Total synthesis of the amaryllidaceae alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions

Article abstract of DOI:10.1002/1521-3773(20020617)41:12<2194::AID-ANIE2194>3.0.CO;2-4

A sequence of polymer-supported reagents and scavengers was used to promote the synthetic transformations in the first total synthesis of (+)-plicamine (1), a member of the amaryllidaceae alkaloid family, starting from L-4-hydroxyphenylglycine (see scheme).

Full text of DOI:10.1002/1521-3773(20020617)41:12<2194::AID-ANIE2194>3.0.CO;2-4

COMMUNICATIONS
À
À
À
Sellmann, E. Bˆhlen, M. Waeber, G. Huttner, L. Zsolnai, Angew.
Chem. 1985, 97, 984; Angew. Chem. Int. Ed. Engl. 1985, 24, 981; f) D.
Sellmann, W. Soglowek, F. Knoch, M. Moll, Angew. Chem. 1989, 101,
1244; Angew. Chem. Int. Ed. Engl. 1989, 28, 1271; g) J. P. Collman,
J. E. Hutchison, M. A. Lopez, R. Guilard, R. A. Reed, J. Am. Chem.
Soc. 1991, 113, 2794; h) D. Sellmann, J. K‰ppler, M. Moll, F. Knoch,
Inorg. Chem. 1993, 32, 960; i) D. Sellmann, K. Engl, F. W. Heinemann,
J. Sieler, Eur. J. Inorg. Chem. 2000, 1079.
[16] Coordination geometry for 2: Re N 2.12(1), Re CO 2.14(1), Re P
À
À
À
2.354(4), NH N 1.251(4), N C 1.36(2), C O 1.12(1) ä; Re-N-N
145(2), N-N-C 123(2)8.
[17] Preliminary investigations show the presence of traces of ammonia in
the final reaction mixture, but no other nitrogen-containing com-
pound was unambiguously identified, and therefore no reaction path
may be reasonably proposed.
[18] Metal-mediated N N or N N bond activation is a topic of current
interest. For some recent examples see: A. K. Verma, S. C. Lee, J. Am.
Chem. Soc. 1999, 121, 10838; R. G. Peters, B. P. Warner, C. J. Burns, J.
Am. Chem. Soc. 1999, 121, 5585; M. A. Aubart, R. G. Bergman,
Organometallics 1999, 18, 811; F. Maseras, M. A. Lockwood, O.
Eisenstein, I. P. Rothwell, J. Am. Chem. Soc. 1998, 120, 6598.
À
ˆ
[2] a) M. R. Smith III, R. L. Keys, G. L. Hillhouse, A. L. Rheingold J.
Am. Chem. Soc. 1989, 111, 8312; b) M. R. Smith III, T.-Y. Cheng, G. L.
Hillhouse, J. Am. Chem. Soc. 1993, 115, 8638; c) T.-Y. Cheng, A.
Ponce, A. L. Rheingold, G. L. Hillhouse, Angew. Chem. 1994, 106,
703; Angew. Chem. Int. Ed. Engl. 1994, 33, 657; d) T.-Y. Cheng, J. C.
Peters, G. L. Hillhouse, J. Am. Chem. Soc. 1994, 116, 204; e) D. Sutton,
Chem. Rev. 1993, 93, 995.
[3] a) G. Albertin, S. Antoniutti, A. Bacchi, E. Bordignon, F. Busatto, G.
Pelizzi, Inorg. Chem. 1997, 36, 1296; b) G. Albertin, S. Antoniutti, E.
Bordignon, S. Pattaro, J. Chem. Soc. Dalton Trans. 1997, 4445; c) G.
Albertin, S. Antoniutti, A. Bacchi, M. Bergamo, E. Bordignon, G.
Pelizzi, Inorg. Chem. 1998, 37, 479.
[4] a) K. H. Geib, P. Harteck, Ber. Dtsch. Chem. Ges. B 1933, 66, 1815;
b) K. H. Geib, P. Harteck, Trans. Faraday Soc. 1934, 30, 131.
[5] a) J. E. Dickens, W. M. Irvine, C. H. DeVries, M. Ohishi, Astrophys. J.
1977, 497, 307; b) G. Winnewisser, C. Kramer, Space Sci. Rev. 1999, 90,
181.
À
[19] Interest in cleavage of the N N bond of hydrazine stems from its
importance to inorganic and bioinorganic reducing system(s): a) A. E.
Shilov, Metal Complexes in Biomimetic Chemical Reactions, CRC,
Boca Raton, FL, 1997; b) R. R. Eady, Chem. Rev. 1996, 96, 3013;
c) G. J. Leigh, Science 1995, 268, 827; d) R. R. Schrock, T. E. Glass-
man, M. G. Vale, J. Am. Chem. Soc. 1991, 113, 725; e) S. M. Malinak,
K. D. Demadis, D. Coucouvanis, J. Am. Chem. Soc. 1995, 117, 3126;
f) D. Sellmann, J. Sutter, Acc. Chem. Res. 1997, 30, 460.
[6] F. Hoyle, N. C. Wickramasinghe, Nature 1976, 264, 45.
[7] P. A. Shapley, J. M. Shusta, J. C. Hunt, Organometallics 1996, 15,
1622.
¬
[8] G. Albertin, S. Antoniutti, S. Garcia-Fontan, R. Carballo, F. Padoan, J.
Chem. Soc. Dalton Trans. 1998, 2071.
Total Synthesis of the Amaryllidaceae Alkaloid
(‡)-Plicamine and Its Unnatural Enantiomer
by Using Solid-Supported Reagents and
Scavengers in a MultistepSequence of
Reactions**
[9] X-ray structural analysis: Philips PW1100 diffractometer equipped
with a scintillation counter, graphite-monochromated MoKa radiation
(l ˆ 0.71069 ä). Data correction for absorption effects by the y scan
method[10] for both compounds, and intensity decay correction (40%)
for 2-BPh4. Structural determination: direct methods[11] and full-
matrix least-squares refinement on all F2.[12] Anisotropic displacement
parameters refined in both cases for all non-hydrogen atoms; hydro-
gen atoms were introduced in idealized positions. Phosphite and
phenyl groups were restrained to agree with typical bonding geometry
from the literature. Crystal data for 2-BPh4: C50H84BN2O13P4Re,
MW ˆ 1242.12, crystal dimensions 0.3  0.2  0.2 mm3, space group
P21/c, monoclinic, a ˆ 13.002(2), b ˆ 24.570(5), c ˆ 20.054(4) ä, b ˆ
Ian R. Baxendale, Steven V. Ley,* and Claudia Piutti
Amaryllidaceae alkaloids are an important class of natural
products especially as many members of the series display a
wide range of potent biological activity. These properties
include anticholinergic, antitumor, immunosuppresive, and
analgesic activity, and they have also been shown to inhibit
various cell cycle mechanisms (including HIV-1 activity), and
have found recent application in the therapeutic treatment of
Alzheimer×s disease.[1] Thus extensive synthetic studies of this
family have been carried out over a number of years.[2, 3]
Furthermore, the search for new members of the series has
proved to be extremely profitable.[3, 4] The recently isolated
compound (‡)-plicamine (1) is especially attractive as it
exemplifies many of the structural features of these natural
95.49(2)8, Vˆ 6377(2) ä3, Z ˆ 4, 1calcd ˆ 1.308 gcmÀ3
,
qmax ˆ 308,
18990 measured reflections (18537unique), 4388 unique observed
(I > 2s(I)), R1 ˆ 0.095, wR2 ˆ 0.26 (on observed data), 176 restraints,
601 parameters, GOF ˆ 0.845. Crystal data for 3-BPh4:
C50H83BNO13P4Re, MW ˆ 1227.11, crystal dimensions 0.4 0.3 Â
3
≈
0.2 mm , space group P1, triclinic, a ˆ 15.393(5), b ˆ 16.977(5), c ˆ
12.916(5) ä, a ˆ 100.02(5), b ˆ 91.63(5), g ˆ 71.08(5)8, Vˆ
3143(2) ä3, Z ˆ 2, 1calcd ˆ 1.290 gcmÀ3, qmax ˆ 288, 15138 measured
unique reflections, 8634 unique observed (I > 2s(I)), R1 ˆ 0.048,
wR2 ˆ 0.115 (on observed data), 611 parameters, 79 restraints,
GOF ˆ 0.912. CCDC-181120 (2-BPh4) and CCDC-181121 (3-BPh4)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-033;
or deposit@ccdc.cam.ac.uk).
[*] Prof. S. V. Ley, I. R. Baxendale
Department of Chemistry
[10] A. C. T. North, D. C. Phillips, F. S. Mathews, Acta. Crystallogr. Sect. A
1968, 24, 351.
[11] SIR97: A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 1994, 27;,
435.
[12] G. M. Sheldrick, SHELXL-97, Program for structure refinement,
University of Gˆttingen, Gˆttingen (Germany), 1997.
[13] W. A. Herrmann, L. K. Bell, M. L. Ziegler, H. Pfisterer, C. Pahl, J.
Organomet. Chem. 1983, 247, 39.
[14] J. Vicente, M. T. Chicote, M. D. Abrisqueta, R. Guerrero, P. G. Jones,
Angew. Chem. 1997, 109, 1252; Angew. Chem. Int. Ed. Engl. 1997, 36,
1203.
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (‡44)1223-336-442
E-mail: svl1000@cam.ac.uk
C. Piutti
Department of Chemistry
Pharmacia S.p.A
Discovery Research Oncology
Viale Pasteur, 10, 20014 Nerviano (MI) (Italy)
[**] We gratefully acknowledge financial support from Pfizer Central
Research for a Postdoctoral Fellowship (to I.R.B.), the BP endowment
and the Novartis Research Fellowship (to S.V.L.), and Pharmacia &
Upjohn (to C.P.).
[15] D. A. Knight, M. A. Dewey, G. A. Stark, B. K. Bennett, A. M. Arif,
J. A. Gladysz, Organometallics 1993, 12, 4523.
2194
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2194 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 12

COMMUNICATIONS
products and has not been
previously synthesized nor
have its biological proper-
ties been fully evaluated.[5]
Here, we report a con-
ceptionally interesting ap-
proach to both enantiom-
ers of plicamine 1 using an
orchestrated multistep se-
quence of reactions, for
methylated by using trimethylsilyldiazomethane and a macro-
porous sulfonic acid exchange resin to give 7.[15] The stereo-
selectivity in this reaction was confirmed by X-ray crystallo-
graphic studies and detailed NOE experiments. Next, the
trifluoroacetate protecting group was removed by treatment
with Ambersep 900 (OHÀ form) in methanol in a sealed tube
microwave reactor at 1008C for 20 min.[16] The intermediate
amino compound 8 was readily alkylated with bromide 10 in
the presence of a solid-supported carbonate base[17] to give 9.
Excess bromide 10 was scavenged by using a mercaptoami-
nomethyl resin[18] and the product was obtained in excellent
yield and purity. It should be noted that the bromide 10 is not
commercially available and was prepared from the corre-
sponding alcohol 11 by using carbon tetrabromide or bromine
and an immobilized triphenylphosphane.[19] The alkylated
material 9 was immediately oxidized to the amide 1 by using
chromium trioxide and 3,5-dimethylpyrazole.[20] This reaction
proved to be the most difficult transformation in the
sequence, requiring scavenging with solid Amberlyst 15 resin
to remove contaminating unoxidized amine and the pyrazole.
The chromium salts could be efficiently removed by passing
the reaction mixture through a mixed-bed column of Varian
Chem Elut CE1005 packing material[21] and montmorillonite
K 10 (1:1 wt/wt), which had been preconditioned by eluting
with a 10:1 mixture of acetonitrile/water. After this process of
scavenging, (‡)-plicamine 1 was obtained in 70% yield and
greater than 90% purity (by HPLC). To obtain analytically
pure material a rapid pass through a short plug of silica gel
was sufficient.[22] Following the same reaction sequence, we
have also been able to prepare the unnatural enantiomer (À)-
plicamine in essentially identical yields and purity starting
from d-4-hydroxyphenylglycine.[23]
MeO
H
Me
O
N
H
O
N
O
O
1
OH
which only solid-supported reagents and scavengers are used
to effect the individual steps.[6] In this way, work-up of the
reaction mixture is greatly facilitated, requiring only the
simple operation of filtration to remove spent or excess
reagents followed by evaporation to afford the product. No
conventional work-up procedures such as chromatography,
crystallization, or distillation are necessary. These methods
not only expediate the synthesis reported here but also have
relevance for chemical compound library generation. For
example, we have previously shown that these approaches can
be used to prepare druglike substances,[7] heterocyclic com-
pounds,[8] and other natural products.[9]
Both enantiomers of plicamine 1 have been synthesized by
the appropriate selection of the commercially available
optically pure form of 4-hydroxyphenylglycine. The synthesis
of (‡)-plicamine reported below, begins with the conversion
of l-4-hydroxyphenylglycine to the amide 2 (see Scheme 1).
The initial reaction with trimethylsilyl chloride (TMSCl) in
methanol resulted in the formation of an intermediate methyl
ester. Subsequent treatment with Amberlyst 21 resin, to act as
a scavenger for hydrochloric acid, produced the free base.
Addition of excess methylamine to the reaction mixture
afforded the amide 2 in essentially quantitative yield. At all
stages of the synthesis the product purity was evaluated by
LC-MS and in all cases was found to be in excess of 95%
unless stated. This level of purity was more than adequate to
progress directly to the next step in the synthesis. Following
procedures reported previously for the synthesis of oxomar-
itidine,[9c] the amino group in 2 was allowed to react with
piperonal 3 and the resulting imine reduced with polymer-
supported borohydride[10] in methanol and dichloromethane
to give the reductively aminated product. The amine was
immediately acylated with trifluoroacetic anhydride to give
the protected amine 4. Polymer-supported aminomethylpy-
ridine (poly-DMAP) in the presence of polyvinylpyridine
(PVP) was used as the catalyst in this transformation.[11] All
these reactions were easily carried out on multigram scale to
give the clean product 4 in 91% overall yield over the six steps
(>97% purity by HPLC; Scheme 1). Phenol oxidative
coupling of 4 gave the spirodieneone 5 (82% yield)[12] through
the use of the solid-supported iodonium diacetate[13] in 2,2,2-
trifluoroethanol as the solvent. Compound 5 was efficiently
cyclized to the tetracyclic lactam 6 by using Nafion-H resin in
dichloromethane (alternatively a solution of HCl in diethyl
ether could be employed). Again the purity of the product at
all stages of this synthesis was excellent, the product required
no chromatography prior to advancing to the next step. The
ketone 6 was stereoselectively reduced by using polymer-
supported borohydride,[14] and the resulting alcohol was
In summary, we have reported the first total synthesis of
(‡)-plicamine (1) and its enantiomer using only a combina-
tion of supported reagents and scavengers to effect all the
synthetic steps. No less than thirteen immobilized systems
were used to produce the clean product. Given the relative
complexity of the molecule, the synthesis is a powerful
demonstration of the ability to achieve multistep transforma-
tions without conventional chromatographic methods.
Received: February 15, 2002 [Z18719]
[1] a) C. W. Fennell, J. van Staden, J. Ethnopharmacol. 2001, 78, 15 26,
and references therein; b) B. S. Min, Y. H. Kim, M. Tomiyama, N.
Nakamura, H. Miyashiro, T. Otake, M. Hattori, Phytother. Res. 2001,
15, 481 486; c) S. Yui, M. Mikami, Y. Mimaki, Y. Sashida, M.
Yamazaki, Yakugaku Zasshi 2001, 121, 167 171; d) E. Furusawa, S.
Furusawa, J. Y. B. Lee, S. Patanavanich, Proc. Soc. Expl. Biol. Med.
1976, 152, 186 197, and references therein; e) E. Furusawa, H. Irie, D.
Combs, W. C. Wildman, Chemotherapy 1980, 26, 36 41; f) E.
Furusawa, S. Furusawa, J. Y. B. Lee, S. Patanavanich, Chemotherapy
1983, 29, 294 302; g) E. Furusawa, S. Furusawa, Onocology 1988, 45,
180 186; h) M. D. Antoun, N. T. Mendoza, Y. R. Rios, G. R. Proctor,
D. B. M. Wickramaratne, J. M. Pezzuto, A, D. Kinghorn, J. Nat. Prod.
1993, 56, 1423 1425; i) E. Furusawa, S. Furusawa, Chemotherapy
¬
1986, 32, 521 529; j) A. Missoum, M.-E. Sinibaldi, D. Vallee-Goyet,
J.-C., Gramain, Synth. Commun. 1997, 27, 453 466.
[2] a) P. W. Jeffs in MTP International Review of Science, Alkaloids,
Organic Chemistry, Series One, Vol. 9 (Eds.: D. H. Hey, K. F.
Wiesner), Butterworth, London, 1973, pp. 273 318; b) S. F. Martin
Angew. Chem. Int. Ed. 2002, 41, No. 12
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2195 $ 20.00+.50/0
2195

COMMUNICATIONS
OH
H2N
CO2H
a) TMSCl/MeOH
NEt2
b)
c) NH2Me
O
OH
OH
O
O
OAc
OAc
O
I
g)
d)
O
3
O
O
NHMe
O
_
+
O
O
O
NMe3BH4
O
e)
f)
N
N
H2N
NHMe
CF3
5
NHMe
CF3
(CF3CO)2O, DCM
N
O
2
4
h)
CF2SO3H
N
N
O
MeO
MeO
H
Me
O
H
H
N
Me
Me
_
+
_
N
+
N
i)
j)
NMe3BH4
k)
NMe3 OH
H
O
O
N
O
H
CF3
TMS-CHN2
SO3H
O
N
H
MeOH
O
N
CF3
O
O
H
O
6
8
O
O
7
_
+
NEt3 (NaCO3)
m)
l)
PPh2
CBr4 or Br2
OH
Br
HO
HO
10
11
SH
n)
N
H
MeO
MeO
H
H
Me
O
H
Me
O
N
N
N
N
o) CrO3
H
O
N
H
O
N
O
SO3H
Clay scavenge
p)
q)
O
O
9
(+)-plicamine 1
OH
OH
Scheme 1. Total synthesis of (‡)-plicamine (1). a) TMSCl (3 equiv), MeOH, RT, 12 h; b) Amberlyst 21 (3 equiv ꢀ3 mmolgÀ1); c) NH2Me (5 equiv), MeOH,
408C, 24 48 h; d) piperonal 3 (1.1 equiv), EtOAc, RT, 45 min; e) PS-borohydride, MeOH/CH2Cl2 (2:1), 2 h; f) (CF3CO)2O, PVP (3 equiv), poly-DMAP
(0.5 equiv), CH2Cl2, 08C, 1 h, (91% over six steps); g) PS-iodinium diacetae (1.5 equiv), 2,2,2-trifluoroethanol, À58C, 82%; h) Nafion-H, 24 h; i) PS-
borohydride, MeOH/CH2Cl2 (1:1) 2 h, quantitative; j) TMS-CHN2, sulfonic acid resin, MeOH/CH2Cl2 (3:2), 95%; k) Ambersep 900 (OHÀ), MeOH,
microwave, 1008C, 20 min, 96%; l) PS-triphenylphosphane (2 equiv), CBr4 (1.5 equiv) or Br2 (1.5 equiv), CH2Cl2, 08C, 1 h, quantitative; m) PS-carbonate
(2 equiv), bromide 10 (1.2 equiv), MeCN, microwave, 1408C, 2 Â 15 min; n) PS-mercaptoaminomethyl resin, 90% (two steps); o) CrO3 (2.5 equiv), 3,5-
dimethylpyrazole (2.5 equiv), CH2Cl2, À458C, 4 h, 82% conversion by LC-MS; p) Amberlyst 15 (10 equiv); q) (1:1 wt/wt) montmorillonite K 10/Varian
Chem Elut CE1005 packing material, 70% (isolation for three steps o q).
2196
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2196 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 12

COMMUNICATIONS
in The Alkaloids, Vol. 30 (Ed.: A. Brossi), Academic Press, New York,
1987, p. 251; c) J. R. Lewis, Nat. Prod. Rep. 2001, 18, 95 128.
[3] a) J. H. Rigby, A. Cavezza, M. J. Goekjian, J. Am. Chem. Soc. 1998,
120, 3613 3622; b) J. D. White, W. K. M. Chong, K. Thirring, J. Org.
Chem. 1983, 48, 2300 2304; c) J. B. Hendrickson, T. L. Bogard, M. E.
Fisch, S. Grossert, N. Yoshimura, J. Am. Chem. Soc. 1974, 96, 7781
7789; d) Y. Tsuda, A. Ukai, K. Isobe, Tetrahedron Lett. 1972, 3153
3156; e) S. J. Danishefsky, J. Morris, G. Mullen, R. Gammill, J. Am.
Chem. Soc. 1982, 104, 7591 7599; f) M. M. Abelman, L. E. Overman,
D. V. Tran, J. Am. Chem. Soc. 1990, 112, 6959 6964; g) L. E.
Overman, H. Wild, Tetrahedron Lett. 1989, 30, 647 650; h) H.
Ishibashi, H. Nakatani, S. Iwami, T. Sato, N. Nakamura, M. Ikeda, J.
Chem. Soc. Chem. Commun. 1989, 1767 1769; i) T. Nishimata, M.
Mori, J. Org. Chem. 1998, 63, 7586 7586; j) D. J. Watson, A. I.
Meyers, Tetrahedron Lett. 2000, 41, 1519 1522.
[4] a) J. Bastida, J. M. Llabres, F. Viladomat, C. Codina, M. Rubiralta, M.
Feliz, Planta Med. 1988, 54, 524 526; b) A. S. Chawla, T. R. Krishnan,
A. H. Jackson, D. A. Scalabrin, Planta Med. 1988, 54, 526 528; c) A.
Linden, G. Akineri, S. Noyan, T. Gozler, M. Hesse, Acta Crystallogr.
Sect. C 1998, 54, 1653 1659; d) N. Unver, S. Noyan, T. Gozler, M. A.
Onur, B. Gozler, M. Hesse, Planta Med. 1999, 65, 347 350; e) L. H.
Pham, E. Grundemann, J. Wagner, M. Bartoszek, W. Dopke,
Phytochemistry 1999, 51, 327 332; f) E. E. Elgorashi, S. E. Drewes,
J. Van Staden, Phytochemistry 1999, 52, 533 536.
[16] A fully automated Coherent Synthesis System microwave machine
was used. This was supplied by Personal Chemistry: Hamnesplanaden
5, 753 19 Uppsala, Sweden; www.personalchemistry.com.
[17] N-(2-mercaptoethyl)aminomethyl polystyrene 1.2 mmolgÀ1 available
from Nova Biochem. (cat. no. 01-64-0180).
[18] Carbonate on polymer support on IRA 900, ꢀ3.5 mmolgÀ1 (NaCO3)
available from Fluka (cat. no. 21850).
[19] Polymer-bound triphenylphosphane ꢀ3 mmolgÀ1 available from
Fluka (cat. no. 93093).
[20] a) W. G. Salmond, M. A. Barta, J. L. Havens, J. Org. Chem. 1978, 43,
2057 2059; b) see also reference [3e].
[21] Varian Chem. Elut Column (cat. no.1219-8007).
[22] (‡)-Plicamine [a]D ˆ ‡77.5 (c ˆ 0.867in MeOH); [ a]lDit ˆ ‡74.4 (c ˆ
0.117in MeOH); 1H NMR (400 MHz, CDCl3): d ˆ 7.59 (s, 1H; H-9),
7.08 (d, J ˆ 8.3 Hz, 2H; H-2' and H-6'), 6.73 (d, J ˆ 8.3 Hz, 2H; H-3'
and H-5'), 6.49 (s, 1H; H-12), 6.01 (s, 2H; OCH2O), 5.81 (d, J ˆ
10.1 Hz, 1H; H-2), 5.36 (d, J ˆ 10.1 Hz, 1H; H-1), 4.51 (ddd, J ˆ 13.8,
8.3, 4.3 Hz, 1H; H-8'a), 4.06 (m, 1H; H-4a), 3.93 (s, 1H; H-6a), 3.87
(dd, J ˆ 12.3, 4.3 Hz, 1H; H-4a), 3.51 (m, 1H; H-8'b), 3.44 (s, 3H;
OMe), 2.93 (m, 2H; H-7'), 2.78 (s, 3H; NMe), 2.58 (m, 1H; H-3b),
1.39 ppm (m, 1H; H-3a); IR (neat): nÄmax ˆ 3292.7, 2976.2, 2983.7,
1705.8, 1668.7, 1613.3, 1514.5, 1482.7, 1442.7, 1400.7, 1386.1, 1348.3,
1233.6, 1158.4, 1102.8, 1036.2, 931.9, 929.8 cmÀ1; HR-MS calcd for
C26H26N2O6Na: 485.1689; found 485.1694. Numbering from original
paper concerning isolation see reference [5a].
[5] a) N. ‹nver, T. Gˆzler, N. Walch, B. Gˆzler, M. Hesse, Phytochemistry
1999, 50, 1255 1261; b) N. ‹nver, S. Noyan, T. Gˆzler, M. Hesse, C.
Werner, Heterocycles 2001, 55, 641 652.
[23] (À)-Plicamine [a]D ˆ À76.5 (c ˆ 0.678 in MeOH).
[6] S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. Ian Storer, S. J. Taylor, J.
Chem. Soc. Perkin Trans. 1 2000; 3815 4196, and references therein.
[7] a) I. R. Baxendale, S. V. Ley, Biorg. Med. Chem. Lett. 2000, 10, 1983
1986; b) S. V. Ley, A. Massi, J. Comb. Chem. 2000, 2, 104 107; c) M.
Caldarelli, J. Habermann, S. V. Ley, Biorg. Med. Chem. Lett. 1999, 9,
2049 2052.
[8] a) S. V. Ley, L. Lumeras, M. Nesi, I. R. Baxendale, Comb. Chem. High
Throughput Screening 2002, 5, 195 197; b) M. Caldarelli, I. R.
Baxendale, S. V. Ley, J. Green Chem. 2000, 43 45; c) M. Caldarelli,
J. Habermann, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1999, 107 110;
d) J. Habermann, S. V. Ley, R. Smits, J. Chem. Soc. Perkin Trans. 1
1999, 2421 2423; e) J. Habermann, S. V. Ley, J. J. Scicinski, J. S. Scott,
R. Smits, A. W. Thomas, J. Chem. Soc. Perkin Trans. 1 1999, 2425
2427; f) J. Habermann, S. V. Ley, J. S. Scott, J. Chem. Soc. Perkin Trans.
1 1998, 3127 3130.
Catalytic Enantioselective Synthesis of
b2-Amino Acids**
Huw M. L. Davies* and Chandrasekar Venkataramani
In recent years the enantioselective synthesis of b-amino
acids has been of considerable interest because b-amino
acids[1] are useful precursors of b-peptides[2] and b-lac-
tams.[2b, 3] Traditionally, the asymmetric synthesis of b2-sub-
stituted amino acids has been achieved by using chiral
auxiliaries in methods such as the alkylation of chiral
enolates[4] and the acylation of metalated phenylacetonitrile
with a chiral carbonyl chloride.[4c] Recently, highly enantiose-
lective, l-proline-catalyzed, asymmetric Mannich-type reac-
tions of N-PMP-protected (PMP ˆ p-(MeO)C6H5) a-imi-
noethyl glyoxylate with aldehydes to generate functionalized
b-amino acids was reported.[5] Herein we report a catalytic
asymmetric synthesis of b2-substituted amino acids. The
[9] a) I. R. Baxendale, G. Brusotti, M. Matsuoka, S. V. Ley, J. Chem. Soc.
Perkin Trans. 1 2002, 2, 143 154; b) I. R. Baxendale, A.-L. Lee, S. V.
Ley, Synlett 2001, 1482 1484; c) S. V. Ley, O. Schucht, A. W. Thomas,
P. J. Murray, J. Chem. Soc. Perkin Trans. 1 1999, 1251 1252; d) J.
Habermann, S. V. Ley, J. S. Scott, J. Chem. Soc. Perkin Trans. 1 1999,
1253 1255.
[10] Borohydride, polymer-supported (borohydride on Amberlite IRA
A-400, ꢀ2.5 mmolgÀ1) available from Aldrich.
[11] Available from Aldrich, dimethylaminopyridine, polymer-bound (cat.
no. 35,988-2); poly(4-vinylpyridine) 2% cross-linked (cat. no. 22,696-3).
[12] Despite the nonquantitative yield, no other material was detectable
after filtration of the resin from the solution. We speculate that, due to
the radical nature of the reaction, possible coupling of the starting
material to the polymer resin has occurred.
À
crucial reaction is an asymmetric C H activation of N-
butoxycarbonyl (Boc)-protected methylamines by means of
À
a [Rh2(S-DOSP)4] (1) induced C H insertion [Eq. (1);
TFA ˆ trifluoroacetic acid].
[13] a) H. Togo, M Katohgi, Synlett 2001, 565 581; b) S. V. Ley, A. W.
Thomas, H. Finch, J. Chem. Soc. Perkin Trans. 1 1999, 669 671; c) H.
Togo, G. Nogami and M. Yokoyama, Synlett 1998, 534; d) for a general
review on hypervalent iodine reagents see: A. Varvoglis, Hypervalent
Iodine In Organic Synthesis, Academic Press, London, 1997; e) see
also reference [3b].
Recently, numerous applications of the rhodium carbe-
À
noid induced intermolecular C H activation strategy in
[*] Prof. H. M. L. Davies, C. Venkataramani
Department of Chemistry, University at Buffalo
The State University of New York
Buffalo, NY 14260-3000 (USA)
Fax : (‡1)716-645-6547
[**] This work was supported by the National Science Foundation (CHE
0092490) and the National Institutes of Health (GM57425).
À
[14] Borohydride on polymer support (Amberlyst A-26 BH4 form, 1.5
4 mmolgÀ1
) available from Fluka (cat. no. 15595). The use of
immobilised borohydride on Amberlite IRA 400[10] resulted in
significant amounts of deprotected amino alcohol material. As an
alternative, polymer-supported cyanoborohydride could be used, but
in this case the reactions required more than 48 h.
[15] MP-TsOH 1.40 mmolgÀ1 available from Argonaut Technologies Inc.
(cat. no. 800286; A15 was not effective in promoting this trans-
formation).
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 12
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4112-2197 $ 20.00+.50/0
2197