Total synthesis of (-)-rosmarinecine by intramolecular cycloaddition of (S)-malic acid derived pyrroline N-oxide

Article abstract of DOI:10.1021/ol015747o

(equation presented) Straightforward total syntheses of (-)-rosmarinecine have been achieved from L-malic acid derived pyrroline N-oxides by two novel useful cascade processes, which join the family of domino reactions. Both strategies, which furnished the target alkaloid in enantioenriched and enantiopure forms, respectively, allow complete control of configuration at all the three newly created contiguous stereogenic centers.

Full text of DOI:10.1021/ol015747o

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1367-1369
Total Synthesis of (−)-Rosmarinecine by
Intramolecular Cycloaddition of (S)-Malic
Acid Derived Pyrroline N-Oxide
Andrea Goti,* Martina Cacciarini, Francesca Cardona, Franca M. Cordero, and
Alberto Brandi*
Dipartimento di Chimica organica “Ugo Schiff”, Centro di Studio C.N.R. sulla
Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni (CSCEA),
UniVersita` degli Studi di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
goti@chimorg.unifi.it
Received February 21, 2001
ABSTRACT
Straightforward total syntheses of (−)-rosmarinecine have been achieved from L-malic acid derived pyrroline N-oxides by two novel useful
cascade processes, which join the family of domino reactions. Both strategies, which furnished the target alkaloid in enantioenriched and
enantiopure forms, respectively, allow complete control of configuration at all the three newly created contiguous stereogenic centers.
We recently reported the synthesis of (-)-hastanecine (3)
In this Letter we report the total synthesis of (-)-
rosmarinecine by the intramolecular version of this strategy.
This variant complements the previous findings, allowing
access to the necine bases possessing the C7-C7a cis relative
stereochemistry with complete control of configuration at
all the new stereogenic centers.
(Scheme 1),1 as well as of related unnatural hydroxypyr-
Scheme 1
(-)-Rosmarinecine (4), the necine base portion of several
pyrrolizidine alkaloids,2 has been chosen as a target com-
pound to test the feasibility of this approach. Among the
polyhydroxylated necines, (-)-rosmarinecine (4) is structur-
ally a considerably challenging target, as proved by only two
successful total syntheses reported so far.3
Tatsuta and co-workers accomplished the first synthesis
of (-)-rosmarinecine (4) in 18 steps and 6.9% overall yield
starting from D-glucosamine.3a Recently, Denmark and co-
workers reported the application of their domino double
rolizidines, based on an intermolecular cycloaddition of
nitrone 1 with dimethyl maleate in the key step. The reaction
gave with a fair preference compound 2, with trans relative
stereochemistry at C3a-C4, derived from an exo-anti
transition state.1
(2) Hartmann, T.; Witte L. In Alkaloids: Chemical & Biological
PerspectiVes, Vol. 9; Pelletier, S. W., Ed.; Pergamon: Oxford, 1995; p
155.
(3) (a) Tatsuta, K.; Takahashi, H.; Amemiya, Y.; Kinoshita, M. J. Am.
Chem. Soc. 1983, 105, 4096. (b) Denmark, S. E.; Thorarensen, A.;
Middleton, D. S. J. Am. Chem. Soc. 1996, 118, 8266.
(1) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi,
A. Eur. J. Org. Chem. 2000, 3633.
10.1021/ol015747o CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/17/2001

cycloaddition strategy4 to a ten-step synthesis of (-)-
rosmarinecine (4) in 97.3% ee and 8.6% overall yield using
a chiral auxiliary.3b
domino Mitsunobu-intramolecular nitrone cycloaddition
process (Scheme 3). Structural assignment of the adduct,
The retrosynthetic sequence for the application of our
strategy (Scheme 2) requires an endo-syn approach of the
Scheme 3a
Scheme 2
partners, which is the less favored in the intermolecular
reaction.1 This stereochemical requirement might instead be
achieved by an intramolecular process. The appropriate
precursor was envisaged in 6, where the reacting moieties
are linked by a removable ester junction. The (R) configu-
ration required at C7 of the final alkaloid is available from
D-malic acid, but it is cheaper to utilize L-malic acid requiring
inversion of configuration at the stereogenic center at some
stage of the synthesis.5 This strategy had been successful in
the synthesis of hastanecine, where the inversion was effected
at an early stage by a Mitsunobu reaction with benzoic acid
on a hydroxydimesylate precursor of the nitrone 1.1 Subse-
quent double nucleophilic displacement with hydroxylamine
followed by oxidation cleanly furnished the desired nitrone
1.1 An analogous procedure for the synthesis of 6, utilizing
maleic acid monomethyl ester (8)6 in place of benzoic acid,
failed in the present case. Indeed, after the Mitsunobu
reaction, hydroxylamine gave preferentially conjugate ad-
dition to the maleic acid moiety rather than nucleophilic
substitution and cyclization.
Then, accomplishment of the inversion after construction
of the nitrone moiety was taken into account. Introduction
of the maleic acid portion of 6 by a Mitsunobu reaction of
8 on the preformed hydroxy-substituted nitrone 7, readily
accessible from the corresponding trialkylsilyl protected
nitrones,7 was then attempted, albeit nothing was previously
reported about the compatibility of a nitrone moiety under
Mitsunobu reaction conditions.8 The reaction afforded ex-
clusively the desired cycloadduct 9 in 70% yield by a clean
a Reagents and conditions: (a) 8 (1.2 equiv), PPh3 (3 equiv),
DEAD (3 equiv), THF, 0 °C, 2 h, 70%; (b) H2 1 atm, 20% Pd(OH)2/
C, MeOH, rt, 24 h, 59%; (c) Red-Al (12 equiv), THF, reflux, 3 h,
90%.
confirmed by NOESY spectra, proved the expected high
preference for an endo-syn TS in the intramolecular cyclo-
addition of the intermediate nitrone 6.7
Isoxazolidine reductive ring opening of 9 turned out to
be troublesome. Molybdenum hexacarbonyl,9 H2/Raney Ni,10
nickel boride,11 and Cu/Zn12 were not able to afford the
desired lactam 10. Hydrogenation over Pd on charcoal10,13
furnished up to a 40% yield of 10, but the reaction was not
14
reproducible. Finally, the use of Pd(OH)2 resulted in the
conversion of 9 to 10 in 55-60% yield. Reduction of lactam
10 was accomplished by the use of Red-Al, which gave (-)-
rosmarinecine (4) in 90% yield after chromatography. This
completes a nine-step, 10.2% overall yield access to this
alkaloid from readily accessible starting materials, namely,
maleic anhydride, (S)-dimethylmalate, and hydroxylamine
hydrochloride. Recrystallization provides analytically pure
material, with spectroscopic properties identical to those
reported for the natural product.3b However, to our disap-
pointment, its physical data (mp 155-157 °C, [R]23D -65.6,
c ) 0.88 in EtOH) did not match those of the natural
compound,3b with the optical rotation corresponding to ca.
55% ee. Repetition of the whole process afforded samples
of (-)-rosmarinecine only enantiomerically enriched in
(4) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
(5) D-Malic acid is ca. 30 times as expensive as its L-enantiomer.
(6) Zilkha, A.; Bachi, M. J. Org. Chem. 1959, 24, 1096.
(7) (a) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org.
Chem. 1997, 62, 3119. (b) Goti, A.; Cacciarini, M.; Cardona, F.; Brandi,
A. Tetrahedron Lett. 1999, 40, 2853.
(8) For reviews on the Mitsunobu reaction, see: (a) Mitsunobu, O.
Synthesis 1981, 1. (b) Castro, B. R. Org. React. 1983, 29, 1. (c) Hughes,
D. L. Org. React. 1992, 42, 335.
1
variable purities, with a 70% ee in the best case. H NMR
analysis of the enantiomeric composition of the precursor
10 after derivatization as the Mosher ester gave a value of
59% ee, in good agreement with that derived from the optical
measurement. Clearly, partial racemization had occurred at
an early stage of the process. Finally, after completion of
the described sequence, it was ascertained that partial
(9) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F. Tetrahedron
Lett. 1990, 31, 3351.
(10) (a) LeBel, N. A.; Post, M. E.; Whang, J. J. J. Am. Chem. Soc. 1964,
86, 3759. (b) Huisgen, R.; Hauck, H.; Grashey, R.; Seidl, H. Chem. Ber.
1968, 101, 2559.
(11) Tufariello, J. J.; Meckler, H.; Senaratne, K. P. A. Tetrahedron 1985,
41, 3447.
(12) Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.; Trombini, C. Liebigs
Ann. Chem. 1992, 1289.
(13) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5048.
(14) DeShong, P.; Leginus, J. M. J. Am. Chem. Soc. 1983, 105, 1686.
1368
Org. Lett., Vol. 3, No. 9, 2001

racemization of the starting nitrone 7 had occurred, since it
was obtained with different degrees of optical purities.7 This
finding was completely unexpected, contrasting with the
behavior previously observed for all the corresponding
protected nitrones.7 It has since been proven that nitrone 7
itself has a low configurational stability, and partial racem-
ization occurs independently on its precursor.15,16 Loss of
stereochemical integrity under Mitsunobu reaction conditions
has been ruled out, since direct esterification of nitrone 7
also provided partially racemized material.
Scheme 4a
An alternative strategy, which considered protection of the
nitrone moiety, was then envisaged for accessing enantiopure
(-)-rosmarinecine. Only two methods have been suggested,
but applied only very occasionally, for such a purpose:
addition of HCN (or a silyl cyanide)17 and cycloaddition of
a suitable dipolarophile.18 The latter method seemed more
suitable to our aim, as preliminarily proved in an analogous
model process.15
Reaction of the tetrahydropyranyl protected nitrone 1115
with styrene gave the two diastereomeric cycloadducts 12
and 13 (Scheme 4) which were easily separated by flash
column chromatography, albeit in principle they can be used
as a mixture, since the stereochemical information at C2 is
lost in the following steps. Deprotection of the hydroxyl
group of 12 to afford 14, followed by Mitsunobu reaction
with 8, assembled the dipolarophile for the intramolecular
cycloaddition while providing the desired inversion of
configuration at C4. On refluxing 15 in o-dichlorobenzene,
a domino cycloreVersion-intramolecular nitrone cycload-
dition process occurred to afford cleanly 9 in good yield.
a Reagents and conditions: (a) styrene (2 equiv), toluene, 80 °C,
11 h, 72% of 12 + 17% of 13; (b) (i) PPTS, absolute EtOH, reflux,
3 h; (ii) Ambersep 900-OH, MeOH, 3 h, 89%; (c) 8 (2.4 equiv),
PPh3 (3 equiv), DEAD (3 equiv), THF, 0 °C then rt, 2 d, 69%; (d)
o-dichlorobenzene, reflux, 14 h, 70%; (e) same procedure as for
steps (b) and (c) in Scheme 3, 10 56%, 4 85%.
In conclusion, the intramolecular version of our chiral
pyrroline N-oxide cycloaddition methodology has been
applied to the total synthesis of (-)-rosmarinecine. The
alkaloid has been obtained enantiomerically enriched (maxi-
mum 70% ee) by a novel domino protocol for inversion of
absolute configuration and control of relative configuration
via a Mitsunobu-intramolecular nitrone cycloaddition pro-
cess and enantiomerically pure by protection of the nitrone
followed by a Mitsunobu reaction and a cycloreversion-
intramolecular nitrone cycloaddition process. The study of
the scope and further application of these procedures is
underway in our laboratory.
The optical rotation value of 9 ([R]27 -53.5, c ) 0.39 in
D
CHCl3), compared to that of the same compound obtained
by the above process in Scheme 3, was consistent with
complete enantiomeric purity of the product. This was
1
confirmed by an H NMR spectrum of the Mosher ester of
lactam 10, which showed only one set of signals. Completion
of the synthesis according to the final steps of Scheme 3
gave enantiomerically pure 4, as confirmed by comparison
of its physical data (mp 166-168 °C, [R]20 -122.3, c )
D
0.61 in EtOH) with those reported for the natural product
(mp 168-170 °C, [R]21D -119.8, c ) 1.01 in EtOH).3b The
total synthesis of enantiopure (-)-rosmarinecine has been,
then, achieved in 11 steps and 7.2% overall yield (based only
on major cycloadduct 12) from diethyl L-malate.
Acknowledgment. We thank MURST (Ministero dell’Uni-
versita` e della Ricerca Scientifica e Tecnologica)-Italy for
financial support (Cofin 2000) and CNR (Consiglio Nazio-
nale delle Ricerche)-Italy for a postdoctoral fellowship to
F. Cardona.
(15) Cordero, F. M.; Gensini, M.; Goti, A.; Brandi, A. Org. Lett. 2000,
2, 2475.
(16) Nitrone 7 obtained by desilylation of the corresponding TBDMS-
and TIPS-protected nitrones has been erroneously reported as enantiomeri-
cally pure in earlier communications.7 Studies are in progress in order to
ascertain the origin and mechanism of this racemization process.
(17) (a) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 6469.
(b) Padwa, A.; Koehler, K. F. J. Chem. Soc., Chem. Commun. 1986, 789.
(18) (a) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.;
Chun Wong, S.; Asrof Ali, Sk. J. Am. Chem. Soc. 1979, 101, 2435. (b)
Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B. J. Am.
Chem. Soc. 1999, 121, 4900.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL015747O
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