Titanium-mediated cyclization of ω-vinyl imides in alkaloid synthesis: Isoretronecanol, trachelanthamidine, 5-epitashiromine, and tashiromine

Article abstract of DOI:10.1021/jo9907383

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of ω-vinyl imides is described. The general procedure involves treatment of readily available ω-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium chloride in the presence of ClTi(O-i-Pr)₃ (1.1 equiv) and subsequent stereoselective reduction of the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively prepared by catalytic hydrogenation (H₂, PtO₂, EtOAc) and NaCNBH₃ reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1-8 in good yields.

Full text of DOI:10.1021/jo9907383

J . Org. Chem. 1999, 64, 6771-6775
6771
Tita n iu m -Med ia ted Cycliza tion of ω-Vin yl Im id es in Alk a loid
Syn th esis: Isor etr on eca n ol, Tr a ch ela n th a m id in e,
5-Ep ita sh ir om in e, a n d Ta sh ir om in e
Se-Ho Kim, Seok-In Kim, Sheng Lai, and J in Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, Alabama 35487
Received May 3, 1999
A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means
of titanium-mediated cyclization of ω-vinyl imides is described. The general procedure involves
treatment of readily available ω-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium
chloride in the presence of ClTi(O-i-Pr)3 (1.1 equiv) and subsequent stereoselective reduction of
the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively
prepared by catalytic hydrogenation (H2, PtO2, EtOAc) and NaCNBH3 reduction (TFA, MeOH),
respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target
alkaloids 1-8 in good yields.
In tr od u ction
Resu lts a n d Discu ssion
Recently, we reported that treatment of readily avail-
able ω-vinyl imides 9 and 10 with 2.5 equiv of cyclopen-
tylmagnesium chloride in the presence of ClTi(O-i-Pr)3
(1.1 equiv) gave, upon hydrolysis, N-acylaminals 11 (55%)
and 12 (55%), respectively.4 The corresponding alcohols
13 (45%) and 14 (60%) were also readily prepared by
simple oxidation with molecular oxygen prior to aqueous
workup.6a It occurred to us that stereocontrolled reduc-
tion of the N-acylaminal function would provide a concise
approach to the key structural elements of the pyrrolizi-
dine and indolizidine alkaloids. A particularly attractive
feature is the possibility of stereoselectively securing both
diastereomers, i.e., lactams with cis-ring hydrogens (e.g.,
15, 17, 19, and 21) and those with trans-ring hydrogens
(e.g., 16, 18, 20, and 22), via common advanced inter-
The pyrrolizidine or indolizidine alkaloids represent a
diverse group of natural products that display a broad
range of biological activity.1,2 These alkaloids have been
popular targets for total synthesis. In addition to inter-
esting biological activity, they have provided a useful
forum to develop a general, efficient method for the con-
struction of the common azabicyclo[3.3.0] or azabicyclo-
[4.3.0] skeleton. There are several elegant synthetic
methods available for these relatively simple structural
subunits.3
We recently developed a new, general route to the
pyrrolizidine and indolizidine skeleton by means of
titanium-mediated cyclization of ω-vinyl imides (Scheme
1),4 which in turn evolved from the Kulinkovich titana-
cyclopropane intermediate.5 As the first foray to pyr-
rolizidine and indolizidine alkaloids, we report herein the
implementation of this annulation to the stereocontrolled
synthesis of their simplest members, 1-8.
(2) For indolizidine alkaloids, see: (a) Daly, J . W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1986; Vol. 4. (b) Rajeswari, S.; Chandrasekharan,
S.; Govindachari, T. R. Heterocycles 1987, 25, 659. (c) Takahata, H.;
Momose, T. In The Alkaloids; Brossi, A., Ed.; Academic Press: San
Diego, 1993; Vol. 44, Chapter 3, p 189. (d) Michael, J . P. Nat. Prod.
Rep. 1994, 11, 639.
(3) For some representative examples of previous work, see: (a)
Tufariello, J . J .; Lee, G. E. J . Am. Chem. Soc. 1980, 102, 373. (b) Keck,
G. E.; Nickell, D. G. J . Am. Chem. Soc. 1980, 102, 3632. (c) Vedejs, E.;
Martinez, G. R. J . Am. Chem. Soc. 1980, 102, 7993. (d) Hart, D. J .;
Tsai, Y.-M. J . Am. Chem. Soc. 1982, 104, 1430. (e) Choi, J .-K.; Hart,
D. J . Tetrahedron 1985, 41, 3959. (f) Hiemstra, H.; Sno, M. H. A. M.;
Vijn, R. J .; Speckamp, W. N. J . Org. Chem. 1985, 50, 4014. (g)
Hudlicky, T.; Frazier, J . O.; Seoane, G.; Tiedje, M.; Seoane, A.; Kwart,
L. D.; Beal, C. J . Am. Chem. Soc. 1986, 108, 3755. (h) Nagao, Y.; Dai,
W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E. J . Am. Chem. Soc. 1988,
110, 289. (i) Keck, G. E.; Cressman, E. N. K.; Enholm, E. J . J . Org.
Chem. 1989, 54, 4345. (j) Pearson, W. H.; Bergmeier, S. C.; Degan, S.;
Lin, K.-C.; Poon, Y.-F.; Schkeryantz, J . M.; Williams, J . P. J . Org.
Chem. 1990, 55, 5719 and references therein.
(4) Lee, J .; Ha, J . D.; Cha, J . K. J . Am. Chem. Soc. 1997, 119, 8127.
(5) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O.
G.; Sviridov, S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T.
S. Zh. Org. Khim. 1991, 27, 294. (c) Kulinkovich, O. G.; Sorokin, V.
L.; Kel’in, A. V. Zh. Org. Khim. 1993, 29, 66.
(6) (a) For several imides, ether is the solvent of choice for the
preparation of primary alcohols, whereas use of THF often results in
varying amounts of the methyl compounds as byproducts: Sung, M.
J .; Cha, J . K. Unpublished results. (b) Kim, S.-H.; Cha, J . K.
Unpublished results.
(1) For pyrrolizidine alkaloids, see: (a) Numata, A.; Ibuka, T. In
The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1987; Vol.
31, Chapter 6, p 193. (b) Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles
1988, 27, 1465. (c) Robins, D. J . Nat. Prod. Rep. 1989, 6, 221. (d)
Hudlicky, T.; Seoane, G.; Price, J . D.; Gadamasetti, K. G. Synlett 1990,
433. (e) Dai, W.-M.; Nagao, Y.; Fujita, E. Heterocycles 1990, 30, 1231.
(f) Robins, D. J . Nat. Prod. Rep. 1993, 10, 487.
10.1021/jo9907383 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/11/1999

6772 J . Org. Chem., Vol. 64, No. 18, 1999
Kim et al.
Sch em e 1
Sch em e 2
5-Epitashiromine (6) was obtained by way of LAH
reduction of lactam 24, followed by desilylation (Scheme
2). These alkaloids were characterized most conveniently
as the borane complexes.11 In passing, we note that the
borane complexes of the trans indolizidines 7 and 8 exist
as two conformational isomers, while only one isomer is
possible for those of the cis isomers 5 and 6, as well as
the pyrrolizidines 1-4. Treatment of the borane com-
plexes with acid furnished the target compounds. Spec-
troscopic data of these pyrrolizidine and indolizidine
alkaloids were found to be in excellent agreement with
literature values.1-3,9-12
mediates. Such a divergent synthesis can be considered
advantageous, since stereoisomers are frequently en-
countered in the naturally occurring alkaloids.
As prototypical examples, reduction of the methyl
derivatives 11 and 12 was first examined.7 Catalytic
hydrogenation of 11 with PtO2 (in EtOAc) in the presence
of a small amount of chloroform as the source of HCl8
afforded exclusively 15 in 90% yield.9 Excellent diaste-
reoselectivity (15:1) was also observed for hydrogenation
of indolizidinone 12 to provide 17 (92%). Reduction with
NaCNBH3 (TFA, MeOH) furnished the corresponding
trans10 isomers 16 and 18 with high selectivity (16: 12:
1, 78-85%; 18: 10:1, 85%).
These reduction protocols were next extended to alco-
hols 13 and 14. Catalytic hydrogenation of 13 under
identical conditions (H2, PtO2, CHCl3-EtOAc) produced
the cis10 isomer 19 in greater than 10:1 diastereoselec-
tivity (85% yield). In contrast, hydrogenation of the
homologue 14 proved to be troublesome due to concomi-
tant overreduction of the desired product 21; despite
considerable experimentation under several different
conditions, coproduction of 17 could not be avoided. This
complication was circumvented by protection of the
primary alcohol prior to reduction (Scheme 2). Thus,
hydrogenation of the TIPS ether 23 took place smoothly
to afford 24 as a single product (94%). Reduction of 13
and 14 with NaCNBH3 reduction (TFA, MeOH) was
uneventful, and good to excellent diastereoselectivity was
observed to furnish the respective lactams 20 (>15:1,
60%-80%) and 22 (20:1, 55-75%).
Discu ssion
Hydrogenation in the presence of Adams catalyst was
first employed for â-enamino esters during the prepara-
tion of pyrrolizidine alkaloids.9a Uniformly high diaste-
reoselectivity was also found in additional examples on
catalytic hydrogenation of related pyrrolizidine, indolizi-
dine, and quinolizidine derivatives.7,9 As outlined in
Scheme 3, the enamides 27 are believed to be the
substrates for hydrogenation. This is supported by our
recent observation that hydrogenation of isomers 29 and
30 under identical conditions produces the same lactam
31 as a sole product.6b Facile formation of 17 in catalytic
Finally, treatment of the lactams 15-20 and 22 with
LAH or diborane (ether, reflux) afforded the correspond-
ing pyrrolizidines and indolizidines in good yields.
(11) For an elegant use of borane for blocking reactivity at the
pyrrolizidine nitrogen, see: White, J . D.; Amedio, J . C., J r.; Gut, S.;
Ohira, S.; J ayasinghe, L. R. J . Org. Chem. 1992, 57, 2270.
(12) The spectroscopic data of these target alkaloids 1-8 were found
to be in excellent agreement with those reported in the literature: (a)
Pandey, G.; Reddy, G. D.; Chakrabarti, D. J . Chem. Soc., Perkin Trans.
1 1996, 219 and Pandey, G.; Reddy, G. D. Tetrahedron Lett. 1992, 33,
6533. (b) Knight, D. W.; Share, A. C.; Gallagher, P. T. J . Chem. Soc.,
Perkin Trans. 1 1997, 2089. Hart, D. J .; Tsai, Y.-M. J . Am. Chem. Soc.
1984, 106, 8209. Mori, M.; Kanda, N.; Oda, I.; Ban, Y. Tetrahedron
1985, 41, 5465. (c) Coldham, I.; Hufton, R.; Snowden, D. J . J . Am.
Chem. Soc. 1996, 118, 5322. (d) Pearson, W. H.; Walavalkar, R.;
Schkeryantz, J . M.; Fang, W.-k.; Blickensdorf, J . D. J . Am. Chem. Soc.
1993, 115, 10183. (e) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1994,
59, 1613.
(7) For a general review on reduction of enamines or enamides,
see: Pitacco, G.; Valentin, E. In The Chemistry of Enamines; Rap-
poport, Z., Ed.; Wiley: New York, 1994; Chapter 17, p 923.
(8) Cf. Secrist, J . A., III; Logue, M. W. J . Org. Chem. 1972, 37, 335.
(9) For related hydrogenation of enamides or enamines, see: (a)
Leonard, N. J .; Sato, T. J . Org. Chem. 1969, 34, 1066. (b) Muchowski,
J . M.; Nelson, P. H. Tetrahedron Lett. 1980, 21, 4585. (c) Miyano, S.;
Fujii, S.; Yamashita, O.; Toraishi, N.; Sumoto, K. J . Org. Chem. 1981,
46, 1737.
(10) (a) The cis/trans nomenclature refers to the relative stereo-
chemistry of the two methine hydrogens. (b) For stereoselective
NaCNBH3 reduction of iminium compounds, see: Ohnuma, T.; Tabe,
M.; Shiiya, K.; Ban, Y. Tetrahedron Lett. 1983, 24, 4249.

Titanium-Mediated Cyclization of ω-Vinyl Imides
J . Org. Chem., Vol. 64, No. 18, 1999 6773
Sch em e 3
a thiol) steps of imides precede the key carbon-carbon
bond formation. On the other hand, the titanium-medi-
ated annulation utilizes the imide function directly for
ring closure. As illustrated in the present work, subse-
quent stereoselective reduction of the N-acylaminal group
provides stereocontrolled access to several specific ste-
reoisomers; the resulting stereochemistry is complemen-
tary to that available from nucleophilic additions to
N-acyliminium ions or R-acylamine radical cyclizations.
Moreover, the N-acylaminal functionality allows consid-
erable flexibility for further elaboration (e.g., a new
carbon-carbon bond construction).
In conclusion, the titanium-mediated annulation reac-
tion of readily available vinyl tethered imides offers a
new method for carbon-carbon bond construction in
alkaloid synthesis. Synthetic studies toward structurally
complex natural products, as well as the development of
an enantioselective process, are currently under way and
will be reported in due course.
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e Tita n iu m -Med ia ted
Cou p lin g of ω-Vin yl Im id es. P r ep a r a tion of (1R*,2R*)-
1-Hyd r oxy-2-m eth yl-6-a za bicyclo[4.3.0]n on a n -7-on e (12).
A solution of the imide 10 (167 mg, 1.0 mmol) in THF (10 mL)
was treated with ClTi(O-i-Pr)3 (1.0 mL of a 1 M hexane
solution) at room temperature. After the reaction mixture was
cooled to 0 °C, cyclopentylmagnesium chloride (1.5 mL of a 2
M Et2O solution; commercially available from Aldrich) in THF
(5 mL) was added during 30 min (via syringe pump). The
mixture was stirred for 20 min, followed by addition of a
mixture of water (0.9 mL) and Et2O (10 mL) and subsequent
stirring for an additional hour at room temperature and drying
with MgSO4. The resultant suspension was filtered through
Celite, and the filter cake was thoroughly washed with Et2O.
The combined filtrate and washings were concentrated in
vacuo to afford the crude product. Purification by column
chromatography on silica gel (8:1.7:0.3 CH2Cl2-EtOAc-
MeOH) afforded 93 mg (55%) of 12: IR (CHCl3) 3367, 1671
Sch em e 4
1
cm-1; H NMR (360 MHz, CDCl3) δ 3.83 (br dd, J ) 12.9, 4.9
Hz, 1 H), 3.45 (br s, -OH, 1 H), 2.84 (ddd, J ) 12.9, 3.6, 1.1
Hz, 1 H), 2.50 (m, 1 H), 2.26 (ddd, J ) 15.3, 10.0, 3.2 Hz, 1 H),
2.12-1.93 (m, 2 H), 1.68 (m, 1 H), 1.58-1.30 (m, 4 H), 0.98 (d,
J ) 6.6 Hz, 3 H); 13C NMR (90 MHz, CDCl3) δ 173.6, 90.1,
41.7, 36.3, 32.6, 29.1, 27.9, 24.6, 15.2; HRMS (M+) calcd for
C9H15NO2 169.1103, found 169.1107.
hydrogenation of the alcohol 14 is believed to involve the
intermediate 28 generated from the enamide.
(1R*,2R*)-1-Hydr oxy-2-m eth yl-5-azabicyclo[3.3.0]octan -
The cyanoborohydride reduction of indolizidine 12 in
acidic methanol was first reported by Ban and co-workers
to take place with a high degree of trans stereoselectiv-
ity,10 which complements cis stereochemistry produced
by catalytic hydrogenation. The stereoselective formation
of the trans indolizidine 18 can be rationalized in terms
of a stereoelectronically preferred axial attack of hydride
ion on the immonium ion bearing the equatorially placed
methyl group. Under carefully controlled conditions at
low temperatures, NaCNBH3 reduction can be carried out
without the involvement of the enamide. For example,
no epimerization was observed at the methyl-bearing
stereocenter during reduction (3.0 equiv of NaCNBH3,
1.5 equiv of TFA, MeOH) of 30 at -78 °C in the prep-
aration of the trans product (structure not shown).6b
Finally, it is noteworthy that the titanium-mediated
coupling-reduction sequence of bicyclic ω-vinyl imides
offers a viable, alternate approach to the well-known
synthetic methods involving nucleophilic additions to
N-acyliminium ions or R-acylamine radical cyclizations
(Scheme 4). In the latter known approaches, the obliga-
tory partial reduction and exchange (with an alcohol or
1
6-on e (11): IR (CHCl3) 3344, 1660 cm-1; H NMR (360 MHz,
CDCl3) δ 3.35 (m, 1 H), 3.20 (dd, J ) 10.9, 9.9 Hz, 1 H), 2.96
(dt, J ) 17.1, 9.3 Hz, 1 H), 2.39 (ddd, J ) 17.1, 9.3, 2.7 Hz, 1
H), 2.20-1.93 (m, 4 H), 1.80 (m, 1 H), 1.05 (d, J ) 6.7 Hz, 3
H); 13C NMR (90 MHz, CDCl3) δ 174.8, 97.6, 43.2, 40.0, 33.7,
33.0, 32.5, 11.9; HRMS (M+) calcd for C8H13NO2 155.0946,
found 155.0951.
Rep r esen ta tive P r oced u r e for th e Tita n iu m -Med ia ted
Cou p lin g of ω-Vin yl Im id es, F ollow ed by Oxid a tive
Wor k u p . P r ep a r a tion of (1R*,2S*)-1-Hyd r oxy-2-h yd r oxy-
m eth yl-6-a za bicyclo[4.3.0]n on a n -7-on e (14). To a solution
of the imide 10 (58 mg, 0.35 mmol) in THF (4 mL) was added
ClTi(O-i-Pr)3 (0.35 mL of a 1 M hexane solution) at room
temperature. After the reaction mixture was cooled to 0 °C,
cyclopentylmagnesium chloride (0.6 mL of a 2 M Et2O solution;
commercially available from Aldrich) in THF (5 mL) was added
during 20 min (via syringe pump). The mixture was then
stirred for an additional 20 min, and oxygen was bubbled
through the mixture for 20 min. A mixture of water (0.5 mL)
and Et2O (5 mL) was added. The resulting suspension was
filtered through Celite, and the filter cake was thoroughly
washed with Et2O. The combined filtrate and washings were
concentrated in vacuo to afford the crude product. The residue
was purified using basic alumina column chromatography (8:

6774 J . Org. Chem., Vol. 64, No. 18, 1999
Kim et al.
1.6:0.4 CH2Cl2-EtOAc-MeOH) to provide 39 mg (60%) of the
acylaminal 14, which was used immediately for the next
(1S*,2S*)-2-Hyd r oxym eth yl-5-a za bicyclo[3.3.0]octa n -6-
on e (19): IR (neat) 3390, 1662, 1424 cm-1; 1H NMR (360 MHz,
CDCl3) δ 4.08 (apparent q, J ) 7.2 Hz, 1 H), 3.63 (dd, J )
10.6, 7.1 Hz, 1 H), 3.54 (dd, J ) 10.6, 7.7 Hz, 1 H), 3.55-3.50
(m, 1 H), 3.03-2.96 (m, 1 H), 2.70-2.60 (m, 2 H), 2.41 (dd, J
) 7.8, 3.9 Hz, 1 H), 2.41 (dd, J ) 7.8, 4.2 Hz, 1 H), 2.31-2.24
(m, 1 H), 2.17-2.04 (m, 2 H), 1.95-1.87 (m, 1 H); 13C NMR
(90 MHz, CDCl3) δ 175.0, 63.3, 61.5, 40.6, 40.1, 34.8, 30.0, 21.4.
(1S*,2S*)-2-Hyd r oxym eth yl-6-a za bicyclo[4.3.0]n on a n -
7-on e (21): 1H NMR (360 MHz, CDCl3) δ 4.10 (m, 1 H), 3.81
(dd, J ) 10.6, 6.5 Hz, 1 H), 3.70 (td, J ) 3.6, 7.0 Hz, 1 H), 3.59
(dd, J ) 10.6, 6.9 Hz, 1 H), 2.66 (td, J ) 5.2, 12.4 Hz, 1 H),
2.35-2.30 (m, 2 H), 2.09-1.94 (m, 4 H), 1.87 (br s, 1 H, -OH),
1.60-1.41 (m, 3 H); 13C NMR (90 MHz, CDCl3) δ 174.3, 59.9,
59.3, 40.3, 39.1, 30.4, 26.5, 20.5, 19.1.
Rep r esen ta tive P r oced u r e for Sod iu m Cya n obor oh y-
d r id e R ed u ct ion of N-Acyla m in a ls. P r ep a r a t ion of
(1S*,2R*)-2-Hyd r oxym eth yl-6-a za bicyclo[4.3.0]n on a n -7-
on e (22). A mixture of 14 (140 mg, 0.76 mmol) and NaBH3-
CN (143 mg, 2.27 mmol) in methanol (5 mL) was cooled to
-78 °C, and TFA (0.25 mL of a 3.0 M MeOH solution) was
added. The mixture was stirred at -78 °C for 2 h and then at
room temperature for an additional 10 h. After water (3 mL)
was added, the mixture was extracted with CH2Cl2 (2 × 10
mL), dried with MgSO4, filtered, and concentrated. The residue
was purified by SiO2 chromatography (9:1 CH2Cl2-MeOH) to
afford 71 mg (55%) of 22: IR (neat) 1694, 1462 cm-1; 1H NMR
(360 MHz, CDCl3) δ 4.11 (br dd, J ) 11.4, 4.3 Hz, 1 H), 3.66
(dd, J ) 10.8, 4.5 Hz, 1 H), 3.58 (dd, J ) 10.8, 5.4 Hz, 1 H),
3.25 (m, 1 H), 2.56 (td, J ) 12.7, 3.2 Hz, 1 H), 2.38-2.23 (m,
3 H), 1.97-1.89 (m, 1 H), 1.88-1.68 (m, 3 H), 1.43-1.25 (m, 3
H); 13C NMR (90 MHz, CDCl3) δ 173.8, 64.3, 59.0, 46.0, 39.9,
30.5, 27.0, 24.5, 24.0; HRMS (M+) calcd for C9H15NO2 169.1103,
found 169.1080.
step: IR (neat) 3350, 1668, 1450 cm-1 1H NMR (360 MHz,
;
CDCl3) δ 4.11 (s, -OH, 1 H), 4.02 (dd, J ) 11.2, 2.1 Hz, 1 H),
3.91 (br dd, J ) 13.0, 4.9 Hz, 1 H), 3.73 (br d, J ) 11.2 Hz, 1
H), 2.92 (ddd, J ) 13.0, 13.0, 2.9 Hz, 1 H), 2.61-2.53 (m, 1 H),
2.51-2.44 (br s, -OH, 1 H), 2.38-2.20 (m, 2 H), 2.16-1.92
(m, 2 H), 1.89-1.81 (m, 1 H), 1.59-1.40 (m, 3 H); HRMS (M+
- H2O) calcd for C9H13NO2 167.0946, found 167.0964.
(1R*,2S*)-1-H yd r oxy-2-h yd r oxym et h yl-5-a za b icyclo-
[3.3.0]octa n -6-on e (13): IR (neat) 3365, 1673, 1454 cm-1; 1H
NMR (360 MHz, CDCl3) δ 3.92 (dd, J ) 12.3, 3.8 Hz, 1 H),
3.78 (dd, J ) 12.3, 6.6 Hz, 1 H), 3.53-3.45 (m, 1 H), 3.28 (br
t, J ) 9.9 Hz, 1 H), 3.02-2.92 (m, 1 H), 2.43 (td, J ) 5.9, 16.9
Hz, 1 H), 2.27-2.22 (m, 3 H), 2.18-2.01 (m, 2 H); 13C NMR
(90 MHz, CDCl3) δ 174.7, 98.1, 60.5, 49.3, 39.8, 34.0, 33.6, 27.3.
This compound was also characterized as the mono-TIPS
ether: 1H NMR (360 MHz, CDCl3) δ 4.19 (br s, 1 H, -OH),
4.07 (dd, J ) 10.5, 3.5 Hz, 1 H), 3.91 (dd, J ) 10.5, 5.5 Hz, 1
H), 3.53 (dt, J ) 11.7, 8.3 Hz, 1 H), 3.31 (br t, J ) 11.7 Hz, 1
H), 2.99 (dt, J ) 16.8, 9.2, 1 H), 2.41 (ddd, J ) 16.8, 9.2, 2.4
Hz, 1 H), 2.30 (m, 1 H), 2.22 (m, 2 H), 2.13 (m, 1 H), 2.04 (m,
1 H), 1.06 (m, 21 H); 13C NMR (90 MHz, CDCl3) δ 174.2, 97.8,
61.6, 49.0, 39.5, 34.3, 33.5, 27.4, 17.9, 11.7; HRMS (M+ - H2O)
calcd for C17H31NO2Si 309.2124, found 309.2120.
(1R *,2S *)-1-H yd r oxy-2-t r iisop r op ylsiloxym e t h yl-6-
a za bicyclo[4.3.0]n on a n -7-on e (23). To a solution of the
alcohol 14 (24 mg, 0.14 mmol) in CH2Cl2 (2 mL) were added
NEt3 (0.1 mL, 1.0 mmol) and TIPSOTf (43 µL, 0.16 mmol)
sequentially at 0 °C. The mixture was stirred at room tem-
perature for 8 h, quenched with water (5 mL), and extracted
with CH2Cl2 (2 × 15 mL). The combined extracts were washed
with brine, dried with MgSO4, and concentrated in vacuo. The
residue was purified by short column chromatography (1:1
hexanes-EtOAc) to give 37 mg (85%) of 23: IR (neat) 3390,
(1S*,2R*)-2-Meth yl-5-a za bicyclo[3.3.0]octa n -6-on e (16):
IR (neat) 1670, 1458 cm-1; 1H NMR (360 MHz, CDCl3) δ 3.46
(dt, J ) 11.7, 8.1 Hz, 1 H), 3.39 (td, J ) 8.0, 7.2 Hz, 1 H), 3.10
(br t, J ) 11.7 Hz, 1 H), 2.66 (m, 1 H), 2.39 (ddd, J ) 16.7, 9.7,
2.2 Hz, 1 H), 2.26-2.15 (m, 2 H), 1.73-1.53 (m, 3 H), 0.99 (d,
J ) 6.3 Hz, 3 H); 13C NMR (90 MHz, CDCl3) δ 174.6, 68.1,
1
1674, 1464 cm-1; H NMR (360 MHz, CDCl3) δ 4.70 (s, -OH,
1 H), 4.17 (dd, J ) 10.3, 2.6 Hz, 1 H), 3.89 (br dd, J ) 13.1,
4.9 Hz, 1 H), 3.80 (dd, J ) 10.3, 2.7 Hz, 1 H), 2.94 (td, J )
13.1, 2.6 Hz, 1 H), 2.61 (m, 1 H), 2.35-2.16 (m, 2 H), 2.15-
1.97 (m, 2 H), 1.83 (m, 1 H), 1.62-1.41(m, 3 H), 1.11 (m, 21
H); 13C NMR (90 MHz, CDCl3) δ 173.6, 90.2, 64.4, 46.6, 36.0,
33.7, 29.0, 24.4, 23.6; HRMS (M+ - H2O) calcd for C18H33NO2-
Si 323.2281, found 323.2271.
40.9, 40.5, 35.5, 34.8, 25.1, 15.2; HRMS (M+) calcd for C8H13
NO 139.0997, found 139.1003.
-
(1S*,2R*)-2-Meth yl-6-azabicyclo[4.3.0]n on an -7-on e (18):
1
IR (neat) 1687 cm-1; H NMR (360 MHz, CDCl3) δ 4.07 (ddt,
Rep r esen ta tive P r oced u r e for Ca ta lytic Hyd r ogen a -
tion of N-Acyla m in a ls. P r ep a r a tion of (1S*,2S*)-2-Tr i-
isop r op ylsiloxym et h yl-6-a za b icyclo[4.3.0]n on a n -7-on e
(24). A solution of 23 (7 mg, 0.02 mmol) in EtOAc (3.5 mL)
was treated with PtO2 (3.5 mg) and CHCl3 (3.8 µL, 0.04 mmol).
The mixture was stirred under an atmosphere of hydrogen
(balloon) for 4 h and filtered through Celite, and the filter cake
was rinsed thoroughly with EtOAc. The combined filtrates
were concentrated in vacuo to afford 6 mg (90%) of 24: IR
(neat) 1694, 1462 cm-1; 1H NMR (360 MHz, CDCl3) δ 4.11 (br
d, J ) 12.0, 1 H), 3.85 (dd, J ) 10.2, 6.8 Hz, 1 H), 3.68 (m, 1
H), 3.59 (dd, J ) 10.2, 6.6 Hz, 1 H), 2.65 (td, J ) 12.0, 5.4 Hz,
1 H), 2.39-2.28 (m, 2 H), 2.14 (m, 1 H), 2.08-1.95 (m, 3 H),
1.54-1.41 (m, 3 H), 1.05 (m, 21 H); 13C NMR (90 MHz, CDCl3)
δ 174.3, 60.7, 59.3, 40.3, 39.6, 30.5, 26.8, 20.5, 19.3, 18.2, 11.9.
J ) 12.8, 4.8, 1.3 Hz, 1 H), 2.90 (td, J ) 9.3, 7.5 Hz, 1 H), 2.52
(td, J ) 12.8, 3.5 Hz, 1 H), 2.31 (m, 2 H), 2.19 (m, 1 H), 1.77
(br d, J ) 12.9 Hz, 1 H), 1.65 (br d, J ) 12.8 Hz, 1 H), 1.55 (m,
1 H), 1.35 (qdd, J ) 12.8, 4.8, 3.6 Hz, 1 H), 1.16 (m, 1 H), 1.09
(m, 1 H), 0.88 (d, J ) 6.3 Hz, 3 H); 13C NMR (90 MHz, CDCl3)
δ 173.5, 63.0, 39.8, 38.7, 32.5, 30.4, 24.4, 23.9, 17.3; HRMS
(M+) calcd for C9H15NO 153.1154, found 153.1151.
(1S*,2R*)-2-Hyd r oxym et h yl-5-a za bicyclo[3.3.0]oct a n -
1
6-on e (20): IR (neat) 3380, 1666, 1443 cm-1; H NMR (360
MHz, acetone-d6) δ 3.78 (t, J ) 5.1 Hz, 1 H, -OH), 3.66 (m, 2
H), 3.55 (m, 1 H), 3.45 (dt, J ) 11.1, 8.6 Hz, 1 H), 2.97 (m, 1
H), 2.51 (m, 1 H), 2.32-2.08 (m, 3 H), 1.88-1.76 (m, 3 H); 13
C
NMR (90 MHz, CDCl3) δ 174.7, 65.2, 63.5, 47.9, 40.6, 34.9,
30.0, 26.7; HRMS (M+) calcd for C8H13NO2 155.0946, found
155.0949.
(1S*,2S*)-2-Meth yl-5-a za bicyclo[3.3.0]octa n -6-on e (15):
IR (neat) 1683, 1456 cm-1; 1H NMR (360 MHz, CDCl3) δ 3.98
(td, J ) 7.4, 5.7 Hz, 1 H), 3.49 (dt, J ) 11.5, 7.6 Hz, 1 H), 3.03
(br t, J ) 11.5 Hz, 1 H), 2.68 (td, J ) 16.7, 9.5 Hz, 1 H), 2.41
(ddd, J ) 16.7, 9.8, 2.8 Hz, 1 H), 2.23-2.13 (m, 2 H), 2.05-
1.96 (m, 1 H), 1.88-1.80 (m, 1 H), 1.78-1.69 (m, 1 H), 0.84 (d,
J ) 7.1 Hz, 3 H); 13C NMR (90 MHz, CDCl3) δ 174.9, 64.5,
39.3, 34.9, 34.7, 33.0, 20.8, 13.4.
(1S*,2S*)-2-Meth yl-6-a za bicyclo[4.3.0]n on a n -7-on e (17):
IR (neat) 1668, 1442 cm-1; 1H NMR (360 MHz, CDCl3) δ 4.11
(ddd, J ) 12.5, 4.6, 3.8 Hz, 1 H), 3.64 (ddd, J ) 8.2, 4.6, 3.9 1
H), 2.63 (td, J ) 12.5, 4.4 Hz, 1 H), 2.36-2.31 (m, 2 H), 2.03
(m, 1 H), 1.92 (m, 1 H), 1.80-1.56 (m, 4 H), 1.45-1.39 (m, 1
H), 0.90 (d, J ) 7.1 Hz 3 H); 13C NMR (90 MHz, CDCl3) δ 173.9,
60.3, 40.2, 31.2, 30.8, 30.3, 20.6, 18.2, 11.1; HRMS (M+) calcd
for C9H15NO 153.1154, found 153.1179.
Rep r esen ta tive P r oced u r e for LAH Red u ction of La c-
t a m s. P r ep a r a t ion of (1S*,2S*)-2-Tr iisop r op ylsiloxy-
m eth yl-6-a za bicyclo[4.3.0]n on a n e (25). To a solution of the
lactam 24 (8 mg, 25 µmol) in Et2O (4 mL) was added LAH (8
mg, 0.2 mmol, 8.0 equiv) at 0 °C. The reaction mixture was
refluxed for 10 min and quenched with water followed by 15%
NaOH solution. The resulting mixture was then stirred for
an additional 10 min, diluted with THF (10 mL), dried with
MgSO4, and filtered through Celite. The filter cake was rinsed
thoroughly with THF. The combined filtrate and rinsings were
concentrated in vacuo to afford 5.7 mg (74%) of 25. The crude
product was used for the next step without purification: IR
1
(neat) 1462 cm-1; H NMR (360 MHz, CDCl3) δ 3.88 (dd, J )
9.9, 5.3 Hz, 1 H), 3.72 (dd, J ) 9.9, 8.0 Hz, 1 H), 3.03-2.93
(m, 2 H), 2.13-1.88 (m, 5 H), 1.73-1.27 (m, 7 H), 1.20 (m, 21
H).

Titanium-Mediated Cyclization of ω-Vinyl Imides
J . Org. Chem., Vol. 64, No. 18, 1999 6775
(()-Heliotr id a n e (1).12a Characterized as the borane com-
MHz, CDCl3) δ 70.2, 64.5, 51.6, 27.3, 25.1, 21.8, 21.7, 19.0,
18.5; HRMS (M+ - H) calcd for C9H19BN 152.1611, found
152.1597.
plex: IR (neat) 2965, 2360, 2266, 1168 cm-1 1H NMR (360
;
MHz, CDCl3) δ 3.57 (td, J ) 8.7, 7.6 Hz, 1 H), 3.42 (m, 1 H),
3.17 (td, J ) 12.0, 6.2 Hz, 1 H), 2.93 (ddd, J ) 12.0, 7.4, 1.5
Hz, 1 H), 2.74 (td, J ) 10.4, 6.0 Hz, 1 H), 2.54 (m, 1 H), 2.02
(m, 1 H), 1.94-1.78 (m, 2 H), 1.64-1.49 (m, 3 H), 1.01 (d, J )
6.9 Hz, 3 H); 13C NMR (90 MHz, CDCl3) δ 76.9, 65.0, 63.5,
(()-5-Ep ita sh ir om in e (6).12e A solution of 25 (5.3 mg) in
THF (4 mL) was treated with a solution of TBAF (0.037 mL
of a 1.0 M solution in THF). After the mixture was stirred at
room temperature for 6 h, it was concentrated in vacuo to
afford the crude product. The residue was purified using
silica gel column chromatography (10:2:0.2 CH2Cl2-MeOH-
NH4OH) to provide 6 (2.8 mg, 83%): IR (neat) 3373, 1462,
34.7, 31.4, 27.4, 24.9, 13.8; HRMS (M+ - H) calcd for C8H17
-
BN 138.1454, found 138.1460.
(()-Isor etr on eca n ol (2).12b Characterized as the free base
1
1379, 1327 cm-1; H NMR (360 MHz, CDCl3) δ 4.18 (dd, J )
and also as the borane complex: IR (neat) 3420, 2972, 2371,
1
2311, 2264, 1166 cm-1; H NMR (360 MHz, CDCl3) δ 3.76-
10.7, 4.0 Hz, 1 H), 3.74 (br d, J ) 10.7 Hz, 1 H), 3.15-3.07 (m,
1 H), 3.05-3.00 (m, 1 H), 2.32-2.24 (m, 1 H), 2.12-1.96 (m, 3
H), 1.95-1.67 (m, 6 H), 1.63-1.45 (m, 2 H); 13C NMR (90 MHz,
CDCl3) δ 66.8, 65.7, 54.5, 53.5, 35.3, 30.6, 25.8, 23.3, 20.8;
HRMS (M+) calcd for C9H17NO 155.1310, found 155.1320.
3.64 (m, 3 H), 3.43 (m, 1 H), 3.24 (td, J ) 11.6, 6.6 Hz, 1 H),
2.99 (ddd, J ) 11.6, 7.7, 2.4 Hz, 1 H), 2.83-2.69 (m, 2 H), 2.12-
1.97 (m, 3 H), 1.87 (m, 1 H), 1.71-1.55 (m, 2 H), 1.34 (t, J )
5.0 Hz, 1 H, -OH); 13C NMR (90 MHz, CDCl3) δ 74.8, 64.5,
62.9, 62.4, 43.0, 27.1, 26.7, 24.8; HRMS (M+ - H) calcd for
C8H17BNO 154.1403, found 154.1406.
(()-Meth ylin d olizid in e (7).12a Characterized as the borane
complex: IR (neat) 2957, 1462 cm-1 1H NMR (360 MHz,
;
(()-P seu d oh eliotr id a n e (3).12c Characterized as the bo-
rane complex: IR (neat) 2963, 2360, 2874, 2361, 2313, 2266,
1457, 1169 cm-1; 1H NMR (360 MHz, CDCl3) δ 3.45-3.39 (m,
1 H), 3.22 (m, 1 H), 3.13 (ddd, J ) 11.4, 9.9, 6.2 Hz, 1 H), 2.93
(ddd, J ) 11.4, 6.6, 4.2 Hz, 1 H), 2.77 (m, 1 H), 2.14 (m, 1 H),
2.00-1.75 (m, 5 H), 1.63 (m, 1 H), 1.18 (d, J ) 6.1 Hz, 3 H);
13C NMR (90 MHz, CDCl3) δ 80.5, 64.2, 63.7, 41.6, 33.0, 30.1,
24.4, 17.6; HRMS (M+ - H) calcd for C8H17BN 138.1454, found
138.1463.
CDCl3) δ 3.14-3.03 (m, 3 H), 2.93 (td, J ) 10.1, 2.9 Hz, 1 H),
2.82 (dd, J ) 10.7, 7.3 Hz, 1 H), 2.54 (m, 1 H), 2.22 (m, 1 H),
1.86 (m, 1 H), 1.77-1.54 (m, 4 H), 1.27 (m, 1 H), 1.12 (qd, J )
12.3, 4.1 Hz, 1 H), 0.91 (d, J ) 6.4 Hz, 3 H); 13C NMR (90
MHz, CDCl3) δ 72.2, 56.2, 54.0, 31.9, 31.2, 27.8, 20.6, 20.0,
19.6; HRMS (M+ - H) calcd for C9H19BN 152.1611, found
152.1584.
(()-Ta sh ir om in e (8):12e IR (neat) 3356, 2931, 1460 cm-1
;
1H NMR (360 MHz, CDCl3) δ 3.61 (dd, J ) 10.9, 4.7 Hz, 1 H),
3.44 (dd, J ) 10.9, 6.5 Hz, 1 H), 3.09-3.02 (m, 2 H), 2.04 (q,
J ) 9.1 Hz, 1 H), 1.97-1.82 (m, 3 H), 1.80-1.40 (m, 7 H), 1.02
(qd, J ) 12.8, 4.7 Hz, 1 H); 13C NMR (90 MHz, CDCl3) δ 65.8,
65.0, 53.6, 52.1, 44.1, 28.5, 27.1, 24.6, 20.2; HRMS (M+) calcd
for C9H17NO 155.1310, found 155.1314.
(()-Tr a ch ela n th a m id in e (4).12b As the free base: 13C
NMR (90 MHz, CDCl3) δ 68.0, 65.6, 54.8, 54.5, 48.1. 31.8, 29.8,
25.7. Also characterized as the borane complex: IR (neat) 3438,
2972, 2877, 2361, 2316, 1167 cm-1; 1H NMR (360 MHz, CDCl3)
δ 3.72 (dd, J ) 10.4, 6.4 Hz, A of AB q, 1 H), 3.70 (dd, J )
10.4, 6.4 Hz, B of AB q, 1 H), 3.48-3.37 (m, 2 H), 3.19 (ddd, J
) 10.8, 8.8, 6.4 Hz, 1 H), 2.98-2.82 (m, 2 H), 2.18 (m, 1 H),
2.11-1.85 (m, 5 H), 1.75 (m, 1 H); 13C NMR (90 MHz, CDCl3)
δ 76.2, 64.6, 63.9, 63.1, 49.0, 31.8, 28.0, 24.5; HRMS (M+ - H)
calcd for C8H17BNO 154.1403, found 154.1411.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM35956) for generous financial sup-
port.
(()-Meth ylin d olizid in e (5).12d Characterized as the borane
complex: IR (neat) 2959, 1462 cm-1 1H NMR (360 MHz,
;
Su p p or tin g In for m a tion Ava ila ble: Photocopies of the
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
CDCl3) δ 3.24 (m, 1 H), 3.14-2.98 (m, 2 H), 2.75 (br d, J )
11.6 Hz, 1 H), 2.59-2.43 (m, 2 H), 2.26 (qt, J ) 13.5, 4.5 Hz,
1 H), 1.96-1.75 (m, 4 H), 1.57-1.43 (m, 2 H), 1.15 (qd, J )
13.5, 4.3 Hz, 1 H), 0.86 (d, J ) 7.0 Hz, 3 H); 13C NMR (90
J O9907383