Li] calcd for C23H39NO3Si: 446.2698; found:
446.2690.
(9) For a review on hydroformylation, see: Breit, B.; Seiche, W.
Synthesis 2001, 1.
(10) (a) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993,
115, 2066. (b) The structure of Biphephos is shown in
Figure 2.
Acknowledgment
MeO
OMe
This work was supported by the Ministère délégué à l’Enseigne-
ment Supérieur et à la Recherche (T.S., E.A., M.D.). The authors
thank Prof. Eric Marcioni et al. (ULP) for GC–MS analysis, and
Patrick Wehrung and Pascale Buisine (IFR 85) for HRMS spectro-
metry.
t-Bu
O
O
t-Bu
P
P
O
O
O
O
References and Notes
(1) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Kobayashi, S.;
Hirano, K.; Sugiura, M. Chem. Commun. 2005, 14.
(c) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc.
2004, 126, 7182. (d) Li, S.-W.; Batey, R. A. Chem.
Commun. 2004, 1382. (e) Vilaivan, T.; Winotapan, C.;
Bauphavichit, V.; Shimada, T.; Ohfune, Y. J. Org. Chem.
2005, 70, 3464.
(2) For a review of the history, chemistry, and biology of
Lobelia alkaloids, see: (a) Felpin, F.-X.; Lebreton, J.
Tetrahedron 2004, 60, 10127. (b) Felpin, F.-X.; Lebreton, J.
J. Org. Chem. 2002, 67, 9192. (c) Cossy, J.; Willis, C.;
Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982.
(3) Mihovilovic, M. D.; Stanetty, P. Angew. Chem. Int. Ed.
2007, 46, 8612; and references therein.
Figure 2
(11) Typical Procedure for Hydroformylation: In a dry
Schlenk glassware under argon were introduced
Rh(CO)2acac (1 mol%) and anhydrous degassed THF (1
mL). Biphephos (2 mol%) was added and CO evolution was
observed. Subsequent addition of homoallylic amide (and
PPTS) was performed. The mixture was transferred via a
syringe in a dry stainless autoclave under argon. The
glassware was rinsed with anhydrous degassed THF (3 ×) to
reach a final concentration of 0.04 M. The autoclave was
purged (3 ×) with H2/CO (1:1) before setting the pressure at
5 bar. The autoclave was heated at 65 °C (internal
(4) Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38, 997.
temperature) by means of an oil bath. Once the reaction was
Synlett 2008, No. 18, 2859–2863 © Thieme Stuttgart · New York