Enantioselective construction of cis-2,6-disubstituted dihydropyrans: Total synthesis of (-)-centrolobine

Article abstract of DOI:10.1021/jo902167r

(Chemical Equation Presentation) This paper presents a simple and efficient route to chiral cis-6-substituted 2-(2-hydroxyethyl)-5,6-dihydro-2H-pyrans, a versatile chiral building block. The strategy is based on three key transformations: enantioselective

Full text of DOI:10.1021/jo902167r

pubs.acs.org/joc
seems to be the most straightforward route to such 6-
Enantioselective Construction of
Cis-2,6-Disubstituted Dihydropyrans: Total
Synthesis of (-)-Centrolobine
membered rings, this approach is relatively rarely em-
ployed.2 This fact can be attributed to the necessity to ensure
not only high enantioselectivity but also diastereoselectivity
of cycloaddition. Moreover, syntheses of properly substi-
tuted sophisticated dienes could be challenging and thus
discourage use of the Diels-Alder strategy. For instance,
out of 18 reported total syntheses of (-)-centrolobine,3 only
one is based on the Diels-Alder reaction strategy.4
Herein, we present an efficient and highly enantioselective
route to cis-6-substituted 2-(2-hydroxyethyl)-5,6-dihydro-
2H-pyrans 1, useful building blocks (Scheme 1).5 The strat-
egy is based on three key transformations: enantioselective
hetero-Diels-Alder (HDA) reaction6 of an aldehyde with
Danishefsky’s diene, a highly selective reduction of carbonyl
function, and the Claisen or related rearrangement.7 Stable
and well-defined salen chromium complexes are the catalysts
of choice for the enantioselective HDA reaction.8 In parti-
cular, the easily accessible sterically modified salen com-
plex 2 (Figure 1)9,10 was shown to catalyze cycloaddition of
Danishefsky’s diene 3 to various aldehydes 4 in high yields
and enantioselctivities.10 Furthermore, Luche reduction11
is a well-established procedure for the conversion of the
pyranones of type 5 to the corresponding allyl alcohols 6
in a completely cis-selective fashion.12 The alcohol 6 was
acetylated to produce ester 7, which was subjected to the
Ireland-Claisen rearrangement.13 Notably, all transforma-
tions (namely: reduction, acetylation, and rearrangement)
Wojciech Chazadaj,† Rafaz Kowalczyk,‡ and
Janusz Jurczak*,†,§
†Institute of Organic Chemistry, Polish Academy of Sciences,
01-224 Warsaw, Poland, ‡Department of Organic Chemistry,
Faculty of Chemistry, Wroczaw University of Technology,
50-370 Wroczaw, Poland, and §Department of Chemistry,
Warsaw University, 02-093 Warsaw, Poland
jurczak@icho.edu.pl
Received October 14, 2009
This paper presents a simple and efficient route to chiral cis-
6-substituted 2-(2-hydroxyethyl)-5,6-dihydro-2H-pyrans, a
versatile chiral building block. The strategy is based on three
key transformations: enantioselective hetero-Diels-Alder
(HDA) reaction of aldehyde with Danishefsky’s diene, selec-
tive reduction of carbonyl function, and Claisen or related
rearrangement. The synthetic utility of the methodology is
illustrated by total synthesis of antibiotic (-)-centolobine.
(4) Washio, T.; Yamaguchi, R.; Abe, T.; Nambu, H.; Anada, M.;
Hashimoto, S. Tetrahedron 2008, 63, 12037.
(5) For examples, see: (a) Bhattacharjee, A.; Soltani, O.; De Brabander, J.
K. Org. Lett. 2002, 4, 481. (b) Paterson, I.; Anderson, E. A.; Dalby, S. M.;
Loiseleur, O. Org. Lett. 2005, 7, 4125. (c) Kang, E. J.; Cho, E. J.; Lee, Y. E.;
Ji, M. K.; Shin, D. M.; Chung, Y. K.; Lee, E. J. Am. Chem. Soc. 2004, 126,
2680. (d) Kang, E. J.; Cho, E. J.; Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S.
Y.; Chung, Y. K.; Kim, J.-S.; Kim, H. -J.; Lee, S. -G.; Lah, M. S.; Lee, E.
J. Org. Chem. 2005, 70, 6321.
(6) For a representative review on the HDA, see: (a) Jorgensen, K. A.
Angew. Chem., Int. Ed. 2000, 39, 2398. (b) Cycloaddition Reaction in Organic
Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2002.
(7) Martin Castro, A. M. Chem. Rev. 2004, 104, 2939.
The tetrahydropyran moiety is a common motif in a
number of natural and synthetic compounds possessing
biological activity.1 Although the oxo-Diels-Alder reaction
(8) (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
403. (b) Aikawa, K.; Irie, R; Katsuki, T. Tetrahedron 2001, 57, 845. (c)
Michara, J.; Aikawa, K.; Uchida, T.; Irie, R.; Katsuki, T. Heterocycles 2001,
54, 395. (d) Kwiatkowski, P.; Asztemborska, M.; Caille, J.-C.; Jurczak, J.
Adv. Synth. Catal. 2003, 345, 506. (e) Kosior, M.; Kwiatkowski, P.; Asztem-
borska, M.; Jurczak, J. Tetrahedron: Asymmetry 2005, 16, 2897. (f) Kwiat-
kowski, P.; Asztemborska, M.; Jurczak, J. Synlett 2004, 1755. (g)
Malinowska, M.; Kwiatkowski, P.; Jurczak, J. Tetrahedron Lett. 2004, 45,
7693. (h) Kwiatkowski, P.; Chazadaj, W.; Malinowskia, M.; Asztemborska,
M.; Jurczak, J. Tetrahedron: Asymmetry 2005, 16, 2959. (i) Chazadaj, W.;
Kwiatkowski, P.; Jurczak, J. Synlett 2006, 3263. (j) Berkesel, A.; Vogel, N.
Eur. J. Org. Chem. 2006, 5029.
(1) For representative examples, see: (a) Morris, J. C.; Phillips, A. J. Nat.
Prod. Rep. 2009, 25, 95. (b) Nicolaou, K. C.; Synder, S. A. Classics in Total
Synthesis: Wiley-VCH: Weinheim, 2003. (b) Smith, A. B. III; Fox, R. J.; Razler,
T. M. Acc. Chem. Res. 2008, 41, 675.
(2) For a brief summary of strategies for construction of tetrahydropyran
ring, see: Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045.
(3) (a) Colobert, F.; Mazery, R. D.; Solladie, G.; Carreno, M. C. Org.
Lett. 2002, 4, 1723. (b) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky,
S. D. Org. Lett. 2002, 4, 3919. (c) Carreno, M. C.; Mazery, R. D.; Urbano, A.;
Colobert, F.; Solladie, G. J. Org. Chem. 2003, 68, 7779. (d) Evans, P. A.; Cui,
J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883. (e) Lee, E.; Kim, H. J.; Jang, W. S.
Bull. Korean Chem. Soc. 2004, 25, 1609. (f) Boulard, L.; BouzBouz, S.; Cossy,
J.; Franck, X.; Figadere, B. Tetrahedron Lett. 2004, 45, 6603. (g) Clarke, P.
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_
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49, 6810.
(11) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
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Chem. 1992, 57, 3261. (c) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K.
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1740 J. Org. Chem. 2010, 75, 1740–1743
Published on Web 01/29/2010
DOI: 10.1021/jo902167r
r
2010 American Chemical Society

Chazadaj et al.
JOCNote
SCHEME 2. Synthetic Route to the Protected 2-((2R,6S)-6-(2-
Hydroxyethyl)-5,6-dihydro-2H-pyran-2-yl)-2-methylpropanoic Acid:
A Building Block Useful in the Synthesis of (þ)-SCH 351448
FIGURE 1. Sterically modified (salen)Cr complex.
SCHEME 1. Synthetic Route to Cis-6-Substituted 2-(2-Hydroxy-
ethyl)-5,6-dihydro-2H-pyrans 1
SCHEME 3. Synthesis of (-)-Centrolobine
were almost quantitative; after typical extractive workup, the
reaction products were sufficiently pure for further transfor-
mations. Finally, the silyl ester 8 was reduced, yielding the
desired cis-6-substituted 2-(2-hydroxyethyl)-5,6-dihydro-
2H-pyran 1, which could be hydrogenated to a tetrahydro-
pyran or further functionalized at the double bond and the
hydroxy group.
Aldehydes 4a-c were converted to the dihydropyrans
1a-c in overall yields and enantioselectivities exceeding
45% yield and 90% ee, respectively. In the case of the least
reactive anisaldehyde, application of 1.5 equiv of Danishefs-
ky’s diene was necessary to ensure high reaction yield; under
standard reaction conditions (1 equiv of diene), the resulting
pyranone was formed in only 61% yield.
The methodology is not limited to the rearrangement of
acetates. In order to show its potential, (R)-2-(2-(benzyloxy)-
ethyl)-2H-pyran-4(3H)-one 10, obtained in the HDA reac-
tion from 3-benzyloxypropionaldehyde 9, was subsequently
reduced to alcohol 11, converted to the isobutyrate 12, and
subjected to the Ireland-Claisen rearrangement (Scheme 2).
The silyl ester 13 was isolated after three steps from 10 in
91% as a sole product employing only extractions but no
chromatography at any step. The compound 13 is an inter-
esting building block that can be utilized in the total synthesis
of (þ)-SCH 351448, a low density lipoprotein receptor
promoter.5c,d,14 To the best of our knowledge, none of the
reported total syntheses methods of (þ)-SCH 351448 em-
ployed the HDA reaction for the construction of tetrahy-
dropyran rings.
(14) (a) Cheung, L. L.; Marumoto, S.; Anderson, C. D.; Rychnovsky, S.
D. Org. Lett. 2008, 10, 3101. (b) Chan, K. -P.; Ling, Y. H.; Loh, T.-P. Chem.
Commun. 2007, 939. (c) Chan, K.-P; Ling, Y. H.; Chan, J. L. T.; Loh, T.-P.
J. Org. Chem. 2005, 70, 6321. (d) Crimmins, M. T.; Vanier, G. S. Org. Lett.
2006, 8, 2887. (e) Backes, J. R.; Koert, U. Eur. J. Org. Chem. 2006, 2777. (f)
Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791. (g) Bolshakov, S.;
Leighton, J. L. Org. Lett. 2005, 7, 3809.
Finally, the aforementioned methodology was employed
to the total synthesis of (-)-centrolobine (Scheme 3). Dihy-
dropyran 1a, obtained from anisaldehyde in 67% yield and
J. Org. Chem. Vol. 75, No. 5, 2010 1741

Chazadaj et al.
JOCNote
TABLE 1. Synthesis of the Cis-6-Substituted 2-(2-Hydroxyethyl)-5,6-
dihydro-2H-pyrans
14.4, 3.4, 1H), 5.51 (dd, J = 6.0, 1.3, 1H), 6.92-6.96 (m, 2H),
7.31-7.35 (m, 2H), 7.45 (dd, J = 6.0, 0.7, 1H); 13C NMR 44.1,
55.3, 80.9, 107.2, 114.2, 127.7, 129.8, 160.1, 163.2, 192.3; IR
(film) ν 3064, 2983, 2957, 2935, 2905, 2834, 1673, 1613, 1592,
1515, 1270, 1247, 1236, 1229, 1181, 1044, 1031; HRMS (M þ
Na)þ calcd for C12H12O3Na 227.0679, found 227.0673; HPLC
(AD-H, n-hexane/PriOH, 9:1, 1 mL/min) tR(R) = 13.2, tR(S)
=
14.4.
(2S,4S)-2-(4-Methoxyphenyl)-3,4-dihydro-2H-pyran-4-ol 6a.
General Procedure for Luche Reduction of 2-Substituted 2H-
Pyran-4(3H)-ones 6. To the solution of CeCl3 7H2O (1.04 g, 2.8
3
mmol) in methanol (5 mL) at -30 °C was added dropwise a
solution of ketone 5a (536 mg, 2.6 mmol) in CH2Cl2 (5 mL),
followed by addition of NaBH4 (106 mg, 2.8 mmol). After being
stirred for 30 min at -30 °C, the reaction mixture was warmed to
rt and NH4Cl (aq, satd., 5 mL) was added dropwise. The mixture
was filtered through a pad of Celite and extracted with CH2Cl2
(3 ꢀ 20 mL). Combined organic extracts were washed with
NH4Cl (aq, satd., 10 mL), dried with MgSO4, and concentrated
yielding titled compound as a yellowish solid (521 mg, 2.5 mmol,
96%), which was sufficiently pure (by NMR) and was used
without further purification: 1H NMR 1.45 (brs, 1H), 2.00 (ddd,
J= 13.2, 11.8, 9.3, 1H), 2.35 (ddt, J= 13.2, 6.6, 2.0, 1H), 3.81 (s,
3H), 4.59 (brt, J= 7.8, 1H), 4.84 (dt, J = 6.2, 2.0, 1H), 4.94 (dd,
J = 11.8, 2.0, 1H), 6.50 (dd, J = 6.2, 1.1, 1H), 6.88-6.92 (m,
2H), 7.27-7.31 (m, 2H); 13C NMR 39.8, 55.3, 63.6, 76.5, 105.6,
114.0, 127.4, 132.4, 145.4, 159.4; IR (film) ν 3296, 3218, 2962,
2931, 2837, 1642, 1615, 1517, 1255, 1228, 1124, 1031; HRMS
(M þ Na)þ calcd for C12H14O3Na 229.0835, found 229.0824.
(2S,4S)-2-(4-Methoxyphenyl)-3,4-dihydro-2H-pyran-4-yl
Acetate 7a. General Procedure for Acetylation of 2-Substituted
3,4-Dihydro-2H-pyran-4-ols 7. To the solution of (2S,4S)-2-(4-
methoxyphenyl)-3,4-dihydro-2H-pyran-4-ol 6a (505 mg, 2.45
mmol), triethylamine (485 μL, 374 mg, 3.7 mmol), and DMAP
(49 mg, 0.4 mmol) in CH2Cl2 (5 mL) cooled to 0 °C was added
dropwise acetic anhydride (350 μL, 377 mg, 3.7 mmol), and the
reaction mixture was warmed to rt and stirred for 4 h. After that
time, CH2Cl2 (20 mL) and NaHCO3 (aq, 5%, 20 mL) were
added, and the mixture was extracted with CH2Cl2 (3 ꢀ 20 mL).
The combined organic phases were washed with NaHCO3 (aq,
satd, 20 mL) and brine (20 mL), dried with MgSO4, filtered
through a thin pad of silica gel (which was then thoroughly
washed with CH2Cl2), and concentrated yielding the title acetate
as a yellowish oil (595 mg, 2.4 mmol, 98%), which was suffi-
ciently pure (by NMR) and was used without further purifica-
tion: 1H NMR 1.92-2.15 (m, 1H), 2.01 (s, 3H), 2.36-2.49 (m,
2H), 3.82 (s, 3H), 4.77-4.84 (m, 1H), 4.96 (dd, J = 12.0, 2.0,
1H), 5.51-5.62 (m, 1H), 6.57 (dd, J = 6.2, 1.0, 1H), 6.84-6.94
(m, 2H), 7.23-7.32 (m, 2H); 13C NMR 21.2, 35.4, 55.3, 66.2,
76.3, 101.3, 113.9, 127.3, 132.0, 146.9, 159.4, 170.8.
entry
R
yield of 5 (%)
yield of 5 f 1 (%)
ee (%)
1
2
3
p-MeOPh
Ph
c-C6H11
91
92
72
74
71
63
b
93a
94b
96b
aDetermined by HPLC on a chiral OD-H column. Determined by
GC on a chiral capillary β-dex 120 column.
93% ee (Table 1, entry 2), was hydrogenated to the corre-
sponding tetrahydropyran. A short reaction time and the use
of ethyl acetate as a solvent were crucial to prevent the
destruction of the tetrahydropyran ring; the reaction carried
out in methanol afforded exclusively the product of subse-
quent hydrogenolysis of the tetrahydropyran ring. The
product of hydrogenation of 1a was oxidized to the aldehyde
14 which was then subjected to reaction with THP-protected
4-hydroxyphenylmagnesium bromide. An acidic workup of
the reaction mixture resulted in deprotection of the phenolic
hydroxy function, yielding the alcohol 15 in 91% yield.
Removal of the hydroxy group at the benzylic position was
accomplished with a combination of NaBH4 and TFA in
THF,15 producing (-)-centrolobine in 73%, with spectral
data and optical rotation in agreement with those reported in
the literature.3,4 Starting from anisaldehyde, (-)-centrolo-
bine was achieved in nine steps only (five of which required
chromatographic purifications) in 40% overall yield and
with enantiomeric purity of 93% ee.
In conclusion, a simple and efficient enantioselective route
to the versatile building blocks such as cis-6-substituted 2-(2-
hydroxyethyl)-5,6-dihydro-2H-pyrans, employing the se-
quence of the hetero-Diels-Alder, the Luche reduction,
and the Ireland-Claisen rearrangement has been presented.
The synthetic utility of this strategy was illustrated by the
enantioselective synthesis of (-)-centrolobine.
Experimental Section
(S)-2-(4-Methoxyphenyl)-2H-pyran-4(3H)-one 5a. General
Procedure for (salen)Cr(III)-Catalyzed Reaction of Aldehydes
with Danishefsky’s Diene 3. The mixture of catalyst (S,S)-2 (0.06
mmol, 2 mol %), MTBE (0.6 mL), and anisaldehyde (408 mg,
3 mmol) under argon atmosphere was cooled to -10 °C, and
Danishefsky diene (0.9 mL, 4.5 mmol) was added dropwise. The
cooling bath was removed, and the reaction mixture was stirred
for 24 h at rt. After that time, CH2Cl2 (3 mL) was added followed
by trifluoracetic acid (ca. 10 drops). After being stirred for 10
min, the reaction mixture was filtered through a pad of Celite,
concentrated, and subjected to chromatography (hexane/
AcOEt 8:2f7:3). The desired product was dried under vacuum
at 40 °C for 3 h, yielding a yellowish solid (557 mg, 2.7 mmol,
91%, 93% ee): mp 50-52 °C (hexane-AcOEt); [R]rtD = 132.7
(c = 1.06, 93% ee, CHCl3); 1H NMR 2.63 (ddd, J = 16.8, 3.4,
1.3, 1H), 2.92 (dd, J = 16.8, 14.4, 1H), 3.82 (s, 3H), 5.37 (dd,
tert-Butyldimethylsilyl 2-((2S,6S)-6-(4-Methoxyphenyl)-5,6-
dihydro-2H-pyran-2-yl)acetate 8a. General Procedure for Ire-
land-Claisen Rearrangement of 2-Substituted 3,4-Dihydro-2H-
pyran-4-yl Esters 8. A solution of (2S,4S)-2-(4-methoxyphenyl)-
3,4-dihydro-2H-pyran-4-yl acetate 7a (574 mg, 2.31 mmol) in
THF (8 mL) was added dropwise at -78 °C under argon
atmosphere to solution of LiHMDS (2.55 mL, 2.55 mmol,
1.0 M in THF) over 10 min, followed by addition of solution
of TBSCl (463 mg, 3.1 mmol) in dry HMPA (1.5 mL). The
slightly brown solution was warmed to rt and heated to 70 °C for
2 h. After being cooled to rt, the reaction mixture was diluted
with petroleum ether (30 mL), treated with NaHCO3 (aq, 5%,
20 mL), and extracted with petroleum ether (4 ꢀ 15 mL). The
combined organic phases were washed with brine (20 mL), dried
with MgSO4, and concentrated yielding the title silyl ester as
lightly orange oil (815 mg, 97%) which was sufficiently pure (by
NMR) and was used without further purification: 1H NMR 0.25
(s, 3H), 0.26 (s, 3H), 0.91 (s, 9H), 2.17-2.33 (m, 2H), 2.55 (dd,
(15) Nutaitis, C. F.; Bernardo, J. E. Synth. Commun. 1990, 20, 487.
1742 J. Org. Chem. Vol. 75, No. 5, 2010

Chazadaj et al.
JOCNote
J = 15.2, 6.6, 1H) 2.68 (dd, J = 15.2, 7.3, 1H), 3.79 (s, 3H), 4.57
(dd, J = 10.3, 3.7, 1H), 4.68-4.74 (m, 1H), 5.75-5.79 (m, 1H),
THF (10 mL), followed by dropwise addition of trifluoroacteic
acid (3 mL) over 30 min. The reaction mixture was stirred for 1 h,
carefully neutralized with of NaOH (aq, 5%, ca. 10 mL), and
extracted with Et2O (4 ꢀ 15 mL). The combined organic phases
were washed with NH4Cl (aq, satd, 15 mL) and brine (15 mL),
dried with MgSO4, concentrated, and subjected to column chro-
matography (hexane/AcOEt 8:2 f 7:3), yielding (-)-centrolobine
as white crystals (227 mg, 0.73 mmol, 73%, 93% ee): mp = 87-
88 °C (lit.3i mp 87-89); [R]rtD = -86.3 (c = 1.02, 93% ee, CHCl3)
[lit.3a ([R]23D = -93.1, c = 0.16, CHCl3)]; 1H NMR 1.28-1.37 (m,
1H), 1.46-1.60 (m, 1H), 1.58-1.76 (m, 3H), 1.79-1.95 (m, 3H),
2.61-2.75 (m, 2H), 3.43-3.47 (m, 1H), 3.79 (s, 3H), 4.29 (dd, J =
11.2, 1.8, 1H), 4.80 (brs, 1H), 6.69-6.72 (m, 2H), 6.87-6.89 (m,
2H), 7.01-7.05 (m, 2H), 7.31-7.40 (m, 2H); 13C NMR 24.0, 30.7,
31.2, 33.3, 38.3, 55.3, 77.2, 79.1, 113.6, 115.1, 127.1, 129.5, 134.6,
135.8, 153.5, 158.7; IR (KBr) ν 3391, 2946, 2925, 2913, 2858, 2832,
1611, 1512, 1244; HRMS (M þ Na)þ calcd for C20H24O3Na
335.1618, found: 335.1633; HPLC (AD-H, n-hexane/PriOH, 9:1,
1 mL/min) tR(-)= 14.8, tR(þ)= 20.0.
5.90-5.95 (m, 1H), 6.83-6.88 (m, 2H), 7.26-7.30 (m, 2H); 13
C
NMR -4.9, -4.8, 17.6, 25.5, 32.8, 42.4, 55.3, 72.6, 75.3, 113.6,
125.6, 127.0, 129.0, 134.7, 158.9, 171.3; IR (film) ν: 2955, 2931,
2899, 2858, 1719, 1515, 1249, 1174, 827; HRMS (M þ Na)þ
calcd for C20H30O4SiNa 385.1806, found 385.1811.
2-((2S,6S)-6-(4-Methoxyphenyl)-5,6-dihydro-2H-pyran-2-yl)-
ethanol 1a. General Procedure for Reduction of Silyl Esters. A
solution of LiAlH4 (2.6 mL, 2.6 mmol, 1.0 M in THF) was added
dropwise at 0 °C to tert-butyldimethylsilyl 2-((2S,6S)-6-(4-
methoxyphenyl)-5,6-dihydro-2H-pyran-2-yl)acetate 8a (815
mg, 2.25 mmol) in THF (10 mL), and the resulting solution
was heated to 65 °C for 3 h. After that time, the reaction was
cooled to 0 °C, and a solution of sodium-potassium tartrate
(aq, satd., 10 mL) was added dropwise. The resulting mixture
was warmed to rt, stirred for 10 min, and extracted with Et2O
(3 ꢀ 20 mL). The combined organic phases were washed with
brine (20 mL), dried with MgSO4, concentrated, and subjected
to column chromatography (hexane/AcOEt 7:3) yielding 1a as
nearly colorless oil (438 mg, 1.87 mmol, 81%): 1H NMR
1.79-186 (m, 1H), 1.90-1.97 (m, 1H), 2.17-2.24 (m, 1H),
2.29-2.38 (m, 1H), 2.55 (brs, 1H), 3.77-3.89 (m, 2H), 3.79 (s,
3H), 4.54-4.61 (m, 2H), 5.66-5.70 (m, 1H), 5.91-5.97 (m, 1H),
6.85-6.89 (m, 2H), 7.24-7.30 (m, 2H); 13C NMR 32.8, 37.2,
55.2, 60.9, 75.8, 76.0, 113.8, 125.4, 127.0, 129.6, 134.5, 159,1; IR
(film) ν 3391, 3033, 2954, 2934, 2836, 1644, 1614, 1515, 1247,
1175, 1098, 1058, 1035, 829; HRMS (M þ Na)þ calcd for
C14H18O3Na 257.1148, found 257.1141.
Acknowledgment. This work was supported by Grant No.
PBZ-KBN-12/T9/2004 from the Polish Ministry of Educa-
tion and Science. The Foundation for Polish Science is
gratefully acknowledged for a grant for R.K. We thank
Mr. Filip Ulatowski for technical assistance with the synth-
esis of (-)-centrolobine.
Supporting Information Available: Experimental proce-
dures and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(-)-Centrolobine. NaBH4 (350 mg, 10 mmol) was added to
vigorously stirred solution of alcohol 15 (328 mg, 1 mmol) in
J. Org. Chem. Vol. 75, No. 5, 2010 1743