Efficient and practical method for synthesizing N-heterocyclic compounds using intramolecular nucleophilic acyl substitution reactions mediated by Ti(O-i-Pr)4/2i-PrMgx reagent. Synthesis of quinolones, pyrroles, indoles, and optically active N-

Article abstract of DOI:10.1021/ja970810j

Treatment of N-(2- or 3-alkynyl)amino esters with a low-valent titanium reagent diisopropoxy(η²-propene)titanium (1), generated in situ by the reaction of Ti(O-i-Pr)₄ and 2i-PrMgCl, resulted in an intramolecular nucleophilic acyl sub

Full text of DOI:10.1021/ja970810j

6984
J. Am. Chem. Soc. 1997, 119, 6984-6990
Efficient and Practical Method for Synthesizing N-Heterocyclic
Compounds Using Intramolecular Nucleophilic Acyl
Substitution Reactions Mediated by Ti(O-i-Pr)4/2i-PrMgX
Reagent. Synthesis of Quinolones, Pyrroles, Indoles, and
Optically Active N-Heterocycles Including Allopumiliotoxin
Alkaloid 267A
Sentaro Okamoto, Masayuki Iwakubo, Katsushige Kobayashi, and Fumie Sato*
Contribution from the Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226, Japan
ReceiVed March 12, 1997X
Abstract: Treatment of N-(2- or 3-alkynyl)amino esters with a low-valent titanium reagent diisopropoxy(η2-propene)-
titanium (1), generated in situ by the reaction of Ti(O-i-Pr)4 and 2i-PrMgCl, resulted in an intramolecular nucleophilic
acyl substitution (INAS) reaction to afford R-alkylidene-pyrrolidinones or -piperidinones. Thus, treatment of
N-propargyl-anthranilates 5, -indole-2-carboxylates 10, or -pyrrole-2-carboxylates 13 with 1 gave 4-quinolones 7,
[1,2-a]indoles, or [1,2-a]pyrroles, respectively. Similarly, N-alkynylated R- or â-amino esters 14 or 15 with 1 afforded
N-heterocycles 18 or 19. In the reaction of N-(2- or 3-alkenyl)amino esters with 1, the resulting INAS product
underwent intramolecular carbonyl addition (ICA) reaction to afford the N-heterocyclic compounds having a
cyclopropanol moiety in good to excellent yields. Thus, the treatment of N-alkenyl-anthranilate 4a, -indole-2-
carboxylates 8 and 9, or -pyrrole-2-carboxylates 11 and 12 with 1 gave the corresponding quinoline derivative 6a,
[1,2-a]indoles, or [1,2-a]pyrroles, respectively. The optically active N-heterocyclic compounds 20 and 21 were
obtained from N-alkenylated R- or â-amino esters 16 or 17. A highly efficient total synthesis of allopumiliotoxin
alkaloid 267A has also been accomplished. Thus, the N-propargyl-2[(1-hydroxy-1-methoxycarbonyl)ethyl]pyrrolidine
24 (from L-proline in six steps) reacted with 1 to afford the corresponding indolidinone 25 in 67% yield, which has
previously been converted to allopumiliotoxin 267A.
Heterocyclic compounds containing nitrogen are widely
(O-i-Pr)2 (1) in an essentially quantitative yield and that 1 acts
as a versatile titanium(II) equivalent.3 In the course of our
studies to develop synthetic methodology based on this reagent,
we have revealed that the reaction with acetylenic esters 2 results
in an intramolecular nucleophilic acyl substitution (INAS)
reaction to afford organotitanium compounds having a carbonyl
functional group in good to excellent yields.4 We5 and the Cha
group6 also independently found that in the reaction with olefinic
ester 3, the resulting INAS products undergo intramolecular
carbonyl addition (ICA) reaction to afford cyclopropanol
derivatives. The mechanistic sequence responsible for these
processes is shown in Scheme 1.
distributed in nature, many of which display important biological
activities; moreover, a vast number of natural and synthetic
N-heterocyclic compounds have found applications as pharma-
ceuticals and agricultural chemicals. A large number of
N-heterocycles also have found practical uses as dyestuffs,
copolymers, antioxidants, and vulcanization accelerators in the
rubber industry and as valuable intermediates in synthesis. The
synthesis of N-heterocyclic compounds, therefore, has attracted
much interest and a variety of synthetic methodologies have
been developed, as many reviews, monographs, and reports have
been released.1 Despite the wide availability of synthetic
methods for these compounds, there still exists a need for
developing more efficient new procedures or methods which
allow the synthesis of optically active compounds. Recent
efforts in this research field have focused on the use of transition
metals.2 However, in comparison with transition-metal-based
routes to carbocyclic systems, routes to N-heterocyclic com-
pounds so far have been explored to a much lesser extent.
Recently, we have found that the reaction of Ti(O-i-Pr)4 with
2 equiv of i-PrMgX (X ) Cl or Br) provides (η2-propene)Ti-
X Abstract published in AdVance ACS Abstracts, July 1, 1997.
(1) General reviews: ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press, New York, 1984. AdVances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York,
1963-1996.
(2) For reviews: Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96,
223. Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96, 271. Negishi, E.;
Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. ReV. 1996, 96, 365. Ojima,
I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2442.
Ohshiro, Y.; Hirao, T. Heterocycles, 1984, 22, 859. For leading refer-
ences: Buchwald, S. L.; Wannamaker, M. W.; Watson, B. T. J. Am. Chem.
Soc. 1989, 111, 776. Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61,
2594 and see also ref 10b.
We have now found that these titanium-mediated INAS and
tandem INAS-ICA reactions open up a method for synthesizing
a variety of N-heterocyclic compounds.2,7 Reported herein are
(i) the synthesis of quinolone, pyrrole, and indole derivatives,
(3) The generation of olefin(derived from the added Grignard reagent)-
titanium complexes of the type (η2-olefin)Ti(O-i-Pr)2 from Ti(OR)4 and
Grignard reagents was first reported by Kulinkovich et al. They utilized
this complex as 1,2-bis-anionic species; see: Kulinkovich, O. G.; Sviridov,
S. V.; Vasilevski, D. A. Synthesis 1991, 234. For the initial reports on the
use of the olefin-titanium complex as a divalent titanium reagent, see:
Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1995,
117, 3881. Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36,
3203. See, also: Takayanagi, Y.; Yamashita, K.; Yoshida, Y.; Sato, F. J.
Chem. Soc., Chem. Commun. 1996, 1725.
(4) (a) Kasatkin, A.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1995, 36,
6075. (b) Zubaidha, P. K.; Kasatkin, A.; Sato, F. J. Chem. Soc., Chem.
Commun. 1996, 197. (c) Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato,
F. J. Am. Chem. Soc. 1996, 118, 2208. (d) Yoshida, Y.; Okamoto, S.; Sato,
F. J. Org. Chem. 1996, 61, 7826.
(5) (a) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 6079. (b)
Kasatkin, A.; Kobayashi, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1996,
37, 1849.
(6) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 291.
S0002-7863(97)00810-X CCC: $14.00 © 1997 American Chemical Society

Synthesizing N-Heterocyclic Compounds
J. Am. Chem. Soc., Vol. 119, No. 30, 1997 6985
Scheme 1
Scheme 2
their reactions with 1, in anticipation that the reaction might
afford quinolone derivatives.9 When a mixture of the N-
allylated derivative 4a and Ti(O-i-Pr)4 was treated with 2 equiv
of i-PrMgCl in ether at -78 °C to room temperature over 2 h,
the expected tandem INAS-ICA reaction product 6a was
obtained in excellent yield, after hydrolysis, as shown in eq 1.
On the other hand, the N-crotylated substrate 4b which has the
(ii) the synthesis of optically active N-heterocycles from chiral
R- and â-amino acids, and (iii) the application of the reaction
for preparing allopumiliotoxin 267A, a dendrobatid alkaloid.
disubstituted double bond did not afford the corresponding
INAS-ICA product. This may be due to steric hindrance as
was observed in the reaction of 1 with olefinic esters 3.4c The
reaction with the N-propargylated compounds 5a,b also pro-
ceeded as expected to afford the corresponding INAS reaction
products 7 in good yields by the reaction with 1; the presence
of an intermediate alkenyltitanium species before the aqueous
workup of the reaction mixture was confirmed by deuterolysis
(eq 2).
Results and Discussion
Synthesis of Quinolone, Pyrrole, and Indole Derivatives.8
As N-allylated and -propargylated anthranilic acid derivatives
4 and 5 can be readily prepared from anthranilic acid ethyl ester
according to the procedure shown in Scheme 2, we carried out
(7) For the transition-metal-based routes to N-heterocyclic compounds
Via the intramolecular carbon-carbon bond forming reaction, see the
following most recent papers and references cited therein: Ti: Hicks, F.
A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 11688. Pd: Goeke, A.;
Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1996,
35, 662. Comins, D. L.; Joseph, S. P.; Zhang, Y.-mei Tetrahedron Lett.
1996, 37, 793. Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Geneˆt, J.-
P. Tetrahedron Lett. 1996, 37, 2003. Yun, W.; Mohan, R. Tetrahedron Lett.
1996, 37, 7189. McAlonan, H.; Montgomery, D.; Stevenson, P. J.
Tetrahedron Lett. 1996, 37, 7151. Rigby, J. H.; Mateo, M. E. Tetrahedron,
1996, 52, 10569. Jiang, H.; Ma, S.; Zhu, G.; Lu, X. Tetrahedron 1996, 52,
10945. Grigg, R.; Sansano, J. M. Tetrahedron 1996, 52, 13441. Boger, D.
L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996,
118, 2109. Latham, E. J.; Stanforth, S. P. J. Chem. Soc., Chem. Commun.
1996, 2253. Ni: Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado,
A. J. Org. Chem. 1996, 61, 5895. Wender, P. A.; Smith, T. E. J. Org.
Chem. 1996, 61, 824. Rh: Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski,
G. A. Angew. Chem., Int. Ed. Engl. 1996, 35, 220. McMills, M. C.; Wright,
D. L. Zubkowski, J. D.; Valente, E. J. Tetrahedron Lett. 1996, 37, 7205.
Doyle, M. P.; Kalinin, A. V. J. Org. Chem. 1996, 61, 2179. Huwe, C. M.;
Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376, and
see also ref 10b. Ru: Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61,
8356. Maarseveen, van J. H.; Hartog, den J. A. J.; Engelen, V.; Finner, E.;
Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996, 37, 8249. Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606. Mo:
Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.; Marshall,
E. L.; Procopiou, P. A. J. Chem. Soc., Chem. Commun. 1997, 55. Martin,
S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pa¨zel. M. Ramser, M. N.;
Wagman, A. S. Tetrahedron 1996, 52, 7251. Co: Krafft, M. E.; Wilson,
A. M.; Dasse, O. A.; Shao, B.; Cheung, Y. Y.; Fu, Z.; Bonaga, L. V. R.;
Mollman, M. K. J. Am. Chem. Soc. 1996, 118, 6080. Alcaide, B.; Polanco,
C.; Sierra, M. A. Tetrahedron Lett. 1996, 37, 6901. Cu: Kondo, Y.;
Matsudaira, T.; Sato, J.; Murata, N.; Sakamoto, T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 736. Baldovini, N.; Bertrand, M.-P.; Carriere, A.; Nouguier,
R.; Plancher, J.-M. J. Org. Chem. 1996, 61, 3205. Lim, H.-J.; Sulikowski,
G. A. Tetrahedron Lett. 1996, 37, 5243. Mn: Galazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron 1996, 52, 1069. Sm, Y: Ha, D.-C.; Yun, C.-S.;
Yu, E. Tetrahedron Lett. 1996, 37, 2577. Aoyagi, Y.; Manabe, T.; Ohta,
A.; Kurihara, T.; Pang, G.-L.; Yuhara, T. Tetrahedron 1996, 52, 869.
Molander, G. A.; Nichols, P. J. J. Org. Chem. 1996, 61, 6040.
Fused [1,2-a]indoles (annulated indoles) represent the basic
skeleton of many naturally occurring indole alkaloids and
pharmaceutically important compounds.10 One attractive method
to construct the [1,2-a]indole-nucleus is annulation of a new
ring to the skeleton of indoles. Since indole 2-carboxylic acid
easily undergoes N-alkylation, thus providing 8, 9, and 10, we
carried out their reaction with 1. As can be seen from Table 1
(entries 1-4), the expected tandem INAS-ICA or INAS reaction
products were obtained in good to excellent yields from 8, 9,
and 10. Similarly, the reaction of 1 with methyl 2-pyrrolecar-
boxylate derivatives having an N-allyl, homoallyl, or propargyl
(9) Reviews on synthesis and utility of quinolones, see: Meth-Cohn, O.
Heterocycles 1993, 35, 539. Radl, S.; Bouzard, D. Heterocycles 1992, 34,
2143. Jones, G. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 2, pp 395-
510. For some recent examples for synthesis of quinolones: Roy, K.;
Srivastava, R. P.; Tekwani, B. L.; Pandey, V. C.; Bhaduri, A. P. Bioorg.
Med. Chem. Lett. 1996, 6, 121. Gao, F.; Johnson, K. F.; Schlenoff, J. B. J.
Chem. Soc., Perkin Trans. 2 1996, 269.
(10) For some recent approaches to fused [1,2-a]indoles, see: (a)
Caddick, S.; Aboutayab, K.; Jenkins, K.; West, R. I. J. Chem. Soc., Perkin
Trans. 1 1996, 675. (b) Wee, A. G. H.; Slobodian, J. J. Org. Chem. 1996,
61, 2897 and references cited therein. For a review of earlier approaches,
see: Verboom, W.; Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1986,
105, 199.
(8) For a preliminary account of this work, see ref 5b.

6986 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Okamoto et al.
Table 1. Synthesis of [1,2-a]Indoles and [1,2-a]Pyrroles by
Titanium(II)-Mediated INAS and INAS-ICA Reactions
Scheme 4
Table 2.a Synthesis of Optically Active N-Heterocycles from
N-Alkylated R- or â-Amino Acid Esters and 1
a Prepared from pyrrole- or indole-2-carboxylate by the reaction with
the corresponding allyl, homoallyl, propargyl, or homopropargyl
bromide in the presence of K2CO3 in CH3CN (65-89% yield).
b Conditions: A; -78 °C to room temperature over 2 h then H2O, B;
-78 to -50 °C over 1 h, -50 °C to -40 °C for 2 h and then H2O at
-40 °C. c Isolated yield. d Deuterolysis of the reaction mixture gave
the product containing >98% D.
Scheme 3
a Reaction conditions: Ti(O-i-Pr)4 (1.3 equiv), i-PrMgCl (2.6 equiv),
ether, -78 °C to room temperature, over 4 h for 16 and 17 or -50 to
-40 °C, 1.5 h for 14 and 15. b The substrates 14 and 16 were prepared
1
from the corresponding L-amino acids. c Yield was determined by H
NMR analysis (by using an internal standard) of the crude product
which was obtained by passing through a pad of silica gel after usual
workup followed by concentration in vacuo and had >90% purity (wt
%). Owing to somewhat low stability on column chromatography, the
pure product could not be isolated. The identification of the product
was also carried out by converting into the corresponding allyl alcohols
by treatment with NaBH4 and CeCl3 in methanol (48-74% yield).18
d Deuterolysis with D2O gave the product with >95% D. e Isolated yield.
f >98% ee.18 g Ratio of two diastereomers. Their relative stereochem-
istries were not determined.
moiety, i.e., 11, 12, or 13 (prepared from pyrrole-2-carboxyl-
ate),11 proceeded as expected to afford, after hydrolysis, [1,2-
a]pyrrole derivatives in good to excellent yields.12 The results
are also shown in Table 1 (entries 5-8).
In summary, the INAS and INAS-ICA reactions mediated
by 1 allow practical access to quinolone, pyrrole, and indole
derivatives from readily available starting materials. Notewor-
thy also is the fact that the products thus synthesized have a
versatile 1-hydroxybicyclo[n.1.0]alkane13 or conjugated enone14
moiety, thus allowing further structural manipulation.
Synthesis of Optically Active Pyrrolidine and Piperidine
Derivatives. Many naturally occurring N-heterocyclic com-
pounds have stereogenic center(s) in the heterocyclic ring; thus,
the development of an enantioselective route to access to
N-heterocycles from readily available nonracemic starting
(13) For the synthetic utility of 1-hydroxybicyclo[n.1.0]alkanes: Re-
views: Ryu, I.; Sonoda, N. J. Syn. Org. Chem. Jpn. 1985, 43, 112.
Nakamura, E. J. Syn. Org. Chem. Jpn. 1989, 47, 931. Kuwajima, I.;
Nakamura, E. Top. Curr. Chem. 1990, 133, 1. Kuwajima, I.; Nakamura, E.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, UK, 1991; Vol. 2, pp 441-454. A leading reference: Sugimura,
T.; Futagawa, T.; Mori, A.; Ryu, I.; Sonoda, N.; Tai, A. J. Org. Chem.
1996, 61, 6100.
(11) Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851 and
references cited therein.
(12) For a review for synthesis of fused [1,2-a]pyrroles, see: Flitsch,
W. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: New York, 1984; Vol. 3, pp 443-495. For
recent syntheses, see: Barluenga, J.; Toma´s, M.; Kouznetsov, V.; Sua´rez-
Sobrino, A.; Rubio, E. J. Org. Chem. 1996, 61, 2185 and references cited
therein.
(14) For the reaction of conjugated enones, see: Patai, S.; Rappoport,
Z., Eds. The Chemistry of Enones; Wiley: Chichester, 1989; Vol 1. Ullenius,
C.; Christenson, B. Pure Appl. Chem. 1988, 60, 57.

Synthesizing N-Heterocyclic Compounds
J. Am. Chem. Soc., Vol. 119, No. 30, 1997 6987
materials has attracted much interest. Starting from optically
active R- and â-amino acids and/or their esters, we planned the
reaction sequence shown in Scheme 3 in anticipation that the
reaction might afford nonracemic N-heterocycles.
Scheme 5a
Starting from natural R-amino acids such as L-phenylalanine,
L-serine, L-gultamic acid, and L-proline, the corresponding
N-allylated, -homoallylated, -propargylated, and/or -homopro-
pargylated methyl esters were synthesized according to the
conventional reaction sequence shown in Scheme 4 and were
subjected to the reactions with 1. The results are summarized
in Table 2. The reaction with the phenyl alanine derivatives
14a and 14b resulted in a smooth INAS reaction providing the
corresponding pyrrolidine and piperidine derivatives 18a and
18b after hydrolysis (entries 1 and 2 in Table 2), while the
corresponding olefinic derivatives 16a and 16b furnished the
INAS-ICA reaction products 20a and 20b, respectively, in
excellent yields (entries 9 and 10). Similarly, from the serine
and glutamic acid derivatives, the corresponding INAS and/or
INAS-ICA products were obtained (entries 3-5 and 11). In
the reaction with proline derivatives, however, only N-homopro-
pargylated compound 14g provided the expected indolizine
derivative 18g (entry 7). The results that 14f, 16d, and 16e
did not afford the expected products (entries 6, 12, and 13) may
be attributable to the fact that the formation of the corresponding
bicyclic transition state leading to INAS products is disfavored
conformationally, because the side chains containing a carbon-
carbon unsaturated bond and an ester group are situated anti to
each other.4c
a (a) Anisole, CH2Cl2, room temperature, 30 min; (b) THF, -78 °C,
1 h; (c) room temperature, 12 h; (d) i-Pr2NEt, THF, room temperature,
2 days; (e) ether, -50 °C to -5 °C over 3 h then H2O or D2O; (f)
Me4NBH(OAc)3, acetone-HOAc, room temperature, 2 days.
amphibian (Dendrobatidae) alkaloids and displays significant
cardiotoxic activity.19
The reaction of the N-Boc-protected (S)-2-acetylpyrrolidine
(22)20c with trifluoroacetic acid in the presence of anisole
provided (S)-2-acetylpyrrolidine trifluoroacetate salt which was
treated with an excess of tris(methylthio)methyl lithium (5 equiv)
in tetrahydrofuran at -78 °C to give the tertiary alcohol 23 in
78% yield with >94:6 diastereoselectivity.21 The tris(meth-
ylthio)methyl group of 23 was converted to a methyl ester group
by treatment with Hg(ClO4)2-H2O in methanol-chloroform, and
then the resulting hydroxyl ester was N-alkylated by the reaction
with (R)-1-bromo-4-methyl-2-octyne22 (65% yield from 23). The
hydroxyl ester 24 thus prepared was subjected to the titanium-
mediated INAS reaction. Accordingly, 24 was reacted with 1.5
equiv of Ti(O-i-Pr)4 and then 4.0 equiv of i-PrMgCl23 in ether
at -78 °C to -5 °C to provide the indolidinone 25 in 67%
yield. The compound 25 has already been synthesized by
Overman as a precursor of allopumiliotoxin 267A, and identity
N-Propargylated and -allylated â-amino esters 15 and 17,
readily prepared by diastereoselective Michael addition of
N-propargylated and -allylated R-phenylethylamine to crotonic
acid ester according to the Davies protocol (eq 3),15 also afforded
the corresponding piperidine derivatives by treatment with 1.
The results are shown in entries 8 and 14 in Table 2.
was established by comparison of the spectral data (1H and 13
C
NMR, MS, IR).20c Finally, a stereospecific reduction of the
keto group in 25 under the Overman conditions afforded (+)-
allopumiliotoxin 267A (96%).24 So far, total syntheses of
allopumiliotoxin 267A have been accomplished by three groups,
and all of them started with N-protected L-proline.20 Compared
The reaction developed here, which allows the synthesis of
optically active pyrrolidine and piperidine derivatives, is practi-
cal since the starting materials are readily available, and the
reaction is operationally simple. Noteworthy also is the fact
that the synthesis reported here represents one of the most
straightforward routes to N-heterocycles from R- or â-amino
acids16 and involves a carbon-carbon bond connection at an
unprecedented position.17
Total Synthesis of Allopumiliotoxin Alkaloid 267A. In an
extension of our methodology for preparation of N-heterocycles
from R- and â-amino acids, we carried out the total synthesis
of a (+)-allopumiliotoxin alkaloid 267A from L-proline (Scheme
5). The target substance is one of the pumiliotoxin A class of
(18) See Experimental Section.
(19) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter
1. Daly, J. W.; Garraffo, H. M.; Spande, T. F. Alkaloids 1993, 43, 185.
(20) (a) Overman, L. E.; Goldstein, S. W.; J. Am. Chem. Soc. 1984, 106,
5360. (b) Overman, L. E.; Robinson, L. A.; Zablocki, J. J. Am. Chem. Soc.
1992, 114, 368. (c) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H.
J. Org. Chem. 1992, 57, 1179. (d) Caderas, C.; Lett, R.; Overman, L. E.;
Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem.
Soc. 1996, 118, 9073. (e) Trost, B. M.; Scanlan, T. S. J. Am. Chem. Soc.
1989, 111, 4988. (f) Aoyagi, S.; Wang. T.-C.; Kibayashi, C. J. Am. Chem.
Soc. 1992, 114, 10653. (g) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am.
Chem. Soc. 1993, 115, 11393. For a review of the total synthesis of
pumiliotoxin A and allopumiliotoxin alkaloids: Franklin, A. S.; Overman,
L. E. Chem. ReV. 1996, 96, 505.
(15) Davies, S. G.; Hedgecock, C. J. R.; McKenna, J. M. Tetrahedron:
Asymmetry 1995, 6, 827 and references cited therein.
(16) Recent review: Tisler, M.; Kolar, P. AdV. Heterocycl. Chem. 1995,
64, 1.
(17) Synthesis of N-heterocycles from amino acids by Dieckmann
condensation which involves the connection at the acid group directly by
using its reactivity has been reported: King, F. E.; King, T. J.; Warwick,
A. J. J. Chem. Soc. 1950, 3590. Brochmann, H.; Stahler, E. A. Naturwis-
senschaften 1965, 52, 391. Katz, E.; Mason, K. T.; Mauger, A. B. Biochem.
Biophys. Res. Commun. 1975, 63, 502. Hershenson, F. M. J. Org. Chem.
1975, 40, 1260. Imai, N.; Terao, Y.; Achiwa, K.; Sekiya, M. Tetrahedron
Lett. 1984, 25, 1579.
(21) Similar high diastereoselectivity was reported in the reaction of 22
with 1-lithio-1-methoxyallene20c or 2-lithio-1,3-dithiane.20f,g
(22) Prepared from (R)-4-methyloct-2-yn-1-ol20g by treatment with CBr4
and PPh3.
(23) Because of the presence of a hydroxyl group in 24, 1 equiv excess
of i-PrMgCl was used.
(24) The spectroscopic data were in good agreement with those reported
in the literature.20c,g

6988 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Okamoto et al.
119.93, 119.52, 108.54, 96.23, 52.98, 36.74, 21.99, 21.18, 17.02; IR
(Nujol) 3380, 2950, 1625, 1325. Anal. Calcd for C13H13NO: C, 78.36;
H, 6.58; N, 7.03. Found: C, 78.33; H, 6.73; N, 6.89.
to these methods, the present synthesis was the shortest (seven
steps) and gave the highest overall yield (27% from N-protected
L-proline). Noteworthy also is the fact that, as deuterolysis of
the reaction mixture of 1 and 24 gave a deuterated compound
26 (>98% D), the present method enables the synthesis of C(10)
deuterium (and probably tritium) labeled allopumiliotoxin 267A.
Pyrrolo[1,2-a]cyclopropa[3,4]pyrrolidin-3-ol (entry 5, Table 1):
1H NMR (300 MHz) δ 6.46 (dd, J ) 3.0, 1.2, 1H), 6.18 (t, J ) 3.0,
1H), 6.00 (dd, J ) 3.4, 1.2, 1H), 4.23 (dd, J ) 11.4, 5.7, 1H), 3.70 (d,
J ) 11.4, 1H), 2.76 (br s, 1H). 2.17 (m, 1H), 1.67 (dd, J ) 9.3, 5.7,
1H), 0.91 (t, J ) 5.3, 1H); 13C NMR (75 MHz) δ 138.48, 113.89,
112.04, 98.35, 61.14, 48.47, 27.48, 23.63; IR (Nujol) 3800, 1580, 1330.
Anal. Calcd for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.01; H, 7.10; N, 7.39.
Pyrrolo[1,2-a]cyclopropa[3,4]piperidin-3-ol (entry 6, Table 1):
1H NMR (300 MHz) δ 6.51 (dd, J ) 2.6, 1.8, 1H), 6.22 (dd, J ) 3.5,
1.7, 1H), 6.12 (t, J ) 3.2, 1H), 3.88 (ddd, J ) 12.9, 5.9, 1.9, 1H), 3.43
(dt, J ) 4.7, 12.9, 1H), 2.16 (ddt, J ) 3.3, 5.6, 13.0, 1H), 2.00 (m,
1H), 1.64 (m, 1H), 1.30 (dd, J ) 9.9, 6.0, 1H), 1.00 (t, J ) 6.0, 1H);
13C NMR (75 MHz) δ 132.86, 119.08, 107.05, 102.87, 52.95, 40.56,
21.51, 21.04, 16.24; IR (Nujol) 3150, 2890, 1630, 1319. Anal. Calcd
for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 71.97; H, 7.61;
N, 9.51.
Procedure for the Reaction of Acetylenic Substrates. To a stirred
solution of N-propargyl- or N-homopropargyl compound 5, 10, or 13
(1.0 mmol) and Ti(O-i-Pr)4 (325 µL, 1.3 mmol) in ether (8-10 mL)
was added i-PrMgCl or i-PrMgBr (1.1-1.7 M in ether, 2.6 mmol) at
-78 °C. The resulting mixture was gradually warmed to -50 °C over
0.5-1 h and stirred for 1-2 h at -50 °C ∼ -40 °C. After addition of
saturated aqueous NaHCO3 (1.0 mL) at -40 °C, the mixture was
warmed to ambient temperature. NaF (2 g) and Celite (2 g) were added,
and the resulting mixture was stirred for 1 h at room temperature. The
mixture was filtered through a pad of Celite, and the filterate was
concentrated in Vacuo. The residue was purified by column chroma-
tography on silica gel to afford the N-heterocycles having a R-alkylidene
ketone moiety.
(E)-1-Benzyl-1,2,3,4-tetrahydro-3-trimethylsilylmethylene-4-qui-
nolone (7a): 1H NMR (300 MHz) δ 8.04 (dd, J ) 1.8, 7.8, 1H), 7.31
(m, 6H), 6.98 (t, J ) 1.8, 1H), 6.75 (m, 2H), 4.54 (s, 2H), 4.24 (d, J
) 1.7, 2H), 0.07 (s, 9H); 13C NMR (75 MHz) δ 189.42, 151.86, 145.91,
138.05, 136.96, 135.49, 129.65, 128.92, 127.44, 127.28, 117.76, 113.12,
54.49, 53.87, -0.74; IR (neat) 2980, 1630, 1583, 1300. Anal. Calcd
for C20H23NOSi: C, 74.72; H, 7.21; N, 4.36. Found: C, 74.61; H,
7.38; N, 4.67.
Conclusion
We have developed a highly efficient method for the
preparation of N-heterocyclic compounds such as quinolone,
indole, and pyrrole derivatives and optically active pyrrolidine
and piperidine derivatives by using the titanium(II)-mediated
INAS or INAS-ICA reaction. The reaction is practical since
the starting organic substrates are readily available. Nontoxic,
inexpensive metallic starting materials are used, and the
procedure is operationally simple. Moreover, the N-heterocycles
obtained here contain a versatile 1-hydroxybicyclo[n.1.0]-
alkane13 or conjugated enone14 moiety. Thus, the reaction may
find wide applicability for synthesizing a variety of N-
heterocyclic compounds.
Experimental Section
General Methods. Infrared spectra were reported in cm-1
.
1H
NMR spectra were measured at 300 MHz with CDCl3 as a solvent at
ambient temperature and the chemical shifts were described in parts
per million downfield from tetramethylsilane (δ ) 0 ppm) or based on
residual CHCl3 (δ ) 7.26 ppm) as an internal standard. 13C NMR
spectra were recorded at 75 MHz with CDCl3 as a solvent and
referenced to the central line of the solvent (δ ) 77.0 ppm). The
coupling constants (J) are reported in hertz. All experiments were
conducted under argon atmosphere in oven-dried flasks. Tetrahydro-
furan and diethyl ether were distilled from sodium benzophenone ketyl
immediately prior to use. The procedure for preparation of the starting
materials 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 and their
spectroscopic data were given in Supporting Information.
Synthesis of Quinolone, [1,2-a]Indole and [1,2-a]Pyrrole Deriva-
tives by Titanium-Mediated INAS or Tandem INAS-ICA Reaction.
Procedure for the Reaction of Olefinic Substrates. To a stirred
solution of N-allyl- or N-homoallyl compound 4, 8, 9, 11, 12, 16, or
17 (1.0 mmol) and Ti(O-i-Pr)4 (385 µL, 1.30 mmol) in ether (6-8
mL) was added i-PrMgCl or i-PrMgBr (1.1-1.8 M in ether, 2.60 mmol)
at -78 °C. The resulting mixture was gradually warmed to room
temperature over 2-2.5 h. After addition of tetrahydrofuran (5 mL)
and water (2.4 mL), the mixture was stirred for 30 min. The organic
layer was separated, and the residue was washed with ether (2 × 10
mL). The combined organic layers were dried over anhydrous
magnesium sulfate and concentrated in Vacuo. The crude product was
purified by column chromatography on silica gel to give the N-
heterocyclic compound having a cyclopropanol moiety.
(E)-1-Benzyl-1,2,3,4-tetrahydro-3-heptylidene-4-quinolone (7b):
1H NMR (300 MHz) δ 8.04 (dd, J ) 1.7, 7.9, 1H), 7.31 (m, 6H), 6.87
(t, J ) 7.7, 1H), 6.75 (t, J ) 7.4, 1H), 6.68 (d, J ) 8.4, 1H), 4.59 (s,
2H), 4.22 (s, 2H), 2.06 (q, J ) 7.4, 2H), 1.43 (m, 2H), 1.25 (m, 6H),
0.87 (t, J ) 6.8, 3H). Anal. Calcd for C23H27NO: C, 82.84; H, 8.16;
N, 4.20. Found: C, 82.11; H, 8.35; N, 4.59.
(E)-4-Trimethylsilylmethyleneindolo[1,2-a]pyrrolidin-3-one (en-
try 3, Table 1): yellow crystalline (recrystallized from hexane); mp
1
125.0-126.5 °C; H NMR (300 MHz) δ 7.77 (d, J ) 8.3, 1H), 7.41
1-Benzylbenzo[b]cyclopropa[3,4]piperidin-4-ol (6a): 1H NMR
(300 MHz) δ 7.62 (dd, J ) 1.7, 7.5, 1H), 7.28 (m, 5H), 7.05 (dt, J )
1,7, 7.8, 1H), 6.83 (t, J ) 7.2, 1H), 6.61 (d, J ) 8.3, 1H), 4.46 (d, J
) 15.5, 1H), 4.22 (d, J ) 15.5, 1H), 3.14 (d, J ) 2.1, 2H), 1.88 (m,
1H), 1.51 (t, J ) 5.5, 1H), 1.23 (dd, J ) 5.0, 9.6, 1H); 13C NMR (75
MHz) δ 142.32, 138.21, 128.83, 128.48, 127.37, 126.91, 126.66, 124.30,
118.00, 112.22, 54.55, 53.27, 45.20, 28.95, 16.47; IR (neat) 3250, 2980,
2950, 1320, 1210. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N,
5.57. Found: C, 80.91; H, 7.20; N, 5.78.
Indolo[1,2-a]cyclopropa[3,4]pyrrolidin-3-ol (entry 1, Table 1):
1H NMR (300 MHz) δ 7.54 (dd, J ) 7.5, 1.5, 1H), 7.09 (m, 3H), 6.33
(s, 1H), 4.18 (dd, J ) 10.7, 5.5, 1H), 3.83 (d, J ) 10.7, 1H), 2.90 (br
s, 1H), 2.31 (m, 1H), 1.76 (dd, J ) 9.4, 5.9, 1H), 1.01 (t, J ) 5.4, 1H);
13C NMR (75 MHz) δ 145.46, 132.88, 132.56, 120.97, 120.81, 119.38,
108.98, 91.99, 60.81, 46.38, 28.42, 24.00; IR (neat) 3340, 2960, 1615,
1332, 1225. Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56.
Found: C, 77.62; H, 6.31; N, 7.83.
(m, 2H), 7.20 (m, 1H), 7.15 (s, 1H), 7.11 (t, J ) 2.3, 1H), 4.99 (d, J
) 2.3, 2H), 0.29 (s, 9H); 13C NMR (75 MHz) δ 181.10, 148.91, 135.73,
134.90, 132.10, 131.80, 125.46, 124.14, 121.68, 110.47, 100.86, 45.59,
-1.09; IR (Nujol) 1702, 1630, 1543, 1353. Anal. Calcd for C15H17-
NOSi: C, 70.54; H, 6.71; N, 5.48. Found: C, 70.17; H, 6.98; N, 5.66.
(E)-4-Heptylideneindolo[1,2-a]pyrrolidin-3-one (entry 4, Table
1
1): H NMR (300 MHz) δ 7.76 (d, J ) 8.2, 1H), 7.38 (m, 2H), 7.19
(m, 1H), 7.09 (d, J ) 1.1, 1H), 6.88 (tt, J ) 7.8, 2.2, 1H), 4.91 (d, J
) 2.2, 2H), 2.30 (q, J ) 7.4, 2H), 1.57 (m, 2H), 1.33 (m, 6H), 0.90 (t,
J ) 6.7, 3H); 13C NMR (75 MHz) δ 182.00, 138.10, 137.79, 136.24,
134.57, 131.72, 125.18, 124.03, 121.44, 110.33, 99.96, 43.96, 31.62,
29.83, 29.09, 28.33, 22.53, 14.03; IR (Nujol) 1708, 1652, 1543, 1350.
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
80.58; H, 8.20; N, 5.27.
(E)-4-Trimethylsilylmethylenepyrrolo[1,2-a]pyrrolidin-3-one (en-
1
try 7, Table 1): H NMR (300 MHz) δ 7.08 (dd, J ) 2.2, 1.1, 1H),
6.94 (t, J ) 2.2, 1H), 6.86 (dd, J ) 4.4, 1.1, 1H), 6.52 (dd, J ) 4.0,
2.2, 1H), 4.86 (d, J ) 2.3, 2H), 0.22 (s, 9H); 13C NMR (75 MHz) δ
177.69, 149.37, 133.08, 122.15, 116.64, 109.46, 107.79, 47.66, -1.08;
IR (Nujol) 1725, 1660, 1560, 1348. Anal. Calcd for C11H15NOSi: C,
64.35; H, 7.36; N, 6.82. Found: C, 64.15; H, 7.46; N, 6.71.
Indolo[1,2-a]cyclopropa[3,4]piperidin-3-ol (entry 2, Table 1):
yellow crystalline (recrystallized from hexane); mp 52.0-53.5 °C; 1H
NMR (300 MHz) δ 7.56 (dd, J ) 7.0, 1.2, 1H), 7.15 (m, 3H), 6.57 (s,
1H), 4.21 (dt, J ) 13.1, 3.8, 1H), 3.41 (dt, J ) 11.9, 9.2, 1H), 2.81 (br
s, 1H), 2.16 (m, 2H), 1.81 (m, 1H), 1.40 (dd, J ) 10.0, 6.2, 1H), 1.13
(t, J ) 6.3, 1H); 13C NMR (75 MHz) δ 140.64, 136.05, 128.03, 120.63,
(E)-4-Heptylidenepyrrolo[1,2-a]pyrrolidin-3-one (entry 8, Table
1): 1H NMR (300 MHz) δ 7.04 (d, J ) 1.7, 1H), 6.81 (m, 1H), 6.70

Synthesizing N-Heterocyclic Compounds
J. Am. Chem. Soc., Vol. 119, No. 30, 1997 6989
(tt, J ) 7.8, 2.1, 1H), 6.50 (dd, J ) 4.0, 2.3, 1H), 4.86 (d, J ) 2.2,
2H), 2.21 (q, J ) 7.6, 2H), 1.52 (m, 2H), 1.42-1.25 (m, 6H), 0.89 (t,
J ) 6.6, 3H); 13C NMR (75 MHz) δ 178.90, 136.34, 135.30, 135.25,
121.84, 116.26, 108.39, 45.89, 31.53, 29.50, 28.94, 28.30, 22.45, 13.95;
IR (neat) 2960, 1718, 1663, 1543, 1329. Anal. Calcd for C14H19NO:
C, 77.38; H, 8.81; N, 6.45. Found: C, 77.11; H, 9.11; N, 6.37.
Synthesis of Optically Active N-Heterocyclic Compounds from
r- or â-Amino Acid Derivatives. Typical Procedure for the
Reaction of Acetylenic Substrates 14 or 15. To a stirred solution of
14d (432 mg, 1.0 mmol) and Ti(O-i-Pr)4 (385 µL, 1.3 mmol) in ether
(10 mL) was added i-PrMgCl (1.94 mL, 1.34 M in ether, 2.6 mmol) at
-78 °C. The resulting mixture was gradually warmed to -50 °C over
1 h and stirred for 2 h at -50 °C ∼ -40 °C. After addition of aqueous
saturated NaHCO3 (0.8 mL) at -40 °C, the mixture was warmed to
ambient temperature. NaF (3 g) and Celite (3 g) were added, and the
resulting mixture was stirred for 30 min at room temperature and filtered
through a pad of Celite. The filtrate was concentrated in Vacuo to
afford the crude product with >90% chemical purity (wt %, determined
146.70, 138.73, 137.50, 134.36, 129.63, 128.70, 128.33, 128.22, 127.22,
126.22, 70.05, 59.18, 54.43, 36.40, -1.34. Optical purity of 18a was
confirmed by the same method as used for 18d, and it was found that
no racemization occurred in these reactions.
(E,S)-1,2-Dibenzyl-4-trimethylsilylmethylene-3-piperidinone (18b):
1H NMR δ 7.15-7.33 (m, 10H), 6.70 (s, 1H), 3.90 (d, J ) 13.5, 1H),
3.56 (d, J ) 13.7, 1H), 3.49 (t, J ) 6.0, 1H), 3.13 (dd, J ) 6.0, 13.7,
1H), 3.20 (dd, J ) 5.5, 13.9, 1H), 3.05 (m, 1H), 3.04-3.14 (m, 1H),
2.55 (m, 1H), 2.51-2.73 (m, 2H), 0.13 (s, 3H); 13C NMR δ 200.45,
148.24, 139.13, 138.31, 129.69, 128.58, 128.22, 127.96, 127.04, 126.12,
71.69, 58.28, 45.70, 36.14, 29.22, -0.85.
(E,S)-1-Benzyl-2-[(tert-butyldimethylsilyl)oxy]methyl-4-trimeth-
1
ylsilylmethylene-3-pyrrolidinone (18c): H NMR δ 7.22-7.43 (m,
5H), 6.70 (t, J ) 2.6, 1H), 4.34 (d, J ) 13.4, 1H), 4.09 (dd, J ) 2.5,
10.6, 1H), 3.85 (dd, J ) 5.2, 10.6, 1H), 3.83 (dd, J ) 2.5, 14.3, 1H),
3.75 (d, J ) 13.4, 1H), 3.33 (dd, J ) 2.7, 14.3, 1H), 3.17 (dd, J ) 2.3,
5.2, 1H), 0.87 (s, 9H), 0.09 (s, 9H), 0.04 and 0.08 (2s, each 3H).
1
1
by H NMR analysis). The yield of 18d was 78% determined by H
NMR analysis of the crude residue using an internal standard. In this
reaction procedure use of D2O (0.8 mL) instead of aqueous saturated
aqueous NaHCO3 gave the product contained >98% D at the olefinic
(E,S)-1-Benzyl-2-(2-methoxycarbonyl)ethyl-4-trimethylsilylmeth-
ylene-3-pyrrolidinone (18e): 1H NMR δ 7.20-7.42 (m, 5H), 6.71 (dd,
J ) 2.3, 2.6, 1H), 4.16 (d, J ) 13.2, 1H), 3.80 (dt, J ) 14.6, 1.4, 1H),
3.64 (s, 3H), 3.42 (d, J ) 13.2, 1H), 3.08 (dd, J ) 3.3, 14.6, 1H), 2.93
(m, 1H), 1.90-2.60 (m, 4H), 0.08 (s, 9H).
1
position which was determined by H NMR analysis. Purification of
18d proved difficult, as this compound decomposed on attempted silica
gel chromatography as well as distillation. Thus the crude enone was
reduced with CeCl3-NaBH4 in MeOH to the corresponding allylic
alcohol (234 mg, 58% yield from 14d, as a mixture of two diastereomers
in a ratio of 70:30).
(S)-1-Aza-4-trimethylsilylmethylenebicyclo[4.3.0]nonan-5-one (18g):
1H NMR δ 6.78 (s, 1H), 3.03-3.25 (m, 2H), 2.72-2.88 (m, 3H), 2.53
(dt, J ) 16.1, 8.9, 1H), 2.38 (q, J ) 12.2, 1H), 1.55-2.18 (m, 4H),
0.17 (s, 9H); 13C NMR δ 198.1, 148.0, 138.6, 71.1, 54.4, 49.7, 30.6,
25.3, 21.7, -0.8.
(E,S)-1-Benzyl-2-[(tert-butyldimethylsilyl)oxy]methyl-3-trimeth-
1
(R,E)-1-[(R)-1-phenylethyl]-2-methyl-5-trimethylsilylmethylene-
4-piperidinone (19). The crude mixture was purified by column
ylsilylmethylene-3-pyrrolidinone (18d): H NMR δ 7.20-7.43 (m,
5H), 6.55 (tt, J ) 2.5, 7.7, 1H), 4.40 (d, J ) 13.4, 1H), 4.10 (dd, J )
2.5, 10.5, 1H), 3.86 (dd, J ) 5.7, 10.5, 1H), 3.74 (d, J ) 12.3, 1H),
3.67 (d, J ) 13.4, 1H), 3.18 (m, 1H), 3.17 (dd, J ) 2.2, 12.3, 1H),
2.03 (dt, J ) 7.7, 7.4, 1H), 1.10-1.48 (m, 6H), 0.88 (s, 9H), 0.85 (t,
J ) 7.2, 3H), 0.09 and 0.05 (2s, each, 3H). Allylic alcohols derived
from 18d by treatment with NaBH4-CeCl3 in MeOH: for a major
chromatography on silica gel (hexane-ether) to give pure 19 as a pale
1
yellow oil; [R]25 +19.5 (c 2.22, THF), +23.9 (c 2.17, CHCl3); H
D
NMR δ 7.19-7.44 (m, 5H), 6.62 (dd, J ) 1.6, 1.7, 1H), 3.87 (q, J )
6.7, 1H), 3.49 (m, 1H), 3.38 (dd, J ) 1.6, 15.1, 1H), 3.31 (dd, J ) 1.7,
15.1, 1H), 2.78 (dd, J ) 5.6, 17.0, 1H), 2.37 (dd, J ) 5.0, 17.0, 1H),
1.37 (d, J ) 6.7, 3H), 1.16 (d, J ) 6.5, 3H), -0.15 (s, 9H); 13C NMR
δ 198.5, 147.8, 144.7, 136.2, 128.3, 127.3, 127.0, 58.8, 49.7, 48.7, 47.2,
16.6, 15.3, -1.2; IR (neat) 2965, 1691, 1590, 1319, 1249. Anal. Calcd
for C18H27NOSi: C, 71.71; H, 9.03; N, 4.65. Found: C, 71.75; H,
9.12; N, 4.49.
1
isomer; H NMR δ 7.20-7.338 (m, 5H), 5.60 (t, J ) 7.4, 1H), 4.46
(m, 1H), 4.09 (d, J ) 13.3, 1H), 3.98 (dd, J ) 5.8, 10.7, 1H), 3.86 (dd,
J ) 4.7, 10.7, 1H), 3.60 (d, J ) 14.4, 1H), 3.39 (d, J ) 13.3, 1H),
2.80 (d, J ) 14.4, 1H), 2.73 (m, 1H), 1.88 (dt, J ) 7.4, 6.7, 2H), 1.17-
1.40 (m, 6H), 0.89 (s, 9H), 0.85 (t, J ) 7.0, 1H), 0.08 and 0.07 (2s,
6H); 13C NMR δ 140.3, 128.7, 126.9, 125.5, 123.2, 74.6, 68.7, 62.2,
58.6, 54.8, 31.5, 29.3, 28.8, 25.8, 22.5, 18.1, 14.0, -5.5; IR (neat) 3417,
2954, 2927, 2856, 1689, 1461, 1388, 1255, 1089, 837, 777, 739, 698;
MS/EI m/e 403 (0.2), 385 (3.2), 328 (5.8), 312 (5.1), 258 (100), 91
(57), 75 (30), 55 (8.7); HRMS (CI) calcd for C24H42NO2Si (M+ + H)
404.2985, found 404.2991. Optical purity of 18d was determined by
1H NMR analysis of the corresponding MTPA esters of the compound
ii which was derived from 18d according to the following procedure:
A mixture of two diastereomers of allylic alcohols i prepared above
was treated with Ac2O in pyridine and then TBAF in THF to give the
corresponding acetoxy-primary-alcohol derivatives ii which were
separated from each other by column chromatography on silica gel.
Thus, the resulting major diastereomer was converted to the corre-
sponding MTPA-esters by using (S)- or (R)-MTPA-Cl. 1H NMR 300
MHz analysis of each MTPA ester showed that no racemization
occurred in these reactions.
Typical Procedure for the Reaction of Olefinic Substrates 16 or
17. To a stirred solution of 16c (181.5 mg, 0.50 mmol) and Ti(O-i-
Pr)4 (192 µL, 0.65 mmol) in ether (5 mL) was added i-PrMgCl (0.970
mL, 1.34 M in ether, 1.30 mmol) at -78 °C. The resulting mixture
was gradually warmed to room temperature over 2 h and stirred for
additional 2 h. After addition of aqueous saturated NaHCO3 (0.6 mL),
the mixture was stirred for 30 min. To this were added NaF (2 g) and
Celite (2 g). After stirring for 30 min, the mixture was filtered through
a pad of Celite, and the filtrate was concentrated in Vacuo. The crude
product was purified by column chromatography on silica gel to give
20c (144.4 mg) in 86% yield as a 72:28 mixture of two diastereomers.
(S)-1-Benzyl-2-[(tert-butyldimethylsilyl)oxy]methylcyclopropa-
[3,4]pyrrolidin-3-ol (20c): a 72:28 mixture of two diastereomers. For
a major isomer: 1H NMR δ 7.16-7.38 (m, 5H), 3.90 (dd, J ) 4.3,
10.7, 1H), 3.82 (dd, J ) 3.0, 10.7, 1H), 3.73 and 3.79 (2d, J ) 13.8,
each 1H), 3.09-3.17 (m, 2H), 2.51 (d, J ) 8.7, 1H), 1.40-1.52 (m,
1H), 1.04 (dd, J ) 5.0, 8.9, 1H), 0.81-0.98 (m, 1H), 0.89 (s, 9H),
0.06 and 0.11 (2s, each 3H); 13C NMR δ 139.9, 128.5, 128.1, 126.7,
64.6, 62.3, 56.0, 54.1, 25.8, 24.3, 20.7, 17.9, 17.0, -5.4, -5.6; IR (neat,
for a mixture of two diastereomers) 3420, 2950, 1360. Anal. Calcd
for C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found (for a mixture of
two diastereomers): C, 68.40; H, 9.51; N, 4.12.
Under the same reaction conditions (quantity, reaction temperature
and period) the following compounds were obtained by the same
procedure described above.
Under the same reaction conditions (quantity, reaction temperature,
and period) the following compounds were obtained by the same
procedure described above.
(E,S)-1,2-Dibenzyl-4-trimethylsilylmethylene-3-pyrrolidinone (18a):
1H NMR δ 7.10-7.40 (m, 10H), 6.73 (t, J ) 2.5, 1H), 4.05 (d, J )
13.2, 1H), 3.75 (dd, J ) 1.1, 13.7, 1H), 3.32 (d, J ) 13.2, 1H), 3.27
(dd, J ) 4.7, 13.7, 1H), 3.19 (dd, J ) 5.4, 5.5, 1H), 3.07 (dd, J ) 2.8,
14.4, 1H), 3.02 (dd, J ) 5.3, 14.4, 1H), 0.07 (s, 9H); 13C NMR δ 201.50,
(S)-1,2-Dibenzylcyclopropa[3,4]pyrrolidin-3-ol (20a): a 82:18
mixture of two diastereomers. For a major diastereomer: 1H NMR
(300 MHz) δ 7.10-7.40 (m, 10H), 3.66 and 3.61 (2d, each J ) 13.9,
each 1H) 3.38 (dd, J ) 5.3, 6.6, 1H), 2.84-3.06 (m, 3H), 2.37 (d, J )
9.3, 1H), 2.27 (br s, 1H), 1.44-1.54 (m, 1H), 0.96 (dd, J ) 4.7, 8.9,
1H), 0.90 (t, J ) 4.5, 1H); 13C NMR δ 140.9, 139.6, 129.4, 128.3,

6990 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Okamoto et al.
128.2, 128.1, 126.8, 125.7, 67.6, 65.4, 56.7, 52.6, 34.3, 24.2, 19.9; IR
(Nujol, for a mixture of two diastereomers) 2971, 2884, 1602.
synthesized according to the procedure reported by Kibayashi20g) by
treatment with triphenylphosphine and CBr4 in CH2Cl2] at room
temperature. After the mixture was stirred for 2 days at room
temperature, to it was added saturated aqueous NaHCO3 (10 mL), and
the mixture was extracted with ether (2 × 15 mL). The combined
organic layers were dried over MgSO4 and concentrated in Vacuo. The
residue was purified by column chromatography on silica gel (hexane-
(S)-1,2-Dibenzylcyclopropa[3,4]piperidin-3-ol (20b): a 92.5:7.5
mixture of two diastereomers. For a major diastereomer: 1H NMR δ
7.10-7.40 (m, 10H), 3.69 (d, J ) 13.8, 1H), 3.55 (d, J ) 13.8, 1H),
3.49 (dd, J ) 5.4, 6.1, 1H), 3.17 (dd, J ) 6.5, 14.0, 1H), 3.14 (dd, J
) 4.8, 14.0, 1H), 2.65 (ddd, J ) 6.7, 6.8, 12.3, 1H), 2.23 (ddd, J )
3.8, 7.8, 12.3, 1H), 1.88-2.00 (m, 1H), 1.56-1.68 (m, 1H), 1.20-
1.30 (m, 1H), 0.96 (dd, J ) 4.5, 6.1, 1H), 0.75 (dd, J ) 4.5, 10.6, 1H);
13C NMR δ 142.07, 139.74, 129.34, 128.37, 128.31, 128.10, 126.77,
125.59, 63.85, 58.68, 58.17, 42.22, 32.95, 22.26, 19.30, 17.75. Anal.
Calcd for C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found (for a mixture
of two diastereomers): C, 81.55; H, 7.86; N, 4.63.
ether to hexane-AcOEt) to give 24 (509 mg, 65% yield): a colorless
1
oil; [R]24 -59.8 (c 1.106, CHCl3); H NMR δ 3.75 (s, 3H, CO2Me),
D
3.34 (dd, J ) 2.1, 17.5, 1H, part of 1′-H2), 3.30 (dd, J ) 5.7, 8.2, 1H,
2-H), 3.12 (dd, J ) 2.1, 17.5, 1H, part of 1′-H2), 2.98 (ddd, J ) 5.1,
5.6, 9.4, 1H, part of 5-H2), 2.84 (ddd, J ) 7.5, 7.7, 9.4, 1H, part of
5-H2), 2.34-2.47 (m, 1H, 4′-H), 1.66-1.96 (m, 4H, 3-H2 and 4-H2),
1.34 (s, 3H, MeCOH), 1.23-1.46 (m, 6H, (CH2)3Me), 1.14 (d, J )
7.0, 3H, C4′-Me), 0.90 (t, J ) 7.1, CH2CH3); 13C NMR δ 176.9, 89.2,
75.1, 75.0, 66.7, 54.1, 51.9, 42.7, 36.7, 29.5, 27.0, 25.7, 24.5, 22.4,
22.2, 21.3, 13.9; IR (neat) 3510, 2958, 2929, 2871, 1743, 1457, 1375,
1322, 1253, 1211, 1191, 1116, 981, 723; MS (EI) m/e 295 (0.1), 236
(15.2), 192 (100), 134 (7.8), 126 (8.0), 112 (5.3), 81 (31.6), 70 (45.0),
67 (28), 55 (34), 53 (23); HRMS (CI) calcd for C17H30NO3 (M++H)
296.2226, found 296.2214.
(R)-1-[(R)-1-Phenylethyl]-2-methylcyclopropa[4,5]piperidin-4-
ol (21): a 56:44 mixture of two diastereomers. The mixture was
recrystallized from hexane to afford two different types of crystals which
were partially separated by tweezers to give analytically pure samples.
1
Major isomer: white needle, mp 133.5-134.5 °C; H NMR δ 7.16-
7.41 (m, 5H), 3.66 (q, J ) 6.8, 1H), 2.89-3.00 (m, 1H), 2.66 (dd, J )
5.6, 11.8, 1H), 2.38 (dd, J ) 5.4, 13.6, 1H), 2.31 (dd, J ) 1.2, 11.8,
1H), 1.84 (ddd, J ) 1.2, 4.6, 13.6, 1H), 1.22 (d, J ) 6.8, 3H), 1.10 (d,
J ) 6.5, 3H), 1.03-1.17 (m, 1H), 0.77 (dd, J ) 4.6, 10.4, 1H), 0.47
(dd, J ) 4.6, 6.1, 1H); 13C NMR δ 144.6, 128.0, 127.4, 126.4, 59.2,
52.1, 46.8, 43.5, 41.0, 20.3, 18.3, 18.1, 13.8. Minor isomer: pale yellow
(8R,8aS)-8-Hydroxy-8-methyl-6-[(Z)-2(R)-methylhexylidene]oc-
tahydroindolizin-7-one (25). To a solution of 24 (34.1 mg, 0.116
mmol) and Ti(O-i-Pr)4 (47.8 µL, 0.174 mmol) in ether (1.16 mL) was
added i-PrMgCl (386 µL, 1.20 M in ether, 0.464 mmol) at -78 °C
and the resulting clear yellow solution was allowed to warm to -50
°C. After having been stirred for 1 h at -50 °C to -40 °C, the mixture
was colored brown, and this was gradually warmed to -5 °C over 1 h.
After addition of aqueous saturated NaHCO3 (0.1 mL) and then stirring
for 10 min at -5 °C, the cooling bath was removed. The mixture was
dried by addition of anhydrous MgSO4 and filtered through a pad of
Celite with ether. The filtrate was concentrated under reduced pressure
to give a crude oil which was purified by column chromatography on
silica gel (Wako C-200, hexane-ether) to afford 25 (20.5 mg, 67%
yield): [R]25D -6.4 (c 0.96, CHCl3), lit.20c [R]25D -6.5 (c 1.1, CHCl3);
1H NMR δ 6.52 (d, J ) 10.6, 1H, 10-H), 4.01 (d, J ) 14.0, 1H, part
of 5-H2), 3.67 (br s, 1H, OH), 3.22 (ddd, J ) 2.8, 5.3, 8.7, part of
3-H2), 2.96 (dd, J ) 2.6, 14.0, 1H, part of 5-H2), 2.25-2.48 (m, 3H,
part of 3-H2, 11-H and 8a-H), 1.78-2.02 (m, 4H, 1-H2 and 2-H2), 1.10-
1.43 (m, 6H, 12-H2, 13-H2 and 14-H2), 1.25 (s, 3H, 9-H3), 1.01 (d, J
) 6.6, 3H, 16-H3), 0.86 (t, J ) 7.1, 3H, 15-H3); 13C NMR δ 197.1,
148.0, 129.6, 77.2, 73.1, 69.2, 55.2, 52.0, 36.3, 32.9, 29.7, 23.6, 22.7,
19.9, 17.8, 14.0; IR (neat) 3419, 2958, 2927, 2871, 2798, 2742, 1698,
1619, 1455, 1371, 1311, 1234, 1122, 979, 754; MS (EI) m/e 265 (7.5),
222 (6.1), 208 (3.1), 196 (2.0), 180 (9.5), 164 (4.0), 153 (1.5), 139
(18.8), 122 (1.9), 112 (14.0), 95 (2.8), 83 (10.0), 70 (100), 55 (18.9);
HRMS (EI) calcd for C16H27NO2 (M+) 265.2042, found 265.2017.
The keto group of 25 thus obtained was reduced stereoselectively
by treatment with tetramethylammonium triacetoxyborohydride and
glacial acetic acid in acetone according to the procedure reported by
Overman20c to provide (+)-allopumiliotoxin 267A [HRMS (EI) calcd
for C16H29NO2 (M+) 267.2198, found 267.3266] in 72% yield (96%
yield based on the conversion) with 25% of unreacted 25. The
spectroscopic data were in good agreement with those reported. The
calculated overall yield of allopumiliotoxin 267A was 27% (based on
conversion yield in the reaction of 25) from N-Boc-L-proline.
1
plates, mp 119.0-120.0 °C; H NMR δ 7.16-7.41 (m, 5H), 4.18 (q,
J ) 7.0, 1H), 2.59-2.71 (m, 1H), 2.55 (dd, J ) 3.7, 11.3, 1H), 2.36
(dd, J ) 1.8, 11.3, 1H), 2.16 (dd, J ) 6.1, 13.8, 1H), 1.97 (dd, J )
10.1, 13.8, 1H), 1.24 (d, J ) 7.0, 3H), 1.03-1.17 (m, 1H), 1.09 (d, J
) 6.2, 3H), 0.60-0.68 (m, 2H); 13C NMR δ 144.7, 127.8 (2C), 126.2,
54.1, 53.0, 50.8, 43.13, 43.07, 21.5, 19.8, 17.7, 9.7. IR (KBr, for a
mixture of two diastereomers) 3411, 2965, 1637,1367. Anal. Calcd
for C15H21NO (for a mixture of two diastereomers): C, 77.88; H, 9.15;
N, 6.05. Found: C, 77.60; H, 9.27; N, 6.06.
Synthesis of Allopumiliotoxin 267A. (2S)-2-[(R)-1-(Hydroxy)-1-
(trimethylthiomethyl)ethyl]pyrrolidine (23). The compound 22
(1.065 g, 5.0 mmol) prepared from L-proline (83% overall yield)
according to the procedure reported by Overman20c and Kibayashi20g
was deprotected by treatment with CF3COOH (3.5 mL) and anisole
(3.5 mL) in CH2Cl2 (3.5 mL) at room temperature for 30 min to give
a trifluoroacetate salt of the amine which was dried by azeotroping
with CH2Cl2 (3 × 3 mL) and then toluene (2 × 3 mL). To a solution
of tris(methylthio)methane (3.326 mL, 25 mmol) in THF (50 mL) was
added dropwise a solution of BuLi (11.7 mL, 2.14 M in hexane, 25
mmol) at -78 °C, and the resulting mixture was allowed to warm to
-20 °C over 1 h. After the mixture was cooled to -78 °C, to it (a
white suspension) was added dropwise a solution of the trifluoroacetate
salt prepared above in THF (15 mL), and the resulting mixture was
stirred for 1 h at -78 °C and gradually warmed to -40 °C over 1 h.
After addition of water (30 mL), the mixture was extracted with ether
(50 mL) and then CHCl3 (20 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in Vacuo. The
residue was chromatographed on Chromatorex NH-gel (DM1020, Fuji
Silysia Chemical Ltd.) using hexane-ether to afford 23 (1.043 g, 78%
1
yield): a colorless oil; [R]25 -65.1 (c 2.196, THF); H NMR δ 3.88
D
(dd, J ) 6.4, 9.6, 1H, 2-H), 3.10 (ddd, J ) 3.1, 7.6, 10.4, 1H, part of
5-H2), 2.84 (ddd, J ) 6.4, 9.1, 10.4, 1H, part of 5-H2), 2.27 (s, 9H,
3SMe), 1.50-1.94 (m, 4H, 3-H2 and 4-H2), 1.47 (s, 3H, MeCOH); 13
NMR δ 81.3, 62.2, 50.9, 45.8, 28.7, 25.9, 22.9, 12.1.
C
Acknowledgment. We thank Dr. Akira Higuchi and Dr.
Naoya Ono (Taisho Pharmaceutical Co., Ltd.) for help with
HRMS. This work was supported by a Grant-in-Aid from the
Ministry of Education, Science, Sports, and Culture, Japan (No.
08245217) and by Toray Industries, Inc. Award in Synthetic
Organic Chemistry, Japan (to S.O.).
(2S)-1-[(R)-4-Methyl-2-octynyl]-2-[(R)-1-(Hydroxy)-1-methoxy-
carbonyl]ethylpyrrolidine (24). To a solution of 23 (710 mg, 2.65
mmol) in MeOH (10 mL) and CHCl3 (10 mL) was added dropwise a
solution of Hg(ClO4)2-3H2O (3.606 g, 7.95 mmol) in MeOH (20 mL)
at room temperature. The resulting white-pink suspension was stirred
for 12 h at room temperature. After careful addition of saturated
aqueous NaHCO3 (20 mL), the mixture was extracted with CHCl3 (3
× 20 mL). The combined extracts were dried over MgSO4 and
concentrated in Vacuo. The residue was passed through a short column
of Chromatorex NH-gel with ether and concentrated in Vacuo to give
a semipurified methyl ester, (2S)-2-[(R)-1-(hydroxy)-1-methoxycarbo-
nyl]ethylpyrrolidine (340 mg), which was subjected to the next reaction.
To a solution of the methyl ester thus obtained and i-Pr2NEt (0.94 mL)
in THF (10 mL) was added (R)-1-bromo-4-methyl-2-octyne [400 mg,
1.97 mmol, prepared from (R)-4-methyl-2-octyn-1-ol (which was
Supporting Information Available: The experimental
procedure for preparation of the starting materials 4, 5, 8, 9,
10, 11, 12, 13, 14, 15, 16, and 17 and their spectroscopic data,
the spectroscopic data of the alcohols derived from 18 by
1
treatment with NaBH4-CeCl3, and H NMR charts of 6, 7,
products from 8-13, 18-21, 25, and (R)-1-bromo-4-methyl-
2-octyne (27 pages). See any current masthead page for
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