Atropselective macrocyclization of diaryl ether ring systems: Application to the synthesis of vancomycin model systems

Article abstract of DOI:10.1021/ja020736r

Vancomycin is the last line of defense available in the clinic for treating multidrug-resistant bacterial infections. Vancomycin contains two 16-membered diaryl ether macrocycles, each of which contains a stereogenic axis across the diaryl ether linkage.

Full text of DOI:10.1021/ja020736r

Published on Web 08/13/2002
Atropselective Macrocyclization of Diaryl Ether Ring Systems:
Application to the Synthesis of Vancomycin Model Systems
K. C. Nicolaou* and Christopher N. C. Boddy
Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received May 24, 2002
Abstract: Vancomycin is the last line of defense available in the clinic for treating multidrug-resistant bacterial
infections. Vancomycin contains two 16-membered diaryl ether macrocycles, each of which contains a
stereogenic axis across the diaryl ether linkage. Since an effective total synthesis of vancomycin requires
that these stereogenic axes be formed in a stereoselective manner, we have developed an atropselective
variation of the triazene mediated diaryl ether forming reaction. This variation introduced an energetic penalty
into the transition state of the undesired atropisomer. This reaction is used to synthesize the C-O-D
diaryl ether macrocycle found in vancomycin with high diastereoselectivity (de > 90%), providing the naturally
occurring atropisomeric configuration.
Introduction
The total synthesis of vancomycin (1, Figure 1)1 has been of
considerable interest to the chemical community over the past
few years. This is due to its unique and extraordinarily
challenging molecular architecture, as well as its critical role
as the last clinical antibiotic effective for treatment of multidrug-
resistant bacterial infections. While three groups, including
ours,2-4 have completed the total synthesis of the vancomycin
aglycon, only one has succeeded in achieving control (5:1) over
the atropisomeric outcome of the diaryl ether forming macro-
cyclization reactions.3 A method that can be applied generally
to the vancomycin macrocyclizations with enhanced atrop-
selectivity is highly desirable.
Figure 1. Structure of vancomycin (1).
* To whom correspondence should be addressed. E-mail: kcn@scripps.edu.
(1) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem.,
Int. Ed. 1999, 38, 2097-2152.
To exemplify this problem, we refer to the diaryl ether
macrocyclizations of our total synthesis of vancomycin.2 The
cyclization of the first vancomycin ring system (C-O-D ring
system) proceeded with no selectivity, affording a ca. 1:1
mixture of atropisomers. The macrocyclization of the second
ring system (D-O-E ring system) occurred in our advanced
model system with complete stereoselectivity for the unnatural
atropisomeric configuration. In our total synthesis of vancomycin
the second ring system was formed with the unnatural atrop-
isomeric configuration favored by a ratio of 3:1 to the natural
configuration.2
A temporary solution to the atropisomer problem was based
on work originally carried out in the Boger laboratories.5
Thermal equilibration of the atropisomers provided a 1:1 mixture
of natural and unnatural configurations. Chromatographic
separation of this mixture provided the necessary quantities of
the isomer possessing the natural atropisomeric configuration.
(2) (a) 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. (b) Nicolaou, K. C.; Jain, N. F.; Natarajan,
S.; Hughes, R.; Solomon, M. E.; Li, H.; Ramanjulu, J. M.; Takayanagi,
M.; Koumbis, A. E.; Bando, T. Angew. Chem., Int. Ed. 1998, 37, 2714-
2717. (c) 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. (d) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger,
N.; Hughes, R.; Bando, T. Angew Chem., Int. Ed. 1999, 38, 240-244. (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, F. Chem. Eur. J. 1999, 5,
2584-2601. (f) Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.;
Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bra¨se, S.; Solomon,
M. E. Chem. Eur. J. 1999, 5, 2602-2621. (g) Nicolaou, K. C.; Koumbis,
A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughes,
R. Chem. Eur. J. 1999, 5, 2622-2647. (h) Nicolaou, K. C.; Mitchell, H.
J.; Jain, N. F.; Bando, T.; Hughes, R.; Winssinger, N.; Natarajan, S.;
Koumbis, A. E. Chem. Eur. J. 1999, 5, 2648-2667.
(3) (a) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow,
J. C.; Katz, J. K. Angew. Chem., Int. Ed. 1998, 37, 2700-2704. (b) Evans,
D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.;
Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704-2708.
(4) (a) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle,
S. L. J. Am. Chem. Soc. 1999, 121, 3226-3227. (b) Boger, D. L.; Miyazaki,
S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 10004-10011.
(5) Boger, D. L.; Miyazaki, S.; Loiseleur, O.; Beresis, R. T.; Castle, S. L.;
Wu, J. H.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 8920-8926.
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A R T I C L E S
Nicolaou and Boddy
While this approach was successfully employed in our2 and the
Boger4 syntheses of the vancomycin aglycon, a more effective
and intellectually pleasing solution was deemed worthy of
pursuit.
Below we present the design and development of a diastereo-
selective macrocyclization forming one or the other atropisomer
of the diaryl ether ring systems. This approach allowed for the
synthesis of a single atropisomer of the vancomycin type
C-O-D diaryl ether ring system. It is also one of the first
examples of the stereoselective synthesis of nonbiaryl stereo-
genic axes.6-8
Experimental Design
From the outset of our investigations toward the development of
the traizine-based diaryl ether forming macrocyclization,9 we considered
the possibility of designing an atropselective version of the reaction.
Three potential mechanisms were identified by which atropselectivity
could be designed into this process. The first approach would involve
the temporary use of bulky substituents on the C and E aromatic rings
to direct the chlorines into the correct orientation through unfavorable
steric interactions. The second method relied on the potential use of
stereogenic centers in the triazine moiety to influence the atropisomeric
outcome of the reaction. The last hypothesis required the possible
development of an asymmetric copper ligand to influence the atrop-
selectivity.
Of these three methods, the first approach was viewed as the most
attractive solution to the problem at hand. Furthermore, the required
system would be the easiest to design and had a high likelihood of
success. In addition, this strategy would be independent from the method
of macrocyclization. Thus, it would, conceivably, be applicable to other
macrocyclization conditions employed in the synthesis of vancomycin
systems such as the popular nitro group activated nucleophilic aromatic
substitution.1,10
The steric hindrance approach was to rely on the â-hydroxy groups
found on the tyrosine residues in vancomycin to provide a handle for
inducing atropselectivity. By placing a bulky auxiliary group in the
ortho position on the tyrosine moiety, an unfavorable steric interaction
with the protected benzylic alcohol would be induced, creating an
energetic penalty that would funnel the reaction down the lower energy
pathway, forming a single atropisomeric product (Figure 2).
In selecting an appropriate substituent to influence the stereogenic
outcome of the reaction, we searched for one that was synthetically
tractable and compatible with our triazene mediated diaryl ether forming
reaction, and, therefore, a protected phenolic group was identified as a
suitable candidate. The required amino acid derivatives could be
generated from readily available starting materials employing the aldol
reaction. Furthermore, on the basis of work by the Evans group,11,12 it
seemed likely that the auxiliary bearing phenolic group could be
successfully removed. Last, the added electron density from the
auxiliary oxygen substituent was expected to improve the efficiency
of our diaryl ether formation by increasing the nucleophilicity of the
Figure 2. Design of an atropselective macrocyclization for a vancomycin
C-O-D ring system. The bulky auxiliary group on the aromatic ring is
expected to generate an unfavorable steric interaction with the â-hydroxy
group on the tyrosine residue. This should favor one atropisomeric transition
state over the other.
phenolic moiety. The fact that the C-O-D ring system of vancomycin
cyclizes with no atropselectivity2f made it an ideal model system to
test this hypothesis.
On the basis of the above considerations, we identified the modified
C-O-D systems 3 and 5 as our targets (Scheme 1). According to our
mechanism, the cyclization of compound 2 was expected to provide
3a as the major product. To further probe the level of control through
this design, it was decided to employ diastereomer 4, which possessed
the opposite stereochemistry at the â-hydroxy group of the tyrosine
residue, as well. Following similar reasoning, this system was expected
to show preference for the atropisomer of opposite configuration, 5b.
Results
Computer Simulations. Before undertaking any experimental
verification of our hypothesis, we performed a preliminary test
by conducting computer simulations. The C-O-D ring systems
3a and 3b, as well as the â-hydroxy group epimers 5a and 5b,
were computationally modeled in order to identify the lowest
energy conformation for each compound. Molecular dynamics
followed by minimization was performed using Discover 3.0
with the CVFF13 and CFF9114 force fields. The results were
similar. Compound 3a was significantly more stable than
compound 3b (-7.3 kcal/mol CVFF; -5.6 kcal/mol CFF91).
Compound 5b, however, was found to be only slightly more
(6) For the stereoselective synthesis of biaryl stereogenic axes, see refs 2e
and 7. For the stereoselective synthesis of nonbiaryl stereogenic axes, see
ref 8.
(7) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051-12052.
(b) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am. Chem. Soc. 2000,
122, 5656-5657. (c) Lloyd-Williams, P.; Giralt, E. Chem. Soc. ReV. 2001,
30, 145-157. (d) Ku, Y.-Y.; Grieme, T.; Raje, P.; Sharma, P.; King, S.
A.; Morton, H. E. J. Am. Chem. Soc. 2002, 124, 4282-4286.
(8) (a) Koide, H.; Uemura, M. Chem. Commun. 1998, 2483-2484. (b)
Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T. J. Org. Chem.
1998, 63, 2634-2640. (c) For a recent example reported after the
completion of this work, see: Layton, M. E.; Morales, C. A.; Shair, M. D.
J. Am. Chem.. Soc. 2002, 124, 773-75.
(13) (a) Lifson, S.; Hagler, A. T.; Dauber, P. J. Am. Chem. Soc. 1979, 101,
5111-5121. (b) Hagler, A. T.; Lifson, S.; Dauber, P. J. Am. Chem. Soc.
1979, 101, 5122-5130. (c) Hagler, A. T.; Dauber, P.; Lifson, S. J. Am.
Chem. Soc. 1979, 101, 5131-5141. (d) Dauber-Osguthorpe, P.; Roberts,
V. A.; Osguthorpe, D. J.; Wolff, J.; Genest, M.; Hagler, A. T. Proteins:
Struct. Func. Gen. 1988, 4, 31-47.
(14) (a) Maple, J. R.; Hwang, M. J.; Stockfisch, T. P.; Dinur, U.; Waldman,
M.; Ewig, C. S.; Hagler, A. T. J. Comput. Chem. 1994, 15, 162-182. (b)
Hwang, M. J.; Stockfisch, T. P.; Hagler, A. T. J. Am. Chem. Soc. 1994,
116, 2515-2525. (c) Maple, J. R.; Hwang, M.-J.; Stockfisch, T. P.; Hagler,
A. T. Isr. J. Chem. 1994, 34, 195-231. (d) Peng, Z.; Ewig, C. S.; Hwang,
M.-J.; Waldman, M.; Hagler, A. T. J. Phys. Chem. A 1997, 101, 7243-
7252. (e) Maple, J. R.; Hwang, M.-J.; Jalkanen, K. J.; Stockfisch, T. P.;
Hagler, A. T. J. Comput. Chem. 1998, 19, 430-458. (f) Hwang, M.-J.; Ni,
X.; Waldman, M.; Ewig, C. S.; Hagler, A. T. Biopolymers 1998, 45, 435-
468.
(9) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Bra¨se,
S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421-3422.
(10) Zhu, J. Synlett 1997, 133-144.
(11) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K. M. J. Am. Chem.
Soc. 1993, 115, 6426-6427.
(12) Evans, D. A.; Dinsmore, C. J. Tetrahedron Lett. 1993, 34, 6029-6032.
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Atopselective Synthesis of a Vancomycin System
A R T I C L E S
Scheme 1. Designed Substrates To Test the Bulky Substituent Hypothesis for Atropselective Macrocyclization
stable than its atropisomer 5a (-2.5 kcal/mol CVFF; -0.4 kcal/
mol CFF91).
On the basis of these calculations, we expected to see dramatic
atropselectivity from the cyclization of compound 2. The
C-O-D model 3a, with the chlorine in the natural configuration
relative to vancomycin, was expected to predominate in a
calculated ratio of greater than 1000:1 to that of C-O-D model
3b (ratio of 3a:3b ca. 33 000:1, CVFF; ca. 2900:1, CFF91).
On the other hand, the cyclization of precursor 4 was expected
to provide only moderate atropselectivity for compound 5b (ratio
of 5b:5a ca. 35:1, CVFF; ca. 2:1, CFF91).
While these data confirmed that the proposed approach could
select for either atropisomeric configuration, the disparity
between the degrees of atropselectivity was, at first, surprising.
Subsequent analysis of the unfavorable atropisomers 3b and 5a
revealed, however, that the large difference in selectivity was
likely due to the low energetic penalty imposed in compound
5a (see Figure 3). Thus, while compound 3b is highly
unfavorable due to the enforced eclipsing of the phenolic TBS
and benzylic OTIPS groups, compound 5a can adopt a staggered
conformation, thereby reducing the unfavorable steric inter-
action.
Atropselective Synthesis of C-O-D Ring Systems. From
the required building blocks 6-9 (Figure 4), compounds 8 and
9 were already in hand from our previous studies.2 Intermediates
6 and 7 (both racemic) were synthesized via aldol-based
chemistry as outlined in Scheme 2.
Figure 3. Newman projections point to the likely cause of the low
atropselectivity predicted by molecular modeling calculations for the
cyclization of compound 4. These projections depict the orientation across
the bond connecting the â-carbon to the aromatic ring. Compound 3b adopts
the highly unfavorable eclipsing orientation, while compound 5a can adopt
the more stable staggered conformation.
Figure 4. Key building blocks (6-9) required for the atropselective
synthesis of the C-O-D ring systems.
providing the monochloro derivative 11. The fully protected
benzaldehyde 13 was obtained by selective protection of the
more acidic phenolic group of 11, furnishing benzyl ether 12
Thus, 2,4-dihydroxybenzaldehyde (10) was selectively chlo-
rinated at the 3-position (NaOCl, NaOH, H2O, 55% yield),15
(15) Hopkins, C. Y.; Chisholm, M. J. Can. J. Res., Sect. B 1946, 24, 208-210.
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A R T I C L E S
Nicolaou and Boddy
Scheme 4. Atropselective Macrocyclization of Precursor 4
Forming C-O-D Ring System 5b in a ca. 2:1 Ratio with Its
Atropisomer 5a
Scheme 2. Synthesis of Racemic â-Hydroxy Amino Acids 6 and 7
Scheme 3. Atropselective Synthesis of the C-O-D Ring System
3a
dipeptide 15 together with its diastereomer in a combined yield
of 77%. Chromatographic purification of 15 followed by
protection of the benzylic hydroxy group gave bis-silyl ether
16 (TIPSCl, imid., 78% yield). Hydrogenolysis of the benzyl
ether from 16 (H2, Pd(OH)2/C, 99% yield) and subsequent
removal of the Boc group formed phenolic amine 18 via
intermediate 17, which was immediately coupled with triazene
carboxylic acid 92 (HOAt-EDC), affording the cyclization
precursor 2 in 85% overall yield from 16.
Ring closure of the latter compound (2) under the standard
cyclization conditions (CuBr‚SMe2, K2CO3, pyr.) furnished
compound 3a in 94% yield as a single atropisomer as determined
1
by H NMR spectroscopic analysis. The stereochemistry of
atropisomer 3a was confirmed by NOE studies (see Figure 5).
This result is consistent with the predictions of the computer
simulation studies described above.
(BnBr, NaHCO3, KI catalyst, 60% yield),16 followed by
treatment with TBSOTf and Et3N (100% yield). Benzaldehyde
13 was condensed with iminoglycinate 1417 under the influence
of KHMDS to provide a 1:2 mixture of racemic â-hydroxy
tyrosines 6 and 7 in a combined yield of 57%.18 The two
diastereoisomers 6 and 7 were chromatographically separated
and employed separately.
To test the atropselectivity in the macrocyclization of the
epimeric â-hydroxy tyrosine series, the required precursor 4 was
assembled as shown in Scheme 4. Thus, racemic 7 was coupled
with carboxylic acid 8 in the presence of HOAt-EDC, leading
to peptide 19 together with its diastereomer in 50% combined
yield. Protection of the hydroxyl group as a TIPS ether (TIPSCl,
imid., 81% yield) gave a mixture of diastereomeric products
(ca. 1:1) from which the desired isomer (20) was chromato-
Scheme 3 depicts the coupling of â-hydroxy tyrosine deriva-
tive (()-6 with carboxylic acid 82 (HOAt, EDC) to furnish the
(16) Mendelson, W. L.; Holmes, M.; Dougherty, J. Synth. Commun. 1996, 26,
593-601.
(17) Stork, G.; Leong, A. Y. W.; Touzin, A. M. J. Org. Chem. 1976, 41, 3491-
(18) Kanemasa, S.; Mori, T.; Wada, E.; Tatsukawa, A. Tetrahedron Lett. 1993,
34, 677-680.
3493.
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Atopselective Synthesis of a Vancomycin System
A R T I C L E S
atropisomer of a cyclopeptide diaryl ether related to the C-O-D
ring system of vancomycin. The design of this highly atrop-
selective macrocyclization relied on prohibiting interactions
between the bulky auxiliary group and the TIPS protecting group
of the â-hydroxy moiety of the tyrosine system for the unwanted
atropisomer. A similar approach using the opposite stereochem-
istry of the â-hydroxy moiety of the tyrosine derivative led to
the undesired atropisomer as the major product, providing
credence to the bulky substituent hypothesis. Interestingly, these
designs were based on computational modeling studies which
predicted the outcome of these ring closures to a high degree
of accuracy. This method could potentially be applied to the
atropselective synthesis of vancomycin and other substances
exhibiting such atropisomers.
Figure 5. Observed NOEs confirming the stereochemistry of atropisomer
3a and 5b. The 1H-1H NOEs were determined via COSY and ROESY
experiments performed in CD3COCD3 using a 600 MHz NMR instrument.
graphically separated. Hydrogenolysis of the benzyl ether,
followed by Boc removal and coupling with the triazene
carboxylic acid 9, led to precursor 4 via amine 22 (35% overall
yield from 20). Treatment of precursor 4 under the standard
cyclization conditions (CuBr‚SMe2, K2CO3, pyr.) provided
compounds 5a and 5b in a combined yield of 55% (5a:5b, ca.
1:2). The stereochemical assignment of compound 5b was
confirmed by NOE studies (see Figure 5).
Acknowledgment. We thank Drs. D. H. Huang and G.
Siuzdak (TSRI) for NMR and mass spectrometric assistance,
and Dr. Swaminathan Natarajan for insightful discussions.
Financial support for this work was provided by The Skaggs
Institute for Chemical Biology and the National Institutes of
Health (USA).
Supporting Information Available: Experimental procedures
and compound characterization (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Conclusion
Through strategic placement of a bulky substituent on the
aromatic ring of the tyrosine residue, we were able to enforce
an atropselective macrocyclization reaction leading to a single
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