Asymmetric syntheses of fused bicyclic lactams

Full text of DOI:10.1021/jo0108865

9056
J . Org. Chem. 2001, 66, 9056-9062
Sch em e 1
Asym m etr ic Syn th eses of F u sed Bicyclic
La cta m s
Sung H. Lim, Sunghoon Ma, and Peter Beak*
Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
beak@scs.uiuc.edu
Received August 29, 2001
Azabicyclic compounds bearing nitrogen at the fusion
of five- and six-membered rings are key structures in
many multistep alkaloid and drug syntheses.1,2 Strategies
for asymmetric syntheses of these compounds generally
have utilized the chiral pool and/or a chiral auxiliary to
provide the diastereoselectivity necessary for enantioen-
richment.2,3 We now report combinations of chiral ligand
mediated lithiation/cyclization or asymmetric catalytic
reduction technology with ring-closing metathesis (RCM)
for asymmetric syntheses of fused bicyclic five-, six-, and
seven-membered lactams. These compounds have the
requisite structure and functional group locations for
further elaborations to synthetic targets, particularly
azabicyclic alkaloids.4 The retrosynthetic analyses are
illustrated in Scheme 1.
We have previously reported efficient methods to
prepare highly enantioenriched N-Boc-2-styrylpyrro-
lidines from achiral N-Boc-N-(3-chloropropyl)cinnamy-
lamines.5 This compound can be efficiently used in a
sequence terminating in a ring-closing metathesis to
provide bicyclic lactams.6
Treatment of N-Boc-N-(2-chloropropyl)cinnamylamine
1 with n-BuLi/(-)-sparteine in Et2O at -78 °C gives (S)-2
in 85% yield with an enantiomeric ratio (er) of 90:10.5
Recrystallization from hexane provides (S)-2 in 60% yield
with an er of 97:3. Removal of the Boc group with
trifluoroacetic acid (TFA) affords 3 which upon treatment
with either vinylacetic acid or pent-4-enoic acid in the
presence of diethyl cyanophosphonate (DEPC) and tri-
ethylamine provides the corresponding dienes 4 and 5
in 85% and 78% yields, respectively (Scheme 2). Treat-
ment of 4 or 5 with the second generation Grubbs catalyst
6 in refluxing methylene chloride affords the correspond-
ing lactams 7 and 8 in 86% and 84% yields, respectively.
With the first generation Grubbs catalyst 9, the reaction
times were much longer and the yields were significantly
lower.7 Alternatively, treatment of 3 with triethylamine
and acryloyl chloride affords 10 in 81% yield. Attempts
to cyclize 10 to prepare (S)-pyrrolam with either Grubbs
catalyst 6 or 9 were unsuccessful. Nakagawa and co-
workers have shown that (-)-coniceine 11, a simple
indolizidine alkaloid, can be synthesized from 7 via
stepwise reduction.3a Their synthesis of 7 involved the
transformation of L-proline to a diene which was cyclized
by ring-closing metathesis.
(1) For a general reference to azabicyclic alkaloids, see: Michael,
J . P. Nat. Prod. Rep. 2000, 17, 579. Laschat, S.; Dickner, T. Synthesis
2000, 1781.
We demonstrated previously that (S)-N-Boc-pipecolic
acid (S)-13 can be prepared by asymmetric hydrogenation
of 2-carboxy-N-Boc-1,4,5,6-tetrahydropyridine 12 using
the Noyori catalyst.8,9 Using highly enantioenriched (S)-
13, alcohol 14 may be prepared with BH3‚THF in 97%
yield (Scheme 3). Swern oxidation of 14 provides the
aldehyde 15, which in a Wittig reaction affords N-Boc-
2-vinylpiperidine 16 in 92% yield for two steps.10 The Boc
group is removed using 10 equiv of TFA in methylene
chloride to afford 17, and subsequent acylation with
acryloyl chloride provides 18. Attempts to cyclize 18 with
the Grubbs catalyst 9 failed, however, using the more
reactive catalyst 6, bicyclic compound 21 is synthesized
in 82% yield. Dienes 19 and 20 were prepared from 17
with the corresponding acids in the presence of DEPC
(2) For recent examples of asymmetric syntheses of azabicyclic
compounds, see: (a) Rasmussen, M. O.; Delair, P.; Greene, A. E. J .
Org. Chem. 2001, 66, 5438. (b) Comins, D. L.; Huang S.; McArdle, C.
L.; Ingalls, C. L. Org. Lett. 2001, 3, 469. (c) Voigtmann, U.; Blechert,
S.; Org. Lett. 2000, 2, 3971. (d) Davis, F. A.; Chao, B. Org. Lett. 2000,
2, 2623. (e) Back, T. G.; Nakajima, K. J . Org. Chem. 2000, 65, 4543.
(f) Gosselin, F.; Lubell, W. D. J . Org. Chem. 2000, 65, 2163. (g) Tang,
X.; Montgomery, J . J . Am. Chem. Soc. 2000, 122, 6950. (h) Brosius, A.
D.; Overman, L. E.; Schwink, L. J . Am. Chem. Soc. 1999, 121, 700.
(3) For previous syntheses of bicyclic lactams, see: (a) Arisawa, M.;
Takahashi, M.; Takezawa, E.; Yamaguchi, T.; Torisawa, Y.; Nishida,
A.; Nakagawa, M. Chem. Pharm. Bull. 2000, 48, 1593. (b) Arisawa,
M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett. 1997,
1179. (c) Tarling, C. A.; Holmes, A. B.; Markwell, R. E.; Pearson, N.
D. J . Chem. Soc., Perkin Trans. 1 1999, 1695 and references therein.
(4) For other uses of bicyclic lactams in asymmetric syntheses, see:
Molander, G. A.; Nichols, J . J . Org. Chem. 1996, 61, 6040. Meyers, A.
I.; Downing, S. V.; Weiser, M. J . J . Org. Chem. 2001, 66, 1413 and
references therein.
(5) Serino, C.; Stehle, N.; Park Y-S.; Florio, S.; Beak, P. J . Org.
Chem. 1999, 64, 1160.
(6) For a review on ring-closing metathesis of nitrogen-containing
compounds, see: Philips, A. J .; Abell, A. D. Aldrichimica Acta 1999,
32, 75.
(7) Sanford, M. S.; Love, J . A.; Gurbbs, R. H. J . Am. Chem. Soc.
2001, 123, 6543.
(8) Wilkinson, T. J .; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155.
Foti, C. J .; Comins, D. L. J . Org. Chem. 1995, 60, 2656.
(9) Both (S)- and (R)-N-Boc-pipecolic acids are commercially avail-
able from Aldrich.
(10) The alcohol was oxidized by the Katzenellenbogen-modified
Swern oxidation to provide the aldehyde which was reacted im-
mediately with the ylide to avoid epimerization. Our previous report
indicated that no epimerization had occurred at the position R to
nitrogen for the synthesis of N-Boc-2-propenyl piperidine from 14.8
10.1021/jo0108865 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/30/2001

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9057
Sch em e 2
Sch em e 3
and triethylamine. Grubbs catalyst 9 is sufficient to carry
out the ring-closing metathesis of 19 or 20 to provide the
corresponding fused bicyclic lactams 22 and 23. Greene
and co-workers have recently demonstrated that the
compound 21 can be transformed into (-)-2-epilentigi-
nosine 24 and (-)-lentiginosine 25 in few steps.2a In their
work, 21 was prepared from (S)-1-(triisopropylphenyl)-
ethanol in 11 steps with 23% overall yield.
This methodology can be extended to diastereoselective
syntheses of 3-substituted octahydro-quinolizin-4-ones.
Hydrogenation of 21 or 22 with PtO2 provides the
corresponding products 26 and 27 in 94% and 85% yields,
respectively (Scheme 4). Treatment of 27 with t-BuLi at
-78 °C followed by reaction with either methyl iodide or
allyl bromide affords 3-substituted octahydro-quinolizin-
4-ones 28 and 29 in 87% and 88% yields with low
diastereoselectivities. The diastereomers of 28 can be
separated by preparative HPLC, and the diastereomers
of 29 can be separated by column chromatography.
Further reaction of the single diastereomer of 29 with
t-BuLi and methyl iodide affords 30 in 78% yield with a
3:1 dr for diastereomers which are separable by column
chromatography.
Our previous work demonstrated access to both cis and
trans 2,6-disubstituted piperidines with high diastereo-
and enantioselectivity.8 This high stereochemical control
allows preparation of a single enantiomer of a 6-substi-
tuted hexahydroquinolizin-4-one. Reaction of aldehyde 15
with the ylide of ethyltriphenylphosphonium bromide
affords 31. Catalytic hydrogenation of 31 with 5% Pd/C
provides 32 in 93% yield. Treatment of 32 with s-BuLi/
TMEDA followed by reaction with DMF affords a 10:90
cis-trans mixture of 33, which can be isomerized with
silica gel to provide an 83:17 cis-trans mixture. The cis
isomer is isolated in 74% yield as a single diastereomer
after flash chromatography. Wittig olefination of alde-

9058 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
Sch em e 4
Sch em e 5
hyde 33 affords the olefin in 66% yield.11 Removal of
the Boc group with TFA, and amidation with vinylacetic
acid and DEPC provides the required diene 34. The
chiral diene is readily cyclized using catalyst 6 in 94%
yield to afford the desired lactam 35 with a >95:5 dr.
Since the cis-trans stereochemistry of 35 can be con-
trolled, this strategy could be useful in the preparation
of alkaloid 195C which is an alkaloid isolated from ants
and frogs.8,12
Extension of this methodology to seven-membered ring
would expand the approach to analogue syntheses.
Synthesis of 39 was accomplished starting from ꢀ-capro-
lactam 36 for the seven-membered ring. Protection of 36
with the Boc group and subsequent reduction of 37 with
DIBAL-H to the corresponding lactamol, followed by
dehydration with a catalytic amount of p-TsOH gives 38
as previously described by Kieter and Sharma (Scheme
5).13 Reaction of 38 with n-BuLi/TMEDA, followed by
reaction with CO2 provides 39 in 56% yield.
Asymmetric hydrogenation of 39 with the Noyori
catalyst generates (S)-41 in 90% yield with a disappoint-
ing 67:33 er. However, with [Rh(COD)-(+)-(2S,5S)-Et-
DuPHOS]OTf as the catalyst, 39 is reduced to provide
(S)-41 in 98% yield with a 95:5 er.14 Table 1 also shows
the results of asymmetric hydrogenation of N-(3,5-dim-
ethylphenyl amide) with either (S)-BINAP-RuCl2 or [Rh-
(COD)-(+)-(2S,5S)-Et-DuPHOS]OTf. A multigram prepa-
ration of (S)-41 can be accomplished in four steps from
commercially available ꢀ-caprolactam in 30% overall
yield.
(11) 1H NMR shows a small amount of impurity around 1.0-2.0 ppm
which was not separated from the product, but was removed in the
following step.
(12) J ones, T. H.; Gorman, J . S.; Snelling, R. R.; Delabie, J . H.; Blum,
M. S.; Garraffo, H. M.; J ain, P.; Daly, J . W.; Spande, T. F. J . Chem.
Ecol. 1999, 25, 1179. Daly, J . W.; Secunda, S. I.; Garraffo, H. M.;
Spande, T. F.; Wisnieski, A.; Nishihira, C.; Cover, J . F. Toxicon 1992,
30, 887. Edwards, M. W.; Daly, J . W. J . Nat. Prod. 1988, 51, 1188.
(13) Kieter, R. K.; Sharma, R. R. J . Org. Chem. 1996, 61, 4180.
(14) Burk, M. J .; Kalberg, C. S.; Pizzano, A. J . Am. Chem. Soc. 1998,
120, 4345.

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9059
Ta ble 1. Red u ction of 39 a n d Der iva tives w ith th e Ca ta lyst
Y
catalyst*
(S)-BINAP-RuCl2
product
yield, %
er
OH
OH
(S)-41
(S)-41
(S)-42
(S)-42
90
98
88
90
67:33
95:5
67:33
97:3
[Rh(COD)-(+)-(2S,5S)-Et-DuPHOS]OTf
(S)-BINAP-RuCl2
NH-3,5-Me2C6H3
NH-3,5-Me2C6H3
[Rh(COD)-(+)-(2S,5S)-Et-DuPHOS]OTf
Sch em e 6
aqueous layer with ether (3×), combination of the organic
phases, drying with MgSO4 and concentration by rotary evapo-
ration.
The acid (S)-41 is reduced with BH3‚THF to provide
43 in 94% yield (Scheme 6). Alcohol 43 is oxidized by a
Swern oxidation to afford 44, which is immediately
reacted with the ylide of methyltriphenylphosphonium
bromide to give 45 in 67% yield for two steps.10 Depro-
tection of the Boc group, and amidation with either
vinylacetic acid or pent-4-enoic acid, provided the corre-
sponding dienes 47 and 48 in 72% and 74% yields,
respectively. Ring-closing metathesis of the diene with
the catalyst 6 provides bicyclic lactams in 49 and 50 in
85% and 58% yields, respectively.
In summary, asymmetric lithiation-substitution or
asymmetric hydrogenation strategies can be combined
with ring-closing metathesis to provide efficient synthe-
ses of the highly enantioenriched bicyclic lactams 7, 8,
21, 22, 23, 30, 35, 49, and 50 with five-, six-, and seven-
membered fused rings. The enantiomers of 21, 22, 23,
30, 35, 49, and 50 could be obtained by use of (R)-
BINAP-RuCl2 or [Rh(COD)-(-)-(2R,5R)-Et-DuPHOS]-
OTf in the catalytic reduction. The enantioenriched
compounds we have reported and the methodology pro-
vided should be useful for the syntheses of many syn-
thetic targets, particularly the azabicyclic alkaloids.
Rep r esen ta tive Dien e P r ep a r a tion : Syn th esis of 1-(2-
Styr ylp yr r olid in -1-yl)bu t-3-en -1-on e (4). To a stirring solu-
tion of (S)-N-Boc-2-styryl-pyrrolidine (220 mg, 0.80 mmol) in 20
mL of CH2Cl2 was added TFA (0.62 mL, 8.00 mmol), and the
reaction mixture was stirred for 2 h. The solvent and excess TFA
was removed under vacuum, and 50 mL of DMF was added.
Triethylamine (0.67 mL, 4.80 mmol), diethyl cyanophosphonate
(0.36 mL, 2.4 mmol), and vinylacetic acid (0.20 mL, 2.4 mmol)
were added to the reaction mixture at 0 °C. After stirring
overnight at room temperature, the reaction mixture was
washed with aqueous 10% NaHCO3. Standard workup and
column chromatography (35% ethyl acetate in hexane) provided
4 (164 mg, 0.68 mmol, 85%) 1H NMR (CDCl3, 500 MHz, sample
rotameric at room temperature) δ 1.90 (m, 2H), 2.01 (m, 1H),
2.19 (m, 1H), 3.15 (m, 2H), 3.61 (m, 2H), 4.57 (bt, J ) 6.5 Hz,
0.7H), 4.86 (bt, J ) 5.8 Hz, 0.3H), 5.13 (m, 2H), 6.02 (m, 1H),
6.16 (m, 1H), 6.43 (m, 1H), 7.32 (m, 5H). 13C NMR (CDCl3, 125
MHz) δ 10.0, 22.0, 24.2, 31.0, 33.4, 39.9, 46.5, 58.3, 59.5, 117.9,
126.6, 126.7, 128.1, 128.6, 128.9, 129.9, 130.4, 170.7. HRMS:
Calcd for C16H19NO: 241.1467; found: 241.1463.
Rep r esen ta tive Rin g-Closin g Meta th esis: P r ep a r a tion
of 2,3,6,8a -Tetr a h yd r o-1H-in d olizin -5-on e (7). To a stirring
solution of 4 (65 mg, 0.27 mmol) in 50 mL of CH2Cl2 was added
the Grubbs catalyst 6 (11.5 mg, 0.014 mmol). The reaction
mixture was refluxed for 28 h, and the solvent was removed
under reduced pressure. The resulting oil was purified by column
chromatography (25% MeOH in ethyl acetate) to afford 7 (32
Exp er im en ta l Section
All air-sensitive reactions were performed in oven- or flame-
dried glassware under nitrogen with freshly distilled solvents.
Methylene chloride was distilled over CaH2, and diethyl ether
and tetrahydrofuran (THF) were distilled from sodium and
benzophenone. Commercially available TMEDA was used to
obtain racemic product and used without purification. n-BuLi
solution in hexanes (1.6 M) was titrated prior to use against
N-pivaloyl-o-toluidine. All other commercial reagents, including
catalysts for RCM and hydrogenation, were used without further
purification.
1
mg, 0.23 mmol, 86%). H NMR (CDCl3, 500 MHz) δ 1.52 (qd, J
) 11.9, 7.5 Hz, 1H), 1.86 (m, 1H), 2.02 (m, 1H), 2.16 (pent, J )
6.4 Hz, 1H), 2.95 (m, 2H), 3.44 (td, J ) 11.2, 2.2 Hz, 1H), 3.74
(ddd, J ) 17.9, 12.0, 9.0 Hz, 1H), 4.06 (bs, 1H), 5.81 (m, 1H),
5.89 (dm, J ) 10.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 22.3,
32.3, 33.1, 44.3, 59.1, 123.2, 125.5, 166.78. HRMS: Calcd for
C8H11NO: 137.0841; found: 137.0841.
1,2,3,6,7,9a -Hexa h yd r o-p yr r olo[1,2-a ]a zep in -5-on e (8).
The general diene preparation was followed using 2 (277 mg,
1.01 mmol) to afford 5 (201 mg, 0.78 mmol, 78%). To a stirring
solution of 5 (75.8 mg, 0.30 mmol) in 100 mL of CH2Cl2 was
added 6 (13 mg, 0.015 mmol) and refluxed for 24 h. The solvent
was removed under reduced pressure, and the resulting oil was
purified by column chromatography (5% MeOH in ethyl acetate)
to afford 8 (38 mg, 0.25 mmol, 84%). 1H NMR (CDCl3, 500 MHz)
δ 1.7-1.9 (m, 3H), 2.29 (m, 2H), 2.44 (m, 2H), 2.92 (td, J ) 14.1,
Purity of the sample is established to be >95% based on 13C
NMR spectra. Elemental analyses were carried out by the
University of Illinois Microanalytical Service Laboratory. All
numbered compounds were obtained as oils unless otherwise
indicated. Diastereomeric purity was determined by 1H NMR
integration. “Standard workup” refers to dilution with diethyl
ether, addition of H2O, separation of phases, extraction of the

9060 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
3.9 Hz, 1H), 3.46 (dt, J ) 15.0, 7.7 Hz, 1H), 3.66 (ddd, J ) 11.8,
7.6, 4.9 Hz, 1H), 4.55 (m, 1H), 5.53 (dq, J ) 11.5, 2.2 Hz, 1H),
5.70 (m, 1H). 13C NMR (CDCl3, 125 MHz) δ 23.4, 25.0, 34.7, 35.2,
46.9, 55.3, 130.1, 130.4, 173.1. HRMS: Calcd for C9H13NO:
151.0997; found: 151.0997.
29.5, 35.5, 40.0, 52.4, 131.0, 131.1, 175.1. HRMS: Calcd for
C
10H15NO: 165.1154; found: 165.1153.
Hexa h yd r o-in d olizin -3-on e (26). To a stirring solution of
21 (72 mg, 0.53 mmol) in 10 mL of MeOH was added PtO2 (12
mg, 0.05 mmol). The heterogeneous mixture was hydrogenated
for 8 h at room temperature using a balloon. The solvent was
removed, and the crude product was purified by flash chroma-
tography (20% MeOH in ethyl acetate) to afford 26 (69 mg, 0.495
mmol, 94%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (m, 1H), 1.36
(m, 2H), 1.57 (m, 1H), 1.68 (m, 1H), 1.86 (m, 2H), 2.19 (m, 1H),
2.34 (m, 2H), 2.60 (td, J ) 12.5, 3.4 Hz, 1H), 3.39 (md, J ) 3.39
Hz, 1H), 4.10 (dm, J ) 13.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz)
δ 23.9, 24.7, 25.6, 30.5, 33.8, 40.4, 57.5, 173.8. HRMS: Calcd
for C8H13NO: 139.0997; found: 138.0921 (M - 1 calcd: 138.0919).
Octa h yd r o-qu in olizin -4-on e (27). To a stirring solution of
22 (200 mg, 1.322 mmol) in 30 mL of MeOH was added PtO2
(30 mg, 0.132 mmol) was added. The heterogeneous mixture was
hydrogenated for 5 h at room temperature using a balloon. The
solvent was removed, and the crude product was purified by
flash chromatography (20% MeOH in ethyl acetate) to afford
27 (172 mg, 1.12 mmol, 85%). 1H NMR (CDCl3, 500 MHz) δ 1.37
(m, 4H), 1.66 (m, 3H), 1.79 (m, 2H), 1.94 (m, 1H), 2.34 (m, 3H),
3.19 (m, 1H), 4.74 (m, 1H). 13C NMR (CDCl3, 125 MHz) δ 19.4,
24.7, 25.6, 30.7, 33.2, 34.2, 42.5, 57.1, 169.5. HRMS: Calcd for
C9H15NO: 153.1154; found: 153.1151.
1-(2-Styr yl-p yr r olid in -1-yl)-p r op en on e (10). To a stirring
solution of 2 (480 mg, 1.73 mmol) in 10 mL of CH2Cl2 was added
TFA (1.33 mL, 17.3 mmol) and stirred for 2 h. The solvent and
excess TFA was removed under vacuum. The resulting oil was
dissolved in 10 mL of CH2Cl2 followed by triethylamine (2.46
mL, 17.3 mmol) and acryloyl chloride (1.40 mL, 17.3 mmol)
treatment. Standard workup and column chromatography pro-
vided 10 (320 mg, 1.41 mmol, 81%). 1H NMR (CDCl3, 500 MHz,
sample rotameric at room temperature) δ 1.92 (m, 2H), 2.05 (m,
1H), 2.20 (m, 1H), 3.64 (m, 1H), 3.72 (m, 1H), 4.66 (bt, J ) 6.5
Hz, 0.8H), 4.94 (bt, J ) 6.5 Hz, 0.2H), 5.16 (dd, J ) 9.7, 3.0 Hz,
0.8H), 5.72 (dd, J ) 10.0, 2.4 Hz, 0.2H), 6.19 (m, 1H), 6.47 (m,
3H), 7.31 (m, 5H). 13C NMR (CDCl3, 125 MHz) δ 10.0, 22.0, 31.0,
33.3, 46.6, 58.5, 59.3, 126.7, 127.7, 128.1, 128.6, 128.9, 129.2,
130.2, 130.6, 136.4, 137.4, 164.8, 165.6. HRMS: Calcd for C15H17
NO: 227.1310; found: 227.1312.
-
6,7,8,8a -Tetr a h yd r o-5H-in d olizin -3-on e (21). To a stirring
solution of 16 (374 mg, 1.77 mmol) in 25 mL of CH2Cl2 was added
TFA (1.35 mL, 17.7 mmol) and stirred for 2 h. The solvent and
excess TFA was removed under vacuum. The resulting oil was
dissolved in 50 mL of THF, and K2CO3 (2.45 g, 17.7 mmol) was
added along with acryloyl chloride (1.43 mL, 17.7 mmol). The
reaction mixture was diluted with 5% HCl (150 mL), after
refluxing for 24 h. The aqueous layer was extracted with ether
(3 × 50 mL), washed with saturated Na2CO3 (pH ) 9.0), and
extracted with CH2Cl2. The combined organic layer was dried
over MgSO4, concentrated, and purified by flash chromatography
(35% ethyl acetate in petroleum ether), providing 1-(2-vinylpi-
peridin-1-yl)propenone 18 (196 mg, 1.18 mmol, 67%). HRMS:
Calcd for C10H15NO: 165.1154; found: 165.1156. General ring-
closing metathesis procedure was followed using 18 (160 mg,
0.965 mmol) in 20 mL of CH2Cl2 and 6 (40 mg, 0.048 mmol) to
afford 21 (109 mg, 0.80 mmol, 82%) after the purification by flash
chromatography (75% ethyl acetate in petroleum ether). 1H NMR
(CDCl3, 500 MHz) δ 1.02 (qd, J ) 12.9, 3.5 Hz, 1H), 1.29 (qdd,
J ) 13.0, 5.1, 3.6 Hz, 1H), 1.51 (qt, J ) 13.2, 3.2 Hz, 1H), 1.75
(dm, J ) 12.9 Hz, 1H), 1.92 (dm, J ) 13.3 Hz, 1H), 2.10 (dm, J
) 13.3 Hz, 1H), 2.83 (td, J ) 12.9, 3.7 Hz, 1H), 3.86 (dm, J )
12.2 Hz, 1H), 4.28 (dd, J ) 13.3, 5.0 Hz, 1H), 6.15 (dd, J ) 5.9,
1.7 Hz, 1H), 7.02 (dd, J ) 5.8, 1.3 hz, 1H). 13C NMR (CDCl3,
125 MHz) δ 23.7, 25.5, 30.9, 39.4, 61.6, 127.6, 147.1, 169.1.
HRMS: Calcd for C8H11NO: 137.0841; found: 137.0844.
3,6,7,8,9,9a -Hexa h yd r o-qu in olizin -4-on e (22). General di-
ene preparation procedure was followed using 16 (1.2 g, 5.68
mmol) to afford 19 (930 mg, 5.18 mmol, 91%). To a stirring
solution of 19 (323 mg, 1.80 mmol) in 35 mL of CH2Cl2 the
Grubbs catalyst 9 (74 mg, 0.09 mmol) was added, and the
reaction mixture was refluxed for 24 h. The solvent was removed
under vacuum, and the crude product was purified by flash
chromatography (65% ethyl acetate in petroleum ether) to afford
22 (254 mg, 1.68 mmol, 93%). 1H NMR (CDCl3, 500 MHz) δ 1.12
(qd, J ) 13.0, 3.1 Hz, 1H), 1.27 (qt, J ) 13.0, 3.7 Hz, 1H), 1.39
(qt, J ) 13.1, 3.7 Hz, 1H), 1.55 (bd, J ) 12.4 Hz, 1H), 1.72 (m,
2H), 2.31 (td, J ) 13.1, 2.6 Hz, 1H), 2.78 (bs, 2H), 3.68 (m, 1H),
4.71, (dm, J ) 13.1 Hz, 1H), 5.45 (dm, J ) 10.7 Hz, 1H), 5.53
(dm, J ) 10.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 24.8, 25.4,
31.8, 34.3, 42.3, 58.4, 121.1, 125.9, 165.8. HRMS: Calcd for
C9H13NO: 151.0997; found: 151.0989.
3-Meth yl-octa h yd r o-qu in olizin -4-on e (28). A solution of
27 (133 mg, 0.869 mmol) in 15 mL of THF was cooled to -78
°C, and t-BuLi (0.61 mL, 1.04 mmol) was added. After stirring
for 10 min, methyl iodide (0.08 mL, 1.30 mmol) was added. After
stirring for 2 h, the solution was warmed to room temperature.
Standard workup and purification by column chromatography
(50% ethyl acetate in hexane) afforded 28 (126 mg, 0.75 mmol,
87%, 3:2 dr; Rf ) 0.30 and 0.25). The diastereomers were
separated using preparative HPLC (30% ethyl acetate in hex-
ane). Ma jor d ia ster eom er : 1H NMR (CDCl3, 500 MHz) δ 1.23
(d, J ) 7.2 Hz, 3H), 1.45 (m, 5H), 1.72 (m, 2H), 1.81 (m, 1H),
1.88 (m, 1H), 2.01 (m, 1H), 2.36 (m, 2H), 3.21 (m, 1H), 4.78 (dm,
J ) 13.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 17.7, 24.5, 25.6,
28.1, 30.2, 34.75, 37.3, 42.6, 57.6, 172.9. HRMS: Calcd for C10H17
-
NO: 167.1310; found: 167.1308. Min or d ia ster eom er : 1H
NMR (CDCl3, 500 MHz) δ 1.25 (d, J ) 7.2 Hz, 3H), 1.45 (m,
5H), 1.72 (m, 2H), 1.87 (m, 2H), 2.01 (m, 1H), 2.42 (m, 2H), 3.25
(m, 1H), 4.76 (dm, J ) 13.2 Hz, 1H). 13C NMR (CDCl3, 125 MHz)
δ 18.2, 24.9, 25.6, 26.5, 27.3, 34.0, 36.8, 43.2, 57.1, 172.9.
HRMS: Calcd for C10H17NO: 167.1310; found: 167.1307.
3-Allyl-octa h yd r o-qu in olizin -4-on e (29). A solution of 27
(73 mg, 0.48 mmol) in 15 mL of THF was cooled to -78 °C, and
t-BuLi (0.34 mL, 0.58 mmol) was added. After stirring for 10
min, allyl bromide (0.06 mL, 0.72 mmol) was added. After
stirring for 2 h, the solution was warmed to room temperature,
providing 29 (81 mg, 88%, ∼2:1 dr). The diastereomers were
separated by flash chromatography (65% ethyl acetate in
petroleum ether). Major diastereomer: 53.4 mg, 0.28 mmol, 58%,
Rf ) 0.40; minor diastereomer: 28 mg, 0.15 mmol, 30%, Rf )
0.32). Ma jor d ia ster eom er : 1H NMR (CDCl3, 400 MHz) δ 1.25
(m, 1H), 1.42 (m, 4H), 1.72 (m, 2H), 1.84 (m, 2H), 2.02 (m, 1H),
2.23 (m, 2H), 2.38 (td, J ) 12.8, 2.8 Hz, 1H), 2.75 (m, 1H), 3.19
(m, 1H), 4.77 (dm, J ) 13.2 Hz, 1H), 5.04 (m, 2H), 5.78 (m, 1H).
13C NMR (CDCl3, 100 MHz) δ 24.5, 24.6, 25.6, 30.1, 34.8, 36.2,
41.9, 42.6, 57.4, 116.6, 137.2, 171.5. HRMS: Calcd for C12H19
-
NO: 193.1467; found: 193.1461. Min or d ia ster eom er : 1H
NMR (CDCl3, 400 MHz) δ 1.42 (m, 4H), 1.67 (m, 5H), 1.86 (m,
2H), 2.25 (m, 1H), 2.39 (m, 2H), 2.66 (m, 1H), 3.25 (m, 1H), 4.76
(dm, J ) 13.4 Hz, 1H), 5.06 (m, 2H), 5.78 (m, 1H). 13C NMR
(CDCl3, 100 MHz) δ 22.7, 25.0, 25.7, 27.2, 34.0, 36.4, 41.5, 43.4,
57.2, 116.8, 137.0, 171.5. HRMS: Calcd for C12H19NO: 193.1467;
found: 193.1462.
1,3,4,7,8,10a -H exa h yd r o-2H -p yr id o[1,2-a ]a zep in -6-on e
(23). General procedure for the diene preparation was followed
using 16 (182 mg, 0.86 mmol) to afford 20 (150 mg, 0.78 mmol,
90%). To a stirring solution of 20 (140 mg, 0.726 mmol) in 15
mL of CH2Cl2 was added the Grubbs catalyst 9 (30 mg, 0.04
mmol), and the reaction mixture was refluxed for 24 h. The
solvent was removed under vacuum, and the crude product was
purified by flash chromatography (65% ethyl acetate in petro-
leum ether) to afford 23 (101 mg, 0.611 mmol, 84%). 1H NMR
(CDCl3, 500 MHz) δ 1.62 (m, 5H), 1.79 (m, 1H), 2.38 (m, 2H),
2.42 (dt, J ) 13.1, 4.6 Hz, 1H), 3.16 (ddd, J ) 13.3, 10.5, 7.0 Hz,
1H), 3.33 (ddd, J ) 13.6, 9.0, 4.2 Hz, 1H), 3.74 (td, J ) 13.3, 4.9
Hz, 1H), 4.62 (m, 1H), 5.56, (dm, J ) 11.1 Hz, 1H), 5.68 (dm, J
) 11.1 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 16.6, 23.2, 25.5,
3-Allyl-3-m eth yl-octa h yd r o-qu in olizin -4-on e (30). A solu-
tion of 29 (35 mg, 0.18 mmol) in 10 mL of THF was cooled to
-78 °C, and t-BuLi (0.13 mL, 0.22 mmol) was added. After
stirring for 10 min, methyl iodide (0.014 mL, 0.23 mmol) was
added. After stirring for 2 h, the solution was warmed to room
temperature, providing 30 (29 mg, 78%, 3:1 dr). The diastere-
omers were separated by flash chromatography (50% ethyl
acetate in petroleum ether). Major diastereomer: 22 mg, 0.11
mmol, 59% Rf ) 0.50; minor diastereomer: 7 mg, 0.03 mmol,
19%, Rf ) 0.42. Ma jor d ia ster eom er : 1H NMR (CDCl3, 500

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9061
MHz) δ 1.18-1.5 (m, 6H), 1.67-1.89 (m, 5H), 2.02 (m, 1H), 2.25
(m, 2H), 2.39 (td, J ) 13.1, 3.2 Hz, 1H), 2.76 (m, 1H), 3.20 (m,
δ 21.17, 23.06, 27.01, 27.91, 28.59, 47.56, 81.06, 117.29, 125.67,
131.06, 137.48, 138.40, 139.21, 153.54, 162.83. LRMS(FAB) calcd
for C20H28N2O3: 344.2; found 345.2 (M+ + H)
1H), 4.78 (dm, J ) 14.3 Hz, 1H), 5.05 (m, 2H), 5.80 (m, 1H). 13
C
NMR (CDCl3, 125 MHz) δ 24.5, 24.6, 25.6, 30.0, 34.7, 36.2, 41.9,
42.6, 57.4, 116.6, 137.2, 164.8. HRMS: Calcd for C13H21NO:
207.1623; found: 207.1621.
Rep r esen ta tive Ca ta lytic Hyd r ogen a tion of En eca r -
ba m a tes: P r ep a r a tion of (S)-Azep a n e-1,2-d ica r boxylic
Acid 1-ter t-Bu tyl Ester (41). [Rh(COD)-(+)-(2S,5S)-Et-Du-
PHOS]OTf (100 mg, 0.138 mmol) was added to a solution of 39
(667 mg, 2.76 mmol) in 10 mL of MeOH. The tube was
pressurized to 1000 psi of hydrogen for 20 h at room tempera-
ture. The solvent was evaporated, and the resulting oil was
purified by flash chromatography to give 41 (659 mg, 98%).
Melting point: 110-112 °C (lit.15 110-113 °C); [R]20 ) -59.1°
(c ) 1.0, MeOH) (lit. [R]20 ) -58°, c ) 1.0, MeOH, S-enantiomer);
1H NMR (500 MHz;CDCl3, sample rotameric at room tempera-
ture) δ 1.21-1.38 (m, 3H), 1.41, 1.46 (s, 9H), 1.85-2.07 (m, 4H),
2.25-2.38 (m, 1H), 2.88-3.04, 3.40-3.41 (bt, 1H), 3.77-3.82,
3.94-4.13 (bd, 1H), 4.38-4.36, 4.63-4.59 (m, 1H), 10.21 (bs, 1H).
13C NMR (125 MHz; CDCl3) δ 14.0, 25.3, 26.1, 28.2, 28.3, 29.1,
29.2, 29.4, 29.5, 29.7, 30.3, 30.5, 43.3, 43.9, 58.0, 59.5, 60.4, 80.3,
155.3, 156.7, 177.8, 178.9. HRMS(EI) m/z calcd for C12H21NO4
241.1314, found 198.1497(M+ - CO2H). The enantiomeric purity
was determined to be 95:5 by CSP-HPLC analysis of the 3,5-
dimethylaniline derivative obtained above on a Pirkle concept
Whelk-O column with 5%(v/v) isopropyl alcohol/hexane mobile
phase by a flow rate 1.5 mL/min. The major enantiomer had a
retention time of 16.7 min, and the minor enantiomer had a
retention time of 11.1 min.
2-P r op yl-6-vin ylp ip er id in e-1-ca r boxylic Acid ter t-Bu tyl
Ester . A suspension of Ph3PCH3Br (1.39g, 3.9 mmol) in 50 mL
of THF was cooled to -78 °C, and n-BuLi (2.06 mL, 3.3 mmol)
was added. After stirring for 10 min, the reaction mixture was
warmed to room temperature and stirred for addition 30 min.
The aldehyde 33 (758 mg, 3.00 mmol) in 10 mL of THF was
slowly added to the ylide at -78 °C. After the reaction mixture
was stirred for 2 h, standard workup and flash chromatography
(7% ethyl acetate in hexane) provided 2-propyl-6-vinylpiperidine-
1
1-carboxylic acid tert-butyl ester (503 mg, 1.99 mmol, 66%). H
NMR (CDCl3, 400 MHz, sample rotameric at room temperature)
Contains impurity, δ 0.8-1.8 (m, >10H), 4.08 (m, 1H), 4.65 (bs,
1H), 4.98 (dt, J ) 10.5, 1.6 Hz, 1H), 5.07 (dt, J ) 17.1, 1.9 Hz,
1H), 5.85 (ddd, J ) 17.5, 10.7, 5.6 Hz, 1H).
1-(2-P r opyl-6-vin ylpiper idin -1-yl)bu t-3-en -1-on e (34). The
standard procedure for the diene synthesis was followed using
2-propyl-6-vinylpiperidine-1-carboxylic acid (400 mg, 1.58 mmol)
to afford 34 (195 mg, 0.88 mmol, 56%) after flash chromatog-
raphy (35% ethyl acetate in hexane). 1H NMR (CDCl3, 500 MHz,
sample rotameric at room temperature) δ 0.86 (m, 3H), 1.2-1.7
(m, 10H), 1.9 (m, 1H), 3.01 (m, 1H), 3.18 (m, 1H), 3.80 (m, 0.33
H), 4.39 (m, 0.33H), 4.64 (m, 0.34H), 5.10 (m, 4H), 5.91 (m, 2H).
13C NMR (CDCl3, 125 MHz) δ 14.2, 14.7, 14.8, 20.62, 27.1, 27.4,
28.2, 29.5, 36.2, 36.7, 39.2, 48.6, 48.9, 53.2, 54.1, 114.8, 115.8,
117.4, 132.5, 139.8, 170.6, 170.9. HRMS: Calcd for C14H23NO:
221.1780; found: 221.1781.
(S )-2-(3,5-Dim e t h ylp h e n ylca r b a m oyl)a ze p a n e -1-ca r -
boxylic Acid ter t-Bu tyl Ester (42). The standard procedure
for the catalytic hydrogenation was followed using 40 (42.5 mg,
0.12 mmol) in 5 mL of MeOH to afford 42 (38 mg, 0.11 mmol,
1
90%). H NMR (500 MHz;CDCl3), δ 1.35 (s, 9H), 1.72-2.20 (m,
6-P r opyl-3,6,7,8,9,9a-h exah ydr o-qu in olizin -4-on e (35). The
standard procedure for the ring-closing metathesis was followed
using 34 (139 mg, 0.628 mmol) and 6 (26.6 mg, 0.03 mmol) to
afford 35 (114 mg, 0.59 mmol, 94%) after flash chromatography
(50% ethyl acetate in hexane). 1H NMR (CDCl3, 500 MHz) δ 0.90
(t, J ) 7.4 Hz, 3H), 1.31 (m, 2H), 1.50 (m, 2H), 1.67 (m, 1H),
1.74 (m, 2H), 1.82 (m, 2H), 2.02 (m, 1H), 2.89 (m, 2H), 3.69 (m,
8H), 2.28(bs, 6H), 2.92-2.97 (bt, 1H), 3.71-3.75 (bd, 1H), 4.57-
4.62(m, 1H), 6.72(bs, 1H), 7.18(bs, 2H), 8.62(bs, 1H); 13C NMR
(125 MHz; CDCl3) δ 21.57, 28.63, 29.61, 58.97, 80.86, 117.55,
125.81, 138.85, 157.81, 170.63. LRMS(FAB) m/z calcd for
C
20H30N2O3 346.4; found 347.2(M+ + H). The enantiomeric
purity was determined to be 97:3 er by CSP-HPLC analysis of
the product obtained above on a Pirkle concept Whelk-O column
with 5% (v/v) isopropyl alcohol/hexane mobile phase by a flow
rate 1.5 mL/min. The major enantiomer had a retention time of
16.91min, and the minor enantiomer had a retention time of
11.06 min.
1H), 3.98 (m, 1H), 5.58 (dm, J ) 10.2 Hz, 1H), 5.70 (m, 1H). 13
C
NMR (CDCl3, 125 MHz) δ 14.3, 19.5, 20.6, 24.8, 31.3, 33.8, 35.9,
55.7, 56.8, 122.4, 127.4, 168.3. HRMS: Calcd for C12H19NO:
193.1467; found: 193.1478. M - 1 calcd for 192.1388; found
192.1391.
2-Hyd r oxym eth yla zep a n e-1-ca r boxylic Acid ter t-Bu tyl
Ester (43). To a stirring solution of 41 (665 mg, 2.73 mmol) in
40 mL of THF cooled to 0 °C was added BH3‚THF (1.0 M in THF,
4.1 mL, 4.1 mmol). The reaction mixture was warmed to room
temperature, and 1 mL of water was added. Potassium carbonate
(700 mg) was added, and the mixture was stirred for 30 min.
Standard workup and flash chromatography (50% ethyl acetate
in petroleum ether) provided 43 (586 mg, 2.56 mmol, 94%). [R]20
) -58.4° (c ) 0.01, CHCl3) (lit.16 [R] ) -62.8°, c ) 0.31, CHCl3,
S-enantiomer); 1H NMR (CDCl3, 500 MHz, sample rotameric at
room temperature) δ 1.16 (m, 3H), 1.37 (m, 9H), 1.39 (m, 1H),
1.59 (m, 1H), 1.72 (m, 2H), 1.92 (m, 1H), 2.69 (m, 0.8H), 3.01
(m, 0.2H), 3.40 (m, 2H), 3.56 (bd, J ) 14.4 Hz, 0.7H), 3.71 (bd,
J ) 14.4 Hz, 0.3H), 3.88 (m, 0.2H), 4.03 (m, 0.8H). 13C NMR
(CDCl3, 125 MHz) δ 25.3, 28.6, 28.6, 29.6, 29.6, 30.1, 42.5, 42.9,
57.5, 57.8, 65.1, 65.7, 79.7, 157.8. HRMS: Calcd for C12H23NO3:
229.1678; found: 229.1680.
2-Vin yla zep a n e-1-ca r boxylic Acid ter t-Bu tyl Ester (45).
A solution of oxalyl chloride (0.27 mL, 3.06 mmol) in 20 mL of
CH2Cl2 under nitrogen was cooled to -78 °C and stirred for 15
min. A solution of DMSO (0.36 mL, 5.1 mmol) in 2 mL of CH2-
Cl2 was added, and the mixture was stirred for 10 min. A
solution of 43 (586 mg, 2.55 mmol) in 5 mL of CH2Cl2 was added
dropwise and stirred for 2 h. Diisopropylethylamine (1.78 mL,
10.2 mmol) was added slowly, and the solution was warmed to
room temperature. The mixture was washed with 1 M HCl (10
mL), and standard workup provided 2-formyl-azepane-1-car-
boxylic acid tert-butyl ester 44 which was used immediately in
the next step. n-BuLi (1.59 mL, 2.55 mmol) was added to a
4,5,6,7-Tetr a h yd r o-a zep in e-1,2-d ica r boxylic Acid 1-ter t-
Bu tyl Ester (39). To a solution of N-Boc-2,3,4,5-tetrahydro-
azepine 38 (12.43g, 63.05 mmol) and TMEDA (9.52g, 81.96
mmol) in anhydrous THF (125 mL, 0.5M) at -65 °C was added
dropwise n-BuLi (53 mL, 81.96 mmol) in hexane. The resulting
yellow mixture was slowly warmed to -30 °C over 3 h and then
stirred additional 45 min at -30 °C. This reaction mixture was
then cooled to -78 °C, and CO2 was passed through the solution
for 30 min. The reaction was allowed to reach to ambient
temperature slowly. Saturated solution of NH4Cl was poured
into the mixture and extracted with ether. The organic layer
was washed with 10% NaOH (pH ) 8-10), and then the
resulting aqueous layer was acidified with 3 M HCl. The aqueous
layer was washed with ether, brine, dried over MgSO4, filtered,
and then concentrated in vacuo. The yellow mixture was purified
by flash chromatography on silica gel to give 39 (8.58 g, 56%).
Melting point 77-80 oC. 1H NMR (500 MHz, CDCl3) 1.42 (s, 9H),
1.40-1.67 (m, 3H), 1.78-1.84 (m, 2H), 2.33-2.39 (m, 2H), 3.49
(bs, 1H), 6.78 (t, 1H). Elemental Anal. Calcd for C12H19NO4: C,
59.73; H, 7.94; N, 5.81. Found: C, 59.38; H, 7.99; N, 5.75. HRMS
(EI) m/z calcd for C12H19NO4 241.1314; found 241.1314.
7-(3,5-Dim et h yl-p h en ylca r b a m oyl)-2,3,4,5-t et r a h yd r o-
a zep in e-1-ca r boxylic Acid ter t-Bu tyl Ester (40). To a solu-
tion of (S)-39 (308 mg, 1.27 mmol), DCC(262 mg, 1.27 mmol),
and HOBT(206 mg, 1.52 mmol) in methylene chloride (15 mL)
was added 3,5-dimethylaniline (185 mg, 1.52 mmol) at room
temperature. The resulting mixture was stirred for 24 h and
filtered through a pad of Celite. The filtrate was concentrated
in vacuo and was purified by flash chromatography on silica gel
to give 40 (279 mg, 64%): Melting point: 139-142 °C. 1H NMR
(500 MHz, CDCl3) δ 1.35 (bs, 9H), 1.44-1.48 (m, 4H), 1.82-
1.89 (t, 2H), 2.26 (s, 6H), 3.50 (bs, 2H), 6.60-6.63 (t, 1H), 6.71
(s, 1H), 7.18 (s, 2H), 7.69 (bs, 1H); 13C NMR (125 MHz; CDCl3)
(15) Pauly, R.; Sasaki, N. A.; Potier, P. Tetrahedron Lett. 1994, 2,
237.
(16) Trost, B. M.; Krische, M. J .; Radinov, R.; Zanoni, G. J . Am.
Chem. Soc. 1996, 118, 6297.

9062 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
stirring suspension of Ph3PCH3Br (1.09 g, 3.06 mmol) in 20 mL
of THF at -78 °C. After stirring for 15 min, the solution was
warmed to room temperature for 30 min. The reaction mixture
was cooled to -78 °C, and 2-formylazepane-1-carboxylic acid tert-
butyl ester was added. After stirring for 1 h, the reaction mixture
was warmed to room temperature. Standard workup and flash
chromatography (10% ethyl acetate in petroleum ether) provided
45 (382 mg, 1.70 mmol, 67%). 1H NMR (CDCl3, 500 MHz, sample
rotameric at room temperature) δ 1.0-1.5 (m, 11H), 1.68 (m,
4H), 2.03 (m, 2H), 2.64 (t, J ) 14.4 Hz, 1H), 3.64 (bd, J ) 14.2
Hz, 0.6H), 3.81 (bd, J ) 13.9 Hz, 0.4H), 4.34 (m, 0.5H), 4.54 (m,
0.5H), 4.94 (m, 2H), 5.68 (m, 1H). 13C NMR (CDCl3, 125 MHz)
δ 25.0, 25.4, 28.5, 28.6, 28.7, 29.3, 29.4, 29.8, 29.9, 33.7, 34.1,
41.9, 42.4, 56.7, 58.0, 112.9, 113.0, 138.4, 138.7, 156.0. HRMS:
Calcd for C13H23NO2: 225.1729; found: 225.1734.
1-(2-Vin yla zep a n -1-yl)bu t-3-en -1-on e (47). The standard
procedure for the diene preparation was followed using 45 (168
mg, 0.745 mmol) to afford 47 (104 mg, 0.53 mmol, 72%) after
flash chromatography (35% ethyl acetate in petroleum ether).
1H NMR (CDCl3, 500 MHz, sample rotameric at room temper-
ature) δ 1.16-2.10 (m, 7H), 2.13 (m, 1H), 2.60 (tm, J ) 12.8 Hz,
1H), 2.95-3.30 (m, 2H), 3.60 (m, 0.5H), 4.20 (m, 1.5H), 5.00 (m,
2H), 5.13 (m, 2H), 5.73 (m, 1H), 5.98 (m, 1H). 13C NMR (CDCl3,
125 MHz) δ 24.8, 25.2, 28.7, 29.6, 29.9, 30.5, 32.9, 34.6, 38.8,
38.9, 41.3, 43.0, 55.4, 59.3, 113.6, 114.0, 117.6, 117.7, 132.4,
137.6, 137.7, 171.5 HRMS: Calcd for C12H19NO: 193.1467;
found: 193.1467.
15.2 Hz, 0.5H), 4.22 (m, 1H), 5.02 (m, 4H), 5.81 (m, 2H). 13C
NMR (CDCl3, 125 MHz) δ 24.9, 25.3, 28.8, 29.6, 30.0, 30.4, 32.7,
32.8, 33.0, 34.7, 41.3, 43.0, 55.4, 59.3, 113.5, 113.9, 115.2, 115.3,
137.7, 137.8, 138.0, 138.02, 172.2. HRMS: Calcd for C13H21NO:
207.1623; found: 207.1618.
6,7,8,9,10,10a -H e xa h yd r o-3H -p yr id o[1,2-a ]a ze p in -4-
on e (49). The standard procedure for the ring closing metathesis
was following using 47 (78 mg, 0.40 mmol) and the Grubbs
catalyst 6 (17 mg, 0.02 mmol) to afford 49 (56 mg, 0.34 mmol,
85%) after flash chromatography (65% ethyl acetate in petroleum
ether). 1H NMR (CDCl3, 500 MHz) δ 1.53 (m, 3H), 1.63 (m, 3H),
1.95 (m, 2H), 2.79 (ddd, J ) 14.2, 10.7, 4.0 Hz, 1H), 2.94 (m,
2H), 3.98 (m, 1H), 4.36 (td, J ) 14.0, 4.7 Hz, 1H), 5.70 (m, 2H).
13C NMR (CDCl3, 125 MHz) δ 24.5, 26.4, 27.4, 32.3, 37.8, 46.1,
60.1, 121.9, 128.0, 167.9. HRMS: Calcd for C10H15NO: 165.1154;
found: 165.1153.
3,4,7,8,9,10,11,11a -Oct a h yd r o-a zep in o[1,2-a ]a zep in -5-
on e (50). The standard procedure for the ring-closing metathesis
was following using 48 (53 mg, 0.27 mmol) and the Grubbs
catalyst 6 (12 mg, 0.014 mmol) to afford 50 (28 mg, 0.16 mmol,
58%) after flash chromatography (5% MeOH in ethyl acetate).
1H NMR (CDCl3, 500 MHz) δ 1.22-1.56 (m, 4H), 1.86 (m, 2H),
1.96 (m, 2H), 2.16 (m, 2H), 2.73 (dd, J ) 14.0, 12.1 Hz, 1H),
2.91 (m, 1H), 3.67 (dm, J ) 17.6 Hz, 1H), 4.78 (m, 1H), 4.24
(dm, J ) 13.8 Hz, 1H), 5.61 (m, 2H). 13C NMR (CDCl3, 125 MHz)
δ 26.6, 29.7, 30.4, 34.8, 34.9, 36.5, 40.1, 56.7, 121.7, 129.1, 164.8.
HRMS: Calcd for C11H17NO: 179.1310; found: 179.1308.
1-(2-Vin yla zep a n -1-yl)p en t-4-en -1-on e (48). The standard
procedure for the diene preparation was followed using 45 (92
mg, 0.41 mmol) to afford 48 (63 mg, 0.30 mmol, 74%) after flash
chromatography (35% ethyl acetate in petroleum ether). 1H NMR
(CDCl3, 500 MHz) δ 1.19-1.98 (m, 7H), 2.14 (m, 1H), 2.30-2.60
(m, 5H), 2.98 (ddd, J ) 15.6, 12.2, 1.1 Hz, 0.5H), 3.61 (dm, J )
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-18874) for support of this
work.
J O0108865