Synthesis of optically active vasicinone based on intramolecular aza-Wittig reaction and asymmetric oxidation

Article abstract of DOI:10.1021/jo9609283

Both optical isomers of a quinazoline alkaloid, vasicinone, were synthesized by two different methods. The first method used (3S)-3-hydroxy-γ-lactam as a chiral synthon, which was, after O-TBDMS protection, o-azidobenzoylated followed by treatment with tri-n-butylphosphine to afford (S)-(-)-vasicinone via the tandem Staudinger/intramolecular aza-Wittig reaction. The second method utilized asymmetric oxygenation of deoxyvasicinone with (1S)-(+)- or (1R)-(-)-(10-camphorsulfonyl)oxaziridine (the Davis reagent), respectively. The aza-enolate anion of deoxyvasicinone was treated with (S)-(+)-reagent to afford (R)-(+)-vasicinone in 71% ee, while the reaction with (R)-(-)-reagent gave (S)-(-)-vasicinone in 62% ee. The optical purity was analyzed by HPLC on specially modified cellulose as a stationary phase. These results provided a facile method to prepare both optical isomers of vasicinone and confirmed the recently reversed stereochemistry of natural (-)-vasicinone.

Full text of DOI:10.1021/jo9609283

7316
J . Org. Chem. 1996, 61, 7316-7319
Syn th esis of Op tica lly Active Va sicin on e Ba sed on In tr a m olecu la r
Aza -Wittig Rea ction a n d Asym m etr ic Oxid a tion 1
Shoji Eguchi,* Toshio Suzuki, Tomohiro Okawa, and Yuji Matsushita
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-01, J apan
Eiji Yashima and Yoshio Okamoto
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-01, J apan
Received May 20, 1996X
Both optical isomers of a quinazoline alkaloid, vasicinone, were synthesized by two different
methods. The first method used (3S)-3-hydroxy-γ-lactam as a chiral synthon, which was, after
O-TBDMS protection, o-azidobenzoylated followed by treatment with tri-n-butylphosphine to afford
(S)-(-)-vasicinone via the tandem Staudinger/intramolecualr aza-Wittig reaction. The second
method utilized asymmetric oxygenation of deoxyvasicinone with (1S)-(+)- or (1R)-(-)-(10-
camphorsulfonyl)oxaziridine (the Davis reagent), respectively. The aza-enolate anion of deoxyva-
sicinone was treated with (S)-(+)-reagent to afford (R)-(+)-vasicinone in 71% ee, while the reaction
with (R)-(-)-reagent gave (S)-(-)-vasicinone in 62% ee. The optical purity was analyzed by HPLC
on specially modified cellulose as a stationary phase. These results provided a facile method to
prepare both optical isomers of vasicinone and confirmed the recently reversed stereochemistry of
natural (-)-vasicinone.
In tr od u ction
to 3S. Several syntheses of vasicinone and deoxyvasici-
none have been reported;5 however, these syntheses
targeted the dl racemic mixture. Therefore, we investi-
gated synthesis of optically active vasicinone by two
methods via the tandem Staudinger/intramolecular aza-
Wittig reaction and/or asymmetric oxidation of deoxyva-
sicinone with the Davis oxidation reagent. This aza-
Wittig methodology has received increased attention for
its utility in the formation of CdN bond-containing
compounds (e.g., imines, imidates, amidines, etc.), and
in particular, nitrogen heterocyclic compounds.6,7 For
example, we and other workers have recently demon-
strated that the intramolecular aza-Wittig reaction is a
powerful tool for the synthesis of 5- to 7-membered
nitrogen heterocycles including natural products, such
as oxazoles,8 imidazolinone,9 iminolactam,10 4(3H)-quin-
azolinones,9,11 1,4-benzodiazepin-5-ones,12 1,3-benzox-
azepines,13 1,3-benzodiazepines,13 and pyrazino[2,3-e][1,4]-
diazepines.14 On the other hand, the intermolecular aza-
Vasicinone is known as one of the pyrrolo[2,1-b]-
quinazoline alkaloids isolated from the leaves and the
inflorescence of Adhatada vasica Nees, which is an
evergreen subherbaceous bush and is used in indigenous
medicine as a remedy for cold, cough, bronchitis, and
asthma, etc.2 Vasicinone has also been found to be
identical with an alkaloid isolated from the seeds of
Pegamum harmala Linn.2 Related pyrrolo[2,1-b]quinazo-
line alkaloids containing, for example, (-)-vasicine (pe-
ganine), (+)-vasicinol (7-hydroxyvasicine), and adhava-
sinone (5-methoxyvasicinone), etc., have been reported
as well. It is shown that (-)-vasicinone can be derived
from (-)-vasicine by autooxidation or by oxidation with
30% H2O2.2 In view of the pharmacological activity of
these molecules, the determination of the absolute ster-
eochemistry and development of convenient synthetic
method are important. However, the reported stereo-
chemical assignment and the optical rotation of natural
vasicinone and related compounds seem to be somewhat
confusing.3,4 Very recently, J oshi and co-workers4 re-
versed the previously assigned 3R configuration of (-)-
vasicinone to the 3S configuration on the bas of the X-ray
crystallographic analysis of (+)-vasicinone hydrobromide
derived from (-)-vasicinone. The previously assigned 3R
stereochemistry of (-)-vasicine has also been reversed
(5) (a) Onaka, T. Tetrahedron Lett. 1971, 4387. (b) Kametani, T.;
Loc, C. V.; Higa, T.; Koizumi, M.; Ihara, K.; Fukumoto, K. J . Am. Chem.
Soc. 1977, 99, 2306. (c) Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y.
Heterocycles 1985, 23, 2803. (d) Grundon, M. F. Nat. Prod. Rep. 1988,
5, 293.
(6) For recent reviews on heterocyclic syntheses by aza-Wittig
reaction, see: (a) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 209. (b) Gololobov, Y. G.; Kasukhin, L. F.
Tetrahedron 1992, 48, 1353. (c) Molina, P.; Vilaplana, M. J . Synthesis
1994, 1197. (d) Wamhoff, H.; Rechardt, G.; Sto¨lben S. Advances in
Heterocyclic Chemistry 1996, Vol. 64, 159.
* To whom correspondence should be addressed. Tel.: +81-(0)-52-
789-4668. Fax: +81-(0)-52-789-3199. E-mail: eguchi@apchem.nagoya-
u.ac.jp.
(7) For recent reviews on iminophosphoranes, see (a) Gololobov, Y.
G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437. (b)
Barluenga, F.; Palacios, F. Org. Prep. Proced. Int. 1991, 23, 1.
(8) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S.
J . Org. Chem. 1989, 54, 431.
(9) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375.
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Synthesis of Novel Carbo- and Heteropolycycles. 41. Part 40:
Okawa, T.; Osakada, N.; Eguchi, S.; Kakehi, A. Submitted for publica-
tion. Part 39: Yamamoto, Y.; Nunokawa, K.; Ohno, M.; Eguchi, S.
Synthesis, in press.
(10) Eguchi, S.; Takeuchi, H. J . Chem. Soc., Chem. Commun. 1989,
602.
(2) (a) Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317. (b) Mehta,
D. R.; Naravane, J . S.; Desai, R. M. J . Org. Chem. 1963, 28, 445. See
also ref 4 and references cited therein.
(3) (a) Choudhury, M. K. Naturwissenschaften 1979, 66, 205. (b)
Bhalla, H. L.; D’Cruz, J . L.; Kokate, C. K. Indian Drugs 1982, 20, 16.
(4) J oshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier,
S. W. Tetrahedron Asymmetry 1996, 7, 25.
(11) (a) Takeuchi, H.; Eguchi, S. Tetrahedron Lett. 1989, 30, 3313.
(b) Takeuchi, H.; Matsushita, Y.; Eguchi, S. J . Org. Chem. 1991, 56,
1535. (c) Eguchi, S.; Takeuchi, H.; Matsushita, Y. Heterocycles 1992,
33, 153. (d) Eguchi, S.; Matsushita, Y.; Takeuchi, H. J . Org. Chem.
1992, 57, 6576. (e) Eguchi, S.; Goto, S. Heterocycl. Commun. 1994, 1,
51.
S0022-3263(96)00928-0 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Optically Active Vasicinone
J . Org. Chem., Vol. 61, No. 21, 1996 7317
Sch em e 1. Syn th esis of d l-Va sicin on e via
Sch em e 2. Syn th esis of l-Va sicin on e via
In tr a m olecu la r Aza -Wittig Rea ction a
In tr a m olecu la r Aza -Wittig Rea ction a
a
Reagents and conditions: (a) NaH, THF, 0 °C f rt, 3 h; (b)
a
Reagents and conditions: (a) SOCl2 (neat), reflux, 2 h; (b) NaH,
n-Bu3P, toluene, rt, 1 h f reflux, 2 h; (c) TBAF, THF, 0 °C f rt,
15 h.
THF, 0 °C f rt, 3 h; (c) n-Bu3P, toluene, rt, 1 h f reflux, 2 h; (d)
TBAF, THF, 0 °C f rt, 15 h. TBAF ) tetra-n-butylammonium
fluoride.
precursor N-(o-azidobenzoyl)-3-(tert-butyldimethylsiloxy)
γ-lactam 4. The addition of tri-n-butylphosphine to 4
initiated the tandem Staudinger/intramolecular aza-
Wittig reaction to give O-tert-butyldimethylsilyl vasici-
none 5 (see the Experimental Section.). The deprotection
of the siloxy substituent by tetra-n-butylammonium
fluoride (TBAF) in THF gave dl-vasicinone in 95% yield
(Scheme 1).
Wittig reaction followed by electrocyclization,
intramolecular cycloaddition, or heterocyclization, i.e., the
tandem aza-Wittig reaction and cyclization sequence, has
been utilized for synthesis of pyridines and pyrimidines,
etc.6c,15-19 We wish to report here two methods of
synthesis of optically active vasicinone by utilizing the
tandem Staudinger/intramolecular aza-Wittig reaction
and/or asymmetric oxidation of deoxyvasicinone with the
Davis reagent.
In the next stage, we investigated the synthesis of (S)-
(-)-vasicinone as follows. The chiral synthon, (3S)-3-
hydroxy γ-lactam derived from L-aspartic acid in five
steps,21 was protected by TBDMSCl to prepare 6 in the
same way. Employing the above-mentioned method for
synthesis of dl-vasicinone enabled (S)-(-)-vasicinone to
be synthesized in 52% overall yield from anthranilic acid
Resu lts a n d Discu ssion
Several examples of the synthesis of deoxyvasicinone
9, 9-pyrrolo[2,1-b]quinazolinone, from anthranilic acid
have been reported,5 whereby dl-vasicinone was synthe-
sized from 9 by NBS/benzoyl peroxide bromination,
followed by acetolysis and hydrolysis.5a Our previous
synthesis of 9 was applied to an alternative synthesis of
dl-vasicinone from 3-hydroxy γ-lactam and anthranilic
acid via the intramolecular aza-Wittig reaction. At first,
according to previous literature,20 3-hydroxy γ-lactam
was prepared from 3-hydroxy γ-lactone and then the
hydroxyl group was protected by TBDMSCl to give 3
(Scheme 1). Next, o-azidobenzoic acid 1 derived from
anthranilic acid by the usual method was converted into
o-azidobenzoyl chloride 2, followed by condensation with
3 by treatment with sodium hydride in THF to afford the
(Scheme 2), ([R]28 -58° (c 0.45 CHCl3), 97% ee). The
D
optical purity of the enantiomers was analyzed by HPLC
on specially modified cellulose as a stationary phase.22
We considered the thus obtained (S)-(-)-vasicinone as
an authentic sample of the defined stereochemistry and
investigated asymmetric oxidation with deoxyvasicinone
9 as a more convenient route by employing (1S)-(+)- or
(1R)-(-)-(10-camphorsulfonyl)oxaziridine, i.e., the Davis
reagents.23 Although, heretofore, the asymmetric oxida-
tion reactions have been mainly reported on achiral
enolates, there have been no reports, except for only one
case,24 on aza-enolates, i.e., imine enolate. This was
3-(phenylthio)-4,5-dihydroisoxazole where 50% ee was
obtained using the LDA-TMEDA system as a base. Aza-
enolate was generated from 9 with various bases in THF
at -78 °C followed by addition of (S)- or (R)-reagents in
THF solution to afford the optically active vasicinone
(Scheme 3). The results are summarized in Table 1.
We obtained the best result for asymmetric oxidation
of imine 9 by Davis reagents using the LDA-TMEDA
system (Table 1, entries 1-4). Asymmetric oxidation of
9 was dependent upon the geometry of Davis reagents
as expected. The results of the entries 1 and 2 suggest
that the intermediate, lithium aza-enolate of 9 was
(12) (a) Eguchi, S.; Yamashita, K.; Matsushita, Y. Synlett 1992, 295.
(b) Eguchi, S.; Yamashita, K.; Matsushita, Y.; Kakehi, A. J . Org. Chem.
1995, 60, 4006. (c) Molina, P.; D´ıaz, I.; Ta´rraga, A. Tetrahedron 1995,
51, 5617.
(13) Kurita, J .; Iwata, T.; Yasuike, S.; Tsuchiya, T. J . Chem. Soc.,
Chem. Commun. 1992, 81.
(14) Okawa, T.; Eguchi, S. Tetrahedron Lett. 1996, 37, 81.
(15) Molina, P.; Alajar´ın, M.; Sa´nchez-Andrada, P.; Carrio´, J . S.;
Mart´ınez-Ripoll, M.; Anderson, J . E.; J imeno, M. L.; Elguero, J . J . Org.
Chem. 1996, 61, 4289.
(16) Wamhoff, H.; Bamberg, C.; Herrmann, S.; Nieger, M. J . Org.
Chem. 1994, 59, 3985.
(17) (a) Katritzky, A. R.; J iang, J .; Steel, P. J . J . Org. Chem. 1994,
59, 4551. (b) Katrirzky, A. R.; Zhang, G.; J iang, J . J . Org. Chem. 1994,
59, 4556.
(21) Miyazawa, T.; Akita, E.; Ito, T. Agric. Biol. Chem. 1976, 40,
1651.
(18) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron Lett. 1996, 37, 2009.
(19) (a) Chavignon, O.; Teulade, J . C.; Roche, D.; Madesclaire, M.;
Blache, Y.; Gueiffier, A.; Chabard, J . L.; Dauphin, G. J . Org. Chem.
1994, 59, 6413. (b) Peinador, C.; Moreira, M. J .; Quintela, J . M.
Tetrahedron 1994, 50, 6705. (c) Palacios, F.; Alonso, C.; Rubiales, G.
Tetrahedron 1995, 51, 3683. (d) Rodrigues, J . A. R.; Leiva, G. C.; de
Sousa, J . D. F. Tetrahedron Lett. 1995, 36, 59.
(22) (a) Chankvetadze, B.; Yashima, E.; Okamoto, Y. J . Chromatogr.
1994, 670, 39. (b) Yashima, E.; Yamamoto, C.; Okamoto, Y. Polym. J .
1995, 27, 856.
(23) (a) Davis, F. A.; Sheppard, A. C.; Chen, B.; Haque, M. S. J .
Am. Chem. Soc. 1990, 112, 6679. (b) Davis, F. A.; Chen, B. Chem.
Rev. 1992, 92, 919. (c) Davis, F. A.; Reddy, G. V.; Chen, B.; Kumar,
A.; Haque, M. S. J . Org. Chem. 1995, 60, 6148.
(20) Goel, O. P.; Krolls, U.; Lewis, E. P. Org. Prep. Proced. Int. 1985,
17, 91.
(24) Davis, F. A.; Kumar, A.; Reddy, R. E.; Chen, B.; Wade, P. A.;
Shah, S. W. J . Org. Chem. 1993, 58, 7691.

7318 J . Org. Chem., Vol. 61, No. 21, 1996
Eguchi et al.
metal cation (Li+ or Na+) had apparently some minor
controlling effects, and furthermore, the steric repulsion
between the quinazoline and camphor skeletons should
be operating considerably.
Sch em e 3. Syn th esis of Va sicin on e by Da vis
Rea gen ta
Con clu sion s
In conclusion, we have reported the synthesis of
racemic vasicinone from 3-hydroxy-γ-lactam and anthra-
nilic acid and the synthesis of (S)-vasicinone (97% ee)
from L-aspartic acid and anthranilic acid utilizing in-
tramolecular aza-Wittig reaction as the key step. In
addition, we investigated the asymmetric oxidation of
deoxyvasicinone 9 by employing (R)- and (S)-Davis
reagents to provide a convenient route to both (S)- and
(R)-vasicinone. We have clarified that l-vasicinone has
the (S)-configuration by comparison of the optical rotation
value of synthetic product in accordance with the recently
reversed stereochemistry of natural vasicinone based on
X-ray crystallographic analysis.4
a
Reagents and conditions: (a) base, Davis reagent (see Table
1), -78 °C.
Ta ble 1. Asym m etr ic Oxid a tion of Deoxyva sicin on e 9
w ith (R)- a n d (S)-Da vis Rea gen t
absolute
oxidant
(equiv)
yieldc confignd
entry
basea
RTb
(%)
(ee, %)
1
2
3
4
5
6
7
8
9
LDA, TMEDA S (1.5)
LDA, TMEDA R (1.5)
LDA, TMEDA S (1.0)
LDA, TMEDA S (0.5)
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
15 min
30 min
36
34
30
24
23
18
25
57
46
37
17
39
R (62)
S (62)
R (66)
R (64)
R (40)
R (66)
R (40)
R (38)
R (46)
R (62)
R (66)
R (71)
LDA
LDA
LDA
NaHMDS
NaHMDS
NaHMDA
S (1.5)
S (1.0)
S (0.5)
S (1.5)
S (1.0)
S (0.5)
Exp er im en ta l Section
Gen er a l Meth od s. Most of the general experimental
methods have been reported previously.12b Optical rotations
were measured with a J ASCO DIP-1000 polarimeter. Flash
chromatography was performed with a silica gel column (Fuji
Davison BW-300 silica gel or ICN Alumina N, Akt. I.) eluted
with mixed solvents (hexane, ethyl acetate). All reagents were
of commercial quality. Solvents were dried prior to use when
deemed necessary: THF was freshly distilled from Na and
benzophenone. Toluene was dried over Na. Pyridine was
dried over KOH.
10
11
12
LDA, TMEDA S (1.0)
NaHMDS S (0.5)
a
1.5 equiv was used. NaHMDS ) sodium bis(trimethylsilyl)-
amide. Reaction time. c Isolated yield. Stereochemical assign-
ment and ee were determined by HPLC on specially modified
cellulose as a stationary phase.
b
d
thoroughly planar (Table 1, entry 1, R 62% ee; entry 2,
S 62% ee). Also, the PM3 semiempirical level calculation
indicated that the lithium aza-enolate of 9 is completely
planar. Taking these results into consideration, 9 was
successfully converted into (R)-vasicinone with (S)-Davis
reagents. However, in the LDA-TMEDA system, the
amount of oxidative reagents had little influence on the
yield and ee of vasicinone (Table 1, entries 1, 3, and 4).
With simple LDA system as the base, the results of yield
and ee were not consistent (Table 1, entries 5-7). In the
case where sodium bis(trimethylsilyl)amide (NaHMDS)
instead of LDA was used, the yields decreased (57% f
46% f 37%) but the stereoselectivity increased (38% ee
f 46% ee f 62% ee) with decreasing amount of Davis
reagents (Table 1, entries 8-10, respectively). Further-
more, when the reaction time was shortened, no change
of ee was observed in the LDA-TMEDA system (Table
1, entries 3 and 11) but the improvement of ee was
observed in the NaHMDS system (Table 1, entries 10 and
12). Bach and co-workers25 previously have reported a
mechanism for oxidation of the lithium enolate of acetal-
dehyde by oxaziridine on the basis of molecular orbital
calculations at the HF/6-31+G*//HF/4-31+G level and
interpreted the oxidation of the lithium enolate of ac-
etaldehyde to proceed by SN2 attack of the â-carbon on
the enolate along the O-N bond of the parent oxaziridine
and that the lithium cation is coordinated to both
nitrogen and oxygen of oxaziridine but not to oxygen of
enolate in the transition state. Taking the above mech-
anism and our results into consideration, the transition
state of asymmetric oxidation of 9 with Davis reagent is
proposed as follows. The â-carbon on the aza-enolate
attacks along the O-N bond of the oxaziridine and the
Syn th esis of d l-Va sicin on e via In tr a m olecu la r a za -
Wittig Reaction . N-(2-Azidoben zoyl)-3-(ter t-bu tyldim eth -
ylsiloxy)-2-p yr r olid in on e (4). To a stirred solution of 3-(tert-
butyldimthylsiloxy) γ-lactam 3 (280 mg, 1.30 mmol), prepared
from 3-hydroxy γ-lactam20 and tert-butyldimethylsilylation by
standard procedure in THF (5.0 mL) under nitrogen at 0 °C
was added sodium hydride (60% dispersion in mineral oil; 57
mg, 1.43 mmol). The stirring was continued for 15 min
followed by addition of o-azidobenzoyl chloride 2, which was
prepared from o-azidobenzoic acid 1 (318 mg, 1.95 mmol) and
thionyl chloride (0.75 mL, 10.3 mmol) in THF (5.0 mL), and
then this mixture was stirred at room temperature for 3 h.
The mixture was poured into ice-cooled water and extracted
with dichloromethane (3 × 10 mL). The combined extracts
were dried (Na2SO4) and concentrated under reduced pressure
to afford a solid residue, which was purified by silica gel
column chromatography (AcOEt:hexane 1:6 as the eluent) to
gain azidobenzoyl derivative 4 (367 mg, 79%): yellow solid;
mp 117-119.5 °C; IR (KBr) 2141, 1761, 1690, 1251, 843 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 0.12 (6H, s), 0.90 (9H, s), 2.05
(1H, ddd, J ) 12.6, 9.6, 1.7 Hz), 2.36-2.51 (1H, m), 3.68 (1H,
ddd, J ) 11.8, 9.6, 7.0 Hz), 4.09 (1H, ddd, J ) 8.9, 6.0, 1.4
Hz), 4.43 (1H, dd, J ) 9.4, 1.8 Hz), 7.16-7.31 (3H, m), 7.49
(1H, ddd, J ) 8.2, 7.0, 1.8 Hz); MS m/ z 275 (M+ - 85, N2 and
t-Bu), 259, 158, 146. Anal. Calcd for C17H24N4O3Si: C, 56.64;
H, 6.71; N, 15.54. Found: C, 56.99; H, 6.76; N, 15.17.
dl-O-(ter t-Bu tyldim eth ylsilyl)vasicin on e (5). To a stirred
solution of azide derivative 4 (520 mg, 1.44 mmol) in toluene
(10 mL) was added dropwise tri-n-butylphosphine (315 mg,
1.56 mmol), and the mixture was stirred for 1 h at room
temperture and 2 h at reflux under nitrogen. After the
mixture was cooled to room temperature, the solvent was
removed under reduced pressure, and the residue was purified
by silica gel column chromatography (AcOEt:hexane 1:6 as the
eluent) to give 5 (455 mg, 100%): white solid; mp 41-42.5 °C;
IR (KBr) 1687, 1631, 1253, 839 cm-1 1H NMR (CDCl3, 200
;
MHz) δ 0.20 (3H, s), 0.26 (3H, s), 0.93 (9H, s), 2.12-2.27 (1H,
m), 2.46 (1H, dddd, J ) 13.2, 7.8, 6.6, 6.4 Hz), 4.09 (1H, ddd,
J ) 12.2, 7.8, 5.5 Hz), 4.27 (1H, ddd, J ) 12.2, 7.8, 6.4 Hz),
(25) Bach, R. D.; Ande´rs, J . L.; Davis, F. A. J . Org. Chem. 1992, 57,
613.

Synthesis of Optically Active Vasicinone
J . Org. Chem., Vol. 61, No. 21, 1996 7319
5.10 (1H, dd, J ) 6.6, 5.0 Hz), 7.44-7.54 (1H, m), 7.73-7.76
(2H, m), 8.31 (1H, dt, J ) 8.0, 1.0 Hz); MS m/ z (relative
intensity) 301 (M+ - 15, 4.0), 260 (31), 259 (100), 185 (11).
Anal. Calcd for C17H24N2O2Si: C, 64.52; H, 7.64; N, 8.85.
Found: C, 64.34; H, 7.69; N, 8.98.
(3S)-O-(ter t-Bu tyld im eth ylsilyl)va sicin on e (8). To a
stirred solution of azide derivtaive 7 (160 mg, 0.44 mmol) in
toluene (3.0 mL) was added dropwise tri-n-butylphosphine (98
mg, 0.48 mmol), and the mixture was stirred for 1 h at room
temperature and 2 h at reflux under nitrogen. After being
cooled to room temperature, the solvent was removed under
reduced pressure, and the residue was purified by silica gel
column chromatography (AcOEt:hexane 1:2 as the eluent) to
give 8 (106 mg, 76%): white solid; mp 44-46 °C; IR (KBr)
1672, 1636, 839, cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.19 (3H,
s), 0.26 (3H, s), 0.93 (9H, s), 2.19 (1H, dddd, J ) 13.0, 7.8, 5.4,
5.4 Hz), 2.46 (1H, dddd, J ) 13.1, 7.8, 6.6, 6.6 Hz), 4.08 (1H,
ddd, J ) 12.2, 7.8, 5.6 Hz), 4.25 (1H, ddd, J ) 12.2, 7.8, 6.2
Hz), 5.10 (1H, dd), 7.45 (1H, ddd, J ) 7.8, 4.4, 3.9 Hz), 7.75
(2H, m), 8.31 (1H, ddd, J ) 7.8, 1.2, 1.0 Hz); 13C NMR (CDCl3,
50 MHz) δ -4.91, -4.26, 18.4, 25.9, 31.3, 43.6, 73.8, 121.4,
126.7, 127.0, 128.1, 134.4, 149.9, 159.2, 161.5; MS m/ z (relative
intensity) 316 (M+, 2.0), 259 (100), 185 (36). Anal. Calcd for
C17H24N2O2Si: C, 64.52; H, 7.64; N, 8.85. Found: C, 64.48;
H, 7.69; N, 8.84.
d l-Va sicin on e. To a stirred solution of 5 (197 mg, 0.622
mmol) in THF (3.0 mL) was added TBAF (1.0 M solution in
THF, 0.63 mL, 0.63 mmol) at 0 °C, and the mixture was stirred
for 15 h at room temperature. The solvent was removed under
reduced pressure, and the residue was purified by silica gel
column chromatography (AcOEt:hexane 10:1 as the eluent) to
give dl-vasicinone (119 mg, 95%): white solid; mp 205-207
°C (lit.2a mp 212-213 °C); IR (KBr) 3423, 1686, 1630 cm-1; 1H
NMR (CDCl3, 200 MHz) δ 2.23-2.41 (1H, m), 2.60-2.77 (2H,
m), 4.05 (1H, dt, J ) 12.4, 7.6 Hz), 4.38 (1H, ddd, J ) 12.4,
8.6, 4.4 Hz), 5.28 (1H, t, J ) 7.2 Hz), 5.95 (1H, br), 7.46-7.54
(1H, m), 7.76 (1H, s), 7.78 (1H, s), 8.32 (1H, d, J ) 8.0 Hz); 13
C
NMR (CDCl3, 50 MHz) δ 29.51, 43.71, 71.93, 121.31, 126.90,
127.02, 127.37, 134.89, 148.84, 160.99, 161.07; MS m/ z (rela-
tive intensity) 202 (M+, 100), 146 (69), 119 (45). Anal. Calcd
for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.24;
H, 5.07; N, 13.78.
l-Va sicin on e. To a stirred solution of 8 (21 mg, 0.066
mmol) in THF (1.5 mL) was added TBAF (1.0 M solution in
THF, 0.066 mL, 0.066 mmol) at 0 °C, and the mixture was
stirred for 15 h at room temperature. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel column chromatography (AcOEt as the eluent) to
(3S)-3-(ter t-Bu tyld im eth ylsiloxy)-2-p yr r olid in on e (6).
To a solution of (3S)-3-hydroxy-2-pyrrolidinone21 (75 mg, 0.75
mmol) in pyridine (0.5 mL) was added TBDMSCl (145 mg, 0.96
mmol) in dichloromthane (1.5 mL). The reaction mixture was
stirred under nitrogen at room temperature overnight, and the
solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography (Et2O as the
eluent) to give 6 as a colorless solid (81 mg, 51%): [R]26D -44°
(c 0.34 CHCl3); mp 54-55 °C; IR (KBr) 3432, 3219, 2932, 2893,
give l-vasicinone (11 mg, 82%, 97% ee): white solid; [R]28
D
-57.8° (c 0.45 CHCl3) (lit.2b natural vsaicinone [R]25 -58° (c
D
0.5 CHCl3); different values have been reported also, see ref
2b-4); mp 200-202 °C (lit.2b mp 201-202 °C); IR (KBr) 1667,
1
1638 cm-1; H NMR (CDCl3, 200 MHz) δ 2.32 (1H, dddd, J )
13.4, 8.6, 7.4, 7.4 Hz), 2.68 (1H, dddd, J ) 13.2, 7.4, 7.2, 4.6
Hz), 4.05 (1H, ddd, J ) 12.4, 7.4, 7.4 Hz), 4.38 (1H, ddd, J )
12.4, 8.6, 4.6 Hz), 5.27 (1H, dd, J ) 7.2, 7.2 Hz), 5.98 (1H,
brs), 7.50 (1H, ddd, J ) 8.0, 4.0, 4.0 Hz), 7.76 (2H, m), 8.31
(1H, ddd, J ) 8.0, 1.2, 1.0 Hz); MS m/ z (relative intensity)
202 (M+, 100), 146 (95), 119 (50); HRMS calcd for C11H10N2O2
202.0742, found 202.0745.
1703 (CdO), 1294, 1254 (SiC), 1154, 995 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 0.15 (3H, s), 0.16 (3H, s), 0.92 (9H, s),
2.03 (1H, m), 2.37 (1H, m), 3.32 (2H, m), 4.27 (1H, t, J ) 7.7
Hz), 6.46 (1H, s). MS m/ z (relative intensity) 200 (M+ - 15,
7.7), 158 (100). Anal. Calcd for C10H21NO2Si: C, 55.77; H,
9.83; N, 6.50. Found: C, 55.94; H, 9.45; N, 6.72.
Asym m etr ic Oxid a tion of Deoxyva sicin on e. To a solu-
tion of prepared base (LDA and NaHMDS, 0.75 mmol) in THF
(1.0 mL) at -78 °C was added deoxyvasicinone9 (93 mg, 0.50
mmol) in THF (3.0 mL), and the mixture was stirred for 1 h
at the same temperature followed by addition of (R)- or (S)-
Davis reagent (0.5-1.5 equiv), which was purchased from
Aldrich Chemical, Inc., in THF (4.0 mL). The reaction was
qunched at -78 °C by addition of saturated aqueous NH4Cl
(1.0 mL) and warmed to room temperature. The mixture was
diluted with AcOEt (10 mL), and the combined organic layers
were washed with water (2.0 mL) and saturated aqueous NaCl
(4.0 mL). The aqueous layer was extracted with AcOEt (2 ×
5.0 mL), and the combined organic layers were dried over
MgSO4. The solvent was removed under reduced pressure,
and the residue was purified by silica gel column chromatog-
raphy (AcOEt as the eluent) to give vasicinone. Furthermore,
the optical purity of enantiomers was analyzed by HPLC on
tris(4-chloro-3-methylphenyl carbamate) or tris(4-fluoro-3-
methylphenyl carbamate) of cellulose as a stationary phase
using hexane/2-propanol (85/15) as the eluent.22 The results
are summarized in Table 1.
(3S)-N-(2-Azid oben zoyl)-3-(ter t-bu tyld im eth ylsiloxy)-
2-p yr r olid in on e (7). To a stirred solution of (3S)-3-(tert-
butyldimethylsiloxy) γ-lactam 6 (120 mg, 0.56 mmol) in THF
(3.0 mL) under nitrogen at 0 °C was added sodium hydride
(60% dispersion in mineral oil, 25 mg, 0.63 mmol). The stirring
was continued for 15 min followed by addition of o-azidoben-
zoyl chloride 2, which was derived from o-azidobenzoic acid 1
(137 mg, 0.84 mmol) and thionyl chloride (0.61 mL, 8.40 mmol),
in THF (2.0 mL0, and then this mixture was stirred at room
temperature for 3 h. The mixture was poured into ice-cooled
water and then extracted with dichloromethane (3 × 10 mL).
The combined extracts were dried (Na2SO4) and concentrated
under reduced pressure to afford a residue that was purified
by silica gel column chromatography (AcOEt:hexane 1:1 as the
eluent) to gain azidobenzoyl derivative 7 (168 mg, 83%):
yellowish solid; [R]28 -25° (c 3.1 CHCl3); mp 86-87 °C; IR
D
(KBr) 2131, 1765, 1680, 1249, 839 cm-1; 1H NMR (CDCl3, 200
MHz) δ 0.12 (6H, s), 0.90 (9H, s), 2.04 (1H, dddd, J ) 12.6,
9.6, 9.4, 8.8 Hz), 2.43 (1H, dddd, J ) 12.6, 7.8, 6.8, 2.6 Hz),
3.68 (1H, ddd, J ) 11.7, 9.6, 6.8 Hz), 4.09 (1H, ddd, J ) 11.7,
8.8, 2.6 Hz), 4.43 (1H, dd, J ) 9.4, 7.8 Hz), 7.19 (2H, m), 7.31
(1H, m), 7.48 (1H, ddd, J ) 8.1, 7.2, 1.8 Hz); 13C NMR (CDCl3,
50 MHz) δ -5.3, -4.7, 18.3, 25.7, 28.3, 41.0, 72.0, 118.6, 125.2,
128.2, 128.9, 131.9, 137.7, 167.9, 173.3. Anal. Calcd for
Ack n ow led gm en t. This work was supported in part
by Grants-in-Aid for Scientific Research from the Min-
istry of Education, Science and Culture, J apan.
C
17H24N4O3Si: C, 56.64; H, 6.71; N, 15.54. Found: C, 56.82;
H, 6.42; N, 15.64.
J O9609283