On the verge of axial chirality: Atroposelective synthesis of the AB-biaryl fragment of vancomycin

Article abstract of DOI:10.1021/ol026182e

(figure presented) Using the "lactone concept", differently substituted AB-biaryl fragments (P)-2 (R = Me, t-Bu) of vancomycin have been synthesized atroposelectively. Their otherwise configurational instability was remedied by inclusion of two chlorine atoms in the B ring to give (M)-29. Starting from a still configurationally unstable lactone-bridged precursor, we obtained this biaryl with high atroposelectivity (dr 94:6) by ring cleavage with dynamic kinetic diastereomeric resolution.

Full text of DOI:10.1021/ol026182e

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2833-2836
On the Verge of Axial Chirality:
Atroposelective Synthesis of the
AB-Biaryl Fragment of Vancomycin†,‡
,§
Gerhard Bringmann,* Dirk Menche,§ Jo1rg Mu1hlbacher,§ Matthias Reichert,§
Nozomi Saito,| Steven S. Pfeiffer,| and Bruce H. Lipshutz*
,|
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland,
D-97074 Wu¨rzburg, Germany, and Department of Chemistry and Biochemistry,
UniVersity of California, Santa Barbara, California 93106
bringman@chemie.uni-wuerzburg.de
Received May 14, 2002
ABSTRACT
Using the “lactone concept”, differently substituted AB-biaryl fragments (P)-2 (R ) Me, t-Bu) of vancomycin have been synthesized
atroposelectively. Their otherwise configurational instability was remedied by inclusion of two chlorine atoms in the B ring to give (M)-29.
Starting from a still configurationally unstable lactone-bridged precursor, we obtained this biaryl with high atroposelectivity (dr 94:6) by ring
cleavage with dynamic kinetic diastereomeric resolution.
Vancomycin (1) and related glycopeptide antibiotics are
valuable medicinal agents that are clinically used against
bacterial infections caused, e.g., by Staphylococcus aureus.1
Their structural framework is unique, with stereogenic centers
and elements of planar and axial chirality2,3 biosynthetically
originating through a series of oxidative cyclization reactions
of a linear heptapeptide chain precursor.4
Although this architecturally challenging target has been
successfully attained by a few groups,5 there is still room
for strategic or methodological improvements. Thus, in the
atroposelective construction of the AB fragment with its
rotationally hindered biaryl axis, problems have arisen with
respect to biaryl coupling yields and atroposelectivities,
where ratios of isomers on the order of 3:1 at best are to be
expected6,7a-f without resorting to alternative strategies.7g
With the presence of O- and C-substituents next to the biaryl
axis, this axially chiral fragment seemed ideal for construc-
tion via “lactone methodology”,8,9 employing a biaryl lactone
precursor of type 3, which, itself, could be prepared by
intramolecular coupling of 6. This halo ester, in turn, should
easily be obtained from the substituted benzoic acid 5
(3) Bringmann, G.; Gu¨nther, G.; Ochse, M.; Schupp, O.; Tasler, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Moore, R. E., Tamm, C., Eds.; Springer-Verlag: New
York, 2001; Vol. 82.
(4) Bischoff, D.; Pelzer, S.; Bister, B.; Nicholson, G. J.; Stockert, S.;
Schirle, M.; Wohlleben, W.; Jung, G.; Su¨ssmuth, R. D. Angew. Chem., Int.
Ed. 2001, 40, 4688-4691.
(5) For a lead reference, see: Boger, D. L.; Miyazaki, S.; Kim, S. H.;
Wu, J. H.; Loiseleur, O.; Castle, S. L. J. Am. Chem. Soc. 1999, 121, 3226-
3227.
(6) To date the only total synthesis of vancomycin to appear has been
achieved by Nicolaou’s group: Nicolaou, K. C.; Mitchel, H. J.; Jain, N.
F.; Winssinger, N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1998,
38, 240-244.
* Corresponding authors. E-mail (B.H.L.): lipshutz@chem.ucsb.edu.
† Dedicated to Professor Dieter Seebach on the occasion of his 65th
birthday.
‡ Part 103 of the Series NoVel Concepts in Directed Biaryl Synthesis.
For part 102, see: Bringmann, G.; Tasler, S.; Pfeifer, R.; Breuning, M. J.
Organomet. Chem., in press.
§ Universita¨t Wu¨rzburg.
| University of California, Santa Barbara.
(1) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1172-1193.
(2) For an excellent review on vancomycin, see: Nicolaou, K. C.; Boddy,
C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-
2152.
10.1021/ol026182e CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/27/2002

(representing ring fragment A) and the phenolic building
block 4, i.e., (R)-p-hydroxyphenylglycine 4 (the proposed
ring B portion). Because of its expected8 configurational
instability, the lactone-bridged biaryl 3 should be subject to
an atroposelective ring cleavage, using, e.g., chiral H-
nucleophiles, to give (P)-2 or, optionally, its (here not
required) atropodiastereomer (M)-2.9
BINAL-H” [(P)-14]16 as the chiral H-nucleophile.17 These
low selectivities already suggested that they might not
represent the actual levels of asymmetric induction as initially
produced in these reaction mixtures, but that at least some
loss of stereochemical purity might have occurred after the
reductive ring cleavage. Indeed, (P)-12 does isomerize slowly
at room temperature, eventually resulting in a ca. 1:1 mixture
of the two atropoisomers, (P)- and (M)-12. This stereochem-
ical lability of (P)-12 was not expected in view of the
configurational stability of structurally closely related biaryls
that bear (besides an OMe group instead of the OH
substituent in ring A) either another substituent in the
methylene unit or a larger, 16-membered ring instead of the
oxazolidine portion.18,19
Scheme 1
Figure 1. Vancomycin.
For a first synthetic approach along these lines, building
block 8 was chosen as a protected precursor for ring A. This
acid, easily obtained from 5 by iodination10 and saponifica-
tion, was esterified with 9, representing the precursor for
fragment B, which in turn was accessible from commercially
available 4 using a known procedure.11 As in so many cases
before,8,12,13 intramolecular coupling of 10 smoothly gave
the indeed configurationally labile lactone 11 in high yield
(90%). Interestingly, attempts to reductively cleave this
bridged key intermediate by previously successful8 borane
reduction in the presence of the chiral oxazaborolidine (S)-
1314 failed, apparently due to low steric hindrance at the
biaryl axis and, thus, a lack of strain-induced reactivity.15
The ring opening of 11 to give (P)-12 gave good chemical
yields but unusually low optical yields (dr 69:31) using “S-
Despite the configurational instability of 12, the good
chemical yields for both the intramolecular coupling of 10
to 11 and the subsequent ring cleavage, together with the
possibility of recycling the chromatographically separable
minor atropisomer (M)-12 (by a similarly almost quantitative,
one-step oxidation using MnO2, Scheme 2),20 still constituted
a clear proof of concept. Further efforts to synthesize a
hopefully configurationally stable AB-fragment were there-
fore warranted, the approach being to replace 9 with a
sterically more hindered building block.
(7) (a) Rama Rao, A. V.; Chakraborty, T. K.; Joshi, S. P. Tetrahedron
Lett. 1992, 33, 4045-4048. (b) Rama Rao, A. V.; Reddy, K. L.; Reddy,
M. M. Tetrahedron Lett. 1997, 35, 5039-5042. (c) Lipshutz, B. H.; Mu¨ller,
P.; Leinweber, D. Tetrahedron Lett. 1999, 40, 3677-3680. (d) Wilhelm,
R.; Widdowson, D. A. Org. Lett. 2001, 3, 3079-3082. (e) Nicolaou, K.
C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T. Y.; Natarajan, S.;
Chu, X.-J.; Bra¨se, S.; Ru¨bsam, R. Chem. Eur. J. 1999, 5, 2584-2601. (f)
Boisnard, S.; Neuville, L.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2000, 2,
2459-2462. (g) Kamikawa, K.; Tachibana, A.; Sugimoto, S.; Uemura, M.
Org. Lett. 2001, 3, 2033-2036.
(8) (a) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 4, 525-
558. (b) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615-624.
(9) For a very similar synthetic approach, albeit with only low coupling
yields and without considering the phenomenon of atropoisomerism, see
ref 7a.
(10) Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 2553-2564.
(11) Beugelmans, R.; Bois-Choussy, M.; Chastanet, J.; Gleuher, M. L.;
Zhu, J. Heterocycles 1993, 36, 2723-2732.
(12) (a) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am.
Chem. Soc. 1994, 116, 1004-1015. (b) Deshpande, P. P.; Martin, O. R.
Tetrahedron Lett. 1990, 44, 6313-6316. (c) Matsumoto, T.; Hosoya, T.;
Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568-3570.
A possible first candidate for this was the O-t-Bu-
substituted biaryl (P)-17 (Scheme 3). Starting from benzoic
(16) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709-6716.
(17) For elucidation of the configuration of (P)-12 by quantum chemical
CD calculations, see Supporting Information.
(18) Structurally closely related and sterically only slightly more hindered
but configurationally stable biaryls are described in refs 7e and 7g.
(19) For atropoisomerization of related biaryls, see refs 5a and 5e.
(20) For a related oxidative recycling back to a lactone intermediate,
see: Bringmann, G.; Menche, D. Angew. Chem., Int. Ed. 2001, 40, 1687-
1690.
(13) In comparison to 10, coupling of the analogous bromoacid proceeded
with only 26% yield; see ref 7a.
(14) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(15) Bringmann, G.; Hinrichs, J.; Kraus, J.; Wuzik, A.; Schulz, T. J.
Org. Chem. 2000, 65, 2508-2516.
2834
Org. Lett., Vol. 4, No. 17, 2002

Scheme 2
Scheme 3
chlorine atoms on a building block such as 26 should be
removable at a later stage of the synthesis (Scheme 4).21
Treatment of commercially available dichlorophenol 18 with
TBDMS-Cl and imidazole in DMF gave 19 in quantitative
yield. Formylation of 19 via chlorine-directed ortho meta-
lation22 followed by acidic workup provided aldehyde 20,
which was converted into benzyl ether 21 in 93% yield (four
steps). The styrene derivative 22 was prepared by Wittig
reaction of 21 in 85% yield. For the enantioselective
functionalization of 22, we examined its Sharpless AA
reaction, which, however, was unsuccessful, both with
BocNNaCl and with CbzNNaCl. Since this vicinal difunc-
tionalization depends on the size of the ortho substituents
on the aromatic rings, it may be assumed that the reaction
was hampered by the bulkiness of the chlorine groups.
Another plan was to apply the Sharpless asymmetric di-
hydroxylation23 to the ortho-disubstituted styrene 22 with
subsequent Mitsunobu inversion.24 Treatment of 22 with AD-
mix â in t-BuOH/H2O followed by selective protection of
the resulting primary alcohol group provided the desired
compound 23 in high chemical and optical yields. Its
acid 5 afforded the suitably functionalized precursor bromo-
acid 15 in a four-step procedure. As before, coupling of the
corresponding ester (not shown) proceeded smoothly to give
16, but the high yields previously obtained with iodoester
10 were not quite reproduced, probably due to the less
reactive Ar-Br bond. Ring cleavage of 16 (here just with
LAH as an achiral reductant) gave a ca. 1:1 mixture of
chromatographically separable atropodiastereomers (M)- and
(P)-17, the configurational stability of which was only
slightly increased as compared to that of 12 [t1/2 ) 15 h for
(P)-17 vs t1/2 ) 12 h for (P)-12], necessitating a yet more
vigorous approach, this time by modifying ring fragment B.
Our goal was ultimately achieved by incorporating an
additional substituent next to the biaryl axis in the lactone,
here by the presence of two halogen atoms meta to the
oxygen function in the phenolic precursor 26, thus avoiding
regioselectivity problems in the coupling step. The two
1
enantiomeric excess was determined by H NMR analysis
of its MTPA ester. Mitsunobu reaction24 of 23 with diphenyl-
phosphoryl azide gave azido diether 24 in very good isolated
yield. Reduction with triphenylphosphine in moist THF gave
the free amine, which was protected as its Boc carbamate.
Fluoride-induced removal of the primary TBS group afforded
alcohol 25 (91% over three steps). Hydrogenolysis of the
(21) (a) Lipshutz, B. H.; Tomioka, T.; Pfeiffer, S. S. Tetrahedron Lett.
2001, 42, 7737-7740. (b) Lipshutz, B. H.; Tomioka, T.; Sato, K. Synlett
2001, 970-973.
(22) Iwao, M. J. Org. Chem. 1990, 55, 3622-3627.
(23) Kolb, H. C.; VanNieuwenhze; Sharpless, K. B. Chem. ReV. 1994,
94, 2483-2547.
(24) Mitsunobu, O. Synthesis 1981, 1-28.
Org. Lett., Vol. 4, No. 17, 2002
2835

Scheme 4
benzyl moiety followed by standard acetonide formation gave
the desired vancomycin B-ring derivative 26 in 86% yield
(two steps).
The assignment of axial configuration in 29 was hampered
by the fact that its experimental CD spectrum did not
resemble that of (P)-12 or that of (M)-12. In this case, the
presence of the two “heavy-atom”-type chlorine substituents
prevented quantum chemical CD calculations, so the con-
figuration of the biaryl bond in (M)-29 had to be deduced
chemically by conversion25 to the corresponding hydro-
dehalogenated compound, the stereochemically well-known
(see above) biaryl (P)-12. Despite the harsh required reaction
conditions, (P)-12 was obtained with a still remaining dr of
66:34,26 again (as above) in favor of the (P)-diastereomer,
the identity of which was confirmed by HPLC coelution and
CD spectroscopy.
Esterification of 26 with iodoacid 8 and subsequent
cyclization of ester 27 gave lactone 28, which was then
submitted to atroposelective ring cleavage reactions. Due to
the increased strain by the additional chloro substituent next
to the axis, borane reduction of 28, assisted by the ox-
azaborolidine (S)-13,8,14 succeeded in this case and gave 29
in a good diastereoselectivity (dr 94:6) and now indeed with
the required complete configurational stability, showing no
signs of isomerization at room temperature.
In conclusion, a novel, highly stereoselective approach to
the AB-fragment of vancomycin (1) has been realized. The
stereochemical key step proceeds in the sense of a dynamic
kinetic resolution of an atropodiastereomeric mixture of a
configurationally labile lactone-bridged intermediate 28. CBS
reduction gives the stereochemically stable biaryl AB frag-
ment (M)-29, which will now be subject to further synthetic
work. For the continuation of the synthesis, it will now be
required to also introduce the amino acid function into ring
A, e.g., following protocols previously established by
Boger,27 Rao,7a or Uemura.7g
Scheme 5
Acknowledgment. Financial support provided by the
Deutsche Forschungsgemeinschaft (SFB 347 and Gra-
duiertenkolleg “Elektronendichte”), the Fonds der Chemis-
chen Industrie (to G.B.), and the NIH (GM 40287; to B.H.L.)
is gratefully acknowledged.
Supporting Information Available: Detailed description
of experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL026182E
(25) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1977, 42, 3491-3494.
(26) That this 66:34 ratio is not the equilibrium value was shown by
heating the mixture further under the same conditions, ultimately leading
to a ca. 53:47 ratio; see Supporting Information.
(27) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996, 61,
3561-3565.
2836
Org. Lett., Vol. 4, No. 17, 2002