Stereochemistry of intramolecular Diels-Alder furan (IMDAF) reactions of furyl-substituted chiral ethanolamides

Article abstract of DOI:10.1039/b307275d

This paper describes the stereoselective outcome of the intramolecular Diels-Alder furan (IMDAF) reaction of substituted (2S,3S)-ethanolamides 9-13, which were synthesised from a furyl substituted cyanohydrin. The latter was obtained from 2-furaldehyde with high enantioselectivity by an oxynitrilase catalysed addition of hydrogen cyanide. The stereochemistry of the IMDAF products was shown to be dependent on the size of the ethanolamide substituents R. Small substituents (H, Me, CN) gave exclusively axo-cycloaddition, whereas more bulky ones (Ph, Et) gave both exo- and endo-addition, the larger phenyl substituent giving a high endo-exo-ratio.

Full text of DOI:10.1039/b307275d

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Stereochemistry of intramolecular Diels–Alder furan (IMDAF)
reactions of furyl-substituted chiral ethanolamides
Reynier A. Tromp, Johannes Brussee* and Arne van der Gen
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502,
2300 RA Leiden, The Netherlands. E-mail: Brussee@Chem.LeidenUniv.nl;
Fax: ϩ31(0)71-5274565; Tel: ϩ31(0)71-5274266
Received 27th June 2003, Accepted 27th August 2003
First published as an Advance Article on the web 19th September 2003
This paper describes the stereoselective outcome of the intramolecular Diels–Alder furan (IMDAF) reaction of
substituted (2S,3S)-ethanolamides 9–13, which were synthesised from a furyl substituted cyanohydrin. The latter
was obtained from 2-furaldehyde with high enantioselectivity by an oxynitrilase catalysed addition of hydrogen
cyanide. The stereochemistry of the IMDAF products was shown to be dependent on the size of the ethanolamide
substituents R. Small substituents (H, Me, CN) gave exclusively exo-cycloaddition, whereas more bulky ones
(Ph, Et) gave both exo- and endo-addition, the larger phenyl substituent giving a high endo–exo-ratio.
Introduction
Cyanohydrins have proved to be versatile starting compounds
in organic synthesis, due to the large number of transform-
ations that they can undergo.1 Transformations at the hydroxyl
function and at the nitrile position provide, e.g.: α-hydroxy
esters,2 ethanolamines,3–5 and aziridines.6 Less attention has
been directed to transformation of the cyanohydrin side chain.
So far, the side chains have been subjected to oxidation,7 ring
closure,8 and chirality transfer reactions.9 The presence of
unsaturation in the cyanohydrin side chains makes them inter-
esting starting materials for the synthesis of complex ring sys-
tems via an intramolecular Diels–Alder reaction. The use of
furans in Diels–Alder reactions is of special interest, since the
oxygen bridge obtained after cyclisation can be opened for fur-
ther manipulation.10 Marchionni and Vogel synthesised highly
substituted ring systems using the furan Diels–Alder reaction.11
Padwa et al. demonstrated the utility of amine-substituted
furan rings in the IMDAF reaction by synthesis of the bio-
Scheme 1 Reagents and conditions: i. (R)-Oxynitrilase, HCN, methyl
logically active compound dendrobine.12 Cauwberghs and de
Clercq applied the IMDAF reaction for the synthesis of peri-
planone B.13 There has been only one report on the IMDAF
reaction of 2-furylamides.14 However, no clear information was
presented on the stereochemistry of the cycloaddition product.
Here we describe the synthesis of several ethanolamides
containing a furyl side chain and their subsequent use in the
IMDAF reaction. Special attention is paid to the influence
of the ethanolamide substitutient R on the stereochemical
outcome of the IMDAF reaction.
tert-butyl ether (MTBE), pH 5.5, 4 ЊC.; ii. TBSCl (1.2 eq.), imidazole
(2.4 eq.), DMF, 0 ЊC to rt; iii. R = H: 1. DIBAL-H (1.2 eq.), Et2O,
Ϫ70 ЊC to Ϫ20 ЊC; 2. MeOH, Ϫ70 ЊC; 3. BnNH2, MeOH, Ϫ70 ЊC to
Ϫ20 ЊC; 4. NaBH4 (2 eq.), Ϫ70 ЊC to rt; R = Me, Et, Ph: 1. RMgX (1.2
eq.), Et2O, reflux; 2. MeOH, Ϫ20 ЊC; 3. BnNH2, MeOH, Ϫ70 ЊC to
Ϫ20 ЊC; 4. NaBH4 (2 eq.), Ϫ70 ЊC to rt; R = CN: 1. DIBAL-H (1.2 eq.),
Et2O, Ϫ70 ЊC to Ϫ20 ЊC; 2. MeOH, Ϫ70 ЊC; 3. BnNH2, MeOH, Ϫ70 ЊC
to Ϫ20 ЊC; 4. NaCN (3.8 eq.), NH4Br (3.8 eq.), MeOH, Ϫ70 ЊC to rt;
iv. Acryloylchloride (1.1 eq.), Na2CO3 (1.2 eq.), CH2Cl2, H2O.
biphasic solvent system, using sodium carbonate as the base, to
provide 9.18
The methyl, ethyl, and phenyl groups were introduced by a
Grignard addition–transimination–reduction reaction as pre-
viously described.4 The appropriate Grignard reagent was
added to protected cyanohydrin 3 in diethyl ether and the
mixture was refluxed for one hour. After addition of meth-
anol, introduction of the benzyl group was accomplished
by transimination. Stereoselective reduction of the resulting
secondary imine with sodium borohydride gave ethanolamines
5–7 with high anti-selectivity (Table 1).19 The acryloyl
group was introduced as described above, yielding ethanol-
amides 10–12.
Introduction of the cyano group was performed as in the
synthesis of β-hydroxy-α-amino acids described by Zandbergen
et al.20 After DIBAL-H reduction of the protected cyanohydrin
and introduction of the benzyl function, the nitrile group was
introduced stereoselectively by addition of in situ formed
Results and discussion
2-Furaldehyde (1) was converted into its corresponding
(S)-cyanohydrin 2 with high conversion and ee (98%) by
(R)-oxynitrilase15 (E.C. 4.1.2.10), as present in defatted almond
meal (Scheme 1).16 Protection with TBSCl in the presence of
imidazole in DMF17 afforded 3 in 88% yield from 1.
For the conversion of the nitrile function of 3 into ethanol-
amine
4 a reduction–transimination–reduction sequence
was applied.5 The cyano group was reduced to the imine by
DIBAL-H at low temperature. Addition of methanol provided
the free imine, which was subjected to a transimination reaction
with benzylamine. The resulting secondary imine was further
reduced with sodium borohydride to provide ethanolamine 4.
The acryloyl function was introduced by stirring crude 4 with
freshly distilled acryloyl chloride in a dichloromethane–water
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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with literature values for comparable compounds.22 Typical
Table 1 Ethanolamines (4–8) and ethanolamides (9–13)
coupling constants are depicted in Fig. 1.
R
syn : anti (4–8)a
Yield (%) (9–13)b
H
Me
Et
Ph
CN
—
30
80
29
72
48
8 : 92
8 : 92
14 : 86
93 : 7
a Based on NMR data of crude product. b From 3 (%).
hydrogen cyanide to the imine, giving 8. Introduction of the
acryloyl group provided 13.
Fig. 1
NMR spectra of crude 13 revealed formation of a small
amount of cyclised product 24 (8%). Except for ethanolamide
13 no spontaneous cycloaddition had occurred. The results of
the synthesis of compounds 9–13 are presented in Table 1.
Next, the substituted furyl-ethanolamides (9–13) were
applied in the IMDAF reaction using elevated temperatures.21
Refluxing in toluene provided a cleaner reaction with higher
yields than refluxing in xylene. Non-benzylated 25 was studied
to investigate the outcome of the IMDAF reaction of a furyl-
ethanolamide in refluxing acetic anhydride (Scheme 2).21 The
results, however, showed no improvement.
Formation of the exo product was deduced from the
coupling of H-7β. Since the dihedral angle between H-7β and
H-8 in both the exo and the endo addition product is close to
90Њ (J ∼ 0 Hz), the only visible coupling of H-7β other than with
H-7α will be, in both instances, with H-6. A large coupling
constant (9.2 Hz; Fig. 1) shows H-6 and H-7β to be present at
the same side of the molecule, thus indicating exo addition.
Endo cyclisation leads to significantly smaller coupling between
H-7β and H-6 (J ∼ 4 Hz).
These findings were supported by NOESY experiments.
Interaction between H-6 and H-10 indicated that these atoms
were present at the same side of the molecule, which is typical
for exo-addition. The NOESY experiments were also used to
determine whether syn- or anti-addition had taken place. (Exo,
anti)-addition showed a clear correlation between H-6 and the
tert-butyl group of the TBS group. This indicated that H-6 and
the silylated hydroxyl function were situated at the same side of
the ring system. Furthermore, no interaction between the alkyl
function with H-6 was observed, such as found for (exo, syn)-
addition product 19. In the latter case coupling between H-2
and H-6 was observed as well. (Endo, anti)-addition showed
correlation between H-2 and H-6, as well as between H-6 and
the alkyl side chain (compunds 18 and 22).
Scheme 2 Reagents: i. Toluene, reflux; ii. Acetic acid anhydride, reflux.
As depicted in Scheme 3, four different stereoisomers can be
formed: endo or exo with the oxygen bridge at the same side of
the molecule as the silyloxy function (syn), or at the opposite
side (anti). In most cases the IMDAF reaction showed high
stereoselectivity (Table 2). 1H-NMR coupling constants
between H-6, H-7, and H-8 were used to investigate if exo- or
endo-addition had occurred. Exo-coupling could be correlated
The structure of 15, as determined by NMR, was confirmed
by X-ray analysis. As shown in Fig. 2, the oxygen bridge and
H-6 are situated on opposite sides of the molecule (exo). Also,
the silyloxy substituent and the oxygen bridge (O-11) are found
on opposite sides (anti). The lactam ring adopted a half-chair
conformation, with H-3β occupying an equatorial position.
Scheme 3 Possible diastereoisomers of the IMDAF reaction products.
Table 2 Product ratioa of the IMDAF reactions
Ethanolamide
R
exo : anti
exo : syn
endo : anti
exo : syn
9
10
13
11
12
H
1
1
1
2
1
—
—
—
1
—
—
—
1
—
—
—
—
—
Me
CN
Et
Ph
—
5
a Based on isolated yields. Ratio for R = Et also based on NMR data.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
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300 cmϪ1, res. 4 cmϪ1). Melting points were determined with a
Büchi melting point apparatus and are uncorrected. Enantio-
meric purity was determined by HPLC using a Daicel Chiralcel
OD column; with hexane–2-propyl alcohol (99.75 : 0.25, v/v)
as eluent. Optical rotations were measured with a Propol
automatic polarimeter, at the sodium D line (λ = 589 nm)
in units of 10Ϫ1 deg cm2 gϪ1. High resolution mass spectro-
scopy was performed on a Finnigan MAT 900 instrument
equipped with an Electrospray interface (ESI). Other masses
were recorded with a Perkin-Elmer Sciex API 165 with ion
spray interface.
(S )-2-(2Ј-Furyl)-2-hydroxyacetonitrile (2)
A suspension of 30 g almond meal in 45 mL of 0.10 M citric
acid buffer pH 5.5, 19.2 g of freshly distilled 2-furaldehyde 1
(200 mmol) and 50 mL of MTBE was stirred at 4 ЊC. A freshly
prepared solution of HCN in MTBE was added dropwise. This
HCN solution was prepared by extracting a mixture of 440
mmol NaCN (2.2 eq.) in 400 mL of H2O (acidified to pH 5.5
with AcOH), three times with 175 mL of MTBE. The resulting
mixture was allowed to stir over the weekend, filtered, and dried
with MgSO4. The solvent was evaporated to yield crude 2 (26.1
g). Ee 99% (HPLC; determined as TBDPS ether). δH (CDCl3)
3.54 (1 H, br s, OH ), 5.55 (1 H, s, H-2), 6.44 (1 H, dd, J 1.8 and
3.3, H-4Ј), 6.61 (1 H, d, J 3.3, H-3Ј) and 7.49 (1 H, d, J 1.8,
H-5Ј); δC (CDCl3) 56.4 (C-2), 109.8, 110.6 (C-3Ј, C-4Ј), 116.9
(C-1), 143.9 (C-5Ј) and 147.3 (C-2Ј).
Fig. 2 Crystal structure of compound 15.23
Due to the presence of a small amount of the syn-dia-
stereoisomer in ethanolamides 10, 11, and 12, a small amount
of cyclisation product resulting from these isomers was found.
In all three cases (16, 20, 23) only the (exo, anti)-diastereo-
isomer was observed. In these cases a NOESY correlation was
observed between H-6, H-10, and the alkyl side chain.
An overview of all stereoisomers obtained is presented in
Table 3.
(S )-2-(2Ј-Furyl)-2-O-(tert-butyldimethylsilyl)acetonitrile (3)
In conclusion, we have shown that, starting from achiral
2-furfural, complex ring systems can be obtained in a limited
number of steps. The IMDAF reaction occurred with high
stereoselectivity when small substituents R (hydrogen, methyl,
nitrile) were present. Exo products were exclusively formed,
with the oxygen bridge and the protected hydroxyl function at
opposite sides of the ring system (exo, anti). The general prefer-
ence for exo-cyclisation is in agreement with literature data for
comparable compounds carrying distinct tethers.24 With the
larger phenyl group, however, endo-cycloaddition was favoured.
Ethyl-substitution seemed to be at the turning point between a
preference for exo- or endo-addition, providing a mixture of
three compounds in a ratio of 2 : 1 : 1. The IMDAF reactions
resulting from the presence of a small amount of diastereo-
isomer in the ethanolamines gave exclusively (exo, anti)-
stereoisomers.
To a solution of 36 g of tert-butyldimethylsilylchloride (240
mmol; 1.2 eq.) in 250 mL of DMF was added 32.7 g of imid-
azole (480 mmol; 2.4 eq.). After 15 minutes the crude cyano-
hydrin 2 was added and the mixture was allowed to warm to rt
overnight. Then water and diethyl ether were added and the
layers separated. The organic phase was washed with water and
brine, dried (MgSO4) and the solvent was evaporated. The
resulting oil was distilled under reduced pressure (96 ЊC, 150 Pa)
to yield 3 (41.6 g, 88%) as a colourless oil. [α]D20 = ϩ18.9 (c = 5,
CHCl3); ν (cmϪ1) 1500, 1473, 1464, 1254, 1146, 1070, 1014,
1006, 834, 779 and 740; δH (CDCl3) 0.14, 0.16 (2 × 3 H, 2 × s,
2 × CH3Si), 0.92 (9 H, s, (CH3)3C), 5.56 (1 H, s, H-2), 6.40 (1 H,
dd, J 1.8 and 3.3, H-4Ј), 6.61 (1 H, d, J 0.7 and 3.3, H-3Ј) and
7.49 (1 H, d, J 0.7 and 1.8, H-5Ј); δC (CDCl3) Ϫ5.4 (2 × CH3Si),
18.0 ((CH3)3C), 25.3 ((CH3)3C), 57.9 (C-2), 109.3, 110.6 (C-3Ј,
C-4Ј), 117.1 (C-1), 143.6 (C-5Ј) and 148.3 (C-2Ј).
Thus, depending on the size of the substituent R in the
(2Ј-furyl)-ethanolamides, IMDAF cyclisation yielded either the
exo- or the endo-product with high stereoselectivity, generally
with the oxygen bridge and the silyloxy function on opposite
sides of the ring system.
(S )-2-N-Benzyl-1-(2Ј-furyl)-1-O-(tert-butyldimethylsilyl)ethane
(4)
To a solution (Ϫ70 ЊC) of 2.37 g of 3 (10 mmol) in 50 mL of
diethyl ether was added 12 mmol of DIBAL-H (12 mL of a 1 M
solution in hexanes; 1.2 eq.) and the mixture was allowed to
warm to Ϫ20 ЊC. Subsequently, 20 mL of MeOH was added
dropwise at Ϫ70 ЊC, followed by a solution of 4.4 mL of
BnNH2 in 10 mL of methanol. After warming up to Ϫ20 ЊC,
20 mmol of NaBH4 (0.76 g, 2 eq.) was added at Ϫ70 ЊC and the
solution was allowed to rise to rt overnight. Diethyl ether was
added and the organic layer was washed two times with 1 M
KHSO4 and once with 1 M NaOH and brine. After drying with
MgSO4, the solvent was evaporated. The crude product (2.2 g)
was used without purification in the next step. δH (CDCl3)
Ϫ0.08, 0.06 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.87 (9 H, s, C(CH3)3),
2.87 (1 H, dd, J 4.8 and 12.1, H-2), 3.02 (1 H, dd, J 7.7 and 12.1,
H-2), 3.82 (2 H, s, CH2 Bn), 4.88 (1 H, dd, J 4.8 and 7.7, H-1),
6.21–6.33 (2 H, m, H-3Ј, H-4Ј) and 7.20–7.40 (6 H, m, H-5Ј, CH
Ph); δC (CDCl3) Ϫ5.4, Ϫ5.2 (2 × Si–CH3), 17.9 (C(CH3)3), 25.5
(C(CH3)3), 53.2, 54.0 (C-2, CH2Ph), 67.8 (C-1), 106.3, 109.9
(C-3Ј, C-4Ј), 126.6, 127.7, 128.1 (CH Ph), 140.0 (Cq Ph), 141.3
(C-5Ј) and 155.4 (C-2Ј).
Finally, it is to be noted that in only five synthetic steps five
chiral centres were introduced.
Experimental
Column chromatography was performed on Baker Silica Gel
(0.063–0.200 mm). For TLC analysis, Schleicher and Schuell
F1500/LS 254 silica plates were used. Spots were visualised with
ultraviolet light, potassium permanganate spray (solution of
KMnO4 (5%) and NaHCO3 (0.5%) in water) or by molybdene
spray (solution of conc. sulfuric acid (10 mL) and (NH4)6-
Mo7O24ؒ4H2O (2.5 g) in 90 mL of water) and heating. 1H NMR
and 13C NMR were recorded with a Bruker AC 200 or a Bruker
DRX-400 instrument. NOESY and COSY experiments were
obtained with a Bruker DRX-400 instrument (Mixing time:
1 s). Tetramethylsilane was used as internal standard; δ in ppm,
J in Hz. Infrared spectra were obtained with a Perkin-Elmer
FT-IR Paragon 1000 spectrometer equipped with a Golden
Gate Diamond ATR, using reflectance technique (neat, 4000–
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
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Table 3
Entry
Ethanolamide
Product
Yield (%)a
90
Entry
Ethanolamide
Product
Yield (%)a
42
1
4
2
74
8
10b
11b
3
42
5
6
87
20
22
7b
47
a After purification by column chromatography. b Due to the presence of a small amount of syn-isomer in the starting material.
General procedure for Grignard–transimination–reduction
reaction
(1S,2S )-2-N-Benzyl-1-(2Ј-furyl)-1-O-(tert-butyldimethylsilyl)-
propane (5)
Yellow oil (3.1 g). δH (CDCl3) Ϫ0.11, 0.05 (2 × 3 H, 2 × s, 2 ×
Si–CH3), 0.88 (9 H, s, C(CH3)3), 1.12 (3 H, d, J 6.2, H-3), 3.00
(1 H, q, J 6.2, H-2), 3.82 (2 H, AB, J 13.5, CH2 Bn), 4.88 (1 H,
dd, J 4.8 and 7.7, H-1), 6.25 (1 H, d, J 3.3, H-3Ј), 6.33 (1 H, dd,
J 1.8 and 3.3, H-4Ј), 7.21–7.32 (5 H, m, CH Ph) and 7.36 (1 H,
dd, J 0.7 and 1.8, H-5Ј); δC (CDCl3) Ϫ5.5, Ϫ5.3 (2 × Si–CH3),
15.9 (C-3), 17.8 (C(CH3)3), 25.5 (C(CH3)3), 50.9 (CH2Ph), 56.4
(C-2), 73.9 (C-1), 107.0, 109.8 (C-3Ј, C-4Ј), 126.5, 127.6, 128.0
(CH Ph), 140.3 (Cq Ph), 141.1 (C-5Ј) and 155.2 (C-2Ј).
To 10 mmol of 3 in 15 mL of dry diethyl ether was added
dropwise 12 mmol of the respective Grignard reagent in a
total volume of 15 mL of dry diethyl ether. The mixture was
refluxed for one hour, cooled to Ϫ20 ЊC, and 10 mL
of MeOH was added dropwise. After cooling the mixture to
Ϫ70 ЊC a solution of 4.4 mL of BnNH2 in 10 mL of
methanol was added dropwise followed by warming
the solution to Ϫ20 ЊC. Subsequently, 20 mmol of NaBH4
(0.76 g, 2 eq.) was added at Ϫ70 ЊC and allowed to warm
to rt overnight. Diethyl ether was added and the organic
layer was washed two times with 1 M KHSO4, 1 M NaOH
and brine. After drying with MgSO4, the solvent was evapor-
ated. The crude product was used without purification in the
next step.
(1S,2S )-2-N-Benzyl-1-(2Ј-furyl)-1-O-(tert-butyldimethylsilyl)-
butane (6)
Dark brown oil (2.2 g). δH (CDCl3) Ϫ0.14, 0.05 (2 × 3 H, 2 × s, 2
× Si–CH3), 0.88 (9 H, s, C(CH3)3), 0.91 (3 H, dd, J 3.3 and 7.6,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
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H-4), 1.38–1.78 (2 H, m, C-3), 2.82 (1 H, m, H-2), 3.69 (2 H,
AB, J 13.2, CH2 Bn), 4.70 (1 H, d, J 5.9, H-1), 6.26 (1 H, d,
J 3.3, H-3Ј), 6.34 (1 H, dd, J 1.8 and 3.3, H-4Ј) and 7.20–7.40
(5 H, m, CH Ph, H-5Ј); δC (CDCl3) Ϫ5.5, Ϫ5.3 (2 × Si–CH3),
9.8 (C-4), 17.8 (C(CH3)3), 22.7 (C-3), 25.5 (C(CH3)3), 51.5
(CH2Ph), 62.3 (C-2), 70.2 (C-1), 107.2, 109.9 (C-3Ј, C-4Ј),
126.4, 127.8, 127.9 (CH Ph), 140.6 (Cq Ph), 141.0 (C-5Ј) and
155.3 (C-2Ј).
and 13.2, H-2), 4.57 (1 H, AB, J 17.2, CH2Ph), 4.7 (1 H, AB,
J 15.0, CH2Ph), 4.81 (0.5 H, dd, J 4.8 and 8.4, H-1), 5.22 (0.5 H,
dd, J 5.1 and 8.0, H-1), 5.66 (0.5 H, dd, J 2.9 and 9.5,
CH᎐CH ), 5.70 (0.5 H, dd, J 2.4 and 10.2, CH᎐CH ), 6.20 (0.5
᎐
᎐
2
2
H, d, J 3.3, H-3Ј), 6.23 (0.5 H, d, J 3.3, H-3Ј), 6.31 (1 H, dd,
J 1.8 and 3.3, H-4Ј), 6.39 (1 H, dd, J 3.3 and 16.8, H-4Ј), 6.53
(0.5 H, dd, J 9.5 and 16.8, CH᎐CH ), 6.72 (0.5 H, dd, J 10.2 and
᎐
2
16.8, CH᎐CH ) and 7.09–7.37 (7 H, m, CH᎐CH , CH Ph,
᎐
᎐
2
2
H-5Ј); δC (CDCl3) Ϫ5.6 (2 × Si–CH3), 17.7 (C(CH3)3), 25.4
(C(CH3)3), 49.1, 51.9, 52.3, 52.6 (C-2, CH2Ph), 66.0, 66.9 (C-1),
106.8, 107.1, 109.8, 110.0 (C-3Ј, C-4Ј), 125.9, 127.0, 127.1,
(1S,2S )-2-N-Benzyl-1-(2Ј-furyl)-1-O-(tert-butyldimethylsilyl)-
2-phenylethane (7)
127.3, 127.5, 127.8, 128.2, 128.4 (CH Ph, CH ᎐CH), 127.7,
᎐
2
After the addition of benzylamine in methanol the temperature
was allowed to rise to room temperature before cooling to
Ϫ70 ЊC. Yellow oil (3.8 g). δH (CDCl3) Ϫ0.30, Ϫ0.27 (2 × 3 H,
2 × s, 2 × Si–CH3), 0.68 (9 H, s, C(CH3)3), 3.54 (2 H, AB, J 13.5,
CH2 Bn), 3.95 (1 H, d, J 7.7, H-2), 4.70 (1 H, d, J 7.7, H-1), 6.21
(1 H, d, J 2.9, H-3Ј), 6.33 (1 H, dd, J 1.8 and 2.9, H-4Ј) and
7.09–7.43 (11 H, m, CH Ph, H-5Ј); δC (CDCl3) Ϫ5.8, Ϫ5.6 (2 ×
Si–CH3), 17.8 (C(CH3)3), 25.4 (C(CH3)3), 50.8 (CH2Ph), 66.3
(C-2), 72.8 (C-1), 107.9, 109.9 (C-3Ј, C-4Ј), 126.5, 127.1, 127.7,
127.8, 128.0, 128.5 (CH Ph), 140.0, 140.0 (Cq Ph), 141.6 (C-5Ј)
and 154.6 (C-2Ј).
128.1 (CH ᎐CH), 136.6, 137.2 (C Ph), 141.5, 141.6 (C-5Ј),
᎐
2
q
153.5, 154.4 (C-2Ј) and 166.5, 166.6 (CON); MS (ESI) m/z
408.1 (M ϩ Naϩ requires 408.6).
(1S,2S )-2-N-Acryloyl-2-N-benzyl-1-(2Ј-furyl)-1-O-(tert-butyl-
dimethylsilyl)propane (10)
Yellow oil (3.2 g, 80%). [α]D20 = Ϫ14.8 (c = 1, CHCl3); ν (cmϪ1
)
1651, 1615, 1422, 1251, 1073, 1006, 857, 835, 777, 728 and 696;
δH (CDCl3) Ϫ0.06, 0.02 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.88 (9 H,
s, C(CH3)3), 1.28 (3 H, d, J 6.8, CH3), 4.16–4.81 (3 H, m, H-2,
CH2Ph), 5.27 (1 H, d, J 6.6, H-1), 5.57 (1 H, dd, J 4.8 and 8.0,
(1S,2R)-2-N-Benzyl-3-(2Ј-furyl)-3-O-(tert-butyldimethylsilyl)-
propionitrile (8)
CH᎐CH ), 6.20–6.35 (3 H, m, CH᎐CH , H-3Ј, H-4Ј) and 7.05–
᎐ ᎐
2 2
7.37 (7 H, m, CH᎐CH ,CH Ph, H-5Ј); δ (CDCl ) Ϫ5.7 (2 × Si–
᎐
2 C 3
CH3), 12.9 (CH3), 17.5 (C(CH3)3), 25.2 (C(CH3)3), 50.1
(CH2Ph), 57.2 (C-2), 69.3 (C-1), 106.7, 109.5 (C-3Ј, C-4Ј),
To a solution (Ϫ70 ЊC) of 3 (10 mmol, 2.37 g) in 50 mL of
diethyl ether was added 12 mmol of DIBAL-H (12 mL of 1 M
in hexanes; 1.2 eq.), which was slowly warmed to Ϫ20 ЊC.
20 mL of MeOH was added dropwise at Ϫ70 ЊC, followed by a
solution of 4.4 mL of BnNH2 in 10 mL of methanol. After
raising the temperature to Ϫ20 ЊC and subsequent cooling, a
solution of 3.75 g of NH4Br and 1.86 g of NaCN in 30 mL of
MeOH was added dropwise at Ϫ70 ЊC and the solution was
allowed to warm to rt overnight. Diethyl ether was added
and the organic layer was washed two times with 1 M KHSO4,
1 M NaOH and brine. After drying with MgSO4, the solvent
was evaporated to provide the crude product as a yellow oil
(2.7 g), which was used without purification in the next step.
δH (CDCl3) Ϫ0.04, 0.12 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.91 (9 H,
s, C(CH3)3), 3.00 (1 H, q, J 6.2), 3.83 (1 H, m, H-2), 3.96 (2 H,
AB, J 13.1, CH2 Bn), 4.98 (1 H, d, J 4.4, H-3), 6.39 (1 H, dd,
J 1.8 and 3.3, H-4Ј), 6.47 (1 H, d, J 3.3, H-3Ј), 7.20–7.37 (5 H,
m, CH Ph) and 7.40 (1 H, dd, J 0.73 and 1.83, H-5Ј); δC (CDCl3)
Ϫ5.8, Ϫ5.6 (2 × Si–CH3), 17.6 (C(CH3)3), 25.2 (C(CH3)3), 50.4
(CH2Ph), 54.4 (C-2), 68.5 (C-3), 108.2, 110.1 (C-3Ј, C-4Ј), 117.7
(CN), 126.9, 127.6, 128.0 (CH Ph), 137.6 (Cq Ph), 141.7 (C-5Ј)
and 151.9 (C-2Ј).
125.5, 126.6, 128.1, 128.4 (CH Ph, CH ᎐CH), 127.4 (CH ᎐
᎐
᎐
2
2
CH), 137.4 (Cq Ph), 140.8 (C-5Ј), 154.4 (C-2Ј) and 166.4
(CON); MS (ESI) m/z 422.6 (M ϩ Naϩ requires 422.2).
(1S,2S )-2-N-Acryloyl-2-N-benzyl-1-(2Ј-furyl)-1-O-(tert-butyl-
dimethylsilyl)butane (11)
Yellow oil (1.2 g, 29%). [α]D = 3.14 (c = 1, CHCl3); ν (cmϪ1
)
20
1649, 1614, 1436, 1421, 1250, 1069, 857, 836, 777, 727 and 698;
δH (CDCl3) Ϫ0.19, Ϫ0.01 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.84
(9 H, s, C(CH3)3), 0.70 (3 H, t, J 7.5, CH2CH3), 1.84–2.21 (2 H,
m, CH2CH3), 4.19–4.80 (4 H, m, H-1, H-2, CH2Ph), 5.59 (1 H,
dd, J 4.6 and 7.7, CH᎐CH ), 6.26 (1 H, dd, J 0.7 and 3.3, H-3Ј),
᎐
2
6.31 (1 H, dd, J 1.8 and 3.3, H-4Ј), 6.34–6.58 (1 H, m, CH᎐
᎐
CH ), 7.01–7.30 (6 H, m, CH᎐CH , CH Ph) and 7.32 (1 H, dd,
᎐
2
2
J 0.7 and 1.8, H-5Ј); δC (CDCl3) Ϫ5.5 (2 × Si–CH3), 11.7
(CH2CH3), 17.8 (C(CH3)3), 21.7 (CH2CH3), 25.5 (C(CH3)3),
44.6 (CH2Ph), 64.3 (C-2), 69.4(C-1), 107.4, 110.1 (C-3Ј, C-4Ј),
126.7, 127.9, 128.2, 128.8 (CH Ph, CH ᎐CH), 137.2, (C Ph),
᎐
2
q
141.0 (C-5Ј), 154.7 (C-2Ј) and 167.1 (CON); MS (ESI) m/z
436.4 (M ϩ Naϩ requires 436.2).
General procedure for aminoacylation
(1S,2S )-2-N-Acryloyl-2-N-benzyl-1-(2Ј-furyl)-2-phenyl-1-O-
(tert-butyldimethylsilyl)ethane (12)
To a vigorously stirred solution of crude ethanolamine (4–8)
and 1.2 eq. of Na2CO3 in 4 mL of CH2Cl2 and 2 mL of water
per mmol of ethanolamine, was added dropwise 1.1 eq. freshly
distilled acryloylchloride. The mixture was allowed to stir over-
night and the layers were separated. The water layer was
extracted once with CH2Cl2. The combined organic layers were
washed with a 10% Na2CO3 solution and brine, dried with
MgSO4 and the solvent was evaporated. The products were
purified by column chromatography (pet. ether (40–60)–EtOAc
90 : 10). Yields determined from 3.
Yellowish solid (3.3 g, 72%). Mp 86–88 ЊC; [α]D20 = Ϫ37.1 (c = 1,
CHCl3); ν (cmϪ1) 1652, 1615, 1436, 1420, 1250, 1223, 1074, 854,
836, 778, 751, 731 and 698; δH (CDCl3) Ϫ0.12, 0.04 (2 × 3 H, 2
× s, 2 × Si–CH3), 0.84 (9 H, s, C(CH3)3), 4.64 (2 H, AB, J 17.7,
CH2Ph), 5.12 (1 H, d, J 7.3, H-1), 5.41 (1 H, d, J 7.3, H-2), 5.60–
5.74 (1 H, m, CH᎐CH ), 6.33 (1 H, dd, J 1.8 and 3.3, H-3Ј),
᎐
2
6.35–6.46 (2 H, m, CH᎐CH , H-4Ј) and 7.13–7.42 (7 H, m, CH᎐
᎐
᎐
2
CH2, CH Ph, H-5Ј); δC (CDCl3) Ϫ5.9, Ϫ5.7 (2 × Si–CH3), 17.5
(C(CH3)3), 25.2 (C(CH3)3), 51.3 (CH2Ph), 67.4 (C-2), 68.0
(C-1), 107.7, 109.8 (C-3Ј, C-4Ј), 126.0, 126.8, 127.3, 127.7,
(S )-2-N-Acryloyl-2-N-benzyl-1-(2Ј-furyl)-1-O-(tert-butyl-
dimethylsilyl)ethane (9)
128.1, 129.1, 129.9 (CH Ph, CH ᎐CH), 127.9 (CH ᎐CH),
᎐ ᎐
2 2
136.4, 138.6 (Cq Ph), 141.1 (C-5Ј), 154.1 (C-2Ј) and 167.2
(CON); MS (ESI) m/z 484.4 (M ϩ Naϩ requires 484.7).
(Two rotamers, 1 : 1). Yellowish oil (1.2 g, 30%). [α]D20 = Ϫ24.0
(c = 1, CHCl3); ν (cmϪ1) 1652, 1616, 1442, 1250, 1220, 1082, 938,
831, 778, 731 and 697; δH (CDCl3) Ϫ0.11, Ϫ0.07, 0.00, 0.06
(6 H, 4 × s, 2 × Si–CH3), 0.85, 0.88 (9 H, 2 × s, C(CH3)3), 3.48
(0.5 H, dd, J 4.8 and 15.7, H-2), 3.51 (0.5 H, dd, J 5.1 and 13.2,
H-2), 3.73 (0.5 H, dd, J 8.4 and 15.7, H-2), 3.81 (0.5 H, dd, J 8.0
(1S,2R)-2-N-Acryloyl-2-N-benzyl-3-(2Ј-furyl)-3-O-(tert-butyl-
dimethylsilyl)propionitrile (13)
20
Colourless oil (48%). [α]D = Ϫ22.6 (c = 1, CHCl3); ν (cmϪ1
)
1660, 1621, 1418, 1240, 1207, 1094, 838, 780, 732 and 696;
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
3596

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δH (CDCl3) Ϫ0.11, 0.06 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.86 (9 H,
s, C(CH3)3), 4.64 (2 H, AB, J 17.90, CH2Ph), 5.15 (1 H, d, J 7.0,
Absorption correction was not applied. The positions of heavy
atoms were determined from a Patterson map (DIFDIF).25 The
atomic scattering factors were taken from the International
Tables for X-ray Crystallography.26 The remainder of the non-
hydrogen atoms was located in subsequent difference Fourier
syntheses. Full-matrix least-squares refinement on F using
XTAL3.4 set of programs27 with the function minimised being
Σw(|Fo|Ϫ|Fc|)2 with w = 1/σ2 (F). Positional refinement of the
non-hydrogen atoms, anisotropic for the non-hydrogen atoms,
fixed isotropic thermal parameters of 0.08 Å2 for the hydrogens,
which were placed at the distance of 0.95 Å from their parent
atoms. Geometric calculations and molecular graphics were
performed with the PLATON package.23
H-2), 5.41 (1 H, d, J 7.0, H-3), 5.72 (1 H, dd, J 2.9 and 8.0, CH᎐
᎐
CH2), 6.37 (1 H, dd, J 1.8 and 3.3, H-3Ј), 6.38–6.46 (2 H, m,
CH᎐CH , H-4Ј), 7.18–7.39 (6 H, m, CH᎐CH , CH Ph) and 7.41
᎐
᎐
2
2
(1 H, dd, J 0.7 and 1.8, H-5Ј); δC (CDCl3) Ϫ5.7 (2 × Si–CH3),
17.5 (C(CH3)3), 25.2 (C(CH3)3), 52.0 (CH2Ph), 53.3 (C-2), 66.8
(C-3), 109.5, 110.3 (C-3Ј, C-4Ј), 114.7 (CN), 125.8, 126.5, 127.5,
128.6 (CH Ph, CH ᎐CH), 130.0 (CH ᎐CH), 135.7 (C Ph),
᎐
᎐
2
2
q
142.6 (C-5Ј), 150.8 (C-2Ј) and 166.4 (CON); MS (ESI) m/z
433.1 (M ϩ Naϩ requires 433.6).
General procedure for intramolecular Diels–Alder reaction
Ethanolamides 9–13 (2 mmol) were dissolved in 10 mL of dry
toluene. The mixtures were refluxed overnight and the solvent
evaporated. The crude compounds were purified by column
Crystal data. C23H33NO3Si, M = 399.22, orthorhombic,
a = 19.214(6), b = 16.341(4), c = 7.1838(9) Å, U = 2255.5(9) Å3,
T = 145 K, space group P2(1)2(1)2(1) (no. 19), Z = 4, µ(MoKα)
= 0.126 mmϪ1, 5389 reflections measured, observed data
[I > 2.0σ(I )] 3287, reflections used 3129, R = 0.042, wR = 0.045,
S = 2.04.
chromatography (pet. ether (40–60)–EtOAc 90 : 10
75 : 25).
Compounds 17 and 18 could not be separated and the yields
were calculated using NMR (combined yield: 0.52 g).
(1S,2S,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-11-oxa-4-
aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (14)
(1S,2S,3R,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
methyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (16)
20
White solid (0.69 g, 90%). Mp 95 ЊC; [α]D = Ϫ57.4 (c = 1,
20
CHCl3); ν (cmϪ1) 1622, 1472, 1455, 1361, 1250, 1114, 1061, 971,
939, 832, 779, 748, 700, 663 and 590; δH (CDCl3) Ϫ0.18, 0.02 (2
× 3 H, 2 × s, 2 × Si–CH3), 0.81 (9 H, s, C(CH3)3), 1.93 (1 H, dd,
J 9.2 and 12.9, H-7β), 2.09 (1 H, dd, J 4.3 and 12.9, H-7α), 2.54
(1 H, dd, J 3.9 and 9.2, H-6), 3.18 (1 H, dd, J 3.1 and 13.0, H-3),
3.49 (1 H, dd, J 2.6 and 13.0, H-3), 4.18 (1 H, t, J 2.7, H-2), 4.24
(1 H, d, J 14.7, CH Bn), 4.92 (1 H, d, J 14.7, CH Bn), 4.97 (1 H,
d, J 4.5, H-8), 6.32 (1 H, d, J 5.8, H-10), 6.39 (1 H, dd, J 1.2 and
5.8, H-9) and 7.21–7.29 (5 H, m, CH Ph); δC (CDCl3) Ϫ5.3,
Ϫ4.8 (2 × Si–CH3), 17.7 (C(CH3)3), 25.5 (C(CH3)3), 32.1 (C-7),
40.8 (C-6), 49.7 (CH2Ph), 50.4 (C-3), 65.0 (C-2), 78.4 (C-8),
88.7 (C-1), 127.2, 128.1, 128.4 (CH Ph), 134.1 (C-10), 136.8 (Cq
Ph), 137.2 (C-9) and 171.2 (C-5); HRMS (ESI) m/z 386.2062
(M ϩ Hϩ requires 386.2151).
Colourless oil (80 mg, 10%). [α]D = 29.8 (c = 1, CHCl3); ν
(cmϪ1) 1659, 1466, 1449, 1435, 1255, 1226, 1121, 1059, 1029,
995, 954, 836, 778, 701 and 588; δH (CDCl3) Ϫ0.18, Ϫ0.10 (2 ×
3 H, 2 × s, 2 × Si–CH3), 0.80 (9 H, s, C(CH3)3), 1.24 (3 H, d,
J 7.0, CHCH3), 1.69 (1 H, dd, J 9.9 and 13.0, H-7β), 2.49 (1 H,
dd, J 4.4 and 13.0, H-7α), 2.52 (1 H, dd, J 4.4 and 9.9, H-6),
3.40 (1 H, dq, J 5.6 and 7.0, H-3), 3.97 (1 H, d, J 5.6, H-2), 3.99
(1 H, d, J 14.7, CH Bn), 4.97 (1 H, dd, J 1.6 and 4.2, H-8), 5.23
(1 H, d, J 14.7, CH Bn), 6.34 (1 H, dd, J 1.4 and 5.8, H-9), 6.42
(1 H, d, J 5.8, H-10) and 7.24–7.34 (5 H, m, CH Ph); δC (CDCl3)
Ϫ5.4, Ϫ5.1 (2 × Si–CH3), 12.6 (CH3C-3), 18.0 (C(CH3)3), 25.6
(C(CH3)3), 29.8 (C-7), 43.7 (C-6), 48.8 (CH2Ph), 55.2 (C-3),
71.3 (C-2), 77.8 (C-8), 91.8 (C-1), 127.5, 128.1, 128.6 (CH Ph),
136.0 (C-10), 136.2 (C-9), 137.3 (Cq Ph) and 170.8 (C-5);
HRMS (ESI) m/z 400.2200 (M ϩ Hϩ requires 400.2307).
(1S,2S,3S,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
methyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (15)
(1S,2S,3S,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
ethyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (17)
20
White solid (0.59 g, 74%). Mp 117 ЊC; [α]D = Ϫ102.9 (c = 1,
Colourless oil (42%). ν (cmϪ1) 1647, 1471, 1462, 1457, 1434,
1258, 1260, 1123, 1082, 1039, 998, 875, 836, 779, 706, 699 and
618; δH (CDCl3) Ϫ0.26, 0.07 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.81
(9 H, s, C(CH3)3), 0.94 (3 H, t, J 7.5, CH3), 1.67–1.79 (1 H, m,
CH2), 1.97 (1 H, dd, J 9.2 and 11.9, H-7β), 1.92–2.04 (1 H, m,
CH2), 2.08 (1 H, dt, J 4.4 and 11.9, H-7α), 2.58 (1 H, dd, J 4.1
and 9.2, H-6), 3.17 (1 H, ddd, J 1.5, 3.2 and 11.2, H-3), 3.83
(1 H, d, J 15.0, CH Bn), 4.31 (1 H, d, J 1.4, H-2), 4.99 (1 H, dd,
J 1.6 and 4.6, H-8), 5.54 (1 H, d, J 15.0, CH Bn), 6.38 (1 H, dd,
J 1.5 and 5.8, H-9), 6.35 (1 H, d, J 5.8, H-10), 7.22–7.34 (5 H,
m, CH Ph); δC (CDCl3) Ϫ5.2, Ϫ4.4 (2 × Si–CH3), 11.7 (CH3),
17.7 (C(CH3)3), 22.5 (CH2), 25.6 (C(CH3)3), 32.3 (C-7), 40.1
(C-6), 47.2 (CH2Ph), 64.7, 64.8 (C-2, C-3), 79.0 (C-8), 88.4
(C-1), 127.1, 128.3, 128.5 (CH Ph), 135.9 (C-10), 136.3 (C-9),
137.2 (Cq Ph) and 171.1 (C-5); HRMS (ESI) m/z 414.2535
(M ϩ Hϩ requires 414.2464).
CHCl3); ν (cmϪ1) 1622, 1472, 1452, 1361, 1250, 1074, 1060, 964,
839, 780, 730, 701, 620 and 588; δH (CDCl3) Ϫ0.26, 0.04 (2 ×
3 H, 2 × s, 2 × Si–CH3), 0.78 (9 H, s, C(CH3)3), 1.31 (3 H, d,
J 7.1, CHCH3), 1.94 (1 H, dd, J 9.2 and 11.9, H-7β), 2.09 (1 H,
dd, J 4.4 and 11.9, H-7α), 2.57 (1 H, dd, J 4.1 and 9.2, H-6),
3.45 (1 H, dq, J 1.8 and 7.1, H-3), 3.83 (1 H, d, J 15.0, CH Bn),
4.09 (1 H, d, J 1.8, H-2), 4.97 (1 H, dd, J 1.6 and 4.5, H-8), 5.50
(1 H, d, J 15.0, CH Bn), 6.31 (1 H, d, J 5.8, H-10), 6.35 (1 H, dd,
J 1.6 and 5.8, H-9) and 7.19–7.28 (5 H, m, CH Ph); δC (CDCl3)
Ϫ5.6, Ϫ4.9 (2 × Si–CH3), 16.2 (CH3C-3), 17.4 (C(CH3)3), 25.3
(C(CH3)3), 32.1 (C-7), 40.0 (C-6), 46.5 (CH2Ph), 57.6 (C-3),
68.6 (C-2), 78.5 (C-8), 88.2 (C-1), 126.8, 127.8, 128.1 (CH Ph),
135.4 (C-10), 136.1 (C-9), 137.0 (Cq Ph) and 170.8 (C-5);
HRMS (ESI) m/z 400.2198 (M ϩ Hϩ requires 400.2307).
Crystal structure determination of compound 15
Single crystals suitable for X-ray analysis† were obtained as
colourless needles by recrystallisation from dichloromethane
and hexane. The reflection intensities were measured on a four-
circle Enraf-Nonius CAD-4 diffractometer using graphite-
monochromated MoKα radiation (λ = 0.71073 Å). The cell
dimensions were determined using 24 independent reflections.
Intensities were corrected for Lorentz and polarisation effects.
(1S,2S,3S,6S,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
ethyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (18)
Colourless oil (20%). ν (cmϪ1) 1647, 1471, 1462, 1457, 1434,
1258, 1260, 1123, 1082, 1039, 998, 875, 836, 779, 706, 699 and
618; 1H NMR δH (CDCl3) Ϫ0.03, 0.04 (2 × 3 H, 2 × s, 2 × Si–
CH3), 0.76 (9 H, s, C(CH3)3), 0.99 (3 H, t, J 7.4, CH3), 1.75 (1 H,
dd, J 4.2 and 11.2, H-7β), 1.78–1.89 (2 H, m, CH2), 2.17 (1 H,
ddd, J 4.6, 9.1 and 11.6, H-7α), 2.56 (1 H, dd, J 4.2 and 9.1,
H-6), 3.32 (1 H, dt, J 3.6 and 7.8, H-3), 3.73 (1 H, d, J 14.6,
CH Bn), 4.28 (1 H, dd J 0.8 and 3.6, H-2), 4.98 (1 H, dd, J 1.6
† CCDC reference numbers 214952. See http://www.rsc.org/suppdata/
ob/b3/b307275d/ for crystallographic data in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
3597

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and 4.6, H-8), 5.30 (1 H, d, J 14.5, CH Bn), 5.84 (1 H, d, J 5.8,
H-10), 6.49 (1 H, ddd, J 1.6, 4.1 and 5.8, H-9) and 7.22–7.34
(5 H, m, CH Ph); δC (CDCl3) Ϫ5.3, Ϫ4.2 (2 × Si–CH3), 9.0
(CH3), 17.8 (C(CH3)3), 24.7 (CH2), 25.5 (C(CH3)3), 29.2 (C-7),
41.9 (C-6), 47.1 (CH2Ph), 66.1 (C-3), 72.1 (C-2), 80.0 (C-8),
89.6 (C-1), 127.5, 128.7 (CH Ph), 130.8 (C-10), 137.0 (Cq Ph),
139.4 (C-9) and 170.6 (C-5); HRMS (ESI) m/z 414.2535
(M ϩ Hϩ requires 414.2464).
746, 697 and 595; δH (CDCl3) Ϫ0.13, 0.10 (2 × 3 H, 2 × s, 2 ×
Si–CH3), 0.82 (9 H, s, C(CH3)3), 2.03 (1 H, dd, J 9.2 and 11.9,
H-7β), 2.20 (1 H, dd, J 4.4 and 11.9, H-7α), 2.68 (1 H, dd, J 4.1,
J 9.2, H-6), 3.39 (1 H, d, J = 14.7, CH Bn), 4.41 (1 H, d, J 1.6,
H-2), 4.60 (1 H, br s, H-3), 4.89 (1 H, dd, J 1.4 and 4.6, H-8),
5.76 (1 H, d, J 14.7, CH Bn), 6.27 (1 H, d, J 5.7, H-10), 6.30
(1 H, dd, J 1.5 and 5.8, H-9) and 7.15–7.35 (10 H, m, CH Ph);
δC (CDCl3) Ϫ5.2, Ϫ4.3 (2 × Si–CH3), 17.7 (C(CH3)3), 25.6
(C(CH3)3), 32.5 (C-7), 40.4 (C-6), 47.5 (CH2Ph), 66.8 (C-3),
69.9 (C-2), 78.9 (C-8), 88.3 (C-1), 127.3, 127.5, 127.7, 128.1,
128.5, 128.6 (CH Ph), 135.4 (C-10), 136.4 (C-9), 136.8, 137.0
(Cq Ph) and 172.2 (C-5); HRMS (ESI) m/z 462.2501 (M ϩ Hϩ
requires 462.2364).
(1R,2S,3S,6S,8R)-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
ethyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (19)
20
Colourless oil (0.18 g, 22%). [α]D = 1.0 (c = 1, CHCl3); ν
(cmϪ1) 1638, 1464, 1453, 1420, 1248, 1126, 1094, 835, 775 and
699; δH (CDCl3) 0.07, 0.08 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.81
(9 H, s, C(CH3)3), 0.83 (3 H, t, J 7.3, CH3), 1.72–1.78 (2 H, m,
CH2), 1.94 (1 H, dd, J 8.9 and 12.0, H-7α), 2.26 (1 H, dd, J 4.2
and 12.0, H-7β), 2.43 (1 H, dd, J 3.7 and 8.9, H-6), 3.53 (1 H,
dq, J 4.1 and 7.5, H-3), 4.03 (1 H, d, J 15.5, CH Bn), 4.39 (1 H,
d, J 7.5, H-2), 5.06 (1 H, dd, J 1.6 and 4.4, H-8), 5.43 (1 H, d,
J 15.5, CH Bn), 6.16 (1 H, d, J 5.7, H-10), 6.40 (1 H, dd, J 1.6
and 5.7, H-9) and 7.17–7.29 (5 H, m, CH Ph); δC (CDCl3) Ϫ4.5,
Ϫ3.8 (2 × Si–CH3), 7.3 (CH3), 18.3 (C(CH3)3), 20.3 (CH2), 25.8
(C(CH3)3), 33.7 (C-7), 43.1 (C-6), 46.8 (CH2Ph), 59.5 (C-3),
66.9 (C-2), 77.8 (C-8), 88.3 (C-1), 126.8, 127.1, 128.3 (CH Ph),
135.3 (C-10), 136.6 (Cq Ph), 137.2 (C-9) and 172.5 (C-5);
HRMS (ESI) m/z 462.2519 (M ϩ Hϩ requires 414.2464).
(1S,2S,3R,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
phenyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (23)
20
Colourless oil (0.10 g, 11%). [α]D = 23.6 (c = 1, CHCl3); ν
(cmϪ1) 1663, 1452, 1423, 1251, 1212, 1125, 1035, 836, 778, 699
and 610; δH (CDCl3) Ϫ0.40, Ϫ0.09 (2 × 3 H, 2 × s, 2 × Si–CH3),
0.84 (9 H, s, C(CH3)3), 1.65 (1 H, dd, J 9.6 and 12.9, H-7β),
2.37–2.43 (2 H, m, H-6, H-7α), 3.67 (1 H, d, J 14.6, CH Bn),
4.20 (1 H, d, J 4.9, H-2), 4.58 (1 H, d, J = 4.9, H-3), 4.94 (1 H,
dd, J 1.6 and 4.1, H-8), 5.76 (1 H, d, J 14.6, CH Bn), 6.06 (1 H,
d, J 5.8, H-10), 6.21 (1 H, ddd, J 0.4, 1.6 and 5.8, H-9) and
7.18–7.51 (10 H, m, CH Ph); δC (CDCl3) Ϫ4.8 (2 × Si–CH3),
18.0 (C(CH3)3), 25.7 (C(CH3)3), 30.5 (C-7), 43.0 (C-6), 49.0
(CH2Ph), 61.3 (C-3), 73.0 (C-2), 77.9 (C-8), 91.0 (C-1), 127.6,
127.7, 127.9, 128.3, 128.4, 128.6, (CH Ph), 135.4 (C-10), 136.0,
136.8 (Cq Ph), 136.4 (C-9) and 172.2 (C-5); HRMS (ESI) m/z
462.2384 (M ϩ Hϩ requires 462.2364).
(1S,2S,3R,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsyl)-3-
ethyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (20)
Colourless oil (60 mg, 7%). [α]D20 = 54.2 (c = 1, CHCl3); ν (cmϪ1
)
1647, 1471, 1462, 1457, 1434, 1258, 1260, 1123, 1082, 1039, 98,
875, 836, 779, 706, 699 and 618; δH (CDCl3) Ϫ0.29, Ϫ0.20 (2 ×
3 H, 2 × s, 2 × Si–CH3), 0.76 (9 H, s, C(CH3)3), 0.88 (3 H, t,
J 7.5, CH3), 1.56–1.62 (1 H, m, CH2), 1.63 (1 H, dd, J 8.1 and
11.3, H-7β), 1.96–2.08 (1 H, m, CH2), 2.50 (1 H, dd, J 4.2 and
8.1, H-6), 2.55 (1 H, dd, J 4.4 and 11.3, H-7α), 3.17 (1 H, dq,
J 4.6 and 5.7, H-3), 3.71 (1 H, d, J 14.4, CH Bn), 3.83 (1 H, d,
J 5.7, H-2), 4.95 (1 H, dd, J 1.6 and 4.4, H-8), 5.62 (1 H, d,
J 14.4, CH Bn), 6.31 (1 H, ddd, J 0.5, 1.6 and 5.8, H-9), 6.39
(1 H, d, J 5.8, H-10) and 7.25–7.34 (5 H, m, CH Ph). δC (CDCl3)
Ϫ5.7, Ϫ5.3 (2 × Si–CH3), 11.9 (CH3), 17.9 (C(CH3)3), 21.1
(CH2), 25.5 (C(CH3)3), 29.5 (C-7), 44.2 (C-6), 50.7 (CH2Ph),
61.3 (C-3), 72.0 (C-2), 77.9 (C-8), 92.4 (C-1), 127.6, 128.5, 128.6
(CH Ph), 136.1 (C-9, C-10), 137.1 (Cq Ph) and 171.1 (C-5);
HRMS (ESI) m/z 414.2540 (M ϩ Hϩ requires 414.2464).
(1S,2S,3R,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
nitrile-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (24)
20
Colourless oil (0.71 g, 87%). [α]D = 54.3 (c = 0.7, CHCl3); ν
(cmϪ1) 1675, 1417, 1253, 1200, 1131, 1044, 999, 948, 878, 838,
753, 702, 668 and 617; δH (CDCl3) Ϫ0.18, 0.11 (2 × 3 H, 2 × s,
2 × Si–CH3), 0.81 (9 H, s, C(CH3)3), 1.72 (1 H, dd, J 8.5 and
11.9, H-7β), 2.56 (1 H, dd, J 4.2 and 11.9, H-7α), 2.79 (1 H, dd,
J 4.0 and 8.5, H-6), 3.94 (1 H, d, J 5.7, H-2), 4.01 (1 H, d, J 14.8,
CH Bn), 4.10 (1 H, d, J 5.7, H-3), 5.02 (1 H, dd, J 1.6 and 4.5,
H-8), 5.38 (1 H, d, J 14.8, CH Bn), 6.40 (1 H, dd, J 1.3 and 5.8,
H-9), 6.54 (1 H, d, J 5.8, H-10) and 7.25–7.39 (5 H, m, CH Ph);
δC (CDCl3) Ϫ5.7, Ϫ5.2 (2 × Si–CH3), 17.8 (C(CH3)3), 25.4
(C(CH3)3), 29.7 (C-7), 44.1 (C-6), 49.1 (CH2Ph), 51.3 (C-3),
70.3 (C-2), 78.5 (C-8), 91.1 (C-1), 115.7 (CN), 128.4, 129.1 (CH
Ph), 134.7 (C-10), 135.0 (Cq Ph), 136.7 (C-9) and 170.4 (C-5);
HRMS (ESI) m/z 433.1976 (M ϩ Naϩ requires 433.1923).
(1S,2S,3S,6S,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
phenyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (21)
20
Colourless oil (0.39 g, 42%). [α]D = Ϫ76.6 (c = 1, CHCl3); ν
(1S,2S )-2-N-Acryloyl-1-(2Ј-furyl)-1-O-(tert-butyldimethyl-
(cmϪ1) 1665, 1416, 1249, 1218, 1160, 1124, 1073, 1017, 971, 867,
835, 778 and 696; δH (CDCl3) Ϫ0.36, Ϫ0.19 (2 × 3 H, 2 × s, 2 ×
Si–CH3), 0.71 (9 H, s, C(CH3)3), 1.85 (1 H, dd, J 4.4 and 11.6,
H-7β), 2.31 (1 H, ddd, J 4.4, 9.2 and 11.6, H-7α), 2.82 (1 H, dd,
J 4.4 and 9.2, H-6), 3.23 (1 H, d, J 14.5, CH Bn), 4.15 (1 H, d,
J 6.2, H-3), 4.43 (1 H, dd, J 0.9 and 6.2, H-2), 5.03 (1 H, dd,
J 1.5 and 4.6, H-8), 5.39 (1 H, d, J 14.5, CH Bn), 5.97 (1 H, d,
J 5.8, H-10), 6.62 (1 H, dt, J 1.5 and 5.8, H-9), 7.07–7.10 (2 H,
m, CH Ph) and 7.25–7.43 (8 H, m, CH Ph); δC (CDCl3) Ϫ5.5,
Ϫ4.7 (2 × Si–CH3), 17.9 (C(CH3)3), 25.6 (C(CH3)3), 29.7 (C-7),
43.2 (C-6), 46.6 (CH2Ph), 68.8 (C-3), 77.0 (C-2), 80.1 (C-8),
88.3 (C-1), 127.5, 127.7, 128.2, 128.5, 128.8, 128.9 (CH Ph),
129.9 (C-10), 136.7, 139.9 (Cq Ph), 140.3 (C-9) and 170.7 (C-5);
HRMS (ESI) m/z 462.2498 (M ϩ Hϩ requires 462.2364).
silyl)propane (25)
To a solution of 20 mmol of 3 in 40 mL of dry diethyl ether was
added dropwise 22 mmol of Grignard reagent in a total volume
of 24 mL of diethyl ether. The mixture was refluxed for one
hour, cooled to Ϫ20 ЊC and 20 mL of MeOH was added. After
further cooling to Ϫ70 ЊC, 40 mmol of NaBH4 (1.52 g, 2 eq.)
was added and the mixture was allowed to warm to rt over-
night. Diethyl ether and water were added. The water layer was
extracted three times with diethyl ether and the combined
organic layers were dried (MgSO4) and the solvent was evapor-
ated. The crude product (brown–yellow oil, 5.75 g) was dissol-
ved in 80 mL of dichloromethane and a solution of 24 mmol of
Na2CO3 (2.74 g) in 40 mL of water was added. After dropwise
addition of freshly distilled acryloylchloride (22 mmol, 1.99 g),
the mixture was stirred overnight and the layers were separated.
The water layer was washed once with CH2Cl2. The combined
organic layers were washed with a 10% Na2CO3 solution and
brine, dried with MgSO4 and the solvent was evaporated. Puri-
fication by column chromatography (pet. ether (40–60)–EtOAc
(1S,2S,3S,6R,8S )-4-Benzyl-2-O-(tert-butyldimethylsilyl)-3-
phenyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (22)
20
Colourless oil (70 mg, 8%). [α]D = Ϫ108.4 (c = 1, CHCl3); ν
(cmϪ1) 1639, 1463, 1448, 1432, 1257, 1091, 1061, 868, 833, 776,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 9 2 – 3 5 9 9
3598

View Article Online
4 J. Brussee and A. van der Gen, Recl. Trav. Chim. Pays-Bas, 1991,
110, 25.
5 P. Zandbergen, A. M. C. H. van den Nieuwendijk, J. Brussee and
A. van der Gen, Tetrahedron, 1992, 48, 3977.
6 F. Effenberger and U. Stelzer, Angew. Chem., Int. Ed. Engl., 1991, 30,
873; F. Effenberger and U. Stelzer, Tetrahedron: Asymmetry, 1995, 6,
283.
85 : 15) yielded 25 as a yellowish oil (4.9 g, 80% from 3).
δH (CDCl3) Ϫ0.12, Ϫ0.01 (2 × 3 H, 2 × s, 2 × Si–CH3), 0.88
(9 H, s, C(CH3)3), 1.06 (3 H, d, J 7.0, H-3), 4.26–4.44 (1 H, m,
H-2), 4.83 (1H, d, J 3.7, H-1), 5.61 (1H, dd, J 1.8 and 10.0, CH᎐
᎐
CH2), 5.86 (1H, d, J 8.0, NH ), 6.06 (1H, dd, J 10.0 and 17.0,
CH᎐CH ), 6.20 (1H, dd, J 0.7 and 2.9, H-3Ј), 6.24 (1H, dd, J 1.8
᎐
2
7 E. G. J. C. Warmerdam, J. Brussee, A. van der Gen and C. G. Kruse,
Helv. Chim. Acta, 1994, 77, 252; R. A. Tromp, M. van der Hoeven,
A. Amore, J. Brussee, M. Overhand, G. A. van der Marel and A. van
der Gen, Tetrahedron: Asymmetry, 2001, 12, 1109; R. A. Tromp,
M. van der Hoeven, A. Amore, J. Brussee, M. Overhand, G. A. van
der Marel and A. van der Gen, Tetrahedron: Asymmetry, 2003, 14,
1645.
8 F. Effenberger, J. Eichhorn and J. Roos, Tetrahedron: Asymmetry,
1995, 6, 271; E. Menéndez, R. Brieva, F. Rebolledo and V. Gotor,
J. Chem. Soc., Chem. Commun., 1995, 989; M. I. Monterde,
S. Nazabadioko, F. Rebolledo, R. Brieva and V. Gotor, Tetrahedron:
Asymmetry, 1999, 10, 3449.
and 17.0, CH᎐CH ), 6.29 (1H, dd, 1.8 and 2.9, H-4Ј) and 7.33
(1H, dd, J 0.7 and 1.8, H-5Ј); δC (CDCl3) Ϫ5.7, Ϫ5.6 (2 × Si–
CH3), 14.2 (CH3), 17.6 (C(CH3)3), 25.2 (C(CH3)3), 49.1 (C-2),
᎐
2
70.1 (C-1), 106.5, 109.5 (C-3Ј, C-4Ј), 125.1 (CH ᎐CH), 131.0
᎐
2
(CH᎐CH ), 141.0 (C-5Ј), 154.4 (C-2Ј) and 166.4 (CON).
᎐
2
(1S,2S,3S,6R,8S )-4-Acetyl-2-O-(tert-butyldimethylsilyl)-3-
methyl-11-oxa-4-aza-tricyclo[6.2.1.01.6]undec-9-en-5-one (26)
Compound 25 (2 mmol) was dissolved in 10 mL of acetic
anhydride and the resulting solution was refluxed overnight.
Excess acetic anhydride was evaporated under reduced pressure
to give a brown oil. Purification by column chromatography
(pet. ether (40–60)–EtOAc 85 : 15) yielded 26 as a white solid
(0.33 g, 47%). Mp. 72 ЊC; δH (CDCl3) 0.10, 0.13 (2 × 3 H, 2 × s,
2 × Si–CH3), 0.84 (9 H, s, C(CH3)3), 1.24 (3 H, d, J 7.2,
CH3C-3), 1.89 (1H, dd, J 9.1 and 12.0, H-7β), 2.14 (1H, dd,
J 4.4 and 12.0, H-7α), 2.41 (3 H, s, CH3CO), 2.65 (1H, dd, J 4.1
and 9.1, H-6), 4.27 (1H, d, J 5.6, H-2), 4.63 (1H, dq, J 2.2 and
7.2, H-3), 4.99 (1H, dd, J 1.5 and 4.6, H-8), 6.36 (1H, d, J 5.8,
H-10) and 6.38 (1H, dd, J 1.5 and 5.8, H-9); δC (CDCl3) Ϫ5.2,
Ϫ5.0 (2 × Si–CH3), 17.4 (CH3C-3), 17.5 (C(CH3)3), 25.3
(C(CH3)3), 26.5 (CH3CO), 31.5 (C-7), 43.4 (C-6), 56.0 (C-3),
68.1 (C-2), 78.8 (C-8), 88.7 (C-1), 135.7 (C-10), 136.6 (C-9) and
173.1, 175.2 (C-5, CH3CO); MS (ESI) m/z 374.1 (M ϩ Naϩ
requires 374.1).
9 T. Mandai, S. Hashio, J. Goto and M. Kawada, Tetrahedron Lett.,
1981, 22, 2187; D. V. Johnson and H. Griengl, Tetrahedron, 1997, 53,
617.
10 C. O. Kappe, S. S. Murphree and A. Padwa, Tetrahedron, 1997, 53,
14179.
11 C. Marchionni and P. Vogel, Helv. Chim. Acta, 2001, 84, 431.
12 A. Padwa, M. Dimitroff and B. Liu, Org. Lett., 2000, 2, 3233.
13 S. G. Cauwberghs and P. J. de Clercq, Tetrahedron Lett., 1988, 29,
6501.
14 K. A. Parker and M. R. Adamchuk, Tetrahedron Lett., 1978, 19,
1689.
15 Designation as the (S)-cyanohydrin results from the fact that,
according to the Cahn–Ingold–Prelog rules, the 2-furyl substituent
takes priority over the nitrile group.
16 P. Zandbergen, J. van der Linden, J. Brussee and A. van der Gen,
Synth. Commun., 1991, 21, 1387.
17 J. Brussee, E. C. Roos and A. van der Gen, Tetrahedron Lett., 1988,
29, 4485; E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc.,
1972, 74, 6190.
18 C. Kouklovsky, A. Pouilhès and Y. Langlois, J. Am. Chem. Soc.,
1990, 112, 6672.
Acknowledgements
19 L. R. Krepski, K. M. Jensen, S. M. Heilmann and J. K. Rasmussen,
Synthesis, 1986, 301.
20 P. Zandbergen, J. Brussee, A. van der Gen and C. G. Kruse,
Tetrahedron: Asymmetry, 1992, 3, 769.
We thank S. Gorter and W. L. Driessen for X-ray measure-
ments, H. van der Elst for MS, and B. Hofte for HRMS
spectroscopy.
21 A. Padwa and T. S. Reger, Can. J. Chem., 2000, 78, 749.
22 B. L. Feringa, O. J. Gelling and L. Meesters, Tetrahedron Lett., 1990,
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Tetrahedron Lett., 1983, 24, 3145.
23 A. L. Spek, PLATON, A multipurpose crystallographic tool,
Utrecht University, The Netherlands, 2000.
24 For examples see: references 21 and 22. P. A. Jacobi and Y. Li, J. Am.
Chem. Soc., 2001, 123, 9307; L. Sader-Bakaouni, O. Charton,
N. Kunesch and F. Tillequin, Tetrahedron, 1998, 54, 1773; F. Pontén
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25 P. T. Beurskens, G. Admiraal, G. Beurskens, W. P. Bosman,
S. Garcia-Granda, R. O. Gould, J. M. M. Smits and C. Smykalla.
The DIRDIF program system, Technical Report of the
Crystallography Laboratory, University of Nijmegen, The
Netherlands, 1992.
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3599