[
Ψ
[CH2NH]Tpg4]Vancomycin Aglycon
A R T I C L E S
conditions4 given the steric constraints of the substrate 20,
providing a separable 1:1.3 mixture of atropisomers (21:22)
slightly favoring the unnatural configuration. Thermal equilibra-
tion of isolated 22 was carried out initially employing our
reported conditions for vancomycin (o-dichlorobenzene, 120 °C,
18 h, 81% recovery of material)7 to afford a 1:1.1 separable
mixture, permitting the recycling of this unnatural atropisomer.
An examination of the parameters for this isomerization (k )
0.12 h-1, t1/2 ) 5.9 h at 120 °C and k ) 0.36 h-1, t1/2 ) 1.8 h
at 135 °C) revealed that it proceeds with an energy of activation
(Ea) of 25.6 kcal/mol (∆Hq ) 24.8 kcal/mol, ∆Sq ) -0.26 eu,
∆Gq ) 24.9 kcal/mol) essentially indistinguishable from that
observed with the authentic vancomycin AB biaryl system, but
it does not result in the analogous 3:1 thermodynamic preference
for the natural atropisomer. However, the unusual and unex-
pected atropisomer stability of the CD ring system allowed us
to improve on the recycling conditions. Heating the mixture in
a microwave reactor at an elevated temperature (210 °C,
o-dichlorobenzene) shortened the reaction time significantly (5
min vs 18 h) and slightly improved the recovery of material
(88% vs 81%). This improvement impacted the efficiency of
the recycling of 22 by allowing multiple equilibrations to be
run in a single day rather than over the course of a week. Silyl
ether deprotection of 21 (1.2 equiv of Bu4NF, THF, 0 °C, 10
min), followed by N-Cbz removal (H2, 10% Pd/C, 1% Cl3-
CCO2H-CH3OH, 15 min, 95%) and methyl ester hydrolysis
(1.0 equiv of LiOH, THF-H2O, 0 °C, 1 h, 96%), gave amino
acid 25. Notably, N-Cbz removal in the absence of Cl3CCO2H5
was much slower (11 h), and these conditions led to competitive
chloride reduction.19 Macrolactamization with closure of the AB
ring system was effected by treatment of 25 with PyBOP (3.0
equiv, 6.0 equiv of NaHCO3, 0.001 M CH2Cl2-DMF 5:1, 0-25
°C, 12 h) to afford the fully functionalized bicyclic ABCD ring
system 26 in good yield (70%) with only trace amounts of
competitive epimerization (<3%). Alternative coupling reagents
(EDCI and HOAt or HOBt, HATU) and reaction conditions
(10-100% DMF-CH2Cl2, 3-5 equiv of Na2CO3, -5 to 0 °C)
led to lower conversions (30-52%) or required extended
reaction times (3 d). N-Boc deprotection (HCO2H-CHCl3 1:1,
10 h, 84%) gave the free amine 27 for coupling with the E ring
tripeptide. Confirmation of the atropisomer stereochemistry and
amide conformational assignments for 26 were established by
2D ROESY 1H-1H NMR. Diagnostic NOE cross-peaks for 26
H, N1 -H/C2 -H, and N1 -H/C4a5-H. Most important in this
spectroscopic assessment was not only the expected confirmation
of the CD and AB atropisomer stereochemistry, but also the
establishment of a vancomycin-like conformation for 26 bearing
6
5
6
5
a cis amide linking the residues 5 and 6 (strong diagnostic C2 -
6
H/C2 -H NOE), maintaining the spatial relationships and
5
orientations of the AB ring system (strong diagnostic C2 -H/
6
C4a5-H and C2 -H/C4a5-H NOEs) and the CD ring system
(diagnostic C6b6-H/C4a4-H NOE). Although this might be
considered unusual on the surface, even the natural atropisomer
of the isolated AB ring system of vancomycin, without the
surrounding CD ring system, adopts a conformation incorporat-
ing this cis amide structure, illustrating that it is the confines
of the AB ring system, not that of the CD ring system, that
defines this key cis amide conformational preference.4 The lack
of discernible NOEs to the methyl carbamate protecting the
amine of the modified amide established that it extends out and
away from the ABCD ring system binding pocket.
Synthesis of the Full Carbon Skeleton. Coupling of 27 and
28 (2.0 equiv of DEPBT,17 2.2 equiv of NaHCO3, THF, 0-25
°C, 14 h, 73%) afforded 29 with excellent diastereoselectivity
(12:1), arising from little competitive racemization (Scheme 4).
These conditions were utilized on the basis of our experience
with the teicoplanin5 and ristocetin6 aglycons and are superior
to those originally reported for vancomycin4 (EDCI) in terms
of diastereoselectivity (12:1 vs 3:1). Closure of the DE ring
system with formation of the key biaryl ether was accomplished
by treatment of 29 with CsF (10 equiv, 20 equiv of CaCO3,20
3-Å molecular sieves, DMF, 25 °C, 17 h) to afford 30 in good
yield (74%) and good atropodiastereoselectivity (6-7:1). No-
tably, the closure of 30 was conducted under milder conditions
than those originally disclosed for vancomycin4,7-10 (DMF vs
DMSO at 25 °C with added 3-Å molecular sieves and CaCO3)
and approaches the kinetic atropisomer diastereoselectivity
observed in our efforts4 (8:1), while surpassing that detailed in
the related efforts by Evans10 (5:1) and contrasting the closure
detailed by Nicolaou21 (1:3), where the unnatural atropisomer
predominated with an alternative substrate and method of ring
closure. Thus, consistent with the adoption of a vancomycin-
like conformation by 26, the amide modification in the ABCD
ring system of 29 had little impact on the ease or diastereose-
lectivity of the DE ring closure. Reduction of the nitro group22
(H2, 10% Pd/C, THF, 8 h, 94%), followed by diazotization of
the resulting amine 32 (1.2 equiv of HBF4, 1.2 equiv of
t-BuONO, CH3CN, 0 °C, 20 min) and Sandmeyer substitution
4
4
4
were observed between C5 -OH/C4b4-H (s), C5 -OH/C6 -
OMe (s), N1 -H/C4a5-H (s), N1 -H/C2 -H (s), N1 -H/C3 -H
7
7
5
7
6
7
6
6
6
(m), N1 -H/C2 -H (m), C5a6-H/C3 -H (s), C5a6-H/C2 -H
(20) Both the added 3-Å molecular sieves and CaCO3 result in cleaner
conversions to product. It is not yet clear whether the soluble base under
these conditions is CsF or Cs2CO3 with precipitation of insoluble CaF2.
(21) (a) 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.
(b) 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. (c) 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. (d)
Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.; Hughes, R.;
Bando, T. Angew. Chem., Int. Ed. 1999, 38, 240. (e) Nicolaou, K. C.; Li,
H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu,
X.-J.; Brase, S.; Rubsam, F. Chem. Eur. J. 1999, 5, 2584. (f) Nicolaou, K.
C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.;
Jain, N. F.; Ramajulu, J. M.; Brase, S.; Solomon, M. E. Chem. Eur. J.
1999, 5, 2602. (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. (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.
6
6
6
6
(s), C5b6-H/N1 -H (m), C3 -OH/N1 -H (s), C5b6-H/C3 -
OH (m), C6b6-H/C5b6-H (s), C6b6-H/C4a4-H (w), N1 -H/
4
4
5
6
C4b4-H (m), N1 -H/C4a4-H (w), C4b5-H/C5 -H (s), C2 -H/
7
C4a5-H, C4b5-H/C1b4-H (m), C4a5-H/C6 -H (w), C4a5-H/
5
5
5
7
7
7
C2 -H (s), C5 -H/C6 -OMe (s), C4 -H/C2 -H (s), C4 -H/
7
7
7
C1b7-H (s), C4 -H/C1a7-H (w), C4 -H/C5b7-OMe (s), C4 -
7
7
5
7
7
H/C6 -H (w), C6 -H/C2 -H (w), C6 -H/C5b7-OMe (s), C6 -
5
6
5
6
6
H/C5a7-OMe (s), C2 -H/C3 -H (m), C2 -H/C2 -H (s), C3 -
6
7
7
H/C2 -H (m), C1 -(MEM-CH2)1/C1a7-H (s), C1 -(MEM-
7
7
7
CH2)1/C1 -(MEM-CH2)2 (s), C2 -H/C1b7-H (s), and C2 -H/
C1a7-H (s), and no NOE cross-peaks were observed between
6
6
6
6
6
7
C5b6-H/C3 -H, C5b6/C2 -H, C2 -H/C3 -OH, N1 -H/N1 -
(19) Use of Raney nickel for N-Cbz removal was also successful, although lower
recoveries (84%) of the product were observed.
(22) Reduction of the nitro group was sensitive to the choice of solvent in terms
of recovery and observance of side products.
9
J. AM. CHEM. SOC. VOL. 128, NO. 9, 2006 2889