Short, stereoselective synthesis of the naturally occurring pyrrolidine radicamine B and a formal synthesis of nectrisine

Article abstract of DOI:10.1021/jo8012989

(Chemical Equation Presented) A short, stereoselective synthesis of the naturally occurring pyrrolidine radicamine B is reported. Garner's (R)-aldehyde, prepared from D-serine, was the chiral starting material. The pyrrolidine ring was stereoselectively created in a very efficient way through a five-step, one-pot transformation. In addition, an intermediate of this synthesis was transformed into an intermediate of a previously published synthesis of the potent α-glucosidase inhibitor nectrisine.

Full text of DOI:10.1021/jo8012989

ago by Kusano and co-workers from Lobelia chinensis Lour.
(Campanulaceae), a plant used in Chinese folk medicine as a
diuretic, a hemostat, and a carcinostatic agent for stomach
cancer.3 Both compounds were found to exhibit inhibitory
activity on R-glucosidase.4 A strong inhibitory ability on
R-glucosidase and other glycosidases has also been found for
the ∆1-dehydropyrrolidine nectrisine 3, initially isolated as
immunomodulator FR-900483 from a strain of the fungus
Nectria lucida.5 The frequent association of this type of
biological property with useful pharmacological applications has
led to a significant synthetic effort on members of this compound
class.6
Short, Stereoselective Synthesis of the Naturally
Occurring Pyrrolidine Radicamine B and a
Formal Synthesis of Nectrisine
Celia Ribes,† Eva Falomir,*,† Miguel Carda,† and
J. Alberto Marco‡
Departamento de Qu´ımica Inorga´nica y Orga´nica, UniV.
Jaume I, E-12071 Castello´n, Spain, and Departamento de
Qu´ımica Orga´nica, UniV. de Valencia,
E-46100 Burjassot, Valencia, Spain
efalomir@qio.uji.es
ReceiVed June 23, 2008
Seven syntheses of nectrisine have been reported, including
one of the non-natural enantiomer.7,8 Various commercially
(3) (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G.
Chem. Pharm. Bull. 2001, 49, 1362–1365. (b) Shibano, M.; Tsukamoto, D.;
Kusano, G. Heterocycles 2002, 57, 1539–1553.
(4) (a) Ganem, B. Acc. Chem. Res. 1996, 29, 340–347. (b) Compain, P.;
Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077–3092. (c) Asano, N.
Glycobiology 2003, 13, 93R–104R.
(5) (a) Shibata, T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.; Terano, H.;
Kohsaka, M. J. Antibiot. 1988, 41, 296–301. (b) Tsujii, E.; Muroi, M.; Shiragami,
N.; Takatsuki, A. Biochem. Biophys. Res. Commun. 1996, 220, 459–466.
(6) (a) Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res. 1993, 26,
182–190. (b) Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927–
964. (c) Enders, D.; Thiebes, C. Pure Appl. Chem. 2001, 73, 573–578. (d) Yoda,
H. Curr. Org. Chem. 2002, 6, 223–243. (e) Cipolla, L.; La Ferla, B.; Nicotra, F.
Curr. Top. Med. Chem. 2003, 3, 485–511. (f) El-Ashry, E. H.; El-Nemr, A.
Carbohydr. Res. 2003, 338, 2265–2290. (g) Pyne, S. G.; Davis, A. S.; Gates,
N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004, 2670–
2680. (h) Popowycz, F.; Gerber-Lemaire, S.; Schu¨tz, C.; Vogel, P. HelV. Chim.
Acta 2004, 87, 800–810. (i) Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.;
Thomas, N. R. Org. Biomol. Chem. 2004, 2, 2418–2420. (j) Ayad, T.; Genisson,
Y.; Baltas, M. Curr. Org. Chem. 2004, 8, 1211–1233. (k) Izquierdo, I.; Plaza,
M. T.; Rodr´ıguez, M.; Franco, F.; Martos, A. Tetrahedron 2005, 61, 11697–
11704. (l) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–
2113. (m) Huang, P.-Q. Synlett 2006, 1133–1149. (n) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213–7256. (o) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. ReV. 2006, 106, 4484–4517. (p) Murruzzu, C.; Riera, A. Tetrahedron:
Asymmetry 2007, 18, 149–154. (q) Håkansson, A. E.; van Ameijde, J.;
Guglielmini, L.; Horne, G.; Nash, R. J.; Evinson, E. L.; Kato, A.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2007, 18, 282–289. (r) Martin, O. Ann. Pharm. Fr.
2007, 65, 5–13.
(7) (a) Chen, S.-H.; Danishefsky, S. J. Tetrahedron Lett. 1990, 31, 2229–
2232. (b) Kayakiri, H.; Nakamura, K.; Takase, S.; Setoi, H.; Uchida, I.; Terano,
H.; Hashimoto, M.; Tada, T.; Koda, S. Chem. Pharm. Bull. 1991, 39, 2807–
2812. (c) Kogoshi, N.; Takatsuki, A.; Kim, Y. J.; Kitahara, T. Heterocycles 1998,
49, 63–66. (d) Kim, Y. J.; Takatsuki, A.; Kogoshi, N.; Kitahara, T. Tetrahedron
1999, 55, 8353–8364. (e) Bosco, M.; Bisseret, P.; Bouix-Peter, C.; Eustache, J.
Tetrahedron Lett. 2001, 42, 7949–7952. (f) Hulme, A. N.; Montgomery, C. H.
Tetrahedron Lett. 2003, 44, 7649–7653. (g) Merino, P.; Delso, I.; Tejero, T.;
Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org.
Chem. 2008, 2929–2947.
A short, stereoselective synthesis of the naturally occurring
pyrrolidine radicamine B is reported. Garner′s (R)-aldehyde,
prepared from D-serine, was the chiral starting material. The
pyrrolidine ring was stereoselectively created in a very
efficient way through a five-step, one-pot transformation. In
addition, an intermediate of this synthesis was transformed
into an intermediate of a previously published synthesis of
the potent R-glucosidase inhibitor nectrisine.
The polyhydroxylated alkaloids (iminosugars) radicamines
A (1) and B (2) are two compounds belonging to the ample
group of the naturally occurring pyrrolidines.1 Members of this
compound class are known to exhibit a broad range of biological
activities.1d,2 Compounds 1 and 2 were isolated a few years
† Univ. Jaume I.
‡ Univ. de Valencia.
(1) (a) Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581–590. (b) O’Hagan, D.
Nat. Prod. Rep. 1997, 14, 637–651. (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17,
435–446. (d) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265–295.
(2) (a) Evans, S. V.; Fellows, L. E.; Shing, T. K. M.; Fleet, G. W. J.
Phytochemistry 1985, 24, 1953–1955. (b) Molyneux, R. J.; Pan, Y. T.; Tropea,
J. E.; Elbein, A. D.; Lawyer, C. H.; Hughes, D. J.; Fleet, G. W. J. J. Nat. Prod.
1993, 56, 1356–1364. (c) Tsuchiya, K.; Kobayashi, S.; Kurokawa, T.; Nakagawa,
T.; Shimada, N. J. Antibiot. 1995, 48, 630–634. (d) Asano, N. Curr. Top. Med.
Chem. 2003, 3, 471–484. (e) Greimel, P.; Spreitz, J.; Stu¨tz, A. E.; Wrodnigg,
T. M. Curr. Top. Med. Chem. 2003, 3, 513–523. (f) Compain, P.; Martin, O. R.
Curr. Top. Med. Chem. 2003, 3, 541–560. (g) Butters, T. D.; Dwek, R. A.; Platt,
F. M. Curr. Top. Med. Chem. 2003, 3, 561–574.
(8) Analogues and surrogates of nectrisine with a similar pharmacological
profile have also been prepared. See: (a) Tschamber, T.; Gessier, F.; Neuburger,
M.; Gurcha, S. S.; Besra, G. S.; Streith, J. Eur. J. Org. Chem. 2003, 2792–
2798. (b) Tschamber, T.; Gessier, F.; Dubost, E.; Newsome, J.; Tarnus, C.;
Kohler, J.; Neuburger, M.; Streith, J. Bioorg. Med. Chem. 2003, 11, 3559–3568.
10.1021/jo8012989 CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7779–7782 7779

SCHEME 2. Attempt at a Stereoselective Synthesis of
Radicamine B
available products (sugar derivatives, diethyl tartrate, D-serine)
were the chiral starting materials. Furthermore, four previous
syntheses of radicamine B (2) have very recently been reported,
one of the natural compound itself and three of its enantiomer.7g,9
These syntheses, which are almost identical and show only
marginal differences, used five-carbon sugars as starting materi-
als and relied on the same synthetic concept with a cyclic nitrone
as a key intermediate. Stereoselective addition of an arylmetal
reagent to the CdN bond of the nitrone was a key step in all
cases.7g,9
We now present an efficient synthesis of 2, performed
according to a different concept shown as a retrosynthetic plan
in Scheme 1. Thus, 2 should be available from mesylate 4 with
pyrrolidine ring formation via intramolecular nucleophilic
substitution. Compound 4 should be prepared from dihydroxy
ester 5, to be obtained in turn from Garner′s (R)-aldehyde via
olefination and dihydroxylation. In addition, compound 5 should
be amenable to an easy conversion into an intermediate of a
previous synthesis of nectrisine (compound 15, see Scheme 4).7f
This would thus amount to a formal synthesis of this natural
compound.
SCHEME 1. Retrosynthetic Analysis of Radicamine B (2)
into Weinreb amide 8.13,14Treatment of 8 with the Grignard
reagent p-benzyloxyphenyl magnesium bromide15 afforded
ketone 9, which was then stereoselectively reduced with
L-selectride to alcohol 10 (obtained as an 87:13 mixture of
diastereoisomers).16 Mesylation of 10 furnished 4, which was
then subjected in crude form to acidic conditions. These were
intended to cause initial cleavage of the acetonide and Boc
groups17 followed by intramolecular nucleophilic displacement
of the mesyl group with closure of the pyrrolidine ring.18
However, the only result was the formation of a ca. 2:1 mixture
(12) For examples of O-benzylation with this method, see: (a) Mislow, K.;
O’Brien, R. E.; Schaefer, H. J. Am. Chem. Soc. 1962, 84, 1940–1944. (b) Takai,
K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247–3251. (c) Marshall, J. A.;
Seletsky, B. M.; Luke, G. P. J. Org. Chem. 1994, 59, 3413–3420. (d) Chen,
M.-D.; He, M.-Z.; Zhou, X.; Huang, L.-Q.; Ruan, Y.-P.; Huang, P.-Q.
Tetrahedron 2005, 61, 1335–1344. (e) Yokokawa, F.; Inaizumia, A.; Shioiri, T.
Tetrahedron 2005, 61, 1459–1480.
(13) For reviews on Weinreb amides, see: (a) Mentzel, M.; Hoffmann,
H. M. R. J. Prakt. Chem. 1997, 339, 517–524. (b) Singh, J.; Satyamurthi, N.;
Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340–347. (c) Khlestkin, V. K.; Mazhukin,
D. G. Curr. Org. Chem. 2003, 7, 967–993.
(14) The conditions used for the preparation of Weinreb amide 8 were taken
from: Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U. H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
(15) Kamada, A.; Sasaki, A.; Kitazawa, N.; Okabe, T.; Nara, K.; Hamaoka,
S.; Araki, S.; Hagiwara, H. Chem. Pharm. Bull 2004, 52, 79–88. The Grignard
reagent has now become commercially available.
This retrosynthetic concept for pyrrolidine 2 was put into
practice as depicted in Scheme 2. The known dihydroxy ester
5 was prepared in two steps and 83% overall yield from Garner′s
(R)-aldehyde10 by means of a modification of the procedure
described for the preparation of the enantiomer.11 In order to
unambiguously confirm the stereostructure of 5, we converted
it into the crystalline acetonide 6.11 An X-ray diffraction analysis
of 6 secured its relative as well as its absolute configuration.
Benzylation of the hydroxyl groups in diol 5 with benzyl
bromide and silver oxide12 gave 7, which was then converted
(9) (a) Yu, C.-Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021–3024. (b) Gurjar,
M. K.; Borhade, R. G.; Puranik, V. G.; Ramana, C. V. Tetrahedron Lett. 2006,
47, 6979–6981. (c) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Goti, A. Synlett
2007, 2651–2654. (d) Liu, C.; Gao, J.; Yang, G.; Wightman, R. H.; Jiang, S.
Lett. Org. Chem. 2007, 4, 556–558.
(10) Prepared from D-serine according to: Campbell, A. D.; Raynham, T. M.;
Taylor, R. J. K. Synthesis 1998, 1707–1709. For a review on Garner’s aldehyde,
see: Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001,
2136–2157.
(11) Dondoni, A.; Merino, P.; Perrone, D. Tetrahedron 1993, 49, 2939–2956.
Our modification consisted in carrying out the dihydroxylation by means of the
Sharpless asymmetric procedure. In this way, the overall yield of 5 from Garner′s
(R)-aldehyde was improved from ca. 50 to 83% (see Experimental Section).
(16) The stereochemical course of the reduction of 9 was assumed to be as
depicted in Scheme 2 upon reliance on the results in the reduction of a ketone
closely related to 9 (with an alkyl residue instead of the aryl group), where the
configuration of the alcohol was secured by means of X-ray diffraction
(unpublished results).
(17) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999; pp 518-525.
(18) For some recent examples of pyrrolidine ring closure via intramolecular
nucleophilic displacement, see for example: (a) Yoda, H.; Asai, F.; Takabe, K.
Synlett 2000, 1001–1003. (b) Merino, P.; Franco, S.; Lafuente, D.; Mercha´n, F.;
Revuelta, J.; Tejero, T. Eur. J. Org. Chem. 2003, 2877–2881. (c) Chandrasekhar,
S.; Chandrasekhar, G.; Vijeender, K.; Sarma, G. D. Tetrahedron: Asymmetry
2006, 17, 2864–2869.
7780 J. Org. Chem. Vol. 73, No. 19, 2008

SCHEME 3. Stereoselective Synthesis of Radicamine B (2)
of stereoisomeric pyrrolidines 11 in low yield, accompanied by
extensive decomposition. This was attributed to the marked
instability of mesylate 4. Most likely, its benzylic nature caused
a marked tendency to react via a SN1 mechanism with formation
of an unstable carbocation and subsequent loss of stereochemical
control.19 We then tried other conditions for mesylation (-20
°C) and other sulfonylating reagents such as TsCl, NsCl, or
ClCH2SO2Cl20 but without success. Either decomposition or no
reaction at all was the only result observed.
In view of these failures in creating the C-N bond by means
of an intramolecular displacement, we modified our synthetic
concept and decided to form the pyrrolidine ring through
reduction of the CdN bond in a cyclic imine. Thus, treatment
of ketone 9 with anhydrous ZnBr2 in dry CH2Cl2 caused Boc
and acetonide cleavage21 with formation of the unstable imine
12, which was not isolated (Scheme 3). When crude 12 was
stirred under a H2 atmosphere in an acidic medium with a
palladium catalyst,22 it only furnished in low overall yield a
mixture of radicamine B (2) and pyrrolidine 13, the non-natural
epimer of 2 at C-5.23,24 Attempts at reduction of 12 with
NaCNBH3 only caused decomposition.6k,25 The instability of
imine 12 suggested that it should be generated and reduced in
situ in an one-pot procedure.26 Indeed, when ketone 9 was stirred
under H2 in the same conditions as above, the desired 2 was
formed as the major compound (ca. 60% yield), together with
small amounts of 13 (3%) and the primary amine 14 (11%), a
hydrogenolysis product of 2 and/or 13.24 It is worth noting here
that 2 is formed in a one-pot manner through of a sequence of
five steps (the precise order is not known): hydrogenolytic
cleavage of the three benzyl groups, acidic cleavage of the Boc
and the acetonide groups, intramolecular imine formation, and
reduction of the imine CdN bond.
SCHEME 4. Formal Synthesis of Nectrisine 3
in terms of overall yield28 than those reported in the previous
syntheses of either 2 or its enantiomer.7g,9 Furthermore, we have
used an intermediate of this synthesis to perform a formal
synthesis of the glycosidase inhibitor nectrisine 3.
As commented above, dihydroxy ester 5 could be readily
converted into an intermediate of a previous synthesis of
nectrisine.7f Acid treatment of 5 caused cleavage of the Boc
and acetonide groups, followed by in situ spontaneous formation
of the lactam ring. This gave a crude triol which was then
subjected to selective silylation of the primary alcohol group
to yield pyrrolidinone 15 in 67% overall yield (eight steps and
47% yield from D-serine). Since 15 was a late intermediate in
Hulme′s synthesis of 3,7f,27 this constitutes a formal synthesis
of this natural compound.
In summary, we have performed an efficient, stereoselective
synthesis of the glycosidase inhibitor radicamine B 2 in six steps
and 38% overall yield from Garner′s (R)-aldehyde. This
corresponds to 10 steps and 32% overall yield from the
commercially available D-serine.10 This result is markedly better
Experimental Section
General experimental features are described in the Supporting
Information.
tert-Butyl (4R)-4-[(1R,2S)-1,2-bis(benzyloxy)-3-(4-benzylox-
yphenyl)-3-oxopropyl]-2,2-dimethyloxazolidine-3-carboxylate (9).
4-Benzyloxyphenylmagnesium bromide was generated from the
corresponding bromide according to the reported procedure.15
Weinreb amide 8 (400 mg, ca. 0.75 mmol) was dissolved under
N2 in dry THF (4 mL) and treated dropwise at 0 °C with the
aforementioned Grignard reagent (3 mmol, 4 equiv). The reaction
mixture was then stirred for 1 h at the same temperature. Workup
(extraction with Et2O) and column chromatography of the oily
residue on silica gel (hexanes-EtOAc, 9:1) provided 9 (436 mg,
1
89%): oil; [R]D -3 (c 1.5, CHCl3); H NMR (500 MHz, DMSO-
d6, 70 °C) δ 8.02 (2H, d, J ) 8.8 Hz), 7.50-7.20 (14H, br m),
7.10 (3H, m), 5.22 (2H, s), 4.76 (1H, br d, J ) 4 Hz), 4.50-4.45
(4H, br m), 4.38 (1H, br d, J ) 11.2 Hz), 4.15 (1H, dd, J ) 8.7,
3.6 Hz), 3.92 (1H, br s), 3.89 (1H, br t, J ) 8 Hz), 1.41 (12H, s),
1.40 (3H, s); 13C NMR (125 MHz, DMSO-d6, 70 °C) δ 208.8*,
162.2, 151.5*, 137.4, 137.3, 136.2, 128.7, 92.9, 79.3 (C), 130.8
(x2), 128.1 (x2), 127.9 (x2), 127.6 (x3), 127.5 (x3), 127.3 (x2),
127.2 (x2), 114.4 (x2), 127.0, 84.2, 78.8*, 58.6* (CH), 74.1, 71.8,
69.4, 62.8 (CH2), 27.8 (x3), 25.6*, 23.9* (starred signals are low
and broad); IR νmax 1690 (br, CdO) cm-1; HR FAB MS m/z
652.3281 (M + H+). Calcd for C40H46NO7, 652.3274.
(19) This idea was suggested by the fact that acidic treatment of alcohol 10
under similar conditions as 4 (TFA, 1 h, 0 °C) also gave a 2:1 mixture of
pyrrolidines 11, together with extensive decomposition.
(20) Shimizu, T.; Ohzeki, T.; Hiramoto, K.; Hori, N.; Nakata, T. Synthesis
1999, 1373–1385.
(21) Ribes, C.; Falomir, E.; Murga, J. Tetrahedron 2006, 62, 1239–1244.
(22) (a) Card, P. J.; Hitz, W. D. J. Org. Chem. 1985, 50, 891–893. (b)
Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 8146–8151. (c) Espelt, L.; Parella, T.; Bujons, J.; Solans,
C.; Joglar, J.; Delgado, A.; Clape´s, P. Chem.sEur. J. 2003, 9, 4887–4899.
(23) Mixtures of 2 and 13 (5-epi-radicamine B) of variable composition were
obtained, with the undesired 13 being always the major compound.
(24) For a synthesis of 13, see: Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-
Q. Tetrahedron 2007, 63, 6346–6357.
tert-Butyl (4R)-4-[(1R,2R,3S)-1,2-bis(benzyloxy)-3-(4-benzy-
loxyphenyl)-3-hydroxypropyl]-2,2-dimethyloxazolidine-3-car-
boxylate (10). A solution of ketone 9 (195 mg, 0.3 mmol) in dry
(25) Wong, C.-H.; Provencher, L.; Jung, S.-H.; Wang, Y.-F.; Chen, L.; Wang,
R.; Steensma, D. H. J. Org. Chem. 1995, 60, 1492–1501.
(26) For a similar situation, see for example: Yu, D.-S.; Xu, W.-X.; Liu,
L.-X.; Huang, P.-Q. Synlett 2008, 1189–1192.
(27) Hulme, A. N.; Montgomery, C. H.; Henderson, D. K. J. Chem. Soc.,
Perkin Trans. 1 2000, 1837–1841.
(28) The syntheses reported in ref 7g, 9 involve reaction sequences of 9-11
steps from D-xylose, L-xylose, or L-arabinose as the starting materials. Overall
yields were in the range from 8 to 17%.
J. Org. Chem. Vol. 73, No. 19, 2008 7781

THF (2 mL/mmol) was cooled under N2 to -78 °C and treated
dropwise with a 1 M solution of L-selectride in THF (0.6 mL, 0.6
mmol). The mixture was stirred for 3 h at the same temperature
and then quenched through addition of 10% aq NaOH (0.7 mL)
and 30% H2O2 (0.45 mL). Further stirring for 20 min at 0 °C and
workup (extraction with Et2O) gave an oily residue which was
chromatographed on silica gel (hexanes-EtOAc, 9:1). This yielded
alcohol 10 as an 87:13 mixture of diastereoisomers (determined
(2H, apparent d, J ) 8.6 Hz), 4.18 (1H, dd, J ) 9, 7.5 Hz), 4.03
(1H, t, J ) 7.5 Hz), 4.00 (1H, br d, J ) 9 Hz), 3.84 (1H, dd, J )
11.5, 4.5 Hz), 3.77 (1H, dd, J ) 11.5, 6.5 Hz), 3.34 (1H, ddd, J )
7.5, 6.5, 4.5 Hz); 13C NMR (125 MHz, D2O) δ 158.5, 133.2 (C),
131.8 (x2), 118.6 (x2), 84.3, 79.8, 66.1, 64.4 (CH), 64.8 (CH2).
Radicamine B (2) and 5-epi-Radicamine B (13) via Imine
12. Ketone 9 (195 mg, 0.3 mmol) was dissolved in dry CH2Cl2 (3
mL) and treated with anhydrous ZnBr2 (675 mg, 3 mmol). The
mixture was then stirred for 20 min at room temperature. Quenching
was performed by means of addition of saturated aq EDTA (15
mL). Extraction with CH2Cl2 (3 × 15 mL), drying of the organic
layer on anhyd Na2SO4, and removal of all volatiles under reduced
pressure gave an oily residue containing 12 which was used directly
in the next reaction. Hydrogenation was performed under the same
conditions as above. The column chromatography on silica gel
afforded a ca. 2:1 mixture of 13 and 2 (24 mg, 35% overall).
1
by H NMR) (174 mg, 89%), which could not be separated. This
mixture was used in the mesylation step.
(2R,3R,4R,5R,S)-3,4-Bis(benzyloxy)-5-(4-benzyloxyphenyl)-2-
hydroxymethylpyrrolidine (11). The mixture of diastereoisomeric
alcohols 10 from above was dissolved under N2 in dry CH2Cl2 (2
mL), cooled to 0 °C, and treated with MsCl (40 µL, ca. 0.5 mmol),
Et3N (140 µL, 1 mmol), and DMAP (3 mg, 0.025 mmol). The
mixture was stirred at 0 °C for 1 h. Workup (extraction with
CH2Cl2) gave an oily residue which was dissolved at 0 °C in dry
CH2Cl2 (1 mL), treated with trifluoroacetic acid (1 mL), and stirred
at the same temperature for 1 h. The volatiles were then removed
under reduced pressure, and the oily residue was dissolved in MeOH
and treated with aqueous ammonia until basic pH. Evaporation to
dryness gave an oily residue which was then chromatographed on
silica gel (CH2Cl2-MeOH, 19:1). This yielded a 2:1 mixture of
diastereoisomers 11 (46 mg, 35%) identified by hydrogenolytic
conversion to a mixture of 2 and 13 (identified in turn through
(3S,4R,5R)-5-(tert-Butyldiphenylsilyloxymethyl)-3,4-dihydrox-
ypyrrolidin-2-one (15). An ice-cooled solution of dihydroxy ester
5 (67 mg, 0.2 mmol) in CH2Cl2 (1 mL) was treated with
trifluoroacetic acid (1 mL). The mixture was then stirred for 2 h at
0 °C. Removal of all volatiles under reduced pressure gave a residue
which was dissolved in dry DMF (2 mL) and treated under N2
with tert-butyldiphenylsilyl chloride (57 µL, 0.22 mmol) and
imidazole (30 mg, 0.45 mmol). The mixture was then stirred for
16 h at room temperature. Workup (extraction with Et2O) and
column chromatography on silica gel (EtOAc) provided 15 (51 mg,
67%): oil; [R]D +10.3 (c 0.9, CHCl3), lit.27 [R]D +11.5 (c 1.1,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.65-7.60 (4H, m),
7.45-7.35 (6H, br m), 6.20 (1H, s, NH), 4.90 (1H, br s, OH), 4.28
(1H, d, J ) 7.5 Hz), 3.99 (1H, t, J ) 7.5 Hz), 3.90 (1H, br s, OH),
3.89 (1H, dd, J ) 10.5, 3 Hz), 3.62 (1H, dd, J ) 10.5, 7.5 Hz),
3.52 (1H, td, J ) 7.5, 3 Hz), 1.05 (9H, s); 13C NMR (125 MHz,
CDCl3) δ 174.3, 132.8, 132.7, 19.2 (C), 135.5, 135.4, 130.1, 130.0,
127.9 (x6), 76.4, 75.9, 58.2 (CH), 64.5 (CH2), 26.9 (x3) (CH3); IR
7g,9,24
1
their H and 13C NMR spectra).
(2R,3R,4R,5R)-2-(Hydroxymethyl)-5-(4-hydroxyphenyl)pyr-
rolidine-3,4-diol, Radicamine B (2). Ten percent palladium on
carbon (Degussa-type E101 NE/W, 180 mg) was suspended in
MeOH (5 mL) and stirred under an H2 atmosphere for 5 min.
Ketone 9 (195 mg, 0.3 mmol) was dissolved in MeOH (20 mL)
and mixed with 6 M aqueous HCl (2 mL). The mixture was then
added via syringe to the catalyst suspension, which was then stirred
for 16 h at room temperature and ambient pressure. Filtration
through Celite and removal of all volatiles under reduced pressure
gave a residue which was dissolved in MeOH (10 mL) and treated
dropwise with 33% aq NH3 until basic pH. Removal of the solvent
under reduced pressure gave a residue which was put on the top of
a ion-exchange resin column (Dowex 50W × 4 200-400, prea-
cidified with 0.5 M HCl). Elution with water (50 mL) and then 1
M aq NH3 (15 mL), followed by removal of the volatiles of the
latter fraction under reduced pressure, gave a brownish residue
which was subjected to column chromatography on silica gel
(CHCl3-MeOH-aq NH3, gradient from 95:4:1 to 70:29:1). This
yielded a mixture of 2, 13, and 14 (50 mg, 74% overall), which
could not be separated by means of standard chromatography. Final
purification took place with the aid of HPLC (LiChroCART
250-10, elution with MeCN/H2O 60:40, 2 mL/min). This gave 2
(40 mg, 60%), 13 (2 mg, 3%), and 14 (7 mg, 11%).
νmax 3300 (br, OH), 1708 (CdO) cm-1
.
Acknowledgment. Financial support has been granted by the
Ministerio de Educacio´n y Ciencia (projects CTQ2005-06688-
C02-01 and CTQ2005-06688-C02-02), and by the BANCAJA-
UJI foundation (projects P1-1A-2005-15 and P1-1B-2005-30).
C.R. further thanks the Ministerio of Educacio´n y Ciencia of
Spain for a FPU fellowship.
Supporting Information Available: Description of general
and experimental features. Graphical 1H and 13C NMR spectra
of compounds 2, 5, 6, 7, 8, 9, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
2: oil; [R]D +73.6 (c 0.1, H2O), lit.3a [R]D +72 (c 0.1, H2O); 1H
NMR (500 MHz, D2O) δ 7.38 (2H, apparent d, J ) 8.6 Hz), 6.98
JO8012989
7782 J. Org. Chem. Vol. 73, No. 19, 2008