Diastereoselective diels - Alder reactions with an allenyl-containing spiro-amido chiral auxiliary

Article abstract of DOI:10.1021/jo902556b

(Chemical Equation Presented) A novel allenyl-containing 1,3-spiro-amido alcohol auxiliary has been prepared and used in a variety of diastereo-selective Diels-Alder reactions providing exclusively endo adducts with diastereomeric ratios ranging from 2:1 to > 99:1.

Full text of DOI:10.1021/jo902556b

pubs.acs.org/joc
research is the use of allene-containing compounds as dieno-
Diastereoselective Diels-Alder Reactions with an
Allenyl-Containing Spiro-Amido Chiral Auxiliary
philes in the Diels-Alder reaction. This application provides
a potentially powerful method for the installation and con-
trol of several stereocenters in addition to the newly formed
ring containing an exocyclic double bond. Although the
use of allene-containing dienophiles activated by one2 and
two3 electron-withdrawing groups have been reported, their
use with chiral auxiliaries have been limited. Diastereo-
selective Diels-Alder reactions with allene-1,3-dicarboxy-
late have generally involved the use of two chiral alcohols
such as menthol,3b,c borneol,3d-f or isoborneol.3d-f For
example, Node et al. have reported the use of allene-1,3-
dicarboxylate dienophile 1 with an isoborneol auxiliary to
prepare intermediate 2 in the formal asymmetric synthesis of
(-)-epibatidine (3) (Scheme 1).3d
Jeff R. Henderson, Julian P. Chesterman, Masood Parvez,
and Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary,
AB, Canada T2N 1N4
keay@ucalgary.ca
Received December 2, 2009
SCHEME 1
To our knowledge, only two examples of diastereoselec-
tive Diels-Alder reactions between a monoester-activated
allene-containing dienophile and the highly reactive diene
cyclopentadiene have been reported. Oppolzer et al. reported
the diastereoselective Diels-Alder reaction of camphor-
derived allenic ester 4 with cyclopentadiene to afford adduct
5 in 99% de that was subsequently converted to (-)-β-
santalene (6) (Scheme 2).4 Similarly, Bertrand et al. demon-
strated the same Diels-Alder reaction with cyclopentadiene
using three additional chiral alcohols.5 Given the paucity of
diastereoselective Diels-Alder reactions with monoester-
activated allenic dienophiles, we decided to expand the scope
of these types of Diels-Alder reactions with less reactive
dienes.
A novel allenyl-containing 1,3-spiro-amido alcohol auxi-
liary has been prepared and used in a variety of diastereo-
selective Diels-Alder reactions providing exclusively
endo adducts with diastereomeric ratios ranging from
2:1 to >99:1.
Allenes are a well-known group of compounds that con-
tain cumulative carbon-carbon double bonds. The synthesis
and numerous applications of allenes have attracted the
attention of many research groups.1 One interesting area of
(1) For general allene information, see: (a) Taylor, D. R. Chem. Rev.
1967, 67, 317. (b) Coppola, G. M.; Schuster, H. F. Allenes in Organic Synthesis;
Wiley: New York, 1984 (c) Modern Allene Chemistry; Krause, N., Hashmi, A. S.
K., Eds.; Wiley-VCH: Weinheim, 2004.
SCHEME 2
(2) For examples of activation of allenes by an ester, see: (a) Ismail, Z. M.;
Hoffmann, H. M. R. J. Org. Chem. 1981, 46, 3549. (b) Jung, M. E.;
Murakami, M. Org. Lett. 2007, 9, 461. (c) De Schrijver, J.; De Clercq, P. J.
Tetrahedron Lett. 1993, 34, 4369. Lactone: (d) Jung, M. E.; Zimmerman, C.
N.; Lowen, G. T.; Khan, S. I. Tetrahedron Lett. 1993, 34, 4453. (e) Fotiadu,
F.; Archaulis, A.; Buono, G. Tetrahedron Lett. 1990, 31, 4859. Ketones: (f)
Gleiter, R.; Sigwart, C. J. Org. Chem. 1994, 59, 1027. (g) Gras, J.-L.; Guerin,
A. Tetrahedron Lett. 1985, 26, 1781. Cyano: (h) Danheiser, R. L.; Casebier,
D. S.; Huboux, A. H. J. Org. Chem. 1994, 59, 4844. Sulfoxides: (i) Padwa, A.;
Bullock, W. H.; Norman, B. H.; Perumattam, J. J. Org. Chem. 1991, 56, 4252.
Sulfones: (j) Hayakawa, K.; Nishiyama, H.; Kanematsu, K. J. Org. Chem.
1985, 50, 512. (k) Braverman, S.; Lior, Z. Tetrahedron Lett. 1994, 35, 6727. (l)
Block, E.; Putman, D. J. Am .Chem. Soc. 1990, 112, 4072.
(3) For examples, see:, (a) Tamura, Y.; Akai, S.; Sasho, M.; Kita, Y.
Tetrahedron Lett. 1984, 25, 1167. (b) Aso, M.; Ikeda, I.; Kawabe, T.; Shiro,
M.; Kanematsu, K. Tetrahedron Lett. 1992, 33, 5787. (c) Ikeda, I.; Honda,
K.; Osawa, E.; Shiro, M.; Aso, M.; Kanematsu, K. J. Org. Chem. 1996, 61,
2031. (d) Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. Chem. Commun.
1998, 2363. (e) Kimura, H.; Fujiwara, T.; Katoh, T.; Nishide, K.; Kajimoto,
T.; Node, M. Chem. Pharm. Bull. 2006, 54, 399. (f) Katoh, T.; Noguchi, C.;
Kimura, H.; Fujiwara, T.; Ichihashi, S.; Nishide, K.; Kajimoto, T.; Node, M.
Tetrahedron: Asymmetry 2006, 17, 2943. (g) Clive, D. L. J.; Yeh, V. S. C.
Tetrahedron Lett. 1998, 39, 4789.
Since 2003, we have reported the synthesis of both enantio-
mers of (1R,5R,6R)-6-(2,2-dimethylpropanamido)-spiro[4.4]-
nonan-1-ol (8) from δ-valerolactone (7) (Scheme 3).6-8 1,3-
Spiro-amido dienophiles 9a-c, derived from 8, were shown to
(4) Oppolzer, W.; Chapuis, C. Tetrahedron Lett. 1983, 24, 4665.
(5) Bertrand, M.; Zahra, J. P. Tetrahedron Lett. 1989, 30, 4117.
(6) (a) Lait, S. M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2003,
14, 749. (b) Lait, S. M.; Parvez, M.; Keay, B. A. Tetrahedron Asymmetry
2004, 15, 155.
(7) Henderson, J. R.; Parvez, M.; Keay, B. A. Org. Lett. 2007, 9, 5167.
(8) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767.
988 J. Org. Chem. 2010, 75, 988–991
Published on Web 01/05/2010
DOI: 10.1021/jo902556b
r
2010 American Chemical Society

Henderson et al.
JOCNote
TABLE 1. Diels-Alder Reactions between Allene (þ)-13 and Various Dienes
endo:exoa
% yieldb
dra
config at Ha
c
entry
Lewis acid
temp (°C)
time (h)
diene
product
1
2
3
4
5
6
7
8
BCl3
BCl3
BCl3
BCl3
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
-78
-78
-78
>-40
-23
-23
-23
0
8
18
18
18
18
18
18
22
cyclopentadiene
(-)-16
(þ)-17
(þ)-18
(þ)-18
(þ)-17
(þ)-18
>99:1
>99:1
75
58
4
>99:1
>99:1
>99:1
S
S
1,3-cyclohexadiene
2,3-dimethyl-1,3-butadiene
2,3-dimethyl-1,3-butadiene
1,3-cyclohexadiene
2,3-dimethyl-1,3-butadiene
anthracene
cmd
62
67
>99:1
>99:1
nr
2:1
2.5:1
anthracene
(þ)-19
>99:1
55
>99:1
c
S
aDiastereomeric ratios determined by integration of 300 MHz NMR spectra and/or by GC analysis. bIsolated yields. Absolute configuration
determined by X-ray crystallography. dComplex mixture of unreacted starting material, Diels-Alder adducts, and byproducts 14 and 15.
SCHEME 4
SCHEME 3
1,3-spiro-amido alcohol 8, smoothly afforded the desired
allene product 13 in 75% yield (Scheme 4).
With allene dienophile 13 in hand, its use in several
Diels-Alder reactions was investigated. As with the previously
reported spiro-amido systems 9a-c,6,7 it was found that 2 equiv
of Lewis acid were necessary to activate the dienophile in 13.13
Treatment of allene (þ)-13 with 2.0 equiv of BCl3 and 10 equiv
of cyclopentadiene at -78 °C exclusively afforded endo-(-)-16
in >99:1 dr and 98% yield (Table 1, entry 1). Similarly,
treatment of allene (þ)-13 with 2.0 equiv of BCl3 and 10 equiv
of 1,3-cyclohexadiene at -78 °C afforded endo-(þ)-17 in
>99:1 dr and 58% yield (Table 1, entry 2). Complications
undergo diastereoselective Diels-Alder reactions by Lewis
acid activation (2 equiv of BCl3 or MeAlCl2) with a variety of
symmetrical and unsymmetrical dienes to give adducts 10. To
expand the scope on the use of 8, we decided to append to it an
allene via an ester linkage.
The proposed 1,3-spiro-amido allenyl dienophile 13 was
arose when using acylic diene 2,3-dimethyl-1,3-butadiene
where, at -78 °C, use of 2.0 equiv BCl3 only afforded 4%
yield of adduct (þ)-18 albeit in >99:1 dr (Table 1, entry 3). In
an effort to increase the yield, it was found that increasing the
reaction temperature to >-40 °C led to an inseparable com-
plex mixture of Diels-Alder adducts (Table 1, entry 4) and two
predicted to be accessible by an in situ base-catalyzed alkyne
byproducts, 14 and 15 (Scheme 5).
As with the previous cyclopropenyl dienophile 9c,7 treat-
ment of allene 13 with 2.0 equiv BCl3 at higher temperatures
to allene rearrangement. Previous reports have shown that
3-butynoic acid or similar esters can undergo facile allene
rearrangements using K2CO3.9 Rearranging 2-butynoic acid
(>-40 °C) led to large amounts of Michael addition bypro-
duct 14 and rearranged chiral auxiliary 1514 (Scheme 5).15 Both
(11), on the other hand, typically requires more strongly
10
basic conditions (NaNH2 or LDA11) or organometallic
byproducts are formed in the presence of HCl impurities16
reagents.12 Surprisingly, treatment of 2-butynoic acid (11)
with pivaloyl chloride in the presence of triethylamine
formed mixed anhydride 12 that, upon treatment with
(13) 1H NMR binding studies indicated the first equivalent of Lewis acid
binds to the pivalamide in 13 (and 9a-c) while the second equivalent of Lewis
acid binds to the ester, thereby activating the dienophile. For more details,
see: Henderson, J. R. Ph.D. Thesis, University of Calgary, 2009.
(9) Eglinton, G.; Jones, E. R. H.; Mansfield, G. H.; Whiting, M. C.
J. Chem. Soc. 1954, 3197.
(14) Byproduct 15 resulted from a series of carbocation rearrangements
followed by the loss of Hþ to form the double bond.
(10) Craig, J. C.; Moyle, M. J. Chem. Soc. 1963, 4402.
(11) Doye, S.; Hotopp, T.; Wartchow, R.; Winterfeldt, E. Chem.;Eur. J.
1998, 4, 1480.
(15) The structure of byproduct 15 had been incorrectly assigned in past
publications (refs 2 and 3), and the correct structure was verified by X-ray
crystallography. See Supporting Information.
(12) Franck-Neumann, M.; Brion, F. Angew. Chem., Int. Ed. Engl. 1979,
18, 688.
(16) We have shown that byproduct 14 can be formed when 13 is treated
with 1.0 M HCl in Et2O at rt.
J. Org. Chem. Vol. 75, No. 3, 2010 989

Henderson et al.
JOCNote
SCHEME 5
(þ)-86 (500 mg, 2.09 mmol) was added as a solid. The mixture
was warmed to room temperature and mixed for 18 h. The
reaction was subsequently quenched with 10% HCl(aq) (10 mL)
and extracted with ether (3 ꢀ 20 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and concen-
trated to a tan colored oil that was purified via flash column
chromatography (5:1 hexanes/EtOAc) to give desired allene
(þ)-13 as a white solid (460 mg, 1.51 mmol, 72%): mp 90-94
°C; [R]20 þ51.4 (c 0.585, CHCl3); IR (film) νmax 3325, 2963,
D
1
2860, 1718, 1632, 1535, 1459, 1167, 871 cm-1; H NMR (300
within the BCl3 and may be minimized by using newly pur-
chased BCl3 at lower reaction temperatures. Compound 14 was
not unexpected, as allenes are known to be good Michael
acceptors.17
MHz, CDCl3) δ 5.93 (d, 1H, J = 7.63 Hz), 5.54 (t, 1H, J = 6.71
Hz), 5.16 (ddd, 2H, J = 20.71, 6.76 Hz), 4.99 (m, 1H), 4.15 (q,
1H, J = 5.51 Hz), 2.08-1.40 (m, 12H), 1.08 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 215.8, 177.2, 164.8, 88.0, 82.1, 79.3, 56.6,
55.5, 38.5, 35.3, 35.2, 32.1, 31.9, 27.4, 20.8, 20.4; MS m/z 305
[Mþ] 220, 204, 179, 164, 153, 128, 120, 102, 93, 85, 79, 67; HRMS
calcd for C18H27NO3 305.1991, found 305.1978. Anal. Calcd for
C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.72; H, 8.57;
N, 4.54.
As previously reported,7 the use of the weaker aluminum-
based Lewis acids does not lead to the formation of bypro-
ducts 14 and 15, and the use of 2 equiv of MeAlCl2 in the
Diels-Alder reaction with 13 afforded more synthetically
useful results. The Diels-Alder reaction between allene (þ)-
13 and 1,3-cyclohexadiene in the presence of 2.0 equiv of
MeAlCl2 did not proceed at -78 °C but at -23 °C only to
afford endo-(þ)-17 in 62% yield and 2:1 dr after 18 h
(Table 1, entry 5). Reaction between allene (þ)-13 and
acyclic 2,3-dimethyl-1,3-butadiene in the presence of
MeAlCl2 afforded adduct (þ)-18 with an improved 67%
yield but a lower dr of 2.5:1 (Table 1, entry 6). Allene (þ)-13
did not undergo a Diels-Alder reaction with anthracene
with MeAlCl2 at -23 °C (Table 1, entry 7), but after warming
of the reaction to 0 °C, adduct (þ)-19 was obtained in 55%
yield and >99:1 dr (Table 1, entry 8). Regardless of the Lewis
acid used or the temperature reported in Table 1, the endo/
exo selectivities were always >99:1.
General Procedure for Diels-Alder Reactions. A flask con-
ꢀ
˚
taining 4 A molecular sieves (100 mg per 100 mmol auxiliary)
was flame-dried under vacuum and back-purged with argon.
Solid dienophile (0.216 mmol) was added, and the flask flushed
with dry nitrogen for 5 min. Freshly distilled dichloromethane
(5.2 mL) was added, and the solution was cooled to -78 °C
before the addition of boron trichloride (1.0 M in dichloro-
methane, 2 equiv). The Lewis acid mixture was allowed to mix
for 30 min, and freshly distilled diene (10-16 equiv, see Sup-
porting Information for exact amounts) was added dropwise
down the side of the flask. After the reaction was complete (see
times in Table 1), the mixture was filtered through a plug of silica
(prewetted with dichloromethane) and flushed with ether. Con-
centration followed by purification by column chromatography
(hexanes/ethyl acetate) resulted in pure Diels-Alder adduct.
(1S)-3-Methylene-bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid
(1R,5R,6R)-6-(2,2-Dimethyl-propionylamino)-spiro[4.4]non-1-yl
Ester ((-)-16). Compound (-)-16 was prepared according the
above general procedure (60 mg, 0.162 mmol, 75%): mp
The endo/exo stereochemistry of adducts (-)-16, (þ)-17,
1
and (þ)-19 were assigned by H NMR spectroscopy, while
the absolute configurations of adducts (-)-16, (þ)-17, and
(þ)-19 were determined by examination of their X-ray
crystal structures.18 X-ray crystal analysis also confirmed
that the major stereoisomer from the Diels-Alder reactions
was endo. Unfortunately, X-ray quality crystals could not be
grown for adduct (þ)-18.
118-120 °C; [R]20 -62.6 (c 0.415, CHCl3); IR (film) νmax
D
3355, 2967, 2860, 1731, 1625, 1529, 1309, 1203, 1173, 884
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.22 (dd, 1H, J = 5.3,
3.2 Hz), 6.10 (dd, 1H, J = 5.3, 3.2 Hz), 5.86 (d, 1H, J = 7.87 Hz),
5.64 (bs, 1H), 5.04 (d, 1H, J = 1.93 Hz), 4.98-4.92 (m, 2H), 4.20
(m, 1H), 3.41 (q, 1H, J = 2.57 Hz), 3.21-3.13 (m, 2H),
2.02-1.41 (m, 13H), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 177.2, 171.7, 148.7, 135.5, 134.6, 105.5, 80.7, 56.6, 56.4, 51.5,
50.4, 49.2, 45.2, 38.7, 34.8, 34.2, 32.0, 31.8, 27.5, 20.8, 20.2; MS
m/z 371 [Mþ] 286, 238, 222, 151, 138, 133, 121, 102, 93, 79, 67;
HRMS calcd for C23H33NO3 371.2460, found 371.2464.
Although the chiral auxiliary was not removed from
adducts 16-19, we have shown that it can be removed
(NaOH, MeOH, 80 °C, 20 h) without loss of the stereo-
chemistry R to the ester.6a
In summary, a novel spiro-amido allenyl dienophile 13 was
efficiently synthesized from 2-butynoic acid and was shown to
undergo facile Lewis acid activated Diels-Alder reactions with
several symmetrical dienes to provide exclusively endo products
with up to >99:1 dr depending on the structure of the diene.
(1S)-3-Methylene-bicyclo[2.2.2]oct-5-ene-2-carboxylic Acid
(1R,5R,6R)-6-(2,2-Dimethyl-propionylamino)-spiro[4.4]non-1-yl
Ester ((þ)-17). Compound (þ)-17 was prepared according the
above general procedure (14.4 mg, 0.037 mmol, 58%): mp
127-130 °C; [R]20 þ17.3 (c 0.54, CHCl3); IR (film) νmax
Experimental Section
D
3461, 3380, 2947, 2866, 1728, 1652, 1504, 1195, 1171, 704
(1R,5R,6R)-Buta-2,3-dienoic Acid 6-(2,2-Dimethyl-propionyl-
amino)-spiro[4.4]non-1-yl Ester ((þ)-13). Anhydrous LiCl (240
mg, 5.70 mmol) was suspended in anhydrous THF (10 mL), and
NEt3 (1.50 mL, 10.8 mmol) was added followed by trimethyl-
acetyl chloride (0.62 mL, 5.03 mmol). After mixing for 10 min
at room temperature, the mixture was cooled to 0 °C, and
2-butynoic acid (200 mg, 2.38 mmol) in THF (6 mL) added
dropwise. After mixing at 0 °C for 1 h, spiro-amido-dienophile
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.27 (m, 2H), 5.86 (d,
1H, J = 7.8 Hz), 4.97-4.89 (m, 2H), 4.87 (m, 1H), 4.18 (m, 1H),
3.25 (ddd, 1H, J = 2.22, 2.17 Hz), 3.05 (m, 1H), 2.91 (m, 1H),
2.00-1.29 (m, 15H), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
177.3, 171.7, 147.5, 132.9, 132.1, 107.0, 80.9, 56.5, 56.4, 50.3,
40.8, 38.6, 34.7, 34.2, 33.9, 31.9, 31.7, 27.5, 25.8, 24.1, 20.7, 20.2;
MS m/z 385 [Mþ] 300, 238, 222, 165, 146, 121, 102, 91, 79, 77, 57;
HRMS calcd for C24H35NO3 385.2617, found 385.2604.
(1S)-3,4-Dimethyl-6-methylene-cyclohex-3-enecarboxylic Acid
(1R,5R,6R)-6-(2,2-Dimethyl-propionylamino)-spiro[4.4]non-1-yl
Ester ((þ)-18). Compound (þ)-18 was prepared as an insepar-
able mixture of two diastereomers according the above general
procedure (170 mg, 0.439 mmol, 67%): mp 85-93 °C;
(17) For examples, see: (a) Padwa, A.; Kline, D. N.; Norman, B. H.
J. Org. Chem. 1989, 54, 810. (b) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M.
P. S. Org. Lett. 2000, 2, 2023. (c) El Achqar, A.; Boumzebra, M.;
Roumestant, M.-L.; Viallefont, P. Tetrahedron 1988, 44, 5319.
(18) See Supporting Information for X-ray crystallographic data.
990 J. Org. Chem. Vol. 75, No. 3, 2010

Henderson et al.
JOCNote
[R]20 þ32.5 (c 0.43, CHCl3); IR (film) νmax 3455, 3364, 2962,
(þ)-13 with 2.0 equiv of BCl3 at >-40 °C during Diels-Alder
D
2864, 1716, 1658, 1509, 1197, 886 cm-1; 1H NMR of mixture of
diastereomers; only major peaks are indicated (300 MHz,
CDCl3) δ 6.00 (d, 1H, J = 8.40 Hz), 5.04 (m, 1H,), 4.89 (bs,
1H), 4.77 (bs, 1H), 4.23 (m, 1H), 3.30 (t, 1H, J = 6.99 Hz), 2.71
(bs, 2H,), 2.58-1.24 (m, 21H), 1.17 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 177.3, 172.4, 143.5, 124.3, 123.9, 109.0, 81.5, 56.5,
55.5, 47.4, 39.0, 38.5, 35.3, 35.1, 34.8, 32.1, 31.6, 27.4, 20.9, 20.2,
18.6, 18.4; MS CI m/z 388 [M þ Hþ]; HRMS calcd for
C24H38NO3 388.2852, found 388.2839.
reactions: IR (film) νmax 3289, 2963, 2864, 1728, 1638, 1512,
1459, 1383, 1094, 1017 cm-1; H NMR (300 MHz, CDCl3) δ
5.82 (bs, 1H), 5.37 (s, 2H), 5.03 (m, 1H), 4.27 (m, 1H), 3.36 (ddd,
1
2H, J = 20.11,16.13 Hz), 2.04-1.43 (m, 12H), 1.16 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 177.2, 168.1, 134.4, 116.7, 82.0, 56.8,
56.1, 45.1, 38.7, 34.7, 34.1, 31.9, 27.5, 20.9, 20.4; HRMS calcd
for C18H28NO3Cl 341.1758, found 341.1751.
N-(2,3,4,5,6,7-Hexahydro-1H-inden-4-yl)-2,2-dimethyl-propio-
namide (15). Compound 15 was formed as a byproduct when
treating any spiro-auxiliary with 2.0 equiv of BCl3 at >-40 °C
during Diels-Alder reactions: IR (film) νmax 3311, 2951, 2868,
endo-(þ)-19. Compound (þ)-19 was prepared according the
above general procedure (17.7 mg, 0.0366 mmol, 55%): mp
174-181 °C; [R]20D þ23.7 (c 0.89, CHCl3); IR (film) νmax 3300,
2965, 2863, 1734, 1655, 1503, 1450 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.32-7.23 (m, 4H), 7.13-7.05 (m, 4H), 5.66 (d, 1H,
J = 8.18 Hz), 5.30 (d, 1H, J = 2.38 Hz), 5.05 (d, 1H, J = 1.86
Hz), 4.88 (m, 1H), 4.74 (s, 1H), 4.63 (d, 1H, J = 2.68 Hz), 4.02
(m, 1H), 3.45 (q, 1H, J = 2.16 Hz), 1.90-1.26 (m, 12H), 1.15 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 176.9, 170.9, 143.7, 142.8,
141.9, 141.3, 140.1, 126.4, 126.2, 126.0, 125.8, 125.1, 123.7,
123.1, 111.1, 80.7, 57.0, 56.3, 55.0, 50.1, 48.0, 38.6, 34.3, 33.4,
31.8, 31.5, 27.4, 20.3, 20.2; MS m/z 483 [Mþ], 263, 244, 222, 217,
215, 202, 178, 121, 102, 79, 67; HRMS calcd for C32H37NO3
483.2773, found 483.2764. Anal. Calcd for C32H37NO3: C,
79.47; H, 7.71; N, 2.90. Found: C, 79.19; H, 7.64; N, 2.87.
(1R,5R,6R)-3-Chloro-but-3-enoic Acid 6-(2,2-Dimethyl-
propionylamino)-spiro[4.4]non-1-yl Ester (14). Compound 14
was formed as a byproduct when treating allene-dienophile
1632, 1631, 1531, 1452, 1200, 748 cm-1; H NMR (300 MHz,
1
CDCl3): δ 5.49 (d, 1H, J = 9.0 Hz), 4.49 (br s, 1H), 2.30 (m, 4H),
2.00-1.60 (m, 12H), 1.19 (s, 9H); 13C NMR (75 MHz, CDCl3): δ
180.0, 139.9, 134.3, 45.3, 38.9, 36.5, 33.3, 30.4, 27.9, 25.9, 21.8,
20.4; MS: m/z 221 [Mþ], 120, 102, 57;HRMS calcd for C14H23NO
221.17796, found 221.17610.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) and
the University of Calgary for financial support.
Supporting Information Available: Full experimental pro-
cedures, spectral data and X-ray crystallographic data for
compounds (þ)-13, 15, (-)-16, (þ)-17 and (þ)-19 is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 991