Catalytic Asymmetric Cyclocarbonylation of Nitrogen-Containing Enynes

Article abstract of DOI:10.1021/jo990384f

The asymmetric Pauson-Khand type cyclization of nitrogen-containing enynes using carbon monoxide and a catalytic amount of (EBTHI)TiMe₂ was examined. The influence of the nitrogen substituent and the concentration of the catalyst on the enantioselectivity of this cyclization was explored, and it has been found that enynes with an octyl-, benzyl-, or allylamino group, positioned β to the alkyne and the olefin, are cyclized with a high degree of enantioselectivity. Substrates with either bulky and/or electron-withdrawing nitrogen substituents are converted to products in low to moderate enantioselectivity.

Full text of DOI:10.1021/jo990384f

J . Org. Chem. 1999, 64, 5547-5550
5547
Ca ta lytic Asym m etr ic Cycloca r bon yla tion of Nitr ogen -Con ta in in g
En yn es
Shana J . Sturla and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received March 3, 1999
The asymmetric Pauson-Khand type cyclization of nitrogen-containing enynes using carbon
monoxide and a catalytic amount of (EBTHI)TiMe2 was examined. The influence of the nitrogen
substituent and the concentration of the catalyst on the enantioselectivity of this cyclization was
explored, and it has been found that enynes with an octyl-, benzyl-, or allylamino group, positioned
â to the alkyne and the olefin, are cyclized with a high degree of enantioselectivity. Substrates
with either bulky and/or electron-withdrawing nitrogen substituents are converted to products in
low to moderate enantioselectivity.
In tr od u ction
diastereoselective cyclization of optically active enynes.
However, the diastereoselectivity can be poor and in-
separable mixtures of isomers are often formed. We were
therefore interested in extending the use of the titanium-
catalyzed asymmetric Pauson-Khand type reaction to
the synthesis of azabicyclopentenones. In this way,
optically active products could be formed from the cy-
clization of readily available, achiral enynes, utilizing a
catalytic amount of enantiomerically pure transition
metal complex.
Initial attempts to cyclize nitrogen-containing enynes
with 1 produced bicyclic cyclopentenones with poor to
moderate levels of enantiomeric excess (ee). It became
evident that the choice of the nitrogen substituent was
critical to the success of the reaction. For example,
replacement of a tert-butoxy carbonyl substituent, on the
nitrogen, with a phenyl group resulted in a significant
decrease in ee (from 74% to 30%). These results prompted
us to undertake the systematic examination of the
reaction for this class of enynes in order to find which
substrates could be cyclized with a high degree of
enantioselectivity.
The transition metal-mediated cyclization of an enyne
with carbon monoxide, a Pauson-Khand type reaction,
is an efficient method for the construction of bicyclic
cyclopentenones.1 We have previously reported a catalytic
version of this reaction utilizing commercially available
Cp2Ti(CO)2 (1).2,3 It was subsequently shown that an
enantiomerically pure analogue of the titanocene com-
plex, (S,S)-(EBTHI)Ti(CO)2 (2) (EBTHI ) ethylene-1,2-
bis(η5-4,5,6,7-tetrahydro-1-indenyl), generated in situ
from (S,S)(EBTHI)TiMe2 (3), can serve as a catalyst for
this reaction.4 Using this method, a variety of 1,6-enynes
could be cyclized with high levels of enantioselectivity
(Scheme 1).5
The intramolecular Pauson-Khand reaction is a useful
method for the preparation of azaheterocycles via the
cyclization of enynes in which there is a nitrogen atom
tethering the alkyne and the olefin (Scheme 1, X ) NR).
Becker and co-workers have explored the use of the
Pauson-Khand reaction for the synthesis of N-protected
azabicyclo[3.3.0]octan-7-ones, which serve as intermedi-
ates in the synthesis of racemic tricyclic diamines and
aza(nor)adamantanes possessing interesting pharmaco-
logical activity.6 The Pauson-Khand reaction has also
been used as the key step in several syntheses of (-)-
kainic acid7 and in the construction of the sesquiterpene
alkaloid (-)-dendrobine.8 In these examples, the enan-
tiomerically enriched products obtained arise from the
Resu lts a n d Discu ssion
To examine how the enantioselectivity of the cycliza-
tion changes when the nature of the N-substituent is
altered, a series of amine-containing enynes was pre-
pared and subjected to the reaction conditions as shown
in Scheme 1.9 The assignment of absolute configuration
was based on the configuration of enone 5d (Table 1)
which was determined unambiguously from the X-ray
crystal structure of the corresponding (S)-(+)-camphor-
sulfonic acid complex.10 The product of the cyclization
(1) For a review of the Pauson-Khand reaction, see: (a) Geis, O.;
Schmalz, H. G.; Angew. Chem., Int. Ed. Engl. 1998, 37, 911. (b) Schore,
N. E. In Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Ed.; Elsevier: New York, 1995; Vol.
12, p 703.
(2) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 9450.
(3) For catalytic Pauson-Khand reactions see work cited in ref 2.
Some subsequent advances in catalytic Pauson-Khand methodology
include (a) Belanger, D. B.; O’Mahony, D. J . R.; Livinghouse T.
Tetrahedron Lett. 1998, 39, 7637. (b) Belanger, D. B.; Livinghouse T.
Tetrahedron Lett. 1998, 39, 7641. (c) Sugihara, T.; Yamaguchi, M. J .
Am. Chem. Soc. 1998, 120, 10782. (d) Sugihara, T.; Yamaguchi, M.
Synlett 1998, 1384. (e) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem.
Lett. 1998, 249. (f) Kim, J . W.; Chung, Y. K. Synthesis 1998, 142. (g)
Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J . Org. Chem. 1997,
62, 3762. (h) Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T. J . Am.
Chem. Soc. 1997, 119, 6187.
(6) (a) Becker, D. P.; Flynn, D. L. Tetrahedron 1993, 49, 5047. (b)
Becker, D. P.; Flynn, D. L. Tetrahedron Lett. 1993, 34, 2087. (c) Flynn,
D. L.; Becker, D. P.; Spangler, D. P.; Nosai, R.; Gullikson, G. W.;
Moummi, C.; Yang, D.-C. Bioorg. Med. Chem. Lett. 1992, 2, 1613.
(7) (a) Yoo, S.-e.; Lee, S. H. J . Org. Chem. 1994, 59, 6968. (b) Yoo,
S.-E.; Lee, S.-H.; J eong, N.; Cho, I. Tetrahedron Lett. 1993, 34, 3435.
(c) Takano, S.; Inomata, K.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1992, 169.
(8) Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett. 1992, 443.
(9) When the substrates for which R ) Me and X ) CH3C(O)N, HN,
or LiN were subjected to the reaction conditions, an intractable mixture
of products resulted.
(4) For a review of the asymmetric Pauson-Khand reaction, see
Ingate S. T.; Marco-Contelles, J . Org. Prep. Proced. Int., 1998, 30, 121.
(5) Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 11688.
(10) X-ray structure parameters have been deposited in the Cam-
bridge database.
10.1021/jo990384f CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

5548 J . Org. Chem., Vol. 64, No. 15, 1999
Sturla and Buchwald
Sch em e 1
Ta ble 1. Cycliza tion of Va r iou s Nitr ogen -Con ta in in g
En yn es
benzyl-substituted enone was formed with low diastere-
oselectivity given that the benzyl-substituted amine (4d )
could be converted to the corresponding enone with a high
degree of enantioselectivity. To determine whether the
decrease in ee was due to an increase in steric bulk of
the N-substituent, the reaction of N-tert-butylamine (4j)
was carried out and found to provide enone of low and
variable ee. Furthermore, the ee of the product isolated
from several experiments varied from 12 to 48% (vide
infra).
entry
R1
R2
mol % (S,S)-2
ee (%)a
yield (%)d
a
b
c
d
e
f
n-octyl
allyl
allyl
Bn
t-Boc
Ts
Me
Me
Ph
Me
Me
Me
Me
10
10
15
15
10
13
10
15
>95b
76
91
81
82
84
93
81
81
94c
92
Ta ble 2. Ster ic Effects of Nitr ogen Su bstitu tion on ee
92c
74
31b
g
h
Ph
30-48c
4-22
t-BuC(O) Me
a
Unless indicated otherwise, ee’s were determined by chiral GC.
ee determined by 1H NMR (reduction of the ketone followed by
b
derivatization as the Mosher ester). c ee determined by chiral
d
HPLC. Yields are the average of two experiments and represent
isolated products of >95% purity by 1H NMR, GC analysis, and
in the case of new compounds, elemental analysis.
catalyzed by (S,S)-(2) was found to be the R isomer.11
Although good yields of enones were obtained in each
case, the ee’s of these products varied considerably (Table
1).12 It was found that enynes joined by an N-octyl,
N-allyl, or N-benzyl group were cyclized with a high
degree of enantioselectivity. In contrast, when the alkene
and alkyne moieties were linked by an aniline, amide,
or sulfonamide, the products were formed with low ee’s.
In the instance where the nitrogen was part of a car-
bamate group, moderate levels of enantioselectivity were
realized. It appears that substrates in which the nitrogen
center is relatively electron-rich are transformed to
enones with much higher levels of enantioselectivity than
in the cases where the nitrogen atom is electron deficient.
The sensitivity of the reaction to the nature of the
nitrogen substituent led us to examine whether the
diastereoselective cyclization of substrate 4i using 12 was
possible. We had hoped that the R-methylbenzyl moiety
would serve as an effective chiral auxiliary. Disappoint-
ingly, the reaction of enantiomerically pure 4i with 1 or
racemic 3 as catalysts gave enone with no diastereose-
lectivity. The reaction of 4i employing either (S,S)- or the
(R,R)-2 resulted in products with similar diastereomeric
ratios; no significant double diastereoselection was ob-
served.13 We were surprised to find that the R-methyl-
a
Yields are the average of two experiments and represent
isolated products of >95% purity by 1H NMR, GC, and elemental
analysis. ee determined by chiral HPLC. c ee determined by
b
d
chiral GC. Unreacted starting material (23%) was detected by
GC analysis.
For certain examples, we observed a dependence of the
enantioselectivity of the reaction on the concentration of
the catalyst. The cyclization of these enynes displayed
very low enantioselectivities which was found to increase
with increasing concentration. For example, reaction of
4g where [(S,S)-3] ) 5, 9, and 13 mM gave 5g with 30,
36, and 48% ee, respectively. The ee of 5h increased from
4 to 22% when the concentration of 3 was increased from
6 to 18 mM for the cyclization of 4h . Attempts to further
increase the ee of the product by performing the cycliza-
tions at higher concentrations resulted in incomplete
conversion of the substrates to products and no signifi-
cant increase in ee. The cyclization of the N-tert-buty-
lamine (4j) was also carried out at various concentrations;
the enantioselectivities of the reaction varied widely and
no correlation with catalyst concentration was observed.
In contrast, for the cyclization of the N-benzyl-substituted
amine (4d ), a substrate which provides enone with a high
ee, similar changes in catalyst concentration had no effect
on the ee of the enone (5d ) which was formed.
(11) We assume that all enones cyclized with the (S,S)-catalyst have
the same absolute configuration.
(12) The cyclization of (N-allyl-N-benzyl)-2-(1-hexynyl)aniline was
carried out under the standard reaction conditions using 15% of the
catalyst. The corresponding azabicyclo[4.3.0]nonenone was isolated in
70% yield, but with an ee of only 55%.
(13) Masamune, S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.

Cyclocarbonylation of Nitrogen-Containing Enynes
J . Org. Chem., Vol. 64, No. 15, 1999 5549
and backfilled with 14 psig CO. The Schlenk tube is sealed
and heated at 95 °C for 12-45 h.18 After cooling the reaction
mixture to room temperature, the CO pressure is carefully
released in the hood. Unless otherwise noted, the crude
reaction mixture is filtered through a plug of silica gel with
the aid of ether, concentrated, and purified by flash chroma-
tography.
Con clu sion
We have investigated the influence of N-substituents,
with different electronic and steric characteristics, on the
enantioselectivity of the cyclocarbonylation of nitrogen-
containing enynes. In addition, we have examined the
effect of catalyst concentration on these reactions. High
levels of enantioselectivity can be achieved for the cy-
clization of nitrogen-containing enynes bearing an elec-
tron rich, sterically small nitrogen-substituent.14 Two of
the nitrogen substituents of choice for the reaction, benzyl
and allyl, are known to be useful protecting groups for
amines.15 Through this study, (EBTHI)Ti(Me)2 (3) has
proven an effective precatalyst for the asymmetric syn-
thesis of nitrogen-containing bicyclic cyclopentenones.
6-Meth yl-3-n -octyl-3-azabicyclo[3.3.0]oct-5-en -7-on e (5a).
The general procedure employing (S,S)-(EBTHI)TiMe2 (12 mg,
0.035 mmol) was used to convert diallyl(2-butynyl)amine (4a )
(45 mg, 0.20 mmol) to the desired product in 23 h. Purification
by flash chromatography (0.5-1% NH3 saturated MeOH,
ether) afforded 37 mg (74% yield) of a yellow oil. The ee was
determined to be >95% due to the presence of only one isomer
19
in the 1H NMR after reduction with NaBH4/CeCl3 and
conversion to the Mosher’s ester with (S)-MTPA.20 [R]23D +154°
(c 3.2, C6D6). 1H NMR (500 MHz, C6D6): δ 3.56 (d, J ) 16.8
Hz, 1 H): 2.88 (t, J ) 7.6 Hz, 1 H); 2.67 (m, 1 H); 2.54 (d, J )
16.8 Hz, 1 H); 2.40 (m, 1 H); 2.25 (m, 2H); 1.73 (dd, J ) 17.4,
3.7 Hz, 1 H); 1.61 (t, J ) 1.1 Hz, 3 H); 1.43-1.10 (m, 13 H);
0.92 (t, J ) 7.0 Hz, 3 H). 13C{1H} NMR (125 MHz, C6D6): δ
177.0, 131.7, 110.5, 58.7, 56.2, 52.5, 43.3, 39.5, 32.3, 30.0, 29.8,
29.0, 27.7, 23.1, 14.4, 8.8.. IR (neat): 1711, 1677. Anal. Calcd
for C16H27NO: C, 77.07; H, 10.91. Found: C, 77.12; H, 10.97.
3-Allyl-6-m eth yl-3-a za bicyclo[3.3.0]oct-5-en -7-on e (5b).
The general procedure employing (S,S)-(EBTHI)TiMe2 (16 mg,
0.047 mmol) was used to convert diallyl(2-butynyl)amine (4b)
(42 mg, 0.28 mmol) to the desired product in 23 h. The reaction
mixture was concentrated without passing through silica.
Purification by flash chromatography (3% NH3 saturated
MeOH, ether) afforded 48 mg (96% yield) of a yellow oil. The
ee was determined to be 94% by chiral HPLC (OJ column).
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All manipulations involving air-
sensitive materials were conducted in a Vacuum Atmospheres
glovebox under an atmosphere of argon or using standard
Schlenk techniques under argon. Anhydrous toluene was
purchased from Aldrich and used as supplied. CO was scien-
tific grade (minimum purity 99.997%) from MG Industries.
Flash chromatography was performed on E. M. Science Kie-
selgel 60 (230-400 mesh). Substrates were stored in the
glovebox to prevent decomposition over long periods of time.
Substrates that were transferred into the glovebox during
periods of the year when the humidity in the lab was high
were filtered through a plug of alumina (in the glovebox) to
remove adventitious moisture. Yields refer to isolated yields
[R]22 +141° (c 4.0, toluene). 1H NMR (500 MHz, CDCl3): δ
D
1
of compounds of greater than 95% purity as estimated by H
5.80 (m, 1 H) 5.11 (dm, J ) 17.5 Hz, 1 H); 5.01 (dd, J ) 7.0,
1.5 Hz, 1 H); 3.52 (d, J ) 17.0 Hz, 1 H); 2.99 (m, 1 H); 2.84 (m,
2 H); 2.63 (m, 1 H); 2.57 (d, J ) 17.0 Hz, 1 H); 2.24 (dm, J )
17.8 Hz, 1 H); 1.70 (dt, J ) 17.5, 3.5 Hz, 1 H); 1.57 (d, J ) 1.0
Hz, 3 H); 1.37 (m, 1 H). 13C{1H} NMR (125 MHz, C6D6): δ
207.2, 176.8, 136.2, 131.8, 116.6, 58.7, 58.2, 52.0, 43.3, 39.4,
8.8. IR (neat): 1711, 1679. Anal. Calcd for C11H15NO: C, 74.54;
H, 8.53. Found: C, 74.59; H, 8.36.
NMR, capillary GC, and in the case of previously unknown
compounds, elemental analysis. Yield s in d ica ted in th is
section r efer to a sin gle exp er im en t, w h ile th ose r e-
p or ted in th e ta bles a r e a n a ver a ge of tw o or m or e r u n s,
so t h e n u m ber s m a y d iffer sligh t ly. Unless otherwise
noted, the enantiomeric excesses (% ee) of the products were
directly measured by chiral GC using a Chiraldex B-PH or
G-TA 20 m × 0.25 mm (ASTEC) capillary column or by chiral
HPLC on a Chiralcel OD or OJ 25 cm × 0.46 cm column (Daicel
Chemical Ind., Ltd.).
3-Allyl-6-p h en yl-3-a za bicyclo[3.3.0]oct-5-en -7-on e (5c).
The general procedure employing (S,S)-(EBTHI)TiMe2 (9 mg,
0.026 mmol) was used to convert diallyl(3-phenylpropargyl)-
amine (34 mg, 0.16 mmol) to the desired product in 26 h.
Purification by flash chromatography (0-20% ethyl acetate,
ether) afforded 31 mg (81% yield) of a yellow oil. The ee was
determined to be 92% by chiral GC (G-TA column). [R]23D -17°
Dim eth yl (S,S)-Eth ylen e-1,2-bis(η5-4,5,6,7-tetr a h yd r o-
1-in d en yl)tita n iu m (3). To a Schlenk tube under argon was
added (S,S)-(EBTHI)TiCl216 (700 mg, 1.83 mmol) and Et2O (50
mL), and the flask was placed in a water bath. A solution of
MeLi in Et2O (1.4 M, 7 mL, 5.0 mmol) was added slowly, and
the reaction was allowed to stir at room temperature for 4 h.
The solvent was removed in vacuo, and the crude product was
taken into the glovebox. The product was dissolved in hexane
(50 mL), and insoluble impurities were removed by filtration
through a plug of Celite, followed by rinsing with hexane. The
solvent was removed in vacuo to yield 520 mg (83% yield) of
the desired product as yellow-orange crystals, mp 78-80 °C.
The 1H NMR spectrum matched the published spectrum.17
1
(c 3.1, CHCl3). H NMR (500 MHz, CDCl3): δ 7.57 (d, J ) 7.8
Hz, 2 H); 7.39 (m, 2 H); 7.31 (m, 1 H); 5.93 (ddt, J ) 17.3,
10.0, 6.4 Hz, 1 H); 5.24 (dd, J ) 17.1, 1.5 Hz, 1 H); 5.15 (dd, J
) 9.8, 1.0 Hz, 1 H); 4.32 (d, J ) 18.6 Hz, 1 H); 3.42 (t, J ) 7.8
Hz, 1 H); 3.36-3.17 (m, 4 H); 2.79 (dd, J ) 17.6, 6.4 Hz, 1 H);
2.31 (dd, J ) 17.6, 3.9 Hz, 1 H); 1.99 (dd, J ) 10.7, 8.3 Hz, 1
H). 13C{1H} NMR (75 MHz, CDCl3): δ 207.0, 179.3, 134.9,
134.2, 131.1, 128.4, 128.1, 127.9, 117.6, 58.7, 57.9, 54.1, 43.4,
41.1. IR (neat): 1706, 1648. Anal. Calcd for C16H17NO: C, 80.3;
H, 7.16. Found: C, 79.84; H, 6.90.
[R]23 +28.0° (c 1.0, toluene).
D
P r oced u r e for th e Asym m etr ic Con ver sion of En yn es
to Cyclop en ten on es. In an argon-filled glovebox, a dry
resealable Schlenk tube is charged with (S,S)-(EBTHI)TiMe2,
toluene (3 mL), and the substrate. The Schlenk tube is sealed,
removed from the glovebox, attached to a Schlenk line,
evacuated, backfilled with ca. 4 psig CO, and then evacuated
3-Ben zyl-6-m eth yl-3-azabicyclo[3.3.0]oct-5-en -7-on e (5d).
The general procedure employing (S,S)-(EBTHI)TiMe2 (11 mg,
0.031 mmol) was used to convert allyl(benzyl)(2-butynyl)amine
(50 mg, 0.25 mmol) to the desired product in 45 h. Purification
by flash chromatography (ether) afforded 43 mg (76% yield)
of a yellow oil. The ee was determined to be 93% by chiral
HPLC (OD column). [R]23D +164° (c 4.2, toluene). 1H NMR (300
MHz, C6D6): δ 7.28-7.08 (m, 5 H); 3.50 (d, J ) 13.2 Hz, 1 H);
3.43 (d, J ) 16.9 Hz, 1 H); 3.29 (d, J ) 13.2 Hz, 1 H);2.79 (t,
J ) 7.4 Hz, 1 H); 2.62 (m, 1 H); 2.51 (d, J ) 16.8 Hz, 1 H);
(14) It should be noted that each of the electron-deficient enyne
substituents is also sterically large, and the low degree of enantiose-
lectivity may be attributed solely to steric effects. The cyclization of
an enyne with a small, electron-withdrawing N-substituent, such as
a formamide, would resolve this issue. However, previous experiments
(footnote 9, X ) CH3C(O)N) indicate this type of substrate to be
incompatible with the catalyst system. We thank a referee for helpful
comments on this issue.
(18) It is important to take appropriate safety precautions when
using carbon monoxide, particularly at elevated pressure. All opera-
tions should be carried out in an efficient fume hood behind a blast
shield.
(19) Clive, D.; Cole, D.; Tao, Y. J . Org. Chem. 1994, 59, 1396.
(20) Ward, D.; Rhee, C. Tetrahedron Lett. 1991, 32, 7165.
(15) Kocienski, P. J . Protecting Groups; Thieme: New York, 1994.
(16) Chin, B.; Buchwald, S. L. J . Org. Chem. 1996, 61, 5650.
(17) Xin, S.; Harrod, J . F. J . Organomet. Chem. 1995, 499, 181.

5550 J . Org. Chem., Vol. 64, No. 15, 1999
Sturla and Buchwald
2.20 (dd, J ) 17.4, 6.4 Hz, 1 H); 1.51 (s, 3 H); 1.66 (dd, J )
17.4, 3.6 Hz, 1 H). 13C{1H} NMR (75 MHz, C6D6): δ 211.5,
176.8, 139.4, 131.8, 128.8, 128.6, 127.4, 60.1, 58.5, 52.3, 43.3,
was concentrated without filtration through silica. Purification
by flash chromatography (85% ether, hexanes) afforded 48 mg
(87% yield) of a yellow oil. The diastereomeric ratio of the
39.4, 8.7. IR (neat): 1710, 1673, 1678. Anal. Calcd for C15H17
NO: C, 79.26; H, 7.54. Found: C, 79.05; H, 7.47.
-
product was determined to be 4.3:1 by 1H NMR integration.
1
[R]22 -20° (c 2.2, CHCl3). H NMR (500 MHz, CDCl3, major
D
isomer): δ 7.37-7.24 (m, 5 H); 4.08 (d, J ) 17.5 Hz, 1 H); 3.46
(q, J ) 6.5 Hz, 1 H); 3.22 (d, J ) 17.5 Hz, 1 H); 3.04 (m, 1 H);
3.00 (m, 1 H); 2.53 (dd, J ) 18.0, 6.0 Hz, 1 H); 2.00 (dd, J )
18.0, 3.0 Hz, 1 H); 1.73 (s, 3 H); 1.45 (d, J ) 6.5 Hz, 3 H).
13C{1H} NMR (75 MHz, CDCl3, major isomer): δ 209.1, 178.4,
144.4, 131.8, 128.4, 127.2, 127.1, 64.9, 57.2, 51.2, 43.1, 39.6,
22.4, 8.6. IR (neat, mixture of isomers): 1710, 1673. Anal.
Calcd for C16H19NO: C, 79.63; H, 7.94. Found: C, 79.81; H,
7.72.
6-Meth yl-3-(ter t-bu tyl)ca r ba m a te-3-a za bicyclo[3.3.0]-
oct-5-en -7-on e (5e). The general procedure employing (S,S)-
(EBTHI)TiMe2 (16 mg, 0.050 mmol) was used to convert tert-
butyl (N-allyl-N-2-butynyl)carbamate21 (105 mg, 0.50 mmol)
to the desired product in 12 h. Purification by flash chroma-
tography (30% ether, hexanes) afforded 102 mg (86% yield) of
an off white solid, mp 88-90 °C. The ee was determined to be
74% by chiral GC (B-PH column). [R]23 +127° (c 0.7, CHCl3).
D
The 1H NMR spectrum matched the published spectrum.5
Ta ble 2, en tr y 3. The same procedure as for Table 2, entry
2, employing (R,R)-(EBTHI)TiMe2 afforded 47 mg (84% yield)
of a yellow solid. The diastereomeric ratio of the product was
6-Meth yl-3-p-tolu en esu lfon yl-3-a za bicyclo[3.3.0]oct-5-
en -7-on e (5f). The general procedure employing (S,S)-(EBT-
HI)TiMe2 (6 mg, 0.018 mmol) was used to convert [N-allyl-N-
(2-butynyl)]-p-toluenesulfonamide (4f) (34 mg, 0.13 mmol) to
the desired product in 19 h. Purification by flash chromatog-
raphy (75% ether, hexanes) afforded 35 mg (94% yield) of a
white solid, mp 108-109 °C. The ee was determined to be 31%
1
determined to be 1:3.5 by H NMR integration. mp 55-58 °C.
1
[R]22 -162° (c 2.9, CHCl3). H NMR (500 MHz, CDCl3, major
D
isomer): δ 7.42-7.24 (m, 5 H); 3.65 (d, J ) 17.6 Hz, 1 H); 3.58
(t, J ) 7.6 Hz, 1 H); 3.47 (q, J ) 6.5 Hz, 1 H); 3.16 (m, 1 H);
2.93 (d, J ) 17.6 Hz, 1 H); 2.64 (dd, J ) 17.6 Hz, 6.4, 1 H);
2.13 (dd, J ) 17.6, 3.4 Hz, 1 H); 1.97 (m, 1 H); 1.73 (m, 1 H);
1.62 (m, 2 H); 1.42 (d, J ) 6.8 Hz, 3 H). 13C{1H} NMR (75
MHz, CDCl3, major isomer): δ 209.5, 178.7, 144.8, 131.7, 128.5,
127.1, 127.0, 65.3, 56.5, 52.3, 43.1, 39.7, 23.0, 8.6. IR (neat,
mixture of isomers): 1706, 1671. Anal. Calcd for C16H19NO:
C, 79.63; H, 7.94. Found: C, 79.78; H, 7.95.
1
by H NMR integration of diastereomers formed after reduc-
tion with NaBH4/CeCl319 and conversion to the Mosher’s ester
with (S)-MTPA.20 [R]24 -44° (c 0.8, CHCl3). 1H NMR (300
D
MHz, CDCl3): δ 7.74 (d, J ) 8.1 Hz, 2 H); 7.35 (d, J ) 8.0 Hz,
2 H); 4.24 (d, J ) 15.9 Hz, 1 H); 4.00 (m, 2 H); 3.01 (bs, 1 H);
2.65-2.54 (m, 3 H); 2.45 (s, 3 H); 2.03 (dd, J ) 14.8, 3.4 Hz, 1
H); 1.69 (s, 3 H). 13C{1H} NMR (125 MHz, CDCl3): δ 207.9,
171.3, 144.2, 134.2, 133.8, 130.1, 127.5, 52.8, 46.9, 41.8, 39.3,
6-Me t h yl-3-t er t -Bu t yl-3-a za b icyclo[3.3.0]oct -5-e n -7-
on e (Ta ble 2, en tr y 4). The general procedure employing
(S,S)-(EBTHI)TiMe2 (18 mg, 0.053 mmol) was used to convert
allyl(tert-butyl)(2-butynyl)amine (86 mg, 0.520 mmol) to the
desired product in 10 h. Unreacted starting material (19%)
was detected by GC analysis. The reaction mixture was
concentrated without filtration through silica. Purification by
flash chromatography (3% NH3 saturated MeOH, ether) af-
forded 62 mg (62% yield) of a yellow solid, mp 70-72 °C. The
ee was determined to be 28% by chiral GC (B-PH column).
21.7, 8.9. IR (neat): 1709, 1680, 1596. Anal. Calcd for C15H17
NO3S: C, 61.84; H, 5.88. Found: C, 61.82; H, 6.26.
-
6-Me t h yl-3-p h e n e t h yl-3-a za b icyclo[3.3.0]oct -5-e n -7-
on e (5g). The general procedure employing (S,S)-(EBTHI)-
TiMe2 (12 mg, 0.036 mmol) was used to convert N-(3-phenyl-
2-butynyl)-N-allylaniline (4g) (60 mg, 0.32 mmol) to the desired
product in 19 h. Purification by flash chromatography (25%
EtOAc, hexanes) afforded 60 mg (88% yield) of a light orange
solid, mp 100-103 °C. The ee was determined to be 43% by
[R]22 +79° (c 1.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ 3.76
1
D
chiral HPLC (OD column). [R]23 -102 (c 2.4, CHCl3). The H
D
(d, J ) 16.5 Hz, 1 H); 3.42 (d, J ) 17.1 Hz, 1 H); 3.30 (t, J )
7.7 Hz, 1 H); 3.10 (bs, 1 H); 2.62 (dd, J ) 17.9 Hz, 6.5, 1 H);
2.09 (m, 2 H); 1.72 (s, 3 H); 1.12 (s, 9 H). 13C{1H} NMR (75
MHz, CDCl3): δ 209.7, 178.8, 131.7, 52.9, 51.3, 45.8, 43.1, 39.8,
25.8, 8.7. IR (neat): 1703, 1666. Anal. Calcd for C12H19NO:
C, 74.55; H, 9.77. Found: C, 74.57; H, 9.91.
NMR spectrum matched the published spectrum.2
3-P iva loyl-6-m et h yl-3-a za bicyclo[3.3.0]oct -5-en -7-on e
(5h ). The general procedure employing (S,S)-(EBTHI)TiMe2
(18 mg, 0.053 mmol) was used to convert [N-allyl-N-(2-
butynyl)]pivalamide (4h ) (67 mg, 0.35 mmol) to the desired
product in 26 h. Purification by flash chromatography (25-
75% ethyl acetate, hexanes) afforded 58 mg (81% yield) of a
white solid, mp 108-110 °C. The ee was determined to be 22%
Ack n ow led gm en t. Dr. Frederick Hicks is gratefully
acknowledged for preliminary experiments and many
helpful discussions. We thank Dr. William Davis for the
X-ray crystal structure of the camphorsulfonic acid
complex of 5d . This work was supported by the National
Institutes of Health (GM 34917). Additional support
from Pfizer, Novartis, and Merck is gratefully acknowl-
edged. S.J .S. thanks the Ford Foundation for a predoc-
toral fellowship.
by chiral GC (B-PH column). [R]23 -4° (c 1.1, CHCl3). 1H
D
NMR (300 MHz, CDCl3): δ 4.50-4.25 (m, 3 H); 3.25-3.15 (bs,
1 H); 3.05-2.95 (m, 1 H); 2.70 (dd, J ) 18.0, 6.2 Hz, 1 H); 2.17
(dd, J ) 18.0, 3.2 Hz, 1 H); 1.79 (s, 3 H); 1.30 (s, 9 H). 13C
NMR (75 MHz, CDCl3): δ 207.9, 176.6, 171.3, 133.4, 52.7, 47.0,
39.2, 38.8, 27.4, 8.6. IR (KBr): 1716, 1684, 1626. Anal. Calcd
for C13H19NO2: C, 70.56; H, 8.65. Found: C, 70.68; H, 8.51.
6-Meth yl-3-(S)-(-)-p h en eth yl-3-a za bicyclo[3.3.0]oct-5-
en -7-on e (Ta ble 2, en tr y 2). The general procedure employ-
ing (S,S)-(EBTHI)TiMe2 (9 mg, 0.026 mmol) was used to
convert allyl(2-butynyl)[(S)-R-methylbenzyl]amine (4i) (49 mg,
0.23 mmol) to the desired product in 24 h. The reaction mixture
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic and analytical characterization of
enyne substrates. See any current masthead page for ordering
and Internet access instructions. This material is available free
of charge via the Internet at http://pubs.acs.org.
(21) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J . Am. Chem.
Soc. 1994, 116, 8593.
J O990384F