First and second generation-total synthesis of the teicoplanin aglycon

Article abstract of DOI:10.1021/ja003835i

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (> 10:1, 76%) without problematic C₂³ epimerization provided the basicity of the reaction is minimized.

Full text of DOI:10.1021/ja003835i

1862
J. Am. Chem. Soc. 2001, 123, 1862-1871
First and Second Generation Total Synthesis of the Teicoplanin
Aglycon
Dale L. Boger,* Seong Heon Kim, Yoshiki Mori, Jian-Hui Weng, Olivier Rogel,
Steven L. Castle, and J. Jeffrey McAtee
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
ReceiVed October 31, 2000
Abstract: Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key
elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the
coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and
sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide
nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed
by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second
generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall).
This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded
coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE
macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach
incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the
natural atropisomer (>10:1, 76%) without problematic C23 epimerization provided the basicity of the reaction
is minimized.
Teicoplanin (1, Figure 1)1,2 is a complex of five closely
related, clinically useful glycopeptide antibiotics isolated from
Actinoplanes teichomyceticus (ATCC 31121) that are related
to vancomycin3-8 which is enlisted as the drug of last resort
for treatment of resistant bacterial infections or for patients
allergic to â-lactam antibiotics.6 It is 2-20-fold more potent
than vancomycin against Gram-positive bacteria,9 possesses a
lower toxicity than vancomycin,1,10 exhibits a longer half-life
(40 vs 6 h) in man,11 and is easier to administer and monitor.12,13
These characteristics along with its structural complexity, the
interest in defining the structural features of glycopeptide
antibiotics contributing to cell wall biosynthesis inhibition in
(1) Parenti, F.; Beretta, G.; Berti, M.; Arioti, V. J. Antibiot. 1978, 31,
276.
(2) Hunt, A. H.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.;
Debono, M. J. Am. Chem. Soc. 1984, 106, 4891. Barna, J. C. J.; Williams,
D. H.; Stone, D. J. M.; Leung, T.-W. C.; Doddrell, D. M. J. Am. Chem.
Soc. 1984, 106, 4895.
(3) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.;
McGuire, J. M. Antibiot. Annu. 1955-1956, 606.
(4) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983,
105, 6915. Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D. H.;
Smith, G. A. Nature 1978, 271, 223. Williams, D. H.; Kalman, J. R. J. Am.
Chem. Soc. 1977, 99, 2768. Williamson, M. P.; Williams, D. H. J. Am.
Chem. Soc. 1981, 103, 6580.
(5) Malabarba, A.; Nicas, T. I.; Thompson, R. C. Med. Res. ReV. 1997,
17, 69.
Figure 1.
sensitive bacteria,7 the emergence of clinical resistance and the
determination of its origin,8 and the potential of reengineering
the glycopeptide antibiotics to overcome this resistance have
(6) Wiedemann, B.; Grimm, H. In Antibiotics in Laboratory Medicine;
Lorian, V., Ed.; Williams and Wilkins: Baltimore, MD, 1996; pp 900-
1168.
(7) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38, 1172.
(8) Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Prahalad, M.; Wu, Z. Chem.
Biol. 1996, 3, 21.
(9) Varaldo, P. E.; Debbia, E.; Schito, G. C. Antimicrob. Agents
Chemother. 1983, 23, 402. Barry, A. L.; Thornsberry, C.; Jones, R. N. J.
Clin. Microbiol. 1986, 23, 100.
(10) De Lalla, F.; Tramarin, A. Drug Saf. 1995, 13, 317. Greenwood,
D. J. Antimicrob. Chemother. 1988, 21 (Suppl. A), 1.
(11) Verbist, L.; Tjandramaga, B.; Hendrickx, B.; Van Hecken, A.; Van
Melle, P.; Verbesselt, R.; Verhaegen, J.; De Schepper, P. J. Antimicrob.
Agents Chemother. 1984, 26, 881. Benet, L. Z.; Williams, R. L. In The
Pharmacological Basis of Therapeutics, 8th ed.; Gilman, A. G., Rall, T.
W., Nies, A. S., Taylor, P., Eds.; Pergamon: New York, 1990; pp 1650-
1735.
10.1021/ja003835i CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/07/2001

Total Synthesis of the Teicoplanin Aglycon
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1863
generated considerable interest in teicoplanin, vancomycin, and
related agents.
Herein we provide full details of the development of the first
total synthesis of the teicoplanin aglycon (2),14 and the
subsequent efforts which have provided an improved second
generation total synthesis. The teicoplanin aglycon bears the
same ABCD ring system and the same CDE atropisomer
stereochemistry as vancomycin, but contains a DE ring that lacks
the sensitive â-hydroxy group of the vancomycin E-ring
substituted phenylalanine (C2 residue) and incorporates a
racemization prone substituted phenylglycine C3 residue.15 It
also contains the additional 14-membered diaryl ether FG ring
system not found in vancomycin, making it an even more
challenging synthetic target than vancomycin.
Complementary to the efforts of Evans16 and Nicolaou,17 we
recently described a total synthesis of the vancomycin agly-
con,18,19 enlisting a defined order to introduction of its CD, AB,
and DE ring systems that permitted selective thermal atropi-
somerism of the newly formed ring systems or their immediate
precursors.20-22 In addition to the diastereoselection that was
achieved in two of the three ring closures, this order permitted
(12) Graninger, W.; Presterl, E.; Wenisch, C.; Schwameis, E.; Breyer,
S.; Vukovich, T. Drugs 1997, 54 (Suppl. 6), 21.
(13) Brogden, R. N.; Peters, D. H. Drugs 1994, 47, 823.
Figure 2. First generation total synthesis.
(14) Boger, D. L.; Kim, S. H.; Miyazaki, S.; Strittmatter, H.; Weng, J.-
H.; Mori, Y.; Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc.
2000, 122, 7416.
(15) Barna, J. C. J.; Williams, D. H.; Strazzolini, P.; Malabarba, A.;
Leung, T.-W. C. J. Antibiot. 1984, 37, 1204.
the recycling of any undesired atropisomer for each ring system
and provided reliable control of the stereochemistry throughout
the synthesis, funneling all synthetic material into the natural
atropisomer. A special attraction of this approach was the
recognition that the common ABCD ring system of vancomycin
and teicoplanin constituted a key intermediate providing, as
realized herein, access to both classes of natural products from
a common advanced synthetic intermediate.
(16) Orienticin C aglycon: Evans, D. A.; Barrow, J. C.; Watson, P. S.;
Ratz, A. M.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K. M.; Ellman, J.
A.; Rychnovsky, S. D.; Lacour, J. J. Am. Chem. Soc. 1997, 119, 3419.
Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C.
J. Am. Chem. Soc. 1997, 119, 3417. Vancomycin aglycon: Evans, D. A.;
Wood. M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L.
Angew. Chem., Int. Ed. 1998, 37, 2700. 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.
(17) 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. Nicolaou, K. C.; Boddy, C. N. C.; Li, H. Koumbis, A. E.; Hughes,
R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Brase, S.; Solomon, M. E.
Chem. Eur. J. 1999, 5, 2602. 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. 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. Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger,
N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1999, 38, 240. 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. 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. Nicolaou, K. C.; Jain, N. F.; Nataranjan, 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.
(18) Vancomycin aglycon: Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu,
J. H.; Loiseleur, O.; Castle, S. L. J. Am. Chem. Soc. 1999, 121, 3226. 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. Teicoplanin aglycon: Boger,
D. L.; Kim. S. H.; Miyazaki, S.; Strittmatter, H.; Weng, J.-H.; Mori, Y.;
Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2000, 122, 7416.
(19) Reviews: Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger,
N. Angew. Chem., Int. Ed. 1999, 38, 2096. Rao, A. V. R.; Gurjar, M. K.;
Reddy, K. L.; Rao, A. S. Chem. ReV. 1995, 95, 2135.
(20) Boger, D. L.; Castle, S. L.; Miyazaki, S.; Wu, J. H.; Beresis, R. T.;
Loiseleur, O. J. Org. Chem. 1999, 64, 70. Boger, D. L.; Beresis, R. T.;
Loiseleur, O.; Wu, J. H.; Castle, S. L. Bioorg. Med. Chem. Lett. 1998, 8,
721. Boger, D. L.; Loiseleur, O.; Castle, S. L.; Beresis, R. T.; Wu, J. H.
Bioorg. Med. Chem. Lett. 1997, 7, 3199. Boger, D. L.; Borzilleri, R. M.;
Nukui, S.; Beresis, R. T. J. Org. Chem. 1997, 62, 4721. Boger, D. L.;
Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem. Lett. 1995, 5, 3091.
(21) 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.
The most conservative implementation of this approach to
teicoplanin was judged to entail sequential introduction of the
DE and FG ring systems onto this preformed ABCD ring system
(Figure 2). Closure of the DE ring system without the constraints
of the FG ring system was expected to permit its mild thermal
atropisomerism to adjust its final stereochemistry should this
prove necessary without affecting the AB or CD atropisomer
stereochemistry (Ea ) 37.8 and 30.4 kcal/mol, respectively).
We recently disclosed studies defining the relative ease of
selective DE atropisomerism of teicoplanin aglycon derivatives
(Ea ) 29.3 kcal/mol) as well as derivatives cleaved at the
N-terminus amide (FG ring system cleaved, Ea ) 24.8 kcal/
mol).22 Although a necessary adjustment in the DE ring system
atropisomer stereochemistry could be conducted with the FG
ring system intact, that conducted with the acyclo FG precursors
proceeds with greater ease. More significant, the C23 center of
teicoplanin readily epimerizes (1% aqueous NaHCO3, 80 °C)
to its more stable (>95:5) unnatural R-configuration under
mildly basic conditions,15,22 and we have shown that this
epimerization occurs less readily on acyclo FG teicoplanin
derivatives.22 The diaryl ether ring closure of the DE ring system
in the absence of the constraints of the FG ring system was
expected to minimize C23 epimerization under the required basic
conditions. Thus, the more conservative first generation total
synthesis enlisted a diastereoselective (3:1) aromatic nucleophilic
substitution macrocyclization with formation of the diaryl
ether20,23 for closure of the DE ring system under racemization
free conditions and a subsequent macrolactamization reaction
for cyclization of the 14-membered FG ring system. The diaryl
ether linkage in the 14-membered FG ring system was also
anticipated to arise from a phenoxide nucleophilic substitution
reaction of an o-fluoronitroaromatic. Although this could
(22) Boger, D. L.; Weng, J.-H.; Miyazaki, S.; McAtee, J. J.; Castle, S.
L.; Kim, S. H.; Mori, Y.; Rogel, O.; Strittmatter, H.; Jin, Q. J. Am. Chem.
Soc. 2000, 122, 10047.

1864 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Boger et al.
Scheme 1
Scheme 2
constitute the key macrocyclization reaction used to close the
3
FG ring system, its propensity for C2 epimerization and the
basic conditions required of the reaction suggested problems
may arise in such an approach. Therefore, an intermolecular
coupling was implemented, enlisting substituted phenylglycinol
derivatives to ensure no racemization would be possible.
The development of a shorter, second generation total
synthesis of 2 reversing the order of FG and DE ring system
macrocyclizations is also described. This less secure route was
found to proceed with superb diastereoselection (>10:1) in the
DE macrocyclization precluding the need for thermal equilibra-
tion of DE ring system atropisomers and, more importantly,
may be implemented under select conditions without competitive
8 was incorporated directly into the synthesis and 11 was further
converted to 13 in three steps. Both the F ring and G ring amino
acid precursors (residues 3 and 1) were utilized as the reduced
phenylglycinols to avoid R-center racemization throughout the
synthesis and oxidized to the corresponding carboxylic acids
immediately prior to use in an amide coupling. Experience
derived from our efforts on vancomycin suggested the requisite
oxidations could be conducted without difficulty.18
3
C2 epimerization.
Synthesis of Precursors to the Teicoplanin Residues 1-3.
The requisite E-ring (R)-(4-fluoro-3-nitrophenyl)alanine 7 (resi-
due 2) was prepared through Schollkopf alkylation of bromide
3 via the transmetalated cuprate24 and the Teoc, Boc, Troc, and
TcBoc derivatives 7a-d were examined in our studies (Scheme
1). The F and G ring phenylglycine precursors were prepared
employing the Sharpless asymmetric aminohydroxylation (AA)
reaction.25 Thus, the styrenes 826 and 1027 were converted to
the (R)- and (S)-phenylglycinols 9 (75%, 97% ee) and 11 (78%,
>99% ee) using the complementary (DHQD)2PHAL and
(DHQ)2PHAL catalysts, respectively. Notably, the quality of
CbzNH2 greatly affected the AA reaction of 10, and freshly
recrystallized material substantially increased the conversion
(78% vs 33%). The product 9 of the Sharpless AA reaction of
Synthesis of the FG Diaryl Ether. Because of concerns over
3
the C2 epimerization observed within the confines of the
teicoplanin FG ring system, we elected to form the FG diaryl
ether by an intermolecular aromatic nucleophilic substitution
reaction using acyclic substrates which are incapable of epimer-
ization. Thus, coupling of 9 and 13 (K2CO3, DMSO, 25 °C)
provided 14 (60-63%), Scheme 2. Reactions conducted in
DMSO could be run at room temperature and were substantially
faster than those conducted in DMF, and the conversions
improved with inclusion of 18-c-6 and 4 Å MS (Scheme 2).
The former serves to accelerate the reaction rate, and 4 Å MS
serves to moderate the basicity of the liberated fluoride, and
presumably this improves the overall conversions. Utilizing the
more accessible G ring precursor 9 in excess (2 equiv) further
improved the conversion based on 13 (70%). Nitro reduction
(H2, Pd/C), diazotization of 15 (t-BuONO, HBF4), and phenol
introduction (Cu2O-Cu(NO3)2) proceeded in superb conversions
(80%) on a large scale, provided that the reaction was vigorously
stirred, and subsequent selective phenol versus primary alcohol
O-methylation of 16 (CH3I, K2CO3) provided 17. Protection of
the primary alcohol (BnBr, NaH, 17-20% DMF-THF), MEM
and N-Boc deprotection of 18 (4 N HCl-EtOAc), and reinstal-
lation of the Boc-protecting group (Boc2O, NaHCO3) afforded
19. Notably, longer reaction times were required, and lower
conversions were obtained when the benzylation was conducted
(23) Zhu, J. Synlett 1997, 133. Beugelmans, R.; Singh, G. P.; Bois-
Choussy, M.; Chastanet, J.; Zhu, J. J. Org. Chem. 1994, 59, 5535. Rao, A.
V. R.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994, 35, 8465. Boger,
D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995, 5, 1187. Boger, D.
L.; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem. Lett. 1995, 5, 3091.
Evans, D. A.; Watson, P. S. Tetrahedron Lett. 1996, 37, 3251.
(24) Bois-Choussy, M.; Neuville, L.; Beugelmans, R.; Zhu, J. J. Org.
Chem. 1996, 61, 9309.
(25) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207.
(26) Rao, A. V. R.; Gurjar, M. K.; Lakshmipathi, P.; Reddy, M. M.;
Nagarajan, M.; Pal, S.; Sarma, B. V. N. B. S.; Tripathy, N. K. Tetrahedron
Lett. 1997, 38, 7433.
(27) Prepared in two steps from 3-hydroxy-5-methoxybenzaldehyde (Ben,
I.; Castedo, L.; Saa, J. M.; Seijas, J. A.; Suau, R.; Tojo, G. J. Org. Chem.
1985, 50, 2236): 1.5 equiv of BnBr, 1.5 equiv of K2CO3, DMF, 60 °C, 3
h, 89%; 2.8 equiv of Ph3PdCH2, THF, -78 to 25 °C, 2 h, 87%.

Total Synthesis of the Teicoplanin Aglycon
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1865
Scheme 3
protecting group (Boc2O, NaHCO3; 94% for two steps), and
low-temperature, two-step oxidation of the primary alcohol 27
(Dess-Martin periodinane, DMF; NaClO2, 20% H2O-DMSO
buffered with NaH2PO4 in the presence of resorcinol) provided
the carboxylic acid 28 (91%). This latter oxidation was sensitive
to epimerization and degradation at the stage of the intermediate
aldehyde analogous to the corresponding acyclo FG derivatives
31 described below. The availability of 28 provided the
opportunity to examine the DE ring system introduction on
substrates containing the preformed FG ring system, and it
constitutes a key intermediate in our second generation total
synthesis. Analogous to the FG ring system in the natural
product itself, 26 displayed a sharp 1H NMR spectrum indicative
1
of a single predominant conformation and 2D H-1H NMR
(CD3OD, 293 K, 500 MHz) cross-peaks consistent with that of
1
the natural product. Strong nOe’s between C2 -H/C4b1-H,
3
1
C4a1-H/C4a3-H, and C2 -H/C4b3-H, only a weak C2 -H/
C4a1-H nOe, and the absence of a C2 -H/C4a3-H nOe
3
established the orientation of the diaryl ether and its relationship
to the backbone peptide chain as shown in Scheme 3.
Model DE Ring System Studies. Key to implementation of
the approach was the construction of the DE ring system by an
intramolecular phenoxide nucleophilic substitution reaction of
an o-fluoronitroaromatic for formation of the 16-membered
diaryl ether. Necessary issues to address upfront included the
inherent ease of C23 racemization under the range of ring closure
conditions available, the establishment of the intrinsic atropi-
somer diastereoselection of the ring closure reaction outside the
confines of the preformed ABCD ring system, the relative ease
of the thermal equilibration and thermodynamic ratio of the DE
ring system atropisomers, and subtle substituent effects that
might contribute to the success of the approach.
in THF, whereas reactions conducted in DMF or >20% DMF-
THF led to additional competitive N-benzylation. N-Trifluoro-
acetamide hydrolysis (K2CO3, CH3OH-H2O) followed by
coupling of 20 with 7a-d provided the substrates 21 on which
both DE and FG macrocyclizations could be examined.
FG Ring System Macrolactamization. Essential to imple-
mentation of the approach was the closure of the FG ring system
at the amide bond linking residues 1 and 2. Both Chakraborty28
and Pearson29 independently conducted macrolactamizations on
teicoplanin or ristocetin model systems and illustrated their
success. In our own efforts, we examined teicoplanin aglycon
derivatives containing acyclic FG ring systems with cleavage
of the residue 1 and 2 amide bond.22 Their macrolactamization
closure established its viability on advanced intermediates
Thus, two-step oxidation of 21 to the corresponding carboxy-
lic acids 31 and subsequent coupling with the free amine 30
derived from 2920,31 provided the substrates 32 necessary for
examining the DE ring closure (Scheme 4). The oxidation
3
reaction proved surprisingly sensitive to C2 epimerization at
the stage of the intermediate aldehyde. Even the use of aqueous
NaHCO3 in the workup of the Dess-Martin oxidation produced
substantial epimerization. As a matter of practice, workup of
the Dess-Martin oxidation was conducted at 0 °C in the absence
of base. Under these conditions, little or no epimerization was
observed (>20:1), and this could be established by TMSCHN2
esterification of 31 to provide the corresponding methyl ester32
whose stereochemical integrity could be established by 1H NMR.
Alternative direct oxidation of 21c to provide 31c was also
examined utilizing TEMPO-NaOCl/KBr and provided the
3
capable of mild C2 epimerization and ultimately provided
intermediates enlisted in the total synthesis (see Scheme 8). With
17 in hand, we examined its coupling with 7a, subsequent
conversion to 25, and its macrolactamization. Thus, hydrolysis
of 17 (K2CO3, H2O-CH3OH, 82%), coupling of 22 with 7a to
provide 23 (PyBop,30 86%), two-step oxidation of the primary
alcohol 23 to the carboxylic acid 24 (Dess-Martin periodinane;
NaClO2 buffered with NaH2PO4 in the presence of resorcinol,
81%), and Teoc deprotection (Bu4NF, THF, 87%) provided 25
(Scheme 3). Macrolactamization effected by treatment with
PyBop30 (NaHCO3, 10% DMF-CH2Cl2, 95%) provided 26 in
superb conversions consistent with related observations made
on advanced synthetic intermediates, and without detectable
epimerization. Simultaneous MEM and N-Boc deprotection of
26 (4 N HCl-dioxane, -5 °C), reinstallation of the N-Boc
(31) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996, 61,
3561.
(32) For the methyl ester of 31a: 1H NMR (CD3OD, 600 MHz) δ 7.91
(d, J ) 5.2 Hz, 1H, C5a2-H), 7.48 (m, 1H, C5b2-H), 7.31-7.05 (m, 9H),
6.51 (s, 1H, C4a3-H), 6.37 (s, 1H, C4b3-H), 6.29 (s, 1H), 5.35 (s, 1H),
4.82 (m, 1H), 4.50-4.30 (m, 5H), 4.07 (m, 2H), 3.83 (br s, 2H), 3.76 (s,
3H), 3.71 (s, 3H), 3.68 (s, 3H, CO2CH3), 3.03 (dd, J ) 6.6, 13.6 Hz, 1H),
2.88 (dd, J ) 8.8, 13.6 Hz, 1H), 1.36 (s, 9H), -0.02 (s, 9H); Diagnostic
signals for the C23 epimer: (CD3OD, 600 MHz) δ 8.00 (d, J ) 5.3 Hz, 1H,
3
C5a2-H), 7.60 (m, 1H, C5b2-H), 6.62 (s, 1H, C4a3-H), 6.46 (s, 1H, C4b
-
(28) Chakraborty, T. K.; Reddy, G. V. J. Org. Chem. 1992, 57, 5462.
(29) Pearson, A. J.; Shin, H. J. Org. Chem. 1994, 59, 2314. Pearson, A.
J.; Belmont, P. O. Tetrahedron Lett. 2000, 41, 1671.
H), 3.67 (s, 3H, CO2CH3). For the methyl ester of 31c: 1H NMR (CD3CN,
600 MHz) δ 7.93 (d, 1H, J ) 6.8 Hz, C5a2-H), 7.48 (m, 1H, C5b2-H),
7.40-7.20 (m, 6H), 7.15 (dd, J ) 2.2, 4.9 Hz, 1H), 7.07 (d, J ) 4.9 Hz,
1H), 7.02 (d, J ) 2.2 Hz, 1H), 6.51 (s, 1H, C4a3-H), 6.41 (s, 1H, C4b3-H),
6.36 (s, 1H), 5.33 (s, 1H), 4.73-4.65 (m, 4H), 4.50 (d, J ) 12.3 Hz, 1H),
4.47 (d, J ) 12.3 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.67 (s, 3H, CO2-
CH3), 3.63-3.56 (m, 2H), 3.12 (dd, J ) 4.9, 14.5 Hz, 1H), 2.92 (dd, J )
(30) Abbreviations: PyBop ) benztriazol-1-yl-oxy-tris(pyrrolidino)-
phosphonium hexafluorophosphate; FDPP ) pentafluorophenyl diphenyl-
phosphinate; HATU ) 2-(1H-7-azabenzotriazol)-1-yl-1,1,3,3-tetramethyl-
uronium hexafluorophosphate; Bop ) (1-benzotriazolyloxy)tris(dimeth-
ylamino)phosphonium hexafluoride; EDCI ) 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide; HOBt ) 1-hydroxybenzotriazole; HOAt ) 1-hydroxy-
7-azabenzotriazole; PyBrop ) bromo-tris(pyrrolidino) phosphonium hexa-
fluorophosphate; TFFH ) fluoro-N,N,N′,N′-tetramethylformamidinium
hexafluorophosphate, DPPA ) diphenyl phosphorazidate.
9.2, 14.5 Hz, 1H), 1.36 (s, 9H); Diagnostic signals for the C23 epimer: (CD3-
2
CN, 600 MHz) δ 7.97 (d, J ) 6.6 Hz, 1H, C5a2-H), 7.58 (m, 1H, C5b
-
H), 6.58 (s, 1H, C4a3-H), 6.46 (s, 1H, C4b3-H), 3.65 (s, 3H, CO2CH3).
The stereochemical integrity of 31b and 31d could be assessed directly.

1866 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Boger et al.
Scheme 4
of two atropisomers of which the unnatural stereochemistry was
slightly preferred (P:M 1:1.5-2.1). N-Teoc deprotection of 33a
(6 equiv of TASF, DMSO, 25 °C, 20 h) served to generate the
free amine 34. More conveniently, enlisting a larger excess of
freshly predried CsF (25-40 equiv) and longer reaction times
(DMSO, 25 °C, 0.007 M, 13-16 h) with 32a led to cyclization
and subsequent in situ deprotection of the N-Teoc with direct
generation of the free amine 34 as a separable mixture of two
atropisomers (67-70%, 1:1.8-3 P:M) and minor amounts of
33a (5-18%). The use of freshly dried CsF was found to be
important for achieving these conversions and especially
important for the N-Teoc deprotection. Untreated CsF provided
slower conversions and little N-Teoc deprotection. Similarly,
treatment of 32a with K2CO3 (10 equiv, 4 Å MS, 0.006 M DMF,
40 °C, 12 h) did not lead to cyclization and provided only
recovered starting material notably without detectable epimer-
ization. An analogous closure of the C2 epimer33 of 32a
3
obtained as a minor component of the coupling of diastereo-
merically impure 31a provided cyclized products35 (30 equiv
CsF, 0.007 M DMSO, 25 °C, 13 h, 90%, P:M of 1.6:1) that
were both chromatographically (lower Rf) and spectroscopically
distinguishable from the two atropisomers of 34. Importantly,
this confirmed that no detectable C23 epimerization accompanied
the cyclization of 32. Reprotection of 34 as its N-Troc derivative
(TrocCl, NaHCO3) provided the DE ring system suitably
protected to serve as models for the total synthesis. The
atropisomer stereochemical assignments were established through
2D 1H-1H NMR of P- and M-34 with observation of diagnostic
nOe’s for the natural P-atropisomer of C3R2-H (δ 3.35)/C5a2-H
(7.78) (s), C3â2-H (2.90)/C5b2-H (7.80) (s), C3R2-H (3.35)/
2
C3â2-H (2.90) (s), and C3R2-H (3.35)/C2 -H (3.89) (m), and
for the unnatural M-atropisomer of C3R2-H (3.38)/C5b2-H
(7.40) (s), C3â2-H (2.98)/C5a2-H (8.09) (s), C3R2-H (3.38)
2
/C3â2-H (2.98) (s), and C3R2-H (3.38)/C2 -H (3.90) (m).
Conversion of the nitro group of P-33b to the corresponding
chloride P-35 by reduction to the aniline (H2, 10% Pd/C),
diazotization (t-BuONO, HBF4), and Sandmeyer substitution
(CuCl-CuCl2) proceeded with complete maintenance of the
atropisomer stereochemistry and provided the fully functional-
ized DE ring system (Scheme 5).
In contrast, both 32c and 32d (Scheme 4) failed to close upon
exposure to a range of macrocyclization conditions and provided
products derived from base-catalyzed cyclization of the N-Troc
or N-TcBoc onto the adjacent backbone amide. Consistent with
these observations, studies with 21c (10 equiv K2CO3-CaCO3,
4 Å MS, DMSO, 25 °C, 5 h, quantitative) and 21d (8 equiv
CsF, DMSO, 25 °C, 1 h, quantitative) revealed that treatment
with mild base led to intramolecular N-Troc or N-TcBoc
cleavage by the adjacent amide precluding their use in macro-
carboxylic acid with little or no epimerization but in lower and
erratic conversions (0-43%). Finally, the coupling reaction of
30 with 31, like those of analogous substrates in the vancomycin
series, proved challenging, providing occasional low conversions
or significant racemization, depending on the reagents or
reaction conditions.33 However, the use of the Goodman DEPBT
reagent34 (0 °C, THF) uniformly provided the best results,
affording good to superb conversions and, importantly, no
detectable racemization.
(35) For the C23 epimer of 34: P-diastereomer: 1H NMR (CD3OD, 600
MHz) δ 7.78 (d, J ) 2.2 Hz, 1H), 7.69 (dd, J ) 2.2, 8.3 Hz, 1H), 7.28-
7.24 (m, 5H), 7.15 (d, J ) 8.3 Hz, 1H), 7.14 (dd, J ) 2.2, 7.9 Hz, 1H),
7.06 (d, J ) 7.9 Hz, 1H), 6.98 (d, J ) 2.2 Hz, 1H), 6.75 (s, 1H), 6.62 (s,
1H), 6.53 (s, 1H), 6.22 (s, 1H), 5.52 (s, 1H), 5.34 (br s, 1H, NH), 5.30 (s,
1H), 4.76 (br s, 1H), 4.60-4.58 (m, 1H), 4.51 (s, 2H), 3.94 (s, 3H), 3.79-
3.77 (m, 2H), 3.75 (s, 3H), 3.68 (s, 3H), 3.62-3.59 (m, 2H), 3.30-3.20
(m, 1H, partially obscured by CD2HOD), 2.80 (dd, J ) 8.3, 11.3 Hz, 1H),
1.41 (s, 9H); MALDIFTMS (DHB) m/z 946.3469 (M+ + Na, C48H53N5O14
requires 946.3481). M-diastereomer: 1H NMR (CD3OD, 500 MHz) δ 8.06
(d, J ) 2.2 Hz, 1H), 7.43 (dd, J ) 2.2, 8.5 Hz, 1H), 7.27-7.24 (m, 6H),
7.14 (dd, J ) 2.2, 8.4 Hz, 1H), 7.06 (d, J ) 8.4 Hz, 1H), 6.98 (d, J ) 2.2
Hz, 1H), 6.70 (s, 1H), 6.61 (br s, 1H), 6.57 (s, 1H), 6.22 (s, 1H), 5.62 (s,
1H), 5.31 (s, 1H), 4.71-4.69 (m, 1H), 4.60 (m, 1H), 4.51 (s, 2H), 3.93 (s,
3H), 3.86-3.83 (m, 2H), 3.75 (s, 3H), 3.68 (s, 3H), 3.60-3.58 (m, 2H),
3.30-3.20 (m, 1H, partially obscured by CD2HOD), 2.82-2.80 (m, 1H),
1.41 (s, 9H); MALDIFTMS (DHB) m/z 946.3463 (M+ + Na, C48H53N5O14
requires 946.3481). The atropisomer stereochemistry is tentatively assigned
The macrocyclization of both 32a and 32b provided 33a or
33b in superb conversions (60-70%) upon treatment with CsF
(10 equiv, DMSO, 25 °C, 0.01-0.007 M, 14-18 h) as a mixture
3
(33) For the C2 epimer of 32a: 1H NMR (CD3OD, 500 MHz) δ 7.98
(d, J ) 8.5 Hz, 1H), 7.52-7.50 (m, 1H), 7.28-7.24 (m, 6H), 7.16-7.12
(m, 2H), 7.06 (d, J ) 8.4 Hz, 1H), 7.02 (d, J ) 2.2 Hz, 1H), 6.73 (s, 1H),
6.67 (s, 1H), 6.38 (s, 2H), 6.29 (s, 1H), 5.49 (br s, 1H), 4.73 (dd, J ) 5.9,
9.2 Hz, 1H), 4.55 (s, 1H), 4.51 (s, 2H), 4.47-4.42 (m, 2H), 4.11-4.02 (m,
2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.64 (dd, J ) 5.5, 11.3 Hz,
1H), 3.62-3.59 (m, 3H), 3.14 (dd, J ) 5.9, 12.5 Hz, 1H), 2.90 (dd, J )
9.2, 12.5 Hz, 1H), 1.40 (s, 9H), -0.03 (s, 9H).
(34) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M.
Org. Lett. 1999, 1, 91. DEPBT ) 3-(diethoxyphosphoryloxy)-1,2,3-
benzotriazin-4(3H)-one.
1
on the basis of 1D H NMR.

Total Synthesis of the Teicoplanin Aglycon
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1867
Scheme 5
Scheme 6
cyclization reactions (eq 1).36 Both 21a and 21b with the N-Teoc
and N-Boc were stable to such base treatment and the former,
because it constitutes an orthogonal protecting group to the
N-terminus Boc group, was enlisted in the natural product total
synthesis.
Preparation of a Fully Functionalized DEFG Ring System.
The viability of an approach employing sequential DE and FG
ring closures was examined with 33c, resulting in the preparation
of 41 constituting a fully functionalized teicoplanin DEFG ring
system. Acetylation of the primary alcohol and phenol of 33c
provided 36, and simultaneous nitro reduction and benzyl ether
deprotection (H2, 10% Pd/C, 1% Cl3CCO2H-CH3OH, 25 °C,
15 min, 74-93%) was accomplished under mild conditions that
had no effect on the reduction-sensitive N-Troc group (Scheme
6). Reduction in the absence of an acid catalyst was problematic,
leading to reduction of the N-Troc group competitive with the
slow O-debenzylation. Other catalysts (Pd(OH)2, Pt(0)) or
conditions were less successful or unsuccessful at converting
36 to 37. The use of 1% HOAc-CH3OH proved marginally
successful at accelerating the O-debenzylation relative to N-Troc
reduction, and this was found to be successively improved with
use of stronger acid catalysts: 1% Cl3CCO2H-CH3OH > 1%
Cl2CHCO2H > 1% ClCH2CO2H > 1% CH3CO2H. In the course
of our use of these conditions, it also appeared as if the use of
freshly dried anhydrous Cl3CCO2H (hygroscopic) provides the
best results although this was not investigated in detail.37 Not
previously examined, the introduction of these conditions (1%
Cl3CCO2H-CH3OH) for conducting hydrogenolysis reactions
in the presence of a N-Troc-protecting group serves to address
a long-standing incompatibility37 and extends its utility as an
orthogonal amine-protecting group. Diazotization and Sand-
meyer introduction of the aryl chloride provided 38 without loss
of the atropisomer stereochemistry, establishing conditions for
implementation in the total synthesis and providing a key
substructure upon which FG ring closure and comparative
thermal atropisomerism studies could be conducted. Without
optimization, two-step oxidation of the alcohol 38 to the
carboxylic acid 39, N-Troc deprotection enlisting 10% Zn-
Pb38 (1 N aqueous NH4OAc/THF), and FG macrolactamization
under the conditions prescribed for 26 (see Scheme 3) provided
41 in satisfactory conversions and without detectable epimer-
ization.
(36) For A: 1H NMR (CD3CN, 600 MHz) δ 7.90 (dd, J ) 2.6, 8.3 Hz,
1H), 7.46 (m, 1H), 7.31-7.26 (m, 5H), 7.21 (dd, J ) 8.3, 11.4 Hz, 1H),
7.13 (dd, J ) 2.2, 8.8 Hz, 1H), 7.06 (d, J ) 8.8 Hz, 1H), 7.00 (d, J ) 2.2
Hz, 1H), 6.38 (br s, 1H, NH), 6.33 (s, 1H), 6.32 (s, 1H), 6.26 (s, 1H), 5.81
(br s, 1H, NH), 4.85 (dd, J ) 4.8, 8.8 Hz, 1H), 4.75 (br s, 1H, OH), 4.49
(d, J ) 12.3 Hz, 1H), 4.46 (d, J ) 12.3 Hz, 1H), 4.34 (m, 1H), 4.18 (m,
1H), 3.82 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.60 (dd, J ) 4.9, 10.1 Hz,
1H), 3.56 (dd, J ) 7.4, 10.1 Hz, 1H), 3.11 (dd, J ) 4.9, 14.1 Hz, 1H), 3.08
(dd, J ) 5.7, 7.0 Hz, 1H), 3.03 (dd, J ) 5.3, 14.1 Hz, 1H), 1.35 (s, 9H);
MALDIFTMS (DHB) m/z 797.2834 (M+ + Na, C40H43N4FO11 requires
797.2810).
Atropisomerism Studies. With samples of 33, 35, and 41
in hand, their relative ease of thermal atropisomerism and
(37) Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett. 1982,
23, 249. Cl3CCO2H was dried under vacuum in the presence of P2O5 (25
°C) prior to use.

1868 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Boger et al.
thermodynamic preferences were established. In each instance,
the thermal isomerism proceeded with ease to provide a
nonselective 1:1 mixture of atropisomers with experimental Ea’s
of 17.2 (33a), 16.2 (33b), 20.0 (35), and 23.3 (41) kcal/mol
comparable to or slightly higher than those observed with the
corresponding derivatives of the isolated vancomycin DE ring
system (ArNO2 Ea ) 16.4-18.8 kcal/mol; ArCl Ea ) 18.7 kcal/
mol). As anticipated, the aryl nitro derivatives 33 isomerize more
readily than the aryl chloride 35, and the constraints of the FG
ring system have a decelerating effect on the rate of isomerism
with 41 proceeding more slowly than 33 or 35. Analogous
observations have been made with the teicoplanin aglycon
derivatives.22 Moreover, even comparisons between an isolated
vancomycin DE ring system (Ea ) 18.7 kcal/mol) and its rate
of DE atropisomerism within the constraints of a vancomycin
aglycon derivative (Ea ) 23.6 kcal/mol) are nearly identical to
those observed with teicoplanin except that the latter are
typically slower. Most importantly, the isomerism studies of
33, 35, and 41 revealed that they occur without problematic
C23 epimerization and under conditions where the stereochem-
istry of the CD (Ea ) 30.4 kcal/mol)20 and O-methylated AB
(Ea ) 37.8 kcal/mol)18 ring systems would be unaffected. Most
remarkable of these observations is that the 16-membered
vancomycin and teicoplanin DE ring systems isomerize at
similar rates relatively independent of the nature of the sub-
stituents or the presence of the teicoplanin FG ring system. Both
isomerize much more readily than the 16-membered CD ring
system even in the absence of the confines of the AB ring
system. The structural similarity of the teicoplanin DE ring
system and the CD ring system, especially in the absence of
the confines of the AB or FG ring systems, might suggest that
the two would have behaved comparably.
Scheme 7a
First Generation Total Synthesis of the Teicoplanin
Aglycon. The coupling of 4218 with 31a was effected by
DEPBT34 (THF, NaHCO3, 0 °C, 2 h, 68-83%) in excellent
conversion and without detectable epimerization (Scheme 7).
This is especially notable since this coupling involves the use
of an activated phenylglycine derivative prone to racemization.
In contrast to DEPBT, typical reagents and conditions including
those enlisted for vancomycin18 provided near 1:1 mixtures of
the C23 diastereomers. Macrocyclization upon treatment of 43a
with freshly dried CsF (15 equiv, 0.007 M DMSO, 25 °C, 10
h) proceeded in superb conversions (74-80%) to provide a
separable 3:1 mixture of P:M atropisomers favoring the natural
stereochemistry.39 Under these conditions, N-Teoc deprotection
was effected providing the free amine 45 directly requiring a
smaller excess of CsF and shorter reaction times than the model
substrate 32a and only trace quantities of the corresponding
N-Teoc derivative 44a were detected (6-13%). The stereo-
chemistry of the DE ring system and the stereochemical integrity
of the ABCD ring system within 45 were established by 2D
1H-1H NMR with the observation of diagnostic nOe’s for the
natural P-atropisomer of C5a2-H (7.92)/C3R2-H (3.42) (s),
a (a) CF3CONMeTBS, 89%; (b) TrocCl, 93%; (c) H2, Pd/C, 1%
Cl3CCO2H-EtOAc; (d) t-BuONO, HBF4; CuCl-CuCl2, 66% from 47.
6
6
6
C3 -H (5.24)/C5a6-H (7.56) (m), C3 -H (5.24)/ C2 -H (4.07)
(s), C4a5-H (7.01)/C2 -H (4.07) (s), C2 -H (4.59)/C2 -H
6
5
6
(4.06) (s), C2 -H (4.59)/C4a5-H (7.01) (w), and for the
5
unnatural M-atropisomer of C5a2-H (8.06)/C3â2-H (2.95) (s),
C5b2-H (7.90)/C3R2-H (3.45) (m), C2 -H (4.05)/C5a6-H (7.57)
6
(m), C2 -H (4.05)/C4a5-H (7.00) (s), C2 -H (4.05)/C3 -H
6
6
6
(38) Overman, L. E.; Freerks, R. L. J. Org. Chem. 1981, 46, 2833. 10%
Zn-Pb couple was prepared in the same manner as 10% Cd-Pb couple
which has been described: yellow lead oxide (PbO, 108 mg, 0.49 mmol)
was dissolved in 5 mL of warm 50% aqueous HOAc (45 °C), and the
solution was slowly added to a vigorously stirred suspension of Zn dust
(320 mg, 4.9 mmol) in deionized water (10 mL). The Zn darkened, as Pb
deposited on its surface, and formed clumps that were gently broken up
with a glass rod. The dark Zn-Pb was collected by filtration, washed with
H2O and then acetone, vacuum-dried, crushed, and stored in a closed vessel.
See: Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron Lett. 1995,
36, 5681.
(5.22) (s), C4a5-H (7.00)/C2 -H (4.60) (s), C3 -H (5.22)/
5
6
C5a6-H (7.57) (s), C2 -H (4.60)/C2 (4.05) (s). An analogous
5
6
treatment of the unnatural C2 diastereomer40 derived from
3
coupling 42 with diastereomerically impure 31a provided the
C23 diastereomer of 4541 as a mixture of two atropisomers (75%,
∼1:1 P:M) which were chromatographically and spectroscopi-
cally distinguishable from 45 ensuring that the closure proceeds
3
without detectable C2 epimerization. Like observations docu-
(39) Conducting the reaction at lower temperature (40 equiv of CsF, 0.007
M 20% DMF-DMSO, 5 °C, 48 h) did not significantly alter the atropisomer
ratio, P:M ) 2.6:1 (64%).
mented with the model DE ring system studies, treatment of
43c42 bearing the N-Troc protecting group with CsF or even

Total Synthesis of the Teicoplanin Aglycon
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1869
K2CO3 (CaCO3, 4 Å MS, 0.08 M DMSO, 25 °C. 3.5 h) failed
to provide evidence of cyclization, but rather provided the cyclic
carbamate derived from reaction with the adjacent backbone
amide (eq 2).42 Protection of the secondary alcohol as its OTBS
ether 46 (CF3CONMeTBS, 89%), N-Troc formation (TrocCl,
NaHCO3, 93%), aryl nitro reduction to the arylamine and
simultaneous O-benzyl deprotection (H2-Pd/C, 1% Cl3CCO2H-
CH3OH), diazotization (t-BuONO, HBF4), and Sandmeyer
substitution (CuCl-CuCl2) provided the key intermediate 49
(66% from 47) and set the stage for closure of the FG ring
system. Analogous to observations made with the model DE
ring system, conversion of 47 to 48 was unsuccessful in the
absence of an acid catalyst, leading to preferential N-Troc
reduction versus O-debenzylation and only modestly successful
employing 1% HOAc-CH3OH (50-60%). The use of 1% Cl3-
CCO2H-CH3OH provided clean and rapid nitro reduction and
O-debenzylation without detection of competitive N-Troc reduc-
tion.
substrate (1 h, 0.001 M final concentration) to a solution of the
coupling reagents (Scheme 8). PyBop30 (66%) and FDPP30
(62%) in the presence of NaHCO3 provided excellent conver-
sions of 51 to 52 in 10-50% DMF-CH2Cl2 with only trace
generation of a C21 epimer. HATU30 and Bop30 were nearly as
effective, but PyBrop,30 TFFH,30 EDCI,30 and DPPA30 were
substantially less effective or unsuccessful. In each case, the
use of i-Pr2NEt in place of NaHCO3 led to more competitive
C21 epimerization. MEM deprotection (B-bromocatecholborane,
CH2Cl2, 0 °C) followed by reprotection of the N-terminus amine
with Boc2O (THF/aqueous NaHCO3, 25 °C) provided 53 (76%,
two steps). Two-step alcohol oxidation (Dess-Martin periodi-
nane, CH2Cl2; NaClO2, DMSO-H2O, in the presence of
resorcinol), provided the carboxylic acid 54 (79%) which was
also esterified with TMSCHN2 (20% CH3OH-toluene, 25 °C)
to afford 55 (74%, three steps). The use of resorcinol in DMSO
proved superior to isobutene/t-BuOH and prevented a competi-
tive aromatic chlorination under the reaction conditions. Comple-
tion of the synthesis was accomplished from either 54 or 55
with the former being two steps shorter and proceeding with
the highest overall conversion. Treatment of 54 with AlBr3-
EtSH served to cleave the six methyl ethers, the C36 OTBS ether
and N-Boc group providing 2 (48%) in superb conversion.
6
Alternatively, deprotection of the C3 OTBS ether of 55 (Bu4-
NF-HOAc, THF, 25 °C, 78%) under conditions that suppress
base-catalyzed retro aldol cleavage of the CD ring system,18,21
and subsequent exhaustive deprotection of the resulting 56
enlisting AlBr3-EtSH (25 °C, 3 h), which served to cleave the
six aryl methyl ethers, the C-terminus methyl ester, and the
N-terminus N-Boc group, also provided the teicoplanin aglycon
identical in all respects with authentic material.
Adjustment of the DE atropisomer stereochemistry could be
accomplished at any one of several stages without competitive
thermal isomerism of the AB or CD ring systems (Figure 3).
Thermal equilibration of M-46 bearing the C36 OTBS ether could
be accomplished under the mildest conditions (DMSO, 110 °C),
permitting the recycling of the unnatural M-atropisomer into
the synthesis. Additional derivatives bearing the DE aryl chloride
and an acyclo FG ring system, and even the derivative 55
incorporating both the DE aryl chloride and the cyclized FG
ring system exhibited selective DE atropisomerism albeit under
increasingly more vigorous thermal conditions.22
This set the stage for the final steps of the first generation
total synthesis (Scheme 8). Two-step primary alcohol oxidation
(Dess-Martin periodinane, CH2Cl2; NaClO2, aqueous NaH2-
PO4, t-BuOH, in the presence of resorcinol) cleanly provided
the carboxylic acid 50 (74%) which was subjected to N-Troc
deprotection (10% Zn-Pb,38 1 N aqueous NH4OAc/THF, 25
°C, 89%) to provide 51, the key amino acid for FG ring closure
by macrolactamization. The N-Troc deprotection was examined
with a range of reagents including Zn (1 M NaH2PO4-THF,
25 °C, 2 h, 50-55%), Cd (1 M NaH2PO4-THF, 25 °C, 12-16
h, 58-83%), and 10% Cd-Pb (1 N NH4OAc/THF, 25 °C, 3-7
h, 50-70%) with the Zn-Pb couple providing the best results.
The closure of 51 was conducted with slow addition of the
3
(40) For the C2 diastereomer of 43a: 1H NMR (CD3OD, 500 MHz) δ
A Second Generation, More Convergent Total Synthesis
of the Teicoplanin Aglycon. The alternative approach of
forming the FG ring system prior to coupling with the ABCD
8.24 (br s, 1H, NH), 7.99 (br s, 1H), 7.61 (s, 1H), 7.55 (br s, 1H), 7.52 (d,
J ) 7.7 Hz, 1H), 7.25-7.23 (m, 6H), 7.08-7.06 (m, 4H), 6.98 (s, 1H),
6.92-6.89 (m, 3H), 6.60 (s, 2H), 6.52 (s, 2H), 6.16 (br s, 1H), 5.97 (br s,
1H), 5.51 (s, 1H), 5.22 (s, 1H), 5.21 (s, 1H), 4.80-4.78 (m, 2H, partially
obscured by H2O), 4.76 (s, 2H), 4.72 (s, 1H), 4.48 (s, 2H), 4.35 (m, 1H),
4.06 (m, 4H), 3.93 (s, 3H), 3.88 (s, 3H), 3.74-3.70 (m, 3H), 3.68 (s, 3H),
3.65 (s, 3H), 3.58-3.55 (m, 8H), 3.46 (s, 3H), 3.37 (s, 3H), 3.20 (dd, J )
6.5, 13.0 Hz, 1H), 2.94 (dd, J ) 8.5, 13.0 Hz, 1H), 1.39 (s, 9H), -0.02 (s,
9H).
(42) For 43c: 1H NMR (CD3OD, 500 MHz) δ 7.92 (d, J ) 6.7 Hz,
1H), 7.64 (d, J ) 2.0 Hz, 1H), 7.49 (dd, J ) 2.0, 8.4 Hz, 1H), 7.46 (br s,
1H), 7.28-7.20 (m, 6H), 7.11 (dd, J ) 2.2, 8.4 Hz, 1H), 7.09-7.03 (m,
3H), 7.04 (d, J ) 2.2 Hz, 1H), 7.02 (d, J ) 8.4 Hz, 1H), 6.97 (br s, 1H),
6.93-6.92 (m, 3H), 6.63 (s, 1H), 6.62 (s, 1H), 6.53 (br s, 1H), 6.46 (s,
1H), 6.43 (s, 1H), 6.32 (s, 1H), 6.23 (s, 1H), 5.79 (s, 1H), 5.30 (s, 1H),
5.22 (s, 1H), 5.21 (s, 1H), 4.90 (s, 1H), 4.76 (s, 2H), 4.72 (s, 1H), 4.47 (s,
2H), 4.36-4.34 (m, 2H), 4.09-4.07 (m, 3H), 4.06 (dd, J ) 8.1, 10.3 Hz,
1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.74-3.69 (m, 2H), 3.67 (s, 3H), 3.61 (s,
3H), 3.58-3.56 (m, 5H), 3.50 (s, 3H), 3.37 (s, 3H), 3.08 (dd, J ) 6.9, 13.9
Hz, 1H), 2.91 (dd, J ) 8.8, 13.9 Hz, 1H), 1.40 (s, 9H); MALDIFTMS
(DHB) m/z 1777.4449 (M+ + Na, C83H87Cl4FN8O25 requires 1777.4418).
For B: 1H NMR (CD3OD, 600 MHz) δ 8.30 (br s, 1H, NH), 7.83 (dd, J )
2.2, 7.9 Hz, 1H), 7.62 (d, J ) 1.7 Hz, 1H), 7.49 (dd, J ) 1.7, 8.8 Hz, 1H),
7.38 (m, 1H), 7.26-7.22 (m, 5H), 7.14 (dd, J ) 2.2, 8.3 Hz, 1H), 7.12 (d,
J ) 8.3 Hz, 1H), 7.09-7.06 (m, 2H), 7.04 (d, J ) 2.2 Hz, 1H), 7.00 (d, J
) 2.2 Hz, 1H), 6.97 (d, J ) 3.5 Hz, 1H), 6.96 (d, J ) 3.5 Hz, 1H), 6.92
(d, J ) 1.7 Hz, 1H), 6.63 (d, J ) 2.2 Hz, 1H), 6.56 (d, J ) 2.2 Hz, 1H),
6.32 (s, 1H), 6.23 (s, 2H), 5.77 (s, 1H), 5.53 (s, 1H), 5.18 (s, 1H), 4.88 (s,
2H), 4.76 (s, 2H), 4.66 (s, 1H), 4.57 (s, 1H), 4.49 (s, 1H), 4.47 (s, 1H),
4.44 (m, 2H), 4.36 (m, 1H), 4.06 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74-
3.72 (m, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.63 (s, 3H), 3.58-3.56 (m, 4H),
3.41 (s, 3H), 3.37 (s, 3H), 3.14 (dd, J ) 4.3, 14.8 Hz, 1H), 3.08 (dd, J )
4.4, 14.8 Hz, 1H), 1.40 (s, 9H); MALDIFTMS (DHB) m/z 1629.5123 (M+
+ Na, C81H84ClFN8O24 requires 1629.5169).
(41) For the C2 diastereomer of 45: P-atropisomer: 1H NMR (CD3-
3
OD, 315 K, 500 MHz) δ 7.82 (s, 1H), 7.66 (br s, 2H), 7.24-7.19 (m, 7H),
7.15 (d, J ) 8.4 Hz, 1H), 7.10-7.08 (m, 3H), 7.04-7.00 (m, 2H), 6.95-
6.90 (m, 2H), 6.93 (s, 1H), 6.81 (m, 1H), 6.61 (s, 1H), 6.59 (br s, 2H), 6.16
(br s, 1H), 5.60 (s, 1H), 5.43 (s, 1H), 5.35 (s, 1H), 5.27 (s, 1H), 5.13 (s,
1H), 4.76-4.74 (m, 2H), 4.58 (s, 1H), 4.47 (s, 2H), 4.35 (m, 1H), 4.13 (s,
3H), 4.08-4.05 (m, 2H), 3.96 (dd, J ) 3.7, 10.6 Hz, 1H), 3.88 (s, 3H),
3.73-3.71 (m, 2H), 3.58-3.56 (m, 4H), 3.51 (s, 3H), 3.49 (s, 3H), 3.48 (s,
3H), 3.46 (s, 3H), 3.36 (s, 3H), 3.20-3.15 (m, 1H, partially obscured by
CD2HOD), 2.80 (m, 1H), 1.38 (s, 9H). M-atropisomer: 1H NMR (CD3OD,
315 K, 500 MHz) δ 8.06 (br s, 1H), 7.58-7.57 (m, 3H), 7.35 (br s, 1H),
7.28-7.19 (m, 7H), 7.10 (br s, 2H), 7.06 (d, J ) 8.8 Hz, 1H), 7.00-6.95
(m, 3H), 6.90 (d, J ) 8.8 Hz, 1H), 6.85 (br s, 1H), 6.59 (s, 1H), 6.37 (br
s, 1H), 6.19 (br s, 1H), 5.80 (s, 1H), 5.34 (s, 1H), 5.25 (s, 1H), 5.13 (br s,
1H), 4.78-4.76 (m, 2H, partially obscured by H2O), 4.49 (s, 2H), 4.34 (m,
1H), 4.11-4.05 (m, 3H), 4.06 (s, 3H), 3.96 (dd, J ) 4.0, 10.3 Hz, 1H),
3.88 (s, 3H), 3.75-3.68 (m, 2H), 3.64 (s, 3H), 3.60 (s, 3H), 3.59 (s, 3H),
3.58-3.57 (m, 4H), 3.56 (s, 3H), 3.50 (m, 2H), 3.39 (s, 3H), 3.20-3.18
(m, 1H, partially obscured by CD2HOD), 2.80 (m, 1H), 1.39 (s, 9H); ESIMS
m/z 1584 (M+ + Na, C80H85ClN8O23 requires 1584).

1870 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Boger et al.
Scheme 8
Figure 3.
a 25 °C, 1-5 h.
Figure 4. Second generation total synthesis.
ring system and DE macrocyclization was also examined (Figure
4). Although it was not clear at the onset of our studies, this
approach proved not to suffer from a potentially problematic
the molecular weight of 58, but it was isolated in insufficient
quantities for unambiguous identification. Either it constitutes
the unnatural M-atropisiomer of the DE ring system (>10:1
diastereoselection), or it is an epimer of 58. Consistent with
the greater sensitivity of 57 and 58 toward base-catalyzed
reactions, efforts to promote the closure of 57 under the required
conditions enlisted for 43a (30 equiv CsF, DMSO, 25 °C, 19
h) resulted in lower isolated yields of 58 (23-37%) and greater
amounts of numerous epimeric or degradation products. Thus,
the use of DMF versus DMSO as the reaction solvent and the
lower reaction temperature (10 versus 25 °C) minimized the
competitive degradation and epimerization reactions. Interest-
ingly, the DE ring closure of 57 appears to proceed with greater
ease than that of 43a, allowing the effective use of these
conditions. Especially notable is the substantial increase in the
atropisomer diastereoselection for this ring closure (>10:1 P:M)
3
C2 epimerization if the basicity of the reaction conditions of
the DE cyclization reaction was minimized. Not only did this
provide a shorter route to 2 removing four steps from the longest
linear sequence from the constituent amino acids, but the DE
ring closure proceeded with superb diastereoselection (>10:1),
providing a further improvement over the first generation total
synthesis.
Thus, coupling of 28 with 4218 (DEPBT,34 THF, 0 °C, 72%)
provided 57 without problematic competitive epimerization of
3
the labile C2 center. Subjection of 57 to tempered reaction
conditions for DE macrocyclization (100 equiv CsF, 0.006 M
DMF, 10 °C, 24 h) provided 58 as a single atropisomer which
possessed the natural stereochemistry. Only trace amounts of
an additional second product (18:1) were detected that possessed

Total Synthesis of the Teicoplanin Aglycon
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1871
Table 1. Diastereoselection of DE Ring Closure
Scheme 9
substrate
P:M
conversion (%)
32
43a
57
1:2-3
65-70
80
76
3:1
>10:1
over that observed with 43a (3:1 P:M) and 32 (1:2-3 P:M).
Not only does the diastereoselection improve when this ring
closure is conducted with the FG ring system intact (>10:1 vs
3:1, 57 vs 43a), but also when it is conducted within the confines
of the ABCD ring system (3:1 vs 1:2-3, 43a vs 32), Table 1.
Conversion of the nitro group to the corresponding chloride
by reduction, diazotization, and Sandmeyer substitution provided
60 without loss of the atropisomer stereochemistry. Protection
6
of the C3 alcohol as its OTBS ether (CF3CONMeTBS, CH3-
CN, 50 °C, 13 h) provided 52 (87%) junctioning with a key
intermediate that was converted to 2 (five steps) in the first
generation total synthesis.
Conclusions
First and second generation total syntheses of the teicoplanin
aglycon were developed, and both enlist the common vanco-
mycin/teicoplanin ABCD ring system as a key intermediate.
The two complementary convergent approaches provide a means
for reliable control of the atropisomer stereochemistry and are
sufficiently concise and modular in nature to be implemented
in the preparation of key structural analogues of either teico-
planin or vancomycin. Such studies are in progress and will be
disclosed in due course.
Experimental Section43
Full experimental details and characterization are provided in the
Supporting Information.
the amino acid subunits, contributions to the supplies of the
EFG tripeptide, and the initiation of studies detailed in Schemes
4 and 6.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA41101) and the
Skaggs Institute for Chemical Biology, the sabbatical leave of
Y.M. (Mitsubishi-Tokyo Pharmaceuticals, Inc., 1999-2001), and
the award of a NIH postdoctoral fellowship (JJM, AI10367).
We thank Dr. Harald Strittmatter for supplying quantities of
Supporting Information Available: Full experimental
details and characterization are provided (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(43) Full experimental details and characterization are provided in the
Supporting Information.
JA003835I