Synthesis of a 1,3-spiro-amino-alcohol-derived chiral auxiliary and its application to Diels-Alder reactions

Article abstract of DOI:10.1016/S0957-4166(03)00051-X

A short synthesis and resolution of (1R,5R,6R)-6-aminospiro[4.4]nonan-1-ol, 11, is reported. The pivalamide derivative (+)-5 gives excellent diastereo- and regiocontrol as well as endo selectivity as a chiral auxiliary in the BCl₃-catalyzed Die

Full text of DOI:10.1016/S0957-4166(03)00051-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 749–756
Synthesis of a 1,3-spiro-amino-alcohol-derived chiral auxiliary
and its application to Diels–Alder reactions
Susan M. Lait, Masood Parvez and Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, Alta, T2N 1N4, Canada
Received 9 December 2002; accepted 1 January 2003
Abstract—A short synthesis and resolution of (1R,5R,6R)-6-aminospiro[4.4]nonan-1-ol, 11, is reported. The pivalamide derivative
(+)-5 gives excellent diastereo- and regiocontrol as well as endo selectivity as a chiral auxiliary in the BCl3-catalyzed Diels–Alder
reaction with a variety of symmetrical and unsymmetrical dienes. The adducts are readily cleaved by saponification, allowing
recovery and reuse of (+)-5. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
alcohols.6 In 2000, we reported that cis,trans-spiro-
amido-alcohol 3,7 a 1,3-amino alcohol derivative, gave
good selectivity in the Diels–Alder reaction; however, it
did not have the optimal geometry for bringing the
blocking group into close proximity to the dienophile as
was the case with the corresponding cis,cis-spiro-diol 4.8
Theepimerof3(i.e. 5)hastheidealcis,cisgeometry. While
3 is an effective auxiliary in its own right,7a its synthesis
is 10 steps long and is not particularly amenable to scale
up. We now report a practical synthesis of 5 as well as
its application to the Diels–Alder reaction with a variety
of symmetrical and unsymmetrical dienes. We also report
that 3 and 5 are complementary auxiliaries that only differ
at the stereocenter containing the hydroxyl group. The
same sense of chirality at the spiro and amido centers,
but differing in the stereochemistry at C-1, led to products
that are enantiomeric. This is particularly useful since the
hydroxyl group in 3 and 5 is readily epimerized (Scheme
1).
Much of the recent work involving chiral auxiliaries has
focused on oxazolines1 and related systems. This type of
auxiliary offers good to excellent stereocontrol but can
be difficult to remove since it is attached via an amide
linkage. An ester, on the other hand, can be readily
saponified, and as such, alcohols should be prime candi-
dates as chiral auxiliaries. In the Diels–Alder reaction,
however, only a few alcohols have shown a reasonable
degree of reactivity and stereocontrol over a wide range
of symmetrical and unsymmetrical dienes. Of all the chiral
auxiliaries reported for use in the Diels–Alder reaction
with an acrylate as the dienophile,2 phenylmenthol 13 and
pantolactone 24 have provided the best selection and
reactivity to date (Scheme 1). In addition, 1,1- and
1,2-amino alcohols have been used extensively as chiral
auxiliaries in a variety of asymmetric transformations;2b,5
however, very little has been reported with 1,3-amino
Scheme 1.
* Corresponding author. E-mail: keay@ucalgary.ca
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00051-X

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S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
2. Results and discussion
formed, its steric bulk prevents formation of the pival-
oate and the reaction stops at (+)-5. For this reason,
while acrylate (−)-12a can be formed by treatment with
acryloyl chloride and Et3N, attachment of larger
dienophiles ((−)-12b and (−)-12c) requires more forcing
conditions (Scheme 3).
Racemic amino alcohol 11 can be prepared with perfect
diastereocontrol (Scheme 2) and without the need for
purification by chromatography since the amino alco-
hol can be separated from cyclization by-products via
acid–base extraction. d-Valerolactone 7 is added to
Grignard reagent 6 to give a diol,9 which is dehydrated
under acidic conditions to 810 (12:1 mixture of endo-
cyclic:exocyclic double bond isomers). Oxidation to the
aldehyde is followed by conversion to oxime 9. Stirring
with bleach subsequently converts the oxime to a nitrile
oxide that undergoes intramolecular 1,3-dipolar
cycloaddition with the olefin, giving 2-isoxazoline ( )-
10. At this stage, the undesirable double bond isomer of
8 is unreactive; thus, there is no need to remove it
earlier in the synthesis. For the purposes of quantifica-
tion and characterization, chromatography of ( )-10 is
reported but LiAlH4 reduction of ( )-10 to ( )-11 is
equally effective on crude ( )-10. Since LiAlH4 reduces
the CꢀN bond before cleaving the NꢁO bond, the cis,cis
geometry of ( )-5 is enforced by the intermediate with
three cis-fused pentacycles (not shown).
Acrylate (−)-12a was reacted with a variety of dienes in
the presence of BCl3 at −78°C (Scheme 4, Table 1,
entries 1–6). The first equivalent of BCl3 coordinated to
the amide while a second equivalent activated the
dienophile.12 Frequently, the efficacy of a chiral auxil-
iary has been demonstrated only for the reaction
between an acrylate (or doubly activated dienophile)
and the highly reactive cyclopentadiene. Despite the
steric bulk of (−)-12a, it reacts not only with cyclopen-
tadiene but with several less reactive dienes (isoprene,
furan, 1-vinylcyclopentene and 1-vinylcyclohexene) to
provide adducts 13a–c,e with high endo selectivity
(>99:1) and high diastereoselectivity (>98% de). Only
furan provided a poor mixture of endo:exo adducts
(−)-13e (2:1). The only noticeable exception to the
generally high diastereoselectivity is the reaction with
1-vinylcyclohexene, where the endo isomer (−)-13f is
formed with high selectivity (endo:exo >99:1) but with
lower de (85%). The reaction with 1-vinylcyclohexene
gives access to a substituted decalin for which no
asymmetric synthesis has been previously reported.13
Similarly, the reaction with 1-vinylcyclopentene gave
access to a substituted bicyclo[4.3.0]nonane, (−)-13f,
that has only been reported in racemic form as the
methyl ester derivative.14 Unfortunately, partial migra-
tion of the double bond into the pentacycle to form an
adduct with a tetrasubsituted double bond was also
observed (see 22,14,15 Table 2). The absolute and rela-
Resolution of ( )-11 was achieved by co-crystallization
with 0.5 equiv. of enantiopure mandelic acid in MeCN.
Co-crystallization with (S)-(+)-mandelic acid gives (−)-
11 with >98% ee11 and 28% yield (74% based on
recovered 11) while co-crystallization with (R)-(−)-man-
delic acid gives (+)-11 with the same yield and enan-
tiomeric purity. As such, both enantiomers are readily
accessible.
Amino alcohol (−)-11 is converted to (+)-5 by nucleo-
philic catalysis (Scheme 3). Once the pivalamide is
Scheme 2.
Scheme 3.

S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
751
Scheme 4.
Table 1. Diels–Alder reaction of chiral dienophiles (−)-12a, (−)-12b and (−)-12c with various dienesa
Diene
Product (yield)b
endo:exo
% dec
(−)-12a
(−)-12a
(−)-12a
(−)-12a
(−)-12a
(−)-12a
(−)-12b
(−)-12c
Cyclopentadiene
Cyclohexadiene
Isoprene
(+)-13a (84%)
(−)-13b (99%)
(−)-13c (78%)
(−)-13d (73%)
\99:1
\99:1
N/a
\98
\98
\98
Furan
2:1
\98 (endo), \98 (exo)
1-Vinylcyclopentene
1-Vinylcyclohexene
Cyclopentadiene
Cyclopentadiene
(−)-13e (94%)
\99d:1
\99:1
7:1e
\98d
(−)-13f (50% [98%])
(+)-14 (63% [90%])e
(−)-15 (64% [74%])
85
85 (endo)e
1:4
77 (endo), 79 (exo)
a All reactions (except crotonate) were performed in CH2Cl2 at −78°C for 8–14 h using 2 equiv. BCl3.
b Isolated yield. Yields in square brackets are based on recovered dienophile.
c The de value was determined from the relative integration in the 400 MHz 1H NMR spectra. In all cases, high temperature reactions were also
performed to ensure that all potential products could be distinguished.
d 3:1 mixture of endo product: product in which double bond has migrated to be tetrasubstituted.
e The crotonate reaction did not proceed at −78°C; results are for reaction at −23°C.
tive stereochemistry and the regiochemistry of the adducts
(−)-13e and (−)-13f were determined by X-ray crystallog-
raphy (Fig. 1).16
Interestingly,
the
diastereomer
(1R,5R,6R)-6-
pivalamido[4.4]spirononan-1-ol (+)-5 gave predomi-
nantly endo adducts from the Diels–Alder reaction
having the R-configuration a to the carboxylic acid.
This is in contrast to the reaction of the diastereomeric
Crotonates are less reactive than acrylates and (−)-12b
does not react at all with cyclopentadiene at −78°C.
Warming to −23°C, however, gives Diels–Alder products
with a 7:1 endo:exo ratio and 85% de for the endo isomer
(+)-14 (Scheme 5, Table 1). Methacrylates are also less
reactive than acrylates; however, (−)-12c did react with
cyclopentadiene at −78°C given a longer reaction time
(Scheme 5). Because the CH3 and CH2 groups are similar
in size, methacrylates generally give atrocious diastereo-
selectivities due to free rotation, which continuously
exchanges the positions of the two groups. As opposed
to the other systems studied herein, the major product
is the exo isomer (−)-15 (carbonyl relative to the bridge),
and it is formed with a respectable 79% de (Table 1).
(1S,5R,6R)-6-(pivalamido)spiro[4.4]nonan-1-ol
(−)-3,
which gave endo Diels–Alder adducts with S-configura-
tion at the stereocenter a to the carboxylic acid.7a Thus,
the same sense of chirality at the spiro and amido
centers, but the differing stereochemistry at C-1, leads
to products that are enantiomeric. Thus, only one
enantiomer of ( )-11 is needed from the resolution to
allow the preparation of both enantiomers from the
Diels–Alder reactions since (−)-3 and (+)-5 are readily
interconverted (Scheme 1).
In conclusion, we have designed and synthesized an
excellent chiral auxiliary (+)-5 for use in the Diels–
Alder reaction. Adducts are generally formed with
excellent diastereo- and stereocontrol and are easily
removed from the chiral auxiliary by saponification to
provide the free carboxylic acids in excellent yields and
the chiral auxiliary (+)-5. Auxiliary (+)-5 is easily sepa-
rated from the acids and reused. We are currently using
enantiopure (−)-11 as a chiral ligand in other Lewis
acid-catalyzed reactions and the results will be reported
in due course.
Aside from excellent diastereocontrol, the main advan-
tage of this auxiliary is its ease of removal. Treatment of
adducts 13a–f, (+)-14 and (−)-15 with NaOH in MeOH
(80°C, 20 h) followed by a quench with 4N HCl gave the
corresponding free carboxylic acids 16–2617–20 and
allowed full recovery of auxiliary (+)-5 (Table 2). No
epimerization was observed at the stereogenic center a to
the carboxylic acid, and no change in the endo:exo ratios
was observed.

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S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
Table 2. Removal of chiral auxiliary from 13–15 to give chiral acidsa
3. Experimental procedures
3.1. Synthesis of alcohol 8
Extraction with EtOAc (3×300 ml), washing with satu-
rated NaHCO3(aq) (200 ml) then brine (200 ml), drying
over MgSO4 and concentration in vacuo gave the diol as
a tan liquid which was used without purification. It was
dissolved in DMSO (400 ml) and water (80 ml). Oxalic
acid dihydrate (22.6 g, 179 mmol) was added, and the
solution was stirred at 120°C for 2 h. After cooling to
room temperature, the solution was extracted with Et2O
(4×150 ml), washed with brine (3×200 ml), dried over
MgSO4 and concentrated in vacuo to give a tan liquid.
Distillation by Kugelrohr (0.25 Torr, 70°C) gave 8 (17.8
g, 127 mmol, 71.4%) as a colourless liquid: bp 50°C/0.05
Torr (air bath); 1H NMR (200 MHz, CDCl3): l 5.38 (m,
1H), 3.66 (t, J=6.4 Hz, 2H), 2.36–1.38 (m, 12H). diol:
bp 110°C/0.1 Torr (air bath); lit.4 bp 88–90°C/0.01 Torr;
1H NMR (200 MHz, CDCl3): l 3.68 (t, J=6.3 Hz, 2H),
1.95–1.40 (m, 14H).
A flask equipped with a condenser was charged with Mg
(24.2 g, 996 mmol), THF (750 ml) and catalytic I2.
Addition of 1,4-dibromobutane (41.8 g, 194 mmol) in
THF (100 ml) over 30 min caused the red–brown colour
to dissipate and the mixture to reflux. After heating under
reflux for 24 h, d-valerolactone (17.8 g, 178 mmol) in
THF (100 ml) was added to the dark grey solution over
1 h. The resulting light grey suspension was heated under
reflux for 5 h and then cooled to room temperature. The
slurry was decanted off and cooled to 0°C, and the
residual Mg was washed with water (200 ml) and EtOAc
(200 ml) which was then added to quench the slurry.
HCl(aq) (10%) was added until no cloudiness remained.

S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
753
Scheme 5.
ring for 15 h, the aqueous phase was extracted with
Et2O (2×200 ml), and the combined organics were
washed with brine (200 ml), dried over MgSO4 and
concentrated in vacuo. Distillation by Kugelrohr (0.2
Torr, 85°C) gave 91 (11.4 g, 74.3 mmol, 94.1%) as a
waxy white solid (mixture of E- and Z-isomers): bp
1
60°C/0.2 Torr (air bath); H NMR (200 MHz, CDCl3):
l 7.44 (t, J=6.1 Hz, 0.5H), 6.74 (t, J=5.5 Hz, 0.5H),
5.36 (m, 1H), 2.48–2.06 (m, 8H), 1.86 (p, J=7.4 Hz,
2H), 1.66 (p, J=7.5 Hz, 2H). aldehyde: bp 90°C/20
1
Torr (air bath); H NMR (200 MHz, CDCl3): l 9.78 (t,
J=1.7 Hz, 1H), 5.36 (m, 1H), 2.44 (td, J=7.3, 1.7 Hz,
2H), 2.38–2.06 (m, 6H), 1.96–1.72 (m, 4H).
3.3. Synthesis of 2-isoxazoline ( )-10
NaOCl(aq) (5.25%, 20.0 ml) was added to a solution of
9 (850 mg, 5.55 mmol) in CH2Cl2 (25 ml) and stirred
vigorously for 15 h. Extraction with CH2Cl2 (3×25 ml),
washing with brine (20 ml), drying over MgSO4 and
concentration in vacuo followed by flash chromatogra-
phy (silica, 9:1 hexanes:EtOAc) gave ( )-10 as a pale
yellow liquid (430 mg, 2.84 mmol, 51.2%): bp 85°C/20
Torr; IR (film) wmax 2955, 2866, 1736, 1645, 1601, 1547,
1449, 1435, 1328, 1304, 1256, 1215, 1023, 952, 912, 889,
1
872, 833 cm−1; H NMR (400 MHz, CDCl3): l 4.75 (m,
1H), 2.45–2.37 (m, 2H), 2.20–1.39 (m, 10H); 13C NMR
(100 MHz, CDCl3): l 171.1 (C), 91.4 (CH), 71.0 (C),
37.9 (CH2), 34.9 (CH2), 34.2 (CH2), 25.6 (CH2), 24.2
(CH2), 20.2 (CH2); MS: m/z 151 (67, M+), 134 (23), 122
(39), 95 (21), 94 (32), 93 (87), 91 (36), 83 (22), 80 (33),
79 (100), 77 (33), 67 (62), 55 (45), 53 (25), 41 (44), 39
(40); HRMS calcd for C9H13NO 151.09971, found
151.09936.
Figure 1. ORTEPs of Diels–Alder adducts (−)-13e and
(−)-13f.
3.2. Synthesis of oxime 9
3.4. Synthesis of amino alcohol ( )-11
To a pale yellow suspension of Dess–Martin periodi-
nane (44.2 g, 104 mmol) in CH2Cl2 (300 ml) was added
8 (11.1 g, 78.9 mmol) in CH2Cl2 (100 ml). After stirring
for 1 h, the mixture was thick with white precipitate. It
was poured into Et2O (350 ml), saturated Na2CO3(aq)
(350 ml) and saturated Na2S2O3(aq) (350 ml) and stirred
for 1 h. The tan aqueous phase was extracted with Et2O
(2×300 ml), and the combined organics were washed
with brine (200 ml), dried over MgSO4 and concen-
trated in vacuo to give the aldehyde as a light yellow
liquid which was used without purification. It was
dissolved in Et2O (250 ml) and added to an aqueous
solution of Na2CO3 (25.2 g, 238 mmol) and
NH2OH·HCl (14.0 g, 201 mmol). After vigorous stir-
( )-10 (1.13 g, 7.45 mmol) in THF (15 ml) was added to
a suspension of LiAlH4 (380 mg, 10.0 mmol) in THF
(15 ml) at 0°C, warmed to 22°C and stirred for 15 h.
The grey suspension was cooled to 0°C and quenched
with NaOH(aq) (10%, 5 ml). Upon warming to room
temperature, enough NaOH(aq) (10%, ꢀ100 ml) was
added to dissolve Al salts. Extraction with Et2O (3×75
ml), washing with brine (75 ml), drying over Na2SO4
and concentration in vacuo gave ( )-11 as a white waxy
solid (1.00 g, 6.43 mmol, 86.3%): bp 45°C/0.2 Torr; IR
(film) wmax 3280, 2953, 2865, 1575, 1455, 1377, 1328,
1
1306, 1157, 1092, 1048, 996, 948, 907, 818 cm−1; H
NMR (200 MHz, CDCl3): l 4.12–4.02 (m, 1H), 3.28 (t,
J=6.3 Hz, 1H), 2.83 (br s, 3H), 2.14–1.21 (m, 12H); 13
C

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S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
NMR (50 MHz, CDCl3): l 79.0 (CH), 59.3 (CH), 56.1
(C), 35.3 (CH2), 35.2 (CH2), 35.1 (CH2), 33.3 (CH2),
21.1 (CH2), 20.9 (CH2); MS: m/z 155 (1, M+), 136 (40),
120 (22), 108 (30), 95 (29), 94 (30), 93 (43), 91 (64), 82
(40), 80 (38), 79 (100), 77 (24), 67 (38), 57 (69), 56 (26),
45 (31), 43 (42), 42 (23), 34 (40); HRMS calcd for
C9H17NO 155.13101, found 155.13257.
to 0°C. Acryloyl chloride (1.00 ml, 12.3 mmol) was
added, and the solution was allowed to warm to room
temperature and stirred for 18 h. The resulting gold
solution was quenched with water (10 ml) then HCl(aq)
(4 M, 50 ml), extracted with CH2Cl2 (3×50 ml), washed
with saturated Na2CO3(aq) (50 ml) and dried over
MgSO4. Concentration in vacuo followed by flash chro-
matography (silica, 5:1 hexanes:EtOAc) gave (−)-12a
(1.37 g, 4.67 mmol, 74.5%) as a fluffy white solid: mp
126–127°C; [h]D22 −56.9 (c 0.91, CHCl3); IR (film) wmax
3470, 3343, 2965, 2871, 1721, 1638, 1530, 1407, 1367,
1296, 1275, 1203, 1102, 1050, 984, 911, 811, 733, 647
3.5. Resolution of amino alcohol 11
( )-11 (991 mg, 6.38 mmol) was dissolved in MeCN (40
ml). (+)-Mandelic acid (482 mg, 3.17 mmol) was dis-
solved in MeCN (40 ml). The two solutions were com-
bined, swirled gently and allowed to sit for 12 h. The
resulting fluffy white needles were filtered off. These
crystals were added to NaOH(aq) (10%, 25 ml). Extrac-
tion with Et2O (3×50 ml), drying over Na2SO4 and
concentration in vacuo gave (−)-11 (277 mg, 1.78 mmol,
27.9%, >99% ee). The filtrate was concentrated in
vacuo, and the resulting light yellow oil was added to
NaOH(aq) (10%, 25 ml). Extraction with Et2O (3×50
ml), drying over Na2SO4 and concentration in vacuo
gave (+)-11 (618 mg, 3.98 mmol, 62.3%, 70–80% ee).
This optically enriched 11 was dissolved in MeCN (20
ml) and added to a solution of (−)-mandelic acid (509
mg, 3.35 mmol) in MeCN (20 ml). Fluffy white needles
formed almost immediately and, after sitting for 12 h,
the crystals were filtered off. Addition of NaOH(aq)
(10%, 15 ml), extraction with Et2O (3×25 ml), drying
over Na2SO4 and concentration in vacuo gave (+)-11
(275 mg, 1.77 mmol, 27.8%, >99% ee) [h]2D3 +79.3 (c 2.0,
CHCl3). Work-up of the filtrate as described above
gave recovery of 11 (282 mg, 1.82 mmol, 28.5%).
1
cm−1; H NMR (200 MHz, CDCl3): l 6.40 (dd, J=
17.2, 1.6 Hz, 1H), 6.10 (dd, J=17.3, 10.2 Hz, 1H), 5.97
(br d, 1H), 5.83 (dd, J=10.2, 1.7 Hz, 1H), 5.12–5.07
(m, 1H), 4.30–4.19 (m, 1H), 2.15–1.45 (m, 12H), 1.14 (s,
9H); 13C NMR (50 MHz, CDCl3): l 177.3 (C), 165.5
(C), 131.0 (CH2), 128.5 (CH), 81.4 (CH), 56.4 (CH),
56.1 (C), 38.6 (C), 35.0 (CH2), 34.9 (CH2), 32.2 (CH2),
31.9 (CH2), 27.5 (CH3), 21.0 (CH2), 20.3 (CH2); MS:
m/z 293 (4, M+), 238 (12), 208 (32), 121 (57), 120 (100),
102 (67), 57 (79); HRMS calcd for C17H27NO3
293.19909, found 293.19849; anal. calcd for C17H27NO3
C, 69.59; H, 9.28; N, 4.77; found: C, 69.65; H, 9.01; N,
4.77%.
3.8. Synthesis of amido-crotonate (−)-12b
(+)-5 (525 mg, 2.19 mmol) and LHMDS·OEt2 (1.11 g,
4.60 mmol) were dissolved in THF (20 ml) and stirred
for 1 h to give a gold suspension. Crotonyl chloride
(450 ml, 4.70 mmol) was added, and the solution was
stirred for 16 h. The resulting gold solution was
quenched with water (10 ml) then HCl(aq) (4 M, 30 ml),
extracted with CH2Cl2 (3×30 ml), washed with satu-
rated Na2CO3(aq) (30 ml) and dried over MgSO4. Con-
centration in vacuo followed by flash chromatography
(silica, 5:1 hexanes:EtOAc) gave (−)-12b (496 mg, 1.61
mmol, 73.7%) as a white solid: mp 113–114°C; [h]D20
−50.8 (c 1.07, CHCl3); IR (film) wmax 3334, 2964, 2950,
2867, 1715, 1630, 1535, 1442, 1309, 1186 cm−1; 1H
NMR (400 MHz, CDCl3): l 6.96 (dq, J=15.5, 6.9 Hz,
1H), 6.05 (br d, 1H), 5.82 (dd, J=15.5, 1.7 Hz, 1H),
5.08 (dd, J=5.6, 2.2 Hz, 1H), 4.23–4.18 (m, 1H),
2.15–1.45 (m, 15H), 1.14 (s, 9H); 13C NMR (100 MHz,
CDCl3): l 177.6 (C), 165.8 (C), 145.3 (CH), 122.7 (CH),
81.0 (CH), 56.6 (CH), 55.7 (C), 38.6 (C), 35.2 (CH2),
35.1 (CH2), 32.3 (CH2), 31.8 (CH2), 27.5 (CH3), 21.1
(CH2), 20.3 (CH2), 18.0 (CH3); MS: m/z 308 (1, [M+1]+
), 238 (19), 222 (67), 221 (54), 179 (38), 136 (65), 121
(73), 120 (100), 117 (75), 102 (96), 91 (92), 79 (84), 57
(77), 41 (80); HRMS calcd for C18H29NO3 307.21474,
found 307.21301; anal. calcd for C18H29NO3 C, 70.32;
H, 9.51; N, 4.56; found: C, 70.11; H, 9.81; N, 4.54%.
3.6. Synthesis of amido alcohol (+)-5
(−)-11 (950 mg, 6.12 mmol) and pyridine (5.0 ml, 62
mmol) were dissolved in CH2Cl2 (40 ml). Trimethyl-
acetic anhydride (4.0 ml, 20 mmol) was added, and the
reaction was stirred at room temperature for 1 day. The
resulting light yellow solution was quenched with water
(10 ml) then HCl(aq) (10%, 20 ml), extracted with
CH2Cl2 (3×50 ml), washed with brine (50 ml) and dried
over MgSO4. Concentration in vacuo followed by flash
chromatography (silica, 7:3 hexanes:EtOAc) gave (+)-5
(1.42 g, 5.94 mmol, 97.0%) as a white solid: mp 101–
103°C; [h]2D0 +5.2 (c 0.46, CHCl3); IR (film) wmax 3346,
2960, 2874, 1634, 1531, 1459, 1361, 1332, 1223, 1099,
1043, 1021, 914, 677 cm−1; 1H NMR (400 MHz,
CDCl3): l 5.89 (br d, 1H), 4.01 (t, J=6.5 Hz, 1H), 3.67
(bs, 1H), 2.1–1.0 (m, 13H), 1.21 (s, 9H); 13C NMR (100
MHz, CDCl3): l 179.5 (C), 77.6 (CH), 60.8 (C), 56.5
(CH), 38.7 (C), 32.4 (CH2), 32.3 (CH2), 32.0 (CH2),
30.9 (CH2), 27.6 (CH3), 20.6 (CH2), 20.0 (CH2); MS:
m/z 239 (4, M+), 121 (20), 120 (37), 102 (100), 57 (38);
HRMS calcd for C14H25NO2 239.18853, found
239.18835; analysis calcd for C14H25NO2 C, 70.25; H,
10.53; N, 5.85, found: C, 70.19; H, 10.83; N, 5.82%.
3.9. Synthesis of amido-methacrylate (−)-12c
(+)-5 (515 mg, 2.15 mmol) and LHMDS·OEt2 (1.11 g,
4.60 mmol) were dissolved in THF (20 ml) and stirred
for 1 h to give a gold suspension. Methacryloyl chloride
(450 ml, 4.61 mmol) was added, and the solution was
stirred for 16 h. The resulting yellow solution was
quenched with water (10 ml) then HCl(aq) (4 M, 30 ml),
3.7. Synthesis of amido acrylate (−)-12a
(+)-5 (1.50 g, 6.27 mmol) and Et3N (2.60 ml, 18.7
mmol) were dissolved in dry CH2Cl2 (60 ml) and cooled

S. M. Lait et al. / Tetrahedron: Asymmetry 14 (2003) 749–756
755
extracted with CH2Cl2 (3×30 ml), washed with satu-
rated Na2CO3(aq) (30 ml) and dried over MgSO4. Con-
centration in vacuo followed by flash chromatography
(silica, 5:1 hexanes:EtOAc) gave (−)-12c (510 mg, 1.66
mmol, 77.2%) as a white solid: mp 89°C; [h]2D0 −75.8 (c
0.87, CHCl3); IR (film) wmax 3353, 2966, 2870, 1702,
hexanes:EtOAc) gave (+)-17 (28.1 mg, 0.185 mmol,
93.2%) as a white solid then (+)-5 (34.4 mg, 0.144
mmol, 72.6%) as a white solid. (+)-17: mp 39–40°C;
lit.21 mp 46–47°C; [h]D19 +46 (c 0.53, MeOH); lit.18 [h]D19
1
+50.9 (MeOH); H NMR (200 MHz, CDCl3): l 10.3
(br s, 1H), 6.40–6.27 (m, 1H), 6.25–6.13 (m, 1H),
3.03–2.93 (m, 1H), 2.75–2.55 (m, 2H), 1.87–1.15 (m,
6H).
1
1631, 1529, 1319, 1162, 937 cm−1; H NMR (200 MHz,
CDCl3): l 6.06 (br s, 1H), 5.84 (br d, 1H), 5.56 (t,
J=1.9 Hz, 1H), 5.08 (br d, 1H), 4.29–4.18 (m, 1H),
2.12–1.50 (m, 15H), 1.12 (s, 9H); 13C NMR (50 MHz,
CDCl3): l 177.2 (C), 166.8 (C), 136.5 (C), 125.5 (CH2),
81.3 (CH), 56.7 (CH), 56.4 (C), 38.6 (C), 35.3 (CH2),
34.6 (CH2), 32.2 (CH2), 32.0 (CH2), 27.5 (CH3), 20.8
(CH2), 20.5 (CH2), 18.3 (CH3); MS: m/z 307 (1, M+),
238 (7), 222 (35), 121 (68), 120 (100), 102 (63), 57 (45);
HRMS calcd for C18H29NO3 307.21474, found
307.21473; anal. calcd for C18H29NO3 C, 70.32; H, 9.51;
N, 4.56; found: C, 70.06; H, 9.68; N, 4.51%.
Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and University
of Calgary for financial support. S.M.L. gratefully
acknowledges receipt of a NSERC scholarship and
Ralph Steinhauer Award of Distinction from the
Alberta Heritage Foundation.
3.10. Typical procedure for the Diels–Alder reaction
A flask containing (−)-12a (100 mg, 0.342 mmol) and 4
References
,
A molecular sieves (140 mg) was flushed with dry N2
for 5 min. Dry CH2Cl2 (6 ml) was added, and the
solution was cooled to −78°C before adding BCl3 (1.0
m in CH2Cl2, 680 ml, 0.68 mmol). After stirring for 30
min, cyclohexadiene (160 ml, 1.68 mmol, pre-cooled to
0°C) was added down the side of the flask. After
stirring for 8 h, the light yellow solution was filtered
through a silica plug (1.8 g, pre-wetted with CH2Cl2)
and flushed through with Et2O. Concentration in vacuo
followed by flash chromatography (silica, 4:1 hex-
anes:EtOAc) gave (−)-13b (127 mg, 0.340 mmol, 99.6%)
as a white solid: mp 98–99°C; [h]2D3 −21.8 (c 0.95,
CHCl3); IR (film) wmax 3465, 3442, 3385, 2948, 2868,
1727, 1651, 1511, 1365, 1320, 1238, 1200, 1103, 1052,
704 cm−1; 1H NMR (400 MHz, CDCl3): l 6.29 (t,
J=7.5 Hz, 1H), 6.16 (t, J=7.3 Hz, 1H), 6.05 (br d,
1H), 5.00–4.95 (m, 1H), 4.18–4.11 (m, 1H), 2.88 (br s,
1H), 2.59 (br s, 2H), 2.05–1.90 (m, 2H), 1.8–1.2 (m,
16H), 1.17 (s, 9H); 13C NMR (50 MHz, CDCl3): l
177.4 (C), 174.5 (C), 135.0 (CH), 131.4 (CH), 81.0
(CH), 56.7 (CH), 55.7 (C), 43.2 (CH), 38.7 (C), 35.1
(CH2), 35.0 (CH2), 32.33 (CH), 32.29 (CH2), 31.7
(CH2), 30.2 (CH2), 29.3 (CH), 27.6 (CH3), 25.4 (CH2),
24.2 (CH2), 21.0 (CH2), 20.3 (CH2); MS: m/z 373 (12,
M+), 288 (31), 238 (28), 222 (78), 121 (79), 120 (100),
102 (81), 79 (52), 57 (47); HRMS calcd for C23H35NO3
373.26169, found 373.26069; anal. calcd for C23H35NO3
C, 73.96; H, 9.44; N, 3.75; found: C, 73.42; H, 9.64; N,
3.74%.
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Scheme 1).
ing.html. Compound 13e: tetragonal P43; a=11.2730(9),
3
,
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,
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1
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´
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