Asymmetric synthesis of a fully protected ent-actinoidinic acid

Article abstract of DOI:10.1021/ol016218n

(equation presented) The asymmetric synthesis of a fully protected ent-actinoidinic acid derivative 14 is described. As key steps, an enantioselective deprotonation of an arenetricarbonylchromium(0) complex and a diastereoselective Suzuki coupling were ap

Full text of DOI:10.1021/ol016218n

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3079-3082
Asymmetric Synthesis of a Fully
Protected ent-Actinoidinic Acid
Rene´ Wilhelm and David A. Widdowson*
Department of Chemistry, Imperial College of Science Technology and Medicine,
London SW7 2AZ, U.K.
d.widdowson@ic.ac.uk
Received June 1, 2001
ABSTRACT
The asymmetric synthesis of a fully protected ent-actinoidinic acid derivative 14 is described. As key steps, an enantioselective deprotonation
of an arenetricarbonylchromium(0) complex and a diastereoselective Suzuki coupling were applied. The asymmetric centers of the amino acid
function were created via stereocontrolled Strecker reactions.
Planar chiral arenetricarbonylchromium(0) complexes have
found, in recent years, a significant place in the range of
organic synthetic protocols.1 Several methods have been
established to produce these complexes in enantiopure form,
viz. resolution of a racemate,2 diastereoselective complex-
ation,3 and diastereoselective4 and enantioselective depro-
tonations.5 Previously we have published our own investi-
gations of arenetricarbonylchromium(0) complex deprotona-
tion with the sparteine/BuLi base system,6 and we now report
the application of the methodology so developed to the
synthesis of the chiral biaryl ent-actinoidinic acid.
antibiotics. Recently total syntheses of vancomycin agly-
cone,8 vancomycin (1) (Figure 1) itself,9 and teicoplanin10
Actinoidinic acid (2) is the biaryl di-aminoacid unit in
vancomycin and related compounds such as teicoplanin. The
vancomycin class of glycopeptide7 antibiotics is widely used
in the treatment of antibiotic-resistant bacteria and also for
bacterial infections in patients allergic to the â-lactam-derived
(1) Rose-Munch, F.; Rose E. Curr. Org. Chem. 1999, 3, 445-467.
(2) For examples, see: (a) Solladie-Cavallo, A. Chiral Arene Chromium
Carbonyl Complexes in Asymmetric Synthesis; JAI Press: London, 1989;
Vol. 1. (b) Bromley, L. A.; Davies S. G.; Goodfellow, C. L. Tetrahedron:
Asymmetry 1991, 2, 139-156.
Figure 1. Vancomycin
(3) For examples, see: (a) Alexakis, A.; Mangeney, P.; Marek, I.; Rose-
Munch, F.; Rose, E.; Semra, A.; Robert, F. J. Am. Chem. Soc. 1992, 114,
8288-8290. (b) Uemura, M.; Minami, T.; Hirotsu, K.; Hayashi, Y. J. Org.
Chem. 1989, 54, 469-477.
(4) For an example, see: Han, J. W.; Son, S. U.; Chung, Y. K. J. Org.
Chem. 1997, 62, 8264-8267.
have been published. Thus far, two groups have reported
the synthesis of a protected actinoidinic acid,11 and there is
one approach for the asymmetric generation of the isolated
10.1021/ol016218n CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

Diastereoselective cross-coupling with arenetricarbonyl-
chromium(0) complexes has been well studied by M.
Uemura,15 and our own investigations of cross-coupling with
arenechromium complexes16 confirmed that, in a Suzuki
coupling with these complexes, the larger of the ortho-groups
of the attacking areneboronic acid will be syn to the
chromium fragment in the biaryl product as indicated in
structure 4. Because of the small size of the liberated formyl
group, deprotection of the acetal function of 4, even at room
temperature, would result in rotation about the biaryl axis
to the thermodynamically more stable diastereomer 3.
Scheme 1
Given the widely different pharmacological effects of
enantiomeric materials, it was of interest to synthesize ent-
actinoidinic acid, but this stereochemistry was, in any case,
dictated by the use of the commercially available (-)-
sparteine and the stereoselectivity stemming from this as set
out below. (+)-Sparteine is not currently commercially
available but can be readily prepared from (-)-lupanine.17
The first target was enantiopure arenetricarbonylchro-
mium(0) complex (pS)-5 (Scheme 2). Commercially avail-
able aldehyde 7 was protected as the acetal 8 (HOCH2CH2-
OH/benzene/∆) in 95% yield. The arene ring of 8 was then
complexed (Cr(CO)6/Bu2O/THF/∆) to produce 9 in 91%
yield. Lithiation of 9 occurs preferentially at C-4 of the aryl
ring, so this position was blocked with a trimethylsilyl group
(BuLi/TMEDA/TMSCl/-78 °C) to produce 10 in 98% yield.
An enantioselective deprotonation of 10 with the (-)-
sparteine/BuLi system removed the 2-pro-(S)-hydrogen, as
previously described,6 and 5 equiv of TMEDA was added
to displace the bulky (-)-sparteine ligand prior to the
addition of a hexachloroethane quench. The addition of
TMEDA to the lithiated complex proved necessary in order
to enhance the reactivity and to optimize the yield. Complex
(pS)-11 was so obtained in 98% yield with an ee of 76%.
During the workup process the (-)-sparteine ligand was
recovered in 95% yield after purification.
biaryl system via an enantioselective cross-coupling reac-
tion.12 Furthermore, after submission of our work Uemura
et al.13 reported their preparation of the chiral AB-system of
vancomycin.
Scheme 1 shows our retro synthetic approach to ent-
actinoidinic acid. We considered that the amino acid stereo-
centers on the two aromatic rings of 2 would be formed using
stereocontrolled Strecker reactions from the dialdehyde 3 or
monoaldehyde 4. The complex 4 would be formed directly
through a diastereoselective coupling of ring A and B
analogues. The planar chiral ring A analogue (pS)-5 would
be prepared by deprotonation of the precursor with the (-)-
sparteine/n-BuLi system and quenching with hexachloro-
ethane, while the ring B analogue 6 would be prepared
according to literature procedures.14
Desilylation of complex (pS)-11 (TBAF/AcOH/THF) gave
(pS)-5 in 96% yield and 76% ee. It was possible to enhance
the ee of complex (pS)-5 by three crystallizations from DCM/
hexane, which gave a 60% recovery in essentially enan-
tiopure form (>95% ee). The process was monitored via
Scheme 2
3080
Org. Lett., Vol. 3, No. 20, 2001

Scheme 3
chiral HPLC (OD-H-column). Interestingly, it was the
racemate that crystallized preferentially, leaving the (pS)-
enantiomer in the mother liquor.
and axial stereochemistry. The acetal function was removed
in 90% yield by subjection of (pS,P)-4 to 2 M H2SO4 in
THF (2:1) for 1 h as shown in Scheme 3. The methoxy group
of ring B in the product (pS,M)-3 was assigned as anti to
the chromium fragment by the upfield shift of the ring B
MeO-group resonance from 3.99 ppm for (pS,P)-4 to 3.84
ppm for (+)-(pS,M)-3 in the proton spectra and by analogy
with the results of Uemura,15 who demonstrated the free axial
rotation when the aldehyde group on the complexed ring was
regenerated.
The dialdehyde (pS,M)-3 was then converted into the
disulfinylimine complex 13 (86%) by treatment with the
sulfinylamine (+)-(S)-12 and titanium tetraethoxide18 in
readiness for a chiral Strecker reaction after Davis et al.19
The Strecker reaction with Et2AlCN gave the desired nitrile
complex, but the complex proved to be very unstable.
Therefore decomplexation with air and light was carried out
immediately during which, interestingly, the sulfoxide group
on ring B was oxidized to the sulfone, while the group on
ring A remained untouched. Since it was inconvenient to
purify the diamino dinitrile product, the crude compound was
directly methanolysed to the methyl ester by treatment with
HCl gas in methanol, a reaction that also removed the
sulfoxide group on ring A. The crude product was then Boc-
protected to give the fully protected ent-actinoidinic acid
derivate 14 in a yield of 21% over the four steps (67%
average per stage). An X-ray analysis confirmed the absolute
stereochemistry.
The enantiopure complex (pS)-5 was then coupled with
boronic acid 614 to form (pS,P)-4 in 88% yield (Scheme 3).
An X-ray analysis of (pS,P)-4 confirmed the absolute planar
(5) For examples see: (a) Pache, S.; Botuha, C.; Franz, R.; Ku¨ndig, E.
P. HelV. Chim. Acta 2000, 83, 2436-2451. (b) Ewin, R. A.; MacLeod, A.
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R. Chem. Commun. 1996, 2359-2360.
(6) Wilhelm, R.; Sebhat, I. K.; White, A. J. P.; Williams, D. J.;
Widdowson, D. A. Tetrahedron: Asymmetry 2000, 11, 5003-5016.
(7) For reviews, see: (a) Williams, D. H.; Bardsley, B. Angew. Chem.,
Int. Ed. 1999, 38, 1173-1193. (b) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se,
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2708. (c) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.;
Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M. Angew.
Chem., Int. Ed. 1998, 37, 2708-2714. (d) Nicolaou, K. C.; Jain, N. F.;
Natarajan, W.; Hughes, R.; Solomon, M. E.; Li, H.; Ramanjulu, J. M.;
Takayanagi, M.; Koumbis, A. E.; Bando, T. Angew. Chem., Int. Ed. Engl.
1998, 37, 2714-2716. (e) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.;
Natarajan, S.; Koumbis, A. E.; Bando, T.; Ramanjulu, J. M. Angew. Chem.,
Int. Ed. 1998, 37, 2717-2719. (f) Boger, D. L.; Miyazaki, S.; Kim, S. H.;
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2459-2462.
As expected, the absolute axial stereochemistry remained
(M), while on ring B an (S)-center was formed, as expected,
(15) For a review, see: Kamikawa, K.; Uemura, M. Synlett 2000, 938-
949.
(12) Nicolaou, K. C.; Lui, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
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Org. Lett., Vol. 3, No. 20, 2001
3081

from sulfoxide stereocontrol19 of the Strecker reaction. In
contrast, on ring A an (R)-center was formed because of the
dominance, over sulfoxide control, of stereodirection by the
tricarbonylchromium unit by which the attacking Et2AlCN
was only able to approach the imine carbon from the side
opposite to the chromium fragment with the imino function
in the preferred conformation anti to the adjacent aryl ring.
This is well know for imine20 and aldehyde21 arenetricarbo-
nylchromium(0) complexes.
between 0 and 20 °C, an efficient method23 that has been
applied to amino acids and peptides without any epimeriza-
tion of the R-center.24
In conclusion, a protected ent-actinoidinic acid was
prepared via a short route involving three elements of
stereocontrol: enantioselective deprotonation of an arenetri-
carbonylchromium(0) complex, a sulfinylimine-directed Streck-
er reaction, and a chromium-directed Strecker reaction. Full
details and further developments will be published in a future
paper.
The fortuitous formation of a sulfonyl group on the ring
B amino function established differential protection of the
amino functions in 14 and hence allows selective deprotec-
tion, a feature essential for further elaboration of the product.
Although the sulfonyl group is generally a very stable
protecting group for amines,22 methods to remove the group
under mild conditions include electrolysis at temperatures
Supporting Information Available: Detailed descrip-
tions of experimental procedures and X-ray structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016218N
(22) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley & Sons: New York, 1991.
(23) Horner, L.; Neumann, H. Chem. Ber. 1965, 98, 3462-3469.
(24) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367-
2371.
(20) For an example, see: Farkhani, D.; Solladie-Cavallo, A. Tetrahedron
Lett. 1986, 27, 1331.
(21) For an example, see: Uemura, M.; Kobayashi, T.; Isobe, K.; Minami,
T.; Hayashi, Y. J. Org. Chem. 1986, 51, 2859-2863.
3082
Org. Lett., Vol. 3, No. 20, 2001