Total synthesis of (5S)-dihydroyashabushiketol

Article abstract of DOI:10.1016/j.tetasy.2011.04.014

Enantiomerically pure (+)-(5S)-dihydroyashabushiketol 1a was obtained by the 1,3-dipolar cycloaddition of a nitrile oxide, generated from oxime 3b, to N-acryloyl bornane[10,2]sultam (2R)-2 (67%, 85% de, then crystallization 81%, 99% de), followed by reduc

Full text of DOI:10.1016/j.tetasy.2011.04.014

Tetrahedron: Asymmetry 22 (2011) 787–790
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Total synthesis of (5S)-dihydroyashabushiketol
Jan Romanski a, , Piotr Nowak a, Christian Chapuis b, , Janusz Jurczak a,b,
⇑
⇑
,
⇑
,à
a Department of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 March 2011
Accepted 19 April 2011
Enantiomerically pure (+)-(5S)-dihydroyashabushiketol 1a was obtained by the 1,3-dipolar cycloaddition
of a nitrile oxide, generated from oxime 3b, to N-acryloyl bornane[10,2]sultam (2R)-2 (67%, 85% de, then
crystallization 81%, 99% de), followed by reduction with DIBAL-H to aldehyde (ꢀ)-6a (67%), Wittig
reaction to isoxazoline (E/Z)-7 (60%), and finally hydrolytic hydrogenation (62%).
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
OH
O
R1
R2
R1
R2
Compound 1a was first isolated from the Japanese yashabushi
flowers (Alnus firma Sieb.) in 1970,1 and was then found in the
male flowers of several other species of Betulaceae, such as Alnus
sieboldiana,2 and Alnus pendula,3 as well as more recently in the rhi-
zome extracts of Chinese Alpinia officinarum (Zingiberaceae),4 and
seeds of Amomum xanthioides.5 This is the simplest representative
of a large family of 5-hydroxy-3-oxo diarylheptanoids (Fig. 1), of
which we mention here only some restrictive examples, such as
1b,6 1c,7 hexahydrocurcumin 1d,8 1e6b,9 and 1f,10 which exhibit
1a R1 = H, R2 = H
1e R1 = H, R2 = OMe
1f R1 = OMe, R2 = OMe
1g R1 = H, R2 = Br
1b R1 = H, R2 = OH
1c R1 = OH, R2 = OH
1d R1 = OMe, R2 = OH
Figure 1.
5a
-reductase inhibitive,4 as well as antiemetic activities against
nitrile oxide formation conditions (NCS, KHCO3, CHCl3, 20 °C), to
afford the 1,3-dipolar cycloadduct 4 in 67% yield and 85% de.
A simple crystallization from iPrOH afforded an optically pure
material (99% de, 81% yield). The diastereoisomeric excess was
determined by chiral HPLC analysis of the corresponding alcohol
5a, previously reported as a racemate,19 after hydride reduction
(L-selectride, THF, 20 °C, 78%). Further conversion to the corre-
sponding bromide 5b20 was performed in 92% yield by treatment
with CBr4/Ph3P in CH2Cl2.21 Subsequent substitution with Ph3P in
refluxing toluene quantitatively afforded the phosphonium salt
5c. Further treatment with nBuLi in THF at ꢀ78 °C to produce ylide
6b, followed by the addition of benzaldehyde, allowed the isolation
of a 4:1 E/Z mixture of isoxazoline 7 in 64% yield. However, chiral
HPLC analysis of this mixture showed complete racemization, pos-
sibly via the reversible opening of the isoxazoline ring of 6b. Since
the Horner–Wadsworth–Emmons reaction gave the same results,
we decided to reverse the Wittig strategy, but were unsuccessful
in the oxidation of alcohol 5a to aldehyde 6a, under various mild
conditions (Swern oxidation; hypervalent IBX; Dess–Martin; TEM-
PO; PCC, PDC). In some instances, ester 6c was detected (up to 38%
with PDC), via the addition of alcohol 5a to aldehyde 6a, and fur-
ther oxidation of the transient hemiacetal. We were also unsuc-
cessful in coupling benzyl magnesium chloride to bromide 5b
using a catalytic amount of an NiCl2–butadiene complex.22 Finally,
this difficulty was circumvented by reducing cycloadduct 4 directly
prostate and liver cancers. This was evident from the in vivo tests
on chickens11a and mice,11b as well as from its ancestral use against
gastro-intestinal disorders in Chinese natural medicine.12 In addi-
tion to racemic syntheses,2,13 optically active approaches are re-
stricted to hydrogenation of yashabushiketol, obtainable either
by an asymmetric synthesis14 or a potential enzymatic resolu-
tion.15 We became interested in this target as a demonstration of
the usefulness of our methodology, based on the nitrile oxide dia-
stereoselective 1,3-dipolar additions of (2R)-bornane[10,2]sultam
derivatives (Scheme 1).16
2. Results and discussion
The known N-acryloyl (2R)-bornane[10,2]sultam 217 was trea-
ted with the reported oxime 3b,18 which can be readily obtained
from the corresponding commercially available aldehyde 3a, under
⇑
Corresponding authors.
E-mail addresses: jarom@chem.uw.edu.pl (J. Romanski), Christian.chapuis@fir
menich.com (C. Chapuis), jurczak@icho.edu.pl (J. Jurczak).
Present address: Firmenich SA, Corporate R&D Division, PO Box 239, CH-1211
Geneva 8, Switzerland. Tel.: +41 22 780 36 10; fax: + 41 22 780 33 34.
à
Tel.: +48 22 632 05 78; fax: +48 22 632 66 81.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.014

788
J. Romanski et al. / Tetrahedron: Asymmetry 22 (2011) 787–790
Ph
X
3a X = O
O
N
(i)
(iii)
3b X = NOH
O
X
O
Ph
(ii)
N
N
S
S
O
5a X = OH
5b X = Br
O
(iv)
(v)
O
O
N
O
2
Ph
(vii)
5c X = PPh3Br
4
(vi)
OH
O
O
N
O
N
(x)
Ph
(viii) or (ix)
X
Ph
Ph
Ph
Ph
R
1a
dihydroyashabushiketol
7
6a X = O, R = H
6b X = PPh3, R = H
6c X = O, R = 5a -H
Scheme 1. Reagents and conditions: (i) NH2OHꢃHCl, THF/H2O, 20 °C, overnight, 94%; (ii) 3b, NCS, KHCO3, CHCl3, 20 °C, 72 h, 67%; (iii) L-selectride, THF, 20 °C, 30 min, 78%;
(iv) CBr4, PPh3, CH2Cl2, 0 °C to rt, 2.5 h, 92%; (v) PPh3, toluene, 110 °C, 96 h, 97.5%; (vi) 5a, PDC, CH2Cl2, 20 °C, overnight, 38%; (vii) DIBAL-H, CH2Cl2, ꢀ78 °C, 67%; (viii) 5c,
nBuLi, PhCHO, THF, ꢀ78 to 20 °C, overnight, 64%; (ix) BnPPh3Br, nBuLi, 6a, ꢀ78 to 20 °C, overnight, 60%; (x) Raney-Ni, H3BO3, H2, MeOH/H2O, 48 h, 62%.
to aldehyde 6a in 67% yield with DIBAL-H in CH2Cl2 at ꢀ78 °C. The
addition of nBuLi to benzyltriphenylphosphonium bromide in THF
at ꢀ78 °C,23 followed by enantiomerically pure aldehyde 6a, affor-
ded the desired heterocycle 7 as a 1:3 E/Z mixture in 60% yield,
without apparent racemization according to chiral HPLC analysis.
Quantitative heterolytic selective hydrogenation of the N–O bond
in 7 was performed over cat. Raney-Ni for 20 h in MeOH/H2O/
H3BO3,13d,24 while subsequent hydrogenation of the phytoestrogen
intermediate,25 earlier isolated from rhizomes of Malaysian Alpinia
mutica Roxb. and Alpina rafflesiana Wall., as well as Thai Curcuma
comosa Roxb. (Zingiberaceae),26 was completed after 48 h, to afford
the enantiomerically pure b-hydroxy ketone 1a in 62% yield. The
well-established diastereoselectivity of 2,16 thus confirms the
absolute configuration, as initially based2a empirically either on
the configuration of the corresponding benzoate27 or on Horeau’s
rules,28 as well as by X-ray anomalous-scattering structure analysis
of analogue 1g.29 It is noteworthy that the sense of its chiroptic
properties depends on the solvent used for the measurement, since
(5S)-1a is a laevogyre in MeOH, but dextrogyre in CHCl3, CCl4 and
1,4-dioxane.6b,29
uncorrected. Optical rotations: JASCO-DIP-360 polarimeter with a
20° thermally jacketed 10-cm cell. IR Spectra: Perkin–Elmer 1640
FT-IR;
m
in cmꢀ1. ‘H and ‘C NMR spectra: Bruker Am-500 (500
and 125 MHz) and Variun Gemini (200 and 50 MHz) spectrometers
using residual CHCl3, as internal reference; d in ppm, J in Hertz.
4.1. (5S)-Dihydroyashabushiketol 1a
To the 1:3 E/Z mixture of compound 7 (34 mg, 0.12 mmol) and
H3BO3 (22.7 mg, 0.36 mmol)) in MeOH/H2O 15:1 (1.6 ml), a cata-
lytic amount of Raney-Ni was added and left under an H2 atmo-
sphere and intensive stirring. After 48 hours the catalyst was
filtered and the solvent evaporated. The residue was dissolved in
AcOEt and washed twice with aq KHCO3 solution. After column
chromatography/SiO2 purification (CHCl3/Et2O 19:1) (5S)-dihydro-
yashabushiketol 1a was obtained in 62% yield. ½a D20
¼ þ13:6 (c 1.0,
ꢁ
CHCl3). The enantiomeric excess was determined by HPLC (OJ-H,
hexane/iPrOH (7:3 v/v), Rtmajor = 10.0 min, Rtminor = 12.1 min). 1H
NMR: 7.26 (q, J = 7.5, 4H); 7.20–7.15 (m, 6H); 4.04 (hept, J = 4,
1H); 2.89 (t, J = 4, 2H); 2.81–2.75 (m, 1H); 2.74 (t, J = 7.5, 2H);
2.69–2.63 (m, 1H); 2.54 (d, J = 3.5, 1H); 2.53 (d, J = 8, 1H); 1.84–
1.76 (m, 1H); 1.70–1.63 (m, 1H); 1.26 (br s, 1OH). 13C NMR:
211.1 (s); 141.8 (s); 140.7 (s); 128.6 (2d); 128.5 (2d); 128.4 (2d);
128.3 (2d); 126.2 (d); 125.9 (d); 66.9 (d); 49.3 (t); 45.0 (t); 38.0
(t); 31.7 (t); 29.5 (t). HRMS-ESI: calculated for C19H22O2 (M+Na)+
305.1518, found: 305.1516. Alternatively, during the synthesis of
the racemic material, the intermediate was quantitatively and
more rapidly hydrogenated over 5% Pd/C.
3. Conclusion
Enantiomerically pure (+)-(5S)-dihydroyashabushiketol 1a was
obtained in 13% overall yield from dipolarophile (2R)-2 in four syn-
thetic steps, which comprised of a diastereoselective cycloaddition
to nitrile oxide derived from 3b (67%, 85% de, then crystallization
81%, 99% de), reduction with DIBAL-H to aldehyde (ꢀ)-6a (67%),
Wittig reaction to isoxazoline (E/Z)-7 (60%), and hydrolytic hydro-
genation (62%). This strategy may be extended to non-symmetric
analogous b-hydroxy ketones, such as gingerol, for example.13d
As previously reported in the racemic series with NaBH4,10,30
5-hydroxy-3-oxo diaryl heptanoids of type 1 also represent ideal
targets for partial asymmetric hydrogenation, or reduction of the
corresponding naturally occurring diketones.31 Alternatively, anal-
ogously simple linear dialkyl b-diketones were partially reduced
with Aspergillus niger or baker’s yeast.32
4.2. 1-{[(5R)-4,5-Dihydro-3-phenethylisoxazole-5-yl]carbonyl]-
hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide 4
At first, N-acryloyl (2R)-bornane[10,2]sultam 2a (710 mg, 2.64
mmol), 3-phenylpropionic aldehyde oxime (590.8 mg, 3.96 mmol),
NCS (528 mg, 3.96 mmol) and KHCO3 (396.5 mg, 3.96 mmol) were
mixed in a flask with CHCl3 (10 ml). The reaction was monitored
using TLC every 24 h and one additional equivalent of NCS was
added portionwise. After complete disappearance of the oxime
(72 h) the mixture was extracted with brine (3ꢂ), the organic
phase was dried with MgSO4, concentrated in vacuo, and purified
by column chromatography/SiO2 using hexane/AcOEt 1:1 to afford
isoxasoline 4 in 67% yield and 85% de. Crystallization from iPrOH
gave 81% of pure diastereoisomer 4 (99% de) in three crops.
4. Experimental
All reactions with acyl chlorides were carried out under Ar with
anhydrous solvents, dried according to the standard procedures.
Flash column chromatography: according to the literature33; Silica
Gel 60 (Merck, 200–400 mesh). TLC: Merck aluminium plates (Sil-
ica Gel 60 F254); visualization with a solution of MoO3 and
Ce2(SO4)3 in 15% H2SO4/H2O. Mp: Kofler hot-stage apparatus;
½
a 2D0
ꢁ
¼ ꢀ192:8 (c 1.0, CHCl3); 1H NMR (500 MHz): 7.32–7.27 (m,
2H), 7.25–7.16 (m, 3H), 5.49 (dd, J = 11, 7, 1H), 3.92 (dd, J = 8, 5,

J. Romanski et al. / Tetrahedron: Asymmetry 22 (2011) 787–790
789
1H), 3.53 (d, J = 13.5, 1H), 3.43 (d, J = 13, 1H), 3.30 (dd, J = 17.5, 6.5,
4.6. (5R)-Formyl-3-phenethylisoxazoline 6a
1H), 3.17 (dd, J = 17.5, 11.5, 1H), 2.92 (t, J = 8, 2H), 2.66 (dq, J = 8.5,
8.5, 2H), 2.22–2.12 (m, 1H), 2.08 (dd, J = 14, 8, 1H), 2.00–1.82 (m,
3H), 1.46–1.30 (m, 2H), 1.18 (s, 3H), 0.98 (s, 3H); 13C NMR
(125 MHz): 168.9 (s); 157.9 (s); 140.7 (s); 128.8 (2d); 128.5 (2d);
126.6 (d); 77.0 (d); 65.5 (d); 53.2 (t); 49.3 (s); 48.1 (s); 44.9 (d);
38.4 (t); 33.1 (t); 32.8 (t); 29.3 (t); 26.7 (t); 21.1 (q); 20.1(q).
To a solution of 4 (156 mg, 0.37 mmol) in CH2Cl2 (2 ml) at
ꢀ78 °C was added an equimolar amount of DIBAL-H (52.6 mg,
0.37 mmol) diluted in CH2Cl2. After 60 min several droplets of
MeOH and aq NH4Cl solution were added. After extraction, drying
over MgSO4 and solvent concentration in vacuo, purification by
column chromatography/SiO2 (hexane/AcOEt 13:7), afforded alde-
HRMS-ESI: calcd for:
439.1626.
C
21H28N2O4S (M+Na)+ 439.1667, found:
hyde 6a in 67% yield. ½a D20
¼ ꢀ119:8 (c 1.0, CHCl3).
ꢁ
Racemic synthesis: To a solution of oxime 3b (30 mg, 0.2 mmol)
in CHCl3 (1 ml) were added acrolein (22.4 mg, 0.4 mmol), KHCO3
(30 mg, 0.3 mmol), and NCS (40 mg, 0.3 mmol). The reaction was
monitored using TLC every 24 h and two additional portions of
NCS were added (2 ꢂ 0.5 equiv). After complete disappearance of
3b, the reaction mixture was extracted with brine (3ꢂ), the organic
phase was dried with MgSO4, concentrated in vacuo, and purified
by column chromatography/SiO2 (hexane/AcOEt 1:1) to afford
quantitatively 6a. 1H NMR: 9.66 (br d, J = 1.2, 1H); 7.34–7.17 (m,
5H); 4.72–4.41 (m, 1H); 2.91 (br t, J = 7.8, 4H); 2.65 (d, J = 6.8,
2H). 13C NMR: 178.0 (d); 158.4 (s); 140.3 (s); 128.6 (2d); 128.2
(2d); 126.4 (d); 76.4 (d); 40.6 (t); 32.4 (t); 29.2 (t). Used directly
for the next step.
4.3. (5R)-Hydroxymethyl-3-phenethylisoxazoline 5a
To a solution of 4 (247 mg, 0.59 mmol) in THF (5 ml) at 20 °C
under Ar was added dropwise a solution of L-Selectride (1 M/
THF, 1.48 ml, 1.48 mmol). After 30 min the reaction was quenched
slowly with H2O and 15% aqueous NaOH and 30% H2O2 was added.
The solution was diluted with AcOEt, dried over MgSO4, concen-
trated in vacuo and purified by column chromatography/SiO2 (hex-
ane/AcOEt 6:4) to afford 5a in 78% yield. ½a D20
¼ þ102:0 (c 1.0,
ꢁ
CHCl3). 1H NMR: 7.34–7.18 (m, 5H); 4.71–4.57 (m, 1H); 3.72 (dd,
J = 3.4, 12.2, 1H); 3.52 (dd, J = 4.6, 12.2, 1H); 2.89 (sext, J = 6.6,
4H); 2.72–2.62 (m, 2H); 2.33 (br t, J = 2.6, 1OH). 13C NMR: 159.3
(s); 140.7 (s); 128.9 (2d); 128.5 (2d); 126.7 (d); 80.3 (d); 63.9 (t);
39.0 (t); 32.8 (t); 29.7 (t). HRMS-ESI calcd for C12H15NO2 (M+Na)+
228.1000, found: 228.0983. HPLC: ADH column, major signal
11.5 min, minor 12.9 min.
4.7. 3-Phenethyl-(5R)-oxymethylisoxazoline 4,5-dihydro-3-
phenethyl isoxazole carboxylate 6c
To a solution of 5a (130 mg, 0.63 mmol) in CH2Cl2 (2.6 ml), PDC
(360 mg, 0.96 mmol) was added and the suspension was stirred at
20 °C overnight. The mixture was diluted with Et2O, extracted with
H2O. The organic phase was dried (MgSO4), concentrated and puri-
fied by column chromatography/SiO2 (CHCl3/Et2O 2:1) to afford 6c
in 38% yield as a 1:1 mixture of stereoisomers. 1H NMR: 7.26–7.10
(m, 10H); 4.88 (t, J = 8.8, 1H); 4.65 (m, 1H); 4.07 (d, J = 5.2, 2H);
3.07 (d, J = 9, 4H); 2.84 (t, J = 7.2, 4H); 2.60 (t, J = 7.6, 4H). 13C
NMR: 170.3 (s); 158.1 (s); 158.2 (s); 140.5 (2s); 128.8 (4d); 128.5
(4d); 126.8 (d); 126.7 (d); 80.2 (d); 77.0 (d); 66.0/63.9 (t); 41.3
(t); 39.7 (t); 32.7 (2t); 29.4 (t); 29.2 (t). HRMS-ESI calcd for
Racemic synthesis: To a solution of oxime 3b (1.39 g, 9.32 mmol)
in CHCl3 (14 ml) were added allyl alcohol (1.35 g, 23.2 mmol),
KHCO3 (1.4 g, 14 mmol), and NCS (1.87 g, 14 mmol). The reaction
was monitored using TLC every 24 h and additional portions of
NCS were added (2 ꢂ 0.5 equiv). After complete disappearance of
3b, the mixture was extracted with brine (3ꢂ), the organic phase
was dried with MgSO4, concentrated in vacuo, and purified by col-
umn chromatography/SiO2 (hexane/AcOEt 6:4) to afford 5a in 90%
yield.
4.4. (5R)-Bromomethyl-3-phenethylisoxazoline 5b
C
24H26N2O4 (M+Na)+ 429.1790, found: 429.1779.
To a mixture of alcohol 5a (75 mg, 0.37 mmol), CBr4 (147.1 mg,
0.44 mmol) in CH2Cl2 (2 ml) was added Ph3P, (115.4 mg,
0.44 mmol) in CH2Cl2 (1 ml) over 30 min. at 0 °C. The solution
turned to a pale brown colour and was stirred for additional 2 h
at 20 °C. The mixture was then concentrated and purified by col-
umn chromatography/SiO2 (chloroform) to afford 5b in 92% yield.
4.8. 3-Phenethyl-(5R)-phenenthenyl-2-isoxazoline 7
An equimolar amount of nBuLi (2.5 M/hex, 0.1 ml, 0.25 mmol)
was added to a solution of BnPh3PBr (130 mg, 0.3 mmol) in THF
(1.5 ml) at ꢀ78 °C. After five minutes an equimolar amount of alde-
hyde 6a (51 mg, 0.25 mmol) dissolved in THF (0.5 ml) was added.
The reaction was kept at ꢀ78 °C for one hour, and then allowed
to warm to 20 °C overnight. After concentration in vacuo, the res-
idue was dissolved in AcOEt and washed with aq satd KHCO3 and
H2O. The organic phase was dried on MgSO4, concentrated in vacuo
and purified by column chromatography/SiO2 (CHCl3/Et2O 19:1) to
afford 7 in 60% yield as a 1:3 E/Z mixture. 1H NMR (500 MHz). Min-
or E-isomer 7.37–7.21 (m, 10H); 6.61 (d, J = 15.5, 1H); 6.15 (dd,
J = 7, 15.5, 1H); 5.10 (dq, J = 1, 8.5, 1H); 3.06 (dd, J = 10, 16.5, 1H);
2.92 (q, J = 7.5, 2H); 2.74–2.65 (m, 3H). Major Z-isomer 7.36–7.20
(m, 10H); 6.69 (d, J = 11.5, 1H); 5.73 (dd, J = 9.5, 11.5, 1H); 5.28
(dq, J = 1, 9.5, 1H); 3.01 (dd, J = 10.5, 17, 1H); 2.93 (q, J = 7, 2H);
2.75–2.59 (m, 3H). 13C NMR (125 MHz) minor E-isomer 158.3 (s);
140.4 (s); 136.1 (s); 132.7 (d); 128.6 (4d); 128.3 (2d); 128.0 (d);
127.3 (d); 126.6 (2d); 126.4 (d); 80.8 (d); 43.3 (t); 31.6 (t); 19.3
(t). Major Z-isomer, 158.4 (s); 140.5 (s); 135.9 (s); 133.7 (d);
129.7 (d); 128.8 (2d); 128.6 (2d); 128.3 (4d); 127.6 (d); 126.4
(d); 76.5 (d); 43.9 (t); 32.7 (t); 29.5 (t). HRMS-ESI: calcd for
½
a 2D0
ꢁ
¼ ꢀ38:5 (c 1.0, CHCl3), 1H NMR (200 MHz) 7.30–7.19 (m,
5H); 4.85–4.70 (m, 1H); 3.42 (dd, J = 4.2, 10.2, 1H); 3.21 (dd, J = 8,
10.2, 1H); 3.11–2.63 (m, 6H). 13C NMR: 158.1 (s); 140.5 (s);
128.9 (2d); 128.5 (2d); 126.7 (d); 78.8 (d); 42.1 (t); 33.6 (t); 32.8
(t); 29.4 (t). HRMS-ESI calcd for C12H14BrNO (M+Na)+ 290.0157,
292.0137, found: 290.0138; 292.0154.
4.5. (5R)-Bromotriphenylphosphinemethyl-3-phenethylisoxaz-
oline 5c
A solution of 5b (77 mg, 0.29 mmol) and triphenylphosphine
(91.8 mg, 0.35 mmol) was heated in toluene (1 ml) at 110 °C for
96 h. The solvent was then concentrated in vacuo and the residue
was purified by column chromatography/SiO2 (CHCl3 then CHCl3/
MeOH 9:1) to afford 5c in 97.5% yield. 1H NMR: 7.82–7.60 (m,
15H); 7.30–7.20 (m, 5H); 5.0–4.80 (m, 2H); 3.56 (dt, J = 5.2, 17.8,
1H); 3.54–3.28, (m, 2H); 2.96 (t, J = 8, 2H); 2.75 (dt, J = 2.2, 6.6,
2H). 13C NMR: 160.7 (s); 140.3 (s); 135.1 (3s); 134.3 (2d); 134.1
(4d); 130.5 (4d); 130.2 (4d); 128.8 (2d); 126.5 (2d); 119.5 (d);
117.7 (d); 74.4 (d); 44.9 (t); 32.4 (t); 28.9 (t); 28.7 (t). HRMS-ESI
calcd for C30H29NOP 450.1987, found: 450.1964.
C
19H19NO (M+Na)+ 300.1364, found: 300.1369. Into a solution of
5c (150 mg, 0.283 mmol) in THF (2.5 ml) cooled to ꢀ78 °C was
added nBuLi (2.5 M/hex, 0.113 ml, 0.283 mmol). After 5 min a solu-
tion of benzaldehyde (30 mg, 0.283 mmol) dissolved in THF was

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J. Romanski et al. / Tetrahedron: Asymmetry 22 (2011) 787–790
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6794; (o) Liu, J.; Eddings, A.; Wallace, R. H. Tetrahedron Lett. 1997, 38, 6795–
6798; (p) Kleinman, E. F.; Campbell, E.; Giordano, L. A.; Cohan, V. L.; Jenkinson,
T. H.; Cheng, J. B.; Shirley, J. T.; Pettipher, E. R.; Salter, E. D.; Hibbs, T. A.;
DiCapua, F. M.; Bordner, J. J. Med. Chem. 1998, 41, 266–270; (q) Kim, S. J.; Lee, J.
Y.; Kim, B. H. Bioorg. Med. Chem. Lett. 1998, 8, 1313–1316; (r) Kim, D.; Lee, J.;
Shim, P. J.; Lim, J. I.; Doi, T.; Kim, S. J. Org. Chem. 2002, 67, 772–781; (s) Jung, J.
Y.; Jung, S. H.; Koh, H. Y. Eur. J. Med. Chem. 2007, 42, 1044–1048. Additionally to
worse regioselectivity, it is noteworthy that due to the linearity of the dipole,
the [3+2] cycloaddition of N-carboxyloyl nitrile oxide bornane[10,2]sultam to
4-phenyl but-1-ene is also potentially less stereoselective. For examples of
nitrile oxide additions using other chiral auxiliaries, asymmetric catalysts or
enzymes, see the references quoted in Ref. 16c.
added. The reaction was kept at ꢀ78 °C for 1 h, and then allowed to
warm to 20 °C overnight. After concentration, the residue was dis-
solved in AcOEt and washed with aq satd NaHCO3 and H2O. The or-
ganic phase was dried over MgSO4, evaporated in vacuo and
purified by column chromatography/SiO2 (CHCl3/Et2O 19:1). The
4:1 E/Z mixture was obtained in 64% yield as a racemate.
Acknowledgement
This work was supported by the University of Warsaw, Grant
BW-191208.
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